@article {pmid38745425, year = {2024}, author = {Nona, RJ and Henderson, RD and McCombe, PA}, title = {Neutrophil-to-lymphocyte ratio at diagnosis as a biomarker for survival of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {452-464}, doi = {10.1080/21678421.2024.2351187}, pmid = {38745425}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; Humans ; *Neutrophils ; *Lymphocytes ; Female ; Male ; Biomarkers/blood ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) has previously been reported to be associated with survival in ALS. To provide further information about the role of NLR as a biomarker in ALS, we performed a systematic review, analyzed data from our local cohort of ALS subjects and performed a meta-analysis.<br><br>METHODS: (1) The systematic review used established methods. (2) Using data from our cohort of subjects, we analyzed the association of NLR with survival. (3) Meta-analysis was performed using previous studies and our local data.<br><br>RESULTS: (1) In the systematic review, higher NLR was associated with shorter survival in all studies. (2) In our subjects, survival was significantly shorter in patients in the highest NLR groups. (3) Meta-analysis showed subjects with highest NLR tertile or with NLR >3 had significantly shorter survival than other subjects.<br><br>DISCUSSION: This study supports NLR as a biomarker in ALS; high NLR is associated with poor survival.}, }
@article {pmid38666601, year = {2024}, author = {Officer, L and Armon, C and Barkhaus, P and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Carbunar, OM and Carter, GT and Crayle, J and Denson, K and Feldman, E and Fullam, T and Heiman-Patterson, T and Jackson, C and Jhooty, S and Levinson, D and Li, X and Linares, A and Mallon, E and Mascias Cadavid, J and Mcdermott, C and Mushannen, T and Ostrow, L and Patel, R and Pattee, G and Ratner, D and Sun, Y and Sladky, J and Wicks, P and Bedlack, R}, title = {ALSUntangled #75: Portable neuromodulation stimulator therapy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {648-652}, doi = {10.1080/21678421.2024.2346825}, pmid = {38666601}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Electric Stimulation Therapy/methods/instrumentation ; }, abstract = {Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.}, }
@article {pmid38561605, year = {2024}, author = {Singh, K and Gupta, JK and Kumar, S and Soni, U}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides.}, journal = {Current protein &amp; peptide science}, volume = {25}, number = {7}, pages = {507-526}, pmid = {38561605}, issn = {1875-5550}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Peptides/therapeutic use/chemistry/pharmacology ; Animals ; Alzheimer Disease/drug therapy/metabolism/pathology ; Parkinson Disease/drug therapy/metabolism/pathology ; Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Oxidative Stress/drug effects ; Huntington Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry ; }, abstract = {Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.}, }
@article {pmid37691199, year = {2024}, author = {Bhat, MA and Dhaneshwar, S}, title = {Neurodegenerative Diseases: New Hopes and Perspectives.}, journal = {Current molecular medicine}, volume = {24}, number = {8}, pages = {1004-1032}, pmid = {37691199}, issn = {1875-5666}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology ; Animals ; }, abstract = {Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Friedrich ataxia are all incurable neurodegenerative diseases defined by the continuous progressive loss of distinct neuronal subtypes. Despite their rising prevalence among the world's ageing population, fewer advances have been made in the concurrent massive efforts to develop newer drugs. Recently, there has been a shift in research focus towards the discovery of new therapeutic agents for neurodegenerative diseases. In this review, we have summarized the recently developed therapies and their status in the management of neurodegenerative diseases.}, }
@article {pmid38318827, year = {2024}, author = {Motamedy, S and Soltani, B and Kameshki, H and Alipour Kermani, A and Saboori Amleshi, R and Nazeri, M and Shabani, M}, title = {The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex[®] - A Cannabis-derived Spray.}, journal = {Mini reviews in medicinal chemistry}, volume = {24}, number = {15}, pages = {1427-1448}, pmid = {38318827}, issn = {1875-5607}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cannabidiol/pharmacology/therapeutic use/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Dronabinol/pharmacology/chemistry/therapeutic use ; Animals ; Multiple Sclerosis/drug therapy ; Cannabis/chemistry ; Drug Combinations ; }, abstract = {Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.}, }
@article {pmid37622689, year = {2024}, author = {Dey, B and Kumar, A and Patel, AB}, title = {Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {22}, number = {11}, pages = {1778-1806}, pmid = {37622689}, issn = {1875-6190}, support = {DST/CSRI/2017/258//Department of Science and Technology (DST), Govt. of India/ ; DBT/JRF/BET-17/1/2017/AL/400//Department of Biotechnology (DBT), Govt. of India/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; Gene-Environment Interaction ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common, adult-onset, progressive motor neurodegenerative disorder that results in death within 3 years of the clinical diagnosis. Due to the clinicopathological heterogeneity, any reliable biomarkers for diagnosis or prognosis of ALS have not been identified till date. Moreover, the only three clinically approved treatments are not uniformly effective in slowing the disease progression. Over the last 15 years, there has been a rapid advancement in research on the complex pathomechanistic landscape of ALS that has opened up new avenues for successful clinical translation of targeted therapeutics. Multiple studies suggest that the age-dependent interaction of risk-associated genes with environmental factors and endogenous modifiers is critical to the multi-step process of ALS pathogenesis. In this review, we provide an updated discussion on the dysregulated cross-talk between intracellular homeostasis processes, the unique molecular networks across selectively vulnerable cell types, and the multisystemic nature of ALS pathomechanisms. Importantly, this work highlights the alteration in epigenetic and epitranscriptomic landscape due to gene-environment interactions, which have been largely overlooked in the context of ALS pathology. Finally, we suggest that precision medicine research in ALS will be largely benefitted from the stratification of patient groups based on the clinical phenotype, onset and progression, genome, exposome, and metabolic identities.}, }
@article {pmid39006715, year = {2024}, author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J}, title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62310}, pmid = {39006715}, issn = {2168-8184}, abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.}, }
@article {pmid39000336, year = {2024}, author = {Bodai, L and Borosta, R and Ferencz, &#xc1; and Kovács, M and Zsindely, N}, title = {The Role of miR-137 in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000336}, issn = {1422-0067}, support = {OTKA 145898//National Research, Development and Innovation Office [Hungary]/ ; }, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; Gene Expression Regulation ; }, abstract = {Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.}, }
@article {pmid38999371, year = {2024}, author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV}, title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.}, journal = {Journal of clinical medicine}, volume = {13}, number = {13}, pages = {}, pmid = {38999371}, issn = {2077-0383}, abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.}, }
@article {pmid38988889, year = {2024}, author = {Ansari, U and Alam, M and Nadora, D and Muttalib, Z and Chen, V and Taguinod, I and FitzPatrick, M and Wen, J and Ansari, Z and Lui, F}, title = {Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {2}, pages = {166-177}, pmid = {38988889}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.}, }
@article {pmid38976599, year = {2024}, author = {Xu, Z and Xu, R}, title = {Current potential diagnostic biomarkers of amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {38976599}, issn = {2191-0200}, abstract = {Amyotrophic lateral sclerosis (ALS) currently lacks the useful diagnostic biomarkers. The current diagnosis of ALS is mainly depended on the clinical manifestations, which contributes to the diagnostic delay and be difficult to make the accurate diagnosis at the early stage of ALS, and hinders the clinical early therapeutics. The more and more pathogenesis of ALS are found at the last 30 years, including excitotoxicity, the oxidative stress, the mitochondrial dysfunction, neuroinflammation, the altered energy metabolism, the RNA misprocessing and the most recent neuroimaging findings. The findings of these pathogenesis bring the new clues for searching the diagnostic biomarkers of ALS. At present, a large number of relevant studies about the diagnostic biomarkers are underway. The ALS pathogenesis related to the diagnostic biomarkers might lessen the diagnostic reliance on the clinical manifestations. Among them, the cortical altered signatures of ALS patients derived from both structural and functional magnetic resonance imaging and the emerging proteomic biomarkers of neuronal loss and glial activation in the cerebrospinal fluid as well as the potential biomarkers in blood, serum, urine, and saliva are leading a new phase of biomarkers. Here, we reviewed these current potential diagnostic biomarkers of ALS.}, }
@article {pmid38837229, year = {2024}, author = {Ó Murchú, SC and O'Halloran, KD}, title = {BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy.}, journal = {The Journal of physiology}, volume = {602}, number = {14}, pages = {3255-3272}, doi = {10.1113/JP280280}, pmid = {38837229}, issn = {1469-7793}, support = {SFI FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {*Muscular Dystrophy, Duchenne/physiopathology/therapy ; Humans ; *Hypoxia/physiopathology ; Animals ; Respiration ; }, abstract = {Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.}, }
@article {pmid38975145, year = {2024}, author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C}, title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e32688}, pmid = {38975145}, issn = {2405-8440}, abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.}, }
@article {pmid38973130, year = {2024}, author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P}, title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2375330}, pmid = {38973130}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.}, }
@article {pmid38969143, year = {2024}, author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM}, title = {Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {102386}, doi = {10.1016/j.arr.2024.102386}, pmid = {38969143}, issn = {1872-9649}, abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.}, }
@article {pmid38760935, year = {2024}, author = {Fiadeiro, MB and Diogo, JC and Silva, AA and Kim, YS and Cristóvão, AC}, title = {NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities.}, journal = {Antioxidants &amp; redox signaling}, volume = {}, number = {}, pages = {}, doi = {10.1089/ars.2023.0002}, pmid = {38760935}, issn = {1557-7716}, abstract = {Significance: The nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme family, located in the central nervous system, is recognized as a source of reactive oxygen species (ROS) in the brain. Despite its importance in cellular processes, excessive ROS generation leads to cell death and is involved in the pathogenesis of neurodegenerative disorders. Recent advances: NOX enzymes contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke, highlighting their potential as targets for future therapeutic development. This review will discuss NOX's contribution and therapeutic targeting potential in neurodegenerative diseases, focusing on PD, AD, ALS, and stroke. Critical issues: Homeostatic and physiological levels of ROS are crucial for regulating several processes, such as development, memory, neuronal signaling, and vascular homeostasis. However, NOX-mediated excessive ROS generation is deeply involved in the damage of DNA, proteins, and lipids, leading to cell death in the pathogenesis of a wide range of diseases, namely neurodegenerative diseases. Future directions: It is essential to understand the role of NOX homologs in neurodegenerative disorders and the pathological mechanisms undergoing neurodegeneration mediated by increased levels of ROS. This further knowledge will allow the development of new specific NOX inhibitors and their application for neurodegenerative disease therapeutics.}, }
@article {pmid38802624, year = {2024}, author = {Riva, N and Domi, T and Pozzi, L and Lunetta, C and Schito, P and Spinelli, EG and Cabras, S and Matteoni, E and Consonni, M and Bella, ED and Agosta, F and Filippi, M and Calvo, A and Quattrini, A}, title = {Update on recent advances in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4693-4723}, pmid = {38802624}, issn = {1432-1459}, support = {IDEALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Marazzina Project//Marazzina Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; }, abstract = {In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients.}, }
@article {pmid38967881, year = {2024}, author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X}, title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {38967881}, issn = {1590-3478}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.}, }
@article {pmid38967655, year = {2024}, author = {Müller, P and Draguhn, A and Egorov, AV}, title = {Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {}, number = {}, pages = {}, pmid = {38967655}, issn = {1432-2013}, support = {HE8155/1-2//Deutsche Forschungsgemeinschaft/ ; EG134/2-1//Deutsche Forschungsgemeinschaft/ ; Treat-ION01GM1907A//Bundesministerium f&#xfc;r Bildung und Forschung/ ; College for Clinician Scientists//Else Kr&#xf6;ner-Fresenius-Stiftung/ ; }, abstract = {Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.}, }
@article {pmid38966756, year = {2024}, author = {Garg, V and Geurten, BRH}, title = {Diving deep: zebrafish models in motor neuron degeneration research.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1424025}, pmid = {38966756}, issn = {1662-4548}, abstract = {In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.}, }
@article {pmid38504592, year = {2024}, author = {Hamilton, HL and Akther, M and Anis, S and Colwell, CB and Vargas, MR and Pehar, M}, title = {Nicotinamide Adenine Dinucleotide Precursor Supplementation Modulates Neurite Complexity and Survival in Motor Neurons from Amyotrophic Lateral Sclerosis Models.}, journal = {Antioxidants &amp; redox signaling}, volume = {}, number = {}, pages = {}, doi = {10.1089/ars.2023.0360}, pmid = {38504592}, issn = {1557-7716}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; }, abstract = {Aims: Increasing nicotinamide adenine dinucleotide (NAD[+]) availability has been proposed as a therapeutic approach to prevent neurodegeneration in amyotrophic lateral sclerosis (ALS). Accordingly, NAD[+] precursor supplementation appears to exert neuroprotective effects in ALS patients and mouse models. The mechanisms mediating neuroprotection remain uncertain but could involve changes in multiple cell types. We investigated a potential direct effect of the NAD[+] precursor nicotinamide mononucleotide (NMN) on the health of cultured induced pluripotent stem cell (iPSC)-derived human motor neurons and in motor neurons isolated from two ALS mouse models, that is, mice overexpressing wild-type transactive response DNA binding protein-43 (TDP-43) or the ALS-linked human superoxide dismutase 1 with the G93A mutation (hSOD1[G93A]). Results: NMN treatment increased the complexity of neuronal processes in motor neurons isolated from both mouse models and in iPSC-derived human motor neurons. In addition, NMN prevented neuronal death induced by trophic factor deprivation. In mouse and human motor neurons expressing ALS-linked mutant superoxide dismutase 1, NMN induced an increase in glutathione levels, but this effect was not observed in nontransgenic or TDP-43 overexpressing motor neurons. In contrast, NMN treatment normalized the TDP-43 cytoplasmic mislocalization induced by its overexpression. Innovation: NMN can directly act on motor neurons to increase the growth and complexity of neuronal processes and prevent the death induced by trophic factor deprivation. Conclusion: Our results support a direct beneficial effect of NAD[+] precursor supplementation on the maintenance of the neuritic arbor in motor neurons. Importantly, this was observed in motor neurons isolated from two different ALS models, with and without involvement of TDP-43 pathology, supporting its therapeutic potential in sporadic and familial ALS.}, }
@article {pmid38965379, year = {2024}, author = {Jacob, SM and Lee, S and Kim, SH and Sharkey, KA and Pfeffer, G and Nguyen, MD}, title = {Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {38965379}, issn = {1759-4766}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3-5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.}, }
@article {pmid38963497, year = {2024}, author = {Yu, G and Bai, Y and Zhang, ZY}, title = {Valosin-Containing Protein (VCP)/p97 Oligomerization.}, journal = {Sub-cellular biochemistry}, volume = {104}, number = {}, pages = {485-501}, pmid = {38963497}, issn = {0306-0225}, mesh = {*Valosin Containing Protein/metabolism/genetics/chemistry ; Humans ; Protein Multimerization ; Animals ; Mutation ; Frontotemporal Dementia/genetics/metabolism ; Adenosine Triphosphatases/metabolism/genetics/chemistry ; Osteitis Deformans/genetics/metabolism ; Cell Cycle Proteins/metabolism/genetics/chemistry ; Myositis, Inclusion Body/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle ; }, abstract = {Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.}, }
@article {pmid38788085, year = {2024}, author = {Mohassel, P and Abdullah, M and Eichler, FS and Dunn, TM}, title = {Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {735-747}, doi = {10.3233/JND-240014}, pmid = {38788085}, issn = {2214-3602}, mesh = {Humans ; *Serine C-Palmitoyltransferase/metabolism/genetics ; *Neurodevelopmental Disorders ; *Neurodegenerative Diseases/metabolism ; *Hereditary Sensory and Autonomic Neuropathies/genetics/metabolism/physiopathology ; Spastic Paraplegia, Hereditary/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Sphingolipids/metabolism ; }, abstract = {Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.}, }
@article {pmid38747014, year = {2024}, author = {Gale, J and Aizenman, E}, title = {The physiological and pathophysiological roles of copper in the nervous system.}, journal = {The European journal of neuroscience}, volume = {60}, number = {1}, pages = {3505-3543}, doi = {10.1111/ejn.16370}, pmid = {38747014}, issn = {1460-9568}, support = {5T32AG021885/NH/NIH HHS/United States ; NS043277/NH/NIH HHS/United States ; 5T32AG021885/NH/NIH HHS/United States ; NS043277/NH/NIH HHS/United States ; }, mesh = {Humans ; *Copper/metabolism ; Animals ; Homeostasis/physiology ; Nervous System/metabolism ; }, abstract = {Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-β-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling.}, }
@article {pmid38451707, year = {2024}, author = {Clayton, EL and Huggon, L and Cousin, MA and Mizielinska, S}, title = {Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2289-2307}, doi = {10.1093/brain/awae074}, pmid = {38451707}, issn = {1460-2156}, support = {//UK Dementia Research Institute/ ; //UK Medical Research Council/ ; /ALZS_/Alzheimer's Society/United Kingdom ; //Alzheimer's Research UK/ ; 204954/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; P2003//Epilepsy Research UK/ ; 529508//Simons Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; *Synapses/pathology ; *Presynaptic Terminals/pathology/metabolism ; Animals ; Mutation ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes that initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway, which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterized by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarize recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism.}, }
@article {pmid38960473, year = {2024}, author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD}, title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {141}, number = {}, pages = {177-201}, doi = {10.1016/bs.apcsb.2023.12.008}, pmid = {38960473}, issn = {1876-1631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Motor Neuron Disease/genetics/metabolism ; Gene Expression Profiling ; }, abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.}, }
@article {pmid38944367, year = {2024}, author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB}, title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.}, journal = {Mitochondrion}, volume = {78}, number = {}, pages = {101926}, doi = {10.1016/j.mito.2024.101926}, pmid = {38944367}, issn = {1872-8278}, abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.}, }
@article {pmid38942541, year = {2024}, author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK}, title = {Drug repurposing for neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {207}, number = {}, pages = {249-319}, doi = {10.1016/bs.pmbts.2024.03.035}, pmid = {38942541}, issn = {1878-0814}, mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.}, }
@article {pmid38933502, year = {2024}, author = {Chen, BR and Wu, T and Chen, TH and Wang, Y}, title = {Neuroimmune interactions and their roles in neurodegenerative diseases.}, journal = {Fundamental research}, volume = {4}, number = {2}, pages = {251-261}, pmid = {38933502}, issn = {2667-3258}, abstract = {The nervous system possesses bidirectional, sophisticated and delicate communications with the immune system. These neuroimmune interactions play a vitally important role in the initiation and development of many disorders, especially neurodegenerative diseases. Although scientific advancements have made tremendous progress in this field during the last few years, neuroimmune communications are still far from being elucidated. By organizing recent research, in this review, we discuss the local and intersystem neuroimmune interactions and their roles in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Unveiling these will help us gain a better understanding of the process of interplay inside the body and how the organism maintains homeostasis. It will also facilitate a view of the diseases from a holistic, pluralistic and interconnected perspective, thus providing a basis of developing novel and effective methods to diagnose, intervene and treat diseases.}, }
@article {pmid38928874, year = {2024}, author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K}, title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, doi = {10.3390/foods13121931}, pmid = {38928874}, issn = {2304-8158}, support = {533-0C20-GS0D-24//University of Gdansk/ ; }, abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.}, }
@article {pmid38928553, year = {2024}, author = {Di Martino, P and Marcozzi, V and Bibbò, S and Ghinassi, B and Di Baldassarre, A and Gaggi, G and Di Credico, A}, title = {Unraveling the Epigenetic Landscape: Insights into Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, doi = {10.3390/brainsci14060553}, pmid = {38928553}, issn = {2076-3425}, support = {MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, Developmental Neurotoxi-city of Endocrine Disruptors from Plastic Pollutants.//NextGenerationEU "MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, De-velopmental Neurotoxicity of Endocrine Disruptors from Plastic Pollutants./ ; }, abstract = {Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are examples of neurodegenerative movement disorders (NMDs), which are defined by a gradual loss of motor function that is frequently accompanied by cognitive decline. Although genetic abnormalities have long been acknowledged as significant factors, new research indicates that epigenetic alterations are crucial for the initiation and development of disease. This review delves into the complex interactions that exist between the pathophysiology of NMDs and epigenetic mechanisms such DNA methylation, histone modifications, and non-coding RNAs. Here, we examine how these epigenetic changes could affect protein aggregation, neuroinflammation, and gene expression patterns, thereby influencing the viability and functionality of neurons. Through the clarification of the epigenetic terrain underpinning neurodegenerative movement disorders, this review seeks to enhance comprehension of the underlying mechanisms of the illness and augment the creation of innovative therapeutic strategies.}, }
@article {pmid38927681, year = {2024}, author = {Adler, GL and Le, K and Fu, Y and Kim, WS}, title = {Human Endogenous Retroviruses in Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, doi = {10.3390/genes15060745}, pmid = {38927681}, issn = {2073-4425}, mesh = {Humans ; *Endogenous Retroviruses/genetics/pathogenicity ; *Neurodegenerative Diseases/virology/genetics ; Amyotrophic Lateral Sclerosis/virology/genetics ; Animals ; }, abstract = {Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.}, }
@article {pmid38927674, year = {2024}, author = {Gotte, G}, title = {Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, doi = {10.3390/genes15060738}, pmid = {38927674}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Ribonuclease, Pancreatic/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; Animals ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.}, }
@article {pmid38921286, year = {2024}, author = {Katz, L and Gur, A}, title = {Psychosocial Intervention for Family Caregivers of ALS Patients: A Systematic Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38921286}, issn = {2227-9032}, abstract = {PROPOSAL: This systematic review aims to comprehensively examine all existing knowledge on psychosocial interventions for family caregivers for ALS patients. Also, the study will present the gaps in knowledge, recommendations for future research, and guidelines for psychosocial interventions that are focused and adapted to the needs of family caregivers of ALS patients.<br><br>MATERIALS AND METHODS: The systematic review was conducted according to the PRISMA guidelines and identified studies on psychosocial intervention for family caregivers of ALS patients, using five electronic databases: PsychNET, PubMed, EBSCO, PRIMO, and PROQUEST. Seven articles met the criteria and were included in the review. A thematic analysis was conducted to extract major themes.<br><br>RESULTS: Three major themes emerged from the data: (1) Personal benefits; (2) Interpersonal benefits; and (3) Charting challenges and pathways to improve psychosocial interventions.<br><br>CONCLUSIONS: Based on the findings, practical guidelines were formulated that focus on the group's composition, the facilitator's role, the contents, the relationships within the group, and the opportunities and limitations of online interventions.}, }
@article {pmid38921029, year = {2024}, author = {Carata, E and Muci, M and Di Giulio, S and Di Giulio, T and Mariano, S and Panzarini, E}, title = {The Neuromuscular Disorder Mediated by Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5999-6017}, doi = {10.3390/cimb46060358}, pmid = {38921029}, issn = {1467-3045}, abstract = {Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in muscular atrophy and eventual paralysis. While much research has concentrated on investigating the impact of major mutations associated with ALS on motor neurons and central nervous system (CNS) cells, recent studies have unveiled that ALS pathogenesis extends beyond CNS imbalances, encompassing dysregulation in other tissues such as skeletal muscle. Evidence from animal models and patients supports this broader perspective. Skeletal muscle, once considered solely as an effector organ, is now recognized as possessing significant secretory activity capable of influencing motor neuron survival. However, the precise cellular and molecular mechanisms underlying the detrimental effects observed in muscle and its associated structures in ALS remain poorly understood. Additionally, emerging data suggest that extracellular vesicles (EVs) may play a role in the establishment and function of the neuromuscular junction (NMJ) under both physiological and pathological conditions and in wasting and regeneration of skeletal muscles, particularly in neurodegenerative diseases like ALS. This review aims to explore the key findings about skeletal muscle involvement in ALS, shedding light on the potential underlying mechanisms and contributions of EVs and their possible application for the design of biosensors.}, }
@article {pmid38726604, year = {2024}, author = {López Gómez, JJ and Díaz Marín, C and Castillo-García, T and Larrad-Sainz, A and Gastaldo-Simeón, R and Juarros-Martínez, S and Leunda-Eizmendi, L and Civera Andrés, M and Matía Martín, P}, title = {[Medical nutrition therapy in amyotrophic lateral sclerosis - Do we act or react? A case report and multidisciplinary review].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {3}, pages = {712-723}, doi = {10.20960/nh.05189}, pmid = {38726604}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; Female ; *Nutrition Therapy/methods ; *Malnutrition/etiology/therapy ; Middle Aged ; Nutritional Status ; }, abstract = {Background: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a progressive course. The current prevalence is between 3 and 6 cases/100,000. Malnutrition is closely related to patient prognosis in ALS. The implications of this conditions have been that we should recommend patient care in a multidisciplinary unit. Case report: the case presented shows the evolution of a patient with ALS. The patient was referred to different clinical departments after neurological evaluation and her nutritional, functional and respiratory status were assessed. There was no nutritional deterioration at diagnosis; however, intake was below energy-protein requirements. The clinical evolution of the patient showed a decrease in muscle mass with preservation of weight and fat mass. "Aggressive" measures to control nutritional status such as gastrostomy were rejected in the initial stages of the disease, but had to be carried out after development of dysphagia and associated malnutrition. This situation of progressive morphofunctional deterioration and the development of disease-related complications made essential the participation of different health services and professionals in its control. Dicussion: the management of ALS in a multidisciplinary manner allows to improve the course of the disease and the quality of life of both the patients and their families. Patient follow-up is based on the adjustment and management of complications. The basis of the relationship with these patients includes maintaining an adequate communication with them and their families, and ensuring joint decision-making about their condition.}, }
@article {pmid38920997, year = {2024}, author = {Nowak, I and Paździor, M and Sarna, R and Madej, M}, title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5436-5453}, doi = {10.3390/cimb46060325}, pmid = {38920997}, issn = {1467-3045}, abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.}, }
@article {pmid38920691, year = {2024}, author = {Ilieva, MS}, title = {Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, doi = {10.3390/cells13121063}, pmid = {38920691}, issn = {2073-4409}, mesh = {Humans ; *RNA, Untranslated/genetics/metabolism ; *Nervous System Diseases/genetics/metabolism ; *Mental Disorders/genetics/metabolism ; RNA, Circular/genetics/metabolism ; Animals ; RNA, Long Noncoding/genetics/metabolism ; Gene Expression Regulation ; MicroRNAs/genetics/metabolism ; }, abstract = {Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.}, }
@article {pmid38918327, year = {2024}, author = {Sharma, V and Sharma, P and Singh, TG}, title = {Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases.}, journal = {Pharmacological reports : PR}, volume = {}, number = {}, pages = {}, pmid = {38918327}, issn = {2299-5684}, abstract = {Neurodegenerative diseases (NDDs) pose a significant issue in healthcare, needing a thorough knowledge of their complex molecular mechanisms. A diverse set of cell signaling mediators and their interactions play critical roles in neuroinflammation. The release of pro-inflammatory mediators in response to neural dysfunction is detrimental to normal cell survival. Moreover, the important role of nuclear factor-κB (NF-κB) in the central nervous system through Toll-like receptor (TLR) activation has been well established. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (TLR-4/NF-κB inhibitors) and neurodegeneration encompassing Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and stroke. Insights garnered from this exploration underscore the potential of TLR-4 as a therapeutic target. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. This review thus serves as a roadmap, guiding future research endeavors toward innovative strategies for combatting the complex interplay between TLR-4 signaling and NDDs.}, }
@article {pmid38915767, year = {2024}, author = {Ambrosini, A and Dalla Bella, E and Ravasi, M and Melazzini, M and Lauria, G}, title = {New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1407912}, pmid = {38915767}, issn = {2296-858X}, abstract = {Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.}, }
@article {pmid38813817, year = {2024}, author = {Sprunger, ML and Jackrel, ME}, title = {The role of Matrin-3 in physiology and its dysregulation in disease.}, journal = {Biochemical Society transactions}, volume = {52}, number = {3}, pages = {961-972}, doi = {10.1042/BST20220585}, pmid = {38813817}, issn = {1470-8752}, mesh = {Humans ; *RNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Nuclear Matrix-Associated Proteins/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; DNA-Binding Proteins/metabolism ; Animals ; DNA Damage ; RNA-Binding Protein FUS/metabolism/chemistry ; }, abstract = {The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.}, }
@article {pmid38713169, year = {2024}, author = {Nikel, LM and Talbot, K and Vahsen, BF}, title = {Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {46}, number = {7}, pages = {e2400054}, doi = {10.1002/bies.202400054}, pmid = {38713169}, issn = {1521-1878}, support = {2023/MNDS/6400/753TALB//MND Scotland/ ; Talbot/Apr22/889-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Humans ; *Microglia/metabolism/pathology ; *Motor Neurons/pathology/metabolism ; Coculture Techniques ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, primarily leading to the degeneration of motor neurons. The traditional focus on motor neuron-centric mechanisms has recently shifted towards understanding the contribution of non-neuronal cells, such as microglia, in ALS pathophysiology. Advances in induced pluripotent stem cell (iPSC) technology have enabled the generation of iPSC-derived microglia monocultures and co-cultures to investigate their role in ALS pathogenesis. Here, we briefly review the insights gained from these studies into the role of microglia in ALS. While iPSC-derived microglia monocultures have revealed intrinsic cellular dysfunction due to ALS-associated mutations, microglia-motor neuron co-culture studies have demonstrated neurotoxic effects of mutant microglia on motor neurons. Based on these findings, we briefly discuss currently unresolved questions and how they could be addressed in future studies. iPSC models hold promise for uncovering disease-relevant pathways in ALS and identifying potential therapeutic targets.}, }
@article {pmid38914810, year = {2024}, author = {Manchia, M and Paribello, P and Pinna, M and Steardo, L and Carpiniello, B and Pinna, F and Pisanu, C and Squassina, A and Hajek, T}, title = {Lithium and its effects: does dose matter?.}, journal = {International journal of bipolar disorders}, volume = {12}, number = {1}, pages = {23}, pmid = {38914810}, issn = {2194-7511}, abstract = {BACKGROUND: Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium's clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations.<br><br>CONTENT: This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors' preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections.<br><br>CONCLUSIONS: Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium's ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.}, }
@article {pmid38914784, year = {2024}, author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP}, title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {}, number = {}, pages = {}, pmid = {38914784}, issn = {1179-190X}, support = {R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; }, abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].}, }
@article {pmid38898687, year = {2024}, author = {Lee, B and Lee, SM and Song, JW and Choi, JW}, title = {Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction.}, journal = {Biomolecules &amp; therapeutics}, volume = {32}, number = {4}, pages = {403-423}, doi = {10.4062/biomolther.2024.009}, pmid = {38898687}, issn = {1976-9148}, abstract = {The human gastrointestinal (GI) tract houses a diverse microbial community, known as the gut microbiome comprising bacteria, viruses, fungi, and protozoa. The gut microbiome plays a crucial role in maintaining the body's equilibrium and has recently been discovered to influence the functioning of the central nervous system (CNS). The communication between the nervous system and the GI tract occurs through a two-way network called the gut-brain axis. The nervous system and the GI tract can modulate each other through activated neuronal cells, the immune system, and metabolites produced by the gut microbiome. Extensive research both in preclinical and clinical realms, has highlighted the complex relationship between the gut and diseases associated with the CNS, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review aims to delineate receptor and target enzymes linked with gut microbiota metabolites and explore their specific roles within the brain, particularly their impact on CNS-related diseases.}, }
@article {pmid38909349, year = {2024}, author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD}, title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {38909349}, issn = {1179-1918}, abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.}, }
@article {pmid38908196, year = {2024}, author = {Donders, Z and Skorupska, IJ and Willems, E and Mussen, F and Broeckhoven, JV and Carlier, A and Schepers, M and Vanmierlo, T}, title = {Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {177}, number = {}, pages = {117009}, doi = {10.1016/j.biopha.2024.117009}, pmid = {38908196}, issn = {1950-6007}, abstract = {Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.}, }
@article {pmid38904729, year = {2024}, author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC}, title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {775}, pmid = {38904729}, issn = {1573-4978}, support = {304496/2023-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; }, abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.}, }
@article {pmid38903602, year = {2024}, author = {Al-Kuraishy, HM and Jabir, MS and Sulaiman, GM and Mohammed, HA and Al-Gareeb, AI and Albuhadily, AK and Jawad, SF and Swelum, AA and Abomughaid, MM}, title = {The role of statins in amyotrophic lateral sclerosis: protective or not?.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422912}, pmid = {38903602}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.}, }
@article {pmid38834164, year = {2024}, author = {Griñán-Ferré, C and Bellver-Sanchis, A and Guerrero, A and Pallàs, M}, title = {Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.}, journal = {Pharmacological research}, volume = {205}, number = {}, pages = {107247}, doi = {10.1016/j.phrs.2024.107247}, pmid = {38834164}, issn = {1096-1186}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/drug therapy/genetics ; *Pharmacogenetics/methods ; *Epigenesis, Genetic/drug effects ; Animals ; Epigenomics/methods ; }, abstract = {About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.}, }
@article {pmid38898538, year = {2024}, author = {Bravo-Miana, RDC and Arizaga-Echebarria, JK and Otaegui, D}, title = {Central nervous system-derived extracellular vesicles: the next generation of neural circulating biomarkers?.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {32}, pmid = {38898538}, issn = {2047-9158}, support = {PI20/1253//Instituto de Salud Carlos III/ ; KK-2021/00009//Departamento de Desarrollo Econ&#xf3;mico, Sostenibilidad y Medio Ambiente/ ; ECTRIMS Postdoctoral Research Fellowship 2023//European Committee for Treatment and Research in Multiple Sclerosis/ ; Predoctoral fellowship//Basque Government/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/blood ; *Central Nervous System/metabolism ; *Neurodegenerative Diseases/blood/diagnosis/metabolism ; Animals ; }, abstract = {The central nervous system (CNS) is integrated by glial and neuronal cells, and both release extracellular vesicles (EVs) that participate in CNS homeostasis. EVs could be one of the best candidates to operate as nanosized biological platforms for analysing multidimensional bioactive cargos, which are protected during systemic circulation of EVs. Having a window into the molecular level processes that are happening in the CNS could open a new avenue in CNS research. This raises a particular point of interest: can CNS-derived EVs in blood serve as circulating biomarkers that reflect the pathological status of neurological diseases? L1 cell adhesion molecule (L1CAM) is a widely reported biomarker to identify CNS-derived EVs in peripheral blood. However, it has been demonstrated that L1CAM is also expressed outside the CNS. Given that principal data related to neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease were obtained using L1CAM-positive EVs, efforts to overcome present challenges related to its specificity are required. In this sense, other surface biomarkers for CNS-derived EVs, such as glutamate aspartate transporter (GLAST) and myelin oligodendrocyte glycoprotein (MOG), among others, have started to be used. Establishing a panel of EV biomarkers to analyse CNS-derived EVs in blood could increase the specificity and sensitivity necessary for these types of studies. This review covers the main evidence related to CNS-derived EVs in cerebrospinal fluid and blood samples of patients with neurological diseases, focusing on the reported biomarkers and the technical possibilities for their isolation. EVs are emerging as a mirror of brain physiopathology, reflecting both localized and systemic changes. Therefore, when the technical hindrances for EV research and clinical applications are overcome, novel disease-specific panels of EV biomarkers would be discovered to facilitate transformation from traditional medicine to personalized medicine.}, }
@article {pmid38898231, year = {2024}, author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N}, title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.}, journal = {Nature reviews. Neuroscience}, volume = {}, number = {}, pages = {}, pmid = {38898231}, issn = {1471-0048}, abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.}, }
@article {pmid38898006, year = {2024}, author = {Nógrádi, B and Nógrádi-Halmi, D and Erdélyi-Furka, B and Kádár, Z and Csont, T and Gáspár, R}, title = {Mechanism of motoneuronal and pyramidal cell death in amyotrophic lateral sclerosis and its potential therapeutic modulation.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {291}, pmid = {38898006}, issn = {2058-7716}, support = {BO/00574/22//Magyar Tudom&#xe1;nyos Akad&#xe9;mia (Hungarian Academy of Sciences)/ ; &#xda;NKP-23-5 -SZTE-711//Emberi Eroforr&#xe1;sok Miniszt&#xe9;riuma (Ministry of Human Capacities)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder clinically characterized by muscle atrophy and progressive paralysis. Loss of motoneurons and pyramidal cells is thought to be the center piece of the complex and multifaceted ALS pathology, however, the exact mechanisms laying behind motoneuronal cell death in the spinal cord and motor cortex are still unknown. It was originally proposed that apoptosis plays a fundamental role in motoneuronal demise, nonetheless, later it became clear that other forms of regulated cell death, including necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, may also contribute to motoneuron loss. Over the past years, multiple studies aimed to improve our understanding of the contributory role of these mechanisms as well as to offer novel targets for potential therapeutic interventions. The pharmacological inhibition of the ferroptotic pathway and the modulation of the autophagic machinery seem to have particularly promising effects, reducing motoneuron loss and slowing disease progression in transgenic models of ALS. Nevertheless, the potential beneficial effects of necroptosis-targeting interventions were mostly disproven in the latest studies. In this review we aim to summarize the current view on regulated cell death mechanisms that lead to motoneuronal and pyramidal cell degeneration in ALS and showcase their applicability as future drug targets.}, }
@article {pmid38892250, year = {2024}, author = {Cerantonio, A and Citrigno, L and Greco, BM and De Benedittis, S and Passarino, G and Maletta, R and Qualtieri, A and Montesanto, A and Spadafora, P and Cavalcanti, F}, title = {The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892250}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *DNA, Mitochondrial/genetics ; *DNA Copy Number Variations ; *Mitochondria/genetics/metabolism ; Huntington Disease/genetics/pathology ; Animals ; }, abstract = {Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.}, }
@article {pmid38891774, year = {2024}, author = {Arnold, FJ and Putka, AF and Raychaudhuri, U and Hsu, S and Bedlack, RS and Bennett, CL and La Spada, AR}, title = {Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891774}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Glutamic Acid/metabolism ; Animals ; Motor Neurons/metabolism/pathology ; Aging/metabolism ; Receptors, AMPA/metabolism ; Endoplasmic Reticulum Stress ; Mitochondria/metabolism ; Excitatory Amino Acid Transporter 2/metabolism ; Astrocytes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.}, }
@article {pmid38891112, year = {2024}, author = {Santos, JR and Park, J}, title = {MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891112}, issn = {2073-4409}, support = {n/a//Canada Research Chairs/ ; 202104PJT-462444-NSB-CEAB-275899/CAPMC/CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Nuclear Matrix-Associated Proteins/metabolism/genetics ; *Gene Expression Regulation ; *Nuclear Matrix/metabolism ; Animals ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.}, }
@article {pmid38891099, year = {2024}, author = {Hernan-Godoy, M and Rouaux, C}, title = {From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891099}, issn = {2073-4409}, support = {ANR-21-CE16-0024//Agence Nationale de la Recherche/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *DNA Methylation/genetics ; *Carbon/metabolism ; Animals ; }, abstract = {The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.}, }
@article {pmid38891059, year = {2024}, author = {Dashtmian, AR and Darvishi, FB and Arnold, WD}, title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891059}, issn = {2073-4409}, support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.}, }
@article {pmid38891021, year = {2024}, author = {Nguyen, L}, title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891021}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.}, }
@article {pmid38891002, year = {2024}, author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS}, title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891002}, issn = {2304-8158}, abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.}, }
@article {pmid38889636, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Tavakol-Afshari, J}, title = {MicroRNA (miRNA) as a biomarker for diagnosis, prognosis, and therapeutics molecules in neurodegenerative disease.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {177}, number = {}, pages = {116899}, doi = {10.1016/j.biopha.2024.116899}, pmid = {38889636}, issn = {1950-6007}, abstract = {Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.}, }
@article {pmid38889403, year = {2024}, author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X}, title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {38889403}, issn = {2191-0200}, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.}, }
@article {pmid38883980, year = {2024}, author = {Azam, HMH and Rößling, RI and Geithe, C and Khan, MM and Dinter, F and Hanack, K and Prüß, H and Husse, B and Roggenbuck, D and Schierack, P and Rödiger, S}, title = {MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1386735}, pmid = {38883980}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination of affected tissue, pathological changes reveal a loss of synapses, misfolded proteins, and activation of immune cells-all indicative of disease progression-before severe clinical symptoms become apparent. Early detection of NDs is crucial for potentially administering targeted medications that may delay disease advancement. Given their complex pathophysiological features and diverse clinical symptoms, there is a pressing need for sensitive and effective diagnostic methods for NDs. Biomarkers such as microRNAs (miRNAs) have been identified as potential tools for detecting these diseases. We explore the pivotal role of miRNAs in the context of NDs, focusing on Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Huntington's disease, and Amyotrophic Lateral Sclerosis. The review delves into the intricate relationship between aging and NDs, highlighting structural and functional alterations in the aging brain and their implications for disease development. It elucidates how miRNAs and RNA-binding proteins are implicated in the pathogenesis of NDs and underscores the importance of investigating their expression and function in aging. Significantly, miRNAs exert substantial influence on post-translational modifications (PTMs), impacting not just the nervous system but a wide array of tissues and cell types as well. Specific miRNAs have been found to target proteins involved in ubiquitination or de-ubiquitination processes, which play a significant role in regulating protein function and stability. We discuss the link between miRNA, PTM, and NDs. Additionally, the review discusses the significance of miRNAs as biomarkers for early disease detection, offering insights into diagnostic strategies.}, }
@article {pmid38878554, year = {2024}, author = {Mincic, AM and Antal, M and Filip, L and Miere, D}, title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {7}, pages = {1832-1849}, doi = {10.1016/j.clnu.2024.05.036}, pmid = {38878554}, issn = {1532-1983}, abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).<br><br>METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.<br><br>RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.<br><br>CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.}, }
@article {pmid38877004, year = {2024}, author = {Costa, RG and Conceição, A and Matos, CA and Nóbrega, C}, title = {The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.}, journal = {Cell death &amp; disease}, volume = {15}, number = {6}, pages = {415}, pmid = {38877004}, issn = {2041-4889}, mesh = {Humans ; *Ataxin-2/metabolism/genetics ; *Peptides/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; }, abstract = {A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.}, }
@article {pmid38874845, year = {2024}, author = {Birbaumer, N}, title = {"Your Thoughts are (were) Free!": Brain-Computer-Interfaces, Neurofeedback, Detection of Deception, and the Future of Mind-Reading.}, journal = {Applied psychophysiology and biofeedback}, volume = {}, number = {}, pages = {}, pmid = {38874845}, issn = {1573-3270}, abstract = {This review describes the historical developement and rationale of clinically relevant research on neurophysiological "mind reading" paradims: Brain- Computer-Interfaces, detection of deception, brain stimulation and neurofeedback and the clinical applications in drug resistant epilepsy, chronic stroke, and communication with paralyzed locked-in persons. The emphasis lies on completely locked-in patients with amyotrophic lateral sclerosis using non-invasive and invasive brain computer interfaces and neurofeedback to restore verbal communication with the social environment. In the second part of the article we argue that success and failure of neurophysiological "mind reading" paradigms may be explained with a motor theory of thinking and emotion in combination with learning theory. The ethical implications of brain computer interface and neurofeedback approaches, particularly for severe chronic paralysis and loss of communication diseases and decisions on hastened death and euthanasia are discussed.}, }
@article {pmid38871941, year = {2024}, author = {Naik, B and Sasikumar, J and Das, SP}, title = {From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {38871941}, issn = {1559-1182}, support = {GIA/2019/000620/PRCGIA//Indian Council of Medical Research/ ; GIA/2019/000620/PRCGIA//Indian Council of Medical Research/ ; }, abstract = {The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.}, }
@article {pmid38870925, year = {2024}, author = {Hamdi, N and Ocab, O and Soliman, R and Ludolph, A and Anwar, W and Logroscino, G and Fahmy, N}, title = {Motor Neuron Disease Population-Based Registry in Egypt: Where Do We Stand?.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1159/000539468}, pmid = {38870925}, issn = {1423-0208}, abstract = {BACKGROUND: There is a growing body of evidence indicating that the worldwide distribution of ALS is far from uniform. This is evident through variations in the epidemiology, genetics, and phenotypical characteristics of amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MND) across different regions. However, comprehensive ALS epidemiological studies are still lacking in many parts of the world, especially in Africa. Therefore, we propose the establishment of a population-based register for ALS/MND in Egypt, an important part of Africa with a population of more than 100 millions of people.<br><br>SUMMARY: Given Egypt's distinctive social and demographic characteristics, it is highly recommended to employ specific, recently developed epidemiological techniques for assessing the prevalence and incidence of these diseases within the country. By utilizing these methods, we can gather invaluable data that will contribute to a deeper understanding of ALS and enable us to effectively address its impact on the population of Egypt.<br><br>KEY MESSAGES: Our goal with this pioneering ALS/MND population-based register in Egypt is to define the burden of ALS in this part of Africa and to increase the chances for this consanguineous population to get access to modern individualized genetic therapies. Additionally, we aspire to uncover potential environmental factors and gene-environment interactions that contribute to the development of ALS. This knowledge of MND individual and group risk in Egypt will not only open doors for interventions but also provide opportunities for future research and discovery.}, }
@article {pmid38869826, year = {2024}, author = {Wang, H and Zeng, R}, title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {38869826}, issn = {1432-1459}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.}, }
@article {pmid38864944, year = {2024}, author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y}, title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Neurochemical research}, volume = {}, number = {}, pages = {}, pmid = {38864944}, issn = {1573-6903}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.}, }
@article {pmid38859699, year = {2024}, author = {Finsterer, J and Strobl, W}, title = {Gastrointestinal involvement in neuromuscular disorders.}, journal = {Journal of gastroenterology and hepatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgh.16650}, pmid = {38859699}, issn = {1440-1746}, abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.}, }
@article {pmid38531340, year = {2024}, author = {Lee, KH and Kim, MH and Kim, J and Nam, HJ}, title = {Acupuncture for Tinnitus: A Scoping Review of Clinical Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {292-301}, doi = {10.1159/000538236}, pmid = {38531340}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Tinnitus/therapy ; Randomized Controlled Trials as Topic ; Acupuncture Points ; }, abstract = {BACKGROUND: Acupuncture treatment for tinnitus has received attention owing to its potential as an alternative to conventional treatment modalities. We conducted a scoping review to identify detailed information on acupuncture treatment methods used in clinical studies and to provide useful information for practitioners, patients, and researchers.<br><br>METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA), and the China National Knowledge Infrastructure (CNKI) were searched from their inception to December 2023. This review included single-arm trials, open-label randomized controlled trials (RCTs), and double-blind RCTs using needle-type acupuncture to treat tinnitus in English, Chinese, and Korean. We investigated basic and detailed information on the acupuncture treatment methods, assessment methods, and study outcomes. Network analysis was also conducted to evaluate the centrality between acupoints in the double-blind RCTs.<br><br>RESULTS: We included 106 articles. There were 11 single-arm trials, 90 open-label RCTs, and 5 double-blind RCTs. Most (89.6%) of these studies were conducted in China. Manual acupuncture was the most common type of acupuncture in treatment group. A total of 119 acupuncture points were used 1,138 times. The most frequently used acupoints were local points around the ear (TE17, GB2, SI19, and TE21). Both local and distant acupoints were used simultaneously in these studies. The treatment duration of 20-39 days, 10 to 19 sessions of treatment, the mean acupuncture duration of 30 min, needle diameter of 0.30 mm &#xd7; 40 mm, and needling depth over 30 mm and less than 50 mm were confirmed as the most common.<br><br>CONCLUSION: These study outcomes will enable future acupuncture studies on tinnitus to perform more effective and standardized acupuncture treatments in selecting acupoints and procedures. Furthermore, the study has implications for informing clinicians and students about more impactful acupuncture strategies for addressing tinnitus.<br><br>UNLABELLED: <title>Hintergrund</title>Die Anwendung von Akupunktur bei Tinnitus erh&#xe4;lt seit einiger Zeit Aufmerksamkeit als potenzielle Alternative zu konventionellen Behandlungsmodalit&#xe4;ten. Wir f&#xfc;hrten einen Scoping-Review durch, um detaillierte Informationen zu den in klinischen Studien angewandten Akupunktur-Behandlungsmethoden zu sammeln und n&#xfc;tzliche Informationen f&#xfc;r Praktiker, Patienten und Forscher bereitzustellen.<title>Methoden</title>MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA) und die China National Knowledge Infrastructure (CNKI) wurden von ihrem jeweiligen Beginn bis Dezember 2023 durchsucht. In diese &#xdc;bersichtsarbeit wurden einarmige Studien, offene, randomisierte, kontrollierte Studien (RCTs) sowie doppelt verblindete RCTs zu Nadel-Akupunktur zur Behandlung von Tinnitus in englischer, chinesischer und koreanischer Sprache einbezogen. Wir untersuchten grundlegende und detaillierte Informationen zu den Akupunktur-Behandlungsmethoden, Untersuchungsmethoden und Studienergebnissen. Au&#xdf;erdem wurden Netzwerkanalysen zur Beurteilung der Zentralit&#xe4;t zwischen Akupunkten in den doppelt verblindeten RCTs durchgef&#xfc;hrt.<title>Ergebnisse</title>106 Artikel wurden eingeschlossen. Sie behandelten 11 einarmige Studien, 90 offene RCTs und 5 doppelt verblindete RCTs. Die meisten (89,6%) dieser Studien waren in China durchgef&#xfc;hrt worden. Manuelle Akupunktur war die h&#xe4;ufigste Form der Akupunktur in den Behandlungsgruppen. 119 Akupunkturpunkte wurden insgesamt 1&#x2019;138 Mal verwendet. Die am h&#xe4;ufigsten verwendeten Akupunkte waren lokale Punkte im Bereich des Ohrs (TE17, GB2, SI19 und TE21). Jedoch wurden in den Studien lokale und entfernte Akupunkte gleichzeitig angewendet. Au&#xdf;erdem wurde festgestellt, dass die Behandlungsdauer am h&#xe4;ufigsten 20 bis 39 Tage betrug, die Zahl der Sitzungen 10 bis 19, die mittlere Akupunkturdauer 30 Minuten, die Nadelgr&#xf6;&#xdf;e 0.30 mm &#xd7; 40 mm und die Einstichtiefe zwischen 30 mm und weniger als 50 mm.<title>Schlussfolgerung</title>Diese Studienergebnisse bieten eine Grundlage f&#xfc;r k&#xfc;nftige Studien zu Akupunktur bei Tinnitus, um durch die Auswahl der Akupunkte und Verfahren wirksamere und standardisierte Akupunkturbehandlungen durchzuf&#xfc;hren. Dar&#xfc;ber hinaus hat die Studie Implikationen f&#xfc;r die Aufkl&#xe4;rung von Praktikern und Sch&#xfc;lern &#xfc;ber wirkungsvollere Akupunkturstrategien zur Behandlung von Tinnitus.}, }
@article {pmid38037913, year = {2024}, author = {Zhong, G and Wang, X and Li, J and Xie, Z and Wu, Q and Chen, J and Wang, Y and Chen, Z and Cao, X and Li, T and Liu, J and Wang, Q}, title = {Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.}, journal = {Current neuropharmacology}, volume = {22}, number = {10}, pages = {1650-1671}, pmid = {38037913}, issn = {1875-6190}, support = {81973918, 82274616//National Natural Science Foundation of China/ ; 2019KSYS005//Key laboratory project of colleges and universities in Guangdong Province/ ; 2020A0505100052//Guangdong province science and technology plan international cooperation project/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Copper/metabolism ; Animals ; Biological Products/therapeutic use/pharmacology ; Homeostasis/drug effects ; Chelating Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.}, }
@article {pmid38856890, year = {2024}, author = {Tripathi, S and Bhawana, }, title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.}, journal = {Neurochemical research}, volume = {}, number = {}, pages = {}, pmid = {38856890}, issn = {1573-6903}, abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.}, }
@article {pmid38856793, year = {2024}, author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R}, title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {38856793}, issn = {1559-1182}, abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.}, }
@article {pmid38560897, year = {2024}, author = {Minatoguchi, S and Fujita, Y and Niizuma, K and Tominaga, T and Yamashita, T and Abe, K and Dezawa, M}, title = {Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.}, journal = {Stem cells translational medicine}, volume = {13}, number = {6}, pages = {532-545}, doi = {10.1093/stcltm/szae018}, pmid = {38560897}, issn = {2157-6580}, support = {//New Energy and Industrial Technology Development Organization/ ; //Japan Agency for Medical Research and Development/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; //Japan Society for the Promotion of Science/ ; //SENSHIN Medical Research Foundation/ ; //Life Science Institute Inc/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Mesenchymal Stem Cell Transplantation/methods ; Immunosuppressive Agents/pharmacology/therapeutic use ; HLA Antigens/metabolism ; Cell Differentiation ; Animals ; Histocompatibility Testing/methods ; }, abstract = {The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.}, }
@article {pmid38855322, year = {2024}, author = {Tsekrekou, M and Giannakou, M and Papanikolopoulou, K and Skretas, G}, title = {Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1383453}, pmid = {38855322}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with severe socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly. Despite significant advancements in understanding ALS mechanisms, the disease remains incurable, with current treatments offering limited clinical benefits. Through a comprehensive analysis, the review focuses on the direct modulation of the misfolded proteins and presents recent discoveries in small molecules and peptides that inhibit SOD1 and TDP-43 aggregation, underscoring their potential as effective treatments to modify disease progression and improve clinical outcomes.}, }
@article {pmid38848023, year = {2024}, author = {Fabi, JP}, title = {The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans.}, journal = {Metabolic brain disease}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11011-024-01369-w}, pmid = {38848023}, issn = {1573-7365}, support = {2013/07914-8//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 307842/2022-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, abstract = {The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.}, }
@article {pmid38846716, year = {2024}, author = {Bradford, D and Rodgers, KE}, title = {Advancements and challenges in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1401706}, pmid = {38846716}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) continues to pose a significant challenge due to the disease complexity and heterogeneous manifestations. Despite recent drug approvals, there remains a critical need for the development of more effective therapies. This review explores the underlying mechanisms involved; including neuroinflammation, glutamate mediated excitotoxicity, mitochondrial dysfunction, and hypermetabolism, and how researchers are trying to develop novel drugs to target these pathways. While progress has been made, the unmet need of ALS patients highlights the urgency for continued research and resource allocation in the pursuit of effective treatments.}, }
@article {pmid38845026, year = {2024}, author = {Kettunen, P and Koistinaho, J and Rolova, T}, title = {Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {152}, pmid = {38845026}, issn = {1742-2094}, support = {334525//Research Council of Finland/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Central Nervous System Infections ; Animals ; }, abstract = {Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.}, }
@article {pmid38844617, year = {2024}, author = {Tyr, A and Heldring, N and Zilg, B}, title = {Examining the use of alternative light sources in medico-legal assessments of blunt-force trauma: a systematic review.}, journal = {International journal of legal medicine}, volume = {}, number = {}, pages = {}, pmid = {38844617}, issn = {1437-1596}, abstract = {The ability to analyze blunt-force trauma is crucial for deciphering valuable clues concerning mechanisms of injury and as evidence for medico-legal investigations. The use of alternate light sources (ALS) has been studied over the past decade, and is proposed to outperform conventional white light (CWL) during bruise assessments. In response to the growing interest of the technology worldwide, a systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to address the ability of ALS to detect and visualize bruising. From an initial 4055 records identified, ten studies met the eligibly criteria and were selected for this review. Evaluation also included a novel framework, referred to as SPICOT, to further systematically assess both scientific evidence and risk of bias in forensic literature. Analysis reveals that narrowband wavelengths within in the infrared or ultraviolet spectral ranges do not significantly outperform CWL in visualizing or detecting bruising. However, wavelengths within the visible spectrum, particularly 415 nm combined with longpass or bandpass yellow filters, are more effective. However, the majority of selected studies only address the sensitivity of ALS, and therefore, results may only be considered valid when the location of a bruise is known. Further investigation is required to understand the specificity of ALS, in particular how the use of topical cosmetic products, previous wounds/scar-tissue, tattoos, moles and freckles may affect detection. The ethical concern regarding the interpretation of enhanced visualized trauma should also be considered in prospect discussions prior to implementing ALS into routine practice. Nevertheless, this review finds that narrowband ALS within the visible spectrum demonstrates potential for improved injury documentation, outperforming CWL in the detection and visualization of bruising.}, }
@article {pmid38831349, year = {2024}, author = {López-Carbonero, JI and García-Toledo, I and Fernández-Hernández, L and Bascuñana, P and Gil-Moreno, MJ and Matías-Guiu, JA and Corrochano, S}, title = {In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {29}, pmid = {38831349}, issn = {2047-9158}, support = {2022-5A/BMD-24221//Consejer&#xed;a de Educaci&#xf3;n, Juventud y Deporte, Comunidad de Madrid/ ; PDI2020-1153-70RB-100/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovaci&#xf3;n/ ; CM23/00094//Instituto de Salud Carlos III/ ; INT20/00079//Instituto de Salud Carlos III/ ; INT23/00017//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *TDP-43 Proteinopathies/diagnosis/metabolism/genetics ; *Biomarkers/analysis/metabolism ; *DNA-Binding Proteins/metabolism ; Brain/metabolism/pathology ; }, abstract = {TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.}, }
@article {pmid38712849, year = {2024}, author = {Ludolph, AC and Corcia, P and Desnuelle, C and Heiman-Patterson, T and Mora, JS and Mansfield, CD and Couratier, P}, title = {Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {1}, pages = {36-41}, doi = {10.1002/mus.28101}, pmid = {38712849}, issn = {1097-4598}, support = {//AB Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Research Design ; Severity of Illness Index ; Outcome Assessment, Health Care/standards ; Clinical Trials as Topic/methods ; Disease Progression ; }, abstract = {The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.}, }
@article {pmid37016529, year = {2024}, author = {Adam, H and Gopinath, SCB and Arshad, MKM and Adam, T and Subramaniam, S and Hashim, U}, title = {An Update on Parkinson's Disease and its Neurodegenerative Counterparts.}, journal = {Current medicinal chemistry}, volume = {31}, number = {19}, pages = {2770-2787}, pmid = {37016529}, issn = {1875-533X}, mesh = {Humans ; *Parkinson Disease/metabolism/pathology/diagnosis ; Neurodegenerative Diseases/metabolism/pathology ; alpha-Synuclein/metabolism ; Multiple System Atrophy/metabolism/diagnosis/pathology ; Animals ; }, abstract = {INTRODUCTION: Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases.<br><br>BACKGROUND: Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism.<br><br>METHOD: Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers.<br><br>RESULTS: Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations.<br><br>CONCLUSION: We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.}, }
@article {pmid38829511, year = {2024}, author = {Jiang, S and Xu, R}, title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {38829511}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.}, }
@article {pmid38822985, year = {2024}, author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB}, title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.}, journal = {Neurochemical research}, volume = {}, number = {}, pages = {}, pmid = {38822985}, issn = {1573-6903}, abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.}, }
@article {pmid38822416, year = {2024}, author = {Yadav, S and Deepika,  and Moar, K and Kumar, A and Khola, N and Pant, A and Kakde, GS and Maurya, PK}, title = {Reconsidering red blood cells as the diagnostic potential for neurodegenerative disorders.}, journal = {Biology of the cell}, volume = {}, number = {}, pages = {e2400019}, doi = {10.1111/boc.202400019}, pmid = {38822416}, issn = {1768-322X}, support = {//Council of Scientific and Industrial Research (CSIR), Government of India/ ; //University Grant Commission (UGC)/ ; HSCIT-3946//Haryana State Council for Science, Innovation, and Technology/ ; //Central University of Haryana, Mahendergarh/ ; //Indian Council of Medical Research (ICMR), Government of India/ ; }, abstract = {BACKGROUND: Red blood cells (RBCs) are usually considered simple cells and transporters of gases to tissues.<br><br>HYPOTHESIS: However, recent research has suggested that RBCs may have diagnostic potential in major neurodegenerative disorders (NDDs).<br><br>RESULTS: This review summarizes the current knowledge on changes in RBC in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other NDDs. It discusses the deposition of neuronal proteins like amyloid-&#x3b2;, tau, and &#x3b1;-synuclein, polyamines, changes in the proteins of RBCs like band-3, membrane transporter proteins, heat shock proteins, oxidative stress biomarkers, and altered metabolic pathways in RBCs during neurodegeneration. It also highlights the comparison of RBC diagnostic markers to other in-market diagnoses and discusses the challenges in utilizing RBCs as diagnostic tools, such as the need for standardized protocols and further validation studies.<br><br>SIGNIFICANCE STATEMENT: The evidence suggests that RBCs have diagnostic potential in neurodegenerative disorders, and this study can pave the foundation for further research which may lead to the development of novel diagnostic approaches and treatments.}, }
@article {pmid38821351, year = {2024}, author = {Pocock, J and Vasilopoulou, F and Svensson, E and Cosker, K}, title = {Microglia and TREM2.}, journal = {Neuropharmacology}, volume = {}, number = {}, pages = {110020}, doi = {10.1016/j.neuropharm.2024.110020}, pmid = {38821351}, issn = {1873-7064}, abstract = {TREM2 is a membrane receptor solely expressed on microglia in normal brain. In this review we outline recent advances in TREM2 biology and its implications for microglial function, with particular emphasis on findings from iPSC-derived microglia (iMG) expressing TREM2 loss-of-function mutations. Alterations in receptor proximal and distal signalling underlie TREM2 risk variants linked to neurodegenerative disease, principally NH-linked FTD, and late-onset AD, but emerging data suggest roles for TREM2 in PD, MS and ALS. TREM2 downstream functions include phagocytosis of myelin debris, amyloid beta peptides, and phosphatidylserine-expressing cells (resulting from damage or stress). Microglial survival, migration, DAMP signalling, inflammasome activation, and intercellular signalling including tau spreading via exosomes, as well as roles for sTREM2 ain protection and as a biomarker are discussed. The role of TREM2 in metabolic homeostasis, and immunometabolic switching are discussed regarding microglial responses to damage and protection. The use of iPSC models to investigate the role of TREM2 in AD, PD, MS, ALS, and other neurodegenerative diseases could prove invaluable due to their ability to recapitulate human pathology, allowing a full understanding of TREM2 and microglial involvement in the underlying disease mechanisms and progression.}, }
@article {pmid38819491, year = {2024}, author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A}, title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {78}, number = {4}, pages = {e22301}, doi = {10.1002/syn.22301}, pmid = {38819491}, issn = {1098-2396}, support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrector&#xed;a de Investigaci&#xf3;n y Estudios de Posgrado, Benem&#xe9;rita Universidad Aut&#xf3;noma de Puebla/ ; TEMS-NAT24-G//Vicerrector&#xed;a de Investigaci&#xf3;n y Estudios de Posgrado, Benem&#xe9;rita Universidad Aut&#xf3;noma de Puebla/ ; }, mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.}, }
@article {pmid38818523, year = {2024}, author = {Shen, J and Wang, X and Wang, M and Zhang, H}, title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1337442}, doi = {10.3389/fphys.2024.1337442}, pmid = {38818523}, issn = {1664-042X}, abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.}, }
@article {pmid38816479, year = {2024}, author = {Mathis, S and Beauvais, D and Duval, F and Solé, G and Le Masson, G}, title = {The various forms of hereditary motor neuron disorders and their historical descriptions.}, journal = {Journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {38816479}, issn = {1432-1459}, abstract = {Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome.}, }
@article {pmid38812793, year = {2024}, author = {Jadhav, SP}, title = {MicroRNAs in microglia: deciphering their role in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1391537}, pmid = {38812793}, issn = {1662-5102}, abstract = {This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.}, }
@article {pmid38811997, year = {2024}, author = {Huang, M and Liu, YU and Yao, X and Qin, D and Su, H}, title = {Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {28}, pmid = {38811997}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/epidemiology/diagnosis ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.}, }
@article {pmid38807021, year = {2024}, author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H}, title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.}, journal = {Neurochemical research}, volume = {}, number = {}, pages = {}, pmid = {38807021}, issn = {1573-6903}, abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.}, }
@article {pmid38805053, year = {2024}, author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S}, title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.}, journal = {Journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {38805053}, issn = {1432-1459}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.}, }
@article {pmid38802184, year = {2024}, author = {Vucic, S and de Carvalho, M and Bashford, J and Alix, JJP}, title = {Contribution of neurophysiology to the diagnosis and monitoring of ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {87-118}, doi = {10.1016/bs.irn.2024.04.001}, pmid = {38802184}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Transcranial Magnetic Stimulation/methods ; *Electromyography/methods ; *Neurophysiology/methods ; Disease Progression ; Motor Cortex/physiopathology ; }, abstract = {This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which to build support for a diagnosis of ALS, demonstrating the pathophysiological processes of motor unit hyperexcitability, denervation and reinnervation. We consider development of the different diagnostic criteria and the role of EMG therein. While not formally recognised by established diagnostic criteria, we discuss the pioneering studies that have demonstrated the diagnostic potential of transcranial magnetic stimulation (TMS) of the motor cortex and highlight the growing evidence for TMS in the diagnostic process. Finally, accurately monitoring disease progression is crucial for the successful implementation of clinical trials. Neurophysiological measures of disease state have been incorporated into clinical trials for over 20 years and we review prominent techniques for assessing disease progression.}, }
@article {pmid38802183, year = {2024}, author = {Moll, T and Harvey, C and Alhathli, E and Gornall, S and O'Brien, D and Cooper-Knock, J}, title = {Non-coding genome contribution to ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {75-86}, doi = {10.1016/bs.irn.2024.04.002}, pmid = {38802183}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Animals ; Genetic Predisposition to Disease/genetics ; }, abstract = {The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.}, }
@article {pmid38802182, year = {2024}, author = {Al-Chalabi, A and Andrews, J and Farhan, S}, title = {Recent advances in the genetics of familial and sporadic ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {49-74}, doi = {10.1016/bs.irn.2024.04.007}, pmid = {38802182}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; }, abstract = {ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.}, }
@article {pmid38802181, year = {2024}, author = {De Cock, L and Bercier, V and Van Den Bosch, L}, title = {New developments in pre-clinical models of ALS to guide translation.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {477-524}, doi = {10.1016/bs.irn.2024.04.008}, pmid = {38802181}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/therapy ; Animals ; *Disease Models, Animal ; Humans ; Translational Research, Biomedical/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating monogenic familial forms, most frequently caused by mutations in SOD1, FUS, TARDBP and C9orf72, although ALS is mostly sporadic and without a clear genetic cause. Rodent models have been developed to study monogenic ALS, but despite numerous pre-clinical studies and clinical trials, few disease-modifying therapies are available. ALS is a heterogeneous disease with complex underlying mechanisms where several genes and molecular pathways appear to play a role. One reason for the high failure rate of clinical translation from the current models could be oversimplification in pre-clinical studies. Here, we review advances in pre-clinical models to better capture the heterogeneous nature of ALS and discuss the value of novel model systems to guide translation and aid in the development of precision medicine.}, }
@article {pmid38802180, year = {2024}, author = {Shelkovnikova, TA and Hautbergue, GM}, title = {RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {455-479}, doi = {10.1016/bs.irn.2024.04.009}, pmid = {38802180}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Ribonucleoproteins/metabolism ; Animals ; *Cytoplasmic Granules/metabolism ; Neurodegenerative Diseases/metabolism ; Organelles/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.}, }
@article {pmid38802179, year = {2024}, author = {Pandya, VA and Patani, R}, title = {The role of glial cells in amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {381-450}, doi = {10.1016/bs.irn.2024.04.005}, pmid = {38802179}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Humans ; *Neuroglia/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.}, }
@article {pmid38802177, year = {2024}, author = {Lee, J and Pye, N and Ellis, L and Vos, K and Mortiboys, H}, title = {Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {269-325}, doi = {10.1016/bs.irn.2024.04.006}, pmid = {38802177}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Oxidative Stress/physiology ; }, abstract = {Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models.}, }
@article {pmid38802176, year = {2024}, author = {Castelli, L and Vasta, R and Allen, SP and Waller, R and Chiò, A and Traynor, BJ and Kirby, J}, title = {From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {209-268}, doi = {10.1016/bs.irn.2024.02.001}, pmid = {38802176}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/therapy ; *Systems Biology/methods ; *Genomics/methods ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.}, }
@article {pmid38802175, year = {2024}, author = {Malaspina, A}, title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {171-207}, doi = {10.1016/bs.irn.2024.04.010}, pmid = {38802175}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; }, abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.}, }
@article {pmid38802174, year = {2024}, author = {Hobson, E and McDermott, C}, title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {119-169}, doi = {10.1016/bs.irn.2024.04.004}, pmid = {38802174}, issn = {2162-5514}, mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; }, abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.}, }
@article {pmid38802173, year = {2024}, author = {Van Es, MA}, title = {Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {1-47}, doi = {10.1016/bs.irn.2024.04.011}, pmid = {38802173}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology/physiopathology ; Diagnosis, Differential ; Frontotemporal Dementia/diagnosis/genetics/physiopathology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.}, }
@article {pmid38795957, year = {2024}, author = {Bhushan, NL and Romano, CD and Gras-Najjar, J and Reno, J and Rockwood, N and Quattrone, W and Adams, ET and Kelly, B and McLeod, L and Bhavnani, SP and Bocell, FD and Campbell, M and Kontson, K and Reasner, D and Zhang, C and Retzky, S}, title = {Remote-Use Applications of the ALSFRS-R Clinical Outcome Assessment Tool: A Scoping Review.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jval.2024.05.005}, pmid = {38795957}, issn = {1524-4733}, abstract = {OBJECTIVES: In 2021, the U.S. Congress passed the ACT for ALS Act. The law encourages development of "tools, methods, and processes" to improve clinical trial efficiency for neurodegenerative diseases. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure administered during in-person clinic visits and used to support investigational studies for persons living with Amyotrophic Lateral Sclerosis (PALS). Availability of a standardized, remote-use version of the ALSFRS-R may promote more inclusive, decentralized clinical trials. A scoping literature review was conducted to identify existing remote-use ALSFRS-R tools, synthesize feasibility and comparability of administration modes, and summarize barriers and facilitators to inform development of a standardized remote-use ALSFRS-R tool.<br><br>METHODS: Included studies reported comparisons between remote and in-person, clinician-reported, ALSFRS-R administration and were published in English (2002-2022). References were identified by searching peer-reviewed and gray literature. Twelve studies met inclusion criteria and were analyzed to compare findings within and across modes of administration.<br><br>RESULTS: Remote modes of ALSFRS-R administration were categorized into four non-mutually exclusive categories: telephone (n = 6), videoconferencing (n = 3), computer or online platforms (n = 3), mobile-apps and wearables (n = 2), and one unspecified telemedicine modality (n = 1). Studies comparing in-person to telephone or videoconferencing administration reported high ALSFRS-R rating correlations and nonsignificant between- mode differences.<br><br>CONCLUSION: There is insufficient information in the ALSFRS-R literature to support remote clinician administration for collecting high quality data. Future research should engage PALS, care partners and providers to develop a standardized remote-use ALSFRS-R version.}, }
@article {pmid38795640, year = {2024}, author = {Li, Z and Zhang, Y and Ji, M and Wu, C and Zhang, Y and Ji, S}, title = {Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {176}, number = {}, pages = {116777}, doi = {10.1016/j.biopha.2024.116777}, pmid = {38795640}, issn = {1950-6007}, abstract = {Neuroimmune and neurodegenerative ailments impose a substantial societal burden. Neuroimmune disorders involve the intricate regulatory interactions between the immune system and the central nervous system. Prominent examples of neuroimmune disorders encompass multiple sclerosis and neuromyelitis optica. Neurodegenerative diseases result from neuronal degeneration or demyelination in the brain or spinal cord, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The precise underlying pathogenesis of these conditions remains incompletely understood. Ferroptosis, a programmed form of cell death characterised by lipid peroxidation and iron overload, plays a pivotal role in neuroimmune and neurodegenerative diseases. In this review, we provide a detailed overview of ferroptosis, its mechanisms, pathways, and regulation during the progression of neuroimmune and neurodegenerative diseases. Furthermore, we summarise the impact of ferroptosis on neuroimmune-related cells (T cells, B cells, neutrophils, and macrophages) and neural cells (glial cells and neurons). Finally, we explore the potential therapeutic implications of ferroptosis inhibitors in diverse neuroimmune and neurodegenerative diseases.}, }
@article {pmid38791160, year = {2024}, author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R}, title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791160}, issn = {1422-0067}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs &amp; derivatives ; }, abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.}, }
@article {pmid38790450, year = {2024}, author = {Eisen, A and Pioro, EP and Goutman, SA and Kiernan, MC}, title = {Nanoplastics and Neurodegeneration in ALS.}, journal = {Brain sciences}, volume = {14}, number = {5}, pages = {}, doi = {10.3390/brainsci14050471}, pmid = {38790450}, issn = {2076-3425}, abstract = {Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood-brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut-brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.}, }
@article {pmid38786016, year = {2024}, author = {Salzinger, A and Ramesh, V and Das Sharma, S and Chandran, S and Thangaraj Selvaraj, B}, title = {Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {10}, pages = {}, pmid = {38786016}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/pathology/physiology ; Animals ; Nerve Net/physiopathology/pathology ; Neuromuscular Junction/physiopathology/pathology ; Disease Models, Animal ; Motor Cortex/physiopathology/pathology ; }, abstract = {The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.}, }
@article {pmid38785539, year = {2024}, author = {Pribac, M and Motataianu, A and Andone, S and Mardale, E and Nemeth, S}, title = {Bridging the Gap: Harnessing Plant Bioactive Molecules to Target Gut Microbiome Dysfunctions in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4471-4488}, doi = {10.3390/cimb46050271}, pmid = {38785539}, issn = {1467-3045}, abstract = {The correlation between neurodegenerative diseases and the gut microbiome is increasingly evident, with amyotrophic lateral sclerosis (ALS) being particularly notable for its severity and lack of therapeutic options. The gut microbiota, implicated in the pathogenesis and development of ALS, plays a crucial role in the disease. Bioactive plant molecules, specifically volatile compounds in essential oils, offer a promising therapeutic avenue due to their anti-inflammatory properties and gut-modulating effects. Our narrative review aimed to identify microbiota-associated bacteria in ALS and analyze the benefits of administering bioactive plant molecules as much-needed therapeutic options in the management of this disease. A comprehensive search of PubMed database articles published before December 2023, encompassing research on cell, human, and animal ALS models, was conducted. After selecting, analyzing, and discussing key articles, bacteria linked to ALS pathogenesis and physiopathology were identified. Notably, positively highlighted bacteria included Akkermansia muciniphila (Verrucomicrobia phylum), Faecalibacterium prausnitzii, and Butyrivibrio spp. (Firmicutes phylum). Conversely, members of the Escherichia coli spp. (Proteobacteria phylum) and Ruminococcus spp. (Firmicutes phylum) stood out negatively in respect to ALS development. These bacteria were associated with molecular changes linked to ALS pathogenesis and evolution. Bioactive plant molecules can be directly associated with improvements in the microbiome, due to their role in reducing inflammation and oxidative stress, emerging as one of the most promising natural agents for enriching present-day ALS treatments.}, }
@article {pmid38784406, year = {2024}, author = {Keselica, M and Peřan, D and Renza, M and Duška, F and Omáčka, D and Schnaubelt, S and Lulic, I and Sýkora, R}, title = {Efficiency of two-member crews in delivering prehospital advanced life support cardiopulmonary resuscitation: A scoping review.}, journal = {Resuscitation plus}, volume = {18}, number = {}, pages = {100661}, pmid = {38784406}, issn = {2666-5204}, abstract = {BACKGROUND: Advanced Life Support (ALS) during cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) is frequently administered by two-member crews. However, ALS CPR is mostly designed for larger crews, and the feasibility and efficacy of implementing ALS guidelines for only two rescuers remain unclear.<br><br>OBJECTIVE: This scoping review aims to examine the existing evidence and identify knowledge gaps in the efficiency of pre-hospital ALS CPR performed by two-member teams.<br><br>DESIGN: A comprehensive search was undertaken across the following databases: PubMed, Web of Science, SCOPUS, Cochrane Library Trials, and ClinicalTrials.gov. The search covered publications in English or German from January 1, 2005, to November 30, 2023. The review included studies that focused on ALS CPR procedures carried out by two-member teams in adult patients in either simulated or clinical settings.<br><br>RESULTS: A total of 22 articles were included in the qualitative synthesis. Seven topics in two-person prehospital ALS/CPR delivery were identified: 1) effect of team configuration on clinical outcome and CPR quality, 2) early airway management and ventilation techniques, 3) mechanical chest compressions, 4) prefilled syringes, 5) additional equipment, 6) adaptation of recommended ALS/CPR protocols, and 7) human factors.<br><br>CONCLUSION: There is a lack of comprehensive data regarding the adaptation of the recommended ALS algorithm in CPR for two-member crews. Although simulation studies indicate potential benefits arising from the employment of mechanical chest compression devices, prefilled syringes, and automation-assisted protocols, the current evidence is too limited to support specific modifications to existing guidelines.}, }
@article {pmid38784093, year = {2024}, author = {Chen, W and Liu, X and Wan, P and Chen, Z and Chen, Y}, title = {Anti-artifacts techniques for neural recording front-ends in closed-loop brain-machine interface ICs.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1393206}, doi = {10.3389/fnins.2024.1393206}, pmid = {38784093}, issn = {1662-4548}, abstract = {In recent years, thanks to the development of integrated circuits, clinical medicine has witnessed significant advancements, enabling more efficient and intelligent treatment approaches. Particularly in the field of neuromedical, the utilization of brain-machine interfaces (BMI) has revolutionized the treatment of neurological diseases such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. The BMI acquires neural signals via recording circuits and analyze them to regulate neural stimulator circuits for effective neurological treatment. However, traditional BMI designs, which are often isolated, have given way to closed-loop brain-machine interfaces (CL-BMI) as a contemporary development trend. CL-BMI offers increased integration and accelerated response speed, marking a significant leap forward in neuromedicine. Nonetheless, this advancement comes with its challenges, notably the stimulation artifacts (SA) problem inherent to the structural characteristics of CL-BMI, which poses significant challenges on the neural recording front-ends (NRFE) site. This paper aims to provide a comprehensive overview of technologies addressing artifacts in the NRFE site within CL-BMI. Topics covered will include: (1) understanding and assessing artifacts; (2) exploring the impact of artifacts on traditional neural recording front-ends; (3) reviewing recent technological advancements aimed at addressing artifact-related issues; (4) summarizing and classifying the aforementioned technologies, along with an analysis of future trends.}, }
@article {pmid38782644, year = {2024}, author = {Corcia, P and Couratier, P and Ingre, C}, title = {Could PLS represent a UMN-predominant ALS syndrome?.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2024.04.006}, pmid = {38782644}, issn = {0035-3787}, abstract = {Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS). This explains the necessity to distinguish both conditions as early as possible. The key hallmark between the two diseases is the involvement of the lower motor neuron (LMN) system which is classically considered spared in PLS contrary to ALS. Although it seemed clinically easy to distinguish PLS from ALS with the aid of clinical and complementary examinations, there is a large body of evidence highlighting that the LMN system might be impaired in PLS. This led us to suggest that PLS might be considered as an almost pure UMN ALS phenotype.}, }
@article {pmid38775852, year = {2024}, author = {Ebrahimi, P and Davoudi, E and Sadeghian, R and Zadeh, AZ and Razmi, E and Heidari, R and Morowvat, MH and Sadeghian, I}, title = {In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {38775852}, issn = {1432-1912}, support = {29849//Shiraz University of Medical Sciences/ ; }, abstract = {Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.}, }
@article {pmid38769202, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {38769202}, issn = {1759-4766}, abstract = {Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.}, }
@article {pmid38577753, year = {2024}, author = {Yellepeddi, VK and Race, JA and McFarland, MM and Constance, JE and Fanaeian, E and Murphy, NA}, title = {Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {6}, pages = {267-277}, doi = {10.5414/CP204538}, pmid = {38577753}, issn = {0946-1965}, mesh = {*Sialorrhea/drug therapy ; Humans ; *Atropine/therapeutic use ; Treatment Outcome ; Salivation/drug effects ; }, abstract = {OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling.<br><br>MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale.<br><br>RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes.<br><br>CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.}, }
@article {pmid38767073, year = {2024}, author = {Napoletano, G and Circosta, F and Basile, G}, title = {Access to medically-assisted procreation: the withdrawal of paternal consent in the maze of law n. 40/2004.}, journal = {La Clinica terapeutica}, volume = {175}, number = {3}, pages = {163-167}, doi = {10.7417/CT.2024.5057}, pmid = {38767073}, issn = {1972-6007}, mesh = {Humans ; *Reproductive Techniques, Assisted/legislation &amp; jurisprudence/ethics ; Italy ; Female ; Male ; Health Services Accessibility/legislation &amp; jurisprudence ; Cryopreservation ; Parental Consent/legislation &amp; jurisprudence ; Informed Consent/legislation &amp; jurisprudence ; }, abstract = {The law (No.40/2004) stipulates that consent to Medically Assisted Procreation (MAP) remains irrevocable post ovum fertilization. Cryo-preservation introduces complexities, enabling embryo implantation requests after a couple's separation and the dissolution of the original parenthood plan. Constitutional Court Ruling No.161 in 2023 affirmed that the prohibition of revoking consent to MAP aligns with the Italian Constitution and the jurisprudence of the European Court of Human Rights. This delicate equilibrium of conflicting interests upholds human freedom, allowing consent revocation prior to ovocyte fertilization. Permitting revocation until implantation could inflict more significant harm: the infertile woman can in fact miss the opportunity to become a mother, impacting her psychophysical well-being and freedom of self-determination. Moreover, the embryo loses the chance to live, remaining in cryopreservation, which violates its dignity. Addressing this issue requires thorough communication by medical profession-als to inform couples about the limitations on consent revocation. An element of objectivity in terms of standards and evidence-based guidelines, from which norms must originate, is of utmost importance. Relying on broadly shared rules, especially at the international level, is vital in light of the unremitting scientific advances in MAP, as in other areas of medicine, which will open up new opportunities for which current legal/regulatory frameworks are inadequate.}, }
@article {pmid38763702, year = {2024}, author = {Dorrity, TJ and Shin, H and Gertie, JA and Chung, H}, title = {The Sixth Sense: Self-nucleic acid sensing in the brain.}, journal = {Advances in immunology}, volume = {161}, number = {}, pages = {53-83}, doi = {10.1016/bs.ai.2024.03.001}, pmid = {38763702}, issn = {1557-8445}, mesh = {Humans ; *Brain/metabolism/immunology ; Animals ; *Receptors, Pattern Recognition/metabolism ; *Immunity, Innate ; *Nucleic Acids/immunology/metabolism ; Homeostasis ; Signal Transduction ; }, abstract = {Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.}, }
@article {pmid38762243, year = {2024}, author = {Ponzini, E}, title = {Tear biomarkers.}, journal = {Advances in clinical chemistry}, volume = {120}, number = {}, pages = {69-115}, doi = {10.1016/bs.acc.2024.03.002}, pmid = {38762243}, issn = {2162-9471}, mesh = {Humans ; *Tears/metabolism/chemistry ; *Biomarkers/analysis/metabolism ; Eye Diseases/diagnosis/metabolism ; }, abstract = {An extensive exploration of lacrimal fluid molecular biomarkers in understanding and diagnosing a spectrum of ocular and systemic diseases is presented. The chapter provides an overview of lacrimal fluid composition, elucidating the roles of proteins, lipids, metabolites, and nucleic acids within the tear film. Pooled versus single-tear analysis is discussed to underline the benefits and challenges associated with both approaches, offering insights into optimal strategies for tear sample analysis. Subsequently, an in-depth analysis of tear collection methods is presented, with a focus on Schirmer's test strips and microcapillary tubes methods. Alternative tear collection techniques are also explored, shedding light on their applicability and advantages. Variability factors, including age, sex, and diurnal fluctuations, are examined in the context of their impact on tear biomarker analysis. The main body of the chapter is dedicated to discussing specific biomarkers associated with ocular discomfort and a wide array of ocular diseases. From dry eye disease and thyroid-associated ophthalmopathy to keratoconus, age-related macular degeneration, diabetic retinopathy, and glaucoma, the intricate relationship between molecular biomarkers and these conditions is thoroughly dissected. Expanding beyond ocular pathologies, the chapter explores the applicability of tear biomarkers in diagnosing systemic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and cancer. This broader perspective underscores the potential of lacrimal fluid analysis in offering non-invasive diagnostic tools for conditions with far-reaching implications.}, }
@article {pmid38759454, year = {2024}, author = {Wei, Y and Zhong, S and Yang, H and Wang, X and Lv, B and Bian, Y and Pei, Y and Xu, C and Zhao, Q and Wu, Y and Luo, D and Wang, F and Sun, H and Chen, Y}, title = {Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.}, journal = {European journal of medicinal chemistry}, volume = {272}, number = {}, pages = {116496}, doi = {10.1016/j.ejmech.2024.116496}, pmid = {38759454}, issn = {1768-3254}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.}, }
@article {pmid38759021, year = {2024}, author = {Pupillo, E and Al-Chalabi, A and Sassi, S and Arippol, E and Tinti, L and Vitelli, E and Copetti, M and Leone, MA and Bianchi, E}, title = {Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A systematic Review.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {}, doi = {10.3233/JND-230217}, pmid = {38759021}, issn = {2214-3602}, abstract = {BACKGROUND: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found.<br><br>OBJECTIVE: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022.<br><br>METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses.<br><br>RESULTS: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < &#x200a;6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was &#x2265;20% in 30.5% trials, while it was not reported for 8.5% .<br><br>CONCLUSION: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.}, }
@article {pmid38758353, year = {2024}, author = {Mavroudis, I and Alexiou, P and Petridis, F and Ciobica, A and Balmus, IM and Gireadă, B and Gurzu, IL and Novac, O and Novac, B}, title = {Patients' and caregivers' attitudes towards patient assisted suicide or euthanasia in amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {38758353}, issn = {2240-2993}, abstract = {Assisted suicide and euthanasia are long debated topics in amyotrophic lateral sclerosis (ALS) patients care. We conducted a meta-analysis to evaluate the attitudes of ALS patients and their caregivers toward physician-assisted suicide (PAS) and euthanasia. Also, we were interested to identify the factors associated with the positive or negative attitude of patients and caregivers towards PAS/euthanasia. A thorough search of the online databases (PubMed, Cochrane Library, and Web of Science) was conducted and eligibility criteria according to the PRISMA guidelines were used to include the studies in the current meta-analysis. The assessment of the quality of the selected studies was carried out using a pre-specified set of criteria by Cochrane. The studies that were selected for this meta-analysis suggested that the expression of the wish to die is more likely correlated with depression, anxiety, hopelessness, and lack of optimism. The overall prevalence of considering PAS/euthanasia significantly varies in a dependent manner over the cultural, legal, and societal factors. In this context, we found that the opinion on this topic can be deeply personal and may vary widely among individuals and communities. Lower quality of life and lower religiosity were associated with a positive attitude toward PAS/euthanasia. On the other hand, patients who are more religious are less likely to choose PAS/euthanasia. Gender does not appear to play a significant role in determining attitudes towards PAS/euthanasia in ALS patients. Other factors, such as education and psychological state, could also be important. In conclusion, end-of-life decisions in ALS patients are complex and require careful consideration of individual values, beliefs, and preferences. Understanding the factors that influence a patient's attitude towards PAS/euthanasia can help healthcare providers to offer appropriate care and support for these patients and their families.}, }
@article {pmid38758193, year = {2024}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/14737175.2024.2355983}, pmid = {38758193}, issn = {1744-8360}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.<br><br>AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.<br><br>EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12&#x2009;months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.}, }
@article {pmid38756356, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Colorectal anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Frontiers in surgery}, volume = {11}, number = {}, pages = {1371567}, doi = {10.3389/fsurg.2024.1371567}, pmid = {38756356}, issn = {2296-875X}, abstract = {BACKGROUND: Anastomotic leaks (ALs) are a significant and feared postoperative complication, with incidence of up to 30% despite advances in surgical techniques. With implications such as additional interventions, prolonged hospital stays, and hospital readmission, ALs have important impacts at the level of individual patients and healthcare providers, as well as healthcare systems as a whole. Challenges in developing unified definitions and grading systems for leaks have proved problematic, despite acknowledgement that colorectal AL is a critical issue in intestinal surgery with serious consequences. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs, and consequences of this postoperative complication.<br><br>METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following keywords: anastomosis, anastomotic leak, colorectal, surgery, grading system, complications, risk factors, and consequences. Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.<br><br>RESULTS: A universally accepted definition and grading system for ALs continues to be lacking, leading to variability in reported incidence in the literature. Additional factors add to variability in estimates, including differences in the anastomotic site and institutional/individual differences in operative technique. Various groups have worked to publish guidelines for defining and grading AL, with the International Study Group of Rectal Cancer (ISGRC/ISREC) definition the current most recommended universal definition for colorectal AL. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.<br><br>CONCLUSIONS: Colorectal AL remains a significant challenge in intestinal surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, }
@article {pmid38741492, year = {2024}, author = {Kanda, S and Kanda, T}, title = {[Multifocal Motor Neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {5}, pages = {526-533}, doi = {10.11477/mf.1416202639}, pmid = {38741492}, issn = {1881-6096}, mesh = {Humans ; *Polyneuropathies/physiopathology/diagnosis ; Immunoglobulins, Intravenous/therapeutic use/administration &amp; dosage ; }, abstract = {Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.}, }
@article {pmid38739934, year = {2024}, author = {Xin, J and Huang, S and Wen, J and Li, Y and Li, A and Satyanarayanan, SK and Yao, X and Su, H}, title = {Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0440}, pmid = {38739934}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.}, }
@article {pmid38734122, year = {2024}, author = {Panchalingam, S and Kasivelu, G}, title = {Exploring the impact of circular RNA on ALS progression: A systematic review.}, journal = {Brain research}, volume = {}, number = {}, pages = {148990}, doi = {10.1016/j.brainres.2024.148990}, pmid = {38734122}, issn = {1872-6240}, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that damages motor neurons and causes gradual muscular weakening and paralysis. Although studies have linked a number of genetic and environmental factors to ALS, the specific causes and mechanisms of the disease are still unclear. The pivotal role of circular RNA in the pathogenesis of ALS is a newly emerging area of research. The term "circular RNA" describes a particular class of RNA molecule that, in contrast to most RNA molecules, has a closed-loop structure. According to recent research, circular RNA might be essential for the development and progression of ALS. It has been discovered that these circular RNAs support important cellular functions related to ALS, including protein turnover, mitochondrial function, RNA processing, and cellular transport. Gaining knowledge about the precise roles and processes of circular RNA in the development of ALS could assist in understanding the pathophysiology of the disease and possibly pave the way for the development of targeted therapies. However, the understanding of circular RNA in ALS is still limited, and more research is needed to fully elucidate its role. In order to gain a comprehensive understanding of the role of circRNAs in ALS, it is imperative to delve into the various mechanisms through which circRNAs may contribute to the development and progression of the disease. Examining the current status of circRNA research in ALS and offering insights into their potential as therapeutic targets and diagnostic markers are the primary objectives of this review.}, }
@article {pmid38733435, year = {2024}, author = {Liu, S and Hong, Y and Wang, BR and Wei, ZQ and Zhao, HD and Jiang, T and Zhang, YD and Shi, JQ}, title = {The presence and clinical significance of autoantibodies in amyotrophic lateral sclerosis: a narrative review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {38733435}, issn = {1590-3478}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.}, }
@article {pmid38732027, year = {2024}, author = {Cantara, S and Simoncelli, G and Ricci, C}, title = {Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, doi = {10.3390/ijms25094809}, pmid = {38732027}, issn = {1422-0067}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Motor Neuron Disease/genetics/therapy ; Animals ; Muscular Atrophy, Spinal/therapy/genetics ; Amyotrophic Lateral Sclerosis/genetics/therapy ; }, abstract = {Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.}, }
@article {pmid38731036, year = {2024}, author = {Ueha, R and Miura, C and Matsumoto, N and Sato, T and Goto, T and Kondo, K}, title = {Vocal Fold Motion Impairment in Neurodegenerative Diseases.}, journal = {Journal of clinical medicine}, volume = {13}, number = {9}, pages = {}, doi = {10.3390/jcm13092507}, pmid = {38731036}, issn = {2077-0383}, abstract = {Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson's disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.}, }
@article {pmid38727285, year = {2024}, author = {Gao, Y and Lu, Y and Liang, X and Zhao, M and Yu, X and Fu, H and Yang, W}, title = {CD4[+] T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.}, journal = {Cells}, volume = {13}, number = {9}, pages = {}, doi = {10.3390/cells13090749}, pmid = {38727285}, issn = {2073-4409}, support = {20230505039ZP//Jilin Province Science and Technology Department/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *CD4-Positive T-Lymphocytes/immunology ; *Cellular Senescence/immunology ; Animals ; Aging/immunology/pathology ; T-Cell Senescence ; }, abstract = {With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4[+] T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4[+] T-cells in NDs. In this review, we summarize the classification and function of CD4[+] T-cell subpopulations, the characteristics of CD4[+] T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4[+] T-cell senescence.}, }
@article {pmid38723906, year = {2024}, author = {Koike, Y}, title = {Molecular mechanisms linking loss of TDP-43 function to amyotrophic lateral sclerosis/frontotemporal dementia-related genes.}, journal = {Neuroscience research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neures.2024.05.001}, pmid = {38723906}, issn = {1872-8111}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including TARDBP. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we provide novel mechanistic insights into the splicing of UNC13A, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in UNC13A are the most common risk factors for ALS/FTD. We found that TDP-43 represses "cryptic exon" inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of UNC13A retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of TARDBP mRNA. We hypothesized that TARDBP methylation is altered by aging, thereby disrupting TDP-43 autoregulation. We found that demethylation reduces the efficiency of alternative splicing and increases TARDBP mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.}, }
@article {pmid38723752, year = {2024}, author = {Singh, K and Sethi, P and Datta, S and Chaudhary, JS and Kumar, S and Jain, D and Gupta, JK and Kumar, S and Guru, A and Panda, SP}, title = {Advances in Gene Therapy Approaches Targeting Neuro-inflammation in Neurodegenerative Diseases.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {102321}, doi = {10.1016/j.arr.2024.102321}, pmid = {38723752}, issn = {1872-9649}, abstract = {Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. In AD, the binding of Aβ with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.}, }
@article {pmid38721118, year = {2024}, author = {Lu, L and Deng, Y and Xu, R}, title = {Current potential therapeutics of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1402962}, pmid = {38721118}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current literature about clinical and experimental ALS treatments. Based on them, this review primarily focused on summarizing the current potential clinical usage and trialing therapeutics of ALS. Currently, the clinical ALS treatments have focused primarily on relieving symptoms to improve the quality of life yet. There are a number of therapeutic approaches such as medicine, gene therapy, neuron protectants, combination therapy and stem cells. Among them, Stem cells including embryonic stem cells, mesenchymal stem cells, neural stem cells, and many other types of stem cells have been used in ALS treatment, and although the short-term efficacy is good, it is worth exploring whether this improved efficacy leads to prolonged patient survival. In addition, the supportive treatments also exert an important effect on improving the quality of life and prolong the survival of ALS patients in absence of effectively care for stopping or reversing the progression of ALS.}, }
@article {pmid37291782, year = {2024}, author = {Dai, S and Qiu, L and Veeraraghavan, VP and Sheu, CL and Mony, U}, title = {Advances in iPSC Technology in Neural Disease Modeling, Drug Screening, and Therapy.}, journal = {Current stem cell research &amp; therapy}, volume = {19}, number = {6}, pages = {809-819}, doi = {10.2174/1574888X18666230608105703}, pmid = {37291782}, issn = {2212-3946}, mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology ; *Drug Evaluation, Preclinical/methods ; Animals ; *Neurodegenerative Diseases/therapy ; Cell- and Tissue-Based Therapy/methods ; Cell Differentiation ; Disease Models, Animal ; }, abstract = {Neurodegenerative disorders (NDs) including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease are all incurable and can only be managed with drugs for the associated symptoms. Animal models of human illnesses help to advance our understanding of the pathogenic processes of diseases. Understanding the pathogenesis as well as drug screening using appropriate disease models of neurodegenerative diseases (NDs) are vital for identifying novel therapies. Human-derived induced pluripotent stem cell (iPSC) models can be an efficient model to create disease in a dish and thereby can proceed with drug screening and identifying appropriate drugs. This technology has many benefits, including efficient reprogramming and regeneration potential, multidirectional differentiation, and the lack of ethical concerns, which open up new avenues for studying neurological illnesses in greater depth. The review mainly focuses on the use of iPSC technology in neuronal disease modeling, drug screening, and cell therapy.}, }
@article {pmid38715858, year = {2021}, author = {Gupta, S and Sharma, U}, title = {Metabolomics of neurological disorders in India.}, journal = {Analytical science advances}, volume = {2}, number = {11-12}, pages = {594-610}, pmid = {38715858}, issn = {2628-5452}, abstract = {Metabolomics is the comprehensive study of the metabolome and its alterations within biological fluids and tissues. Over the years, applications of metabolomics have been explored in several areas, including personalised medicine in diseases, metabolome-wide association studies (MWAS), pharmacometabolomics and in combination with other branches of omics such as proteomics, transcriptomics and genomics. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the major analytical techniques widely employed in metabolomics. In addition, MS is coupled with chromatography techniques like gas chromatography (GC) and liquid chromatography (LC) to separate metabolites before analysis. These analytical techniques have made possible identification and quantification of large numbers of metabolites, encompassing characterization of diseases and facilitating a systematic and rational therapeutic strategy based on metabolic patterns. In recent years, the metabolomics approach has been used to obtain a deeper insight into the underlying biochemistry of neurodegenerative disorders and the discovery of biomarkers of clinical implications. The current review mainly focuses on an Indian perspective of metabolomics for the identification of metabolites and metabolic alterations serving as potential diagnostic biomarkers for neurological diseases including acute spinal cord injury, amyotrophic lateral sclerosis, tethered cord syndrome, spina bifida, stroke, Parkinson's disease, glioblastoma and neurological disorders with inborn errors of metabolism.}, }
@article {pmid38708921, year = {2024}, author = {Monteiro, KLC and Dos Santos Alcântara, MG and de Aquino, TM and da Silva-Júnior, EF}, title = {Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).}, journal = {Current neuropharmacology}, volume = {22}, number = {7}, pages = {1169-1188}, pmid = {38708921}, issn = {1875-6190}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Biological Products/therapeutic use/pharmacology ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Plants, Medicinal/chemistry ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons and consequent muscle paralysis. Despite many efforts to address it, current therapy targeting ALS remains limited, increasing the interest in complementary therapies. Over the years, several herbal preparations and medicinal plants have been studied to prevent and treat this disease, which has received remarkable attention due to their blood-brain barrier penetration properties and low toxicity. Thus, this review presents the therapeutic potential of a variety of medicinal herbs and their relationship with ALS and their physiopathological pathways.}, }
@article {pmid38705104, year = {2024}, author = {Dharmadasa, T and Pavey, N and Tu, S and Menon, P and Huynh, W and Mahoney, CJ and Timmins, HC and Higashihara, M and van den Bos, M and Shibuya, K and Kuwabara, S and Grosskreutz, J and Kiernan, MC and Vucic, S}, title = {Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {68-89}, doi = {10.1016/j.clinph.2024.04.010}, pmid = {38705104}, issn = {1872-8952}, abstract = {Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.}, }
@article {pmid38702287, year = {2024}, author = {Tazir, M and Nouioua, S}, title = {Distal hereditary motor neuropathies.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2023.09.005}, pmid = {38702287}, issn = {0035-3787}, abstract = {Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically. Recent cohort studies showed that HSPB1, GARS, BICB2 and DNAJB2 are among the most frequent dHMN genes and that the prevalence of the disease was calculated as 2.14 and 2.3 per 100,000. The determination of the different genes involved in dHMNs made it possible to observe a genotypic overlap with some other neurogenetic disorders and other hereditary neuropathies such as CMT2, mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission and recently observed with SORD gene of AR transmission which seems relatively frequent and potentially curable. Distal hereditary motor neuropathy that predominates in the upper limbs is linked mainly to three genes: GARS, BSCL2 and REEP1, whereas dHMN with vocal cord palsy is associated with SLC5A7, DCTN1 and TRPV4 genes. Among the rare AR forms of dHMN like IGHMBP2 and DNAJB2, the SIGMAR1 gene mutations as well as VRK1 variants are associated with a motor neuropathy phenotype often associated with upper motoneuron involvement. The differential diagnosis of these latter arises with juvenile forms of amyotrophic lateral sclerosis, that could be caused also by variations of these genes, as well as hereditary spastic paraplegia. A differential diagnosis of dHMN related to Brown Vialetto Van Laere syndrome due to riboflavin transporter deficiency is important to consider because of the therapeutic possibility.}, }
@article {pmid38700207, year = {2024}, author = {Keeley, O and Coyne, AN}, title = {Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease.}, journal = {Nucleus (Austin, Tex.)}, volume = {15}, number = {1}, pages = {2349085}, doi = {10.1080/19491034.2024.2349085}, pmid = {38700207}, issn = {1949-1042}, mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; Cell Nucleus/metabolism ; Frontotemporal Dementia/metabolism/pathology/genetics ; Endosomes/metabolism ; }, abstract = {The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.}, }
@article {pmid38408864, year = {2024}, author = {Odierna, GL and Vucic, S and Dyer, M and Dickson, T and Woodhouse, A and Blizzard, C}, title = {How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1610-1621}, doi = {10.1093/brain/awae039}, pmid = {38408864}, issn = {1460-2156}, support = {//Motor Neuron Disease Research Australia/ ; //National Health and Medical Research Council of Australia/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Motor Neurons/physiology ; *Glutamic Acid/metabolism ; Animals ; Motor Cortex/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the 'dying forward' excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. Many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not all are effective. As such, there is a growing tension between the rising tide of evidence for the 'dying forward' excitotoxicity hypothesis and the failure of therapies that target neuronal activation. One possible solution to these contradictory outcomes is that our interpretation of the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays we use to study it. In this review we provide an evaluation of evidence relevant to the 'dying forward' excitotoxicity hypothesis and by doing so, identify key gaps in our knowledge that need to be addressed. We hope to provide a road map from hyperexcitability to excitotoxicity so that we can better develop therapies for patients suffering from amyotrophic lateral sclerosis. We conclude that studies of upper motor neuron activity and their synaptic output will play a decisive role in the future of amyotrophic lateral sclerosis therapy.}, }
@article {pmid38694387, year = {2024}, author = {Arora, H and Javed, B and Kutikuppala, LVS and Chaurasia, M and Khullar, K and Kannan, S and Golla, V}, title = {ST2 levels and neurodegenerative diseases: is this a significant relation?.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {2812-2817}, doi = {10.1097/MS9.0000000000001939}, pmid = {38694387}, issn = {2049-0801}, abstract = {Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.}, }
@article {pmid38459794, year = {2024}, author = {Campagne, S}, title = {U1 snRNP Biogenesis Defects in Neurodegenerative Diseases.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {9}, pages = {e202300864}, doi = {10.1002/cbic.202300864}, pmid = {38459794}, issn = {1439-7633}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Ribonucleoprotein, U1 Small Nuclear/metabolism/chemistry ; Animals ; }, abstract = {The U1 small ribonucleoprotein (U1 snRNP) plays a pivotal role in the intricate process of gene expression, specifically within nuclear RNA processing. By initiating the splicing reaction and modulating 3'-end processing, U1 snRNP exerts precise control over RNA metabolism and gene expression. This ribonucleoparticle is abundantly present, and its complex biogenesis necessitates shuttling between the nuclear and cytoplasmic compartments. Over the past three decades, extensive research has illuminated the crucial connection between disrupted U snRNP biogenesis and several prominent human diseases, notably various neurodegenerative conditions. The perturbation of U1 snRNP homeostasis has been firmly established in diseases such as Spinal Muscular Atrophy, Pontocerebellar hypoplasia, and FUS-mediated Amyotrophic Lateral Sclerosis. Intriguingly, compelling evidence suggests a potential correlation in Fronto-temporal dementia and Alzheimer's disease as well. Although the U snRNP biogenesis pathway is conserved across all eukaryotic cells, neurons, in particular, appear to be highly susceptible to alterations in spliceosome homeostasis. In contrast, other cell types exhibit a greater resilience to such disturbances. This vulnerability underscores the intricate relationship between U1 snRNP dynamics and the health of neuronal cells, shedding light on potential avenues for understanding and addressing neurodegenerative disorders.}, }
@article {pmid38691665, year = {2024}, author = {Singh, P and Belliveau, P and Towle, J and Neculau, AE and Dima, L}, title = {Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.}, journal = {American journal of therapeutics}, volume = {31}, number = {3}, pages = {e258-e267}, doi = {10.1097/MJT.0000000000001742}, pmid = {38691665}, issn = {1536-3686}, mesh = {*Edaravone/administration &amp; dosage/pharmacology/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/administration &amp; dosage/therapeutic use/adverse effects ; Administration, Oral ; Suspensions ; Biological Availability ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.<br><br>MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.<br><br>PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.<br><br>CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.<br><br>THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.}, }
@article {pmid38676818, year = {2024}, author = {Kubat, GB and Picone, P}, title = {Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {38676818}, issn = {1590-3478}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons and severe skeletal muscle atrophy. The etiology of ALS is linked to skeletal muscle, which can activate a retrograde signaling cascade that destroys motor neurons. This is why satellite cells and mitochondria play a crucial role in the health and performance of skeletal muscles. This review presents current knowledge on the involvement of mitochondrial dysfunction, skeletal muscle atrophy, muscle satellite cells, and neuromuscular junction (NMJ) in ALS. It also discusses current therapeutic strategies, including exercise, drugs, stem cells, gene therapy, and the prospective use of mitochondrial transplantation as a viable therapeutic strategy.}, }
@article {pmid38676672, year = {2024}, author = {Kutlubaev, MA}, title = {[Promising approaches to the pathogenetic therapy of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4}, pages = {13-21}, doi = {10.17116/jnevro202412404113}, pmid = {38676672}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Neuroprotective Agents/therapeutic use ; Genetic Therapy ; Antioxidants/therapeutic use ; Stem Cell Transplantation ; Gastrointestinal Microbiome ; Immunologic Factors/therapeutic use ; Immunomodulating Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis is a severe incurable disease of the nervous system. Currently only methods of palliative care for the patients with this disease are available. Few medications for the pathogenetic therapy are registered in some countries, i.e. riluzole, edaravon, sodium phenylbutyrate/taurursodiol as well as tofersen (conditionally). Their efficacy is relatively low. The main directions in the development of pathogenetic therapy of ALS include gene therapy, use of stem cells, immunomodulators, agents affecting gut microbiota. A search is also underway for low-molecular compounds with neuroprotective and antioxidant properties. Perspective direction is prevention of ALS. This will be possible when biomarkers for identification of patients in pre-manifest/prodromal stage are detected.}, }
@article {pmid38674921, year = {2024}, author = {Wang, W and Pan, D and Liu, Q and Chen, X and Wang, S}, title = {L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review.}, journal = {Nutrients}, volume = {16}, number = {8}, pages = {}, pmid = {38674921}, issn = {2072-6643}, mesh = {Humans ; *Carnitine/therapeutic use ; *Nervous System Diseases/drug therapy ; *Mental Disorders/drug therapy ; Dietary Supplements ; }, abstract = {OBJECTIVE: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research.<br><br>METHODS: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search.<br><br>RESULTS: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud's syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation.<br><br>CONCLUSION: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer's disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.}, }
@article {pmid38674431, year = {2024}, author = {Shahim, P and Norato, G and Sinaii, N and Zetterberg, H and Blennow, K and Chan, L and Grunseich, C}, title = {Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Genes}, volume = {15}, number = {4}, pages = {}, pmid = {38674431}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis/cerebrospinal fluid ; Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Intermediate Filaments/metabolism/genetics ; Prognosis ; }, abstract = {BACKGROUND: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS.<br><br>METHODS: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.<br><br>RESULTS: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.<br><br>DISCUSSION: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.}, }
@article {pmid38672416, year = {2024}, author = {Cheslow, L and Snook, AE and Waldman, SA}, title = {Biomarkers for Managing Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672416}, issn = {2218-273X}, support = {1R01 CA204881, 1R01 CA206026, 1R21 1NS130388, 1R01 DK1388341/NH/NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/metabolism/diagnosis/therapy ; *Alzheimer Disease/metabolism/diagnosis/therapy ; Amyotrophic Lateral Sclerosis/metabolism/therapy/diagnosis ; Parkinson Disease/metabolism/diagnosis/therapy ; Animals ; }, abstract = {Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).}, }
@article {pmid38670433, year = {2024}, author = {Sitruk-Ware, R and Sussman, H and Brinton, R and Schumacher, M and Singer, P and Kumar, N and De Nicola, AF and El-Etr, M and Guennoun, R and V Borlongan, C}, title = {Nestorone (segesterone acetate) effects on neuroregeneration.}, journal = {Frontiers in neuroendocrinology}, volume = {}, number = {}, pages = {101136}, doi = {10.1016/j.yfrne.2024.101136}, pmid = {38670433}, issn = {1095-6808}, abstract = {Nestorone® (segesterone acetate) is a progestin with a chemical structure closely related to progesterone with high affinity and selectivity for the progesterone receptor without significant interaction with other steroid receptors. It has been developed for female and male contraception and is FDA-approved in a first long-acting contraceptive vaginal system for female contraception. Its safety has been extensively demonstrated in both preclinical and clinical studies for contraceptive indications. Nestorone was found to display neuroprotective and neuroregenerative activity in animal models of various central nervous system diseases, including multiple sclerosis, stroke, and amyotrophic lateral sclerosis. Reviewed herein are neuroprotective and myelin- regenerating properties of Nestorone in various animal models and its translational potential as a therapeutic agent for debilitating neurological diseases for which limited therapeutic options are available (Table 1).}, }
@article {pmid38667285, year = {2024}, author = {Alzahrani, FA and Riza, YM and Eid, TM and Almotairi, R and Scherschinski, L and Contreras, J and Nadeem, M and Perez, SE and Raikwar, SP and Jha, RM and Preul, MC and Ducruet, AF and Lawton, MT and Bhatia, K and Akhter, N and Ahmad, S}, title = {Exosomes in Vascular/Neurological Disorders and the Road Ahead.}, journal = {Cells}, volume = {13}, number = {8}, pages = {}, pmid = {38667285}, issn = {2073-4409}, mesh = {*Exosomes/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/pathology ; Vascular Diseases/metabolism/pathology ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.}, }
@article {pmid38664109, year = {2024}, author = {Hastings, RL and Valdez, G}, title = {Origin, identity, and function of terminal Schwann cells.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2024.03.007}, pmid = {38664109}, issn = {1878-108X}, abstract = {The highly specialized nonmyelinating glial cells present at somatic peripheral nerve endings, known collectively as terminal Schwann cells (TSCs), play critical roles in the development, function and repair of their motor and sensory axon terminals and innervating tissue. Over the past decades, research efforts across various vertebrate species have revealed that while TSCs are a diverse group of cells, they share a number of features among them. In this review, we summarize the state-of-knowledge about each TSC type and explore the opportunities that TSCs provide to treat conditions that afflict peripheral axon terminals.}, }
@article {pmid38644578, year = {2024}, author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F}, title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {4}, pages = {e14721}, pmid = {38644578}, issn = {1755-5949}, support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; *Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.<br><br>AIMS: Several studies have demonstrated an elevation in the expression level of C/EBP&#x3b2; among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBP&#x3b2; expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBP&#x3b2; can be a new therapeutic target for AD.<br><br>METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.<br><br>RESULTS: Overexpression of C/EBP&#x3b2; exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including &#x3b4;-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).<br><br>DISCUSSION: The correlation between overexpression of C/EBP&#x3b2; and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBP&#x3b2; regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBP&#x3b2; overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).<br><br>CONCLUSION: The overexpression of C/EBP&#x3b2; accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBP&#x3b2; plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBP&#x3b2; could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.}, }
@article {pmid38631798, year = {2024}, author = {Gerecht, RB and Nable, JV}, title = {Out-of-Hospital Cardiac Arrest.}, journal = {Cardiology clinics}, volume = {42}, number = {2}, pages = {317-331}, doi = {10.1016/j.ccl.2024.02.014}, pmid = {38631798}, issn = {1558-2264}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest ; *Cardiopulmonary Resuscitation ; *Emergency Medical Services ; }, abstract = {Survival from out-of-hospital cardiac arrest (OHCA) is predicated on a community and system-wide approach that includes rapid recognition of cardiac arrest, capable bystander CPR, effective basic and advanced life support (BLS and ALS) by EMS providers, and coordinated postresuscitation care. Management of these critically ill patients continues to evolve. This article focuses on the management of OHCA by EMS providers.}, }
@article {pmid38630299, year = {2024}, author = {Wolff, A and Demleitner, AF and Feneberg, E and Lingor, P}, title = {[Smell the smoke before one sees the fire-The oligosymptomatic prodromal phase of neurodegenerative diseases].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, pmid = {38630299}, issn = {1433-0407}, abstract = {BACKGROUND: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing.<br><br>OBJECTIVE: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences.<br><br>MATERIAL AND METHODS: Selective literature search, discussion of basic research and expert recommendations.<br><br>RESULTS: Many neurodegenerative diseases have a&#xa0;prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose.<br><br>DISCUSSION: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a&#xa0;neurodegenerative disease can be referred to centers for clinical trials and observational studies.}, }
@article {pmid38628839, year = {2023}, author = {Uzunoglu-Ozyurek, E and Önal, G and Dökmeci, S}, title = {Investigating the Therapeutics Effects of Oral Cavity Derived Stem Cells on Neurodegenerative Diseases: A Systematic Review.}, journal = {Basic and clinical neuroscience}, volume = {14}, number = {5}, pages = {565-584}, pmid = {38628839}, issn = {2008-126X}, abstract = {INTRODUCTION: Published data obtained from in vitro and in vivo studies was reviewed systematically and analyzed critically to evaluate the effect of oral cavity-derived stem cells (OCDSCs) on the recovery or therapy of neurodegenerative diseases (NDs), such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington (HD) diseases, and Parkinson disease (PD).<br><br>METHODS: An electronic search was accomplished. References of included articles were also manually searched. Studies were critically evaluated for suitability against the inclusion/exclusion criteria and the data was extracted. Bias risk evaluation of the studies and evidence synthesis were conducted.<br><br>RESULTS: A total of 14 in vivo and 10 in vitro studies met the inclusion criteria. PD was induced in 10 in vivo and 7 in vitro studies, while AD was induced in 2 in vivo and 4 in vitro studies. Two studies (1 in vitro and 1 in vivo) evaluated ALS disease and 1 in vivo study evaluated HD. Moderate evidence was found for in vitro studies reporting the positive effect of OCDSCs on PD or AD recovery. Strong evidence was found for in vivo studies in which PD animal models were used; meanwhile, moderate evidence was found for the impact of OCDSCs on AD recovery. Limited evidence was found for in vivo studies evaluating HD and ALS.<br><br>CONCLUSION: Although studies reported favorable data regarding the OCDSCs on NDs, they presented a considerable risk of bias. Because of heterogeneous study characteristics, the current study recommends improving standardized methods to evaluate the therapeutic effects of OCDSCs on the NDs.}, }
@article {pmid38623278, year = {2024}, author = {Inci, OK and Basırlı, H and Can, M and Yanbul, S and Seyrantepe, V}, title = {Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Journal of lipids}, volume = {2024}, number = {}, pages = {4530255}, pmid = {38623278}, issn = {2090-3030}, abstract = {Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.}, }
@article {pmid38621750, year = {2024}, author = {Kosmachevskaya, OV and Novikova, NN and Yakunin, SN and Topunov, AF}, title = {Formation of Supplementary Metal-Binding Centers in Proteins under Stress Conditions.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S180-S204}, doi = {10.1134/S0006297924140104}, pmid = {38621750}, issn = {1608-3040}, mesh = {*Metals/chemistry/metabolism ; *Oxidative Stress ; Oxidation-Reduction ; Protein Processing, Post-Translational ; }, abstract = {In many proteins, supplementary metal-binding centers appear under stress conditions. They are known as aberrant or atypical sites. Physico-chemical properties of proteins are significantly changed after such metal binding, and very stable protein aggregates are formed, in which metals act as "cross-linking" agents. Supplementary metal-binding centers in proteins often arise as a result of posttranslational modifications caused by reactive oxygen and nitrogen species and reactive carbonyl compounds. New chemical groups formed as a result of these modifications can act as ligands for binding metal ions. Special attention is paid to the role of cysteine SH-groups in the formation of supplementary metal-binding centers, since these groups are the main target for the action of reactive species. Supplementary metal binding centers may also appear due to unmasking of amino acid residues when protein conformation changing. Appearance of such centers is usually considered as a pathological process. Such unilateral approach does not allow to obtain an integral view of the phenomenon, ignoring cases when formation of metal complexes with altered proteins is a way to adjust protein properties, activity, and stability under the changed redox conditions. The role of metals in protein aggregation is being studied actively, since it leads to formation of non-membranous organelles, liquid condensates, and solid conglomerates. Some proteins found in such aggregates are typical for various diseases, such as Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and some types of cancer.}, }
@article {pmid38621743, year = {2024}, author = {Rezvykh, A and Shteinberg, D and Bronovitsky, E and Ustyugov, A and Funikov, S}, title = {Animal Models of FUS-Proteinopathy: A Systematic Review.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S34-S56}, doi = {10.1134/S0006297924140037}, pmid = {38621743}, issn = {1608-3040}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Mutation ; Disease Models, Animal ; }, abstract = {Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.}, }
@article {pmid38614367, year = {2024}, author = {Roghani, AK and Garcia, RI and Roghani, A and Reddy, A and Khemka, S and Reddy, RP and Pattoor, V and Jacob, M and Reddy, PH and Sehar, U}, title = {Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.}, journal = {Ageing research reviews}, volume = {97}, number = {}, pages = {102291}, doi = {10.1016/j.arr.2024.102291}, pmid = {38614367}, issn = {1872-9649}, abstract = {The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.}, }
@article {pmid38612804, year = {2024}, author = {Giri, PM and Banerjee, A and Ghosal, A and Layek, B}, title = {Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612804}, issn = {1422-0067}, support = {P20 GM109024/GM/NIGMS NIH HHS/United States ; 2P20M109024/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Neuroinflammatory Diseases ; Inflammation/therapy ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; }, abstract = {Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.}, }
@article {pmid38612448, year = {2024}, author = {Homma, H and Tanaka, H and Fujita, K and Okazawa, H}, title = {Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612448}, issn = {1422-0067}, mesh = {Humans ; *HMGB1 Protein ; *Neurodegenerative Diseases ; Neuroinflammatory Diseases ; Necrosis ; Cell Death ; }, abstract = {The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying new subtypes of necrotic neuronal cell death. The present review provides an updated summary of necrosis subtypes and discusses their potential roles in neurodegenerative cell death. Among numerous necrosis subtypes, including necroptosis, paraptosis, ferroptosis, and pyroptosis, transcriptional repression-induced atypical cell death (TRIAD) has been identified as a potential mechanism of neuronal cell death. TRIAD is induced by functional deficiency of TEAD-YAP and self-amplifies via the release of HMGB1. TRIAD is a feasible potential mechanism of neuronal cell death in Alzheimer's disease and other neurodegenerative diseases. In addition to induction of cell death, HMGB1 released during TRIAD activates brain inflammatory responses, which is a potential link between neurodegeneration and neuroinflammation.}, }
@article {pmid38610192, year = {2024}, author = {Papadopoulou, M and Papapostolou, A and Dimakopoulos, R and Salakou, S and Koropouli, E and Fanouraki, S and Bakola, E and Moschovos, C and Tsivgoulis, G}, title = {Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {38610192}, issn = {2227-9032}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS.<br><br>AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials.<br><br>MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients.<br><br>CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.}, }
@article {pmid38610012, year = {2024}, author = {Liu, X and Shen, L and Wan, M and Xie, H and Wang, Z}, title = {Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {170}, pmid = {38610012}, issn = {1477-3155}, support = {82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&amp;D Program of China/ ; }, mesh = {Humans ; Prospective Studies ; *Extracellular Vesicles ; *Exosomes ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.}, }
@article {pmid38609750, year = {2024}, author = {Sellier, C and Corcia, P and Vourc'h, P and Dupuis, L}, title = {C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2024.03.008}, pmid = {38609750}, issn = {0035-3787}, abstract = {The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death. We will particularly focus on the broad phenotypic presentation of C9ORF72-related diseases, that goes well beyond the classical phenotypes observed in ALS and FTD patients. Last, we will comment the possible therapeutical hopes for patients carrying a C9ORF72 HRE.}, }
@article {pmid38609644, year = {2024}, author = {Khalil, M and Teunissen, CE and Lehmann, S and Otto, M and Piehl, F and Ziemssen, T and Bittner, S and Sormani, MP and Gattringer, T and Abu-Rumeileh, S and Thebault, S and Abdelhak, A and Green, A and Benkert, P and Kappos, L and Comabella, M and Tumani, H and Freedman, MS and Petzold, A and Blennow, K and Zetterberg, H and Leppert, D and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders - towards clinical application.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {38609644}, issn = {1759-4766}, abstract = {Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.}, }
@article {pmid38607083, year = {2024}, author = {Tamberi, L and Belloni, A and Pugnaloni, A and Rippo, MR and Olivieri, F and Procopio, AD and Bronte, G}, title = {The Influence of Myeloid-Derived Suppressor Cell Expansion in Neuroinflammation and Neurodegenerative Diseases.}, journal = {Cells}, volume = {13}, number = {7}, pages = {}, pmid = {38607083}, issn = {2073-4409}, mesh = {Humans ; *Myeloid-Derived Suppressor Cells/pathology ; Neuroinflammatory Diseases ; *Neurodegenerative Diseases/pathology ; Inflammation/pathology ; Cell Proliferation ; }, abstract = {The neuro-immune axis has a crucial function both during physiological and pathological conditions. Among the immune cells, myeloid-derived suppressor cells (MDSCs) exert a pivotal role in regulating the immune response in many pathological conditions, influencing neuroinflammation and neurodegenerative disease progression. In chronic neuroinflammation, MDSCs could lead to exacerbation of the inflammatory state and eventually participate in the impairment of cognitive functions. To have a complete overview of the role of MDSCs in neurodegenerative diseases, research on PubMed for articles using a combination of terms made with Boolean operators was performed. According to the search strategy, 80 papers were retrieved. Among these, 44 papers met the eligibility criteria. The two subtypes of MDSCs, monocytic and polymorphonuclear MDSCs, behave differently in these diseases. The initial MDSC proliferation is fundamental for attenuating inflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), but not in amyotrophic lateral sclerosis (ALS), where MDSC expansion leads to exacerbation of the disease. Moreover, the accumulation of MDSC subtypes in distinct organs changes during the disease. The proliferation of MDSC subtypes occurs at different disease stages and can influence the progression of each neurodegenerative disorder differently.}, }
@article {pmid38603949, year = {2024}, author = {Shin-Yi Lin, C and Howells, J and Rutkove, S and Nandedkar, S and Neuwirth, C and Noto, YI and Shahrizaila, N and Whittaker, RG and Bostock, H and Burke, D and Tankisi, H}, title = {Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {162}, number = {}, pages = {91-120}, doi = {10.1016/j.clinph.2024.03.015}, pmid = {38603949}, issn = {1872-8952}, abstract = {This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.}, }
@article {pmid38600725, year = {2024}, author = {Madhubala, D and Patra, A and Khan, MR and Mukherjee, AK}, title = {Phytomedicine for neurodegenerative diseases: The road ahead.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.8192}, pmid = {38600725}, issn = {1099-1573}, support = {//IASST/ ; EMR/2017/001829//Science and Engineering Research Board/ ; }, abstract = {Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.}, }
@article {pmid38599171, year = {2024}, author = {Castro-Gomez, S and Heneka, MT}, title = {Innate immune activation in neurodegenerative diseases.}, journal = {Immunity}, volume = {57}, number = {4}, pages = {790-814}, doi = {10.1016/j.immuni.2024.03.010}, pmid = {38599171}, issn = {1097-4180}, mesh = {Humans ; *Neurodegenerative Diseases ; Receptors, Pattern Recognition ; Immune System ; Inflammation Mediators ; Immunity, Innate ; }, abstract = {Activation of the innate immune system following pattern recognition receptor binding has emerged as one of the major pathogenic mechanisms in neurodegenerative disease. Experimental, epidemiological, pathological, and genetic evidence underscores the meaning of innate immune activation during the prodromal as well as clinical phases of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Importantly, innate immune activation and the subsequent release of inflammatory mediators contribute mechanistically to other hallmarks of neurodegenerative diseases such as aberrant proteostatis, pathological protein aggregation, cytoskeleton abnormalities, altered energy homeostasis, RNA and DNA defects, and synaptic and network disbalance and ultimately to the induction of neuronal cell death. In this review, we discuss common mechanisms of innate immune activation in neurodegeneration, with particular emphasis on the pattern recognition receptors (PRRs) and other receptors involved in the detection of damage-associated molecular patterns (DAMPs).}, }
@article {pmid38595972, year = {2024}, author = {Zhou, L and Xie, M and Wang, X and Xu, R}, title = {The usage and advantages of several common amyotrophic lateral sclerosis animal models.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1341109}, pmid = {38595972}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis is a fatal, multigenic, multifactorial neurodegenerative disease characterized by upper and lower motor neuron loss. Animal models are essential for investigating pathogenesis and reflecting clinical manifestations, particularly in developing reasonable prevention and therapeutic methods for human diseases. Over the decades, researchers have established a host of different animal models in order to dissect amyotrophic lateral sclerosis (ALS), such as yeast, worms, flies, zebrafish, mice, rats, pigs, dogs, and more recently, non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms of motor neuron degeneration in ALS, contributing to the development of new promising therapeutics. In this review, we describe several common animal models in ALS, classified by the naturally occurring and experimentally induced, pointing out their features in modeling, the onset and progression of the pathology, and their specific pathological hallmarks. Moreover, we highlight the pros and cons aimed at helping the researcher select the most appropriate among those common experimental animal models when designing a preclinical ALS study.}, }
@article {pmid38592845, year = {2024}, author = {Lerose, V and Ponticelli, M and Benedetto, N and Carlucci, V and Lela, L and Tzvetkov, NT and Milella, L}, title = {Withania somnifera (L.) Dunal, a Potential Source of Phytochemicals for Treating Neurodegenerative Diseases: A Systematic Review.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {6}, pages = {}, pmid = {38592845}, issn = {2223-7747}, support = {CUP: B34I20000320005//Project RESO - REsilienza e SOstenibilit&#xe0; delle filiere ortofrutticole e cerealicole per valorizzare i territori" - cod. identif. ARS01_01224 -/ ; CUP: G49J19001350004//Project SPIA-Valorization of by-products from the agro-food chain/ ; CUP: ECS00000036//Project NODES - Ecosistema dell'Innovazione "Nord Ovest Digitale e Sostenibile"/ ; }, abstract = {Withania somnifera (L.) Dunal is a medicinal plant belonging to the traditional Indian medical system, showing various therapeutic effects such as anti-cancer, anti-inflammatory, anti-microbial, anti-diabetic, and hepatoprotective activity. Of great interest is W. somnifera's potential beneficial effect against neurodegenerative diseases, since the authorized medicinal treatments can only delay disease progression and provide symptomatic relief and are not without side effects. A systematic search of PubMed and Scopus databases was performed to identify preclinical and clinical studies focusing on the applications of W. somnifera in preventing neurodegenerative diseases. Only English articles and those containing the keywords (Withania somnifera AND "neurodegenerative diseases", "neuroprotective effects", "Huntington", "Parkinson", "Alzheimer", "Amyotrophic Lateral Sclerosis", "neurological disorders") in the title or abstract were considered. Reviews, editorials, letters, meta-analyses, conference papers, short surveys, and book chapters were not considered. Selected articles were grouped by pathologies and summarized, considering the mechanism of action. The quality assessment and the risk of bias were performed using the Cochrane Handbook for Systematic Reviews of Interventions checklist. This review uses a systematic approach to summarize the results from 60 investigations to highlight the potential role of W. somnifera and its specialized metabolites in treating or preventing neurodegenerative diseases.}, }
@article {pmid38588013, year = {2024}, author = {El Hajj, R and Al Sagheer, T and Ballout, N}, title = {Optogenetics in chronic neurodegenerative diseases, controlling the brain with light: A systematic review.}, journal = {Journal of neuroscience research}, volume = {102}, number = {4}, pages = {e25321}, doi = {10.1002/jnr.25321}, pmid = {38588013}, issn = {1097-4547}, mesh = {Animals ; Optogenetics/methods ; *Neurodegenerative Diseases/therapy/drug therapy ; Brain/physiology ; Basal Ganglia ; *Parkinson Disease/genetics ; }, abstract = {Neurodegenerative diseases are progressive disorders characterized by synaptic loss and neuronal death. Optogenetics combines optical and genetic methods to control the activity of specific cell types. The efficacy of this approach in neurodegenerative diseases has been investigated in many reviews, however, none of them tackled it systematically. Our study aimed to review systematically the findings of optogenetics and its potential applications in animal models of chronic neurodegenerative diseases and compare it with deep brain stimulation and designer receptors exclusively activated by designer drugs techniques. The search strategy was performed based on the PRISMA guidelines and the risk of bias was assessed following the Systematic Review Centre for Laboratory Animal Experimentation tool. A total of 247 articles were found, of which 53 were suitable for the qualitative analysis. Our data revealed that optogenetic manipulation of distinct neurons in the brain is efficient in rescuing memory impairment, alleviating neuroinflammation, and reducing plaque pathology in Alzheimer's disease. Similarly, this technique shows an advanced understanding of the contribution of various neurons involved in the basal ganglia pathways with Parkinson's disease motor symptoms and pathology. However, the optogenetic application using animal models of Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis was limited. Optogenetics is a promising technique that enhanced our knowledge in the research of neurodegenerative diseases and addressed potential therapeutic solutions for managing these diseases' symptoms and delaying their progression. Nevertheless, advanced investigations should be considered to improve optogenetic tools' efficacy and safety to pave the way for their translatability to the clinic.}, }
@article {pmid38586597, year = {2024}, author = {Zhang, T and Bao, L and Chen, H}, title = {Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and NOTCH2NLC-Related GGC Repeat Expansion Disorders.}, journal = {Neurology. Genetics}, volume = {10}, number = {2}, pages = {e200132}, pmid = {38586597}, issn = {2376-7839}, abstract = {Neuronal intranuclear inclusion disease (NIID) is an underdiagnosed neurodegenerative disorder caused by pathogenic GGC expansions in NOTCH2NLC. However, an increasing number of reports of NOTCH2NLC GGC expansions in patients with Alzheimer disease, essential tremor, Parkinson disease, amyotrophic lateral sclerosis, and oculopharyngodistal myopathy have led to the proposal of a new concept known as NOTCH2NLC-related GGC repeat expansion disorders (NREDs). The majority of studies have mainly focused on screening for NOTCH2NLC GGC repeat variation in populations previously diagnosed with the associated disease, subsequently presenting it as a novel causative gene for the condition. These studies appear to be clinically relevant but do have their limitations because they may incorrectly regard the lack of MRI abnormalities as an exclusion criterion for NIID or overlook concomitant clinical presentations not typically observed in the associated diseases. Besides, in many instances within these reports, patients lack pathologic evidence or undergo long-term follow-up to conclusively rule out NIID. In this review, we will systematically review the research on NOTCH2NLC 5' untranslated region GGC repeat expansions and their association with related neurologic disorders, explaining the limitations of the relevant reports. Furthermore, we will integrate subsequent studies to further demonstrate that these patients actually experienced distinct clinical phenotypes of NIID.}, }
@article {pmid38585631, year = {2024}, author = {Pinilla-González, V and Montecinos-Barrientos, B and Martin-Kommer, C and Chichiarelli, S and Saso, L and Rodrigo, R}, title = {Exploring antioxidant strategies in the pathogenesis of ALS.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220842}, pmid = {38585631}, issn = {2391-5412}, abstract = {The central nervous system is essential for maintaining homeostasis and controlling the body's physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3-5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease.}, }
@article {pmid38585368, year = {2024}, author = {Jamet, M and Dupuis, L and Gonzalez De Aguilar, JL}, title = {Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1375330}, pmid = {38585368}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal adult-onset neurodegenerative disorders that share clinical, neuropathological and genetic features, which forms part of a multi-system disease spectrum. The pathological process leading to ALS and FTD is the result of the combination of multiple mechanisms that operate within specific populations of neurons and glial cells. The implication of oligodendrocytes has been the subject of a number of studies conducted on patients and related animal models. In this review we summarize our current knowledge on the alterations specific to myelin and the oligodendrocyte lineage occurring in ALS and FTD. We also consider different ways by which specific oligodendroglial alterations influence neurodegeneration and highlight the important role of oligodendrocytes in these two intrinsically associated neurodegenerative diseases.}, }
@article {pmid38583129, year = {2024}, author = {Thal, DR and Gawor, K and Moonen, S}, title = {Regulated cell death and its role in Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {69}, pmid = {38583129}, issn = {1432-0533}, support = {22-AAIIA-963171/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Regulated Cell Death ; Cell Death ; Motor Neurons ; }, abstract = {Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or "cellular suicide" represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.}, }
@article {pmid38575486, year = {2024}, author = {Chandran, SK and Doucet, M}, title = {Neurogenic Dysphagia.}, journal = {Otolaryngologic clinics of North America}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.otc.2024.02.023}, pmid = {38575486}, issn = {1557-8259}, abstract = {This article provides an overview of neurogenic dysphagia, describing the evaluation and management of swallowing dysfunction in various neurologic diseases. The article will focus on stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.}, }
@article {pmid38570095, year = {2024}, author = {Wiblin, L}, title = {An introduction to neuropalliative care: A growing need.}, journal = {Clinical medicine (London, England)}, volume = {24}, number = {2}, pages = {100038}, doi = {10.1016/j.clinme.2024.100038}, pmid = {38570095}, issn = {1473-4893}, abstract = {Palliative care (PC) defined as 'an approach improving the quality of life of patients and their families facing problems associated with life-limiting illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual' aims to enhance the improve the remaining time that patients have, emphasising choice for patients and families.[1] Patients with neurological disease such as Parkinson's (PD) and motor neurone disease (MND) benefit from PC earlier in disease with increasing emphasis over time. Understanding and communicating uncertain trajectories, honest prognostic communication when patients are ready and careful symptom control has been shown to enhance quality of life in patients and caregivers, giving greater autonomy to these patients when supported in decision-making by a palliative approach. Although obstacles to palliative care are frequent, there are strategies which can help overcome them.}, }
@article {pmid38563162, year = {2024}, author = {Pastora, LE and Namburu, NS and Arora, K and Christov, PP and Wilson, JT}, title = {STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases.}, journal = {ACS applied bio materials}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsabm.3c01305}, pmid = {38563162}, issn = {2576-6422}, abstract = {Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151-as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.}, }
@article {pmid38563056, year = {2024}, author = {Umar, TP and Jain, N and Papageorgakopoulou, M and Shaheen, RS and Alsamhori, JF and Muzzamil, M and Kostiks, A}, title = {Artificial intelligence for screening and diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2024.2334836}, pmid = {38563056}, issn = {2167-9223}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurological disease that leads to progressive motor function degeneration. Diagnosing ALS is challenging due to the absence of a specific detection test. The use of artificial intelligence (AI) can assist in the investigation and treatment of ALS.<br><br>METHODS: We searched seven databases for literature on the application of AI in the early diagnosis and screening of ALS in humans. The findings were summarized using random-effects summary receiver operating characteristic curve. The risk of bias (RoB) analysis was carried out using QUADAS-2 or QUADAS-C tools.<br><br>RESULTS: In the 34 analyzed studies, a meta-prevalence of 47% for ALS was noted. For ALS detection, the pooled sensitivity of AI models was 94.3% (95% CI - 63.2% to 99.4%) with a pooled specificity of 98.9% (95% CI - 92.4% to 99.9%). For ALS classification, the pooled sensitivity of AI models was 90.9% (95% CI - 86.5% to 93.9%) with a pooled specificity of 92.3% (95% CI - 84.8% to 96.3%). Based on type of input for classification, the pooled sensitivity of AI models for gait, electromyography, and magnetic resonance signals was 91.2%, 92.6%, and 82.2%, respectively. The pooled specificity for gait, electromyography, and magnetic resonance signals was 94.1%, 96.5%, and 77.3%, respectively.<br><br>CONCLUSIONS: Although AI can play a significant role in the screening and diagnosis of ALS due to its high sensitivities and specificities, concerns remain regarding quality of evidence reported in the literature.}, }
@article {pmid38558150, year = {2024}, author = {Pensato, U and Cortelli, P}, title = {Soccer (football) and brain health.}, journal = {Journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {38558150}, issn = {1432-1459}, abstract = {Soccer is one of the most popular sports worldwide, played by over 270 million people and followed by many more. Several brain health benefits are promoted by practising soccer and physical exercise at large, which helps contrast the cognitive decline associated with ageing by enhancing neurogenesis processes. However, sport-related concussions have been increasingly recognised as a pressing public health concern, not only due to their acute impact but also, more importantly, due to mounting evidence indicating an elevated risk for the development of neurological sequelae following recurrent head traumas, especially chronic traumatic encephalopathy (CTE). While soccer players experience less frequent concussions compared with other contact or combat sports, such as American football or boxing, it stands alone in its purposeful use of the head to hit the ball (headings), setting its players apart as the only athletes exposed to intentional, sub-concussive head impacts. Additionally, an association between soccer and amyotrophic lateral sclerosis has been consistently observed, suggesting a potential "soccer-specific" risk factor. In this review, we discuss the neurological sequelae related to soccer playing, the emerging evidence of a detrimental effect related to recurrent headings, and the need for implementation of comprehensive strategies aimed at preventing and managing the burden of head impact in soccer.}, }
@article {pmid38552851, year = {2024}, author = {Yang, L and Guttman, L and Dawson, VL and Dawson, TM}, title = {Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke.}, journal = {Biochemical pharmacology}, volume = {}, number = {}, pages = {116174}, doi = {10.1016/j.bcp.2024.116174}, pmid = {38552851}, issn = {1873-2968}, support = {R01 AG085688/AG/NIA NIH HHS/United States ; R01 NS067525/NS/NINDS NIH HHS/United States ; }, abstract = {Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition.}, }
@article {pmid38550565, year = {2024}, author = {Di Nardo, AA and Prochiantz, A}, title = {Therapeutic value of homeoprotein signaling pathways.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1359523}, pmid = {38550565}, issn = {1662-4548}, abstract = {Cell signaling based on homeoprotein transfer is a pathway with developmental and physiological functions. For a few transcription factors of this family, primarily ENGRAILED1, ENGRAILED2 and OTX2, their physiological functions have led to therapeutic strategies in animal models of human diseases, including Parkinson's disease, amyotrophic lateral sclerosis, amblyopia and anxiety-related disorders. In mesencephalic dopaminergic neurons which degenerate in Parkinson's disease, ENGRAILED1/2 have cell autonomous activities, but their transducing properties enables their use as therapeutic proteins. In contrast, in spinal alpha-motoneurons, which are lost in amyotrophic lateral sclerosis, ENGRAILED1 is supplied by V1 interneurons. Thus, its use as a therapeutic protein to protect alpha-motoneurons against degeneration mimics its normal non-cell autonomous neurotrophic activity. OTX2, synthesized and secreted by the choroid plexus, is transferred to parvalbumin interneurons and exerts regulatory functions controlling cerebral cortex plasticity. Understanding the latter OTX2 function has led to strategies for manipulating visual acuity and anxiety-like behavior in adult mice. In this review, we describe these cases and what is known about the involved molecular mechanisms. Because the transduction sequences are conserved in most of the few hundred homeoproteins, we argue how this family of molecules constitutes an important reservoir of physiological knowledge, with potential consequences in the search for new therapeutic strategies.}, }
@article {pmid38548126, year = {2024}, author = {Krut', VG and Kalinichenko, AL and Maltsev, DI and Jappy, D and Shevchenko, EK and Podgorny, OV and Belousov, VV}, title = {Optogenetic and chemogenetic approaches for modeling neurological disorders in vivo.}, journal = {Progress in neurobiology}, volume = {235}, number = {}, pages = {102600}, doi = {10.1016/j.pneurobio.2024.102600}, pmid = {38548126}, issn = {1873-5118}, mesh = {Animals ; Humans ; Optogenetics/methods ; *Epilepsy ; Models, Animal ; *Parkinson Disease ; Neuropathology ; }, abstract = {Animal models of human neurological disorders provide valuable experimental tools which enable us to study various aspects of disorder pathogeneses, ranging from structural abnormalities and disrupted metabolism and signaling to motor and mental deficits, and allow us to test novel therapies in preclinical studies. To be valid, these animal models should recapitulate complex pathological features at the molecular, cellular, tissue, and behavioral levels as closely as possible to those observed in human subjects. Pathological states resembling known human neurological disorders can be induced in animal species by toxins, genetic factors, lesioning, or exposure to extreme conditions. In recent years, novel animal models recapitulating neuropathologies in humans have been introduced. These animal models are based on synthetic biology approaches: opto- and chemogenetics. In this paper, we review recent opto- and chemogenetics-based animal models of human neurological disorders. These models allow for the creation of pathological states by disrupting specific processes at the cellular level. The artificial pathological states mimic a range of human neurological disorders, such as aging-related dementia, Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, and ataxias. Opto- and chemogenetics provide new opportunities unavailable with other animal models of human neurological disorders. These techniques enable researchers to induce neuropathological states varying in severity and ranging from acute to chronic. We also discuss future directions for the development and application of synthetic biology approaches for modeling neurological disorders.}, }
@article {pmid38542497, year = {2024}, author = {Nemeth, C and Banik, NL and Haque, A}, title = {Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542497}, issn = {1422-0067}, support = {1R21NS118393-01/NH/NIH HHS/United States ; }, mesh = {Humans ; Neuromuscular Junction/metabolism ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/metabolism ; Spinal Cord/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Spinal Cord Injuries/metabolism ; }, abstract = {The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.}, }
@article {pmid38542306, year = {2024}, author = {Marshall Moscon, SL and Connor, JR}, title = {HFE Mutations in Neurodegenerative Disease as a Model of Hormesis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542306}, issn = {1422-0067}, mesh = {Mice ; Animals ; *Neurodegenerative Diseases/genetics ; Hemochromatosis Protein/genetics ; Histocompatibility Antigens Class I/genetics ; Hormesis ; Mutation ; Iron/metabolism ; }, abstract = {Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.}, }
@article {pmid38540795, year = {2024}, author = {Gascón, E and Zaragoza, P and Calvo, AC and Osta, R}, title = {Sporadic Amyotrophic Lateral Sclerosis Skeletal Muscle Transcriptome Analysis: A Comprehensive Examination of Differentially Expressed Genes.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540795}, issn = {2218-273X}, support = {PI17/00949//Instituto de Salud Carlos III/ ; A19_23R//"LAGENBIO GRUPO INVESTIGACION"/ ; CIBER-358 NED-612-CB18/05/00037//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; }, mesh = {Humans ; Transcriptome/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Muscle, Skeletal/metabolism ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) that comprises sporadic (sALS) and familial (fALS) cases, is a devastating neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle atrophy and various clinical manifestations. However, the complex underlying mechanisms affecting this disease are not yet known. On the other hand, there is also no good prognosis of the disease due to the lack of biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, sALS-affected muscle tissue was analyzed using the GEO GSE41414 dataset, identifying 397 differentially expressed genes (DEGs). Functional analysis revealed 320 up-regulated DEGs associated with muscle development and 77 down-regulated DEGs linked to energy metabolism. Protein-protein interaction network analysis identified 20 hub genes, including EIF4A1, HNRNPR and NDUFA4. Furthermore, miRNA target gene networks revealed 17 miRNAs linked to hub genes, with hsa-mir-206, hsa-mir-133b and hsa-mir-100-5p having been previously implicated in ALS. This study presents new potential biomarkers and therapeutic targets for ALS by correlating the information obtained with a comprehensive literature review, providing new potential targets to study their role in ALS.}, }
@article {pmid38540709, year = {2024}, author = {Stoklund Dittlau, K and Freude, K}, title = {Astrocytes: The Stars in Neurodegeneration?.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540709}, issn = {2218-273X}, support = {R434-2023-242//Lundbeck Foundation/ ; 2078-00002B//Innovation Fund Denmark/ ; NNF21OC0071571//Novo Nordisk Foundation/ ; N/A//Alzheimer Foundation Denmark/ ; }, mesh = {Humans ; Astrocytes/physiology ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.}, }
@article {pmid38540369, year = {2024}, author = {Souza, PVS and Serrano, PL and Farias, IB and Machado, RIL and Badia, BML and Oliveira, HB and Barbosa, AS and Pereira, CA and Moreira, VF and Chieia, MAT and Barbosa, AR and Braga, VL and Pinto, WBVR and Oliveira, ASB}, title = {Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges.}, journal = {Genes}, volume = {15}, number = {3}, pages = {}, pmid = {38540369}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Motor Neurons ; Neuroimaging ; }, abstract = {Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally. Despite several upper motor neuron-dominant forms being generally associated with long-standing motor symptoms and slowly progressive course, certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap. For some monogenic forms, there is a well-established genotypic-phenotypic correlation. There are no specific biochemical and neuroimaging biomarkers for the diagnosis of juvenile Amyotrophic Lateral Sclerosis. There are several inherited neurodegenerative and neurometabolic disorders which can lead to the signs of motor neuron impairment. This review emphasizes the importance of high clinical suspicion, assessment, and proper diagnostic work-up for juvenile Amyotrophic Lateral Sclerosis.}, }
@article {pmid38538275, year = {2024}, author = {Ceccarelli, L and Verriello, L and Pauletto, G and Valente, M and Spadea, L and Salati, C and Zeppieri, M and Ius, T}, title = {The Role of Human Pluripotent Stem Cells in Amyotrophic Lateral Sclerosis: From Biological Mechanism to Practical Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {3}, pages = {114}, doi = {10.31083/j.fbl2903114}, pmid = {38538275}, issn = {2768-6698}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism ; *Pluripotent Stem Cells/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3-5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.}, }
@article {pmid38535081, year = {2024}, author = {Liampas, I and Danga, F and Kyriakoulopoulou, P and Siokas, V and Stamati, P and Messinis, L and Dardiotis, E and Nasios, G}, title = {The Contribution of Functional Near-Infrared Spectroscopy (fNIRS) to the Study of Neurodegenerative Disorders: A Narrative Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {38535081}, issn = {2075-4418}, abstract = {Functional near-infrared spectroscopy (fNIRS) is an innovative neuroimaging method that offers several advantages over other commonly used modalities. This narrative review investigated the potential contribution of this method to the study of neurodegenerative disorders. Thirty-four studies involving patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), frontotemporal dementia (FTD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) and healthy controls were reviewed. Overall, it was revealed that the prefrontal cortex of individuals with MCI may engage compensatory mechanisms to support declining brain functions. A rightward shift was suggested to compensate for the loss of the left prefrontal capacity in the course of cognitive decline. In parallel, some studies reported the failure of compensatory mechanisms in MCI and early AD; this lack of appropriate hemodynamic responses may serve as an early biomarker of neurodegeneration. One article assessing FTD demonstrated a heterogeneous cortical activation pattern compared to AD, indicating that fNIRS may contribute to the challenging distinction of these conditions. Regarding PD, there was evidence that cognitive resources (especially executive function) were recruited to compensate for locomotor impairments. As for ALS, fNIRS data support the involvement of extra-motor networks in ALS, even in the absence of measurable cognitive impairment.}, }
@article {pmid38534355, year = {2024}, author = {Cohen, J and Mathew, A and Dourvetakis, KD and Sanchez-Guerrero, E and Pangeni, RP and Gurusamy, N and Aenlle, KK and Ravindran, G and Twahir, A and Isler, D and Sosa-Garcia, SR and Llizo, A and Bested, AC and Theoharides, TC and Klimas, NG and Kempuraj, D}, title = {Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders.}, journal = {Cells}, volume = {13}, number = {6}, pages = {}, pmid = {38534355}, issn = {2073-4409}, mesh = {Humans ; Neuroinflammatory Diseases ; Endothelial Cells ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Inflammation ; }, abstract = {Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.}, }
@article {pmid38533300, year = {2024}, author = {Moskvin, SV}, title = {A brief literature review of low-level laser therapy for treating amyotrophic lateral sclerosis and confirmation of its effectiveness.}, journal = {BioMedicine}, volume = {14}, number = {1}, pages = {1-9}, pmid = {38533300}, issn = {2211-8020}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a steadily progressive course due to the death of central and peripheral motor neurons responsible for voluntary movements. Low-level laser therapy (LLLT) is a treatment method unique in its universality and efficacy, particularly for neurodegenerative diseases.<br><br>METHODS: In this review, we discuss the effect and application of LLLT in the treatment of ALS. A literature search for English and Russian publications for the keywords "Amyotrophic Lateral Sclerosis", "Low-Level Laser Therapy" was performed using PubMed, Scopus, Google Scholar, Web of Science and Russian Science Citation Index (RSCI) databases.<br><br>RESULTS: The article provided a brief literature review, substantiated the potential use of low-level laser therapy for ALS. The particular techniques of LLLT were developed.<br><br>CONCLUSION: Based on the results of several studies and many years of successful experience with low-level laser therapy in Russia we conclude that a LLLT technique, including intravenous laser blood illumination (ILBI), noninvasive laser blood illumination (NLBI), and local exposure, is a promising treatment method for ALS.}, }
@article {pmid38525704, year = {2024}, author = {Shirai, R and Yamauchi, J}, title = {Emerging Evidence of Golgi Stress Signaling for Neuropathies.}, journal = {Neurology international}, volume = {16}, number = {2}, pages = {334-348}, pmid = {38525704}, issn = {2035-8385}, abstract = {The Golgi apparatus is an intracellular organelle that modifies cargo, which is transported extracellularly through the nucleus, endoplasmic reticulum, and plasma membrane in order. First, the general function of the Golgi is reviewed and, then, Golgi stress signaling is discussed. In addition to the six main Golgi signaling pathways, two pathways that have been increasingly reported in recent years are described in this review. The focus then shifts to neurological disorders, examining Golgi stress reported in major neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The review also encompasses findings related to other diseases, including hypomyelinating leukodystrophy, frontotemporal spectrum disorder/amyotrophic lateral sclerosis, microcephaly, Wilson's disease, and prion disease. Most of these neurological disorders cause Golgi fragmentation and Golgi stress. As a result, strong signals may act to induce apoptosis.}, }
@article {pmid38524401, year = {2024}, author = {Pota, V and Sansone, P and De Sarno, S and Aurilio, C and Coppolino, F and Barbarisi, M and Barbato, F and Fiore, M and Cosenza, G and Passavanti, MB and Pace, MC}, title = {Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.}, journal = {Behavioural neurology}, volume = {2024}, number = {}, pages = {1228194}, pmid = {38524401}, issn = {1875-8584}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Pain Measurement ; Quality of Life ; *Neurodegenerative Diseases/complications ; Pain/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.}, }
@article {pmid38517530, year = {2024}, author = {Kotsia, E and Chroni, E and Alexandropoulou, A and Mills, C and Veltsista, D and Kefalopoulou, ZM and Michou, E}, title = {Dysphagia Assessments as Criteria in the 'Decision-Making Process' for Percutaneous Endoscopic Gastrostomy Placement in People with Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Dysphagia}, volume = {}, number = {}, pages = {}, pmid = {38517530}, issn = {1432-0460}, abstract = {To review the assessment methods of dysphagia as a criterion for the decision-making process for Percutaneous Endoscopic Gastrostomy (PEG) placement in patients with Amyotrophic Lateral Sclerosis (ALS). Systematic review. A search was conducted in three databases (EMBASE, CINAHL, PUBMED) in December 2022 and updated in July 2023. Two reviewers independently screened, selected, and extracted data. Study quality was appraised using the Joanna Briggs Institute Critical Appraisal Tools. Systematic review registration number in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42022385461. The searches identified 240 records. The 10 eligible studies included 2 case reports, 4 retrospective studies, 3 prospective studies, and 1 cohort observational study. Study quality was low, with most studies having moderate to high risk of bias. Dysphagia is a common criterion for decision-making. Dysphagia assessment is usually in the form of either self-reports, objective instrumental assessments, or both. Dysphagia is a common criterion for the decision-making process, yet is missing in clinical guidelines. Establishing the optimal means of dysphagia assessment is important for timely decision-making procedures, so that life-threatening consequences of dysphagia are minimized.}, }
@article {pmid38516735, year = {2024}, author = {Li, X and Bedlack, R}, title = {Evaluating emerging drugs in phase II &amp; III for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/14728214.2024.2333420}, pmid = {38516735}, issn = {1744-7623}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis is a rapidly progressive motor neuron disorder causing severe disability and premature death. Owing to the advances in uncovering ALS pathophysiology, efficient clinical trial design and research advocacy program, several disease-modifying drugs have been approved for treating ALS. Despite this progress, ALS remains a rapidly disabling and life shortening condition. There is a critical need for more effective therapies.<br><br>AREAS COVERED: Here, we reviewed the emerging ALS therapeutics undergoing phase II &amp; III clinical trials. To identify the investigational drugs, we searched ALS and phase II/III trials that are active and recruiting or not yet recruiting on clinicaltrials.gov and Pharmaprojects database.<br><br>EXPERT OPINION: The current pipeline is larger and more diverse than ever, with drugs targeting potential genetic and retroviral causes of ALS and drugs targeting a wide array of downstream pathways, including RNA metabolism, protein aggregation, integrated stress response and neuroinflammation.We remain most excited about those that target direct causes of ALS, e.g. antisense oligonucleotides targeting causative genes. Drugs that eliminate abnormal protein aggregates are also up-and-coming. Eventually, because of the heterogeneity of ALS pathophysiology, biomarkers that determine which biological events are most important for an individual ALS patient are needed.}, }
@article {pmid38515787, year = {2024}, author = {Wang, L and Fang, X and Ling, B and Wang, F and Xia, Y and Zhang, W and Zhong, T and Wang, X}, title = {Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1359453}, pmid = {38515787}, issn = {1662-5102}, abstract = {Globally, millions of individuals are impacted by neurodegenerative disorders including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Although a great deal of energy and financial resources have been invested in disease-related research, breakthroughs in therapeutic approaches remain elusive. The breakdown of cells usually happens together with the onset of neurodegenerative diseases. However, the mechanism that triggers neuronal loss is unknown. Lipid peroxidation, which is iron-dependent, causes a specific type of cell death called ferroptosis, and there is evidence its involvement in the pathogenic cascade of neurodegenerative diseases. However, the specific mechanisms are still not well known. The present article highlights the basic processes that underlie ferroptosis and the corresponding signaling networks. Furthermore, it provides an overview and discussion of current research on the role of ferroptosis across a variety of neurodegenerative conditions.}, }
@article {pmid38514815, year = {2024}, author = {Baxter, RC}, title = {Endocrine and cellular physiology and pathology of the insulin-like growth factor acid-labile subunit.}, journal = {Nature reviews. Endocrinology}, volume = {}, number = {}, pages = {}, pmid = {38514815}, issn = {1759-5037}, abstract = {The acid-labile subunit (ALS) of the insulin-like growth factor (IGF) binding protein (IGFBP) complex, encoded in humans by IGFALS, has a vital role in regulating the endocrine transport and bioavailability of IGF-1 and IGF-2. Accordingly, ALS has a considerable influence on postnatal growth and metabolism. ALS is a leucine-rich glycoprotein that forms high-affinity ternary complexes with IGFBP-3 or IGFBP-5 when they are occupied by either IGF-1 or IGF-2. These complexes constitute a stable reservoir of circulating IGFs, blocking the potentially hypoglycaemic activity of unbound IGFs. ALS is primarily synthesized by hepatocytes and its expression is lower in non-hepatic tissues. ALS synthesis is strongly induced by growth hormone and suppressed by IL-1β, thus potentially serving as a marker of growth hormone secretion and/or activity and of inflammation. IGFALS mutations in humans and Igfals deletion in mice cause modest growth retardation and pubertal delay, accompanied by decreased osteogenesis and enhanced adipogenesis. In hepatocellular carcinoma, IGFALS is described as a tumour suppressor; however, its contribution to other cancers is not well delineated. This Review addresses the endocrine physiology and pathology of ALS, discusses the latest cell and proteomic studies that suggest emerging cellular roles for ALS and outlines its involvement in other disease states.}, }
@article {pmid38512820, year = {2024}, author = {Bartolomé-Nafría, A and García-Pardo, J and Ventura, S}, title = {Mutations in human prion-like domains: pathogenic but not always amyloidogenic.}, journal = {Prion}, volume = {18}, number = {1}, pages = {28-39}, pmid = {38512820}, issn = {1933-690X}, mesh = {Humans ; *Prions/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mutation ; }, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.}, }
@article {pmid38510000, year = {2024}, author = {Ditan, ID and Turalde, CWR}, title = {Treatment gaps in the care of amyotrophic lateral sclerosis in the Philippines: A scoping review.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27944}, pmid = {38510000}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting both the upper and lower motor neurons. Much of the management of ALS is supportive with the goal of maximizing patient quality of life. While the Philippines was participative in the "Ice Bucket Challenge" in 2014, it is up for investigation whether substantial changes occurred to improve healthcare for ALS patients. This study aims to evaluate the treatment gaps in the management of ALS in the Philippines through a scoping review. Data on epidemiology, health systems, and pharmacotherapy available regarding ALS in the local setting were synthesized. Nine articles were included. As of July 2023, there were only four indexed studies on ALS from the Philippines. Five of the included articles investigated ALS in Filipino populations but were not authored by Filipinos nor affiliated with Philippine institutions. The available literature showed a distinct lack of local ALS epidemiologic data, as well as limited availability in diagnostic centers, medications, health financing options, and digestible information for Filipinos. The limitations in managing ALS in the country are multifactorial - from political, medical, and social. It is imperative to establish a national database, financing systems, support groups, and accessible diagnostic centers for ALS patients.}, }
@article {pmid38500677, year = {2024}, author = {Zhou, L and Xu, R}, title = {Invertebrate genetic models of amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1328578}, pmid = {38500677}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by the progressive death of motor neurons in the cerebral cortex, brain stem, and spinal cord. The exact mechanisms underlying the pathogenesis of ALS remain unclear. The current consensus regarding the pathogenesis of ALS suggests that the interaction between genetic susceptibility and harmful environmental factors is a promising cause of ALS onset. The investigation of putative harmful environmental factors has been the subject of several ongoing studies, but the use of transgenic animal models to study ALS has provided valuable information on the onset of ALS. Here, we review the current common invertebrate genetic models used to study the pathology, pathophysiology, and pathogenesis of ALS. The considerations of the usage, advantages, disadvantages, costs, and availability of each invertebrate model will also be discussed.}, }
@article {pmid38499161, year = {2024}, author = {Bashir, S and Aiman, A and Shahid, M and Chaudhary, AA and Sami, N and Basir, SF and Hassan, I and Islam, A}, title = {Amyloid-induced neurodegeneration: A comprehensive review through aggregomics perception of proteins in health and pathology.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102276}, doi = {10.1016/j.arr.2024.102276}, pmid = {38499161}, issn = {1872-9649}, mesh = {Humans ; Amyloid/metabolism ; *Amyloidosis/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; Perception ; }, abstract = {Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.}, }
@article {pmid38498721, year = {2024}, author = {Kertesz, A and Finger, E and Munoz, DG}, title = {Progress in Primary Progressive Aphasia: A Review.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {37}, number = {1}, pages = {3-12}, pmid = {38498721}, issn = {1543-3641}, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/genetics ; *Supranuclear Palsy, Progressive/genetics/pathology ; Syndrome ; *Aphasia, Primary Progressive ; }, abstract = {We present a review of the definition, classification, and epidemiology of primary progressive aphasia (PPA); an update of the taxonomy of the clinical syndrome of PPA; and recent advances in the neuroanatomy, pathology, and genetics of PPA, as well as the search for biomarkers and treatment. PPA studies that have contributed to concepts of language organization and disease propagation in neurodegeneration are also reviewed. In addition, the issues of heterogeneity versus the relationships of the clinical phenotypes and their relationship to biological, pathological, and genetic advances are discussed, as is PPA's relationship to other conditions such as frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, and amyotrophic lateral sclerosis. Arguments are presented in favor of considering these conditions as one entity versus many.}, }
@article {pmid38490348, year = {2024}, author = {Chatterjee, A and Kumar, S and Roy Sarkar, S and Halder, R and Kumari, R and Banerjee, S and Sarkar, B}, title = {Dietary polyphenols represent a phytotherapeutic alternative for gut dysbiosis associated neurodegeneration: A systematic review.}, journal = {The Journal of nutritional biochemistry}, volume = {129}, number = {}, pages = {109622}, doi = {10.1016/j.jnutbio.2024.109622}, pmid = {38490348}, issn = {1873-4847}, abstract = {Globally, neurodegeneration and cerebrovascular disease are common and growing causes of morbidity and mortality. Pathophysiology of this group of diseases encompasses various factors from oxidative stress to gut microbial dysbiosis. The study of the etiology and mechanisms of oxidative stress as well as gut dysbiosis-induced neurodegeneration in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism spectrum disorder, and Huntington's disease has recently received a lot of attention. Numerous studies lend credence to the notion that changes in the intestinal microbiota and enteric neuroimmune system have an impact on the initiation and severity of these diseases. The prebiotic role of polyphenols can influence the makeup of the gut microbiota in neurodegenerative disorders by modulating intracellular signalling pathways. Metabolites of polyphenols function directly as neurotransmitters by crossing the blood-brain barrier or indirectly via influencing the cerebrovascular system. This assessment aims to bring forth an interlink between the consumption of polyphenols biotransformed by gut microbiota which in turn modulate the gut microbial diversity and biochemical changes in the brain. This systematic review will further augment research towards the association of dietary polyphenols in the management of gut dysbiosis-associated neurodegenerative diseases.}, }
@article {pmid38489867, year = {2024}, author = {Tausendfreund, O and Bidlingmaier, M and Martini, S and Müller, K and Rippl, M and Schilbach, K and Schmidmaier, R and Drey, M}, title = {Growth hormone treatment in aged patients with comorbidities: A systematic review.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {75}, number = {}, pages = {101584}, doi = {10.1016/j.ghir.2024.101584}, pmid = {38489867}, issn = {1532-2238}, mesh = {Aged ; Humans ; Comorbidity ; Growth Hormone ; *Human Growth Hormone/adverse effects/therapeutic use ; Insulin-Like Growth Factor I ; Quality of Life ; Randomized Controlled Trials as Topic ; *Aging/pathology ; }, abstract = {OBJECTIVE: Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects.<br><br>DESIGN: A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library.<br><br>INCLUSION CRITERIA: participants aged over 65&#xa0;years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis.<br><br>RESULTS: The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3&#xd7;/week), doses (0.41&#xa0;mg-2.6&#xa0;mg; mean 1.3&#xa0;mg per 60&#xa0;kg patient) and duration (1-12&#xa0;months; mean 7&#xa0;months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life.<br><br>CONCLUSION: Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.}, }
@article {pmid38483631, year = {2024}, author = {Perera, A and Brock, O and Ahmed, A and Shaw, C and Ashkan, K}, title = {Taking the knife to neurodegeneration: a review of surgical gene therapy delivery to the CNS.}, journal = {Acta neurochirurgica}, volume = {166}, number = {1}, pages = {136}, pmid = {38483631}, issn = {0942-0940}, mesh = {Humans ; *Central Nervous System ; Genetic Therapy/methods ; Genetic Vectors ; *Neurodegenerative Diseases/genetics/therapy ; }, abstract = {Gene supplementation and editing for neurodegenerative disorders has emerged in recent years as the understanding of the genetic mechanisms underlying several neurodegenerative disorders increases. The most common medium to deliver genetic material to cells is via viral vectors; and with respect to the central nervous system, adeno-associated viral (AAV) vectors are a popular choice. The most successful example of AAV-based gene therapy for neurodegenerative disorders is Zolgensma© which is a transformative intravenous therapy given to babies with spinal muscular atrophy. However, the field has stalled in achieving safe drug delivery to the central nervous system in adults for which treatments for disorders such as amyotrophic lateral sclerosis are desperately needed. Surgical gene therapy delivery has been proposed as a potential solution to this problem. While the field of the so-called regenerative neurosurgery has yielded pre-clinical optimism, several challenges have emerged. This review seeks to explore the field of regenerative neurosurgery with respect to AAV-based gene therapy for neurodegenerative diseases, its progress so far and the challenges that need to be overcome.}, }
@article {pmid38477419, year = {2024}, author = {de Fátima Dos Santos Sampaio, M and de Paiva, YB and Sampaio, TB and Pereira, MG and Coimbra, NC}, title = {Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {134}, number = {5}, pages = {574-601}, doi = {10.1111/bcpt.13997}, pmid = {38477419}, issn = {1742-7843}, support = {2014/11869-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2020/15050-7//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; PDJ grant 155489/2018-6//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; Research Grant (NAP-USP-NuPNE; process IaPq2012-15//Universidade de S&#xe3;o Paulo/ ; 374/2022//Funda&#xe7;&#xe3;o de Apoio ao Ensino, Pesquisa e Assist&#xea;ncia do Hospital das Cl&#xed;nicas da Faculdade de Medicina de Ribeir&#xe3;o Preto da Universidade de S&#xe3;o Paulo/ ; 302605/2021-5//CNPq/ ; 301341/2015-0//CNPq/ ; 301905/2010-0//CNPq/ ; 155489/2018-6//CNPq/ ; }, mesh = {Humans ; *Cannabidiol/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; *Multiple Sclerosis/drug therapy ; Receptor, Serotonin, 5-HT1A/therapeutic use ; *Cannabinoids/pharmacology/therapeutic use ; *Epilepsy/drug therapy ; *Mental Disorders/drug therapy ; Comorbidity ; }, abstract = {Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.}, }
@article {pmid38474719, year = {2024}, author = {Noor Eddin, A and Alfuwais, M and Noor Eddin, R and Alkattan, K and Yaqinuddin, A}, title = {Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Nutrients}, volume = {16}, number = {5}, pages = {}, pmid = {38474719}, issn = {2072-6643}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; *Microbiota ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a highly fatal neurodegenerative disorder characterized by the progressive wasting and paralysis of voluntary muscle. Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited. However, recent evidence implicates gut dysbiosis and gut-brain axis (GBA) dysfunction in ALS pathogenesis. Alterations to the composition and diversity of microbial communities within the gut flora have been consistently observed in ALS patients. These changes are often correlated with disease progression and patient outcome, suggesting that GBA modulation may have therapeutic potential. Indeed, targeting the gut microbiota has been shown to be neuroprotective in several animal models, alleviating motor symptoms and mitigating disease progression. However, the translation of these findings to human patients is challenging due to the complexity of ALS pathology and the varying diversity of gut microbiota. This review comprehensively summarizes the current literature on ALS-related gut dysbiosis, focusing on the implications of GBA dysfunction. It delineates three main mechanisms by which dysbiosis contributes to ALS pathology: compromised intestinal barrier integrity, metabolic dysfunction, and immune dysregulation. It also examines preclinical evidence on the therapeutic potential of gut-microbiota-modulating agents (categorized as prebiotics, probiotics, and postbiotics) in ALS.}, }
@article {pmid38474416, year = {2024}, author = {Tzeplaeff, L and Jürs, AV and Wohnrade, C and Demleitner, AF}, title = {Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474416}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Treatment Outcome ; Clinical Trials as Topic ; }, abstract = {Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.}, }
@article {pmid38474399, year = {2024}, author = {Manora, L and Borlongan, CV and Garbuzova-Davis, S}, title = {Cellular and Noncellular Approaches for Repairing the Damaged Blood-CNS-Barrier in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474399}, issn = {2073-4409}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS132576/NS/NINDS NIH HHS/United States ; 1R21NS132576-01/NS/NINDS NIH HHS/United States ; 1R01NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Endothelial Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Stem Cells/metabolism ; }, abstract = {Numerous reports have demonstrated the breakdown of the blood-CNS barrier (B-CNS-B) in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Re-establishing barrier integrity in the CNS is critical to prevent further motor neuron degeneration from harmful components in systemic circulation. Potential therapeutic strategies for repairing the B-CNS-B may be achieved by the replacement of damaged endothelial cells (ECs) via stem cell administration or enhancement of endogenous EC survival through the delivery of bioactive particles secreted by stem cells. These cellular and noncellular approaches are thoroughly discussed in the present review. Specific attention is given to certain stem cell types for EC replacement. Also, various nanoparticles secreted by stem cells as well as other biomolecules are elucidated as promising agents for endogenous EC repair. Although the noted in vitro and in vivo studies show the feasibility of the proposed therapeutic approaches to the repair of the B-CNS-B in ALS, further investigation is needed prior to clinical transition.}, }
@article {pmid38474192, year = {2024}, author = {Yamashita, T and Abe, K}, title = {Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38474192}, issn = {1422-0067}, support = {23K08543, 21K19572//Grant-in-Aid for Scientific Research/ ; }, mesh = {Animals ; Female ; Pregnancy ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; Antipyrine ; Edaravone/pharmacology/therapeutic use ; Free Radical Scavengers/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology ; Placenta ; }, abstract = {The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.}, }
@article {pmid38473944, year = {2024}, author = {Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Bordoni, M and Pansarasa, O}, title = {New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38473944}, issn = {1422-0067}, support = {Ricerca Corrente 2022-2024//Ministero della Salute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; Antioxidants/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Inflammation/drug therapy ; }, abstract = {Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.}, }
@article {pmid38463392, year = {2024}, author = {Chen, Y and Mateski, J and Gerace, L and Wheeler, J and Burl, J and Prakash, B and Svedin, C and Amrick, R and Adams, BD}, title = {Non-coding RNAs and neuroinflammation: implications for neurological disorders.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10120}, pmid = {38463392}, issn = {1535-3699}, mesh = {Humans ; Neuroinflammatory Diseases ; *Nervous System Diseases/genetics ; Microglia/metabolism ; *MicroRNAs/genetics/metabolism ; Cytokines/metabolism ; Chemokines/metabolism ; }, abstract = {Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.}, }
@article {pmid38452377, year = {2024}, author = {Rajabi, D and Khanmohammadi, S and Rezaei, N}, title = {The role of long noncoding RNAs in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {38452377}, issn = {2191-0200}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis leading to death. The diagnosis and treatment of ALS are inherently challenging due to its complex pathomechanism. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides involved in different cellular processes, incisively gene expression. In recent years, more studies have been conducted on lncRNA classes and interference in different disease pathologies, showing their promising contribution to diagnosing and treating neurodegenerative diseases. In this review, we discussed the role of lncRNAs like NEAT1 and C9orf72-as in ALS pathogenesis mechanisms caused by mutations in different genes, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), superoxide dismutase type 1 (SOD1). NEAT1 is a well-established lncRNA in ALS pathogenesis; hence, we elaborate on its involvement in forming paraspeckles, stress response, inflammatory response, and apoptosis. Furthermore, antisense lncRNAs (as-lncRNAs), a key group of transcripts from the opposite strand of genes, including ZEB1-AS1 and ATXN2-AS, are discussed as newly identified components in the pathology of ALS. Ultimately, we review the current standing of using lncRNAs as biomarkers and therapeutic agents and the future vision of further studies on lncRNA applications.}, }
@article {pmid38430933, year = {2024}, author = {Li, D and Zhou, L and Cao, Z and Wang, J and Yang, H and Lyu, M and Zhang, Y and Yang, R and Wang, J and Bian, Y and Xu, W and Wang, Y}, title = {Associations of environmental factors with neurodegeneration: An exposome-wide Mendelian randomization investigation.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102254}, doi = {10.1016/j.arr.2024.102254}, pmid = {38430933}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Exposome ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Multiple Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.}, }
@article {pmid38430277, year = {2024}, author = {Jagaraj, CJ and Shadfar, S and Kashani, SA and Saravanabavan, S and Farzana, F and Atkin, JD}, title = {Molecular hallmarks of ageing in amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {111}, pmid = {38430277}, issn = {1420-9071}, support = {1095215//National Institute for Dementia Research/ ; Peter Stearne Familial MND Research Grant//Motor Neurone Disease Australia/ ; Linda Rynalski Bridge Funding Grant//Motor Neurone Disease Australia/ ; 51909/00//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Longevity ; Autophagy/genetics ; Brain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.}, }
@article {pmid38429818, year = {2024}, author = {Darabi, S and Ariaei, A and Rustamzadeh, A and Afshari, D and Charkhat Gorgich, EA and Darabi, L}, title = {Cerebrospinal fluid and blood exosomes as biomarkers for amyotrophic lateral sclerosis; a systematic review.}, journal = {Diagnostic pathology}, volume = {19}, number = {1}, pages = {47}, pmid = {38429818}, issn = {1746-1596}, mesh = {Humans ; *Exosomes ; *Amyotrophic Lateral Sclerosis/diagnosis ; Superoxide Dismutase-1 ; Biomarkers ; DNA-Binding Proteins ; Disease Progression ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Due to the limited knowledge about potential biomarkers that help in early diagnosis and monitoring disease progression, today's diagnoses are based on ruling out other diseases, neurography, and electromyography examination, which takes a time-consuming procedure.<br><br>METHODS: PubMed, ScienceDirect, and Web of Science were explored to extract articles published from January 2015 to June 2023. In the searching strategy following keywords were included; amyotrophic lateral sclerosis, biomarkers, cerebrospinal fluid, serum, and plama.<br><br>RESULTS: A total number of 6 studies describing fluid-based exosomal biomarkers were included in this study. Aggregated proteins including SOD1, TDP-43, pTDP-43, and FUS could be detected in the microvesicles (MVs). Moreover, TDP-43 and NFL extracted from plasma exosomes could be used as prognostic biomarkers. Also, downregulated miR-27a-3p detected through exoEasy Maxi and exoQuick Kit in the plasma could be measured as a diagnostic biomarker. Eventually, the upregulated level of CORO1A could be used to monitor disease progression.<br><br>CONCLUSION: Based on the results, each biomarker alone is insufficient to evaluate ALS. CNS-derived exosomes contain multiple ALS-related biomarkers (SOD1, TDP-43, pTDP-43, FUS, and miRNAs) that are detectable in cerebrospinal fluid and blood is a proper alternation. Exosome detecting kits listed as exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus, and Exo-Flow, are helpful to reach this purpose.}, }
@article {pmid38429379, year = {2024}, author = {de Luzy, IR and Lee, MK and Mobley, WC and Studer, L}, title = {Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.}, journal = {Nature aging}, volume = {4}, number = {3}, pages = {309-318}, pmid = {38429379}, issn = {2662-8465}, support = {ASAP-020370//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Aging ; Cellular Senescence/physiology ; Neurons ; *Pluripotent Stem Cells ; }, abstract = {Age remains the central risk factor for many neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Although the mechanisms of aging are complex, the age-related accumulation of senescent cells in neurodegeneration is well documented and their clearance can alleviate disease-related features in preclinical models. Senescence-like characteristics are observed in both neuronal and glial lineages, but their relative contribution to aging and neurodegeneration remains unclear. Human pluripotent stem cell-derived neurons provide an experimental model system to induce neuronal senescence. However, the extensive heterogeneity in the profile of senescent neurons and the methods to assess senescence remain major challenges. Here, we review the evidence of cellular senescence in neuronal aging and disease, discuss human pluripotent stem cell-based model systems used to investigate neuronal senescence and propose a panel of cellular and molecular hallmarks to characterize senescent neurons. Understanding the role of neuronal senescence may yield novel therapeutic opportunities in neurodegenerative disease.}, }
@article {pmid38428126, year = {2024}, author = {Wahbeh, F and Restifo, D and Laws, S and Pawar, A and Parikh, NS}, title = {Impact of tobacco smoking on disease-specific outcomes in common neurological disorders: A scoping review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {10-18}, pmid = {38428126}, issn = {1532-2653}, support = {K23 AG073524/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation ; Smoking/adverse effects/epidemiology ; Tobacco Smoking ; *Stroke/epidemiology/etiology/therapy ; *Multiple Sclerosis ; }, abstract = {Although the association of smoking with the risk of incident neurological disorders is well established, less is known about the impact of smoking and smoking cessation on outcomes of these conditions. The objective of this scoping review was to synthesize what is known about the impact of smoking and smoking cessation on disease-specific outcomes for seven common neurological disorders. We included 67 studies on the association of smoking and smoking cessation on disease-specific outcomes. For multiple sclerosis, smoking was associated with greater clinical and radiological disease progression, relapses, risk for disease-related death, cognitive decline, and mood symptoms, in addition to reduced treatment effectiveness. For stroke and transient ischemic attack, smoking was associated with greater rates of stroke recurrence, post-stroke cardiovascular outcomes, post-stroke mortality, post-stroke cognitive impairment, and functional impairment. In patients with cognitive impairment and dementia, smoking was associated with faster cognitive decline, and smoking was also associated with greater cognitive decline in Parkinson's disease, but not motor symptom worsening. Patients with amyotrophic lateral sclerosis who smoked faced increased mortality. Last, in patients with cluster headache, smoking was associated with more frequent and longer cluster attack periods. Conversely, for multiple sclerosis and stroke, smoking cessation was associated with improved disease-specific outcomes. In summary, whereas smoking is detrimentally associated with disease-specific outcomes in common neurological conditions, there is growing evidence that smoking cessation may improve outcomes. Effective smoking cessation interventions should be leveraged in the management of common neurological disorders to improve patient outcomes.}, }
@article {pmid38417517, year = {2024}, author = {Li, M and Qiu, J and Yan, G and Zheng, X and Li, A}, title = {How does the neurotoxin β-N-methylamino-L-alanine exist in biological matrices and cause toxicity?.}, journal = {The Science of the total environment}, volume = {922}, number = {}, pages = {171255}, doi = {10.1016/j.scitotenv.2024.171255}, pmid = {38417517}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurotoxins/chemistry ; *Amino Acids, Diamino/toxicity/chemistry ; Cyanobacteria Toxins ; Oxidative Stress ; }, abstract = {The neurotoxin β-N-methylamino-L-alanine (BMAA) has been deemed as a risk factor for some neurodegenerative diseases such as amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). This possible link has been proved in some primate models and cell cultures with the appearance that BMAA exposure can cause excitotoxicity, formation of protein aggregates, and/or oxidative stress. The neurotoxin BMAA extensively exists in the environment and can be transferred through the food web to human beings. In this review, the occurrence, toxicological mechanisms, and characteristics of BMAA were comprehensively summarized, and proteins and peptides were speculated as its possible binding substances in biological matrices. It is difficult to compare the published data from previous studies due to the inconsistent analytical methods and components of BMAA. The binding characteristics of BMAA should be focused on to improve our understanding of its health risk to human health in the future.}, }
@article {pmid38415696, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {What is the extent of reliability and validity evidence for screening tools for cognitive and behavioral change in people with ALS? A systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, pmid = {38415696}, issn = {2167-9223}, abstract = {Objective: This systematic review provides an updated summary of the existing literature on the validity of screening tools for cognitive and behavioral impairment in people with Amyotrophic Lateral Sclerosis (pwALS), and also focuses on their reliability. Method: The following cognitive and behavioral screening tools were assessed in this review: the Edinburgh Cognitive and Behavioral ALS Screen (ECAS); the ALS Cognitive Behavioral Screen (ALS-CBS), the Mini Addenbrooke's Cognitive Examination (Mini-ACE), the Beaumont Behavioral Interview (BBI); the MND Behavior Scale (MiND-B); and the ALS-FTD Questionnaire (ALS-FTD-Q). A search, using Medline, PsychINFO and Embase (21/09/2023), generated 37 results after exclusion criteria were applied. Evidence of internal consistency, item-total correlations, inter-rater reliability, clinical validity, convergent validity, and structural validity were extracted and assessed and risk of bias was evaluated. Results: The cognitive component of the ECAS was the tool with most evidence of reliability and validity for the assessment of cognitive impairment in ALS. It is well-suited to accommodate physical symptoms of ALS. For behavioral assessment, the BBI or ALS-FTD-Q had the most evidence of reliability and validity. The BBI is more thorough, but the ALS-FTD-Q is briefer. Conclusions: There is good but limited evidence for the reliability and validity of cognitive and behavioral screens. Further evidence of clinical and convergent validity would increase confidence in their clinical and research use.}, }
@article {pmid38414054, year = {2024}, author = {Ma, YY and Li, X and Yu, JT and Wang, YJ}, title = {Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {12}, pmid = {38414054}, issn = {2047-9158}, support = {92249305//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; *Parkinson Disease/therapy ; }, abstract = {The aetiologies and origins of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), are complex and multifaceted. A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases. Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases. This narrative review examines the alterations in the gut microbiome in AD, PD, ALS and HD, highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases. Processes that mediate the gut microbiome-brain communication in neurodegenerative diseases, including the immunological, vagus nerve and circulatory pathways, are evaluated. Furthermore, we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites, including diets, probiotics and prebiotics, microbial metabolites, antibacterials and faecal microbiome transplantation. Finally, current challenges and future directions are discussed.}, }
@article {pmid38411425, year = {2024}, author = {D'Urso, B and Weil, R and Génin, P}, title = {[Optineurin and mitochondrial dysfunction in neurodegeneration].}, journal = {Medecine sciences : M/S}, volume = {40}, number = {2}, pages = {167-175}, doi = {10.1051/medsci/2023220}, pmid = {38411425}, issn = {1958-5381}, mesh = {Humans ; Ubiquitin ; *Amyotrophic Lateral Sclerosis/genetics ; Cytosol ; Mitochondria/genetics ; *Mitochondrial Diseases ; }, abstract = {Optineurin (OPTN) is a multifunctional protein playing a crucial role as a receptor in selective autophagy. OPTN gene mutations are linked to diseases such as normal-tension glaucoma and amyotrophic lateral sclerosis. Recognized as a critical receptor for mitophagy, OPTN is pivotal in selectively degrading damaged mitochondria. This process is essential to prevent their accumulation, the generation of reactive oxygen species, and the release of pro-apoptotic factors. Mitophagy's quality control is governed by the PINK1 kinase and the cytosolic ubiquitin ligase Parkin, whose mutations are associated with Parkinson's disease. This review highlights recent insights emphasizing OPTN's role in mitophagy and its potential involvement in neurodegenerative diseases.}, }
@article {pmid38411261, year = {2024}, author = {Sakowski, SA and Koubek, EJ and Chen, KS and Goutman, SA and Feldman, EL}, title = {Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {635-652}, pmid = {38411261}, issn = {1531-8249}, support = {R01TS000327/CC/CDC HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01TS000289/CC/CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Exposome ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; }, abstract = {Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.}, }
@article {pmid38401571, year = {2024}, author = {Cheng, F and Chapman, T and Zhang, S and Morsch, M and Chung, R and Lee, A and Rayner, SL}, title = {Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102246}, doi = {10.1016/j.arr.2024.102246}, pmid = {38401571}, issn = {1872-9649}, mesh = {Humans ; RNA Splicing ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; DNA-Binding Proteins/genetics/metabolism ; Neurons/metabolism ; }, abstract = {TAR DNA binding protein-43 (TDP-43) is a key component in RNA splicing which plays a crucial role in the aging process. In neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, TDP-43 can be mutated, mislocalised out of the nucleus of neurons and glial cells and form cytoplasmic inclusions. These TDP-43 alterations can lead to its RNA splicing dysregulation and contribute to mis-splicing of various types of RNA, such as mRNA, microRNA, and circular RNA. These changes can result in the generation of an altered transcriptome and proteome within cells, ultimately changing the diversity and quantity of gene products. In this review, we summarise the findings of novel atypical RNAs resulting from TDP-43 dysfunction and their potential as biomarkers or targets for therapeutic development.}, }
@article {pmid38401191, year = {2024}, author = {Lemon, R}, title = {The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {160}, number = {}, pages = {56-67}, doi = {10.1016/j.clinph.2024.02.001}, pmid = {38401191}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Pyramidal Tracts/physiology ; *Amyotrophic Lateral Sclerosis ; Motor Neurons/physiology ; Primates ; Axons ; }, abstract = {Corticospinal neurons located in motor areas of the cerebral neocortex project corticospinal axons which synapse with the spinal network; a parallel corticobulbar system projects to the cranial motor network and to brainstem motor pathways. The primate corticospinal system has a widespread cortical origin and an extensive range of different fibre diameters, including thick, fast-conducting axons. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand alpha motoneurons are a recent evolutionary feature, that is well developed in dexterous primates and particularly in humans. Many of these projections originate from the caudal subdivision of area 4 ('new' M1: primary motor cortex). They arise from corticospinal neurons of varied soma size, including those with fast- and relatively slow-conducting axons. This CM system has been shown to be involved in the control of skilled movements, carried out with fractionation of the distal extremities and at low force levels. During movement, corticospinal neurons are activated quite differently from 'lower' motoneurons, and there is no simple or fixed functional relationship between a so-called 'upper' motoneuron and its target lower motoneuron. There are key differences in the organisation and function of the corticospinal and CM system in primates versus non-primates, such as rodents. These differences need to be recognized when making the choice of animal model for understanding disorders such as amyotrophic lateral sclerosis (ALS). In this neurodegenerative brain disease there is a selective loss of fast-conducting corticospinal axons, and their synaptic connections, and this is reflected in responses to non-invasive cortical stimuli and measures of cortico-muscular coherence. The loss of CM connections influencing distal limb muscles results in a differential loss of muscle strength or 'split-hand' phenotype. Importantly, there is also a unique impairment in the coordination of skilled hand tasks that require fractionation of digit movement. Scores on validated tests of skilled hand function could be used to assess disease progression.}, }
@article {pmid38399458, year = {2024}, author = {Al Shaer, D and Al Musaimi, O and Albericio, F and de la Torre, BG}, title = {2023 FDA TIDES (Peptides and Oligonucleotides) Harvest.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399458}, issn = {1424-8247}, abstract = {A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.}, }
@article {pmid38399373, year = {2024}, author = {Cha, Y and Kagalwala, MN and Ross, J}, title = {Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399373}, issn = {1424-8247}, abstract = {Recent advances in machine learning hold tremendous potential for enhancing the way we develop new medicines. Over the years, machine learning has been adopted in nearly all facets of drug discovery, including patient stratification, lead discovery, biomarker development, and clinical trial design. In this review, we will discuss the latest developments linking machine learning and CNS drug discovery. While machine learning has aided our understanding of chronic diseases like Alzheimer's disease and Parkinson's disease, only modest effective therapies currently exist. We highlight promising new efforts led by academia and emerging biotech companies to leverage machine learning for exploring new therapies. These approaches aim to not only accelerate drug development but to improve the detection and treatment of neurodegenerative diseases.}, }
@article {pmid38397838, year = {2024}, author = {Peggion, C and Calì, T and Brini, M}, title = {Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397838}, issn = {2076-3921}, abstract = {Neurodegenerative diseases (NDs) encompass an assorted array of disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, each characterised by distinct clinical manifestations and underlying pathological mechanisms. While some cases have a genetic basis, many NDs occur sporadically. Despite their differences, these diseases commonly feature chronic neuroinflammation as a hallmark. Consensus has recently been reached on the possibility that mitochondria dysfunction and protein aggregation can mutually contribute to the activation of neuroinflammatory response and thus to the onset and progression of these disorders. In the present review, we discuss the contribution of mitochondria dysfunction and neuroinflammation to the aetiology and progression of NDs, highlighting the possibility that new potential therapeutic targets can be identified to tackle neurodegenerative processes and alleviate the progression of these pathologies.}, }
@article {pmid38396996, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches.}, journal = {International journal of molecular sciences}, volume = {25}, number = {4}, pages = {}, pmid = {38396996}, issn = {1422-0067}, support = {R01 DK129241 and DK126662/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy/pathology ; *Parkinson Disease/genetics/therapy/pathology ; *Alzheimer Disease/pathology ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs-amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.}, }
@article {pmid38396946, year = {2024}, author = {Anilkumar, AK and Vij, P and Lopez, S and Leslie, SM and Doxtater, K and Khan, MM and Yallapu, MM and Chauhan, SC and Maestre, GE and Tripathi, MK}, title = {Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {4}, pages = {}, pmid = {38396946}, issn = {1422-0067}, support = {R16 GM146696/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/pathology ; *RNA, Long Noncoding/genetics ; *Alzheimer Disease ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.}, }
@article {pmid38393299, year = {2024}, author = {García-Parra, B and Guiu, JM and Povedano, M and Mariño, EL and Modamio, P}, title = {Geographical distribution of clinical trials in amyotrophic lateral sclerosis: a scoping review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {376-381}, doi = {10.1080/21678421.2024.2320881}, pmid = {38393299}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/therapy ; Belgium ; France ; Germany ; United Kingdom ; }, abstract = {Introduction: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.}, }
@article {pmid38392286, year = {2024}, author = {Jackson, WS and Bauer, S and Kaczmarczyk, L and Magadi, SS}, title = {Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies.}, journal = {Biology}, volume = {13}, number = {2}, pages = {}, pmid = {38392286}, issn = {2079-7737}, support = {grant # 990868//the Konung Gustaf V:s och Drottning Victorias Stiftelse; the Wallenberg Center for Molecular Medicine;the Hereditary Disease Foundation/ ; }, abstract = {Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.}, }
@article {pmid38391754, year = {2024}, author = {Leão Batista Simões, J and Webler Eichler, S and Raitz Siqueira, ML and de Carvalho Braga, G and Bagatini, MD}, title = {Amyotrophic Lateral Sclerosis in Long-COVID Scenario and the Therapeutic Potential of the Purinergic System in Neuromodulation.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391754}, issn = {2076-3425}, support = {Proj. No 404256/2021-0 and 310606/2021-7).//National Council for Scientific and Technological Development/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves the degeneration of motor neurons and debilitating and possibly fatal symptoms. The COVID-19 pandemic directly affected the quality of life of this group, and the SARS-CoV-2 infection accelerated the present neuroinflammatory process. Furthermore, studies indicate that the infection may have led to the development of the pathology. Thus, the scenario after this pandemic presents "long-lasting COVID" as a disease that affects people who have been infected. From this perspective, studying the pathophysiology behind ALS associated with SARS-CoV-2 infection and possible supporting therapies becomes necessary when we understand the impact on the quality of life of these patients. Thus, the purinergic system was trained to demonstrate how its modulation can add to the treatment, reduce disease progression, and result in better prognoses. From our studies, we highlight the P2X7, P2X4, and A2AR receptors and how their activity can directly influence the ALS pathway.}, }
@article {pmid38391732, year = {2024}, author = {Yang, K and Liu, Y and Zhang, M}, title = {The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391732}, issn = {2076-3425}, support = {82271478//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes displaying reactive phenotypes are characterized by their ability to remodel morphologically, molecularly, and functionally in response to pathological stimuli. This process results in the loss of their typical astrocyte functions and the acquisition of neurotoxic or neuroprotective roles. A growing body of research indicates that these reactive astrocytes play a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS), involving calcium homeostasis imbalance, mitochondrial dysfunction, abnormal lipid and lactate metabolism, glutamate excitotoxicity, etc. This review summarizes the characteristics of reactive astrocytes, their role in the pathogenesis of ALS, and recent advancements in astrocyte-targeting strategies.}, }
@article {pmid38390994, year = {2024}, author = {Nájera-Maldonado, JM and Salazar, R and Alvarez-Fitz, P and Acevedo-Quiroz, M and Flores-Alfaro, E and Hernández-Sotelo, D and Espinoza-Rojo, M and Ramírez, M}, title = {Phenolic Compounds of Therapeutic Interest in Neuroprotection.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {227-246}, pmid = {38390994}, issn = {2039-4713}, support = {A1-S-34290 to Monica Ramirez//Consejo Nacional de Humanidades, Ciencias y Tecnolog&#xed;as/ ; }, abstract = {The number of elderly people is projected to double in the next 50 years worldwide, resulting in an increased prevalence of neurodegenerative diseases. Aging causes changes in brain tissue homeostasis, thus contributing to the development of neurodegenerative disorders. Current treatments are not entirely effective, so alternative treatments or adjuvant agents are being actively sought. Antioxidant properties of phenolic compounds are of particular interest for neurodegenerative diseases whose psychopathological mechanisms strongly rely on oxidative stress at the brain level. Moreover, phenolic compounds display other advantages such as the permeability of the blood-brain barrier (BBB) and the interesting molecular mechanisms that we reviewed in this work. We began by briefly outlining the physiopathology of neurodegenerative diseases to understand the mechanisms that result in irreversible brain damage, then we provided an overall classification of the phenolic compounds that would be addressed later. We reviewed in vitro and in vivo studies, as well as some clinical trials in which neuroprotective mechanisms were demonstrated in models of different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemia, and traumatic brain injury (TBI).}, }
@article {pmid38382884, year = {2024}, author = {Jiao, LL and Dong, HL and Liu, MM and Wu, PL and Cao, Y and Zhang, Y and Gao, FG and Zhu, HY}, title = {The potential roles of salivary biomarkers in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106442}, doi = {10.1016/j.nbd.2024.106442}, pmid = {38382884}, issn = {1095-953X}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Reproducibility of Results ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Huntington Disease/diagnosis ; Biomarkers ; }, abstract = {Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, β-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.}, }
@article {pmid38381656, year = {2024}, author = {Wang, XX and Chen, WZ and Li, C and Xu, RS}, title = {Current potential pathogenic mechanisms of copper-zinc superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {38381656}, issn = {2191-0200}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN and LMN) innervating the muscles of the trunk, extremities, head, neck and face in cerebrum, brain stem and spinal cord, which results in the progressive weakness, atrophy and fasciculation of muscle innervated by the related UMN and LMN, accompanying with the pathological signs leaded by the cortical spinal lateral tract lesion. The pathogenesis about ALS is not fully understood, and no specific drugs are available to cure and prevent the progression of this disease at present. In this review, we reviewed the structure and associated functions of copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 is crucial to the pathogenesis of ALS, and outline the pathogenic mechanisms of SOD1 in ALS that have been identified at recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, axonal transport disruption, prion-like propagation, and the non-cytologic toxicity of glial cells. This review will help us to deeply understand the current progression in this field of SOD1 pathogenic mechanisms in ALS.}, }
@article {pmid38380436, year = {2024}, author = {Nakaso, K}, title = {Roles of Microglia in Neurodegenerative Diseases.}, journal = {Yonago acta medica}, volume = {67}, number = {1}, pages = {1-8}, pmid = {38380436}, issn = {0513-5710}, abstract = {In recent years, microglia have attracted attention owing to their roles in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia, which are brain-resident macrophages, not only act as immune cells but also perform other functions in the body. Interestingly, they exert contrasting effects on different neurodegenerative diseases. In addition to the previously reported M1 (toxic) and M2 (protective) types, microglia now also include disease-associated microglia owing to a more elaborate classification. Understanding this detailed classification is necessary to elucidate the association between microglia and neurodegenerative diseases. In this review, we discuss the diverse roles of microglia in neurodegenerative diseases and highlight their potential as therapeutic targets.}, }
@article {pmid38378992, year = {2024}, author = {Song, M and Qiang, Y and Zhao, X and Song, F}, title = {Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {38378992}, issn = {1559-1182}, abstract = {Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.}, }
@article {pmid38378788, year = {2024}, author = {Rim, C and You, MJ and Nahm, M and Kwon, MS}, title = {Emerging role of senescent microglia in brain aging-related neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {10}, pmid = {38378788}, issn = {2047-9158}, support = {2023R1A2C1006622//National Research Foundation (NRF)/ ; RS-2023-00265515//National Research Foundation (NRF)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; Microglia/pathology ; Brain/pathology ; Cellular Senescence ; *Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain aging and the pathogenesis of these conditions remains inadequately understood. Cellular senescence is considered to contribute to cellular dysfunction and inflammaging. According to the threshold theory of senescent cell accumulation, the vulnerability to neurodegenerative diseases is associated with the rates of senescent cell generation and clearance within the brain. Given the role of microglia in eliminating senescent cells, the accumulation of senescent microglia may lead to the acceleration of brain aging, contributing to inflammaging and increased vulnerability to neurodegenerative diseases. In this review, we propose the idea that the senescence of microglia, which is notably vulnerable to aging, could potentially serve as a central catalyst in the progression of neurodegenerative diseases. The senescent microglia are emerging as a promising target for mitigating neurodegenerative diseases.}, }
@article {pmid38370434, year = {2024}, author = {Chen, C and Qi, J and Li, Y and Li, D and Wu, L and Li, R and Chen, Q and Sun, N}, title = {Applications of Raman spectroscopy in the diagnosis and monitoring of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1301107}, pmid = {38370434}, issn = {1662-4548}, abstract = {Raman scattering is an inelastic light scattering that occurs in a manner reflective of the molecular vibrations of molecular structures and chemical conditions in a given sample of interest. Energy changes in the scattered light can be assessed to determine the vibration mode and associated molecular and chemical conditions within the sample, providing a molecular fingerprint suitable for sample identification and characterization. Raman spectroscopy represents a particularly promising approach to the molecular analysis of many diseases owing to clinical advantages including its instantaneous nature and associated high degree of stability, as well as its ability to yield signal outputs corresponding to a single molecule type without any interference from other molecules as a result of its narrow peak width. This technology is thus ideally suited to the simultaneous assessment of multiple analytes. Neurodegenerative diseases represent an increasingly significant threat to global public health owing to progressive population aging, imposing a severe physical and social burden on affected patients who tend to develop cognitive and/or motor deficits beginning between the ages of 50 and 70. Owing to a relatively limited understanding of the etiological basis for these diseases, treatments are lacking for the most common neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The present review was formulated with the goal of briefly explaining the principle of Raman spectroscopy and discussing its potential applications in the diagnosis and evaluation of neurodegenerative diseases, with a particular emphasis on the research prospects of this novel technological platform.}, }
@article {pmid38369520, year = {2024}, author = {Adashek, JJ and Pandya, C and Maragakis, NJ and De, P and Cohen, PR and Kato, S and Kurzrock, R}, title = {Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {74}, pmid = {38369520}, issn = {1741-7015}, support = {U10 CA180888/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neoplasms/genetics ; *Neuregulin-1/genetics/metabolism ; *Receptor, ErbB-4/genetics/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions.<br><br>MAIN BODY: Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS.<br><br>CONCLUSION: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.}, }
@article {pmid38368936, year = {2024}, author = {Herman, M and Randall, GW and Spiegel, JL and Maldonado, DJ and Simoes, S}, title = {Endo-lysosomal dysfunction in neurodegenerative diseases: opinion on current progress and future direction in the use of exosomes as biomarkers.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {379}, number = {1899}, pages = {20220387}, pmid = {38368936}, issn = {1471-2970}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Exosomes ; *Alzheimer Disease/diagnosis ; Lysosomes/metabolism ; Biomarkers/metabolism ; }, abstract = {Over the past two decades, increased research has highlighted the connection between endosomal trafficking defects and neurodegeneration. The endo-lysosomal network is an important, complex cellular system specialized in the transport of proteins, lipids, and other metabolites, essential for cell homeostasis. Disruption of this pathway is linked to a wide range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and frontotemporal dementia. Furthermore, there is strong evidence that defects in this pathway create opportunities for diagnostic and therapeutic intervention. In this Opinion piece, we concisely address the role of endo-lysosomal dysfunction in five neurodegenerative diseases and discuss how future research can investigate this intracellular pathway, including extracellular vesicles with a specific focus on exosomes for the identification of novel disease biomarkers. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.}, }
@article {pmid38367748, year = {2024}, author = {La Cognata, V and Morello, G and Guarnaccia, M and Cavallaro, S}, title = {The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology.}, journal = {Progress in neurobiology}, volume = {235}, number = {}, pages = {102587}, doi = {10.1016/j.pneurobio.2024.102587}, pmid = {38367748}, issn = {1873-5118}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Signal Transduction ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS. Findings in preclinical models implicate these signaling pathways in motor neuron toxicity and neuroprotection, while in ALS patients dysregulation of CXCLs/CXCRs has been shown at both central and peripheral levels. Immunological monitoring of CXC-ligands in ALS may allow tracking of disease progression, while pharmacological modulation of CXC-receptors provides a novel therapeutic strategy. A deeper understanding of the interplay between CXC-mediated neuroinflammation and ALS is crucial to advance research into treatments for this debilitating uncurable disorder.}, }
@article {pmid38367681, year = {2024}, author = {Arsuffi-Marcon, R and Souza, LG and Santos-Miranda, A and Joviano-Santos, JV}, title = {Neurotoxicity of Pyrethroids in neurodegenerative diseases: From animals' models to humans' studies.}, journal = {Chemico-biological interactions}, volume = {391}, number = {}, pages = {110911}, doi = {10.1016/j.cbi.2024.110911}, pmid = {38367681}, issn = {1872-7786}, mesh = {Animals ; Humans ; *Pyrethrins/toxicity ; *Insecticides/toxicity ; *Neurodegenerative Diseases/chemically induced ; *Neurotoxicity Syndromes ; *Pesticides/toxicity ; Mammals ; }, abstract = {Neurodegenerative diseases are associated with diverse symptoms, both motor and mental. Genetic and environmental factors can trigger neurodegenerative diseases. Chemicals as pesticides are constantly used in agriculture and also domestically. In this regard, pyrethroids (PY), are a class of insecticides in which its main mechanism of action is through disruption of voltage-dependent sodium channels function in insects. However, in mammals, they can also induce oxidative stress and enzyme dysfunction. This review investigates the association between PY and neurodegenerative diseases as Alzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis, and Autism in animal models and humans. Published works using specific and non-specific models for these diseases were selected. We showed a tendency toward the development and/or aggravating of these neurodegenerative diseases following exposure to PYs. In animal models, the biochemical mechanisms of the diseases and their interaction with the insecticides are more deeply investigated. Nonetheless, only a few studies considered the specific model for each type of disease to analyze the impacts of the exposure. The choice of a specific model during the research is an important step and our review highlights the knowledge gaps of PYs effects using these models reinforcing the importance of them during the design of the experiments.}, }
@article {pmid38367047, year = {2024}, author = {Sun, W and Liu, SH and Wei, XJ and Sun, H and Ma, ZW and Yu, XF}, title = {Potential of neuroimaging as a biomarker in amyotrophic lateral sclerosis: from structure to metabolism.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2238-2257}, pmid = {38367047}, issn = {1432-1459}, support = {No. JLSWSRCZX2023-13//the Medical and Health Talents Special Foundation of Jilin Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Humans ; *Neuroimaging/methods/standards ; *Biomarkers/metabolism ; Brain/diagnostic imaging/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. The development of ALS involves metabolite alterations leading to tissue lesions in the nervous system. Recent advances in neuroimaging have significantly improved our understanding of the underlying pathophysiology of ALS, with findings supporting the corticoefferent axonal disease progression theory. Current studies on neuroimaging in ALS have demonstrated inconsistencies, which may be due to small sample sizes, insufficient statistical power, overinterpretation of findings, and the inherent heterogeneity of ALS. Deriving meaningful conclusions solely from individual imaging metrics in ALS studies remains challenging, and integrating multimodal imaging techniques shows promise for detecting valuable ALS biomarkers. In addition to giving an overview of the principles and techniques of different neuroimaging modalities, this review describes the potential of neuroimaging biomarkers in the diagnosis and prognostication of ALS. We provide an insight into the underlying pathology, highlighting the need for standardized protocols and multicenter collaborations to advance ALS research.}, }
@article {pmid38364912, year = {2024}, author = {Du, L and Roy, S and Wang, P and Li, Z and Qiu, X and Zhang, Y and Yuan, J and Guo, B}, title = {Unveiling the future: Advancements in MRI imaging for neurodegenerative disorders.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102230}, doi = {10.1016/j.arr.2024.102230}, pmid = {38364912}, issn = {1872-9649}, mesh = {Humans ; *Diffusion Tensor Imaging/methods ; Artificial Intelligence ; Brain/pathology ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/pathology ; }, abstract = {Neurodegenerative disorders represent a significant and growing global health challenge, necessitating continuous advancements in diagnostic tools for accurate and early detection. This work explores the recent progress in Magnetic Resonance Imaging (MRI) techniques and their application in the realm of neurodegenerative disorders. The introductory section provides a comprehensive overview of the study's background, significance, and objectives. Recognizing the current challenges associated with conventional MRI, the manuscript delves into advanced imaging techniques such as high-resolution structural imaging (HR-MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and positron emission tomography-MRI (PET-MRI) fusion. Each technique is critically examined regarding its potential to address theranostic limitations and contribute to a more nuanced understanding of the underlying pathology. A substantial portion of the work is dedicated to exploring the applications of advanced MRI in specific neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS). In addressing the future landscape, the manuscript examines technological advances, including the integration of machine learning and artificial intelligence in neuroimaging. The conclusion summarizes key findings, outlines implications for future research, and underscores the importance of these advancements in reshaping our understanding and approach to neurodegenerative disorders.}, }
@article {pmid38357638, year = {2024}, author = {Gerritzen, EV and Lee, AR and McDermott, O and Coulson, N and Orrell, M}, title = {Online peer support for people with Amyotrophic Lateral Sclerosis (ALS): a narrative synthesis systematic review.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1138530}, pmid = {38357638}, issn = {2673-253X}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) significantly impacts the lives of people with the diagnosis and their families. A supportive social environment is important for people with ALS to adopt effective coping strategies and health behaviours, and reduce depressive symptoms. Peer support can provide a supportive social environment and can happen in-person and online. Advantages of online peer support are that people can engage from their own home, at their own time and pace, and that it offers a variety of different platforms and modes of communication.<br><br>OBJECTIVES: To (1) explore the benefits and challenges of online peer support for people with ALS, and (2) identify successful elements of online peer support for people with ALS.<br><br>METHODS: The method selected for this systematic review was a narrative synthesis. Six databases were systematically searched in April 2020 for articles published between 1989 and 2020. The search was updated in June 2022. The quality of the included studies was assessed with the Critical Appraisal Skills Programme qualitative research checklist.<br><br>RESULTS: 10,987 unique articles were identified through the systematic database search. Of those, 9 were included in this review. One of the main benefits of online peer support was that people could communicate using text rather than needing verbal communication, which can be challenging for some with ALS. Successful elements included using profile pages and graphics to identify others with similar or relevant experiences. Challenges included ALS symptoms which could make it difficult to use technological devices.<br><br>CONCLUSIONS: Peer support can provide a non-judgmental and supportive environment for people with ALS, in which they can exchange experiences and emotional support, which can help people in developing adaptive coping strategies. However, ALS symptoms may make it more difficult for people to use technological devices and engage in online peer support. More research is needed to identify what kind of specific barriers people with ALS experience, and how these could be overcome.}, }
@article {pmid38354985, year = {2024}, author = {Zamani, A and Thomas, E and Wright, DK}, title = {Sex biology in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102228}, doi = {10.1016/j.arr.2024.102228}, pmid = {38354985}, issn = {1872-9649}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Brain/pathology ; Biology ; }, abstract = {Although sex differences in amyotrophic lateral sclerosis (ALS) have not been studied systematically, numerous clinical and preclinical studies have shown sex to be influential in disease prognosis. Moreover, with the development of advanced imaging tools, the difference between male and female brain in structure and function and their response to neurodegeneration are more definitive. As discussed in this review, ALS patients exhibit a sex bias pertaining to the features of the disease, and their clinical, pathological, (and pathophysiological) phenotypes. Several epidemiological studies have indicated that this sex disparity stems from various aetiologies, including sex-specific brain structure and neural functioning, genetic predisposition, age, gonadal hormones, susceptibility to traumatic brain injury (TBI)/head trauma and lifestyle factors.}, }
@article {pmid38350967, year = {2024}, author = {Rodriguez-Mogeda, C and van Ansenwoude, CMJ and van der Molen, L and Strijbis, EMM and Mebius, RE and de Vries, HE}, title = {The role of CD56[bright] NK cells in neurodegenerative disorders.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {48}, pmid = {38350967}, issn = {1742-2094}, mesh = {Humans ; Killer Cells, Natural ; Cytokines ; Cell Differentiation ; *Antineoplastic Agents ; *Neurodegenerative Diseases ; }, abstract = {Emerging evidence suggests a potential role for natural killer (NK) cells in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise function of NK cells in these diseases remains ambiguous. The existence of two NK cell subsets, CD56[bright] and CD56[dim] NK cells, complicates the understanding of the contribution of NK cells in neurodegeneration as their functions within the context of neurodegenerative diseases may differ significantly. CD56[bright] NK cells are potent cytokine secretors and are considered more immunoregulatory and less terminally differentiated than their mostly cytotoxic CD56[dim] counterparts. Hence, this review focusses on NK cells, specifically on CD56[bright] NK cells, and their role in neurodegenerative diseases. Moreover, it explores the mechanisms underlying their ability to enter the central nervous system. By consolidating current knowledge, we aim to provide a comprehensive overview on the role of CD56[bright] NK cells in neurodegenerative diseases. Elucidating their impact on neurodegeneration may have implications for future therapeutic interventions, potentially ameliorating disease pathogenesis.}, }
@article {pmid38349514, year = {2024}, author = {Xu, Y and Lin, F and Liao, G and Sun, J and Chen, W and Zhang, L}, title = {Ripks and Neuroinflammation.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {38349514}, issn = {1559-1182}, support = {81971098//National Natural Science Foundation of China/ ; 82104144//National Natural Science Foundation of China/ ; }, abstract = {Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).}, }
@article {pmid38349395, year = {2024}, author = {Soni, S and Lukhey, MS and Thawkar, BS and Chintamaneni, M and Kaur, G and Joshi, H and Ramniwas, S and Tuli, HS}, title = {A current review on P2X7 receptor antagonist patents in the treatment of neuroinflammatory disorders: a patent review on antagonists.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {38349395}, issn = {1432-1912}, abstract = {Chronic inflammation is defined by an activated microglial state linked to all neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (a motor neuron disease that affects the brain and spinal cord). P2X7 receptors (P2X7R) are ATP-activated ion-gated channels present on microglial surfaces. Prolonged ATP release under pathological settings results in sustained P2X7R activation, which leads to inflammasome development and cytokine release. P2X7R and its enabling roles have recently been linked to neurodegenerative diseases, making it a potential research subject. This research provides an overview of current patents for chemicals, biologics, and medicinal applications. The World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), and the United States Patent and Trademark Office (USPTO) databases were searched for patents using the keywords "P2X7R and Neuroinflammation." During the study period from 2015 to 2021, 103 patents were examined. The countries that protected these innovations were the United States, PCT (Patent Cooperation Treaty states), Europe, Canada, Australia, and India. Janssen Pharmaceutica NV had the most applications, followed by Acetelion Pharmaceuticals LTD., Renovis Inc., Kelly Michael G, Kincaid Jhon, Merck Patent GMBH, H Lundbeck A/S, and many more. The P2X7R is a possible diagnostic and therapeutic target for cancer, pain disorders, and inflammation. For P2X7 R, several compounds have been discovered and are presently the subject of clinical trial investigations. This study featured patents for P2X7R antagonists, which help treat conditions including neuroinflammation.}, }
@article {pmid38348223, year = {2024}, author = {Orfali, R and Alwatban, AZ and Orfali, RS and Lau, L and Chea, N and Alotaibi, AM and Nam, YW and Zhang, M}, title = {Oxidative stress and ion channels in neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1320086}, pmid = {38348223}, issn = {1664-042X}, abstract = {Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson's, Alzheimer's, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington's disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson's disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.}, }
@article {pmid38347638, year = {2024}, author = {Li, W and Li, HL and Wang, JZ and Liu, R and Wang, X}, title = {Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.}, journal = {Cell &amp; bioscience}, volume = {14}, number = {1}, pages = {22}, pmid = {38347638}, issn = {2045-3701}, support = {92049107//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; 31929002//National Natural Science Foundation of China/ ; }, abstract = {Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.}, }
@article {pmid38339149, year = {2024}, author = {Lee, A and Henderson, R and Aylward, J and McCombe, P}, title = {Gut Symptoms, Gut Dysbiosis and Gut-Derived Toxins in ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339149}, issn = {1422-0067}, support = {There were no grant numbers//Wesley Medical Research/ ; There were no grant numbers//MND Research Australia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; Brain ; }, abstract = {Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.}, }
@article {pmid38339035, year = {2024}, author = {Sun, Y and Islam, S and Michikawa, M and Zou, K}, title = {Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339035}, issn = {1422-0067}, support = {C19K07846//The Grant-in-Aid for Scientific Research/ ; 22K07352//The Ministry of Education, Culture, Sports, Science, and Technology, Japan./ ; JP20dk0207050h0001 and JP20de010702//AMED/ ; no//The 24th General Assembly of the Japanese Association of Medical Sciences/ ; no//Daiko Foundation/ ; no//Hirose International Scholarship Foundation/ ; no//Hori Sciences and Arts Foundation/ ; no//Daiwa Securities Foundation/ ; no//Hirose Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Neurodegenerative Diseases/etiology ; Amyloid Precursor Protein Secretases/metabolism ; Presenilin-1/genetics/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Apolipoproteins E ; Presenilin-2/genetics/metabolism ; }, abstract = {Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.}, }
@article {pmid38339026, year = {2024}, author = {Potenza, RL and Armida, M and Popoli, P}, title = {Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339026}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease ; *Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.}, }
@article {pmid38338912, year = {2024}, author = {Duranti, E and Cordani, N and Villa, C}, title = {Edaravone: A Novel Possible Drug for Cancer Treatment?.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338912}, issn = {1422-0067}, mesh = {Humans ; Edaravone/therapeutic use ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; *Neoplasms/drug therapy/chemically induced ; Free Radical Scavengers/pharmacology ; }, abstract = {Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.}, }
@article {pmid38337058, year = {2024}, author = {Choi, BJ and Park, MH and Jin, HK and Bae, JS}, title = {Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.}, journal = {Experimental &amp; molecular medicine}, volume = {56}, number = {2}, pages = {301-310}, pmid = {38337058}, issn = {2092-6413}, mesh = {Animals ; Humans ; Mice ; *Alzheimer Disease/drug therapy ; Brain ; *Multiple Sclerosis ; *Nervous System Diseases ; Sphingomyelin Phosphodiesterase/genetics ; }, abstract = {Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.}, }
@article {pmid38334639, year = {2024}, author = {Cunha-Oliveira, T and Montezinho, L and Simões, RF and Carvalho, M and Ferreiro, E and Silva, FSG}, title = {Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334639}, issn = {2073-4409}, support = {PTDC/MED-FAR/29391/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; POCI-01-0145-FEDER-029391//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; PTDC/BTM-SAL/29297/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; POCI-01-0145-FEDER-029297//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; PTDC/BTM-ORG/0055/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; DL57/2016/CP1448/CT0016//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; CEECIND/00322/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; 2022.00011.CEECIND//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDP/04539/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDB/04539/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDB/00081/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; Motor Neurons/pathology ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.}, }
@article {pmid38334609, year = {2024}, author = {Noori, L and Saqagandomabadi, V and Di Felice, V and David, S and Caruso Bavisotto, C and Bucchieri, F and Cappello, F and Conway de Macario, E and Macario, AJL and Scalia, F}, title = {Putative Roles and Therapeutic Potential of the Chaperone System in Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334609}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Multiple Sclerosis/therapy ; Molecular Chaperones/metabolism ; Heat-Shock Proteins/metabolism ; }, abstract = {The putative pathogenic roles and therapeutic potential of the chaperone system (CS) in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are reviewed to provide a bibliographic and conceptual platform for launching research on the diagnostic and therapeutic applications of CS components. Various studies suggest that dysfunction of the CS contributes to the pathogenesis of ALS and MS, and here, we identify some of the implicated CS members. The physiology and pathophysiology of the CS members can be properly understood if they are studied or experimentally or clinically manipulated for diagnostic or therapeutic purposes, bearing in mind that they belong to a physiological system with multiple interacting and dynamic components, widespread throughout the body, intra- and extracellularly. Molecular chaperones, some called heat shock protein (Hsp), are the chief components of the CS, whose canonical functions are cytoprotective. However, abnormal chaperones can be etiopathogenic factors in a wide range of disorders, chaperonopathies, including ALS and MS, according to the data reviewed. Chaperones typically form teams, and these build functional networks to maintain protein homeostasis, the canonical role of the CS. However, members of the CS also display non-canonical functions unrelated to protein homeostasis. Therefore, chaperones and other members of the CS, if abnormal, may disturb not only protein synthesis, maturation, and migration but also other physiological processes. Thus, in elucidating the role of CS components in ALS and MS, one must look at protein homeostasis abnormalities and beyond, following the clues emerging from the works discussed here.}, }
@article {pmid38334254, year = {2024}, author = {Mohammadi, S and Ghaderi, S and Fatehi, F}, title = {MRI biomarkers and neuropsychological assessments of hippocampal and parahippocampal regions affected by ALS: A systematic review.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {2}, pages = {e14578}, pmid = {38334254}, issn = {1755-5949}, mesh = {Humans ; Diffusion Tensor Imaging/methods ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases/pathology ; *Frontotemporal Dementia ; Magnetic Resonance Imaging ; Hippocampus/pathology ; Biomarkers ; Neuropsychological Tests ; Atrophy/pathology ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive motor and extra-motor neurodegenerative disease. This systematic review aimed to examine MRI biomarkers and neuropsychological assessments of the hippocampal and parahippocampal regions in patients with ALS.<br><br>METHODS: A systematic review was conducted in the Scopus and PubMed databases for studies published between January 2000 and July 2023. The inclusion criteria were (1) MRI studies to assess hippocampal and parahippocampal regions in ALS patients, and (2) studies reporting neuropsychological data in patients with ALS.<br><br>RESULTS: A total of 46 studies were included. Structural MRI revealed hippocampal atrophy, especially in ALS-FTD, involving specific subregions (CA1, dentate gyrus). Disease progression and genetic factors impacted atrophy patterns. Diffusion tensor imaging (DTI) showed increased mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and decreased fractional anisotropy (FA) in the hippocampal tracts and adjacent regions, indicating loss of neuronal and white matter integrity. Functional MRI (fMRI) revealed reduced functional connectivity (FC) between the hippocampus, parahippocampus, and other regions, suggesting disrupted networks. Perfusion MRI showed hypoperfusion in parahippocampal gyri. Magnetic resonance spectroscopy (MRS) found changes in the hippocampus, indicating neuronal loss. Neuropsychological tests showed associations between poorer memory and hippocampal atrophy or connectivity changes. CA1-2, dentate gyrus, and fimbria atrophy were correlated with worse memory.<br><br>CONCLUSIONS: The hippocampus and the connected regions are involved in ALS. Hippocampal atrophy disrupted connectivity and metabolite changes correlate with cognitive and functional decline. Specific subregions can be particularly affected. The hippocampus is a potential biomarker for disease monitoring and prognosis.}, }
@article {pmid38330475, year = {2024}, author = {Stavros, K}, title = {Genetic Myelopathies.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {1}, pages = {119-132}, pmid = {38330475}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Muscular Atrophy, Spinal/diagnosis ; *Spastic Paraplegia, Hereditary/diagnosis ; *Spinal Cord Diseases/diagnosis/genetics/therapy ; }, abstract = {OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy.<br><br>LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia.<br><br>ESSENTIAL POINTS: Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.}, }
@article {pmid38329887, year = {2024}, author = {Sanghai, N and Vuong, B and Burak Berk, A and Afridi, MSK and Tranmer, GK}, title = {Current Small Molecule-Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics.}, journal = {ChemMedChem}, volume = {}, number = {}, pages = {e202300705}, doi = {10.1002/cmdc.202300705}, pmid = {38329887}, issn = {1860-7187}, support = {//Department of Human Anatomy and Cell Science, University of Manitoba/ ; //College of Pharmacy, Department of Pharmacology &amp; Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba/ ; }, abstract = {Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule-based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Further, the highly lipoidal blood-brain barrier (BBB) limits the uptake of many therapeutic molecules into the brain and is a complicating factor in the development of new agents to treat neurodegeneration. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule-based novel approaches to target NDDs over the last few decades, such as designing lipophilic molecules and applying prodrug strategies. Attempts have been made to utilize a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web-based computational tools. To increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal chemists in the pre-clinical phase as a further screening measure of small organic molecules. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs, with the intention of increasing our awareness of neurodegenerative therapeutics.}, }
@article {pmid38325473, year = {2024}, author = {Xu, Y and Nie, J and Lu, C and Hu, C and Chen, Y and Ma, Y and Huang, Y and Lu, L}, title = {Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.}, journal = {The Science of the total environment}, volume = {919}, number = {}, pages = {170670}, doi = {10.1016/j.scitotenv.2024.170670}, pmid = {38325473}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/chemically induced ; *Alzheimer Disease ; *Parkinson Disease/etiology/metabolism ; Brain/metabolism ; Oxidative Stress/physiology ; }, abstract = {Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.}, }
@article {pmid38323662, year = {2024}, author = {Garcés, P and Amaro, A and Montecino, M and van Zundert, B}, title = {Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD.}, journal = {Biochemical Society transactions}, volume = {52}, number = {1}, pages = {123-135}, doi = {10.1042/BST20230257}, pmid = {38323662}, issn = {1470-8752}, mesh = {Animals ; Mice ; Humans ; *Frontotemporal Dementia/metabolism/therapy ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/metabolism ; Polyphosphates ; *Alzheimer Disease ; *Parkinson Disease ; Mammals ; }, abstract = {Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.}, }
@article {pmid38321352, year = {2024}, author = {Sathyamurthy, VH and Nagarajan, Y and Parvathi, VD}, title = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS): A New Axis in Neuronal Degeneration and Regeneration.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {38321352}, issn = {1559-1182}, abstract = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS) are dynamic structures whose physiological interaction is vital to direct life and death of the cell. A bevy of tethering proteins, mitofusin-1/2 (Mfn-1/2), glucose-regulated protein-75 (Grp-75), voltage-dependent anion channel-1 (VDAC1), and dynamic-related protein-1 (Drp1), plays an integral role in establishing and regulating this intricate intracellular communication. Dysregulation of this interplay leads to various neurodegenerative disorders, like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Although there is an absence of a well-defined molecular background that dictates the pathway of MERCS, adequate exploration has resulted in preliminary data that suggests its cardinal role in neuroregeneration. The juxtaposition of mitochondria and ER has a critical function in cell senescence, thus regulating regeneration. Axonal regeneration and brain tissue regeneration, using reactive astrocytes, are studied most extensively. Overexpression of Grp-75 promoted axonal regeneration post a nerve injury. Attempts have been made to exploit MERCS as potential therapeutic drug targets for enhancing neuroregeneration and impeding neurodegeneration. Novel strategies have been developed to aid the delivery of mitochondria into the neuronal cell body, which in turn establishes a network with the presiding ER resulting in contact site formation. The fascinating aspect of this mechanism is that despite the lack of inherent regenerative capacity in neurons, it can be induced by modifying MERCS.}, }
@article {pmid38318532, year = {2024}, author = {Geng, Y and Cai, Q}, title = {Role of C9orf72 hexanucleotide repeat expansions in ALS/FTD pathogenesis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1322720}, pmid = {38318532}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurological disorders that share neurodegenerative pathways and features. The most prevalent genetic causes of ALS/FTD is the GGGGCC hexanucleotide repeat expansions in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene. In this review, we comprehensively summarize the accumulating evidences elucidating the pathogenic mechanism associated with hexanucleotide repeat expansions in ALS/FTD. These mechanisms encompass the structural polymorphism of DNA and transcribed RNA, the formation of RNA foci via phase separation, and the cytoplasmic accumulation and toxicities of dipeptide-repeat proteins. Additionally, the formation of G-quadruplex structures significantly impairs the expression and normal function of the C9orf72 protein. We also discuss the sequestration of specific RNA binding proteins by GGGGCC RNA, which further contributes to the toxicity of C9orf72 hexanucleotide repeat expansions. The deeper understanding of the pathogenic mechanism of hexanucleotide repeat expansions in ALS/FTD provides multiple potential drug targets for these devastating diseases.}, }
@article {pmid38314277, year = {2024}, author = {Mohan, S and Alhazmi, HA and Hassani, R and Khuwaja, G and Maheshkumar, VP and Aldahish, A and Chidambaram, K}, title = {Role of ferroptosis pathways in neuroinflammation and neurological disorders: From pathogenesis to treatment.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24786}, pmid = {38314277}, issn = {2405-8440}, abstract = {Ferroptosis is a newly discovered non-apoptotic and iron-dependent type of cell death. Ferroptosis mainly takes place owing to the imbalance of anti-oxidation and oxidation in the body. It is regulated via a number of factors and pathways both inside and outside the cell. Ferroptosis is closely linked with brain and various neurological disorders (NDs). In the human body, the brain contains the highest levels of polyunsaturated fatty acids, which are known as lipid peroxide precursors. In addition, there is also a connection of glutathione depletion and lipid peroxidation with NDs. There is growing evidence regarding the possible link between neuroinflammation and multiple NDs, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and stroke. Recent studies have demonstrated that disruptions of lipid reactive oxygen species (ROS), glutamate excitatory toxicity, iron homeostasis, and various other manifestations linked with ferroptosis can be identified in various neuroinflammation-mediated NDs. It has also been reported that damage-associated molecular pattern molecules including ROS are generated during the events of ferroptosis and can cause glial activation via activating neuroimmune pathways, which subsequently leads to the generation of various inflammatory factors that play a role in various NDs. This review summarizes the regulation pathways of ferroptosis, the link between ferroptosis as well as inflammation in NDs, and the potential of a range of therapeutic agents that can be used to target ferroptosis and inflammation in the treatment of neurological disorders.}, }
@article {pmid38302810, year = {2024}, author = {Teixeira, LCR and Mamede, I and Luizon, MR and Gomes, KB}, title = {Role of long non-coding RNAs in the pathophysiology of Alzheimer's disease and other dementias.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {270}, pmid = {38302810}, issn = {1573-4978}, mesh = {Humans ; *Alzheimer Disease/genetics ; *RNA, Long Noncoding/genetics ; Amyloid beta-Peptides ; *Frontotemporal Dementia ; }, abstract = {Dementia is the term used to describe a group of cognitive disorders characterized by a decline in memory, thinking, and reasoning abilities that interfere with daily life activities. Examples of dementia include Alzheimer's Disease (AD), Frontotemporal dementia (FTD), Amyotrophic lateral sclerosis (ALS), Vascular dementia (VaD) and Progressive supranuclear palsy (PSP). AD is the most common form of dementia. The hallmark pathology of AD includes formation of β-amyloid (Aβ) oligomers and tau hyperphosphorylation in the brain, which induces neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal apoptosis. Emerging studies have associated long non-coding RNAs (lncRNAs) with the pathogenesis and progression of the neurodegenerative diseases. LncRNAs are defined as RNAs longer than 200 nucleotides that lack the ability to encode functional proteins. LncRNAs play crucial roles in numerous biological functions for their ability to interact with different molecules, such as proteins and microRNAs, and subsequently regulate the expression of their target genes at transcriptional and post-transcriptional levels. In this narrative review, we report the function and mechanisms of action of lncRNAs found to be deregulated in different types of dementia, with the focus on AD. Finally, we discuss the emerging role of lncRNAs as biomarkers of dementias.}, }
@article {pmid38300375, year = {2024}, author = {Sarkar, S and Patranabis, S}, title = {Emerging Role of Extracellular Vesicles in Intercellular Communication in the Brain: Implications for Neurodegenerative Diseases and Therapeutics.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {38300375}, issn = {1559-0283}, abstract = {Extracellular vesicles (EVs) are minute lipid-bilayer sacs discharged by cells, encompassing a diverse array of proteins, nucleic acids, and lipids. The identification of EVs as pivotal agents in intercellular communication has sparked compelling research pathways in the realms of cell biology and neurodegenerative diseases. Utilizing EVs for medicinal reasons has garnered interest due to the adaptability of EV-mediated communication. EVs can be classified based on their physical characteristics, biochemical composition, or cell of origin following purification. This review delves into the primary sub-types of EVs, providing an overview of the biogenesis of each type. Additionally, it explores the diverse environmental conditions triggering EV release and the originating cells, including stem cells and those from the Central Nervous System. Within the brain, EVs play a pivotal role as essential mediators of intercellular communication, significantly impacting synaptic plasticity, brain development, and the etiology of neurological diseases. Their potential diagnostic and therapeutic applications in various brain-related conditions are underscored, given their ability to carry specific cargo. Specially engineered EVs hold promise for treating diverse diseases, including neurodegenerative disorders. This study primarily emphasizes the diagnostic and potential therapeutic uses of EVs in neurological disorders such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Prions disease. It also summarizes innovative techniques for detecting EVs in the brain, suggesting that EVs could serve as non-invasive biomarkers for early detection, disease monitoring, and prognosis in neurological disorders.}, }
@article {pmid38291418, year = {2024}, author = {Cai, Y and Peng, Z and He, Q and Sun, P}, title = {Behavioral variant frontotemporal dementia associated with GRN and ErbB4 gene mutations: a case report and literature review.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {43}, pmid = {38291418}, issn = {1755-8794}, mesh = {Male ; Humans ; Middle Aged ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Positron Emission Tomography Computed Tomography ; Progranulins/genetics ; Mutation ; }, abstract = {OBJECTIVE: To report the clinical manifestation and genetic characteristics of a patient having frontotemporal dementia (FTD) with abnormal behavior and unstable walking.<br><br>METHODS: The clinical and imaging features of a patient who was eventually diagnosed with FTD were analyzed. The patient's neuropsychological, PET-CT, electromyography, and genetic data were collected. Furthermore, the patient's blood samples were examined for FTD-related genes.<br><br>RESULTS: The patient was a 52-year-old man with hidden onset. The symptoms progressed gradually, presenting with abnormal behaviors, including repeated shopping, taking away other people's things, constantly eating snacks, and frequently calling friends at night. The patient also exhibited executive dysfunction, such as the inability to cook and multiple driving problems, e.g., constantly deviates from his lane while driving. In addition, the patient showed personality changes such as irritability, indifference, and withdrawal, as well as motor symptoms, including unstable walking and frequent falls when walking. Brain magnetic resonance imaging revealed hippocampal sclerosis along with widening and deepening of the bilateral temporal lobe sulcus. Brain metabolic imaging via PET-CT demonstrated decreased metabolism in the bilateral prefrontal lobe, with the abnormal energy metabolism indicating FTD. Lastly, blood sample analysis detected mutations in the amyotrophic lateral sclerosis (ALS)-related GRN gene c.1352C&#x2009;>&#x2009;T (p.P451L) and ErbB4 gene c.256&#x2009;T&#x2009;>&#x2009;C (p.Y86H).<br><br>CONCLUSION: This is the first case of heterozygous mutations in the GRN and ErbB4 genes in FTD alone. The GRN and ErbB4 genes are likely to be important in the pathogenesis of FTD, expanding the common genetic profile of ALS and FTD.}, }
@article {pmid38290651, year = {2024}, author = {Lõhelaid, H and Saarma, M and Airavaara, M}, title = {CDNF and ER stress: Pharmacology and therapeutic possibilities.}, journal = {Pharmacology &amp; therapeutics}, volume = {254}, number = {}, pages = {108594}, doi = {10.1016/j.pharmthera.2024.108594}, pmid = {38290651}, issn = {1879-016X}, mesh = {Animals ; Humans ; *Parkinson Disease/drug therapy ; Nerve Growth Factors/therapeutic use/metabolism ; Recombinant Proteins/therapeutic use ; }, abstract = {Cerebral dopamine neurotrophic factor (CDNF) is an endogenous protein in humans and other vertebrates, and it has been shown to have protective and restorative effects on cells in various disease models. Although it is named as a neurotrophic factor, its actions are drastically different from classical neurotrophic factors such as neurotrophins or the glial cell line-derived neurotrophic family of proteins. Like all secreted proteins, CDNF has a signal sequence at the N-terminus, but unlike common growth factors it has a KDEL-receptor retrieval sequence at the C-terminus. Thus, CDNF is mainly located in the ER. In response to adverse effects, such as ER stress, the expression of CDNF is upregulated and can alleviate ER stress. Also different from other neurotrophic factors, CDNF reduces protein aggregation and inflammation in disease models. Although it is an ER luminal protein, it can surprisingly directly interact with alpha-synuclein, a protein involved in the pathogenesis of synucleinopathies e.g., Parkinson's disease. Pleiotropic CDNF has therapeutic potential and has been tested as a recombinant human protein and gene therapy. The neuroprotective and neurorestorative effects have been described in a number of preclinical studies of Parkinson's disease, stroke and amyotrophic lateral sclerosis. Currently, it was successfully evaluated for safety in a phase 1/2 clinical trial for Parkinson's disease. Collectively, based on recent findings on the mode of action and therapeutic potential of CDNF, its use as a drug could be expanded to other ER stress-related diseases.}, }
@article {pmid38289193, year = {2024}, author = {Nolan, M and Scott, C and Hof, PR and Ansorge, O}, title = {Betz cells of the primary motor cortex.}, journal = {The Journal of comparative neurology}, volume = {532}, number = {1}, pages = {e25567}, pmid = {38289193}, issn = {1096-9861}, support = {ANSORGE/OCT14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L022656/1/MRC_/Medical Research Council/United Kingdom ; 14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Humans ; Animals ; *Motor Cortex ; *Amyotrophic Lateral Sclerosis ; Pyramidal Cells ; Motor Neurons ; Primates ; Mammals ; }, abstract = {Betz cells, named in honor of Volodymyr Betz (1834-1894), who described them as "giant pyramids" in the primary motor cortex of primates and other mammalian species, are layer V extratelencephalic projection (ETP) neurons that directly innervate α-motoneurons of the brainstem and spinal cord. Despite their large volume and circumferential dendritic architecture, to date, no single molecular criterion has been established that unequivocally distinguishes adult Betz cells from other layer V ETP neurons. In primates, transcriptional signatures suggest the presence of at least two ETP neuron clusters that contain mature Betz cells; these are characterized by an abundance of axon guidance and oxidative phosphorylation transcripts. How neurodevelopmental programs drive the distinct positional and morphological features of Betz cells in humans remains unknown. Betz cells display a distinct biphasic firing pattern involving early cessation of firing followed by delayed sustained acceleration in spike frequency and magnitude. Few cell type-specific transcripts and electrophysiological characteristics are conserved between rodent layer V ETP neurons of the motor cortex and primate Betz cells. This has implications for the modeling of disorders that affect the motor cortex in humans, such as amyotrophic lateral sclerosis (ALS). Perhaps vulnerability to ALS is linked to the evolution of neural networks for fine motor control reflected in the distinct morphomolecular architecture of the human motor cortex, including Betz cells. Here, we discuss histological, molecular, and functional data concerning the position of Betz cells in the emerging taxonomy of neurons across diverse species and their role in neurological disorders.}, }
@article {pmid38288970, year = {2024}, author = {Lini, RS and Scanferla, DTP and de Oliveira, NG and Aguera, RG and Santos, TDS and Teixeira, JJV and Kaneshima, AMS and Mossini, SAG}, title = {Fungicides as a risk factor for the development of neurological diseases and disorders in humans: a systematic review.}, journal = {Critical reviews in toxicology}, volume = {54}, number = {1}, pages = {35-54}, doi = {10.1080/10408444.2024.2303481}, pmid = {38288970}, issn = {1547-6898}, mesh = {Humans ; *Fungicides, Industrial/toxicity ; *Insecticides ; Prospective Studies ; *Pesticides ; *Nervous System Diseases/chemically induced ; Risk Factors ; }, abstract = {Although studies show that pesticides, especially insecticides, may be toxic to humans, publications on the neurological effects of fungicides are scarce. As fungicides are used widely in Brazil, it is necessary to gather evidence to support actions aimed at safely using of these chemicals. We investigated through a systematic review of publications on the use of fungicides and consequences of exposure related to nervous system diseases or neurological disorders in humans. The protocol review was registered on PROSPERO and followed the guidelines of the PRISMA-Statement. As far as it is known, there is no apparent systematic review in the literature on this topic. The search was comprised of the following databases: PubMed; Web of Science; Scopus and EMBASE, using groups of Mesh terms and strategies specific to each database. Thirteen articles were selected for this review. Regarding the substances analyzed in the studies, some reported the use of fungicides in general, without separating them by type, while others summarized the categories of all pesticides by their function (insecticides, herbicides, fungicides, etc.) or chemical class (dithiocarbamate, dicarboximide, inorganic, etc.). However, most of the articles referred to fungicides that contain the metal manganese (Mn) in their composition. As for neurological disorders, articles addressed Parkinson's disease (PD), neurodevelopmental outcomes, extrapyramidal syndrome resembling PD, cognitive disorders, depression, neural tube defects, motor neurone disease, and amyotrophic lateral sclerosis. Most investigations pointed to exposure to fungicides, mainly maneb and mancozeb, leading to the development of at least one neurological disease, which suggests the need for further multicentric clinical trials and prospective studies for greater clarity of the research problem.}, }
@article {pmid38287907, year = {2024}, author = {Pan, MT and Zhang, H and Li, XJ and Guo, XY}, title = {Genetically modified non-human primate models for research on neurodegenerative diseases.}, journal = {Zoological research}, volume = {45}, number = {2}, pages = {263-274}, pmid = {38287907}, issn = {2095-8137}, mesh = {Humans ; Animals ; Chlorocebus aethiops ; *Neurodegenerative Diseases/genetics/therapy/veterinary ; Animals, Genetically Modified ; Disease Models, Animal ; *Parkinson Disease/pathology/veterinary ; Macaca mulatta ; }, abstract = {Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.}, }
@article {pmid38276084, year = {2024}, author = {Vacchiano, V and Bonan, L and Liguori, R and Rizzo, G}, title = {Primary Lateral Sclerosis: An Overview.}, journal = {Journal of clinical medicine}, volume = {13}, number = {2}, pages = {}, pmid = {38276084}, issn = {2077-0383}, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.}, }
@article {pmid38270797, year = {2024}, author = {Singh, S and Borkar, MR and Bhatt, LK}, title = {Transposable Elements: Emerging Therapeutic Targets in Neurodegenerative Diseases.}, journal = {Neurotoxicity research}, volume = {42}, number = {1}, pages = {9}, pmid = {38270797}, issn = {1476-3524}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; DNA Transposable Elements/genetics ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; *Parkinson Disease ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of neuronal function and structure. While several genetic and environmental factors have been implicated in the pathogenesis of these disorders, emerging evidence suggests that transposable elements (TEs), once considered "junk DNA," play a significant role in their development and progression. TEs are mobile genetic elements capable of moving within the genome, and their dysregulation has been associated with genomic instability, altered gene expression, and neuroinflammation. This review provides an overview of TEs, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and endogenous retroviruses (ERVs), mechanisms of repression and derepression, and their potential impact on neurodegeneration. The evidence linking TEs to AD, PD, and ALS by shedding light on the complex interactions between TEs and neurodegeneration has been discussed. Furthermore, the therapeutic potential of targeting TEs in neurodegenerative diseases has been explored. Understanding the role of TEs in neurodegeneration holds promise for developing novel therapeutic strategies aimed at mitigating disease progression and preserving neuronal health.}, }
@article {pmid38267984, year = {2024}, author = {Irwin, KE and Sheth, U and Wong, PC and Gendron, TF}, title = {Fluid biomarkers for amyotrophic lateral sclerosis: a review.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {9}, pmid = {38267984}, issn = {1750-1326}, support = {R01NS095969/NH/NIH HHS/United States ; R01 NS095969/NS/NINDS NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; P01NS084974/NH/NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Biomarkers ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.}, }
@article {pmid38266701, year = {2024}, author = {Eisen, A and Nedergaard, M and Gray, E and Kiernan, MC}, title = {The glymphatic system and Amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {234}, number = {}, pages = {102571}, doi = {10.1016/j.pneurobio.2024.102571}, pmid = {38266701}, issn = {1873-5118}, mesh = {Humans ; *Glymphatic System/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; Sleep ; }, abstract = {The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutamate, both major elements in disease pathogenesis. Flow is propelled by arterial pulsation, respiration, posture, as well as the positioning and proportion of aquaporin-4 channels (AQP4). Non-REM slow wave sleep is the is key to glymphatic drainage which discontinues during wakefulness. In Parkinson's disease and Alzheimer's disease, sleep impairment is known to predate the development of characteristic clinical features by several years and is associated with progressive accumulation of toxic proteinaceous products. While sleep issues are well described in ALS, consideration of preclinical sleep impairment or the potential of a failing glymphatic system in ALS has rarely been considered. Here we review how the glymphatic system may impact ALS. Preclinical sleep impairment as an unrecognized major risk factor for ALS is considered, while potential therapeutic options to improve glymphatic flow are explored.}, }
@article {pmid38265475, year = {2024}, author = {Xiang, Y and Song, X and Long, D}, title = {Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.}, journal = {Archives of toxicology}, volume = {98}, number = {3}, pages = {579-615}, pmid = {38265475}, issn = {1432-0738}, support = {81673227//National Natural Science Foundation of China/ ; 2020JJ4080//Natural Science Foundation of&#xa0;Hunan Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; NF-E2-Related Factor 2/metabolism ; *Ferroptosis ; Oxidative Stress/physiology ; Antioxidants/metabolism ; }, abstract = {This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.}, }
@article {pmid38259504, year = {2023}, author = {Rashid, S and Dimitriadi, M}, title = {Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1307636}, pmid = {38259504}, issn = {1662-5102}, abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.}, }
@article {pmid38256091, year = {2024}, author = {Iskusnykh, IY and Zakharova, AA and Kryl'skii, ED and Popova, TN}, title = {Aging, Neurodegenerative Disorders, and Cerebellum.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256091}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases ; Cerebellum ; *Alzheimer Disease ; *Huntington Disease ; Aging ; }, abstract = {An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control. Despite decades of research, the functional contributions of the cerebellum and the underlying molecular mechanisms in aging and neurodegenerative disorders remain largely unknown. Therefore, this review will highlight the molecular and cellular events in the cerebellum that are disrupted during the process of aging and the development of neurodegenerative disorders. We believe that deeper insights into the pathophysiological mechanisms of the cerebellum during aging and the development of neurodegenerative disorders will be essential for the design of new effective strategies for neuroprotection and the alleviation of some neurodegenerative disorders.}, }
@article {pmid38256050, year = {2024}, author = {Bruno, A and Milillo, C and Anaclerio, F and Buccolini, C and Dell'Elice, A and Angilletta, I and Gatta, M and Ballerini, P and Antonucci, I}, title = {Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256050}, issn = {1422-0067}, mesh = {Female ; Pregnancy ; Humans ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Huntington Disease/therapy ; *Parkinson Disease/therapy ; Stem Cells ; }, abstract = {Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.}, }
@article {pmid38254150, year = {2024}, author = {Khalil, B and Linsenmeier, M and Smith, CL and Shorter, J and Rossoll, W}, title = {Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {8}, pmid = {38254150}, issn = {1750-1326}, support = {R33NS110960/NS/NINDS NIH HHS/United States ; R21AG061784/AG/NIA NIH HHS/United States ; RF1AG076122/AG/NIA NIH HHS/United States ; R21AG065854/AG/NIA NIH HHS/United States ; R01AG077771/AG/NIA NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; RF1AG068581/AG/NIA NIH HHS/United States ; R33 NS110960/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R01GM099836/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Active Transport, Cell Nucleus ; DNA-Binding Proteins ; *Prions ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.}, }
@article {pmid38254109, year = {2024}, author = {Nagy, ZF and Pál, M and Engelhardt, JI and Molnár, MJ and Klivényi, P and Széll, M}, title = {Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {30}, pmid = {38254109}, issn = {1755-8794}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; DNA Copy Number Variations ; Genes, Regulator ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.}, }
@article {pmid38250776, year = {2024}, author = {Du, P and Zhang, X and Lian, X and Hölscher, C and Xue, G}, title = {O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {3}, pages = {1051-1068}, doi = {10.3233/JAD-230955}, pmid = {38250776}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Processing, Post-Translational ; Proteins/metabolism ; *Alzheimer Disease/pathology ; Acetylglucosamine/metabolism ; Disease Progression ; N-Acetylglucosaminyltransferases/metabolism ; }, abstract = {As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.}, }
@article {pmid38249779, year = {2024}, author = {de Carvalho, M and Swash, M}, title = {[Not Available].}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {27-38}, pmid = {38249779}, issn = {2467-981X}, abstract = {Accurate and rapid diagnosis of amyotrophic lateral sclerosis (ALS) is essential in order to provide accurate information for patient and family, to avoid time-consuming investigations and to permit an appropriate management plan. ALS is variable regarding presentation, disease progression, genetic profile and patient reaction to the diagnosis. It is obviously important to exclude treatable conditions but, in most patients, for experienced neurologists the diagnosis is clear-cut, depending on the presence of progressive upper and lower motor neuron signs. Patients with signs of restricted lower motor neuron (LMN) or upper motor neuron (UMN) dysfunction may present diagnostic difficulty, but electromyography (EMG) is often a determinant diagnostic test since it may exclude other disorders. Transcranial magnetic stimulation may aid detection of UMN dysfunction, and brain and spinal cord MRI, ultrasound and blood neurofilament measurements, have begun to have clinical impact, although none are themselves diagnostic tests. Several sets of diagnostic criteria have been proposed in the past; all rely on clinical LMN and UMN signs in different anatomic territories, EMG changes, exclusion of other disorders, and disease progression, in particular evidence of spreading to other anatomic territories. Fasciculations are a characteristic clinical feature and increased importance is now attached to fasciculation potentials detected by EMG, when associated with classical signs of denervation and reinnervation. The Gold Coast diagnostic criteria rely on the presence of UMN and LMN signs in one (or more) anatomic territory, or LMN signs in two (or more) anatomic territories, recognizing the fundamental clinical requirements of disease progression and exclusion of other diseases. Recent studies confirm a high sensitivity without loss of specificity using these Gold Coast criteria. In considering the diagnosis of ALS a critical question for future understanding is whether ALS should be considered a syndrome or a specific clinico-pathologic entity; this can only be addressed in the light of more complete knowledge.}, }
@article {pmid38249738, year = {2023}, author = {Croucher, KM and Fleming, SM}, title = {ATP13A2 (PARK9) and basal ganglia function.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1252400}, pmid = {38249738}, issn = {1664-2295}, support = {R01 ES031124/ES/NIEHS NIH HHS/United States ; }, abstract = {ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.}, }
@article {pmid38249293, year = {2023}, author = {Krishnamurthy, K and Pradhan, RK}, title = {Emerging perspectives of synaptic biomarkers in ALS and FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1279999}, pmid = {38249293}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.}, }
@article {pmid38247879, year = {2024}, author = {Shehjar, F and Almarghalani, DA and Mahajan, R and Hasan, SA and Shah, ZA}, title = {The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy.}, journal = {Cells}, volume = {13}, number = {2}, pages = {}, pmid = {38247879}, issn = {2073-4409}, support = {R01 NS112642/NS/NINDS NIH HHS/United States ; R01NS112642/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Actin Depolymerizing Factors ; alpha-Synuclein ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; *Stroke/metabolism ; }, abstract = {This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aβ plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.}, }
@article {pmid38247869, year = {2024}, author = {Smeele, PH and Cesare, G and Vaccari, T}, title = {ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.}, journal = {Cells}, volume = {13}, number = {2}, pages = {}, pmid = {38247869}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Dipeptides ; *Frontotemporal Dementia/genetics ; *Proteostasis ; }, abstract = {Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin-proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.}, }
@article {pmid38246117, year = {2024}, author = {de Jonge, S and Potters, WV and Verhamme, C}, title = {Artificial intelligence for automatic classification of needle EMG signals: A scoping review.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {159}, number = {}, pages = {41-55}, doi = {10.1016/j.clinph.2023.12.134}, pmid = {38246117}, issn = {1872-8952}, mesh = {Humans ; *Artificial Intelligence ; *Amyotrophic Lateral Sclerosis ; Electromyography ; Needles ; }, abstract = {OBJECTIVE: This scoping review provides an overview of artificial intelligence (AI), including machine and deep learning techniques, in the interpretation of clinical needle electromyography (nEMG) signals.<br><br>METHODS: A comprehensive search of Medline, Embase and Web of Science was conducted to find peer-reviewed journal articles. All papers published after 2010 were included. The methodological quality of the included studies was assessed with CLAIM (checklist for artificial intelligence in medical imaging).<br><br>RESULTS: 51 studies were identified that fulfilled the inclusion criteria. 61% used open-source EMGlab data set to develop models to classify nEMG signal in healthy, amyotrophic lateral sclerosis (ALS) and myopathy (25 subjects). Only two articles developed models to classify signals recorded at rest. Most articles reported high performance accuracies, but many were subject to bias and overtraining.<br><br>CONCLUSIONS: Current AI-models of nEMG signals are not sufficient for clinical implementation. Suggestions for future research include emphasizing the need for an optimal training and validation approach using large datasets of clinical nEMG data from a diverse patient population.<br><br>SIGNIFICANCE: The outcomes of this study and the suggestions made aim to contribute to developing AI-models that can effectively handle signal quality variability and are suitable for daily clinical practice in interpreting nEMG signals.}, }
@article {pmid38245992, year = {2024}, author = {Robertson, DJ and Jeziorczak, PM and Aprahamian, CJ}, title = {Diaphragmatic pacing for respiratory failure in children.}, journal = {Seminars in pediatric surgery}, volume = {33}, number = {1}, pages = {151386}, doi = {10.1016/j.sempedsurg.2024.151386}, pmid = {38245992}, issn = {1532-9453}, mesh = {Child ; Humans ; *Amyotrophic Lateral Sclerosis/complications ; Diaphragm ; Phrenic Nerve/surgery ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {Diaphragm pacing is a ventilation strategy in respiratory failure. Most of the literature on pacing involves adults with common indications being spinal cord injury and amyotrophic lateral sclerosis (ALS). Previous reports in pediatric patients consist of case reports or small series; most describe direct phrenic nerve stimulation for central hypoventilation syndrome. This differs from adult reports that focus most commonly on spinal cord injuries and the rehabilitative nature of diaphragm pacing. This review describes the current state of diaphragm pacing in pediatric patients. Indications, current available technologies, surgical techniques, advantages, and pitfalls/problems are discussed.}, }
@article {pmid38244235, year = {2024}, author = {Kim, SH and Oh, KW and Noh, MY and Kwon, MS}, title = {Optimal Therapeutic Strategy of Bone Marrow-Originated Autologous Mesenchymal Stromal/Stem Cells for ALS.}, journal = {Stem cells translational medicine}, volume = {13}, number = {4}, pages = {309-316}, pmid = {38244235}, issn = {2157-6580}, support = {NRF//National Research Foundation/ ; MSIT; RS-2023-00265515//Korean government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Bone Marrow ; Biomarkers ; *Mesenchymal Stem Cells ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive neurodegenerative changes in motor neural networks. Given the system complexity, including anatomically distributed sites of degeneration from the motor cortex to the spinal cord and chronic pro-inflammatory conditions, a cell-based therapeutic strategy could be an alternative approach to treating ALS. Lessons from previous mesenchymal stromal/stem cell (MSC) trials in ALS realized the importance of 3 aspects in current and future MSC therapy, including the preparation of MSCs, administration routes and methods, and recipient-related factors. This review briefly describes the current status and future prerequisites for an optimal strategy using bone-marrow-originated MSCs to treat ALS. We suggest mandatory factors in the optimized therapeutic strategy focused on advanced therapy medicinal products produced according to Good Manufacturing Practice, an optimal administration method, the selection of proper patients, and the importance of biomarkers.}, }
@article {pmid38241161, year = {2024}, author = {Klemmensen, MM and Borrowman, SH and Pearce, C and Pyles, B and Chandra, B}, title = {Mitochondrial dysfunction in neurodegenerative disorders.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {1}, pages = {e00292}, pmid = {38241161}, issn = {1878-7479}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/drug therapy ; Mitochondria ; Reactive Oxygen Species/therapeutic use ; *Alzheimer Disease/pathology ; *Mitochondrial Diseases/genetics/therapy ; }, abstract = {Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.}, }
@article {pmid38239833, year = {2023}, author = {Eck, RJ and Stair, JG and Kraemer, BC and Liachko, NF}, title = {Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1300705}, pmid = {38239833}, issn = {1662-4548}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; F31 AG082391/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; RF1 AG055474/AG/NIA NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; I01 BX002619/BX/BLRD VA/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; }, abstract = {The nematode Caenorhabditis elegans are a powerful model system to study human disease, with numerous experimental advantages including significant genetic and cellular homology to vertebrate animals, a short lifespan, and tractable behavioral, molecular biology and imaging assays. Beginning with the identification of SOD1 as a genetic cause of amyotrophic lateral sclerosis (ALS), C. elegans have contributed to a deeper understanding of the mechanistic underpinnings of this devastating neurodegenerative disease. More recently this work has expanded to encompass models of other types of ALS and the related disease frontotemporal lobar degeneration (FTLD-TDP), including those characterized by mutation or accumulation of the proteins TDP-43, C9orf72, FUS, HnRNPA2B1, ALS2, DCTN1, CHCHD10, ELP3, TUBA4A, CAV1, UBQLN2, ATXN3, TIA1, KIF5A, VAPB, GRN, and RAB38. In this review we summarize these models and the progress and insights from the last ten years of using C. elegans to study the neurodegenerative diseases ALS and FTLD-TDP.}, }
@article {pmid38226086, year = {2023}, author = {AlMadan, N and AlMajed, A and AlAbbad, M and AlNashmi, F and Aleissa, A}, title = {Dental Management of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e50602}, pmid = {38226086}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons with upper and lower motor neuron manifestations. It is divided into two variants: a spinal onset and a bulbar onset. The first starts as focal muscle weakness and wasting that spreads with disease progression, while the second phenotype presents with dysarthria, dysphonia, and dysphagia. Moreover, an extra-motor manifestation could be reported with the most commonly reported symptoms being the change in cognition and sleep disorder. Oral manifestations include increased salivation, limited mouth opening, and dysphagia. Patients with ALS have difficulty maintaining oral hygiene, and it is important for the practitioner and the caregiver to take care of this group of population. We herein provide a short review of the disease with a focus on the oral manifestations and dental considerations for management for this group.}, }
@article {pmid38223824, year = {2024}, author = {Lee, MY and Kim, M}, title = {Effects of Red ginseng on neuroinflammation in neurodegenerative diseases.}, journal = {Journal of ginseng research}, volume = {48}, number = {1}, pages = {20-30}, pmid = {38223824}, issn = {1226-8453}, abstract = {Red ginseng (RG) is widely used as a herbal medicine. As the human lifespan has increased, numerous diseases have developed, and RG has also been used to treat various diseases. Neurodegenerative diseases are major problems that modern people face through their lives. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are featured by progressive nerve system damage. Recently, neuroinflammation has emerged as a degenerative factor and is an immune response in which cytokines with nerve cells that constitute the nervous system. RG, a natural herbal medicine with fewer side effects than chemically synthesized drugs, is currently in the spotlight. Therefore, we reviewed studies reporting the roles of RG in treating neuroinflammation and neurodegenerative diseases and found that RG might help alleviate neurodegenerative diseases by regulating neuroinflammation.}, }
@article {pmid38218077, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Bączyk, M and de Carvalho, M and Dileone, M and Dubbioso, R and Fernandes, S and Kozak, G and Motolese, F and Ziemann, U}, title = {Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {114-136}, doi = {10.1016/j.clinph.2023.12.012}, pmid = {38218077}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Transcranial Direct Current Stimulation ; *Motor Neuron Disease/diagnosis/therapy ; Motor Neurons/physiology ; Brain ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.}, }
@article {pmid38216448, year = {2024}, author = {Van Daele, SH and Masrori, P and Van Damme, P and Van Den Bosch, L}, title = {The sense of antisense therapies in ALS.}, journal = {Trends in molecular medicine}, volume = {30}, number = {3}, pages = {252-262}, doi = {10.1016/j.molmed.2023.12.003}, pmid = {38216448}, issn = {1471-499X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Oligonucleotides, Antisense/therapeutic use ; RNA Splicing ; }, abstract = {Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.}, }
@article {pmid38214845, year = {2024}, author = {Fang, A and Zhao, Y and Yang, P and Zhang, X and Giovannucci, EL}, title = {Vitamin D and human health: evidence from Mendelian randomization studies.}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {38214845}, issn = {1573-7284}, support = {81803219//National Natural Science Foundation of China/ ; 2018A030310335//Natural Science Foundation of Guangdong Province/ ; }, abstract = {We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.}, }
@article {pmid38213309, year = {2024}, author = {Eisen, A and Vucic, S and Mitsumoto, H}, title = {History of ALS and the competing theories on pathogenesis: IFCN handbook chapter.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {1-12}, pmid = {38213309}, issn = {2467-981X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the human motor system, first described in the 19th Century. The etiology of ALS appears to be multifactorial, with a complex interaction of genetic, epigenetic, and environmental factors underlying the onset of disease. Importantly, there are no known naturally occurring animal models, and transgenic mouse models fail to faithfully reproduce ALS as it manifests in patients. Debate as to the site of onset of ALS remain, with three competing theories proposed, including (i) the dying-forward hypothesis, whereby motor neuron degeneration is mediated by hyperexcitable corticomotoneurons via an anterograde transsynaptic excitotoxic mechanism, (ii) dying-back hypothesis, proposing the ALS begins in the peripheral nervous system with a toxic factor(s) retrogradely transported into the central nervous system and mediating upper motor neuron dysfunction, and (iii) independent hypothesis, suggesting that upper and lower motor neuron degenerated independently. Transcranial magnetic stimulation studies, along with pathological and genetic findings have supported the dying forward hypothesis theory, although the science is yet to be settled. The review provides a historical overview of ALS, discusses phenotypes and likely pathogenic mechanisms.}, }
@article {pmid38203614, year = {2023}, author = {Wu, Y and Chen, Y and Yu, X and Zhang, M and Li, Z}, title = {Towards Understanding Neurodegenerative Diseases: Insights from Caenorhabditis elegans.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203614}, issn = {1422-0067}, support = {2002472//National Health and Medical Research Council/ ; }, mesh = {Animals ; Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Alzheimer Disease ; *Huntington Disease ; *Parkinson Disease ; Mammals ; }, abstract = {The elevated occurrence of debilitating neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Machado-Joseph disease (MJD), demands urgent disease-modifying therapeutics. Owing to the evolutionarily conserved molecular signalling pathways with mammalian species and facile genetic manipulation, the nematode Caenorhabditis elegans (C. elegans) emerges as a powerful and manipulative model system for mechanistic insights into neurodegenerative diseases. Herein, we review several representative C. elegans models established for five common neurodegenerative diseases, which closely simulate disease phenotypes specifically in the gain-of-function aspect. We exemplify applications of high-throughput genetic and drug screenings to illustrate the potential of C. elegans to probe novel therapeutic targets. This review highlights the utility of C. elegans as a comprehensive and versatile platform for the dissection of neurodegenerative diseases at the molecular level.}, }
@article {pmid38203300, year = {2023}, author = {Wei, J and Wong, LC and Boland, S}, title = {Lipids as Emerging Biomarkers in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203300}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Alzheimer Disease/diagnosis ; *Parkinson Disease ; Biomarkers ; Monoglycerides ; }, abstract = {Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.}, }
@article {pmid38202163, year = {2023}, author = {Ueha, R and Cotaoco, C and Kondo, K and Yamasoba, T}, title = {Management and Treatment for Dysphagia in Neurodegenerative Disorders.}, journal = {Journal of clinical medicine}, volume = {13}, number = {1}, pages = {}, pmid = {38202163}, issn = {2077-0383}, abstract = {Patients with neurodegenerative disorders (NDDs) often experience functional dysphagia, which may involve dysfunction in a specific phase of swallowing or in the entire process. This review outlines the approach to dysphagia in the setting of NDDs. Distinguishing the etiology of dysphagia can be difficult, and it is important to always look out for signs pointing to NDD as the cause. Thorough diagnostic work-up is essential, and it includes a comprehensive history and physical examination, alongside swallowing function tests, such as fiberoptic endoscopic evaluation of swallowing, videofluoroscopic swallowing study, and high-resolution manometry. Management requires a multidisciplinary approach with a treatment plan tailored to each patient. This involves dietary guidance, swallowing rehabilitation, and surgery in cases in which improvement with rehabilitation is inadequate. Surgery may involve altering certain pharyngolaryngeal structures to facilitate swallowing and reduce the risk of aspiration (swallowing improvement surgery) or separating the airway and digestive tract while sacrificing laryngeal function, with the main goal of preventing aspiration (aspiration prevention surgery). Proper management stems from recognizing the impact of these disorders on swallowing and consistently finding ways to improve the quality of life of patients.}, }
@article {pmid38201932, year = {2023}, author = {Sharma, H and Sharma, N and An, SSA}, title = {Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.}, journal = {Nutrients}, volume = {16}, number = {1}, pages = {}, pmid = {38201932}, issn = {2072-6643}, support = {RS-2023-00251396 and 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {*Neuroprotective Agents/pharmacology ; *Cordyceps ; *Agaricales ; Neuroprotection ; Adenosine ; }, abstract = {Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N[6]-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.}, }
@article {pmid38201303, year = {2024}, author = {Chen, L and Zhang, S and Liu, S and Gao, S}, title = {Amyotrophic Lateral Sclerosis Mechanism: Insights from the Caenorhabditis elegans Models.}, journal = {Cells}, volume = {13}, number = {1}, pages = {}, pmid = {38201303}, issn = {2073-4409}, support = {32020103007//Major International (Regional) Joint Research Project/ ; 2022YFA1206001//National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Caenorhabditis elegans ; Motor Neurons ; Protein Aggregates ; Signal Transduction ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a debilitating neurodegenerative condition characterized by the progressive degeneration of motor neurons. Despite extensive research in various model animals, the cellular signal mechanisms of ALS remain elusive, impeding the development of efficacious treatments. Among these models, a well-characterized and diminutive organism, Caenorhabditis elegans (C. elegans), has emerged as a potent tool for investigating the molecular and cellular dimensions of ALS pathogenesis. This review summarizes the contributions of C. elegans models to our comprehension of ALS, emphasizing pivotal findings pertaining to genetics, protein aggregation, cellular pathways, and potential therapeutic strategies. We analyze both the merits and constraints of the C. elegans system in the realm of ALS research and point towards future investigations that could bridge the chasm between C. elegans foundational discoveries and clinical applications.}, }
@article {pmid38195712, year = {2024}, author = {Ravichandran, KA and Heneka, MT}, title = {Inflammasomes in neurological disorders - mechanisms and therapeutic potential.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {2}, pages = {67-83}, pmid = {38195712}, issn = {1759-4766}, mesh = {Humans ; Inflammasomes/metabolism ; *Nervous System Diseases/drug therapy ; *Stroke ; *Multiple Sclerosis ; Brain/metabolism ; }, abstract = {Inflammasomes are molecular scaffolds that are activated by damage-associated and pathogen-associated molecular patterns and form a key element of innate immune responses. Consequently, the involvement of inflammasomes in several diseases that are characterized by inflammatory processes, such as multiple sclerosis, is widely appreciated. However, many other neurological conditions, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, stroke, epilepsy, traumatic brain injury, sepsis-associated encephalopathy and neurological sequelae of COVID-19, all involve persistent inflammation in the brain, and increasing evidence suggests that inflammasome activation contributes to disease progression in these conditions. Understanding the biology and mechanisms of inflammasome activation is, therefore, crucial for the development of inflammasome-targeted therapies for neurological conditions. In this Review, we present the current evidence for and understanding of inflammasome activation in neurological diseases and discuss current and potential interventional strategies that target inflammasome activation to mitigate its pathological consequences.}, }
@article {pmid38194198, year = {2024}, author = {Xu, A and Luo, Y and Tang, Y and Yang, F and Gao, X and Qiao, G and Zhu, X and Zhou, J}, title = {Chitinases as a potential diagnostic and prognostic biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {38194198}, issn = {1590-3478}, support = {2023AFD128//Hubei Provincial Natural Science Foundation and the Innovation and Development of Traditional Chinese Medicine of China/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS.}, }
@article {pmid38189033, year = {2023}, author = {Moreno-Roco, J and Del Valle, L and Jiménez, D and Acosta, I and Castillo, JL and Dharmadasa, T and Kiernan, MC and Matamala, JM}, title = {Diagnostic utility of transcranial magnetic stimulation for neurodegenerative disease: a critical review.}, journal = {Dementia &amp; neuropsychologia}, volume = {17}, number = {}, pages = {e20230048}, pmid = {38189033}, issn = {1980-5764}, abstract = {Neurodegenerative diseases pose significant challenges due to their impact on brain structure, function, and cognition. As life expectancy rises, the prevalence of these disorders is rapidly increasing, resulting in substantial personal, familial, and societal burdens. Efforts have been made to optimize the diagnostic and therapeutic processes, primarily focusing on clinical, cognitive, and imaging characterization. However, the emergence of non-invasive brain stimulation techniques, specifically transcranial magnetic stimulation (TMS), offers unique functional insights and diagnostic potential. TMS allows direct evaluation of brain function, providing valuable information inaccessible through other methods. This review aims to summarize the current and potential diagnostic utility of TMS in investigating neurodegenerative diseases, highlighting its relevance to the field of cognitive neuroscience. The findings presented herein contribute to the growing body of research focused on improving our understanding and management of these debilitating conditions, particularly in regions with limited resources and a pressing need for innovative approaches.}, }
@article {pmid38188146, year = {2024}, author = {Shao, BZ and Jiang, JJ and Zhao, YC and Zheng, XR and Xi, N and Zhao, GR and Huang, XW and Wang, SL}, title = {Neutrophil extracellular traps in central nervous system (CNS) diseases.}, journal = {PeerJ}, volume = {12}, number = {}, pages = {e16465}, pmid = {38188146}, issn = {2167-8359}, mesh = {Humans ; *Extracellular Traps ; *Central Nervous System Diseases ; *Multiple Sclerosis ; Central Nervous System ; Neutrophils ; }, abstract = {Excessive induction of inflammatory and immune responses is widely considered as one of vital factors contributing to the pathogenesis and progression of central nervous system (CNS) diseases. Neutrophils are well-studied members of inflammatory and immune cell family, contributing to the innate and adaptive immunity. Neutrophil-released neutrophil extracellular traps (NETs) play an important role in the regulation of various kinds of diseases, including CNS diseases. In this review, current knowledge on the biological features of NETs will be introduced. In addition, the role of NETs in several popular and well-studied CNS diseases including cerebral stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and neurological cancers will be described and discussed through the reviewing of previous related studies.}, }
@article {pmid38188011, year = {2023}, author = {Ansari, U and Chen, V and Sedighi, R and Syed, B and Muttalib, Z and Ansari, K and Ansari, F and Nadora, D and Razick, D and Lui, F}, title = {Role of the UNC13 family in human diseases: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {388-400}, pmid = {38188011}, issn = {2373-7972}, abstract = {This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC13C, and UNC13D, in the pathogenesis of various human diseases. These proteins, which are evolutionarily conserved and crucial for synaptic vesicle priming and exocytosis, have been implicated in a range of disorders, spanning from neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) to immune-related conditions such as familial hemophagocytic lymphohistiocytosis (FHL). The involvement of UNC13A in neurotransmitter release and synaptic plasticity is linked to ALS and FTD, with genetic variations affecting disease progression. UNC13B, which is closely related to UNC13A, plays a role in autism spectrum disorders (ASD), epilepsy, and schizophrenia. UNC13C is implicated in oral squamous cell carcinoma (OSCC) and hepatocellular carcinoma (HCC), and has a neuroprotective role in Alzheimer's disease (AD). UNC13D has an essential role in immune cell function, making it a key player in FHL. This review highlights the distinct molecular functions of each UNC13 family member and their implications in disease contexts, shedding light on potential therapeutic strategies and avenues for future research. Understanding these proteins' roles offers new insights into the management and treatment of neurological and immunological disorders.}, }
@article {pmid38188002, year = {2023}, author = {Ansari, U and Wen, J and Taguinod, I and Nadora, D and Nadora, D and Lui, F}, title = {Exploring dietary approaches in the prevention and management of Amyotrophic Lateral Sclerosis: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {376-387}, pmid = {38188002}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and complex neurodegenerative disease of upper and lower motor neurons of the central nervous system. The pathogenesis of this multifaceted disease is unknown. However, diet has emerged as a modifiable risk factor that has neuroprotective effects towards other neurological disorders such as Alzheimer's, Parkinson's and dementia. Thus, this review aims to explore how diet can potentially influence ALS onset and/or progression. In this review, five popular diets (Mediterranean, Vegan, Carnivore, Paleolithic and Ketogenic) and their distinct macromolecule composition, nutritional profile, biochemical pathways and their potential therapeutic effects for ALS are thoroughly examined. However, the composition of these diets varies, and the data is controversial, with conflicting studies on the effectiveness of nutrient intake of several of these diets. Although these five diets show that a higher intake of foods containing anti-inflammatory and antioxidant compounds have a positive correlation towards reducing the oxidative stress of ALS, further research is needed to directly compare the effects of these diets and the mechanisms leading to ALS and its progression.}, }
@article {pmid38178841, year = {2023}, author = {Zhao, S and Chen, R and Gao, Y and Lu, Y and Bai, X and Zhang, J}, title = {Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1319706}, pmid = {38178841}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons (MNs) in the brain and spinal cord. It is caused by multiple factors, including mutations in any one of several specific genes. Optineurin (OPTN) mutation is an essential cause of some familial and sporadic ALS. Besides, as a multifunctional protein, OPTN is highly expressed and conserved in the central nervous system. OPTN exerts its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more core proteins related to autophagy and inflammation, etc. OPTN mutation mainly results in its function deficiency, which alters these interactions, leading to functional impairment in many processes. Meanwhile, OPTN immunopositive inclusions are also confirmed in the cases of ALS due to C9ORF72, FUS, TARDBP, and SOD1 mutations. Therefore, OPTN gene may play fundamental roles in the molecular pathology of ALS in addition to OPTN mutation. In this review, we summarize the recent advances in the ALS pathology of OPTN defect, such as mitophagy disorder, neuroinflammation, neuronal axonal degeneration, vesicular transport dysfunction, etc., which will provide a reference for research on the pathogenesis and treatment of ALS.}, }
@article {pmid38176936, year = {2023}, author = {Windhorst, U and Dibaj, P}, title = {Plastic Spinal Motor Circuits in Health and Disease.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {6}, pages = {167}, doi = {10.31083/j.jin2206167}, pmid = {38176936}, issn = {0219-6352}, mesh = {Animals ; Humans ; Spinal Cord ; *Amyotrophic Lateral Sclerosis ; *Muscular Atrophy, Spinal/pathology ; *Spinal Cord Injuries/pathology ; Disease Models, Animal ; *Stroke/pathology ; }, abstract = {In the past, the spinal cord was considered a hard-wired network responsible for spinal reflexes and a conduit for long-range connections. This view has changed dramatically over the past few decades. It is now recognized as a plastic structure that has the potential to adapt to changing environments. While such changes occur under physiological conditions, the most dramatic alterations take place in response to pathological events. Many of the changes that occur following such pathological events are maladaptive, but some appear to help adapt to the new conditions. Although a number of studies have been devoted to elucidating the underlying mechanisms, in humans and animal models, the etiology and pathophysiology of various diseases impacting the spinal cord are still not well understood. In this review, we summarize current understanding and outstanding challenges for a number of diseases, including spinal muscular atrophy (SMA), amyotrophic laterals sclerosis (ALS), and spinal cord injury (SCI), with occasional relations to stroke. In particular, we focus on changes resulting from SCI (and stroke), and various influencing factors such as cause, site and extent of the afflicted damage.}, }
@article {pmid38151890, year = {2023}, author = {Talebi, S and Khodagholi, F and Bahaeddin, Z and Ansari Dezfouli, M and Zeinaddini-Meymand, A and Berchi Kankam, S and Foolad, F and Alijaniha, F and Fayazi Piranghar, F}, title = {Does hazelnut consumption affect brain health and function against neurodegenerative diseases?.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/1028415X.2023.2296164}, pmid = {38151890}, issn = {1476-8305}, abstract = {INTRODUCTION: A healthy daily diet and consuming certain nutrients, such as polyphenols, vitamins, and unsaturated fatty acids, may help neuronal health maintenance. Polyphenolic chemicals, which have antioxidant and anti-inflammatory properties, are involved in the neuroprotective pathway. Because of their nutritional value, nuts have been shown in recent research to be helpful in neuroprotection.<br><br>OBJECTIVE: Hazelnut is often consumed worldwide in various items, including processed foods, particularly in bakery, chocolate, and confectionery products. This nut is an excellent source of vitamins, amino acids, tocopherols, phytosterols, polyphenols, minerals, and unsaturated fatty acids. Consuming hazelnut may attenuate the risk of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease due to its anti-inflammatory and anti-oxidant qualities.<br><br>RESULTS: Many documents introduce hazelnut as an excellent choice to provide neuroprotection against neurodegenerative disorders and there is some direct proof of its neuroprotective effects.<br><br>DISCUSSION: So hazelnut consumption in daily diet may reduce neurodegenerative disease risk and be advantageous in reducing the imposed costs of dealing with neurodegenerative diseases.}, }
@article {pmid38151482, year = {2024}, author = {Taha, MA and Morren, JA}, title = {The role of artificial intelligence in electrodiagnostic and neuromuscular medicine: Current state and future directions.}, journal = {Muscle &amp; nerve}, volume = {69}, number = {3}, pages = {260-272}, doi = {10.1002/mus.28023}, pmid = {38151482}, issn = {1097-4598}, mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain ; Electromyography ; }, abstract = {The rapid advancements in artificial intelligence (AI), including machine learning (ML), and deep learning (DL) have ushered in a new era of technological breakthroughs in healthcare. These technologies are revolutionizing the way we utilize medical data, enabling improved disease classification, more precise diagnoses, better treatment selection, therapeutic monitoring, and highly accurate prognostication. Different ML and DL models have been used to distinguish between electromyography signals in normal individuals and those with amyotrophic lateral sclerosis and myopathy, with accuracy ranging from 67% to 99.5%. DL models have also been successfully applied in neuromuscular ultrasound, with the use of segmentation techniques achieving diagnostic accuracy of at least 90% for nerve entrapment disorders, and 87% for inflammatory myopathies. Other successful AI applications include prediction of treatment response, and prognostication including prediction of intensive care unit admissions for patients with myasthenia gravis. Despite these remarkable strides, significant knowledge, attitude, and practice gaps persist, including within the field of electrodiagnostic and neuromuscular medicine. In this narrative review, we highlight the fundamental principles of AI and draw parallels with the intricacies of human brain networks. Specifically, we explore the immense potential that AI holds for applications in electrodiagnostic studies, neuromuscular ultrasound, and other aspects of neuromuscular medicine. While there are exciting possibilities for the future, it is essential to acknowledge and understand the limitations of AI and take proactive steps to mitigate these challenges. This collective endeavor holds immense potential for the advancement of healthcare through the strategic and responsible integration of AI technologies.}, }
@article {pmid38147116, year = {2024}, author = {Louro, H and Vettorazzi, A and López de Cerain, A and Spyropoulou, A and Solhaug, A and Straumfors, A and Behr, AC and Mertens, B and Žegura, B and Fæste, CK and Ndiaye, D and Spilioti, E and Varga, E and Dubreil, E and Borsos, E and Crudo, F and Eriksen, GS and Snapkow, I and Henri, J and Sanders, J and Machera, K and Gaté, L and Le Hegarat, L and Novak, M and Smith, NM and Krapf, S and Hager, S and Fessard, V and Kohl, Y and Silva, MJ and Dirven, H and Dietrich, J and Marko, D}, title = {Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health.}, journal = {Archives of toxicology}, volume = {98}, number = {2}, pages = {425-469}, pmid = {38147116}, issn = {1432-0738}, support = {101057014//European Commission/ ; }, mesh = {Humans ; *Perylene ; Alternaria/metabolism ; *Mycotoxins/toxicity/analysis ; Mutagens/toxicity/metabolism ; Lactones/toxicity/metabolism ; Risk Assessment ; Food Contamination/analysis ; }, abstract = {Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.}, }
@article {pmid38136659, year = {2023}, author = {Cilleros-Holgado, P and Gómez-Fernández, D and Piñero-Pérez, R and Romero-Domínguez, JM and Reche-López, D and López-Cabrera, A and Álvarez-Córdoba, M and Munuera-Cabeza, M and Talaverón-Rey, M and Suárez-Carrillo, A and Romero-González, A and Sánchez-Alcázar, JA}, title = {Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {13}, number = {12}, pages = {}, pmid = {38136659}, issn = {2218-273X}, support = {FIS PI19/00377 and PI22/00142 grants//Instituto de Salud Carlos III/ ; CTS-5725, PY18-850, and UPO-FEDER 2018 (UPO-1380614)//Regional Government of Andalusia/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Mitochondrial Diseases ; Aging ; Unfolded Protein Response ; }, abstract = {Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.}, }
@article {pmid38132330, year = {2023}, author = {Spisni, E and Valerii, MC and Massimino, ML}, title = {Essential Oil Molecules Can Break the Loop of Oxidative Stress in Neurodegenerative Diseases.}, journal = {Biology}, volume = {12}, number = {12}, pages = {}, pmid = {38132330}, issn = {2079-7737}, support = {0000//Xeda international (1397 Route Nationale 7, Zac la Crau, 13670 Saint Andiol, France)./ ; }, abstract = {Essential oils (EOs) are mixtures of volatile compounds, extracted from aromatic plants, with multiple activities including antioxidant and anti-inflammatory ones. EOs are complex mixtures easy to find on the market and with low costs. In this mini narrative review, we have collected the results of in vitro and in vivo studies, which tested these EOs on validated models of neurodegeneration and in particular of the two main neurodegenerative diseases (NDs) that afflict humans: Alzheimer's and Parkinson's. Since EO compositions can vary greatly, depending on the environmental conditions, plant cultivar, and extraction methods, we focused our attention to studies involving single EO molecules, and in particular those that have demonstrated the ability to cross the blood-brain barrier. These single EO molecules, alone or in defined mixtures, could be interesting new therapies to prevent or slow down oxidative and inflammatory processes which are common mechanisms that contribute to neuronal death in all NDs.}, }
@article {pmid38131803, year = {2023}, author = {Miteva, D and Vasilev, GV and Velikova, T}, title = {Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis.}, journal = {Antibodies (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {38131803}, issn = {2073-4468}, support = {BG-RRP-2.004-0008//the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria/ ; }, abstract = {Neurodegenerative diseases (NDDs) affect millions of people worldwide. They develop due to the pathological accumulation and aggregation of various misfolded proteins, axonal and synaptic loss and dysfunction, inflammation, cytoskeletal abnormalities, defects in DNA and RNA, and neuronal death. This leads to the activation of immune responses and the release of the antibodies against them. Recently, it has become clear that autoantibodies (Aabs) can contribute to demyelination, axonal loss, and brain and cognitive dysfunction. This has significantly changed the understanding of the participation of humoral autoimmunity in neurodegenerative disorders. It is crucial to understand how neuroinflammation is involved in neurodegeneration, to aid in improving the diagnostic and therapeutic value of Aabs in the future. This review aims to provide data on the immune system's role in NDDs, the pathogenic role of some specific Aabs against molecules associated with the most common NDDs, and their potential role as biomarkers for monitoring and diagnosing NDDs. It is suggested that the autoimmune aspects of NDDs will facilitate early diagnosis and help to elucidate previously unknown aspects of the pathobiology of these diseases.}, }
@article {pmid38116771, year = {2023}, author = {Máčová, L and Kancheva, R and Bičíková, M}, title = {Molecular Regulation of the CNS by Vitamin D.}, journal = {Physiological research}, volume = {72}, number = {S4}, pages = {S339-S356}, doi = {10.33549/physiolres.935248}, pmid = {38116771}, issn = {1802-9973}, mesh = {Humans ; Vitamin D/therapeutic use ; Vitamins ; *Alzheimer Disease ; *Nervous System Diseases ; *Parkinson Disease ; }, abstract = {Vitamin D is a lipid-soluble vitamin that can be found in some foods. It is also produced endogenously (in the presence of ultraviolet light), transported through the blood to the targets organs and this is the reason to consider vitamin D as a hormone. It is known that vitamin D has genomic and non-genomic effects. This review is focused mainly on the vitamin D receptors, the importance of vitamin D as a neuromodulator, the role of vitamin D in the pathophysiology of devastating neurological disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and the benefit of vitamin D and its derivates in alleviating these disorders.}, }
@article {pmid38112345, year = {2023}, author = {Battaglini, M and Marino, A and Montorsi, M and Carmignani, A and Ceccarelli, MC and Ciofani, G}, title = {Nanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders.}, journal = {Advanced healthcare materials}, volume = {}, number = {}, pages = {e2304180}, doi = {10.1002/adhm.202304180}, pmid = {38112345}, issn = {2192-2659}, abstract = {Microglia play a pivotal role in the central nervous system (CNS) homeostasis, acting as housekeepers and defenders of the surrounding environment. These cells can elicit their functions by shifting into two main phenotypes: pro-inflammatory classical phenotype, M1, and anti-inflammatory alternative phenotype, M2. Despite their pivotal role in CNS homeostasis, microglia phenotypes can influence the development and progression of several CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injuries, and even brain cancer. It is thus clear that the possibility of modulating microglia activation has gained attention as a therapeutic tool against many CNS pathologies. Nanomaterials are an unprecedented tool for manipulating microglia responses, in particular, to specifically target microglia and elicit an in situ immunomodulation activity. This review focuses the discussion on two main aspects: analyzing the possibility of using nanomaterials to stimulate a pro-inflammatory response of microglia against brain cancer and introducing nanostructures able to foster an anti-inflammatory response for treating neurodegenerative disorders. The final aim is to stimulate the analysis of the development of new microglia nano-immunomodulators, paving the way for innovative and effective therapeutic approaches for the treatment of CNS disorders.}, }
@article {pmid38110839, year = {2024}, author = {Benatar, M and Ostrow, LW and Lewcock, JW and Bennett, F and Shefner, J and Bowser, R and Larkin, P and Bruijn, L and Wuu, J}, title = {Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.}, journal = {Annals of neurology}, volume = {95}, number = {2}, pages = {211-216}, pmid = {38110839}, issn = {1531-8249}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U01 NS107027/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Superoxide Dismutase-1 ; Intermediate Filaments ; Biomarkers ; Prognosis ; Neurofilament Proteins ; }, abstract = {OBJECTIVE: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use.<br><br>METHODS: Consensus discussion among academic, industry, and patient advocacy group representatives.<br><br>RESULTS: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers. Although NfL has not yet been formally qualified for any of these contexts-of-use, the US Food and Drug Administration has provided accelerated approval for an SOD1-lowering antisense oligonucleotide, based partially on the recognition that a reduction in NfL is reasonably likely to predict a clinical benefit.<br><br>INTERPRETATION: The increasing incorporation of NfL into ALS therapy development plans provides evidence that its utility-as a prognostic, response, risk/susceptibility, and/or safety biomarker-is already widely accepted by the community. The willingness of the US Food and Drug Administration to base regulatory decisions on rigorous peer-reviewed data-absent formal qualification, leads us to conclude that formal qualification, despite some benefits, is not essential for ongoing and future use of NfL as a tool to aid ALS therapy development. Although the balance of considerations for and against seeking NfL biomarker qualification will undoubtedly vary across different diseases and contexts-of-use, the robustness of the published data and careful deliberations of the ALS community may offer valuable insights for other disease communities grappling with the same issues. ANN NEUROL 2024;95:211-216.}, }
@article {pmid38108952, year = {2024}, author = {Xiao, X and Rui, Y and Jin, Y and Chen, M}, title = {Relationship of Sleep Disorder with Neurodegenerative and Psychiatric Diseases: An Updated Review.}, journal = {Neurochemical research}, volume = {49}, number = {3}, pages = {568-582}, pmid = {38108952}, issn = {1573-6903}, support = {82371541//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; Brain/metabolism ; *Huntington Disease/metabolism ; *Sleep Wake Disorders/metabolism ; }, abstract = {Sleep disorders affect many people worldwide and can accompany neurodegenerative and psychiatric diseases. Sleep may be altered before the clinical manifestations of some of these diseases appear. Moreover, some sleep disorders affect the physiological organization and function of the brain by influencing gene expression, accelerating the accumulation of abnormal proteins, interfering with the clearance of abnormal proteins, or altering the levels of related hormones and neurotransmitters, which can cause or may be associated with the development of neurodegenerative and psychiatric diseases. However, the detailed mechanisms of these effects are unclear. This review mainly focuses on the relationship between and mechanisms of action of sleep in Alzheimer's disease, depression, and anxiety, as well as the relationships between sleep and Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This summary of current research hotspots may provide researchers with better clues and ideas to develop treatment solutions for neurodegenerative and psychiatric diseases associated with sleep disorders.}, }
@article {pmid38105925, year = {2023}, author = {Mimic, S and Aru, B and Pehlivanoğlu, C and Sleiman, H and Andjus, PR and Yanıkkaya Demirel, G}, title = {Immunology of amyotrophic lateral sclerosis - role of the innate and adaptive immunity.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1277399}, pmid = {38105925}, issn = {1662-4548}, abstract = {This review aims to summarize the latest evidence about the role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurodegenerative disease affecting upper and lower motor neurons, which involves essential cells of the immune system that play a basic role in innate or adaptive immunity, that can be neurotoxic or neuroprotective for neurons. However, distinguishing between the sole neurotoxic or neuroprotective function of certain cells such as astrocytes can be challenging due to intricate nature of these cells, the complexity of the microenvironment and the contextual factors. In this review, in regard to innate immunity we focus on the involvement of monocytes/macrophages, microglia, the complement, NK cells, neutrophils, mast cells, and astrocytes, while regarding adaptive immunity, in addition to humoral immunity the most important features and roles of T and B cells are highlighted, specifically different subsets of CD4[+] as well as CD8[+] T cells. The role of autoantibodies and cytokines is also discussed in distinct sections of this review.}, }
@article {pmid38105307, year = {2024}, author = {Hamad, AA and Amer, BE and Hawas, Y and Mabrouk, MA and Meshref, M}, title = {Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {1861-1873}, pmid = {38105307}, issn = {1590-3478}, mesh = {Animals ; *Neuroprotective Agents/therapeutic use ; Piperidines ; Pyridines/therapeutic use ; Benzamides/therapeutic use ; *Thiazoles ; }, abstract = {OBJECTIVES: Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib's neuroprotective activities from preclinical to clinical studies.<br><br>METHODS: This scoping review was conducted following the guidelines described by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies.<br><br>RESULTS: A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer's disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity.<br><br>CONCLUSION: The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use.}, }
@article {pmid38105306, year = {2024}, author = {Katerelos, A and Alexopoulos, P and Economou, P and Polychronopoulos, P and Chroni, E}, title = {Cognitive function in amyotrophic lateral sclerosis: a cross-sectional and prospective pragmatic clinical study with review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2075-2085}, pmid = {38105306}, issn = {1590-3478}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Cognition Disorders/etiology/complications ; Neuropsychological Tests ; Prospective Studies ; Quality of Life ; Cross-Sectional Studies ; Cognition/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) can present with either bulbar or spinal symptoms, and in some cases, both types of symptoms may be present. In addition, cognitive impairment has been observed in ALS. The study aimed to evaluate the frontal and general cognitive performance in ALS not only cross-sectionally but also longitudinally.<br><br>METHODS AND MATERIALS: The Frontal Assessment Battery (FAB) and the Montreal Cognitive Assessment (MoCA) were employed to assess cognitive function in 52 adults with ALS and 52 cognitively healthy individuals. The statistical analyses encompassed the Pearson Chi square test, the Skillings-Mack test, the Spearman's rank correlation coefficient, and the Proportional Odds Logistic Regression Model (POLR).<br><br>RESULTS: Cross-sectionally, lower cognitive performance was associated with ALS diagnosis, older age, and motor functional decline. The cognitive impairment of individuals with bulbar and spinal-bulbar symptoms showed faster deterioration compared to those with spinal symptoms. The spinal subgroup consistently performed worst in delayed recall and attention, while the spinal-bulbar and bulbar subgroups exhibited inferior scores in delayed recall, attention, visuospatial skills, orientation, and verbal fluency.<br><br>CONCLUSION: The incorporation of cognitive screening in the diagnostic workup of ALS may be beneficial, as early detection can enhance symptom management and improve the quality of life for both individuals with ALS and their care partners.}, }
@article {pmid38103074, year = {2023}, author = {Villavicencio-Tejo, F and Olesen, MA and Navarro, L and Calisto, N and Iribarren, C and García, K and Corsini, G and Quintanilla, RA}, title = {Gut-Brain Axis Deregulation and Its Possible Contribution to Neurodegenerative Disorders.}, journal = {Neurotoxicity research}, volume = {42}, number = {1}, pages = {4}, pmid = {38103074}, issn = {1476-3524}, support = {1200178//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; }, mesh = {Animals ; Humans ; Brain-Gut Axis ; *Amyotrophic Lateral Sclerosis ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/pathology ; Central Nervous System ; *Parkinson Disease/pathology ; *Huntington Disease/pathology ; *Alzheimer Disease ; }, abstract = {The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.}, }
@article {pmid38102715, year = {2023}, author = {Stringer, RN and Weiss, N}, title = {Pathophysiology of ion channels in amyotrophic lateral sclerosis.}, journal = {Molecular brain}, volume = {16}, number = {1}, pages = {82}, pmid = {38102715}, issn = {1756-6606}, support = {#22-23242S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; VEGA #2/0073/22//Agent&#xfa;ra Ministerstva &#x160;kolstva, Vedy, V&#xfd;skumu a &#x160;portu SR/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Ion Channels ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.}, }
@article {pmid38101818, year = {2024}, author = {Ryan, L and Rubinsztein, DC}, title = {The autophagy of stress granules.}, journal = {FEBS letters}, volume = {598}, number = {1}, pages = {59-72}, doi = {10.1002/1873-3468.14787}, pmid = {38101818}, issn = {1873-3468}, support = {//Raymond and Beverly Sackler Fund/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; //UK Dementia Research Institute/ ; }, mesh = {Humans ; *Stress Granules ; Proteins ; Autophagy ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Our understanding of stress granule (SG) biology has deepened considerably in recent years, and with this, increased understanding of links has been made between SGs and numerous neurodegenerative diseases. One of the proposed mechanisms by which SGs and any associated protein aggregates may become pathological is based upon defects in their autophagic clearance, and so the precise processes governing the degradation of SGs are important to understand. Mutations and disease-associated variants implicated in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and frontotemporal lobar dementia compromise autophagy, whilst autophagy-inhibiting drugs or knockdown of essential autophagy proteins result in the persistence of SGs. In this review, we will consider the current knowledge regarding the autophagy of SG.}, }
@article {pmid38100267, year = {2024}, author = {Qi, S and Peng, Y and Wang, G and Zhang, X and Liu, M and He, L}, title = {A tale of dual functions of SERF family proteins in regulating amyloid formation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {5}, pages = {e202300727}, doi = {10.1002/cbic.202300727}, pmid = {38100267}, issn = {1439-7633}, support = {2018YFE0202301//National Key R&amp;D Program of China/ ; 2018YFE0202300//National Key R&amp;D Program of China/ ; 22174151//National Natural Sciences Foundation of China/ ; 21991080//National Natural Sciences Foundation of China/ ; XDB0540000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 2023AFA041//Hubei Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; Caenorhabditis elegans ; *Neurodegenerative Diseases ; Amyloidogenic Proteins ; Amyloid beta-Peptides ; *Alzheimer Disease ; *Caenorhabditis elegans Proteins ; }, abstract = {The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and β-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.}, }
@article {pmid38096601, year = {2024}, author = {Chiba, K and Niwa, S}, title = {Autoinhibition and activation of kinesin-1 and their involvement in amyotrophic lateral sclerosis.}, journal = {Current opinion in cell biology}, volume = {86}, number = {}, pages = {102301}, doi = {10.1016/j.ceb.2023.102301}, pmid = {38096601}, issn = {1879-0410}, mesh = {Humans ; *Kinesins/metabolism ; *Amyotrophic Lateral Sclerosis ; Neurons/metabolism ; Biological Transport ; }, abstract = {Kinesin-1, composed of kinesin heavy chain and kinesin light chain, is a founding member of kinesin superfamily and transports various neuronal cargos. Kinesin-1 is one of the most abundant ATPases in the cell and thus need to be tightly regulated to avoid wastage of energy. It has been well established that kinesin-1 is regulated by the autoinhibition mechanism. This review focuses on the recent researches that have contributed to the understanding of mechanisms for the autoinhibition of kinesin-1 and its unlocking. Recent electron microscopic studies have shown an unanticipated structure of autoinhibited kinesin-1. Biochemical reconstitution have revealed detailed molecular mechanisms how the autoinhibition is unlocked. Importantly, misregulation of kinesin-1 is emerging as one of the major causes of amyotrophic lateral sclerosis.}, }
@article {pmid38093670, year = {2024}, author = {Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Current challenges in primary lateral sclerosis diagnosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {1}, pages = {45-53}, doi = {10.1080/14737175.2023.2295010}, pmid = {38093670}, issn = {1744-8360}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnosis ; Neuroimaging ; Diagnosis, Differential ; Biomarkers ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Primary lateral sclerosis (PLS) is a rare, adult-onset and slowly progressive motor neuron disorder whose clinical core is characterized by upper motor neuron (UMN) dysfunction. Its formal diagnosis is clinically based and disease duration-dependent. Differentiating PLS from other disorders involving UMN can be challenging, particularly in the early stages.<br><br>AREAS COVERED: Our review covers and discusses different aspects of the PLS field, including the diagnostic criteria and its limitations, its differential diagnosis and their major pitfalls, and the actual role of neurophysiology, neuroimaging, genetics, and molecular biomarkers. Symptomatic treatment of the different manifestations is also addressed. The authors searched MEDLINE and Scopus. They also searched the reference lists of articles identified by our search strategy and reviewed and selected those deemed relevant. They selected papers and studies based on the quality of the report, significance of the findings, and on the author's critical appraise and expertise.<br><br>EXPERT OPINION: It is important to investigate novel molecular biomarkers and plan multicenter clinical trials for PLS. However, this will require a large international project to recruit enough patients, particularly given the diagnostic uncertainty of the current clinical criteria. A better understanding of PLS pathophysiology is crucial for designing disease-targeted therapies.}, }
@article {pmid38092270, year = {2024}, author = {Deng, C and Chen, H}, title = {Brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling in spinal muscular atrophy and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {190}, number = {}, pages = {106377}, doi = {10.1016/j.nbd.2023.106377}, pmid = {38092270}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Brain-Derived Neurotrophic Factor ; Motor Neurons/physiology ; Tropomyosin ; *Muscular Atrophy, Spinal ; Receptor, trkB ; }, abstract = {Tropomyosin receptor kinase B (TrkB) and its primary ligand brain-derived neurotrophic factor (BDNF) are expressed in the neuromuscular system, where they affect neuronal survival, differentiation, and functions. Changes in BDNF levels and full-length TrkB (TrkB-FL) signaling have been revealed in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), two common forms of motor neuron diseases that are characterized by defective neuromuscular junctions in early disease stages and subsequently progressive muscle weakness. This review summarizes the current understanding of BDNF/TrkB-FL-related research in SMA and ALS, with an emphasis on their alterations in the neuromuscular system and possible BDNF/TrkB-FL-targeting therapeutic strategies. The limitations of current studies and future directions are also discussed, giving the hope of discovering novel and effective treatments.}, }
@article {pmid38090405, year = {2023}, author = {Gupta, D and Vagha, S and Dhingra, H and Shirsath, H}, title = {Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48691}, pmid = {38090405}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly CNS neurodegenerative disease. The way ALS is now managed, from diagnosis to prognosis, is still not ideal despite many studies. Early diagnosis can help ALS patients live longer since prompt treatment can halt the disease's development. Two medications, riluzole and edaravone, have recently been licensed for use in therapy, and they very slightly increase life expectancy. Still, a lot of cutting-edge experimental medications are being developed. In the following article, we give a synopsis of the innovative medications and genetic remodeling that have emerged recently and help to halt the course of the illness. Studies have also been conducted on a few symptomatic and rehabilitative therapies that enhance the quality of life for ALS patients.}, }
@article {pmid38087359, year = {2023}, author = {Nayab, DE and Din, FU and Ali, H and Kausar, WA and Urooj, S and Zafar, M and Khan, I and Shabbir, K and Khan, GM}, title = {Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {477}, pmid = {38087359}, issn = {1477-3155}, support = {20-14604/NRPU/R&amp;D/HEC/2021//Higher Education Commision, Pakistan/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Brain ; Blood-Brain Barrier ; Drug Delivery Systems/methods ; Nanotechnology ; }, abstract = {Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.}, }
@article {pmid38078970, year = {2024}, author = {Sun, Z and Zhang, B and Peng, Y}, title = {Development of novel treatments for amyotrophic lateral sclerosis.}, journal = {Metabolic brain disease}, volume = {39}, number = {3}, pages = {467-482}, pmid = {38078970}, issn = {1573-7365}, support = {No. 82073835, and 81872855//National Natural Sciences Foundation of China/ ; No. 2021-I2M-1-054//CAMS Innovation Fund for Medical Sciences/ ; 201920200802//Disciplines construction project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes paralysis whose etiology and pathogenesis have not been fully elucidated. Presently it is incurable and rapidly progressive with a survival of 2-5 years from onset, and no treatments could cure it. Therefore, it is urgent to identify which therapeutic target(s) are more promising to develop treatments that could effectively treat ALS. So far, more than 90 novel treatments for ALS patients have been registered on ClinicalTrials.gov, of which 23 are in clinical trials, 12 have been terminated and the rest suspended. This review will systematically summarize the possible targets of these novel treatments under development or failing based on published literature and information released by sponsors, so as to provide basis and support for subsequent drug research and development.}, }
@article {pmid38072117, year = {2024}, author = {Alaoui Mansouri, M and Kharbach, M and Bouklouze, A}, title = {Current Applications of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) in Pharmaceutical Analysis: Review.}, journal = {Journal of pharmaceutical sciences}, volume = {113}, number = {4}, pages = {856-865}, doi = {10.1016/j.xphs.2023.12.004}, pmid = {38072117}, issn = {1520-6017}, mesh = {Least-Squares Analysis ; *Biopharmaceutics ; Pharmaceutical Preparations ; Multivariate Analysis ; }, abstract = {The present review encompasses various applications of multivariate curve resolution- alternating least squares (MCR-ALS) as a promising data handling, which is issued by analytical techniques in pharmaceutics. It involves different sections starting from a concise theory of MCR-ALS and four detailed applications in drugs analysis. Dissolution, stability, polymorphism, and quantification are the main four detailed applications. The data generated by analytical techniques associated with MCR-ALS deals accurately with different challenges compared to other chemometric tools. For each reviewed purpose, it was explained how MCR-ALS was applied and detailed information was given. Different approaches were introduced to overcome challenges that limit the use of MCR-ALS efficiently in pharmaceutical mixture were also discussed.}, }
@article {pmid38070961, year = {2023}, author = {Krall, JTW and Chakravartty, A and Caress, JB and Files, DC}, title = {Identification and Management of Acute Neuromuscular Respiratory Failure in the ICU.}, journal = {Chest}, volume = {164}, number = {6}, pages = {1454-1461}, doi = {10.1016/j.chest.2023.09.009}, pmid = {38070961}, issn = {1931-3543}, mesh = {Humans ; *Neuromuscular Diseases/complications/diagnosis/therapy ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; Prognosis ; Intensive Care Units ; }, abstract = {Respiratory failure is a common and potentially life-threatening complication of neuromuscular diseases. Prompt recognition and accurate diagnosis of new or worsening chronic neuromuscular disease have important clinical management and prognostic implications. In this article, we present an approach to the acute presentation of undifferentiated neuromuscular respiratory failure in the ICU and guidance for determination and respiratory management of the underlying disorder.}, }
@article {pmid38069329, year = {2023}, author = {Kim, H and Kim, GS and Hyun, SH and Kim, E}, title = {Advancements in 2D and 3D In Vitro Models for Studying Neuromuscular Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069329}, issn = {1422-0067}, support = {NRF-2021R1C1C2007132//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neuromuscular Diseases ; Muscle, Skeletal ; Neuromuscular Junction ; Motor Neurons ; Organoids ; }, abstract = {Neuromuscular diseases (NMDs) are a genetically or clinically heterogeneous group of diseases that involve injury or dysfunction of neuromuscular tissue components, including peripheral motor neurons, skeletal muscles, and neuromuscular junctions. To study NMDs and develop potential therapies, remarkable progress has been made in generating in vitro neuromuscular models using engineering approaches to recapitulate the complex physical and biochemical microenvironments of 3D human neuromuscular tissues. In this review, we discuss recent studies focusing on the development of in vitro co-culture models of human motor neurons and skeletal muscles, with the pros and cons of each approach. Furthermore, we explain how neuromuscular in vitro models recapitulate certain aspects of specific NMDs, including amyotrophic lateral sclerosis and muscular dystrophy. Research on neuromuscular organoids (NMO) will continue to co-develop to better mimic tissues in vivo and will provide a better understanding of the development of the neuromuscular tissue, mechanisms of NMD action, and tools applicable to preclinical studies, including drug screening and toxicity tests.}, }
@article {pmid38069154, year = {2023}, author = {Belosludtseva, NV and Matveeva, LA and Belosludtsev, KN}, title = {Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069154}, issn = {1422-0067}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Energy Metabolism ; Disease Progression ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.}, }
@article {pmid38062079, year = {2023}, author = {Bowden, M and Beswick, E and Tam, J and Perry, D and Smith, A and Newton, J and Chandran, S and Watts, O and Pal, S}, title = {A systematic review and narrative analysis of digital speech biomarkers in Motor Neuron Disease.}, journal = {NPJ digital medicine}, volume = {6}, number = {1}, pages = {228}, pmid = {38062079}, issn = {2398-6352}, abstract = {Motor Neuron Disease (MND) is a progressive and largely fatal neurodegeneritve disorder with a lifetime risk of approximately 1 in 300. At diagnosis, up to 25% of people with MND (pwMND) exhibit bulbar dysfunction. Currently, pwMND are assessed using clinical examination and diagnostic tools including the ALS Functional Rating Scale Revised (ALS-FRS(R)), a clinician-administered questionnaire with a single item on speech intelligibility. Here we report on the use of digital technologies to assess speech features as a marker of disease diagnosis and progression in pwMND. Google Scholar, PubMed, Medline and EMBASE were systematically searched. 40 studies were evaluated including 3670 participants; 1878 with a diagnosis of MND. 24 studies used microphones, 5 used smartphones, 6 used apps, 2 used tape recorders and 1 used the Multi-Dimensional Voice Programme (MDVP) to record speech samples. Data extraction and analysis methods varied but included traditional statistical analysis, CSpeech, MATLAB and machine learning (ML) algorithms. Speech features assessed also varied and included jitter, shimmer, fundamental frequency, intelligible speaking rate, pause duration and syllable repetition. Findings from this systematic review indicate that digital speech biomarkers can distinguish pwMND from healthy controls and can help identify bulbar involvement in pwMND. Preliminary evidence suggests digitally assessed acoustic features can identify more nuanced changes in those affected by voice dysfunction. No one digital speech biomarker alone is consistently able to diagnose or prognosticate MND. Further longitudinal studies involving larger samples are required to validate the use of these technologies as diagnostic tools or prognostic biomarkers.}, }
@article {pmid38052682, year = {2024}, author = {Festa, LK and Grinspan, JB and Jordan-Sciutto, KL}, title = {White matter injury across neurodegenerative disease.}, journal = {Trends in neurosciences}, volume = {47}, number = {1}, pages = {47-57}, pmid = {38052682}, issn = {1878-108X}, support = {R01 MH098742/MH/NIMH NIH HHS/United States ; R01 MH126773/MH/NIMH NIH HHS/United States ; R21 MH118121/MH/NIMH NIH HHS/United States ; T32 AI007632/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *White Matter/metabolism ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We discuss clinical data implicating white matter injury as a key feature of these disorders, as well as shared and divergent phenotypes between them. We examine the cellular and molecular mechanisms underlying the alterations to OLs, including chronic neuroinflammation, aggregation of proteins, lipid dysregulation, and organellar stress. Last, we highlight prospects for therapeutic intervention targeting the OL lineage to restore function.}, }
@article {pmid38046601, year = {2023}, author = {Quan, W and Chan, Z and Wei, P and Mao, Y and Bartels, D and Liu, X}, title = {PHD finger proteins function in plant development and abiotic stress responses: an overview.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1297607}, pmid = {38046601}, issn = {1664-462X}, abstract = {The plant homeodomain (PHD) finger with a conserved Cys4-His-Cys3 motif is a common zinc-binding domain, which is widely present in all eukaryotic genomes. The PHD finger is the "reader" domain of methylation marks in histone H3 and plays a role in the regulation of gene expression patterns. Numerous proteins containing the PHD finger have been found in plants. In this review, we summarize the functional studies on PHD finger proteins in plant growth and development and responses to abiotic stresses in recent years. Some PHD finger proteins, such as VIN3, VILs, and Ehd3, are involved in the regulation of flowering time, while some PHD finger proteins participate in the pollen development, for example, MS, TIP3, and MMD1. Furthermore, other PHD finger proteins regulate the plant tolerance to abiotic stresses, including Alfin1, ALs, and AtSIZ1. Research suggests that PHD finger proteins, as an essential transcription regulator family, play critical roles in various plant biological processes, which is helpful in understanding the molecular mechanisms of novel PHD finger proteins to perform specific function.}, }
@article {pmid38033869, year = {2023}, author = {Vukolova, MN and Yen, LY and Khmyz, MI and Sobolevsky, AI and Yelshanskaya, MV}, title = {Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis-emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1252953}, pmid = {38033869}, issn = {2296-634X}, support = {R01 AR078814/AR/NIAMS NIH HHS/United States ; R01 CA206573/CA/NCI NIH HHS/United States ; R01 NS083660/NS/NINDS NIH HHS/United States ; R01 NS107253/NS/NINDS NIH HHS/United States ; }, abstract = {Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.}, }
@article {pmid38029395, year = {2023}, author = {Song, J}, title = {Molecular mechanisms of phase separation and amyloidosis of ALS/FTD-linked FUS and TDP-43.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2023.1118}, pmid = {38029395}, issn = {2152-5250}, abstract = {FUS and TDP-43, two RNA-binding proteins from the heterogeneous nuclear ribonucleoprotein family, have gained significant attention in the field of neurodegenerative diseases due to their association with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). They possess folded domains for binding ATP and various nucleic acids including DNA and RNA, as well as substantial intrinsically disordered regions (IDRs) including prion-like domains (PLDs) and RG-/RGG-rich regions. They play vital roles in various cellular processes, including transcription, splicing, microRNA maturation, RNA stability and transport and DNA repair. In particular, they are key components for forming ribonucleoprotein granules and stress granules (SGs) through homotypic or heterotypic liquid-liquid phase separation (LLPS). Strikingly, liquid-like droplets formed by FUS and TDP-43 may undergo aging to transform into less dynamic assemblies such as hydrogels, inclusions, and amyloid fibrils, which are the pathological hallmarks of ALS and FTD. This review aims to synthesize and consolidate the biophysical knowledge of the sequences, structures, stability, dynamics, and inter-domain interactions of FUS and TDP-43 domains, so as to shed light on the molecular mechanisms underlying their liquid-liquid phase separation (LLPS) and amyloidosis. The review further delves into the mechanisms through which ALS-causing mutants of the well-folded hPFN1 disrupt the dynamics of LLPS of FUS prion-like domain, providing key insights into a potential mechanism for misfolding/aggregation-prone proteins to cause neurodegenerative diseases and aging by gain of functions. With better understanding of different biophysical aspects of FUS and TDP-43, the ultimate goal is to develop drugs targeting LLPS and amyloidosis, which could mediate protein homeostasis within cells and lead to new treatments for currently intractable diseases, particularly neurodegenerative diseases such as ALS, FTD and aging. However, the study of membrane-less organelles and condensates is still in its infancy and therefore the review also highlights key questions that require future investigation.}, }
@article {pmid38022117, year = {2023}, author = {Jain, A and Madkan, S and Patil, P}, title = {The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47861}, pmid = {38022117}, issn = {2168-8184}, abstract = {Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.}, }
@article {pmid38020546, year = {2023}, author = {de Brito Siqueira, ALG and Cremasco, PVV and Bahú, JO and Pioli da Silva, A and Melo de Andrade, LR and González, PGA and Crivellin, S and Cárdenas Concha, VO and Krambeck, K and Lodi, L and Severino, P and Souto, EB}, title = {Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection.}, journal = {Journal of traditional and complementary medicine}, volume = {13}, number = {6}, pages = {575-587}, pmid = {38020546}, issn = {2225-4110}, abstract = {Scientific evidence exists about the association between neurological diseases (i.e., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss) and oxidative damage. The increasing worldwide incidence of such diseases is attracting the attention of researchers to find palliative medications to reduce the symptoms and promote quality of life, in particular, in developing countries, e.g., South America and Africa. Among potential alternatives, extracts of Cannabis Sativa L. are suitable for people who have neurological disorders, spasticity, and pain, nausea, resulting from diseases such as cancer and arthritis. In this review, we discuss the latest developments in the use of Cannabis, its subtypes and constituents, extraction methods, and relevant pharmacological effects. Biomedical applications, marketed products, and prospects for the worldwide use of Cannabis Sativa L. extracts are also discussed, providing the bibliometric maps of scientific literature published in representative countries from South America (i.e., Brazil) and Africa (i.e., South Africa). A lack of evidence on the effectiveness and safety of Cannabis, besides the concerns about addiction and other adverse events, has led many countries to act with caution before changing Cannabis-related regulations. Recent findings are expected to increase the social acceptance of Cannabis, while new technologies seem to boost the global cannabis market because the benefits of (-)-trans-delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) use have been proven in several studies in addition to the potential to general new employment.}, }
@article {pmid38018119, year = {2024}, author = {Brown, A and Armon, C and Barkhaus, P and Beauchamp, M and Bertorini, T and Bromberg, M and Cadavid, JM and Carter, GT and Crayle, J and Feldman, EL and Heiman-Patterson, T and Jhooty, S and Linares, A and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Nathaniel, G and Pattee, G and Pierce, K and Ratner, D and Slactova, L and Wicks, P and Bedlack, R}, title = {ALSUntangled #72: Insulin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {416-419}, doi = {10.1080/21678421.2023.2288110}, pmid = {38018119}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Insulin/adverse effects ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.}, }
@article {pmid38010626, year = {2024}, author = {Zhong, R and Rua, MT and Wei-LaPierre, L}, title = {Targeting mitochondrial Ca[2+] uptake for the treatment of amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {8}, pages = {1519-1549}, pmid = {38010626}, issn = {1469-7793}, support = {R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; R56 NS117429/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.}, }
@article {pmid38007795, year = {2023}, author = {Feng, T}, title = {Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.}, journal = {Studies in health technology and informatics}, volume = {308}, number = {}, pages = {648-655}, doi = {10.3233/SHTI230896}, pmid = {38007795}, issn = {1879-8365}, mesh = {Humans ; Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; Machine Learning ; Natural Language Processing ; }, abstract = {Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.}, }
@article {pmid38004577, year = {2023}, author = {Niazi, SK}, title = {Non-Invasive Drug Delivery across the Blood-Brain Barrier: A Prospective Analysis.}, journal = {Pharmaceutics}, volume = {15}, number = {11}, pages = {}, pmid = {38004577}, issn = {1999-4923}, abstract = {Non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive procedures and devices have been developed or are currently being investigated to enhance drug delivery across the BBB. This paper presents a review and a prospective analysis of the art and science that address pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.}, }
@article {pmid38003309, year = {2023}, author = {Toader, C and Dobrin, N and Brehar, FM and Popa, C and Covache-Busuioc, RA and Glavan, LA and Costin, HP and Bratu, BG and Corlatescu, AD and Popa, AA and Ciurea, AV}, title = {From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003309}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/diagnosis ; Biomarkers/metabolism ; }, abstract = {With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.}, }
@article {pmid38002924, year = {2023}, author = {Genin, EC and Abou-Ali, M and Paquis-Flucklinger, V}, title = {Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002924}, issn = {2073-4425}, support = {ANR-16-CE16-0024-01//Agence Nationale de la Recherche/ ; MND202004011475//Fondation pour la Recherche M&#xe9;dicale/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Cell Death/genetics ; Mitochondrial Proteins/genetics/metabolism ; }, abstract = {Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.}, }
@article {pmid38002659, year = {2023}, author = {O'Day, DH}, title = {Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets.}, journal = {Journal of clinical medicine}, volume = {12}, number = {22}, pages = {}, pmid = {38002659}, issn = {2077-0383}, abstract = {Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington's disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson's disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases.}, }
@article {pmid38002264, year = {2023}, author = {Duranti, E and Villa, C}, title = {Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics.}, journal = {Biomolecules}, volume = {13}, number = {11}, pages = {}, pmid = {38002264}, issn = {2218-273X}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology ; Motor Neurons/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/metabolism ; Paralysis/complications/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.}, }
@article {pmid38001967, year = {2023}, author = {Seki, S and Kitaoka, Y and Kawata, S and Nishiura, A and Uchihashi, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S}, title = {Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001967}, issn = {2227-9059}, support = {21K17088//JSPS KAKENHI/ ; 20H03887//JSPS KAKENHI/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.}, }
@article {pmid38001926, year = {2023}, author = {Reddy, VP}, title = {Oxidative Stress in Health and Disease.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001926}, issn = {2227-9059}, abstract = {Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as N[e]-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).}, }
@article {pmid38001557, year = {2024}, author = {Genge, A and Wainwright, S and Vande Velde, C}, title = {Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {225-236}, doi = {10.1080/21678421.2023.2278503}, pmid = {38001557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.}, }
@article {pmid37999738, year = {2024}, author = {Ovsepian, SV and O'Leary, VB and Martinez, S}, title = {Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.}, journal = {Brain structure &amp; function}, volume = {229}, number = {1}, pages = {1-14}, pmid = {37999738}, issn = {1863-2661}, support = {Innovation Fund Award 2022//University of Greenwich/ ; COOPERATIO-207036//VBO, Charles University/ ; SAF2017-83702-R//Una manera de hacer Europa/ ; }, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.}, }
@article {pmid37992921, year = {2024}, author = {Li, L and Lei, T and Xing, C and Du, H}, title = {Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128308}, doi = {10.1016/j.ijbiomac.2023.128308}, pmid = {37992921}, issn = {1879-0003}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Microfluidics ; *Alzheimer Disease ; Amyloid beta-Peptides ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.}, }
@article {pmid37988405, year = {2024}, author = {Nusrath, S and Kalluru, P and Shukla, S and Dharanikota, A and Basude, M and Jonnada, P and Abualjadayel, M and Alabbad, S and Mir, TA and Broering, DC and Raju, K and Rao, TS and Vashist, YK}, title = {Current status of indocyanine green fluorescent angiography in assessing perfusion of gastric conduit and oesophago-gastric anastomosis.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {2}, pages = {1079-1089}, pmid = {37988405}, issn = {1743-9159}, mesh = {Humans ; *Indocyanine Green ; *Coloring Agents ; Angiography/adverse effects ; Anastomotic Leak/diagnostic imaging/etiology ; Anastomosis, Surgical/adverse effects/methods ; Esophagectomy/adverse effects/methods ; Perfusion ; }, abstract = {Anastomotic leak (AL) remains a significant complication after esophagectomy. Indocyanine green fluorescent angiography (ICG-FA) is a promising and safe technique for assessing gastric conduit (GC) perfusion intraoperatively. It provides detailed visualization of tissue perfusion and has demonstrated usefulness in oesophageal surgery. GC perfusion analysis by ICG-FA is crucial in constructing the conduit and selecting the anastomotic site and enables surgeons to make necessary adjustments during surgery to potentially reduce ALs. However, anastomotic integrity involves multiple factors, and ICG-FA must be combined with optimization of patient and procedural factors to decrease AL rates. This review summarizes ICG-FA's current applications in assessing esophago-gastric anastomosis perfusion, including qualitative and quantitative analysis and different imaging systems. It also explores how fluorescent imaging could decrease ALs and aid clinicians in utilizing ICG-FA to improve esophagectomy outcomes.}, }
@article {pmid37982993, year = {2023}, author = {Tsui, A and Kouznetsova, VL and Kesari, S and Fiala, M and Tsigelny, IF}, title = {Role of Senataxin in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {11-12}, pages = {996-1009}, pmid = {37982993}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Gene Expression Regulation ; Mutation ; DNA Helicases/genetics ; RNA Helicases/genetics/metabolism ; Multifunctional Enzymes/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.}, }
@article {pmid37982655, year = {2024}, author = {Mossa, A and Mayahara, M and Emezue, C and Paun, O}, title = {The Impact of Rapidly Progressing Neurodegenerative Disorders on Caregivers: An Integrative Literature Review.}, journal = {Journal of hospice and palliative nursing : JHPN : the official journal of the Hospice and Palliative Nurses Association}, volume = {26}, number = {2}, pages = {E62-E73}, pmid = {37982655}, issn = {1539-0705}, mesh = {Humans ; *Quality of Life ; Caregivers ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Death ; }, abstract = {Neurodegenerative disorders affect over 6 million people in the United States. A subset of these patients experiences symptoms that progress rapidly, along with a 5- to 10-year life expectancy (amyotrophic lateral sclerosis). This subgroup often becomes dependent on family caregivers. Managing care demands at the end of life that are brought on by rapid disease progression has a negative impact on caregiver quality of life. The purpose of this integrative review is to highlight the gaps in the existing body of research on the effect of neuropalliative care on quality of life of this caregiver population. A total of 13 articles met inclusion criteria and were selected for review. The most frequently occurring themes and findings in the literature shed light on neuropalliative care and provided some insight into both caregivers and patients' perspective at the end of life. What sets this population apart from caregivers and patients of other terminal diseases is the nature of disease progression and the rapid life adjustments that come along with it. Integration of neuropalliative has shown to provide additional support for caregivers and patients; however, it remains underused. To promote equitable access to these services, it is necessary to address several structural barriers.}, }
@article {pmid37981468, year = {2024}, author = {Sutter, PA and Lavoie, ER and Lombardo, ET and Pinter, MK and Crocker, SJ}, title = {Emerging Role of Astrocyte-Derived Extracellular Vesicles as Active Participants in CNS Neuroimmune Responses.}, journal = {Immunological investigations}, volume = {53}, number = {1}, pages = {26-39}, doi = {10.1080/08820139.2023.2281621}, pmid = {37981468}, issn = {1532-4311}, mesh = {Humans ; *Astrocytes ; *Extracellular Vesicles ; Cell Communication ; Biomarkers ; }, abstract = {Astrocyte-derived extracellular vesicles (ADEVs) have garnered attention as a fundamental mechanism of intercellular communication in health and disease. In the context of neurological diseases, for which prodromal diagnosis would be advantageous, ADEVs are also being explored for their potential utility as biomarkers. In this review, we provide the current state of data supporting our understanding on the manifold roles of ADEVs in several common neurological disorders. We also discuss these findings from a unique emerging perspective that ADEVs represent a means by which the central nervous system may broadcast influence over other systems in the body to affect neuroinflammatory processes, with both dual potential to either propagate illness or restore health and homeostasis.}, }
@article {pmid37981175, year = {2023}, author = {Wang, C and Cui, Y and Xu, T and Zhou, Y and Yang, R and Wang, T}, title = {New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {218}, number = {}, pages = {115923}, doi = {10.1016/j.bcp.2023.115923}, pmid = {37981175}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Glycogen Synthase Kinase 3 ; *Parkinson Disease ; *Alzheimer Disease ; *Diabetes Mellitus/drug therapy ; Glycogen Synthase Kinase 3 beta ; }, abstract = {Glycogen synthase kinase 3 (GSK-3) is a highly conserved protein serine/threonine kinase that plays a central role in a wide variety of cellular processes to coordinate catabolic and anabolic pathways and regulate cell growth and fate. There is increasing evidence showing that abnormal glycogen synthase kinase 3 (GSK-3) is associated with the pathogenesis and progression of many disorders, such as cancer, diabetes, psychiatric diseases, and neurodegenerative diseases. In this review, we summarize recent findings about the regulatory role of GSK-3 in the occurrence and development of multiple neurodegenerative diseases, mainly focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The aim of this study is to provide new insight into the shared working mechanism of GSK-3 as a therapeutic target of multiple neurodegenerative diseases.}, }
@article {pmid37975798, year = {2024}, author = {Saini, A and Chawla, PA}, title = {Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16140}, doi = {10.1111/ene.16140}, pmid = {37975798}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Oligonucleotides/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease.<br><br>METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary.<br><br>RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS.<br><br>CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.}, }
@article {pmid37974959, year = {2023}, author = {Bhargava, S and Kulkarni, R and Dewangan, B and Kulkarni, N and Jiaswar, C and Kumar, K and Kumar, A and Bodhe, PR and Kumar, H and Sahu, B}, title = {Microtubule stabilising peptides: new paradigm towards management of neuronal disorders.}, journal = {RSC medicinal chemistry}, volume = {14}, number = {11}, pages = {2192-2205}, pmid = {37974959}, issn = {2632-8682}, abstract = {Neuronal cells made of soma, axon, and dendrites are highly compartmentalized and possess a specialized transport system that can convey long-distance electrical signals for the cross-talk. The transport system is made up of microtubule (MT) polymers and MT-binding proteins. MTs play vital and diverse roles in various cellular processes. Therefore, defects and dysregulation of MTs and their binding proteins lead to many neurological disorders as exemplified by Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and many others. MT-stabilising agents (MSAs) altering the MT-associated protein connections have shown great potential for several neurodegenerative disorders. Peptides are an important class of molecules with high specificity, biocompatibility and are devoid of side effects. In the past, peptides have been explored in various neuronal disorders as therapeutics. Davunetide, a MT-stabilising octapeptide, has entered into phase II clinical trials for schizophrenia. Numerous examples of peptides emerging as MSAs reflect the emergence of a new paradigm for peptides which can be explored further as drug candidates for neuronal disorders. Although small molecule-based MSAs have been reviewed in the past, there is no systematic review in recent years focusing on peptides as MSAs apart from davunetide in 2013. Therefore, a systematic updated review on MT stabilising peptides may shed light on many hidden aspects and enable researchers to develop new therapies for diseases related to the CNS. In this review we have summarised the recent examples of peptides as MSAs.}, }
@article {pmid37974227, year = {2023}, author = {Awuah, WA and Ahluwalia, A and Ghosh, S and Roy, S and Tan, JK and Adebusoye, FT and Ferreira, T and Bharadwaj, HR and Shet, V and Kundu, M and Yee, ALW and Abdul-Rahman, T and Atallah, O}, title = {The molecular landscape of neurological disorders: insights from single-cell RNA sequencing in neurology and neurosurgery.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {529}, pmid = {37974227}, issn = {2047-783X}, mesh = {Humans ; *Neurosurgery ; Neurosurgical Procedures ; *Neurology ; *Brain Neoplasms/genetics ; Sequence Analysis, RNA ; Tumor Microenvironment ; }, abstract = {Single-cell ribonucleic acid sequencing (scRNA-seq) has emerged as a transformative technology in neurological and neurosurgical research, revolutionising our comprehension of complex neurological disorders. In brain tumours, scRNA-seq has provided valuable insights into cancer heterogeneity, the tumour microenvironment, treatment resistance, and invasion patterns. It has also elucidated the brain tri-lineage cancer hierarchy and addressed limitations of current models. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have been molecularly subtyped, dysregulated pathways have been identified, and potential therapeutic targets have been revealed using scRNA-seq. In epilepsy, scRNA-seq has explored the cellular and molecular heterogeneity underlying the condition, uncovering unique glial subpopulations and dysregulation of the immune system. ScRNA-seq has characterised distinct cellular constituents and responses to spinal cord injury in spinal cord diseases, as well as provided molecular signatures of various cell types and identified interactions involved in vascular remodelling. Furthermore, scRNA-seq has shed light on the molecular complexities of cerebrovascular diseases, such as stroke, providing insights into specific genes, cell-specific expression patterns, and potential therapeutic interventions. This review highlights the potential of scRNA-seq in guiding precision medicine approaches, identifying clinical biomarkers, and facilitating therapeutic discovery. However, challenges related to data analysis, standardisation, sample acquisition, scalability, and cost-effectiveness need to be addressed. Despite these challenges, scRNA-seq has the potential to transform clinical practice in neurological and neurosurgical research by providing personalised insights and improving patient outcomes.}, }
@article {pmid37973672, year = {2023}, author = {Lo Giudice, M and Cocco, A and Reggiardo, G and Lalli, S and Albanese, A}, title = {Tauro-Urso-Deoxycholic Acid Trials in Amyotrophic Lateral Sclerosis: What is Achieved and What to Expect.}, journal = {Clinical drug investigation}, volume = {43}, number = {12}, pages = {893-903}, pmid = {37973672}, issn = {1179-1918}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates ; Taurochenodeoxycholic Acid/adverse effects ; }, abstract = {Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-label follow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.}, }
@article {pmid37972860, year = {2023}, author = {Rizzuti, M and Sali, L and Melzi, V and Scarcella, S and Costamagna, G and Ottoboni, L and Quetti, L and Brambilla, L and Papadimitriou, D and Verde, F and Ratti, A and Ticozzi, N and Comi, GP and Corti, S and Gagliardi, D}, title = {Genomic and transcriptomic advances in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102126}, doi = {10.1016/j.arr.2023.102126}, pmid = {37972860}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Transcriptome/genetics ; Gene Expression Profiling/methods ; *MicroRNAs/genetics/metabolism ; Biomarkers ; Epigenomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.}, }
@article {pmid37966813, year = {2023}, author = {Fang, M and Liu, Y and Huang, C and Fan, S}, title = {Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders.}, journal = {BioFactors (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1002/biof.2017}, pmid = {37966813}, issn = {1872-8081}, abstract = {Stress granules (SGs) are membraneless organelles formed by eukaryotic cells in response to stress to promote cell survival through their pleiotropic cytoprotective effects. SGs recruit a variety of components to enhance their physiological function, and play a critical role in the propagation of pathological proteins, a key factor in neurodegeneration. Recent advances indicate that SG dynamic disorders exacerbate neuronal susceptibility to stress in neurodegenerative diseases (NDs) including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) and Parkinson's disease (PD). Here, we outline the biological functions of SGs, highlight SG dynamic disorders in NDs, and emphasize therapeutic approaches for enhancing SG dynamics to provide new insights into ND intervention.}, }
@article {pmid37966683, year = {2024}, author = {Ansari, MA and Tripathi, T and Venkidasamy, B and Monziani, A and Rajakumar, G and Alomary, MN and Alyahya, SA and Onimus, O and D'souza, N and Barkat, MA and Al-Suhaimi, EA and Samynathan, R and Thiruvengadam, M}, title = {Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.}, journal = {Molecular neurobiology}, volume = {61}, number = {5}, pages = {3042-3089}, pmid = {37966683}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Animals ; *Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Multifunctional Nanoparticles/chemistry ; }, abstract = {Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.}, }
@article {pmid37960284, year = {2023}, author = {Zheng, Y and Bonfili, L and Wei, T and Eleuteri, AM}, title = {Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders.}, journal = {Nutrients}, volume = {15}, number = {21}, pages = {}, pmid = {37960284}, issn = {2072-6643}, support = {Fondi Studenti PhD//University of Camerino/ ; }, mesh = {Humans ; Brain-Gut Axis ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Alzheimer Disease/therapy ; *Parkinson Disease/therapy ; Brain ; Dysbiosis/therapy ; }, abstract = {The gut-brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs.}, }
@article {pmid37958929, year = {2023}, author = {Boylan, MA and Pincetic, A and Romano, G and Tatton, N and Kenkare-Mitra, S and Rosenthal, A}, title = {Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958929}, issn = {1422-0067}, mesh = {Humans ; Progranulins/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; *Frontotemporal Dementia/genetics ; Neurons/pathology ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer's disease (AD), Parkinson's disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain's immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state.}, }
@article {pmid37958596, year = {2023}, author = {Stoka, V and Vasiljeva, O and Nakanishi, H and Turk, V}, title = {The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958596}, issn = {1422-0067}, support = {J1-2473, P1-0140//Slovenian Research Agency/ ; }, mesh = {Humans ; *Cysteine Proteases ; *Neurodegenerative Diseases ; Cysteine/metabolism ; Cathepsin B ; *Neoplasms ; Lysosomes/metabolism ; }, abstract = {Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Recently, cysteine cathepsins have been found to be present outside the lysosomes and often participate in various pathological processes. Hence, they have been considered key signalling molecules. Their potentially hazardous proteolytic activities are tightly regulated. This review aims to discuss recent advances in understanding the structural aspects of these four cathepsins, mechanisms of their zymogen activation, regulation of their activities, and functional aspects of these enzymes in neurodegeneration and cancer. Neurodegenerative effects have been evaluated, particularly in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuropsychiatric disorders. Cysteine cathepsins also participate in tumour progression and metastasis through the overexpression and secretion of proteases, which trigger extracellular matrix degradation. To our knowledge, this is the first review to provide an in-depth analysis regarding the roles of cysteine cathepsins B, H, C, and X in neurodegenerative diseases and cancer. Further advances in understanding the functions of cysteine cathepsins in these conditions will result in the development of novel, targeted therapeutic strategies.}, }
@article {pmid37955299, year = {2023}, author = {Yuan, YH and Mao, ND and Duan, JL and Zhang, H and Garrido, C and Lirussi, F and Gao, Y and Xie, T and Ye, XY}, title = {Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents.}, journal = {Journal of enzyme inhibition and medicinal chemistry}, volume = {38}, number = {1}, pages = {2279906}, pmid = {37955299}, issn = {1475-6374}, mesh = {Humans ; *Protein Serine-Threonine Kinases ; *Antiviral Agents/pharmacology ; Phosphorylation ; Pain ; }, abstract = {Adaptor associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of Ser/Thr kinases, is a specific key kinase regulating Thr156 phosphorylation at the μ2 subunit of the adapter complex-2 (AP-2) protein. Due to their important biological functions, AAK1 systems have been validated in clinics for neuropathic pain therapy, and are being explored as potential therapeutic targets for diseases caused by various viruses such as Hepatitis C (HCV), Dengue, Ebola, and COVID-19 viruses and for amyotrophic lateral sclerosis (ALS). Centreing on the advances of drug discovery programs in this field up to 2023, AAK1 inhibitors are discussed from the aspects of the structure-based rational molecular design, pharmacology, toxicology and synthetic routes for the compounds of interest in this review. The aim is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in the field of AAK1 small molecule inhibitors.}, }
@article {pmid37952981, year = {2023}, author = {Okano, H and Morimoto, S and Kato, C and Nakahara, J and Takahashi, S}, title = {Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {167}, number = {5}, pages = {603-614}, doi = {10.1111/jnc.16005}, pmid = {37952981}, issn = {1471-4159}, support = {JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Drug Evaluation, Preclinical ; *Neurodegenerative Diseases/metabolism ; Translational Research, Biomedical ; Randomized Controlled Trials as Topic ; }, abstract = {It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.}, }
@article {pmid37949994, year = {2023}, author = {McMackin, R and Bede, P and Ingre, C and Malaspina, A and Hardiman, O}, title = {Biomarkers in amyotrophic lateral sclerosis: current status and future prospects.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {12}, pages = {754-768}, pmid = {37949994}, issn = {1759-4766}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Prognosis ; Disease Progression ; Drug Development ; }, abstract = {Disease heterogeneity in amyotrophic lateral sclerosis poses a substantial challenge in drug development. Categorization based on clinical features alone can help us predict the disease course and survival, but quantitative measures are also needed that can enhance the sensitivity of the clinical categorization. In this Review, we describe the emerging landscape of diagnostic, categorical and pharmacodynamic biomarkers in amyotrophic lateral sclerosis and their place in the rapidly evolving landscape of new therapeutics. Fluid-based markers from cerebrospinal fluid, blood and urine are emerging as useful diagnostic, pharmacodynamic and predictive biomarkers. Combinations of imaging measures have the potential to provide important diagnostic and prognostic information, and neurophysiological methods, including various electromyography-based measures and quantitative EEG-magnetoencephalography-evoked responses and corticomuscular coherence, are generating useful diagnostic, categorical and prognostic markers. Although none of these biomarker technologies has been fully incorporated into clinical practice or clinical trials as a primary outcome measure, strong evidence is accumulating to support their clinical utility.}, }
@article {pmid37946793, year = {2023}, author = {Rogers, ML and Schultz, DW and Karnaros, V and Shepheard, SR}, title = {Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad287}, pmid = {37946793}, issn = {2632-1297}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.}, }
@article {pmid37946741, year = {2023}, author = {Ebrahimi, A and Kamyab, A and Hosseini, S and Ebrahimi, S and Ashkani-Esfahani, S}, title = {Involvement of Coenzyme Q10 in Various Neurodegenerative and Psychiatric Diseases.}, journal = {Biochemistry research international}, volume = {2023}, number = {}, pages = {5510874}, pmid = {37946741}, issn = {2090-2247}, abstract = {Coenzyme Q10 (CoQ10), commonly known as ubiquinone, is a vitamin-like component generated in mitochondrial inner membranes. This molecule is detected broadly in different parts of the human body in various quantities. This molecule can be absorbed by the digestive system from various nutritional sources as supplements. CoQ10 exists in three states: in a of reduced form (ubiquinol), in a semiquinone radical form, and in oxidized ubiquinone form in different organs of the body, playing a crucial role in electron transportation and contributing to energy metabolism and oxygen utilization, especially in the musculoskeletal and nervous systems. Since the early 1980s, research about CoQ10 has become the interest for two reasons. First, CoQ10 deficiency has been found to have a link with cardiovascular, neurologic, and cancer disorders. Second, this molecule has an antioxidant and free-radical scavenger nature. Since then, several investigations have indicated that the drug may benefit patients with cardiovascular, neuromuscular, and neurodegenerative illnesses. CoQ10 may protect the neurological system from degeneration and degradation due to its antioxidant and energy-regulating activity in mitochondria. This agent has shown its efficacy in preventing and treating neurological diseases such as migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. This study reviews the literature to highlight this agent's potential therapeutic effects in the mentioned neurological disorders.}, }
@article {pmid37946655, year = {2023}, author = {Lochbaum, R and Hoffmann, TK and Greve, J and Hahn, J}, title = {[Medikamente als Auslöser Bradykinin-vermittelter Angioödeme - mehr als ACE-Hemmer].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {11}, pages = {1283-1290}, doi = {10.1111/ddg.15154_g}, pmid = {37946655}, issn = {1610-0387}, }
@article {pmid37944521, year = {2024}, author = {Yang, K and Tang, Z and Xing, C and Yan, N}, title = {STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges.}, journal = {Neuron}, volume = {112}, number = {4}, pages = {539-557}, pmid = {37944521}, issn = {1097-4199}, support = {R01 AI151708/AI/NIAID NIH HHS/United States ; R01 NS117424/NS/NINDS NIH HHS/United States ; R01 NS122825/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Brain/pathology ; *Nervous System Diseases ; Signal Transduction ; }, abstract = {Stimulator of interferon genes (STING) is an innate immune signaling protein critical to infections, autoimmunity, and cancer. STING signaling is also emerging as an exciting and integral part of many neurological diseases. Here, we discuss recent advances in STING signaling in the brain. We summarize how molecular threats activate STING signaling in the diseased brain and how STING signaling activities in glial and neuronal cells cause neuropathology. We also review human studies of STING neurobiology and consider therapeutic challenges in targeting STING to treat neurological diseases.}, }
@article {pmid37942130, year = {2023}, author = {Piñeros-Fernández, MC}, title = {Artificial Intelligence Applications in the Diagnosis of Neuromuscular Diseases: A Narrative Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48458}, pmid = {37942130}, issn = {2168-8184}, abstract = {The accurate diagnosis of neuromuscular diseases (NMD) is in many cases difficult; the starting point is the clinical approach based on the course of the disease and a careful physical examination of the patient. Electrodiagnostic tests, imaging, muscle biopsy, and genetics are fundamental complementary studies for the diagnosis of NMD. The large volume of data obtained from such studies makes it necessary to look for efficient solutions, such as artificial intelligence (AI) applications, which can help classify, synthesize, and organize the information of patients with NMD to facilitate their accurate and timely diagnosis. The objective of this study was to describe the usefulness of AI applications in the diagnosis of patients with neuromuscular diseases. A narrative review was done, including publications on artificial intelligence applied to the diagnostic methods of NMD currently existing. Twelve studies were included. Two of the studies focused on muscle ultrasound, five of the studies on muscle MRI, two studies on electromyography, two studies on amyotrophic lateral sclerosis (ALS) biomarkers, and one study on genes related to myopathies. The accuracy of classification using different classification algorithms used in each of the studies included in this narrative review was already 90% in most studies. In conclusion, the future design of more accurate algorithms applied to NMD with greater precision will have an impact on the earlier diagnosis of this group of diseases.}, }
@article {pmid37941028, year = {2023}, author = {Huang, Y and Liu, B and Sinha, SC and Amin, S and Gan, L}, title = {Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {79}, pmid = {37941028}, issn = {1750-1326}, support = {R01 AG074541/AG/NIA NIH HHS/United States ; R01AG072758/AG/NIA NIH HHS/United States ; R01AG074541/AG/NIA NIH HHS/United States ; R01AG054214/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Signal Transduction/physiology ; Nucleotidyltransferases/genetics/metabolism ; DNA/metabolism ; *Interferon Type I/genetics/metabolism ; *Nervous System Diseases ; }, abstract = {DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.}, }
@article {pmid37939160, year = {2023}, author = {Gendron, TF and Petrucelli, L}, title = {Immunological drivers of amyotrophic lateral sclerosis.}, journal = {Science translational medicine}, volume = {15}, number = {721}, pages = {eadj9332}, doi = {10.1126/scitranslmed.adj9332}, pmid = {37939160}, issn = {1946-6242}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease involving complex genetic and environmental factors, is associated with neuroinflammation. Preclinical and clinical studies support immune system involvement in ALS pathogenesis, thereby spurring investigations into potential pathogenic mechanisms, immune response biomarkers, and ALS therapeutics.}, }
@article {pmid37938192, year = {2023}, author = {Maharaj, D and Kaur, K and Saltese, A and Gouvea, J}, title = {Personalized Precision Immunotherapy for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {2}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023048372}, pmid = {37938192}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Immunotherapy ; Brain ; Cytokines ; Inflammation ; }, abstract = {Neurological syndrome amyotrophic lateral sclerosis (ALS) affects motor neurons and is characterized by progressive motor neuron loss in the brain and spinal cord. ALS starts with mainly focal onset but when the disease progresses, it spreads to different parts of the body, with survival limits of 2-5 years after disease initiation. To date, only supportive care is provided for ALS patients, and no effective treatment or cure has been discovered. This review is focused on clinical and immunological aspects of ALS patients, based on our case studies, and we discuss the treatment we have provided to those patients based on a detailed evaluation of their peripheral blood immune cells and blood-derived serum secreted factors, cytokines, chemokines and growth factors. We show that using a personalized approach of low dose immunotherapy there is an improvement in the effects on inflammation and immunological dysfunction.}, }
@article {pmid37928737, year = {2023}, author = {Johnson, GA and Krishnamoorthy, RR and Stankowska, DL}, title = {Modulating mitochondrial calcium channels (TRPM2/MCU/NCX) as a therapeutic strategy for neurodegenerative disorders.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1202167}, pmid = {37928737}, issn = {1662-4548}, support = {T32 AG020494/AG/NIA NIH HHS/United States ; }, abstract = {Efficient cellular communication is essential for the brain to regulate diverse functions like muscle contractions, memory formation and recall, decision-making, and task execution. This communication is facilitated by rapid signaling through electrical and chemical messengers, including voltage-gated ion channels and neurotransmitters. These messengers elicit broad responses by propagating action potentials and mediating synaptic transmission. Calcium influx and efflux are essential for releasing neurotransmitters and regulating synaptic transmission. Mitochondria, which are involved in oxidative phosphorylation, and the energy generation process, also interact with the endoplasmic reticulum to store and regulate cytoplasmic calcium levels. The number, morphology, and distribution of mitochondria in different cell types vary based on energy demands. Mitochondrial damage can cause excess reactive oxygen species (ROS) generation. Mitophagy is a selective process that targets and degrades damaged mitochondria via autophagosome-lysosome fusion. Defects in mitophagy can lead to a buildup of ROS and cell death. Numerous studies have attempted to characterize the relationship between mitochondrial dysfunction and calcium dysregulation in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, and aging. Interventional strategies to reduce mitochondrial damage and accumulation could serve as a therapeutic target, but further research is needed to unravel this potential. This review offers an overview of calcium signaling related to mitochondria in various neuronal cells. It critically examines recent findings, exploring the potential roles that mitochondrial dysfunction might play in multiple neurodegenerative diseases and aging. Furthermore, the review identifies existing gaps in knowledge to guide the direction of future research.}, }
@article {pmid37926865, year = {2024}, author = {Xiao, X and Li, M and Ye, Z and He, X and Wei, J and Zha, Y}, title = {FUS gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {1-15}, doi = {10.1080/21678421.2023.2272170}, pmid = {37926865}, issn = {2167-9223}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Mutation/genetics ; Mutation, Missense ; *Neurodegenerative Diseases ; Retrospective Studies ; RNA-Binding Protein FUS/genetics ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by progressive muscle weakness, atrophy, and paralysis. The FUS mutation-associated ALS has been classified as ALS6. We reported a case of ALS6 with de novo mutation and investigated retrospectively the characteristics of cases with FUS mutation.<br><br>METHODS: We reported a male patient with a new heterozygous variant of the FUS gene and comprehensively reviewed 173 ALS cases with FUS mutation. The literature was reviewed from the PubMed MEDLINE electronic database (https://www.ncbi.nlm.nih.gov/pubmed) using "Amyotrophic Lateral Sclerosis and Fus mutation" or "Fus mutation" as key words from 1 January 2009 to 1 January 2022.<br><br>RESULTS: We report a case of ALS6 with a new mutation point (c.1225-1227delGGA) and comprehensively review 173 ALS cases with FUS mutation. Though ALS6 is all with FUS mutation, it is still a highly heterogenous subtype. The average onset age of ALS6 is 35.2&#xa0;&#xb1;&#xa0;1.3 years, which is much lower than the average onset age of ALS (60 years old). Juvenile FUS mutations have an aggressive progression of disease, with an average time from onset to death or tracheostomy of 18.2&#xa0;&#xb1;&#xa0;0.5 months. FUS gene has the characteristics of early onset, faster progress, and shorter survival, especially in deletion mutation p.G504Wfs *12 and missense mutation of p.P525L.<br><br>CONCLUSIONS: ALS6 is a highly heterogenous subtype. Our study could allow clinicians to better understand the non-ALS typical symptoms, phenotypes, and pathophysiology of ALS6.}, }
@article {pmid37922093, year = {2024}, author = {Jellinger, KA}, title = {Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {2}, pages = {107-115}, pmid = {37922093}, issn = {1435-1463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; Depression/complications ; Quality of Life ; Affect ; *Neurodegenerative Diseases/complications ; }, abstract = {Depression with an average prevalence of 25-40% is a serious condition in amyotrophic lateral sclerosis (ALS) that can impact quality of life and survival of patients and caregiver burden, yet the underlying neurobiology is poorly understood. Preexisting depression has been associated with a higher risk of developing ALS, while people with ALS have a significantly higher risk of developing depression that can cause multiple complications. Depression may be a prodromal or subclinical symptom prior to motor involvement, although its relations with disease progression and impairment of quality of life are under discussion. Unfortunately, there are no studies existing that explore the pathogenic mechanisms of depression associated with the basic neurodegenerative process, and no specific neuroimaging data or postmortem findings for the combination of ALS and depression are currently available. Experience from other neurodegenerative processes suggests that depressive symptoms in ALS may be the consequence of cortical thinning in prefrontal regions and other cortex areas, disruption of mood-related brain networks, dysfunction of neurotransmitter systems, changing cortisol levels and other, hitherto unknown mechanisms. Treatment of both ALS and depression is a multidisciplinary task, depression generally being treated with a combination of antidepressant medication, physiotherapy, psychological and other interventions, while electroconvulsive therapy and deep brain stimulation might not be indicated in the majority of patients in view of their poor prognosis. Since compared to depression in other neurodegenerative diseases, our knowledge of its molecular basis in ALS is missing, multidisciplinary clinicopathological studies to elucidate the pathomechanism of depression in motor system disorders including ALS are urgently warranted.}, }
@article {pmid37920473, year = {2023}, author = {Lemos, JP and Tenório, LPG and Mouly, V and Butler-Browne, G and Mendes-da-Cruz, DA and Savino, W and Smeriglio, P}, title = {T cell biology in neuromuscular disorders: a focus on Duchenne Muscular Dystrophy and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1202834}, pmid = {37920473}, issn = {1664-3224}, mesh = {Humans ; *Muscular Dystrophy, Duchenne/therapy ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Neuromuscular Diseases ; Muscles ; Genetic Therapy/methods ; }, abstract = {Growing evidence demonstrates a continuous interaction between the immune system, the nerve and the muscle in neuromuscular disorders of different pathogenetic origins, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS), the focus of this review. Herein we highlight the complexity of the cellular and molecular interactions involving the immune system in neuromuscular disorders, as exemplified by DMD and ALS. We describe the distinct types of cell-mediated interactions, such as cytokine/chemokine production as well as cell-matrix and cell-cell interactions between T lymphocytes and other immune cells, which target cells of the muscular or nervous tissues. Most of these interactions occur independently of exogenous pathogens, through ligand-receptor binding and subsequent signal transduction cascades, at distinct levels of specificity. Although this issue reveals the complexity of the system, it can also be envisioned as a window of opportunity to design therapeutic strategies (including synthetic moieties, cell and gene therapy, as well as immunotherapy) by acting upon one or more targets. In this respect, we discuss ongoing clinical trials using VLA-4 inhibition in DMD, and in ALS, with a focus on regulatory T cells, both revealing promising results.}, }
@article {pmid37919089, year = {2023}, author = {Moda, F and Ciullini, A and Dellarole, IL and Lombardo, A and Campanella, N and Bufano, G and Cazzaniga, FA and Giaccone, G}, title = {Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {10}, pages = {255}, doi = {10.31083/j.fbl2810255}, pmid = {37919089}, issn = {2768-6698}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/pathology ; Protein Aggregates ; *Lewy Body Disease/metabolism/pathology ; *Synucleinopathies ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; tau Proteins/metabolism ; *Prion Diseases ; Amyloid beta-Peptides ; *Frontotemporal Lobar Degeneration ; }, abstract = {The presence of protein aggregates is a hallmark of many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Traditionally, each disease has been associated with the aggregation of specific proteins, which serve as disease-specific biomarkers. For example, aggregates of α-synuclein (α-syn) are found in α-synucleinopathies such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Similarly, AD is characterized by aggregates of amyloid-beta (Aβ) and tau proteins. However, it has been observed that these protein aggregates can also occur in other neurodegenerative diseases, contributing to disease progression. For instance, α-syn aggregates have been detected in AD, Down syndrome, Huntington's disease, prion diseases, and various forms of FTLD. Similarly, Aβ aggregates have been found in conditions like DLB and PD. Tau aggregates, in addition to being present in primary tauopathies, have been identified in prion diseases, α-synucleinopathies, and cognitively healthy aged subjects. Finally, aggregates of TDP-43, typically associated with FTLD and amyotrophic lateral sclerosis (ALS), have been observed in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MSA, DLB, and other neurodegenerative diseases. These findings highlight the complexity of protein aggregation in neurodegeneration and suggest potential interactions and common mechanisms underlying different diseases. A deeper understating of this complex scenario may eventually lead to the identification of a better elucidation of the pathogenetic mechanisms of these devastating conditions and hopefully new therapeutic stragegies.}, }
@article {pmid37909610, year = {2023}, author = {Reis, AHO and Figalo, LB and Orsini, M and Lemos, B}, title = {The implications of DNA methylation for amyotrophic lateral sclerosis.}, journal = {Anais da Academia Brasileira de Ciencias}, volume = {95}, number = {suppl 2}, pages = {e20230277}, doi = {10.1590/0001-3765202320230277}, pmid = {37909610}, issn = {1678-2690}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA Methylation/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and serious neurodegenerative disorder that develops in consequence of the progressive loss of the upper and lower motor neurons. Cases of ALS are classified as sporadic (sALS), or familial (fALS). Over 90% of cases are sALS, while roughly 10% are related to inherited genetic mutations (fALS). Approximately 70% of the genetic mutations that contribute to fALS have been identified. On the other hand, the majority of the sALS cases have an undetermined genetic contributor and few mutations have been described, despite the advanced genetic analysis methods. Also, several factors contribute to the onset and progression of ALS. Numerous lines of evidence indicate that epigenetic changes are linked to aging, as well as neurodegenerative disorders, such as ALS. In most cases, they act as the heritable regulation of transcription by DNA methylation, histone modification and expression of noncoding RNAs. Mechanisms involving aberrant DNA methylation could be relevant to human ALS pathobiology and therapeutic targeting. Despite advances in research to find factors associated with ALS and more effective treatments, this disease remains complex and has low patient survival. Here, we provide a narrative review of the role of DNA methylation for this complex neurodegenerative disorder.}, }
@article {pmid37907717, year = {2024}, author = {Yamamoto, K and Itoi, T and Matsunami, Y and Sofuni, A and Tsuchiya, T and Mukai, S and Kojima, H and Minami, H and Nakatsubo, R and Tonozuka, R}, title = {Early and late effects of endoscopic interventions in patients with malignant afferent loop syndrome: A single-center experience and literature review.}, journal = {Journal of hepato-biliary-pancreatic sciences}, volume = {31}, number = {2}, pages = {120-132}, doi = {10.1002/jhbp.1380}, pmid = {37907717}, issn = {1868-6982}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; *Cholestasis/etiology ; Drainage ; Endoscopy ; Endosonography ; Liver/pathology ; Retrospective Studies ; Stents/adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND/PURPOSE: Afferent loop syndrome (ALS) is a rare adverse event after gastrointestinal surgery requiring appropriate early decompression treatment. Several endoscopic interventions have been attempted for treatment, including endoscopic enteral metal stent placement (EMSP), endoscopic ultrasound (EUS)-guided entero-enterostomy (EUS-EE), and EUS-guided hepaticogastrostomy (EUS-HGS). However, there are limited data on outcomes, including duration of stent patency. In this study, we evaluated the usefulness of each endoscopic intervention for malignant ALS.<br><br>METHODS: We retrospectively investigated nine patients with malignant ALS who underwent EMSP, EUS-EE, or EUS-HGS. Information on technical success, clinical efficacy, adverse events, stent dysfunction, and overall survival was collected and analyzed.<br><br>RESULTS: The most common symptoms were abdominal pain and cholangitis. ALS was treated by EMSP in three patients, EUS-EE in three patients, and EUS-HGS in three patients. Stent placement was successful and clinically effective in all patients with no adverse events. During follow-up, stent dysfunction occurred in two patients treated by EUS-HGS. Eight patients died of primary disease during a median follow-up of 157&#x2009;days.<br><br>CONCLUSIONS: Each of the available endoscopic interventions for malignant ALS can be expected to produce similar outcomes, including duration of stent patency. The choice of endoscopic intervention should be made based on the characteristics of each treatment.}, }
@article {pmid37907134, year = {2023}, author = {Birajdar, SV and Mazahir, F and Alam, MI and Kumar, A and Yadav, AK}, title = {Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {961}, number = {}, pages = {176117}, doi = {10.1016/j.ejphar.2023.176117}, pmid = {37907134}, issn = {1879-0712}, mesh = {Humans ; Mice ; Animals ; Hypoglycemic Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/drug therapy ; Drug Repositioning ; Neuroinflammatory Diseases ; *Alzheimer Disease/drug therapy ; Insulin/metabolism ; *Metformin/pharmacology ; }, abstract = {The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid β metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aβ deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aβ monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders.}, }
@article {pmid37904013, year = {2024}, author = {Chen, X and Luo, J and Zheng, W and Huang, Q and Du, C and Yuan, H and Xiao, F}, title = {Hyperhidrosis as the initial symptom in FUS mutation-associated amyotrophic lateral sclerosis: a case report and comprehensive literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1523-1527}, pmid = {37904013}, issn = {1590-3478}, mesh = {Female ; Humans ; Young Adult ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Hyperhidrosis/genetics ; Mutation ; *Neurodegenerative Diseases ; Quality of Life ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis.<br><br>METHOD: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted.<br><br>RESULT: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene.<br><br>CONCLUSION: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis.}, }
@article {pmid37895110, year = {2023}, author = {Provenzano, F and Torazza, C and Bonifacino, T and Bonanno, G and Milanese, M}, title = {The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895110}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Glutamic Acid/metabolism ; Astrocytes/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; }, abstract = {In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the "astrocytic signature" in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as "producers" and "targets" of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation.}, }
@article {pmid37895020, year = {2023}, author = {Davis, SE and Cirincione, AB and Jimenez-Torres, AC and Zhu, J}, title = {The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895020}, issn = {1422-0067}, support = {R01 DA057866/DA/NIDA NIH HHS/United States ; F31 DA057163/DA/NIDA NIH HHS/United States ; R01 DA047924/DA/NIDA NIH HHS/United States ; R01 DA035714/DA/NIDA NIH HHS/United States ; DA047924/NH/NIH HHS/United States ; DA035714/NH/NIH HHS/United States ; DA057866/NH/NIH HHS/United States ; DA057163/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Alzheimer Disease/pathology ; Brain/pathology ; *Huntington Disease/pathology ; *HIV Infections/pathology ; }, abstract = {Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease. In addition to these, 50% of people living with HIV develop a spectrum of cognitive, motor, and/or mood problems collectively referred to as HIV-Associated Neurocognitive Disorders (HAND) despite the widespread use of a combination of antiretroviral therapies. Neuroinflammation and neurotransmitter systems have a pathological correlation and play a critical role in developing neurodegenerative diseases. Each of these diseases has a unique pattern of dysregulation of the neurotransmitter system, which has been attributed to different forms of cell-specific neuronal loss. In this review, we will focus on a discussion of the regulation of dopaminergic and cholinergic systems, which are more commonly disturbed in neurodegenerative disorders. Additionally, we will provide evidence for the hypothesis that disturbances in neurotransmission contribute to the neuronal loss observed in neurodegenerative disorders. Further, we will highlight the critical role of dopamine as a mediator of neuronal injury and loss in the context of NeuroHIV. This review will highlight the need to further investigate neurotransmission systems for their role in the etiology of neurodegenerative disorders.}, }
@article {pmid37894774, year = {2023}, author = {Moțățăianu, A and Șerban, G and Andone, S}, title = {The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894774}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; Aged ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Fatty Acids, Volatile/metabolism ; Fatty Acids/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.}, }
@article {pmid37893165, year = {2023}, author = {De Marchi, F and Munitic, I and Vidatic, L and Papić, E and Rački, V and Nimac, J and Jurak, I and Novotni, G and Rogelj, B and Vuletic, V and Liscic, RM and Cannon, JR and Buratti, E and Mazzini, L and Hecimovic, S}, title = {Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893165}, issn = {2227-9059}, abstract = {Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.}, }
@article {pmid37892126, year = {2023}, author = {Ramos, V and Reis, M and Ferreira, L and Silva, AM and Ferraz, R and Vieira, M and Vasconcelos, V and Martins, R}, title = {Stalling the Course of Neurodegenerative Diseases: Could Cyanobacteria Constitute a New Approach toward Therapy?.}, journal = {Biomolecules}, volume = {13}, number = {10}, pages = {}, pmid = {37892126}, issn = {2218-273X}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress ; *Parkinson Disease/drug therapy ; Antioxidants/pharmacology ; *Cyanobacteria/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive and irreversible neuronal loss, accompanied by a range of pathological pathways, including aberrant protein aggregation, altered energy metabolism, excitotoxicity, inflammation, and oxidative stress. Some of the most common NDs include Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD). There are currently no available cures; there are only therapeutic approaches that ameliorate the progression of symptoms, which makes the search for new drugs and therapeutic targets a constant battle. Cyanobacteria are ancient prokaryotic oxygenic phototrophs whose long evolutionary history has resulted in the production of a plethora of biomedically relevant compounds with anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective properties, that can be valuable in this field. This review summarizes the major NDs and their pathophysiology, with a focus on the anti-neurodegenerative properties of cyanobacterial compounds and their main effects.}, }
@article {pmid37891890, year = {2023}, author = {Korczowska-Łącka, I and Słowikowski, B and Piekut, T and Hurła, M and Banaszek, N and Szymanowicz, O and Jagodziński, PP and Kozubski, W and Permoda-Pachuta, A and Dorszewska, J}, title = {Disorders of Endogenous and Exogenous Antioxidants in Neurological Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891890}, issn = {2076-3921}, abstract = {In diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and even epilepsy and migraine, oxidative stress load commonly surpasses endogenous antioxidative capacity. While oxidative processes have been robustly implicated in the pathogenesis of these diseases, the significance of particular antioxidants, both endogenous and especially exogenous, in maintaining redox homeostasis requires further research. Among endogenous antioxidants, enzymes such as catalase, superoxide dismutase, and glutathione peroxidase are central to disabling free radicals, thereby preventing oxidative damage to cellular lipids, proteins, and nucleic acids. Whether supplementation with endogenously occurring antioxidant compounds such as melatonin and glutathione carries any benefit, however, remains equivocal. Similarly, while the health benefits of certain exogenous antioxidants, including ascorbic acid (vitamin C), carotenoids, polyphenols, sulforaphanes, and anthocyanins are commonly touted, their clinical efficacy and effectiveness in particular neurological disease contexts need to be more robustly defined. Here, we review the current literature on the cellular mechanisms mitigating oxidative stress and comment on the possible benefit of the most common exogenous antioxidants in diseases such as AD, PD, ALS, HD, stroke, epilepsy, and migraine. We selected common neurological diseases of a basically neurodegenerative nature.}, }
@article {pmid37890889, year = {2023}, author = {Ilieva, H and Vullaganti, M and Kwan, J}, title = {Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.}, journal = {BMJ (Clinical research ed.)}, volume = {383}, number = {}, pages = {e075037}, pmid = {37890889}, issn = {1756-1833}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Pathology, Molecular ; Disease Progression ; }, abstract = {Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.}, }
@article {pmid37887017, year = {2023}, author = {You, J and Youssef, MMM and Santos, JR and Lee, J and Park, J}, title = {Microglia and Astrocytes in Amyotrophic Lateral Sclerosis: Disease-Associated States, Pathological Roles, and Therapeutic Potential.}, journal = {Biology}, volume = {12}, number = {10}, pages = {}, pmid = {37887017}, issn = {2079-7737}, abstract = {Microglial and astrocytic reactivity is a prominent feature of amyotrophic lateral sclerosis (ALS). Microglia and astrocytes have been increasingly appreciated to play pivotal roles in disease pathogenesis. These cells can adopt distinct states characterized by a specific molecular profile or function depending on the different contexts of development, health, aging, and disease. Accumulating evidence from ALS rodent and cell models has demonstrated neuroprotective and neurotoxic functions from microglia and astrocytes. In this review, we focused on the recent advancements of knowledge in microglial and astrocytic states and nomenclature, the landmark discoveries demonstrating a clear contribution of microglia and astrocytes to ALS pathogenesis, and novel therapeutic candidates leveraging these cells that are currently undergoing clinical trials.}, }
@article {pmid37872558, year = {2023}, author = {Schmitz, J and Liebold, F and Hinkelbein, J and Nöhl, S and Thal, SC and Sellmann, T}, title = {Cardiopulmonary resuscitation during hyperbaric oxygen therapy: a comprehensive review and recommendations for practice.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {31}, number = {1}, pages = {57}, pmid = {37872558}, issn = {1757-7241}, mesh = {Humans ; *Cardiopulmonary Resuscitation ; *Heart Arrest/therapy ; Heart Massage ; *Hyperbaric Oxygenation ; Ventricular Fibrillation ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) during hyperbaric oxygen therapy (HBOT) presents unique challenges due to limited access to patients in cardiac arrest (CA) and the distinct physiological conditions present during hyperbaric therapy. Despite these challenges, guidelines specifically addressing CPR during HBOT are lacking. This review aims to consolidate the available evidence and offer recommendations for clinical practice in this context.<br><br>MATERIALS AND METHODS: A comprehensive literature search was conducted in PubMed, EMBASE, Cochrane Library, and CINAHL using the search string: "(pressure chamber OR decompression OR hyperbaric) AND (cardiac arrest OR cardiopulmonary resuscitation OR advanced life support OR ALS OR life support OR chest compression OR ventricular fibrillation OR heart arrest OR heart massage OR resuscitation)". Additionally, relevant publications and book chapters not identified through this search were included.<br><br>RESULTS: The search yielded 10,223 publications, with 41 deemed relevant to the topic. Among these, 18 articles (primarily case reports) described CPR or defibrillation in 22 patients undergoing HBOT. The remaining 23 articles provided information or recommendations pertaining to CPR during HBOT. Given the unique physiological factors during HBOT, the limitations of current resuscitation guidelines are discussed.<br><br>CONCLUSIONS: CPR in the context of HBOT is a rare, yet critical event requiring special considerations. Existing guidelines should be adapted to address these unique circumstances and integrated into regular training for HBOT practitioners. This review serves as a valuable contribution to the literature on "CPR under special circumstances".}, }
@article {pmid37870685, year = {2023}, author = {Zhou, L and Chen, W and Jiang, S and Xu, R}, title = {In Vitro Models of Amyotrophic Lateral Sclerosis.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {8}, pages = {3783-3799}, pmid = {37870685}, issn = {1573-6830}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism ; Mutation/genetics ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons in the cerebral cortex, brain stem and spinal cord. The dysfunction and death of motor neurons lead to the progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately the whole paralysis of body. Despite the identification of several genetic mutations associated with the pathogenesis of ALS, including mutations in chromosome 9 open reading frame 72 leading to the abnormal expansion of GGGGCC repeat sequence, TAR DNA-binding protein 43, fused in sarcoma/translocated in liposarcoma, copper/zinc superoxide dismutase 1 (SOD1) and TANK-binding kinase 1, the exact mechanisms underlying the specific degeneration of motor neurons that causes ALS remain incompletely understood. At present, since the transgenic model expressed SOD1 mutants was established, multiple in vitro models of ALS have been developed for studying the pathology, pathophysiology and pathogenesis of ALS as well as searching the effective neurotherapeutics. This review reviewed the details of present established in vitro models used in studying the pathology, pathophysiology and pathogenesis of ALS. Meanwhile, we also discussed the advantages, disadvantages, cost and availability of each models.}, }
@article {pmid37868386, year = {2023}, author = {Hoxhaj, P and Hastings, N and Kachhadia, MP and Gupta, R and Sindhu, U and Durve, SA and Azam, A and Auz Vinueza, MJ and Bhuvan,  and Win, SH and Rathod, DC and Afsar, AP}, title = {Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects.}, journal = {Cureus}, volume = {15}, number = {9}, pages = {e45489}, pmid = {37868386}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease requiring a multidisciplinary treatment approach and a collaborative therapeutic effort. A combination of both upper and lower motor neuron degeneration ultimately leads to respiratory failure, similar to other dementia-type neurodegenerative diseases. The aim of this paper is to pioneer current ALS research by carrying out a narrative literature review of the current treatment modalities of the disease. Through these efforts, we hope to condense the most pertinent information regarding current treatments and enhance the management of ALS patients as a whole, giving these patients a better quality of life as the search for a cure continues. We used a Pubmed search strategy and specific MeSH terms for the selection of the literature articles using the keywords "ALS," "new treatment," "treatment," and "symptomatic treatment." A combination of pharmaceutical interventions, psychological support, and physical rehabilitation has been most effective in enhancing the quality of life of patients with ALS (PALS). Among potential pharmacological therapies, only a few have been approved by the US Food and Drug Administration(FDA) to be used to treat ALS and its symptoms. Other treatment modalities being considered include gene therapy, cellular therapy, psychological therapy, physical therapy, and speech therapy, alongside robotics, alternative feeding methods, and communication devices.}, }
@article {pmid37865833, year = {2023}, author = {Wu, YK and Wecht, JM and Bloom, OE and Panza, GS and Harel, NY}, title = {Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.}, journal = {Current opinion in neurology}, volume = {36}, number = {6}, pages = {523-530}, doi = {10.1097/WCO.0000000000001216}, pmid = {37865833}, issn = {1473-6551}, mesh = {Adult ; Humans ; *Myocardial Infarction ; *Stroke ; *Spinal Cord Injuries ; Hypoxia ; }, abstract = {PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC.<br><br>RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis.<br><br>SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.}, }
@article {pmid37864389, year = {2024}, author = {Xiao, F and He, Z and Wang, S and Li, J and Fan, X and Yan, T and Yang, M and Yang, D}, title = {Regulatory mechanism of circular RNAs in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {4}, pages = {e14499}, pmid = {37864389}, issn = {1755-5949}, support = {//China Scholarship Council/ ; //National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics ; RNA, Circular/metabolism ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease ; Biomarkers ; }, abstract = {BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins.<br><br>AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases.<br><br>METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases.<br><br>RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD.<br><br>CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.}, }
@article {pmid37862967, year = {2023}, author = {Rabeh, N and Hajjar, B and Maraka, JO and Sammanasunathan, AF and Khan, M and Alkhaaldi, SMI and Mansour, S and Almheiri, RT and Hamdan, H and Abd-Elrahman, KS}, title = {Targeting mGluR group III for the treatment of neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {168}, number = {}, pages = {115733}, doi = {10.1016/j.biopha.2023.115733}, pmid = {37862967}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Signal Transduction/physiology ; Glutamic Acid ; Neurotransmitter Agents ; Neurons ; *Receptors, Metabotropic Glutamate/physiology ; }, abstract = {Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.}, }
@article {pmid37858176, year = {2023}, author = {Xie, M and Pallegar, PN and Parusel, S and Nguyen, AT and Wu, LJ}, title = {Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {75}, pmid = {37858176}, issn = {1750-1326}, support = {R35 NS132326/NS/NINDS NIH HHS/United States ; RF1AG082314/AG/NIA NIH HHS/United States ; RF1 AG082314/AG/NIA NIH HHS/United States ; U19AG 069701/AG/NIA NIH HHS/United States ; R35NS132326/NS/NINDS NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Neuroglia/pathology ; Microglia/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.}, }
@article {pmid37857264, year = {2024}, author = {Kiene, H and Hamre, HJ}, title = {A Fundamental Question for Complementary Medicine: Are There Other Forces in the Natural World Besides the Physical Forces?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {71-77}, doi = {10.1159/000534592}, pmid = {37857264}, issn = {2504-2106}, mesh = {*Complementary Therapies ; *Homeopathy ; DNA ; RNA ; }, abstract = {BACKGROUND: The integration of conventional and complementary medicine reflects the pluralism in science. Still, a critical issue is the conception of the natural world. Many complementary therapy systems seem to contradict the reductionist-atomistic paradigm that all of natural reality is essentially based on the physical interactions of atoms and molecules. Thus, a fundamental question about the natural world is: Do other than the physical forces exist?<br><br>SUMMARY: The assumption that no other than physical forces exist and work in the natural world is not tenable. For example, the formation and maintenance of the functional Gestalt of organisms cannot possibly be explained by molecular processes (e.g., from DNA to RNA and further to amino acids and proteins). The processes on each structural level - from molecules, organelles, cells, organs up to the whole organism - are regulated in regard to the formation of the next higher level. Specific Gestalt-forming forces exist and can be systematically investigated. Their existence implies an extended conception of matter. The Gestalt-forming forces and the extended concept of matter may be relevant for the scientific assessment of complementary therapies.<br><br>KEY MESSAGES: (i) In the natural world, specific Gestalt-forming forces exist in addition to the physical forces, and can be systematically investigated. (ii) The existence of these forces implies an extended conception of matter. (iii) These forces and this extended concept of matter may be relevant for the scientific assessment of complementary therapies, e.g., homeopathy.<br><br>UNLABELLED: <title>Hintergrund</title>In der Integration von konventioneller und komplement&#xe4;rer Medizin spiegelt sich der Methodenpluralismus der Wissenschaft. Die Ontologien vieler komplement&#xe4;rmedizinisches Systeme liegen allerdings au&#xdf;erhalb der Erkl&#xe4;rbarkeit durch die Kr&#xe4;fte der Physik. Eine zentrale Frage ist deshalb: Gibt es Kr&#xe4;fte in der Natur, die eine materielle Wirkung haben, deren Ursprung aber nicht in Atomen oder Molek&#xfc;len und in diesem Sinne nicht in der Materie liegt?<title>Zusammenfassung</title>Die Annahme, dass in der Natur keine anderen als die mit Atomen und Molek&#xfc;len assoziierten physikalischen Kr&#xe4;fte existent und wirksam seien, ist wissenschaftlich nicht begr&#xfc;ndet. Beispielsweise ist die Bildung und Erhaltung der funktionsf&#xe4;higen Gestalt von Organismen nicht durch molekulare Prozesse (z.B. von der DNA zur RNA und weiter zu Aminos&#xe4;uren und Proteinen) erkl&#xe4;rbar. Die Prozesse auf jeder strukturellen Ebene &#x2013; von den Molek&#xfc;len, Organellen, Zellen, Organen bis hinauf zum Gesamtorganismus &#x2013; sind in Hinblick auf die Bildung der funktionsf&#xe4;higen Gestalt der jeweils n&#xe4;chsth&#xf6;heren Ebene gesteuert. F&#xfc;r diese Gestaltbildung gibt es spezifische Kr&#xe4;fte, die systematisch erforscht werden k&#xf6;nnen. Ihre Existenz impliziert eine erweiterte Konzeption von Materie. Diese Gestalt-bildenden Kr&#xe4;fte und dieses erweiterte Konzept von Materie sind relevant f&#xfc;r die wissenschaftliche Erfassung komplement&#xe4;rmedizinischer Systeme.<title>Zentrale Aussagen</title>(i) In der Natur sind au&#xdf;er den physikalischen Kr&#xe4;ften noch weitere spezifische Kr&#xe4;fte wirksam, beispielsweise bei der Bildung und Erhaltung der funktionsf&#xe4;higen Gestalt von Organismen. Diese Kr&#xe4;fte k&#xf6;nnen systematisch erforscht werden. (ii) Die Existenz dieser Kr&#xe4;fte impliziert eine erweitere Konzeption von Materie. (iii) Diese Kr&#xe4;fte und das erweiterte Materiekonzept sind relevant f&#xfc;r die wissenschaftliche Erfassung komplement&#xe4;rmedizinischer Systeme, beispielsweise der Hom&#xf6;opathie.}, }
@article {pmid37855949, year = {2023}, author = {Suh, A and Ong, J and Kamran, SA and Waisberg, E and Paladugu, P and Zaman, N and Sarker, P and Tavakkoli, A and Lee, AG}, title = {Retina Oculomics in Neurodegenerative Disease.}, journal = {Annals of biomedical engineering}, volume = {51}, number = {12}, pages = {2708-2721}, pmid = {37855949}, issn = {1573-9686}, support = {80NSSC20K183//NASA Grant/ ; }, mesh = {Humans ; *Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; Quality of Life ; Retina/diagnostic imaging ; Tomography, Optical Coherence/methods ; Biomarkers ; }, abstract = {Ophthalmic biomarkers have long played a critical role in diagnosing and managing ocular diseases. Oculomics has emerged as a field that utilizes ocular imaging biomarkers to provide insights into systemic diseases. Advances in diagnostic and imaging technologies including electroretinography, optical coherence tomography (OCT), confocal scanning laser ophthalmoscopy, fluorescence lifetime imaging ophthalmoscopy, and OCT angiography have revolutionized the ability to understand systemic diseases and even detect them earlier than clinical manifestations for earlier intervention. With the advent of increasingly large ophthalmic imaging datasets, machine learning models can be integrated into these ocular imaging biomarkers to provide further insights and prognostic predictions of neurodegenerative disease. In this manuscript, we review the use of ophthalmic imaging to provide insights into neurodegenerative diseases including Alzheimer Disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, and Huntington Disease. We discuss recent advances in ophthalmic technology including eye-tracking technology and integration of artificial intelligence techniques to further provide insights into these neurodegenerative diseases. Ultimately, oculomics opens the opportunity to detect and monitor systemic diseases at a higher acuity. Thus, earlier detection of systemic diseases may allow for timely intervention for improving the quality of life in patients with neurodegenerative disease.}, }
@article {pmid37855859, year = {2023}, author = {Vieira, TCRG and Barros, CA and Domingues, R and Outeiro, TF}, title = {PrP meets alpha-synuclein: Molecular mechanisms and implications for disease.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnc.15992}, pmid = {37855859}, issn = {1471-4159}, support = {SFB1286 (B8)//Deutsche Forschungsgemeinschaft/ ; EXC 2067/1-390729940//Deutsche Forschungsgemeinschaft/ ; //Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro (FAPERJ)/ ; //Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico (CNPq)/ ; }, abstract = {The discovery of prions has challenged dogmas and has revolutionized our understanding of protein-misfolding diseases. The concept of self-propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha-synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor-mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrP[C]) may play a crucial role in this process. PrP[C] has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrP[C] and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrP[C] 's role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrP[C] may offer potential treatment options for synucleinopathies.}, }
@article {pmid37851042, year = {2023}, author = {Izenberg, A}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1538-1563}, pmid = {37851042}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Biomarkers ; }, abstract = {OBJECTIVE: This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases.<br><br>LATEST DEVELOPMENTS: A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023.<br><br>ESSENTIAL POINTS: There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.}, }
@article {pmid37845811, year = {2024}, author = {Holt, MW and Robinson, EC and Shlobin, NA and Hanson, JT and Bozkurt, I}, title = {Intracortical brain-computer interfaces for improved motor function: a systematic review.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {2}, pages = {213-223}, pmid = {37845811}, issn = {2191-0200}, mesh = {Humans ; Male ; *Brain-Computer Interfaces ; Electrodes, Implanted ; Quadriplegia ; *Spinal Cord Injuries/therapy ; *Stroke ; }, abstract = {In this systematic review, we address the status of intracortical brain-computer interfaces (iBCIs) applied to the motor cortex to improve function in patients with impaired motor ability. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Guidelines for Systematic Reviews. Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) and the Effective Public Health Practice Project (EPHPP) were used to assess bias and quality. Advances in iBCIs in the last two decades demonstrated the use of iBCI to activate limbs for functional tasks, achieve neural typing for communication, and other applications. However, the inconsistency of performance metrics employed by these studies suggests the need for standardization. Each study was a pilot clinical trial consisting of 1-4, majority male (64.28 %) participants, with most trials featuring participants treated for more than 12 months (55.55 %). The systems treated patients with various conditions: amyotrophic lateral sclerosis, stroke, spinocerebellar degeneration without cerebellar involvement, and spinal cord injury. All participants presented with tetraplegia at implantation and were implanted with microelectrode arrays via pneumatic insertion, with nearly all electrode locations solely at the precentral gyrus of the motor cortex (88.88 %). The development of iBCI devices using neural signals from the motor cortex to improve motor-impaired patients has enhanced the ability of these systems to return ability to their users. However, many milestones remain before these devices can prove their feasibility for recovery. This review summarizes the achievements and shortfalls of these systems and their respective trials.}, }
@article {pmid37843219, year = {2024}, author = {Liu, X and Liu, Y and Liu, J and Zhang, H and Shan, C and Guo, Y and Gong, X and Cui, M and Li, X and Tang, M}, title = {Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {833-845}, pmid = {37843219}, issn = {1673-5374}, abstract = {A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis. As a contributing factor, microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota's diverse microorganisms, and for both neuroimmune and neuroendocrine systems. Here, we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases, with an emphasis on multi-omics studies and the gut virome. The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated. Finally, we discuss the role of diet, prebiotics, probiotics, postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases.}, }
@article {pmid37843214, year = {2024}, author = {Wang, X and Hu, Y and Xu, R}, title = {The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {800-806}, pmid = {37843214}, issn = {1673-5374}, abstract = {The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia, brainstem, and spinal cord, and commonly involves the muscles of the upper and/or lower extremities, and the muscles of the bulbar and/or respiratory regions. However, as the disease progresses, it affects the adjacent body regions, leading to generalized muscle weakness, occasionally along with memory, cognitive, behavioral, and language impairments; respiratory dysfunction occurs at the final stage of the disease. The disease has a complicated pathophysiology and currently, only riluzole, edaravone, and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries. The TAR DNA-binding protein 43 inclusions are observed in 97% of those diagnosed with amyotrophic lateral sclerosis. This review provides a preliminary overview of the potential effects of TAR DNA-binding protein 43 in the pathogenesis of amyotrophic lateral sclerosis, including the abnormalities in nucleoplasmic transport, RNA function, post-translational modification, liquid-liquid phase separation, stress granules, mitochondrial dysfunction, oxidative stress, axonal transport, protein quality control system, and non-cellular autonomous functions (e.g., glial cell functions and prion-like propagation).}, }
@article {pmid37843208, year = {2024}, author = {King, PH}, title = {Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {747-753}, pmid = {37843208}, issn = {1673-5374}, support = {I01 BX001148/BX/BLRD VA/United States ; I01 BX005899/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target. Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis, there is considerable heterogeneity, including clinical presentation, progression, and the underlying triggers for disease initiation. Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations, it has become apparent that overt disease is preceded by a prodromal phase, possibly in years, where compensatory mechanisms delay symptom onset. Since 85-90% of amyotrophic lateral sclerosis is sporadic, there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration. Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease. Skeletal muscle, including the neuromuscular junction, manifests abnormalities at the earliest stages of the disease, before motor neuron loss, making it a promising source for identifying biomarkers of the prodromal phase. The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time. The advent of "omics" technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle, ranging from coding and non-coding RNAs to proteins and metabolites. This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms. A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease. There are two major goals of this review. The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity, evidence of a similar dysregulation in the SOD1[G93A] mouse during presymptomatic stages, and evidence of progressive change during disease progression. The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression, and as such, their potential as therapeutic targets in amyotrophic lateral sclerosis.}, }
@article {pmid37837507, year = {2024}, author = {Hamad, AA and Amer, BE and Abbas, NB and Alnajjar, AZ and Meshref, M}, title = {Prevalence and correlates of fatigue in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {2}, pages = {485-493}, pmid = {37837507}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Prevalence ; Quality of Life ; Fatigue/etiology/complications ; }, abstract = {OBJECTIVES: This systematic review and meta-analysis aimed to determine the frequency and correlates of fatigue in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Three databases were searched up to 2nd May 2023 to identify studies reporting fatigue frequency in ALS. Studies included had to identify ALS patients through one of ALS diagnostic criteria and measure fatigue by a validated tool with a specific cut-off value. Meta-analysis was conducted using RStudio's "meta" package with a random-effects model. Subgroup analyses and meta-regression explored the relationship between fatigue frequency in ALS and different covariates.<br><br>RESULTS: Eleven studies, compromising 1072 patients, met the inclusion criteria and were included in our analysis. The pooled frequency of fatigue across all studies was 48% (95% CI&#x2009;=&#x2009;40% to 57%). Our subgroup analysis based on the ALSFRS-R revealed a higher frequency of fatigue in studies with lower scores (<&#x2009;30) compared to those with higher scores (&#x2265;&#x2009;30), with a pooled frequency of 62% (95% CI&#x2009;=&#x2009;43% to 79%) and 43% (95% CI&#x2009;=&#x2009;37% to 49%), respectively. Also, the meta-regression analysis showed a significant negative association between fatigue and ALSFRS-R mean (P&#x2009;=&#x2009;0.02). The included studies reported an association between fatigue and lower functional status and poorer quality of life in patients with ALS.<br><br>CONCLUSION: Our findings suggest that fatigue is prevalent in almost half of ALS patients and is associated with lower functional status and poorer quality of life, highlighting the importance of assessing and managing fatigue in ALS patients.}, }
@article {pmid37834407, year = {2023}, author = {Baj, J and Flieger, W and Barbachowska, A and Kowalska, B and Flieger, M and Forma, A and Teresiński, G and Portincasa, P and Buszewicz, G and Radzikowska-Büchner, E and Flieger, J}, title = {Consequences of Disturbing Manganese Homeostasis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834407}, issn = {1422-0067}, mesh = {Humans ; Manganese/toxicity/metabolism ; *Diabetes Mellitus, Type 2 ; *Manganese Poisoning/metabolism ; Homeostasis ; *Neurodegenerative Diseases ; }, abstract = {Manganese (Mn) is an essential trace element with unique functions in the body; it acts as a cofactor for many enzymes involved in energy metabolism, the endogenous antioxidant enzyme systems, neurotransmitter production, and the regulation of reproductive hormones. However, overexposure to Mn is toxic, particularly to the central nervous system (CNS) due to it causing the progressive destruction of nerve cells. Exposure to manganese is widespread and occurs by inhalation, ingestion, or dermal contact. Associations have been observed between Mn accumulation and neurodegenerative diseases such as manganism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. People with genetic diseases associated with a mutation in the gene associated with impaired Mn excretion, kidney disease, iron deficiency, or a vegetarian diet are at particular risk of excessive exposure to Mn. This review has collected data on the current knowledge of the source of Mn exposure, the experimental data supporting the dispersive accumulation of Mn in the brain, the controversies surrounding the reference values of biomarkers related to Mn status in different matrices, and the competitiveness of Mn with other metals, such as iron (Fe), magnesium (Mg), zinc (Zn), copper (Cu), lead (Pb), calcium (Ca). The disturbed homeostasis of Mn in the body has been connected with susceptibility to neurodegenerative diseases, fertility, and infectious diseases. The current evidence on the involvement of Mn in metabolic diseases, such as type 2 diabetes mellitus/insulin resistance, osteoporosis, obesity, atherosclerosis, and non-alcoholic fatty liver disease, was collected and discussed.}, }
@article {pmid37834374, year = {2023}, author = {Oprisan, AL and Popescu, BO}, title = {Dysautonomia in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834374}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Motor Neurons/pathology ; *Primary Dysautonomias/etiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized in its typical presentation by a combination of lower and upper motor neuron symptoms, with a progressive course and fatal outcome. Due to increased recognition of the non-motor symptoms, it is currently considered a multisystem disorder with great heterogeneity, regarding genetical, clinical, and neuropathological features. Often underestimated, autonomic signs and symptoms have been described in patients with ALS, and various method analyses have been used to assess autonomic nervous system involvement. The aim of this paper is to offer a narrative literature review on autonomic disturbances in ALS, based on the scarce data available to date.}, }
@article {pmid37834128, year = {2023}, author = {Huber, K and Szerenos, E and Lewandowski, D and Toczylowski, K and Sulik, A}, title = {The Role of Adipokines in the Pathologies of the Central Nervous System.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834128}, issn = {1422-0067}, mesh = {Humans ; Adipokines/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Adipose Tissue/metabolism ; }, abstract = {Adipokines are protein hormones secreted by adipose tissue in response to disruptions in physiological homeostasis within the body's systems. The regulatory functions of adipokines within the central nervous system (CNS) are multifaceted and intricate, and they have been identified in a number of pathologies. Therefore, specific adipokines have the potential to be used as biomarkers for screening purposes in neurological dysfunctions. The systematic review presented herein focuses on the analysis of the functions of various adipokines in the pathogenesis of CNS diseases. Thirteen proteins were selected for analysis through scientific databases. It was found that these proteins can be identified within the cerebrospinal fluid either by their ability to modify their molecular complex and cross the blood-brain barrier or by being endogenously produced within the CNS itself. As a result, this can correlate with their measurability during pathological processes, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, or brain tumors.}, }
@article {pmid37834094, year = {2023}, author = {Jellinger, KA}, title = {The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834094}, issn = {1422-0067}, support = {000//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Brain/pathology ; *Cognition Disorders/pathology ; *Cognitive Dysfunction/pathology ; *Neurodegenerative Diseases/pathology ; *Pick Disease of the Brain/pathology ; }, abstract = {Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.}, }
@article {pmid37832609, year = {2023}, author = {Rezaee, D and Saadatpour, F and Akbari, N and Zoghi, A and Najafi, S and Beyranvand, P and Zamani-Rarani, F and Rashidi, MA and Bagheri-Mohammadi, S and Bakhtiari, M}, title = {The role of microRNAs in the pathophysiology of human central nervous system: A focus on neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102090}, doi = {10.1016/j.arr.2023.102090}, pmid = {37832609}, issn = {1872-9649}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Amyloid beta-Peptides ; *Alzheimer Disease/genetics/metabolism ; Central Nervous System/metabolism ; *Neoplasms ; }, abstract = {microRNAs (miRNAs) are suggested to play substantial roles in regulating the development and various physiologic functions of the central nervous system (CNS). These include neurogenesis, cell fate and differentiation, morphogenesis, formation of dendrites, and targeting non-neural mRNAs. Notably, deregulation of an increasing number of miRNAs is associated with several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and CNS tumors. They are particularly known to affect the amyloid β (Aβ) cleavage and accumulation, tau protein homeostasis, and expression of alpha-synuclein (α-syn), Parkin, PINK1, and brain-derived neurotrophic factor (BDNF) that play pivotal roles in the pathogenesis of neurodegenerative diseases. These include miR-16, miR-17-5p, miR-20a, miR-106a, miR-106b, miR-15a, miR-15b, miR-103, miR-107, miR-298, miR-328, miR-195, miR-485, and miR-29. In CNS tumors, several miRNAs, including miR-31, miR-16, and miR-21 have been identified to modulate tumorigenesis through impacting tumor invasion and apoptosis. In this review article, we have a look at the recent advances on our knowledge about the role of miRNAs in human brain development and functions, neurodegenerative diseases, and their clinical potentials.}, }
@article {pmid37830099, year = {2023}, author = {Berlowitz, DJ and Mathers, S and Hutchinson, K and Hogden, A and Carey, KA and Graco, M and Whelan, BM and Charania, S and Steyn, F and Allcroft, P and Crook, A and Sheers, NL}, title = {The complexity of multidisciplinary respiratory care in amyotrophic lateral sclerosis.}, journal = {Breathe (Sheffield, England)}, volume = {19}, number = {3}, pages = {220269}, pmid = {37830099}, issn = {1810-6838}, abstract = {UNLABELLED: Motor neurone disease/amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no known cure, where death is usually secondary to progressive respiratory failure. Assisting people with ALS through their disease journey is complex and supported by clinics that provide comprehensive multidisciplinary care (MDC). This review aims to apply both a respiratory and a complexity lens to the key roles and areas of practice within the MDC model in ALS. Models of noninvasive ventilation care, and considerations in the provision of palliative therapy, respiratory support, and speech and language therapy are discussed. The impact on people living with ALS of both inequitable funding models and the complexity of clinical care decisions are illustrated using case vignettes. Considerations of the impact of emerging antisense and gene modifying therapies on MDC challenges are also highlighted. The review seeks to illustrate how MDC members contribute to collective decision-making in ALS, how the sum of the parts is greater than any individual care component or health professional, and that the MDC per se adds value to the person living with ALS. Through this approach we hope to support clinicians to navigate the space between what are minimum, guideline-driven, standards of care and what excellent, person-centred ALS care that fully embraces complexity could be.<br><br>EDUCATIONAL AIMS: To highlight the complexities surrounding respiratory care in ALS.To alert clinicians to the risk that complexity of ALS care may modify the effectiveness of any specific, evidence-based therapy for ALS.To describe the importance of person-centred care and shared decision-making in optimising care in ALS.}, }
@article {pmid37828541, year = {2023}, author = {Richardson, PJ and Smith, DP and de Giorgio, A and Snetkov, X and Almond-Thynne, J and Cronin, S and Mead, RJ and McDermott, CJ and Shaw, PJ}, title = {Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {47}, pmid = {37828541}, issn = {2047-9158}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Janus Kinase Inhibitors/therapeutic use ; *Neurodegenerative Diseases ; Central Nervous System/metabolism ; Janus Kinases/metabolism/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.}, }
@article {pmid37828358, year = {2023}, author = {Abrahams, S}, title = {Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {11}, pages = {655-667}, pmid = {37828358}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Frontotemporal Dementia/complications ; *Neurodegenerative Diseases ; *Cognitive Dysfunction ; *Cognition Disorders/diagnosis/etiology ; Neuropsychological Tests ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS-FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS-FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes.}, }
@article {pmid37827960, year = {2023}, author = {Todd, TW and Shao, W and Zhang, YJ and Petrucelli, L}, title = {The endolysosomal pathway and ALS/FTD.}, journal = {Trends in neurosciences}, volume = {46}, number = {12}, pages = {1025-1041}, pmid = {37827960}, issn = {1878-108X}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Mutation ; Autophagy ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered to be part of a disease spectrum that is associated with causative mutations and risk variants in a wide range of genes. Mounting evidence indicates that several of these genes are linked to the endolysosomal system, highlighting the importance of this pathway in ALS/FTD. Although many studies have focused on how disruption of this pathway impacts on autophagy, recent findings reveal that this may not be the whole picture: specifically, disrupting autophagy may not be sufficient to induce disease, whereas disrupting the endolysosomal system could represent a crucial pathogenic driver. In this review we discuss the connections between ALS/FTD and the endolysosomal system, including a breakdown of how disease-associated genes are implicated in this pathway. We also explore the potential downstream consequences of disrupting endolysosomal activity in the brain, outside of an effect on autophagy.}, }
@article {pmid37827904, year = {2023}, author = {Santiago, JA and Karthikeyan, M and Lackey, M and Villavicencio, D and Potashkin, JA}, title = {Diabetes: a tipping point in neurodegenerative diseases.}, journal = {Trends in molecular medicine}, volume = {29}, number = {12}, pages = {1029-1044}, pmid = {37827904}, issn = {1471-499X}, support = {R01 AG062176/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Brain/metabolism ; *Diabetes Mellitus/metabolism ; }, abstract = {Diabetes is associated with an increased risk and progression of Alzheimer's (AD) and Parkinson's (PD) diseases. Conversely, diabetes may confer neuroprotection against amyotrophic lateral sclerosis (ALS). It has been posited that perturbations in glucose and insulin regulation, cholesterol metabolism, and mitochondrial bioenergetics defects may underlie the molecular underpinnings of diabetes effects on the brain. Nevertheless, the precise molecular mechanisms remain elusive. Here, we discuss the evidence from molecular, epidemiological, and clinical studies investigating the impact of diabetes on neurodegeneration and highlight shared dysregulated pathways between these complex comorbidities. We also discuss promising antidiabetic drugs, molecular diagnostics currently in clinical trials, and outstanding questions and challenges for future pursuit.}, }
@article {pmid37827137, year = {2024}, author = {Heckmann, JG and Kiem, M and Immich, G}, title = {Forest Therapy as a Nature-Based Intervention: An Option for Neurological Rehabilitation?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {56-63}, doi = {10.1159/000534533}, pmid = {37827137}, issn = {2504-2106}, mesh = {Humans ; *Medicine ; *Neurological Rehabilitation ; *Sleep Wake Disorders ; *Stroke/therapy ; *Dementia ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Forest therapy demonstrates positive effects on mood, immune system, stress levels, and general well-being. Studies on depression, stress-related illnesses, sleep disorders, and arterial hypertension have provided evidence-based proof of this.<br><br>SUMMARY: The aim of this review was to examine the possible effects of forest therapy with regard to its evidence in the treatment of chronic neurological diseases such as stroke in the rehabilitation phase, Parkinson's disease, dementia, and multiple sclerosis. Therefore, the electronic databases Medline, Scopus, and Cochrane were searched for such clinical trials for the years 1970 to mid-2023 without language restriction. The literature search revealed only few studies with positive indications but too few cases to be able to make generalizable evidence-based statements. In terms of improvement in the Hamilton Depression Scale analysis of two studies in stroke patients showed slight benefits in the forest therapy group (standard mean difference -0.43; 95% CI: -0.76 to -0.10; p < 0.01). One observational study revealed a higher rate of stroke survival in patients living in marked greenness. Few nature-based interventions in dementia patients showed certain benefits in particular details.<br><br>KEY MESSAGES: There are no evidence-based results on the benefit of forest therapy for chronic neurological diseases. However, there are hints that forest therapy could have a positive benefit. Therefore, a proposal for forest therapy as a component of multimodal neurological rehabilitation is presented.<br><br>UNLABELLED: <title>Hintergrund</title>Die Waldtherapie zeigt positive Auswirkungen auf die Stimmung, das Immunsystem, das Stressniveau und das allgemeine Wohlbefinden. Studien zu Depressionen, stressbedingten Erkrankungen, Schlafst&#xf6;rungen und arteriellem Bluthochdruck haben dies evidenzbasiert belegt.<title>Zusammenfassung</title>Ziel dieser &#xdc;bersichtsarbeit war es, die m&#xf6;glichen Wirkungen der Waldtherapie im Hinblick auf ihre Evidenz bei der Behandlung chronischer neurologischer Erkrankungen wie Schlaganfall in der Rehabilitationsphase, Morbus Parkinson, Demenz und Multiple Sklerose zu untersuchen. Dazu wurden die elektronischen Datenbanken Medline, Scopus und Cochrane f&#xfc;r die Jahre 1970 bis Mitte 2023 ohne sprachliche Einschr&#xe4;nkung nach solchen klinischen Studien durchsucht. Die Literaturrecherche ergab nur wenige Studien mit positiven Indikationen, aber zu wenigen F&#xe4;llen, um verallgemeinerbare evidenzbasierte Aussagen machen zu k&#xf6;nnen. Im Hinblick auf Verbesserung in der Hamilton Depressionsskala zeigte die Analyse von 2 Studien bei Schlaganfallpatienten leichte Vorteile der Waldtherapiegruppen (Standard Mean Difference &#x2212;0.43; 95% CI: -0.76- -0,10; <italic>p</italic> < 0.01). Eine Beobachtungsstudie ergab eine h&#xf6;here Schlaganfall-&#xdc;berlebensrate bei Patienten, die in ausgepr&#xe4;gtem Gr&#xfc;n leben. Einige naturbasierte Interventionen bei Demenzpatienten zeigten in einzelnen Parametern gewisse Vorteile.<title>Fazit</title>Es gibt bis dato keine verallgemeinerbaren evidenzbasierten Ergebnisse zum Nutzen der Waldtherapie bei chronischen neurologischen Erkrankungen. Es gibt jedoch Hinweise, dass die Waldtherapie einen positiven Nutzen haben k&#xf6;nnte. Es wird daher ein Vorschlag f&#xfc;r eine Waldtherapie als Bestandteil einer multimodalen neurologischen Rehabilitation vorgestellt.}, }
@article {pmid37816542, year = {2024}, author = {McHenry, KL}, title = {Airway Clearance Strategies and Secretion Management in Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {69}, number = {2}, pages = {227-237}, pmid = {37816542}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Respiratory Therapy/methods ; *Chest Wall Oscillation ; Bodily Secretions ; *Insufflation/methods ; Cough/etiology ; *Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative motor neuron disease that affects voluntary muscle movement. Often, difficulty in coughing, breathing, and swallowing are sequela associated with the condition, and the presence of bulbar muscle predominant weakness results in deleterious effects on airway clearance and secretion management. This narrative review will provide practical guidance for clinicians treating this population. Cough insufficiency in this population typically manifests as a prolonged, slow, weak cough effort that impedes the clearability of secretions and airway protection. Dystussia and dysphagia frequently occur simultaneously in bulbar dysfunction, subsequently impacting respiratory health. Measures of respiratory strength should be obtained and monitored every 3-6 months, preferably in a multidisciplinary clinic setting. Cough augmentation, whether manual or mechanical techniques, should be sought as early in the disease progression as possible to adequately control secretions in the proximal airways. This airway clearance strategy can aid in the prevention and treatment of respiratory tract infections (RTIs), which can pose a significant clinical hurdle to those with ALS. The use of mechanical insufflation-exsufflation may be complicated by severe bulbar dysfunction rendering this technique ineffective. Though peripheral airway clearance strategies, such as high-frequency chest-wall compression, have the advantage of being less impacted by bulbar dysfunction, it is only recommended this modality be used in conjunction with, versus in lieu of, proximal strategies. Salivary secretion management includes the use of anticholinergics, botulinum toxin, and radiation therapy depending on severity and desire for relief.}, }
@article {pmid37813308, year = {2023}, author = {Babazadeh, A and Rayner, SL and Lee, A and Chung, RS}, title = {TDP-43 as a therapeutic target in neurodegenerative diseases: Focusing on motor neuron disease and frontotemporal dementia.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102085}, doi = {10.1016/j.arr.2023.102085}, pmid = {37813308}, issn = {1872-9649}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/therapy ; *Motor Neuron Disease/therapy/pathology ; *Neurodegenerative Diseases/therapy ; }, abstract = {A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases.}, }
@article {pmid37807406, year = {2023}, author = {Anderson, G}, title = {Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Cancer.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {28}, pages = {2699-2719}, doi = {10.2174/0115680266253465230920114223}, pmid = {37807406}, issn = {1873-4294}, mesh = {Humans ; *Melatonin/metabolism ; *Alzheimer Disease ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Neoplasms ; Tumor Microenvironment ; }, abstract = {Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including in the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.}, }
@article {pmid37800457, year = {2023}, author = {Billings, JL and Hilton, JBW and Liddell, JR and Hare, DJ and Crouch, PJ}, title = {Fundamental Neurochemistry Review: Copper availability as a potential therapeutic target in progressive supranuclear palsy: Insight from other neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {167}, number = {3}, pages = {337-346}, doi = {10.1111/jnc.15978}, pmid = {37800457}, issn = {1471-4159}, mesh = {Humans ; *Supranuclear Palsy, Progressive/diagnosis/pathology ; Copper ; *Neurodegenerative Diseases/therapy ; Superoxide Dismutase-1 ; *Neurochemistry ; *Parkinson Disease/pathology ; }, abstract = {Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD-like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper-deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP.}, }
@article {pmid37797620, year = {2023}, author = {Yonekura, K and Maki-Yonekura, S and Takaba, K}, title = {Applications and limitations of electron 3D crystallography.}, journal = {Structure (London, England : 1993)}, volume = {31}, number = {11}, pages = {1328-1334}, doi = {10.1016/j.str.2023.09.007}, pmid = {37797620}, issn = {1878-4186}, mesh = {Crystallography/methods ; *Electrons ; Crystallography, X-Ray ; *Proteins/chemistry ; Microscopy, Electron, Transmission ; Peptides ; }, abstract = {Three-dimensional electron diffraction (3D ED) is a measurement and analysis technique in transmission electron microscopy that is used for determining atomic structures from small crystals. Diverse targets such as proteins, polypeptides, and organic compounds, whose crystals exist in aqueous solutions and organic solvents, or as dried powders, can be studied with 3D ED. We have been involved in the development of this technique, which can now rapidly process a large number of data collected through AI control, enabling efficient structure determination. Here, we introduce this method and describe our recent results. These include the structures and pathogenic mechanisms of wild-type and mutant polypeptides associated with the debilitating disease amyotrophic lateral sclerosis (ALS), the double helical structure of nanographene promoting nanofiber formation, and the structural properties of an organic semiconductor containing disordered regions. We also discuss the limitations and prospects of 3D ED compared to microcrystallography with X-ray free electron lasers.}, }
@article {pmid37795580, year = {2023}, author = {Rodriguez, P and Blakely, RD}, title = {Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?.}, journal = {Journal of cellular physiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcp.31125}, pmid = {37795580}, issn = {1097-4652}, support = {22A01//Florida Department of Health Ed/ ; }, abstract = {Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.}, }
@article {pmid37795273, year = {2023}, author = {Venediktov, AA and Bushueva, OY and Kudryavtseva, VA and Kuzmin, EA and Moiseeva, AV and Baldycheva, A and Meglinski, I and Piavchenko, GA}, title = {Closest horizons of Hsp70 engagement to manage neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1230436}, pmid = {37795273}, issn = {1662-5099}, abstract = {Our review seeks to elucidate the current state-of-the-art in studies of 70-kilodalton-weighed heat shock proteins (Hsp70) in neurodegenerative diseases (NDs). The family has already been shown to play a crucial role in pathological aggregation for a wide spectrum of brain pathologies. However, a slender boundary between a big body of fundamental data and its implementation has only recently been crossed. Currently, we are witnessing an anticipated advancement in the domain with dozens of studies published every month. In this review, we briefly summarize scattered results regarding the role of Hsp70 in the most common NDs including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We also bridge translational studies and clinical trials to portray the output for medical practice. Available options to regulate Hsp70 activity in NDs are outlined, too.}, }
@article {pmid37787835, year = {2023}, author = {Li, S and Zhao, L and Xiao, J and Guo, Y and Fu, R and Zhang, Y and Xu, S}, title = {The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {37787835}, issn = {1573-4919}, support = {No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; }, abstract = {There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.}, }
@article {pmid37783557, year = {2023}, author = {Chen, D and Huang, H and Saberi, H and Sharma, HS}, title = {Positive and negative cell therapy in randomized control trials for central nervous system diseases.}, journal = {International review of neurobiology}, volume = {171}, number = {}, pages = {241-254}, doi = {10.1016/bs.irn.2023.05.017}, pmid = {37783557}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; *Central Nervous System Diseases/therapy ; Cell- and Tissue-Based Therapy ; *Parkinson Disease/therapy ; Brain Damage, Chronic ; }, abstract = {Neurorestorative cell therapies have been tested to treat patients with nervous system diseases for over 20 years. Now it is still hard to answer which kinds of cells can really play a role on improving these patients' quality of life. Non-randomized clinical trials or studies could not provide strong evidences in answering this critical question. In this review, we summarized randomized clinical trials of cell therapies for central nervous diseases, such as stroke, spinal cord injury, cerebral palsy (CP), Parkinson's disease (PD), multiple sclerosis (MS), brain trauma, amyotrophic lateral sclerosis (ALS), etc. Most kinds of cell therapies demonstrated negative results for stoke, brain trauma and amyotrophic lateral sclerosis. A few kinds of cell therapies showed neurorestorative effects in this level of evidence-based medicine, such as olfactory ensheating cells for chronic ischemic stroke. Some kinds of cells showed positive or negative effects from different teams in the same or different diseases. We analyzed the possible failed reasons of negative results and the cellular bio-propriety basis of positive results. Based on therapeutic results of randomized control trials and reasonable analysis, we recommend: (1) to further conduct trials for successful cell therapies with positive results to increase neurorestorative effects; (2) to avoid in repeating failed cell therapies with negative results in same diseases because it is nonsense for them to be done with similar treatment methods, such as cell dosage, transplanting way, time of window, etc. Furthermore, we strongly suggest not to do non-randomized clinical trials for cells that had shown negative results in randomized clinical trials.}, }
@article {pmid37782813, year = {2023}, author = {Pennisi, F and Lo Presti, T and Ricciardi, GE and Dalla Valle, Z and Minerva, M and Privitera, G and Signorelli, C}, title = {Training and career opportunities for residencies in Hygiene and Preventive Medicine: results of a survey on 39 Italian schools.}, journal = {Igiene e sanita pubblica}, volume = {80}, number = {4}, pages = {94-100}, pmid = {37782813}, issn = {0019-1639}, mesh = {Humans ; *Internship and Residency ; State Medicine ; Public Health/education ; Hygiene/education ; Universities ; Preventive Medicine/education ; }, abstract = {INTRODUCTION: The Italian National Health Service (SSN) is currently grappling. with a complex situation, characterized by a persistent shortage of medical personnel and the divergent aspirations of young medical graduates. Additionally, recent regulatory developments concerning specialist training further contribute to the intricacies of the landscape, calling for a comprehensive analysis of the challenges and opportunities within the sector. This study aims to provide an updated overview of the current placement of medical graduates, residents and specialists in the specific hygiene and preventive medicine (Public Health) field.<br><br>METHODS: Data on admissions, withdrawals and resignations were obtained from the Ministries of Universities and Health and from the archives of the "Associazione Liberi Specializzandi" (ALS). Information regarding the professional prospects for specialists and residents in the field of Public Health was gathered through a tailored survey conducted by the "Consulta dei Medici in Formazione Specialistica" (Council of Medical Residents) of the Italian Society of Hygiene (SItI).<br><br>RESULTS: In 2022, a total of 483 specialization contracts were granted, indicating a decrease of 37% compared to the previous year. Notably, 85 positions (17.6%) remained unallocated or resulted in dropouts. Six months after completing their residency, 1.5% of hygiene residents were still actively seeking employment. On a positive note, 75.4% of fourth-year residents secured contracts under the "Decreto Calabria". Career opportunities within the Italian SSN have witnessed growth, with a significant proportion of placements in territorial services and hospital medical directorates.<br><br>DISCUSSION AND CONCLUSIONS: The updating of training programs provided by residency schools and the exploration of innovative approaches are of paramount importance to address the urgent need for high-quality training and to cater to the requirements of the national health system.}, }
@article {pmid37781096, year = {2023}, author = {Yu, H and Xiong, M and Zhang, Z}, title = {The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1209703}, pmid = {37781096}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and so on. They are characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system and share several cellular and molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, and chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase that is believed to play a pivotal role in the pathogenesis of NDDs. Here we summarize the structure and physiological functions of GSK3β and explore its involvement in NDDs. We also discussed its potential as a therapeutic target.}, }
@article {pmid37776476, year = {2023}, author = {Ocharán-Mercado, A and Loaeza-Loaeza, J and Castro-Coronel, Y and Acosta-Saavedra, LC and Hernández-Kelly, LC and Hernández-Sotelo, D and Ortega, A}, title = {RNA-Binding Proteins: A Role in Neurotoxicity?.}, journal = {Neurotoxicity research}, volume = {41}, number = {6}, pages = {681-697}, pmid = {37776476}, issn = {1476-3524}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/metabolism ; RNA-Binding Proteins/metabolism ; Neurons/metabolism ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Despite sustained efforts to treat neurodegenerative diseases, little is known at the molecular level to understand and generate novel therapeutic approaches for these malignancies. Therefore, it is not surprising that neurogenerative diseases are among the leading causes of death in the aged population. Neurons require sophisticated cellular mechanisms to maintain proper protein homeostasis. These cells are generally sensitive to loss of gene expression control at the post-transcriptional level. Post-translational control responds to signals that can arise from intracellular processes or environmental factors that can be regulated through RNA-binding proteins. These proteins recognize RNA through one or more RNA-binding domains and form ribonucleoproteins that are critically involved in the regulation of post-transcriptional processes from splicing to the regulation of association of the translation machinery allowing a relatively rapid and precise modulation of the transcriptome. Neurotoxicity is the result of the biological, chemical, or physical interaction of agents with an adverse effect on the structure and function of the central nervous system. The disruption of the proper levels or function of RBPs in neurons and glial cells triggers neurotoxic events that are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), and frontotemporal dementia (FTD) among many others. The connection between RBPs and neurodegenerative diseases opens a new landscape for potentially novel therapeutic targets for the intervention of these neurodegenerative pathologies. In this contribution, a summary of the recent findings of the molecular mechanisms involved in the plausible role of RBPs in RNA processing in neurodegenerative disease is discussed.}, }
@article {pmid37770379, year = {2023}, author = {Souza, INO and Roychaudhuri, R and de Belleroche, J and Mothet, JP}, title = {d-Amino acids: new clinical pathways for brain diseases.}, journal = {Trends in molecular medicine}, volume = {29}, number = {12}, pages = {1014-1028}, doi = {10.1016/j.molmed.2023.09.001}, pmid = {37770379}, issn = {1471-499X}, mesh = {Humans ; *Amino Acids/metabolism ; Critical Pathways ; Central Nervous System/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Free d-amino acids (d-AAs) are emerging as a novel and important class of signaling molecules in many organs, including the brain and endocrine systems. There has been considerable progress in our understanding of the fundamental roles of these atypical messengers, with increasingly recognized implications in a wide range of neuropathologies, including schizophrenia (SCZ), epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), substance abuse, and chronic pain, among others. Research has enabled the discovery that d-serine, d-aspartate and more recently d-cysteine are essential for the healthy development and function of the central nervous system (CNS). We discuss recent progress that has profoundly transformed our vision of numerous physiological processes but has also shown how d-AAs are now offering therapeutic promise in clinical settings for several human diseases.}, }
@article {pmid37762599, year = {2023}, author = {Taneva, SG and Todinova, S and Andreeva, T}, title = {Morphometric and Nanomechanical Screening of Peripheral Blood Cells with Atomic Force Microscopy for Label-Free Assessment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762599}, issn = {1422-0067}, support = {KP-06-H31/8//Bulgarian Science Fund/ ; funding programme Open Access Publishing//Baden-W&#xfc;rttemberg Ministry of Science, Research and Culture/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Alzheimer Disease/diagnosis ; Microscopy, Atomic Force ; Blood Cells ; }, abstract = {Neurodegenerative disorders (NDDs) are complex, multifactorial disorders with significant social and economic impact in today's society. NDDs are predicted to become the second-most common cause of death in the next few decades due to an increase in life expectancy but also to a lack of early diagnosis and mainly symptomatic treatment. Despite recent advances in diagnostic and therapeutic methods, there are yet no reliable biomarkers identifying the complex pathways contributing to these pathologies. The development of new approaches for early diagnosis and new therapies, together with the identification of non-invasive and more cost-effective diagnostic biomarkers, is one of the main trends in NDD biomedical research. Here we summarize data on peripheral biomarkers, biofluids (cerebrospinal fluid and blood plasma), and peripheral blood cells (platelets (PLTs) and red blood cells (RBCs)), reported so far for the three most common NDDs-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PLTs and RBCs, beyond their primary physiological functions, are increasingly recognized as valuable sources of biomarkers for NDDs. Special attention is given to the morphological and nanomechanical signatures of PLTs and RBCs as biophysical markers for the three pathologies. Modifications of the surface nanostructure and morphometric and nanomechanical signatures of PLTs and RBCs from patients with AD, PD, and ALS have been revealed by atomic force microscopy (AFM). AFM is currently experiencing rapid and widespread adoption in biomedicine and clinical medicine, in particular for early diagnostics of various medical conditions. AFM is a unique instrument without an analog, allowing the generation of three-dimensional cell images with extremely high spatial resolution at near-atomic scale, which are complemented by insights into the mechanical properties of cells and subcellular structures. Data demonstrate that AFM can distinguish between the three pathologies and the normal, healthy state. The specific PLT and RBC signatures can serve as biomarkers in combination with the currently used diagnostic tools. We highlight the strong correlation of the morphological and nanomechanical signatures between RBCs and PLTs in PD, ALS, and AD.}, }
@article {pmid37762112, year = {2023}, author = {Gimenez, J and Spalloni, A and Cappelli, S and Ciaiola, F and Orlando, V and Buratti, E and Longone, P}, title = {TDP-43 Epigenetic Facets and Their Neurodegenerative Implications.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762112}, issn = {1422-0067}, support = {PathensTDP//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; JPND2020-568-078//EU Joint Programme - Neurodegenerative Disease Research/ ; }, mesh = {Humans ; *Chromatin ; Cytoplasm ; *DNA-Binding Proteins/genetics ; Epigenesis, Genetic ; Epigenomics ; }, abstract = {Since its initial involvement in numerous neurodegenerative pathologies in 2006, either as a principal actor or as a cofactor, new pathologies implicating transactive response (TAR) DNA-binding protein 43 (TDP-43) are regularly emerging also beyond the neuronal system. This reflects the fact that TDP-43 functions are particularly complex and broad in a great variety of human cells. In neurodegenerative diseases, this protein is often pathologically delocalized to the cytoplasm, where it irreversibly aggregates and is subjected to various post-translational modifications such as phosphorylation, polyubiquitination, and cleavage. Until a few years ago, the research emphasis has been focused particularly on the impacts of this aggregation and/or on its widely described role in complex RNA splicing, whether related to loss- or gain-of-function mechanisms. Interestingly, recent studies have strengthened the knowledge of TDP-43 activity at the chromatin level and its implication in the regulation of DNA transcription and stability. These discoveries have highlighted new features regarding its own transcriptional regulation and suggested additional mechanistic and disease models for the effects of TPD-43. In this review, we aim to give a comprehensive view of the potential epigenetic (de)regulations driven by (and driving) this multitask DNA/RNA-binding protein.}, }
@article {pmid37761265, year = {2023}, author = {Anghel, L and Ciubară, A and Nechita, A and Nechita, L and Manole, C and Baroiu, L and Ciubară, AB and Mușat, CL}, title = {Sleep Disorders Associated with Neurodegenerative Diseases.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {13}, number = {18}, pages = {}, pmid = {37761265}, issn = {2075-4418}, abstract = {Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington's disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients' quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care.}, }
@article {pmid37760050, year = {2023}, author = {Rubino, V and La Rosa, G and Pipicelli, L and Carriero, F and Damiano, S and Santillo, M and Terrazzano, G and Ruggiero, G and Mondola, P}, title = {Insights on the Multifaceted Roles of Wild-Type and Mutated Superoxide Dismutase 1 in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {37760050}, issn = {2076-3921}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease. Cell damage in ALS is the result of many different, largely unknown, pathogenetic mechanisms. Astrocytes and microglial cells play a critical role also for their ability to enhance a deranged inflammatory response. Excitotoxicity, due to excessive glutamate levels and increased intracellular Ca[2+] concentration, has also been proposed to play a key role in ALS pathogenesis/progression. Reactive Oxygen Species (ROS) behave as key second messengers for multiple receptor/ligand interactions. ROS-dependent regulatory networks are usually mediated by peroxides. Superoxide Dismutase 1 (SOD1) physiologically mediates intracellular peroxide generation. About 10% of ALS subjects show a familial disease associated with different gain-of-function SOD1 mutations. The occurrence of sporadic ALS, not clearly associated with SOD1 defects, has been also described. SOD1-dependent pathways have been involved in neuron functional network as well as in immune-response regulation. Both, neuron depolarization and antigen-dependent T-cell activation mediate SOD1 exocytosis, inducing increased interaction of the enzyme with a complex molecular network involved in the regulation of neuron functional activity and immune response. Here, alteration of SOD1-dependent pathways mediating increased intracellular Ca[2+] levels, altered mitochondria functions and defective inflammatory process regulation have been proposed to be relevant for ALS pathogenesis/progression.}, }
@article {pmid37759656, year = {2023}, author = {Angelopoulou, E and Pyrgelis, ES and Ahire, C and Suman, P and Mishra, A and Piperi, C}, title = {Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases.}, journal = {Biology}, volume = {12}, number = {9}, pages = {}, pmid = {37759656}, issn = {2079-7737}, abstract = {During the aging of the global population, the prevalence of neurodegenerative diseases will be continuously growing. Although each disorder is characterized by disease-specific protein accumulations, several common pathophysiological mechanisms encompassing both genetic and environmental factors have been detected. Among them, protein arginine methyltransferases (PRMTs), which catalyze the methylation of arginine of various substrates, have been revealed to regulate several cellular mechanisms, including neuronal cell survival and excitability, axonal transport, synaptic maturation, and myelination. Emerging evidence highlights their critical involvement in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, Huntington's disease (HD), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA). Underlying mechanisms include the regulation of gene transcription and RNA splicing, as well as their implication in various signaling pathways related to oxidative stress responses, apoptosis, neuroinflammation, vacuole degeneration, abnormal protein accumulation and neurotransmission. The targeting of PRMTs is a therapeutic approach initially developed against various forms of cancer but currently presents a novel potential strategy for neurodegenerative diseases. In this review, we discuss the accumulating evidence on the role of PRMTs in the pathophysiology of neurodegenerative diseases, enlightening their pathogenesis and stimulating future research.}, }
@article {pmid37759540, year = {2023}, author = {Sanghai, N and Tranmer, GK}, title = {Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.}, journal = {Cells}, volume = {12}, number = {18}, pages = {}, pmid = {37759540}, issn = {2073-4409}, abstract = {Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.}, }
@article {pmid37755677, year = {2024}, author = {Hu, C and Yan, Y and Jin, Y and Yang, J and Xi, Y and Zhong, Z}, title = {Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases.}, journal = {Neuroscience bulletin}, volume = {40}, number = {2}, pages = {241-254}, pmid = {37755677}, issn = {1995-8218}, mesh = {Humans ; *Prions ; *Neurodegenerative Diseases/pathology ; Amyloid beta-Peptides ; *Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; *Parkinson Disease ; }, abstract = {The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.}, }
@article {pmid37751856, year = {2023}, author = {Martin Schaff, C and Kurent, JE and Kolodziejczak, S and Milic, M and Foster, LA and Mehta, AK}, title = {Neuroprognostication for Patients with Amyotrophic Lateral Sclerosis: An Updated, Evidence-Based Review.}, journal = {Seminars in neurology}, volume = {43}, number = {5}, pages = {776-790}, doi = {10.1055/s-0043-1775595}, pmid = {37751856}, issn = {1098-9021}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Quality of Life ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that presents and progresses in various ways, making prognostication difficult. Several paradigms exist for providers to elucidate prognosis in a way that addresses not only the amount of time a patient has to live, but also a patient's quality of their life moving forward. Prognostication, with regard to both survivability and quality of life, is impacted by several features that include, but are not limited to, patient demographics, clinical features on presentation, and over time, access to therapy, and access to multidisciplinary clinics. An understanding of the impact that these features have on the life of a patient with ALS can help providers to develop a better and more personalized approach for patients related to their clinical prognosis after a diagnosis is made. The ultimate goal of prognostication is to empower patients with ALS to take control and make decisions with their care teams to ensure that their goals are addressed and met.}, }
@article {pmid37751804, year = {2023}, author = {Wang, Z and Zhang, C and Fan, C and Liu, Y}, title = {Post-translational modifications in stress granule and their implications in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {4}, pages = {194989}, doi = {10.1016/j.bbagrm.2023.194989}, pmid = {37751804}, issn = {1876-4320}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Stress Granules ; Protein Processing, Post-Translational ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; RNA, Messenger/metabolism ; }, abstract = {Stress granules (SGs) arise as formations of mRNAs and proteins in response to translation initiation inhibition during stress. These dynamic compartments adopt a fluidic nature through liquid-liquid phase separation (LLPS), exhibiting a composition subject to constant change within cellular contexts. Research has unveiled an array of post-translational modifications (PTMs) occurring on SG proteins, intricately orchestrating SG dynamics. In the realm of neurodegenerative diseases, pathological mutant proteins congregate into insoluble aggregates alongside numerous SG proteins, manifesting resilience against disassembly. Specific PTMs conspicuously label these aggregates, designating them for subsequent degradation. The strategic manipulation of aberrant SGs via PTMs emerges as a promising avenue for therapeutic intervention. This review discerns recent strides in comprehending the impact of PTMs on LLPS behavior and the assembly/disassembly kinetics of SGs. By delving into the roles of PTMs in governing SG dynamics, we augment our cognizance of the molecular underpinnings of neurodegeneration. Furthermore, we offer invaluable insights into potential targets for therapeutic intervention in neurodegenerative afflictions, encompassing conditions like amyotrophic lateral sclerosis and frontotemporal dementia.}, }
@article {pmid37748443, year = {2024}, author = {Jütte, R}, title = {Involving Voters and Consumers in Decision-Making about the Health Care System - The Swiss Case: A Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {78-83}, doi = {10.1159/000534268}, pmid = {37748443}, issn = {2504-2106}, mesh = {Humans ; Switzerland ; *Voting ; *Complementary Therapies ; Evidence-Based Medicine ; }, abstract = {BACKGROUND: Behind the principle of involving users and voters directly in decision-making about the health care system are ideas relating to empowerment. This implies a challenge to the traditional view that scientific knowledge is generally believed to be of higher value than empirical knowledge, as it is the case with CAM. The objectives of this review are (a) to show that this assumption disregards the fact that CAM is as scientific as conventional medicine but has different basic assumptions what the world is being made of and consequently uses different/adapted scientific methods; (b) to demonstrate how a perspective of the history of medicine and science as well as direct democracy mechanisms such as stipulated in the Swiss constitution can be used to achieve the acceptance of CAM in a modern medical health care system. A public health care system financed by levies from the population should also reflect the widely documented desire in the population for medical pluralism (provided that therapeutical alternatives are not risky). Otherwise, the problem of social inequality arises because only people with a good financial background can afford this medicine.<br><br>SUMMARY: From the perspective of scientific theory and the history of science, the answer to the question of whether complementary medicine and conventional medical procedures must provide proof of efficacy according to a uniform scientific is quite controversial according to epistemologically oriented studies on this issue.<br><br>KEY MESSAGES: This review found strong evidence for involving voters and consumers directly in decision-making about the provision of CAM in the health care system. It also seems necessary to step back in the debate on evidence-based medicine, taking a history of medicine and science perspective, as the role which the proper method occupies and plays in medicine is defined by the scientific nature of the world view.<br><br>UNLABELLED: Hinter dem Grundsatz, Nutzer und W&#xe4;hler direkt in die Entscheidungsfindung &#xfc;ber das Gesundheitssystem einzubeziehen, stehen Vorstellungen von Empowerment. Dies impliziert eine Infragestellung der traditionellen Ansicht, dass wissenschaftliches Wissen im Allgemeinen als wertvoller angesehen wird als empirisches Wissen und erprobte Erfahrung, wie es bei der Komplement&#xe4;rmedizin der Fall ist. Die Ziele dieser &#xdc;bersichtsarbeit sind: (a) zu zeigen, dass diese Annahme die Tatsache au&#xdf;er Acht l&#xe4;sst, dass die Komplement&#xe4;rmedizin ebenso wissenschaftlich ist wie die Schulmedizin, aber von anderen Grundannahmen ausgeht, wie die Welt beschaffen ist, und folglich andere/angepasste wissenschaftliche Methoden anwendet; (b) aufzuzeigen, wie eine medizin- und wissenschaftsgeschichtliche Perspektive sowie Mechanismen der direkten Demokratie, wie sie in der Schweizer Verfassung vorgesehen sind, genutzt werden k&#xf6;nnen, um die Akzeptanz der Komplement&#xe4;rmedizin in einem modernen medizinischen Gesundheitssystem zu erreichen. Ein &#xf6;ffentliches, durch Abgaben der Bev&#xf6;lkerung finanziertes Gesundheitssystem sollte auch dem vielfach dokumentierten Wunsch der Bev&#xf6;lkerung nach medizinischem Pluralismus Rechnung tragen (sofern die therapeutischen Alternativen nicht riskant sind). Andernfalls stellt sich das Problem der sozialen Ungleichheit, weil sich nur Menschen mit einem guten finanziellen Hintergrund diese Medizin leisten k&#xf6;nnen.}, }
@article {pmid37746513, year = {2023}, author = {Singh, A and Arora, S and Chavan, M and Shahbaz, S and Jabeen, H}, title = {An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions.}, journal = {Cureus}, volume = {15}, number = {8}, pages = {e44051}, pmid = {37746513}, issn = {2168-8184}, abstract = {For both short-term and long-term treatment of bipolar disorder, lithium is a prototypical mood stabilizer. Lithium's neuroprotective properties were revealed by cumulative translational research, which opened the door to reforming the chemical as a treatment for neurodegenerative illnesses. The control of homeostatic systems such as oxidative stress, autophagy, apoptosis, mitochondrial function, and inflammation underlies lithium's neuroprotective characteristics. The fact that lithium inhibits the enzymes inositol monophosphatase (IMPase) and glycogen synthase kinase (GSK)-3 may be the cause of the various intracellular reactions. In this article, we review lithium's neurobiological properties, as demonstrated by its neurotrophic and neuroprotective capabilities, as well as translational studies in cells in culture and in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease, amyotrophic lateral sclerosis (ALS), ischemic stroke, and neuronal ceroid lipofuscinosis (NCL), discussing the justification for the drug's use in the treatment of these neurodegenerative disorders.}, }
@article {pmid37741764, year = {2024}, author = {Ducharme, S and Pijnenburg, Y and Rohrer, JD and Huey, E and Finger, E and Tatton, N}, title = {Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {32}, number = {1}, pages = {98-113}, doi = {10.1016/j.jagp.2023.08.017}, pmid = {37741764}, issn = {1545-7214}, support = {MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; *Neurodegenerative Diseases/diagnosis/genetics ; *Psychiatry ; }, abstract = {Neuropsychiatric symptoms (NPS) are common manifestations of neurodegenerative disorders and are often early signs of those diseases. Among those neurodegenerative diseases, TDP-43 proteinopathies are an increasingly recognized cause of early neuropsychiatric manifestations. TDP-43-related diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE). The majority of TDP-43-related diseases are sporadic, but a significant proportion is hereditary, with progranulin (GRN) mutations and C9orf72 repeat expansions as the most common genetic etiologies. Studies reveal that NPS can be the initial manifestation of those diseases or can complicate disease course, but there is a lack of awareness among clinicians about TDP-43-related diseases, which leads to common diagnostic mistakes or delays. There is also emerging evidence that TDP-43 accumulations could play a role in late-onset primary psychiatric disorders. In the absence of robust biomarkers for TDP-43, the diagnosis remains primarily based on clinical assessment and neuroimaging. Given the association with psychiatric symptoms, clinical psychiatrists have a key role in the early identification of patients with TDP-43-related diseases. This narrative review provides a comprehensive overview of the pathobiology of TDP-43, resulting clinical presentations, and associated neuropsychiatric manifestations to help guide clinical practice.}, }
@article {pmid37739217, year = {2023}, author = {Chakraborty, J and Chakraborty, S and Chakraborty, S and Narayan, MN}, title = {Entanglement of MAPK pathways with gene expression and its omnipresence in the etiology for cancer and neurodegenerative disorders.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {4}, pages = {194988}, doi = {10.1016/j.bbagrm.2023.194988}, pmid = {37739217}, issn = {1876-4320}, mesh = {Humans ; Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System/genetics ; *Neoplasms/genetics/drug therapy ; *Neurodegenerative Diseases/genetics ; Gene Expression ; }, abstract = {Mitogen Activated Protein Kinase (MAPK) is one of the most well characterized cellular signaling pathways that controls fundamental cellular processes including proliferation, differentiation, and apoptosis. These cellular functions are consequences of transcription of regulatory genes that are influenced and regulated by the MAP-Kinase signaling cascade. MAP kinase components such as Receptor Tyrosine Kinases (RTKs) sense external cues or ligands and transmit these signals via multiple protein complexes such as RAS-RAF, MEK, and ERKs and eventually modulate the transcription factors inside the nucleus to induce transcription and other regulatory functions. Aberrant activation, dysregulation of this signaling pathway, and genetic alterations in any of these components results in the developmental disorders, cancer, and neurodegenerative disorders. Over the years, the MAPK pathway has been a prime pharmacological target, to treat complex human disorders that are genetically linked such as cancer, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current review re-visits the mechanism of MAPK pathways in gene expression regulation. Further, a current update on the progress of the mechanistic understanding of MAPK components is discussed from a disease perspective.}, }
@article {pmid37738797, year = {2023}, author = {Dong, W and Peng, Q and Liu, Z and Xie, Z and Guo, X and Li, Y and Chen, C}, title = {Estrogen plays an important role by influencing the NLRP3 inflammasome.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {167}, number = {}, pages = {115554}, doi = {10.1016/j.biopha.2023.115554}, pmid = {37738797}, issn = {1950-6007}, abstract = {The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important part of the natural immune system that plays an important role in many diseases. Estrogen is a sex hormone that plays an important role in controlling reproduction and regulates many physiological and pathological processes. Recent studies have indicated that estrogen is associated with disease progression. Estrogen can ameliorate some diseases (e. g, sepsis, mood disturbances, cerebral ischemia, some hepatopathy, Parkinson's disease, amyotrophic lateral sclerosis, inflammatory bowel disease, spinal cord injury, multiple sclerosis, myocardial ischemia/reperfusion injury, osteoarthritis, and renal fibrosis) by inhibiting the NLRP3 inflammasome. Estrogen can also promote the development of diseases (e.g., ovarian endometriosis, dry eye disease, and systemic lupus erythematosus) by upregulating the NLRP3 inflammasome. In addition, estrogen has a dual effect on the development of cancers and asthma. However, the mechanism of these effects is not summarized. This article reviewed the progress in understanding the effects of estrogen on the NLRP3 inflammasome and its mechanisms in recent years to provide a theoretical basis for an in-depth study.}, }
@article {pmid37735909, year = {2023}, author = {Irie, T and Sawa, M}, title = {CDC7 kinase inhibitors: a survey of recent patent literature (2017-2022).}, journal = {Expert opinion on therapeutic patents}, volume = {33}, number = {7-8}, pages = {493-501}, doi = {10.1080/13543776.2023.2262138}, pmid = {37735909}, issn = {1744-7674}, mesh = {Humans ; *Cell Cycle Proteins/metabolism ; Patents as Topic ; Protein Serine-Threonine Kinases ; DNA Replication ; *Neoplasms ; }, abstract = {INTRODUCTION: CDC7 is a serine/threonine kinase which plays an important role in DNA replication. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas inhibition of CDC7 in normal cells does not cause cell death and only leads to cell cycle arrest at the DNA replication checkpoint. Therefore, CDC7 has been recognized as a potential target for novel therapeutic interventions in cancers.<br><br>AREAS COVERED: Patent literature claiming novel small molecule compounds inhibiting CDC7 disclosed from 2017 to 2022.<br><br>EXPERT OPINION: Despite the indisputable positive impact of CDC7 as a drug target, there have been reported only a handful of chemical scaffolds as CDC7 inhibitors. Several CDC7 inhibitors have been progressed into clinical trials for cancer treatments, but they did not result in satisfactory efficacies in those trials. One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.}, }
@article {pmid37735622, year = {2023}, author = {Sarkar, S and Elliott, EC and Henry, HR and Ludovico, ID and Melchior, JT and Frazer-Abel, A and Webb-Robertson, BJ and Davidson, WS and Holers, VM and Rewers, MJ and Metz, TO and Nakayasu, ES}, title = {Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response.}, journal = {Clinical proteomics}, volume = {20}, number = {1}, pages = {38}, pmid = {37735622}, issn = {1542-6416}, support = {P30 DK116073/DK/NIDDK NIH HHS/United States ; R01 DK032493/DK/NIDDK NIH HHS/United States ; U01 DK127505/DK/NIDDK NIH HHS/United States ; U01 DK127786/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development.<br><br>METHODS: This systematic review was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria.<br><br>RESULTS: A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development.<br><br>CONCLUSIONS: Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.}, }
@article {pmid37735487, year = {2023}, author = {Gao, C and Jiang, J and Tan, Y and Chen, S}, title = {Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {359}, pmid = {37735487}, issn = {2059-3635}, mesh = {Animals ; *Neurodegenerative Diseases/genetics ; Microglia ; Neuroinflammatory Diseases ; Protein Aggregates ; *Alzheimer Disease/genetics ; }, abstract = {Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.}, }
@article {pmid37734449, year = {2023}, author = {Hayashi, K and Sasaki, K}, title = {Number of kinesins engaged in axonal cargo transport: A novel biomarker for neurological disorders.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {25-30}, doi = {10.1016/j.neures.2023.09.004}, pmid = {37734449}, issn = {1872-8111}, mesh = {Humans ; *Kinesins/metabolism ; Axonal Transport/physiology ; Axons/metabolism ; Dyneins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Kinesin motor proteins play crucial roles in anterograde transport of cargo vesicles in neurons, moving them along axons from the cell body towards the synaptic region. Not only the transport force and velocity of single motor protein, but also the number of kinesin molecules involved in transporting a specific cargo, is pivotal for synapse formation. This collective transport by multiple kinesins ensures stable and efficient cargo transport in neurons. Abnormal increases or decreases in the number of engaged kinesin molecules per cargo could potentially act as biomarkers for neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), spastic paraplegia, polydactyly syndrome, and virus transport disorders. We review here a model constructed using physical measurements to quantify the number of kinesin molecules associated with their cargo, which could shed light on the molecular mechanisms of neurodegenerative diseases related to axonal transport.}, }
@article {pmid37730668, year = {2023}, author = {Zhu, L and Li, S and Li, XJ and Yin, P}, title = {Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {46}, pmid = {37730668}, issn = {2047-9158}, mesh = {Humans ; Animals ; Swine ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Brain ; }, abstract = {In order to dissect amyotrophic lateral sclerosis (ALS), a multigenic, multifactorial, and progressive neurodegenerative disease with heterogeneous clinical presentations, researchers have generated numerous animal models to mimic the genetic defects. Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics. However, most genetically modified rodent models lack overt pathological features, imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms. Recent studies using large animals, including pigs and non-human primates, have uncovered important events that resemble neurodegeneration in patients' brains but could not be produced in small animals. Here we describe common features as well as discrepancies among these models, highlighting new insights from these models. Furthermore, we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models.}, }
@article {pmid37725878, year = {2023}, author = {Singh, N and Vishwas, S and Kaur, A and Kaur, H and Kakoty, V and Khursheed, R and Chaitanya, MVNL and Babu, MR and Awasthi, A and Corrie, L and Harish, V and Yanadaiah, P and Gupta, S and Sayed, AA and El-Sayed, A and Ali, I and Kensara, OA and Ghaboura, N and Gupta, G and Dou, AM and Algahtani, M and El-Kott, AF and Dua, K and Singh, SK and Abdel-Daim, MM}, title = {Harnessing role of sesamol and its nanoformulations against neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {167}, number = {}, pages = {115512}, doi = {10.1016/j.biopha.2023.115512}, pmid = {37725878}, issn = {1950-6007}, abstract = {Sesamol is a lignan of sesame seeds and a natural phenolic molecule that has emerged as a useful medical agent. Sesamol is a non-toxic phytoconstituent, which exerts certain valuable effects in the management of cancer, diabetes, cardiovascular diseases, neurodegenerative diseases (NDs), etc. Sesamol is known to depict its neuroprotective role by various mechanisms, such as metabolic regulators, action on oxidative stress, neuroinflammation, etc. However, its poor oral bioavailability, rapid excretion (as conjugates), and susceptibility to gastric irritation/toxicity (particularly in rats' forestomach) may restrict its effectiveness. To overcome the associated limitations, novel drug delivery system-based formulations of sesamol are emerging and being researched extensively. These can conjugate with sesamol and enhance the bioavailability and solubility of free sesamol, along with delivery at the target site. In this review, we have summarized various research works highlighting the role of sesamol on various NDs, including Alzheimer's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Parkinson's disease. Moreover, the formulation strategies and neuroprotective role of sesamol-based nano-formulations have also been discussed.}, }
@article {pmid37725216, year = {2024}, author = {Dar, NJ and John, U and Bano, N and Khan, S and Bhat, SA}, title = {Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4).}, journal = {Molecular neurobiology}, volume = {61}, number = {3}, pages = {1507-1526}, pmid = {37725216}, issn = {1559-1182}, mesh = {Humans ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Ferroptosis ; Cell Death ; Oxidation-Reduction ; *Neurodegenerative Diseases ; Glutathione Peroxidase/metabolism ; Glutathione/metabolism ; Lipid Peroxidation ; }, abstract = {Oxytosis/ferroptosis is an iron-dependent oxidative form of cell death triggered by lethal accumulation of phospholipid hydroperoxides (PLOOHs) in membranes. Failure of the intricate PLOOH repair system is a principle cause of ferroptotic cell death. Glutathione peroxidase 4 (GPX4) is distinctly vital for converting PLOOHs in membranes to non-toxic alcohols. As such, GPX4 is known as the master regulator of oxytosis/ferroptosis. Ferroptosis has been implicated in a number of disorders such as neurodegenerative diseases (amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), etc.), ischemia/reperfusion injury, and kidney degeneration. Reduced function of GPX4 is frequently observed in degenerative disorders. In this study, we examine how diminished GPX4 function may be a critical event in triggering oxytosis/ferroptosis to perpetuate or initiate the neurodegenerative diseases and assess the possible therapeutic importance of oxytosis/ferroptosis in neurodegenerative disorders. These discoveries are important for advancing our understanding of neurodegenerative diseases because oxytosis/ferroptosis may provide a new target to slow the course of the disease.}, }
@article {pmid37721281, year = {2024}, author = {Jourdi, G and Fleury, S and Boukhatem, I and Lordkipanidzé, M}, title = {Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?.}, journal = {Neural regeneration research}, volume = {19}, number = {3}, pages = {536-541}, pmid = {37721281}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are often misdiagnosed, especially when the diagnosis is based solely on clinical symptoms. The p75 neurotrophic receptor (p75[NTR]) has been studied as an index of sensory and motor nerve development and maturation. Its cleavable extracellular domain (ECD) is readily detectable in various biological fluids including plasma, serum and urine. There is evidence for increased p75[NTR] ECD levels in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, age-related dementia, schizophrenia, and diabetic neuropathy. Whether p75[NTR] ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders, and whether it could potentially lead to the development of targeted therapies, remains an open question. In this review, we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases. We also highlight areas that require further investigation to better understand the role of p75[NTR] ECD in the clinical diagnosis and management of neurodegenerative disorders.}, }
@article {pmid37720552, year = {2023}, author = {Naskar, A and Nayak, A and Salaikumaran, MR and Vishal, SS and Gopal, PP}, title = {Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1242925}, pmid = {37720552}, issn = {1662-5099}, abstract = {Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.}, }
@article {pmid37720544, year = {2023}, author = {McGoldrick, P and Robertson, J}, title = {Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1247297}, pmid = {37720544}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that are part of a common disease spectrum due to clinical, genetic, and pathological overlap. A prominent genetic factor contributing to both diseases is a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene. This mutation in C9orf72 leads to nuclear depletion and cytoplasmic aggregation of Tar DNA-RNA binding protein 43 (TDP-43). TDP-43 pathology is characteristic of the majority of ALS cases, irrespective of disease causation, and is present in ~50% of FTD cases. Defects in nucleocytoplasmic transport involving the nuclear pore complex, the Ran-GTPase cycle, and nuclear transport factors have been linked with the mislocalization of TDP-43. Here, we will explore and discuss the implications of these system abnormalities of nucleocytoplasmic transport in C9orf72-ALS/FTD, as well as in other forms of familial and sporadic ALS.}, }
@article {pmid37712858, year = {2024}, author = {Al-Kuraishy, HM and Jabir, MS and Al-Gareeb, AI and Saad, HM and Batiha, GE and Klionsky, DJ}, title = {The beneficial role of autophagy in multiple sclerosis: Yes or No?.}, journal = {Autophagy}, volume = {20}, number = {2}, pages = {259-274}, pmid = {37712858}, issn = {1554-8635}, support = {R35 GM131919/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Multiple Sclerosis/metabolism ; Leukocytes, Mononuclear/metabolism ; Autophagy ; Central Nervous System ; *Encephalomyelitis, Autoimmune, Experimental ; Mice, Inbred C57BL ; }, abstract = {Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS) due to an increase of abnormal peripherally auto-reactive T lymphocytes which elicit autoimmunity. The main pathophysiology of MS is myelin sheath damage by immune cells and a defect in the generation of myelin by oligodendrocytes. Macroautophagy/autophagy is a critical degradation process that eliminates dysfunctional or superfluous cellular components. Autophagy has the property of a double-edged sword in MS in that it may have both beneficial and detrimental effects on MS neuropathology. Therefore, this review illustrates the protective and harmful effects of autophagy with regard to this disease. Autophagy prevents the progression of MS by reducing oxidative stress and inflammatory disorders. In contrast, over-activated autophagy is associated with the progression of MS neuropathology and in this case the use of autophagy inhibitors may alleviate the pathogenesis of MS. Furthermore, autophagy provokes the activation of different immune and supporting cells that play an intricate role in the pathogenesis of MS. Autophagy functions in the modulation of MS neuropathology by regulating cell proliferation related to demyelination and remyelination. Autophagy enhances remyelination by increasing the activity of oligodendrocytes, and astrocytes. However, autophagy induces demyelination by activating microglia and T cells. In conclusion, specific autophagic activators of oligodendrocytes, and astrocytes, and specific autophagic inhibitors of dendritic cells (DCs), microglia and T cells induce protective effects against the pathogenesis of MS.Abbreviations: ALS: amyotrophic lateral sclerosis; APCs: antigen-presenting cells; BBB: blood-brain barrier; CSF: cerebrospinal fluid; CNS: central nervous system; DCs: dendritic cells; EAE: experimental autoimmune encephalomyelitis; ER: endoplasmic reticulum; LAP: LC3-associated phagocytosis; MS: multiple sclerosis; NCA: non-canonical autophagy; OCBs: oligoclonal bands; PBMCs: peripheral blood mononuclear cells; PD: Parkinson disease; ROS: reactive oxygen species; UPR: unfolded protein response.}, }
@article {pmid37709948, year = {2023}, author = {Goutman, SA and Savelieff, MG and Jang, DG and Hur, J and Feldman, EL}, title = {The amyotrophic lateral sclerosis exposome: recent advances and future directions.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {10}, pages = {617-634}, pmid = {37709948}, issn = {1759-4766}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/genetics ; *Exposome ; Environmental Exposure/adverse effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2-5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene-time-environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome - the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventing disease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research.}, }
@article {pmid37706096, year = {2023}, author = {Stipa, G and Ancidoni, A and Vanacore, N and Bellomo, G}, title = {Raw Water and ALS: A Unifying Hypothesis for the Environmental Agents Involved in ALS.}, journal = {Annals of neurosciences}, volume = {30}, number = {2}, pages = {124-132}, pmid = {37706096}, issn = {0972-7531}, abstract = {Different studies identified the presence of several altered genes in familial and sporadic amyotrophic lateral sclerosis (ALS) forms. The experimental data, together with the epidemiological data, would seem to suggest the existence of molecular mechanisms (e.g., axonal transport) related to these genes, together with a susceptibility of the same genes to certain environmental factors that would therefore suggest an impact of the environment on the etiopathogenesis of ALS. In our review, we considered the most relevant environmental clusters around the world, collecting different hypotheses and underlining common environmental factors among the different clusters. Moreover, further epidemiological data identified a higher risk of ALS in professional athletes and, in particular, in soccer and football players. Despite this increased risk of ALS highlighted by the epidemiological evidence in aforementioned sports, the mechanisms remain unclear. At last, the use of raw water has been associated with ALS risk. The aim of the present review is to characterize a possible relationship between these clusters, to be explored in the context of the interaction between genetic and environmental factors on the etiopathogenesis of ALS.}, }
@article {pmid37697342, year = {2023}, author = {Li, Z and Wang, X and Wang, X and Yi, X and Wong, YK and Wu, J and Xie, F and Hu, D and Wang, Q and Wang, J and Zhong, T}, title = {Research progress on the role of extracellular vesicles in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {43}, pmid = {37697342}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy ; *Extracellular Vesicles ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, affect millions of people worldwide. Tremendous efforts have been put into disease-related research, but few breakthroughs have been made in diagnostic and therapeutic approaches. Extracellular vesicles (EVs) are heterogeneous cell-derived membrane structures that arise from the endosomal system or are directly separated from the plasma membrane. EVs contain many biomolecules, including proteins, nucleic acids, and lipids, which can be transferred between different cells, tissues, or organs, thereby regulating cross-organ communication between cells during normal and pathological processes. Recently, EVs have been shown to participate in various aspects of neurodegenerative diseases. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the advanced research progress on EVs in the pathological processes of several neurodegenerative diseases. Moreover, we outline the latest research on the roles of EVs in neurodegenerative diseases and their therapeutic potential for the diseases.}, }
@article {pmid37694369, year = {2023}, author = {Verde, F and Aiello, EN and Adobbati, L and Poletti, B and Solca, F and Tiloca, C and Sangalli, D and Maranzano, A and Muscio, C and Ratti, A and Zago, S and Ticozzi, N and Frisoni, GB and Silani, V}, title = {Coexistence of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: Case Report and Review of the Literature.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {95}, number = {4}, pages = {1383-1399}, doi = {10.3233/JAD-230562}, pmid = {37694369}, issn = {1875-8908}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Cognitive Dysfunction/complications ; Brain/diagnostic imaging ; *Frontotemporal Dementia/complications/diagnostic imaging/genetics ; }, abstract = {We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer's disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order to recognize AD.}, }
@article {pmid37692101, year = {2023}, author = {Stansberry, WM and Pierchala, BA}, title = {Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1238453}, pmid = {37692101}, issn = {1662-5099}, support = {R01 NS089585/NS/NINDS NIH HHS/United States ; }, abstract = {The discovery of the neurotrophins and their potent survival and trophic effects led to great enthusiasm about their therapeutic potential to rescue dying neurons in neurodegenerative diseases. The further discovery that brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) had potent survival-promoting activity on motor neurons led to the proposal for their use in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). In this review we synthesize the literature pertaining to the role of NGF, BDNF, CNTF and GDNF on the development and physiology of spinal motor neurons, as well as the preclinical studies that evaluated their potential for the treatment of ALS. Results from the clinical trials of these molecules will also be described and, with the aid of decades of hindsight, we will discuss what can reasonably be concluded and how this information can inform future clinical development of neurotrophic factors for ALS.}, }
@article {pmid37691335, year = {2023}, author = {Corcoran, J and Kluger, BM}, title = {Prognosis in chronic progressive neurologic disease: a narrative review.}, journal = {Annals of palliative medicine}, volume = {12}, number = {5}, pages = {952-962}, doi = {10.21037/apm-22-1338}, pmid = {37691335}, issn = {2224-5839}, mesh = {Humans ; *Parkinson Disease/diagnosis/therapy ; *Nervous System Diseases ; Prognosis ; Palliative Care ; Chronic Disease ; *Dementia ; }, abstract = {BACKGROUND AND OBJECTIVE: Prognostication is the process of predicting a patient's likely outcome from their medical condition, and consists of determining both how well and how long a patient may live. There are few disease-specific prognostic tools to estimate a patient's individualized prognosis in terms of symptom burden and mortality. Here we summarize relevant literature on prognosis in four progressive neurologic diseases-dementia, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis-as well as on best practices on communicating prognosis with patients and care partners.<br><br>METHODS: We conducted a PubMed search for terms including "prognosis", "mortality" and "prognostic indicators" in addition to specific diseases, and for terms including "prognosis AND communication". Only English-language papers were included in this review. The time frame of our literature search was 1965 through March 1, 2023.<br><br>KEY CONTENT AND FINDINGS: There is some literature to help clinicians in predicting disease progression and survival. These include both general factors (e.g., age, medical co-morbidities) and disease-specific factors (e.g., postural instability in Parkinson's disease). There is also literature on communication of prognosis in neurologic and non-neurologic disease which demonstrates that many patients and care partners prefer to hear prognosis early after diagnosis and to have prognosis discussed as a roadmap of disease.<br><br>CONCLUSIONS: More work is needed to develop tools for individualized prognostication and communication for patients with neurologic disease. While there is limited literature on disease-specific prognostic models, existing literature combined with palliative care approaches may improve prognostic guidance for patients.}, }
@article {pmid37689642, year = {2023}, author = {Bustamante-Barrientos, FA and Luque-Campos, N and Araya, MJ and Lara-Barba, E and de Solminihac, J and Pradenas, C and Molina, L and Herrera-Luna, Y and Utreras-Mendoza, Y and Elizondo-Vega, R and Vega-Letter, AM and Luz-Crawford, P}, title = {Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {613}, pmid = {37689642}, issn = {1479-5876}, mesh = {Humans ; Mitochondria ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Parkinson Disease ; Central Nervous System ; }, abstract = {Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.}, }
@article {pmid37689321, year = {2023}, author = {Donini, L and Tanel, R and Zuccarino, R and Basso, M}, title = {Protein biomarkers for the diagnosis and prognosis of Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {31-41}, doi = {10.1016/j.neures.2023.09.002}, pmid = {37689321}, issn = {1872-8111}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Prognosis ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease, still incurable. The disease is highly heterogenous both genetically and phenotypically. Therefore, developing efficacious treatments is challenging in many aspects because it is difficult to predict the rate of disease progression and stratify the patients to minimize statistical variability in clinical studies. Moreover, there is a lack of sensitive measures of therapeutic effect to assess whether a pharmacological intervention ameliorates the disease. There is also urgency of markers that reflect a molecular mechanism dysregulated by ALS pathology and can be rescued when a treatment relieves the condition. Here, we summarize and discuss biomarkers tested in multicentered studies and across different laboratories like neurofilaments, the most used marker in ALS clinical studies, neuroinflammatory-related proteins, p75[ECD], p-Tau/t-Tau, and UCHL1. We also explore the applicability of muscle proteins and extracellular vesicles as potential biomarkers.}, }
@article {pmid37688751, year = {2023}, author = {Khakha, N and Khan, H and Kaur, A and Singh, TG}, title = {Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration.}, journal = {Pharmacological reports : PR}, volume = {75}, number = {5}, pages = {1152-1165}, pmid = {37688751}, issn = {2299-5684}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Neurodegenerative Diseases/drug therapy/genetics ; Phosphorylation ; Response Elements ; Humans ; }, abstract = {Neurodegeneration is a condition of the central nervous system (CNS) characterized by loss of neural structures and function. The most common neurodegenerative disorders (NDDs) include Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), motor neuron disorders, psychological disorders, dementia with vascular dementia (VaD), Lewy body dementia (DLB), epilepsy, cerebral ischemia, mental illness, and behavioral disorders. CREB (cAMP-response element-binding protein) represent a nuclear protein that regulates gene transcriptional activity. The primary focus of the review pertains to the exploration of CREB expression and activation within the context of neurodegenerative diseases, specifically in relation to the phosphorylation and dephosphorylation events that occur within the CREB signaling pathway under normal physiological conditions. The findings mentioned have contributed to the elucidation of the regulatory mechanisms governing CREB activity. Additionally, they have provided valuable insights into the potential mediation of diverse biological processes, such as memory consolidation and neuroprotective effects, by various related studies. The promotion of synaptic plasticity and neurodevelopment in the central nervous system through the targeting of CREB proteins has the potential to contribute to the prevention or delay of the onset of neurodegenerative disorders. Multiple drugs have been found to initiate downstream signaling pathways, leading to neuroprotective advantages in both animal model studies and clinical trials. The clinical importance of the cAMP-response element-binding protein (CREB) is examined in this article, encompassing its utility as both a predictive/prognostic marker and a target for therapeutic interventions.}, }
@article {pmid37686737, year = {2023}, author = {Zhou, J and Zhang, W and Cao, Z and Lian, S and Li, J and Nie, J and Huang, Y and Zhao, K and He, J and Liu, C}, title = {Association of Selenium Levels with Neurodegenerative Disease: A Systemic Review and Meta-Analysis.}, journal = {Nutrients}, volume = {15}, number = {17}, pages = {}, pmid = {37686737}, issn = {2072-6643}, support = {81903294//National Natural Science Foundation of China/ ; 202102020120//Guangzhou Basic and Applied Basic Research Foundation/ ; A2022080//Medical Scientific Research Foundation of Guangdong Province of China/ ; }, mesh = {Humans ; *Selenium ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Databases, Factual ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) have posed significant challenges to public health, and it is crucial to understand their mechanisms in order to develop effective therapeutic strategies. Recent studies have highlighted the potential role of selenium in ND pathogenesis, as it plays a vital role in maintaining cellular homeostasis and preventing oxidative damage. However, a comprehensive analysis of the association between selenium and NDs is still lacking.<br><br>METHOD: Five public databases, namely PubMed, Web of Science, EMBASE, Cochrane and Clinical Trials, were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I[2]), Cochrane's Q test and Tau2 were calculated to evaluate the heterogeneity.<br><br>RESULT: The association of selenium in ND patients with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) was studied. A statistically significant relationship was only found for AD patients (SMD = -0.41, 95% CI (-0.64, -0.17), p < 0.001), especially for erythrocytes. However, no significant relationship was observed in the analysis of the other four diseases.<br><br>CONCLUSION: Generally, this meta-analysis indicated that AD patients are strongly associated with lower selenium concentrations compared with healthy people, which may provide a clinical reference in the future. However, more studies are urgently needed for further study and treatment of neurodegenerative diseases.}, }
@article {pmid37681887, year = {2023}, author = {Vasconcelos, CFM and Ribas, VT and Petrs-Silva, H}, title = {Shared Molecular Pathways in Glaucoma and Other Neurodegenerative Diseases: Insights from RNA-Seq Analysis and miRNA Regulation for Promising Therapeutic Avenues.}, journal = {Cells}, volume = {12}, number = {17}, pages = {}, pmid = {37681887}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; RNA-Seq ; Homeostasis ; *Glaucoma/genetics/therapy ; *MicroRNAs/genetics ; }, abstract = {Advances in RNA-sequencing technologies have led to the identification of molecular biomarkers for several diseases, including neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's diseases and Amyotrophic Lateral Sclerosis. Despite the nature of glaucoma as a neurodegenerative disorder with several similarities with the other above-mentioned diseases, transcriptional data about this disease are still scarce. microRNAs are small molecules (~17-25 nucleotides) that have been found to be specifically expressed in the CNS as major components of the system regulating the development signatures of neurodegenerative diseases and the homeostasis of the brain. In this review, we sought to identify similarities between the functional mechanisms and the activated pathways of the most common neurodegenerative diseases, as well as to discuss how those mechanisms are regulated by miRNAs, using RNA-Seq as an approach to compare them. We also discuss therapeutically suitable applications for these disease hallmarks in clinical future studies.}, }
@article {pmid37680538, year = {2023}, author = {Dunn, E and Zhang, B and Sahota, VK and Augustin, H}, title = {Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1230467}, pmid = {37680538}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.}, }
@article {pmid37679883, year = {2024}, author = {de Boer, EMJ and Demaegd, KC and de Bie, CI and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {53-60}, doi = {10.1080/21678421.2023.2255621}, pmid = {37679883}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; *Frontotemporal Dementia/genetics ; Prospective Studies ; *Motor Neuron Disease/epidemiology/genetics/pathology ; *Muscular Atrophy, Spinal/epidemiology/genetics ; }, abstract = {OBJECTIVE: To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature.<br><br>METHODS: Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family.<br><br>RESULTS: We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant (C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant.<br><br>CONCLUSIONS: The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.}, }
@article {pmid37671427, year = {2023}, author = {Gastelum, S and Michael, AF and Bolger, TA}, title = {Saccharomyces cerevisiae as a research tool for RNA-mediated human disease.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {}, number = {}, pages = {e1814}, doi = {10.1002/wrna.1814}, pmid = {37671427}, issn = {1757-7012}, support = {R01 GM136827/GM/NIGMS NIH HHS/United States ; GM136827/GM/NIGMS NIH HHS/United States ; }, abstract = {The budding yeast, Saccharomyces cerevisiae, has been used for decades as a powerful genetic tool to study a broad spectrum of biological topics. With its ease of use, economic utility, well-studied genome, and a highly conserved proteome across eukaryotes, it has become one of the most used model organisms. Due to these advantages, it has been used to study an array of complex human diseases. From broad, complex pathological conditions such as aging and neurodegenerative disease to newer uses such as SARS-CoV-2, yeast continues to offer new insights into how cellular processes are affected by disease and how affected pathways might be targeted in therapeutic settings. At the same time, the roles of RNA and RNA-based processes have become increasingly prominent in the pathology of many of these same human diseases, and yeast has been utilized to investigate these mechanisms, from aberrant RNA-binding proteins in amyotrophic lateral sclerosis to translation regulation in cancer. Here we review some of the important insights that yeast models have yielded into the molecular pathology of complex, RNA-based human diseases. This article is categorized under: RNA in Disease and Development > RNA in Disease.}, }
@article {pmid37666602, year = {2023}, author = {Chen, X and Ma, Y and Huang, M and Li, W and Zeng, D and Li, J and Wang, Y}, title = {Multiple herbicide resistance in a Cyperus difformis population in rice field from China.}, journal = {Pesticide biochemistry and physiology}, volume = {195}, number = {}, pages = {105576}, doi = {10.1016/j.pestbp.2023.105576}, pmid = {37666602}, issn = {1095-9939}, mesh = {*Oryza/genetics ; *2-Methyl-4-chlorophenoxyacetic Acid ; *Cyperus ; Herbicide Resistance/genetics ; China ; ATP-Binding Cassette Transporters ; *Acetolactate Synthase/genetics ; *Herbicides/pharmacology ; Indoleacetic Acids ; }, abstract = {Herbicide resistance is rapidly emerging in Cyperus difformis in rice fields across China. The response of a C. difformis population GX-35 was tested against five acetolactate synthase (ALS)-inhibiting herbicides, auxin herbicide MCPA and photosynthesis II (PSII)-inhibitor bentazone. Population GX-35 evolved multiple resistance to ALS-inhibiting herbicides (penoxsulam, bispyribac‑sodium, pyrazosulfuron-ethyl, halosulfuron-methly and imazapic) and auxin herbicide MCPA, with resistance levels of 140-, 1253-, 578-, 18-, 13-, and 21-fold, respectively, compared to the susceptible population. In this population, ALS gene expression was similar to that of the susceptible population. However, an Asp376Glu mutation in ALS gene was observed, leading to reduced inhibition of in-vitro ALS activities by five ALS-inhibiting herbicides. Furthermore, CYP71D8, CYP77A3, CYP78A5 and three ABC transporter genes (cluster-14412.23067, cluster-14412.25321, and cluster-14412.24716) over-expressed in absence of penoxsulam. On the other hand, an UGT73C1 and an ABC transporter (cluster-14412.25038) were induced by penoxsulam. Additionally, both over-expression and induction were observed for CYP74, CYP71A1, UGT88A1 and an ABC transporter (cluster-14412.21723). The GX-35 population has indeed evolved multiple herbicide resistance in China. Therefore, a diverse range of weed control tactics should be implemented in rice field.}, }
@article {pmid37664456, year = {2023}, author = {Garodia, P and Hegde, M and Kunnumakkara, AB and Aggarwal, BB}, title = {Curcumin, inflammation, and neurological disorders: How are they linked?.}, journal = {Integrative medicine research}, volume = {12}, number = {3}, pages = {100968}, pmid = {37664456}, issn = {2213-4220}, abstract = {BACKGROUND: Despite the extensive research in recent years, the current treatment modalities for neurological disorders are suboptimal. Curcumin, a polyphenol found in Curcuma genus, has been shown to mitigate the pathophysiology and clinical sequalae involved in neuroinflammation and neurodegenerative diseases.<br><br>METHODS: We searched PubMed database for relevant publications on curcumin and its uses in treating neurological diseases. We also reviewed relevant clinical trials which appeared on searching PubMed database using 'Curcumin and clinical trials'.<br><br>RESULTS: This review details the pleiotropic immunomodulatory functions and neuroprotective properties of curcumin, its derivatives and formulations in various preclinical and clinical investigations. The effects of curcumin on neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumors, epilepsy, Huntington's disorder (HD), ischemia, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI) with a major focus on associated signalling pathways have been thoroughly discussed.<br><br>CONCLUSION: This review demonstrates curcumin can suppress spinal neuroinflammation by modulating diverse astroglia mediated cascades, ensuring the treatment of neurological disorders.}, }
@article {pmid37662922, year = {2023}, author = {Cao, W and Fan, D}, title = {Neutrophils: a subgroup of neglected immune cells in ALS.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1246768}, pmid = {37662922}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Neutrophils ; *Neurodegenerative Diseases ; Motor Neurons ; Immunity, Innate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease characterized by the loss of motor neurons. Dysregulated peripheral immunity has been identified as a hallmark of ALS. Neutrophils, as the front-line responders of innate immunity, contribute to host defense through pathogen clearance. However, they can concurrently play a detrimental role in chronic inflammation. With the unveiling of novel functions of neutrophils in neurodegenerative diseases, it becomes essential to review our current understanding of neutrophils and to recognize the gap in our knowledge about their role in ALS. Thus, a detailed comprehension of the biological processes underlying neutrophil-induced pathogenesis in ALS may assist in identifying potential cell-based therapeutic strategies to delay disease progression.}, }
@article {pmid37658972, year = {2023}, author = {Singh, S and Shukla, R}, title = {Nanovesicular-Mediated Intranasal Drug Therapy for Neurodegenerative Disease.}, journal = {AAPS PharmSciTech}, volume = {24}, number = {7}, pages = {179}, pmid = {37658972}, issn = {1530-9932}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Nose ; Drug Delivery Systems ; Brain ; *Glioblastoma ; }, abstract = {Numerous neurodegenerative conditions, such as Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and glioblastoma multiform are now becoming significant concerns of global health. Formulation-related issues, physiological and anatomical barriers, post-administration obstacles, physical challenges, regulatory limitations, environmental hurdles, and health and safety issues have all hindered successful delivery and effective outcomes despite a variety of treatment options. In the current review, we covered the intranasal route, an alternative strategic route targeting brain for improved delivery across the BBB. The trans-nasal pathway is non-invasive, directing therapeutics directly towards brain, circumventing the barrier and reducing peripheral exposure. The delivery of nanosized vesicles loaded with drugs was also covered in the review. Nanovesicle systems are organised in concentric bilayered lipid membranes separated with aqueous layers. These carriers surmount the disadvantages posed by intranasal delivery of rapid mucociliary clearance and enzymatic degradation, and enhance retention of drug to reach the site of target. In conclusion, the review covers in-depth conclusions on numerous aspects of formulation of drug-loaded vesicular system delivery across BBB, current marketed nasal devices, significant jeopardies, potential therapeutic aids, and current advancements followed by future perspectives.}, }
@article {pmid37657967, year = {2023}, author = {Ryan, SK and Ugalde, CL and Rolland, AS and Skidmore, J and Devos, D and Hammond, TR}, title = {Therapeutic inhibition of ferroptosis in neurodegenerative disease.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {10}, pages = {674-688}, doi = {10.1016/j.tips.2023.07.007}, pmid = {37657967}, issn = {1873-3735}, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/drug therapy ; Iron ; }, abstract = {Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.}, }
@article {pmid37657945, year = {2023}, author = {Cristi, AC and Rapuri, S and Coyne, AN}, title = {Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration.}, journal = {FEBS letters}, volume = {597}, number = {20}, pages = {2546-2566}, pmid = {37657945}, issn = {1873-3468}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Nuclear Pore/metabolism ; Active Transport, Cell Nucleus/physiology ; Nuclear Envelope ; Nuclear Pore Complex Proteins/genetics/metabolism ; Endosomal Sorting Complexes Required for Transport/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT-III pathway emerges as a critical player in the surveillance and preservation of well-assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT-III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear-cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.}, }
@article {pmid37657764, year = {2023}, author = {Zhou, S and Zhou, Y and Zhong, W and Su, Z and Qin, Z}, title = {Involvement of protein L-isoaspartyl methyltransferase in the physiopathology of neurodegenerative diseases: Possible substrates associated with synaptic function.}, journal = {Neurochemistry international}, volume = {170}, number = {}, pages = {105606}, doi = {10.1016/j.neuint.2023.105606}, pmid = {37657764}, issn = {1872-9754}, mesh = {Humans ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/metabolism ; *Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; Isoaspartic Acid/metabolism ; Aspartic Acid/metabolism ; }, abstract = {Synaptic dysfunction is a typical pathophysiologic change in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Hintington's disease (HD) and amyotrophic lateral sclerosis (ALS), which involves protein post-translational modifications (PTMs) including L-isoaspartate (L-isoAsp) formed by isomerization of aspartate or deamidation of asparagine. The formation of L-isoAsp could be repaired by protein L-isoaspartyl methyltransferase (PIMT). Some synaptic proteins have been identified as PIMT potential substrates and play an essential role in ensuring synaptic function. In this review, we discuss the role of certain synaptic proteins as PIMT substrates in neurodegenerative disease, thus providing therapeutic synapse-centered targets for the treatment of NDs.}, }
@article {pmid37654673, year = {2023}, author = {Fischetti, F and Poli, L and De Tommaso, M and Paolicelli, D and Greco, G and Cataldi, S}, title = {The role of exercise parameters on small extracellular vesicles and microRNAs cargo in preventing neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1241010}, pmid = {37654673}, issn = {1664-042X}, abstract = {Physical activity (PA), which includes exercise, can reduce the risk of developing various non-communicable diseases, including neurodegenerative diseases (NDs), and mitigate their adverse effects. However, the mechanisms underlying this ability are not yet fully understood. Among several possible mechanisms proposed, such as the stimulation of brain-derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), the possible involvement of particular vesicular structures enclosed in lipid membranes known as extracellular vesicles (EVs) has recently been investigated. These EVs would appear to exert a paracrine and systemic action through their ability to carry various molecules, particularly so-called microRNAs (miRNAs), performing a function as mediators of intercellular communication. Interestingly, EVs and miRNAs are differentially expressed following PA, but evidence on how different exercise parameters may differentially affect EVs and the miRNAs they carry is still scarce. In this review we summarized the current human findings on the effects of PA and different exercise parameters exerted on EVs and their cargo, focusing on miRNAs molecules, and discussing how this may represent one of the biological mechanisms through which exercise contributes to preventing and slowing NDs.}, }
@article {pmid37651420, year = {2023}, author = {Williams, W and Theron, E and Khan, W and Stassen, W}, title = {Developing a South African curriculum for education in neonatal critical care retrieval: An initial exploration.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0290972}, pmid = {37651420}, issn = {1932-6203}, mesh = {Infant, Newborn ; Humans ; South Africa ; Retrospective Studies ; Educational Status ; *Curriculum ; *Critical Care ; }, abstract = {BACKGROUND: Owing to limited or centralised neonatal critical care resources, the interfacility transfer of neonates is inevitable. In many high-income settings, dedicated Critical Care Retrieval Services (CCRS) with additional education and training undertake neonatal critical care retrieval (CCR). In South Africa, however, these transfers are mostly conducted by advanced paramedics with limited education in neonatal care, and this may lead to high adverse event rates. In SA, a shortage of skilled neonatal interfacility transport services has been identified as one of the top ten avoidable causes of under-5 mortality. In order to address this gap in neonatal transfer education for paramedics in South Africa, the aim of this study is to develop a curriculum for neonatal critical care retrieval in South Africa.<br><br>METHODS: Using Kern's approach to curriculum development, a general and targeted needs assessment was conducted through semi-structured interviews with experts in the field and a focus group discussion with a prospective student group. Interviews were preceded and informed by a literature review and retrospective chart review of neonates who underwent CCR in SA over a one-year period. Audio recordings of interviews were transcribed verbatim and subjected to inductive-dominant content analysis. Finally, qualitative codes were expanded into course outcome and a curriculum map was developed.<br><br>RESULTS: Six experts in neonatal critical care and retrieval participated in semi-structured interviews with a mean duration of 59 minutes. Following transcription and analysis, 372 codes were developed. Seven prehospital providers (prospective students) who are involved in neonatal transfers in South Africa participated in a focus group discussion with a duration of 91 minutes. The audio recording was transcribed and analysed with 97 codes extracted. The main categories were: Current status of neonatal CCR in South Africa; learning and education in neonatal CCR; and proposed curriculum structure. The proposed curriculum structure described 13 broad course outcomes to be delivered as a blended postgraduate programme. Participants noted that funding, employer buy-in and internet resources would be required. The targeted prospective student group should be all Advanced Life Support (ALS) providers with a change in their scope of practice on completion.<br><br>CONCLUSION: This study described the need for additional education in neonatal critical care retrieval due to the limitations in the current and past education systems. This study provides a curriculum structure with course outcomes that can be used as a basis for the development of a complete curriculum for education in neonatal CCR, with the potential to greatly reduce adverse event rates.}, }
@article {pmid37646130, year = {2023}, author = {Pattee, GL and Genge, A and Couratier, P and Lunetta, C and Sobue, G and Aoki, M and Yoshino, H and Jackson, CE and Wymer, J and Salah, A and Nelson, S}, title = {Oral Edaravone - Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {23}, number = {10}, pages = {859-866}, doi = {10.1080/14737175.2023.2251687}, pmid = {37646130}, issn = {1744-8360}, mesh = {Humans ; Edaravone/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/drug therapy ; Free Radical Scavengers/pharmacology ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications.<br><br>AREAS COVERED: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed.<br><br>EXPERT OPINION: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.}, }
@article {pmid37642362, year = {2023}, author = {Bireley, JD and Morren, JA}, title = {CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {8}, pages = {677-683}, doi = {10.1080/13543784.2023.2252738}, pmid = {37642362}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Quality of Life ; Drugs, Investigational/therapeutic use ; }, abstract = {INTRODUCTION: Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment.<br><br>AREAS COVERED: In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment.<br><br>EXPERT OPINION: Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.}, }
@article {pmid37642165, year = {2023}, author = {Shelash Al-Hawary, SI and Yahya Ali, A and Mustafa, YF and Margiana, R and Maksuda Ilyasovna, S and Ramadan, MF and Almalki, SG and Alwave, M and Alkhayyat, S and Alsalamy, A}, title = {The microRNAs (miRs) overexpressing mesenchymal stem cells (MSCs) therapy in neurological disorders; hope or hype.}, journal = {Biotechnology progress}, volume = {39}, number = {6}, pages = {e3383}, doi = {10.1002/btpr.3383}, pmid = {37642165}, issn = {1520-6033}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Nervous System Diseases/genetics/therapy/metabolism ; *Mesenchymal Stem Cells/metabolism ; *Parkinson Disease/therapy ; Neurogenesis ; }, abstract = {Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene-based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs-overexpressing MSCs to ameliorate functional deficits in neurological conditions.}, }
@article {pmid37641631, year = {2023}, author = {Fetit, R}, title = {Celebrating the life and research of BNA Past-President Colin Blakemore.}, journal = {Brain and neuroscience advances}, volume = {7}, number = {}, pages = {23982128231195514}, pmid = {37641631}, issn = {2398-2128}, abstract = {Professor Sir Colin Blakemore was a remarkable neuroscientist, persuasive communicator, and brave advocate for animal research who, sadly, passed away in June 2022 from amyotrophic lateral sclerosis. His work helped establish the concept of neuronal plasticity, which was fundamental to our understanding of the postnatal brain and continues to impact our outlook on neurodegenerative disorders. The BNA2023 Festival of Neuroscience dedicated its last plenary session in his honour, bringing together five prominent neuroscientists whose careers were shaped by Professor Blakemore. Here, we summarise the speakers' reflections on how Colin's support, generosity, and foresight influenced their academic paths, inspired their research, and changed their outlook on life.}, }
@article {pmid37641443, year = {2023}, author = {Maragakis, NJ and de Carvalho, M and Weiss, MD}, title = {Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {11}, pages = {1948-1971}, pmid = {37641443}, issn = {2328-9503}, support = {R01 NS117604/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases ; Biomarkers ; }, abstract = {Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS-relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well-established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.}, }
@article {pmid37638324, year = {2023}, author = {Zhou, W and Xu, R}, title = {Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1189470}, pmid = {37638324}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that leads to the massive loss of motor neurons in cerebrum, brain stem and spinal cord. It affects not only motor neurons but also other neurons and glial cells, resulting in the progressive muscle atrophy, the severe disability and the eventual death due to the respiratory failure. The pathogenesis of ALS is not fully understood. Currently, several factors are considered to be involved in the pathogenesis of ALS, such as genetic factors, imbalances in protein homeostasis, RNA metabolism disorders, mitochondrial dysfunctions, glutamate-mediated excitatory toxicities and intra-neuronal material transport disorders in neurons. The study of genetic mutations related to ALS pathogenesis will link the molecular and cellular mechanisms of the disease, thus enhancing the understanding of its occurrence and progression, thereby providing new insights for the pathogenesis of ALS. This review summarizes the current insights in the molecular genetic pathogenesis of ALS.}, }
@article {pmid37636591, year = {2023}, author = {Jamali, AM and Kethamreddy, M and Burkett, BJ and Port, JD and Pandey, MK}, title = {PET and SPECT Imaging of ALS: An Educational Review.}, journal = {Molecular imaging}, volume = {2023}, number = {}, pages = {5864391}, pmid = {37636591}, issn = {1536-0121}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Positron-Emission Tomography ; Tomography, Emission-Computed, Single-Photon ; Brain/diagnostic imaging ; Fluorodeoxyglucose F18 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease leading to progressive motor degeneration and ultimately death. It is a complex disease that can take a significantly long time to be diagnosed, as other similar pathological conditions must be ruled out for a definite diagnosis of ALS. Noninvasive imaging of ALS has shed light on disease pathology and altered biochemistry in the ALS brain. Other than magnetic resonance imaging (MRI), two types of functional imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have provided valuable data about what happens in the brain of ALS patients compared to healthy controls. PET imaging has revealed a specific pattern of brain metabolism through [[18]F]FDG, while other radiotracers have uncovered neuroinflammation, changes in neuronal density, and protein aggregation. SPECT imaging has shown a general decrease in regional cerebral blood flow (rCBF) in ALS patients. This educational review summarizes the current state of ALS imaging with various PET and SPECT radiopharmaceuticals to better understand the pathophysiology of ALS.}, }
@article {pmid37636024, year = {2023}, author = {Nouri Nojadeh, J and Bildiren Eryilmaz, NS and Ergüder, BI}, title = {CRISPR/Cas9 genome editing for neurodegenerative diseases.}, journal = {EXCLI journal}, volume = {22}, number = {}, pages = {567-582}, pmid = {37636024}, issn = {1611-2156}, abstract = {Gene therapy has emerged as a promising therapeutic strategy for various conditions, including blood disorders, ocular disease, cancer, and nervous system disorders. The advent of gene editing techniques has facilitated the ability of researchers to specifically target and modify the eukaryotic cell genome, making it a valuable tool for gene therapy. This can be performed through either in vivo or ex vivo approaches. Gene editing tools, such as zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR-Cas-associated nucleases, can be employed for gene therapy purposes. Among these tools, CRISPR-Cas-based gene editing stands out because of its ability to introduce heritable genome changes by designing short guide RNAs. This review aims to provide an overview of CRISPR-Cas technology and summarizes the latest research on the application of CRISPR/Cas9 genome editing technology for the treatment of the most prevalent neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Spinocerebellar ataxia.}, }
@article {pmid37633753, year = {2023}, author = {Singh, J and Habean, ML and Panicker, N}, title = {Inflammasome assembly in neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {46}, number = {10}, pages = {814-831}, pmid = {37633753}, issn = {1878-108X}, support = {R00 AG066862/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Inflammasomes ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Neurodegenerative disorders are characterized by the progressive dysfunction and death of selectively vulnerable neuronal populations, often associated with the accumulation of aggregated host proteins. Sustained brain inflammation and hyperactivation of inflammasome complexes have been increasingly demonstrated to contribute to neurodegenerative disease progression. Here, we review molecular mechanisms leading to inflammasome assembly in neurodegeneration. We focus primarily on four degenerative brain disorders in which inflammasome hyperactivation has been well documented: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discuss shared and divergent principles of inflammasome assembly across these disorders, and underscore the differences between neurodegeneration-associated inflammasome activation pathways and their peripheral-immune counterparts. We examine how aberrant assembly of inflammasome complexes may amplify pathology in neurodegeneration, including misfolded protein aggregation, and highlight prospects for neurotherapeutic interventions based on targeting inflammasome pathways.}, }
@article {pmid37631001, year = {2023}, author = {Yan, J and Bading, H}, title = {The Disruption of NMDAR/TRPM4 Death Signaling with TwinF Interface Inhibitors: A New Pharmacological Principle for Neuroprotection.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {37631001}, issn = {1424-8247}, abstract = {With the discovery that the acquisition of toxic features by extrasynaptic NMDA receptors (NMDARs) involves their physical interaction with the non-selective cation channel, TRPM4, it has become possible to develop a new pharmacological principle for neuroprotection, namely the disruption of the NMDAR/TRPM4 death signaling complex. This can be accomplished through the expression of the TwinF domain, a 57-amino-acid-long stretch of TRPM4 that mediates its interaction with NMDARs, but also using small molecule TwinF interface (TI) inhibitors, also known as NMDAR/TRPM4 interaction interface inhibitors. Both TwinF and small molecule TI inhibitors detoxify extrasynaptic NMDARs without interfering with synaptic NMDARs, which serve important physiological functions in the brain. As the toxic signaling of extrasynaptic NMDARs contributes to a wide range of neurodegenerative conditions, TI inhibitors may offer therapeutic options for currently untreatable human neurodegenerative diseases including Amyotrophic Lateral Sclerosis, Alzheimer's disease, and Huntington's disease.}, }
@article {pmid37629277, year = {2023}, author = {Fernandes, F and Barbalho, I and Bispo Júnior, A and Alves, L and Nagem, D and Lins, H and Arrais Júnior, E and Coutinho, KD and Morais, AHF and Santos, JPQ and Machado, GM and Henriques, J and Teixeira, C and Dourado Júnior, MET and Lindquist, ARR and Valentim, RAM}, title = {Digital Alternative Communication for Individuals with Amyotrophic Lateral Sclerosis: What We Have.}, journal = {Journal of clinical medicine}, volume = {12}, number = {16}, pages = {}, pmid = {37629277}, issn = {2077-0383}, support = {132/2018//Brazilian Ministry of Health/ ; 132/2018//Norte-Grandense Foundation for Research and Culture and the Federal University of Rio Grande do Norte (FUNPEC)/ ; }, abstract = {Amyotrophic Lateral Sclerosis is a disease that compromises the motor system and the functional abilities of the person in an irreversible way, causing the progressive loss of the ability to communicate. Tools based on Augmentative and Alternative Communication are essential for promoting autonomy and improving communication, life quality, and survival. This Systematic Literature Review aimed to provide evidence on eye-image-based Human-Computer Interaction approaches for the Augmentative and Alternative Communication of people with Amyotrophic Lateral Sclerosis. The Systematic Literature Review was conducted and guided following a protocol consisting of search questions, inclusion and exclusion criteria, and quality assessment, to select primary studies published between 2010 and 2021 in six repositories: Science Direct, Web of Science, Springer, IEEE Xplore, ACM Digital Library, and PubMed. After the screening, 25 primary studies were evaluated. These studies showcased four low-cost, non-invasive Human-Computer Interaction strategies employed for Augmentative and Alternative Communication in people with Amyotrophic Lateral Sclerosis. The strategies included Eye-Gaze, which featured in 36% of the studies; Eye-Blink and Eye-Tracking, each accounting for 28% of the approaches; and the Hybrid strategy, employed in 8% of the studies. For these approaches, several computational techniques were identified. For a better understanding, a workflow containing the development phases and the respective methods used by each strategy was generated. The results indicate the possibility and feasibility of developing Human-Computer Interaction resources based on eye images for Augmentative and Alternative Communication in a control group. The absence of experimental testing in people with Amyotrophic Lateral Sclerosis reiterates the challenges related to the scalability, efficiency, and usability of these technologies for people with the disease. Although challenges still exist, the findings represent important advances in the fields of health sciences and technology, promoting a promising future with possibilities for better life quality.}, }
@article {pmid37628709, year = {2023}, author = {De Marchi, F and Tondo, G and Corrado, L and Menegon, F and Aprile, D and Anselmi, M and D'Alfonso, S and Comi, C and Mazzini, L}, title = {Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants.}, journal = {Genes}, volume = {14}, number = {8}, pages = {}, pmid = {37628709}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Neuroinflammatory Diseases ; Oxidative Stress ; Astrocytes ; Mitochondrial Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10-15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.}, }
@article {pmid37627588, year = {2023}, author = {Giménez-Bejarano, A and Alegre-Cortés, E and Yakhine-Diop, SMS and Gómez-Suaga, P and Fuentes, JM}, title = {Mitochondrial Dysfunction in Repeat Expansion Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {8}, pages = {}, pmid = {37627588}, issn = {2076-3921}, support = {CIBERNED CB06/05/0041//Instituto de Salud Carlos III/ ; }, abstract = {Repeat expansion diseases are a group of neuromuscular and neurodegenerative disorders characterized by expansions of several successive repeated DNA sequences. Currently, more than 50 repeat expansion diseases have been described. These disorders involve diverse pathogenic mechanisms, including loss-of-function mechanisms, toxicity associated with repeat RNA, or repeat-associated non-ATG (RAN) products, resulting in impairments of cellular processes and damaged organelles. Mitochondria, double membrane organelles, play a crucial role in cell energy production, metabolic processes, calcium regulation, redox balance, and apoptosis regulation. Its dysfunction has been implicated in the pathogenesis of repeat expansion diseases. In this review, we provide an overview of the signaling pathways or proteins involved in mitochondrial functioning described in these disorders. The focus of this review will be on the analysis of published data related to three representative repeat expansion diseases: Huntington's disease, C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis, and myotonic dystrophy type 1. We will discuss the common effects observed in all three repeat expansion disorders and their differences. Additionally, we will address the current gaps in knowledge and propose possible new lines of research. Importantly, this group of disorders exhibit alterations in mitochondrial dynamics and biogenesis, with specific proteins involved in these processes having been identified. Understanding the underlying mechanisms of mitochondrial alterations in these disorders can potentially lead to the development of neuroprotective strategies.}, }
@article {pmid37627315, year = {2023}, author = {Kandeel, M and Morsy, MA and Alkhodair, KM and Alhojaily, S}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627315}, issn = {2218-273X}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Mesenchymal Stem Cells ; *Adult Stem Cells ; *Alzheimer Disease ; *Extracellular Vesicles ; *Huntington Disease ; *Multiple Sclerosis ; *Parkinson Disease/diagnosis/therapy ; }, abstract = {Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.}, }
@article {pmid37627263, year = {2023}, author = {Rühmkorf, A and Harbauer, AB}, title = {Role of Mitochondria-ER Contact Sites in Mitophagy.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627263}, issn = {2218-273X}, mesh = {Humans ; *Mitophagy ; Mitochondria ; Mitochondrial Membranes ; *Amyotrophic Lateral Sclerosis ; Apoptosis ; Mitochondrial Proteins ; Receptors, Estrogen ; }, abstract = {Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.}, }
@article {pmid37626421, year = {2023}, author = {Wang, S and Sun, S}, title = {Translation dysregulation in neurodegenerative diseases: a focus on ALS.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {58}, pmid = {37626421}, issn = {1750-1326}, support = {R21 AG072078/AG/NIA NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Nerve Degeneration ; Homeostasis ; RNA ; }, abstract = {RNA translation is tightly controlled in eukaryotic cells to regulate gene expression and maintain proteome homeostasis. RNA binding proteins, translation factors, and cell signaling pathways all modulate the translation process. Defective translation is involved in multiple neurological diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder and poses a major public health challenge worldwide. Over the past few years, tremendous advances have been made in the understanding of the genetics and pathogenesis of ALS. Dysfunction of RNA metabolisms, including RNA translation, has been closely associated with ALS. Here, we first introduce the general mechanisms of translational regulation under physiological and stress conditions and review well-known examples of translation defects in neurodegenerative diseases. We then focus on ALS-linked genes and discuss the recent progress on how translation is affected by various mutant genes and the repeat expansion-mediated non-canonical translation in ALS.}, }
@article {pmid37620293, year = {2023}, author = {Kuiper, EFE and Prophet, SM and Schlieker, C}, title = {Coordinating nucleoporin condensation and nuclear pore complex assembly.}, journal = {FEBS letters}, volume = {597}, number = {20}, pages = {2534-2545}, doi = {10.1002/1873-3468.14725}, pmid = {37620293}, issn = {1873-3468}, support = {//Dystonia Medical Research Foundation/ ; ALTF 910-2022//European Molecular Biology Organization/ ; 019.222EN.007//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; PR200788//U.S. Department of Defense/ ; }, abstract = {The nuclear pore complex (NPC) is among the most elaborate protein complexes in eukaryotes. While ribosomes and proteasomes are known to require dedicated assembly machinery, our understanding of NPC assembly is at a relatively early stage. Defects in NPC assembly or homeostasis are tied to movement disorders, including dystonia and amyotrophic lateral sclerosis (ALS), as well as aging, requiring a better understanding of these processes to enable therapeutic intervention. Here, we discuss recent progress in the understanding of NPC assembly and highlight how related defects in human disorders can shed light on NPC biogenesis. We propose that the condensation of phenylalanine-glycine repeat nucleoporins needs to be carefully controlled during NPC assembly to prevent aberrant condensation, aggregation, or amyloid formation.}, }
@article {pmid37620092, year = {2023}, author = {Fink, JK}, title = {The hereditary spastic paraplegias.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {59-88}, doi = {10.1016/B978-0-323-98817-9.00022-3}, pmid = {37620092}, issn = {0072-9752}, mesh = {Child, Preschool ; Humans ; *Spastic Paraplegia, Hereditary/genetics ; Biological Transport ; *Cerebral Palsy ; Exercise ; Family ; }, abstract = {The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments ("uncomplicated HSP") or when accompanied by other neurologic deficits ("complicated HSP"), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, autosomal recessive, X-linked, and maternal (mitochondrial) traits. Symptoms that begin in early childhood may be nonprogressive and resemble spastic diplegic cerebral palsy. Symptoms that begin later, typically progress insidiously over a number of years. Genetic testing is able to confirm the diagnosis for many subjects. Insights from gene discovery indicate that abnormalities in diverse molecular processes underlie various forms of HSP, including disturbance in axon transport, endoplasmic reticulum morphogenesis, vesicle transport, lipid metabolism, and mitochondrial function. Pathologic studies in "uncomplicated" HSP have shown axon degeneration particularly involving the distal ends of corticospinal tracts and dorsal column fibers. Treatment is limited to symptom reduction including amelioration of spasticity, reducing urinary urgency, proactive physical therapy including strengthening, stretching, balance, and agility exercise.}, }
@article {pmid37620088, year = {2023}, author = {Muzio, L and Ghirelli, A and Agosta, F and Martino, G}, title = {Novel therapeutic approaches for motor neuron disease.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {523-537}, doi = {10.1016/B978-0-323-98817-9.00027-2}, pmid = {37620088}, issn = {0072-9752}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases ; *Motor Neuron Disease/therapy ; *Amyotrophic Lateral Sclerosis/therapy ; Motor Neurons ; Cognition ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the neurodegeneration and death of upper and lower motor neurons (MNs). Although MNs are the main cells involved in the process of neurodegeneration, a growing body of evidence points toward other cell types as concurrent to disease initiation and propagation. Given the current absence of effective therapies, the quest for other therapeutic targets remains open and still challenges the scientific community. Both neuronal and extra-neuronal mechanisms of cellular stress and damage have been studied and have posed the basis for the development of novel therapies that have been investigated on both animal models and humans. In this chapter, a thorough review of the main mechanisms of cellular damage and the respective therapeutic attempts targeting them is reported. The main areas covered include neuroinflammation, protein aggregation, RNA metabolism, and oxidative stress.}, }
@article {pmid37620070, year = {2023}, author = {Younger, DS and Brown, RH}, title = {Amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {203-229}, doi = {10.1016/B978-0-323-98817-9.00031-4}, pmid = {37620070}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Motor Neurons ; Syndrome ; }, abstract = {The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a comprehensive review of the genetic basis of amyotrophic lateral sclerosis, highlighting factors that contribute to its heritability and phenotypic manifestations, and an overview of past, present, and upcoming therapeutic strategies.}, }
@article {pmid37619957, year = {2023}, author = {Chaves-Filho, AB and Diniz, LS and Santos, RS and Lima, RS and Oreliana, H and Pinto, IFD and Dantas, LS and Inague, A and Faria, RL and Medeiros, MHG and Glezer, I and Festuccia, WT and Yoshinaga, MY and Miyamoto, S}, title = {Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {208}, number = {}, pages = {285-298}, doi = {10.1016/j.freeradbiomed.2023.08.019}, pmid = {37619957}, issn = {1873-4596}, mesh = {Rats ; Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Oxylipins ; *Neurodegenerative Diseases ; Mass Spectrometry ; Superoxide Dismutase-1/genetics/metabolism ; Inflammation ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons, systemic hypermetabolism, and inflammation. In this context, oxylipins have been investigated as signaling molecules linked to neurodegeneration, although their specific role in ALS remains unclear. Importantly, most methods focused on oxylipin analysis are based on low-resolution mass spectrometry, which usually confers high sensitivity, but not great accuracy for molecular characterization, as provided by high-resolution MS (HRMS). Here, we established an ultra-high performance liquid chromatography HRMS (LC-HRMS) method for simultaneous analysis of 126 oxylipins in plasma. Intra- and inter-day method validation showed high sensitivity (0.3-25 pg), accuracy and precision for more than 90% of quality controls. This method was applied in plasma of ALS rats overexpressing the mutant human Cu/Zn-superoxide dismutase gene (SOD1-G93A) at asymptomatic (ALS 70 days old) and symptomatic stages (ALS 120 days old), and their respective age-matched wild type controls. From the 56 oxylipins identified in plasma, 17 species were significantly altered. Remarkably, most of oxylipins linked to inflammation and oxidative stress derived from arachidonic acid (AA), like prostaglandins and mono-hydroxides, were increased in ALS 120 d rats. In addition, ketones derived from AA and linoleic acid (LA) were increased in both WT 120 d and ALS 120 d groups, supporting that age also modulates oxylipin metabolism in plasma. Interestingly, the LA-derived diols involved in fatty acid uptake and β-oxidation, 9(10)-DiHOME and 12(13)-DiHOME, were decreased in ALS 120 d rats and showed significant synergic effects between age and disease factors. In summary, we validated a high-throughput LC-HRMS method for oxylipin analysis and provided a comprehensive overview of plasma oxylipins involved in ALS disease progression. Noteworthy, the oxylipins altered in plasma have potential to be investigated as biomarkers for inflammation and hypermetabolism in ALS.}, }
@article {pmid37619619, year = {2023}, author = {Wang, Y and Lv, MN and Zhao, WJ}, title = {Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {91}, number = {}, pages = {102035}, doi = {10.1016/j.arr.2023.102035}, pmid = {37619619}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Ferroptosis ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease ; }, abstract = {Ferroptosis is an iron- and lipid peroxidation (LPO)-mediated programmed cell death type. Recently, mounting evidence has indicated the involvement of ferroptosis in neurodegenerative diseases, especially in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and so on. Treating ferroptosis presents opportunities as well as challenges for neurodegenerative diseases. This review provides a comprehensive overview of typical features of ferroptosis and the underlying mechanisms that contribute to its occurrence, as well as their implications in the pathogenesis and advancement of major neurodegenerative disorders. Meanwhile, we summarize the utilization of ferroptosis inhibition in both experimental and clinical approaches for the treatment of major neurodegenerative disorders. In addition, we specifically summarize recent advances in developing therapeutic means targeting ferroptosis in these diseases, which may guide future approaches for the effective management of these devastating medical conditions.}, }
@article {pmid37614471, year = {2023}, author = {Bhattacharya, MRC}, title = {A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1166146}, pmid = {37614471}, issn = {1663-4365}, support = {R01 NS105680/NS/NINDS NIH HHS/United States ; }, abstract = {The degeneration of axons and their terminals occurs following traumatic, toxic, or genetically-induced insults. Common molecular mechanisms unite these disparate triggers to execute a conserved nerve degeneration cascade. In this review, we will discuss how models of peripheral nerve injury and neuropathy in Drosophila have led the way in advancing molecular understanding of axon degeneration and nerve injury pathways. Both neuron-intrinsic as well as glial responses to injury will be highlighted. Finally, we will offer perspective on what additional questions should be answered to advance these discoveries toward clinical interventions for patients with neuropathy.}, }
@article {pmid37614251, year = {2023}, author = {Hussein, S and Pingili, S and Makkena, VK and Jaramillo, AP and Awosusi, BL and Ayyub, J and Dabhi, KN and Gohil, NV and Tanveer, N and Hamid, P}, title = {The Impact of Serum Uric Acid on the Progression of Amyotrophic Lateral Sclerosis in Adults Aged 18 and Older: A Systematic Review.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e42312}, pmid = {37614251}, issn = {2168-8184}, abstract = {We have conducted this review to see if serum uric acid (UA) is associated with slowing amyotrophic lateral sclerosis (ALS) progression in adult patients who are at least 18 years old. Understanding the effects of this biomarker for future use is critical because of its easy accessibility. This systematic review paper examined five previous years of recent studies and reports, published in English and limited to human investigations from the Cochrane, PubMed, and Google Scholar databases. Using instruments for assessing the eligibility and quality of systematic and narrative reviews, we narrowed our search to 11 reports that show evidence of a positive association between high blood uric acid and the progression of ALS. However, this claim still needs confirmation by future studies to confirm that possibility. The results of this systematic review may provide a strong foundation for future studies on this biomarker, demonstrating the significance of blood uric acid levels in ALS and highlighting the necessity of using that biomarker to track the disease's progression.}, }
@article {pmid37611905, year = {2023}, author = {Huang, Q and Wang, Y and Chen, S and Liang, F}, title = {Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2023.0807}, pmid = {37611905}, issn = {2152-5250}, abstract = {Neurodegenerative diseases (ND) are conditions defined by progressive deterioration of the structure and function of the nervous system. Some major examples include Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). These diseases lead to various dysfunctions, like impaired cognition, memory, and movement. Chronic neuroinflammation may underlie numerous neurodegenerative disorders. Microglia, an important immunocell in the brain, plays a vital role in defending against neuroinflammation. When exposed to different stimuli, microglia are activated and assume different phenotypes, participating in immune regulation of the nervous system and maintaining tissue homeostasis. The immunological activity of activated microglia is affected by glucose metabolic alterations. However, in the context of chronic neuroinflammation, specific alterations of microglial glucose metabolism and their mechanisms of action remain unclear. Thus, in this paper, we review the glycometabolic reprogramming of microglia in ND. The key molecular targets and main metabolic pathways are the focus of this research. Additionally, this study explores the mechanisms underlying microglial glucose metabolism reprogramming in ND and offers an analysis of the most recent therapeutic advancements. The ultimate aim is to provide insights into the development of potential treatments for ND.}, }
@article {pmid37610446, year = {2023}, author = {Bombaci, A and Lupica, A and Pozzi, FE and Remoli, G and Manera, U and Di Stefano, V}, title = {Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review.}, journal = {Journal of neurology}, volume = {270}, number = {12}, pages = {5677-5691}, pmid = {37610446}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Neurodegenerative Diseases ; Quality of Life ; Motor Neurons/physiology ; Electromyography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and non-motor symptoms. Recent evidence suggests that ALS is indeed a multisystem disorder, associated with cognitive impairment, dysautonomia, pain and fatigue, excess of secretions, and sensory symptoms. To evaluate whether sensory neuropathy could broaden its spectrum, we systematically reviewed its presence and characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, and genetic features. Sensory neuropathy can be found in up to 20% of ALS patients, affecting both large and small fibers, although there is a great heterogeneity related to different techniques used for its detection (electromyography vs skin biopsy vs nerve biopsy). Moreover, the association between CIDP-like neuropathy and ALS needs to be better explored, although it could be interpreted as part of the neuroinflammatory process in the latter disease. Sensory neuropathy in ALS may be associated with a spinal onset and might be more frequent in SOD1 patients. Moreover, it seems mutually exclusive with cognitive impairment. No associations with sex and other genetic mutation were observed. All these data in the literature reveal the importance of actively looking for sensory neuropathy in ALS patients, and suggest including sensory neuropathy among ALS non-motor features, as it may explain sensory symptoms frequently reported throughout the course of the disease. Its early identification could help avoid diagnostic delays and improve patients' treatment and quality of life.}, }
@article {pmid37598759, year = {2023}, author = {Rani, N and Alam, MM and Jamal, A and Bin Ghaffar, U and Parvez, S}, title = {Caenorhabditis elegans: A transgenic model for studying age-associated neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {91}, number = {}, pages = {102036}, doi = {10.1016/j.arr.2023.102036}, pmid = {37598759}, issn = {1872-9649}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/genetics ; Caenorhabditis elegans/metabolism ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Huntington Disease/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.}, }
@article {pmid37592793, year = {2024}, author = {Manera, U and Matteoni, E and Canosa, A and Callegaro, S and Casale, F and Marchis, D and Vasta, R and Moglia, C and Chiò, A and Calvo, A}, title = {Mycotoxins and Amyotrophic Lateral Sclerosis: Food Exposure, Nutritional Implications and Dietary Solutions.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {23}, number = {5}, pages = {562-572}, pmid = {37592793}, issn = {1996-3181}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Mycotoxins/toxicity ; Animals ; Environmental Exposure/adverse effects ; Food Contamination ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder determined by a combination of both genetic and environmental factors. Despite wide investigations, the role of chronic exposure to environmental pollutants is still rather unknown. Among natural toxins, the mycotoxins have received major attention only in the last few years, due to both technical and scientific achievements that allowed to disentangle many important features of the complex fungal biology. Whereas the effects of acute and high-dose mycotoxin exposure are well known, the potential effects of chronic and low-dose exposure on neurodegeneration have not been broadly elucidated. In this review, we have summarized all the studies concerning environmental exposure to unknown substances that caused ALS outbreaks all over the world, reinterpreting in light of the new scientific acquisitions and highlighting the potential and neglected role of mycotoxins. Then, we focused on recent papers about food exposure to mycotoxin, mycobiome and fungal infections in ALS and other neurodegenerative diseases. We analyzed the gaps of current literature that lead to an undervaluation of mycotoxins as detrimental molecules. By listing all the most important mycotoxins and analyzing all the biological pathways that they can affect, we explained the reasons why they need to be considered in the next epidemiological studies on ALS and other neurodegenerative and neuroinflammatory diseases. In conclusion, after suggesting some possible solutions to mitigate mycotoxin exposure risk, we affirm that future collaborations between scientists and policymakers are important to develop sustainable interventions and promote health through dietary diversity.}, }
@article {pmid37590965, year = {2023}, author = {Rani, A and Saini, V and Patra, P and Prashar, T and Pandey, RK and Mishra, A and Jha, HC}, title = {Epigallocatechin Gallate: A Multifaceted Molecule for Neurological Disorders and Neurotropic Viral Infections.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {17}, pages = {2968-2980}, doi = {10.1021/acschemneuro.3c00368}, pmid = {37590965}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease ; *Epstein-Barr Virus Infections ; Glycogen Synthase Kinase 3 ; Phosphatidylinositol 3-Kinases ; *Zika Virus Infection ; Herpesvirus 4, Human ; *Zika Virus ; *Nervous System Diseases ; }, abstract = {Epigallocatechin-3-gallate (EGCG), a polyphenolic moiety found in green tea extracts, exhibits pleiotropic bioactivities to combat many diseases including neurological ailments. These neurological diseases include Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. For instance, in the case of Alzheimer's disease, the formation of a β-sheet in the region of the 10th-21st amino acids was significantly reduced in EGCG-induced oligomeric samples of Aβ40. Its interference induces the formation of Aβ structures with an increase in intercenter-of-mass distances, reduction in interchain/intrachain contacts, reduction in β-sheet propensity, and increase in α-helix. Besides, numerous neurotropic viruses are known to instigate or aggravate neurological ailments. It exerts an effect on the oxidative damage caused in neurodegenerative disorders by acting on GSK3-β, PI3K/Akt, and downstream signaling pathways via caspase-3 and cytochrome-c. EGCG also diminishes these viral-mediated effects, such as EGCG delayed HSV-1 infection by blocking the entry for virions, inhibitory effects on NS3/4A protease or NS5B polymerase of HCV and potent inhibitor of ZIKV NS2B-NS3pro/NS3 serine protease (NS3-SP). It showed a reduction in the neurotoxic properties of HIV-gp120 and Tat in the presence of IFN-γ. EGCG also involves numerous viral-mediated inflammatory cascades, such as JAK/STAT. Nonetheless, it also inhibits the Epstein-Barr virus replication protein (Zta and Rta). Moreover, it also impedes certain viruses (influenza A and B strains) by hijacking the endosomal and lysosomal compartments. Therefore, the current article aims to describe the importance of EGCG in numerous neurological diseases and its inhibitory effect against neurotropic viruses.}, }
@article {pmid37587387, year = {2023}, author = {Hamad, AA and Amer, BE and Al Mawla, AM and Goufa, E and Abdelwahab, MM and Serag, I}, title = {Clinical characteristics, course, and outcomes of amyotrophic lateral sclerosis overlapping with pregnancy: a systematic review of 38 published cases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {12}, pages = {4219-4231}, pmid = {37587387}, issn = {1590-3478}, mesh = {Female ; Infant, Newborn ; Humans ; Pregnancy ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Neurodegenerative Diseases/complications ; Prognosis ; Health Status ; Databases, Factual ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease that can overlap with pregnancy, but little is known about its clinical characteristics, course, and outcomes in this context. This systematic review aimed to synthesize the current evidence on ALS overlapping with pregnancy.<br><br>METHODS: We comprehensively searched four databases on February 2, 2023, to identify case studies reporting cases of ALS overlapping with pregnancy. Joanna Brigs Institute tool was followed to assess the quality of the included studies.<br><br>RESULTS: Twenty-six articles reporting 38 cases were identified and included in our study. Out of the 38 cases, 18 were aged&#x2009;<&#x2009;30&#xa0;years. The onset of ALS was before pregnancy in 18 cases, during pregnancy in 16 cases, and directly after pregnancy in 4 cases. ALS progression course was rapid or severe in 55% of the cases during pregnancy, and this percentage reached 61% in cases with an onset of ALS before pregnancy. While ALS progression course after pregnancy was rapid or severe in 63% and stable in 37% of the cases. Most cases (95%) were able to complete the pregnancy and gave live birth. However, preterm delivery was common. For neonates, 86% were healthy without any complications.<br><br>CONCLUSION: While pregnancy with ALS is likely to survive and result in giving birth to healthy infants, it could be associated with rapid or severe progression of ALS and result in a worse prognosis, highlighting the importance of close monitoring and counselling for patients and healthcare providers.}, }
@article {pmid37579835, year = {2023}, author = {Yadav, H and Jaldhi,  and Bhardwaj, R and Anamika,  and Bakshi, A and Gupta, S and Maurya, SK}, title = {Unveiling the role of gut-brain axis in regulating neurodegenerative diseases: A comprehensive review.}, journal = {Life sciences}, volume = {330}, number = {}, pages = {122022}, doi = {10.1016/j.lfs.2023.122022}, pmid = {37579835}, issn = {1879-0631}, mesh = {Humans ; *Neurodegenerative Diseases ; Brain-Gut Axis ; *Parkinson Disease/therapy ; *Gastrointestinal Microbiome/physiology ; *Probiotics/therapeutic use ; Brain ; }, abstract = {Emerging evidence have shown the importance of gut microbiota in regulating brain functions. The diverse molecular mechanisms involved in cross-talk between gut and brain provide insight into importance of this communication in maintenance of brain homeostasis. It has also been observed that disturbed gut microbiota contributes to neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and aging. Recently, gut microbiome-derived exosomes have also been reported to play an essential role in the development and progression of neurodegenerative diseases and could thereby act as a therapeutic target. Further, pharmacological interventions including antibiotics, prebiotics and probiotics can influence gut microbiome-mediated management of neurological diseases. However, extensive research is warranted to better comprehend this interconnection in maintenance of brain homeostasis and its implication in neurological diseases. Thus, the present review is aimed to provide a detailed understanding of gut-brain axis followed by possibilities to target the gut microbiome for improving neurological health.}, }
@article {pmid37579081, year = {2023}, author = {Sulistyo, A and Abrahao, A and Freitas, ME and Ritsma, B and Zinman, L}, title = {Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {8}, number = {8}, pages = {CD004030}, pmid = {37579081}, issn = {1469-493X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Deglutition Disorders/therapy/complications ; Enteral Nutrition/methods ; Intubation, Gastrointestinal ; *Motor Neuron Disease/complications ; }, abstract = {BACKGROUND: Maintaining adequate nutrition is critical for people with amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Enteral tube feeding is offered to people experiencing difficulty swallowing (dysphagia) to prevent weight loss and aspiration pneumonia. Among the types of enteral tube feeding, percutaneous endoscopic gastrostomy (PEG) is the typical procedure offered to people with ALS and will be mainly discussed here.<br><br>OBJECTIVES: To examine the effectiveness of percutaneous endoscopic gastrostomy or other enteral tube feeding in people with ALS, compared to oral feeds without enteral tube feeding on: 1. survival; 2. nutritional status; 3. quality of life. To examine the incidence of minor and major complications of percutaneous endoscopic gastrostomy (PEG) and other enteral tube feeding procedures in people with ALS.<br><br>SEARCH METHODS: On 3 January 2020 and 6 February 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE. Embase, ClinicalTrials.gov and WHO ICTRP. We screened the results to identify randomized controlled studies on enteral tube feeding in ALS. We reviewed all references from the search in published articles to identify any additional references.<br><br>SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs, and cross-over trials evaluating the effectiveness and complications of PEG or other enteral tube feeding placement in ALS.<br><br>DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.<br><br>MAIN RESULTS: We found no RCTs or quasi-RCTs comparing the effectiveness of enteral tube feeding versus oral feeds without enteral tube feeding.<br><br>AUTHORS' CONCLUSIONS: There are no RCTs or quasi-RCTs to indicate whether enteral tube feeding is effective compared to continuation of oral feeding for any of the outcome measures. Such RCTs are very unlikely to be performed for ethical reasons. RCTs evaluating the effect of different enteral tube insertion techniques and timings of tube placement on survival and quality of life of people with ALS dysphagia are feasible and warranted.}, }
@article {pmid37575227, year = {2023}, author = {Terrabuio, E and Zenaro, E and Constantin, G}, title = {The role of the CD8+ T cell compartment in ageing and neurodegenerative disorders.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1233870}, pmid = {37575227}, issn = {1664-3224}, mesh = {Humans ; *CD8-Positive T-Lymphocytes ; Cytokines ; Central Nervous System ; *Amyotrophic Lateral Sclerosis ; }, abstract = {CD8+ lymphocytes are adaptive immunity cells with the particular function to directly kill the target cell following antigen recognition in the context of MHC class I. In addition, CD8+ T cells may release pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and a plethora of other cytokines and chemoattractants modulating immune and inflammatory responses. A role for CD8+ T cells has been suggested in aging and several diseases of the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, limbic encephalitis-induced temporal lobe epilepsy and Susac syndrome. Here we discuss the phenotypic and functional alterations of CD8+ T cell compartment during these conditions, highlighting similarities and differences between CNS disorders. Particularly, we describe the pathological changes in CD8+ T cell memory phenotypes emphasizing the role of senescence and exhaustion in promoting neuroinflammation and neurodegeneration. We also discuss the relevance of trafficking molecules such as selectins, mucins and integrins controlling the extravasation of CD8+ T cells into the CNS and promoting disease development. Finally, we discuss how CD8+ T cells may induce CNS tissue damage leading to neurodegeneration and suggest that targeting detrimental CD8+ T cells functions may have therapeutic effect in CNS disorders.}, }
@article {pmid37572163, year = {2023}, author = {Teli, P and Kale, V and Vaidya, A}, title = {Beyond animal models: revolutionizing neurodegenerative disease modeling using 3D in vitro organoids, microfluidic chips, and bioprinting.}, journal = {Cell and tissue research}, volume = {394}, number = {1}, pages = {75-91}, pmid = {37572163}, issn = {1432-0878}, abstract = {Neurodegenerative diseases (NDs) are characterized by uncontrolled loss of neuronal cells leading to a progressive deterioration of brain functions. The transition rate of numerous neuroprotective drugs against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, leading to FDA approval, is only 8-14% in the last two decades. Thus, in spite of encouraging preclinical results, these drugs have failed in human clinical trials, demonstrating that traditional cell cultures and animal models cannot accurately replicate human pathophysiology. Hence, in vitro three-dimensional (3D) models have been developed to bridge the gap between human and animal studies. Such technological advancements in 3D culture systems, such as human-induced pluripotent stem cell (iPSC)-derived cells/organoids, organ-on-a-chip technique, and 3D bioprinting, have aided our understanding of the pathophysiology and underlying mechanisms of human NDs. Despite these recent advances, we still lack a 3D model that recapitulates all the key aspects of NDs, thus making it difficult to study the ND's etiology in-depth. Hence in this review, we propose developing a combinatorial approach that allows the integration of patient-derived iPSCs/organoids with 3D bioprinting and organ-on-a-chip technique as it would encompass the neuronal cells along with their niche. Such a 3D combinatorial approach would characterize pathological processes thoroughly, making them better suited for high-throughput drug screening and developing effective novel therapeutics targeting NDs.}, }
@article {pmid37570771, year = {2023}, author = {Liu, X and Zhao, X and He, J and Wang, S and Shen, X and Liu, Q and Wang, S}, title = {Advances in the Structure of GGGGCC Repeat RNA Sequence and Its Interaction with Small Molecules and Protein Partners.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {15}, pages = {}, pmid = {37570771}, issn = {1420-3049}, support = {22274050//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics ; Base Sequence ; DNA Repeat Expansion ; RNA/genetics/chemistry ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC)n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC)n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC)n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC)n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC)n. In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC)n, its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC)n and its influence on partner binding. Given the crucial role of r(GGGGCC)n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC)n RNA.}, }
@article {pmid37567819, year = {2024}, author = {Marrie, RA and Maxwell, CJ and Rotstein, DL and Tsai, CC and Tremlett, H}, title = {Prodromes in demyelinating disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer's dementia.}, journal = {Revue neurologique}, volume = {180}, number = {3}, pages = {125-140}, doi = {10.1016/j.neurol.2023.07.002}, pmid = {37567819}, issn = {0035-3787}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Parkinson Disease/complications/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; *Multiple Sclerosis ; Prodromal Symptoms ; }, abstract = {A prodrome is an early set of symptoms, which indicates the onset of a disease; these symptoms are often non-specific. Prodromal phases are now recognized in multiple central nervous system diseases. The depth of understanding of the prodromal phase varies across diseases, being more nascent for multiple sclerosis for example, than for Parkinson disease or Alzheimer's disease. Key challenges when identifying the prodromal phase of a disease include the lack of specificity of prodromal symptoms, and consequent need for accessible and informative biomarkers. Further, heterogeneity of the prodromal phase may be influenced by age, sex, genetics and other poorly understood factors. Nonetheless, recognition that an individual is in the prodromal phase of disease offers the opportunity for earlier diagnosis and with it the opportunity for earlier intervention.}, }
@article {pmid37566027, year = {2023}, author = {Bagyinszky, E and Hulme, J and An, SSA}, title = {Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy.}, journal = {Cells}, volume = {12}, number = {15}, pages = {}, pmid = {37566027}, issn = {2073-4409}, mesh = {Humans ; Child ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Neurodegenerative Diseases ; Proteomics ; DNA-Binding Proteins/metabolism ; Superoxide Dismutase-1 ; Biomarkers ; Risk Factors ; DNA Helicases ; RNA Helicases ; Multifunctional Enzymes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5-10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially "at risk" individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.}, }
@article {pmid37565183, year = {2023}, author = {Sheers, NL and O'Sullivan, R and Howard, ME and Berlowitz, DJ}, title = {The role of lung volume recruitment therapy in neuromuscular disease: a narrative review.}, journal = {Frontiers in rehabilitation sciences}, volume = {4}, number = {}, pages = {1164628}, pmid = {37565183}, issn = {2673-6861}, abstract = {Respiratory muscle weakness results in substantial discomfort, disability, and ultimately death in many neuromuscular diseases. Respiratory system impairment manifests as shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing, and chronic ventilatory failure. Ventilatory support (i.e., non-invasive ventilation) is an established and key treatment for the latter. As survival outcomes improve for people living with many neuromuscular diseases, there is a shift towards more proactive and preventative chronic disease multidisciplinary care models that aim to manage symptoms, improve morbidity, and reduce mortality. Clinical care guidelines typically recommend therapies to improve cough effectiveness and mobilise mucus, with the aim of averting acute respiratory compromise or respiratory tract infections. Moreover, preventing recurrent infective episodes may prevent secondary parenchymal pathology and further lung function decline. Regular use of techniques that augment lung volume has similarly been recommended (volume recruitment). It has been speculated that enhancing lung inflation in people with respiratory muscle weakness when well may improve respiratory system "flexibility", mitigate restrictive chest wall disease, and slow lung volume decline. Unfortunately, clinical care guidelines are based largely on clinical rationale and consensus opinion rather than level A evidence. This narrative review outlines the physiological changes that occur in people with neuromuscular disease and how these changes impact on breathing, cough, and respiratory tract infections. The biological rationale for lung volume recruitment is provided, and the clinical trials that examine the immediate, short-term, and longer-term outcomes of lung volume recruitment in paediatric and adult neuromuscular diseases are presented and the results synthesised.}, }
@article {pmid37564648, year = {2023}, author = {Calafatti, M and Cocozza, G and Limatola, C and Garofalo, S}, title = {Microglial crosstalk with astrocytes and immune cells in amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1223096}, pmid = {37564648}, issn = {1664-3224}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Microglia/pathology ; Astrocytes/pathology ; Motor Neurons/pathology ; }, abstract = {In recent years, biomedical research efforts aimed to unravel the mechanisms involved in motor neuron death that occurs in amyotrophic lateral sclerosis (ALS). While the main causes of disease progression were first sought in the motor neurons, more recent studies highlight the gliocentric theory demonstrating the pivotal role of microglia and astrocyte, but also of infiltrating immune cells, in the pathological processes that take place in the central nervous system microenvironment. From this point of view, microglia-astrocytes-lymphocytes crosstalk is fundamental to shape the microenvironment toward a pro-inflammatory one, enhancing neuronal damage. In this review, we dissect the current state-of-the-art knowledge of the microglial dialogue with other cell populations as one of the principal hallmarks of ALS progression. Particularly, we deeply investigate the microglia crosstalk with astrocytes and immune cells reporting in vitro and in vivo studies related to ALS mouse models and human patients. At last, we highlight the current experimental therapeutic approaches that aim to modulate microglial phenotype to revert the microenvironment, thus counteracting ALS progression.}, }
@article {pmid37563264, year = {2023}, author = {Nag, S and Schneider, JA}, title = {Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {9}, pages = {525-541}, pmid = {37563264}, issn = {1759-4766}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG042210/AG/NIA NIH HHS/United States ; R01 AG067482/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; RF1 AG022018/AG/NIA NIH HHS/United States ; }, mesh = {Adult ; Humans ; Aged, 80 and over ; *Neurodegenerative Diseases ; *Amyotrophic Lateral Sclerosis/complications ; *Frontotemporal Lobar Degeneration/diagnosis ; *Alzheimer Disease/pathology ; *Frontotemporal Dementia/pathology ; DNA-Binding Proteins ; }, abstract = {TAR DNA-binding protein 43 (TDP43) is a focus of research in late-onset dementias. TDP43 pathology in the brain was initially identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and later in Alzheimer disease (AD), other neurodegenerative diseases and ageing. Limbic-predominant age-related TDP43 encephalopathy (LATE), recognized as a clinical entity in 2019, is characterized by amnestic dementia resembling AD dementia and occurring most commonly in adults over 80 years of age. Neuropathological findings in LATE, referred to as LATE neuropathological change (LATE-NC), consist of neuronal and glial cytoplasmic TDP43 localized predominantly in limbic areas with or without coexisting hippocampal sclerosis and/or AD neuropathological change and without frontotemporal lobar degeneration or amyotrophic lateral sclerosis pathology. LATE-NC is frequently associated with one or more coexisting pathologies, mainly AD neuropathological change. The focus of this Review is the pathology, genetic risk factors and nature of the cognitive impairments and dementia in pure LATE-NC and in LATE-NC associated with coexisting pathologies. As the clinical and cognitive profile of LATE is currently not easily distinguishable from AD dementia, it is important to develop biomarkers to aid in the diagnosis of this condition in the clinic. The pathogenesis of LATE-NC should be a focus of future research to form the basis for the development of preventive and therapeutic strategies.}, }
@article {pmid37562878, year = {2023}, author = {Weil, EL and Nakawah, MO and Masdeu, JC}, title = {Advances in the neuroimaging of motor disorders.}, journal = {Handbook of clinical neurology}, volume = {195}, number = {}, pages = {359-381}, doi = {10.1016/B978-0-323-98818-6.00039-X}, pmid = {37562878}, issn = {0072-9752}, mesh = {Humans ; Diffusion Tensor Imaging ; *Motor Disorders ; Neuroimaging/methods ; Magnetic Resonance Imaging/methods ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnostic imaging ; }, abstract = {Neuroimaging is a valuable adjunct to the history and examination in the evaluation of motor system disorders. Conventional imaging with computed tomography or magnetic resonance imaging depicts important anatomic information and helps to identify imaging patterns which may support diagnosis of a specific motor disorder. Advanced imaging techniques can provide further detail regarding volume, functional, or metabolic changes occurring in nervous system pathology. This chapter is an overview of the advances in neuroimaging with particular emphasis on both standard and less well-known advanced imaging techniques and findings, such as diffusion tensor imaging or volumetric studies, and their application to specific motor disorders. In addition, it provides reference to emerging imaging biomarkers in motor system disorders such as Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease, and briefly reviews the neuroimaging findings in different causes of myelopathy and peripheral nerve disorders.}, }
@article {pmid37562867, year = {2023}, author = {Mahjoub, Y and Martino, D}, title = {Immunology and microbiome: Implications for motor systems.}, journal = {Handbook of clinical neurology}, volume = {195}, number = {}, pages = {135-157}, doi = {10.1016/B978-0-323-98818-6.00001-7}, pmid = {37562867}, issn = {0072-9752}, mesh = {Animals ; Humans ; *Gastrointestinal Microbiome/physiology ; Dysbiosis ; *Tourette Syndrome ; *Microbiota ; *Parkinson Disease ; }, abstract = {Immune-inflammatory mechanisms seem to play a relevant role in neurodegenerative disorders affecting motor systems, particularly Parkinson's disease, where activity changes in inflammatory cells and evidence of neuroinflammation in experimental models and patients is available. Amyotrophic lateral sclerosis is also characterized by neuroinflammatory changes that involve primarily glial cells, both microglia and astrocytes, as well as systemic immune dysregulation associated with more rapid progression. Similarly, the exploration of gut dysbiosis in these two prototypical neurodegenerative motor disorders is advancing rapidly. Altered composition of gut microbial constituents and related metabolic and putative functional pathways is supporting a pathophysiological link that is currently explored in preclinical, germ-free animal models. Less compelling, but still intriguing, evidence suggests that motor neurodevelopmental disorders, e.g., Tourette syndrome, are associated with abnormal trajectories of maturation that include also immune system development. Microglia has a key role also in these disorders, and new therapeutic avenues aiming at its modulation are exciting prospects. Preclinical and clinical research on the role of gut dysbiosis in Tourette syndrome and related behavioral disorders is still in its infancy, but early findings support the rationale to delve deeper into its contribution to neural and immune maturation abnormalities in its spectrum.}, }
@article {pmid37558082, year = {2024}, author = {Giannini, M and Porrua, O}, title = {Senataxin: A key actor in RNA metabolism, genome integrity and neurodegeneration.}, journal = {Biochimie}, volume = {217}, number = {}, pages = {10-19}, doi = {10.1016/j.biochi.2023.08.001}, pmid = {37558082}, issn = {1638-6183}, mesh = {Humans ; RNA Helicases/genetics/metabolism ; DNA Helicases/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; Transcription, Genetic ; Mutation ; Multifunctional Enzymes/genetics/metabolism ; RNA ; }, abstract = {The RNA/DNA helicase senataxin (SETX) has been involved in multiple crucial processes related to genome expression and integrity such us transcription termination, the regulation of transcription-replication conflicts and the resolution of R-loops. SETX has been the focus of numerous studies since the discovery that mutations in its coding gene are the root cause of two different neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and a juvenile form of Amyotrophic Lateral Sclerosis (ALS4). A plethora of cellular phenotypes have been described as the result of SETX deficiency, yet the precise molecular function of SETX as well as the molecular pathways leading from SETX mutations to AOA2 and ALS4 pathologies have remained unclear. However, recent data have shed light onto the biochemical activities and biological roles of SETX, thus providing new clues to understand the molecular consequences of SETX mutation. In this review we summarize near two decades of scientific effort to elucidate SETX function, we discuss strengths and limitations of the approaches and models used thus far to investigate SETX-associated diseases and suggest new possible research avenues for the study of AOA2 and ALS4 pathogenesis.}, }
@article {pmid37549725, year = {2023}, author = {Fan, H and Bai, Q and Yang, Y and Shi, X and Du, G and Yan, J and Shi, J and Wang, D}, title = {The key roles of reactive oxygen species in microglial inflammatory activation: Regulation by endogenous antioxidant system and exogenous sulfur-containing compounds.}, journal = {European journal of pharmacology}, volume = {956}, number = {}, pages = {175966}, doi = {10.1016/j.ejphar.2023.175966}, pmid = {37549725}, issn = {1879-0712}, mesh = {Humans ; *Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; *Microglia ; Sulfur Compounds/metabolism/pharmacology ; Neuroinflammatory Diseases ; Cysteine/pharmacology ; Sulfur/metabolism/pharmacology ; }, abstract = {Aberrant innate immunity in the brain has been implicated in the pathogenesis of several central nervous system (CNS) disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and depression. Except for extraparenchymal CNS-associated macrophages, which predominantly afford protection against peripheral invading pathogens, it has been reported that microglia, a population of macrophage-like cells governing CNS immune defense in nearly all neurological diseases, are the main CNS resident immune cells. Although microglia have been recognized as the most important source of reactive oxygen species (ROS) in the CNS, ROS also may underlie microglial functions, especially M1 polarization, by modulating redox-sensitive signaling pathways. Recently, endogenous antioxidant systems, including glutathione, hydrogen sulfide, superoxide dismutase, and methionine sulfoxide reductase A, were found to be involved in regulating microglia-mediated neuroinflammation. A series of natural sulfur-containing compounds, including S-adenosyl methionine, S-methyl-L-cysteine, sulforaphane, DMS, and S-alk(enyl)-l-cysteine sulfoxide, modulating endogenous antioxidant systems have been discovered. We have summarized the current knowledge on the involvement of endogenous antioxidant systems in regulating microglial inflammatory activation and the effects of sulfur-containing compounds on endogenous antioxidant systems. Finally, we discuss the possibilities associated with compounds targeting the endogenous antioxidant system to treat neuroinflammation-associated diseases.}, }
@article {pmid37543480, year = {2023}, author = {Petrić Howe, M and Patani, R}, title = {Nonsense-mediated mRNA decay in neuronal physiology and neurodegeneration.}, journal = {Trends in neurosciences}, volume = {46}, number = {10}, pages = {879-892}, doi = {10.1016/j.tins.2023.07.001}, pmid = {37543480}, issn = {1878-108X}, support = {/CRUK_/Cancer Research UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Nonsense Mediated mRNA Decay ; *Protein Biosynthesis ; Neurons ; }, abstract = {The processes of mRNA export from the nucleus and subsequent mRNA translation in the cytoplasm are of particular relevance in eukaryotic cells. In highly polarised cells such as neurons, finely-tuned molecular regulation of these processes serves to safeguard the spatiotemporal fidelity of gene expression. Nonsense-mediated mRNA decay (NMD) is a cytoplasmic translation-dependent quality control process that regulates gene expression in a wide range of scenarios in the nervous system, including neurodevelopment, learning, and memory formation. Moreover, NMD dysregulation has been implicated in a broad range of neurodevelopmental and neurodegenerative disorders. We discuss how NMD and related aspects of mRNA translation regulate key neuronal functions and, in particular, we focus on evidence implicating these processes in the molecular pathogenesis of neurodegeneration. Finally, we discuss the therapeutic potential and challenges of targeting mRNA translation and NMD across the spectrum of largely untreatable neurological diseases.}, }
@article {pmid37535076, year = {2023}, author = {Yang, X and Zhang, Y and Luo, JX and Zhu, T and Ran, Z and Mu, BR and Lu, MH}, title = {Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {396}, number = {12}, pages = {3503-3528}, pmid = {37535076}, issn = {1432-1912}, mesh = {Animals ; Humans ; Mitophagy/physiology ; Mitochondria/metabolism ; *Parkinson Disease/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.}, }
@article {pmid37529232, year = {2023}, author = {Wen, T and Zhang, Z}, title = {Cellular mechanisms of fibrin (ogen): insight from neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1197094}, pmid = {37529232}, issn = {1662-4548}, abstract = {Neurodegenerative diseases are prevalent and currently incurable conditions that progressively impair cognitive, behavioral, and psychiatric functions of the central or peripheral nervous system. Fibrinogen, a macromolecular glycoprotein, plays a crucial role in the inflammatory response and tissue repair in the human body and interacts with various nervous system cells due to its unique molecular structure. Accumulating evidence suggests that fibrinogen deposits in the brains of patients with neurodegenerative diseases. By regulating pathophysiological mechanisms and signaling pathways, fibrinogen can exacerbate the neuro-pathological features of neurodegenerative diseases, while depletion of fibrinogen contributes to the amelioration of cognitive function impairment in patients. This review comprehensively summarizes the molecular mechanisms and biological functions of fibrinogen in central nervous system cells and neurodegenerative diseases, including Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, Vascular dementia, Huntington's disease, and Amyotrophic Lateral Sclerosis. Additionally, we discuss the potential of fibrinogen-related treatments in the management of neurodegenerative disorders.}, }
@article {pmid37525497, year = {2024}, author = {Chong, ZZ and Menkes, DL and Souayah, N}, title = {Pathogenesis underlying hexanucleotide repeat expansions in C9orf72 gene in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {1}, pages = {85-97}, pmid = {37525497}, issn = {2191-0200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; Proteins/genetics/metabolism ; Dipeptides/genetics/metabolism ; RNA ; Arginine ; Alanine ; Glycine ; Proline ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.}, }
@article {pmid37524128, year = {2023}, author = {Bernstein, HG and Smalla, KH and Keilhoff, G and Dobrowolny, H and Kreutz, MR and Steiner, J}, title = {The many "Neurofaces" of Prohibitins 1 and 2: Crucial for the healthy brain, dysregulated in numerous brain disorders.}, journal = {Journal of chemical neuroanatomy}, volume = {132}, number = {}, pages = {102321}, doi = {10.1016/j.jchemneu.2023.102321}, pmid = {37524128}, issn = {1873-6300}, mesh = {Humans ; *Prohibitins ; Endothelial Cells/metabolism ; Mitochondria/metabolism ; Brain/metabolism ; *Brain Diseases/metabolism ; }, abstract = {Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are proteins that are nearly ubiquitously expressed. They are localized in mitochondria, cytosol and cell nuclei. In the healthy CNS, they occur in neurons and non-neuronal cells (oligodendrocytes, astrocytes, microglia, and endothelial cells) and fulfill pivotal functions in brain development and aging, the regulation of brain metabolism, maintenance of structural integrity, synapse formation, aminoacidergic neurotransmission and, probably, regulation of brain action of certain hypothalamic-pituitary hormones.With regard to the diseased brain there is increasing evidence that prohibitins are prominently involved in numerous major diseases of the CNS, which are summarized and discussed in the present review (brain tumors, neurotropic viruses, Alzheimer disease, Down syndrome, Fronto-temporal and vascular dementia, dementia with Lewy bodies, Parkinson disease, Huntington disease, Multiple sclerosis, Amyotrophic lateral sclerosis, stroke, alcohol use disorder, schizophrenia and autism). Unfortunately, there is no PHB-targeted therapy available for any of these diseases.}, }
@article {pmid37522557, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A}, title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023047235}, pmid = {37522557}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.}, }
@article {pmid37519177, year = {2023}, author = {Blagov, A and Borisov, E and Grechko, A and Popov, M and Sukhorukov, V and Orekhov, A}, title = {The Role of Impaired Mitochondrial Transport in the Development of Neurodegenerative Diseases.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {4}, pages = {86}, doi = {10.31083/j.jin2204086}, pmid = {37519177}, issn = {0219-6352}, support = {23-25-00237//Russian Science Foundation/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Mitochondria ; *Alzheimer Disease ; *Parkinson Disease ; *Huntington Disease ; }, abstract = {The fight against neurodegenerative diseases is one of the key direction of modern medicine. Unfortunately, the difficulties in understanding the factors underlying the development of neurodegeneration hinder the development of breakthrough therapeutics that can stop or at least greatly slow down the progression of these diseases. In this review, it is considered the disruption of mitochondrial transport as one of the pathogenesis factors contributing to neurodegeneration using the examples of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Here, the mechanism of mitochondrial transport under normal conditions and the mechanisms of disturbances for the indicated diseases will be considered.}, }
@article {pmid37516410, year = {2023}, author = {Ying, Z and Ye, N and Ma, Q and Chen, F and Li, N and Zhen, X}, title = {Targeted to neuronal organelles for CNS drug development.}, journal = {Advanced drug delivery reviews}, volume = {200}, number = {}, pages = {115025}, doi = {10.1016/j.addr.2023.115025}, pmid = {37516410}, issn = {1872-8294}, mesh = {Humans ; Mitochondria/metabolism/pathology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Parkinson Disease ; Central Nervous System/metabolism/pathology ; Drug Development ; Central Nervous System Agents/pharmacology ; }, abstract = {Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug targets displaying great therapeutic potential. Although the basic biological mechanism underlying the dynamics of intracellular organelles has been extensively studied, relative drug development is still limited. In the present review, we show that due to the development of technical advanced imaging tools, especially live cell imaging methods, intracellular organelle dynamics (including mitochondrial dynamics and membrane contact sites) can be dissected at the molecular level. Based on these identified molecular targets, we review and discuss the potential of drug development to target organelle dynamics, especially mitochondria dynamics and ER-organelle membrane contact dynamics, in the central nervous system for treating human diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid37511491, year = {2023}, author = {Antonioni, A and Raho, EM and Lopriore, P and Pace, AP and Latino, RR and Assogna, M and Mancuso, M and Gragnaniello, D and Granieri, E and Pugliatti, M and Di Lorenzo, F and Koch, G}, title = {Frontotemporal Dementia, Where Do We Stand? A Narrative Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511491}, issn = {1422-0067}, mesh = {Middle Aged ; Humans ; *Frontotemporal Dementia/diagnosis/therapy/pathology ; *Neurodegenerative Diseases ; *Pick Disease of the Brain ; *Amyotrophic Lateral Sclerosis/pathology ; Temporal Lobe/pathology ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.}, }
@article {pmid37511443, year = {2023}, author = {Kittipeerapat, N and Fabian, R and Bernsen, S and Weydt, P and Castro-Gomez, S}, title = {Creatine Kinase MB Isoenzyme Is a Complementary Biomarker in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511443}, issn = {1422-0067}, support = {390873048//Deutsche Forschungsgemeinschaft/ ; 21060//Alzheimer Forschung Initiative/ ; 0001//Alle-Lieben-Schmidt e.V/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Isoenzymes ; *Neurodegenerative Diseases ; Creatine Kinase, MB Form ; Creatine Kinase ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited therapeutic options. There is an urgent need for novel biomarkers to be used as surrogates for new therapeutic trials and disease monitoring. In this study, we sought to systematically study creatine kinase isoenzyme MB (CK-MB) in a real-world cohort of ALS patients, assess the diagnostic performance, and evaluate its association with other laboratory and clinical parameters. We reviewed data from 194 consecutive patients that included 130 ALS patients and 64 disease control patients (primary lateral sclerosis [PLS], benign fasciculations syndrome [BFS], Huntington's disease [HD] and Alzheimer's disease [AD]). CK-MB was elevated in the sera of more than half of all patients with ALS. In patients with spinal-onset ALS, CK-MB levels were significantly higher than in patients with other neurodegenerative diseases. Patients with slower rates of functional decline had a significantly higher baseline CK-MB. Furthermore, CK-MB elevations correlated with cardiac troponin T (cTnT) and with revised ALS Functional Rating Scale (ALSFRS-R) bulbar subcategory. We posit that measuring CK-MB in ALS patients in a complimentary fashion could potentially aid in the diagnostic workup of ALS and help discriminate the disease from some ALS mimics and other neurodegenerative diseases. CK-MB levels also may provide valuable prognostic information regarding disease aggressiveness as well as correlations with specific phenotypic presentations.}, }
@article {pmid37511056, year = {2023}, author = {Bettendorff, L}, title = {Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511056}, issn = {1422-0067}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/drug therapy ; Thiamine/pharmacology/therapeutic use ; Thiamine Pyrophosphate ; Coenzymes ; }, abstract = {Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer's disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.}, }
@article {pmid37511037, year = {2023}, author = {Xiang, L and Wang, Y and Liu, S and Liu, B and Jin, X and Cao, X}, title = {Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511037}, issn = {1422-0067}, support = {32000387//National Natural Science Foundation of China/ ; LY23C060001//Zhejiang Provincial Natural Science Foundation/ ; 2021LFR053//Scientific Research Foundation of Zhejiang A&amp;F University/ ; 19 0069//Swedish Cancer Society/ ; VR 2019-03604//Swedish Research Council/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; *Biological Products/pharmacology/therapeutic use ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.}, }
@article {pmid37511010, year = {2023}, author = {Carata, E and Muci, M and Di Giulio, S and Mariano, S and Panzarini, E}, title = {Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511010}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Neuroinflammatory Diseases ; Macrophages/metabolism ; Inflammation/metabolism ; *Extracellular Vesicles/metabolism ; }, abstract = {Neuroinflammation is a common pathological feature of amyotrophic lateral sclerosis (ALS). Although scientific evidence to date does not allow defining neuroinflammation as an ALS trigger, its role in exacerbating motor neuron (MNs) degeneration and disease progression is attracting research interest. Activated CNS (Central Nervous System) glial cells, proinflammatory peripheral and infiltrated T lymphocytes and monocytes/macrophages, as well as the immunoreactive molecules they release, represent the active players for the role of immune dysregulation enhancing neuroinflammation. The crosstalk between the peripheral and CNS immune cells significantly correlates with the survival of ALS patients since the modification of peripheral macrophages can downregulate inflammation at the periphery along the nerves and in the CNS. As putative vehicles for misfolded protein and inflammatory mediators between cells, extracellular vesicles (EVs) have also drawn particular attention in the field of ALS. Both CNS and peripheral immune cells release EVs, which are able to modulate the behavior of neighboring recipient cells; unfortunately, the mechanisms involved in EVs-mediated communication in neuroinflammation remain unclear. This review aims to synthesize the current literature regarding EV-mediated cell-to-cell communication in the brain under ALS, with a particular point of view on the role of peripheral macrophages in responding to inflammation to understand the biological process and exploit it for ALS management.}, }
@article {pmid37508574, year = {2023}, author = {Malhotra, S and Miras, MCM and Pappolla, A and Montalban, X and Comabella, M}, title = {Liquid Biopsy in Neurological Diseases.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508574}, issn = {2073-4409}, mesh = {Humans ; Liquid Biopsy/methods ; *Cell-Free Nucleic Acids ; *MicroRNAs ; *Central Nervous System Neoplasms ; Biomarkers ; }, abstract = {The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.}, }
@article {pmid37508558, year = {2023}, author = {Wu, LY and Song, YJ and Zhang, CL and Liu, J}, title = {KV Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508558}, issn = {2073-4409}, mesh = {*Neurons/metabolism ; Carrier Proteins/metabolism ; Kv Channel-Interacting Proteins/genetics/metabolism ; Cell Membrane/metabolism ; *Cardiovascular System/metabolism ; }, abstract = {KV channel-interacting proteins (KChIP1-4) belong to a family of Ca[2+]-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the fast inactivating-KV4 currents. As the auxiliary subunit, KChIPs are critically involved in regulating the surface protein expression and gating properties of KV4 channels. Mechanistically, KChIP1, KChIP2, and KChIP3 promote the translocation of KV4 channels to the cell membrane, accelerate voltage-dependent activation, and slow the recovery rate of inactivation, which increases KV4 currents. By contrast, KChIP4 suppresses KV4 trafficking and eliminates the fast inactivation of KV4 currents. In the heart, IKs, ICa,L, and INa can also be regulated by KChIPs. ICa,L and INa are positively regulated by KChIP2, whereas IKs is negatively regulated by KChIP2. Interestingly, KChIP3 is also known as downstream regulatory element antagonist modulator (DREAM) because it can bind directly to the downstream regulatory element (DRE) on the promoters of target genes that are implicated in the regulation of pain, memory, endocrine, immune, and inflammatory reactions. In addition, all the KChIPs can act as transcription factors to repress the expression of genes involved in circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of several neurological and cardiovascular diseases. For example, KChIP2 is decreased in failing hearts, while loss of KChIP2 leads to increased susceptibility to arrhythmias. KChIP3 is increased in Alzheimer's disease and amyotrophic lateral sclerosis, but decreased in epilepsy and Huntington's disease. In the present review, we summarize the progress of recent studies regarding the structural properties, physiological functions, and pathological roles of KChIPs in both health and disease. We also summarize the small-molecule compounds that regulate the function of KChIPs. This review will provide an overview and update of the regulatory mechanism of the KChIP family and the progress of targeted drug research as a reference for researchers in related fields.}, }
@article {pmid37505455, year = {2023}, author = {Dos Santos, MM and Ishida, K}, title = {We need to talk about Candida tropicalis: Virulence factors and survival mechanisms.}, journal = {Medical mycology}, volume = {61}, number = {8}, pages = {}, doi = {10.1093/mmy/myad075}, pmid = {37505455}, issn = {1460-2709}, support = {2022/08516-5//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 001 - 88887.663125/2022-00//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 306041/2022-7//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Animals ; *Candida tropicalis/genetics ; *Antifungal Agents/therapeutic use ; Virulence Factors/genetics/metabolism ; Candida ; Candida albicans ; Drug Resistance, Fungal ; Microbial Sensitivity Tests/veterinary ; }, abstract = {Candida tropicalis is a notable species of the Candida genus representing an impressive epidemiology in tropical regions, especially in South America and Asia, where India already presents the species as the first in Candida epidemiology. Candida tropicalis has also shown a worrying antifungal resistance profile in recent years. It is essential to highlight that each pathogenic species of the Candida genus has a particular biology; however, Candida virulence factors are almost entirely based on studies with C. albicans. The intrinsic resistance of C. krusei to some azoles, the intrinsic osmotolerance of C. tropicalis, and the multidrug resistance of C. auris are just a few examples of how the biology of each Candida species is unique. Despite being a phylogenetically close species, C. tropicalis can support 15% NaCl, antagonistically metabolize and signal N-acetylglucosamine, encode 16 reported ALS genes, and other specificities discussed here compared to C. albicans. It is essential to clarify the details of the C. tropicalis infectious process, including identifying the participating secreted enzyme(s), the factors responsible for tissue damage, and the mechanisms underlying the morphogenesis and tolerance signaling pathways. In this review, we thoroughly assembled what is known about the main virulence factors of C. tropicalis, highlighting the missing pieces to stimulate further research with C. tropicalis and other non-Candida albicans species.}, }
@article {pmid37500993, year = {2023}, author = {Ludolph, A and Dupuis, L and Kasarskis, E and Steyn, F and Ngo, S and McDermott, C}, title = {Nutritional and metabolic factors in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {9}, pages = {511-524}, pmid = {37500993}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; Energy Metabolism ; Prognosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.}, }
@article {pmid37495165, year = {2023}, author = {Sammeta, SS and Banarase, TA and Rahangdale, SR and Wankhede, NL and Aglawe, MM and Taksande, BG and Mangrulkar, SV and Upaganlawar, AB and Koppula, S and Kopalli, SR and Umekar, MJ and Kale, MB}, title = {Molecular understanding of ER-MT communication dysfunction during neurodegeneration.}, journal = {Mitochondrion}, volume = {72}, number = {}, pages = {59-71}, doi = {10.1016/j.mito.2023.07.005}, pmid = {37495165}, issn = {1872-8278}, mesh = {Humans ; Endoplasmic Reticulum/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/pathology ; }, abstract = {Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca[2+] homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.}, }
@article {pmid37494786, year = {2023}, author = {Jin, S and Zhang, L and Wang, L}, title = {Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {165}, number = {}, pages = {115215}, doi = {10.1016/j.biopha.2023.115215}, pmid = {37494786}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy ; Kaempferols/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.}, }
@article {pmid37493197, year = {2024}, author = {Sun, Y and Benatar, M and Mascías Cadavid, J and Ennist, D and Wicks, P and Staats, K and Beauchamp, M and Jhooty, S and Pattee, G and Brown, A and Bertorini, T and Barkhaus, P and Bromberg, M and Carter, G and Bedlack, R and Li, X}, title = {ALSUntangled #71: Nuedexta.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {218-222}, doi = {10.1080/21678421.2023.2239292}, pmid = {37493197}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Dextromethorphan/therapeutic use ; Drug Combinations ; *Quinidine/therapeutic use ; }, abstract = {Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.}, }
@article {pmid37489441, year = {2023}, author = {Ramakrishna, K and Nalla, LV and Naresh, D and Venkateswarlu, K and Viswanadh, MK and Nalluri, BN and Chakravarthy, G and Duguluri, S and Singh, P and Rai, SN and Kumar, A and Singh, V and Singh, SK}, title = {WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.}, journal = {Diseases (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {37489441}, issn = {2079-9721}, abstract = {Wnt/β-catenin (WβC) signaling pathway is an important signaling pathway for the maintenance of cellular homeostasis from the embryonic developmental stages to adulthood. The canonical pathway of WβC signaling is essential for neurogenesis, cell proliferation, and neurogenesis, whereas the noncanonical pathway (WNT/Ca[2+] and WNT/PCP) is responsible for cell polarity, calcium maintenance, and cell migration. Abnormal regulation of WβC signaling is involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and spinal muscular atrophy (SMA). Hence, the alteration of WβC signaling is considered a potential therapeutic target for the treatment of neurodegenerative disease. In the present review, we have used the bibliographical information from PubMed, Google Scholar, and Scopus to address the current prospects of WβC signaling role in the abovementioned neurodegenerative diseases.}, }
@article {pmid37488888, year = {2024}, author = {Zhou, M and Li, S and Huang, C}, title = {Physiological and pathological functions of circular RNAs in the nervous system.}, journal = {Neural regeneration research}, volume = {19}, number = {2}, pages = {342-349}, pmid = {37488888}, issn = {1673-5374}, abstract = {Circular RNAs (circRNAs) are a class of covalently closed single-stranded RNAs that are expressed during the development of specific cells and tissues. CircRNAs play crucial roles in physiological and pathological processes by sponging microRNAs, modulating gene transcription, controlling the activity of certain RNA-binding proteins, and producing functional peptides. A key focus of research at present is the functionality of circRNAs in the nervous system and several advances have emerged over the last 2 years. However, the precise role of circRNAs in the nervous system has yet to be comprehensively reviewed. In this review, we first summarize the recently described roles of circRNAs in brain development, maturity, and aging. Then, we focus on the involvement of circRNAs in various diseases of the central nervous system, such as brain cancer, chronic neurodegenerative diseases, acute injuries of the nervous system, and neuropathic pain. A better understanding of the functionality of circRNAs will help us to develop potential diagnostic, prognostic, and therapeutic strategies to treat diseases of the nervous system.}, }
@article {pmid37488879, year = {2024}, author = {Yu, Z and Teng, Y and Yang, J and Yang, L}, title = {The role of exosomes in adult neurogenesis: implications for neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {19}, number = {2}, pages = {282-288}, pmid = {37488879}, issn = {1673-5374}, abstract = {Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness. Exosomes are widely distributed in a range of body fluids, including urine, blood, milk, and saliva. Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells. As an important form of intercellular communication, exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids, proteins, mRNAs, and microRNAs between cells, and because they can regulate physiological and pathological processes in the central nervous system. Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches: the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus. An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches. In recent studies, exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo, thereby participating in the progression of neurodegenerative disorders in patients and in various disease models. Here, we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases. We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults. In addition, exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.}, }
@article {pmid37488847, year = {2024}, author = {Huber, CC and Wang, H}, title = {Pathogenic and therapeutic role of exosomes in neurodegenerative disorders.}, journal = {Neural regeneration research}, volume = {19}, number = {1}, pages = {75-79}, pmid = {37488847}, issn = {1673-5374}, support = {P20 GM103443/GM/NIGMS NIH HHS/United States ; P20 RR016479/RR/NCRR NIH HHS/United States ; RF1 AG072510/AG/NIA NIH HHS/United States ; T32 GM136503/GM/NIGMS NIH HHS/United States ; }, abstract = {Neurodegenerative disorders affect millions of people worldwide, and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years. While therapies exist to aid in symptomatic relief, effective treatments that can stop or reverse the progress of each neurodegenerative disease are lacking. Recently, research on the role of extracellular vesicles as disease markers and therapeutics has been intensively studied. Exosomes, 30-150 nm in diameter, are one type of extracellular vesicles facilitating cell-to-cell communication. Exosomes are thought to play a role in disease propagation in a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Accordingly, the exosomes derived from the patients are an invaluable source of disease biomarkers. On the other hand, exosomes, especially those derived from stem cells, could serve as a therapeutic for these disorders, as seen by a rapid increase in clinical trials investigating the therapeutic efficacy of exosomes in different neurological diseases. This review summarizes the pathological burden and therapeutic approach of exosomes in neurodegenerative disorders. We also highlight how heat shock increases the yield of exosomes while still maintaining their therapeutic efficacy. Finally, this review concludes with outstanding questions that remain to be addressed in exosomal research.}, }
@article {pmid37483353, year = {2023}, author = {Shi, Y and Zhao, Y and Lu, L and Gao, Q and Yu, D and Sun, M}, title = {CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1223777}, pmid = {37483353}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.}, }
@article {pmid37481642, year = {2023}, author = {Yang, R and Yang, B and Liu, W and Tan, C and Chen, H and Wang, X}, title = {Emerging role of non-coding RNAs in neuroinflammation mediated by microglia and astrocytes.}, journal = {Journal of neuroinflammation}, volume = {20}, number = {1}, pages = {173}, pmid = {37481642}, issn = {1742-2094}, support = {32102749//National Natural Science Foundation of China/ ; 32122086//National Natural Science Foundation of China/ ; 2022M721277//China Postdoctoral Science Foundation/ ; 2021YFD1800800//National Key Research and Development Program of China/ ; 2021CFA016//Natural Science Foundation of Hubei Province/ ; 2662023PY005//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Humans ; Astrocytes ; Microglia ; Neuroinflammatory Diseases ; *RNA, Long Noncoding/genetics ; *MicroRNAs ; }, abstract = {Neuroinflammation has been implicated in the initiation and progression of several central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injury, spinal cord injury, viral encephalitis, and bacterial encephalitis. Microglia and astrocytes are essential in neural development, maintenance of synaptic connections, and homeostasis in a healthy brain. The activation of astrocytes and microglia is a defense mechanism of the brain against damaged tissues and harmful pathogens. However, their activation triggers neuroinflammation, which can exacerbate or induce CNS injury. Non-coding RNAs (ncRNAs) are functional RNA molecules that lack coding capabilities but can actively regulate mRNA expression and function through various mechanisms. ncRNAs are highly expressed in astrocytes and microglia and are potential mediators of neuroinflammation. We reviewed the recent research progress on the role of miRNAs, lncRNAs, and circRNAs in regulating neuroinflammation in various CNS diseases. Understanding how these ncRNAs affect neuroinflammation will provide important therapeutic insights for preventing and managing CNS dysfunction.}, }
@article {pmid37475885, year = {2023}, author = {Acosta-Galeana, I and Hernández-Martínez, R and Reyes-Cruz, T and Chiquete, E and Aceves-Buendia, JJ}, title = {RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1193636}, pmid = {37475885}, issn = {1662-5099}, abstract = {The neurodegenerative and inflammatory illnesses of amyotrophic lateral sclerosis and multiple sclerosis were once thought to be completely distinct entities that did not share any remarkable features, but new research is beginning to reveal more information about their similarities and differences. Here, we review some of the pathophysiological features of both diseases and their experimental models: RNA-binding proteins, energy balance, protein transportation, and protein degradation at the molecular level. We make a thorough analysis on TDP-43 and hnRNP A1 dysfunction, as a possible common ground in both pathologies, establishing a potential link between neurodegeneration and pathological immunity. Furthermore, we highlight the putative variations that diverge from a common ground in an atemporal course that proposes three phases for all relevant molecular events.}, }
@article {pmid37475056, year = {2023}, author = {Yang, S and Park, JH and Lu, HC}, title = {Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {49}, pmid = {37475056}, issn = {1750-1326}, support = {R01 NS086794/NS/NINDS NIH HHS/United States ; NS086794/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/metabolism ; NAD/metabolism ; Aging/metabolism ; Axons/metabolism ; Energy Metabolism ; Glucose/metabolism ; }, abstract = {Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD[+]) homeostasis, an essential molecule for energy metabolism processes, including NAD[+] biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD[+] homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.}, }
@article {pmid37470509, year = {2023}, author = {Strnad, P and San Martin, J}, title = {RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {7}, pages = {571-581}, doi = {10.1080/13543784.2023.2239707}, pmid = {37470509}, issn = {1744-7658}, mesh = {Humans ; *Protein Aggregates ; RNA Interference ; RNAi Therapeutics ; *alpha 1-Antitrypsin Deficiency/complications/genetics/therapy ; RNA, Small Interfering ; }, abstract = {INTRODUCTION: Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism.<br><br>AREAS COVERED: This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases.<br><br>EXPERT OPINION: Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.}, }
@article {pmid37469832, year = {2023}, author = {Mora, S and Allodi, I}, title = {Neural circuit and synaptic dysfunctions in ALS-FTD pathology.}, journal = {Frontiers in neural circuits}, volume = {17}, number = {}, pages = {1208876}, pmid = {37469832}, issn = {1662-5110}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/complications/genetics/pathology ; Brain ; Cognition ; }, abstract = {Action selection is a capital feature of cognition that guides behavior in processes that range from motor patterns to executive functions. Here, the ongoing actions need to be monitored and adjusted in response to sensory stimuli to increase the chances of reaching the goal. As higher hierarchical processes, these functions rely on complex neural circuits, and connective loops found within the brain and the spinal cord. Successful execution of motor behaviors depends, first, on proper selection of actions, and second, on implementation of motor commands. Thus, pathological conditions crucially affecting the integrity and preservation of these circuits and their connectivity will heavily impact goal-oriented motor behaviors. Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders known to share disease etiology and pathophysiology. New evidence in the field of ALS-FTD has shown degeneration of specific neural circuits and alterations in synaptic connectivity, contributing to neuronal degeneration, which leads to the impairment of motor commands and executive functions. This evidence is based on studies performed on animal models of disease, post-mortem tissue, and patient derived stem cells. In the present work, we review the existing evidence supporting pathological loss of connectivity and selective impairment of neural circuits in ALS and FTD, two diseases which share strong genetic causes and impairment in motor and executive functions.}, }
@article {pmid37469125, year = {2023}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Batouli, SAH}, title = {MRI biomarkers for memory-related impairment in amyotrophic lateral sclerosis: a systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/21678421.2023.2236651}, pmid = {37469125}, issn = {2167-9223}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with cognitive and behavioral impairments and motor symptoms. Magnetic resonance imaging (MRI) biomarkers have been investigated as potential tools for detecting and monitoring memory-related impairment in ALS. Our objective was to examine the importance of identifying MRI biomarkers for memory-related impairment in ALS, motor neuron disease (MND), and ALS frontotemporal dementia (FTD) (ALS-FTD) patients. Methods: PubMed and Scopus databases were searched. Keywords covering magnetic resonance imaging, ALS, MND, and memory impairments were searched. There were a total of 25 studies included in our work here. Results: The structural MRI (sMRI) studies reported gray matter (GM) atrophy in the regions associated with memory processing, such as the hippocampus and parahippocampal gyrus (PhG), in ALS patients. The diffusion tensor imaging (DTI) studies showed white matter (WM) alterations in the corticospinal tract (CST) and other tracts that are related to motor and extra-motor functions, and these alterations were associated with memory and executive function impairments in ALS. The functional MRI (fMRI) studies also demonstrated an altered activation in the prefrontal cortex, limbic system, and other brain regions involved in memory and emotional processing in ALS patients. Conclusion: MRI biomarkers show promise in uncovering the neural mechanisms of memory-related impairment in ALS. Nonetheless, addressing challenges such as sample sizes, imaging protocols, and longitudinal studies is crucial for future research. Ultimately, MRI biomarkers have the potential to be a tool for detecting and monitoring memory-related impairments in ALS.}, }
@article {pmid37467887, year = {2023}, author = {Troxell, DA and Bach, JR and Nilsestuen, JO}, title = {Mechanical Insufflation-Exsufflation Implementation and Management, Aided by Graphics Analysis.}, journal = {Chest}, volume = {164}, number = {6}, pages = {1505-1511}, doi = {10.1016/j.chest.2023.07.007}, pmid = {37467887}, issn = {1931-3543}, mesh = {Humans ; *Insufflation ; Respiration, Artificial ; Lung ; *Respiratory Insufficiency/therapy ; Cough ; }, abstract = {Mechanical insufflation-exsufflation (MIE) facilitates airway clearance to mitigate respiratory infection, decompensation, and ultimately the need for intubation and placement of a tracheostomy tube. Despite widespread adoption as a respiratory support intervention for motor neuron disease, muscular dystrophy, spinal cord injury, and other diseases associated with ventilatory pump failure and ineffective cough peak flow, there is debate in the clinical community about how to optimize settings when MIE is implemented. This article will demonstrate the clinical utility of MIE graphics in titrating the initial MIE settings, guiding upper airway and lung protective strategies and providing insight to clinicians for ongoing clinical management.}, }
@article {pmid37465321, year = {2023}, author = {Gnoni, V and Zoccolella, S and Giugno, A and Urso, D and Tamburrino, L and Filardi, M and Logroscino, G}, title = {Hypothalamus and amyotrophic lateral sclerosis: potential implications in sleep disorders.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1193483}, pmid = {37465321}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both motor and non-motor functions, including sleep regulation. Emerging evidence suggests that the hypothalamus, a brain region that plays a critical role in sleep-wake regulation, may be involved in the pathogenesis of ALS-related sleep disturbances. In this review, we have summarized results of studies on sleep disorders in ALS published between 2000 and 2023. Thereafter, we examined possible mechanisms by which hypothalamic dysfunctions may contribute to ALS-related sleep disturbances. Achieving a deeper understanding of the relationship between hypothalamic dysfunction and sleep disturbances in ALS can help improve the overall management of ALS and reduce the burden on patients and their families.}, }
@article {pmid37463628, year = {2023}, author = {Soumya, BS and Shreenidhi, VP and Agarwal, A and Gandhirajan, RK and Dharmarajan, A and Warrier, S}, title = {Unwinding the role of Wnt signaling cascade and molecular triggers of motor neuron degeneration in amyotrophic lateral sclerosis (ALS).}, journal = {Cellular signalling}, volume = {110}, number = {}, pages = {110807}, doi = {10.1016/j.cellsig.2023.110807}, pmid = {37463628}, issn = {1873-3913}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Wnt Signaling Pathway ; Motor Neurons/metabolism ; Oxidative Stress ; Nerve Degeneration/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition, triggered by various factors causing the degeneration of upper and lower motor neurons, resulting in progressive muscle wasting, paralysis, and death. Multiple in vivo and in vitro models have been established to unravel the molecular events leading to the deterioration of motor neurons in ALS. The canonical and non-canonical Wnt signaling pathway has been implicated to play a crucial role in the progression of neurodegenerative disorders. This review discusses the role of Wnt signaling in the reported causes of ALS such as oxidative stress, mitochondrial dysfunction, autophagy, and apoptosis. Mutations in ALS-associated genes such as SOD1, C9orf72, TDP43, FUS, and OPTN cause an imbalance in neuronal integrity and homeostasis leading to motor neuron demise. Wnt signaling is also observed to play a crucial role in the muscle sparing of oculomotor neurons. The non-canonical Wnt/Ca[2+] pathway which regulates intrinsic electrophysiological properties and mobilizes calcium ions to maintain neuronal integrity has been found to be altered in the stem cell-derived ALS model. Thus, the interplay of dysregulated canonical and non-canonical Wnt pathways in multiple motor neuron disease models has shown that Wnt contributes to disease progression indicating it to be utilized as a potential target for ALS.}, }
@article {pmid37458987, year = {2023}, author = {Gupta, R and Advani, D and Yadav, D and Ambasta, RK and Kumar, P}, title = {Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6476-6529}, pmid = {37458987}, issn = {1559-1182}, mesh = {Humans ; Aged ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Huntington Disease ; *Amyotrophic Lateral Sclerosis ; *Depressive Disorder, Major ; *Autism Spectrum Disorder ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs) are two common causes of death in elderly people, which includes progressive neuronal cell death and behavioral changes. NDDs include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and motor neuron disease, characterized by cognitive defects and memory impairment, whereas NPDs include depression, seizures, migraine headaches, eating disorders, addictions, palsies, major depressive disorders, anxiety, and schizophrenia, characterized by behavioral changes. Mounting evidence demonstrated that NDDs and NPDs share an overlapping mechanism, which includes post-translational modifications, the microbiota-gut-brain axis, and signaling events. Mounting evidence demonstrated that various drug molecules, namely, natural compounds, repurposed drugs, multitarget directed ligands, and RNAs, have been potentially implemented as therapeutic agents against NDDs and NPDs. Herein, we highlighted the overlapping mechanism, the role of anxiety/stress-releasing factors, cytosol-to-nucleus signaling, and the microbiota-gut-brain axis in the pathophysiology of NDDs and NPDs. We summarize the therapeutic application of natural compounds, repurposed drugs, and multitarget-directed ligands as therapeutic agents. Lastly, we briefly described the application of RNA interferences as therapeutic agents in the pathogenesis of NDDs and NPDs. Neurodegenerative diseases and neuropsychiatric diseases both share a common signaling molecule and molecular phenomenon, namely, pro-inflammatory cytokines, γCaMKII and MAPK/ERK, chemokine receptors, BBB permeability, and the gut-microbiota-brain axis. Studies have demonstrated that any alterations in the signaling mentioned above molecules and molecular phenomena lead to the pathophysiology of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and neuropsychiatric disorders, such as bipolar disorder, schizophrenia, depression, anxiety, autism spectrum disorder, and post-traumatic stress disorder.}, }
@article {pmid37457842, year = {2023}, author = {Mavridis, IN and Pyrgelis, ES}, title = {Nucleus accumbens changes in amyotrophic lateral sclerosis.}, journal = {American journal of neurodegenerative disease}, volume = {12}, number = {3}, pages = {85-88}, pmid = {37457842}, issn = {2165-591X}, abstract = {Amyotrophic lateral sclerosis (ALS), a representative example of motor neuron disease, is a progressive and fatal neurodegenerative disorder. The nucleus accumbens (NA) is the ventral striatum's main part and is considered as a modulator of the human brain's reward network. The purpose of this article is to review the current knowledge regarding NA changes in ALS patients. The NA involvement in ALS includes volumetric, cellular and molecular changes. There are recent imaging and pathological studies revealing NA atrophy in ALS, a finding which seems to be related to neuronal loss and protein deposition in this area. The clinical significance of NA atrophy in these patients is not currently fully understood. Perhaps it could be correlated with apathy, behavioral disturbances and cognitive impairment that ALS patients sometimes manifest.}, }
@article {pmid37456581, year = {2023}, author = {Giovannelli, L and Bari, E and Jommi, C and Tartara, F and Armocida, D and Garbossa, D and Cofano, F and Torre, ML and Segale, L}, title = {Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access.}, journal = {Bioactive materials}, volume = {29}, number = {}, pages = {16-35}, pmid = {37456581}, issn = {2452-199X}, abstract = {Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.}, }
@article {pmid37450673, year = {2023}, author = {Mushtaq, U}, title = {EP1 receptor: Devil in emperors coat.}, journal = {Journal of cellular biochemistry}, volume = {124}, number = {8}, pages = {1105-1114}, doi = {10.1002/jcb.30436}, pmid = {37450673}, issn = {1097-4644}, mesh = {Receptors, Prostaglandin E, EP1 Subtype/genetics ; *Signal Transduction/physiology ; *Protein Kinase C/metabolism ; }, abstract = {EP1 receptor belongs to prostanoid receptors and is activated by prostaglandin E2. The receptor performs contrasting functions in central nervous system (CNS) and other tissues. Although the receptor is neurotoxic and proapoptotic in CNS, it has also been reported to act in an antiapoptotic manner by modulating cell survival, proliferation, invasion, and migration in different types of cancers. The receptor mediates its neurotoxic effects by increasing cytosolic Ca[2+] levels, leading to the activation of its downstream target, protein kinase C, in different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and epilepsy. Antagonists ONO-8713, SC51089, and SC51322 against EP1 receptor ameliorate the neurotoxic effect by attenuating the neuroinflammation. The receptor also shows increased expression in different types of cancers and has been found to activate different signaling pathways, which lead to the development, progression, and metastasis of different cancers. The receptor stimulates the cell survival pathway by phosphorylating the AKT and PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways. Although there are limited studies about this receptor and not a single clinical trial has been targeting the EP1 receptor for different neurological disorders or cancer, the receptor is appearing as a potential candidate for therapeutic targets. The aim of this article is to review the recent progress in understanding the pathogenic roles of EP1 receptors in different pathological conditions.}, }
@article {pmid37450244, year = {2023}, author = {Dubowsky, M and Theunissen, F and Carr, JM and Rogers, ML}, title = {The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6330-6345}, pmid = {37450244}, issn = {1559-1182}, support = {1950//Motor Neurone Disease Australia/ ; 1950//Andrew Butcher Grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Endogenous Retroviruses ; *Motor Neuron Disease/pathology ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; *HIV Infections/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder, characterised by the death of upper and lower motor neurons. The aetiology of ALS remains unknown, and treatment options are limited. Endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the propagation of neurodegeneration in ALS. ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. A hallmark of ALS pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In ALS, TDP-43 aggregates within the cytoplasm and facilitates neurodegeneration. The involvement of ERVs in ALS pathology is thought to occur through TDP-43 and neuroinflammatory mediators. In this review, the proposed involvement of TDP-43, HERV-K and immune regulators on the onset and progression of ALS will be discussed. Furthermore, the evidence supporting a therapy based on targeting ERVs in ALS will be reviewed.}, }
@article {pmid37445986, year = {2023}, author = {Ciurea, AV and Mohan, AG and Covache-Busuioc, RA and Costin, HP and Glavan, LA and Corlatescu, AD and Saceleanu, VM}, title = {Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37445986}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Huntington Disease/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.}, }
@article {pmid37445890, year = {2023}, author = {Kousparou, C and Fyrilla, M and Stephanou, A and Patrikios, I}, title = {DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37445890}, issn = {1422-0067}, mesh = {Humans ; Eicosapentaenoic Acid/pharmacology ; Docosahexaenoic Acids/therapeutic use/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Fatty Acids, Omega-3/therapeutic use ; Fatty Acids, Unsaturated/metabolism ; Arachidonic Acid/metabolism ; Linoleic Acids ; Inflammation/drug therapy ; }, abstract = {Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing.}, }
@article {pmid37443797, year = {2023}, author = {Afonso, GJM and Cavaleiro, C and Valero, J and Mota, SI and Ferreiro, E}, title = {Recent Advances in Extracellular Vesicles in Amyotrophic Lateral Sclerosis and Emergent Perspectives.}, journal = {Cells}, volume = {12}, number = {13}, pages = {}, pmid = {37443797}, issn = {2073-4409}, support = {PTDC/BTM-ORG/0055/2021, UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020, 2022.13281.BD, DL57/2016/CP1448/CT0027, CEECIND/00322/2017, 2022.00011.CEECIND.//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; *Extracellular Vesicles ; Motor Neurons ; *Exosomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease characterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease characterized by high patient-to-patient heterogeneity, which makes its study arduous and complex. Extracellular vesicles (EVs) have emerged as important players in the development of ALS. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargo through the secretion of EVs, even in distant tissues. Importantly, owing to their nature and composition, EVs' formation and cargo can be exploited for better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new therapeutic strategies.}, }
@article {pmid37443723, year = {2023}, author = {Spalloni, A and de Stefano, S and Gimenez, J and Greco, V and Mercuri, NB and Chiurchiù, V and Longone, P}, title = {The Ying and Yang of Hydrogen Sulfide as a Paracrine/Autocrine Agent in Neurodegeneration: Focus on Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {13}, pages = {}, pmid = {37443723}, issn = {2073-4409}, support = {RF-2018-12365509//Italian Ministry of Health/ ; Ricerca Corrente (Linea di Ricerca 2)//Governo Italiano/ ; }, mesh = {Humans ; *Hydrogen Sulfide ; *Neurodegenerative Diseases ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; Nitric Oxide ; }, abstract = {Ever since its presence was reported in the brain, the nature and role of hydrogen sulfide (H2S) in the Central Nervous System (CNS) have changed. Consequently, H2S has been elected as the third gas transmitter, along with carbon monoxide and nitric oxide, and a number of studies have focused on its neuromodulatory and protectant functions in physiological conditions. The research on H2S has highlighted its many facets in the periphery and in the CNS, and its role as a double-faced compound, switching from protective to toxic depending on its concentration. In this review, we will focus on the bell-shaped nature of H2S as an angiogenic factor and as a molecule released by glial cells (mainly astrocytes) and non-neuronal cells acting on the surrounding environment (paracrine) or on the releasing cells themselves (autocrine). Finally, we will discuss its role in Amyotrophic Lateral Sclerosis, a paradigm of a neurodegenerative disease.}, }
@article {pmid37440197, year = {2023}, author = {Yang, J and Li, H and Zhao, Y}, title = {Dessert or Poison? The Roles of Glycosylation in Alzheimer's, Parkinson's, Huntington's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {24}, number = {16}, pages = {e202300017}, doi = {10.1002/cbic.202300017}, pmid = {37440197}, issn = {1439-7633}, mesh = {Humans ; Aged ; *Huntington Disease ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; Glycosylation ; *Poisons ; Quality of Life ; }, abstract = {Ministry of Education and Key Laboratory of Neurons and glial cells of the central nervous system (CNS) are modified by glycosylation and rely on glycosylation to achieve normal neural function. Neurodegenerative disease is a common disease of the elderly, affecting their healthy life span and quality of life, and no effective treatment is currently available. Recent research implies that various glycosylation traits are altered during neurodegenerative diseases, suggesting a potential implication of glycosylation in disease pathology. Herein, we summarized the current knowledge about glycosylation associated with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS) pathogenesis, focusing on their promising functional avenues. Moreover, we collected research aimed at highlighting the need for such studies to provide a wealth of disease-related glycosylation information that will help us better understand the pathophysiological mechanisms and hopefully specific glycosylation information to provide further diagnostic and therapeutic directions for neurodegenerative diseases.}, }
@article {pmid37433768, year = {2023}, author = {Zhang, W and Xiao, D and Mao, Q and Xia, H}, title = {Role of neuroinflammation in neurodegeneration development.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {267}, pmid = {37433768}, issn = {2059-3635}, support = {UL1 TR002538/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Inflammation/genetics ; Neuroinflammatory Diseases ; *Parkinson Disease/genetics ; Protein Aggregates ; Humans ; Clinical Trials as Topic ; Disease Models, Animal ; }, abstract = {Studies in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, Huntington's disease, and so on, have suggested that inflammation is not only a result of neurodegeneration but also a crucial player in this process. Protein aggregates which are very common pathological phenomenon in neurodegeneration can induce neuroinflammation which further aggravates protein aggregation and neurodegeneration. Actually, inflammation even happens earlier than protein aggregation. Neuroinflammation induced by genetic variations in CNS cells or by peripheral immune cells may induce protein deposition in some susceptible population. Numerous signaling pathways and a range of CNS cells have been suggested to be involved in the pathogenesis of neurodegeneration, although they are still far from being completely understood. Due to the limited success of traditional treatment methods, blocking or enhancing inflammatory signaling pathways involved in neurodegeneration are considered to be promising strategies for the therapy of neurodegenerative diseases, and many of them have got exciting results in animal models or clinical trials. Some of them, although very few, have been approved by FDA for clinical usage. Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. We also summarize the current strategies, both in animal models and in the clinic, for the treatment of neurodegenerative diseases.}, }
@article {pmid37429415, year = {2023}, author = {Asveda, T and Talwar, P and Ravanan, P}, title = {Exploring microglia and their phenomenal concatenation of stress responses in neurodegenerative disorders.}, journal = {Life sciences}, volume = {328}, number = {}, pages = {121920}, doi = {10.1016/j.lfs.2023.121920}, pmid = {37429415}, issn = {1879-0631}, mesh = {Humans ; Microglia/metabolism ; *Neurodegenerative Diseases/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Neuronal cells are highly functioning but also extremely stress-sensitive cells. By defending the neuronal cells against pathogenic insults, microglial cells, a unique cell type, act as the frontline cavalry in the central nervous system (CNS). Their remarkable and unique ability to self-renew independently after their creation is crucial for maintaining normal brain function and neuroprotection. They have a wide range of molecular sensors that help maintain CNS homeostasis during development and adulthood. Despite being the protector of the CNS, studies have revealed that persistent microglial activation may be the root cause of innumerable neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS). From our vigorous review, we state that there is a possible interlinking between pathways of Endoplasmic reticulum (ER) stress response, inflammation, and oxidative stress resulting in dysregulation of the microglial population, directly influencing the accumulation of pro-inflammatory cytokines, complement factors, free radicals, and nitric oxides leading to cell death via apoptosis. Recent research uses the suppression of these three pathways as a therapeutic approach to prevent neuronal death. Hence, in this review, we have spotlighted the advancement in microglial studies, which focus on their molecular defenses against multiple stresses, and current therapeutic strategies indirectly targeting glial cells for neurodevelopmental diseases.}, }
@article {pmid37427325, year = {2023}, author = {Najafi, S and Najafi, P and Kaffash Farkhad, N and Hosseini Torshizi, G and Assaran Darban, R and Boroumand, AR and Sahab-Negah, S and Khodadoust, MA and Tavakol-Afshari, J}, title = {Mesenchymal stem cell therapy in amyotrophic lateral sclerosis (ALS) patients: A comprehensive review of disease information and future perspectives.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {8}, pages = {872-881}, pmid = {37427325}, issn = {2008-3866}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare deadly progressive neurological disease that primarily affects the upper and lower motor neurons with an annual incidence rate of 0.6 to 3.8 per 100,000 people. Weakening and gradual atrophy of the voluntary muscles are the first signs of the disease onset affecting all aspects of patients' lives, including eating, speaking, moving, and even breathing. Only 5-10% of patients have a familial type of the disease and show an autosomal dominant pattern, but the cause of the disease is unknown in the remaining 90% of patients (Sporadic ALS). However, in both types of disease, the patient's survival is 2 to 5 years from the disease onset. Some clinical and molecular biomarkers, magnetic resonance imaging (MRI), blood or urine test, muscle biopsy, and genetic testing are complementary methods for disease diagnosis. Unfortunately, with the exception of Riluzole, the only medically approved drug for the management of this disease, there is still no definitive cure for it. In this regard, the use of mesenchymal stem cells (MSCs) for the treatment or management of the disease has been common in preclinical and clinical studies for many years. MSCs are multipotent cells having immunoregulatory, anti-inflammatory, and differentiation ability that makes them a good candidate for this purpose. This review article aims to discuss multiple aspects of ALS disease and focus on MSCs' role in disease management based on performed clinical trials.}, }
@article {pmid37408276, year = {2023}, author = {Hosaka, T and Tsuji, H and Kwak, S}, title = {Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets.}, journal = {Cells}, volume = {12}, number = {10}, pages = {}, pmid = {37408276}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; RNA, Circular/genetics/metabolism ; RNA Editing/genetics ; RNA/genetics/metabolism ; Aging/genetics ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca[2+] influx through Ca[2+]-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.}, }
@article {pmid37407098, year = {2023}, author = {Kious, BM}, title = {Medical Assistance in Dying in Neurology.}, journal = {Neurologic clinics}, volume = {41}, number = {3}, pages = {443-454}, doi = {10.1016/j.ncl.2023.03.002}, pmid = {37407098}, issn = {1557-9875}, mesh = {Humans ; *Suicide, Assisted/psychology ; *Alzheimer Disease ; Medical Assistance ; *Neurology ; }, abstract = {An increasing number of jurisdictions have legalized medical assistance in dying (MAID) with significant variation in the procedures and eligibility criteria used. In the United States, MAID is available for persons with terminal illnesses but is frequently sought by persons with neurologic conditions. Persons with conditions that cause cognitive impairment, such as Alzheimer dementia, are often ineligible for MAID, as their illness is not considered terminal in its early stages, whereas in later stages, they may have impaired decision-making capacity.}, }
@article {pmid37395272, year = {2023}, author = {Hurtle, BT and Xie, L and Donnelly, CJ}, title = {Disrupting pathologic phase transitions in neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {13}, pages = {}, pmid = {37395272}, issn = {1558-8238}, support = {R01 NS127187/NS/NINDS NIH HHS/United States ; L30 AG048607/AG/NIA NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Aged ; *TDP-43 Proteinopathies/pathology ; *Neurodegenerative Diseases/pathology ; *Frontotemporal Lobar Degeneration/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Proteins ; }, abstract = {Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical protein signatures and abnormal protein depositions that often correlate with disease pathogenesis. Recent evidence indicates that many pathologic proteins assemble into liquid-like protein phases through the highly coordinated process of liquid-liquid phase separation. Over the last decade, biomolecular phase transitions have emerged as a fundamental mechanism of cellular organization. Liquid-like condensates organize functionally related biomolecules within the cell, and many neuropathology-associated proteins reside within these dynamic structures. Thus, examining biomolecular phase transitions enhances our understanding of the molecular mechanisms mediating toxicity across diverse neurodegenerative diseases. This Review explores the known mechanisms contributing to aberrant protein phase transitions in neurodegenerative diseases, focusing on tau and TDP-43 proteinopathies and outlining potential therapeutic strategies to regulate these pathologic events.}, }
@article {pmid37394036, year = {2023}, author = {Arnold, FJ and Nguyen, AD and Bedlack, RS and Bennett, CL and La Spada, AR}, title = {Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106218}, doi = {10.1016/j.nbd.2023.106218}, pmid = {37394036}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; Protein Aggregates ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.}, }
@article {pmid37392160, year = {2023}, author = {Hivare, P and Mujmer, K and Swarup, G and Gupta, S and Bhatia, D}, title = {Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {24}, number = {10}, pages = {434-452}, doi = {10.1111/tra.12906}, pmid = {37392160}, issn = {1600-0854}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α-Syn, Huntingtin, Prions, SOD1, TDP-43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.}, }
@article {pmid37391647, year = {2023}, author = {Karati, D and Mukherjee, S and Roy, S}, title = {Molecular and Structural Insight into Adenosine A2A Receptor in Neurodegenerative Disorders: A Significant Target for Efficient Treatment Approach.}, journal = {Molecular neurobiology}, volume = {60}, number = {10}, pages = {5987-6000}, pmid = {37391647}, issn = {1559-1182}, mesh = {Humans ; *Adenosine/pharmacology ; Receptor, Adenosine A2A/metabolism ; Ligands ; *Neurodegenerative Diseases/drug therapy ; Purinergic P1 Receptor Antagonists/therapeutic use ; Receptors, Purinergic P1 ; }, abstract = {All biological tissues and bodily fluids include the autacoid adenosine. The P1 class of purinergic receptors includes adenosine receptors. Four distinct G-protein-coupled receptors on the cellular membrane mediate the effects of adenosine, whose cytoplasmic content is regulated by producing/degrading enzymes and nucleoside transporters. A2A receptor has received a great deal of attention in recent years because it has a wide range of potential therapeutic uses. A2B and, more significantly, A2A receptors regulate numerous physiological mechanisms in the central nervous system (CNS). The inferior targetability of A2B receptors towards adenosine points that they might portray a promising medicinal target since they are triggered only under pharmacological circumstances (when adenosine levels rise up to micromolar concentrations). The accessibility of specific ligands for A2B receptors would permit the exploration of such a theory. A2A receptors mediate both potentially neurotoxic and neuroprotective actions. Hence, it is debatable to what extent they play a role in neurodegenerative illnesses. However, A2A receptor blockers have demonstrated clear antiparkinsonian consequences, and a significant attraction exists in the role of A2A receptors in other neurodegenerative disorders. Amyloid peptide extracellular accumulation and tau hyperphosphorylation are the pathogenic components of AD that lead to neuronal cell death, cognitive impairment, and memory loss. Interestingly, in vitro and in vivo research has shown that A2A adenosine receptor antagonists may block each of these clinical symptoms, offering a crucial new approach to combat a condition for which, regrettably, only symptomatic medications are currently available. At least two requirements must be met to determine whether such receptors are a target for diseases of the CNS: a complete understanding of the mechanisms governing A2A-dependent processes and the availability of ligands that can distinguish between the various receptor populations. This review concisely summarises the biological effects mediated by A2A adenosine receptors in neurodegenerative disorders and discusses the chemical characteristics of A2A adenosine receptor antagonists undergoing clinical trials. Selective A2A receptor blocker against neurodegenerative disorders.}, }
@article {pmid37391243, year = {2023}, author = {Gerecht, RB and Nable, JV}, title = {Out-of-Hospital Cardiac Arrest.}, journal = {Emergency medicine clinics of North America}, volume = {41}, number = {3}, pages = {433-453}, doi = {10.1016/j.emc.2023.03.002}, pmid = {37391243}, issn = {1558-0539}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/diagnosis/therapy ; *Emergency Medical Services ; }, abstract = {Survival from out-of-hospital cardiac arrest (OHCA) is predicated on a community and system-wide approach that includes rapid recognition of cardiac arrest, capable bystander CPR, effective basic and advanced life support (BLS and ALS) by EMS providers, and coordinated postresuscitation care. Management of these critically ill patients continues to evolve. This article focuses on the management of OHCA by EMS providers.}, }
@article {pmid37390744, year = {2023}, author = {Eskandari, S and Rezayof, A and Asghari, SM and Hashemizadeh, S}, title = {Neurobiochemical characteristics of arginine-rich peptides explain their potential therapeutic efficacy in neurodegenerative diseases.}, journal = {Neuropeptides}, volume = {101}, number = {}, pages = {102356}, doi = {10.1016/j.npep.2023.102356}, pmid = {37390744}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Arginine ; Oxidative Stress ; Peptides/metabolism ; *Nucleic Acids/metabolism/therapeutic use ; *Alzheimer Disease/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer̕ s disease (AD), Parkinson̕ s disease (PD), Huntington̕ s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) require special attention to find new potential treatment methods. This review aims to summarize the current knowledge of the relationship between the biochemical properties of arginine-rich peptides (ARPs) and their neuroprotective effects to deal with the harmful effects of risk factors. It seems that ARPs have portrayed a promising and fantastic landscape for treating neurodegeneration-associated disorders. With multimodal mechanisms of action, ARPs play various unprecedented roles, including as the novel delivery platforms for entering the central nervous system (CNS), the potent antagonists for calcium influx, the invader molecules for targeting mitochondria, and the protein stabilizers. Interestingly, these peptides inhibit the proteolytic enzymes and block protein aggregation to induce pro-survival signaling pathways. ARPs also serve as the scavengers of toxic molecules and the reducers of oxidative stress agents. They also have anti-inflammatory, antimicrobial, and anti-cancer properties. Moreover, by providing an efficient nucleic acid delivery system, ARPs can play an essential role in developing various fields, including gene vaccines, gene therapy, gene editing, and imaging. ARP agents and ARP/cargo therapeutics can be raised as an emergent class of neurotherapeutics for neurodegeneration. Part of the aim of this review is to present recent advances in treating neurodegenerative diseases using ARPs as an emerging and powerful therapeutic tool. The applications and progress of ARPs-based nucleic acid delivery systems have also been discussed to highlight their usefulness as a broad-acting class of drugs.}, }
@article {pmid37387467, year = {2023}, author = {Timmins, HC and Vucic, S and Kiernan, MC}, title = {Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {353-359}, doi = {10.1097/WCO.0000000000001162}, pmid = {37387467}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Motor Neurons ; Transcranial Magnetic Stimulation/methods ; *Frontotemporal Dementia/diagnosis/genetics ; Biomarkers ; }, abstract = {PURPOSE OF REVIEW: Identification of upper motor neuron involvement remains a critical component of a diagnosis of amyotrophic lateral sclerosis (ALS), although supportive clinical signs are often not easily appreciated, particularly in the early symptomatic stages of the disease. Although diagnostic criteria have been developed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains problematic.<br><br>RECENT FINDINGS: Recent evidence has emerged about pathophysiological processes, particularly glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the C9orf72 gene, have changed concepts of ALS, from being classified as a neuromuscular disease to a disease that forms a continuum with other primary neurodegenerative disorders, particularly frontotemporal dementia. Transcranial magnetic stimulation has been utilized to provide pathophysiological insights, leading to the development of diagnostic and therapeutic biomarkers, which are now being introduced into the clinical setting.<br><br>SUMMARY: Specifically, the advent of cortical hyperexcitability has been consistently identified as an early and intrinsic feature of ALS. With greater accessibility of TMS techniques promoting clinical utilization, TMS measures of cortical function may develop as a diagnostic biomarker, with further potential utility in the clinical trial setting for monitoring of neuroprotective and genetic-based therapies.}, }
@article {pmid37385457, year = {2023}, author = {DuMont, M and Agostinis, A and Singh, K and Swan, E and Buttle, Y and Tropea, D}, title = {Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106214}, doi = {10.1016/j.nbd.2023.106214}, pmid = {37385457}, issn = {1095-953X}, mesh = {Humans ; Male ; Female ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; *Attention Deficit Disorder with Hyperactivity ; }, abstract = {Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.}, }
@article {pmid37383106, year = {2023}, author = {Wu, C and Feng, Y}, title = {Exploring the potential of mindfulness-based therapy in the prevention and treatment of neurodegenerative diseases based on molecular mechanism studies.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1097067}, pmid = {37383106}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (ND) have received increasing attention due to their irreversibility, but there is still no means to completely cure ND in clinical practice. Mindfulness therapy (MT), including Qigong, Tai Chi, meditation, and yoga, etc., has become an effective complementary treatment modality in solving clinical and subclinical problems due to its advantages of low side effects, less pain, and easy acceptance by patients. MT is primarily used to treat mental and emotional disorders. In recent years, evidence has shown that MT has a certain therapeutic effect on ND with a potential molecular basis. In this review, we summarize the pathogenesis and risk factors of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), relating to telomerase activity, epigenetics, stress, and the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) mediated inflammatory response, and analyze the molecular mechanism basis of MT to prevent and treat ND, to provide possible explanations for the potential of MT treatments for ND.}, }
@article {pmid37382103, year = {2023}, author = {Benatar, M and Turner, MR and Wuu, J}, title = {Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {360-364}, pmid = {37382103}, issn = {1473-6551}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/prevention &amp; control ; *Frontotemporal Dementia/genetics ; Longitudinal Studies ; Biomarkers ; Asymptomatic Diseases ; }, abstract = {PURPOSE OF REVIEW: Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)].<br><br>RECENT FINDINGS: The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1 -ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk.<br><br>SUMMARY: The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.}, }
@article {pmid37380145, year = {2023}, author = {Mercadante, S and Al-Husinat, L}, title = {Palliative Care in Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {66}, number = {4}, pages = {e485-e499}, doi = {10.1016/j.jpainsymman.2023.06.029}, pmid = {37380145}, issn = {1873-6513}, mesh = {Humans ; Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Quality of Life ; *Neurodegenerative Diseases ; *Hospice and Palliative Care Nursing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of the motor neurons. Given the evolutive characteristics of this disease, palliative care principles should be a foundation of ALS care. A multidisciplinary medical intervention is of paramount importance in the different phases of disease. The involvement of the palliative care team improves quality of life and symptoms, and prognosis. Early initiation is of paramount importance to ensuring patient-centered care, when the patient has still the capability to communicate effectively and participate in his medical care. Advance care planning supports patients and family members in understanding and sharing their preferences according to their personal values and life goals regarding future medical treatment. The principal problems which require intensive supportive care include cognitive disturbances, psychological distress, pain, sialorrhrea, nutrition, and ventilatory support. Communication skills of health-care professionals are mandatory to manage the inevitability of death. Palliative sedation has peculiar aspects in this population, particularly with the decision of withdrawing ventilatory support.}, }
@article {pmid37373667, year = {2023}, author = {Sipilä, JOT}, title = {Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do.}, journal = {Journal of clinical medicine}, volume = {12}, number = {12}, pages = {}, pmid = {37373667}, issn = {2077-0383}, abstract = {Finland is a relatively small genetic isolate with a genetically non-homogenous population. Available Finnish data on neuroepidemiology of adult-onset disorders are limited, and this paper describes the conclusions that can be drawn and their implications. Apparently, Finnish people have a (relatively) high risk of developing Unverricht-Lundborg disease (EPM1), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Spinal muscular atrophy, Jokela type (SMAJ) and adult-onset dystonia. On the other hand, some disorders, such as Friedreich's ataxia (FRDA) and Wilson's disease (WD), are almost absent or completely absent in the population. Valid and timely data concerning even many common disorders, such as stroke, migraine, neuropathy, Alzheimer's disease and Parkinson's disease, are unavailable, and there are virtually no data on many less-common neurological disorders, such as neurosarcoidosis or autoimmune encephalitides. There also appear to be marked regional differences in the incidence and prevalence of many diseases, suggesting that non-granular nationwide data may be misleading in many cases. Concentrated efforts to advance neuroepidemiological research in the country would be of clinical, administrative and scientific benefit, but currently, all progress is blocked by administrative and financial obstacles.}, }
@article {pmid37371694, year = {2023}, author = {De Marchi, F and Franjkic, T and Schito, P and Russo, T and Nimac, J and Chami, AA and Mele, A and Vidatic, L and Kriz, J and Julien, JP and Apic, G and Russell, RB and Rogelj, B and Cannon, JR and Baralle, M and Agosta, F and Hecimovic, S and Mazzini, L and Buratti, E and Munitic, I}, title = {Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.}, journal = {Biomedicines}, volume = {11}, number = {6}, pages = {}, pmid = {37371694}, issn = {2227-9059}, abstract = {Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.}, }
@article {pmid37371389, year = {2023}, author = {Górska, A and Markiewicz-Gospodarek, A and Markiewicz, R and Chilimoniuk, Z and Borowski, B and Trubalski, M and Czarnek, K}, title = {Distribution of Iron, Copper, Zinc and Cadmium in Glia, Their Influence on Glial Cells and Relationship with Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {13}, number = {6}, pages = {}, pmid = {37371389}, issn = {2076-3425}, abstract = {Recent data on the distribution and influence of copper, zinc and cadmium in glial cells are summarized. This review also examines the relationship between those metals and their role in neurodegenerative diseases like Alzheimer disease, multiple sclerosis, Parkinson disease and Amyotrophic lateral sclerosis, which have become a great challenge for today's physicians. The studies suggest that among glial cells, iron has the highest concentration in oligodendrocytes, copper in astrocytes and zinc in the glia of hippocampus and cortex. Previous studies have shown neurotoxic effects of copper, iron and manganese, while zinc can have a bidirectional effect, i.e., neurotoxic but also neuroprotective effects depending on the dose and disease state. Recent data point to the association of metals with neurodegeneration through their role in the modulation of protein aggregation. Metals can accumulate in the brain with aging and may be associated with age-related diseases.}, }
@article {pmid37369861, year = {2023}, author = {Zhu, Q and Xu, D and Huang, H and Li, D and Yang, D and Zhou, J and Zhao, Y}, title = {The safety and effectiveness of high-calorie therapy for treating amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4729-4743}, pmid = {37369861}, issn = {1432-1459}, support = {2022BCA055//Department of Science and Technology, Hubei Provincial People's Government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Lipids/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons, which can lead to death from respiratory failure within 3-5 years after the onset of this disease. Nowadays, no drug can effectively slow down the progression of this disease. High-calorie therapy, an emerging complementary alternative treatment, has been reported in studies to prolong the survival time of patients, prevent muscle atrophy and provide a better prognosis. However, no systematic review and meta-analysis were performed to summarize the evidence of this therapy. This meta-analysis comprehensively evaluates the effectiveness and safety of high-calorie therapy for treating ALS.<br><br>METHODS: We searched the electronic databases from inception to 1 April 2023: PubMed, Embase, Web of Science, Cochrane Library, Scopus, Ovid/Medline, and ProQuest. Randomized controlled trials (RCTs) that met the inclusion criteria were performed by meta-analysis. All statistical analyses were performed in STATA software.<br><br>RESULTS: A total of six eligible RCTs were included in this meta-analysis, involving 370 ALS patients. The meta-analyses showed that high-calorie therapy had superiority in improving body weight (SMD&#x2009;=&#x2009;1, 95% CI 0.36, 1.65) and BMI (SMD&#x2009;=&#x2009;0.83, 95% CI 0.02, 1.63). With respect to safety, there was no difference between the high-calorie therapy and the control group regarding the number of adverse events (RR&#x2009;=&#x2009;3.61, 95% CI 0.08, 162.49). However, ALSFRS-R scores (SMD&#x2009;=&#x2009;0.34, 95% CI -&#x2009;0.4, 1.08), survival rate (RR&#x2009;=&#x2009;1.23, 95% CI 0.98, 1.55), and lipid profile (LDL: SMD&#x2009;=&#x2009;0.21, 95% CI -&#x2009;0.33, 0.75; HDL: SMD&#x2009;=&#x2009;0.17, 95% CI -&#x2009;0.37, 0.71; TC: SMD&#x2009;=&#x2009;0.21, 95% CI -&#x2009;0.33, 0.75), CRP (SMD&#x2009;=&#x2009;0.85, 95% CI -&#x2009;1.37, 3.06) showed no significant difference compared to the control groups.<br><br>CONCLUSIONS: High-calorie therapy is effective in gaining weight and BMI with few side effects. However, no significant superiority was detected in ALSFRS-R scores, survival time, lipid profile, and CRP indicator. The overall quality of the included studies is high, and the results have some credibility, but future corroboration by high-quality RCTs is also expected.}, }
@article {pmid37366506, year = {2022}, author = {Erustes, AG and Guarache, GC and Guedes, EDC and Leão, AHFF and Pereira, GJDS and Smaili, SS}, title = {α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease.}, journal = {Contact (Thousand Oaks (Ventura County, Calif.))}, volume = {5}, number = {}, pages = {25152564221119347}, pmid = {37366506}, issn = {2515-2564}, abstract = {Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson's disease pathology.}, }
@article {pmid37358003, year = {2023}, author = {Canever, JB and Queiroz, LY and Soares, ES and de Avelar, NCP and Cimarosti, HI}, title = {Circadian rhythm alterations affecting the pathology of neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnc.15883}, pmid = {37358003}, issn = {1471-4159}, support = {//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; }, abstract = {The circadian rhythm is a nearly 24-h oscillation found in various physiological processes in the human brain and body that is regulated by environmental and genetic factors. It is responsible for maintaining body homeostasis and it is critical for essential functions, such as metabolic regulation and memory consolidation. Dysregulation in the circadian rhythm can negatively impact human health, resulting in cardiovascular and metabolic diseases, psychiatric disorders, and premature death. Emerging evidence points to a relationship between the dysregulation circadian rhythm and neurodegenerative diseases, suggesting that the alterations in circadian function might play crucial roles in the pathogenesis and progression of neurodegenerative diseases. Better understanding this association is of paramount importance to expand the knowledge on the pathophysiology of neurodegenerative diseases, as well as, to provide potential targets for the development of new interventions based on the dysregulation of circadian rhythm. Here we review the latest findings on dysregulation of circadian rhythm alterations in Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and multiple-system atrophy, focusing on research published in the last 3 years.}, }
@article {pmid37356043, year = {2023}, author = {Nguyen, QT and Thanh, LN and Hoang, VT and Phan, TTK and Heke, M and Hoang, DM}, title = {Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {7}, pages = {3211-3250}, pmid = {37356043}, issn = {1573-6830}, mesh = {Humans ; *Autism Spectrum Disorder ; Bone Marrow ; *Stroke/therapy ; Bone Marrow Cells ; }, abstract = {Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.}, }
@article {pmid37355220, year = {2023}, author = {Balog, BM and Sonti, A and Zigmond, RE}, title = {Neutrophil biology in injuries and diseases of the central and peripheral nervous systems.}, journal = {Progress in neurobiology}, volume = {228}, number = {}, pages = {102488}, pmid = {37355220}, issn = {1873-5118}, support = {F32 NS122918/NS/NINDS NIH HHS/United States ; R01 NS114891/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neutrophils ; *Axons/physiology ; Nerve Regeneration/physiology ; Peripheral Nervous System ; Biology ; }, abstract = {The role of inflammation in nervous system injury and disease is attracting increased attention. Much of that research has focused on microglia in the central nervous system (CNS) and macrophages in the peripheral nervous system (PNS). Much less attention has been paid to the roles played by neutrophils. Neutrophils are part of the granulocyte subtype of myeloid cells. These cells, like macrophages, originate and differentiate in the bone marrow from which they enter the circulation. After tissue damage or infection, neutrophils are the first immune cells to infiltrate into tissues and are directed there by specific chemokines, which act on chemokine receptors on neutrophils. We have reviewed here the basic biology of these cells, including their differentiation, the types of granules they contain, the chemokines that act on them, the subpopulations of neutrophils that exist, and their functions. We also discuss tools available for identification and further study of neutrophils. We then turn to a review of what is known about the role of neutrophils in CNS and PNS diseases and injury, including stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal cord and traumatic brain injuries, CNS and PNS axon regeneration, and neuropathic pain. While in the past studies have focused on neutrophils deleterious effects, we will highlight new findings about their benefits. Studies on their actions should lead to identification of ways to modify neutrophil effects to improve health.}, }
@article {pmid37349906, year = {2023}, author = {Shojaie, A and Rota, S and Al Khleifat, A and Ray Chaudhuri, K and Al-Chalabi, A}, title = {Non-motor symptoms in amyotrophic lateral sclerosis: lessons from Parkinson's disease.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2220748}, pmid = {37349906}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis and Parkinson's disease are neurodegenerative diseases of the motor system which are now recognized also to affect non-motor pathways. Non-motor symptoms have been acknowledged as important determinants of quality of life in Parkinson's disease, and there is increasing interest in understanding the extent and role of non-motor symptoms in amyotrophic lateral sclerosis. We therefore reviewed what is known about non-motor symptoms in amyotrophic lateral sclerosis, using lessons from Parkinson's disease.}, }
@article {pmid37345437, year = {2023}, author = {Rush, CL and Lester, EG and Manglani, H and Woodworth, E and Vitolo, O and Fava, M and Berry, JD and Brizzi, K and Babu, S and Lindenberger, EC and Curtis, JR and Vranceanu, AM}, title = {Resilient together-ALS: leveraging the NDD transdiagnostic framework to develop an early dyadic intervention for people with amyotrophic lateral sclerosis and their informal care-partners.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2023.2224400}, pmid = {37345437}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and eventual death, usually within 3-5 years. An ALS diagnosis is associated with substantial emotional distress for both the affected person and their family care-partners which impairs the ability to engage in important conversations about long term care planning, negatively impacts ALS symptoms for the patient, and quality of life for both patient and care-partner. Here we 1) discuss published works identified by the authors about psychosocial interventions for the ALS population, 2) identify a lack of early, dyadic interventions to support psychosocial needs of people with ALS and care-partners; 3) describe the Neurodegenerative Diseases (NDD) framework for early dyadic intervention development and 4) propose an adaptation of an evidence-based early dyadic psychosocial intervention, Recovering Together, for the unique needs of people with ALS and their care-partners (Resilient Together-ALS; RT-ALS) using the NDD framework. Future work will use stakeholder feedback to optimize the intervention for subsequent efficacy testing.}, }
@article {pmid37341302, year = {2023}, author = {Wang, Y and Wu, S and Li, Q and Sun, H and Wang, H}, title = {Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {10}, number = {24}, pages = {e2300325}, pmid = {37341302}, issn = {2198-3844}, support = {81260196//National Natural Science Foundation of China/ ; 81450036//National Natural Science Foundation of China/ ; 2020YK02//Science Foundation of AMHT/ ; 2021YK05//Science Foundation of AMHT/ ; 2022YK01//Science Foundation of AMHT/ ; YN202104//Science Foundation of ASCH/ ; YN202305//Science Foundation of ASCH/ ; 2020MS08175//Natural Science Foundation of Inner Mongolia Autonomous Region/ ; 2021LHMS08024//Natural Science Foundation of Inner Mongolia Autonomous Region/ ; 2022MS08046//Natural Science Foundation of Inner Mongolia Autonomous Region/ ; YC202305//Science Foundation of Inner Mongolia Key Laboratory of human genetic diseases/ ; YC202304//Science Foundation of Inner Mongolia Key Laboratory of human genetic diseases/ ; }, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/drug therapy ; *Stroke/drug therapy ; Cell Death ; }, abstract = {Emerging evidence suggests that ferroptosis, a unique regulated cell death modality that is morphologically and mechanistically different from other forms of cell death, plays a vital role in the pathophysiological process of neurodegenerative diseases, and strokes. Accumulating evidence supports ferroptosis as a critical factor of neurodegenerative diseases and strokes, and pharmacological inhibition of ferroptosis as a therapeutic target for these diseases. In this review article, the core mechanisms of ferroptosis are overviewed and the roles of ferroptosis in neurodegenerative diseases and strokes are described. Finally, the emerging findings in treating neurodegenerative diseases and strokes through pharmacological inhibition of ferroptosis are described. This review demonstrates that pharmacological inhibition of ferroptosis by bioactive small-molecule compounds (ferroptosis inhibitors) could be effective for treatments of these diseases, and highlights a potential promising therapeutic avenue that could be used to prevent neurodegenerative diseases and strokes. This review article will shed light on developing novel therapeutic regimens by pharmacological inhibition of ferroptosis to slow down the progression of these diseases in the future.}, }
@article {pmid37338894, year = {2023}, author = {Burg, T and Van Den Bosch, L}, title = {Abnormal energy metabolism in ALS: a key player?.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {338-345}, pmid = {37338894}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/pathology ; Motor Neurons/pathology ; Energy Metabolism ; Precision Medicine ; }, abstract = {PURPOSE OF THE REVIEW: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance.<br><br>RECENT FINDINGS: The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach.<br><br>SUMMARY: Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.}, }
@article {pmid37338820, year = {2023}, author = {Willemse, SW and van Es, MA}, title = {Susceptibility and disease modifier genes in amyotrophic lateral sclerosis: from genetic associations to therapeutic implications.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {365-370}, pmid = {37338820}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Genes, Modifier ; Superoxide Dismutase-1/genetics/therapeutic use ; Motor Neurons ; Mutation ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies.<br><br>RECENT FINDINGS: The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations.<br><br>SUMMARY: Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow.}, }
@article {pmid37338307, year = {2023}, author = {Tripathi, SJ and Chakraborty, S and Miller, E and Pieper, AA and Paul, BD}, title = {Hydrogen sulfide signalling in neurodegenerative diseases.}, journal = {British journal of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {37338307}, issn = {1476-5381}, support = {P30 AG062428/AG/NIA NIH HHS/United States ; R01 AG071512/AG/NIA NIH HHS/United States ; RO1AG066707/AG/NIA NIH HHS/United States ; 1 U01 AG073323/AG/NIA NIH HHS/United States ; RM1 GM142002/GM/NIGMS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; P50 DA044123/DA/NIDA NIH HHS/United States ; 1 P30 AGO62428-01/AG/NIA NIH HHS/United States ; R01AG071512/AG/NIA NIH HHS/United States ; I01 BX005976/BX/BLRD VA/United States ; 1R21AG073684-01/AG/NIA NIH HHS/United States ; DA044123/DA/NIDA NIH HHS/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; }, abstract = {The gaseous neurotransmitter hydrogen sulfide (H2 S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signalling events. Unlike conventional neurotransmitters, H2 S cannot be stored in vesicles due to its gaseous nature. Instead, it is either locally synthesized or released from endogenous stores. Sulfhydration affords both specific and general neuroprotective effects and is critically diminished in several neurodegenerative disorders. Conversely, some forms of neurodegenerative disease are linked to excessive cellular H2 S. Here, we review the signalling roles of H2 S across the spectrum of neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, Down syndrome, traumatic brain injury, the ataxias, and amyotrophic lateral sclerosis, as well as neurodegeneration generally associated with ageing.}, }
@article {pmid37337289, year = {2023}, author = {Nango, H and Tsuruta, K and Miyagishi, H and Aono, Y and Saigusa, T and Kosuge, Y}, title = {Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {32}, pmid = {37337289}, issn = {2047-9158}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/pathology ; Mice, Transgenic ; Dinoprostone/metabolism/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.}, }
@article {pmid37336982, year = {2023}, author = {Nikom, D and Zheng, S}, title = {Alternative splicing in neurodegenerative disease and the promise of RNA therapies.}, journal = {Nature reviews. Neuroscience}, volume = {24}, number = {8}, pages = {457-473}, pmid = {37336982}, issn = {1471-0048}, support = {R01 MH116220/MH/NIMH NIH HHS/United States ; R01 NS125276/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Alternative Splicing/genetics ; RNA/genetics/metabolism ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; RNA Splicing ; Protein Isoforms/genetics/metabolism ; *Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia/genetics ; }, abstract = {Alternative splicing generates a myriad of RNA products and protein isoforms of different functions from a single gene. Dysregulated alternative splicing has emerged as a new mechanism broadly implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson disease and repeat expansion diseases. Understanding the mechanisms and functional outcomes of abnormal splicing in neurological disorders is vital in developing effective therapies to treat mis-splicing pathology. In this Review, we discuss emerging research and evidence of the roles of alternative splicing defects in major neurodegenerative diseases and summarize the latest advances in RNA-based therapeutic strategies to target these disorders.}, }
@article {pmid37333000, year = {2023}, author = {Boostani, R and Olfati, N and Shamshiri, H and Salimi, Z and Fatehi, F and Hedjazi, SA and Fakharian, A and Ghasemi, M and Okhovat, AA and Basiri, K and Haghi Ashtiani, B and Ansari, B and Raissi, GR and Khatoonabadi, SA and Sarraf, P and Movahed, S and Panahi, A and Ziaadini, B and Yazdchi, M and Bakhtiyari, J and Nafissi, S}, title = {Iranian clinical practice guideline for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1154579}, pmid = {37333000}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations.}, }
@article {pmid37332910, year = {2023}, author = {Rather, MA and Khan, A and Wang, L and Jahan, S and Rehman, MU and Makeen, HA and Mohan, S}, title = {TRP channels: Role in neurodegenerative diseases and therapeutic targets.}, journal = {Heliyon}, volume = {9}, number = {6}, pages = {e16910}, pmid = {37332910}, issn = {2405-8440}, abstract = {TRP (Transient receptor potential) channels are integral membrane proteins consisting of a superfamily of cation channels that allow permeability of both monovalent and divalent cations. TRP channels are subdivided into six subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, and TRPA, and are expressed in almost every cell and tissue. TRPs play an instrumental role in the regulation of various physiological processes. TRP channels are extensively represented in brain tissues and are present in both prokaryotes and eukaryotes, exhibiting responses to several mechanisms, including physical, chemical, and thermal stimuli. TRP channels are involved in the perturbation of Ca[2+] homeostasis in intracellular calcium stores, both in neuronal and non-neuronal cells, and its discrepancy leads to several neuronal disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). TRPs participate in neurite outgrowth, receptor signaling, and excitotoxic cell death in the central nervous system. Understanding the mechanism of TRP channels in neurodegenerative diseases may extend to developing novel therapies. Thus, this review articulates TRP channels' physiological and pathological role in exploring new therapeutic interventions in neurodegenerative diseases.}, }
@article {pmid37331636, year = {2023}, author = {Zhang, H and Qi, G and Wang, K and Yang, J and Shen, Y and Yang, X and Chen, X and Yao, X and Gu, X and Qi, L and Zhou, C and Sun, H}, title = {Oxidative stress: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {214}, number = {}, pages = {115664}, doi = {10.1016/j.bcp.2023.115664}, pmid = {37331636}, issn = {1873-2968}, mesh = {Humans ; *Muscular Atrophy/metabolism ; Oxidative Stress ; Muscle, Skeletal/metabolism ; *Sarcopenia/drug therapy/metabolism/pathology ; Antioxidants/metabolism ; Chronic Disease ; }, abstract = {Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.}, }
@article {pmid37327376, year = {2023}, author = {Shefner, JM and Musaro, A and Ngo, ST and Lunetta, C and Steyn, FJ and Robitaille, R and De Carvalho, M and Rutkove, S and Ludolph, AC and Dupuis, L}, title = {Skeletal muscle in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4425-4436}, pmid = {37327376}, issn = {1460-2156}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Neuromuscular Junction/pathology ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.}, }
@article {pmid37323141, year = {2023}, author = {Khatoon, S and Kalam, N and Rashid, S and Bano, G}, title = {Effects of gut microbiota on neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1145241}, pmid = {37323141}, issn = {1663-4365}, abstract = {A progressive degradation of the brain's structure and function, which results in a reduction in cognitive and motor skills, characterizes neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The morbidity linked to NDs is growing, which poses a severe threat to human being's mental and physical ability to live well. The gut-brain axis (GBA) is now known to have a crucial role in the emergence of NDs. The gut microbiota is a conduit for the GBA, a two-way communication system between the gut and the brain. The myriad microorganisms that make up the gut microbiota can affect brain physiology by transmitting numerous microbial chemicals from the gut to the brain via the GBA or neurological system. The synthesis of neurotransmitters, the immunological response, and the metabolism of lipids and glucose have all been demonstrated to be impacted by alterations in the gut microbiota, such as an imbalance of helpful and harmful bacteria. In order to develop innovative interventions and clinical therapies for NDs, it is crucial to comprehend the participation of the gut microbiota in these conditions. In addition to using antibiotics and other drugs to target particular bacterial species that may be a factor in NDs, this also includes using probiotics and other fecal microbiota transplantation to maintain a healthy gut microbiota. In conclusion, the examination of the GBA can aid in understanding the etiology and development of NDs, which may benefit the improvement of clinical treatments for these disorders and ND interventions. This review indicates existing knowledge about the involvement of microbiota present in the gut in NDs and potential treatment options.}, }
@article {pmid37316681, year = {2023}, author = {Blair, HA}, title = {Tofersen: First Approval.}, journal = {Drugs}, volume = {83}, number = {11}, pages = {1039-1043}, pmid = {37316681}, issn = {1179-1950}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase/genetics ; Oligonucleotides/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Tofersen (Qalsody[™]) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.}, }
@article {pmid37316101, year = {2023}, author = {Tavazzi, E and Longato, E and Vettoretti, M and Aidos, H and Trescato, I and Roversi, C and Martins, AS and Castanho, EN and Branco, R and Soares, DF and Guazzo, A and Birolo, G and Pala, D and Bosoni, P and Chiò, A and Manera, U and de Carvalho, M and Miranda, B and Gromicho, M and Alves, I and Bellazzi, R and Dagliati, A and Fariselli, P and Madeira, SC and Di Camillo, B}, title = {Artificial intelligence and statistical methods for stratification and prediction of progression in amyotrophic lateral sclerosis: A systematic review.}, journal = {Artificial intelligence in medicine}, volume = {142}, number = {}, pages = {102588}, doi = {10.1016/j.artmed.2023.102588}, pmid = {37316101}, issn = {1873-2860}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Artificial Intelligence ; Brain ; Cluster Analysis ; Databases, Factual ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive loss of motor neurons in the brain and spinal cord. The fact that ALS's disease course is highly heterogeneous, and its determinants not fully known, combined with ALS's relatively low prevalence, renders the successful application of artificial intelligence (AI) techniques particularly arduous.<br><br>OBJECTIVE: This systematic review aims at identifying areas of agreement and unanswered questions regarding two notable applications of AI in ALS, namely the automatic, data-driven stratification of patients according to their phenotype, and the prediction of ALS progression. Differently from previous works, this review is focused on the methodological landscape of AI in ALS.<br><br>METHODS: We conducted a systematic search of the Scopus and PubMed databases, looking for studies on data-driven stratification methods based on unsupervised techniques resulting in (A) automatic group discovery or (B) a transformation of the feature space allowing patient subgroups to be identified; and for studies on internally or externally validated methods for the prediction of ALS progression. We described the selected studies according to the following characteristics, when applicable: variables used, methodology, splitting criteria and number of groups, prediction outcomes, validation schemes, and metrics.<br><br>RESULTS: Of the starting 1604 unique reports (2837 combined hits between Scopus and PubMed), 239 were selected for thorough screening, leading to the inclusion of 15 studies on patient stratification, 28 on prediction of ALS progression, and 6 on both stratification and prediction. In terms of variables used, most stratification and prediction studies included demographics and features derived from the ALSFRS or ALSFRS-R scores, which were also the main prediction targets. The most represented stratification methods were K-means, and hierarchical and expectation-maximisation clustering; while random forests, logistic regression, the Cox proportional hazard model, and various flavours of deep learning were the most widely used prediction methods. Predictive model validation was, albeit unexpectedly, quite rarely performed in absolute terms (leading to the exclusion of 78 eligible studies), with the overwhelming majority of included studies resorting to internal validation only.<br><br>CONCLUSION: This systematic review highlighted a general agreement in terms of input variable selection for both stratification and prediction of ALS progression, and in terms of prediction targets. A striking lack of validated models emerged, as well as a general difficulty in reproducing many published studies, mainly due to the absence of the corresponding parameter lists. While deep learning seems promising for prediction applications, its superiority with respect to traditional methods has not been established; there is, instead, ample room for its application in the subfield of patient stratification. Finally, an open question remains on the role of new environmental and behavioural variables collected via novel, real-time sensors.}, }
@article {pmid37310359, year = {2023}, author = {Fang, J and Huang, Y and Wu, J and Shen, B and Yang, Y and Ju, M}, title = {Fluorogenic methodology for visualization of phase separation in chemical biology.}, journal = {Organic &amp; biomolecular chemistry}, volume = {21}, number = {25}, pages = {5140-5149}, doi = {10.1039/d3ob00660c}, pmid = {37310359}, issn = {1477-0539}, mesh = {Humans ; *Alzheimer Disease ; Biology ; }, abstract = {Phase separation is a common biological phenomenon in the liquid environment of organisms. Phase separation has been shown to be a key cause of many existing incurable diseases, such as the protein aggregates formed by phase separation of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, etc. Tracking the occurrence of phase separation in vivo is critical to many disease detection methods and solving many treatment problems. Its physicochemical properties and visual detection methods have flourished in the last few years in chemical biology, among which the fluorogenic toolbox has great application potential compared to the traditional detection methods that cannot visualize the phase separation process intuitively, but just show some parameters indirectly. This paper reviews the mechanism and disease correlation proven in recent years for phase separation and analyzes the detection methods for phase separation, including functional microscope imaging techniques, turbidity monitoring, macromolecule congestion sensing, in silico analysis, etc. It is worth mentioning that the qualitative and quantitative analysis of aggregates formed by phase separation using in vitro parameters has successfully provided basic physical and chemical properties for phase separation aggregates, and is an important cornerstone for researchers to carry forward the past and break through the existing technical shackles to create new in vivo monitoring methods such as fluorescence methodology. Crucially, fluorescence methods for cell microenvironment imaging based on different mechanisms are discussed, such as AIE-based probes, TICT-based probes and FRET-based probes, etc.}, }
@article {pmid37307822, year = {2024}, author = {Chen, S and Cai, X and Lao, L and Wang, Y and Su, H and Sun, H}, title = {Brain-Gut-Microbiota Axis in Amyotrophic Lateral Sclerosis: A Historical Overview and Future Directions.}, journal = {Aging and disease}, volume = {15}, number = {1}, pages = {74-95}, pmid = {37307822}, issn = {2152-5250}, mesh = {Humans ; Aged ; Child, Preschool ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Neurodegenerative Diseases/complications ; *Gastrointestinal Microbiome/physiology ; Brain-Gut Axis ; Brain ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease which is strongly associated with age. The incidence of ALS increases from the age of 40 and peaks between the ages of 65 and 70. Most patients die of respiratory muscle paralysis or lung infections within three to five years of the appearance of symptoms, dealing a huge blow to patients and their families. With aging populations, improved diagnostic methods and changes in reporting criteria, the incidence of ALS is likely to show an upward trend in the coming decades. Despite extensive researches have been done, the cause and pathogenesis of ALS remains unclear. In recent decades, large quantities of studies focusing on gut microbiota have shown that gut microbiota and its metabolites seem to change the evolvement of ALS through the brain-gut-microbiota axis, and in turn, the progression of ALS will exacerbate the imbalance of gut microbiota, thereby forming a vicious cycle. This suggests that further exploration and identification of the function of gut microbiota in ALS may be crucial to break the bottleneck in the diagnosis and treatment of this disease. Hence, the current review summarizes and discusses the latest research advancement and future directions of ALS and brain-gut-microbiota axis, so as to help relevant researchers gain correlative information instantly.}, }
@article {pmid37307819, year = {2024}, author = {He, D and Xu, Y and Liu, M and Cui, L}, title = {The Inflammatory Puzzle: Piecing together the Links between Neuroinflammation and Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {15}, number = {1}, pages = {96-114}, pmid = {37307819}, issn = {2152-5250}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Neuroinflammatory Diseases ; *Neurodegenerative Diseases/complications ; Central Nervous System ; Signal Transduction/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has a complex genetic basis. Through advancements in genetic screening, researchers have identified more than 40 mutant genes associated with ALS, some of which impact immune function. Neuroinflammation, with abnormal activation of immune cells and excessive production of inflammatory cytokines in the central nervous system, significantly contributes to the pathophysiology of ALS. In this review, we examine recent evidence on the involvement of ALS-associated mutant genes in immune dysregulation, with a specific focus on the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and N6-methyladenosine (m[6]A)-mediated immune regulation in the context of neurodegeneration. We also discuss the perturbation of immune cell homeostasis in both the central nervous system and peripheral tissues in ALS. Furthermore, we explore the advancements made in the emerging genetic and cell-based therapies for ALS. This review underscores the complex relationship between ALS and neuroinflammation, highlighting the potential to identify modifiable factors for therapeutic intervention. A deeper understanding of the connection between neuroinflammation and the risk of ALS is crucial for advancing effective treatments for this debilitating disorder.}, }
@article {pmid37306196, year = {2023}, author = {Lloyd, EM and Pinniger, GJ and Murphy, RM and Grounds, MD}, title = {Slow or fast: Implications of myofibre type and associated differences for manifestation of neuromuscular disorders.}, journal = {Acta physiologica (Oxford, England)}, volume = {238}, number = {4}, pages = {e14012}, doi = {10.1111/apha.14012}, pmid = {37306196}, issn = {1748-1716}, mesh = {Male ; Animals ; Female ; *Muscle Fibers, Fast-Twitch ; *Muscle Fibers, Slow-Twitch ; Muscle, Skeletal/physiology ; Muscle Contraction/physiology ; Aging ; Mammals ; }, abstract = {Many neuromuscular disorders can have a differential impact on a specific myofibre type, forming the central premise of this review. The many different skeletal muscles in mammals contain a spectrum of slow- to fast-twitch myofibres with varying levels of protein isoforms that determine their distinctive contractile, metabolic, and other properties. The variations in functional properties across the range of classic 'slow' to 'fast' myofibres are outlined, combined with exemplars of the predominantly slow-twitch soleus and fast-twitch extensor digitorum longus muscles, species comparisons, and techniques used to study these properties. Other intrinsic and extrinsic differences are discussed in the context of slow and fast myofibres. These include inherent susceptibility to damage, myonecrosis, and regeneration, plus extrinsic nerves, extracellular matrix, and vasculature, examined in the context of growth, ageing, metabolic syndrome, and sexual dimorphism. These many differences emphasise the importance of carefully considering the influence of myofibre-type composition on manifestation of various neuromuscular disorders across the lifespan for both sexes. Equally, understanding the different responses of slow and fast myofibres due to intrinsic and extrinsic factors can provide deep insight into the precise molecular mechanisms that initiate and exacerbate various neuromuscular disorders. This focus on the influence of different myofibre types is of fundamental importance to enhance translation for clinical management and therapies for many skeletal muscle disorders.}, }
@article {pmid37304072, year = {2023}, author = {Santiago, JA and Potashkin, JA}, title = {Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1185671}, pmid = {37304072}, issn = {1663-4365}, abstract = {Neurodegenerative diseases have reached alarming numbers in the past decade. Unfortunately, clinical trials testing potential therapeutics have proven futile. In the absence of disease-modifying therapies, physical activity has emerged as the single most accessible lifestyle modification with the potential to fight off cognitive decline and neurodegeneration. In this review, we discuss findings from epidemiological, clinical, and molecular studies investigating the potential of lifestyle modifications in promoting brain health. We propose an evidence-based multidomain approach that includes physical activity, diet, cognitive training, and sleep hygiene to treat and prevent neurodegenerative diseases.}, }
@article {pmid37300059, year = {2023}, author = {Stateczny, A and Halicki, A and Specht, M and Specht, C and Lewicka, O}, title = {Review of Shoreline Extraction Methods from Aerial Laser Scanning.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {11}, pages = {}, pmid = {37300059}, issn = {1424-8220}, support = {LIDER/10/0030/L-11/19/NCBR/2020//National Centre for Research and Development in Poland/ ; WN/2023/PZ/05//Gdynia Maritime University/ ; }, abstract = {Autonomous technologies are increasingly used in various areas of science. The use of unmanned vehicles for hydrographic surveys in shallow coastal areas requires accurate estimation of shoreline position. This is a nontrivial task, which can be performed using a wide range of sensors and methods. The aim of the publication is to review shoreline extraction methods based solely on data from aerial laser scanning (ALS). This narrative review discusses and critically analyses seven publications drawn up in the last ten years. The discussed papers employed nine different shoreline extraction methods based on aerial light detection and ranging (LiDAR) data. It should be noted that unambiguous evaluation of shoreline extraction methods is difficult or impossible. This is because not all of the methods reported achieved accuracy, the methods were assessed on different datasets, the measurements were conducted using different devices, the water areas differed in geometrical and optical properties, the shorelines had different geometries, and the extent of anthropogenic transformation. The methods proposed by the authors were compared with a wide range of reference methods.}, }
@article {pmid37298586, year = {2023}, author = {Cerasuolo, M and Di Meo, I and Auriemma, MC and Trojsi, F and Maiorino, MI and Cirillo, M and Esposito, F and Polito, R and Colangelo, AM and Paolisso, G and Papa, M and Rizzo, MR}, title = {Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298586}, issn = {1422-0067}, mesh = {Humans ; Iron/metabolism ; *Alzheimer Disease/metabolism ; *Ferroptosis ; *Neurodegenerative Diseases/metabolism ; *Cognitive Dysfunction/drug therapy/etiology/metabolism ; }, abstract = {Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson's disease, multiple sclerosis, Alzheimer's disease, prion diseases such as Creutzfeldt-Jakob's disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer's disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment.}, }
@article {pmid37298554, year = {2023}, author = {Michetti, F and Clementi, ME and Di Liddo, R and Valeriani, F and Ria, F and Rende, M and Di Sante, G and Romano Spica, V}, title = {The S100B Protein: A Multifaceted Pathogenic Factor More Than a Biomarker.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298554}, issn = {1422-0067}, mesh = {Humans ; Biomarkers/metabolism ; *Nervous System Diseases ; *Parkinson Disease/metabolism ; *S100 Calcium Binding Protein beta Subunit ; }, abstract = {S100B is a calcium-binding protein mainly concentrated in astrocytes in the nervous system. Its levels in biological fluids are recognized as a reliable biomarker of active neural distress, and more recently, mounting evidence points to S100B as a Damage-Associated Molecular Pattern molecule, which, at high concentration, triggers tissue reactions to damage. S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease. In addition, in experimental models of diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic and vascular acute neural injury, epilepsy, and inflammatory bowel disease, alteration of S100B levels correlates with the occurrence of clinical and/or toxic parameters. In general, overexpression/administration of S100B worsens the clinical presentation, whereas deletion/inactivation of the protein contributes to the amelioration of the symptoms. Thus, the S100B protein may be proposed as a common pathogenic factor in different disorders, sharing different symptoms and etiologies but appearing to share some common pathogenic processes reasonably attributable to neuroinflammation.}, }
@article {pmid37298512, year = {2023}, author = {Guo, Z}, title = {Ganglioside GM1 and the Central Nervous System.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298512}, issn = {1422-0067}, support = {R35 GM131686/GM/NIGMS NIH HHS/United States ; R35GM131686/NH/NIH HHS/United States ; }, mesh = {Humans ; *G(M1) Ganglioside/metabolism ; *Gangliosidosis, GM1 ; Central Nervous System/metabolism ; Brain/metabolism ; Glycosphingolipids/metabolism ; }, abstract = {GM1 is one of the major glycosphingolipids (GSLs) on the cell surface in the central nervous system (CNS). Its expression level, distribution pattern, and lipid composition are dependent upon cell and tissue type, developmental stage, and disease state, which suggests a potentially broad spectrum of functions of GM1 in various neurological and neuropathological processes. The major focus of this review is the roles that GM1 plays in the development and activities of brains, such as cell differentiation, neuritogenesis, neuroregeneration, signal transducing, memory, and cognition, as well as the molecular basis and mechanisms for these functions. Overall, GM1 is protective for the CNS. Additionally, this review has also examined the relationships between GM1 and neurological disorders, such as Alzheimer's disease, Parkinson's disease, GM1 gangliosidosis, Huntington's disease, epilepsy and seizure, amyotrophic lateral sclerosis, depression, alcohol dependence, etc., and the functional roles and therapeutic applications of GM1 in these disorders. Finally, current obstacles that hinder more in-depth investigations and understanding of GM1 and the future directions in this field are discussed.}, }
@article {pmid37298129, year = {2023}, author = {Molinaro, P and Sanguigno, L and Casamassa, A and Valsecchi, V and Sirabella, R and Pignataro, G and Annunziato, L and Formisano, L}, title = {Emerging Role of DREAM in Healthy Brain and Neurological Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298129}, issn = {1422-0067}, support = {PE0000006//Ministry of Education, Universities and Research/ ; PE0000012//Ministry of Education, Universities and Research/ ; CN00000041//Ministry of Education, Universities and Research/ ; 2017JL8SRX//Ministry of Education, Universities and Research/ ; 20173EAZ2Z//Ministry of Education, Universities and Research/ ; 2017WJZ9W9//Ministry of Education, Universities and Research/ ; }, mesh = {*Kv Channel-Interacting Proteins/metabolism ; *Repressor Proteins/genetics ; Brain/metabolism ; Dynorphins/metabolism ; Cell Nucleus/metabolism ; }, abstract = {The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca[2+]-sensitive protein exerting a dual mechanism of action to regulate several Ca[2+]-dependent processes. Upon sumoylation, DREAM enters in nucleus where it downregulates the expression of several genes provided with a consensus sequence named dream regulatory element (DRE). On the other hand, DREAM could also directly modulate the activity or the localization of several cytosolic and plasma membrane proteins. In this review, we summarize recent advances in the knowledge of DREAM dysregulation and DREAM-dependent epigenetic remodeling as a central mechanism in the progression of several diseases affecting central nervous system, including stroke, Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and neuropathic pain. Interestingly, DREAM seems to exert a common detrimental role in these diseases by inhibiting the transcription of several neuroprotective genes, including the sodium/calcium exchanger isoform 3 (NCX3), brain-derived neurotrophic factor (BDNF), pro-dynorphin, and c-fos. These findings lead to the concept that DREAM might represent a pharmacological target to ameliorate symptoms and reduce neurodegenerative processes in several pathological conditions affecting central nervous system.}, }
@article {pmid37296644, year = {2023}, author = {Tzeplaeff, L and Wilfling, S and Requardt, MV and Herdick, M}, title = {Current State and Future Directions in the Therapy of ALS.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296644}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Riluzole/therapeutic use ; Motor Neurons/pathology ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.}, }
@article {pmid37296571, year = {2023}, author = {Valori, CF and Sulmona, C and Brambilla, L and Rossi, D}, title = {Astrocytes: Dissecting Their Diverse Roles in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296571}, issn = {2073-4409}, mesh = {Animals ; *Astrocytes ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases. Consistently, pathological inclusions of the same proteins as well as mutations in the same genes can be identified in both ALS/FTD. Although many studies have described several disrupted pathways within neurons, glial cells are also regarded as crucial pathogenetic contributors in ALS/FTD. Here, we focus our attention on astrocytes, a heterogenous population of glial cells that perform several functions for optimal central nervous system homeostasis. Firstly, we discuss how post-mortem material from ALS/FTD patients supports astrocyte dysfunction around three pillars: neuroinflammation, abnormal protein aggregation, and atrophy/degeneration. Furthermore, we summarize current attempts at monitoring astrocyte functions in living patients using either novel imaging strategies or soluble biomarkers. We then address how astrocyte pathology is recapitulated in animal and cellular models of ALS/FTD and how we used these models both to understand the molecular mechanisms driving glial dysfunction and as platforms for pre-clinical testing of therapeutics. Finally, we present the current clinical trials for ALS/FTD, restricting our discussion to treatments that modulate astrocyte functions, directly or indirectly.}, }
@article {pmid37288069, year = {2023}, author = {Corrigan, F and Wee, IC and Collins-Praino, LE}, title = {Chronic motor performance following different traumatic brain injury severity-A systematic review.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1180353}, pmid = {37288069}, issn = {1664-2295}, abstract = {INTRODUCTION: Traumatic brain injury (TBI) is now known to be a chronic disease, causing ongoing neurodegeneration and linked to increased risk of neurodegenerative motor diseases, such as Parkinson's disease and amyotrophic lateral sclerosis. While the presentation of motor deficits acutely following traumatic brain injury is well-documented, however, less is known about how these evolve in the long-term post-injury, or how the initial severity of injury affects these outcomes. The purpose of this review, therefore, was to examine objective assessment of chronic motor impairment across the spectrum of TBI in both preclinical and clinical models.<br><br>METHODS: PubMed, Embase, Scopus, and PsycINFO databases were searched with a search strategy containing key search terms for TBI and motor function. Original research articles reporting chronic motor outcomes with a clearly defined TBI severity (mild, repeated mild, moderate, moderate-severe, and severe) in an adult population were included.<br><br>RESULTS: A total of 97 studies met the inclusion criteria, incorporating 62 preclinical and 35 clinical studies. Motor domains examined included neuroscore, gait, fine-motor, balance, and locomotion for preclinical studies and neuroscore, fine-motor, posture, and gait for clinical studies. There was little consensus among the articles presented, with extensive differences both in assessment methodology of the tests and parameters reported. In general, an effect of severity was seen, with more severe injury leading to persistent motor deficits, although subtle fine motor deficits were also seen clinically following repeated injury. Only six clinical studies investigated motor outcomes beyond 10 years post-injury and two preclinical studies to 18-24 months post-injury, and, as such, the interaction between a previous TBI and aging on motor performance is yet to be comprehensively examined.<br><br>CONCLUSION: Further research is required to establish standardized motor assessment procedures to fully characterize chronic motor impairment across the spectrum of TBI with comprehensive outcomes and consistent protocols. Longitudinal studies investigating the same cohort over time are also a key for understanding the interaction between TBI and aging. This is particularly critical, given the risk of neurodegenerative motor disease development following TBI.}, }
@article {pmid37285737, year = {2023}, author = {Taheri, M and Askari, A and Hussen, BM and Eghbali, A and Ghafouri-Fard, S}, title = {A review on the role of MYC-induced long non-coding RNA in human disorders.}, journal = {Pathology, research and practice}, volume = {248}, number = {}, pages = {154568}, doi = {10.1016/j.prp.2023.154568}, pmid = {37285737}, issn = {1618-0631}, mesh = {Humans ; *Carcinoma, Hepatocellular/pathology ; Gene Expression Regulation, Neoplastic ; *Liver Neoplasms/pathology ; *MicroRNAs/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; }, abstract = {MINCR (MYC-Induced Long Non-Coding RNA) is classified as an lncRNA. It has a significant correlation with MYC gene. MINCR has important roles in the carcinogenesis. It has been approved that this lncRNA can act as molecular sponge for miR-28-5p, miR-708-5p, miR-876-5p and miR-146a-5p. Dysregulated levels of MINCR has been observed in different types of cancer, especially hepatocellular carcinoma. In addition to malignant conditions, schizophrenia and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are associated with dysregulation of expression patterns of MINCR. This review outlines MINCR molecular mechanisms of action in different disorders.}, }
@article {pmid37277972, year = {2023}, author = {Mori, K and Gotoh, S and Ikeda, M}, title = {Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA.}, journal = {Journal of neurochemistry}, volume = {166}, number = {2}, pages = {156-171}, doi = {10.1111/jnc.15847}, pmid = {37277972}, issn = {1471-4159}, mesh = {Humans ; C9orf72 Protein/genetics ; Proteins/genetics/metabolism ; RNA/genetics/metabolism ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Repeat Expansion/genetics ; }, abstract = {An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much about the disease since the identification of the mutation in 2011, how the expanded repeat causes a particular type of fronto-temporal lobe dominant neurodegeneration and/or motor neuron degeneration is not yet clear. In this review, we summarize and discuss the current understandings of molecular mechanism of this repeat expansion mutation with focuses on the degradation and translation of the repeat containing RNA transcripts.}, }
@article {pmid37274187, year = {2023}, author = {Santarelli, S and Londero, C and Soldano, A and Candelaresi, C and Todeschini, L and Vernizzi, L and Bellosta, P}, title = {Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1082047}, pmid = {37274187}, issn = {1662-4548}, abstract = {Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.}, }
@article {pmid37269968, year = {2023}, author = {Alqahtani, T and Deore, SL and Kide, AA and Shende, BA and Sharma, R and Dadarao Chakole, R and Nemade, LS and Kishor Kale, N and Borah, S and Shrikant Deokar, S and Behera, A and Dhawal Bhandari, D and Gaikwad, N and Kalam Azad, A and Ghosh, A}, title = {Mitochondrial dysfunction and oxidative stress in Alzheimer's disease, and Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis -An updated review.}, journal = {Mitochondrion}, volume = {71}, number = {}, pages = {83-92}, doi = {10.1016/j.mito.2023.05.007}, pmid = {37269968}, issn = {1872-8278}, mesh = {Humans ; *Parkinson Disease/pathology ; *Alzheimer Disease/pathology ; *Huntington Disease/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Oxidative Stress/physiology ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; }, abstract = {Misfolded proteins in the central nervous system can induce oxidative damage, which can contribute to neurodegenerative diseases in the mitochondria. Neurodegenerative patients face early mitochondrial dysfunction, impacting energy utilization. Amyloid-ß and tau problems both have an effect on mitochondria, which leads to mitochondrial malfunction and, ultimately, the onset of Alzheimer's disease. Cellular oxygen interaction yields reactive oxygen species within mitochondria, initiating oxidative damage to mitochondrial constituents. Parkinson's disease, linked to oxidative stress, α-synuclein aggregation, and inflammation, results from reduced brain mitochondria activity. Mitochondrial dynamics profoundly influence cellular apoptosis via distinct causative mechanisms. The condition known as Huntington's disease is characterized by an expansion of polyglutamine, primarily impactingthe cerebral cortex and striatum. Research has identified mitochondrial failure as an early pathogenic mechanism contributing to HD's selective neurodegeneration. The mitochondria are organelles that exhibit dynamism by undergoing fragmentation and fusion processes to attain optimal bioenergetic efficiency. They can also be transported along microtubules and regulateintracellular calcium homeostasis through their interaction with the endoplasmic reticulum. Additionally, the mitochondria produce free radicals. The functions of eukaryotic cells, particularly in neurons, have significantly deviated from the traditionally assigned role of cellular energy production. Most of them areimpaired in HD, which may lead to neuronal dysfunction before symptoms manifest. This article summarizes the most important changes in mitochondrial dynamics that come from neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's and Amyotrophic Lateral Sclerosis. Finally, we discussed about novel techniques that can potentially treat mitochondrial malfunction and oxidative stress in four most dominating neuro disorders.}, }
@article {pmid37269231, year = {2024}, author = {Alqallaf, A and Cates, DW and Render, KP and Patel, KA}, title = {Sodium Phenylbutyrate and Taurursodiol: A New Therapeutic Option for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {58}, number = {2}, pages = {165-173}, doi = {10.1177/10600280231172802}, pmid = {37269231}, issn = {1542-6270}, mesh = {United States ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/adverse effects ; }, abstract = {OBJECTIVE: To review the safety and efficacy of sodium phenylbutyrate and taurursodiol (SP + T) in slowing progression of amyotrophic lateral sclerosis (ALS) compared with pre-existing therapies.<br><br>DATA SOURCES: A PubMed (from January 1, 2009, to April 13, 2023) and ClinicalTrials.gov search conducted using sodium phenylbutyrate, taurursodiol, AMX0035, riluzole, and edaravone. Additional articles were identified by hand from references.<br><br>This included English-language articles evaluating SP + T efficacy or safety in humans for decreasing neuronal death and slowing the progression of ALS.<br><br>DATA SYNTHESIS: In one phase II clinical trial that encompassed an open-label extension phase, disease severity, assessed by the rate of decline in overall score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised with higher scores indicating more functional ability, was -1.24 points per month with active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = 0.03). Post hoc analysis found survival benefit of median 4.8 months with active medication compared with placebo.<br><br>SP + T is a new US Food and Drug Administration-approved oral suspension for the treatment of ALS. Patients who received active medication through the phase II trial showed decreased rates of disease progression. Overall, SP + T could be considered a potential agent for the treatment of ALS which has a high unmet need.<br><br>CONCLUSION: SP + T is an option for the treatment of ALS; however, additional data regarding efficacy in phase III trials with long-term safety profile considerations, as well as trials to compare current therapy with SP + T, are needed.}, }
@article {pmid37268555, year = {2024}, author = {Fakim, H and Vande Velde, C}, title = {The implications of physiological biomolecular condensates in amyotrophic lateral sclerosis.}, journal = {Seminars in cell &amp; developmental biology}, volume = {156}, number = {}, pages = {176-189}, doi = {10.1016/j.semcdb.2023.05.006}, pmid = {37268555}, issn = {1096-3634}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Biomolecular Condensates ; DNA-Binding Proteins/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mutation/genetics ; RNA ; }, abstract = {In recent years, there has been an emphasis on the role of phase-separated biomolecular condensates, especially stress granules, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). This is largely due to several ALS-associated mutations occurring in genes involved in stress granule assembly and observations that pathological inclusions detected in ALS patient neurons contain stress granule proteins, including the ALS-linked proteins TDP-43 and FUS. However, protein components of stress granules are also found in numerous other phase-separated biomolecular condensates under physiological conditions which are inadequately discussed in the context of ALS. In this review, we look beyond stress granules and describe the roles of TDP-43 and FUS in physiological condensates occurring in the nucleus and neurites, such as the nucleolus, Cajal bodies, paraspeckles and neuronal RNA transport granules. We also discuss the consequences of ALS-linked mutations in TDP-43 and FUS on their ability to phase separate into these stress-independent biomolecular condensates and perform their respective functions. Importantly, biomolecular condensates sequester multiple overlapping protein and RNA components, and their dysregulation could contribute to the observed pleiotropic effects of both sporadic and familial ALS on RNA metabolism.}, }
@article {pmid37266849, year = {2023}, author = {Ugale, V and Deshmukh, R and Lokwani, D and Narayana Reddy, P and Khadse, S and Chaudhari, P and Kulkarni, PP}, title = {GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {1-28}, pmid = {37266849}, issn = {1573-501X}, abstract = {N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure-function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.}, }
@article {pmid37259916, year = {2023}, author = {Berth, SH and Lloyd, TE}, title = {Disruption of axonal transport in neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {11}, pages = {}, pmid = {37259916}, issn = {1558-8238}, support = {K08 NS118123/NS/NINDS NIH HHS/United States ; R01 NS082563/NS/NINDS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; P30 NS050274/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Axonal Transport/physiology ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.}, }
@article {pmid37259156, year = {2023}, author = {Ionescu, A and Altman, T and Perlson, E}, title = {Looking for answers far away from the soma-the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {35}, pmid = {37259156}, issn = {1750-1326}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Axons/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; Neuromuscular Junction ; }, abstract = {Axon degeneration and Neuromuscular Junction (NMJ) disruption are key pathologies in the fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Despite accumulating evidence that axons and NMJs are impacted at a very early stage of the disease, current knowledge about the mechanisms leading to their degeneration remains elusive. Cytoplasmic mislocalization and accumulation of the protein TDP-43 are considered key pathological hallmarks of ALS, as they occur in ~ 97% of ALS patients, both sporadic and familial. Recent studies have identified pathological accumulation of TDP-43 in intramuscular nerves of muscle biopsies collected from pre-diagnosed, early symptomatic ALS patients. These findings suggest a gain of function for TDP-43 in axons, which might facilitate early NMJ disruption. In this review, we dissect the process leading to axonal TDP-43 accumulation and phosphorylation, discuss the known and hypothesized roles TDP-43 plays in healthy axons, and review possible mechanisms that connect TDP-43 pathology to the axon and NMJ degeneration in ALS.}, }
@article {pmid37258447, year = {2023}, author = {Liu, J and Duan, W and Deng, Y and Zhang, Q and Li, R and Long, J and Ahmed, W and Gu, C and Qiu, Y and Cai, H and Hu, Y and Chen, L}, title = {New Insights into Molecular Mechanisms Underlying Neurodegenerative Disorders.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {3}, pages = {58}, doi = {10.31083/j.jin2203058}, pmid = {37258447}, issn = {0219-6352}, support = {2022YFA1104900//National Key R&amp;D Program of China/ ; 2022YFA1104904//National Key R&amp;D Program of China/ ; 2021A1515010013//Natural Science Foundation of Guangdong Province/ ; 2021ZDZX2011//Department of Education of Guangdong Province/ ; 20221275//Traditional Chinese Medicine Bureau of Guangdong Province/ ; 202201011760//Guangzhou Municipal Science and Technology Project/ ; 1202101003//President Foundation of Integrated Hospital of Traditional Chinese Medicine of Southern Medical University/ ; 1202103007//President Foundation of Integrated Hospital of Traditional Chinese Medicine of Southern Medical University/ ; }, mesh = {Humans ; Quality of Life ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/etiology/therapy/metabolism ; Oxidative Stress ; }, abstract = {As a large and heterogeneous group of disorders, neurodegenerative diseases are characterized by the progressive loss of structure or function in neurons, finally leading to neuronal death. Neurodegenerative diseases cause serious threat to a patient's quality of life and the most common are Alzheimer's disease and Parkinson's disease. Currently, little is known of the detailed etiology of these disorders; as such, there are no effective treatments available. Furthermore, the lack of targeted, effective, and resolvable therapy for neurodegenerative diseases, represents an expanding research field for the discovery of new therapeutic strategies. Investigations of the potential pathogenesis of neurodegenerative diseases will become the basis of preventing the occurrence and development of neurodegenerative diseases and finding effective therapies. Existing theories and mechanisms, such as genetic and environmental factors, abnormal protein accumulation, and oxidative stress, are intricately associated with each other. However, there is no molecular theory that can entirely explain the pathological processes underlying neurodegenerative diseases. Due to the development of experimental technology and the support of multidisciplinary integration, it has been possible to perform more in-depth research on potential targets for neurodegenerative diseases and there have been many exciting discoveries in terms of original theories and underlying mechanisms. With this review, we intend to review the existing literature and provide new insights into the molecular mechanisms underlying neurodegenerative diseases.}, }
@article {pmid37257665, year = {2023}, author = {Lazo, PA and Morejón-García, P}, title = {VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases.}, journal = {Neurobiology of disease}, volume = {183}, number = {}, pages = {106172}, doi = {10.1016/j.nbd.2023.106172}, pmid = {37257665}, issn = {1095-953X}, mesh = {Humans ; Coiled Bodies/metabolism ; Syndrome ; Mutation ; *Motor Neuron Disease/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; *Charcot-Marie-Tooth Disease/genetics ; }, abstract = {Distal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some the origin is unknown. Recently, rare pathogenic variants of the human VRK1 gene have been associated with these neurological phenotypes. All VRK1 pathogenic variants are recessive, and their clinical presentation occurs in either homozygous or compound heterozygous patients. The pathogenic VRK1 gene pathogenic variants are located in three clusters within the protein sequence. The main, and initial, shared clinical phenotype among VRK1 pathogenic variants is a distal progressive loss of motor and/or sensory function, which includes diseases such as spinal muscular atrophy, Charcot-Marie-Tooth, amyotrophic lateral sclerosis and hereditary spastic paraplegia. In most cases, symptoms start early in infancy, or in utero, and are slowly progressive. Additional neurological symptoms vary among non-related patients, probably because of their different VRK1 variants and their genetic background. The underlying common pathogenic mechanism, by its functional impairment, is a likely consequence of the roles that the VRK1 protein plays in the regulation on the stability and assembly of Cajal bodies, which affect RNA maturation and processing, neuronal migration of RNPs along axons, and DNA-damage responses. Alterations of these processes are associated with several neuro sensory or motor syndromes. The clinical heterogeneity of the neurological phenotypes associated with VRK1 is a likely consequence of the protein complexes in which VRK1 is integrated, which include several proteins known to be associated with Cajal bodies and DNA damage responses. Several hereditary distal neurological diseases are a consequence of pathogenic variants in genes that alter these cellular functions. We conclude that VRK1-related distal hereditary neuropathies and motor neuron diseases represent a novel subgroup of Cajal body related neurological syndromes.}, }
@article {pmid37256332, year = {2023}, author = {Tayebi, H and Azadnajafabad, S and Maroufi, SF and Pour-Rashidi, A and Khorasanizadeh, M and Faramarzi, S and Slavin, KV}, title = {Applications of brain-computer interfaces in neurodegenerative diseases.}, journal = {Neurosurgical review}, volume = {46}, number = {1}, pages = {131}, pmid = {37256332}, issn = {1437-2320}, mesh = {Humans ; *Brain-Computer Interfaces ; Electroencephalography/methods ; *Neurodegenerative Diseases/therapy ; Brain ; Central Nervous System ; }, abstract = {Brain-computer interfaces (BCIs) provide the central nervous system with channels of direct communication to the outside world, without having to go through the peripheral nervous system. Neurodegenerative diseases (NDs) are notoriously incurable and burdensome medical conditions that will result in progressive deterioration of the nervous system. The applications of BCIs in NDs have been studied for decades now through different approaches, resulting in a considerable amount of literature in all related areas. In this study, we begin by introducing BCIs and proceed by explaining the principles of BCI-based neurorehabilitation. Then, we go through four specific types of NDs, including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and spinal muscular atrophy, and review some of the applications of BCIs in the neural rehabilitation of these diseases. We conclude with a discussion of the characteristics, challenges, and future possibilities of research in the field. Going through the uses of BCIs in NDs, we can see that approaches and strategies employed to tackle the wide range of limitations caused by NDs are numerous and diverse. Furthermore, NDs can fall under different categories based on the target area of neurodegeneration and thus require different methods of BCI-based rehabilitation. In recent years, neurotechnology companies have substantially invested in research on BCIs, focusing on commercializing BCIs and bringing BCI-based technologies from bench to bedside. This can mean the beginning of a new era for BCI-based neurorehabilitation, with an anticipated spike in interest among researchers, practitioners, engineers, and entrepreneurs alike.}, }
@article {pmid37254833, year = {2023}, author = {White, S and O'Cathain, A and Halliday, V and Croot, L and McDermott, CJ}, title = {Factors influencing decisions people with motor neuron disease make about gastrostomy placement and ventilation: A qualitative evidence synthesis.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {26}, number = {4}, pages = {1418-1435}, pmid = {37254833}, issn = {1369-7625}, support = {NIHR301592//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Gastrostomy/psychology ; Quality of Life ; *Motor Neuron Disease/therapy/complications/psychology ; Health Personnel ; Caregivers/psychology ; }, abstract = {BACKGROUND: People with motor neuron disease (pwMND) are routinely offered gastrostomy feeding tube placement and (non-invasive and invasive) ventilation to manage the functional decline associated with the disease. This study aimed to synthesise the findings from the qualitative literature to understand how individual, clinical team and organisational factors influence pwMND decisions about these interventions.<br><br>METHODS: The study design was guided by the enhancing transparency in reporting the synthesis of qualitative research (ENTREC) statement. The search of five bibliography databases and an extensive supplementary search strategy identified 27 papers that included qualitative accounts of pwMND, caregivers and healthcare professionals' (HCPs) experiences of making decisions about gastrostomy and ventilation. The findings from each study were included in a thematic synthesis.<br><br>FINDINGS: Making decisions about interventions is an emotional rather than simply a functional issue for pwMND. The interventions can signal an end to normality, and increasing dependence, where pwMND consider the balance between quality of life and extending survival. Interactions with multiple HCPs and caregivers can influence the process of decision-making and the decisions made. These interactions contribute to the autonomy pwMND are able to exert during decision-making. HCPs can both promote and threaten pwMND perceived agency over decisions through how they approach discussions about these interventions. Though there is uncertainty over the timing of interventions, pwMND who agree to interventions report reaching a tipping point where they accept the need for change.<br><br>CONCLUSION: Discussion of gastrostomy and ventilation options generate an emotional response in pwMND. Decisions are the consequence of interactions with multiple external agents, including HCPs treading a complex ethical path when trying to improve health outcomes while respecting pwMND right to autonomy. Future decision support interventions that address the emotional response and seek to support autonomy have the potential to enable pwMND to make informed and timely decisions about gastrostomy placement and ventilation.<br><br>The lead author collaborated with several patient and participant involvement (PPI) groups with regards to the conceptualisation and design of this project. Decisions that have been influenced by discussions with multiple PPI panels include widening the scope of decisions about ventilation in addition to gastrostomy placement and the perceptions of all stakeholders involved (i.e., pwMND, caregivers and HCPs).}, }
@article {pmid37253318, year = {2023}, author = {Liu, W and Ma, R and Sun, C and Xu, Y and Liu, Y and Hu, J and Ma, Y and Wang, D and Wen, D and Yu, Y}, title = {Implications from proteomic studies investigating circadian rhythm disorder-regulated neurodegenerative disease pathology.}, journal = {Sleep medicine reviews}, volume = {70}, number = {}, pages = {101789}, doi = {10.1016/j.smrv.2023.101789}, pmid = {37253318}, issn = {1532-2955}, mesh = {Humans ; *Neurodegenerative Diseases ; Proteomics ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Chronobiology Disorders ; Circadian Rhythm/genetics ; }, abstract = {Neurodegenerative diseases (NDs) affect 15% of the world's population and are becoming an increasingly common cause of morbidity and mortality worldwide. Circadian rhythm disorders (CRDs) have been reported to be involved in the pathogenic regulation of various neurologic diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Proteomic technology is helpful to explore treatment targets for CRDs in patients with NDs. Here, we review the key differentially expressed (DE) proteins identified in previous proteomic studies investigating NDs, CRDs and associated models and the related pathways identified by enrichment analysis. Furthermore, we summarize the advantages and disadvantages of the above studies and propose new proteomic technologies for the precise study of circadian disorder-mediated regulation of ND pathology. This review provides a theoretical and technical reference for the precise study of circadian disorder-mediated regulation of ND pathology.}, }
@article {pmid37250416, year = {2023}, author = {Wang, H and Guan, L and Deng, M}, title = {Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1170996}, pmid = {37250416}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. The causes of ALS are not fully understood. About 10% of ALS cases were associated with genetic factors. Since the discovery of the first familial ALS pathogenic gene SOD1 in 1993 and with the technology advancement, now over 40 ALS genes have been found. Recent studies have identified ALS related genes including ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. These genetic discoveries contribute to a better understanding of ALS and show the potential to aid the development of better ALS treatments. Besides, several genes appear to be associated with other neurological disorders, such as CCNF and ANXA11 linked to FTD. With the deepening understanding of the classic ALS genes, rapid progress has been made in gene therapies. In this review, we summarize the latest progress on classical ALS genes and clinical trials for these gene therapies, as well as recent findings on newly discovered ALS genes.}, }
@article {pmid37249667, year = {2023}, author = {Nourelden, AZ and Kamal, I and Hagrass, AI and Tawfik, AG and Elhady, MM and Fathallah, AH and Eshag, MME and Zaazouee, MS}, title = {Safety and efficacy of edaravone in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3429-3442}, pmid = {37249667}, issn = {1590-3478}, mesh = {United States ; Humans ; Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/chemically induced ; Prospective Studies ; Quality of Life ; Severity of Illness Index ; }, abstract = {AIM: The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research.<br><br>METHODS: We conducted a comprehensive search of the Embase, PubMed, Cochrane Library, Web of Science, and Scopus databases for randomized controlled trials and observational studies up until September 2022. We evaluated the studies' quality using the Cochrane risk of bias tool and the National Institutes of Health tool.<br><br>RESULTS: We included 11 studies with 2845 ALS patients. We found that edaravone improved the survival rate at 18, 24, and 30&#xa0;months (risk ratio (RR)&#x2009;=&#x2009;1.03, 95% confidence interval (CI) [1.02 to 1.24], P&#x2009;=&#x2009;0.02), (RR&#x2009;=&#x2009;1.22, 95% CI [1.06 to 1.41], P&#x2009;=&#x2009;0.007), and (RR&#x2009;=&#x2009;1.17, 95% CI [1.01 to 1.34], P&#x2009;=&#x2009;0.03), respectively. However, the administration of edaravone did not result in any significant difference in adverse effects or efficacy outcomes between the two groups, as indicated by a P value greater than 0.05.<br><br>CONCLUSION: Edaravone improves survival rates of ALS patients at 18, 24, and 30&#xa0;months with no adverse effects. However, edaravone does not affect functional outcomes. In order to ensure the validity of our findings and assess the results in accordance with the disease stage, it is essential to carry out additional prospective, rigorous, and high-quality clinical trials. The current study offers preliminary indications regarding the effectiveness and safety of edaravone. However, further comprehensive research is required to establish the generalizability and sustainability of the findings.}, }
@article {pmid37248728, year = {2023}, author = {Young, HM and Kilaberia, TR and Whitney, R and Link, BM and Bell, JF and Tonkikh, O and Famula, J and Oskarsson, B}, title = {Needs of persons living with ALS at home and their family caregivers: A scoping review.}, journal = {Muscle &amp; nerve}, volume = {68}, number = {3}, pages = {240-249}, doi = {10.1002/mus.27849}, pmid = {37248728}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Caregivers/psychology ; Cross-Sectional Studies ; *Home Care Services ; Emotions ; }, abstract = {INTRODUCTION/AIMS: Most persons with amyotrophic lateral sclerosis (ALS) live at home with support of family caregivers, with escalating complexity of care over the trajectory of the disease requiring resources and support to mitigate negative physical, social, and emotional outcomes.<br><br>METHODS: This scoping review identifies the home health/home care needs of persons with ALS and their caregivers as a basis for creating a home health medical standard. We used the PRISMA Extension for Scoping Reviews (PRISMA-ScR) to examine studies describing home care needs published between 2011 and 2021.<br><br>RESULTS: Our search yielded 481 articles, of which 44 were included with a total of 3592 (9-273) participants. Most studies used a cross-sectional design and 20 (45%) were rated as high quality. We grouped the needs identified as emotional/psychological, assistive devices and technology, information and education, and human resources and professional services. Most studies demonstrated persistent unmet needs and that available interventions were helpful while needs generally were not met proactively, despite the predictable trajectory.<br><br>DISCUSSION: This review describes biopsychosocial and equipment interventions over the trajectory of ALS with implications for anticipatory planning by clinicians, as well as policy for coverage of necessary services and supports. Interdisciplinary expert teams could develop consensus around needs across the trajectory and recommended services and supports. To make knowledge more accessible, encourage availability of services, and clarify the need for coverage of services, we aim to develop an expert consensus-based ALS home health medical standard guidance document in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine.}, }
@article {pmid37247505, year = {2023}, author = {Moreno, R and Recio, J and Barber, S and Gil, C and Martinez, A}, title = {The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies.}, journal = {European journal of medicinal chemistry}, volume = {257}, number = {}, pages = {115511}, doi = {10.1016/j.ejmech.2023.115511}, pmid = {37247505}, issn = {1768-3254}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; MAP Kinase Kinase Kinases ; Cell Death ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {Selective and brain-permeable protein kinase inhibitors are in preclinical development for treating neurodegenerative diseases. Among them, MLK3 inhibitors, with a potent neuroprotective biological action have emerged as valuable agents for the treatment of pathologies such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis. In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment.}, }
@article {pmid37245265, year = {2023}, author = {Biglari, N and Mehdizadeh, A and Vafaei Mastanabad, M and Gharaeikhezri, MH and Gol Mohammad Pour Afrakoti, L and Pourbala, H and Yousefi, M and Soltani-Zangbar, MS}, title = {Application of mesenchymal stem cells (MSCs) in neurodegenerative disorders: History, findings, and prospective challenges.}, journal = {Pathology, research and practice}, volume = {247}, number = {}, pages = {154541}, doi = {10.1016/j.prp.2023.154541}, pmid = {37245265}, issn = {1618-0631}, mesh = {Humans ; Prospective Studies ; *Neurodegenerative Diseases/metabolism/therapy ; *Mesenchymal Stem Cells/metabolism ; *Parkinson Disease ; *Alzheimer Disease/metabolism ; }, abstract = {Over the past few decades, the application of mesenchymal stem cells has captured the attention of researchers and practitioners worldwide. These cells can be obtained from practically every tissue in the body and are used to treat a broad variety of conditions, most notably neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Studies are still being conducted, and the results of these studies have led to the identification of several different molecular pathways involved in the neuroglial speciation process. These molecular systems are closely regulated and interconnected due to the coordinated efforts of many components that make up the machinery responsible for cell signaling. Within the scope of this study, we compared and contrasted the numerous mesenchymal cell sources and their cellular features. These many sources of mesenchymal cells included adipocyte cells, fetal umbilical cord tissue, and bone marrow. In addition, we investigated whether these cells can potentially treat and modify neurodegenerative illnesses.}, }
@article {pmid37243319, year = {2023}, author = {Elmansy, MF and Reidl, CT and Rahaman, M and Özdinler, PH and Silverman, RB}, title = {Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis.}, journal = {Medicinal research reviews}, volume = {43}, number = {6}, pages = {2260-2302}, pmid = {37243319}, issn = {1098-1128}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Neurodegenerative Diseases/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP-43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.}, }
@article {pmid37240836, year = {2023}, author = {Barbieri, R and Nizzari, M and Zanardi, I and Pusch, M and Gavazzo, P}, title = {Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {5}, pages = {}, pmid = {37240836}, issn = {2075-1729}, abstract = {The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively, are important players in the initiation and propagation of action potentials and in turn of the neural network activity. In the context of neurological diseases, mutations in the genes encoding Nav1.1, 1.2, 1.3 and 1.6 are responsible for many forms of genetic epilepsy and for Nav1.1 also of hemiplegic migraine. Several pharmacological therapeutic approaches targeting these channels are used or are under study. Mutations of genes encoding VGSCs are also involved in autism and in different types of even severe intellectual disability (ID). It is conceivable that in these conditions their dysfunction could indirectly cause a certain level of neurodegenerative processes; however, so far, these mechanisms have not been deeply investigated. Conversely, VGSCs seem to have a modulatory role in the most common neurodegenerative diseases such as Alzheimer's, where SCN8A expression has been shown to be negatively correlated with disease severity.}, }
@article {pmid37240459, year = {2023}, author = {Carlucci, A and Fusar Poli, B}, title = {Getting It Right in Restrictive Lung Disease.}, journal = {Journal of clinical medicine}, volume = {12}, number = {10}, pages = {}, pmid = {37240459}, issn = {2077-0383}, abstract = {Restrictive lung disease (predominantly in patients with neuromuscular disease (NMD) and ribcage deformity) may induce chronic hypercapnic respiratory failure, which represents an absolute indication to start home NIV (HNIV). However, in the early phases of NMD, patients may present only diurnal symptoms or orthopnoea and sleep disturbances with normal diurnal gas exchange. The evaluation of respiratory function decline may predict the presence of sleep disturbances (SD) and nocturnal hypoventilation that can be respectively diagnosed with polygraphy and PCO2 transcutaneous monitoring. If nocturnal hypoventilation and/or apnoea/hypopnea syndrome are detected, HNIV should be introduced. Once HNIV has been started, adequate follow-up is mandatory. The ventilator's built-in software provides important information about patient adherence and eventual leaks to correct. Detailed data about pressure and flow curves may suggest the presence of upper airway obstruction (UAO) during NIV that may occur with or without decrease in respiratory drive. Etiology and treatment of these two different forms of UAO are different. For this reason, in some circumstances, it might be useful to perform a polygraph. PtCO2 monitoring, together with pulse-oximetry, seem to be very important tools to optimize HNIV. The role of HNIV in neuromuscular disease is to correct diurnal and nocturnal hypoventilation with the consequence of improving quality of life, symptoms, and survival.}, }
@article {pmid37240368, year = {2023}, author = {Singh, J and Goodman-Vincent, E and Santosh, P}, title = {Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders-Implications for Individuals with Rett Syndrome: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37240368}, issn = {1422-0067}, support = {RE16403//Reverse Rett/ ; RE16403//Reverse Rett/ ; }, mesh = {Humans ; *Rett Syndrome/therapy/drug therapy ; Gene Editing ; Tissue Distribution ; Methyl-CpG-Binding Protein 2/genetics/metabolism ; Brain/metabolism ; Genetic Therapy ; }, abstract = {This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.}, }
@article {pmid37240018, year = {2023}, author = {Pardo-Moreno, T and Mohamed-Mohamed, H and Suleiman-Martos, S and Ramos-Rodriguez, JJ and Rivas-Dominguez, A and Melguizo-Rodríguez, L and Gómez-Urquiza, JL and Bermudez-Pulgarin, B and Garcia-Morales, V}, title = {Amyotrophic Lateral Sclerosis and Serum Lipid Level Association: A Systematic Review and Meta-Analytic Study.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37240018}, issn = {1422-0067}, support = {P18-RT-3324//Regional Government of Andalusia/ ; 20-01293 and PECART-0096-2020//Regional Government of Andalusia/ ; P20-01061//Regional Government of Andalusia/ ; PID2019-110960GB-I00//Ministry of Science and Innovation, Spain/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Triglycerides ; Cholesterol, HDL ; Cholesterol, LDL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. Many metabolic alterations occur during ALS progress and can be used as a method of pre-diagnostic and early diagnosis. Dyslipidemia is one of the physiological changes observed in numerous ALS patients. The aim of this study is to analyze the possible relationship between the rate of disease progression (functional rating scale (ALS-FRS)) and the plasma lipid levels at the early stage of ALS. A systematic review was carried out in July 2022. The search equation was "Triglycerides AND amyotrophic lateral sclerosis" and its variants. Four meta-analyses were performed. Four studies were included in the meta-analysis. No significant differences were observed between the lipid levels (total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol) and the ALS-FRS score at the onset of the disease. Although the number of studies included in this research was low, the results of this meta-analytic study suggest that there is no clear relationship between the symptoms observed in ALS patients and the plasma lipid levels. An increase in research, as well as an expansion of the geographical area, would be of interest.}, }
@article {pmid37238732, year = {2023}, author = {Maksimovic, K and Youssef, M and You, J and Sung, HK and Park, J}, title = {Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.}, journal = {Biomolecules}, volume = {13}, number = {5}, pages = {}, pmid = {37238732}, issn = {2218-273X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Models, Animal ; Glucose/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.}, }
@article {pmid37238605, year = {2023}, author = {Zhang, H and Dai, S and Yang, Y and Wei, J and Li, X and Luo, P and Jiang, X}, title = {Role of Sirtuin 3 in Degenerative Diseases of the Central Nervous System.}, journal = {Biomolecules}, volume = {13}, number = {5}, pages = {}, pmid = {37238605}, issn = {2218-273X}, mesh = {Humans ; Central Nervous System/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; *Sirtuin 3/metabolism ; }, abstract = {An NAD[+]-dependent deacetylase called Sirtuin 3 (Sirt3) is involved in the metabolic processes of the mitochondria, including energy generation, the tricarboxylic acid cycle, and oxidative stress. Sirt3 activation can slow down or prevent mitochondrial dysfunction in response to neurodegenerative disorders, demonstrating a strong neuroprotective impact. The mechanism of Sirt3 in neurodegenerative illnesses has been elucidated over time; it is essential for neuron, astrocyte, and microglial function, and its primary regulatory factors include antiapoptosis, oxidative stress, and the maintenance of metabolic homeostasis. Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), may benefit from a thorough and in-depth investigation of Sirt3. In this review, we primarily cover Sirt3's role and its regulation in the nerve cells and the connection between Sirt3 and neurodegenerative disorders.}, }
@article {pmid37231108, year = {2023}, author = {Berriat, F and Lobsiger, CS and Boillée, S}, title = {The contribution of the peripheral immune system to neurodegeneration.}, journal = {Nature neuroscience}, volume = {26}, number = {6}, pages = {942-954}, pmid = {37231108}, issn = {1546-1726}, mesh = {Humans ; Central Nervous System ; *Alzheimer Disease/metabolism ; *Neurodegenerative Diseases/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Leukocytes/metabolism ; }, abstract = {Microglial cells are the major immune cells of the central nervous system (CNS), and directly react to neurodegeneration, but other immune cell types are also able to react to pathology and can modify the course of neurodegenerative processes. These mainly include monocytes/macrophages and lymphocytes. While these peripheral immune cells were initially considered to act only after infiltrating the CNS, recent evidence suggests that some of them can also act directly from the periphery. We will review the existing and emerging evidence for a role of peripheral immune cells in neurodegenerative diseases, both with and without CNS infiltration. Our focus will be on amyotrophic lateral sclerosis, but we will also compare to Alzheimer's disease and Parkinson's disease to highlight similarities or differences. Peripheral immune cells are easily accessible, and therefore may be an attractive therapeutic target for neurodegenerative diseases. Thus, understanding how these peripheral immune cells communicate with the CNS deserves deeper investigation.}, }
@article {pmid37219417, year = {2023}, author = {Sales de Campos, P and Olsen, WL and Wymer, JP and Smith, BK}, title = {Respiratory therapies for Amyotrophic Lateral Sclerosis: A state of the art review.}, journal = {Chronic respiratory disease}, volume = {20}, number = {}, pages = {14799731231175915}, pmid = {37219417}, issn = {1479-9731}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Respiration, Artificial ; Cough ; Hypoxia ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition noteworthy for upper and lower motor neuron death. Involvement of respiratory motor neuron pools leads to progressive pathology. These impairments include decreases in neural activation and muscle coordination, progressive airway obstruction, weakened airway defenses, restrictive lung disease, increased risk of pulmonary infections, and weakness and atrophy of respiratory muscles. These neural, airway, pulmonary, and neuromuscular changes deteriorate integrated respiratory-related functions including sleep, cough, swallowing, and breathing. Ultimately, respiratory complications account for a large portion of morbidity and mortality in ALS. This state-of-the-art review highlights applications of respiratory therapies for ALS, including lung volume recruitment, mechanical insufflation-exsufflation, non-invasive ventilation, and respiratory strength training. Therapeutic acute intermittent hypoxia, an emerging therapeutic tool for inducing respiratory plasticity will also be introduced. A focus on emerging evidence and future work underscores the common goal to continue to improve survival for patients living with ALS.}, }
@article {pmid37217723, year = {2023}, author = {Nguyen, TT and Nguyen-Thi, PT and Nguyen, THA and Ho, TT and Tran, NM and Van Vo, T and Van Vo, G}, title = {Recent Advancements in Nanomaterials: A Promising Way to Manage Neurodegenerative Disorders.}, journal = {Molecular diagnosis &amp; therapy}, volume = {27}, number = {4}, pages = {457-473}, pmid = {37217723}, issn = {1179-2000}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Alzheimer Disease/diagnosis/drug therapy ; Brain/metabolism ; Blood-Brain Barrier/metabolism ; *Nanoparticles/therapeutic use/chemistry ; }, abstract = {Neurodegenerative diseases (NDs) such as dementia, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis are some of the most prevalent disorders currently afflicting healthcare systems. Many of these diseases share similar pathological hallmarks, including elevated oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity, and neuroinflammation, all of which contribute to the deterioration of the nervous system's structure and function. The development of diagnostic and therapeutic materials in the monitoring and treatment of these diseases remains challenging. One of the biggest challenges facing therapeutic and diagnostic materials is the blood-brain barrier (BBB). The BBB is a multifunctional membrane possessing a plethora of biochemical, cellular, and immunological features that ensure brain homeostasis by preventing the entry and accumulation of unwanted compounds. With regards to neurodegenerative diseases, the recent application of tailored nanomaterials (nanocarriers and nanoparticles) has led to advances in diagnostics and therapeutics. In this review, we provide an overview of commonly used nanoparticles and their applications in NDs, which may offer new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, }
@article {pmid37209406, year = {2023}, author = {Gwathmey, KG and Corcia, P and McDermott, CJ and Genge, A and Sennfält, S and de Carvalho, M and Ingre, C}, title = {Diagnostic delay in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {9}, pages = {2595-2601}, doi = {10.1111/ene.15874}, pmid = {37209406}, issn = {1468-1331}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; *Neurodegenerative Diseases ; Retrospective Studies ; *General Practitioners ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease-modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater.<br><br>METHODS: We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey.<br><br>RESULTS: Diagnostic delay is influenced by general practitioners' lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non-neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior-which impacts diagnostic delay-and their site of symptom onset. Limb-onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy.<br><br>CONCLUSION: Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease-modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non-neurologists and unnecessary diagnostic workup.}, }
@article {pmid37207075, year = {2023}, author = {Sato, K and Takayama, KI and Inoue, S}, title = {Role of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1157818}, pmid = {37207075}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by neuronal loss and dysfunction. Despite remarkable improvements in our understanding of these pathogeneses, serious worldwide problems with significant public health burdens are remained. Therefore, new efficient diagnostic and therapeutic strategies are urgently required. PIWI-interacting RNAs (piRNAs) are a major class of small non-coding RNAs that silence gene expression through transcriptional and post-transcriptional processes. Recent studies have demonstrated that piRNAs, originally found in the germ line, are also produced in non-gonadal somatic cells, including neurons, and further revealed the emerging roles of piRNAs, including their roles in neurodevelopment, aging, and neurodegenerative diseases. In this review, we aimed to summarize the current knowledge regarding the piRNA roles in the pathophysiology of neurodegenerative diseases. In this context, we first reviewed on recent updates on neuronal piRNA functions, including biogenesis, axon regeneration, behavior, and memory formation, in humans and mice. We also discuss the aberrant expression and dysregulation of neuronal piRNAs in neurodegenerative diseases, such as AD, PD, and ALS. Moreover, we review pioneering preclinical studies on piRNAs as biomarkers and therapeutic targets. Elucidation of the mechanisms underlying piRNA biogenesis and their functions in the brain would provide new perspectives for the clinical diagnosis and treatment of AD and various neurodegenerative diseases.}, }
@article {pmid37196683, year = {2023}, author = {Prasad Panda, S and Kesharwani, A and Prasanna Mallick, S and Prasanth, D and Kumar Pasala, P and Bharadwaj Tatipamula, V}, title = {Viral-induced neuronal necroptosis: Detrimental to brain function and regulation by necroptosis inhibitors.}, journal = {Biochemical pharmacology}, volume = {213}, number = {}, pages = {115591}, doi = {10.1016/j.bcp.2023.115591}, pmid = {37196683}, issn = {1873-2968}, mesh = {Humans ; *Protein Kinases/metabolism ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Necroptosis ; Neuroinflammatory Diseases ; Apoptosis ; Necrosis ; Caspase 1/metabolism ; Receptors, Death Domain/metabolism ; Interleukin-1/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism ; *MicroRNAs ; }, abstract = {Neuronal necroptosis (programmed necrosis) in the CNS naturally occurs through a caspase-independent way and, especially in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parknson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and viral infections. Understanding necroptosis pathways (death receptor-dependent and independent), and its connections with other cell death pathways could lead to new insights into treatment. Receptor-interacting protein kinase (RIPK) mediates necroptosis via mixed-lineage kinase-like (MLKL) proteins. RIPK/MLKL necrosome contains FADD, procaspase-8-cellular FLICE-inhibitory proteins (cFLIPs), RIPK1/RIPK3, and MLKL. The necrotic stimuli cause phosphorylation of MLKL and translocate to the plasma membrane, causing an influx of Ca[2+] and Na[+] ions and, the immediate opening of mitochondrial permeability transition pore (mPTP) with the release of inflammatory cell damage-associated molecular patterns (DAMPs) like mitochondrial DNA (mtDNA), high-mobility group box1 (HMGB1), and interleukin1 (IL-1). The MLKL translocates to the nucleus to induce transcription of the NLRP3 inflammasome complex elements. MLKL-induced NLRP3 activity causes caspase-1 cleavage and, IL-1 activation which promotes neuroinflammation. RIPK1-dependent transcription increases illness-associated microglial and lysosomal abnormalities to facilitate amyloid plaque (Aβ) aggregation in AD. Recent research has linked neuroinflammation and mitochondrial fission with necroptosis. MicroRNAs (miRs) such as miR512-3p, miR874, miR499, miR155, and miR128a regulate neuronal necroptosis by targeting key components of necroptotic pathways. Necroptosis inhibitors act by inhibiting the membrane translocation of MLKL and RIPK1 activity. This review insights into the RIPK/MLKL necrosome-NLRP3 inflammasome interactions during death receptor-dependent and independent neuronal necroptosis, and clinical intervention by miRs to protect the brain from NDDs.}, }
@article {pmid37191604, year = {2023}, author = {Thomson, CG and Hutchinson, PR and Stern, PJ}, title = {Misdiagnosis in Amyotrophic Lateral Sclerosis.}, journal = {The Journal of hand surgery}, volume = {48}, number = {8}, pages = {822-826}, doi = {10.1016/j.jhsa.2023.03.023}, pmid = {37191604}, issn = {1531-6564}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/surgery ; Referral and Consultation ; *Cubital Tunnel Syndrome ; Diagnostic Errors ; Neurosurgical Procedures ; }, abstract = {The symptoms of amyotrophic lateral sclerosis (ALS) can mimic those of compressive neuropathies, such as carpal and cubital tunnel syndromes, especially early in a patient's clinical course. We surveyed members of the American Society for Surgery of the Hand and found that 11% of active and retired members have performed nerve decompression surgeries on patients later diagnosed with ALS. Hand surgeons are commonly the first providers to evaluate patients with undiagnosed ALS. As such, it is important to be aware of the history, signs, and symptoms of ALS to provide an accurate diagnosis and prevent unnecessary morbidities, such as nerve decompression surgery, which invariably results in poor outcomes. The major "red flag" symptoms warranting further work-up include weakness without sensory symptoms, profound weakness and atrophy in multiple nerve distributions, progressively bilateral and global symptoms, presence of bulbar symptoms (such as tongue fasciculations and speech/swallowing difficulties), and, if surgery is performed, failure to improve. If any of these red flags are present, we recommend neurodiagnostic testing and prompt referral to a neurologist for further work-up and treatment.}, }
@article {pmid37191427, year = {2023}, author = {Huang, Y and Zhao, M and Chen, X and Zhang, R and Le, A and Hong, M and Zhang, Y and Jia, L and Zang, W and Jiang, C and Wang, J and Fan, X and Wang, J}, title = {Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies.}, journal = {Aging and disease}, volume = {14}, number = {3}, pages = {858-878}, pmid = {37191427}, issn = {2152-5250}, abstract = {The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders.}, }
@article {pmid37190097, year = {2023}, author = {Dorn, GW}, title = {Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {8}, pages = {}, pmid = {37190097}, issn = {2073-4409}, support = {R42 NS113642/NH/NIH HHS/United States ; R42 NS115184/NH/NIH HHS/United States ; R35 HL135736/NH/NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Apoptosis ; Mitochondria/metabolism ; Mitochondrial Dynamics/physiology ; *Neurodegenerative Diseases/metabolism ; Humans ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform.}, }
@article {pmid37190090, year = {2023}, author = {Sanchez-Tejerina, D and Llaurado, A and Sotoca, J and Lopez-Diego, V and Vidal Taboada, JM and Salvado, M and Juntas-Morales, R}, title = {Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications.}, journal = {Cells}, volume = {12}, number = {8}, pages = {}, pmid = {37190090}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Neurodegenerative Diseases ; Prospective Studies ; Biomarkers/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the "fit-for-purpose" concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.}, }
@article {pmid37189772, year = {2023}, author = {Barker, S and Paul, BD and Pieper, AA}, title = {Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189772}, issn = {2227-9059}, support = {P50 DA044123/DA/NIDA NIH HHS/United States ; R01 AG071512/AG/NIA NIH HHS/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; }, abstract = {Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer's disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease.}, }
@article {pmid37189749, year = {2023}, author = {Reddy, VP and Aryal, P and Soni, P}, title = {RAGE Inhibitors in Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189749}, issn = {2227-9059}, abstract = {Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer's disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood-brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE-RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE-RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE-RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.}, }
@article {pmid37189617, year = {2023}, author = {Chiarini, A and Gui, L and Viviani, C and Armato, U and Dal Prà, I}, title = {NLRP3 Inflammasome's Activation in Acute and Chronic Brain Diseases-An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189617}, issn = {2227-9059}, support = {FUR 2020//Italian Ministry of University &amp; Research/ ; }, abstract = {Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer's disease, Parkinson's disease, Huntington's disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3's and other inflammasomes' regulation, while minimizing failure risks in candidate drug trials.}, }
@article {pmid37186678, year = {2024}, author = {Samanta, S and Chakraborty, S and Bagchi, D}, title = {Pathogenesis of Neurodegenerative Diseases and the Protective Role of Natural Bioactive Components.}, journal = {Journal of the American Nutrition Association}, volume = {43}, number = {1}, pages = {20-32}, doi = {10.1080/27697061.2023.2203235}, pmid = {37186678}, issn = {2769-707X}, mesh = {Humans ; *Neurodegenerative Diseases/prevention &amp; control ; Antioxidants/therapeutic use ; Reactive Oxygen Species/metabolism ; Neuroinflammatory Diseases ; Vitamins ; Flavonoids/pharmacology ; }, abstract = {Neurodegenerative diseases are a serious problem throughout the world. There are several causes of neurodegenerative diseases; these include genetic predisposition, accumulation of misfolded proteins, oxidative stress, neuroinflammation, and excitotoxicity. Oxidative stress increases the production of reactive oxygen species (ROS) that advance lipid peroxidation, DNA damage, and neuroinflammation. The cellular antioxidant system (superoxide dismutase, catalase, peroxidase, and reduced glutathione) plays a crucial role in scavenging free radicals. An imbalance in the defensive actions of antioxidants and overproduction of ROS intensify neurodegeneration. The formation of misfolded proteins, glutamate toxicity, oxidative stress, and cytokine imbalance promote the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Antioxidants are now attractive molecules to fight against neurodegeneration. Certain vitamins (A, E, C) and polyphenolic compounds (flavonoids) show excellent antioxidant properties. Diet is the major source of antioxidants. However, diet medicinal herbs are also rich sources of numerous flavonoids. Antioxidants prevent ROS-mediated neuronal degeneration in post-oxidative stress conditions. The present review is focused on the pathogenesis of neurodegenerative diseases and the protective role of antioxidants. KEY TEACHING POINTSThis review shows that multiple factors are directly or indirectly associated with the pathogenesis of neurodegenerative diseases.Failure to cellular antioxidant capacity increases oxidative stress that intensifies neuroinflammation and disease progression.Different vitamins, carotenoids, and flavonoids, having antioxidant capacity, can be considered protective agents.}, }
@article {pmid37185741, year = {2023}, author = {López-Pingarrón, L and Almeida, H and Soria-Aznar, M and Reyes-Gonzales, MC and Terrón, MP and García, JJ}, title = {Role of Oxidative Stress on the Etiology and Pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and Its Relation with the Enteric Nervous System.}, journal = {Current issues in molecular biology}, volume = {45}, number = {4}, pages = {3315-3332}, pmid = {37185741}, issn = {1467-3045}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the spinal cord, cerebral cortex, and medulla oblongata. Most patients present a clinical phenotype of classic ALS-with predominant atrophy, muscle weakness, and fasciculations-and survival of 3 to 5 years following diagnosis. In the present review, we performed a literature search to provide an update on the etiology and pathophysiological mechanisms involved in ALS. There are two types of ALS: the familial form with genetic involvement, and the sporadic form with a multifactorial origin. ALS pathophysiology is characterized by involvement of multiple processes, including oxidative stress, glutamate excitotoxicity, and neuroinflammation. Moreover, it is proposed that conditioning risk factors affect ALS development, such as susceptibility to neurodegeneration in motor neurons, the intensity of performed physical activity, and intestinal dysbiosis with involvement of the enteric nervous system, which supports the existing theories of disease generation. To improve patients' prognosis and survival, it is necessary to further deepen our understanding of the etiopathogenesis of ALS.}, }
@article {pmid37182892, year = {2023}, author = {Lim, WF and Rinaldi, C}, title = {RNA Transcript Diversity in Neuromuscular Research.}, journal = {Journal of neuromuscular diseases}, volume = {10}, number = {4}, pages = {473-482}, pmid = {37182892}, issn = {2214-3602}, mesh = {Humans ; *RNA Splice Sites ; *Alternative Splicing ; RNA Splicing/genetics ; Exons ; Introns ; }, abstract = {Three decades since the Human Genome Project began, scientists have now identified more then 25,000 protein coding genes in the human genome. The vast majority of the protein coding genes (> 90%) are multi-exonic, with the coding DNA being interrupted by intronic sequences, which are removed from the pre-mRNA transcripts before being translated into proteins, a process called splicing maturation. Variations in this process, i.e. by exon skipping, intron retention, alternative 5' splice site (5'ss), 3' splice site (3'ss), or polyadenylation usage, lead to remarkable transcriptome and proteome diversity in human tissues. Given its critical biological importance, alternative splicing is tightly regulated in a tissue- and developmental stage-specific manner. The central nervous system and skeletal muscle are amongst the tissues with the highest number of differentially expressed alternative exons, revealing a remarkable degree of transcriptome complexity. It is therefore not surprising that splicing mis-regulation is causally associated with a myriad of neuromuscular diseases, including but not limited to amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), and myotonic dystrophy type 1 and 2 (DM1, DM2). A gene's transcript diversity has since become an integral and an important consideration for drug design, development and therapy. In this review, we will discuss transcript diversity in the context of neuromuscular diseases and current approaches to address splicing mis-regulation.}, }
@article {pmid37179826, year = {2023}, author = {Casanova, A and Wevers, A and Navarro-Ledesma, S and Pruimboom, L}, title = {Mitochondria: It is all about energy.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1114231}, pmid = {37179826}, issn = {1664-042X}, abstract = {Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.}, }
@article {pmid37176144, year = {2023}, author = {Valles, SL and Singh, SK and Campos-Campos, J and Colmena, C and Campo-Palacio, I and Alvarez-Gamez, K and Caballero, O and Jorda, A}, title = {Functions of Astrocytes under Normal Conditions and after a Brain Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37176144}, issn = {1422-0067}, mesh = {Humans ; Rats ; Animals ; *Astrocytes/pathology ; Neuroglia/pathology ; Neurons/pathology ; Microglia/physiology ; *Alzheimer Disease/pathology ; }, abstract = {In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS.}, }
@article {pmid37175665, year = {2023}, author = {Khan, AW and Farooq, M and Hwang, MJ and Haseeb, M and Choi, S}, title = {Autoimmune Neuroinflammatory Diseases: Role of Interleukins.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37175665}, issn = {1422-0067}, support = {HN21C1058//Korea Drug Development Fund funded by the Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare/ ; 2022M3A9G1014520, 2023R1A2C2003034, 2019M3D1A1078940, and 2019R1A6A1A11051471//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neuroinflammatory Diseases ; Interleukin-17 ; Interleukin-6 ; Interleukins ; Inflammation/drug therapy ; Cytokines ; Th17 Cells ; Interleukin-1/therapeutic use ; *Autoimmune Diseases ; }, abstract = {Autoimmune neuroinflammatory diseases are a group of disorders resulting from abnormal immune responses in the nervous system, causing inflammation and tissue damage. The interleukin (IL) family of cytokines, especially IL-1, IL-6, and IL-17, plays a critical role in the pathogenesis of these diseases. IL-1 is involved in the activation of immune cells, production of pro-inflammatory cytokines, and promotion of blood-brain barrier breakdown. IL-6 is essential for the differentiation of T cells into Th17 cells and has been implicated in the initiation and progression of neuroinflammation. IL-17 is a potent pro-inflammatory cytokine produced by Th17 cells that plays a crucial role in recruiting immune cells to sites of inflammation. This review summarizes the current understanding of the roles of different interleukins in autoimmune neuroinflammatory diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, neuromyelitis optica, and autoimmune encephalitis, and discusses the potential of targeting ILs as a therapeutic strategy against these diseases. We also highlight the need for further research to better understand the roles of ILs in autoimmune neuroinflammatory diseases and to identify new targets for treating these debilitating diseases.}, }
@article {pmid37174703, year = {2023}, author = {Kinger, S and Dubey, AR and Kumar, P and Jagtap, YA and Choudhary, A and Kumar, A and Prajapati, VK and Dhiman, R and Mishra, A}, title = {Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {9}, pages = {}, pmid = {37174703}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Proteostasis ; Molecular Chaperones/metabolism ; HSP40 Heat-Shock Proteins ; Mutant Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones' involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.}, }
@article {pmid37168679, year = {2023}, author = {Yang, X and Ma, Z and Lian, P and Xu, Y and Cao, X}, title = {Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1172197}, pmid = {37168679}, issn = {1662-5099}, abstract = {Many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins and abnormal localization of organelles. These pathological features may be related to axonal transport deficits in neurons, which lead to failures in pathological protein targeting to specific sites for degradation and organelle transportation to designated areas needed for normal physiological functioning. Axonal transport deficits are most likely early pathological events in such diseases and gradually lead to the loss of axonal integrity and other degenerative changes. In this review, we investigated reports of mechanisms underlying the development of axonal transport deficits in a variety of common neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease to provide new ideas for therapeutic targets that may be used early in the disease process. The mechanisms can be summarized as follows: (1) motor protein changes including expression levels and post-translational modification alteration; (2) changes in microtubules including reducing stability and disrupting tracks; (3) changes in cargoes including diminished binding to motor proteins. Future studies should determine which axonal transport defects are disease-specific and whether they are suitable therapeutic targets in neurodegenerative diseases.}, }
@article {pmid37167080, year = {2023}, author = {Gold, ND and Mallard, AJ and Hermann, JC and Zeifman, RJ and Pagni, BA and Bogenschutz, MP and Ross, S}, title = {Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of palliative medicine}, volume = {26}, number = {10}, pages = {1408-1418}, doi = {10.1089/jpm.2022.0604}, pmid = {37167080}, issn = {1557-7740}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Hallucinogens/therapeutic use ; *Neurodegenerative Diseases ; *Motor Neuron Disease ; *Ketamine ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is an aggressive, terminal neurodegenerative disease that causes death of motor neurons and has an average survival time of 3-4 years. ALS is the most common motor neuron degenerative disease and is increasing in prevalence. There is a pressing need for more effective ALS treatments as available pharmacotherapies do not reverse disease progression or provide substantial clinical benefit. Furthermore, despite psychological distress being highly prevalent in ALS patients, psychological treatments remain understudied. Psychedelics (i.e., serotonergic psychedelics and related compounds like ketamine) have seen a resurgence of research into therapeutic applications for treating a multitude of neuropsychiatric conditions, including psychiatric and existential distress in life-threatening illnesses. Methods: We conducted a narrative review to examine the potential of psychedelic assisted-psychotherapy (PAP) to alleviate psychiatric and psychospiritual distress in ALS. We also discussed the safety of using psychedelics in this population and proposed putative neurobiological mechanisms that may therapeutically intervene on ALS neuropathology. Results: PAP has the potential to treat psychological dimensions and may also intervene on neuropathological dimensions of ALS. Robust improvements in psychiatric and psychospiritual distress from PAP in other populations provide a strong rationale for utilizing this therapy to treat ALS-related psychiatric and existential distress. Furthermore, relevant neuroprotective properties of psychedelics warrant future preclinical trials to investigate this area in ALS models. Conclusion: PAP has the potential to serve as an effective treatment in ALS. Given the lack of effective treatment options, researchers should rigorously explore this therapy for ALS in future trials.}, }
@article {pmid37166702, year = {2023}, author = {Malar, DS and Thitilertdecha, P and Ruckvongacheep, KS and Brimson, S and Tencomnao, T and Brimson, JM}, title = {Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.}, journal = {CNS drugs}, volume = {37}, number = {5}, pages = {399-440}, pmid = {37166702}, issn = {1179-1934}, mesh = {Humans ; *Receptors, sigma/metabolism/therapeutic use ; *Amyotrophic Lateral Sclerosis ; Neurons/metabolism ; *Huntington Disease ; *Neurodevelopmental Disorders/drug therapy/metabolism ; }, abstract = {The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.}, }
@article {pmid37162686, year = {2023}, author = {Mangrulkar, SV and Wankhede, NL and Kale, MB and Upaganlawar, AB and Taksande, BG and Umekar, MJ and Anwer, MK and Dailah, HG and Mohan, S and Behl, T}, title = {Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.}, journal = {Neurotoxicity research}, volume = {41}, number = {6}, pages = {708-729}, pmid = {37162686}, issn = {1476-3524}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; DNA, Mitochondrial/genetics/metabolism/therapeutic use ; Oxidative Stress ; Aging ; }, abstract = {Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.}, }
@article {pmid37153665, year = {2023}, author = {Hong, D and Zhang, C and Wu, W and Lu, X and Zhang, L}, title = {Modulation of the gut-brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1133546}, pmid = {37153665}, issn = {1664-2295}, abstract = {There are trillions of different microorganisms in the human digestive system. These gut microbes are involved in the digestion of food and its conversion into the nutrients required by the body. In addition, the gut microbiota communicates with other parts of the body to maintain overall health. The connection between the gut microbiota and the brain is known as the gut-brain axis (GBA), and involves connections via the central nervous system (CNS), the enteric nervous system (ENS), and endocrine and immune pathways. The gut microbiota regulates the central nervous system bottom-up through the GBA, which has prompted researchers to pay considerable attention to the potential pathways by which the gut microbiota might play a role in the prevention and treatment of amyotrophic lateral sclerosis (ALS). Studies with animal models of ALS have shown that dysregulation of the gut ecology leads to dysregulation of brain-gut signaling. This, in turn, induces changes in the intestinal barrier, endotoxemia, and systemic inflammation, which contribute to the development of ALS. Through the use of antibiotics, probiotic supplementation, phage therapy, and other methods of inducing changes in the intestinal microbiota that can inhibit inflammation and delay neuronal degeneration, the clinical symptoms of ALS can be alleviated, and the progression of the disease can be delayed. Therefore, the gut microbiota may be a key target for effective management and treatment of ALS.}, }
@article {pmid37150307, year = {2023}, author = {Westi, EW and Andersen, JV and Aldana, BI}, title = {Using stable isotope tracing to unravel the metabolic components of neurodegeneration: Focus on neuron-glia metabolic interactions.}, journal = {Neurobiology of disease}, volume = {182}, number = {}, pages = {106145}, doi = {10.1016/j.nbd.2023.106145}, pmid = {37150307}, issn = {1095-953X}, mesh = {*Neuroglia ; *Neurons/metabolism ; Astrocytes/metabolism ; Synaptic Transmission ; Isotopes/metabolism ; }, abstract = {Disrupted brain metabolism is a critical component of several neurodegenerative diseases. Energy metabolism of both neurons and astrocytes is closely connected to neurotransmitter recycling via the glutamate/GABA-glutamine cycle. Neurons and astrocytes hereby work in close metabolic collaboration which is essential to sustain neurotransmission. Elucidating the mechanistic involvement of altered brain metabolism in disease progression has been aided by the advance of techniques to monitor cellular metabolism, in particular by mapping metabolism of substrates containing stable isotopes, a technique known as isotope tracing. Here we review key aspects of isotope tracing including advantages, drawbacks and applications to different cerebral preparations. In addition, we narrate how isotope tracing has facilitated the discovery of central metabolic features in neurodegeneration with a focus on the metabolic cooperation between neurons and astrocytes.}, }
@article {pmid37143081, year = {2023}, author = {Fisher, EMC and Greensmith, L and Malaspina, A and Fratta, P and Hanna, MG and Schiavo, G and Isaacs, AM and Orrell, RW and Cunningham, TJ and Arozena, AA}, title = {Opinion: more mouse models and more translation needed for ALS.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {30}, pmid = {37143081}, issn = {1750-1326}, support = {223022/Z/21//WT_/Wellcome Trust/United Kingdom ; MR/S005021/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; 107116/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; Mutation ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potential therapies have been developed mainly using a limited set of mouse models, and through lack of alternatives, in the past these have been tested on patients regardless of aetiology. Cancer researchers have undertaken therapy development with similar challenges; they have responded by producing complex mouse models that have transformed understanding of pathological processes, and they have implemented patient stratification in multi-centre trials, leading to the effective translation of basic research findings to the clinic. ALS researchers have successfully adopted this combined approach, and now to increase our understanding of key disease pathologies, and our rate of progress for moving from mouse models to mechanism to ALS therapies we need more, innovative, complex mouse models to address specific questions.}, }
@article {pmid37138438, year = {2024}, author = {Barbero Mazzucca, C and Cappellano, G and Chiocchetti, A}, title = {Nutrition, Immunity and Aging: Current Scenario and Future Perspectives in Neurodegenerative Diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {23}, number = {5}, pages = {573-587}, pmid = {37138438}, issn = {1996-3181}, support = {//Fondazione Cariplo/ ; }, mesh = {Humans ; *Aging/immunology/physiology ; *Neurodegenerative Diseases/immunology ; Inflammation ; Alzheimer Disease/immunology ; Nutritional Status ; Amyotrophic Lateral Sclerosis/immunology ; Parkinson Disease/immunology ; Animals ; Immunity/physiology ; }, abstract = {Aging is a gradual decline of physiological function and tissue homeostasis and, in many instances, is related to increased (neuro)-degeneration, together with inflammation, becoming one of the most important risks for developing neurodegenerative diseases. Certain individual nutrients or foods in combination may counteract aging and associated neurodegenerative diseases by promoting a balance between the pro- and anti-inflammatory responses. Thus, nutrition could represent a powerful modulator of this fine balance, other than a modifiable risk factor to contrast inflammaging. This narrative review explores from a broad perspective the impact of nutrition on the hallmarks of aging and inflammation in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis Syndrome (ALS), starting from nutrients up to single foods and complex dietary patterns.}, }
@article {pmid37137507, year = {2023}, author = {D'Cruz, RF and Kaltsakas, G and Suh, ES and Hart, N}, title = {Quality of life in patients with chronic respiratory failure on home mechanical ventilation.}, journal = {European respiratory review : an official journal of the European Respiratory Society}, volume = {32}, number = {168}, pages = {}, pmid = {37137507}, issn = {1600-0617}, mesh = {Humans ; Respiration, Artificial/adverse effects ; Quality of Life ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; *Neuromuscular Diseases/complications/diagnosis/therapy ; *Pulmonary Disease, Chronic Obstructive/diagnosis/therapy ; *Home Care Services ; }, abstract = {Home mechanical ventilation (HMV) is a treatment for chronic respiratory failure that has shown clinical and cost effectiveness in patients with underlying COPD, obesity-related respiratory failure and neuromuscular disease (NMD). By treating chronic respiratory failure with adequate adherence to HMV, improvement in patient-reported outcomes including health-related quality of life (HRQoL) have been evaluated using general and disease-specific quantitative, semi-qualitative and qualitative methods. However, the treatment response in terms of trajectory of change in HRQoL is not uniform across the restrictive and obstructive disease groups. In this review, the effect of HMV on HRQoL across the domains of symptom perception, physical wellbeing, mental wellbeing, anxiety, depression, self-efficacy and sleep quality in stable and post-acute COPD, rapidly progressive NMD (such as amyotrophic lateral sclerosis), inherited NMD (including Duchenne muscular dystrophy) and obesity-related respiratory failure will be discussed.}, }
@article {pmid37127082, year = {2023}, author = {Nicoletti, A and Baschi, R and Cicero, CE and Iacono, S and Re, VL and Luca, A and Schirò, G and Monastero, R and , }, title = {Sex and gender differences in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis: A narrative review.}, journal = {Mechanisms of ageing and development}, volume = {212}, number = {}, pages = {111821}, doi = {10.1016/j.mad.2023.111821}, pmid = {37127082}, issn = {1872-6216}, mesh = {Male ; Female ; Humans ; *Alzheimer Disease/diagnosis/epidemiology ; *Parkinson Disease/diagnosis/epidemiology/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Sex Factors ; Biomarkers ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), exhibit high phenotypic variability and they are very common in the general population. These diseases are associated with poor prognosis and a significant burden on patients and their caregivers. Although increasing evidence suggests that biological sex is an important factor for the development and phenotypical expression of some NDs, the role of sex and gender in the diagnosis and prognosis of NDs has been poorly explored. Current knowledge relating to sex- and gender-related differences in the epidemiology, clinical features, biomarkers, and treatment of AD, PD, and ALS will be summarized in this narrative review. The cumulative evidence hitherto collected suggests that sex and gender are factors to be considered in explaining the heterogeneity of these NDs. Clarifying the role of sex and gender in AD, PD, and ALS is a key topic in precision medicine, which will facilitate sex-specific prevention and treatment strategies to be implemented in the near future.}, }
@article {pmid37125006, year = {2023}, author = {Patocka, C and Lockey, A and Lauridsen, KG and Greif, R}, title = {Impact of accredited advanced life support course participation on in-hospital cardiac arrest patient outcomes: A systematic review.}, journal = {Resuscitation plus}, volume = {14}, number = {}, pages = {100389}, pmid = {37125006}, issn = {2666-5204}, abstract = {AIM: Advanced life support courses have a clear educational impact; however, it is important to determine whether participation of one or more members of the resuscitation team in an accredited advanced life support course improves in-hospital cardiac arrest patient survival outcomes.<br><br>METHODS: We searched EMBASE.com, Medline, Cochrane and CINAHL from inception to 1 November 2022. Included studies were randomised or non-randomised interventional studies assessing the impact of attendance at accredited life support courses on patient outcomes. Accredited life support courses were classified into 3 contexts: Advanced Life Support (ALS), Neonatal Resuscitation Training (NRT), and Helping Babies Breathe (HBB). Existing systematic reviews were identified for each of the contexts and an adolopment process was pursued. Appropriate risk of bias assessment tools were used across all outcomes. When meta-analysis was appropriate a random-effects model was used to produce a summary of effect sizes for each outcome.<br><br>RESULTS: Of 2714 citations screened, 19 studies (1 ALS; 7 NRT; 11 HBB) were eligible for inclusion. Three systematic reviews which satisfied AMSTAR-2 criteria for methodological quality, included 16 of the studies we identified in our search. Among adult patients all outcomes including return of spontaneous circulation, survival to discharge and survival to 30&#xa0;days were consistently better with accredited ALS training. Among neonatal patients there were reductions in stillbirths and early neonatal mortality.<br><br>CONCLUSION: These results support the recommendation that accredited advanced life support courses, specifically Advanced Life Support, Neonatal Resuscitation Training, and Helping Babies Breathe improve patient outcomes.}, }
@article {pmid37124925, year = {2023}, author = {Banarase, TA and Sammeta, SS and Wankhede, NL and Mangrulkar, SV and Rahangdale, SR and Aglawe, MM and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Kale, MB}, title = {Mitophagy regulation in aging and neurodegenerative disease.}, journal = {Biophysical reviews}, volume = {15}, number = {2}, pages = {239-255}, pmid = {37124925}, issn = {1867-2450}, abstract = {Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.}, }
@article {pmid37123415, year = {2023}, author = {Davidson, K and Pickering, AM}, title = {The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1124907}, pmid = {37123415}, issn = {2296-634X}, support = {RF1 AG065301/AG/NIA NIH HHS/United States ; }, abstract = {The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, and polyubiquitinated proteins. The proteasome plays critical roles in nervous system processes. This includes maintenance of cellular homeostasis in neurons. It also includes roles in long-term potentiation via modulation of CREB signaling. The proteasome also possesses roles in promoting dendritic spine growth driven by proteasome localization to the dendritic spines in an NMDA/CaMKIIα dependent manner. Proteasome inhibition experiments in varied organisms has been shown to impact memory, consolidation, recollection and extinction. The proteasome has been further shown to impact circadian rhythm through modulation of a range of 'clock' genes, and glial function. Proteasome function is impaired as a consequence both of aging and neurodegenerative diseases. Many studies have demonstrated an impairment in 26S proteasome function in the brain and other tissues as a consequence of age, driven by a disassembly of 26S proteasome in favor of 20S proteasome. Some studies also show proteasome augmentation to correct age-related deficits. In amyotrophic lateral sclerosis Alzheimer's, Parkinson's and Huntington's disease proteasome function is impaired through distinct mechanisms with impacts on disease susceptibility and progression. Age and neurodegenerative-related deficits in the function of the constitutive proteasome are often also accompanied by an increase in an alternative form of proteasome called the immunoproteasome. This article discusses the critical role of the proteasome in the nervous system. We then describe how proteasome dysfunction contributes to brain aging and neurodegenerative disease.}, }
@article {pmid37122628, year = {2023}, author = {Sánchez-Vidaña, DI and Li, J and Abokyi, S and Chan, JN and Ngai, SP and Lau, BW}, title = {In vitro methods in autophagy research: Applications in neurodegenerative diseases and mood disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1168948}, pmid = {37122628}, issn = {1662-5099}, abstract = {BACKGROUND: Autophagy is a conserved physiological intracellular mechanism responsible for the degradation and recycling of cytoplasmic constituents (e.g., damaged organelles, and protein aggregates) to maintain cell homeostasis. Aberrant autophagy has been observed in neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD), and recently aberrant autophagy has been associated with mood disorders, such as depression. Several in vitro methods have been developed to study the complex and tightly regulated mechanisms of autophagy. In vitro methods applied to autophagy research are used to identify molecular key players involved in dysfunctional autophagy and to screen autophagy regulators with therapeutic applications in neurological diseases and mood disorders. Therefore, the aims of this narrative review are (1) to compile information on the cell-based methods used in autophagy research, (2) to discuss their application, and (3) to create a catalog of traditional and novel in vitro methods applied in neurodegenerative diseases and depression.<br><br>METHODS: Pubmed and Google Scholar were used to retrieve relevant in vitro studies on autophagy mechanisms in neurological diseases and depression using a combination of search terms per mechanism and disease (e.g., "macroautophagy" and "Alzheimer's disease"). A total of 37 studies were included (14 in PD, 8 in AD, 5 in ALS, 5 in %, and 5 in depression).<br><br>RESULTS: A repertoire of traditional and novel approaches and techniques was compiled and discussed. The methods used in autophagy research focused on the mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy. The in vitro tools presented in this review can be applied to explore pathophysiological mechanisms at a molecular level and to screen for potential therapeutic agents and their mechanism of action, which can be of great importance to understanding disease biology and potential therapeutic options in the context of neurodegenerative disorders and depression.<br><br>CONCLUSION: This is the first review to compile, discuss, and provide a catalog of traditional and novel in vitro models applied to neurodegenerative disorders and depression.}, }
@article {pmid37121991, year = {2023}, author = {Gangfuß, A and Kohl, Z}, title = {[Amyotrophic lateral sclerosis-Motor neuron disease with a wide clinical and genetic spectrum].}, journal = {Der Nervenarzt}, volume = {94}, number = {6}, pages = {494-500}, pmid = {37121991}, issn = {1433-0407}, mesh = {Young Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Diagnosis, Differential ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Besides a timely diagnosis, precise knowledge of the clinical manifestations and differential diagnoses is essential. While most patients develop the disease at an older age, hereditary causes play a more frequent role in the juvenile forms.<br><br>OBJECTIVE: What is the current state of ALS diagnostics, which new treatment options exist?<br><br>MATERIAL AND METHOD: Literature search using Pubmed.gov.<br><br>RESULTS: The main focus is on an individualized symptomatic treatment as no curative treatment approaches exist. However, new insights into the genetic and pathophysiological principles of the different forms of ALS open the way for future disease-modifying treatment options.<br><br>CONCLUSION: In cases of a clinical suspicion of ALS molecular genetic diagnostics should be considered, particularly in juvenile and young adult patients, to exclude differential diagnoses and to enable patients access to new treatment approaches.}, }
@article {pmid37116688, year = {2024}, author = {Moreno-Jiménez, L and Benito-Martín, MS and Sanclemente-Alamán, I and Matías-Guiu, JA and Sancho-Bielsa, F and Canales-Aguirre, A and Mateos-Díaz, JC and Matías-Guiu, J and Aguilar, J and Gómez-Pinedo, U}, title = {Murine experimental models of amyotrophic lateral sclerosis: an update.}, journal = {Neurologia}, volume = {39}, number = {3}, pages = {282-291}, doi = {10.1016/j.nrleng.2021.07.004}, pmid = {37116688}, issn = {2173-5808}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases ; DNA-Binding Proteins/genetics ; Mutation ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose aetiology is unknown. It is characterised by upper and lower motor neuron degeneration. Approximately 90% of cases of ALS are sporadic, whereas the other 10% are familial. Regardless of whether the case is familial o sporadic, patients will develop progressive weakness, muscle atrophy with spasticity, and muscle contractures. Life expectancy of these patients is generally 2 to 5 years after diagnosis.<br><br>DEVELOPMENT: In vivo models have helped to clarify the aetiology and pathogenesis of ALS, as well as the mechanisms of the disease. However, as these mechanisms are not yet fully understood, experimental models are essential to the continued study of the pathogenesis of ALS, as well as in the search for possible therapeutic targets. Although 90% of cases are sporadic, most of the models used to study ALS pathogenesis are based on genetic mutations associated with the familial form of the disease; the pathogenesis of sporadic ALS remains unknown. Therefore, it would be critical to establish models based on the sporadic form.<br><br>CONCLUSIONS: This article reviews the main genetic and sporadic experimental models used in the study of this disease, focusing on those that have been developed using rodents.}, }
@article {pmid37115318, year = {2023}, author = {Holloway, K and Neherin, K and Dam, KU and Zhang, H}, title = {Cellular senescence and neurodegeneration.}, journal = {Human genetics}, volume = {142}, number = {8}, pages = {1247-1262}, pmid = {37115318}, issn = {1432-1203}, mesh = {Mice ; Animals ; *Amyloid beta-Peptides ; Cellular Senescence/genetics ; *Alzheimer Disease/genetics ; Aging/physiology ; }, abstract = {Advancing age is a major risk factor of Alzheimer's disease (AD). The worldwide prevalence of AD is approximately 50 million people, and this number is projected to increase substantially. The molecular mechanisms underlying the aging-associated susceptibility to cognitive impairment in AD are largely unknown. As a hallmark of aging, cellular senescence is a significant contributor to aging and age-related diseases including AD. Senescent neurons and glial cells have been detected to accumulate in the brains of AD patients and mouse models. Importantly, selective elimination of senescent cells ameliorates amyloid beta and tau pathologies and improves cognition in AD mouse models, indicating a critical role of cellular senescence in AD pathogenesis. Nonetheless, the mechanisms underlying when and how cellular senescence contributes to AD pathogenesis remain unclear. This review provides an overview of cellular senescence and discusses recent advances in the understanding of the impact of cellular senescence on AD pathogenesis, with brief discussions of the possible role of cellular senescence in other neurodegenerative diseases including Down syndrome, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.}, }
@article {pmid37115110, year = {2023}, author = {Rhine, K and Odeh, HM and Shorter, J and Myong, S}, title = {Regulation of Biomolecular Condensates by Poly(ADP-ribose).}, journal = {Chemical reviews}, volume = {123}, number = {14}, pages = {9065-9093}, pmid = {37115110}, issn = {1520-6890}, support = {F31 NS113439/NS/NINDS NIH HHS/United States ; RF1 AG071326/AG/NIA NIH HHS/United States ; R21 AG079609/AG/NIA NIH HHS/United States ; R01 GM138690/GM/NIGMS NIH HHS/United States ; RF1 NS113636/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; }, mesh = {*Poly Adenosine Diphosphate Ribose/metabolism ; *Poly(ADP-ribose) Polymerases/chemistry/metabolism ; Biomolecular Condensates ; Poly ADP Ribosylation ; Protein Processing, Post-Translational ; }, abstract = {Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these condensates by accelerating the self-association of proteins. Poly(ADP-ribose) (PAR) chains are remarkably transient modifications with turnover rates on the order of minutes, yet they can be required for the formation of granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation of PAR is linked with adverse phase transitions in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide a primer on how PAR is synthesized and regulated, the diverse structures and chemistries of ADP-ribosylation modifications, and protein-PAR interactions. We review substantial progress in recent efforts to determine the molecular mechanism of PAR-mediated phase separation, and we further delineate how inhibitors of PAR polymerases may be effective treatments for neurodegenerative pathologies. Finally, we highlight the need for rigorous biochemical interrogation of ADP-ribosylation in vivo and in vitro to clarify the exact pathway from PARylation to condensate formation.}, }
@article {pmid37108873, year = {2023}, author = {Lipke, PN and Ragonis-Bachar, P}, title = {Sticking to the Subject: Multifunctionality in Microbial Adhesins.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {9}, number = {4}, pages = {}, pmid = {37108873}, issn = {2309-608X}, abstract = {Bacterial and fungal adhesins mediate microbial aggregation, biofilm formation, and adhesion to host. We divide these proteins into two major classes: professional adhesins and moonlighting adhesins that have a non-adhesive activity that is evolutionarily conserved. A fundamental difference between the two classes is the dissociation rate. Whereas moonlighters, including cytoplasmic enzymes and chaperones, can bind with high affinity, they usually dissociate quickly. Professional adhesins often have unusually long dissociation rates: minutes or hours. Each adhesin has at least three activities: cell surface association, binding to a ligand or adhesive partner protein, and as a microbial surface pattern for host recognition. We briefly discuss Bacillus subtilis TasA, pilin adhesins, gram positive MSCRAMMs, and yeast mating adhesins, lectins and flocculins, and Candida Awp and Als families. For these professional adhesins, multiple activities include binding to diverse ligands and binding partners, assembly into molecular complexes, maintenance of cell wall integrity, signaling for cellular differentiation in biofilms and in mating, surface amyloid formation, and anchorage of moonlighting adhesins. We summarize the structural features that lead to these diverse activities. We conclude that adhesins resemble other proteins with multiple activities, but they have unique structural features to facilitate multifunctionality.}, }
@article {pmid37108835, year = {2023}, author = {Sandrelli, F and Bisaglia, M}, title = {Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108835}, issn = {1422-0067}, mesh = {Humans ; Adult ; *Amyotrophic Lateral Sclerosis/metabolism ; Protein Deglycase DJ-1/genetics/metabolism ; Motor Neurons/metabolism ; Mutation ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset disease which causes the progressive degeneration of cortical and spinal motoneurons, leading to death a few years after the first symptom onset. ALS is mainly a sporadic disorder, and its causative mechanisms are mostly unclear. About 5-10% of cases have a genetic inheritance, and the study of ALS-associated genes has been fundamental in defining the pathological pathways likely also involved in the sporadic forms of the disease. Mutations affecting the DJ-1 gene appear to explain a subset of familial ALS forms. DJ-1 is involved in multiple molecular mechanisms, acting primarily as a protective agent against oxidative stress. Here, we focus on the involvement of DJ-1 in interconnected cellular functions related to mitochondrial homeostasis, reactive oxygen species (ROS) levels, energy metabolism, and hypoxia response, in both physiological and pathological conditions. We discuss the possibility that impairments in one of these pathways may affect the others, contributing to a pathological background in which additional environmental or genetic factors may act in favor of the onset and/or progression of ALS. These pathways may represent potential therapeutic targets to reduce the likelihood of developing ALS and/or slow disease progression.}, }
@article {pmid37108335, year = {2023}, author = {Teruel-Peña, B and Gómez-Urquiza, JL and Suleiman-Martos, N and Prieto, I and García-Cózar, FJ and Ramírez-Sánchez, M and Fernández-Martos, C and Domínguez-Vías, G}, title = {Systematic Review and Meta-Analyses of Aminopeptidases as Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108335}, issn = {1422-0067}, support = {PPJIA2022.09//University of Granada/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Aminopeptidases ; Genome-Wide Association Study ; *Neurodegenerative Diseases ; Prognosis ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. Biomarkers for ALS are essential for disease detection and to provide information on potential therapeutic targets. Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of protein or substrates such as neuropeptides. Since certain aminopeptidases are known to increase the risk of neurodegeneration, such mechanisms may reveal new targets to determine their association with ALS risk and their interest as a diagnostic biomarker. The authors performed a systematic review and meta-analyses of genome-wide association studies (GWASs) to identify reported aminopeptidases genetic loci associated with the risk of ALS. PubMed, Scopus, CINAHL, ISI Web of Science, ProQuest, LILACS, and Cochrane databases were searched to retrieve eligible studies in English or Spanish, published up to 27 January 2023. A total of 16 studies were included in this systematic review, where a series of aminopeptidases could be related to ALS and could be promising biomarkers (DPP1, DPP2, DPP4, LeuAP, pGluAP, and PSA/NPEPPS). The literature reported the association of single-nucleotide polymorphisms (SNPs: rs10260404 and rs17174381) with the risk of ALS. The genetic variation rs10260404 in the DPP6 gene was identified to be highly associated with ALS susceptibility, but meta-analyses of genotypes in five studies in a matched cohort of different ancestry (1873 cases and 1861 control subjects) showed no ALS risk association. Meta-analyses of eight studies for minor allele frequency (MAF) also found no ALS association for the "C" allele. The systematic review identified aminopeptidases as possible biomarkers. However, the meta-analyses for rs1060404 of DPP6 do not show a risk associated with ALS.}, }
@article {pmid37107340, year = {2023}, author = {Rey, F and Berardo, C and Maghraby, E and Mauri, A and Messa, L and Esposito, L and Casili, G and Ottolenghi, S and Bonaventura, E and Cuzzocrea, S and Zuccotti, G and Tonduti, D and Esposito, E and Paterniti, I and Cereda, C and Carelli, S}, title = {Redox Imbalance in Neurological Disorders in Adults and Children.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107340}, issn = {2076-3921}, abstract = {Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus-Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.}, }
@article {pmid37102648, year = {2023}, author = {Dabi, YT and Ajagbe, AO and Degechisa, ST}, title = {Toll-like receptors in pathogenesis of neurodegenerative diseases and their therapeutic potential.}, journal = {Immunity, inflammation and disease}, volume = {11}, number = {4}, pages = {e839}, pmid = {37102648}, issn = {2050-4527}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/drug therapy ; Toll-Like Receptors/metabolism ; Inflammation/metabolism ; Microglia/metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Toll-like receptors (TLRs) are a family of pattern-recognition receptors triggered by pathogen-derived and tissue-damage-related ligands. TLRs were previously believed to only be expressed in immune cells. However, it is now confirmed that they are ubiquitously expressed in cells within the body including neurons, astrocytes, and microglia of the central nervous system (CNS). Activation of TLRs is capable of inducing immunologic and inflammatory responses to injury or infection of CNS. This response is self-limiting that usually resolves once the infection has been eradicated or the tissue damage has been repaired. However, the persistence of inflammation-inducing insults or a failure in normal resolution mechanisms may result in overwhelming inflammation which may induce neurodegeneration. This implies that TLRs may play a role in mediating the link between inflammation and neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. So, new therapeutic approaches that specifically target TLRs may be developed by better understanding TLR expression mechanisms in the CNS and their connections to particular neurodegenerative disorders. Therefore, this review paper discussed the role of TLRs in neurodegenerative diseases.}, }
@article {pmid37100932, year = {2023}, author = {Guo, C and Chen, L and Wang, Y}, title = {Substance abuse and neurodegenerative diseases: focus on ferroptosis.}, journal = {Archives of toxicology}, volume = {97}, number = {6}, pages = {1519-1528}, pmid = {37100932}, issn = {1432-0738}, support = {81973404//National Natural Science Foundation of China/ ; 2022-MS-224//Natural Science Foundation of Liaoning Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/chemically induced ; *Ferroptosis ; Oxidative Stress/physiology ; *Parkinson Disease ; *Alzheimer Disease/drug therapy ; Lipid Peroxidation ; }, abstract = {Psychostimulants and alcohol are widely abused substances with the adverse effects on global public health. Substance abuse seriously harms people's health and causes various diseases, especially neurodegenerative diseases. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The pathogenesis of neurodegenerative diseases is complex and diverse, usually involving oxidative stress, mitochondrial dysfunction, metal homeostasis disorder, and neuro-inflammation. The precise molecular mechanisms underlying neurodegeneration remain unclear, which is a major obstacle to therapeutic approaches. Therefore, it is urgent to improve the understanding of the molecular mechanisms of neurodegenerative processes and to identify the therapeutic targets for treatment and prevention. Ferroptosis is a regulatory cell necrosis caused by iron ion catalysis and lipid peroxidation induced by reactive oxygen species (ROS), which is thought to be associated with nervous system diseases, particularly neurodegenerative diseases. This review overviewed the ferroptosis process and explored the relationship of ferroptosis with substance abuse and neurodegenerative diseases, which provides a new way to study the molecular mechanisms of neurodegenerative diseases induced by alcohol, cocaine, and methamphetamine (MA), and also provides the potential therapeutic targets for substance abuse-induced neurodegenerative diseases.}, }
@article {pmid37090799, year = {2023}, author = {Castelnovo, V and Canu, E and De Mattei, F and Filippi, M and Agosta, F}, title = {Basal ganglia alterations in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1133758}, pmid = {37090799}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) has traditionally been associated with brain damage involving the primary motor cortices and corticospinal tracts. In the recent decades, most of the research studies in ALS have focused on extra-motor and subcortical brain regions. The aim of these studies was to detect additional biomarkers able to support the diagnosis and to predict disease progression. The involvement of the frontal cortices, mainly in ALS cases who develop cognitive and/or behavioral impairment, is amply recognized in the field. A potential involvement of fronto-temporal and fronto-striatal connectivity changes in the disease evolution has also been reported. On this latter regard, there is still a shortage of studies which investigated basal ganglia (BG) alterations and their role in ALS clinical manifestation and progression. The present review aims to provide an overview on the magnetic resonance imaging studies reporting structural and/or functional BG alterations in patients with ALS, to clarify the role of BG damage in the disease clinical evolution and to propose potential future developments in this field.}, }
@article {pmid37090492, year = {2023}, author = {Pingle, SC and Lin, F and Anekoji, MS and Patro, CPK and Datta, S and Jones, LD and Kesari, S and Ashili, S}, title = {Exploring the role of cerebrospinal fluid as analyte in neurologic disorders.}, journal = {Future science OA}, volume = {9}, number = {4}, pages = {FSO851}, pmid = {37090492}, issn = {2056-5623}, abstract = {The cerebrospinal fluid (CSF) is a clear ultrafiltrate of blood that envelopes and protects the central nervous system while regulating neuronal function through the maintenance of interstitial fluid homeostasis in the brain. Due to its anatomic location and physiological functions, the CSF can provide a reliable source of biomarkers for the diagnosis and treatment monitoring of different neurological diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and primary and secondary brain malignancies. The incorporation of CSF biomarkers into the drug discovery and development can improve the efficiency of drug development and increase the chances of success. This review aims to consolidate the current use of CSF biomarkers in clinical practice and explore future perspectives for the field.}, }
@article {pmid37089709, year = {2023}, author = {Wijeweera, G and Wijekoon, N and Gonawala, L and Imran, Y and Mohan, C and De Silva, KRD}, title = {Therapeutic Implications of Some Natural Products for Neuroimmune Diseases: A Narrative of Clinical Studies Review.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2023}, number = {}, pages = {5583996}, pmid = {37089709}, issn = {1741-427X}, abstract = {Neuroimmune diseases are a group of disorders that occur due to the dysregulation of both the nervous and immune systems, and these illnesses impact tens of millions of people worldwide. However, patients who suffer from these debilitating conditions have very few FDA-approved treatment options. Neuroimmune crosstalk is important for controlling the immune system both centrally and peripherally to maintain tissue homeostasis. This review aims to provide readers with information on how natural products modulate neuroimmune crosstalk and the therapeutic implications of natural products, including curcumin, epigallocatechin-3-gallate (EGCG), ginkgo special extract, ashwagandha, Centella asiatica, Bacopa monnieri, ginseng, and cannabis to mitigate the progression of neuroimmune diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, depression, and anxiety disorders. The majority of the natural products based clinical studies mentioned in this study have yielded positive results. To achieve the expected results from natural products based clinical studies, researchers should focus on enhancing bioavailability and determining the synergistic mechanisms of herbal compounds and extracts, which will lead to the discovery of more effective phytomedicines while averting the probable negative effects of natural product extracts. Therefore, future studies developing nutraceuticals to mitigate neuroimmune diseases that incorporate phytochemicals to produce synergistic effects must analyse efficacy, bioavailability, gut-brain axis function safety, chemical modifications, and encapsulation with nanoparticles.}, }
@article {pmid37084987, year = {2023}, author = {Ma, Y and Farny, NG}, title = {Connecting the dots: Neuronal senescence, stress granules, and neurodegeneration.}, journal = {Gene}, volume = {871}, number = {}, pages = {147437}, pmid = {37084987}, issn = {1879-0038}, support = {R03 AG077140/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Stress Granules ; Cytoplasmic Granules/genetics/metabolism/pathology ; Neurons/metabolism ; Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Cellular senescence increases with aging. While senescence is associated with an exit of the cell cycle, there is ample evidence that post-mitotic cells including neurons can undergo senescence as the brain ages, and that senescence likely contributes significantly to the progression of neurodegenerative diseases (ND) such as Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Stress granules (SGs) are stress-induced cytoplasmic biomolecular condensates of RNA and proteins, which have been linked to the development of AD and ALS. The SG seeding hypothesis of NDs proposes that chronic stress in aging neurons results in static SGs that progress into pathological aggregates Alterations in SG dynamics have also been linked to senescence, though studies that link SGs and senescence in the context of NDs and the aging brain have not yet been performed. In this Review, we summarize the literature on senescence, and explore the contribution of senescence to the aging brain. We describe senescence phenotypes in aging neurons and glia, and their links to neuroinflammation and the development of AD and ALS. We further examine the relationships of SGs to senescence and to ND. We propose a new hypothesis that neuronal senescence may contribute to the mechanism of SG seeding in ND by altering SG dynamics in aged cells, thereby providing additional aggregation opportunities within aged neurons.}, }
@article {pmid37084148, year = {2023}, author = {Wuerch, E and Urgoiti, GR and Yong, VW}, title = {The Promise of Niacin in Neurology.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {4}, pages = {1037-1054}, pmid = {37084148}, issn = {1878-7479}, mesh = {Humans ; *Niacin/therapeutic use/metabolism ; Amyloid beta-Peptides ; *Pellagra/metabolism ; *Nervous System Diseases ; *Alzheimer Disease ; *Neurology ; }, abstract = {Niacin (vitamin B3) is an essential nutrient that treats pellagra, and prior to the advent of statins, niacin was commonly used to counter dyslipidemia. Recent evidence has posited niacin as a promising therapeutic for several neurological disorders. In this review, we discuss the biochemistry of niacin, including its homeostatic roles in NAD[+] supplementation and metabolism. Niacin also has roles outside of metabolism, largely through engaging hydroxycarboxylic acid receptor 2 (Hcar2). These receptor-mediated activities of niacin include regulation of immune responses, phagocytosis of myelin debris after demyelination or of amyloid beta in models of Alzheimer's disease, and cholesterol efflux from cells. We describe the neurological disorders in which niacin has been investigated or has been proposed as a candidate medication. These are multiple sclerosis, Alzheimer's disease, Parkinson's disease, glioblastoma and amyotrophic lateral sclerosis. Finally, we explore the proposed mechanisms through which niacin may ameliorate neuropathology. While several questions remain, the prospect of niacin as a therapeutic to alleviate neurological impairment is promising.}, }
@article {pmid37069469, year = {2023}, author = {Hamad, AA and Attia, AN and Al-Dardery, NM and Mohamed, SF and Meshref, M}, title = {Safety and efficacy of lithium in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {9}, pages = {3029-3036}, pmid = {37069469}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Lithium/adverse effects ; Valproic Acid/adverse effects ; Randomized Controlled Trials as Topic ; Vital Capacity ; }, abstract = {OBJECTIVES: This study provides a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the safety and efficacy of lithium in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: PubMed, Web of Science, Cochrane CENTRAL, Scopus, and Your Journals@Ovid were searched up to 9 December 2022. RCTs investigating lithium, either alone or with any supplement, in ALS patients were included. Meta-analysis was performed using RevMan and results are presented in forest plot.<br><br>RESULTS: Four RCTs with 469 patients met the inclusion criteria and were included in our study. Lithium doses varied among the included studies and one study used a combined therapy of lithium with valproate. Meta-analysis showed no difference between lithium and placebo regarding severe adverse events (odds ratio&#x2009;=&#x2009;1.13, 95% confidence interval: 0.73 to 1.75, P&#x2009;=&#x2009;0.58). No significant differences were observed with regard to survival rate between the two groups (hazard ratio&#x2009;=&#x2009;0.95, 95% confidence interval: 0.65 to 1.37, P&#x2009;=&#x2009;0.77). There were also no significant differences between the two groups with regard to average changes of revised amyotrophic lateral sclerosis functional rating scale (P&#x2009;=&#x2009;0.35) and forced vital capacity percentage predicted (P&#x2009;=&#x2009;0.73). Subgroup analysis showed no significant differences regarding all investigated outcomes either for lithium alone or lithium with valproate.<br><br>CONCLUSION: Current evidence suggests a safety profile with no benefit of lithium for ALS. However, given the limited number of RCTs and the safety findings, we recommend further well-designed RCTs to investigate lithium and valproate in ALS patients.}, }
@article {pmid37068329, year = {2023}, author = {Vucic, S and Stanley Chen, KH and Kiernan, MC and Hallett, M and Benninger, DH and Di Lazzaro, V and Rossini, PM and Benussi, A and Berardelli, A and Currà, A and Krieg, SM and Lefaucheur, JP and Long Lo, Y and Macdonell, RA and Massimini, M and Rosanova, M and Picht, T and Stinear, CM and Paulus, W and Ugawa, Y and Ziemann, U and Chen, R}, title = {Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {150}, number = {}, pages = {131-175}, pmid = {37068329}, issn = {1872-8952}, support = {Z99 NS999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Transcranial Magnetic Stimulation/methods ; *Nervous System Diseases ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; Evoked Potentials, Motor/physiology ; }, abstract = {The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.}, }
@article {pmid37063844, year = {2023}, author = {Yu, X and Liu, MM and Zheng, CY and Liu, YT and Wang, Z and Wang, ZY}, title = {Telomerase reverse transcriptase and neurodegenerative diseases.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1165632}, pmid = {37063844}, issn = {1664-3224}, mesh = {Humans ; Cellular Senescence ; *Neurodegenerative Diseases/therapy ; *Telomerase/genetics ; Telomere Shortening ; T-Lymphocytes ; }, abstract = {Neurodegenerative diseases (NDs) are chronic conditions that result in progressive damage to the nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Age is a major risk factor for NDs. Telomere shortening is a biological marker of cellular aging, and telomerase reverse transcriptase (TERT) has been shown to slow down this process by maintaining telomere length. The blood-brain barrier (BBB) makes the brain a unique immune organ, and while the number of T cells present in the central nervous system is limited, they play an important role in NDs. Research suggests that NDs can be influenced by modulating peripheral T cell immune responses, and that TERT may play a significant role in T cell senescence and NDs. This review focuses on the current state of research on TERT in NDs and explores the potential connections between TERT, T cells, and NDs. Further studies on aging and telomeres may provide valuable insights for developing therapeutic strategies for age-related diseases.}, }
@article {pmid37062503, year = {2023}, author = {Alavi, MS and Karimi, G and Ghanimi, HA and Roohbakhsh, A}, title = {The potential of CYP46A1 as a novel therapeutic target for neurological disorders: An updated review of mechanisms.}, journal = {European journal of pharmacology}, volume = {949}, number = {}, pages = {175726}, doi = {10.1016/j.ejphar.2023.175726}, pmid = {37062503}, issn = {1879-0712}, mesh = {Humans ; Cholesterol 24-Hydroxylase/metabolism ; *Cholesterol/metabolism ; *Alzheimer Disease/metabolism ; Brain/metabolism ; }, abstract = {Cholesterol is a key component of the cell membrane that impacts the permeability, fluidity, and functions of membrane-bound proteins. It also participates in synaptogenesis, synaptic function, axonal growth, dendrite outgrowth, and microtubule stability. Cholesterol biosynthesis and metabolism are in balance in the brain. Its metabolism in the brain is mediated mainly by CYP46A1 or cholesterol 24-hydroxylase. It is responsible for eliminating about 80% of the cholesterol excess from the human brain. CYP46A1 converts cholesterol to 24S-hydroxycholesterol (24HC) that readily crosses the blood-brain barrier and reaches the liver for the final elimination process. Studies show that cholesterol and 24HC levels change during neurological diseases and conditions. So, it was hypothesized that inhibition or activation of CYP46A1 would be an effective therapeutic strategy. Accordingly, preclinical studies, using genetic and pharmacological interventions, assessed the role of CYP46A1 in main neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, spinocerebellar ataxias, and amyotrophic lateral sclerosis. In addition, its role in seizures and brain injury was evaluated. The recent development of soticlestat, as a selective and potent CYP46A1 inhibitor, with significant anti-seizure effects in preclinical and clinical studies, suggests the importance of this target for future drug developments. Previous studies have shown that both activation and inhibition of CYP46A1 are of therapeutic value. This article, using recent studies, highlights the role of CYP46A1 in various brain diseases and insults.}, }
@article {pmid37061287, year = {2023}, author = {Yoshimura, A and Ohyagi, M and Ito, M}, title = {T cells in the brain inflammation.}, journal = {Advances in immunology}, volume = {157}, number = {}, pages = {29-58}, doi = {10.1016/bs.ai.2022.10.001}, pmid = {37061287}, issn = {1557-8445}, mesh = {Humans ; CD8-Positive T-Lymphocytes ; *Alzheimer Disease ; *Neurodegenerative Diseases ; *Infectious Encephalitis ; *Encephalitis ; Cerebral Infarction ; Inflammation ; }, abstract = {The immune system is deeply involved in autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis, N-methyl-d-aspartate (NMDA) receptor encephalitis, and narcolepsy. Additionally, the immune system is involved in various brain diseases including cerebral infarction and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In particular, reports related to T cells are increasing. T cells may also play important roles in brain deterioration and dementia that occur with aging. Our understanding of the role of immune cells in the context of the brain has been greatly improved by the use of acute ischemic brain injury models. Additionally, similar neural damage and repair events are shown to occur in more chronic brain neurodegenerative brain diseases. In this review, we focus on the role of T cells, including CD4[+] T cells, CD8[+] T cells and regulatory T cells (Tregs) in cerebral infarction and neurodegenerative diseases.}, }
@article {pmid37055865, year = {2023}, author = {Shadfar, S and Parakh, S and Jamali, MS and Atkin, JD}, title = {Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {18}, pmid = {37055865}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Oxidative Stress/genetics ; Oxidation-Reduction ; Reactive Oxygen Species/therapeutic use ; Antioxidants/therapeutic use ; DNA Damage/genetics ; }, abstract = {Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a result of imbalance between pro-oxidants and antioxidant species. Oxidative stress perturbs many cellular activities, including processes that maintain the integrity of DNA. Nucleic acids are highly reactive and therefore particularly susceptible to damage. The DNA damage response detects and repairs these DNA lesions. Efficient DNA repair processes are therefore essential for maintaining cellular viability, but they decline considerably during aging. DNA damage and deficiencies in DNA repair are increasingly described in age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Furthermore, oxidative stress has long been associated with these conditions. Moreover, both redox dysregulation and DNA damage increase significantly during aging, which is the biggest risk factor for neurodegenerative diseases. However, the links between redox dysfunction and DNA damage, and their joint contributions to pathophysiology in these conditions, are only just emerging. This review will discuss these associations and address the increasing evidence for redox dysregulation as an important and major source of DNA damage in neurodegenerative disorders. Understanding these connections may facilitate a better understanding of disease mechanisms, and ultimately lead to the design of better therapeutic strategies based on preventing both redox dysregulation and DNA damage.}, }
@article {pmid37047320, year = {2023}, author = {Bianco, A and Antonacci, Y and Liguori, M}, title = {Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities.}, journal = {International journal of molecular sciences}, volume = {24}, number = {7}, pages = {}, pmid = {37047320}, issn = {1422-0067}, mesh = {Male ; Female ; Humans ; *Neurodegenerative Diseases/therapy/pathology ; Sex Factors ; Sex Characteristics ; *Parkinson Disease/pathology ; Neurons/pathology ; }, abstract = {The term "neurodegenerative diseases" (NDs) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evidence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more "classical" NDs, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals' responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care.}, }
@article {pmid37047273, year = {2023}, author = {Russo, C and Valle, MS and Casabona, A and Malaguarnera, L}, title = {Chitinase Signature in the Plasticity of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {7}, pages = {}, pmid = {37047273}, issn = {1422-0067}, support = {E63C22002080006//This research was founded by PNRR: "Health Extended ALliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision"/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; *Chitinases/genetics ; Neuroinflammatory Diseases ; Biomarkers ; *Multiple Sclerosis ; }, abstract = {Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.}, }
@article {pmid37044239, year = {2023}, author = {Bernal, AF and Mota, N and Pamplona, R and Area-Gomez, E and Portero-Otin, M}, title = {Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1869}, number = {6}, pages = {166716}, doi = {10.1016/j.bbadis.2023.166716}, pmid = {37044239}, issn = {1879-260X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/pathology ; Mitochondrial Membranes/metabolism ; Mitochondria/metabolism ; Endoplasmic Reticulum/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.}, }
@article {pmid37037874, year = {2023}, author = {Qian, K and Jiang, X and Liu, ZQ and Zhang, J and Fu, P and Su, Y and Brazhe, NA and Liu, D and Zhu, LQ}, title = {Revisiting the critical roles of reactive astrocytes in neurodegeneration.}, journal = {Molecular psychiatry}, volume = {28}, number = {7}, pages = {2697-2706}, pmid = {37037874}, issn = {1476-5578}, mesh = {Humans ; Astrocytes/metabolism ; *Neurodegenerative Diseases ; *Huntington Disease ; Blood-Brain Barrier/metabolism ; *Alzheimer Disease/pathology ; }, abstract = {Astrocytes, an integral component of the central nervous system (CNS), contribute to the maintenance of physiological homeostasis through their roles in synaptic function, K[+] buffering, blood-brain barrier (BBB) maintenance, and neuronal metabolism. Reactive astrocytes refer to astrocytes undergoing morphological, molecular and functional remodelling in response to pathological stimuli. The activation and differentiation of astrocytes are implicated in the pathogenesis of multiple neurodegenerative diseases. However, there are still controversies regarding their subset identification, function and nomenclature in neurodegeneration. In this review, we revisit the multidimensional roles of reactive astrocytes in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Furthermore, we propose a precise linkage between astrocyte subsets and their functions based on single-cell sequencing analyses.}, }
@article {pmid37032500, year = {2024}, author = {Qi, W and Guan, W}, title = {A Comprehensive Review on the Importance of MiRNA-206 in the Animal Model and Human Diseases.}, journal = {Current neuropharmacology}, volume = {22}, number = {6}, pages = {1064-1079}, pmid = {37032500}, issn = {1875-6190}, support = {81900551//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; *MicroRNAs/genetics/metabolism ; *Neoplasms/genetics ; Biomarkers ; Models, Animal ; *Osteoarthritis/genetics ; Gene Expression Regulation, Neoplastic ; }, abstract = {MicroRNA-206 (miR-206) is a microRNA that is involved in many human diseases, such as myasthenia gravis, osteoarthritis, depression, cancers, etc. Both inhibition effects and progression roles of miR-206 have been reported for the past few years. High expression of miR-206 was observed in patients with osteoarthritis, gastric cancer and epithelial ovarian cancer compared to normal people. The study also showed that miR-206 promotes cancer progression in breast cancer patients and avascular necrosis of the femoral head. Meanwhile, several studies have shown that expression levels of miR-206 were down-regulated in laryngeal carcinoma cell multiplication, as well as in hepatocellular carcinoma, non-small lung cancer and infantile hemangioma. Moreover, miR-206 was up-regulated in the mild stage of amyotrophic lateral sclerosis patients and then down-regulated in the moderate and severe stages, indicating that miR-206 has the double effects of starting and aggravating the disease. In neuropsychiatric disorders, such as depression, miR-206 also plays an important role in the progression of the disease; the level of miR-206 is most highly expressed in the brains of patients with depression. In the current review, we summarize the role of miR-206 in various diseases, and miR-206 may be developed as a new biomarker for diagnosing diseases in the near future.}, }
@article {pmid37031723, year = {2023}, author = {Zhang, YY and Li, XS and Ren, KD and Peng, J and Luo, XJ}, title = {Restoration of metal homeostasis: a potential strategy against neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {87}, number = {}, pages = {101931}, doi = {10.1016/j.arr.2023.101931}, pmid = {37031723}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; Ion Channels/metabolism/therapeutic use ; Homeostasis ; }, abstract = {Metal homeostasis is critical to normal neurophysiological activity. Metal ions are involved in the development, metabolism, redox and neurotransmitter transmission of the central nervous system (CNS). Thus, disturbance of homeostasis (such as metal deficiency or excess) can result in serious consequences, including neurooxidative stress, excitotoxicity, neuroinflammation, and nerve cell death. The uptake, transport and metabolism of metal ions are highly regulated by ion channels. There is growing evidence that metal ion disorders and/or the dysfunction of ion channels contribute to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, metal homeostasis-related signaling pathways are emerging as promising therapeutic targets for diverse neurological diseases. This review summarizes recent advances in the studies regarding the physiological and pathophysiological functions of metal ions and their channels, as well as their role in neurodegenerative diseases. In addition, currently available metal ion modulators and in vivo quantitative metal ion imaging methods are also discussed. Current work provides certain recommendations based on literatures and in-depth reflections to improve neurodegenerative diseases. Future studies should turn to crosstalk and interactions between different metal ions and their channels. Concomitant pharmacological interventions for two or more metal signaling pathways may offer clinical advantages in treating the neurodegenerative diseases.}, }
@article {pmid37031050, year = {2023}, author = {Alberini, CM}, title = {IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {46}, number = {6}, pages = {488-502}, pmid = {37031050}, issn = {1878-108X}, support = {R01 MH065635/MH/NIMH NIH HHS/United States ; R37 MH065635/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease ; Brain/metabolism ; *Neurodegenerative Diseases/metabolism ; *Neurodevelopmental Disorders ; *Parkinson Disease ; Humans ; }, abstract = {Insulin-like growth factor 2 (IGF2) emerged as a critical mechanism of synaptic plasticity and learning and memory. Deficits in IGF2 in the brain, serum, or cerebrospinal fluid (CSF) are associated with brain diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Increasing IGF2 levels enhances memory in healthy animals and reverses numerous symptoms in laboratory models of aging, neurodevelopmental disorders, and neurodegenerative diseases. These effects occur via the IGF2 receptor (IGF2R) - a receptor that is highly expressed in neurons and regulates protein trafficking, synthesis, and degradation. Here, I summarize the current knowledge regarding IGF2 expression and functions in the brain, particularly in memory, and propose a novel conceptual model for IGF2/IGF2R mechanisms of action in brain health and diseases.}, }
@article {pmid37027074, year = {2023}, author = {Cecerska-Heryć, E and Pękała, M and Serwin, N and Gliźniewicz, M and Grygorcewicz, B and Michalczyk, A and Heryć, R and Budkowska, M and Dołęgowska, B}, title = {The Use of Stem Cells as a Potential Treatment Method for Selected Neurodegenerative Diseases: Review.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {6}, pages = {2643-2673}, pmid = {37027074}, issn = {1573-6830}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/therapy ; *Amyotrophic Lateral Sclerosis/therapy ; Stem Cells ; *Huntington Disease/pathology/therapy ; *Alzheimer Disease ; *Parkinson Disease/therapy ; }, abstract = {Stem cells have been the subject of research for years due to their enormous therapeutic potential. Most neurological diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are incurable or very difficult to treat. Therefore new therapies are sought in which autologous stem cells are used. They are often the patient's only hope for recovery or slowing down the progress of the disease symptoms. The most important conclusions arise after analyzing the literature on the use of stem cells in neurodegenerative diseases. The effectiveness of MSC cell therapy has been confirmed in ALS and HD therapy. MSC cells slow down ALS progression and show early promising signs of efficacy. In HD, they reduced huntingtin (Htt) aggregation and stimulation of endogenous neurogenesis. MS therapy with hematopoietic stem cells (HSCs) inducted significant recalibration of pro-inflammatory and immunoregulatory components of the immune system. iPSC cells allow for accurate PD modeling. They are patient-specific and therefore minimize the risk of immune rejection and, in long-term observation, did not form any tumors in the brain. Extracellular vesicles derived from bone marrow mesenchymal stromal cells (BM-MSC-EVs) and Human adipose-derived stromal/stem cells (hASCs) cells are widely used to treat AD. Due to the reduction of Aβ42 deposits and increasing the survival of neurons, they improve memory and learning abilities. Despite many animal models and clinical trial studies, cell therapy still needs to be refined to increase its effectiveness in the human body.}, }
@article {pmid37026513, year = {2023}, author = {Li, F and Liu, A and Zhao, M and Luo, L}, title = {Astrocytic Chitinase-3-like protein 1 in neurological diseases: Potential roles and future perspectives.}, journal = {Journal of neurochemistry}, volume = {165}, number = {6}, pages = {772-790}, doi = {10.1111/jnc.15824}, pmid = {37026513}, issn = {1471-4159}, support = {2021-ZZ-JC030//Project of Shaanxi Provincial Administration of Traditional Chinese Medicine/ ; 82204425//National Natural Science Foundation of China/ ; 32241007//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Chitinase-3-Like Protein 1/metabolism ; Astrocytes/metabolism ; *Chitinases/metabolism ; *Neurodegenerative Diseases/metabolism ; Synapsins/metabolism ; *Brain Neoplasms/metabolism ; }, abstract = {Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with multiple neurological disorders and serves as a biomarker for the early detection of several neurodegenerative diseases. Aberrant CHI3L1 expression is also reportedly associated with brain tumor migration and metastasis, as well as contributions to immune escape, playing important roles in brain tumor progression. CHI3L1 is synthesized and secreted mainly by reactive astrocytes in the central nervous system. Thus, targeting astrocytic CHI3L1 could be a promising approach for the treatment of neurological diseases, such as traumatic brain injury, ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and glioma. Based on current knowledge of CHI3L1, we assume that it acts as a molecule mediating several signaling pathways driving the initiation and progression of neurological disorders. This narrative review is the first to introduce the potential roles of astrocytic CHI3L1 in neurological disorders. We also equally explore astrocytic CHI3L1 mRNA expression under physiological and pathological conditions. Inhibiting CHI3L1 and disrupting its interaction with its receptors through multiple mechanisms of action are briefly discussed. These endeavors highlight the pivotal roles of astrocytic CHI3L1 in neurological disorders and could contribute to the development of effective inhibitors based on the strategy of structure-based drug discovery, which could be an attractive therapeutic approach for neurological disease treatment.}, }
@article {pmid37024676, year = {2023}, author = {Akçimen, F and Lopez, ER and Landers, JE and Nath, A and Chiò, A and Chia, R and Traynor, BJ}, title = {Amyotrophic lateral sclerosis: translating genetic discoveries into therapies.}, journal = {Nature reviews. Genetics}, volume = {24}, number = {9}, pages = {642-658}, pmid = {37024676}, issn = {1471-0064}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation ; Gene-Environment Interaction ; }, abstract = {Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and gene-environment interactions. We also propose a high-level model to synthesize the interdependent effects of genetics, environmental and lifestyle factors, and ageing into a unified theory of ALS. Furthermore, we summarize the current status of therapies developed on the basis of genetic knowledge established for ALS over the past 30 years, and we discuss how developing treatments for ALS will advance our understanding of targeting other neurological diseases.}, }
@article {pmid37021679, year = {2023}, author = {Shammas, MK and Huang, TH and Narendra, DP}, title = {CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy.}, journal = {Biochemical Society transactions}, volume = {51}, number = {2}, pages = {797-809}, doi = {10.1042/BST20221365}, pmid = {37021679}, issn = {1470-8752}, support = {ZIA NS003169/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Transcription Factors/genetics/metabolism ; Mitochondria/metabolism ; Mutation ; *Parkinson Disease/metabolism ; Mitochondrial Proteins/genetics/metabolism ; }, abstract = {In the last decade, dominant mutations in the mitochondrial protein CHCHD10 (p.R15L and p.S59L) and its paralog CHCHD2 (p.T61I) were shown to cause familial amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), respectively, with phenotypes that often resemble the idiopathic forms of the diseases. Different mutations in CHCHD10 cause additional neuromuscular disorders, including the lower motor neuron disease Spinal Muscular Atrophy Jokela type (SMAJ) (p.G66V) and autosomal dominant isolated mitochondrial myopathy (IMMD) (p.G58R). Modeling these disorders is revealing how mitochondrial dysfunction may drive ALS and PD pathogenesis by a gain of function mechanism, driven by protein misfolding of CHCHD2 and CHCHD10 into toxic species. It is also laying the groundwork for precision therapy of CHCHD2/CHCHD10-related neurodegeneration. In this review, we address the normal function of CHCHD2 and CHCHD10, the mechanisms of their disease pathogenesis, the strong genotype-phenotype correlations that have emerged for CHCHD10, and potential therapeutic strategies for these disorders.}, }
@article {pmid37015866, year = {2023}, author = {Favron-Godbout, C and Racine, E}, title = {[Not Available].}, journal = {Journal international de bioethique et d'ethique des sciences}, volume = {33}, number = {3}, pages = {95-128}, doi = {10.3917/jibes.333.0095}, pmid = {37015866}, issn = {2608-1008}, mesh = {Humans ; *Suicide, Assisted ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Morals ; Medical Assistance ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that leads some people with the disease to consider medical assistance in dying (MAiD). In this article, we describe how a variety of moral problems can emerge from this particular context and affect the well-being of people with ALS, their loved ones, and their caregivers. As MAiD is framed by specific eligibility criteria, broadening its eligibility is often proposed to address these issues. This critical review of the literature aims to identify moral issues relating to ALS that may persist or arise in the event of such widening. The MEDLINE, EMBASE CINAHL and Web of Science databases were searched using 4 search combinations to capture insights from existing literature on ethics, MAiD and ALS (N=41). A thematic content analysis highlighted 3 contextual categories where moral issues emerge (the experience of the disease, the choice of how to die, and the implementation of MAiD). Two important observations are discussed: 1) there are differences in perspective between stakeholders, which can lead to disagreement, but some similarities of perspective also exist; 2) the widening of MAiD eligibility mainly concerns moral issues related to the choice of how to die, and thus constitutes a partial solution to the problems identified.}, }
@article {pmid37014255, year = {2023}, author = {Ravaria, P and Saxena, P and Laksmi Bs, S and Ranjan, V and Abidi, SWF and Saha, P and Ramamoorthy, S and Ahmad, F and Rana, SS}, title = {Molecular mechanisms of neuroprotective offerings by rosmarinic acid against neurodegenerative and other CNS pathologies.}, journal = {Phytotherapy research : PTR}, volume = {37}, number = {5}, pages = {2119-2143}, doi = {10.1002/ptr.7825}, pmid = {37014255}, issn = {1099-1573}, support = {VIT SEED Grant - RGEMS Fund (Sanction Order No. SG20220054)//Vellore Institute of Technology, Vellore/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; *Alzheimer Disease/drug therapy ; Neuroprotection ; Cinnamates/pharmacology/therapeutic use/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rosmarinic Acid ; }, abstract = {Rosmarinic acid (RA) is a natural phenolic compound present in culinary herbs of the Boraginaceae, Lamiaceae/Labiatae, and Nepetoideae families. While the medicinal applications of these plants have been known for ages, RA has only been relatively recently established as an effective ameliorative agent against various disorders including cardiac diseases, cancer, and neuropathologies. In particular, several studies have confirmed the neuroprotective potential of RA in multiple cellular and animal models, as well as in clinical studies. The neuroprotective effects mediated by RA stem from its multimodal actions on a plethora of cellular and molecular pathways; including oxidative, bioenergetic, neuroinflammatory, and synaptic signaling. In recent years, RA has garnered tremendous interest as an ideal therapeutic candidate for treating neurodegenerative diseases. This review first briefly discusses the pharmacokinetics of RA and then proceeds to detail the neuroprotective mechanisms of RA at the molecular levels. Finally, the authors focus on the ameliorative potential of RA against several central nervous system (CNS) disorders, ranging from neuropsychological stress and epilepsy to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, and amyotrophic lateral sclerosis.}, }
@article {pmid37009800, year = {2023}, author = {Choi, HJ and Lee, JY and Kim, K}, title = {Glutathionylation on RNA-binding proteins: a regulator of liquid‒liquid phase separation in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Experimental &amp; molecular medicine}, volume = {55}, number = {4}, pages = {735-744}, pmid = {37009800}, issn = {2092-6413}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Protein Processing, Post-Translational ; *Neurodegenerative Diseases ; Protein Aggregates ; }, abstract = {RNA-binding proteins (RBPs) containing low-sequence complexity domains mediate the formation of cellular condensates and membrane-less organelles with biological functions via liquid‒liquid phase separation (LLPS). However, the abnormal phase transition of these proteins induces the formation of insoluble aggregates. Aggregates are pathological hallmarks of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). The molecular mechanisms underlying aggregate formation by ALS-associated RPBs remain largely unknown. This review highlights emerging studies on various posttranslational modifications (PTMs) related to protein aggregation. We begin with the introduction of several ALS-associated RBPs that form aggregates induced by phase separation. In addition, we highlight our recent discovery of a new PTM involved in the phase transition during the pathogenesis of fused-in-sarcoma (FUS)-associated ALS. We suggest a molecular mechanism through which LLPS mediates glutathionylation in FUS-linked ALS. This review aims to provide a detailed overview of the key molecular mechanisms of LLPS-mediated aggregate formation by PTMs, which will help further the understanding of the pathogenesis and development of ALS therapeutics.}, }
@article {pmid37006471, year = {2023}, author = {Diab, R and Pilotto, F and Saxena, S}, title = {Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1086895}, pmid = {37006471}, issn = {1662-5102}, abstract = {The proper functioning of the cell clearance machinery is critical for neuronal health within the central nervous system (CNS). In normal physiological conditions, the cell clearance machinery is actively involved in the elimination of misfolded and toxic proteins throughout the lifetime of an organism. The highly conserved and regulated pathway of autophagy is one of the important processes involved in preventing and neutralizing pathogenic buildup of toxic proteins that could eventually lead to the development of neurodegenerative diseases (NDs) such as Alzheimer's disease or Amyotrophic lateral sclerosis (ALS). The most common genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide expansion consisting of GGGGCC (G4C2) repeats in the chromosome 9 open reading frame 72 gene (C9ORF72). These abnormally expanded repeats have been implicated in leading to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs). In this review, we discuss the normal physiological role of C9ORF72 in the autophagy-lysosome pathway (ALP), and present recent research deciphering how dysfunction of the ALP synergizes with C9ORF72 haploinsufficiency, which together with the gain of toxic mechanisms involving hexanucleotide repeat expansions and DPRs, drive the disease process. This review delves further into the interactions of C9ORF72 with RAB proteins involved in endosomal/lysosomal trafficking, and their role in regulating various steps in autophagy and lysosomal pathways. Lastly, the review aims to provide a framework for further investigations of neuronal autophagy in C9ORF72-linked ALS-FTD as well as other neurodegenerative diseases.}, }
@article {pmid37005761, year = {2023}, author = {Dahlmanns, M and Dahlmanns, JK and Savaskan, N and Steiner, HH and Yakubov, E}, title = {Glial Glutamate Transporter-Mediated Plasticity: System xc[-]/xCT/SLC7A11 and EAAT1/2 in Brain Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {3}, pages = {57}, doi = {10.31083/j.fbl2803057}, pmid = {37005761}, issn = {2768-6698}, mesh = {Humans ; Amino Acid Transport System X-AG ; *Amyotrophic Lateral Sclerosis ; Cystine/metabolism ; *Parkinson Disease ; *Alzheimer Disease ; Antioxidants ; Glutamic Acid/metabolism ; Microglia/metabolism ; *Multiple Sclerosis ; *Glioma ; Amino Acid Transport System y+/genetics/metabolism ; }, abstract = {Glial cells play an essential role in the complex function of the nervous system. In particular, astrocytes provide nutritive support for neuronal cells and are involved in regulating synaptic transmission. Oligodendrocytes ensheath axons and support information transfer over long distances. Microglial cells constitute part of the innate immune system in the brain. Glial cells are equipped with the glutamate-cystine-exchanger xCT (SLC7A11), the catalytic subunit of system xc-, and the excitatory amino acid transporter 1 (EAAT1, GLAST) and EAAT2 (GLT-1). Thereby, glial cells maintain balanced extracellular glutamate levels that enable synaptic transmission and prevent excitotoxic states. Expression levels of these transporters, however, are not fixed. Instead, expression of glial glutamate transporters are highly regulated in reaction to the external situations. Interestingly, such regulation and homeostasis is lost in diseases such as glioma, (tumor-associated) epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. Upregulation of system xc- (xCT or SLC7A11) increases glutamate export from the cell, while a downregulation of EAATs decreases intracellular glutamate import. Occurring simultaneously, these reactions entail excitotoxicity and thus harm neuronal function. The release of glutamate via the antiporter system xc- is accompanied by the import of cystine-an amino acid essential in the antioxidant glutathione. This homeostasis between excitotoxicity and intracellular antioxidant response is plastic and off-balance in central nervous system (CNS) diseases. System xc- is highly expressed on glioma cells and sensitizes them to ferroptotic cell death. Hence, system xc- is a potential target for chemotherapeutic add-on therapy. Recent research reveals a pivotal role of system xc- and EAAT1/2 in tumor-associated and other types of epilepsy. Numerous studies show that in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, these glutamate transporters are dysregulated-and disease mechanisms could be interposed by targeting system xc- and EAAT1/2. Interestingly, in neuroinflammatory diseases such as multiple sclerosis, there is growing evidence for glutamate transporter involvement. Here, we propose that the current knowledge strongly suggest a benefit from rebalancing glial transporters during treatment.}, }
@article {pmid37004595, year = {2023}, author = {Liu, Y}, title = {Zebrafish as a Model Organism for Studying Pathologic Mechanisms of Neurodegenerative Diseases and other Neural Disorders.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {6}, pages = {2603-2620}, pmid = {37004595}, issn = {1573-6830}, support = {ZR2022MC192//Shandong Provincial Natural Science Foundation/ ; 2021boshi01//the Doctoral Research Startup Funding from Qingdao Huanghai University , China/ ; hhxyjg2021//the School Teaching Reform Project of Qingdao Huanghai University, China/ ; }, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/genetics/pathology ; Zebrafish/genetics ; }, abstract = {Zebrafish are widely considered an excellent vertebrate model for studying the pathogenesis of human diseases because of their transparency of embryonic development, easy breeding, high similarity with human genes, and easy gene manipulation. Previous studies have shown that zebrafish as a model organism provides an ideal operating platform for clarifying the pathological and molecular mechanisms of neurodegenerative diseases and related human diseases. This review mainly summarizes the achievements and prospects of zebrafish used as model organisms in the research of neurodegenerative diseases and other human diseases related to the nervous system in recent years. In the future study of human disease mechanisms, the application of the zebrafish model will continue to provide a valuable operating platform and technical support for investigating and finding better prevention and treatment of these diseases, which has broad application prospects and practical significance. Zebrafish models used in neurodegenerative diseases and other diseases related to the nervous system.}, }
@article {pmid37004330, year = {2023}, author = {Wei, X and Huang, G and Liu, J and Ge, J and Zhang, W and Mei, Z}, title = {An update on the role of Hippo signaling pathway in ischemia-associated central nervous system diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {162}, number = {}, pages = {114619}, doi = {10.1016/j.biopha.2023.114619}, pmid = {37004330}, issn = {1950-6007}, mesh = {Humans ; Hippo Signaling Pathway ; *Brain Ischemia/metabolism ; Blood-Brain Barrier/metabolism ; *Parkinson Disease ; *Alzheimer Disease ; Ischemia ; *Ischemic Stroke ; }, abstract = {The most frequent reason of morbidity and mortality in the world, cerebral ischemia sets off a chain of molecular and cellular pathologies that associated with some central nervous system (CNS) disorders mainly including ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy and other CNS diseases. In recent times, despite significant advancements in the treatment of the pathological processes underlying various neurological illnesses, effective therapeutic approaches that are specifically targeted to minimizing the damage of such diseases remain absent. Hippo signaling pathway, characterized by enzyme linked reactions between MSTI/2, LAST1/2, and YAP or TAZ proteins, controls cell division, survival, and differentiation, as well as being engaged in a variety of biological activities, such as the development and transformation of the nervous system. Recently, accumulating studies demonstrated that Hippo pathway takes part in the processes of ischemic stroke, AD, PD, etc., including but not limited to oxidative stress, inflammatory response, blood-brain barrier damage, mitochondrial disorders, and neural cells death. Thus, it's crucial to understand the molecular basis of the Hippo signaling pathway for determining potential new therapeutic targets against ischemia-associated CNS diseases. Here, we discuss latest advances in the deciphering of the Hippo signaling pathway and highlight the therapeutic potential of targeting the pathway in treating ischemia-associated CNS diseases.}, }
@article {pmid36998125, year = {2024}, author = {De Marchi, F and Venkatesan, S and Saraceno, M and Mazzini, L and Grossini, E}, title = {Acetyl-L-carnitine and Amyotrophic Lateral Sclerosis: Current Evidence and Potential use.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {23}, number = {5}, pages = {588-601}, pmid = {36998125}, issn = {1996-3181}, support = {//Universit&#xe0; degli Studi del Piemonte Orientale/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Acetylcarnitine/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; Mitochondria/drug effects/metabolism ; Animals ; }, abstract = {BACKGROUND: The management of neurodegenerative diseases can be frustrating for clinicians, given the limited progress of conventional medicine in this context.<br><br>AIM: For this reason, a more comprehensive, integrative approach is urgently needed. Among various emerging focuses for intervention, the modulation of central nervous system energetics, oxidative stress, and inflammation is becoming more and more promising.<br><br>METHODS: In particular, electrons leakage involved in the mitochondrial energetics can generate reactive oxygen-free radical-related mitochondrial dysfunction that would contribute to the etiopathology of many disorders, such as Alzheimer's and other dementias, Parkinson's disease, multiple sclerosis, stroke, and amyotrophic lateral sclerosis (ALS).<br><br>RESULTS: In this context, using agents, like acetyl L-carnitine (ALCAR), provides mitochondrial support, reduces oxidative stress, and improves synaptic transmission.<br><br>CONCLUSION: This narrative review aims to update the existing literature on ALCAR molecular profile, tolerability, and translational clinical potential use in neurodegeneration, focusing on ALS.}, }
@article {pmid36997360, year = {2023}, author = {Favron-Godbout, C and Racine, E}, title = {[Not Available].}, journal = {Journal international de bioethique et d'ethique des sciences}, volume = {33}, number = {3}, pages = {95-128}, doi = {10.54695/jibes.333.0095}, pmid = {36997360}, issn = {2608-1008}, mesh = {Humans ; *Suicide, Assisted ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Morals ; Medical Assistance ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that leads some people with the disease to consider medical assistance in dying (MAiD). In this article, we describe how a variety of moral problems can emerge from this particular context and affect the well-being of people with ALS, their loved ones, and their caregivers. As MAiD is framed by specific eligibility criteria, broadening its eligibility is often proposed to address these issues. This critical review of the literature aims to identify moral issues relating to ALS that may persist or arise in the event of such widening. The MEDLINE, EMBASE CINAHL and Web of Science databases were searched using 4 search combinations to capture insights from existing literature on ethics, MAiD and ALS (N=41). A thematic content analysis highlighted 3 contextual categories where moral issues emerge (the experience of the disease, the choice of how to die, and the implementation of MAiD). Two important observations are discussed: 1) there are differences in perspective between stakeholders, which can lead to disagreement, but some similarities of perspective also exist; 2) the widening of MAiD eligibility mainly concerns moral issues related to the choice of how to die, and thus constitutes a partial solution to the problems identified.}, }
@article {pmid36991279, year = {2023}, author = {Mueller, S and Decker, L and Menge, S and Ludolph, AC and Freischmidt, A}, title = {The Fragile X Protein Family in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {60}, number = {7}, pages = {3898-3910}, pmid = {36991279}, issn = {1559-1182}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; RNA-Binding Proteins/genetics ; Motor Neurons/metabolism ; DNA Damage ; RNA-Binding Protein FUS/genetics ; Fragile X Mental Retardation Protein/genetics ; }, abstract = {The fragile X protein (FXP) family comprises the multifunctional RNA-binding proteins FMR1, FXR1, and FXR2 that play an important role in RNA metabolism and regulation of translation, but also in DNA damage and cellular stress responses, mitochondrial organization, and more. FMR1 is well known for its implication in neurodevelopmental diseases. Recent evidence suggests substantial contribution of this protein family to amyotrophic lateral sclerosis (ALS) pathogenesis. ALS is a highly heterogeneous neurodegenerative disease with multiple genetic and unclear environmental causes and very limited treatment options. The loss of motoneurons in ALS is still poorly understood, especially because pathogenic mechanisms are often restricted to patients with mutations in specific causative genes. Identification of converging disease mechanisms evident in most patients and suitable for therapeutic intervention is therefore of high importance. Recently, deregulation of the FXPs has been linked to pathogenic processes in different types of ALS. Strikingly, in many cases, available data points towards loss of expression and/or function of the FXPs early in the disease, or even at the presymptomatic state. In this review, we briefly introduce the FXPs and summarize available data about these proteins in ALS. This includes their relation to TDP-43, FUS, and ALS-related miRNAs, as well as their possible contribution to pathogenic protein aggregation and defective RNA editing. Furthermore, open questions that need to be addressed before definitively judging suitability of these proteins as novel therapeutic targets are discussed.}, }
@article {pmid36990317, year = {2023}, author = {Heo, AJ and Kim, SB and Kwon, YT and Ji, CH}, title = {The N-degron pathway: From basic science to therapeutic applications.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {2}, pages = {194934}, doi = {10.1016/j.bbagrm.2023.194934}, pmid = {36990317}, issn = {1876-4320}, mesh = {Humans ; *Amino Acids/metabolism ; Autophagy ; Proteasome Endopeptidase Complex/metabolism ; *Proteolysis ; Ubiquitin/metabolism ; }, abstract = {The N-degron pathway is a degradative system in which single N-terminal (Nt) amino acids regulate the half-lives of proteins and other biological materials. These determinants, called N-degrons, are recognized by N-recognins that link them to the ubiquitin (Ub)-proteasome system (UPS) or autophagy-lysosome system (ALS). In the UPS, the Arg/N-degron pathway targets the Nt-arginine (Nt-Arg) and other N-degrons to assemble Lys48 (K48)-linked Ub chains by UBR box N-recognins for proteasomal proteolysis. In the ALS, Arg/N-degrons are recognized by the N-recognin p62/SQSTSM-1/Sequestosome-1 to induce cis-degradation of substrates and trans-degradation of various cargoes such as protein aggregates and subcellular organelles. This crosstalk between the UPS and ALP involves reprogramming of the Ub code. Eukaryotic cells developed diverse ways to target all 20 principal amino acids for degradation. Here we discuss the components, regulation, and functions of the N-degron pathways, with an emphasis on the basic mechanisms and therapeutic applications of Arg/N-degrons and N-recognins.}, }
@article {pmid36982324, year = {2023}, author = {Panizzutti, B and Skvarc, D and Lin, S and Croce, S and Meehan, A and Bortolasci, CC and Marx, W and Walker, AJ and Hasebe, K and Kavanagh, BE and Morris, MJ and Mohebbi, M and Turner, A and Gray, L and Berk, L and Walder, K and Berk, M and Dean, OM}, title = {Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, pmid = {36982324}, issn = {1422-0067}, mesh = {Humans ; Minocycline/therapeutic use ; *Schizophrenia/drug therapy ; *Bipolar Disorder/drug therapy ; *Obsessive-Compulsive Disorder ; Anti-Inflammatory Agents/therapeutic use ; }, abstract = {Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.}, }
@article {pmid36982315, year = {2023}, author = {Balbi, M and Bonanno, G and Bonifacino, T and Milanese, M}, title = {The Physio-Pathological Role of Group I Metabotropic Glutamate Receptors Expressed by Microglia in Health and Disease with a Focus on Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, pmid = {36982315}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Microglia/metabolism ; Neurons/metabolism ; *Receptors, Metabotropic Glutamate/metabolism ; }, abstract = {Microglia cells are the resident immune cells of the central nervous system. They act as the first-line immune guardians of nervous tissue and central drivers of neuroinflammation. Any homeostatic alteration that can compromise neuron and tissue integrity could activate microglia. Once activated, microglia exhibit highly diverse phenotypes and functions related to either beneficial or harmful consequences. Microglia activation is associated with the release of protective or deleterious cytokines, chemokines, and growth factors that can in turn determine defensive or pathological outcomes. This scenario is complicated by the pathology-related specific phenotypes that microglia can assume, thus leading to the so-called disease-associated microglia phenotypes. Microglia express several receptors that regulate the balance between pro- and anti-inflammatory features, sometimes exerting opposite actions on microglial functions according to specific conditions. In this context, group I metabotropic glutamate receptors (mGluRs) are molecular structures that may contribute to the modulation of the reactive phenotype of microglia cells, and this is worthy of exploration. Here, we summarize the role of group I mGluRs in shaping microglia cells' phenotype in specific physio-pathological conditions, including some neurodegenerative disorders. A significant section of the review is specifically focused on amyotrophic lateral sclerosis (ALS) since it represents an entirely unexplored topic of research in the field.}, }
@article {pmid36980310, year = {2023}, author = {Du, H and Huo, Z and Chen, Y and Zhao, Z and Meng, F and Wang, X and Liu, S and Zhang, H and Zhou, F and Liu, J and Zhang, L and Zhou, S and Guan, Y and Wang, X}, title = {Induced Pluripotent Stem Cells and Their Applications in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {6}, pages = {}, pmid = {36980310}, issn = {2073-4409}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Cell- and Tissue-Based Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. Most studies have applied animal or single-gene intervention cell lines as ALS disease models, but they cannot accurately reflect the pathological characteristics of ALS. Induced pluripotent stem cells (iPSCs) can be reprogrammed from somatic cells, possessing the ability to self-renew and differentiate into a variety of cells. iPSCs can be obtained from ALS patients with different genotypes and phenotypes, and the genetic background of the donor cells remains unchanged during reprogramming. iPSCs can differentiate into neurons and glial cells related to ALS. Therefore, iPSCs provide an excellent method to evaluate the impact of diseases on ALS patients. Moreover, patient-derived iPSCs are obtained from their own somatic cells, avoiding ethical concerns and posing only a low risk of immune rejection. The iPSC technology creates new hope for ALS treatment. Here, we review recent studies on iPSCs and their applications in disease modeling, drug screening and cell therapy in ALS, with a particular focus on the potential for ALS treatment.}, }
@article {pmid36980297, year = {2023}, author = {Schreiber, S and Bernal, J and Arndt, P and Schreiber, F and Müller, P and Morton, L and Braun-Dullaeus, RC and Valdés-Hernández, MDC and Duarte, R and Wardlaw, JM and Meuth, SG and Mietzner, G and Vielhaber, S and Dunay, IR and Dityatev, A and Jandke, S and Mattern, H}, title = {Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity.}, journal = {Cells}, volume = {12}, number = {6}, pages = {}, pmid = {36980297}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Motor Cortex/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Motor Neurons/pathology ; Blood-Brain Barrier/pathology ; }, abstract = {Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood-brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.}, }
@article {pmid36980167, year = {2023}, author = {Figueiredo, AS and Loureiro, JR and Macedo-Ribeiro, S and Silveira, I}, title = {Advances in Nucleotide Repeat Expansion Diseases: Transcription Gets in Phase.}, journal = {Cells}, volume = {12}, number = {6}, pages = {}, pmid = {36980167}, issn = {2073-4409}, mesh = {Humans ; *DNA Repeat Expansion/genetics ; Mutation ; Proteins/genetics ; *Neuromuscular Diseases/genetics ; RNA/genetics ; Nucleotides ; }, abstract = {Unstable DNA repeat expansions and insertions have been found to cause more than 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. One of the main hallmarks of repeat expansion diseases is the formation of abnormal RNA or protein aggregates in the neuronal cells of affected individuals. Recent evidence indicates that alterations of the dynamic or material properties of biomolecular condensates assembled by liquid/liquid phase separation are critical for the formation of these aggregates. This is a thermodynamically-driven and reversible local phenomenon that condenses macromolecules into liquid-like compartments responsible for compartmentalizing molecules required for vital cellular processes. Disease-associated repeat expansions modulate the phase separation properties of RNAs and proteins, interfering with the composition and/or the material properties of biomolecular condensates and resulting in the formation of abnormal aggregates. Since several repeat expansions have arisen in genes encoding crucial players in transcription, this raises the hypothesis that wide gene expression dysregulation is common to multiple repeat expansion diseases. This review will cover the impact of these mutations in the formation of aberrant aggregates and how they modify gene transcription.}, }
@article {pmid36979898, year = {2023}, author = {Monroy, GR and Murguiondo Pérez, R and Weintraub Ben Zión, E and Vidal Alcántar-Garibay, O and Loza-López, EC and Tejerina Marion, E and Blancarte Hernández, E and Navarro-Torres, L and Ibarra, A}, title = {Immunization with Neural-Derived Peptides in Neurodegenerative Diseases: A Narrative Review.}, journal = {Biomedicines}, volume = {11}, number = {3}, pages = {}, pmid = {36979898}, issn = {2227-9059}, abstract = {Neurodegenerative diseases (NDDs) are a major health problem worldwide. Statistics suggest that in America in 2030 there will be more than 12 million people suffering from a neurodegenerative pathology. Furthermore, the increase in life expectancy enhances the importance of finding new and better therapies for these pathologies. NDDs could be classified into chronic or acute, depending on the time required for the development of clinical symptoms and brain degeneration. Nevertheless, both chronic and acute stages share a common immune and inflammatory pathway in their pathophysiology. Immunization with neural-derived peptides (INDP) is a novel therapy that has been studied during the last decade. By inoculating neural-derived peptides obtained from the central nervous system (CNS), this therapy aims to boost protective autoimmunity, an autoreactive response that leads to a protective phenotype that produces a healing environment and neuroregeneration instead of causing damage. INDP has shown promising findings in studies performed either in vitro, in vivo or even in some pre-clinical trials of different NDDs, standing as a potentially beneficial therapy. In this review, we will describe some of the studies in which the effect of INDP strategies have been explored in different (chronic and acute) neurodegenerative diseases.}, }
@article {pmid36979413, year = {2023}, author = {Roussos, A and Kitopoulou, K and Borbolis, F and Palikaras, K}, title = {Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {13}, number = {3}, pages = {}, pmid = {36979413}, issn = {2218-273X}, mesh = {Animals ; Humans ; *Caenorhabditis elegans/metabolism ; Quality of Life ; Disease Models, Animal ; *Neurodegenerative Diseases/metabolism ; }, abstract = {In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases and increase human life expectancy. However, longevity is accompanied by an accretion in the frequency of age-related neurodegenerative diseases, creating a growing burden, with pervasive social impact for human societies. The cost of managing such chronic disorders and the lack of effective treatments highlight the need to decipher their molecular and genetic underpinnings, in order to discover new therapeutic targets. In this effort, the nematode Caenorhabditis elegans serves as a powerful tool to recapitulate several disease-related phenotypes and provides a highly malleable genetic model that allows the implementation of multidisciplinary approaches, in addition to large-scale genetic and pharmacological screens. Its anatomical transparency allows the use of co-expressed fluorescent proteins to track the progress of neurodegeneration. Moreover, the functional conservation of neuronal processes, along with the high homology between nematode and human genomes, render C. elegans extremely suitable for the study of human neurodegenerative disorders. This review describes nematode models used to study neurodegeneration and underscores their contribution in the effort to dissect the molecular basis of human diseases and identify novel gene targets with therapeutic potential.}, }
@article {pmid36979267, year = {2023}, author = {Gandla, K and Babu, AK and Unnisa, A and Sharma, I and Singh, LP and Haque, MA and Dashputre, NL and Baig, S and Siddiqui, FA and Khandaker, MU and Almujally, A and Tamam, N and Sulieman, A and Khan, SL and Emran, TB}, title = {Carotenoids: Role in Neurodegenerative Diseases Remediation.}, journal = {Brain sciences}, volume = {13}, number = {3}, pages = {}, pmid = {36979267}, issn = {2076-3425}, abstract = {Numerous factors can contribute to the development of neurodegenerative disorders (NDs), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Oxidative stress (OS), a fairly common ND symptom, can be caused by more reactive oxygen species being made. In addition, the pathological state of NDs, which includes a high number of protein aggregates, could make chronic inflammation worse by activating microglia. Carotenoids, often known as "CTs", are pigments that exist naturally and play a vital role in the prevention of several brain illnesses. CTs are organic pigments with major significance in ND prevention. More than 600 CTs have been discovered in nature, and they may be found in a wide variety of creatures. Different forms of CTs are responsible for the red, yellow, and orange pigments seen in many animals and plants. Because of their unique structure, CTs exhibit a wide range of bioactive effects, such as anti-inflammatory and antioxidant effects. The preventive effects of CTs have led researchers to find a strong correlation between CT levels in the body and the avoidance and treatment of several ailments, including NDs. To further understand the connection between OS, neuroinflammation, and NDs, a literature review has been compiled. In addition, we have focused on the anti-inflammatory and antioxidant properties of CTs for the treatment and management of NDs.}, }
@article {pmid36979000, year = {2023}, author = {Iova, OM and Marin, GE and Lazar, I and Stanescu, I and Dogaru, G and Nicula, CA and Bulboacă, AE}, title = {Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Neurodegenerative Disorders-An Overview.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {36979000}, issn = {2076-3921}, abstract = {Nitric oxide, a ubiquitous molecule found throughout the natural world, is a key molecule implicated in many central and benefic molecular pathways and has a well-established role in the function of the central nervous system, as numerous studies have previously shown. Dysregulation of its metabolism, mainly the upregulation of nitric oxide production, has been proposed as a trigger and/or aggravator for many neurological affections. Increasing evidence supports the implication of this molecule in prevalent neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. The mechanisms proposed for its neurotoxicity mainly center around the increased quantities of nitric oxide that are produced in the brain, their cause, and, most importantly, the pathological metabolic cascades created. These cascades lead to the formation of neuronal toxic substances that impair the neurons' function and structure on multiple levels. The purpose of this review is to present the main causes of increased pathological production, as well as the most important pathophysiological mechanisms triggered by nitric oxide, mechanisms that could help explain a part of the complex picture of neurodegenerative diseases and help develop targeted therapies.}, }
@article {pmid36977124, year = {2023}, author = {Nugumanova, G and Ponomarev, ED and Askarova, S and Fasler-Kan, E and Barteneva, NS}, title = {Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases.}, journal = {Toxins}, volume = {15}, number = {3}, pages = {}, pmid = {36977124}, issn = {2072-6651}, mesh = {Animals ; Humans ; Cyanobacteria Toxins ; *Neurodegenerative Diseases ; Ecosystem ; *Amino Acids, Diamino/metabolism ; Fresh Water/microbiology ; Amino Acids/metabolism ; *Cyanobacteria/metabolism ; Mammals ; }, abstract = {Cyanobacteria produce a wide range of structurally diverse cyanotoxins and bioactive cyanopeptides in freshwater, marine, and terrestrial ecosystems. The health significance of these metabolites, which include genotoxic- and neurotoxic agents, is confirmed by continued associations between the occurrence of animal and human acute toxic events and, in the long term, by associations between cyanobacteria and neurodegenerative diseases. Major mechanisms related to the neurotoxicity of cyanobacteria compounds include (1) blocking of key proteins and channels; (2) inhibition of essential enzymes in mammalian cells such as protein phosphatases and phosphoprotein phosphatases as well as new molecular targets such as toll-like receptors 4 and 8. One of the widely discussed implicated mechanisms includes a misincorporation of cyanobacterial non-proteogenic amino acids. Recent research provides evidence that non-proteinogenic amino acid BMAA produced by cyanobacteria have multiple effects on translation process and bypasses the proof-reading ability of the aminoacyl-tRNA-synthetase. Aberrant proteins generated by non-canonical translation may be a factor in neuronal death and neurodegeneration. We hypothesize that the production of cyanopeptides and non-canonical amino acids is a more general mechanism, leading to mistranslation, affecting protein homeostasis, and targeting mitochondria in eukaryotic cells. It can be evolutionarily ancient and initially developed to control phytoplankton communities during algal blooms. Outcompeting gut symbiotic microorganisms may lead to dysbiosis, increased gut permeability, a shift in blood-brain-barrier functionality, and eventually, mitochondrial dysfunction in high-energy demanding neurons. A better understanding of the interaction between cyanopeptides metabolism and the nervous system will be crucial to target or to prevent neurodegenerative diseases.}, }
@article {pmid36975449, year = {2023}, author = {Tsalikidis, C and Mitsala, A and Mentonis, VI and Romanidis, K and Pappas-Gogos, G and Tsaroucha, AK and Pitiakoudis, M}, title = {Predictive Factors for Anastomotic Leakage Following Colorectal Cancer Surgery: Where Are We and Where Are We Going?.}, journal = {Current oncology (Toronto, Ont.)}, volume = {30}, number = {3}, pages = {3111-3137}, pmid = {36975449}, issn = {1718-7729}, mesh = {Humans ; *Anastomotic Leak/etiology/diagnosis/epidemiology ; Anastomosis, Surgical/adverse effects ; Risk Factors ; Biomarkers ; *Colorectal Neoplasms/surgery/complications ; }, abstract = {Anastomotic leakage (AL) remains one of the most severe complications following colorectal cancer (CRC) surgery. Indeed, leaks that may occur after any type of intestinal anastomosis are commonly associated with a higher reoperation rate and an increased risk of postoperative morbidity and mortality. At first, our review aims to identify specific preoperative, intraoperative and perioperative factors that eventually lead to the development of anastomotic dehiscence based on the current literature. We will also investigate the role of several biomarkers in predicting the presence of ALs following colorectal surgery. Despite significant improvements in perioperative care, advances in surgical techniques, and a high index of suspicion of this complication, the incidence of AL remained stable during the last decades. Thus, gaining a better knowledge of the risk factors that influence the AL rates may help identify high-risk surgical patients requiring more intensive perioperative surveillance. Furthermore, prompt diagnosis of this severe complication may help improve patient survival. To date, several studies have identified predictive biomarkers of ALs, which are most commonly associated with the inflammatory response to colorectal surgery. Interestingly, early diagnosis and evaluation of the severity of this complication may offer a significant opportunity to guide clinical judgement and decision-making.}, }
@article {pmid36973580, year = {2023}, author = {Marra, JM and de Castro Vieira, PV and de Senna Migueletto, AM and de Oliveira, LFA and de Souza, ECF and Marquini, GV}, title = {Neurogenic Disorders and the Lower Urinary Tract Dysfunction: Proposed Approach for the Gynecologist.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {30}, number = {7}, pages = {2087-2091}, pmid = {36973580}, issn = {1933-7205}, mesh = {Humans ; *Urinary Bladder ; *Urinary Bladder, Neurogenic/diagnosis/therapy/etiology ; Quality of Life ; Activities of Daily Living ; Gynecologists ; }, abstract = {BACKGROUND: The scenario of the patient with neuropathies, which are related to urinary disorders, impacts the quality of life. Symptoms can lead to social isolation, impair activities of daily living, and shorten life expectancy. This study aims to make a practical and integrative review of current recommendations for the urogynecological approach of patients with neuropathy and urinary dysfunction.<br><br>METHODS: The authors searched for data on combinations of the terms "lower urinary tract symptoms" AND "neurogenic voiding dysfunction" from January 2012 to January 2022 in the following scientific databases: PUBMED, MEDLINE, EMBASE, and The Cochrane Library.<br><br>INCLUSION CRITERIA: randomized clinical trials, protocols from specialized societies and articles before that period, and according to clinical relevance.<br><br>EXCLUSION CRITERIA: case series or reports, expert opinions not endorsed by medical societies in the area.<br><br>RESULTS: From the 25 studies mentioned, 09 studies were selected according to pre-established criteria and qualitative analysis of relevance. The authors add 2 references for relevance in the area of &#x200b;&#x200b;urogynecology and neurological diseases. According to the selected scientific references, the main neuropathies that can cause urinary dysfunction are CNS injuries such as stroke, spinal cord injury, meningomyelocele, and amyotrophic lateral sclerosis. Ten steps below were compiled to facilitate the gynecological approach, according to the researched literature.<br><br>CONCLUSION: It is important for the medical assistant to pay close attention to careful anamnesis and post-emptying urinary residual volume. The treatment in general addresses greater fluid intake, maneuvers to favor bladder emptying, medications, and/or intermittent self-catheterization. The approach of a multidisciplinary team can make a difference in the patient's prognosis and quality of life.}, }
@article {pmid36968195, year = {2023}, author = {Jagtap, YA and Kumar, P and Kinger, S and Dubey, AR and Choudhary, A and Gutti, RK and Singh, S and Jha, HC and Poluri, KM and Mishra, A}, title = {Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1146564}, pmid = {36968195}, issn = {2296-634X}, abstract = {The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson's disease, Amyotrophic Lateral Sclerosis, and Alzheimer's disease, along with protein misfolding. The aberrantly folded proteins are known to link with impaired mitochondrial pathways, further contributing to disease pathogenesis. Despite their central significance, the implications of mitochondrial homeostasis disruption on other organelles and cellular processes remain insufficiently explored. Here, we have reviewed the dysfunction in mitochondrial physiology, under neuron degenerating conditions. The disease misfolded proteins impact quality control mechanisms of mitochondria, such as fission, fusion, mitophagy, and proteasomal clearance, to the detriment of neuron. The adversely affected mitochondrial functional roles, like oxidative phosphorylation, calcium homeostasis, and biomolecule synthesis as well as its axes and contacts with endoplasmic reticulum and lysosomes are also discussed. Mitochondria sense and respond to multiple cytotoxic stress to make cell adapt and survive, though chronic dysfunction leads to cell death. Mitochondria and their proteins can be candidates for biomarkers and therapeutic targets. Investigation of internetworking between mitochondria and neurodegeneration proteins can enhance our holistic understanding of such conditions and help in designing more targeted therapies.}, }
@article {pmid36967829, year = {2023}, author = {Nilaver, BI and Urbanski, HF}, title = {Mechanisms underlying TDP-43 pathology and neurodegeneration: An updated Mini-Review.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1142617}, pmid = {36967829}, issn = {1663-4365}, support = {P30 AG066518/AG/NIA NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; RF1 AG062220/AG/NIA NIH HHS/United States ; }, abstract = {TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases. The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43's normal function. Overall, the present article summarizes current knowledge regarding TDP-43's normal and pathological cell functions and sheds light on possible mechanisms that underlie its causal role in neurodegeneration.}, }
@article {pmid36964253, year = {2023}, author = {Kim, J and Kim, HS and Chung, JH}, title = {Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway.}, journal = {Experimental &amp; molecular medicine}, volume = {55}, number = {3}, pages = {510-519}, pmid = {36964253}, issn = {2092-6413}, mesh = {Humans ; *DNA, Mitochondrial/genetics/metabolism ; Immunity, Innate ; *Inflammasomes/metabolism ; Inflammation/metabolism ; Mitochondria/metabolism ; Nucleotidyltransferases/genetics ; Signal Transduction ; Membrane Proteins/metabolism ; }, abstract = {In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin. In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid36963381, year = {2023}, author = {Piol, D and Robberechts, T and Da Cruz, S}, title = {Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis.}, journal = {Neuron}, volume = {111}, number = {9}, pages = {1355-1380}, doi = {10.1016/j.neuron.2023.02.028}, pmid = {36963381}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Mutation ; Neuromuscular Junction/metabolism ; RNA, Messenger ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Key early features of amyotrophic lateral sclerosis (ALS) are denervation of neuromuscular junctions and axonal degeneration. Motor neuron homeostasis relies on local translation through controlled regulation of axonal mRNA localization, transport, and stability. Yet the composition of the local transcriptome, translatome (mRNAs locally translated), and proteome during health and disease remains largely unexplored. This review covers recent discoveries on axonal translation as a critical mechanism for neuronal maintenance/survival. We focus on two RNA binding proteins, transactive response DNA binding protein-43 (TDP-43) and fused in sarcoma (FUS), whose mutations cause ALS and frontotemporal dementia (FTD). Emerging evidence points to their essential role in the maintenance of axons and synapses, including mRNA localization, transport, and local translation, and whose dysfunction may contribute to ALS. Finally, we describe recent advances in omics-based approaches mapping compartment-specific local RNA and protein compositions, which will be invaluable to elucidate fundamental local processes and identify key targets for therapy development.}, }
@article {pmid36963363, year = {2023}, author = {Mo, J and Hu, J and Cheng, X}, title = {The role of high mobility group box 1 in neuroinflammatory related diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {161}, number = {}, pages = {114541}, doi = {10.1016/j.biopha.2023.114541}, pmid = {36963363}, issn = {1950-6007}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Brain Injuries, Traumatic ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; Inflammation ; Neuroinflammatory Diseases ; }, abstract = {High mobility group box 1 (HMGB1) is a ubiquitous and highly conserved non-histone DNA-binding protein with different biological functions according to its subcellular localization. It is widely believed that HMGB1, which is released into the extracellular space, plays a key role in the inflammatory response. In recent years, numerous studies have shown that the development of various neurological diseases such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), cerebrovascular disease and traumatic brain injury (TBI) are inextricably linked to inflammation. We will review the mechanisms of HMGB1 and its receptors in nervous system inflammation to provide a basis for further development of new HMGB1-based therapies.}, }
@article {pmid36950516, year = {2023}, author = {Karvandi, MS and Sheikhzadeh Hesari, F and Aref, AR and Mahdavi, M}, title = {The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1105247}, pmid = {36950516}, issn = {1662-5102}, abstract = {Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.}, }
@article {pmid36949305, year = {2023}, author = {Nainu, F and Mamada, SS and Harapan, H and Emran, TB}, title = {Inflammation-Mediated Responses in the Development of Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1411}, number = {}, pages = {39-70}, pmid = {36949305}, issn = {0065-2598}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/genetics ; Neuroinflammatory Diseases ; Genome-Wide Association Study ; Inflammation ; }, abstract = {Since its first description over a century ago, neurodegenerative diseases (NDDs) have impaired the lives of millions of people worldwide. As one of the major threats to human health, NDDs are characterized by progressive loss of neuronal structure and function, leading to the impaired function of the CNS. While the precise mechanisms underlying the emergence of NDDs remains elusive, association of neuroinflammation with the emergence of NDDs has been suggested. The immune system is tightly controlled to maintain homeostatic milieu and failure in doing so has been shown catastrophic. Here, we review current concepts on the cellular and molecular drivers responsible in the induction of neuroinflammation and how such event further promotes neuronal damage leading to neurodegeneration. Experimental data generated from cell culture and animal studies, gross and molecular pathologies of human CNS samples, and genome-wide association study are discussed to provide deeper insights into the mechanistic details of neuroinflammation and its roles in the emergence of NDDs.}, }
@article {pmid36935218, year = {2023}, author = {Copley, KE and Shorter, J}, title = {Repetitive elements in aging and neurodegeneration.}, journal = {Trends in genetics : TIG}, volume = {39}, number = {5}, pages = {381-400}, pmid = {36935218}, issn = {0168-9525}, support = {R21 NS090205/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; F31 NS129101/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 AG061784/AG/NIA NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *DNA Transposable Elements/genetics ; Mutagenesis, Insertional ; RNA, Small Interfering/genetics ; *Neurodegenerative Diseases/genetics ; Aging/genetics ; Mammals/genetics ; }, abstract = {Repetitive elements (REs), such as transposable elements (TEs) and satellites, comprise much of the genome. Here, we review how TEs and (peri)centromeric satellite DNA may contribute to aging and neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Alterations in RE expression, retrotransposition, and chromatin microenvironment may shorten lifespan, elicit neurodegeneration, and impair memory and movement. REs may cause these phenotypes via DNA damage, protein sequestration, insertional mutagenesis, and inflammation. We discuss several TE families, including gypsy, HERV-K, and HERV-W, and how TEs interact with various factors, including transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and the siRNA and piwi-interacting (pi)RNA systems. Studies of TEs in neurodegeneration have focused on Drosophila and, thus, further examination in mammals is needed. We suggest that therapeutic silencing of REs could help mitigate neurodegenerative disorders.}, }
@article {pmid36933816, year = {2023}, author = {Oliveira, NAS and Pinho, BR and Oliveira, JMA}, title = {Swimming against ALS: How to model disease in zebrafish for pathophysiological and behavioral studies.}, journal = {Neuroscience and biobehavioral reviews}, volume = {148}, number = {}, pages = {105138}, doi = {10.1016/j.neubiorev.2023.105138}, pmid = {36933816}, issn = {1873-7528}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis ; Zebrafish/genetics ; Swimming ; *Neurodegenerative Diseases ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to progressive disability and motor impairment. Existing therapies provide modest improvements in patient survival, raising a need for new treatments for ALS. Zebrafish is a promising model animal for translational and fundamental research in ALS - it is an experimentally tractable vertebrate, with high homology to humans and an ample experimental toolbox. These advantages allow high-throughput study of behavioral and pathophysiological phenotypes. The last decade saw an increased interest in modelling ALS in zebrafish, leading to the current abundance and variety of available methods and models. Additionally, the rise of gene editing techniques and toxin combination studies has created novel opportunities for ALS studies in zebrafish. In this review, we address the relevance of zebrafish as a model animal for ALS studies, the strategies for model induction and key phenotypical evaluation. Furthermore, we discuss established and emerging zebrafish models of ALS, analyzing their validity, including their potential for drug testing, and highlighting research opportunities in this area.}, }
@article {pmid36927428, year = {2023}, author = {Rahman, MM and Tumpa, MAA and Rahaman, MS and Islam, F and Sutradhar, PR and Ahmed, M and Alghamdi, BS and Hafeez, A and Alexiou, A and Perveen, A and Ashraf, GM}, title = {Emerging Promise of Therapeutic Approaches Targeting Mitochondria in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {21}, number = {5}, pages = {1081-1099}, pmid = {36927428}, issn = {1875-6190}, mesh = {Humans ; Oxidative Stress/physiology ; *Mitochondrial Diseases/drug therapy/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/drug therapy/genetics ; DNA, Mitochondrial/metabolism/therapeutic use ; }, abstract = {Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.}, }
@article {pmid36925418, year = {2023}, author = {Prajjwal, P and Shashank, S and Al-Ezzi, SMS and Sharma, B and Aubourg, O and Kaushish, A and Marsool, MDM and Nagre, A and Asharaf, S}, title = {Frontotemporal dementia: Addressing the scattered harbingers of genetics and its relationship with glucose metabolism, bipolar disorder, and amyotrophic lateral sclerosis.}, journal = {Disease-a-month : DM}, volume = {69}, number = {5}, pages = {101545}, doi = {10.1016/j.disamonth.2023.101545}, pmid = {36925418}, issn = {1557-8194}, mesh = {Humans ; *Pick Disease of the Brain ; *Frontotemporal Dementia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Bipolar Disorder/diagnosis/genetics ; Brain/diagnostic imaging ; Glucose ; }, abstract = {Frontotemporal Dementia, also known by the name Pick's disease, is a rare form of dementia that can run for several generations. The two key characteristics are argyrophilic, spherical intraneuronal inclusions, which most frequently impact the frontal and temporal poles, and localized cortical atrophy (Pick bodies). Although personality decline and memory loss are frequently more severe than the visuospatial and apraxia disorders that are common in Alzheimer's disease, clinical overlap with other non-Alzheimer degenerative disorders is being increasingly recognized. The limbic system, which includes the hippocampus, entorhinal cortex, and amygdala, typically experiences the greatest levels of neuronal loss and degeneration. In the hippocampus's dentate fascia, several Pick bodies are frequently seen. Leukoencephalopathy and inflated cortical neurons are less specific symptoms (Pick cells). In this paper, we review the factors leading to Picks disease along with its pathophysiology, clinical manifestations, diagnosis, imaging, treatment, prognosis, and a comprehensive discussion on the same. We have also discussed the relationship of frontotemporal dementia with glucose metabolism, bipolar disorder, and amyotrophic lateral sclerosis, all of which are emerging fields of interest and need more studies.}, }
@article {pmid36923490, year = {2023}, author = {Calderón-Garcidueñas, L and Torres-Jardón, R and Greenough, GP and Kulesza, R and González-Maciel, A and Reynoso-Robles, R and García-Alonso, G and Chávez-Franco, DA and García-Rojas, E and Brito-Aguilar, R and Silva-Pereyra, HG and Ayala, A and Stommel, EW and Mukherjee, PS}, title = {Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders-Denial is not an option.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1117695}, pmid = {36923490}, issn = {1664-2295}, abstract = {Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ1 - 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.}, }
@article {pmid36922834, year = {2023}, author = {Mehta, PR and Brown, AL and Ward, ME and Fratta, P}, title = {The era of cryptic exons: implications for ALS-FTD.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {16}, pmid = {36922834}, issn = {1750-1326}, support = {102186/B/13/Z/WT_/Wellcome Trust/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *TDP-43 Proteinopathies/metabolism ; Neurons/metabolism ; Exons/genetics ; *Neurodegenerative Diseases/metabolism ; }, abstract = {TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer's disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.}, }
@article {pmid36922023, year = {2023}, author = {Hansen-Flaschen, J and Ackrivo, J}, title = {Practical Guide to Management of Long-Term Noninvasive Ventilation for Adults With Chronic Neuromuscular Disease.}, journal = {Respiratory care}, volume = {68}, number = {8}, pages = {1123-1157}, pmid = {36922023}, issn = {1943-3654}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Humans ; Respiration, Artificial ; *Noninvasive Ventilation ; Quality of Life ; *Respiratory Insufficiency/etiology/therapy ; Chronic Disease ; *Neuromuscular Diseases/complications/therapy ; }, abstract = {Recent technological advances in respiratory support and monitoring have dramatically enhanced the utility of long-term noninvasive ventilation (NIV). Improved quality of life and prolonged survival have been demonstrated for several common chronic neuromuscular diseases. Many adults with progressive neuromuscular respiratory disease can now comfortably maintain normal ventilation at home to near total respiratory muscle paralysis without needing a tracheostomy. However, current practice in many communities falls short of that potential. Mastery of the new technology calls for detailed awareness of the respiratory cycle; expert knowledge of mechanical devices, facial interfaces, and quantitative monitoring tools for home ventilation; and a willingness to stay current in a rapidly expanding body of clinical research. The depth and breadth of the expertise required to manage home assisted ventilation has given rise to a new focused medical subspecialty in chronic respiratory failure at the interface between pulmonology, critical care, and sleep medicine. For clinicians seeking pragmatic "how to" guidance, this primer presents a comprehensive, physician-directed management approach to long-term NIV of adults with chronic neuromuscular respiratory disease. Bi-level devices, portable ventilators, ventilation modalities, terminology, and monitoring strategies are reviewed in detail. Building on that knowledge base, we present a step-by-step guide to initiation, refinement, and maintenance of home NIV tailored to patient-centered goals of therapy. The quantitative approach recommended incorporates routine monitoring of home ventilation using technologies that have only recently become widely available including cloud-based device telemonitoring and noninvasive measurements of blood gases. Strategies for troubleshooting and problem solving are included.}, }
@article {pmid36918362, year = {2023}, author = {Chapman, L and Cooper-Knock, J and Shaw, PJ}, title = {Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {5}, pages = {1745-1757}, pmid = {36918362}, issn = {1460-2156}, support = {BRC-1215-20017/DH_/Department of Health/United Kingdom ; 216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; NF-SI-0617-10077/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease/drug therapy ; Exercise ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. The only established epidemiological risk factors for ALS are male sex and increasing age. The role of physical activity has been debated as an environmental risk factor. Over the last decade multiple studies have attempted to delineate the architecture of ALS. These have not yet established definite risk factors, often due to low-powered studies, lack of focus on at-risk genotypes and sub-optimal methodology. We have conducted a review of all the studies published between 2009 and December 2021. The free text search terms were [(motor neuron disease) OR (MND) OR (Amyotrophic Lateral Sclerosis) OR (ALS)] AND [(Exercise) or (Physical Activity) or (PA) or (sport)]. We identified common themes, for example soccer, head injury and the physiological mechanisms that differ in ALS patients. We have analysed the relevant, available studies (n = 93), highlighting the underlying reasons for any reported discrepancies. Overall, we have found that the more highly powered studies using validated exposure methodologies, linked strenuous, anaerobic physical activity as a risk factor for ALS. Future large-scale studies focusing on specific at-risk genotypes and physical activity should be conducted to confirm this finding. This will strengthen the evidence already surrounding strenuous physical activity as an environmental risk factor for ALS and allow advice to be given to at-risk family members. Increasing our understanding of the genetic-environmental interactions in the pathophysiology of ALS will allow for the possibility of developing preventative therapeutic approaches.}, }
@article {pmid36913894, year = {2023}, author = {Jin, T and Zhang, Y and Botchway, BOA and Huang, M and Lu, Q and Liu, X}, title = {Quercetin activates the Sestrin2/AMPK/SIRT1 axis to improve amyotrophic lateral sclerosis.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {161}, number = {}, pages = {114515}, doi = {10.1016/j.biopha.2023.114515}, pmid = {36913894}, issn = {1950-6007}, mesh = {Humans ; AMP-Activated Protein Kinases/metabolism ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Quercetin/pharmacology/therapeutic use ; Sirtuin 1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease with poor prognosis. The intricacies surrounding its pathophysiology could partly account for the lack of effective treatment for ALS. Sestrin2 has been reported to improve metabolic, cardiovascular and neurodegenerative diseases, and is involved in the direct and indirect activation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) axis. Quercetin, as a phytochemical, has considerable biological activities, such as anti-oxidation, anti-inflammation, anti-tumorigenicity, and neuroprotection. Interestingly, quercetin can activate the AMPK/SIRT1 signaling pathway to reduce endoplasmic reticulum stress, and alleviate apoptosis and inflammation. This report examines the molecular relationship between Sestrin2 and AMPK/SIRT1 axis, as well as the main biological functions and research progress of quercetin, together with the correlation between quercetin and Sestrin2/AMPK/SIRT1 axis in neurodegenerative diseases.}, }
@article {pmid36905838, year = {2023}, author = {Barone, M and Leo, AD and de van der Schueren, MAE}, title = {Malnutrition assessment by Global Leadership Initiative on Malnutrition criteria in patients with amyotrophic lateral sclerosis.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {109}, number = {}, pages = {111997}, doi = {10.1016/j.nut.2023.111997}, pmid = {36905838}, issn = {1873-1244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Leadership ; Reproducibility of Results ; *Malnutrition/diagnosis/etiology ; Weight Loss ; Nutrition Assessment ; Nutritional Status ; }, abstract = {Malnutrition can play an important prognostic role in terms of survival in patients with amyotrophic lateral sclerosis (ALS). In this clinical context, applying criteria defining malnutrition requires particular attention, especially in the initial stage of the disease. This article discusses the application of the most recent criteria used for the definition of malnutrition when applied to patients with ALS. Currently, the Global Leadership Initiative on Malnutrition (GLIM) criteria, which have received a worldwide consensus, are based on parameters such as unintentional weight loss, low body mass index (BMI), and reduced muscle mass (phenotypic criteria) in combination with reduced food intake and assimilation or inflammation and disease (etiologic criteria). However, as discussed in this review, the initial unintentional weight loss and the consequent BMI reduction could be attributed, at least in part, to muscle atrophy, which also alters the reliability of muscle mass assessment. Moreover, the condition of hypermetabolism, which is observed in up to 50% of these patients, may complicate the calculation of total energy requirements. Finally, it remains to be established if the presence of neuroinflammation can be considered a type of inflammatory process able to induce malnutrition in these patients. In conclusion, the monitoring of BMI, associated with body composition evaluation by bioimpedance measurement or specific formulas, could be a practicable approach to the diagnosis of malnutrition in patients with ALS. In addition, attention should be given to dietary intake (e.g., in patients with dysphagia) and excessive involuntary weight loss. On the other hand, as suggested by GLIM criteria, a single assessment of BMI resulting in <20 kg/m[2] or <22 kg/m[2] in patients aged <70 y and ≥70 y, respectively, should always be considered a sign of malnutrition.}, }
@article {pmid36902233, year = {2023}, author = {Potes, Y and Cachán-Vega, C and Antuña, E and García-González, C and Menéndez-Coto, N and Boga, JA and Gutiérrez-Rodríguez, J and Bermúdez, M and Sierra, V and Vega-Naredo, I and Coto-Montes, A and Caballero, B}, title = {Benefits of the Neurogenic Potential of Melatonin for Treating Neurological and Neuropsychiatric Disorders.}, journal = {International journal of molecular sciences}, volume = {24}, number = {5}, pages = {}, pmid = {36902233}, issn = {1422-0067}, support = {PI21/01596//Instituto de Salud Carlos III/ ; IDI/2021/000033//Foundation for the Promotion of Applied Scientific Research and Technology in Asturias/ ; 2021-030-INTRAMURALES-POOCY//Instituto de Investigaci&#xf3;n Sanitaria del Principado de Asturias/ ; }, mesh = {*Melatonin/pharmacology ; *Neural Stem Cells ; Hippocampus ; Neurogenesis ; Neurons ; }, abstract = {There are several neurological diseases under which processes related to adult brain neurogenesis, such cell proliferation, neural differentiation and neuronal maturation, are affected. Melatonin can exert a relevant benefit for treating neurological disorders, given its well-known antioxidant and anti-inflammatory properties as well as its pro-survival effects. In addition, melatonin is able to modulate cell proliferation and neural differentiation processes in neural stem/progenitor cells while improving neuronal maturation of neural precursor cells and newly created postmitotic neurons. Thus, melatonin shows relevant pro-neurogenic properties that may have benefits for neurological conditions associated with impairments in adult brain neurogenesis. For instance, the anti-aging properties of melatonin seem to be linked to its neurogenic properties. Modulation of neurogenesis by melatonin is beneficial under conditions of stress, anxiety and depression as well as for the ischemic brain or after a brain stroke. Pro-neurogenic actions of melatonin may also be beneficial for treating dementias, after a traumatic brain injury, and under conditions of epilepsy, schizophrenia and amyotrophic lateral sclerosis. Melatonin may represent a pro-neurogenic treatment effective for retarding the progression of neuropathology associated with Down syndrome. Finally, more studies are necessary to elucidate the benefits of melatonin treatments under brain disorders related to impairments in glucose and insulin homeostasis.}, }
@article {pmid36902042, year = {2023}, author = {Gulino, R}, title = {Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {5}, pages = {}, pmid = {36902042}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Motor Neurons/pathology ; *Neurodegenerative Diseases/pathology ; Synapses/pathology ; Neuronal Plasticity/physiology ; }, abstract = {Recent evidence has supported the hypothesis that amyotrophic lateral sclerosis (ALS) is a multi-step disease, as the onset of symptoms occurs after sequential exposure to a defined number of risk factors. Despite the lack of precise identification of these disease determinants, it is known that genetic mutations may contribute to one or more of the steps leading to ALS onset, the remaining being linked to environmental factors and lifestyle. It also appears evident that compensatory plastic changes taking place at all levels of the nervous system during ALS etiopathogenesis may likely counteract the functional effects of neurodegeneration and affect the timing of disease onset and progression. Functional and structural events of synaptic plasticity probably represent the main mechanisms underlying this adaptive capability, causing a significant, although partial and transient, resiliency of the nervous system affected by a neurodegenerative disease. On the other hand, the failure of synaptic functions and plasticity may be part of the pathological process. The aim of this review was to summarize what it is known today about the controversial involvement of synapses in ALS etiopathogenesis, and an analysis of the literature, although not exhaustive, confirmed that synaptic dysfunction is an early pathogenetic process in ALS. Moreover, it appears that adequate modulation of structural and functional synaptic plasticity may likely support function sparing and delay disease progression.}, }
@article {pmid36899898, year = {2023}, author = {Kupershmidt, L and Youdim, MBH}, title = {The Neuroprotective Activities of the Novel Multi-Target Iron-Chelators in Models of Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Aging.}, journal = {Cells}, volume = {12}, number = {5}, pages = {}, pmid = {36899898}, issn = {2073-4409}, mesh = {Mice ; Animals ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Hydroxyquinolines/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Iron Chelating Agents/therapeutic use ; Mice, Transgenic ; *Parkinson Disease/pathology ; Aging ; Iron/metabolism ; }, abstract = {The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques. These novel iron chelators exhibit neuroprotective activities by attenuating relevant neurodegenerative pathology, promoting positive behavior changes, and up-regulating neuroprotective signaling pathways. Taken together, these results suggest that our multifunctional iron-chelating compounds can upregulate several neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders, such as PD, AD, ALS, and aging-related cognitive decline, in which oxidative stress and iron-mediated toxicity and dysregulation of iron homeostasis have been implicated.}, }
@article {pmid36899889, year = {2023}, author = {Abdelhamid, RF and Nagano, S}, title = {Crosstalk between Oxidative Stress and Aging in Neurodegeneration Disorders.}, journal = {Cells}, volume = {12}, number = {5}, pages = {}, pmid = {36899889}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases ; Oxidative Stress ; Aging ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {The world population is aging rapidly, and increasing lifespan exacerbates the burden of age-related health issues. On the other hand, premature aging has begun to be a problem, with increasing numbers of younger people suffering aging-related symptoms. Advanced aging is caused by a combination of factors: lifestyle, diet, external and internal factors, as well as oxidative stress (OS). Although OS is the most researched aging factor, it is also the least understood. OS is important not only in relation to aging but also due to its strong impact on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). In this review, we will discuss the aging process in relation to OS, the function of OS in neurodegenerative disorders, and prospective therapeutics capable of relieving neurodegenerative symptoms associated with the pro-oxidative condition.}, }
@article {pmid36899872, year = {2023}, author = {Vidovic, M and Müschen, LH and Brakemeier, S and Machetanz, G and Naumann, M and Castro-Gomez, S}, title = {Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {5}, pages = {}, pmid = {36899872}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases ; Delayed Diagnosis ; Motor Neurons/pathology ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.}, }
@article {pmid36896705, year = {2023}, author = {Dilliott, AA and Al Nasser, A and Elnagheeb, M and Fifita, J and Henden, L and Keseler, IM and Lenz, S and Marriott, H and Mccann, E and Mesaros, M and Opie-Martin, S and Owens, E and Palus, B and Ross, J and Wang, Z and White, H and Al-Chalabi, A and Andersen, PM and Benatar, M and Blair, I and Cooper-Knock, J and Harrington, EA and Heckmann, J and Landers, J and Moreno, C and Nel, M and Rampersaud, E and Roggenbuck, J and Rouleau, G and Traynor, B and Van Blitterswijk, M and Van Rheenen, W and Veldink, J and Weishaupt, J and Drury, L and Harms, MB and Farhan, SMK and , }, title = {Clinical testing panels for ALS: global distribution, consistency, and challenges.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {420-435}, pmid = {36896705}, issn = {2167-9223}, support = {AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; U24 HG009650/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Mutation ; Genetic Testing/methods ; C9orf72 Protein/genetics ; }, abstract = {Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.}, }
@article {pmid36895420, year = {2023}, author = {Koike, Y and Onodera, O}, title = {Implications of miRNAs dysregulation in amyotrophic lateral sclerosis: Challenging for clinical applications.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1131758}, pmid = {36895420}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons. Currently, there are no effective biomarkers and fundamental therapies for this disease. Dysregulation in RNA metabolism plays a critical role in the pathogenesis of ALS. With the contribution of Next Generation Sequencing, the functions of non-coding RNAs (ncRNAs) have gained increasing interests. Especially, micro RNAs (miRNAs), which are tissue-specific small ncRNAs of about 18-25 nucleotides, have emerged as key regulators of gene expression to target multiple molecules and pathways in the central nervous system (CNS). Despite intensive recent research in this field, the crucial links between ALS pathogenesis and miRNAs remain unclear. Many studies have revealed that ALS-related RNA binding proteins (RBPs), such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), regulate miRNAs processing in both the nucleus and cytoplasm. Of interest, Cu[2+]/Zn[2+] superoxide dismutase (SOD1), a non-RBP associated with familial ALS, shows partially similar properties to these RBPs via the dysregulation of miRNAs in the cellular pathway related to ALS. The identification and validation of miRNAs are important to understand the physiological gene regulation in the CNS, and the pathological implications in ALS, leading to a new avenue for early diagnosis and gene therapies. Here, we offer a recent overview regarding the mechanism underlying the functions of multiple miRNAs across TDP-43, FUS, and SOD1 with the context of cell biology, and challenging for clinical applications in ALS.}, }
@article {pmid36894028, year = {2023}, author = {Costa, I and Barbosa, DJ and Benfeito, S and Silva, V and Chavarria, D and Borges, F and Remião, F and Silva, R}, title = {Molecular mechanisms of ferroptosis and their involvement in brain diseases.}, journal = {Pharmacology &amp; therapeutics}, volume = {244}, number = {}, pages = {108373}, doi = {10.1016/j.pharmthera.2023.108373}, pmid = {36894028}, issn = {1879-016X}, mesh = {Humans ; Cell Death/physiology ; *Ferroptosis ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation ; *Brain Diseases/drug therapy ; }, abstract = {Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.}, }
@article {pmid36889133, year = {2023}, author = {Ma, L and Li, X and Petersen, RB and Peng, A and Huang, K}, title = {Probing the interactions between amyloidogenic proteins and bio-membranes.}, journal = {Biophysical chemistry}, volume = {296}, number = {}, pages = {106984}, doi = {10.1016/j.bpc.2023.106984}, pmid = {36889133}, issn = {1873-4200}, mesh = {Humans ; Amyloidogenic Proteins/metabolism ; *Diabetes Mellitus, Type 2/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease ; }, abstract = {Protein misfolding diseases (PMDs) in humans are characterized by the deposition of protein aggregates in tissues, including Alzheimer's disease, Parkinson's disease, type 2 diabetes, and amyotrophic lateral sclerosis. Misfolding and aggregation of amyloidogenic proteins play a central role in the onset and progression of PMDs, and these processes are regulated by multiple factors, especially the interaction between proteins and bio-membranes. Bio-membranes induce conformational changes in amyloidogenic proteins and affect their aggregation; on the other hand, the aggregates of amyloidogenic proteins may cause membrane damage or dysfunction leading to cytotoxicity. In this review, we summarize the factors that affect the binding of amyloidogenic proteins and membranes, the effects of bio-membranes on the aggregation of amyloidogenic proteins, mechanisms of membrane disruption by amyloidogenic aggregates, technical approaches for detecting these interactions, and finally therapeutic strategies targeting membrane damage caused by amyloidogenic proteins.}, }
@article {pmid36880940, year = {2023}, author = {Arslan, B and Zetterberg, H}, title = {Neurofilament light chain as neuronal injury marker - what is needed to facilitate implementation in clinical laboratory practice?.}, journal = {Clinical chemistry and laboratory medicine}, volume = {61}, number = {7}, pages = {1140-1149}, pmid = {36880940}, issn = {1437-4331}, mesh = {Humans ; Laboratories, Clinical ; Intermediate Filaments ; Neurofilament Proteins ; *Alzheimer Disease ; Biomarkers ; *Nervous System Diseases/diagnosis ; }, abstract = {Neurobiomarkers have attracted significant attention over the last ten years. One promising biomarker is the neurofilament light chain protein (NfL). Since the introduction of ultrasensitive assays, NfL has been developed into a widely used axonal damage marker of relevance to the diagnosis, prognostication, follow-up, and treatment monitoring of a range of neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. The marker is increasingly used clinically, as well as in clinical trials. Even if we have validated precise, sensitive, and specific assays for NfL quantification in both cerebrospinal fluid and blood, there are analytical, as well as pre- and post-analytical aspects of the total NfL testing process, including biomarker interpretation, to consider. Although the biomarker is already in use in specialised clinical laboratory settings, a more general use requires some further work. In this review, we provide brief basic information and opinions on NfL as a biomarker of axonal injury in neurological diseases and pinpoint additional work needed to facilitate biomarker implementation in clinical practice.}, }
@article {pmid36875937, year = {2023}, author = {Donohue, C and Carnaby, G and Reilly, MC and Colquhoun, RJ and Lacomis, D and Garand, KLF}, title = {A meta-analysis of post-exercise outcomes in people with amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {31}, number = {}, pages = {100452}, pmid = {36875937}, issn = {2405-6502}, abstract = {OBJECTIVE: To systematically evaluate post-exercise outcomes related to function and quality of life in people with ALS.<br><br>METHODS: PRISMA guidelines were used for identifying and extracting articles. Levels of evidence and quality of articles were judged based on The Oxford Centre for Evidence-based Medicine Levels of Evidence and the QualSyst. Outcomes were analyzed with Comprehensive Meta-Analysis V2 software, random effects models, and Hedge's G. Effects were examined at 0-4&#xa0;months, up to 6&#xa0;months, and&#xa0;>&#xa0;6&#xa0;months. Pre-specified sensitivity analyses were performed for 1) controlled trials vs. all studies and 2) ALSFRS-R bulbar, respiratory, and motor subscales. Heterogeneity of pooled outcomes was computed with the I[2] statistic.<br><br>RESULTS: 16 studies and seven functional outcomes met inclusion for the meta-analysis. Of the outcomes explored, the ALSFRS-R demonstrated a favorable summary effect size and had acceptable heterogeneity and dispersion. While FIM scores demonstrated a favorable summary effect size, heterogeneity limited interpretations. Other outcomes did not demonstrate a favorable summary effect size and/or could not be reported due to few studies reporting outcomes.<br><br>CONCLUSIONS: This study provides inconclusive guidance regarding exercise regimens to maintain function and quality of life in people with ALS due to study limitations (e.g., small sample size, high attrition rate, heterogeneity in methods and participants, etc.). Future research is warranted to determine optimal treatment regimens and dosage parameters in this patient population.}, }
@article {pmid36875699, year = {2023}, author = {Jeon, YM and Kwon, Y and Lee, S and Kim, HJ}, title = {Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1047897}, pmid = {36875699}, issn = {1663-4365}, abstract = {The endoplasmic reticulum (ER) is a major organelle involved in protein quality control and cellular homeostasis. ER stress results from structural and functional dysfunction of the organelle, along with the accumulation of misfolded proteins and changes in calcium homeostasis, it leads to ER stress response pathway such as unfolded protein response (UPR). Neurons are particularly sensitive to the accumulation of misfolded proteins. Thus, the ER stress is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion disease and motor neuron disease (MND). Recently, the complex involvement of ER stress pathways has been demonstrated in experimental models of amyotrophic lateral sclerosis (ALS)/MND using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive response to ER stress. Here, we aim to provide recent evidence demonstrating that the ER stress pathway is an essential pathological mechanism of ALS. In addition, we also provide therapeutic strategies that can help treat diseases by targeting the ER stress pathway.}, }
@article {pmid36875645, year = {2023}, author = {Pan, X and Dutta, D and Lu, S and Bellen, HJ}, title = {Sphingolipids in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1137893}, pmid = {36875645}, issn = {1662-4548}, abstract = {Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich's ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.}, }
@article {pmid36860617, year = {2023}, author = {Spencer, PS and Palmer, VS and Kisby, GE and Lagrange, E and Horowitz, BZ and Valdes Angues, R and Reis, J and Vernoux, JP and Raoul, C and Camu, W}, title = {Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology via lifetime exposome research.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1005096}, pmid = {36860617}, issn = {1662-4548}, abstract = {The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.}, }
@article {pmid36857887, year = {2023}, author = {Zhang, N and Chen, KL and Huang, YY and Chen, SF and Dong, Q and Tan, L and Yu, JT}, title = {A new ERBB4 variant in amyotrophic lateral sclerosis type 19: Case report and review of the literature.}, journal = {Clinical neurology and neurosurgery}, volume = {227}, number = {}, pages = {107636}, doi = {10.1016/j.clineuro.2023.107636}, pmid = {36857887}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation/genetics ; Receptor, ErbB-4/genetics ; }, }
@article {pmid36855480, year = {2023}, author = {Ramsay, D and Miller, A and Baykeens, B and Hassan, H and Gentleman, S}, title = {Football (Soccer) as a Probable Cause of Long-Term Neurological Impairment and Neurodegeneration: A Narrative Review of the Debate.}, journal = {Cureus}, volume = {15}, number = {1}, pages = {e34279}, pmid = {36855480}, issn = {2168-8184}, abstract = {Football (soccer) is the most widely played sport across the globe. Due to some recent high-profile cases and epidemiological studies suggesting football can lead to neurodegeneration, scientific and public interest has been piqued. This has resulted in research into whether an association between football participation and neurodegeneration or neurological impairment is present. It has been theorised that a combination of repeated sub-concussive and concussive injuries, due to ball-heading and head collisions, may lead to neurodegeneration. However, evidence remains conflicting. Due to the popularity of the sport, and the serious conditions it has been linked to, it is important to determine whether repeated head impacts during football participation can play a causative role in neurodegenerative disease. To answer this question, a review of the current literature was carried out. Epidemiological evidence showed a higher incidence of amyotrophic lateral sclerosis amongst amateur and professional footballers and that footballers in positions that involve less contact and heading, e.g., goalkeepers lead significantly longer lives. Additionally, imaging studies reach a similar conclusion, reporting changes in brain structure, blood flow, and inflammatory markers in footballers when compared to controls. However, studies looking at an association between heading frequency and cognition show a lack of consensus on whether a higher heading exposure results in reduced cognition. Similarly, in neuropathological studies, signs of chronic traumatic encephalopathy (CTE) have been found in some former players, with contrasting studies suggesting low levels of CTE-type pathology are found in the general population, regardless of exposure to head trauma. The majority of studies suggest a link between football and neurodegenerative disease. However, the high prevalence of retrospective cohort and cross-sectional studies, often plagued by recall bias, undermine the conclusions drawn. Therefore, until larger prospective cohort studies are conducted, concrete conclusions cannot be made. However, caution can be exercised to limit head impacts.}, }
@article {pmid36854331, year = {2023}, author = {Lim, SM and Nahm, M and Kim, SH}, title = {Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {19}, number = {2}, pages = {101-114}, pmid = {36854331}, issn = {1738-6586}, support = {NRF-2018M3C7A1056512//National Research Foundation of Korea/Korea ; }, abstract = {The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are essential for maintaining both the structure and function of the brain. However, aging, cellular stress conditions, and genetic contributions cause disturbances in proteostasis and ribostasis that lead to protein misfolding, insoluble aggregate deposition, and abnormal ribonucleoprotein granule dynamics. In addition to neurons being primarily postmitotic, nondividing cells, they are more susceptible to the persistent accumulation of abnormal aggregates. Indeed, defects associated with the failure to maintain proteostasis and ribostasis are common pathogenic components of age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, the neuronal deposition of misfolded and aggregated proteins can cause both increased toxicity and impaired physiological function, which lead to neuronal dysfunction and cell death. There is recent evidence that irreversible liquid-liquid phase separation (LLPS) is responsible for the pathogenic aggregate formation of disease-related proteins, including tau, α-synuclein, and RNA-binding proteins, including transactive response DNA-binding protein 43, fused in sarcoma, and heterogeneous nuclear ribonucleoprotein A1. Investigations of LLPS and its control therefore suggest that chaperone/disaggregase, which reverse protein aggregation, are valuable therapeutic targets for effective treatments for neurological diseases. Here we review and discuss recent studies to highlight the importance of understanding the common cell death mechanisms of proteostasis and ribostasis in neurodegenerative diseases.}, }
@article {pmid36836867, year = {2023}, author = {Alessenko, AV and Gutner, UA and Shupik, MA}, title = {Involvement of Lipids in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {36836867}, issn = {2075-1729}, support = {&#x2116; 122041400080-0.//Ministry of Science and Higher Education of the Russian Federation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. To study its underlying mechanisms, a variety of models are currently used at the cellular level and in animals with mutations in multiple ALS associated genes, including SOD1, C9ORF72, TDP-43, and FUS. Key mechanisms involved in the disease include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammatory, and immune reactions. In addition, significant metabolism alterations of various lipids classes, including phospholipids, fatty acids, sphingolipids, and others have been increasingly recognized. Recently, the mechanisms of programmed cell death (apoptosis), which may be responsible for the degeneration of motor neurons observed in the disease, have been intensively studied. In this context, sphingolipids, which are the most important sources of secondary messengers transmitting signals for cell proliferation, differentiation, and apoptosis, are gaining increasing attention in the context of ALS pathogenesis given their role in the development of neuroinflammatory and immune responses. This review describes changes in lipids content and activity of enzymes involved in their metabolism in ALS, both summarizing current evidence from animal models and clinical studies and discussing the potential of new drugs among modulators of lipid metabolism enzymes.}, }
@article {pmid36835277, year = {2023}, author = {El Ouaamari, Y and Van den Bos, J and Willekens, B and Cools, N and Wens, I}, title = {Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36835277}, issn = {1422-0067}, support = {DOCPRO42551//Intern funding of the University of Antwerp: DOCPRO4 BOF PhD fellowship at the University of Antwerp/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Nerve Growth Factors/metabolism ; *Parkinson Disease/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases. Here, we discuss the current state of knowledge, challenges, and future perspectives of NTFs with a direct regenerative effect in chronic inflammatory and degenerative disorders. Various systems for delivery of NTFs, such as stem and immune cells, viral vectors, and biomaterials, have been applied to deliver exogenous NTFs to the central nervous system, with promising results. The challenges that currently need to be overcome include the amount of NTFs delivered, the invasiveness of the delivery route, the blood-brain barrier permeability, and the occurrence of side effects. Nevertheless, it is important to continue research and develop standards for clinical applications. In addition to the use of single NTFs, the complexity of chronic inflammatory and degenerative diseases may require combination therapies targeting multiple pathways or other possibilities using smaller molecules, such as NTF mimetics, for effective treatment.}, }
@article {pmid36834853, year = {2023}, author = {Weng, YT and Chang, YM and Chern, Y}, title = {The Impact of Dysregulated microRNA Biogenesis Machinery and microRNA Sorting on Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36834853}, issn = {1422-0067}, support = {AS-IA-108-L06//Academia Sinica/ ; }, mesh = {Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease ; *Parkinson Disease ; *Huntington Disease ; RNA, Messenger ; }, abstract = {MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs involved in the differentiation, development, and function of cells in the body by targeting the 3'- untranslated regions (UTR) of mRNAs for degradation or translational inhibition. miRNAs not only affect gene expression inside the cells but also, when sorted into exosomes, systemically mediate the communication between different types of cells. Neurodegenerative diseases (NDs) are age-associated, chronic neurological diseases characterized by the aggregation of misfolded proteins, which results in the progressive degeneration of selected neuronal population(s). The dysregulation of biogenesis and/or sorting of miRNAs into exosomes was reported in several NDs, including Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). Many studies support the possible roles of dysregulated miRNAs in NDs as biomarkers and therapeutic treatments. Understanding the molecular mechanisms underlying the dysregulated miRNAs in NDs is therefore timely and important for the development of diagnostic and therapeutic interventions. In this review, we focus on the dysregulated miRNA machinery and the role of RNA-binding proteins (RBPs) in NDs. The tools that are available to identify the target miRNA-mRNA axes in NDs in an unbiased manner are also discussed.}, }
@article {pmid36834792, year = {2023}, author = {Tsoi, PS and Quan, MD and Ferreon, JC and Ferreon, ACM}, title = {Aggregation of Disordered Proteins Associated with Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36834792}, issn = {1422-0067}, support = {R01 GM122763/GM/NIGMS NIH HHS/United States ; R01 NS105874/NS/NINDS NIH HHS/United States ; R21 NS107792/NS/NINDS NIH HHS/United States ; R21 NS109678/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/chemistry ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; *Parkinson Disease/metabolism ; tau Proteins ; *Intrinsically Disordered Proteins ; }, abstract = {Cellular deposition of protein aggregates, one of the hallmarks of neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, and truncations are common molecular underpinnings in the formation of aberrant protein conformations that seed aggregation. The major proteins involved in neurodegeneration include amyloid beta (Aβ) and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TAR DNA-binding protein (TDP-43) in amyotrophic lateral sclerosis (ALS). These proteins are described as intrinsically disordered and possess enhanced ability to partition into biomolecular condensates. In this review, we discuss the role of protein misfolding and aggregation in neurodegenerative diseases, specifically highlighting implications of changes to the primary/secondary (mutations, posttranslational modifications, and truncations) and the quaternary/supramolecular (oligomerization and condensation) structural landscapes for the four aforementioned proteins. Understanding these aggregation mechanisms provides insights into neurodegenerative diseases and their common underlying molecular pathology.}, }
@article {pmid36834611, year = {2023}, author = {Pizcueta, P and Vergara, C and Emanuele, M and Vilalta, A and Rodríguez-Pascau, L and Martinell, M}, title = {Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36834611}, issn = {1422-0067}, support = {SPW-EER/DRDT/DPjR/DEMO/ML/D&#xe9;f-8296//Region Wallonne/ ; }, mesh = {Humans ; *Central Nervous System Diseases/metabolism ; *Neurodegenerative Diseases/metabolism ; Neuroinflammatory Diseases ; PPAR gamma/metabolism ; }, abstract = {Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood-brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.}, }
@article {pmid36834005, year = {2023}, author = {Sanchez-Andrades, MJ and Vinolo-Gil, MJ and Casuso-Holgado, MJ and Barón-López, J and Rodríguez-Huguet, M and Martín-Valero, R}, title = {Measurement Properties of Self-Report Questionnaires for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis of Commonly Used Instruments.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {4}, pages = {}, pmid = {36834005}, issn = {1660-4601}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Quality of Life ; Self Report ; *Neurodegenerative Diseases ; Reproducibility of Results ; Surveys and Questionnaires ; }, abstract = {(1) Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. There is no evidence on the analysis of the measurement instruments available to assess quality of life in these patients, following the consensus-based standards for the selection of health measurement instruments (COSMIN) checklist; (2) Methods: A systematic review was performed in PubMed, Embase, PEDro, Web of Science and Cochrane. The psychometric properties of the questionnaires were determined by using the COSMIN checklist. Two searches were carried out. This systematic review was registered in PROSPERO (CRD42021249005); (3) Results: There were four published articles that analysed the measurement properties in patients with ALS for the following scales: Amyotrophic Lateral Sclerosis Assessment Questionnaire 40, Amyotrophic Lateral Sclerosis-Specific Quality of Life Questionnaire, Short Form 36 Healthy Survey, Epworth Sleepiness Scale and Sickness Impact Profile. Another five scales also met the inclusion criteria: ALS-Depression-Inventory, State Trait Anxiety-Inventory, World Health Organization Quality of Life, Schedule for the Evaluation of Individual Quality of Life, Amyotrophic Lateral Sclerosis Assessment Questionnaire 5. Most Patient Reported Outcome Measures (PROMs) present a low-quality synthesis of evidence. It was observed an excellent pooled reliability of 0.92 (95% Confidence Interval: 0.83-0.96, I[2] = 87.3%) for four dimensions for questionnaires ALSAQ-40. (4) Conclusions: There is little evidence on generic instruments. Future studies are necessary to develop new tools.}, }
@article {pmid36833252, year = {2023}, author = {Barbo, M and Ravnik-Glavač, M}, title = {Extracellular Vesicles as Potential Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {14}, number = {2}, pages = {}, pmid = {36833252}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Biomarkers ; *Extracellular Vesicles/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is described as a fatal and rapidly progressive neurodegenerative disorder caused by the degeneration of upper motor neurons in the primary motor cortex and lower motor neurons of the brainstem and spinal cord. Due to ALS's slowly progressive characteristic, which is often accompanied by other neurological comorbidities, its diagnosis remains challenging. Perturbations in vesicle-mediated transport and autophagy as well as cell-autonomous disease initiation in glutamatergic neurons have been revealed in ALS. The use of extracellular vesicles (EVs) may be key in accessing pathologically relevant tissues for ALS, as EVs can cross the blood-brain barrier and be isolated from the blood. The number and content of EVs may provide indications of the disease pathogenesis, its stage, and prognosis. In this review, we collected a recent study aiming at the identification of EVs as a biomarker of ALS with respect to the size, quantity, and content of EVs in the biological fluids of patients compared to controls.}, }
@article {pmid36831264, year = {2023}, author = {Cordts, I and Wachinger, A and Scialo, C and Lingor, P and Polymenidou, M and Buratti, E and Feneberg, E}, title = {TDP-43 Proteinopathy Specific Biomarker Development.}, journal = {Cells}, volume = {12}, number = {4}, pages = {}, pmid = {36831264}, issn = {2073-4409}, mesh = {Humans ; *TDP-43 Proteinopathies ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/pathology ; Biomarkers ; DNA-Binding Proteins/metabolism ; }, abstract = {TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer's dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life would help to stratify patients according to their definite diagnosis of pathology, rather than in clinical subgroups of uncertain pathology. For therapies developed to target pathological proteins that cause the disease a biomarker to detect and track the underlying pathology would greatly enhance such undertakings. This article reviews the latest developments and outlooks of deriving TDP-43-specific biomarkers from the pathophysiological processes involved in the development of TDP-43 proteinopathy and studies using biosamples from clinical entities associated with TDP-43 pathology to investigate biomarker candidates.}, }
@article {pmid36831041, year = {2023}, author = {Marsili, L and Sharma, J and Outeiro, TF and Colosimo, C}, title = {Stem Cell Therapies in Movement Disorders: Lessons from Clinical Trials.}, journal = {Biomedicines}, volume = {11}, number = {2}, pages = {}, pmid = {36831041}, issn = {2227-9059}, abstract = {Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts.}, }
@article {pmid36830306, year = {2023}, author = {Castagneto-Gissey, L and Russo, MF and Casella-Mariolo, J and Serao, A and Marcellinaro, R and D'Andrea, V and Carlini, M and Casella, G}, title = {The Role of Antibiotic Prophylaxis in Anastomotic Leak Prevention during Elective Colorectal Surgery: Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {36830306}, issn = {2079-6382}, abstract = {Introduction: Despite several perioperative care advancements and innovations in surgical procedures and technologies, the incidence rate of anastomotic leaks (ALs) after colorectal surgery has not substantially decreased. Gut microbiota can play a critical role in the healing process of anastomotic tissue and alterations in its composition may be largely to blame for anastomotic insufficiency. The use of specific antibiotics for preoperative large bowel decontamination could significantly influence the rate of ALs. The aim of this study was to systematically assess the various antibiotic prophylactic regimen strategies for primary prevention of ALs during colorectal surgery, in view of the available evidence. Methods: A systematic review of the literature was conducted, and randomized clinical trials (RCTs) analyzing prophylactic antibiotic bowel preparation in colorectal surgery were included. PubMed, Embase, the Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials were searched from inception through to 30 November 2022. The methodological quality of the included trials was evaluated. The primary outcome was AL rate; secondary outcomes were superficial/deep surgical site infections (SSIs). The PRISMA guidelines were used to carry out the present systematic review. Results: Thirteen RCTs published between 1977 and 2022, with a total of 4334 patients were included in the meta-analysis. Antibiotic prophylaxis was administered orally in 11/13 studies and intravenously in 2 studies. Patients randomly assigned to antibiotic prophylaxis, regardless of the regimen, had a reduced risk of ALs (p = 0.003) compared to mechanical bowel preparation (MBP) alone. The use of antibiotic prophylaxis was also more effective in significantly reducing SSIs (p < 0.001). Conclusions: The evidence points to an advantage of oral antibiotic prophylaxis in terms of AL rate, a significant contributor to perioperative morbidity, mortality, and rising healthcare expenditures. In light of such results, the use of antibiotic prophylaxis should be strongly encouraged prior to colorectal surgery.}, }
@article {pmid36830075, year = {2023}, author = {Olufunmilayo, EO and Gerke-Duncan, MB and Holsinger, RMD}, title = {Oxidative Stress and Antioxidants in Neurodegenerative Disorders.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {36830075}, issn = {2076-3921}, abstract = {Neurodegenerative disorders constitute a substantial proportion of neurological diseases with significant public health importance. The pathophysiology of neurodegenerative diseases is characterized by a complex interplay of various general and disease-specific factors that lead to the end point of neuronal degeneration and loss, and the eventual clinical manifestations. Oxidative stress is the result of an imbalance between pro-oxidant species and antioxidant systems, characterized by an elevation in the levels of reactive oxygen and reactive nitrogen species, and a reduction in the levels of endogenous antioxidants. Recent studies have increasingly highlighted oxidative stress and associated mitochondrial dysfunction to be important players in the pathophysiologic processes involved in neurodegenerative conditions. In this article, we review the current knowledge of the general effects of oxidative stress on the central nervous system, the different specific routes by which oxidative stress influences the pathophysiologic processes involved in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Huntington's disease, and how oxidative stress may be therapeutically reversed/mitigated in order to stall the pathological progression of these neurodegenerative disorders to bring about clinical benefits.}, }
@article {pmid36828272, year = {2023}, author = {Dave, BP and Shah, KC and Shah, MB and Chorawala, MR and Patel, VN and Shah, PA and Shah, GB and Dhameliya, TM}, title = {Unveiling the modulation of Nogo receptor in neuroregeneration and plasticity: Novel aspects and future horizon in a new frontier.}, journal = {Biochemical pharmacology}, volume = {210}, number = {}, pages = {115461}, doi = {10.1016/j.bcp.2023.115461}, pmid = {36828272}, issn = {1873-2968}, mesh = {Humans ; *Myelin Proteins/genetics/metabolism ; Nogo Proteins ; Nerve Regeneration/physiology ; Nerve Growth Factors ; *Neurodegenerative Diseases ; Nogo Receptors ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Multiple Sclerosis, Hereditary Spastic Paraplegia, and Amyotrophic Lateral Sclerosis have emerged as the most dreaded diseases due to a lack of precise diagnostic tools and efficient therapies. Despite the fact that the contributing factors of NDs are still unidentified, mounting evidence indicates the possibility that genetic and cellular changes may lead to the significant production of abnormally misfolded proteins. These misfolded proteins lead to damaging effects thereby causing neurodegeneration. The association between Neurite outgrowth factor (Nogo) with neurological diseases and other peripheral diseases is coming into play. Three isoforms of Nogo have been identified Nogo-A, Nogo-B and Nogo-C. Among these, Nogo-A is mainly responsible for neurological diseases as it is localized in the CNS (Central Nervous System), whereas Nogo-B and Nogo-C are responsible for other diseases such as colitis, lung, intestinal injury, etc. Nogo-A, a membrane protein, had first been described as a CNS-specific inhibitor of axonal regeneration. Several recent studies have revealed the role of Nogo-A proteins and their receptors in modulating neurite outgrowth, branching, and precursor migration during nervous system development. It may also modulate or affect the inhibition of growth during the developmental processes of the CNS. Information about the effects of other ligands of Nogo protein on the CNS are yet to be discovered however several pieces of evidence have suggested that it may also influence the neuronal maturation of CNS and targeting Nogo-A could prove to be beneficial in several neurodegenerative diseases.}, }
@article {pmid36825209, year = {2023}, author = {Joshi, T and Ahuja, N}, title = {The Prion Basis of Progressive Neurodegenerative Disorders.}, journal = {Interdisciplinary perspectives on infectious diseases}, volume = {2023}, number = {}, pages = {6687264}, pmid = {36825209}, issn = {1687-708X}, abstract = {The discovery of proteinaceous infectious agents by Prusiner in 1982 was sensational. All previously known pathogens contained nucleic acids, the code of life, that enabled them to reproduce. In contrast, the proteinaceous agents of disease, called prion proteins (PrP), lacked nucleic acids and propagated by binding to the functional, endogenous form of cellular prion protein (referred to as PrP[C]) and altering its conformation to produce the infectious disease-causing misfolded protein (referred to as PrP[Sc]). The accumulation and aggregation of these infectious prion proteins within the brain cause destruction of neural tissue and lead to fatal spongiform encephalopathies. In this review, we present the molecular pathology of prion-based diseases. These insights are of particular importance since the principles of prion pathogenesis apply to other neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Collectively, the global prevalence of these diseases is rapidly increasing while effective therapies against them are still lacking. Thus, the need to understand their etiology and pathogenesis is urgent, and it holds profound implications for societal health.}, }
@article {pmid36824265, year = {2023}, author = {Chen, X and He, E and Su, C and Zeng, Y and Xu, J}, title = {Huntingtin-associated protein 1-associated intracellular trafficking in neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1100395}, pmid = {36824265}, issn = {1663-4365}, abstract = {Huntingtin-associated protein 1 (HAP1), the first identified HTT-binding partner, is highly expressed in the central nervous system, and has been found to associated with neurological diseases. Mounting evidence suggests that HAP1 functions as a component of cargo-motor molecules to bind various proteins and participates in intracellular trafficking. It is known that the failure of intracellular transport is a key contributor to the progression of neurodegenerative disorders (NDs) including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA) and spinocerebellar ataxia (SCA). The link between HAP1 and various NDs is supported by growing evidence. This review aims to provide a comprehensive overview of the intracellular trafficking function of HAP1 and its involvement in NDs.}, }
@article {pmid36822629, year = {2023}, author = {Zhang, B and Burke, R}, title = {Copper homeostasis and the ubiquitin proteasome system.}, journal = {Metallomics : integrated biometal science}, volume = {15}, number = {3}, pages = {}, pmid = {36822629}, issn = {1756-591X}, mesh = {Humans ; *Proteasome Endopeptidase Complex ; Ubiquitin/metabolism ; Copper/metabolism ; *Neurodegenerative Diseases/metabolism ; Homeostasis ; Copper Transport Proteins ; }, abstract = {Copper is involved in many physiological pathways and important biological processes as a cofactor of several copper-dependent enzymes. Given the requirement for copper and its potential toxicity, intracellular copper levels are tightly controlled. Disturbances of human copper homeostasis are characterized by disorders of copper overload (Wilson's disease) or copper deficiency (Menkes disease). The maintenance of cellular copper levels involves numerous copper transporters and copper chaperones. Recently, accumulating evidence has revealed that components of the ubiquitin proteasome system (UPS) participate in the posttranslational regulation of these proteins, suggesting that they might play a role in maintaining copper homeostasis. Cellular copper levels could also affect the activity of the UPS, indicating that copper homeostasis and the UPS are interdependent. Copper homeostasis and the UPS are essential to the integrity of normal brain function and while separate links between neurodegenerative diseases and UPS inhibition/copper dyshomeostasis have been extensively reported, there is growing evidence that these two networks might contribute synergistically to the occurrence of neurodegenerative diseases. Here, we review the role of copper and the UPS in the development of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and discuss the genetic interactions between copper transporters/chaperones and components of the UPS.}, }
@article {pmid36822211, year = {2023}, author = {Günther, R}, title = {[Gene Therapies in Motor Neuron Diseases ALS and SMA].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {91}, number = {4}, pages = {153-163}, doi = {10.1055/a-2002-5215}, pmid = {36822211}, issn = {1439-3522}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Genetic Therapy/methods ; *Motor Neuron Disease/genetics/therapy/diagnosis ; *Muscular Atrophy, Spinal/genetics/therapy ; }, abstract = {In the past, the diagnosis of motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and 5q-associated spinal muscular atrophy (SMA) meant powerlessness in the face of seemingly untreatable diseases with severe motor-functional limitations and sometimes fatal courses. Recent advances in an understanding of the genetic causalities of these diseases, combined with success in the development of targeted gene therapy strategies, spell hope for effective, innovative therapeutic approaches, pioneering the ability to treat neurodegenerative diseases. While gene therapies have been approved for SMA since a few years, gene therapy research in ALS is still in clinical trials with encouraging results. This article provides an overview of the genetic background of ALS and SMA known to date and gene therapy approaches to them with a focus on therapy candidates that are in clinical trials or have already gained market approval.}, }
@article {pmid36816743, year = {2023}, author = {Zang, Y and Lai, X and Li, C and Ding, D and Wang, Y and Zhu, Y}, title = {The Role of Gut Microbiota in Various Neurological and Psychiatric Disorders-An Evidence Mapping Based on Quantified Evidence.}, journal = {Mediators of inflammation}, volume = {2023}, number = {}, pages = {5127157}, pmid = {36816743}, issn = {1466-1861}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Depressive Disorder, Major ; *Autism Spectrum Disorder/microbiology ; Bacteria ; Firmicutes ; Bacteroidetes ; Clostridiales ; }, abstract = {METHODS: We searched PubMed, Cochrane Library, and Epistemonikos to identify systematic reviews and meta-analysis (SRs). We searched for neurological diseases and psychiatric disorders, including Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), anorexia nervosa (AN), bipolar disorder (BD), eating disorder (ED), generalized anxiety disorder (GAD), major depressive disorder (MDD), multiple sclerosis (MS), obsessive compulsive disorder (OCD), Parkinson's disease (PD), posttraumatic stress disorder (PTSD), spinal cord injury (SCI), schizophrenia, and stroke. We used A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) to evaluate the quality of included SRs. We also created an evidence map showing the role of gut microbiota in neurological diseases and the certainty of the evidence.<br><br>RESULTS: In total, 42 studies were included in this evidence mapping. Most findings were obtained from observational studies. According to the AMSTAR-2 assessment, 21 SRs scored "critically low" in terms of methodological quality, 16 SR scored "low," and 5 SR scored "moderate." A total of 15 diseases have been investigated for the potential association between gut microbiome alpha diversity and disease, with the Shannon index and Simpson index being the most widely studied. A total of 12 diseases were investigated for potential link between beta diversity and disease. At the phylum level, Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia were more researched. At the genus level, Prevotella, Coprococcus, Parabacteroides, Phascolarctobacterium, Escherichia Shigella, Alistipes, Sutteralla, Veillonella, Odoribacter, Faecalibacterium, Bacteroides, Bifidobacterium, Dialister, and Blautia were more researched. Some diseases have been found to have specific flora changes, and some diseases have been found to have common intestinal microbiological changes.<br><br>CONCLUSION: We found varied levels of evidence for the associations between gut microbiota and neurological diseases; some gut microbiota increased the risk of neurological diseases, whereas others showed evidence of benefit that gut microbiota might be promising therapeutic targets for such diseases.}, }
@article {pmid36812393, year = {2023}, author = {Bongioanni, P and Borasio, GD and Oliver, DJ and Romagnoli, A and Kapitza, KP and Sidle, K and Tramonti, F}, title = {Methods for informing people with amyotrophic lateral sclerosis/motor neuron disease of their diagnosis.}, journal = {The Cochrane database of systematic reviews}, volume = {2}, number = {2}, pages = {CD007593}, pmid = {36812393}, issn = {1469-493X}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/psychology/therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), causes increasing physical impairment and disability. People with ALS/MND face huge physical challenges, and the diagnosis can be a source of great psychological distress for both people with ALS/MND and their carers. In such a context, how news of the diagnosis is broken is important. At present, there are no systematic reviews of methods for informing people with ALS/MND of their diagnosis.<br><br>OBJECTIVES: To examine the effects and effectiveness of different methods for informing people of a diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), including effects on the person's knowledge and understanding of their disease, its treatment, and care; and on coping and adjustment to the effects of ALS/MND, its treatment, and care.<br><br>SEARCH METHODS: We searched the Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers (February 2022). We contacted individuals or organisations to locate studies. We contacted study authors to obtain additional unpublished data.<br><br>SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs of techniques for informing people with ALS/MND of their diagnosis. We planned to include adults (aged 17 years or over) with ALS/MND, according to the El Escorial criteria.<br><br>DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed the results of the search to identify RCTs, and three review authors identified non-randomised studies to include in the discussion section. We planned that two review authors would independently extract data, and three would assess the risk of bias in any included trials.<br><br>MAIN RESULTS: We did not identify any RCTs that met our inclusion criteria.<br><br>AUTHORS' CONCLUSIONS: There are no RCTs that evaluate different communication strategies for breaking the bad news for people diagnosed with ALS/MND. Focused research studies are needed to assess the effectiveness and efficacy of different communication methods.}, }
@article {pmid36805318, year = {2023}, author = {Soto-Lara, M and Silva-Loredo, M and Monroy-Córdoba, JR and Flores-Ordoñez, P and Cervera-Delgadillo, NG and Carrillo-Mora, P}, title = {Alternative medicine therapies in neurological disorders: Prevalence, reasons and associated factors. A systematic review.}, journal = {Complementary therapies in medicine}, volume = {73}, number = {}, pages = {102932}, doi = {10.1016/j.ctim.2023.102932}, pmid = {36805318}, issn = {1873-6963}, mesh = {Adult ; Humans ; Female ; Middle Aged ; Male ; Prevalence ; Cross-Sectional Studies ; Retrospective Studies ; *Complementary Therapies/methods ; *Nervous System Diseases/epidemiology/therapy ; *Stroke ; }, abstract = {OBJECTIVE: This systematic review aimed to identify the prevalence of CAM use in patients with neurological disorders, and also to know most frequent types of CAM used.<br><br>METHODS: Five databases: PubMed, Science Direct, EBSCO, Latindex and Scielo (in English and Spanish) were searched from January 2010 to May 2021. Only original cross-sectional, retrospective and cohort studies were included, whose primary objective was to describe the frequency of CAM use in neurological disorders and/or the related factors to its use in adults. Based on the data, a descriptive analysis was performed, covering the characteristics of studies, measuring methods, prevalence, types and related factors. To control the risk of bias, a quality assessment of each study was performed using STROBE checklist.<br><br>RESULTS: For the final analysis, 40 studies were included. Most common pathologies observed in the studies were multiple sclerosis, headache, stroke, Parkinson and epilepsy. The STROBE score of studies ranged from 13 to 22 points, with an average of 18.2. Prevalence of CAM use was highly variable from one study to another (16% in stroke patients, to 100% in amyotrophic lateral sclerosis or spinal cord injury patients). Biological therapies (dietary supplements and herbal medicine) were the most commonly CAM types used. The associated factors identified were female sex, an age between 40 and 50 years, and higher socioeconomic level. Not all studies investigated about the results of CAMs but these ranged from 35% to more than 80% of reporting positive effects.<br><br>CONCLUSIONS: The prevalence of CAM use in neurological diseases is highly variable (16%-100%); the most used type of CAM was biological therapies and the associated factors were female sex, age between 40 and 50 years old and high socioeconomic level.}, }
@article {pmid36804755, year = {2023}, author = {Kooshki, L and Zarneshan, SN and Fakhri, S and Moradi, SZ and Echeverria, J}, title = {The pivotal role of JAK/STAT and IRS/PI3K signaling pathways in neurodegenerative diseases: Mechanistic approaches to polyphenols and alkaloids.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {112}, number = {}, pages = {154686}, doi = {10.1016/j.phymed.2023.154686}, pmid = {36804755}, issn = {1618-095X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Janus Kinases/metabolism ; Phosphatidylinositol 3-Kinase/metabolism ; Polyphenols/pharmacology ; Signal Transduction ; *Alkaloids/pharmacology ; *Biological Products ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunctionality which results in disability and human life-threatening events. In recent decades, NDDs are on the rise. Besides, conventional drugs have not shown potential effectiveness to attenuate the complications of NDDs. So, exploring novel therapeutic agents is an urgent need to combat such disorders. Accordingly, growing evidence indicates that polyphenols and alkaloids are promising natural candidates, possessing several beneficial pharmacological effects against diseases. Considering the complex pathophysiological mechanisms behind NDDs, Janus kinase (JAK), insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT) seem to play critical roles during neurodegeneration/neuroregeneration. In this line, modulation of the JAK/STAT and IRS/PI3K signaling pathways and their interconnected mediators by polyphenols/alkaloids could play pivotal roles in combating NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), stroke, aging, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression and other neurological disorders.<br><br>PURPOSE: Thus, the present study aimed to investigate the neuroprotective roles of polyphenols/alkaloids as multi-target natural products against NDDs which are critically passing through the modulation of the JAK/STAT and IRS/PI3K signaling pathways.<br><br>STUDY DESIGN AND METHODS: A systematic and comprehensive review was performed to highlight the modulatory roles of polyphenols and alkaloids on the JAK/STAT and IRS/PI3K signaling pathways in NDDs, according to the PRISMA guideline, using scholarly electronic databases, including Scopus, PubMed, ScienceDirect, and associated reference lists.<br><br>RESULTS: In the present study 141 articles were included from a total of 1267 results. The results showed that phenolic compounds such as curcumin, epigallocatechin-3-gallate, and quercetin, and alkaloids such as berberine could be introduced as new strategies in combating NDDs through JAK/STAT and IRS/PI3K signaling pathways. This is the first systematic review that reveals the correlation between the JAK/STAT and IRS/PI3K axis which is targeted by phytochemicals in NDDs. Hence, this review highlighted promising insights into the neuroprotective potential of polyphenols and alkaloids through the JAK/STAT and IRS/PI3K signaling pathway and interconnected mediators toward neuroprotection.<br><br>CONCLUSION: Amongst natural products, phenolic compounds and alkaloids are multi-targeting agents with the most antioxidants and anti-inflammatory effects possessing the potential of combating NDDs with high efficacy and lower toxicity. However, additional reports are needed to prove the efficacy and possible side effects of natural products.}, }
@article {pmid36801857, year = {2023}, author = {Wang, P and Wei, Q and Li, H and Wu, ZY}, title = {Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations.}, journal = {Chinese medical journal}, volume = {136}, number = {2}, pages = {176-183}, pmid = {36801857}, issn = {2542-5641}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Helicases/genetics ; Genetic Association Studies ; Multifunctional Enzymes/genetics ; Mutation/genetics ; RNA Helicases/genetics ; RNA-Binding Protein FUS/genetics ; Serine C-Palmitoyltransferase/genetics ; Child, Preschool ; Child ; Adolescent ; Young Adult ; }, abstract = {BACKGROUND: Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS. SPTLC1 was recently identified as a disease-causative gene for JALS, which has rarely been reported in Asian populations. Little is known regarding the difference in clinical features between JALS patients carrying FUS and SPTLC1 mutations. This study aimed to screen mutations in JALS patients and to compare the clinical features between JALS patients with FUS and SPTLC1 mutations.<br><br>METHODS: Sixteen JALS patients were enrolled, including three newly recruited patients between July 2015 and August 2018 from the Second Affiliated Hospital, Zhejiang University School of Medicine. Mutations were screened by whole-exome sequencing. In addition, clinical features such as AAO, onset site and disease duration were extracted and compared between JALS patients carrying FUS and SPTLC1 mutations through a literature review.<br><br>RESULTS: A novel and de novo SPTLC1 mutation (c.58G>A, p.A20T) was identified in a sporadic patient. Among 16 JALS patients, 7/16 carried FUS mutations and 5/16 carried respective SPTLC1 , SETX , NEFH , DCTN1 , and TARDBP mutations. Compared with FUS mutation patients, those with SPTLC1 mutations had an earlier AAO (7.9&#x200a;&#xb1;&#x200a;4.6 years vs. 18.1&#x200a;&#xb1;&#x200a;3.9 years, P &#x200a;<&#x200a;0.01), much longer disease duration (512.0 [416.7-607.3] months vs. 33.4 [21.6-45.1] months, P &#x200a;<&#x200a;0.01), and no onset of bulbar.<br><br>CONCLUSION: Our findings expand the genetic and phenotypic spectrum of JALS and help to better understand the genotype-phenotype correlation of JALS.}, }
@article {pmid36800114, year = {2023}, author = {de Oliveira, LMG and Carreira, RB and de Oliveira, JVR and do Nascimento, RP and Dos Santos Souza, C and Trias, E and da Silva, VDA and Costa, SL}, title = {Impact of Plant-Derived Compounds on Amyotrophic Lateral Sclerosis.}, journal = {Neurotoxicity research}, volume = {41}, number = {3}, pages = {288-309}, pmid = {36800114}, issn = {1476-3524}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Riluzole ; Edaravone/therapeutic use ; Glutamic Acid ; Phytochemicals/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by progressive motor neuron degeneration. Conventional therapies for ALS are based on treatment of symptoms, and the disease remains incurable. Molecular mechanisms are unclear, but studies have been pointing to involvement of glia, neuroinflammation, oxidative stress, and glutamate excitotoxicity as a key factor. Nowadays, we have few treatments for this disease that only delays death, but also does not stop the neurodegenerative process. These treatments are based on glutamate blockage (riluzole), tyrosine kinase inhibition (masitinib), and antioxidant activity (edaravone). In the past few years, plant-derived compounds have been studied for neurodegenerative disorder therapies based on neuroprotection and glial cell response. In this review, we describe mechanisms of action of natural compounds associated with neuroprotective effects, and the possibilities for new therapeutic strategies in ALS.}, }
@article {pmid36795184, year = {2023}, author = {Sharma, VK and Singh, TG and Mehta, V and Mannan, A}, title = {Biomarkers: Role and Scope in Neurological Disorders.}, journal = {Neurochemical research}, volume = {48}, number = {7}, pages = {2029-2058}, pmid = {36795184}, issn = {1573-6903}, mesh = {Humans ; *Nervous System Diseases/diagnosis ; Biomarkers ; Brain ; }, abstract = {Neurological disorders pose a great threat to social health and are a major cause for mortality and morbidity. Effective drug development complemented with the improved drug therapy has made considerable progress towards easing symptoms associated with neurological illnesses, yet poor diagnosis and imprecise understanding of these disorders has led to imperfect treatment options. The scenario is complicated by the inability to extrapolate results of cell culture studies and transgenic models to clinical applications which has stagnated the process of improving drug therapy. In this context, the development of biomarkers has been viewed as beneficial to easing various pathological complications. A biomarker is measured and evaluated in order to gauge the physiological process or a pathological progression of a disease and such a marker can also indicate the clinical or pharmacological response to a therapeutic intervention. The development and identification of biomarkers for neurological disorders involves several issues including the complexity of the brain, unresolved discrepant data from experimental and clinical studies, poor clinical diagnostics, lack of functional endpoints, and high cost and complexity of techniques yet research in the area of biomarkers is highly desired. The present work describes existing biomarkers for various neurological disorders, provides support for the idea that biomarker development may ease our understanding underlying pathophysiology of these disorders and help to design and explore therapeutic targets for effective intervention.}, }
@article {pmid36794866, year = {2024}, author = {Sibley, AK and McQuaid, W and Jain, TN and Mills, A and Travers, A}, title = {Paramedic Interventions and Adverse Patient Events during Prolonged Interfacility Ground Transport in a "Drip and Ship" Pharmacoinvasive Model of STEMI Care.}, journal = {Prehospital emergency care}, volume = {28}, number = {2}, pages = {375-380}, doi = {10.1080/10903127.2023.2179707}, pmid = {36794866}, issn = {1545-0066}, mesh = {Male ; Humans ; Middle Aged ; Female ; *ST Elevation Myocardial Infarction/therapy ; *Emergency Medical Services/methods ; *Myocardial Infarction/etiology ; *Percutaneous Coronary Intervention/adverse effects ; Paramedics ; Retrospective Studies ; }, abstract = {OBJECTIVE: Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI). However, when primary PCI is not available in a timely fashion, fibrinolysis and early transfer for routine PCI is recommended. Prince Edward Island (PEI) is the only province in Canada without a PCI facility, and distances to the nearest PCI-capable facilities are between 290 and 374 kilometers. This results in prolonged out-of-hospital time for critically ill patients. We sought to characterize and quantify paramedic interventions and adverse patient events during prolonged ground transport to PCI facilities post-fibrinolysis.<br><br>METHODS: We performed a retrospective chart review of patients presenting to any of four emergency departments (ED) on PEI during the calendar years 2016 and 2017. We identified patients through administrative discharge data and cross referenced with emergent out-of-province ambulance transfers. All included patients were managed as STEMIs in the EDs and subsequently transferred (primary PCI, pharmacoinvasive) directly from the EDs to PCI facilities. We excluded patients having STEMIs on inpatient wards and those transported by other means. We reviewed electronic and paper ED charts plus paper EMS records. We performed summary statistics.<br><br>RESULTS: We identified 149 patients meeting inclusion criteria. Most patients were males (77.9%), mean age 62.1 (SD 13.8) years. The mean transport interval was 202 (SD 29.0) minutes. Thirty-two adverse events occurred during 24 transports (16.1%). There was one death, and four patients required diversion to non-PCI facilities. Hypotension was the most common adverse event (n&#x2009;=&#x2009;13, 8.7%), and fluid bolus (n&#x2009;=&#x2009;11, 7.4%) was the most common intervention. Three (2.0%) patients required electrical therapy. Nitrates (n&#x2009;=&#x2009;65, 43.6%) and opioid analgesics (n&#x2009;=&#x2009;51, 34.2%) were the most common drugs administered during transport.<br><br>CONCLUSION: In a setting where primary PCI is not feasible due to distance, a pharmacoinvasive model of STEMI care is associated with a 16.1% proportion of adverse events. Crew configuration including ALS clinicians is the key in managing these events.}, }
@article {pmid36794629, year = {2023}, author = {Çoban, M and Bilge, U and Balseven, H and Uysal, H and Artut, B}, title = {The economic evaluation of ALS care: quality and cost.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {502-513}, doi = {10.1080/21678421.2023.2176776}, pmid = {36794629}, issn = {2167-9223}, mesh = {Humans ; Cost-Benefit Analysis ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Social Support ; Research Design ; }, abstract = {Objective: The study aims to analyze the quality of studies that make economic evaluations for amyotrophic lateral sclerosis (ALS). Assessing the quality of studies can guide policy-making and planning. Methods: One of the most recognized checklists "The Consensus on Health Economic Criteria" (CHEC)-list designed by Evers et al. in 2005 aims to answer two important questions: is the methodology of the study appropriate, and are the results of the study valid? We reviewed studies focusing on ALS and its economic costs, and evaluated the studies with (CHEC)-list. Results: We examined 25 articles in terms of their cost evaluation and quality. It is seen that they mainly focus on medical costs, ignoring social care costs. When the quality of the studies is examined, it is seen that the studies overall achieve high scores in terms of their purpose and research question, but some of the studies score low in terms of ethical dimension, comprehensiveness of expenditure items, their application of sensitivity analyses and their study design. Conclusions: The main recommendation of our study for future cost evaluation studies is that they should focus on the questions in the checklist that are scored low overall by the 25 articles, and consider the social care costs as well as medical costs. Our recommendations when designing cost studies can be applied to other chronic diseases with long-term economic costs like ALS.}, }
@article {pmid36793534, year = {2023}, author = {Mori, K and Gotoh, S and Uozumi, R and Miyamoto, T and Akamine, S and Kawabe, Y and Tagami, S and Ikeda, M}, title = {RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to C9orf72 Hexanucleotide Repeat Expansion.}, journal = {JMA journal}, volume = {6}, number = {1}, pages = {9-15}, pmid = {36793534}, issn = {2433-3298}, abstract = {Neuropathological features of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) due to C9orf72 GGGGCC hexanucleotide repeat expansion include early dipeptide repeats, repeat RNA foci, and subsequent TDP-43 pathologies. Since the discovery of the repeat expansion, extensive studies have elucidated the disease mechanism of how the repeat causes neurodegeneration. In this review, we summarize our current understanding of abnormal repeat RNA metabolism and repeat-associated non-AUG translation in C9orf72 frontotemporal lobar degeneration/ALS. For repeat RNA metabolism, we specifically focus on the role of hnRNPA3, the repeat RNA-binding protein, and the EXOSC10/RNA exosome complex, an intracellular RNA-degrading enzyme. In addition, the mechanism of repeat-associated non-AUG translation inhibition via TMPyP4, a repeat RNA-binding compound, is discussed.}, }
@article {pmid36791650, year = {2023}, author = {Aguilar, P and Bourgeois, T and Maria, A and Couzi, P and Demondion, E and Bozzolan, F and Gassias, E and Force, E and Debernard, S}, title = {Methoprene-tolerant and Krüppel homolog 1 are actors of juvenile hormone-signaling controlling the development of male sexual behavior in the moth Agrotis ipsilon.}, journal = {Hormones and behavior}, volume = {150}, number = {}, pages = {105330}, doi = {10.1016/j.yhbeh.2023.105330}, pmid = {36791650}, issn = {1095-6867}, mesh = {Animals ; Male ; Female ; Methoprene/pharmacology ; *Moths/physiology ; *Sex Attractants/pharmacology/metabolism ; Juvenile Hormones/pharmacology/metabolism ; Signal Transduction ; RNA, Messenger ; }, abstract = {In insects, juvenile hormone (JH) is critical for the orchestration of male reproductive maturation. For instance, in the male moth, Agrotis ipsilon, the behavioral response and the neuronal sensitivity within the primary olfactory centers, the antennal lobes (ALs), to the female-emitted sex pheromone increase with fertility during adulthood and the coordination between these events is governed by JH. However, the molecular basis of JH action in the development of sexual behavior remains largely unknown. Here, we show that the expression of the paralogous JH receptors, Methoprene-tolerant 1 and 2 (Met1, Met2) and of the JH-inducible transcription factor, Krüppel homolog 1 (Kr-h1) within ALs raised from the third day of adult life and this dynamic is correlated with increased behavioral responsiveness to sex pheromone. Met1-, Met2- and Kr-h1-depleted sexually mature males exhibited altered sex pheromone-guided orientation flight. Moreover, injection of JH-II into young males enhanced the behavioral response to sex pheromone with increased AL Met1, Met2 and Kr-h1 mRNA levels. By contrast, JH deficiency suppressed the behavioral response to sex pheromone coupled with reduced AL Met1, Met2 and Kr-h1 mRNA levels in allatectomized old males and these inhibitions were compensated by an injection of JH-II in operated males. Our results demonstrated that JH acts through Met-Kr-h1 signaling pathway operating in ALs, to promote the pheromone information processing and consequently the display of sexual behavior in synchronization with fertility to optimize male reproductive fitness. Thus, this study provides insights into the molecular mechanisms underlying the hormonal regulation of reproductive behavior in insects.}, }
@article {pmid36788871, year = {2023}, author = {Neupane, P and Thada, PK and Singh, P and Faisal, AR and Rai, N and Poudel, P and Waleed, MS and Quinonez, J and Ruxmohan, S and Jain, E}, title = {Investigating Edaravone Use for Management of Amyotrophic Lateral Sclerosis (ALS): A Narrative Review.}, journal = {Cureus}, volume = {15}, number = {1}, pages = {e33746}, pmid = {36788871}, issn = {2168-8184}, abstract = {The use of Edaravone, given orally, for the treatment of amyotrophic lateral sclerosis (ALS) was officially approved by the Federal Drug Association (FDA) in 2017. ALS is a rare and progressive degenerative disease that worsens over time. It attacks and destroys the nerve cells that control voluntary muscles, thus leading to weakness, eventual paralysis, and, ultimately death. Edaravone was given initially intravenously, but recent evidence shows better results with oral suspension. This narrative review is aimed to investigate the benefit of Edaravone for the management of ALS, compare it to Riluzole, discuss its mechanism of action, route of use, and side effects, and ultimately discuss future implications of this pharmacotherapy.}, }
@article {pmid36788405, year = {2023}, author = {Khalid, MU and Masroor, T}, title = {The promise of stem cells in amyotrophic lateral sclerosis: a review of clinical trials.}, journal = {JPMA. The Journal of the Pakistan Medical Association}, volume = {73(Suppl 1)}, number = {2}, pages = {S138-S142}, doi = {10.47391/JPMA.AKUS-22}, pmid = {36788405}, issn = {0030-9982}, mesh = {Humans ; Child ; *Amyotrophic Lateral Sclerosis/drug therapy ; Quality of Life ; Stem Cells ; Treatment Outcome ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition with high cost of care, poor treatment outcomes, and a significant decrease in quality of life, eventually culminating in high mortality rates. Stem cells present an attractive alternative to conventional therapies as they can regenerate tissue and introduce growth factors to slow down the progression of disease. We conducted a comprehensive review of literature available in the MEDLINE (PUBMED), Scopus, and Cochrane Library databases, of current usage of stem cells and stem cell-based biomaterials for ALS treatment. Clinical trials, less than 10 years old, on human subjects were included in the study. Overall, stem cells, whether mesenchymal, non-lineage, or neural stem cells all seem safe for use in therapy for ALS. However, due to the chronic nature of the disease the efficacy of the treatment is not proven and warrants further investigation.}, }
@article {pmid36787643, year = {2023}, author = {Fontana, IC and Souza, DG and Souza, DO and Gee, A and Zimmer, ER and Bongarzone, S}, title = {A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases.}, journal = {Journal of medicinal chemistry}, volume = {66}, number = {4}, pages = {2330-2346}, pmid = {36787643}, issn = {1520-4804}, support = {WT203148/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Excitatory Amino Acid Transporter 2/metabolism ; *Neurodegenerative Diseases/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Chemistry, Pharmaceutical ; Brain/metabolism ; Glutamic Acid/metabolism ; Mammals/metabolism ; }, abstract = {The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure-activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).}, }
@article {pmid36786126, year = {2023}, author = {Merjane, J and Chung, R and Patani, R and Lisowski, L}, title = {Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno-associated viral vectors.}, journal = {Medicinal research reviews}, volume = {43}, number = {4}, pages = {829-854}, doi = {10.1002/med.21937}, pmid = {36786126}, issn = {1098-1128}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Neurodegenerative Diseases ; Genetic Therapy ; Dependovirus/genetics ; }, abstract = {Despite the devastating clinical outcome of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), its etiology remains mysterious. Approximately 90% of ALS is characterized as sporadic, signifying that the patient has no family history of the disease. The development of an impactful disease modifying therapy across the ALS spectrum has remained out of grasp, largely due to the poorly understood mechanisms of disease onset and progression. Currently, ALS is invariably fatal and rapidly progressive. It is hypothesized that multiple factors can lead to the development of ALS, however, treatments are often focused on targeting specific familial forms of the disease (10% of total cases). There is a strong need to develop disease modifying treatments for ALS that can be effective across the full ALS spectrum of familial and sporadic cases. Although the onset of disease varies significantly between patients, there are general disease mechanisms and progressions that can be seen broadly across ALS patients. Therefore, this review explores the targeting of these widespread disease mechanisms as possible areas for therapeutic intervention to treat ALS broadly. In particular, this review will focus on targeting mechanisms of defective protein homeostasis and RNA processing, which are both increasingly recognized as design principles of ALS pathogenesis. Additionally, this review will explore the benefits of gene therapy as an approach to treating ALS, specifically focusing on the use of adeno-associated virus (AAV) as a vector for gene delivery to the CNS and recent advances in the field.}, }
@article {pmid36779014, year = {2023}, author = {Nik Akhtar, S and Bunner, WP and Brennan, E and Lu, Q and Szatmari, EM}, title = {Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1084769}, pmid = {36779014}, issn = {1662-5102}, support = {R01 GM146257/GM/NIGMS NIH HHS/United States ; }, abstract = {Neurodegeneration is associated with defects in cytoskeletal dynamics and dysfunctions of the vesicular trafficking and sorting systems. In the last few decades, studies have demonstrated that the key regulators of cytoskeletal dynamics are proteins from the Rho family GTPases, meanwhile, the central hub for vesicle sorting and transport between target membranes is the Rab family of GTPases. In this regard, the role of Rho and Rab GTPases in the induction and maintenance of distinct functional and morphological neuronal domains (such as dendrites and axons) has been extensively studied. Several members belonging to these two families of proteins have been associated with many neurodegenerative disorders ranging from dementia to motor neuron degeneration. In this analysis, we attempt to present a brief review of the potential crosstalk between the Rab and Rho family members in neurodegenerative pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease, and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid36778117, year = {2023}, author = {Cano, A and Ettcheto, M and Bernuz, M and Puerta, R and Esteban de Antonio, E and Sánchez-López, E and Souto, EB and Camins, A and Martí, M and Pividori, MI and Boada, M and Ruiz, A}, title = {Extracellular vesicles, the emerging mirrors of brain physiopathology.}, journal = {International journal of biological sciences}, volume = {19}, number = {3}, pages = {721-743}, pmid = {36778117}, issn = {1449-2288}, mesh = {Humans ; *Extracellular Vesicles ; *Exosomes ; *Alzheimer Disease ; *Parkinson Disease ; Blood-Brain Barrier ; }, abstract = {Extracellular vesicles are secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Their molecular cargo reflects the physiological processes that their cells of origin are undergoing. Thus, many studies have suggested that extracellular vesicles could be a promising biomarker tool for many diseases, mainly due to their biological relevance and easy accessibility to a broad range of body fluids. Moreover, since their biological composition leads them to cross the blood-brain barrier bidirectionally, growing evidence points to extracellular vesicles as emerging mirrors of brain diseases processes. In this regard, this review explores the biogenesis and biological functions of extracellular vesicles, their role in different physiological and pathological processes, their potential in clinical practice, and the recent outstanding studies about the role of exosomes in major human brain diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or brain tumors.}, }
@article {pmid36776399, year = {2022}, author = {Wu, C and Jiang, ML and Jiang, R and Pang, T and Zhang, CJ}, title = {The roles of fungus in CNS autoimmune and neurodegeneration disorders.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1077335}, pmid = {36776399}, issn = {1664-3224}, mesh = {Central Nervous System ; *Central Nervous System Diseases/drug therapy ; *Multiple Sclerosis ; *Neurodegenerative Diseases ; Fungi ; Inflammation ; }, abstract = {Fungal infection or proliferation in our body is capable of initiation of strong inflammation and immune responses that result in different consequences, including infection-trigged organ injury and inflammation-related remote organ dysfunction. Fungi associated infectious diseases have been well recognized in the clinic. However, whether fungi play an important role in non-infectious central nervous system disease is still to be elucidated. Recently, a growing amount of evidence point to a non-negligible role of peripheral fungus in triggering unique inflammation, immune response, and exacerbation of a range of non-infectious CNS disorders, including Multiple sclerosis, Neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis et al. In this review, we summarized the recent advances in recognizing patterns and inflammatory signaling of fungi in different subsets of immune cells, with a specific focus on its function in CNS autoimmune and neurodegeneration diseases. In conclusion, the fungus is capable of triggering unique inflammation by multiple mechanisms in the progression of a body of CNS non-infectious diseases, suggesting it serves as a key factor and critical novel target for the development of potential therapeutic strategies.}, }
@article {pmid36774721, year = {2023}, author = {Ketabforoush, AHME and Chegini, R and Barati, S and Tahmasebi, F and Moghisseh, B and Joghataei, MT and Faghihi, F and Azedi, F}, title = {Masitinib: The promising actor in the next season of the Amyotrophic Lateral Sclerosis treatment series.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {160}, number = {}, pages = {114378}, doi = {10.1016/j.biopha.2023.114378}, pmid = {36774721}, issn = {1950-6007}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases ; Quality of Life ; Seasons ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.}, }
@article {pmid36773012, year = {2023}, author = {Corcia, P and Lunetta, C and Vourc'h, P and Pradat, PF and Blasco, H}, title = {Time for optimism in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {5}, pages = {1459-1464}, doi = {10.1111/ene.15738}, pmid = {36773012}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Motor Neuron Disease ; Biomarkers ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is among the most common motor neuron diseases in adults. Nevertheless, ALS remains fatal, despite decades of research and clinical trials, which has led to negative conclusions until recently in regard to four specific treatments. It is well known that we can learn from failures, and we consider that the time has come to present positive insight on this disease.<br><br>METHODS: We did a literature search using PubMed and Scopus for articles published in English from 1 January 2016, to 30 June 2022 dealing with "amyotrophic lateral sclerosis", diagnosis, treatment, and biomarkers.<br><br>RESULTS: A comprehensive review of the literature on diagnosis, monitoring, and treatment of this condition showed convincing evidence that we are now able to diagnose earlier as well as to better monitor and treat ALS.<br><br>CONCLUSIONS: Although ALS is often difficult to diagnose and remains incurable, there are many indications that an optimistic view of ALS management in the coming years is now realistic.}, }
@article {pmid36768596, year = {2023}, author = {Pathak, D and Sriram, K}, title = {Molecular Mechanisms Underlying Neuroinflammation Elicited by Occupational Injuries and Toxicants.}, journal = {International journal of molecular sciences}, volume = {24}, number = {3}, pages = {}, pmid = {36768596}, issn = {1422-0067}, support = {9390BN0 (to KS)//National Institute for Occupational Safety and Health/ ; 9390KK9 (to KS)//National Institute for Occupational Safety and Health/ ; }, mesh = {Humans ; *Occupational Injuries ; Neuroinflammatory Diseases ; Gliosis/metabolism ; Central Nervous System/metabolism ; *Neurodegenerative Diseases/metabolism ; Microglia/metabolism ; }, abstract = {Occupational injuries and toxicant exposures lead to the development of neuroinflammation by activating distinct mechanistic signaling cascades that ultimately culminate in the disruption of neuronal function leading to neurological and neurodegenerative disorders. The entry of toxicants into the brain causes the subsequent activation of glial cells, a response known as 'reactive gliosis'. Reactive glial cells secrete a wide variety of signaling molecules in response to neuronal perturbations and thus play a crucial role in the progression and regulation of central nervous system (CNS) injury. In parallel, the roles of protein phosphorylation and cell signaling in eliciting neuroinflammation are evolving. However, there is limited understanding of the molecular underpinnings associated with toxicant- or occupational injury-mediated neuroinflammation, gliosis, and neurological outcomes. The activation of signaling molecules has biological significance, including the promotion or inhibition of disease mechanisms. Nevertheless, the regulatory mechanisms of synergism or antagonism among intracellular signaling pathways remain elusive. This review highlights the research focusing on the direct interaction between the immune system and the toxicant- or occupational injury-induced gliosis. Specifically, the role of occupational injuries, e.g., trips, slips, and falls resulting in traumatic brain injury, and occupational toxicants, e.g., volatile organic compounds, metals, and nanoparticles/nanomaterials in the development of neuroinflammation and neurological or neurodegenerative diseases are highlighted. Further, this review recapitulates the recent advancement related to the characterization of the molecular mechanisms comprising protein phosphorylation and cell signaling, culminating in neuroinflammation.}, }
@article {pmid36768231, year = {2023}, author = {Behler, A and Müller, HP and Ludolph, AC and Kassubek, J}, title = {Diffusion Tensor Imaging in Amyotrophic Lateral Sclerosis: Machine Learning for Biomarker Development.}, journal = {International journal of molecular sciences}, volume = {24}, number = {3}, pages = {}, pmid = {36768231}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Diffusion Tensor Imaging/methods ; Magnetic Resonance Imaging ; Biomarkers ; Machine Learning ; }, abstract = {Diffusion tensor imaging (DTI) allows the in vivo imaging of pathological white matter alterations, either with unbiased voxel-wise or hypothesis-guided tract-based analysis. Alterations of diffusion metrics are indicative of the cerebral status of patients with amyotrophic lateral sclerosis (ALS) at the individual level. Using machine learning (ML) models to analyze complex and high-dimensional neuroimaging data sets, new opportunities for DTI-based biomarkers in ALS arise. This review aims to summarize how different ML models based on DTI parameters can be used for supervised diagnostic classifications and to provide individualized patient stratification with unsupervised approaches in ALS. To capture the whole spectrum of neuropathological signatures, DTI might be combined with additional modalities, such as structural T1w 3-D MRI in ML models. To further improve the power of ML in ALS and enable the application of deep learning models, standardized DTI protocols and multi-center collaborations are needed to validate multimodal DTI biomarkers. The application of ML models to multiparametric MRI/multimodal DTI-based data sets will enable a detailed assessment of neuropathological signatures in patients with ALS and the development of novel neuroimaging biomarkers that could be used in the clinical workup.}, }
@article {pmid36766772, year = {2023}, author = {Borbolis, F and Mytilinaiou, E and Palikaras, K}, title = {The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.}, journal = {Cells}, volume = {12}, number = {3}, pages = {}, pmid = {36766772}, issn = {2073-4409}, mesh = {Animals ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Cell Physiological Phenomena ; *Gastrointestinal Microbiome ; Central Nervous System/metabolism ; }, abstract = {Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut-brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.}, }
@article {pmid36766521, year = {2023}, author = {Gambino, CM and Ciaccio, AM and Lo Sasso, B and Giglio, RV and Vidali, M and Agnello, L and Ciaccio, M}, title = {The Role of TAR DNA Binding Protein 43 (TDP-43) as a CandiDate Biomarker of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {36766521}, issn = {2075-4418}, abstract = {BACKGROUND: TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly supports the pathogenetic role of TDP-43 in ALS pathogenesis, the role of TDP-43 as a biomarker of ALS is controversial. We performed a systematic review and meta-analysis to assess the diagnostic performance of TDP-43 for ALS.<br><br>METHODS: Relevant publications were identified by a systematic literature search on PubMed and Web of Science from their inception to 8 April 2022.<br><br>RESULTS: Seven studies, including 472 individuals, of whom 254 had ALS according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, met the inclusion criteria for our meta-analysis. According to the random-effects model, CSF TDP-43 levels are higher in ALS patients compared with control groups.<br><br>CONCLUSIONS: CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions.}, }
@article {pmid36762798, year = {2023}, author = {Martinez-Gonzalez, L and Martinez, A}, title = {Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {2}, pages = {141-160}, doi = {10.1080/13543784.2023.2178416}, pmid = {36762798}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Drugs, Investigational/pharmacology/therapeutic use ; Drug Discovery ; Motor Neurons ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motoneuron death with a median survival time of 3-5 years since disease onset. There are no effective treatments to date. However, a variety of innovative investigational drugs and biological-based therapies are under clinical development.<br><br>AREAS COVERED: This review provides an overview of the clinical investigational small molecules as well as a brief summary of the biological-based therapies that are currently undergoing clinical trials for the treatment of ALS. All the data were obtained from ClinicalTrials.gov (registered through November 1).<br><br>EXPERT OPINION: Drug discovery for ALS is an active and evolving field, where many investigational clinical drugs are in different trials. There are several mechanisms of action supporting all these new therapies, although proteostasis is gaining stage. Probably, small orally bioavailable molecules able to recover functional TDP-43 homeostasis may have solid chances to modify ALS progression.}, }
@article {pmid36760367, year = {2023}, author = {Walters, GC and Usachev, YM}, title = {Mitochondrial calcium cycling in neuronal function and neurodegeneration.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1094356}, pmid = {36760367}, issn = {2296-634X}, support = {R01 NS113189/NS/NINDS NIH HHS/United States ; R01 NS125884/NS/NINDS NIH HHS/United States ; R01 NS127428/NS/NINDS NIH HHS/United States ; T32 GM067795/GM/NIGMS NIH HHS/United States ; }, abstract = {Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca[2+]) buffering, and apoptotic signaling. In neurons, Ca[2+] buffering is particularly important as it helps to shape Ca[2+] signals and to regulate numerous Ca[2+]-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca[2+] uniporter (MCU) and other molecular components of mitochondrial Ca[2+] transport has provided insight into the roles that mitochondrial Ca[2+] regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca[2+] uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca[2+]-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca[2+] uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.}, }
@article {pmid36753012, year = {2023}, author = {Soliman, R and Rashed, HR and Moustafa, RR and Hamdi, N and Swelam, MS and Osman, A and Fahmy, N}, title = {Egyptian adaptation and validation of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-EG).}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {6}, pages = {1871-1880}, pmid = {36753012}, issn = {1590-3478}, mesh = {Adult ; Humans ; *Cognition Disorders/etiology/complications ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/psychology ; Reproducibility of Results ; Egypt ; Prospective Studies ; Cognition/physiology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common, fatal adult neuromuscular disease. It is a multi-system disorder characterized primarily by motor manifestations, but there is established evidence for cognitive and behavioral impairment, which is associated with poor prognosis, hence, the importance of tools for its assessment. The Edinburgh Cognitive and Behavioral Assessment Screen (ECAS) is an invaluable assessment tool for cognition in ALS-front temporal spectrum dementia (FTSD), as it accommodates physical challenges that usually confound traditional neuropsychological testing in those patients.<br><br>OBJECTIVE AND METHODS: To validate the Egyptian Arabic version of ECAS (ECAS-EG) based on the original English scale. This is a prospective study. The ECAS was adapted and administered to 62 Egyptian ALS patients and 60 healthy controls. Patients were recruited from the Neuromuscular Unit, Ain Shams University Hospital. The ECAS was adapted to Egyptian Arabic after being translated using the back translation method. Internal consistency of the test, inter-rater reliability, and construct validity were assessed.<br><br>RESULTS: The Egyptian Arabic version of ECAS (ECAS-EG) showed good internal consistency using Cronbach's alpha of 0.84. Inter-rater reliability was tested, values for all variables were compared, and no statistically significant differences were found (ICC = .997). ECAS-EG discriminated significantly between the patients from the control subjects (p-value of 0.001). There was a strong positive correlation between the ECAS-EG total score and the MoCA total score with a p-value of 0.001, thus indicating convergent validity. The test showed that 63% of Egyptian ALS patients were cognitively affected; most affected domains were executive functions and verbal fluency.<br><br>CONCLUSION: The current study proves that the Egyptian version of the ECAS (ECAS-EG) is valid and reliable among Egyptian ALS patients and it would be applicable to the general Arabic-speaking population.}, }
@article {pmid36751781, year = {2023}, author = {Calvo, PM and Hernández, RG and de la Cruz, RR and Pastor, AM}, title = {Role of vascular endothelial growth factor as a critical neurotrophic factor for the survival and physiology of motoneurons.}, journal = {Neural regeneration research}, volume = {18}, number = {8}, pages = {1691-1696}, pmid = {36751781}, issn = {1673-5374}, abstract = {Vascular endothelial growth factor (VEGF) was discovered by its angiogenic activity. However, during evolution, it appeared earlier as a neurotrophic factor required for the development of the nervous system in invertebrates lacking a circulatory system. We aimed at reviewing recent evidence indicating that VEGF has neuroprotective effects in neurons exposed to a variety of insults. Of particular interest is the link established between VEGF and motoneurons, especially after the design of the VEGF[δ/δ] mutant mice. These mice are characterized by low levels of VEGF and develop muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis. The administration of VEGF through several routes to animal models of amyotrophic lateral sclerosis delays motor impairment and motoneuron degeneration and increases life expectancy. There are new recent advances in the role of VEGF in the physiology of motoneurons. Our experimental aims use the extraocular (abducens) motoneurons lesioned by axotomy as a model for studying VEGF actions. Axotomized abducens motoneurons exhibit severe alterations in their discharge activity and a loss of synaptic boutons. The exogenous administration of VEGF to axotomized abducens motoneurons, either from the transected nerve or intraventricularly, fully restores the synaptic and discharge properties of abducens motoneurons, despite being axotomized. In addition, when an anti-VEGF neutralizing antibody is delivered from the muscle to intact, uninjured abducens motoneurons, these cells display alterations in their discharge pattern and a loss of synaptic boutons that resemble the state of axotomy. All these data indicate that VEGF is an essential neurotrophic factor for motoneurons.}, }
@article {pmid36751779, year = {2023}, author = {Imbimbo, BP and Triaca, V and Imbimbo, C and Nisticò, R}, title = {Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials.}, journal = {Neural regeneration research}, volume = {18}, number = {8}, pages = {1679-1683}, pmid = {36751779}, issn = {1673-5374}, abstract = {We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.}, }
@article {pmid36738893, year = {2023}, author = {Li, K and Wang, Z}, title = {lncRNA NEAT1: Key player in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {86}, number = {}, pages = {101878}, doi = {10.1016/j.arr.2023.101878}, pmid = {36738893}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis ; *Huntington Disease/genetics ; *Neurodegenerative Diseases/genetics/drug therapy ; *Parkinson Disease ; *RNA, Long Noncoding/genetics ; }, abstract = {Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic tests, there is an urgent need to identify potential biomarkers and new therapeutic targets. Long non-coding RNAs (lncRNAs) have recently emerged as powerful regulatory molecules in neurodegenerative diseases. Among them, lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be upregulated in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). However, whether this is part of a protective or harmful mechanism is still unclear. This review summarizes our current knowledge of the role of NEAT1 in neurodegenerative diseases and its association with the characteristic aggregation of misfolded proteins: amyloid-β and tau in AD, α-synuclein in PD, mutant huntingtin in HD, and TAR DNA-binding protein-43 fused in sarcoma/translocated in liposarcoma in ALS. The aim of this review is to stimulate further research on more precise and effective treatments for neurodegenerative diseases.}, }
@article {pmid36737245, year = {2023}, author = {Willemse, SW and Harley, P and van Eijk, RPA and Demaegd, KC and Zelina, P and Pasterkamp, RJ and van Damme, P and Ingre, C and van Rheenen, W and Veldink, JH and Kiernan, MC and Al-Chalabi, A and van den Berg, LH and Fratta, P and van Es, MA}, title = {UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {94}, number = {8}, pages = {649-656}, pmid = {36737245}, issn = {1468-330X}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; MR/W005190/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/complications ; *Frontotemporal Dementia/pathology ; *Neurodegenerative Diseases/complications ; Nerve Tissue Proteins/genetics ; Polymorphism, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.}, }
@article {pmid36729314, year = {2023}, author = {Yang, L and Cheng, Y and Zhu, Y and Cui, L and Li, X}, title = {The Serotonergic System and Amyotrophic Lateral Sclerosis: A Review of Current Evidence.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {6}, pages = {2387-2414}, pmid = {36729314}, issn = {1573-6830}, support = {81750002//National Natural Science Foundation of China/ ; 320.6750.17092//the WJP medical foundation/ ; 2021-I2M-C&amp;T-A-003//CAMS Innovation Fund for Medical Sciences (CIFMS)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Serotonin ; Motor Neurons/metabolism ; Glutamic Acid/metabolism ; Neurotransmitter Agents ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the premature death of motor neurons. Serotonin (5-HT) is a crucial neurotransmitter, and its dysfunction, whether as a contributor or by-product, has been implicated in ALS pathogenesis. Here, we summarize current evidence linking serotonergic alterations to ALS, including results from post-mortem and neuroimaging studies, biofluid testing, and studies of ALS animal models. We also discuss the possible role of 5-HT in modulating some important mechanisms of ALS (i.e. glutamate excitotoxity and neuroinflammation) and in regulating ALS phenotypes (i.e. breathing dysfunction and metabolic defects). Finally, we discuss the promise and limitations of the serotonergic system as a target for the development of ALS biomarkers and therapeutic approaches. However, due to a relative paucity of data and standardized methodologies in previous studies, proper interpretation of existing results remains a challenge. Future research is needed to unravel the mechanisms linking serotonergic pathways and ALS and to provide valid, reproducible, and translatable findings.}, }
@article {pmid36727091, year = {2022}, author = {Basri, R and Awan, FM and Yang, BB and Awan, UA and Obaid, A and Naz, A and Ikram, A and Khan, S and Haq, IU and Khan, SN and Aqeel, MB}, title = {Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1078441}, pmid = {36727091}, issn = {1662-5099}, abstract = {Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich's ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.}, }
@article {pmid36726375, year = {2023}, author = {Sato, Y and Terawaki, S and Oikawa, D and Shimizu, K and Okina, Y and Ito, H and Tokunaga, F}, title = {Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular biosciences}, volume = {10}, number = {}, pages = {1089213}, pmid = {36726375}, issn = {2296-889X}, abstract = {In neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), the progressive accumulation of ubiquitin-positive cytoplasmic inclusions leads to proteinopathy and neurodegeneration. Along with the seven types of Lys-linked ubiquitin chains, the linear ubiquitin chain assembly complex (LUBAC)-mediated Met1-linked linear ubiquitin chain, which activates the canonical NF-κB pathway, is also involved in cytoplasmic inclusions of tau in AD and TAR DNA-binding protein 43 in ALS. Post-translational modifications, including heterologous ubiquitination, affect proteasomal and autophagic degradation, inflammatory responses, and neurodegeneration. Single nucleotide polymorphisms (SNPs) in SHARPIN and RBCK1 (which encodes HOIL-1L), components of LUBAC, were recently identified as genetic risk factors of AD. A structural biological simulation suggested that most of the SHARPIN SNPs that cause an amino acid replacement affect the structure and function of SHARPIN. Thus, the aberrant LUBAC activity is related to AD. Protein ubiquitination and ubiquitin-binding proteins, such as ubiquilin 2 and NEMO, facilitate liquid-liquid phase separation (LLPS), and linear ubiquitination seems to promote efficient LLPS. Therefore, the development of therapeutic approaches that target ubiquitination, such as proteolysis-targeting chimeras (PROTACs) and inhibitors of ubiquitin ligases, including LUBAC, is expected to be an additional effective strategy to treat neurodegenerative diseases.}, }
@article {pmid36725099, year = {2023}, author = {Wong, C and Gregory, JM and Liao, J and Egan, K and Vesterinen, HM and Ahmad Khan, A and Anwar, M and Beagan, C and Brown, FS and Cafferkey, J and Cardinali, A and Chiam, JY and Chiang, C and Collins, V and Dormido, J and Elliott, E and Foley, P and Foo, YC and Fulton-Humble, L and Gane, AB and Glasmacher, SA and Heffernan, &#xc1; and Jayaprakash, K and Jayasuriya, N and Kaddouri, A and Kiernan, J and Langlands, G and Leighton, D and Liu, J and Lyon, J and Mehta, AR and Meng, A and Nguyen, V and Park, NH and Quigley, S and Rashid, Y and Salzinger, A and Shiell, B and Singh, A and Soane, T and Thompson, A and Tomala, O and Waldron, FM and Selvaraj, BT and Chataway, J and Swingler, R and Connick, P and Pal, S and Chandran, S and Macleod, M}, title = {Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.}, journal = {BMJ open}, volume = {13}, number = {2}, pages = {e064169}, pmid = {36725099}, issn = {2044-6055}, support = {MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; MRF_MRF-024-0001-RG-PARM-C0860/MRF/MRF/United Kingdom ; }, mesh = {Humans ; Consensus ; Induced Pluripotent Stem Cells ; *Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.<br><br>METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.<br><br>RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.<br><br>DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.}, }
@article {pmid36714551, year = {2023}, author = {Katiyar, D and Singhal, S and Bansal, P and Nagarajan, K and Grover, P}, title = {Nutraceuticals and phytotherapeutics for holistic management of amyotrophic lateral sclerosis.}, journal = {3 Biotech}, volume = {13}, number = {2}, pages = {62}, pmid = {36714551}, issn = {2190-572X}, abstract = {Amyotrophic lateral sclerosis" (ALS) is a progressive neuronal disorder that affects sensory neurons in the brain and spinal cord, causing loss of muscle control. Moreover, additional neuronal subgroups as well as glial cells such as microglia, astrocytes, and oligodendrocytes are also thought to play a role in the aetiology. The disease affects upper motor neurons and lowers motor neurons and leads to that either lead to muscle weakness and wasting in the arms, legs, trunk and periventricular area. Oxidative stress, excitotoxicity, programmed cell death, altered neurofilament activity, anomalies in neurotransmission, abnormal protein processing and deterioration, increased inflammation, and mitochondrial dysfunction may all play a role in the progression of ALS. There are presently hardly FDA-approved drugs used to treat ALS, and they are only beneficial in slowing the progression of the disease and enhancing functions in certain individuals with ALS, not really in curing or preventing the illness. These days, researchers focus on understanding the pathogenesis of the disease by targeting several mechanisms aiming to develop successful treatments for ALS. This review discusses the epidemiology, risk factors, diagnosis, clinical features, pathophysiology, and disease management. The compilation focuses on alternative methods for the management of symptoms of ALS with nutraceuticals and phytotherapeutics.}, }
@article {pmid36705941, year = {2023}, author = {Sun, Y and Li, X and Bedlack, R}, title = {An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {23}, number = {1}, pages = {1-7}, doi = {10.1080/14737175.2023.2174018}, pmid = {36705941}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative motor neuron disease. Despite the overwhelming need for effective therapeutics for ALS, riluzole and edaravone were the only two FDA-approved disease-modifying therapies prior to 2022. The randomized, double-blind, multicenter, placebo-controlled CENTAUR trial demonstrated the safety and efficacy of sodium phenylbutyrate-taurursodiol (PB-TURSO) in persons with ALS (PALS), leading to its conditional approval in Canada in June 2022 and full approval in the USA in September 2022.<br><br>AREAS COVERED: Herein, the authors provide a review of the pharmacology and clinical trials evaluating sodium phenylbutyrate and/or taurursodiol in PALS.<br><br>EXPERT OPINION: The safety and tolerability of both PB and TURSO were previously demonstrated in small PALS trials. The phase 2 CENTAUR study and its open-label extension demonstrated the safety and efficacy of AMX0035 (a sachet containing a fixed co-formulation of 3&#xa0;g of PB and 1&#xa0;g of TURSO given twice daily) in PALS. A phase 3 PHOENIX trial (NCT05021536) will offer more insight into safety and efficacy of AMX0035. AMX0035 currently costs $ 158,000 annually in the US, which may become a financial barrier for PALS to receive the medication.}, }
@article {pmid36704819, year = {2023}, author = {Steinruecke, M and Lonergan, RM and Selvaraj, BT and Chandran, S and Diaz-Castro, B and Stavrou, M}, title = {Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {43}, number = {5}, pages = {642-654}, pmid = {36704819}, issn = {1559-7016}, support = {MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/T000708/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Neuroinflammatory Diseases ; Motor Neurons ; Spinal Cord ; Astrocytes/metabolism ; Disease Models, Animal ; }, abstract = {There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment of the blood-central nervous system barrier (BCNSB) occurs during the pre-symptomatic stages of ALS, the mechanisms underlying this pathology are likely also involved in the ALS disease process. In this review, we explore how drivers of ALS disease, particularly mitochondrial dysfunction, astrocyte pathology and neuroinflammation, may contribute to BCNSB impairment. Mitochondria are highly abundant in BCNSB tissue and mitochondrial dysfunction in ALS contributes to motor neuron death. Likewise, astrocytes adopt key physical, transport and metabolic functions at the barrier, many of which are impaired in ALS. Astrocytes also show raised expression of inflammatory markers in ALS and ablating ALS-causing transgenes in astrocytes slows disease progression. In addition, key drivers of neuroinflammation, including TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation and systemic inflammation, affect BCNSB integrity in ALS. Finally, we discuss the translational implications of BCNSB dysfunction in ALS, including the development of biomarkers for disease onset and progression, approaches aimed at restoring BCNSB integrity and in vitro modelling of the neurogliovascular system.}, }
@article {pmid36703583, year = {2023}, author = {Lustoza Rodrigues, TCM and de Sousa, NF and Dos Santos, AMF and Aires Guimarães, RD and Scotti, MT and Scotti, L}, title = {Challenges and Discoveries in Polypharmacology of Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {5}, pages = {349-370}, doi = {10.2174/1568026623666230126112628}, pmid = {36703583}, issn = {1873-4294}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Molecular Docking Simulation ; Polypharmacology ; Acetylcholinesterase ; *Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Neurological disorders are composed of several diseases that affect the central and peripheral nervous system; among these are neurodegenerative diseases, which lead to neuronal death. Many of these diseases have treatment for the disease and symptoms, leading patients to use several drugs that cause side effects.<br><br>INTRODUCTION: The search for new treatments has led to the investigation of multi-target drugs.<br><br>METHODS: This review aimed to investigate in the literature the multi-target effect in neurological disorders through an in silico approach. Studies were reviewed on the diseases such as epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, cerebral ischemia, and Parkinson's disease.<br><br>RESULTS: As a result, the study emphasize the relevance of research by computational techniques such as quantitative structure-activity relationship (QSAR) prediction models, pharmacokinetic prediction models, molecular docking, and molecular dynamics, besides presenting possible drug candidates with multi-target activity.<br><br>CONCLUSION: It was possible to identify several targets with pharmacological activities. Some of these targets had diseases in common such as carbonic anhydrase, acetylcholinesterase, NMDA, and MAO being relevant for possible multi-target approaches.}, }
@article {pmid36699516, year = {2022}, author = {Zoccolella, S and Giugno, A and Logroscino, G}, title = {Split phenomena in amyotrophic lateral sclerosis: Current evidences, pathogenetic hypotheses and diagnostic implications.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1100040}, pmid = {36699516}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and has emerged among the disorders with the largest increasing incidence in Western countries. Although the diagnosis is based on clinical grounds, electromyography (EMG), and nerve conduction studies (NCS) play a crucial role to exclude other potential etiologies of lower motor neuron (LMN) dysfunction. Based on clinical grounds, a peculiar pattern of dissociated atrophy of the intrinsic hand and foot muscles, termed the "split-hand" (SH) and "split-leg" (SL) signs, has been described in a significant proportion of subjects with ALS, even at the early stages of the disease, when symptoms are focal. These signs are rare in neurological and non-neurological diseases other than ALS. In this review, we discussed current evidences concerning SH and SL signs, their pathogenetic hypotheses and neurophysiological findings. We also analyze whether SH and SL signs can be reliable markers in the differential diagnosis and in the prognosis of ALS.}, }
@article {pmid36698966, year = {2023}, author = {Matrone, C}, title = {The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {923-930}, pmid = {36698966}, issn = {2001-0370}, abstract = {Neurodegenerative diseases are characterized by the progressive decline of neuronal function in several brain areas, and are always associated with cognitive, psychiatric, or motor deficits due to the atrophy of certain neuronal populations. Most neurodegenerative diseases share common pathological mechanisms, such as neurotoxic protein misfolding, oxidative stress, and impairment of autophagy machinery. Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset motor neuron disorders worldwide. It is clinically characterized by the selective and progressive loss of motor neurons in the motor cortex, brain stem, and spinal cord, ultimately leading to muscle atrophy and rapidly progressive paralysis. Multiple recent studies have indicated that the amyloid precursor protein (APP) and its proteolytic fragments are not only drivers of Alzheimer's disease (AD) but also one of the earliest signatures in ALS, preceding or anticipating neuromuscular junction instability and denervation. Indeed, altered levels of APP peptides have been found in the brain, muscles, skin, and cerebrospinal fluid of ALS patients. In this short review, we discuss the nature and extent of research evidence on the role of APP peptides in ALS, focusing on the intracellular C-terminal peptide and its regulatory motif 682YENPTY687, with the overall aim of providing new frameworks and perspectives for intervention and identifying key questions for future investigations.}, }
@article {pmid36698017, year = {2022}, author = {Klimpel, M and Kovalenko, MV and Kravchyk, KV}, title = {Advances and challenges of aluminum-sulfur batteries.}, journal = {Communications chemistry}, volume = {5}, number = {1}, pages = {77}, pmid = {36698017}, issn = {2399-3669}, abstract = {The search for cost-effective stationary energy storage systems has led to a surge of reports on novel post-Li-ion batteries composed entirely of earth-abundant chemical elements. Among the plethora of contenders in the 'beyond lithium' domain, the aluminum-sulfur (Al-S) batteries have attracted considerable attention in recent years due to their low cost and high theoretical volumetric and gravimetric energy densities (3177 Wh L[-1] and 1392 Wh kg[-1]). In this work, we offer an overview of historical and present research pursuits in the development of Al-S batteries with particular emphasis on their fundamental problem-the dissolution of polysulfides. We examine both experimental and computational approaches to tailor the chemical interactions between the sulfur host materials and polysulfides, and conclude with our view on research directions that could be pursued further.}, }
@article {pmid36694292, year = {2023}, author = {Fullam, T and Armon, C and Barkhaus, P and Barnes, B and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Mascias Cadavid, J and Carter, GT and Dimachkie, M and Ennist, D and Feldman, EL and Heiman-Patterson, T and Jhooty, S and Lund, I and Mcdermott, C and Pattee, G and Ratner, D and Wicks, P and Bedlack, R}, title = {ALSUntangled # 69: astaxanthin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {553-557}, doi = {10.1080/21678421.2023.2171302}, pmid = {36694292}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Complementary Therapies ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified "ALS reversal" occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.}, }
@article {pmid36690163, year = {2023}, author = {Sironi, F and De Marchi, F and Mazzini, L and Bendotti, C}, title = {Cell therapy in ALS: An update on preclinical and clinical studies.}, journal = {Brain research bulletin}, volume = {194}, number = {}, pages = {64-81}, doi = {10.1016/j.brainresbull.2023.01.008}, pmid = {36690163}, issn = {1873-2747}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Stem Cell Transplantation/methods ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and neuromuscular impairment leading to complete paralysis, respiratory failure and premature death. The pathogenesis of the disease is multifactorial and noncell-autonomous involving the central and peripheral compartments of the neuromuscular axis and the skeletal muscle. Advanced clinical trials on specific ALS-related pathways have failed to significantly slow the disease. Therapy with stem cells from different sources has provided a promising strategy to protect the motor units exerting their effect through multiple mechanisms including neurotrophic support and excitotoxicity and neuroinflammation modulation, as evidenced from preclinical studies. Several phase I and II clinical trial of ALS patients have been developed showing positive effects in terms of safety and tolerability. However, the modest results on functional improvement in ALS patients suggest that only a coordinated effort between basic and clinical researchers could solve many problems, such as selecting the ideal stem cell source, identifying their mechanism of action and expected clinical outcomes. A promising approach may be stem cells selected or engineered to deliver optimal growth factor support at multiple sites along the neuromuscular pathway. This review covers recent advances in stem cell therapies in animal models of ALS, as well as detailing the human clinical trials that have been done and are currently undergoing development.}, }
@article {pmid36688174, year = {2022}, author = {Kabir, F and Atkinson, R and Cook, AL and Phipps, AJ and King, AE}, title = {The role of altered protein acetylation in neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1025473}, pmid = {36688174}, issn = {1663-4365}, abstract = {Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.}, }
@article {pmid36684437, year = {2022}, author = {Castillo Bautista, CM and Sterneckert, J}, title = {Progress and challenges in directing the differentiation of human iPSCs into spinal motor neurons.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {1089970}, pmid = {36684437}, issn = {2296-634X}, abstract = {Motor neuron (MN) diseases, including amyotrophic lateral sclerosis, progressive bulbar palsy, primary lateral sclerosis and spinal muscular atrophy, cause progressive paralysis and, in many cases, death. A better understanding of the molecular mechanisms of pathogenesis is urgently needed to identify more effective therapies. However, studying MNs has been extremely difficult because they are inaccessible in the spinal cord. Induced pluripotent stem cells (iPSCs) can generate a theoretically limitless number of MNs from a specific patient, making them powerful tools for studying MN diseases. However, to reach their potential, iPSCs need to be directed to efficiently differentiate into functional MNs. Here, we review the reported differentiation protocols for spinal MNs, including induction with small molecules, expression of lineage-specific transcription factors, 2-dimensional and 3-dimensional cultures, as well as the implementation of microfluidics devices and co-cultures with other cell types, including skeletal muscle. We will summarize the advantages and disadvantages of each strategy. In addition, we will provide insights into how to address some of the remaining challenges, including reproducibly obtaining mature and aged MNs.}, }
@article {pmid36681358, year = {2023}, author = {Jericó, I and Vicuña-Urriza, J and Blanco-Luquin, I and Macias, M and Martinez-Merino, L and Roldán, M and Rojas-Garcia, R and Pagola-Lorz, I and Carbayo, A and De Luna, N and Zelaya, V and Mendioroz, M}, title = {Profiling TREM2 expression in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {109}, number = {}, pages = {117-126}, doi = {10.1016/j.bbi.2023.01.013}, pmid = {36681358}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; Biomarkers/cerebrospinal fluid ; Inflammation ; DNA-Binding Proteins ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: There is growing evidence of the contribution of neuroinflammation, and in particular microglia, in the pathogenesis of amyotrophic lateral sclerosis (ALS). TREM2 gene plays a crucial role in shaping microglia in neurodegenerative conditions. To deepen the understanding of TREM2 in ALS and investigate the performance of TREM2 as a biomarker, we profiled TREM2 expression levels in spinal cord, cerebrospinal fluid and blood of patients with sporadic ALS. We also wanted to investigate whether the combined measurement of sTREM2 in fluids could improve the diagnostic yield of total and phosphorylated TDP-43 levels.<br><br>METHODS: We performed a case-control study to profile overall and transcript-specific TREM2 mRNA levels by RT-qPCR and protein expression levels by Western-blot in postmortem specimens of spinal cord from ALS patients and controls. In parallel, we measured soluble TREM2 (sTREM2) protein levels and full length and phosphorylated TDP-43 (tTDP-43 and pTDP-43) by ELISA in CSF and serum from ALS patients vs healthy controls. Patients were prospectively recruited from an ALS unit of a tertiary hospital and fulfilled El Escorial revised criteria. After bivariate analysis, a logistic regression model was developed to identify adjusted estimates of the association of sTREM2 levels in CSF and serum with ALS status.<br><br>RESULTS: Overall and transcript-specific TREM2 mRNA were upregulated in the spinal cord of ALS patients (n&#xa0;=&#xa0;21) compared to controls (n&#xa0;=&#xa0;19). Similar changes were observed in TREM2 protein levels (p&#xa0;<&#xa0;0.01) in spinal cord of ALS patients vs healthy controls. We also detected significantly higher sTREM2 levels in CSF (p-value&#xa0;<&#xa0;0.01) of ALS patients (n&#xa0;=&#xa0;46) vs controls (n&#xa0;=&#xa0;46) and serum (p-value&#xa0;<&#xa0;0.001) of ALS patients (n&#xa0;=&#xa0;100) vs controls (n&#xa0;=&#xa0;100). In a logistic regression model, both CSF and serum sTREM2 remained independently associated with ALS status with OR&#xa0;=&#xa0;3.41 (CI 95&#xa0;%=1.34-8.66) (p-value&#xa0;<&#xa0;0.05) and OR&#xa0;=&#xa0;3.38 (CI 95&#xa0;%: 1.86-6.16) (p-value&#xa0;<&#xa0;0.001), respectively. We also observed that pTDP-43 levels in CSF is an independent predictor of ALS (p-value&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: Our results support the role of TREM2 in ALS pathophysiology and demonstrates that the three TREM2 transcripts are deregulated in ALS in postmortem human specimens of spinal cord. We hypothesise about the possible influence of systemic-peripheral inflammation in the disease. Finally, we conclude that pTDP-43 levels in CSF could be a biomarker of ALS, and sTREM2 measurement in CSF and blood emerge as potential non-invasive biomarker in ALS.}, }
@article {pmid36681253, year = {2023}, author = {Liu, H and Lan, S and Shi, XJ and Fan, FC and Liu, QS and Cong, L and Cheng, Y}, title = {Systematic review and meta-analysis on microRNAs in amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {194}, number = {}, pages = {82-89}, doi = {10.1016/j.brainresbull.2023.01.005}, pmid = {36681253}, issn = {1873-2747}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Biomarkers ; }, abstract = {MicroRNAs (miRNAs) exhibit a crucial role in the pathogenesis and progress of neurodegenerative disorders. Recent studies have shown abnormal levels of miRNA expression in patients with amyotrophic lateral sclerosis (ALS). Clinical data also confirmed that miRNAs in these patients are inconsistent across studies. A comprehensive systematic review and meta-analysis of current studies can help recognize the important roles of miRNAs during ALS development. Therefore, we initially aimed to perform a systematic literature review on the muscle or serum miRNAs in patients with ALS and healthy individuals. Subsequently, we quantitatively summarized the clinical data of muscle or serum miRNA of patients with ALS and healthy individuals using a meta-analytical technique. 11 studies comprising 281 patients with ALS and 244 healthy control (HC) controls were identified from PubMed and Web of Science for meta-analysis. A systematic review revealed that miRNA levels are closely associated with the occurrence of ALS disease. The expression levels of the most relevant miRNAs were either increased or decreased. The random-effects meta-analysis indicated that the levels of miR-206, miR-133b, and miR-338-3p were significantly elevated in patients with ALS than in HC subjects. By contrast, there was no significant differences in the miR-133a levels between patients with ALS and HC subjects. Collectively, our outcomes demonstrated that serum miR-206, miR-133b, and miR-338-3p were significantly increased in patients with ALS. We speculated that the increased expression levels of miR-206, miR-133b and miR-338-3p are potential promising biomarkers for ALS.}, }
@article {pmid36678841, year = {2023}, author = {Andrade, S and Nunes, D and Dabur, M and Ramalho, MJ and Pereira, MC and Loureiro, JA}, title = {Therapeutic Potential of Natural Compounds in Neurodegenerative Diseases: Insights from Clinical Trials.}, journal = {Pharmaceutics}, volume = {15}, number = {1}, pages = {}, pmid = {36678841}, issn = {1999-4923}, support = {LA/P/0045/2020 (ALiCE)//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDB/00511/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDP/00511/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; NORTE-01-0145-FEDER-000054//European Regional Development Fund/ ; EXPL/NAN-MAT/0209/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UI/BD/150946/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; SFRH/BD/040932/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; CEEC-IND/01741/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; CEEC-INST/00049/2018//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, abstract = {Neurodegenerative diseases are caused by the gradual loss of neurons' function. These neurological illnesses remain incurable, and current medicines only alleviate the symptoms. Given the social and economic burden caused by the rising frequency of neurodegenerative diseases, there is an urgent need for the development of appropriate therapeutics. Natural compounds are gaining popularity as alternatives to synthetic drugs due to their neuroprotective properties and higher biocompatibility. While natural compounds' therapeutic effects for neurodegenerative disease treatment have been investigated in numerous in vitro and in vivo studies, only few have moved to clinical trials. This article provides the first systematic review of the clinical trials evaluating natural compounds' safety and efficacy for the treatment of the five most prevalent neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid36676070, year = {2022}, author = {McCluskey, G and Morrison, KE and Donaghy, C and Rene, F and Duddy, W and Duguez, S}, title = {Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36676070}, issn = {2075-1729}, abstract = {Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease and is the most common adult motor neuron disease. The disease pathogenesis is complex with the perturbation of multiple pathways proposed, including mitochondrial dysfunction, RNA processing, glutamate excitotoxicity, endoplasmic reticulum stress, protein homeostasis and endosomal transport/extracellular vesicle (EV) secretion. EVs are nanoscopic membrane-bound particles that are released from cells, involved in the intercellular communication of proteins, lipids and genetic material, and there is increasing evidence of their role in ALS. After discussing the biogenesis of EVs, we review their roles in the propagation of pathological proteins in ALS, such as TDP-43, SOD1 and FUS, and their contribution to disease pathology. We also discuss the ALS related genes which are involved in EV formation and vesicular trafficking, before considering the EV protein and RNA dysregulation found in ALS and how these have been investigated as potential biomarkers. Finally, we highlight the potential use of EVs as therapeutic agents in ALS, in particular EVs derived from mesenchymal stem cells and EVs as drug delivery vectors for potential treatment strategies.}, }
@article {pmid36675966, year = {2022}, author = {Singh, AK}, title = {Hsrω and Other lncRNAs in Neuronal Functions and Disorders in Drosophila.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36675966}, issn = {2075-1729}, support = {BT/RHD/35/02/2006//Department of Biotechnology/ ; }, abstract = {Long noncoding RNAs (lncRNAs) have a crucial role in epigenetic, transcriptional and posttranscriptional regulation of gene expression. Many of these regulatory lncRNAs, such as MALAT1, NEAT1, HOTAIR, etc., are associated with different neurodegenerative diseases in humans. The lncRNAs produced by the hsrω gene are known to modulate neurotoxicity in polyQ and amyotrophic lateral sclerosis disease models of Drosophila. Elevated expression of hsrω lncRNAs exaggerates, while their genetic depletion through hsrω-RNAi or in an hsrω-null mutant background suppresses, the disease pathogenicity. This review discusses the possible mechanistic details and implications of the functions of hsrω lncRNAs in the modulation of neurodegenerative diseases.}, }
@article {pmid36675095, year = {2023}, author = {Rahic, Z and Buratti, E and Cappelli, S}, title = {Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36675095}, issn = {1422-0067}, support = {project NOSRESCUEALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; COVID-19/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/genetics/metabolism ; SARS-CoV-2/metabolism ; *TDP-43 Proteinopathies/genetics/metabolism ; *Virus Diseases/genetics/metabolism ; }, abstract = {Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler's murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions.}, }
@article {pmid36674643, year = {2023}, author = {Lejman, J and Panuciak, K and Nowicka, E and Mastalerczyk, A and Wojciechowska, K and Lejman, M}, title = {Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674643}, issn = {1422-0067}, mesh = {Infant ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Quality of Life ; *Muscular Atrophy, Spinal/genetics/therapy ; *Motor Neuron Disease ; Genetic Therapy ; }, abstract = {Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. As a result, there has been an increasing interest in the use of these therapies to treat motor neuron diseases (MNDs), for which many potential molecular targets have been discovered. MNDs are neurodegenerative disorders that, in their most severe forms, can lead to respiratory failure and death, for instance, spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). Despite the fact that SMA has been known for many years, it is still one of the most common genetic diseases causing infant mortality. The introduction of drugs based on ASOs-nusinersen; small molecules-risdiplam; and replacement therapy (GRT)-Zolgensma has shown a significant improvement in both event-free survival and the quality of life of patients after using these therapies in the available trial results. Although there is still no drug that would effectively alleviate the course of the disease in ALS, the experience gained from SMA gene therapy gives hope for a positive outcome of the efforts to produce an effective and safe drug. The aim of this review is to present current progress and prospects for the use of gene therapy in the treatment of both SMA and ALS.}, }
@article {pmid36674517, year = {2023}, author = {Matheson, JT and Holsinger, RMD}, title = {The Role of Fecal Microbiota Transplantation in the Treatment of Neurodegenerative Diseases: A Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674517}, issn = {1422-0067}, mesh = {Humans ; Fecal Microbiota Transplantation ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Microbiota ; *Clostridium Infections/therapy ; Dysbiosis/therapy ; }, abstract = {Neurodegenerative diseases are highly prevalent but poorly understood, and with few treatment options despite decades of intense research, attention has recently shifted toward other mediators of neurological disease that may present future targets for therapeutic research. One such mediator is the gut microbiome, which communicates with the brain through the gut-brain axis and has been implicated in various neurological disorders. Alterations in the gut microbiome have been associated with numerous neurological and other diseases, and restoration of the dysbiotic gut has been shown to improve disease conditions. One method of restoring a dysbiotic gut is via fecal microbiota transplantation (FMT), recolonizing the "diseased" gut with normal microbiome. Fecal microbiota transplantation is a treatment method traditionally used for Clostridium difficile infections, but it has recently been used in neurodegenerative disease research as a potential treatment method. This review aims to present a summary of neurodegenerative research that has used FMT, whether as a treatment or to investigate how the microbiome influences pathogenesis.}, }
@article {pmid36671665, year = {2023}, author = {Louit, A and Galbraith, T and Berthod, F}, title = {In Vitro 3D Modeling of Neurodegenerative Diseases.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {36671665}, issn = {2306-5354}, support = {ND//National Ataxia Foundation/ ; }, abstract = {The study of neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis) is very complex due to the difficulty in investigating the cellular dynamics within nervous tissue. Despite numerous advances in the in vivo study of these diseases, the use of in vitro analyses is proving to be a valuable tool to better understand the mechanisms implicated in these diseases. Although neural cells remain difficult to obtain from patient tissues, access to induced multipotent stem cell production now makes it possible to generate virtually all neural cells involved in these diseases (from neurons to glial cells). Many original 3D culture model approaches are currently being developed (using these different cell types together) to closely mimic degenerative nervous tissue environments. The aim of these approaches is to allow an interaction between glial cells and neurons, which reproduces pathophysiological reality by co-culturing them in structures that recapitulate embryonic development or facilitate axonal migration, local molecule exchange, and myelination (to name a few). This review details the advantages and disadvantages of techniques using scaffolds, spheroids, organoids, 3D bioprinting, microfluidic systems, and organ-on-a-chip strategies to model neurodegenerative diseases.}, }
@article {pmid36671411, year = {2022}, author = {Zalewska, T and Pawelec, P and Ziabska, K and Ziemka-Nalecz, M}, title = {Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia.}, journal = {Biomolecules}, volume = {13}, number = {1}, pages = {}, pmid = {36671411}, issn = {2218-273X}, support = {2017/27/B/NZ3/00582//National Science Center/ ; }, mesh = {Male ; Female ; Humans ; *Neurodegenerative Diseases/genetics ; Sex Characteristics ; Brain ; *Brain Diseases ; *Brain Ischemia ; }, abstract = {Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are achieved through the complex interplay of several factors contributing to this phenomenon, such as sex hormones, as well as genetic and epigenetic differences. Despite recent advances, the precise link between these factors and brain disorders is incompletely understood. This review aims to briefly outline the most relevant aspects that differ between men and women in ischemia and neurodegenerative disorders (AD, PD, HD, ALS, and SM). Recognition of disparities between both sexes could aid the development of individual approaches to ameliorate or slow the progression of intractable disorders.}, }
@article {pmid36670248, year = {2023}, author = {Zheng, X and Wang, S and Huang, J and Lin, J and Yang, T and Xiao, Y and Jiang, Q and Huang, R and Li, C and Shang, H}, title = {Physical activity as risk factor in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {270}, number = {5}, pages = {2438-2450}, pmid = {36670248}, issn = {1432-1459}, support = {grant No. 2021YFC2501203//the National Key Research and Development Program of China/ ; 2021YFC2501205//the National Key Research and Development Program of China/ ; grant No. 2022ZDZX0023//the Sichuan Science and Technology Program/ ; 2020YJ0457//the Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Risk Factors ; Exercise ; Cohort Studies ; Life Style ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with rapid progression and high mortality. Physical activity (PA) has been identified as a major risk factor for ALS. However, the results across studies are still controversial. We aimed to explore the association between different types of PA and ALS.<br><br>METHODS: The PubMed, EMBASE, Cochrane and Web of Science databases were systematically searched for case-control and cohort studies which explored the relationship between PA and ALS from inception to October 2022. The data were analyzed to generate a pooled effect and 95% confidence interval (CI).<br><br>RESULTS: A total of 16,686 articles were included in the systematic search. After filtering, 28 studies from online database and 6 studies from references of relevant articles remained in the analysis. Individuals with a history of vigorous physical activity (OR 1.26, 95% CI 1.06-1.49), occupational-related activity (OR 1.14, 95% CI 1.04-1.25), leisure time activity (OR 1.08, 95% CI 1.04-1.12), unclassified PA (OR 1.05 95% CI 1.02-1.09) and professional athletes (SMR 5.23, 95% CI 2.67-10.25; SIR 2.54, 95% CI 1.37-4.69) were in higher risk of developing ALS. In contrast, sport-related activity (OR 0.97, 95% CI 0.76-1.26) was not associated with ALS.<br><br>CONCLUSIONS: Vigorous physical activity, occupational-related activity, leisure time activity, unclassified PA and professional athletes were associated with a higher risk of ALS, while sport-related activity showed no association with ALS. Our findings clarified the relation between different types of PA and ALS and provided some practicable advice for the lifestyle of high-risk populations.}, }
@article {pmid36662637, year = {2023}, author = {Millar, SR and Huang, JQ and Schreiber, KJ and Tsai, YC and Won, J and Zhang, J and Moses, AM and Youn, JY}, title = {A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules.}, journal = {Chemical reviews}, volume = {123}, number = {14}, pages = {9036-9064}, pmid = {36662637}, issn = {1520-6890}, mesh = {Humans ; *Proteome ; Proteomics ; Stress Granules ; *Amyotrophic Lateral Sclerosis/pathology ; RNA ; }, abstract = {Stress granules (SGs) are cytosolic biomolecular condensates that form in response to cellular stress. Weak, multivalent interactions between their protein and RNA constituents drive their rapid, dynamic assembly through phase separation coupled to percolation. Though a consensus model of SG function has yet to be determined, their perceived implication in cytoprotective processes (e.g., antiviral responses and inhibition of apoptosis) and possible role in the pathogenesis of various neurodegenerative diseases (e.g., amyotrophic lateral sclerosis and frontotemporal dementia) have drawn great interest. Consequently, new studies using numerous cell biological, genetic, and proteomic methods have been performed to unravel the mechanisms underlying SG formation, organization, and function and, with them, a more clearly defined SG proteome. Here, we provide a consensus SG proteome through literature curation and an update of the user-friendly database RNAgranuleDB to version 2.0 (http://rnagranuledb.lunenfeld.ca/). With this updated SG proteome, we use next-generation phase separation prediction tools to assess the predisposition of SG proteins for phase separation and aggregation. Next, we analyze the primary sequence features of intrinsically disordered regions (IDRs) within SG-resident proteins. Finally, we review the protein- and RNA-level determinants, including post-translational modifications (PTMs), that regulate SG composition and assembly/disassembly dynamics.}, }
@article {pmid36660079, year = {2022}, author = {Chakraborty, A and Diwan, A}, title = {Biomarkers and molecular mechanisms of Amyotrophic Lateral Sclerosis.}, journal = {AIMS neuroscience}, volume = {9}, number = {4}, pages = {423-443}, pmid = {36660079}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in adults involving non-demyelinating motor disorders. About 90% of ALS cases are sporadic, while 10-12% of cases are due to some genetic reasons. Mutations in superoxide dismutase 1 (SOD1), TAR, c9orf72 (chromosome 9 open reading frame 72) and VAPB genes are commonly found in ALS patients. Therefore, the mechanism of ALS development involves oxidative stress, endoplasmic reticulum stress, glutamate excitotoxicity and aggregation of proteins, neuro-inflammation and defective RNA function. Cholesterol and LDL/HDL levels are also associated with ALS development. As a result, sterols could be a suitable biomarker for this ailment. The main mechanisms of ALS development are reticulum stress, neuroinflammation and RNA metabolism. The multi-nature development of ALS makes it more challenging to pinpoint a treatment.}, }
@article {pmid36655874, year = {2023}, author = {Ackrivo, J}, title = {Pulmonary care for ALS: Progress, gaps, and paths forward.}, journal = {Muscle &amp; nerve}, volume = {67}, number = {5}, pages = {341-353}, pmid = {36655874}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; K23 HL-151879/NH/NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Respiration, Artificial ; *Noninvasive Ventilation ; Ventilators, Mechanical ; Tracheostomy ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {INTRODUCTION: Adults with amyotrophic lateral sclerosis (ALS) have been using home mechanical ventilation for over 50 years. More recently, home respiratory care has evolved to include portable home ventilators, airway clearance devices, and physiological assessments with telemonitoring capability.<br><br>National organizations currently offer incentives for providing a pulmonary care specialist within a multidisciplinary ALS clinic; however, several critical gaps exist between the available technology and employing a clinician with the necessary expertise.<br><br>GAPS IN CARE: Lack of formal training and poor financial incentives have led to a paucity of both clinicians and active clinical research engaging in the home respiratory care of ALS. Criteria for noninvasive ventilation (NIV) initiation are controversial, and few guidelines exist on the ideal subsequent adjustments of NIV with evolving disease. Consequently, many patients with ALS tolerate NIV poorly and must face the harrowing decision of hospice vs tracheostomy. Advancement of respiratory care in ALS has been hindered by critical gaps in pulmonologist availability, training in chronic respiratory failure, financial support, clinical research, and clarity on ventilation management beyond initiation.<br><br>Only a multifaceted approach will suffice for addressing the voids in ALS respiratory care, including various education initiatives, financial incentives, clinical research programs, and elevating the standard of respiratory care.}, }
@article {pmid36648959, year = {2023}, author = {Vignaroli, F and Mele, A and Tondo, G and De Giorgis, V and Manfredi, M and Comi, C and Mazzini, L and De Marchi, F}, title = {The Need for Biomarkers in the ALS-FTD Spectrum: A Clinical Point of View on the Role of Proteomics.}, journal = {Proteomes}, volume = {11}, number = {1}, pages = {}, pmid = {36648959}, issn = {2227-7382}, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are severely debilitating and progressive neurodegenerative disorders. A distinctive pathological feature of several neurodegenerative diseases, including ALS and FTD, is the deposition of aberrant protein inclusions in neuronal cells, which leads to cellular dysfunction and neuronal damage and loss. Despite this, to date, the biological process behind developing these protein inclusions must be better clarified, making the development of disease-modifying treatment impossible until this is done. Proteomics is a powerful tool to characterize the expression, structure, functions, interactions, and modifications of proteins of tissue and biological fluid, including plasma, serum, and cerebrospinal fluid. This protein-profiling characterization aims to identify disease-specific protein alteration or specific pathology-based mechanisms which may be used as markers of these conditions. Our narrative review aims to highlight the need for biomarkers and the potential use of proteomics in clinical practice for ALS-FTD spectrum disorders, considering the emerging rationale in proteomics for new drug development. Certainly, new data will emerge in the near future in this regard and support clinicians in the development of personalized medicine.}, }
@article {pmid36646255, year = {2023}, author = {Ashique, S and Afzal, O and Yasmin, S and Hussain, A and Altamimi, MA and Webster, TJ and Altamimi, ASA}, title = {Strategic nanocarriers to control neurodegenerative disorders: Concept, challenges, and future perspective.}, journal = {International journal of pharmaceutics}, volume = {633}, number = {}, pages = {122614}, doi = {10.1016/j.ijpharm.2023.122614}, pmid = {36646255}, issn = {1873-3476}, mesh = {Humans ; *Nanoparticles ; Blood-Brain Barrier ; Brain ; Drug Delivery Systems ; Nanomedicine ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Various neurodegenerative diseases (parkinson, huntington, alzheimer, and amyotrophic lateral sclerosis) are becoming serious global health challenges. Despite various treatment options, successful delivery and effective outcomes have been challenged with several physiological-anatomical barriers, formulation related issues, post-administration hurdles, regulatory constraints, physical hurdles, environmental issues, and safety concern. In the present review, we addressed a brief understanding of pathological and normal condition of blood brain barrier (BBB), rational for brain delivery using nanocarriers, major challenges, advantages of nanomedicine, critical aspects of nanomedicine to translate from bed to clinics, and strategic approaches for improved delivery across BBB. The review addressed various mechanistic perspective for delivery of drug loaded nanocarriers across BBB. Moreover, several reports have been published wherein phytomedicine, exosomes, magnetic nanopartilces, functionalized nanocarriers, cationic nanopartilces, and nano-phytomedicine were investigated for remarkable improvement in neurological disorders. These findings are informative for healthcare professionals, researchers, and scientists working in the domains. The successful application and convincing outcomes of nanomedicines were envisaged with clinical trials conducted on various drugs intended to control neurological disorders (NDs). Conclusively, the review addressed comprehensive findings on various aspects of drug loaded nanocarrier delivery across BBB, considerable risks, potential therapeutic benefits, clinical trial based outcomes, and recent advances followed by future perspectives.}, }
@article {pmid36635726, year = {2023}, author = {Udine, E and Jain, A and van Blitterswijk, M}, title = {Advances in sequencing technologies for amyotrophic lateral sclerosis research.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {4}, pmid = {36635726}, issn = {1750-1326}, support = {NS121125/NS/NINDS NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; NS123052/NS/NINDS NIH HHS/United States ; TL1 TR002380/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Genome-Wide Association Study ; High-Throughput Nucleotide Sequencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies. More recently, next-generation sequencing methods, such as whole-exome and whole-genome sequencing, have been introduced. While those methods have been particularly useful in discovering new ALS-linked genes, methodological advances are becoming increasingly important, especially given the complex genetics of ALS. Novel sequencing technologies, like long-read sequencing, are beginning to be used to uncover the contribution of repeat expansions and other types of structural variation, which may help explain missing heritability in ALS. In this review, we discuss how popular and/or upcoming methods are being used to discover ALS genes, highlighting emerging long-read sequencing platforms and their role in aiding our understanding of this challenging disease.}, }
@article {pmid36621656, year = {2023}, author = {Van't Spijker, HM and Almeida, S}, title = {How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD.}, journal = {Gene}, volume = {858}, number = {}, pages = {147167}, pmid = {36621656}, issn = {1879-0038}, support = {R21 NS112766/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; C9orf72 Protein/genetics ; Dipeptides/genetics ; DNA Repeat Expansion/genetics ; Proteins/genetics/metabolism ; RNA ; }, abstract = {A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic alteration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These neurodegenerative diseases share genetic, clinical and pathological features. The mutation in C9ORF72 appears to drive pathogenesis through a combination of loss of C9ORF72 normal function and gain of toxic effects due to the repeat expansion, which result in aggregation prone expanded RNAs and dipeptide repeat (DPR) proteins. Studies in cellular and animal models indicate that the DPR proteins are the more toxic species. Thus, a large body of research has focused on identifying the cellular pathways most directly impacted by these toxic proteins, with the goal of characterizing disease pathogenesis and nominating potential targets for therapeutic development. The preventative block of the production of the toxic proteins before they can cause harm is a second strategy of intense focus. Despite the considerable amount of effort dedicated to this prophylactic approach, it is still unclear how the DPR proteins are synthesized from RNAs harboring repeat expansions. In this review, we summarize our current knowledge of the specific protein translation mechanisms shown to account for the synthesis of DPR proteins. We will then discuss how enhanced understanding of the composition of these toxic effectors could help in refining disease mechanisms, and paving the way to identify and design effective prophylactic therapies for C9ORF72 ALS-FTD.}, }
@article {pmid36620769, year = {2022}, author = {Aversano, S and Caiazza, C and Caiazzo, M}, title = {Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1069482}, pmid = {36620769}, issn = {1663-4365}, abstract = {Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.}, }
@article {pmid36614266, year = {2023}, author = {Voronin, MV and Abramova, EV and Verbovaya, ER and Vakhitova, YV and Seredenin, SB}, title = {Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614266}, issn = {1422-0067}, support = {Project FHFG-2022-0001//Ministry of Science and Higher Education of the Russian Federation/ ; }, mesh = {Humans ; Neuroprotection ; *Neuroprotective Agents/pharmacology/therapeutic use ; Ligands ; Molecular Chaperones/metabolism ; Unfolded Protein Response ; Endoplasmic Reticulum Stress ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones.}, }
@article {pmid36614144, year = {2022}, author = {Duranti, E and Villa, C}, title = {Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614144}, issn = {1422-0067}, support = {2020-ATE-0024//University of Milano-Bicocca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Aggregates ; DNA-Binding Proteins/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.}, }
@article {pmid36614029, year = {2022}, author = {Anderson, G}, title = {Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614029}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/physiopathology ; Astrocytes/metabolism ; *Gastrointestinal Microbiome ; *Melatonin/metabolism ; Muscles/metabolism ; Reactive Oxygen Species ; *Herbicides/toxicity ; Glyphosate ; }, abstract = {The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications.}, }
@article {pmid36613531, year = {2022}, author = {Plantone, D and Primiano, G and Manco, C and Locci, S and Servidei, S and De Stefano, N}, title = {Vitamin D in Neurological Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613531}, issn = {1422-0067}, mesh = {Humans ; Vitamin D/metabolism ; Vitamins/therapeutic use ; *Multiple Sclerosis/drug therapy ; *Parkinson Disease/drug therapy ; *Vitamin D Deficiency/complications/drug therapy/metabolism ; *Diabetic Neuropathies/drug therapy ; }, abstract = {Vitamin D may have multiple effects on the nervous system and its deficiency can represent a possible risk factor for the development of many neurological diseases. Recent studies are also trying to clarify the different effects of vitamin D supplementation over the course of progressive neurological diseases. In this narrative review, we summarise vitamin D chemistry, metabolism, mechanisms of action, and the recommended daily intake. The role of vitamin D on gene transcription and the immune response is also reviewed. Finally, we discuss the scientific evidence that links low 25-hydroxyvitamin D concentrations to the onset and progression of severe neurological diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, migraine, diabetic neuropathy and amyotrophic lateral sclerosis. Completed and ongoing clinical trials on vitamin D supplementation in neurological diseases are listed.}, }
@article {pmid36610130, year = {2023}, author = {Bai, X and Bian, Z and Zhang, M}, title = {Targeting the Nrf2 signaling pathway using phytochemical ingredients: A novel therapeutic road map to combat neurodegenerative diseases.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {109}, number = {}, pages = {154582}, doi = {10.1016/j.phymed.2022.154582}, pmid = {36610130}, issn = {1618-095X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/drug therapy ; *Parkinson Disease ; Signal Transduction ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a classical nuclear transcription factor that regulates the system's anti-oxidative stress response. The activation of Nrf2 induces the expression of antioxidant proteins and improves the system's anti-oxidative stress ability. Accumulating evidence suggests that Nrf2-centered signaling pathways may be a key pharmacological target for the treatment of neurodegenerative diseases (NDDs). However, phytochemicals as new therapeutic agents against NDDs have not been clearly delineated.<br><br>PURPOSE: To review the therapeutic effects of phytochemical ingredients on NDDs by activating Nrf2 and reducing oxidative stress injury.<br><br>METHODS: A comprehensive search of published articles was performed using various literature databases including PubMed, Google Scholar, and China National Knowledge Infrastructure. The search terms included "Nrf2", "phytochemical ingredients", "natural bioactive agents", "neurodegenerative diseases", "Antioxidant", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", "amyotrophic lateral sclerosis" "multiple sclerosis", "toxicity", and combinations of these keywords. A total of 769 preclinical studies were retrieved until August 2022, and we included 39 of these articless on phytochemistry, pharmacology, toxicology and other fields.<br><br>RESULTS: Numerous in vivo and in vitro studies showed that phytochemical ingredients could act as an Nrf2 activator in the treatment of NDDs through the antioxidant defense mechanism. These phytochemical ingredients, such as salidroside, naringenin, resveratrol, sesaminol, ellagic acid, ginsenoside Re, tanshinone I, sulforaphane, curcumin, naringin, tetramethylpyrazine, withametelin, magnolol, piperine, and myricetin, had the potential to improve Nrf2 signaling, thereby combatting NDDs.<br><br>CONCLUSION: As Nrf2 activators, phytochemical ingredients may provide a novel potential strategy for the treatment of NDDs. Here, we reviewed the interaction between phytochemical ingredients, Nrf2, and its antioxidant damaging pathway in NDDs and explored the advantages of phytochemical ingredients in anti-oxidative stress, which provides a reliable basis for improving the treatment of NDDs. However, further clinical trials are needed to determine the safety and efficacy of Nrf2 activators for NDDs.}, }
@article {pmid36599511, year = {2023}, author = {Mazzola, MA and Russell, JA}, title = {Neurology ethics at the end of life.}, journal = {Handbook of clinical neurology}, volume = {191}, number = {}, pages = {235-257}, doi = {10.1016/B978-0-12-824535-4.00012-4}, pmid = {36599511}, issn = {0072-9752}, mesh = {Humans ; *Terminal Care ; Palliative Care ; Death ; *Neurology ; *Suicide, Assisted ; Ethics, Medical ; }, abstract = {Ethical challenges in medical decision making are commonly encountered by clinicians caring for patients afflicted by neurological injury or disease at the end of life (EOL). In many of these cases, there are conflicting opinions as to what is right and wrong originating from multiple sources. There is a particularly high prevalence of impaired patient judgment and decision-making capacity in this population that may result in a misrepresentation of their premorbid values and goals. Conflict may originate from a discordance between what is legal or from stakeholders who view and value life and existence differently from the patient, at times due to religious or cultural influences. Promotion of life, rather than preservation of existence, is the goal of many patients and the foundation on which palliative care is built. Those who provide EOL care, while being respectful of potential cultural, religious, and legal stakeholder perspectives, must at the same time recognize that these perspectives may conflict with the optimal ethical course to follow. In this chapter, we will attempt to review some of the more notable ethical challenges that may arise in the neurologically afflicted at the EOL. We will identify what we believe to be the most compelling ethical arguments both in support of and opposition to specific EOL issues. At the same time, we will consider how ethical analysis may be influenced by these legal, cultural, and religious considerations that commonly arise.}, }
@article {pmid36599506, year = {2023}, author = {Shoesmith, C}, title = {Palliative care principles in ALS.}, journal = {Handbook of clinical neurology}, volume = {191}, number = {}, pages = {139-155}, doi = {10.1016/B978-0-12-824535-4.00007-0}, pmid = {36599506}, issn = {0072-9752}, mesh = {Humans ; Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy ; *Deglutition Disorders ; *Neurodegenerative Diseases/complications ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with progressive dysphagia, dysarthria, extremity weakness, and dyspnea. Although there are some disease-modifying pharmacological treatments available which can modestly slow disease progression, the disease is relentlessly progressive and is ultimately fatal. Patients living with ALS should be supported using the principles of palliative care, and in particular, the use of a holistic approach to support the patients and their families. Evidence would support management of patients living with ALS by a multidisciplinary ALS specialty clinic. These multidisciplinary clinics will help support the multitude of symptoms a patient living with ALS can experience, including dysphagia, communication impairments, dexterity impairments, mobility deficits, and respiratory insufficiency. Formal involvement of specialist-trained palliative practitioners can occur throughout the course of the illness, or when the patient is open to their involvement. There are several models of palliative care that can be followed, including integration of palliative care into the multidisciplinary ALS clinic, separate involvement of a palliative care specialty team, home-based palliative care, telemedicine supported care, and hospice care. Key components of palliative care in ALS are goals-of-care discussions advance directive planning, symptoms management, and end-of-life support.}, }
@article {pmid36596480, year = {2023}, author = {Asakawa, K and Handa, H and Kawakami, K}, title = {[Optogenetic interrogation of TDP-43 cytotoxicity in a zebrafish ALS model].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {158}, number = {1}, pages = {16-20}, doi = {10.1254/fpj.22085}, pmid = {36596480}, issn = {0015-5691}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Zebrafish/metabolism ; Optogenetics ; Motor Neurons/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an evolutionarily conserved RNA/DNA-binding protein that is nuclear-enriched in healthy cells, but deposited in the cytoplasm as aggregates in affected neurons in certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We have previously developed an optogenetic TDP-43 variant (opTDP-43h) whose oligomerization status can be modulated via the CRY2olig tag, which self-assembles upon absorption of blue light. Illumination of zebrafish spinal motor neurons expressing opTDP-43h with a blue light triggers its cytoplasmic mislocalization, eventually leading to cytoplasmic deposition of opTDP-43h aggregates. Intriguingly, a light illumination-dependent transient opTDP-43 mislocalization can halt motor axon outgrowth, even in the absence of cytoplasmic deposition of opTDP-43 aggregates. These observations point toward an oligomerization-dependent, but aggregation-independent, cytotoxic effect of TDP-43 that might contribute to pathogenesis of ALS. In the present review, we would like to overview the zebrafish ALS model based on the optogenetic TDP-43, and then discuss about the potential mechanisms of TDP-43 cytotoxicity that trigger and/or promote motor neuron degeneration in ALS.}, }
@article {pmid36596053, year = {2022}, author = {Zhang, A and Xu, H and Huang, J and Gong, H and Guo, S and Lei, X and He, D}, title = {Coexisting amyotrophic lateral sclerosis and chorea: A case report and literature review.}, journal = {Medicine}, volume = {101}, number = {52}, pages = {e32452}, pmid = {36596053}, issn = {1536-5964}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Chorea/etiology/genetics ; Mutation ; Mutation Rate ; DNA Helicases/genetics ; RNA Helicases/genetics ; Multifunctional Enzymes ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) coexisting with chorea is very rare.<br><br>CASE REPORT: We present the case of a 48-year-old man with ALS and chorea; the diagnostic certainty was high based on clinical examination results. Combining the data from literature, we analyzed the characteristics of patients with ALS and chorea. We found that ALS coexisting with chorea is very rare, but is often hereditary with a genetic mutation. Most patients with ALS and chorea are caused by abnormal amplification of a CAG sequence in the HTT gene, and these patients have a mild course of disease. The FUS, VCP, and SETX genes also have low mutation frequencies in patients with ALS and chorea.<br><br>CONCLUSION: The abnormal amplification of a CAG sequence in the HTT gene in ALS with chorea has an obvious familial genetic tendency, and most patients have a mild disease course.}, }
@article {pmid36583079, year = {2022}, author = {Singh, J and Patten, SA}, title = {Modeling neuromuscular diseases in zebrafish.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1054573}, pmid = {36583079}, issn = {1662-5099}, abstract = {Neuromuscular diseases are a diverse group of conditions that affect the motor system and present some overlapping as well as distinct clinical manifestations. Although individually rare, the combined prevalence of NMDs is similar to Parkinson's. Over the past decade, new genetic mutations have been discovered through whole exome/genome sequencing, but the pathogenesis of most NMDs remains largely unexplored. Little information on the molecular mechanism governing the progression and development of NMDs accounts for the continual failure of therapies in clinical trials. Different aspects of the diseases are typically investigated using different models from cells to animals. Zebrafish emerges as an excellent model for studying genetics and pathogenesis and for developing therapeutic interventions for most NMDs. In this review, we describe the generation of different zebrafish genetic models mimicking NMDs and how they are used for drug discovery and therapy development.}, }
@article {pmid36579600, year = {2022}, author = {Anakor, E and Duddy, WJ and Duguez, S}, title = {The Cellular and Molecular Signature of ALS in Muscle.}, journal = {Journal of personalized medicine}, volume = {12}, number = {11}, pages = {}, pmid = {36579600}, issn = {2075-4426}, abstract = {Amyotrophic lateral sclerosis is a disease affecting upper and lower motor neurons. Although motor neuron death is the core event of ALS pathology, it is increasingly recognized that other tissues and cell types are affected in the disease, making potentially major contributions to the occurrence and progression of pathology. We review here the known cellular and molecular characteristics of muscle tissue affected by ALS. Evidence of toxicity in skeletal muscle tissue is considered, including metabolic dysfunctions, impaired proteostasis, and deficits in muscle regeneration and RNA metabolism. The role of muscle as a secretory organ, and effects on the skeletal muscle secretome are also covered, including the increase in secretion of toxic factors or decrease in essential factors that have consequences for neuronal function and survival.}, }
@article {pmid36578193, year = {2023}, author = {Wu, CCH and Brindise, E and Abiad, RE and Khashab, MA}, title = {The Role of Endoscopic Management in Afferent Loop Syndrome.}, journal = {Gut and liver}, volume = {17}, number = {3}, pages = {351-359}, pmid = {36578193}, issn = {2005-1212}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; Endoscopy ; Endosonography/methods ; Stents ; Ultrasonography, Interventional ; }, abstract = {Afferent loop syndrome (ALS) is a morbid complication that may occur after gastrectomy and gastrojejunostomy reconstruction. The aim of this article is to review the different endoscopic treatment options of ALS. We describe the evolution of the endoscopic treatment of ALS and its limitations despite the overall propitious profile. We analyze the advantages of endoscopic ultrasound-guided entero-enterostomy (EUS EE) over enteroscopy-guided intervention, and the clinical outcomes of EUS EE. We expound on pre-procedural considerations, intra-procedural techniques and post-procedural care following EUS EE. We conclude that given the simplification of the technique and the ability to place a stent away from the tumor, EUS EE is a promising technique that will likely be established as the treatment of choice for ALS.}, }
@article {pmid36575535, year = {2022}, author = {Lépine, S and Castellanos-Montiel, MJ and Durcan, TM}, title = {TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {56}, pmid = {36575535}, issn = {2047-9158}, support = {PJT - 169095//CIHR/Canada ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology ; Neuromuscular Junction/metabolism/pathology ; Motor Neurons/pathology ; Synaptic Transmission ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease characterized by upper and lower motor neuron (MN) loss with a signature feature of cytoplasmic aggregates containing TDP-43, which are detected in nearly all patients. Mutations in the gene that encodes TDP-43 (TARBDP) are known to result in both familial and sporadic ALS. In ALS, disruption of neuromuscular junctions (NMJs) constitutes a critical event in disease pathogenesis, leading to denervation atrophy, motor impairments and disability. Morphological defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro, linking TDP-43 dysregulation to the loss of NMJ integrity in ALS. Through the lens of the dying-back and dying-forward hypotheses of ALS, this review discusses the roles of TDP-43 related to synaptic function, with a focus on the potential molecular mechanisms occurring within MNs, skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.}, }
@article {pmid36573359, year = {2023}, author = {De Carvalho, M and Swash, M}, title = {Transcranial magnetic stimulation to monitor disease progression in ALS: a review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {362-368}, doi = {10.1080/21678421.2022.2160649}, pmid = {36573359}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Transcranial Magnetic Stimulation/methods ; Muscle, Skeletal ; Time Factors ; Evoked Potentials, Motor/physiology ; Disease Progression ; }, abstract = {Objectives: Transcranial magnetic stimulation (TMS) is a technique to assess motor system function which has been used extensively in amyotrophic lateral sclerosis (ALS). Information on the changes during disease progression is scarce. We aimed to collect this information in a single source. Methods: Literature search tools and personal searching were used to find relevant data. Results: In ALS, 1. Motor threshold tends to increase in hand muscles over disease progression. 2. Central motor conduction time is not a sensitive measurement. 3. Motor evoked potential amplitude decreases, in particular in lower limbs. 4. Primary peak from the peristimulus time histogram (PSTH) reduces in amplitude and synchronicity, but longer duration. 5. Inhibitory responses using PSTH are more pronounced over the disease course. 6. In hand muscles central silent period (CSP) is shorter early in the disease but increases with time. 7. Short inhibitory cortical interval (SICI) is abnormal in the very early disease stage and shows greater abnormality over time. 8. Area and volume in cortical maps of hand muscle decrease markedly with disease progression. Discussion: TMS studies evaluating changes over time in ALS suggest that measuring interneuronal inhibitory dysfunction is a promising method to track progression but motor amplitude and cortical maps should be investigated further. Conclusions: Available TMS studies quantifying central motor dysfunction are insufficient to propose a single physiological measurement for evaluating progression in ALS.}, }
@article {pmid36571338, year = {2023}, author = {Martinelli, I and Zucchi, E and Simonini, C and Gianferrari, G and Zamboni, G and Pinti, M and Mandrioli, J}, title = {The landscape of cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {18}, number = {7}, pages = {1427-1433}, pmid = {36571338}, issn = {1673-5374}, abstract = {Although mutations in the superoxide dismutase 1 gene account for only a minority of total amyotrophic lateral sclerosis cases, the discovery of this gene has been crucial for amyotrophic lateral sclerosis research. Since the identification of superoxide dismutase 1 in 1993, the field of amyotrophic lateral sclerosis genetics has considerably widened, improving our understanding of the diverse pathogenic basis of amyotrophic lateral sclerosis. In this review, we focus on cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis patients. Literature has mostly reported that cognition remains intact in superoxide dismutase 1-amyotrophic lateral sclerosis patients, but recent reports highlight frontal lobe function frailty in patients carrying different superoxide dismutase 1-amyotrophic lateral sclerosis mutations. We thoroughly reviewed all the various mutations reported in the literature to contribute to a comprehensive database of superoxide dismutase 1-amyotrophic lateral sclerosis genotype-phenotype correlation. Such a resource could ultimately improve our mechanistic understanding of amyotrophic lateral sclerosis, enabling a more robust assessment of how the amyotrophic lateral sclerosis phenotype responds to different variants across genes, which is important for the therapeutic strategy targeting genetic mutations. Cognition in superoxide dismutase 1-amyotrophic lateral sclerosis deserves further longitudinal research since this peculiar frailty in patients with similar mutations can be conditioned by external factors, including environment and other unidentified agents including modifier genes.}, }
@article {pmid36570463, year = {2022}, author = {Zhang, J}, title = {Investigating neurological symptoms of infectious diseases like COVID-19 leading to a deeper understanding of neurodegenerative disorders such as Parkinson's disease.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {968193}, pmid = {36570463}, issn = {1664-2295}, abstract = {Apart from common respiratory symptoms, neurological symptoms are prevalent among patients with COVID-19. Research has shown that infection with SARS-CoV-2 accelerated alpha-synuclein aggregation, induced Lewy-body-like pathology, caused dopaminergic neuron senescence, and worsened symptoms in patients with Parkinson's disease (PD). In addition, SARS-CoV-2 infection can induce neuroinflammation and facilitate subsequent neurodegeneration in long COVID, and increase individual vulnerability to PD or parkinsonism. These findings suggest that a post-COVID-19 parkinsonism might follow the COVID-19 pandemic. In order to prevent a possible post-COVID-19 parkinsonism, this paper reviewed neurological symptoms and related findings of COVID-19 and related infectious diseases (influenza and prion disease) and neurodegenerative disorders (Alzheimer's disease, PD and amyotrophic lateral sclerosis), and discussed potential mechanisms underlying the neurological symptoms and the relationship between the infectious diseases and the neurodegenerative disorders, as well as the therapeutic and preventive implications in the neurodegenerative disorders. Infections with a relay of microbes (SARS-CoV-2, influenza A viruses, gut bacteria, etc.) and prion-like alpha-synuclein proteins over time may synergize to induce PD. Therefore, a systematic approach that targets these pathogens and the pathogen-induced neuroinflammation and neurodegeneration may provide cures for neurodegenerative disorders. Further, antiviral/antimicrobial drugs, vaccines, immunotherapies and new therapies (e.g., stem cell therapy) need to work together to treat, manage or prevent these disorders. As medical science and technology advances, it is anticipated that better vaccines for SARS-CoV-2 variants, new antiviral/antimicrobial drugs, effective immunotherapies (alpha-synuclein antibodies, vaccines for PD or parkinsonism, etc.), as well as new therapies will be developed and made available in the near future, which will help prevent a possible post-COVID-19 parkinsonism in the 21st century.}, }
@article {pmid36567359, year = {2022}, author = {Ng, W and Ng, SY}, title = {Remodeling of astrocyte secretome in amyotrophic lateral sclerosis: uncovering novel targets to combat astrocyte-mediated toxicity.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {54}, pmid = {36567359}, issn = {2047-9158}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Astrocytes/metabolism ; Motor Neurons/pathology ; *Secretome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset paralytic disease characterized by progressive degeneration of upper and lower motor neurons in the motor cortex, brainstem and spinal cord. Motor neuron degeneration is typically caused by a combination of intrinsic neuronal (cell autonomous) defects as well as extrinsic (non-cell autonomous) factors such as astrocyte-mediated toxicity. Astrocytes are highly plastic cells that react to their microenvironment to mediate relevant responses. In neurodegeneration, astrocytes often turn reactive and in turn secrete a slew of factors to exert pro-inflammatory and neurotoxic effects. Various efforts have been carried out to characterize the diseased astrocyte secretome over the years, revealing that pro-inflammatory chemokines, cytokines and microRNAs are the main players in mediating neuronal death. As metabolomic technologies mature, these studies begin to shed light on neurotoxic metabolites such as secreted lipids. In this focused review, we will discuss changes in the astrocyte secretome during ALS. In particular, we will discuss the components of the reactive astrocyte secretome that contribute to neuronal death in ALS.}, }
@article {pmid36555492, year = {2022}, author = {Vrettou, S and Wirth, B}, title = {S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555492}, issn = {1422-0067}, support = {project 956185; SMABEYOND//European Union/ ; project 398410809//Deutsche Forschungsgemeinschaft/ ; project 384170921//Deutsche Forschungsgemeinschaft/ ; project 417989143//Deutsche Forschungsgemeinschaft/ ; project 269018619//Deutsche Forschungsgemeinschaft/ ; project 431549029-A01//Deutsche Forschungsgemeinschaft/ ; project ID 233886668//Deutsche Forschungsgemeinschaft/ ; CMMC project C18//University Hospital Cologne/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/physiology ; Oxidation-Reduction ; Proteins/metabolism ; Homeostasis ; }, abstract = {Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell’s sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Friedreich’s ataxia.}, }
@article {pmid36555399, year = {2022}, author = {Riku, Y and Yoshida, M and Iwasaki, Y and Sobue, G and Katsuno, M and Ishigaki, S}, title = {TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555399}, issn = {1422-0067}, support = {JP20ek0109392 (M.Y.), JP20ek0109391 (M.Y.), 21dm0207116 (S.I.), and 21ek0109497 (S.I.)//AMED/ ; JP20K16586 (Y.R.) and 21H02838 (S.I.)//JSPS KAKENHI/ ; 30-8 (M.Y.)//Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP/ ; no number applicable (Y.I.)//Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour, and Welfare Sciences Research Grants, the Ministry of Health, Labour, and Welfare/ ; }, mesh = {Humans ; tau Proteins/genetics/metabolism ; *Tauopathies/genetics/pathology ; *TDP-43 Proteinopathies/metabolism ; *Neurodegenerative Diseases ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; }, abstract = {Transactivation response DNA binding protein 43 kDa (TDP-43) and tau are major pathological proteins of neurodegenerative disorders, of which neuronal and glial aggregates are pathological hallmarks. Interestingly, accumulating evidence from neuropathological studies has shown that comorbid TDP-43 pathology is observed in a subset of patients with tauopathies, and vice versa. The concomitant pathology often spreads in a disease-specific manner and has morphological characteristics in each primary disorder. The findings from translational studies have suggested that comorbid TDP-43 or tau pathology has clinical impacts and that the comorbid pathology is not a bystander, but a part of the disease process. Shared genetic risk factors or molecular abnormalities between TDP-43 proteinopathies and tauopathies, and direct interactions between TDP-43 and tau aggregates, have been reported. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets.}, }
@article {pmid36555161, year = {2022}, author = {Rubio, MA and Herrando-Grabulosa, M and Navarro, X}, title = {Sensory Involvement in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555161}, issn = {1422-0067}, support = {RTI2018-096386-B-I00//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Neuroimaging ; Autonomic Nervous System ; DNA-Binding Proteins ; }, abstract = {Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean that their pathological significance is not relevant. In this review, we have made an extensive description of the involvement of sensory and autonomic systems described to date in ALS, from clinical, neurophysiological, neuroimaging, neuropathological, functional, and molecular perspectives.}, }
@article {pmid36550377, year = {2023}, author = {Verma, AK and Singh, S and Rizvi, SI}, title = {Therapeutic potential of melatonin and its derivatives in aging and neurodegenerative diseases.}, journal = {Biogerontology}, volume = {24}, number = {2}, pages = {183-206}, pmid = {36550377}, issn = {1573-6768}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases ; *Melatonin ; Aging/physiology ; Antioxidants ; Mitochondria ; Mammals ; }, abstract = {Aging is associated with increasing impairments in brain homeostasis and represents the main risk factor across most neurodegenerative disorders. Melatonin, a neuroendocrine hormone that regulates mammalian chronobiology and endocrine functions is well known for its antioxidant potential, exhibiting both cytoprotective and chronobiotic abilities. Age-related decline of melatonin disrupting mitochondrial homeostasis and cytosolic DNA-mediated inflammatory reactions in neurons is a major contributory factor in the emergence of neurological abnormalities. There is scattered literature on the possible use of melatonin against neurodegenerative mechanisms in the aging process and its associated diseases. We have searched PUBMED with many combinations of key words for available literature spanning two decades. Based on the vast number of experimental papers, we hereby review recent advancements concerning the potential impact of melatonin on cellular redox balance and mitochondrial dynamics in the context of neurodegeneration. Next, we discuss a broader explanation of the involvement of disrupted redox homeostasis in the pathophysiology of age-related diseases and its connection to circadian mechanisms. Our effort may result in the discovery of novel therapeutic approaches. Finally, we summarize the current knowledge on molecular and circadian regulatory mechanisms of melatonin to overcome neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, however, these findings need to be confirmed by larger, well-designed clinical trials. This review is also expected to uncover the associated molecular alterations in the aging brain and explain how melatonin-mediated circadian restoration of neuronal homeodynamics may increase healthy lifespan in age-related NDDs.}, }
@article {pmid36548189, year = {2022}, author = {Tsiamalou, A and Dardiotis, E and Paterakis, K and Fotakopoulos, G and Liampas, I and Sgantzos, M and Siokas, V and Brotis, AG}, title = {EEG in Neurorehabilitation: A Bibliometric Analysis and Content Review.}, journal = {Neurology international}, volume = {14}, number = {4}, pages = {1046-1061}, pmid = {36548189}, issn = {2035-8385}, abstract = {BACKGROUND: There is increasing interest in the role of EEG in neurorehabilitation. We primarily aimed to identify the knowledge base through highly influential studies. Our secondary aims were to imprint the relevant thematic hotspots, research trends, and social networks within the scientific community.<br><br>METHODS: We performed an electronic search in Scopus, looking for studies reporting on rehabilitation in patients with neurological disabilities. We used the most influential papers to outline the knowledge base and carried out a word co-occurrence analysis to identify the research hotspots. We also used depicted collaboration networks between universities, authors, and countries after analyzing the cocitations. The results were presented in summary tables, plots, and maps. Finally, a content review based on the top-20 most cited articles completed our study.<br><br>RESULTS: Our current bibliometric study was based on 874 records from 420 sources. There was vivid research interest in EEG use for neurorehabilitation, with an annual growth rate as high as 14.3%. The most influential paper was the study titled "Brain-computer interfaces, a review" by L.F. Nicolas-Alfonso and J. Gomez-Gill, with 997 citations, followed by "Brain-computer interfaces in neurological rehabilitation" by J. Daly and J.R. Wolpaw (708 citations). The US, Italy, and Germany were among the most productive countries. The research hotspots shifted with time from the use of functional magnetic imaging to EEG-based brain-machine interface, motor imagery, and deep learning.<br><br>CONCLUSIONS: EEG constitutes the most significant input in brain-computer interfaces (BCIs) and can be successfully used in the neurorehabilitation of patients with stroke symptoms, amyotrophic lateral sclerosis, and traumatic brain and spinal injuries. EEG-based BCI facilitates the training, communication, and control of wheelchair and exoskeletons. However, research is limited to specific scientific groups from developed countries. Evidence is expected to change with the broader availability of BCI and improvement in EEG-filtering algorithms.}, }
@article {pmid36547203, year = {2022}, author = {Yoshikawa, S and Taniguchi, K and Sawamura, H and Ikeda, Y and Tsuji, A and Matsuda, S}, title = {Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis.}, journal = {Diseases (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {36547203}, issn = {2079-9721}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, the pathogenesis of which is based on alternations in the mitochondria of motor neurons, causing their progressive death. A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. Mitophagy has been considered one of the main mechanisms responsible for mitochondrial quality control. Since ALS is characterized by enormous oxidative stress, several edible phytochemicals that can activate mitophagy to remove damaged mitochondria could be considered a promising option to treat ALS by providing neuroprotection. Therefore, it is of great significance to explore the mechanisms of mitophagy in ALS and to understand the effects and/or molecular mechanisms of phytochemical action, which could translate into a treatment for neurodegenerative diseases, including ALS.}, }
@article {pmid36543887, year = {2023}, author = {Mead, RJ and Shan, N and Reiser, HJ and Marshall, F and Shaw, PJ}, title = {Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation.}, journal = {Nature reviews. Drug discovery}, volume = {22}, number = {3}, pages = {185-212}, pmid = {36543887}, issn = {1474-1784}, support = {MR/V027735/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Motor Neurons ; Drug Discovery/methods ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10-15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.}, }
@article {pmid36543326, year = {2022}, author = {Ashhurst, JF and Tu, S and Timmins, HC and Kiernan, MC}, title = {Progress, development, and challenges in amyotrophic lateral sclerosis clinical trials.}, journal = {Expert review of neurotherapeutics}, volume = {22}, number = {11-12}, pages = {905-913}, doi = {10.1080/14737175.2022.2161893}, pmid = {36543326}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers ; Phenotype ; Disease Progression ; Precision Medicine ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) brings unique challenges to a clinical trial setting, due in part to relatively low disease prevalence coupled with a poor prognosis, in addition to the complexities linked to disease heterogeneity. As critical understanding of the disease develops, particularly in relation to clinical phenotype and the mechanisms of disease progression, so too new concepts evolve in relation to clinical trials, including the advent of precision therapy, targeted to subgroups of ALS patients.<br><br>AREAS COVERED: Individualized, or precision medicine in ALS recognizes the heterogeneous nature of the disease and utilizes information such as the clinical phenotype of the disease, clinical biomarkers, and genotyping to promote a tailored approach to treatment. Separate to these considerations, the present review will discuss clinical trial design and how this can be improved to better match patient and investigator needs in ALS clinical trials.<br><br>EXPERT OPINION: Precision therapy will promote a more focused treatment approach, with the goal of improving clinical outcomes for ALS patients. An increased community awareness of ALS, coupled with significant industry and philanthropic funding for ALS research, is accelerating this process.}, }
@article {pmid36538890, year = {2022}, author = {Adriaenssens, E and Ferrari, L and Martens, S}, title = {Orchestration of selective autophagy by cargo receptors.}, journal = {Current biology : CB}, volume = {32}, number = {24}, pages = {R1357-R1371}, doi = {10.1016/j.cub.2022.11.002}, pmid = {36538890}, issn = {1879-0445}, mesh = {*Ubiquitinated Proteins/metabolism ; *Macroautophagy ; Autophagy ; Autophagosomes/metabolism ; Carrier Proteins/metabolism ; }, abstract = {Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo material. This is achieved by the sequestration of the cargo within double-membrane vesicles termed autophagosomes, which form de novo around the cargo and subsequently deliver their content to lysosomes for degradation. The importance of selective autophagy is exemplified by the various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. It has become evident that cargo receptors are acting as Swiss army knives in selective autophagy by recognizing the cargo, orchestrating the recruitment of the machinery for autophagosome biogenesis, and closely aligning the membrane with the cargo. Furthermore, cargo receptors sequester ubiquitinated proteins into larger condensates upstream of autophagy induction. Here, we review recent insights into the mechanisms of action of cargo receptors in selective autophagy by focusing on the roles of sequestosome-like cargo receptors in the degradation of misfolded, ubiquitinated proteins and damaged mitochondria. We also highlight at which steps defects in their function result in the accumulation of harmful material and how this knowledge may guide the design of future therapies.}, }
@article {pmid36531961, year = {2022}, author = {Liao, QQ and Dong, QQ and Zhang, H and Shu, HP and Tu, YC and Yao, LJ}, title = {Contributions of SGK3 to transporter-related diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {1007924}, pmid = {36531961}, issn = {2296-634X}, abstract = {Serum- and glucocorticoid-induced kinase 3 (SGK3), which is ubiquitously expressed in mammals, is regulated by estrogens and androgens. SGK3 is activated by insulin and growth factors through signaling pathways involving phosphatidylinositol-3-kinase (PI3K), 3-phosphoinositide-dependent kinase-1 (PDK-1), and mammalian target of rapamycin complex 2 (mTORC2). Activated SGK3 can activate ion channels (TRPV5/6, SOC, Kv1.3, Kv1.5, Kv7.1, BKCa, Kir2.1, Kir2.2, ENaC, Nav1.5, ClC-2, and ClC Ka), carriers and receptors (Npt2a, Npt2b, NHE3, GluR1, GluR6, SN1, EAAT1, EAAT2, EAAT4, EAAT5, SGLT1, SLC1A5, SLC6A19, SLC6A8, and NaDC1), and Na[+]/K[+]-ATPase, promoting the transportation of calcium, phosphorus, sodium, glucose, and neutral amino acids in the kidney and intestine, the absorption of potassium and neutral amino acids in the renal tubules, the transportation of glutamate and glutamine in the nervous system, and the transportation of creatine. SGK3-sensitive transporters contribute to a variety of physiological and pathophysiological processes, such as maintaining calcium and phosphorus homeostasis, hydro-salinity balance and acid-base balance, cell proliferation, muscle action potential, cardiac and neural electrophysiological disturbances, bone density, intestinal nutrition absorption, immune function, and multiple substance metabolism. These processes are related to kidney stones, hypophosphorous rickets, multiple syndromes, arrhythmia, hypertension, heart failure, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, glaucoma, ataxia idiopathic deafness, and other diseases.}, }
@article {pmid36528916, year = {2023}, author = {Li, W and Gao, M and Hu, C and Chen, X and Zhou, Y}, title = {NMNAT2: An important metabolic enzyme affecting the disease progression.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {158}, number = {}, pages = {114143}, doi = {10.1016/j.biopha.2022.114143}, pmid = {36528916}, issn = {1950-6007}, mesh = {Humans ; Axons ; NAD/metabolism ; Wallerian Degeneration/metabolism/pathology ; *Neurodegenerative Diseases/pathology ; Disease Progression ; *Nicotinamide-Nucleotide Adenylyltransferase/genetics/metabolism ; }, abstract = {Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an evolutionarily conserved nicotinamide adenine dinucleotide (NAD[+]) synthase located in the cytoplasm and Golgi apparatus. NMNAT2 has an important role in neurodegenerative diseases, malignant tumors, and other diseases that seriously endanger human health. NMNAT2 exerts a neuroprotective function through its NAD synthase activity and chaperone function. Among them, the NMNAT2-NAD[+]-Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) axis is closely related to Wallerian degeneration. Physical injury or pathological stimulation will cause a decrease in NMNAT2, which activates SARM1, leading to axonal degeneration and the occurrence of amyotrophic lateral sclerosis (ALS), Alzheimer's disease, peripheral neuropathy, and other neurodegenerative diseases. In addition, NMNAT2 exerts a cancer-promoting role in solid tumors, including colorectal cancer, lung cancer, ovarian cancer, and glioma, and is closely related to tumor occurrence and development. This paper reviews the chromosomal and subcellular localization of NMNAT2 and its basic biological functions. We also summarize the NMNAT2-related signal transduction pathway and the role of NMNAT2 in diseases. We aimed to provide a new perspective to comprehensively understand the relationship between NMNAT2 and its associated diseases.}, }
@article {pmid36528839, year = {2023}, author = {Sanya, DRA and Cava, C and Onésime, D}, title = {Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer.}, journal = {Human cell}, volume = {36}, number = {2}, pages = {493-514}, pmid = {36528839}, issn = {1749-0774}, mesh = {Humans ; *COVID-19 ; *MicroRNAs/genetics ; RNA-Binding Proteins/genetics ; *Nervous System Diseases ; *Neoplasms ; }, abstract = {RNA-binding proteins (RBPs) have emerged as important players in multiple biological processes including transcription regulation, splicing, R-loop homeostasis, DNA rearrangement, miRNA function, biogenesis, and ribosome biogenesis. A large number of RBPs had already been identified by different approaches in various organisms and exhibited regulatory functions on RNAs' fate. RBPs can either directly or indirectly interact with their target RNAs or mRNAs to assume a key biological function whose outcome may trigger disease or normal biological events. They also exert distinct functions related to their canonical and non-canonical forms. This review summarizes the current understanding of a wide range of RBPs' functions and highlights their emerging roles in the regulation of diverse pathways, different physiological processes, and their molecular links with diseases. Various types of diseases, encompassing colorectal carcinoma, non-small cell lung carcinoma, amyotrophic lateral sclerosis, and Severe acute respiratory syndrome coronavirus 2, aberrantly express RBPs. We also highlight some recent advances in the field that could prompt the development of RBPs-based therapeutic interventions.}, }
@article {pmid36528620, year = {2022}, author = {Khalilian, S and Hosseini Imani, SZ and Ghafouri-Fard, S}, title = {Emerging roles and mechanisms of miR-206 in human disorders: a comprehensive review.}, journal = {Cancer cell international}, volume = {22}, number = {1}, pages = {412}, pmid = {36528620}, issn = {1475-2867}, abstract = {As a member of the miR-1 family, miR-206 is located between IL-17 and PKHD1 genes in human. This miRNA has been shown to be involved in the pathogenic processes in a variety of human disorders including cancers, amyotrophic lateral sclerosis, Alzheimer's disease, atherosclerosis, bronchopulmonary dysplasia, coronary artery disease, chronic obstructive pulmonary disease, epilepsy, nonalcoholic fatty liver disease, Hirschsprung disease, muscular dystrophies, pulmonary arterial hypertension, sepsis and ulcerative colitis. In the current review, we summarize the role of miR-206 in both malignant and non-malignant situations and explain its possible therapeutic implications.}, }
@article {pmid36527565, year = {2023}, author = {Ashraf, SS and Hosseinpour Sarmadi, V and Larijani, G and Naderi Garahgheshlagh, S and Ramezani, S and Moghadamifar, S and Mohebi, SL and Brouki Milan, P and Haramshahi, SMA and Ahmadirad, N and Amini, N}, title = {Regenerative medicine improve neurodegenerative diseases.}, journal = {Cell and tissue banking}, volume = {24}, number = {3}, pages = {639-650}, pmid = {36527565}, issn = {1573-6814}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Parkinson Disease ; *Alzheimer Disease/therapy ; Regenerative Medicine ; *Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {Regenerative medicine is a subdivision of medicine that improves methods to regrow, repair or replace unhealthy cells and tissues to return to normal function. Cell therapy, gene therapy, nanomedicine as choices used to cure neurodegenerative disease. Recently, studies related to the treatment of neurodegenerative disorders have been focused on stem cell therapy and Nano-drugs beyond other than regenerative medicine. Hence, by data from experimental models and clinical trials, we review the impact of stem cell therapy, gene therapy, and nanomedicine on the treatment of Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). Indeed, improved knowledge and continued research on gene therapy and nanomedicine in treating Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis lead to advancements in effective and practical treatments for neurodegenerative diseases.}, }
@article {pmid36523957, year = {2022}, author = {Butler, R and Bradford, D and Rodgers, KE}, title = {Analysis of shared underlying mechanism in neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1006089}, pmid = {36523957}, issn = {1663-4365}, abstract = {In this review, the relationship between bioenergetics, mitochondrial dysfunction, and inflammation will be and how they contribute to neurodegeneration, specifically in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) will be reviewed. Long-term changes in mitochondrial function, autophagy dysfunction, and immune activation are commonalities shared across these age-related disorders. Genetic risk factors for these diseases support an autophagy-immune connection in the underlying pathophysiology. Critical areas of deeper evaluation in these bioenergetic processes may lead to potential therapeutics with efficacy across multiple neurodegenerative diseases.}, }
@article {pmid36522273, year = {2023}, author = {Dufrayer, MC and Monteiro, YMC and Carlesse, FAMC and Motta, F and Daudt, LE and Michalowski, MB}, title = {Antibiotic prophylaxis in acute childhood leukemia: What is known so far?.}, journal = {Hematology, transfusion and cell therapy}, volume = {45}, number = {4}, pages = {473-482}, pmid = {36522273}, issn = {2531-1387}, abstract = {INTRODUCTION: The treatment of acute lymphoblastic leukemia (ALL) has evolved in recent decades, reaching an overall survival rate close to 90%. Currently, approximately 4% of patients with ALL die from secondary complications of chemotherapy. Among these complications, the most frequent is febrile neutropenia (FN). The treatment of acute myeloid leukemias (AMLs) is even more aggressive, being consequently related to a considerable amount of treatment-related toxicity with a high risk of severe infection and death.<br><br>METHOD: In order to reduce the infection-related risks in these groups of patients, systemic antibacterial prophylaxis has emerged as a possible approach.<br><br>RESULTS: Antibiotic prophylaxis during neutropenia periods in those undergoing chemotherapy have .already been proven in adults with acute leukemias (ALs). Among the possible available therapeutic options for bacterial prophylaxis in children with cancer, fluoroquinolones emerged with the most amount of evidence. Within this class, levofloxacin became the best choice.<br><br>CONCLUSION: Therefore, the use of levofloxacin seems to be indicated in very specific situations: in children who are known to be neutropenic for a long time, secondary to intensive chemotherapy; in children with AL undergoing chemotherapy to induce remission; or in children undergoing hematopoietic stem cell transplantation (HSCT). This article aims to describe recent evidence focusing on antibiotic prophylaxis in children with ALs.}, }
@article {pmid36518658, year = {2022}, author = {Jiang, J and Wang, Y and Deng, M}, title = {New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1054006}, pmid = {36518658}, issn = {1663-9812}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. In the recent past, there have been just two drugs approved for treatment, riluzole and edaravone, which only prolong survival by a few months. However, there are many novel experimental drugs in development. In this review, we summarize 53 new drugs that have been evaluated in clinical trials from 2020 to 2022, which we have classified into eight mechanistic groups (anti-apoptotic, anti-inflammatory, anti-excitotoxicity, regulated integrated stress response, neurotrophic factors and neuroprotection, anti-aggregation, gene therapy and other). Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone.}, }
@article {pmid36515764, year = {2023}, author = {Assoni, AF and Foijer, F and Zatz, M}, title = {Amyotrophic Lateral Sclerosis, FUS and Protein Synthesis Defects.}, journal = {Stem cell reviews and reports}, volume = {19}, number = {3}, pages = {625-638}, pmid = {36515764}, issn = {2629-3277}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases ; Motor Neurons/pathology ; Mutation ; Cytoplasm/genetics/metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system. It is a very heterogeneous disorder, so far more than 40 genes have been described as responsible for ALS. The cause of motor neuron degeneration is not yet fully understood, but there is consensus in the literature that it is the result of a complex interplay of several pathogenic processes, which include alterations in nucleocytoplasmic transport, defects in transcription and splicing, altered formation and/or disassembly of stress granules and impaired proteostasis. These defects result in protein aggregation, impaired DNA repair, mitochondrial dysfunction and oxidative stress, neuroinflammation, impaired axonal transport, impaired vesicular transport, excitotoxicity, as well as impaired calcium influx. We argue here that all the above functions ultimately lead to defects in protein synthesis. Fused in Sarcoma (FUS) is one of the genes associated with ALS. It causes ALS type 6 when mutated and is found mislocalized to the cytoplasm in the motor neurons of sporadic ALS patients (without FUS mutations). In addition, FUS plays a role in all cellular functions that are impaired in degenerating motor neurons. Moreover, ALS patients with FUS mutations present the first symptoms significantly earlier than in other forms of the disease. Therefore, the aim of this review is to further discuss ALS6, detail the cellular functions of FUS, and suggest that the localization of FUS, as well as protein synthesis rates, could be hallmarks of the ALS phenotype and thus good therapeutic targets.}, }
@article {pmid36510311, year = {2022}, author = {Xia, X and Wang, Y and Zheng, JC}, title = {Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {53}, pmid = {36510311}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy/pathology ; *Extracellular Vesicles/pathology ; *Alzheimer Disease/pathology ; Brain/pathology ; Central Nervous System/pathology ; Biomarkers ; }, abstract = {Extracellular vesicles (EVs) are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells. Being a key intercellular communicator, EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease through delivery of bioactive cargos within the central nervous system (CNS). Importantly, CNS cell-derived EVs can be purified via immunoprecipitation, and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs. Given the essential impact of EVs on the pathogenesis of NDs, pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs. In this review, we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs, summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs, and comprehensively discuss promising potential of EVs as therapeutic targets, agents, and drug delivery systems in treating NDs, together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.}, }
@article {pmid36507340, year = {2022}, author = {Peter, J and Ferraioli, F and Mathew, D and George, S and Chan, C and Alalade, T and Salcedo, SA and Saed, S and Tatti, E and Quartarone, A and Ghilardi, MF}, title = {Movement-related beta ERD and ERS abnormalities in neuropsychiatric disorders.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1045715}, pmid = {36507340}, issn = {1662-4548}, abstract = {Movement-related oscillations in the beta range (from 13 to 30 Hz) have been observed over sensorimotor areas with power decrease (i.e., event-related desynchronization, ERD) during motor planning and execution followed by an increase (i.e., event-related synchronization, ERS) after the movement's end. These phenomena occur during active, passive, imaged, and observed movements. Several electrophysiology studies have used beta ERD and ERS as functional indices of sensorimotor integrity, primarily in diseases affecting the motor system. Recent literature also highlights other characteristics of beta ERD and ERS, implying their role in processes not strictly related to motor function. Here we review studies about movement-related ERD and ERS in diseases characterized by motor dysfunction, including Parkinson's disease, dystonia, stroke, amyotrophic lateral sclerosis, cerebral palsy, and multiple sclerosis. We also review changes of beta ERD and ERS reported in physiological aging, Alzheimer's disease, and schizophrenia, three conditions without overt motor symptoms. The review of these works shows that ERD and ERS abnormalities are present across the spectrum of the examined pathologies as well as development and aging. They further suggest that cognition and movement are tightly related processes that may share common mechanisms regulated by beta modulation. Future studies with a multimodal approach are warranted to understand not only the specific topographical dynamics of movement-related beta modulation but also the general meaning of beta frequency changes occurring in relation to movement and cognitive processes at large. Such an approach will provide the foundation to devise and implement novel therapeutic approaches to neuropsychiatric disorders.}, }
@article {pmid36503675, year = {2023}, author = {Camu, W and De La Cruz, E and Esselin, F}, title = {Therapeutic tools for familial ALS.}, journal = {Revue neurologique}, volume = {179}, number = {1-2}, pages = {49-53}, doi = {10.1016/j.neurol.2022.10.001}, pmid = {36503675}, issn = {0035-3787}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Superoxide Dismutase-1/genetics ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; Genetic Therapy/methods ; }, abstract = {Familial ALS (FALS) accounts for 10 to 15% of ALS cases. In more than 70% of FALS patients, a causal gene is identified and animal models have been developed for a subset of them, mainly for the most frequently mutated genes. Therapeutic tools to treat those patients are dominated by gene-specific therapy and the most advanced approaches target the SOD1 gene mutations. Either by direct delivery of antisense oligonucleotides (ASO) or using viral vectors such as adenoviruses (AAV) to deliver ASOs, gene specific therapies have shown promising results in animal models. The recent use of subpial injections of AAV9+anti SOD1 ASO now shows that the disease is completely prevented or stopped in the animal, depending on the moment of injection, e.g., before or after disease onset. However, the use of viral vectors in humans seems to be limited at least by their immunogenicity. Antibody-based therapies are also efficient to treat animal models, but to a lesser extent. Most of the experiments targeted the SOD1 protein in its misfolded conformation. This approach seems better tolerated than the AAV one, an important limit being the choice of the epitope. Unexpectedly, some advances in treating the C9ORF72 animal model have been obtained using a modulation of microbiota, and this strategy has the great advantage to have an easy route of administration and a good safety profile. The landscape of experimental FALS treatment is rapidly evolving and results are promising. This is an important unmet need for ALS patients and several human phase I, II and III trials are ongoing.}, }
@article {pmid36503299, year = {2023}, author = {Genge, A and Chio, A}, title = {The future of ALS diagnosis and staging: where do we go from here?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {3-4}, pages = {165-174}, doi = {10.1080/21678421.2022.2150555}, pmid = {36503299}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, progressive multi-system neurodegenerative disorder. Its clinical presentation varies considerably leading to delays in diagnosis, which has dire consequences in a disease where early intervention is key to optimize outcomes and limit care giver burden. There are a range of diagnostic criteria available to aid ALS diagnosis, as well staging methods to assess disease progression. However, they all suffer from inter-rater variability, complexity, and confusion in use. Such difficulties, when medical appointment times are limited and becoming more virtually based, have the potential to amplify uncertainty and errors in ALS diagnosis and prognosis. This review provides a clinical overview of the best way to balance the needs of evidence-based medicine and the patient. We focus on ALS diagnostic criteria and staging systems currently in use in clinical practice and explore factors that could enhance diagnostic efficiency and assessment of disease progression.}, }
@article {pmid36501161, year = {2022}, author = {Bayazid, AB and Lim, BO}, title = {Quercetin Is An Active Agent in Berries against Neurodegenerative Diseases Progression through Modulation of Nrf2/HO1.}, journal = {Nutrients}, volume = {14}, number = {23}, pages = {}, pmid = {36501161}, issn = {2072-6643}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/prevention &amp; control/metabolism ; Heme Oxygenase-1/metabolism ; Quercetin/pharmacology/therapeutic use ; Oxidative Stress ; Antioxidants/pharmacology/therapeutic use/metabolism ; }, abstract = {Berries are well-known fruits for their antioxidant effects due to their high content of flavonoids, and quercetin is one of the potent bioactive flavonoids. Although oxidative stress is an inevitable outcome in cells due to energy uptake and metabolism and other factors, excessive oxidative stress is considered a pivotal mediator for the cell death and leads to the progression of neurodegenerative diseases (NDDs). Furthermore, oxidative stress triggers inflammation that leads to neuronal cell loss. Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and so on are the main neurodegenerative diseases. Hence, AD and PD are the most affected NDDs and cause the most lethality without any effective cure. Since AD and PD are the most common NDDs, therefore, in this study, we will describe the effect of oxidative stress on AD and PD. Targeting oxidative stress could be a very effective way to prevent and cure NDDs. Thus, the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO1) are potent endogenous antioxidant modulatory pathways, which also show cytoprotective activities. Modulation of Nrf2/HO1 signaling pathways through a biological approach could be an effective way to treat with NDDs. Quercetin is a natural polyphenol, which protects neurodegeneration, remarkably by suppressing oxidative stress and inflammation. Thus, quercetin could be a very effective agent against NDDs. We will discuss the benefits and challenges of quercetin to treat against NDDs, focusing on molecular biology.}, }
@article {pmid36500540, year = {2022}, author = {Angelopoulou, E and Pyrgelis, ES and Piperi, C}, title = {Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {23}, pages = {}, pmid = {36500540}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; Phosphoric Diester Hydrolases ; Proteasome Endopeptidase Complex ; Pyridines/pharmacology ; Ubiquitin ; }, abstract = {Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer's disease, Parkinson's disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome-lysosome pathway dysregulation, impaired ubiquitin-proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin-proteasome and autophagosome-lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions.}, }
@article {pmid36499746, year = {2022}, author = {Romano, R and Del Fiore, VS and Bucci, C}, title = {Role of the Intermediate Filament Protein Peripherin in Health and Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499746}, issn = {1422-0067}, support = {DUP 246 of 2019//Regione Puglia/ ; }, mesh = {Peripherins/genetics/metabolism ; *Intermediate Filaments/metabolism ; *Nerve Tissue Proteins/metabolism ; Membrane Glycoproteins/metabolism ; Axonal Transport ; }, abstract = {Intermediate filaments are the most heterogeneous class among cytoskeletal elements. While some of them have been well-characterized, little is known about peripherin. Peripherin is a class III intermediate filament protein with a specific expression in the peripheral nervous system. Epigenetic modifications are involved in this cell-type-specific expression. Peripherin has important roles in neurite outgrowth and stability, axonal transport, and axonal myelination. Moreover, peripherin interacts with proteins involved in vesicular trafficking, signal transduction, DNA/RNA processing, protein folding, and mitochondrial metabolism, suggesting a role in all these processes. This review collects information regarding peripherin gene regulation, post-translational modifications, and functions and its involvement in the onset of a number of diseases.}, }
@article {pmid36499600, year = {2022}, author = {Aragón-González, A and Shaw, PJ and Ferraiuolo, L}, title = {Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499600}, issn = {1422-0067}, support = {MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; 765704//European Union's Horizon 2020 research and innovation programme under the Marie Sk&#x142;odowska-Curie grant agreement/ ; MR/V000470/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Blood-Brain Barrier/pathology ; *Neurodegenerative Diseases/pathology ; Biological Transport ; Brain/pathology ; Drug Delivery Systems ; }, abstract = {The blood-brain barrier (BBB) is a highly specialized and dynamic compartment which regulates the uptake of molecules and solutes from the blood. The relevance of the maintenance of a healthy BBB underpinning disease prevention as well as the main pathomechanisms affecting BBB function will be detailed in this review. Barrier disruption is a common aspect in both neurodegenerative diseases, such as amyotrophic lateral sclerosis, and neurodevelopmental diseases, including autism spectrum disorders. Throughout this review, conditions altering the BBB during the earliest and latest stages of life will be discussed, revealing common factors involved. Due to the barrier's role in protecting the brain from exogenous components and xenobiotics, drug delivery across the BBB is challenging. Potential therapies based on the BBB properties as molecular Trojan horses, among others, will be reviewed, as well as innovative treatments such as stem cell therapies. Additionally, due to the microbiome influence on the normal function of the brain, microflora modulation strategies will be discussed. Finally, future research directions are highlighted to address the current gaps in the literature, emphasizing the idea that common therapies for both neurodevelopmental and neurodegenerative pathologies exist.}, }
@article {pmid36499544, year = {2022}, author = {Giallongo, S and Longhitano, L and Denaro, S and D'Aprile, S and Torrisi, F and La Spina, E and Giallongo, C and Mannino, G and Lo Furno, D and Zappalà, A and Giuffrida, R and Parenti, R and Li Volti, G and Tibullo, D and Vicario, N}, title = {The Role of Epigenetics in Neuroinflammatory-Driven Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499544}, issn = {1422-0067}, support = {(FUV)//F.T. was supported by the Fondazione Umberto Veronesi./ ; R&amp;I 2014-2020-E68D19001340001//C.G. was supported by the PON AIM/ ; R&amp;I 2014-2020-E66C18001240007//N.V. was supported by the PON AIM/ ; }, mesh = {Humans ; *Histones/metabolism ; Neuroinflammatory Diseases ; Epigenesis, Genetic ; Epigenomics ; *Neurodegenerative Diseases/genetics ; }, abstract = {Neurodegenerative disorders are characterized by the progressive loss of central and/or peripheral nervous system neurons. Within this context, neuroinflammation comes up as one of the main factors linked to neurodegeneration progression. In fact, neuroinflammation has been recognized as an outstanding factor for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). Interestingly, neuroinflammatory diseases are characterized by dramatic changes in the epigenetic profile, which might provide novel prognostic and therapeutic factors towards neuroinflammatory treatment. Deep changes in DNA and histone methylation, along with histone acetylation and altered non-coding RNA expression, have been reported at the onset of inflammatory diseases. The aim of this work is to review the current knowledge on this field.}, }
@article {pmid36499159, year = {2022}, author = {Calderaro, A and Patanè, GT and Tellone, E and Barreca, D and Ficarra, S and Misiti, F and Laganà, G}, title = {The Neuroprotective Potentiality of Flavonoids on Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499159}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Butyrylcholinesterase/metabolism ; Flavonoids/pharmacology/therapeutic use ; Acetylcholinesterase/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD), due to its spread, has become a global health priority, and is characterized by senile dementia and progressive disability. The main cause of AD and other neurodegenerations (Huntington, Parkinson, Amyotrophic Lateral Sclerosis) are aggregated protein accumulation and oxidative damage. Recent research on secondary metabolites of plants such as polyphenols demonstrated that they may slow the progression of AD. The flavonoids' mechanism of action in AD involved the inhibition of acetylcholinesterase, butyrylcholinesterase, Tau protein aggregation, β-secretase, oxidative stress, inflammation, and apoptosis through modulation of signaling pathways which are implicated in cognitive and neuroprotective functions, such as ERK, PI3-kinase/Akt, NFKB, MAPKs, and endogenous antioxidant enzymatic systems. This review focuses on flavonoids and their role in AD, in terms of therapeutic potentiality for human health, antioxidant potential, and specific AD molecular targets.}, }
@article {pmid36498933, year = {2022}, author = {Silvestri, B and Mochi, M and Garone, MG and Rosa, A}, title = {Emerging Roles for the RNA-Binding Protein HuD (ELAVL4) in Nervous System Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36498933}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *ELAV-Like Protein 4/genetics ; RNA-Binding Proteins/genetics ; *Parkinson Disease/genetics ; }, abstract = {The main goal of this review is to provide an updated overview of the involvement of the RNA-binding protein (RBP) HuD, encoded by the ELAVL4 gene, in nervous system development, maintenance, and function, and its emerging role in nervous system diseases. A particular focus is on recent studies reporting altered HuD levels, or activity, in disease models and patients. Substantial evidence suggests HuD involvement in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Interestingly, while possible disease-causing mutations in the ELAVL4 gene remain elusive, a common theme in these diseases seems to be the altered regulation of HuD at multiple steps, including post-transcriptional and post-translational levels. In turn, the changed activity of HuD can have profound implications for its target transcripts, which are overly stabilized in case of HuD gain of function (as proposed in PD and ALS) or reduced in case of decreased HuD binding (as suggested by some studies in AD). Moreover, the recent discovery that HuD is a component of pathological cytoplasmic inclusion in both familial and sporadic ALS patients might help uncover the common molecular mechanisms underlying such complex diseases. We believe that deepening our understanding of the involvement of HuD in neurodegeneration could help developing new diagnostic and therapeutic tools.}, }
@article {pmid36498538, year = {2022}, author = {Verghese, JP and Terry, A and de Natale, ER and Politis, M}, title = {Research Evidence of the Role of the Glymphatic System and Its Potential Pharmacological Modulation in Neurodegenerative Diseases.}, journal = {Journal of clinical medicine}, volume = {11}, number = {23}, pages = {}, pmid = {36498538}, issn = {2077-0383}, abstract = {The glymphatic system is a unique pathway that utilises end-feet Aquaporin 4 (AQP4) channels within perivascular astrocytes, which is believed to cause cerebrospinal fluid (CSF) inflow into perivascular space (PVS), providing nutrients and waste disposal of the brain parenchyma. It is theorised that the bulk flow of CSF within the PVS removes waste products, soluble proteins, and products of metabolic activity, such as amyloid-β (Aβ). In the experimental model, the glymphatic system is selectively active during slow-wave sleep, and its activity is affected by both sleep dysfunction and deprivation. Dysfunction of the glymphatic system has been proposed as a potential key driver of neurodegeneration. This hypothesis is indirectly supported by the close relationship between neurodegenerative diseases and sleep alterations, frequently occurring years before the clinical diagnosis. Therefore, a detailed characterisation of the function of the glymphatic system in human physiology and disease would shed light on its early stage pathophysiology. The study of the glymphatic system is also critical to identifying means for its pharmacological modulation, which may have the potential for disease modification. This review will critically outline the primary evidence from literature about the dysfunction of the glymphatic system in neurodegeneration and discuss the rationale and current knowledge about pharmacological modulation of the glymphatic system in the animal model and its potential clinical applications in human clinical trials.}, }
@article {pmid36498223, year = {2022}, author = {Wyszkowska, J and Pritchard, C}, title = {Open Questions on the Electromagnetic Field Contribution to the Risk of Neurodegenerative Diseases.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {23}, pages = {}, pmid = {36498223}, issn = {1660-4601}, mesh = {Humans ; Electromagnetic Fields/adverse effects ; *Neurodegenerative Diseases/epidemiology/etiology ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Parkinson Disease/epidemiology/complications ; Odds Ratio ; }, abstract = {This work presents the current state of knowledge about the possible contributory influence of the electromagnetic field on the occurrence of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Up-to-date literature indicates both favourable and adverse effects of electromagnetic exposure on human health, making it difficult to come to valid and unambiguous conclusions. The epidemiological data analysis from the World Health Organization statistics shows a substantial rise in neurological mortality compared with rises in total populations in developed countries over a mere 15-year period. The largest of the analysed countries produced odds ratios of >100%. The contribution of electromagnetic exposure to the incidence of neurodegenerative diseases is still undoubtedly open to discussion, and it requires further in-depth research to assess the action mechanism of electromagnetic fields in neurodegenerative diseases. The limitations of research published hitherto and the problem of drawing unequivocal conclusions are also in focus.}, }
@article {pmid36497163, year = {2022}, author = {Geraghty, NJ and Satapathy, S and Wilson, MR}, title = {The Emerging Roles of Extracellular Chaperones in Complement Regulation.}, journal = {Cells}, volume = {11}, number = {23}, pages = {}, pmid = {36497163}, issn = {2073-4409}, mesh = {Humans ; *Molecular Chaperones/metabolism ; Proteostasis ; *Neurodegenerative Diseases/metabolism ; Complement System Proteins/metabolism ; }, abstract = {The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of protein homeostasis (proteostasis) is essential for normal cellular and organismal function, and has been implicated in processes controlling immunity and infection. Chaperones are key players in maintaining proteostasis in both the intra- and extracellular environments. Whilst intracellular proteostasis is well-characterised, the role of constitutively secreted extracellular chaperones (ECs) is less well understood. ECs may interact with invading pathogens, and elements of the subsequent immune response, including the complement pathway. Both ECs and complement can influence the progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, as well as other diseases including kidney diseases and diabetes. This review will examine known and recently discovered ECs, and their roles in immunity, with a specific focus on the complement pathway.}, }
@article {pmid36481799, year = {2023}, author = {Giovannelli, I and Higginbottom, A and Kirby, J and Azzouz, M and Shaw, PJ}, title = {Prospects for gene replacement therapies in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {1}, pages = {39-52}, pmid = {36481799}, issn = {1759-4766}, support = {MR/V030140/1/MRC_/Medical Research Council/United Kingdom ; NECTAR/OCT15/974-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Neurodegenerative Diseases/therapy ; Motor Neurons ; *Motor Neuron Disease ; Genetic Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. ALS causes death, usually within 2-5 years of diagnosis. Riluzole, the only drug currently approved in Europe for the treatment of this condition, offers only a modest benefit, increasing survival by 3 months on average. Recent advances in our understanding of causative or disease-modifying genetic variants and in the development of genetic therapy strategies present exciting new therapeutic opportunities for ALS. In addition, the approval of adeno-associated virus-mediated delivery of functional copies of the SMN1 gene to treat spinal muscular atrophy represents an important therapeutic milestone and demonstrates the potential of gene replacement therapies for motor neuron disorders. In this Review, we describe the current landscape of genetic therapies in ALS, highlighting achievements and critical challenges. In particular, we discuss opportunities for gene replacement therapy in subgroups of people with ALS, and we describe loss-of-function mutations that are known to contribute to the pathophysiology of ALS and could represent novel targets for gene replacement therapies.}, }
@article {pmid36480040, year = {2023}, author = {Manjupriya, R and Pouthika, K and Madhumitha, G and Roopan, SM}, title = {Biological aspects of nitrogen heterocycles for amyotrophic lateral sclerosis.}, journal = {Applied microbiology and biotechnology}, volume = {107}, number = {1}, pages = {43-56}, pmid = {36480040}, issn = {1432-0614}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Nitrogen/pharmacology ; Riluzole/pharmacology/therapeutic use ; Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, cumulative neurological deteriorating disease that disturbs the neurons (nerve cells) that control voluntary muscle movement (those muscles we choose to move). Currently, the Food and Drug Administration (FDA) approved drugs such as Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta to treat ALS. Given the wide range of pharmaceutical applications of heterocyclic compounds, especially those containing the nitrogen ring systems such as pyridine, pyrimidine, and indole. These molecular frameworks have piqued the interest of medicinal chemists for further investigation in a variety of diseases. We have found several review works done on this research topic. Until now, no reviews published on the nitrogen heterocycles for treating ALS. This review examines the major causes of ALS, a brief history of medications that have been used to treat it so far, and the most recent breakthroughs in nitrogen ring systems for treating ALS. The novelty of this study provides insights on several effective synthetic techniques for nitrogen-based heterocyclic medications that operate as potent anti-inflammatory treatments and guard against ALS. KEY POINTS: • Pharmacological activity of heterocyclic compounds. • Neurodegenerative diseases and their drawbacks are discussed in detail. • Recent survey of nitrogen heterocycles in treating ALS disease are highlighted.}, }
@article {pmid36478742, year = {2022}, author = {Luo, HM and Xu, J and Huang, DX and Chen, YQ and Liu, YZ and Li, YJ and Chen, H}, title = {Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {1030390}, pmid = {36478742}, issn = {2296-634X}, abstract = {Neurodegenerative diseases (NDDs) are disorders in which neurons are lost owing to various factors, resulting in a series of dysfunctions. Their rising prevalence and irreversibility have brought physical pain to patients and economic pressure to both individuals and society. However, the pathogenesis of NDDs has not yet been fully elucidated, hampering the use of precise medication. Induced pluripotent stem cell (IPSC) modeling provides a new method for drug discovery, and exploring the early pathological mechanisms including mitochondrial dysfunction, which is not only an early but a prominent pathological feature of NDDs. In this review, we summarize the iPSC modeling approach of Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, as well as outline typical mitochondrial dysfunction and recapitulate corresponding therapeutic strategies.}, }
@article {pmid36477638, year = {2022}, author = {Tian, Y and Hu, D and Li, Y and Yang, L}, title = {Development of therapeutic vaccines for the treatment of diseases.}, journal = {Molecular biomedicine}, volume = {3}, number = {1}, pages = {40}, pmid = {36477638}, issn = {2662-8651}, abstract = {Vaccines are one of the most effective medical interventions to combat newly emerging and re-emerging diseases. Prophylactic vaccines against rabies, measles, etc., have excellent effectiveness in preventing viral infection and associated diseases. However, the host immune response is unable to inhibit virus replication or eradicate established diseases in most infected people. Therapeutic vaccines, expressing specific endogenous or exogenous antigens, mainly induce or boost cell-mediated immunity via provoking cytotoxic T cells or elicit humoral immunity via activating B cells to produce specific antibodies. The ultimate aim of a therapeutic vaccine is to reshape the host immunity for eradicating a disease and establishing lasting memory. Therefore, therapeutic vaccines have been developed for the treatment of some infectious diseases and chronic noncommunicable diseases. Various technological strategies have been implemented for the development of therapeutic vaccines, including molecular-based vaccines (peptide/protein, DNA and mRNA vaccines), vector-based vaccines (bacterial vector vaccines, viral vector vaccines and yeast-based vaccines) and cell-based vaccines (dendritic cell vaccines and genetically modified cell vaccines) as well as combinatorial approaches. This review mainly summarizes therapeutic vaccine-induced immunity and describes the development and status of multiple types of therapeutic vaccines against infectious diseases, such as those caused by HPV, HBV, HIV, HCV, and SARS-CoV-2, and chronic noncommunicable diseases, including cancer, hypertension, Alzheimer's disease, amyotrophic lateral sclerosis, diabetes, and dyslipidemia, that have been evaluated in recent preclinical and clinical studies.}, }
@article {pmid36464916, year = {2023}, author = {Gonçalves, F and Teixeira, MI and Magalhães, B}, title = {The role of spirituality in people with amyotrophic lateral sclerosis and their caregivers: Scoping review.}, journal = {Palliative &amp; supportive care}, volume = {21}, number = {5}, pages = {914-924}, doi = {10.1017/S1478951522001511}, pmid = {36464916}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Caregivers/psychology ; Spirituality ; Quality of Life/psychology ; Qualitative Research ; }, abstract = {BACKGROUND: There are few studies evaluating the role of spirituality and the role of spiritually integrated interventions in people with amyotrophic lateral sclerosis (PALS) and their caregivers.<br><br>OBJECTIVES: A scoping review was conducted to examine the nature and breadth of peer-reviewed literature on the role of spirituality, interventions integrating spirituality, and outcomes for PALS and their caregivers.<br><br>METHODS: A literature review was performed, following the methods from the Joanna Briggs Institute Reviewers, based on all articles published between January 2006 and April 2022, identified in the CINAHL Complete, MEDLINE Complete, MedicLatina, Psychology and Behavioral Sciences Collection, and SPORTDiscus with full-text databases using key terms. Extracted data included research aims, study design, population and characteristics, theme description, and measures or type of intervention.<br><br>RESULTS: A total of 18 articles were included in this study: 14 qualitative, 3 quantitative, and 1 protocol of a quantitative study. Eight studies were based in Europe. The search identified different main themes related to spirituality for caregivers and patients, 2 spiritual measure scales, and one intervention. However, many studies were limited in sample size, generalizability, and transferability and used less sophisticated research designs.<br><br>SIGNIFICANCE OF THE RESULTS: This scoping review illustrates the importance given to spirituality by caregivers and PALS and reveals a very heterogeneous response. Thus, experimental studies in the area of spirituality are needed to systematically explore the impact of spiritual interventions, and the results of these studies could advance practice and policy by enhancing the quality of life for PALS and their caregivers.}, }
@article {pmid36453400, year = {2023}, author = {Ruffo, P and De Amicis, F and Giardina, E and Conforti, FL}, title = {Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {18}, number = {6}, pages = {1243-1248}, pmid = {36453400}, issn = {1673-5374}, abstract = {The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation. Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA. In this context, non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels. Long-noncoding RNAs, consisting of more than 200 nucleotides, have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Long-noncoding RNAs are abundantly expressed in the central nervous system, suggesting that their deregulation could trigger neuronal degeneration through RNA modifications. The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.}, }
@article {pmid36453392, year = {2023}, author = {Requejo-Aguilar, R}, title = {Cdk5 and aberrant cell cycle activation at the core of neurodegeneration.}, journal = {Neural regeneration research}, volume = {18}, number = {6}, pages = {1186-1190}, pmid = {36453392}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are caused by the progressive loss of specific neurons. The exact mechanisms of action of these diseases are unknown, and many studies have focused on pathways related to abnormal accumulation and processing of proteins, mitochondrial dysfunction, and oxidative stress leading to apoptotic death. However, a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration. The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms, including c-Jun N-terminal kinases, p38 mitogen-activated protein kinases, and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades; post-translational modifications such as Tau-phosphorylation; and DNA damage response. In all these events, implicated Cdk5, a proline-directed serine/threonine protein kinase, seems to be responsible for several cellular processes in neurons including axon growth, neurotransmission, synaptic plasticity, neuronal migration, and maintenance of neuronal survival. However, under pathological conditions, Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons. Thus, Cdk5 hyperactivation, by its physiologic activator p25, hyper-phosphorylates downstream substrates related to neurodegenerative diseases. This review summarizes factors such as oxidative stress, DNA damage response, signaling pathway disturbance, and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons. It also describes how all these factors are linked to a greater or lesser extent with Cdk5. Thus, it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by cell cycle activation.}, }
@article {pmid36453391, year = {2023}, author = {Yap, KH and Azmin, S and Makpol, S and Damanhuri, HA and Mustapha, M and Hamzah, JC and Ibrahim, NM}, title = {Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases: a systematic review.}, journal = {Neural regeneration research}, volume = {18}, number = {6}, pages = {1179-1185}, pmid = {36453391}, issn = {1673-5374}, abstract = {Trehalose, a unique nonreducing crystalline disaccharide, is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging, intrinsic mutations, or autophagy dysregulation. This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders (tau pathology, synucleinopathy, polyglutamine tract, and motor neuron diseases). All animal studies on neurodegenerative diseases treated with trehalose published in Medline (accessed via EBSCOhost) and Scopus were considered. Of the 2259 studies screened, 29 met the eligibility criteria. According to the SYstematic Review Center for Laboratory Animal Experiment (SYRCLE) risk of bias tool, we reported 22 out of 29 studies with a high risk of bias. The present findings support the purported role of trehalose in autophagic flux and protein refolding. This review identified several other lesser-known pathways, including modifying amyloid precursor protein processing, inhibition of reactive gliosis, the integrity of the blood-brain barrier, activation of growth factors, upregulation of the downstream antioxidant signaling pathway, and protection against mitochondrial defects. The absence of adverse events and improvements in the outcome parameters were observed in some studies, which supports the transition to human clinical trials. It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways. However, heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion. Translational studies on trehalose would need to clarify three important questions: 1) bioavailability with oral administration, 2) optimal time window to confer neuroprotective benefits, and 3) optimal dosage to confer neuroprotection.}, }
@article {pmid36453390, year = {2023}, author = {Levite, M}, title = {Neuro faces of beneficial T cells: essential in brain, impaired in aging and neurological diseases, and activated functionally by neurotransmitters and neuropeptides.}, journal = {Neural regeneration research}, volume = {18}, number = {6}, pages = {1165-1178}, pmid = {36453390}, issn = {1673-5374}, abstract = {T cells are essential for a healthy life, performing continuously: immune surveillance, recognition, protection, activation, suppression, assistance, eradication, secretion, adhesion, migration, homing, communications, and additional tasks. This paper describes five aspects of normal beneficial T cells in the healthy or diseased brain. First, normal beneficial T cells are essential for normal healthy brain functions: cognition, spatial learning, memory, adult neurogenesis, and neuroprotection. T cells decrease secondary neuronal degeneration, increase neuronal survival after central nervous system (CNS) injury, and limit CNS inflammation and damage upon injury and infection. Second, while pathogenic T cells contribute to CNS disorders, recent studies, mostly in animal models, show that specific subpopulations of normal beneficial T cells have protective and regenerative effects in several neuroinflammatory and neurodegenerative diseases. These include Multiple Sclerosis (MS), Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), stroke, CNS trauma, chronic pain, and others. Both T cell-secreted molecules and direct cell-cell contacts deliver T cell neuroprotective, neuroregenerative and immunomodulatory effects. Third, normal beneficial T cells are abnormal, impaired, and dysfunctional in aging and multiple neurological diseases. Different T cell impairments are evident in aging, brain tumors (mainly Glioblastoma), severe viral infections (including COVID-19), chronic stress, major depression, schizophrenia, Parkinson's disease, Alzheimer's disease, ALS, MS, stroke, and other neuro-pathologies. The main detrimental mechanisms that impair T cell function are activation-induced cell death, exhaustion, senescence, and impaired T cell stemness. Fourth, several physiological neurotransmitters and neuropeptides induce by themselves multiple direct, potent, beneficial, and therapeutically-relevant effects on normal human T cells, via their receptors in T cells. This scientific field is called "Nerve-Driven Immunity". The main neurotransmitters and neuropeptides that induce directly activating and beneficial effects on naïve normal human T cells are: dopamine, glutamate, GnRH-II, neuropeptide Y, calcitonin gene-related peptide, and somatostatin. Fifth, "Personalized Adoptive Neuro-Immunotherapy". This is a novel unique cellular immunotherapy, based on the "Nerve-Driven Immunity" findings, which was recently designed and patented for safe and repeated rejuvenation, activation, and improvement of impaired and dysfunctional T cells of any person in need, by ex vivo exposure of the person's T cells to neurotransmitters and neuropeptides. Personalized adoptive neuro-immunotherapy includes an early ex vivo personalized diagnosis, and subsequent ex vivo → in vivo personalized adoptive therapy, tailored according to the diagnosis. The Personalized Adoptive Neuro-Immunotherapy has not yet been tested in humans, pending validation of safety and efficacy in clinical trials, especially in brain tumors, chronic infectious diseases, and aging, in which T cells are exhausted and/or senescent and dysfunctional.}, }
@article {pmid36450968, year = {2023}, author = {Vansteensel, MJ and Klein, E and van Thiel, G and Gaytant, M and Simmons, Z and Wolpaw, JR and Vaughan, TM}, title = {Towards clinical application of implantable brain-computer interfaces for people with late-stage ALS: medical and ethical considerations.}, journal = {Journal of neurology}, volume = {270}, number = {3}, pages = {1323-1336}, pmid = {36450968}, issn = {1432-1459}, support = {P41 EB018783/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; Electroencephalography/methods ; *Brain-Computer Interfaces ; *Amyotrophic Lateral Sclerosis/therapy ; Speech ; *Self-Help Devices ; }, abstract = {Individuals with amyotrophic lateral sclerosis (ALS) frequently develop speech and communication problems in the course of their disease. Currently available augmentative and alternative communication technologies do not present a solution for many people with advanced ALS, because these devices depend on residual and reliable motor activity. Brain-computer interfaces (BCIs) use neural signals for computer control and may allow people with late-stage ALS to communicate even when conventional technology falls short. Recent years have witnessed fast progression in the development and validation of implanted BCIs, which place neural signal recording electrodes in or on the cortex. Eventual widespread clinical application of implanted BCIs as an assistive communication technology for people with ALS will have significant consequences for their daily life, as well as for the clinical management of the disease, among others because of the potential interaction between the BCI and other procedures people with ALS undergo, such as tracheostomy. This article aims to facilitate responsible real-world implementation of implanted BCIs. We review the state of the art of research on implanted BCIs for communication, as well as the medical and ethical implications of the clinical application of this technology. We conclude that the contribution of all BCI stakeholders, including clinicians of the various ALS-related disciplines, will be needed to develop procedures for, and shape the process of, the responsible clinical application of implanted BCIs.}, }
@article {pmid36445400, year = {2023}, author = {Zambon, AA and Pini, V and Bosco, L and Falzone, YM and Munot, P and Muntoni, F and Previtali, SC}, title = {Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {3}, pages = {806-822}, pmid = {36445400}, issn = {1460-2156}, mesh = {Humans ; *Charcot-Marie-Tooth Disease/genetics ; *Muscular Atrophy, Spinal/genetics ; Phenotype ; Genetic Testing ; }, abstract = {Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement. Their cumulative estimated prevalence is 2.14/100 000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive,and X-linked inheritance. Despite the advances of next generation sequencing, more than 60% of patients with HMN remain genetically uncharacterized. Of note, we are increasingly aware of the broad range of phenotypes caused by pathogenic variants in the same gene and of the considerable clinical and genetic overlap between HMN and other conditions, such as Charcot-Marie-Tooth type 2 (axonal), spinal muscular atrophy with lower extremities predominance, neurogenic arthrogryposis multiplex congenita and juvenile amyotrophic lateral sclerosis. Considering that most HMN present during childhood, in this review we primarily aim to summarize key clinical features of paediatric forms, including recent data on novel phenotypes, to help guide differential diagnosis and genetic testing. Second, we describe newly identified causative genes and molecular mechanisms, and discuss how the discovery of these is changing the paradigm through which we approach this group of conditions.}, }
@article {pmid36443979, year = {2023}, author = {Goswami, D and Anuradha, U and Angati, A and Kumari, N and Singh, RK}, title = {Pharmacological and Pathological Relevance of S100 Proteins in Neurological Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {22}, number = {10}, pages = {1403-1416}, doi = {10.2174/1871527322666221128160653}, pmid = {36443979}, issn = {1996-3181}, mesh = {Humans ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; S100 Proteins ; *Amyotrophic Lateral Sclerosis ; *Nervous System Diseases/drug therapy ; tau Proteins/metabolism ; }, abstract = {The S100 protein is one of the calcium-binding proteins associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. S100 proteins are expressed in the central nervous system by oligodendrocytes, astrocytes and neurons during both normal and disease conditions. Although amyloid-beta aggregation and hyperphosphorylated tau plaques are the main pathological hallmarks of Alzheimer's disease, the S100 protein family is closely associated with neuroinflammation in several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis in addition to various types of cancer and other brain diseases. This review aims to present the key role of S100 proteins and their different relevant isoforms, along with the various approaches used for the regulation of these proteins in several neurodegenerative disorders.}, }
@article {pmid36442745, year = {2023}, author = {Camilus, N and Quintero Arias, C and Martic, S}, title = {Role of Triggers on the Structural and Functional Facets of TAR DNA-binding Protein 43.}, journal = {Neuroscience}, volume = {511}, number = {}, pages = {110-130}, doi = {10.1016/j.neuroscience.2022.11.027}, pmid = {36442745}, issn = {1873-7544}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Cell Nucleus/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Nuclear TAR DNA-binding protein 43 (TDP-43) mitigates cellular function, but the dynamic nucleus-cytoplasm shuttling of TDP-43 is disrupted in diseases, such as Amyotrophic Lateral Sclerosis (ALS). The polymorphic nature of the TDP-43 structures in vitro and in vivo is a result of environmental factors leading to the protein pathogenesis. Once the triggers which mitigate TDP-43 biochemistry are identified, new therapies can be developed. This review aims to illustrate recent discoveries in the diversity of TDP-43 structures (amyloidogenic and non-amyloidogenic) and highlight the triggers which result in their formation.}, }
@article {pmid36439561, year = {2022}, author = {Hussain, H and Djurin, T and Rodriguez, J and Daneelian, L and Sundi, S and Fadel, A and Saadoon, Z}, title = {Transactivation Response DNA-Binding Protein of 43 (TDP-43) and Glial Cell Roles in Neurological Disorders.}, journal = {Cureus}, volume = {14}, number = {10}, pages = {e30639}, pmid = {36439561}, issn = {2168-8184}, abstract = {The trans-activation response DNA-binding protein of 43kDa (TDP-43) is involved in the pathogenesis of multiple brain disorders. As scientists are unraveling TDP-43 function and its impact on various diseases, we have begun to subcategorize them into TDP-43 proteinopathies. Furthermore, glial cell dysfunction contributes to various disorders, and TDP-43 is involved with glial cells via multiple pathways (direct or indirect) that aggravate the pathophysiology of such disorders. We are only now discovering and understanding the vast and diverse roles TDP-43 plays on neuronal cells and its effects on gliosis and neurodegenerative pathologies. It has multiple roles: mRNA maturation and splicing, transporting and maintaining mRNA stability, a component of stress granules and ubiquitination of dysfunctional or misfolded proteins, transcription of microtubule "Futsch" protein, and a role in maintaining synapse integrity and possibly more as we continue to research and uncover the labyrinth of the neuronal network. TDP-43 could also have a detrimental impact on glial cell activation and pathophysiology in diseases where TDP-43 is associated with its pathogenesis. We will review the pathophysiology of various neurological disorders that are associated with the alteration of the TDP-43 levels along with glial cell activation. Further, multiple diseases have glial cell participation in the pathogenesis, and the role of TDP-43 has not yet been investigated. We, therefore, explore those disorders in the context of both TDP-43 and glial cells involvement. This step will enhance the understanding of neurodegeneration where further research could prompt curative modalities with the advancement of technology.}, }
@article {pmid36438184, year = {2022}, author = {Wang, ZY and Wen, ZJ and Xu, HM and Zhang, Y and Zhang, YF}, title = {Exosomal noncoding RNAs in central nervous system diseases: biological functions and potential clinical applications.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1004221}, pmid = {36438184}, issn = {1662-5099}, abstract = {Central nervous system (CNS) disease is a general term for a series of complex and diverse diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), CNS tumors, stroke, epilepsy, and amyotrophic lateral sclerosis (ALS). Interneuron and neuron-glia cells communicate with each other through their homeostatic microenvironment. Exosomes in the microenvironment have crucial impacts on interneuron and neuron-glia cells by transferring their contents, such as proteins, lipids, and ncRNAs, constituting a novel form of cell-to-cell interaction and communication. Exosomal noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI-interacting RNAs (piRNAs), regulate physiological functions and maintain CNS homeostasis. Exosomes are regarded as extracellular messengers that transfer ncRNAs between neurons and body fluids due to their ability to cross the blood-brain barrier. This review aims to summarize the current understanding of exosomal ncRNAs in CNS diseases, including prospective diagnostic biomarkers, pathological regulators, therapeutic strategies and clinical applications. We also provide an all-sided discussion of the comparison with some similar CNS diseases and the main limitations and challenges for exosomal ncRNAs in clinical applications.}, }
@article {pmid36430421, year = {2022}, author = {Lee, DG and Kim, YK and Baek, KH}, title = {The bHLH Transcription Factors in Neural Development and Therapeutic Applications for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {22}, pages = {}, pmid = {36430421}, issn = {1422-0067}, support = {NRF-2019R1A6A1A03032888//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Neurogenesis ; *Neural Stem Cells ; Neurons/physiology ; }, abstract = {The development of functional neural circuits in the central nervous system (CNS) requires the production of sufficient numbers of various types of neurons and glial cells, such as astrocytes and oligodendrocytes, at the appropriate periods and regions. Hence, severe neuronal loss of the circuits can cause neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Treatment of such neurodegenerative diseases caused by neuronal loss includes some strategies of cell therapy employing stem cells (such as neural progenitor cells (NPCs)) and gene therapy through cell fate conversion. In this report, we review how bHLH acts as a regulator in neuronal differentiation, reprogramming, and cell fate determination. Moreover, several different researchers are conducting studies to determine the importance of bHLH factors to direct neuronal and glial cell fate specification and differentiation. Therefore, we also investigated the limitations and future directions of conversion or transdifferentiation using bHLH factors.}, }
@article {pmid36430144, year = {2022}, author = {Bonnechère, B and Amin, N and van Duijn, C}, title = {What Are the Key Gut Microbiota Involved in Neurological Diseases? A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {23}, number = {22}, pages = {}, pmid = {36430144}, issn = {1422-0067}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Nervous System Diseases ; *Parkinson Disease/microbiology ; *Microbiota ; Akkermansia ; *Multiple Sclerosis/microbiology ; Prevotella ; Clostridiaceae ; Clostridiales ; *Stroke ; }, abstract = {There is a growing body of evidence highlighting there are significant changes in the gut microbiota composition and relative abundance in various neurological disorders. We performed a systematic review of the different microbiota altered in a wide range of neurological disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and stroke). Fifty-two studies were included representing 5496 patients. At the genus level, the most frequently involved microbiota are Akkermansia, Faecalibacterium, and Prevotella. The overlap between the pathologies was strongest for MS and PD, sharing eight genera (Akkermansia, Butyricicoccus, Bifidobacterium, Coprococcus, Dorea, Faecalibacterium, Parabacteroides, and Prevotella) and PD and stroke, sharing six genera (Enterococcus, Faecalibacterium, Lactobacillus, Parabacteroides, Prevotella, and Roseburia). The identification signatures overlapping for AD, PD, and MS raise the question of whether these reflect a common etiology or rather common consequence of these diseases. The interpretation is hampered by the low number and low power for AD, ALS, and stroke with ample opportunity for false positive and false negative findings.}, }
@article {pmid36429058, year = {2022}, author = {Sileo, P and Simonin, C and Melnyk, P and Chartier-Harlin, MC and Cotelle, P}, title = {Crosstalk between the Hippo Pathway and the Wnt Pathway in Huntington's Disease and Other Neurodegenerative Disorders.}, journal = {Cells}, volume = {11}, number = {22}, pages = {}, pmid = {36429058}, issn = {2073-4409}, mesh = {Humans ; Wnt Signaling Pathway ; beta Catenin/metabolism ; Hippo Signaling Pathway ; *Huntington Disease ; Protein Serine-Threonine Kinases ; *Neurodegenerative Diseases ; }, abstract = {The Hippo pathway consists of a cascade of kinases that controls the phosphorylation of the co-activators YAP/TAZ. When unphosphorylated, YAP and TAZ translocate into the nucleus, where they mainly bind to the TEAD transcription factor family and activate genes related to cell proliferation and survival. In this way, the inhibition of the Hippo pathway promotes cell survival, proliferation, and stemness fate. Another pathway can modulate these processes, namely the Wnt/β-catenin pathway that is indeed involved in cellular functions such as proliferation and cell survival, as well as apoptosis, growth, and cell renewal. Wnt signaling can act in a canonical or noncanonical way, depending on whether β-catenin is involved in the process. In this review, we will focus only on the canonical Wnt pathway. It has emerged that YAP/TAZ are components of the β-catenin destruction complex and that there is a close relationship between the Hippo pathway and the canonical Wnt pathway. Furthermore, recent data have shown that both of these pathways may play a role in neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease, or Amyotrophic Lateral Sclerosis. Thus, this review analyzes the Hippo pathway and the Wnt pathway, their crosstalk, and their involvement in Huntington's disease, as well as in other neurodegenerative disorders. Altogether, these data suggest possible therapeutic approaches targeting key players of these pathways.}, }
@article {pmid36426927, year = {2022}, author = {Maj, E and Jamroży, M and Bielecki, M and Bartoszek, M and Gołębiowski, M and Wojtaszek, M and Kuźma-Kozakiewicz, M}, title = {Role of DTI-MRI parameters in diagnosis of ALS: useful biomarkers for daily practice? Tertiary centre experience and literature review.}, journal = {Neurologia i neurochirurgia polska}, volume = {56}, number = {6}, pages = {490-498}, doi = {10.5603/PJNNS.a2022.0070}, pmid = {36426927}, issn = {0028-3843}, mesh = {Humans ; *Diffusion Tensor Imaging/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; Magnetic Resonance Imaging ; Biomarkers ; }, abstract = {INTRODUCTION: Despite the rapid development of neuroimaging techniques, the diagnosis of amyotrophic lateral sclerosis (ALS) remains a significant challenge. Magnetic resonance imaging (MRI) is important for ruling out ALS mimickers, while Diffusion Tensor Imaging (DTI) is a useful tool for the identification of cortical tract damage. The aim of this study was to identify the optimal set of DTI parameters to support the diagnosis of ALS that could be applied to everyday MRI and be used as a disease biomarker in daily practice.<br><br>MATERIAL AND METHODS: Forty-seven ALS patients and 55 age- and gender-matched healthy individuals underwent MRI using a 1.5-Tesla scanner including a DTI sequence with 30 spatial directions and a b-value 0/1,000 s/mm2. Two independent researchers measured the DTI parameters: fractional anisotropy (FA), TRACE and apparent diffusion coefficient (ADC) using freehand regions of interest (ROIs) placed along both corticospinal tracts (CSTs), starting at the level of the internal capsule and ending at the medulla.<br><br>RESULTS: Statistical significance was only achieved for fractional anisotropy (FA) (ALS vs controls, p < 0.001). The highest sensitivity was found in the brainstem (cerebral peduncles, pons and pyramids) where it ranged from 72.3% to 80.9%, whereas the highest specificity was observed at the level of the internal capsule (94.6%). The combined highest sensitivity and specificity was obtained in the pons (72.3% and 72.7%, respectively). Classifier based positive predictive values for Youden index cut-off scores varied between 60.7% and 69.4%.<br><br>CONCLUSIONS: Fractional anisotropy (FA) measured at the level of the brainstem was shown to be the single most relevant parameter in differentiating patients with ALS from healthy subjects. This has the potential to become an ALS-specific biomarker for patient identification in daily practice.}, }
@article {pmid36422727, year = {2023}, author = {Hu, N and Wang, X}, title = {The level of homocysteine in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {4}, pages = {1185-1192}, pmid = {36422727}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Homocysteine ; Vitamin B 12 ; Folic Acid ; Dietary Supplements ; }, abstract = {OBJECTIVE: To investigate the differences of the level of homocysteine (Hcy) between ALS patients and controls.<br><br>METHODS: PubMed, EMBASE, OVID, and other databases were searched systematically up to October 2022 for relevant reports about the level of Hcy, folic acid, and vitamin B12 (VB12) among ALS patients. Two reviewers screened and selected the titles and abstracts of the studies independently during the database searches and performed full-text reviews and extracted available data. The MD (mean difference) and 95%CI (credibility interval) of the level of Hcy, folic acid, and VB12 between ALS group and control group were calculated.<br><br>RESULTS: Pooled results of nine studies including 812 ALS patients and 2632 controls showed that the MD in plasma levels of HCY between ALS patients and controls was 1.56 (95%CI:&#x2009;-&#x2009;0.07, 3.19) &#x3bc;mol/L with remarkable heterogeneity (I[2]&#x2009;=&#x2009;94%). The mean CSF levels of Hcy among ALS patients were significantly higher than that of controls (MD: 0.23, 95%CI: 0.21, 0.24&#xa0;&#x3bc;mol/L) with no significant heterogeneity (I[2]&#x2009;=&#x2009;0%). No significant difference in the plasma level of folic acid (MD:&#x2009;-&#x2009;0.52, 95%CI:&#x2009;-&#x2009;1.89, 0.84&#xa0;ng/mL) or VB12 (MD:&#x2009;-&#x2009;9.76, 95%CI:&#x2009;-&#x2009;83.41, 63.89) was found between ALS patients and controls.<br><br>CONCLUSION: There was no significant difference in the plasma level of Hcy, folic acid, or VB12 between ALS patients and controls. The CSF level of Hcy among ALS population was remarkably higher than that among controls. Vitamin supplements including folate and VB12 might be recommended to ALS patients with the complication of deficiencies.}, }
@article {pmid36422289, year = {2022}, author = {Moresi, V and Renzini, A and Cavioli, G and Seelaender, M and Coletti, D and Gigli, G and Cedola, A}, title = {Functional Nutrients to Ameliorate Neurogenic Muscle Atrophy.}, journal = {Metabolites}, volume = {12}, number = {11}, pages = {}, pmid = {36422289}, issn = {2218-1989}, abstract = {Neurogenic muscle atrophy is a debilitating condition that occurs from nerve trauma in association with diseases or during aging, leading to reduced interaction between motoneurons and skeletal fibers. Current therapeutic approaches aiming at preserving muscle mass in a scenario of decreased nervous input include physical activity and employment of drugs that slow down the progression of the condition yet provide no concrete resolution. Nutritional support appears as a precious tool, adding to the success of personalized medicine, and could thus play a relevant part in mitigating neurogenic muscle atrophy. We herein summarize the molecular pathways triggered by denervation of the skeletal muscle that could be affected by functional nutrients. In this narrative review, we examine and discuss studies pertaining to the use of functional ingredients to counteract neurogenic muscle atrophy, focusing on their preventive or curative means of action within the skeletal muscle. We reviewed experimental models of denervation in rodents and in amyotrophic lateral sclerosis, as well as that caused by aging, considering the knowledge generated with use of animal experimental models and, also, from human studies.}, }
@article {pmid36422108, year = {2022}, author = {Vasilopoulou, C and Duguez, S and Duddy, W}, title = {Genome-Wide Gene-Set Analysis Approaches in Amyotrophic Lateral Sclerosis.}, journal = {Journal of personalized medicine}, volume = {12}, number = {11}, pages = {}, pmid = {36422108}, issn = {2075-4426}, support = {No number//Department for the Economy/ ; }, abstract = {The rapid increase in the number of genetic variants identified to be associated with Amyotrophic Lateral Sclerosis (ALS) through genome-wide association studies (GWAS) has created an emerging need to understand the functional pathways that are implicated in the pathology of ALS. Gene-set analysis (GSA) is a powerful method that can provide insight into the associated biological pathways, determining the joint effect of multiple genetic markers. The main contribution of this review is the collection of ALS GSA studies that employ GWAS or individual-based genotype data, investigating their methodology and results related to ALS-associated molecular pathways. Furthermore, the limitations in standard single-gene analyses are summarized, highlighting the power of gene-set analysis, and a brief overview of the statistical properties of gene-set analysis and related concepts is provided. The main aims of this review are to investigate the reproducibility of the collected studies and identify their strengths and limitations, in order to enhance the experimental design and therefore the quality of the results of future studies, deepening our understanding of this devastating disease.}, }
@article {pmid36412643, year = {2022}, author = {Neylon, J and Fuller, JN and van der Poel, C and Church, JE and Dworkin, S}, title = {Organophosphate Insecticide Toxicity in Neural Development, Cognition, Behaviour and Degeneration: Insights from Zebrafish.}, journal = {Journal of developmental biology}, volume = {10}, number = {4}, pages = {}, pmid = {36412643}, issn = {2221-3759}, support = {3.2509.07.48//La Trobe University/ ; }, abstract = {Organophosphate (OP) insecticides are used to eliminate agricultural threats posed by insects, through inhibition of the neurotransmitter acetylcholinesterase (AChE). These potent neurotoxins are extremely efficacious in insect elimination, and as such, are the preferred agricultural insecticides worldwide. Despite their efficacy, however, estimates indicate that only 0.1% of organophosphates reach their desired target. Moreover, multiple studies have shown that OP exposure in both humans and animals can lead to aberrations in embryonic development, defects in childhood neurocognition, and substantial contribution to neurodegenerative diseases such as Alzheimer's and Motor Neurone Disease. Here, we review the current state of knowledge pertaining to organophosphate exposure on both embryonic development and/or subsequent neurological consequences on behaviour, paying particular attention to data gleaned using an excellent animal model, the zebrafish (Danio rerio).}, }
@article {pmid36408510, year = {2022}, author = {Peng, S and Tian, Y and Chang, W and Yang, Y and Li, S and Ni, J and Zhu, W}, title = {Current state of research on acupuncture for the treatment of amyotrophic lateral sclerosis: A scoping review.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1019156}, pmid = {36408510}, issn = {1664-2295}, abstract = {OBJECTIVE: To provide an overview of the range and characteristics of existing evidence, research gaps, and future research priorities in treating amyotrophic lateral sclerosis (ALS) with acupuncture.<br><br>METHOD: Clinical studies on acupuncture treatment for ALS were searched in 9 databases and two websites. Two independent researchers screened the literature according to the inclusion and exclusion criteria; extracted the demographic data, interventions, and significant findings of the studies; and comprehensively analyzed the characteristics and limitations of the included articles.<br><br>RESULTS: A total of 2,326 studies were retrieved, of which 92 were included. Most of the studies were conducted in China, with the number increasing over time. Study designs included case reports, case series, randomized controlled trials (RCTs), and before-and-after studies, among which case reports were the most frequently used. A total of 1,388 patients were enrolled, of whom 1,031 had ALS, 274 had progressive bulbar palsy (PBP), 60 had progressive muscle atrophy (PMA), and 23 had primary lateral sclerosis (PLS). Acupuncture interventions included body acupuncture, electroacupuncture, acupoint injection, scalp acupuncture, acupoint massage, Sa-am acupuncture, needle-embedding therapy, auricular acupuncture, venom pharmacopuncture therapy, plum blossom needling, acupoint paste, electroacupuncture, and needle warming through moxibustion. The most frequently used acupoints were ST36, LI4, SP6, and LI11. Acupuncture is often applied in combination with other treatments, such as herbal or Western medicine. The frequency of treatment ranged from once a month to three times a day, and the duration of treatment ranged from 5 days to 3 years. Clinical symptoms, muscle strength, and effective rates were the most frequently used outcomes. Most studies reported significant efficacy, and only a few studies reported adverse events explicitly.<br><br>CONCLUSION: Evidence gaps include poor study design, complex interventions, limited significance of the selected outcomes, and limited study reporting. The promotion of acupuncture treatment for ALS still faces several obstacles. Rigorous study design and conduct, standardized intervention and outcome measurements, and normative reporting are needed to investigate the efficacy and safety of acupuncture treatment for ALS.}, }
@article {pmid36408113, year = {2022}, author = {Limone, F and Klim, JR and Mordes, DA}, title = {Pluripotent stem cell strategies for rebuilding the human brain.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1017299}, pmid = {36408113}, issn = {1663-4365}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; }, abstract = {Neurodegenerative disorders have been extremely challenging to treat with traditional drug-based approaches and curative therapies are lacking. Given continued progress in stem cell technologies, cell replacement strategies have emerged as concrete and potentially viable therapeutic options. In this review, we cover advances in methods used to differentiate human pluripotent stem cells into several highly specialized types of neurons, including cholinergic, dopaminergic, and motor neurons, and the potential clinical applications of stem cell-derived neurons for common neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, and amyotrophic lateral sclerosis. Additionally, we summarize cellular differentiation techniques for generating glial cell populations, including oligodendrocytes and microglia, and their conceivable translational roles in supporting neural function. Clinical trials of specific cell replacement therapies in the nervous system are already underway, and several attractive avenues in regenerative medicine warrant further investigation.}, }
@article {pmid36406749, year = {2022}, author = {Hashim, HM and Makpol, S}, title = {A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1007166}, pmid = {36406749}, issn = {1662-5102}, abstract = {As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota (BGM) axis, which is a bidirectional link between the gastrointestinal tract (GIT) and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Here, we reviewed the role of the gut microbiome in aging and neurodegenerative diseases, as well as provided a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review will provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.}, }
@article {pmid36402404, year = {2023}, author = {Soares, P and Silva, C and Chavarria, D and Silva, FSG and Oliveira, PJ and Borges, F}, title = {Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {83}, number = {}, pages = {101790}, doi = {10.1016/j.arr.2022.101790}, pmid = {36402404}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Edaravone/therapeutic use ; Riluzole/therapeutic use ; Oxidative Stress ; Drug Discovery ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major regulators of hypoxia and inflammation - HIF and NF-κB - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi-target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.}, }
@article {pmid36398749, year = {2023}, author = {Sun, Y and Barkhaus, P and Barnes, B and Beauchamp, M and Benatar, M and Bertorini, T and Bromberg, M and Carter, GT and Crayle, J and Cudkowicz, M and Dimachkie, M and Feldman, EL and Fullam, T and Heiman-Patterson, T and Jhooty, S and Lund, I and Mcdermott, C and Pattee, G and Pierce, K and Ratner, D and Wicks, P and Bedlack, R}, title = {ALSUntangled #68: ozone therapy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {548-552}, doi = {10.1080/21678421.2022.2145904}, pmid = {36398749}, issn = {2167-9223}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Disease Models, Animal ; Mitochondria ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.}, }
@article {pmid36389059, year = {2022}, author = {Guo, Y and Wang, S and Chao, X and Li, D and Wang, Y and Guo, Q and Chen, T}, title = {Multi-omics studies reveal ameliorating effects of physical exercise on neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1026688}, pmid = {36389059}, issn = {1663-4365}, abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment.<br><br>METHOD: Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics.<br><br>RESULT: We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.<br><br>CONCLUSION: Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.}, }
@article {pmid36388178, year = {2022}, author = {Mao, D and Zheng, Y and Xu, F and Han, X and Zhao, H}, title = {HMGB1 in nervous system diseases: A common biomarker and potential therapeutic target.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1029891}, pmid = {36388178}, issn = {1664-2295}, abstract = {High-mobility group box-1 (HMGB1) is a nuclear protein associated with early inflammatory changes upon extracellular secretion expressed in various cells, including neurons and microglia. With the progress of research, neuroinflammation is believed to be involved in the pathogenesis of neurological diseases such as Parkinson's, epilepsy, and autism. As a key promoter of neuroinflammation, HMGB1 is thought to be involved in the pathogenesis of Parkinson's disease, stroke, traumatic brain injury, epilepsy, autism, depression, multiple sclerosis, and amyotrophic lateral sclerosis. However, in the clinic, HMGB1 has not been described as a biomarker for the above-mentioned diseases. However, the current preclinical research results show that HMGB1 antagonists have positive significance in the treatment of Parkinson's disease, stroke, traumatic brain injury, epilepsy, and other diseases. This review discusses the possible mechanisms by which HMGB1 mediates Parkinson's disease, stroke, traumatic brain injury, epilepsy, autism, depression, multiple sclerosis, amyotrophic lateral sclerosis, and the potential of HMGB1 as a biomarker for these diseases. Future research needs to further explore the underlying molecular mechanisms and clinical translation.}, }
@article {pmid36385663, year = {2023}, author = {Xu, Y and Zhao, J and Zhao, Y and Zhou, L and Qiao, H and Xu, Q and Liu, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {50}, number = {2}, pages = {1655-1661}, pmid = {36385663}, issn = {1573-4978}, support = {82172147//National Natural Science Foundation of China/ ; 81571880//National Natural Science Foundation of China/ ; 81373147//National Natural Science Foundation of China/ ; 30901555//National Natural Science Foundation of China/ ; 30972870//National Natural Science Foundation of China/ ; 81360080//National Natural Science Foundation of China/ ; 2021JJ30900//Natural Science Foundation of&#xa0;Hunan Province/ ; 2016JJ2157//Natural Science Foundation of&#xa0;Hunan Province/ ; 2020zzts222//Fundamental Research Funds for Central Universities of the Central South University/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; *Ferroptosis/genetics ; Apoptosis ; Cell Death ; Oxidative Stress/physiology ; }, abstract = {Ferroptosis is newly identified as a non-apoptotic form of programmed cell death. It is characterized by iron-dependent intracellular accumulation of lipid peroxides which ultimately leads to oxidative stress and cell death. Ferroptosis has been identified in several diseases, such as cancer, renal failure, liver injury, and ischemia-reperfusion injury. Besides, it has been reported to be involved in the pathological mechanism of neurodegenerative diseases (NDD). In addition, interventions targeting ferroptosis can influence the course of NDD, making it a potential therapeutic target for NDD. By summarizing the current research on ferroptosis and its impact on many neurological diseases, we hope to provide valuable strategies for the underlying mechanisms and treatment of these neurological diseases.}, }
@article {pmid36383961, year = {2022}, author = {Papadopoulou, K and Karsai, S and Böer-Auer, A}, title = {Disseminierte papulöse Variante des Morbus Dowling-Degos: Histopathologische Merkmale bei POGLUT1-Mutation.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {20}, number = {11}, pages = {1423-1429}, doi = {10.1111/ddg.14897_g}, pmid = {36383961}, issn = {1610-0387}, abstract = {Der Morbus Dowling-Degos ist eine seltene, benigne Genodermatose. Charakteristisch sind lentiginöse Hyperpigmentierungen sowie rotbraune Papeln und Plaques. Häufig sind die Beugeseiten und Intertrigines betroffen, das klinische Bild kann jedoch variieren. Verantwortlich für die klinische Ausprägung sind Mutationen in unterschiedlichen Genen. Während Mutationen im Keratin 5 (KRT5)-Gen ein retikuläres Verteilungsmuster begünstigen, führen Mutationen im POGLUT1-Gen zu einem disseminierten, papulösen klinischen Bild. Die akantholytische Variante des Morbus Dowling-Degos wird historisch als Morbus Galli-Galli bezeichnet, unsere Falluntersuchung zeigt jedoch, dass die histopathologischen Veränderungen auch innerhalb eines Patienten variieren können. Bisher gibt es kein einheitliches Therapiekonzept. Keratolytische Maßnahmen stehen im Vordergrund, mit unterschiedlich gutem Ansprechen. Neue Therapieansätze mit Hilfe der Lasertechnologie scheinen eine vielversprechende Behandlungsoption zu sein.}, }
@article {pmid36382478, year = {2022}, author = {Acewicz, A and Stępień, T and Felczak, P and Tarka, S and Wierzba-Bobrowicz, T}, title = {Incidence and morphology of secondary TDP-43 proteinopathies: Part 1.}, journal = {Folia neuropathologica}, volume = {60}, number = {3}, pages = {267-276}, doi = {10.5114/fn.2022.120314}, pmid = {36382478}, issn = {1509-572X}, mesh = {Humans ; *Alzheimer Disease/pathology ; DNA-Binding Proteins/metabolism ; Incidence ; *Multiple System Atrophy ; *Supranuclear Palsy, Progressive/pathology ; *TDP-43 Proteinopathies/genetics ; }, abstract = {Transactive response DNA binding protein of 43 kDa (TDP-43) is considered to play an essential role in the pathogenesis of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Growing body of evidence indicate that pathological TDP-43 inclusions frequently occur in the context of other distinctive hallmark pathologies, referred to as secondary TDP-43 proteinopathies. Comorbid TDP-43 pathology is well-documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, or progressive supranuclear palsy. It may also appear as a consequence of less obvious disease etiologies, i.e. post-traumatic (chronic traumatic encephalopathy), neoplastic (pilocytic astrocytoma), or post-infectious (post-encephalitic parkinsonism). The aim of the present review was to evaluate the incidence, morphology, and role of TDP-43 pathology in the secondary TDP-43 proteinopathies. This article (Part 1) discussed TDP-43 pathology in more common neurodegenerative diseases, including Alzheimer's disease, Lewy body disease, Huntington's disease, multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy. A follow-up article (Part 2) will describe abnormal TDP-43 changes in rare neurodegenerative diseases or neurological diseases with nondegenerative etiology.}, }
@article {pmid36381733, year = {2022}, author = {Rokade, AV and Yelne, P and Giri, A}, title = {Riluzole and Edavarone: The Hope Against Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {14}, number = {10}, pages = {e30035}, pmid = {36381733}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most frequent motor neuron illnesses. Motor neuron illnesses are various disorders that include upper and lower motor neuron abnormalities. Amyotrophic lateral sclerosis accounts for roughly 80% of motor neuron disorders. ALS is a fatal motor neuron disease that involves the loss of motor neurons in the spinal cord and brain, resulting in gliosis and muscle weakening and wasting in the upper, lower, and respiratory muscles, reducing life expectancy to 2-5 years from the onset of symptoms. Up until now, oral riluzole, a glutamatergic neurotransmitter inhibitor, has been used to manage ALS, the only drug for the management of ALS that has been approved by the United States (US) Food and Drug Administration (FDA). In recent studies, edaravone has been used through intravenous mode to halt the progression of ALS. We conducted a systematic search on PubMed; we selected Google Scholar, PubMed, websites regarding ALS, WebMD, Researchgate, als.org, consultant360, and the relevant articles for the review. It shows us riluzole and edaravone's efficacy for managing A.L.S. and how it can increase the life span of the patients.}, }
@article {pmid36371266, year = {2023}, author = {Finsterer, J}, title = {Phenotype and management of neurologic intronic repeat disorders (NIRDs).}, journal = {Revue neurologique}, volume = {179}, number = {3}, pages = {173-182}, doi = {10.1016/j.neurol.2022.09.004}, pmid = {36371266}, issn = {0035-3787}, mesh = {Humans ; *Myotonic Dystrophy/genetics ; Introns ; *Spinocerebellar Ataxias/genetics ; DNA Repeat Expansion ; *Nervous System Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Phenotype ; }, abstract = {During recent years an increasing number of neurologic disorders due to expanded tri-, tetra-, penta-, or hexa-nucleotide repeat motifs in introns of various genes have been described (neurologic intronic repeat disorders (NIRDs)). The repeat may be pathogenic in the heterozygous or homozygous form. Repeat lengths vary considerably and can be stable or unstable during transmission to the next generation. The most well-known NIRDs are Friedreich ataxia, spinocerebellar ataxia types-10, -31, and -36, CANVAS, C9Orf72 familial amyotrophic lateral sclerosis (fALS), and myotonic dystrophy-2 (MD2). Phenotypically, NIRDs manifest as mono-organ (e.g. spinocerebellar ataxia type 31) or multi-organ disease (e.g. Friedreich ataxia, myotonic dystrophy-2). A number of other more rare NIRDs have been recently detected. This review aims at summarising and discussing previous findings and recent advances concerning the etiology, pathophysiology, clinical presentation, and therapeutic management of the most common NIRDs.}, }
@article {pmid36366843, year = {2023}, author = {Kumar, R and Malik, Z and Singh, M and Rachana, R and Mani, S and Ponnusamy, K and Haider, S}, title = {Amyotrophic Lateral Sclerosis Risk Genes and Suppressor.}, journal = {Current gene therapy}, volume = {23}, number = {2}, pages = {148-162}, doi = {10.2174/1566523223666221108113330}, pmid = {36366843}, issn = {1875-5631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to death by progressive paralysis and respiratory failure within 2-4 years of onset. About 90-95% of ALS cases are sporadic (sALS), and 5-10% are inherited through family (fALS). Though the mechanisms of the disease are still poorly understood, so far, approximately 40 genes have been reported as ALS causative genes. The mutations in some crucial genes, like SOD1, C9ORF72, FUS, and TDP-43, are majorly associated with ALS, resulting in ROS-associated oxidative stress, excitotoxicity, protein aggregation, altered RNA processing, axonal and vesicular trafficking dysregulation, and mitochondrial dysfunction. Recent studies show that dysfunctional cellular pathways get restored as a result of the repair of a single pathway in ALS. In this review article, our aim is to identify putative targets for therapeutic development and the importance of a single suppressor to reduce multiple symptoms by focusing on important mutations and the phenotypic suppressors of dysfunctional cellular pathways in crucial genes as reported by other studies.}, }
@article {pmid36364033, year = {2022}, author = {Dailah, HG}, title = {Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {21}, pages = {}, pmid = {36364033}, issn = {1420-3049}, support = {RUP-5//Deputyship for Research &amp; Innovation, Ministry of Education in Saudi Arabia/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis ; Apoptosis/physiology ; Caspases ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Neurodegenerative disorders (NDs) include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the common feature of NDs is the progressive death of specific neurons in the brain. Apoptosis is very important in developing the nervous system, nonetheless an elevated level of cell death has been observed in the case of NDs. NDs are different in terms of their neuronal vulnerability and clinical manifestations, however they have some overlapping neurodegenerative pathways. It has been demonstrated by several studies with cell lines and animal models that apoptosis has a significant contribution to make in advancing AD, ALS, HD, and PD. Numerous dying neurons were also identified in the brains of individuals with NDs and these conditions were found to be linked with substantial cell loss along with common characteristics of apoptosis including activation of caspases and cysteine-proteases, DNA fragmentation, and chromatin condensation. It has been demonstrated that several therapeutic agents including antioxidants, minocycline, GAPDH ligands, p53 inhibitors, JNK (c-Jun N-Terminal Kinase) inhibitors, glycogen synthase kinase-3 inhibitor, non-steroidal anti-inflammatory drugs, D2 dopamine receptor agonists, FK506, cell cycle inhibitors, statins, drugs targeting peroxisome proliferator-activated receptors, and gene therapy have the potential to provide protection to neurons against apoptosis. Therefore, the use of these potential therapeutic agents might be beneficial in the treatment of NDs. In this review, we have summarized the pathways that are linked with apoptotic neuronal death in the case of various NDs. We have particularly focused on the therapeutic agents that have neuroprotective properties and the potential to regulate apoptosis in NDs.}, }
@article {pmid36361750, year = {2022}, author = {Ruggiero, M and Calvello, R and Porro, C and Messina, G and Cianciulli, A and Panaro, MA}, title = {Neurodegenerative Diseases: Can Caffeine Be a Powerful Ally to Weaken Neuroinflammation?.}, journal = {International journal of molecular sciences}, volume = {23}, number = {21}, pages = {}, pmid = {36361750}, issn = {1422-0067}, mesh = {Humans ; Caffeine/pharmacology ; Coffee ; *Neurodegenerative Diseases/etiology ; Neuroinflammatory Diseases ; }, abstract = {In recent years, there has been considerable research showing that coffee consumption seems to be beneficial to human health, as it contains a mixture of different bioactive compounds such as chlorogenic acids, caffeic acid, alkaloids, diterpenes and polyphenols. Neurodegenerative diseases (NDs) are debilitating, and non-curable diseases associated with impaired central, peripheral and muscle nervous systems. Several studies demonstrate that neuroinflammation mediated by glial cells-such as microglia and astrocytes-is a critical factor contributing to neurodegeneration that causes the dysfunction of brain homeostasis, resulting in a progressive loss of structure, function, and number of neuronal cells. This happens over time and leads to brain damage and physical impairment. The most known chronic NDs are represented by Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). According to epidemiological studies, regular coffee consumption is associated with a lower risk of neurodegenerative diseases. In this review, we summarize the latest research about the potential effects of caffeine in neurodegenerative disorders prevention and discuss the role of controlled caffeine delivery systems in maintaining high plasma caffeine concentrations for an extended time.}, }
@article {pmid36359871, year = {2022}, author = {Zayed, MA and Sultan, S and Alsaab, HO and Yousof, SM and Alrefaei, GI and Alsubhi, NH and Alkarim, S and Al Ghamdi, KS and Bagabir, SA and Jana, A and Alghamdi, BS and Atta, HM and Ashraf, GM}, title = {Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders.}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359871}, issn = {2073-4409}, mesh = {Animals ; *Nervous System Diseases/therapy ; Stem Cell Transplantation ; *Huntington Disease/metabolism ; *Parkinson Disease/metabolism ; Motor Neurons/pathology ; }, abstract = {Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.}, }
@article {pmid36359835, year = {2022}, author = {Younesian, S and Yousefi, AM and Momeny, M and Ghaffari, SH and Bashash, D}, title = {The DNA Methylation in Neurological Diseases.}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359835}, issn = {2073-4409}, mesh = {Humans ; DNA Methylation/genetics ; *Neurodegenerative Diseases/genetics ; Epigenesis, Genetic ; DNA/metabolism ; *Alzheimer Disease/genetics ; }, abstract = {DNA methylation is critical for the normal development and functioning of the human brain, such as the proliferation and differentiation of neural stem cells, synaptic plasticity, neuronal reparation, learning, and memory. Despite the physical stability of DNA and methylated DNA compared to other epigenetic modifications, some DNA methylation-based biomarkers have translated into clinical practice. Increasing reports indicate a strong association between DNA methylation profiles and various clinical outcomes in neurological diseases, making DNA methylation profiles valuable as novel clinical markers. In this review, we aim to discuss the latest evidence concerning DNA methylation alterations in the development of neurodegenerative, neurodevelopmental, and neuropsychiatric diseases. We also highlighted the relationship of DNA methylation alterations with the disease progression and outcome in many neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and autism.}, }
@article {pmid36353727, year = {2022}, author = {Sundaramoorthy, TH and Castanho, I}, title = {The Neuroepigenetic Landscape of Vertebrate and Invertebrate Models of Neurodegenerative Diseases.}, journal = {Epigenetics insights}, volume = {15}, number = {}, pages = {25168657221135848}, pmid = {36353727}, issn = {2516-8657}, support = {MC_PC_14127/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Vertebrate and invertebrate models of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, have been paramount to our understanding of the pathophysiology of these conditions; however, the brain epigenetic landscape is less well established in these disease models. DNA methylation, histone modifications, and microRNAs are among commonly studied mechanisms of epigenetic regulation. Genome-wide studies and candidate studies of specific methylation marks, histone marks, and microRNAs have demonstrated the dysregulation of these mechanisms in models of neurodegenerative diseases; however, the studies to date are scarce and inconclusive and the implications of many of these changes are still not fully understood. In this review, we summarize epigenetic changes reported to date in the brain of vertebrate and invertebrate models used to study neurodegenerative diseases, specifically diseases affecting the aging population. We also discuss caveats of epigenetic research so far and the use of disease models to understand neurodegenerative diseases, with the aim of improving the use of model organisms in this context in future studies.}, }
@article {pmid36352320, year = {2023}, author = {Cyske, Z and Gaffke, L and Pierzynowska, K and Węgrzyn, G}, title = {Tubulin Cytoskeleton in Neurodegenerative Diseases-not Only Primary Tubulinopathies.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {5}, pages = {1867-1884}, pmid = {36352320}, issn = {1573-6830}, support = {531-D020-D242-22//University of Gdansk/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Tubulin/therapeutic use ; Cytoskeleton/pathology ; Microtubules ; *Alzheimer Disease/genetics ; }, abstract = {Neurodegenerative diseases represent a large group of disorders characterized by gradual loss of neurons and functions of the central nervous systems. Their course is usually severe, leading to high morbidity and subsequent inability of patients to independent functioning. Vast majority of neurodegenerative diseases is currently untreatable, and only some symptomatic drugs are available which efficacy is usually very limited. To develop novel therapies for this group of diseases, it is crucial to understand their pathogenesis and to recognize factors which can influence the disease course. One of cellular structures which dysfunction appears to be relatively poorly understood in the light of neurodegenerative diseases is tubulin cytoskeleton. On the other hand, its changes, both structural and functional, can considerably influence cell physiology, leading to pathological processes occurring also in neurons. In this review, we summarize and discuss dysfunctions of tubulin cytoskeleton in various neurodegenerative diseases different than primary tubulinopathies (caused by mutations in genes encoding the components of the tubulin cytoskeleton), especially Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, and neuronopathic mucopolysaccharidoses. It is also proposed that correction of these disorders might attenuate the progress of specific diseases, thus, finding newly recognized molecular targets for potential drugs might become possible.}, }
@article {pmid36345044, year = {2022}, author = {Agrawal, I and Lim, YS and Ng, SY and Ling, SC}, title = {Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {48}, pmid = {36345044}, issn = {2047-9158}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Translational Science, Biomedical ; Motor Neurons/pathology ; *Motor Neuron Disease/metabolism ; Ceramides/metabolism ; }, abstract = {Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids.}, }
@article {pmid36339819, year = {2022}, author = {Braun, MM and Puglielli, L}, title = {Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1031153}, pmid = {36339819}, issn = {1662-5102}, support = {R01 AG078794/AG/NIA NIH HHS/United States ; R01 NS094154/NS/NINDS NIH HHS/United States ; }, abstract = {The selective degradation of mitochondria through mitophagy is a crucial process for maintaining mitochondrial function and cellular health. Mitophagy is a specialized form of selective autophagy that uses unique machinery to recognize and target damaged mitochondria for mitophagosome- and lysosome-dependent degradation. This process is particularly important in cells with high metabolic activity like neurons, and the accumulation of defective mitochondria is a common feature among neurodegenerative disorders. Here, we describe essential steps involved in the induction and progression of mitophagy, and then highlight the various mechanisms that specifically contribute to defective mitophagy in highly prevalent neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis.}, }
@article {pmid36339574, year = {2022}, author = {Parrella, E and Porrini, V and Scambi, I and Gennari, MM and Gussago, C and Bankole, O and Benarese, M and Mariotti, R and Pizzi, M}, title = {Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1017364}, pmid = {36339574}, issn = {1663-9812}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, progressive paralysis and finally death. Despite the research efforts, currently there is no cure for ALS. In recent years, multiple epigenetic mechanisms have been associated with neurodegenerative diseases. A pathological role for histone hypoacetylation and the abnormal NF-κB/RelA activation involving deacetylation of lysines, with the exclusion of lysine 310, has been established in ALS. Recent findings indicate that the pathological acetylation state of NF-κB/RelA and histone 3 (H3) occurring in the SOD1(G93A) murine model of ALS can be corrected by the synergistic combination of low doses of the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator resveratrol and the histone deacetylase (HDAC) inhibitors MS-275 (entinostat) or valproate. The combination of the epigenetic drugs, by rescuing RelA and the H3 acetylation state, promotes a beneficial and sexually dimorphic effect on disease onset, survival and motor neurons degeneration. In this mini review, we discuss the potential of the epigenetic combination of resveratrol with HDAC inhibitors in the ALS treatment.}, }
@article {pmid36339573, year = {2022}, author = {Kuroda, Y and Oguma, Y and Hall, K and Dezawa, M}, title = {Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1027961}, pmid = {36339573}, issn = {1663-9812}, abstract = {Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.}, }
@article {pmid36336493, year = {2023}, author = {Corcia, P and Blasco, H and Beltran, S and Piegay, AS and Vourc'h, P}, title = {Treatment of hereditary amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {179}, number = {1-2}, pages = {54-60}, doi = {10.1016/j.neurol.2022.09.001}, pmid = {36336493}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Mutation ; Riluzole ; }, abstract = {Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.}, }
@article {pmid36328774, year = {2023}, author = {Ishihara, K and Fukui, T and Kawamura, M and Shiota, JI and Nakano, I}, title = {Symptomatology and Neuropathology of patients presenting with focal cortical signs.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {43}, number = {1}, pages = {27-43}, doi = {10.1111/neup.12854}, pmid = {36328774}, issn = {1440-1789}, mesh = {Male ; Female ; Humans ; Aged ; Middle Aged ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; *Dementia/pathology ; Temporal Lobe/pathology ; *Apraxias/pathology ; }, abstract = {Here, we describe two patients who presented with focal cortical signs and underwent neuropathological examination. Case 1 was a 73-year-old woman with progressive speech disorder and abnormal behavior. She showed agraphia of the frontal lobe type, featured by the omission of kana letters when writing, other than pyramidal tract signs, pseudobulbar palsy, and frontal lobe dementia. Neuropathological examination, including TAR DNA-binding protein 43 (TDP-43) immunohistochemistry, revealed bilateral frontal and anterior temporal lobe lesions accentuated in the precentral gyrus and posterior part of the middle frontal gyrus. Both upper and lower motor neurons showed pathological changes compatible with amyotrophic lateral sclerosis. Case 2 was a 62-year-old man with progressive speech disorder and hand clumsiness. He had a motor speech disorder, compatible with apraxia of speech, and limb apraxia of the limb-kinetic and ideomotor type. Neuropathological examination revealed degeneration in the left frontal lobe, including the precentral gyrus, anterior temporal, and parietal lobe cortices. Moreover, numerous argyrophilic neuronal intracytoplasmic inclusions (Pick body) and ballooned neurons were observed in these lesions and the limbic system. The pathological diagnosis was Pick disease involving the peri-Rolandic area and parietal lobe. In these two cases, the distribution of neuropathological changes in the cerebral cortices correlated with the clinical symptoms observed.}, }
@article {pmid36326951, year = {2023}, author = {Kaur, S and Sharma, N and Kumar, V and Sharma, D and Devi, B and Kapil, L and Singh, C and Singh, A}, title = {The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {5}, pages = {1849-1865}, pmid = {36326951}, issn = {1573-6830}, mesh = {Humans ; Mitophagy/physiology ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Parkinson Disease/metabolism ; Autophagy/physiology ; }, abstract = {Mitochondria are critical to multiple cellular processes, from the production of adenosine triphosphate (ATP), maintenance of calcium homeostasis, synthesis of key metabolites, and production of reactive oxygen species (ROS) to maintain necrosis, apoptosis, and autophagy. Therefore, proper clearance and regulation are essential to maintain various physiological processes carried out by the cellular mechanism, including mitophagy and autophagy, by breaking down the damaged intracellular connections under the influence of various genes and proteins and protecting against various neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), and Huntington disease (HD). In this review, we will discuss the role of autophagy, selective macroautophagy, or mitophagy, and its role in neurodegenerative diseases along with normal physiology. In addition, this review will provide a better understanding of the pathways involved in neuron autophagy and mitophagy and how mutations affect these pathways in the various genes involved in neurodegenerative diseases. Various new findings indicate that the pathways that remove dysfunctional mitochondria are impaired in these diseases, leading to the deposition of damaged mitochondria. Apart from that, we have also discussed the therapeutic strategies targeting autophagy and mitophagy in neurodegenerative diseases. The mitophagy cycle results in the degradation of damaged mitochondria and the biogenesis of new healthy mitochondria, also highlighting different stages at which a particular neurodegenerative disease could occur.}, }
@article {pmid36325336, year = {2022}, author = {Lang, R and Li, H and Luo, X and Liu, C and Zhang, Y and Guo, S and Xu, J and Bao, C and Dong, W and Yu, Y}, title = {Expression and mechanisms of interferon-stimulated genes in viral infection of the central nervous system (CNS) and neurological diseases.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1008072}, pmid = {36325336}, issn = {1664-3224}, mesh = {Humans ; *Interferons/metabolism ; Antiviral Agents ; *Virus Diseases/genetics ; Immunity, Innate ; Central Nervous System/metabolism ; Membrane Proteins/metabolism ; RNA-Binding Proteins ; }, abstract = {Interferons (IFNs) bind to cell surface receptors and activate the expression of interferon-stimulated genes (ISGs) through intracellular signaling cascades. ISGs and their expression products have various biological functions, such as antiviral and immunomodulatory effects, and are essential effector molecules for IFN function. ISGs limit the invasion and replication of the virus in a cell-specific and region-specific manner in the central nervous system (CNS). In addition to participating in natural immunity against viral infections, studies have shown that ISGs are essential in the pathogenesis of CNS disorders such as neuroinflammation and neurodegenerative diseases. The aim of this review is to present a macroscopic overview of the characteristics of ISGs that restrict viral neural invasion and the expression of the ISGs underlying viral infection of CNS cells. Furthermore, we elucidate the characteristics of ISGs expression in neurological inflammation, neuropsychiatric disorders such as depression as well as neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Finally, we summarize several ISGs (ISG15, IFIT2, IFITM3) that have been studied more in recent years for their antiviral infection in the CNS and their research progress in neurological diseases.}, }
@article {pmid36322369, year = {2023}, author = {Andersen, JV and Schousboe, A}, title = {Glial Glutamine Homeostasis in Health and Disease.}, journal = {Neurochemical research}, volume = {48}, number = {4}, pages = {1100-1128}, pmid = {36322369}, issn = {1573-6903}, support = {n/a//SSADH Association/ ; n/a//H&#xf8;rslev Foundation/ ; }, mesh = {*Glutamine/metabolism ; *Glutamic Acid/metabolism ; Astrocytes/metabolism ; Homeostasis/physiology ; Neurotransmitter Agents/metabolism ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {Glutamine is an essential cerebral metabolite. Several critical brain processes are directly linked to glutamine, including ammonia homeostasis, energy metabolism and neurotransmitter recycling. Astrocytes synthesize and release large quantities of glutamine, which is taken up by neurons to replenish the glutamate and GABA neurotransmitter pools. Astrocyte glutamine hereby sustains the glutamate/GABA-glutamine cycle, synaptic transmission and general brain function. Cerebral glutamine homeostasis is linked to the metabolic coupling of neurons and astrocytes, and relies on multiple cellular processes, including TCA cycle function, synaptic transmission and neurotransmitter uptake. Dysregulations of processes related to glutamine homeostasis are associated with several neurological diseases and may mediate excitotoxicity and neurodegeneration. In particular, diminished astrocyte glutamine synthesis is a common neuropathological component, depriving neurons of an essential metabolic substrate and precursor for neurotransmitter synthesis, hereby leading to synaptic dysfunction. While astrocyte glutamine synthesis is quantitatively dominant in the brain, oligodendrocyte-derived glutamine may serve important functions in white matter structures. In this review, the crucial roles of glial glutamine homeostasis in the healthy and diseased brain are discussed. First, we provide an overview of cellular recycling, transport, synthesis and metabolism of glutamine in the brain. These cellular aspects are subsequently discussed in relation to pathological glutamine homeostasis of hepatic encephalopathy, epilepsy, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the multifaceted roles of cerebral glutamine will not only increase our understanding of the metabolic collaboration between brain cells, but may also aid to reveal much needed therapeutic targets of several neurological pathologies.}, }
@article {pmid36316501, year = {2023}, author = {Brandebura, AN and Paumier, A and Onur, TS and Allen, NJ}, title = {Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders.}, journal = {Nature reviews. Neuroscience}, volume = {24}, number = {1}, pages = {23-39}, pmid = {36316501}, issn = {1471-0048}, support = {F32 NS117776/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Astrocytes/physiology ; Proteomics ; *Neurodegenerative Diseases/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Neurons/pathology ; }, abstract = {There is increasing appreciation that non-neuronal cells contribute to the initiation, progression and pathology of diverse neurodegenerative disorders. This Review focuses on the role of astrocytes in disorders including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. The important roles astrocytes have in supporting neuronal function in the healthy brain are considered, along with studies that have demonstrated how the physiological properties of astrocytes are altered in neurodegenerative disorders and may explain their contribution to neurodegeneration. Further, the question of whether in neurodegenerative disorders with specific genetic mutations these mutations directly impact on astrocyte function, and may suggest a driving role for astrocytes in disease initiation, is discussed. A summary of how astrocyte transcriptomic and proteomic signatures are altered during the progression of neurodegenerative disorders and may relate to functional changes is provided. Given the central role of astrocytes in neurodegenerative disorders, potential strategies to target these cells for future therapeutic avenues are discussed.}, }
@article {pmid36315040, year = {2023}, author = {Snowden, JS}, title = {Changing perspectives on frontotemporal dementia: A review.}, journal = {Journal of neuropsychology}, volume = {17}, number = {2}, pages = {211-234}, doi = {10.1111/jnp.12297}, pmid = {36315040}, issn = {1748-6653}, mesh = {Humans ; *Frontotemporal Dementia/genetics/diagnosis ; tau Proteins/genetics/metabolism ; *Pick Disease of the Brain/genetics ; *Motor Neuron Disease/diagnosis/genetics/pathology ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {This article examines the evolution in understanding of frontotemporal dementia (FTD) during the last four decades. A central theme is the recognition of heterogeneity. Originally construed as a disorder of behaviour and executive impairment, FTD is now known also to be associated with alterations in language, conceptual knowledge and praxis. An absence of neurological signs is the hallmark of many FTD patients, but there is also an established association with motor neurone disease (MND), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). FTD is commonly defined as an early onset dementia, yet about a quarter of patients present after the age of 65. The underlying pathological protein is tau, TDP-43 or more rarely fused-in-sarcoma (FUS). Distinct genetic mutations have been identified in familial FTD. There are predictable relationships between clinical phenotype, pathological substrate and genetic mutation. For example, a circumscribed semantic disorder predicts TDP-43 pathology, and speech or limb apraxia tau pathology. The co-occurrence of MND predicts TDP-43 pathology, and PSP and CBD tau pathology. FUS pathology is associated with very youthful onset, stereotyped behaviours and caudate atrophy. Non-fluent aphasia is linked to progranulin (GRN) mutations and MND and psychosis to repeat expansions in the C9orf72 gene. Despite striking worldwide consensus in findings there remain some issues of contention, largely related to the classification of FTD and its sub-variants. Understanding the diverse nature of FTD is crucial for effective diagnosis, management and the development of targeted therapies.}, }
@article {pmid36314424, year = {2022}, author = {Han, X and Zhan, F and Yao, Y and Cao, L and Liu, J and Yao, S}, title = {Clinical heterogeneity in a family with flail arm syndrome and review of hnRNPA1-related spectrum.}, journal = {Annals of clinical and translational neurology}, volume = {9}, number = {12}, pages = {1910-1917}, pmid = {36314424}, issn = {2328-9503}, mesh = {Humans ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; *Amyotrophic Lateral Sclerosis/metabolism ; Mutation ; Exome Sequencing ; }, abstract = {OBJECTIVE: Flail arm syndrome (FAS) is one of the atypical subtypes of amyotrophic lateral sclerosis (ALS). Mutations in hnRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare genetic cause of ALS. Herein, marked clinical heterogeneity of FAS in a pedigree with a known hnRNPA1 variant was described to raise early awareness of the ALS variant. Furtherly, a literature review of the hnRNPA1-related spectrum was made to summarize the clinical and genetic characteristics.<br><br>METHODS: Detailed clinical evaluation, muscle pathology, and whole-exome sequencing were performed. The sequence and co-segregation of the mutation among the family members were confirmed by Sanger sequencing.<br><br>RESULTS: The great clinical variability was found in a FAS pedigree. Muscle pathology revealed a cluster distribution of angulated or rounded atrophic fibers, accompanied by significant multi-nucleus aggregation. Immunohistochemical staining showed that mutant hnRNPA1 proteins accumulated in muscle fiber cytoplasm. Exome sequencing identified a documented variant in hnRNPA1 gene c.1018C&#x2009;>&#x2009;T (p.P340S), which co-segregated with disease in the family. Besides, highly phenotypic heterogeneity was also found in other hnRNPA1-related diseases.<br><br>INTERPRETATION: We described a Chinese pedigree with hnRNPA1-related FAS, which showed significant clinical variability among the intrafamilial members. FAS is a relatively milder variant of ALS, due to the highly heterogeneous clinical spectrum, early observation is of paramount importance. In addition, the highly phenotypic heterogeneity and molecular genetic mechanism of the hnRNPA1-related spectrum are still beyond fully understood. Further, the detailed molecular mechanism underlying the clinical diversity is warranted to be explored.}, }
@article {pmid36311026, year = {2022}, author = {Chia, K and Klingseisen, A and Sieger, D and Priller, J}, title = {Zebrafish as a model organism for neurodegenerative disease.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {940484}, pmid = {36311026}, issn = {1662-5099}, abstract = {The zebrafish is increasingly recognized as a model organism for translational research into human neuropathology. The zebrafish brain exhibits fundamental resemblance with human neuroanatomical and neurochemical pathways, and hallmarks of human brain pathology such as protein aggregation, neuronal degeneration and activation of glial cells, for example, can be modeled and recapitulated in the fish central nervous system. Genetic manipulation, imaging, and drug screening are areas where zebrafish excel with the ease of introducing mutations and transgenes, the expression of fluorescent markers that can be detected in vivo in the transparent larval stages overtime, and simple treatment of large numbers of fish larvae at once followed by automated screening and imaging. In this review, we summarize how zebrafish have successfully been employed to model human neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We discuss advantages and disadvantages of choosing zebrafish as a model for these neurodegenerative conditions.}, }
@article {pmid36309345, year = {2022}, author = {Wang, MJ and Kang, L and Wang, YZ and Yang, BR and Zhang, C and Lu, YF and Kang, L}, title = {Microglia in motor neuron disease: Signaling evidence from last 10 years.}, journal = {Developmental neurobiology}, volume = {82}, number = {7-8}, pages = {625-638}, pmid = {36309345}, issn = {1932-846X}, mesh = {Humans ; Microglia/metabolism ; Superoxide Dismutase/metabolism ; *Motor Neuron Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; }, abstract = {Motor neuron disease (MND), including amyotrophic lateral sclerosis, spinal muscular atrophy and others, involved the upper or lower motor neurons selective loss, is characterized by neurodegeneration and neuroinflammation, in conjunction with microglia. We summarized that pathways and key mediators are associated with microglia, such as fractalkine signaling, purinergic signaling, NF-κB signaling, p38 MAPK signaling, TREM2-APOE signaling, ROCK signaling, C1q signaling, and Ion channel, which are involved in the activation, proliferation, and inflammation of microglia. This review aims to identify the microglia-related molecular target and explore potential treatment strategies for MND based on that target.}, }
@article {pmid36308619, year = {2023}, author = {Sharma, V and Singh, TG and Kaur, A and Mannan, A and Dhiman, S}, title = {Brain-Derived Neurotrophic Factor: A Novel Dynamically Regulated Therapeutic Modulator in Neurological Disorders.}, journal = {Neurochemical research}, volume = {48}, number = {2}, pages = {317-339}, pmid = {36308619}, issn = {1573-6903}, mesh = {Adult ; Humans ; Brain-Derived Neurotrophic Factor/genetics/metabolism ; *Depressive Disorder, Major/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; *Bipolar Disorder/metabolism ; Receptor, trkB/metabolism ; }, abstract = {The growth factor brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin-related kinase receptor type B (TrkB) play an active role in numerous areas of the adult brain, where they regulate the neuronal activity, function, and survival. Upregulation and downregulation of BDNF expression are critical for the physiology of neuronal circuits and functioning in the brain. Loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric disorders. This article reviews the BDNF gene structure, transport, secretion, expression and functions in the brain. This article also implicates BDNF in several brain-related disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, major depressive disorder, schizophrenia, epilepsy and bipolar disorder.}, }
@article {pmid36308570, year = {2022}, author = {Karbowski, M and Oshima, Y and Verhoeven, N}, title = {Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {11}, pages = {574}, pmid = {36308570}, issn = {1420-9071}, support = {R01 GM129584/GM/NIGMS NIH HHS/United States ; 129584/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Ubiquitin/metabolism ; Mitophagy ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; }, abstract = {Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline. Various quality control pathways, such as mitochondrial unfolded protein response (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy), respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria. This work provides a concise review of mechanisms by which disease-linked aberrant proteins affect mitochondrial function and an overview of mitochondrial quality control pathways that counteract mitochondrial proteotoxicity. We focus on mitochondrial quality control mechanisms relying on the Ub-mediated protein degradation, such as mitochondria-specific autophagy and the mitochondrial arm of the Ub proteasome system (UPS). We highlight the importance of a widening perspective of how these pathways protect mitochondria from proteotoxic stress to better understand mitochondrial proteotoxicity in overlapping pathophysiological pathways. Implications of these mechanisms in disease development are also briefly summarized.}, }
@article {pmid36301938, year = {2023}, author = {Khalimonchuk, O and Becker, DF}, title = {Molecular Determinants of Mitochondrial Shape and Function and Their Role in Glaucoma.}, journal = {Antioxidants &amp; redox signaling}, volume = {38}, number = {13-15}, pages = {896-919}, pmid = {36301938}, issn = {1557-7716}, support = {R01 GM132640/GM/NIGMS NIH HHS/United States ; R35 GM131701/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Mitochondria/metabolism ; Oxidative Stress/physiology ; Aging/physiology ; *Glaucoma/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Significance: Cells depend on well-functioning mitochondria for essential processes such as energy production, redox signaling, coordination of metabolic pathways, and cofactor biosynthesis. Mitochondrial dysfunction, metabolic decline, and protein stress have been implicated in the etiology of multiple late-onset diseases, including various ataxias, diabetes, sarcopenia, neuromuscular disorders, and neurodegenerative diseases such as parkinsonism, amyotrophic lateral sclerosis, and glaucoma. Recent Advances: New evidence supports that increased energy metabolism protects neuron function during aging. Key energy metabolic enzymes, however, are susceptible to oxidative damage making it imperative that the mitochondrial proteome is protected. More than 40 different enzymes have been identified as important factors for guarding mitochondrial health and maintaining a dynamic pool of mitochondria. Critical Issues: Understanding shared mechanisms of age-related disorders of neurodegenerative diseases such as glaucoma, Alzheimer's disease, and Parkinson's disease is important for developing new therapies. Functional mitochondrial shape and dynamics rely on complex interactions between mitochondrial proteases and membrane proteins. Identifying the sequence of molecular events that lead to mitochondrial dysfunction and metabolic stress is a major challenge. Future Directions: A critical need exists for new strategies that reduce mitochondrial protein stress and promote mitochondrial dynamics in age-related neurological disorders. Discovering how mitochondria-associated degradation is related to proteostatic mechanisms in mitochondrial compartments may reveal new opportunities for therapeutic interventions. Also, little is known about how protein and membrane contacts in the inner and outer mitochondrial membrane are regulated, even though they are pivotal for mitochondrial architecture. Future work will need to delineate the molecular details of these processes.}, }
@article {pmid36297602, year = {2022}, author = {Latif, S and Kang, YS}, title = {Blood-Brain Barrier Solute Carrier Transporters and Motor Neuron Disease.}, journal = {Pharmaceutics}, volume = {14}, number = {10}, pages = {}, pmid = {36297602}, issn = {1999-4923}, support = {2019R1F1A1044048//National Research Foundation of Korea/ ; }, abstract = {Defective solute carrier (SLC) transporters are responsible for neurotransmitter dysregulation, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We provided the role and kinetic parameters of transporters such as ASCTs, Taut, LAT1, CAT1, MCTs, OCTNs, CHT, and CTL1, which are mainly responsible for the transport of essential nutrients, acidic, and basic drugs in blood-brain barrier (BBB) and motor neuron disease. The affinity for LAT1 was higher in the BBB than in the ALS model cell line, whereas the capacity was higher in the NSC-34 cell lines than in the BBB. Affinity for MCTs was lower in the BBB than in the NSC-34 cell lines. CHT in BBB showed two affinity sites, whereas no expression was observed in ALS cell lines. CTL1 was the main transporter for choline in ALS cell lines. The half maximal inhibitory concentration (IC50) analysis of [[3]H]choline uptake indicated that choline is sensitive in TR-BBB cells, whereas amiloride is most sensitive in ALS cell lines. Knowledge of the transport systems in the BBB and motor neurons will help to deliver drugs to the brain and develop the therapeutic strategy for treating CNS and neurological diseases.}, }
@article {pmid36294741, year = {2022}, author = {Khamaysa, M and Pradat, PF}, title = {Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas.}, journal = {Journal of personalized medicine}, volume = {12}, number = {10}, pages = {}, pmid = {36294741}, issn = {2075-4426}, abstract = {Amyotrophic lateral sclerosis (ALS) is an extremely heterogeneous disease of motor neurons that eventually leads to death. Despite impressive advances in understanding the genetic, molecular, and pathological mechanisms of the disease, the only drug approved to date by both the FDA and EMA is riluzole, with a modest effect on survival. In this opinion view paper, we will discuss how to address some challenges for drug development in ALS at the conceptual, technological, and methodological levels. In addition, socioeconomic and ethical issues related to the legitimate need of patients to benefit quickly from new treatments will also be addressed. In conclusion, this brief review takes a more optimistic view, given the recent approval of two new drugs in some countries and the development of targeted gene therapies.}, }
@article {pmid36293477, year = {2022}, author = {Hernaiz, A and Toivonen, JM and Bolea, R and Martín-Burriel, I}, title = {Epigenetic Changes in Prion and Prion-like Neurodegenerative Diseases: Recent Advances, Potential as Biomarkers, and Future Perspectives.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293477}, issn = {1422-0067}, support = {IIU/2023/2017//Gobierno de Arag&#xf3;n/ ; A19-20R//Gobierno de Arag&#xf3;n/ ; AGL2015-67945-P//Ministry of Economy, Industry and Competitiveness/ ; A19-20R//Fondo Europeo de Desarrollo Regional (FEDER)/ ; }, mesh = {Humans ; *Prions/metabolism ; Prion Proteins/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism ; Histones/genetics/metabolism ; *Prion Diseases/metabolism ; Biomarkers ; Epigenesis, Genetic ; *MicroRNAs/genetics ; }, abstract = {Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by a conformational conversion of the native cellular prion protein (PrP[C]) to an abnormal, infectious isoform called PrP[Sc]. Amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's diseases are also known as prion-like diseases because they share common features with prion diseases, including protein misfolding and aggregation, as well as the spread of these misfolded proteins into different brain regions. Increasing evidence proposes the involvement of epigenetic mechanisms, namely DNA methylation, post-translational modifications of histones, and microRNA-mediated post-transcriptional gene regulation in the pathogenesis of prion-like diseases. Little is known about the role of epigenetic modifications in prion diseases, but recent findings also point to a potential regulatory role of epigenetic mechanisms in the pathology of these diseases. This review highlights recent findings on epigenetic modifications in TSEs and prion-like diseases and discusses the potential role of such mechanisms in disease pathology and their use as potential biomarkers.}, }
@article {pmid36293457, year = {2022}, author = {Mantle, D and Hargreaves, IP}, title = {Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293457}, issn = {1422-0067}, mesh = {Humans ; NAD/metabolism ; *Thioctic Acid/therapeutic use/metabolism ; Mitochondria/metabolism ; Dietary Supplements ; *Multiple System Atrophy/metabolism ; Vitamins/therapeutic use/metabolism ; Carnitine/metabolism ; Vitamin D/metabolism ; Adenosine Triphosphate/metabolism ; }, abstract = {Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy. This article is concerned specifically with mitochondrial dysfunction as defined by reduced capacity for ATP production, the role of depleted levels of key nutritionally related metabolites, and the potential benefit of supplementation with specific nutrients of relevance to normal mitochondrial function in the above neurodegenerative disorders. The article provides a rationale for a combination of CoQ10, B-vitamins/NADH, L-carnitine, vitamin D, and alpha-lipoic acid for the treatment of the above neurodegenerative disorders.}, }
@article {pmid36293362, year = {2022}, author = {Tamaki, Y and Urushitani, M}, title = {Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293362}, issn = {1422-0067}, support = {JP20K22682//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Frontotemporal Lobar Degeneration/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia ; *Prions/metabolism ; RNA-Binding Proteins ; RNA ; DNA ; }, abstract = {TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) and a substantial proportion of frontotemporal lobar degeneration (FTLD) cases. TDP-43 dysfunctions and cytoplasmic aggregation seem to be the central pathogenicity in ALS and FTLD. Therefore, unraveling both the physiological and pathological mechanisms of TDP-43 may enable the exploration of novel therapeutic strategies. This review highlights the current understanding of TDP-43 biology and pathology, describing the cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid-liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions.}, }
@article {pmid36291345, year = {2022}, author = {Schirò, G and Di Stefano, V and Iacono, S and Lupica, A and Brighina, F and Monastero, R and Balistreri, CR}, title = {Advances on Cellular Clonotypic Immunity in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {12}, number = {10}, pages = {}, pmid = {36291345}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by the progressive degeneration of the upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence concerning the role of the clonotypic immune system is growing. Adaptive immunity cells often appear changed in number, or in terms of their activation profiles, both peripherally and centrally; however, their role in ALS appears conflictive. Data from human and animal model studies, which are currently reported in the literature, show that each subset of lymphocytes and their mediators may mediate a protective or toxic mechanism in ALS, affecting both its progression and risk of death. In the present review, an attempt is made to shed light on the actual role of cellular clonotypic immunity in ALS by integrating recent clinical studies and experimental observations.}, }
@article {pmid36291129, year = {2022}, author = {Li, A and Yi, J and Li, X and Dong, L and Ostrow, LW and Ma, J and Zhou, J}, title = {Deficient Sarcolemma Repair in ALS: A Novel Mechanism with Therapeutic Potential.}, journal = {Cells}, volume = {11}, number = {20}, pages = {}, pmid = {36291129}, issn = {2073-4409}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 AG071676/AG/NIA NIH HHS/United States ; R01 HL138570/HL/NHLBI NIH HHS/United States ; R01 AG072430/AG/NIA NIH HHS/United States ; R01 AR057404/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Annexins/metabolism ; Carrier Proteins/metabolism ; Caveolins/metabolism ; Dysferlin/metabolism ; Membrane Proteins/metabolism ; *Sarcolemma/metabolism/pathology ; *Regeneration ; }, abstract = {The plasma membrane (sarcolemma) of skeletal muscle myofibers is susceptible to injury caused by physical and chemical stresses during normal daily movement and/or under disease conditions. These acute plasma membrane disruptions are normally compensated by an intrinsic membrane resealing process involving interactions of multiple intracellular proteins including dysferlin, annexin, caveolin, and Mitsugumin 53 (MG53)/TRIM72. There is new evidence for compromised muscle sarcolemma repair mechanisms in Amyotrophic Lateral Sclerosis (ALS). Mitochondrial dysfunction in proximity to neuromuscular junctions (NMJs) increases oxidative stress, triggering MG53 aggregation and loss of its function. Compromised membrane repair further worsens sarcolemma fragility and amplifies oxidative stress in a vicious cycle. This article is to review existing literature supporting the concept that ALS is a disease of oxidative-stress induced disruption of muscle membrane repair that compromise the integrity of the NMJs and hence augmenting muscle membrane repair mechanisms could represent a viable therapeutic strategy for ALS.}, }
@article {pmid36289799, year = {2022}, author = {Urso, D and Zoccolella, S and Gnoni, V and Logroscino, G}, title = {Amyotrophic Lateral Sclerosis-The Complex Phenotype-From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features.}, journal = {Biomedicines}, volume = {10}, number = {10}, pages = {}, pmid = {36289799}, issn = {2227-9059}, support = {B84I18000540002//Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is growing evidence that the neurodegeneration during the course of the disease can also involve other motor and non-motor regions. In this review, we analyzed and discussed available data from epidemiological population-based studies on extrapyramidal and non-motor features during the course of ALS.}, }
@article {pmid36289738, year = {2022}, author = {Ferrero, ME}, title = {Neuron Protection by EDTA May Explain the Successful Outcomes of Toxic Metal Chelation Therapy in Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {10}, number = {10}, pages = {}, pmid = {36289738}, issn = {2227-9059}, abstract = {Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of toxic metals in the pathogenesis of ND demonstrate the efficacy of treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA) in eliminating toxic metal burden in all ND patients, improving their symptoms. Lead, cadmium, aluminum, nickel, and mercury were the most important toxic metals detected in these patients. Here, I provide an updated review on the damage to neurons promoted by toxic metals and on the impact of EDTA chelation therapy in ND patients, along with the clinical description of a representative case.}, }
@article {pmid36281554, year = {2022}, author = {Liano, D and Monti, L and Chowdhury, S and Raguseo, F and Di Antonio, M}, title = {Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance.}, journal = {Chemical communications (Cambridge, England)}, volume = {58}, number = {92}, pages = {12753-12762}, pmid = {36281554}, issn = {1364-548X}, mesh = {Humans ; *G-Quadruplexes ; DNA/chemistry ; Telomere ; Guanine ; Molecular Structure ; }, abstract = {Guanine-rich DNA sequences are known to fold into secondary structures called G-quadruplexes (G4s), which can form from either individual DNA strands (intra-molecular) or multiple DNA strands (inter-molecular, iG4s). Intra-molecular G4s have been the object of extensive biological investigation due to their enrichment in gene-promoters and telomers. On the other hand, iG4s have never been considered in biological contexts, as the interaction between distal sequences of DNA to form an iG4 in cells was always deemed as highly unlikely. In this feature article, we challenge this dogma by presenting our recent discovery of the first human protein (CSB) displaying astonishing picomolar affinity and binding selectivity for iG4s. These findings suggest potential for iG4 structures to form in cells and highlight the need of further studies to unravel the fundamental biological roles of these inter-molecular DNA structures. Furthermore, we discuss how the potential for formation of iG4s in neuronal cells, triggered by repeat expansions in the C9orf72 gene, can lead to the formation of nucleic-acids based pathological aggregates in neurodegenerative diseases like ALS and FTD. Finally, based on our recent work on short LNA-modified probes, we provide a prespective on how the rational design of G4-selective chemical tools can be leveraged to further elucidate the biological relevance of iG4 structures in the context of ageing-related diseases.}, }
@article {pmid36280108, year = {2022}, author = {Jiang, Q and Lin, J and Wei, Q and Li, C and Hou, Y and Cao, B and Zhang, L and Ou, R and Liu, K and Yang, T and Xiao, Y and Shang, H}, title = {Genetic analysis of and clinical characteristics associated with ANXA11 variants in a Chinese cohort with amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {175}, number = {}, pages = {105907}, doi = {10.1016/j.nbd.2022.105907}, pmid = {36280108}, issn = {1095-953X}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Annexins/genetics/metabolism ; East Asian People/genetics ; *Frontotemporal Dementia/genetics ; Mutation ; }, abstract = {BACKGROUND: Variants in the annexin A11 gene (ANXA11) have been reported to be associated with amyotrophic lateral sclerosis (ALS). These variants may be involved in the pathogenesis of ALS by causing defects in intracellular protein trafficking. However, the genetic spectrum and clinical characteristics of ALS patients with ANXA11 variants are largely unknown.<br><br>METHODS: Genetic analysis was performed on 1587 Chinese patients with ALS. Eight software packages were used to predict the deleteriousness of missense variants. In addition, we searched PubMed, Embase, and Web of Science for relevant literature and meta-analysed variant frequencies.<br><br>RESULTS: In our ALS cohort, we identified 20 non-synonymous variants in 29 ALS patients, including one stop-gain, one frameshift, and 18 rare missense variants with seven predicted pathogenic variants. In a literature review of 11 reported studies that included 69 patients, 37 ANXA11 variants were reported, with a frequency of 1.7%, which was similar to that in our cohort (1.8%). Both our cohort and previous reports showed that ANXA11 carriers were more commonly males than females (12/17 vs. 19/31). Patients carrying ANXA11 variants affecting the C-terminal of the protein had earlier disease onset and shorter survival times than those carrying variants affecting the N-terminal. We found a relatively longer median survival time than that previously reported (53.6&#xa0;months vs. 46.0&#xa0;months). Additionally, Caucasian ANXA11 carriers were more likely to have cognitive impairment, typically frontotemporal dementia (FTD) than their Asian counterparts (20.0% vs. 14.3%). While more than half of the patients in our cohort had cognitive impairment, none had FTD.<br><br>CONCLUSION: In our and previously published cases, ALS-associated ANXA11 variants predominantly affected the N- and C-terminal conserved domains. ANXA11 variant carriers are typically male and cognitively impaired. Our study extends the genotypic and phenotypic spectra of ALS patients with ANXA11 variants. Further expansion of the sample size is needed to analyse the clinical and non-motor symptom characteristics of patients and to deepen the understanding of the pathogenesis of ANXA11-associated ALS.}, }
@article {pmid36275622, year = {2022}, author = {Baier, A and Szyszka, R}, title = {CK2 and protein kinases of the CK1 superfamily as targets for neurodegenerative disorders.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {916063}, pmid = {36275622}, issn = {2296-889X}, abstract = {Casein kinases are involved in a variety of signaling pathways, and also in inflammation, cancer, and neurological diseases. Therefore, they are regarded as potential therapeutic targets for drug design. Recent studies have highlighted the importance of the casein kinase 1 superfamily as well as protein kinase CK2 in the development of several neurodegenerative pathologies, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. CK1 kinases and their closely related tau tubulin kinases as well as CK2 are found to be overexpressed in the mammalian brain. Numerous substrates have been detected which play crucial roles in neuronal and synaptic network functions and activities. The development of new substances for the treatment of these pathologies is in high demand. The impact of these kinases in the progress of neurodegenerative disorders, their bona fide substrates, and numerous natural and synthetic compounds which are able to inhibit CK1, TTBK, and CK2 are discussed in this review.}, }
@article {pmid36270439, year = {2023}, author = {Gruchot, J and Herrero, F and Weber-Stadlbauer, U and Meyer, U and Küry, P}, title = {Interplay between activation of endogenous retroviruses and inflammation as common pathogenic mechanism in neurological and psychiatric disorders.}, journal = {Brain, behavior, and immunity}, volume = {107}, number = {}, pages = {242-252}, doi = {10.1016/j.bbi.2022.10.007}, pmid = {36270439}, issn = {1090-2139}, mesh = {Humans ; *Endogenous Retroviruses/genetics ; *Mental Disorders/genetics ; }, abstract = {Human endogenous retroviruses (ERVs) are ancestorial retroviral elements that were integrated into our genome through germline infections and insertions during evolution. They have repeatedly been implicated in the aetiology and pathophysiology of numerous human disorders, particularly in those that affect the central nervous system. In addition to the known association of ERVs with multiple sclerosis and amyotrophic lateral sclerosis, a growing number of studies links the induction and expression of these retroviral elements with the onset and severity of neurodevelopmental and psychiatric disorders. Although these disorders differ in terms of overall disease pathology and causalities, a certain degree of (subclinical) chronic inflammation can be identified in all of them. Based on these commonalities, we discuss the bidirectional relationship between ERV expression and inflammation and highlight that numerous entry points to this reciprocal sequence of events exist, including initial infections with ERV-activating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements is disrupted.}, }
@article {pmid36267702, year = {2022}, author = {Wang, Q and Xue, H and Yue, Y and Hao, S and Huang, SH and Zhang, Z}, title = {Role of mitophagy in the neurodegenerative diseases and its pharmacological advances: A review.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1014251}, pmid = {36267702}, issn = {1662-5099}, abstract = {Neurodegenerative diseases are a class of incurable and debilitating diseases characterized by progressive degeneration and death of cells in the central nervous system. They have multiple underlying mechanisms; however, they all share common degenerative features, such as mitochondrial dysfunction. According to recent studies, neurodegenerative diseases are associated with the accumulation of dysfunctional mitochondria. Selective autophagy of mitochondria, called mitophagy, can specifically degrade excess or dysfunctional mitochondria within cells. In this review, we highlight recent findings on the role of mitophagy in neurodegenerative disorders. Multiple studies were collected, including those related to the importance of mitochondria, the mechanism of mitophagy in protecting mitochondrial health, and canonical and non-canonical pathways in mitophagy. This review elucidated the important function of mitophagy in neurodegenerative diseases, discussed the research progress of mitophagy in neurodegenerative diseases, and summarized the role of mitophagy-related proteins in neurological diseases. In addition, we also highlight pharmacological advances in neurodegeneration.}, }
@article {pmid36263379, year = {2022}, author = {Gelon, PA and Dutchak, PA and Sephton, CF}, title = {Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1000183}, pmid = {36263379}, issn = {1662-5099}, abstract = {Synaptic loss is a pathological feature of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a disease of the cortical and spinal motor neurons resulting in fatal paralysis due to denervation of muscles. FTD is a form of dementia that primarily affects brain regions controlling cognition, language and behavior. Once classified as two distinct diseases, ALS and FTD are now considered as part of a common disease spectrum based on overlapping clinical, pathological and genetic evidence. At the cellular level, aggregation of common proteins and overlapping gene susceptibilities are shared in both ALS and FTD. Despite the convergence of these two fields of research, the underlying disease mechanisms remain elusive. However, recent discovers from ALS and FTD patient studies and models of ALS/FTD strongly suggests that synaptic dysfunction is an early event in the disease process and a unifying hallmark of these diseases. This review provides a summary of the reported anatomical and cellular changes that occur in cortical and spinal motor neurons in ALS and FTD tissues and models of disease. We also highlight studies that identify changes in the proteome and transcriptome of ALS and FTD models and provide a conceptual overview of the processes that contribute to synaptic dysfunction in these diseases. Due to space limitations and the vast number of publications in the ALS and FTD fields, many articles have not been discussed in this review. As such, this review focuses on the three most common shared mutations in ALS and FTD, the hexanucleuotide repeat expansion within intron 1 of chromosome 9 open reading frame 72 (C9ORF72), transactive response DNA binding protein 43 (TARDBP or TDP-43) and fused in sarcoma (FUS), with the intention of highlighting common pathways that promote synaptic dysfunction in the ALS-FTD disease spectrum.}, }
@article {pmid36259386, year = {2023}, author = {Morrone, JJ}, title = {When phylogenetics met biogeography: Willi Hennig, Lars Brundin and the roots of phylogenetic and cladistic biogeography.}, journal = {Cladistics : the international journal of the Willi Hennig Society}, volume = {39}, number = {1}, pages = {58-69}, doi = {10.1111/cla.12517}, pmid = {36259386}, issn = {1096-0031}, mesh = {Animals ; Phylogeny ; Phylogeography ; South America ; *Chironomidae ; Australia ; }, abstract = {Willi Hennig's (Beitr. Ent. 1960, 10, 15) Die Dipteren-Fauna von Neuseeland als systematisches und tiergeographisches Problem applied a phylogenetic approach to examine the distributional patterns exhibited by the Diptera of New Zealand. Hennig showed how phylogenetic trees may be used to infer dispersal, based on the progression and deviation rules, and also discussed the existence of vicariance patterns. The most important author who applied Hennig's phylogenetic biogeography was Lars Brundin, when analysing the phylogenetic relationships of two taxa of Chironomidae (Diptera) and using them to examine the biogeographic relationships of Australia, New Zealand, South America and South Africa. The relevance of Brundin's contribution was noted by several authors, as it began the cladistic or vicariance approach to biogeography, that implies the discovery of vicariance events shared by different monophyletic groups. Both phylogenetic and cladistic biogeography have a place in contemporary biogeography, the former for analysing taxon biogeography and the latter when addressing Earth or biota biogeography. The recent use of the term "phylogenetic biogeography" to refer to a posteriori methods of cladistic biogeography is erroneous and should be avoided.}, }
@article {pmid36253101, year = {2022}, author = {Doll, SG and Cingolani, G}, title = {Importin α/β and the tug of war to keep TDP-43 in solution: quo vadis?.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {44}, number = {12}, pages = {e2200181}, pmid = {36253101}, issn = {1521-1878}, support = {R01 GM122844/GM/NIGMS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; R35 GM140733/GM/NIGMS NIH HHS/United States ; R01 GM122844/GF/NIH HHS/United States ; }, mesh = {Humans ; alpha Karyopherins/metabolism ; Karyopherins ; *Frontotemporal Lobar Degeneration/genetics/metabolism ; DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; }, abstract = {The transactivation response-DNA binding protein of 43 kDa (TDP-43) is an aggregation-prone nucleic acid-binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP-43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP-43 are altered in the disease state where TDP-43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C-terminal prion-like domain. Here, we review three emerging and poorly understood aspects of TDP-43 biology linked to its aggregation. First, how post-translational modifications in the proximity of TDP-43 N-terminal domain (NTD) promote aggregation. Second, how TDP-43 engages FG-nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP-43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone.}, }
@article {pmid36251310, year = {2022}, author = {Shefner, JM and Bedlack, R and Andrews, JA and Berry, JD and Bowser, R and Brown, R and Glass, JD and Maragakis, NJ and Miller, TM and Rothstein, JD and Cudkowicz, ME}, title = {Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers: A Review.}, journal = {JAMA neurology}, volume = {79}, number = {12}, pages = {1312-1318}, doi = {10.1001/jamaneurol.2022.3282}, pmid = {36251310}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Outcome Assessment, Health Care ; Biomarkers ; Prognosis ; }, abstract = {IMPORTANCE: Clinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics.<br><br>OBSERVATIONS: By restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale-Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome.<br><br>CONCLUSIONS AND RELEVANCE: It is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.}, }
@article {pmid36243357, year = {2022}, author = {George, M and Tharakan, M and Culberson, J and Reddy, AP and Reddy, PH}, title = {Role of Nrf2 in aging, Alzheimer's and other neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {82}, number = {}, pages = {101756}, doi = {10.1016/j.arr.2022.101756}, pmid = {36243357}, issn = {1872-9649}, support = {R41 AG060836/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; NF-E2-Related Factor 2/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/genetics ; Aging/metabolism ; Oxidative Stress/physiology ; }, abstract = {Nuclear Factor-Erythroid Factor 2 (Nrf2) is an important transcription factor that regulates the expression of large number of genes in healthy and disease states. Nrf2 is made up of 605 amino acids and contains 7 conserved regions known as Nrf2-ECH homology domains. Nrf2 regulates the expression of several key components of oxidative stress, mitochondrial biogenesis, mitophagy, autophagy and mitochondrial function in all organs of the human body, in the peripheral and central nervous systems. Mounting evidence also suggests that altered expression of Nrf2 is largely involved in aging, neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's diseases, Amyotrophic lateral sclerosis, Stroke, Multiple sclerosis and others. The purpose of this article is to detail the essential role of Nrf2 in oxidative stress, antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic/mitophagic degradation, and metabolism in aging and neurodegenerative diseases. This article also highlights the Nrf2 structural and functional activities in healthy and disease states, and also discusses the current status of Nrf2 research and therapeutic strategies to treat aging and neurodegenerative diseases.}, }
@article {pmid36241096, year = {2022}, author = {Zhang, L and Liu, Y and Lu, Y and Wang, G}, title = {Targeting epigenetics as a promising therapeutic strategy for treatment of neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {206}, number = {}, pages = {115295}, doi = {10.1016/j.bcp.2022.115295}, pmid = {36241096}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/genetics ; Epigenesis, Genetic ; DNA Methylation ; Histones/metabolism ; Chromatin Assembly and Disassembly ; }, abstract = {Nowadays, epigenetics is of great research value as a new gateway that can solve the sophisticated mysteries behind neurodegenerative diseases. Epigenetic mechanisms, including DNA methylation, various post-translational modifications of histones, chromatin remodeling enzymes, and long non-coding RNAs, are robust modulators of gene expression levels. Over the past years, epigenetic processes have emerged as important factors in many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. Here, we review the diverse types of epigenetic modifications and how these mechanisms become dysregulated across the lifespan. We then discuss the various promising strategies for the treatment of neurodegenerative diseases targeting epigenetics, paving the way for the development of novel treatment strategies in neurodegenerative diseases.}, }
@article {pmid36233034, year = {2022}, author = {Reddy, DS and Abeygunaratne, HN}, title = {Experimental and Clinical Biomarkers for Progressive Evaluation of Neuropathology and Therapeutic Interventions for Acute and Chronic Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {19}, pages = {}, pmid = {36233034}, issn = {1422-0067}, support = {U01 NS117209/NS/NINDS NIH HHS/United States ; U01 NS117278/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease ; Biomarkers/metabolism ; Chronic Disease ; Humans ; *Nervous System Diseases/diagnosis/metabolism/therapy ; Neuropathology ; }, abstract = {This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.}, }
@article {pmid36232667, year = {2022}, author = {Glavač, D and Mladinić, M and Ban, J and Mazzone, GL and Sámano, C and Tomljanović, I and Jezernik, G and Ravnik-Glavač, M}, title = {The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS.}, journal = {International journal of molecular sciences}, volume = {23}, number = {19}, pages = {}, pmid = {36232667}, issn = {1422-0067}, support = {P3-0427 and P1-0170//Slovenian Research Agency/ ; IP-2016-06-7060//Croatian Science Foundation/ ; uniri-biomed-18-258-6427, uniri-prirod-18-290-1463 and uniri-sp-biomed-19-50-1560//University of Rijeka/ ; CRP/CRO14-03//International Centre for Genetic Engineering and Biotechnology/ ; FONCYT, PICT-2020-SERIEA-00928//Austral University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Animals ; Biomarkers/metabolism ; Humans ; Mammals/genetics ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; RNA, Untranslated/metabolism ; }, abstract = {Neurodegenerative diseases are one of the greatest medical burdens of the modern age, being mostly incurable and with limited prognostic and diagnostic tools. Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the loss of motoneurons, with a complex etiology, combining genetic, epigenetic, and environmental causes. The neuroprotective therapeutic approaches are very limited, while the diagnostics rely on clinical examination and the exclusion of other diseases. The recent advancement in the discovery of molecular pathways and gene mutations involved in ALS has deepened the understanding of the disease pathology and opened the possibility for new treatments and diagnostic procedures. Recently, 15 risk loci with distinct genetic architectures and neuron-specific biology were identified as linked to ALS through common and rare variant association analyses. Interestingly, the quantity of related proteins to these genes has been found to change during early postnatal development in mammalian spinal cord tissue (opossum Monodelphis domestica) at the particular time when neuroregeneration stops being possible. Here, we discuss the possibility that the ALS-related genes/proteins could be connected to neuroregeneration and development. Moreover, since the regulation of gene expression in developmental checkpoints is frequently regulated by non-coding RNAs, we propose that studying the changes in the composition and quantity of non-coding RNA molecules, both in ALS patients and in the developing central nervous (CNS) system of the opossum at the time when neuroregeneration ceases, could reveal potential biomarkers useful in ALS prognosis and diagnosis.}, }
@article {pmid36231055, year = {2022}, author = {Tortorella, I and Argentati, C and Emiliani, C and Morena, F and Martino, S}, title = {Biochemical Pathways of Cellular Mechanosensing/Mechanotransduction and Their Role in Neurodegenerative Diseases Pathogenesis.}, journal = {Cells}, volume = {11}, number = {19}, pages = {}, pmid = {36231055}, issn = {2073-4409}, mesh = {*Alzheimer Disease/metabolism ; Humans ; Mechanotransduction, Cellular ; Mutant Proteins/therapeutic use ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {In this review, we shed light on recent advances regarding the characterization of biochemical pathways of cellular mechanosensing and mechanotransduction with particular attention to their role in neurodegenerative disease pathogenesis. While the mechanistic components of these pathways are mostly uncovered today, the crosstalk between mechanical forces and soluble intracellular signaling is still not fully elucidated. Here, we recapitulate the general concepts of mechanobiology and the mechanisms that govern the mechanosensing and mechanotransduction processes, and we examine the crosstalk between mechanical stimuli and intracellular biochemical response, highlighting their effect on cellular organelles' homeostasis and dysfunction. In particular, we discuss the current knowledge about the translation of mechanosignaling into biochemical signaling, focusing on those diseases that encompass metabolic accumulation of mutant proteins and have as primary characteristics the formation of pathological intracellular aggregates, such as Alzheimer's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Parkinson's Disease. Overall, recent findings elucidate how mechanosensing and mechanotransduction pathways may be crucial to understand the pathogenic mechanisms underlying neurodegenerative diseases and emphasize the importance of these pathways for identifying potential therapeutic targets.}, }
@article {pmid36226313, year = {2022}, author = {Nowowiejska, J and Baran, A and Flisiak, I}, title = {Psoriasis and neurodegenerative diseases-a review.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {917751}, pmid = {36226313}, issn = {1662-5099}, abstract = {Psoriasis is a chronic skin disease with underlying genetic, inflammatory and immunological background, which is a great medical problem, currently regarded as a systemic condition. Neurodegenerative diseases (NDs) are characterized by a progressive loss of nervous tissue, which affects elderly people more frequently; therefore, it is suspected that, due to society's aging, morbidity is going to increase. We performed a thorough review in order to investigate for the first time whether psoriasis may predispose to different particular neurodegenerative diseases-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PubMed search resulted in the retrieval of 833 records, of which 77 eligible were included in the review. Our thorough analysis revealed there are some potential links between psoriasis and NDs (inflammation, oxidative stress, genetics, cardiometabolic disorders), but there is no strong evidence that psoriasis may predispose to NDs. Based on the evidence, it seems that the risk of PD in psoriatics is not increased, and the evidence for increased risk of AD slightly prevails the data that state the opposite. ALS risk does not seem to be increased in psoriatics. The paucity of original studies does not allow for the formulation of definitive conclusions but encourages to perform further investigations.}, }
@article {pmid36226074, year = {2022}, author = {Berth, SH and Rich, DJ and Lloyd, TE}, title = {The role of autophagic kinases in regulation of axonal function.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {996593}, pmid = {36226074}, issn = {1662-5102}, abstract = {Autophagy is an essential process for maintaining cellular homeostasis. Highlighting the importance of proper functioning of autophagy in neurons, disruption of autophagy is a common finding in neurodegenerative diseases. In recent years, evidence has emerged for the role of autophagy in regulating critical axonal functions. In this review, we discuss kinase regulation of autophagy in neurons, and provide an overview of how autophagic kinases regulate axonal processes, including axonal transport and axonal degeneration and regeneration. We also examine mechanisms for disruption of this process leading to neurodegeneration, focusing on the role of TBK1 in pathogenesis of Amyotrophic Lateral Sclerosis.}, }
@article {pmid36207571, year = {2022}, author = {Coleman, MP}, title = {Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1133-1144}, pmid = {36207571}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Armadillo Domain Proteins/genetics/metabolism ; Cytoskeletal Proteins/genetics/metabolism ; Axons/pathology ; DNA-Binding Proteins/metabolism ; Biology ; }, abstract = {This review addresses the longstanding debate over whether amyotrophic lateral sclerosis (ALS) is a 'dying back' or 'dying forward' disorder in the light of new gene identifications and the increased understanding of mechanisms of action for previously identified ALS genes. While the topological pattern of pathology in animal models, and more anecdotally in patients is indeed 'dying back', this review discusses how this fits with the fact that many of the major initiating events are thought to occur within the soma. It also discusses how widely varying ALS risk factors, including some impacting axons directly, may combine to drive a common pathway involving TAR DNA binding protein 43 (TDP-43) and neuromuscular junction (NMJ) denervation. The emerging association between sterile alpha and TIR motif-containing 1 (SARM1), a protein so far mostly associated with axon degeneration, and sporadic ALS is another major theme. The strengths and limitations of the current evidence supporting an association are considered, along with ways in which SARM1 could become activated in ALS. The final section addresses SARM1-based therapies along with the prospects for targeting other axonal steps in ALS pathogenesis.}, }
@article {pmid36206551, year = {2022}, author = {Mundkar, M and Bijalwan, A and Soni, D and Kumar, P}, title = {Neuroprotective potential of Moringa oleifera mediated by NF-kB/Nrf2/HO-1 signaling pathway: A review.}, journal = {Journal of food biochemistry}, volume = {46}, number = {12}, pages = {e14451}, doi = {10.1111/jfbc.14451}, pmid = {36206551}, issn = {1745-4514}, mesh = {Humans ; Animals ; Antioxidants/pharmacology/therapeutic use ; *Moringa oleifera ; NF-kappa B ; NF-E2-Related Factor 2/genetics ; *Moringa ; Signal Transduction ; }, abstract = {Moringa oleifera is a traditional Indian herb belonging to the Moringaceae family, it is commonly known as the horse-radish tree, drumstick, or sahajna. In developing countries, Moringa is used as feed for both humans and animals due to its well-known antioxidant, anti-inflammatory, and anti-apoptotic properties owing to its several phytoconstituents including β-carotene, quercetin, kaempferol, ascorbic acid, flavonoids, phenolic acid, rhamnose, glycosylates, glucomoringin, and isothiocyanates. These constituents help to maintain the brain antioxidant enzyme levels, mitochondrial functions, and neurogenesis, showing neuroprotective effects in several neurodegenerative disorders including Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, and Amyotrophic lateral sclerosis. This review discusses various phytoconstituent of moringa and their therapeutic potential in various neurological disorders. Additionally, we also concise the safety and toxicity profile, of different molecular pathways involved in the neuroprotective effect of M. oleifera including M. oleifera nanoparticles for better therapeutic value. PRACTICAL APPLICATIONS: Several clinical and preclinical studies on Moringa oleifera have been conducted, and the outcomes indicate moringa could be used in the treatment of brain disorders. As a result, we conclude that moringa and its nanoformulations could be employed to treat neurological problems. In the future, M. oleifera phytoconstituents could be evaluated against specific signaling pathways, which could aid researchers in discovering their mechanism of action. Furthermore, the use of moringa as a nutraceutical owing to its myriad pharmacological potential will go a long way in boosting the economy of countries that grow moringa on a large scale.}, }
@article {pmid36204830, year = {2023}, author = {Wakatsuki, S and Araki, T}, title = {Novel insights into the mechanism of reactive oxygen species-mediated neurodegeneration.}, journal = {Neural regeneration research}, volume = {18}, number = {4}, pages = {746-749}, pmid = {36204830}, issn = {1673-5374}, abstract = {Neurite degeneration, a major component of many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, is not part of the typical apoptosis signaling mechanism, but rather it appears that a self-destructive process is in action. Oxidative stress is a well-known inducer of neurodegenerative pathways: neuronal cell death and neurite degeneration. Although oxidative stress exerts cytotoxic effects leading to neuronal loss, the pathogenic mechanisms and precise signaling pathways by which oxidative stress causes neurite degeneration have remained entirely unknown. We previously reported that reactive oxygen species generated by NADPH oxidases induce activation of the E3 ubiquitin ligase ZNRF1 in neurons, which promotes neurite degeneration. In this process, the phosphorylation of an NADPH oxidase subunit p47-phox at the 345[th] serine residue serves as an important checkpoint to initiate the ZNRF1-dependent neurite degeneration. Evidence provides new insights into the mechanism of reactive oxygen species-mediated neurodegeneration. In this review, we focus specifically on reactive oxygen species-induced neurite degeneration by highlighting a phosphorylation-dependent regulation of the molecular interaction between ZNRF1 and the NADPH oxidase complex.}, }
@article {pmid36202258, year = {2022}, author = {Volonté, C and Amadio, S}, title = {Rethinking purinergic concepts and updating the emerging role of P2X7 and P2X4 in amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {221}, number = {}, pages = {109278}, doi = {10.1016/j.neuropharm.2022.109278}, pmid = {36202258}, issn = {1873-7064}, mesh = {Animals ; Adenosine Triphosphate/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Receptors, Purinergic P2X4/metabolism ; Receptors, Purinergic P2X7/metabolism ; Signal Transduction ; Humans ; }, abstract = {The topic of the present review regards the ubiquitous and phylogenetically most ancient prototype of intercellular signaling, the one mediated by extracellular nucleosides and nucleotides, bearing a strong influence on pathophysiological processes in the nervous system. Not by chance, purine and pyrimidine molecules are the most prevalent and ubiquitous chemical messengers in the animal and plant kingdoms, operating through a large plethora of purinergic metabolizing enzymes, P1 and P2 receptors, nucleoside and nucleotide channels and transporters. Because ectonucleotidases degrade the agonists of P2 receptors while simultaneously generate the agonists for P1 receptors, and because several agonists, or antagonists, simultaneously bind and activate, or inhibit, more than one receptor subtype, it follows that an all-inclusive "purinergic network" perspective should be better considered when looking at purinergic actions. This becomes particularly crucial during pathological conditions as for instance amyotrophic lateral sclerosis, where the contribution of purinergic signaling has been demonstrated to differ according to each target cell phenotype and stage of disease progression. Here we will present some newly updated results about P2X7 and P2X4 as the most thoroughly investigated P2 receptors in amyotrophic lateral sclerosis, being aware that the comprehension of their actions is still in progress, and that the purinergic rationale for studying this disease must be however wide-ranging and all-inclusive. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.}, }
@article {pmid36200031, year = {2022}, author = {Lu, Y and Gao, Q and Ren, X and Li, J and Yang, D and Zhang, Z and Han, J}, title = {Incidence and prevalence of 121 rare diseases in China: Current status and challenges: 2022 revision.}, journal = {Intractable &amp; rare diseases research}, volume = {11}, number = {3}, pages = {96-104}, pmid = {36200031}, issn = {2186-3644}, abstract = {The current study updated data on the incidence and prevalence of 121 rare diseases listed in China's First List of Rare Diseases to provide rationales and references for the development and promotion of rare-disease-related policies. The National Health Commission of the People's Republic of China issued the Rare Disease Diagnosis and Treatment Guide (2019) (denoted here as China's Rare Disease Diagnosis and Treatment Guide). Then 121 diseases were registered with the national rare disease diagnosis and treatment network. The incidence/prevalence of 121 rare diseases varied from country to country. Data are available for a total of 76 rare diseases (76 of 121 rare diseases, 62.81%) in China, including data on the incidence of 23 rare diseases (19.01%) and data on the prevalence of 66 (54.55%). There are data on the incidence/prevalence of 112 rare diseases (112 of 121 rare diseases, 92.56%) at the global level, including data on the incidence of 86 rare diseases (71.07%) and data on the prevalence of 91 (75.21%). On average, the incidence of progressive muscular dystrophies, hyperphenylalaninemia, citrullinemia, and methylmalonic acidemia is over 1/10,000 in China. The prevalence of coronary artery ectasia, congenital scoliosis, retinitis pigmentosa, severe congenital neutropenia, congenital hyperinsulinemic hypoglycemia, and osteogenesis imperfecta is over 1/10,000 in China. All of these figures are beyond the cut-off of 1/10,000 according to the 2021 definition of rare diseases in China. As registration and investigation of rare diseases continues, the spectrum of rare diseases in some provinces is expanding. Diseases such as idiopathic pulmonary arterial hypertension, hepatolenticular degeneration, hemophilia, amyotrophic lateral sclerosis, idiopathic pulmonary fibrosis, and multiple sclerosis are relatively prevalent in some regions and cities of China. Registration efforts promote the correction of incidence/prevalence data, development of orphan drugs, coverage by medical insurance, and development of clinical and diagnostic pathways.}, }
@article {pmid36188541, year = {2022}, author = {Yadav, E and Yadav, P and Khan, MMU and Singh, H and Verma, A}, title = {Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {922232}, pmid = {36188541}, issn = {1663-9812}, abstract = {Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.}, }
@article {pmid36188213, year = {2022}, author = {Rhine, K and Al-Azzam, N and Yu, T and Yeo, GW}, title = {Aging RNA granule dynamics in neurodegeneration.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {991641}, pmid = {36188213}, issn = {2296-889X}, abstract = {Disordered RNA-binding proteins and repetitive RNA sequences are the main genetic causes of several neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease. Importantly, these components also seed the formation of cytoplasmic liquid-like granules, like stress granules and P bodies. Emerging evidence demonstrates that healthy granules formed via liquid-liquid phase separation can mature into solid- or gel-like inclusions that persist within the cell. These solidified inclusions are a precursor to the aggregates identified in patients, demonstrating that dysregulation of RNA granule biology is an important component of neurodegeneration. Here, we review recent literature highlighting how RNA molecules seed proteinaceous granules, the mechanisms of healthy turnover of RNA granules in cells, which biophysical properties underly a transition to solid- or gel-like material states, and why persistent granules disrupt the cellular homeostasis of neurons. We also identify various methods that will illuminate the contributions of disordered proteins and RNAs to neurodegeneration in ongoing research efforts.}, }
@article {pmid36187357, year = {2022}, author = {Bergh, S and Cheong, RY and Petersén, &#xc5; and Gabery, S}, title = {Oxytocin in Huntington's disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {984317}, pmid = {36187357}, issn = {1662-5099}, abstract = {Neurodegenerative disorders (NDDs) such as Huntington's disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human post-mortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs.}, }
@article {pmid36187344, year = {2022}, author = {Ghaffari, LT and Trotti, D and Haeusler, AR and Jensen, BK}, title = {Breakdown of the central synapses in C9orf72-linked ALS/FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1005112}, pmid = {36187344}, issn = {1662-5099}, support = {RF1 AG057882/AG/NIA NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that leads to the death of motor and cortical neurons. The clinical manifestations of ALS are heterogenous, and efficacious treatments to significantly slow the progression of the disease are lacking. Cortical hyper-excitability is observed pre-symptomatically across disease-causative genetic variants, as well as in the early stages of sporadic ALS, and typically precedes motor neuron involvement and overt neurodegeneration. The causes of cortical hyper-excitability are not yet fully understood but is mainly agreed to be an early event. The identification of the nucleotide repeat expansion (GGGGCC)n in the C9ORF72 gene has provided evidence that ALS and another neurodegenerative disease, frontotemporal dementia (FTD), are part of a disease spectrum with common genetic origins. ALS and FTD are diseases in which synaptic dysfunction is reported throughout disease onset and stages of progression. It has become apparent that ALS/FTD-causative genes, such as C9ORF72, may have roles in maintaining the normal physiology of the synapse, as mutations in these genes often manifest in synaptic dysfunction. Here we review the dysfunctions of the central nervous system synapses associated with the nucleotide repeat expansion in C9ORF72 observed in patients, organismal, and cellular models of ALS and FTD.}, }
@article {pmid36184826, year = {2023}, author = {Jiao, F and Zhou, B and Meng, L}, title = {The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {29}, number = {1}, pages = {37-59}, pmid = {36184826}, issn = {1755-5949}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Autophagy ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Lysosomes ; }, abstract = {The autophagy-lysosomal pathway (ALP) is involved in the degradation of protein aggregates and damaged organelles. Transcription factor EB (TFEB), a major regulator of ALP, has emerged as a leading factor in addressing neurodegenerative disease pathology, including Alzheimer's disease (AD), Parkinson's disease (PD), PolyQ diseases, and Amyotrophic lateral sclerosis (ALS). In this review, we delineate the regulation of TFEB expression and its functions in ALP. Dysfunctions of TFEB and its role in the pathogenesis of several neurodegenerative diseases are reviewed. We summarize the protective effects and molecular mechanisms of some TFEB-targeted agonists in neurodegenerative diseases. We also offer our perspective on analyzing the pros and cons of these agonists in the treatment of neurodegenerative diseases from the perspective of drug development. More studies on the regulatory mechanisms of TFEB in other biological processes will aid our understanding of the application of TFEB-targeted therapy in neurodegeneration.}, }
@article {pmid36184105, year = {2023}, author = {Sataer, X and Qifeng, Z and Yingying, Z and Chunhua, H and Bingzhenga, F and Zhiran, X and Wanli, L and Yuwei, Y and Shuangfeng, C and Lingling, W and Hongri, H and Jibing, C and Xiaoping, R and Hongjun, G}, title = {Exosomal microRNAs as diagnostic biomarkers and therapeutic applications in neurodegenerative diseases.}, journal = {Neurological research}, volume = {45}, number = {3}, pages = {191-199}, doi = {10.1080/01616412.2022.2129768}, pmid = {36184105}, issn = {1743-1328}, mesh = {Humans ; *MicroRNAs/genetics/therapeutic use/metabolism ; *Neurodegenerative Diseases/diagnosis/genetics/therapy ; *Alzheimer Disease/metabolism ; *Huntington Disease ; Biomarkers/metabolism ; }, abstract = {Originating from slow irreversible and progressive loss and dysfunction of neurons and synapses in the nervous system, neurodegenerative diseases (NDDs) affect millions of people worldwide. Common NDDs include Parkinson's disease, Alzheimer's disease multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Currently, no sensitive biomarkers are available to monitor the progression and treatment response of NDDs or to predict their prognosis. Exosomes (EXOs) are small bilipid layer-enclosed extracellular vesicles containing numerous biomolecules, including proteins, nucleic acids, and lipids. Recent evidence indicates that EXOs are pathogenic participants in the spread of neurodegenerative diseases, contributing to disease progression and spread. EXOs are also important tools for diagnosis and treatment. Recently, studies have proposed exosomal microRNAs (miRNAs) as the targets for therapies or biomarkers of NDDs. In this review, we outline the latest research on the roles of exosomal miRNAs in NDDs and their applications as potential diagnostic and therapeutic biomarkers, targets, and drugs for NDDs.}, }
@article {pmid36181767, year = {2022}, author = {Monsour, M and Garbuzova-Davis, S and Borlongan, CV}, title = {Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis.}, journal = {Stem cells translational medicine}, volume = {11}, number = {12}, pages = {1196-1209}, pmid = {36181767}, issn = {2157-6580}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Spinal Cord/metabolism ; Central Nervous System ; Stem Cells/pathology ; Permeability ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating disease with poor prognosis. The pathophysiology of ALS is commonly debated, with theories involving inflammation, glutamate excitotoxity, oxidative stress, mitochondria malfunction, neurofilament accumulation, inadequate nutrients or growth factors, and changes in glial support predominating. These underlying pathological mechanisms, however, act together to weaken the blood brain barrier and blood spinal cord barrier, collectively considered as the blood central nervous system barrier (BCNSB). Altering the impermeability of the BCNSB impairs the neurovascular unit, or interdependent relationship between the brain and advances the concept that ALS is has a significant neurovascular component contributing to its degenerative presentation. This unique categorization of ALS opens a variety of treatment options targeting the reestablishment of BCNSB integrity. This review will critically assess the evidence implicating the significant neurovascular components of ALS pathophysiology, while also offering an in-depth discussion regarding the use of stem cells to repair these pathological changes within the neurovascular unit.}, }
@article {pmid36180986, year = {2022}, author = {Gureev, AP and Sadovnikova, IS and Popov, VN}, title = {Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue.}, journal = {Biochemistry. Biokhimiia}, volume = {87}, number = {9}, pages = {940-956}, doi = {10.1134/S0006297922090073}, pmid = {36180986}, issn = {1608-3040}, mesh = {Methylene Blue/metabolism/pharmacology/therapeutic use ; Mitochondria/metabolism ; Monoamine Oxidase/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Nitric Oxide Synthase/metabolism ; }, abstract = {Methylene blue (MB) is the first fully synthetic compound that had found its way into medicine over 120 years ago as a treatment against malaria. MB has been approved for the treatment of methemoglobinemia, but there are premises for its repurposing as a neuroprotective agent based on the efficacy of this compound demonstrated in the models of Alzheimer's, Parkinson's, and Huntington's diseases, traumatic brain injury, amyotrophic lateral sclerosis, depressive disorders, etc. However, the goal of this review was not so much to focus on the therapeutic effects of MB in the treatment of various neurodegeneration diseases, but to delve into the mechanisms of direct or indirect effect of this drug on the signaling pathways. MB can act as an alternative electron carrier in the mitochondrial respiratory chain in the case of dysfunctional electron transport chain. It also displays the anti-inflammatory and anti-apoptotic effects, inhibits monoamine oxidase (MAO) and nitric oxide synthase (NOS), activates signaling pathways involved in the mitochondrial pool renewal (mitochondrial biogenesis and autophagy), and prevents aggregation of misfolded proteins. Comprehensive understanding of all aspects of direct and indirect influence of MB, and not just some of its effects, can help in further research of this compound, including its clinical applications.}, }
@article {pmid36178320, year = {2022}, author = {Elbasiouny, SM}, title = {Motoneuron excitability dysfunction in ALS: Pseudo-mystery or authentic conundrum?.}, journal = {The Journal of physiology}, volume = {600}, number = {22}, pages = {4815-4825}, pmid = {36178320}, issn = {1469-7793}, support = {R01 AG067758/AG/NIA NIH HHS/United States ; R01AG067758/AG/NIA NIH HHS/United States ; R01NS091836/NS/NINDS NIH HHS/United States ; R01 NS091836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons/physiology ; Disease Progression ; }, abstract = {In amyotrophic lateral sclerosis (ALS), abnormalities in motoneuronal excitability are seen in early pathogenesis and throughout disease progression. Fully understanding motoneuron excitability dysfunction may lead to more effective treatments. Yet decades of research have not produced consensus on the nature, role or underlying mechanisms of motoneuron excitability dysfunction in ALS. For example, contrary to Ca excitotoxicity theory, predictions of motoneuronal hyper-excitability, normal and hypo-excitability have also been seen at various disease stages and in multiple ALS lines. Accordingly, motoneuron excitability dysfunction in ALS is a disputed topic in the field. Specifically, the form (hyper, hypo or unchanged) and what role excitability dysfunction plays in the disease (pathogenic or downstream of other pathologies; neuroprotective or detrimental) are currently unclear. Although several motoneuron properties that determine cellular excitability change in the disease, some of these changes are pro-excitable, whereas others are anti-excitable, making dynamic fluctuations in overall 'net' excitability highly probable. Because various studies assess excitability via differing methods and at differing disease stages, the conflicting reports in the literature are not surprising. Hence, the overarching process of excitability degradation and motoneuron degeneration is not fully understood. Consequently, the discrepancies on motoneuron excitability dysfunction in the literature represent a substantial barrier to our understanding of the disease. Emerging studies suggest that biological variables, variations in experimental protocols, issues of rigor and sampling/analysis strategies are key factors that may underlie conflicting data in the literature. This review highlights potential confounding factors for researchers to consider and also offers ideas on avoiding pitfalls and improving robustness of data.}, }
@article {pmid36176198, year = {2023}, author = {Corcia, P and Lejeune, P and Vourc'h, P and Beltran, S and Piegay, AS and Blasco, H and Meininger, V}, title = {Comparison between PFN1 and SOD1 mutations in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {2}, pages = {552-554}, doi = {10.1111/ene.15583}, pmid = {36176198}, issn = {1468-1331}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Mutation/genetics ; Profilins/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: The objective of this study was to characterize the prototypical phenotype of patients with amyotrophic lateral sclerosis (ALS) associated with PFN1 mutations in profilin 1 (PFN1) and to determine clinical indications to test for mutations in this gene.<br><br>MATERIAL AND METHODS: The phenotype of three relatives carrying the M114V PFN1 mutation are detailed here and are compared with those of patients with ALS linked to PFN1 previously reported in the literature.<br><br>RESULTS: In this pedigree and in the literature, the main clinical findings which best describe familial ALS linked to PFN1 might be the following characteristics: pedigrees over five cases, age of onset around 50&#x2009;years, site of onset systematically lower limbs and the absence of cognitive impairment.<br><br>CONCLUSION: First, the infrequent incidence of patients with ALS linked to PFN1 mutation supports the pursuit of a precise characterization of the phenotype linked to PFN1 mutations. Then, the numerous similarities between the phenotype amongst patients linked to SOD1 and PFN1 mutations and between histological features amongst both mice models prompts a review of the current ALS classifications, taking into consideration both phenotype and genotype.}, }
@article {pmid36176016, year = {2022}, author = {Roohbakhsh, A and Etemad, L and Karimi, G}, title = {Resolvin D1: A key endogenous inhibitor of neuroinflammation.}, journal = {BioFactors (Oxford, England)}, volume = {48}, number = {5}, pages = {1005-1026}, doi = {10.1002/biof.1891}, pmid = {36176016}, issn = {1872-8081}, support = {//Mashhad University of Medical Sciences/ ; }, mesh = {Anti-Inflammatory Agents/pharmacology ; Aspirin ; *Docosahexaenoic Acids/pharmacology/therapeutic use ; Humans ; Inflammation/drug therapy ; *Neuroinflammatory Diseases ; }, abstract = {After the initiation of inflammation, a series of processes start to resolve the inflammation. A group of endogenous lipid mediators, namely specialized pro-resolving lipid mediators is at the top list of inflammation resolution. Resolvin D1 (RvD1), is one of the lipid mediators with significant anti-inflammatory properties. It is produced from docosahexaenoic acid (omega-3 polyunsaturated fatty acid) in the body. In this article, we aimed to review the most recent findings concerning the pharmacological effects of RvD1 in the central nervous system with a focus on major neurological diseases and dysfunctions. A literature review of the past studies demonstrated that RvD1 plasma level changes during mania, depression, and Parkinson's disease. Furthermore, RVD1 and its epimer, aspirin-triggered RvD1 (AT-RvD1), have significant therapeutic effects on experimental models of ischemic and traumatic brain injuries, memory dysfunction, pain, depression, amyotrophic lateral sclerosis, and Alzheimer's and Parkinson's diseases. Interestingly, the beneficial effects of RvD1 and AT-RvD1 were mostly induced at nanomolar and micromolar concentrations implying the significant potency of these lipid mediators in treating diseases with inflammation.}, }
@article {pmid36173507, year = {2023}, author = {Alijanpour, S and Miryounesi, M and Ghafouri-Fard, S}, title = {The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders.}, journal = {Metabolic brain disease}, volume = {38}, number = {1}, pages = {1-16}, pmid = {36173507}, issn = {1573-7365}, mesh = {Animals ; Humans ; Excitatory Amino Acid Transporter 2/genetics/metabolism ; *Epilepsy/genetics ; *Schizophrenia/metabolism ; Biological Transport ; Glutamic Acid/metabolism ; Mammals/metabolism ; }, abstract = {Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Excitatory amino acid transporters (EAATs) have important roles in the uptake of glutamate and termination of glutamatergic transmission. Up to now, five EAAT isoforms (EAAT1-5) have been identified in mammals. The main focus of this review is EAAT2. This protein has an important role in the pathoetiology of epilepsy. De novo dominant mutations, as well as inherited recessive mutation in this gene, have been associated with epilepsy. Moreover, dysregulation of this protein is implicated in a range of neurological diseases, namely amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, schizophrenia, epilepsy, and autism. In this review, we summarize the role of EAAT2 in epilepsy and other neurological disorders, then provide an overview of the therapeutic modulation of this protein.}, }
@article {pmid36167285, year = {2023}, author = {Alejos, M and Vázquez-Bourgon, J and Santurtún, M and Riancho, J and Santurtún, A}, title = {Do patients diagnosed with a neurological disease present increased risk of suicide?.}, journal = {Neurologia}, volume = {38}, number = {1}, pages = {41-46}, doi = {10.1016/j.nrleng.2020.03.005}, pmid = {36167285}, issn = {2173-5808}, mesh = {Humans ; *Suicide/psychology ; Suicidal Ideation ; Suicide Prevention ; *Parkinson Disease/psychology ; *Epilepsy/psychology ; }, abstract = {INTRODUCTION: Neurological diseases are the leading cause of disability and the second leading cause of death worldwide. Physical and psychological pain, despair, and disconnection with the environment are observed after the diagnosis of numerous neurological processes, particularly neurodegenerative diseases.<br><br>DEVELOPMENT: A higher risk of suicide is observed in patients with such common neurological diseases as epilepsy, migraine, and multiple sclerosis, as well as in those with such degenerative disorders as Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and Parkinson's disease. In most cases, suicidal ideation appears in the early stages after diagnosis, in the presence of disabling symptoms, and/or in patients with psychiatric comorbidities (often associated with these neurological diseases).<br><br>CONCLUSIONS: Effective suicide prevention in this population group requires assessment of the risk of suicide mainly in newly diagnosed patients, in patients showing unmistakable despair or disabling symptoms, and in patients presenting psychiatric comorbidities (especially depressive symptoms). It is essential to train specialists to detect warning signs in order that they may adopt a suitable approach and determine when psychiatric assessment is required.}, }
@article {pmid36161717, year = {2022}, author = {Yang, C and Zhang, X}, title = {Research progress on vesicular trafficking in amyotrophic lateral sclerosis.}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {51}, number = {3}, pages = {380-387}, pmid = {36161717}, issn = {1008-9292}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; Humans ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases ; Proteostasis Deficiencies ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Vesicular trafficking is a basic physiological process by which vesicles transport materials between cells and environment (intercellular transport) and between different cellular compartments (intracellular trafficking). In recent years, more and more evidences have suggested that vesicular trafficking dysfunction plays a key role in pathogenesis of neurodegenerative diseases. Abnormal vesicular trafficking promotes the propagation of misfolded proteins by mechanisms involving endocytosis, endosomal-lysosomal pathway, endosomal escape and exosome release, leading to further acceleration of disease progression. Amyotrophic lateral sclerosis (ALS), as a neurodegenerative disease, is characterized by the selective death of upper and lower motor neurons. A variety of causative genes for ALS have been implicated in vesicle trafficking dysfunction, such as C9ORF72, TARDBP and SOD1. Therefore, the aggregation and propagation of misfolded proteins may be prevented through regulation of vesicle trafficking-related proteins, thus delay the progression of ALS. A more in-depth understanding of vesicular trafficking in ALS will be helpful in revealing the mechanism and clinical treatment of ALS. This review focuses on molecular mechanisms of vesicular trafficking in ALS, to provide reference for exploring new therapeutic strategies.}, }
@article {pmid36158556, year = {2022}, author = {Aiello, EN and Feroldi, S and De Luca, G and Guidotti, L and Arrigoni, E and Appollonio, I and Solca, F and Carelli, L and Poletti, B and Verde, F and Silani, V and Ticozzi, N}, title = {Primary progressive aphasia and motor neuron disease: A review.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1003792}, pmid = {36158556}, issn = {1663-4365}, abstract = {BACKGROUND: This study aims at reviewing, within the framework of motor neuron disease-frontotemporal degeneration (MND-FTD)-spectrum disorders, evidence on the co-occurrence between primary progressive aphasia (PPA) and MND in order to profile such a complex at pathological, genetic and clinical levels.<br><br>METHODS: This review was pre-registered (osf.io/ds8m4) and performed in accordance with the 2020 PRISMA guidelines. Case reports/series and group studies were included if addressing (1) progressive non-fluent aphasia (PNFA) or semantic dementia (SD) with MND or (2) MND patients with co-morbid PNFA/SD.<br><br>RESULTS: Out of 546 initial records, 56 studies were included. As to case reports/series (N = 35), which included 61 PPA-MND patients, the following findings yielded: (1) PNFA is more frequent than SD in PPA-MND; (2) in PPA-MND, the most prevalent motor phenotypes are amyotrophic lateral sclerosis and predominant-upper MND, with bulbar involvement being ubiquitous; (3) extrapyramidal features are moderately frequent in PPA-MND; (4) PPA-MND patients usually display frontotemporal, left-greater-than-right involvement; (5) TDP-43-B is the typical pathological substrate of PPA-MND; (6) TBK1 mutations represent the most frequent genetic risk factors for PPA-MND.As to group studies, including 121 patients, proportional meta-analytic procedures revealed that: (1) the lifetime prevalence of MND in PPA is 6%; (2) PPA occurs in 19% of patients with co-morbid MND and FTD; (3) MND is more frequent in PNFA (10%) than in SD patients (3%).<br><br>DISCUSSION: Insights herewith delivered into the clinical, neuropathological and genetic features of PPA-MND patients prompt further investigations aimed at improving clinical practice within the MND-FTD spectrum.}, }
@article {pmid36158555, year = {2022}, author = {Li, Y and Li, F and Qin, D and Chen, H and Wang, J and Wang, J and Song, S and Wang, C and Wang, Y and Liu, S and Gao, D and Wang, ZH}, title = {The role of brain derived neurotrophic factor in central nervous system.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {986443}, pmid = {36158555}, issn = {1663-4365}, abstract = {Brain derived neurotrophic factor (BDNF) has multiple biological functions which are mediated by the activation of two receptors, tropomyosin receptor kinase B (TrkB) receptor and the p75 neurotrophin receptor, involving in physiological and pathological processes throughout life. The diverse presence and activity of BDNF indicate its potential role in the pathogenesis, progression and treatment of both neurological and psychiatric disorders. This review is to provide a comprehensive assessment of the current knowledge and future directions in BDNF-associated research in the central nervous system (CNS), with an emphasis on the physiological and pathological functions of BDNF as well as its potential treatment effects in CNS diseases, including depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cerebral ischemic stroke.}, }
@article {pmid36158221, year = {2022}, author = {Ikeda, A and Imai, Y and Hattori, N}, title = {Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two?.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {996061}, pmid = {36158221}, issn = {2296-634X}, abstract = {Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are mitochondrial proteins that are thought to be genes which duplicated during evolution and are the causative genes for Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal lobe dementia, respectively. CHCHD2 forms a heterodimer with CHCHD10 and a homodimer with itself, both of which work together within the mitochondria. Various pathogenic and disease-risk variants have been identified; however, how these mutations cause neurodegeneration in specific diseases remains a mystery. This review focuses on important new findings published since 2019 and discusses avenues to solve this mystery.}, }
@article {pmid36158183, year = {2022}, author = {Tran, NN and Lee, BH}, title = {Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {931968}, pmid = {36158183}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which motor neurons in spinal cord and motor cortex are progressively lost. About 15% cases of ALS also develop the frontotemporal dementia (FTD), in which the frontotemporal lobar degeneration (FTLD) occurs in the frontal and temporal lobes of the brain. Among the pathologic commonalities in ALS and FTD is ubiquitin-positive cytoplasmic aggregation of TDP-43 that may reflect both its loss-of-function and gain-of-toxicity from proteostasis impairment. Deep understanding of how protein quality control mechanisms regulate TDP-43 proteinopathies still remains elusive. Recently, a growing body of evidence indicates that ubiquitinating and deubiquitinating pathways are critically engaged in the fate decision of aberrant or pathological TDP-43 proteins. E3 ubiquitin ligases coupled with deubiquitinating enzymes may influence the TDP-43-associated proteotoxicity through diverse events, such as protein stability, translocation, and stress granule or inclusion formation. In this article, we recapitulate our current understanding of how ubiquitinating and deubiquitinating mechanisms can modulate TDP-43 protein quality and its pathogenic nature, thus shedding light on developing targeted therapies for ALS and FTD by harnessing protein degradation machinery.}, }
@article {pmid36157078, year = {2022}, author = {Mégret, L and Mendoza, C and Arrieta Lobo, M and Brouillet, E and Nguyen, TT and Bouaziz, O and Chambaz, A and Néri, C}, title = {Precision machine learning to understand micro-RNA regulation in neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {914830}, pmid = {36157078}, issn = {1662-5099}, abstract = {Micro-RNAs (miRNAs) are short (∼21 nt) non-coding RNAs that regulate gene expression through the degradation or translational repression of mRNAs. Accumulating evidence points to a role of miRNA regulation in the pathogenesis of a wide range of neurodegenerative (ND) diseases such as, for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington disease (HD). Several systems level studies aimed to explore the role of miRNA regulation in NDs, but these studies remain challenging. Part of the problem may be related to the lack of sufficiently rich or homogeneous data, such as time series or cell-type-specific data obtained in model systems or human biosamples, to account for context dependency. Part of the problem may also be related to the methodological challenges associated with the accurate system-level modeling of miRNA and mRNA data. Here, we critically review the main families of machine learning methods used to analyze expression data, highlighting the added value of using shape-analysis concepts as a solution for precisely modeling highly dimensional miRNA and mRNA data such as the ones obtained in the study of the HD process, and elaborating on the potential of these concepts and methods for modeling complex omics data.}, }
@article {pmid36157072, year = {2022}, author = {Lum, JS and Yerbury, JJ}, title = {Misfolding at the synapse: A role in amyotrophic lateral sclerosis pathogenesis?.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {997661}, pmid = {36157072}, issn = {1662-5099}, abstract = {A growing wave of evidence has placed the concept of protein homeostasis at the center of the pathogenesis of amyotrophic lateral sclerosis (ALS). This is due primarily to the presence of pathological transactive response DNA-binding protein (TDP-43), fused in sarcoma (FUS) or superoxide dismutase-1 (SOD1) inclusions within motor neurons of ALS postmortem tissue. However, the earliest pathological alterations associated with ALS occur to the structure and function of the synapse, prior to motor neuron loss. Recent evidence demonstrates the pathological accumulation of ALS-associated proteins (TDP-43, FUS, C9orf72-associated di-peptide repeats and SOD1) within the axo-synaptic compartment of motor neurons. In this review, we discuss this recent evidence and how axo-synaptic proteome dyshomeostasis may contribute to synaptic dysfunction in ALS.}, }
@article {pmid36156207, year = {2022}, author = {Sturmey, E and Malaspina, A}, title = {Blood biomarkers in ALS: challenges, applications and novel frontiers.}, journal = {Acta neurologica Scandinavica}, volume = {146}, number = {4}, pages = {375-388}, pmid = {36156207}, issn = {1600-0404}, support = {TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Biomarkers ; DNA-Binding Proteins ; Humans ; *Motor Neuron Disease ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease among adults. With diagnosis reached relatively late into the disease process, extensive motor cell loss narrows the window for therapeutic opportunities. Clinical heterogeneity in ALS and the lack of disease-specific biomarkers have so far led to large-sized clinical trials with long follow-up needed to define clinical outcomes. In advanced ALS patients, there is presently limited scope to use imaging or invasive cerebrospinal fluid (CSF) collection as a source of disease biomarkers. The development of more patient-friendly and accessible blood biomarker assays is hampered by analytical hurdles like the matrix effect of blood components. However, blood also provides the opportunity to identify disease-specific adaptive changes of the stoichiometry and conformation of target proteins and the endogenous immunological response to low-abundance brain peptides, such as neurofilaments (Nf). Among those biomarkers under investigation in ALS, the change in concentration before or after diagnosis of Nf has been shown to aid prognostication and to allow the a priori stratification of ALS patients into smaller sized and clinically more homogeneous cohorts, supporting more affordable clinical trials. Here, we discuss the technical hurdles affecting reproducible and sensitive biomarker measurement in blood. We also summarize the state of the art of non-CSF biomarkers in the study of prognosis, disease progression, and treatment response. We will then address the potential as disease-specific biomarkers of the newly discovered cryptic peptides which are formed down-stream of TDP-43 loss of function, the hallmark of ALS pathobiology.}, }
@article {pmid36155944, year = {2022}, author = {Yvanka de Soysa, T and Therrien, M and Walker, AC and Stevens, B}, title = {Redefining microglia states: Lessons and limits of human and mouse models to study microglia states in neurodegenerative diseases.}, journal = {Seminars in immunology}, volume = {60}, number = {}, pages = {101651}, doi = {10.1016/j.smim.2022.101651}, pmid = {36155944}, issn = {1096-3618}, support = {T32 NS007473/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; *Neurodegenerative Diseases/metabolism ; Microglia ; Macrophages/metabolism ; Disease Models, Animal ; Brain ; }, abstract = {Microglia are resident macrophages of the brain parenchyma and play an essential role in various aspects of brain development, plasticity, and homeostasis. With recent advances in single-cell RNA-sequencing, heterogeneous microglia transcriptional states have been identified in both animal models of neurodegenerative disorders and patients. However, the functional roles of these microglia states remain unclear; specifically, the question of whether individual states or combinations of states are protective or detrimental (or both) in the context of disease progression. To attempt to answer this, the field has largely relied on studies employing mouse models, human in vitro and chimeric models, and human post-mortem tissue, all of which have their caveats, but used in combination can enable new biological insight and validation of candidate disease pathways and mechanisms. In this review, we summarize our current understanding of disease-associated microglia states and phenotypes in neurodegenerative disorders, discuss important considerations when comparing mouse and human microglia states and functions, and identify areas of microglia biology where species differences might limit our understanding of microglia state.}, }
@article {pmid36154605, year = {2023}, author = {Koerich, S and Parreira, GM and de Almeida, DL and Vieira, RP and de Oliveira, ACP}, title = {Receptors for Advanced Glycation End Products (RAGE): Promising Targets Aiming at the Treatment of Neurodegenerative Conditions.}, journal = {Current neuropharmacology}, volume = {21}, number = {2}, pages = {219-234}, pmid = {36154605}, issn = {1875-6190}, support = {APQ-01532-18, APQ-02559-17//FAPEMIG, Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; 140585/2019-2, 310347/2018-1//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico- CNPq/ ; 001//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de Nivel Superior, Brazil (CAPES)/ ; }, mesh = {Humans ; *Alzheimer Disease ; Amyloid beta-Peptides ; Glycation End Products, Advanced/metabolism ; *Neurodegenerative Diseases ; Receptor for Advanced Glycation End Products/metabolism ; }, abstract = {Advanced glycation end products (AGEs) are compounds formed after the non-enzymatic addition of reducing sugars to lipids, proteins, and nucleic acids. They are associated with the development of various clinical complications observed in diabetes and cardiovascular diseases, such as retinopathy, nephropathy, diabetic neuropathy, and others. In addition, compelling evidence indicates that these molecules participate in the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Multiple cellular and molecular alterations triggered by AGEs that could alter homeostasis have been identified. One of the main targets for AGE signaling is the receptor for advanced glycation end-products (RAGE). Importantly, this receptor is the target of not only AGEs, but also amyloid β peptides, HMGB1 (high-mobility group box-1), members of the S100 protein family, and glycosaminoglycans. The activation of this receptor induces intracellular signaling cascades that are involved in pathological processes and cell death. Therefore, RAGE represents a key target for pharmacological interventions in neurodegenerative diseases. This review will discuss the various effects of AGEs and RAGE activation in the pathophysiology of neurodegenerative diseases, as well as the currently available pharmacological tools and promising drug candidates.}, }
@article {pmid36153580, year = {2022}, author = {Fernández-Calle, R and Konings, SC and Frontiñán-Rubio, J and García-Revilla, J and Camprubí-Ferrer, L and Svensson, M and Martinson, I and Boza-Serrano, A and Venero, JL and Nielsen, HM and Gouras, GK and Deierborg, T}, title = {APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer's disease pathology and brain diseases.}, journal = {Molecular neurodegeneration}, volume = {17}, number = {1}, pages = {62}, pmid = {36153580}, issn = {1750-1326}, mesh = {Humans ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Apolipoprotein E2/genetics ; Apolipoprotein E3/genetics ; Apolipoprotein E4/genetics ; Apolipoproteins E/metabolism ; Genotype ; *Neurodegenerative Diseases/genetics ; Plaque, Amyloid/pathology ; tau Proteins/genetics ; }, abstract = {ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.}, }
@article {pmid36145298, year = {2022}, author = {Ashraf, H and Solla, P and Sechi, LA}, title = {Current Advancement of Immunomodulatory Drugs as Potential Pharmacotherapies for Autoimmunity Based Neurological Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {36145298}, issn = {1424-8247}, abstract = {Dramatic advancement has been made in recent decades to understand the basis of autoimmunity-mediated neurological diseases. These diseases create a strong influence on the central nervous system (CNS) and the peripheral nervous system (PNS), leading to various clinical manifestations and numerous symptoms. Multiple sclerosis (MS) is the most prevalent autoimmune neurological disease while NMO spectrum disorder (NMOSD) is less common. Furthermore, evidence supports the presence of autoimmune mechanisms contributing to the pathogenesis of amyotrophic lateral sclerosis (ALS), which is a neurodegenerative disorder characterized by the progressive death of motor neurons. Additionally, autoimmunity is believed to be involved in the basis of Alzheimer's and Parkinson's diseases. In recent years, the prevalence of autoimmune-based neurological disorders has been elevated and current findings strongly suggest the role of pharmacotherapies in controlling the progression of autoimmune diseases. Therefore, this review focused on the current advancement of immunomodulatory drugs as novel approaches in the management of autoimmune neurological diseases and their future outlook.}, }
@article {pmid36144449, year = {2022}, author = {Reddy, VP and Aryal, P and Darkwah, EK}, title = {Advanced Glycation End Products in Health and Disease.}, journal = {Microorganisms}, volume = {10}, number = {9}, pages = {}, pmid = {36144449}, issn = {2076-2607}, abstract = {Advanced glycation end products (AGEs), formed through the nonenzymatic reaction of reducing sugars with the side-chain amino groups of lysine or arginine of proteins, followed by further glycoxidation reactions under oxidative stress conditions, are involved in the onset and exacerbation of a variety of diseases, including diabetes, atherosclerosis, and Alzheimer's disease (AD) as well as in the secondary stages of traumatic brain injury (TBI). AGEs, in the form of intra- and interprotein crosslinks, deactivate various enzymes, exacerbating disease progression. The interactions of AGEs with the receptors for the AGEs (RAGE) also result in further downstream inflammatory cascade events. The overexpression of RAGE and the AGE-RAGE interactions are especially involved in cases of Alzheimer's disease and other neurodegenerative diseases, including TBI and amyotrophic lateral sclerosis (ALS). Maillard reactions are also observed in the gut bacterial species. The protein aggregates found in the bacterial species resemble those of AD and Parkinson's disease (PD), and AGE inhibitors increase the life span of the bacteria. Dietary AGEs alter the gut microbiota composition and elevate plasma glycosylation, thereby leading to systemic proinflammatory effects and endothelial dysfunction. There is emerging interest in developing AGE inhibitor and AGE breaker compounds to treat AGE-mediated pathologies, including diabetes and neurodegenerative diseases. Gut-microbiota-derived enzymes may also function as AGE-breaker biocatalysts. Thus, AGEs have a prominent role in the pathogenesis of various diseases, and the AGE inhibitor and AGE breaker approach may lead to novel therapeutic candidates.}, }
@article {pmid36144268, year = {2022}, author = {Lanznaster, D and Dingeo, G and Samey, RA and Emond, P and Blasco, H}, title = {Metabolomics as a Crucial Tool to Develop New Therapeutic Strategies for Neurodegenerative Diseases.}, journal = {Metabolites}, volume = {12}, number = {9}, pages = {}, pmid = {36144268}, issn = {2218-1989}, support = {SLAMAIT//ARD CVL/ ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS), share common pathological mechanisms, including metabolism alterations. However, their specific neuronal cell types affected and molecular biomarkers suggest that there are both common and specific alterations regarding metabolite levels. In this review, we were interested in identifying metabolite alterations that have been reported in preclinical models of NDs and that have also been documented as altered in NDs patients. Such alterations could represent interesting targets for the development of targeted therapy. Importantly, the translation of such findings from preclinical to clinical studies is primordial for the study of possible therapeutic agents. We found that N-acetyl-aspartate (NAA), myo-inositol, and glutamate are commonly altered in the three NDs investigated here. We also found other metabolites commonly altered in both AD and PD. In this review, we discuss the studies reporting such alterations and the possible pathological mechanism underlying them. Finally, we discuss clinical trials that have attempted to develop treatments targeting such alterations. We conclude that the treatment combination of both common and differential alterations would increase the chances of patients having access to efficient treatments for each ND.}, }
@article {pmid36143200, year = {2022}, author = {McCluskey, G and Donaghy, C and Morrison, KE and McConville, J and Duddy, W and Duguez, S}, title = {The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases.}, journal = {Journal of personalized medicine}, volume = {12}, number = {9}, pages = {}, pmid = {36143200}, issn = {2075-4426}, support = {Clinical Research Fellowship//Association of British Neurologists/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to neurodegeneration. Several lipid markers have been shown to predict prognosis in ALS. Sphingolipids are complex lipids enriched in the central nervous system and are integral to key cellular functions including membrane stability and signalling pathways, as well as being mediators of neuroinflammation and neurodegeneration. This review highlights the metabolism of sphingomyelin (SM), the most abundant sphingolipid, and of its metabolite ceramide, and its role in the pathophysiology of neurodegeneration, focusing on MNDs. We also review published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12 demonstrated upregulation of multiple SM species and 6 demonstrated upregulation of ceramides. SM species also correlated with markers of clinical progression in five of six studies. These data highlight the potential use of SM and ceramide as biomarkers in ALS. Finally, we review potential therapeutic strategies for targeting sphingolipid metabolism in neurodegeneration.}, }
@article {pmid36140184, year = {2022}, author = {Proaño, B and Casani-Cubel, J and Benlloch, M and Rodriguez-Mateos, A and Navarro-Illana, E and Lajara-Romance, JM and de la Rubia Ortí, JE}, title = {Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?.}, journal = {Biomedicines}, volume = {10}, number = {9}, pages = {}, pmid = {36140184}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently no medical cure, and riluzole and edaravone are the only two known approved drugs for treating this condition. However, they have limited efficacy, and hence there is a need to find new molecules. Dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase (5AR) enzymes, the therapeutic purposes of which, to date, are the treatment of benign prostatic hyperplasia and androgenic alopecia, shows great anti-ALS properties by the molecular-topology methodology. Based on this evidence, this review aims to assess the effects of dutasteride on testosterone (T), progesterone (PROG) and 17β-estradiol (17BE) as a therapeutic alternative for the clinical improvement of ALS, based on the hormonal, metabolic and molecular pathways related to the pathogenesis of the disease. According to the evidence found, dutasteride shows great neuroprotective, antioxidant and anti-inflammatory effects. It also appears effective against glutamate toxicity, and it is capable of restoring altered dopamine activity (DA). These effects are achieved both directly and through steroid hormones. Therefore, dutasteride seems to be a promising molecule for the treatment of ALS, although clinical studies are required for confirmation.}, }
@article {pmid36138898, year = {2022}, author = {Wilson, E and Lee, JS and Wenzel, D and Faull, C}, title = {The Use of Mechanical Ventilation Support at the End of Life in Motor Neurone Disease/Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {Brain sciences}, volume = {12}, number = {9}, pages = {}, pmid = {36138898}, issn = {2076-3425}, support = {Anne McLaren Fellowship//University of Nottingham/ ; }, abstract = {There has been an increase in the use of mechanical ventilation (MV) in motor neurone disease (MND) to alleviate symptoms related to hypoventilation. Little is known about its use at the end of life, and the withdrawal of MV is a challenging topic. A scoping review was conducted to map the existing evidence of ventilation use at the end of life in MND. The Joanna Briggs Institute methodological framework was used, and a total of 31 documents were included in the data extraction. Boarder themes around place, planning, cause and comments on death were identified. Our findings show that the focus of the literature has been on the process of the withdrawal of ventilation, creating the subthemes of timing and reason for withdrawal, along with ethical, emotional, and practical issues, medications used and the time until death. There is a foundation of evidence to guide the process and discuss the ethical and emotional issues of withdrawing ventilation. However, there remains limited evidence from patient and family member perspectives. Importantly, there is almost no evidence exploring dying with ventilation in place, the active or passive decisions around this process, how the interface might impact the dying process, or what families think about this.}, }
@article {pmid36135369, year = {2022}, author = {Hegde, KN and Srivastava, A}, title = {Drosophila melanogaster as a Tool for Amyotrophic Lateral Sclerosis Research.}, journal = {Journal of developmental biology}, volume = {10}, number = {3}, pages = {}, pmid = {36135369}, issn = {2221-3759}, support = {None//Gatton Academy of Mathematics and Science in Kentucky/ ; }, abstract = {Reliable animal model systems are an integral part of biological research. Ever since Thomas Hunt Morgan won a Nobel Prize for genetic work done using the fruit fly (Drosophila melanogaster) as a model organism, it has played a larger and more important role in genetic research. Drosophila models have long been used to study neurodegenerative diseases and have aided in identifying key disease progression biological pathways. Due to the availability of a vast array of genetic manipulation tools, its relatively short lifespan, and its ability to produce many progenies, D. melanogaster has provided the ability to conduct large-scale genetic screens to elucidate possible genetic and molecular interactions in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's Disease, and Amyotrophic Lateral Sclerosis (ALS). With regards to ALS, many of the gene mutations that have been discovered to be linked to the disease have been modeled in Drosophila to provide a look into a detailed model of pathogenesis. The aim of this review is to summarize key and newer developments in ALS research that have utilized Drosophila and to provide insight into the profound use of Drosophila as a tool for modeling this disease.}, }
@article {pmid36122597, year = {2022}, author = {Parameswari, RP and Lakshmi, T}, title = {Microalgae as a potential therapeutic drug candidate for neurodegenerative diseases.}, journal = {Journal of biotechnology}, volume = {358}, number = {}, pages = {128-139}, doi = {10.1016/j.jbiotec.2022.09.009}, pmid = {36122597}, issn = {1873-4863}, mesh = {Amino Acids, Essential/metabolism ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Anti-Obesity Agents/metabolism ; Antioxidants/metabolism ; Biomass ; Carbon Dioxide/metabolism ; Carotenoids/metabolism ; Humans ; *Microalgae/metabolism ; *Neurodegenerative Diseases/drug therapy ; Nitrogen/metabolism ; Pharmaceutical Preparations/metabolism ; Phosphates ; Polysaccharides/metabolism ; Sterols/metabolism ; }, abstract = {Microalgae are highly photosynthetic unicellular organism that have increased demand in the recent days owing to the presence of valuable cellular metabolites. They are ubiquitous in terrestrial and aquatic habitats, rich in species diversity and are capable of generating significant biomass by efficiently using CO2, light and other nutrients like nitrogen, phosphate etc., The microalgal biomass has upsurged in economic potential and is used as both food and feed in many countries across the world, accounting for more than 75 % of annual microalgal biomass production in the past decades. The microalgal cells are sustainable resource that synthesize various secondary metabolites such as carotenoids, polysaccharides, polyphenols, essential amino acids, sterols, and polyunsaturated fatty acids (PUFA). Microalgae and its derived compounds possess significant pharmacological and biological effects such as antioxidant, anti-inflammatory, anti-cancer, immunomodulatory and anti-obesity. Because of their potential health promoting properties, the utilization of microalgae and its derived substances in food, pharmaceutical and cosmetic industries has skyrocketed in recent years. In this context, the current review discusses about the benefits of microalgae and its bioactive compounds against several neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid36121612, year = {2022}, author = {Johnson, SA and Fang, T and De Marchi, F and Neel, D and Van Weehaeghe, D and Berry, JD and Paganoni, S}, title = {Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents.}, journal = {Drugs}, volume = {82}, number = {13}, pages = {1367-1388}, pmid = {36121612}, issn = {1179-1950}, support = {T32 GM007753/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; *Biological Products/therapeutic use ; Clinical Trials as Topic ; Disease Progression ; Edaravone/therapeutic use ; Humans ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder involving loss of upper and lower motor neurons, with most cases ending in death within 3-5 years of onset. Several molecular and cellular pathways have been identified to cause ALS; however, treatments to stop or reverse disease progression are yet to be found. Riluzole, a neuroprotective agent offering only a modest survival benefit, has long been the sole disease-modifying therapy for ALS. Edaravone, which demonstrated statistically significant slowing of ALS disease progression, is gaining approval in an increasing number of countries since its first approval in 2015. Sodium phenylbutyrate and taurursodiol (PB-TURSO) was conditionally approved in Canada in 2022, having shown significant slowing of disease progression and prolonged survival. Most clinical trials have focused on testing small molecules affecting common cellular pathways in ALS: targeting glutamatergic, apoptotic, inflammatory, and oxidative stress mechanisms among others. More recently, clinical trials utilizing stem cell transplantation and other biologics have emerged. This rich and ever-growing pipeline of investigational products, along with innovative clinical trial designs, collaborative trial networks, and an engaged ALS community', provide renewed hope to finding a cure for ALS. This article reviews existing ALS therapies and the current clinical drug development pipeline.}, }
@article {pmid36121037, year = {2024}, author = {Calvo, PM and Hernández, RG and Pastor, AM and de la Cruz, RR}, title = {VEGF and Neuronal Survival.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {30}, number = {1}, pages = {71-86}, doi = {10.1177/10738584221120803}, pmid = {36121037}, issn = {1089-4098}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Motor Neurons/metabolism ; Vascular Endothelial Growth Factors/metabolism ; Disease Models, Animal ; }, abstract = {Vascular endothelial growth factor (VEGF) is well known for its angiogenic activity, but recent evidence has revealed a neuroprotective action of this factor on injured or diseased neurons. In the present review, we summarize the most relevant findings that have contributed to establish a link between VEGF deficiency and neuronal degeneration. At issue, 1) mutant mice with reduced levels of VEGF show adult-onset muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis (ALS), 2) administration of VEGF to different animal models of motoneuron degeneration improves motor performance and ameliorates motoneuronal degeneration, and 3) there is an association between low plasmatic levels of VEGF and human ALS. Altogether, the results presented in this review highlight VEGF as an essential motoneuron neurotrophic factor endowed with promising therapeutic potential for the treatment of motoneuron disorders.}, }
@article {pmid36116464, year = {2022}, author = {Feldman, EL and Goutman, SA and Petri, S and Mazzini, L and Savelieff, MG and Shaw, PJ and Sobue, G}, title = {Amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {400}, number = {10360}, pages = {1363-1380}, pmid = {36116464}, issn = {1474-547X}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers ; Forecasting ; Humans ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis is a fatal CNS neurodegenerative disease. Despite intensive research, current management of amyotrophic lateral sclerosis remains suboptimal from diagnosis to prognosis. Recognition of the phenotypic heterogeneity of amyotrophic lateral sclerosis, global CNS dysfunction, genetic architecture, and development of novel diagnostic criteria is clarifying the spectrum of clinical presentation and facilitating diagnosis. Insights into the pathophysiology of amyotrophic lateral sclerosis, identification of disease biomarkers and modifiable risks, along with new predictive models, scales, and scoring systems, and a clinical trial pipeline of mechanism-based therapies, are changing the prognostic landscape. Although most recent advances have yet to translate into patient benefit, the idea of amyotrophic lateral sclerosis as a complex syndrome is already having tangible effects in the clinic. This Seminar will outline these insights and discuss the status of the management of amyotrophic lateral sclerosis for the general neurologist, along with future prospects that could improve care and outcomes for patients with amyotrophic lateral sclerosis.}, }
@article {pmid36113750, year = {2022}, author = {Gurfinkel, Y and Polain, N and Sonar, K and Nice, P and Mancera, RL and Rea, SL}, title = {Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {174}, number = {}, pages = {105859}, doi = {10.1016/j.nbd.2022.105859}, pmid = {36113750}, issn = {1095-953X}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Lobar Degeneration/genetics/pathology ; Mutation, Missense ; *Frontotemporal Dementia/genetics ; Mutation ; Protein Serine-Threonine Kinases/genetics ; }, abstract = {Mutations in the Tank-binding kinase 1 (TBK1) gene were identified in 2015 in individuals with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). They account for ∼3-4% of cases. To date, over 100 distinct mutations, including missense, nonsense, deletion, insertion, duplication, and splice-site mutations have been reported. While nonsense mutations are predicted to cause disease via haploinsufficiency, the mechanisms underlying disease pathogenesis with missense mutations is not fully elucidated. TBK1 is a kinase involved in neuroinflammation, which is commonly observed in these diseases. TBK1 also phosphorylates key autophagy mediators, thereby regulating proteostasis, a pathway that is dysregulated in ALS-FTLD. Recently, several groups have characterised various missense mutations with respect to their effects on the phosphorylation of known TBK1 substrates, TBK1 homodimerization, interaction with optineurin, and the regulation of autophagy and neuroinflammatory pathways. Further, the effects of either global or conditional heterozygous knock-out of Tbk1, or the heterozygous or homozygous knock-in of ALS-FTLD associated mutations, alone or when crossed with the SOD1[G93A] classical ALS mouse model or a TDP-43 mouse model, have been reported. In this review we summarise the known functional effects of TBK1 missense mutations. We also present novel modelling data that predicts the structural effects of missense mutations and discuss how they correlate with the known functional effects of these mutations.}, }
@article {pmid36111770, year = {2023}, author = {Dhasmana, S and Dhasmana, A and Kotnala, S and Mangtani, V and Narula, AS and Haque, S and Jaggi, M and Yallapu, MM and Chauhan, SC}, title = {Boosting Mitochondrial Potential: An Imperative Therapeutic Intervention in Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {21}, number = {5}, pages = {1117-1138}, pmid = {36111770}, issn = {1875-6190}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Mitochondria/metabolism ; Oxidative Stress/physiology ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and terminal neurodegenerative disorder. Mitochondrial dysfunction, imbalance of cellular bioenergetics, electron chain transportation and calcium homeostasis are deeply associated with the progression of this disease. Impaired mitochondrial functions are crucial in rapid neurodegeneration. The mitochondria of ALS patients are associated with deregulated Ca[2+] homeostasis and elevated levels of reactive oxygen species (ROS), leading to oxidative stress. Overload of mitochondrial calcium and ROS production leads to glutamatereceptor mediated neurotoxicity. This implies mitochondria are an attractive therapeutic target.<br><br>OBJECTIVE: The aim of this review is to brief the latest developments in the understanding of mitochondrial pathogenesis in ALS and emphasize the restorative capacity of therapeutic candidates.<br><br>RESULTS: In ALS, mitochondrial dysfunction is a well-known phenomenon. Various therapies targeted towards mitochondrial dysfunction aim at decreasing ROS generation, increasing mitochondrial biogenesis, and inhibiting apoptotic pathways. Some of the therapies briefed in this review may be categorized as synthetic, natural compounds, genetic materials, and cellular therapies.<br><br>CONCLUSION: The overarching goals of mitochondrial therapies in ALS are to benefit ALS patients by slowing down the disease progression and prolonging overall survival. Despite various therapeutic approaches, there are many hurdles in the development of a successful therapy due to the multifaceted nature of mitochondrial dysfunction and ALS progression. Intensive research is required to precisely elucidate the molecular pathways involved in the progression of mitochondrial dysfunctions that ultimately lead to ALS. Because of the multifactorial nature of ALS, a combination therapy approach may hold the key to cure and treat ALS in the future.}, }
@article {pmid36106861, year = {2023}, author = {Li, X and Armon, C and Barkhaus, P and Barnes, B and Benatar, M and Bertorini, T and Bromberg, M and Carter, GT and Crayle, J and Cudkowicz, M and Dimachkie, M and Feldman, EL and Glass, J and Goslinga, J and Heiman-Patterson, T and Jhooty, S and Lichtenstein, R and Lund, I and Mcdermott, C and Pattee, G and Pierce, K and Ratner, D and Salmon, K and Wicks, P and Bedlack, R}, title = {ALSUntangled #67: rituximab.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {544-547}, doi = {10.1080/21678421.2022.2122845}, pmid = {36106861}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Off-Label Use ; *Rituximab/therapeutic use ; }, abstract = {ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS who ask about them. Here we review rituximab, a drug which specifically depletes B lymphocytes. We show a current lack of evidence for a role of these cells in ALS progression. The one patient we found who described using Rituximab for their ALS found no benefit. Given all this, and the known serious risks of rituximab, we advise against its use as an ALS treatment.}, }
@article {pmid36105357, year = {2022}, author = {Amorós, MA and Choi, ES and Cofré, AR and Dokholyan, NV and Duzzioni, M}, title = {Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {962881}, pmid = {36105357}, issn = {2296-634X}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; }, abstract = {The development of cell culture models that recapitulate the etiology and features of nervous system diseases is central to the discovery of new drugs and their translation onto therapies. Neuronal tissues are inaccessible due to skeletal constraints and the invasiveness of the procedure to obtain them. Thus, the emergence of induced pluripotent stem cell (iPSC) technology offers the opportunity to model different neuronal pathologies. Our focus centers on iPSCs derived from amyotrophic lateral sclerosis (ALS) patients, whose pathology remains in urgent need of new drugs and treatment. In this sense, we aim to revise the process to obtain motor neurons derived iPSCs (iPSC-MNs) from patients with ALS as a drug screening model, review current 3D-models and offer a perspective on bioinformatics as a powerful tool that can aid in the progress of finding new pharmacological treatments.}, }
@article {pmid36101390, year = {2022}, author = {Girdhar, A and Guo, L}, title = {Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.}, journal = {Biology}, volume = {11}, number = {7}, pages = {}, pmid = {36101390}, issn = {2079-7737}, support = {Developing Therapeutic Agents to Rescue Neurotoxicity of FUS Aberrant Phase Transition//Dr. Ralph and Marian Falk Medical Research Trust/ ; RF1 NS121143/NS/NINDS NIH HHS/United States ; Develop Protein Disagregase and RNA Oligonucleotides to Mitigate Aberrant Phase Transition of FUS//Frick Foundation for ALS Research/ ; R35GM138109/GM/NIGMS NIH HHS/United States ; RF1NS121143/NS/NINDS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, abstract = {RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major event observed in ageing and in neurodegenerative disorders. Nuclear import receptors (NIRs) regulate the nucleocytoplasmic transport of different RBPs bearing a nuclear localization signal by restoring their nuclear localization. NIRs can also specifically dissolve or prevent the aggregation and liquid-liquid phase separation of wild-type or disease-linked mutant RBPs, due to their chaperoning activity. This review focuses on the LLPS of intrinsically disordered proteins and the role of NIRs in regulating LLPS in neurodegeneration. This review also discusses the implication of NIRs as therapeutic agents in neurogenerative diseases.}, }
@article {pmid36100788, year = {2022}, author = {Singh, S and Hema,  and Sharma, N and Sachdeva, M and Behl, T and Zahoor, I and Fuloria, NK and Sekar, M and Fuloria, S and Subramaniyan, V and Alsubayiel, AM and Dailah, HG and Naved, T and Bhatia, S and Al-Harrasi, A and Aleya, L}, title = {Focusing the pivotal role of nanotechnology in Huntington's disease: an insight into the recent advancements.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {49}, pages = {73809-73827}, pmid = {36100788}, issn = {1614-7499}, mesh = {Glutamine ; Humans ; *Huntington Disease/genetics/metabolism/pathology ; Liposomes ; Nanoparticles ; Nanotechnology ; }, abstract = {Neurodegeneration is the loss of neuronal capacity and structure over time which causes neurodegenerative disorders like Alzheimer, amyotrophic lateral sclerosis, Parkinson, and Huntington's disease (HD). This review is primarily concerned with HD, which was fully described by George Huntington in 1872. In developed countries, HD has become another common single-gene neurological disorder. Because of its autosomal dominant inheritance, the sickness affects both individuals and their families. Huntington disease has been recognized as a disorder that affects the complete body and brain in which the mutant huntingtin polyglutamine (polyQ) sequence is extensively increased and gets correlated to CAG trinucleotide which codes for glutamine (Q). These proteins have characteristics that produce apoptosis and dysfunction. HD is a lethal condition which needs an immediate diagnosis and treatment, and therefore, nanoparticle has come into sight out as opportunistic strategies for treatment of HD. Nanostructures have great potential to cross the blood brain barrier and also prevent breakdown of active molecule and reduces the drug toxicity. This review explains the distinguishing symptoms, genetics, and stages during the development of Huntington's disease, and also provides an overview of HD with an emphasis on its epidemiology, pathogenesis, and management. This review focuses on the latest studies on nanotechnology-related technologies, i.e., magnetic nanoparticle, solid lipid nanoparticle, and polymeric nanoparticle for Huntington's disease treatment. The pioneering patents and in-progress clinical trials related to Huntington's disease has also been summarized in this review.}, }
@article {pmid36100191, year = {2022}, author = {Pallier, PN and Ferrara, M and Romagnolo, F and Ferretti, MT and Soreq, H and Cerase, A}, title = {Chromosomal and environmental contributions to sex differences in the vulnerability to neurological and neuropsychiatric disorders: Implications for therapeutic interventions.}, journal = {Progress in neurobiology}, volume = {219}, number = {}, pages = {102353}, doi = {10.1016/j.pneurobio.2022.102353}, pmid = {36100191}, issn = {1873-5118}, mesh = {Animals ; Female ; Male ; Sex Factors ; Sex Characteristics ; *Schizophrenia ; *Brain Diseases ; *Autism Spectrum Disorder ; }, abstract = {Neurological and neuropsychiatric disorders affect men and women differently. Multiple sclerosis, Alzheimer's disease, anxiety disorders, depression, meningiomas and late-onset schizophrenia affect women more frequently than men. By contrast, Parkinson's disease, autism spectrum condition, attention-deficit hyperactivity disorder, Tourette's syndrome, amyotrophic lateral sclerosis and early-onset schizophrenia are more prevalent in men. Women have been historically under-recruited or excluded from clinical trials, and most basic research uses male rodent cells or animals as disease models, rarely studying both sexes and factoring sex as a potential source of variation, resulting in a poor understanding of the underlying biological reasons for sex and gender differences in the development of such diseases. Putative pathophysiological contributors include hormones and epigenetics regulators but additional biological and non-biological influences may be at play. We review here the evidence for the underpinning role of the sex chromosome complement, X chromosome inactivation, and environmental and epigenetic regulators in sex differences in the vulnerability to brain disease. We conclude that there is a pressing need for a better understanding of the genetic, epigenetic and environmental mechanisms sustaining sex differences in such diseases, which is critical for developing a precision medicine approach based on sex-tailored prevention and treatment.}, }
@article {pmid36080253, year = {2022}, author = {Skrzypczak-Wiercioch, A and Sałat, K}, title = {Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {17}, pages = {}, pmid = {36080253}, issn = {1420-3049}, support = {N42/DBS/000290//Jagiellonian University/ ; DEC-2021/43/I/NZ7/00342//National Science Center/ ; }, mesh = {Cytokines ; Humans ; Inflammation/pathology ; *Lipopolysaccharides/adverse effects ; Microglia/pathology ; *Neuroinflammatory Diseases ; }, abstract = {Despite advances in antimicrobial and anti-inflammatory therapies, inflammation and its consequences still remain a significant problem in medicine. Acute inflammatory responses are responsible for directly life-threating conditions such as septic shock; on the other hand, chronic inflammation can cause degeneration of body tissues leading to severe impairment of their function. Neuroinflammation is defined as an inflammatory response in the central nervous system involving microglia, astrocytes, and cytokines including chemokines. It is considered an important cause of neurodegerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Lipopolysaccharide (LPS) is a strong immunogenic particle present in the outer membrane of Gram-negative bacteria. It is a major triggering factor for the inflammatory cascade in response to a Gram-negative bacteria infection. The use of LPS as a strong pro-inflammatory agent is a well-known model of inflammation applied in both in vivo and in vitro studies. This review offers a summary of the pathogenesis associated with LPS exposure, especially in the field of neuroinflammation. Moreover, we analyzed different in vivo LPS models utilized in the area of neuroscience. This paper presents recent knowledge and is focused on new insights in the LPS experimental model.}, }
@article {pmid36076972, year = {2022}, author = {Diz-Chaves, Y and Mastoor, Z and Spuch, C and González-Matías, LC and Mallo, F}, title = {Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {17}, pages = {}, pmid = {36076972}, issn = {1422-0067}, support = {H2020-BBIJTI- 2019-887259//European Union/ ; }, mesh = {Brain/*metabolism ; Glucagon-Like Peptide 1/metabolism ; *Glucagon-Like Peptide-1 Receptor/metabolism ; Humans ; Inflammation/drug therapy ; Neurodegenerative Diseases/drug therapy/*metabolism ; }, abstract = {The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain and displays a critical role in neuroprotection and inflammation by activating the GLP-1 receptor signaling pathways. Several studies in vivo and in vitro using preclinical models of neurodegenerative diseases show that GLP-1R activation has anti-inflammatory properties. This review explores the molecular mechanistic action of GLP-1 RAS in relation to inflammation in the brain. These findings update our knowledge of the potential benefits of GLP-1RAS actions in reducing the inflammatory response. These molecules emerge as a potential therapeutic tool in treating neurodegenerative diseases and neuroinflammatory pathologies.}, }
@article {pmid36076537, year = {2022}, author = {Wang, Q and Lu, M and Zhu, X and Gu, X and Zhang, T and Xia, C and Yang, L and Xu, Y and Zhou, M}, title = {The role of microglia immunometabolism in neurodegeneration: Focus on molecular determinants and metabolic intermediates of metabolic reprogramming.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {153}, number = {}, pages = {113412}, doi = {10.1016/j.biopha.2022.113412}, pmid = {36076537}, issn = {1950-6007}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Macrophages ; Microglia/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Microglia, resident macrophages that act as the brain's innate immune cells, play a key role in initiating a defense response to the infection or neuroinflammation of the host. Once a broad spectrum of dangers is confronted, microglia get triggered and transform their role against immune stimuli. Recent studies have shown that remarkable metabolic changes present in activated microglia affect their immune function. Given that the important role of microglia in the progression of neurodegeneration is widely recognized, it is crucial to know whether metabolic reprogramming of microglia also presents in neurodegeneration and how this may influence their role in neurodegeneration progression. This paper provides an overview of the metabolic reprogramming of microglia, the major pathways involved in recent advances in five major neurodegenerative diseases of aging (NDAs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), etc. And then we elucidated their impacts on the disease progression of neurodegeneration. Furthermore, growing evidence suggests that microbiota-derived metabolites, including acetate, N[6]-carboxymethyllysine (CML), and isoamylamine (IAA), regulate metabolic pathways and functions of microglia, and play a crucial role in cellular homeostasis. We shed light on this topic and concluded these metabolites are potential therapeutic targets for NDAs.}, }
@article {pmid36076353, year = {2022}, author = {J Paul, D and Wright, M and M Palmer, J and B Russell, T}, title = {Perioperative management of patients with amyotrophic lateral sclerosis: A narrative review.}, journal = {Anaesthesia and intensive care}, volume = {50}, number = {5}, pages = {345-360}, doi = {10.1177/0310057X211065042}, pmid = {36076353}, issn = {0310-057X}, mesh = {*Amyotrophic Lateral Sclerosis/surgery ; Humans ; *Perioperative Care ; }, abstract = {Amyotrophic lateral sclerosis, or motor neuron disease, is an uncommon progressive neurological disorder. Professionals working in the perioperative field may encounter patients with amyotrophic lateral sclerosis only rarely. The relevant published literature on amyotrophic lateral sclerosis is broad in scope, but a contemporary review focused on the perioperative period is absent. This structured narrative review seeks to provide a summary of the contemporary management of patients and then focuses on eliciting if there are perioperative management considerations specific to amyotrophic lateral sclerosis that can be optimised. A comprehensive structured narrative literature review, including grey literature searching, indicated worsening ventilatory failure is of prime concern but that patients may present with a broad range of neurological symptoms, and that cardiovascular and cognitive dysfunction specific to amyotrophic lateral sclerosis may exist and be occult. Exacerbation of neuromuscular weakness during the perioperative period is multifaceted and requires the application of a high standard of the core principles of surgical and anaesthetic management of neuromuscular disease. Standard perioperative approaches require rigorous attention and potential exists for significant alteration. There is a potential high risk of postoperative increased morbidity from neurological decline and mortality from pulmonary complications. A meticulous approach to planning preoperative assessment, shared decision-making, intraoperative and postoperative care is required.}, }
@article {pmid36070178, year = {2022}, author = {Spead, O and Zaepfel, BL and Rothstein, JD}, title = {Nuclear Pore Dysfunction in Neurodegeneration.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1050-1060}, pmid = {36070178}, issn = {1878-7479}, mesh = {Humans ; *Nuclear Pore/metabolism ; Active Transport, Cell Nucleus/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; Cytoplasm/metabolism ; Cell Nucleus/metabolism ; }, abstract = {The nuclear pore complex (NPC) is a large multimeric structure that is interspersed throughout the membrane of the nucleus and consists of at least 33 protein components. Individual components cooperate within the nuclear pore to facilitate selective passage of materials between the nucleus and cytoplasm while simultaneously performing pore-independent roles throughout the cell. NPC dysfunction is a hallmark of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). NPC components can become mislocalized or altered in expression in neurodegeneration. These alterations in NPC structure are often detrimental to the neuronal function and ultimately lead to neuronal loss. This review highlights the importance of nucleocytoplasmic transport and NPC integrity and how dysfunction of such may contribute to neurodegeneration.}, }
@article {pmid36070155, year = {2023}, author = {Mercer, RCC and Harris, DA}, title = {Mechanisms of prion-induced toxicity.}, journal = {Cell and tissue research}, volume = {392}, number = {1}, pages = {81-96}, pmid = {36070155}, issn = {1432-0878}, support = {R01 NS065244/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Prions/metabolism ; *Prion Diseases/metabolism/pathology ; Prion Proteins ; *Neurodegenerative Diseases ; *Alzheimer Disease ; }, abstract = {Prion diseases are devastating neurodegenerative diseases caused by the structural conversion of the normally benign prion protein (PrP[C]) to an infectious, disease-associated, conformer, PrP[Sc]. After decades of intense research, much is known about the self-templated prion conversion process, a phenomenon which is now understood to be operative in other more common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide the current state of knowledge concerning a relatively poorly understood aspect of prion diseases: mechanisms of neurotoxicity. We provide an overview of proposed functions of PrP[C] and its interactions with other extracellular proteins in the central nervous system, in vivo and in vitro models used to delineate signaling events downstream of prion propagation, the application of omics technologies, and the emerging appreciation of the role played by non-neuronal cell types in pathogenesis.}, }
@article {pmid36069419, year = {2022}, author = {Del Tredici, K and Braak, H}, title = {Neuropathology and neuroanatomy of TDP-43 amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {660-671}, doi = {10.1097/WCO.0000000000001098}, pmid = {36069419}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Inclusion Bodies/metabolism/pathology ; Neuroanatomy ; }, abstract = {PURPOSE OF REVIEW: Intracellular inclusions consisting of the abnormal TDP-43 protein and its nucleocytoplasmic mislocalization in selected cell types are hallmark pathological features of sALS. Descriptive (histological, morphological), anatomical, and molecular studies all have improved our understanding of the neuropathology of sporadic amyotrophic lateral sclerosis (sALS). This review highlights some of the latest developments in the field.<br><br>RECENT FINDINGS: Increasing evidence exists from experimental models for the prion-like nature of abnormal TDP-43, including a strain-effect, and with the help of neuroimaging-based studies, for spreading of disease along corticofugal connectivities in sALS. Progress has also been made with respect to finding and establishing reliable biomarkers (neurofilament levels, diffusor tensor imaging).<br><br>SUMMARY: The latest findings may help to elucidate the preclinical phase of sALS and to define possible mechanisms for delaying or halting disease development and progression.}, }
@article {pmid36068427, year = {2022}, author = {Meijboom, KE and Brown, RH}, title = {Approaches to Gene Modulation Therapy for ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1159-1179}, pmid = {36068427}, issn = {1878-7479}, support = {R01 NS111990/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Oligonucleotides, Antisense/genetics/therapeutic use ; *MicroRNAs ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease mechanisms and genetics in combination with innovations in gene modulation strategies creates promising new options for the development of ALS therapies. In recent years, six gene modulation therapies have been tested in ALS patients. These target gain-of-function pathology of the most common ALS genes, SOD1, C9ORF72, FUS, and ATXN2, using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs). Here, we review the latest clinical and preclinical advances in gene modulation approaches for ALS, including gene silencing, gene correction, and gene augmentation. These techniques have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease.}, }
@article {pmid36066832, year = {2022}, author = {Durand, J and Filipchuk, A}, title = {Electrical and Morphological Properties of Developing Motoneurons in Postnatal Mice and Early Abnormalities in SOD1 Transgenic Mice.}, journal = {Advances in neurobiology}, volume = {28}, number = {}, pages = {353-373}, pmid = {36066832}, issn = {2190-5215}, mesh = {Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Motor Neurons ; *Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {In this chapter, we review electrical and morphological properties of lumbar motoneurons during postnatal development in wild-type (WT) and transgenic superoxide dismutase 1 (SOD1) mice, models of amyotrophic lateral sclerosis. First we showed that sensorimotor reflexes do not develop normally in transgenic SOD1[G85R] pups. Fictive locomotor activity recorded in in vitro whole brainstem/spinal cord preparations was not induced in these transgenic SOD1[G85R] mice using NMDA and 5HT in contrast to WT mice. Further, abnormal electrical properties were detected as early as the second postnatal week in lumbar motoneurons of SOD1 mice while they develop clinical symptoms several months after birth. We compared two different strains of mice (G85R and G93A) at the same postnatal period using intracellular recordings and patch clamp recordings of WT and SOD1 motoneurons. We defined three types of motoneurons according to their discharge firing pattern (transient, sustained and delayed onset firing) when motor units are not yet mature. The delayed-onset firing motoneurons had the higher rheobase compared to the transient and sustained firing groups in the WT mice. We demonstrated hypoexcitability in the delayed onset-firing motoneurons of SOD1 mice. Intracellular staining of motoneurons revealed dendritic overbranching in SOD1 lumbar motoneurons that was more pronounced in the sustained firing motoneurons. We suggested that motoneuronal hypoexcitability is an early pathological sign affecting a subset of lumbar motoneurons in the spinal cord of SOD1 mice.}, }
@article {pmid36062310, year = {2024}, author = {Rayner, SL and Hogan, A and Davidson, JM and Cheng, F and Luu, L and Morsch, M and Blair, I and Chung, R and Lee, A}, title = {Cyclin F, Neurodegeneration, and the Pathogenesis of ALS/FTD.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {30}, number = {2}, pages = {214-228}, doi = {10.1177/10738584221120182}, pmid = {36062310}, issn = {1089-4098}, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cyclins/genetics/metabolism ; Motor Neurons/metabolism ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease and is characterized by the degeneration of upper and lower motor neurons of the brain and spinal cord. ALS is also linked clinically, genetically, and pathologically to a form of dementia known as frontotemporal dementia (FTD). Identifying gene mutations that cause ALS/FTD has provided valuable insight into the disease process. Several ALS/FTD-causing mutations occur within proteins with roles in protein clearance systems. This includes ALS/FTD mutations in CCNF, which encodes the protein cyclin F: a component of a multiprotein E3 ubiquitin ligase that mediates the ubiquitylation of substrates for their timely degradation. In this review, we provide an update on the link between ALS/FTD CCNF mutations and neurodegeneration.}, }
@article {pmid36062302, year = {2022}, author = {Chen, Y and Wang, W and Wang, J and Chen, X and Zhu, Z and Li, J and He, M}, title = {Normal range of ocular biometry in healthy children: A systemic review and meta-analysis of 33,559 individuals under seven years of age.}, journal = {Ophthalmic &amp; physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists)}, volume = {42}, number = {6}, pages = {1264-1275}, doi = {10.1111/opo.13043}, pmid = {36062302}, issn = {1475-1313}, mesh = {*Anterior Chamber/diagnostic imaging ; Anterior Eye Segment/diagnostic imaging ; Axial Length, Eye/anatomy &amp; histology ; Biometry ; Child ; Child, Preschool ; *Cornea/anatomy &amp; histology ; Humans ; Infant, Newborn ; Reference Values ; Refraction, Ocular ; }, abstract = {PURPOSE: To conduct a systemic review and meta-analysis on the normative range of ocular biometry in healthy children under seven years of age.<br><br>METHODS: A literature search was performed using the PubMed (MEDLINE) database. The main outcomes were normative values of axial length (AL), central corneal thickness (CCT), cornea curvature (CC), anterior chamber depth (ACD), lens thickness (LT) and vitreous chamber depth (VCD). Pooled estimates were obtained with a random-effects meta-analysis. Multivariate meta-regressions ascertained the moderator-related trends.<br><br>RESULTS: We included 47 studies for a total of 33,559 subjects. The pooled ALs for 0.0-1.9&#x2009;years, 2.0-3.9&#x2009;years and 4.0-6.9&#x2009;years were 18.33&#x2009;mm (95% confidence interval [CI] 17.57-19.09), 21.71&#x2009;mm (21.49-21.93) and 22.37&#x2009;mm (22.29-22.45), respectively. Children aged 0.0-1.9&#x2009;years had a greater CCT (576.70&#x2009;&#x3bc;m, 567.20-586.21), steeper cornea (7.41&#x2009;mm, 7.16-7.65) and shallower ACD (2.46&#x2009;mm, 2.23-2.69). LT ranged from 3.65 to 3.74&#x2009;mm for 0-6&#x2009;years, and VCD increased from 11.94&#x2009;mm at birth to 15.36&#x2009;mm at 4.0-6.9&#x2009;years. Differences in AL between East Asian and non-East Asian children were found below two years of age (17.30&#x2009;mm vs. 18.40&#x2009;mm, p&#xa0;=&#x2009;0.008) and for CC at 4.0-6.9&#x2009;years of age (7.82&#x2009;mm vs. 7.79&#x2009;mm, p&#xa0;=&#x2009;0.004). In a multivariate meta-regression, AL, CC, ACD and VCD increased with age (p&#xa0;<&#x2009;0.05 for all), while CCT decreased with age (p&#xa0;=&#x2009;0.0007).<br><br>CONCLUSIONS: This study reports normative data for ocular biometry in children. Few differences were found with ethnicity in the ocular biometry of infants and pre-schoolers.}, }
@article {pmid36061999, year = {2022}, author = {Juengling, FD and Wuest, F and Kalra, S and Agosta, F and Schirrmacher, R and Thiel, A and Thaiss, W and Müller, HP and Kassubek, J}, title = {Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease-A clinico-radiological and neuroscientific perspective.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {890425}, pmid = {36061999}, issn = {1664-2295}, abstract = {Neuroimaging assessment of motor neuron disease has turned into a cornerstone of its clinical workup. Amyotrophic lateral sclerosis (ALS), as a paradigmatic motor neuron disease, has been extensively studied by advanced neuroimaging methods, including molecular imaging by MRI and PET, furthering finer and more specific details of the cascade of ALS neurodegeneration and symptoms, facilitated by multicentric studies implementing novel methodologies. With an increase in multimodal neuroimaging data on ALS and an exponential improvement in neuroimaging technology, the need for harmonization of protocols and integration of their respective findings into a consistent model becomes mandatory. Integration of multimodal data into a model of a continuing cascade of functional loss also calls for the best attempt to correlate the different molecular imaging measurements as performed at the shortest inter-modality time intervals possible. As outlined in this perspective article, simultaneous PET/MRI, nowadays available at many neuroimaging research sites, offers the perspective of a one-stop shop for reproducible imaging biomarkers on neuronal damage and has the potential to become the new gold standard for characterizing motor neuron disease from the clinico-radiological and neuroscientific perspectives.}, }
@article {pmid36061599, year = {2022}, author = {Jiang, T and Wang, Y and Wang, X and Xu, J}, title = {CHCHD2 and CHCHD10: Future therapeutic targets in cognitive disorder and motor neuron disorder.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {988265}, pmid = {36061599}, issn = {1662-4548}, abstract = {CHCHD2 and CHCHD10 are homolog mitochondrial proteins that play key roles in the neurological, cardiovascular, and reproductive systems. They are also involved in the mitochondrial metabolic process. Although previous research has concentrated on their functions within mitochondria, their functions within apoptosis, synaptic plasticity, cell migration as well as lipid metabolism remain to be concluded. The review highlights the different roles played by CHCHD2 and/or CHCHD10 binding to various target proteins (such as OPA-1, OMA-1, PINK, and TDP43) and reveals their non-negligible effects in cognitive impairments and motor neuron diseases. This review focuses on the functions of CHCHD2 and/or CHCHD10. This review reveals protective effects and mechanisms of CHCHD2 and CHCHD10 in neurodegenerative diseases characterized by cognitive and motor deficits, such as frontotemporal dementia (FTD), Lewy body dementia (LBD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). However, there are numerous specific mechanisms that have yet to be elucidated, and additional research into these mechanisms is required.}, }
@article {pmid36060010, year = {2022}, author = {Rauf, A and Rahman, MM}, title = {Potential therapeutics against neurological disorders: Natural products-based drugs.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {950457}, pmid = {36060010}, issn = {1663-9812}, abstract = {Neurodegenerative disorders, which are defined by the breakdown of neurons over time, are affecting an increasing number of people. Stroke, Alzheimer's, Parkinson's, Multiple Sclerosis, Migraine, and Amyotrophic Lateral Sclerosis are just a few examples of brain disorders that have no cure. Besides, there is a huge demand for drugs that can cure the diseases mentioned above because the majority of the medications we use to treat them only alleviate diseases. Different neurological disorders have responded satisfactorily to the pharmacological effects of medicinal plants. Despite the numerous multiple types of plants in the world, only a small number of them have been investigated for neurological disorders. As a result, there are many opportunities in this area for further research on plants and their bioactive chemicals. The search for natural therapeutic alternatives that promote faster healing and adverse effects avoidance has gained popularity in recent years. The aim of this mini-review is to explore some natural products that have strong therapeutic effects on neurodegenerative disorders such as Stroke, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Migraine, Amyotrophic Lateral Sclerosis, and others. We have also shown the safety of natural products to improve their appropriate usage in neurological disorders from recent literature.}, }
@article {pmid36059131, year = {2023}, author = {Shi, W and Tan, C and Liu, C and Chen, D}, title = {Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {34}, number = {3}, pages = {275-294}, pmid = {36059131}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Dynamins/metabolism ; Mitochondrial Dynamics ; Mitochondria/metabolism ; *Alzheimer Disease/metabolism ; Membrane Proteins/metabolism ; Mitochondrial Proteins/metabolism ; }, abstract = {In recent years, the role of mitochondrial dynamics in neurodegenerative diseases has becoming increasingly important. More and more evidences have shown that in pathological conditions, abnormal mitochondrial divisions, especially Drp1-Fis1-mediated divisions, play an important role in the occurrence and development of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, and other neurodegenerative diseases. This review highlights several new mechanisms of physiological fission of mitochondria and the difference/connection of physiological/pathological mitochondrial fission. In addition, we described the relationship between abnormal mitochondrial dynamics and neurodegenerative diseases in detail and emphatically summarized its detection indicators in basic experiments, trying to provide references for further mechanism exploration and therapeutic targets.}, }
@article {pmid36055710, year = {2022}, author = {Dawson, B and McConvey, K and Gofton, TE}, title = {When to initiate palliative care in neurology.}, journal = {Handbook of clinical neurology}, volume = {190}, number = {}, pages = {105-125}, doi = {10.1016/B978-0-323-85029-2.00011-7}, pmid = {36055710}, issn = {0072-9752}, mesh = {Humans ; Medical Oncology ; *Nervous System Diseases/therapy ; *Neurology ; Palliative Care/psychology ; }, abstract = {Life-limiting and life-threatening neurologic conditions often progress slowly. Patients live with a substantial symptom burden over a long period of time, and there is often a high degree of functional and cognitive impairment. Because of this, the most appropriate time to initiate neuropalliative care is often difficult to identify. Further challenges to the incorporation of neuropalliative care include communication barriers, such as profound dysarthria or language impairments, and loss of cognitive function and decision-making capacity that prevent shared decision making and threaten patient autonomy. As a result, earlier initiation of at least some components of palliative care is paramount to ensuring patient-centered care while the patient is still able to communicate effectively and participate as fully as possible in their medical care. For these reasons, neuropalliative care is also distinct from palliative care in oncology, and there is a growing evidence base to guide timely initiation and integration of neuropalliative care. In this chapter, we will focus on when to initiate palliative care in patients with life-limiting, life-threatening, and advanced neurologic conditions. We will address three main questions, which patients with neurologic conditions will benefit from initiation of palliative care, what aspects of neurologic illness are most amenable to neuropalliative care, and when to initiate neuropalliative care?}, }
@article {pmid36053340, year = {2022}, author = {Zago, S and Lorusso, L and Aiello, EN and Ugolini, M and Poletti, B and Ticozzi, N and Silani, V}, title = {Cognitive and behavioral involvement in ALS has been known for more than a century.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {12}, pages = {6741-6760}, pmid = {36053340}, issn = {1590-3478}, mesh = {Humans ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis/genetics ; Neuropsychological Tests ; *Cognitive Dysfunction/complications ; Cognition ; }, abstract = {BACKGROUND: Among clinicians and researchers, it is common knowledge that, in ALS, cognitive and behavioral involvement within the spectrum of frontotemporal degenerations (FTDs) begun to be regarded as a fact in the late 1990s of the twentieth century. By contrast, a considerable body of evidence on cognitive/behavioral changes in ALS can be traced in the literature dating from the late nineteenth century.<br><br>METHODS: Worldwide reports on cognitive/behavioral involvement in ALS dating from 1886 to 1981 were retrieved thanks to Biblioteca di Area Medica "Adolfo Ferrate," Sistema Bibliotecario di Ateneo, University of Pavia, Pavia, Italy and qualitatively synthetized.<br><br>RESULTS: One-hundred and seventy-four cases of ALS with co-occurring FTD-like cognitive/behavioral changes, described in Europe, America, and Asia, were detected. Neuropsychological phenotypes were consistent with the revised Strong et al.'s consensus criteria. Clinical observations were not infrequently supported by histopathological, post-mortem verifications of extra-motor, cortical/sub-cortical alterations, as well as by in vivo instrumental exams-i.e., assessments of brain morphology/physiology and psychometric testing. In this regard, as earlier as 1907, the notion of motor and cognitive/behavioral features in ALS yielding from the same underlying pathology was acknowledged. Hereditary occurrences of ALS with cognitive/behavioral dysfunctions were reported, as well as familial associations with ALS-unrelated brain disorders. Neuropsychological symptoms often occurred before motor ones. Bulbar involvement was at times acknowledged as a risk factor for cognitive/behavioral changes in ALS.<br><br>DISCUSSION: Historical observations herewith delivered can be regarded as the antecedents of current knowledge on cognitive/behavioral impairment in the ALS-FTD spectrum.}, }
@article {pmid36044181, year = {2022}, author = {Sen, T and Thummer, RP}, title = {CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics.}, journal = {Neurotoxicity research}, volume = {40}, number = {5}, pages = {1597-1623}, pmid = {36044181}, issn = {1476-3524}, support = {BT/PR16655/NER/95/132/2015//by North Eastern Region - Biotechnology Programme Management Cell (NERBPMC), Department of Biotechnology, Government of India/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Cell Line ; Gene Editing ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; }, abstract = {Neurodegenerative diseases are prominent causes of pain, suffering, and death worldwide. Traditional approaches modelling neurodegenerative diseases are deficient, and therefore, improved strategies that effectively recapitulate the pathophysiological conditions of neurodegenerative diseases are the need of the hour. The generation of human-induced pluripotent stem cells (iPSCs) has transformed our ability to model neurodegenerative diseases in vitro and provide an unlimited source of cells (including desired neuronal cell types) for cell replacement therapy. Recently, CRISPR/Cas9-based genome editing has also been gaining popularity because of the flexibility they provide to generate and ablate disease phenotypes. In addition, the recent advancements in CRISPR/Cas9 technology enables researchers to seamlessly target and introduce precise modifications in the genomic DNA of different human cell lines, including iPSCs. CRISPR-iPSC-based disease modelling, therefore, allows scientists to recapitulate the pathological aspects of most neurodegenerative processes and investigate the role of pathological gene variants in healthy non-patient cell lines. This review outlines how iPSCs, CRISPR/Cas9, and CRISPR-iPSC-based approaches accelerate research on neurodegenerative diseases and take us closer to a cure for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and so forth.}, }
@article {pmid36043795, year = {2023}, author = {Almikhlafi, MA and Karami, MM and Jana, A and Alqurashi, TM and Majrashi, M and Alghamdi, BS and Ashraf, GM}, title = {Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {21}, number = {5}, pages = {1165-1183}, pmid = {36043795}, issn = {1875-6190}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/genetics ; Mitochondria/metabolism ; *Alzheimer Disease/drug therapy ; DNA, Mitochondrial/genetics/metabolism/therapeutic use ; *Parkinson Disease/metabolism ; }, abstract = {Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or for unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondriatargeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria- directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.}, }
@article {pmid36043794, year = {2022}, author = {Tao, Y and Leng, SX and Zhang, H}, title = {Ketogenic Diet: An Effective Treatment Approach for Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {20}, number = {12}, pages = {2303-2319}, pmid = {36043794}, issn = {1875-6190}, mesh = {Humans ; *Diet, Ketogenic ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease/metabolism ; *Parkinson Disease ; Treatment Outcome ; }, abstract = {This review discusses the effects and mechanisms of a ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, mediumprotein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of the ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of the ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.}, }
@article {pmid36041453, year = {2023}, author = {Olson, KE and Mosley, RL and Gendelman, HE}, title = {The potential for treg-enhancing therapies in nervous system pathologies.}, journal = {Clinical and experimental immunology}, volume = {211}, number = {2}, pages = {108-121}, pmid = {36041453}, issn = {1365-2249}, support = {P01 NS031492/NS/NINDS NIH HHS/United States ; R01 AG043540/AG/NIA NIH HHS/United States ; P01 MH064570/MH/NIMH NIH HHS/United States ; P01 DA028555/DA/NIDA NIH HHS/United States ; P30 MH062261/MH/NIMH NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; R01 NS036126/NS/NINDS NIH HHS/United States ; P20 GM103427/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *T-Lymphocytes, Regulatory ; *Multiple Sclerosis ; Immune Tolerance ; Inflammation/pathology ; }, abstract = {While inflammation may not be the cause of disease, it is well known that it contributes to disease pathogenesis across a multitude of peripheral and central nervous system disorders. Chronic and overactive inflammation due to an effector T-cell-mediated aberrant immune response ultimately leads to tissue damage and neuronal cell death. To counteract peripheral and neuroinflammatory responses, research is being focused on regulatory T cell enhancement as a therapeutic target. Regulatory T cells are an immunosuppressive subpopulation of CD4+ T helper cells essential for maintaining immune homeostasis. The cells play pivotal roles in suppressing immune responses to maintain immune tolerance. In so doing, they control T cell proliferation and pro-inflammatory cytokine production curtailing autoimmunity and inflammation. For nervous system pathologies, Treg are known to affect the onset and tempo of neural injuries. To this end, we review recent findings supporting Treg's role in disease, as well as serving as a therapeutic agent in multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome, Parkinson's and Alzheimer's diseases, and amyotrophic lateral sclerosis. An ever-broader role for Treg in the control of neurologic disease has been shown for traumatic brain injury, stroke, neurotrophic pain, epilepsy, and psychiatric disorders. To such ends, this review serves to examine the role played by Tregs in nervous system diseases with a focus on harnessing their functional therapeutic role(s).}, }
@article {pmid36038019, year = {2022}, author = {Li, SH and Abd-Elrahman, KS and Ferguson, SSG}, title = {Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases.}, journal = {Pharmacology &amp; therapeutics}, volume = {239}, number = {}, pages = {108275}, doi = {10.1016/j.pharmthera.2022.108275}, pmid = {36038019}, issn = {1879-016X}, support = {PJT-148656//CIHR/Canada ; PJT-153317//CIHR/Canada ; PJT-165967//CIHR/Canada ; }, mesh = {Humans ; *Receptors, Metabotropic Glutamate/metabolism ; Presynaptic Terminals/metabolism ; Glutamic Acid/metabolism ; Neurons/metabolism ; }, abstract = {Glutamate is the primary excitatory neurotransmitter in the brain and plays critical roles in all aspects of neuronal function. Disruption of normal glutamate transmission has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. Glutamate exerts its effect through ionotropic and metabotropic glutamate receptors (mGluRs). mGluR2 and mGluR3 are members of the Group II mGluR family and their activation leads to the inhibition of glutamate release from presynaptic nerve terminals and is also poised upstream of a myriad of signaling pathways in postsynaptic nerve terminals and neuroglia. Therefore, mGluR2 and mGluR3 have been considered as potential drug targets for the treatment of many neurological conditions and several compounds targeting these receptors have been developed. In this review, we discuss what is currently known regarding the contribution of mGluR2 and mGluR3 to the pathophysiology of some neurodegenerative and neuropsychiatric diseases including Amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's diseases, schizophrenia and depression as well as drug addiction. We then highlight the evidence supporting the use of various drugs including orthosteric and allosteric ligands acting on either mGluR2, mGluR3 or both for the management of these brain disorders.}, }
@article {pmid36035996, year = {2022}, author = {Gennari, L and Rendina, D and Merlotti, D and Cavati, G and Mingiano, C and Cosso, R and Materozzi, M and Pirrotta, F and Abate, V and Calabrese, M and Falchetti, A}, title = {Update on the pathogenesis and genetics of Paget's disease of bone.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {932065}, pmid = {36035996}, issn = {2296-634X}, abstract = {Studies over the past two decades have led to major advances in the pathogenesis of Paget's disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome "Inclusion Body Myopathy, PDB, Fronto-temporal Dementia," characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades.}, }
@article {pmid36034312, year = {2022}, author = {Levin, LA and Patrick, C and Choudry, NB and Sharif, NA and Goldberg, JL}, title = {Neuroprotection in neurodegenerations of the brain and eye: Lessons from the past and directions for the future.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {964197}, pmid = {36034312}, issn = {1664-2295}, support = {P30 EY026877/EY/NEI NIH HHS/United States ; }, abstract = {BACKGROUND: Neurological and ophthalmological neurodegenerative diseases in large part share underlying biology and pathophysiology. Despite extensive preclinical research on neuroprotection that in many cases bridges and unifies both fields, only a handful of neuroprotective therapies have succeeded clinically in either.<br><br>MAIN BODY: Understanding the commonalities among brain and neuroretinal neurodegenerations can help develop innovative ways to improve translational success in neuroprotection research and emerging therapies. To do this, analysis of why translational research in neuroprotection fails necessitates addressing roadblocks at basic research and clinical trial levels. These include optimizing translational approaches with respect to biomarkers, therapeutic targets, treatments, animal models, and regulatory pathways.<br><br>CONCLUSION: The common features of neurological and ophthalmological neurodegenerations are useful for outlining a path forward that should increase the likelihood of translational success in neuroprotective therapies.}, }
@article {pmid36032763, year = {2022}, author = {Cao, M and Zhang, K and Zhang, S and Wang, Y and Chen, C}, title = {Advanced Light Source Analytical Techniques for Exploring the Biological Behavior and Fate of Nanomedicines.}, journal = {ACS central science}, volume = {8}, number = {8}, pages = {1063-1080}, pmid = {36032763}, issn = {2374-7943}, abstract = {Exploration of the biological behavior and fate of nanoparticles, as affected by the nanomaterial-biology (nano-bio) interaction, has become progressively critical for guiding the rational design and optimization of nanomedicines to minimize adverse effects, support clinical translation, and aid in evaluation by regulatory agencies. Because of the complexity of the biological environment and the dynamic variations in the bioactivity of nanomedicines, in-situ, label-free analysis of the transport and transformation of nanomedicines has remained a challenge. Recent improvements in optics, detectors, and light sources have allowed the expansion of advanced light source (ALS) analytical technologies to dig into the underexplored behavior and fate of nanomedicines in vivo. It is increasingly important to further develop ALS-based analytical technologies with higher spatial and temporal resolution, multimodal data fusion, and intelligent prediction abilities to fully unlock the potential of nanomedicines. In this Outlook, we focus on several selected ALS analytical technologies, including imaging and spectroscopy, and provide an overview of the emerging opportunities for their applications in the exploration of the biological behavior and fate of nanomedicines. We also discuss the challenges and limitations faced by current approaches and tools and the expectations for the future development of advanced light sources and technologies. Improved ALS imaging and spectroscopy techniques will accelerate a profound understanding of the biological behavior of new nanomedicines. Such advancements are expected to inspire new insights into nanomedicine research and promote the development of ALS capabilities and methods more suitable for nanomedicine evaluation with the goal of clinical translation.}, }
@article {pmid36031314, year = {2022}, author = {Taran, S and McCredie, VA and Goligher, EC}, title = {Noninvasive and invasive mechanical ventilation for neurologic disorders.}, journal = {Handbook of clinical neurology}, volume = {189}, number = {}, pages = {361-386}, doi = {10.1016/B978-0-323-91532-8.00015-X}, pmid = {36031314}, issn = {0072-9752}, mesh = {Airway Extubation ; *Guillain-Barre Syndrome ; Humans ; *Neuromuscular Diseases ; Respiration, Artificial ; *Respiratory Insufficiency ; }, abstract = {Patients with acute neurologic injuries frequently require mechanical ventilation due to diminished airway protective reflexes, cardiopulmonary failure secondary to neurologic insults, or to facilitate gas exchange to precise targets. Mechanical ventilation enables tight control of oxygenation and carbon dioxide levels, enabling clinicians to modulate cerebral hemodynamics and intracranial pressure with the goal of minimizing secondary brain injury. In patients with acute spinal cord injuries, neuromuscular conditions, or diseases of the peripheral nerve, mechanical ventilation enables respiratory support under conditions of impending or established respiratory failure. Noninvasive ventilatory approaches may be carefully considered for certain disease conditions, including myasthenia gravis and amyotrophic lateral sclerosis, but may be inappropriate in patients with Guillain-Barré syndrome or when relevant contra-indications exist. With regard to discontinuing mechanical ventilation, considerable uncertainty persists about the best approach to wean patients, how to identify patients ready for extubation, and when to consider primary tracheostomy. Recent consensus guidelines highlight these and other knowledge gaps that are the focus of active research efforts. This chapter outlines important general principles to consider when initiating, titrating, and discontinuing mechanical ventilation in patients with acute neurologic injuries. Important disease-specific considerations are also reviewed where appropriate.}, }
@article {pmid36031308, year = {2022}, author = {Vianello, A and Racca, F and Vita, GL and Pierucci, P and Vita, G}, title = {Motor neuron, peripheral nerve, and neuromuscular junction disorders.}, journal = {Handbook of clinical neurology}, volume = {189}, number = {}, pages = {259-270}, doi = {10.1016/B978-0-323-91532-8.00014-8}, pmid = {36031308}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis ; *Guillain-Barre Syndrome ; Humans ; Motor Neurons ; *Myasthenia Gravis ; *Neuromuscular Diseases ; *Neuromuscular Junction Diseases ; Peripheral Nerves ; *Respiratory Insufficiency ; }, abstract = {In amyotrophic lateral sclerosis (ALS), Guillain-Barré syndrome (GBS), and neuromuscular junction disorders, three mechanisms may lead, singly or together, to respiratory emergencies and increase the disease burden and mortality: (i) reduced strength of diaphragm and accessory muscles; (ii) oropharyngeal dysfunction with possible aspiration of saliva/bronchial secretions/drink/food; and (iii) inefficient cough due to weakness of abdominal muscles. Breathing deficits may occur at onset or more often along the chronic course of the disease. Symptoms and signs are dyspnea on minor exertion, orthopnea, nocturnal awakenings, excessive daytime sleepiness, fatigue, morning headache, poor concentration, and difficulty in clearing bronchial secretions. The "20/30/40 rule" has been proposed to early identify GBS patients at risk for respiratory failure. The mechanical in-exsufflator is a device that assists ALS patients in clearing bronchial secretions. Noninvasive ventilation is a safe and helpful support, especially in ALS, but has some contraindications. Myasthenic crisis is a clinical challenge and is associated with substantial morbidity including prolonged mechanical ventilation and 5%-12% mortality. Emergency room physicians and consultant pulmonologists and neurologists must know such respiratory risks, be able to recognize early signs, and treat properly.}, }
@article {pmid36017737, year = {2022}, author = {Xiong, LL and Chen, L and Deng, IB and Zhou, XF and Wang, TH}, title = {P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases.}, journal = {The European journal of neuroscience}, volume = {56}, number = {8}, pages = {5299-5318}, doi = {10.1111/ejn.15810}, pmid = {36017737}, issn = {1460-9568}, mesh = {Biomarkers ; Drug Development ; Humans ; Nerve Growth Factors ; *Nervous System Diseases/drug therapy ; *Receptor, Nerve Growth Factor/metabolism ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation-induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in-depth investigations on p75NTR-based drug development are required to shed light on effective treatment of numerous neurological disorders.}, }
@article {pmid36017725, year = {2023}, author = {Guzman, BB and Son, A and Litberg, TJ and Huang, Z and Dominguez, D and Horowitz, S}, title = {Emerging roles for G-quadruplexes in proteostasis.}, journal = {The FEBS journal}, volume = {290}, number = {19}, pages = {4614-4625}, pmid = {36017725}, issn = {1742-4658}, support = {T32 GM135095/GM/NIGMS NIH HHS/United States ; R35 GM142864/GM/NIGMS NIH HHS/United States ; R35 GM142442/GM/NIGMS NIH HHS/United States ; }, mesh = {*G-Quadruplexes ; Proteostasis ; DNA/chemistry ; Proteins ; RNA/genetics ; }, abstract = {How nucleic acids interact with proteins, and how they affect protein folding, aggregation, and misfolding is a still-evolving area of research. Considerable effort is now focusing on a particular structure of RNA and DNA, G-quadruplexes, and their role in protein homeostasis and disease. In this state-of-the-art review, we track recent reports on how G-quadruplexes influence protein aggregation, proteolysis, phase separation, and protein misfolding diseases, and pose currently unanswered questions in the advance of this scientific field.}, }
@article {pmid36012622, year = {2022}, author = {Roberts, B and Theunissen, F and Mastaglia, FL and Akkari, PA and Flynn, LL}, title = {Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012622}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; Lewy Bodies/metabolism ; *Lewy Body Disease/pathology ; *Multiple System Atrophy/pathology ; *Synucleinopathies ; alpha-Synuclein/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with "synucleinopathy disorders". We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.}, }
@article {pmid36012603, year = {2022}, author = {Motataianu, A and Serban, G and Barcutean, L and Balasa, R}, title = {Oxidative Stress in Amyotrophic Lateral Sclerosis: Synergy of Genetic and Environmental Factors.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012603}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Unitatea Executiva Pentru Finantarea Invatamantului Superior a Cercetarii Dezvoltarii si Inovarii/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/etiology ; Electromagnetic Fields ; Humans ; *Neurodegenerative Diseases/complications ; Oxidative Stress ; *Pesticides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular processes. Notably, oxidative stress has been demonstrated to play a crucial role in ALS pathogenesis. In addition to already recognized and exhaustively studied genetic mutations involved in oxidative stress production, exposure to various environmental factors (e.g., electromagnetic fields, solvents, pesticides, heavy metals) has been suggested to enhance oxidative damage. This review aims to describe the main processes influenced by the most frequent genetic mutations and environmental factors concurring in oxidative stress occurrence in ALS and the potential therapeutic molecules capable of diminishing the ALS related pro-oxidative status.}, }
@article {pmid36012599, year = {2022}, author = {Morén, C and deSouza, RM and Giraldo, DM and Uff, C}, title = {Antioxidant Therapeutic Strategies in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012599}, issn = {1422-0067}, mesh = {Antioxidants/metabolism/therapeutic use ; Humans ; *Melatonin/metabolism/therapeutic use ; Mitochondria/metabolism ; *Neurodegenerative Diseases/pathology ; Oxidative Stress ; }, abstract = {The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using antioxidant molecules towards redox equilibrium have been widely used for the treatment of several brain pathologies. Globally, polyphenols, carotenes and vitamins are among the most typical exogenous antioxidant agents that have been tested in neurodegeneration as adjunctive therapies. However, other types of antioxidants, including hormones, such as the widely used melatonin, are also considered neuroprotective agents and have been used in different neurodegenerative contexts. This review highlights the most relevant mitochondrial antioxidant targets in the main neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease and also in the less represented amyotrophic lateral sclerosis, as well as traumatic brain injury, while summarizing the latest randomized placebo-controlled trials.}, }
@article {pmid36012563, year = {2022}, author = {Raghunathan, R and Turajane, K and Wong, LC}, title = {Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012563}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Biomarkers ; Humans ; *Neurodegenerative Diseases/diagnosis ; *Parkinson Disease ; Proteomics ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are both characterized by pathogenic protein aggregates that correlate with the progressive degeneration of neurons and the loss of behavioral functions. Both diseases lack biomarkers for diagnosis and treatment efficacy. Proteomics is an unbiased quantitative tool capable of the high throughput quantitation of thousands of proteins from minimal sample volumes. We review recent proteomic studies in human tissues, plasma, cerebrospinal fluid (CSF), and exosomes in ALS and PD that identify proteins with potential utility as biomarkers. Further, we review disease-related post-translational modifications in key proteins TDP43 in ALS and α-synuclein in PD studies, which may serve as biomarkers. We compare relative and absolute quantitative proteomic approaches in key biomarker studies in ALS and PD and discuss recent technological advancements which may identify suitable biomarkers for the early-diagnosis treatment efficacy of these diseases.}, }
@article {pmid36012480, year = {2022}, author = {Strope, TA and Birky, CJ and Wilkins, HM}, title = {The Role of Bioenergetics in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012480}, issn = {1422-0067}, support = {U54 HD090216/HD/NICHD NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Energy Metabolism ; Humans ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Bioenergetic and mitochondrial dysfunction are common hallmarks of neurodegenerative diseases. Decades of research describe how genetic and environmental factors initiate changes in mitochondria and bioenergetics across Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Mitochondria control many cellular processes, including proteostasis, inflammation, and cell survival/death. These cellular processes and pathologies are common across neurodegenerative diseases. Evidence suggests that mitochondria and bioenergetic disruption may drive pathological changes, placing mitochondria as an upstream causative factor in neurodegenerative disease onset and progression. Here, we discuss evidence of mitochondrial and bioenergetic dysfunction in neurodegenerative diseases and address how mitochondria can drive common pathological features of these diseases.}, }
@article {pmid36011394, year = {2022}, author = {Sánchez-Tejerina, D and Restrepo-Vera, JL and Rovira-Moreno, E and Codina-Sola, M and Llauradó, A and Sotoca, J and Salvado, M and Raguer, N and García-Arumí, E and Juntas-Morales, R}, title = {An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature.}, journal = {Genes}, volume = {13}, number = {8}, pages = {}, pmid = {36011394}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; Motor Neurons/pathology ; *Neurodegenerative Diseases/pathology ; Penetrance ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants.}, }
@article {pmid36010666, year = {2022}, author = {Masi, M and Attanzio, A and Racchi, M and Wolozin, B and Borella, S and Biundo, F and Buoso, E}, title = {Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1.}, journal = {Cells}, volume = {11}, number = {16}, pages = {}, pmid = {36010666}, issn = {2073-4409}, mesh = {Cytoplasmic Granules/metabolism ; *Frontotemporal Dementia/metabolism ; Humans ; Neoplasm Proteins/metabolism ; Proteostasis ; Receptors for Activated C Kinase/metabolism ; *Ribosomal Proteins/metabolism ; Stress Granules ; }, abstract = {The role of protein misfolding, deposition, and clearance has been the dominant topic in the last decades of investigation in the field of neurodegeneration. The impairment of protein synthesis, along with RNA metabolism and RNA granules, however, are significantly emerging as novel potential targets for the comprehension of the molecular events leading to neuronal deficits. Indeed, defects in ribosome activity, ribosome stalling, and PQC-all ribosome-related processes required for proteostasis regulation-can contribute to triggering stress conditions and promoting the formation of stress granules (SGs) that could evolve in the formation of pathological granules, usually occurring during neurodegenerating effects. In this review, the interplay between proteostasis, mRNA metabolism, and SGs has been explored in a neurodegenerative context with a focus on Alzheimer's disease (AD), although some defects in these same mechanisms can also be found in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are discussed here. Finally, we highlight the role of the receptor for activated C kinase 1 (RACK1) in these pathologies and note that, besides its well characterized function as a scaffold protein, it has an important role in translation and can associate to stress granules (SGs) determining cell fate in response to diverse stress stimuli.}, }
@article {pmid36009818, year = {2022}, author = {Schweingruber, C and Hedlund, E}, title = {The Cell Autonomous and Non-Cell Autonomous Aspects of Neuronal Vulnerability and Resilience in Amyotrophic Lateral Sclerosis.}, journal = {Biology}, volume = {11}, number = {8}, pages = {}, pmid = {36009818}, issn = {2079-7737}, support = {2021//Radala Foundation/ ; 2020-01049//Swedish Research Council/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is defined by the loss of upper motor neurons (MNs) that project from the cerebral cortex to the brain stem and spinal cord and of lower MNs in the brain stem and spinal cord which innervate skeletal muscles, leading to spasticity, muscle atrophy, and paralysis. ALS involves several disease stages, and multiple cell types show dysfunction and play important roles during distinct phases of disease initiation and progression, subsequently leading to selective MN loss. Why MNs are particularly vulnerable in this lethal disease is still not entirely clear. Neither is it fully understood why certain MNs are more resilient to degeneration in ALS than others. Brain stem MNs of cranial nerves III, IV, and VI, which innervate our eye muscles, are highly resistant and persist until the end-stage of the disease, enabling paralyzed patients to communicate through ocular tracking devices. MNs of the Onuf's nucleus in the sacral spinal cord, that innervate sphincter muscles and control urogenital functions, are also spared throughout the disease. There is also a differential vulnerability among MNs that are intermingled throughout the spinal cord, that directly relate to their physiological properties. Here, fast-twitch fatigable (FF) MNs, which innervate type IIb muscle fibers, are affected early, before onset of clinical symptoms, while slow-twitch (S) MNs, that innervate type I muscle fibers, remain longer throughout the disease progression. The resilience of particular MN subpopulations has been attributed to intrinsic determinants and multiple studies have demonstrated their unique gene regulation and protein content in health and in response to disease. Identified factors within resilient MNs have been utilized to protect more vulnerable cells. Selective vulnerability may also, in part, be driven by non-cell autonomous processes and the unique surroundings and constantly changing environment close to particular MN groups. In this article, we review in detail the cell intrinsic properties of resilient and vulnerable MN groups, as well as multiple additional cell types involved in disease initiation and progression and explain how these may contribute to the selective MN resilience and vulnerability in ALS.}, }
@article {pmid36009055, year = {2022}, author = {Assogna, M and Di Lorenzo, F and Martorana, A and Koch, G}, title = {Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {12}, number = {8}, pages = {}, pmid = {36009055}, issn = {2218-273X}, mesh = {*Alzheimer Disease/drug therapy ; Amides ; Animals ; Ethanolamines ; *Neurodegenerative Diseases/drug therapy ; Palmitic Acids/pharmacology/therapeutic use ; }, abstract = {Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients' studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.}, }
@article {pmid36008956, year = {2022}, author = {Ramos-Martínez, E and Ramos-Martínez, I and Sánchez-Betancourt, I and Ramos-Martínez, JC and Peña-Corona, SI and Valencia, J and Saucedo, R and Almeida-Aguirre, EKP and Cerbón, M}, title = {Association between Galectin Levels and Neurodegenerative Diseases: Systematic Review and Meta-Analysis.}, journal = {Biomolecules}, volume = {12}, number = {8}, pages = {}, pmid = {36008956}, issn = {2218-273X}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Galectin 3 ; Galectins/metabolism ; Humans ; *Neurodegenerative Diseases ; }, abstract = {Galectins are a family of proteins with an affinity for β-galactosides that have roles in neuroprotection and neuroinflammation. Several studies indicate that patients with neurodegenerative diseases have alterations in the concentration of galectins in their blood and brain. However, the results of the studies are contradictory; hence, a meta-analysis is performed to clarify whether patients with neurodegenerative diseases have elevated galectin levels compared to healthy individuals. Related publications are obtained from the databases: PubMed, Central-Conchrane, Web of Science database, OVID-EMBASE, Scope, and EBSCO host until February 2022. A pooled standard mean difference (SMD) with a 95% confidence interval (CI) is calculated by fixed-effect or random-effect model analysis. In total, 17 articles are included in the meta-analysis with a total of 905 patients. Patients with neurodegenerative diseases present a higher level of galectin expression compared to healthy individuals (MDS = 0.70, 95% CI 0.28-1.13, p = 0.001). In the subgroup analysis by galectin type, a higher galectin-3 expression is observed in patients with neurodegenerative diseases. Patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALD), and Parkinson's disease (PD) expressed higher levels of galectin-3. Patients with multiple sclerosis (MS) have higher levels of galectin-9. In conclusion, our meta-analysis shows that patients with neurovegetative diseases have higher galectin levels compared to healthy individuals. Galectin levels are associated with the type of disease, sample, detection technique, and region of origin of the patients.}, }
@article {pmid36005581, year = {2022}, author = {Jiang, L and Ngo, ST}, title = {Altered TDP-43 Structure and Function: Key Insights into Aberrant RNA, Mitochondrial, and Cellular and Systemic Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Metabolites}, volume = {12}, number = {8}, pages = {}, pmid = {36005581}, issn = {2218-1989}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA binding protein-43 (TDP-43) cytoplasmic inclusions. TDP-43 is a ubiquitously expressed RNA binding protein with the capacity to bind over 6000 RNA and DNA targets-particularly those involved in RNA, mitochondrial, and lipid metabolism. Here, we review the unique structure and function of TDP-43 and its role in affecting the aforementioned metabolic processes in ALS. Considering evidence published specifically in TDP-43-relevant in vitro, in vivo, and ex vivo models we posit that TDP-43 acts in a positive feedback loop with mRNA transcription/translation, stress granules, cytoplasmic aggregates, and mitochondrial proteins causing a relentless cycle of disease-like pathology eventuating in neuronal toxicity. Given its undeniable presence in ALS pathology, TDP-43 presents as a promising target for mechanistic disease modelling and future therapeutic investigations.}, }
@article {pmid35997522, year = {2023}, author = {Goslinga, JA and Terrelonge, M and Bedlack, R and Barkhaus, P and Barnes, B and Bertorini, T and Bromberg, M and Carter, G and Chen, A and Crayle, J and Dimachkie, M and Jiang, L and Levitsky, G and Lund, I and Martin, S and Mcdermott, C and Pattee, G and Pierce, K and Ratner, D and Slachtova, L and Sun, Y and Wicks, P}, title = {ALSUntangled #65: glucocorticoid corticosteroids.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {3-4}, pages = {351-357}, doi = {10.1080/21678421.2022.2099746}, pmid = {35997522}, issn = {2167-9223}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Glucocorticoids/therapeutic use ; Disease Models, Animal ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.}, }
@article {pmid35996223, year = {2022}, author = {Nepal, G and Kharel, S and Coghlan, MA and Yadav, JK and Parajuli, P and Pandit, K and Shing, YK and Ojha, R}, title = {Amyotrophic lateral sclerosis and retinal changes in optical coherence tomography: A systematic review and meta-analysis.}, journal = {Brain and behavior}, volume = {12}, number = {9}, pages = {e2741}, pmid = {35996223}, issn = {2162-3279}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Cognitive Dysfunction/pathology ; Humans ; Retina/diagnostic imaging/pathology ; Tomography, Optical Coherence/methods ; }, abstract = {INTRODUCTION: Increasing evidence suggests Amyotrophic Lateral Sclerosis (ALS) as a widespread pathological process comprising nonmotor features like fatigue, mild sensory symptoms, cognitive decline, and visual impairment. Measurements of retinal nerve fiber layer (RNFL) thickness using Optical Coherence Tomography (OCT) may correlate with the neurodegeneration associated with ALS. In addition to RNFL thickness, other OCT parameters have been explored in the context of diagnosing ALS and predicting disease severity. In this study, we explore the possibility that OCT parameters of patients with ALS may differ significantly from those of healthy controls and thus serve as biomarkers for the disease and its progression.<br><br>MATERIALS AND METHODS: Between 2010 and 2021, the PubMed and EMBASE databases were examined for English language literature. ALS severity was assessed using the revised ALS functional rating scale (ALSFRS-R). The pooled mean differences in RNFL thickness between ALS patients and controls were calculated using the Standard Mean Difference (Hedges's g) with a 95% confidence interval (CI) in STATA software version 16.<br><br>RESULTS: Eleven studies were reviewed for data collection. RNFL thickness was not statistically significantly different between ALS patients (n&#xa0;=&#xa0;412) and controls (n&#xa0;=&#xa0;376) (Hedges's g&#xa0;=&#xa0;-0.22; 95% CI: -0.51 to 0.07, I[2] =&#xa0;73.04%, p&#xa0;=&#xa0;.14). However, the thickness of inner nuclear layer was significantly different between ALS patients and controls (Hedges's g&#xa0;=&#xa0;-0.38; 95% CI: -0.61 to 0.14, I[2] =&#xa0;14.85%, p&#xa0;=&#xa0;.00).<br><br>CONCLUSION: Our meta-analysis found that RNFL thickness as a whole or by individual quadrants was not significantly different between ALS patients and controls while the inner nuclear layer (INL) was substantially thinner.}, }
@article {pmid35986916, year = {2022}, author = {Sarmet, M and Kabani, A and Maragakis, NJ and Mehta, AK}, title = {Appetite and quality of life in amyotrophic lateral sclerosis: A scoping review.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {6}, pages = {653-660}, doi = {10.1002/mus.27694}, pmid = {35986916}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Quality of Life ; Appetite ; Surveys and Questionnaires ; Nutritional Status ; }, abstract = {Loss of appetite is related to undesirable loss of weight in amyotrophic lateral sclerosis (ALS) and affects up to two thirds of people with this disease. Little is known about the instruments used to measure appetite loss, its impact on quality of life (QoL), or strategies used to improve loss of appetite. In this study we aim to characterize the existing literature on the symptom of appetite loss in ALS through a systematic scoping review following the framework by Arksey and O'Malley and PRISMA guidelines. Studies assessing appetite in people with ALS (pALS) published in English and indexed on Web of Science, PubMed, and Scopus databases were included. A total of 156 full references were identified, of which 10 articles met the inclusion criteria and were eligible for data synthesis after screening. Seven unique instruments were used to assess appetite across the included studies, most commonly the Council of Nutrition Appetite Questionnaire. No studies included a subjective assessment of appetite loss. A total of 12 unique potential associated factors across five studies were identified. QoL was measured in seven studies using nine different QoL measurement tools. Few studies measure appetite in pALS and there is no consensus on the assessment tool used. Few studies evaluated the impact of appetite as a symptom on QoL. Furthermore, the heterogeneity of outcomes and risk factors of the existing data limit the clinical application of these findings. Future studies are needed to guide clinical management and interventions for people with ALS and appetite loss.}, }
@article {pmid35982439, year = {2022}, author = {Bilbao, A and Spanagel, R}, title = {Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {259}, pmid = {35982439}, issn = {1741-7015}, mesh = {*Cannabinoids/adverse effects ; *Chronic Pain/drug therapy ; Dronabinol/adverse effects ; Humans ; Nausea ; Vomiting ; }, abstract = {BACKGROUND: Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.<br><br>METHODS: We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools.<br><br>RESULTS: In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD&#x2009;-&#x2009;0.5[CI&#x2009;-&#x2009;0.62,&#x2009;-&#x2009;0.38] high grade) and Parkinsonism (-&#x2009;0.41[CI&#x2009;-&#x2009;0.75,&#x2009;-&#x2009;0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (-&#x2009;0.31[CI&#x2009;-&#x2009;0.46,&#x2009;-&#x2009;0.15]), appetite (-&#x2009;0.51[CI&#x2009;-&#x2009;0.87,&#x2009;-&#x2009;0.15]) and Tourette (-&#x2009;1.01[CI&#x2009;-&#x2009;1.58,&#x2009;-&#x2009;0.44]) and moderate evidence for nabiximols on chronic pain (-&#x2009;0.25[-&#x2009;0.37,&#x2009;-&#x2009;0.14]), spasticity (-&#x2009;0.36[CI&#x2009;-&#x2009;0.54,&#x2009;-&#x2009;0.19]), sleep (-&#x2009;0.24[CI&#x2009;-&#x2009;0.35,&#x2009;-&#x2009;0.14]) and SUDs (-&#x2009;0.48[CI&#x2009;-&#x2009;0.92,&#x2009;-&#x2009;0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.<br><br>CONCLUSIONS: Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.}, }
@article {pmid35980063, year = {2023}, author = {Jaberi, KR and Alamdari-Palangi, V and Jaberi, AR and Esmaeli, Z and Shakeri, A and Gheibi Hayat, SM and Tajbakhsh, A and Savardashtaki, A}, title = {The Regulation, Functions, and Signaling of miR-153 in Neurological Disorders, and Its Potential as a Biomarker and Therapeutic Target.}, journal = {Current molecular medicine}, volume = {23}, number = {9}, pages = {863-875}, doi = {10.2174/1566524023666220817145638}, pmid = {35980063}, issn = {1875-5666}, mesh = {Humans ; Animals ; Mice ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease ; Neurogenesis ; Biomarkers ; *Biological Phenomena ; }, abstract = {Treatment of neurological disorders has always been one of the challenges facing scientists due to poor prognosis and symptom overlap, as well as the progress of the disease process. Neurological disorders such as Huntington's, Parkinson's, Alzheimer's diseases, and Amyotrophic Lateral Sclerosis are very debilitating. Therefore, finding a biomarker is essential for early diagnosis and treatment goals. Recent studies have focused more on molecular factors and gene manipulation to find effective diagnostic and therapeutic biomarkers. Among these factors, microRNAs (miRNAs/ miRs) have attracted much attention. On the other hand, a growing correlation between miRNAs and neurological disorders has caused scientists to consider it as a diagnostic and therapeutic target. In this line, the miR-153 is one of the most important and highly conserved miRNAs in mice and humans, whose expression level is not only altered in neurological disorders but also improves neurogenesis. MiR-153 can regulate multiple biological processes by targeting various factors. Furthermore, the miR-153 expression also can be regulated by important regulators, such as long non-coding RNAs (e.g., KCNQ1OT1) and some compounds (e.g., Tanshinone IIA) altering the expression of miR-153. Given the growing interest in miR-153 as a biomarker and therapeutic target for neurological diseases as well as the lack of comprehensive investigation of miR-153 function in these disorders, it is necessary to identify the downstream and upstream targets and also it's potential as a therapeutic biomarker target. In this review, we will discuss the critical role of miR-153 in neurological disorders for novel diagnostic and prognostic purposes and its role in multi-drug resistance.}, }
@article {pmid35978311, year = {2022}, author = {Singh, D}, title = {Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer's disease.}, journal = {Journal of neuroinflammation}, volume = {19}, number = {1}, pages = {206}, pmid = {35978311}, issn = {1742-2094}, support = {5/3/8/58/ITR-F/2020//Indian Council of Medical Research/ ; }, mesh = {*Alzheimer Disease/pathology ; Astrocytes/metabolism ; Humans ; *Microglia/metabolism ; Neuroinflammatory Diseases ; }, abstract = {Neuroinflammation is instigated by the misfiring of immune cells in the central nervous system (CNS) involving microglia and astrocytes as key cell-types. Neuroinflammation is a consequence of CNS injury, infection, toxicity, or autoimmunity. It is favorable as well as a detrimental process for neurodevelopment and associated processes. Transient activation of inflammatory response involving release of cytokines and growth factors positively affects the development and post-injury tissue. However, chronic or uncontrolled inflammatory responses may lead to various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, and multiple sclerosis. These diseases have variable clinical and pathological features, but are underlaid by the aggregation of misfolded proteins with a cytotoxic effect. Notably, abnormal activation of glial cells could mediate neuroinflammation, leading to the neurodegenerative condition. Microglia, a type of glial cell, a resident immune cell, form the forefront defense of the CNS immune system. Dysfunctional microglia and astrocyte, a different kind of glial cell with homeostatic function, impairs the protein aggregate (amyloid-beta plaque) clearance in AD. Studies have shown that microglia and astrocytes undergo alterations in their genetic profile, cellular and molecular responses, and thus promote dysfunctional immune cross-talk in AD. Hence, targeting microglia and astrocytes-driven molecular pathways could resolve the particular layers of neuroinflammation and set a reliable therapeutic intervention in AD progression.}, }
@article {pmid35971743, year = {2022}, author = {Murakami, K and Ono, K}, title = {Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {36}, number = {9}, pages = {e22493}, doi = {10.1096/fj.202200235R}, pmid = {35971743}, issn = {1530-6860}, mesh = {Amyloid/metabolism ; Amyloid beta-Peptides ; Amyloidogenic Proteins ; *Amyloidosis ; Humans ; *Neurodegenerative Diseases/metabolism ; }, abstract = {The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease. From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, α-synuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy.}, }
@article {pmid35965036, year = {2022}, author = {Mitchell, GS and Baker, TL}, title = {Respiratory neuroplasticity: Mechanisms and translational implications of phrenic motor plasticity.}, journal = {Handbook of clinical neurology}, volume = {188}, number = {}, pages = {409-432}, doi = {10.1016/B978-0-323-91534-2.00016-3}, pmid = {35965036}, issn = {0072-9752}, mesh = {Humans ; Hypoxia ; Motor Neurons/physiology ; *Neuronal Plasticity/physiology ; Respiration ; *Spinal Cord Injuries ; }, abstract = {Widespread appreciation that neuroplasticity is an essential feature of the neural system controlling breathing has emerged only in recent years. In this chapter, we focus on respiratory motor plasticity, with emphasis on the phrenic motor system. First, we define related but distinct concepts: neuromodulation and neuroplasticity. We then focus on mechanisms underlying two well-studied models of phrenic motor plasticity: (1) phrenic long-term facilitation following brief exposure to acute intermittent hypoxia; and (2) phrenic motor facilitation after prolonged or recurrent bouts of diminished respiratory neural activity. Advances in our understanding of these novel and important forms of plasticity have been rapid and have already inspired translation in multiple respects: (1) development of novel therapeutic strategies to preserve/restore breathing function in humans with severe neurological disorders, such as spinal cord injury and amyotrophic lateral sclerosis; and (2) the discovery that similar plasticity also occurs in nonrespiratory motor systems. Indeed, the realization that similar plasticity occurs in respiratory and nonrespiratory motor neurons inspired clinical trials to restore leg/walking and hand/arm function in people living with chronic, incomplete spinal cord injury. Similar application may be possible to other clinical disorders that compromise respiratory and non-respiratory movements.}, }
@article {pmid35955847, year = {2022}, author = {De Plano, LM and Calabrese, G and Conoci, S and Guglielmino, SPP and Oddo, S and Caccamo, A}, title = {Applications of CRISPR-Cas9 in Alzheimer's Disease and Related Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {15}, pages = {}, pmid = {35955847}, issn = {1422-0067}, support = {AIM 1872330//AIM Linea 1 -Salute to A.C./ ; }, mesh = {*Alzheimer Disease/genetics/therapy ; Animals ; CRISPR-Cas Systems/genetics ; Gene Editing/methods ; Genetic Therapy/methods ; Humans ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders.}, }
@article {pmid35954258, year = {2022}, author = {Amzallag, E and Hornstein, E}, title = {Crosstalk between Biomolecular Condensates and Proteostasis.}, journal = {Cells}, volume = {11}, number = {15}, pages = {}, pmid = {35954258}, issn = {2073-4409}, mesh = {Biomolecular Condensates ; Humans ; *Neurodegenerative Diseases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; *Proteostasis ; Ubiquitin/metabolism ; }, abstract = {Proper homeostasis of the proteome, referred to as proteostasis, is maintained by chaperone-dependent refolding of misfolded proteins and by protein degradation via the ubiquitin-proteasome system and the autophagic machinery. This review will discuss a crosstalk between biomolecular condensates and proteostasis, whereby the crowding of proteostasis factors into macromolecular assemblies is often established by phase separation of membraneless biomolecular condensates. Specifically, ubiquitin and other posttranslational modifications come into play as agents of phase separation, essential for the formation of condensates and for ubiquitin-proteasome system activity. Furthermore, an intriguing connection associates malfunction of the same pathways to the accumulation of misfolded and ubiquitinated proteins in aberrant condensates, the formation of protein aggregates, and finally, to the pathogenesis of neurodegenerative diseases. The crosstalk between biomolecular condensates and proteostasis is an emerging theme in cellular and disease biology and further studies will focus on delineating specific molecular pathways involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.}, }
@article {pmid35950263, year = {2022}, author = {Petzold, A}, title = {The 2022 Lady Estelle Wolfson lectureship on neurofilaments.}, journal = {Journal of neurochemistry}, volume = {163}, number = {3}, pages = {179-219}, pmid = {35950263}, issn = {1471-4159}, mesh = {Humans ; *Intermediate Filaments/metabolism ; Neurofilament Proteins/metabolism ; *Charcot-Marie-Tooth Disease/genetics ; Biomarkers ; Protein Isoforms ; }, abstract = {Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), α -internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot-Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post-translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease. Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33 meta-analyses on Nf body fluid levels. The review concludes with considerations for clinical trial design and an outlook for future research.}, }
@article {pmid35950246, year = {2023}, author = {Shang, D and Huang, M and Wang, B and Yan, X and Wu, Z and Zhang, X}, title = {mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {21}, number = {3}, pages = {578-598}, pmid = {35950246}, issn = {1875-6190}, mesh = {Humans ; DNA, Mitochondrial/genetics/metabolism/therapeutic use ; *Neurodegenerative Diseases/metabolism ; *Mitochondrial Diseases/drug therapy/genetics/metabolism ; Mitochondria/metabolism ; Aging ; ATPases Associated with Diverse Cellular Activities/metabolism/therapeutic use ; Membrane Proteins/metabolism ; Mitochondrial Proteins/metabolism ; }, abstract = {Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA.}, }
@article {pmid35950245, year = {2023}, author = {Vishwas, S and Kumar, R and Khursheed, R and Ramanunny, AK and Kumar, R and Awasthi, A and Corrie, L and Porwal, O and Arshad, MF and Alshammari, MK and Alghitran, AA and Qumayri, AN and Alkhaldi, SM and Alshammari, AK and Chellappan, DK and Gupta, G and Collet, T and Adams, J and Dua, K and Gulati, M and Singh, SK}, title = {Expanding Arsenal against Neurodegenerative Diseases Using Quercetin Based Nanoformulations: Breakthroughs and Bottlenecks.}, journal = {Current neuropharmacology}, volume = {21}, number = {7}, pages = {1558-1574}, pmid = {35950245}, issn = {1875-6190}, mesh = {Humans ; Quercetin/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Nanoparticles ; }, abstract = {Quercetin (Qu), a dietary flavonoid, is obtained from many fruits and vegetables such as coriander, broccoli, capers, asparagus, onion, figs, radish leaves, cranberry, walnuts, and citrus fruits. It has proven its role as a nutraceutical owing to numerous pharmacological effects against various diseases in preclinical studies. Despite these facts, Qu and its nanoparticles are less explored in clinical research as a nutraceutical. The present review covers various neuroprotective actions of Qu against various neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. A literature search was conducted to systematically review the various mechanistic pathways through which Qu elicits its neuroprotective actions and the challenges associated with raw Qu that compromise therapeutic efficacy. The nanoformulations developed to enhance Qu's therapeutic efficacy are also covered. Various ongoing/completed clinical trials related to Qu in treating various diseases, including NDs, are also tabulated. Despite these many successes, the exploration of research on Qu-loaded nanoformulations is limited mostly to preclinical studies, probably due to poor drug loading and stability of the formulation, time-consuming steps involved in the formulation, and their poor scale-up capacity. Hence, future efforts are required in this area to reach Qu nanoformulations to the clinical level.}, }
@article {pmid35949142, year = {2022}, author = {Alves, G and Ornellas, MH and Liehr, T}, title = {The role of Calmodulin Binding Transcription Activator 1 (CAMTA1) gene and its putative genetic partners in the human nervous system.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {22}, number = {6}, pages = {869-878}, doi = {10.1111/psyg.12881}, pmid = {35949142}, issn = {1479-8301}, mesh = {Humans ; *Trans-Activators/genetics/metabolism ; Calcium-Binding Proteins/genetics/metabolism ; Calmodulin/metabolism ; *Neuroblastoma/genetics/metabolism/pathology ; Nervous System/metabolism/pathology ; }, abstract = {The Calmodulin Binding Transcription Activator 1 (CAMTA1) gene plays a central role in the human nervous system. Here evidence-based perspectives on its clinical value for the screening of CAMTA1 malfunction is provided and argued that in future, patients suffering from brain tumours and/or neurological disorders could benefit from this diagnostic. In neuroblastomas as well as in low-grade gliomas, the influence of reduced expression of CAMTA1 results in opposite prognosis, probably because of different carcinogenic pathways in which CAMTA1 plays different roles, but the exact genetics bases remains unsolved. Rearrangements, mutations and variants of CAMTA1 were associated with human neurodegenerative disorders, while some CAMTA1 single nucleotide polymorphisms were associated with poorer memory in clinical cases and also amyotrophic lateral sclerosis. So far, the follow-up of patients with neurological diseases with alterations in CAMTA1 indicates that defects (expression, mutations, and rearrangements) in CAMTA1 alone are not sufficient to drive carcinogenesis. It is necessary to continue studying CAMTA1 rearrangements and expression in more cases than done by now. To understand the influence of CAMTA1 variants and their role in nervous system tumours and in several psychiatric disorders is currently a challenge.}, }
@article {pmid35946801, year = {2022}, author = {Logroscino, G and Urso, D and Tortelli, R}, title = {The challenge of amyotrophic lateral sclerosis descriptive epidemiology: to estimate low incidence rates across complex phenotypes in different geographic areas.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {678-685}, pmid = {35946801}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Humans ; Incidence ; *Motor Neuron Disease/epidemiology ; *Neurodegenerative Diseases ; Phenotype ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rare progressive neurodegenerative disease of motor neurons with a fatal outcome. The rareness of the disease and the rapidly fatal course are the main challenges for the ALS epidemiological research. The understanding of ALS has clearly advanced in the recent years both in the genetics and in the leading pathways of disease determinants. Epidemiological research has played a primary role in these discoveries.<br><br>RECENT FINDINGS: Epidemiological studies have shown a variation of incidence, mortality and prevalence of ALS between geographical areas and different populations, supporting the notion that genetic factors, linked to populations' ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. The burden of motor neuron diseases is increasing and currently more relevant in high-income countries but increasing at the highest rate in low and middle-income countries. The ALS phenotype is not restricted to motor functions. C9orf72 repeat expansion seems to present a recognizable phenotype characterized by earlier disease onset, the presence of cognitive and behavioural impairment.<br><br>SUMMARY: Population-based disease registries have played a major role in developing new knowledge on ALS, in characterizing genotype-phenotype correlations, in discovering new genetic modifiers and finally in planning research and health services, considering the high cost of motor neuron disease care. Epidemiological research based on multicentre international collaboration is essential to provide new data on ALS, especially in some regions of the world with poor data.}, }
@article {pmid35946443, year = {2022}, author = {Si, P and Zhu, C}, title = {Biological and neurological activities of astaxanthin (Review).}, journal = {Molecular medicine reports}, volume = {26}, number = {4}, pages = {}, pmid = {35946443}, issn = {1791-3004}, mesh = {Animals ; Antioxidants/pharmacology/therapeutic use ; Blood-Brain Barrier ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Xanthophylls/pharmacology/therapeutic use ; }, abstract = {Astaxanthin is a lipid‑soluble carotenoid produced by various microorganisms and marine animals, including bacteria, yeast, fungi, microalgae, shrimps and lobsters. Astaxanthin has antioxidant, anti‑inflammatory and anti‑apoptotic properties. These characteristics suggest that astaxanthin has health benefits and protects against various diseases. Owing to its ability to cross the blood‑brain barrier, astaxanthin has received attention for its protective effects against neurological disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia/reperfusion, subarachnoid hemorrhage, traumatic brain injury, spinal cord injury, cognitive impairment and neuropathic pain. Previous studies on the neurological effects of astaxanthin are mostly based on animal models and cellular experiments. Thus, the biological effects of astaxanthin on humans and its underlying mechanisms are still not fully understood. The present review summarizes the neuroprotective effects of astaxanthin, explores its mechanisms of action and draws attention to its potential clinical implications as a therapeutic agent.}, }
@article {pmid35945397, year = {2022}, author = {Beswick, E and Fawcett, T and Hassan, Z and Forbes, D and Dakin, R and Newton, J and Abrahams, S and Carson, A and Chandran, S and Perry, D and Pal, S}, title = {A systematic review of digital technology to evaluate motor function and disease progression in motor neuron disease.}, journal = {Journal of neurology}, volume = {269}, number = {12}, pages = {6254-6268}, pmid = {35945397}, issn = {1432-1459}, support = {MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Digital Technology ; *Motor Neuron Disease/diagnosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common subtype of motor neuron disease (MND). The current gold-standard measure of progression is the ALS Functional Rating Scale-Revised (ALS-FRS(R)), a clinician-administered questionnaire providing a composite score on physical functioning. Technology offers a potential alternative for assessing motor progression in both a clinical and research capacity that is more sensitive to detecting smaller changes in function. We reviewed studies evaluating the utility and suitability of these devices to evaluate motor function and disease progression in people with MND (pwMND). We systematically searched Google Scholar, PubMed and EMBASE applying no language or date restrictions. We extracted information on devices used and additional assessments undertaken. Twenty studies, involving 1275 (median 28 and ranging 6-584) pwMND, were included. Sensor type included accelerometers (n = 9), activity monitors (n = 4), smartphone apps (n = 4), gait (n = 3), kinetic sensors (n = 3), electrical impedance myography (n = 1) and dynamometers (n = 2). Seventeen (85%) of studies used the ALS-FRS(R) to evaluate concurrent validity. Participant feedback on device utility was generally positive, where evaluated in 25% of studies. All studies showed initial feasibility, warranting larger longitudinal studies to compare device sensitivity and validity beyond ALS-FRS(R). Risk of bias in the included studies was high, with a large amount of information to determine study quality unclear. Measurement of motor pathology and progression using technology is an emerging, and promising, area of MND research. Further well-powered longitudinal validation studies are needed.}, }
@article {pmid35942674, year = {2022}, author = {Witzel, S and Mayer, K and Oeckl, P}, title = {Biomarkers for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {699-704}, doi = {10.1097/WCO.0000000000001094}, pmid = {35942674}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers ; Humans ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs.<br><br>RECENT FINDINGS: The diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72 . Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment.<br><br>SUMMARY: The first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.}, }
@article {pmid35942673, year = {2022}, author = {Brenner, D and Freischmidt, A}, title = {Update on genetics of amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {672-677}, doi = {10.1097/WCO.0000000000001093}, pmid = {35942673}, issn = {1473-6551}, mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; C9orf72 Protein/genetics ; Cytoskeletal Proteins/genetics/metabolism ; Humans ; Kinesins ; Motor Neurons/pathology ; Mutation/genetics ; }, abstract = {PURPOSE OF REVIEW: ALS genetics are highly dynamic and of great interest for the ALS research community. Each year, by using ever-growing datasets and cutting-edge methodology, an array of novel ALS-associated genes and downstream pathomechanisms are discovered. The increasing plenty and complexity of insights warrants regular summary by-reviews.<br><br>RECENT FINDINGS: Most recent disease gene discoveries constitute the candidate and risk genes SPTLC1 , KANK1 , CAV1 , HTT , and WDR7 , as well as seven novel risk loci. Cell type and functional enrichment analyses enlighten the genetic basis of selective motor neuron vulnerability in ALS demonstrating high expression of ALS-associated genes in cortical motor neurons and highlight the pathogenic significance of cell-autonomous processes. Major pathomechanistic insights have been gained regarding known ALS genes/proteins, specifically C9orf72 , TDP43, ANXA11 , and KIF5A . The first ASO-based gene-specific therapy trials in familial forms of ALS have yielded equivocal results stressing the re-evaluation of pathomechanisms linked to SOD1 and C9orf72 mutations.<br><br>SUMMARY: The genetic and molecular basis of ALS is increasingly examined on single-cell resolution. In the past 2 years, the understanding of the downstream mechanisms of several ALS genes and TDP-43 proteinopathy has been considerably extended. These insights will result in novel gene specific therapy approaches for sporadic ALS and genetic subtypes.}, }
@article {pmid35942672, year = {2022}, author = {Dorst, J and Genge, A}, title = {Clinical studies in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {686-692}, doi = {10.1097/WCO.0000000000001099}, pmid = {35942672}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Follow-Up Studies ; Humans ; Longitudinal Studies ; }, abstract = {PURPOSE OF REVIEW: The purpose of this review is to discuss the most important recent clinical studies in amyotrophic lateral sclerosis (ALS), including their impact on clinical practice, their methodology, and open questions to be addressed in the future.<br><br>RECENT FINDINGS: This article focuses on studies, which provided either a positive primary endpoint or positive post hoc analysis, including edaravone, sodium phenylbutyrate-taurursodiol, rasagiline, tofersen, and high-caloric, fat-rich nutrition. It also covers recent developments in the design of clinical ALS studies with regard to inclusion criteria, stratification factors, and outcome parameters.<br><br>SUMMARY: Recent clinical studies have indicated various substances to be considered for treatment of ALS. Edaravone has been approved by the US Food and Drug Association (FDA) but not by the European Medicines Agency (EMA), and further studies testing oral formulations are currently conducted. A follow-up study with sodium phenylbutyrate-taurursodiol is ongoing, while follow-up studies for rasagiline and high-caloric, fat-rich nutrition are planned. A phase III study with tofersen was negative but nevertheless yielded promising results. Important developments regarding the design of clinical ALS studies include the implementation of neurofilament light chain (NfL) levels as a standard outcome parameter and the consideration of progression rate for therapeutic response and stratification.}, }
@article {pmid35936442, year = {2022}, author = {Marino, A and Battaglini, M and Moles, N and Ciofani, G}, title = {Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {7}, number = {30}, pages = {25974-25990}, pmid = {35936442}, issn = {2470-1343}, abstract = {Natural antioxidants are a very large diversified family of molecules classified by activity (enzymatic or nonenzymatic), chemical-physical properties (e.g., hydrophilic or lipophilic), and chemical structure (e.g., vitamins, polyphenols, etc.). Research on natural antioxidants in various fields, such as pharmaceutics, nutraceutics, and cosmetics, is among the biggest challenges for industry and science. From a biomedical point of view, the scavenging activity of reactive oxygen species (ROS) makes them a potential tool for the treatment of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS). In addition to the purified phytochemical compounds, a variety of natural extracts characterized by a complex mixture of antioxidants and anti-inflammatory molecules have been successfully exploited to rescue preclinical models of these diseases. Extracts derived from Ginkgo biloba, grape, oregano, curcumin, tea, and ginseng show multitherapeutic effects by synergically acting on different biochemical pathways. Furthermore, the reduced toxicity associated with many of these compounds limits the occurrence of side effects. The support of nanotechnology for improving brain delivery, controlling release, and preventing rapid degradation and excretion of these compounds is of fundamental importance. This review reports on the most promising results obtained on in vitro systems, in vivo models, and in clinical trials, by exploiting natural-derived antioxidant compounds and extracts, in their free form or encapsulated in nanocarriers.}, }
@article {pmid35935951, year = {2022}, author = {Shi, Y and Wei, B and Li, L and Wang, B and Sun, M}, title = {Th17 cells and inflammation in neurological disorders: Possible mechanisms of action.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {932152}, pmid = {35935951}, issn = {1664-3224}, mesh = {Cytokines ; *Depressive Disorder, Major ; Humans ; Inflammation ; *Nervous System Diseases ; Th17 Cells ; }, abstract = {Neurological disorders (NDs) are one of the leading causes of global death. A sustained neuroinflammatory response has been reported to be associated with the pathogenesis of multiple NDs, including Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and major depressive disorder (MDD). Accumulating evidence shows that the recruitment of abundant lymphocytes in the central nervous system may contribute to promoting the development and progress of inflammation in neurological disorders. As one subset of T lymphocytes, CD4[+] T cells have a critical impact on the inflammation of neurological disorders. T helper (Th) 17 is one of the most studied CD4[+] Th subpopulations that produces cytokines (e.g., IL-17A, IL-23, IL-21, IL-6, and IFN-γ), leading to the abnormal neuroinflammatory response including the excessive activation of microglia and the recruitment of other immune cell types. All these factors are involved in several neurological disorders. However, the possible mechanisms of Th17 cells and their associated cytokines in the immunopathology of the abovementioned neurological disorders have not been clarified completely. This review will summarize the mechanisms by which encephalitogenic inflammatory Th17 cells and their related cytokines strongly contribute to chronic neuroinflammation, thus perpetuating neurodegenerative processes in NDs. Finally, the potential therapeutic prospects of Th17 cells and their cytokines in NDs will also be discussed.}, }
@article {pmid35926782, year = {2022}, author = {Jose, S and Groves, NJ and Roper, KE and Gordon, R}, title = {Mechanisms of NLRP3 activation and pathology during neurodegeneration.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {151}, number = {}, pages = {106273}, doi = {10.1016/j.biocel.2022.106273}, pmid = {35926782}, issn = {1878-5875}, mesh = {Amyloid beta-Peptides ; Caspase 1/metabolism ; Humans ; *Inflammasomes/metabolism ; Inflammation ; Interleukin-18 ; Interleukin-1beta/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Neurodegenerative Diseases/pathology ; Protein Aggregates ; alpha-Synuclein ; }, abstract = {Inflammasomes are multiprotein complexes that are mainly present in resident and infiltrating immune cells in the central nervous system. Inflammasomes function as intracellular sensors of immunometabolic stress, infection and changes in the local microenvironment. Inflammasome assembly in response to these 'danger signals', triggers recruitment and cluster-dependent activation of caspase-1 and the subsequent proteolytic activation of inflammatory cytokines such as interleukin-1β and interleukin-18. This is typically followed by a form of inflammatory cell death through pyroptosis. Since the discovery of inflammasomes in 2002, they have come to be recognized as central regulators of acute and chronic inflammation, a hallmark of progressive neurological diseases. Indeed, over the last decade, extensive inflammasome activation has been found at the sites of neuropathology in all progressive neurodegenerative diseases. Disease-specific misfolded protein aggregates which accumulate in neurodegenerative diseases, such as alpha synuclein or beta amyloid, have been found to be important triggers of NLRP3 inflammasome activation in the central nervous system. Together, these discoveries have transformed our understanding of how chronic inflammation is triggered and sustained in the central nervous system, and how it can contribute to neuronal death and disease progression in age-related neurodegenerative diseases. Therapeutic strategies around inhibition of NLRP3 activation in the central nervous system are already being evaluated to determine their effectiveness to slow progressive neurodegeneration. This review summarizes current understanding of inflammasomes in the most prevalent neurodegenerative diseases and discusses current knowledge gaps and inflammasome inhibition as a therapeutic strategy.}, }
@article {pmid35923520, year = {2022}, author = {Ronquest, NA and Paret, K and Lucas, A and Ciepielewska, M and Hagan, M}, title = {Quantifying the Value of Introducing an Oral Drug Delivery Option for Edaravone: A Review of Analyses Evaluating the Economic Impact of Oral versus Intravenous Formulations.}, journal = {ClinicoEconomics and outcomes research : CEOR}, volume = {14}, number = {}, pages = {499-511}, pmid = {35923520}, issn = {1178-6981}, abstract = {BACKGROUND: Drug formulation and route of administration can have an impact on not only patients' quality of life and disease outcomes but also costs of care. It is essential for decision makers to use appropriate economic modeling methods to guide drug coverage policies and to support patients' decision-making.<br><br>PURPOSE: To illustrate key cost considerations for decision makers in economic evaluation of innovative oral formulations as alternatives to intravenous medication.<br><br>MATERIALS AND METHODS: A structured literature review was conducted using the PubMed database to examine methods used for quantifying the economic impact of introducing a new oral pharmaceutical formulation as an alternative to intravenous medication. To illustrate the methods described in this review, a cost-minimization analysis was conducted to quantify the impact of introducing an oral formulation of a medication originally developed as an intravenous treatment for amyotrophic lateral sclerosis.<br><br>RESULTS: We identified 14 published evaluations of oral and intravenous formulations from 10 countries across a variety of disease areas. The identified studies used cost-effectiveness (n=10), cost-minimization (n=2), and cost-calculation (n=2) modeling approaches. All but one (13/14) reported outcomes from payers' perspective, while societal perspectives were also incorporated in 3 of the reviewed evaluations. One study estimated costs from a public hospital's perspective. Only a subset of the identified studies accounted for the effects of safety (n=6) or efficacy (n=8) differences on treatment costs when estimating the costs of a formulation choice. Many studies that omitted these aspects did not include rationales for their decisions.<br><br>CONCLUSION: We found significant design variations in published models that estimated the impact of an additional formulation option on the treatment costs to payers and the society. Models need to be accompanied with clear descriptions on rationales for their time horizons and assumptions on how different formulations may affect healthcare costs from the selected perspectives.}, }
@article {pmid35922223, year = {2022}, author = {Tang, L and Fan, DS}, title = {[Cu/Zn superoxide dismutase and amyotrophic lateral sclerosis: a review of the current state of basic research and clinical trials].}, journal = {Zhonghua nei ke za zhi}, volume = {61}, number = {8}, pages = {948-952}, doi = {10.3760/cma.j.cn112138-20210802-00519}, pmid = {35922223}, issn = {0578-1426}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Clinical Trials as Topic ; Humans ; Mutation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Zinc ; }, }
@article {pmid35921237, year = {2022}, author = {Mazumder, S and Kiernan, MC and Halliday, GM and Timmins, HC and Mahoney, CJ}, title = {The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neuropathology and applied neurobiology}, volume = {48}, number = {7}, pages = {e12845}, pmid = {35921237}, issn = {1365-2990}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Knowledge Discovery ; Brain/pathology ; Neurons/pathology ; United Kingdom ; }, abstract = {Over the past decade, considerable efforts have been made to accelerate pathophysiological understanding of fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with brain banks at the forefront. In addition to exploratory disease mechanisms, brain banks have aided our understanding with regard to clinical diagnosis, genetics and cell biology. Across neurodegenerative disorders, the impact of brain tissue in ALS research has yet to be quantified. This review aims to outline (i) how postmortem tissues from brain banks have influenced our understanding of ALS over the last 15 years, (ii) correlate the location of dedicated brain banks with the geographical prevalence of ALS, (iii) identify the frequency of features reported from postmortem studies and (iv) propose common reporting standards for materials obtained from dedicated brain banks. A systematic review was conducted using PubMed and Web of Science databases using key words. From a total of 1439 articles, 73 articles were included in the final review, following PRISMA guidelines. Following a thematic analysis, articles were categorised into five themes; clinico-pathological (13), genetic (20), transactive response DNA binding protein 43 (TDP-43) pathology (12), non-TDP-43 neuronal pathology (nine) and extraneuronal pathology (19). Research primarily focused on the genetics of ALS, followed by protein pathology. About 63% of the brain banks were in the United States of America and United Kingdom. The location of brain banks overall aligned with the incidence of ALS worldwide with 88% of brain banks situated in Europe and North America. An overwhelming lack of consistency in reporting and replicability was observed, strengthening the need for a standardised reporting system. Overall, postmortem material from brain banks generated substantial new knowledge in areas of genetics and proteomics and supports their ongoing role as an important research tool.}, }
@article {pmid35916975, year = {2022}, author = {Abdolahi, S and Zare-Chahoki, A and Noorbakhsh, F and Gorji, A}, title = {A Review of Molecular Interplay between Neurotrophins and miRNAs in Neuropsychological Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {10}, pages = {6260-6280}, pmid = {35916975}, issn = {1559-1182}, mesh = {*Alzheimer Disease ; Brain-Derived Neurotrophic Factor/metabolism ; *Epilepsy ; Humans ; *MicroRNAs/genetics/metabolism ; Neuronal Plasticity/genetics ; Signal Transduction/physiology ; }, abstract = {Various neurotrophins (NTs), including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4, promote cellular differentiation, survival, and maintenance, as well as synaptic plasticity, in the peripheral and central nervous system. The function of microRNAs (miRNAs) and other small non-coding RNAs, as regulators of gene expression, is pivotal for the appropriate control of cell growth and differentiation. There are positive and negative loops between NTs and miRNAs, which exert modulatory effects on different signaling pathways. The interplay between NTs and miRNAs plays a crucial role in the regulation of several physiological and pathological brain procedures. Emerging evidence suggests the diagnostic and therapeutic roles of the interactions between NTs and miRNAs in several neuropsychological disorders, including epilepsy, multiple sclerosis, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, anxiety disorders, depression, post-traumatic stress disorder, bipolar disorder, and drug abuse. Here, we review current data regarding the regulatory interactions between NTs and miRNAs in neuropsychological disorders, for which novel diagnostic and/or therapeutic strategies are emerging. Targeting NTs-miRNAs interactions for diagnostic or therapeutic approaches needs to be validated by future clinical studies.}, }
@article {pmid35913017, year = {2023}, author = {Pierce, ES and Barkhaus, P and Beauchamp, M and Bromberg, M and Carter, GT and Goslinga, J and Greeley, D and Kihuwa-Mani, S and Levitsky, G and Lund, I and McDermott, C and Pattee, G and Pierce, K and Polak, M and Ratner, D and Wicks, P and Bedlack, R}, title = {ALSUntangled #66: antimycobacterial antibiotics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {539-543}, doi = {10.1080/21678421.2022.2104650}, pmid = {35913017}, issn = {2167-9223}, mesh = {Animals ; Humans ; Anti-Bacterial Agents/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Crohn Disease/etiology/microbiology ; *Mycobacterium avium subsp. paratuberculosis ; *Motor Neuron Disease/complications ; }, abstract = {Several infections have been associated with motor neuron diseases resembling ALS, including species of viruses, bacteria, and parasites. Mycobacterium avium subspecies paratuberculosis (MAP), most known for its probable etiologic association with Crohn's disease, has been suggested as another possible infectious cause of motor neuron disease. Two published case reports describe the successful treatment of ALS-like symptoms with antimycobacterial antibiotics. Both cases had atypical features. Based on these, we believe it would be reasonable to begin performing chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between mycobacteria and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.}, }
@article {pmid35907175, year = {2022}, author = {Heo, YA}, title = {Sodium Phenylbutyrate and Ursodoxicoltaurine: First Approval.}, journal = {CNS drugs}, volume = {36}, number = {9}, pages = {1007-1013}, pmid = {35907175}, issn = {1179-1934}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Pharmaceutical Preparations ; Phenylbutyrates/pharmacology/therapeutic use ; Taurochenodeoxycholic Acid ; }, abstract = {An oral, fixed-dose coformulation of sodium phenylbutyrate and ursodoxicoltaurine (ALBRIOZA[™]; hereafter denoted sodium phenylbutyrate/ursodoxicoltaurine) is being developed by Amylyx Pharmaceuticals for the treatment of neurodegenerative diseases. In June 2022, the coformulation received its first approval with conditions in Canada for the treatment of amyotrophic lateral sclerosis (ALS) in adults. The approval was based on results from the multicentre, phase II CENTAUR trial, in which slowing of ALS progression was demonstrated with sodium phenylbutyrate/ursodoxicoltaurine relative to placebo. This article summarizes the milestones in the development of sodium phenylbutyrate/ursodoxicoltaurine leading to this first approval.}, }
@article {pmid35905138, year = {2022}, author = {Li, Z and Liu, X and Liu, M}, title = {Stress Granule Homeostasis, Aberrant Phase Transition, and Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {13}, number = {16}, pages = {2356-2370}, doi = {10.1021/acschemneuro.2c00262}, pmid = {35905138}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Cytoplasmic Granules/pathology ; Humans ; Mutation ; *Neurodegenerative Diseases ; Stress Granules ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, a large number of ALS-related mutations have been discovered to have a strong link to stress granules (SGs). SGs are cytoplasmic ribonucleoprotein condensates mediated by liquid-liquid phase separation (LLPS) of biomacromolecules. They help cells cope with stress. The normal physiological functions of SGs are dependent on three key aspects of SG "homeostasis": SG assembly, disassembly, and SG components. Any of these three aspects can be disrupted, resulting in abnormalities in the cellular stress response and leading to cytotoxicity. Several ALS-related pathogenic mutants have abnormal LLPS abilities that disrupt SG homeostasis, and some of them can even cause aberrant phase transitions. As a result, ALS-related mutants may disrupt various aspects of SG homeostasis by directly disturbing the intermolecular interactions or affecting core SG components, thus disrupting the phase equilibrium of the cytoplasm during stress. Considering that the importance of the "global view" of SG homeostasis in ALS pathogenesis has not received enough attention, we first systematically summarize the physiological regulatory mechanism of SG homeostasis based on LLPS and then examine ALS pathogenesis from the perspective of disrupted SG homeostasis and aberrant phase transition of biomacromolecules.}, }
@article {pmid35898304, year = {2022}, author = {Ishiguro, A and Ishihama, A}, title = {Essential Roles and Risks of G-Quadruplex Regulation: Recognition Targets of ALS-Linked TDP-43 and FUS.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {957502}, pmid = {35898304}, issn = {2296-889X}, abstract = {A non-canonical DNA/RNA structure, G-quadruplex (G4), is a unique structure formed by two or more guanine quartets, which associate through Hoogsteen hydrogen bonding leading to form a square planar arrangement. A set of RNA-binding proteins specifically recognize G4 structures and play certain unique physiological roles. These G4-binding proteins form ribonucleoprotein (RNP) through a physicochemical phenomenon called liquid-liquid phase separation (LLPS). G4-containing RNP granules are identified in both prokaryotes and eukaryotes, but extensive studies have been performed in eukaryotes. We have been involved in analyses of the roles of G4-containing RNAs recognized by two G4-RNA-binding proteins, TDP-43 and FUS, which both are the amyotrophic lateral sclerosis (ALS) causative gene products. These RNA-binding proteins play the essential roles in both G4 recognition and LLPS, but they also carry the risk of agglutination. The biological significance of G4-binding proteins is controlled through unique 3D structure of G4, of which the risk of conformational stability is influenced by environmental conditions such as monovalent metals and guanine oxidation.}, }
@article {pmid35895572, year = {2022}, author = {Rahmani, B and Ghashghayi, E and Zendehdel, M and Baghbanzadeh, A and Khodadadi, M}, title = {Molecular mechanisms highlighting the potential role of COVID-19 in the development of neurodegenerative diseases.}, journal = {Physiology international}, volume = {109}, number = {2}, pages = {135-162}, doi = {10.1556/2060.2022.00019}, pmid = {35895572}, issn = {2498-602X}, mesh = {Aged ; Alzheimer Disease/genetics/virology ; COVID-19/*complications ; Humans ; Neurodegenerative Diseases/*genetics/*virology ; Parkinson Disease/genetics/virology ; *SARS-CoV-2 ; }, abstract = {Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the pulmonary manifestations, COVID-19 patients may present a wide range of neurological disorders as extrapulmonary presentations. In this view, several studies have recently documented the worsening of neurological symptoms within COVID-19 morbidity in patients previously diagnosed with neurodegenerative diseases (NDs). Moreover, several cases have also been reported in which the patients presented parkinsonian features after initial COVID-19 symptoms. These data raise a major concern about the possibility of communication between SARS-CoV-2 infection and the initiation and/or worsening of NDs. In this review, we have collected compelling evidence suggesting SARS-CoV-2, as an environmental factor, may be capable of developing NDs. In this respect, the possible links between SARS-CoV-2 infection and molecular pathways related to most NDs and the pathophysiological mechanisms of the NDs such as Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis will be explained.}, }
@article {pmid35889517, year = {2022}, author = {Basile, MS and Bramanti, P and Mazzon, E}, title = {Inosine in Neurodegenerative Diseases: From the Bench to the Bedside.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {14}, pages = {}, pmid = {35889517}, issn = {1420-3049}, support = {Current Research Funds 2022//Ministry of Health, Italy/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/metabolism/therapeutic use ; Humans ; Inosine/therapeutic use ; *Multiple Sclerosis/drug therapy ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/drug therapy ; Quality of Life ; Uric Acid/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), currently represent major unmet medical needs. Therefore, novel therapeutic strategies are needed in order to improve patients' quality of life and prognosis. Since oxidative stress can be strongly involved in neurodegenerative diseases, the potential use of inosine, known for its antioxidant properties, in this context deserves particular attention. The protective action of inosine treatment could be mediated by its metabolite urate. Here, we review the current preclinical and clinical studies investigating the use of inosine in AD, PD, ALS, and MS. The most important properties of inosine seem to be its antioxidant action and its ability to raise urate levels and to increase energetic resources by improving ATP availability. Inosine appears to be generally safe and well tolerated; however, the possible formation of kidney stones should be monitored, and data on its effectiveness should be further explored since, so far, they have been controversial. Overall, inosine could be a promising potential strategy in the management of neurodegenerative diseases, and additional studies are needed in order to further investigate its safety and efficacy and its use as a complementary therapy along with other approved drugs.}, }
@article {pmid35888698, year = {2022}, author = {De Silva, S and Turner, BJ and Perera, ND}, title = {Metabolic Dysfunction in Motor Neuron Disease: Shedding Light through the Lens of Autophagy.}, journal = {Metabolites}, volume = {12}, number = {7}, pages = {}, pmid = {35888698}, issn = {2218-1989}, abstract = {Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.}, }
@article {pmid35887567, year = {2022}, author = {Alarcan, H and Al Ojaimi, Y and Lanznaster, D and Escoffre, JM and Corcia, P and Vourc'h, P and Andres, CR and Veyrat-Durebex, C and Blasco, H}, title = {Taking Advantages of Blood-Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?.}, journal = {Journal of personalized medicine}, volume = {12}, number = {7}, pages = {}, pmid = {35887567}, issn = {2075-4426}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.}, }
@article {pmid35887167, year = {2022}, author = {Marlin, E and Viu-Idocin, C and Arrasate, M and Aragón, T}, title = {The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {14}, pages = {}, pmid = {35887167}, issn = {1422-0067}, support = {PID2020-120497RB-I00//MCIN/AEI/10.13039/501100011033/ ; 0011-0537-2018-000006//Predoctoral Fellowship Gobierno de Navarra/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Cell Death ; Disease Progression ; Humans ; Motor Neurons/metabolism ; }, abstract = {In amyotrophic lateral sclerosis (ALS) patients, loss of cellular homeostasis within cortical and spinal cord motor neurons triggers the activation of the integrated stress response (ISR), an intracellular signaling pathway that remodels translation and promotes a gene expression program aimed at coping with stress. Beyond its neuroprotective role, under regimes of chronic or excessive stress, ISR can also promote cell/neuronal death. Given the two-edged sword nature of ISR, many experimental attempts have tried to establish the therapeutic potential of ISR enhancement or inhibition in ALS. This review discusses the complex interplay between ISR and disease progression in different models of ALS, as well as the opportunities and limitations of ISR modulation in the hard quest to find an effective therapy for ALS.}, }
@article {pmid35887154, year = {2022}, author = {Tringali, C and Giussani, P}, title = {Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy.}, journal = {International journal of molecular sciences}, volume = {23}, number = {14}, pages = {}, pmid = {35887154}, issn = {1422-0067}, support = {grant PSR2020_PG, grant PSR2021_PG//Piano sostegno alla ricerca BIOMETRA-Linea B/ ; }, mesh = {Animals ; *Ceramides/metabolism ; Lysophospholipids ; *Neurodegenerative Diseases/metabolism ; Phosphates ; Sphingolipids/metabolism ; Sphingosine/analogs &amp; derivatives/metabolism ; }, abstract = {Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.}, }
@article {pmid35883554, year = {2022}, author = {Hestad, K and Alexander, J and Rootwelt, H and Aaseth, JO}, title = {The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {12}, number = {7}, pages = {}, pmid = {35883554}, issn = {2218-273X}, mesh = {Cytokines ; Humans ; Kynurenine/metabolism ; *Neurodegenerative Diseases/metabolism ; *Quinolinic Acid/metabolism ; Tryptophan/metabolism ; }, abstract = {Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.}, }
@article {pmid35866707, year = {2023}, author = {Finsel, J and Uttner, I and Vázquez Medrano, CR and Ludolph, AC and Lulé, D}, title = {Cognition in the course of ALS-a meta-analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {1-2}, pages = {2-13}, doi = {10.1080/21678421.2022.2101379}, pmid = {35866707}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Cross-Sectional Studies ; Cognition ; *Cognitive Dysfunction ; *Cognition Disorders/diagnosis ; }, abstract = {Objective: The goal of this meta-analysis is to improve insight into the development of cognition over the course of ALS and to assess predictors of cognitive performance.Method: A literature search was conducted in Pubmed and Web of Science on 29 July 2019 and 16 March 2021. Data were screened in Endnote[®] Version X9 (London, UK). Meta-analyses and meta-regressions were calculated for cross-sectional data using Rstudio[®]. Studies were assigned to temporal and physical categories and Hedges' g was calculated for the respective categories to provide an estimate of a cognitive course based on cross-sectional data. Due to low numbers and heterogeneity in reporting, longitudinal studies were analyzed descriptively.Results: A total of N = 45 cross-sectional and N = 13 longitudinal studies were included. Impairments in all cognitive domains, except verbal IQ, were found in ALS patients (PALS). PALS showed stable cognitive performances in cross-sectional and in most longitudinal studies. PALS with symptoms for 18-24 months and PALS who had an ALSFRS-R score of 40-36 were the most frequently reported subgroup regarding neuropsychology. Age was related to visuospatial functioning, and depressiveness to attention. In longitudinal studies, impact of site of onset and cognitive status at baseline on cognitive course was found.Conclusion: Despite vast evidence for cognitive impairment at disease onset in different domains, evidence for evolution of these deficits is rather limited, suggesting that PALS present with cognitive impairment early in the course possibly in a sense of disease trait.}, }
@article {pmid35864981, year = {2022}, author = {Abulseoud, OA and Alasmari, F and Hussein, AM and Sari, Y}, title = {Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {841036}, pmid = {35864981}, issn = {1662-4548}, abstract = {Dysregulation of glutamate homeostasis is a well-established core feature of neuropsychiatric disorders. Extracellular glutamate concentration is regulated by glutamate transporter 1 (GLT-1). The discovery of a beta-lactam antibiotic, ceftriaxone (CEF), as a safe compound with unique ability to upregulate GLT-1 sparked the interest in testing its efficacy as a novel therapeutic agent in animal models of neuropsychiatric disorders with hyperglutamatergic states. Indeed, more than 100 preclinical studies have shown the efficacy of CEF in attenuating the behavioral manifestations of various hyperglutamatergic brain disorders such as ischemic stroke, amyotrophic lateral sclerosis (ALS), seizure, Huntington's disease, and various aspects of drug use disorders. However, despite rich and promising preclinical data, only one large-scale clinical trial testing the efficacy of CEF in patients with ALS is reported. Unfortunately, in that study, there was no significant difference in survival between placebo- and CEF-treated patients. In this review, we discussed the translational potential of preclinical efficacy of CEF based on four different parameters: (1) initiation of CEF treatment in relation to induction of the hyperglutamatergic state, (2) onset of response in preclinical models in relation to onset of GLT-1 upregulation, (3) mechanisms of action of CEF on GLT-1 expression and function, and (4) non-GLT-1-mediated mechanisms for CEF. Our detailed review of the literature brings new insights into underlying molecular mechanisms correlating the preclinical efficacy of CEF. We concluded here that CEF may be clinically effective in selected cases in acute and transient hyperglutamatergic states such as early drug withdrawal conditions.}, }
@article {pmid35863917, year = {2022}, author = {Verschueren, A and Palminha, C and Delmont, E and Attarian, S}, title = {Changes in neuromuscular function in elders: Novel techniques for assessment of motor unit loss and motor unit remodeling with aging.}, journal = {Revue neurologique}, volume = {178}, number = {8}, pages = {780-787}, doi = {10.1016/j.neurol.2022.03.019}, pmid = {35863917}, issn = {0035-3787}, mesh = {Aged ; Aging/physiology ; *Amyotrophic Lateral Sclerosis/diagnosis ; Electromyography/methods ; Humans ; *Motor Neuron Disease ; Motor Neurons/physiology ; Muscle, Skeletal ; }, abstract = {Functional muscle fiber denervation is a major contributor to the decline in physical function observed with aging and is now a recognized cause of sarcopenia, a muscle disorder characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength. There is an interrelationship between muscle strength, motor unit (MU) number, and aging, which suggests that a portion of muscle weakness in seniors may be attributable to the loss of functional MUs. During normal aging, there is a time-related progression of MU loss, an adaptive sprouting followed by a maladaptive sprouting, and continuing recession of terminal Schwann cells leading to a reduced capacity for compensatory reinnervation in elders. In amyotrophic lateral sclerosis, increasing age at onset predicts worse survival ALS and it is possible that age-related depletion of the motor neuron pool may worsen motor neuron disease. MUNE methods are used to estimate the number of functional MU, data from MUNIX arguing for motor neuron loss with aging will be reviewed. Recently, a new MRI technique MU-MRI could be used to assess the MU recruitment or explore the activity of a single MU. This review presents published studies on the changes of neuromuscular function with aging, then focusing on these two novel techniques for assessment of MU loss and MU remodeling.}, }
@article {pmid35859075, year = {2022}, author = {García-Revilla, J and Boza-Serrano, A and Espinosa-Oliva, AM and Soto, MS and Deierborg, T and Ruiz, R and de Pablos, RM and Burguillos, MA and Venero, JL}, title = {Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration.}, journal = {Cell death &amp; disease}, volume = {13}, number = {7}, pages = {628}, pmid = {35859075}, issn = {2041-4889}, mesh = {*Alzheimer Disease/genetics ; Galectin 3/genetics ; Humans ; Microglia ; *Parkinson Disease ; }, abstract = {The advent of high-throughput single-cell transcriptomic analysis of microglia has revealed different phenotypes that are inherently associated with disease conditions. A common feature of some of these activated phenotypes is the upregulation of galectin-3. Representative examples of these phenotypes include disease-associated microglia (DAM) and white-associated microglia (WAM), whose role(s) in neuroprotection/neurotoxicity is a matter of high interest in the microglia community. In this review, we summarise the main findings that demonstrate the ability of galectin-3 to interact with key pattern recognition receptors, including, among others, TLR4 and TREM2 and the importance of galectin-3 in the regulation of microglia activation. Finally, we discuss increasing evidence supporting the involvement of this lectin in the main neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, and stroke.}, }
@article {pmid35856508, year = {2022}, author = {Maurya, SK and Gupta, S and Bakshi, A and Kaur, H and Jain, A and Senapati, S and Baghel, MS}, title = {Targeting mitochondria in the regulation of neurodegenerative diseases: A comprehensive review.}, journal = {Journal of neuroscience research}, volume = {100}, number = {10}, pages = {1845-1861}, doi = {10.1002/jnr.25110}, pmid = {35856508}, issn = {1097-4547}, mesh = {Homeostasis ; Humans ; Inflammation/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondria are one of the essential cellular organelles. Apart from being considered as the powerhouse of the cell, mitochondria have been widely known to regulate redox reaction, inflammation, cell survival, cell death, metabolism, etc., and are implicated in the progression of numerous disease conditions including neurodegenerative diseases. Since brain is an energy-demanding organ, mitochondria and their functions are important for maintaining normal brain homeostasis. Alterations in mitochondrial gene expression, mutations, and epigenetic modification contribute to inflammation and neurodegeneration. Dysregulation of reactive oxygen species production by mitochondria and aggregation of proteins in neurons leads to alteration in mitochondria functions which further causes neuronal death and progression of neurodegeneration. Pharmacological studies have prioritized mitochondria as a possible drug target in the regulation of neurodegenerative diseases. Therefore, the present review article has been intended to provide a comprehensive understanding of mitochondrial role in the development and progression of neurodegenerative diseases mainly Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis followed by possible intervention and future treatment strategies to combat mitochondrial-mediated neurodegeneration.}, }
@article {pmid35855239, year = {2022}, author = {Jayasinghe, M and Jena, R and Singhal, M and Jain, S and Karnakoti, S and Silva, MS and Kayani, AMA}, title = {Ethnical Disparities in Response to Edaravone in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {14}, number = {6}, pages = {e25960}, pmid = {35855239}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease characterized by the weakness of voluntary muscles due to the loss of motor neurons. Symptoms ultimately culminate in the form of respiratory failure due to the involvement of the diaphragm. Unfortunately, there is no known cure for this disease. Hence, supportive therapy is the only available option in most terminal cases. However, Riluzole and Edaravone (EDA) are the only two known drugs approved by the U.S. Food and Drug Administration (FDA) for treating this condition. In 2017, EDA was approved for the treatment of ALS. It is hypothesized that Riluzole and EDA work via a mechanism involving antioxidants, which nullifies the oxidative stress believed to be involved in ALS. However, most studies in several countries have found a wide range of disparities in the efficacy of this drug. In this review, we aim to summarize the differences in results from epidemiological studies across 10 different countries and hypothesize the potential causes of these differences.}, }
@article {pmid35853395, year = {2022}, author = {Mominur Rahman, M and Afsana Mim, S and Afroza Alam Tumpa, M and Taslim Sarker, M and Ahmed, M and Alghamdi, BS and Hafeez, A and Alexiou, A and Perveen, A and Md Ashraf, G}, title = {Exploring the management approaches of cytokines including viral infection and neuroinflammation for neurological disorders.}, journal = {Cytokine}, volume = {157}, number = {}, pages = {155962}, doi = {10.1016/j.cyto.2022.155962}, pmid = {35853395}, issn = {1096-0023}, mesh = {*Alzheimer Disease ; Cytokines/physiology ; Humans ; *Nervous System Diseases/therapy ; Neuroinflammatory Diseases ; *Virus Diseases ; }, abstract = {Considerable evidence supports that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in various neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. The purpose of this study is to discuss the recent research on treating cytokine storm and amyloids, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's condition, Multi-sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). Neuroinflammation observed in neurological disorders has a pivotal role in exacerbating Aβ burden and tau hyperphosphorylation, suggesting that stimulating cytokines in response to an undesirable external response could be a checkpoint for treating neurological disorders. Furthermore, the pro-inflammatory cytokines help our immune system through a neuroprotective mechanism in clearing viral infection by recruiting mononuclear cells. This study reveals that cytokine applications may play a vital role in providing novel regulation and methods for the therapeutic approach to neurological disorders and the causes of the deregulation, which is responsible for neuroinflammation and viral infection. However, it needs to be further investigated to clarify better the mechanisms of cytokine release in response to various stimuli, which could be the central point for treating neurological disorders.}, }
@article {pmid35850103, year = {2022}, author = {Tatu, L and Bogousslavsky, J}, title = {Treatments in Neurology: The Winding Road from 1897 to 2022.}, journal = {European neurology}, volume = {85}, number = {5}, pages = {367-370}, doi = {10.1159/000525689}, pmid = {35850103}, issn = {1421-9913}, mesh = {*Amyotrophic Lateral Sclerosis ; *Brain Neoplasms ; Humans ; *Multiple Sclerosis/therapy ; *Neurology ; *Parkinson Disease/therapy ; }, abstract = {BACKGROUND: For many years, neurology was seen as a purely observational discipline, focused on pathology and with little interest in treatments.<br><br>SUMMARY: From the creation in 1897 of Monatsschrift f&#xfc;r Psychiatrie und Neurologie, the forebear of European Neurology, to nowadays, there have been great changes in the paradigms and concepts of treatments in neurology. We present an overview of the evolution of neurological treatments from 1897 to 2022.<br><br>KEY MESSAGES: However, the last 125 years have not consisted of constant progress. The exceptional advances made in some diseases (multiple sclerosis or surgical treatment of Parkinson's disease) cannot hide the stagnation in others (certain brain tumors or amyotrophic lateral sclerosis).}, }
@article {pmid35845350, year = {2022}, author = {Lu, G and Wang, Y and Shi, Y and Zhang, Z and Huang, C and He, W and Wang, C and Shen, HM}, title = {Autophagy in health and disease: From molecular mechanisms to therapeutic target.}, journal = {MedComm}, volume = {3}, number = {3}, pages = {e150}, pmid = {35845350}, issn = {2688-2663}, abstract = {Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.}, }
@article {pmid35843039, year = {2022}, author = {Yoo, HS and Shanmugalingam, U and Smith, PD}, title = {Potential roles of branched-chain amino acids in neurodegeneration.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {103-104}, number = {}, pages = {111762}, doi = {10.1016/j.nut.2022.111762}, pmid = {35843039}, issn = {1873-1244}, mesh = {Humans ; *Amino Acids, Branched-Chain/metabolism ; *Neurodegenerative Diseases ; Oxidative Stress ; Neurotransmitter Agents ; }, abstract = {Despite having disease-specific pathologic features and symptoms, neurodegenerative diseases share common mechanisms, such as excitotoxicity, neuroinflammation, and neurotransmitter dysregulation. Although the common underlying cause of these neurodegenerative processes has yet to be identified, accumulating evidence suggests that branched-chain amino acids (BCAAs) could be involved. BCAAs have been shown to not only influence the central levels of neurotransmitters but also to induce excitotoxicity, hyperexcitability, inflammation, and oxidative stress. Furthermore, emerging evidence indicates that BCAA metabolism may be dysregulated in major neurodegenerative diseases, namely Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. In this review, we identified the neurodegenerative mechanisms of BCAAs and outlined their potential roles in neurodegenerative diseases, suggesting that targeting BCAA metabolism may represent a new approach to identifying new therapeutic targets for multifaceted neurodegenerative diseases.}, }
@article {pmid35842587, year = {2022}, author = {Rahbaran, M and Zekiy, AO and Bahramali, M and Jahangir, M and Mardasi, M and Sakhaei, D and Thangavelu, L and Shomali, N and Zamani, M and Mohammadi, A and Rahnama, N}, title = {Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects.}, journal = {Cellular &amp; molecular biology letters}, volume = {27}, number = {1}, pages = {56}, pmid = {35842587}, issn = {1689-1392}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/therapy ; Animals ; *Mesenchymal Stem Cell Transplantation ; *Mesenchymal Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; }, abstract = {Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs.}, }
@article {pmid37323688, year = {2021}, author = {Zhang, Y and Yang, H and Wei, D and Zhang, X and Wang, J and Wu, X and Chang, J}, title = {Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.}, journal = {Exploration (Beijing, China)}, volume = {1}, number = {3}, pages = {20210115}, pmid = {37323688}, issn = {2766-2098}, abstract = {Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.}, }
@article {pmid36911507, year = {2021}, author = {Mentis, AA and Bougea, AM and Chrousos, GP}, title = {Amyotrophic lateral sclerosis (ALS) and the endocrine system: Are there any further ties to be explored?.}, journal = {Aging brain}, volume = {1}, number = {}, pages = {100024}, pmid = {36911507}, issn = {2589-9589}, abstract = {Amyotrophic Lateral Sclerosis (ALS) belongs to the family of neurodegenerative disorders and is classified as fronto-temporal dementia (FTD), progressive muscular atrophy, primary lateral sclerosis, and pseudobulbar palsy. Even though endocrine dysfunction independently impacts the ALS-related survival rate, the complex connection between ALS and the endocrine system has not been studied in depth. Here we review earlier and recent findings on how ALS interacts with hormones a) of the hypothalamus and pituitary gland, b) the thyroid gland, c) the pancreas, d) the adipose tissue, e) the parathyroid glands, f) the bones, g) the adrenal glands, and h) the gonads (ovaries and testes). Of note, endocrine issues should always be explored in patients with ALS, especially those with low skeletal muscle and bone mass, vitamin D deficiency, and decreased insulin sensitivity (diabetes mellitus). Because ALS is a progressively deteriorating disease, addressing any potential endocrine co-morbidities in patients with this malady is quite important for decreasing the overall ALS-associated disease burden. Importantly, as this burden is estimated to increase globally in the decades to follow, in part because of an increasingly aging population, it is high time for future multi-center, multi-ethnic studies to assess the link between ALS and the endocrine system in significantly larger patient populations. Last, the psychosocial stress experienced by patients with ALS and its psycho-neuro-endocrinological sequelae, including hypothalamic-pituitaryadrenal dysregulation, should become an area of intensive study in the future.}, }
@article {pmid38505660, year = {2021}, author = {Romero, E and Jones, BS and Hogg, BN and Rué Casamajo, A and Hayes, MA and Flitsch, SL and Turner, NJ and Schnepel, C}, title = {Enzymkatalysierte späte Modifizierungen: Besser spät als nie.}, journal = {Angewandte Chemie (Weinheim an der Bergstrasse, Germany)}, volume = {133}, number = {31}, pages = {16962-16993}, pmid = {38505660}, issn = {0044-8249}, }
@article {pmid37786905, year = {2021}, author = {Huang, ZQ and Ba, ZS and Huang, NQ and Li, YY and Luo, Y}, title = {Aberrant TDP-43 phosphorylation: a key wind gap from TDP-43 to TDP-43 proteinopathy.}, journal = {Ibrain}, volume = {7}, number = {2}, pages = {119-131}, pmid = {37786905}, issn = {2769-2795}, abstract = {TDP-43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA-binding protein of 43-kDa molecular weight (TDP-43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP-43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP-43 plays an important role in triggering or promoting the occurrence and progression of TDP-43 proteinopathy. The hyperphosphorylation of TDP-43 is undoubtedly an important factor in triggering or promoting the process of TDP-43 proteinopathy. Hyperphosphorylation of TDP-43 can inhibit the degradation of TDP-43, aggravate the aggregation of TDP-43 protein, increase the wrong localization of TDP-43 in cells, and enhance the cytotoxicity of TDP-43. More and more evidences show that the hyperphosphorylation of TDP-43 plays an important role in the pathogenesis of TDP-43 proteinopathy. Inhibition of TDP-43 hyperphosphorylation may be one of the important strategies for the treatment of TDP-43 proteinopathy. Therefore, this article reviews the role of TDP-43 phosphorylation in TDP-43 proteinopathy and the related mechanisms.}, }
@article {pmid37427003, year = {2021}, author = {Horowitz, AJ and Guger, C and Korostenskaja, M}, title = {What Internal Variables Affect Sensorimotor Rhythm Brain-Computer Interface (SMR-BCI) Performance?.}, journal = {HCA healthcare journal of medicine}, volume = {2}, number = {3}, pages = {163-179}, pmid = {37427003}, issn = {2689-0216}, abstract = {Description In this review article, we aimed to create a summary of the effects of internal variables on the performance of sensorimotor rhythm-based brain computer interfaces (SMR-BCIs). SMR-BCIs can be potentially used for interfacing between the brain and devices, bypassing usual central nervous system output, such as muscle activity. The careful consideration of internal factors, affecting SMR-BCI performance, can maximize BCI application in both healthy and disabled people. Internal variables may be generalized as descriptors of the processes mainly dependent on the BCI user and/or originating within the user. The current review aimed to critically evaluate and summarize the currently accumulated body of knowledge regarding the effect of internal variables on SMR-BCI performance. The examples of such internal variables include motor imagery, hand coordination, attention, motivation, quality of life, mood and neurophysiological signals other than SMR. We will conclude our review with the discussion about the future developments regarding the research on the effects of internal variables on SMR-BCI performance. The end-goal of this review paper is to provide current BCI users and researchers with the reference guide that can help them optimize the SMR-BCI performance by accounting for possible influences of various internal factors.}, }
@article {pmid37366377, year = {2021}, author = {Borgese, N and Navone, F and Nukina, N and Yamanaka, T}, title = {Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?.}, journal = {Contact (Thousand Oaks (Ventura County, Calif.))}, volume = {4}, number = {}, pages = {25152564211022515}, pmid = {37366377}, issn = {2515-2564}, abstract = {Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.}, }
@article {pmid37387779, year = {2021}, author = {Huang, H and Chen, L and Chopp, M and Young, W and Robert Bach, J and He, X and Sarnowaska, A and Xue, M and Chunhua Zhao, R and Shetty, A and Siniscalco, D and Guo, X and Khoshnevisan, A and Hawamdeh, Z}, title = {The 2020 Yearbook of Neurorestoratology.}, journal = {Journal of neurorestoratology}, volume = {9}, number = {1}, pages = {1-12}, pmid = {37387779}, issn = {2324-2426}, abstract = {COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020. Facing this dangerous situation, many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients, and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology. Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. Therapeutic progress during this year included advances in cell therapies, neurostimulation/neuromodulation, brain-computer interface (BCI), and pharmaceutical neurorestorative therapies, which improved neurological functions and quality of life for patients. Four clinical guidelines or standards of Neurorestoratology were published in 2020. Milestone examples include: 1) a multicenter randomized, double-blind, placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements; 2) patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis; 3) a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential (SSVEP)-based BCI to achieve accurate and speedy computer input; 4) a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions. We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.}, }
@article {pmid36132559, year = {2021}, author = {Sungjemmenla,  and Soni, CB and Kumar, V}, title = {Recent advances in cathode engineering to enable reversible room-temperature aluminium-sulfur batteries.}, journal = {Nanoscale advances}, volume = {3}, number = {6}, pages = {1569-1581}, pmid = {36132559}, issn = {2516-0230}, abstract = {The rigorous requirements, such as high abundance, cost-effectiveness, and increased storage capacities, pose severe challenges to the existing Li-ion batteries' long-term sustainability. Room-temperature aluminum-sulfur (Al-S) chemistry, in particular, is gaining importance due to its high theoretical energy density (1700 W h kg[-1]). Al-S battery technology is one of the emerging metal-sulfur candidates that can surpass current Li-ion chemistries. When coupled with sulfur, aluminum metal brings a cheap and energy-rich option to existing battery technologies. Owing to the unique virtues of the Al-S battery, it has garnered increasing interest among scientific communities. Al-S chemistry has been investigated for quite some time, yet the cell performance remained in its infancy, which poses a challenge to this technology's viability. Besides stabilizing the Al metal anode, the most important challenge in the practical development of Al-S batteries is the development of a suitable sulfur cathode material. Owing to the complexity of this multivalent system, numerous factors have been taken into account, but the best sulfur cathode is yet to be identified. A detailed exploration of sulfur cathodes and their implications on the battery performance are discussed in this mini-review article. We present a detailed picture of cathode materials that may serve as the reference guide for developing more practical cathode materials. Also, fundamental principles and challenges encountered in the development of the sulfur cathodes are highlighted. Through the knowledge disseminated in this mini-review, the development in the multivalent post-Li-ion battery can be accelerated. A glimpse of the future outlook on the Al-S battery system with different potential solutions is also discussed.}, }
@article {pmid35837484, year = {2022}, author = {Sun, Y and Xia, X and Basnet, D and Zheng, JC and Huang, J and Liu, J}, title = {Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {904152}, pmid = {35837484}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a diverse class of diseases attributed to chronic progressive neuronal degeneration and synaptic loss in the brain and/or spinal cord, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. The pathogenesis of neurodegenerative diseases is complex and diverse, often involving mitochondrial dysfunction, neuroinflammation, and epigenetic changes. However, the pathogenesis of neurodegenerative diseases has not been fully elucidated. Recently, accumulating evidence revealed that ferroptosis, a newly discovered iron-dependent and lipid peroxidation-driven type of programmed cell death, provides another explanation for the occurrence and progression of neurodegenerative diseases. Here, we provide an overview of the process and regulation mechanisms of ferroptosis, and summarize current research progresses that support the contribution of ferroptosis to the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the emerging roles of ferroptosis in neurodegenerative diseases will shed light on the development of novel therapeutic technologies and strategies for slowing down the progression of these diseases.}, }
@article {pmid35837234, year = {2022}, author = {Yoshida, S}, title = {Therapeutic Strategies and Metal-Induced Oxidative Stress: Application of Synchrotron Radiation Microbeam to Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {884439}, pmid = {35837234}, issn = {1664-2295}, abstract = {A series of extensive gene-environment studies on amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in Guam Island, USA, and the Kii Peninsula of Japan, including Auyu Jakai, West New Guinea, have led us to hypothesize that a prolonged low calcium (Ca) and magnesium (Mg) intake, especially over generation, may cause oxidative stress to motor and nigral neurons by an increased uptake of environment metallic elements, i.e., aluminum (Al), manganese (Mn), and iron (Fe). Otherwise, 5-10% of total ALS cases are familial ALS (fALS), of which 20% of the fALS cases linked to a point mutation of Cu/Zn superoxide dismutase (SOD1). In the vicinity of the Kii Peninsula, about 7% of the ALS cases are also linked to the SOD1 mutation. Using synchrotron radiation (SR) microbeam, conglomerate inclusion (SOD1 aggregates) within a spinal motor neuron of the fALS case in the vicinity revealed a loss of copper (Cu) in contrast to extremely high contents of Zinc (Zn) and Ca. That means an exceptionally low Cu/Zn ratio with an increased Ca content, indicating the abnormalities of the active site of SOD1 protein of the fALS. Furthermore, sALS in the southernmost high incidence areas of the Kii Peninsula showed a low Cu/Zn ratio within a motor neuron, suggesting a fragility of SOD1 proteins. From the perspective of gene-environment interactions, the above two research trends may show a common oxidative stress underlying the neuronal degenerative process of ALS/PDC in the Kii Peninsula of Japan. Therefore, it is a crucial point for the prospect of therapeutic strategy to clarify a role of transition metals in the oxidative process in both ALS/PDC, including ALS elsewhere in the world. This paper reviews a history of the genetic epidemiological studies, especially from the aspect of gene-environment interaction, on ALS/PDC in the Kii and Guam high incidence foci and the results of a series of analytical research on trace metallic elements within neurons of both sALS and fALS cases, especially using a synchrotron radiation (SR) microbeam of Spring-8 and Photon Factory of Japan. The SR microbeam is an ideal X-ray source, which supplies an extremely high brilliance (high-intensity photon) and tunability (energy variability) to investigate trace metallic elements contained in biological specimens at the cellular level, even more without any damages. This research will provide a valuable information about the mechanism of oxidative stress involved in neuronal cell death in ALS and related neurodegenerative disorders. To elucidate the physicochemical mechanism of the oxidative process in neuronal degeneration, it will shed a new light on the therapeutic strategies for ALS/PDC in near future.}, }
@article {pmid35819713, year = {2022}, author = {Fournier, CN}, title = {Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1180-1192}, pmid = {35819713}, issn = {1878-7479}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Reproducibility of Results ; Clinical Trials as Topic ; Biomarkers ; Disease Progression ; }, abstract = {Thoughtful clinical trial design is critical for efficient therapeutic development, particularly in the field of amyotrophic lateral sclerosis (ALS), where trials often aim to detect modest treatment effects among a population with heterogeneous disease progression. Appropriate outcome measure selection is necessary for trials to provide decisive and informative results. Investigators must consider the outcome measure's reliability, responsiveness to detect change when change has actually occurred, clinical relevance, and psychometric performance. ALS clinical trials can also be performed more efficiently by utilizing statistical enrichment techniques. Innovations in ALS prediction models allow for selection of participants with less heterogeneity in disease progression rates without requiring a lead-in period, or participants can be stratified according to predicted progression. Statistical enrichment can reduce the needed sample size and improve study power, but investigators must find a balance between optimizing statistical efficiency and retaining generalizability of study findings to the broader ALS population. Additional progress is still needed for biomarker development and validation to confirm target engagement in ALS treatment trials. Selection of an appropriate biofluid biomarker depends on the treatment mechanism of interest, and biomarker studies should be incorporated into early phase trials. Inclusion of patients with ALS as advisors and advocates can strengthen clinical trial design and study retention, but more engagement efforts are needed to improve diversity and equity in ALS research studies. Another challenge for ALS therapeutic development is identifying ways to respect patient autonomy and improve access to experimental treatment, something that is strongly desired by many patients with ALS and ALS advocacy organizations. Expanded access programs that run concurrently to well-designed and adequately powered randomized controlled trials may provide an opportunity to broaden access to promising therapeutics without compromising scientific integrity or rushing regulatory approval of therapies without adequate proof of efficacy.}, }
@article {pmid35813998, year = {2022}, author = {Miny, L and Maisonneuve, BGC and Quadrio, I and Honegger, T}, title = {Modeling Neurodegenerative Diseases Using In Vitro Compartmentalized Microfluidic Devices.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {10}, number = {}, pages = {919646}, pmid = {35813998}, issn = {2296-4185}, abstract = {The human brain is a complex organ composed of many different types of cells interconnected to create an organized system able to efficiently process information. Dysregulation of this delicately balanced system can lead to the development of neurological disorders, such as neurodegenerative diseases (NDD). To investigate the functionality of human brain physiology and pathophysiology, the scientific community has been generated various research models, from genetically modified animals to two- and three-dimensional cell culture for several decades. These models have, however, certain limitations that impede the precise study of pathophysiological features of neurodegeneration, thus hindering therapeutical research and drug development. Compartmentalized microfluidic devices provide in vitro minimalistic environments to accurately reproduce neural circuits allowing the characterization of the human central nervous system. Brain-on-chip (BoC) is allowing our capability to improve neurodegeneration models on the molecular and cellular mechanism aspects behind the progression of these troubles. This review aims to summarize and discuss the latest advancements of microfluidic models for the investigations of common neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid35813507, year = {2022}, author = {Konopka, A and Atkin, JD}, title = {The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {836885}, pmid = {35813507}, issn = {1662-5102}, abstract = {Damage to DNA is generally considered to be a harmful process associated with aging and aging-related disorders such as neurodegenerative diseases that involve the selective death of specific groups of neurons. However, recent studies have provided evidence that DNA damage and its subsequent repair are important processes in the physiology and normal function of neurons. Neurons are unique cells that form new neural connections throughout life by growth and re-organisation in response to various stimuli. This "plasticity" is essential for cognitive processes such as learning and memory as well as brain development, sensorial training, and recovery from brain lesions. Interestingly, recent evidence has suggested that the formation of double strand breaks (DSBs) in DNA, the most toxic form of damage, is a physiological process that modifies gene expression during normal brain activity. Together with subsequent DNA repair, this is thought to underlie neural plasticity and thus control neuronal function. Interestingly, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease, manifest by a decline in cognitive functions, which are governed by plasticity. This suggests that DNA damage and DNA repair processes that normally function in neural plasticity may contribute to neurodegeneration. In this review, we summarize current understanding about the relationship between DNA damage and neural plasticity in physiological conditions, as well as in the pathophysiology of neurodegenerative diseases.}, }
@article {pmid35812232, year = {2022}, author = {Huang, J and Li, C and Shang, H}, title = {Astrocytes in Neurodegeneration: Inspiration From Genetics.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {882316}, pmid = {35812232}, issn = {1662-4548}, abstract = {Despite the discovery of numerous molecules and pathologies, the pathophysiology of various neurodegenerative diseases remains unknown. Genetics participates in the pathogenesis of neurodegeneration. Neural dysfunction, which is thought to be a cell-autonomous mechanism, is insufficient to explain the development of neurodegenerative disease, implying that other cells surrounding or related to neurons, such as glial cells, are involved in the pathogenesis. As the primary component of glial cells, astrocytes play a variety of roles in the maintenance of physiological functions in neurons and other glial cells. The pathophysiology of neurodegeneration is also influenced by reactive astrogliosis in response to central nervous system (CNS) injuries. Furthermore, those risk-gene variants identified in neurodegenerations are involved in astrocyte activation and senescence. In this review, we summarized the relationships between gene variants and astrocytes in four neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and provided insights into the implications of astrocytes in the neurodegenerations.}, }
@article {pmid35809130, year = {2022}, author = {Farace, C and Fiorito, G and Pisano, A and Etzi, F and Sabalic, A and Fenu, G and Asara, Y and Solinas, G and Madeddu, R}, title = {Human tissue lead (Pb) levels and amyotrophic lateral sclerosis: a systematic review and meta-analysis of case-control studies.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {10}, pages = {5851-5859}, pmid = {35809130}, issn = {1590-3478}, support = {FAR-2020//Universit&#xe0; degli Studi di Sassari/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; Case-Control Studies ; Humans ; Lead ; }, abstract = {AIM: To combine the current scientific literature evidence and elucidate the differences of lead (Pb) bioaccumulation in human tissues by comparing amyotrophic lateral sclerosis (ALS) patients and healthy controls.<br><br>METHODS: We systematically searched for case-control studies on the association of Pb levels with ALS, in human cells, tissues, and body fluids (nervous tissue, muscle, blood, cerebrospinal fluid, urine, skin appendages). Then, we performed a meta-analysis for all the tissues in which at least five case-control studies were available: whole blood (9 studies), serum/plasma (5 studies), and cerebrospinal fluid (CSF) (6 studies). Differences between cases and controls were evaluated using standardized mean difference, and combined estimates were derived using random effect maximum likelihood (REML) meta-analyses.<br><br>RESULTS: Among 1734 records, we identified 46 full-text studies, of which 14 case-control studies met the meta-analysis inclusion criteria. We found higher Pb levels in ALS cases than controls in blood (standardized mean difference (SMD)&#x2009;=&#x2009;0.61; 95% confidence interval (CI) 0.20, 1.01; p&#x2009;=&#x2009;0.003), plasma/serum (SMD&#x2009;=&#x2009;0.27; 95% CI&#x2009;-&#x2009;0.16, 0.70; p&#x2009;=&#x2009;0.26), and CSF (SMD&#x2009;=&#x2009;0.53; 95% CI&#x2009;-&#x2009;0.09, 1.15; p&#x2009;=&#x2009;0.09).<br><br>CONCLUSIONS: This work provides further evidence of the association between Pb bioaccumulation and ALS in body fluids. The lack of association studies in solid tissues did not allow a robust meta-analysis. Future prospective studies are needed to clarify the causality in the association of Pb bioaccumulation with ALS.}, }
@article {pmid35807977, year = {2022}, author = {Waris, A and Ali, A and Khan, AU and Asim, M and Zamel, D and Fatima, K and Raziq, A and Khan, MA and Akbar, N and Baset, A and Abourehab, MAS}, title = {Applications of Various Types of Nanomaterials for the Treatment of Neurological Disorders.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {12}, number = {13}, pages = {}, pmid = {35807977}, issn = {2079-4991}, support = {22UQU4290565DSR22//Umm Al-Qura University Saudi Arabia/ ; }, abstract = {Neurological disorders (NDs) are recognized as one of the major health concerns globally. According to the World Health Organization (WHO), neurological disorders are one of the main causes of mortality worldwide. Neurological disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Prion disease, Brain tumor, Spinal cord injury, and Stroke. These diseases are considered incurable diseases because no specific therapies are available to cross the blood-brain barrier (BBB) and reach the brain in a significant amount for the pharmacological effect in the brain. There is a need for the development of strategies that can improve the efficacy of drugs and circumvent BBB. One of the promising approaches is the use of different types of nano-scale materials. These nano-based drugs have the ability to increase the therapeutic effect, reduce toxicity, exhibit good stability, targeted delivery, and drug loading capacity. Different types and shapes of nanomaterials have been widely used for the treatment of neurological disorders, including quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These nanoparticles have unique characteristics, including sensitivity, selectivity, and the ability to cross the BBB when used in nano-sized particles, and are widely used for imaging studies and treatment of NDs. In this review, we briefly summarized the recent literature on the use of various nanomaterials and their mechanism of action for the treatment of various types of neurological disorders.}, }
@article {pmid35805149, year = {2022}, author = {Fang, T and Je, G and Pacut, P and Keyhanian, K and Gao, J and Ghasemi, M}, title = {Gene Therapy in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {11}, number = {13}, pages = {}, pmid = {35805149}, issn = {2073-4409}, support = {P50 HD060848/HD/NICHD NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Genetic Therapy ; Humans ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Since the discovery of Cu/Zn superoxide dismutase (SOD1) gene mutation, in 1993, as the first genetic abnormality in amyotrophic lateral sclerosis (ALS), over 50 genes have been identified as either cause or modifier in ALS and ALS/frontotemporal dementia (FTD) spectrum disease. Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. During the last three decades, tremendous effort has been made worldwide to reveal biological pathways underlying the pathogenesis of these gene mutations in ALS/FTD. Accordingly, targeting etiologic genes (i.e., gene therapies) to suppress their toxic effects have been investigated widely. It includes four major strategies: (i) removal or inhibition of abnormal transcribed RNA using microRNA or antisense oligonucleotides (ASOs), (ii) degradation of abnormal mRNA using RNA interference (RNAi), (iii) decrease or inhibition of mutant proteins (e.g., using antibodies against misfolded proteins), and (iv) DNA genome editing with methods such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas). The promising results of these studies have led to the application of some of these strategies into ALS clinical trials, especially for C9orf72 and SOD1. In this paper, we will overview advances in gene therapy in ALS/FTD, focusing on C9orf72, SOD1, TARDBP, and FUS genes.}, }
@article {pmid35805131, year = {2022}, author = {Zhao, J and Wang, X and Huo, Z and Chen, Y and Liu, J and Zhao, Z and Meng, F and Su, Q and Bao, W and Zhang, L and Wen, S and Wang, X and Liu, H and Zhou, S}, title = {The Impact of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {11}, number = {13}, pages = {}, pmid = {35805131}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Calcium/metabolism ; Humans ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and highly fatal neurodegenerative disease. Although the pathogenesis of ALS remains unclear, increasing evidence suggests that a key contributing factor is mitochondrial dysfunction. Mitochondria are organelles in eukaryotic cells responsible for bioenergy production, cellular metabolism, signal transduction, calcium homeostasis, and immune responses and the stability of their function plays a crucial role in neurons. A single disorder or defect in mitochondrial function can lead to pathological changes in cells, such as an impaired calcium buffer period, excessive generation of free radicals, increased mitochondrial membrane permeability, and oxidative stress (OS). Recent research has also shown that these mitochondrial dysfunctions are also associated with pathological changes in ALS and are believed to be commonly involved in the pathogenesis of the disease. This article reviews the latest research on mitochondrial dysfunction and its impact on the progression of ALS, with specific attention to the potential of novel therapeutic strategies targeting mitochondrial dysfunction.}, }
@article {pmid35805105, year = {2022}, author = {Spurgat, MS and Tang, SJ}, title = {Single-Cell RNA-Sequencing: Astrocyte and Microglial Heterogeneity in Health and Disease.}, journal = {Cells}, volume = {11}, number = {13}, pages = {}, pmid = {35805105}, issn = {2073-4409}, support = {R01 NS095747/NS/NINDS NIH HHS/United States ; R01 NS079166/NS/NINDS NIH HHS/United States ; R01 DA057195/DA/NIDA NIH HHS/United States ; R01 DA050530/DA/NIDA NIH HHS/United States ; R01 DA036165/DA/NIDA NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism ; *HIV Infections/genetics/metabolism ; Humans ; Microglia/metabolism ; Neurons/metabolism ; RNA/metabolism ; }, abstract = {Astrocytes and microglia are non-neuronal cells that maintain homeostasis within the central nervous system via their capacity to regulate neuronal transmission and prune synapses. Both astrocytes and microglia can undergo morphological and transcriptomic changes in response to infection with human immunodeficiency virus (HIV). While both astrocytes and microglia can be infected with HIV, HIV viral proteins in the local environment can interact with and activate these cells. Given that both astrocytes and microglia play critical roles in maintaining neuronal function, it will be critical to have an understanding of their heterogeneity and to identify genes and mechanisms that modulate their responses to HIV. Heterogeneity may include a depletion or increase in one or more astrocyte or microglial subtypes in different regions of the brain or spine as well as the gain or loss of a specific function. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool that can be used to characterise these changes within a given population. The use of this method facilitates the identification of subtypes and changes in cellular transcriptomes that develop in response to activation and various disease processes. In this review, we will examine recent studies that have used scRNA-seq to explore astrocyte and microglial heterogeneity in neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis as well as in response to HIV infection. A careful review of these studies will expand our current understanding of cellular heterogeneity at homeostasis and in response to specific disease states.}, }
@article {pmid35799963, year = {2022}, author = {Hadilou, M and Gholami, L and Ghojazadeh, M and Emadi, N}, title = {Prevalence and extension of the anterior loop of the mental nerve in different populations and CBCT imaging settings: A systematic review and meta-analysis.}, journal = {Imaging science in dentistry}, volume = {52}, number = {2}, pages = {141-153}, pmid = {35799963}, issn = {2233-7822}, abstract = {PURPOSE: This study aimed to identify the prevalence and extension of the anterior loop (AL) of the mental nerve in different populations and according to different cone-beam computed tomography (CBCT) imaging settings.<br><br>MATERIALS AND METHODS: Medline/PubMed, Embase, Scopus, Web of Science, and ProQuest were searched. The main inclusion criterion was ALs evaluated in CBCT images. The quality of studies was assessed with the Joanna Briggs Institute risk of bias checklist. Subgroup analyses were conducted for sex, side, continent, voxel size, field of view, and type of CBCT-reconstruction images with a random-effects model.<br><br>RESULTS: Sixty-three studies with 13,743 participants (27,075 hemimandibles) were included. An AL was found in 40.6% (95% CI: 32.8%-48.9%, P<0.05) of participants and 36.0% (95% CI: 27.5%-45.5%, P<0.05) of hemimandibles, in 34.9% (95% CI: 25.1%-46.2%, P<0.05) of males and 34.5% (95% CI: 23.5%-47.4%, P<0.05) of females. The average length of ALs was 2.39 mm (95% CI: 2.07-2.70 mm, P<0.05). Their extension was 2.13 mm (95% CI: 1.54-2.73 mm, P<0.05) in males and 1.85 mm (95% CI: 1.35-2.36 mm, P<0.05) in females. Significant differences were observed regarding the prevalence and length of ALs among continents and for its measured length on different CBCT-reconstruction images, but not between other subgroups.<br><br>CONCLUSION: AL was a relatively common finding. The voxel size and fields of view of CBCT devices were adequate for assessing AL; however, a 2-mm safety margin from anatomical structures (such as the AL) could be recommended to be considered when using CBCT imaging.}, }
@article {pmid35799510, year = {2023}, author = {Lupinski, I and Liang, AS and McKinnon, RD}, title = {Security breach: peripheral nerves provide unrestricted access for toxin delivery into the central nervous system.}, journal = {Neural regeneration research}, volume = {18}, number = {1}, pages = {64-67}, pmid = {35799510}, issn = {1673-5374}, abstract = {We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense, the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport. This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general, with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis. We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment, where external surfaces were not exposed to concentrated neurotoxins.}, }
@article {pmid35799502, year = {2023}, author = {Sharif, NA}, title = {Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors.}, journal = {Neural regeneration research}, volume = {18}, number = {1}, pages = {5-17}, pmid = {35799502}, issn = {1673-5374}, abstract = {Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and thromboxane-A2 interact with five major receptors (and their sub-types) to elicit specific downstream cellular and tissue actions. In general, prostaglandins have been associated with pain, inflammation, and edema when they are present at high local concentrations and involved on a chronic basis. However, in acute settings, certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation, providing cellular protection, regulating sleep, and enhancing blood flow, to lowering intraocular pressure to prevent the development of glaucoma, a blinding disease. Several classes of prostaglandins are implicated (or are considered beneficial) in certain central nervous system dysfunctions (e.g., Alzheimer's, Parkinson's, and Huntington's diseases; amyotrophic lateral sclerosis and multiple sclerosis; stroke, traumatic brain injuries and pain) and in ocular disorders (e.g., ocular hypertension and glaucoma; allergy and inflammation; edematous retinal disorders). This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease, and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists, polyunsaturated fatty acids, and cyclooxygenase inhibitors.}, }
@article {pmid35796900, year = {2022}, author = {Plewka, P and Raczynska, KD}, title = {Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {9}, pages = {5785-5808}, pmid = {35796900}, issn = {1559-1182}, support = {UMO-2018/30/E/NZ2/00295//Narodowe Centrum Nauki/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/pathology ; *RNA, Long Noncoding/genetics ; }, abstract = {Long intergenic noncoding RNAs (lincRNAs) are a class of independently transcribed molecules longer than 200 nucleotides that do not overlap known protein-coding genes. LincRNAs have diverse roles in gene expression and participate in a spectrum of biological processes. Dysregulation of lincRNA expression can abrogate cellular homeostasis, cell differentiation, and development and can also deregulate the immune and nervous systems. A growing body of literature indicates their important and multifaceted roles in the pathogenesis of several different diseases. Furthermore, certain lincRNAs can be considered potential therapeutic targets and valuable diagnostic or prognostic biomarkers capable of predicting the onset of a disease, its degree of activity, or the progression phase. In this review, we discuss possible mechanisms and molecular functions of lincRNAs in the pathogenesis of selected autoimmune and neurodegenerative disorders: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This summary can provide new ideas for future research, diagnosis, and treatment of these highly prevalent and devastating diseases.}, }
@article {pmid35794507, year = {2022}, author = {Jiao, L and Du, X and Li, Y and Jiao, Q and Jiang, H}, title = {Role of Mitophagy in neurodegenerative Diseases and potential tagarts for Therapy.}, journal = {Molecular biology reports}, volume = {49}, number = {11}, pages = {10749-10760}, pmid = {35794507}, issn = {1573-4978}, support = {Innovative Research Team of High-Level Local Universities in Shanghai//Innovative Research Team of High-Level Local Universities in Shanghai/ ; 32171131//National Natural Science Foundation of China/ ; 82071429//Natural Science Foundation of Jilin Province/ ; ZR2019ZD31//Natural Science Foundation of Shandong Province/ ; ZR2020MC072//Natural Science Foundation of Shandong Province/ ; 2021ZDSYS11//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Mitophagy ; *Neurodegenerative Diseases/therapy/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Autophagy ; }, abstract = {Mitochondria dysfunction has been defined as one of the hallmarks of aging-related diseases as is characterized by the destroyed integrity, abnormal distribution and size, insufficient ATP supply, increased ROS production, and subsequently damage and oxidize the proteins, lipids and nucleic acid. Mitophagy, an efficient way of removing damaged or defective mitochondria by autophagy, plays a pivotal role in maintaining the mitochondrial quantity and quality control enabling the degradation of unwanted mitochondria, and thus rescues cellular homeostasis in response to stress. Accumulating evidence demonstrates that impaired mitophagy has been associated with many neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) in a variety of patients and disease models with neural death, oxidative stress and disturbed metabolism, either as the cause or consequence. These findings suggest that modulation of mitophagy may be considered as a valid therapeutic strategy in neurodegenerative diseases. In this review, we summarize recent findings on the mechanisms of mitophagy and its role in neurodegenerative diseases, with a particular focus on mitochondrial proteins acting as receptors that mediate mitophagy in these diseases.}, }
@article {pmid35793106, year = {2023}, author = {Rey, F and Messa, L and Maghraby, E and Casili, G and Ottolenghi, S and Barzaghini, B and Raimondi, MT and Cereda, C and Cuzzocrea, S and Zuccotti, G and Esposito, E and Paterniti, I and Carelli, S}, title = {Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation.}, journal = {Antioxidants &amp; redox signaling}, volume = {38}, number = {1-3}, pages = {160-182}, doi = {10.1089/ars.2022.0046}, pmid = {35793106}, issn = {1557-7716}, mesh = {Humans ; Oxygen/metabolism ; *Neurodegenerative Diseases/metabolism ; Hypoxia/metabolism ; Reactive Oxygen Species/metabolism ; *Hyperoxia ; }, abstract = {Significance: Oxygen (O2) sensing is the fundamental process through which organisms respond to changes in O2 levels. Complex networks exist allowing the maintenance of O2 levels through the perception, capture, binding, transport, and delivery of molecular O2. The brain extreme sensitivity to O2 balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases (NDs). In this study, we wish to review the most relevant advances in O2 sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recent Advances: Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O2 imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation. Critical Issues: There is still a gap in knowledge concerning how O2 sensing plays a role in the above indicated neurodegenerations. Specifically, O2 concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O2 sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained. Future Directions: Future studies should focus on the precise characterization of O2 level disruption and O2 sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O2 sensing dysfunctions in these diseases. There is also the need to develop innovative therapies targeting this precise mechanism rather than its secondary effects, as early intervention is necessary. Antioxid. Redox Signal. 38, 160-182.}, }
@article {pmid35791387, year = {2022}, author = {Coskuner-Weber, O and Mirzanli, O and Uversky, VN}, title = {Intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases.}, journal = {Biophysical reviews}, volume = {14}, number = {3}, pages = {679-707}, pmid = {35791387}, issn = {1867-2450}, abstract = {Many different intrinsically disordered proteins and proteins with intrinsically disordered regions are associated with neurodegenerative diseases. These types of proteins including amyloid-β, tau, α-synuclein, CHCHD2, CHCHD10, and G-protein coupled receptors are increasingly becoming evaluated as potential drug targets in the pharmaceutical-based treatment approaches. Here, we focus on the neurobiology of this class of proteins, which lie at the center of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Charcot-Marie-Tooth diseases, spinal muscular atrophy, and mitochondrial myopathy. Furthermore, we discuss the current treatment design strategies involving intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases. In addition, we emphasize that although the G-protein coupled receptors are traditionally investigated using structural biology-based models and approaches, current studies show that these receptors are proteins with intrinsically disordered regions and therefore they require new ways for their analysis.}, }
@article {pmid35790708, year = {2022}, author = {Hayes, LR and Kalab, P}, title = {Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1061-1084}, pmid = {35790708}, issn = {1878-7479}, support = {R03 NS127011/NS/NINDS NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; K08 NS104273/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/therapy/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Retroelements ; RNA Precursors/metabolism ; *TDP-43 Proteinopathies/genetics/therapy/metabolism ; DNA-Binding Proteins/genetics/metabolism ; RNA-Binding Proteins/genetics ; }, abstract = {Nuclear clearance and cytoplasmic mislocalization of the essential RNA binding protein, TDP-43, is a pathologic hallmark of amyotrophic lateral sclerosis, frontotemporal dementia, and related neurodegenerative disorders collectively termed "TDP-43 proteinopathies." TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms. Loss of TDP-43 nuclear RNA processing function destabilizes the transcriptome by multiple mechanisms including disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid-liquid phase separation and aggregation, traps TDP-43 in the cytoplasm and disrupts a host of downstream processes including the trafficking of RNA granules, local translation within axons, and mitochondrial function. In this review, we will discuss the TDP-43 therapy development pipeline, beginning with therapies in current and upcoming clinical trials, which are primarily focused on accelerating the clearance of TDP-43 aggregates. Then, we will look ahead to emerging strategies from preclinical studies, first from high-throughput genetic and pharmacologic screens, and finally from mechanistic studies focused on the upstream cause(s) of TDP-43 disruption in ALS/FTD. These include modulation of stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and correction of aberrant splicing events.}, }
@article {pmid35790411, year = {2022}, author = {Odnoshivkina, UG and Kuznetsova, EA and Petrov, AM}, title = {25-Hydroxycholesterol as a Signaling Molecule of the Nervous System.}, journal = {Biochemistry. Biokhimiia}, volume = {87}, number = {6}, pages = {524-537}, pmid = {35790411}, issn = {1608-3040}, mesh = {Brain/metabolism ; *Cholesterol/metabolism ; *Hydroxycholesterols/metabolism/pharmacology ; Signal Transduction ; }, abstract = {Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular homeostasis of cholesterol; they can pass across the membrane and vascular barriers and act distantly as para- and endocrine agents. A small amount of 25-hydroxycholesterol (25-HC) is produced in the endoplasmic reticulum of most cells, where it serves as a potent regulator of the synthesis, intracellular transport, and storage of cholesterol. Production of 25-HC is strongly increased in the macrophages, dendrite cells, and microglia at the inflammatory response. The synthesis of 25-HC can be also upregulated in some neurological disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, spastic paraplegia type 5, and X-linked adrenoleukodystrophy. However, it is unclear whether 25-HC aggravates these pathologies or has the protective properties. The molecular targets for 25-HC are transcriptional factors (LX receptors, SREBP2, ROR), G protein-coupled receptor (GPR183), ion channels (NMDA receptors, SLO1), adhesive molecules (α5β1 and ανβ3 integrins), and oxysterol-binding proteins. The diversity of 25-HC-binding proteins points to the ability of HC to affect many physiological and pathological processes. In this review, we focused on the regulation of 25-HC production and its universal role in the control of cellular cholesterol homeostasis, as well as the effects of 25-HC as a signaling molecule mediating the influence of inflammation on the processes in the neuromuscular system and brain. Based on the evidence collected, it can be suggested that 25-HC prevents accumulation of cellular cholesterol and serves as a potent modulator of neuroinflammation, synaptic transmission, and myelinization. An increased production of 25-HC in response to a various type of damage can have a protective role and reduce neuronal loss. At the same time, an excess of 25-HC may exert the neurotoxic effects.}, }
@article {pmid35787292, year = {2022}, author = {Olesen, MA and Villavicencio-Tejo, F and Quintanilla, RA}, title = {The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {36}, pmid = {35787292}, issn = {2047-9158}, mesh = {*Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Fibroblasts ; Humans ; *Huntington Disease/metabolism/pathology ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; *Parkinson Disease/metabolism ; }, abstract = {Neurological disorders (NDs) are characterized by progressive neuronal dysfunction leading to synaptic failure, cognitive impairment, and motor injury. Among these diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) have raised a significant research interest. These disorders present common neuropathological signs, including neuronal dysfunction, protein accumulation, oxidative damage, and mitochondrial abnormalities. In this context, mitochondrial impairment is characterized by a deficiency in ATP production, excessive production of reactive oxygen species, calcium dysregulation, mitochondrial transport failure, and mitochondrial dynamics deficiencies. These defects in mitochondrial health could compromise the synaptic process, leading to early cognitive dysfunction observed in these NDs. Interestingly, skin fibroblasts from AD, PD, HD, and ALS patients have been suggested as a useful strategy to investigate and detect early mitochondrial abnormalities in these NDs. In this context, fibroblasts are considered a viable model for studying neurodegenerative changes due to their metabolic and biochemical relationships with neurons. Also, studies of our group and others have shown impairment of mitochondrial bioenergetics in fibroblasts from patients diagnosed with sporadic and genetic forms of AD, PD, HD, and ALS. Interestingly, these mitochondrial abnormalities have been observed in the brain tissues of patients suffering from the same pathologies. Therefore, fibroblasts represent a novel strategy to study the genesis and progression of mitochondrial dysfunction in AD, PD, HD, and ALS. This review discusses recent evidence that proposes fibroblasts as a potential target to study mitochondrial bioenergetics impairment in neurological disorders and consequently to search for new biomarkers of neurodegeneration.}, }
@article {pmid35785436, year = {2022}, author = {Frater, JL and Shirai, CL and Brestoff, JR}, title = {Technological features of blast identification in the cerebrospinal fluid: A systematic review of flow cytometry and laboratory haematology methods.}, journal = {International journal of laboratory hematology}, volume = {44 Suppl 1}, number = {Suppl 1}, pages = {45-53}, pmid = {35785436}, issn = {1751-553X}, support = {DP5 OD028125/OD/NIH HHS/United States ; R01 AI168044/AI/NIAID NIH HHS/United States ; DP5 OD028125/CD/ODCDC CDC HHS/United States ; #1019648//Burroughs Wellcome Fund Career Award for Medical Scientists/ ; }, mesh = {Adult ; Cerebrospinal Fluid ; Child ; Flow Cytometry/methods ; *Hematology/methods ; Humans ; *Leukemia ; Leukocyte Count ; Technology ; }, abstract = {BACKGROUND: Involvement of the central nervous system (CNS) by acute leukemias (ALs) has important implications for risk stratification and disease outcome. The clinical laboratory plays an essential role in assessment of cerebrospinal fluid (CSF) specimens from patients with ALs at initial diagnosis, at the end of treatment, and when CNS involvement is clinically suspected. The two challenges for the laboratory are 1) to accurately provide a cell count of the CSF and 2) to successfully distinguish blasts from other cell types. These tasks are classically performed using manual techniques, which suffer from suboptimal turnaround time, imprecision, and inconsistent inter-operator performance. Technological innovations in flow cytometry and hematology analyzer technology have provided useful complements and/or alternatives to conventional manual techniques.<br><br>AIMS: We performed a PRISMA-compliant systematic review to address the medical literature regarding the development and current state of the art of CSF blast identification using flow cytometry and laboratory hematology technologies.<br><br>MATERIALS AND METHODS: We searched the peer reviewed medical literature using MEDLINE (PubMed interface), Web of Science, and Embase using the keywords "CSF or cerebrospinal" AND "blasts(s)".<br><br>RESULTS: 108 articles were suitable for inclusion in our systematic review. These articles covered 1) clinical rationale for CSF blast identification; 2) morphology-based CSF blast identification; 3) the role of flow cytometry; 4) use of hematology analyzers for CSF blast identification; and 5) quality issues. [9] /L, which is much lower than the original machine count and platelet transfusion was warranted.<br><br>DISCUSSION: 1) Clinical laboratory testing plays a central role in risk stratification and clinical management of patients with acute leukemias, most clearly in pediatric ALs; 2) studies focused on other patient populations, including adults and patients with AML are less prevalent in the literature; 3) improvements in instrumentation may provide better performance for the classification of CSF specimens.<br><br>CONCLUSION: Current challenges include: 1) more precisely characterizing the natural history of AL involvement of the CNS, 2) improvements in automated cell count technology of low cellularity specimens, 3) defining the role of flow MRD testing of CSF specimens and 4) improved recognition of specimen quality by clinicians and laboratory personnel.}, }
@article {pmid35783556, year = {2022}, author = {Gosset, P and Camu, W and Raoul, C and Mezghrani, A}, title = {Prionoids in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {4}, number = {3}, pages = {fcac145}, pmid = {35783556}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most frequent neurodegenerative disease after Alzheimer's and Parkinson's disease. ALS is characterized by the selective and progressive loss of motoneurons in the spinal cord, brainstem and cerebral cortex. Clinical manifestations typically occur in midlife and start with focal muscle weakness, followed by the rapid and progressive wasting of muscles and subsequent paralysis. As with other neurodegenerative diseases, the condition typically begins at an initial point and then spreads along neuroanatomical tracts. This feature of disease progression suggests the spreading of prion-like proteins called prionoids in the affected tissues, which is similar to the spread of prion observed in Creutzfeldt-Jakob disease. Intensive research over the last decade has proposed the ALS-causing gene products Cu/Zn superoxide dismutase 1, TAR DNA-binding protein of 43 kDa, and fused in sarcoma as very plausible prionoids contributing to the spread of the pathology. In this review, we will discuss the molecular and cellular mechanisms leading to the propagation of these prionoids in ALS.}, }
@article {pmid35783140, year = {2022}, author = {Zhao, C and Liao, Y and Rahaman, A and Kumar, V}, title = {Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {892518}, pmid = {35783140}, issn = {1663-4365}, abstract = {Biological stress due to the aberrant buildup of misfolded/unfolded proteins in the endoplasmic reticulum (ER) is considered a key reason behind many human neurodegenerative diseases. Cells adapted to ER stress through the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by degeneration of the motor system. It has largely been known that ER stress plays an important role in the pathogenesis of ALS through the dysregulation of proteostasis. Moreover, accumulating evidence indicates that ER stress and UPR are important players in TDP-43 pathology. In this mini-review, the complex interplay between ER stress and the UPR in ALS and TDP-43 pathology will be explored by taking into account the studies from in vitro and in vivo models of ALS. We also discuss therapeutic strategies to control levels of ER stress and UPR signaling components that have contrasting effects on ALS pathogenesis.}, }
@article {pmid35783101, year = {2022}, author = {Cuartas, J and Gangwani, L}, title = {R-loop Mediated DNA Damage and Impaired DNA Repair in Spinal Muscular Atrophy.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {826608}, pmid = {35783101}, issn = {1662-5102}, support = {R01 NS115834/NS/NINDS NIH HHS/United States ; }, abstract = {Defects in DNA repair pathways are a major cause of DNA damage accumulation leading to genomic instability and neurodegeneration. Efficient DNA damage repair is critical to maintain genomicstability and support cell function and viability. DNA damage results in the activation of cell death pathways, causing neuronal death in an expanding spectrum of neurological disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and spinal muscular atrophy (SMA). SMA is a neurodegenerative disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motor neurons due to low levels of the SMN protein. The molecular mechanism of selective motor neuron degeneration in SMA was unclear for about 20 years. However, several studies have identified biochemical and molecular mechanisms that may contribute to the predominant degeneration of motor neurons in SMA, including the RhoA/ROCK, the c-Jun NH2-terminal kinase (JNK), and p53-mediated pathways, which are involved in mediating DNA damage-dependent cell death. Recent studies provided insight into selective degeneration of motor neurons, which might be caused by accumulation of R-loop-mediated DNA damage and impaired non-homologous end joining (NHEJ) DNA repair pathway leading to genomic instability. Here, we review the latest findings involving R-loop-mediated DNA damage and defects in neuron-specific DNA repair mechanisms in SMA and discuss these findings in the context of other neurodegenerative disorders linked to DNA damage.}, }
@article {pmid35779869, year = {2022}, author = {Castillo-Álvarez, F and Marzo-Sola, ME}, title = {Role of the gut microbiota in the development of various neurological diseases.}, journal = {Neurologia}, volume = {37}, number = {6}, pages = {492-498}, doi = {10.1016/j.nrleng.2019.03.026}, pmid = {35779869}, issn = {2173-5808}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Gastrointestinal Microbiome ; Humans ; *Multiple Sclerosis ; *Nervous System Diseases ; *Neuromyelitis Optica ; *Parkinson Disease ; }, abstract = {INTRODUCTION: In recent years, the scientific evidence supporting a relationship between the microbiota and various diseases has increased significantly; this trend has also been observed for neurological diseases. This has given rise to the concept of the gut-brain axis and the idea of a relationship between the gut microbiota and several neurological diseases whose aetiopathogenesis is yet to be clearly defined.<br><br>DEVELOPMENT: We review the role of the gut microbiota in the gut-brain axis and analyse those neurological diseases in which alterations in the gut microbiota have been described as a result of human studies: specifically, Parkinson's disease, Alzheimer disease, amyotrophic lateral sclerosis, neuromyelitis optica, and multiple sclerosis.<br><br>CONCLUSIONS: The body of evidence linking the gut microbiota to various neurological diseases has grown considerably. Several interesting studies show a relationship between the gut microbiota and Parkinson's disease, Alzheimer disease, neuromyelitis optica, and multiple sclerosis, whereas other controversial studies implicate it in amyotrophic lateral sclerosis. Many of these studies place considerable emphasis on modulation of inflammation, particularly by bacteria capable of producing short-chain fatty acids. Despite these encouraging results, many questions remain, and there is a need to demonstrate causality, determine the role of fungi or viruses, and research possible treatment through diet, probiotics, or faecal microbiota transplantation.}, }
@article {pmid35776055, year = {2022}, author = {Fu, YW and Xu, HS and Liu, SJ}, title = {COVID-19 and neurodegenerative diseases.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {12}, pages = {4535-4544}, doi = {10.26355/eurrev_202206_29093}, pmid = {35776055}, issn = {2284-0729}, mesh = {Aged ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *COVID-19 ; Humans ; *Neurodegenerative Diseases ; *Parkinson Disease ; Peptidyl-Dipeptidase A/metabolism ; SARS-CoV-2 ; }, abstract = {OBJECTIVE: The pandemic of Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues, and SARS-CoV-2 variants continue to emerge. In addition to typical fever and respiratory symptoms, many patients with COVID-19 experience a variety of neurological complications. In this review, we analyzed and reviewed the current status and possible mechanisms between COVID-19 and several typical neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, hoping to propose the potential direction of further research and concern.<br><br>MATERIALS AND METHODS: Electronic literature search of the databases (Medline/PubMed, Web of Science, and Google Scholar). The keywords used were COVID-19, SARS-CoV-2, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The retrieved relevant articles were reviewed and critically analyzed.<br><br>RESULTS: SARS-CoV-2 is a highly neuroinvasive neurotropic virus that invades cells through angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway. SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may contribute to the pathogenesis of neurodegenerative diseases.<br><br>CONCLUSIONS: Some patients with neurodegenerative diseases have already shown more susceptibility to SARS-CoV-2 infection and significantly higher mortality due to the elderly population with underlying diseases. Moreover, SARS-CoV-2 could cause damage to the central nervous system (CNS) that may substantially increase the incidence of neurodegenerative diseases and accelerate the progression of them.}, }
@article {pmid35773551, year = {2022}, author = {Nelson, AT and Trotti, D}, title = {Altered Bioenergetics and Metabolic Homeostasis in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1102-1118}, pmid = {35773551}, issn = {1878-7479}, support = {F31 NS118838/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/metabolism ; Energy Metabolism/physiology ; Homeostasis ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects motor neurons and causes muscle atrophy, paralysis, and death. While a great deal of progress has been made in deciphering the underlying pathogenic mechanisms, no effective treatments for the disease are currently available. This is mainly due to the high degree of complexity and heterogeneity that characterizes the disease. Over the last few decades of research, alterations to bioenergetic and metabolic homeostasis have emerged as a common denominator across many different forms of ALS. These alterations are found at the cellular level (e.g., mitochondrial dysfunction and impaired expression of monocarboxylate transporters) and at the systemic level (e.g., low BMI and hypermetabolism) and tend to be associated with survival or disease outcomes in patients. Furthermore, an increasing amount of preclinical evidence and some promising clinical evidence suggests that targeting energy metabolism could be an effective therapeutic strategy. This review examines the evidence both for and against these ALS-associated metabolic alterations and highlights potential avenues for therapeutic intervention.}, }
@article {pmid35770772, year = {2022}, author = {Hastings, N and Kuan, WL and Osborne, A and Kotter, MRN}, title = {Therapeutic Potential of Astrocyte Transplantation.}, journal = {Cell transplantation}, volume = {31}, number = {}, pages = {9636897221105499}, pmid = {35770772}, issn = {1555-3892}, support = {MR/S005528/1/MRC_/Medical Research Council/United Kingdom ; CS-2015-15-023/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Astrocytes/metabolism ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/metabolism ; *Stroke/metabolism ; }, abstract = {Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS); moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinson's, Alzheimer's, and Huntington's diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. In this review, we examine these convergent pathways leading to astrocyte dysfunction, and explore the existing evidence for a therapeutic potential of transplantation of healthy astrocytes in various models. Existing literature presents a wide variety of methods to generate astrocytes, or relevant precursor cells, for subsequent transplantation, while described outcomes of this type of treatment also differ between studies. We take technical differences between methodologies into account to understand the variability of therapeutic benefits, or lack thereof, at a deeper level. We conclude by discussing some key requirements of an astrocyte graft that would be most suitable for clinical applications.}, }
@article {pmid35768750, year = {2022}, author = {Kirola, L and Mukherjee, A and Mutsuddi, M}, title = {Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Molecular neurobiology}, volume = {59}, number = {9}, pages = {5673-5694}, pmid = {35768750}, issn = {1559-1182}, support = {SPF/2021/000004//Science and Engineering Research Board, GoI/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology ; Genetic Association Studies ; Genome-Wide Association Study ; Heat-Shock Proteins/genetics ; Humans ; Kinesins ; Membrane Transport Proteins/genetics ; Mitochondrial Proteins/genetics ; Molecular Chaperones ; Multifactorial Inheritance ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10-15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain. Other overlapping genes (VCP, FUS, SQSTM1, TBK1, CHCHD10) are also involved in similar functions that include RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Recent advances in genome sequencing have identified new genes that are involved in these disorders (TBK1, CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, DNAJC7). Additional risk factors and modifiers have been also identified in genome-wide association studies and array-based studies. However, the newly identified genes show higher disease frequencies in combination with known genes that are implicated in pathogenesis, thus indicating probable digenetic/polygenic inheritance models, along with epistatic interactions. Studies suggest that these genes play a pleiotropic effect on ALS-FTD and other diseases such as Alzheimer's disease, Ataxia, and Parkinsonism. Besides, there have been numerous improvements in the genotype-phenotype correlations as well as clinical trials on stem cell and gene-based therapies. This review discusses the possible genetic models of ALS and FTD, the latest therapeutics, and signaling pathways involved in ALS-FTD.}, }
@article {pmid35767076, year = {2024}, author = {Sarmet, M and Santos, DB and Mangilli, LD and Million, JL and Maldaner, V and Zeredo, JL}, title = {Chronic respiratory failure negatively affects speech function in patients with bulbar and spinal onset amyotrophic lateral sclerosis: retrospective data from a tertiary referral center.}, journal = {Logopedics, phoniatrics, vocology}, volume = {49}, number = {1}, pages = {17-26}, doi = {10.1080/14015439.2022.2092209}, pmid = {35767076}, issn = {1651-2022}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Retrospective Studies ; Speech ; Tertiary Care Centers ; Cross-Sectional Studies ; Voice Quality ; *Respiratory Insufficiency/etiology/complications ; }, abstract = {Background: Although dysarthria and respiratory failure are widely described in literature as part of the natural history of Amyotrophic lateral sclerosis (ALS), the specific interaction between them has been little explored.Aim: To investigate the relationship between chronic respiratory failure and the speech of ALS patients.Materials and methods: In this cross-sectional retrospective study we reviewed the medical records of all patients diagnosed with ALS that were accompanied by a tertiary referral center. In order to determine the presence and degree of speech impairment, the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) speech sub-scale was used. Respiratory function was assessed through spirometry and through venous blood gasometry obtained from a morning peripheral venous sample. To determine whether differences among groups classified by speech function were significant, maximum and mean spirometry values of participants were compared using multivariate analysis of variance (MANOVA) with Tukey's post hoc test.Results: Seventy-five cases were selected, of which 73.3% presented speech impairment and 70.7% respiratory impairment. Respiratory and speech functions were moderately correlated (seated FVC r = 0.64; supine FVC r = 0.60; seated FEV1 r = 0.59 and supine FEV1 r = 0.54, p < .001). Multivariable logistic regression revealed that the following variables were significantly associated with the presence of speech impairment after adjusting for other risk factors: seated FVC (odds ratio [OR] = 0.862) and seated FEV1 (OR = 1.106). The final model was 81.1% predictive of speech impairment. The presence of daytime hypercapnia was not correlated to increasing speech impairment.Conclusion: The restrictive pattern developed by ALS patients negatively influences speech function. Speech is a complex and multifactorial process, and lung volume presents a pivotal role in its function. Thus, we were able to find that lung volumes presented a significant correlation to speech function, especially in those with bulbar onset and respiratory impairment. Neurobiological and physiological aspects of this relationship should be explored in further studies with the ALS population.}, }
@article {pmid35760105, year = {2022}, author = {Korupolu, R and Malik, A and Ratcliff, C and Robinson-Whelen, S and Taylor, HB}, title = {Feasibility, Acceptability, and Efficacy of Mindfulness Training in People With Upper Motor Neuron Disorders: A Systematic Review.}, journal = {Archives of physical medicine and rehabilitation}, volume = {103}, number = {12}, pages = {2410-2428}, doi = {10.1016/j.apmr.2022.05.020}, pmid = {35760105}, issn = {1532-821X}, support = {KL2 TR003168/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Mindfulness ; Quality of Life/psychology ; Feasibility Studies ; Fatigue ; Motor Neurons ; }, abstract = {OBJECTIVES: This systematic review aims to gain a comprehensive understanding of the feasibility, acceptability, and efficacy of mindfulness-based interventions (MBIs) on depression, anxiety, fatigue, and health-related quality of life among individuals with upper motor neuron disorders (UMNDs).<br><br>DATA SOURCES: PubMed, PsycINFO, Excerpta Medica Database, and Cumulative Index to Nursing and Allied Health Literature were searched for relevant studies published between January 2001 and June 2021.<br><br>STUDY SELECTION: Clinical trials published in English evaluating MBIs in adults with the 4 most common UMNDs (multiple sclerosis, brain injury including stroke, spinal cord injury, amyotrophic lateral sclerosis) were included.<br><br>DATA EXTRACTION: Two reviewers independently performed the risk of bias assessment using standardized tools and extracted desired data electronically.<br><br>DATA SYNTHESIS: A total of 44 studies were included: 26 randomized controlled trials, 10 nonrandomized controlled trials, and 8 pre-post intervention studies. The average &#xb1; SD duration of MBIs was 8&#xb1;2 weeks. On average, 85%&#xb1;14% of participants completed the MBI, and the retention rate at follow-up was 80%&#xb1;16%. Only 14% of the studies delivered MBIs virtually, and feasibility metrics were similar to in-person studies. Among studies reporting acceptability data, most participants reported satisfaction with the MBI. Randomized controlled trials that evaluated the effects of MBI on depression, anxiety, fatigue, and quality of life revealed greater relative improvement in these outcomes among MBI participants compared with controls, with differences greater when compared with passive control than active control participants. None of the studies included in this review studied dose response.<br><br>CONCLUSIONS: Based on current data, MBIs are feasible and offer a promising approach to address the biopsychosocial needs of individuals with UMNDs. MBIs are associated with a high acceptance rate among participants, with notable improvements in depression, anxiety, fatigue, and quality of life post intervention. Future studies are needed to evaluate alternate models of delivery of MBIs and the dose-response relationship.}, }
@article {pmid35760047, year = {2023}, author = {Bassani, TB and Bartolomeo, CS and Oliveira, RB and Ureshino, RP}, title = {Progestogen-Mediated Neuroprotection in Central Nervous System Disorders.}, journal = {Neuroendocrinology}, volume = {113}, number = {1}, pages = {14-35}, doi = {10.1159/000525677}, pmid = {35760047}, issn = {1423-0194}, mesh = {Female ; Humans ; *Progestins/pharmacology/therapeutic use/metabolism ; Progesterone/pharmacology/therapeutic use/metabolism ; Neuroprotection ; *Alzheimer Disease/metabolism ; Neurons/metabolism ; }, abstract = {Neuroactive steroids can be synthetic or endogenous molecules produced by neuronal and glial cells and peripheral glands. Examples include estrogens, testosterone, progesterone and its reduced metabolites such as 5α-dihydro-progesterone and allopregnanolone. Steroids produced by neurons and glia target the nervous system and are called neurosteroids. Progesterone and analog molecules, known as progestogens, have been shown to exhibit neurotrophic, neuroprotective, antioxidant, anti-inflammatory, glial modulatory, promyelinating, and remyelinating effects in several experimental models of neurodegenerative and injury conditions. Pleiotropic mechanisms of progestogens may act synergistically to prevent neuron degeneration, astrocyte and microglial reactivity, reducing morbidity and mortality. The aim of this review is to summarize the significant findings related to the actions of progesterone and other progestogens in experimental models and epidemiological and clinical trials of some of the most prevalent and debilitating chronic neurodegenerative disorders, namely, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. We evaluated progestogen alterations under pathological conditions, how pathology modifies their levels, as well as the intracellular mechanisms and glial interactions underlying their neuroprotective effects. Furthermore, an analysis of the potential of natural progestogens and synthetic progestins as neuroprotective and regenerative agents, when administered as hormone replacement therapy in menopause, is also discussed.}, }
@article {pmid35756994, year = {2022}, author = {Kors, S and Costello, JL and Schrader, M}, title = {VAP Proteins - From Organelle Tethers to Pathogenic Host Interactors and Their Role in Neuronal Disease.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {895856}, pmid = {35756994}, issn = {2296-634X}, support = {MR/T019409/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) are ubiquitous ER-resident tail-anchored membrane proteins in eukaryotic cells. Their N-terminal major sperm protein (MSP) domain faces the cytosol and allows them to interact with a wide variety of cellular proteins. Therefore, VAP proteins are vital to many cellular processes, including organelle membrane tethering, lipid transfer, autophagy, ion homeostasis and viral defence. Here, we provide a timely overview of the increasing number of VAPA/B binding partners and discuss the role of VAPA/B in maintaining organelle-ER interactions and cooperation. Furthermore, we address how viruses and intracellular bacteria hijack VAPs and their binding partners to induce interactions between the host ER and pathogen-containing compartments and support pathogen replication. Finally, we focus on the role of VAP in human disease and discuss how mutated VAPB leads to the disruption of cellular homeostasis and causes amyotrophic lateral sclerosis.}, }
@article {pmid35756499, year = {2022}, author = {Zhou, Y and Zhen, Y and Wang, G and Liu, B}, title = {Deconvoluting the Complexity of Reactive Oxygen Species (ROS) in Neurodegenerative Diseases.}, journal = {Frontiers in neuroanatomy}, volume = {16}, number = {}, pages = {910427}, pmid = {35756499}, issn = {1662-5129}, abstract = {Neurodegenerative diseases (NDs) are becoming a serious public health concern as the world's population continues to age, demanding the discovery of more effective therapies. Excessive formation of reactive oxygen species (ROS) can result in oxidative stress (OS), which can be regarded as one of the common causes of neurodegenerative diseases (NDs). Thus, in this review, we focus on summarizing the consequences of ROS NDs, while taking the four prevalent NDs as examples, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), to illustrate the key signaling pathways and relevant drugs. Together, these findings may shed new light on a field in which ROS-related pathways play a key role; thereby setting the groundwork for the future therapeutic development of neurodegenerative diseases.}, }
@article {pmid35754952, year = {2022}, author = {Zampatti, S and Peconi, C and Campopiano, R and Gambardella, S and Caltagirone, C and Giardina, E}, title = {C9orf72-Related Neurodegenerative Diseases: From Clinical Diagnosis to Therapeutic Strategies.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {907122}, pmid = {35754952}, issn = {1663-4365}, abstract = {Hexanucleotide expansion in C9orf72 has been related to several phenotypes to date, complicating the clinical recognition of these neurodegenerative disorders. An early diagnosis can improve the management of patients, promoting early administration of therapeutic supportive strategies. Here, we report known clinical presentations of C9orf72-related neurodegenerative disorders, pointing out suggestive phenotypes that can benefit the genetic characterization of patients. Considering the high variability of C9orf72-related disorder, frequent and rare manifestations are described, with detailed clinical, instrumental evaluation, and supportive therapeutical approaches. Furthermore, to improve the understanding of molecular pathways of the disease and potential therapeutical targets, a detailed description of the cellular mechanisms related to the pathological effect of C9orf72 is reported. New promising therapeutical strategies and ongoing studies are reported highlighting their molecular role in cellular pathological pathways of C9orf72. These therapeutic approaches are particularly promising because they seem to stop the disease before neuronal damage. The knowledge of clinical and molecular features of C9orf72-related neurodegenerative disorders improves the therapeutical application of known strategies and will lay the basis for the development of new potential therapies.}, }
@article {pmid35749150, year = {2022}, author = {Legault, EM and Bouquety, J and Drouin-Ouellet, J}, title = {Disease Modeling of Neurodegenerative Disorders Using Direct Neural Reprogramming.}, journal = {Cellular reprogramming}, volume = {24}, number = {5}, pages = {228-251}, doi = {10.1089/cell.2021.0172}, pmid = {35749150}, issn = {2152-4998}, mesh = {Astrocytes ; Cell Differentiation ; Cellular Reprogramming ; Humans ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Neurons ; }, abstract = {Understanding the pathophysiology of CNS-associated neurological diseases has been hampered by the inaccessibility of patient brain tissue to perform live analyses at the molecular level. To this end, neural cells obtained by differentiation of patient-derived induced pluripotent stem cells (iPSCs) are considerably helpful, especially in the context of monogenic-based disorders. More recently, the use of direct reprogramming to convert somatic cells to neural cells has emerged as an alternative to iPSCs to generate neurons, astrocytes, and oligodendrocytes. This review focuses on the different studies that used direct neural reprogramming to study disease-associated phenotypes in the context of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid35745610, year = {2022}, author = {Suzen, S and Tucci, P and Profumo, E and Buttari, B and Saso, L}, title = {A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {6}, pages = {}, pmid = {35745610}, issn = {1424-8247}, abstract = {Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents.}, }
@article {pmid35743271, year = {2022}, author = {Azman, KF and Zakaria, R}, title = {Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {12}, pages = {}, pmid = {35743271}, issn = {1422-0067}, support = {None//Universiti Sains Malaysia/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuronal Plasticity/physiology ; *Parkinson Disease/metabolism ; }, abstract = {Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.}, }
@article {pmid35741724, year = {2022}, author = {Pfeffer, G and Lee, G and Pontifex, CS and Fanganiello, RD and Peck, A and Weihl, CC and Kimonis, V}, title = {Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis.}, journal = {Genes}, volume = {13}, number = {6}, pages = {}, pmid = {35741724}, issn = {2073-4425}, support = {UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/diagnosis/genetics/pathology ; Humans ; Mutation ; *Osteitis Deformans/diagnosis/genetics/pathology ; *Valosin Containing Protein/genetics ; }, abstract = {In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in VCP cause multisystem proteinopathy (VCP-MSP), an autosomal dominant, adult-onset disorder causing dysfunction in several tissue types. It can result in complex neurodegenerative conditions including inclusion body myopathy, frontotemporal dementia, amyotrophic lateral sclerosis, or combinations of these. There is also an association with other neurodegenerative phenotypes such as Alzheimer-type dementia and Parkinsonism. Non-neurological presentations include Paget disease of bone and may also include cardiac dysfunction. We provide a detailed discussion of genotype-phenotype correlations, recommendations for genetic diagnosis, and genetic counselling implications of VCP-MSP.}, }
@article {pmid35737276, year = {2023}, author = {Vafaei Mastanabad, M and Nooraei, A and Hassan Zadeh Tabatabaei, MS and Akbari Fakhrabadi, A and Jafarzadeh, F}, title = {Granulocyte-colony stimulating factor (G-CSF): an emerging therapeutic approach for amyotrophic lateral sclerosis (ALS).}, journal = {Acta neurologica Belgica}, volume = {123}, number = {3}, pages = {763-771}, pmid = {35737276}, issn = {2240-2993}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy ; Granulocyte Colony-Stimulating Factor/pharmacology/therapeutic use/metabolism ; Cytokines/metabolism ; Hematopoietic Stem Cells/metabolism ; Granulocytes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by neuronal degeneration and inflammation in the nerves. G-CSF is a 19.6-kDa hematopoietic growth factor which is essential for the proliferation and differentiation of granulocyte hematopoietic progenitors. G-CSF exerts neuroprotective activities by induction of neuronal regeneration, inhibition of neuronal apoptosis, mobilization of Hematopoietic stem cells (HSCs), regulation of pro and anti-inflammatory cytokines, and activation of angiogenesis. Pre-clinical studies have shown significant efficacy of G-CSF therapy in mSOD1[G93A] mice models. G-CSF treatments were able to increase the survival of mice. However, clinical studies on ALS patients failed to clone pre-clinical results. Considering the potential role of G-CSF in nervous system regeneration, this study aimed to comprehensively review the clinical and pre-clinical studies addressing G-CSF in ALS treatment.}, }
@article {pmid35735343, year = {2021}, author = {Acosta, I and Bastías, P and Matamala, JM}, title = {[Fasciculations and cramps: physiological bases and clinical approach of a complex phenomenon].}, journal = {Revista medica de Chile}, volume = {149}, number = {12}, pages = {1751-1764}, doi = {10.4067/s0034-98872021001201751}, pmid = {35735343}, issn = {0717-6163}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; Electromyography/adverse effects ; *Fasciculation/diagnosis/etiology/therapy ; Humans ; Motor Neurons/physiology ; Muscle Cramp/diagnosis/etiology/therapy ; }, abstract = {Fasciculations and cramps originate in the motor unit, a functional unit that includes the lower motor neuron and their innervated muscle fibres. Both are common complaints in outpatient practice. These symptoms can be secondary to neurological or medical pathology, presenting a broad differential diagnosis and a complex approach. Recent neurophysiological studies have increased the knowledge of their origin mainly in amyotrophic lateral sclerosis. The symptomatic management of fasciculations and cramps depends on their etiology and includes pharmacological and non-pharmacological treatments. This article aims to present an updated review of the most relevant aspects of physiopathology, clinical approach, and differential diagnosis of both phenomena.}, }
@article {pmid35727341, year = {2022}, author = {Abati, E and Manini, A and Comi, GP and Corti, S}, title = {Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {7}, pages = {374}, pmid = {35727341}, issn = {1420-9071}, support = {Ricerca corrente//Ministero della Salute/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Disease Models, Animal ; Humans ; Muscle, Skeletal/metabolism ; Muscular Atrophy/metabolism ; *Muscular Atrophy, Spinal/drug therapy/genetics ; Myostatin/genetics/metabolism/therapeutic use ; Signal Transduction ; }, abstract = {Myostatin is a negative regulator of skeletal muscle growth secreted by skeletal myocytes. In the past years, myostatin inhibition sparked interest among the scientific community for its potential to enhance muscle growth and to reduce, or even prevent, muscle atrophy. These characteristics make it a promising target for the treatment of muscle atrophy in motor neuron diseases, namely, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), which are rare neurological diseases, whereby the degeneration of motor neurons leads to progressive muscle loss and paralysis. These diseases carry a huge burden of morbidity and mortality but, despite this unfavorable scenario, several therapeutic advancements have been made in the past years. Indeed, a number of different curative therapies for SMA have been approved, leading to a revolution in the life expectancy and outcomes of SMA patients. Similarly, tofersen, an antisense oligonucleotide, is now undergoing clinical trial phase for use in ALS patients carrying the SOD1 mutation. However, these therapies are not able to completely halt or reverse progression of muscle damage. Recently, a trial evaluating apitegromab, a myostatin inhibitor, in SMA patients was started, following positive results from preclinical studies. In this context, myostatin inhibition could represent a useful strategy to tackle motor symptoms in these patients. The aim of this review is to describe the myostatin pathway and its role in motor neuron diseases, and to summarize and critically discuss preclinical and clinical studies of myostatin inhibitors in SMA and ALS. Then, we will highlight promises and pitfalls related to the use of myostatin inhibitors in the human setting, to aid the scientific community in the development of future clinical trials.}, }
@article {pmid35721008, year = {2022}, author = {Russo, T and Riessland, M}, title = {Age-Related Midbrain Inflammation and Senescence in Parkinson's Disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {917797}, pmid = {35721008}, issn = {1663-4365}, abstract = {Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive. In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic (DA) neurons in PD.}, }
@article {pmid35716729, year = {2022}, author = {Lambert-Smith, IA and Saunders, DN and Yerbury, JJ}, title = {Proteostasis impairment and ALS.}, journal = {Progress in biophysics and molecular biology}, volume = {174}, number = {}, pages = {3-27}, doi = {10.1016/j.pbiomolbio.2022.06.001}, pmid = {35716729}, issn = {1873-1732}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Proteome ; Proteostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease that results from the loss of both upper and lower motor neurons. It is the most common motor neuron disease and currently has no effective treatment. There is mounting evidence to suggest that disturbances in proteostasis play a significant role in ALS pathogenesis. Proteostasis is the maintenance of the proteome at the right level, conformation and location to allow a cell to perform its intended function. In this review, we present a thorough synthesis of the literature that provides evidence that genetic mutations associated with ALS cause imbalance to a proteome that is vulnerable to such pressure due to its metastable nature. We propose that the mechanism underlying motor neuron death caused by defects in mRNA metabolism and protein degradation pathways converges on proteostasis dysfunction. We propose that the proteostasis network may provide an effective target for therapeutic development in ALS.}, }
@article {pmid35714755, year = {2022}, author = {Liu, X and Henty-Ridilla, JL}, title = {Multiple roles for the cytoskeleton in ALS.}, journal = {Experimental neurology}, volume = {355}, number = {}, pages = {114143}, pmid = {35714755}, issn = {1090-2430}, support = {R35 GM133485/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cytoskeleton/metabolism ; Humans ; Kinesins ; Microtubules/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; Profilins/genetics/metabolism ; Spastin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by more than sixty genes identified through classic linkage analysis and new sequencing methods. Yet no clear mechanism of onset, cure, or effective treatment is known. Popular discourse classifies the proteins encoded from ALS-related genes into four disrupted processes: proteostasis, mitochondrial function and ROS, nucleic acid regulation, and cytoskeletal dynamics. Surprisingly, the mechanisms detailing the contribution of the neuronal cytoskeletal in ALS are the least explored, despite involvement in these cell processes. Eight genes directly regulate properties of cytoskeleton function and are essential for the health and survival of motor neurons, including: TUBA4A, SPAST, KIF5A, DCTN1, NF, PRPH, ALS2, and PFN1. Here we review the properties and studies exploring the contribution of each of these genes to ALS.}, }
@article {pmid35713146, year = {2022}, author = {Azari, A and Goodarzi, A and Jafarkhani, B and Eghbali, M and Karimi, Z and Hosseini Balef, SS and Irannejad, H}, title = {Novel Molecular Targets and Mechanisms for Neuroprotective Modulation in Neurodegenerative Disorders.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {22}, number = {2}, pages = {88-107}, doi = {10.2174/1871524922666220616092132}, pmid = {35713146}, issn = {1875-6166}, mesh = {Autophagy/genetics ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neurons/metabolism ; *alpha-Synuclein/metabolism ; }, abstract = {BACKGROUND: Neuronal death underlies the symptoms of several human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis and their precise pathophysiology have not yet been elucidated. According to various studies, the prohibition is the best therapy with neuroprotective approaches, which are advanced and safe methods.<br><br>METHODS: This review summarizes some of the already-known and newly emerged neuroprotective targets and strategies and their experimental effects have also been reported. Accordingly, literature was studied from 2000 to 2021, and appropriate articles were searched in Google Scholar and Scopus with the keywords given in the keywords section of the current review.<br><br>RESULTS: Lewy bodies are the histopathologic characteristics of neurodegenerative disorders and are protein-rich intracellular deposits in which Alpha-synuclein is its major protein. Alphasynuclein's toxic potential provides a compelling rationale for therapeutic strategies aimed at decreasing its burden in neuronal cells through numerous pathways, including ubiquitin-proteasome system and autophagy-lysosome pathway, proteolytic breakdown via cathepsin D, kallikrein-6 (neurosin), calpain-1 or MMP9, heat shock proteins, and proteolysis targeting chimera which consists of a target protein-ligand and an E3 ubiquitin ligase (E3) followed by target protein ubiquitination (PROTACs). Other targets that have been noticed recently are the mutant huntingtin, tau proteins and glycogen synthase kinase 3&#x3b2;; their accumulation proceeds extensive neuronal damage and up to the minute approach such as proteolysis targeting chimera promotes its degradation in cells. Various studies demonstrated that Mendelian gene mutations can result in neurodegenerative diseases. An additional target that has gained much interest is epigenetics, such as mutation, phosphodiesterase, RNA binding proteins and Nuclear respiratory factor 1.<br><br>CONCLUSION: The novel molecular targets and new strategies compiled and introduced here can be used by scientists to design and discover more efficient small molecule drugs against neurodegenerative diseases. And also, the genes in which their mutations can lead to the &#x3b1;-synuclein aggregation or accumulation have been discussed and considered a valuable information on epigenetics in dementia.}, }
@article {pmid35711736, year = {2022}, author = {Tang, F and Fan, J and Zhang, X and Zou, Z and Xiao, D and Li, X}, title = {The Role of Vti1a in Biological Functions and Its Possible Role in Nervous System Disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {918664}, pmid = {35711736}, issn = {1662-5099}, abstract = {Vesicle transport through interaction with t-SNAREs 1A (Vti1a), a member of the N-ethylmaleimide-sensitive factor attachment protein receptor protein family, is involved in cell signaling as a vesicular protein and mediates vesicle trafficking. Vti1a appears to have specific roles in neurons, primarily by regulating upstream neurosecretory events that mediate exocytotic proteins and the availability of secretory organelles, as well as regulating spontaneous synaptic transmission and postsynaptic efficacy to control neurosecretion. Vti1a also has essential roles in neural development, autophagy, and unconventional extracellular transport of neurons. Studies have shown that Vti1a dysfunction plays critical roles in pathological mechanisms of Hepatic encephalopathy by influencing spontaneous neurotransmission. It also may have an unknown role in amyotrophic lateral sclerosis. A VTI1A variant is associated with the risk of glioma, and the fusion product of the VTI1A gene and the adjacent TCF7L2 gene is involved in glioma development. This review summarizes Vti1a functions in neurons and highlights the role of Vti1a in the several nervous system disorders.}, }
@article {pmid35708843, year = {2022}, author = {Cozzi, M and Ferrari, V}, title = {Autophagy Dysfunction in ALS: from Transport to Protein Degradation.}, journal = {Journal of molecular neuroscience : MN}, volume = {72}, number = {7}, pages = {1456-1481}, pmid = {35708843}, issn = {1559-1166}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy/genetics ; Humans ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/pathology ; Proteins/metabolism ; Proteolysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Since the identification of the first ALS mutation in 1993, more than 40 genes have been associated with the disorder. The most frequent genetic causes of ALS are represented by mutated genes whose products challenge proteostasis, becoming unable to properly fold and consequently aggregating into inclusions that impose proteotoxic stress on affected cells. In this context, increasing evidence supports the central role played by autophagy dysfunctions in the pathogenesis of ALS. Indeed, in early stages of disease, high levels of proteins involved in autophagy are present in ALS MNs; but at the same time, with neurodegeneration progression, autophagy-mediated degradation decreases, often as a result of the accumulation of toxic protein aggregates in affected cells. Autophagy is a complex multistep pathway that has a central role in maintaining cellular homeostasis. Several proteins are involved in its tight regulation, and importantly a relevant fraction of ALS-related genes encodes products that directly take part in autophagy, further underlining the relevance of this key protein degradation system in disease onset and progression. In this review, we report the most relevant findings concerning ALS genes whose products are involved in the several steps of the autophagic pathway, from phagophore formation to autophagosome maturation and transport and finally to substrate degradation.}, }
@article {pmid35708081, year = {2023}, author = {Birmann, PT and Casaril, AM and Abenante, L and Penteado, F and Brüning, CA and Savegnago, L and Lenardão, EJ}, title = {Neuropharmacology of Organoselenium Compounds in Mental Disorders and Degenerative Diseases.}, journal = {Current medicinal chemistry}, volume = {30}, number = {21}, pages = {2357-2395}, doi = {10.2174/0929867329666220615124412}, pmid = {35708081}, issn = {1875-533X}, mesh = {Humans ; Neuropharmacology ; Antioxidants/pharmacology/therapeutic use/chemistry ; *Mental Disorders/drug therapy ; *Organoselenium Compounds/pharmacology/therapeutic use/chemistry ; }, abstract = {Neurodegenerative and mental disorders are a public health burden with pharmacological treatments of limited efficacy. Organoselenium compounds are receiving great attention in medicinal chemistry mainly because of their antioxidant and immunomodulatory activities, with a multi-target profile that can favor the treatment of multifactorial diseases. Therefore, the purpose of this review is to discuss recent preclinical studies about organoselenium compounds as therapeutic agents for the management of mental (e.g., depression, anxiety, bipolar disorder, and schizophrenia) and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis). We have summarized around 70 peer-reviewed articles from 2016 to the present that used in silico, in vitro, and/or in vivo approaches to assess the neuropharmacology of selenium- containing compounds. Among the diversity of organoselenium molecules investigated in the last five years, diaryl diselenides, Ebselen-derivatives, and Se-containing heterocycles are the most representative. Ultimately, this review is expected to provide disease-oriented information regarding the neuropharmacology of organoselenium compounds that can be useful for the design, synthesis, and pharmacological characterization of novel bioactive molecules that can potentially be clinically viable candidates.}, }
@article {pmid35708049, year = {2023}, author = {Alugoju, P and Krishna Swamy, VKD and Anthikapalli, NVA and Tencomnao, T}, title = {Health benefits of astaxanthin against age-related diseases of multiple organs: A comprehensive review.}, journal = {Critical reviews in food science and nutrition}, volume = {63}, number = {31}, pages = {10709-10774}, doi = {10.1080/10408398.2022.2084600}, pmid = {35708049}, issn = {1549-7852}, mesh = {Male ; Humans ; *Quality of Life ; *Antioxidants/pharmacology/therapeutic use ; Aging ; Carotenoids ; Ischemia/drug therapy ; }, abstract = {Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a substantial impact on social and health care expenditure. Anti-aging strategies aim to mitigate, delay and reverse aging-associated diseases, thereby improving quality of life and reducing the burden of age-related pathologies. The natural dietary antioxidant supplementation offers substantial pharmacological and therapeutic effects against various disease conditions. Astaxanthin is one such natural carotenoid with superior antioxidant activity than other carotenoids, as well as well as vitamins C and E, and additionally, it is known to exhibit a plethora of pharmacological effects. The present review summarizes the protective molecular mechanisms of actions of astaxanthin on age-related diseases of multiple organs such as Neurodegenerative diseases [Alzheimer's disease (AD), Parkinson's disease (PD), Stroke, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Status Epilepticus (SE)], Bone Related Diseases [Osteoarthritis (OA) and Osteoporosis], Cancers [Colon cancer, Prostate cancer, Breast cancer, and Lung Cancer], Cardiovascular disorders [Hypertension, Atherosclerosis and Myocardial infarction (MI)], Diabetes associated complications [Diabetic nephropathy (DN), Diabetic neuropathy, and Diabetic retinopathy (DR)], Eye disorders [Age related macular degeneration (AMD), Dry eye disease (DED), Cataract and Uveitis], Gastric Disorders [Gastritis, Colitis, and Functional dyspepsia], Kidney Disorders [Nephrolithiasis, Renal fibrosis, Renal Ischemia reperfusion (RIR), Acute kidney injury (AKI), and hyperuricemia], Liver Diseases [Nonalcoholic fatty liver disease (NAFLD), Alcoholic Liver Disease (AFLD), Liver fibrosis, and Hepatic Ischemia-Reperfusion (IR) Injury], Pulmonary Disorders [Pulmonary Fibrosis, Acute Lung injury (ALI), and Chronic obstructive pulmonary disease (COPD)], Muscle disorders (skeletal muscle atrophy), Skin diseases [Atopic dermatitis (ATD), Skin Photoaging, and Wound healing]. We have also briefly discussed astaxanthin's protective effects on reproductive health.}, }
@article {pmid35693938, year = {2022}, author = {Martín-Guerrero, SM and Markovinovic, A and Mórotz, GM and Salam, S and Noble, W and Miller, CCJ}, title = {Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {915931}, pmid = {35693938}, issn = {2296-634X}, support = {MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. There are no cures or effective treatments for FTD or ALS and so new targets for therapeutic intervention are required but this is hampered by the large number of physiological processes that are damaged in FTD/ALS. Many of these damaged functions are now known to be regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by "tethering" proteins that serve to recruit ER to mitochondria. One tether strongly associated with FTD/ALS involves an interaction between the ER protein VAPB and the mitochondrial protein PTPIP51. Recent studies have shown that ER-mitochondria signaling is damaged in FTD/ALS and that this involves breaking of the VAPB-PTPIP51 tethers. Correcting disrupted tethering may therefore correct many other downstream damaged features of FTD/ALS. Here, we review progress on this topic with particular emphasis on targeting of the VAPB-PTPIP51 tethers as a new drug target.}, }
@article {pmid35691950, year = {2023}, author = {Suzuki, N and Nishiyama, A and Warita, H and Aoki, M}, title = {Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy.}, journal = {Journal of human genetics}, volume = {68}, number = {3}, pages = {131-152}, pmid = {35691950}, issn = {1435-232X}, support = {21bm0804003h0003//Japan Agency for Medical Research and Development (AMED)/ ; 20H03586//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 21K07411//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics/therapeutic use ; Genome-Wide Association Study ; Mutation ; DNA-Binding Proteins/genetics ; Genetic Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing on SOD1, fused in sarcoma (FUS), and transacting response DNA-binding protein. The frequency of the C9ORF72 mutation is low in Japan, unlike in Europe and the United States, while SOD1 and FUS are more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.}, }
@article {pmid35691696, year = {2022}, author = {Campos, ST and Bruno, MJ}, title = {Endoscopic Papillectomy.}, journal = {Gastrointestinal endoscopy clinics of North America}, volume = {32}, number = {3}, pages = {545-562}, doi = {10.1016/j.giec.2022.01.005}, pmid = {35691696}, issn = {1558-1950}, mesh = {*Adenoma/diagnosis ; *Ampulla of Vater/diagnostic imaging/pathology/surgery ; *Common Bile Duct Neoplasms/diagnostic imaging/surgery ; Endoscopy, Gastrointestinal ; Humans ; Treatment Outcome ; }, abstract = {Most ampullary lesions (ALs) are sporadic, involve the major papilla, and are premalignant (adenomas). They are often diagnosed as an incidental finding during endoscopy or imaging procedures. Diagnosis and staging of ALs include endoscopic, histologic, and radiological evaluations. Currently, endoscopic papillectomy is the preferred treatment for ALs in most situations. In this article, we will describe the diagnostic work-up and focus on the endoscopic treatment, including indications, technique, outcomes, complications, and follow-up.}, }
@article {pmid35691453, year = {2022}, author = {Fan, Y and Shu, X and Leung, KCM and Lo, ECM}, title = {Associations of general health conditions with masticatory performance and maximum bite force in older adults: A systematic review of cross-sectional studies.}, journal = {Journal of dentistry}, volume = {123}, number = {}, pages = {104186}, doi = {10.1016/j.jdent.2022.104186}, pmid = {35691453}, issn = {1879-176X}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis ; Bite Force ; Cross-Sectional Studies ; Humans ; Mastication ; *Sarcopenia ; *Stroke ; }, abstract = {OBJECTIVES: To give an overview of the current evidence on the associations of general health conditions with masticatory performance and maximum bite force in older adults.<br><br>DATA/SOURCES: Three electronic databases (Medline via PubMed, Embase via Ovid and CINAHL Plus via EBSCOhost) were searched up to September 2021 for cross-sectional studies on general health conditions and masticatory performance or maximum bite force in older adults. Methodological quality of the included studies was independently evaluated based on Joanna Briggs Institute critical appraisal checklist for analytical cross-sectional studies. Data on the associations between general health conditions and masticatory performance or maximum bite force were extracted.<br><br>STUDY SELECTION: Of the 5133 records identified, 39 studies (43 articles) were included in this review. Significant negative associations were found between masticatory performance and stroke, sarcopenia, amyotrophic lateral sclerosis, chronic obstructive pulmonary disease, dyspepsia, dysphagia, anorexia, and carotid atherosclerosis. Significant negative association was found between maximum bite force and sarcopenia. There were equivocal results on the association between masticatory performance and diabetes mellitus, and between maximum bite force and stroke, and amyotrophic lateral sclerosis. There was no significant association between masticatory performance and metabolic syndrome, and between maximum bite force and progress of Parkinson's disease. Most studies revealed positive associations of physical function with masticatory performance and maximum bite force.<br><br>CONCLUSIONS: Negative associations between masticatory function of older adults and presence of several systemic diseases have been reported in a number of studies while there are positive associations between masticatory function and some physical function indicators.<br><br>CLINICAL SIGNIFICANCE: This study provides valuable information on the association of masticatory function with general health, which draws clinicians' attention to the masticatory function of older adults who suffer from certain systemic diseases or physical dysfunction, and to the need to improve their masticatory ability to achieve healthy aging.}, }
@article {pmid35684340, year = {2022}, author = {Nandwana, V and Nandwana, NK and Das, Y and Saito, M and Panda, T and Das, S and Almaguel, F and Hosmane, NS and Das, BC}, title = {The Role of Microbiome in Brain Development and Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {11}, pages = {}, pmid = {35684340}, issn = {1420-3049}, mesh = {Animals ; *Autism Spectrum Disorder/pathology ; Boron ; Brain/pathology ; *Microbiota ; *Neurodegenerative Diseases/pathology ; *Probiotics/therapeutic use ; }, abstract = {Hundreds of billions of commensal microorganisms live in and on our bodies, most of which colonize the gut shortly after birth and stay there for the rest of our lives. In animal models, bidirectional communications between the central nervous system and gut microbiota (Gut-Brain Axis) have been extensively studied, and it is clear that changes in microbiota composition play a vital role in the pathogenesis of various neurodevelopmental and neurodegenerative disorders, such as Autism Spectrum Disorder, Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, anxiety, stress, and so on. The makeup of the microbiome is impacted by a variety of factors, such as genetics, health status, method of delivery, environment, nutrition, and exercise, and the present understanding of the role of gut microbiota and its metabolites in the preservation of brain functioning and the development of the aforementioned neurological illnesses is summarized in this review article. Furthermore, we discuss current breakthroughs in the use of probiotics, prebiotics, and synbiotics to address neurological illnesses. Moreover, we also discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. In addition, in the coming years, boron reagents will play a significant role to improve dysbiosis and will open new areas for researchers.}, }
@article {pmid35684025, year = {2022}, author = {Evans, JA and Mendonca, P and Soliman, KFA}, title = {Neuroprotective Effects and Therapeutic Potential of the Citrus Flavonoid Hesperetin in Neurodegenerative Diseases.}, journal = {Nutrients}, volume = {14}, number = {11}, pages = {}, pmid = {35684025}, issn = {2072-6643}, support = {G12 MD007582/MD/NIMHD NIH HHS/United States ; U54 MD007582/MD/NIMHD NIH HHS/United States ; U54 MD 007582/MD/NIMHD NIH HHS/United States ; }, mesh = {Anti-Inflammatory Agents ; *Citrus ; Flavonoids/pharmacology/therapeutic use ; *Hesperidin/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative disorders affect more than fifty million Americans each year and represent serious health threats as the population ages. Neuroinflammation and oxidative stress are critical in the onset, progression, and pathogenesis of neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS). A wide range of natural compounds has been investigated because of their antioxidant, anti-inflammatory, and neuroprotective properties. The citrus flavonoid hesperetin (HPT), an aglycone of hesperidin found in oranges, mandarins, and lemons, has been extensively reported to exert neuroprotective effects in experimental models of neurogenerative diseases. This review has compiled multiple studies on HPT in both in vivo and in vitro models to study neurodegeneration. We focused on the modulatory effects of hesperetin on the release of cellular anti-inflammatory and antioxidative stress mediators. Additionally, this review discusses the hesperetin effect in maintaining the levels of microRNA (miRNA) and modulating autophagy as it relates to hesperetin's protective mechanisms against neurodegeneration. Moreover, this review is focused on providing experimental data for hesperetin's potential as a neuroprotective compound and discusses reported evidence that HPT crosses the blood-brain barrier. In summary, this review shows the evidence available in the literature to indicate the efficacy of hesperetin in delaying the onset of neurodegenerative diseases.}, }
@article {pmid35682615, year = {2022}, author = {Teleanu, DM and Niculescu, AG and Lungu, II and Radu, CI and Vladâcenco, O and Roza, E and Costăchescu, B and Grumezescu, AM and Teleanu, RI}, title = {An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {11}, pages = {}, pmid = {35682615}, issn = {1422-0067}, mesh = {Antioxidants/therapeutic use ; Humans ; *Neurodegenerative Diseases/pathology ; Neuroinflammatory Diseases ; Oxidative Stress/physiology ; Reactive Oxygen Species ; }, abstract = {Oxidative stress has been linked with a variety of diseases, being involved in the debut and/or progress of several neurodegenerative disorders. This review intends to summarize some of the findings that correlate the overproduction of reactive oxygen species with the pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Oxidative stress was also noted to modify the inflammatory response. Even though oxidative stress and neuroinflammation are two totally different pathological events, they are linked and affect one another. Nonetheless, there are still several mechanisms that need to be understood regarding the onset and the progress of neurodegenerative diseases in order to develop efficient therapies. As antioxidants are a means to alter oxidative stress and slow down the symptoms of these neurodegenerative diseases, the most common antioxidants, enzymatic as well as non-enzymatic, have been mentioned in this paper as therapeutic options for the discussed disorders.}, }
@article {pmid35682574, year = {2022}, author = {Kim, S and Kim, DK and Jeong, S and Lee, J}, title = {The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.}, journal = {International journal of molecular sciences}, volume = {23}, number = {11}, pages = {}, pmid = {35682574}, issn = {1422-0067}, support = {NRF-2020M3A9D8038660//National Research Foundation of Korea/ ; }, mesh = {Animals ; Autophagy ; Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum Stress/genetics ; Humans ; *Neurodegenerative Diseases/metabolism ; Unfolded Protein Response ; }, abstract = {Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.}, }
@article {pmid35670332, year = {2023}, author = {Mora, T and Domínguez, R and Assialioui, A and Paipa, A and Moreno, R and Corbella, X and Martínez-Yelamos, A and Povedano, M}, title = {Direct health costs of amyotrophic lateral sclerosis in a multidisciplinary ALS unit in Catalonia (Spain).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {1-2}, pages = {133-138}, doi = {10.1080/21678421.2022.2080560}, pmid = {35670332}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Spain ; Health Care Costs ; }, abstract = {Our research project computed the direct health costs of patients with amyotrophic lateral sclerosis (ALS) in a Spanish multidisciplinary unit and explored the main factors associated. Besides analyzing a context with universal health care provision, we used an administrative health care dataset from the most crucial center unit treating ALS in Catalonia (80% of total patients). Our results show that the direct health cost of caring for an ALS patient in our unit was 5,158€per patient/year. This cost was not influenced by the onset of the disease, sex or age, but it increased if the patient lived near our center since this facilitates the frequency of follow-up visits. Finally, the higher the educational level, the lower the direct health costs.}, }
@article {pmid35663577, year = {2022}, author = {Wang, X and Zhang, Y and Jin, T and Botchway, BOA and Fan, R and Wang, L and Liu, X}, title = {Adipose-Derived Mesenchymal Stem Cells Combined With Extracellular Vesicles May Improve Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {830346}, pmid = {35663577}, issn = {1663-4365}, abstract = {The complexity of central nervous system diseases together with their intricate pathogenesis complicate the establishment of effective treatment strategies. Presently, the superiority of adipose-derived mesenchymal stem cells (ADSCs) on neuronal injuries has attracted significant attention. Similarly, extracellular vesicles (EVs) are potential interventional agents that could identify and treat nerve injuries. Herein, we reviewed the potential effects of ADSCs and EVs on amyotrophic lateral sclerosis (ALS) injured nerves, and expound on their practical application in the clinic setting. This article predominantly focused on the therapeutic role of ADSCs concerning the pathogenesis of ALS, the protective and reparative effects of EVs on nerve injury, as well as the impact following the combined usage of ADSCs and EVs in ALS.}, }
@article {pmid35661277, year = {2022}, author = {Mou, Y and Li, M and Liu, M and Wang, J and Zhu, G and Zha, Y}, title = {OPTN variants in ALS cases: a case report of a novel mutation and literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {9}, pages = {5391-5396}, pmid = {35661277}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Cell Cycle Proteins/genetics ; Female ; Heterozygote ; Humans ; Male ; Mutation/genetics ; Phenotype ; *Transcription Factor TFIIIA/genetics ; }, abstract = {INTRODUCTION: Optineurin (OPTN)-associated mutations have been implicated in the development of type 12 amyotrophic lateral sclerosis (ALS12). We reported a case of ALS with a new OPTN variant (p.D527fs) and reviewed relevant literature to better understand the phenotypes and pathophysiological mechanisms of ALS12.<br><br>METHODS: We report a case of a 55-year-old female patient with a new heterozygous variant of the OPTN gene. A literature search of ALS cases associated with the OPTN gene mutations was performed in PubMed with the search criteria as [("amyotrophic lateral sclerosis") OR ("motor neuron disease")] AND ("OPTN").<br><br>RESULTS: The case of ALS with a new OPTN variant (p.D527fs) in our report manifested with bulbar involvement in onset and a rapidly progressive course. A literature review of 37 ALS patients with OPTN mutations included 20 males and 16 females with another patient whose gender was not described. The mean onset age of 37 ALS12 patients was 48 with the youngest 23 and the oldest 83 years old. Differences in onset age between male and female patients were not significant. Mean time from initiation to death was 61.8 &#xb1; 12.0 months. Patients present with either limb onset (73.5% cases) or bulbar onset (23.5% cases).<br><br>CONCLUSION: Through the literature review, we summarized the clinical characteristics of ALS12. The phenotypes of the reported patients elucidate the genetic profiles and clinical phenotypes of ALS12. Clinicians should pay close attention to the role of receptor-interacting kinase 1 (RIPK1)-dependent necroptosis in the pathophysiologic development of ALS12, since necroptosis inhibitors are expected as potential therapeutic agents for treating ALS12.}, }
@article {pmid35659112, year = {2022}, author = {Khalaf, K and Tornese, P and Cocco, A and Albanese, A}, title = {Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {33}, pmid = {35659112}, issn = {2047-9158}, support = {755094/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Bile Acids and Salts/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Taurochenodeoxycholic Acid/metabolism/pharmacology/therapeutic use ; }, abstract = {Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA's neuroprotective action derives from animal models of Alzheimer's disease, Parkinson's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.}, }
@article {pmid35653243, year = {2022}, author = {Nolan, JP and Soar, J}, title = {Temperature control after cardiac arrest: friend or foe.}, journal = {Current opinion in critical care}, volume = {28}, number = {3}, pages = {244-249}, pmid = {35653243}, issn = {1531-7072}, mesh = {*Cardiopulmonary Resuscitation ; Coma/etiology/therapy ; *Heart Arrest/complications/therapy ; Humans ; *Hypothermia, Induced ; Temperature ; }, abstract = {PURPOSE OF REVIEW: Most patients who are successfully resuscitated after cardiac arrest are initially comatose and require mechanical ventilation and other organ support in an ICU. Best practice has been to cool these patients and control their temperature at a constant value in the range of 32-36 oC for at least 24 h. But the certainty of the evidence for this practice is increasingly being challenged. This review will summarize the evidence on key aspects of temperature control in comatose postcardiac arrest patients.<br><br>RECENT FINDINGS: The Targeted Temperature Management 2 (TTM-2) trial documented no difference in 6-month mortality among comatose postcardiac arrest patients managed at 33&#x200a;oC vs. targeted normothermia. A systematic review and meta-analysis completed by the Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR) concluded that temperature control with a target of 32-34&#x200a;&#xb0;C did not improve survival or favourable functional outcome after cardiac arrest. Two observational studies have documented an association between predicted moderate hypoxic-ischaemic brain injury and better outcome with temperature control at 33-34&#x200a;oC compared with 35-36&#x200a;oC.<br><br>SUMMARY: We suggest actively preventing fever by targeting a temperature 37.5&#x200a;oC or less for those patients who remain comatose following return of spontaneous circulation (ROSC) after cardiac arrest.}, }
@article {pmid35653060, year = {2022}, author = {Boros, BD and Schoch, KM and Kreple, CJ and Miller, TM}, title = {Antisense Oligonucleotides for the Study and Treatment of ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1145-1158}, pmid = {35653060}, issn = {1878-7479}, support = {RF1 MH126723/MH/NIMH NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Oligonucleotides, Antisense/therapeutic use/genetics ; C9orf72 Protein ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.}, }
@article {pmid35652543, year = {2022}, author = {Sun, JM and Zhang, CJ and Wang, L and Bi, HY}, title = {Clinical phenotype of familial amyotrophic lateral sclerosis with SOD1 gene mutation mimicking proximal myopathy: A case report and literature review.}, journal = {Clinical neuropathology}, volume = {41}, number = {5}, pages = {219-225}, doi = {10.5414/NP301459}, pmid = {35652543}, issn = {0722-5091}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; DNA ; Humans ; *Muscular Diseases/genetics ; Mutation ; Phenotype ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disorder with strong clinical and genetic heterogeneity, and its pathogenic mechanism has not been completely clarified. Proximal myopathy is rare in clinical manifestations of ALS. Here, we describe a 34-year-old woman with a 1-year history of symmetrical, proximal limb weakness, and muscle atrophy, with slow progression and no upper motor neuron (UMN) signs. The clinical phenotype was similar to myopathy and was initially misdiagnosed as proximal myopathy. Electromyography (EMG) and muscle and nerve biopsy were performed. The genomic DNA from the patient's peripheral blood lymphocytes was analyzed. The EMG and pathologic examinations revealed chronic neurogenic changes and mild mixed peripheral neuropathy. DNA analysis revealed a heterozygous missense mutation in exon 1 at codon 50 (c.50>C) of SOD1, and a heterozygous missense mutation in exon 11 at codon 1013 (c.1013G>A) of CPT1C that has not been reported previously. The patient was diagnosed as familial ALS (FALS) type 1, and the patient had a family history of autosomal dominant (AD) pattern. This report expands the knowledge of the clinical phenotype of FALS. For patients with clinical manifestations mimicking proximal myopathy, the possibility of underlying ALS should be considered.}, }
@article {pmid35649654, year = {2022}, author = {Masdeu, JC and Pascual, B and Fujita, M}, title = {Imaging Neuroinflammation in Neurodegenerative Disorders.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {63}, number = {Suppl 1}, pages = {45S-52S}, doi = {10.2967/jnumed.121.263200}, pmid = {35649654}, issn = {1535-5667}, mesh = {Animals ; Humans ; Inflammation/diagnostic imaging/pathology ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; Neuroinflammatory Diseases ; Positron-Emission Tomography/methods ; *Receptors, GABA/metabolism ; }, abstract = {Neuroinflammation plays a major role in the etiopathology of neurodegenerative diseases, including Alzheimer and Parkinson diseases, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. In vivo monitoring of neuroinflammation using PET is critical to understand this process, and data are accumulating in this regard, thus a review is useful. From PubMed, we retrieved publications using any of the available PET tracers to image neuroinflammation in humans as well as selected articles dealing with experimental animal models or the chemistry of currently used or potential radiotracers. We reviewed 280 articles. The most common PET neuroinflammation target, translocator protein (TSPO), has limitations, lacking cellular specificity and the ability to separate neuroprotective from neurotoxic inflammation. However, TSPO PET is useful to define the amount and location of inflammation in the brain of people with neurodegenerative disorders. We describe the characteristics of TSPO and other potential PET neuroinflammation targets and PET tracers available or in development. Despite target and tracer limitations, in recent years there has been a sharp increase in the number of reports of neuroinflammation PET in humans. The most studied has been Alzheimer disease, in which neuroinflammation seems initially neuroprotective and neurotoxic later in the progression of the disease. We describe the findings in all the major neurodegenerative disorders. Neuroinflammation PET is an indispensable tool to understand the process of neurodegeneration, particularly in humans, as well as to validate target engagement in therapeutic clinical trials.}, }
@article {pmid35646086, year = {2022}, author = {Castelli, LM and Benson, BC and Huang, WP and Lin, YH and Hautbergue, GM}, title = {RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {886563}, pmid = {35646086}, issn = {1664-8021}, support = {MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Short repeated sequences of 3-6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches.}, }
@article {pmid35645791, year = {2022}, author = {Budgett, RF and Bakker, G and Sergeev, E and Bennett, KA and Bradley, SJ}, title = {Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {893422}, pmid = {35645791}, issn = {1663-9812}, abstract = {The type 5 metabotropic glutamate receptor, mGlu5, has been proposed as a potential therapeutic target for the treatment of several neurodegenerative diseases. In preclinical neurodegenerative disease models, novel allosteric modulators have been shown to improve cognitive performance and reduce disease-related pathology. A common pathological hallmark of neurodegenerative diseases is a chronic neuroinflammatory response, involving glial cells such as astrocytes and microglia. Since mGlu5 is expressed in astrocytes, targeting this receptor could provide a potential mechanism by which neuroinflammatory processes in neurodegenerative disease may be modulated. This review will discuss current evidence that highlights the potential of mGlu5 allosteric modulators to treat neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review will explore the role of mGlu5 in neuroinflammatory responses, and the potential for this G protein-coupled receptor to modulate neuroinflammation.}, }
@article {pmid35643264, year = {2022}, author = {Ziukelis, ET and Mak, E and Dounavi, ME and Su, L and T O'Brien, J}, title = {Fractal dimension of the brain in neurodegenerative disease and dementia: A systematic review.}, journal = {Ageing research reviews}, volume = {79}, number = {}, pages = {101651}, doi = {10.1016/j.arr.2022.101651}, pmid = {35643264}, issn = {1872-9649}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {*Alzheimer Disease/pathology ; Atrophy/pathology ; Brain/diagnostic imaging/pathology ; Fractals ; Humans ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; }, abstract = {Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric's utility.}, }
@article {pmid35633168, year = {2022}, author = {Christidi, F and Karavasilis, E and Argyropoulos, GD and Velonakis, G and Zouvelou, V and Murad, A and Evdokimidis, I and Rentzos, M and Seimenis, I and Bede, P}, title = {Neurometabolic Alterations in Motor Neuron Disease: Insights from Magnetic Resonance Spectroscopy.}, journal = {Journal of integrative neuroscience}, volume = {21}, number = {3}, pages = {87}, doi = {10.31083/j.jin2103087}, pmid = {35633168}, issn = {0219-6352}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Spectroscopy ; *Motor Neuron Disease/diagnostic imaging/pathology ; }, abstract = {Magnetic resonance spectroscopy (MRS) has contributed important academic insights in motor neuron diseases (MNDs), particularly in amyotrophic lateral sclerosis (ALS). Over the past three decades momentous methodological advances took place, including the emergence of high-field magnetic resonance imaging (MRI) platforms, multi-voxel techniques, whole-brain protocols, novel head-coil designs, and a multitude of open-source imaging suites. Technological advances in MRS are complemented by important conceptual developments in MND, such as the recognition of the importance of extra-motor brain regions, multi-timepoint longitudinal study designs, assessment of asymptomatic mutation carriers, description of genotype-associated signatures, and the gradual characterisation of non-ALS MND phenotypes. We have conducted a systematic review of published MRS studies in MND to identify important emerging research trends, key lessons from pioneering studies, and stereotyped shortcomings. We also sought to highlight notable gaps in the current literature so that research priorities for future studies can be outlined. While MRS remains relatively underutilised in MND compared to other structural, diffusivity and functional imaging modalities, our review suggests that MRS can not only advance our academic understanding of MND biology, but has a multitude of practical benefits for clinical and pharmaceutical trial applications.}, }
@article {pmid35629192, year = {2022}, author = {Gentile, G and Morello, G and La Cognata, V and Guarnaccia, M and Conforti, FL and Cavallaro, S}, title = {Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases.}, journal = {Journal of personalized medicine}, volume = {12}, number = {5}, pages = {}, pmid = {35629192}, issn = {2075-4426}, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are representative neurodegenerative diseases (NDs) characterized by degeneration of selective neurons, as well as the lack of effective biomarkers and therapeutic treatments. In the last decade, microRNAs (miRNAs) have gained considerable interest in diagnostics and therapy of NDs, owing to their aberrant expression and their ability to target multiple molecules and pathways. Here, we provide an overview of dysregulated miRNAs in fluids (blood or cerebrospinal fluid) and nervous tissue of AD, PD, and ALS patients. By emphasizing those that are commonly dysregulated in these NDs, we highlight their potential role as biomarkers or therapeutical targets and describe the use of antisense oligonucleotides as miRNA therapies.}, }
@article {pmid35629180, year = {2022}, author = {Ruffo, P and Cavallaro, S and Conforti, FL}, title = {The Advent of Omics Sciences in Clinical Trials of Motor Neuron Diseases.}, journal = {Journal of personalized medicine}, volume = {12}, number = {5}, pages = {}, pmid = {35629180}, issn = {2075-4426}, abstract = {The "omics revolution" has totally changed the scientific research approach and is contributing to the development of personalized therapies. In motor neuron diseases (MNDs), a set of complex, multifactorial, late-onset and chronic neurodegenerative diseases, the use of multi-omics approaches in clinical trials is providing new opportunities to stratify patients and develop target therapies. To show how omics science is gaining momentum in MNDs, in this work, we review the interventional clinical trials for MNDs based on the application of omics sciences. We analyze a total of 62 clinical trials listed in the ClinicalTrials database where different omics approaches have been applied in an initial phase, for diagnosis or patient selection, or in subsequent stages to cluster subjects, identify molecular signatures or evaluate drugs security or efficacy. The rise of omics sciences in clinical experimentation of MNDs is leading to an upheaval in their diagnosis and therapy that will require significant investments and means to ensure the correct and rapid evolution of personalized medicine.}, }
@article {pmid35627250, year = {2022}, author = {Calvo, AC and Valledor-Martín, I and Moreno-Martínez, L and Toivonen, JM and Osta, R}, title = {Lessons to Learn from the Gut Microbiota: A Focus on Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {13}, number = {5}, pages = {}, pmid = {35627250}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Dysbiosis ; *Gastrointestinal Microbiome/physiology ; Humans ; Prebiotics ; *Probiotics/therapeutic use ; }, abstract = {The gut microbiota is able to modulate the development and homeostasis of the central nervous system (CNS) through the immune, circulatory, and neuronal systems. In turn, the CNS influences the gut microbiota through stress responses and at the level of the endocrine system. This bidirectional communication forms the "gut microbiota-brain axis" and has been postulated to play a role in the etiopathology of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Numerous studies in animal models of ALS and in patients have highlighted the close communication between the immune system and the gut microbiota and, therefore, it is possible that alterations in the gut microbiota may have a direct impact on neuronal function and survival in ALS patients. Consequently, if the gut dysbiosis does indeed play a role in ALS-related neurodegeneration, nutritional immunomodulatory interventions based on probiotics, prebiotics, and/or postbiotics could emerge as innovative therapeutic strategies. This review aimed to shed light on the impact of the gut microbiota in ALS disease and on the use of potential nutritional interventions based on different types of biotics to ameliorate ALS symptoms.}, }
@article {pmid35625943, year = {2022}, author = {Luo, J}, title = {TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications.}, journal = {Biomedicines}, volume = {10}, number = {5}, pages = {}, pmid = {35625943}, issn = {2227-9059}, support = {R01 NS092868/NS/NINDS NIH HHS/United States ; RF1 AG059694/AG/NIA NIH HHS/United States ; R01NS092868, RF1AG059694/NH/NIH HHS/United States ; }, abstract = {Astrocytes are essential for normal brain development and functioning. They respond to brain injury and disease through a process referred to as reactive astrogliosis, where the reactivity is highly heterogenous and context-dependent. Reactive astrocytes are active contributors to brain pathology and can exert beneficial, detrimental, or mixed effects following brain insults. Transforming growth factor-β (TGF-β) has been identified as one of the key factors regulating astrocyte reactivity. The genetic and pharmacological manipulation of the TGF-β signaling pathway in animal models of central nervous system (CNS) injury and disease alters pathological and functional outcomes. This review aims to provide recent understanding regarding astrocyte reactivity and TGF-β signaling in brain injury, aging, and neurodegeneration. Further, it explores how TGF-β signaling modulates astrocyte reactivity and function in the context of CNS disease and injury.}, }
@article {pmid35625841, year = {2022}, author = {Godoy-Corchuelo, JM and Fernández-Beltrán, LC and Ali, Z and Gil-Moreno, MJ and López-Carbonero, JI and Guerrero-Sola, A and Larrad-Sainz, A and Matias-Guiu, J and Matias-Guiu, JA and Cunningham, TJ and Corrochano, S}, title = {Lipid Metabolic Alterations in the ALS-FTD Spectrum of Disorders.}, journal = {Biomedicines}, volume = {10}, number = {5}, pages = {}, pmid = {35625841}, issn = {2227-9059}, support = {MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS-FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.}, }
@article {pmid35625805, year = {2022}, author = {Meacci, E and Pierucci, F and Garcia-Gil, M}, title = {Skeletal Muscle and COVID-19: The Potential Involvement of Bioactive Sphingolipids.}, journal = {Biomedicines}, volume = {10}, number = {5}, pages = {}, pmid = {35625805}, issn = {2227-9059}, support = {2020//research grant from Associazione Voglia di Vivere Italy to F.P./ ; 2022//Ministry of Education, Universities and Research/ ; }, abstract = {SARS-CoV-2 virus infection is the cause of the coronavirus disease 2019 (COVID-19), which is still spreading over the world. The manifestation of this disease can range from mild to severe and can be limited in time (weeks) or persist for months in about 30-50% of patients. COVID-19 is considered a multiple organ dysfunction syndrome and the musculoskeletal system manifestations are beginning to be considered of absolute importance in both COVID-19 patients and in patients recovering from the SARS-CoV-2 infection. Musculoskeletal manifestations of COVID-19 and other coronavirus infections include loss of muscle mass, muscle weakness, fatigue or myalgia, and muscle injury. The molecular mechanisms by which SARS-CoV-2 can cause damage to skeletal muscle (SkM) cells are not yet well understood. Sphingolipids (SLs) represent an important class of eukaryotic lipids with structural functions as well as bioactive molecules able to modulate crucial processes, including inflammation and viral infection. In the last two decades, several reports have highlighted the role of SLs in modulating SkM cell differentiation, regeneration, aging, response to insulin, and contraction. This review summarizes the consequences of SARS-CoV-2 infection on SkM and the potential involvement of SLs in the tissue responses to virus infection. In particular, we highlight the role of sphingosine 1-phosphate signaling in order to aid the prediction of novel targets for preventing and/or treating acute and long-term musculoskeletal manifestations of virus infection in COVID-19.}, }
@article {pmid35625641, year = {2022}, author = {Dusek, P and Hofer, T and Alexander, J and Roos, PM and Aaseth, JO}, title = {Cerebral Iron Deposition in Neurodegeneration.}, journal = {Biomolecules}, volume = {12}, number = {5}, pages = {}, pmid = {35625641}, issn = {2218-273X}, mesh = {Brain/pathology ; Humans ; Iron/pharmacology ; *Iron Metabolism Disorders/pathology ; *Neuroaxonal Dystrophies/pathology ; *Neurodegenerative Diseases/pathology ; }, abstract = {Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.}, }
@article {pmid35625595, year = {2022}, author = {Landolfo, E and Cutuli, D and Petrosini, L and Caltagirone, C}, title = {Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans.}, journal = {Biomolecules}, volume = {12}, number = {5}, pages = {}, pmid = {35625595}, issn = {2218-273X}, mesh = {Amides ; Animals ; Ethanolamines/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; Palmitic Acids/pharmacology/therapeutic use ; *Rodentia ; }, abstract = {Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. The properties of PEA, especially of its micronized or ultra-micronized forms maximizing bioavailability and efficacy, have sparked a series of innovative research to evaluate its possible application as therapeutic agent for neurodegenerative diseases. Neurodegenerative diseases are widespread throughout the world, and although they are numerous and different, they share common patterns of conditions that result from progressive damage to the brain areas involved in mobility, muscle coordination and strength, mood, and cognition. The present review is aimed at illustrating in vitro and in vivo research, as well as human studies, using PEA treatment, alone or in combination with other compounds, in the presence of neurodegeneration. Namely, attention has been paid to the effects of PEA in counteracting neuroinflammatory conditions and in slowing down the progression of diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Literature research demonstrated the efficacy of PEA in addressing the damage typical of major neurodegenerative diseases.}, }
@article {pmid35624964, year = {2022}, author = {Al-Nasser, MN and Mellor, IR and Carter, WG}, title = {Is L-Glutamate Toxic to Neurons and Thereby Contributes to Neuronal Loss and Neurodegeneration? A Systematic Review.}, journal = {Brain sciences}, volume = {12}, number = {5}, pages = {}, pmid = {35624964}, issn = {2076-3425}, support = {xx//Cultural Bureau and King Faisal University PhD Scholarship, Kingdom of Saudi Arabia./ ; }, abstract = {L-glutamate (L-Glu) is a nonessential amino acid, but an extensively utilised excitatory neurotransmitter with critical roles in normal brain function. Aberrant accumulation of L-Glu has been linked to neurotoxicity and neurodegeneration. To investigate this further, we systematically reviewed the literature to evaluate the effects of L-Glu on neuronal viability linked to the pathogenesis and/or progression of neurodegenerative diseases (NDDs). A search in PubMed, Medline, Embase, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between L-Glu and pathology for five NDDs: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Together, 4060 studies were identified, of which 71 met eligibility criteria. Despite several inadequacies, including small sample size, employment of supraphysiological concentrations, and a range of administration routes, it was concluded that exposure to L-Glu in vitro or in vivo has multiple pathogenic mechanisms that influence neuronal viability. These mechanisms include oxidative stress, reduced antioxidant defence, neuroinflammation, altered neurotransmitter levels, protein accumulations, excitotoxicity, mitochondrial dysfunction, intracellular calcium level changes, and effects on neuronal histology, cognitive function, and animal behaviour. This implies that clinical and epidemiological studies are required to assess the potential neuronal harm arising from excessive intake of exogenous L-Glu.}, }
@article {pmid35624667, year = {2022}, author = {Matuz-Mares, D and González-Andrade, M and Araiza-Villanueva, MG and Vilchis-Landeros, MM and Vázquez-Meza, H}, title = {Mitochondrial Calcium: Effects of Its Imbalance in Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {5}, pages = {}, pmid = {35624667}, issn = {2076-3921}, support = {IN218821//UNAM-PAPIIT/ ; IN203222//UNAM-PAPIIT/ ; }, abstract = {Calcium is used in many cellular processes and is maintained within the cell as free calcium at low concentrations (approximately 100 nM), compared with extracellular (millimolar) concentrations, to avoid adverse effects such as phosphate precipitation. For this reason, cells have adapted buffering strategies by compartmentalizing calcium into mitochondria and the endoplasmic reticulum (ER). In mitochondria, the calcium concentration is in the millimolar range, as it is in the ER. Mitochondria actively contribute to buffering cellular calcium, but if matrix calcium increases beyond physiological demands, it can promote the opening of the mitochondrial permeability transition pore (mPTP) and, consequently, trigger apoptotic or necrotic cell death. The pathophysiological implications of mPTP opening in ischemia-reperfusion, liver, muscle, and lysosomal storage diseases, as well as those affecting the central nervous system, for example, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) have been reported. In this review, we present an updated overview of the main cellular mechanisms of mitochondrial calcium regulation. We specially focus on neurodegenerative diseases related to imbalances in calcium homeostasis and summarize some proposed therapies studied to attenuate these diseases.}, }
@article {pmid35623834, year = {2022}, author = {Essat, M and Coates, E and Clowes, M and Beever, D and Hackney, G and White, S and Stavroulakis, T and Halliday, V and McDermott, C and , }, title = {Understanding the current nutritional management for people with amyotrophic lateral sclerosis - A mapping review.}, journal = {Clinical nutrition ESPEN}, volume = {49}, number = {}, pages = {328-340}, doi = {10.1016/j.clnesp.2022.03.026}, pmid = {35623834}, issn = {2405-4577}, support = {RP-PG-1016-20006/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Gastrostomy ; Humans ; Nutrition Assessment ; *Nutrition Therapy ; Nutritional Support ; }, abstract = {BACKGROUND &amp; AIMS: Poor nutritional outcomes are observed in people with Amyotrophic Lateral Sclerosis (pwALS) including weight loss and poor dietary intake. Surveys of healthcare professionals have highlighted the lack of evidence and knowledge regarding nutritional management of ALS throughout the disease course. Furthermore, national evidence-based guidance is lacking. This mapping review aims to understand the structure and input of nutritional management services for pwALS.<br><br>METHODS: Systematic searches were conducted across eight electronic databases to identify qualitative and quantitative research on structure and input of nutritional care in ALS. Supplementary searches included grey literature, citation and reference list searching of included studies and key reviews, web searching and contacting experts and organisations that provide ALS services to identify guidelines. Study selection and data extraction were undertaken independently by at least two reviewers. Data was synthesised using a narrative approach.<br><br>RESULTS: One hundred and nine documents were identified. These consisted of journal articles, guidelines and related documents that contributed evidence towards mapping of nutritional management of pwALS. No evidence on commissioning of nutritional care was identified. Guidelines provided high-level overviews and gave general guidance or recommendations for care; however, these typically focused on gastrostomy with limited guidance on broader aspects, including oral nutrition support. Evidence from primary studies found nutritional care delivery in ALS consisted of multiple types of nutritional management, at different time points during the disease course and involving a range of professionals. There was little evidence relating to proactive nutritional care. Details of healthcare setting, number of professionals involved in care, team composition and how services were delivered in community settings were sparse. Although the role of the speech and language therapist in swallowing assessment and provision of advice on the management of swallowing difficulties was consistent; there was limited evidence on care provided by dietitians. In addition, a small number of studies reported on the use of screening tools. Overall, evidence was consistent that weight management, including monitoring of weight change by professionals and patients, was central and recommended that this should be part of nutritional assessment and follow-up.<br><br>CONCLUSIONS: The evidence identified in this mapping review has highlighted the requirement for further primary research providing specific details on how nutritional management of pwALS is structured and delivered.}, }
@article {pmid35623389, year = {2022}, author = {Calabrese, G and Molzahn, C and Mayor, T}, title = {Protein interaction networks in neurodegenerative diseases: From physiological function to aggregation.}, journal = {The Journal of biological chemistry}, volume = {298}, number = {7}, pages = {102062}, pmid = {35623389}, issn = {1083-351X}, support = {PJT-148489//CIHR/Canada ; }, mesh = {Aged ; Humans ; Molecular Chaperones/metabolism ; *Neurodegenerative Diseases/genetics/metabolism ; Protein Folding ; Protein Interaction Maps ; Proteomics ; }, abstract = {The accumulation of protein inclusions is linked to many neurodegenerative diseases that typically develop in older individuals, due to a combination of genetic and environmental factors. In rare familial neurodegenerative disorders, genes encoding for aggregation-prone proteins are often mutated. While the underlying mechanism leading to these diseases still remains to be fully elucidated, efforts in the past 20 years revealed a vast network of protein-protein interactions that play a major role in regulating the aggregation of key proteins associated with neurodegeneration. Misfolded proteins that can oligomerize and form insoluble aggregates associate with molecular chaperones and other elements of the proteolytic machineries that are the frontline workers attempting to protect the cells by promoting clearance and preventing aggregation. Proteins that are normally bound to aggregation-prone proteins can become sequestered and mislocalized in protein inclusions, leading to their loss of function. In contrast, mutations, posttranslational modifications, or misfolding of aggregation-prone proteins can lead to gain of function by inducing novel or altered protein interactions, which in turn can impact numerous essential cellular processes and organelles, such as vesicle trafficking and the mitochondria. This review examines our current knowledge of protein-protein interactions involving several key aggregation-prone proteins that are associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis. We aim to provide an overview of the protein interaction networks that play a central role in driving or mitigating inclusion formation, while highlighting some of the key proteomic studies that helped to uncover the extent of these networks.}, }
@article {pmid35622209, year = {2022}, author = {Santos Silva, C and Gromicho, M and Oliveira Santos, M and Pinto, S and Swash, M and de Carvalho, M}, title = {Thyroid dysfunction in Portuguese amyotrophic lateral sclerosis patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {9}, pages = {5625-5627}, pmid = {35622209}, issn = {1590-3478}, support = {GA101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology ; Humans ; *Hyperthyroidism/complications/epidemiology ; *Hypothyroidism/complications/drug therapy/epidemiology ; Portugal/epidemiology ; *Thyroid Diseases/complications/epidemiology ; }, abstract = {INTRODUCTION: Thyroid hormones influence neuromuscular function, and it has been thought that this might contribute to degeneration of motor neurons.<br><br>METHODS: We used case-control methods to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) in ALS patients followed in our centre, between 2015 and 2020. Data from patients with neuromuscular disorders not derived from thyroid dysfunction, followed within the same time frame, were used as controls. Thyroid dysfunction was defined by previous thyroid replacement medication managed by an endocrinologist. We used odds ratios (OR) with a 95% confidence interval (CI) to compare 579 ALS patients and 415 age-gender-matched disease controls. Additionally, we provide a summarized review of the literature.<br><br>RESULTS: Hypothyroidism (prevalence of 5.0 versus 8.6%; OR = 0.56, 95% CI 0.34-0.92, p = 0.023), hyperthyroidism (prevalence of 0.3 versus 1.2%; OR = 0.28, 95% CI 0.06-1.47, p = 0.134) and overall thyroid dysfunction (prevalence of 5.4 versus 9.9%; OR = 0.52, 95% CI 0.32-0.84, p = 0.015) were less prevalent in ALS patients than in controls, but similar to the national epidemiological data for thyroid disease. Our data are in line with the findings of most previous studies.<br><br>CONCLUSIONS: We conclude that thyroid dysfunction is not associated with ALS.}, }
@article {pmid35620141, year = {2022}, author = {Smukowski, SN and Maioli, H and Latimer, CS and Bird, TD and Jayadev, S and Valdmanis, PN}, title = {Progress in Amyotrophic Lateral Sclerosis Gene Discovery: Reflecting on Classic Approaches and Leveraging Emerging Technologies.}, journal = {Neurology. Genetics}, volume = {8}, number = {3}, pages = {e669}, pmid = {35620141}, issn = {2376-7839}, support = {K08 AG065426/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prominent motor neuron disease in humans. Its etiology consists of progressive motor neuron degeneration resulting in a rapid decline in motor function starting in the limbs or bulbar muscles and eventually fatally impairing central organs most typically resulting in loss of respiration. Pathogenic variants in 4 main genes, SOD1, TARDBP, FUS, and C9orf72, have been well characterized as causative for more than a decade now. However, these only account for a small fraction of all ALS cases. In this review, we highlight many additional variants that appear to be causative or confer increased risk for ALS, and we reflect on the technologies that have led to these discoveries. Next, we call attention to new challenges and opportunities for ALS and suggest next steps to increase our understanding of ALS genetics. Finally, we conclude with a synopsis of gene therapy paradigms and how increased understanding of ALS genetics can lead us to developing effective treatments. Ultimately, a consolidated update of the field can provide a launching point for researchers and clinicians to improve our search for ALS-related genes, defining pathogenic mechanisms, form diagnostics, and develop therapies.}, }
@article {pmid35620137, year = {2022}, author = {Breevoort, S and Gibson, S and Figueroa, K and Bromberg, M and Pulst, S}, title = {Expanding Clinical Spectrum of C9ORF72-Related Disorders and Promising Therapeutic Strategies: A Review.}, journal = {Neurology. Genetics}, volume = {8}, number = {3}, pages = {e670}, pmid = {35620137}, issn = {2376-7839}, support = {R37 NS033123/NS/NINDS NIH HHS/United States ; }, abstract = {In 2011, a pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was discovered to be the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Before this, the C9ORF72 gene and its protein were unknown. The repeat expansion was found to cause both haploinsufficiency and gain of toxicity through aggregating RNA products and dipeptide repeat proteins. A worldwide effort was then initiated to define C9ORF72 ALS/FTD and unravel the pathogenic mechanism for the development of therapeutic options. A decade later, C9ORF72 genetic testing is readily available. There is now an increasing appreciation that C9ORF72 not only is the leading genetic cause of ALS/FTD but may contribute to a spectrum of disorders. This article reviews what is currently known about the C9ORF72 expansion and how C9ORF72 expansion manifests in ALS, FTD, psychiatric disorders, and movement disorders. With therapeutic strategies fast approaching the clinic, earlier recognition of possible C9ORF72 expansion related disorders is even more paramount to improve patient care.}, }
@article {pmid35616813, year = {2022}, author = {Hu, N and Ji, H}, title = {Medications on hypertension, hyperlipidemia, diabetes, and risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {9}, pages = {5189-5199}, pmid = {35616813}, issn = {1590-3478}, mesh = {Adrenergic beta-Antagonists/therapeutic use ; *Amyotrophic Lateral Sclerosis/complications ; Angiotensin-Converting Enzyme Inhibitors/adverse effects ; Antihypertensive Agents/therapeutic use ; Calcium Channel Blockers/therapeutic use ; *Diabetes Mellitus/drug therapy/epidemiology ; Diuretics/therapeutic use ; Humans ; *Hypertension/complications/drug therapy/epidemiology ; *Metformin/therapeutic use ; }, abstract = {OBJECTIVE: To investigate the association between the use of common medications on hypertension, hyperlipidemia, diabetes, and the risk of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: PubMed, EMBASE, OVID, and Web of Science were searched systematically until December 2021 for studies quantitatively investigating the effect of medications on hypertension, hyperlipidemia, and diabetes on the risk of ALS. We conducted a fixed-effects model or random-effects meta-analysis to calculate the summary ORs (odds ratios) and 95%CIs (confidence intervals).<br><br>RESULTS: Regular intake of angiotensin-converting enzyme inhibitors (ACEIs) (OR: 0.81, 95%CI: 0.74, 0.89), beta-blockers (OR: 0.82, 95%CI: 0.76, 0.90), calcium-channel blockers (CCBs) (OR: 0.85, 95%CI: 0.79, 0.93), or diuretics (OR: 0.87, 95%CI: 0.81, 0.93) was inversely associated with the incidence of ALS. There was no significant association between statin use and risk of ALS (OR: 0.92, 95%CI: 0.83, 1.03). Metformin (OR: 0.83, 95%CI: 0.75, 0.93) and sulfonylureas (OR: 0.79, 95%CI:0.71, 0.89) use could significantly reduce the risk of ALS.<br><br>CONCLUSION: Regular use of anti-hypertensive drugs and anti-diabetes including ACEIs, beta-blockers, CCBs, diuretics, metformin, and sulfonylureas could protect against the incidence of ALS. No significant association between anti-hyperlipidemia drug use and risk of ALS was revealed. Regular medications for hypertension, hyperlipidemia, and diabetes should be recommended regardless of the diagnosis of ALS.}, }
@article {pmid35614479, year = {2022}, author = {Cummings, J and Montes, A and Kamboj, S and Cacho, JF}, title = {The role of basket trials in drug development for neurodegenerative disorders.}, journal = {Alzheimer's research &amp; therapy}, volume = {14}, number = {1}, pages = {73}, pmid = {35614479}, issn = {1758-9193}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease ; Biomarkers ; Drug Development ; Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Parkinson Disease ; }, abstract = {BACKGROUND: Drug development for neurodegenerative disorders (NDDs) is a long, complex, and expensive enterprise. Methods to optimize drug development for NDDs are needed. Basket trials have been widely used in oncology and have been promoted by the Food and Drug Administration as a means of enhancing the efficiency of drug development.<br><br>DISCUSSION: We reviewed clinical trials for NDDs registered on clinicaltrials.gov in the past 10 years. We identified 59 basket trials assessing the impact of treatment on more than one NDD in the trial. Forty-one of the trials were for 25 agents addressing symptoms of NDD such as motor impairment, hypotension, or psychosis. Eighteen of the trials assessed 14 disease-modifying therapies; the principal targets were mitochondrial function, tau biology, or alpha-synuclein aggregation. Basket trials are most common in phase 2 but have been conducted in phase 1, phase 3, and phase 4. The duration and size of the basket trials are highly variable depending on their developmental phase and the intent of the trial. Parkinson's disease was the most common disorder included in basket trials of symptomatic agents, and Alzheimer's disease was the most common disorder included in basket trials of disease-modifying therapies. Most of the basket trials of symptomatic agents were sponsored by pharmaceutical companies (29 of 41 trials); similarly, most of the basket trials investigating DMTs in basket trials were sponsored by the biopharmaceutical industry (11/17 trials).<br><br>CONCLUSIONS: Basket trials may increase drug development efficiency by reducing redundancy in trial implementation, enhancing recruitment, sharing placebo groups, and using biomarkers relevant to the mechanism of action of the treatment across NDDs. There have been relatively few basket trials including multiple NDDs in the same trial conducted over the past 10 years. The use of the basket trial strategy may represent an opportunity to increase the efficiency of development programs for agents to treat NDDs.}, }
@article {pmid35612658, year = {2022}, author = {Hayden, CD and Murphy, BP and Hardiman, O and Murray, D}, title = {Measurement of upper limb function in ALS: a structured review of current methods and future directions.}, journal = {Journal of neurology}, volume = {269}, number = {8}, pages = {4089-4101}, pmid = {35612658}, issn = {1432-1459}, support = {MRCG-2018-03//Health Research Board Ireland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Upper Extremity ; }, abstract = {Measurement of upper limb function is critical for tracking clinical severity in amyotrophic lateral sclerosis (ALS). The Amyotrophic Lateral Sclerosis Rating Scale-revised (ALSFRS-r) is the primary outcome measure utilised in clinical trials and research in ALS. This scale is limited by floor and ceiling effects within subscales, such that clinically meaningful changes for subjects are often missed, impacting upon the evaluation of new drugs and treatments. Technology has the potential to provide sensitive, objective outcome measurement. This paper is a structured review of current methods and future trends in the measurement of upper limb function with a particular focus on ALS. Technologies that have the potential to radically change the upper limb measurement field and explore the limitations of current technological sensors and solutions in terms of costs and user suitability are discussed. The field is expanding but there remains an unmet need for simple, sensitive and clinically meaningful tests of upper limb function in ALS along with identifying consensus on the direction technology must take to meet this need.}, }
@article {pmid35593746, year = {2022}, author = {James, E and Ellis, C and Brassington, R and Sathasivam, S and Young, CA}, title = {Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.}, journal = {The Cochrane database of systematic reviews}, volume = {5}, number = {5}, pages = {CD006981}, pmid = {35593746}, issn = {1469-493X}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *Botulinum Toxins, Type A/therapeutic use ; Clinical Trials, Phase II as Topic ; *Deglutition Disorders/complications/etiology ; Diarrhea/complications ; Humans ; *Motor Neuron Disease/complications ; Nausea ; Randomized Controlled Trials as Topic ; Saliva ; Scopolamine Derivatives ; *Sialorrhea/drug therapy/etiology ; }, abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011.<br><br>OBJECTIVES: To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery.<br><br>SEARCH METHODS: On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers.<br><br>SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND.<br><br>DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.<br><br>MAIN RESULTS: We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect.&#xa0;Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment.<br><br>AUTHORS' CONCLUSIONS: There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.}, }
@article {pmid35592876, year = {2022}, author = {Elgohary, M and Palazzo, FS and Breckwoldt, J and Cheng, A and Pellegrino, J and Schnaubelt, S and Greif, R and Lockey, A}, title = {Blended learning for accredited life support courses - A systematic review.}, journal = {Resuscitation plus}, volume = {10}, number = {}, pages = {100240}, pmid = {35592876}, issn = {2666-5204}, abstract = {AIM: To evaluate the effectiveness on educational and resource outcomes of blended compared to non-blended learning approaches for participants undertaking accredited life support courses.<br><br>METHODS: This review was conducted in adherence with PRISMA standards. We searched EMBASE.com (including all journals listed in Medline), CINAHL and Cochrane from 1 January 2000 to 6 August 2021. Randomised and non-randomised studies were eligible for inclusion. Study screening, data extraction, risk of bias assessment (using RoB2 and ROBINS-I tools), and certainty of evidence evaluation (using GRADE) were all independently performed in duplicate. The systematic review was registered with PROSPERO (CRD42022274392).<br><br>RESULTS: From 2,420 studies, we included data from 23 studies covering fourteen basic life support (BLS) with 2,745 participants, eight advanced cardiac life support (ALS) with 33,579 participants, and one Advanced Trauma Life Support (ATLS) with 92 participants. Blended learning is at least as effective as non-blended learning for participant satisfaction, knowledge, skills, and attitudes. There is potential for cost reduction and eventual net profit in using blended learning despite high set up costs. The certainty of evidence was very low due to a high risk of bias and inconsistency. Heterogeneity across studies precluded any meta-analysis.<br><br>CONCLUSION: Blended learning is at least as effective as non-blended learning for accredited BLS, ALS, and ATLS courses. Blended learning is associated with significant long term cost savings and thus provides a more efficient method of teaching. Further research is needed to investigate specific delivery methods and the effect of blended learning on other accredited life support courses.}, }
@article {pmid35592702, year = {2022}, author = {Barbé, L and Finkbeiner, S}, title = {Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {750629}, pmid = {35592702}, issn = {1663-4365}, abstract = {Repeat diseases, such as fragile X syndrome, myotonic dystrophy, Friedreich ataxia, Huntington disease, spinocerebellar ataxias, and some forms of amyotrophic lateral sclerosis, are caused by repetitive DNA sequences that are expanded in affected individuals. The age at which an individual begins to experience symptoms, and the severity of disease, are partially determined by the size of the repeat. However, the epigenetic state of the area in and around the repeat also plays an important role in determining the age of disease onset and the rate of disease progression. Many repeat diseases share a common epigenetic pattern of increased methylation at CpG islands near the repeat region. CpG islands are CG-rich sequences that are tightly regulated by methylation and are often found at gene enhancer or insulator elements in the genome. Methylation of CpG islands can inhibit binding of the transcriptional regulator CTCF, resulting in a closed chromatin state and gene down regulation. The downregulation of these genes leads to some disease-specific symptoms. Additionally, a genetic and epigenetic interplay is suggested by an effect of methylation on repeat instability, a hallmark of large repeat expansions that leads to increasing disease severity in successive generations. In this review, we will discuss the common epigenetic patterns shared across repeat diseases, how the genetics and epigenetics interact, and how this could be involved in disease manifestation. We also discuss the currently available stem cell and mouse models, which frequently do not recapitulate epigenetic patterns observed in human disease, and propose alternative strategies to study the role of epigenetics in repeat diseases.}, }
@article {pmid35592701, year = {2022}, author = {Yu, W and He, J and Cai, X and Yu, Z and Zou, Z and Fan, D}, title = {Neuroimmune Crosstalk Between the Peripheral and the Central Immune System in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {890958}, pmid = {35592701}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the degeneration and death of motor neurons. Systemic neuroinflammation contributes to the pathogenesis of ALS. The proinflammatory milieu depends on the continuous crosstalk between the peripheral immune system (PIS) and central immune system (CIS). Central nervous system (CNS) resident immune cells interact with the peripheral immune cells via immune substances. Dysfunctional CNS barriers, including the blood-brain barrier, and blood-spinal cord barrier, accelerate the inflammatory process, leading to a systemic self-destructive cycle. This review focuses on the crosstalk between PIS and CIS in ALS. Firstly, we briefly introduce the cellular compartments of CIS and PIS, respectively, and update some new understanding of changes specifically occurring in ALS. Then, we will review previous studies on the alterations of the CNS barriers, and discuss their crucial role in the crosstalk in ALS. Finally, we will review the moveable compartments of the crosstalk, including cytokines, chemokines, and peripheral immune cells which were found to infiltrate the CNS, highlighting the interaction between PIS and CIS. This review aims to provide new insights into pathogenic mechanisms and innovative therapeutic approaches for ALS.}, }
@article {pmid35589220, year = {2022}, author = {Mazivila, SJ and Soares, JX and Santos, JLM}, title = {A tutorial on multi-way data processing of excitation-emission fluorescence matrices acquired from semiconductor quantum dots sensing platforms.}, journal = {Analytica chimica acta}, volume = {1211}, number = {}, pages = {339216}, doi = {10.1016/j.aca.2021.339216}, pmid = {35589220}, issn = {1873-4324}, mesh = {Algorithms ; Calibration ; Least-Squares Analysis ; *Quantum Dots ; Semiconductors ; Spectrometry, Fluorescence/methods ; }, abstract = {This tutorial demonstrates how to exploit the second-order advantage on excitation-emission fluorescence matrices (EEFMs) acquired from sensing platforms based on analyte-triggered semiconductor quantum dots (QDs) fluorescence modulation (quenching/enhancing). The advantage in processing such second-order EEFMs data from complex samples, seeking successful quantification, is comprehensively addressed. It is worth emphasizing that, aiming to exploit the second-order advantage, the selection of the most appropriate advanced chemometric model should rely on the matching between the data structure and the physicochemical chemometric model assumption. In this sense, the achievement of second-order advantage after EEFMs' processing is extensively addressed throughout this tutorial taking into consideration three different analytical situations, each involving a specific data structure: i) parallel factor analysis (PARAFAC), which is applied in a real dataset stacked in a three-way data array containing a trilinear data structure acquired from QDs-based detection with non-selective species; ii) multivariate curve resolution - alternating least-squares (MCR-ALS), which is also employed in a real dataset arranged in an augmented data matrix containing non-trilinear data structure acquired from QDs-based detection with a single breaking mode caused by background signals; iii) unfolded partial least-squares with residual bilinearization (U-PLS/RBL), which is applied in a dataset containing non-trilinear data acquired from a classical fluorescence system with two breaking modes caused by inner filter effect (IFE) in both instrumental modes (excitation and emission). The latter challenging data structure can be acquired via fluorescence quenching from IFE-based sensing platforms and chemometrically handled in two main steps. First, a set of calibration EEFMs data is converted into an unfolded data matrix during the unfolding process, followed by applying U-PLS model. Second, a post-calibration procedure using RBL analysis is applied to a test sample of EEFM maintained in its matrix form, in order to handle potential interferents. In the last section, the state-of-the-art of second-order EEFMs data acquired from semiconductor QDs-based sensing platforms and coupled to multi-way fluorescence data processing to accomplish a successful quantification, even with substantial interfering species, is critically reviewed.}, }
@article {pmid35588987, year = {2022}, author = {Williams, ET and Chen, X and Otero, PA and Moore, DJ}, title = {Understanding the contributions of VPS35 and the retromer in neurodegenerative disease.}, journal = {Neurobiology of disease}, volume = {170}, number = {}, pages = {105768}, pmid = {35588987}, issn = {1095-953X}, support = {R01 NS105432/NS/NINDS NIH HHS/United States ; R01 NS117137/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease/genetics/metabolism ; Endosomes/metabolism ; Humans ; Mutation ; *Neurodegenerative Diseases/genetics/metabolism ; *Parkinson Disease/metabolism ; Vesicular Transport Proteins/genetics/metabolism ; }, abstract = {Perturbations of the endolysosomal pathway have been suggested to play an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Specifically, VPS35 and the retromer complex play an important role in the endolysosomal system and are implicated in the pathophysiology of these diseases. A single missense mutation in VPS35, Asp620Asn (D620N), is known to cause late-onset, autosomal dominant familial PD. In this review, we focus on the emerging role of the PD-linked D620N mutation in causing retromer dysfunction and dissect its implications in neurodegeneration. Additionally, we will discuss how VPS35 and the retromer are linked to AD, amyotrophic lateral sclerosis, and primary tauopathies. Interestingly, reduced levels of VPS35 and other retromer components have been observed in post-mortem brain tissue, suggesting a role for the retromer in the pathophysiology of these diseases. This review will provide a comprehensive dive into the mechanisms of VPS35 dysfunction in neurodegenerative diseases. Furthermore, we will highlight outstanding questions in the field and the retromer as a therapeutic target for neurodegenerative disease at large.}, }
@article {pmid35586308, year = {2022}, author = {West, RL and Otto, Q and Drennan, IR and Rudd, S and Böttiger, BW and Parnia, S and Soar, J}, title = {CPR-related cognitive activity, consciousness, awareness and recall, and its management: A scoping review.}, journal = {Resuscitation plus}, volume = {10}, number = {}, pages = {100241}, pmid = {35586308}, issn = {2666-5204}, abstract = {BACKGROUND: There are increasing numbers of reports of cognitive activity, consciousness, awareness and recall related to cardiopulmonary resuscitation (CPR) and interventions such as the use of sedative and analgesic drugs during CPR.<br><br>OBJECTIVES: This scoping review aims to describe the available evidence concerning CPR-related cognitive activity, consciousness, awareness and recall and interventions such as the use of sedative and analgesic drugs during CPR.<br><br>METHODS: A literature search was conducted of Medline, Embase and CINAHL from inception to 21 October 2021. We included case studies, observational studies, review studies and grey literature.<br><br>RESULTS: We identified 8 observational studies including 40,317 patients and 464 rescuers, and 26 case reports including 33 patients. The reported prevalence of CPR-induced consciousness was between 0.23% to 0.9% of resuscitation attempts, with 48-59% of experienced professional rescuers surveyed estimated to have observed CPR-induced consciousness. CPR-induced consciousness is associated with professional rescuer CPR, witnessed arrest, a shockable rhythm, increased return of spontaneous circulation (ROSC), and survival to hospital discharge when compared to patients without CPR-induced consciousness. Few studies of sedation for CPR-induced consciousness were identified. Although local protocols for treating CPR-induced consciousness exist, there is no widely accepted guidance.<br><br>CONCLUSIONS: CPR-related cognitive activity, consciousness, awareness and recall is uncommon but increasingly reported by professional rescuers. The data available was heterogeneous in nature and not suitable for progression to a systematic review process. Although local treatment protocols exist for management of CPR-induced consciousness, there are no widely accepted treatment guidelines. More studies are required to investigate the management of CPR-induced consciousness.}, }
@article {pmid35584781, year = {2022}, author = {Weng, S and Zhang, D and Yang, M and Wang, L and Yuan, Y}, title = {Vemurafenib effectively controlled Chemotherapy-refractory Intrahepatic Cholangiocarcinoma with BRAF V600E Mutation: a case report and literature review.}, journal = {Zeitschrift fur Gastroenterologie}, volume = {60}, number = {12}, pages = {1787-1791}, doi = {10.1055/a-1826-2814}, pmid = {35584781}, issn = {1439-7803}, support = {the Provincial Key R&amp;D Program of Zhejiang Province//2021C03125/ ; National Natural Science Foundation of China//81872481/ ; }, mesh = {Humans ; Vemurafenib/therapeutic use ; Mutation/genetics ; *Proto-Oncogene Proteins B-raf ; }, abstract = {Die Chemotherapie ist die erste Behandlungsoption für das lokal fortgeschrittene oder metastasierte intrahepatische Cholangiokarzinom (ICC). Nach einer Erstlinien-Chemotherapie gibt es jedoch keine Standardzweitlinienbehandlung oder zielgerichtete Wirkstoffe für diese Patienten. FALLPRäSENTATION: Hier stellen wir einen fortgeschrittenen ICC-Patienten vor, der eine radikale Entfernung und eine adjuvante Chemotherapie (Gemcitabin + Cisplatin) erhalten hat. Aber der Patient bleibt nur 6 Monate frei von Krankheitsanzeichen (No Evidence of Disease) nach dem Ende der Chemotherapie. Dann erhielt er eine palliative Operation, Strahlentherapie und systemische Chemotherapie (Tegafur+Oxaliplatin (SOX) und Nab-Paclitaxel+Gemcitabin (AG)). Leider war die Krankheit immer noch nicht unter Kontrolle. Als eine BRAF-V600E-Mutation im Tumorgewebe durch eine Next Generation Sequencing Analyse (NGS) gezeigt wurde, begann dieser Patient mit der Einnahme von Vemurafenib in einer Dosierung von 720-960 mg zweimal täglich und erreichte ein progressionsfreies Überleben von 7 Monaten mit signifikanter Remission der klinischen Symptome. SCHLüSSELWöRTER: Die BRAF V600E Mutation ist bei ICC ziemlich selten, daher wird sie in der Klinik nicht routinemäßig untersucht. Allerdings kann Präzisionsmedizin durch die NGS-Technologie verwirklicht werden, sodass die Ärzte bei der Behandlung der auf Chemotherapie-refraktären ICC die personalisierten genomischen Informationen nutzen können.}, }
@article {pmid35573690, year = {2022}, author = {Houghton, OH and Mizielinska, S and Gomez-Suaga, P}, title = {The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {838402}, pmid = {35573690}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia are neurodegenerative disorders that lie on a disease spectrum, sharing genetic causes and pathology, and both without effective therapeutics. Two pathways that have been shown to play major roles in disease pathogenesis are autophagy and RNA homeostasis. Intriguingly, there is an increasing body of evidence suggesting a critical interplay between these pathways. Autophagy is a multi-stage process for bulk and selective clearance of malfunctional cellular components, with many layers of regulation. Although the majority of autophagy research focuses on protein degradation, it can also mediate RNA catabolism. ALS/FTD-associated proteins are involved in many stages of autophagy and autophagy-mediated RNA degradation, particularly converging on the clearance of persistent pathological stress granules. In this review, we will summarise the progress in understanding the autophagy-RNA homeostasis interplay and how that knowledge contributes to our understanding of the pathobiology of ALS/FTD.}, }
@article {pmid35572138, year = {2022}, author = {Konopka, A and Atkin, JD}, title = {DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {786420}, pmid = {35572138}, issn = {1663-4365}, abstract = {DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the "DNA damage response." Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects both upper and lower motor neurons in the brain, brainstem and spinal cord, leading to muscle wasting due to denervation. DNA damage is increasingly implicated in the pathophysiology of ALS, and interestingly, the number of DNA damage or repair proteins linked to ALS is steadily growing. This includes TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein that is present in a pathological form in almost all (97%) cases of ALS. Hence TDP-43 pathology is central to neurodegeneration in this condition. Fused in Sarcoma (FUS) bears structural and functional similarities to TDP-43 and it also functions in DNA repair. Chromosome 9 open reading frame 72 (C9orf72) is also fundamental to ALS because mutations in C9orf72 are the most frequent genetic cause of both ALS and related condition frontotemporal dementia, in European and North American populations. Genetic variants encoding other proteins involved in the DNA damage response (DDR) have also been described in ALS, including FUS, SOD1, SETX, VCP, CCNF, and NEK1. Here we review recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS.}, }
@article {pmid35571129, year = {2022}, author = {Lacroix, C and Alleman-Brimault, I and Zalta, A and Rouby, F and Cassé-Perrot, C and Jouve, E and Attolini, L and Guilhaumou, R and Micallef, J and Blin, O}, title = {What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {883987}, pmid = {35571129}, issn = {1663-9812}, abstract = {Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.}, }
@article {pmid35569547, year = {2022}, author = {Majkutewicz, I}, title = {Dimethyl fumarate: A review of preclinical efficacy in models of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {926}, number = {}, pages = {175025}, doi = {10.1016/j.ejphar.2022.175025}, pmid = {35569547}, issn = {1879-0712}, mesh = {Animals ; Dimethyl Fumarate/pharmacology/therapeutic use ; Fumarates/pharmacology ; Humans ; Mice ; *Multiple Sclerosis/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction ; }, abstract = {Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified.}, }
@article {pmid35568100, year = {2022}, author = {Hu, L and Mao, S and Lin, L and Bai, G and Liu, B and Mao, J}, title = {Stress granules in the spinal muscular atrophy and amyotrophic lateral sclerosis: The correlation and promising therapy.}, journal = {Neurobiology of disease}, volume = {170}, number = {}, pages = {105749}, doi = {10.1016/j.nbd.2022.105749}, pmid = {35568100}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; *Muscular Atrophy, Spinal/genetics/metabolism/therapy ; Mutation ; RNA-Binding Protein FUS/genetics/metabolism ; Stress Granules ; }, abstract = {Increasing genetic and biochemical evidence has broadened our view of the pathomechanisms that lead to Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), two fatal neurodegenerative diseases with similar symptoms and causes. Stress granules are dynamic cytosolic storage hubs for mRNAs in response to stress exposures, that are evolutionarily conserved cytoplasmic RNA granules in somatic cells. A lot of previous studies have shown that the impaired stress granules are crucial events in SMA/ALS pathogenesis. In this review, we described the key stress granules related RNA binding proteins (SMN, TDP-43, and FUS) involved in SMA/ALS, summarized the reported mutations in these RNA binding proteins involved in SMA/ALS pathogenesis, and discussed the mechanisms through which stress granules dynamics participate in the diseases. Meanwhile, we described the applications and limitation of current therapies targeting SMA/ALS. We futher proposed the promising targets on stress granules in the future therapeutic interventions of SMA/ALS.}, }
@article {pmid35565972, year = {2022}, author = {Das, BC and Nandwana, NK and Das, S and Nandwana, V and Shareef, MA and Das, Y and Saito, M and Weiss, LM and Almaguel, F and Hosmane, NS and Evans, T}, title = {Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {9}, pages = {}, pmid = {35565972}, issn = {1420-3049}, support = {R01 AI132614/AI/NIAID NIH HHS/United States ; R01AI132614-01A1, R21 AA027374-01, 1R01NS109423-01A1/NH/NIH HHS/United States ; }, mesh = {*Boranes ; *Boron/chemistry ; Boron Compounds/chemistry ; Bortezomib ; Drug Discovery ; Enzyme Inhibitors/pharmacology ; Humans ; }, abstract = {A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different human diseases.In addition, we also describe the synthesis, key structure-activity relationship, and associated biological activities, such as antimicrobial, antituberculosis, antitumor, antiparasitic, antiprotozoal, anti-inflammatory, antifolate, antidepressant, antiallergic, anesthetic, and anti-Alzheimer's agents, as well as proteasome and lipogenic inhibitors. This compilation could be very useful in the exploration of novel boron-derived compounds against different diseases, with promising efficacy and lesser side effects.}, }
@article {pmid35565953, year = {2022}, author = {Holeček, M}, title = {Serine Metabolism in Health and Disease and as a Conditionally Essential Amino Acid.}, journal = {Nutrients}, volume = {14}, number = {9}, pages = {}, pmid = {35565953}, issn = {2072-6643}, support = {the Cooperatio Program, research area METD//Charles University/ ; }, mesh = {*Amino Acid Metabolism, Inborn Errors ; Amino Acids, Essential ; Humans ; Phospholipids ; *Serine ; Sphingolipids/metabolism ; }, abstract = {L-serine plays an essential role in a broad range of cellular functions including protein synthesis, neurotransmission, and folate and methionine cycles and synthesis of sphingolipids, phospholipids, and sulphur containing amino acids. A hydroxyl side-chain of L-serine contributes to polarity of proteins, and serves as a primary site for binding a phosphate group to regulate protein function. D-serine, its D-isoform, has a unique role. Recent studies indicate increased requirements for L-serine and its potential therapeutic use in some diseases. L-serine deficiency is associated with impaired function of the nervous system, primarily due to abnormal metabolism of phospholipids and sphingolipids, particularly increased synthesis of deoxysphingolipids. Therapeutic benefits of L-serine have been reported in primary disorders of serine metabolism, diabetic neuropathy, hyperhomocysteinemia, and amyotrophic lateral sclerosis. Use of L-serine and its metabolic products, specifically D-serine and phosphatidylserine, has been investigated for the therapy of renal diseases, central nervous system injury, and in a wide range of neurological and psychiatric disorders. It is concluded that there are disorders in which humans cannot synthesize L-serine in sufficient quantities, that L-serine is effective in therapy of disorders associated with its deficiency, and that L-serine should be classified as a "conditionally essential" amino acid.}, }
@article {pmid35563884, year = {2022}, author = {Kasindi, A and Fuchs, DT and Koronyo, Y and Rentsendorj, A and Black, KL and Koronyo-Hamaoui, M}, title = {Glatiramer Acetate Immunomodulation: Evidence of Neuroprotection and Cognitive Preservation.}, journal = {Cells}, volume = {11}, number = {9}, pages = {}, pmid = {35563884}, issn = {2073-4409}, support = {R01 AG056478/AG/NIA NIH HHS/United States ; R01 AG055865/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cognition ; *Encephalomyelitis, Autoimmune, Experimental ; Glatiramer Acetate/pharmacology/therapeutic use ; Humans ; Immunomodulation ; *Neuroprotection ; Randomized Controlled Trials as Topic ; }, abstract = {Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate-GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential mechanism of action (MOA) and outcomes of GA immunization in patients. Furthermore, results from these and animal studies suggest that GA has a direct immunomodulatory effect on adaptive and innate immune cell phenotypes and responses. These MOAs have been postulated to have a common neuroprotective impact in several neuroinflammatory and neurodegenerative diseases. Notably, several clinical studies report that the use of GA mitigated MS-associated cognitive decline. Its propensity to ameliorate neuro-proinflammatory and degenerative processes ignites increased interest in potential alternate uses such as in age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). Preclinical studies are exploring less frequent subcutaneous administration of GA, such as once weekly or monthly or a single dosing regimen. Indeed, cognitive functions were found to be either preserved, reversed, or improved after the less frequent treatment regimens with GA in animal models of AD. In this systematic review, we examine the potential novel uses of GA across clinical and pre-clinical studies, with evidence for its beneficial impact on cognition. Future investigation in large-size, double-blind clinical trials is warranted to establish the impact of GA immunomodulation on neuroprotection and cognitive preservation in various neurological conditions.}, }
@article {pmid35563826, year = {2022}, author = {Schmidt, SI and Blaabjerg, M and Freude, K and Meyer, M}, title = {RhoA Signaling in Neurodegenerative Diseases.}, journal = {Cells}, volume = {11}, number = {9}, pages = {}, pmid = {35563826}, issn = {2073-4409}, mesh = {Humans ; *Huntington Disease/metabolism ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; *Parkinson Disease/metabolism ; Signal Transduction/physiology ; rhoA GTP-Binding Protein/metabolism ; }, abstract = {Ras homolog gene family member A (RhoA) is a small GTPase of the Rho family involved in regulating multiple signal transduction pathways that influence a diverse range of cellular functions. RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells. Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we summarize the current knowledge of RhoA regulation and downstream cellular functions with an emphasis on the role of RhoA signaling in neurodegenerative diseases and the therapeutic potential of RhoA inhibition in neurodegeneration.}, }
@article {pmid35563476, year = {2022}, author = {Ito, A and Fukaya, M and Okamoto, H and Sakagami, H}, title = {Physiological and Pathological Roles of the Cytohesin Family in Neurons.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563476}, issn = {1422-0067}, support = {20K07250//KAKENHI from Japan Society for the Promotion of Science/ ; }, mesh = {*ADP-Ribosylation Factors/metabolism ; *Cell Adhesion Molecules/metabolism ; GTPase-Activating Proteins/metabolism ; Neurons/metabolism ; }, abstract = {The cytohesin proteins, consisting of four closely related members (cytohesins-1, -2, -3, and -4), are a subfamily of the Sec7 domain-containing guanine nucleotide exchange factors for ADP ribosylation factors (Arfs), which are critical regulators of membrane trafficking and actin cytoskeleton remodeling. Recent advances in molecular biological techniques and the development of a specific pharmacological inhibitor for cytohesins, SecinH3, have revealed the functional involvement of the cytohesin-Arf pathway in diverse neuronal functions from the formation of axons and dendrites, axonal pathfinding, and synaptic vesicle recycling, to pathophysiological processes including chronic pain and neurotoxicity induced by proteins related to neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's disease. Here, we review the physiological and pathological roles of the cytohesin-Arf pathway in neurons and discuss the future directions of this research field.}, }
@article {pmid35563214, year = {2022}, author = {Chamakioti, M and Karantzelis, N and Taraviras, S}, title = {Advanced Gene-Targeting Therapies for Motor Neuron Diseases and Muscular Dystrophies.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563214}, issn = {1422-0067}, mesh = {Genetic Therapy/methods ; Humans ; *Motor Neuron Disease/genetics/therapy ; *Muscular Atrophy, Spinal/drug therapy/therapy ; *Muscular Dystrophy, Duchenne/drug therapy/therapy ; Oligonucleotides, Antisense/genetics/therapeutic use ; }, abstract = {Gene therapy is a revolutionary, cutting-edge approach to permanently ameliorate or amend many neuromuscular diseases by targeting their genetic origins. Motor neuron diseases and muscular dystrophies, whose genetic causes are well known, are the frontiers of this research revolution. Several genetic treatments, with diverse mechanisms of action and delivery methods, have been approved during the past decade and have demonstrated remarkable results. However, despite the high number of genetic treatments studied preclinically, those that have been advanced to clinical trials are significantly fewer. The most clinically advanced treatments include adeno-associated virus gene replacement therapy, antisense oligonucleotides, and RNA interference. This review provides a comprehensive overview of the advanced gene therapies for motor neuron diseases (i.e., amyotrophic lateral sclerosis and spinal muscular atrophy) and muscular dystrophies (i.e., Duchenne muscular dystrophy, limb-girdle muscular dystrophy, and myotonic dystrophy) tested in clinical trials. Emphasis has been placed on those methods that are a few steps away from their authoritative approval.}, }
@article {pmid35563107, year = {2022}, author = {Nguyen, TPN and Kumar, M and Fedele, E and Bonanno, G and Bonifacino, T}, title = {MicroRNA Alteration, Application as Biomarkers, and Therapeutic Approaches in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563107}, issn = {1422-0067}, support = {2018.AAI629.U730/SD/pv//Compagnia di San Paolo/ ; 2017F2A2C5-002//Ministry of Education, Universities and Research/ ; April16/848-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers ; Humans ; *Huntington Disease/diagnosis/genetics/therapy ; *MicroRNAs/metabolism ; *Neurodegenerative Diseases/diagnosis/genetics/therapy ; }, abstract = {MicroRNAs (miRNAs) are essential post-transcriptional gene regulators involved in various neuronal and non-neuronal cell functions and play a key role in pathological conditions. Numerous studies have demonstrated that miRNAs are dysregulated in major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease. Hence, in the present work, we constructed a comprehensive overview of individual microRNA alterations in various models of the above neurodegenerative diseases. We also provided evidence of miRNAs as promising biomarkers for prognostic and diagnostic approaches. In addition, we summarized data from the literature about miRNA-based therapeutic applications via inhibiting or promoting miRNA expression. We finally identified the overlapping miRNA signature across the diseases, including miR-128, miR-140-5p, miR-206, miR-326, and miR-155, associated with multiple etiological cellular mechanisms. However, it remains to be established whether and to what extent miRNA-based therapies could be safely exploited in the future as effective symptomatic or disease-modifying approaches in the different human neurodegenerative disorders.}, }
@article {pmid35563001, year = {2022}, author = {Doroszkiewicz, J and Groblewska, M and Mroczko, B}, title = {Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563001}, issn = {1422-0067}, support = {SUB/1/DN/22/005/1198, SUB/1/DN/22/003/1198//Medical University of Bia&#x142;ystok/ ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Disease Progression ; Early Diagnosis ; *Exosomes/genetics ; Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/diagnosis/genetics ; }, abstract = {The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs-i.e., Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)-as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.}, }
@article {pmid35562894, year = {2022}, author = {Bassani, D and Pavan, M and Federico, S and Spalluto, G and Sturlese, M and Moro, S}, title = {The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35562894}, issn = {1422-0067}, support = {2017MT3993//Ministry of Education, Universities and Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Humans ; Motor Neurons ; Receptors, G-Protein-Coupled ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease.}, }
@article {pmid35556172, year = {2023}, author = {Potente, P and Buoite Stella, A and Vidotto, M and Passerini, M and Furlanis, G and Naccarato, M and Manganotti, P}, title = {Application of Ultrasonography in Neurogenic Dysphagia: A Systematic Review.}, journal = {Dysphagia}, volume = {38}, number = {1}, pages = {65-75}, pmid = {35556172}, issn = {1432-0460}, mesh = {Humans ; *Deglutition Disorders/diagnostic imaging/etiology ; Quality of Life ; Deglutition/physiology ; *Nervous System Diseases/complications ; Ultrasonography ; }, abstract = {Swallowing disorders are common in neurological diseases, with dysphagia representing one of the most prevalent complications that may cause poor quality of life, reduce independence, and increase mortality. Rapid identification of dysphagia is necessary to reduce the risk of penetration and aspiration, and to early start rehabilitation protocols. Among the methods that can be used to evaluate dysphagia and its components, ultrasound imaging has been suggested to support the evaluation of dysphagia by providing measures of both static and dynamic anatomical components. The aim of this systematic review is to evaluate the usefulness of ultrasonography in neurogenic dysphagia according to current literature. From 2000 to 2020, 633 studies with the appropriate search terms for ultrasound and dysphagia were identified. After screening them, 10 studies were included in the qualitative analysis. Patients with the following neurologic conditions were studied with ultrasonography for dysphagia: Parkinson's disease, muscle dystrophy, amyotrophic lateral sclerosis, and stroke. The main outcomes of ultrasonography were swallowing muscles thickness (e.g., tongue), and dynamic measures such as hyoid displacement. The different protocols used in the studies, as well as their outcomes, did not allow to provide standard procedures and normative or cut-off values in the presented diseases. Because there are a variety of tools, methods, and techniques that have been used in the studies that were reviewed, it is difficult to evaluate them using established standards. However, ultrasonography correlates well with clinical evaluation of dysphagia and therefore has prognostic and rehabilitation potential. Future studies should aim to develop and utilize a common interdisciplinary protocol that includes standard procedures and outcomes to define normative values applicable in the different conditions.}, }
@article {pmid35547626, year = {2022}, author = {Zang, X and Chen, S and Zhu, J and Ma, J and Zhai, Y}, title = {The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {872134}, pmid = {35547626}, issn = {1663-4365}, abstract = {For decades, it has been widely believed that the blood-brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.}, }
@article {pmid35545058, year = {2022}, author = {Tuerxun, K and He, J and Ibrahim, I and Yusupu, Z and Yasheng, A and Xu, Q and Tang, R and Aikebaier, A and Wu, Y and Tuerdi, M and Nijiati, M and Zou, X and Xu, T}, title = {Bioartificial livers: a review of their design and manufacture.}, journal = {Biofabrication}, volume = {14}, number = {3}, pages = {}, doi = {10.1088/1758-5090/ac6e86}, pmid = {35545058}, issn = {1758-5090}, mesh = {Bioreactors ; Hepatocytes/metabolism ; Humans ; *Liver Failure, Acute/metabolism/therapy ; *Liver, Artificial ; }, abstract = {Acute liver failure (ALF) is a rapidly progressive disease with high morbidity and mortality rates. Liver transplantation and artificial liver (AL) support systems, such as ALs and bioartificial livers (BALs), are the two major therapies for ALF. Compared to ALs, BALs are composed of functional hepatocytes that provide essential liver functions, including detoxification, metabolite synthesis, and biotransformation. Furthermore, BALs can potentially provide effective support as a form of bridging therapy to liver transplantation or spontaneous recovery for patients with ALF. In this review, we systematically discussed the currently available state-of-the-art designs and manufacturing processes for BAL support systems. Specifically, we classified the cell sources and bioreactors that are applied in BALs, highlighted the advanced technologies of hepatocyte culturing and bioreactor fabrication, and discussed the current challenges and future trends in developing next-generation BALs for large-scale clinical applications.}, }
@article {pmid35538301, year = {2022}, author = {Iida, T and Yanai, K and Yoshikawa, T}, title = {Histamine and Microglia.}, journal = {Current topics in behavioral neurosciences}, volume = {59}, number = {}, pages = {241-259}, pmid = {35538301}, issn = {1866-3370}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Brain/metabolism ; Cytokines/metabolism ; *Histamine/metabolism/pharmacology/therapeutic use ; Humans ; *Microglia ; }, abstract = {Microglia, a category of glial cells in the central nervous system (CNS), have attracted much attention because of their important role in neuroinflammation. Many translational studies are currently ongoing to discover novel drugs targeting microglia for the treatment of various CNS disorders, such as Alzheimer's disease, Parkinson's disease (PD), and depression. Recent studies have shown that brain histamine, a neurotransmitter essential for the regulation of diverse brain functions, controls glial cells and neurons. In vitro studies using primary microglia and microglial cell lines have reported that histamine receptors are expressed in microglia and control microglial functions, including chemotaxis, migration, cytokine secretion, and autophagy. In vivo studies have demonstrated that histamine-related reagents could ameliorate abnormal symptoms in animal models of human diseases, such as amyotrophic lateral sclerosis (ALS), PD, and brain ischemia. Several human studies have revealed alterations in histamine receptor levels in ALS and PD, emphasizing the importance of the CNS histamine system, including histamine-dependent microglial modulation, as a therapeutic target for these disorders. In this review article, we summarize histamine-related research focusing on microglial functions.}, }
@article {pmid35535867, year = {2022}, author = {Chipika, RH and Mulkerrin, G and Pradat, PF and Murad, A and Ango, F and Raoul, C and Bede, P}, title = {Cerebellar pathology in motor neuron disease: neuroplasticity and neurodegeneration.}, journal = {Neural regeneration research}, volume = {17}, number = {11}, pages = {2335-2341}, pmid = {35535867}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition. The clinical picture is dominated by upper and lower motor neuron degeneration, but extra-motor pathology is increasingly recognized, including cerebellar pathology. Post-mortem and neuroimaging studies primarily focus on the characterization of supratentorial disease, despite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis. Cardinal clinical features of amyotrophic lateral sclerosis, such as dysarthria, dysphagia, cognitive and behavioral deficits, saccade abnormalities, gait impairment, respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology. This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral sclerosis. Structural imaging studies consistently capture cerebellar grey matter volume reductions, diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alterations and functional imaging studies commonly report increased functional connectivity with supratentorial regions. Increased functional connectivity is commonly interpreted as evidence of neuroplasticity representing compensatory processes despite the lack of post-mortem validation. There is a scarcity of post-mortem studies focusing on cerebellar alterations, but these detect pTDP-43 in cerebellar nuclei. Cerebellar pathology is an overlooked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms, widespread connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.}, }
@article {pmid35525633, year = {2022}, author = {Saracino, D and Le Ber, I}, title = {How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases.}, journal = {Revue neurologique}, volume = {178}, number = {5}, pages = {426-436}, doi = {10.1016/j.neurol.2022.03.007}, pmid = {35525633}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; Asymptomatic Diseases ; Biomarkers ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/diagnosis/genetics ; Humans ; Prodromal Symptoms ; }, abstract = {Repeat expansions in C9orf72 gene are the main genetic cause of frontotemporal dementia, amyotrophic lateral sclerosis and related phenotypes. With the advent of disease-modifying treatments, the presymptomatic disease phase is getting increasing interest as an ideal time window in which innovant therapeutic approaches could be administered. Recommendations issued from international study groups distinguish between a preclinical disease stage, during which lesions accumulate in absence of any symptoms or signs, and a prodromal stage, marked by the appearance the first subtle cognitive, behavioral, psychiatric and motor signs, before the full-blown disease. This paper summarizes the current definitions and criteria for these stages, in particular focusing on how fluid-based, neuroimaging and cognitive biomarkers can be useful to monitor disease trajectory across the presymptomatic phase, as well as to detect the earliest signs of clinical conversion. Continuous advances in the knowledge of C9orf72 pathophysiology, and the integration of biomarkers in the clinical evaluation of mutation carriers will allow a better diagnostic definition of C9orf72 disease spectrum from the earliest stages, with relevant impact on the possibility of disease prevention.}, }
@article {pmid35525310, year = {2022}, author = {Sen, S and Lagas, S and Roy, A and Kumar, H}, title = {Cytoskeleton saga: Its regulation in normal physiology and modulation in neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {925}, number = {}, pages = {175001}, doi = {10.1016/j.ejphar.2022.175001}, pmid = {35525310}, issn = {1879-0712}, mesh = {*Cytoskeleton/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Huntington Disease/metabolism ; *Microtubules/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Cells are fundamental units of life. To ensure the maintenance of homeostasis, integrity of structural and functional counterparts is needed to be essentially balanced. The cytoskeleton plays a vital role in regulating the cellular morphology, signalling and other factors involved in pathological conditions. Microtubules, actin (microfilaments), intermediate filaments (IF) and their interactions are required for these activities. Various proteins associated with these components are primary requirements for directing their functions. Disruption of this organization due to faulty genetics, oxidative stress or impaired transport mechanisms are the major causes of dysregulated signalling cascades leading to various pathological conditions like Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP) or any traumatic injury like spinal cord injury (SCI). Novel or conventional therapeutic approaches may be specific or non-specific, targeting either three basic components of the cytoskeleton or various cascades that serve as a cue to numerous pathways like ROCK signalling or the GSK-3β pathway. An enormous number of drugs have been redirected for modulating the cytoskeletal dynamics and thereby may pave the way for inhibiting the progression of these diseases and their complications.}, }
@article {pmid35524757, year = {2022}, author = {Neel, DV and Basu, H and Gunner, G and Chiu, IM}, title = {Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis.}, journal = {Immunological reviews}, volume = {311}, number = {1}, pages = {130-150}, pmid = {35524757}, issn = {1600-065X}, support = {R01 AI130019/AI/NIAID NIH HHS/United States ; R01 DK127257/DK/NIDDK NIH HHS/United States ; T32 GM007753/GM/NIGMS NIH HHS/United States ; T32 GM144273/GM/NIGMS NIH HHS/United States ; }, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Apoptosis ; Humans ; Inflammation/metabolism ; Motor Neurons/metabolism ; Necrosis/metabolism ; }, abstract = {In the central nervous system (CNS), execution of programmed cell death (PCD) is crucial for proper neurodevelopment. However, aberrant activation of these pathways in adult CNS leads to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. In ALS, a fatal neuromuscular disorder marked by progressive death of lower and upper motor neurons, several cell types in the CNS express machinery for multiple PCD pathways. The specific cell types engaging PCD, and ultimate mechanisms by which neuronal death occurs in ALS are not well defined. Here, we provide an overview of different PCD pathways implicated in ALS. We also examine immune activation in ALS and differentiate apoptosis from necrotic mechanisms based on downstream immunological consequences. Lastly, we highlight therapeutic strategies that target cell death pathways in the treatment of neurodegeneration and inflammation in ALS.}, }
@article {pmid35512313, year = {2022}, author = {Mckenzie, ADJ and Garrett, TR and Werry, EL and Kassiou, M}, title = {Purinergic P2X7 Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {13}, number = {10}, pages = {1479-1490}, doi = {10.1021/acschemneuro.2c00133}, pmid = {35512313}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by upper and lower motor neuron loss. The pathomechanisms of ALS are still poorly understood with current hypotheses involving genetic mutations, excitotoxicity, and reactive oxygen species formation. In the absence of a disease-altering clinically approved therapeutic, there is an ever-increasing need to identify new targets to develop drugs that delay disease onset and/or progression. The purinergic P2X7 receptor (P2X7R) has been implicated widely across the ALS realm, providing a potential therapeutic strategy. This review summarizes the current understanding of ALS, the P2X7R and its role in ALS, the current landscape of P2X7R antagonists, and the in vivo potential of these antagonists in preclinical ALS models.}, }
@article {pmid35499795, year = {2022}, author = {Liao, YZ and Ma, J and Dou, JZ}, title = {The Role of TDP-43 in Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {59}, number = {7}, pages = {4223-4241}, pmid = {35499795}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; *Neurodegenerative Diseases ; *TDP-43 Proteinopathies/metabolism/pathology ; Ubiquitination ; }, abstract = {In recent years, more and more neurodegenerative diseases, such as ALS, FTLD and AD, have been found to share a common pathological feature, which is the depletion of TDP-43 in the nucleus and the accumulation of TDP-43 in the cytoplasm through hyperphosphorylation, ubiquitination and cleavage. Therefore, this kind of neurodegenerative disease is also called TDP-43 proteinopathy. This suggests that TDP-43 plays a role in the pathogenesis of disease. Current studies show that the pathophysiological mechanism of TDP-43 in neurodegeneration is very complex. In this review, we describe the structure of TDP-43, its main physiological functions, the possible pathogenesis and how TDP-43 provides a new pathway to treat neurodegenerative diseases.}, }
@article {pmid35495059, year = {2022}, author = {Das, R and Paul, S and Mourya, GK and Kumar, N and Hussain, M}, title = {Recent Trends and Practices Toward Assessment and Rehabilitation of Neurodegenerative Disorders: Insights From Human Gait.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {859298}, pmid = {35495059}, issn = {1662-4548}, abstract = {The study of human movement and biomechanics forms an integral part of various clinical assessments and provides valuable information toward diagnosing neurodegenerative disorders where the motor symptoms predominate. Conventional gait and postural balance analysis techniques like force platforms, motion cameras, etc., are complex, expensive equipment requiring specialist operators, thereby posing a significant challenge toward translation to the clinics. The current manuscript presents an overview and relevant literature summarizing the umbrella of factors associated with neurodegenerative disorder management: from the pathogenesis and motor symptoms of commonly occurring disorders to current alternate practices toward its quantification and mitigation. This article reviews recent advances in technologies and methodologies for managing important neurodegenerative gait and balance disorders, emphasizing assessment and rehabilitation/assistance. The review predominantly focuses on the application of inertial sensors toward various facets of gait analysis, including event detection, spatiotemporal gait parameter measurement, estimation of joint kinematics, and postural balance analysis. In addition, the use of other sensing principles such as foot-force interaction measurement, electromyography techniques, electrogoniometers, force-myography, ultrasonic, piezoelectric, and microphone sensors has also been explored. The review also examined the commercially available wearable gait analysis systems. Additionally, a summary of recent progress in therapeutic approaches, viz., wearables, virtual reality (VR), and phytochemical compounds, has also been presented, explicitly targeting the neuro-motor and functional impairments associated with these disorders. Efforts toward therapeutic and functional rehabilitation through VR, wearables, and different phytochemical compounds are presented using recent examples of research across the commonly occurring neurodegenerative conditions [viz., Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)]. Studies exploring the potential role of Phyto compounds in mitigating commonly associated neurodegenerative pathologies such as mitochondrial dysfunction, α-synuclein accumulation, imbalance of free radicals, etc., are also discussed in breadth. Parameters such as joint angles, plantar pressure, and muscle force can be measured using portable and wearable sensors like accelerometers, gyroscopes, footswitches, force sensors, etc. Kinetic foot insoles and inertial measurement tools are widely explored for studying kinematic and kinetic parameters associated with gait. With advanced correlation algorithms and extensive RCTs, such measurement techniques can be an effective clinical and home-based monitoring and rehabilitation tool for neuro-impaired gait. As evident from the present literature, although the vast majority of works reported are not clinically and extensively validated to derive a firm conclusion about the effectiveness of such techniques, wearable sensors present a promising impact toward dealing with neurodegenerative motor disorders.}, }
@article {pmid35490912, year = {2022}, author = {Bashirzade, AA and Zabegalov, KN and Volgin, AD and Belova, AS and Demin, KA and de Abreu, MS and Babchenko, VY and Bashirzade, KA and Yenkoyan, KB and Tikhonova, MA and Amstislavskaya, TG and Kalueff, AV}, title = {Modeling neurodegenerative disorders in zebrafish.}, journal = {Neuroscience and biobehavioral reviews}, volume = {138}, number = {}, pages = {104679}, doi = {10.1016/j.neubiorev.2022.104679}, pmid = {35490912}, issn = {1873-7528}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism ; Zebrafish ; }, abstract = {Neurodegeneration is a major cause of Alzheimer's, Parkinson's, Huntington's, multiple and amyotrophic lateral sclerosis, pontocerebellar hypoplasia, dementia and other related brain disorders. Their complex pathogenesis commonly includes genetic and neurochemical deficits, misfolded protein toxicity, demyelination, apoptosis and mitochondrial dysfunctions. Albeit differing in specific underlying mechanisms, neurodegenerative disorders typically display evolutionarily conserved mechanisms across taxa. Here, we review the role of zebrafish models in recapitulating major human and rodent neurodegenerative conditions, demonstrating this species as a highly relevant experimental model for research on neurodegenerative diseases, and discussing how these fish models can further clarify the underlying genetic, neurochemical, neuroanatomical and behavioral pathogenic mechanisms.}, }
@article {pmid35488039, year = {2022}, author = {Coyne, AN and Rothstein, JD}, title = {Nuclear pore complexes - a doorway to neural injury in neurodegeneration.}, journal = {Nature reviews. Neurology}, volume = {18}, number = {6}, pages = {348-362}, pmid = {35488039}, issn = {1759-4766}, support = {P01 NS099114/NS/NINDS NIH HHS/United States ; K99 NS123242/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; *Frontotemporal Dementia/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Nuclear Pore/metabolism/pathology ; Nuclear Pore Complex Proteins/genetics/metabolism ; }, abstract = {The genetic underpinnings and end-stage pathological hallmarks of neurodegenerative diseases are increasingly well defined, but the cellular pathophysiology of disease initiation and propagation remains poorly understood, especially in sporadic forms of these diseases. Altered nucleocytoplasmic transport is emerging as a prominent pathomechanism of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and Huntington disease. The nuclear pore complex (NPC) and interactions between its individual nucleoporin components and nuclear transport receptors regulate nucleocytoplasmic transport, as well as genome organization and gene expression. Specific nucleoporin abnormalities have been identified in sporadic and familial forms of neurodegenerative disease, and these alterations are thought to contribute to disrupted nucleocytoplasmic transport. The specific nucleoporins and nucleocytoplasmic transport proteins that have been linked to different neurodegenerative diseases are partially distinct, suggesting that NPC injury contributes to the cellular specificity of neurodegenerative disease and could be an early initiator of the pathophysiological cascades that underlie neurodegenerative disease. This concept is consistent with the fact that rare genetic mutations in some nucleoporins cause cell-type-specific neurological disease. In this Review, we discuss nucleoporin and NPC disruptions and consider their impact on cellular function and the pathophysiology of neurodegenerative disease.}, }
@article {pmid35487823, year = {2022}, author = {Blum, JA and Gitler, AD}, title = {Singling out motor neurons in the age of single-cell transcriptomics.}, journal = {Trends in genetics : TIG}, volume = {38}, number = {9}, pages = {904-919}, pmid = {35487823}, issn = {0168-9525}, support = {R35 NS097263/NS/NINDS NIH HHS/United States ; T32 MH020016/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/genetics ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism ; Spinal Cord ; Transcriptome/genetics ; }, abstract = {Motor neurons are a remarkably powerful cell type in the central nervous system. They innervate and control the contraction of virtually every muscle in the body and their dysfunction underlies numerous neuromuscular diseases. Some motor neurons seem resistant to degeneration whereas others are vulnerable. The intrinsic heterogeneity of motor neurons in adult organisms has remained elusive. The development of high-throughput single-cell transcriptomics has changed the paradigm, empowering rapid isolation and profiling of motor neuron nuclei, revealing remarkable transcriptional diversity within the skeletal and autonomic nervous systems. Here, we discuss emerging technologies for defining motor neuron heterogeneity in the adult motor system as well as implications for disease and spinal cord injury. We establish a roadmap for future applications of emerging techniques - such as epigenetic profiling, spatial RNA sequencing, and single-cell somatic mutational profiling to adult motor neurons, which will revolutionize our understanding of the healthy and degenerating adult motor system.}, }
@article {pmid35469721, year = {2022}, author = {Wei, KC and Hsiao, MY and Wang, TG}, title = {The kinematic features of hyoid bone movement during swallowing in different disease populations: A narrative review.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {121}, number = {10}, pages = {1892-1899}, doi = {10.1016/j.jfma.2022.04.007}, pmid = {35469721}, issn = {0929-6646}, mesh = {*Amyotrophic Lateral Sclerosis ; Biomechanical Phenomena ; Deglutition/physiology ; *Deglutition Disorders/diagnostic imaging/etiology ; *Head and Neck Neoplasms ; Humans ; Hyoid Bone/diagnostic imaging/physiology ; *Parkinson Disease ; *Stroke ; }, abstract = {The anterior-superior movement of the hyoid bone plays a significant role in securing the airway and smooth passage of food through the cricopharyngeal muscle. The hyoid bone can be detected easily with instruments such as the videofluoroscopic swallow study (VFSS) and ultrasonography (US), which have made quantitative kinematic analysis possible. Dysphagia is a critical issue in different diseases, including stroke, Parkinson's disease (PD), head and neck cancer, and amyotrophic lateral sclerosis (ALS), and the data obtained on these diseases from swallowing kinematic analysis has been accumulating. In this review article, we aimed to present the distinct features of kinematic analysis of hyoid movement in stroke, PD, head and neck cancer, and ALS. We also present the possible relationship between altered hyoid kinematics and dysphagia.}, }
@article {pmid35469482, year = {2023}, author = {Thomas, PT and Warrier, MG and Arun, S and Bhuvaneshwari, B and Vengalil, S and Nashi, S and Preethish-Kumar, V and Polavarapu, K and Rajaram, P and Nalini, A}, title = {An individualised psychosocial intervention program for persons with MND/ALS and their families in low resource settings.}, journal = {Chronic illness}, volume = {19}, number = {2}, pages = {458-471}, doi = {10.1177/17423953221097076}, pmid = {35469482}, issn = {1745-9206}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Psychosocial Intervention ; Feasibility Studies ; }, abstract = {OBJECTIVE: To develop individualised psychosocial intervention program for people with MND and their families in India.<br><br>METHODS: People with MND and healthcare staff were constructively involved in co-designing the intervention program in four phases adapted from the MRC framework: 1. A detailed need assessment phase where 30 participants shared their perceptions of psychosocial needs 2. Developing the intervention module (synthesis of narrative review, identified needs); 3. Feasibility testing of the intervention program among seven participants; 4. Feedback from participants on the feasibility (acceptance, practicality adaptation). The study adopted an exploratory research design.<br><br>RESULTS: Intervention program of nine sessions, addressing psychosocial challenges through the different stages of progression of the illness and ways to handle the challenges, specific to the low resource settings, was developed and was found to be feasible. People with MND and families who participated in the feasibility study shared the perceived benefit through feedback interviews.<br><br>CONCLUSION: MND has changing needs and challenges. Intervention programme was found to be feasible to be implemented among larger group to establish efficacy.}, }
@article {pmid35465886, year = {2022}, author = {Rothrock, RJ and Elarjani, T and Levi, AD}, title = {Neurosurgical Mimics.}, journal = {Neurologic clinics}, volume = {40}, number = {2}, pages = {455-469}, doi = {10.1016/j.ncl.2021.11.013}, pmid = {35465886}, issn = {1557-9875}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Neurosurgical Procedures ; }, abstract = {The goal of the following article is to help the practicing physician learn to recognize conditions that mimic conditions requiring neurosurgical intervention. Each case vignette is presented with relevant clinical history and examination, imaging studies and findings, as well as other testing results. The management for the corresponding diagnosis is presented. Finally, the relevant mimics and differentiating features are discussed.}, }
@article {pmid35461975, year = {2022}, author = {Yu, QY and Ye, LQ and Li, HL}, title = {Molecular interaction of stress granules with Tau and autophagy in Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {157}, number = {}, pages = {105342}, doi = {10.1016/j.neuint.2022.105342}, pmid = {35461975}, issn = {1872-9754}, mesh = {*Alzheimer Disease/metabolism ; Autophagy/physiology ; Cytoplasmic Granules/genetics/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism ; Phagocytosis ; RNA, Messenger/metabolism ; RNA-Binding Proteins/metabolism ; Stress Granules ; Stress, Physiological ; tau Proteins/metabolism ; }, abstract = {Stress Granules (SGs) are RNA granules composed of untranslated mRNA and associated proteins, which are related to the cytoplasmic metabolism of mRNA in response to cellular stress and certain drug stimuli. Physiological SGs are dynamic structures that protect cells from the effects of stress, and continuous stress ripens the SGs into more stable complexes. Numerous studies have found that dysregulation of RNA metabolism in stress response led to misfolded protein aggregation in the pathophysiology of neurodegenerative diseases. For example, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD), SGs aggregation is mainly due to up-regulation of SGs formation and down-regulation of SGs clearance. Recent studies have revealed the role of SGs in the pathogenesis and pathology of AD, especially the interaction of SGs and RNA-binding proteins with Tau and autophagy. Aggregation of SGs and increased RNA-binding proteins, especially TIA1, can facilitate Tau misfolding and propagation, and vice versa. Autophagy dysfunction disrupts the normal pathway of SGs clearance. In this review, we summarized the regulation of SGs and their relationship with Tau protein and autophagy, as well as the pathological mechanisms of AD such as RNA splicing, microglial cell proliferation and phagocytosis.}, }
@article {pmid35459796, year = {2022}, author = {Kanekura, K and Kuroda, M}, title = {How can we interpret the relationship between liquid-liquid phase separation and amyotrophic lateral sclerosis?.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {102}, number = {9}, pages = {912-918}, doi = {10.1038/s41374-022-00791-x}, pmid = {35459796}, issn = {1530-0307}, mesh = {*Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia ; Humans ; Inclusion Bodies ; Neurons ; Superoxide Dismutase ; }, abstract = {One of the critical definitions of neurodegenerative diseases is the formation of insoluble intracellular inclusion body. These inclusions are found in various neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and frontotemporal dementia (FTD). Each inclusion body contains disease-specific proteins and is also resistant to common detergent treatments. These aggregates are generally ubiquitinated and thus recognized as misfolded by the organism. They are observed in residual neurons at the affected sites in each disease, suggesting a contribution to disease pathogenesis. The molecular mechanisms for the formation of these inclusion bodies remain unclear. Some proteins, such as superoxide dismutase 1 (SOD1) mutant that causes familial ALS, are highly aggregative due to altered folding caused by point mutations. Still, the aggregates observed in neurodegenerative diseases contain wild-type proteins. In recent years, it has been reported that the proteins responsible for neurodegenerative diseases undergo liquid-liquid phase separation (LLPS). In particular, the ALS/FTD causative proteins such as TAR DNA-binding protein 43 kDa (TDP-43) and fused-in-sarcoma (FUS) undergo LLPS. LLPS increases the local concentration of these proteins, and these proteins eventually change their phase from liquid to solid (liquid-solid phase transition) due to abnormal folding during repetitive separation cycles into two phases and recovery to one phase. In addition to the inclusion body formation, sequestration of essential proteins into the LLPS droplets or changes in the LLPS status can directly impair neural functions and cause diseases. In this review, we will discuss the relationship between the LLPS observed in ALS causative proteins and the pathogenesis of the disease and outline potential therapeutic approaches.}, }
@article {pmid35459141, year = {2022}, author = {Fu, J and Huang, Y and Bao, T and Liu, C and Liu, X and Chen, X}, title = {The role of Th17 cells/IL-17A in AD, PD, ALS and the strategic therapy targeting on IL-17A.}, journal = {Journal of neuroinflammation}, volume = {19}, number = {1}, pages = {98}, pmid = {35459141}, issn = {1742-2094}, support = {2017YFC09007703//National key Research and development program of China/ ; 2020YJ0281//science and technology planning project in Sichuan Province/ ; ZYJC18038//1&#xb7;3&#xb7;5 project for disciplines of excellence West China Hospital Sichuan University/ ; 2019-112//cadres health care project in Sichuan Province/ ; }, mesh = {*Alzheimer Disease/immunology/metabolism ; *Amyotrophic Lateral Sclerosis/immunology/pathology ; Humans ; *Interleukin-17/immunology ; Neurodegenerative Diseases/immunology/pathology ; *Parkinson Disease/immunology ; *Th17 Cells/immunology ; }, abstract = {Neurodegenerative diseases are a group of disorders characterized by progressive loss of certain populations of neurons, which eventually lead to dysfunction. These diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Immune pathway dysregulation is one of the common features of neurodegeneration. Recently, there is growing interest in the specific role of T helper Th 17 cells and Interleukin-17A (IL-17A), the most important cytokine of Th 17 cells, in the pathogenesis of the central nervous system (CNS) of neurodegenerative diseases. In the present study, we summarized current knowledge about the function of Th17/IL-17A, the physiology of Th17/IL-17A in diseases, and the contribution of Th17/IL-17A in AD, PD, and ALS. We also update the findings on IL-17A-targeting drugs as potentially immunomodulatory therapeutic agents for neurodegenerative diseases. Although the specific mechanism of Th17/IL-17A in this group of diseases is still controversial, uncovering the molecular pathways of Th17/IL-17A in neurodegeneration allows the identification of suitable targets to modulate these cellular processes. Therapeutics targeting IL-17A might represent potentially novel anti-neurodegeneration drugs.}, }
@article {pmid35458139, year = {2022}, author = {Russell, RD and Black, LJ and Begley, A}, title = {Nutrition Education Programs for Adults with Neurological Diseases Are Lacking: A Scoping Review.}, journal = {Nutrients}, volume = {14}, number = {8}, pages = {}, pmid = {35458139}, issn = {2072-6643}, mesh = {Adult ; Counseling ; Diet ; Health Education ; Humans ; *Nervous System Diseases ; *Nutrition Therapy ; }, abstract = {The nutrition recommendation for most common neurological diseases is to follow national dietary guidelines. This is to mitigate malnutrition, reduce the risk of diet-related diseases, and to help manage some common symptoms, including constipation. Nutrition education programs can support people in adhering to guidelines; hence the aim of this scoping review was to explore what programs have been implemented for adults with neurological diseases. We conducted this review according to a published a priori protocol. From 2555 articles screened, 13 were included (dementia n = 6; multiple sclerosis n = 4; stroke survivors n = 2; Parkinson's n = 1). There were no programs for epilepsy, Huntington's, and motor neurone disease. Program duration and number of sessions varied widely; however, weekly delivery was most common. Just over half were delivered by dietitians. Most did not report using a behavior change theory. Commonly used behavior change techniques were instruction on how to perform a behavior, credible source, and behavioral practice/rehearsal. Evidence of nutrition education programs for adults with neurological diseases is lacking. Of those that are published, many do not meet best practice principles for nutrition education regarding delivery, educator characteristics, and evaluation. More programs aligning with best practice principles are needed to assess characteristics that lead to behavior change.}, }
@article {pmid35456932, year = {2022}, author = {Ots, HD and Tracz, JA and Vinokuroff, KE and Musto, AE}, title = {CD40-CD40L in Neurological Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {8}, pages = {}, pmid = {35456932}, issn = {1422-0067}, mesh = {B-Lymphocytes ; CD40 Antigens ; *CD40 Ligand ; Central Nervous System ; Humans ; *Multiple Sclerosis ; }, abstract = {Immune-inflammatory conditions in the central nervous system (CNS) rely on molecular and cellular interactions which are homeostatically maintained to protect neural tissue from harm. The CD40-CD40L interaction upregulates key proinflammatory molecules, a function best understood in the context of infection, during which B-cells are activated via CD40 signaling to produce antibodies. However, the role of CD40 in neurological disease of non-infectious etiology is unclear. We review the role of CD40-CD40L in traumatic brain injury, Alzheimer's Disease, Parkinson's Disease, stroke, epilepsy, nerve injury, multiple sclerosis, ALS, myasthenia gravis and brain tumors. We also highlight therapeutic advancements targeting the CD40 system to either attenuate the neuroinflammatory response or leverage the downstream effects of CD40 signaling for direct tumor cell lysis.}, }
@article {pmid35456894, year = {2022}, author = {Dilliott, AA and Andary, CM and Stoltz, M and Petropavlovskiy, AA and Farhan, SMK and Duennwald, ML}, title = {DnaJC7 in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {8}, pages = {}, pmid = {35456894}, issn = {1422-0067}, support = {n/a//ALS Society of Canada/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Molecular Chaperones/genetics/metabolism ; Mutation ; Protein Folding ; Superoxide Dismutase-1/genetics ; }, abstract = {Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin-proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones' machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.}, }
@article {pmid35455429, year = {2022}, author = {Shibuya, K and Otani, R and Suzuki, YI and Kuwabara, S and Kiernan, MC}, title = {Neuronal Hyperexcitability and Free Radical Toxicity in Amyotrophic Lateral Sclerosis: Established and Future Targets.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {35455429}, issn = {1424-8247}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses anti-glutamatergic properties, while edaravone eliminates free radicals (FRs). Glutamate is the excitatory neurotransmitter in the brain and spinal cord and binds to several inotropic receptors. Excessive activation of these receptors generates FRs, inducing neurodegeneration via damage to intracellular organelles and upregulation of proinflammatory mediators. FRs bind to intracellular structures, leading to cellular impairment that contributes to neurodegeneration. As such, excitotoxicity and FR toxicities have been considered as key pathophysiological mechanisms that contribute to the cascade of degeneration that envelopes neurons in ALS. Recent advanced technologies, including neurophysiological, imaging, pathological and biochemical techniques, have concurrently identified evidence of increased excitability in ALS. This review focuses on the relationship between FRs and excitotoxicity in motor neuronal degeneration in ALS and introduces concepts linked to increased excitability across both compartments of the human nervous system. Within this cellular framework, future strategies to promote therapeutic development in ALS, from the perspective of neuronal excitability and function, will be critically appraised.}, }
@article {pmid35453590, year = {2022}, author = {Rosmus, DD and Lange, C and Ludwig, F and Ajami, B and Wieghofer, P}, title = {The Role of Osteopontin in Microglia Biology: Current Concepts and Future Perspectives.}, journal = {Biomedicines}, volume = {10}, number = {4}, pages = {}, pmid = {35453590}, issn = {2227-9059}, abstract = {The innate immune landscape of the central nervous system (CNS), including the brain and the retina, consists of different myeloid cell populations with distinct tasks to fulfill. Whereas the CNS borders harbor extraparenchymal CNS-associated macrophages whose main duty is to build up a defense against invading pathogens and other damaging factors from the periphery, the resident immune cells of the CNS parenchyma and the retina, microglia, are highly dynamic cells with a plethora of functions during homeostasis and disease. Therefore, microglia are constantly sensing their environment and closely interacting with surrounding cells, which is in part mediated by soluble factors. One of these factors is Osteopontin (OPN), a multifunctional protein that is produced by different cell types in the CNS, including microglia, and is upregulated in neurodegenerative and neuroinflammatory conditions. In this review, we discuss the current literature about the interaction between microglia and OPN in homeostasis and several disease entities, including multiple sclerosis (MS), Alzheimer's and cerebrovascular diseases (AD, CVD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD) and diabetic retinopathy (DR), in the context of the molecular pathways involved in OPN signaling shaping the function of microglia. As nearly all CNS diseases are characterized by pathological alterations in microglial cells, accompanied by the disturbance of the homeostatic microglia phenotype, the emergence of disease-associated microglia (DAM) states and their interplay with factors shaping the DAM-signature, such as OPN, is of great interest for therapeutical interventions in the future.}, }
@article {pmid35453510, year = {2022}, author = {Virgilio, E and De Marchi, F and Contaldi, E and Dianzani, U and Cantello, R and Mazzini, L and Comi, C}, title = {The Role of Tau beyond Alzheimer's Disease: A Narrative Review.}, journal = {Biomedicines}, volume = {10}, number = {4}, pages = {}, pmid = {35453510}, issn = {2227-9059}, abstract = {Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively recognized as a valuable neuronal biomarker in several neurological conditions, not only Alzheimer's disease (AD). Cerebrospinal fluid and serum Tau have been extensively investigated in several neurodegenerative disorders, from classically defined proteinopathy, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), but also in inflammatory conditions such as multiple sclerosis (MS), as a marker of axonal damage. In MS, total Tau (t-Tau) may represent, along with other proteins, a marker with diagnostic and prognostic value. In ALS, t-Tau and, mainly, the phosphorylated-Tau/t-Tau ratio alone or integrated with transactive DNA binding protein of ~43 kDa (TDP-43), may represent a tool for both diagnosis and differential diagnosis of other motoneuron diseases or tauopathies. Evidence indicated the crucial role of the Tau protein in the pathogenesis of PD and other parkinsonian disorders. This narrative review summarizes current knowledge regarding non-AD neurodegenerative diseases and the Tau protein.}, }
@article {pmid35453299, year = {2022}, author = {Peggion, C and Scalcon, V and Massimino, ML and Nies, K and Lopreiato, R and Rigobello, MP and Bertoli, A}, title = {SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {4}, pages = {}, pmid = {35453299}, issn = {2076-3921}, support = {BIRD202151/20//University of Padova/ ; RIGO_ALFREVE21_01 - Bando POR Veneto FESR 2014-2020//University of Padova/ ; RIGO_FINA18_01 _ DSB, UNIPD//University of Padova/ ; RIGO_PRIV21_03_, Progetto MUR DM 1062/2021 PON &quot;Ricerca e innovazione&quot; 2014-2020//MUR - Italian Ministry of Research/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. While the exact causes of ALS are still unclear, the discovery that familial cases of ALS are related to mutations in the Cu/Zn superoxide dismutase (SOD1), a key antioxidant enzyme protecting cells from the deleterious effects of superoxide radicals, suggested that alterations in SOD1 functionality and/or aberrant SOD1 aggregation strongly contribute to ALS pathogenesis. A new scenario was opened in which, thanks to the generation of SOD1 related models, different mechanisms crucial for ALS progression were identified. These include excitotoxicity, oxidative stress, mitochondrial dysfunctions, and non-cell autonomous toxicity, also implicating altered Ca[2+] metabolism. While most of the literature considers motor neurons as primary target of SOD1-mediated effects, here we mainly discuss the effects of SOD1 mutations in non-neuronal cells, such as glial and skeletal muscle cells, in ALS. Attention is given to the altered redox balance and Ca[2+] homeostasis, two processes that are strictly related with each other. We also provide original data obtained in primary myocytes derived from hSOD1(G93A) transgenic mice, showing perturbed expression of Ca[2+] transporters that may be responsible for altered mitochondrial Ca[2+] fluxes. ALS-related SOD1 mutants are also responsible for early alterations of fundamental biological processes in skeletal myocytes that may impinge on skeletal muscle functions and the cross-talk between muscle cells and motor neurons during disease progression.}, }
@article {pmid35451811, year = {2022}, author = {Kulkarni, R and Thakur, A and Kumar, H}, title = {Microtubule Dynamics Following Central and Peripheral Nervous System Axotomy.}, journal = {ACS chemical neuroscience}, volume = {13}, number = {9}, pages = {1358-1369}, doi = {10.1021/acschemneuro.2c00189}, pmid = {35451811}, issn = {1948-7193}, mesh = {Axonal Transport/physiology ; *Axons/metabolism ; Axotomy ; Microtubules ; Nerve Regeneration/physiology ; *Peripheral Nervous System/physiology ; }, abstract = {Disturbance in the neuronal network leads to instability in the microtubule (MT) railroad of axons, causing hindrance in the intra-axonal transport and making it difficult to re-establish the broken network. Peripheral nervous system (PNS) neurons can stabilize their MTs, leading to the formation of regeneration-promoting structures called "growth cones". However, central nervous system (CNS) neurons lack this intrinsic reparative capability and, instead, form growth-incompetent structures called "retraction bulbs", which have a disarrayed MT network. It is evident from various studies that although axonal regeneration depends on both cell-extrinsic and cell-intrinsic factors, any therapy that aims at axonal regeneration ultimately converges onto MTs. Understanding the neuronal MT dynamics will help develop effective therapeutic strategies in diseases where the MT network gets disrupted, such as spinal cord injury, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis. It is also essential to know the factors that aid or inhibit MT stabilization. In this review, we have discussed the MT dynamics postaxotomy in the CNS and PNS, and factors that can directly influence MT stability in various diseases.}, }
@article {pmid35450015, year = {2022}, author = {Zhang, S and Zhao, J and Quan, Z and Li, H and Qing, H}, title = {Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {853911}, pmid = {35450015}, issn = {1662-4548}, abstract = {The contribution of organelles to neural development has received increasing attention. Studies have shown that organelles such as mitochondria, endoplasmic reticulum (ER), lysosomes, and endosomes play important roles in neurogenesis. Specifically, metabolic switching, reactive oxygen species production, mitochondrial dynamics, mitophagy, mitochondria-mediated apoptosis, and the interaction between mitochondria and the ER all have roles in neurogenesis. Lysosomes and endosomes can regulate neurite growth and extension. Moreover, metabolic reprogramming represents a novel strategy for generating functional neurons. Accordingly, the exploration and application of mechanisms underlying metabolic reprogramming will be beneficial for neural conversion and regenerative medicine. There is adequate evidence implicating the dysfunction of cellular organelles-especially mitochondria-in neurodegenerative disorders, and that improvement of mitochondrial function may reverse the progression of these diseases through the reinforcement of adult neurogenesis. Therefore, these organelles have potential as therapeutic targets for the treatment of neurodegenerative diseases. In this review, we discuss the function of these organelles, especially mitochondria, in neural development, focusing on their potential as therapeutic targets in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid35446507, year = {2022}, author = {Goerdt, LV and Schneider, SW and Booken, N}, title = {Kutane Angiosarkome: molekulare Pathogenese und neue therapeutische Ansätze.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {20}, number = {4}, pages = {429-444}, doi = {10.1111/ddg.14694_g}, pmid = {35446507}, issn = {1610-0387}, abstract = {Das kutane Angiosarkom (CAS) ist ein hochaggressiver maligner Tumor mit schlechter Prognose. Das primäre, spontane CAS (pCAS) und das sekundäre, mit einer Bestrahlung oder einem Lymphödem assoziierte CAS (sCAS) unterscheiden sich klinisch sowie molekular. Die Amplifikation/Überexpression von Myc ist ein charakteristisches, wenn auch nicht ausschließliches Merkmal von sCAS, während der Verlust von TP53 selektiv bei pCAS vorkommt. Detaillierte molekulare Analysen mit modernen Multi-Omics-Ansätzen haben gezeigt, dass sowohl pCAS als auch sCAS eine erhebliche molekulare Heterogenität aufweisen. Die betroffenen Gene und ihre molekularen Regulatoren sind mögliche therapeutische Zielstrukturen. Darüber hinaus kann das pCAS in Cluster mit hoher Mutationsrate und/oder ausgeprägten Entzündungssignaturen eingeteilt werden, die als Grundlage für die künftige Stratifizierung von pCAS-Patienten in immuntherapeutischen klinischen Studien dienen können. Während die Aufklärung der der Erkrankung zugrunde liegenden molekularen Veränderungen zügig voranschreitet, verläuft die Entwicklung daraus abgeleiteter neuer Therapien für das CAS jedoch bisher eher langsam. Dennoch wurden einige über die Standardtherapien wie Operation und Radiochemotherapie hinausgehende klinische Studien zu neuen Behandlungsmöglichkeiten initiiert. Dazu gehören zielgerichtete Therapien gegen VEGF und VEGFR1-3 wie Bevacizumab und Pazopanib, sowie β-Adrenozeptorenblocker wie Propranolol. Derzeit werden auch Immuntherapien entwickelt, unter anderem unter Verwendung der Immuncheckpoint-Inhibitoren Pembrolizumab und Nivolumab sowie des Anti-RANKL-Antikörper Denosumab.}, }
@article {pmid35440308, year = {2022}, author = {Benmelouka, AY and Ouerdane, Y and Outani, O and Alnasser, YT and Alghamdi, BS and Perveen, A and Ashraf, GM and Ebada, MA}, title = {Alzheimer's Disease-Related Psychosis: An Overview of Clinical Manifestations, Pathogenesis, and Current Treatment.}, journal = {Current Alzheimer research}, volume = {19}, number = {4}, pages = {285-301}, doi = {10.2174/1567205019666220418151914}, pmid = {35440308}, issn = {1875-5828}, mesh = {*Alzheimer Disease/complications/diagnosis ; Comorbidity ; Delusions/genetics ; Hallucinations/genetics ; Humans ; *Psychotic Disorders/diagnosis/etiology/therapy ; Risk Factors ; }, abstract = {Behavioral and psychotic manifestations, including aggression, delusions, and hallucinations, are frequent comorbidities in patients with debilitating nervous illnesses such as Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Parkinson's disease. ADrelated psychosis may be linked to a poor disease prognosis, highlighting that early detection and management are mandatory. The manifestations are variable and may be very heterogeneous, imposing a real diagnostic issue. Some assessment tools such as BEHAVE-AD, CERAD-BRSD, and the Psycho-Sensory Hallucinations Scale have been designed to facilitate the diagnosis. The mechanisms behind neurodegeneration-related psychosis are complex and are not fully understood, imposing a burden on researchers to find appropriate management modalities. Familial history and some genetic disturbances may have a determinant role in these delusions and hallucinations in cases with AD. The loss of neuronal cells, atrophy in some regions of the central nervous, and synaptic dysfunction may also contribute to these comorbidities. Furthermore, inflammatory disturbances triggered by pro-inflammatory agents such as interleukins and tumor necrosis factors are stratified among the potential risk factors for the onset of numerous psychotic symptoms in Alzheimer's patients. Little is known about the possible management tools; therefore, it is urgent to conduct well-designed trials to investigate pharmacological and non-pharmacological interventions that can improve the care process of these patients. This review summarizes the current findings regarding the AD-related psychosis symptoms, pathological features, assessment, and management.}, }
@article {pmid35436682, year = {2022}, author = {Nabizadeh, F and Nikfarjam, M and Azami, M and Sharifkazemi, H and Sodeifian, F}, title = {Pseudobulbar affect in neurodegenerative diseases: A systematic review and meta-analysis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {100}, number = {}, pages = {100-107}, doi = {10.1016/j.jocn.2022.04.009}, pmid = {35436682}, issn = {1532-2653}, mesh = {*Alzheimer Disease/complications ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Crying ; Humans ; *Laughter ; *Multiple Sclerosis/complications/epidemiology ; *Neurodegenerative Diseases/complications/epidemiology ; *Parkinson Disease/complications ; Quality of Life ; }, abstract = {BACKGROUND: Pseudobulbar affect (PBA) is characterized by uncontrolled episodes of crying and laughing which is associated with a variety of neurological diseases including traumatic brain injury, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), brain tumors, stroke, Parkinson's disease (PD), Alzheimer's disease (AD) and other dementias. However, there is a lack of exact estimated prevalence of PBA among neurological disorders.<br><br>AIM: In this systematic review and meta-analysis study we aimed to assess the prevalence of PBA in four neurodegenerative diseases including ALS, MS, AD, and PD.<br><br>METHODS: PubMed, Scopus, and Web of Science were searched in July 2021 for studies that reported the prevalence of PBA in ALS, MS, AD, and PD patients. The mean point of PBA prevalence and odds ratios were calculated as effect size (ES) using the random-effect model with a 95% confidence interval (CI).<br><br>RESULTS: The summarized prevalence of PBA was of PBA in PD patients were ranged between 1% and 31% with an overall meta-analysis prevalence of 16.5% and high heterogeneity (I[2]: 98.7%, p: 0.000). Patients with ALS showed a PBA prevalence of 38.5%, which is higher than other neurodegenerative diseases (CI 95%: 31%-45%, I[2]: 61.4%, p: 0.034). Moreover, the prevalence of PBA in MS patients in the analysis was 23.3% ranging between 11% and 35% with high-level heterogeneity according to the I[2] value (I[2]: 98.9%, p: 0.000). Also, our meta-analysis showed that the PBA prevalence in AD was 16.4% (CI 95%: 7%-25%) with high heterogeneity (I[2]: 97.8%, p: 0.000).<br><br>CONCLUSION: This review showed that PBA is common in patients with neurodegenerative diseases including PD, AD, MS, and especially ALS. Due to the lack of proper recognition, medication and treatment would not be effective and sufficient. Therefore, it can dramatically lower the quality of life in PBA patients and decrease their social interactions.}, }
@article {pmid35435648, year = {2022}, author = {Turner, V and Husain, M}, title = {Anhedonia in Neurodegenerative Diseases.}, journal = {Current topics in behavioral neurosciences}, volume = {58}, number = {}, pages = {255-277}, pmid = {35435648}, issn = {1866-3370}, support = {206330/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Alzheimer Disease ; *Anhedonia ; Brain/pathology ; Humans ; *Neurodegenerative Diseases ; Parkinson Disease ; }, abstract = {Neurodegenerative diseases are increasingly recognised to be an important cause of brain disorders, particularly in late age. Associated with a wide range of pathologies, they lead to progressive loss of neurons in different regions of the nervous system. Although anhedonia is common in a variety of neurodegenerative diseases, to date it has not been extensively studied in most of these conditions. Here we review the current literature on studies assessing the association between anhedonia and neurodegenerative diseases including Parkinson's Disease, Dementia with Lewy Bodies, Parkinson's Plus Syndromes, Alzheimer's Disease, Vascular Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis and Huntington's Disease. Much of the research has been conducted in Parkinson's disease where it is evident that there are strong links between apathy (loss of motivation) and anhedonia, although the two syndromes can be dissociated. Intriguingly, drugs that improve apathy can also lead to amelioration of anhedonia in some cases. Overlaps between the two syndromes may also exist across other neurodegenerative conditions, including Frontotemporal Dementia in which imaging has revealed atrophy of both common brain regions associated with anhedonia and apathy, as well as a set of unique brain regions associated with anhedonia. A transdiagnostic perspective might be helpful to investigate whether a common network of brain regions is dysfunctional with anhedonia across neurodegenerative conditions.}, }
@article {pmid35428871, year = {2023}, author = {Vujosevic, S and Parra, MM and Hartnett, ME and O'Toole, L and Nuzzi, A and Limoli, C and Villani, E and Nucci, P}, title = {Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children.}, journal = {Eye (London, England)}, volume = {37}, number = {2}, pages = {203-219}, pmid = {35428871}, issn = {1476-5454}, support = {P30 EY014800/EY/NEI NIH HHS/United States ; R01 EY015130/EY/NEI NIH HHS/United States ; R01 EY017011/EY/NEI NIH HHS/United States ; }, mesh = {Adult ; Humans ; Child ; *Tomography, Optical Coherence/methods ; Retinal Ganglion Cells ; Neuroinflammatory Diseases ; Retina/diagnostic imaging ; *Neuromyelitis Optica/diagnosis ; Biomarkers ; }, abstract = {The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington's disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.}, }
@article {pmid35426061, year = {2022}, author = {Kim, G and Chen, X and Yang, Y}, title = {Pathogenic Extracellular Vesicle (EV) Signaling in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1119-1132}, pmid = {35426061}, issn = {1878-7479}, support = {RF1 AG059610/AG/NIA NIH HHS/United States ; R01 NS118747/NS/NINDS NIH HHS/United States ; R01 NS125490/NS/NINDS NIH HHS/United States ; R01 AG078728/AG/NIA NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Protein Aggregates ; *Extracellular Vesicles/metabolism ; *Exosomes/metabolism ; Biomarkers/metabolism ; }, abstract = {Extracellular vesicles (EVs), once considered a pathway for cells to remove waste, have now emerged as an important mechanism for intercellular communication. EVs are particularly appealing in understanding the central nervous system (CNS) communication, given that there are very diverse cell types in the CNS and constant communications among various cells to respond to the frequently changing environment. While they are heterogeneous and new vesicles are continuously to be discovered, EVs are primarily classified as plasma membrane-derived microvesicles (MVs) and endosome-derived exosomes. Secretion of EVs has been shown from all CNS cell types in vitro and intercellular EV signaling has been implicated in neural development, axon integrity, neuron to glia communication, and propagation of protein aggregates formed by disease pathogenic proteins. However, significant hurdles remain to be tackled in understanding their physiological and pathological roles as well as how they can be developed as biomarkers or new therapeutics. Here we provide our summary on the known cell biology of EVs and discuss opportunities and challenges in understanding EV biology in the CNS and particularly their involvement in ALS pathogenesis.}, }
@article {pmid35422699, year = {2022}, author = {Loch-Neckel, G and Matos, AT and Vaz, AR and Brites, D}, title = {Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {839790}, pmid = {35422699}, issn = {1663-9812}, abstract = {Small extracellular vesicles (sEVs) have ∼30-200 nm diameter size and may act as carriers of different cargoes, depending on the cell of origin or on the physiological/pathological condition. As endogenous nanovesicles, sEVs are important in intercellular communication and have many of the desirable features of an ideal drug delivery system. sEVs are naturally biocompatible, with superior targeting capability, safety profile, nanometric size, and can be loaded with both lipophilic and hydrophilic agents. Because of their biochemical and physical properties, sEVs are considered a promising strategy over other delivery vehicles in the central nervous system (CNS) since they freely cross the blood-brain barrier and they can be directed to specific nerve cells, potentiating a more precise targeting of their cargo. In addition, sEVs remain stable in the peripheral circulation, making them attractive nanocarrier systems to promote neuroregeneration. This review focuses on the recent progress in methods for manufacturing, isolating, and engineering sEVs that can be used as a therapeutic strategy to overcome neurodegeneration associated with pathologies of the CNS, with particular emphasis on Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis diseases, as well as on brain tumors.}, }
@article {pmid35419363, year = {2022}, author = {Ondaro, J and Hernandez-Eguiazu, H and Garciandia-Arcelus, M and Loera-Valencia, R and Rodriguez-Gómez, L and Jiménez-Zúñiga, A and Goikolea, J and Rodriguez-Rodriguez, P and Ruiz-Martinez, J and Moreno, F and Lopez de Munain, A and Holt, IJ and Gil-Bea, FJ and Gereñu, G}, title = {Defects of Nutrient Signaling and Autophagy in Neurodegeneration.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {836196}, pmid = {35419363}, issn = {2296-634X}, abstract = {Neurons are post-mitotic cells that allocate huge amounts of energy to the synthesis of new organelles and molecules, neurotransmission and to the maintenance of redox homeostasis. In neurons, autophagy is not only crucial to ensure organelle renewal but it is also essential to balance nutritional needs through the mobilization of internal energy stores. A delicate crosstalk between the pathways that sense nutritional status of the cell and the autophagic processes to recycle organelles and macronutrients is fundamental to guarantee the proper functioning of the neuron in times of energy scarcity. This review provides a detailed overview of the pathways and processes involved in the balance of cellular energy mediated by autophagy, which when defective, precipitate the neurodegenerative cascade of Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.}, }
@article {pmid35415778, year = {2022}, author = {Li, W and Pandya, D and Pasternack, N and Garcia-Montojo, M and Henderson, L and Kozak, CA and Nath, A}, title = {Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1085-1101}, pmid = {35415778}, issn = {1878-7479}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; DNA Transposable Elements ; Macaca mulatta/genetics/metabolism ; RNA, Small Interfering ; *Endogenous Retroviruses/genetics/metabolism ; *HIV Infections/drug therapy/genetics ; Oligonucleotides, Antisense ; RNA-Directed DNA Polymerase/genetics/metabolism ; }, abstract = {The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs.}, }
@article {pmid35410603, year = {2022}, author = {Bojja, SL and Singh, N and Kolathur, KK and Rao, CM}, title = {What is the Role of Lithium in Epilepsy?.}, journal = {Current neuropharmacology}, volume = {20}, number = {10}, pages = {1850-1864}, pmid = {35410603}, issn = {1875-6190}, mesh = {*Epilepsy/drug therapy ; Humans ; *Lithium/pharmacology/therapeutic use ; Lithium Compounds/pharmacology/therapeutic use ; Mood Disorders/drug therapy ; Neuroprotection ; }, abstract = {Lithium is a well-known FDA-approved treatment for bipolar and mood disorders. Lithium has been an enigmatic drug with multifaceted actions involving various neurotransmitters and intricate cell signalling cascades. Recent studies highlight the neuroprotective and neurotrophic actions of lithium in amyotrophic lateral sclerosis, Alzheimer's disease, intracerebral hemorrhage, and epilepsy. Of note, lithium holds a significant interest in epilepsy, where the past reports expose its non-specific proconvulsant action, followed lately by numerous studies for anti-convulsant action. However, the exact mechanism of action of lithium for any of its effects is still largely unknown. The present review integrates findings from several reports and provides detailed possible mechanisms of how a single molecule exhibits marked pro-epileptogenic as well as anti-convulsant action. This review also provides clarity regarding the safety of lithium therapy in epileptic patients.}, }
@article {pmid35409239, year = {2022}, author = {Haouari, S and Vourc'h, P and Jeanne, M and Marouillat, S and Veyrat-Durebex, C and Lanznaster, D and Laumonnier, F and Corcia, P and Blasco, H and Andres, CR}, title = {The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {23}, number = {7}, pages = {}, pmid = {35409239}, issn = {1422-0067}, mesh = {Endosomal Sorting Complexes Required for Transport/genetics/metabolism ; Humans ; Nedd4 Ubiquitin Protein Ligases/genetics/metabolism ; *Parkinson Disease ; Ubiquitin/metabolism ; *Ubiquitin-Protein Ligases/genetics/metabolism ; Ubiquitination ; }, abstract = {The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons in the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them.}, }
@article {pmid35408984, year = {2022}, author = {Tolay, N and Buchberger, A}, title = {Role of the Ubiquitin System in Stress Granule Metabolism.}, journal = {International journal of molecular sciences}, volume = {23}, number = {7}, pages = {}, pmid = {35408984}, issn = {1422-0067}, support = {GRK2243/2, BU951/5-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Cytoplasmic Granules/metabolism ; RNA-Binding Proteins/metabolism ; Stress Granules ; Stress, Physiological ; *Ubiquitin/metabolism ; }, abstract = {Eukaryotic cells react to various stress conditions with the rapid formation of membrane-less organelles called stress granules (SGs). SGs form by multivalent interactions between RNAs and RNA-binding proteins and are believed to protect stalled translation initiation complexes from stress-induced degradation. SGs contain hundreds of different mRNAs and proteins, and their assembly and disassembly are tightly controlled by post-translational modifications. The ubiquitin system, which mediates the covalent modification of target proteins with the small protein ubiquitin ('ubiquitylation'), has been implicated in different aspects of SG metabolism, but specific functions in SG turnover have only recently emerged. Here, we summarize the evidence for the presence of ubiquitylated proteins at SGs, review the functions of different components of the ubiquitin system in SG formation and clearance, and discuss the link between perturbed SG clearance and the pathogenesis of neurodegenerative disorders. We conclude that the ubiquitin system plays an important, medically relevant role in SG biology.}, }
@article {pmid35406714, year = {2022}, author = {Deschenes, MR and Flannery, R and Hawbaker, A and Patek, L and Mifsud, M}, title = {Adaptive Remodeling of the Neuromuscular Junction with Aging.}, journal = {Cells}, volume = {11}, number = {7}, pages = {}, pmid = {35406714}, issn = {2073-4409}, support = {R15 AR060637/AR/NIAMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; *Diabetes Mellitus, Type 2/metabolism ; Humans ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; }, abstract = {Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as "sarcopenia", is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with aging and disease is described, along with the measures that might be taken to effectively mitigate, if not fully prevent, that degeneration.}, }
@article {pmid35405261, year = {2022}, author = {Johnson, MA and Klickstein, JA and Khanna, R and Gou, Y and ,  and Raman, M}, title = {The Cure VCP Scientific Conference 2021: Molecular and clinical insights into neurodegeneration and myopathy linked to multisystem proteinopathy-1 (MSP-1).}, journal = {Neurobiology of disease}, volume = {169}, number = {}, pages = {105722}, pmid = {35405261}, issn = {1095-953X}, support = {K12 GM133314/GM/NIGMS NIH HHS/United States ; R01 GM127557/GM/NIGMS NIH HHS/United States ; R21 NS123631/NS/NINDS NIH HHS/United States ; R35 GM133772/GM/NIGMS NIH HHS/United States ; }, mesh = {Cell Cycle Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/therapy ; Humans ; Merozoite Surface Protein 1/genetics ; Muscular Dystrophies, Limb-Girdle ; Mutation ; *Myositis, Inclusion Body/genetics/therapy ; Osteitis Deformans ; Valosin Containing Protein/genetics ; }, abstract = {The 2021 VCP Scientific Conference took place virtually from September 9-10, 2021. This conference, planned and organized by the nonprofit patient advocacy group Cure VCP Disease, Inc. (https://www.curevcp.org), was the first VCP focused meeting since the 215th ENMC International Workshop VCP-related multi-system proteinopathy in 2016 (Evangelista et al., 2016). Mutations in VCP cause a complex and heterogenous disease termed inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), or multisystem proteinopathy 1 (MSP-1) Kimonis (n.d.), Kovach et al. (2001), Kimonis et al. (2000). In addition, VCP mutations also cause other age-related neurodegenerative disorders including amyptrophic lateral sclerosis (ALS), Parkinsonism, Charcot-Marie type II-B, vacuolar tauopathy among others (Korb et al., 2022). The objectives of this conference were as follows: (1) to provide a forum that facilitates sharing of published and unpublished information on physiological roles of p97/VCP, and on how mutations of VCP lead to diseases; (2) to bolster understanding of mechanisms involved in p97/VCP-relevant diseases and to enable identification of therapeutics to treat these conditions; (3) to identify gaps and barriers of further discoveries and translational research in the p97/VCP field; (4) to set a concrete basic and translational research agenda for future studies including crucial discussions on biomarker discoveries and patient longitudinal studies to facilitate near-term clinical trials; (5) to accelerate cross-disciplinary research collaborations among p97/VCP researchers; (6) to enable attendees to learn about new tools and reagents with the potential to facilitate p97/VCP research; (7) to assist trainees in propelling their research and to foster mentorship from leaders in the field; and (8) to promote diversity and inclusion of under-represented minorities in p97/VCP research as diversity is critically important for strong scientific research. Given the range of topics, the VCP Scientific Conference brought together over one hundred and forty individuals representing a diverse group of research scientists, trainees, medical practitioners, industry representatives, and patient advocates. Twenty-five institutions with individuals from thirteen countries attended this virtual meeting. In this report, we summarize the major topics presented at this conference by a range of experts.}, }
@article {pmid35402235, year = {2022}, author = {Ghafouri-Fard, S and Hussen, BM and Mohaqiq, M and Shoorei, H and Baniahmad, A and Taheri, M and Jamali, E}, title = {Interplay Between Non-Coding RNAs and Programmed Cell Death Proteins.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {808475}, pmid = {35402235}, issn = {2234-943X}, abstract = {Programmed cell death (PDCD) family of proteins includes at least 12 members, function of seven of them being more investigated. These members are PDCD1, PDCD2, PDCD4, PDCD5, PDCD6, PDCD7 and PDCD10. Consistent with the important roles of these proteins in the regulation of apoptosis, dysregulation of PDCDs is associated with diverse disorders ranging from intervertebral disc degeneration, amyotrophic lateral sclerosis, immune thrombocytopenia, type 1 diabetes, congenital hypothyroidism, Alzheimer's disease to different types of cancers. More recently, the interaction between non-coding RNAs and different members of PDCD family is being discovered. In the current study, we described the functional interactions between PDCDs and two classes of non-coding RNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miR-21 and miR-183 are two miRNAs whose interactions with PDCDs have been assessed in different contexts. The lncRNAs interaction with PDCDs is mainly assessed in the context of neoplasia indicating the role of MALAT1, MEG3, SNHG14 and LINC00473 in this process.}, }
@article {pmid35401084, year = {2022}, author = {Stefani, A and Pierantozzi, M and Cardarelli, S and Stefani, L and Cerroni, R and Conti, M and Garasto, E and Mercuri, NB and Marini, C and Sucapane, P}, title = {Neurotrophins as Therapeutic Agents for Parkinson's Disease; New Chances From Focused Ultrasound?.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {846681}, pmid = {35401084}, issn = {1662-4548}, abstract = {Magnetic Resonance-guided Focused Ultrasound (MRgFUS) represents an effective micro-lesioning approach to target pharmaco-resistant tremor, mostly in patients afflicted by essential tremor (ET) and/or Parkinson's disease (PD). So far, experimental protocols are verifying the clinical extension to other facets of the movement disorder galaxy (i.e., internal pallidus for disabling dyskinesias). Aside from those neurosurgical options, one of the most intriguing opportunities of this technique relies on its capability to remedy the impermeability of blood-brain barrier (BBB). Temporary BBB opening through low-intensity focused ultrasound turned out to be safe and feasible in patients with PD, Alzheimer's disease, and amyotrophic lateral sclerosis. As a mere consequence of the procedures, some groups described even reversible but significant mild cognitive amelioration, up to hippocampal neurogenesis partially associated to the increased of endogenous brain-derived neurotrophic factor (BDNF). A further development elevates MRgFUS to the status of therapeutic tool for drug delivery of putative neurorestorative therapies. Since 2012, FUS-assisted intravenous administration of BDNF or neurturin allowed hippocampal or striatal delivery. Experimental studies emphasized synergistic modalities. In a rodent model for Huntington's disease, engineered liposomes can carry glial cell line-derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex through pulsed FUS exposures with microbubbles; in a subacute MPTP-PD model, the combination of intravenous administration of neurotrophic factors (either through protein or gene delivery) plus FUS did curb nigrostriatal degeneration. Here, we explore these arguments, focusing on the current, translational application of neurotrophins in neurodegenerative diseases.}, }
@article {pmid35395400, year = {2022}, author = {Liu, W and Wang, G and Wang, Z and Wang, G and Huang, J and Liu, B}, title = {Repurposing small-molecule drugs for modulating toxic protein aggregates in neurodegenerative diseases.}, journal = {Drug discovery today}, volume = {27}, number = {7}, pages = {1994-2007}, doi = {10.1016/j.drudis.2022.04.003}, pmid = {35395400}, issn = {1878-5832}, mesh = {Aged ; *Alzheimer Disease/drug therapy ; Drug Repositioning ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Parkinson Disease ; Protein Aggregates ; Proteins/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDs) are often age-related disorders that can cause dementia in people, usually over 65 years old, are still lacking effective therapies. Some NDs have recently been linked to toxic protein aggregates, for example Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington disease; therefore, mulating toxic protein aggregates would be a promising therapeutic strategy. Moreover, drug repurposing, in other words exploiting drugs that are already in use for another indication, has been attracting mounting attention for potential therapeutic purposes in NDs. Thus, in this review, we focus on summarizing a series of repurposed small-molecule drugs for eliminating or inhibiting toxic protein aggregates and further discuss their intricate molecular mechanisms to improve the current ND treatment. Taken together, these findings will shed new light on exploiting more repurposed small-molecule drugs targeting different types of toxic proteins to fight NDs in the future.}, }
@article {pmid35393134, year = {2022}, author = {Dong, Y and Yong, VW}, title = {Oxidized phospholipids as novel mediators of neurodegeneration.}, journal = {Trends in neurosciences}, volume = {45}, number = {6}, pages = {419-429}, doi = {10.1016/j.tins.2022.03.002}, pmid = {35393134}, issn = {1878-108X}, support = {3527//CIHR/Canada ; FDN 167270//CIHR/Canada ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Microglia ; Oxidation-Reduction ; Oxidative Stress ; Phosphatidylcholines/toxicity ; *Phospholipids ; }, abstract = {Neurodegeneration drives the progression of many neurological diseases. Inflammation and oxidative stress occurring in the CNS promote lipid peroxidation, leading to the generation of oxidized phospholipids such as oxidized phosphatidylcholines (OxPCs). OxPCs have been proposed as biomarkers of oxidative stress, where their detection in lesions in multiple sclerosis (MS), frontotemporal lobe dementia, spinal cord injury, and amyotrophic lateral sclerosis (ALS) implies that oxidative insult had occurred. However, recent findings highlight OxPCs as potent neurotoxic species requiring neutralization by microglia. Here, we summarize the science of OxPCs, including lessons from non-CNS diseases. We discuss the potential of OxPCs as common drivers of injury across neurological conditions and encourage investigations of OxPCs as novel neurotoxins.}, }
@article {pmid35390335, year = {2022}, author = {Chen, W and Guo, L and Li, M and Wei, C and Li, S and Xu, R}, title = {The pathogenesis of amyotrophic lateral sclerosis: Mitochondrial dysfunction, protein misfolding and epigenetics.}, journal = {Brain research}, volume = {1786}, number = {}, pages = {147904}, doi = {10.1016/j.brainres.2022.147904}, pmid = {35390335}, issn = {1872-6240}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Epigenesis, Genetic ; Humans ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with multiple complex mechanisms involved. Among them, mitochondrial dysfunction plays an important role in ALS. Multiple studies have shown that mitochondria are closely associated with reactive oxygen species production and oxidative stress and exhibit different functional states in different genetic backgrounds. In this review we explored the roles of Ca[2+], autophagy, mitochondrial quality control in the regulation of mitochondrial homeostasis and their relationship with ALS. In addition, we also summarized and analyzed the roles of protein misfolding and abnormal aggregation in the pathogenesis of ALS. Moreover, we also discussed how epigenetic mechanisms such as DNA methylation and protein post-translational modification affect initiation and progression of ALS. Nevertheless, existing events still cannot fully explain the pathogenesis of ALS at present, more studies are required to explore pathological mechanisms of ALS.}, }
@article {pmid35380400, year = {2022}, author = {Zahra, W and Birla, H and Singh, SS and Rathore, AS and Dilnashin, H and Singh, R and Keshri, PK and Gautam, P and Singh, SP}, title = {Neuroprotection by Mucuna pruriens in Neurodegenerative Diseases.}, journal = {Neurochemical research}, volume = {47}, number = {7}, pages = {1816-1829}, pmid = {35380400}, issn = {1573-6903}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Male ; *Mucuna ; *Neurodegenerative Diseases/drug therapy ; Neuroprotection ; *Parkinson Disease/drug therapy ; Plant Extracts/pharmacology/therapeutic use ; Seeds ; *Stroke/drug therapy ; }, abstract = {The medicinal plant Mucuna pruriens (Fabaceae) is widely known for its anti-oxidative and anti-inflammatory properties. It is a well-established drug in Ayurveda and has been widely used for the treatment of neurological disorders and male infertility for ages. The seeds of the plant have potent medicinal value and its extract has been tested in different models of neurodegenerative diseases, especially Parkinson's disease (PD). Apart from PD, Mucuna pruriens is now being studied in models of other nervous systems disorders such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and stroke because of its neuroprotective importance. This review briefly discusses the pathogenesis of PD, AD, ALS and stroke. It aims to summarize the medicinal importance of Mucuna pruriens in treatment of these diseases, and put forward the potential targets where Mucuna pruriens can act for therapeutic interventions. In this review, the effect of Mucuna pruriens on ameliorating the neurodegeneration evident in PD, AD, ALS and stroke is briefly discussed. The potential targets for neuroprotection by the plant are delineated, which can be studied further to validate the hypothesis regarding the use of Mucuna pruriens for the treatment of these diseases.}, }
@article {pmid35372839, year = {2022}, author = {Kubinski, S and Claus, P}, title = {Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA.}, journal = {Neuroscience insights}, volume = {17}, number = {}, pages = {26331055221087740}, pmid = {35372839}, issn = {2633-1055}, abstract = {Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases which are characterized by the loss of motoneurons within the central nervous system. SMA is a monogenic disease caused by reduced levels of the Survival of motoneuron protein, whereas ALS is a multi-genic disease with over 50 identified disease-causing genes and involvement of environmental risk factors. Although these diseases have different causes, they partially share identical phenotypes and pathomechanisms. To analyze and identify functional connections and to get a global overview of altered pathways in both diseases, protein network analyses are commonly used. Here, we used an in silico tool to test for functional associations between proteins that are involved in actin cytoskeleton dynamics, fatty acid metabolism, skeletal muscle metabolism, stress granule dynamics as well as SMA or ALS risk factors, respectively. In network biology, interactions are represented by edges which connect proteins (nodes). Our approach showed that only a few edges are necessary to present a complex protein network of different biological processes. Moreover, Superoxide dismutase 1, which is mutated in ALS, and the actin-binding protein profilin1 play a central role in the connectivity of the aforementioned pathways. Our network indicates functional links between altered processes that are described in either ALS or SMA. These links may not have been considered in the past but represent putative targets to restore altered processes and reveal overlapping pathomechanisms in both diseases.}, }
@article {pmid35372346, year = {2022}, author = {Lin, TJ and Cheng, GC and Wu, LY and Lai, WY and Ling, TY and Kuo, YC and Huang, YH}, title = {Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {851613}, pmid = {35372346}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3-5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.}, }
@article {pmid35372329, year = {2022}, author = {Milicevic, K and Rankovic, B and Andjus, PR and Bataveljic, D and Milovanovic, D}, title = {Emerging Roles for Phase Separation of RNA-Binding Proteins in Cellular Pathology of ALS.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {840256}, pmid = {35372329}, issn = {2296-634X}, abstract = {Liquid-liquid phase separation (LLPS) is emerging as a major principle for the mesoscale organization of proteins, RNAs, and membrane-bound organelles into biomolecular condensates. These condensates allow for rapid cellular responses to changes in metabolic activities and signaling. Nowhere is this regulation more important than in neurons and glia, where cellular physiology occurs simultaneously on a range of time- and length-scales. In a number of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), misregulation of biomolecular condensates leads to the formation of insoluble aggregates-a pathological hallmark of both sporadic and familial ALS. Here, we summarize how the emerging knowledge about the LLPS of ALS-related proteins corroborates with their aggregation. Understanding the mechanisms that lead to protein aggregation in ALS and how cells respond to these aggregates promises to open new directions for drug development.}, }
@article {pmid35371602, year = {2022}, author = {Tian, H and Hu, Z and Wang, C}, title = {The Therapeutic Potential of tRNA-derived Small RNAs in Neurodegenerative Disorders.}, journal = {Aging and disease}, volume = {13}, number = {2}, pages = {389-401}, pmid = {35371602}, issn = {2152-5250}, abstract = {Gene expressions and functions at various levels, namely post-transcriptional, transcriptional, and epigenetic, can be regulated by transfer RNA (tRNA)-derived small RNAs (tsRNAs), which are as well-established as tRNA fragments or tRFs. This regulation occurs when tsRNAs are created through the special endonuclease-mediated cleavage of mature or precursor tRNAs. However, tsRNAs are newly discovered entities, and molecular functions associated with tsRNAs are still not clearly understood. There is increasingly robust evidence suggesting that specific tsRNAs perform fundamental tasks in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders. Indeed, the patterns of tsRNA expression are uncertain and could be altered in patients suffering from Parkinson's disease, pontocerebellar hypoplasia, amyotrophic lateral sclerosis, Alzheimer's disease, and other neurodegenerative disorders. In the present article, a review is conducted of recent domestic and international progress in research on the potential cellular and molecular mechanisms of tsRNA biogenesis. We also describe endogenous tsRNAs during neuronal development and neurodegenerative disorders, thereby providing theoretical support and guidance for further revealing the therapeutic potential of tsRNAs in neurodegenerative disorders.}, }
@article {pmid35370875, year = {2022}, author = {Yang, X and Qiang, Q and Li, N and Feng, P and Wei, W and Hölscher, C}, title = {Neuroprotective Mechanisms of Glucagon-Like Peptide-1-Based Therapies in Ischemic Stroke: An Update Based on Preclinical Research.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {844697}, pmid = {35370875}, issn = {1664-2295}, abstract = {The public and social health burdens of ischemic stroke have been increasing worldwide. Hyperglycemia leads to a greater risk of stroke. This increased risk is commonly seen among patients with diabetes and is in connection with worsened clinical conditions and higher mortality in patients with acute ischemic stroke (AIS). Therapy for stroke focuses mainly on restoring cerebral blood flow (CBF) and ameliorating neurological impairment caused by stroke. Although choices of stroke treatment remain limited, much advance have been achieved in assisting patients in recovering from ischemic stroke, along with progress of recanalization therapy through pharmacological and mechanical thrombolysis. However, it is still necessary to develop neuroprotective therapies for AIS to protect the brain against injury before and during reperfusion, prolong the time window for intervention, and consequently improve neurological prognosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are broadly regarded as effective drugs in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data on GLP-1 and GLP-1 RAs have displayed an impressive neuroprotective efficacy in stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Based on the preclinical studies in the past decade, we review recent progress in the biological roles of GLP-1 and GLP-1 RAs in ischemic stroke. Emphasis will be placed on their neuroprotective effects in experimental models of cerebral ischemia stroke at cellular and molecular levels.}, }
@article {pmid35369731, year = {2022}, author = {Resende, R and Fernandes, T and Pereira, AC and Marques, AP and Pereira, CF}, title = {Endoplasmic Reticulum-Mitochondria Contacts Modulate Reactive Oxygen Species-Mediated Signaling and Oxidative Stress in Brain Disorders: The Key Role of Sigma-1 Receptor.}, journal = {Antioxidants &amp; redox signaling}, volume = {37}, number = {10-12}, pages = {758-780}, doi = {10.1089/ars.2020.8231}, pmid = {35369731}, issn = {1557-7716}, mesh = {*Brain Diseases/metabolism ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; Humans ; Lipids ; Membrane Proteins/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Receptors, sigma ; Sigma-1 Receptor ; }, abstract = {Significance: Mitochondria-Associated Membranes (MAMs) are highly dynamic endoplasmic reticulum (ER)-mitochondria contact sites that, due to the transfer of lipids and Ca[2+] between these organelles, modulate several physiologic processes, such as ER stress response, mitochondrial bioenergetics and fission/fusion events, autophagy, and inflammation. In addition, these contacts are implicated in the modulation of the cellular redox status since several MAMs-resident proteins are involved in the generation of reactive oxygen species (ROS), which can act as both signaling mediators and deleterious molecules, depending on their intracellular levels. Recent Advances: In the past few years, structural and functional alterations of MAMs have been associated with the pathophysiology of several neurodegenerative diseases that are closely associated with the impairment of several MAMs-associated events, including perturbation of the redox state on the accumulation of high ROS levels. Critical Issues: Inter-organelle contacts must be tightly regulated to preserve cellular functioning by maintaining Ca[2+] and protein homeostasis, lipid metabolism, mitochondrial dynamics and energy production, as well as ROS signaling. Simultaneously, these contacts should avoid mitochondrial Ca[2+] overload, which might lead to energetic deficits and deleterious ROS accumulation, culminating in oxidative stress-induced activation of apoptotic cell death pathways, which are common features of many neurodegenerative diseases. Future Directions: Given that Sig-1R is an ER resident chaperone that is highly enriched at the MAMs and that controls ER to mitochondria Ca[2+] flux, as well as oxidative and ER stress responses, its potential as a therapeutic target for neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer, Parkinson, and Huntington diseases should be further explored. Antioxid. Redox Signal. 37, 758-780.}, }
@article {pmid35367757, year = {2022}, author = {Liu, J and Yang, J}, title = {Mitochondria-associated membranes: A hub for neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {149}, number = {}, pages = {112890}, doi = {10.1016/j.biopha.2022.112890}, pmid = {35367757}, issn = {1950-6007}, mesh = {*Alzheimer Disease/metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; *Neurodegenerative Diseases/pathology ; }, abstract = {In eukaryotic cells, organelles could coordinate complex mechanisms of signaling transduction metabolism and gene expression through their functional interactions. The functional domain between ER and mitochondria, called mitochondria-associated membranes (MAM), is closely associated with various physiological functions including intracellular lipid transport, Ca[2+] transfer, mitochondria function maintenance, and autophagosome formation. In addition, more evidence suggests that MAM modulate cellular functions in health and disease. Studies have also demonstrated the association of MAM with numerous diseases, including neurodegenerative diseases, cancer, viral infection, obesity, and diabetes. In fact, recent evidence revealed a close relationship of MAM with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. In this view, elucidating the role of MAM in neurodegenerative diseases is particularly important. This review will focus the main tethering protein complexes of MAM and functions of MAM. Besides, the role of MAM in the regulation of neurodegenerative diseases and the potential molecular mechanisms is introduced to provide a new understanding of the pathogenesis of these diseases.}, }
@article {pmid35366105, year = {2022}, author = {Han, J and Chitu, V and Stanley, ER and Wszolek, ZK and Karrenbauer, VD and Harris, RA}, title = {Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {4}, pages = {219}, pmid = {35366105}, issn = {1420-9071}, support = {P30CA013330/CA/NCI NIH HHS/United States ; Grant R01NS091519//Foundation for the National Institutes of Health/ ; P30CA013330 NCI Cancer Center Grant/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; U54 HD090260/HD/NICHD NIH HHS/United States ; U54 HD090260 support for the Rose F. Kennedy//Intellectual and Developmental Disabilities Research Center/ ; R01 NS091519/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Colony-Stimulating Factors/pharmacology/therapeutic use ; Microglia/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Parkinson Disease/drug therapy ; }, abstract = {Microglia are specialized dynamic immune cells in the central nervous system (CNS) that plays a crucial role in brain homeostasis and in disease states. Persistent neuroinflammation is considered a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (MS). Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models. Research using CSF-1R inhibitors has now been extended into non-human primates and humans. This review article summarizes the most recent advances using CSF-1R inhibitors in different neurodegenerative conditions including AD, PD, HD, ALS and MS. Potential challenges for translating these findings into clinical practice are presented.}, }
@article {pmid35364656, year = {2022}, author = {Rybakowski, JK}, title = {Antiviral, immunomodulatory, and neuroprotective effect of lithium.}, journal = {Journal of integrative neuroscience}, volume = {21}, number = {2}, pages = {68}, doi = {10.31083/j.jin2102068}, pmid = {35364656}, issn = {0219-6352}, mesh = {Animals ; Antiviral Agents/pharmacology/therapeutic use ; *Bipolar Disorder/drug therapy ; Lithium/pharmacology/therapeutic use ; Lithium Compounds/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Currently, in psychiatry, lithium is a drug of choice as a mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most important psychiatric use of lithium is probably increasing the efficacy of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium exerts antisuicidal, antiviral, immunomodulatory, and neuroprotective effects. The goal of the review is to describe the experimental and clinical studies on the last three properties of lithium. Antiviral effects of lithium pertain mostly to DNA viruses, especially herpes viruses. The therapeutic effects of lithium in systemic and topical administration on labial and genital herpes were demonstrated in clinical studies. There is also some evidence, mostly in experimental studies, that lithium possesses antiviral activity against RNA viruses, including coronaviruses. The immunomodulatory effect of lithium can mitigate "low-grade inflammatory" conditions in bipolar illness. The neuroprotective properties of lithium make this ion a plausible candidate for the prevention and treatment of neurodegenerative disorders. A favorable effect of lithium was shown in experimental models of neurodegenerative disorders. On the clinical level, some preventive action against dementia and moderately therapeutic activity in Alzheimer's disease, and mild cognitive impairment were observed. Despite promising results of lithium obtained in animal models of Huntington's disease and amyotrophic lateral sclerosis, they have not been confirmed in clinical studies. A suggestion for common mechanisms of antiviral, immunomodulatory, and neuroprotective effects of lithium is advanced.}, }
@article {pmid35363449, year = {2022}, author = {Shojai, S and Haeri Rohani, SA and Moosavi-Movahedi, AA and Habibi-Rezaei, M}, title = {Human serum albumin in neurodegeneration.}, journal = {Reviews in the neurosciences}, volume = {33}, number = {7}, pages = {803-817}, doi = {10.1515/revneuro-2021-0165}, pmid = {35363449}, issn = {2191-0200}, mesh = {Adult ; Aged ; *Alzheimer Disease/metabolism ; Amino Acids ; Amyloid beta-Peptides/metabolism ; Antioxidants ; Fatty Acids, Nonesterified ; Hormones ; Humans ; Serum Albumin ; *Serum Albumin, Human/metabolism ; }, abstract = {Serum albumin (SA) exists in relatively high concentrations, in close contact with most cells. However, in the adult brain, except for cerebrospinal fluid (CSF), SA concentration is relatively low. It is mainly produced in the liver to serve as the main protein of the blood plasma. In the plasma, it functions as a carrier, chaperon, antioxidant, source of amino acids, osmoregulator, etc. As a carrier, it facilitates the stable presence and transport of the hydrophobic and hydrophilic molecules, including free fatty acids, steroid hormones, medicines, and metal ions. As a chaperon, SA binds to and protects other proteins. As an antioxidant, thanks to a free sulfhydryl group (-SH), albumin is responsible for most antioxidant properties of plasma. These functions qualify SA as a major player in, and a mirror of, overall health status, aging, and neurodegeneration. The low concentration of SA is associated with cognitive deterioration in the elderly and negative prognosis in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). SA has been shown to be structurally modified in neurological conditions such as Alzheimer's disease (AD). During blood-brain barrier damage albumin enters the brain tissue and could trigger epilepsy and neurodegeneration. SA is able to bind to the precursor agent of the AD, amyloid-beta (Aβ), preventing its toxic effects in the periphery, and is being tested for treating this disease. SA therapy may also be effective in brain rejuvenation. In the current review, we will bring forward the prominent properties and roles of SA in neurodegeneration.}, }
@article {pmid35360111, year = {2022}, author = {Martin, S and Battistini, C and Sun, J}, title = {A Gut Feeling in Amyotrophic Lateral Sclerosis: Microbiome of Mice and Men.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {839526}, pmid = {35360111}, issn = {2235-2988}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; *Gastrointestinal Microbiome/physiology ; Humans ; Immunity, Innate ; *Microbiota ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. ALS etiology and pathophysiology are not well understood. It could be the consequences of complex interactions among host factors, microbiome, and the environmental factors. Recent data suggest the novel roles of intestinal dysfunction and microbiota in ALS etiology and progression. Although microbiome may indeed play a critical role in ALS pathogenesis, studies implicating innate immunity and intestinal changes in early disease pathology are limited. The gastrointestinal symptoms in the ALS patients before their diagnosis are largely ignored in the current medical practice. This review aims to explore existing evidence of gastrointestinal symptoms and progress of microbiome in ALS pathogenesis from human and animal studies. We discuss dietary, metabolites, and possible therapeutic approaches by targeting intestinal function and microbiome. Finally, we evaluate existing evidence and identify gaps in the knowledge for future directions in ALS. It is essential to understanding the microbiome and intestinal pathogenesis that determine when, where, and whether microbiome and metabolites critical to ALS progression. These studies will help us to develop more accurate diagnosis and better treatment not only for this challenging disease, but also for other neurodegenerative diseases.}, }
@article {pmid35359573, year = {2022}, author = {Ni, YQ and Xu, H and Liu, YS}, title = {Roles of Long Non-coding RNAs in the Development of Aging-Related Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {844193}, pmid = {35359573}, issn = {1662-5099}, abstract = {Aging-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.}, }
@article {pmid35353593, year = {2022}, author = {Brewah, H and Borrett, K and Tavares, N and Jarrett, N}, title = {Perceptions of people with motor neurone disease, families and HSCPs: a literature review.}, journal = {British journal of community nursing}, volume = {27}, number = {4}, pages = {188-198}, doi = {10.12968/bjcn.2022.27.4.188}, pmid = {35353593}, issn = {1462-4753}, mesh = {*COVID-19 ; Humans ; *Motor Neuron Disease ; Pandemics ; Social Support ; Social Work ; }, abstract = {Motor neurone disease or amyotrophic lateral sclerosis is a rapidly progressive terminal neurodegenerative condition caused by degeneration of the upper and lower motor neurones in the central nervous system of the brain. The effects of motor neurone disease are multifaceted, leading to many adjustments in everyday life. This literature review asked what the experiences of people living with motor neurone disease was before and during the COVID-19 pandemic and during the COVID-19 pandemic, especially in terms of their condition and the support they received from health and social care services. A key theme identified was lack of knowledge among professionals when they cared for people living with motor neurone disease and their families. This lack of knowledge often resulted in delayed diagnosis and poor standards of care. COVID-19 impacted on the care of people living with motor neurone disease and their families, and there is a paucity of evidence on how services were perceived by these groups during the COVID-19 pandemic. The experiences of people living with motor neurone disease and their families are currently missing in the literature. In conclusion, further studies are required to include care of people living with motor neurone disease and their families.}, }
@article {pmid35352575, year = {2023}, author = {Kutlubaev, MA and Caga, J and Xu, Y and Areprintseva, DK and Pervushina, EV and Kiernan, MC}, title = {Apathy in amyotrophic lateral sclerosis: systematic review and meta-analysis of frequency, correlates, and outcomes.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {1-2}, pages = {14-23}, doi = {10.1080/21678421.2022.2053721}, pmid = {35352575}, issn = {2167-9223}, mesh = {Humans ; *Apathy ; *Amyotrophic Lateral Sclerosis/diagnosis ; Brain ; *Cognitive Dysfunction ; Prognosis ; }, abstract = {Objectives: To determine the frequency and correlates of apathy in amyotrophic lateral sclerosis (ALS) and its influence on the prognosis of the disease.Methods: Three databases were searched: MEDLINE, PubMed, and Google Scholar. Quantitative synthesis of the frequency of apathy in ALS was conducted using random effects in Stata (College Station, TX). Meta-regression and subgroup analyses were conducted to investigate the association between frequency of apathy in ALS and different covariates.Results: Fifty-two studies (51 cohorts) were included in the analysis. The pooled frequency of apathy in ALS was 25% (95% confidence interval (CI) 14-35%) according to the studies that used self-rated tools and 34% (95% CI 27-41%) according to studies that used informant-rated tools. The emergence of apathy was associated with cognitive decline and bulbar onset of the disease. There was no consistent relationship between apathy and disease stage or the severity of depression. Structural brain imaging studies established that ALS patients with apathy exhibited more prominent changes with structural and functional brain imaging particularly involving fronto-subcortical regions of the brain. Overall, apathy worsened the long-term prognosis of ALS.Discussion: Apathy affects up to a third of ALS patients аnd develops in the context of progressive neurodegeneration. Increased awareness and understanding of non-motor symptoms in ALS highlights the potential utility of apathy as an outcome measure in future clinical trial design.}, }
@article {pmid35341748, year = {2022}, author = {Bazarek, S and Johnston, BR and Sten, M and Mandeville, R and Eggan, K and Wainger, BJ and Brown, JM}, title = {Spinal motor neuron transplantation to enhance nerve reconstruction strategies: Towards a cell therapy.}, journal = {Experimental neurology}, volume = {353}, number = {}, pages = {114054}, doi = {10.1016/j.expneurol.2022.114054}, pmid = {35341748}, issn = {1090-2430}, mesh = {Axons/physiology ; Cell- and Tissue-Based Therapy ; Humans ; *Induced Pluripotent Stem Cells/transplantation ; Motor Neurons/physiology ; Nerve Regeneration/physiology ; *Spinal Cord Injuries ; }, abstract = {Nerve transfers have become a powerful intervention to restore function following devastating paralyzing injuries. A major limitation to peripheral nerve repair and reconstructive strategies is the progressive, fibrotic degeneration of the distal nerve and denervated muscle, eventually precluding recovery of these targets and thus defining a time window within which reinnervation must occur. One proven strategy in the clinic has been the sacrifice and transfer of an adjacent distal motor nerve to provide axons to occupy, and thus preserve (or "babysit"), the target muscle. However, available nearby nerves are limited in severe brachial plexus or spinal cord injury. An alternative and novel proposition is the transplantation of spinal motor neurons (SMNs) derived from human induced pluripotent stem cells (iPSCs) into the target nerve to extend their axons to occupy and preserve the targets. These cells could potentially be delivered through minimally invasive or percutaneous techniques. Several reports have demonstrated survival, functional innervation, and muscular preservation following transplantation of SMNs into rodent nerves. Advances in the generation, culture, and differentiation of human iPSCs now offer the possibility for an unlimited supply of clinical grade SMNs. This review will discuss the previous reports of peripheral SMN transplantation, outline key considerations, and propose next steps towards advancing this approach to clinic. Stem cells have garnered great enthusiasm for their potential to revolutionize medicine. However, this excitement has often led to premature clinical studies with ill-defined cell products and mechanisms of action, particularly in spinal cord injury. We believe the peripheral transplantation of a defined SMN population to address neuromuscular degeneration will be transformative in augmenting current reconstructive strategies. By thus removing the current barriers of time and distance, this strategy would dramatically enhance the potential for reconstruction and functional recovery in otherwise hopeless paralyzing injuries. Furthermore, this strategy may be used as a permanent axon replacement following destruction of lower motor neurons and would enable exogenous stimulation options, such as pacing of transplanted SMN axons in the phrenic nerve to avoid mechanical ventilation in high cervical cord injury or amyotrophic lateral sclerosis.}, }
@article {pmid35340618, year = {2022}, author = {Sonkodi, B and Hortobágyi, T}, title = {Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes - watch out for Piezo2.}, journal = {Open medicine (Warsaw, Poland)}, volume = {17}, number = {1}, pages = {397-402}, pmid = {35340618}, issn = {2391-5463}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, multisystem neurodegenerative disease that causes the death of motoneurons (MNs) progressively and eventually leads to paralysis. In contrast, delayed onset muscle soreness (DOMS) is defined as delayed onset soreness, muscle stiffness, loss of force-generating capacity, reduced joint range of motion, and decreased proprioceptive function. Sensory deficits and impaired proprioception are common symptoms of both ALS and DOMS, as impairment at the proprioceptive sensory terminals in the muscle spindle is theorized to occur in both. The important clinical distinction is that extraocular muscles (EOM) are relatively spared in ALS, in contrast to limb skeletal muscles; however, the blink reflex goes through a gradual impairment in a later stage of disease progression. Noteworthy is, that, the stretch of EOM induces the blink reflex. The current authors suggest that the impairment of proprioceptive sensory nerve terminals in the EOM muscle spindles are partially responsible for lower blink reflex, beyond central origin, and implies the critical role of Piezo2 ion channels and Wnt-PIP2 signaling in this pathomechanism. The proposed microinjury of Piezo2 on muscle spindle proprioceptive terminals could provide an explanation for the painless dying-back noncontact injury mechanism theory of ALS.}, }
@article {pmid35336787, year = {2022}, author = {Kumari, M and Anji, A}, title = {Small but Mighty-Exosomes, Novel Intercellular Messengers in Neurodegeneration.}, journal = {Biology}, volume = {11}, number = {3}, pages = {}, pmid = {35336787}, issn = {2079-7737}, abstract = {Exosomes of endosomal origin are one class of extracellular vesicles that are important in intercellular communication. Exosomes are released by all cells in our body and their cargo consisting of lipids, proteins and nucleic acids has a footprint reflective of their parental origin. The exosomal cargo has the power to modulate the physiology of recipient cells in the vicinity of the releasing cells or cells at a distance. Harnessing the potential of exosomes relies upon the purity of exosome preparation. Hence, many methods for isolation have been developed and we provide a succinct summary of several methods. In spite of the seclusion imposed by the blood-brain barrier, cells in the CNS are not immune from exosomal intrusive influences. Both neurons and glia release exosomes, often in an activity-dependent manner. A brief description of exosomes released by different cells in the brain and their role in maintaining CNS homeostasis is provided. The hallmark of several neurodegenerative diseases is the accumulation of protein aggregates. Recent studies implicate exosomes' intercellular communicator role in the spread of misfolded proteins aiding the propagation of pathology. In this review, we discuss the potential contributions made by exosomes in progression of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Understanding contributions made by exosomes in pathogenesis of neurodegeneration opens the field for employing exosomes as therapeutic agents for drug delivery to brain since exosomes do cross the blood-brain barrier.}, }
@article {pmid35334234, year = {2022}, author = {Goutman, SA and Hardiman, O and Al-Chalabi, A and Chió, A and Savelieff, MG and Kiernan, MC and Feldman, EL}, title = {Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {21}, number = {5}, pages = {465-479}, pmid = {35334234}, issn = {1474-4465}, support = {AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01TS000289/ACL/ACL HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; R01 ES030049/ES/NIEHS NIH HHS/United States ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; R01 TS000289/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Genetic Association Studies ; Humans ; Mutation/genetics ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors.}, }
@article {pmid35334233, year = {2022}, author = {Goutman, SA and Hardiman, O and Al-Chalabi, A and Chió, A and Savelieff, MG and Kiernan, MC and Feldman, EL}, title = {Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {21}, number = {5}, pages = {480-493}, pmid = {35334233}, issn = {1474-4465}, support = {R01TS000289/ACL/ACL HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 ES030049/ES/NIEHS NIH HHS/United States ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; R01 TS000289/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers ; Disease Progression ; Electromyography/methods ; Humans ; Prognosis ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.}, }
@article {pmid35334073, year = {2022}, author = {Yin, P and Li, S and Li, XJ and Yang, W}, title = {New pathogenic insights from large animal models of neurodegenerative diseases.}, journal = {Protein &amp; cell}, volume = {13}, number = {10}, pages = {707-720}, pmid = {35334073}, issn = {1674-8018}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; Brain/pathology ; Disease Models, Animal ; Gene Editing ; *Neurodegenerative Diseases/genetics/pathology ; Swine ; }, abstract = {Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.}, }
@article {pmid35330152, year = {2022}, author = {Garone, C and Pietra, A and Nesci, S}, title = {From the Structural and (Dys)Function of ATP Synthase to Deficiency in Age-Related Diseases.}, journal = {Life (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {35330152}, issn = {2075-1729}, support = {RLM2017//Italian Minister of University and Research - Rita Levi Montalcini Program - Rientro cervelli/ ; 2021.0058//CARISBO Foundation/ ; 2021.0173//CARISBO Foundation/ ; }, abstract = {The ATP synthase is a mitochondrial inner membrane complex whose function is essential for cell bioenergy, being responsible for the conversion of ADP into ATP and playing a role in mitochondrial cristae morphology organization. The enzyme is composed of 18 protein subunits, 16 nuclear DNA (nDNA) encoded and two mitochondrial DNA (mtDNA) encoded, organized in two domains, FO and F1. Pathogenetic variants in genes encoding structural subunits or assembly factors are responsible for fatal human diseases. Emerging evidence also underlines the role of ATP-synthase in neurodegenerative diseases as Parkinson's, Alzheimer's, and motor neuron diseases such as Amyotrophic Lateral Sclerosis. Post-translational modification, epigenetic modulation of ATP gene expression and protein level, and the mechanism of mitochondrial transition pore have been deemed responsible for neuronal cell death in vivo and in vitro models for neurodegenerative diseases. In this review, we will explore ATP synthase assembly and function in physiological and pathological conditions by referring to the recent cryo-EM studies and by exploring human disease models.}, }
@article {pmid35328666, year = {2022}, author = {Ribarič, S}, title = {Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer's Disease Patients.}, journal = {International journal of molecular sciences}, volume = {23}, number = {6}, pages = {}, pmid = {35328666}, issn = {1422-0067}, support = {P3-0171//Slovenian Research Agency/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis ; Animals ; *Cognitive Dysfunction/metabolism ; Exercise ; Humans ; Inflammation/drug therapy ; Neuroinflammatory Diseases ; *Parkinson Disease ; }, abstract = {This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer's disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual's mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.}, }
@article {pmid35327513, year = {2022}, author = {Gagliardi, D and Pagliari, E and Meneri, M and Melzi, V and Rizzo, F and Comi, GP and Corti, S and Taiana, M and Nizzardo, M}, title = {Stathmins and Motor Neuron Diseases: Pathophysiology and Therapeutic Targets.}, journal = {Biomedicines}, volume = {10}, number = {3}, pages = {}, pmid = {35327513}, issn = {2227-9059}, support = {2020-3623//Fondazione Cariplo/ ; Grant Call 2019//SMA Europe/ ; Ricerca Corrente//Ministero della Salute/ ; }, abstract = {Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some of the main players underlying the pathogenesis of these disorders. Microtubules are key components of the neuronal cytoskeleton characterized by dynamic instability, switching between rapid polymerization and shrinkage. Proteins of the stathmin family affect microtubule dynamics regulating the assembly and the dismantling of tubulin. Stathmin-2 (STMN2) is one of the most abundantly expressed genes in MNs. Following axonal injury, STMN2 expression is upregulated, and the protein is transported toward the growth cones of regenerating axons. STMN2 has a critical role in axonal maintenance, and its dysregulation plays an important role in neurodegenerative processes. Stathmin-1 (STMN1) is a ubiquitous protein that is highly expressed during the development of the nervous system, and its phosphorylation controls microtubule dynamics. In the present review, we summarize what is currently known about the involvement of stathmin alterations in MNDs and the potential therapeutic effect of their modulation, with a specific focus on the most common forms of MND, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).}, }
@article {pmid35326500, year = {2022}, author = {Dorn, GW and Dang, X}, title = {Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.}, journal = {Cells}, volume = {11}, number = {6}, pages = {}, pmid = {35326500}, issn = {2073-4409}, support = {R35 HL135736/HL/NHLBI NIH HHS/United States ; R42NS115184/NH/NIH HHS/United States ; R35135736/NH/NIH HHS/United States ; Research Grant//Muscular Dystrophy Association/ ; }, mesh = {*Charcot-Marie-Tooth Disease ; *Friedreich Ataxia ; Humans ; Mitochondria/physiology ; Mitochondrial Dynamics ; *Neurodegenerative Diseases/genetics ; }, abstract = {Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich's ataxia, dominant optic atrophy, and Alzheimer's, Huntington's, and Parkinson's diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis.}, }
@article {pmid35326301, year = {2022}, author = {Jopowicz, A and Wiśniowska, J and Tarnacka, B}, title = {Cognitive and Physical Intervention in Metals' Dysfunction and Neurodegeneration.}, journal = {Brain sciences}, volume = {12}, number = {3}, pages = {}, pmid = {35326301}, issn = {2076-3425}, abstract = {Metals-especially iron, copper and manganese-are important elements of brain functions and development. Metal-dysregulation homeostasis is associated with brain-structure damage to the motor, cognitive and emotional systems, and leads to neurodegenerative processes. There is more and more evidence that specialized cognitive and motor exercises can enhance brain function and attenuate neurodegeneration in mechanisms, such as improving neuroplasticity by altering the synaptic structure and function in many brain regions. Psychological and physical methods of rehabilitation are now becoming increasingly important, as pharmacological treatments for movement, cognitive and emotional symptoms are limited. The present study describes physical and cognitive rehabilitation methods of patients associated with metal-induced neurotoxicity such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and Wilson's disease. In our review, we describe physical (e.g., virtual-reality environments, robotic-assists training) and psychological (cognitive training, cognitive stimulation, neuropsychological rehabilitation and cognitive-behavioral and mindfulness-based therapies) methods, significantly improving the quality of life and independence of patients associated with storage diseases. Storage diseases are a diverse group of hereditary metabolic defects characterized by the abnormal cumulation of storage material in cells. This topic is being addressed due to the fact that rehabilitation plays a vital role in the treatment of neurodegenerative diseases. Unfortunately so far there are no specific guidelines concerning physiotherapy in neurodegenerative disorders, especially in regards to duration of exercise, type of exercise and intensity, as well as frequency of exercise. This is in part due to the variety of symptoms of these diseases and the various levels of disease progression. This further proves the need for more research to be carried out on the role of exercise in neurodegenerative disorder treatment.}, }
@article {pmid35323676, year = {2022}, author = {Candelise, N and Salvatori, I and Scaricamazza, S and Nesci, V and Zenuni, H and Ferri, A and Valle, C}, title = {Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship.}, journal = {Metabolites}, volume = {12}, number = {3}, pages = {}, pmid = {35323676}, issn = {2218-1989}, support = {HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 2018//French Muscular Dystrophy Association/ ; 21021//French Muscular Dystrophy Association/ ; RF2019-12369105//Ministry of Health, Italy/ ; PGR01040//Ministry of Health, Italy-United States of America/ ; Individual Grant 2021//Fondazione Umberto Veronesi/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu-Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial "metabolic threshold", which may appear pivotal in ALS pathogenesis.}, }
@article {pmid35321094, year = {2022}, author = {Bjork, RT and Mortimore, NP and Loganathan, S and Zarnescu, DC}, title = {Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {840357}, pmid = {35321094}, issn = {1662-4548}, support = {R01 NS091299/NS/NINDS NIH HHS/United States ; R21 NS115514/NS/NINDS NIH HHS/United States ; }, abstract = {Local control of gene expression provides critical mechanisms for regulating development, maintenance and plasticity in the nervous system. Among the strategies known to govern gene expression locally, mRNA transport and translation have emerged as essential for a neuron's ability to navigate developmental cues, and to establish, strengthen and remove synaptic connections throughout lifespan. Substantiating the role of RNA processing in the nervous system, several RNA binding proteins have been implicated in both developmental and age dependent neurodegenerative disorders. Of these, TDP-43 is an RNA binding protein that has emerged as a common denominator in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related disorders due to the identification of causative mutations altering its function and its accumulation in cytoplasmic aggregates observed in a significant fraction of ALS/FTD cases, regardless of etiology. TDP-43 is involved in multiple aspects of RNA processing including splicing, transport and translation. Given that one of the early events in disease pathogenesis is mislocalization from the nucleus to the cytoplasm, several studies have focused on elucidating the pathogenic role of TDP-43 in cytoplasmic translation. Here we review recent findings describing TDP-43 translational targets and potential mechanisms of translation dysregulation in TDP-43 proteinopathies across multiple experimental models including cultured cells, flies, mice and patient derived neurons.}, }
@article {pmid35320398, year = {2022}, author = {Carlos, AF and Josephs, KA}, title = {Frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43): its journey of more than 100 years.}, journal = {Journal of neurology}, volume = {269}, number = {8}, pages = {4030-4054}, pmid = {35320398}, issn = {1432-1459}, support = {R01 AG037491/AG/NIA NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Brain/pathology ; *DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/genetics ; *Frontotemporal Lobar Degeneration/genetics/pathology ; Humans ; *Neurodegenerative Diseases/genetics ; Ubiquitin/metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) with TDP-43-immunoreactive inclusions (FTLD-TDP) is a neurodegenerative disease associated with clinical, genetic, and neuropathological heterogeneity. An association between TDP-43, FTLD and amyotrophic lateral sclerosis (ALS) was first described in 2006. However, a century before immunohistochemistry existed, atypical dementias displaying behavioral, language and/or pyramidal symptoms and showing non-specific FTLD with superficial cortical neuronal loss, gliosis and spongiosis were often confused with Alzheimer's or Pick's disease. Initially this pathology was termed dementia lacking distinctive histopathology (DLDH), but this was later renamed when ubiquitinated inclusions originally found in ALS were also discovered in (DLDH), thus warranting a recategorization as FTLD-U (ubiquitin). Finally, the ubiquitinated protein was identified as TDP-43, which aggregates in cortical, subcortical, limbic and brainstem neurons and glial cells. The topography and morphology of TDP-43 inclusions associate with specific clinical syndromes and genetic mutations which implies different pathomechanisms that are yet to be discovered; hence, the TDP-43 journey has actually just begun. In this review, we describe how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.}, }
@article {pmid35309870, year = {2022}, author = {Erdmann, A and Spoden, C and Hirschberg, I and Neitzke, G}, title = {Talking about the end of life: communication patterns in amyotrophic lateral sclerosis - a scoping review.}, journal = {Palliative care and social practice}, volume = {16}, number = {}, pages = {26323524221083676}, pmid = {35309870}, issn = {2632-3524}, abstract = {Amyotrophic lateral sclerosis (ALS) leads to death on average 2-4 years after the onset of symptoms. Although many people with the disease decide in favour of life-sustaining measures, some consider hastening death. The objectives of this review are to provide an insight into the following questions: (1) How do people with amyotrophic lateral sclerosis (PALS), their families and health care professionals (HCPs) communicate about life-sustaining and life-shortening options? (2) What are the challenges for all involved in decision making and communication about this topic? To answer these questions, we searched eight databases for publications in English and German on end-of-life issues of PALS. We included texts published between 2008 and 2018, and updated our search to May 2020. Sources were analysed in MAXQDA using deductively and inductively generated codes. After the final analysis, 123 full texts were included in this review. We identified a wide range of communicative challenges and six different and, in part, opposite communication patterns: avoiding or delaying communication on end-of-life issues, openly considering dying and actively seeking assistance, ignoring or disregarding patients' wishes, discussing and respecting the patients' wishes, engaging in advance care planning and avoiding or delaying advance care planning. The literature reveals a very heterogeneous response to end-of-life issues in ALS, despite several good-practice suggestions, examples and guidelines. We derive a strong need for harmonization and quality assurance concerning communication with PALS. Avoiding or delaying communication, decision making and planning, as well as ignoring or disregarding the patient's will by HCP can be judged as a violation of the ethical principles of autonomy and non-maleficence.}, }
@article {pmid35304941, year = {2022}, author = {Kehrer-Sawatzki, H and Bäzner, U and Krämer, J and Lewerenz, J and Pfeiffer, C}, title = {Das NF1-Mikrodeletions-Syndrom: Die frühzeitige genetische Diagnose erleichtert den Umgang mit einer klinisch definierten Erkrankung.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {20}, number = {3}, pages = {273-278}, doi = {10.1111/ddg.14707_g}, pmid = {35304941}, issn = {1610-0387}, abstract = {Neurofibromatose Typ-1 (NF1) ist ein Genodermatose, die häufig in der Dermatologie behandelt wird. Bei vielen Patienten mit NF1 wird die Diagnose aufgrund klinischer Merkmale erstellt wie Café-au-Lait-Flecken, Freckling und plexiformen Neurofibromen, die schon während der frühen Kindheit auftreten können. Später im Leben sind oft kutane Neurofibrome weitere wichtige diagnostische Merkmale. Die NF1 ist durch ausgeprägte klinische Variabilität und eine breite Heterogenität der NF1-Genmutationen charakterisiert, was Genotyp/Phänotyp-Korrelationen erschwert. Wichtige Ausnahmen sind NF1-Mikrodeletionen, die bei 5-11 % aller NF1-Patienten auftreten. Patienten mit NF1-Mikrodeletionen zeigen häufig spezifische Merkmale wie Gesichtsdysmorphien und sind von großer Statur. Zudem sind früh auftretende kutane und subkutane Neurofibrome, schwere Entwicklungsverzögerungen in multiplen Bereichen sowie kognitive Einschränkungen pathognomonisch für das NF1-Mikrodeletions-Syndrom. Darüber hinaus sind NF1-Mikrodeletionen mit einem Risiko für maligne periphere Nervenscheidentumoren assoziiert, das etwa zweifach höher ist als bei intragenischen NF1-Mutationen. Die schweren klinischen Manifestationen bei Patienten mit NF1-Mikrodeletionen machen eine frühe multidisziplinäre klinische Betreuung und häufige Tumor-Überwachung der Patienten notwendig. Wenn bei einem Patienten Red-Flag-Symptome für das NF1-Mikrodeletions-Syndrom auftreten, ist eine frühzeitige genetische Untersuchung notwendig, um eine NF1-Mikrodeletion zu bestätigen oder auszuschließen.}, }
@article {pmid35303907, year = {2022}, author = {Masrori, P and Beckers, J and Gossye, H and Van Damme, P}, title = {The role of inflammation in neurodegeneration: novel insights into the role of the immune system in C9orf72 HRE-mediated ALS/FTD.}, journal = {Molecular neurodegeneration}, volume = {17}, number = {1}, pages = {22}, pmid = {35303907}, issn = {1750-1326}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/pathology ; Humans ; Immune System ; Inflammation/genetics ; }, abstract = {Neuroinflammation is an important hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). An inflammatory reaction to neuronal injury is deemed vital for neuronal health and homeostasis. However, a continued activation of the inflammatory response can be detrimental to remaining neurons and aggravate the disease process. Apart from a disease modifying role, some evidence suggests that neuroinflammation may also contribute to the upstream cause of the disease. In this review, we will first focus on the role of neuroinflammation in the pathogenesis of chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansions (HRE)-mediated ALS/FTD (C9-ALS/FTD). Additionally, we will discuss evidence from ex vivo and in vivo studies and finally, we briefly summarize the trials and progress of anti-inflammatory therapies.}, }
@article {pmid35302047, year = {2022}, author = {Gallego, I and Villate-Beitia, I and Saenz-Del-Burgo, L and Puras, G and Pedraz, JL}, title = {Therapeutic Opportunities and Delivery Strategies for Brain Revascularization in Stroke, Neurodegeneration, and Aging.}, journal = {Pharmacological reviews}, volume = {74}, number = {2}, pages = {439-461}, doi = {10.1124/pharmrev.121.000418}, pmid = {35302047}, issn = {1521-0081}, mesh = {Aging ; *Alzheimer Disease ; *Central Nervous System Diseases ; *Cerebral Revascularization ; Humans ; *Stroke/therapy ; }, abstract = {Central nervous system (CNS) diseases, especially acute ischemic events and neurodegenerative disorders, constitute a public health problem with no effective treatments to allow a persistent solution. Failed therapies targeting neuronal recovery have revealed the multifactorial and intricate pathophysiology underlying such CNS disorders as ischemic stroke, Alzheimeŕs disease, amyotrophic lateral sclerosis, vascular Parkisonism, vascular dementia, and aging, in which cerebral microvasculature impairment seems to play a key role. In fact, a reduction in vessel density and cerebral blood flow occurs in these scenarios, contributing to neuronal dysfunction and leading to loss of cognitive function. In this review, we provide an overview of healthy brain microvasculature structure and function in health and the effect of the aforementioned cerebral CNS diseases. We discuss the emerging new therapeutic opportunities, and their delivery approaches, aimed at recovering brain vascularization in this context. SIGNIFICANCE STATEMENT: The lack of effective treatments, mainly focused on neuron recovery, has prompted the search of other therapies to treat cerebral central nervous system diseases. The disruption and degeneration of cerebral microvasculature has been evidenced in neurodegenerative diseases, stroke, and aging, constituting a potential target for restoring vascularization, neuronal functioning, and cognitive capacities by the development of therapeutic pro-angiogenic strategies.}, }
@article {pmid35291879, year = {2022}, author = {Jha, NK and Chen, WC and Kumar, S and Dubey, R and Tsai, LW and Kar, R and Jha, SK and Gupta, PK and Sharma, A and Gundamaraju, R and Pant, K and Mani, S and Singh, SK and Maccioni, RB and Datta, T and Singh, SK and Gupta, G and Prasher, P and Dua, K and Dey, A and Sharma, C and Mughal, YH and Ruokolainen, J and Kesari, KK and Ojha, S}, title = {Molecular mechanisms of developmental pathways in neurological disorders: a pharmacological and therapeutic review.}, journal = {Open biology}, volume = {12}, number = {3}, pages = {210289}, pmid = {35291879}, issn = {2046-2441}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/metabolism ; Blood-Brain Barrier/metabolism ; Hedgehog Proteins/metabolism ; Humans ; *Nervous System Diseases/drug therapy/etiology/metabolism ; Signal Transduction ; }, abstract = {Developmental signalling pathways such as Wnt/β-catenin, Notch and Sonic hedgehog play a central role in nearly all the stages of neuronal development. The term 'embryonic' might appear to be a misnomer to several people because these pathways are functional during the early stages of embryonic development and adulthood, albeit to a certain degree. Therefore, any aberration in these pathways or their associated components may contribute towards a detrimental outcome in the form of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke. In the last decade, researchers have extensively studied these pathways to decipher disease-related interactions, which can be used as therapeutic targets to improve outcomes in patients with neurological abnormalities. However, a lot remains to be understood in this domain. Nevertheless, there is strong evidence supporting the fact that embryonic signalling is indeed a crucial mechanism as is manifested by its role in driving memory loss, motor impairments and many other processes after brain trauma. In this review, we explore the key roles of three embryonic pathways in modulating a range of homeostatic processes such as maintaining blood-brain barrier integrity, mitochondrial dynamics and neuroinflammation. In addition, we extensively investigated the effect of these pathways in driving the pathophysiology of a range of disorders such as Alzheimer's, Parkinson's and diabetic neuropathy. The concluding section of the review is dedicated to neurotherapeutics, wherein we identify and list a range of biological molecules and compounds that have shown enormous potential in improving prognosis in patients with these disorders.}, }
@article {pmid35281504, year = {2022}, author = {Garrett, LR and Niccoli, T}, title = {Frontotemporal Dementia and Glucose Metabolism.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {812222}, pmid = {35281504}, issn = {1662-4548}, support = {MR/V003585/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Frontotemporal dementia (FTD), hallmarked by antero-temporal degeneration in the human brain, is the second most common early onset dementia. FTD is a diverse disease with three main clinical presentations, four different identified proteinopathies and many disease-associated genes. The exact pathophysiology of FTD remains to be elucidated. One common characteristic all forms of FTD share is the dysregulation of glucose metabolism in patients' brains. The brain consumes around 20% of the body's energy supply and predominantly utilizes glucose as a fuel. Glucose metabolism dysregulation could therefore be extremely detrimental for neuronal health. Research into the association between glucose metabolism and dementias has recently gained interest in Alzheimer's disease. FTD also presents with glucose metabolism dysregulation, however, this remains largely an unexplored area. A better understanding of the link between FTD and glucose metabolism may yield further insight into FTD pathophysiology and aid the development of novel therapeutics. Here we review our current understanding of FTD and glucose metabolism in the brain and discuss the evidence of impaired glucose metabolism in FTD. Lastly, we review research potentially suggesting a causal relationship between FTD proteinopathies and impaired glucose metabolism in FTD.}, }
@article {pmid35280341, year = {2021}, author = {Meyer, JH and Braga, J}, title = {Development and Clinical Application of Positron Emission Tomography Imaging Agents for Monoamine Oxidase B.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {773404}, pmid = {35280341}, issn = {1662-4548}, abstract = {Monoamine oxidase B (MAO-B) is a high-density protein in the brain mainly found on outer mitochondrial membranes, primarily in astroglia, but additionally in serotonergic neurons and in the substantia nigra in the midbrain. It is an enzyme that participates in the oxidative metabolism of important monoamines including dopamine, norepinephrine, benzylamine, and phenylethylamine. Elevated MAO-B density may be associated with astrogliosis and inhibiting MAO-B may reduce astrogliosis. MAO-B density is elevated in postmortem sampling of pathology for many neuropsychiatric diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and alcohol use disorder. Initial development of positron emission tomography (PET) imaging agents focused on analogs of [[11]C]L-deprenyl, with the most commonly applied being the deuterium substituted [[11]C]L-deprenyl-D2. This latter radiotracer was modeled with an irreversible trapping compartment reflecting its irreversible binding to MAO-B. Subsequently, [[11]C]SL25.1188, a reversible binding MAO-B radioligand with outstanding properties including high specific binding and excellent reversibility was developed. [[11]C]SL25.1188 PET was applied to discover a substantive elevation of MAO-B binding in the prefrontal cortex in major depressive disorder (MDD) with an effect size of more than 1.5. Longer duration of MDD was associated with greater MAO-B binding throughout most gray matter regions in the brain, suggesting progressive astrogliosis. Important applications of [[11]C]L-deprenyl-D2 PET are detecting a 40% loss in radiotracer accumulation in cigarette smokers, and substantial occupancy of novel therapeutics like EVT301 and sembragiline. Given the number of diseases with elevations of MAO-B density and astrogliosis, and the advance of [[11]C]SL25.1188, clinical applications of MAO-B imaging are still at an early stage.}, }
@article {pmid35273561, year = {2022}, author = {Scarian, E and Fiamingo, G and Diamanti, L and Palmieri, I and Gagliardi, S and Pansarasa, O}, title = {The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {841394}, pmid = {35273561}, issn = {1664-2295}, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurological diseases which, respectively, and primarily affect motor neurons and frontotemporal lobes. Although they can lead to different signs and symptoms, it is now evident that these two pathologies form a continuum and that hallmarks of both diseases can be present within the same person in the so-called ALS-FTD spectrum. Many studies have focused on the genetic overlap of these pathologies and it is now clear that different genes, such as C9orf72, TARDBP, SQSTM1, FUS, and p97/VCP can be mutated in both the diseases. VCP was one of the first genes associated with both FTD and ALS representing an early example of gene overlapping. VCP belongs to the type II AAA (ATPases Associated with diverse cellular activities) family and is involved in ubiquitinated proteins degradation, autophagy, lysosomal clearance and mitochondrial quality control. Since its numerous roles, mutations in this gene lead to different pathological features, first and foremost TDP-43 mislocalization. This review aims to outline recent findings on VCP roles and on how its mutations are linked to the neuropathology of ALS and FTD.}, }
@article {pmid35272595, year = {2022}, author = {Chavda, VP and Patel, C and Modh, D and Ertas, YN and Sonak, SS and Munshi, NK and Anand, K and Soni, A and Pande, S}, title = {Therapeutic Approaches to Amyotrophic Lateral Sclerosis from the Lab to the Clinic.}, journal = {Current drug metabolism}, volume = {23}, number = {3}, pages = {200-222}, doi = {10.2174/1389200223666220310113110}, pmid = {35272595}, issn = {1875-5453}, support = {118C346//T&#xdc;B&#x130;TAK/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Animals ; Genetic Therapy ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a terminal neuro-degenerative disorder that is clinically recognized as a gradual degeneration of the upper and lower motor neurons, with an average duration of 3 to 5 years from initial of symptoms to death. The mechanisms underlying the pathogenesis and progression of the disease are multifactorial. Therefore, to find effective treatments, it is necessary to understand the heterogeneity underlying the progression of ALS. Recent developments in gene therapy have opened a new avenue to treat this condition, especially for the characterized genetic types. Gene therapy methods have been studied in various pre-clinical settings and clinical trials, and they may be a promising path for developing an effective and safe ALS cure. A growing body of evidence demonstrates abnormalities in metabolic energy at the cellular and whole-body level in animal models and people living with ALS. Using and incorporatig high-throughput "omics" methods have radically transformed our thoughts about ALS, strengthened our understanding of the disease's dynamic molecular architecture, differentiated distinct patient subtypes, and created a reasonable basis for identifying biomarkers and novel individualised treatments. Future clinical and laboratory trials would also focus on the diverse relationships between metabolism and ALS to address the issue of whether targeting poor metabolism in ALS is an effective way to change disease progression. In this review, we focus on the detailed pathogenesis of ALS and highlight principal genes, i.e., SOD1, TDP-43, C9orf72, and FUS, as well as targeted ALS therapies. An attempt is made to provide up-to-date clinical outcomes, including various biomarkers that are thought to be important players in early ALS detection.}, }
@article {pmid35269723, year = {2022}, author = {Pansarasa, O and Garofalo, M and Scarian, E and Dragoni, F and Garau, J and Di Gerlando, R and Diamanti, L and Bordoni, M and Gagliardi, S}, title = {Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35269723}, issn = {1422-0067}, support = {GR-2016-02361552//Ministero della Salute/ ; RC2020-2021//Ministero della Salute/ ; MLOpathy//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Biomarkers/metabolism ; Humans ; Leukocytes, Mononuclear/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the progressive loss of lower motor neurons, weakness and muscle atrophy. ALS lacks an effective cure and diagnosis is often made by exclusion. Thus, it is imperative to search for biomarkers. Biomarkers can help in understanding ALS pathomechanisms, identification of targets for treatment and development of effective therapies. Peripheral blood mononuclear cells (PBMCs) represent a valid source for biomarkers compared to cerebrospinal fluid, as they are simple to collect, and to plasma, because of the possibility of detecting lower expressed proteins. They are a reliable model for patients' stratification. This review provides an overview on PBMCs as a potential source of biomarkers in ALS. We focused on altered RNA metabolism (coding/non-coding RNA), including RNA processing, mRNA stabilization, transport and translation regulation. We addressed protein abnormalities (aggregation, misfolding and modifications); specifically, we highlighted that SOD1 appears to be the most characterizing protein in ALS. Finally, we emphasized the correlation between biological parameters and disease phenotypes, as regards prognosis, severity and clinical features. In conclusion, even though further studies are needed to standardize the use of PBMCs as a tool for biomarker investigation, they represent a promising approach in ALS research.}, }
@article {pmid35269543, year = {2022}, author = {Sever, B and Ciftci, H and DeMirci, H and Sever, H and Ocak, F and Yulug, B and Tateishi, H and Tateishi, T and Otsuka, M and Fujita, M and Başak, AN}, title = {Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35269543}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Combined Modality Therapy/*methods ; Deep Brain Stimulation ; Drug Discovery ; Edaravone/therapeutic use ; Humans ; Induced Pluripotent Stem Cells/transplantation ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.}, }
@article {pmid35268572, year = {2022}, author = {Arslanbaeva, L and Bisaglia, M}, title = {Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {5}, pages = {}, pmid = {35268572}, issn = {1420-3049}, support = {PG_25_2020//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {*NF-E2-Related Factor 2 ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal disease that causes motoneurons degeneration and functional impairment of voluntary muscles, with limited and poorly efficient therapies. Alterations in the Nrf2-ARE pathway are associated with ALS pathology and result in aberrant oxidative stress, making the stimulation of the Nrf2-mediated antioxidant response a promising therapeutic strategy in ALS to reduce oxidative stress. In this review, we first introduce the involvement of the Nrf2 pathway in the pathogenesis of ALS and the role played by astrocytes in modulating such a protective pathway. We then describe the currently developed activators of Nrf2, used in both preclinical animal models and clinical studies, taking into consideration their potentialities as well as the possible limitations associated with their use.}, }
@article {pmid35265969, year = {2022}, author = {Smethurst, P and Franklin, H and Clarke, BE and Sidle, K and Patani, R}, title = {The role of astrocytes in prion-like mechanisms of neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {145}, number = {1}, pages = {17-26}, pmid = {35265969}, issn = {1460-2156}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Astrocytes/metabolism ; Humans ; *Neurodegenerative Diseases/pathology ; *Prion Diseases/pathology ; *Prions/metabolism ; Protein Aggregates ; Protein Folding ; }, abstract = {Accumulating evidence suggests that neurodegenerative diseases are not merely neuronal in nature but comprise multicellular involvement, with astrocytes emerging as key players. The pathomechanisms of several neurodegenerative diseases involve the deposition of misfolded protein aggregates in neurons that have characteristic prion-like behaviours such as template-directed seeding, intercellular propagation, distinct conformational strains and protein-mediated toxicity. The role of astrocytes in dealing with these pathological prion-like protein aggregates and whether their responses either protect from or conspire with the disease process is currently unclear. Here we review the existing literature implicating astrocytes in multiple neurodegenerative proteinopathies with a focus on prion-like behaviour in this context.}, }
@article {pmid35262502, year = {2022}, author = {Gopal, A and Hsu, WY and Allen, DD and Bove, R}, title = {Remote Assessments of Hand Function in Neurological Disorders: Systematic Review.}, journal = {JMIR rehabilitation and assistive technologies}, volume = {9}, number = {1}, pages = {e33157}, pmid = {35262502}, issn = {2369-2529}, abstract = {BACKGROUND: Loss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted.<br><br>OBJECTIVE: Remote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction.<br><br>METHODS: PubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development.<br><br>RESULTS: In total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were heterogeneous across studies, statistically significant correlations with traditional in-clinic metrics were most commonly reported for telerehabilitation and smartphone or tablet apps. The most readily implementable assessments were smartphone or tablet-based.<br><br>CONCLUSIONS: The findings show that remote assessment of hand function is feasible in neurological disorders. Although varied, the assessments allow clinicians to objectively record performance in multiple hand function domains, improving the reliability of traditional in-clinic assessments. Remote assessments, particularly via telerehabilitation and smartphone- or tablet-based apps that align with in-clinic metrics, facilitate clinic to home transitions, have few barriers to implementation, and prompt remote identification and treatment of hand function impairments.}, }
@article {pmid35262473, year = {2023}, author = {Hoekstra, F and Trigo, F and Sibley, KM and Graham, ID and Kennefick, M and Mrklas, KJ and Nguyen, T and Vis-Dunbar, M and ,  and Gainforth, HL}, title = {Systematic overviews of partnership principles and strategies identified from health research about spinal cord injury and related health conditions: A scoping review.}, journal = {The journal of spinal cord medicine}, volume = {46}, number = {4}, pages = {614-631}, pmid = {35262473}, issn = {2045-7723}, mesh = {Humans ; *Cerebral Palsy ; *Parkinson Disease ; *Spinal Cord Injuries ; *Multiple Sclerosis ; }, abstract = {STUDY DESIGN: Scoping review.<br><br>OBJECTIVE: To identify and provide systematic overviews of partnership principles and strategies identified from health research about spinal cord injury (SCI) and related health conditions.<br><br>METHODS: Four health electronic databases (Medline, Embase, CINAHL, PsycINFO) were searched from inception to March 2019. We included articles that described, reflected, and/or evaluated one or more collaborative research activities in health research about SCI, stroke, multiple sclerosis, Parkinson's disease, amputation, cerebral palsy, spina bifida, amyotrophic lateral sclerosis, acquired brain injury, or wheelchair-users. Partnership principles (i.e. norms or values) and strategies (i.e. observable actions) were extracted and analyzed using directed qualitative content analysis.<br><br>RESULTS: We included 39 articles about SCI (n&#x2009;=&#x2009;13), stroke (n&#x2009;=&#x2009;15), multiple sclerosis (n&#x2009;=&#x2009;5), amputation (n&#x2009;=&#x2009;2), cerebral palsy (n&#x2009;=&#x2009;2), Parkinson's disease (n&#x2009;=&#x2009;1), and wheelchair users (n&#x2009;=&#x2009;1). We extracted 110 principles and synthesized them into 13 overarching principles. Principles related to building and maintaining relationships between researchers and research users were most frequently reported. We identified 32 strategies that could be applied at various phases of the research process and 26 strategies that were specific to a research phase (planning, conduct, or dissemination).<br><br>CONCLUSION: We provided systematic overviews of principles and strategies for research partnerships. These could be used by researchers and research users who want to work in partnership to plan, conduct and/or disseminate their SCI research. The findings informed the development of the new SCI Integrated Knowledge Translation Guiding Principles (www.iktprinciples.com) and will support the implementation of these Principles within the SCI research system.}, }
@article {pmid35260846, year = {2022}, author = {Todd, TW and Petrucelli, L}, title = {Modelling amyotrophic lateral sclerosis in rodents.}, journal = {Nature reviews. Neuroscience}, volume = {23}, number = {4}, pages = {231-251}, pmid = {35260846}, issn = {1471-0048}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; Disease Models, Animal ; Humans ; Mutation/genetics ; Rodentia ; }, abstract = {The efficient study of human disease requires the proper tools, one of the most crucial of which is an accurate animal model that faithfully recapitulates the human condition. The study of amyotrophic lateral sclerosis (ALS) is no exception. Although the majority of ALS cases are considered sporadic, most animal models of this disease rely on genetic mutations identified in familial cases. Over the past decade, the number of genes associated with ALS has risen dramatically and, with each new genetic variant, there is a drive to develop associated animal models. Rodent models are of particular importance as they allow for the study of ALS in the context of a living mammal with a comparable CNS. Such models not only help to verify the pathogenicity of novel mutations but also provide critical insight into disease mechanisms and are crucial for the testing of new therapeutics. In this Review, we aim to summarize the full spectrum of ALS rodent models developed to date.}, }
@article {pmid35259819, year = {2022}, author = {Langlie, J and Mittal, R and Finberg, A and Bencie, NB and Mittal, J and Omidian, H and Omidi, Y and Eshraghi, AA}, title = {Unraveling pathological mechanisms in neurological disorders: the impact of cell-based and organoid models.}, journal = {Neural regeneration research}, volume = {17}, number = {10}, pages = {2131-2140}, pmid = {35259819}, issn = {1673-5374}, abstract = {Cell-based models are a promising tool in deciphering the molecular mechanisms underlying the pathogenesis of neurological disorders as well as aiding in the discovery and development of future drug therapies. The greatest challenge is creating cell-based models that encapsulate the vast phenotypic presentations as well as the underlying genotypic etiology of these conditions. In this article, we discuss the recent advancements in cell-based models for understanding the pathophysiology of neurological disorders. We reviewed studies discussing the progression of cell-based models to the advancement of three-dimensional models and organoids that provide a more accurate model of the pathophysiology of neurological disorders in vivo. The better we understand how to create more precise models of the neurological system, the sooner we will be able to create patient-specific models and large libraries of these neurological disorders. While three-dimensional models can be used to discover the linking factors to connect the varying phenotypes, such models will also help to understand the early pathophysiology of these neurological disorders and how they are affected by their environment. The three-dimensional cell models will allow us to create more specific treatments and uncover potentially preventative measures in neurological disorders such as autism spectrum disorder, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid35257321, year = {2022}, author = {Andrew, RD and Hartings, JA and Ayata, C and Brennan, KC and Dawson-Scully, KD and Farkas, E and Herreras, O and Kirov, SA and Müller, M and Ollen-Bittle, N and Reiffurth, C and Revah, O and Robertson, RM and Shuttleworth, CW and Ullah, G and Dreier, JP}, title = {The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention.}, journal = {Neurocritical care}, volume = {37}, number = {Suppl 1}, pages = {83-101}, pmid = {35257321}, issn = {1556-0961}, support = {P20 GM109089/GM/NIGMS NIH HHS/United States ; R01 NS083858/NS/NINDS NIH HHS/United States ; R01 NS106901/NS/NINDS NIH HHS/United States ; }, mesh = {*Brain Injuries/therapy ; Consensus ; *Cortical Spreading Depression/physiology ; Glutamic Acid ; Humans ; *Stroke ; }, abstract = {BACKGROUND: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD.<br><br>METHODS: In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na[+]/K[+] pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate.<br><br>RESULTS: We discuss how SD has been investigated with various pitfalls&#xa0;in numerous experimental preparations, how overtaxing the Na[+]/K[+] ATPase elicits SD. Elevated K[+] or glutamate are unlikely natural activators of SD.&#xa0;We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling.<br><br>CONCLUSIONS: Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as&#xa0;compared with SD theory.}, }
@article {pmid35257286, year = {2022}, author = {Wasielewska, JM and White, AR}, title = {"Focused Ultrasound-mediated Drug Delivery in Humans - a Path Towards Translation in Neurodegenerative Diseases".}, journal = {Pharmaceutical research}, volume = {39}, number = {3}, pages = {427-439}, pmid = {35257286}, issn = {1573-904X}, mesh = {*Alzheimer Disease ; Blood-Brain Barrier ; Brain ; Drug Delivery Systems ; Humans ; *Induced Pluripotent Stem Cells ; Microbubbles ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {The blood-brain barrier (BBB) has a major protective function in preventing the entry of harmful molecules into the brain, but is simultaneously limiting the delivery of drugs, restricting their potential clinical application in neurodegenerative diseases. Recent preclinical evidence demonstrates that following application of focused ultrasound with microbubbles (FUS+MB), the BBB becomes reversibly accessible to compounds that normally are brain-impermeable, suggesting FUS+MB as a promising new platform for delivery of therapeutic agents into the central nervous system. As a step towards translation, small cohort clinical studies were performed demonstrating safe BBB opening in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) patients following FUS+MB, however improved drug delivery has not yet been achieved in human. Simultaneously, rapid progress in the human induced pluripotent stem cell (hiPSC) modeling technology allowed for development of novel Alzheimer's disease patient-derived BBB in vitro model that reacts to FUS+MB with BBB opening and can be used to answer fundamental questions of human BBB responses to FUS+MB in health and disease. This review summarizes key features of the BBB that contribute to limited drug delivery, recapitulates recent advances in the FUS+MB mediated human BBB opening in vivo and in vitro in the context of neurodegenerative disorders, and highlights potential strategies for fast-track translation of the FUS+MB to improve bioavailability of drugs to the human brain. With safe and effective application, this innovative FUS+MB technology may open new avenues for therapeutic interventions in neurodegenerative diseases leading to improved clinical outcomes for patients.}, }
@article {pmid35250543, year = {2022}, author = {Guo, S and Wang, H and Yin, Y}, title = {Microglia Polarization From M1 to M2 in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {815347}, pmid = {35250543}, issn = {1663-4365}, abstract = {Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there's a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases. Previous studies showed that balancing microglia M1/M2 polarization had a promising therapeutic prospect in neurodegenerative diseases. We suggest that shifting microglia from M1 to M2 may be significant and we focus on the modulation of microglia polarization from M1 to M2, especially by important signal pathways, in neurodegenerative diseases.}, }
@article {pmid35249012, year = {2022}, author = {Qin, K and Xu, S and Han, Y and Wang, S and Yan, J and Shao, X}, title = {Research Progress of Collapse Response Mediator Proteins in Neurodegenerative Diseases.}, journal = {Developmental neuroscience}, volume = {44}, number = {6}, pages = {429-437}, doi = {10.1159/000523875}, pmid = {35249012}, issn = {1421-9859}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Nerve Tissue Proteins/metabolism ; }, abstract = {Collapse response mediator proteins (CRMPs) are a family of cytoplasmic phosphorylated proteins, and the mechanism of action has always been the research focus of neurological diseases. Previous studies on the CRMPs family have revealed that CRMPs mediate the growth and development of neuronal cytoskeleton through different signaling pathways in the body. It plays an important role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, which has attracted the attention of researchers. This article reviews the recent literature on the biological characteristics and mechanisms of CRMPs in different neurodegenerative diseases.}, }
@article {pmid35246032, year = {2022}, author = {O'Day, DH and Huber, RJ}, title = {Calmodulin binding proteins and neuroinflammation in multiple neurodegenerative diseases.}, journal = {BMC neuroscience}, volume = {23}, number = {1}, pages = {10}, pmid = {35246032}, issn = {1471-2202}, mesh = {*Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Calcium/metabolism ; Calmodulin/metabolism ; Calmodulin-Binding Proteins/metabolism ; Humans ; *Neurodegenerative Diseases ; Neuroinflammatory Diseases ; }, abstract = {Calcium dysregulation ("Calcium Hypothesis") is an early and critical event in Alzheimer's and other neurodegenerative diseases. Calcium binds to and regulates the small regulatory protein calmodulin that in turn binds to and regulates several hundred calmodulin binding proteins. Initial and continued research has shown that many calmodulin binding proteins mediate multiple events during the onset and progression of Alzheimer's disease, thus establishing the "Calmodulin Hypothesis". To gain insight into the general applicability of this hypothesis, the involvement of calmodulin in neuroinflammation in Alzheimer's, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, frontotemporal dementia, and other dementias was explored. After a literature search for calmodulin binding, 11 different neuroinflammatory proteins (TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, ABCA1, CH3L1/YKL-40 and NLRP3) were scanned for calmodulin binding domains using the Calmodulin Target Database. This analysis revealed the presence of at least one binding domain within which visual scanning demonstrated the presence of valid binding motifs. Coupled with previous research that identified 13 other neuroinflammation linked proteins (BACE1, BIN1, CaMKII, PP2B, PMCA, NOS, NMDAR, AchR, Ado A2AR, Aβ, APOE, SNCA, TMEM175), this work shows that at least 24 critical proteins involved in neuroinflammation are putative or proven calmodulin binding proteins. Many of these proteins are linked to multiple neurodegenerative diseases indicating that calmodulin binding proteins lie at the heart of neuroinflammatory events associated with multiple neurodegenerative diseases. Since many calmodulin-based pharmaceuticals have been successfully used to treat Huntington's and other neurodegenerative diseases, these findings argue for their immediate therapeutic implementation.}, }
@article {pmid35235032, year = {2022}, author = {Diver, EM and Regan, J}, title = {Use of Pharyngeal High-Resolution Manometry to Evaluate Dysphagia in Adults with Motor Neurone Disease: A Scoping Review.}, journal = {Dysphagia}, volume = {37}, number = {6}, pages = {1697-1714}, pmid = {35235032}, issn = {1432-0460}, mesh = {Adult ; Humans ; *Deglutition Disorders/diagnosis/etiology ; Deglutition/physiology ; Manometry/methods ; Pharynx ; *Motor Neuron Disease ; }, abstract = {There has been a recent shift towards proactive dysphagia intervention in motor neurone disease (MND) to maintain physiological reserve. Pharyngeal high-resolution manometry (PHRM) can quantify swallowing pathophysiology to inform and evaluate proactive dysphagia intervention. This study aims to explore the current use of PHRM as a dysphagia evaluation in adults with MND. A scoping review based on the Joanna Briggs Framework was completed. Four electronic databases (PubMed, EMBASE, CINAHL and Web of Science core) were searched (inception to March 2021) by two independent researchers. Data were analysed according to (i) PHRM protocol and analysis methods and the feasibility of same, (ii) swallow biomechanics data and (iii) dysphagia intervention effects as measured by PHRM. Six studies with 78 people with MND (PwMND) were included. There was considerable variation in PHRM protocol and analysis methods. Five studies reported a 100% completion rate and three studies reported no adverse events. Swallow biomechanics data were reported across all studies. The effects of sensory stimulation, increased bolus consistency, effortful swallow and cricopharyngeal myotomy were evaluated using PHRM with 20 PwMND across four studies with varying effects. Literature on the use of PHRM in PwMND is limited. Variability in PHRM methods restricts comparison of metrics. PHRM appears to be a feasible tool for PwMND. PHRM can provide novel swallow physiology data in PwMND and quantify discrete effects of compensatory and surgical dysphagia interventions not detectable by videofluoroscopy or FEES. Further research on the effects of proactive dysphagia intervention as measured by PHRM is required.}, }
@article {pmid35232339, year = {2022}, author = {Catarzi, D and Varano, F and Vigiani, E and Lambertucci, C and Spinaci, A and Volpini, R and Colotta, V}, title = {Casein Kinase 1δ Inhibitors as Promising Therapeutic Agents for Neurodegenerative Disorders.}, journal = {Current medicinal chemistry}, volume = {29}, number = {27}, pages = {4698-4737}, doi = {10.2174/0929867329666220301115124}, pmid = {35232339}, issn = {1875-533X}, support = {PRIN2017MT3993_004//Italian Ministry for University and Research (MIUR)/ ; }, mesh = {Casein Kinase I/metabolism ; *Casein Kinase Idelta/genetics/metabolism ; Circadian Rhythm/physiology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Protein Isoforms ; }, abstract = {Casein kinase 1 (CK1) belongs to the serine-threonine kinase family and is expressed in all eukaryotic organisms. At least six human isoforms of CK1 (termed α, γ1-3, δ and ε) have been cloned and characterized. CK1δ isoform modulates several physiological processes, including DNA damage repair, circadian rhythm, cellular proliferation and apoptosis. Therefore, CK1δ dysfunction may trigger diverse pathologies, such as cancer, inflammation and central nervous system disorders. Overexpression and aberrant activity of CK1δ have been connected to hyperphosphorylation of key proteins implicated in the development of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases and Amyotrophic Lateral Sclerosis. Thus, CK1δ inhibitors have attracted attention as potential drugs for these pathologies and several compounds have been synthesized or isolated from natural sources to be evaluated for their CK1δ inhibitory activity. Here we report a comprehensive review on the development of CK1δ inhibitors, with a particular emphasis on structure-activity relationships and computational studies, which provide useful insight for the design of novel inhibitors.}, }
@article {pmid35232295, year = {2022}, author = {Lu, T and Yang, J and Luo, L and Wei, D}, title = {FUS mutations in Asian amyotrophic lateral sclerosis patients: a case report and literature review of genotype-phenotype correlations.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {7-8}, pages = {580-584}, doi = {10.1080/21678421.2021.2023189}, pmid = {35232295}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; RNA-Binding Protein FUS/genetics ; *Neurodegenerative Diseases ; Genetic Association Studies ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive weakness and muscular atrophy in the upper or lower limbs, ultimately leading to paralysis and death. Genetic studies have demonstrated that mutation in the gene encoding fused in sarcoma (FUS) is an uncommon cause of ALS. Here, we report a case of a 31-year-old Asian man with ALS with rare onset of dropped-head syndrome. Symptoms, including asymmetric proximal weakness of the upper limbs, hoarseness, dysphagia, and nocturnal dyspnea, emerged over a period of 5 months. After genetic testing, the patient was confirmed to harbor a novel pathogenic heterozygous mutation, c.1558C > T (p.R520C). We summarize the genotype-clinical phenotype relationships in 42 Asian patients with ALS-FUS.}, }
@article {pmid35229468, year = {2022}, author = {Baud, A and Derbis, M and Tutak, K and Sobczak, K}, title = {Partners in crime: Proteins implicated in RNA repeat expansion diseases.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {13}, number = {4}, pages = {e1709}, pmid = {35229468}, issn = {1757-7012}, support = {101003385/MCCC_/Marie Curie/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Crime ; DNA Repeat Expansion/genetics ; *Fragile X Syndrome/genetics ; Humans ; RNA/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {Short tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNA[exp]) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNA[exp] molecules and multiple protein partners, in this review, we discuss the roles of selected RNA-binding proteins (RBPs) that interact with RNA[exp] and thus act as "partners in crime" in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNA[exp] life cycle, such as transcription, splicing, transport, and AUG-independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNA[exp] within nuclear foci and those which participate in RNA[exp] -dependent innate immunity activation. Moreover, we discuss the utility of selected RBPs as targets in the development of therapeutic strategies. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.}, }
@article {pmid35229461, year = {2022}, author = {Lye, YS and Chen, YR}, title = {TAR DNA-binding protein 43 oligomers in physiology and pathology.}, journal = {IUBMB life}, volume = {74}, number = {8}, pages = {794-811}, doi = {10.1002/iub.2603}, pmid = {35229461}, issn = {1521-6551}, support = {MOST 108-2113-M-001-027//Ministry of Sciences and Technology, Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; *DNA-Binding Proteins/genetics ; Humans ; *Neurodegenerative Diseases/pathology ; RNA-Binding Proteins/genetics ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA/DNA-binding protein involved in RNA regulation and diseases. In 2006, TDP-43 inclusions were found in the disease lesions of several neurodegenerative diseases. It is the pathological hallmark in both amyotrophic lateral sclerosis and frontotemporal lobar dementia. It also presents in a large portion of patients with Alzheimer's disease. TDP-43 is prone to aggregate; however, the role of TDP-43 oligomers remains poorly understood in both physiological and pathological conditions. In this review, we emphasize the role of oligomeric TDP-43 in both physiological and pathological conditions and discuss the potential mechanisms of oligomer formation. Finally, we suggest therapeutic strategies against the TDP-43 oligomers in neurodegenerative diseases.}, }
@article {pmid35228271, year = {2022}, author = {Tornese, P and Lalli, S and Cocco, A and Albanese, A}, title = {Review of disease-modifying drug trials in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {93}, number = {5}, pages = {521-529}, doi = {10.1136/jnnp-2021-328470}, pmid = {35228271}, issn = {1468-330X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {We analysed clinical trials of pharmacological interventions on patients with amyotrophic lateral sclerosis (ALS), and compared study quality and design features. The systematic review included articles published in PubMed and trials registered in ClinicalTrials.gov. Included studies were randomised double-blind placebo-controlled clinical trials assessing a disease-modifying pharmacological intervention. Studies were excluded if primary end points were safety or dose finding. A total of 28 735 articles and 721 current trials were identified. 76 published articles and 23 ongoing trials met inclusion criteria; they referred to distinct populations comprising 22 817 participants with ALS. Most articles and all current trials had parallel group design; few articles had cross-over design. A run-in observation period was included in about 20% of published studies and ongoing trials. Primary end points included functional assessment, survival, muscle strength, respiratory function, biomarkers and composite measures. Most recent trials had only functional assessment and survival. Risk of bias was high in 23 articles, moderate in 35, low in 18. A disease modification effect was observed for 10 interventions in phase II studies, two of which were confirmed in phase III. Three confirmatory phase III studies are currently underway. The present review provides cues for the design of future trials. Functional decline and survival, as single or composite measures, stand as the reference end points. Post hoc analyses should not be performed, particularly in studies using composite end points. There is a general agreement on diagnostic criteria; but eligibility criteria must be improved. Run-in observations may be used for censoring patients but are discouraged for refining participants' eligibility. The ALS Functional Rating Scale-Revised needs improvement for use as an ordinal measure of functional decline.}, }
@article {pmid35225861, year = {2022}, author = {Taniguchi, K and Sawamura, H and Ikeda, Y and Tsuji, A and Kitagishi, Y and Matsuda, S}, title = {D-Amino Acids as a Biomarker in Schizophrenia.}, journal = {Diseases (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {35225861}, issn = {2079-9721}, abstract = {D-amino acids may play key roles for specific physiological functions in different organs including the brain. Importantly, D-amino acids have been detected in several neurological disorders such as schizophrenia, amyotrophic lateral sclerosis, and age-related disorders, reflecting the disease conditions. Relationships between D-amino acids and neurophysiology may involve the significant contribution of D-Serine or D-Aspartate to the synaptic function, including neurotransmission and synaptic plasticity. Gut-microbiota could play important roles in the brain-function, since bacteria in the gut provide a significant contribution to the host pool of D-amino acids. In addition, the alteration of the composition of the gut microbiota might lead to schizophrenia. Furthermore, D-amino acids are known as a physiologically active substance, constituting useful biomarkers of several brain disorders including schizophrenia. In this review, we wish to provide an outline of the roles of D-amino acids in brain health and neuropsychiatric disorders with a focus on schizophrenia, which may shed light on some of the superior diagnoses and/or treatments of schizophrenia.}, }
@article {pmid35225121, year = {2022}, author = {Sun, Y and Bedlack, R and Armon, C and Beauchamp, M and Bertorini, T and Bowser, R and Bromberg, M and Caress, J and Carter, G and Crayle, J and Cudkowicz, ME and Glass, JD and Jackson, C and Lund, I and Martin, S and Paganoni, S and Pattee, G and Ratner, D and Salmon, K and Wicks, P}, title = {ALSUntangled #64: butyrates.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {7-8}, pages = {638-643}, doi = {10.1080/21678421.2022.2045323}, pmid = {35225121}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Butyrates/therapeutic use ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review butyrate and its different chemical forms (butyrates). Butyrates have plausible mechanisms for slowing ALS progression and positive pre-clinical studies. One trial suggests that sodium phenylbutyrate (NaPB) in combination with Tauroursodeoxycholic acid (TUDCA) can slow ALS progression and prolong survival, but the specific contribution of NaPB toward this effect is unclear. Butyrates appear reasonably safe for use in humans. Based on the above information, we support a trial of a butyrate in PALS, but we cannot yet recommend one as a treatment.}, }
@article {pmid35224258, year = {2022}, author = {Yamagishi, H and Shigematsu, K}, title = {Perspectives on Stem Cell-Based Regenerative Medicine with a Particular Emphasis on Mesenchymal Stem Cell Therapy.}, journal = {JMA journal}, volume = {5}, number = {1}, pages = {36-43}, pmid = {35224258}, issn = {2433-3298}, abstract = {Regenerative medicine is a medical treatment that aims to restore lost human body functions by regenerating missing or dysfunctional organs and tissues using stem cells, etc. There are three major types of stem cells used in regenerative medicine: induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), and mesenchymal stem cells (MSCs). MSCs are expected to be widely applied to regenerative medicine because of their ability to differentiate into various types of cells, repair cells and tissues; anti-inflammatory effects; secretion of various growth factors; and resolution of abnormally accumulated protein amyloid. MSCs can be derived from bone marrow, dental pulp, and other sources, but adipose tissue-derived stem cells (ADSCs) may be superior in that they can be harvested with the least amount of invasion, and therefore, a sufficient amount of stem cells can be cultured relatively easily. When MSCs are administered systemically by intravenous infusion, they tend to accumulate at the site of disease, a property known as "homing," which is extremely advantageous for clinical applications. In Japan, stem cell therapy can be performed only after the research or treatment plan has been reviewed and approved by the "Committee for Specific Approval of Regenerative Medicine" and submitted to the Ministry of Health, Labor and Welfare for approval in accordance with the "Act on Securing the Safety of Regenerative Medicine" and after approval by the ethics committee of the facility where the therapy is performed. In this review, the characteristics of MSCs, the actual status of their clinical application, and their future prospects are presented.}, }
@article {pmid35222082, year = {2022}, author = {Wang, S and Wang, B and Shang, D and Zhang, K and Yan, X and Zhang, X}, title = {Ion Channel Dysfunction in Astrocytes in Neurodegenerative Diseases.}, journal = {Frontiers in physiology}, volume = {13}, number = {}, pages = {814285}, pmid = {35222082}, issn = {1664-042X}, abstract = {Astrocytes play an important role in the central nervous system (CNS). Ion channels in these cells not only function in ion transport, and maintain water/ion metabolism homeostasis, but also participate in physiological processes of neurons and glial cells by regulating signaling pathways. Increasing evidence indicates the ion channel proteins of astrocytes, such as aquaporins (AQPs), transient receptor potential (TRP) channels, adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels, and P2X7 receptors (P2X7R), are strongly associated with oxidative stress, neuroinflammation and characteristic proteins in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Since ion channel protein dysfunction is a significant pathological feature of astrocytes in neurodegenerative diseases, we discuss these critical proteins and their signaling pathways in order to understand the underlying molecular mechanisms, which may yield new therapeutic targets for neurodegenerative disorders.}, }
@article {pmid35222067, year = {2021}, author = {Chu, AJ and Williams, JM}, title = {Astrocytic MicroRNA in Ageing, Inflammation, and Neurodegenerative Disease.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {826697}, pmid = {35222067}, issn = {1664-042X}, abstract = {Astrocytes actively regulate numerous cell types both within and outside of the central nervous system in health and disease. Indeed, astrocyte morphology, gene expression and function, alongside the content of astrocyte-derived extracellular vesicles (ADEVs), is significantly altered by ageing, inflammatory processes and in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Here, we review the relevant emerging literature focussed on perturbation in expression of microRNA (miRNA), small non-coding RNAs that potently regulate gene expression. Synthesis of this literature shows that ageing-related processes, neurodegenerative disease-associated mutations or peptides and cytokines induce dysregulated expression of miRNA in astrocytes and in some cases can lead to selective incorporation of miRNA into ADEVs. Analysis of the miRNA targets shows that the resulting downstream consequences of alterations to levels of miRNA include release of cytokines, chronic activation of the immune response, increased apoptosis, and compromised cellular functioning of both astrocytes and ADEV-ingesting cells. We conclude that perturbation of these functions likely exacerbates mechanisms leading to neuropathology and ultimately contributes to the cognitive or motor symptoms of neurodegenerative diseases. This field requires comprehensive miRNA expression profiling of both astrocytes and ADEVs to fully understand the effect of perturbed astrocytic miRNA expression in ageing and neurodegenerative disease.}, }
@article {pmid35204309, year = {2022}, author = {Xu, J and Su, X and Burley, SK and Zheng, XFS}, title = {Nuclear SOD1 in Growth Control, Oxidative Stress Response, Amyotrophic Lateral Sclerosis, and Cancer.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204309}, issn = {2076-3921}, support = {R25 ES020721/ES/NIEHS NIH HHS/United States ; NJCSCR-19IRG070//New Jersey Commission on Spinal Cord Injury Research/ ; R01CA260006, R01DK124897/NH/NIH HHS/United States ; }, abstract = {SOD1 is the major superoxide dismutase responsible for catalyzing dismutation of superoxide to hydrogen peroxide and molecular oxygen. It is well known as an essential antioxidant enzyme for maintaining cellular redox homeostasis. SOD1 dysregulation has been associated with many diseases, including amyotrophic lateral sclerosis (ALS), cancer, accelerated aging, and age-related diseases. Recent studies also revealed that SOD1 can serve as a regulatory protein in cell signaling, transcription, and ribosome biogenesis. Notably, SOD1 is localized in the nucleus under both normal and pathological conditions, contributing to oxidative stress response and growth control. Moreover, increasing evidence points to the importance of nuclear SOD1 in the pathogenesis of ALS and cancer.}, }
@article {pmid35204286, year = {2022}, author = {Goldsteins, G and Hakosalo, V and Jaronen, M and Keuters, MH and Lehtonen, &#x160; and Koistinaho, J}, title = {CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204286}, issn = {2076-3921}, support = {334525//Academy of Finland/ ; }, abstract = {A single paragraph of about 200 words maximum. Neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, pose a global challenge in the aging population due to the lack of treatments for their cure. Despite various disease-specific clinical symptoms, ND have some fundamental common pathological mechanisms involving oxidative stress and neuroinflammation. The present review focuses on the major causes of central nervous system (CNS) redox homeostasis imbalance comprising mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial disturbances, leading to reduced mitochondrial function and elevated reactive oxygen species (ROS) production, are thought to be a major contributor to the pathogenesis of ND. ER dysfunction has been implicated in ND in which protein misfolding evidently causes ER stress. The consequences of ER stress ranges from an increase in ROS production to altered calcium efflux and proinflammatory signaling in glial cells. Both pathological pathways have links to ferroptotic cell death, which has been implicated to play an important role in ND. Pharmacological targeting of these pathological pathways may help alleviate or slow down neurodegeneration.}, }
@article {pmid35204078, year = {2022}, author = {Cha, SJ and Kim, K}, title = {Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204078}, issn = {2076-3921}, support = {2021//Soonchunhyang University/ ; 2019R1F1A1045639//Ministry of Science and ICT (Korea)/ ; }, abstract = {Edaravone, the first known free radical scavenger, has demonstrated cellular protective properties in animals and humans. Owing to its antioxidant activity, edaravone modulates oxidative damage in various diseases, especially neurodegenerative diseases. In 2015, edaravone was approved in Japan to treat amyotrophic lateral sclerosis. The distinguishing pathogenic features of neurodegenerative diseases include high reactive oxygen species levels and mitochondrial dysfunction. However, the correlation between mitochondria and edaravone has not been elucidated. This review highlights recent studies on novel therapeutic perspectives of edaravone in terms of its effect on oxidative stress and mitochondrial function.}, }
@article {pmid35202463, year = {2022}, author = {Katzeff, JS and Bright, F and Phan, K and Kril, JJ and Ittner, LM and Kassiou, M and Hodges, JR and Piguet, O and Kiernan, MC and Halliday, GM and Kim, WS}, title = {Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {145}, number = {5}, pages = {1598-1609}, pmid = {35202463}, issn = {1460-2156}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics/pathology ; Humans ; *Neurodegenerative Diseases/pathology ; *Pick Disease of the Brain ; }, abstract = {Frontotemporal dementia refers to a group of neurodegenerative disorders characterized by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by loss of motor neurons resulting in muscle wasting and paralysis. Frontotemporal dementia and amyotrophic lateral sclerosis are considered to exist on a disease spectrum given substantial overlap of genetic and molecular signatures. The predominant genetic abnormality in both frontotemporal dementia and amyotrophic lateral sclerosis is an expanded hexanucleotide repeat sequence in the C9orf72 gene. In terms of brain pathology, abnormal aggregates of TAR-DNA-binding protein-43 are predominantly present in frontotemporal dementia and amyotrophic lateral sclerosis patients. Currently, sensitive and specific diagnostic and disease surveillance biomarkers are lacking for both diseases. This has impeded the capacity to monitor disease progression during life and the development of targeted drug therapies for the two diseases. The purpose of this review is to examine the status of current biofluid biomarker discovery and development in frontotemporal dementia and amyotrophic lateral sclerosis. The major pathogenic proteins implicated in different frontotemporal dementia and amyotrophic lateral sclerosis molecular subtypes and proteins associated with neurodegeneration and the immune system will be discussed. Furthermore, the use of mass spectrometry-based proteomics as an emerging tool to identify new biomarkers in frontotemporal dementia and amyotrophic lateral sclerosis will be summarized.}, }
@article {pmid35201675, year = {2022}, author = {Kharel, S and Ojha, R and Preethish-Kumar, V and Bhagat, R}, title = {C-reactive protein levels in patients with amyotrophic lateral sclerosis: A systematic review.}, journal = {Brain and behavior}, volume = {12}, number = {3}, pages = {e2532}, pmid = {35201675}, issn = {2162-3279}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; C-Reactive Protein ; Disease Progression ; Humans ; *Neurodegenerative Diseases ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting cortical and spinal motor neurons. There is a lack of optimal biomarkers to diagnose and prognosticate the ALS patients. C-reactive protein (CRP), an inflammatory marker, has shown promising results in ALS patients.<br><br>MATERIALS AND METHODS: PubMed, Embase, and Google Scholar databases were searched from 2000 to June 1, 2021 for suitable studies showing the relationship between CRP and ALS. The concentration of CRP levels was assessed between ALS patients and controls. Further, end outcomes like ALS functional rating scale (ALSFRS-R), survival status, and mortality risks were assessed in relation to CRP levels.<br><br>RESULTS: Eleven studies including five case-control, five cohorts, and one randomized control study were assessed. There were 2785 ALS patients and 3446 healthy controls. A significant increment in CRP levels among ALS patients in comparison with healthy controls were seen in most of the studies. ALSFRS-R and disease progression were found to be significantly correlated with CRP levels. Overall accuracy of CRP in CSF was 62% described in a single study.<br><br>CONCLUSION: Although CRP has shown promise as a prognostic biomarker, extensive cohort studies are required to assess its prognostic value and accuracy in diagnosing ALS taking into account the confounding factors.}, }
@article {pmid35199552, year = {2021}, author = {Rauchová, H}, title = {Coenzyme Q10 effects in neurological diseases.}, journal = {Physiological research}, volume = {70}, number = {Suppl4}, pages = {S683-S714}, pmid = {35199552}, issn = {1802-9973}, mesh = {Animals ; Antioxidants/pharmacology ; Electron Transport ; Humans ; Mitochondria/metabolism ; *Mitochondrial Diseases/metabolism ; *Nervous System Diseases/drug therapy/metabolism ; Ubiquinone/analogs &amp; derivatives/therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).}, }
@article {pmid35198559, year = {2022}, author = {Arkov, AL}, title = {Looking at the Pretty "Phase" of Membraneless Organelles: A View From Drosophila Glia.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {801953}, pmid = {35198559}, issn = {2296-634X}, abstract = {Membraneless granules assemble in different cell types and cellular loci and are the focus of intense research due to their fundamental importance for cellular organization. These dynamic organelles are commonly assembled from RNA and protein components and exhibit soft matter characteristics of molecular condensates currently characterized with biophysical approaches and super-resolution microscopy imaging. In addition, research on the molecular mechanisms of the RNA-protein granules assembly provided insights into the formation of abnormal granules and molecular aggregates, which takes place during many neurodegenerative disorders including Parkinson's diseases (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). While these disorders are associated with formation of abnormal granules, membraneless organelles are normally assembled in neurons and contribute to translational control and affect stability of neuronal RNAs. More recently, a new subtype of membraneless granules was identified in Drosophila glia (glial granules). Interestingly, glial granules were found to contain proteins which are the principal components of the membraneless granules in germ cells (germ granules), indicating some similarity in the functional assembly of these structures in glia and germline. This mini review highlights recent research on glial granules in the context of other membraneless organelles, including their assembly mechanisms and potential functions in the nervous system.}, }
@article {pmid35188908, year = {2022}, author = {Bromberg, MB}, title = {What Is in the Literature.}, journal = {Journal of clinical neuromuscular disease}, volume = {23}, number = {3}, pages = {124-132}, doi = {10.1097/CND.0000000000000399}, pmid = {35188908}, issn = {1537-1611}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Humans ; }, abstract = {This issue of What Is in the Literature focuses on articles on amyotrophic lateral sclerosis over the past year. Amyotrophic lateral sclerosis remains a challenging disorder with progression to death. Within the past year, a phase 2 trial of a drug combination showed slowing in the rate of progression. While awaiting a phase 3 trial or approval by the Food and Drug Administration, selected articles that aid the diagnosis, contribute to care, or add to general knowledge about the disease are reviewed.}, }
@article {pmid35187086, year = {2022}, author = {Carey, JL and Guo, L}, title = {Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {826719}, pmid = {35187086}, issn = {2296-889X}, support = {R35 GM138109/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; }, abstract = {Liquid-liquid phase separation of RNA-binding proteins mediates the formation of numerous membraneless organelles with essential cellular function. However, aberrant phase transition of these proteins leads to the formation of insoluble protein aggregates, which are pathological hallmarks of neurodegenerative diseases including ALS and FTD. TDP-43 and FUS are two such RNA-binding proteins that mislocalize and aggregate in patients of ALS and FTD. They have similar domain structures that provide multivalent interactions driving their phase separation in vitro and in the cellular environment. In this article, we review the factors that mediate and regulate phase separation of TDP-43 and FUS. We also review evidences that connect the phase separation property of TDP-43 and FUS to their functional roles in cells. Aberrant phase transition of TDP-43 and FUS leads to protein aggregation and disrupts their regular cell function. Therefore, restoration of functional protein phase of TDP-43 and FUS could be beneficial for neuronal cells. We discuss possible mechanisms for TDP-43 and FUS aberrant phase transition and aggregation while reviewing the methods that are currently being explored as potential therapeutic strategies to mitigate aberrant phase transition and aggregation of TDP-43 and FUS.}, }
@article {pmid35185590, year = {2022}, author = {Li, J and Yu, H and Yang, C and Ma, T and Dai, Y}, title = {Therapeutic Potential and Molecular Mechanisms of Echinacoside in Neurodegenerative Diseases.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {841110}, pmid = {35185590}, issn = {1663-9812}, abstract = {Echinacoside (ECH) is a natural phenylethanoid glycoside (PhG) in Cistanche tubulosa. A large number of studies have shown that ECH has very promising potential in the inhibition of neurodegenerative disease progression. Experimental studies strongly suggest that ECH exhibits a variety of beneficial effects associated with in neuronal function, including protecting mitochondrial function, anti-oxidative stress, anti-inflammatory, anti-endoplasmic reticulum stress (ERS), regulating autophagy and so on. The aim of this paper is to provide an extensive and actual summarization of ECH and its neuroprotective efficacy in prevention and treatment of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and so on, based on published data from both in vivo and in vitro studies. There is a growing evidence that ECH may serve as an efficacious and safe substance in the future to counteract neurodegenerative disease.}, }
@article {pmid35185458, year = {2022}, author = {Versluys, L and Ervilha Pereira, P and Schuermans, N and De Paepe, B and De Bleecker, JL and Bogaert, E and Dermaut, B}, title = {Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {815765}, pmid = {35185458}, issn = {1662-4548}, abstract = {TAR DNA-binding protein 43, mostly referred to as TDP-43 (encoded by the TARDBP gene) is strongly linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). From the identification of TDP-43 positive aggregates in the brains and spinal cords of ALS/FTD patients, to a genetic link between TARBDP mutations and the development of TDP-43 pathology in ALS, there is strong evidence indicating that TDP-43 plays a pivotal role in the process of neuronal degeneration. What this role is, however, remains to be determined with evidence ranging from gain of toxic properties through the formation of cytotoxic aggregates, to an inability to perform its normal functions due to nuclear depletion. To add to an already complex subject, recent studies highlight a role for TDP-43 in muscle physiology and disease. We here review the biophysical, biochemical, cellular and tissue-specific properties of TDP-43 in the context of neurodegeneration and have a look at the nascent stream of evidence that positions TDP-43 in a myogenic context. By integrating the neurogenic and myogenic pathological roles of TDP-43 we provide a more comprehensive and encompassing view of the role and mechanisms associated with TDP-43 across the various cell types of the motor system, all the way from brain to limbs.}, }
@article {pmid35181393, year = {2022}, author = {Yoshida, S and Hasegawa, T}, title = {Deciphering the prion-like behavior of pathogenic protein aggregates in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {155}, number = {}, pages = {105307}, doi = {10.1016/j.neuint.2022.105307}, pmid = {35181393}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Prions/chemistry/genetics/metabolism ; Protein Aggregates ; Protein Folding ; }, abstract = {Neurodegenerative diseases are hitherto classified based on their core clinical features, the anatomical distribution of neurodegeneration, and the cell populations mainly affected. On the other hand, the wealth of neuropathological, genetic, molecular and biochemical studies have identified the existence of distinct insoluble protein aggregates in the affected brain regions. These findings have spread the use of a collective term, proteinopathy, for neurodegenerative disorders with particular type of structurally altered protein accumulation. Particularly, a recent breakthrough in this field came with the discovery that these protein aggregates can transfer from one cell to another, thereby converting normal proteins to potentially toxic, misfolded species in a prion-like manner. In this review, we focus specifically on the molecular and cellular basis that underlies the seeding activity and transcellular spreading phenomenon of neurodegeneration-related protein aggregates, and discuss how these events contribute to the disease progression.}, }
@article {pmid35178253, year = {2022}, author = {Renga, V}, title = {Brain Connectivity and Network Analysis in Amyotrophic Lateral Sclerosis.}, journal = {Neurology research international}, volume = {2022}, number = {}, pages = {1838682}, pmid = {35178253}, issn = {2090-1852}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment or cure. ALS is characterized by the death of lower motor neurons (LMNs) in the spinal cord and upper motor neurons (UMNs) in the brain and their networks. Since the lower motor neurons are under the control of UMN and the networks, cortical degeneration may play a vital role in the pathophysiology of ALS. These changes that are not apparent on routine imaging with CT scans or MRI brain can be identified using modalities such as diffusion tensor imaging, functional MRI, arterial spin labelling (ASL), electroencephalogram (EEG), magnetoencephalogram (MEG), functional near-infrared spectroscopy (fNIRS), and positron emission tomography (PET) scan. They can help us generate a representation of brain networks and connectivity that can be visualized and parsed out to characterize and quantify the underlying pathophysiology in ALS. In addition, network analysis using graph measures provides a novel way of understanding the complex network changes occurring in the brain. These have the potential to become biomarker for the diagnosis and treatment of ALS. This article is a systematic review and overview of the various connectivity and network-based studies in ALS.}, }
@article {pmid35173667, year = {2021}, author = {Schumacher-Schuh, A and Bieger, A and Borelli, WV and Portley, MK and Awad, PS and Bandres-Ciga, S}, title = {Advances in Proteomic and Metabolomic Profiling of Neurodegenerative Diseases.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {792227}, pmid = {35173667}, issn = {1664-2295}, abstract = {Proteomics and metabolomics are two emerging fields that hold promise to shine light on the molecular mechanisms causing neurodegenerative diseases. Research in this area may reveal and quantify specific metabolites and proteins that can be targeted by therapeutic interventions intended at halting or reversing the neurodegenerative process. This review aims at providing a general overview on the current status of proteomic and metabolomic profiling in neurodegenerative diseases. We focus on the most common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We discuss the relevance of state-of-the-art metabolomics and proteomics approaches and their potential for biomarker discovery. We critically review advancements made so far, highlighting how metabolomics and proteomics may have a significant impact in future therapeutic and biomarker development. Finally, we further outline technologies used so far as well as challenges and limitations, placing the current information in a future-facing context.}, }
@article {pmid35170406, year = {2022}, author = {Gianferrara, T and Cescon, E and Grieco, I and Spalluto, G and Federico, S}, title = {Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases.}, journal = {Current medicinal chemistry}, volume = {29}, number = {27}, pages = {4631-4697}, doi = {10.2174/0929867329666220216113517}, pmid = {35170406}, issn = {1875-533X}, support = {2017MT3993//Italian Ministry of University and Research (MUR), PRIN2017/ ; }, mesh = {Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy ; Neuroinflammatory Diseases ; *Parkinson Disease/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: GSK-3β activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer's disease is the most studied neurodegenerative disease, but GSK-3β seems to be involved in almost all neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and the autoimmune disease multiple sclerosis.<br><br>OBJECTIVE: This review aims to help researchers both working on this research topic or not to have a comprehensive overview of GSK-3&#x3b2; in the context of neuroinflammation and neurodegeneration.<br><br>METHODS: Literature has been searched using PubMed and SciFinder databases by inserting specific keywords. A total of more than 500 articles have been discussed.<br><br>RESULTS: First of all, the structure and regulation of the kinase were briefly discussed, and then, specific GSK-3&#x3b2; implications in neuroinflammation and neurodegenerative diseases were illustrated with the help of figures, to conclude with a comprehensive overview on the most important GSK-3&#x3b2; and multitarget inhibitors. The structure and IC50 values at the target kinase have been reported for all the discussed compounds.<br><br>CONCLUSION: GSK-3&#x3b2; is involved in several signaling pathways in neurons, glial cells and immune cells. The fine regulation and interconnection of all these pathways are at the base of the rationale use of GSK-&#x3b2; inhibitors in neuroinflammation and neurodegeneration. Some compounds are now under clinical trials. Despite this, the compounds' pharmacodynamic and ADME/Tox profiles were often not fully characterized which is deleterious in such a complex system.}, }
@article {pmid35163773, year = {2022}, author = {Lamptey, RNL and Chaulagain, B and Trivedi, R and Gothwal, A and Layek, B and Singh, J}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163773}, issn = {1422-0067}, support = {U54 GM128729/GM/NIGMS NIH HHS/United States ; RO1 AG051574, RF1 AG068034, 1P20 GM109024, U54GM128729//National Institute of Health/ ; }, mesh = {Blood-Brain Barrier/pathology ; Brain/pathology ; Drug Delivery Systems ; Early Diagnosis ; Humans ; Nanoparticles/*administration &amp; dosage ; Neurodegenerative Diseases/*diagnosis/*drug therapy ; Theranostic Nanomedicine ; }, abstract = {Neurodegenerative disorders are primarily characterized by neuron loss. The most common neurodegenerative disorders include Alzheimer's and Parkinson's disease. Although there are several medicines currently approved for managing neurodegenerative disorders, a large majority of them only help with associated symptoms. This lack of pathogenesis-targeting therapies is primarily due to the restrictive effects of the blood-brain barrier (BBB), which keeps close to 99% of all "foreign substances" out of the brain. Since their discovery, nanoparticles have been successfully used for targeted delivery into many organs, including the brain. This review briefly describes the pathophysiology of Alzheimer's, Parkinson's disease, and amyotrophic lateral sclerosis, and their current management approaches. We then highlight the major challenges of brain-drug delivery, followed by the role of nanotherapeutics for the diagnosis and treatment of various neurological disorders.}, }
@article {pmid35163653, year = {2022}, author = {Luís, JP and Simões, CJV and Brito, RMM}, title = {The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163653}, issn = {1422-0067}, mesh = {Animals ; Central Nervous System Diseases/*immunology ; Humans ; Neuroinflammatory Diseases/*immunology ; Receptors, Interleukin-1 Type I/*immunology ; }, abstract = {The interleukin-1 receptor type 1 (IL-1R1) holds pivotal roles in the immune system, as it is positioned at the "epicenter" of the inflammatory signaling networks. Increased levels of the cytokine IL-1 are a recognized feature of the immune response in the central nervous system (CNS) during injury and disease, i.e., neuroinflammation. Despite IL-1/IL-1R1 signaling within the CNS having been the subject of several studies, the roles of IL-1R1 in the CNS cellular milieu still cause controversy. Without much doubt, however, the persistent activation of the IL-1/IL-1R1 signaling pathway is intimately linked with the pathogenesis of a plethora of CNS disease states, ranging from Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), all the way to schizophrenia and prion diseases. Importantly, a growing body of evidence is showing that blocking IL-1R1 signaling via pharmacological or genetic means in different experimental models of said CNS diseases leads to reduced neuroinflammation and delayed disease progression. The aim of this paper is to review the recent progress in the study of the biological roles of IL-1R1, as well as to highlight key aspects that render IL-1R1 a promising target for the development of novel disease-modifying treatments for multiple CNS indications.}, }
@article {pmid35163252, year = {2022}, author = {Chandra, S and Lusk, CP}, title = {Emerging Connections between Nuclear Pore Complex Homeostasis and ALS.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163252}, issn = {1422-0067}, support = {R01 NS122236/NS/NINDS NIH HHS/United States ; R01 NS122236/NH/NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/physiology ; Amyotrophic Lateral Sclerosis/*genetics ; Homeostasis/*genetics ; Humans ; Motor Neurons/physiology ; Nuclear Pore/*genetics ; }, abstract = {Developing effective treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) requires understanding of the underlying pathomechanisms that contribute to the motor neuron loss that defines the disease. As it causes the largest fraction of familial ALS cases, considerable effort has focused on hexanucleotide repeat expansions in the C9ORF72 gene, which encode toxic repeat RNA and dipeptide repeat (DPR) proteins. Both the repeat RNA and DPRs interact with and perturb multiple elements of the nuclear transport machinery, including shuttling nuclear transport receptors, the Ran GTPase and the nucleoporin proteins (nups) that build the nuclear pore complex (NPC). Here, we consider recent work that describes changes to the molecular composition of the NPC in C9ORF72 model and patient neurons in the context of quality control mechanisms that function at the nuclear envelope (NE). For example, changes to NPC structure may be caused by the dysregulation of a conserved NE surveillance pathway mediated by the endosomal sorting complexes required for the transport protein, CHMP7. Thus, these studies are introducing NE and NPC quality control pathways as key elements in a pathological cascade that leads to C9ORF72 ALS, opening entirely new experimental avenues and possibilities for targeted therapeutic intervention.}, }
@article {pmid35163103, year = {2022}, author = {Toledo, ARL and Monroy, GR and Salazar, FE and Lee, JY and Jain, S and Yadav, H and Borlongan, CV}, title = {Gut-Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163103}, issn = {1422-0067}, support = {R21 AG072379/AG/NIA NIH HHS/United States ; R56 AG064075/AG/NIA NIH HHS/United States ; R56 AG069676/AG/NIA NIH HHS/United States ; RF1 AG071762/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Brain-Gut Axis ; *Gastrointestinal Microbiome ; Humans ; Neurodegenerative Diseases/microbiology/*pathology/*therapy ; }, abstract = {Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs.}, }
@article {pmid35159390, year = {2022}, author = {Kobeissy, F and Kobaisi, A and Peng, W and Barsa, C and Goli, M and Sibahi, A and El Hayek, S and Abdelhady, S and Ali Haidar, M and Sabra, M and Orešič, M and Logroscino, G and Mondello, S and Eid, AH and Mechref, Y}, title = {Glycomic and Glycoproteomic Techniques in Neurodegenerative Disorders and Neurotrauma: Towards Personalized Markers.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159390}, issn = {2073-4409}, support = {GR-2013-02354960//Ministero della Salute/ ; 1R01GM112490-08/NH/NIH HHS/United States ; 1U01CA225753-04/NH/NIH HHS/United States ; R01 GM130091/GM/NIGMS NIH HHS/United States ; }, mesh = {Biomarkers/metabolism ; *Glycomics ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Proteome ; Proteomics/methods ; }, abstract = {The proteome represents all the proteins expressed by a genome, a cell, a tissue, or an organism at any given time under defined physiological or pathological circumstances. Proteomic analysis has provided unparalleled opportunities for the discovery of expression patterns of proteins in a biological system, yielding precise and inclusive data about the system. Advances in the proteomics field opened the door to wider knowledge of the mechanisms underlying various post-translational modifications (PTMs) of proteins, including glycosylation. As of yet, the role of most of these PTMs remains unidentified. In this state-of-the-art review, we present a synopsis of glycosylation processes and the pathophysiological conditions that might ensue secondary to glycosylation shortcomings. The dynamics of protein glycosylation, a crucial mechanism that allows gene and pathway regulation, is described. We also explain how-at a biomolecular level-mutations in glycosylation-related genes may lead to neuropsychiatric manifestations and neurodegenerative disorders. We then analyze the shortcomings of glycoproteomic studies, putting into perspective their downfalls and the different advanced enrichment techniques that emanated to overcome some of these challenges. Furthermore, we summarize studies tackling the association between glycosylation and neuropsychiatric disorders and explore glycoproteomic changes in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington disease, multiple sclerosis, and amyotrophic lateral sclerosis. We finally conclude with the role of glycomics in the area of traumatic brain injury (TBI) and provide perspectives on the clinical application of glycoproteomics as potential diagnostic tools and their application in personalized medicine.}, }
@article {pmid35159383, year = {2022}, author = {Liu, J and Zhou, F and Guan, Y and Meng, F and Zhao, Z and Su, Q and Bao, W and Wang, X and Zhao, J and Huo, Z and Zhang, L and Zhou, S and Chen, Y and Wang, X}, title = {The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159383}, issn = {2073-4409}, support = {81871006//National Natural Science Foundation of China/ ; ZR2020MH150 and ZR2020MH149//Shandong Province Natural Science Foundation of China/ ; Grant No. 2019KJK004//Support Program for Youth Innovation Technology in Colleges and Universities of Shandong Province of China/ ; J18KZ013//Key Project of Shandong Province Higher Educational Science and Technology Program of China/ ; N/A//The Brigham and Women's Hospital BRI Fund to Sustain Research Excellence (to X.W.)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Biomarkers/metabolism ; Humans ; *MicroRNAs/genetics/metabolism ; Motor Neurons/pathology ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.}, }
@article {pmid35159348, year = {2022}, author = {Mirzalieva, O and Juncker, M and Schwartzenburg, J and Desai, S}, title = {ISG15 and ISGylation in Human Diseases.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159348}, issn = {2073-4409}, support = {P60 AA009803/AA/NIAAA NIH HHS/United States ; T32 AA007577/AA/NIAAA NIH HHS/United States ; R21 NS060960/NS/NINDS NIH HHS/United States ; }, mesh = {*Brain Injuries, Traumatic ; *Cytokines/metabolism ; Humans ; Interferons/metabolism ; *Neoplasms/genetics ; Ubiquitination ; *Ubiquitins/genetics/metabolism ; }, abstract = {Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β-grasp fold in both UBL domains. UBL2 domain has a conserved C-terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN-dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a "double-edged sword" for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside.}, }
@article {pmid35159280, year = {2022}, author = {Papa, A and Pasquini, S and Contri, C and Gemma, S and Campiani, G and Butini, S and Varani, K and Vincenzi, F}, title = {Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159280}, issn = {2073-4409}, support = {20175SA5JJ//Italian Ministry for University and Research/ ; }, mesh = {*Central Nervous System Diseases/drug therapy ; Endocannabinoids/metabolism ; Humans ; Monoacylglycerol Lipases/metabolism ; *Neurodegenerative Diseases/drug therapy ; Polypharmacology ; }, abstract = {Polypharmacology breaks up the classical paradigm of "one-drug, one target, one disease" electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.}, }
@article {pmid35159225, year = {2022}, author = {Tarantino, N and Canfora, I and Camerino, GM and Pierno, S}, title = {Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159225}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Ion Channels ; Muscle, Skeletal/metabolism ; *Neurodegenerative Diseases/pathology ; Riluzole/pharmacology/therapeutic use ; }, abstract = {Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue.}, }
@article {pmid35159176, year = {2022}, author = {Lee, J and An, S and Lee, SJ and Kang, JS}, title = {Protein Arginine Methyltransferases in Neuromuscular Function and Diseases.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159176}, issn = {2073-4409}, mesh = {*Antineoplastic Agents/pharmacology ; Humans ; Methylation ; *Neoplasms ; *Neuromuscular Diseases ; Protein-Arginine N-Methyltransferases/metabolism ; Quality of Life ; }, abstract = {Neuromuscular diseases (NMDs) are characterized by progressive loss of muscle mass and strength that leads to impaired body movement. It not only severely diminishes the quality of life of the patients, but also subjects them to increased risk of secondary medical conditions such as fall-induced injuries and various chronic diseases. However, no effective treatment is currently available to prevent or reverse the disease progression. Protein arginine methyltransferases (PRMTs) are emerging as a potential therapeutic target for diverse diseases, such as cancer and cardiovascular diseases. Their expression levels are altered in the patients and molecular mechanisms underlying the association between PRMTs and the diseases are being investigated. PRMTs have been shown to regulate development, homeostasis, and regeneration of both muscle and neurons, and their association to NMDs are emerging as well. Through inhibition of PRMT activities, a few studies have reported suppression of cytotoxic phenotypes observed in NMDs. Here, we review our current understanding of PRMTs' involvement in the pathophysiology of NMDs and potential therapeutic strategies targeting PRMTs to address the unmet medical need.}, }
@article {pmid35156160, year = {2022}, author = {Rastegar-Moghaddam, SH and Ebrahimzadeh-Bideskan, A and Shahba, S and Malvandi, AM and Mohammadipour, A}, title = {MicroRNA-22: a Novel and Potent Biological Therapeutics in Neurological Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {5}, pages = {2694-2701}, pmid = {35156160}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Brain/pathology ; *Brain Ischemia/pathology ; Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/pathology ; }, abstract = {MicroRNAs (miRs) are regulatory RNAs with 18-25 nucleotides lengths involved in various biological processes. Some miRs, including miR-22, play an essential role in regulating neurological disorders. MiR-22 is a brain-enriched regulatory element involved in angiogenesis, energy supply, adjustment of ionic channels, and suppression of malignant cell proliferation, migration, and invasion. This article discusses the protective and therapeutic effects of miR-22 on neurological diseases and injuries, including cerebral ischemia, neurodegenerative diseases, epilepsy, and brain malignancies. We also correlated miR-22 with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), panic disorders, schizophrenia, neural tube defect (anencephaly), and traumatic brain injury. This work provides a therapeutic perspective for miR-22 as a new approach in treating neurological disorders.}, }
@article {pmid35151849, year = {2022}, author = {Goldoni, R and Dolci, C and Boccalari, E and Inchingolo, F and Paghi, A and Strambini, L and Galimberti, D and Tartaglia, GM}, title = {Salivary biomarkers of neurodegenerative and demyelinating diseases and biosensors for their detection.}, journal = {Ageing research reviews}, volume = {76}, number = {}, pages = {101587}, doi = {10.1016/j.arr.2022.101587}, pmid = {35151849}, issn = {1872-9649}, mesh = {*Alzheimer Disease ; Biomarkers ; *Biosensing Techniques ; *Demyelinating Diseases ; Humans ; }, abstract = {Salivary analysis is gaining increasing interest as a novel and promising field of research for the diagnosis of neurodegenerative and demyelinating diseases related to aging. The collection of saliva offers several advantages, being noninvasive, stress-free, and repeatable. Moreover, the detection of biomarkers directly in saliva could allow an early diagnosis of the disease, leading to timely treatments. The aim of this manuscript is to highlight the most relevant researchers' findings relatively to salivary biomarkers of neurodegenerative and demyelinating diseases, and to describe innovative and advanced biosensing strategies for the detection of salivary biomarkers. This review is focused on five relevant aging-related neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Multiple Sclerosis) and the salivary biomarkers most commonly associated with them. Advanced biosensors enabling molecular diagnostics for the detection of salivary biomarkers are presented, in order to stimulate future research in this direction and pave the way for their clinical application.}, }
@article {pmid35149361, year = {2022}, author = {Wankhede, NL and Kale, MB and Upaganlawar, AB and Taksande, BG and Umekar, MJ and Behl, T and Abdellatif, AAH and Bhaskaran, PM and Dachani, SR and Sehgal, A and Singh, S and Sharma, N and Makeen, HA and Albratty, M and Dailah, HG and Bhatia, S and Al-Harrasi, A and Bungau, S}, title = {Involvement of molecular chaperone in protein-misfolding brain diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {147}, number = {}, pages = {112647}, doi = {10.1016/j.biopha.2022.112647}, pmid = {35149361}, issn = {1950-6007}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy/physiology ; Brain/metabolism ; Huntington Disease/pathology ; *Molecular Chaperones/metabolism ; Parkinson Disease/pathology ; Proteasome Endopeptidase Complex/metabolism ; Proteostasis/physiology ; *Proteostasis Deficiencies/pathology ; Ubiquitin/metabolism ; Humans ; }, abstract = {Protein misfolding causes aggregation and build-up in a variety of brain diseases. There are numeral molecules that are linked with the protein homeostasis mechanism. Molecular chaperones are one of such molecules that are responsible for protection against protein misfolded and aggregation-induced neurotoxicity. Many studies have explored the participation of molecular chaperones in Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, and Huntington's diseases. In this review, we highlighted the constructive role of molecular chaperones in neurological diseases characterized by protein misfolding and aggregation and their capability to control aberrant protein interactions at an early stage thus successfully suppressing pathogenic cascades. A comprehensive understanding of the protein misfolding associated with brain diseases and the molecular basis of involvement of chaperone against aggregation-induced cellular stress might lead to the progress of new therapeutic intrusion-related to protein misfolding and aggregation.}, }
@article {pmid35147103, year = {2022}, author = {Zhao, X and Feng, X and Li, X and Mou, J and Liu, H and Chen, J and Wu, J}, title = {The G41D mutation in SOD1-related amyotrophic lateral sclerosis exhibits phenotypic heterogeneity among individuals: A case report and literature review.}, journal = {Medicine}, volume = {101}, number = {6}, pages = {e28771}, pmid = {35147103}, issn = {1536-5964}, support = {Z171100001017019//Beijing Municipal Science &amp; Technology Commission/ ; DFL20152201//Beijing Municipal Administration of Hospitals' Ascent Plan/ ; 2013-2-034//Beijing Municipal Health Bureau project/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/mortality ; DNA Mutational Analysis ; Fatal Outcome ; Female ; Genetic Predisposition to Disease ; Humans ; Middle Aged ; Mutation ; Mutation, Missense ; Pedigree ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1/*genetics ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. However, the misdiagnosis of ALS always occurs because of atypical clinical manifestations. Since mutations in Cu/Zn superoxide dismutase 1 (SOD1) have been implicated as causative and account for 20% of fALS cases, early genetic sequencing of suspected individuals in ALS pedigrees could be helpful.<br><br>PATIENT CONCERNS: Here we report a Chinese family spanning three generations with fALS. A heterozygous c.125G>A (p.Gly42Asp) missense mutation in exon 2 of SOD1 gene was detected in our proband as well as her 2 siblings and next generation. Phenotypic diversity was also reported among symptomatic individuals.<br><br>DIAGNOSES: Peripheral blood samples from the proband were collected and sent for polymerase chain reaction (PCR) and Sanger sequencing of the SOD1 gene at Sanvalley Diagnostics. The other 11 members in the studied family then underwent locus verification.<br><br>INTERVENTIONS: Butylphthalide, Vitamin B12, Coenzyme Q10 and mouse nerve growth factor is given to the symptomatic members.<br><br>OUTCOMES: The symptoms of our proband was not improved by treatments at a late stage. She passed away the fourth year of the disease due to respiratory failure. Two siblings of the proband were given active treatments once verified as carrier. Their symptoms are still limited to limb weakness.<br><br>LESSONS: This study suggests genetic sequencing is a powerful tool for the diagnosis of familial ALS. Phenotypic heterogeneity exists among G41D-mutated individuals, which further highlights the importance of genomic strategies for early diagnosis.}, }
@article {pmid35146883, year = {2022}, author = {Róbert, L and Kuroli, E and Bottlik, G and Hidvégi, B}, title = {[Not Available].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {20}, number = {2}, pages = {141-149}, doi = {10.1111/ddg.14677_g}, pmid = {35146883}, issn = {1610-0387}, abstract = {Calcinosis cutis, die heterotope Ablagerung von Kalziumsalzen in der Haut, wurde in einigen Fällen als spät auftretende Komplikation von Brandnarben beschrieben. Sie unterscheidet sich diesbezüglich von heterotoper Ossifikation, die eine früh einsetzende Komplikation von Brandverletzungen sein kann. Die Diagnose einer Kalzinose kann radiographisch, sonographisch, computertomographisch, magnetresonanztomographisch oder histologisch bestätigt werden. Nahezu alle Fälle einer spätmanifesten Kalzinose bei Brandnarben imponieren als nicht heilendes Ulkus an den unteren Extremitäten in der Nähe der Kontrakturbänder. Es wird diskutiert, dass diese Lokalisation auf die häufigeren Mikrotraumen an den unteren Extremitäten zurückzuführen ist, und dass die Ulzeration aufgrund der Kalziumablagerungen als Fremdkörper auftritt. In unserer Studie betrug das Durchschnittsalter zum Zeitpunkt der Brandverletzung 12,5 ± 8,27 Jahre und die Kalzinose entwickelte sich im Mittel nach einer Zeitspanne von 37,5 ± 14,95 Jahren (das Durchschnittsalter bei Beginn war 50,5 ± 14,53 Jahre). Es gab keinen signifikanten Unterschied zwischen Brandnarben, die mittels Hauttransplantation behandelt wurden, und solchen, bei denen keine Hauttransplantation durchgeführt wurde. Die Ulzera verheilten nach Resektion oder Extraktion der Ablagerungen ohne Rezidiv an derselben Stelle. Im Gegensatz zu früher gemeldeten Fällen beobachteten wir zwei Fälle einer spät einsetzenden Kalzinose ohne Ulzeration bei Brandnarben an den oberen Extremitäten.}, }
@article {pmid35143965, year = {2022}, author = {Davidson, JM and Chung, RS and Lee, A}, title = {The converging roles of sequestosome-1/p62 in the molecular pathways of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).}, journal = {Neurobiology of disease}, volume = {166}, number = {}, pages = {105653}, doi = {10.1016/j.nbd.2022.105653}, pmid = {35143965}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Autophagy/physiology ; *Frontotemporal Dementia/pathology ; Humans ; *Pick Disease of the Brain ; Proteostasis ; }, abstract = {Investigations into the pathogenetic mechanisms underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have provided significant insight into the disease. At the cellular level, ALS and FTD are classified as proteinopathies, which is motor neuron degeneration and death characterized by pathological protein aggregates or dysregulated proteostasis. At both the clinical and molecular level there are common signaling pathways dysregulated across the ALS and FTD spectrum (ALS/FTD). Sequestosome-1/p62 is a multifunctional scaffold protein with roles in several signaling pathways including proteostasis, protein degradation via the ubiquitin proteasome system and autophagy, the antioxidant response, inflammatory response, and apoptosis. Notably these pathways are dysregulated in ALS and FTD. Mutations in the functional domains of p62 provide links to the pathogenetic mechanisms of p62 and dyshomeostasis of p62 levels is noted in several types of ALS and FTD. We present here that the dysregulated ALS and FTD signaling pathways are linked, with p62 converging the molecular mechanisms. This review summarizes the current literature on the complex role of p62 in the pathogenesis across the ALS/FTD spectrum. The focus is on the underlying convergent molecular mechanisms of ALS and FTD-associated proteins and pathways that dysregulate p62 levels or are dysregulated by p62, with emphasis on how p62 is implicated across the ALS/FTD spectrum.}, }
@article {pmid35143130, year = {2022}, author = {Thibaut, A and Beaudart, C and Quinet, M and Bouquiaux, O and Delstanche, S and Lievens, I and Grosjean, D and Ortmans, I and Kaux, JF and Halleux, C}, title = {[Psychological and cognitive interventions in end-of-life support of patients with amyotrophic lateral sclerosis. A review.].}, journal = {Revue medicale de Liege}, volume = {77}, number = {2}, pages = {104-109}, pmid = {35143130}, issn = {0370-629X}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Cognition ; Death ; Humans ; Palliative Care ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by muscle atrophy leading to complete paralysis. Once diagnosed, the average life expectancy is three to five years. In this context, palliative and end-of-life care are essential, as well as the development of cognitive and/or psychological therapies to improve the quality of life of patients. In this context, we conducted a review of the pertinent literature about psychological and cognitive interventions in end-of-life support for ALS patients. We identified 504 references out of which only four studies met our inclusion criteria. Two studies focused on dignity therapy, one study on the delay between the diagnosis and the start of psychological care in a specialized centre, and one case-report on psychological therapy combined with a computer-assisted communication system. The results of these studies, although very limited, suggest that psychological interventions may improve the management and quality of life of end-of-life ALS patients. Further studies should investigate the impact of psychological support adapted to ALS, using, for example, computer-assisted communication allowing to implement these interventions in a larger number of patients and over the long term.}, }
@article {pmid35138963, year = {2022}, author = {Heckler, I and Venkataraman, I}, title = {Phosphorylated neurofilament heavy chain: a potential diagnostic biomarker in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {127}, number = {3}, pages = {737-745}, doi = {10.1152/jn.00398.2021}, pmid = {35138963}, issn = {1522-1598}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers ; Humans ; Intermediate Filaments/metabolism ; Neurofilament Proteins/metabolism ; Retrospective Studies ; }, abstract = {Neuroaxonal damage is a feature of various neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Phosphorylated neurofilament heavy chain (pNfH) is a cytoskeletal structural protein released as a result of axonal damage into the cerebrospinal fluid (CSF), and subsequently into the blood. Due to high specificity for neuronal cell damage, pNfH is advantageous over other biomarkers, for ALS disease identification. Here, we review the structure and function of neurofilaments and their role in detection of various neurodegenerative conditions. In addition, a retrospective meta-analysis was performed to depict the significance of pNfH as a valuable diagnostic and prognostic biomarker in ALS.}, }
@article {pmid35134659, year = {2022}, author = {Maggio, MG and Piazzitta, D and Andaloro, A and Latella, D and Sciarrone, F and Casella, C and Naro, A and Manuli, A and Calabrò, RS}, title = {Embodied cognition in neurodegenerative disorders: What do we know so far? A narrative review focusing on the mirror neuron system and clinical applications.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {98}, number = {}, pages = {66-72}, doi = {10.1016/j.jocn.2022.01.028}, pmid = {35134659}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/psychology ; Cognition/physiology ; Humans ; *Mirror Neurons/physiology ; *Neurodegenerative Diseases ; *Parkinson Disease ; }, abstract = {Embodied cognition is a theoretical perspective that considers every form of human knowledge and cognition "embodied", as they pass through bodily experience. The aim of this narrative review is to investigate the importance of mirror neurons system in EC, as well as the EC role in neurodegenerative diseases. This narrative review shows deep connections between body and mind: body states influence mental functions such as perception and reasoning, while mental states cause changes in the body, especially in neurodegenerative disorders. Indeed, abnormalities in EC were found in dementia, Parkinson's Disease and Amyotrophic Lateral sclerosis, also in the absence of other cognitive deficits, negatively affecting patients' outcomes. Exploiting EC mechanisms for rehabilitation purposes, also using innovation technologies, could be a promising therapeutic way to increase motor and cognitive outcomes in patients affected by different neurological disorders.}, }
@article {pmid35129196, year = {2022}, author = {Markovinovic, A and Greig, J and Martín-Guerrero, SM and Salam, S and Paillusson, S}, title = {Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases.}, journal = {Journal of cell science}, volume = {135}, number = {3}, pages = {}, doi = {10.1242/jcs.248534}, pmid = {35129196}, issn = {1477-9137}, support = {MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; /ALZS_/Alzheimer's Society/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; *Frontotemporal Dementia/metabolism ; Humans ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; }, abstract = {Recent advances have revealed common pathological changes in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis with related frontotemporal dementia (ALS/FTD). Many of these changes can be linked to alterations in endoplasmic reticulum (ER)-mitochondria signaling, including dysregulation of Ca2+ signaling, autophagy, lipid metabolism, ATP production, axonal transport, ER stress responses and synaptic dysfunction. ER-mitochondria signaling involves specialized regions of ER, called mitochondria-associated membranes (MAMs). Owing to their role in neurodegenerative processes, MAMs have gained attention as they appear to be associated with all the major neurodegenerative diseases. Furthermore, their specific role within neuronal maintenance is being revealed as mutant genes linked to major neurodegenerative diseases have been associated with damage to these specialized contacts. Several studies have now demonstrated that these specialized contacts regulate neuronal health and synaptic transmission, and that MAMs are damaged in patients with neurodegenerative diseases. This Review will focus on the role of MAMs and ER-mitochondria signaling within neurons and how damage of the ER-mitochondria axis leads to a disruption of vital processes causing eventual neurodegeneration.}, }
@article {pmid35125081, year = {2023}, author = {Brahadeeswaran, S and Lateef, M and Calivarathan, L}, title = {An Insight into the Molecular Mechanism of Mitochondrial Toxicant-induced Neuronal Apoptosis in Parkinson's Disease.}, journal = {Current molecular medicine}, volume = {23}, number = {1}, pages = {63-75}, doi = {10.2174/1566524022666220203163631}, pmid = {35125081}, issn = {1875-5666}, mesh = {Humans ; *Parkinson Disease/genetics ; Mitochondria ; Apoptosis ; }, abstract = {Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders affecting approximately 1% of the world's population at the age of 50 and above. Majority of PD cases are sporadic and show symptoms after the age of 60 and above. At that time, most of the dopaminergic neurons in the region of substantia nigra pars compacta have been degenerated. Although in past decades, discoveries of genetic mutations linked to PD have significantly impacted our current understanding of the pathogenesis of this devastating disorder, it is likely that the environment also plays a critical role in the etiology of sporadic PD. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural and industrial chemicals, may contribute to the pathogenesis of several neurodegenerative disorders, including PD. Furthermore, there is a strong correlation between mitochondrial dysfunction and several forms of neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and PD. Interestingly, substantia nigra of patients with PD has been shown to have a mild deficiency in mitochondrial respiratory electron transport chain NADH dehydrogenase (Complex I) activity. This review discusses the role of mitochondrial toxicants in the selective degeneration of dopaminergic neurons targeting the electron transport system that leads to Parkinsonism.}, }
@article {pmid35120619, year = {2022}, author = {Okano, H and Morimoto, S}, title = {iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders.}, journal = {Cell stem cell}, volume = {29}, number = {2}, pages = {189-208}, doi = {10.1016/j.stem.2022.01.007}, pmid = {35120619}, issn = {1875-9777}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Cell- and Tissue-Based Therapy ; Drug Discovery ; Humans ; *Induced Pluripotent Stem Cells/pathology ; *Neurodegenerative Diseases/drug therapy/pathology ; }, abstract = {It has been 15 years since the birth of human induced pluripotent stem cell (iPSC) technology in 2007, and the scope of its application has been expanding. In addition to the development of cell therapies using iPSC-derived cells, pathological analyses using disease-specific iPSCs and clinical trials to confirm the safety and efficacy of drugs developed using iPSCs are progressing. With the innovation of related technologies, iPSC applications are about to enter a new stage. This review outlines advances in iPSC modeling and therapeutic development for cardinal neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.}, }
@article {pmid35115992, year = {2021}, author = {Reyes-Leiva, D and Dols-Icardo, O and Sirisi, S and Cortés-Vicente, E and Turon-Sans, J and de Luna, N and Blesa, R and Belbin, O and Montal, V and Alcolea, D and Fortea, J and Lleó, A and Rojas-García, R and Illán-Gala, I}, title = {Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {750543}, pmid = {35115992}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.}, }
@article {pmid35114781, year = {2021}, author = {Dey, A and Assaedi, E and Johnston, W and Kalra, S and Das, S}, title = {Mixed pathologies mimicking motor neuron disease: a case report and review of the literature.}, journal = {Folia neuropathologica}, volume = {59}, number = {4}, pages = {403-408}, doi = {10.5114/fn.2021.111486}, pmid = {35114781}, issn = {1509-572X}, mesh = {Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Cognitive Dysfunction ; *Frontotemporal Dementia/diagnosis ; Humans ; Male ; *Motor Neuron Disease/diagnosis ; Neuropathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is classified as a motor neuron disease (MND) that can present with both upper and lower motor neuron signs. Concurrent ALS and frontotemporal dementia (FTD) is also a well-known phenomenon. Examples of other primary disorders mimicking ALS or ALS-FTD have been reported in the literature and recognition of these entities is important to ensure proper clinical management. We present here an unusual case of an 86-year-old male patient, clinically diagnosed with ALS and severe cognitive impairment thought to be due to FTD. Postmortem neuropathological examination of his brain and spinal cord did not reveal the typical findings of ALS or FTD. Rather, it revealed multiple non-ALS pathologies including argyrophilic grain disease (AGD), cerebrovascular disease, and Alzheimer's type pathology. This case raises the possibility that mixed pathologies could mimic motor neuron disease.}, }
@article {pmid35111126, year = {2021}, author = {Arjmand, B and Kokabi Hamidpour, S and Rabbani, Z and Tayanloo-Beik, A and Rahim, F and Aghayan, HR and Larijani, B}, title = {Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {788462}, pmid = {35111126}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis is a pernicious neurodegenerative disorder that is associated with the progressive degeneration of motor neurons, the disruption of impulse transmission from motor neurons to muscle cells, and the development of mobility impairments. Clinically, muscle paralysis can spread to other parts of the body. Hence it may have adverse effects on swallowing, speaking, and even breathing, which serves as major problems facing these patients. According to the available evidence, no definite treatment has been found for amyotrophic lateral sclerosis (ALS) that results in a significant outcome, although some pharmacological and non-pharmacological treatments are currently applied that are accompanied by some positive effects. In other words, available therapies are only used to relieve symptoms without any significant treatment effects that highlight the importance of seeking more novel therapies. Unfortunately, the process of discovering new drugs with high therapeutic potential for ALS treatment is fraught with challenges. The lack of a broad view of the disease process from early to late-stage and insufficiency of preclinical studies for providing validated results prior to conducting clinical trials are other reasons for the ALS drug discovery failure. However, increasing the combined application of different fields of regenerative medicine, especially tissue engineering and stem cell therapy can be considered as a step forward to develop more novel technologies. For instance, organ on a chip is one of these technologies that can provide a platform to promote a comprehensive understanding of neuromuscular junction biology and screen candidate drugs for ALS in combination with pluripotent stem cells (PSCs). The structure of this technology is based on the use of essential components such as iPSC- derived motor neurons and iPSC-derived skeletal muscle cells on a single miniaturized chip for ALS modeling. Accordingly, an organ on a chip not only can mimic ALS complexities but also can be considered as a more cost-effective and time-saving disease modeling platform in comparison with others. Hence, it can be concluded that lab on a chip can make a major contribution as a biomimetic micro-physiological system in the treatment of neurodegenerative disorders such as ALS.}, }
@article {pmid35107690, year = {2023}, author = {Rastegar-Moghaddam, SH and Ebrahimzadeh-Bideskan, A and Shahba, S and Malvandi, AM and Mohammadipour, A}, title = {Roles of the miR-155 in Neuroinflammation and Neurological Disorders: A Potent Biological and Therapeutic Target.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {2}, pages = {455-467}, pmid = {35107690}, issn = {1573-6830}, mesh = {Humans ; Neuroinflammatory Diseases ; *Parkinson Disease/metabolism ; *Multiple Sclerosis ; *Epilepsy ; *MicroRNAs/physiology ; }, abstract = {Neuroinflammation plays a crucial role in the development and progression of neurological disorders. MicroRNA-155 (miR-155), a miR is known to play in inflammatory responses, is associated with susceptibility to inflammatory neurological disorders and neurodegeneration, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis as well as epilepsy, stroke, and brain malignancies. MiR-155 damages the central nervous system (CNS) by enhancing the expression of pro-inflammatory cytokines, like IL-1β, IL-6, TNF-α, and IRF3. It also disturbs the blood-brain barrier by decreasing junctional complex molecules such as claudin-1, annexin-2, syntenin-1, and dedicator of cytokinesis 1 (DOCK-1), a hallmark of many neurological disorders. This review discusses the molecular pathways which involve miR-155 as a critical component in the progression of neurological disorders, representing miR-155 as a viable therapeutic target.}, }
@article {pmid35105727, year = {2022}, author = {Dreger, M and Steinbach, R and Otto, M and Turner, MR and Grosskreutz, J}, title = {Cerebrospinal fluid biomarkers of disease activity and progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {93}, number = {4}, pages = {422-435}, pmid = {35105727}, issn = {1468-330X}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid ; Disease Progression ; Humans ; Multivariate Analysis ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease, and only modest disease-modifying strategies have been established to date. Numerous clinical trials have been conducted in the past years, but have been severely hampered by the wide-ranging heterogeneity of both the biological origins and clinical characteristics of the disease. Thus, reliable biomarkers of disease activity are urgently needed to stratify patients into homogenous groups with aligned disease trajectories to allow a more effective design of clinical trial. In this review, the most promising candidate biomarkers in the cerebrospinal fluid (CSF) of patients with ALS will be summarised. Correlations between biomarker levels and clinical outcome parameters are discussed, while highlighting potential pitfalls and intercorrelations of these clinical parameters. Several CSF molecules have shown potential as biomarkers of progression and prognosis, but large, international, multicentric and longitudinal studies are crucial for validation. A more standardised choice of clinical endpoints in these studies, as well as the application of individualised models of clinical progression, would allow the quantification of disease trajectories, thereby allowing a more accurate analysis of the clinical implications of candidate biomarkers. Additionally, a comparative analysis of several biomarkers and ideally the application of a multivariate analysis including comprehensive genotypic, phenotypic and clinical characteristics collectively contributing to biomarker levels in the CSF, could promote their verification. Thus, reliable prognostic markers and markers of disease activity may improve clinical trial design and patient management in the direction of precision medicine.}, }
@article {pmid35101542, year = {2022}, author = {Keating, SS and San Gil, R and Swanson, MEV and Scotter, EL and Walker, AK}, title = {TDP-43 pathology: From noxious assembly to therapeutic removal.}, journal = {Progress in neurobiology}, volume = {211}, number = {}, pages = {102229}, doi = {10.1016/j.pneurobio.2022.102229}, pmid = {35101542}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; *DNA-Binding Proteins/chemistry/metabolism ; Frontotemporal Dementia ; Humans ; Protein Folding ; *TDP-43 Proteinopathies/metabolism ; }, abstract = {Our understanding of amyotrophic lateral sclerosis and frontotemporal dementia has advanced dramatically since the discovery of cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions as the hallmark pathology of these neurodegenerative diseases. Recent studies have provided insights into the physiological function of TDP-43 as an essential DNA-/RNA-modulating protein, and the triggers and consequences of TDP-43 dysfunction and aggregation. The formation of TDP-43 pathology is a progressive process, involving the generation of multiple distinct protein species, each with varying biophysical properties and roles in neurodegeneration. Here, we explore how the pathogenic changes to TDP-43, including mislocalisation, misfolding, aberrant liquid-liquid phase separation, stress granule assembly, oligomerisation, and post-translational modification, drive disease-associated aggregation in TDP-43 proteinopathies. We highlight how pathological TDP-43 species are formed and contribute to cellular dysfunction and toxicity, via both loss-of-function and gain-of-function mechanisms. We also review the role of protein homeostasis mechanisms, namely the ubiquitin proteasome system, autophagy-lysosome pathway, heat-shock response, and chaperone-mediated autophagy, in combating TDP-43 aggregation and discuss how their dysfunction likely promotes disease pathogenesis and progression. Finally, we evaluate pre-clinical studies aimed at enhancing TDP-43 protein clearance via these mechanisms and provide insight on promising strategies for future therapeutic advances. Harnessing the mechanisms that protect against or ameliorate TDP-43 pathology presents promising opportunities for developing disease-modifying treatments for these neurodegenerative diseases.}, }
@article {pmid35099768, year = {2022}, author = {Luo, S and Rabbani, Q and Crone, NE}, title = {Brain-Computer Interface: Applications to Speech Decoding and Synthesis to Augment Communication.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {1}, pages = {263-273}, pmid = {35099768}, issn = {1878-7479}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {*Brain-Computer Interfaces ; Communication ; Electrocorticography ; Humans ; Quality of Life ; Speech/physiology ; }, abstract = {Damage or degeneration of motor pathways necessary for speech and other movements, as in brainstem strokes or amyotrophic lateral sclerosis (ALS), can interfere with efficient communication without affecting brain structures responsible for language or cognition. In the worst-case scenario, this can result in the locked in syndrome (LIS), a condition in which individuals cannot initiate communication and can only express themselves by answering yes/no questions with eye blinks or other rudimentary movements. Existing augmentative and alternative communication (AAC) devices that rely on eye tracking can improve the quality of life for people with this condition, but brain-computer interfaces (BCIs) are also increasingly being investigated as AAC devices, particularly when eye tracking is too slow or unreliable. Moreover, with recent and ongoing advances in machine learning and neural recording technologies, BCIs may offer the only means to go beyond cursor control and text generation on a computer, to allow real-time synthesis of speech, which would arguably offer the most efficient and expressive channel for communication. The potential for BCI speech synthesis has only recently been realized because of seminal studies of the neuroanatomical and neurophysiological underpinnings of speech production using intracranial electrocorticographic (ECoG) recordings in patients undergoing epilepsy surgery. These studies have shown that cortical areas responsible for vocalization and articulation are distributed over a large area of ventral sensorimotor cortex, and that it is possible to decode speech and reconstruct its acoustics from ECoG if these areas are recorded with sufficiently dense and comprehensive electrode arrays. In this article, we review these advances, including the latest neural decoding strategies that range from deep learning models to the direct concatenation of speech units. We also discuss state-of-the-art vocoders that are integral in constructing natural-sounding audio waveforms for speech BCIs. Finally, this review outlines some of the challenges ahead in directly synthesizing speech for patients with LIS.}, }
@article {pmid35093159, year = {2022}, author = {Korb, M and Peck, A and Alfano, LN and Berger, KI and James, MK and Ghoshal, N and Healzer, E and Henchcliffe, C and Khan, S and Mammen, PPA and Patel, S and Pfeffer, G and Ralston, SH and Roy, B and Seeley, WW and Swenson, A and Mozaffar, T and Weihl, C and Kimonis, V and , }, title = {Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy.}, journal = {Orphanet journal of rare diseases}, volume = {17}, number = {1}, pages = {23}, pmid = {35093159}, issn = {1750-1172}, support = {P50HD087351/NH/NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; UL1 TR001863/TR/NCATS NIH HHS/United States ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01AR074457/NH/NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; UL1 TR001414/TR/NCATS NIH HHS/United States ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Cell Cycle Proteins/genetics ; Humans ; Mutation ; *Myositis, Inclusion Body ; *Osteitis Deformans/genetics ; Standard of Care ; Valosin Containing Protein/genetics ; }, abstract = {Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.}, }
@article {pmid35083279, year = {2021}, author = {Salem, A and Wilson, CJ and Rutledge, BS and Dilliott, A and Farhan, S and Choy, WY and Duennwald, ML}, title = {Matrin3: Disorder and ALS Pathogenesis.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {794646}, pmid = {35083279}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons in the brain and spinal cord. ALS is associated with protein misfolding and inclusion formation involving RNA-binding proteins, including TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS). The 125-kDa Matrin3 is a highly conserved nuclear DNA/RNA-binding protein that is implicated in many cellular processes, including binding and stabilizing mRNA, regulating mRNA nuclear export, modulating alternative splicing, and managing chromosomal distribution. Mutations in MATR3, the gene encoding Matrin3, have been identified as causal in familial ALS (fALS). Matrin3 lacks a prion-like domain that characterizes many other ALS-associated RNA-binding proteins, including TDP-43 and FUS, however, our bioinformatics analyses and preliminary studies document that Matrin3 contains long intrinsically disordered regions that may facilitate promiscuous interactions with many proteins and may contribute to its misfolding. In addition, these disordered regions in Matrin3 undergo numerous post-translational modifications, including phosphorylation, ubiquitination and acetylation that modulate the function and misfolding of the protein. Here we discuss the disordered nature of Matrin3 and review the factors that may promote its misfolding and aggregation, two elements that might explain its role in ALS pathogenesis.}, }
@article {pmid35081899, year = {2022}, author = {Sivagurunathan, N and Ambatt, ATS and Calivarathan, L}, title = {Role of Long Non-coding RNAs in the Pathogenesis of Alzheimer's and Parkinson's Diseases.}, journal = {Current aging science}, volume = {15}, number = {2}, pages = {84-96}, doi = {10.2174/1874609815666220126095847}, pmid = {35081899}, issn = {1874-6128}, mesh = {Aged ; *Alzheimer Disease/genetics ; Biomarkers/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/therapy ; *Parkinson Disease/genetics ; *RNA, Long Noncoding/genetics ; }, abstract = {Neurodegenerative diseases are a diverse group of diseases that are now one of the leading causes of morbidity in the elderly population. These diseases include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), etc. Although these diseases have a common characteristic feature of progressive neuronal loss from various parts of the brain, they differ in the clinical symptoms and risk factors, leading to the development and progression of the diseases. AD is a neurological condition that leads to dementia and cognitive decline due to neuronal cell death in the brain, whereas PD is a movement disorder affecting neuro-motor function and develops due to the death of the dopaminergic neurons in the brain, resulting in decreased dopamine levels. Currently, the only treatment available for these neurodegenerative diseases involves reducing the rate of progression of neuronal loss. This necessitates the development of efficient early biomarkers and effective therapies for these diseases. Long non-coding RNAs (LncRNAs) belong to a large family of non-coding transcripts with a minimum length of 200 nucleotides. They are implied to be involved in the development of the brain, a variety of diseases, and epigenetic, transcriptional, and posttranscriptional levels of gene regulation. Aberrant expression of lncRNAs in the CNS is considered to play a major role in the development and progression of AD and PD, two of the most leading causes of morbidity among elderly populations. In this mini-review, we discuss the role of various long non-coding RNAs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, which can further be studied for the development of potential biomarkers and therapeutic targets for various neurodegenerative diseases.}, }
@article {pmid35081276, year = {2022}, author = {Chen, JF and Wang, F and Huang, NX and Xiao, L and Mei, F}, title = {Oligodendrocytes and myelin: Active players in neurodegenerative brains?.}, journal = {Developmental neurobiology}, volume = {82}, number = {2}, pages = {160-174}, doi = {10.1002/dneu.22867}, pmid = {35081276}, issn = {1932-846X}, mesh = {Animals ; Axons ; Central Nervous System ; *Myelin Sheath/physiology ; Neuroglia ; *Oligodendroglia/physiology ; }, abstract = {Oligodendrocytes (OLs) are a major type of glial cells in the central nervous system that generate multiple myelin sheaths to wrap axons. Myelin ensures fast and efficient propagation of action potentials along axons and supports neurons with nourishment. The decay of OLs and myelin has been implicated in age-related neurodegenerative diseases and these changes are generally considered as an inevitable result of neuron loss and axon degeneration. Noticeably, OLs and myelin undergo dynamic changes in healthy adult brains, that is, newly formed OLs are continuously added throughout life from the differentiation of oligodendrocyte precursor cells (OPCs) and the pre-existing myelin sheaths may undergo degeneration or remodeling. Increasing evidence has shown that changes in OLs and myelin are present in the early stages of neurodegenerative diseases, and even prior to significant neuronal loss and functional deficits. More importantly, oligodendroglia-specific manipulation, by either deletion of the disease gene or enhancement of myelin renewal, can alleviate functional impairments in neurodegenerative animal models. These findings underscore the possibility that OLs and myelin are not passively but actively involved in neurodegenerative diseases and may play an important role in modulating neuronal function and survival. In this review, we summarize recent work characterizing by OLs and myelin changes in both healthy and neurodegenerative brains and discuss the potential of targeting oligodendroglial cells in treating neurodegenerative diseases.}, }
@article {pmid35078537, year = {2022}, author = {Verma, M and Lizama, BN and Chu, CT}, title = {Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {3}, pmid = {35078537}, issn = {2047-9158}, support = {R01 AG026389/AG/NIA NIH HHS/United States ; R01 NS065789/NS/NINDS NIH HHS/United States ; R01 NS101628/NS/NINDS NIH HHS/United States ; T32 NS086749/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Glutamic Acid/metabolism ; Mammals/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.}, }
@article {pmid35076930, year = {2022}, author = {van Eijk, RPA and Roes, KCB and de Greef-van der Sandt, I and van den Berg, LH and Lu, Y}, title = {Functional Loss and Mortality in Randomized Clinical Trials for Amyotrophic Lateral Sclerosis: To Combine, or Not to Combine-That is the Estimand.}, journal = {Clinical pharmacology and therapeutics}, volume = {111}, number = {4}, pages = {817-825}, pmid = {35076930}, issn = {1532-6535}, support = {R01 HL089778/HL/NHLBI NIH HHS/United States ; P30 CA124435/CA/NCI NIH HHS/United States ; UL1 TR003142/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressive disease leading to death in, on average, 3-5 years after first symptom onset. Consequently, there are frequently a non-negligible number of patients who die during the course of a clinical trial. This introduces bias in end points such as daily functioning, muscle strength, and quality of life. In this paper, we outline how the choice of strategy to handle death affects the interpretation of the trial results. We provide a general overview of the considerations, positioned in the estimand framework, and discuss the possibility that not every strategy provides a clinically relevant answer in each setting. The relevance of a strategy changes as a function of the intended trial duration, hypothesized treatment effect, and population included. It is important to consider this trade-off at the design stage of a clinical trial, as this will clarify the exact research question that is being answered, and better guide the planning, design, and analysis of the study.}, }
@article {pmid35074333, year = {2022}, author = {Hassan, MN and Nabi, F and Khan, AN and Hussain, M and Siddiqui, WA and Uversky, VN and Khan, RH}, title = {The amyloid state of proteins: A boon or bane?.}, journal = {International journal of biological macromolecules}, volume = {200}, number = {}, pages = {593-617}, doi = {10.1016/j.ijbiomac.2022.01.115}, pmid = {35074333}, issn = {1879-0003}, mesh = {*Neurodegenerative Diseases ; }, abstract = {Proteins and their aggregation is significant field of research due to their association with various conformational maladies including well-known neurodegenerative diseases like Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases. Amyloids despite being given negative role for decades are also believed to play a functional role in bacteria to humans. In this review, we discuss both facets of amyloid. We have shed light on AD, which is one of the most common age-related neurodegenerative disease caused by accumulation of Aβ fibrils as extracellular senile plagues. We also discuss PD caused by the aggregation and deposition of α-synuclein in form of Lewy bodies and neurites. Other amyloid-associated diseases such as HD and amyotrophic lateral sclerosis (ALS) are also discussed. We have also reviewed functional amyloids that have various biological roles in both prokaryotes and eukaryotes that includes formation of biofilm and cell attachment in bacteria to hormone storage in humans, We discuss in detail the role of Curli fibrils' in biofilm formation, chaplins in cell attachment to peptide hormones, and Pre-Melansomal Protein (PMEL) roles. The disease-related and functional amyloids are compared with regard to their structural integrity, variation in regulation, and speed of forming aggregates and elucidate how amyloids have turned from foe to friend.}, }
@article {pmid35073950, year = {2022}, author = {Staats, KA and Borchelt, DR and Tansey, MG and Wymer, J}, title = {Blood-based biomarkers of inflammation in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {17}, number = {1}, pages = {11}, pmid = {35073950}, issn = {1750-1326}, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; Humans ; Inflammation ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease in which many processes are detected including (neuro)inflammation. Many drugs have been tested for ALS in clinical trials but most have failed to reach their primary endpoints. The development and inclusion of different types of biomarkers in diagnosis and clinical trials can assist in determining target engagement of a drug, in distinguishing between ALS and other diseases, and in predicting disease progression rate, drug responsiveness, or an adverse event. Ideally, among other characteristics, a biomarker in ALS correlates highly with a disease process in the central nervous system or with disease progression and is conveniently obtained in a peripheral tissue. Here, we describe the state of biomarkers of inflammation in ALS by focusing on peripherally detectable and cellular responses from blood cells, and provide new (combinatorial) directions for exploration that are now feasible due to technological advancements.}, }
@article {pmid35073206, year = {2022}, author = {Sakamaki, T and Furusawa, Y and Hayashi, A and Otsuka, M and Fernandez, J}, title = {Remote Patient Monitoring for Neuropsychiatric Disorders: A Scoping Review of Current Trends and Future Perspectives from Recent Publications and Upcoming Clinical Trials.}, journal = {Telemedicine journal and e-health : the official journal of the American Telemedicine Association}, volume = {28}, number = {9}, pages = {1235-1250}, pmid = {35073206}, issn = {1556-3669}, mesh = {Clinical Trials as Topic ; *Epilepsy ; Humans ; Monitoring, Physiologic ; *Parkinson Disease/diagnosis/therapy ; *Telemedicine ; *Wearable Electronic Devices ; }, abstract = {Introduction: Telemedicine and remote patient monitoring are rapidly growing fields. This scoping review provides an update on remote patient monitoring for neuropsychiatric disorders from recent publications and upcoming clinical trials. Methods: Publications (PubMed and ICHUSHI; published January 2010 to February 2021) and trials (ClinicalTrials.gov and Japanese registries; active or recruiting by March 2021) that assessed wearable devices for remote management and/or monitoring of patients with neuropsychiatric disorders were searched. The review focuses on disorders with ≥3 publications. Results: We identified 44 publications and 51 active or recruiting trials, mostly from 2019 or 2020. Research on digital devices was most common for Parkinson's disease (11 publications and 19 trials), primarily for monitoring motor symptoms and/or preventing falls. Other disorders (3-5 publications each) included epilepsy (electroencephalogram [EEG] and seizure prediction), sleep disorder (sleep outcomes and behavioral therapies), multiple sclerosis (physical activity and symptoms), depression (physical activity, symptoms, and behavioral therapies), and amyotrophic lateral sclerosis (symptoms). Very few studies focused on newly emerging technologies (e.g., in-ear EEG and portable oximeters), and few studies integrated remote symptom monitoring with telemedicine. Discussion: Currently, development of digital devices for daily symptom monitoring is focused on Parkinson's disease. For the diseases reviewed, studies mostly focused on physical activity rather than psychiatric or nonmotor symptoms. Although the validity and usefulness of many devices are established, models for implementing remote patient monitoring in telehealth settings have not been established. Conclusions: Verification of the clinical effectiveness of digital devices combined with telemedicine is needed to further advance remote patient care for neuropsychiatric disorders.}, }
@article {pmid35067760, year = {2022}, author = {Fourier, A and Quadrio, I}, title = {Proteinopathies associated to repeat expansion disorders.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {129}, number = {2}, pages = {173-185}, pmid = {35067760}, issn = {1435-1463}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics ; Humans ; *Neurodegenerative Diseases/genetics ; }, abstract = {The most common neurodegenerative disorders, such as Alzheimer's or Parkinson's diseases, are characterized by synaptic dysfunction, neuronal loss and proteinaceous aggregates in central nervous system. The deposition of misfolded proteins constitutes neuropathological hallmarks of these diseases, grouped in the generic term of proteinopathies. Apart from these, other neurodegenerative diseases are characterized by genetic abnormalities like unstable repetitive simple sequence tracts (microsatellites) dispersed throughout the human genome. They are called repeat expansion disorders and include, for example, Huntington's disease or frontotemporal dementia/amyotrophic lateral sclerosis phenotypes associated to an expansion in C9ORF72. The presence of the expanded DNA tract leads to molecular alterations at the DNA, RNA and protein levels associated to distinct mechanisms, such as loss-of-function (LOF), gain-of-function (GOF) including misfolding of physiological or mutant proteins, favoring their polymerization and aggregation. Therefore, specific proteinopathies also arise from these repeat expansion disorders. The molecular description of the nature and location of expanded tracts, highlighting the consequences onto clinical phenotypes will be first described. Specific focuses on the three pathomechanisms of the repeat expansions associated to proteinopathies will then be addressed. Lastly, we will show how progress in the understanding of these different mechanisms has led to recent advances in new/innovative therapeutic approaches and emergence of associated biomarkers.}, }
@article {pmid35066762, year = {2022}, author = {Brahadeeswaran, S and Sivagurunathan, N and Calivarathan, L}, title = {Inflammasome Signaling in the Aging Brain and Age-Related Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {59}, number = {4}, pages = {2288-2304}, pmid = {35066762}, issn = {1559-1182}, support = {JRF//Science and Engineering Research Board/ ; }, mesh = {Aging ; Animals ; Brain/metabolism ; Caspases/metabolism ; *Inflammasomes/metabolism ; Macrophages/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Inflammasomes are intracellular protein complexes, members of the innate immune system, and their activation and regulation play an essential role in maintaining homeostatic conditions against exogenous and endogenous stimuli. Inflammasomes occur as cytosolic proteins and assemble into a complex during the recognition of pathogen-associated or danger-associated molecular patterns by pattern-recognition receptors in host cells. The formation of the inflammasome complex elicits signaling molecules of proinflammatory cytokines such as interleukin-1β and interleukin 18 via activation of caspase-1 in the canonical inflammasome pathway whereas caspase-11 in the case of a mouse and caspase-4 and caspase-5 in the case of humans in the non-canonical inflammasome pathway, resulting in pyroptotic or inflammatory cell death which ultimately leads to neuroinflammation and neurodegenerative diseases. Inflammasome activation, particularly in microglial cells and macrophages, has been linked to aging as well as age-related neurodegenerative diseases. The accumulation of abnormal/ misfolded proteins acts as a ligand for inflammasome activation in neurodegenerative diseases. Although recent studies have revealed the inflammasomes' functionality in both in vitro and in vivo models, many inflammasome signaling cascade activations during biological aging, neuroinflammation, and neurodegeneration are still ambiguous. In this review, we comprehensively unveil the cellular and molecular mechanisms of inflammasome activation during neuronal aging and age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prion disease, and amyotrophic lateral sclerosis.}, }
@article {pmid35065989, year = {2022}, author = {Singh, T and Thapliyal, S and Bhatia, S and Singh, V and Singh, M and Singh, H and Kumar, A and Mishra, A}, title = {Reconnoitering the transformative journey of minocycline from an antibiotic to an antiepileptic drug.}, journal = {Life sciences}, volume = {293}, number = {}, pages = {120346}, doi = {10.1016/j.lfs.2022.120346}, pmid = {35065989}, issn = {1879-0631}, mesh = {Animals ; Anti-Bacterial Agents/*therapeutic use ; Anticonvulsants/*therapeutic use ; Drug Repositioning/*methods/trends ; Epilepsy/*drug therapy/metabolism ; Humans ; Minocycline/*therapeutic use ; Nervous System Diseases/drug therapy/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Minocycline, a second-generation tetracycline antibiotic is being widely tested in animals as well as clinical settings for the management of multiple neurological disorders. The drug has shown to exert protective action in a multitude of neurological disorders including spinal-cord injury, stroke, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Being highly lipophilic, minocycline easily penetrates the blood brain barrier and is claimed to have excellent oral absorption (~100% bioavailability). Minocycline possesses anti-inflammatory, immunomodulatory, and anti-apoptotic properties, thereby supporting its use in treating neurological disorders. The article henceforth reviews all the recent advances in the transformation of this antibiotic into a potential antiepileptic/antiepileptogenic agent. The article also gives an account of all the clinical trials undertaken till now validating the antiepileptic potential of minocycline. Based on the reported studies, minocycline seems to be an important molecule for treating epilepsy. However, the practical therapeutic implementations of this molecule require extensive mechanism-based in-vitro (cell culture) and in-vivo (animal models) studies followed by its testing in randomized, placebo controlled and double-blind clinical trials in large population as well as in different form of epilepsies.}, }
@article {pmid35064780, year = {2022}, author = {Pampalakis, G and Angelis, G and Zingkou, E and Vekrellis, K and Sotiropoulou, G}, title = {A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis.}, journal = {Clinical and translational medicine}, volume = {12}, number = {1}, pages = {e657}, pmid = {35064780}, issn = {2001-1326}, support = {1876//Hellenic Foundation for Research and Innovation (HFRI) and General Secretariat for Research and Innovation (GSRI)/ ; T1EDK-03884//BIOLUMINPD/ ; NSRF 2014-2020//Competitiveness, Entrepreneurship and Innovation/ ; //Greece and the European Union (European Regional Development Fund)/ ; //Research Committee of the University of Patras/ ; }, mesh = {Amino Acids, Diamino/adverse effects ; Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/metabolism ; Animals ; Cyanobacteria Toxins/adverse effects ; Cycas/adverse effects/metabolism ; Disease Models, Animal ; Mice ; }, abstract = {ALS is a fatal untreatable disease involving degeneration of motor neurons. Μultiple causative genes encoding proteins with versatile functions have been identified indicating that diverse biological pathways lead to ALS. Chemical entities still represent a promising choice to delay ALS progression, attenuate symptoms and/or increase life expectancy, but also gene-based and stem cell-based therapies are in the process of development, and some are tested in clinical trials. Various compounds proved effective in transgenic models overexpressing distinct ALS causative genes unfortunately though, they showed no efficacy in clinical trials. Notably, while animal models provide a uniform genetic background for preclinical testing, ALS patients are not stratified, and the distinct genetic forms of ALS are treated as one group, which could explain the observed discrepancies between treating genetically homogeneous mice and quite heterogeneous patient cohorts. We suggest that chemical entity-genotype correlation should be exploited to guide patient stratification for pharmacotherapy, that is administered drugs should be selected based on the ALS genetic background.}, }
@article {pmid35062955, year = {2022}, author = {Hartmaier, SL and Rhodes, T and Cook, SF and Schlusser, C and Chen, C and Han, S and Zach, N and Murthy, V and Davé, S}, title = {Qualitative measures that assess functional disability and quality of life in ALS.}, journal = {Health and quality of life outcomes}, volume = {20}, number = {1}, pages = {12}, pmid = {35062955}, issn = {1477-7525}, mesh = {*Amyotrophic Lateral Sclerosis ; *Disabled Persons ; Disease Progression ; Humans ; Quality of Life ; }, abstract = {BACKGROUND: Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials.<br><br>METHODS: We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies.<br><br>RESULTS: In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials.<br><br>CONCLUSION: This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.}, }
@article {pmid35062074, year = {2022}, author = {Kabir, MT and Rahman, MH and Shah, M and Jamiruddin, MR and Basak, D and Al-Harrasi, A and Bhatia, S and Ashraf, GM and Najda, A and El-Kott, AF and Mohamed, HRH and Al-Malky, HS and Germoush, MO and Altyar, AE and Alwafai, EB and Ghaboura, N and Abdel-Daim, MM}, title = {Therapeutic promise of carotenoids as antioxidants and anti-inflammatory agents in neurodegenerative disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {146}, number = {}, pages = {112610}, doi = {10.1016/j.biopha.2021.112610}, pmid = {35062074}, issn = {1950-6007}, mesh = {Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Carotenoids/classification/pharmacology/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis have various disease-specific causal factors and pathological features. A very common characteristic of NDs is oxidative stress (OS), which takes place due to the elevated generation of reactive oxygen species during the progression of NDs. Furthermore, the pathological condition of NDs including an increased level of protein aggregates can further lead to chronic inflammation because of the microglial activation. Carotenoids (CTs) are naturally occurring pigments that play a significant role in averting brain disorders. More than 750 CTs are present in nature, and they are widely available in plants, microorganisms, and animals. CTs are accountable for the red, yellow, and orange pigments in several animals and plants, and these colors usually indicate various types of CTs. CTs exert various bioactive properties because of its characteristic structure, including anti-inflammatory and antioxidant properties. Due to the protective properties of CTs, levels of CTs in the human body have been markedly linked with the prevention and treatment of multiple diseases including NDs. In this review, we have summarized the relationship between OS, neuroinflammation, and NDs. In addition, we have also particularly focused on the antioxidants and anti-inflammatory properties of CTs in the management of NDs.}, }
@article {pmid35059816, year = {2022}, author = {Pugliese, R and Sala, R and Regondi, S and Beltrami, B and Lunetta, C}, title = {Emerging technologies for management of patients with amyotrophic lateral sclerosis: from telehealth to assistive robotics and neural interfaces.}, journal = {Journal of neurology}, volume = {269}, number = {6}, pages = {2910-2921}, pmid = {35059816}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; *COVID-19 ; Humans ; Motor Neurons ; Pandemics ; *Telemedicine ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and subsequently paralysis. It begins subtly with focal weakness but spreads relentlessly to involve most muscles, thus proving to be effectively incurable. Typically, death due to respiratory paralysis occurs in 3-5 years. To date, it has been shown that the management of ALS patients is best achieved with a multidisciplinary approach, and with the help of emerging technologies ranging from multidisciplinary teleconsults (for monitoring the dysphagia, respiratory function, and nutritional status) to brain-computer interfaces and eye tracking for alternative augmentative communication, until robotics, it may increase effectiveness. The COVID-19 pandemic created a spasmodic need to accelerate the development and implementation of such technologies in clinical practice, to improve the daily lives of both ALS patients and caregivers. However, despite the remarkable strides that have been made in the field, there are still issues to be addressed. This review will be discussed on the eureka moment of emerging technologies for ALS, used as a blueprint not only for neurodegenerative diseases, examining the current technologies already in place or being evaluated, highlighting the pros and cons for future clinical applications.}, }
@article {pmid35057544, year = {2022}, author = {Chrysanthou, M and Miro Estruch, I and Rietjens, IMCM and Wichers, HJ and Hoppenbrouwers, T}, title = {In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration.}, journal = {Nutrients}, volume = {14}, number = {2}, pages = {}, pmid = {35057544}, issn = {2072-6643}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Cell Line ; Diet/methods ; Glycation End Products, Advanced/*metabolism ; Humans ; Mice ; Microglia/metabolism ; Monocytes/metabolism ; Multiple Sclerosis/metabolism ; Neurodegenerative Diseases/*metabolism ; Neuroinflammatory Diseases/*metabolism ; Neurons/metabolism ; Parkinson Disease/metabolism ; Rats ; Receptor for Advanced Glycation End Products/metabolism ; }, abstract = {Advanced glycation end products (AGEs) can be present in food or be endogenously produced in biological systems. Their formation has been associated with chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The implication of AGEs in neurodegeneration is related to their ability to bind to AGE-specific receptors and the ability of their precursors to induce the so-called "dicarbonyl stress", resulting in cross-linking and protein damage. However, the mode of action underlying their role in neurodegeneration remains unclear. While some research has been carried out in observational clinical studies, further in vitro studies may help elucidate these underlying modes of action. This review presents and discusses in vitro methodologies used in research on the potential role of AGEs in neuroinflammation and neurodegeneration. The overview reveals the main concepts linking AGEs to neurodegeneration, the current findings, and the available and advisable in vitro models to study their role. Moreover, the major questions regarding the role of AGEs in neurodegenerative diseases and the challenges and discrepancies in the research field are discussed.}, }
@article {pmid35055625, year = {2022}, author = {Giordano, A and De Panfilis, L and Perin, M and Servidio, L and Cascioli, M and Grasso, MG and Lugaresi, A and Pucci, E and Veronese, S and Solari, A}, title = {Advance Care Planning in Neurodegenerative Disorders: A Scoping Review.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {2}, pages = {}, pmid = {35055625}, issn = {1660-4601}, mesh = {*Advance Care Planning ; Caregivers ; Health Personnel ; Humans ; *Neurodegenerative Diseases/therapy ; Palliative Care/methods ; }, abstract = {Advance care planning (ACP) is increasingly acknowledged as a key step to enable patients to define their goals/preferences for future medical care, together with their carers and health professionals. We aimed to map the evidence on ACP in neurodegenerative disorders. We conducted a scoping review by searching PubMed (inception-December 28, 2020) in addition to trial, review, and dissertation registers. From 9367 records, we included 53 studies, mostly conducted in Europe (45%) and US-Canada (41%), within the last five years. Twenty-six percent of studies were qualitative, followed by observational (21%), reviews (19%), randomized controlled trials (RCTs, 19%), quasi-experimental (11%), and mixed-methods (4%). Two-thirds of studies addressed dementia, followed by amyotrophic lateral sclerosis (13%), and brain tumors (9%). The RCT interventions (all in dementia) consisted of educational programs, facilitated discussions, or videos for patients and/or carers. In conclusion, more research is needed to investigate barriers and facilitators of ACP uptake, as well as to develop/test interventions in almost all the neurodegenerative disorders. A common set of outcome measures targeting each discrete ACP behavior, and validated across the different diseases and cultures is also needed.}, }
@article {pmid35054808, year = {2022}, author = {Grekhnev, DA and Kaznacheyeva, EV and Vigont, VA}, title = {Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling.}, journal = {International journal of molecular sciences}, volume = {23}, number = {2}, pages = {}, pmid = {35054808}, issn = {1422-0067}, support = {Research Project N 075-15-2020-795, local identifier 13.1902.21.0027//Ministry of Science and Higher Education of Russia/ ; }, mesh = {Animals ; *Calcium Signaling ; Cell- and Tissue-Based Therapy ; Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells/*pathology ; *Models, Biological ; Neurodegenerative Diseases/*metabolism/*pathology/therapy ; }, abstract = {The development of cell reprogramming technologies became a breakthrough in the creation of new models of human diseases, including neurodegenerative pathologies. The iPSCs-based models allow for the studying of both hereditary and sporadic cases of pathologies and produce deep insight into the molecular mechanisms underlying neurodegeneration. The use of the cells most vulnerable to a particular pathology makes it possible to identify specific pathological mechanisms and greatly facilitates the task of selecting the most effective drugs. To date, a large number of studies on patient-specific models of neurodegenerative diseases has been accumulated. In this review, we focused on the alterations of such a ubiquitous and important intracellular regulatory pathway as calcium signaling. Here, we reviewed and analyzed the data obtained from iPSCs-based models of different neurodegenerative disorders that demonstrated aberrant calcium signaling.}, }
@article {pmid35053794, year = {2021}, author = {D'Alvano, G and Buonanno, D and Passaniti, C and De Stefano, M and Lavorgna, L and Tedeschi, G and Siciliano, M and Trojsi, F}, title = {Support Needs and Interventions for Family Caregivers of Patients with Amyotrophic Lateral Sclerosis (ALS): A Narrative Review with Report of Telemedicine Experiences at the Time of COVID-19 Pandemic.}, journal = {Brain sciences}, volume = {12}, number = {1}, pages = {}, pmid = {35053794}, issn = {2076-3425}, abstract = {Family caregivers of people with amyotrophic lateral sclerosis (ALS), a severely disabling neurodegenerative disease due to the degeneration of both upper and lower motor neurons, have a very demanding role in managing their relatives, thereby often experiencing heavy care burden. Previous literature has widely highlighted that this situation reduces caregivers' quality of life and increases their psychological distress and risk of health problems, but there are relatively few studies that focus on psychological interventions for these situations. Family support is more-not less-important during crisis. However, during the COVID-19 pandemic, maintaining public safety has required restricting the physical presence of families for hospitalized patients. Caregivers of ALS patients felt increased sense of loneliness and experienced greater difficulties in the access to both hospital and home assistance. In response, health systems rapidly adapted family-centric procedures and tools to circumvent restrictions on physical presence. In this regard, internet-based and telehealth solutions have been adopted to facilitate the routine, predictable, and structured communication, crucial to family-centered care. This narrative review aims at addressing more current matters on support needs and interventions for improving wellbeing of caregivers of ALS patients. In particular, we aimed at highlighting several gaps related to the complex needs of caregivers of ALS patients, to the interventions carried out in order to respond to these needs, and to the changes that COVID-19 pandemic caused from 2020 to nowadays in clinical managing of ALS patients. Finally, we report ongoing experiences of psychological support for family caregivers of ALS patients through telehealth solutions, which have been reinforced in case of needing of physical distancing during the COVID-19 pandemic.}, }
@article {pmid35053088, year = {2022}, author = {Kaur, G and Rathod, SSS and Ghoneim, MM and Alshehri, S and Ahmad, J and Mishra, A and Alhakamy, NA}, title = {DNA Methylation: A Promising Approach in Management of Alzheimer's Disease and Other Neurodegenerative Disorders.}, journal = {Biology}, volume = {11}, number = {1}, pages = {}, pmid = {35053088}, issn = {2079-7737}, support = {(FP-017-43).//The Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia/ ; }, abstract = {DNA methylation, in the mammalian genome, is an epigenetic modification that involves the transfer of a methyl group on the C5 position of cytosine to derive 5-methylcytosine. The role of DNA methylation in the development of the nervous system and the progression of neurodegenerative diseases such as Alzheimer's disease has been an interesting research area. Furthermore, mutations altering DNA methylation affect neurodevelopmental functions and may cause the progression of several neurodegenerative diseases. Epigenetic modifications in neurodegenerative diseases are widely studied in different populations to uncover the plausible mechanisms contributing to the development and progression of the disease and detect novel biomarkers for early prognosis and future pharmacotherapeutic targets. In this manuscript, we summarize the association of DNA methylation with the pathogenesis of the most common neurodegenerative diseases, such as, Alzheimer's disease, Parkinson's disease, Huntington diseases, and amyotrophic lateral sclerosis, and discuss the potential of DNA methylation as a potential biomarker and therapeutic tool for neurogenerative diseases.}, }
@article {pmid35053075, year = {2022}, author = {Miceli, M and Exertier, C and Cavaglià, M and Gugole, E and Boccardo, M and Casaluci, RR and Ceccarelli, N and De Maio, A and Vallone, B and Deriu, MA}, title = {ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules.}, journal = {Biology}, volume = {11}, number = {1}, pages = {}, pmid = {35053075}, issn = {2079-7737}, support = {GSP20005_PAsIAHSP007//Telethon Foundation/ ; }, abstract = {Infantile-onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis and Juvenile Amyotrophic Lateral Sclerosis are all motor neuron diseases related to mutations on the ALS2 gene, encoding for a 1657 amino acids protein named Alsin. This ~185 kDa multi-domain protein is ubiquitously expressed in various human tissues, mostly in the brain and the spinal cord. Several investigations have indicated how mutations within Alsin's structured domains may be responsible for the alteration of Alsin's native oligomerization state or Alsin's propensity to interact with protein partners. In this review paper, we propose a description of differences and similarities characterizing the above-mentioned ALS2-related rare neurodegenerative disorders, pointing attention to the effects of ALS2 mutation from molecule to organ and at the system level. Known cases were collected through a literature review and rationalized to deeply elucidate the neurodegenerative clinical outcomes as consequences of ALS2 mutations.}, }
@article {pmid35052668, year = {2022}, author = {Rodríguez, LR and Lapeña-Luzón, T and Benetó, N and Beltran-Beltran, V and Pallardó, FV and Gonzalez-Cabo, P and Navarro, JA}, title = {Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052668}, issn = {2076-3921}, support = {PID2020-115190RB-100//Ministry of Economy, Industry and Competitiveness/ ; PI19/01084//Instituto de Salud Carlos III/ ; PROMETEO/2018/135//Generalitat Valenciana/ ; ACCI-2019-22//Centre for Biomedical Network Research on Rare Diseases/ ; ACCI-2020//Centre for Biomedical Network Research on Rare Diseases/ ; Plan GenT CDEI-04/20-C//Conselleria de Sanitat/ ; }, abstract = {Calcium (Ca[2+]) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca[2+] homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca[2+] exchange is mediated by appositions, termed endoplasmic reticulum-mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca[2+] influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich's ataxia, and Charcot-Marie-Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca[2+] handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca[2+] signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca[2+] uptake as an emergent approach for neurological diseases.}, }
@article {pmid35052556, year = {2021}, author = {Sanghai, N and Tranmer, GK}, title = {Hydrogen Peroxide and Amyotrophic Lateral Sclerosis: From Biochemistry to Pathophysiology.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052556}, issn = {2076-3921}, support = {FOAP 320125-348000-2000//Research Manitoba New Investigator Operating Grant/ ; }, abstract = {Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.}, }
@article {pmid35052512, year = {2021}, author = {Boas, SM and Joyce, KL and Cowell, RM}, title = {The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052512}, issn = {2076-3921}, support = {1R01 NS124037/NH/NIH HHS/United States ; 1R21 NS124209/NH/NIH HHS/United States ; 5R01 NS101958/NH/NIH HHS/United States ; R01 NS124037/NS/NINDS NIH HHS/United States ; R01 NS101958/NS/NINDS NIH HHS/United States ; }, abstract = {Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a number of strategies have been proposed to activate these pathways to promote neuroprotection. Here, we briefly review the biology of the transcription factors of the NFE2/NRF family in the brain and provide evidence for the differential cellular localization of NFE2/NRF family members in the cells of the nervous system. We then discuss these findings in the context of the oxidative stress observed in two neurodegenerative diseases, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and present current strategies for activating NFE2/NRF-dependent transcription. Based on the expression of the NFE2/NRF family members in restricted populations of neurons and glia, we propose that, when designing strategies to engage these pathways for neuroprotection, the relative contributions of neuronal and non-neuronal cell types to the overall oxidative state of tissue should be considered, as well as the cell types which have the greatest intrinsic capacity for producing antioxidant enzymes.}, }
@article {pmid35052506, year = {2021}, author = {Mantle, D and Heaton, RA and Hargreaves, IP}, title = {Coenzyme Q10, Ageing and the Nervous System: An Overview.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052506}, issn = {2076-3921}, abstract = {The ageing brain is characterised by changes at the physical, histological, biochemical and physiological levels. This ageing process is associated with an increased risk of developing a number of neurological disorders, notably Alzheimer's disease and Parkinson's disease. There is evidence that mitochondrial dysfunction and oxidative stress play a key role in the pathogenesis of such disorders. In this article, we review the potential therapeutic role in these age-related neurological disorders of supplementary coenzyme Q10, a vitamin-like substance of vital importance for normal mitochondrial function and as an antioxidant. This review is concerned primarily with studies in humans rather than in vitro studies or studies in animal models of neurological disease. In particular, the reasons why the outcomes of clinical trials supplementing coenzyme Q10 in these neurological disorders is discussed.}, }
@article {pmid35048358, year = {2022}, author = {Pan, Y and Nicolazzo, JA}, title = {Altered blood-brain barrier and blood-spinal cord barrier dynamics in amyotrophic lateral sclerosis: Impact on medication efficacy and safety.}, journal = {British journal of pharmacology}, volume = {179}, number = {11}, pages = {2577-2588}, doi = {10.1111/bph.15802}, pmid = {35048358}, issn = {1476-5381}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Blood-Brain Barrier ; Central Nervous System ; Humans ; Spinal Cord ; }, abstract = {The access of drugs into the central nervous system (CNS) is regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). A large body of evidence supports perturbation of these barriers in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Modifications to the BBB and BSCB are also reported in amyotrophic lateral sclerosis (ALS), albeit these modifications have received less attention relative to those in other neurodegenerative diseases. Such alterations to the BBB and BSCB have the potential to impact on CNS exposure of drugs in ALS, modulating the effectiveness of drugs intended to reach the brain and the toxicity of drugs that are not intended to reach the brain. Given the clinical importance of these phenomena, this review will summarise reported modifications to the BBB and BSCB in ALS, discuss their impact on CNS drug exposure, and suggest further research directions so as to optimise medicine use in people with ALS.}, }
@article {pmid35043375, year = {2022}, author = {Eldeeb, MA and Ragheb, MA and Soliman, MH and Fahlman, RP}, title = {Regulation of Neurodegeneration-associated Protein Fragments by the N-degron Pathways.}, journal = {Neurotoxicity research}, volume = {40}, number = {1}, pages = {298-318}, pmid = {35043375}, issn = {1476-3524}, mesh = {Animals ; Mammals/metabolism ; Molecular Chaperones/metabolism ; *Neurodegenerative Diseases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; *Ubiquitin/metabolism ; }, abstract = {Among the most salient features that underpin the development of aging-related neurodegenerative disorders are the accumulation of protein aggregates and the decrease in cellular degradation capacity. Mammalian cells have evolved sophisticated quality control mechanisms to repair or eliminate the otherwise abnormal or misfolded proteins. Chaperones identify unstable or abnormal conformations in proteins and often help them regain their correct conformation. However, if repair is not an option, abnormal proteins are selectively degraded to prevent undesired interactions with other proteins or oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of abnormal or aberrant protein fragments. Despite an increasing understanding regarding the molecular responses that counteract the formation and clearance of dysfunctional protein aggregates, the role of N-degrons in these processes is poorly understood. Previous work demonstrated that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of neurodegeneration-associated proteins, thereby regulating crucial signaling hubs that modulate the progression of neurodegenerative diseases. Herein, we discuss the functional interconnection between N-degron pathways and proteins associated with neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. We also highlight some future prospects related to how the molecular insights gained from these processes will help unveil novel therapeutic approaches.}, }
@article {pmid35039149, year = {2022}, author = {Rhinn, H and Tatton, N and McCaughey, S and Kurnellas, M and Rosenthal, A}, title = {Progranulin as a therapeutic target in neurodegenerative diseases.}, journal = {Trends in pharmacological sciences}, volume = {43}, number = {8}, pages = {641-652}, doi = {10.1016/j.tips.2021.11.015}, pmid = {35039149}, issn = {1873-3735}, mesh = {*Frontotemporal Dementia/drug therapy/genetics/metabolism ; Humans ; Microglia ; Mutation ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Progranulins/genetics/metabolism ; }, abstract = {Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action.}, }
@article {pmid35038284, year = {2022}, author = {Agrawal, I and Tripathi, P and Biswas, S}, title = {Mass spectrometry based protein biomarkers and drug target discovery and clinical diagnosis in Age-Related progressing neurodegenerative diseases.}, journal = {Drug metabolism reviews}, volume = {54}, number = {1}, pages = {22-36}, doi = {10.1080/03602532.2022.2029475}, pmid = {35038284}, issn = {1097-9883}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/pathology ; Biomarkers ; Brain/metabolism ; Humans ; Mass Spectrometry ; *Neurodegenerative Diseases/diagnosis/drug therapy ; }, abstract = {Neurodegenerative diseases correspond to overly complex health disorders that are driven by intersecting pathophysiology that are often trapped in vicious cycles of degeneration and cognitive decline. The usual diagnostic route of these diseases is based on postmortem examination that involves identifying pathology that is specific to the disease in the brain. However, in such cases, accurate diagnosis of the specific disease is limited because clinical disease presentations are often complex that do not easily allow to discriminate patient's cognitive, behavioral, and functional impairment profiles. Additionally, an early identification and therapeutic intervention of these diseases is pivotal to slow the progression of neurodegeneration and extend healthy life span. Mass spectrometry-based techniques have proven to be hugely promising in biological sample analysis and discovery of biomarkers including protein and peptide biomarkers for potential drug target discovery. Recent studies on these biomarkers have demonstrated their potential for applications in early diagnostics and identifying therapeutic targets to battle against neurodegenerative diseases. In this review, we have presented principles of mass spectrometry (MS) and the associated workflows in analyzing and imaging biological samples for discovery of biomarkers. We have especially focused on age-related progressing neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) and the related MS-based biomarker developments for these diseases. Finally, we present a future perspective discussing the potential research directions ahead.}, }
@article {pmid35034773, year = {2022}, author = {Udayar, V and Chen, Y and Sidransky, E and Jagasia, R}, title = {Lysosomal dysfunction in neurodegeneration: emerging concepts and methods.}, journal = {Trends in neurosciences}, volume = {45}, number = {3}, pages = {184-199}, pmid = {35034773}, issn = {1878-108X}, support = {Z99 HG999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Humans ; Lysosomes/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {The understanding of lysosomes has come a long way since the initial discovery of their role in degrading cellular waste. The lysosome is now recognized as a highly dynamic organelle positioned at the crossroads of cell signaling, transcription, and metabolism. Underscoring its importance is the observation that, in addition to rare monogenic lysosomal storage disorders, genes regulating lysosomal function are implicated in common sporadic neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Developing therapies for these disorders is particularly challenging, largely due to gaps in knowledge of the underlying molecular and cellular processes. In this review, we discuss technological advances that have propelled deeper understanding of the lysosome in neurodegeneration, from elucidating the functions of lysosome-related disease risk variants at the level of the organelle, cell, and tissue, to the development of disease-specific biological models that recapitulate disease manifestations. Finally, we identify key questions to be addressed to successfully bridge the gap to the clinic.}, }
@article {pmid35034352, year = {2022}, author = {Stephenson, D and Ollivier, C and Brinton, R and Barrett, J}, title = {Can Innovative Trial Designs in Orphan Diseases Drive Advancement of Treatments for Common Neurological Diseases?.}, journal = {Clinical pharmacology and therapeutics}, volume = {111}, number = {4}, pages = {799-806}, pmid = {35034352}, issn = {1532-6535}, mesh = {Drug Approval ; Humans ; *Muscular Dystrophy, Duchenne/drug therapy ; Orphan Drug Production ; Pandemics ; Rare Diseases/drug therapy ; *COVID-19 Drug Treatment ; }, abstract = {Global regulatory agencies have transformed their approach to approvals in their processes for formal review of the safety and efficacy of new drugs. Opportunities for innovation have expanded because of the coronavirus disease 2019 (COVID-19) pandemic. Several regulatory-led initiatives have progressed rapidly during the past year, including patient-focused drug development, model-informed drug development, real-world evidence, and complex innovative trial designs. Collectively, these initiatives have accelerated the rate of approvals. Despite demands to focus on urgent needs imposed by the COVID-19 pandemic, the number of new drug approvals over the past year, particularly for rare diseases, has outpaced expectations. Advancing therapeutics for nervous system disorders requires adaptive strategies that align with rapid developments in the field. Three relentlessly progressive diseases, amyotrophic lateral sclerosis, Duchenne muscular dystrophy, and Parkinson's disease are in urgent need of new treatments. Herein, we propose new regulatory initiatives, including innovative trial designs and patient-focused drug development that accelerate clinical trial conduct while meeting critical regulatory requirements for therapeutic approval.}, }
@article {pmid35028646, year = {2021}, author = {Chou, SC and Aggarwal, A and Dawson, VL and Dawson, TM and Kam, TI}, title = {Recent advances in preventing neurodegenerative diseases.}, journal = {Faculty reviews}, volume = {10}, number = {}, pages = {81}, pmid = {35028646}, issn = {2732-432X}, abstract = {The worldwide health-care burden of neurodegenerative diseases is on the rise-a crisis created through a combination of increased caseload and lack of effective treatments. The limitations of pharmacotherapy in these disorders have led to an urgent shift toward research and clinical trials for the development of novel compounds, interventions, and methods that target shared features across the spectrum of neurodegenerative diseases. Research targets include neuronal cell death, mitochondrial dysfunction, protein aggregation, and neuroinflammation. In the past few years, there has been a growth in understanding of the pathophysiologic mechanisms of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. This increase in knowledge has led to the discovery of numerous novel neuroprotective therapeutic targets. In this context, we reviewed and summarized recent advancements in neuroprotective strategies in neurodegenerative diseases.}, }
@article {pmid35027459, year = {2022}, author = {Dharmadasa, T and Scaber, J and Edmond, E and Marsden, R and Thompson, A and Talbot, K and Turner, MR}, title = {Genetic testing in motor neurone disease.}, journal = {Practical neurology}, volume = {22}, number = {2}, pages = {107-116}, pmid = {35027459}, issn = {1474-7766}, support = {MR/L002167/1/MRC_/Medical Research Council/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; SCABER/JULY13/945-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {C9orf72 Protein/genetics ; *DNA Repeat Expansion ; *Frontotemporal Dementia/diagnosis/genetics/pathology ; Genetic Testing ; Humans ; Proteins/genetics ; }, abstract = {A minority (10%-15%) of cases of amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), are currently attributable to pathological variants in a single identifiable gene. With the emergence of new therapies targeting specific genetic subtypes of ALS, there is an increasing role for routine genetic testing for all those with a definite diagnosis. However, potential harm to both affected individuals and particularly to asymptomatic relatives can arise from the indiscriminate use of genetic screening, not least because of uncertainties around incomplete penetrance and variants of unknown significance. The most common hereditary cause of ALS, an intronic hexanucleotide repeat expansion in C9ORF72, may be associated with frontotemporal dementia independently within the same pedigree. The boundary of what constitutes a possible family history of MND has therefore extended to include dementia and associated psychiatric presentations. Notwithstanding the important role of clinical genetics specialists, all neurologists need a basic understanding of the current place of genetic testing in MND, which holds lessons for other neurological disorders.}, }
@article {pmid35017414, year = {2022}, author = {Zahedipour, F and Hosseini, SA and Henney, NC and Barreto, GE and Sahebkar, A}, title = {Phytochemicals as inhibitors of tumor necrosis factor alpha and neuroinflammatory responses in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {17}, number = {8}, pages = {1675-1684}, pmid = {35017414}, issn = {1673-5374}, abstract = {Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders. Tumor necrosis factor alpha has been reported to play a major role in the central nervous system in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and many other neurodegenerative diseases. Therefore, a potent proinflammatory/proapoptotic tumor necrosis factor alpha could be a strong candidate for targeted therapy. Plant derivatives have now become promising candidates as therapeutic agents because of their antioxidant and chemical characteristics, and anti-inflammatory features. Recently, phytochemicals including flavonoids, terpenoids, alkaloids, and lignans have generated interest as tumor necrosis factor alpha inhibitor candidates for a number of diseases involving inflammation within the nervous system. In this review, we discuss how phytochemicals as tumor necrosis factor alpha inhibitors are a therapeutic strategy targeting neurodegeneration.}, }
@article {pmid35017408, year = {2022}, author = {Liu, B and Li, M and Zhang, L and Chen, Z and Lu, P}, title = {Motor neuron replacement therapy for amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {17}, number = {8}, pages = {1633-1639}, pmid = {35017408}, issn = {1673-5374}, support = {I01 RX002264/RX/RRD VA/United States ; }, abstract = {Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig's disease in the United States, Charcot's disease in France, and motor neuron disease in the UK. The loss of motor neurons causes muscle wasting, paralysis, and eventually death, which is commonly related to respiratory failure, within 3-5 years after onset of the disease. Although there are a limited number of drugs approved for amyotrophic lateral sclerosis, they have had little success at treating the associated symptoms, and they cannot reverse the course of motor neuron degeneration. Thus, there is still a lack of effective treatment for this debilitating neurodegenerative disorder. Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers, particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons. Stem cell therapies may also be able to re-establish the motor control of voluntary muscles. Here, we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis. We focus on MN progenitor cells derived from fetal central nervous system tissue, embryonic stem cells, and induced pluripotent stem cells. In our recent studies, we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well, differentiate into motor neurons, and extend axons into the host white matter, not only in the rostrocaudal direction, but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord. Furthermore, the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis, particularly as a variety of stem cell derivatives, including induced pluripotent stem cells, are being considered for clinical trials for various diseases.}, }
@article {pmid35011673, year = {2021}, author = {Kuczynska, Z and Metin, E and Liput, M and Buzanska, L}, title = {Covering the Role of PGC-1α in the Nervous System.}, journal = {Cells}, volume = {11}, number = {1}, pages = {}, pmid = {35011673}, issn = {2073-4409}, support = {No. 2019/35/B/NZ3/04383//National Science Center/ ; }, mesh = {Central Nervous System/*metabolism ; Humans ; Organelle Biogenesis ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism ; }, abstract = {The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.}, }
@article {pmid35009270, year = {2021}, author = {Niccolini, B and Palmieri, V and De Spirito, M and Papi, M}, title = {Opportunities Offered by Graphene Nanoparticles for MicroRNAs Delivery for Amyotrophic Lateral Sclerosis Treatment.}, journal = {Materials (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {35009270}, issn = {1996-1944}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration and death of motor neurons. This neurodegenerative disease leads to muscle atrophy, paralysis, and death due to respiratory failure. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) with a length of 19 to 25 nucleotides, participating in the regulation of gene expression. Different studies have demonstrated that miRNAs deregulation is critical for the onset of a considerable number of neurodegenerative diseases, including ALS. Some studies have underlined how miRNAs are deregulated in ALS patients and for this reason, design therapies are used to correct the aberrant expression of miRNAs. With this rationale, delivery systems can be designed to target specific miRNAs. Specifically, these systems can be derived from viral vectors (viral systems) or synthetic or natural materials, including exosomes, lipids, and polymers. Between many materials used for non-viral vectors production, the two-dimensional graphene and its derivatives represent a good alternative for efficiently delivering nucleic acids. The large surface-to-volume ratio and ability to penetrate cell membranes are among the advantages of graphene. This review focuses on the specific pathogenesis of miRNAs in ALS and on graphene delivery systems designed for gene delivery to create a primer for future studies in the field.}, }
@article {pmid35008771, year = {2021}, author = {Liu, Y and Ding, R and Xu, Z and Xue, Y and Zhang, D and Zhang, Y and Li, W and Li, X}, title = {Roles and Mechanisms of the Protein Quality Control System in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {1}, pages = {}, pmid = {35008771}, issn = {1422-0067}, support = {81872626//National Natural Science Foundation of China/ ; 82003454//National Natural Science Foundation of China/ ; CNS-BMSG2020A63//Bright Moon Seaweed Group Nutrition and Health Research Fund/ ; CNS-ZD2019066//Zhen Dong National Physical Fitness and Health Research Fund/ ; No. 212102310219//Key R&amp;D and promotion projects in Henan Province/ ; }, mesh = {Alzheimer Disease/*metabolism/pathology ; Animals ; Autophagy ; Clinical Trials as Topic ; Endoplasmic Reticulum Stress ; Humans ; Lysosomes/metabolism ; Proteins/*metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs), as well as neuronal dysfunctions in the brain, but in fact, patients have shown a sustained disease progression for at least 10 to 15 years before these pathologic biomarkers can be detected. Consequently, as the most common chronic neurological disease in the elderly, the challenge of AD treatment is that it is short of effective biomarkers for early diagnosis. The protein quality control system is a collection of cellular pathways that can recognize damaged proteins and thereby modulate their turnover. Abundant evidence indicates that the accumulation of abnormal proteins in AD is closely related to the dysfunction of the protein quality control system. In particular, it is the synthesis, degradation, and removal of essential biological components that have already changed in the early stage of AD, which further encourages us to pay more attention to the protein quality control system. The review mainly focuses on the endoplasmic reticulum system (ERS), autophagy-lysosome system (ALS) and the ubiquitin-proteasome system (UPS), and deeply discusses the relationship between the protein quality control system and the abnormal proteins of AD, which can not only help us to understand how and why the complex regulatory system becomes malfunctional during AD progression, but also provide more novel therapeutic strategies to prevent the development of AD.}, }
@article {pmid35008513, year = {2021}, author = {Zingale, VD and Gugliandolo, A and Mazzon, E}, title = {MiR-155: An Important Regulator of Neuroinflammation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {1}, pages = {}, pmid = {35008513}, issn = {1422-0067}, support = {Current Research Funds 2021//Ministero della Salute/ ; }, mesh = {Animals ; Central Nervous System/pathology ; Humans ; MicroRNAs/*genetics ; Neuroinflammatory Diseases/*genetics/pathology ; }, abstract = {MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and that play an important role in many cellular processes, including modulation of inflammation. MiRNAs are present in high concentrations in the central nervous system (CNS) and are spatially and temporally expressed in a specific way. Therefore, an imbalance in the expression pattern of these small molecules can be involved in the development of neurological diseases. Generally, CNS responds to damage or disease through the activation of an inflammatory response, but many neurological disorders are characterized by uncontrolled neuroinflammation. Many studies support the involvement of miRNAs in the activation or inhibition of inflammatory signaling and in the promotion of uncontrolled neuroinflammation with pathological consequences. MiR-155 is a pro-inflammatory mediator of the CNS and plays an important regulatory role. The purpose of this review is to summarize how miR-155 is regulated and the pathological consequences of its deregulation during neuroinflammatory disorders, including multiple sclerosis, Alzheimer's disease and other neuroinflammatory disorders. Modulation of miRNAs' expression could be used as a therapeutic strategy in the treatment of pathological neuroinflammation.}, }
@article {pmid35002606, year = {2021}, author = {Benson, BC and Shaw, PJ and Azzouz, M and Highley, JR and Hautbergue, GM}, title = {Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {783624}, pmid = {35002606}, issn = {1662-4548}, support = {MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; MR/S004920/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.}, }
@article {pmid35000037, year = {2022}, author = {Liu, L and Li, J and Ke, Y and Zeng, X and Gao, J and Ba, X and Wang, R}, title = {The key players of parthanatos: opportunities for targeting multiple levels in the therapy of parthanatos-based pathogenesis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {1}, pages = {60}, pmid = {35000037}, issn = {1420-9071}, support = {31900557//National Natural Science Foundation of China/ ; 31970686//National Natural Science Foundation of China/ ; 31801182//National Natural Science Foundation of China/ ; 2019M662431//Postdoctoral Research Foundation of China/ ; }, mesh = {Active Transport, Cell Nucleus/physiology ; Apoptosis Inducing Factor/metabolism ; *DNA Fragmentation ; Humans ; Intramolecular Oxidoreductases/*metabolism ; Macrophage Migration-Inhibitory Factors/*metabolism ; Mitochondria/metabolism ; Neurodegenerative Diseases/drug therapy/*pathology ; Parthanatos/*physiology ; Poly (ADP-Ribose) Polymerase-1/*metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; }, abstract = {Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis.}, }
@article {pmid34997540, year = {2022}, author = {Verma, S and Khurana, S and Vats, A and Sahu, B and Ganguly, NK and Chakraborti, P and Gourie-Devi, M and Taneja, V}, title = {Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {59}, number = {3}, pages = {1502-1527}, pmid = {34997540}, issn = {1559-1182}, support = {09/591(0150)/2018-EMR-I//council&#xa0;of&#xa0;scientific and industrial research, india/ ; BMS/Adhoc/BIOCHEM/2015-0430//indian council of medical research/ ; 3/1/3/JRF-2012/HRD//indian council of medical research/ ; BIC/05 (09)/Indo-Russian/2016//indian council of medical research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Humans ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Neuromuscular Junction ; Superoxide Dismutase-1 ; Synapses/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting "dying back" hypothesis. Despite several evidences, series of events triggering NMJ disassembly in ALS are still obscure. Neuromuscular junction is a specialized tripartite chemical synapse which involves a well-coordinated communication among the presynaptic motor neuron, postsynaptic skeletal muscle, and terminal Schwann cells. This review provides comprehensive insight into the role of NMJ in ALS pathogenesis. We have emphasized the molecular alterations in cellular components of NMJ leading to loss of effective neuromuscular transmission in ALS. Further, we provide a preview into research involved in exploring NMJ as potential target for designing effective therapies for ALS.}, }
@article {pmid34995492, year = {2022}, author = {Giacomelli, E and Vahsen, BF and Calder, EL and Xu, Y and Scaber, J and Gray, E and Dafinca, R and Talbot, K and Studer, L}, title = {Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation.}, journal = {Cell stem cell}, volume = {29}, number = {1}, pages = {11-35}, pmid = {34995492}, issn = {1875-9777}, support = {R21 NS116545/NS/NINDS NIH HHS/United States ; R01 NS093872/NS/NINDS NIH HHS/United States ; TALBOT/OCT15/886-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 AG054720/AG/NIA NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; TALBOT-MUTIHAC/APR15/832-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Induced Pluripotent Stem Cells ; Neuroglia ; Neurons ; }, abstract = {Neurodegenerative diseases are characterized by progressive cell loss leading to disruption of the structure and function of the central nervous system. Amyotrophic lateral sclerosis (ALS) was among the first of these disorders modeled in patient-specific iPSCs, and recent findings have translated into some of the earliest iPSC-inspired clinical trials. Focusing on ALS as an example, we evaluate the status of modeling neurodegenerative diseases using iPSCs, including methods for deriving and using disease-relevant neuronal and glial lineages. We further highlight the remaining challenges in exploiting the full potential of iPSC technology for understanding and potentially treating neurodegenerative diseases such as ALS.}, }
@article {pmid34994876, year = {2022}, author = {Turalde, CWR and Moalong, KMC and Espiritu, AI and Prado, MB}, title = {Perampanel for amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {2}, pages = {889-897}, pmid = {34994876}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neurodegenerative Diseases ; Nitriles ; Pyridones/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease. There is still no established cost-effective treatment that can improve functional status and survival of ALS patients. Perampanel, by inhibiting neuronal calcium ion influx and preventing dyslocalization of nuclear proteins, has the potential to ameliorate ALS neurodegeneration.<br><br>OBJECTIVES: This study aims to determine the efficacy and safety of perampanel among ALS patients in terms of improvement in functional status using a review of relevant studies.<br><br>METHODS: MedLine, Cochrane Central Register for Controlled Trials, Scopus, Embase, Literatura Latino-Americana e do Caribe em Ci&#xea;ncias da Sa&#xfa;de, ClinicalTrials.gov website, and HERDIN databases were searched from inception to August 2021 for relevant studies.<br><br>RESULTS: The search yielded 132 articles; 3 studies were included in the analysis. Pooled evidence shows that perampanel compared to placebo significantly improves cortical motor hyperexcitability but not the ALS functional rating scale-revised score. Perampanel is associated with adverse events such as aggression, somnolence, anger, and dysarthria.<br><br>CONCLUSION: There is no sufficient evidence to support the role of perampanel in improving functional status of ALS patients. Although it can ameliorate motor cortical hyperexcitability, its clinical benefit has not yet been elucidated. Perampanel is not well tolerated among ALS patients as it is associated with adverse events such as aggression, somnolence, anger, and dysarthria. Further studies investigating the role of perampanel early in the ALS disease course, excluding ALS patients with frontotemporal lobe degeneration features and C9ORF72 repeat expansion, and using gradual drug titration schedule are needed to evaluate the potential benefit of perampanel in ALS.}, }
@article {pmid34992959, year = {2021}, author = {Edwards, WF and Malik, S and Peters, J and Chippendale, I and Ravits, J}, title = {Delivering Bad News in Amyotrophic Lateral Sclerosis: Proposal of Specific Technique ALS ALLOW.}, journal = {Neurology. Clinical practice}, volume = {11}, number = {6}, pages = {521-526}, pmid = {34992959}, issn = {2163-0402}, abstract = {PURPOSE OF REVIEW: Physician communication skills are a critical part of care for amyotrophic lateral sclerosis (ALS) patients and caregivers. They shape the development of autonomy and quality of life, and they mitigate emotional trauma. Communication skills are especially critical at 2 different time points in the course of the disease: early when delivering and establishing the diagnosis, and later when clarifying goals of care.<br><br>RECENT FINDINGS: Several techniques for physician communication of difficult information are available, including SPIKES (Setting up the interview, assessing the patient's Perception, obtaining the patient's Invitation, giving Knowledge and information to the patient, addressing the patient's Emotions with Empathetic responses, and Strategy and Summary), ABCDE (Advance preparation, Build a therapeutic environment/relationship, Communicate well, Deal with patient and family reactions, Encourage and validate emotions), and BREAKS (Background, Rapport, Exploring, Announce, Kindling, Summarize). These emphasize the physician's accountability and responsibility for communicating effectively. Formal training in these techniques is limited, and their applicability specifically to ALS is inexact.<br><br>SUMMARY: We propose an ALS-specific technique which we call ALS ALLOW to guide physicians in conducting difficult communications with ALS patients and caregivers to develop their understanding, establish autonomy, set goals, and mitigate emotional trauma. The techniques are useful in discussions both early and late stages in the disease.}, }
@article {pmid34992533, year = {2021}, author = {Shah, S and Dooms, MM and Amaral-Garcia, S and Igoillo-Esteve, M}, title = {Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {768023}, pmid = {34992533}, issn = {1663-9812}, abstract = {Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.}, }
@article {pmid34989812, year = {2022}, author = {Singh, S and Sahu, K and Singh, C and Singh, A}, title = {Lipopolysaccharide induced altered signaling pathways in various neurological disorders.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {395}, number = {3}, pages = {285-294}, pmid = {34989812}, issn = {1432-1912}, mesh = {Animals ; Cytokines/metabolism ; Humans ; Lipopolysaccharides/*toxicity ; Nervous System Diseases/*physiopathology ; Neuroinflammatory Diseases/*physiopathology ; Signal Transduction/physiology ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptors/metabolism ; }, abstract = {Neuroinflammation is defined as an inflammatory response within the brain or spinal cord, whereas the brain's innate immune system is triggered by various inflammatory challenges such as injury, infection, exposure to toxin (LPS) and ageing, which result in cognitive impairment and neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Lipopolysaccharide (LPS) is a main structural component of the outer membrane of gram-negative bacteria, widely used systematically to stimulate the immune system and to generate profound physiological and behavioural changes. It consists of three parts: lipid A, a core oligosaccharide and an O side chain. It is reported by several scientists that, besides the systemic alteration, LPS also induces neurodegeneration by promoting neuroinflammation upon binding with the stimulation of Toll-like receptor-4 (TLR4) receptors present on glial cells. The mammalian Toll-like receptor (TLR) family consists of 13 membranes and TLR was discovered as a crucial pattern recognition receptor (PPR) involved in the recognition of pathogen-associated molecular patterns (PAMPs). Future studies will show that damage/danger-associated molecular patterns (DAMPs) are recognised by the involvement of PPRs, generated by the host itself. The stimulation of TLR4 by lipopolysaccharide phosphorylates two signalling pathways, namely the MyD88-dependent pathway and the MyD88-independent pathway. This activation subsequently triggers the release of various pro-inflammatory cytokines that are necessary to activate innate immune responses, and then promotes neuroinflammation. In this review, we critically demonstrated the epidemiology of neuroinflammation, types of TLRs, the molecular mechanism of TLR4 and management of neuroinflammation.}, }
@article {pmid34983696, year = {2022}, author = {Jablonka, S and Hennlein, L and Sendtner, M}, title = {Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders.}, journal = {Neurological research and practice}, volume = {4}, number = {1}, pages = {2}, pmid = {34983696}, issn = {2524-3489}, support = {JA 1823/3-1//deutsche forschungsgemeinschaft/ ; 2-1//deutsche forschungsgemeinschaft/ ; SE 697/6-1//deutsche forschungsgemeinschaft/ ; 4-2//deutsche forschungsgemeinschaft/ ; 5-2//deutsche forschungsgemeinschaft/ ; 7-1//deutsche forschungsgemeinschaft/ ; CalsER Network//bmbf/ ; JAB1920//cure sma/ ; }, abstract = {BACKGROUND: Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration.<br><br>MAIN BODY: Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders.<br><br>CONCLUSION: RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.}, }
@article {pmid34979259, year = {2022}, author = {Ma, R and Kutchy, NA and Chen, L and Meigs, DD and Hu, G}, title = {Primary cilia and ciliary signaling pathways in aging and age-related brain disorders.}, journal = {Neurobiology of disease}, volume = {163}, number = {}, pages = {105607}, pmid = {34979259}, issn = {1095-953X}, support = {R01 DA043138/DA/NIDA NIH HHS/United States ; R01 MH112848/MH/NIMH NIH HHS/United States ; R21 DA042704/DA/NIDA NIH HHS/United States ; P30 MH062261/MH/NIMH NIH HHS/United States ; R21 DA046831/DA/NIDA NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Animals ; Astrocytes/metabolism ; Brain/*metabolism ; Brain Diseases/*metabolism ; Cilia/*metabolism ; Humans ; Neurons/metabolism ; Signal Transduction/*physiology ; }, abstract = {Brain disorders are characterized by the progressive loss of structure and function of the brain as a consequence of progressive degeneration and/or death of nerve cells. Aging is a major risk factor for brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. Various cellular and molecular events have been shown to play a role in the progress of neurodegenerative diseases. Emerging studies suggest that primary cilia could be a key regulator in brain diseases. The primary cilium is a singular cellular organelle expressed on the surface of many cell types, such as astrocytes and neurons in the mature brain. Primary cilia detect extracellular cues, such as Sonic Hedgehog (SHH) protein, and transduce these signals into cells to regulate various signaling pathways. Abnormalities in ciliary length and frequency (ratio of ciliated cells) have been implicated in various human diseases, including brain disorders. This review summarizes current findings and thoughts on the role of primary cilia and ciliary signaling pathways in aging and age-related brain disorders.}, }
@article {pmid34975460, year = {2021}, author = {Gao, P and Li, X and Du, X and Liu, S and Xu, Y}, title = {Diagnostic and Therapeutic Potential of Exosomes in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {790863}, pmid = {34975460}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are closely related to brain function and the progression of the diseases are irreversible. Due to brain tissue being not easy to acquire, the study of the pathophysiology of neurodegenerative disorders has many limitations-lack of reliable early biomarkers and personalized treatment. At the same time, the blood-brain barrier (BBB) limits most of the drug molecules into the damaged areas of the brain, which makes a big drop in the effect of drug treatment. Exosomes, a kind of endogenous nanoscale vesicles, play a key role in cell signaling through the transmission of genetic information and proteins between cells. Because of the ability to cross the BBB, exosomes are expected to link peripheral changes to central nervous system (CNS) events as potential biomarkers, and can even be used as a therapeutic carrier to deliver molecules specifically to CNS. Here we summarize the role of exosomes in pathophysiology, diagnosis, prognosis, and treatment of some neurodegenerative diseases (Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis).}, }
@article {pmid34975412, year = {2021}, author = {Pasniceanu, IS and Atwal, MS and Souza, CDS and Ferraiuolo, L and Livesey, MR}, title = {Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {784833}, pmid = {34975412}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.}, }
@article {pmid34975400, year = {2021}, author = {Wang, H and Kodavati, M and Britz, GW and Hegde, ML}, title = {DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {784361}, pmid = {34975400}, issn = {1662-5099}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.}, }
@article {pmid34974309, year = {2022}, author = {Vasta, R and Chia, R and Traynor, BJ and Chiò, A}, title = {Unraveling the complex interplay between genes, environment, and climate in ALS.}, journal = {EBioMedicine}, volume = {75}, number = {}, pages = {103795}, pmid = {34974309}, issn = {2352-3964}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/etiology/genetics ; Biodiversity ; Genetic Predisposition to Disease ; Humans ; Temperature ; }, abstract = {Various genetic and environmental risk factors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, the cause of most ALS cases remains obscure. In this review, we describe the current evidence implicating genetic and environmental factors in motor neuron degeneration. While the risk exerted by many environmental factors may appear small, their effect could be magnified by the presence of a genetic predisposition. We postulate that gene-environment interactions account for at least a portion of the unknown etiology in ALS. Climate underlies multiple environmental factors, some of which have been implied in ALS etiology, and the impact of global temperature increase on the gene-environment interactions should be carefully monitored. We describe the main concepts underlying such interactions. Although a lack of large cohorts with detailed genetic and environmental information hampers the search for gene-environment interactions, newer algorithms and machine learning approaches offer an opportunity to break this stalemate. Understanding how genetic and environmental factors interact to cause ALS may ultimately pave the way towards precision medicine becoming an integral part of ALS care.}, }
@article {pmid34974247, year = {2022}, author = {Xu, K and Ji, H and Hu, N}, title = {Cardiovascular comorbidities in amyotrophic lateral sclerosis: A systematic review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {96}, number = {}, pages = {43-49}, doi = {10.1016/j.jocn.2021.12.021}, pmid = {34974247}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; *Cardiovascular Diseases/epidemiology ; Comorbidity ; Humans ; *Hypertension/epidemiology ; Incidence ; }, abstract = {OBJECTIVE: To summarize the prevalence of the cardiovascular comorbidities in patients with amyotrophic lateral sclerosis (ALS) and explore the impacts of cardiovascular diseases on ALS.<br><br>METHODS: PubMed, EMBASE, OVID and Web of Science were searched systematically until July 2021 for studies on the prevalence of cardiovascular diseases among ALS patients or quantitatively investigating the effects of cardiovascular comorbidities on incidence, progression or survival of ALS. We conducted a fixed-effects or random-effects meta-analysis to calculate the summary rate or ORs (odds ratios) with 95 %CIs (confidence intervals).<br><br>RESULTS: The comorbidity of hypertension in France (56.9%) was the highest, followed by Portugal (48%). Only 15% of Chinese ALS patients suffered from hypertension. A quarter of ALS patients in America had coronary heart disease while only 4-5% of patients with ALS in Australia or the Netherlands suffered from coronary heart disease. There was significant relationship between hypertension and survival of ALS (OR: 1.04, 95%CI: 1.01, 1.07). Coronary heart disease was considerably related to ALS onset (OR: 1.19, 95%CI: 1.14, 1.24) and heart failure could noticeably accelerate the progression rate of ALS (OR: 6.33, 95%CI: 1.55, 24.84).<br><br>CONCLUSIONS: Cardiovascular comorbidities in ALS patients varied significantly with different regions. Hypertension could reduce the survival of ALS so the intensive treatment of chronic hypertension should be recommended to ALS patients in clinical practice. Coronary heart disease could increase the risk of ALS and heart failure was a negative prognostic factor for ALS, which deserved more attention of clinicians.}, }
@article {pmid34973105, year = {2022}, author = {Re, DB and Yan, B and Calderón-Garcidueñas, L and Andrew, AS and Tischbein, M and Stommel, EW}, title = {A perspective on persistent toxicants in veterans and amyotrophic lateral sclerosis: identifying exposures determining higher ALS risk.}, journal = {Journal of neurology}, volume = {269}, number = {5}, pages = {2359-2377}, pmid = {34973105}, issn = {1432-1459}, support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Environmental Exposure/adverse effects ; Humans ; *Military Personnel ; Risk Factors ; United States/epidemiology ; *Veterans ; }, abstract = {Multiple studies indicate that United States veterans have an increased risk of developing amyotrophic lateral sclerosis (ALS) compared to civilians. However, the responsible etiological factors are unknown. In the general population, specific occupational (e.g. truck drivers, airline pilots) and environmental exposures (e.g. metals, pesticides) are associated with an increased ALS risk. As such, the increased prevalence of ALS in veterans strongly suggests that there are exposures experienced by military personnel that are disproportionate to civilians. During service, veterans may encounter numerous neurotoxic exposures (e.g. burn pits, engine exhaust, firing ranges). So far, however, there is a paucity of studies investigating environmental factors contributing to ALS in veterans and even fewer assessing their exposure using biomarkers. Herein, we discuss ALS pathogenesis in relation to a series of persistent neurotoxicants (often emitted as mixtures) including: chemical elements, nanoparticles and lipophilic toxicants such as dioxins, polycyclic aromatic hydrocarbons and polychlorinated biphenyls. We propose these toxicants should be directly measured in veteran central nervous system tissue, where they may have accumulated for decades. Specific toxicants (or mixtures thereof) may accelerate ALS development following a multistep hypothesis or act synergistically with other service-linked exposures (e.g. head trauma/concussions). Such possibilities could explain the lower age of onset observed in veterans compared to civilians. Identifying high-risk exposures within vulnerable populations is key to understanding ALS etiopathogenesis and is urgently needed to act upon modifiable risk factors for military personnel who deserve enhanced protection during their years of service, not only for their short-term, but also long-term health.}, }
@article {pmid34971691, year = {2022}, author = {Newell, ME and Adhikari, S and Halden, RU}, title = {Systematic and state-of the science review of the role of environmental factors in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease.}, journal = {The Science of the total environment}, volume = {817}, number = {}, pages = {152504}, doi = {10.1016/j.scitotenv.2021.152504}, pmid = {34971691}, issn = {1879-1026}, mesh = {*Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; Animals ; Formaldehyde ; Humans ; *Mercury ; Mice ; *Selenium ; Zinc ; }, abstract = {The etiology of sporadic amyotrophic lateral sclerosis (ALS) is still unclear. We evaluate environmental factors suspected to be associated with ALS for their potential linkage to disease causality and to model geographic distributions of susceptible populations and expected cases worldwide. A PRISMA systematic literature review was performed 2021. Bradford Hill criteria were used to identify and rank environmental factors and a secondary review of ALS diagnoses in population studies and ALS case or cohort studies was conducted. Prevalence rate projection informed estimates of impacted regions and populations. Among 1710 papers identified, 258 met the inclusion criteria, of which 173 responded to at least one of nine Bradford Hill criteria among 83 literature-identified ALS environmental factors. Environmental determinants of ALS in order of decreasing significance were β-N-methylamino-L-alanine (BMAA), formaldehyde, selenium, and heavy metals including manganese, mercury, zinc, and copper. Murine animal models were the most common methodology for exploring environmental factors. Another line of investigation of 62 population exposure studies implicated the same group of environmental agents (mean odds ratios): BMAA (2.32), formaldehyde (1.54), heavy metals (2.99), manganese (3.85), mercury (2.74), and zinc (2.78). An age-adjusted incidence model estimated current total ALS cases globally at ~85,000 people compared to only ~1600 cases projected from the reported ALS incidence in the literature. Modeling with the prevalence microscope equation forecasted an increase in U.S. ALS cases from 16,707 confirmed in 2015 to ~22,650 projected for 2040. Two orthogonal methods employed implicate BMAA, formaldehyde, manganese, mercury, and zinc as environmental factors with strong ALS associations. ALS cases likely are significantly underreported globally, and high vulnerability exists in regions with large aging populations. Recent studies on other diseases with environmental determinants suggest the need to consider additional potential triggers and mechanisms, including exposures to microbial agents and epigenetic modifications.}, }
@article {pmid34970118, year = {2021}, author = {Liu, E and Karpf, L and Bohl, D}, title = {Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {767041}, pmid = {34970118}, issn = {1662-5099}, abstract = {Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.}, }
@article {pmid34965490, year = {2022}, author = {Chaudhary, R and Agarwal, V and Rehman, M and Kaushik, AS and Mishra, V}, title = {Genetic architecture of motor neuron diseases.}, journal = {Journal of the neurological sciences}, volume = {434}, number = {}, pages = {120099}, doi = {10.1016/j.jns.2021.120099}, pmid = {34965490}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Motor Neuron Disease/genetics/pathology ; Motor Neurons/pathology ; *Muscular Atrophy, Spinal/genetics ; *Spastic Paraplegia, Hereditary/genetics ; }, abstract = {Motor neuron diseases (MNDs) are rare and frequently fatal neurological disorders in which motor neurons within the brainstem and spinal cord regions slowly die. MNDs are primarily caused by genetic mutations, and > 100 different mutant genes in humans have been discovered thus far. Given the fact that many more MND-related genes have yet to be discovered, the growing body of genetic evidence has offered new insights into the diverse cellular and molecular mechanisms involved in the aetiology and pathogenesis of MNDs. This search may aid in the selection of potential candidate genes for future investigation and, eventually, may open the door to novel interventions to slow down disease progression. In this review paper, we have summarized detailed existing research findings of different MNDs, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal bulbar muscle atrophy (SBMA) and hereditary spastic paraplegia (HSP) in relation to their complex genetic architecture.}, }
@article {pmid34963564, year = {2022}, author = {Altinoz, MA and Guloksuz, S and Ozpinar, A}, title = {Immunomodifying and neuroprotective effects of noscapine: Implications for multiple sclerosis, neurodegenerative, and psychiatric disorders.}, journal = {Chemico-biological interactions}, volume = {352}, number = {}, pages = {109794}, doi = {10.1016/j.cbi.2021.109794}, pmid = {34963564}, issn = {1872-7786}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Bradykinin/metabolism ; Histamine Antagonists/pharmacology ; Humans ; Immunomodulating Agents/*pharmacology ; Ion Channels/drug effects ; Mental Disorders/drug therapy ; Multiple Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/*pharmacology ; Noscapine/administration &amp; dosage/blood/*pharmacology ; Oligodendroglia/drug effects ; Parkinsonian Disorders/drug therapy ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/drug effects ; Stroke/drug therapy ; }, abstract = {Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.}, }
@article {pmid34962222, year = {2022}, author = {Ketola, J and Jahangiri, E and Hakko, H and Riipinen, P and Räsänen, S}, title = {Assisted living for mentally ill-a systematic literature review and its recommendations.}, journal = {Nordic journal of psychiatry}, volume = {76}, number = {6}, pages = {403-422}, doi = {10.1080/08039488.2021.2001568}, pmid = {34962222}, issn = {1502-4725}, mesh = {Adult ; Hospitals, Psychiatric ; Housing ; Humans ; Male ; *Mental Disorders/therapy ; *Mentally Ill Persons ; Quality of Life ; }, abstract = {BACKGROUND: The reduction in psychiatric hospital beds in the past decades has created a need for assisted living (AL). Even though AL is widely used, studies on it are scarce.<br><br>AIMS: To identify (1) study characteristics of the reviewed articles, (2) characteristics of inhabitants and characteristics of different types of AL, (3) financial costs in different types of AL, (4) the individual outcomes in AL inhabitants and quality of care.<br><br>METHODS: A systematic literature review on AL for the mentally ill focusing on inhabitant and AL features and their costs was conducted. Articles written in English from January 2000 to June of 2020, concerning adults were included. Simple Taxonomy of Supported Housing (STAX-SA) was applied and used for categorizing types of AL.<br><br>RESULTS: Twenty-five papers met our criteria. The majority of inhabitants were unemployed single male with psychotic disorders. The type of AL is mainly categorized according to staffing, provided support, and housing arrangement. In UK ALs with moderate support (STAX-SA 2-3) had the best quality of care while ALs with low support (STAX-SA 4) was the cheapest. Quality of care was better in small units with preset expected length of stay for inhabitants. Hospital treatment was significantly more expensive than any type of AL. Living in AL improved quality of life compared to hospital treatment, also psychiatric symptoms were reduced.<br><br>CONCLUSION: There is an evident need for evidence-based studies in a longitudinal comprehensive manner that evaluates different AL types, function of the inhabitants, and costs with respect to the quality of AL and care and outcome.}, }
@article {pmid34960353, year = {2021}, author = {Breasail, M&#xd3; and Biswas, B and Smith, MD and Mazhar, MKA and Tenison, E and Cullen, A and Lithander, FE and Roudaut, A and Henderson, EJ}, title = {Wearable GPS and Accelerometer Technologies for Monitoring Mobility and Physical Activity in Neurodegenerative Disorders: A Systematic Review.}, journal = {Sensors (Basel, Switzerland)}, volume = {21}, number = {24}, pages = {}, pmid = {34960353}, issn = {1424-8220}, support = {GAT3676//The Gatsby Foundation/ ; }, mesh = {Accelerometry ; Exercise ; Geographic Information Systems ; Humans ; *Neurodegenerative Diseases ; Technology ; *Wearable Electronic Devices ; }, abstract = {Neurodegenerative disorders (NDDs) constitute an increasing global burden and can significantly impair an individual's mobility, physical activity (PA), and independence. Remote monitoring has been difficult without relying on diaries/questionnaires which are more challenging for people with dementia to complete. Wearable global positioning system (GPS) sensors and accelerometers present a cost-effective and noninvasive way to passively monitor mobility and PA. In addition, changes in sensor-derived outcomes (such as walking behaviour, sedentary, and active activity) may serve as potential biomarkers of disease onset, progression, and response to treatment. We performed a systematic search across four databases to identify papers published within the past 5 years, in which wearable GPS or accelerometers were used to monitor mobility or PA in patients with common NDDs (Parkinson's disease, Alzheimer's disease, motor neuron diseases/amyotrophic lateral sclerosis, vascular parkinsonism, and vascular dementia). Disease and technology-specific vocabulary were searched singly, and then in combination, identifying 4985 papers. Following deduplication, we screened 3115 papers and retained 28 studies following a full text review. One study used wearable GPS and accelerometers, while 27 studies used solely accelerometers in NDDs. GPS-derived measures had been validated against current gold standard measures in one Parkinson's cohort, suggesting that the technology may be applicable to other NDDs. In contrast, accelerometers are widely utilised in NDDs and have been operationalised in well-designed clinical trials.}, }
@article {pmid34959661, year = {2021}, author = {Ozturk, M and Nilsen-Hamilton, M and Ilgu, M}, title = {Aptamer Applications in Neuroscience.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {34959661}, issn = {1424-8247}, abstract = {Being the predominant cause of disability, neurological diseases have received much attention from the global health community. Over a billion people suffer from one of the following neurological disorders: dementia, epilepsy, stroke, migraine, meningitis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, prion disease, or brain tumors. The diagnosis and treatment options are limited for many of these diseases. Aptamers, being small and non-immunogenic nucleic acid molecules that are easy to chemically modify, offer potential diagnostic and theragnostic applications to meet these needs. This review covers pioneering studies in applying aptamers, which shows promise for future diagnostics and treatments of neurological disorders that pose increasingly dire worldwide health challenges.}, }
@article {pmid34959337, year = {2021}, author = {González, LF and Bevilacqua, LE and Naves, R}, title = {Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases.}, journal = {Pharmaceutics}, volume = {13}, number = {12}, pages = {}, pmid = {34959337}, issn = {1999-4923}, support = {1191874//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; }, abstract = {Mitochondria are vital organelles in eukaryotic cells that control diverse physiological processes related to energy production, calcium homeostasis, the generation of reactive oxygen species, and cell death. Several studies have demonstrated that structural and functional mitochondrial disturbances are involved in the development of different neuroinflammatory (NI) and neurodegenerative (ND) diseases (NI&amp;NDDs) such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Remarkably, counteracting mitochondrial impairment by genetic or pharmacologic treatment ameliorates neurodegeneration and clinical disability in animal models of these diseases. Therefore, the development of nanosystems enabling the sustained and selective delivery of mitochondria-targeted drugs is a novel and effective strategy to tackle NI&amp;NDDs. In this review, we outline the impact of mitochondrial dysfunction associated with unbalanced mitochondrial dynamics, altered mitophagy, oxidative stress, energy deficit, and proteinopathies in NI&amp;NDDs. In addition, we review different strategies for selective mitochondria-specific ligand targeting and discuss novel nanomaterials, nanozymes, and drug-loaded nanosystems developed to repair mitochondrial function and their therapeutic benefits protecting against oxidative stress, restoring cell energy production, preventing cell death, inhibiting protein aggregates, and improving motor and cognitive disability in cellular and animal models of different NI&amp;NDDs.}, }
@article {pmid34958957, year = {2022}, author = {Rossi Sebastiano, M and Ermondi, G and Hadano, S and Caron, G}, title = {AI-based protein structure databases have the potential to accelerate rare diseases research: AlphaFoldDB and the case of IAHSP/Alsin.}, journal = {Drug discovery today}, volume = {27}, number = {6}, pages = {1652-1660}, doi = {10.1016/j.drudis.2021.12.018}, pmid = {34958957}, issn = {1878-5832}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Artificial Intelligence ; Databases, Protein ; Humans ; Rare Diseases/drug therapy ; *Spastic Paraplegia, Hereditary ; }, abstract = {Artificial intelligence (AI)-based protein structure databases are expected to have an impact on drug discovery. Here, we show how AlphaFold could support rare diseases research programs. We focus on Alsin, a protein responsible for rare motor neuron diseases, such as infantile-onset ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS), and involved in some cases of amyotrophic lateral sclerosis (ALS). First, we compared the AlphaFoldDB human Alsin model with homology models of Alsin domains. We then evaluated the flexibility profile of Alsin and of experimentally characterized mutants present in patients with IAHSP. Next, we compared preliminary models of dimeric/tetrameric Alsin responsible for its physiological action with hypothetical models reported in the literature. Finally, we suggest the best animal model for drug candidates testing. Overall, we computationally show that drug discovery efforts toward Alsin-involving diseases should be pursued.}, }
@article {pmid34958750, year = {2022}, author = {Mitra, A and Sarkar, N}, title = {The role of intra and inter-molecular disulfide bonds in modulating amyloidogenesis: A review.}, journal = {Archives of biochemistry and biophysics}, volume = {716}, number = {}, pages = {109113}, doi = {10.1016/j.abb.2021.109113}, pmid = {34958750}, issn = {1096-0384}, mesh = {Alzheimer Disease/etiology ; Amyloidogenic Proteins/*chemistry/metabolism ; Amyloidosis/*etiology ; Amyotrophic Lateral Sclerosis/etiology ; Diabetes Mellitus, Type 2/etiology ; Disulfides/*chemistry/metabolism ; Humans ; Insulin/chemistry ; Intramolecular Lyases/chemistry ; Models, Molecular ; Phosphatidylinositols/metabolism ; Prion Diseases/ethnology ; Protein Aggregates ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; }, abstract = {All proteins have the inherent ability to undergo transformation from their native structure to a β sheet rich fibrillar structure, called amyloid when subjected to specific conditions. Proteins with a high propensity to form amyloid fibrils have been implicated in a variety of disorders like Alzheimer's disease, Parkinson's disease, Type II diabetes, Amyotrophic Lateral Sclerosis (ALS) and prion diseases. Among the various critical factors that modulate the process of amyloid formation, disulfide bonds have been identified as one of the key determinants of amyloid propensity in proteins. Studies have shown that intra-molecular disulfide bonds impart stability to the native structure of a protein and decrease the tendency for amyloid aggregation, whereas intermolecular disulfide bonds aid in the process of aggregation. In this review, we will analyze the varying effects of both intra as well as inter-molecular disulfide bonds on the amyloid aggregation propensities of a few proteins associated with amyloid disorders.}, }
@article {pmid34955753, year = {2021}, author = {Taylor, HBC and Jeans, AF}, title = {Friend or Foe? The Varied Faces of Homeostatic Synaptic Plasticity in Neurodegenerative Disease.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {782768}, pmid = {34955753}, issn = {1662-5102}, support = {G0802812/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Homeostatic synaptic plasticity (HSP) regulates synaptic strength both pre- and postsynaptically to ensure stability and efficient information transfer in neural networks. A number of neurological diseases have been associated with deficits in HSP, particularly diseases characterised by episodic network instability such as migraine and epilepsy. Recently, it has become apparent that HSP also plays a role in many neurodegenerative diseases. In this mini review, we present an overview of the evidence linking HSP to each of the major neurodegenerative diseases, finding that HSP changes in each disease appear to belong to one of three broad functional categories: (1) deficits in HSP at degenerating synapses that contribute to pathogenesis or progression; (2) HSP induced in a heterosynaptic or cell non-autonomous manner to support the function of networks of which the degenerating synapses or cells are part; and (3) induction of HSP within the degenerating population of synapses to preserve function and to resist the impact of synapse loss. Understanding the varied manifestations of HSP in neurodegeneration will not only aid understanding mechanisms of disease but could also inspire much-needed novel approaches to therapy.}, }
@article {pmid34948191, year = {2021}, author = {Obsilova, V and Honzejkova, K and Obsil, T}, title = {Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948191}, issn = {1422-0067}, support = {19-00121S and 20-00058S//Czech Science Foundation/ ; 1160120//Charles University/ ; RVO:67985823//Czech Academy of Sciences/ ; }, mesh = {14-3-3 Proteins/metabolism ; Animals ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Endoplasmic Reticulum Stress ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Kinase Kinase 5/genetics/*metabolism/*physiology/ultrastructure ; MAP Kinase Kinase Kinases/genetics/metabolism ; MAP Kinase Signaling System ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Protein Interaction Maps/genetics/physiology ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer's, Parkinson's and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.}, }
@article {pmid34948077, year = {2021}, author = {García-García, R and Martín-Herrero, L and Blanca-Pariente, L and Pérez-Cabello, J and Roodveldt, C}, title = {Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948077}, issn = {1422-0067}, support = {RTI2018-098432-B-I00//Ministry of Economy, Industry and Competitiveness/ ; CIVP19A5938//Fundaci&#xf3;n Ram&#xf3;n Areces/ ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/immunology/metabolism ; Frontotemporal Dementia/drug therapy/*enzymology/immunology/metabolism ; Humans ; Immune System/*enzymology/metabolism ; *Inflammation ; Phosphotransferases/antagonists &amp; inhibitors/*metabolism ; *Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3-5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling.}, }
@article {pmid34946884, year = {2021}, author = {Lehky, T and Grunseich, C}, title = {Juvenile Amyotrophic Lateral Sclerosis: A Review.}, journal = {Genes}, volume = {12}, number = {12}, pages = {}, pmid = {34946884}, issn = {2073-4425}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genetic Association Studies ; Humans ; Mutation ; }, abstract = {Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases. JALS is defined as onset before age 25. We conducted a literature review of JALS and gene mutations associated with JALS. Results of the literature review show that the most common gene mutations associated with JALS are FUS, SETX, and ALS2. In familial cases, the gene mutations are mostly inherited in an autosomal recessive pattern and mutations in SETX are inherited in an autosomal dominant fashion. Disease prognosis varies from rapidly progressive to an indolent course. Distinct clinical features may emerge with specific gene mutations in addition to the clinical finding of combined upper and lower motor neuron degeneration. In conclusion, patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations. Hereditary patterns and coexisting features may be useful in determining prognosis.}, }
@article {pmid34945679, year = {2021}, author = {D'Antona, S and Caramenti, M and Porro, D and Castiglioni, I and Cava, C}, title = {Amyotrophic Lateral Sclerosis: A Diet Review.}, journal = {Foods (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {34945679}, issn = {2304-8158}, support = {1157625//"INnovazione, nuovi modelli TEcnologici e Reti per curare la SLA" (INTERSLA)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease related to upper and lower motor neurons degeneration. Although the environmental and genetic causes of this disease are still unclear, some factors involved in ALS onset such as oxidative stress may be influenced by diet. A higher risk of ALS has been correlated with a high fat and glutamate intake and β-methylamino-L-alanine. On the contrary, a diet based on antioxidant and anti-inflammatory compounds, such as curcumin, creatine, coenzyme Q10, vitamin E, vitamin A, vitamin C, and phytochemicals could reduce the risk of ALS. However, data are controversial as there is a discrepancy among different studies due to a limited number of samples and the many variables that are involved. In addition, an improper diet could lead to an altered microbiota and consequently to an altered metabolism that could predispose to the ALS onset. In this review we summarized some research that involve aspects related to ALS such as the epidemiology, the diet, the eating behaviour, the microbiota, and the metabolic diseases. Further research is needed to better comprehend the role of diet and the metabolic diseases in the mechanisms leading to ALS onset and progression.}, }
@article {pmid34944418, year = {2021}, author = {Cocozza, G and Garofalo, S and Capitani, R and D'Alessandro, G and Limatola, C}, title = {Microglial Potassium Channels: From Homeostasis to Neurodegeneration.}, journal = {Biomolecules}, volume = {11}, number = {12}, pages = {}, pmid = {34944418}, issn = {2218-273X}, mesh = {Animals ; Biomarkers/metabolism ; Disease Progression ; Gene Expression Regulation ; Homeostasis ; Humans ; Microglia/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism ; Potassium Channels/*metabolism ; }, abstract = {The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers of the microglia phenotype could find application in a wide range of human diseases, and creates opportunities for the discovery and development of tailored therapeutic interventions. Among these, recent studies highlight the pivotal role of the potassium channels in regulating microglial functions in physiological and pathological conditions such as Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. In this review, we summarize the current knowledge of the involvement of the microglial potassium channels in several neurodegenerative diseases and their role as modulators of microglial homeostasis and dysfunction in CNS disorders.}, }
@article {pmid34943897, year = {2021}, author = {Gaweda-Walerych, K and Sitek, EJ and Narożańska, E and Buratti, E}, title = {Parkin beyond Parkinson's Disease-A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies.}, journal = {Cells}, volume = {10}, number = {12}, pages = {}, pmid = {34943897}, issn = {2073-4409}, mesh = {*Down-Regulation ; Humans ; Mitochondria/pathology ; Parkinson Disease/*metabolism/pathology ; Phenotype ; TDP-43 Proteinopathies/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {Parkin and PINK1 are key regulators of mitophagy, an autophagic pathway for selective elimination of dysfunctional mitochondria. To this date, parkin depletion has been associated with recessive early onset Parkinson's disease (PD) caused by loss-of-function mutations in the PARK2 gene, while, in sporadic PD, the activity and abundance of this protein can be compromised by stress-related modifications. Intriguingly, research in recent years has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases-especially those characterized by TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we discuss the evidence of parkin downregulation in these disease phenotypes, its emerging connections with TDP-43, and its possible functional implications.}, }
@article {pmid34943020, year = {2021}, author = {Zhao, Y and Liu, B and Xu, L and Yu, S and Fu, J and Wang, J and Yan, X and Su, J}, title = {ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {34943020}, issn = {2076-3921}, support = {82102733, 81772794//National Natural Science Foundation of China/ ; 20200703009ZP, 20190201164JC, 20191008011TC//Jilin Provincial Research Foundation for the Development of Science and Technology Projects/ ; 2021JC034, 2018SCZ021//Jilin Provincial Health Technology Innovation Project/ ; }, abstract = {One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, is microglia-mediated and astrocyte-mediated neuroinflammation. Although inhibitions of both harmful proteins and aggregation are major treatments for neurodegenerative diseases, whether the phenomenon of non-normal protein or peptide aggregation is causally related to neuronal loss and synaptic damage is still controversial. Currently, excessive production of reactive oxygen species (ROS), which induces mitochondrial dysfunction in neurons that may play a key role in the regulation of immune cells, is proposed as a regulator in neurological disorders. In this review, we propose that mitochondrial DNA (mtDNA) release due to ROS may act on microglia and astrocytes adjacent to neurons to induce inflammation through activation of innate immune responses (such as cGAS/STING). Elucidating the relationship between mtDNA and the formation of a pro-inflammatory microenvironment could contribute to a better understanding of the mechanism of crosstalk between neuronal and peripheral immune cells and lead to the development of novel therapeutic approaches to neurodegenerative diseases.}, }
@article {pmid34941670, year = {2021}, author = {Alvarez-Flores, MP and Gomes, RN and Trevisan-Silva, D and Oliveira, DS and Batista, IFC and Buri, MV and Alvarez, AM and DeOcesano-Pereira, C and de Souza, MM and Chudzinski-Tavassi, AM}, title = {Lonomia obliqua Envenoming and Innovative Research.}, journal = {Toxins}, volume = {13}, number = {12}, pages = {}, pmid = {34941670}, issn = {2072-6651}, mesh = {Animals ; Arthropod Venoms/*toxicity ; Brazil/epidemiology ; Butterflies/*physiology ; Humans ; Insect Bites and Stings/epidemiology/*therapy ; Larva/physiology ; }, abstract = {As a tribute to Butantan Institute in its 120th anniversary, this review describes some of the scientific research efforts carried out in the study of Lonomia envenoming in Brazil, a country where accidents with caterpillars reach over 42,000 individuals per year (especially in South and Southeast Brazil). Thus, the promising data regarding the studies with Lonomia's toxins contributed to the creation of new research centers specialized in toxinology based at Butantan Institute, as well as to the production of the antilonomic serum (ALS), actions which are in line with the Butantan Institute mission "to research, develop, manufacture, and provide products and services for the health of the population". In addition, the study of the components of the Lonomia obliqua bristle extract led to the discovery of new molecules with peculiar properties, opening a field of knowledge that could lead to the development and innovation of new drugs aimed at cell regeneration and inflammatory diseases.}, }
@article {pmid34937577, year = {2021}, author = {Zhang, L and Dai, L and Li, D}, title = {Mitophagy in neurological disorders.}, journal = {Journal of neuroinflammation}, volume = {18}, number = {1}, pages = {297}, pmid = {34937577}, issn = {1742-2094}, support = {2017SZ0055//science and technology bureau of sichuan province/ ; }, mesh = {Animals ; Humans ; Mitochondria/pathology ; *Mitophagy ; Nervous System Diseases/*pathology ; Neurodegenerative Diseases ; }, abstract = {Selective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic-ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.}, }
@article {pmid34937437, year = {2022}, author = {Caga, J and Kiernan, MC and Piguet, O}, title = {A Systematic Review of Caregiver Coping Strategies in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {35}, number = {6}, pages = {763-777}, doi = {10.1177/08919887211060016}, pmid = {34937437}, issn = {0891-9887}, mesh = {Humans ; Caregivers/psychology ; *Frontotemporal Dementia/psychology ; *Amyotrophic Lateral Sclerosis/psychology ; Adaptation, Psychological ; Emotions ; }, abstract = {Caregivers of patients diagnosed with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) often experience distressing symptoms related to their caregiving role. This review evaluates the existing literature on coping and their relationship to ALS and FTD caregiver psychological wellbeing. Published articles were identified via a systematic search of four databases (Cinahl Complete, Medline, Embase and PsycINFO). Overall, problem-focused coping strategies such as active coping and planning was used most often by ALS and FTD caregivers. Positive emotion-focused coping strategies such as acceptance were also frequently used by FTD caregivers. In contrast, dysfunctional coping strategies such as self-oriented reactions including self-blame, denial and self-preoccupation appeared to be the most salient coping strategy negatively impacting on caregiver psychological wellbeing. Six different coping measures were used and their psychometric properties were typically under-reported or satisfactory at best when reported. While coping is as an important aspect of caregivers' experience, it remains unclear how the temporal dimensions of the coping process as well as stressor specificity influences psychological adaptation, and consequently, development of targeted caregiver intervention. The need for future studies to define the coping process more clearly in order to capture the unique stressors encountered by ALS and FTD caregivers throughout the different disease stages is emphasised.}, }
@article {pmid34935174, year = {2022}, author = {Paganoni, S and Berry, JD and Quintana, M and Macklin, E and Saville, BR and Detry, MA and Chase, M and Sherman, AV and Yu, H and Drake, K and Andrews, J and Shefner, J and Chibnik, LB and Vestrucci, M and Cudkowicz, ME and , }, title = {Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development.}, journal = {Annals of neurology}, volume = {91}, number = {2}, pages = {165-175}, doi = {10.1002/ana.26285}, pmid = {34935174}, issn = {1531-8249}, support = {//ALS Finding A Cure/ ; //ALS One/ ; //AMG Charitable Foundation/ ; //Arthur M. Blank Family Foundation/ ; //I AM ALS/ ; //Muscular Dystrophy Association/ ; //Tackle ALS/ ; //Tambourine ALS Collaborative/ ; //The ALS Association/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Biomarkers ; *Clinical Trials as Topic/legislation &amp; jurisprudence ; Endpoint Determination ; Humans ; *Research Design ; }, abstract = {Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165-175.}, }
@article {pmid34933675, year = {2021}, author = {Yang, W and Chen, X and Li, S and Li, XJ}, title = {Genetically modified large animal models for investigating neurodegenerative diseases.}, journal = {Cell &amp; bioscience}, volume = {11}, number = {1}, pages = {218}, pmid = {34933675}, issn = {2045-3701}, support = {32070534//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; }, abstract = {Neurodegenerative diseases represent a large group of neurological disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Although this group of diseases show heterogeneous clinical and pathological phenotypes, they share important pathological features characterized by the age-dependent and progressive degeneration of nerve cells that is caused by the accumulation of misfolded proteins. The association of genetic mutations with neurodegeneration diseases has enabled the establishment of various types of animal models that mimic genetic defects and have provided important insights into the pathogenesis. However, most of genetically modified rodent models lack the overt and selective neurodegeneration seen in the patient brains, making it difficult to use the small animal models to validate the effective treatment on neurodegeneration. Recent studies of pig and monkey models suggest that large animals can more faithfully recapitulate pathological features of neurodegenerative diseases. In this review, we discuss the important differences in animal models for modeling pathological features of neurodegenerative diseases, aiming to assist the use of animal models to better understand the pathogenesis and to develop effective therapeutic strategies.}, }
@article {pmid34930382, year = {2021}, author = {Meneses, A and Koga, S and O'Leary, J and Dickson, DW and Bu, G and Zhao, N}, title = {TDP-43 Pathology in Alzheimer's Disease.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {84}, pmid = {34930382}, issn = {1750-1326}, support = {P01 AG026276/AG/NIA NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; U54 NS110435/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/*metabolism ; *Frontotemporal Dementia/pathology ; *Frontotemporal Lobar Degeneration/genetics ; Humans ; Neurofibrillary Tangles/metabolism ; }, abstract = {Transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer's disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. These findings provide strong evidence that TDP-43 pathology is an integral part of multiple neurodegenerative conditions, including AD. Here, we review the biology and pathobiology of TDP-43 with a focus on its role in AD. We emphasize the need for studies on the mechanisms that lead to TDP-43 pathology, especially in the setting of age-related disorders such as AD.}, }
@article {pmid34927545, year = {2022}, author = {Aldalaqan, S and Dalgliesh, C and Luzzi, S and Siachisumo, C and Reynard, LN and Ehrmann, I and Elliott, DJ}, title = {Cryptic splicing: common pathological mechanisms involved in male infertility and neuronal diseases.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {21}, number = {3}, pages = {219-227}, pmid = {34927545}, issn = {1551-4005}, support = {BB/S008039/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/P006612/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Alternative Splicing/genetics ; Female ; Humans ; *Infertility, Male/genetics ; Male ; *Nervous System Diseases ; Neurons ; RNA Splicing ; }, abstract = {High levels of transcription and alternative splicing are recognized hallmarks of gene expression in the testis and largely driven by cells in meiosis. Because of this, the male meiosis stage of the cell cycle is often viewed as having a relatively permissive environment for gene expression. In this review, we highlight recent findings that identify the RNA binding protein RBMXL2 as essential for male meiosis. RBMXL2 functions as a "guardian of the transcriptome" that protects against the use of aberrant (or "cryptic") splice sites that would disrupt gene expression. This newly discovered protective role during meiosis links with a wider field investigating mechanisms of cryptic splicing control that protect neurons from amyotrophic lateral sclerosis and Alzheimer's disease. We discuss how the mechanism repressing cryptic splicing patterns during meiosis evolved, and why it may be essential for sperm production and male fertility.}, }
@article {pmid34927200, year = {2021}, author = {Popper, B and Scheidt, T and Schieweck, R}, title = {RNA-binding protein dysfunction in neurodegeneration.}, journal = {Essays in biochemistry}, volume = {65}, number = {7}, pages = {975-986}, doi = {10.1042/EBC20210024}, pmid = {34927200}, issn = {1744-1358}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; RNA/genetics ; RNA, Messenger/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Protein homeostasis (proteostasis) is a prerequisite for cellular viability and plasticity. In particular, post-mitotic cells such as neurons rely on a tightly regulated safeguard system that allows for regulated protein expression. Previous investigations have identified RNA-binding proteins (RBPs) as crucial regulators of protein expression in nerve cells. However, during neurodegeneration, their ability to control the proteome is progressively disrupted. In this review, we examine the malfunction of key RBPs such as TAR DNA-binding protein 43 (TDP-43), Fused in Sarcoma (FUS), Staufen, Pumilio and fragile-X mental retardation protein (FMRP). Therefore, we focus on two key aspects of RBP dysfunctions in neurodegeneration: protein aggregation and dysregulation of their target RNAs. Moreover, we discuss how the chaperone system responds to changes in the RBP-controlled transcriptome. Based on recent findings, we propose a two-hit model in which both, harmful RBP deposits and target mRNA mistranslation contribute to neurodegeneration observed in RBPathologies.}, }
@article {pmid34925464, year = {2021}, author = {Ruffo, P and Strafella, C and Cascella, R and Caputo, V and Conforti, FL and Andò, S and Giardina, E}, title = {Deregulation of ncRNA in Neurodegenerative Disease: Focus on circRNA, lncRNA and miRNA in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {784996}, pmid = {34925464}, issn = {1664-8021}, abstract = {Parallel and massive sequencing of total RNA samples derived from different samples are possible thanks to the use of NGS (Next Generation Sequencing) technologies. This allowed characterizing the transcriptomic profile of both cell and tissue populations, increasing the knowledge of the molecular pathological processes of complex diseases, such as neurodegenerative diseases (NDs). Among the NDs, Amyotrophic Lateral Sclerosis (ALS) is caused by the progressive loss of motor neurons (MNs), and, to date, the diagnosis is often made by exclusion because there is no specific symptomatologic picture. For this reason, it is important to search for biomarkers that are clinically useful for carrying out a fast and accurate diagnosis of ALS. Thanks to various studies, it has been possible to propose several molecular mechanisms associated with the disease, some of which include the action of non-coding RNA, including circRNAs, miRNAs, and lncRNAs which will be discussed in the present review. The evidence analyzed in this review highlights the importance of conducting studies to better characterize the different ncRNAs in the disease to use them as possible diagnostic, prognostic, and/or predictive biomarkers of ALS and other NDs.}, }
@article {pmid34924930, year = {2021}, author = {Kisby, GE and Spencer, PS}, title = {Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {752153}, pmid = {34924930}, issn = {1662-4548}, abstract = {Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer's disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.}, }
@article {pmid34923167, year = {2022}, author = {Sujkowski, A and Hong, L and Wessells, RJ and Todi, SV}, title = {The protective role of exercise against age-related neurodegeneration.}, journal = {Ageing research reviews}, volume = {74}, number = {}, pages = {101543}, pmid = {34923167}, issn = {1872-9649}, support = {R01 AG059683/AG/NIA NIH HHS/United States ; R01 NS086778/NS/NINDS NIH HHS/United States ; R21 NS121276/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease ; Animals ; Exercise ; Humans ; *Huntington Disease ; *Parkinson Disease ; }, abstract = {Endurance exercise is a widely accessible, low-cost intervention with a variety of benefits to multiple organ systems. Exercise improves multiple indices of physical performance and stimulates pronounced health benefits reducing a range of pathologies including metabolic, cardiovascular, and neurodegenerative disorders. Endurance exercise delays brain aging, preserves memory and cognition, and improves symptoms of neurodegenerative pathologies like Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and various ataxias. Potential mechanisms underlying the beneficial effects of exercise include neuronal survival and plasticity, neurogenesis, epigenetic modifications, angiogenesis, autophagy, and the synthesis and release of neurotrophins and cytokines. In this review, we discuss shared benefits and molecular pathways driving the protective effects of endurance exercise on various neurodegenerative diseases in animal models and in humans.}, }
@article {pmid34920755, year = {2021}, author = {Deng, Z and Zhou, X and Lu, JH and Yue, Z}, title = {Autophagy deficiency in neurodevelopmental disorders.}, journal = {Cell &amp; bioscience}, volume = {11}, number = {1}, pages = {214}, pmid = {34920755}, issn = {2045-3701}, support = {R01NS060123/NH/NIH HHS/United States ; R01AG072520/NH/NIH HHS/United States ; MoST-2017YFE0120100//National Major Science and Technology Projects of China/ ; }, abstract = {Autophagy is a cell self-digestion pathway through lysosome and plays a critical role in maintaining cellular homeostasis and cytoprotection. Characterization of autophagy related genes in cell and animal models reveals diverse physiological functions of autophagy in various cell types and tissues. In central nervous system, by recycling injured organelles and misfolded protein complexes or aggregates, autophagy is integrated into synaptic functions of neurons and subjected to distinct regulation in presynaptic and postsynaptic neuronal compartments. A plethora of studies have shown the neuroprotective function of autophagy in major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Recent human genetic and genomic evidence has demonstrated an emerging, significant role of autophagy in human brain development and prevention of spectrum of neurodevelopmental disorders. Here we will review the evidence demonstrating the causal link of autophagy deficiency to congenital brain diseases, the mechanism whereby autophagy functions in neurodevelopment, and therapeutic potential of autophagy.}, }
@article {pmid34920148, year = {2022}, author = {Wang, Y and Yang, X and Han, Q and Liu, M and Zhou, C}, title = {Prevalence of Sialorrhea Among Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.}, journal = {Journal of pain and symptom management}, volume = {63}, number = {4}, pages = {e387-e396}, doi = {10.1016/j.jpainsymman.2021.12.005}, pmid = {34920148}, issn = {1873-6513}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology ; Humans ; Prevalence ; Quality of Life ; Salivation ; *Sialorrhea/epidemiology/etiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease (MND), and sialorrhea is a known symptom in patients with ALS, which may cause a social embarrassment and discomfort. However, people do not pay attention to sialorrhea up to now. This study is aimed at conducting a systematic review and meta-analysis of the pooled prevalence of sialorrhea in ALS patients all around the world and raising awareness of salivation.<br><br>METHODS: We searched PubMed and EMBASE databases to obtain the comprehensive literatures which reported the prevalence of sialorrhea. We used AHRQ and NOS to evaluate the literature quality. Subgroup analyses were performed based on screening instruments and severity of sialorrhea. At the meantime, sensitivity analyses was also conducted to identify the source of heterogeneity.<br><br>RESULTS: A total of 17 eligible studies which included 21 groups of data reported prevalence of sialorrhea. The pooled prevalence of sialorrhea among ALS patients was 30.8% (95% CI: 20.0%-44.2%). For studies using ALSFRS-R, direct questioning, postal survey, and ALSSoL average and ALSFRS-R, the pooled prevalence of sialorrhea was 22.7%, 25.8%, 29.8% and 52.0% respectively. According to the severity of sialorrhea, the prevalence of mild, moderate, and severe sialorrhea were 25.1%, 11.2%, and 10.5%, respectively. And none of the studies alone had a significant effect on the overall prevalence of sialorrhea after we eliminated each study separately in sensitivity analyses.<br><br>CONCLUSIONS: Sialorrhea is a relatively common symptom in ALS patients with a comparatively high prevalence. In our study, we found that the prevalence of sialorrhea in ALS patients is relatively higher than the results based on direct questioning or postal survey. Therefore, we deduced that sialorrhea should be evaluated by more complex professional assessment scales to improve the quality of life and improve early prognosis of disease.}, }
@article {pmid34916412, year = {2022}, author = {Charif, SE and Vassallu, MF and Salvañal, L and Igaz, LM}, title = {Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neural regeneration research}, volume = {17}, number = {7}, pages = {1423-1430}, pmid = {34916412}, issn = {1673-5374}, abstract = {Protein synthesis is essential for cells to perform life metabolic processes. Pathological alterations of protein content can lead to particular diseases. Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding, accumulation, aggregation or mislocalization occur. Some of them (like the unfolded protein response) represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis (also known as proteostasis). This is even more important in neurons, as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age. Several neurodegenerative pathologies such as Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct, unbalanced protein overload. In amyotrophic lateral sclerosis and frontotemporal dementia, the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa (TDP-43). TDP-43 is an RNA binding protein that participates in RNA metabolism, among other functions. Dysregulation of TDP-43 (e.g. aggregation and mislocalization) can dramatically affect neurons, and this has been linked to disease development. Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum. These variants can be causative of degeneration onset and progression. Most neurodegenerative diseases (including amyotrophic lateral sclerosis and frontotemporal dementia) have no cure at the moment; however, modulating translation has recently emerged as an attractive approach that can be performed at several steps (i.e. regulating activation of initiation and elongation factors, inhibiting unfolded protein response activation or inducing chaperone expression and activity). This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis. We strive to highlight the importance of research on drugs that, not only restore protein imbalance without compromising translational activity of cells, but are also as safe as possible for the patients.}, }
@article {pmid34916411, year = {2022}, author = {Martinez, B and Peplow, PV}, title = {MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {17}, number = {7}, pages = {1412-1422}, pmid = {34916411}, issn = {1673-5374}, abstract = {Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.}, }
@article {pmid34912464, year = {2021}, author = {Suh, WJ and Seo, Y and Jin, C and Cho, SY and Park, SU and Jung, WS and Moon, SK and Park, JM and Ko, CN and Kwon, S and Cho, KH}, title = {Traditional East Asian Herbal Medicine for Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {5674142}, pmid = {34912464}, issn = {1741-427X}, abstract = {This study aimed to analyze and summarize the existing evidence regarding herbal medicine treatments for amyotrophic lateral sclerosis (ALS). Studies on herbal medicine treatment in patients with ALS were searched within English, Chinese, Japanese, and Korean databases up to July 31, 2021. In the selected studies, we collected the following information: the first author, year of publication, country, language, study methodology, sample size, demographic characteristics of the study participants, disease duration, diagnostic criteria, treatment method, treatment periods, evaluation tools, results, and side effects. The organized data were classified and analyzed narratively. This study included 59 studies. The first clinical study on the effect of herbal medicine was published in 1995; moreover, most studies were conducted in China. Among the 59 selected studies, 47.5% were observational studies, including case reports and case series. Moreover, there was one meta-analysis. The El Escorial criteria were the most commonly used diagnostic criterion for ALS; moreover, the ALS functional rating scale was the most common evaluation tool. Buzhongyiqitang, Sijunzitangjiawei, and Jianpiyifeitang were the most commonly used herbal medicines, with anti-inflammatory, protein aggregation, and anti-oxidant effects. There remain evidence of gaps in the effectiveness of herbal medicine for ALS. To allow effective treatment of patients with ALS using herbal medicine, large-scale and rigorously designed high-quality clinical studies should be performed.}, }
@article {pmid34910602, year = {2022}, author = {Kanekura, K and Hayamizu, Y and Kuroda, M}, title = {Order controls disordered droplets: structure-function relationships in C9ORF72-derived poly(PR).}, journal = {American journal of physiology. Cell physiology}, volume = {322}, number = {2}, pages = {C197-C204}, doi = {10.1152/ajpcell.00372.2021}, pmid = {34910602}, issn = {1522-1563}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; C9orf72 Protein/chemistry/*metabolism ; Dipeptides/chemistry/*metabolism/toxicity ; Frontotemporal Dementia/metabolism/pathology ; Humans ; Neurodegenerative Diseases/metabolism/pathology ; Peptide Fragments/chemistry/*metabolism/toxicity ; Structure-Activity Relationship ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have been thought as two distinct neurodegenerative diseases. However, recent genetic screening and careful investigations found the genetic and pathological overlap among these disorders. Hexanucleotide expansions in intron 1 of C9ORF72 are a leading cause of familial ALS and familial FTD. These expansions facilitate the repeat-associated non-ATG-initiated translation (RAN translation), producing five dipeptide repeat proteins (DRPs), including Arg-rich poly(PR: Pro-Arg) and poly(GR: Gly-Arg) peptides. Arg is a positively charged, highly polar amino acid that facilitates interactions with anionic molecules such as nucleic acids and acidic amino acids via electrostatic forces and aromatic amino acids via cation-π interaction, suggesting that Arg-rich DRPs underlie the pathophysiology of ALS via Arg-mediated molecular interactions. Arg-rich DRPs have also been reported to induce neurodegeneration in cellular and animal models via multiple mechanisms; however, it remains unclear why the Arg-rich DRPs exhibit such diverse toxic properties, because not all Arg-rich peptides are toxic. In this mini-review, we discuss the current understanding of the pathophysiology of Arg-rich C9ORF72 DRPs and introduce recent findings on the role of Arg distribution as a determinant of the toxicity and its contribution to the pathogenesis of ALS.}, }
@article {pmid34909657, year = {2021}, author = {Khatri, DK and Kadbhane, A and Patel, M and Nene, S and Atmakuri, S and Srivastava, S and Singh, SB}, title = {Gauging the role and impact of drug interactions and repurposing in neurodegenerative disorders.}, journal = {Current research in pharmacology and drug discovery}, volume = {2}, number = {}, pages = {100022}, pmid = {34909657}, issn = {2590-2571}, abstract = {Neurodegenerative diseases (ND) are of vast origin which are characterized by gradual progressive loss of neurons in the brain region. ND can be classified according to the clinical symptoms present (e.g. Cognitive decline, hyperkinetic, and hypokinetic movements disorder) or by the pathological protein deposited (e.g., Amyloid, tau, Alpha-synuclein, TDP-43). Alzheimer's disease preceded by Parkinson's is the most prevalent form of ND world-wide. Multiple factors like aging, genetic mutations, environmental factors, gut microbiota, blood-brain barrier microvascular complication, etc. may increase the predisposition towards ND. Genetic mutation is a major contributor in increasing the susceptibility towards ND, the concept of one disease-one gene is obsolete and now multiple genes are considered to be involved in causing one particular disease. Also, the involvement of multiple pathological mechanisms like oxidative stress, neuroinflammation, mitochondrial dysfunction, etc. contributes to the complexity and makes them difficult to be treated by traditional mono-targeted ligands. In this aspect, the Poly-pharmacological drug approach which targets multiple pathological pathways at the same time provides the best way to treat such complex networked CNS diseases. In this review, we have provided an overview of ND and their pathological origin, along with a brief description of various genes associated with multiple diseases like Alzheimer's, Parkinson's, Multiple sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Huntington's and a comprehensive detail about the Poly-pharmacology approach (MTDLs and Fixed-dose combinations) along with their merits over the traditional single-targeted drug is provided. This review also provides insights into current repurposing strategies along with its regulatory considerations.}, }
@article {pmid34907472, year = {2022}, author = {Kumari, A and Sedehizadeh, S and Brook, JD and Kozlowski, P and Wojciechowska, M}, title = {Differential fates of introns in gene expression due to global alternative splicing.}, journal = {Human genetics}, volume = {141}, number = {1}, pages = {31-47}, pmid = {34907472}, issn = {1432-1203}, support = {G0802629/MRC_/Medical Research Council/United Kingdom ; P2019/33/B/NZ5/02473//Narodowe Centrum Nauki/ ; 2020/39/B/NZ3/01811//Narodowe Centrum Nauki/ ; }, mesh = {*Alternative Splicing ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Cell Nucleus/genetics ; Disease/*genetics ; Frontotemporal Dementia/genetics ; *Gene Expression ; Humans ; *Introns ; Mammals/genetics ; Muscular Dystrophy, Duchenne/genetics ; Myotonic Dystrophy/genetics ; RNA, Circular/*physiology ; RNA, Messenger/*physiology ; }, abstract = {The discovery of introns over four decades ago revealed a new vision of genes and their interrupted arrangement. Throughout the years, it has appeared that introns play essential roles in the regulation of gene expression. Unique processing of excised introns through the formation of lariats suggests a widespread role for these molecules in the structure and function of cells. In addition to rapid destruction, these lariats may linger on in the nucleus or may even be exported to the cytoplasm, where they remain stable circular RNAs (circRNAs). Alternative splicing (AS) is a source of diversity in mature transcripts harboring retained introns (RI-mRNAs). Such RNAs may contain one or more entire retained intron(s) (RIs), but they may also have intron fragments resulting from sequential excision of smaller subfragments via recursive splicing (RS), which is characteristic of long introns. There are many potential fates of RI-mRNAs, including their downregulation via nuclear and cytoplasmic surveillance systems and the generation of new protein isoforms with potentially different functions. Various reports have linked the presence of such unprocessed transcripts in mammals to important roles in normal development and in disease-related conditions. In certain human neurological-neuromuscular disorders, including myotonic dystrophy type 2 (DM2), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Duchenne muscular dystrophy (DMD), peculiar processing of long introns has been identified and is associated with their pathogenic effects. In this review, we discuss different mechanisms involved in the processing of introns during AS and the functions of these large sections of the genome in our biology.}, }
@article {pmid34901853, year = {2021}, author = {Wong, C and Stavrou, M and Elliott, E and Gregory, JM and Leigh, N and Pinto, AA and Williams, TL and Chataway, J and Swingler, R and Parmar, MKB and Stallard, N and Weir, CJ and Parker, RA and Chaouch, A and Hamdalla, H and Ealing, J and Gorrie, G and Morrison, I and Duncan, C and Connelly, P and Carod-Artal, FJ and Davenport, R and Reitboeck, PG and Radunovic, A and Srinivasan, V and Preston, J and Mehta, AR and Leighton, D and Glasmacher, S and Beswick, E and Williamson, J and Stenson, A and Weaver, C and Newton, J and Lyle, D and Dakin, R and Macleod, M and Pal, S and Chandran, S}, title = {Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.}, journal = {Brain communications}, volume = {3}, number = {4}, pages = {fcab242}, pmid = {34901853}, issn = {2632-1297}, support = {MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/T000708/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.}, }
@article {pmid34899861, year = {2021}, author = {Titus, MB and Chang, AW and Olesnicky, EC}, title = {Exploring the Diverse Functional and Regulatory Consequences of Alternative Splicing in Development and Disease.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {775395}, pmid = {34899861}, issn = {1664-8021}, abstract = {Alternative splicing is a fundamental mechanism of eukaryotic RNA regulation that increases the transcriptomic and proteomic complexity within an organism. Moreover, alternative splicing provides a framework for generating unique yet complex tissue- and cell type-specific gene expression profiles, despite using a limited number of genes. Recent efforts to understand the negative consequences of aberrant splicing have increased our understanding of developmental and neurodegenerative diseases such as spinal muscular atrophy, frontotemporal dementia and Parkinsonism linked to chromosome 17, myotonic dystrophy, and amyotrophic lateral sclerosis. Moreover, these studies have led to the development of innovative therapeutic treatments for diseases caused by aberrant splicing, also known as spliceopathies. Despite this, a paucity of information exists on the physiological roles and specific functions of distinct transcript spliceforms for a given gene. Here, we will highlight work that has specifically explored the distinct functions of protein-coding spliceforms during development. Moreover, we will discuss the use of alternative splicing of noncoding exons to regulate the stability and localization of RNA transcripts.}, }
@article {pmid34899176, year = {2021}, author = {Anoar, S and Woodling, NS and Niccoli, T}, title = {Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {786076}, pmid = {34899176}, issn = {1662-4548}, support = {MR/V003585/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by declining motor and cognitive functions. Even though these diseases present with distinct sets of symptoms, FTD and ALS are two extremes of the same disease spectrum, as they show considerable overlap in genetic, clinical and neuropathological features. Among these overlapping features, mitochondrial dysfunction is associated with both FTD and ALS. Recent studies have shown that cells derived from patients' induced pluripotent stem cells (iPSC)s display mitochondrial abnormalities, and similar abnormalities have been observed in a number of animal disease models. Drosophila models have been widely used to study FTD and ALS because of their rapid generation time and extensive set of genetic tools. A wide array of fly models have been developed to elucidate the molecular mechanisms of toxicity for mutations associated with FTD/ALS. Fly models have been often instrumental in understanding the role of disease associated mutations in mitochondria biology. In this review, we discuss how mutations associated with FTD/ALS disrupt mitochondrial function, and we review how the use of Drosophila models has been pivotal to our current knowledge in this field.}, }
@article {pmid34890834, year = {2022}, author = {Pateraki, G and Anargyros, K and Aloizou, AM and Siokas, V and Bakirtzis, C and Liampas, I and Tsouris, Z and Ziogka, P and Sgantzos, M and Folia, V and Peristeri, E and Dardiotis, E}, title = {Therapeutic application of rTMS in neurodegenerative and movement disorders: A review.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {62}, number = {}, pages = {102622}, doi = {10.1016/j.jelekin.2021.102622}, pmid = {34890834}, issn = {1873-5711}, mesh = {Humans ; *Motor Cortex ; Movement ; Muscle, Skeletal ; *Parkinson Disease ; Transcranial Magnetic Stimulation ; }, abstract = {Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that makes use of the magnetic field generated when an electric current passes through a magnetic coil placed over the scalp. It can be applied as a single stimulus at a time, in pairs of stimuli, or repetitively in trains of stimuli (repetitive TMS, rTMS). RTMS can induce changes in brain activity, whose after-effects reflect the processes of long-term potentiation and long-term depression, as certain protocols, namely those using low frequencies (≤1 Hz) seem to suppress cortical excitability, while those using high frequencies (>1 Hz) seem to enhance it. It is a technique with very few and mostly mild side-effects, whose effects can persist for long time periods, and as such, it has been studied as a potential treatment option in a multitude of neurodegenerative diseases, including those affecting movement. Although rTMS has received approval as a treatment strategy of only a few aspects in movement disorders in the latest guidelines, its further use seems to also be promising in their context. In this review, we gathered the available literature on the therapeutic application of rTMS in movement disorders, namely Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Dystonia, Tic disorders and Essential Tremor.}, }
@article {pmid34890791, year = {2022}, author = {Cai, Q and Ganesan, D}, title = {Regulation of neuronal autophagy and the implications in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {162}, number = {}, pages = {105582}, pmid = {34890791}, issn = {1095-953X}, support = {R01 GM135326/GM/NIGMS NIH HHS/United States ; R01 NS089737/NS/NINDS NIH HHS/United States ; }, mesh = {Autophagy/physiology ; Axons/metabolism ; Humans ; Lysosomes/metabolism ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; }, abstract = {Neurons are highly polarized and post-mitotic cells with the specific requirements of neurotransmission accompanied by high metabolic demands that create a unique challenge for the maintenance of cellular homeostasis. Thus, neurons rely heavily on autophagy that constitutes a key quality control system by which dysfunctional cytoplasmic components, protein aggregates, and damaged organelles are sequestered within autophagosomes and then delivered to the lysosome for degradation. While mature lysosomes are predominantly located in the soma of neurons, the robust, constitutive biogenesis of autophagosomes occurs in the synaptic terminal via a conserved pathway that is required to maintain synaptic integrity and function. Following formation, autophagosomes fuse with late endosomes and then are rapidly and efficiently transported by the microtubule-based cytoplasmic dynein motor along the axon toward the soma for lysosomal clearance. In this review, we highlight the recent knowledge of the roles of autophagy in neuronal health and disease. We summarize the available evidence about the normal functions of autophagy as a protective factor against neurodegeneration and discuss the mechanism underlying neuronal autophagy regulation. Finally, we describe how autophagy function is affected in major neurodegenerative diseases with a special focus on Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.}, }
@article {pmid34886717, year = {2022}, author = {Garnett, ER and Raines, RT}, title = {Emerging biological functions of ribonuclease 1 and angiogenin.}, journal = {Critical reviews in biochemistry and molecular biology}, volume = {57}, number = {3}, pages = {244-260}, pmid = {34886717}, issn = {1549-7798}, support = {R01 CA073808/CA/NCI NIH HHS/United States ; }, mesh = {Endoribonucleases ; RNA ; *Ribonuclease, Pancreatic/chemistry/genetics/metabolism ; *Ribonucleases/genetics/metabolism ; }, abstract = {Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. These enzymes catalyze the degradation of many RNA substrates and thereby mediate a variety of biological functions. Though the homology of ptRNases has informed biochemical characterization and evolutionary analyses, the understanding of their biological roles is incomplete. Here, we review the functions of two ptRNases: RNase 1 and angiogenin. RNase 1, which is an abundant ptRNase with high catalytic activity, has newly discovered roles in inflammation and blood coagulation. Angiogenin, which promotes neovascularization, is now known to play roles in the progression of cancer and amyotrophic lateral sclerosis, as well as in the cellular stress response. Ongoing work is illuminating the biology of these and other ptRNases.}, }
@article {pmid34884368, year = {2021}, author = {Chojecka, D and Pytlos, J and Zawadka, M and Andruszkiewicz, P and Szarpak, &#x141; and Dzieciątkowski, T and Jaguszewski, MJ and Filipiak, KJ and Gąsecka, A}, title = {How to Maintain Safety and Maximize the Efficacy of Cardiopulmonary Resuscitation in COVID-19 Patients: Insights from the Recent Guidelines.}, journal = {Journal of clinical medicine}, volume = {10}, number = {23}, pages = {}, pmid = {34884368}, issn = {2077-0383}, abstract = {Since December 2019, the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has remained a challenge for governments and healthcare systems all around the globe. SARS-CoV-2 infection is associated with increased rates of hospital admissions and significant mortality. The pandemic increased the rate of cardiac arrest and the need for cardiopulmonary resuscitation (CPR). COVID-19, with its pathophysiology and detrimental effects on healthcare, influenced the profile of patients suffering from cardiac arrest, as well as the conditions of performing CPR. To ensure both the safety of medical personnel and the CPR efficacy for patients, resuscitation societies have published modified guidelines addressing the specific reality of the COVID-19 pandemic. In this review, we briefly describe the transmission and pathophysiology of COVID-19, present the challenges of CPR in SARS-CoV-2-infected patients, summarize the current recommendations regarding the algorithms of basic life support (BLS), advanced life support (ALS) and pediatric life support, and discuss other aspects of CPR in COVID-19 patients, which potentially affect the risk-to-benefit ratio of medical procedures and therefore should be considered while formulating further recommendations.}, }
@article {pmid34881804, year = {2022}, author = {Hall, B and George, JG and Allen, SP}, title = {Adenosine deaminase, not immune to a mechanistic rethink in central nervous system disorders?.}, journal = {Histology and histopathology}, volume = {37}, number = {3}, pages = {189-212}, pmid = {34881804}, issn = {1699-5848}, support = {SBF005\1064//Sheffield Neuroscience Institute and Academy of Medical Sciences/ ; }, mesh = {Adenosine ; Adenosine Deaminase/metabolism ; *Amyotrophic Lateral Sclerosis ; Brain/metabolism ; Humans ; *Neurodegenerative Diseases ; }, abstract = {Adenosine deaminase (ADA) is a purine metabolism enzyme that catalyses the breakdown of adenosine and deoxyadenosine. The enzyme is important in several cellular processes, including the innate immune response and cellular differentiation, and it is also an important enzyme for the maintenance of brain homeostasis, in part due to its regulation of adenosine. Aberrant regulation of ADA enzyme activity has been linked to several neurodegenerative diseases and diseases that can result in neurological impairment. However, the mechanisms behind altered ADA regulation and how this leads to the development of neurological dysfunction are poorly characterised. This review summarises the current research on ADA and its role and regulation in disease pathology, with a focus on the central nervous system (CNS) and the neurodegenerative disease, amyotrophic lateral sclerosis (ALS).}, }
@article {pmid34881087, year = {2021}, author = {Yuan, M and Wang, Y and Wang, S and Huang, Z and Jin, F and Zou, Q and Li, J and Pu, Y and Cai, Z}, title = {Bioenergetic Impairment in the Neuro-Glia-Vascular Unit: An Emerging Physiopathology during Aging.}, journal = {Aging and disease}, volume = {12}, number = {8}, pages = {2080-2095}, pmid = {34881087}, issn = {2152-5250}, support = {R01 NS079792/NS/NINDS NIH HHS/United States ; }, abstract = {An emerging concept termed the "neuro-glia-vascular unit" (NGVU) has been established in recent years to understand the complicated mechanism of multicellular interactions among vascular cells, glial cells, and neurons. It has been proverbially reported that the NGVU is significantly associated with neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Physiological aging is an inevitable progression associated with oxidative damage, bioenergetic alterations, mitochondrial dysfunction, and neuroinflammation, which is partially similar to the pathology of AD. Thus, senescence is regarded as the background for the development of neurodegenerative diseases. With the exacerbation of global aging, senescence is an increasingly serious problem in the medical field. In this review, the coupling of each component, including neurons, glial cells, and vascular cells, in the NGVU is described in detail. Then, various mechanisms of age-dependent impairment in each part of the NGVU are discussed. Moreover, the potential bioenergetic alterations between different cell types in the NGVU are highlighted, which seems to be an emerging physiopathology associated with the aged brain. Bioenergetic intervention in the NGVU may be a new direction for studies on delaying or diminishing aging in the future.}, }
@article {pmid34879411, year = {2021}, author = {Meyer, T}, title = {[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {146}, number = {24-25}, pages = {1613-1618}, doi = {10.1055/a-1562-7882}, pmid = {34879411}, issn = {1439-4413}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disorder which is characterized by progressive motor symptoms, such as muscle weakness, muscle atrophy and spasticity. In Germany, 6000-8000 people are affected by ALS. Between 1200 and 1600 newly diagnosed patients are expected each year. Protein deposits in the cytoplasm of motor neurons are a molecular feature of ALS. The most common protein aggregates result from excessive deposition of TDP-43. Familial ALS is present in 5 to 10 % of all ALS patients. Common causal genes include C9orf72, SOD1, FUS, and TARDBP. Genetic factors may be involved even without a family history of ALS and may be underestimated. The disease course and progression are highly variable. Symptom severity and rate of progression are determined by the ALS Functional Scale (ALSFRS-R). Beyond clinical symptoms and the patient's perception of disease burden, measurement of slow vital capacity (SVC), peak cough flow (PCF), and body mass index (BMI) are used to underscore the indications for ventilatory and nutritional interventions, as well as palliative care. The validity of the biomarker neurofilament light chain (NF-L) for estimating prognosis is currently being investigated. ALS is not curable - however, various individual treatment options have to be considered for improving survival, symptom control and social participation. The care in specialized ALS centers is recommended to ensure optimal treatment regarding symptomatic medication, assistive devices, nutrition support and ventilation therapy. Optimal care is achieved by interdisciplinary collaboration of general practitioners, specialized physicians, neurologists and ALS experts being integrated in multiprofessional care networks.}, }
@article {pmid34876200, year = {2021}, author = {Nguyen, B and Bix, G and Yao, Y}, title = {Basal lamina changes in neurodegenerative disorders.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {81}, pmid = {34876200}, issn = {1750-1326}, support = {R21AG064422/AG/NIA NIH HHS/United States ; R21 AG064422/AG/NIA NIH HHS/United States ; R21 AG073862/AG/NIA NIH HHS/United States ; RF1 AG065345/AG/NIA NIH HHS/United States ; R01 HL146574/HL/NHLBI NIH HHS/United States ; R01HL146574/HL/NHLBI NIH HHS/United States ; R21AG073862/AG/NIA NIH HHS/United States ; RF1AG065345/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; Basement Membrane/metabolism/pathology ; Blood-Brain Barrier/metabolism ; *Glymphatic System/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism ; }, abstract = {BACKGROUND: Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation.<br><br>MAIN BODY: The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed.<br><br>CONCLUSIONS: Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.}, }
@article {pmid34874625, year = {2022}, author = {Xie, M and Zhao, S and Bosco, DB and Nguyen, A and Wu, LJ}, title = {Microglial TREM2 in amyotrophic lateral sclerosis.}, journal = {Developmental neurobiology}, volume = {82}, number = {1}, pages = {125-137}, pmid = {34874625}, issn = {1932-846X}, support = {U19 AG069701/AG/NIA NIH HHS/United States ; R21 AG064159/AG/NIA NIH HHS/United States ; R01 NS088627/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Central Nervous System/metabolism ; Humans ; *Membrane Glycoproteins/genetics/metabolism ; *Microglia/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Receptors, Immunologic/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.}, }
@article {pmid34873637, year = {2022}, author = {Liu, Y and Jiang, H and Qin, X and Tian, M and Zhang, H}, title = {PET imaging of reactive astrocytes in neurological disorders.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {49}, number = {4}, pages = {1275-1287}, pmid = {34873637}, issn = {1619-7089}, mesh = {*Alzheimer Disease/pathology ; Astrocytes/pathology ; Humans ; *Nervous System Diseases/diagnostic imaging ; Positron-Emission Tomography ; Tomography, X-Ray Computed ; }, abstract = {The reactive astrocytes manifest molecular, structural, and functional remodeling in injury, infection, or diseases of the CNS, which play a critical role in the pathological mechanism of neurological diseases. A growing need exists for dependable approach to better characterize the activation of astrocyte in vivo. As an advanced molecular imaging technology, positron emission tomography (PET) has the potential for visualizing biological activities at the cellular levels. In the review, we summarized the PET visualization strategies for reactive astrocytes and discussed the applications of astrocyte PET imaging in neurological diseases. Future studies are needed to pay more attention to the development of specific imaging agents for astrocytes and further improve our exploration of reactive astrocytes in various diseases.}, }
@article {pmid34864683, year = {2022}, author = {Querin, G and Biferi, MG and Pradat, PF}, title = {Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials.}, journal = {Journal of neuromuscular diseases}, volume = {9}, number = {1}, pages = {25-37}, pmid = {34864683}, issn = {2214-3602}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/pathology ; Animals ; *Biomarkers ; Calcium Channels/*genetics ; Gray Matter/*diagnostic imaging/pathology ; Humans ; *Neuroimaging ; White Matter/*diagnostic imaging/pathology ; }, abstract = {The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.}, }
@article {pmid34864338, year = {2022}, author = {Boillée, S}, title = {Local and remote interactions between macrophages and microglia in neurological conditions.}, journal = {Current opinion in immunology}, volume = {74}, number = {}, pages = {118-124}, doi = {10.1016/j.coi.2021.11.006}, pmid = {34864338}, issn = {1879-0372}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/pathology ; Central Nervous System ; Humans ; Macrophages/pathology ; Microglia ; }, abstract = {In the central nervous system (CNS) parenchymal macrophages are called microglial cells and have a distinct developmental origin and can self-renew. However, during pathological conditions, when the blood-brain-barrier becomes leaky, including after injury, in multiple sclerosis or with glioblastoma, monocyte-derived macrophages (MDM) infiltrate the CNS and cohabit with microglia. In neurodegenerative diseases such as Alzheimer's disease or ALS, MDM mostly do not enter the CNS, and instead microglia take several identities. In the specific case of ALS, the affected motor neurons are even surrounded locally by microglia, while along the peripheral nerves, by MDM-derived macrophages. The specific functions and interactions of these different myeloid cells are only starting to be recognized, but hold high promise for more targeted therapies.}, }
@article {pmid34864194, year = {2022}, author = {Brown, DG and Wobst, HJ}, title = {A survey of the clinical pipeline in neuroscience.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {56}, number = {}, pages = {128482}, doi = {10.1016/j.bmcl.2021.128482}, pmid = {34864194}, issn = {1464-3405}, mesh = {Chronic Pain/*drug therapy ; Epilepsy/*drug therapy ; Humans ; Mental Disorders/*drug therapy ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/*therapeutic use ; Neurosciences ; }, abstract = {Many new first-in-class drugs for neuroscience indications have been introduced in the past decade including new treatments for migraine, amyotrophic lateral sclerosis, depression, and multiple sclerosis. However, significant unmet patient needs remain in areas such as chronic pain, neurodegeneration, psychiatric diseases, and epilepsy. This review summarizes some of the advanced clinical compounds for these indications. Additionally, current opportunities and challenges that remain with respect to genetic validation, biomarkers, and translational models are discussed.}, }
@article {pmid34863451, year = {2021}, author = {Spagnoli, C and Schiavoni, S and Rizzi, S and Salerno, GG and Frattini, D and Koskenvuo, J and Fusco, C}, title = {SPG6 (NIPA1 variant): A report of a case with early-onset complex hereditary spastic paraplegia and brief literature review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {94}, number = {}, pages = {281-285}, doi = {10.1016/j.jocn.2021.10.026}, pmid = {34863451}, issn = {1532-2653}, mesh = {Child ; *Epilepsy ; Humans ; Membrane Proteins/genetics ; Mutation, Missense ; *Spastic Paraplegia, Hereditary/diagnosis/genetics ; }, abstract = {SPG6, caused by NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome) gene pathogenic variants, is mainly considered as a pure autosomal dominant hereditary spastic paraplegia (AD-HSP), even if descriptions of complex cases have also been reported. We detected the common c.316G > A, p.(Gly106Arg) pathogenic de novo substitution in a 10-year-old patient with HSP and drug-resistant eyelid myoclonia with absences. In order to assess the significance of this association, we reviewed the literature to find that 25/110 (23%) SPG6 cases are complex, including a heterogeneous spectrum of comorbidities, in which epilepsy is most represented (10%), but also featuring peripheral neuropathy (5.5%), amyotrophic lateral sclerosis (3.6%), memory deficits (3.6%) or cognitive impairment (2.7%), tremor (2.7%) and dystonia (0.9%). From this literature review and our single case experience, two main conclusions can be drawn. First, SPG6 is an AD-HSP with both pure and complex presentation, and frequent occurrence of epilepsy within the spectrum of genetic generalized epilepsies (absences, bilateral tonic-clonic, bilateral tonic-clonic with upper limbs myoclonic seizures and eyelid myoclonia with absences). Second, opposed to previous descriptions, seizures might not always be drug responsive.}, }
@article {pmid34858980, year = {2021}, author = {Wang, K and Li, Y and Ren, C and Wang, Y and He, W and Jiang, Y}, title = {Extracellular Vesicles as Innovative Treatment Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {754630}, pmid = {34858980}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron degenerative disease, and it is hard to diagnose in the early stage, and treatment means are limited, and the treatment effect is unsatisfactory. Therefore, exploring a new effective treatment strategy is urgently needed for ALS patients. Extracellular vesicles (EVs) are a heterogeneous group of natural membrane vesicles containing many bioactive substances, and they play important roles in the paracrine pathway and exhibit neuroprotection effects. A growing body of evidence shows that EVs have great application potential in diagnosis, treatment, and drug delivery in ALS, and they represent an innovative treatment strategy for ALS. In this review, we will briefly introduce the biogenesis of EVs and focus on discussing the role of EVs in ALS treatment to further enrich and boost the development of EVs as an innovative treatment strategy for ALS.}, }
@article {pmid34836059, year = {2021}, author = {Goncharova, PS and Davydova, TK and Popova, TE and Novitsky, MA and Petrova, MM and Gavrilyuk, OA and Al-Zamil, M and Zhukova, NG and Nasyrova, RF and Shnayder, NA}, title = {Nutrient Effects on Motor Neurons and the Risk of Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {13}, number = {11}, pages = {}, pmid = {34836059}, issn = {2072-6643}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*physiopathology ; Animals ; Diet/adverse effects ; Disease Models, Animal ; Disease Progression ; Humans ; Motor Neurons/*physiology ; Nutrients/deficiency/*metabolism ; Nutritional Physiological Phenomena/*physiology ; Risk Factors ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is an incurable chronic progressive neurodegenerative disease with the progressive degeneration of motor neurons in the motor cortex and lower motor neurons in the spinal cord and the brain stem. The etiology and pathogenesis of ALS are being actively studied, but there is still no single concept. The study of ALS risk factors can help to understand the mechanism of this disease development and, possibly, slow down the rate of its progression in patients and also reduce the risk of its development in people with a predisposition toward familial ALS. The interest of researchers and clinicians in the protective role of nutrients in the development of ALS has been increasing in recent years. However, the role of some of them is not well-understood or disputed. The objective of this review is to analyze studies on the role of nutrients as environmental factors affecting the risk of developing ALS and the rate of motor neuron degeneration progression.<br><br>METHODS: We searched the PubMed, Springer, Clinical keys, Google Scholar, and E-Library databases for publications using keywords and their combinations. We analyzed all the available studies published in 2010-2020.<br><br>DISCUSSION: We analyzed 39 studies, including randomized clinical trials, clinical cases, and meta-analyses, involving ALS patients and studies on animal models of ALS. This review demonstrated that the following vitamins are the most significant protectors of ALS development: vitamin B12, vitamin E > vitamin C > vitamin B1, vitamin B9 > vitamin D > vitamin B2, vitamin B6 > vitamin A, and vitamin B7. In addition, this review indicates that the role of foods with a high content of cholesterol, polyunsaturated fatty acids, urates, and purines plays a big part in ALS development.<br><br>CONCLUSION: The inclusion of vitamins and a ketogenic diet in disease-modifying ALS therapy can reduce the progression rate of motor neuron degeneration and slow the rate of disease progression, but the approach to nutrient selection must be personalized. The roles of vitamins C, D, and B7 as ALS protectors need further study.}, }
@article {pmid34834611, year = {2021}, author = {Gherekhloo, J and Hassanpour-Bourkheili, S and Hejazirad, P and Golmohammadzadeh, S and Vazquez-Garcia, JG and De Prado, R}, title = {Herbicide Resistance in Phalaris Species: A Review.}, journal = {Plants (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {34834611}, issn = {2223-7747}, abstract = {Weeds, such as Phalaris spp., can drastically reduce the yield of crops, and the evolution of resistance to herbicides has further exacerbated this issue. Thus far, 23 cases of herbicide resistance in 11 countries have been reported in Phalaris spp., including Phalaris minor Retz., Phalaris paradoxa L., and Phalaris brachystachys L., for photosystem II (PS-II), acetyl-CoA carboxylase (ACCase), and acetolactate synthase (ALS)-inhibiting herbicides. This paper will first review the cases of herbicide resistance reported in P. minor, P. paradoxa, and P. brachystachys. Then, the mechanisms of resistance in Phalaris spp. are discussed in detail. Finally, the fitness cost of herbicide resistance and the literature on the management of herbicide-resistant weeds from these species are reviewed.}, }
@article {pmid34831228, year = {2021}, author = {Rossi, S and Cozzolino, M}, title = {Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia.}, journal = {Cells}, volume = {10}, number = {11}, pages = {}, pmid = {34831228}, issn = {2073-4409}, support = {SPLICEALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Astrocytes/*metabolism/pathology ; Humans ; Inflammation/pathology ; Microglia/*metabolism/pathology ; Neurons/metabolism/pathology ; RNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis is a neurological disease that primarily affects motor neurons in the cortex, brainstem, and spinal cord. The process that leads to motor neuron degeneration is strongly influenced by non-motor neuronal events that occur in a variety of cell types. Among these, neuroinflammatory processes mediated by activated astrocytes and microglia play a relevant role. In recent years, it has become clear that dysregulation of essential steps of RNA metabolism, as a consequence of alterations in RNA-binding proteins (RBPs), is a central event in the degeneration of motor neurons. Yet, a causal link between dysfunctional RNA metabolism and the neuroinflammatory processes mediated by astrocytes and microglia in ALS has been poorly defined. In this review, we will discuss the available evidence showing that RBPs and associated RNA processing are affected in ALS astrocytes and microglia, and the possible mechanisms involved in these events.}, }
@article {pmid34831153, year = {2021}, author = {Anakor, E and Le Gall, L and Dumonceaux, J and Duddy, WJ and Duguez, S}, title = {Exosomes in Ageing and Motor Neurone Disease: Biogenesis, Uptake Mechanisms, Modifications in Disease and Uses in the Development of Biomarkers and Therapeutics.}, journal = {Cells}, volume = {10}, number = {11}, pages = {}, pmid = {34831153}, issn = {2073-4409}, mesh = {Aging/*metabolism ; Animals ; Biomarkers/*metabolism ; Exosomes/*metabolism ; Humans ; Motor Neuron Disease/*metabolism ; Nerve Degeneration/therapy ; Signal Transduction ; }, abstract = {Intercellular communication between neurons and their surrounding cells occurs through the secretion of soluble molecules or release of vesicles such as exosomes into the extracellular space, participating in brain homeostasis. Under neuro-degenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer's or Parkinson's disease, exosomes are suspected to propagate toxic proteins. The topic of this review is the role of exosomes in ageing conditions and more specifically in ALS. Our current understanding of exosomes and exosome-related mechanisms is first summarized in a general sense, including their biogenesis and secretion, heterogeneity, cellular interaction and intracellular fate. Their role in the Central Nervous System (CNS) and ageing of the neuromotor system is then considered in the context of exosome-induced signaling. The review then focuses on exosomes in age-associated neurodegenerative disease. The role of exosomes in ALS is highlighted, and their use as potential biomarkers to diagnose and prognose ALS is presented. The therapeutic implications of exosomes for ALS are considered, whether as delivery vehicles, neurotoxic targets or as corrective drugs in and of themselves. A diverse set of mechanisms underpin the functional roles, both confirmed and potential, of exosomes, generally in ageing and specifically in motor neurone disease. Aspects of their contents, biogenesis, uptake and modifications offer many plausible routes towards the development of novel biomarkers and therapeutics.}, }
@article {pmid34830115, year = {2021}, author = {Bonifacino, T and Zerbo, RA and Balbi, M and Torazza, C and Frumento, G and Fedele, E and Bonanno, G and Milanese, M}, title = {Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830115}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/history/metabolism/therapy ; Animals ; *Disease Models, Animal ; Dogs ; Guinea Pigs ; History, 20th Century ; History, 21st Century ; Humans ; Mice ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.}, }
@article {pmid34830074, year = {2021}, author = {Koski, L and Ronnevi, C and Berntsson, E and Wärmländer, SKTS and Roos, PM}, title = {Metals in ALS TDP-43 Pathology.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830074}, issn = {1422-0067}, support = {001//Magnus Bergvall foundation/ ; 001//Kamprad Research Foundation/ ; 001//Ulla-Carin Lindquist Foundation for ALS Research/ ; 001//Karolinska Institutet IMM strategic grants/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/etiology/genetics/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Environmental Exposure/*adverse effects ; Humans ; *Metals/metabolism/toxicity ; *Mutation ; Protein Aggregation, Pathological/etiology/genetics/metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.}, }
@article {pmid34830069, year = {2021}, author = {Vanneste, J and Van Den Bosch, L}, title = {The Role of Nucleocytoplasmic Transport Defects in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830069}, issn = {1422-0067}, mesh = {*Active Transport, Cell Nucleus ; Aging/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism ; Animals ; Brain/metabolism ; Humans ; Nuclear Pore/chemistry/physiology ; Nucleocytoplasmic Transport Proteins/metabolism ; ran GTP-Binding Protein/physiology ; }, abstract = {There is ample evidence that nucleocytoplasmic-transport deficits could play an important role in the pathology of amyotrophic lateral sclerosis (ALS). However, the currently available data are often circumstantial and do not fully clarify the exact causal and temporal role of nucleocytoplasmic transport deficits in ALS patients. Gaining this knowledge will be of great significance in order to be able to target therapeutically nucleocytoplasmic transport and/or the proteins involved in this process. The availability of good model systems to study the nucleocytoplasmic transport process in detail will be especially crucial in investigating the effect of different mutations, as well as of other forms of stress. In this review, we discuss the evidence for the involvement of nucleocytoplasmic transport defects in ALS and the methods used to obtain these data. In addition, we provide an overview of the therapeutic strategies which could potentially counteract these defects.}, }
@article {pmid34828382, year = {2021}, author = {Lundt, S and Ding, S}, title = {NAD[+] Metabolism and Diseases with Motor Dysfunction.}, journal = {Genes}, volume = {12}, number = {11}, pages = {}, pmid = {34828382}, issn = {2073-4425}, support = {R01 NS094539/NS/NINDS NIH HHS/United States ; R01 NS069726/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Charcot-Marie-Tooth Disease/genetics/*metabolism ; Circadian Clocks ; Clinical Trials as Topic ; DNA Repair ; Energy Metabolism ; Humans ; NAD/*biosynthesis ; }, abstract = {Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson's disease and Huntington's disease. Nicotinamide adenine dinucleotide (NAD[+]) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD[+] can be reversibly oxidized-reduced or directly consumed by NAD[+]-dependent proteins. NAD[+] is synthesized in cells via three different paths: the de novo, Preiss-Handler, or NAD[+] salvage pathways, with the salvage pathway being the primary producer of NAD[+] in mammalian cells. NAD[+] metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD[+] homeostasis, looking at NAD[+] biosynthesis and consumption, with a focus on the NAD[+] salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD[+] in MNDs and other neurodegenerative diseases with motor dysfunction.}, }
@article {pmid34827556, year = {2021}, author = {Festoff, BW and Dockendorff, C}, title = {The Evolving Concept of Neuro-Thromboinflammation for Neurodegenerative Disorders and Neurotrauma: A Rationale for PAR1-Targeting Therapies.}, journal = {Biomolecules}, volume = {11}, number = {11}, pages = {}, pmid = {34827556}, issn = {2218-273X}, support = {R15HL127636/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases ; *Receptor, PAR-1 ; Thromboinflammation ; }, abstract = {Interest in the role of coagulation and fibrinolysis in the nervous system was active in several laboratories dating back before cloning of the functional thrombin receptor in 1991. As one of those, our attention was initially on thrombin and plasminogen activators in synapse formation and elimination in the neuromuscular system, with orientation towards diseases such as amyotrophic lateral sclerosis (ALS) and how clotting and fibrinolytic pathways fit into its pathogenesis. This perspective is on neuro-thromboinflammation, emphasizing this emerging concept from studies and reports over more than three decades. It underscores how it may lead to novel therapeutic approaches to treat the ravages of neurotrauma and neurodegenerative diseases, with a focus on PAR1, ALS, and parmodulins.}, }
@article {pmid34827436, year = {2021}, author = {Johri, A and Chandra, A}, title = {Connection Lost, MAM: Errors in ER-Mitochondria Connections in Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {11}, number = {11}, pages = {}, pmid = {34827436}, issn = {2076-3425}, abstract = {Mitochondria associated membranes (MAMs), as the name suggests, are the membranes that physically and biochemically connect mitochondria with endoplasmic reticulum. MAMs not only structurally but also functionally connect these two important organelles within the cell which were previously thought to exist independently. There are multiple points of communication between ER-mitochondria and MAMs play an important role in both ER and mitochondria functions such as Ca[2+] homeostasis, proteostasis, mitochondrial bioenergetics, movement, and mitophagy. The number of disease-related proteins and genes being associated with MAMs has been continually on the rise since its discovery. There is an overwhelming overlap between the biochemical functions of MAMs and processes affected in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Thus, MAMs have received well-deserving and much delayed attention as modulators for ER-mitochondria communication and function. This review briefly discusses the recent progress made in this now fast developing field full of promise for very exciting future therapeutic discoveries.}, }
@article {pmid34825873, year = {2022}, author = {Viegas, FPD and Gontijo, VS and de Freitas Silva, M and Ortiz, CJC and Dos Reis Rosa Franco, G and Ernesto, JT and Damasio, CM and Silva, IMF and Campos, TG and Viegas, C}, title = {Curcumin, Resveratrol and Cannabidiol as Natural Key Prototypes in Drug Design for Neuroprotective Agents.}, journal = {Current neuropharmacology}, volume = {20}, number = {7}, pages = {1297-1328}, pmid = {34825873}, issn = {1875-6190}, support = {001//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior - Brazil (CAPES)/ ; }, mesh = {*Cannabidiol/pharmacology/therapeutic use ; *Curcumin/pharmacology/therapeutic use ; Drug Design ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Resveratrol/pharmacology/therapeutic use ; }, abstract = {Nowadays, neurodegenerative diseases (NDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a great challenge in different scientific fields, such as neuropharmacology, medicinal chemistry, molecular biology and medicine, as all these pathologies remain incurable, with high socioeconomic impacts and high costs for governmental health services. Due to their severity and multifactorial pathophysiological complexity, the available approved drugs for clinic have not yet shown adequate effectiveness and exhibited very restricted options in the therapeutic arsenal; this highlights the need for continued drug discovery efforts in the academia and industry. In this context, natural products, such as curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) have been recognized as important sources, with promising chemical entities, prototype models and starting materials for medicinal organic chemistry, as their molecular architecture, multifunctional properties and single chemical diversity could facilitate the discovery, optimization and development of innovative drug candidates with improved pharmacodynamics and pharmacokinetics compared to the known drugs and, perhaps, provide a chance for discovering novel effective drugs to combat NDs. In this review, we report the most recent efforts of medicinal chemists worldwide devoted to the exploration of curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) as starting materials or privileged scaffolds in the design of multi-target directed ligands (MTDLs) with potential therapeutic properties against NDs, which have been published in the scientific literature during the last 10 years of research and are available in PubMed, SCOPUS and Web of Science databases.}, }
@article {pmid34819914, year = {2021}, author = {Cook, SF and Rhodes, T and Schlusser, C and Han, S and Chen, C and Zach, N and Murthy, V and Davé, S}, title = {A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {770001}, pmid = {34819914}, issn = {1664-2295}, abstract = {Understanding patient clinical progression is a key gateway to planning effective clinical trials and ultimately enabling bringing treatments to patients in need. In a rare disease like amyotrophic lateral sclerosis (ALS), studies of disease natural history critically depend on collaboration between clinical centers, regions, and countries to enable creation of platforms to allow patients, caregivers, clinicians, and researchers to come together and more fully understand the condition. Rare disease registries and collaborative platforms such as those developed in ALS collect real-world data (RWD) in standardized formats, including clinical and biological specimen data used to evaluate risk factors and natural history of disease, treatment patterns and clinical (ClinROs) and patient- reported outcomes (PROs) and validate novel endpoints. Importantly, these data support the development of new therapeutics by supporting the evaluation of feasibility and design of clinical trials and offer valuable information on real-world disease trajectory and outcomes outside of the clinical trial setting for comparative purposes. RWD may help to accelerate therapy development by identifying and validating outcome measures and disease subpopulations. RWD can also make potential contributions to the evaluation of the safety and effectiveness of new indications for approved products and to satisfy post-approval regulatory and market access requirements. There is a lack of amalgamated information on available registries, databases, and other sources of real-world data on ALS; thus, a global review of all available resources was warranted. This targeted review identifies and describes ALS registries, biobanks and collaborative research networks that are collecting and synthesizing RWD for the purposes of increasing patient awareness and advancing scientific knowledge with the hope of expediting future development of new therapies.}, }
@article {pmid34813019, year = {2022}, author = {Guan, L and Han, Y and Yang, C and Lu, S and Du, J and Li, H and Lin, J}, title = {CRISPR-Cas9-Mediated Gene Therapy in Neurological Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {2}, pages = {968-982}, pmid = {34813019}, issn = {1559-1182}, support = {81801127//National Natural Science Foundation of China/ ; 81771226//National Natural Science Foundation of China/ ; 81800792//National Natural Science Foundation of China/ ; U1804186//National Natural Science Foundation of China/ ; 202300410307//Natural Science Foundation of Henan Province for Distinguished Young Scholars/ ; 19IRTSTHN003//Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province/ ; 212102310215//Henan Province Science and Technology Project/ ; 20172DCG-03//Major Cultivation Plan of Scientific and Technological Achievements from Natural Science class of Xinxiang Medical University/ ; 21A180023//Key Scientific Research Program of Higher Education in Henan Province/ ; GG2019009//Xinxiang Scientific and Technological Project/ ; XYBSKYZZ201523//Doctoral Scientific Research Program Foundation of Xinxiang Medical University/ ; ZDSYS2015004//Open Program of Henan Key Lab of Biological Psychiatry/ ; }, mesh = {*CRISPR-Cas Systems/genetics ; Gene Editing ; Genetic Therapy ; Humans ; *Muscular Dystrophy, Duchenne ; }, abstract = {Neurological disorders are primarily diseases with sophisticated etiology that are always refractory and recrudescent. The major obstruction to effective therapies for neurological disorders is the poor understanding of their pathogenic mechanisms. CRISPR-Cas9 technology, which allows precise and effective gene editing in almost any cell type and organism, is accelerating the pace of basic biological research. An increasing number of groups are focusing on uncovering the molecular mechanisms of neurological disorders and developing novel therapies using the CRISPR-Cas9 system. This review highlights the application of CRISPR-Cas9 technology in the treatment of neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis and/or frontotemporal dementia, Duchenne muscular dystrophy, Dravet syndrome, epilepsy, Huntington's disease, and Parkinson's disease. Hopefully, it will improve our understanding of neurological disorders and give insights into future treatments for neurological disorders.}, }
@article {pmid34804368, year = {2021}, author = {Adeyemi, OS and Awakan, OJ and Afolabi, LB and Rotimi, DE and Oluwayemi, E and Otuechere, CA and Ibraheem, O and Elebiyo, TC and Alejolowo, O and Arowolo, AT}, title = {Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer's Disease.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {5522981}, pmid = {34804368}, issn = {1942-0994}, mesh = {Alzheimer Disease/drug therapy/metabolism/*pathology ; Animals ; Humans ; Hypoxia/*physiopathology ; Kynurenine/*metabolism ; *Metabolic Networks and Pathways ; }, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease predominantly pose a significant socioeconomic burden. Characterized by progressive neural dysfunction coupled with motor or intellectual impairment, the pathogenesis of ND may result from contributions of certain environmental and molecular factors. One such condition is hypoxia, characterized by reduced organ/tissue exposure to oxygen. Reduced oxygen supply often occurs during the pathogenesis of ND and the aging process. Despite the well-established relationship between these two conditions (i.e., hypoxia and ND), the underlying molecular events or mechanisms connecting hypoxia to ND remain ill-defined. However, the relatedness may stem from the protective or deleterious effects of the transcription factor, hypoxia-inducible factor 1-alpha (HIF-1α). The upregulation of HIF-1α occurs in the pathogenesis of most NDs. The dual function of HIF-1α in acting as a "killer factor" or a "protective factor" depends on the prevailing local cellular condition. The kynurenine pathway is a metabolic pathway involved in the oxidative breakdown of tryptophan. It is essential in neurotransmission and immune function and, like hypoxia, associated with ND. Thus, a good understanding of factors, including hypoxia (i.e., the biochemical implication of HIF-1α) and kynurenine pathway activation in NDs, focusing on Alzheimer's disease could prove beneficial to new therapeutic approaches for this disease, thus the aim of this review.}, }
@article {pmid34803886, year = {2021}, author = {Fishman, PS and Fischell, JM}, title = {Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {749047}, pmid = {34803886}, issn = {1664-2295}, abstract = {The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.}, }
@article {pmid34803658, year = {2021}, author = {Pfrieger, FW}, title = {Neurodegenerative Diseases and Cholesterol: Seeing the Field Through the Players.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {766587}, pmid = {34803658}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, namely Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD) together with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), devastate millions of lives per year worldwide and impose an increasing socio-economic burden across nations. Consequently, these diseases occupy a considerable portion of biomedical research aiming to understand mechanisms of neurodegeneration and to develop efficient treatments. A potential culprit is cholesterol serving as an essential component of cellular membranes, as a cofactor of signaling pathways, and as a precursor for oxysterols and hormones. This article uncovers the workforce studying research on neurodegeneration and cholesterol using the TeamTree analysis. This new bibliometric approach reveals the history and dynamics of the teams and exposes key players based on citation-independent metrics. The team-centered view reveals the players on an important field of biomedical research.}, }
@article {pmid34803655, year = {2021}, author = {Villegas, L and Nørremølle, A and Freude, K and Vilhardt, F}, title = {Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington's Disease?.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {736734}, pmid = {34803655}, issn = {1663-4365}, abstract = {Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by neuronal loss and tissue atrophy mainly in the striatum and cortex. In the early stages of the disease, impairment of neuronal function, synaptic dysfunction and white matter loss precedes neuronal death itself. Relative to other neurodegenerative diseases such as Alzheimer's and Parkinson's disease and Amyotrophic Lateral Sclerosis, where the effects of either microglia or NADPH oxidases (NOXs) are recognized as important contributors to disease pathogenesis and progression, there is a pronounced lack of information in HD. This information void contrasts with evidence from human HD patients where blood monocytes and microglia are activated well before HD clinical symptoms (PET scans), and the clear signs of oxidative stress and inflammation in post mortem HD brain. Habitually, NOX activity and oxidative stress in the central nervous system (CNS) are equated with microglia, but research of the last two decades has carved out important roles for NOX enzyme function in neurons. Here, we will convey recent information about the function of NOX enzymes in neurons, and contemplate on putative roles of neuronal NOX in HD. We will focus on NOX-produced reactive oxygen species (ROS) as redox signaling molecules in/among neurons, and the specific roles of NOXs in important processes such as neurogenesis and lineage specification, neurite outgrowth and growth cone dynamics, and synaptic plasticity where NMDAR-dependent signaling, and long-term depression/potentiation are redox-regulated phenomena. HD animal models and induced pluripotent stem cell (iPSC) studies have made it clear that the very same physiological processes are also affected in HD, and we will speculate on possible roles for NOX in the pathogenesis and development of disease. Finally, we also take into account the limited information on microglia in HD and relate this to any contribution of NOX enzymes.}, }
@article {pmid34801512, year = {2022}, author = {Dhasmana, S and Dhasmana, A and Narula, AS and Jaggi, M and Yallapu, MM and Chauhan, SC}, title = {The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder.}, journal = {Life sciences}, volume = {288}, number = {}, pages = {120156}, doi = {10.1016/j.lfs.2021.120156}, pmid = {34801512}, issn = {1879-0631}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Humans ; Nervous System Diseases/*pathology/*therapy ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease affecting both upper and lower motor neurons. In the United States alone, there are 16,000-20,000 established cases of ALS. The early disease diagnosis is challenging due to many overlapping pathophysiologies with other neurological diseases. The etiology of ALS is unknown; however, it is divided into two categories: familial ALS (fALS) which occurs due to gene mutations &amp; contributes to 5-10% of ALS, and sporadic ALS (sALS) which is due to environmental factors &amp; contributes to 90-95% of ALS. There is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. In this review, we provide a panoramic view of ALS, which includes epidemiology, risk factors, pathophysiologies, biomarkers, diagnosis, therapeutics (natural, synthetic, gene-based, pharmacological, stem cell, extracellular vesicles, and physical therapy), controversies (in the clinical trials of ALS), the scope of nanomedicine in ALS, and future perspectives.}, }
@article {pmid34800850, year = {2022}, author = {Sorrentino, S and Polini, A and Arima, V and Romano, A and Quattrini, A and Gigli, G and Mozetic, P and Moroni, L}, title = {Neurovascular signals in amyotrophic lateral sclerosis.}, journal = {Current opinion in biotechnology}, volume = {74}, number = {}, pages = {75-83}, doi = {10.1016/j.copbio.2021.10.021}, pmid = {34800850}, issn = {1879-0429}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; }, }
@article {pmid34800247, year = {2022}, author = {Nguyen, TT and Nguyen, TTD and Tran, NM and Van Vo, G}, title = {Lipid-Based Nanocarriers via Nose-to-Brain Pathway for Central Nervous System Disorders.}, journal = {Neurochemical research}, volume = {47}, number = {3}, pages = {552-573}, pmid = {34800247}, issn = {1573-6903}, mesh = {Brain/metabolism ; *Central Nervous System Diseases/drug therapy/metabolism ; Drug Delivery Systems ; Humans ; Lipids/chemistry ; Liposomes ; *Nanoparticles ; }, abstract = {Neurodegenerative disorders are distinguished by the gradual deterioration of the nervous system's structure and function due to oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity, and neuroinflammation. Among these NDs, Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis characterized an increasing dysfunction and loss of neuronal structure leading to neuronal cell death. Although there is currently no drug to totally reverse the effects of NDs, such novel formulations and administration routes are developed for better management and nose-to-brain delivery is one of delivery for treating NDs. This review aimed to highlight advances in research on various lipid based nanocarriers such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, and cubosomes which are reported to treat and alleviate the symptoms of NDs via nose-to-brain route. The challenges during clinical translation of lipid nanocarriers from bench to bed side is also discussed.}, }
@article {pmid34798972, year = {2022}, author = {Rosendale, N}, title = {Social Determinants of Health in Neurology.}, journal = {Neurologic clinics}, volume = {40}, number = {1}, pages = {231-247}, doi = {10.1016/j.ncl.2021.08.012}, pmid = {34798972}, issn = {1557-9875}, mesh = {Health Status Disparities ; Humans ; *Neurology ; *Social Determinants of Health ; }, abstract = {Neurologic health disparities are created and perpetuated by structural and social determinants of health. These factors include, but are not limited to, interpersonal bias, institutional factors that lead to disparate access to care, and neighborhood-level factors, such as socioeconomic status, segregation, and access to healthy food. Effects of these determinants of health can be seen throughout neurology, including in stroke, epilepsy, headache, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Interventions to improve neurologic health equity require multilayered approaches to address these interdependent factors that create and perpetuate disparate neurologic health access and outcomes.}, }
@article {pmid34791088, year = {2022}, author = {Julian, TH and Boddy, S and Islam, M and Kurz, J and Whittaker, KJ and Moll, T and Harvey, C and Zhang, S and Snyder, MP and McDermott, C and Cooper-Knock, J and Shaw, PJ}, title = {A review of Mendelian randomization in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {145}, number = {3}, pages = {832-842}, pmid = {34791088}, issn = {1460-2156}, support = {S10 OD025212/OD/NIH HHS/United States ; /DH_/Department of Health/United Kingdom ; R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; *Diabetes Mellitus, Type 2 ; Genome-Wide Association Study/methods ; Humans ; Lipids ; Mendelian Randomization Analysis/methods ; *Neurodegenerative Diseases ; Reproducibility of Results ; }, abstract = {Amyotrophic lateral sclerosis is a relatively common and rapidly progressive neurodegenerative disease that, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies combined with the advent of Mendelian randomization is opening significant new opportunities to identify environmental exposures that increase or decrease the risk of amyotrophic lateral sclerosis. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so, rigorous methodological standards must be applied in the performance of Mendelian randomization. We have reviewed Mendelian randomization studies performed in amyotrophic lateral sclerosis to date. We identified 20 Mendelian randomization studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the Mendelian randomization literature and the STROBE-Mendelian randomization checklist. Where discrepancies exist between Mendelian randomization studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of amyotrophic lateral sclerosis; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, Mendelian randomization studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure single nucleotide polymorphisms (SNPs) to make up the Mendelian randomization instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as amyotrophic lateral sclerosis and make recommendations to mitigate this potentially important confounder. For Mendelian randomization to be useful to the amyotrophic lateral sclerosis field, high methodological standards must be applied to ensure reproducibility. Mendelian randomization is already an impactful tool, but poor-quality studies will lead to incorrect interpretations by a field that includes non-statisticians, wasted resources and missed opportunities.}, }
@article {pmid34789332, year = {2021}, author = {Theunissen, F and West, PK and Brennan, S and Petrović, B and Hooshmand, K and Akkari, PA and Keon, M and Guennewig, B}, title = {New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {10}, number = {1}, pages = {46}, pmid = {34789332}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Cytoskeleton/metabolism/pathology ; Humans ; Mitochondria/metabolism ; Motor Neurons/pathology ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS.}, }
@article {pmid34783101, year = {2021}, author = {Riku, Y and Yoshida, M and Tamura, T and Kamijo, M and Yasui, K and Kameyama, T and Katsuno, M and Sobue, G and Iwasaki, Y}, title = {Unexpected postmortem diagnoses in cases of clinically diagnosed amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {41}, number = {6}, pages = {457-467}, doi = {10.1111/neup.12744}, pmid = {34783101}, issn = {1440-1789}, support = {Number JP20K16586//JSPS KAKENHI/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Autopsy ; Disease Progression ; Humans ; *Motor Neuron Disease ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that is clinically and pathologically characterized by impairment of the upper and lower motor neurons. The clinical diagnosis of ALS is not always straightforward because of the lack of specific biomarkers and clinical heterogeneity. This review presents the clinical and pathological findings of four autopsied cases that had been diagnosed with ALS before death. These cases had demonstrated definite and progressive motor neuron signs and symptoms, whereas postmortem assessment revealed miscellaneous disorders, including fungal infection, paraneoplastic syndrome, and amyloidosis. Importantly, nonmotor neuron signs and symptoms, including seizures, extra-pyramidal signs, ocular movement disorders, sensory disturbance, and dysautonomia, had also been documented during the disease course of the cases in the present study. The ALS-unlike symptoms were indicative of the "true" diagnosis in each case when those symptoms were isolated from motor neuron signs/symptoms.}, }
@article {pmid34781865, year = {2022}, author = {Goyal, S and Seth, B and Chaturvedi, RK}, title = {Polyphenols and Stem Cells for Neuroregeneration in Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {28}, number = {10}, pages = {806-828}, doi = {10.2174/1381612827666211115154450}, pmid = {34781865}, issn = {1873-4286}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Nerve Regeneration ; *Neural Stem Cells ; *Parkinson Disease/pathology/therapy ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons, respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, and anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.}, }
@article {pmid34778762, year = {2021}, author = {Quinn, JP and Kandigian, SE and Trombetta, BA and Arnold, SE and Carlyle, BC}, title = {VGF as a biomarker and therapeutic target in neurodegenerative and psychiatric diseases.}, journal = {Brain communications}, volume = {3}, number = {4}, pages = {fcab261}, pmid = {34778762}, issn = {2632-1297}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; R01 AG062306/AG/NIA NIH HHS/United States ; RF1 AG059856/AG/NIA NIH HHS/United States ; }, abstract = {Neurosecretory protein VGF (non-acronymic) belongs to the granin family of neuropeptides. VGF and VGF-derived peptides have been repeatedly identified in well-powered and well-designed multi-omic studies as dysregulated in neurodegenerative and psychiatric diseases. New therapeutics is urgently needed for these devastating and costly diseases, as are new biomarkers to improve disease diagnosis and mechanistic understanding. From a list of 537 genes involved in Alzheimer's disease pathogenesis, VGF was highlighted by the Accelerating Medicines Partnership in Alzheimer's disease as the potential therapeutic target of greatest interest. VGF levels are consistently decreased in brain tissue and CSF samples from patients with Alzheimer's disease compared to controls, and its levels correlate with disease severity and Alzheimer's disease pathology. In the brain, VGF exists as multiple functional VGF-derived peptides. Full-length human VGF1-615 undergoes proteolytic processing by prohormone convertases and other proteases in the regulated secretory pathway to produce at least 12 active VGF-derived peptides. In cell and animal models, these VGF-derived peptides have been linked to energy balance regulation, neurogenesis, synaptogenesis, learning and memory, and depression-related behaviours throughout development and adulthood. The C-terminal VGF-derived peptides, TLQP-62 (VGF554-615) and TLQP-21 (VGF554-574) have differential effects on Alzheimer's disease pathogenesis, neuronal and microglial activity, and learning and memory. TLQP-62 activates neuronal cell-surface receptors and regulates long-term hippocampal memory formation. TLQP-62 also prevents immune-mediated memory impairment, depression-like and anxiety-like behaviours in mice. TLQP-21 binds to microglial cell-surface receptors, triggering microglial chemotaxis and phagocytosis. These actions were reported to reduce amyloid-β plaques and decrease neuritic dystrophy in a transgenic mouse model of familial Alzheimer's disease. Expression differences of VGF-derived peptides have also been associated with frontotemporal lobar dementias, amyotrophic lateral sclerosis, Lewy body diseases, Huntington's disease, pain, schizophrenia, bipolar disorder, depression and antidepressant response. This review summarizes current knowledge and highlights questions for future investigation regarding the roles of VGF and its dysregulation in neurodegenerative and psychiatric disease. Finally, the potential of VGF and VGF-derived peptides as biomarkers and novel therapeutic targets for neurodegenerative and psychiatric diseases is highlighted.}, }
@article {pmid34778273, year = {2021}, author = {Fralish, Z and Lotz, EM and Chavez, T and Khodabukus, A and Bursac, N}, title = {Neuromuscular Development and Disease: Learning From in vitro and in vivo Models.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {764732}, pmid = {34778273}, issn = {2296-634X}, support = {R01 AR065873/AR/NIAMS NIH HHS/United States ; R01 AR055226/AR/NIAMS NIH HHS/United States ; R01 AR070543/AR/NIAMS NIH HHS/United States ; U01 EB028901/EB/NIBIB NIH HHS/United States ; UG3 TR002142/TR/NCATS NIH HHS/United States ; }, abstract = {The neuromuscular junction (NMJ) is a specialized cholinergic synaptic interface between a motor neuron and a skeletal muscle fiber that translates presynaptic electrical impulses into motor function. NMJ formation and maintenance require tightly regulated signaling and cellular communication among motor neurons, myogenic cells, and Schwann cells. Neuromuscular diseases (NMDs) can result in loss of NMJ function and motor input leading to paralysis or even death. Although small animal models have been instrumental in advancing our understanding of the NMJ structure and function, the complexities of studying this multi-tissue system in vivo and poor clinical outcomes of candidate therapies developed in small animal models has driven the need for in vitro models of functional human NMJ to complement animal studies. In this review, we discuss prevailing models of NMDs and highlight the current progress and ongoing challenges in developing human iPSC-derived (hiPSC) 3D cell culture models of functional NMJs. We first review in vivo development of motor neurons, skeletal muscle, Schwann cells, and the NMJ alongside current methods for directing the differentiation of relevant cell types from hiPSCs. We further compare the efficacy of modeling NMDs in animals and human cell culture systems in the context of five NMDs: amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, myotonic dystrophy, and Pompe disease. Finally, we discuss further work necessary for hiPSC-derived NMJ models to function as effective personalized NMD platforms.}, }
@article {pmid34777211, year = {2021}, author = {Huang, B and Li, X and Zhu, X}, title = {The Role of GM130 in Nervous System Diseases.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {743787}, pmid = {34777211}, issn = {1664-2295}, abstract = {Golgi matrix protein 130 (GM130) is a Golgi-shaping protein located on the cis surface of the Golgi apparatus (GA). It is one of the most studied Golgin proteins so far. Its biological functions are involved in many aspects of life processes, including mitosis, autophagy, apoptosis, cell polarity, and directed migration at the cellular level, as well as intracellular lipid and protein transport, microtubule formation and assembly, lysosome function maintenance, and glycosylation modification. Mutation inactivation or loss of expression of GM130 has been detected in patients with different diseases. GM130 plays an important role in the development of the nervous system, but the studies on it are limited. This article reviewed the current research progress of GM130 in nervous system diseases. It summarized the physiological functions of GM130 in the occurrence and development of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), microcephaly (MCPH), sepsis associated encephalopathy (SAE), and Ataxia, aiming to provide ideas for the further study of GM130 in nervous system disease detection and treatment.}, }
@article {pmid34776851, year = {2021}, author = {de Melo Reis, RA and Isaac, AR and Freitas, HR and de Almeida, MM and Schuck, PF and Ferreira, GC and Andrade-da-Costa, BLDS and Trevenzoli, IH}, title = {Quality of Life and a Surveillant Endocannabinoid System.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {747229}, pmid = {34776851}, issn = {1662-4548}, abstract = {The endocannabinoid system (ECS) is an important brain modulatory network. ECS regulates brain homeostasis throughout development, from progenitor fate decision to neuro- and gliogenesis, synaptogenesis, brain plasticity and circuit repair, up to learning, memory, fear, protection, and death. It is a major player in the hypothalamic-peripheral system-adipose tissue in the regulation of food intake, energy storage, nutritional status, and adipose tissue mass, consequently affecting obesity. Loss of ECS control might affect mood disorders (anxiety, hyperactivity, psychosis, and depression), lead to drug abuse, and impact neurodegenerative (Alzheimer's, Parkinson, Huntington, Multiple, and Amyotrophic Lateral Sclerosis) and neurodevelopmental (autism spectrum) disorders. Practice of regular physical and/or mind-body mindfulness and meditative activities have been shown to modulate endocannabinoid (eCB) levels, in addition to other players as brain-derived neurotrophic factor (BDNF). ECS is involved in pain, inflammation, metabolic and cardiovascular dysfunctions, general immune responses (asthma, allergy, and arthritis) and tumor expansion, both/either in the brain and/or in the periphery. The reason for such a vast impact is the fact that arachidonic acid, a precursor of eCBs, is present in every membrane cell of the body and on demand eCBs synthesis is regulated by electrical activity and calcium shifts. Novel lipid (lipoxins and resolvins) or peptide (hemopressin) players of the ECS also operate as regulators of physiological allostasis. Indeed, the presence of cannabinoid receptors in intracellular organelles as mitochondria or lysosomes, or in nuclear targets as PPARγ might impact energy consumption, metabolism and cell death. To live a better life implies in a vigilant ECS, through healthy diet selection (based on a balanced omega-3 and -6 polyunsaturated fatty acids), weekly exercises and meditation therapy, all of which regulating eCBs levels, surrounded by a constructive social network. Cannabidiol, a diet supplement has been a major player with anti-inflammatory, anxiolytic, antidepressant, and antioxidant activities. Cognitive challenges and emotional intelligence might strengthen the ECS, which is built on a variety of synapses that modify human behavior. As therapeutically concerned, the ECS is essential for maintaining homeostasis and cannabinoids are promising tools to control innumerous targets.}, }
@article {pmid34770082, year = {2021}, author = {Calderón-Garcidueñas, L and Stommel, EW and Rajkumar, RP and Mukherjee, PS and Ayala, A}, title = {Particulate Air Pollution and Risk of Neuropsychiatric Outcomes. What We Breathe, Swallow, and Put on Our Skin Matters.}, journal = {International journal of environmental research and public health}, volume = {18}, number = {21}, pages = {}, pmid = {34770082}, issn = {1660-4601}, mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/analysis/statistics &amp; numerical data ; Dust ; Particulate Matter/analysis/toxicity ; Vehicle Emissions/analysis ; }, abstract = {We appraise newly accumulated evidence of the impact of particle pollution on the brain, the portals of entry, the neural damage mechanisms, and ultimately the neurological and psychiatric outcomes statistically associated with exposures. PM pollution comes from natural and anthropogenic sources such as fossil fuel combustion, engineered nanoparticles (NP ≤ 100 nm), wildfires, and wood burning. We are all constantly exposed during normal daily activities to some level of particle pollution of various sizes-PM2.5 (≤2.5 µm), ultrafine PM (UFP ≤ 100 nm), or NPs. Inhalation, ingestion, and dermal absorption are key portals of entry. Selected literature provides context for the US Environmental Protection Agency (US EPA) ambient air quality standards, the conclusions of an Independent Particulate Matter Review Panel, the importance of internal combustion emissions, and evidence suggesting UFPs/NPs cross biological barriers and reach the brain. NPs produce oxidative stress and neuroinflammation, neurovascular unit, mitochondrial, endoplasmic reticulum and DNA damage, protein aggregation and misfolding, and other effects. Exposure to ambient PM2.5 concentrations at or below current US standards can increase the risk for TIAs, ischemic and hemorrhagic stroke, cognitive deficits, dementia, and Alzheimer's and Parkinson's diseases. Residing in a highly polluted megacity is associated with Alzheimer neuropathology hallmarks in 99.5% of residents between 11 months and ≤40 y. PD risk and aggravation are linked to air pollution and exposure to diesel exhaust increases ALS risk. Overall, the literature supports that particle pollution contributes to targeted neurological and psychiatric outcomes and highlights the complexity of the pathophysiologic mechanisms and the marked differences in pollution profiles inducing neural damage. Factors such as emission source intensity, genetics, nutrition, comorbidities, and others also play a role. PM2.5 is a threat for neurological and psychiatric diseases. Thus, future research should address specifically the potential role of UFPs/NPs in inducing neural damage.}, }
@article {pmid34769512, year = {2021}, author = {Maximova, A and Werry, EL and Kassiou, M}, title = {Senolytics: A Novel Strategy for Neuroprotection in ALS?.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34769512}, issn = {1422-0067}, support = {APP1132524//National Health and Medical Research Council/ ; APP1154692//National Health and Medical Research Council/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neuroinflammatory Diseases/*drug therapy/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Senotherapeutics/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.}, }
@article {pmid34769277, year = {2021}, author = {Jurcau, A}, title = {Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34769277}, issn = {1422-0067}, mesh = {Animals ; Humans ; Mitochondria/genetics/*metabolism/pathology ; Mitochondrial Diseases/genetics/*metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; *Oxidative Stress ; }, abstract = {As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.}, }
@article {pmid34759799, year = {2021}, author = {de Mena, L and Lopez-Scarim, J and Rincon-Limas, DE}, title = {TDP-43 and ER Stress in Neurodegeneration: Friends or Foes?.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {772226}, pmid = {34759799}, issn = {1662-5099}, support = {R01 AG059871/AG/NIA NIH HHS/United States ; }, abstract = {Nuclear depletion, abnormal modification, and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are linked to a group of fatal neurodegenerative diseases called TDP-43 proteinopathies, which include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Although our understanding of the physiological function of TDP-43 is rapidly advancing, the molecular mechanisms associated with its pathogenesis remain poorly understood. Accumulating evidence suggests that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are important players in TDP-43 pathology. However, while neurons derived from autopsied ALS and FTLD patients revealed TDP-43 deposits in the ER and displayed UPR activation, data originated from in vitro and in vivo TDP-43 models produced contradictory results. In this review, we will explore the complex interplay between TDP-43 pathology, ER stress, and the UPR by breaking down the evidence available in the literature and addressing the reasons behind these discrepancies. We also highlight underexplored areas and key unanswered questions in the field. A better synchronization and integration of methodologies, models, and mechanistic pathways will be crucial to discover the true nature of the TDP-43 and ER stress relationship and, ultimately, to uncover the full therapeutic potential of the UPR.}, }
@article {pmid34744700, year = {2021}, author = {Li, T and Tan, X and Li, S and Al-Nusaif, M and Le, W}, title = {Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {765395}, pmid = {34744700}, issn = {1663-4365}, abstract = {Extracellular vesicles (EVs), as nano-sized vesicles secreted by almost all cells, have been recognized as the essential transmitter for cell-to-cell communication and participating in multiple biological processes. Neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, share common mechanisms of the aggregation and propagation of distinct pathologic proteins among cells in the nervous systems and neuroinflammatory reactions mediated by glia during the pathogenic process. This feature indicates the vital role of crosstalk between neurons and glia in the pathogenesis of ND. In recent years, glia-derived EVs have been investigated as potential mediators of signals between neurons and glia, which provides a new direction and strategy for understanding ND. By a comprehensive summary, it can be concluded that glia-derived EVs have both a beneficial and/or a detrimental effect in the process of ND. Therefore, this review article conveys the role of glia-derived EVs in the pathogenesis of ND and raises current limitations of their potential application in the diagnosis and treatment of ND.}, }
@article {pmid34744635, year = {2021}, author = {Sharpe, JL and Harper, NS and Garner, DR and West, RJH}, title = {Modeling C9orf72-Related Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Drosophila.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {770937}, pmid = {34744635}, issn = {1662-5102}, abstract = {An intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced C9orf72 transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. Drosophila models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of C9orf72-related FTD/ALS. There is no C9orf72 homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of Drosophila C9orf72 models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to C9orf72 toxicity. In this review, we discuss how Drosophila models have shaped our understanding of C9orf72 gain of function toxicity, and address opportunities to utilize these models for further research.}, }
@article {pmid34744606, year = {2021}, author = {Proulx, J and Park, IW and Borgmann, K}, title = {Cal'MAM'ity at the Endoplasmic Reticulum-Mitochondrial Interface: A Potential Therapeutic Target for Neurodegeneration and Human Immunodeficiency Virus-Associated Neurocognitive Disorders.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {715945}, pmid = {34744606}, issn = {1662-4548}, support = {F31 DA053151/DA/NIDA NIH HHS/United States ; R01 DA039789/DA/NIDA NIH HHS/United States ; }, abstract = {The endoplasmic reticulum (ER) is a multifunctional organelle and serves as the primary site for intracellular calcium storage, lipid biogenesis, protein synthesis, and quality control. Mitochondria are responsible for producing the majority of cellular energy required for cell survival and function and are integral for many metabolic and signaling processes. Mitochondria-associated ER membranes (MAMs) are direct contact sites between the ER and mitochondria that serve as platforms to coordinate fundamental cellular processes such as mitochondrial dynamics and bioenergetics, calcium and lipid homeostasis, autophagy, apoptosis, inflammation, and intracellular stress responses. Given the importance of MAM-mediated mechanisms in regulating cellular fate and function, MAMs are now known as key molecular and cellular hubs underlying disease pathology. Notably, neurons are uniquely susceptible to mitochondrial dysfunction and intracellular stress, which highlights the importance of MAMs as potential targets to manipulate MAM-associated mechanisms. However, whether altered MAM communication and connectivity are causative agents or compensatory mechanisms in disease development and progression remains elusive. Regardless, exploration is warranted to determine if MAMs are therapeutically targetable to combat neurodegeneration. Here, we review key MAM interactions and proteins both in vitro and in vivo models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We further discuss implications of MAMs in HIV-associated neurocognitive disorders (HAND), as MAMs have not yet been explored in this neuropathology. These perspectives specifically focus on mitochondrial dysfunction, calcium dysregulation and ER stress as notable MAM-mediated mechanisms underlying HAND pathology. Finally, we discuss potential targets to manipulate MAM function as a therapeutic intervention against neurodegeneration. Future investigations are warranted to better understand the interplay and therapeutic application of MAMs in glial dysfunction and neurotoxicity.}, }
@article {pmid34742724, year = {2022}, author = {Gupta, R and Ambasta, RK and Kumar, P}, title = {Multifaced role of protein deacetylase sirtuins in neurodegenerative disease.}, journal = {Neuroscience and biobehavioral reviews}, volume = {132}, number = {}, pages = {976-997}, doi = {10.1016/j.neubiorev.2021.10.047}, pmid = {34742724}, issn = {1873-7528}, mesh = {*Alzheimer Disease/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; *Parkinson Disease/metabolism ; *Sirtuins/metabolism/therapeutic use ; }, abstract = {Sirtuins, a class III histone/protein deacetylase, is a central regulator of metabolic function and cellular stress response. This plays a pivotal role in the pathogenesis and progression of diseases such as cancer, neurodegeneration, metabolic syndromes, and cardiovascular disease. Sirtuins regulate biological and cellular processes, for instance, mitochondrial biogenesis, lipid and fatty acid oxidation, oxidative stress, gene transcriptional activity, apoptosis, inflammatory response, DNA repair mechanism, and autophagic cell degradation, which are known components for the progression of the neurodegenerative diseases (NDDs). Emerging evidence suggests that sirtuins are the useful molecular targets against NDDs like, Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). However, the exact mechanism of neuroprotection mediated through sirtuins remains unsettled. The manipulation of sirtuins activity with its modulators, calorie restriction (CR), and micro RNAs (miR) is a novel therapeutic approach for the treatment of NDDs. Herein, we reviewed the current putative therapeutic role of sirtuins in regulating synaptic plasticity and cognitive functions, which are mediated through the different molecular phenomenon to prevent neurodegeneration. We also explained the implications of sirtuin modulators, and miR based therapies for the treatment of life-threatening NDDs.}, }
@article {pmid34738851, year = {2022}, author = {Alves De Siqueira Carvalho, A and Antônio Troccoli Chieia, M and Braga Farias, I and Bulle Oliveira, AS and Pinto, WBVR and Souza, PVS}, title = {The expanding clinical and genetic spectrum of alsin-related disorders: the first cohort of Brazilian patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {16-24}, doi = {10.1080/21678421.2021.1910306}, pmid = {34738851}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/genetics/pathology ; Brazil/epidemiology ; Guanine Nucleotide Exchange Factors/genetics ; Humans ; *Motor Neuron Disease/genetics ; *Spastic Paraplegia, Hereditary/genetics ; }, abstract = {There are three types of autosomal recessive disorders involving pathogenic variants in the ALS2 gene (OMIM*606352), infantile ascending hereditary spastic paraplegia (IAHSP), juvenile primary lateral sclerosis (JPLS) and juvenile amyotrophic lateral sclerosis (JALS), which are rare and related to retrograde degeneration of motor neurons. ALS2 pathogenic variants are distributed widely across the entire coding sequence and mostly result in a loss of protein function. Rarely, patients with JALS have been reported with lower motor neuron involvement. Here, we report the first Brazilian cohort (six patients) of JPLS with novel ALS2 pathogenic variants, and we propose an expanding clinical and genetic spectrum of alsin-related disorders. A review of the literature in PubMed from 2001 to September 2020 allowed us to identify 26 publications about the three different phenotypes caused by ALS2 variants (only case reports or families), encompassing 35 nonrelated families. We compiled data (sex, age, age at onset, first symptoms, atypical clinical features, molecular data, and clinical evolution (improvement or death)) from these studies and analyzed them in a general context on the basis of demographic features.}, }
@article {pmid34734492, year = {2021}, author = {Chen, S and Zou, JL and He, S and Li, W and Zhang, JW and Li, SJ}, title = {More autosomal dominant SPG18 cases than recessive? The first AD-SPG18 pedigree in Chinese and literature review.}, journal = {Brain and behavior}, volume = {11}, number = {12}, pages = {e32395}, pmid = {34734492}, issn = {2162-3279}, mesh = {Adolescent ; Asian People/genetics ; China ; Heterozygote ; Humans ; Mutation ; Pedigree ; *Spastic Paraplegia, Hereditary/genetics ; }, abstract = {OBJECTIVE: Hereditary spastic paraplegia (HSP) due to ERLIN2 gene mutations was designated as spastic paraplegia 18 (SPG18). To date, SPG18 families/cases are still rarely reported. All early reported cases shared the autosomal recessive (AR) inheritance pattern. Over the past 3 years, autosomal dominant (AD) or sporadic SPG18 cases had been continuously reported. Here, we reported the clinical and genetic features of the first autosomal dominant SPG18 pedigree in Chinese.<br><br>METHODS: We conducted detailed medical history inquiry, neurological examinations of the proband and his family members, and charted the family tree. The proband underwent brain and cervical magnetic resonance imaging (MRI), electromyography (EMG), and whole exome sequencing. Sanger sequencing was performed to verify the genetic variation in the proband and some family members. A literature review of all reported SPG18 families/cases was carried out to summarize the clinical-genetic characteristics of SPG18 under different inheritance patterns.<br><br>RESULTS: Four patients were clinically diagnosed as chronic spastic paraplegia in three consecutive generations with the autosomal dominant inheritance model. All the patients presented juvenile-adolescent onset and gradually worsening pure HSP phenotype. Clinical phenotypes were consistent within the family. Whole exome sequencing in the proband identified a previously reported heterozygous c.502G&#xa0;>&#xa0;A (p.V168M) mutation in exon 8 of ERLIN2 gene. This mutation was cosegregated with the phenotype in the family and was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. To date, eight AR-SPG18 families, five AD-SPG18 families, and three sporadic cases had been reported. Clinical phenotype of AD-SPG18 was juvenile-adolescent onset pure HSP, while the phenotype of AR-SPG18 was mostly complicated HSP with earlier onset and more severe conditions. In rare cases, the initial spastic paraplegia could evolve to rapidly progressive amyotrophic lateral sclerosis (ALS).<br><br>CONCLUSIONS: We reported the first autosomal dominant SPG18 pedigree in Chinese Han population, which added more pathogenic evidence for V168M mutation. As more SPG18 cases reported, the essentials of SPG18 need to be updated in clinical practice. Special attentions should be given in gene test for upper motor neuron disorders in case of missing heterozygous mutations in ERLIN2.}, }
@article {pmid34729157, year = {2021}, author = {Kocar, TD and Müller, HP and Ludolph, AC and Kassubek, J}, title = {Feature selection from magnetic resonance imaging data in ALS: a systematic review.}, journal = {Therapeutic advances in chronic disease}, volume = {12}, number = {}, pages = {20406223211051002}, pmid = {34729157}, issn = {2040-6223}, abstract = {BACKGROUND: With the advances in neuroimaging in amyotrophic lateral sclerosis (ALS), it has been speculated that multiparametric magnetic resonance imaging (MRI) is capable to contribute to early diagnosis. Machine learning (ML) can be regarded as the missing piece that allows for the useful integration of multiparametric MRI data into a diagnostic classifier. The major challenges in developing ML classifiers for ALS are limited data quantity and a suboptimal sample to feature ratio which can be addressed by sound feature selection.<br><br>METHODS: We conducted a systematic review to collect MRI biomarkers that could be used as features by searching the online database PubMed for entries in the recent 4 years that contained cross-sectional neuroimaging data of subjects with ALS and an adequate control group. In addition to the qualitative synthesis, a semi-quantitative analysis was conducted for each MRI modality that indicated which brain regions were most commonly reported.<br><br>RESULTS: Our search resulted in 151 studies with a total of 221 datasets. In summary, our findings highly resembled generally accepted neuropathological patterns of ALS, with degeneration of the motor cortex and the corticospinal tract, but also in frontal, temporal, and subcortical structures, consistent with the neuropathological four-stage model of the propagation of pTDP-43 in ALS.<br><br>CONCLUSIONS: These insights are discussed with respect to their potential for MRI feature selection for future ML-based neuroimaging classifiers in ALS. The integration of multiparametric MRI including DTI, volumetric, and texture data using ML may be the best approach to generate a diagnostic neuroimaging tool for ALS.}, }
@article {pmid34724212, year = {2022}, author = {Ebrahimi, R and Golestani, A}, title = {The emerging role of noncoding RNAs in neuroinflammation: Implications in pathogenesis and therapeutic approaches.}, journal = {Journal of cellular physiology}, volume = {237}, number = {2}, pages = {1206-1224}, doi = {10.1002/jcp.30624}, pmid = {34724212}, issn = {1097-4652}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/therapy ; Neuroinflammatory Diseases ; *RNA, Long Noncoding/genetics ; RNA, Untranslated/genetics/metabolism ; }, abstract = {Noncoding RNAs (ncRNAs) are important regulators of gene expression in different cell processes. Due to their ability in monitoring neural development genes, these transcripts confer neurons with the potential to exert broad control over the expression of genes for performing neurobiological functions. Although the change of ncRNA expression in different neurodegenerative diseases has been reviewed elsewhere, only recent evidence drove our attention to unravel the involvement of these molecules in neuroinflammation within these devastating disorders. Remarkably, the interactions between ncRNAs and inflammatory pathways are not fully recognized. Therefore, this review has focused on the interplay between diverse inflammatory pathways and the related ncRNAs, including microRNAs, long noncoding RNAs, and competing endogenous RNAs in Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, Huntington's disease, and prion diseases. Providing novel insights in the field of combining biomarkers is a critical step for using them as diagnostic tools and therapeutic targets in clinical settings.}, }
@article {pmid34719771, year = {2022}, author = {Pathak, N and Vimal, SK and Tandon, I and Agrawal, L and Hongyi, C and Bhattacharyya, S}, title = {Neurodegenerative Disorders of Alzheimer, Parkinsonism, Amyotrophic Lateral Sclerosis and Multiple Sclerosis: An Early Diagnostic Approach for Precision Treatment.}, journal = {Metabolic brain disease}, volume = {37}, number = {1}, pages = {67-104}, pmid = {34719771}, issn = {1573-7365}, mesh = {Aged ; *Alzheimer Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Humans ; *Multiple Sclerosis ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Parkinson Disease ; }, abstract = {Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic-lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.}, }
@article {pmid34714469, year = {2022}, author = {Vatsa, P and Negi, R and Ansari, UA and Khanna, VK and Pant, AB}, title = {Insights of Extracellular Vesicles of Mesenchymal Stem Cells: a Prospective Cell-Free Regenerative Medicine for Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {1}, pages = {459-474}, pmid = {34714469}, issn = {1559-1182}, mesh = {Animals ; Extracellular Vesicles/*metabolism ; Humans ; Mesenchymal Stem Cells/*metabolism ; Neurodegenerative Diseases/metabolism/*therapy ; Regenerative Medicine/*methods ; }, abstract = {Mesenchymal stem cells (MSCs) are multipotent, adult stem cells which are found in numerous tissues like the umbilical cord, Wharton's jelly, bone marrow, and adipose tissue. They possess the capacity of self-renewal by dividing and differentiating into various cellular lineages. Their characteristic therapeutic potential exploited so far has made them a desirable candidate in regenerative medicine. Neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke have been treated with MSCs and MSC-derived products. Over the past few decades, we have witnessed significant contributions in discovering the etiology of various NDs and their possible therapeutic solutions. One of the MSC-based therapeutics is extracellular vesicles (EVs), which contain multiple biologically active molecules like nucleic acids and proteins. The contents of EVs are ferried between cells for intercellular communication which then leads to regulation of the homeostasis of recipient cells. EVs serve as a considerable means of cell-free therapies like for tissue repair or regeneration as EVs can maintain therapeutically effective cargo of parent cells and are free of various ethical issues in cell-based therapies. Due to paucity of standard protocols in extraction procedures of EVs and their pharmacological properties and mechanisms, the development of new EV dependent therapies is challenging. With this review, an attempt has been made to annotate these mechanisms, which can help advance the novel therapeutic approaches towards the treat and define a more narrowed down approach for each ND to devise effective MSC-based therapies to cure and avert these diseases.}, }
@article {pmid34713302, year = {2021}, author = {Blyufer, A and Lhamo, S and Tam, C and Tariq, I and Thavornwatanayong, T and Mahajan, SS}, title = {Riluzole: A neuroprotective drug with potential as a novel anti‑cancer agent (Review).}, journal = {International journal of oncology}, volume = {59}, number = {5}, pages = {}, pmid = {34713302}, issn = {1791-2423}, support = {SC1 GM131929/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Mice ; Neoplasms/*drug therapy/pathology ; Riluzole/*pharmacology/therapeutic use ; Xenograft Model Antitumor Assays ; }, abstract = {Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti‑neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca[2+] homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin‑resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple‑negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.}, }
@article {pmid34710283, year = {2021}, author = {Eisen, A and Bede, P}, title = {The strength of corticomotoneuronal drive underlies ALS split phenotypes and reflects early upper motor neuron dysfunction.}, journal = {Brain and behavior}, volume = {11}, number = {12}, pages = {e2403}, pmid = {34710283}, issn = {2162-3279}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Motor Neurons/physiology ; Neuroimaging ; Phenotype ; Transcranial Magnetic Stimulation/methods ; }, abstract = {BACKGROUND: Split phenotypes, (split hand, elbow, leg, and foot), are probably unique to ALS, and are characterized by having a shared peripheral input of both affected and unaffected muscles. This implies an anatomical origin rostral to the spinal cord, primarily within the cerebral cortex. Therefore, split phenotypes are a potential marker of ALS upper motor neuron pathology. However, to date, reports documenting upper motor neuron dysfunction in split phenotypes have been limited to using transcranial magnetic stimulation and cortical threshold tracking techniques. Here, we consider several other potential methodologies that could confirm a primary upper motor neuron pathology in split phenotypes.<br><br>METHODS: We review the potential of: 1. measuring the compound excitatory post-synaptic potential recorded from a single activated motor unit, 2. cortical-muscular coherence, and 3. new advanced modalities of neuroimaging (high-resolution imaging protocols, ultra-high field MRI platforms [7T], and novel Non-Gaussian diffusion models).<br><br>CONCLUSIONS: We propose that muscles involved in split phenotypes are those functionally involved in the human motor repertoire used particularly in complex activities. Their anterior horn cells receive the strongest corticomotoneuronal input. This is also true of the weakest muscles that are the earliest to be affected in ALS. Descriptions of split hand in non-ALS cases and proposals that peripheral nerve or muscle dysfunction may be causative are contentious. Only a few carefully controlled cases of each form of split phenotype, using upper motor neuron directed methodologies, are necessary to prove our postulate.}, }
@article {pmid34706979, year = {2022}, author = {Nedelsky, NB and Taylor, JP}, title = {Pathological phase transitions in ALS-FTD impair dynamic RNA-protein granules.}, journal = {RNA (New York, N.Y.)}, volume = {28}, number = {1}, pages = {97-113}, pmid = {34706979}, issn = {1469-9001}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Binding Sites ; Biomolecular Condensates/*chemistry/metabolism ; Cell Death/genetics ; Cytoplasmic Ribonucleoprotein Granules/*chemistry/genetics/metabolism ; Frontotemporal Dementia/*genetics/metabolism/pathology ; Humans ; Molecular Dynamics Simulation ; Mutation ; Nerve Tissue Proteins/chemistry/genetics/metabolism ; Neurons/metabolism/pathology ; Phase Transition ; Protein Binding ; RNA/*chemistry/genetics/metabolism ; RNA-Binding Proteins/*chemistry/genetics/metabolism ; Ribonucleoproteins/chemistry/genetics/metabolism ; }, abstract = {The genetics of human disease serves as a robust and unbiased source of insight into human biology, both revealing fundamental cellular processes and exposing the vulnerabilities associated with their dysfunction. Over the last decade, the genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have epitomized this concept, as studies of ALS-FTD-causing mutations have yielded fundamental discoveries regarding the role of biomolecular condensation in organizing cellular contents while implicating disturbances in condensate dynamics as central drivers of neurodegeneration. Here we review this genetic evidence, highlight its intersection with patient pathology, and discuss how studies in model systems have revealed a role for aberrant condensation in neuronal dysfunction and death. We detail how multiple, distinct types of disease-causing mutations promote pathological phase transitions that disturb the dynamics and function of ribonucleoprotein (RNP) granules. Dysfunction of RNP granules causes pleiotropic defects in RNA metabolism and can drive the evolution of these structures to end-stage pathological inclusions characteristic of ALS-FTD. We propose that aberrant phase transitions of these complex condensates in cells provide a parsimonious explanation for the widespread cellular abnormalities observed in ALS as well as certain histopathological features that characterize late-stage disease.}, }
@article {pmid34705082, year = {2021}, author = {Lee, JD and Woodruff, TM}, title = {The emerging role of complement in neuromuscular disorders.}, journal = {Seminars in immunopathology}, volume = {43}, number = {6}, pages = {817-828}, pmid = {34705082}, issn = {1863-2300}, mesh = {Complement Activation ; Complement Inactivating Agents/therapeutic use ; Complement System Proteins ; Humans ; *Myasthenia Gravis/drug therapy ; *Neuromuscular Diseases/drug therapy/etiology ; }, abstract = {The complement cascade is a key arm of the immune system that protects the host from exogenous and endogenous toxic stimuli through its ability to potently regulate inflammation, phagocytosis, and cell lysis. Due to recent clinical trial successes and drug approvals for complement inhibitors, there is a resurgence in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several diseases. In particular, neuromuscular diseases are undergoing a recent focus, with demonstrated links between complement activation and disease pathology. This review aims to provide a comprehensive overview of complement activation and its role during the initiation and progression of neuromuscular disorders including myasthenia gravis, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. We will review the preclinical and clinical evidence for complement in these diseases, with an emphasis on the complement-targeting drugs in clinical trials for these indications.}, }
@article {pmid34704267, year = {2022}, author = {Ito, D}, title = {Promise of Nucleic Acid Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {91}, number = {1}, pages = {13-20}, doi = {10.1002/ana.26259}, pmid = {34704267}, issn = {1531-8249}, support = {//Serika Fund/ ; //the Foundation of Japan Amyotrophic Lateral Sclerosis Association/ ; //the Ice Bucket Challenge Grant (Japan Amyotrophic Lateral Sclerosis Association)/ ; 21H02812//the Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Gene Expression Regulation/*drug effects ; Humans ; Nucleic Acids/*therapeutic use ; }, abstract = {Nucleic acid therapeutics have been attracting attention as novel drug discovery modalities for intractable diseases, including amyotrophic lateral sclerosis. This review provides an overview of the current status and prospects of antisense oligonucleotide treatment for amyotrophic lateral sclerosis. Recently, the results of a phase I/II study using the antisense oligonucleotides Tofersen to treat familial amyotrophic lateral sclerosis with superoxide dismutase 1 mutation have been reported. Intrathecal Tofersen administration resulted in a 36% reduction in superoxide dismutase 1 level in the cerebrospinal fluid. Another report described 2 patients with mutant superoxide dismutase 1 treated with an adeno-associated virus encoding a microRNA targeting superoxide dismutase 1. The first patient, who possessed the fast progressive mutant A5V, received a single intrathecal infusion. Although the patient died of respiratory arrest 16 months after treatment, autopsy findings showed a reduction of >90% in superoxide dismutase 1 level in the spinal cord. Clinical trials on antisense oligonucleotide therapies targeting other major amyotrophic lateral sclerosis-causative genes, fused in sarcoma and chromosome 9 open reading frame 72, are ongoing. To attenuate the pathology of TDP-43, strategies targeting regulators of TDP-43 (ataxin 2) and proteins downstream of TDP-43 (stathmin 2) by antisense oligonucleotides are being developed. The advent of nucleic acid therapeutics has enabled to specifically attack the molecules in the amyotrophic lateral sclerosis pathological cascade, expanding the options for therapeutic targets. ANN NEUROL 2022;91:13-20.}, }
@article {pmid34704111, year = {2021}, author = {Anderl-Straub, S and Schuster, J and Dorst, J and Ludolph, AC}, title = {[Amyotrophic lateral sclerosis and frontotemporal dementia-On the way to common gene-specific treatment approaches].}, journal = {Der Nervenarzt}, volume = {92}, number = {12}, pages = {1219-1226}, pmid = {34704111}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/diagnosis/genetics/therapy ; Humans ; Mutation/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common neuropathological features and in the case of a gene mutation, also a genetic cause. To date five ALS-FTD genes are described in the literature in addition to other rare variants.<br><br>OBJECTIVE: The current state of research on treatment options for ALS and FTD is presented and an outlook on possible gene-specific approaches for ALS-FTD is provided.<br><br>MATERIAL AND METHODS: Analysis of the progression of ALS and FTD research by considering the increasing state of knowledge on the underlying pathomechanisms of the diseases.<br><br>RESULTS: In addition to anti-inflammatory approaches and stabilization of protein folding, promising gene-specific treatment approaches are currently being developed, which target common causes of ALS and FTD and therefore have an effect on both diseases.<br><br>CONCLUSION: So far there are no causal treatment options for ALS and FTD. The increasing importance of genetic causes directs the focus to the development of gene-specific treatment.}, }
@article {pmid34697770, year = {2022}, author = {Bandiwadekar, A and Jose, J and Khayatkashani, M and Habtemariam, S and Khayat Kashani, HR and Nabavi, SM}, title = {Emerging Novel Approaches for the Enhanced Delivery of Natural Products for the Management of Neurodegenerative Diseases.}, journal = {Journal of molecular neuroscience : MN}, volume = {72}, number = {3}, pages = {653-676}, pmid = {34697770}, issn = {1559-1166}, mesh = {Antioxidants/pharmacology/therapeutic use ; *Biological Products/pharmacology/therapeutic use ; *Curcumin/therapeutic use ; Drug Delivery Systems ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, and prion disease affect any part of the brain. The complete mechanism of ND is unknown, but there are some molecular mechanism and chemical process. Natural compounds have better compatibility with the human body along with lesser side effects. Moreover, several studies showed that various natural compounds have significant neuroprotective, potent antioxidant, and anti-inflammatory properties, which are effective for treating the different type of ND. In ND, natural compounds act by various mechanisms such as preventing the generation of reactive oxygen species (ROS), eliminating destructed biomolecules before their accumulation affects cell metabolism, and improving the disease conditions. But due to the presence of the blood-brain barrier (BBB) layer and unfavorable pharmacokinetic properties of natural compounds, their delivery into the brain is limited. To minimize this problem and enhance drug delivery into the brain with an effective therapeutic dose, there is a need to develop a practical novel approach. The various studies showed that nanoformulations and microneedles (MN) containing natural compounds such as quercetin, curcumin, resveratrol, chrysin, piperine, ferulic acid, huperzine A, berberine, baicalein, hesperetin, and retinoic acid effectively improved many ND. In this review, the effect of such natural drug-loaded nanoformulation and MN patches on ND management is discussed, along with their merits and demerits. This review aims to introduce different novel approaches for enhancing natural drug delivery into the brain to manage various neurodegenerative diseases.}, }
@article {pmid34694422, year = {2022}, author = {Gaisendrees, C and Walter, S and Sabashnikov, A and Adler, C and Wahlers, T}, title = {[Extracorporeal cardiopulmonary resuscitation for treatment of out-of-hospital cardiac arrest].}, journal = {Der Anaesthesist}, volume = {71}, number = {5}, pages = {392-399}, pmid = {34694422}, issn = {1432-055X}, mesh = {*Cardiopulmonary Resuscitation ; *Extracorporeal Membrane Oxygenation ; Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) affects ca. 75,000 people each year in Germany and is associated with a limited prognosis and a high mortality. Extracorporeal cardiopulmonary resuscitation (eCPR) using arteriovenous extracorporeal membrane oxygenation (av-ECMO) systems is an additional option for treatment, which is increasingly more widespread and since 2020 anchored in the guideline algorithm.<br><br>METHODS: A selective search of the literature was carried out in PubMed and Embase focusing on studies that investigated eCPR for OHCA. Furthermore, clinical studies on this topic that are currently recruiting and running are summarized.<br><br>RESULTS: The available data on the benefits of eCPR for OHCA are mostly based on retrospective cohort studies. A survival advantage and an advantage in the neurological outcome could be derived from these data for selected patients treated with eCPR vs. conventionally resuscitated patients (CPR). This effect could be confirmed by two current randomized controlled studies. Studies which are currently running are investigating if out-of-hospital ECMO cannulation at the earliest time possible at the site of OHCA of patients could be associated with a better survival.<br><br>CONCLUSION: Despite a current scarcity of data, a survival advantage for eCPR treatment in selected OHCA patients must be assumed. If this can be substantiated by other high-quality studies, it seems to be indicated to evaluate if and to what extent resource-intensive eCPR programs can be comprehensively established.}, }
@article {pmid34690692, year = {2021}, author = {Jensen, TL and Gøtzsche, CR and Woldbye, DPD}, title = {Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {695937}, pmid = {34690692}, issn = {1662-5099}, abstract = {In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.}, }
@article {pmid34689261, year = {2022}, author = {Hommen, F and Bilican, S and Vilchez, D}, title = {Protein clearance strategies for disease intervention.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {129}, number = {2}, pages = {141-172}, pmid = {34689261}, issn = {1435-1463}, mesh = {Autophagy ; Humans ; *Neurodegenerative Diseases/metabolism/therapy ; Proteasome Endopeptidase Complex/metabolism ; *Proteolysis ; Ubiquitin/metabolism ; }, abstract = {Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.}, }
@article {pmid34685964, year = {2021}, author = {Chadha, A and Florentine, S}, title = {Biology, Ecology, Distribution and Control of the Invasive Weed, Lactuca serriola L. (Wild Lettuce): A Global Review.}, journal = {Plants (Basel, Switzerland)}, volume = {10}, number = {10}, pages = {}, pmid = {34685964}, issn = {2223-7747}, abstract = {Lactuca serriola L. (wild lettuce) is a highly invasive C3 weed in many countries, including Australia, Canada, and the USA. This weed is a severe threat to agricultural systems, especially in crops grown with reduced or no-tillage approaches, which commonly include wheat, cereals and pulses. Owing to the vertical orientation of its leaves in the north-south plane and its root architecture, L. serriola can maintain high water use efficiency under drought conditions, giving it the ability to expand its range under a drying climate. Each plant can produce up to 100,000 seeds which have no primary dormancy and form a short-term seedbank lasting up to three years. Most seedlings emerge in autumn and overwinter as a rosette, with a small flush of emergence in spring depicting staggered germination. Research into control methods for this weed has been performed, and these methods include chemical herbicides applied alone and in combination, the establishment of plant competition, tillage, mowing and bioherbicide. Herbicides can provide effective control when applied in the seedling or rosette stage; however, spring germination is difficult to control, as it skips the rosette stage. Some biotypes are now resistant to ALS inhibitor and synthetic auxins, causing concern regarding using herbicides. A dedicated integrated management plan for 3-4 years is recommended for the control of this troublesome species. This review will explore the biology, ecology, distribution, current control techniques and previous research on this weed, allowing us to make recommendations for its future research and management.}, }
@article {pmid34685574, year = {2021}, author = {Wang, L and Bergkvist, L and Kumar, R and Winblad, B and Pavlov, PF}, title = {Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases.}, journal = {Cells}, volume = {10}, number = {10}, pages = {}, pmid = {34685574}, issn = {2073-4409}, support = {2018-02843//Swedish Research Council/ ; AF940014//Alzheimer Foundation/ ; Fo 2019-0140//Brain Foundation/ ; 2021-00681//Foundation for Geriatric Diseases at Karolinska Institutet/ ; 0//Gunvor and Josef An&#xe9;rs Foundation/ ; 0//Gun and Bertil Stohnes Foundation/ ; 0//Tore Nilssons Foundation for medical research/ ; 0//Mar-garetha af Ugglas Foundation/ ; 2020-01028//the Foundation for Old Servants/ ; 0//Magnus Bergvalls Foundation/ ; }, mesh = {Humans ; Molecular Chaperones/*metabolism ; Neurodegenerative Diseases/*genetics/pathology ; }, abstract = {The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein-protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.}, }
@article {pmid34685498, year = {2021}, author = {Tedeschi, V and La Russa, D and Franco, C and Vinciguerra, A and Amantea, D and Secondo, A}, title = {Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases.}, journal = {Cells}, volume = {10}, number = {10}, pages = {}, pmid = {34685498}, issn = {2073-4409}, mesh = {Animals ; Calcium/*metabolism ; Calcium Channels/metabolism ; Cell Membrane/*metabolism ; Humans ; Membrane Proteins/metabolism ; Neoplasm Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism ; Stromal Interaction Molecule 1/*metabolism ; }, abstract = {Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca[2+]. Then, STIM1 translocates into discrete ER-plasma membrane (PM) junctions where it directly interacts with and activates plasma membrane Orai1 channels to refill ER with Ca[2+]. Furthermore, Ca[2+] entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store-operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca[2+]. Furthermore, it is now clear that STIM1 may inhibit Ca[2+] currents mediated by L-type Ca[2+] channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca[2+] homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection.}, }
@article {pmid34682763, year = {2021}, author = {Stopińska, K and Radziwoń-Zaleska, M and Domitrz, I}, title = {The Microbiota-Gut-Brain Axis as a Key to Neuropsychiatric Disorders: A Mini Review.}, journal = {Journal of clinical medicine}, volume = {10}, number = {20}, pages = {}, pmid = {34682763}, issn = {2077-0383}, abstract = {The central nervous system (CNS) is closely related to the gastrointestinal tract, mainly through regulating its function and homeostasis. Simultaneously, the gut flora affects the CNS and plays an essential role in the pathogenesis of neurologic and neuropsychological disorders such as Parkinson's and Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or autism spectrum disorder. The population of gut microorganisms contains more than one billion bacteria. The most common are six phyla: Proteobacteria, Actinomyces, Verucomicrobia, Fusobacteria, and dominant Bacteroides with Firmicutes. The microbiota-gut-brain axis is a bidirectional nervous, endocrine, and immune communication between these two organs. They are connected through a variety of pathways, including the vagus nerve, the immune system, microbial metabolites such as short-chain fatty acids (SCFAs), the enteric nervous system, and hormones. Age, diet, antibiotics influence the balance of gut microorganisms and probably lead to the development of neurodegenerative disorders. In this article, a review is presented and discussed, with a specific focus on the changes of gut microbiota, gut-brain axis, related disorders, and the factors that influence gut imbalance.}, }
@article {pmid34681616, year = {2021}, author = {Hosaka, T and Tsuji, H and Kwak, S}, title = {RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681616}, issn = {1422-0067}, support = {19K23957//Japan Society for the Promotion of Science/ ; 202010135//Uehara Memorial Foundation/ ; }, mesh = {Adenosine Deaminase/genetics/metabolism ; Amyotrophic Lateral Sclerosis/*genetics/pathology/therapy ; Calcium/metabolism ; Genetic Therapy ; Humans ; Nervous System Diseases/*genetics/pathology/therapy ; RNA Editing/*genetics ; Receptors, AMPA/genetics/metabolism ; }, abstract = {The conversion of adenosine to inosine in RNA editing (A-to-I RNA editing) is recognized as a critical post-transcriptional modification of RNA by adenosine deaminases acting on RNAs (ADARs). A-to-I RNA editing occurs predominantly in mammalian and human central nervous systems and can alter the function of translated proteins, including neurotransmitter receptors and ion channels; therefore, the role of dysregulated RNA editing in the pathogenesis of neurological diseases has been speculated. Specifically, the failure of A-to-I RNA editing at the glutamine/arginine (Q/R) site of the GluA2 subunit causes excessive permeability of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to Ca[2+], inducing fatal status epilepticus and the neurodegeneration of motor neurons in mice. Therefore, an RNA editing deficiency at the Q/R site in GluA2 due to the downregulation of ADAR2 in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients suggests that Ca[2+]-permeable AMPA receptors and the dysregulation of RNA editing are suitable therapeutic targets for ALS. Gene therapy has recently emerged as a new therapeutic opportunity for many heretofore incurable diseases, and RNA editing dysregulation can be a target for gene therapy; therefore, we reviewed neurological diseases associated with dysregulated RNA editing and a new therapeutic approach targeting dysregulated RNA editing, especially one that is effective in ALS.}, }
@article {pmid34681219, year = {2021}, author = {Orlandi, P and Solini, A and Banchi, M and Brunetto, MR and Cioni, D and Ghiadoni, L and Bocci, G}, title = {Antiangiogenic Drugs in NASH: Evidence of a Possible New Therapeutic Approach.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {34681219}, issn = {1424-8247}, support = {PRA//University of Pisa/ ; }, abstract = {Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). Lifestyle changes, which are capable of improving the prognosis, are hard to achieve, whereas a pharmacologic therapy able to combine efficacy and safety is still lacking. Looking at the pathophysiology of various liver diseases, such as NASH, fibrosis, cirrhosis, and HCC, the process of angiogenesis is a key mechanism influencing the disease progression. The relationship between the worsening of chronic liver disease and angiogenesis may suggest a possible use of drugs with antiangiogenic activity as a tool to stop or slow the progression of the disorder. In this review, we highlight the available preclinical data supporting a role of known antiangiogenic drugs (e.g., sorafenib), or phytotherapeutic compounds with multiple mechanism of actions, including also antiangiogenic activities (e.g., berberine), in the treatment of NASH.}, }
@article {pmid34680401, year = {2021}, author = {Rai, SN and Singh, P and Steinbusch, HWM and Vamanu, E and Ashraf, G and Singh, MP}, title = {The Role of Vitamins in Neurodegenerative Disease: An Update.}, journal = {Biomedicines}, volume = {9}, number = {10}, pages = {}, pmid = {34680401}, issn = {2227-9059}, abstract = {Acquiring the recommended daily allowance of vitamins is crucial for maintaining homeostatic balance in humans and other animals. A deficiency in or dysregulation of vitamins adversely affects the neuronal metabolism, which may lead to neurodegenerative diseases. In this article, we discuss how novel vitamin-based approaches aid in attenuating abnormal neuronal functioning in neurodegeneration-based brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Prion disease. Vitamins show their therapeutic activity in Parkinson's disease by antioxidative and anti-inflammatory activity. In addition, different water- and lipid-soluble vitamins have also prevented amyloid beta and tau pathology. On the other hand, some results also show no correlation between vitamin action and the prevention of neurodegenerative diseases. Some vitamins also exhibit toxic activity too. This review discusses both the beneficial and null effects of vitamin supplementation for neurological disorders. The detailed mechanism of action of both water- and lipid-soluble vitamins is addressed in the manuscript. Hormesis is also an essential factor that is very helpful to determine the effective dose of vitamins. PubMed, Google Scholar, Web of Science, and Scopus were employed to conduct the literature search of original articles, review articles, and meta-analyses.}, }
@article {pmid34679420, year = {2021}, author = {Carelli, L and Solca, F and Tagini, S and Torre, S and Verde, F and Ticozzi, N and Consonni, M and Ferrucci, R and Pravettoni, G and Poletti, B and Silani, V}, title = {Emotional Processing and Experience in Amyotrophic Lateral Sclerosis: A Systematic and Critical Review.}, journal = {Brain sciences}, volume = {11}, number = {10}, pages = {}, pmid = {34679420}, issn = {2076-3425}, abstract = {Even though increasing literature describes changes in emotional processing in Amyotrophic Lateral Sclerosis (ALS), efforts to summarize relevant findings are lacking in the field. A systematic literature review was performed to provide a critical and up-to-date account of emotional abilities in ALS. References were identified by searches of PubMed, Web of Science and Scopus (1980-2021, English literature), with the following key terms: ("Amyotrophic Lateral Sclerosis" or "Primary Lateral Sclerosis" or "Motor Neuron") and "Emotion*" and ("Processing" or "Attribution" or "Elaboration" or "Perception" or "Recognition"). Studies concerning only caregivers, pseudobulbar affect, and social cognition were excluded. Forty-one articles were included, all concerning ALS, and seven topics were identified: Emotion recognition, Emotional responsiveness, Emotional reactivity, Faces approachability rating, Valence rating, Memory for emotional materials and Alexithymia. The majority of these aspects have only been sparsely addressed. The evidence confirms altered emotional processing in ALS. The most consistent findings regard the recognition of facial expressions for negative emotions, but also alterations in the subjective responsiveness to emotional stimuli (arousal, valence and approachability), in psychophysiological and cerebral reactivity and in emotional memory, together with alexithymia traits, were reported. According to this evidence, emotional abilities should be included in the clinical assessment and therapeutic interventions.}, }
@article {pmid34679204, year = {2021}, author = {Torres, P and Cabral-Miranda, F and Gonzalez-Teuber, V and Hetz, C}, title = {Proteostasis deregulation as a driver of C9ORF72 pathogenesis.}, journal = {Journal of neurochemistry}, volume = {159}, number = {6}, pages = {941-957}, doi = {10.1111/jnc.15529}, pmid = {34679204}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Autophagy/physiology ; C9orf72 Protein/genetics/*metabolism ; Endoplasmic Reticulum Stress/physiology ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Humans ; Proteostasis/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4 C2) in C9ORF72 gene has been causally linked to both ALS and FTD emergence, thus opening a novel potential therapeutic target for disease intervention. The main driver of C9ORF72 pathology is the disruption of distinct cellular processes involved in the function of the proteostasis network. Here we discuss main findings relating to the induction of neurodegeneration by C9ORF72 mutation and proteostasis deregulation, highlighting the role of the endoplasmic reticulum stress, nuclear transport, and autophagy in the disease process. We further discuss possible points of intervention to target proteostasis mediators to treat C9ORF72-linked ALS/FTD.}, }
@article {pmid34676349, year = {2021}, author = {Verma, R and Hoda, F and Arshad, M and Iqubal, A and Siddiqui, AN and Khan, MA and Haque, SE and Akhtar, M and Najmi, AK}, title = {Cannabis, a Miracle Drug with Polyvalent Therapeutic Utility: Preclinical and Clinical-Based Evidence.}, journal = {Medical cannabis and cannabinoids}, volume = {4}, number = {1}, pages = {43-60}, pmid = {34676349}, issn = {2504-3889}, abstract = {Cannabis sativa L. is an annual herbaceous dioecious plant which was first cultivated by agricultural human societies in Asia. Over the period of time, various parts of the plant like leaf, flower, and seed were used for recreational as well as therapeutic purposes. The main chemical components of Cannabis sativa are termed as cannabinoids, among them the key psychoactive constituent is Δ-9-tetrahydrocannabinol and cannabidiol (CBD) as active nonpsychotic constituent. Upon doing extensive literature review, it was found that cannabis has been widely studied for a number of disorders. Very recently, a pure CBD formulation, named Epidiolex, got a green flag from both United States Food and Drug Administration and Drug Enforcement Administration for 2 rare types of epilepsies. This laid a milestone in medical cannabis research. This review intends to give a basic and extensive assessment, from past till present, of the ethnological, plant, chemical, pharmacological, and legal aspects of C. sativa. Further, this review contemplates the evidence the studies obtained of cannabis components on Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, emesis, epilepsy, chronic pain, and cancer as a cytotoxic agent as well as a palliative therapy. The assessment in this study was done by reviewing in extensive details from studies on historical importance, ethnopharmacological aspects, and legal grounds of C. sativa from extensive literature available on the scientific databases, with a vision for elevating further pharmaceutical research to investigate its total potential as a therapeutic agent.}, }
@article {pmid34675123, year = {2022}, author = {Fan, Y and Xu, Y and Shi, C}, title = {NOTCH2NLC-related disorders: the widening spectrum and genotype-phenotype correlation.}, journal = {Journal of medical genetics}, volume = {59}, number = {1}, pages = {1-9}, doi = {10.1136/jmedgenet-2021-107883}, pmid = {34675123}, issn = {1468-6244}, mesh = {Asian People/genetics ; Genetic Association Studies ; Humans ; Intercellular Signaling Peptides and Proteins/*genetics ; Intranuclear Inclusion Bodies/genetics/metabolism ; Nerve Tissue Proteins/*genetics ; Neurodegenerative Diseases/genetics/*metabolism ; *Trinucleotide Repeat Expansion ; }, abstract = {GGC repeat expansion in the 5' untranslated region of NOTCH2NLC is the most common causative factor in neuronal intranuclear inclusion disease (NIID) in Asians. Such expanded GGC repeats have been identified in patients with leukoencephalopathy, essential tremor (ET), multiple system atrophy, Parkinson's disease (PD), amyotrophic lateral sclerosis and oculopharyngodistal myopathy (OPDM). Herein, we review the recently reported NOTCH2NLC-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be NOTCH2NLC-specific and should be investigated in other patients with NOTCH2NLC mutations. NOTCH2NLC GGC repeat expansion was rarely identified in patients of European ancestry, whereas the actual prevalence of the expansion in European patients may be potentially higher than reported, and the CGG repeats in LRP12/GIPC1 are suggested to be screened in European patients with NIID. The repeat size and interruptions in NOTCH2NLC GGC expansion confer pleiotropic effects on clinical phenotype, a pure and stable ET phenotype may be an early symptom of NIID, and GGC repeats in NOTCH2NLC possibly give rise to ET. An association may also exist between intermediate-length NOTCH2NLC GGC repeat expansion and patients affected by PD and ET. NOTCH2NLC-OPDM highly resembles NOTCH2NLC-NIID, the two disorders may be the variations of a single neurodegenerative disease, and there may be a disease-causing upper limit in size of GGC repeats in NOTCH2NLC, repeats over which may be non-pathogenic. The haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.}, }
@article {pmid34666575, year = {2022}, author = {D'souza, J and Biswas, A and Gada, P and Mangroliya, J and Natarajan, M}, title = {Barriers leading to increased disability in neurologically challenged populations during COVID-19 pandemic: a scoping review.}, journal = {Disability and rehabilitation}, volume = {44}, number = {24}, pages = {7693-7706}, doi = {10.1080/09638288.2021.1986747}, pmid = {34666575}, issn = {1464-5165}, mesh = {Humans ; *COVID-19/epidemiology ; Pandemics ; *Disabled Persons ; *Telerehabilitation/methods ; *Telemedicine ; }, abstract = {PURPOSE: The objective of this scoping review was to get an overview of barriers emerging across the globe from the pandemic that are likely to increase the level of pre-existing disability status of neurologically challenged populations.<br><br>METHODS: Database searches (PubMed/MEDLINE, CINAHL, ProQuest, Ovid, Scopus, and Web of Science) updated to December 2020 were conducted. Articles that identified challenges or barriers to neuro-rehabilitation, impact on disability status and health care services were included. Full-text articles limited to the English language with no restrictions on study design were included. Data was synthesized based on recurrent themes that were identified.<br><br>RESULTS: Thirty-seven studies were included in this review. Neurological populations considered: stroke, multiple sclerosis, amyotrophic lateral sclerosis, parkinson's disease, autism, developmental disabilities, and those who required neurosurgical care. Barriers were grouped into categories as increased disease risk and complications, delayed or restricted access to neuro-rehabilitation, limited hospital access, telerehabilitation limitations, and shutdown of special centers of aid.<br><br>CONCLUSIONS: COVID-19 pandemic has given rise to barriers that affect almost every aspect of healthcare and rehabilitation in neurologically challenged populations prompting an increase in their disability level. This can assist policymakers in designing mitigation strategies to minimize the detrimental effects on this vulnerable population.Implications for rehabilitationPandemic has led to the worsening of existing motor and non-motor symptoms, which need to be monitored, assessed and managed medically, and through rehabilitation in neurologically challenged populations.Notable decline of cognition and physical activity in neurologically challenged populations needs to be assessed and efforts to reverse these outcomes should be attempted.Rehabilitation services, hospital care and centers of aid need to be made more accessible for neurologically challenged populations with COVID-19 precautionary measures.Telemedicine and telerehabilitation need to be upgraded to enhance further face to face like interactions and for tracking of progressive disease.}, }
@article {pmid34663738, year = {2021}, author = {Benarroch, E}, title = {What Is the Role of Oligodendrocytes in Amyotrophic Lateral Sclerosis?.}, journal = {Neurology}, volume = {97}, number = {16}, pages = {776-779}, doi = {10.1212/WNL.0000000000012706}, pmid = {34663738}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Humans ; Oligodendroglia/*metabolism/*pathology ; }, }
@article {pmid34663413, year = {2021}, author = {Bono, S and Feligioni, M and Corbo, M}, title = {Impaired antioxidant KEAP1-NRF2 system in amyotrophic lateral sclerosis: NRF2 activation as a potential therapeutic strategy.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {71}, pmid = {34663413}, issn = {1750-1326}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Antioxidants/metabolism/pharmacology ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/physiology ; Signal Transduction/physiology ; }, abstract = {BACKGROUND: Oxidative stress (OS) is an imbalance between oxidant and antioxidant species and, together with other numerous pathological mechanisms, leads to the degeneration and death of motor neurons (MNs) in amyotrophic lateral sclerosis (ALS).<br><br>MAIN BODY: Two of the main players in the molecular and cellular response to OS are NRF2, the transcription nuclear factor erythroid 2-related factor 2, and its principal negative regulator, KEAP1, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1. Here we first provide an overview of the structural organization, regulation, and critical role of the KEAP1-NRF2 system in counteracting OS, with a focus on its alteration in ALS. We then examine several compounds capable of promoting NRF2 activity thereby inducing cytoprotective effects, and which are currently in different stages of clinical development for many pathologies, including neurodegenerative diseases.<br><br>CONCLUSIONS: Although challenges associated with some of these compounds remain, important advances have been made in the development of safer and more effective drugs that could actually represent a breakthrough for fatal degenerative diseases such as ALS.}, }
@article {pmid34663153, year = {2022}, author = {Arab, A and Mostafalou, S}, title = {Neurotoxicity of pesticides in the context of CNS chronic diseases.}, journal = {International journal of environmental health research}, volume = {32}, number = {12}, pages = {2718-2755}, doi = {10.1080/09603123.2021.1987396}, pmid = {34663153}, issn = {1369-1619}, mesh = {Pregnancy ; Female ; Humans ; *Pesticides/toxicity ; Environmental Exposure/adverse effects ; *Neurotoxicity Syndromes/etiology ; Chronic Disease ; *Attention Deficit Disorder with Hyperactivity/chemically induced ; }, abstract = {Following the introduction and application of pesticides in human life, they have always been along with health concerns both in acute poisoning and chronic toxicities. Neurotoxicity of pesticides in chronic exposures has been known as one of the most important human health problems, as most of these chemicals act through interacting with some elements of nervous system. Pesticide-induced neurotoxicity can be defined in different categories of neurological disorders including neurodegenerative (Alzheimer, Parkinson, amyotrophic lateral sclerosis, multiple sclerosis), neurodevelopmental (attention deficit hyperactivity disorder, autism spectrum disorders, developmental delay, and intellectual disability), neurobehavioral and neuropsychiatric (depression/suicide attempt, anxiety/insomnia, and cognitive impairment) disorders some of which are among the most debilitating human health problems. In this review, neurotoxicity of pesticides in the mentioned categories and sub-categories of neurological diseases have been systematically presented in relation to different route of exposures including general, occupational, environmental, prenatal, postnatal, and paternal.}, }
@article {pmid34655056, year = {2022}, author = {Parambi, DGT and Alharbi, KS and Kumar, R and Harilal, S and Batiha, GE and Cruz-Martins, N and Magdy, O and Musa, A and Panda, DS and Mathew, B}, title = {Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {59}, number = {1}, pages = {191-233}, pmid = {34655056}, issn = {1559-1182}, mesh = {*Genetic Therapy ; Genetic Vectors ; Humans ; Intercellular Signaling Peptides and Proteins/*genetics ; Neurodegenerative Diseases/genetics/*therapy ; Treatment Outcome ; }, abstract = {The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.}, }
@article {pmid34649360, year = {2021}, author = {Rodríguez-Arce, E and Saldías, M}, title = {Antioxidant properties of flavonoid metal complexes and their potential inclusion in the development of novel strategies for the treatment against neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {143}, number = {}, pages = {112236}, doi = {10.1016/j.biopha.2021.112236}, pmid = {34649360}, issn = {1950-6007}, mesh = {Animals ; Antioxidants/chemistry/*pharmacology ; Coordination Complexes/chemistry/*pharmacology ; Flavonoids/chemistry/*pharmacology ; Humans ; Molecular Structure ; *Nerve Degeneration ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; *Oxidative Stress ; Quercetin/analogs &amp; derivatives/chemistry/pharmacology ; Rutin/analogs &amp; derivatives/chemistry/pharmacology ; Structure-Activity Relationship ; }, abstract = {The increased oxidative stress in the acceleration of the aging process and development of the neuronal disorder are the common feature detected in neurodegenerative illness, such as Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Searching for new treatment against these diseases, the inclusion of exogenous antioxidant agents has shown good results. Flavonoids are polyphenols compounds present in plants, fruits and vegetables that exhibit potent antioxidant and biological properties, which are related to their chemical structure that to confer an excellent radical scavenging ability. The design of metal-flavonoid complexes allows to obtain compounds with improved biological and physicochemical properties, generating important increase of the flavonoid antioxidant properties. This evidence we motive to propose that antioxidant properties of the metal flavonoids compounds can play an important role in the design of potential novel therapeutic strategies. This review presents the structure-activity relationship on the antioxidant properties of three series of metal-flavonoid complexes: M-(quercetin), M-(morin), and M-(rutin). In general, we observed that the coordination sites, the metal ion type used, and the molar ratio metal:flavonoid present in the complexes, are important factors for to increase the antioxidant activity. On these evidences we motive to propose that the development of metal-flavonoid compounds is a potentially viable approach for combating neurodegenerative diseases.}, }
@article {pmid34649336, year = {2021}, author = {Paul, S and Chakraborty, S and Anand, U and Dey, S and Nandy, S and Ghorai, M and Saha, SC and Patil, MT and Kandimalla, R and Proćków, J and Dey, A}, title = {Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {143}, number = {}, pages = {112175}, doi = {10.1016/j.biopha.2021.112175}, pmid = {34649336}, issn = {1950-6007}, mesh = {Animals ; Antiviral Agents/isolation &amp; purification/pharmacology ; COVID-19/virology ; *Ethnopharmacology ; Humans ; Neuroprotective Agents/isolation &amp; purification/pharmacology/toxicity ; Patient Safety ; Phytochemicals/isolation &amp; purification/*pharmacology/toxicity ; Plant Extracts/isolation &amp; purification/*pharmacology/toxicity ; Plant Roots ; Psychotropic Drugs/isolation &amp; purification/pharmacology/toxicity ; Risk Assessment ; SARS-CoV-2/drug effects/pathogenicity ; *Withania/chemistry ; COVID-19 Drug Treatment ; }, abstract = {Withania somnifera (L.) Dunal (Solanaceae) has been used as a traditional Rasayana herb for a long time. Traditional uses of this plant indicate its ameliorative properties against a plethora of human medical conditions, viz. hypertension, stress, diabetes, asthma, cancer etc. This review presents a comprehensive summary of the geographical distribution, traditional use, phytochemistry, and pharmacological activities of W. somnifera and its active constituents. In addition, it presents a detailed account of its presence as an active constituent in many commercial preparations with curative properties and health benefits. Clinical studies and toxicological considerations of its extracts and constituents are also elucidated. Comparative analysis of relevant in-vitro, in-vivo, and clinical investigations indicated potent bioactivity of W. somnifera extracts and phytochemicals as anti-cancer, anti-inflammatory, apoptotic, immunomodulatory, antimicrobial, anti-diabetic, hepatoprotective, hypoglycaemic, hypolipidemic, cardio-protective and spermatogenic agents. W. somnifera was found to be especially active against many neurological and psychological conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke, sleep deprivation, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, bipolar disorder, anxiety, depression, schizophrenia and obsessive-compulsive disorder. The probable mechanism of action that imparts the pharmacological potential has also been explored. However, in-depth studies are needed on the clinical use of W. somnifera against human diseases. Besides, detailed toxicological analysis is also to be performed for its safe and efficacious use in preclinical and clinical studies and as a health-promoting herb.}, }
@article {pmid34645313, year = {2023}, author = {Bedlack, R and Barkhaus, PE and Barnes, B and Beauchamp, M and Bertorini, T and Bromberg, MB and Carter, GT and Chaudry, V and Cudkowicz, M and Jackson, C and Levitsky, G and Lund, I and McDermott, C and Novella, S and Olby, N and Ostrow, L and Pattee, GL and Heiman-Patterson, T and Ratner, D and Salmon, K and Steves, S and Terrelonge, M and Wicks, P and Wills, AM}, title = {ALSUntangled #63: ketogenic diets.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {1-2}, pages = {159-163}, doi = {10.1080/21678421.2021.1990346}, pmid = {34645313}, issn = {2167-9223}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/diet therapy ; *Diet, Ketogenic ; Disease Models, Animal ; }, abstract = {ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.}, }
@article {pmid34638733, year = {2021}, author = {Borgonetti, V and Coppi, E and Galeotti, N}, title = {Targeting the RNA-Binding Protein HuR as Potential Thera-Peutic Approach for Neurological Disorders: Focus on Amyo-Trophic Lateral Sclerosis (ALS), Spinal Muscle Atrophy (SMA) and Multiple Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {19}, pages = {}, pmid = {34638733}, issn = {1422-0067}, support = {2019/R-Single/036 (EC)//Fondazione Italiana Sclerosi Multipla/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Cell Differentiation/genetics ; Cytokines/genetics/metabolism ; *ELAV-Like Protein 1/genetics/metabolism ; Humans ; *Multiple Sclerosis/genetics/metabolism/therapy ; *Muscular Atrophy, Spinal/genetics/metabolism/therapy ; Neurons/metabolism ; RNA, Messenger/genetics/metabolism ; }, abstract = {The importance of precise co- and post-transcriptional processing of RNA in the regulation of gene expression has become increasingly clear. RNA-binding proteins (RBPs) are a class of proteins that bind single- or double-chain RNA, with different affinities and selectivity, thus regulating the various functions of RNA and the fate of the cells themselves. ELAV (embryonic lethal/abnormal visual system)/Hu proteins represent an important family of RBPs and play a key role in the fate of newly transcribed mRNA. ELAV proteins bind AU-rich element (ARE)-containing transcripts, which are usually present on the mRNA of proteins such as cytokines, growth factors, and other proteins involved in neuronal differentiation and maintenance. In this review, we focused on a member of ELAV/Hu proteins, HuR, and its role in the development of neurodegenerative disorders, with a particular focus on demyelinating diseases.}, }
@article {pmid34638636, year = {2021}, author = {Laneve, P and Tollis, P and Caffarelli, E}, title = {RNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective.}, journal = {International journal of molecular sciences}, volume = {22}, number = {19}, pages = {}, pmid = {34638636}, issn = {1422-0067}, support = {PRIN 2017 (prot. 2017P352Z4)//Ministero dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; Motor Neurons/pathology ; Neurodegenerative Diseases/genetics ; RNA, Untranslated/*genetics ; }, abstract = {RNA metabolism is central to cellular physiopathology. Almost all the molecular pathways underpinning biological processes are affected by the events governing the RNA life cycle, ranging from transcription to degradation. The deregulation of these processes contributes to the onset and progression of human diseases. In recent decades, considerable efforts have been devoted to the characterization of noncoding RNAs (ncRNAs) and to the study of their role in the homeostasis of the nervous system (NS), where they are highly enriched. Acting as major regulators of gene expression, ncRNAs orchestrate all the steps of the differentiation programs, participate in the mechanisms underlying neural functions, and are crucially implicated in the development of neuronal pathologies, among which are neurodegenerative diseases. This review aims to explore the link between ncRNA dysregulation and amyotrophic lateral sclerosis (ALS), the most frequent motoneuron (MN) disorder in adults. Notably, defective RNA metabolism is known to be largely associated with this pathology, which is often regarded as an RNA disease. We also discuss the potential role that these transcripts may play as diagnostic biomarkers and therapeutic targets.}, }
@article {pmid34637802, year = {2022}, author = {Vose, AK and Welch, JF and Nair, J and Dale, EA and Fox, EJ and Muir, GD and Trumbower, RD and Mitchell, GS}, title = {Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.}, journal = {Experimental neurology}, volume = {347}, number = {}, pages = {113891}, pmid = {34637802}, issn = {1090-2430}, support = {R01 HD081274/HD/NICHD NIH HHS/United States ; R01 HL147554/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Hypoxia ; Neuromuscular Diseases/*therapy ; Spinal Cord Injuries/*therapy ; *Translational Research, Biomedical ; }, abstract = {We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.}, }
@article {pmid34635325, year = {2022}, author = {Spencer, PS}, title = {Parkinsonism and motor neuron disorders: Lessons from Western Pacific ALS/PDC.}, journal = {Journal of the neurological sciences}, volume = {433}, number = {}, pages = {120021}, doi = {10.1016/j.jns.2021.120021}, pmid = {34635325}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; Humans ; Motor Neurons/pathology ; *Neurodegenerative Diseases/etiology ; Neurotoxins/toxicity ; *Parkinsonian Disorders/chemically induced/epidemiology ; }, abstract = {Recognized worldwide as an unusual "overlap" syndrome, Parkinsonism and motor neuron disease, with or without dementia, is best exemplified by the former high-incidence clusters of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) in Guam, USA, in the Kii Peninsula of Honshu Island, Japan, and in Papua, Indonesia, on the western side of New Guinea. Western Pacific ALS/PDC is a disappearing neurodegenerative disorder with multiple and sometime overlapping phenotypes (ALS, atypical parkinsonism, dementia) that appear to constitute a single disease of environmental origin, in particular from exposure to genotoxins/neurotoxins in seed of cycad plants (Cycas spp.) formerly used as a traditional source of food (Guam) and/or medicine (Guam, Kii-Japan, Papua-Indonesia). Seed compounds include the principal cycad toxin cycasin, its active metabolite methylazoxymethanol (MAM) and a non-protein amino acid β-N-methylamino-L-alanine (L-BMAA); each reproduces components of ALS/PDC neuropathology when individually administered to laboratory species in single doses perinatally (MAM, L-BMAA) or repeatedly for prolonged periods to young adult animals (L-BMAA). Human exposure to MAM, a potent DNA-alkylating mutagen, also has potential relevance to the high incidence of diverse mutations found among Guamanians with/without ALS/PDC. In sum, seven decades of intensive study of ALS/PDC has revealed field and laboratory approaches leading to discovery of disease etiology that are now being applied to sporadic neurodegenerative disorders such as ALS beyond the Western Pacific region. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.}, }
@article {pmid34635103, year = {2021}, author = {Chang, CP and Wu, KC and Lin, CY and Chern, Y}, title = {Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.}, journal = {Journal of biomedical science}, volume = {28}, number = {1}, pages = {70}, pmid = {34635103}, issn = {1423-0127}, support = {AS-BRPT-110-11//academia sinica/ ; MOST 110-2321-B-001-011//ministry of science and technology, taiwan/ ; }, mesh = {Adenosine/*physiology ; Brain/*physiopathology ; *Homeostasis ; Humans ; Neurodegenerative Diseases/*physiopathology ; Proteins/*metabolism ; }, abstract = {In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.}, }
@article {pmid34630027, year = {2021}, author = {Muzio, L and Viotti, A and Martino, G}, title = {Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {742065}, pmid = {34630027}, issn = {1662-4548}, abstract = {Microglia are the resident macrophages of the central nervous system (CNS) acting as the first line of defense in the brain by phagocytosing harmful pathogens and cellular debris. Microglia emerge from early erythromyeloid progenitors of the yolk sac and enter the developing brain before the establishment of a fully mature blood-brain barrier. In physiological conditions, during brain development, microglia contribute to CNS homeostasis by supporting cell proliferation of neural precursors. In post-natal life, such cells contribute to preserving the integrity of neuronal circuits by sculpting synapses. After a CNS injury, microglia change their morphology and down-regulate those genes supporting homeostatic functions. However, it is still unclear whether such changes are accompanied by molecular and functional modifications that might contribute to the pathological process. While comprehensive transcriptome analyses at the single-cell level have identified specific gene perturbations occurring in the "pathological" microglia, still the precise protective/detrimental role of microglia in neurological disorders is far from being fully elucidated. In this review, the results so far obtained regarding the role of microglia in neurodegenerative disorders will be discussed. There is solid and sound evidence suggesting that regulating microglia functions during disease pathology might represent a strategy to develop future therapies aimed at counteracting brain degeneration in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid34623437, year = {2021}, author = {Moll, T and Marshall, JNG and Soni, N and Zhang, S and Cooper-Knock, J and Shaw, PJ}, title = {Membrane lipid raft homeostasis is directly linked to neurodegeneration.}, journal = {Essays in biochemistry}, volume = {65}, number = {7}, pages = {999-1011}, pmid = {34623437}, issn = {1744-1358}, support = {TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; NF-SI-0617-10077/DH_/Department of Health/United Kingdom ; }, mesh = {*Alzheimer Disease/metabolism ; Homeostasis ; Humans ; *Membrane Lipids/metabolism/therapeutic use ; Membrane Microdomains/metabolism ; }, abstract = {Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are an unmet health need, with significant economic and societal implications, and an ever-increasing prevalence. Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that provide a platform for intracellular trafficking and signal transduction, particularly within neurons. Dysregulation of MLRs leads to disruption of neurotrophic signalling and excessive apoptosis which mirrors the final common pathway for neuronal death in ALS, PD and AD. Sphingomyelinase (SMase) and phospholipase (PL) enzymes process components of MLRs and therefore play central roles in MLR homeostasis and in neurotrophic signalling. We review the literature linking SMase and PL enzymes to ALS, AD and PD with particular attention to attractive therapeutic targets, where functional manipulation has been successful in preclinical studies. We propose that dysfunction of these enzymes is upstream in the pathogenesis of neurodegenerative diseases and to support this we provide new evidence that ALS risk genes are enriched with genes involved in ceramide metabolism (P=0.019, OR = 2.54, Fisher exact test). Ceramide is a product of SMase action upon sphingomyelin within MLRs, and it also has a role as a second messenger in intracellular signalling pathways important for neuronal survival. Genetic risk is necessarily upstream in a late age of onset disease such as ALS. We propose that manipulation of MLR structure and function should be a focus of future translational research seeking to ameliorate neurodegenerative disorders.}, }
@article {pmid34616356, year = {2021}, author = {Liu, P and Yuan, Y and Zhang, N and Liu, X and Yu, L and Luo, B}, title = {Mirror Movements in Acquired Neurological Disorders: A Mini-Review.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {736115}, pmid = {34616356}, issn = {1664-2295}, abstract = {Mirror movements (MMs) are specifically defined as involuntary movements occurring on one side of homologous muscles when performing unilateral movements with the contralateral limb. MMs have been considered a kind of soft neurological signs, and the persistence or reappearance of MMs in adults is usually pathologic. In addition to some congenital syndrome, MMs have been also described in age-related neurological diseases including pyramidal system diseases (e.g., stroke, amyotrophic lateral sclerosis) and extrapyramidal disorders (e.g., Parkinson's disease, essential tremor). With the advances in instrumentation and detection means, subtle or subclinical MMs have been deeply studied. Furthermore, the underlying mechanism is also being further elucidated. In this mini-review, we firstly discuss the MM examination means, and then review the literature regarding MMs in individuals with acquired neurological disorders, in order to further understand the pathogenesis of MMs.}, }
@article {pmid34606852, year = {2021}, author = {Gupta, R and Jha, A and Ambasta, RK and Kumar, P}, title = {Regulatory mechanism of cyclins and cyclin-dependent kinases in post-mitotic neuronal cell division.}, journal = {Life sciences}, volume = {285}, number = {}, pages = {120006}, doi = {10.1016/j.lfs.2021.120006}, pmid = {34606852}, issn = {1879-0631}, mesh = {Acetylation ; Animals ; Cyclin-Dependent Kinases/*metabolism ; Cyclins/*metabolism ; Histone Deacetylases/metabolism ; Humans ; *Mitosis ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurons/*metabolism/*pathology ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) are the most common life-threatening disease of the central nervous system and it cause the progressive loss of neuronal cells. The exact mechanism of the disease's progression is not clear and thus line of treatment for NDDs is a baffling issue. During the progression of NDDs, oxidative stress and DNA damage play an important regulatory function, and ultimately induces neurodegeneration. Recently, aberrant cell cycle events have been demonstrated in the progression of different NDDs. However, the pertinent role of signaling mechanism, for instance, post-translational modifications, oxidative stress, DNA damage response pathway, JNK/p38 MAPK, MEK/ERK cascade, actively participated in the aberrant cell cycle reentry induced neuronal cell death. Mounting evidence has demonstrated that aberrant cell cycle re-entry is a major contributing factor in the pathogenesis of NDDs rather than a secondary phenomenon. In the brain of AD patients with mild cognitive impairment, post miotic cell division can be seen in the early stage of the disease. However, in the brain of PD patients, response to various neurotoxic signals, the cell cycle re-entry has been observed that causes neuronal apoptosis. On contrary, the contributing factors that leads to the induction of cell cycle events in mature neurons in HD and ALS brain pathology is remain unclear. Various pharmacological drugs have been developed to reduce the pathogenesis of NDDs, but they are still not helpful in eliminating the cause of these NDDs.}, }
@article {pmid34603008, year = {2021}, author = {Zuccaro, E and Piol, D and Basso, M and Pennuto, M}, title = {Motor Neuron Diseases and Neuroprotective Peptides: A Closer Look to Neurons.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {723871}, pmid = {34603008}, issn = {1663-4365}, abstract = {Motor neurons (MNs) are specialized neurons responsible for muscle contraction that specifically degenerate in motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Distinct classes of MNs degenerate at different rates in disease, with a particular class named fast-fatigable MNs (FF-MNs) degenerating first. The etiology behind the selective vulnerability of FF-MNs is still largely under investigation. Among the different strategies to target MNs, the administration of protective neuropeptides is one of the potential therapeutic interventions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with beneficial effects in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and more recently SBMA. Another neuropeptide that has a neurotrophic effect on MNs is insulin-like growth factor 1 (IGF-1), also known as somatomedin C. These two peptides are implicated in the activation of neuroprotective pathways exploitable in the amelioration of pathological outcomes related to MNDs.}, }
@article {pmid34602979, year = {2021}, author = {Stifani, S}, title = {Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {707861}, pmid = {34602979}, issn = {1662-5102}, abstract = {Astrocytes are a large group of glial cells that perform a variety of physiological functions in the nervous system. They provide trophic, as well as structural, support to neuronal cells. Astrocytes are also involved in neuroinflammatory processes contributing to neuronal dysfunction and death. Growing evidence suggests important roles for astrocytes in non-cell autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Understanding these mechanisms necessitates the combined use of animal and human cell-based experimental model systems, at least in part because human astrocytes display a number of unique features that cannot be recapitulated in animal models. Human induced pluripotent stem cell (hiPSC)-based approaches provide the opportunity to generate disease-relevant human astrocytes to investigate the roles of these cells in ALS. These approaches are facing the growing recognition that there are heterogenous populations of astrocytes in the nervous system which are not functionally equivalent. This review will discuss the importance of taking astrocyte heterogeneity into consideration when designing hiPSC-based strategies aimed at generating the most informative preparations to study the contribution of astrocytes to ALS pathophysiology.}, }
@article {pmid34602215, year = {2021}, author = {Kang, X and Quan, D}, title = {Electrodiagnostic Assessment of Motor Neuron Disease.}, journal = {Neurologic clinics}, volume = {39}, number = {4}, pages = {1071-1081}, doi = {10.1016/j.ncl.2021.06.008}, pmid = {34602215}, issn = {1557-9875}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Electromyography ; Humans ; *Motor Neuron Disease/diagnosis ; Motor Neurons ; *Muscular Atrophy, Spinal/diagnosis ; }, abstract = {Motor neuron diseases involve degeneration of motor neurons in the brain (upper motor neurons), brain stem, and spinal cord (lower motor neurons). Symptoms vary depending on the degree of upper and lower neuron involvement, but progressive painless weakness is the predominant complaint. Motor neuron disease includes numerous specific disorders, including amyotrophic lateral sclerosis, spinal muscular atrophy, spinal bulbar muscular atrophy, and other inherited and acquired conditions. Abnormalities on nerve conduction studies, repetitive nerve stimulation, needle electromyography, and other electrodiagnostic techniques help to distinguish these disorders from each other, and from other disorders with progressive weakness.}, }
@article {pmid34596729, year = {2021}, author = {Pradhan, N and Singh, C and Singh, A}, title = {Coenzyme Q10 a mitochondrial restorer for various brain disorders.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {394}, number = {11}, pages = {2197-2222}, pmid = {34596729}, issn = {1432-1912}, mesh = {Animals ; Antioxidants/pharmacology ; Brain Diseases/*drug therapy/physiopathology ; Humans ; Mitochondria/drug effects/pathology ; Mitochondrial Diseases/*drug therapy/physiopathology ; Neurodegenerative Diseases/drug therapy/physiopathology ; Ubiquinone/*analogs &amp; derivatives/pharmacology ; }, abstract = {Coenzyme Q10 (ubiquinone or CoQ10) is a lipid molecule that acts as an electron mobile carrier of the electron transport chain and also contains antioxidant properties. Supplementation of CoQ10 has been very useful to treat mitochondrial diseases. CoQ10 along with its synthetic analogue, idebenone, is used largely to treat various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Friedreich's ataxia and additional brain disease condition like autism, multiple sclerosis, epilepsy, depression, and bipolar disorder, which are related to mitochondrial impairment. In this article, we have reviewed numerous physiological functions of CoQ10 and the rationale for its use in clinical practice in different brain disorders.}, }
@article {pmid34590512, year = {2022}, author = {Vucic, S and Wray, N and Henders, A and Henderson, RD and Talman, P and Mathers, S and Bellgard, M and Aoun, S and Birks, C and Thomas, G and Hansen, C and Thomas, G and Hogden, A and Needham, M and Schultz, D and Soulis, T and Sheean, B and Milne, J and Rowe, D and Zoing, M and Kiernan, MC}, title = {MiNDAUS partnership: a roadmap for the cure and management of motor Neurone disease.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {321-328}, doi = {10.1080/21678421.2021.1980889}, pmid = {34590512}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis ; Australia ; Caregivers ; Data Collection ; Humans ; *Motor Neuron Disease/therapy ; }, abstract = {An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.}, }
@article {pmid34583569, year = {2022}, author = {Sethi, A and Everett, E and Mehta, A and Besbris, J and Burke, C and Pedowitz, E and Kilpatrick, M and Foster, L and Maiser, S}, title = {The Role of Specialty Palliative Care for Amyotrophic Lateral Sclerosis.}, journal = {The American journal of hospice &amp; palliative care}, volume = {39}, number = {7}, pages = {865-873}, doi = {10.1177/10499091211049386}, pmid = {34583569}, issn = {1938-2715}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Humans ; *Medicine ; *Neurodegenerative Diseases ; Palliative Care/methods ; Quality of Life/psychology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive and incurable neurodegenerative disease resulting in the loss of motor neurons, eventually leading to death. ALS results in complex physical, emotional, and spiritual care needs. Specialty Palliative Care (SPC) is a medical specialty for patients with serious illness that provides an extra layer of support through complicated symptom management, goals of care conversations, and support to patients and families during hard times. Using MEDLINE, APA Psychinfo, and Dynamed databases, we reviewed the literature of SPC in ALS to inform and support an expert opinion perspective on this topic. This manuscript focuses on several key areas of SPC for ALS including insurance and care models, advance care planning, symptom management, quality of life, caregiver support, and end-of-life care. Recommendations to improve specialty palliative care for patients with ALS are reviewed in the discussion section.}, }
@article {pmid34575995, year = {2021}, author = {Jankovic, M and Novakovic, I and Gamil Anwar Dawod, P and Gamil Anwar Dawod, A and Drinic, A and Abdel Motaleb, FI and Ducic, S and Nikolic, D}, title = {Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34575995}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/therapy ; Animals ; Axonal Transport/genetics ; Calcium/metabolism ; Electron Transport/genetics ; Humans ; *Mitochondria/genetics/metabolism/pathology ; Mitophagy/genetics ; Oxidative Phosphorylation ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.}, }
@article {pmid34573888, year = {2021}, author = {Park, HR and Yang, EJ}, title = {Oxidative Stress as a Therapeutic Target in Amyotrophic Lateral Sclerosis: Opportunities and Limitations.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {34573888}, issn = {2075-4418}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) and Lou Gehrig's disease, is characterized by a loss of the lower motor neurons in the spinal cord and the upper motor neurons in the cerebral cortex. Due to the complex and multifactorial nature of the various risk factors and mechanisms that are related to motor neuronal degeneration, the pathological mechanisms of ALS are not fully understood. Oxidative stress is one of the known causes of ALS pathogenesis. This has been observed in patients as well as in cellular and animal models, and is known to induce mitochondrial dysfunction and the loss of motor neurons. Numerous therapeutic agents have been developed to inhibit oxidative stress and neuroinflammation. In this review, we describe the role of oxidative stress in ALS pathogenesis, and discuss several anti-inflammatory and anti-oxidative agents as potential therapeutics for ALS. Although oxidative stress and antioxidant fields are meaningful approaches to delay disease progression and prolong the survival in ALS, it is necessary to investigate various animal models or humans with different subtypes of sporadic and familial ALS.}, }
@article {pmid34573864, year = {2021}, author = {Krause, K and Wulf, M and Sommer, P and Barkovits, K and Vorgerd, M and Marcus, K and Eggers, B}, title = {CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {34573864}, issn = {2075-4418}, abstract = {Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications.}, }
@article {pmid34573134, year = {2021}, author = {Haidar, M and Viden, A and Turner, BJ}, title = {Advances in Gene Delivery Methods to Label and Modulate Activity of Upper Motor Neurons: Implications for Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {11}, number = {9}, pages = {}, pmid = {34573134}, issn = {2076-3425}, support = {1137024//National Health and Medical Research Council/ ; 2020//FightMND/ ; 2020//Stafford Fox Medical Research Foundation/ ; }, abstract = {The selective degeneration of both upper motor neurons (UMNs) and lower motor neurons (LMNs) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Unlike the simple organisation of LMNs in the brainstem and spinal cord, UMNs are embedded in the complex cytoarchitecture of the primary motor cortex, which complicates their identification. UMNs therefore remain a challenging neuronal population to study in ALS research, particularly in the early pre-symptomatic stages of animal models. A better understanding of the mechanisms that lead to selective UMN degeneration requires unequivocal visualization and cellular identification of vulnerable UMNs within the heterogeneous cortical neuronal population and circuitry. Here, we review recent novel gene delivery methods developed to cellularly identify vulnerable UMNs and modulate their activity in various mouse models. A critical overview of retrograde tracers, viral vectors encoding reporter genes and transgenic reporter mice used to visualize UMNs in mouse models of ALS is provided. Functional targeting of UMNs in vivo with the advent of optogenetic and chemogenetic technology is also discussed. These exciting gene delivery techniques will facilitate improved anatomical mapping, cell-specific gene expression profiling and targeted manipulation of UMN activity in mice. These advancements in the field pave the way for future work to uncover the precise role of UMNs in ALS and improve future therapeutic targeting of UMNs.}, }
@article {pmid34572087, year = {2021}, author = {Argueti-Ostrovsky, S and Alfahel, L and Kahn, J and Israelson, A}, title = {All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration.}, journal = {Cells}, volume = {10}, number = {9}, pages = {}, pmid = {34572087}, issn = {2073-4409}, support = {284/19//Israel Science Foundation/ ; 2017118//United States - Israel Binational Science Foundation/ ; 1-1425-415.13/2017//German-Israeli Foundation for Scientific Research and Development/ ; }, mesh = {*Active Transport, Cell Nucleus ; Animals ; *Endoplasmic Reticulum Stress ; Humans ; Mitochondria/*pathology ; Neurodegenerative Diseases/etiology/*pathology ; *Oxidative Stress ; }, abstract = {Multiple neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.}, }
@article {pmid34571990, year = {2021}, author = {Perkins, HT and Allan, V}, title = {Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases.}, journal = {Cells}, volume = {10}, number = {9}, pages = {}, pmid = {34571990}, issn = {2073-4409}, support = {EP/N509565/1//Engineering and Physical Sciences Research Council/ ; }, mesh = {Animals ; Cytoskeleton ; Endoplasmic Reticulum/*metabolism/*pathology/*physiology ; Humans ; Lipids/biosynthesis ; Membrane Proteins/metabolism ; Microtubules ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Nuclear Envelope/metabolism ; Structure-Activity Relationship ; }, abstract = {The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker sheet-like regions in the perinuclear region are linked to the nuclear envelope. It is becoming apparent that the complex morphology and dynamics of the ER are linked to its function. Mutations in the proteins involved in regulating ER structure and movement are implicated in many diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). The ER is also hijacked by pathogens to promote their replication. Bacteria such as Legionella pneumophila and Chlamydia trachomatis, as well as the Zika virus, bind to ER morphology and dynamics-regulating proteins to exploit the functions of the ER to their advantage. This review covers our understanding of ER morphology, including the functional subdomains and membrane contact sites that the organelle forms. We also focus on ER dynamics and the current efforts to quantify ER motion and discuss the diseases related to ER morphology and dynamics.}, }
@article {pmid34571896, year = {2021}, author = {Zhang, Y and Gu, J and Sun, Q}, title = {Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis.}, journal = {Cells}, volume = {10}, number = {9}, pages = {}, pmid = {34571896}, issn = {2073-4409}, support = {91754113, 31970695, 31771525//National Natural Science Foundation of China/ ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/*pathology ; Animals ; Cytoplasmic Granules/*pathology ; Humans ; *Macroautophagy ; }, abstract = {Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.}, }
@article {pmid34569965, year = {2021}, author = {Kitani-Morii, F and Friedland, RP and Yoshida, H and Mizuno, T}, title = {Drosophila as a Model for Microbiota Studies of Neurodegeneration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {84}, number = {2}, pages = {479-490}, pmid = {34569965}, issn = {1875-8908}, mesh = {Alzheimer Disease/immunology/metabolism ; Amyotrophic Lateral Sclerosis/immunology/metabolism ; Animals ; Brain-Gut Axis/*immunology ; *Drosophila melanogaster/metabolism/microbiology ; Dysbiosis ; *Gastrointestinal Tract/metabolism/microbiology ; Humans ; Longevity ; Parkinson Disease/immunology/metabolism ; Proteomics ; }, abstract = {Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly's gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior.}, }
@article {pmid34569233, year = {2023}, author = {Cassidy, K and Zhao, H}, title = {Redefining the Scope of Targeted Protein Degradation: Translational Opportunities in Hijacking the Autophagy-Lysosome Pathway.}, journal = {Biochemistry}, volume = {62}, number = {3}, pages = {580-587}, doi = {10.1021/acs.biochem.1c00330}, pmid = {34569233}, issn = {1520-4995}, mesh = {Animals ; *Autophagy ; Lysosomes ; Mammals ; Proteasome Endopeptidase Complex ; Proteolysis ; Proteolysis Targeting Chimera ; Ubiquitin ; Ubiquitin-Protein Ligases ; }, abstract = {The advent of multi-specific targeted protein degradation (TPD) therapies has made it possible to drug targets that have long been considered to be inaccessible. For this reason, the foremost TPD modalities - molecular glues and proteolysis targeting chimeras (PROTACs) -have been widely adopted and developed in therapeutic programs across the pharmaceutical and biotechnology industries. While there are many clear advantages to these two approaches, there are also blind spots. Specifically, PROTACs and molecular glues are inherently mechanistically analogous in that targets of both are degraded via the 26s proteasome; however, not all disease-relevant targets are suitable for ubiquitin proteasome system (UPS)-mediated degradation. The alternative mammalian protein degradation pathway, the autophagy-lysosome system (or ALS), is capable of degrading targets that elude the UPS such as long-lived proteins, insoluble protein aggregates, and even abnormal organelles. Emerging TPD strategies- such as ATTEC, AUTAC, and LYTAC- take advantage of the substrate diversity of the ALS to greatly expand the clinical utility of TPD. In this Perspective, we will discuss the array of current TPD modalities, with a focus on critical evaluation of these novel ALS-mediated degradation techniques.}, }
@article {pmid34568332, year = {2021}, author = {Chen, QY and Wen, T and Wu, P and Jia, R and Zhang, R and Dang, J}, title = {Exosomal Proteins and miRNAs as Mediators of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {718803}, pmid = {34568332}, issn = {2296-634X}, abstract = {Recent advances in the neurobiology and neurogenerative diseases have attracted growing interest in exosomes and their ability to carry and propagate active biomolecules as a means to reprogram recipient cells. Alterations in exosomal protein content and nucleic acid profiles found in human biological fluids have been correlated with various diseases including amyotrophic lateral sclerosis (ALS). In ALS pathogenesis, these lipid-bound nanoscale vesicles have emerged as valuable candidates for diagnostic biomarkers. Moreover, their capacity to spread misfolded proteins and functional non-coding RNAs to interconnected neuronal cells make them putative mediators for the progressive motor degeneration found remarkably apparent in ALS. This review outlines current knowledge concerning the biogenesis, heterogeneity, and function of exosomes in the brain as well as a comprehensive probe of currently available literature on ALS-related exosomal proteins and microRNAs. Lastly, with the rapid development of employing nanoparticles for drug delivery, we explore the therapeutic potentials of exosomes as well as underlying limitations in current isolation and detection methodologies.}, }
@article {pmid34565621, year = {2022}, author = {Walusinski, O}, title = {Louis Duménil (1823-1890), surgeon and pioneer in neurology.}, journal = {Revue neurologique}, volume = {178}, number = {4}, pages = {298-305}, doi = {10.1016/j.neurol.2021.06.011}, pmid = {34565621}, issn = {0035-3787}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis ; France ; *Guillain-Barre Syndrome ; History, 19th Century ; *Neurology/history ; *Neurosyphilis ; Paralysis ; *Surgeons ; }, abstract = {Louis-Stanislas Duménil (1823-1890) was a surgeon from Normandy who was a contemporary of Jean-Martin Charcot (1825-1893). Throughout his career, Duménil published annotated observations of neurological pathologies. One year before Guillaume Duchenne de Boulogne (1806-1875), he reported a case of "progressive muscular paralysis of the tongue, soft palate, and lips". He added five other cases of progressive muscular atrophy in 1867, together with histological examinations which showed atrophy in the anterior horns of the spinal cord. Charcot, who described amyotrophic lateral sclerosis, did not fail to pay homage to Duménil for his contribution. In 1862, Duménil added clinical observations of progressive locomotor ataxia, one of the first to do so. This included anatomopathological examinations, thus significantly completing the clinical picture presented by Duchenne in 1858. He confirmed the damage to the roots and posterior tracts of the spinal cord. Finally, by providing multiple observations of the syndrome described by Octave Landry (1826-1865) in 1859, he contributed to the clinical picture of "acute ascending paralysis" which has come down to us as Guillain-Barré syndrome, with no mention of the perspicacious physicians of the previous century who had already perfectly recognised this disease. Finally, Augusta Dejerine-Klumpke (1859-1927) paid a warm tribute to Duménil in her 1889 thesis, calling him one of the pioneers in understanding "the individuality and autonomy of the peripheral nervous system." He was indeed a pioneer, although he has been often overlooked.}, }
@article {pmid34565247, year = {2022}, author = {Longinetti, E and Pupillo, E and Belometti, C and Bianchi, E and Poloni, M and Fang, F and Beghi, E}, title = {Geographical clusters of amyotrophic lateral sclerosis and the Bradford Hill criteria.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {329-343}, doi = {10.1080/21678421.2021.1980891}, pmid = {34565247}, issn = {2167-9223}, mesh = {*Amino Acids, Diamino ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/etiology ; Humans ; Phenotype ; }, abstract = {With the aim of shedding further light on the role of environmental factors in amyotrophic lateral sclerosis (ALS) etiology, we hereby conducted a historical narrative review to critically appraise the published reports on ALS geographical clusters using the modern interpretation of the Bradford Hill criteria for causation. Our research hypothesis was that the more criteria were met, the greater was the evidence supporting a causal association. We found that cluster studies that met the greatest number of Bradford's Hill criteria regarded the non-protein amino acid β-N-methylamino-L-alanine (L-BMAA) and exposure to metals and minerals, but the evidence for causation was at best moderate and was poor for other environmental factors. This defective picture might be attributed not only to the methodological approach adopted by published studies, but also to the inherent difficulties in the application of Bradford Hill criteria, due to the complexity of the disease phenotype and the underlying pathogenic mechanisms.}, }
@article {pmid34561985, year = {2022}, author = {Chen, K and Lai, C and Su, Y and Bao, WD and Yang, LN and Xu, PP and Zhu, LQ}, title = {cGAS-STING-mediated IFN-I Response in Host Defense and Neuroinflammatory Diseases.}, journal = {Current neuropharmacology}, volume = {20}, number = {2}, pages = {362-371}, pmid = {34561985}, issn = {1875-6190}, support = {82030032, 32070960, 81961128005, 81829002, 81871108, 31721002//National Natural Science Foundation of China/ ; 2019KFYXKJC076//Fundamental Research Funds for the Central Universities', HUST/ ; 2020CFB811//Hubei Provincial Natural Science Foundation/ ; }, mesh = {DNA/immunology ; Humans ; Immunity, Innate ; *Interferon Type I/metabolism ; *Membrane Proteins/genetics/metabolism ; *Neuroinflammatory Diseases/immunology ; *Nucleotidyltransferases/genetics/metabolism ; }, abstract = {The presence of foreign or misplaced nucleic acids is a dangerous signal that triggers innate immune responses by activating cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and binding to its downstream signaling effector stimulator of interferon genes (STING). Then the cGAS-STING pathway activation links nucleic acid-sensing to immune responses and pathogenic entities clearance. However, the overactivation of this signaling pathway leads to fatal immune disorders and contributes to the progression of many human inflammatory diseases. Therefore, optimal activation of this pathway is crucial for the elimination of invading pathogens and the maintenance of immune homeostasis. In this review, we will summarize its fundamental roles in initiating host defense against invading pathogens and discuss its pathogenic roles in multiple neuro-inflammatory diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurodegenerative diseases.}, }
@article {pmid34561341, year = {2021}, author = {Barry, C and Larner, E and Copsey, H and Smith, M and Peryer, G}, title = {Non-invasive ventilation support for people with amyotrophic lateral sclerosis: multidisciplinary team management.}, journal = {Current opinion in supportive and palliative care}, volume = {15}, number = {4}, pages = {214-218}, pmid = {34561341}, issn = {1751-4266}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Noninvasive Ventilation ; Patient Care Team ; Respiration, Artificial ; }, abstract = {PURPOSE OF REVIEW: To summarise recent developments in the use of noninvasive ventilation (NIV) for people with amyotrophic lateral sclerosis (pwALS), with a specific focus on how multidisciplinary teams (MDT) can support best practice.<br><br>RECENT FINDINGS: We included 13 papers, 12 with observational designs and one qualitative interview design. The review is structured using four content domains: prognosis, the effectiveness of NIV, NIV tolerance, and MDT structure and delivery. Findings suggest a modest survival benefit of NIV for pwALS. Further evidence is needed to consider the appropriate time of initiation in the context of respiratory status and the influence of NIV on cognitive function over the course of the disease. A key emerging determinant of tolerability of NIV is secretion load. Palliative care professionals within the MDT can play a key role in supporting pwALS to consider the potential benefits of NIV in the context of their preferences, prognosis, symptom burden, and ALS variant.<br><br>SUMMARY: ALS MDTs allow timely information sharing about NIV between experts that is likely to improve outcomes. MDT practice must continually adapt to reflect pwALS's preferences for care and ensure those caring for them at home have access to support using digital innovations.}, }
@article {pmid34560374, year = {2021}, author = {Sahu, R and Upadhayay, S and Mehan, S}, title = {Inhibition of extracellular regulated kinase (ERK)-1/2 signaling pathway in the prevention of ALS: Target inhibitors and influences on neurological dysfunctions.}, journal = {European journal of cell biology}, volume = {100}, number = {7-8}, pages = {151179}, doi = {10.1016/j.ejcb.2021.151179}, pmid = {34560374}, issn = {1618-1298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Cell Proliferation ; Humans ; MAP Kinase Signaling System ; Neurons ; Signal Transduction ; }, abstract = {Cell signal transduction pathways are essential modulators of several physiological and pathological processes in the brain. During overactivation, these signaling processes may lead to disease progression. Abnormal protein kinase activation is associated with several biological dysfunctions that facilitate neurodegeneration under different biological conditions. As a result, these signaling pathways are essential in understanding brain disorders' development or progression. Recent research findings indicate the crucial role of extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling during the neuronal development process. ERK-1/2 is a key component of its mitogen-activated protein kinase (MAPK) group, controlling certain neurological activities by regulating metabolic pathways, cell proliferation, differentiation, and apoptosis. ERK-1/2 also influences neuronal elastic properties, nerve growth, and neurological and cognitive processing during brain injuries. The primary goal of this review is to elucidate the activation of ERK1/2 signaling, which is involved in the development of several ALS-related neuropathological dysfunctions. ALS is a rare neurological disorder category that mainly affects the nerve cells responsible for regulating voluntary muscle activity. ALS is progressive, which means that the symptoms are getting worse over time, and there is no cure for ALS and no effective treatment to avoid or reverse. Genetic abnormalities, oligodendrocyte degradation, glial overactivation, and immune deregulation are associated with ALS progression. Furthermore, the current review also identifies ERK-1/2 signaling inhibitors that can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of ALS. As a result, in the future, the potential ERK-1/2 signaling inhibitors could be used in the treatment of ALS and related neurocomplications.}, }
@article {pmid34558138, year = {2022}, author = {Erekat, NS}, title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {35}, number = {1}, pages = {65-78}, doi = {10.1002/ca.23792}, pmid = {34558138}, issn = {1098-2353}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.}, }
@article {pmid34558120, year = {2022}, author = {Prater, KE and Latimer, CS and Jayadev, S}, title = {Glial TDP-43 and TDP-43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes.}, journal = {Glia}, volume = {70}, number = {2}, pages = {239-255}, pmid = {34558120}, issn = {1098-1136}, support = {RF1 AG063540/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; K08 AG065426/AG/NIA NIH HHS/United States ; R01 NS073848/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/*metabolism ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Humans ; Neuroglia/metabolism ; Syndrome ; *TDP-43 Proteinopathies/pathology ; }, abstract = {Since its discovery in 2006, TAR DNA binding protein 43 (TDP-43) has driven rapidly evolving research in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). TDP-43 mislocalization or aggregation is the hallmark of TDP-43 proteinopathy and is associated with cognitive impairment that can be mapped to its regional deposition. Studies in human tissue and model systems demonstrate that TDP-43 may potentiate other proteinopathies such as the amyloid or tau pathology seen in Alzheimer's Disease (AD) in the combination of AD+LATE. Despite this growing body of literature, there remain gaps in our understanding of whether there is heterogeneity in TDP-43 driven mechanisms across cell types. The growing observations of correlation between TDP-43 proteinopathy and glial pathology suggest a relationship between the two, including pathogenic glial cell-autonomous dysfunction and dysregulated glial immune responses to neuronal TDP-43. In this review, we discuss the available data on TDP-43 in glia within the context of the neurodegenerative diseases ALS and FTLD and highlight the current lack of information about glial TDP-43 interaction in AD+LATE. TDP-43 has proven to be a significant modulator of cognitive and neuropathological outcomes. A deeper understanding of its role in diverse cell types may provide relevant insights into neurodegenerative syndromes.}, }
@article {pmid34557668, year = {2021}, author = {Lubben, N and Ensink, E and Coetzee, GA and Labrie, V}, title = {The enigma and implications of brain hemispheric asymmetry in neurodegenerative diseases.}, journal = {Brain communications}, volume = {3}, number = {3}, pages = {fcab211}, pmid = {34557668}, issn = {2632-1297}, support = {R01 NS113894/NS/NINDS NIH HHS/United States ; }, abstract = {The lateralization of the human brain may provide clues into the pathogenesis and progression of neurodegenerative diseases. Though differing in their presentation and underlying pathologies, neurodegenerative diseases are all devastating and share an intriguing theme of asymmetrical pathology and clinical symptoms. Parkinson's disease, with its distinctive onset of motor symptoms on one side of the body, stands out in this regard, but a review of the literature reveals asymmetries in several other neurodegenerative diseases. Here, we review the lateralization of the structure and function of the healthy human brain and the common genetic and epigenetic patterns contributing to the development of asymmetry in health and disease. We specifically examine the role of asymmetry in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and interrogate whether these imbalances may reveal meaningful clues about the origins of these diseases. We also propose several hypotheses for how lateralization may contribute to the distinctive and enigmatic features of asymmetry in neurodegenerative diseases, suggesting a role for asymmetry in the choroid plexus, neurochemistry, protein distribution, brain connectivity and the vagus nerve. Finally, we suggest how future studies may reveal novel insights into these diseases through the lens of asymmetry.}, }
@article {pmid34555670, year = {2021}, author = {Rahmati, M and Malakoutinia, F}, title = {Aerobic, resistance and combined exercise training for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Physiotherapy}, volume = {113}, number = {}, pages = {12-28}, doi = {10.1016/j.physio.2021.04.005}, pmid = {34555670}, issn = {1873-1465}, mesh = {Activities of Daily Living ; *Amyotrophic Lateral Sclerosis ; Exercise ; Exercise Therapy/methods ; Humans ; Quality of Life ; *Resistance Training ; }, abstract = {OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the effect of aerobic, resistance and combined exercise training in patients with ALS.<br><br>DATA SOURCE: A comprehensive systematic search of CENTRAL, CINAHL, SPORTDiscuss, Embase, Scopus, ProQuest was performed from inception to February 2021.<br><br>ELIGIBILITY CRITERIA: The systematic review included all studies that examined the effect of exercise training in ALS patients. Meta-analysis was also carried out on randomized controlled trials (RCTs).<br><br>Data related to primary outcomes (functional ability, respiratory function, fatigue, pain, quality of life, upper-body strength, lower-body strength and Vo2peak) and secondary outcomes (adverse events and feasibility of exercises) was extracted from all studies and systematically reviewed.<br><br>RESULTS: 16 trials including 532 patients met the inclusion criteria; of these, eight studies were included in this meta-analysis. The meta-analysis found a statistically significant difference in favor of exercise in functional ability (P=0.001), overall quality of life (P=0.03) and Vo2peak (P=0.01). The included trials were generally of poor quality and had a risk of bias. However, the results of sensitivity analysis, after omitting studies with high risk of bias, showed no statistically significant difference in functional ability (P=0.05), overall quality of life (P=0.12) and Vo2peak (P=0.13). Finally, no significant difference was found in respiratory function, fatigue, pain, and upper-body and lower-body strength.<br><br>CONCLUSIONS: The safety and effectiveness of exercise therapy in ALS patients remains unclear and further high quality RCTs with larger sample size are needed. Systematic Review Registration Number PROSPERO CRD42019140011.}, }
@article {pmid34554894, year = {2021}, author = {Chiò, A and Canosa, A and Calvo, A and Moglia, C and Cicolin, A and Mora, G}, title = {Developments in the assessment of non-motor disease progression in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {21}, number = {12}, pages = {1419-1440}, doi = {10.1080/14737175.2021.1984883}, pmid = {34554894}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; *Cognitive Dysfunction ; Disease Progression ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: The burden of non-motor symptoms is a major determinant of quality of life and outcome in amyotrophic lateral sclerosis (ALS) and has profound negative effect also on caregivers.<br><br>AREAS COVERED: Non-motor symptoms in ALS include cognitive impairment, neurobehavioral symptoms, depression and anxiety, suicidal ideation, pain, disordered sleep, fatigue, weight loss and reduced appetite, and autonomic dysfunctions. This review summarizes the measures used for the assessment of non-motor symptoms and their properties and recaps the frequency and progression of these symptoms along the course of ALS.<br><br>EXPERT OPINION: Non-motor symptoms in ALS represent a major component of the disease and span over several domains. These symptoms require a high level of medical attention and should be checked at each visit using ad hoc questionnaires and proactively treated. Several instruments assessing non-motor symptoms have been used in ALS. Specific screening questionnaires for non-motor symptoms can be used for monitoring patients during telehealth visits and for remote surveillance through sensors and apps installed on smartphones. Novel trials for non-motor symptoms treatment specifically designed for ALS are necessary to increase and refine the therapeutic armamentarium. Finally, scales assessing the most frequent and burdensome non-motor symptoms should be included in clinical trials.}, }
@article {pmid34539339, year = {2021}, author = {Valori, CF and Neumann, M}, title = {Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {724891}, pmid = {34539339}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD-TDP-43 or ALS/FTLD-FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.}, }
@article {pmid34536490, year = {2022}, author = {Chidambaram, SB and Essa, MM and Rathipriya, AG and Bishir, M and Ray, B and Mahalakshmi, AM and Tousif, AH and Sakharkar, MK and Kashyap, RS and Friedland, RP and Monaghan, TM}, title = {Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle.}, journal = {Pharmacology &amp; therapeutics}, volume = {231}, number = {}, pages = {107988}, doi = {10.1016/j.pharmthera.2021.107988}, pmid = {34536490}, issn = {1879-016X}, mesh = {Autophagy ; Brain/metabolism ; Dysbiosis/metabolism/pathology/therapy ; *Gastrointestinal Microbiome/physiology ; Humans ; Immunity ; *Neurodegenerative Diseases/metabolism ; }, abstract = {The human microbiota comprises trillions of symbiotic microorganisms and is involved in regulating gastrointestinal (GI), immune, nervous system and metabolic homeostasis. Recent observations suggest a bidirectional communication between the gut microbiota and the brain via immune, circulatory and neural pathways, termed the Gut-Brain Axis (GBA). Alterations in gut microbiota composition, such as seen with an increased number of pathobionts and a decreased number of symbionts, termed gut dysbiosis or microbial intestinal dysbiosis, plays a prominent role in the pathogenesis of central nervous system (CNS)-related disorders. Clinical reports confirm that GI symptoms often precede neurological symptoms several years before the development of neurodegenerative diseases (NDDs). Pathologically, gut dysbiosis disrupts the integrity of the intestinal barrier leading to ingress of pathobionts and toxic metabolites into the systemic circulation causing GBA dysregulation. Subsequently, chronic neuroinflammation via dysregulated immune activation triggers the accumulation of neurotoxic misfolded proteins in and around CNS cells resulting in neuronal death. Emerging evidence links gut dysbiosis to the aggravation and/or spread of proteinopathies from the peripheral nervous system to the CNS and defective autophagy-mediated proteinopathies. This review summarizes the current understanding of the role of gut microbiota in NDDs, and highlights a vicious cycle of gut dysbiosis, immune-mediated chronic neuroinflammation, impaired autophagy and proteinopathies, which contributes to the development of neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We also discuss novel therapeutic strategies targeting the modulation of gut dysbiosis through prebiotics, probiotics, synbiotics or dietary interventions, and faecal microbial transplantation (FMT) in the management of NDDs.}, }
@article {pmid34535505, year = {2022}, author = {Mentis, AA and Vlachakis, D and Papakonstantinou, E and Zaganas, I and Patrinos, GP and Chrousos, GP and Dardiotis, E}, title = {A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum.}, journal = {Cold Spring Harbor molecular case studies}, volume = {8}, number = {2}, pages = {}, pmid = {34535505}, issn = {2373-2873}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Cytoplasmic Dyneins/genetics/metabolism ; Dyneins/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Humans ; Phenotype ; Exome Sequencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) belongs to the ALS-frontotemporal dementia (FTD) spectrum and is hallmarked by upper and lower motor neuron degeneration. Here, we present a patient with a cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) pathogenic variant who fulfilled the ALS El Escorial criteria, and we review relevant literature. Using whole-exome sequencing, we identified a deleterious point variant in DYNC1H1 (c.4106A > G (p. Q1369R)) as a likely contributor to the ALS phenotype. In silico structural analysis, molecular dynamics simulation, and protein stability analysis predicted that this variant may increase DYNC1H1 protein stability. Moreover, this variant may disrupt binding of the transcription factor TFAP4, thus potentially acting as duon. Because (a) DYNC1H1 forms part of a ubiquitous eukaryotic motor protein complex, and (b) disruption of dynein function by perturbation of the dynein-dynactin protein complex is implicated in other motor neuron degenerative conditions, this variant could disrupt processes like retrograde axonal transport, neuronal migration, and protein recycling. Our findings expand the heterogenous spectrum of the DYNC1H1 pathogenic variant-associated phenotype and prompt further investigations of the role of this gene in ALS.}, }
@article {pmid34527672, year = {2021}, author = {Zhou, S and Yu, X and Wang, M and Meng, Y and Song, D and Yang, H and Wang, D and Bi, J and Xu, S}, title = {Long Non-coding RNAs in Pathogenesis of Neurodegenerative Diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {719247}, pmid = {34527672}, issn = {2296-634X}, abstract = {Emerging evidence addresses the link between the aberrant epigenetic regulation of gene expression and numerous diseases including neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). LncRNAs, a class of ncRNAs, have length of 200 nt or more, some of which crucially regulate a variety of biological processes such as epigenetic-mediated chromatin remodeling, mRNA stability, X-chromosome inactivation and imprinting. Aberrant regulation of the lncRNAs contributes to pathogenesis of many diseases, such as the neurological disorders at the transcriptional and post-transcriptional levels. In this review, we highlight the latest research progress on the contributions of some lncRNAs to the pathogenesis of neurodegenerative diseases via varied mechanisms, such as autophagy regulation, Aβ deposition, neuroinflammation, Tau phosphorylation and α-synuclein aggregation. Meanwhile, we also address the potential challenges on the lncRNAs-mediated epigenetic study to further understand the molecular mechanism of the neurodegenerative diseases.}, }
@article {pmid34516952, year = {2021}, author = {Ravula, AR and Teegala, SB and Kalakotla, S and Pasangulapati, JP and Perumal, V and Boyina, HK}, title = {Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review.}, journal = {European journal of pharmacology}, volume = {910}, number = {}, pages = {174492}, doi = {10.1016/j.ejphar.2021.174492}, pmid = {34516952}, issn = {1879-0712}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Disease Models, Animal ; Flavonols/*pharmacology/therapeutic use ; Glycation End Products, Advanced/metabolism ; Glycolysis/drug effects ; Humans ; Long-Term Potentiation/drug effects ; Memory/drug effects ; Nervous System Diseases/*drug therapy/immunology/pathology ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Signal Transduction/drug effects ; }, abstract = {Neurodegenerative disorders pose a significant health burden and imprint a debilitative impact on the quality of life. Importantly, aging is intricately intertwined with the progression of these disorders, and their prevalence increases with a rise in the aging population worldwide. In recent times, fisetin emerged as one of the potential miracle molecules to address neurobehavioral and cognitive abnormalities. These effects were attributed to its actions on several macromolecules and multiple molecular mechanisms. Fisetin belongs to a class of flavonoids, which is found abundantly in several fruits and vegetables. Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes. This review aimed to evaluate the potential mechanisms and pharmacological effects of fisetin in treating several neurological diseases. This review also provides comprehensive data on up-to-date recent literature and highlights the various mechanistic pathways pertaining to fisetin's neuroprotective role.}, }
@article {pmid34513831, year = {2021}, author = {Xu, S and Zhang, X and Liu, C and Liu, Q and Chai, H and Luo, Y and Li, S}, title = {Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {688789}, pmid = {34513831}, issn = {2296-634X}, abstract = {Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD[+], in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.}, }
@article {pmid34512775, year = {2021}, author = {Pan, H and Wang, H and Tao, Y and Yuan, J and Xu, S and Ni, J and Huang, M and Wu, X and Liu, T}, title = {Evidence-Based Research Strategy of Traditional Chinese Medicine for Amyotrophic Lateral Sclerosis.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {3402753}, pmid = {34512775}, issn = {1741-427X}, abstract = {Among adult-onset motor neuron diseases, amyotrophic lateral sclerosis (ALS) is the most common. ALS involves the increasing loss of lower and upper motor neurons. Within a few years of onset, ALS causes patient death via progressive paralysis of respiratory muscles. However, the current drugs used to treat ALS, riluzole, edaravone, and dextromethorphan/quinidine, can only delay the progression of the disease and alleviate a small number of symptoms in some patients, and no completely effective treatment is available. Traditional Chinese medicine (TCM) has shown significant advantages in the treatment of ALS in China and Asia; however, the mechanism of its efficacy is unclear. This review discusses the pathogenetic hypothesis of ALS in detail from the level of neurons and glial cells and uses two current experimental animal models of ALS to design experimental strategies to study TCM treatment. We aim to provide a scientific explanation of the mechanism of the effect of TCM in the treatment of ALS, which will help clinicians and research scientists to accept the theory of TCM to treat ALS and promote the development of TCM modernization.}, }
@article {pmid34511007, year = {2023}, author = {Cave, R and Bloch, S}, title = {The use of speech recognition technology by people living with amyotrophic lateral sclerosis: a scoping review.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {18}, number = {7}, pages = {1043-1055}, doi = {10.1080/17483107.2021.1974961}, pmid = {34511007}, issn = {1748-3115}, mesh = {Humans ; Speech ; Dysarthria/etiology ; *Amyotrophic Lateral Sclerosis/complications ; *Speech Perception ; Speech Recognition Software ; Quality of Life ; Speech Disorders ; }, abstract = {BACKGROUND: More than 80% of people living with Amyotrophic Lateral Sclerosis (plwALS) develop difficulties with their speech, affecting communication, self-identity and quality of life. Automatic speech recognition technology (ASR) is becoming a common way to interact with a broad range of devices, to find information and control the environment.ASR can be problematic for people with acquired neurogenic motor speech difficulties (dysarthria). Given that the field is rapidly developing, a scoping review is warranted.<br><br>AIMS: This study undertakes a scoping review on the use of ASR technology by plwALS and identifies research gaps in the existing literature.<br><br>MATERIALS AND METHODS: Electronic databases and relevant grey literature were searched from 1990 to 2020. Eleven research papers and articles were identified that included participants living with ALS using ASR technology. Relevant data were extracted from the included sources, and a narrative summary of the findings presented.Outcomes and Results: Eleven publications used recordings of plwALS to assess word recognition rate (WRR) word error rate (WER) or phoneme error rate (PER) and appropriacy of responses by ASR devices. All were found to be linked to severity of dysarthria and the ASR technology used. One article examined how speech modification may improve ASR accuracy. The final article completed thematic analysis of Amazon.com reviews for the Amazon Echo and plwALS were reported to use ASR devices to control the environment and summon assistance.<br><br>CONCLUSIONS: There are gaps in the evidence base: understanding expectations of plwALS and how they use ASR technology; how WER/PER/WRR relates to usability; how ASR use changes as ALS progresses.Implications for rehabilitationDevices that people can interact with using speech are becoming ubiquitous. As movement and mobility are likely to be affected by ALS and progress over time, speech interaction could be very helpful for accessing information and environmental control.However, many people living with ALS (plwALS) also have impaired speech (dysarthria) and experience trouble using voice interaction technology because it may not understand them.Although advances in automated speech recognition (ASR) technology promise better understanding of dysarthric speech, future research needs to investigate how plwALS use ASR, how accurate it needs to be to be functionally useful, and how useful it may be over time as the disease progresses.}, }
@article {pmid34510431, year = {2021}, author = {Amor, S and Nutma, E and Marzin, M and Puentes, F}, title = {Imaging immunological processes from blood to brain in amyotrophic lateral sclerosis.}, journal = {Clinical and experimental immunology}, volume = {206}, number = {3}, pages = {301-313}, pmid = {34510431}, issn = {1365-2249}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/immunology/*pathology ; Animals ; Brain/*diagnostic imaging/pathology ; Disease Models, Animal ; Disease Progression ; Humans ; Inflammation/pathology ; Magnetic Resonance Imaging/*methods ; Magnetic Resonance Spectroscopy/*methods ; Neuroinflammatory Diseases/diagnostic imaging/pathology ; Positron-Emission Tomography/*methods ; }, abstract = {Neuropathology studies of amyotrophic lateral sclerosis (ALS) and animal models of ALS reveal a strong association between aberrant protein accumulation and motor neurone damage, as well as activated microglia and astrocytes. While the role of neuroinflammation in the pathology of ALS is unclear, imaging studies of the central nervous system (CNS) support the idea that innate immune activation occurs early in disease in both humans and rodent models of ALS. In addition, emerging studies also reveal changes in monocytes, macrophages and lymphocytes in peripheral blood as well as at the neuromuscular junction. To more clearly understand the association of neuroinflammation (innate and adaptive) with disease progression, the use of biomarkers and imaging modalities allow monitoring of immune parameters in the disease process. Such approaches are important for patient stratification, selection and inclusion in clinical trials, as well as to provide readouts of response to therapy. Here, we discuss the different imaging modalities, e.g. magnetic resonance imaging, magnetic resonance spectroscopy and positron emission tomography as well as other approaches, including biomarkers of inflammation in ALS, that aid the understanding of the underlying immune mechanisms associated with motor neurone degeneration in ALS.}, }
@article {pmid34506674, year = {2022}, author = {Sampedro, F and Kulisevsky, J}, title = {Intracortical surface-based MR diffusivity to investigate neurologic and psychiatric disorders: a review.}, journal = {Journal of neuroimaging : official journal of the American Society of Neuroimaging}, volume = {32}, number = {1}, pages = {28-35}, doi = {10.1111/jon.12930}, pmid = {34506674}, issn = {1552-6569}, support = {#PI15/00962//Instituto de Salud Carlos III/ ; #PI18/01717//Instituto de Salud Carlos III/ ; #2014/U/477//Fundaci&#xf3; la Marat&#xf3; de TV3/ ; #20142910//Fundaci&#xf3; la Marat&#xf3; de TV3/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; *Diffusion Tensor Imaging/methods ; Gray Matter ; Humans ; Neuroimaging ; }, abstract = {Diffusion tensor imaging (DTI) allows the quantification of water diffusivity within the cerebral cortex. Alterations in cortical mean diffusivity (MD) have been suggested to reflect microstructural damage. Interestingly, microstructural changes can be detected in the absence of macrostructural alterations such as cortical thinning or gray matter volume loss. However, volume-based neuroimaging techniques for the study of cortical MD have shown some limitations in terms of intersubject registration, partial volume correction, and smoothing artifacts. In this review, we summarize how a surface-based approach for the assessment of intracortical MD has not only overcome these technical limitations, but also provided important contributions to the fields of neurology and psychiatry. Since its proposal in 2018, the use of this neuroimaging technique has revealed cortical microstructural alterations in a wide range of clinical contexts, including Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and primary progressive aphasia. In most cases, the detection of early intracortical MD alterations preceded the identification of macrostructural changes. Importantly, microstructural damage significantly correlated with cognitive performance and biomarker measures, suggesting a potential role for its use in clinical trials as a sensitive imaging marker of neurodegeneration. Given that DTI is a widely available imaging modality, these encouraging results motivate further research using this novel neuroimaging metric in other clinical contexts. Overall, this technique has shed light into the key role of early cortical degeneration in many diseases where cortical involvement was previously thought to have limited clinical and biological significance.}, }
@article {pmid34506621, year = {2021}, author = {Lim, SJ and Mohamad Ali, MS and Sabri, S and Muhd Noor, ND and Salleh, AB and Oslan, SN}, title = {Opportunistic yeast pathogen Candida spp.: Secreted and membrane-bound virulence factors.}, journal = {Medical mycology}, volume = {59}, number = {12}, pages = {1127-1144}, doi = {10.1093/mmy/myab053}, pmid = {34506621}, issn = {1460-2709}, support = {FRGS/1/2019/STG05/UPM/02/1//Ministry of Higher Education, Malaysia/ ; }, mesh = {Animals ; Antifungal Agents/therapeutic use ; *Candida ; Candida albicans ; *Candidiasis, Invasive/drug therapy/veterinary ; Virulence Factors ; }, abstract = {UNLABELLED: Candidiasis is a fungal infection caused by Candida spp. especially Candida albicans, C. glabrata, C. parapsilosis and C. tropicalis. Although the medicinal therapeutic strategies have rapidly improved, the mortality rate as candidiasis has continuously increased. The secreted and membrane-bound virulence factors (VFs) are responsible for fungal invasion, damage and translocation through the host enterocytes besides the evasion from host immune system. VFs such as agglutinin-like sequences (Als), heat shock protein 70, phospholipases, secreted aspartyl proteinases (Sap), lipases, enolases and phytases are mostly hydrolases which degrade or interact with the enterocyte membrane components. Candidalysin, however, acts as a peptide toxin to induce necrotic cell lysis. To date, structural studies of the VFs remain underexplored, hindering their functional analyses. Among the VFs, only Sap and Als have their structures deposited in Protein Data Bank (PDB). Therefore, this review scrutinizes the mechanisms of these VFs by discussing the VF-deficient studies of several Candida spp. and their abilities to produce these VFs. Nonetheless, their latest reported sequential and structural analyses are discussed to impart a wider perception of the host-pathogen interactions and potential vaccine or antifungal drug targets. This review signifies that more VFs structural investigations and mining in the emerging Candida spp. are required to decipher their pathogenicity and virulence mechanisms compared to the prominent C. albicans.<br><br>LAY SUMMARY: Candida virulence factors (VFs) including mainly enzymes and proteins play vital roles in breaching the human intestinal barrier and causing deadly invasive candidiasis. Limited VFs' structural studies hinder deeper comprehension of their mechanisms and thus the design of vaccines and antifungal drugs against fungal infections.}, }
@article {pmid34503413, year = {2022}, author = {Kumar, R and Harilal, S and Parambi, DGT and Kanthlal, SK and Rahman, MA and Alexiou, A and Batiha, GE and Mathew, B}, title = {The Role of Mitochondrial Genes in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {20}, number = {5}, pages = {824-835}, pmid = {34503413}, issn = {1875-6190}, mesh = {*Amyotrophic Lateral Sclerosis ; DNA, Mitochondrial/genetics ; Genes, Mitochondrial ; Humans ; *Mitochondrial Diseases ; Mutation ; *Neurodegenerative Diseases/genetics ; *Parkinson Disease/genetics ; }, abstract = {Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.}, }
@article {pmid34502501, year = {2021}, author = {Zgorzynska, E and Dziedzic, B and Walczewska, A}, title = {An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {17}, pages = {}, pmid = {34502501}, issn = {1422-0067}, support = {503/0-079-04/503-01-001//Uniwersytet Medyczny w Lodzi/ ; 502-03/0-079-04/502-04-035//Uniwersytet Medyczny w Lodzi/ ; }, mesh = {Alzheimer Disease/genetics ; Antioxidant Response Elements/genetics/*physiology ; Antioxidants/metabolism ; Humans ; Huntington Disease/genetics ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; NF-E2-Related Factor 2/*metabolism/physiology ; Neurodegenerative Diseases/*metabolism/physiopathology ; Oxidative Stress/physiology ; Signal Transduction/physiology ; }, abstract = {Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Free Nrf2 enters the nucleus, dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs), and binds to the antioxidant response element (ARE) sequence of the target genes. Since oxidative stress, next to neuroinflammation and mitochondrial dysfunction, is one of the hallmarks of neurodegenerative pathologies, a molecular intervention into Nrf2/ARE signaling and the enhancement of the transcriptional activity of particular genes are targets for prevention or delaying the onset of age-related and inherited neurogenerative diseases. In this study, we review evidence for the Nrf2/ARE-driven pathway dysfunctions leading to various neurological pathologies, such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as amyotrophic lateral sclerosis, and the beneficial role of natural and synthetic molecules that are able to interact with Nrf2 to enhance its protective efficacy.}, }
@article {pmid34502125, year = {2021}, author = {Semmelink, MFW and Steen, A and Veenhoff, LM}, title = {Measuring and Interpreting Nuclear Transport in Neurodegenerative Disease-The Example of C9orf72 ALS.}, journal = {International journal of molecular sciences}, volume = {22}, number = {17}, pages = {}, pmid = {34502125}, issn = {1422-0067}, support = {NWO BBOL2018-737.016.016//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; C9orf72 Protein/*genetics/*metabolism ; Cell Nucleus/metabolism ; *Disease Susceptibility ; Gene Expression Regulation ; Humans ; Neurodegenerative Diseases/*etiology/*metabolism/pathology ; Protein Transport ; }, abstract = {Transport from and into the nucleus is essential to all eukaryotic life and occurs through the nuclear pore complex (NPC). There are a multitude of data supporting a role for nuclear transport in neurodegenerative diseases, but actual transport assays in disease models have provided diverse outcomes. In this review, we summarize how nuclear transport works, which transport assays are available, and what matters complicate the interpretation of their results. Taking a specific type of ALS caused by mutations in C9orf72 as an example, we illustrate these complications, and discuss how the current data do not firmly answer whether the kinetics of nucleocytoplasmic transport are altered. Answering this open question has far-reaching implications, because a positive answer would imply that widespread mislocalization of proteins occurs, far beyond the reported mislocalization of transport reporters, and specific proteins such as FUS, or TDP43, and thus presents a challenge for future research.}, }
@article {pmid34496365, year = {2022}, author = {Mohammadi, A and Hosseinzadeh Colagar, A and Khorshidian, A and Amini, SM}, title = {The Functional Roles of Curcumin on Astrocytes in Neurodegenerative Diseases.}, journal = {Neuroimmunomodulation}, volume = {29}, number = {1}, pages = {4-14}, doi = {10.1159/000517901}, pmid = {34496365}, issn = {1423-0216}, mesh = {Animals ; Astrocytes ; Brain ; *Curcumin/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; Neurons ; }, abstract = {Progressive abnormality and loss of axons and neurons in the central nervous system (CNS) cause neurodegenerative diseases (NDs). Protein misfolding and its collection are the most important pathological features of NDs. Astrocytes are the most plentiful cells in the mammalian CNS (about 20-40% of the human brain) and have several central functions in the maintenance of the health and correct function of the CNS. Astrocytes have an essential role in the preservation of brain homeostasis, and it is not surprising that these multifunctional cells have been implicated in the onset and progression of several NDs. Thus, they become an exciting target for the study of NDs. Over almost 15 years, it was revealed that curcumin has several therapeutic effects in a wide variety of diseases' treatment. Curcumin is a valuable ingredient present in turmeric spice and has several essential roles, including those which are anticarcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic, and anti-infectious. Furthermore, curcumin can suppress inflammation; promote angiogenesis; and treat diabetes, pulmonary problems, and neurological dysfunction. Here, we review the effects of curcumin on astrocytes in NDs, with a focus on Alzheimer's disease, Parkinson's disease, multiple scleroses, Huntington's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid34494536, year = {2021}, author = {Chen, WY and Qian, Y and Chen, TY and Gu, XP}, title = {[Research Progress of CD4[+]T Cells-mediated Regulation of Neuroinflammation Involved in Neurodegenerative Diseases].}, journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae}, volume = {43}, number = {4}, pages = {628-633}, doi = {10.3881/j.issn.1000-503X.13146}, pmid = {34494536}, issn = {1000-503X}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Humans ; *Neurodegenerative Diseases ; *Parkinson Disease ; T-Lymphocytes ; }, abstract = {Neurodegenerative diseases are associated with neuroinflammation,oxidative stress,and aging,which can lead to cognitive and motor dysfunctions.Recent studies suggest that the development of neurodegenerative diseases is related to adaptive immunity,in which CD4[+]T cells are involved as adaptive immune cells.Through different pathways,CD4[+]T cells differentiate into effector and regulatory subsets,which may have different effects on the progression of neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease,multiple sclerosis,and amyotrophic lateral sclerosis.Here,we review the role and research progress of CD4[+]T cells in neurodegenerative diseases.}, }
@article {pmid34493165, year = {2022}, author = {Moretti, M and Rodrigues, ALS}, title = {Functional role of ascorbic acid in the central nervous system: a focus on neurogenic and synaptogenic processes.}, journal = {Nutritional neuroscience}, volume = {25}, number = {11}, pages = {2431-2441}, doi = {10.1080/1028415X.2021.1956848}, pmid = {34493165}, issn = {1476-8305}, mesh = {Adult ; Humans ; Ascorbic Acid/pharmacology/therapeutic use ; *Depressive Disorder, Major/drug therapy ; Central Nervous System ; Neurogenesis ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Ascorbic acid, a water-soluble vitamin, is highly concentrated in the brain and participates in neuronal modulation and regulation of central nervous system (CNS) homeostasis. Ascorbic acid has emerged as a neuroprotective compound against neurotoxicants and neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Moreover, it improves behavioral and biochemical alterations in psychiatric disorders, including schizophrenia, anxiety, major depressive disorder, and bipolar disorder. Some recent studies have advanced the knowledge on the mechanisms associated with the preventive and therapeutic effects of ascorbic acid by showing that they are linked to improved neurogenesis and synaptic plasticity. This review shows that ascorbic acid has the potential to regulate positively stem cell generation and proliferation. Moreover, it improves neuronal differentiation of precursors cells, promotes adult hippocampal neurogenesis, and has synaptogenic effects that are possibly linked to its protective or therapeutic effects in the brain.}, }
@article {pmid34492237, year = {2022}, author = {Subbarayan, MS and Joly-Amado, A and Bickford, PC and Nash, KR}, title = {CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases.}, journal = {Pharmacology &amp; therapeutics}, volume = {231}, number = {}, pages = {107989}, doi = {10.1016/j.pharmthera.2021.107989}, pmid = {34492237}, issn = {1879-016X}, support = {IK6 BX004214/BX/BLRD VA/United States ; }, mesh = {CX3C Chemokine Receptor 1/metabolism ; *Chemokine CX3CL1/metabolism ; Humans ; Microglia/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroglia/metabolism ; }, abstract = {Neuroinflammation was initially thought of as a consequence of neurodegenerative disease pathology, but more recently it is becoming clear that it plays a significant role in the development and progression of disease. Thus, neuroinflammation is seen as a realistic and valuable therapeutic target for neurodegeneration. Neuroinflammation can be modulated by neuron-glial signaling through various soluble factors, and one such critical modulator is Fractalkine or C-X3-C Motif Chemokine Ligand 1 (CX3CL1). CX3CL1 is produced in neurons and is a unique chemokine that is initially translated as a transmembrane protein but can be proteolytically processed to generate a soluble chemokine. CX3CL1 has been shown to signal through its sole receptor CX3CR1, which is located on microglial cells within the central nervous system (CNS). Although both the membrane bound and soluble forms of CX3CL1 appear to interact with CX3CR1, they do seem to have different signaling capabilities. It is believed that the predominant function of CX3CL1 within the CNS is to reduce the proinflammatory response and many studies have shown neuroprotective effects. However, in some cases CX3CL1 appears to be promoting neurodegeneration. This review focusses on presenting a comprehensive overview of the complex nature of CX3CL1/CX3CR1 signaling in neurodegeneration and how it may present as a therapeutic in some neurodegenerative diseases but not others. The role of CX3CL1/CXCR1 is reviewed in the context of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ischemia, retinopathies, spinal cord and neuropathic pain, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy.}, }
@article {pmid34491551, year = {2022}, author = {Kaliszewska, A and Allison, J and Col, TT and Shaw, C and Arias, N}, title = {Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis.}, journal = {Cerebellum (London, England)}, volume = {21}, number = {4}, pages = {681-714}, pmid = {34491551}, issn = {1473-4230}, support = {PSI2017-83893-R//Ministry of Science and Technology/ ; PID2020-117259RB-I00//Ministry of Science and Technology/ ; PSI2017-90806-REDT//Ministerio de Econom&#xed;a y Competitividad/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Dipeptides/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Humans ; RNA ; }, abstract = {A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely absent from the cerebellum, the pathological hallmarks of RNA foci and dipeptide repeat protein (DPR) inclusions are most abundant. Here, we present a systematic literature search in the databases of PubMed, Scopus, Embase, Web of Science and Science Direct up until March 5, 2021, which yielded 19,515 publications. Following the exclusion criteria, 72 articles were included having referred to C9orf72, synapses and the cerebellum. Meta-analyses were conducted on studies which reported experimental and control groups with means and standard deviations extracted from figures using the online tool PlotDigitizer. This revealed dendritic defects (P = 0.03), reduced C9orf72 in human patients (P = 0.005) and DPR-related neuronal loss (P = 0.0006) but no neuromuscular junction abnormalities (P = 0.29) or cerebellar neuronal loss (P = 0.23). Our results suggest that dendritic arborisation defects, synaptic gene dysregulation and altered synaptic neurotransmission may drive cerebellar synaptic dysfunction in C9-ALS/FTD. In this review, we discuss how the chronological appearance of the different pathological hallmarks alters synaptic integrity which may have profound implications for disease progression. We conclude that a reduction in C9orf72 protein levels combined with the accumulation of RNA foci and DPRs act synergistically to drive C9 synaptopathy in the cerebellum of C9-ALS/FTD patients.}, }
@article {pmid34488599, year = {2022}, author = {Pain, S and Brot, S and Gaillard, A}, title = {Neuroprotective Effects of Neuropeptide Y against Neurodegenerative Disease.}, journal = {Current neuropharmacology}, volume = {20}, number = {9}, pages = {1717-1725}, pmid = {34488599}, issn = {1875-6190}, mesh = {Animals ; Brain/metabolism ; Humans ; *Huntington Disease/metabolism ; Mammals/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuropeptide Y/metabolism ; *Neuroprotective Agents/metabolism/pharmacology/therapeutic use ; }, abstract = {Neuropeptide Y (NPY), a 36 amino acid peptide, is widely expressed in the mammalian brain. Changes in NPY levels in different brain regions and plasma have been described in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Machado-Joseph disease. The changes in NPY levels may reflect the attempt to set up an endogenous neuroprotective mechanism to counteract the degenerative process. Accumulating evidence indicates that NPY can function as an anti-apoptotic, anti-inflammatory, and pro-phagocytic agent, which may be used effectively to halt or to slow down the progression of the disease. In this review, we will focus on the neuroprotective roles of NPY in several neuropathological conditions, with a particular focus on the anti-inflammatory properties of NPY.}, }
@article {pmid34484106, year = {2021}, author = {McKenna, MC and Corcia, P and Couratier, P and Siah, WF and Pradat, PF and Bede, P}, title = {Frontotemporal Pathology in Motor Neuron Disease Phenotypes: Insights From Neuroimaging.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {723450}, pmid = {34484106}, issn = {1664-2295}, abstract = {Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.}, }
@article {pmid34483848, year = {2021}, author = {Guo, C and Ma, YY}, title = {Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders.}, journal = {Frontiers in neural circuits}, volume = {15}, number = {}, pages = {711564}, pmid = {34483848}, issn = {1662-5110}, support = {R01 AA025784/AA/NIAAA NIH HHS/United States ; R01 AG072897/AG/NIA NIH HHS/United States ; R21 NS108128/NS/NINDS NIH HHS/United States ; }, mesh = {*Calcium/metabolism ; Glutamic Acid ; Humans ; *Nervous System Diseases/metabolism ; *Receptors, AMPA/metabolism ; Receptors, Calcium-Sensing ; }, abstract = {Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca[2+] influx-triggered excitotoxicity through Ca[2+]-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.}, }
@article {pmid34481908, year = {2021}, author = {Nishimoto, Y and Nakagawa, S and Okano, H}, title = {NEAT1 lncRNA and amyotrophic lateral sclerosis.}, journal = {Neurochemistry international}, volume = {150}, number = {}, pages = {105175}, doi = {10.1016/j.neuint.2021.105175}, pmid = {34481908}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; C9orf72 Protein/genetics/*metabolism ; Cell Death/physiology ; Cell Nucleus/genetics/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Inflammation Mediators/metabolism ; Motor Neurons/*metabolism/pathology ; RNA, Long Noncoding/genetics/*metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a representative neurological disease that is known to devastate entire motor neurons within a period of just a few years. Discoveries of the specific pathologies of relevant RNA-binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), and the causative genes of both familial and sporadic ALS have provided crucial information that could lead to a cure. In recent ALS research the GGGGCC-repeat expansion in the C9orf72 gene was identified as one of the most important pathological findings, suggesting the significance of both nuclear dysfunction due to dipeptide repeat proteins (DPRs) and RNA toxicity (such as pathological alterations of non-coding RNAs). In research on model animals carrying ALS-related molecules, the determination of whether a factor is protective or toxic has been controversial. Herein, we review the findings regarding NEAT1 RNA and C9orf72 GGGGCC repeats associated with ALS, from the viewpoint of conversion from the protective stage in the nucleus in early-phase ALS to late-phase induction of cell death. This review will provide insights for the development of RNA effectors as novel ALS treatments.}, }
@article {pmid34479020, year = {2021}, author = {Nguyen, TT and Dung Nguyen, TT and Vo, TK and Tran, NM and Nguyen, MK and Van Vo, T and Van Vo, G}, title = {Nanotechnology-based drug delivery for central nervous system disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {143}, number = {}, pages = {112117}, doi = {10.1016/j.biopha.2021.112117}, pmid = {34479020}, issn = {1950-6007}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System Agents/*administration &amp; dosage/chemistry/metabolism ; Central Nervous System Diseases/*drug therapy/metabolism ; *Drug Carriers ; Drug Compounding ; Drug Development ; Drug Discovery ; Humans ; *Nanomedicine ; *Nanoparticles ; Permeability ; Translational Research, Biomedical ; }, abstract = {Drug delivery to central nervous system (CNS) diseases is very challenging since the presence of the innate blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier that impede drug delivery. Among new strategies to overcome these limitations and successfully deliver drugs to the CNS, nanotechnology-based drug delivery platform, offers potential therapeutic approach for the treatment of some common neurological disorders like Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease. This review aimed to highlight advances in research on the development of nano-based therapeutics for their implications in therapy of CNS disorders. The challenges during clinical translation of nanomedicine from bench to bed side is also discussed.}, }
@article {pmid34472461, year = {2022}, author = {Rey, F and Ottolenghi, S and Zuccotti, GV and Samaja, M and Carelli, S}, title = {Mitochondrial dysfunctions in neurodegenerative diseases: role in disease pathogenesis, strategies for analysis and therapeutic prospects.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {754-758}, pmid = {34472461}, issn = {1673-5374}, abstract = {Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes, the mitochondria are required for multiple pivotal processes that include the production of biological energy, the biosynthesis of reactive oxygen species, the control of calcium homeostasis, and the triggering of cell death. The disruption of anyone of these processes has been shown to impact strongly the function of all cells, but especially of neurons. In this review, we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis, Parkinson's disease and Alzheimer's disease. We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle: fusion, fission, production of reactive oxygen species and energy failure. Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes. Therefore, in order to get in depth insights into their health status in neurodegenerative diseases, we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes. Current techniques include Mitostress, Mitotracker, transmission electron microscopy, oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health. We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction. These include canonical drugs, natural compounds, supplements, lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy. In conclusion, because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases, it is critical to develop novel methods to measure the mitochondrial state, and novel therapeutic strategies aimed at improving their health.}, }
@article {pmid34472458, year = {2022}, author = {Martinez, B and Peplow, PV}, title = {MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {728-740}, pmid = {34472458}, issn = {1673-5374}, abstract = {A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals.}, }
@article {pmid34472454, year = {2022}, author = {Ritala, JF and Lyne, SB and Sajanti, A and Girard, R and Koskimäki, J}, title = {Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {701-704}, pmid = {34472454}, issn = {1673-5374}, abstract = {The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75[NTR]) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75[NTR] in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75[NTR] for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level.}, }
@article {pmid34469619, year = {2022}, author = {Hartmann, H and Ho, WY and Chang, JC and Ling, SC}, title = {Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon?.}, journal = {The FEBS journal}, volume = {289}, number = {24}, pages = {7688-7709}, doi = {10.1111/febs.16175}, pmid = {34469619}, issn = {1742-4658}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Central Nervous System/metabolism ; Cholesterol ; Blood-Brain Barrier/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease, is characterized by the selective degeneration of motor neurons leading to paralysis and eventual death. Multiple pathogenic mechanisms, including systemic dysmetabolism, have been proposed to contribute to ALS. Among them, dyslipidemia, i.e., abnormal level of cholesterol and other lipids in the circulation and central nervous system (CNS), has been reported in ALS patients, but without a consensus. Cholesterol is a constituent of cellular membranes and a precursor of steroid hormones, oxysterols, and bile acids. Consequently, optimal cholesterol levels are essential for health. Due to the blood-brain barrier (BBB), cholesterol cannot move between the CNS and the rest of the body. As such, cholesterol metabolism in the CNS is proposed to operate autonomously. Despite its importance, it remains elusive how cholesterol dyshomeostasis may contribute to ALS. In this review, we aim to describe the current state of cholesterol metabolism research in ALS, identify unresolved issues, and provide potential directions.}, }
@article {pmid34464655, year = {2022}, author = {Odeh, HM and Fare, CM and Shorter, J}, title = {Nuclear-Import Receptors Counter Deleterious Phase Transitions in Neurodegenerative Disease.}, journal = {Journal of molecular biology}, volume = {434}, number = {1}, pages = {167220}, pmid = {34464655}, issn = {1089-8638}, support = {R21 NS090205/NS/NINDS NIH HHS/United States ; F31 NS111870/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 AG061784/AG/NIA NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Phase Transition ; Protein Aggregation, Pathological ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism ; }, abstract = {Nuclear-import receptors (NIRs) engage nuclear-localization signals (NLSs) of polypeptides in the cytoplasm and transport these cargo across the size-selective barrier of the nuclear-pore complex into the nucleoplasm. Beyond this canonical role in nuclear transport, NIRs operate in the cytoplasm to chaperone and disaggregate NLS-bearing clients. Indeed, NIRs can inhibit and reverse functional and deleterious phase transitions of their cargo, including several prominent neurodegenerative disease-linked RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as TDP-43, FUS, EWSR1, TAF15, hnRNPA1, and hnRNPA2. Importantly, elevated NIR expression can mitigate degenerative phenotypes connected to aberrant cytoplasmic aggregation of RBPs with PrLDs. Here, we review recent discoveries that NIRs can also antagonize aberrant interactions and toxicity of arginine-rich, dipeptide-repeat proteins that are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by G4C2 hexanucleotide repeat expansions in the first intron of C9ORF72. We also highlight recent findings that multiple NIR family members can prevent and reverse liquid-liquid phase separation of specific clients bearing RGG motifs in an NLS-independent manner. Finally, we discuss strategies to enhance NIR activity or expression, which could have therapeutic utility for several neurodegenerative disorders, including ALS, FTD, multisystem proteinopathy, limbic-predominant age-related TDP-43 encephalopathy, tauopathies, and related diseases.}, }
@article {pmid34458829, year = {2021}, author = {Francois-Moutal, L and Scott, DD and Khanna, M}, title = {Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape.}, journal = {RSC chemical biology}, volume = {2}, number = {4}, pages = {1158-1166}, pmid = {34458829}, issn = {2633-0679}, abstract = {Tar DNA binding (TDP)-43 proteinopathy, typically described as cytoplasmic accumulation of highly modified and misfolded TDP-43 molecules, is characteristic of several neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 proposed proteinopathies include homeostatic imbalance between nuclear and cytoplasmic localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and an increase in protein truncation of cytoplasmic TDP-43. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Antibodies, peptides and compounds have been designed or found to recognize specific TDP-43 sequences but alleviate TDP-43 toxicity through different mechanisms. While two antibodies described here were able to induce degradation of pathological TDP-43, the peptides and small molecules were primarily designed to reduce aggregation of TDP-43. Furthermore, we discuss promising emerging therapeutic targets.}, }
@article {pmid34458253, year = {2021}, author = {Murk, K and Ornaghi, M and Schiweck, J}, title = {Profilin Isoforms in Health and Disease - All the Same but Different.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {681122}, pmid = {34458253}, issn = {2296-634X}, abstract = {Profilins are small actin binding proteins, which are structurally conserved throughout evolution. They are probably best known to promote and direct actin polymerization. However, they also participate in numerous cell biological processes beyond the roles typically ascribed to the actin cytoskeleton. Moreover, most complex organisms express several profilin isoforms. Their cellular functions are far from being understood, whereas a growing number of publications indicate that profilin isoforms are involved in the pathogenesis of various diseases. In this review, we will provide an overview of the profilin family and "typical" profilin properties including the control of actin dynamics. We will then discuss the profilin isoforms of higher animals in detail. In terms of cellular functions, we will focus on the role of Profilin 1 (PFN1) and Profilin 2a (PFN2a), which are co-expressed in the central nervous system. Finally, we will discuss recent findings that link PFN1 and PFN2a to neurological diseases, such as amyotrophic lateral sclerosis (ALS), Fragile X syndrome (FXS), Huntington's disease and spinal muscular atrophy (SMA).}, }
@article {pmid34445429, year = {2021}, author = {Sini, P and Dang, TBC and Fais, M and Galioto, M and Padedda, BM and Lugliè, A and Iaccarino, C and Crosio, C}, title = {Cyanobacteria, Cyanotoxins, and Neurodegenerative Diseases: Dangerous Liaisons.}, journal = {International journal of molecular sciences}, volume = {22}, number = {16}, pages = {}, pmid = {34445429}, issn = {1422-0067}, support = {2018-1-IT02-KA107-047494//Erasmus+/ ; CCI2014IT16M2OP005//PON/ ; Fondo di Ateneo per la Ricerca 2019-Crosio//UNISS/ ; Fondo di Ateneo per la Ricerca 2019-Iaccarino//UNISS/ ; Bando 2017- Iaccarino//Fondazione di Sardegna/ ; }, mesh = {Animals ; Bacterial Toxins/*toxicity ; Cyanobacteria/metabolism/*pathogenicity ; Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*etiology/genetics/microbiology ; }, abstract = {The prevalence of neurodegenerative disease (ND) is increasing, partly owing to extensions in lifespan, with a larger percentage of members living to an older age, but the ND aetiology and pathogenesis are not fully understood, and effective treatments are still lacking. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are generally thought to progress as a consequence of genetic susceptibility and environmental influences. Up to now, several environmental triggers have been associated with NDs, and recent studies suggest that some cyanotoxins, produced by cyanobacteria and acting through a variety of molecular mechanisms, are highly neurotoxic, although their roles in neuropathy and particularly in NDs are still controversial. In this review, we summarize the most relevant and recent evidence that points at cyanotoxins as environmental triggers in NDs development.}, }
@article {pmid34443678, year = {2021}, author = {Koike, H and Iguchi, Y and Sahashi, K and Katsuno, M}, title = {Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {16}, pages = {}, pmid = {34443678}, issn = {1420-3049}, support = {20FC1022//The Ministry of Health, Labor and Welfare of Japan/ ; }, mesh = {Amyloid/*metabolism ; Amyloidosis/*physiopathology/*therapy ; Animals ; Humans ; Organ Specificity ; Protein Aggregates ; Schwann Cells/pathology ; }, abstract = {Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer's disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer's disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.}, }
@article {pmid34441299, year = {2021}, author = {Jankovska, N and Matej, R}, title = {Molecular Pathology of ALS: What We Currently Know and What Important Information Is Still Missing.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {34441299}, issn = {2075-4418}, support = {00064165//MH CZ - DRO: Conceptual Development of Research Organization, the General University Hospital, Prague/ ; 00064190//MH CZ - DRO: Conceptual Development of Research Organization, the Thomayer University Hospital, Prague/ ; NV19-04-00090//the Grants Agency of the Ministry of Health/ ; NV18-04-00179//the Grants Agency of the Ministry of Health/ ; GAUK 142120//Univerzita Karlova v Praze/ ; Project Progress Q27/LF1//Univerzita Karlova v Praze/ ; }, abstract = {Despite an early understanding of amyotrophic lateral sclerosis (ALS) as a disease affecting the motor system, including motoneurons in the motor cortex, brainstem, and spinal cord, today, many cases involving dementia and behavioral disorders are reported. Therefore, we currently divide ALS not only based on genetic predisposition into the most common sporadic variant (90% of cases) and the familial variant (10%), but also based on cognitive and/or behavioral symptoms, with five specific subgroups of clinical manifestation-ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, the fully developed behavioral variant of frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer's disease (AD). Generally, these cases are referred to as amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD). Clinical behaviors and the presence of the same pathognomonic deposits suggest that FTLD and ALS could be a continuum of one entity. This review was designed primarily to compare neuropathological findings in different types of ALS relative to their characteristic locations as well as the immunoreactivity of the inclusions, and thus, foster a better understanding of the immunoreactivity, distribution, and morphology of the pathological deposits in relation to genetic mutations, which can be useful in specifying the final diagnosis.}, }
@article {pmid34440761, year = {2021}, author = {Bonaventura, G and Munafò, A and Bellanca, CM and La Cognata, V and Iemmolo, R and Attaguile, GA and Di Mauro, R and Di Benedetto, G and Cantarella, G and Barcellona, ML and Cavallaro, S and Bernardini, R}, title = {Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440761}, issn = {2073-4409}, mesh = {Alzheimer Disease/metabolism/pathology/physiopathology/surgery ; Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology/surgery ; Animals ; Central Nervous System/immunology/metabolism/pathology/*physiopathology ; Humans ; *Nerve Degeneration ; *Nerve Regeneration ; Neural Stem Cells/immunology/metabolism/*transplantation ; Neurodegenerative Diseases/metabolism/pathology/physiopathology/*surgery ; Neuroimmunomodulation ; Parkinson Disease/metabolism/pathology/physiopathology/surgery ; Phenotype ; Recovery of Function ; *Stem Cell Transplantation/adverse effects ; }, abstract = {Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease).}, }
@article {pmid34440645, year = {2021}, author = {Cen, X and Zhang, M and Zhou, M and Ye, L and Xia, H}, title = {Mitophagy Regulates Neurodegenerative Diseases.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440645}, issn = {2073-4409}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Humans ; Mitochondria/metabolism/*pathology ; *Mitophagy ; *Nerve Degeneration ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; Signal Transduction ; }, abstract = {Mitochondria play an essential role in supplying energy for the health and survival of neurons. Mitophagy is a metabolic process that removes dysfunctional or redundant mitochondria. This process preserves mitochondrial health. However, defective mitophagy triggers the accumulation of damaged mitochondria, causing major neurodegenerative disorders. This review introduces molecular mechanisms and signaling pathways behind mitophagy regulation. Furthermore, we focus on the recent advances in understanding the potential role of mitophagy in the pathogenesis of major neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's, etc.) and aging. The findings will help identify the potential interventions of mitophagy regulation and treatment strategies of neurodegenerative diseases.}, }
@article {pmid34440634, year = {2021}, author = {Borgese, N and Iacomino, N and Colombo, SF and Navone, F}, title = {The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440634}, issn = {2073-4409}, support = {Fondazione Regionale per la Ricerca Biomedica [TRANS-ALS grant no. 2015-0023].//Regione Lombardia/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Genetic Predisposition to Disease ; Haploinsufficiency ; Humans ; *Mutation ; Neurons/*metabolism/pathology ; Phenotype ; Risk Factors ; Signal Transduction ; Vesicular Transport Proteins/*genetics/metabolism ; }, abstract = {The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca[2+] signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.}, }
@article {pmid34440231, year = {2021}, author = {Mori, A and Cross, B and Uchida, S and Kerrick Walker, J and Ristuccia, R}, title = {How Are Adenosine and Adenosine A2A Receptors Involved in the Pathophysiology of Amyotrophic Lateral Sclerosis?.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440231}, issn = {2227-9059}, support = {n/a//Kyowa Kirin/ ; }, abstract = {Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson's disease, and there is now growing interest in its role in amyotrophic lateral sclerosis (ALS). The motor neurons affected in ALS are responsive to adenosine receptor function, and there is accumulating evidence for beneficial effects of adenosine A2A receptor antagonism. In this article, we focus on recent evidence from ALS clinical pathology and animal models that support dynamism of the adenosinergic system (including changes in adenosine levels and receptor changes) in ALS. We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, potential biomarkers and the acute symptomatic pharmacology, including respiratory motor neuron control, of A2A receptor antagonism to explore the potential of the A2A receptor as target for ALS therapy.}, }
@article {pmid34440204, year = {2021}, author = {Obrador, E and Salvador-Palmer, R and López-Blanch, R and Dellinger, RW and Estrela, JM}, title = {NAD[+] Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440204}, issn = {2227-9059}, support = {OTR2018-19337INVES//University of Valencia and Elysium Health Inc./ ; OTR2017-18255INVES//University of Valencia and Elysium Health Inc./ ; }, abstract = {Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD[+]-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD[+] generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.}, }
@article {pmid34440173, year = {2021}, author = {Sahana, TG and Zhang, K}, title = {Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440173}, issn = {2227-9059}, support = {R01 NS117461/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates.}, }
@article {pmid34439911, year = {2021}, author = {Barp, A and Ferrero, A and Casagrande, S and Morini, R and Zuccarino, R}, title = {Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New.}, journal = {Biomolecules}, volume = {11}, number = {8}, pages = {}, pmid = {34439911}, issn = {2218-273X}, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Animals ; Antibodies/chemistry ; Biomarkers/*blood ; Creatine Kinase/*metabolism ; Disease Progression ; Humans ; Intermediate Filaments/chemistry/metabolism ; Mice ; MicroRNAs/metabolism ; Models, Biological ; Motor Neuron Disease/metabolism ; Muscular Dystrophy, Duchenne/*blood ; Neuromuscular Diseases ; Reproducibility of Results ; }, abstract = {The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less "time-consuming". In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers.}, }
@article {pmid34439577, year = {2021}, author = {Menon, P and Vucic, S}, title = {The Upper Motor Neuron-Improved Knowledge from ALS and Related Clinical Disorders.}, journal = {Brain sciences}, volume = {11}, number = {8}, pages = {}, pmid = {34439577}, issn = {2076-3425}, support = {GNT1123026//National Health and Medical Research Council/ ; }, abstract = {Upper motor neuron (UMN) is a term traditionally used for the corticospinal or pyramidal tract neuron synapsing with the lower motor neuron (LMN) in the anterior horns of the spinal cord. The upper motor neuron controls resting muscle tone and helps initiate voluntary movement of the musculoskeletal system by pathways which are not completely understood. Dysfunction of the upper motor neuron causes the classical clinical signs of spasticity, weakness, brisk tendon reflexes and extensor plantar response, which are associated with clinically well-recognised, inherited and acquired disorders of the nervous system. Understanding the pathophysiology of motor system dysfunction in neurological disease has helped promote a greater understanding of the motor system and its complex cortical connections. This review will focus on the pathophysiology underlying progressive dysfunction of the UMN in amyotrophic lateral sclerosis and three other related adult-onset, progressive neurological disorders with prominent UMN signs, namely, primary lateral sclerosis, hereditary spastic paraplegia and primary progressive multiple sclerosis, to help promote better understanding of the human motor system and, by extension, related cortical systems.}, }
@article {pmid34439576, year = {2021}, author = {Novak, V and Rogelj, B and Župunski, V}, title = {Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439576}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.}, }
@article {pmid34436458, year = {2021}, author = {Renzini, A and Riera, CS and Minic, I and D'Ercole, C and Lozanoska-Ochser, B and Cedola, A and Gigli, G and Moresi, V and Madaro, L}, title = {Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target.}, journal = {Metabolites}, volume = {11}, number = {8}, pages = {}, pmid = {34436458}, issn = {2218-1989}, support = {2020//Sapienza Universit&#xe0; di Roma/ ; XX//FUNDACION ONCE/ ; 2019//French Muscular Dystrophy Association/ ; 2019//Roche Italia/ ; }, abstract = {Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions.}, }
@article {pmid34435242, year = {2021}, author = {Düzel, E and Costagli, M and Donatelli, G and Speck, O and Cosottini, M}, title = {Studying Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis with 7-T magnetic resonance.}, journal = {European radiology experimental}, volume = {5}, number = {1}, pages = {36}, pmid = {34435242}, issn = {2509-9280}, mesh = {*Alzheimer Disease/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; *Parkinson Disease/diagnostic imaging ; }, abstract = {Ultra-high-field (UHF) magnetic resonance (MR) scanners, that is, equipment operating at static magnetic field of 7 tesla (7 T) and above, enable the acquisition of data with greatly improved signal-to-noise ratio with respect to conventional MR systems (e.g., scanners operating at 1.5 T and 3 T). The change in tissue relaxation times at UHF offers the opportunity to improve tissue contrast and depict features that were previously inaccessible. These potential advantages come, however, at a cost: in the majority of UHF-MR clinical protocols, potential drawbacks may include signal inhomogeneity, geometrical distortions, artifacts introduced by patient respiration, cardiac cycle, and motion. This article reviews the 7 T MR literature reporting the recent studies on the most widespread neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid34434087, year = {2021}, author = {Tejido, C and Pakravan, D and Bosch, LVD}, title = {Potential Therapeutic Role of HDAC Inhibitors in FUS-ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {686995}, pmid = {34434087}, issn = {1662-5099}, abstract = {Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). However, the exact pathogenic mechanism of mutant fused in sarcoma (FUS) protein is not completely understood. FUS is an RNA binding protein (RBP) localized predominantly in the nucleus, but ALS-linked FUS mutations can affect its nuclear localization signal impairing its import into the nucleus. This mislocalization to the cytoplasm facilitates FUS aggregation in cytoplasmic inclusions. Therapies targeting post translational modifications are rising as new treatments for ALS, in particular acetylation which could have a role in the dynamics of RBPs. Research using histone deacetylase (HDAC) inhibitors in FUS-ALS models showed that HDACs can influence cytoplasmic FUS localization. Inhibition of HDACs could promote acetylation of the FUS RNA binding domain (RRM) and altering its RNA interactions resulting in FUS maintenance in the nucleus. In addition, acetylation of FUS RRMs might also favor or disfavor its incorporation into pathological inclusions. In this review, we summarize and discuss the evidence for the potential role of HDACs in the context of FUS-ALS and we propose a new hypothesis based on this overview.}, }
@article {pmid34432256, year = {2022}, author = {Shan, L and Martens, GJM and Swaab, DF}, title = {Histamine-4 Receptor: Emerging Target for the Treatment of Neurological Diseases.}, journal = {Current topics in behavioral neurosciences}, volume = {59}, number = {}, pages = {131-145}, pmid = {34432256}, issn = {1866-3370}, mesh = {Animals ; Anti-Inflammatory Agents ; Genome-Wide Association Study ; *Histamine ; Histamine Antagonists/therapeutic use ; Humans ; *Neurodegenerative Diseases ; Receptors, Histamine/genetics ; }, abstract = {A major challenge in the field of the biogenic amine histamine is the search for new-generation histamine receptor specific drugs. Daniel Bovet and Sir James Black received their Nobel Prizes for Medicine for their work on histamine-1 receptor (H1R) and H2R antagonists to treat allergies and gastrointestinal disorders. The first H3R-targeting drug to reach the market was approved for the treatment of the neurological disorder narcolepsy in 2018. The antagonists for the most recently identified histamine receptor, H4R, are currently under clinical evaluation for their potential therapeutic effects on inflammatory diseases such as atopic dermatitis and pruritus. In this chapter, we propose that H4R antagonists are endowed with prominent anti-inflammatory and immune effects, including in the brain. To substantiate this proposition, we combine data from transcriptional analyses of postmortem human neurodegenerative disease brain samples, human genome-wide association studies (GWAS), and translational animal model studies. The results prompt us to suggest the potential involvement of the H4R in various neurodegenerative diseases and how manipulating the H4R may create new therapeutic opportunities in central nervous system diseases.}, }
@article {pmid34429642, year = {2021}, author = {Hannaford, A and Vucic, S and Kiernan, MC and Simon, NG}, title = {Review Article "Spotlight on Ultrasonography in the Diagnosis of Peripheral Nerve Disease: The Evidence to Date".}, journal = {International journal of general medicine}, volume = {14}, number = {}, pages = {4579-4604}, pmid = {34429642}, issn = {1178-7074}, abstract = {Neuromuscular ultrasound is rapidly becoming incorporated into clinical practice as a standard tool in the assessment of peripheral nerve diseases. Ultrasound complements clinical phenotyping and electrodiagnostic evaluation, providing critical structural anatomical information to enhance diagnosis and identify structural pathology. This review article examines the evidence supporting neuromuscular ultrasound in the diagnosis of compressive mononeuropathies, traumatic nerve injury, generalised peripheral neuropathy and motor neuron disease. Extending the sonographic evaluation of nerves beyond simple morphological measurements has the potential to improve diagnostics in peripheral neuropathy, as well as advancing the understanding of pathological mechanisms, which in turn will promote precise therapies and improve therapeutic outcomes.}, }
@article {pmid34422879, year = {2021}, author = {Milošević, M and Arsić, A and Cvetković, Z and Vučić, V}, title = {Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition.}, journal = {Frontiers in nutrition}, volume = {8}, number = {}, pages = {688086}, pmid = {34422879}, issn = {2296-861X}, abstract = {Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome-brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.}, }
@article {pmid34419715, year = {2021}, author = {Sharma, S and Modi, P and Sharma, G and Deep, S}, title = {Kinetics theories to understand the mechanism of aggregation of a protein and to design strategies for its inhibition.}, journal = {Biophysical chemistry}, volume = {278}, number = {}, pages = {106665}, doi = {10.1016/j.bpc.2021.106665}, pmid = {34419715}, issn = {1873-4200}, mesh = {*Amyloid/chemistry ; Kinetics ; Peptides/chemistry ; *Protein Aggregates ; Thermodynamics ; }, abstract = {Protein aggregation phenomenon is closely related to the formation of amyloids which results in many neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis. In order to prevent and treat these diseases, a clear understanding of the mechanism of misfolding and self-assembly of peptides and proteins is very crucial. The aggregation of a protein may involve various microscopic events. Multiple simulations utilizing the solutions of the master equation have given a better understanding of the kinetic profiles involved in the presence and absence of a particular microscopic event. This review focuses on understanding the contribution of these molecular events to protein aggregation based on the analysis of kinetic profiles of aggregation. We also discuss the effect of inhibitors, which target various species of aggregation pathways, on the kinetic profile of protein aggregation. At the end of this review, some strategies for the inhibition of aggregation that can be utilized by combining the chemical kinetics approach with thermodynamics are proposed.}, }
@article {pmid34415015, year = {2021}, author = {Katzeff, JS and Kim, WS}, title = {ATP-binding cassette transporters and neurodegenerative diseases.}, journal = {Essays in biochemistry}, volume = {65}, number = {7}, pages = {1013-1024}, doi = {10.1042/EBC20210012}, pmid = {34415015}, issn = {1744-1358}, mesh = {ATP-Binding Cassette Transporters/chemistry/metabolism ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/genetics ; Brain/metabolism ; Humans ; *Neurodegenerative Diseases ; }, abstract = {ATP-binding cassette (ABC) transporters are one of the largest groups of transporter families in humans. ABC transporters mediate the translocation of a diverse range of substrates across cellular membranes, including amino acids, nucleosides, lipids, sugars and xenobiotics. Neurodegenerative diseases are a group of brain diseases that detrimentally affect neurons and other brain cells and are usually associated with deposits of pathogenic proteins in the brain. Major neurodegenerative diseases include Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. ABC transporters are highly expressed in the brain and have been implicated in a number of pathological processes underlying neurodegenerative diseases. This review outlines the current understanding of the role of ABC transporters in neurodegenerative diseases, focusing on some of the most important pathways, and also suggests future directions for research in this field.}, }
@article {pmid34414870, year = {2022}, author = {Belkozhayev, AM and Al-Yozbaki, M and George, A and Ye Niyazova, R and Sharipov, KO and Byrne, LJ and Wilson, CM}, title = {Extracellular Vesicles, Stem Cells and the Role of miRNAs in Neurodegeneration.}, journal = {Current neuropharmacology}, volume = {20}, number = {8}, pages = {1450-1478}, pmid = {34414870}, issn = {1875-6190}, mesh = {*Extracellular Vesicles/metabolism ; Humans ; *Mesenchymal Stem Cells ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Prion Diseases/metabolism ; }, abstract = {There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington's disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.}, }
@article {pmid34402459, year = {2021}, author = {Appel, SH and Beers, DR and Zhao, W}, title = {Amyotrophic lateral sclerosis is a systemic disease: peripheral contributions to inflammation-mediated neurodegeneration.}, journal = {Current opinion in neurology}, volume = {34}, number = {5}, pages = {765-772}, doi = {10.1097/WCO.0000000000000983}, pmid = {34402459}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Cytokines ; Humans ; Inflammation ; Motor Neurons ; Neuroinflammatory Diseases ; }, abstract = {PURPOSE OF REVIEW: Neuroinflammation is an important mediator of the pathogenesis of disease in amyotrophic lateral sclerosis (ALS). Genetic mutations such as C9orf72 have begun to define the numerous cell autonomous pathways that initiate motor neuron injury. Yet, it is the signalling to surrounding glia and peripherally derived immune cells that initiates the noncell autonomous inflammatory process and promotes self-propagating motor neuron cell death. The purpose of this review is to explore the systemic immune/inflammatory contributions to the pathogenesis of ALS: what are the peripheral pro-inflammatory signatures, what initiates their presence and do they represent potential therapeutic targets.<br><br>RECENT FINDINGS: In ALS, motor neuron cell death is initiated by multiple cell autonomous pathways leading to misfolded proteins, oxidative stress, altered mitochondria, impaired autophagy and altered RNA metabolism, which collectively promote noncell autonomous inflammatory reactivity. The resulting disease is characterized by activated microglia and astrocytes as well as peripherally derived pro-inflammatory innate and adaptive immune cells. In this unrelenting disorder, circulating blood monocytes and natural killer cells are pro-inflammatory. Furthermore, regulatory T lymphocytes are dysfunctional, and pro-inflammatory cytokines and acute phase proteins are elevated.<br><br>SUMMARY: The collective dysregulation of cells and cytokines in patients with ALS accurately reflect increased disease burdens, more rapid progression rates and reduced survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses. These increased systemic pro-inflammatory immune constituents provide potentially meaningful therapeutic targets.}, }
@article {pmid34400291, year = {2021}, author = {Oli, V and Gupta, R and Kumar, P}, title = {FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders.}, journal = {Journal of chemical neuroanatomy}, volume = {116}, number = {}, pages = {102012}, doi = {10.1016/j.jchemneu.2021.102012}, pmid = {34400291}, issn = {1873-6300}, mesh = {Animals ; Forkhead Box Protein O1/*metabolism ; Forkhead Transcription Factors/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Neurons/*metabolism/pathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others, are characterized by progressive loss of neuronal cells, which causes memory impairment and cognitive decline. Mounting evidence demonstrated the possible implications of diverse biological processes, namely oxidative stress, mitochondrial dysfunction, aberrant cell cycle re-entry, post-translational modifications, protein aggregation, impaired proteasome dysfunction, autophagy, and many others that cause neuronal cell death. The condition worsens as there is no effective treatment for such diseases due to their complex pathogenesis and mechanism. Mounting evidence demonstrated the role of regulatory transcription factors, such as NFκβ, FoxO, Myc, CREB, and others that regulate the biological processes and diminish the disease progression and pathogenesis. Studies demonstrated that forkhead box O (FoxO) transcription factors had been implicated in the regulation of aging and longevity. Further, the functions of FoxO proteins are regulated by different post-translational modifications (PTMs), namely acetylation, and ubiquitination. Various studies concluded that FoxO proteins exert both neuroprotective and neurotoxic properties depending on their regulation mechanism and activity in the brain. Thus, understanding the nature of FoxO expression and activity in the brain will help develop effective therapeutic strategies. Herein, firstly, we discuss the role of FoxO protein in cell cycle regulation and cell proliferation, followed by the regulation of FoxO proteins through acetylation and ubiquitination. We also briefly explain the activity and expression pattern of FoxO proteins in the neuronal cells and explain the mechanism through which FoxO proteins are rescued from oxidative stress-induced neurotoxicity. Later on, we present a detailed view of the implication of FoxO proteins in neurodegenerative disease and FoxO proteins as an effective therapeutic target.}, }
@article {pmid34399235, year = {2021}, author = {Lim, D and Dematteis, G and Tapella, L and Genazzani, AA and Calì, T and Brini, M and Verkhratsky, A}, title = {Ca[2+] handling at the mitochondria-ER contact sites in neurodegeneration.}, journal = {Cell calcium}, volume = {98}, number = {}, pages = {102453}, doi = {10.1016/j.ceca.2021.102453}, pmid = {34399235}, issn = {1532-1991}, mesh = {Apoptosis ; Calcium/metabolism ; *Endoplasmic Reticulum/metabolism ; Mitochondria ; *Mitochondrial Membranes ; }, abstract = {Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are morpho-functional units, formed at the loci of close apposition of the ER-forming endomembrane and outer mitochondrial membrane (OMM). These sites contribute to fundamental cellular processes including lipid biosynthesis, autophagy, apoptosis, ER-stress and calcium (Ca[2+]) signalling. At MERCS, Ca[2+] ions are transferred from the ER directly to mitochondria through a core protein complex composed of inositol-1,4,5 trisphosphate receptor (InsP3R), voltage-gated anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU) and adaptor protein glucose-regulated protein 75 (Grp75); this complex is regulated by several associated proteins. Deregulation of ER-mitochondria Ca[2+] transfer contributes to pathogenesis of neurodegenerative and other diseases. The efficacy of Ca[2+] transfer between ER and mitochondria depends on the protein composition of MERCS, which controls ER-mitochondria interaction regulating, for example, the transversal distance between ER membrane and OMM and the extension of the longitudinal interface between ER and mitochondria. These parameters are altered in neurodegeneration. Here we overview the ER and mitochondrial Ca[2+] homeostasis, the composition of ER-mitochondrial Ca[2+] transfer machinery and alterations of the ER-mitochondria Ca[2+] transfer in three major neurodegenerative diseases: motor neurone diseases, Parkinson disease and Alzheimer's disease.}, }
@article {pmid34392931, year = {2021}, author = {Tedeschi, V and Petrozziello, T and Secondo, A}, title = {Ca[2+] dysregulation in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {International review of cell and molecular biology}, volume = {363}, number = {}, pages = {21-47}, doi = {10.1016/bs.ircmb.2021.02.014}, pmid = {34392931}, issn = {1937-6448}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; Calcium/*metabolism ; Endoplasmic Reticulum/metabolism ; Homeostasis ; Humans ; Lysosomes/metabolism ; Mitochondria/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease without appropriate cure. One of the main reasons for the lack of a proper pharmacotherapy in ALS is the narrow knowledge on the molecular causes of the disease. In this respect, the identification of dysfunctional pathways in ALS is now considered a critical medical need. Among the causative factors involved in ALS, Ca[2+] dysregulation is one of the most important pathogenetic mechanisms of the disease. Of note, Ca[2+] dysfunction may induce, directly or indirectly, motor neuron degeneration and loss. Interestingly, both familial (fALS) and sporadic ALS (sALS) share the progressive dysregulation of Ca[2+] homeostasis as a common noxious mechanism. Mechanicistically, Ca[2+] dysfunction involves both plasma membrane and intracellular mechanisms, including AMPA receptor (AMPAR)-mediated excitotoxicity, voltage-gated Ca[2+] channels (VGCCs) and Ca[2+] transporter dysregulation, endoplasmic reticulum (ER) Ca[2+] deregulation, mitochondria-associated ER membranes (MAMs) dysfunction, lysosomal Ca[2+] leak, etc. Here, a comprehensive analysis of the main pathways involved in the dysregulation of Ca[2+] homeostasis has been reported with the aim to focus the attention on new putative druggable targets.}, }
@article {pmid34392299, year = {2021}, author = {Hautbergue, GM and Cleary, JD and Guo, S and Ranum, LPW}, title = {Therapeutic strategies for C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Current opinion in neurology}, volume = {34}, number = {5}, pages = {748-755}, pmid = {34392299}, issn = {1473-6551}, support = {R37 NS040389/NS/NINDS NIH HHS/United States ; MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; P01 NS058901/NS/NINDS NIH HHS/United States ; R01 NS098819/NS/NINDS NIH HHS/United States ; R01 NS117910/NS/NINDS NIH HHS/United States ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/therapy ; Humans ; Proteins ; Stress Granules ; }, abstract = {PURPOSE OF REVIEW: An intronic G4C2 expansion mutation in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Although there are currently no treatments for this insidious, fatal disease, intense research has led to promising therapeutic strategies, which will be discussed here.<br><br>RECENT FINDINGS: Therapeutic strategies for C9-ALS/FTD have primarily focused on reducing the toxic effects of mutant expansion RNAs or the dipeptide repeat proteins (DPRs). The pathogenic effects of G4C2 expansion transcripts have been targeted using approaches aimed at promoting their degradation, inhibiting nuclear export or silencing transcription. Other promising strategies include immunotherapy to reduce the DPRs themselves, reducing RAN translation, removing the repeats using DNA or RNA editing and manipulation of downstream disease-altered stress granule pathways. Finally, understanding the molecular triggers that lead to pheno-conversion may lead to opportunities that can delay symptomatic disease onset.<br><br>SUMMARY: A large body of evidence implicates RAN-translated DPRs as a main driver of C9-ALS/FTD. Promising therapeutic strategies for these devastating diseases are being rapidly developed with several approaches already in or approaching clinical trials.}, }
@article {pmid34391870, year = {2021}, author = {Eisen, A and Lemon, R}, title = {The motor deficit of ALS reflects failure to generate muscle synergies for complex motor tasks, not just muscle strength.}, journal = {Neuroscience letters}, volume = {762}, number = {}, pages = {136171}, doi = {10.1016/j.neulet.2021.136171}, pmid = {34391870}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Humans ; Motor Skills/*physiology ; Muscle Strength/*physiology ; Muscle Weakness/physiopathology ; Muscle, Skeletal/*physiopathology ; Neural Pathways/physiopathology ; }, abstract = {Customarily the motor deficits that develop in ALS are considered in terms of muscle weakness. Functional rating scales used to assess ALS in terms of functional decline do not measure the deficits when performing complex motor tasks, that make up the human skilled motor repertoire, best exemplified by tasks requiring skilled hand and finger movement. This repertoire depends primarily upon the strength of direct corticomotoneuronal (CM) connectivity from primary motor cortex to the motor units subserving skilled movements. Our review prompts the question: if accumulating evidence suggests involvement of the CM system in the early stages of ALS, what kinds of motor deficit might be expected to result, and is current methodology able to identify such deficits? We point out that the CM system is organized not in "commands" to individual muscles, but rather encodes the building blocks of complex and intricate movements, which depend upon synergy between not only the prime mover muscles, but other muscles that stabilize the limb during skilled movement. Our knowledge of the functional organization of the CM system has come both from invasive studies in non-human primates and from advanced imaging and neurophysiological techniques in humans, some of which are now being applied in ALS. CM pathology in ALS has consequences not only for muscle strength, but importantly in the failure to generate complex motor tasks, often involving elaborate muscle synergies. Our aim is to encourage innovative methodology specifically directed to assessing complex motor tasks, failure of which is likely a very early clinical deficit in ALS.}, }
@article {pmid34388383, year = {2021}, author = {Rao, PPN and Shakeri, A and Zhao, Y and Calon, F}, title = {Strategies in the design and development of (TAR) DNA-binding protein 43 (TDP-43) binding ligands.}, journal = {European journal of medicinal chemistry}, volume = {225}, number = {}, pages = {113753}, doi = {10.1016/j.ejmech.2021.113753}, pmid = {34388383}, issn = {1768-3254}, mesh = {Animals ; DNA-Binding Proteins/*antagonists &amp; inhibitors/chemistry/metabolism ; *Drug Development ; Humans ; Ligands ; Molecular Structure ; Oligonucleotides/chemical synthesis/chemistry/*pharmacology ; Peptides/chemical synthesis/chemistry/*pharmacology ; Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology ; }, abstract = {The human transactive responsive (TAR) DNA-binding protein 43 (TDP-43) is involved in a number of physiological processes in the body. Its primary function involves RNA regulation. The TDP-43 protein is also involved in many diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD) and even cancers. These TDP-43 mediated diseases are collectively called as TDP-43 proteinopathies. Intense research in the last decade has increased our understanding on TDP-43 structure and function in biology. The three-dimensional structures of TDP-43 domains such as N-terminal domain (NTD), RNA-recognition motif-1 (RRM1), RNA-recognition motif-2 (RRM2) and the C-terminal domain (CTD) or low-complexity domain (LCD) have been solved. These structures have yielded insights into novel binding sites and pockets at various TDP-43 domains, which can be targeted by designing a diverse library of ligands including small molecules, peptides and oligonucleotides as molecular tools to (i) study TDP-43 function, (ii) develop novel diagnostic agents and (iii) discover disease-modifying therapies to treat TDP-43 proteinopathies. This review provides a summary on recent progress in the development of TDP-43 binding ligands and uses the solved structures of various TDP-43 domains to investigate putative ligand binding regions that can be exploited to discover novel molecular probes to modulate TDP-43 structure and function.}, }
@article {pmid34386317, year = {2021}, author = {Ahsan, A and Liu, M and Zheng, Y and Yan, W and Pan, L and Li, Y and Ma, S and Zhang, X and Cao, M and Wu, Z and Hu, W and Chen, Z and Zhang, X}, title = {Natural compounds modulate the autophagy with potential implication of stroke.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {7}, pages = {1708-1720}, pmid = {34386317}, issn = {2211-3835}, abstract = {Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.}, }
@article {pmid34376973, year = {2021}, author = {Conti, N and Gatti, M and Raschi, E and Diemberger, I and Potena, L}, title = {Evidence and Current Use of Levosimendan in the Treatment of Heart Failure: Filling the Gap.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {3391-3409}, pmid = {34376973}, issn = {1177-8881}, mesh = {Adenosine Triphosphate/metabolism ; Cardiotonic Agents/adverse effects/*pharmacology ; Heart Failure/*drug therapy/physiopathology ; Humans ; Phosphodiesterase 3 Inhibitors/adverse effects/pharmacology ; Simendan/*pharmacology ; Vasodilator Agents/adverse effects/pharmacology ; }, abstract = {Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.}, }
@article {pmid34372914, year = {2021}, author = {Xu, X and Shen, D and Gao, Y and Zhou, Q and Ni, Y and Meng, H and Shi, H and Le, W and Chen, S and Chen, S}, title = {A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?.}, journal = {Translational neurodegeneration}, volume = {10}, number = {1}, pages = {29}, pmid = {34372914}, issn = {2047-9158}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Clinical Trials as Topic/*methods ; *Disease Management ; *Disease Progression ; Edaravone/therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Stem Cell Transplantation/methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.}, }
@article {pmid34370636, year = {2022}, author = {Fakhri, S and Piri, S and Moradi, SZ and Khan, H}, title = {Phytochemicals Targeting Oxidative Stress, Interconnected Neuroinflammatory, and Neuroapoptotic Pathways Following Radiation.}, journal = {Current neuropharmacology}, volume = {20}, number = {5}, pages = {836-856}, pmid = {34370636}, issn = {1875-6190}, mesh = {Antioxidants/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress ; Phytochemicals/metabolism/pharmacology/therapeutic use ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {The radiation for therapeutic purposes has shown positive effects in different contexts; however, it can increase the risk of many age-related and neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Parkinson's disease (PD). These different outcomes highlight a dose-response phenomenon called hormesis. Prevailing studies indicate that high doses of radiation could play several destructive roles in triggering oxidative stress, neuroapoptosis, and neuroinflammation in neurodegeneration. However, there is a lack of effective treatments in combating radiation-induced neurodegeneration, and the present drugs suffer from some drawbacks, including side effects and drug resistance. Among natural entities, polyphenols are suggested as multi-target agents affecting the dysregulated pathogenic mechanisms in neurodegenerative disease. This review discusses the destructive effects of radiation on the induction of neurodegenerative diseases by dysregulating oxidative stress, apoptosis, and inflammation. We also describe the promising effects of polyphenols and other candidate phytochemicals in preventing and treating radiation-induced neurodegenerative disorders, aiming to find novel/potential therapeutic compounds against such disorders.}, }
@article {pmid34366786, year = {2021}, author = {Terryn, J and Verfaillie, CM and Van Damme, P}, title = {Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {713031}, pmid = {34366786}, issn = {1662-5099}, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease, leading to behavioral changes and language difficulties. Heterozygous loss-of-function mutations in progranulin (GRN) induce haploinsufficiency of the protein and are associated with up to one-third of all genetic FTD cases worldwide. While the loss of GRN is primarily associated with neurodegeneration, the biological functions of the secreted growth factor-like protein are more diverse, ranging from wound healing, inflammation, vasculogenesis, and metabolic regulation to tumor cell growth and metastasis. To date, no disease-modifying treatments exist for FTD, but different therapeutic approaches to boost GRN levels in the central nervous system are currently being developed (including AAV-mediated GRN gene delivery as well as anti-SORT1 antibody therapy). In this review, we provide an overview of the multifaceted regulation of GRN levels and the corresponding therapeutic avenues. We discuss the opportunities, advantages, and potential drawbacks of the diverse approaches. Additionally, we highlight the therapeutic potential of elevating GRN levels beyond patients with loss-of-function mutations in GRN.}, }
@article {pmid34366183, year = {2022}, author = {Sternburg, EL and Gruijs da Silva, LA and Dormann, D}, title = {Post-translational modifications on RNA-binding proteins: accelerators, brakes, or passengers in neurodegeneration?.}, journal = {Trends in biochemical sciences}, volume = {47}, number = {1}, pages = {6-22}, doi = {10.1016/j.tibs.2021.07.004}, pmid = {34366183}, issn = {0968-0004}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; Protein Processing, Post-Translational ; RNA-Binding Protein FUS/genetics ; RNA-Binding Proteins/metabolism ; }, abstract = {RNA-binding proteins (RBPs) are critical players in RNA expression and metabolism, thus, the proper regulation of this class of proteins is critical for cellular health. Regulation of RBPs often occurs through post-translational modifications (PTMs), which allow the cell to quickly and efficiently respond to cellular and environmental stimuli. PTMs have recently emerged as important regulators of RBPs implicated in neurodegenerative disorders, in particular amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we summarize how disease-associated PTMs influence the biophysical properties, molecular interactions, subcellular localization, and function of ALS/FTD-linked RBPs, such as FUS and TDP-43. We will discuss how PTMs are believed to play pathological, protective, or ambiguous roles in these neurodegenerative disorders.}, }
@article {pmid34361850, year = {2021}, author = {Schiavone, S and Morgese, MG and Tucci, P and Trabace, L}, title = {The Therapeutic Potential of Celastrol in Central Nervous System Disorders: Highlights from In Vitro and In Vivo Approaches.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {15}, pages = {}, pmid = {34361850}, issn = {1420-3049}, support = {2017AY8BP4//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; 2017YZF7MA//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Animals ; Brain Diseases/*drug therapy/metabolism/pathology ; Humans ; Neuroprotective Agents/chemistry/therapeutic use ; *Pentacyclic Triterpenes/chemistry/therapeutic use ; Plant Roots/*chemistry ; Tripterygium/*chemistry ; }, abstract = {Celastrol, the most abundant compound derived from the root of Tripterygium wilfordii, largely used in traditional Chinese medicine, has shown preclinical and clinical efficacy for a broad range of disorders, acting via numerous mechanisms, including the induction of the expression of several neuroprotective factors, the inhibition of cellular apoptosis, and the decrease of reactive oxygen species (ROS). Given the crucial implication of these pathways in the pathogenesis of Central Nervous System disorders, both in vitro and in vivo studies have focused their attention on the possible use of this compound in these diseases. However, although most of the available studies have reported significant neuroprotective effects of celastrol in cellular and animal models of these pathological conditions, some of these data could not be replicated. This review aims to discuss current in vitro and in vivo lines of evidence on the therapeutic potential of celastrol in neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and cadmium-induced neurodegeneration, as well as in psychiatric disorders, such as psychosis and depression. In vitro and in vivo studies focused on celastrol effects in cerebral ischemia, ischemic stroke, traumatic brain injury, and epilepsy are also described.}, }
@article {pmid34360978, year = {2021}, author = {Chien, HM and Lee, CC and Huang, JJ}, title = {The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360978}, issn = {1422-0067}, support = {MOST-110-2113-M-001-055//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Amyloid/*metabolism ; Animals ; Cytoplasmic Granules/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Humans ; Lipid Droplets/*metabolism ; Protein Domains ; TDP-43 Proteinopathies/*metabolism ; }, abstract = {Transactive response DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein that is involved in transcription and translation regulation, non-coding RNA processing, and stress granule assembly. Aside from its multiple functions, it is also known as the signature protein in the hallmark inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients. TDP-43 is built of four domains, but its low-complexity domain (LCD) has become an intense research focus that brings to light its possible role in TDP-43 functions and involvement in the pathogenesis of these neurodegenerative diseases. Recent endeavors have further uncovered the distinct biophysical properties of TDP-43 under various circumstances. In this review, we summarize the multiple structural and biochemical properties of LCD in either promoting the liquid droplets or inducing fibrillar aggregates. We also revisit the roles of the LCD in paraspeckles, stress granules, and cytoplasmic inclusions to date.}, }
@article {pmid34360966, year = {2021}, author = {Trudler, D and Ghatak, S and Lipton, SA}, title = {Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360966}, issn = {1422-0067}, support = {DA041722/NH/NIH HHS/United States ; NS086890/NH/NIH HHS/United States ; R01 AG078756/AG/NIA NIH HHS/United States ; DISC2-11070//California Institute of Regenerative Medicine/ ; AG051129/NH/NIH HHS/United States ; R01 AG056259/AG/NIA NIH HHS/United States ; R01 NS086890/NS/NINDS NIH HHS/United States ; DA048882/NH/NIH HHS/United States ; AG056259/NH/NIH HHS/United States ; AG057409/NH/NIH HHS/United States ; R35 AG071734/AG/NIA NIH HHS/United States ; R01 DA048882/DA/NIDA NIH HHS/United States ; RF1 AG057409/AG/NIA NIH HHS/United States ; 11721/AS/Autism Speaks/United States ; DP1 DA041722/DA/NIDA NIH HHS/United States ; U24 AG051129/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy ; Drug Discovery/*methods ; Humans ; Induced Pluripotent Stem Cells/cytology/*drug effects/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Precision Medicine/methods ; }, abstract = {Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.}, }
@article {pmid34360586, year = {2021}, author = {Tarnacka, B and Jopowicz, A and Maślińska, M}, title = {Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360586}, issn = {1422-0067}, mesh = {Ceruloplasmin/*deficiency ; Copper/*adverse effects ; Humans ; Iron/*adverse effects ; Iron Metabolism Disorders/chemically induced/etiology/*pathology ; Manganese/*adverse effects ; Manganese Poisoning/complications ; Metabolic Diseases/chemically induced/*pathology ; Metalloproteins/metabolism ; Neuroaxonal Dystrophies/chemically induced/*pathology ; Neurodegenerative Diseases/etiology/*pathology ; Oxidative Stress ; }, abstract = {Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.}, }
@article {pmid34360544, year = {2021}, author = {Bright, F and Chan, G and van Hummel, A and Ittner, LM and Ke, YD}, title = {TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360544}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/etiology/metabolism/*pathology ; Animals ; DNA-Binding Proteins/*genetics ; Frontotemporal Dementia/etiology/metabolism/*pathology ; Humans ; Inflammation/classification/*complications ; *Mutation ; }, abstract = {The abnormal mislocalisation and ubiquitinated protein aggregation of the TAR DNA binding protein 43 (TDP-43) within the cytoplasm of neurons and glia in the central nervous system (CNS) is a pathological hallmark of early-onset neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathomechanisms underlying abnormal mislocalisation and aggregation of TDP-43 remain unknown. However, there is a growing body of evidence implicating neuroinflammation and immune-mediated mechanisms in the pathogenesis of neurodegeneration. Importantly, most of the evidence for an active role of immunity and inflammation in the pathogenesis of ALS and FTD relates specifically to TDP-43, posing the question as to whether immune-mediated mechanisms could hold the key to understanding TDP-43's underlying role in neurodegeneration in both diseases. Therefore, this review aims to piece together key lines of evidence for the specific association of TDP-43 with key immune and inflammatory pathways to explore the nature of this relationship and the implications for potential pathomechanisms underlying neurodegeneration in ALS and FTD.}, }
@article {pmid34359958, year = {2021}, author = {Chen, J and Bassot, A and Giuliani, F and Simmen, T}, title = {Amyotrophic Lateral Sclerosis (ALS): Stressed by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs).}, journal = {Cells}, volume = {10}, number = {7}, pages = {}, pmid = {34359958}, issn = {2073-4409}, support = {PS162449//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Stress/*physiology ; Humans ; Mitochondria/*metabolism ; Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. Progress in the characterization of other neurodegenerative mechanisms has shifted the spotlight onto an intracellular structure called mitochondria-endoplasmic reticulum (ER) contacts (MERCs) whose ER portion can be biochemically isolated as mitochondria-associated membranes (MAMs). Within the central nervous system (CNS), these structures control the metabolic output of mitochondria and keep sources of oxidative stress in check via autophagy. The most relevant MERC controllers in the ALS pathogenesis are vesicle-associated membrane protein-associated protein B (VAPB), a mitochondria-ER tether, and the ubiquitin-specific chaperone valosin containing protein (VCP). These two systems cooperate to maintain mitochondrial energy output and prevent oxidative stress. In ALS, mutant VAPB and VCP take a central position in the pathology through MERC dysfunction that ultimately alters or compromises mitochondrial bioenergetics. Intriguingly, both proteins are targets themselves of other ALS mutant proteins, including C9orf72, FUS, or TDP-43. Thus, a new picture emerges, where different triggers cause MERC dysfunction in ALS, subsequently leading to well-known pathological changes including endoplasmic reticulum (ER) stress, inflammation, and motor neuron death.}, }
@article {pmid34359358, year = {2021}, author = {Youn, BY and Ko, Y and Moon, S and Lee, J and Ko, SG and Kim, JY}, title = {Digital Biomarkers for Neuromuscular Disorders: A Systematic Scoping Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {34359358}, issn = {2075-4418}, abstract = {Biomarkers play a vital role in clinical care. They enable early diagnosis and treatment by identifying a patient's condition and disease course and act as an outcome measure that accurately evaluates the efficacy of a new treatment or drug. Due to the rapid development of digital technologies, digital biomarkers are expected to grow tremendously. In the era of change, this scoping review was conducted to see which digital biomarkers are progressing in neuromuscular disorders, a diverse and broad-range disease group among the neurological diseases, to discover available evidence for their feasibility and reliability. Thus, a total of 10 studies were examined: 9 observational studies and 1 animal study. Of the observational studies, studies were conducted with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA) patients. Non-peer reviewed poster presentations were not considered, as the articles may lead to erroneous results. The only animal study included in the present review investigated the mice model of ALS for detecting rest disturbances using a non-invasive digital biomarker.}, }
@article {pmid34357138, year = {2021}, author = {Pikatza-Menoio, O and Elicegui, A and Bengoetxea, X and Naldaiz-Gastesi, N and López de Munain, A and Gerenu, G and Gil-Bea, FJ and Alonso-Martín, S}, title = {The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis.}, journal = {Journal of personalized medicine}, volume = {11}, number = {7}, pages = {}, pmid = {34357138}, issn = {2075-4426}, support = {PI19/00175//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.}, }
@article {pmid34356140, year = {2021}, author = {Geevasinga, N and Van den Bos, M and Menon, P and Vucic, S}, title = {Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {11}, number = {7}, pages = {}, pmid = {34356140}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.}, }
@article {pmid34356087, year = {2021}, author = {Costantino, I and Nicodemus, J and Chun, J}, title = {Genomic Mosaicism Formed by Somatic Variation in the Aging and Diseased Brain.}, journal = {Genes}, volume = {12}, number = {7}, pages = {}, pmid = {34356087}, issn = {2073-4425}, support = {U01 MH114828/MH/NIMH NIH HHS/United States ; R01 AG071465/AG/NIA NIH HHS/United States ; R01 AG065541/AG/NIA NIH HHS/United States ; T32 AG066596/AG/NIA NIH HHS/United States ; T32 GM007198/GM/NIGMS NIH HHS/United States ; }, mesh = {Aging/genetics/*metabolism ; Aneuploidy ; Animals ; Brain/cytology/metabolism ; Brain Diseases/*genetics/metabolism/physiopathology ; DNA Copy Number Variations/genetics ; Genome/genetics ; Genomics/methods ; Humans ; Hybrid Cells/cytology/*physiology ; Mosaicism ; Mutation/genetics ; Single-Cell Analysis/methods ; }, abstract = {Over the past 20 years, analyses of single brain cell genomes have revealed that the brain is composed of cells with myriad distinct genomes: the brain is a genomic mosaic, generated by a host of DNA sequence-altering processes that occur somatically and do not affect the germline. As such, these sequence changes are not heritable. Some processes appear to occur during neurogenesis, when cells are mitotic, whereas others may also function in post-mitotic cells. Here, we review multiple forms of DNA sequence alterations that have now been documented: aneuploidies and aneusomies, smaller copy number variations (CNVs), somatic repeat expansions, retrotransposons, genomic cDNAs (gencDNAs) associated with somatic gene recombination (SGR), and single nucleotide variations (SNVs). A catch-all term of DNA content variation (DCV) has also been used to describe the overall phenomenon, which can include multiple forms within a single cell's genome. A requisite step in the analyses of genomic mosaicism is ongoing technology development, which is also discussed. Genomic mosaicism alters one of the most stable biological molecules, DNA, which may have many repercussions, ranging from normal functions including effects of aging, to creating dysfunction that occurs in neurodegenerative and other brain diseases, most of which show sporadic presentation, unlinked to causal, heritable genes.}, }
@article {pmid34355526, year = {2022}, author = {Muraleedharan, R and Dasgupta, B}, title = {AMPK in the brain: its roles in glucose and neural metabolism.}, journal = {The FEBS journal}, volume = {289}, number = {8}, pages = {2247-2262}, doi = {10.1111/febs.16151}, pmid = {34355526}, issn = {1742-4658}, support = {R01 NS075291/NS/NINDS NIH HHS/United States ; R01 NS099162/NS/NINDS NIH HHS/United States ; }, mesh = {*AMP-Activated Protein Kinases/genetics/metabolism ; Animals ; Astrocytes/metabolism ; Brain/metabolism ; Energy Metabolism/physiology ; *Glucose/metabolism ; Glycogen/metabolism ; Mice ; }, abstract = {The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important role in orchestrating intertissue metabolic signaling. AMPK regulates cell survival, metabolism, and cellular homeostasis basally as well as in response to various metabolic stresses. Studies so far show that the AMPK pathway is associated with neurodegeneration and CNS pathology, but the mechanisms involved remain unclear. AMPK dysregulation has been reported in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neuropathies. AMPK activation appears to be both neuroprotective and pro-apoptotic, possibly dependent upon neural cell types, the nature of insults, and the intensity and duration of AMPK activation. While embryonic brain development in AMPK null mice appears to proceed normally without any overt structural abnormalities, our recent study confirmed the full impact of AMPK loss in the postnatal and aging brain. Our studies revealed that Ampk deletion in neurons increased basal neuronal excitability and reduced latency to seizure upon stimulation. Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in the brain. AMPK's regulation of aerobic glycolysis in astrocytic metabolism warrants further deliberation, particularly glycogen turnover and shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation. In this minireview, we focus on recent advances in AMPK and energy-sensing in the brain.}, }
@article {pmid34349634, year = {2021}, author = {Yu, W and Ying, J and Wang, X and Liu, X and Zhao, T and Yoon, S and Zheng, Q and Fang, Y and Yang, D and Hua, F}, title = {The Involvement of Lactosylceramide in Central Nervous System Inflammation Related to Neurodegenerative Disease.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {691230}, pmid = {34349634}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a class of slow-progressing terminal illnesses characterized by neuronal lesions, such as multiple sclerosis [MS, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)]. Their incidence increases with age, and the associated burden on families and society will become increasingly more prominent with aging of the general population. In recent years, there is growing studies have shown that lactosylceramide (LacCer) plays a crucial role in the progression of neurodegeneration, although these diseases have different pathogenic mechanisms and etiological characteristics. Based on latest research progress, this study expounds the pathogenic role of LacCer in driving central nervous system (CNS) inflammation, as well as the role of membrane microstructure domain (lipid rafts) and metabolite gangliosides, and discusses in detail their links with the pathogenesis of neurodegenerative diseases, with a view to providing new strategies and ideas for the study of pathological mechanisms and drug development for neurodegenerative diseases in the future.}, }
@article {pmid34349625, year = {2021}, author = {Zaepfel, BL and Rothstein, JD}, title = {RNA Is a Double-Edged Sword in ALS Pathogenesis.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {708181}, pmid = {34349625}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10-15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.}, }
@article {pmid34343141, year = {2021}, author = {Cooper-Knock, J and Harvey, C and Zhang, S and Moll, T and Timpanaro, IS and Kenna, KP and Iacoangeli, A and Veldink, JH}, title = {Advances in the genetic classification of amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {34}, number = {5}, pages = {756-764}, pmid = {34343141}, issn = {1473-6551}, support = {/WT_/Wellcome Trust/United Kingdom ; 216596/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Humans ; Machine Learning ; Phenotype ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease wherein disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture, which will be necessary for comprehensive disease subclassification.<br><br>RECENT FINDINGS: We summarize recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach, including clinicians, geneticists and pathologists.<br><br>SUMMARY: The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant, but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.}, }
@article {pmid34343139, year = {2021}, author = {Guillot, SJ and Bolborea, M and Dupuis, L}, title = {Dysregulation of energy homeostasis in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {34}, number = {5}, pages = {773-780}, pmid = {34343139}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Energy Metabolism ; Homeostasis ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting upper and lower motor neurons, inexorably leading to an early death. Defects in energy metabolism have been associated with ALS, including weight loss, increased energy expenditure, decreased body fat mass and increased use of lipid nutrients at the expense of carbohydrates. We review here recent findings on impaired energy metabolism in ALS, and its clinical importance.<br><br>RECENT FINDINGS: Hypothalamic atrophy, as well as alterations in hypothalamic peptides controlling energy metabolism, have been associated with metabolic derangements. Recent studies showed that mutations causing familial ALS impact various metabolic pathways, in particular mitochondrial function, and lipid and carbohydrate metabolism, which could underlie these metabolic defects in patients. Importantly, slowing weight loss, through high caloric diets, is a promising therapeutic strategy, and early clinical trials indicated that it might improve survival in at least a subset of patients. More research is needed to improve these therapeutic strategies, define pharmacological options, and refine the population of ALS patients that would benefit from these approaches.<br><br>SUMMARY: Dysfunctional energy homeostasis is a major feature of ALS clinical picture and emerges as a potential therapeutic target.}, }
@article {pmid34335276, year = {2021}, author = {Wang, X and Zhang, JB and He, KJ and Wang, F and Liu, CF}, title = {Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {713963}, pmid = {34335276}, issn = {1663-9812}, abstract = {Neurodegenerative disease (NDD), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by the progressive loss of neurons which leads to the decline of motor and/or cognitive function. Currently, the prevalence of NDD is rapidly increasing in the aging population. However, valid drugs or treatment for NDD are still lacking. The clinical heterogeneity and complex pathogenesis of NDD pose a great challenge for the development of disease-modifying therapies. Numerous animal models have been generated to mimic the pathological conditions of these diseases for drug discovery. Among them, zebrafish (Danio rerio) models are progressively emerging and becoming a powerful tool for in vivo study of NDD. Extensive use of zebrafish in pharmacology research or drug screening is due to the high conserved evolution and 87% homology to humans. In this review, we summarize the zebrafish models used in NDD studies, and highlight the recent findings on pharmacological targets for NDD treatment. As high-throughput platforms in zebrafish research have rapidly developed in recent years, we also discuss the application prospects of these new technologies in future NDD research.}, }
@article {pmid34333668, year = {2021}, author = {Cao, L and Yan, Y and Zhao, G}, title = {NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {10}, pages = {4055-4062}, pmid = {34333668}, issn = {1590-3478}, support = {81570698 and 81520108010//National Natural Science Foundation of China/ ; LY16H070003//the Natural Science Foundation of Zhejiang Province/ ; 2018RC004, 2019DZ021, 2020RC061//the General Medical and Health Project of Zhejiang Province/ ; 2021RC065//the General Medical and Health Project of Zhejiang Province/ ; }, mesh = {*Essential Tremor ; *Frontotemporal Dementia ; Humans ; Intranuclear Inclusion Bodies ; *Multiple System Atrophy/genetics ; Trinucleotide Repeat Expansion/genetics ; }, abstract = {The NOTCH2NLC gene 5' untranslated region (UTR) GGC repeat expansion mutations were identified as a genetic contributor of neuronal intranuclear inclusion disease (NIID) in 2019. Since then, the number of reported cases with NOTCH2NLC GGC repeat expansion in Asian and European populations has increased rapidly, indicating that the expanded mutation not only leads to the onset or progression of the NIID, but also may play an important role in multiple progressive neurological disorders, including Parkinson's disease, essential tremor, multiple system atrophy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, leukoencephalopathy, and oculopharyngodistal myopathy type 3. Nevertheless, the underlying pathogenic mechanism of the NOTCH2NLC 5' UTR region GGC repeat expansion in these disorders remains largely unknown. This review aims to present recent breakthroughs on this mutation and improve our knowledge of a newly defined spectrum of disease: NOTCH2NLC-related repeat expansion disorder.}, }
@article {pmid34325826, year = {2021}, author = {Mutti, C and Rausa, F and Parrino, L}, title = {Sleep in Neurologic Disorders.}, journal = {Sleep medicine clinics}, volume = {16}, number = {3}, pages = {499-512}, doi = {10.1016/j.jsmc.2021.05.002}, pmid = {34325826}, issn = {1556-4088}, mesh = {Humans ; *Nervous System Diseases/epidemiology ; *Sleep/physiology ; *Sleep Wake Disorders/epidemiology ; }, abstract = {Sleep is a complex brain state with fundamental relevance for cognitive functions, synaptic plasticity, brain resilience, and autonomic balance. Sleep pathologies may interfere with cerebral circuit organization, leading to negative consequences and favoring the development of neurologic disorders. Conversely, the latter can interfere with sleep functions. Accordingly, assessment of sleep quality is always recommended in the diagnosis of patients with neurologic disorders and during neurorehabilitation programs. This review investigates the complex interplay between sleep and brain pathologies, focusing on diseases in which the association with sleep disturbances is commonly overlooked and whereby major benefits may derive from their proper management.}, }
@article {pmid34322715, year = {2021}, author = {Liguori, F and Amadio, S and Volonté, C}, title = {Fly for ALS: Drosophila modeling on the route to amyotrophic lateral sclerosis modifiers.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {78}, number = {17-18}, pages = {6143-6160}, pmid = {34322715}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Animals, Genetically Modified/metabolism ; Ataxin-2/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Drosophila/*metabolism ; Drosophila Proteins/genetics/metabolism ; Humans ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, devastating disease, causing movement impairment, respiratory failure and ultimate death. A plethora of genetic, cellular and molecular mechanisms are involved in ALS signature, although the initiating causes and progressive pathological events are far from being understood. Drosophila research has produced seminal discoveries for more than a century and has been successfully used in the past 25 years to untangle the process of ALS pathogenesis, and recognize potential markers and novel strategies for therapeutic solutions. This review will provide an updated view of several ALS modifiers validated in C9ORF72, SOD1, FUS, TDP-43 and Ataxin-2 Drosophila models. We will discuss basic and preclinical findings, illustrating recent developments and novel breakthroughs, also depicting unsettled challenges and limitations in the Drosophila-ALS field. We intend to stimulate a renewed debate on Drosophila as a screening route to identify more successful disease modifiers and neuroprotective agents.}, }
@article {pmid34314817, year = {2021}, author = {Jiménez-Villegas, J and Ferraiuolo, L and Mead, RJ and Shaw, PJ and Cuadrado, A and Rojo, AI}, title = {NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS.}, journal = {Free radical biology &amp; medicine}, volume = {173}, number = {}, pages = {125-141}, doi = {10.1016/j.freeradbiomed.2021.07.022}, pmid = {34314817}, issn = {1873-4596}, support = {BRC-1215-20017/DH_/Department of Health/United Kingdom ; MR/S004920/1/MRC_/Medical Research Council/United Kingdom ; NF-SI-0617-10077/DH_/Department of Health/United Kingdom ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Antioxidants ; Gene Expression Regulation ; Humans ; Motor Neurons/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating heterogeneous disease with still no convincing therapy. To identify the most strategically significant hallmarks for therapeutic intervention, we have performed a comprehensive transcriptomics analysis of dysregulated pathways, comparing datasets from ALS patients and healthy donors. We have identified crucial alterations in RNA metabolism, intracellular transport, vascular system, redox homeostasis, proteostasis and inflammatory responses. Interestingly, the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) has significant effects in modulating these pathways. NRF2 has been classically considered as the master regulator of the antioxidant cellular response, although it is currently considered as a key component of the transduction machinery to maintain coordinated control of protein quality, inflammation, and redox homeostasis. Herein, we will summarize the data from NRF2 activators in ALS pre-clinical models as well as those that are being studied in clinical trials. As we will discuss, NRF2 is a promising target to build a coordinated transcriptional response to motor neuron injury, highlighting its therapeutic potential to combat ALS.}, }
@article {pmid34307464, year = {2021}, author = {Yang, C and Qi, Y and Sun, Z}, title = {The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {711710}, pmid = {34307464}, issn = {2296-889X}, abstract = {The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.}, }
@article {pmid34305573, year = {2021}, author = {Pikuleva, IA and Cartier, N}, title = {Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {696778}, pmid = {34305573}, issn = {1663-4365}, support = {R01 AG067552/AG/NIA NIH HHS/United States ; }, abstract = {Cholesterol, an essential component of the brain, and its local metabolism are involved in many neurodegenerative diseases. The blood-brain barrier is impermeable to cholesterol; hence, cholesterol homeostasis in the central nervous system represents a balance between in situ biosynthesis and elimination. Cytochrome P450 46A1 (CYP46A1), a central nervous system-specific enzyme, converts cholesterol to 24-hydroxycholesterol, which can freely cross the blood-brain barrier and be degraded in the liver. By the dual action of initiating cholesterol efflux and activating the cholesterol synthesis pathway, CYP46A1 is the key enzyme that ensures brain cholesterol turnover. In humans and mouse models, CYP46A1 activity is altered in Alzheimer's and Huntington's diseases, spinocerebellar ataxias, glioblastoma, and autism spectrum disorders. In mouse models, modulations of CYP46A1 activity mitigate the manifestations of Alzheimer's, Huntington's, Nieman-Pick type C, and Machao-Joseph (spinocerebellar ataxia type 3) diseases as well as amyotrophic lateral sclerosis, epilepsy, glioblastoma, and prion infection. Animal studies revealed that the CYP46A1 activity effects are not limited to cholesterol maintenance but also involve critical cellular pathways, like gene transcription, endocytosis, misfolded protein clearance, vesicular transport, and synaptic transmission. How CYP46A1 can exert central control of such essential brain functions is a pressing question under investigation. The potential therapeutic role of CYP46A1, demonstrated in numerous models of brain disorders, is currently being evaluated in early clinical trials. This review summarizes the past 70 years of research that has led to the identification of CYP46A1 and brain cholesterol homeostasis as powerful therapeutic targets for severe pathologies of the CNS.}, }
@article {pmid34305533, year = {2021}, author = {Lotz, SK and Blackhurst, BM and Reagin, KL and Funk, KE}, title = {Microbial Infections Are a Risk Factor for Neurodegenerative Diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {691136}, pmid = {34305533}, issn = {1662-5102}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, comprise a family of disorders characterized by progressive loss of nervous system function. Neuroinflammation is increasingly recognized to be associated with many neurodegenerative diseases but whether it is a cause or consequence of the disease process is unclear. Of growing interest is the role of microbial infections in inciting degenerative neuroinflammatory responses and genetic factors that may regulate those responses. Microbial infections cause inflammation within the central nervous system through activation of brain-resident immune cells and infiltration of peripheral immune cells. These responses are necessary to protect the brain from lethal infections but may also induce neuropathological changes that lead to neurodegeneration. This review discusses the molecular and cellular mechanisms through which microbial infections may increase susceptibility to neurodegenerative diseases. Elucidating these mechanisms is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of neurodegenerative diseases.}, }
@article {pmid34297914, year = {2021}, author = {Mann, JR and Donnelly, CJ}, title = {RNA modulates physiological and neuropathological protein phase transitions.}, journal = {Neuron}, volume = {109}, number = {17}, pages = {2663-2681}, pmid = {34297914}, issn = {1097-4199}, support = {L30 AG048607/AG/NIA NIH HHS/United States ; R21 AG064940/AG/NIA NIH HHS/United States ; T32 NS041234/NS/NINDS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R21 AG067201/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism ; *Protein Folding ; Proteostasis Deficiencies/*metabolism ; RNA/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; }, abstract = {Aggregation of RNA-binding proteins (RBPs) is a pathological hallmark of neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In these diseases, TDP-43 and FUS RBPs are depleted from the nuclear compartment, where they are normally localized, and found within cytoplasmic inclusions in degenerating regions of affected individuals' postmortem tissue. The mechanisms responsible for aggregation of these proteins has remained elusive, but recent studies suggest liquid-liquid phase separation (LLPS) might serve as a critical nucleation step in formation of pathological inclusions. The process of phase separation also underlies the formation and maintenance of several functional membraneless organelles (MLOs) throughout the cell, some of which contain TDP-43, FUS, and other disease-linked RBPs. One common ligand of disease-linked RBPs, RNA, is a major component of MLOs containing RBPs and has been demonstrated to be a strong modulator of RBP phase transitions. Although early evidence suggested a largely synergistic effect of RNA on RBP phase separation and MLO assembly, recent work indicates that RNA can also antagonize RBP phase behavior under certain physiological and pathological conditions. In this review, we describe the mechanisms underlying RNA-mediated phase transitions of RBPs and examine the molecular properties of these interactions, such as RNA length, sequence, and secondary structure, that mediate physiological or pathological LLPS.}, }
@article {pmid34296769, year = {2021}, author = {Lee, J and Madhavan, A and Krajewski, E and Lingenfelter, S}, title = {Assessment of dysarthria and dysphagia in patients with amyotrophic lateral sclerosis: Review of the current evidence.}, journal = {Muscle &amp; nerve}, volume = {64}, number = {5}, pages = {520-531}, doi = {10.1002/mus.27361}, pmid = {34296769}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Deglutition Disorders/diagnosis/etiology ; Dysarthria/diagnosis/etiology ; Humans ; Quality of Life ; Speech ; }, abstract = {Bulbar dysfunction is a common presentation of amyotrophic lateral sclerosis (ALS) and significantly impacts quality of life of people with ALS (PALS). The current paper reviews measurements of dysarthria and dysphagia specific to ALS to identify efficient and valid assessment measures. Using such assessment measures will lead to improved management of bulbar dysfunction in ALS. Measures reviewed for dysarthria in PALS are organized into three categories: acoustic, kinematic, and strength. A set of criteria are used to evaluate the effectiveness of the measures' identification of speech impairments, measurement of functional verbal communication, and clinical applicability. Assessments reviewed for dysphagia in PALS are organized into six categories: patient reported outcomes, dietary intake, pulmonary function and airway defense capacity, bulbar function, dysphagia/aspiration screens, and instrumental evaluations. Measurements that have good potential for clinical use are highlighted in both topic areas. Additionally, areas of improvement for clinical practice and research are identified and discussed. In general, no single speech measure fulfilled all the criteria, although a few measures were identified as potential diagnostic tools. Similarly, few objective measures that were validated and replicated with large sample sizes were found for diagnosis of dysphagia in PALS. Importantly, clinical applicability was found to be limited; thus, a collaborative team focused on implementation science would be helpful to improve the clinical uptake of assessments. Overall, the review highlights the need for further development of clinically viable and efficient measurements that use a multidisciplinary approach.}, }
@article {pmid34295920, year = {2021}, author = {Paß, T and Wiesner, RJ and Pla-Martín, D}, title = {Selective Neuron Vulnerability in Common and Rare Diseases-Mitochondria in the Focus.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {676187}, pmid = {34295920}, issn = {2296-889X}, abstract = {Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca[2+] handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as in rare neurological disorders, including Huntington's disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.}, }
@article {pmid34295897, year = {2021}, author = {Sykova, E and Cizkova, D and Kubinova, S}, title = {Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {695900}, pmid = {34295897}, issn = {2296-634X}, abstract = {Preclinical and clinical studies with various stem cells, their secretomes, and extracellular vesicles (EVs) indicate their use as a promising strategy for the treatment of various diseases and tissue defects, including neurodegenerative diseases such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). Autologous and allogenic mesenchymal stem cells (MSCs) are so far the best candidates for use in regenerative medicine. Here we review the effects of the implantation of MSCs (progenitors of mesodermal origin) in animal models of SCI and ALS and in clinical studies. MSCs possess multilineage differentiation potential and are easily expandable in vitro. These cells, obtained from bone marrow (BM), adipose tissue, Wharton jelly, or even other tissues, have immunomodulatory and paracrine potential, releasing a number of cytokines and factors which inhibit the proliferation of T cells, B cells, and natural killer cells and modify dendritic cell activity. They are hypoimmunogenic, migrate toward lesion sites, induce better regeneration, preserve perineuronal nets, and stimulate neural plasticity. There is a wide use of MSC systemic application or MSCs seeded on scaffolds and tissue bridges made from various synthetic and natural biomaterials, including human decellularized extracellular matrix (ECM) or nanofibers. The positive effects of MSC implantation have been recorded in animals with SCI lesions and ALS. Moreover, promising effects of autologous as well as allogenic MSCs for the treatment of SCI and ALS were demonstrated in recent clinical studies.}, }
@article {pmid34293378, year = {2021}, author = {Aslani, M and Mortazavi-Jahromi, SS and Mirshafiey, A}, title = {Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology.}, journal = {Immunology letters}, volume = {238}, number = {}, pages = {1-20}, doi = {10.1016/j.imlet.2021.07.004}, pmid = {34293378}, issn = {1879-0542}, mesh = {Animals ; *Biomarkers ; Diagnosis, Differential ; Disease Management ; Disease Susceptibility ; *Gene Expression Regulation ; Humans ; MicroRNAs/*genetics ; Neuroimmunomodulation/genetics/immunology ; Neuroinflammatory Diseases/diagnosis/*etiology/*metabolism/therapy ; *RNA Interference ; Signal Transduction ; }, abstract = {Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.}, }
@article {pmid34291086, year = {2021}, author = {Farina, S and Esposito, F and Battistoni, M and Biamonti, G and Francia, S}, title = {Post-Translational Modifications Modulate Proteinopathies of TDP-43, FUS and hnRNP-A/B in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {693325}, pmid = {34291086}, issn = {2296-889X}, abstract = {It has been shown that protein low-sequence complexity domains (LCDs) induce liquid-liquid phase separation (LLPS), which is responsible for the formation of membrane-less organelles including P-granules, stress granules and Cajal bodies. Proteins harbouring LCDs are widely represented among RNA binding proteins often mutated in ALS. Indeed, LCDs predispose proteins to a prion-like behaviour due to their tendency to form amyloid-like structures typical of proteinopathies. Protein post-translational modifications (PTMs) can influence phase transition through two main events: i) destabilizing or augmenting multivalent interactions between phase-separating macromolecules; ii) recruiting or excluding other proteins and/or nucleic acids into/from the condensate. In this manuscript we summarize the existing evidence describing how PTM can modulate LLPS thus favouring or counteracting proteinopathies at the base of neurodegeneration in ALS.}, }
@article {pmid34285065, year = {2021}, author = {Corcia, P and Bede, P and Pradat, PF and Couratier, P and Vucic, S and de Carvalho, M}, title = {Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {92}, number = {10}, pages = {1126-1130}, doi = {10.1136/jnnp-2021-326266}, pmid = {34285065}, issn = {1468-330X}, mesh = {Action Potentials/*physiology ; Amyotrophic Lateral Sclerosis/*physiopathology ; Atrophy/physiopathology ; Humans ; Motor Neurons/*physiology ; Nerve Degeneration/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons. A key clinical feature of ALS is the absence of accurate, early-stage diagnostic indicators. 'Split-hand syndrome' was first described in ALS at the end of the last century and a considerable body of literature suggests that the split-hand phenomenon may be an important clinical feature of ALS. Considering the published investigations, it is conceivable that the 'split-hand syndrome' results from the associated upper and lower motor neuron degeneration, whose interaction remains to be fully clarified. Additionally, other split syndromes have been described in ALS involving upper or lower limbs, with a nuanced description of clinical and neurophysiological manifestations that may further aid ALS diagnosis. In this review, we endeavour to systematically present the spectrum of the 'split syndromes' in ALS from a clinical and neurophysiology perspective and discuss their diagnostic and pathogenic utility.}, }
@article {pmid34276318, year = {2021}, author = {Gamarra, M and de la Cruz, A and Blanco-Urrejola, M and Baleriola, J}, title = {Local Translation in Nervous System Pathologies.}, journal = {Frontiers in integrative neuroscience}, volume = {15}, number = {}, pages = {689208}, pmid = {34276318}, issn = {1662-5145}, abstract = {Dendrites and axons can extend dozens to hundreds of centimeters away from the cell body so that a single neuron can sense and respond to thousands of stimuli. Thus, for an accurate function of dendrites and axons the neuronal proteome needs to be asymmetrically distributed within neurons. Protein asymmetry can be achieved by the transport of the protein itself or the transport of the mRNA that is then translated at target sites in neuronal processes. The latter transport mechanism implies local translation of localized mRNAs. The role of local translation in nervous system (NS) development and maintenance is well established, but recently there is growing evidence that this mechanism and its deregulation are also relevant in NS pathologies, including neurodegenerative diseases. For instance, upon pathological signals disease-related proteins can be locally synthesized in dendrites and axons. Locally synthesized proteins can exert their effects at or close to the site of translation, or they can be delivered to distal compartments like the nucleus and induce transcriptional responses that lead to neurodegeneration, nerve regeneration and other cell-wide responses. Relevant key players in the process of local protein synthesis are RNA binding proteins (RBPs), responsible for mRNA transport to neurites. Several neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis or spinal motor atrophy, are characterized by mutations in genes encoding for RBPs and consequently mRNA localization and local translation are impaired. In other diseases changes in the local mRNA repertoire and altered local protein synthesis have been reported. In this review, we will discuss how deregulation of localized translation at different levels can contribute to the development and progression of nervous system pathologies.}, }
@article {pmid34273246, year = {2022}, author = {Lin, BC and Higgins, NR and Phung, TH and Monteiro, MJ}, title = {UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD.}, journal = {The FEBS journal}, volume = {289}, number = {20}, pages = {6132-6153}, pmid = {34273246}, issn = {1742-4658}, support = {R01 NS098243/NS/NINDS NIH HHS/United States ; R01 NS100008/NS/NINDS NIH HHS/United States ; RF1 NS098243/NS/NINDS NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Autophagy-Related Proteins/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Mitochondrial Proteins/genetics ; Mutation ; Nuclear Proteins/genetics ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitins/genetics/metabolism ; }, abstract = {Ubiquilin (UBQLN) proteins are a dynamic and versatile family of proteins found in all eukaryotes that function in the regulation of proteostasis. Besides their canonical function as shuttle factors in delivering misfolded proteins to the proteasome and autophagy systems for degradation, there is emerging evidence that UBQLN proteins play broader roles in proteostasis. New information suggests the proteins function as chaperones in protein folding, protecting proteins prior to membrane insertion, and as guardians for mitochondrial protein import. In this review, we describe the evidence for these different roles, highlighting how different domains of the proteins impart these functions. We also describe how changes in the structure and phase separation properties of UBQLNs may regulate their activity and function. Finally, we discuss the pathogenic mechanisms by which mutations in UBQLN2 cause amyotrophic lateral sclerosis and frontotemporal dementia. We describe the animal model systems made for different UBQLN2 mutations and how lessons learnt from these systems provide fundamental insight into the molecular mechanisms by which UBQLN2 mutations drive disease pathogenesis through disturbances in proteostasis.}, }
@article {pmid34269186, year = {2022}, author = {Marques, RF and Duncan, KE}, title = {SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology.}, journal = {Neural regeneration research}, volume = {17}, number = {2}, pages = {266-270}, pmid = {34269186}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNA-Seq screening approach to a standard model of TAR DNA-binding protein-43 (TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.}, }
@article {pmid34269182, year = {2022}, author = {Panes, JD and Wendt, A and Ramirez-Molina, O and Castro, PA and Fuentealba, J}, title = {Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure.}, journal = {Neural regeneration research}, volume = {17}, number = {2}, pages = {237-245}, pmid = {34269182}, issn = {1673-5374}, abstract = {The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.}, }
@article {pmid34266598, year = {2021}, author = {Ahmed, RM and Halliday, G and Hodges, JR}, title = {Hypothalamic symptoms of frontotemporal dementia disorders.}, journal = {Handbook of clinical neurology}, volume = {182}, number = {}, pages = {269-280}, doi = {10.1016/B978-0-12-819973-2.00019-8}, pmid = {34266598}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis ; Cognition ; Disease Progression ; Feeding Behavior ; *Frontotemporal Dementia ; Humans ; Hypothalamus ; }, abstract = {Frontotemporal dementia (FTD) has traditionally been regarded as a disease of cognition and behavior, but emerging evidence suggests that the disease also affects body functions including changes in eating behavior and metabolism, autonomic function, sleep behavior, and sexual function. Central to these changes are potentially complex neural networks involving the hypothalamus, with hypothalamic atrophy shown in behavioral variant FTD. The physiological changes found in FTD are reviewed and the key neural networks and neuroendocrine changes mediating these changes in function discussed, including the ability to use these changes as biomarkers to aid in disease diagnosis, monitoring disease progression, and as potential treatment targets.}, }
@article {pmid34263556, year = {2021}, author = {Bennett, CL and La Spada, AR}, title = {SUMOylated Senataxin functions in genome stability, RNA degradation, and stress granule disassembly, and is linked with inherited ataxia and motor neuron disease.}, journal = {Molecular genetics &amp; genomic medicine}, volume = {9}, number = {12}, pages = {e1745}, pmid = {34263556}, issn = {2324-9269}, support = {R35 NS122140/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Ataxia/diagnosis/*etiology/*metabolism ; Biomarkers ; DNA Helicases/genetics/*metabolism ; DNA-Directed DNA Polymerase/metabolism ; Disease Susceptibility ; Exosomes/metabolism ; Gene Expression Regulation ; Genetic Predisposition to Disease ; *Genomic Instability ; Humans ; Motor Neuron Disease/*etiology/*metabolism ; Multifunctional Enzymes/genetics/*metabolism ; Mutation ; Neurodegenerative Diseases/diagnosis/etiology/metabolism ; RNA Helicases/genetics/*metabolism ; RNA Polymerase II/metabolism ; *RNA Stability ; S Phase ; S Phase Cell Cycle Checkpoints ; Stress Granules/*metabolism ; Sumoylation ; }, abstract = {BACKGROUND: Senataxin (SETX) is a DNA/RNA helicase critical for neuron survival. SETX mutations underlie two inherited neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and Amyotrophic Lateral Sclerosis type 4 (ALS4).<br><br>METHODS: This review examines SETX key cellular processes and we hypothesize that SETX requires SUMO posttranslational modification to function properly.<br><br>RESULTS: SETX is localized to distinct foci during S-phase of the cell cycle, and these foci represent sites of DNA polymerase/RNA polymerase II (RNAP) collision, as they co-localize with DNA damage markers 53BP1 and H2AX. At such sites, SETX directs incomplete RNA transcripts to the nuclear exosome for degradation via interaction with exosome component 9 (Exosc9), a key component of the nuclear exosome. These processes require SETX SUMOylation. SETX was also recently localized within stress granules (SGs), and found to regulate SG disassembly, a process that similarly requires SUMOylation.<br><br>CONCLUSION: SETX undergoes SUMO modification to function at S-phase foci in cycling cells to facilitate RNA degradation. SETX may regulate similar processes in non-dividing neurons at sites of RNAP II bidirectional self-collision. Finally, SUMOylation of SETX appears to be required for SG disassembly. This SETX function may be crucial for neuron survival, as altered SG dynamics are linked to ALS disease pathogenesis. In addition, AOA2 point mutations have been shown to block SETX SUMOylation. Such mutations induce an ataxia phenotype indistinguishable from those with SETX null mutation, underscoring the importance of this modification.}, }
@article {pmid34261001, year = {2021}, author = {Miranda, DR and Voss, AA and Bannister, RA}, title = {Into the spotlight: RGK proteins in skeletal muscle.}, journal = {Cell calcium}, volume = {98}, number = {}, pages = {102439}, pmid = {34261001}, issn = {1532-1991}, support = {R01 NS103777/NS/NINDS NIH HHS/United States ; R03 AG065626/AG/NIA NIH HHS/United States ; R15 NS099850/NS/NINDS NIH HHS/United States ; R56 NS103777/NS/NINDS NIH HHS/United States ; }, mesh = {Calcium Channels, L-Type ; *Diabetes Mellitus, Type 2 ; Humans ; *Monomeric GTP-Binding Proteins/metabolism ; Muscle, Skeletal/metabolism ; }, abstract = {The RGK (Rad, Rem, Rem2 and Gem/Kir) family of small GTPases are potent endogenous inhibitors of voltage-gated Ca[2+] channels (VGCCs). While the impact of RGK proteins on cardiac physiology has been investigated extensively, much less is known regarding their influence on skeletal muscle biology. Thus, the purpose of this article is to establish a basis for future investigation into the role of RGK proteins in regulating the skeletal muscle excitation-contraction (EC) coupling complex via modulation of the L-type CaV1.1 VGCC. The pathological consequences of elevated muscle RGK protein expression in Type II Diabetes, Amyotrophic Lateral Sclerosis (ALS), Duchenne's Muscular Dystrophy and traumatic nerve injury are also discussed.}, }
@article {pmid34253298, year = {2021}, author = {Stoica, R and Rusu, CM and Staicu, CE and Burlacu, AE and Radu, M and Radu, BM}, title = {Ca[2+] homeostasis in brain microvascular endothelial cells.}, journal = {International review of cell and molecular biology}, volume = {362}, number = {}, pages = {55-110}, doi = {10.1016/bs.ircmb.2021.01.001}, pmid = {34253298}, issn = {1937-6448}, mesh = {Animals ; Brain/*blood supply ; Calcium/*metabolism ; Endothelial Cells/*metabolism ; *Homeostasis ; Humans ; Ion Channels/metabolism ; Microvessels/*cytology ; }, abstract = {Blood brain barrier (BBB) is formed by the brain microvascular endothelial cells (BMVECs) lining the wall of brain capillaries. Its integrity is regulated by multiple mechanisms, including up/downregulation of tight junction proteins or adhesion molecules, altered Ca[2+] homeostasis, remodeling of cytoskeleton, that are confined at the level of BMVECs. Beside the contribution of BMVECs to BBB permeability changes, other cells, such as pericytes, astrocytes, microglia, leukocytes or neurons, etc. are also exerting direct or indirect modulatory effects on BBB. Alterations in BBB integrity play a key role in multiple brain pathologies, including neurological (e.g. epilepsy) and neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis etc.). In this review, the principal Ca[2+] signaling pathways in brain microvascular endothelial cells are discussed and their contribution to BBB integrity is emphasized. Improving the knowledge of Ca[2+] homeostasis alterations in BMVECa is fundamental to identify new possible drug targets that diminish/prevent BBB permeabilization in neurological and neurodegenerative disorders.}, }
@article {pmid34248597, year = {2021}, author = {Asadi, MR and Sadat Moslehian, M and Sabaie, H and Jalaiei, A and Ghafouri-Fard, S and Taheri, M and Rezazadeh, M}, title = {Stress Granules and Neurodegenerative Disorders: A Scoping Review.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {650740}, pmid = {34248597}, issn = {1663-4365}, abstract = {Cytoplasmic ribonucleoproteins called stress granules (SGs) are considered as one of the main cellular solutions against stress. Their temporary presence ends with stress relief. Any factor such as chronic stress or mutations in the structure of the components of SGs that lead to their permanent presence can affect their interactions with pathological aggregations and increase the degenerative effects. SGs involved in RNA mechanisms are important factors in the pathophysiology of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and Alzheimer's diseases (AD). Although many studies have been performed in the field of SGs and neurodegenerative disorders, so far, no systematic studies have been executed in this field. The purpose of this study is to provide a comprehensive perspective of all studies about the role of SGs in the pathogenesis of neurodegenerative disorders with a focus on the protein ingredients of these granules. This scoping review is based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted until December 2020. Publications were screened independently by two reviewers and quantitative and qualitative analysis was performed on the extracted data. Bioinformatics analysis was used to plot the network and predict interprotein interactions. In addition, GO analysis was performed. A total of 48 articles were identified that comply the inclusion criteria. Most studies on neurodegenerative diseases have been conducted on ALS, AD, and FTD using human post mortem tissues. Human derived cell line studies have been used only in ALS. A total 29 genes of protein components of SGs have been studied, the most important of which are TDP-43, TIA-1, PABP-1. Bioinformatics studies have predicted 15 proteins to interact with the protein components of SGs, which may be the constituents of SGs. Understanding the interactions between SGs and pathological aggregations in neurodegenerative diseases can provide new targets for treatment of these disorders.}, }
@article {pmid34247168, year = {2021}, author = {Brown, CA and Lally, C and Kupelian, V and Flanders, WD}, title = {Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants.}, journal = {Neuroepidemiology}, volume = {55}, number = {5}, pages = {342-353}, doi = {10.1159/000516752}, pmid = {34247168}, issn = {1423-0208}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/genetics ; C9orf72 Protein/genetics ; Humans ; Incidence ; Prevalence ; Superoxide Dismutase ; Superoxide Dismutase-1/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder characterized by progressive deterioration of motor neurons. Assessment of the size/geographic distribution of the ALS population, including ALS with genetic origin, is needed to understand the burden of the disease and the need for clinical intervention and therapy.<br><br>OBJECTIVES: The main objective of this study was to estimate the number of prevalent and incident ALS cases overall and superoxide dismutase 1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) ALS in 22 countries across Europe (Belgium, France, Germany, Ireland, Italy, Netherlands, Norway, Russia, Spain, Sweden, and UK), North America (USA and Canada), Latin America (Argentina, Brazil, Colombia, Mexico, and Uruguay), and Asia (China, Japan, South Korea, and Taiwan).<br><br>METHODS: A comprehensive literature search was conducted to identify population-based studies reporting ALS prevalence and/or incidence rates. Pooled prevalence and incidence rates were obtained using a meta-analysis approach at the country and regional geographic level. A country-level pooled estimate was used when &#x2265;2 studies were available per country and geographic regional pooled estimates were used otherwise. The proportion of cases with a SOD1 or C9orf72 mutation among sporadic (sALS) and familial (fALS) cases were obtained from a previous systematic review and meta-analysis.<br><br>RESULTS: Pooled prevalence rates (per 100,000 persons) and incidence rates (per 100,000 person-years) were 6.22 and 2.31 for Europe, 5.20 and 2.35 for North America, 3.41 and 1.25 for Latin America, 3.01 and 0.93 for Asian countries excluding Japan, and 7.96 and 1.76 for Japan, respectively. Significant heterogeneity in reported incidence and prevalence was observed within and between countries/geographic regions. The estimated number of 2020 ALS cases across the 22 countries is 121,028 prevalent and 41,128 incident cases. The total estimated number of prevalent SOD1 cases is 2,876 cases, of which, 1,342 (47%) were fALS and 1,534 (53%) were sALS, and the number of incident SOD1 cases is 946 (434 [46%] fALS and 512 [54%] sALS). The total estimated number of prevalent C9orf72 cases is 4,545 (1,198 [26%] fALS, 3,347 [74%] sALS), and the number of incident C9orf72 cases is 1,706 (450 [26%] fALS and 1,256 [74%] sALS).<br><br>DISCUSSION: The estimated number of patients with SOD1 and C9orf72 ALS suggests that although the proportions of SOD1 and C9orf72 are higher among those with fALS, the majority of SOD1 and C9orf72 ALS cases may be found among those with sALS (about 53 and 74%, respectively). These results suggest that classification of fALS based on reported family history does not capture the full picture of ALS of genetic origin.}, }
@article {pmid34243604, year = {2021}, author = {Mirzaei, R and Bouzari, B and Hosseini-Fard, SR and Mazaheri, M and Ahmadyousefi, Y and Abdi, M and Jalalifar, S and Karimitabar, Z and Teimoori, A and Keyvani, H and Zamani, F and Yousefimashouf, R and Karampoor, S}, title = {Role of microbiota-derived short-chain fatty acids in nervous system disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {139}, number = {}, pages = {111661}, doi = {10.1016/j.biopha.2021.111661}, pmid = {34243604}, issn = {1950-6007}, mesh = {Animals ; Fatty Acids, Volatile/*metabolism ; Gastrointestinal Microbiome/*physiology ; Humans ; Microbiota/*physiology ; Nervous System Diseases/*metabolism/*microbiology ; }, abstract = {During the past decade, accumulating evidence from the research highlights the suggested effects of bacterial communities of the human gut microbiota and their metabolites on health and disease. In this regard, microbiota-derived metabolites and their receptors, beyond the immune system, maintain metabolism homeostasis, which is essential to maintain the host's health by balancing the utilization and intake of nutrients. It has been shown that gut bacterial dysbiosis can cause pathology and altered bacterial metabolites' formation, resulting in dysregulation of the immune system and metabolism. The short-chain fatty acids (SCFAs), such as butyrate, acetate, and succinate, are produced due to the fermentation process of bacteria in the gut. It has been noted remodeling in the gut microbiota metabolites associated with the pathophysiology of several neurological disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, stress, anxiety, depression, autism, vascular dementia, schizophrenia, stroke, and neuromyelitis optica spectrum disorders, among others. This review will discuss the current evidence from the most significant studies dealing with some SCFAs from gut microbial metabolism with selected neurological disorders.}, }
@article {pmid34238153, year = {2022}, author = {Mannan, A and Singh, TG and Singh, V and Garg, N and Kaur, A and Singh, M}, title = {Insights into the Mechanism of the Therapeutic Potential of Herbal Monoamine Oxidase Inhibitors in Neurological Diseases.}, journal = {Current drug targets}, volume = {23}, number = {3}, pages = {286-310}, doi = {10.2174/1389450122666210707120256}, pmid = {34238153}, issn = {1873-5592}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; }, abstract = {Monoamine oxidase (MAO) is an enzyme that catalyzes the deamination of monoamines and other proteins. MAO's hyperactivation results in the massive generation of reactive oxygen species, which leads to a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and depression-like disorders. Although synthetic MAO inhibitors are clinically available, they are associated with side effects such as hepatotoxicity, cheese reaction, hypertensive crisis, and so on, necessitating the investigation of alternative MAO inhibitors from a natural source with a safe profile. Herbal medications have a significant impact on the prevention of many diseases; additionally, they have fewer side effects and serve as a precursor for drug development. This review discusses the potential of herbal MAO inhibitors as well as their associated mechanism of action, with an aim to foster future research on herbal MAO inhibitors as a potential treatment for neurological diseases.}, }
@article {pmid34237390, year = {2021}, author = {Tang, W and Li, Y and Li, Y and Wang, Q}, title = {Caveolin-1, a novel player in cognitive decline.}, journal = {Neuroscience and biobehavioral reviews}, volume = {129}, number = {}, pages = {95-106}, doi = {10.1016/j.neubiorev.2021.06.044}, pmid = {34237390}, issn = {1873-7528}, mesh = {Caveolae/metabolism ; *Caveolin 1/metabolism ; *Cognitive Dysfunction/metabolism ; Humans ; Oxidative Stress ; Quality of Life ; }, abstract = {Cognitive decline (CD), which related to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and diabetes mellitus, is a growing health concern that has a great impact on the patients' quality of life. Although extensive efforts, the mechanisms of CD are still far from being clarified, not to mention the effective treatment and prevention strategies. Caveolin-1 (Cav-1), a trans-membrane protein, is a major component of the caveolae structure and scaffolding proteins. Recently, ample evidence depicts a strong correlation between Cav-1 and CD, however, the specific role of Cav-1 in CD has not been clearly examined and how they might be connected have yet to be identified. This review seeks to provide a comprehensive overview about how Cav-1 modulates pathogeneses of CD-associated diseases. In summary, Cav-1 can promote structural and functional plasticity of neurons, improve neurogenesis, relieve mitochondrial dysfunction, inhibit inflammation and suppress oxidative stress, which have shed light on the idea that Cav-1 may be an efficacious therapeutic target to treat CD.}, }
@article {pmid34237230, year = {2021}, author = {Angelini, C and Siciliano, G}, title = {An updated review on the role of prescribed exercise in the management of Amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {21}, number = {8}, pages = {871-879}, doi = {10.1080/14737175.2021.1951706}, pmid = {34237230}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Exercise ; Exercise Therapy ; Humans ; Muscle Weakness ; Pain ; }, abstract = {Introduction: Amyotrophic Lateral Sclerosis is a group of sporadic or familial disorders, characterized by upper and lower motor neuron involvement, with variable progression.Areas covered: The authors present the role of exercise in counteracting muscle disuse, particularly on limb weakness, that might antagonize denervation. The persistence of inactivity can affect many systems and the patient can develop deconditioning, muscle joint tightness, which causes contractures and pain. The main area of the review is the evaluation of the studies done on ALS exercise rehabilitation protocols, this was done by the evaluation of outcome function and patient independence exerting a positive psychological impact on both patients and caregivers. A second target is underlying differences between endurance and resistance exercise protocols, which may throw light on the biological mechanism of skeletal muscle repair, functional performance, and metabolism. The authors present not only exercise trials but also molecular biomarkers that might help define changes induced by physical rehabilitation. Our findings might help to achieve the best rehabilitation program. A standardized rehabilitation protocol is important: the instructed patients may continue therapy at home or be followed by telemedicine.Expert opinion: This review evaluates exercise rehabilitation, a controversial issue, evidence is weak and non-conclusive but represents the art status.}, }
@article {pmid34234641, year = {2021}, author = {Verde, F and Otto, M and Silani, V}, title = {Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {679199}, pmid = {34234641}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer's disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo. However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.}, }
@article {pmid34225938, year = {2021}, author = {Ahmed, RM and Steyn, F and Dupuis, L}, title = {Hypothalamus and weight loss in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {180}, number = {}, pages = {327-338}, doi = {10.1016/B978-0-12-820107-7.00020-3}, pmid = {34225938}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Hypothalamus ; Weight Loss ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder. While initially pathophysiology was thought to be restricted to motor deficits, it is increasingly recognized that patients develop prominent changes in weight and eating behavior that result from and mediate the underlying neurodegenerative process. These changes include alterations in metabolism, lipid levels, and insulin resistance. Emerging research suggests that these alterations may be mediated through changes in the hypothalamic function, with atrophy of the hypothalamus shown in both ALS patients and also presymptomatic genetic at-risk patients. This chapter reviews the evidence for hypothalamic involvement in ALS, including melanocortin pathways and potential treatment targets.}, }
@article {pmid34225924, year = {2021}, author = {Stewart, CA and Finger, EC}, title = {The supraoptic and paraventricular nuclei in healthy aging and neurodegeneration.}, journal = {Handbook of clinical neurology}, volume = {180}, number = {}, pages = {105-123}, doi = {10.1016/B978-0-12-820107-7.00007-0}, pmid = {34225924}, issn = {0072-9752}, mesh = {*Healthy Aging ; Humans ; Hypothalamus ; *Neurodegenerative Diseases ; Paraventricular Hypothalamic Nucleus ; Supraoptic Nucleus ; }, abstract = {The supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus undergo structural and functional changes over the course of healthy aging. These nuclei and their connections are also heterogeneously affected by several different neurodegenerative diseases. This chapter reviews the involvement of the SON and PVN, the hypothalamic-pituitary axes, and the peptide hormones produced in both nuclei in healthy aging and in neurodegeneration, with a focus on Alzheimer's disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis, progressive supranuclear palsy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy, and Huntington's disease. Although age-related changes occur in several regions of the hypothalamus, the SON and PVN are relatively preserved during aging and in many neurodegenerative disorders. With aging, these nuclei do undergo some sexually dimorphic changes including changes in size and levels of vasopressin and corticotropin-releasing hormone, likely due to age-related changes in sex hormones. In contrast, oxytocinergic cells and circulating levels of thyrotropin-releasing hormone remain stable. A relative resistance to many forms of neurodegenerative pathology is also observed, in comparison to other hypothalamic and brain regions. Mirroring the pattern observed in aging, pathologic hallmarks of AD, and some subtypes of FTD are observed in the PVN, though to a milder degree than are observed in other brain regions, while the SON is relatively spared. In contrast, the SON appears more vulnerable to alpha-synuclein pathology of DLB and PD. The consequences of these alterations may help to inform several of the physiologic changes observed in aging and neurodegenerative disease.}, }
@article {pmid34225614, year = {2022}, author = {Mohi-Ud-Din, R and Mir, RH and Wani, TU and Shah, AJ and Mohi-Ud-Din, I and Dar, MA and Pottoo, FH}, title = {Novel Drug Delivery System for Curcumin: Implementation to Improve Therapeutic Efficacy against Neurological Disorders.}, journal = {Combinatorial chemistry &amp; high throughput screening}, volume = {25}, number = {4}, pages = {607-615}, doi = {10.2174/1386207324666210705114058}, pmid = {34225614}, issn = {1875-5402}, mesh = {Biological Availability ; *Curcumin/chemistry/pharmacology/therapeutic use ; Drug Delivery Systems ; Humans ; Micelles ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {BACKGROUND: Curcumin, a hydrophobic polyphenolic compound present in Curcuma longa Linn. (Turmeric), has been used to improve various neurodegenerative conditions, including Amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Prion disease, stroke, anxiety, depression, and ageing. However, the Blood-Brain Barrier (BBB) impedes the delivery of curcumin to the brain, limiting its therapeutic potential.<br><br>OBJECTIVE/AIM: This review summarises the recent advances towards the therapeutic efficacy of curcumin along with various novel strategies to overcome its poor bioavailability across the bloodbrain barrier.<br><br>METHODS: The data for the compilation of this review work were searched in PubMed Scopus, Google Scholar, and Science Direct.<br><br>RESULTS: Various approaches have been opted to expedite the delivery of curcumin across the blood-brain barrier, including liposomes, micelles, polymeric nanoparticles, exosomes, dualtargeting nanoparticles, etc. Conclusion: The review also summarises the numerous toxicological studies and the role of curcumin in CNS disorders.}, }
@article {pmid34223392, year = {2021}, author = {Donoghue, A and Navarro, K and Diederich, E and Auerbach, M and Cheng, A}, title = {Deliberate practice and mastery learning in resuscitation education: A scoping review.}, journal = {Resuscitation plus}, volume = {6}, number = {}, pages = {100137}, pmid = {34223392}, issn = {2666-5204}, abstract = {STUDY AIM: To summarize the current state of knowledge of deliberate practice and mastery learning (DP and/or ML) as teaching methods for resuscitation education.<br><br>METHODS: A scoping review of PubMed, Scopus, and Embase was conducted through March 1, 2021. Studies examining the effect of the incorporation of either deliberate practice and/or mastery learning during resuscitation education were eligible for inclusion. Included studies were dichotomized into studies comparing deliberate practice and/or mastery learning to other training methods (randomized controlled trials) and studies examining before and after impact of deliberate practice and/or mastery learning alone (observational studies). Studies and findings were tabulated and summarized using the scoping review methodology published by Arksey and O'Malley.<br><br>RESULTS: 63 published studies were screened; sixteen studies met all inclusion criteria (4 randomized controlled trials and 12 observational studies). One randomized controlled trial and eleven observational studies demonstrated improvement in skill and/or knowledge following educational interventions using deliberate practice and/or mastery learning. Significant variability between studies with regard to research designs, learner groups, comparators, and outcomes of interest made quantitative summarization of findings difficult.<br><br>CONCLUSIONS: The incorporation of deliberate practice and/or mastery learning in resuscitation education may be associated with improved educational outcomes and less skill decay than other educational methods. Current literature on DP and ML suffers from a lack of consistency in research methodology, subjects, and outcomes. Future research should employ uniform definitions for deliberate practice and mastery learning, follow research design that isolates its effect, and examine generalizable and translatable outcomes.}, }
@article {pmid34223327, year = {2021}, author = {Lockey, A and Conaghan, P and Bland, A and Astin, F}, title = {Educational theory and its application to advanced life support courses: a narrative review.}, journal = {Resuscitation plus}, volume = {5}, number = {}, pages = {100053}, pmid = {34223327}, issn = {2666-5204}, abstract = {The knowledge, skills and attitudes taught on Advanced Life Support (ALS) courses are an important learning requirement for healthcare professionals who are involved with the care of acutely unwell patients. It is essential that the course design and delivery is appropriately planned to ensure that it optimises the learning opportunities for all learners. This paper offers a narrative review of how the application of educational theory has positively influenced the evolution of ALS courses since their inception in the late twentieth century. By embracing and understanding the relevant educational theories, the ALS course design has transformed from a predominantly lecture-based and behaviourist approach, to a more participative and social constructivist approach to learning. In addition, the advent of smarter technology and the challenges posed by the COVID-19 pandemic have facilitated a more connectivist approach to learning. It can therefore be demonstrated that the ALS course is influenced by a combination of theoretical approaches and provides a diverse framework of teaching and learning strategies that cater for many individual learning styles. Any further evolution and development of the course should be based upon contemporary educational theory to ensure that it remains fit for purpose.}, }
@article {pmid34222330, year = {2021}, author = {Ruano, D}, title = {Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {658742}, pmid = {34222330}, issn = {2296-889X}, abstract = {Aging is a biological and multifactorial process characterized by a progressive and irreversible deterioration of the physiological functions leading to a progressive increase in morbidity. In the next decades, the world population is expected to reach ten billion, and globally, elderly people over 80 are projected to triple in 2050. Consequently, it is also expected an increase in the incidence of age-related pathologies such as cancer, diabetes, or neurodegenerative disorders. Disturbance of cellular protein homeostasis (proteostasis) is a hallmark of normal aging that increases cell vulnerability and might be involved in the etiology of several age-related diseases. This review will focus on the molecular alterations occurring during normal aging in the most relevant protein quality control systems such as molecular chaperones, the UPS, and the ALS. Also, alterations in their functional cooperation will be analyzed. Finally, the role of inflammation, as a synergistic negative factor of the protein quality control systems during normal aging, will also be addressed. A better comprehension of the age-dependent modifications affecting the cellular proteostasis, as well as the knowledge of the mechanisms underlying these alterations, might be very helpful to identify relevant risk factors that could be responsible for or contribute to cell deterioration, a fundamental question still pending in biomedicine.}, }
@article {pmid34220504, year = {2021}, author = {Islam, MS and Quispe, C and Hossain, R and Islam, MT and Al-Harrasi, A and Al-Rawahi, A and Martorell, M and Mamurova, A and Seilkhan, A and Altybaeva, N and Abdullayeva, B and Docea, AO and Calina, D and Sharifi-Rad, J}, title = {Neuropharmacological Effects of Quercetin: A Literature-Based Review.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {665031}, pmid = {34220504}, issn = {1663-9812}, abstract = {Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer's disease, Amyloid β peptide, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.}, }
@article {pmid34219266, year = {2021}, author = {Lünemann, JD and Malhotra, S and Shinohara, ML and Montalban, X and Comabella, M}, title = {Targeting Inflammasomes to Treat Neurological Diseases.}, journal = {Annals of neurology}, volume = {90}, number = {2}, pages = {177-188}, doi = {10.1002/ana.26158}, pmid = {34219266}, issn = {1531-8249}, mesh = {Animals ; Anti-Inflammatory Agents/administration &amp; dosage ; Drug Delivery Systems/*methods/trends ; Humans ; Inflammasomes/*antagonists &amp; inhibitors/metabolism ; Inflammation Mediators/*antagonists &amp; inhibitors/metabolism ; Nervous System Diseases/*drug therapy/metabolism ; Treatment Outcome ; }, abstract = {Inflammasomes are multimeric protein complexes that can sense a plethora of microbe- and damage-associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome-mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL-18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune-mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021;90:177-188.}, }
@article {pmid34217018, year = {2021}, author = {Tolkovsky, A and Kipervasser, S and Fainmesser, Y and Alcalay, Y and Gadoth, A}, title = {A paraneoplastic syndrome misdiagnosed as ALS: What are the red flags? A case report and review of the literature.}, journal = {Journal of neuroimmunology}, volume = {358}, number = {}, pages = {577635}, doi = {10.1016/j.jneuroim.2021.577635}, pmid = {34217018}, issn = {1872-8421}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/*cerebrospinal fluid/*diagnosis ; *Diagnostic Errors ; Humans ; Male ; Paraneoplastic Syndromes, Nervous System/blood/*cerebrospinal fluid/*diagnosis ; }, abstract = {Background Paraneoplastic motor neuron disease (PMND) is a rare, non-classical form of paraneoplastic neurological syndrome (PNS). Anti-Hu and anti-CV2/CRMP5 PNS are mostly associated with small-cell lung cancer (SCLC) and consist of highly variable clinical syndromes, including sensory neuronopathy, cerebellar ataxia and/or limbic encephalitis. However, substantial motor impairment is uncommon, particularly when no sensory dysfunction co-exists. Case A 72-year-old man with a recent diagnosis of amyotrophic lateral sclerosis (ALS) was referred to our department of neurology for evaluation. The patient sub-acutely developed progressive neurological dysfunction including erectile dysfunction, behavioral changes, limb weakness, dysphagia, anorexia, as well as worsening stridor that necessitated tracheostomy due to bilateral vocal cord paralysis (BVCP). Neurological examination revealed motor weakness of upper and lower motor neuron origin with autonomic and cognitive dysfunction. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis, elevated protein, presence of oligoclonal bands (OCB), and neuronal antibody testing was positive for anti-Hu and anti-CV2/CRMP5. Based on these findings a diagnosis of a PNS was made. Evaluation for malignancy was negative, and immunosuppressive/immunomodulatory treatment was initiated but had little effect during fifteen months of follow-up. Conclusions Although PMND is very rare, in an atypical presentation, especially with features that are not usually present in ALS such as autonomic dysfunction, sensory disturbance or cognitive decline, this etiology should be in the differential diagnosis.}, }
@article {pmid34215308, year = {2021}, author = {Querfurth, H and Lee, HK}, title = {Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {44}, pmid = {34215308}, issn = {1750-1326}, mesh = {Animals ; Humans ; Nerve Degeneration/*metabolism/*pathology ; Neurodegenerative Diseases/*metabolism/*pathology ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found in the diverse signaling pathways of the Mammalian/mechanistic target of rapamycin (mTOR). As a nutrient sensor, mTOR has important homeostatic functions to regulate energy metabolism and support neuronal growth and plasticity. However, in Alzheimer's disease (AD), mTOR alternately plays important pathogenic roles by inhibiting both insulin signaling and autophagic removal of β-amyloid (Aβ) and phospho-tau (ptau) aggregates. It also plays a role in the cerebrovascular dysfunction of AD. mTOR is a serine/threonine kinase residing at the core in either of two multiprotein complexes termed mTORC1 and mTORC2. Recent data suggest that their balanced actions also have implications for Parkinson's disease (PD) and Huntington's disease (HD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Beyond rapamycin; an mTOR inhibitor, there are rapalogs having greater tolerability and micro delivery modes, that hold promise in arresting these age dependent conditions.}, }
@article {pmid34212304, year = {2021}, author = {Rana, T and Behl, T and Sehgal, A and Mehta, V and Singh, S and Bhatia, S and Al-Harrasi, A and Bungau, S}, title = {Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {58}, number = {10}, pages = {4886-4905}, pmid = {34212304}, issn = {1559-1182}, mesh = {Animals ; Autophagosomes/drug effects/*metabolism/pathology ; Autophagy/drug effects/*physiology ; Cell Survival/drug effects/physiology ; Humans ; Lysosomes/drug effects/metabolism/pathology ; MTOR Inhibitors/pharmacology/therapeutic use ; Metformin/pharmacology/therapeutic use ; Neurodegenerative Diseases/drug therapy/*metabolism/pathology ; Neurons/drug effects/*metabolism/pathology ; Trehalose/pharmacology/therapeutic use ; }, abstract = {Autophagy is a catabolic pathway by which misfolded proteins or damaged organelles are engulfed by autophagosomes and then transported to lysosomes for degradation. Recently, a great improvement has been done to explain the molecular mechanisms and roles of autophagy in several important cellular metabolic processes. Besides being a vital clearance pathway or a cell survival pathway in response to different stresses, autophagy dysfunction, either upregulated or down-regulated, has been suggested to be linked with numerous neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Impairment at different stages of autophagy results in the formation of large protein aggregates and damaged organelles, which leads to the onset and progression of different neurodegenerative disorders. This article elucidates the recent progress about the role of autophagy in neurodegenerative disorders and explains how autophagy dysfunction is linked with the pathogenesis of such disorders as well as the novel potential autophagy-associated therapies for treating them.}, }
@article {pmid34212303, year = {2022}, author = {Lynch, E and Peek, E and Reilly, M and FitzGibbons, C and Robertson, S and Suzuki, M}, title = {Current Progress in the Creation, Characterization, and Application of Human Stem Cell-derived in Vitro Neuromuscular Junction Models.}, journal = {Stem cell reviews and reports}, volume = {18}, number = {2}, pages = {768-780}, pmid = {34212303}, issn = {2629-3277}, support = {R01 NS091540/NS/NINDS NIH HHS/United States ; R01 AR077191/AR/NIAMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/therapy ; Animals ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; *Muscular Atrophy, Spinal ; Neuromuscular Junction/metabolism ; }, abstract = {Human pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) are of great value for studying developmental processes, disease modeling, and drug testing. One area in which the use of human PSCs has become of great interest in recent years is for in vitro models of the neuromuscular junction (NMJ). The NMJ is a synapse at which a motor neuron releases acetylcholine to bind to skeletal muscle and stimulate contraction. Degeneration of the NMJ and subsequent loss of muscle function is a common feature of many neuromuscular diseases such as myasthenia gravis, spinal muscular atrophy, and amyotrophic lateral sclerosis. In order to develop new therapies for patients with neuromuscular diseases, it is essential to understand mechanisms taking place at the NMJ. However, we have limited ability to study the NMJ in living human patients, and animal models are limited by physiological relevance. Therefore, an in vitro model of the NMJ consisting of human cells is of great value. The use of stem cells for in vitro NMJ models is still in progress and requires further optimization in order to yield reliable, reproducible results. The objective of this review is (1) to outline the current progress towards fully PSC-derived in vitro co-culture models of the human NMJ and (2) to discuss future directions and challenges that must be overcome in order to create reproducible fully PSC-derived models that can be used for developmental studies, disease modeling, and drug testing.}, }
@article {pmid34211575, year = {2021}, author = {Lin, M and Hu, X and Chang, S and Chang, Y and Bian, W and Hu, R and Wang, J and Zhu, Q and Qiu, J}, title = {Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6678422}, pmid = {34211575}, issn = {1741-427X}, abstract = {Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.}, }
@article {pmid34209133, year = {2021}, author = {D'Amico, E and Grosso, G and Nieves, JW and Zanghì, A and Factor-Litvak, P and Mitsumoto, H}, title = {Metabolic Abnormalities, Dietary Risk Factors and Nutritional Management in Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {13}, number = {7}, pages = {}, pmid = {34209133}, issn = {2072-6643}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*metabolism ; Body Mass Index ; *Diet ; Humans ; Malnutrition/complications ; *Nutritional Status ; Risk Factors ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.}, }
@article {pmid34208136, year = {2021}, author = {Sindona, C and Schepici, G and Contestabile, V and Bramanti, P and Mazzon, E}, title = {NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {57}, number = {6}, pages = {}, pmid = {34208136}, issn = {1648-9144}, support = {//Ministero della Salute/ ; }, mesh = {*Coronavirus Infections ; Humans ; *Neurodegenerative Diseases ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {Coronavirus disease 2019 (COVID-19) is a rapidly spreading contagious infectious disease caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that primarily affects the respiratory tract as well as the central nervous system (CNS). SARS-CoV-2 infection occurs through the interaction of the viral protein Spike with the angiotensin II receptor (ACE 2), leading to an increase of angiotensin II and activation of nicotinamide adenine dinucleotide phosphate oxidase2 (NOX2), resulting in the release of both reactive oxygen species (ROS) and inflammatory molecules. The purpose of the review is to explain that SARS-CoV-2 infection can determine neuroinflammation that induces NOX2 activation in microglia. To better understand the role of NOX2 in inflammation, an overview of its involvement in neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) is provided. To write this manuscript, we performed a PubMed search to evaluate the possible relationship of SARS-CoV-2 infection in NOX2 activation in microglia, as well as the role of NOX2 in NDs. Several studies highlighted that NOX2 activation in microglia amplifies neuroinflammation. To date, there is no clinical treatment capable of counteracting its activation, however, NOX2 could be a promising pharmaceutical target useful for both the treatment and prevention of NDs and COVID-19 treatment.}, }
@article {pmid34207859, year = {2021}, author = {Quessada, C and Bouscary, A and René, F and Valle, C and Ferri, A and Ngo, ST and Loeffler, JP}, title = {Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?.}, journal = {Cells}, volume = {10}, number = {6}, pages = {}, pmid = {34207859}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Male ; Muscle, Skeletal/*metabolism/pathology ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose-fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.}, }
@article {pmid34207355, year = {2021}, author = {Takahashi, S}, title = {Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {12}, pages = {}, pmid = {34207355}, issn = {1422-0067}, support = {19K08002//Japan Society for the Promotion of Science/ ; Grant Number 19K08002//JSPS KAKENHI/ ; }, mesh = {Animals ; Astrocytes/*metabolism ; *Glycolysis ; Humans ; NF-E2-Related Factor 2/metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Pentose Phosphate Pathway ; Stroke/genetics/*metabolism ; }, abstract = {Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.}, }
@article {pmid34206738, year = {2021}, author = {Kovács, Z and Brunner, B and Ari, C}, title = {Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases.}, journal = {Nutrients}, volume = {13}, number = {7}, pages = {}, pmid = {34206738}, issn = {2072-6643}, support = {12/2020//ELTE BDPK Excellence Program 12/2020/ ; 003//Ketone Technologies LLC/ ; }, mesh = {3-Hydroxybutyric Acid/blood ; Aging/*drug effects ; Alzheimer Disease ; *Diet, Ketogenic ; *Dietary Supplements ; Epigenomics ; Esters ; Histones ; Humans ; Ketone Bodies/*metabolism ; Ketones/blood ; Ketosis/blood ; Learning/drug effects ; Longevity ; Memory/drug effects ; Mitochondria/metabolism ; Mitochondrial Diseases ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease ; Proteostasis ; Stem Cells ; }, abstract = {Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.}, }
@article {pmid34204831, year = {2021}, author = {Karpe, Y and Chen, Z and Li, XJ}, title = {Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {34204831}, issn = {1424-8247}, support = {2019//Spastic Paraplegia Foundation/ ; R01NS118066/NS/NINDS NIH HHS/United States ; R21NS109837/NS/NINDS NIH HHS/United States ; R21 NS109837/NS/NINDS NIH HHS/United States ; R01 NS118066/NS/NINDS NIH HHS/United States ; 2016//The Blazer Foundation/ ; }, abstract = {Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.}, }
@article {pmid34204536, year = {2021}, author = {Aliperti, V and Skonieczna, J and Cerase, A}, title = {Long Non-Coding RNA (lncRNA) Roles in Cell Biology, Neurodevelopment and Neurological Disorders.}, journal = {Non-coding RNA}, volume = {7}, number = {2}, pages = {}, pmid = {34204536}, issn = {2311-553X}, abstract = {Development is a complex process regulated both by genetic and epigenetic and environmental clues. Recently, long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression in several tissues including the brain. Altered expression of lncRNAs has been linked to several neurodegenerative, neurodevelopmental and mental disorders. The identification and characterization of lncRNAs that are deregulated or mutated in neurodevelopmental and mental health diseases are fundamental to understanding the complex transcriptional processes in brain function. Crucially, lncRNAs can be exploited as a novel target for treating neurological disorders. In our review, we first summarize the recent advances in our understanding of lncRNA functions in the context of cell biology and then discussing their association with selected neuronal development and neurological disorders.}, }
@article {pmid34204060, year = {2021}, author = {Limoni, G}, title = {Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34204060}, issn = {1422-0067}, mesh = {Animals ; Axon Guidance/*physiology ; *Cues ; Humans ; *Models, Neurological ; Neuronal Plasticity/physiology ; Neurons/*physiology ; Semaphorins/*metabolism ; }, abstract = {The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.}, }
@article {pmid34202494, year = {2021}, author = {Yang, X and Ji, Y and Wang, W and Zhang, L and Chen, Z and Yu, M and Shen, Y and Ding, F and Gu, X and Sun, H}, title = {Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {7}, pages = {}, pmid = {34202494}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.}, }
@article {pmid34201812, year = {2021}, author = {Kim, K}, title = {Glutathione in the Nervous System as a Potential Therapeutic Target to Control the Development and Progression of Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {7}, pages = {}, pmid = {34201812}, issn = {2076-3921}, support = {2017R1C1B1008825//Ministry of Science and ICT, South Korea/ ; 2019R1F1A1045639//Ministry of Science and ICT, South Korea/ ; 2021//Soonchunhyang University/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that affects the motor neurons responsible for regulating muscle movement. However, the molecular pathogenic mechanisms of ALS remain poorly understood. A deficiency in the antioxidant tripeptide glutathione (GSH) in the nervous system appears to be involved in several neurodegenerative diseases characterized by the loss of neuronal cells. Impaired antioxidant defense systems, and the accumulation of oxidative damage due to increased dysfunction in GSH homeostasis are known to be involved in the development and progression of ALS. Aberrant GSH metabolism and redox status following oxidative damage are also associated with various cellular organelles, including the mitochondria and nucleus, and are crucial factors in neuronal toxicity induced by ALS. In this review, we provide an overview of the implications of imbalanced GSH homeostasis and its molecular characteristics in various experimental models of ALS.}, }
@article {pmid34201693, year = {2021}, author = {Savinetti, I and Papagna, A and Foti, M}, title = {Human Monocytes Plasticity in Neurodegeneration.}, journal = {Biomedicines}, volume = {9}, number = {7}, pages = {}, pmid = {34201693}, issn = {2227-9059}, support = {0941.2013//Cariplo Foundation/ ; }, abstract = {Monocytes play a crucial role in immunity and tissue homeostasis. They constitute the first line of defense during the inflammatory process, playing a role in the pathogenesis and progression of diseases, making them an attractive therapeutic target. They are heterogeneous in morphology and surface marker expression, which suggest different molecular and physiological properties. Recent evidences have demonstrated their ability to enter the brain, and, as a consequence, their hypothetical role in different neurodegenerative diseases. In this review, we will discuss the current knowledge about the correlation between monocyte dysregulation in the brain and/or in the periphery and neurological diseases in humans. Here we will focus on the most common neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis.}, }
@article {pmid34199845, year = {2021}, author = {Péladeau, C and Sandhu, JK}, title = {Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34199845}, issn = {1422-0067}, mesh = {Animals ; Humans ; Inflammasomes/*metabolism ; Inflammation/complications/metabolism/*pathology ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Neuromuscular Diseases/etiology/metabolism/*pathology ; }, abstract = {Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.}, }
@article {pmid34199367, year = {2021}, author = {Chen, HJ and Mitchell, JC}, title = {Mechanisms of TDP-43 Proteinopathy Onset and Propagation.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34199367}, issn = {1422-0067}, support = {Chen/Apr17/858-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; Mitchell/Apr14/828-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; (internal funding)//KCL Van Geest foundation fellowship/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; DNA-Binding Proteins/*genetics ; Frontotemporal Dementia/genetics/pathology ; Humans ; Mutation/genetics ; Protein Aggregation, Pathological/*genetics ; RNA-Binding Proteins/*genetics ; TDP-43 Proteinopathies/*genetics/pathology ; }, abstract = {TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease.}, }
@article {pmid34198557, year = {2021}, author = {Obrador, E and Salvador-Palmer, R and López-Blanch, R and Jihad-Jebbar, A and Vallés, SL and Estrela, JM}, title = {The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS.}, journal = {International journal of molecular sciences}, volume = {22}, number = {12}, pages = {}, pmid = {34198557}, issn = {1422-0067}, support = {OTR2017-18255INVES//Universitat de Val&#xe8;ncia/ ; OTR2018-19337INVES//Elysium Health Inc., USA/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Animals ; *Energy Metabolism ; Humans ; Mitochondria/*metabolism ; Motor Neurons/pathology ; Oxidation-Reduction ; *Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3-5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.}, }
@article {pmid34196307, year = {2021}, author = {Singh, A and Dawson, TM and Kulkarni, S}, title = {Neurodegenerative disorders and gut-brain interactions.}, journal = {The Journal of clinical investigation}, volume = {131}, number = {13}, pages = {}, pmid = {34196307}, issn = {1558-8238}, support = {P50 NS038377/NS/NINDS NIH HHS/United States ; R01 AG066768/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/etiology/physiopathology ; Amyotrophic Lateral Sclerosis/etiology/physiopathology ; Animals ; Brain/physiopathology ; Digestive System/innervation/physiopathology ; Disease Models, Animal ; Disease Progression ; Dysbiosis/physiopathology ; Enteric Nervous System/*physiopathology ; Gastrointestinal Microbiome/physiology ; Humans ; Huntington Disease/etiology/physiopathology ; Models, Neurological ; Mutation ; Neurodegenerative Diseases/*etiology/microbiology/*physiopathology ; Parkinson Disease/etiology/physiopathology ; }, abstract = {Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other's functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.}, }
@article {pmid34196236, year = {2022}, author = {Castanheira, A and Swash, M and De Carvalho, M}, title = {Percutaneous gastrostomy in amyotrophic lateral sclerosis: a review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {176-189}, doi = {10.1080/21678421.2021.1946089}, pmid = {34196236}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/complications/surgery ; *Gastrostomy/methods ; Humans ; Prospective Studies ; Quality of Life ; Retrospective Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) causes dysphagia and consequent poor nutrition. Sometimes enteral feeding is offered. Percutaneous endoscopic gastrostomy (PEG) is currently the technique of choice for enteral nutrition of these patients. This systematic review addresses the role of PEG and other enteral feeding techniques in maintaining ALS patients' survival and quality of life and in identifying prognostic factors for survival, in order to optimize their usefulness. We also evaluated the mortality of enteral feeding in the first 30 days after each procedure and its complications. Studies were retrieved from Pubmed, Google Scholar, and Cochrane databases, using the relevant keywords, and by hand search. The inclusion criteria were prospective and retrospective designs of studies of people with clinically diagnosed ALS in whom gastrostomy or nasogastric enteral feeding were used in management, published in English. Studies with sample sizes <40, or which focused on a specific gastrostomy technique utilizing less than 30 subjects were excluded in order to avoid small sample bias. We conclude that PEG is safe and probably prolongs survival in non-malnourished ALS patients. However, older age at onset, marked loss of weight or reduced body mass index from symptomatic onset, and marked respiratory dysfunction negatively influence the outcome after PEG insertion. The currently available evidence does not meaningfully address the impact of PEG on quality of life in ALS. The literature about other enteral feeding techniques is insufficient for reliable conclusions. The optimum time for PEG insertion and preferences for specific gastrostomy techniques also require more investigation.}, }
@article {pmid34194489, year = {2021}, author = {Wang, L and Yu, CC and Liu, XY and Deng, XN and Tian, Q and Du, YJ}, title = {Epigenetic Modulation of Microglia Function and Phenotypes in Neurodegenerative Diseases.}, journal = {Neural plasticity}, volume = {2021}, number = {}, pages = {9912686}, pmid = {34194489}, issn = {1687-5443}, mesh = {DNA Methylation ; *Epigenesis, Genetic ; Histone Code ; Humans ; Microglia/*physiology ; Neurodegenerative Diseases/*genetics ; Neuroinflammatory Diseases/genetics/pathology ; Phenotype ; }, abstract = {Microglia-mediated neuroinflammation is one of the most remarkable hallmarks of neurodegenerative diseases (NDDs), including AD, PD, and ALS. Accumulating evidence indicates that microglia play both neuroprotective and detrimental roles in the onset and progression of NDDs. Yet, the specific mechanisms of action surrounding microglia are not clear. Modulation of microglia function and phenotypes appears to be a potential strategy to reverse NDDs. Until recently, research into the epigenetic mechanisms of diseases has been gradually developed, making it possible to elucidate the molecular mechanisms underlying the epigenetic regulation of microglia in NDDs. This review highlights the function and phenotypes of microglia, elucidates the relationship between microglia, epigenetic modifications, and NDDs, as well as the possible mechanisms underlying the epigenetic modulation of microglia in NDDs with a focus on potential intervention strategies.}, }
@article {pmid34194300, year = {2021}, author = {Nagano, S and Araki, T}, title = {Axonal Transport and Local Translation of mRNA in Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {697973}, pmid = {34194300}, issn = {1662-5099}, abstract = {Since neurons have long neurites including axons, it is crucial for the axons to transport many intracellular substances such as proteins and mitochondria in order to maintain their morphology and function. In addition, mRNAs have also been shown to be transported within axons. RNA-binding proteins form complexes with mRNAs, and regulate transport of the mRNAs to axons, as well as locally translate them into proteins. Local translation of mRNAs actively occurs during the development and damage of neurons, and plays an important role in axon elongation, regeneration, and synapse formation. In recent years, it has been reported that impaired axonal transport and local translation of mRNAs may be involved in the pathogenesis of some neurodegenerative diseases. In this review, we discuss the significance of mRNA axonal transport and their local translation in amyotrophic lateral sclerosis/frontotemporal dementia, spinal muscular atrophy, Alzheimer's disease, and fragile X syndrome.}, }
@article {pmid34194298, year = {2021}, author = {Zhu, X and Zhang, Y and Yang, X and Hao, C and Duan, H}, title = {Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {618171}, pmid = {34194298}, issn = {1662-5099}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) is complex and diverse. Over the decades, our understanding of NDD has been limited to pathological features. However, recent advances in gene sequencing have facilitated elucidation of NDD at a deeper level. Gene editing techniques have uncovered new genetic links to phenotypes, promoted the development of novel treatment strategies and equipped researchers with further means to construct effective cell and animal models. The current review describes the history of evolution of gene editing tools, with the aim of improving overall understanding of this technology, and focuses on the four most common NDD disorders to demonstrate the potential future applications and research directions of gene editing.}, }
@article {pmid34183988, year = {2021}, author = {Pervin, Z and Stephen, JM}, title = {Effect of alcohol on the central nervous system to develop neurological disorder: pathophysiological and lifestyle modulation can be potential therapeutic options for alcohol-induced neurotoxication.}, journal = {AIMS neuroscience}, volume = {8}, number = {3}, pages = {390-413}, pmid = {34183988}, issn = {2373-7972}, abstract = {The central nervous system (CNS) is the major target for adverse effects of alcohol and extensively promotes the development of a significant number of neurological diseases such as stroke, brain tumor, multiple sclerosis (MS), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Excessive alcohol consumption causes severe neuro-immunological changes in the internal organs including irreversible brain injury and it also reacts with the defense mechanism of the blood-brain barrier (BBB) which in turn leads to changes in the configuration of the tight junction of endothelial cells and white matter thickness of the brain. Neuronal injury associated with malnutrition and oxidative stress-related BBB dysfunction may cause neuronal degeneration and demyelination in patients with alcohol use disorder (AUD); however, the underlying mechanism still remains unknown. To address this question, studies need to be performed on the contributing mechanisms of alcohol on pathological relationships of neurodegeneration that cause permanent neuronal damage. Moreover, alcohol-induced molecular changes of white matter with conduction disturbance in neurotransmission are a likely cause of myelin defect or axonal loss which correlates with cognitive dysfunctions in AUD. To extend our current knowledge in developing a neuroprotective environment, we need to explore the pathophysiology of ethanol (EtOH) metabolism and its effect on the CNS. Recent epidemiological studies and experimental animal research have revealed the association between excessive alcohol consumption and neurodegeneration. This review supports an interdisciplinary treatment protocol to protect the nervous system and to improve the cognitive outcomes of patients who suffer from alcohol-related neurodegeneration as well as clarify the pathological involvement of alcohol in causing other major neurological disorders.}, }
@article {pmid34179015, year = {2021}, author = {Desole, C and Gallo, S and Vitacolonna, A and Montarolo, F and Bertolotto, A and Vivien, D and Comoglio, P and Crepaldi, T}, title = {HGF and MET: From Brain Development to Neurological Disorders.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {683609}, pmid = {34179015}, issn = {2296-634X}, abstract = {Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, encoded by the MET cellular proto-oncogene, are expressed in the nervous system from pre-natal development to adult life, where they are involved in neuronal growth and survival. In this review, we highlight, beyond the neurotrophic action, novel roles of HGF-MET in synaptogenesis during post-natal brain development and the connection between deregulation of MET expression and developmental disorders such as autism spectrum disorder (ASD). On the pharmacology side, HGF-induced MET activation exerts beneficial neuroprotective effects also in adulthood, specifically in neurodegenerative disease, and in preclinical models of cerebral ischemia, spinal cord injuries, and neurological pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). HGF is a key factor preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms. Recent evidence suggests that HGF acts on neural stem cells to enhance neuroregeneration. The possible therapeutic application of HGF and HGF mimetics for the treatment of neurological disorders is discussed.}, }
@article {pmid34177918, year = {2021}, author = {Passaro, AP and Lebos, AL and Yao, Y and Stice, SL}, title = {Immune Response in Neurological Pathology: Emerging Role of Central and Peripheral Immune Crosstalk.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {676621}, pmid = {34177918}, issn = {1664-3224}, mesh = {Alzheimer Disease/*immunology ; Animals ; Blood-Brain Barrier/immunology ; Brain Injuries/*immunology ; Brain Neoplasms/*immunology ; Central Nervous System/immunology ; Humans ; Immune System/*immunology ; *Immunity ; Inflammation/immunology ; Multiple Sclerosis/*immunology ; Neuroimmunomodulation/*immunology ; Parkinson Disease/*immunology ; Stroke/*immunology ; }, abstract = {Neuroinflammation is a key component of neurological disorders and is an important therapeutic target; however, immunotherapies have been largely unsuccessful. In cases where these therapies have succeeded, particularly multiple sclerosis, they have primarily focused on one aspect of the disease and leave room for improvement. More recently, the impact of the peripheral immune system is being recognized, since it has become evident that the central nervous system is not immune-privileged, as once thought. In this review, we highlight key interactions between central and peripheral immune cells in neurological disorders. While traditional approaches have examined these systems separately, the immune responses and processes in neurological disorders consist of substantial crosstalk between cells of the central and peripheral immune systems. Here, we provide an overview of major immune effector cells and the role of the blood-brain barrier in regard to neurological disorders and provide examples of this crosstalk in various disorders, including stroke and traumatic brain injury, multiple sclerosis, neurodegenerative diseases, and brain cancer. Finally, we propose targeting central-peripheral immune interactions as a potential improved therapeutic strategy to overcome failures in clinical translation.}, }
@article {pmid34177463, year = {2021}, author = {Pham, TK and Buczek, WA and Mead, RJ and Shaw, PJ and Collins, MO}, title = {Proteomic Approaches to Study Cysteine Oxidation: Applications in Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {678837}, pmid = {34177463}, issn = {1662-5099}, support = {MR/S004920/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Oxidative stress appears to be a key feature of many neurodegenerative diseases either as a cause or consequence of disease. A range of molecules are subject to oxidation, but in particular, proteins are an important target and measure of oxidative stress. Proteins are subject to a range of oxidative modifications at reactive cysteine residues, and depending on the level of oxidative stress, these modifications may be reversible or irreversible. A range of experimental approaches has been developed to characterize cysteine oxidation of proteins. In particular, mass spectrometry-based proteomic methods have emerged as a powerful means to identify and quantify cysteine oxidation sites on a proteome scale; however, their application to study neurodegenerative diseases is limited to date. Here we provide a guide to these approaches and highlight the under-exploited utility of these methods to measure oxidative stress in neurodegenerative diseases for biomarker discovery, target engagement and to understand disease mechanisms.}, }
@article {pmid34175843, year = {2021}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.}, journal = {Neuroimmunomodulation}, volume = {28}, number = {4}, pages = {204-212}, doi = {10.1159/000516926}, pmid = {34175843}, issn = {1423-0216}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Motor Neurons ; Neuroglia ; Spinal Cord ; Superoxide Dismutase ; }, abstract = {ALS is a human neurodegenerative disorder that induces a progressive paralysis of voluntary muscles due to motor neuron loss. The causes are unknown, and there is no curative treatment available. Mitochondrial dysfunction is a hallmark of ALS pathology; however, it is currently unknown whether it is a cause or a consequence of disease progression. Recent evidence indicates that glial mitochondrial function changes to cope with energy demands and critically influences neuronal death and disease progression. Aberrant glial cells detected in the spinal cord of diseased animals are characterized by increased proliferation rate and reduced mitochondrial bioenergetics. These features can be compared with cancer cell behavior of adapting to nutrient microenvironment by altering energy metabolism, a concept known as metabolic reprogramming. We focus on data that suggest that aberrant glial cells in ALS undergo metabolic reprogramming and profound changes in glial mitochondrial activity, which are associated with motor neuron death in ALS. This review article emphasizes on the association between metabolic reprogramming and glial reactivity, bringing new paradigms from the area of cancer research into neurodegenerative diseases. Targeting glial mitochondrial function and metabolic reprogramming may result in promising therapeutic strategies for ALS.}, }
@article {pmid34174223, year = {2021}, author = {D'Errico, M and Parlanti, E and Pascucci, B and Filomeni, G and Mastroberardino, PG and Dogliotti, E}, title = {The interplay between mitochondrial functionality and genome integrity in the prevention of human neurologic diseases.}, journal = {Archives of biochemistry and biophysics}, volume = {710}, number = {}, pages = {108977}, doi = {10.1016/j.abb.2021.108977}, pmid = {34174223}, issn = {1096-0384}, mesh = {DNA Damage ; DNA Repair ; DNA, Mitochondrial/genetics/metabolism ; Genome, Human ; Genome, Mitochondrial ; Genomic Instability ; Humans ; Metabolic Networks and Pathways ; Mitochondria/*genetics/*metabolism ; Mitochondrial Dynamics ; Mitophagy ; Models, Neurological ; Mutation ; Neurodegenerative Diseases/*genetics/*metabolism/prevention &amp; control ; Reactive Oxygen Species/metabolism ; }, abstract = {As mitochondria are vulnerable to oxidative damage and represent the main source of reactive oxygen species (ROS), they are considered key tuners of ROS metabolism and buffering, whose dysfunction can progressively impact neuronal networks and disease. Defects in DNA repair and DNA damage response (DDR) may also affect neuronal health and lead to neuropathology. A number of congenital DNA repair and DDR defective syndromes, indeed, show neurological phenotypes, and a growing body of evidence indicate that defects in the mechanisms that control genome stability in neurons acts as aging-related modifiers of common neurodegenerative diseases such as Alzheimer, Parkinson's, Huntington diseases and Amyotrophic Lateral Sclerosis. In this review we elaborate on the established principles and recent concepts supporting the hypothesis that deficiencies in either DNA repair or DDR might contribute to neurodegeneration via mechanisms involving mitochondrial dysfunction/deranged metabolism.}, }
@article {pmid34173837, year = {2021}, author = {Kok, JR and Palminha, NM and Dos Santos Souza, C and El-Khamisy, SF and Ferraiuolo, L}, title = {DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {78}, number = {15}, pages = {5707-5729}, pmid = {34173837}, issn = {1420-9071}, support = {MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; 103844/WT_/Wellcome Trust/United Kingdom ; MR/R015902/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; # SBF002\1142/WT_/Wellcome Trust/United Kingdom ; 137661//Lister Institute of Preventive Medicine/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Animals ; Astrocytes/*pathology ; DNA Damage/*genetics ; Humans ; Motor Neurons/pathology ; Mutation/genetics ; Neurodegenerative Diseases/*genetics/*pathology ; }, abstract = {Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.}, }
@article {pmid34162530, year = {2021}, author = {Burns, TC and Quinones-Hinojosa, A}, title = {Regenerative medicine for neurological diseases-will regenerative neurosurgery deliver?.}, journal = {BMJ (Clinical research ed.)}, volume = {373}, number = {}, pages = {n955}, doi = {10.1136/bmj.n955}, pmid = {34162530}, issn = {1756-1833}, support = {R01 CA216855/CA/NCI NIH HHS/United States ; R01 CA195503/CA/NCI NIH HHS/United States ; R01 CA200399/CA/NCI NIH HHS/United States ; R21 NS109770/NS/NINDS NIH HHS/United States ; R01 NS059770/NS/NINDS NIH HHS/United States ; R43 CA221490/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Genetic Therapy/methods ; Humans ; Nervous System Diseases/*surgery ; Neurosurgery/methods ; Regenerative Medicine/*methods/trends ; Stem Cell Transplantation/methods ; }, abstract = {Regenerative medicine aspires to transform the future practice of medicine by providing curative, rather than palliative, treatments. Healing the central nervous system (CNS) remains among regenerative medicine's most highly prized but formidable challenges. "Regenerative neurosurgery" provides access to the CNS or its surrounding structures to preserve or restore neurological function. Pioneering efforts over the past three decades have introduced cells, neurotrophins, and genes with putative regenerative capacity into the CNS to combat neurodegenerative, ischemic, and traumatic diseases. In this review we critically evaluate the rationale, paradigms, and translational progress of regenerative neurosurgery, harnessing access to the CNS to protect, rejuvenate, or replace cell types otherwise irreversibly compromised by neurological disease. We discuss the evidence surrounding fetal, somatic, and pluripotent stem cell derived implants to replace endogenous neuronal and glial cell types and provide trophic support. Neurotrophin based strategies via infusions and gene therapy highlight the motivation to preserve neuronal circuits, the complex fidelity of which cannot be readily recreated. We specifically highlight ongoing translational efforts in Parkinson's disease, amyotrophic lateral sclerosis, stroke, and spinal cord injury, using these to illustrate the principles, challenges, and opportunities of regenerative neurosurgery. Risks of associated procedures and novel neurosurgical trials are discussed, together with the ethical challenges they pose. After decades of efforts to develop and refine necessary tools and methodologies, regenerative neurosurgery is well positioned to advance treatments for refractory neurological diseases. Strategic multidisciplinary efforts will be critical to harness complementary technologies and maximize mechanistic feedback, accelerating iterative progress toward cures for neurological diseases.}, }
@article {pmid34160330, year = {2022}, author = {Dressman, D and Elyaman, W}, title = {T Cells: A Growing Universe of Roles in Neurodegenerative Diseases.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {28}, number = {4}, pages = {335-348}, doi = {10.1177/10738584211024907}, pmid = {34160330}, issn = {1089-4098}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Animals ; Central Nervous System ; Humans ; *Neurodegenerative Diseases ; *Parkinson Disease ; T-Lymphocytes ; }, abstract = {T cells play a central role in homeostasis and host defense against infectious diseases. T cell dysregulation can lead to recognizing self-antigens as foreign antigens, causing a detrimental autoimmune response. T cell involvement in multiple sclerosis (MS), long understood to be an autoimmune-mediated neurodegenerative disease, is well characterized. More recently, a role for T cells has also been identified for the neurodegenerative diseases Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Interestingly, several alleles and variants of human leukocyte antigen (HLA) genes have been classified as AD and PD risk genes. HLA codes for components of major histocompatibility complex (MHC) class I or class II, both of which are expressed by microglia, the innate immune cells of the central nervous system (CNS). Thus, both microglia and T cells may potentially interact in an antigen-dependent or independent fashion to shape the inflammatory cascade occurring in neurodegenerative diseases. Dissecting the antigen specificity of T cells may lead to new options for disease-modifying treatments in neurodegenerative diseases. Here, we review the current understanding of T cells in neurodegenerative diseases. We summarize the subsets of T cells, their phenotype and potential functions in animal models and in human studies of neurodegenerative diseases.}, }
@article {pmid34156104, year = {2021}, author = {Serruya, MD and Rosenwasser, RH}, title = {An artificial nervous system to treat chronic stroke.}, journal = {Artificial organs}, volume = {45}, number = {8}, pages = {804-812}, doi = {10.1111/aor.13998}, pmid = {34156104}, issn = {1525-1594}, mesh = {Animals ; Brain-Computer Interfaces ; Chronic Disease ; Humans ; Nerve Transfer ; Neurofeedback ; Neuronal Plasticity ; Prostheses and Implants ; Recovery of Function ; Stroke Rehabilitation/*methods ; Wearable Electronic Devices ; }, abstract = {Despite remarkable advances in the treatment of numerous medical conditions, neurological disease and injury remains an outstanding challenge and cause of disability worldwide. The decreased regenerative capacity and extreme complexity and heterogeneity of nervous tissue, in particular the brain, and the fact that the brain remains the least understood organ, have hampered our ability to provide definitive treatments for prevalent conditions such as stroke. Stroke is the second-leading cause of death worldwide, and the nervous system is intimately involved in other prevalent conditions including ischemic heart disease, diabetes mellitus, and hypertension. Advances in neuromodulation, electroceuticals, microsurgical techniques, optogenetics, brain-computer interfaces, and autologous constructs offer potential solutions to address the otherwise permanent neurological deficits of stroke and other conditions. Here we review these various approaches to build an "artificial nervous system" that could restore function and independence in people living with these conditions. We focus on stroke both because it is the leading cause of neurological disability worldwide and because we anticipate that advances in the reversal of stroke-related deficits will have ripple effects benefiting people with other neurological conditions including spinal cord injury, traumatic brain injury, ALS, and muscular dystrophy.}, }
@article {pmid34153344, year = {2021}, author = {De Marchi, F and Munitic, I and Amedei, A and Berry, JD and Feldman, EL and Aronica, E and Nardo, G and Van Weehaeghe, D and Niccolai, E and Prtenjaca, N and Sakowski, SA and Bendotti, C and Mazzini, L}, title = {Interplay between immunity and amyotrophic lateral sclerosis: Clinical impact.}, journal = {Neuroscience and biobehavioral reviews}, volume = {127}, number = {}, pages = {958-978}, pmid = {34153344}, issn = {1873-7528}, support = {R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Immune System ; *Neurodegenerative Diseases ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease. Despite decades of research and many new insights into disease biology over the 150 years since the disease was first described, causative pathogenic mechanisms in ALS remain poorly understood, especially in sporadic cases. Our understanding of the role of the immune system in ALS pathophysiology, however, is rapidly expanding. The aim of this manuscript is to summarize the recent advances regarding the immune system involvement in ALS, with particular attention to clinical translation. We focus on the potential pathophysiologic mechanism of the immune system in ALS, discussing local and systemic factors (blood, cerebrospinal fluid, and microbiota) that influence ALS onset and progression in animal models and people. We also explore the potential of Positron Emission Tomography to detect neuroinflammation in vivo, and discuss ongoing clinical trials of therapies targeting the immune system. With validation in human patients, new evidence in this emerging field will serve to identify novel therapeutic targets and provide realistic hope for personalized treatment strategies.}, }
@article {pmid34151652, year = {2022}, author = {Kriss, A and Jenkins, T}, title = {Muscle MRI in motor neuron diseases: a systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {161-175}, doi = {10.1080/21678421.2021.1936062}, pmid = {34151652}, issn = {2167-9223}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Biomarkers ; Cross-Sectional Studies ; Humans ; Magnetic Resonance Imaging/methods ; *Motor Neuron Disease/complications/diagnostic imaging ; Muscle, Skeletal/diagnostic imaging/pathology ; }, abstract = {Objective: To summarize applications of muscle magnetic resonance imaging (MRI) in cross-sectional assessment and longitudinal monitoring of motor neuron diseases and evaluate associations with clinical assessment techniques.Methods: PubMed and Scopus were searched for research published up to May 2021 relating to muscle MRI in motor neuron diseases, according to predefined inclusion and exclusion criteria. Studies were systematically appraised for bias and data were extracted for discussion.Results: Twenty-eight papers met inclusion criteria. The studies assessed muscle T1- and T2-weighted signal, diffusion, muscle volume, and fat infiltration, employing quantitative, qualitative, and semi-quantitative approaches. Various regions of interest were considered; changes in thigh and calf muscles were most frequently reported. Preliminary evidence of concordance between clinical and radiological findings and utility as an objective longitudinal biomarker is emerging.Conclusion: Muscle MRI appears a promising objective, versatile, and practical biomarker to assess motor neuron diseases.}, }
@article {pmid34146626, year = {2021}, author = {Zhang, L and Sun, H and Zhao, J and Lee, J and Ee Low, L and Gong, L and Chen, Y and Wang, N and Zhu, C and Lin, P and Liang, Z and Wei, M and Ling, D and Li, F}, title = {Dynamic nanoassemblies for imaging and therapy of neurological disorders.}, journal = {Advanced drug delivery reviews}, volume = {175}, number = {}, pages = {113832}, doi = {10.1016/j.addr.2021.113832}, pmid = {34146626}, issn = {1872-8294}, mesh = {Animals ; Brain/diagnostic imaging/drug effects/pathology ; Humans ; Magnetite Nanoparticles ; *Nanoparticle Drug Delivery System ; Nanoparticles/metabolism ; Nervous System Diseases/diagnostic imaging/*drug therapy ; Neuroinflammatory Diseases/diagnostic imaging/drug therapy/pathology ; }, abstract = {The past decades have witnessed an increased incidence of neurological disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and epilepsy, which significantly lower patients' life quality and increase the economic and social burden. Recently, nanomedicines composed of imaging and/or therapeutic agents have been explored to diagnose and/or treat NDs due to their enhanced bioavailability, blood-brain barrier (BBB) permeability, and targeting capacity. Intriguingly, dynamic nanoassemblies self-assembled from functional nanoparticles to simultaneously interfere with multiple pathogenic substances and pathological changes, have been regarded as one of the foremost candidates to improve the diagnostic and therapeutic efficacy of NDs. To help readers better understand this emerging field, in this review, the pathogenic mechanism of different types of NDs is briefly introduced, then the functional nanoparticles used as building blocks in the construction of dynamic nanoassemblies for NDs theranostics are summarized. Furthermore, dynamic nanoassemblies that can actively cross the BBB to target brain lesions, sensitively and efficiently diagnose or treat NDs, and effectively promote neuroregeneration are highlighted. Finally, we conclude with our perspectives on the future development in this field.}, }
@article {pmid34140671, year = {2021}, author = {Malik, I and Kelley, CP and Wang, ET and Todd, PK}, title = {Molecular mechanisms underlying nucleotide repeat expansion disorders.}, journal = {Nature reviews. Molecular cell biology}, volume = {22}, number = {9}, pages = {589-607}, pmid = {34140671}, issn = {1471-0080}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; R01 NS114253/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS112291/NS/NINDS NIH HHS/United States ; R01 AG058636/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; DNA Repeat Expansion/*genetics ; Gene Silencing ; Genomic Instability ; Humans ; Mutation ; Neurodegenerative Diseases/*genetics/pathology/physiopathology ; Organ Specificity ; Protein Biosynthesis ; R-Loop Structures ; RNA/chemistry/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {The human genome contains over one million short tandem repeats. Expansion of a subset of these repeat tracts underlies over fifty human disorders, including common genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72), polyglutamine-associated ataxias and Huntington disease, myotonic dystrophy, and intellectual disability disorders such as Fragile X syndrome. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.}, }
@article {pmid34138412, year = {2022}, author = {De Nicola, AF and Meyer, M and Garay, L and Kruse, MS and Schumacher, M and Guennoun, R and Gonzalez Deniselle, MC}, title = {Progesterone and Allopregnanolone Neuroprotective Effects in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Cellular and molecular neurobiology}, volume = {42}, number = {1}, pages = {23-40}, pmid = {34138412}, issn = {1573-6830}, support = {PIP 112 20120100016//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; 20020100100062//Universidad de Buenos Aires/ ; 2002010010008//Universidad de Buenos Aires/ ; PICT2012-0009//Ministry of Science and Technology/ ; PICT 2019 3292//Ministry of Science and Technology/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; Disease Models, Animal ; Mice ; Motor Neurons ; *Neuroprotective Agents/metabolism/pharmacology/therapeutic use ; Pregnanolone/metabolism/pharmacology/therapeutic use ; Progesterone/metabolism/pharmacology/therapeutic use ; Spinal Cord/metabolism ; }, abstract = {Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.}, }
@article {pmid34137510, year = {2022}, author = {Park, Y and Page, N and Salamon, I and Li, D and Rasin, MR}, title = {Making sense of mRNA landscapes: Translation control in neurodevelopment.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {13}, number = {1}, pages = {e1674}, doi = {10.1002/wrna.1674}, pmid = {34137510}, issn = {1757-7012}, support = {R01 NS075367/NS/NINDS NIH HHS/United States ; }, mesh = {Alternative Splicing ; Animals ; *RNA/metabolism ; RNA Stability ; RNA, Messenger ; *RNA-Binding Proteins/metabolism ; }, abstract = {Like all other parts of the central nervous system, the mammalian neocortex undergoes temporally ordered set of developmental events, including proliferation, differentiation, migration, cellular identity, synaptogenesis, connectivity formation, and plasticity changes. These neurodevelopmental mechanisms have been characterized by studies focused on transcriptional control. Recent findings, however, have shown that the spatiotemporal regulation of post-transcriptional steps like alternative splicing, mRNA traffic/localization, mRNA stability/decay, and finally repression/derepression of protein synthesis (mRNA translation) have become just as central to the neurodevelopment as transcriptional control. A number of dynamic players act post-transcriptionally in the neocortex to regulate these steps, as RNA binding proteins (RBPs), ribosomal proteins (RPs), long non-coding RNAs, and/or microRNA. Remarkably, mutations in these post-transcriptional regulators have been associated with neurodevelopmental, neurodegenerative, inherited, or often co-morbid disorders, such as microcephaly, autism, epilepsy, intellectual disability, white matter diseases, Rett-syndrome like phenotype, spinocerebellar ataxia, and amyotrophic lateral sclerosis. Here, we focus on the current state, advanced methodologies and pitfalls of this exciting and upcoming field of RNA metabolism with vast potential in understanding fundamental neurodevelopmental processes and pathologies. This article is categorized under: Translation > Translation Regulation RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.}, }
@article {pmid34137441, year = {2021}, author = {Giagnorio, E and Malacarne, C and Mantegazza, R and Bonanno, S and Marcuzzo, S}, title = {MyomiRs and their multifaceted regulatory roles in muscle homeostasis and amyotrophic lateral sclerosis.}, journal = {Journal of cell science}, volume = {134}, number = {12}, pages = {}, doi = {10.1242/jcs.258349}, pmid = {34137441}, issn = {1477-9137}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Homeostasis ; Humans ; Motor Neurons ; Muscle, Skeletal ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of both upper and lower motor neurons (MNs). The main clinical features of ALS are motor function impairment, progressive muscle weakness, muscle atrophy and, ultimately, paralysis. Intrinsic skeletal muscle deterioration plays a crucial role in the disease and contributes to ALS progression. Currently, there are no effective treatments for ALS, highlighting the need to obtain a deeper understanding of the molecular events underlying degeneration of both MNs and muscle tissue, with the aim of developing successful therapies. Muscle tissue is enriched in a group of microRNAs called myomiRs, which are effective regulators of muscle homeostasis, plasticity and myogenesis in both physiological and pathological conditions. After providing an overview of ALS pathophysiology, with a focus on the role of skeletal muscle, we review the current literature on myomiR network dysregulation as a contributing factor to myogenic perturbations and muscle atrophy in ALS. We argue that, in view of their critical regulatory function at the interface between MNs and skeletal muscle fiber, myomiRs are worthy of further investigation as potential molecular targets of therapeutic strategies to improve ALS symptoms and counteract disease progression.}, }
@article {pmid34130692, year = {2021}, author = {Fernandes, F and Barbalho, I and Barros, D and Valentim, R and Teixeira, C and Henriques, J and Gil, P and Dourado Júnior, M}, title = {Biomedical signals and machine learning in amyotrophic lateral sclerosis: a systematic review.}, journal = {Biomedical engineering online}, volume = {20}, number = {1}, pages = {61}, pmid = {34130692}, issn = {1475-925X}, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; Disease Progression ; Humans ; Machine Learning ; }, abstract = {INTRODUCTION: The use of machine learning (ML) techniques in healthcare encompasses an emerging concept that envisages vast contributions to the tackling of rare diseases. In this scenario, amyotrophic lateral sclerosis (ALS) involves complexities that are yet not demystified. In ALS, the biomedical signals present themselves as potential biomarkers that, when used in tandem with smart algorithms, can be useful to applications within the context of the disease.<br><br>METHODS: This Systematic Literature Review (SLR) consists of searching for and investigating primary studies that use ML techniques and biomedical signals related to ALS. Following the definition and execution of the SLR protocol, 18 articles met the inclusion, exclusion, and quality assessment criteria, and answered the SLR research questions.<br><br>DISCUSSIONS: Based on the results, we identified three classes of ML applications combined with biomedical signals in the context of ALS: diagnosis (72.22%), communication (22.22%), and survival prediction (5.56%).<br><br>CONCLUSIONS: Distinct algorithmic models and biomedical signals have been reported and present promising approaches, regardless of their classes. In summary, this SLR provides an overview of the primary studies analyzed as well as directions for the construction and evolution of technology-based research within the scope of ALS.}, }
@article {pmid34130251, year = {2021}, author = {Bashford, J and Chan, WK and Coutinho, E and Norwood, F and Mills, K and Shaw, CE}, title = {Demystifying the spontaneous phenomena of motor hyperexcitability.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {132}, number = {8}, pages = {1830-1844}, doi = {10.1016/j.clinph.2021.03.053}, pmid = {34130251}, issn = {1872-8952}, support = {BASHFORD/JUN16/947-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; MR/P000983/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Electromyography/*methods ; Fasciculation/diagnosis/*physiopathology ; Humans ; Isaacs Syndrome/diagnosis/*physiopathology ; Motor Neurons/*physiology ; Myokymia/diagnosis/*physiopathology ; Peripheral Nervous System Diseases/diagnosis/physiopathology ; }, abstract = {Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control by the central nervous system, a hierarchical network of these specialist neurons ensures muscular strength is coordinated, gradated and adaptable. However, spontaneous activation of these cells and their axons can result in abnormal muscular twitching. The muscular twitch is the common building block of several distinct clinical patterns, namely fasciculation, myokymia and neuromyotonia. When attempting to distinguish these entities electromyographically, their unique temporal and morphological profiles must be appreciated. Detection and quantification of burst duration, firing frequency, multiplet patterns and amplitude are informative. A common feature is their persistence during sleep. In this review, we explain the accepted terminology used to describe the spontaneous phenomena of motor hyperexcitability, highlighting potential pitfalls amidst a bemusing and complex collection of overlapping terms. We outline the relevance of these findings within the context of disease, principally amyotrophic lateral sclerosis, Isaacs syndrome and Morvan syndrome. In addition, we highlight the use of high-density surface electromyography, suggesting that more widespread use of this non-invasive technique is likely to provide an enhanced understanding of these motor hyperexcitability syndromes.}, }
@article {pmid34127244, year = {2021}, author = {Tăuţan, AM and Ionescu, B and Santarnecchi, E}, title = {Artificial intelligence in neurodegenerative diseases: A review of available tools with a focus on machine learning techniques.}, journal = {Artificial intelligence in medicine}, volume = {117}, number = {}, pages = {102081}, doi = {10.1016/j.artmed.2021.102081}, pmid = {34127244}, issn = {1873-2860}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; *Artificial Intelligence ; Humans ; Machine Learning ; *Neurodegenerative Diseases/diagnosis ; }, abstract = {Neurodegenerative diseases have shown an increasing incidence in the older population in recent years. A significant amount of research has been conducted to characterize these diseases. Computational methods, and particularly machine learning techniques, are now very useful tools in helping and improving the diagnosis as well as the disease monitoring process. In this paper, we provide an in-depth review on existing computational approaches used in the whole neurodegenerative spectrum, namely for Alzheimer's, Parkinson's, and Huntington's Diseases, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy. We propose a taxonomy of the specific clinical features, and of the existing computational methods. We provide a detailed analysis of the various modalities and decision systems employed for each disease. We identify and present the sleep disorders which are present in various diseases and which represent an important asset for onset detection. We overview the existing data set resources and evaluation metrics. Finally, we identify current remaining open challenges and discuss future perspectives.}, }
@article {pmid34125683, year = {2021}, author = {Gonzalez, H and George, R and Muzaffar, S and Acevedo, J and Hoppner, S and Mayr, C and Yoo, J and Fitzek, F and Elfadel, I}, title = {Hardware Acceleration of EEG-Based Emotion Classification Systems: A Comprehensive Survey.}, journal = {IEEE transactions on biomedical circuits and systems}, volume = {15}, number = {3}, pages = {412-442}, doi = {10.1109/TBCAS.2021.3089132}, pmid = {34125683}, issn = {1940-9990}, mesh = {Acceleration ; *Autism Spectrum Disorder ; Computers ; Electroencephalography ; Emotions ; Humans ; }, abstract = {Recent years have witnessed a growing interest in EEG-based wearable classifiers of emotions, which could enable the real-time monitoring of patients suffering from neurological disorders such as Amyotrophic Lateral Sclerosis (ALS), Autism Spectrum Disorder (ASD), or Alzheimer's. The hope is that such wearable emotion classifiers would facilitate the patients' social integration and lead to improved healthcare outcomes for them and their loved ones. Yet in spite of their direct relevance to neuro-medicine, the hardware platforms for emotion classification have yet to fill up some important gaps in their various approaches to emotion classification in a healthcare context. In this paper, we present the first hardware-focused critical review of EEG-based wearable classifiers of emotions and survey their implementation perspectives, their algorithmic foundations, and their feature extraction methodologies. We further provide a neuroscience-based analysis of current hardware accelerators of emotion classifiers and use it to map out several research opportunities, including multi-modal hardware platforms, accelerators with tightly-coupled cores operating robustly in the near/supra-threshold region, and pre-processing libraries for universal EEG-based datasets.}, }
@article {pmid34125534, year = {2021}, author = {P, P and Justin, A and Ananda Kumar, TD and Chinaswamy, M and Kumar, BRP}, title = {Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {13}, pages = {2261-2272}, doi = {10.1021/acschemneuro.1c00085}, pmid = {34125534}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; PPAR gamma ; *Parkinson Disease/drug therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Quality of Life ; *Thiazolidinediones ; }, abstract = {Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects. Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.}, }
@article {pmid34122112, year = {2021}, author = {Zhu, FD and Hu, YJ and Yu, L and Zhou, XG and Wu, JM and Tang, Y and Qin, DL and Fan, QZ and Wu, AG}, title = {Nanoparticles: A Hope for the Treatment of Inflammation in CNS.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {683935}, pmid = {34122112}, issn = {1663-9812}, abstract = {Neuroinflammation, an inflammatory response within the central nervous system (CNS), is a main hallmark of common neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others. The over-activated microglia release pro-inflammatory cytokines, which induces neuronal death and accelerates neurodegeneration. Therefore, inhibition of microglia over-activation and microglia-mediated neuroinflammation has been a promising strategy for the treatment of neurodegenerative diseases. Many drugs have shown promising therapeutic effects on microglia and inflammation. However, the blood-brain barrier (BBB)-a natural barrier preventing brain tissue from contact with harmful plasma components-seriously hinders drug delivery to the microglial cells in CNS. As an emerging useful therapeutic tool in CNS-related diseases, nanoparticles (NPs) have been widely applied in biomedical fields for use in diagnosis, biosensing and drug delivery. Recently, many NPs have been reported to be useful vehicles for anti-inflammatory drugs across the BBB to inhibit the over-activation of microglia and neuroinflammation. Therefore, NPs with good biodegradability and biocompatibility have the potential to be developed as an effective and minimally invasive carrier to help other drugs cross the BBB or as a therapeutic agent for the treatment of neuroinflammation-mediated neurodegenerative diseases. In this review, we summarized various nanoparticles applied in CNS, and their mechanisms and effects in the modulation of inflammation responses in neurodegenerative diseases, providing insights and suggestions for the use of NPs in the treatment of neuroinflammation-related neurodegenerative diseases.}, }
@article {pmid34122008, year = {2021}, author = {Huang, X and Su, Y and Wang, N and Li, H and Li, Z and Yin, G and Chen, H and Niu, J and Yi, C}, title = {Astroglial Connexins in Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {657514}, pmid = {34122008}, issn = {1662-5099}, abstract = {Astrocytes play a crucial role in the maintenance of the normal functions of the Central Nervous System (CNS). During the pathogenesis of neurodegenerative diseases, astrocytes undergo morphological and functional remodeling, a process called reactive astrogliosis, in response to the insults to the CNS. One of the key aspects of the reactive astrocytes is the change in the expression and function of connexins. Connexins are channel proteins that highly expressed in astrocytes, forming gap junction channels and hemichannels, allowing diffusional trafficking of small molecules. Alterations of astrocytic connexin expression and function found in neurodegenerative diseases have been shown to affect the disease progression by changing neuronal function and survival. In this review, we will summarize the role of astroglial connexins in neurodegenerative diseases including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Also, we will discuss why targeting connexins can be a plausible therapeutic strategy to manage these neurodegenerative diseases.}, }
@article {pmid34121923, year = {2021}, author = {Soar, J and Böttiger, BW and Carli, P and Couper, K and Deakin, CD and Djärv, T and Lott, C and Olasveengen, T and Paal, P and Pellis, T and Perkins, GD and Sandroni, C and Nolan, JP}, title = {[Adult advanced life support].}, journal = {Notfall &amp; rettungsmedizin}, volume = {24}, number = {4}, pages = {406-446}, pmid = {34121923}, issn = {1434-6222}, abstract = {These European Resuscitation Council Advanced Life Support guidelines are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. This section provides guidelines on the prevention of and ALS treatments for both in-hospital cardiac arrest and out-of-hospital cardiac arrest.}, }
@article {pmid34118310, year = {2021}, author = {Vucic, S and Pavey, N and Haidar, M and Turner, BJ and Kiernan, MC}, title = {Cortical hyperexcitability: Diagnostic and pathogenic biomarker of ALS.}, journal = {Neuroscience letters}, volume = {759}, number = {}, pages = {136039}, doi = {10.1016/j.neulet.2021.136039}, pmid = {34118310}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Cerebral Cortex/*physiopathology ; Humans ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {Cortical hyperexcitability is an early and intrinsic feature of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS).. Importantly, cortical hyperexcitability appears to be associated with motor neuron degeneration, possibly via an anterograde glutamate-mediated excitotoxic process, thereby forming a pathogenic basis for ALS. The presence of cortical hyperexcitability in ALS patients may be readily determined by transcranial magnetic stimulation (TMS), a neurophysiological tool that provides a non-invasive and painless method for assessing cortical function. Utilising the threshold tracking TMS technique, cortical hyperexcitability has been established as a robust diagnostic biomarker that distinguished ALS from mimicking disorders at early stages of the disease process. The present review discusses the pathophysiological and diagnostic utility of cortical hyperexcitability in ALS.}, }
@article {pmid34118308, year = {2021}, author = {Braems, E and Tziortzouda, P and Van Den Bosch, L}, title = {Exploring the alternative: Fish, flies and worms as preclinical models for ALS.}, journal = {Neuroscience letters}, volume = {759}, number = {}, pages = {136041}, doi = {10.1016/j.neulet.2021.136041}, pmid = {34118308}, issn = {1872-7972}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Caenorhabditis elegans ; *Disease Models, Animal ; *Drosophila melanogaster ; *Zebrafish ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterized by the loss of upper and lower motor neurons. In general, patients succumb to respiratory insufficiency due to respiratory muscle weakness. Despite many promising therapeutic strategies primarily identified in rodent models, patient trials remain rather unsuccessful. There is a clear need for alternative approaches, which could provide directions towards the justified use of rodents and which increase the likelihood to identify new promising clinical candidates. In the last decades, the use of fast genetic approaches and the development of high-throughput screening platforms in the nematode Caenorhabditis elegans, in the fruit fly (Drosophila melanogaster) and in zebrafish (Danio rerio) have contributed to new insights into ALS pathomechanisms, disease modifiers and therapeutic targets. In this mini-review, we provide an overview of these alternative small animal studies, modeling the most common ALS genes and discuss the most recent preclinical discoveries. We conclude that small animal models will not replace rodent models, yet they clearly represent an important asset for preclinical studies.}, }
@article {pmid34118305, year = {2021}, author = {Yang, S and Yang, H and Luo, Y and Deng, X and Zhou, Y and Hu, B}, title = {Long non-coding RNAs in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {148}, number = {}, pages = {105096}, doi = {10.1016/j.neuint.2021.105096}, pmid = {34118305}, issn = {1872-9754}, mesh = {Animals ; Biomarkers ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics/therapy ; RNA, Long Noncoding/drug effects/*genetics ; }, abstract = {Neurodegenerative diseases are gradually becoming the main burden of society. The morbidity and mortality caused by neurodegenerative diseases remain significant health-care concerns. For most neurodegenerative diseases, there are no effective treatments. Over the past few decades, in a quest to exploit efficacious disease-modifying therapies for the treatment of neurodegenerative diseases, disease mechanisms, reliable biomarkers and therapeutic targets have become a research priority. At present, lncRNA is an area with potential research value. In this article, we first summarize some of the existing results of research into lncRNAs, including origin, molecular characteristics, location types, and functional types. We then introduce the possible functions of lncRNAs in different neurodegenerative diseases. Furthermore, some lncRNAs which show promise as biomarkers or potential therapeutic targets are systematically summarized.}, }
@article {pmid34112310, year = {2021}, author = {Wang, X and Huang, S and Xia, Z and Yao, S and Xia, H}, title = {[Application progress of ultrasound monitoring of diaphragm function in clinic].}, journal = {Zhonghua wei zhong bing ji jiu yi xue}, volume = {33}, number = {5}, pages = {638-640}, doi = {10.3760/cma.j.cn121430-20200824-00591}, pmid = {34112310}, issn = {2095-4352}, mesh = {Airway Extubation ; Critical Care ; *Diaphragm/diagnostic imaging ; Humans ; *Respiration, Artificial ; Ultrasonography ; }, abstract = {In recent years, point of care ultrasound (POCUS) has developed rapidly in the fields of anesthesia and critical care. POCUS is widely used in clinic to monitor the function of human tissues and organs such as the heart, lungs, and diaphragm due to its visual, non-invasive, portable, and repeatable characters at the bedside. Diaphragm is an important structure to maintain respiratory function. Diaphragm paralysis or dysfunction can cause a significant decrease in inspiratory function. The patient's diaphragm function can be assessed through monitoring diaphragm thickness and activity by POCUS, and combined with other clinical indicators, the patient's recovery of respiratory function can be comprehensively evaluated, and rapidly identify the pathological conditions, such as diaphragm paralysis, diaphragm atrophy, diaphragmatic hypoplasia and amyotrophic lateral sclerosis. Dynamic evaluation of the process from diaphragmatic dysfunction to recovery can provide guidance for weaning and extubation, and real-time feedback on the treatment effect. This article reviews the ultrasound evaluation methods and clinical applications to the diaphragm, in order to guide clinicians to use relevant indicators to comprehensively evaluate the structure and function of the diaphragm, and then diagnose and treat diaphragm dysfunction, which may help making clinical decision.}, }
@article {pmid34111479, year = {2021}, author = {Ambekar, T and Pawar, J and Rathod, R and Patel, M and Fernandes, V and Kumar, R and Singh, SB and Khatri, DK}, title = {Mitochondrial quality control: Epigenetic signatures and therapeutic strategies.}, journal = {Neurochemistry international}, volume = {148}, number = {}, pages = {105095}, doi = {10.1016/j.neuint.2021.105095}, pmid = {34111479}, issn = {1872-9754}, mesh = {Animals ; Energy Metabolism/physiology ; Epigenesis, Genetic/*drug effects/genetics ; Humans ; Mitochondria/*metabolism ; Mitophagy/drug effects/physiology ; Neurodegenerative Diseases/*drug therapy/metabolism ; Oxidative Stress/drug effects/physiology ; }, abstract = {Mitochondria are semi-autonomous organelle staging a crucial role in cellular stress response, energy metabolism and cell survival. Maintaining mitochondrial quality control is very important for its homeostasis. Pathological conditions such as oxidative stress and neurodegeneration, disrupt this quality control, and involvement of genetic and epigenetic materials in this disruption have been reported. These regulatory factors trigger mitochondrial imbalance, as seen in many neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. The dynamic regulatory pathways i.e. mitophagy, biogenesis, permeability pore transitioning, fusion-fission are affected as a consequence and have been reviewed in this article. Moreover, several epigenetic mechanisms such as DNA methylation and histone modulation participating in such neurological disorders have also been discussed. Apart from it, therapeutic approaches targeting mitochondrial quality control have been tremendously explored showing ameliorative effects for these diseases, and have been discussed here with a novel perspective.}, }
@article {pmid34108859, year = {2021}, author = {Gaetani, L and Parnetti, L and Calabresi, P and Di Filippo, M}, title = {Tracing Neurological Diseases in the Presymptomatic Phase: Insights From Neurofilament Light Chain.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {672954}, pmid = {34108859}, issn = {1662-4548}, abstract = {The identification of neurological diseases in their presymptomatic phase will be a fundamental aim in the coming years. This step is necessary both to optimize early diagnostics and to verify the effectiveness of experimental disease modifying drugs in the early stages of diseases. Among the biomarkers that can detect neurological diseases already in their preclinical phase, neurofilament light chain (NfL) has given the most promising results. Recently, its measurement in serum has enabled the identification of neurodegeneration in diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD) up to 6-10 years before the onset of symptoms. Similar results have been obtained in conditions such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), up to 2 years before clinical onset. Study of the longitudinal dynamics of serum NfL has also revealed interesting aspects of the pathophysiology of these diseases in the preclinical phase. This review sought to discuss these very recent findings on serum NfL in the presymptomatic phase of neurological diseases.}, }
@article {pmid34101196, year = {2022}, author = {Alhindi, A and Boehm, I and Chaytow, H}, title = {Small junction, big problems: Neuromuscular junction pathology in mouse models of amyotrophic lateral sclerosis (ALS).}, journal = {Journal of anatomy}, volume = {241}, number = {5}, pages = {1089-1107}, pmid = {34101196}, issn = {1469-7580}, support = {//Anatomical Society/ ; //My Name'5 Doddie Foundation/ ; //King Abdulaziz University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; C9orf72 Protein/genetics ; Disease Models, Animal ; Mice ; Neuromuscular Junction/pathology ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with an extremely heterogeneous clinical and genetic phenotype. In our efforts to find therapies for ALS, the scientific community has developed a plethora of mouse models, each with their own benefits and drawbacks. The peripheral nervous system, specifically the neuromuscular junction (NMJ), is known to be affected in ALS patients and shows marked dysfunction across mouse models. Evidence of pathology at the NMJ includes denervated NMJs, changes in endplate size and loss of terminal Schwann cells. This review compares the temporal disease progression with severity of disease at the NMJ in mouse models with the most commonly mutated genes in ALS patients (SOD1, C9ORF72, TARDBP and FUS). Despite variability, early NMJ dysfunction seems to be a common factor in models with SOD1, TARDBP and FUS mutations, while C9ORF72 models do not appear to follow the same pattern of pathology. Further work into determining the timing of NMJ pathology, particularly in newer ALS mouse models, will confirm its pivotal role in ALS pathogenesis and therefore highlight the NMJ as a potential therapeutic target.}, }
@article {pmid34099897, year = {2021}, author = {Moujalled, D and Strasser, A and Liddell, JR}, title = {Molecular mechanisms of cell death in neurological diseases.}, journal = {Cell death and differentiation}, volume = {28}, number = {7}, pages = {2029-2044}, pmid = {34099897}, issn = {1476-5403}, support = {101671/WT_/Wellcome Trust/United Kingdom ; 1020363//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 101671/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Autophagy ; Brain/pathology/*physiopathology ; Humans ; Neurodegenerative Diseases/pathology/*physiopathology/therapy ; Neurons/*pathology ; *Regulated Cell Death ; Signal Transduction ; }, abstract = {Tightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.}, }
@article {pmid34097109, year = {2021}, author = {Abdunnur, R and Kaufmann, A}, title = {[Künstliche Harnsphincter zur Behandlung von Stress-Harninkontinenz - eine oft nicht ausgelastete Behandlungsoption in Deutschland].}, journal = {Der Urologe. Ausg. A}, volume = {60}, number = {6}, pages = {696-705}, pmid = {34097109}, issn = {1433-0563}, mesh = {Animals ; Female ; Humans ; Prostheses and Implants ; Swine ; Urethra ; *Urinary Incontinence, Stress/surgery ; }, abstract = {Harninkontinenz ist in Deutschland weit verbreitet und betrifft Millionen von Frauen und Männern. Vor allem Männer, die postoperativ dauerhaft inkontinent sind, werden hierzulande trotz der ausreichenden Verfügbarkeit chirurgischer Optionen unterbehandelt. Der künstliche Schließmuskel wird seit Jahrzehnten erfolgreich zur Behandlung angeborener und erworbener Stress-Harninkontinenz bei Männern und Frauen sowie neurogener Harninkontinenz eingesetzt und wird in Form neuer Modelle weiterentwickelt. Aufgrund der guten Ergebnisse, Es gilt jetzt als Standardtherapie für Männer mit anhaltender, mittelschwerer bis schwerer Harninkontinenz. Die operationstechnische Technik ist anspruchsvoll, kann aber erlernt werden. Die meisten Komplikationen können in erfahrenen Händen deutlich reduziert werden. Patientenzufriedenheit mit künstlichen Harnsphinctern (AUS) ist hoch und korreliert mit der Kontinenzrate und nicht mit der relativ hohen Revisionsrate, weshalb diese Behandlungsoption in Deutschland zunehmend mehr Patienten mit mittelschwerer bis schwerer Harninkontinenz angeboten werden sollte. Urologen in der allgemeinen Praxis spielen in diesem Zusammenhang eine zentrale Rolle.}, }
@article {pmid34092572, year = {2021}, author = {Okita, Y and Narita, Y}, title = {[Significance of Quality of Life Evaluation for Glioma Patients].}, journal = {No shinkei geka. Neurological surgery}, volume = {49}, number = {3}, pages = {660-664}, doi = {10.11477/mf.1436204440}, pmid = {34092572}, issn = {0301-2603}, mesh = {*Glioma/therapy ; Humans ; *Quality of Life ; }, abstract = {Typically, overall and progression-free survival are used as endpoints in clinical tri-als investigating gliomas, while health-related quality of life(HRQOL)plays a key role in cancer research and may be useful for individual patient care. Previous studies have shown that HRQOL parameters can serve as independent prognostic factors for survival in patients with cancer, while recent studies have highlighted the usefulness of HRQOL in information management and decision-making in cancer treatment. However, a few studies have shown differences between patients' and physicians' perceptions of cancer treatment. In the future, physicians will be expected to recog-nize the importance of the QOL evaluation tool, not only in clinical trials, but also in general practice for gliomas, considering the characteristics of patients with brain tu-mors. In this study, we reviewed the methods of major HRQOL evaluation and sum-marized the first clinical trials incorporating QOL in glioma treatment.}, }
@article {pmid34084973, year = {2021}, author = {Sadanandan, N and Lee, JY and Garbuzova-Davis, S}, title = {Extracellular vesicle-based therapy for amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {7}, number = {1}, pages = {23-28}, pmid = {34084973}, issn = {2455-4626}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as a neurodegenerative disorder characterized by the rapid progression of motor neuron loss in the brain and spinal cord. Unfortunately, treatment options for ALS are limited, and therefore, novel therapies that prevent further motor neuron degeneration are of dire need. In ALS, the infiltration of pathological elements from the blood to the central nervous system (CNS) compartment that spur motor neuron damage may be prevented via restoration of the impaired blood-CNS-barrier. Transplantation of human bone marrow endothelial progenitor cells (hBM-EPCs) demonstrated therapeutic promise in a mouse model of ALS due to their capacity to mitigate the altered blood-CNS-barrier by restoring endothelial cell (EC) integrity. Remarkably, the hBM-EPCs can release angiogenic factors that endogenously ameliorate impaired ECs. In addition, these cells may produce extracellular vesicles (EVs) that carry a wide range of vesicular factors, which aid in alleviating EC damage. In an in vitro study, hBM-EPC-derived EVs were effectively uptaken by the mouse brain endothelial cells (mBECs) and cell damage was significantly attenuated. Interestingly, the incorporation of EVs into mBECs was inhibited via β1 integrin hindrance. This review explores preclinical studies of the therapeutic potential of hBM-EPCs, specifically via hBM-EPC-derived EVs, for the repair of the damaged blood-CNS-barrier in ALS as a novel treatment approach.}, }
@article {pmid34080741, year = {2021}, author = {Sun, J and Huang, T and Debelius, JW and Fang, F}, title = {Gut microbiome and amyotrophic lateral sclerosis: A systematic review of current evidence.}, journal = {Journal of internal medicine}, volume = {290}, number = {4}, pages = {758-788}, doi = {10.1111/joim.13336}, pmid = {34080741}, issn = {1365-2796}, support = {802091/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology ; Animals ; Disease Progression ; *Gastrointestinal Microbiome ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS), characterized by a loss of motor neurons in the brain and spinal cord, is a relatively rare but currently incurable neurodegenerative disease. The global incidence of ALS is estimated as 1.75 per 100,000 person-years and the global prevalence is estimated as 4.1-8.4 per 100,000 individuals. Contributions from outside the central nervous system to the etiology of ALS have been increasingly recognized. Gut microbiome is one of the most quickly growing fields of research for ALS. In this article, we performed a comprehensive review of the results from existing animal and human studies, to provide an up-to-date summary of the current research on gut microbiome and ALS. In brief, we found relatively consistent results from animal studies, suggesting an altered gut microbiome composition in experimental ALS. Publication bias might however be a concern. Findings from human studies are largely inconclusive. A few animal and human studies demonstrated the usefulness of intervention with microbial-derived metabolites in modulating the disease progression of ALS. We discussed potential methodological concerns in these studies, including study design, statistical power, handling process of biospecimens and sequencing data, as well as statistical methods and interpretation of results. Finally, we made a few proposals for continued microbiome research in ALS, with the aim to provide valid, reproducible, and translatable findings.}, }
@article {pmid34074012, year = {2021}, author = {Dobrowolny, G and Barbiera, A and Sica, G and Scicchitano, BM}, title = {Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications.}, journal = {Cells}, volume = {10}, number = {6}, pages = {}, pmid = {34074012}, issn = {2073-4409}, mesh = {Aging/*metabolism ; Animals ; *DNA Methylation ; *Epigenesis, Genetic ; *Histone Code ; Humans ; Muscle, Skeletal/metabolism ; Neuromuscular Junction/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system.}, }
@article {pmid34073730, year = {2021}, author = {Giménez-Orenga, K and Oltra, E}, title = {Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {34073730}, issn = {1424-8247}, support = {2020-270-001//Universidad Cat&#xf3;lica de Valencia San Vicente M&#xe0;rtir/ ; }, abstract = {Human endogenous retroviruses (HERVs) are ancient retroviral DNA sequences established into germline. They contain regulatory elements and encoded proteins few of which may provide benefits to hosts when co-opted as cellular genes. Their tight regulation is mainly achieved by epigenetic mechanisms, which can be altered by environmental factors, e.g., viral infections, leading to HERV activation. The aberrant expression of HERVs associates with neurological diseases, such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), inflammatory processes and neurodegeneration. This review summarizes the recent advances on the epigenetic mechanisms controlling HERV expression and the pathogenic effects triggered by HERV de-repression. This article ends by describing new, promising therapies, targeting HERV elements, one of which, temelimab, has completed phase II trials with encouraging results in treating MS. The information gathered here may turn helpful in the design of new strategies to unveil epigenetic failures behind HERV-triggered diseases, opening new possibilities for druggable targets and/or for extending the use of temelimab to treat other associated diseases.}, }
@article {pmid34072616, year = {2021}, author = {Han, R and Liang, J and Zhou, B}, title = {Glucose Metabolic Dysfunction in Neurodegenerative Diseases-New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34072616}, issn = {1422-0067}, support = {2020M670103//China Postdoctoral Science Foundation/ ; }, mesh = {Animals ; Brain/metabolism ; Carbohydrate Metabolism/drug effects ; Cellular Reprogramming/drug effects ; Disease Management ; *Disease Susceptibility ; Energy Metabolism ; Glucose/*metabolism ; Humans ; Hypoxia/drug therapy/metabolism ; Molecular Targeted Therapy ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; Neurons/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {Glucose is the main circulating energy substrate for the adult brain. Owing to the high energy demand of nerve cells, glucose is actively oxidized to produce ATP and has a synergistic effect with mitochondria in metabolic pathways. The dysfunction of glucose metabolism inevitably disturbs the normal functioning of neurons, which is widely observed in neurodegenerative disease. Understanding the mechanisms of metabolic adaptation during disease progression has become a major focus of research, and interventions in these processes may relieve the neurons from degenerative stress. In this review, we highlight evidence of mitochondrial dysfunction, decreased glucose uptake, and diminished glucose metabolism in different neurodegeneration models such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss how hypoxia, a metabolic reprogramming strategy linked to glucose metabolism in tumor cells and normal brain cells, and summarize the evidence for hypoxia as a putative therapy for general neurodegenerative disease.}, }
@article {pmid34071951, year = {2021}, author = {Prabhakaran, J and Molotkov, A and Mintz, A and Mann, JJ}, title = {Progress in PET Imaging of Neuroinflammation Targeting COX-2 Enzyme.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {11}, pages = {}, pmid = {34071951}, issn = {1420-3049}, support = {R01 AG070042/AG/NIA NIH HHS/United States ; R01AG070042/NH/NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Blood-Brain Barrier/drug effects ; Brain/diagnostic imaging/metabolism ; Celecoxib/pharmacology ; Central Nervous System Diseases/*drug therapy ; Chemistry, Pharmaceutical/methods ; Cyclooxygenase 2/*metabolism ; Female ; Humans ; Inflammation/*metabolism ; Kinetics ; Ligands ; Magnetic Resonance Imaging ; Male ; Mice ; Papio ; Permeability ; Positron-Emission Tomography/*methods ; Rats ; }, abstract = {Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.}, }
@article {pmid34071875, year = {2021}, author = {Harmon, KK and Stout, JR and Fukuda, DH and Pabian, PS and Rawson, ES and Stock, MS}, title = {The Application of Creatine Supplementation in Medical Rehabilitation.}, journal = {Nutrients}, volume = {13}, number = {6}, pages = {}, pmid = {34071875}, issn = {2072-6643}, mesh = {Adolescent ; Adult ; Child ; *Creatine/pharmacology/therapeutic use ; *Dietary Supplements ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/drug effects/physiology ; Muscular Diseases/drug therapy/physiopathology/rehabilitation ; *Rehabilitation ; Young Adult ; }, abstract = {Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle mass and function in a variety of acute and chronic conditions. A review of the literature was conducted to assess the current state of knowledge regarding the effects of creatine supplementation on rehabilitation from immobilization and injury, neurodegenerative diseases, cardiopulmonary disease, and other muscular disorders. Several of the findings are encouraging, showcasing creatine's potential efficacy as a supplemental agent via preservation of muscle mass, strength, and physical function; however, the results are not consistent. For multiple diseases, only a few creatine studies with small sample sizes have been published, making it difficult to draw definitive conclusions. Rationale for discordant findings is further complicated by differences in disease pathologies, intervention protocols, creatine dosing and duration, and patient population. While creatine supplementation demonstrates promise as a therapeutic aid, more research is needed to fill gaps in knowledge within medical rehabilitation.}, }
@article {pmid34071457, year = {2021}, author = {Lee, B and Shin, M and Park, Y and Won, SY and Cho, KS}, title = {Physical Exercise-Induced Myokines in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34071457}, issn = {1422-0067}, support = {2017-A019-0582//Konkuk University/ ; }, mesh = {Alzheimer Disease/metabolism/physiopathology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Cytokines/*metabolism ; Exercise/*physiology ; Humans ; Huntington Disease/metabolism/physiopathology ; Muscle, Skeletal/*metabolism ; Neurodegenerative Diseases/*metabolism/physiopathology ; Parkinson Disease/metabolism/physiopathology ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.}, }
@article {pmid34071187, year = {2021}, author = {Dharmadasa, T}, title = {Cortical Excitability across the ALS Clinical Motor Phenotypes.}, journal = {Brain sciences}, volume = {11}, number = {6}, pages = {}, pmid = {34071187}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.}, }
@article {pmid34070550, year = {2021}, author = {Mayl, K and Shaw, CE and Lee, YB}, title = {Disease Mechanisms and Therapeutic Approaches in C9orf72 ALS-FTD.}, journal = {Biomedicines}, volume = {9}, number = {6}, pages = {}, pmid = {34070550}, issn = {2227-9059}, support = {MC_PC_17115/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0300329/MRC_/Medical Research Council/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; SHAW/APR15/970-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; }, abstract = {A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. The body of work overall suggests that toxic gain of function arising from bidirectionally transcribed repeat RNA is likely to be the primary driver of disease. In this review, we outline the key pathogenic mechanisms that have been proposed to date and discuss some of the novel therapeutic approaches currently in development.}, }
@article {pmid34069857, year = {2021}, author = {Kinoshita, C and Kubota, N and Aoyama, K}, title = {Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {10}, pages = {}, pmid = {34069857}, issn = {1422-0067}, support = {N/A//Naito Science and Engineering Foundation/ ; A//Teikyo University School of Medicine/ ; }, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Humans ; Huntington Disease/genetics ; MicroRNAs/biosynthesis/*genetics/metabolism ; Neurodegenerative Diseases/*genetics/metabolism ; Parkinson Disease/genetics ; RNA-Binding Proteins/genetics/*metabolism/physiology ; }, abstract = {The number of patients with neurodegenerative diseases (NDs) is increasing, along with the growing number of older adults. This escalation threatens to create a medical and social crisis. NDs include a large spectrum of heterogeneous and multifactorial pathologies, such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple system atrophy, and the formation of inclusion bodies resulting from protein misfolding and aggregation is a hallmark of these disorders. The proteinaceous components of the pathological inclusions include several RNA-binding proteins (RBPs), which play important roles in splicing, stability, transcription and translation. In addition, RBPs were shown to play a critical role in regulating miRNA biogenesis and metabolism. The dysfunction of both RBPs and miRNAs is often observed in several NDs. Thus, the data about the interplay among RBPs and miRNAs and their cooperation in brain functions would be important to know for better understanding NDs and the development of effective therapeutics. In this review, we focused on the connection between miRNAs, RBPs and neurodegenerative diseases.}, }
@article {pmid34069159, year = {2021}, author = {Kamagata, K and Andica, C and Kato, A and Saito, Y and Uchida, W and Hatano, T and Lukies, M and Ogawa, T and Takeshige-Amano, H and Akashi, T and Hagiwara, A and Fujita, S and Aoki, S}, title = {Diffusion Magnetic Resonance Imaging-Based Biomarkers for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {10}, pages = {}, pmid = {34069159}, issn = {1422-0067}, support = {JP19dm0307024 and JP19dm030710//Program for Brain/MINDS Beyond Program of the Japan Agency for Medical Research and Development/ ; //MEXT-Supported Program for the Private University Research Branding Project/ ; JP16K10327//Japan Society for the Promotion of Science (JSPS) KAKENHI/ ; }, mesh = {Alzheimer Disease/diagnostic imaging ; *Biomarkers/analysis ; Brain/*diagnostic imaging/pathology ; Diffusion Magnetic Resonance Imaging/*methods ; Diffusion Tensor Imaging/methods ; Early Diagnosis ; Humans ; Image Processing, Computer-Assisted/methods ; Neurites ; Neurodegenerative Diseases/*diagnostic imaging ; Parkinson Disease/diagnostic imaging ; }, abstract = {There has been an increasing prevalence of neurodegenerative diseases with the rapid increase in aging societies worldwide. Biomarkers that can be used to detect pathological changes before the development of severe neuronal loss and consequently facilitate early intervention with disease-modifying therapeutic modalities are therefore urgently needed. Diffusion magnetic resonance imaging (MRI) is a promising tool that can be used to infer microstructural characteristics of the brain, such as microstructural integrity and complexity, as well as axonal density, order, and myelination, through the utilization of water molecules that are diffused within the tissue, with displacement at the micron scale. Diffusion tensor imaging is the most commonly used diffusion MRI technique to assess the pathophysiology of neurodegenerative diseases. However, diffusion tensor imaging has several limitations, and new technologies, including neurite orientation dispersion and density imaging, diffusion kurtosis imaging, and free-water imaging, have been recently developed as approaches to overcome these constraints. This review provides an overview of these technologies and their potential as biomarkers for the early diagnosis and disease progression of major neurodegenerative diseases.}, }
@article {pmid34066053, year = {2021}, author = {Lemon, RN}, title = {The Cortical "Upper Motoneuron" in Health and Disease.}, journal = {Brain sciences}, volume = {11}, number = {5}, pages = {}, pmid = {34066053}, issn = {2076-3425}, abstract = {Upper motoneurons (UMNs) in motor areas of the cerebral cortex influence spinal and cranial motor mechanisms through the corticospinal tract (CST) and through projections to brainstem motor pathways. The primate corticospinal system has a diverse cortical origin and a wide spectrum of fibre diameters, including large diameter fibres which are unique to humans and other large primates. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand motoneurons are a late evolutionary feature only present in dexterous primates and best developed in humans. CM projections are derived from a more restricted cortical territory ('new' M1, area 3a) and arise not only from corticospinal neurons with large, fast axons but also from those with relatively slow-conducting axons. During movement, corticospinal neurons are organised and recruited quite differently from 'lower' motoneurons. Accumulating evidence strongly implicates the corticospinal system in the early stages of ALS, with particular involvement of CM projections to distal limb muscles, but also to other muscle groups influenced by the CM system. There are important species differences in the organisation and function of the corticospinal system, and appropriate animal models are needed to understand disorders involving the human corticospinal system.}, }
@article {pmid34064596, year = {2021}, author = {Fullam, T and Statland, J}, title = {Upper Motor Neuron Disorders: Primary Lateral Sclerosis, Upper Motor Neuron Dominant Amyotrophic Lateral Sclerosis, and Hereditary Spastic Paraplegia.}, journal = {Brain sciences}, volume = {11}, number = {5}, pages = {}, pmid = {34064596}, issn = {2076-3425}, abstract = {Following the exclusion of potentially reversible causes, the differential for those patients presenting with a predominant upper motor neuron syndrome includes primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), or upper motor neuron dominant ALS (UMNdALS). Differentiation of these disorders in the early phases of disease remains challenging. While no single clinical or diagnostic tests is specific, there are several developing biomarkers and neuroimaging technologies which may help distinguish PLS from HSP and UMNdALS. Recent consensus diagnostic criteria and use of evolving technologies will allow more precise delineation of PLS from other upper motor neuron disorders and aid in the targeting of potentially disease-modifying therapeutics.}, }
@article {pmid34062930, year = {2021}, author = {La Cognata, V and Morello, G and Cavallaro, S}, title = {Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {34062930}, issn = {1422-0067}, support = {CTN01_00177_817708//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Biomarkers/metabolism ; Computational Biology ; *Genomics ; Humans ; *Metabolomics ; Neurodegenerative Diseases/*genetics/pathology ; Parkinson Disease/genetics/pathology ; Precision Medicine ; *Proteomics ; }, abstract = {Molecular and clinical heterogeneity is increasingly recognized as a common characteristic of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. This heterogeneity makes difficult the development of early diagnosis and effective treatment approaches, as well as the design and testing of new drugs. As such, the stratification of patients into meaningful disease subgroups, with clinical and biological relevance, may improve disease management and the development of effective treatments. To this end, omics technologies-such as genomics, transcriptomics, proteomics and metabolomics-are contributing to offer a more comprehensive view of molecular pathways underlying the development of NDs, helping to differentiate subtypes of patients based on their specific molecular signatures. In this article, we discuss how omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches, bringing us closer to the goal of personalized medicine in neurology.}, }
@article {pmid34057020, year = {2022}, author = {Chua, JP and De Calbiac, H and Kabashi, E and Barmada, SJ}, title = {Autophagy and ALS: mechanistic insights and therapeutic implications.}, journal = {Autophagy}, volume = {18}, number = {2}, pages = {254-282}, pmid = {34057020}, issn = {1554-8635}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R25 NS089450/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Autophagy/physiology ; *Frontotemporal Dementia/genetics ; Humans ; Proteostasis ; Unfolded Protein Response ; }, abstract = {Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseases.Abbreviations: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein.}, }
@article {pmid34055771, year = {2021}, author = {Beatriz, M and Vilaça, R and Lopes, C}, title = {Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {635104}, pmid = {34055771}, issn = {2296-634X}, abstract = {Extracellular vesicles (EVs) are nano-sized membrane-enclosed particles released by cells that participate in intercellular communication through the transfer of biologic material. EVs include exosomes that are small vesicles that were initially associated with the disposal of cellular garbage; however, recent findings point toward a function as natural carriers of a wide variety of genetic material and proteins. Indeed, exosomes are vesicle mediators of intercellular communication and maintenance of cellular homeostasis. The role of exosomes in health and age-associated diseases is far from being understood, but recent evidence implicates exosomes as causative players in the spread of neurodegenerative diseases. Cells from the central nervous system (CNS) use exosomes as a strategy not only to eliminate membranes, toxic proteins, and RNA species but also to mediate short and long cell-to-cell communication as carriers of important messengers and signals. The accumulation of protein aggregates is a common pathological hallmark in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. Protein aggregates can be removed and delivered to degradation by the endo-lysosomal pathway or can be incorporated in multivesicular bodies (MVBs) that are further released to the extracellular space as exosomes. Because exosome transport damaged cellular material, this eventually contributes to the spread of pathological misfolded proteins within the brain, thus promoting the neurodegeneration process. In this review, we focus on the role of exosomes in CNS homeostasis, their possible contribution to the development of neurodegenerative diseases, the usefulness of exosome cargo as biomarkers of disease, and the potential benefits of plasma circulating CNS-derived exosomes.}, }
@article {pmid34054944, year = {2021}, author = {He, M and Zhang, HN and Tang, ZC and Gao, SG}, title = {Diagnostic and Therapeutic Potential of Exosomal MicroRNAs for Neurodegenerative Diseases.}, journal = {Neural plasticity}, volume = {2021}, number = {}, pages = {8884642}, pmid = {34054944}, issn = {1687-5443}, mesh = {Animals ; Biomarkers ; Genetic Therapy/*methods ; Humans ; MicroRNAs/*therapeutic use ; Neurodegenerative Diseases/*diagnosis/*therapy ; }, abstract = {Neurodegenerative disorders (NDs) are characterized by a gradual loss of neurons and functions that eventually leads to progressive neurological impairment. In view of the heavy burden on the healthcare system, efficient and reliable biomarkers for early diagnosis and therapeutic treatments to reverse the progression of NDs are in urgent need. There has been an increasing interest in using exosomal miRNAs as biomarkers or targeted therapies for neurological diseases recently. In this review, we overviewed the updated studies on exosomal miRNAs as biomarkers and potential therapeutic approaches in NDs, as well as their association with the pathophysiology of this group of disorders, especially Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The exosomal miRNAs that are commonly dysregulated across different NDs or are commonly used as therapeutic candidates were also identified and summarized. In summary, the feasibility of exosomal miRNAs as biomarkers and potential targeted therapy for NDs has been verified. However, due to the limitations of existing studies and the discrepancies across different studies, high quality laboratory and clinical investigations are still required.}, }
@article {pmid34054547, year = {2021}, author = {Garcia-Gil, M and Camici, M and Allegrini, S and Pesi, R and Tozzi, MG}, title = {Metabolic Aspects of Adenosine Functions in the Brain.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {672182}, pmid = {34054547}, issn = {1663-9812}, abstract = {Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5'-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington's disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.}, }
@article {pmid34045943, year = {2021}, author = {Guo, M and Hao, Y and Feng, Y and Li, H and Mao, Y and Dong, Q and Cui, M}, title = {Microglial Exosomes in Neurodegenerative Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {630808}, pmid = {34045943}, issn = {1662-5099}, abstract = {Microglia play an important role in neurodegenerative disease [i.e., Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)]. These diseases share some similar pathological changes and several microglia-associated processes, including immune response, neuroinflammation, phagocytosis, elimination of synapses et al. Microglia in the central nervous system (CNS) has been described as having both destructive and protective effects in neurological disorders. Besides, considerable evidence also indicates that microglia play a significant role in neurogenesis, neuronal cell death, and synaptic interactions. The communication between microglia and neurons is of vital role in regulating complex functions which are key to appropriate the activity of the brain. Accumulating studies have also demonstrated that exosomes with sizes ranging from 40-100 nm, released by microglia, could serve as key mediators in intercellular signaling. These exosomes, identified in terms of cellular origin in many kinds of biological fluids, exert their effects by delivering specific cargos such as proteins, microRNAs (miRNAs), and mRNAs. It was shown that microglial exosomes could transport to and be uptake by neurons, which may either be beneficial or instead, detrimental to CNS diseases. The focus of this review is to summarize the involvement of microglial exosomes in critical pathologies associated with neurodegenerative disease and how they contribute to these disorders, including PD, AD, and ALS. We also review the application of microglia exosomes as potential biomarkers in monitoring disease progression, as well as focusing on their roles as drug delivery vehicles in treating neurodegenerative disorders.}, }
@article {pmid34042659, year = {2021}, author = {Giannaki, M and Gallos, P and Liaskos, J and Zogas, S and Mantas, J}, title = {An Online Tool to Inform and Educate Caregivers on Amyotrophic Lateral Sclerosis (ALS).}, journal = {Studies in health technology and informatics}, volume = {281}, number = {}, pages = {664-665}, doi = {10.3233/SHTI210254}, pmid = {34042659}, issn = {1879-8365}, mesh = {*Amyotrophic Lateral Sclerosis ; *Caregivers ; Health Promotion ; Humans ; Quality of Life ; Reproducibility of Results ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common Motor Neuron Disease. This paper presents the design, development, and evaluation of an online tool that provides information and training materials to caregivers about ALS, to promote health care and quality of life of patients. To collect the appropriate content, a literature review was conducted, and a Content Management System (CMS) was used for the development of the tool. For its evaluation, reliability, acceptance, effectiveness and usefulness were examined through semi-structured interviews. The online tool was positively evaluated by the caregivers, who participated in the evaluation process.}, }
@article {pmid34034831, year = {2021}, author = {Chintalaphani, SR and Pineda, SS and Deveson, IW and Kumar, KR}, title = {An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics.}, journal = {Acta neuropathologica communications}, volume = {9}, number = {1}, pages = {98}, pmid = {34034831}, issn = {2051-5960}, mesh = {Animals ; DNA Repeat Expansion/*genetics ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Microsatellite Repeats/*genetics ; Nervous System Diseases/*diagnosis/*genetics ; Sequence Analysis, DNA/*methods ; }, abstract = {BACKGROUND: Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington's disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia.<br><br>MAIN BODY: STR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic 'AAGGG' repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of 'CGG' repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e.g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion.<br><br>CONCLUSION: We anticipate that long-read sequencing will rapidly transform the detection of short tandem&#xa0;repeat expansion disorders for both clinical diagnosis and gene discovery.}, }
@article {pmid34033211, year = {2021}, author = {Pascual, M and Calvo-Rodriguez, M and Núñez, L and Villalobos, C and Ureña, J and Guerri, C}, title = {Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage.}, journal = {IUBMB life}, volume = {73}, number = {7}, pages = {900-915}, doi = {10.1002/iub.2510}, pmid = {34033211}, issn = {1521-6551}, support = {AICO/2019/087//GVA/ ; VA294P18//Junta de Castilla y Leon/ ; PNSD-2018-I003//Spanish Ministry of Health, Consumption and Social Welfare/ ; PNSD-2019-I039//Spanish Ministry of Health, Consumption and Social Welfare/ ; RTI2018-099298-B-100//The Spanish Ministry of Science, Innovation and Universities/ ; }, mesh = {Alcoholism/etiology/*physiopathology ; Animals ; Brain/*drug effects/physiopathology ; Exosomes/pathology/physiology ; Gene Expression ; Humans ; Immunity, Innate ; MicroRNAs/genetics/metabolism ; Neurodegenerative Diseases/*etiology/therapy ; Neuroinflammatory Diseases/*etiology/therapy ; Toll-Like Receptors/*physiology ; }, abstract = {Toll-like receptors (TLRs) or pattern recognition receptors respond to pathogen-associated molecular patterns (PAMPs) or internal damage-associated molecular patterns (DAMPs). TLRs are integral membrane proteins with both extracellular leucine-rich and cytoplasmic domains that initiate downstream signaling through kinases by activating transcription factors like AP-1 and NF-κB, which lead to the release of various inflammatory cytokines and immune modulators. In the central nervous system, different TLRs are expressed mainly in microglia and astroglial cells, although some TLRs are also expressed in oligodendroglia and neurons. Activation of TLRs triggers signaling cascades by the host as a defense mechanism against invaders to repair damaged tissue. However, overactivation of TLRs disrupts the sustained immune homeostasis-induced production of pro-inflammatory molecules, such as cytokines, miRNAs, and inflammatory components of extracellular vesicles. These inflammatory mediators can, in turn, induce neuroinflammation, and neural tissue damage associated with many neurodegenerative diseases. This review discusses the critical role of TLRs response in Alzheimer's disease, Parkinson's disease, ischemic stroke, amyotrophic lateral sclerosis, and alcohol-induced brain damage and neurodegeneration.}, }
@article {pmid34025454, year = {2021}, author = {Clark, BC and Rutkove, S and Lupton, EC and Padilla, CJ and Arnold, WD}, title = {Potential Utility of Electrical Impedance Myography in Evaluating Age-Related Skeletal Muscle Function Deficits.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {666964}, pmid = {34025454}, issn = {1664-042X}, abstract = {Skeletal muscle function deficits associated with advancing age are due to several physiological and morphological changes including loss of muscle size and quality (conceptualized as a reduction in the intrinsic force-generating capacity of a muscle when adjusted for muscle size). Several factors can contribute to loss of muscle quality, including denervation, excitation-contraction uncoupling, increased fibrosis, and myosteatosis (excessive levels of inter- and intramuscular adipose tissue and intramyocellular lipids). These factors also adversely affect metabolic function. There is a major unmet need for tools to rapidly and easily assess muscle mass and quality in clinical settings with minimal patient and provider burden. Herein, we discuss the potential for electrical impedance myography (EIM) as a tool to evaluate muscle mass and quality in older adults. EIM applies weak, non-detectible (e.g., 400 μA), mutifrequency (e.g., 1 kHz-1 MHz) electrical currents to a muscle (or muscle group) through two excitation electrodes, and resulting voltages are measured via two sense electrodes. Measurements are fast (~5 s/muscle), simple to perform, and unaffected by factors such as hydration that may affect other simple measures of muscle status. After nearly 2 decades of study, EIM has been shown to reflect muscle health status, including the presence of atrophy, fibrosis, and fatty infiltration, in a variety of conditions (e.g., developmental growth and maturation, conditioning/deconditioning, and obesity) and neuromuscular diseases states [e.g., amyotrophic lateral sclerosis (ALS) and muscular dystrophies]. In this article, we describe prior work and current evidence of EIM's potential utility as a measure of muscle health in aging and geriatric medicine.}, }
@article {pmid34025358, year = {2021}, author = {Smeyers, J and Banchi, EG and Latouche, M}, title = {C9ORF72: What It Is, What It Does, and Why It Matters.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {661447}, pmid = {34025358}, issn = {1662-5102}, abstract = {When the non-coding repeat expansion in the C9ORF72 gene was discovered to be the most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in 2011, this gene and its derived protein, C9ORF72, were completely unknown. The mutation appeared to produce both haploinsufficiency and gain-of-function effects in the form of aggregating expanded RNAs and dipeptide repeat proteins (DPRs). An unprecedented effort was then unleashed to decipher the pathogenic mechanisms and the functions of C9ORF72 in order to design therapies. A decade later, while the toxicity of accumulating gain-of-function products has been established and therapeutic strategies are being developed to target it, the contribution of the loss of function starts to appear more clearly. This article reviews the current knowledge about the C9ORF72 protein, how it is affected by the repeat expansion in models and patients, and what could be the contribution of its haploinsufficiency to the disease in light of the most recent findings. We suggest that these elements should be taken into consideration to refine future therapeutic strategies, compensating for the decrease of C9ORF72 or at least preventing a further reduction.}, }
@article {pmid34024773, year = {2021}, author = {Nash, Y and Sitty, M}, title = {Non-Motor Symptoms of Amyotrophic Lateral Sclerosis: A Multi-Faceted Disorder.}, journal = {Journal of neuromuscular diseases}, volume = {8}, number = {4}, pages = {699-713}, doi = {10.3233/JND-210632}, pmid = {34024773}, issn = {2214-3602}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers ; Disease Progression ; Humans ; Quality of Life ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor pathways. A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms as well, which can have a significant impact on patients' quality of life. These symptoms could also, in turn, provide useful information as biomarkers for disease progression, and can shed insight on ALS mechanisms. Here we aim to review a wide range of non-motor symptoms of ALS, with emphasis on their importance to research and clinical treatment of patients.}, }
@article {pmid34024497, year = {2021}, author = {Jishi, A and Qi, X and Miranda, HC}, title = {Implications of mRNA translation dysregulation for neurological disorders.}, journal = {Seminars in cell &amp; developmental biology}, volume = {114}, number = {}, pages = {11-19}, pmid = {34024497}, issn = {1096-3634}, support = {R21 NS107897/NS/NINDS NIH HHS/United States ; R01 AG065240/AG/NIA NIH HHS/United States ; R01 NS121374/NS/NINDS NIH HHS/United States ; K01 NS116119/NS/NINDS NIH HHS/United States ; R01 NS115903/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Nervous System Diseases/*genetics ; RNA, Messenger/*genetics ; }, abstract = {The translation of information encoded in the DNA into functional proteins is one of the tenets of cellular biology. Cell survival and function depend on the tightly controlled processes of transcription and translation. Growing evidence suggests that dysregulation in mRNA translation plays an important role in the pathogenesis of several neurodevelopmental diseases, such as autism spectrum disorder (ASD) and fragile X syndrome (FXS) as well as neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In this review, we provide an overview of mRNA translation and its modes of regulation that have been implicated in neurological disease.}, }
@article {pmid34023917, year = {2021}, author = {Wolff, L and Strathmann, EA and Müller, I and Mählich, D and Veltman, C and Niehoff, A and Wirth, B}, title = {Plastin 3 in health and disease: a matter of balance.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {78}, number = {13}, pages = {5275-5301}, pmid = {34023917}, issn = {1420-9071}, support = {Wi 945/17-1//Deutsche Forschungsgemeinschaft/ ; FOR2722, project ID 407176282//Deutsche Forschungsgemeinschaft/ ; SFB 1451, project-ID 431549029 - A01//Deutsche Forschungsgemeinschaft/ ; GRK1960, project ID 233886668//Deutsche Forschungsgemeinschaft/ ; Marie Sk&#x142;odowska-Curie grant agreement No 956185 (SMABEYOND)//H2020 European Research Council/ ; C18//Center for Molecular Medicine Cologne, University of Cologne/ ; }, mesh = {Animals ; Humans ; Membrane Glycoproteins/genetics/*metabolism ; Microfilament Proteins/genetics/*metabolism ; Motor Neurons/*physiology ; Muscular Atrophy, Spinal/*physiopathology ; Osteoclasts/cytology/*physiology ; Osteoporosis/*physiopathology ; }, abstract = {For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.}, }
@article {pmid34023421, year = {2021}, author = {Do, HA and Baek, KH}, title = {Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {69}, number = {}, pages = {101367}, doi = {10.1016/j.arr.2021.101367}, pmid = {34023421}, issn = {1872-9649}, mesh = {Deubiquitinating Enzymes ; Endoplasmic Reticulum-Associated Degradation ; Humans ; *Neurodegenerative Diseases ; Ubiquitin/metabolism ; Ubiquitination ; }, abstract = {Neurodegenerative diseases are one of the most common diseases in mankind. Although there are reports of several candidates that cause neurodegenerative diseases, the exact mechanism of pathogenesis is poorly understood. The ubiquitin-proteasome system (UPS) is an important posttranslational modification for protein degradation and control of homeostasis. Enzymes such as E1, E2, E3 ligases, and deubiquitinating enzymes (DUBs) participating in UPS, regulate disease-inducing proteins by controlling the degree of ubiquitination. Therefore, the development of treatments targeting enzymes for degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is emerging as an attractive perspective. In particular, as DUBs are able to regulate one or more degenerative disease-related proteins, the potential as a therapeutic target is even more evident. DUBs influence the regulation of toxic proteins that cause neurodegenerative diseases by not only their removal, but also by regulating signals associated with mitophagy, autophagy, and endoplasmic reticulum-associated degradation (ERAD). In this review, we analyze not only the cellular processes of DUBs, which control neurodegenerative disease-inducing proteins, but also their potentials as a therapeutic agent for neurodegenerative diseases.}, }
@article {pmid34019093, year = {2021}, author = {Pasha, T and Zatorska, A and Sharipov, D and Rogelj, B and Hortobágyi, T and Hirth, F}, title = {Karyopherin abnormalities in neurodegenerative proteinopathies.}, journal = {Brain : a journal of neurology}, volume = {144}, number = {10}, pages = {2915-2932}, pmid = {34019093}, issn = {1460-2156}, support = {HIRTH/OCT13/868-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; HIRTH/OCT16/890-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Animals ; Brain/drug effects/metabolism ; Humans ; Karyopherins/genetics/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Proteostasis Deficiencies/drug therapy/*metabolism ; }, abstract = {Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma and mutant huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and β proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.}, }
@article {pmid34018075, year = {2021}, author = {Shandilya, A and Mehan, S}, title = {Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {8}, pages = {3145-3166}, pmid = {34018075}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Glucagon-Like Peptide 1 ; Humans ; *Insulin-Like Growth Factor I ; Signal Transduction ; }, abstract = {The prominent causes for motor neuron diseases like ALS are demyelination, immune dysregulation, and neuroinflammation. Numerous research studies indicate that the downregulation of IGF-1 and GLP-1 signaling pathways plays a significant role in the progression of ALS pathogenesis and other neurological disorders. In the current review, we discussed the dysregulation of IGF-1/GLP-1 signaling in neurodegenerative manifestations of ALS like a genetic anomaly, oligodendrocyte degradation, demyelination, glial overactivation, immune deregulation, and neuroexcitation. In addition, the current review reveals the IGF-1 and GLP-1 activators based on the premise that the restoration of abnormal IGF-1/GLP-1 signaling could result in neuroprotection and neurotrophic effects for the clinical-pathological presentation of ALS and other brain diseases. Thus, the potential benefits of IGF-1/GLP-1 signal upregulation in the development of disease-modifying therapeutic strategies may prevent ALS and associated neurocomplications.}, }
@article {pmid34013172, year = {2021}, author = {Chhangani, D and Martín-Peña, A and Rincon-Limas, DE}, title = {Molecular, functional, and pathological aspects of TDP-43 fragmentation.}, journal = {iScience}, volume = {24}, number = {5}, pages = {102459}, pmid = {34013172}, issn = {2589-0042}, support = {R01 AG059871/AG/NIA NIH HHS/United States ; }, abstract = {Transactive response DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in transcriptional regulation and RNA processing. It is linked to sporadic and familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is predominantly nuclear, but it translocates to the cytoplasm under pathological conditions. Cytoplasmic accumulation, phosphorylation, ubiquitination and truncation of TDP-43 are the main hallmarks of TDP-43 proteinopathies. Among these processes, the pathways leading to TDP-43 fragmentation remain poorly understood. We review here the molecular and biochemical properties of several TDP-43 fragments, the mechanisms and factors mediating their production, and their potential role in disease progression. We also address the presence of TDP-43 C-terminal fragments in several neurological disorders, including Alzheimer's disease, and highlight their respective implications. Finally, we discuss features of animal models expressing TDP-43 fragments as well as recent therapeutic strategies to approach TDP-43 truncation.}, }
@article {pmid34012311, year = {2021}, author = {Soldatov, VO and Kukharsky, MS and Belykh, AE and Sobolev, AM and Deykin, AV}, title = {Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms.}, journal = {Eye and brain}, volume = {13}, number = {}, pages = {131-146}, pmid = {34012311}, issn = {1179-2744}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in a gradual loss of motor neuron function. Although ophthalmic complaints are not presently considered a classic symptom of ALS, retinal changes such as thinning, axonal degeneration and inclusion bodies have been found in many patients. Retinal abnormalities observed in postmortem human tissues and animal models are similar to spinal cord changes in ALS. These findings are not dramatically unexpected because retina shares an ontogenetic relationship with the brain, and many genes are associated both with neurodegeneration and retinal diseases. Experimental studies have demonstrated that ALS affects many "vulnerable points" of the retina. Aggregate deposition, impaired nuclear protein import, endoplasmic reticulum stress, glutamate excitotoxicity, vascular regression, and mitochondrial dysfunction are factors suspected as being the main cause of motor neuron damage in ALS. Herein, we show that all of these pathways can affect retinal cells in the same way as motor neurons. Furthermore, we suppose that understanding the patterns of neuro-ophthalmic interaction in ALS can help in the diagnosis and treatment of this disease.}, }
@article {pmid34010004, year = {2021}, author = {Ediriweera, GR and Chen, L and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Non-Viral Vector-Mediated Gene Therapy for ALS: Challenges and Future Perspectives.}, journal = {Molecular pharmaceutics}, volume = {18}, number = {6}, pages = {2142-2160}, doi = {10.1021/acs.molpharmaceut.1c00297}, pmid = {34010004}, issn = {1543-8392}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; CRISPR-Cas Systems/genetics ; Cells, Cultured ; Clinical Trials, Phase III as Topic ; Disease Models, Animal ; Gene Transfer Techniques/*adverse effects/trends ; Genetic Therapy/adverse effects/*methods/trends ; Genetic Vectors/*administration &amp; dosage/adverse effects ; Humans ; Nanoparticles/administration &amp; dosage ; Primary Cell Culture ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, for which no effective treatment is yet available to either slow or terminate it. Recent advances in gene therapy renew hope for developing an effective approach to control this disease. Non-viral vectors, such as lipid- and polymer-based nanoparticles, cationic polymers, and exosomes, can effectively transfer genes into primary neurons. The resulting gene expression can be long-term, stable, and without immunological complications, which is essential for the effective management of neurological disorders. This Review will first describe the current research and clinical stage of novel therapies for ALS. It will then touch on the journey of non-viral vector use in ALS, subsequently highlighting the application of non-viral vector-mediated gene therapy. The bottlenecks in the translation of non-viral vectors for ALS treatment are also discussed, including the biological barriers of systemic administration and the issues of "when, where, and how much?" for effective gene delivery. The prospect of employing emerging techniques, such as CRISPR-Cas9 gene editing, stem cell methodology, and low-intensity focused ultrasound for fueling the transport of non-viral vectors to the central nervous system for personalized gene therapy, is briefly discussed in the context of ALS. Despite the challenging road that lies ahead, with the current expansion in interest and technological advancement in non-viral vector-delivered gene therapy for ALS, we hold hope that the field is headed toward a positive future.}, }
@article {pmid34006386, year = {2021}, author = {Van Harten, ACM and Phatnani, H and Przedborski, S}, title = {Non-cell-autonomous pathogenic mechanisms in amyotrophic lateral sclerosis.}, journal = {Trends in neurosciences}, volume = {44}, number = {8}, pages = {658-668}, pmid = {34006386}, issn = {1878-108X}, support = {R01 NS116350/NS/NINDS NIH HHS/United States ; R01 NS117583/NS/NINDS NIH HHS/United States ; R01 NS107442/NS/NINDS NIH HHS/United States ; R21 AG064596/AG/NIA NIH HHS/United States ; RM1 HG011014/HG/NHGRI NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; R01 NS118183/NS/NINDS NIH HHS/United States ; R21 NS111176/NS/NINDS NIH HHS/United States ; R01 AG066831/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Astrocytes ; Humans ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized mainly by a loss of motor neurons (MNs) in the CNS. Over the past decades, thanks to intense investigations performed in both in vivo and in vitro models of ALS, major progress has been made toward gaining insights into the pathobiology of this incurable, fatal disorder. Among these advances is the growing recognition that non-neuronal cells participate in the degeneration of MNs in ALS, which could transform our understanding of the neurobiology of disease and the ability to devise effective disease-modifying therapies. In this review, we examine the contribution of non-cell-autonomous processes to the pathogenesis of ALS, with a focus on glial cells and in particular on astrocytes.}, }
@article {pmid34002641, year = {2022}, author = {, }, title = {ALSUntangled #61: melatonin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {157-160}, doi = {10.1080/21678421.2021.1927103}, pmid = {34002641}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy ; Humans ; *Melatonin/therapeutic use ; Retrospective Studies ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (ALS). Here we review melatonin. We show that it has plausible mechanisms, some positive (and some negative) pre-clinical studies, two cases in which cocktails of supplements including melatonin were associated with recovery of lost motor function, and a very small, flawed retrospective study suggesting that patients in the PRO-ACT database who reported taking melatonin progressed more slowly and lived longer compared to those who were not taking it. Melatonin appears safe, but an optimal dose and route of administration for ALS have not been determined. Based on all this, we support a pilot trial of melatonin in people with ALS but we cannot yet recommend it as a treatment.}, }
@article {pmid33994936, year = {2021}, author = {Zhang, X and Alshakhshir, N and Zhao, L}, title = {Glycolytic Metabolism, Brain Resilience, and Alzheimer's Disease.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {662242}, pmid = {33994936}, issn = {1662-4548}, support = {R01 AG061038/AG/NIA NIH HHS/United States ; R01 AG071682/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene - ApoE[∗]ϵ2, ApoE[∗]ϵ3, and ApoE[∗]ϵ4 - that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.}, }
@article {pmid33993457, year = {2021}, author = {Mahoney, CJ and Ahmed, RM and Huynh, W and Tu, S and Rohrer, JD and Bedlack, RS and Hardiman, O and Kiernan, MC}, title = {Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {CNS drugs}, volume = {35}, number = {5}, pages = {483-505}, pmid = {33993457}, issn = {1179-1934}, support = {MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Cognitive Dysfunction/etiology/physiopathology/*therapy ; Disease Progression ; Humans ; Outcome Assessment, Health Care ; Research Design ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.}, }
@article {pmid33989700, year = {2021}, author = {An, H and de Meritens, CR and Shelkovnikova, TA}, title = {Connecting the "dots": RNP granule network in health and disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1868}, number = {8}, pages = {119058}, doi = {10.1016/j.bbamcr.2021.119058}, pmid = {33989700}, issn = {1879-2596}, support = {MRF_MRF-060-0001-RG-SHELK/MRF/MRF/United Kingdom ; SHELKOVNIKOVA/OCT17/968-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Cytoplasmic Granules/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Ribonucleoproteins/*metabolism ; }, abstract = {All cells contain ribonucleoprotein (RNP) granules - large membraneless structures composed of RNA and proteins. Recent breakthroughs in RNP granule research have brought a new appreciation of their crucial role in organising virtually all cellular processes. Cells widely exploit the flexible, dynamic nature of RNP granules to adapt to a variety of functional states and the ever-changing environment. Constant exchange of molecules between the different RNP granules connects them into a network. This network controls basal cellular activities and is remodelled to enable efficient stress response. Alterations in RNP granule structure and regulation have been found to lead to fatal human diseases. The interconnectedness of RNP granules suggests that the RNP granule network as a whole becomes affected in disease states such as a representative neurodegenerative disease amyotrophic lateral sclerosis (ALS). In this review, we summarize available evidence on the communication between different RNP granules and on the RNP granule network disruption as a primary ALS pathomechanism.}, }
@article {pmid33982658, year = {2022}, author = {Kursun, O and Karatas, H and Bariskaner, H and Ozturk, S}, title = {Arachidonic Acid Metabolites in Neurologic Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {21}, number = {2}, pages = {150-159}, doi = {10.2174/1871527320666210512013648}, pmid = {33982658}, issn = {1996-3181}, mesh = {Alzheimer Disease/metabolism ; Animals ; Arachidonic Acid/*metabolism ; Docosahexaenoic Acids/metabolism ; Humans ; Inflammation/metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVE: Arachidonic acid (ARA) is essential for the fluidity, selective permeability, and flexibility of the cell membrane. It is an important factor for the function of all cells, particularly in the nervous system, immune system, and vascular endothelium. ARA is the second most common polyunsaturated fatty acid in the phospholipids of the nerve cell membrane after docosahexaenoic acid. ARA metabolites have many kinds of physiologic roles. The major action of ARA metabolites is the promotion of the acute inflammatory response, mediated by the production of pro-inflammatory mediators such as PGE2 and PGI2, followed by the formation of lipid mediators, which have pro-resolving effects. Another important action of ARA derivatives, especially COX, is the regulation of vascular reactivity through PGs and TXA2. There is significant involvement of ARA metabolites in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and neuropsychiatric disorders. ARA derivatives also make an important contribution to acute stroke, global ischemia, subarachnoid hemorrhage, and anticoagulation-related hemorrhagic transformation.<br><br>CONCLUSION: In this review, we have discussed experimental and human study results of neurologic disorders related to ARA and its metabolites in line with treatment options.}, }
@article {pmid33971224, year = {2021}, author = {Michetti, F and Di Sante, G and Clementi, ME and Sampaolese, B and Casalbore, P and Volonté, C and Romano Spica, V and Parnigotto, PP and Di Liddo, R and Amadio, S and Ria, F}, title = {Growing role of S100B protein as a putative therapeutic target for neurological- and nonneurological-disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {127}, number = {}, pages = {446-458}, doi = {10.1016/j.neubiorev.2021.04.035}, pmid = {33971224}, issn = {1873-7528}, mesh = {Astrocytes ; Biomarkers ; Humans ; *Nervous System Diseases ; *Parkinson Disease ; S100 Calcium Binding Protein beta Subunit ; }, abstract = {S100B is a calcium-binding protein mainly expressed by astrocytes, but also localized in other definite neural and extra-neural cell types. While its presence in biological fluids is widely recognized as a reliable biomarker of active injury, growing evidence now indicates that high levels of S100B are suggestive of pathogenic processes in different neural, but also extra-neural, disorders. Indeed, modulation of S100B levels correlates with the occurrence of clinical and/or toxic parameters in experimental models of diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, acute neural injury, inflammatory bowel disease, uveal and retinal disorders, obesity, diabetes and cancer, thus directly linking the levels of S100B to pathogenic mechanisms. In general, deletion/inactivation of the protein causes the improvement of the disease, whereas its over-expression/administration induces a worse clinical presentation. This scenario reasonably proposes S100B as a common therapeutic target for several different disorders, also offering new clues to individuate possible unexpected connections among these diseases.}, }
@article {pmid33970243, year = {2021}, author = {Creekmore, BC and Chang, YW and Lee, EB}, title = {The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Aggregates.}, journal = {Journal of neuropathology and experimental neurology}, volume = {80}, number = {6}, pages = {514-529}, pmid = {33970243}, issn = {1554-6578}, support = {R01 NS039572/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; P01 AG010120/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R56 AG063344/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; U54 NS115322/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides/metabolism ; *Cryoelectron Microscopy ; Disease Progression ; Humans ; Inclusion Bodies/*ultrastructure ; Neurodegenerative Diseases/metabolism/*pathology ; Protein Aggregates/*physiology ; }, abstract = {Neurogenerative diseases are characterized by diverse protein aggregates with a variety of microscopic morphologic features. Although ultrastructural studies of human neurodegenerative disease tissues have been conducted since the 1960s, only recently have near-atomic resolution structures of neurodegenerative disease aggregates been described. Solid-state nuclear magnetic resonance spectroscopy and X-ray crystallography have provided near-atomic resolution information about in vitro aggregates but pose logistical challenges to resolving the structure of aggregates derived from human tissues. Recent advances in cryo-electron microscopy (cryo-EM) have provided the means for near-atomic resolution structures of tau, amyloid-β (Aβ), α-synuclein (α-syn), and transactive response element DNA-binding protein of 43 kDa (TDP-43) aggregates from a variety of diseases. Importantly, in vitro aggregate structures do not recapitulate ex vivo aggregate structures. Ex vivo tau aggregate structures indicate individual tauopathies have a consistent aggregate structure unique from other tauopathies. α-syn structures show that even within a disease, aggregate heterogeneity may correlate to disease course. Ex vivo structures have also provided insight into how posttranslational modifications may relate to aggregate structure. Though there is less cryo-EM data for human tissue-derived TDP-43 and Aβ, initial structural studies provide a basis for future endeavors. This review highlights structural variations across neurodegenerative diseases and reveals fundamental differences between experimental systems and human tissue derived protein inclusions.}, }
@article {pmid33965562, year = {2021}, author = {Goossens, JF and Thuru, X and Bailly, C}, title = {Properties and reactivity of the folic acid and folate photoproduct 6-formylpterin.}, journal = {Free radical biology &amp; medicine}, volume = {171}, number = {}, pages = {1-10}, doi = {10.1016/j.freeradbiomed.2021.05.002}, pmid = {33965562}, issn = {1873-4596}, mesh = {*Folic Acid ; Histocompatibility Antigens Class I ; Pterins ; *Ultraviolet Rays ; }, abstract = {Folates (vitamin B9) are essential components of our diet and our gut microbiota. They are omnipresent in our cells and blood. Folates are necessary for DNA synthesis, methylation, and other vital bioprocesses. Folic acid (FA), as the synthetic form of folates, is largely found in supplements and fortified foods. FA and folate drugs are also extensively used as therapeutics. Therefore, we are continuously exposed to the pterin derivatives, and their photo-degradation products, such as 6-formylpterin (6-FPT) and pterin-6-carboxylic acid. During ultraviolet radiation, these two photolytic products generate reactive oxygen species (ROS) responsible for the cellular oxidative stress. 6-FPT can exhibit variable pro/anti-oxidative roles depending on the cell type and its environment (acting as a cell protector in normal cells, or as an enhancer of drug-induced cell death in cancer cells). The ROS-modulating capacity of 6-FPT is well-known, whereas its intrinsic reactivity has been much less investigated. Here, we have reviewed the properties of 6-FPT and highlighted its capacity to form covalent adducts with the ROS-scavenging drug edaravone (used to treat stroke and amyotrophic lateral sclerosis) as well as its implication in immune surveillance. 6-FPT and its analogue acetyl-6-FPT function as small molecule antigens, recognized by the major histocompatibility complex-related class I-like molecule, MR1, for presentation to mucosal-associated invariant T (MAIT) cells. As modulators of the MR1/MAIT machinery, 6-FPT derivatives could play a significant immuno-regulatory role in different diseases. This brief review shed light on the multiple properties and cellular activities of 6-FPT, well beyond its primary ROS-generating activity.}, }
@article {pmid33949928, year = {2021}, author = {Petrella, C and Di Certo, MG and Gabanella, F and Barbato, C and Ceci, FM and Greco, A and Ralli, M and Polimeni, A and Angeloni, A and Severini, C and Vitali, M and Ferraguti, G and Ceccanti, M and Lucarelli, M and Severi, C and Fiore, M}, title = {Mediterranean Diet, Brain and Muscle: Olive Polyphenols and Resveratrol Protection in Neurodegenerative and Neuromuscular Disorders.}, journal = {Current medicinal chemistry}, volume = {28}, number = {37}, pages = {7595-7613}, doi = {10.2174/0929867328666210504113445}, pmid = {33949928}, issn = {1875-533X}, mesh = {Brain ; *Diet, Mediterranean ; Humans ; Muscles ; *Olea ; Olive Oil ; Polyphenols/pharmacology/therapeutic use ; Resveratrol ; }, abstract = {The Mediterranean diet is worldwide recognized as a good prototype of nutrition due to the conspicuous intake of olive oil, nuts, red wine, legumes, fruit, and vegetables, all fundamental elements rich in antioxidant substances and polyphenols. Polyphenols are a wide range of phytochemicals and/or synthetic chemical compounds with proven beneficial properties for human health. In the present review, we critically summarize the wellcharacterized antioxidant and anti-inflammatory properties of polyphenols contained in the olives and extra virgin olive oil and of resveratrol, a non-flavonoid phenolic compound. We discuss the potential use of these polyphenols as pharmaceutical formulations for the treatment of human diseases. We also show the emerging importance of their consumption in the prevention and management of crucial neurodegenerative conditions (alcohol-related brain disorders and aging) and in neuromuscular disorders (Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy), where oxidative stress plays a predominant role.}, }
@article {pmid33949169, year = {2021}, author = {Icer, MA and Arslan, N and Gezmen-Karadag, M}, title = {Effects of vitamin E on neurodegenerative diseases: an update.}, journal = {Acta neurobiologiae experimentalis}, volume = {81}, number = {1}, pages = {21-33}, doi = {10.21307/ane-2021-003}, pmid = {33949169}, issn = {1689-0035}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; Stroke/*metabolism ; Vitamin E/*metabolism ; }, abstract = {Vitamin E deficiency is associated with many neurological problems. Although the mechanisms of vitamin E action in neurodegenerative diseases are not clear, there are many possible mechanisms. Examples of such mechanisms are the protective effects of vitamin E against oxidative stress damage and its suppressive role in the expression of many genes involved in the development of neurodegeneration. Many studies have evaluated the relationship between vitamin E intake or vitamin E levels in body fluids and neurodegenerative diseases. Some studies concluded that vitamin E can play a protective role in neurodegeneration with respect to diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke and amyotrophic lateral sclerosis (ALS). Vitamin E supplementation was also associated with risk factors for some neurodegenerative diseases. In this review, we discuss the possible effects of vitamin E on the development and course of AD, PD, stroke and ALS, and the potential mechanisms involved. Vitamin E deficiency is associated with many neurological problems. Although the mechanisms of vitamin E action in neurodegenerative diseases are not clear, there are many possible mechanisms. Examples of such mechanisms are the protective effects of vitamin E against oxidative stress damage and its suppressive role in the expression of many genes involved in the development of neurodegeneration. Many studies have evaluated the relationship between vitamin E intake or vitamin E levels in body fluids and neurodegenerative diseases. Some studies concluded that vitamin E can play a protective role in neurodegeneration with respect to diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and amyotrophic lateral sclerosis (ALS). Vitamin E supplementation was also associated with risk factors for some neurodegenerative diseases. In this review, we discuss the possible effects of vitamin E on the development and course of AD, PD, stroke and ALS, and the potential mechanisms involved.}, }
@article {pmid33948878, year = {2021}, author = {Athira, KV and Sadanandan, P and Chakravarty, S}, title = {Repurposing Vorinostat for the Treatment of Disorders Affecting Brain.}, journal = {Neuromolecular medicine}, volume = {23}, number = {4}, pages = {449-465}, pmid = {33948878}, issn = {1559-1174}, mesh = {Brain ; *Drug Repositioning ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; *Hydroxamic Acids/pharmacology ; Vorinostat/pharmacology/therapeutic use ; }, abstract = {Based on the findings in recent years, we summarize the therapeutic potential of vorinostat (VOR), the first approved histone deacetylase (HDAC) inhibitor, in disorders of brain, and strategies to improve drug efficacy and reduce side effects. Scientific evidences provide a strong case for the therapeutic utility of VOR in various disorders affecting brain, including stroke, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, X-linked adrenoleukodystrophy, epilepsy, Niemann-Pick type C disease, and neuropsychiatric disorders. Further elucidation of the neuroprotective and neurorestorative properties of VOR using proper clinical study designs could provide momentum towards its clinical application. To improve the therapeutic prospect, concerns on systemic toxicity and off-target actions need to be addressed along with the improvement in formulation and delivery aspects, especially with respect to solubility, permeability, and pharmacokinetic properties. Newer approaches in this regard include poly(ethylene glycol)-b-poly(DL-lactic acid) micelles, VOR-pluronic F127 micelles, encapsulation of iron complexes of VOR into PEGylated liposomes, human serum albumin bound VOR nanomedicine, magnetically guided layer-by-layer assembled nanocarriers, as well as convection-enhanced delivery. Even though targeting specific class or isoform of HDAC is projected as advantageous over pan-HDAC inhibitor like VOR, in terms of adverse effects and efficacy, till clinical validation, the idea is debated. As the VOR treatment-related adverse changes are mostly found reversible, further optimization of the therapeutic strategies with respect to dose, dosage regimen, and formulations of VOR could propel its clinical prospects.}, }
@article {pmid33946763, year = {2021}, author = {Wood, A and Gurfinkel, Y and Polain, N and Lamont, W and Lyn Rea, S}, title = {Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33946763}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology ; Animals ; Autophagy ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Disease Models, Animal ; Frontotemporal Lobar Degeneration/*etiology/metabolism/pathology ; Gene Expression Regulation ; Humans ; Models, Neurological ; Mutation ; Neurons/metabolism/pathology ; Protein Aggregation, Pathological/etiology/metabolism/pathology ; Protein Processing, Post-Translational ; TDP-43 Proteinopathies/*etiology/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.}, }
@article {pmid33946349, year = {2021}, author = {Subedi, L and Gaire, BP and Parveen, A and Kim, SY}, title = {Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33946349}, issn = {1422-0067}, support = {318027-04-2-HD030//Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry/ ; }, mesh = {Animals ; Anti-Inflammatory Agents/chemistry/*pharmacology/therapeutic use ; Drug Discovery ; Humans ; Inflammation/*drug therapy/metabolism ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/chemistry/*pharmacology/therapeutic use ; Nitric Oxide/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress/drug effects ; Phytochemicals/chemistry/*pharmacology/therapeutic use ; Reactive Nitrogen Species/metabolism ; }, abstract = {Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.}, }
@article {pmid33937264, year = {2021}, author = {Cappella, M and Elouej, S and Biferi, MG}, title = {The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {662837}, pmid = {33937264}, issn = {2296-634X}, abstract = {The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) represents a major advance for the development of human disease models. The emerging of this technique fostered the concept of "disease in a dish," which consists into the generation of patient-specific models in vitro. Currently, iPSCs are used to study pathological molecular mechanisms caused by genetic mutations and they are considered a reliable model for high-throughput drug screenings. Importantly, precision-medicine approaches to treat monogenic disorders exploit iPSCs potential for the selection and validation of lead candidates. For example, antisense oligonucleotides (ASOs) were tested with promising results in myoblasts or motor neurons differentiated from iPSCs of patients affected by either Duchenne muscular dystrophy or Amyotrophic lateral sclerosis. However, the use of iPSCs needs additional optimization to ensure translational success of the innovative strategies based on gene delivery through adeno associated viral vectors (AAV) for these diseases. Indeed, to establish an efficient transduction of iPSCs with AAV, several aspects should be optimized, including viral vector serotype, viral concentration and timing of transduction. This review will outline the use of iPSCs as a model for the development and testing of gene therapies for neuromuscular and motor neuron disorders. It will then discuss the advantages for the use of this versatile tool for gene therapy, along with the challenges associated with the viral vector transduction of iPSCs.}, }
@article {pmid33927394, year = {2021}, author = {Vahsen, BF and Gray, E and Thompson, AG and Ansorge, O and Anthony, DC and Cowley, SA and Talbot, K and Turner, MR}, title = {Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers.}, journal = {Nature reviews. Neurology}, volume = {17}, number = {6}, pages = {333-348}, pmid = {33927394}, issn = {1759-4766}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/*metabolism ; Animals ; Astrocytes/*immunology/*metabolism ; Biomarkers/metabolism ; DNA-Binding Proteins/genetics/immunology ; Humans ; Microglia/*immunology/*metabolism ; Motor Neurons/immunology/pathology ; }, abstract = {The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.}, }
@article {pmid33926896, year = {2021}, author = {Oldan, JD and Jewells, VL and Pieper, B and Wong, TZ}, title = {Complete Evaluation of Dementia: PET and MRI Correlation and Diagnosis for the Neuroradiologist.}, journal = {AJNR. American journal of neuroradiology}, volume = {42}, number = {6}, pages = {998-1007}, pmid = {33926896}, issn = {1936-959X}, mesh = {*Alzheimer Disease ; *Frontotemporal Dementia ; Humans ; *Lewy Body Disease/diagnostic imaging ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; }, abstract = {This article will familiarize neuroradiologists with the pathophysiology, clinical findings, and standard MR imaging and PET imaging features of multiple forms of dementia as well as new emerging techniques. Cases were compiled from multiple institutions with the goal of improved diagnostic accuracy and improved patient care as well as information about biomarkers on the horizon. Dementia topics addressed include the following: Alzheimer disease, frontotemporal dementia, cerebral amyloid angiopathy, Lewy body dementia, Parkinson disease and Parkinson disease variants, amyotrophic lateral sclerosis, multisystem atrophy, Huntington disease vascular dementia, and Creutzfeldt-Jakob disease.}, }
@article {pmid33925625, year = {2021}, author = {Bonaventura, G and Iemmolo, R and Attaguile, GA and La Cognata, V and Pistone, BS and Raudino, G and D'Agata, V and Cantarella, G and Barcellona, ML and Cavallaro, S}, title = {iPSCs: A Preclinical Drug Research Tool for Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33925625}, issn = {1422-0067}, support = {CIP 2014.IT.05.SFOP.014/3/10.4/9.2.10/0008//European Social Fund/ ; }, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Drug Discovery/methods/trends ; Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells/*metabolism/*physiology ; Models, Biological ; Nervous System Diseases/*therapy ; Neurodegenerative Diseases/therapy ; Parkinson Disease/therapy ; Pharmaceutical Preparations ; Stem Cell Transplantation/methods/trends ; }, abstract = {The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).}, }
@article {pmid33925602, year = {2021}, author = {Lake, J and Storm, CS and Makarious, MB and Bandres-Ciga, S}, title = {Genetic and Transcriptomic Biomarkers in Neurodegenerative Diseases: Current Situation and the Road Ahead.}, journal = {Cells}, volume = {10}, number = {5}, pages = {}, pmid = {33925602}, issn = {2073-4409}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Biomarkers/*metabolism ; Humans ; Multifactorial Inheritance/genetics ; Mutation/genetics ; Neurodegenerative Diseases/*genetics ; Transcriptome/*genetics ; }, abstract = {Neurodegenerative diseases are etiologically and clinically heterogeneous conditions, often reflecting a spectrum of disease rather than well-defined disorders. The underlying molecular complexity of these diseases has made the discovery and validation of useful biomarkers challenging. The search of characteristic genetic and transcriptomic indicators for preclinical disease diagnosis, prognosis, or subtyping is an area of ongoing effort and interest. The next generation of biomarker studies holds promise by implementing meaningful longitudinal and multi-modal approaches in large scale biobank and healthcare system scale datasets. This work will only be possible in an open science framework. This review summarizes the current state of genetic and transcriptomic biomarkers in Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, providing a comprehensive landscape of recent literature and future directions.}, }
@article {pmid33925493, year = {2021}, author = {Pradhan, J and Bellingham, MC}, title = {Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review.}, journal = {Brain sciences}, volume = {11}, number = {5}, pages = {}, pmid = {33925493}, issn = {2076-3425}, support = {GIA//Motor Neurone Disease Research Institute of Australia/ ; Translational Research Grant//FightMND/ ; APP1065884//National Health and Medical Research Council of Australia/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the mechanisms that underlie cortical hyper-excitability are not completely understood, the molecular and cellular mechanisms that cause enhanced neuronal intrinsic excitability and changes in excitatory and inhibitory synaptic activity are starting to emerge. Here, we review the evidence for an anterograde glutamatergic excitotoxic process, leading to cortical hyper-excitability via intrinsic cellular and synaptic mechanisms and for the role of interneurons in establishing disinhibition in clinical and experimental settings. Understanding the mechanisms that lead to these complex pathological processes will likely produce key insights towards developing novel therapeutic strategies to rescue upper MNs, thus alleviating the impact of this fatal disease.}, }
@article {pmid33925236, year = {2021}, author = {Salman, MM and Al-Obaidi, Z and Kitchen, P and Loreto, A and Bill, RM and Wade-Martins, R}, title = {Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33925236}, issn = {1422-0067}, support = {MR/P007058/1/MRC_/Medical Research Council/United Kingdom ; K-1003/PUK_/Parkinson's UK/United Kingdom ; G-1003/PUK_/Parkinson's UK/United Kingdom ; BB/D012910/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; H-1102/PUK_/Parkinson's UK/United Kingdom ; MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; H-1301/PUK_/Parkinson's UK/United Kingdom ; 182/ALZS_/Alzheimer's Society/United Kingdom ; J-0901/PUK_/Parkinson's UK/United Kingdom ; 210904/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; G-0801/PUK_/Parkinson's UK/United Kingdom ; G0400144/MRC_/Medical Research Council/United Kingdom ; MR/N029453/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; *Drug Design ; Humans ; Huntington Disease ; Molecular Docking Simulation/methods/trends ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease ; }, abstract = {Neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.}, }
@article {pmid33925147, year = {2021}, author = {Ziabska, K and Ziemka-Nalecz, M and Pawelec, P and Sypecka, J and Zalewska, T}, title = {Aberrant Complement System Activation in Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33925147}, issn = {1422-0067}, support = {2017/27/B/NZ3/00582//National Science Centre, Poland/ ; }, mesh = {Animals ; Brain/immunology/metabolism ; Complement Activation/immunology/*physiology ; Complement System Proteins/*immunology ; Humans ; Nervous System Diseases/*immunology ; Neurodegenerative Diseases/immunology/metabolism ; Neurons/immunology/metabolism ; }, abstract = {The complement system is an assembly of proteins that collectively participate in the functions of the healthy and diseased brain. The complement system plays an important role in the maintenance of uninjured (healthy) brain homeostasis, contributing to the clearance of invading pathogens and apoptotic cells, and limiting the inflammatory immune response. However, overactivation or underregulation of the entire complement cascade within the brain may lead to neuronal damage and disturbances in brain function. During the last decade, there has been a growing interest in the role that this cascading pathway plays in the neuropathology of a diverse array of brain disorders (e.g., acute neurotraumatic insult, chronic neurodegenerative diseases, and psychiatric disturbances) in which interruption of neuronal homeostasis triggers complement activation. Dysfunction of the complement promotes a disease-specific response that may have either beneficial or detrimental effects. Despite recent advances, the explicit link between complement component regulation and brain disorders remains unclear. Therefore, a comprehensible understanding of such relationships at different stages of diseases could provide new insight into potential therapeutic targets to ameliorate or slow progression of currently intractable disorders in the nervous system. Hence, the aim of this review is to provide a summary of the literature on the emerging role of the complement system in certain brain disorders.}, }
@article {pmid33925016, year = {2021}, author = {Basavarajappa, BS and Subbanna, S}, title = {Histone Methylation Regulation in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33925016}, issn = {1422-0067}, support = {R01 AA019443/AA/NIAAA NIH HHS/United States ; AA019443/NH/NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Epigenesis, Genetic ; Histone Code/*genetics/*physiology ; Histones/genetics/metabolism ; Humans ; Huntington Disease/genetics/metabolism ; Methylation ; Neurodegenerative Diseases/*genetics/*metabolism ; Parkinson Disease/genetics/metabolism ; Protein Processing, Post-Translational ; Substance-Related Disorders/genetics/metabolism ; }, abstract = {Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.}, }
@article {pmid33924890, year = {2021}, author = {Kulczyńska-Przybik, A and Mroczko, P and Dulewicz, M and Mroczko, B}, title = {The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33924890}, issn = {1422-0067}, mesh = {Animals ; Carrier Proteins/*metabolism ; Humans ; Membrane Proteins/*metabolism ; Molecular Targeted Therapy ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/diagnosis/*metabolism/therapy ; Nogo Proteins/*metabolism ; }, abstract = {Reticulons (RTNs) are crucial regulatory factors in the central nervous system (CNS) as well as immune system and play pleiotropic functions. In CNS, RTNs are transmembrane proteins mediating neuroanatomical plasticity and functional recovery after central nervous system injury or diseases. Moreover, RTNs, particularly RTN4 and RTN3, are involved in neurodegeneration and neuroinflammation processes. The crucial role of RTNs in the development of several neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neurological conditions such as brain injury or spinal cord injury, has attracted scientific interest. Reticulons, particularly RTN-4A (Nogo-A), could provide both an understanding of early pathogenesis of neurodegenerative disorders and be potential therapeutic targets which may offer effective treatment or inhibit disease progression. This review focuses on the molecular mechanisms and functions of RTNs and their potential usefulness in clinical practice as a diagnostic tool or therapeutic strategy.}, }
@article {pmid33924878, year = {2021}, author = {Park, H and Kim, J and Shin, C and Lee, S}, title = {Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {5}, pages = {}, pmid = {33924878}, issn = {2076-3921}, support = {2020R1A2C1101827//the Ministry of Science and ICT of Korea Government/ ; 2016R1A6A3A04006478//the Ministry of Education of Korea Government/ ; }, abstract = {Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.}, }
@article {pmid33924240, year = {2021}, author = {Yamashita, T and Kushida, Y and Abe, K and Dezawa, M}, title = {Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases.}, journal = {Cells}, volume = {10}, number = {4}, pages = {}, pmid = {33924240}, issn = {2073-4409}, mesh = {Animals ; Apoptosis ; Clinical Trials as Topic ; Humans ; Mesenchymal Stem Cells/cytology ; Neoplasms/*pathology ; Nervous System Diseases/*therapy ; Pluripotent Stem Cells/*pathology ; }, abstract = {Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.}, }
@article {pmid33923609, year = {2021}, author = {Jin, Y and Vadukul, DM and Gialama, D and Ge, Y and Thrush, R and White, JT and Aprile, FA}, title = {The Diagnostic Potential of Amyloidogenic Proteins.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33923609}, issn = {1422-0067}, support = {MR/S033947/1/MRC_/Medical Research Council/United Kingdom ; ARUK-PG2019B-020//Alzheimer's Research UK/ ; 511/ALZS_/Alzheimer's Society/United Kingdom ; UKRI Future Leaders Fellowship MR/S033947/1//UK Research and Innovation/ ; }, mesh = {Amyloid/chemistry/genetics/*metabolism ; Animals ; Biomarkers/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Protein Aggregation, Pathological/*metabolism/pathology ; }, abstract = {Neurodegenerative disorders are a highly prevalent class of diseases, whose pathological mechanisms start before the appearance of any clear symptoms. This fact has prompted scientists to search for biomarkers that could aid early treatment. These currently incurable pathologies share the presence of aberrant aggregates called amyloids in the nervous system, which are composed of specific proteins. In this review, we discuss how these proteins, their conformations and modifications could be exploited as biomarkers for diagnostic purposes. We focus on proteins that are associated with the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and frontotemporal dementia. We also describe current challenges in detection, the most recent techniques with diagnostic potentials and possible future developments in diagnosis.}, }
@article {pmid33923599, year = {2021}, author = {Benameur, T and Soleti, R and Porro, C}, title = {The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases.}, journal = {Nutrients}, volume = {13}, number = {4}, pages = {}, pmid = {33923599}, issn = {2072-6643}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacokinetics ; Apoptosis/drug effects ; Biological Availability ; Brain/drug effects ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Drug Delivery Systems ; Humans ; MicroRNAs/*drug effects ; Microglia/drug effects ; Nervous System Diseases/*drug therapy/*prevention &amp; control ; Neuroprotective Agents/*pharmacokinetics ; Quercetin/*pharmacokinetics ; }, abstract = {Chronic neuroinflammation is a pathological condition of numerous central nervous system (CNS) diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and many others. Neuroinflammation is characterized by the microglia activation and concomitant production of pro-inflammatory cytokines leading to an increasing neuronal cell death. The decreased neuroinflammation could be obtained by using natural compounds, including flavonoids known to modulate the inflammatory responses. Among flavonoids, quercetin possess multiple pharmacological applications including anti-inflammatory, antitumoral, antiapoptotic and anti-thrombotic activities, widely demonstrated in both in vitro and in vivo studies. In this review, we describe the recent findings about the neuroprotective action of quercetin by acting with different mechanisms on the microglial cells of CNS. The ability of quercetin to influence microRNA expression represents an interesting skill in the regulation of inflammation, differentiation, proliferation, apoptosis and immune responses. Moreover, in order to enhance quercetin bioavailability and capacity to target the brain, we discuss an innovative drug delivery system. In summary, this review highlighted an important application of quercetin in the modulation of neuroinflammation and prevention of neurological disorders.}, }
@article {pmid33922607, year = {2021}, author = {Piscopo, P and Bellenghi, M and Manzini, V and Crestini, A and Pontecorvi, G and Corbo, M and Ortona, E and Carè, A and Confaloni, A}, title = {A Sex Perspective in Neurodegenerative Diseases: microRNAs as Possible Peripheral Biomarkers.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33922607}, issn = {1422-0067}, support = {Project nr: AB32//CCPP/ ; }, mesh = {Biomarkers/*analysis ; Humans ; MicroRNAs/analysis/*genetics ; Neurodegenerative Diseases/*diagnosis/genetics ; Sex Factors ; }, abstract = {Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients.}, }
@article {pmid33922505, year = {2021}, author = {Margiotta, A}, title = {Role of SNAREs in Neurodegenerative Diseases.}, journal = {Cells}, volume = {10}, number = {5}, pages = {}, pmid = {33922505}, issn = {2073-4409}, mesh = {Animals ; *Exocytosis ; Humans ; *Membrane Fusion ; Neurodegenerative Diseases/metabolism/*physiopathology ; SNARE Proteins/*metabolism ; *Synaptic Transmission ; }, abstract = {Neurodegenerative diseases are pathologies of the central and peripheral nervous systems characterized by loss of brain functions and problems in movement which occur due to the slow and progressive degeneration of cellular elements. Several neurodegenerative diseases are known such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and many studies on the molecular mechanisms underlying these pathologies have been conducted. Altered functions of some key proteins and the presence of intraneuronal aggregates have been identified as responsible for the development of the diseases. Interestingly, the formation of the SNARE complex has been discovered to be fundamental for vesicle fusion, vesicle recycling and neurotransmitter release. Indeed, inhibition of the formation of the SNARE complex, defects in the SNARE-dependent exocytosis and altered regulation of SNARE-mediated vesicle fusion have been associated with neurodegeneration. In this review, the biological aspects of neurodegenerative diseases and the role of SNARE proteins in relation to the onset of these pathologies are described.}, }
@article {pmid33921446, year = {2021}, author = {Liguori, F and Amadio, S and Volonté, C}, title = {Where and Why Modeling Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33921446}, issn = {1422-0067}, support = {Ricerca Corrente FSL//Ministero della Salute/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/therapy ; Animals ; Animals, Genetically Modified/*genetics ; Caenorhabditis elegans/genetics ; Disease Models, Animal ; Dogs ; Guinea Pigs ; Humans ; Mice ; Neurodegenerative Diseases/*genetics/pathology/therapy ; Rats ; Zebrafish/genetics ; }, abstract = {Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS.}, }
@article {pmid33920577, year = {2021}, author = {Ding, B and Sepehrimanesh, M}, title = {Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33920577}, issn = {1422-0067}, support = {R21 NS112910/NS/NINDS NIH HHS/United States ; NS112910/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; Aging/*metabolism ; Animals ; Humans ; Neurodegenerative Diseases/*metabolism ; Nuclear Pore/*metabolism ; }, abstract = {Nucleocytoplasmic transport (NCT) across the nuclear envelope is precisely regulated in eukaryotic cells, and it plays critical roles in maintenance of cellular homeostasis. Accumulating evidence has demonstrated that dysregulations of NCT are implicated in aging and age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Huntington disease (HD). This is an emerging research field. The molecular mechanisms underlying impaired NCT and the pathogenesis leading to neurodegeneration are not clear. In this review, we comprehensively described the components of NCT machinery, including nuclear envelope (NE), nuclear pore complex (NPC), importins and exportins, RanGTPase and its regulators, and the regulatory mechanisms of nuclear transport of both protein and transcript cargos. Additionally, we discussed the possible molecular mechanisms of impaired NCT underlying aging and neurodegenerative diseases, such as ALS/FTD, HD, and AD.}, }
@article {pmid33918215, year = {2021}, author = {Harley, J and Clarke, BE and Patani, R}, title = {The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {33918215}, issn = {2076-3921}, support = {MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/ 1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.}, }
@article {pmid33918092, year = {2021}, author = {Källstig, E and McCabe, BD and Schneider, BL}, title = {The Links between ALS and NF-κB.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33918092}, issn = {1422-0067}, support = {721802//Horizon 2020/ ; }, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/*etiology/*metabolism/pathology ; Animals ; Biomarkers ; *Disease Susceptibility ; Environment ; Enzyme Activation ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Microglia/metabolism/pathology ; NF-kappa B/*metabolism ; Neurons/metabolism/pathology ; Oligodendroglia/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease wherein motor neuron degeneration leads to muscle weakness, progressive paralysis, and death within 3-5 years of diagnosis. Currently, the cause of ALS is unknown but, as with several neurodegenerative diseases, the potential role of neuroinflammation has become an increasingly popular hypothesis in ALS research. Indeed, upregulation of neuroinflammatory factors have been observed in both ALS patients and animal models. One such factor is the inflammatory inducer NF-κB. Besides its connection to inflammation, NF-κB activity can be linked to several genes associated to familial forms of ALS, and many of the environmental risk factors of the disease stimulate NF-κB activation. Collectively, this has led many to hypothesize that NF-κB proteins may play a role in ALS pathogenesis. In this review, we discuss the genetic and environmental connections between NF-κB and ALS, as well as how this pathway may affect different CNS cell types, and finally how this may lead to motor neuron degeneration.}, }
@article {pmid33917816, year = {2021}, author = {Jiang, X and Guan, Y and Zhao, Z and Meng, F and Wang, X and Gao, X and Liu, J and Chen, Y and Zhou, F and Zhou, S and Wang, X}, title = {Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {10}, number = {4}, pages = {}, pmid = {33917816}, issn = {2073-4409}, support = {81871006//National Natural Science Foundation of China/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Axons/metabolism/pathology ; Humans ; Ligands ; Neuromuscular Junction/metabolism/pathology ; Wnt Proteins/metabolism ; *Wnt Signaling Pathway ; }, abstract = {The WNT signaling pathway plays an important role in the physiological and pathophysiological processes of the central nervous system and the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We reviewed the literature pertinent to WNT/β-catenin signaling in ALS from cellular studies, animal models, and human clinical trials. WNT, WNT receptors, and other components of the WNT signaling pathway are expressed in both ALS patients and transgenic mice, and are involved in the pathogenesis of ALS. Studies have shown that abnormal activation of the WNT/β-catenin signaling pathway is related to neuronal degeneration and glial cell proliferation. WNT/Ca[2+] signaling is associated with the pro-inflammatory phenotype of microglia; data on the muscle skeletal receptor Tyr kinase receptor in superoxide dismutase-1-G93A mice indicate that gene therapy is necessary for successful treatment of ALS. The varying profiles of lipoprotein receptor-related protein 4 antibodies in different ethnic groups suggest that individual treatment and multifactorial personalized approaches may be necessary for effective ALS therapy. In conclusion, the WNT signaling pathway is important to the ALS disease process, making it a likely therapeutic target.}, }
@article {pmid33917673, year = {2021}, author = {Riku, Y and Seilhean, D and Duyckaerts, C and Boluda, S and Iguchi, Y and Ishigaki, S and Iwasaki, Y and Yoshida, M and Sobue, G and Katsuno, M}, title = {Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33917673}, issn = {1422-0067}, support = {JP20K16586//JSPS KAKENHI/ ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*etiology/*metabolism ; Biomarkers ; DNA-Binding Proteins/genetics/*metabolism ; *Disease Susceptibility ; Frontotemporal Lobar Degeneration/diagnosis/*etiology/*metabolism ; Gain of Function Mutation ; Humans ; Immunohistochemistry ; Loss of Function Mutation ; Neurons/*metabolism ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Binding ; *Signal Transduction ; tau Proteins/metabolism ; }, abstract = {Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations.}, }
@article {pmid33913406, year = {2022}, author = {Mohi-Ud-Din, R and Mir, RH and Shah, AJ and Sabreen, S and Wani, TU and Masoodi, MH and Akkol, EK and Bhat, ZA and Khan, H}, title = {Plant-Derived Natural Compounds for the Treatment of Amyotrophic Lateral Sclerosis: An Update.}, journal = {Current neuropharmacology}, volume = {20}, number = {1}, pages = {179-193}, pmid = {33913406}, issn = {1875-6190}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Motor Neuron Disease ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects.<br><br>OBJECTIVE/AIM: The current study aims to thoroughly review plant-derived compounds with welldefined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS.<br><br>METHODS: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct.<br><br>RESULTS: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms Conclusion: These plant-derived compounds may be considered as supplements for conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structureactivity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.}, }
@article {pmid33912591, year = {2021}, author = {Clarke, JP and Thibault, PA and Salapa, HE and Levin, MC}, title = {A Comprehensive Analysis of the Role of hnRNP A1 Function and Dysfunction in the Pathogenesis of Neurodegenerative Disease.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {659610}, pmid = {33912591}, issn = {2296-889X}, abstract = {Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a member of the hnRNP family of conserved proteins that is involved in RNA transcription, pre-mRNA splicing, mRNA transport, protein translation, microRNA processing, telomere maintenance and the regulation of transcription factor activity. HnRNP A1 is ubiquitously, yet differentially, expressed in many cell types, and due to post-translational modifications, can vary in its molecular function. While a plethora of knowledge is known about the function and dysfunction of hnRNP A1 in diseases other than neurodegenerative disease (e.g., cancer), numerous studies in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, multiple sclerosis, spinal muscular atrophy, Alzheimer's disease, and Huntington's disease have found that the dysregulation of hnRNP A1 may contribute to disease pathogenesis. How hnRNP A1 mechanistically contributes to these diseases, and whether mutations and/or altered post-translational modifications contribute to pathogenesis, however, is currently under investigation. The aim of this comprehensive review is to first describe the background of hnRNP A1, including its structure, biological functions in RNA metabolism and the post-translational modifications known to modify its function. With this knowledge, the review then describes the influence of hnRNP A1 in neurodegenerative disease, and how its dysfunction may contribute the pathogenesis.}, }
@article {pmid33905071, year = {2022}, author = {Kiaei, L and Kiaei, M}, title = {RNA as a source of biomarkers for amyotrophic lateral sclerosis.}, journal = {Metabolic brain disease}, volume = {37}, number = {6}, pages = {1697-1702}, pmid = {33905071}, issn = {1573-7365}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; Biomarkers ; Humans ; Motor Neurons/pathology ; *Neurodegenerative Diseases ; RNA/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, leads to the loss of motor neurons. There are currently no effective therapies to treat this disease as the molecular mechanisms of motor neuron degeneration are largely unknown. The diagnosis of ALS, or motor neuron disease, is not a simple process that can be carried out with one doctor visit or a single simple test. This has created a major problem for patients with ALS and their physicians since they are often not diagnosed until about a year into the disease. In order to combat this issue, new techniques of detecting the clinical and pathological changes of the disease are critical. These techniques are currently being studied and developed which can revolutionize the diagnosis of ALS. Once this technology is established, it may have application to monitor the progression of the disease. RNA-Seq is a powerful tool that has potential to identify RNA as small molecules in patients' biological samples (Plasma, Cerebral Spinal Fluid) which can be used to inform the system changes in patients with ALS. In this review, we will explore and discuss our current work on RNA-Seq and its development of biomarkers to diagnose and assess the rate of progression in the disease.}, }
@article {pmid33902945, year = {2021}, author = {Couratier, P and Lautrette, G and Luna, JA and Corcia, P}, title = {Phenotypic variability in amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {177}, number = {5}, pages = {536-543}, doi = {10.1016/j.neurol.2021.03.001}, pmid = {33902945}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis ; Biological Variation, Population ; DNA-Binding Proteins ; Humans ; Inclusion Bodies ; Motor Neurons ; }, abstract = {Clinically, ALS phenotypes depend on the areas of the body that are affected, the different degrees of involvement of upper and lower motor neurons, the degrees of involvement of other systems, particularly cognition and behavior, and rates of progression. Phenotypic variability of ALS is characteristic and can be declined on the distribution of motor manifestations but also on the presence of extra-motor signs present in a variable manner in ALS patients. Neuropathologically, ALS is defined by the loss of UMN and LMN and the presence of two representative motor neuronal cytoplasmic inclusions, Bunina bodies and 43kDa Transactivation Response DNA Binding Protein (TDP-43) - positive cytoplasmic inclusions. The distribution of cytopathology and neuronal loss in patients is variable and this variability is directly related to phenotypic variability. Key regulators of phenotypic variability in ALS have not been determined. The functional decrement of TDP-43, and region-specific neuronal susceptibility to ALS, may be involved. Due to the selective vulnerability among different neuronal systems, lesions are multicentric, region-oriented, and progress at different rates. They may vary from patient to patient, which may be linked to the clinicopathological variability across patients.}, }
@article {pmid33901506, year = {2021}, author = {Mao, XY and Yin, XX and Guan, QW and Xia, QX and Yang, N and Zhou, HH and Liu, ZQ and Jin, WL}, title = {Dietary nutrition for neurological disease therapy: Current status and future directions.}, journal = {Pharmacology &amp; therapeutics}, volume = {226}, number = {}, pages = {107861}, doi = {10.1016/j.pharmthera.2021.107861}, pmid = {33901506}, issn = {1879-016X}, mesh = {Evidence-Based Practice ; Forecasting ; Humans ; *Nervous System Diseases/diet therapy ; }, abstract = {Adequate food intake and relative abundance of dietary nutrients have undisputed effects on the brain function. There is now substantial evidence that dietary nutrition aids in the prevention and remediation of neurologic symptoms in diverse pathological conditions. The newly described influences of dietary factors on the alterations of mitochondrial dysfunction, epigenetic modification and neuroinflammation are important mechanisms that are responsible for the action of nutrients on the brain health. In this review, we discuss the state of evidence supporting that distinct dietary interventions including dietary supplement and dietary restriction have the ability to tackle neurological disorders using Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis as examples. Additionally, it is also highlighting that diverse potential mechanisms such as metabolic control, epigenetic modification, neuroinflammation and gut-brain axis are of utmost importance for nutrient supply to the risk of neurologic condition and therapeutic response. Finally, we also highlight the novel concept that dietary nutrient intervention reshapes metabolism-epigenetics-immunity cycle to remediate brain dysfunction. Targeting metabolism-epigenetics-immunity network will delineate a new blueprint for combating neurological weaknesses.}, }
@article {pmid33898525, year = {2021}, author = {Schisa, JA and Elaswad, MT}, title = {An Emerging Role for Post-translational Modifications in Regulating RNP Condensates in the Germ Line.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {658020}, pmid = {33898525}, issn = {2296-889X}, support = {R15 GM109337/GM/NIGMS NIH HHS/United States ; }, abstract = {RNA-binding proteins undergo regulated phase transitions in an array of cell types. The phase separation of RNA-binding proteins, and subsequent formation of RNP condensates or granules, occurs during physiological conditions and can also be induced by stress. Some RNP granules have roles in post-transcriptionally regulating mRNAs, and mutations that prevent the condensation of RNA-binding proteins can reduce an organism's fitness. The reversible and multivalent interactions among RNP granule components can result in RNP complexes that transition among diffuse and condensed states, the latter of which can be pathological; for example, in neurons solid RNP aggregates contribute to disease states such as amyotrophic lateral sclerosis (ALS), and the dysregulation of RNP granules in human germ cells may be involved in Fragile X-associated primary ovarian insufficiency. Thus, regulating the assembly of mRNAs and RNA-binding proteins into discrete granules appears to provide important functions at both cellular and physiological levels. Here we review our current understanding of the role of post-translational modifications (PTMs) in regulating the condensation of RNA-binding proteins in the germ line. We compare and contrast the in vitro evidence that methylation inhibits phase separation of RNA binding proteins, with the extent to which these results apply to the in vivo germ line environment of several model systems. We also focus on the role of phosphorylation in modulating the dynamics of RNP granules in the germ line. Finally, we consider the gaps that exist in our understanding of the role of PTMs in regulating germ line RNP granules.}, }
@article {pmid33897410, year = {2021}, author = {Hu, C and Chen, C and Dong, XP}, title = {Impact of COVID-19 Pandemic on Patients With Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {664965}, pmid = {33897410}, issn = {1663-4365}, abstract = {COVID-19 pandemic has already produced great impacts on global health security and social-economy. Elderly, particularly those with underlying diseases, are suffering from higher fatality rate. Neurodegenerative diseases are a group of incurable neurological disorders of loss of neuron and/or myelin sheath, which affect hundreds of millions of elderly populations and usually need long-term care. Older population is one of the most vulnerable to COVID-19 pandemic. In this report, we reviewed the current status of COVID-19 on the patients with several neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis. Meanwhile, the potential mechanisms of SARS-CoV-2 infection in the pathogenesis of neurodegenerative diseases were also summarized.}, }
@article {pmid33896522, year = {2021}, author = {Singh, TD and Wijdicks, EFM}, title = {Neuromuscular Respiratory Failure.}, journal = {Neurologic clinics}, volume = {39}, number = {2}, pages = {333-353}, doi = {10.1016/j.ncl.2021.01.010}, pmid = {33896522}, issn = {1557-9875}, mesh = {Humans ; Neuromuscular Diseases/*complications/*diagnosis ; Respiratory Insufficiency/*etiology ; }, abstract = {Neuromuscular respiratory failure can result from any disease that causes weakness of bulbar and/or respiratory muscles. Once compensatory mechanisms are overwhelmed, hypoxemic and hypercapnic respiratory failure ensues. The diagnosis of neuromuscular respiratory failure is primarily clinical, but arterial blood gases, bedside spirometry, and diaphragmatic ultrasonography can help in early assessment. Intensive care unit (ICU) admission is indicated for patients with severe bulbar weakness or rapidly progressing appendicular weakness. Intubation should be performed electively, particularly in patients with dysautonomia. Patients with an underlying treatable cause have the potential to regain functional independence with meticulous ICU care.}, }
@article {pmid33892003, year = {2021}, author = {Ferraiuolo, L and Maragakis, NJ}, title = {Mini-Review: Induced pluripotent stem cells and the search for new cell-specific ALS therapeutic targets.}, journal = {Neuroscience letters}, volume = {755}, number = {}, pages = {135911}, doi = {10.1016/j.neulet.2021.135911}, pmid = {33892003}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Cell Differentiation/drug effects/physiology ; Cellular Reprogramming Techniques/*methods/trends ; Central Nervous System Agents/administration &amp; dosage ; Coculture Techniques ; Drug Evaluation, Preclinical/methods/trends ; Humans ; Induced Pluripotent Stem Cells/drug effects/physiology/*transplantation ; Organoids/cytology/drug effects/physiology ; Stem Cell Transplantation/*methods/trends ; }, abstract = {Amongst the most important discoveries in ALS pathobiology are the works demonstrating that multiple cell types contribute to disease onset and progression. However, a significant limitation in ALS research is the inability to obtain tissues from ALS patient brain and spinal cord during the course of the disease. In vivo modeling has provided insights into the role of these cell subtypes in disease onset and progression. However, in vivo models also have shortcomings, including the reliance on a limited number of models based upon hereditary forms of the disease. Therefore, using human induced pluripotent stem cells (iPSC) reprogrammed from somatic cells of ALS patients, with both hereditary and sporadic forms of the disease, and differentiated into cell subtypes of both the central nervous system (CNS) and peripheral nervous system (PNS), have become powerful complementary tools for investigating basic mechanisms of disease as well as a platform for drug discovery. Motor neuron and other neuron subtypes, as well as non-neuronal cells have been differentiated from human iPSC and studied for their potential contributions to ALS pathobiology. As iPSC technologies have advanced, 3D modeling with multicellular systems organised in microfluidic chambers or organoids are the next step in validating the pathways and therapeutic targets already identified. Precision medicine approaches with iPSC using either traditional strategies of screening drugs that target a known pathogenic mechanism as well as "blind-to-target" drug screenings that allow for patient stratification based on drug response rather than clinical characteristics are now being employed.}, }
@article {pmid33882469, year = {2021}, author = {Akgenc, B and Sarikurt, S and Yagmurcukardes, M and Ersan, F}, title = {Aluminum and lithium sulfur batteries: a review of recent progress and future directions.}, journal = {Journal of physics. Condensed matter : an Institute of Physics journal}, volume = {33}, number = {25}, pages = {}, doi = {10.1088/1361-648X/abfa5e}, pmid = {33882469}, issn = {1361-648X}, abstract = {Advanced materials with various micro-/nanostructures have attracted plenty of attention for decades in energy storage devices such as rechargeable batteries (ion- or sulfur based batteries) and supercapacitors. To improve the electrochemical performance of batteries, it is uttermost important to develop advanced electrode materials. Moreover, the cathode material is also important that it restricts the efficiency and practical application of aluminum-ion batteries. Among the potential cathode materials, sulfur has become an important candidate material for aluminum-ion batteries cause of its considerable specific capacity. Two-dimensional materials are currently potential candidates as electrodes from lab-scale experiments to possible pragmatic theoretical studies. In this review, the fundamental principles, historical progress, latest developments, and major problems in Li-S and Al-S batteries are reviewed. Finally, future directions in terms of the experimental and theoretical applications have prospected.}, }
@article {pmid33879715, year = {2021}, author = {Kim, JY and Oh, HJ and Kim, Y and Seok, JM}, title = {Sporadic amyotrophic lateral sclerosis with seropositive neuromyelitis optica spectrum disorder: A case report.}, journal = {Medicine}, volume = {100}, number = {16}, pages = {e25580}, pmid = {33879715}, issn = {1536-5964}, support = {no//Soonchunhyang University Research Fund/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Aquaporin 4/*immunology ; Autoantibodies/*blood ; Female ; Humans ; Middle Aged ; Neuromyelitis Optica/blood/*immunology ; }, abstract = {RATIONALE: Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system with an autoantibody against aquaporin-4 protein (AQP4), and amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We report a female patient with ALS who had asymptomatic AQP4 antibody at the diagnosis of ALS, and NMOSD occurred 4 years later after the diagnosis of ALS.<br><br>PATIENT CONCERNS: She was already bedridden and had tracheostomy because of ALS which was diagnosed at her age of 55. At the time of her ALS diagnosis, she had no brain or spinal cord lesions, but was seropositive for AQP4 antibody. At her age of 59, new-onset complete paralysis of all extremities and severe pain on the posterior neck and both shoulders occurred and visited the hospital.<br><br>DIAGNOSIS: Longitudinally extensive transverse myelitis was diagnosed, which was the onset attack of seropositive NMOSD. The diagnosis was confirmed based on the international consensus diagnostic criteria for NMOSD with MR imaging, cerebrospinal fluid exam and laboratory work-ups with AQP4 antibody test.<br><br>INTERVENTIONS: High dose methylprednisolone was administered for 5&#x200a;days. Plasma exchange as a further treatment was recommended, but she and her family refused.<br><br>OUTCOMES: Her pain was relieved after steroid treatment, but there was no improvement of her leg weakness.<br><br>LESSONS: This case is a rare combination of neuroinflammatory and neurodegenerative diseases. Considering the alterations of blood-brain barrier along with the progression of ALS, it highlights that the consequence of ALS pathogenesis might affect the development of NMOSD. And the careful follow-up is recommended even in patients with profound weakness, especially if those who were at risk of developing certain neurological disorders.}, }
@article {pmid33878947, year = {2021}, author = {Ainslie, A and Huiting, W and Barazzuol, L and Bergink, S}, title = {Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?.}, journal = {Open biology}, volume = {11}, number = {4}, pages = {200296}, pmid = {33878947}, issn = {2046-2441}, mesh = {Amyloidogenic Proteins/genetics/metabolism ; Animals ; DNA Damage ; DNA Repair ; *Disease Susceptibility ; Gene Expression ; Genetic Predisposition to Disease ; *Genomic Instability ; Humans ; Neurodegenerative Diseases/*etiology/*metabolism/pathology ; Oxidative Stress ; Phenotype ; Protein Aggregation, Pathological ; *Proteostasis/genetics ; }, abstract = {Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.}, }
@article {pmid33867942, year = {2021}, author = {Dafinca, R and Barbagallo, P and Talbot, K}, title = {The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {653688}, pmid = {33867942}, issn = {1662-5102}, support = {TALBOT-MUTIHAC/APR15/832-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TALBOT/OCT15/886-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; TALBOT/OCT16/889-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.}, }
@article {pmid33865016, year = {2021}, author = {Bai, X and Fu, RJ and Zhang, S and Yue, SJ and Chen, YY and Xu, DQ and Tang, YP}, title = {Potential medicinal value of celastrol and its synthesized analogues for central nervous system diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {139}, number = {}, pages = {111551}, doi = {10.1016/j.biopha.2021.111551}, pmid = {33865016}, issn = {1950-6007}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Central Nervous System Agents/pharmacology/*therapeutic use ; Central Nervous System Diseases/*drug therapy ; Central Nervous System Neoplasms/drug therapy ; Humans ; Pentacyclic Triterpenes/*therapeutic use ; Tripterygium/chemistry ; }, abstract = {The central nervous system (CNS) is a vital part of the human nervous system, and the incidence of CNS disease is increasing year by year, which has become a major public health problem and a prominent social problem. At present, the drugs most commonly used in the clinic are receptor regulators, and neurotransmitter inhibitors, but they are accompanied by serious side effects. Therefore, the identification of new drugs and treatment strategies for CNS disease has been a research hotspot in the medical field. Celastrol, a highly bio-active pentacyclic triterpenoid isolated from Tripterygium wilfordii Hook. F, has been proved to have a wide range of pharmacological effects, such as anti-inflammation, immunosuppression, anti-obesity and anti-tumor activity. However, due to its poor water solubility, low bioavailability and toxicity, the clinical development and trials of celastrol have been postponed. However, in recent years, the extensive medical value of celastrol in the treatment of CNS diseases such as nervous system tumors, Alzheimer's disease, Parkinson's disease, cerebral ischemia, multiple sclerosis, spinal cord injury, and amyotrophic lateral sclerosis has gradually attracted intensive attention worldwide. In particular, celastrol has non-negligible anti-tumor efficacy, and as there are no 100% effective anti-tumor drugs, the study of its structural modification to obtain better leading compounds with higher efficiency and lower toxicity has aroused strong interest in pharmaceutical chemists. In this review, research progress on celastrol in CNS diseases and the synthesis of celastrol-type triterpenoid analogues and their application evaluation in disease models, such as CNS diseases and autotoxicity-related target organ cancers in the past decade are summarized in detail, in order to provide reference for future better application in the treatment of CNS diseases.}, }
@article {pmid33862143, year = {2021}, author = {Consonni, M and Dalla Bella, E and Bersano, E and Lauria, G}, title = {Cognitive and behavioural impairment in amyotrophic lateral sclerosis: A landmark of the disease? A mini review of longitudinal studies.}, journal = {Neuroscience letters}, volume = {754}, number = {}, pages = {135898}, doi = {10.1016/j.neulet.2021.135898}, pmid = {33862143}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis/psychology ; Cognitive Dysfunction/diagnosis/*epidemiology/etiology/psychology ; Disease Progression ; Humans ; Longitudinal Studies ; Neuropsychological Tests ; Problem Behavior/*psychology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease marked by progressive loss of motor abilities. Approximately half of patents with ALS experience cognitive (ALSci) or behavioural impairment (ALSbi) during the course of the disease, with a small percentage developing overt frontotemporal dementia (FTD). ALSci and/or ALSbi can occur simultaneously with motor neuron degeneration or develop in advanced stages of the disease, but it can even precede motor involvement in some cases, namely in ALS patients meeting criteria for FTD. Despite clear evidence that cognitive/behavioural impairment may appear early in the course of ALS, no prominent deterioration seems to occur with disease progression. Longitudinal studies have failed to reach conclusive results on the progression of cognitive and behavioural involvement in ALS. This may be due to some structural limitations of the studies, such as attrition rate, practice effect, short-time interval between neuropsychological assessments, but it can also be due to the heterogeneity of ALS phenotypes. The objective of this review is to provide a comprehensive and critical analysis of results of longitudinal studies highlighting cognitive and behavioural domains mainly affected by neurodegeneration pointing out the determinants that might be associate with the development and worsening of frontotemporal symptoms in ALS. At this regard, older age, rapidly progressing ALS, bulbar-onset, advanced disease stages are among factors mainly associated with cognitive and behavioural involvement. Moreover, the progression of cognitive and behavioural deficits seems to be not directly related to the slope of motor disability, thus suggesting the independence of neuropsychological and motor functional decline in ALS. Cognitive and motor involvement may indeed present with distinct trajectories suggesting a differential vulnerability of motor and non-motor cortical networks. In this scenario, determining the progression of extra-motor involvement in ALS may help refine understanding of the clinical implications of cognitive and behavioural abnormalities, and provide clues to the aetiology of the disease.}, }
@article {pmid33861641, year = {2021}, author = {Atif, M and Alsrhani, A and Naz, F and Imran, M and Imran, M and Ullah, MI and Alameen, AAM and Gondal, TA and Raza, Q}, title = {Targeting Adenosine Receptors in Neurological Diseases.}, journal = {Cellular reprogramming}, volume = {23}, number = {2}, pages = {57-72}, doi = {10.1089/cell.2020.0087}, pmid = {33861641}, issn = {2152-4998}, mesh = {Animals ; Humans ; Nervous System Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*pharmacology ; Receptors, Purinergic P1/*chemistry/metabolism ; Signal Transduction ; }, abstract = {Adenosine plays a significant role in neurotransmission process by controlling the blood pressure, while adenosine triphosphate (ATP) acts as a neuromodulator and neurotransmitter and by activation of P2 receptors, regulates the contractility of the heart. Adenosine signaling is essential in the process of regeneration by regulating proliferation, differentiation, and apoptosis of stem cells. In this review, we have selected neurological disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy) with clinical trials using antagonists and epigenetic tools targeting adenosine receptor as a therapeutic approach in the treatment of these disorders. Promising results have been reported from many clinical trials. It has been found that higher expression levels of A2A and P2X7 receptors in neurological disorders further complicate the disease condition. Therefore, modulations of these receptors by using antagonists of these receptors or SAM (S-adenosylmethionine) therapy as an epigenetic tool could be useful in reversing the complications of these disorders. Finally, we suggest that modulation of adenosine receptors in neurological disorders can increase the regenerative phase by increasing the rate of proliferation and differentiation in the damaged tissues.}, }
@article {pmid33861265, year = {2021}, author = {Wang, Y and Wang, Q and Han, X and Ma, Y and Zhang, Z and Zhao, L and Guan, F and Ma, S}, title = {Fucoidan: a promising agent for brain injury and neurodegenerative disease intervention.}, journal = {Food &amp; function}, volume = {12}, number = {9}, pages = {3820-3830}, doi = {10.1039/d0fo03153d}, pmid = {33861265}, issn = {2042-650X}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Antiviral Agents/pharmacology/therapeutic use ; Apoptosis/drug effects ; Brain Injuries/*drug therapy/physiopathology ; Cholinergic Agents/pharmacology/therapeutic use ; Drug Therapy, Combination ; Humans ; Mitochondria/drug effects/physiology ; Neurites/drug effects/physiology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Polysaccharides/pharmacokinetics/pharmacology/*therapeutic use ; }, abstract = {Brain injury and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are urgent medical problems, which severely threaten the life quality of patients and their carers. However, there are currently no effective therapies. Fucoidan is a natural compound found in brown algae and some animals, which has multiple biological and pharmacological activities, such as antioxidant, anti-tumor, anti-coagulant, anti-thrombotic, immunoregulatory, anti-viral, and anti-inflammatory effects. A growing number of studies have shown that fucoidan also exerts a neuroprotective function. Particularly, recent findings have indicated that fucoidan could slow down the neurodegenerative processes and show protective effects against brain injury, which might be of therapeutic value for intervening in brain injury and neurodegenerative diseases. In this review, we have discussed the pharmacokinetics of fucoidan as well as the molecular mechanisms by which fucoidan exerts its neuroprotective effect on some neurological disorders. Along with this, we have also summarized the potential benefits of fucoidan in combination with other drugs in the treatment of neurodegenerative diseases and brain injury. Although the extraction process of fucoidan has been improved well, more efforts should be devoted to the translational research and clinical trials of fucoidan in the near future.}, }
@article {pmid33860329, year = {2021}, author = {Creekmore, BC and Chang, YW and Lee, EB}, title = {The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors.}, journal = {Journal of neuropathology and experimental neurology}, volume = {80}, number = {6}, pages = {494-513}, pmid = {33860329}, issn = {1554-6578}, support = {R01 NS039572/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; P01 AG010120/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P01 AG062413/AG/NIA NIH HHS/United States ; R56 AG063344/AG/NIA NIH HHS/United States ; U54 NS115322/NS/NINDS NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; }, mesh = {Aging/physiology ; *Cryoelectron Microscopy/methods ; Humans ; Neurodegenerative Diseases/*pathology ; Proteasome Endopeptidase Complex/*ultrastructure ; Protein Aggregates/physiology ; Proteostasis/*physiology ; }, abstract = {Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.}, }
@article {pmid33854883, year = {2021}, author = {Andrzejewska, A and Dabrowska, S and Lukomska, B and Janowski, M}, title = {Mesenchymal Stem Cells for Neurological Disorders.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {8}, number = {7}, pages = {2002944}, pmid = {33854883}, issn = {2198-3844}, mesh = {Humans ; Mesenchymal Stem Cell Transplantation/*methods ; Nervous System Diseases/*therapy ; }, abstract = {Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.}, }
@article {pmid33853652, year = {2021}, author = {Perrone, F and Cacace, R and van der Zee, J and Van Broeckhoven, C}, title = {Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases.}, journal = {Genome medicine}, volume = {13}, number = {1}, pages = {59}, pmid = {33853652}, issn = {1756-994X}, mesh = {Brain Diseases/*genetics ; *Genetic Variation ; Genome-Wide Association Study ; Humans ; Inheritance Patterns/genetics ; Neurodegenerative Diseases/*genetics/pathology ; Risk Factors ; Exome Sequencing ; }, abstract = {Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing (NGS) technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. NGS technology exposed large numbers of rare genetic variants of uncertain significance (VUS) in coding regions, highlighting the genetic complexity of NBD. Since experimental studies of these coding rare VUS are largely lacking, the potential contributions of VUS to NBD etiology remain unknown. In this review, we summarize novel findings in NBD genetic etiology driven by NGS and the impact of rare VUS on NBD etiology. We consider different mechanisms by which rare VUS can act and influence NBD pathophysiology and discuss why a better understanding of rare VUS is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD. New knowledge might open avenues for effective personalized therapies.}, }
@article {pmid33850034, year = {2021}, author = {Nath, U and Regnard, C and Lee, M and Lloyd, KA and Wiblin, L}, title = {Physician-assisted suicide and physician-assisted euthanasia: evidence from abroad and implications for UK neurologists.}, journal = {Practical neurology}, volume = {21}, number = {3}, pages = {205-211}, doi = {10.1136/practneurol-2020-002811}, pmid = {33850034}, issn = {1474-7766}, mesh = {*Euthanasia ; Humans ; Neurologists ; *Physicians ; *Suicide, Assisted ; United Kingdom ; }, abstract = {In this article, we consider the arguments for and against physician-assisted suicide (AS) and physician-assisted euthanasia (Eu). We assess the evidence around law and practice in three jurisdictions where one or both are legal, with emphasis on data from Oregon. We compare the eligibility criteria in these different regions and review the range of approved disorders. Cancer is the most common cause for which requests are granted, with neurodegenerative diseases, mostly motor neurone disease, ranking second. We review the issues that may drive requests for a physician-assisted death, such as concerns around loss of autonomy and the possible role of depression. We also review the effectiveness and tolerability of some of the life-ending medications used. We highlight significant variation in regulatory oversight across the different models. A large amount of data are missing or unavailable. We explore physician-AS and physician-assisted Eu within the wider context of end-of-life practice.}, }
@article {pmid33845074, year = {2021}, author = {Duffy, SS and Hayes, JP and Fiore, NT and Moalem-Taylor, G}, title = {The cannabinoid system and microglia in health and disease.}, journal = {Neuropharmacology}, volume = {190}, number = {}, pages = {108555}, doi = {10.1016/j.neuropharm.2021.108555}, pmid = {33845074}, issn = {1873-7064}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Anxiety Disorders/metabolism ; Arachidonic Acids/metabolism ; Chronic Pain/metabolism ; Depressive Disorder/metabolism ; Endocannabinoids/*metabolism/physiology ; Glycerides/metabolism ; Humans ; Mental Disorders/*metabolism ; Microglia/*metabolism/physiology ; Multiple Sclerosis/*metabolism ; Neuralgia/metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; Polyunsaturated Alkamides/metabolism ; Receptor, Cannabinoid, CB1/*metabolism ; Receptor, Cannabinoid, CB2/*metabolism ; Schizophrenia/metabolism ; }, abstract = {Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.}, }
@article {pmid33842068, year = {2021}, author = {de Boer, EMJ and Barritt, AW and Elamin, M and Anderson, SJ and Broad, R and Nisbet, A and Goedee, HS and Vázquez Costa, JF and Prudlo, J and Vedeler, CA and Fernandez, JP and Panades, MP and Albertí Aguilo, MA and Bella, ED and Lauria, G and Pinto, WBVR and de Souza, PVS and Oliveira, ASB and Toro, C and van Iersel, J and Parson, M and Harschnitz, O and van den Berg, LH and Veldink, JH and Al-Chalabi, A and Leigh, PN and van Es, MA}, title = {Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.}, journal = {Neurology. Clinical practice}, volume = {11}, number = {2}, pages = {147-157}, pmid = {33842068}, issn = {2163-0402}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; P30 CA008748/CA/NCI NIH HHS/United States ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN).<br><br>RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases.<br><br>SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.}, }
@article {pmid33839324, year = {2021}, author = {Amado, DA and Davidson, BL}, title = {Gene therapy for ALS: A review.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {29}, number = {12}, pages = {3345-3358}, pmid = {33839324}, issn = {1525-0024}, support = {F32 NS009435/NS/NINDS NIH HHS/United States ; K08 NS114106/NS/NINDS NIH HHS/United States ; S10 OD012006/OD/NIH HHS/United States ; U01 NS111671/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics ; Dependovirus/genetics ; Genetic Therapy/methods ; Humans ; Oligonucleotides, Antisense/genetics/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.}, }
@article {pmid33834472, year = {2021}, author = {Cheng, Y and Chen, Y and Shang, H}, title = {[Advance in research on biomarkers for amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {38}, number = {4}, pages = {383-387}, doi = {10.3760/cma.j.cn511374-20200328-00213}, pmid = {33834472}, issn = {1003-9406}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Biomarkers ; Humans ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless, progressive, and presently incurable neurodegenerative disease. Its drug development has been hampered by the lack of effective biomarkers for early diagnosis, progression and prognosis. Recently, significant progress has been made for the identification of body fluid biomarkers for ALS, which conferred both theoretical and practical feasibility for the early diagnosis and progression monitoring. Meanwhile, it also facilitated identification of genes and/or pathways for the pathogenesis of ALS. This review summarized biomarkers identified from cerebrospinal fluid, blood and urine of ALS patients and their clinical implications.}, }
@article {pmid33832769, year = {2021}, author = {Klim, JR and Pintacuda, G and Nash, LA and Guerra San Juan, I and Eggan, K}, title = {Connecting TDP-43 Pathology with Neuropathy.}, journal = {Trends in neurosciences}, volume = {44}, number = {6}, pages = {424-440}, doi = {10.1016/j.tins.2021.02.008}, pmid = {33832769}, issn = {1878-108X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Axons ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia ; Humans ; Mutation ; }, abstract = {Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.}, }
@article {pmid33827397, year = {2021}, author = {Vinogradova, ES and Nikonov, OS and Nikonova, EY}, title = {Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase.}, journal = {Biochemistry. Biokhimiia}, volume = {86}, number = {Suppl 1}, pages = {S12-S23}, pmid = {33827397}, issn = {1608-3040}, mesh = {Charcot-Marie-Tooth Disease/enzymology/genetics/physiopathology ; Female ; Glycine-tRNA Ligase/*genetics ; Humans ; Male ; Muscular Atrophy, Spinal/enzymology/genetics/physiopathology ; *Mutation ; Nervous System Diseases/*enzymology/genetics/physiopathology ; Neurons/enzymology/physiology ; }, abstract = {Aminoacyl-RNA synthetases (aaRSs) are among the key enzymes of protein biosynthesis. They are responsible for conducting the first step in the protein biosynthesis, namely attaching amino acids to the corresponding tRNA molecules both in cytoplasm and mitochondria. More and more research demonstrates that mutations in the genes encoding aaRSs lead to the development of various neurodegenerative diseases, such as incurable Charcot-Marie-Tooth disease (CMT) and distal spinal muscular atrophy. Some mutations result in the loss of tRNA aminoacylation activity, while other mutants retain their classical enzyme activity. In the latter case, disease manifestations are associated with additional neuron-specific functions of aaRSs. At present, seven aaRSs (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, MetRS, and LysRS) are known to be involved in the CMT etiology with glycyl-tRNA synthetase (GlyRS) being the most studied of them.}, }
@article {pmid33823304, year = {2022}, author = {Miccio, A and Antoniou, P and Ciura, S and Kabashi, E}, title = {Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {30}, number = {1}, pages = {47-53}, pmid = {33823304}, issn = {1525-0024}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Gene Editing ; Humans ; Infant ; *Muscular Atrophy, Spinal/genetics/metabolism/therapy ; Oligonucleotides/metabolism ; RNA Splicing ; Survival of Motor Neuron 1 Protein/genetics/metabolism ; }, abstract = {Motor neuron diseases are untreatable with common pharmacological approaches. Spinal muscular atrophy (SMA) is caused by SMN1 gene mutations leading to lowered SMN expression. Symptoms are alleviated in infants with a higher copy number of the SMN2 gene, which, however, displays a splicing defect resulting in low SMN levels. Amyotrophic lateral sclerosis (ALS) is caused by a number of mutations, with C9orf72 repeat expansions the most common genetic cause and SOD1 gain-of-function mutations the first genetic cause identified for this disease. Genetic therapies based on oligonucleotides that enhance SMN2 splicing and SMN production or lower SOD1 expression have shown promise in initial clinical trials for individuals with SMA and ALS harboring SOD1 mutations, respectively. Gene addition/silencing approaches using adeno-associated viruses (AAVs) are also currently under clinical investigation in trials for SMA and ALS. Here we provide a brief overview of these efforts and their advantages and challenges. We also review genome editing approaches aimed at correcting the disease-causing mutations or modulating the expression of genetic modifiers, e.g., by repairing SOD1 mutations or the SMN2 splicing defect or deleting C9orf72 expanded repeats. These studies have shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders.}, }
@article {pmid33818491, year = {2021}, author = {Bhuiyan, P and Wang, YW and Sha, HH and Dong, HQ and Qian, YN}, title = {Neuroimmune connections between corticotropin-releasing hormone and mast cells: novel strategies for the treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {16}, number = {11}, pages = {2184-2197}, pmid = {33818491}, issn = {1673-5374}, abstract = {Corticotropin-releasing hormone is a critical component of the hypothalamic-pituitary-adrenal axis, which plays a major role in the body's immune response to stress. Mast cells are both sensors and effectors in the interaction between the nervous and immune systems. As first responders to stress, mast cells can initiate, amplify and prolong neuroimmune responses upon activation. Corticotropin-releasing hormone plays a pivotal role in triggering stress responses and related diseases by acting on its receptors in mast cells. Corticotropin-releasing hormone can stimulate mast cell activation, influence the activation of immune cells by peripheral nerves and modulate neuroimmune interactions. The latest evidence shows that the release of corticotropin-releasing hormone induces the degranulation of mast cells under stress conditions, leading to disruption of the blood-brain barrier, which plays an important role in neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder and amyotrophic lateral sclerosis. Recent studies suggest that stress increases intestinal permeability and disrupts the blood-brain barrier through corticotropin-releasing hormone-mediated activation of mast cells, providing new insight into the complex interplay between the brain and gastrointestinal tract. The neuroimmune target of mast cells is the site at which the corticotropin-releasing hormone directly participates in the inflammatory responses of nerve terminals. In this review, we focus on the neuroimmune connections between corticotropin-releasing hormone and mast cells, with the aim of providing novel potential therapeutic targets for inflammatory, autoimmune and nervous system diseases.}, }
@article {pmid33816488, year = {2021}, author = {Asakawa, K and Handa, H and Kawakami, K}, title = {Illuminating ALS Motor Neurons With Optogenetics in Zebrafish.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {640414}, pmid = {33816488}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Spinal motor neurons align along the spinal cord length within the vertebral column, and extend long axons to connect with skeletal muscles covering the body surface. Due to this anatomy, spinal motor neurons are among the most difficult cells to observe in vivo. Larval zebrafish have transparent bodies that allow non-invasive visualization of whole cells of single spinal motor neurons, from somas to the neuromuscular synapses. This unique feature, combined with its amenability to genome editing, pharmacology, and optogenetics, enables functional analyses of ALS-associated proteins in the spinal motor neurons in vivo with subcellular resolution. Here, we review the zebrafish skeletal neuromuscular system and the optical methods used to study it. We then introduce a recently developed optogenetic zebrafish ALS model that uses light illumination to control oligomerization, phase transition and aggregation of the ALS-associated DNA/RNA-binding protein called TDP-43. Finally, we will discuss how this disease-in-a-fish ALS model can help solve key questions about ALS pathogenesis and lead to new ALS therapeutics.}, }
@article {pmid33815964, year = {2021}, author = {Mofatteh, M}, title = {Neurodegeneration and axonal mRNA transportation.}, journal = {American journal of neurodegenerative disease}, volume = {10}, number = {1}, pages = {1-12}, pmid = {33815964}, issn = {2165-591X}, abstract = {The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to tackle the global issue of neurodegeneration in the future. A better understanding of the potential molecular mechanism causing neurodegeneration can shed light on dysfunctional processes in diseased neurons, which can pave the way to design and synthesize novel targets for early diagnosis during the asymptomatic phase of the disease. Abnormal protein aggregation is a hallmark of neurodegenerative diseases which can hamper transportation of cargoes into axons. Recent evidence suggests that disruption of local protein synthesis has been observed in neurodegenerative diseases. Because of their highly asymmetric structure, highly polarized neurons require trafficking of cargoes from the cell body to different subcellular regions to meet the extensive demands of cellular physiology. Localization of mRNAs and subsequent local translation to corresponding proteins in axons is a mechanism which allows neurons to rapidly respond to external stimuli as well as establishing neuronal networks by synthesizing proteins on demand. Axonal protein synthesis is required for axon guidance, synapse formation and plasticity, axon maintenance and regeneration in response to injury. Different types of excitatory and inhibitory neurons in the central and peripheral nervous systems have been shown to localize mRNA. Rising evidence suggests that the repertoire of localizing mRNA in axons can change during aging, indicating a connection between axonal mRNA trafficking and aging diseases such as neurodegeneration. Here, I briefly review the latest findings on the importance of mRNA localization and local translation in neurons and the consequences of their disruption in neurodegenerative diseases. In addition, I discuss recent evidence that dysregulation of mRNA localization and local protein translation can contribute to the formation of neurodegenerative diseases such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. In addition, I discuss recent findings on mRNAs localizing to mitochondria in neurodegeneration.}, }
@article {pmid33815058, year = {2021}, author = {Ng Kee Kwong, KC and Harbham, PK and Selvaraj, BT and Gregory, JM and Pal, S and Hardingham, GE and Chandran, S and Mehta, AR}, title = {40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {647895}, pmid = {33815058}, issn = {1662-5099}, support = {MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.}, }
@article {pmid33814055, year = {2021}, author = {Howard, IM and Burgess, K}, title = {Telehealth for Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {32}, number = {2}, pages = {239-251}, doi = {10.1016/j.pmr.2020.12.003}, pmid = {33814055}, issn = {1558-1381}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; COVID-19/epidemiology ; Health Services Accessibility ; Humans ; Multiple Sclerosis/*physiopathology/*therapy ; Pandemics ; Patient Care Team ; Physical Examination ; SARS-CoV-2 ; Telemedicine/*methods ; }, abstract = {Amyotrophic lateral sclerosis and multiple sclerosis are neurodegenerative diseases requiring interdisciplinary rehabilitation services to maximize function, manage symptoms, prevent complications, and promote higher quality of life. Distance and disability may pose barriers to access of subspecialized care. Telehealth is one solution to facilitate access and was rapidly expanded during the COVID-19 pandemic. This article details the utility of telehealth services across the disease spectrum-including to establish a diagnosis, monitor progression for ongoing management, and identify and manage symptoms and provide therapy interventions. The challenges and promise of telehealth services for clinical care and research will be explored.}, }
@article {pmid33812867, year = {2021}, author = {Yamaguchi, M and Lee, IS and Jantrapirom, S and Suda, K and Yoshida, H}, title = {Drosophila models to study causative genes for human rare intractable neurological diseases.}, journal = {Experimental cell research}, volume = {403}, number = {1}, pages = {112584}, doi = {10.1016/j.yexcr.2021.112584}, pmid = {33812867}, issn = {1090-2422}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Charcot-Marie-Tooth Disease/genetics/*metabolism ; DNA-Binding Proteins/metabolism ; Drosophila/metabolism ; Humans ; Motor Neurons/*metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective therapeutic targets are discussed.}, }
@article {pmid33812000, year = {2021}, author = {Root, J and Merino, P and Nuckols, A and Johnson, M and Kukar, T}, title = {Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {154}, number = {}, pages = {105360}, pmid = {33812000}, issn = {1095-953X}, support = {K99 AG032362/AG/NIA NIH HHS/United States ; R01 NS105971/NS/NINDS NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R01 NS093362/NS/NINDS NIH HHS/United States ; R00 AG032362/AG/NIA NIH HHS/United States ; T32 NS096050/NS/NINDS NIH HHS/United States ; F31 NS117129/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Autophagy/physiology ; Frontotemporal Dementia/genetics/*metabolism/*pathology ; Humans ; Lysosomes/genetics/*metabolism/*pathology ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that are thought to exist on a clinical and pathological spectrum. FTD and ALS are linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) and neuropathology, such as inclusions of ubiquitinated, misfolded proteins (e.g. TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes that cause FTD or ALS when mutated encode proteins that localize to the lysosome or modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, lysosomal acidification, autophagy, or TFEB activity. In this review, we summarize evidence that lysosomal dysfunction, caused by genetic mutations (e.g. C9orf72, GRN, MAPT, TMEM106B) or toxic-gain of function (e.g. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS. Further studies into the normal function of many of these proteins are required and will help uncover the mechanisms that cause lysosomal dysfunction in FTD and ALS. Mutations or polymorphisms in genes that encode proteins important for endosome-lysosome function also occur in other age-dependent neurodegenerative diseases, including Alzheimer's (e.g. APOE, PSEN1, APP) and Parkinson's (e.g. GBA, LRRK2, ATP13A2) disease. A more complete understanding of the common and unique features of lysosome dysfunction across the spectrum of neurodegeneration will help guide the development of therapies for these devastating diseases.}, }
@article {pmid33810837, year = {2021}, author = {Amador, MD and Muratet, F and Teyssou, E and Boillée, S and Millecamps, S}, title = {New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases.}, journal = {Revue neurologique}, volume = {177}, number = {5}, pages = {524-535}, doi = {10.1016/j.neurol.2021.01.008}, pmid = {33810837}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia ; Genetic Testing ; Genetic Therapy ; Humans ; Mutation ; }, abstract = {Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.}, }
@article {pmid33810425, year = {2021}, author = {Traiffort, E and Morisset-Lopez, S and Moussaed, M and Zahaf, A}, title = {Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {7}, pages = {}, pmid = {33810425}, issn = {1422-0067}, support = {RAK19097LLP//Association pour la Recherche sur la Scl&#xe9;rose Lat&#xe9;rale Amyotrophique et autres Maladies du Motoneurone/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Astrocytes/cytology ; Axons/metabolism ; Cell Death ; Cell Lineage ; Cell Proliferation ; DNA-Binding Proteins/chemistry ; Demyelinating Diseases/*physiopathology ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Motor Neurons/metabolism ; Myelin Sheath/metabolism ; Neuroglia/metabolism ; Oligodendroglia/*cytology ; Oxygen/chemistry ; Prosencephalon/metabolism ; Rats ; Spinal Cord/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Motor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.}, }
@article {pmid33809941, year = {2021}, author = {Tobal, IE and Bautista, R and Diez, D and Garrido, NM and García-García, P}, title = {1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {6}, pages = {}, pmid = {33809941}, issn = {1420-3049}, mesh = {*Cycloaddition Reaction ; Molecular Structure ; *Polyenes/chemical synthesis/chemistry/therapeutic use ; Stereoisomerism ; }, abstract = {In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels-Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics-it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.}, }
@article {pmid33809730, year = {2021}, author = {Hemerková, P and Vališ, M}, title = {Role of Oxidative Stress in the Pathogenesis of Amyotrophic Lateral Sclerosis: Antioxidant Metalloenzymes and Therapeutic Strategies.}, journal = {Biomolecules}, volume = {11}, number = {3}, pages = {}, pmid = {33809730}, issn = {2218-273X}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*pathology/*therapy ; Animals ; Antioxidants/*metabolism ; Genetic Predisposition to Disease ; Humans ; Metalloproteins/*metabolism ; *Oxidative Stress ; Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) affects motor neurons in the cerebral cortex, brainstem and spinal cord and leads to death due to respiratory failure within three to five years. Although the clinical symptoms of this disease were first described in 1869 and it is the most common motor neuron disease and the most common neurodegenerative disease in middle-aged individuals, the exact etiopathogenesis of ALS remains unclear and it remains incurable. However, free oxygen radicals (i.e., molecules containing one or more free electrons) are known to contribute to the pathogenesis of this disease as they very readily bind intracellular structures, leading to functional impairment. Antioxidant enzymes, which are often metalloenzymes, inactivate free oxygen radicals by converting them into a less harmful substance. One of the most important antioxidant enzymes is Cu[2+]Zn[2+] superoxide dismutase (SOD1), which is mutated in 20% of cases of the familial form of ALS (fALS) and up to 7% of sporadic ALS (sALS) cases. In addition, the proper functioning of catalase and glutathione peroxidase (GPx) is essential for antioxidant protection. In this review article, we focus on the mechanisms through which these enzymes are involved in the antioxidant response to oxidative stress and thus the pathogenesis of ALS and their potential as therapeutic targets.}, }
@article {pmid33808458, year = {2021}, author = {Rusina, R and Vandenberghe, R and Bruffaerts, R}, title = {Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {4}, pages = {}, pmid = {33808458}, issn = {2075-4418}, support = {NV18-01-00399, NV19-04-00090//Grant Agency of the Ministry of Health, Czech Republic/ ; TN64190//Ministry of Health, Czech Republic/ ; Progress Q35/LF3//Charles University, Prague, Czech Republic/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has long been considered to be a purely motor disorder. However, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is now used in these circumstances. This review is intended to be an overview of the cognitive and behavioral manifestations commonly encountered in ALS patients with the goal of improving case-oriented management in clinical practice. We introduce the principal ALS-FTSD subtypes and comment on their principal clinical manifestations, neuroimaging findings, neuropathological and genetic background, and summarize available therapeutic options. Diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestations, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment. Cognitive impairment is found in up to 65%, while frank dementia affects about 15% of ALS patients. ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved. Dementia can precede or develop after the appearance of motor symptoms. ALS-FTSD patients have a worse prognosis and shorter survival rates than patients with ALS or frontotemporal dementia alone. Important negative prognostic factors are behavioral and personality changes. From the clinician's perspective, there are five major distinguishable ALS-FTSD subtypes: ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, fully developed frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer's disease. Although the most consistent ALS and ALS-FTSD pathology is a disturbance in transactive response DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein metabolism have also been observed in ALS-FTSD. Early detection and careful monitoring of cognitive deficits in ALS are crucial for patient and caregiver support and enable personalized management of individual patient needs.}, }
@article {pmid33807572, year = {2021}, author = {Raffaele, S and Boccazzi, M and Fumagalli, M}, title = {Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives.}, journal = {Cells}, volume = {10}, number = {3}, pages = {}, pmid = {33807572}, issn = {2073-4409}, support = {GPR17ALS-1//Fondazione AriSLA/ ; "Department of excellence" 2018-2022//Italian Ministry of University and Research (MIUR)/ ; 2019_BS_006//Italian Multiple Sclerosis Foundation (FISM)/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Oligodendroglia/*metabolism ; }, abstract = {Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.}, }
@article {pmid33807542, year = {2021}, author = {Kim, W and Kim, DY and Lee, KH}, title = {RNA-Binding Proteins and the Complex Pathophysiology of ALS.}, journal = {International journal of molecular sciences}, volume = {22}, number = {5}, pages = {}, pmid = {33807542}, issn = {1422-0067}, support = {2017R1D1A1B03033241//National Research Foundation of Korea/ ; 2018R1A5A2025272//National Research Foundation of Korea/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; RNA/metabolism ; RNA-Binding Proteins/*metabolism ; }, abstract = {Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.}, }
@article {pmid33805772, year = {2021}, author = {Kim, J}, title = {Pre-Clinical Neuroprotective Evidences and Plausible Mechanisms of Sulforaphane in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {22}, number = {6}, pages = {}, pmid = {33805772}, issn = {1422-0067}, support = {2020R1I1A1A01054684//National Research Foundation of Korea/ ; }, mesh = {Alzheimer Disease/*drug therapy/genetics/metabolism/physiopathology ; Amyloid beta-Peptides/antagonists &amp; inhibitors/*genetics/metabolism ; Animals ; Biomarkers/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Drug Administration Schedule ; Drug Evaluation, Preclinical ; Gene Expression Regulation ; Humans ; Isothiocyanates/*pharmacology ; Memory Disorders/genetics/metabolism/physiopathology/*prevention &amp; control ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Protein Aggregates/drug effects/genetics ; Sulfoxides/*pharmacology ; tau Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-β, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.}, }
@article {pmid33805659, year = {2021}, author = {Parobkova, E and Matej, R}, title = {Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degenerations: Similarities in Genetic Background.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {33805659}, issn = {2075-4418}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal progressive degenerative disorder of motor neurons that overlaps with frontotemporal lobar degeneration (FTLD) clinically, morphologically, and genetically. Although many distinct mutations in various genes are known to cause amyotrophic lateral sclerosis, it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Many of the gene mutations are in proteins that share similar functions. They can be grouped into those associated with cell axon dynamics and those associated with cellular phagocytic machinery, namely protein aggregation and metabolism, apoptosis, and intracellular nucleic acid transport. Analysis of pathways implicated by mutant ALS genes has provided new insights into the pathogenesis of both familial forms of ALS (fALS) and sporadic forms (sALS), although, regrettably, this has not yet yielded definitive treatments. Many genes play an important role, with TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly, C9orf72 being critical genetic players in these neurological disorders. In this mini-review, we will focus on the molecular mechanisms of these two diseases.}, }
@article {pmid33805182, year = {2021}, author = {Hussain, A and Ding, X and Alariqi, M and Manghwar, H and Hui, F and Li, Y and Cheng, J and Wu, C and Cao, J and Jin, S}, title = {Herbicide Resistance: Another Hot Agronomic Trait for Plant Genome Editing.}, journal = {Plants (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {33805182}, issn = {2223-7747}, support = {2019ZX08010-003, 2016YFD0100203-9, 027Y2018-007//National R&amp;D Project of Transgenic Crops of Ministry of Science and Technology (2019ZX08010-003), National Key Research and Development Plan (2016YFD0100203-9) of China and grants from China Na-tional Tobacco Corporation Hubei Branch (027Y2018-007)./ ; }, abstract = {Weeds have continually interrupted crop plants since their domestication, leading to a greater yield loss compared to diseases and pests that necessitated the practice of weed control measures. The control of weeds is crucial to ensuring the availability of sufficient food for a rapidly increasing human population. Chemical weed control (herbicides) along with integrated weed management (IWM) practices can be the most effective and reliable method of weed management programs. The application of herbicides for weed control practices calls for the urgency to develop herbicide-resistant (HR) crops. Recently, genome editing tools, especially CRISPR-Cas9, have brought innovation in genome editing technology that opens up new possibilities to provide sustainable farming in modern agricultural industry. To date, several non-genetically modified (GM) HR crops have been developed through genome editing that can present a leading role to combat weed problems along with increasing crop productivity to meet increasing food demand around the world. Here, we present the chemical method of weed control, approaches for herbicide resistance development, and possible advantages and limitations of genome editing in herbicide resistance. We also discuss how genome editing would be effective in combating intensive weed problems and what would be the impact of genome-edited HR crops in agriculture.}, }
@article {pmid33804658, year = {2021}, author = {Silvestro, S and Sindona, C and Bramanti, P and Mazzon, E}, title = {A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {6}, pages = {}, pmid = {33804658}, issn = {1422-0067}, support = {//Ministero della Salute/ ; }, mesh = {Animals ; Antioxidants/chemistry/*pharmacology/therapeutic use ; Clinical Studies as Topic ; Diarylheptanoids/chemistry/*pharmacology/therapeutic use ; Disease Management ; Disease Models, Animal ; Disease Susceptibility ; Drug Evaluation, Preclinical ; Humans ; Neurodegenerative Diseases/drug therapy/etiology/metabolism ; Structure-Activity Relationship ; Treatment Outcome ; }, abstract = {Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.}, }
@article {pmid33804386, year = {2021}, author = {Guidotti, G and Scarlata, C and Brambilla, L and Rossi, D}, title = {Tumor Necrosis Factor Alpha in Amyotrophic Lateral Sclerosis: Friend or Foe?.}, journal = {Cells}, volume = {10}, number = {3}, pages = {}, pmid = {33804386}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a massive neuroinflammatory reaction, which plays a key role in the progression of the disease. One of the major mediators of the inflammatory response is the pleiotropic cytokine tumor necrosis factor α (TNFα), mainly released within the central nervous system (CNS) by reactive astrocytes and microglia. Increased levels of TNFα and its receptors (TNFR1 and TNFR2) have been described in plasma, serum, cerebrospinal fluid and CNS tissue from both ALS patients and transgenic animal models of disease. However, the precise role exerted by TNFα in the context of ALS is still highly controversial, since both protective and detrimental functions have been reported. These opposing actions depend on multiple factors, among which includes the type of TNFα receptor activated. In fact, TNFR2 seems to mediate a harmful role being involved in motor neuron cell death, whereas TNFR1 signaling mediates neuroprotective effects, promoting the expression and secretion of trophic factors. This suggests that a better understanding of the cytokine impact on ALS progression may enable the development of effective therapies aimed at strengthening the protective roles of TNFα and at suppressing the detrimental ones.}, }
@article {pmid33801336, year = {2021}, author = {Scaricamazza, S and Salvatori, I and Ferri, A and Valle, C}, title = {Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?.}, journal = {Cells}, volume = {10}, number = {3}, pages = {}, pmid = {33801336}, issn = {2073-4409}, support = {HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 2018//AFM-T&#xe9;l&#xe9;thon/ ; 21021//AFM-T&#xe9;l&#xe9;thon/ ; PGR01040//Ministero della Salute/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Muscle, Skeletal/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the "dying back" phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.}, }
@article {pmid33800571, year = {2021}, author = {Lavorgna, L and Brigo, F and Esposito, S and Abbadessa, G and Sparaco, M and Lanzillo, R and Moccia, M and Inglese, M and Bonfanti, L and Trojsi, F and Spina, E and Russo, A and De Micco, P and Clerico, M and Tedeschi, G and Bonavita, S}, title = {Public Engagement and Neurology: An Update.}, journal = {Brain sciences}, volume = {11}, number = {4}, pages = {}, pmid = {33800571}, issn = {2076-3425}, abstract = {BACKGROUND: Public engagement (PE) is defined as the involvement of "specialists who listen, develop their understanding, and interact with non-specialists in non-profit activities of educational, cultural, and social nature to engage the public in science-related matters". The public health relevance of PE consists in building up a scientifically literate society, able to participate in and support scientific and technological developments and their implications for educational settings. Neurological disorders account for 35% of all diseases. PE could have a positive impact on the lives of people affected by neurological diseases.<br><br>METHOD: This review evaluates the role of PE in dementia, stroke, epilepsy, multiple sclerosis, Parkinson's disease, migraine, neurogenetics, and amyotrophic lateral sclerosis.<br><br>RESULTS AND CONCLUSIONS: PE can provide accessible information, support research activities and prevention through appropriate lifestyles, and increase knowledge and awareness of neurological disorders, improving their diagnosis and treatment.}, }
@article {pmid33799628, year = {2021}, author = {Sah, E and Krishnamurthy, S and Ahmidouch, MY and Gillispie, GJ and Milligan, C and Orr, ME}, title = {The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {33799628}, issn = {2075-1729}, support = {P30 AG044271/AG/NIA NIH HHS/United States ; IK2 BX003804/BX/BLRD VA/United States ; R01 AG068293/AG/NIA NIH HHS/United States ; R01AG068293/AG/NIA NIH HHS/United States ; }, abstract = {In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed "senescence". For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as "senescence") now is recognized as a complex stress response that culminates with a change in cell fate. Instead of reacting to cellular/DNA damage by proliferation or apoptosis, senescent cells survive in a stable cell cycle arrest. Senescent cells simultaneously contribute to chronic tissue degeneration by secreting deleterious molecules that negatively impact surrounding cells. These fields have finally collided. Neuroscientists have begun applying concepts of senescence to the brain, including post-mitotic cells. This initially presented conceptual challenges to senescence cell biologists. Nonetheless, efforts to understand senescence in the context of brain aging and neurodegenerative disease and injury emerged and are advancing the field. The present review uses pre-defined criteria to evaluate evidence for post-mitotic brain cell senescence. A closer interaction between neuro and senescent cell biologists has potential to advance both disciplines and explain fundamental questions that have plagued their fields for decades.}, }
@article {pmid33799485, year = {2021}, author = {DePew, AT and Mosca, TJ}, title = {Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development.}, journal = {Journal of developmental biology}, volume = {9}, number = {1}, pages = {}, pmid = {33799485}, issn = {2221-3759}, support = {F31-NS120718/NH/NIH HHS/United States ; R01-NS110907/NH/NIH HHS/United States ; F31 NS120718/NS/NINDS NIH HHS/United States ; R00-DC013059/NH/NIH HHS/United States ; }, abstract = {As the nervous system develops, connections between neurons must form to enable efficient communication. This complex process of synaptic development requires the coordination of a series of intricate mechanisms between partner neurons to ensure pre- and postsynaptic differentiation. Many of these mechanisms employ transsynaptic signaling via essential secreted factors and cell surface receptors to promote each step of synaptic development. One such cell surface receptor, LRP4, has emerged as a synaptic organizer, playing a critical role in conveying extracellular signals to initiate diverse intracellular events during development. To date, LRP4 is largely known for its role in development of the mammalian neuromuscular junction, where it functions as a receptor for the synaptogenic signal Agrin to regulate synapse development. Recently however, LRP4 has emerged as a synapse organizer in the brain, where new functions for the protein continue to arise, adding further complexity to its already versatile roles. Additional findings indicate that LRP4 plays a role in disorders of the nervous system, including myasthenia gravis, amyotrophic lateral sclerosis, and Alzheimer's disease, demonstrating the need for further study to understand disease etiology. This review will highlight our current knowledge of how LRP4 functions in the nervous system, focusing on the diverse developmental roles and different modes this essential cell surface protein uses to ensure the formation of robust synaptic connections.}, }
@article {pmid33799036, year = {2021}, author = {Heidari, ME and Nadali, J and Parouhan, A and Azarafraz, M and Tabatabai, SM and Irvani, SSN and Eskandari, F and Gharebaghi, A}, title = {Prevalence of depression among amyotrophic lateral sclerosis (ALS) patients: A systematic review and meta-analysis.}, journal = {Journal of affective disorders}, volume = {287}, number = {}, pages = {182-190}, doi = {10.1016/j.jad.2021.03.015}, pmid = {33799036}, issn = {1573-2517}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; *Depressive Disorder ; Humans ; Prevalence ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) people have a high risk of severe mental disorders, like depression, which impacts their function, quality of life, and mobility. However, there are no estimates of depression based paper published. This study aimed conduct a systematic review and meta-analysis of the prevalence of depression in ALS patients around the world.<br><br>METHODS: PubMed/Medline, Web of science, Scopus, Embase, and Ovid are searched to identify papers that reporting the prevalence of depression. Studies are included in random-effects meta-analyses of the prevalence of depression. Subgroup analyses are performed on the severity of depression, instruments of depression, type of studies, and study regions.<br><br>RESULTS: 46 eligible studies reported prevalence of depression. The pooled prevalence of depression among ALS people was 34% (27%-41%). According to the severity of depression, mild, moderate, and severe depression were 29%, 16%, and 8%, respectively. For studies using BDI, PHQ, and HADS, the pooled prevalence of depression was 50%, 20%, and 15%, respectively.<br><br>CONCLUSIONS: ALS people have a high prevalence of depression. The high prevalence of depression causes a reduction of quality of life and mobility. The study identifies a population group at high risk needing special attention in clinical practice.}, }
@article {pmid33792056, year = {2021}, author = {Cicardi, ME and Marrone, L and Azzouz, M and Trotti, D}, title = {Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis.}, journal = {The EMBO journal}, volume = {40}, number = {10}, pages = {e106389}, pmid = {33792056}, issn = {1460-2075}, support = {RF1 AG057882/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; DNA-Binding Proteins/metabolism ; Endocytosis/physiology ; Exocytosis/physiology ; Humans ; Motor Neurons/*metabolism ; Protein Folding ; RNA-Binding Protein FUS/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose exact causative mechanisms are still under intense investigation. Several lines of evidence suggest that the anatomical and temporal propagation of pathological protein species along the neural axis could be among the main driving mechanisms for the fast and irreversible progression of ALS pathology. Many ALS-associated proteins form intracellular aggregates as a result of their intrinsic prion-like properties and/or following impairment of the protein quality control systems. During the disease course, these mutated proteins and aberrant peptides are released in the extracellular milieu as soluble or aggregated forms through a variety of mechanisms. Internalization by recipient cells may seed further aggregation and amplify existing proteostatic imbalances, thus triggering a vicious cycle that propagates pathology in vulnerable cells, such as motor neurons and other susceptible neuronal subtypes. Here, we provide an in-depth review of ALS pathology with a particular focus on the disease mechanisms of seeding and transmission of the most common ALS-associated proteins, including SOD1, FUS, TDP-43, and C9orf72-linked dipeptide repeats. For each of these proteins, we report historical, biochemical, and pathological evidence of their behaviors in ALS. We further discuss the possibility to harness pathological proteins as biomarkers and reflect on the implications of these findings for future research.}, }
@article {pmid33787039, year = {2021}, author = {Saka, B and Zirtil, C and Erten, SN and Akpinar, TS and Altinkaynak, M and Akyuz, F and Cavus, B and Ozmen, B and Buyukdemir, S and Tascıoglu, C}, title = {Indications, effectiveness and safety of percutaneous endoscopic gastrostomy: A single center experience and literature review.}, journal = {Asia Pacific journal of clinical nutrition}, volume = {30}, number = {1}, pages = {42-50}, doi = {10.6133/apjcn.202103_30(1).0006}, pmid = {33787039}, issn = {1440-6047}, mesh = {*Enteral Nutrition ; *Gastrostomy ; Humans ; Nutritional Status ; Retrospective Studies ; Serum Albumin ; }, abstract = {BACKGROUND AND OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) has been widely used since 1980 in enteral feeding of patients that are not able to be fed orally for a long time. The aim of this study is to evaluate the PEG indications, effectiveness and PEG related complications from a single center in Istanbul, Turkey.<br><br>METHODS AND STUDY DESIGN: 265 patients with PEG who were followed up by the clinical nutrition team of a university hospital between 2010-2018 were evaluated retrospectively. Nutritional Risk Screening-2002 (NRS-2002) test, anthropometric measurements, bioelectrical impedance analysis and laboratory data were used to evaluate the patients' nutritional status.<br><br>RESULTS: The most common indications for PEG were dementia (35.1%), amyotrophic lateral sclerosis (22.6%), stroke (15.8%), and cancer (14%). The mean body weight of the patients was increased after PEG (63.5&#xb1;12.2 vs 62.0&#xb1;12.7 kg). Mid upper arm circumference and calf circumference of the patients increased after PEG (27.5&#xb1;2.5 vs 25.4&#xb1;3.1 cm and 32.2&#xb1;7.9 vs 29.6&#xb1;5.9 cm, respectively). Serum albumin of the patients was increased significantly after PEG (3.34&#xb1;0.69 g/dL to 3.64&#xb1;0.65 g/dL) without any significant change in serum CRP. Subgroup analyses showed a significant increase in the mean serum albumin of patients with dementia after PEG (3.23&#xb1;0.67 g/dL to 3.54&#xb1;0.58 g/dL). Local insertion site infection occurred in 15 patients (5.6%) and only 3 patients had systemic inflammatory symptoms after local infection (1.1%).<br><br>CONCLUSIONS: The results of our study showed that long-term enteral feeding with PEG is an effective and safe method that provides improvement in nutritional status.}, }
@article {pmid33783642, year = {2022}, author = {Leandro, GS and Dourado Júnior, MET and Santana, GC and Dantas, LSX}, title = {Coping strategies among amyotrophic lateral sclerosis (ALS) patients: an integrative review.}, journal = {Journal of neurology}, volume = {269}, number = {2}, pages = {693-702}, pmid = {33783642}, issn = {1432-1459}, mesh = {Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis ; Emotions ; Humans ; Social Support ; }, abstract = {OBJECTIVE: To identify coping strategies used by amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: Integrative literature review using the Virtual Health Library, MEDLINE, and ScienceDirect databases.<br><br>RESULTS: Eighteen studies were included. "Seeking social support" was the main coping strategy, while "Confrontive coping" and "Distancing" were the least mentioned.<br><br>CONCLUSION: The coping strategies used by ALS patients do not seem to focus on emotions or stress-triggering problems. Age and gender did not modify the chosen strategy.}, }
@article {pmid33783512, year = {2021}, author = {Lee, PJ and Yang, S and Sun, Y and Guo, JU}, title = {Regulation of nonsense-mediated mRNA decay in neural development and disease.}, journal = {Journal of molecular cell biology}, volume = {13}, number = {4}, pages = {269-281}, pmid = {33783512}, issn = {1759-4685}, support = {DP2 GM132930/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/*growth &amp; development ; Codon, Nonsense ; *Gene Expression Regulation, Developmental ; Humans ; Mutation ; Neurodevelopmental Disorders/*genetics ; *Nonsense Mediated mRNA Decay ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics/metabolism ; }, abstract = {Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon but also as a posttranscriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood. In humans, mutations in genes encoding core NMD factors cause specific developmental and neurological syndromes, suggesting a critical role of NMD in the central nervous system. Here, we review the accumulating biochemical and genetic evidence on the developmental regulation and physiological functions of NMD as well as an emerging role of NMD dysregulation in neurodegenerative diseases.}, }
@article {pmid33782648, year = {2021}, author = {Maher, P}, title = {Preventing and Treating Neurological Disorders with the Flavonol Fisetin.}, journal = {Brain plasticity (Amsterdam, Netherlands)}, volume = {6}, number = {2}, pages = {155-166}, pmid = {33782648}, issn = {2213-6312}, support = {RF1 AG054714/AG/NIA NIH HHS/United States ; }, abstract = {Neurological disorders, including neurodegenerative diseases, have a significant negative impact on both patients and society at large. Since the prevalence of most of these disorders increases with age, the consequences for our aging population are only going to grow. It is now acknowledged that neurological disorders are multi-factorial involving disruptions in multiple cellular systems. While each disorder has specific initiating mechanisms and pathologies, certain common pathways appear to be involved in most, if not all, neurological disorders. Thus, it is becoming increasingly important to identify compounds that can modulate the multiple pathways that contribute to disease development or progression. One of these compounds is the flavonol fisetin. Fisetin has now been shown in preclinical models to be effective at preventing the development and/or progression of multiple neurological disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke (both ischemic and hemorrhagic) and traumatic brain injury as well as to reduce age-associated changes in the brain. These beneficial effects stem from its actions on multiple pathways associated with the different neurological disorders. These actions include its well characterized anti-inflammatory and anti-oxidant effects as well as more recently described effects on the regulated cell death oxytosis/ferroptosis pathway, the gut microbiome and its senolytic activity. Therefore, the growing body of pre-clinical data, along with fisetin's ability to modulate a large number of pathways associated with brain dysfunction, strongly suggest that it would be worthwhile to pursue its therapeutic effects in humans.}, }
@article {pmid33781562, year = {2021}, author = {Corcia, P and Beltran, S and Bakkouche, SE and Couratier, P}, title = {Therapeutic news in ALS.}, journal = {Revue neurologique}, volume = {177}, number = {5}, pages = {544-549}, doi = {10.1016/j.neurol.2020.12.003}, pmid = {33781562}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Genetic Therapy ; Humans ; Motor Neurons ; Riluzole ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.}, }
@article {pmid33781464, year = {2021}, author = {Olivieri, AC}, title = {A down-to-earth analyst view of rotational ambiguity in second-order calibration with multivariate curve resolution - a tutorial.}, journal = {Analytica chimica acta}, volume = {1156}, number = {}, pages = {338206}, doi = {10.1016/j.aca.2021.338206}, pmid = {33781464}, issn = {1873-4324}, abstract = {Rotational ambiguity is a phenomenon with the potential of generating an uncertainty in the estimation of analyte concentrations in protocols based on matrix instrumental data processed by multivariate curve resolution - alternating least-squares (MCR-ALS). This is particularly relevant when the second-order advantage is to be achieved, i.e., when selected analytes are determined in unknown samples having unexpected constituents, not considered in the calibration set of samples. It is therefore imperative that analytical chemists developing second-order multivariate calibration methods using MCR-ALS acknowledge the relevance of this issue, and more importantly, have access to the required tools to size the relative impact of this potential source of uncertainty on the estimated analyte concentrations. The purpose of this tutorial is to provide a down-to-earth view of rotational ambiguity, by studying in detail a synthetic example mimicking a typical chromatographic-spectral experiment, where a set of calibration samples is joined with an unknown sample having an uncalibrated interference. After explaining the background information needed to understand the origin of the phenomenon, the available tools for the estimation of the feasible MCR-ALS solutions and the derived uncertainty on analyte predictions will be discussed. A multi-component experimental system will also be discussed, stressing the fact that rotational ambiguity uncertainties, however small, should always be estimated and reported.}, }
@article {pmid33779439, year = {2021}, author = {Francis, R and Attrill, S and Doeltgen, S}, title = {The impact of cognitive decline in amyotrophic lateral sclerosis on swallowing. A scoping review.}, journal = {International journal of speech-language pathology}, volume = {23}, number = {6}, pages = {604-613}, doi = {10.1080/17549507.2021.1894235}, pmid = {33779439}, issn = {1754-9515}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *Cognitive Dysfunction/etiology ; Deglutition ; *Deglutition Disorders/etiology ; Humans ; }, abstract = {Purpose: Impaired swallowing is a serious symptom of amyotrophic lateral sclerosis (ALS) impacting on health and wellbeing. Little is known about how cognitive impairment in amyotrophic lateral sclerosis impacts on oropharyngeal swallowing. A scoping review was undertaken to explore how cognitive impairment impacts on a person living with ALS's (plwALS) ability to understand and manage oropharyngeal swallowing function.Method: Subject headings and keywords were searched across MEDLINE, SCOPUS, CINAHL, PsychINFO, Emcare and Google Scholar in May 2019. Articles containing information on amyotrophic lateral sclerosis and cognition and swallowing were reviewed. A secondary search was conducted in July 2020 with broadened search terms.Result: The primary search identified 1055 articles, and 47 were included for full-text review. Of these, no articles directly met the inclusion criteria of both cognitive impairment and swallowing. The secondary search with broadened terms identified an additional 762 studies, and 9 were included for full-text review, but none met the inclusion criteria. Consequently, thematic analysis was completed on articles from the full-text review to identify themes that related to both cognition and swallowing. The themes identified were: (i) early specialised multidisciplinary management of ALS achieves better outcomes; (ii) cognitive impairment impacts on management; and (iii) impaired swallowing occurs in nearly all people living with ALS and is a serious symptom of the disease.Conclusion: The interaction between cognitive impairment and oropharyngeal swallowing function in ALS has not been investigated. This is important, as cognitive impairment impacts insight and decision-making and may have implications for oropharyngeal swallowing management.}, }
@article {pmid33777106, year = {2021}, author = {Molitor, L and Bacher, S and Burczyk, S and Niessing, D}, title = {The Molecular Function of PURA and Its Implications in Neurological Diseases.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {638217}, pmid = {33777106}, issn = {1664-8021}, abstract = {In recent years, genome-wide analyses of patients have resulted in the identification of a number of neurodevelopmental disorders. Several of them are caused by mutations in genes that encode for RNA-binding proteins. One of these genes is PURA, for which in 2014 mutations have been shown to cause the neurodevelopmental disorder PURA syndrome. Besides intellectual disability (ID), patients develop a variety of symptoms, including hypotonia, metabolic abnormalities as well as epileptic seizures. This review aims to provide a comprehensive assessment of research of the last 30 years on PURA and its recently discovered involvement in neuropathological abnormalities. Being a DNA- and RNA-binding protein, PURA has been implicated in transcriptional control as well as in cytoplasmic RNA localization. Molecular interactions are described and rated according to their validation state as physiological targets. This information will be put into perspective with available structural and biophysical insights on PURA's molecular functions. Two different knock-out mouse models have been reported with partially contradicting observations. They are compared and put into context with cell biological observations and patient-derived information. In addition to PURA syndrome, the PURA protein has been found in pathological, RNA-containing foci of patients with the RNA-repeat expansion diseases such as fragile X-associated tremor ataxia syndrome (FXTAS) and amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) spectrum disorder. We discuss the potential role of PURA in these neurodegenerative disorders and existing evidence that PURA might act as a neuroprotective factor. In summary, this review aims at informing researchers as well as clinicians on our current knowledge of PURA's molecular and cellular functions as well as its implications in very different neuronal disorders.}, }
@article {pmid33776778, year = {2021}, author = {Holbrook, JA and Jarosz-Griffiths, HH and Caseley, E and Lara-Reyna, S and Poulter, JA and Williams-Gray, CH and Peckham, D and McDermott, MF}, title = {Neurodegenerative Disease and the NLRP3 Inflammasome.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {643254}, pmid = {33776778}, issn = {1663-9812}, support = {MC_PC_17230/MRC_/Medical Research Council/United Kingdom ; MR/R007446/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.}, }
@article {pmid33772353, year = {2021}, author = {De Marchi, F and Carrarini, C and De Martino, A and Diamanti, L and Fasano, A and Lupica, A and Russo, M and Salemme, S and Spinelli, EG and Bombaci, A and , }, title = {Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {6}, pages = {2211-2222}, pmid = {33772353}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Cognitive Dysfunction ; Humans ; Longitudinal Studies ; Neuropsychological Tests ; }, abstract = {BACKGROUND AND AIM: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline.<br><br>CONCLUSIONS: To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.}, }
@article {pmid33766600, year = {2021}, author = {Wells, C and Brennan, S and Keon, M and Ooi, L}, title = {The role of amyloid oligomers in neurodegenerative pathologies.}, journal = {International journal of biological macromolecules}, volume = {181}, number = {}, pages = {582-604}, doi = {10.1016/j.ijbiomac.2021.03.113}, pmid = {33766600}, issn = {1879-0003}, mesh = {Amyloid/*metabolism ; Animals ; Drug Delivery Systems ; Humans ; Nerve Degeneration/*metabolism/*pathology/therapy ; Protein Aggregates ; *Protein Multimerization ; }, abstract = {Many neurodegenerative diseases are rooted in the activities of amyloid-like proteins which possess conformations that spread to healthy proteins. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). While their clinical manifestations vary, their protein-level mechanisms are remarkably similar. Aberrant monomeric proteins undergo conformational shifts, facilitating aggregation and formation of solid fibrils. However, there is growing evidence that intermediate oligomeric stages are key drivers of neuronal toxicity. Analysis of protein dynamics is complicated by the fact that nucleation and growth of amyloid-like proteins is not a linear pathway. Feedback within this pathway results in exponential acceleration of aggregation, but activities exerted by oligomers and fibrils can alter cellular interactions and the cellular environment as a whole. The resulting cascade of effects likely contributes to the late onset and accelerating progression of amyloid-like protein disorders and the widespread effects they have on the body. In this review we explore the amyloid-like proteins associated with AD, PD, HD and ALS, as well as the common mechanisms of amyloid-like protein nucleation and aggregation. From this, we identify core elements of pathological progression which have been targeted for therapies, and which may become future therapeutic targets.}, }
@article {pmid33763767, year = {2021}, author = {Banerjee, A and Pradhan, LK and Sahoo, PK and Jena, KK and Chauhan, NR and Chauhan, S and Das, SK}, title = {Unravelling the potential of gut microbiota in sustaining brain health and their current prospective towards development of neurotherapeutics.}, journal = {Archives of microbiology}, volume = {203}, number = {6}, pages = {2895-2910}, pmid = {33763767}, issn = {1432-072X}, support = {2020-9620//Indian Council of Medical Research/ ; }, mesh = {Animals ; Brain/*physiology ; Gastrointestinal Microbiome/*physiology ; Humans ; Neurodegenerative Diseases/*etiology ; }, abstract = {Increasing incidences of neurological disorders, such as Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are being reported, but an insight into their pathology remains elusive. Findings have suggested that gut microbiota play a major role in regulating brain functions through the gut-brain axis. A unique bidirectional communication between gut microbiota and maintenance of brain health could play a pivotal role in regulating incidences of neurodegenerative diseases. Contrarily, the present life style with changing food habits and disturbed circadian rhythm may contribute to gut homeostatic imbalance and dysbiosis leading to progression of several neurological disorders. Therefore, dysbiosis, as a primary factor behind intestinal disorders, may also augment inflammation, intestinal and blood-brain barrier permeability through microbiota-gut-brain axis. This review primarily focuses on the gut-brain axis functions, specific gut microbial population, metabolites produced by gut microbiota, their role in regulating various metabolic processes and role of gut microbiota towards development of neurodegenerative diseases. However, several studies have reported a decrease in abundance of a specific gut microbial population and a corresponding increase in other microbial family, with few findings revealing some contradictions. Reports also showed that colonization of gut microbiota isolated from patients suffering from neurodegenerative disease leads to the development of enhance pathological outcomes in animal models. Hence, a systematic understanding of the dominant role of specific gut microbiome towards development of different neurodegenerative diseases could possibly provide novel insight into the use of probiotics and microbial transplantation as a substitute approach for treating/preventing such health maladies.}, }
@article {pmid33762926, year = {2021}, author = {Wang, B and Huang, M and Shang, D and Yan, X and Zhao, B and Zhang, X}, title = {Mitochondrial Behavior in Axon Degeneration and Regeneration.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {650038}, pmid = {33762926}, issn = {1663-4365}, abstract = {Mitochondria are organelles responsible for bioenergetic metabolism, calcium homeostasis, and signal transmission essential for neurons due to their high energy consumption. Accumulating evidence has demonstrated that mitochondria play a key role in axon degeneration and regeneration under physiological and pathological conditions. Mitochondrial dysfunction occurs at an early stage of axon degeneration and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, defects in mitochondrial transport, and mitophagy dysregulation. The restoration of these defective mitochondria by enhancing mitochondrial transport, clearance of reactive oxidative species (ROS), and improving bioenergetic can greatly contribute to axon regeneration. In this paper, we focus on the biological behavior of axonal mitochondria in aging, injury (e.g., traumatic brain and spinal cord injury), and neurodegenerative diseases (Alzheimer's disease, AD; Parkinson's disease, PD; Amyotrophic lateral sclerosis, ALS) and consider the role of mitochondria in axon regeneration. We also compare the behavior of mitochondria in different diseases and outline novel therapeutic strategies for addressing abnormal mitochondrial biological behavior to promote axonal regeneration in neurological diseases and injuries.}, }
@article {pmid33760195, year = {2021}, author = {Xing, J and Xu, C}, title = {Role of connexins in neurodegenerative diseases (Review).}, journal = {Molecular medicine reports}, volume = {23}, number = {5}, pages = {}, doi = {10.3892/mmr.2021.12034}, pmid = {33760195}, issn = {1791-3004}, mesh = {Adenosine Triphosphate/genetics ; Aging/genetics ; Alzheimer Disease/*genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Calcium/metabolism ; Connexins/*genetics/metabolism ; Humans ; Huntington Disease/*genetics/metabolism/pathology ; Nerve Degeneration/genetics/pathology ; Neurodegenerative Diseases/genetics/pathology ; Neuroglia/metabolism/pathology ; Neurons/metabolism/pathology ; Parkinson Disease/*genetics/metabolism/pathology ; }, abstract = {Neurodegenerative diseases are neurological disorders characterized by progressive neuronal degeneration, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. The neuronal damage caused by these diseases may be associated with abnormal alterations of connexins in glia. These changes may cause glia to lose their ability to support and protect neurons and induce abnormal increases in levels of ions and metabolites, such as calcium ions, glutamate and ATP, around neurons. These processes eventuallys lead to neuronal death. In the present review, the abnormal expression of connexin and its primary role in neurodegenerative diseases was investigated.}, }
@article {pmid33757892, year = {2021}, author = {Gillespie, J and Przybylak-Brouillard, A and Watt, CL}, title = {The Palliative Care Information Needs of Patients with Amyotrophic Lateral Sclerosis and their Informal Caregivers: A Scoping Review.}, journal = {Journal of pain and symptom management}, volume = {62}, number = {4}, pages = {848-862}, doi = {10.1016/j.jpainsymman.2021.03.008}, pmid = {33757892}, issn = {1873-6513}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Caregivers ; Humans ; *Neurodegenerative Diseases ; Palliative Care ; Quality of Life ; }, abstract = {CONTEXT: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, associated with impaired quality of life for patients and caregivers. As treatment is largely supportive, early involvement of palliative care (PC) is recommended as standard of care. Despite this, literature surrounding PC information needs is limited.<br><br>OBJECTIVES: To explore the PC information needs of patients with ALS and their caregivers and identify gaps in the literature.<br><br>METHODS: A scoping review using MEDLINE, EMBASE, CINAHL and PsycINFO databases (2000-2019) was conducted. Articles examining PC information needs as stated by ALS patients and/or current/bereaved caregivers were included. Studies examining other diagnoses and those focused on healthcare workers were excluded. Thematic synthesis was used to summarize and identify prevalent domains and themes in the literature.<br><br>RESULTS: 581 articles underwent primary screening, with thirty-two ultimately included (26 original articles, six reviews). Fourteen examined information needs of both patients and caregivers, 13 caregivers only, 5 patients only. The most common PC information needs were as follows: for patients, disease course/prognosis (n&#x202f;=&#x202f;10), general disease information (n&#x202f;=&#x202f;9), decision-making (n&#x202f;=&#x202f;7) and symptoms (n&#x202f;=&#x202f;6); for caregivers, services and resources (n&#x202f;=&#x202f;15), disease course/prognosis (n&#x202f;=&#x202f;14), general disease information (n&#x202f;=&#x202f;13) and skills (n&#x202f;=&#x202f;10). There was substantial variability in information needs, both between patients and caregivers and among members of the same group.<br><br>CONCLUSION: ALS patients and caregivers have unique and varying PC information needs. Future research should better characterize these needs to improve patient and caregiver quality of life. The delivery of information must be tailored to individual patient or caregiver preferences.}, }
@article {pmid33748103, year = {2021}, author = {Lee, K and Jo, YY and Chung, G and Jung, JH and Kim, YH and Park, CK}, title = {Functional Importance of Transient Receptor Potential (TRP) Channels in Neurological Disorders.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {611773}, pmid = {33748103}, issn = {2296-634X}, abstract = {Transient receptor potential (TRP) channels are transmembrane protein complexes that play important roles in the physiology and pathophysiology of both the central nervous system (CNS) and the peripheral nerve system (PNS). TRP channels function as non-selective cation channels that are activated by several chemical, mechanical, and thermal stimuli as well as by pH, osmolarity, and several endogenous or exogenous ligands, second messengers, and signaling molecules. On the pathophysiological side, these channels have been shown to play essential roles in the reproductive system, kidney, pancreas, lung, bone, intestine, as well as in neuropathic pain in both the CNS and PNS. In this context, TRP channels have been implicated in several neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and epilepsy. Herein, we focus on the latest involvement of TRP channels, with a special emphasis on the recently identified functional roles of TRP channels in neurological disorders related to the disruption in calcium ion homeostasis.}, }
@article {pmid33732107, year = {2021}, author = {Broce, IJ and Castruita, PA and Yokoyama, JS}, title = {Moving Toward Patient-Tailored Treatment in ALS and FTD: The Potential of Genomic Assessment as a Tool for Biological Discovery and Trial Recruitment.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {639078}, pmid = {33732107}, issn = {1662-4548}, support = {K01 AG070376/AG/NIA NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; R03 AG063260/AG/NIA NIH HHS/United States ; T32 AG058529/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and intertwined neurodegenerative diseases. Historically, ALS and FTD were considered distinct disorders given differences in presenting clinical symptoms, disease duration, and predicted risk of developing each disease. However, research over recent years has highlighted the considerable clinical, pathological, and genetic overlap of ALS and FTD, and these two syndromes are now thought to represent different manifestations of the same neuropathological disease spectrum. In this review, we discuss the need to shift our focus from studying ALS and FTD in isolation to identifying the biological mechanisms that drive these diseases-both common and distinct-to improve treatment discovery and therapeutic development success. We also emphasize the importance of genomic data to facilitate a "precision medicine" approach for treating ALS and FTD.}, }
@article {pmid33729613, year = {2021}, author = {Krishnamurthy, K and Pasinelli, P}, title = {Synaptic dysfunction in amyotrophic lateral sclerosis/frontotemporal dementia: Therapeutic strategies and novel biomarkers.}, journal = {Journal of neuroscience research}, volume = {99}, number = {6}, pages = {1499-1503}, pmid = {33729613}, issn = {1097-4547}, support = {R01 NS109150/NS/NINDS NIH HHS/United States ; R56 NS092572/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology/*therapy ; Animals ; Biomarkers ; Frontotemporal Dementia/diagnosis/*physiopathology/*therapy ; Humans ; }, }
@article {pmid33722167, year = {2021}, author = {Tsai, YL and Manley, JL}, title = {Multiple ways to a dead end: diverse mechanisms by which ALS mutant genes induce cell death.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {20}, number = {7}, pages = {631-646}, pmid = {33722167}, issn = {1551-4005}, support = {R35 GM118136/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Autophagy/physiology ; C9orf72 Protein/*genetics/metabolism ; Cell Death/*physiology ; DNA Damage/physiology ; DNA-Binding Proteins/*genetics/metabolism ; Humans ; Mutation/*physiology ; RNA-Binding Protein FUS/*genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a deadly neuromuscular disorder caused by progressive motor neuron loss in the brain and spinal cord. Over the past decades, a number of genetic mutations have been identified that cause or are associated with ALS disease progression. Numerous genes harbor ALS mutations, and they encode proteins displaying a wide range of physiological functions, with limited overlap. Despite the divergent functions, mutations in these genes typically trigger protein aggregation, which can confer gain- and/or loss-of-function to a number of essential cellular processes. Nuclear processes such as mRNA splicing and the response to DNA damage are significantly affected in ALS patients. Cytoplasmic organelles such as mitochondria are damaged by ALS mutant proteins. Processes that maintain cellular homeostasis such as autophagy, nonsense-mediated mRNA decay and nucleocytoplasmic transport, are also impaired by ALS mutations. Here, we review the multiple mechanisms by which mutations in major ALS-associated genes, such as TARDBP, C9ORF72 and FUS, lead to impairment of essential cellular processes.}, }
@article {pmid33719693, year = {2021}, author = {Ward, MJ and Blong, AE and Walton, RA}, title = {Feline cardiopulmonary resuscitation: Getting the most out of all nine lives.}, journal = {Journal of feline medicine and surgery}, volume = {23}, number = {5}, pages = {447-461}, doi = {10.1177/1098612X211004811}, pmid = {33719693}, issn = {1532-2750}, mesh = {Animal Husbandry ; Animals ; *Cardiopulmonary Resuscitation/veterinary ; *Cat Diseases/therapy ; Cats ; *Dog Diseases ; Dogs ; *Heart Arrest/therapy/veterinary ; Humans ; *Veterinarians ; }, abstract = {PRACTICAL RELEVANCE: Cardiopulmonary arrest (CPA) can occur in any veterinary or animal care setting and is a particular risk in scenarios involving ill, injured or anesthetized patients. Education of all staff on the prevention and recognition of CPA, as well as the performance of cardiopulmonary resuscitation (CPR), is vital to influencing outcome.<br><br>EVIDENCE BASE: While there is a plethora of information regarding CPA and CPR in human medicine, there are comparably few studies in the veterinary literature. Many of the current veterinary guidelines are extrapolated from human medicine or studies based on animal models. Ongoing work is needed to tailor guidelines and recommendations to our domestic feline (and canine) patients in a clinical setting.<br><br>AIM: The aim of this article, which is intended for veterinarians in all areas of small animal practice, is to provide an evidence-based review of CPA and CPR in feline patients. The authors have drawn heavily on detailed recommendations published by the Reassessment Campaign on Veterinary Resuscitation (RECOVER) initiative - one of the few resources specific to the veterinary clinical setting - as well as reviewing the available peer-reviewed literature studies, in constructing this article. Among the topics discussed are recognizing and preventing CPA, staff training and clinic preparedness, basic life support and advanced life support interventions, and appropriate post-cardiac arrest care.}, }
@article {pmid33718353, year = {2021}, author = {Jeon, P and Lee, JA}, title = {Dr. Jekyll and Mr. Hyde? Physiology and Pathology of Neuronal Stress Granules.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {609698}, pmid = {33718353}, issn = {2296-634X}, abstract = {Stress granules (SGs) are membraneless cytosolic granules containing dense aggregations of RNA-binding proteins and RNAs. They appear in the cytosol under stress conditions and inhibit the initiation of mRNA translation. SGs are dynamically assembled under stressful conditions and rapidly disassembled after stress removal. They are heterogeneous in their RNA and protein content and are cell type- and stress-specific. In post-mitotic neurons, which do not divide, the dynamics of neuronal SGs are tightly regulated, implying that their dysregulation leads to neurodegeneration. Mutations in RNA-binding proteins are associated with SGs. SG components accumulate in cytosolic inclusions in many neurodegenerative diseases, such as frontotemporal dementia and amyotrophic lateral sclerosis. Although SGs primarily mediate a pro-survival adaptive response to cellular stress, abnormal persistent SGs might develop into aggregates and link to the pathogenesis of diseases. In this review, we present recent advances in the study of neuronal SGs in physiology and pathology, and discuss potential therapeutic approaches to remove abnormal, persistent SGs associated with neurodegeneration.}, }
@article {pmid33715827, year = {2022}, author = {Lopez-Lee, C and Kodama, L and Gan, L}, title = {Sex Differences in Neurodegeneration: The Role of the Immune System in Humans.}, journal = {Biological psychiatry}, volume = {91}, number = {1}, pages = {72-80}, pmid = {33715827}, issn = {1873-2402}, support = {U54 NS100717/NS/NINDS NIH HHS/United States ; T32 GM007618/GM/NIGMS NIH HHS/United States ; R01 AG051390/AG/NIA NIH HHS/United States ; R01 AG054214/AG/NIA NIH HHS/United States ; F30 AG062043/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/genetics ; Female ; Humans ; Immune System ; Male ; *Neurodegenerative Diseases/genetics ; *Parkinson Disease ; Sex Characteristics ; }, abstract = {Growing evidence supports significant involvement of immune dysfunction in the etiology of neurodegenerative diseases, several of which also display prominent sex differences across prevalence, pathology, and symptomology. In this review, we summarize evidence from human studies of established and recent findings of sex differences in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discuss how sex-specific central nervous system innate immune activity could contribute to downstream sex differences in these diseases. We examine human genomic and transcriptomics studies in each neurodegenerative disease through the lens of sex differences in the neuroimmune system and highlight the importance of stratifying sex in clinical and translational research studies. Finally, we discuss the limitations of the existing studies and outline recommendations for further advancing sex-based analyses to uncover novel disease mechanisms that could ultimately help treat both sexes.}, }
@article {pmid33709256, year = {2021}, author = {Asakawa, K and Handa, H and Kawakami, K}, title = {Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {78}, number = {10}, pages = {4453-4465}, pmid = {33709256}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/*complications/metabolism/pathology ; Animals ; DNA-Binding Proteins/chemistry/*metabolism ; Humans ; Motor Neuron Disease/etiology/metabolism/*pathology ; }, abstract = {Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS.}, }
@article {pmid33706937, year = {2021}, author = {Wang, JKT}, title = {Uniting homeostatic plasticity and exosome biology: A revision of the conceptual framework for drug discovery in neurodegenerative diseases?.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {90}, number = {}, pages = {277-306}, doi = {10.1016/bs.apha.2020.10.002}, pmid = {33706937}, issn = {1557-8925}, mesh = {Animals ; Disease Models, Animal ; *Drug Discovery ; Exosomes/*metabolism ; *Homeostasis ; Humans ; MicroRNAs/genetics/metabolism ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) are in need of new drug discovery approaches. Our previous systematic analyses of Huntington's Disease (HD) literature for protein-protein interactors (PPIs) and modifiers of mutant Huntingtin-driven phenotypes revealed enrichment for PPIs of genes required for homeostatic synaptic plasticity (HSP) and exosome (EV) function and exosomal proteins, which in turn highly overlapped each other and with PPIs of genes associated with other NDDs. We proposed that HSP and EVs are linked to each other and are also involved in NDD pathophysiology. Recent studies showed that HSP is indeed altered in HD and AD, and that presynaptic homeostatic plasticity in motoneurons compensates for ALS pathology. Eliminating it causes earlier degeneration and death. If this holds true in other NDDs, drug discovery in animal models should then include elucidation of homeostatic compensation that either masks phenotypes of physiologically expressed mutant genes or are overridden by their overexpression. In this new conceptual framework, enhancing such underlying homeostatic compensation forms the basis for novel therapeutic strategies to slow progression of NDDs. Moreover, if EVs are linked to HSP, then their ability to penetrate the brain, target cell types, deliver miRNA and other molecules can be leveraged to develop attractive drug modalities. Testing this new framework is posed as four questions on model development and mechanistic studies progressing from higher throughput platforms to mouse models. Similar approaches may apply to other CNS disorders including schizophrenia, autism, Rett and Fragile X syndromes due to potential links of their susceptibility genes to HSP and EVs.}, }
@article {pmid33705931, year = {2021}, author = {Robichaud, PP and Arseneault, M and O'Connell, C and Ouellette, RJ and Morin, PJ}, title = {Circulating cell-free DNA as potential diagnostic tools for amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {750}, number = {}, pages = {135813}, doi = {10.1016/j.neulet.2021.135813}, pmid = {33705931}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*blood/diagnosis/genetics ; Animals ; Biomarkers/blood ; Cell-Free Nucleic Acids/*blood/genetics ; DNA Methylation ; Humans ; }, abstract = {DNA methylation has garnered much attention in recent years for its diagnostic potential in multiple conditions including cancer and neurodegenerative diseases. Conversely, advances regarding the potential diagnostic relevance of DNA methylation status have been sparse in the field of amyotrophic lateral sclerosis (ALS) even though patients diagnosed with this condition would significantly benefit from improved molecular assays aimed at furthering the current diagnostic and therapeutic options available. This review will provide an overview of the current diagnostic approaches available for ALS diagnosis and discuss the potential clinical usefulness of DNA methylation. We will also present examples of DNA methylation as a diagnostic tool in various types of cancer and neurodegenerative conditions and expand on how circulating cfDNA methylation may be leveraged for the early detection of ALS. In general, this article will reinforce the importance of cfDNA methylation as diagnostic tools and will further highlight its clinical relevance for persons diagnosed with ALS.}, }
@article {pmid33683159, year = {2022}, author = {Bedlack, R and Barkhaus, P and Barnes, B and Bereman, M and Bertorini, T and Carter, G and Crayle, J and Kihuwa-Mani, S and Bowser, R and Kittrell, P and McDermott, C and Pattee, G and Salmon, K and Wicks, P}, title = {ALSUntangled #60: light therapy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {315-319}, doi = {10.1080/21678421.2021.1883668}, pmid = {33683159}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Phototherapy ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.}, }
@article {pmid33679328, year = {2021}, author = {Schmitz, A and Pinheiro Marques, J and Oertig, I and Maharjan, N and Saxena, S}, title = {Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {637548}, pmid = {33679328}, issn = {1662-5102}, abstract = {The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine-alanine (GA) and glycine-arginine (GR) from the sense strand, proline-alanine (PA), and proline-arginine (PR) from the antisense strand, and glycine-proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.}, }
@article {pmid33677159, year = {2021}, author = {Nedelec, S and Martinez-Arias, A}, title = {In vitro models of spinal motor circuit's development in mammals: achievements and challenges.}, journal = {Current opinion in neurobiology}, volume = {66}, number = {}, pages = {240-249}, doi = {10.1016/j.conb.2020.12.002}, pmid = {33677159}, issn = {1873-6882}, support = {MR/R017190/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Interneurons ; Mammals ; Mice ; Motor Neurons ; *Spinal Cord ; }, abstract = {The connectivity patterns of neurons sustaining the functionality of spinal locomotor circuits rely on the specification of hundreds of motor neuron and interneuron subtypes precisely arrayed within the embryonic spinal cord. Knowledge acquired by developmental biologists on the molecular mechanisms underpinning this process in vivo has supported the development of 2D and 3D differentiation strategies to generate spinal neuronal diversity from mouse and human pluripotent stem cells (PSCs). Here, we review recent breakthroughs in this field and the perspectives opened up by models of in vitro embryogenesis to approach the mechanisms underlying neuronal diversification and the formation of functional mouse and human locomotor circuits. Beyond serving fundamental investigations, these new approaches should help engineering neuronal circuits differentially impacted in neuromuscular disorders, such as amyotrophic lateral sclerosis or spinal muscular atrophies, and thus open new avenues for disease modeling and drug screenings.}, }
@article {pmid33673524, year = {2021}, author = {Eisen, A}, title = {The Dying Forward Hypothesis of ALS: Tracing Its History.}, journal = {Brain sciences}, volume = {11}, number = {3}, pages = {}, pmid = {33673524}, issn = {2076-3425}, abstract = {The site of origin of amyotrophic lateral sclerosis (ALS), although unsettled, is increasingly recognized as being cortico-fugal, which is a dying-forward process primarily starting in the corticomotoneuronal system. A variety of iterations of this concept date back to over 150 years. Recently, the hallmark TAR DNA-binding protein 43 (TDP-43) pathology, seen in >95% of patients with ALS, has been shown to be largely restricted to corticofugal projecting neurons ("dying forward"). Possibly, soluble but toxic cytoplasmic TDP-43 could enter the axoplasm of Betz cells, subsequently causing dysregulation of nuclear protein in the lower brainstem and spinal cord anterior horn cells. As the disease progresses, cortical involvement in ALS becomes widespread, including or starting with frontotemporal dementia, implying a broader view of ALS as a brain disease. The onset at the motor and premotor cortices should be considered a nidus at the edge of multiple cortical networks which eventually become disrupted, causing failure of a widespread cortical connectome.}, }
@article {pmid33672485, year = {2021}, author = {Casani-Cubel, J and Benlloch, M and Sanchis-Sanchis, CE and Marin, R and Lajara-Romance, JM and de la Rubia Orti, JE}, title = {The Impact of Microbiota on the Pathogenesis of Amyotrophic Lateral Sclerosis and the Possible Benefits of Polyphenols. An Overview.}, journal = {Metabolites}, volume = {11}, number = {2}, pages = {}, pmid = {33672485}, issn = {2218-1989}, support = {2017-216-001//Universidad Cat&#xf3;lica de Valencia San Vicente M&#xe0;rtir/ ; }, abstract = {The relationship between gut microbiota and neurodegenerative diseases is becoming clearer. Among said diseases amyotrophic lateral sclerosis (ALS) stands out due to its severity and, as with other chronic pathologies that cause neurodegeneration, gut microbiota could play a fundamental role in its pathogenesis. Therefore, polyphenols could be a therapeutic alternative due to their anti-inflammatory action and probiotic effect. Thus, the objective of our narrative review was to identify those bacteria that could have connection with the mentioned disease (ALS) and to analyze the benefits produced by administering polyphenols. Therefore, an extensive search was carried out selecting the most relevant articles published between 2005 and 2020 on the PubMed and EBSCO database on research carried out on cell, animal and human models of the disease. Thereby, after selecting, analyzing and debating the main articles on this topic, the bacteria related to the pathogenesis of ALS have been identified, among which we can positively highlight the presence mainly of Akkermansia muciniphila, but also Lactobacillus spp., Bifidobacterium spp. or Butyrivibrio fibrisolvens. Nevertheless, the presence of Escherichia coli or Ruminococcus torques stand out negatively for the disease. In addition, most of these bacteria are associated with molecular changes also linked to the pathogenesis of ALS. However, once the main polyphenols related to improvements in any of these three ALS models were assessed, many of them show positive results that could improve the prognosis of the disease. Nonetheless, epigallocatechin gallate (EGCG), curcumin and resveratrol are the polyphenols considered to show the most promising results as a therapeutic alternative for ALS through changes in microbiota.}, }
@article {pmid33672391, year = {2021}, author = {Leal, NS and Martins, LM}, title = {Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {9}, number = {2}, pages = {}, pmid = {33672391}, issn = {2227-9059}, support = {MC_U132674518/MRC_/Medical Research Council/United Kingdom ; MC_UU_00025/3/MRC_/Medical Research Council/United Kingdom ; MC_UU_00025/3(RG94521)/MRC_/Medical Research Council/United Kingdom ; }, abstract = {The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria-ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer's disease as well as Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer's disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.}, }
@article {pmid33672031, year = {2021}, author = {Harcha, PA and Garcés, P and Arredondo, C and Fernández, G and Sáez, JC and van Zundert, B}, title = {Mast Cell and Astrocyte Hemichannels and Their Role in Alzheimer's Disease, ALS, and Harmful Stress Conditions.}, journal = {International journal of molecular sciences}, volume = {22}, number = {4}, pages = {}, pmid = {33672031}, issn = {1422-0067}, mesh = {Alzheimer Disease/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Astrocytes/*metabolism ; Cell Degranulation ; Connexins/*metabolism ; Cytokines/metabolism ; Humans ; Ion Channels/*metabolism ; Mast Cells/immunology/*metabolism ; *Stress, Physiological ; }, abstract = {Considered relevant during allergy responses, numerous observations have also identified mast cells (MCs) as critical effectors during the progression and modulation of several neuroinflammatory conditions, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). MC granules contain a plethora of constituents, including growth factors, cytokines, chemokines, and mitogen factors. The release of these bioactive substances from MCs occurs through distinct pathways that are initiated by the activation of specific plasma membrane receptors/channels. Here, we focus on hemichannels (HCs) formed by connexins (Cxs) and pannexins (Panxs) proteins, and we described their contribution to MC degranulation in AD, ALS, and harmful stress conditions. Cx/Panx HCs are also expressed by astrocytes and are likely involved in the release of critical toxic amounts of soluble factors-such as glutamate, adenosine triphosphate (ATP), complement component 3 derivate C3a, tumor necrosis factor (TNFα), apoliprotein E (ApoE), and certain miRNAs-known to play a role in the pathogenesis of AD, ALS, and other neurodegenerative disorders. We propose that blocking HCs on MCs and glial cells offers a promising novel strategy for ameliorating the progression of neurodegenerative diseases by reducing the release of cytokines and other pro-inflammatory compounds.}, }
@article {pmid33671500, year = {2021}, author = {Sivandzade, F and Cucullo, L}, title = {Regenerative Stem Cell Therapy for Neurodegenerative Diseases: An Overview.}, journal = {International journal of molecular sciences}, volume = {22}, number = {4}, pages = {}, pmid = {33671500}, issn = {1422-0067}, support = {1R01-DA049737/DA/NIDA NIH HHS/United States ; 2R01-DA029121/DA/NIDA NIH HHS/United States ; R01 DA029121/DA/NIDA NIH HHS/United States ; R01 DA049737/DA/NIDA NIH HHS/United States ; 1R01NS117906/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell Differentiation ; Humans ; Neurodegenerative Diseases/*therapy ; Neurons/pathology/physiology ; Regeneration/physiology ; Regenerative Medicine/*methods ; Stem Cell Transplantation/*methods ; Stem Cells/classification ; }, abstract = {Neurodegenerative diseases resulting from the progressive loss of structure and/or function of neurons contribute to different paralysis degrees and loss of cognition and sensation. The lack of successful curative therapies for neurodegenerative disorders leads to a considerable burden on society and a high economic impact. Over the past 20 years, regenerative cell therapy, also known as stem cell therapy, has provided an excellent opportunity to investigate potentially powerful innovative strategies for treating neurodegenerative diseases. This is due to stem cells' capability to repair injured neuronal tissue by replacing the damaged or lost cells with differentiated cells, providing a conducive environment that is in favor of regeneration, or protecting the existing healthy neurons and glial cells from further damage. Thus, in this review, the various types of stem cells, the current knowledge of stem-cell-based therapies in neurodegenerative diseases, and the recent advances in this field are summarized. Indeed, a better understanding and further studies of stem cell technologies cause progress into realistic and efficacious treatments of neurodegenerative disorders.}, }
@article {pmid33671084, year = {2021}, author = {Ohkawara, B and Ito, M and Ohno, K}, title = {Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology.}, journal = {International journal of molecular sciences}, volume = {22}, number = {5}, pages = {}, pmid = {33671084}, issn = {1422-0067}, support = {JP17K07094//Grants-in-Aid from the Japan Society for the Promotion of Science/ ; JP18K06483//Grants-in-Aid from the Japan Society for the Promotion of Science/ ; JP20H03561//Grants-in-Aid from the Japan Society for the Promotion of Science/ ; 20FC1036//Ministry of Health, Labour and Welfare/ ; 20gm1010002//Japan Agency for Medical Research and Development/ ; JP20ek0109488//Japan Agency for Medical Research and Development/ ; 20bm0804005//Japan Agency for Medical Research and Development/ ; 2-5//National Center of Neurology and Psychiatry/ ; Year 2017//Hori Sciences and Arts Foundation/ ; }, mesh = {Animals ; Humans ; Muscle Proteins/*metabolism ; Neuromuscular Agents/*metabolism ; Neuromuscular Junction/*physiology ; Neuromuscular Junction Diseases/*physiopathology ; Signal Transduction ; }, abstract = {: Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, Schwartz-Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.}, }
@article {pmid33670164, year = {2021}, author = {Piancone, F and La Rosa, F and Marventano, I and Saresella, M and Clerici, M}, title = {The Role of the Inflammasome in Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {4}, pages = {}, pmid = {33670164}, issn = {1420-3049}, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; Inflammasomes/*genetics ; Interleukin-18/genetics ; Interleukin-1beta/genetics ; Multiple Sclerosis/genetics/pathology ; NLR Family, Pyrin Domain-Containing 3 Protein/*genetics ; Neurodegenerative Diseases/*genetics/pathology ; Parkinson Disease/genetics/pathology ; Signal Transduction/genetics ; }, abstract = {Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1β and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.}, }
@article {pmid33669787, year = {2021}, author = {Abd Rashed, A and Abd Rahman, AZ and Rathi, DNG}, title = {Essential Oils as a Potential Neuroprotective Remedy for Age-Related Neurodegenerative Diseases: A Review.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {4}, pages = {}, pmid = {33669787}, issn = {1420-3049}, mesh = {Aging/*pathology ; Humans ; Neurodegenerative Diseases/*drug therapy ; *Neuroprotection ; Neuroprotective Agents/*therapeutic use ; Oils, Volatile/*therapeutic use ; Publications ; }, abstract = {Despite the improvements in life expectancy, neurodegenerative conditions have arguably become the most dreaded maladies of older people. The neuroprotective and anti-ageing potentials of essential oils (EOs) are widely evaluated around the globe. The objective of this review is to analyse the effectiveness of EOs as neuroprotective remedies among the four common age-related neurodegenerative diseases. The literature was extracted from three databases (PubMed, Web of Science and Google Scholar) between the years of 2010 to 2020 using the medical subject heading (MeSH) terms "essential oil", crossed with "Alzheimer's disease (AD)", "Huntington's disease (HD)", "Parkinson's disease (PD)" or "amyotrophic lateral sclerosis (ALS)". Eighty three percent (83%) of the studies were focused on AD, while another 12% focused on PD. No classifiable study was recorded on HD or ALS. EO from Salvia officinalis has been recorded as one of the most effective acetylcholinesterase and butyrylcholinesterase inhibitors. However, only Cinnamomum sp. has been assessed for its effectiveness in both AD and PD. Our review provided useful evidence on EOs as potential neuroprotective remedies for age-related neurodegenerative diseases.}, }
@article {pmid33669593, year = {2021}, author = {Gupta, S and You, P and SenGupta, T and Nilsen, H and Sharma, K}, title = {Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases.}, journal = {Biology}, volume = {10}, number = {2}, pages = {}, pmid = {33669593}, issn = {2079-7737}, support = {279922//Helse S&#xf8;r-&#xd8;st RHF/ ; 302483//Norges Forskningsr&#xe5;d/ ; }, abstract = {Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.}, }
@article {pmid33668641, year = {2021}, author = {De Marchi, F and Contaldi, E and Magistrelli, L and Cantello, R and Comi, C and Mazzini, L}, title = {Telehealth in Neurodegenerative Diseases: Opportunities and Challenges for Patients and Physicians.}, journal = {Brain sciences}, volume = {11}, number = {2}, pages = {}, pmid = {33668641}, issn = {2076-3425}, support = {n/a//AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), University of Piemonte Orientale, Novara, Italy/ ; }, abstract = {Telehealth, by definition, is distributing health-related services while using electronic technologies. This narrative Review describes the technological health services (telemedicine and telemonitoring) for delivering care in neurodegenerative diseases, Alzheimer's disease, Parkinson's Disease, and amyotrophic lateral Sclerosis, among others. This paper aims to illustrate this approach's primary experience and application, highlighting the strengths and weaknesses, with the goal of understanding which could be the most useful application for each one, in order to facilitate telehealth improvement and use in standard clinical practice. We also described the potential role of the COVID-19 pandemic to speed up this service's use, avoiding a sudden interruption of medical care.}, }
@article {pmid33667787, year = {2021}, author = {Feng, YS and Tan, ZX and Wu, LY and Dong, F and Zhang, F}, title = {The involvement of NLRP3 inflammasome in the treatment of neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {138}, number = {}, pages = {111428}, doi = {10.1016/j.biopha.2021.111428}, pmid = {33667787}, issn = {1950-6007}, mesh = {Animals ; Drug Delivery Systems/*methods/trends ; Humans ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors/*metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*administration &amp; dosage/metabolism ; Treatment Outcome ; }, abstract = {In an ageing society, neurodegenerative diseases have attracted attention because of their high incidence worldwide. Despite extensive research, there is a lack of conclusive insights into the pathogenesis of neurodegenerative diseases, which limit the strategies for symptomatic treatment. Therefore, better elucidation of the molecular mechanisms involved in neurodegenerative diseases can provide an important theoretical basis for the discovery of new and effective prevention and treatment methods. The innate immune system is activated during the ageing process and in response to neurodegenerative diseases. Inflammasomes are multiprotein complexes that play an important role in the activation of the innate immune system. They mediate inflammatory reactions and pyroptosis, which are closely involved in neurodegeneration. There are different types of inflammasomes, although the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is the most common inflammasome; NLRP3 plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we will discuss the mechanisms that are involved in the activation of the NLRP3 inflammasome and its crucial role in the pathology of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. We will also review various treatments that target the NLRP3 inflammasome pathway and alleviate neuroinflammation. Finally, we will summarize the novel treatment strategies for neurodegenerative disorders.}, }
@article {pmid33664161, year = {2021}, author = {Galea, MP}, title = {Does respiratory muscle training improve respiratory function compared to sham training, no training, standard treatment or breathing exercises in children and adults with neuromuscular disease? A Cochrane Review summary with commentary.}, journal = {NeuroRehabilitation}, volume = {48}, number = {2}, pages = {243-245}, doi = {10.3233/NRE-218000}, pmid = {33664161}, issn = {1878-6448}, mesh = {Adult ; Breathing Exercises/*methods ; Child ; Female ; Humans ; Male ; Muscle Strength/*physiology ; Muscle Weakness/physiopathology/therapy ; Neuromuscular Diseases/physiopathology/*therapy ; Quality of Life ; Respiratory Function Tests/methods ; Respiratory Muscles/*physiology ; }, abstract = {BACKGROUND: Progressive muscle weakness is a feature of neuromuscular diseases (NMDs), a heterogeneous group of conditions with variable onset, presentation and prognosis that affect both children and adults. Respiratory muscle weakness compromises respiratory function and may lead to respiratory failure.<br><br>OBJECTIVE: To assess the effects of respiratory muscle training (RMT) in adults and children with NMD.<br><br>METHODS: A Cochrane Review by Silva et al. was summarized with comments.<br><br>RESULTS: Eleven studies involving 250 randomized participants with NMD were included. While the studies showed that RMT may lead to improvements in lung function and respiratory muscle strength in people with ALS and DMD, this was not a consistent finding. The evidence from all the included trials was of low or very low certainty.<br><br>CONCLUSIONS: There may be some improvement in lung capacity and respiratory muscle strength following RMT in some NMD. There appears to be no clinically meaningful effect of RMT on physical functioning and quality of life in ALS. The low certainty of the evidence means that the results need to be interpreted with caution.}, }
@article {pmid33663328, year = {2022}, author = {Jiang, L and Zhang, T and Lu, K and Qi, S}, title = {The progress in C9orf72 research: ALS/FTD pathogenesis, functions and structure.}, journal = {Small GTPases}, volume = {13}, number = {1}, pages = {56-76}, pmid = {33663328}, issn = {2154-1256}, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; Autophagy/genetics ; GTPase-Activating Proteins ; }, abstract = {The hexanucleotide repeat (GGGGCC) expansion in C9orf72 is accounted for a large proportion of the genetic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The hypotheses of how the massive G4C2 repeats in C9orf72 destroy the neurons and lead to ALS/FTD are raised and improving. As a multirole player, C9orf72 exerts critical roles in many cellular processes, including autophagy, membrane trafficking, immune response, and so on. Notably, the partners of C9orf72, through which C9orf72 participates in the cell activities, have been identified. Notably, the structures of the C9orf72-SMCR8-WDR41 complex shed light on its activity as GTPase activating proteins (GAP). In this manuscript, we reviewed the latest research progress in the C9orf72-mediated ALS/FTD, the physiological functions of C9orf72, and the putative function models of C9orf72/C9orf72-containing complex.}, }
@article {pmid33659944, year = {2020}, author = {Gittings, LM and Sattler, R}, title = {Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies.}, journal = {Faculty reviews}, volume = {9}, number = {}, pages = {12}, pmid = {33659944}, issn = {2732-432X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by degeneration of both upper and lower motor neurons and subsequent progressive loss of muscle function. Within the last decade, significant progress has been made in the understanding of the etiology and pathobiology of the disease; however, treatment options remain limited and only two drugs, which exert a modest effect on survival, are approved for ALS treatment in the US. Therefore, the search for effective ALS therapies continues, and over 60 clinical trials are in progress for patients with ALS and other therapeutics are at the pre-clinical stage of development. Recent advances in understanding the genetics, pathology, and molecular mechanisms of ALS have led to the identification of novel targets and strategies that are being used in emerging ALS therapeutic interventions. Here, we review the current status and mechanisms of action of a selection of emerging ALS therapies in pre-clinical or early clinical development, including gene therapy, immunotherapy, and strategies that target neuroinflammation, phase separation, and protein clearance.}, }
@article {pmid33655876, year = {2021}, author = {Ahmed, LA and Al-Massri, KF}, title = {Directions for Enhancement of the Therapeutic Efficacy of Mesenchymal Stem Cells in Different Neurodegenerative and Cardiovascular Diseases: Current Status and Future Perspectives.}, journal = {Current stem cell research &amp; therapy}, volume = {16}, number = {7}, pages = {858-876}, doi = {10.2174/1574888X16666210303151237}, pmid = {33655876}, issn = {2212-3946}, mesh = {*Cardiovascular Diseases/therapy ; Humans ; *Mesenchymal Stem Cell Transplantation ; *Mesenchymal Stem Cells ; *Myocardial Infarction/therapy ; *Neurodegenerative Diseases/therapy ; }, abstract = {Mesenchymal stem cells (MSCs) have shown promising therapeutic effects in a wide variety of medical conditions, including neurodegenerative disorders and cardiovascular diseases. Although preliminary research has emphasized the ability of MSCs to engraft at sites of injury, several studies have revealed that MSCs mediate their effects through the release of various paracrine factors and through their antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. The clinical implications of MSCs application are limited due to their low survival rate in conditions of inflammation, oxidative stress, and nutrient restriction in damaged areas. Furthermore, the function of isolated MSCs is usually affected by the patient's health. Therefore, it is necessary to develop new methods to enhance the therapeutic efficacy of MSCs under pathophysiological conditions. This review provides an overview of the general properties of MSCs, their therapeutic potential in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, as well as cardiovascular diseases such as myocardial infarction, diabetic cardiomyopathy, and dilated cardiomyopathy, and their related mechanisms. In addition, this review also discusses potential problems and side effects, as well as current and future directions for improvement of MSCs therapy and their implications and applications.}, }
@article {pmid33655733, year = {2021}, author = {Lin, JZ and Duan, MR and Lin, N and Zhao, WJ}, title = {The emerging role of the chondroitin sulfate proteoglycan family in neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {32}, number = {7}, pages = {737-750}, doi = {10.1515/revneuro-2020-0146}, pmid = {33655733}, issn = {2191-0200}, mesh = {Central Nervous System ; *Chondroitin Sulfate Proteoglycans ; Extracellular Matrix ; Humans ; *Neurodegenerative Diseases ; }, abstract = {Chondroitin sulfate (CS) is a kind of linear polysaccharide that is covalently linked to proteins to form proteoglycans. Chondroitin sulfate proteoglycans (CSPGs) consist of a core protein, with one or more CS chains covalently attached. CSPGs are precisely regulated and they exert a variety of physiological functions by binding to adhesion molecules and growth factors. Widely distributed in the nervous system in human body, CSPGs contribute to the major component of extracellular matrix (ECM), where they play an important role in the development and maturation of the nervous system, as well as in the pathophysiological response to damage to the central nervous system (CNS). While there are more than 30 types of CSPGs, this review covers the roles of the most important ones, including versican, aggrecan, neurocan and NG2 in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. The updated reports of the treatment of neurodegenerative diseases are involving CSPGs.}, }
@article {pmid33654312, year = {2021}, author = {Tziortzouda, P and Van Den Bosch, L and Hirth, F}, title = {Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation.}, journal = {Nature reviews. Neuroscience}, volume = {22}, number = {4}, pages = {197-208}, pmid = {33654312}, issn = {1471-0048}, support = {HIRTH/OCT16/890-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0701498/MRC_/Medical Research Council/United Kingdom ; G-0714/PUK_/Parkinson's UK/United Kingdom ; MR/L010666/1/MRC_/Medical Research Council/United Kingdom ; HIRTH/OCT13/868-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; DNA-Binding Proteins/*metabolism ; Homeostasis/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 - achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport - safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease.}, }
@article {pmid33652720, year = {2021}, author = {Shacham, T and Patel, C and Lederkremer, GZ}, title = {PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?.}, journal = {Biomolecules}, volume = {11}, number = {3}, pages = {}, pmid = {33652720}, issn = {2218-273X}, support = {Legacy Heritage Fund (2394/17)//Israel Science Foundation/ ; }, mesh = {Animals ; Endoplasmic Reticulum/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Signal Transduction/physiology ; Unfolded Protein Response/physiology ; eIF-2 Kinase/*metabolism ; }, abstract = {With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer's disease (AD) and Parkinson's disease (PD), the less frequent Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.}, }
@article {pmid33650716, year = {2021}, author = {Ahani-Nahayati, M and Shariati, A and Mahmoodi, M and Olegovna Zekiy, A and Javidi, K and Shamlou, S and Mousakhani, A and Zamani, M and Hassanzadeh, A}, title = {Stem cell in neurodegenerative disorders; an emerging strategy.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {81}, number = {4}, pages = {291-311}, doi = {10.1002/jdn.10101}, pmid = {33650716}, issn = {1873-474X}, mesh = {Animals ; Humans ; *Neural Stem Cells ; Neurodegenerative Diseases/*therapy ; *Pluripotent Stem Cells ; Stem Cell Transplantation/*methods ; }, abstract = {Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)-derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.}, }
@article {pmid33643818, year = {2021}, author = {Zhang, L and Hu, K and Shao, T and Hou, L and Zhang, S and Ye, W and Josephson, L and Meyer, JH and Zhang, MR and Vasdev, N and Wang, J and Xu, H and Wang, L and Liang, SH}, title = {Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {2}, pages = {373-393}, pmid = {33643818}, issn = {2211-3835}, abstract = {The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.}, }
@article {pmid33642372, year = {2021}, author = {Falzone, YM and Russo, T and Domi, T and Pozzi, L and Quattrini, A and Filippi, M and Riva, N}, title = {Current application of neurofilaments in amyotrophic lateral sclerosis and future perspectives.}, journal = {Neural regeneration research}, volume = {16}, number = {10}, pages = {1985-1991}, pmid = {33642372}, issn = {1673-5374}, abstract = {Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons. Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far. Unfortunately, diagnostic and prognostic biomarkers are lacking in clinical practice. Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum. Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis, reflecting the extensive damage of motor neurons and axons. Hence, neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis. The potential usefulness of neurofilaments regards various aspects, including diagnosis, prognosis, patient stratification in clinical trials and evaluation of treatment response. In this review paper, we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis. We also discuss the open issues concerning the use of neurofilaments clinical practice, as no overall guideline exists to date; finally, we address the most recent evidence and future perspectives.}, }
@article {pmid33642365, year = {2021}, author = {Lu, JX and Wang, Y and Zhang, YJ and Shen, MF and Li, HY and Yu, ZQ and Chen, G}, title = {Axonal mRNA localization and local translation in neurodegenerative disease.}, journal = {Neural regeneration research}, volume = {16}, number = {10}, pages = {1950-1957}, pmid = {33642365}, issn = {1673-5374}, abstract = {The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function. Many human neurodegenerative diseases, such as fragile X syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, and spinal muscular atrophy, have been characterized by pathological changes in neuronal axons, including abnormal mRNA translation, the loss of protein expression, or abnormal axon transport. Moreover, the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks. In this review, we briefly examine fragile X syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, and spinal muscular atrophy, with a focus on disease pathogenesis with regard to local mRNA translation and axon transport, suggesting possible treatment directions.}, }
@article {pmid33642358, year = {2021}, author = {Marshall, KL and Farah, MH}, title = {Axonal regeneration and sprouting as a potential therapeutic target for nervous system disorders.}, journal = {Neural regeneration research}, volume = {16}, number = {10}, pages = {1901-1910}, pmid = {33642358}, issn = {1673-5374}, abstract = {Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages. Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconnection from their targets, which in turn leads to functional impairment. During the course of many of neurologic diseases, axons can regenerate or sprout in an attempt to reconnect with the target and restore synapse function. In amyotrophic lateral sclerosis (ALS), distal motor axons retract from neuromuscular junctions early in the disease-course before significant motor neuron death. There is evidence of compensatory motor axon sprouting and reinnervation of neuromuscular junctions in ALS that is usually quickly overtaken by the disease course. Potential drugs that enhance compensatory sprouting and encourage reinnervation may slow symptom progression and retain muscle function for a longer period of time in ALS and in other diseases that exhibit dying-back axonopathy. There remain many outstanding questions as to the impact of distinct disease-causing mutations on axonal outgrowth and regeneration, especially in regards to motor neurons derived from patient induced pluripotent stem cells. Compartmentalized microfluidic chambers are powerful tools for studying the distal axons of human induced pluripotent stem cells-derived motor neurons, and have recently been used to demonstrate striking regeneration defects in human motor neurons harboring ALS disease-causing mutations. Modeling the human neuromuscular circuit with human induced pluripotent stem cells-derived motor neurons will be critical for developing drugs that enhance axonal regeneration, sprouting, and reinnervation of neuromuscular junctions. In this review we will discuss compensatory axonal sprouting as a potential therapeutic target for ALS, and the use of compartmentalized microfluidic devices to find drugs that enhance regeneration and axonal sprouting of motor axons.}, }
@article {pmid33640250, year = {2021}, author = {Falabella, M and Vernon, HJ and Hanna, MG and Claypool, SM and Pitceathly, RDS}, title = {Cardiolipin, Mitochondria, and Neurological Disease.}, journal = {Trends in endocrinology and metabolism: TEM}, volume = {32}, number = {4}, pages = {224-237}, pmid = {33640250}, issn = {1879-3061}, support = {MR/S002065/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Cardiolipins/metabolism ; Central Nervous System ; Humans ; *Mitochondria/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Neurons/metabolism ; }, abstract = {Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.}, }
@article {pmid33639280, year = {2021}, author = {Pandya, VA and Patani, R}, title = {Region-specific vulnerability in neurodegeneration: lessons from normal ageing.}, journal = {Ageing research reviews}, volume = {67}, number = {}, pages = {101311}, pmid = {33639280}, issn = {1872-9649}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Humans ; *Parkinson Disease ; }, abstract = {A number of age-associated neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), possess a shared characteristic of region-specific neurodegeneration. However, the mechanisms which determine why particular regions within the nervous system are selectively vulnerable to neurodegeneration, whilst others remain relatively unaffected throughout disease progression, remain elusive. Here, we review how regional susceptibility to the ubiquitous physiological phenomenon of normal ageing might underlie the vulnerability of these same regions to neurodegeneration, highlighting three regions archetypally associated with AD, PD and ALS (the hippocampus, substantia nigra pars compacta and ventral spinal cord, respectively), as especially prone to age-related alterations. Placing particular emphasis on these three regions, we comprehensively explore differential regional susceptibility to nervous system tissue, cellular and molecular level ageing to provide an integrated perspective on why age-related neurodegenerative diseases exhibit region-selective vulnerability. Combining these principles with increasingly recognised differences between chronological and biological ageing (termed differential or 'delta' ageing) might ultimately guide therapeutic approaches for these devastating neurodegenerative diseases, for which a paucity of disease modifying and/or life promoting treatments currently exist.}, }
@article {pmid33639271, year = {2021}, author = {Jhanji, R and Behl, T and Sehgal, A and Bungau, S}, title = {Mitochondrial dysfunction and traffic jams in amyotrophic lateral sclerosis.}, journal = {Mitochondrion}, volume = {58}, number = {}, pages = {102-110}, doi = {10.1016/j.mito.2021.02.008}, pmid = {33639271}, issn = {1872-8278}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Brain/metabolism ; Disease Progression ; Energy Metabolism ; Humans ; Mitochondria/*physiology ; Motor Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss anatomically or physiologically and accumulation of protein in the cells. Mitochondria provide energy to these neuronal cells consuming 20% of the body's oxygen. Mitochondria are the dynamic membrane-bound cell organelles that function to generate ATP, regulate calcium homeostasis, and produce reactive oxygen species. Because of alterations in the electron transport chain, mutation, and environmental toxins, there is reduced ATP production, calcium dyshomeostasis, and increased oxidative stress, resulting in mitochondrial dysfunction, leading to the pathogenesis of neurodegenerative diseases such as ALS. ALS is described as the loss of upper and lower motor neurons resulting in progressive muscle denervation and loss of voluntary movements. There are multiple shreds of evidence in the literature regarding the mechanism involved in mitochondrial dysfunction and possible therapeutic targets to treat the condition. Moreover, different studies reported the role of different gene mutations and malfunctions in transport system responsible for the accumulation and aggregation of the proteins inside the brain cells. This accumulation and/or aggregation of proteins in the neuronal cells is known as neuronal traffic jam, which also plays the leading role in the progressive neurodegenerative diseases. In this review, we have elucidated the critical insights into mitochondrial dysfunction and neuronal traffic jam; and its role in the initiation and progression of ALS. Moreover, the pharmacological targets and possible conducts to this scenario are also brought together.}, }
@article {pmid33634144, year = {2021}, author = {Belli, S and Prince, I and Savio, G and Paracchini, E and Cattaneo, D and Bianchi, M and Masocco, F and Bellanti, MT and Balbi, B}, title = {Airway Clearance Techniques: The Right Choice for the Right Patient.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {544826}, pmid = {33634144}, issn = {2296-858X}, abstract = {The management of bronchial secretions is one of the main problems encountered in a wide spectrum of medical conditions ranging from respiratory disorders, neuromuscular disorders and patients undergoing either thoracic or abdominal surgery. The purpose of this review is illustrate to the reader the different ACTs currently available and the related evidence present in literature. Alongside methods with a strong background behind as postural drainage, manual techniques or PEP systems, the current orientation is increasingly aimed at devices that can mobilize and / or remove secretions. Cough Assist, Vacuum Techniques, systems that modulate airflow have more and more scientific evidence. Different principles combination is a new field of investigation that goes toward an increasing of clinical complexity that will facing us.}, }
@article {pmid33632084, year = {2021}, author = {Je, G and Keyhanian, K and Ghasemi, M}, title = {Overview of stem cells therapy in amyotrophic lateral sclerosis.}, journal = {Neurological research}, volume = {43}, number = {8}, pages = {616-632}, doi = {10.1080/01616412.2021.1893564}, pmid = {33632084}, issn = {1743-1328}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*physiopathology/*therapy ; Animals ; Cell Differentiation/physiology ; Clinical Trials as Topic/methods ; Humans ; Stem Cell Transplantation/*methods/trends ; Stem Cells/*physiology ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons with high burden on society. Despite tremendous efforts over the last several decades, there is still no definite cure for ALS. Up to now, only two disease-modifying agents, riluzole and edaravone, are approved by U.S. Food and Drug Administration (FDA) for ALS treatment, which only modestly improves survival and disease progression. Major challenging issues to find an effective therapy are heterogeneity in the pathogenesis and genetic variability of ALS. As such, stem cell therapy has been recently a focus of both preclinical and clinical investigations of ALS. This is because stem cells have multifaceted features that can potentially target multiple pathogenic mechanisms in ALS even though its underlying mechanisms are not completely elucidated. Methods &amp; Results: Here, we will have an overview of stem cell therapy in ALS, including their therapeutic mechanisms, the results of recent clinical trials as well as ongoing clinical trials. In addition, we will further discuss complications and limitations of stem cell therapy in ALS. Conclusion: The determination of whether stem cells offer a viable treatment strategy for ALS rests on well-designed and appropriately powered future clinical trials. Randomized, double-blinded, and sham-controlled studies would be valuable.}, }
@article {pmid33632058, year = {2021}, author = {Beckers, J and Tharkeshwar, AK and Van Damme, P}, title = {C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels.}, journal = {Autophagy}, volume = {17}, number = {11}, pages = {3306-3322}, pmid = {33632058}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/physiopathology ; Animals ; Autophagosomes/genetics/pathology/physiology ; Autophagy/*genetics/physiology ; Axonal Transport/genetics/physiology ; C9orf72 Protein/*genetics/physiology ; DNA Repeat Expansion/genetics/physiology ; DNA-Binding Proteins/genetics/physiology ; Frontotemporal Dementia/*genetics/pathology/physiopathology ; Genetic Therapy ; Humans ; Lysosomes/*genetics/physiology ; Models, Neurological ; Nerve Degeneration/genetics/pathology/physiopathology ; Protein Aggregation, Pathological/genetics/physiopathology ; Proteostasis/genetics/physiology ; RNA-Binding Proteins/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct classes of neurodegenerative disorders. Yet, they share a range of genetic, cellular, and molecular features. Hexanucleotide repeat expansions (HREs) in the C9orf72 gene and the accumulation of toxic protein aggregates in the nervous systems of the affected individuals are among such common features. Though the mechanisms by which HREs cause toxicity is not clear, the toxic gain of function due to transcribed HRE RNA or dipeptide repeat proteins (DPRs) produced by repeat-associated non-AUG translation together with a reduction in C9orf72 expression are proposed as the contributing factors for disease pathogenesis in ALS and FTD. In addition, several recent studies point toward alterations in protein homeostasis as one of the root causes of the disease pathogenesis. In this review, we discuss the effects of the C9orf72 HRE in the autophagy-lysosome pathway based on various recent findings. We suggest that dysfunction of the autophagy-lysosome pathway synergizes with toxicity from C9orf72 repeat RNA and DPRs to drive disease pathogenesis.Abbreviation: ALP: autophagy-lysosome pathway; ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related; ASO: antisense oligonucleotide; C9orf72: C9orf72-SMCR8 complex subunit; DENN: differentially expressed in normal and neoplastic cells; DPR: dipeptide repeat protein; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; ER: endoplasmic reticulum; FTD: frontotemporal dementia; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; HRE: hexanucleotide repeat expansion; iPSC: induced pluripotent stem cell; ISR: integrated stress response; M6PR: mannose-6-phosphate receptor, cation dependent; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MN: motor neuron; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: neurodegenerative disorder; RAN: repeat-associated non-ATG; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SLC66A1/PQLC2: solute carrier family 66 member 1; SMCR8: SMCR8-C9orf72 complex subunit; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; WDR41: WD repeat domain 41.}, }
@article {pmid33624404, year = {2021}, author = {Sotoudeh, H and Sarrami, AH and Wang, JX and Saadatpour, Z and Razaei, A and Gaddamanugu, S and Choudhary, G and Shafaat, O and Singhal, A}, title = {Susceptibility-Weighted Imaging in Neurodegenerative Disorders: A Review.}, journal = {Journal of neuroimaging : official journal of the American Society of Neuroimaging}, volume = {31}, number = {3}, pages = {459-470}, doi = {10.1111/jon.12841}, pmid = {33624404}, issn = {1552-6569}, mesh = {Alzheimer Disease/diagnostic imaging/pathology ; Brain/pathology ; Cerebral Amyloid Angiopathy/diagnostic imaging/pathology ; Cerebral Arterial Diseases/*diagnostic imaging/pathology ; Dementia, Vascular/diagnostic imaging/pathology ; Humans ; Lewy Body Disease/diagnostic imaging/pathology ; Magnetic Resonance Imaging/*methods ; Male ; Neurodegenerative Diseases/*diagnostic imaging/pathology ; Neuroimaging/*methods ; Parkinson Disease/diagnostic imaging ; }, abstract = {As human life expectancy increases, there is an increased prevalence of neurodegenerative disorders and dementia. There are many ongoing research trials for early diagnosis and management of dementia, and neuroimaging is a critical part of such studies. However, conventional neuroimaging often fails to provide enough diagnostic findings in patients with neurodegenerative disorders. In this context, different MRI sequences are currently under investigation to facilitate the accurate diagnosis of such disorders. Susceptibility-weighted imaging (SWI) is an innovative MRI technique that utilizes "magnitude" and "phase" images to produce an image contrast that is sensitive for the detection of susceptibility differences of the tissues. As many neurodegenerative disorders are associated with accelerated iron deposition and/or microhemorrhages in different parts of the brain, SWI can be applied to detect these diagnostic clues. For instance, in cerebral amyloid angiopathy, SWI can demonstrate cortical microhemorrhages, which are predominantly in the frontal and parietal regions. Or in Parkinson disease, abnormal swallow-tail sign on high-resolution SWI is highly diagnostic. Also, SWI is a useful sequence to detect the low signal intensity of precentral cortices in patients with amyotrophic lateral sclerosis. Being familiar with SWI findings in neurodegenerative disorders is critical for an accurate diagnosis. In this paper, the authors review the technical parameters of SWI, physiologic, and pathologic iron deposition in the brain, and the role of SWI in the evaluation of neurodegenerative disorders in daily practice.}, }
@article {pmid33617919, year = {2021}, author = {Xiao, Y and Wang, SK and Zhang, Y and Rostami, A and Kenkare, A and Casella, G and Yuan, ZQ and Li, X}, title = {Role of extracellular vesicles in neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {201}, number = {}, pages = {102022}, doi = {10.1016/j.pneurobio.2021.102022}, pmid = {33617919}, issn = {1873-5118}, mesh = {Alzheimer Disease ; Blood-Brain Barrier ; *Extracellular Vesicles ; Humans ; *Neurodegenerative Diseases/therapy ; Parkinson Disease ; }, abstract = {Extracellular vesicles (EVs) are heterogeneous cell-derived membranous structures that arise from the endosome system or directly detach from the plasma membrane. In recent years, many advances have been made in the understanding of the clinical definition and pathogenesis of neurodegenerative diseases, but translation into effective treatments is hampered by several factors. Current research indicates that EVs are involved in the pathology of diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Besides, EVs are also involved in the process of myelin formation, and can also cross the blood-brain barrier to reach the sites of CNS injury. It is suggested that EVs have great potential as a novel therapy for the treatment of neurodegenerative diseases. Here, we reviewed the advances in understanding the role of EVs in neurodegenerative diseases and addressed the critical function of EVs in the CNS. We have also outlined the physiological mechanisms of EVs in myelin regeneration and highlighted the therapeutic potential of EVs in neurodegenerative diseases.}, }
@article {pmid33616931, year = {2021}, author = {Trinh, D and Israwi, AR and Arathoon, LR and Gleave, JA and Nash, JE}, title = {The multi-faceted role of mitochondria in the pathology of Parkinson's disease.}, journal = {Journal of neurochemistry}, volume = {156}, number = {6}, pages = {715-752}, doi = {10.1111/jnc.15154}, pmid = {33616931}, issn = {1471-4159}, mesh = {Animals ; Humans ; Mitochondria/*metabolism/*pathology ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/pathology ; Parkinson Disease/*metabolism/*pathology ; }, abstract = {Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity. These roles are especially important for neurons, which have higher energy demands and greater susceptibility to stress. Dysfunction of mitochondria has been associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, Glaucoma and Amyotrophic Lateral Sclerosis. The focus of this review is on how and why mitochondrial function is linked to the pathology of Parkinson's disease (PD). Many of the PD-linked genetic mutations which have been identified result in dysfunctional mitochondria, through a wide-spread number of mechanisms. In this review, we describe how susceptible neurons are predisposed to be vulnerable to the toxic events that occur during the neurodegenerative process of PD, and how mitochondria are central to these pathways. We also discuss ways in which proteins linked with familial PD control mitochondrial function, both physiologically and pathologically, along with their implications in genome-wide association studies and risk assessment. Finally, we review potential strategies for disease modification through mitochondrial enhancement. Ultimately, agents capable of both improving and/or restoring mitochondrial function, either alone, or in conjunction with other disease-modifying agents may halt or slow the progression of neurodegeneration in Parkinson's disease.}, }
@article {pmid33613416, year = {2020}, author = {Ranieri, F and Mariotto, S and Dubbioso, R and Di Lazzaro, V}, title = {Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {605335}, pmid = {33613416}, issn = {1664-2295}, abstract = {In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited "dosage" of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.}, }
@article {pmid33609524, year = {2021}, author = {Dudás, EF and Huynen, MA and Lesk, AM and Pastore, A}, title = {Invisible leashes: The tethering VAPs from infectious diseases to neurodegeneration.}, journal = {The Journal of biological chemistry}, volume = {296}, number = {}, pages = {100421}, pmid = {33609524}, issn = {1083-351X}, support = {/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Communicable Diseases/*metabolism ; Humans ; Lipid Metabolism ; Mutation ; Neurodegenerative Diseases/*metabolism ; Vesicular Transport Proteins/genetics/*metabolism ; }, abstract = {Intracellular organelles do not, as thought for a long time, act in isolation but are dynamically tethered together by entire machines responsible for interorganelle trafficking and positioning. Among the proteins responsible for tethering is the family of VAMP-associated proteins (VAPs) that appear in all eukaryotes and are localized primarily in the endoplasmic reticulum. The major functional role of VAPs is to tether the endoplasmic reticulum with different organelles and regulate lipid metabolism and transport. VAPs have gained increasing attention because of their role in human pathology where they contribute to infections by viruses and bacteria and participate in neurodegeneration. In this review, we discuss the structure, evolution, and functions of VAPs, focusing more specifically on VAP-B for its relationship with amyotrophic lateral sclerosis and other neurodegenerative diseases.}, }
@article {pmid33608813, year = {2021}, author = {Shafiq, K and Sanghai, N and Guo, Y and Kong, J}, title = {Implication of post-translationally modified SOD1 in pathological aging.}, journal = {GeroScience}, volume = {43}, number = {2}, pages = {507-515}, pmid = {33608813}, issn = {2509-2723}, mesh = {Aging/*pathology ; *Amyotrophic Lateral Sclerosis ; Humans ; *Parkinson Disease ; Protein Folding ; *Protein Processing, Post-Translational ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {Why certain people relish healthy aging throughout their life span while others suffer pathological consequences? In this review, we focus on some of the dominant paradigms of pathological aging, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), and predict that the antioxidant superoxide dismutase 1 (SOD1), when post-translationally modified by aging-associated oxidative stress, acts as a mechanism to accelerated aging in these age-related neurodegenerative diseases. Oxidative modifications of natively reduced SOD1 induce pathological confirmations such as misfolding, leading to a subsequent formation of monomeric, oligomeric, and multimeric aggregates. Misfolded SOD1 propagates like prions from cell to cell. These modified conformations are detected in brain tissues in ALS, AD, and PD, and are considered a contributing factor to their initial pathogenesis. We have also elaborated on oxidative stress-induced non-native modifications of SOD1 and offered a logistic argument on their global implication in accelerated or pathological aging in the context of ALS, AD, and PD.}, }
@article {pmid33604874, year = {2021}, author = {Akbari Dilmaghani, N and Hussen, BM and Nateghinia, S and Taheri, M and Ghafouri-Fard, S}, title = {Emerging role of microRNAs in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Metabolic brain disease}, volume = {36}, number = {5}, pages = {737-749}, pmid = {33604874}, issn = {1573-7365}, mesh = {Animals ; Biomarkers/metabolism ; Brachial Plexus Neuritis/genetics/*metabolism ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Humans ; MicroRNAs/genetics/*metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly motor neuron disease (MND) and the most frequent MND in adults. ALS is recognized by degenerative alterations in both upper and lower motor neurons. This disorder is classified to familial and sporadic classes. Disease-causing mutations in SOD1, C9ORF72, FUS, and TARDBP have been recognized in familial ALS cases. However, in spite of conduction of several genetic association studies, heritable genetic risk elements in sporadic have not been identified completely. Several miRNAs have been dysregulated in the serum samples or brain tissues of ALS patients. Moreover, a number of miRNAs have been suggested as putative biomarkers for sporadic ALS. In the current manuscript, we review of miRNAs in the development of ALS.}, }
@article {pmid33602015, year = {2020}, author = {Pioro, EP and Turner, MR and Bede, P}, title = {Neuroimaging in primary lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {sup1}, pages = {18-27}, doi = {10.1080/21678421.2020.1837176}, pmid = {33602015}, issn = {2167-9223}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; *Motor Neuron Disease ; Neuroimaging ; }, abstract = {Increased interest in the underlying pathogenesis of primary lateral sclerosis (PLS) and its relationship to amyotrophic lateral sclerosis (ALS) has corresponded to a growing number of CNS imaging studies, especially in the past decade. Both its rarity and uncertainty of definite diagnosis prior to 4 years from symptom onset have resulted in PLS being less studied than ALS. In this review, we highlight most relevant papers applying magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) to analyzing CNS changes in PLS, often in relation to ALS. In patients with PLS, mostly brain, but also spinal cord has been evaluated since significant neurodegeneration is essentially restricted to upper motor neuron (UMN) structures and related pathways. Abnormalities of cortex and subcortical white matter tracts have been identified by structural and functional MRI and MRS studies, while metabolic and cell-specific changes in PLS brain have been revealed using various PET radiotracers. Future neuroimaging studies will continue to explore the interface between the PLS-ALS continuum, identify more changes unique to PLS, apply novel MRI and MRS sequences showing greater structural and neurochemical detail, as well as expand the repertoire of PET radiotracers that reveal various cellular pathologies. Neuroimaging has the potential to play an important role in the evaluation of novel therapies for patients with PLS.}, }
@article {pmid33602010, year = {2020}, author = {Mackenzie, IRA}, title = {Neuropathology of primary lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {sup1}, pages = {47-51}, doi = {10.1080/21678421.2020.1837173}, pmid = {33602010}, issn = {2167-9223}, support = {74580//CIHR/Canada ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Brain/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Inclusion Bodies/metabolism ; *Motor Neuron Disease ; Motor Neurons/metabolism ; }, abstract = {Published descriptions of the neuropathology of clinically defined primary lateral sclerosis (PLS) are reviewed in order to clarify the pathogenesis and the relationship between PLS and classical amyotrophic lateral sclerosis (ALS). Degeneration of the primary motor cortex and corticospinal tracts with preservation of lower motor neurons (LMN) has been reported in most cases. Studies that employed immunohistochemistry found ubiquitin and/or TDP-43-positive neuronal inclusions in the motor cortex and often in the extramotor neocortex. Ubiquitin/TDP-43-immunoreactive inclusions in LMN have been reported in just over half of cases; however, these have never been numerous. The finding of TDP-43 pathology in most cases indicates that PLS and ALS are closely related conditions; however, the fact that cases of PLS consistently show minimal involvement of LMN suggests that PLS represents a distinct entity, rather than an early stage of ALS.}, }
@article {pmid33596293, year = {2021}, author = {Persano, F and Batasheva, S and Fakhrullina, G and Gigli, G and Leporatti, S and Fakhrullin, R}, title = {Recent advances in the design of inorganic and nano-clay particles for the treatment of brain disorders.}, journal = {Journal of materials chemistry. B}, volume = {9}, number = {12}, pages = {2756-2784}, doi = {10.1039/d0tb02957b}, pmid = {33596293}, issn = {2050-7518}, mesh = {Animals ; Blood-Brain Barrier/drug effects ; Brain Diseases/*drug therapy ; Clay/*chemistry ; Drug Carriers/chemistry ; *Drug Design ; Humans ; Nanoparticles/*chemistry ; Particle Size ; Porosity ; Silicon Dioxide/chemistry/*pharmacology ; }, abstract = {Inorganic materials, in particular nanoclays and silica nanoparticles, have attracted enormous attention due to their versatile and tuneable properties, making them ideal candidates for a wide range of biomedical applications, such as drug delivery. This review aims at overviewing recent developments of inorganic nanoparticles (like porous or mesoporous silica particles) and different nano-clay materials (like montmorillonite, laponites or halloysite nanotubes) employed for overcoming the blood brain barrier (BBB) in the treatment and therapy of major brain diseases such as Alzheimer's, Parkinson's, glioma or amyotrophic lateral sclerosis. Recent strategies of crossing the BBB through invasive and not invasive administration routes by using different types of nanoparticles compared to nano-clays and inorganic particles are overviewed.}, }
@article {pmid33590603, year = {2021}, author = {Gadgil, A and Raczyńska, KD}, title = {U7 snRNA: A tool for gene therapy.}, journal = {The journal of gene medicine}, volume = {23}, number = {4}, pages = {e3321}, pmid = {33590603}, issn = {1521-2254}, mesh = {Binding Sites/genetics ; Cell Nucleus/*genetics ; *Genetic Therapy ; Histones/*genetics ; Humans ; Protein Binding/genetics ; RNA, Small Nuclear/*genetics ; Ribonucleoproteins, Small Nuclear/genetics/therapeutic use ; }, abstract = {Most U-rich small nuclear ribonucleoproteins (snRNPs) are complexes that mediate the splicing of pre-mRNAs. U7 snRNP is an exception in that it is not involved in splicing but is a key factor in the unique 3' end processing of replication-dependent histone mRNAs. However, by introducing controlled changes in the U7 snRNA histone binding sequence and in the Sm motif, it can be used as an effective tool for gene therapy. The modified U7 snRNP (U7 Sm OPT) is thus not involved in the processing of replication-dependent histone pre-mRNA but targets splicing by inducing efficient skipping or inclusion of selected exons. U7 Sm OPT is of therapeutic importance in diseases that are an outcome of splicing defects, such as myotonic dystrophy, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, β-thalassemia, HIV-1 infection and spinal muscular atrophy. The benefits of using U7 Sm OPT for gene therapy are its compact size, ability to accumulate in the nucleus without causing any toxic effects in the cells, and no immunoreactivity. The risk of transgene misregulation by using U7 Sm OPT is also low because it is involved in correcting the expression of an endogenous gene controlled by its own regulatory elements. Altogether, using U7 Sm OPT as a tool in gene therapy can ensure lifelong treatment, whereas an oligonucleotide or other drug/compound would require repeated administration. It would thus be strategic to harness these unique properties of U7 snRNP and deploy it as a tool in gene therapy.}, }
@article {pmid33586315, year = {2022}, author = {Bhattarai, A and Egan, GF and Talman, P and Chua, P and Chen, Z}, title = {Magnetic Resonance Iron Imaging in Amyotrophic Lateral Sclerosis.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {55}, number = {5}, pages = {1283-1300}, doi = {10.1002/jmri.27530}, pmid = {33586315}, issn = {1522-2586}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; Iron ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Spectroscopy ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) results in progressive impairment of upper and lower motor neurons. Increasing evidence from both in vivo and ex vivo studies suggest that iron accumulation in the motor cortex is a neuropathological hallmark in ALS. An in vivo neuroimaging marker of iron dysregulation in ALS would be useful in disease diagnosis and prognosis. Magnetic resonance imaging (MRI), with its unique capability to generate a variety of soft tissue contrasts, provides opportunities to image iron distribution in the human brain with millimeter to sub-millimeter anatomical resolution. Conventionally, MRI T1-weighted, T2-weighted, and T2*-weighted images have been used to investigate iron dysregulation in the brain in vivo. Susceptibility weighted imaging has enhanced contrast for para-magnetic materials that provides superior sensitivity to iron in vivo. Recently, the development of quantitative susceptibility mapping (QSM) has realized the possibility of using quantitative assessments of magnetic susceptibility measures in brain tissues as a surrogate measurement of in vivo brain iron. In this review, we provide an overview of MRI techniques that have been used to investigate iron dysregulation in ALS in vivo. The potential uses, strengths, and limitations of these techniques in clinical trials, disease diagnosis, and prognosis are presented and discussed. We recommend further longitudinal studies with appropriate cohort characterization to validate the efficacy of these techniques. We conclude that quantitative iron assessment using recent advances in MRI including QSM holds great potential to be a sensitive diagnostic and prognostic marker in ALS. The use of multimodal neuroimaging markers in combination with iron imaging may also offer improved sensitivity in ALS diagnosis and prognosis that could make a major contribution to clinical care and treatment trials. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.}, }
@article {pmid33585610, year = {2020}, author = {Fletcher, DJ and Boller, M}, title = {Fluid Therapy During Cardiopulmonary Resuscitation.}, journal = {Frontiers in veterinary science}, volume = {7}, number = {}, pages = {625361}, pmid = {33585610}, issn = {2297-1769}, abstract = {Cardiopulmonary arrest (CPA), the acute cessation of blood flow and ventilation, is fatal if left untreated. Cardiopulmonary resuscitation (CPR) is targeted at restoring oxygen delivery to tissues to mitigate ischemic injury and to provide energy substrate to the tissues in order to achieve return of spontaneous circulation (ROSC). In addition to basic life support (BLS), targeted at replacing the mechanical aspects of circulation and ventilation, adjunctive advanced life support (ALS) interventions, such as intravenous fluid therapy, can improve the likelihood of ROSC depending on the specific characteristics of the patient. In hypovolemic patients with CPA, intravenous fluid boluses to improve preload and cardiac output are likely beneficial, and the use of hypertonic saline may confer additional neuroprotective effects. However, in euvolemic patients, isotonic or hypertonic crystalloid boluses may be detrimental due to decreased tissue blood flow caused by compromised tissue perfusion pressures. Synthetic colloids have not been shown to be beneficial in patients in CPA, and given their documented potential for harm, they are not recommended. Patients with documented electrolyte abnormalities such as hypokalemia or hyperkalemia benefit from therapy targeted at those disturbances, and patients with CPA induced by lipid soluble toxins may benefit from intravenous lipid emulsion therapy. Patients with prolonged CPA that have developed significant acidemia may benefit from intravenous buffer therapy, but patients with acute CPA may be harmed by buffers. In general, ALS fluid therapies should be used only if specific indications are present in the individual patient.}, }
@article {pmid33584177, year = {2020}, author = {Rich, KA and Roggenbuck, J and Kolb, SJ}, title = {Searching Far and Genome-Wide: The Relevance of Association Studies in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {603023}, pmid = {33584177}, issn = {1662-4548}, abstract = {Genome-wide association studies (GWAS) and rare variant association studies (RVAS) are applied across many areas of complex disease to analyze variation in whole genomes of thousands of unrelated patients. These approaches are able to identify variants and/or biological pathways which are associated with disease status and, in contrast to traditional linkage studies or candidate gene approaches, do so without requiring multigenerational affected families, prior hypotheses, or known genes of interest. However, the novel associations identified by these methods typically have lower effect sizes than those found in classical family studies. In the motor neuron disease amyotrophic lateral sclerosis (ALS), GWAS, and RVAS have been used to identify multiple disease-associated genes but have not yet resulted in novel therapeutic interventions. There is significant urgency within the ALS community to identify additional genetic markers of disease to uncover novel biological mechanisms, stratify genetic subgroups of disease, and drive drug development. Given the widespread and increasing application of genetic association studies of complex disease, it is important to recognize the strengths and limitations of these approaches. Here, we review ALS gene discovery via GWAS and RVAS.}, }
@article {pmid33583639, year = {2021}, author = {Rodrigues Lima-Junior, J and Sulzer, D and Lindestam Arlehamn, CS and Sette, A}, title = {The role of immune-mediated alterations and disorders in ALS disease.}, journal = {Human immunology}, volume = {82}, number = {3}, pages = {155-161}, pmid = {33583639}, issn = {1879-1166}, support = {R01 NS095435/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Autoimmunity ; Brain/*pathology ; Humans ; Immunity, Cellular ; Neurogenic Inflammation ; Neuroglia/*immunology ; Neurons/*pathology ; Signal Transduction ; Spinal Cord/*pathology ; T-Lymphocytes/*immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to neuronal death in the brain and spinal cord. Over the last decades, evidence has emerged regarding the functional diversity of astrocytes, microglia, and T cells in the central nervous system (CNS), and the role of neuroinflammation in ALS. In this review, we summarize current knowledge regarding neuroinflammation in ALS, both at the level of specific molecular pathways and potential cellular pathways as well as outline questions about the immune mechanisms involved in ALS pathogenesis.}, }
@article {pmid33581222, year = {2021}, author = {Tucker-Bartley, A and Lemme, J and Gomez-Morad, A and Shah, N and Veliu, M and Birklein, F and Storz, C and Rutkove, S and Kronn, D and Boyce, AM and Kraft, E and Upadhyay, J}, title = {Pain Phenotypes in Rare Musculoskeletal and Neuromuscular Diseases.}, journal = {Neuroscience and biobehavioral reviews}, volume = {124}, number = {}, pages = {267-290}, pmid = {33581222}, issn = {1873-7528}, support = {R21 MH122967/MH/NIMH NIH HHS/United States ; Z99 DE999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Cross-Sectional Studies ; Humans ; *Neuromuscular Diseases/complications/genetics ; Pain ; Phenotype ; Retrospective Studies ; }, abstract = {For patients diagnosed with a rare musculoskeletal or neuromuscular disease, pain may transition from acute to chronic; the latter yielding additional challenges for both patients and care providers. We assessed the present understanding of pain across a set of ten rare, noninfectious, noncancerous disorders; Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Achondroplasia, Fibrodysplasia Ossificans Progressiva, Fibrous Dysplasia/McCune-Albright Syndrome, Complex Regional Pain Syndrome, Duchenne Muscular Dystrophy, Infantile- and Late-Onset Pompe disease, Charcot-Marie-Tooth Disease, and Amyotrophic Lateral Sclerosis. Through the integration of natural history, cross-sectional, retrospective, clinical trials, &amp; case studies we described pathologic and genetic factors, pain sources, phenotypes, and lastly, existing therapeutic approaches. We highlight that while rare diseases possess distinct core pathologic features, there are a number of shared pain phenotypes and mechanisms that may be prospectively examined and therapeutically targeted in a parallel manner. Finally, we describe clinical and research approaches that may facilitate more accurate diagnosis, monitoring, and treatment of pain as well as elucidation of the evolving nature of pain phenotypes in rare musculoskeletal or neuromuscular illnesses.}, }
@article {pmid33575483, year = {2021}, author = {Roggenbuck, J}, title = {C9orf72 and the Care of the Patient With ALS or FTD: Progress and Recommendations After 10 Years.}, journal = {Neurology. Genetics}, volume = {7}, number = {1}, pages = {e542}, pmid = {33575483}, issn = {2376-7839}, abstract = {The 2011 discovery of the pathogenic hexanucleotide repeat expansion (HRE) in C9orf72, the leading genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), marked a breakthrough in the effort to unravel the etiology of these conditions. Ten years later, clinicians are still working to integrate the implications of this discovery into the care of individuals with ALS and/or FTD. Consensus management guidelines for ALS do not comprehensively address the issue of genetic testing, and questions remain about whom to test, what counseling should be provided before and after testing, laboratory methods, and test interpretation. These challenges have contributed to inconsistent clinical practices and present barriers to patients wishing to access testing. This review summarizes the clinical impact of the discovery of the C9orf72 HRE, outlines ongoing challenges, and provides recommendations for C9orf72 testing, counseling, and research.}, }
@article {pmid33575042, year = {2021}, author = {Peters, N and Bello-Haas, VD and Packham, T and Mehdipour, A and Kuspinar, A}, title = {Psychometric Properties of Preference-Based Measures for Economic Evaluation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Neurology research international}, volume = {2021}, number = {}, pages = {6681554}, pmid = {33575042}, issn = {2090-1852}, abstract = {OBJECTIVE: The aim of this review was to synthesize the psychometric properties of generic preference-based measures (PBMs) of health-related quality of life (HRQL) in Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four databases were searched from inception to April 2019: OVID Medline, Embase, PsycINFO, and CINAHL. Studies were included if (1) the sample represented individuals with ALS, (2) a generic PBM was utilized and reported on, and (3) information on the psychometric property of a generic PBM was provided.<br><br>RESULTS: Ninety-one articles were screened, and 39 full-text articles were reviewed. Seven full-text articles were included in this review. The mean age of participants ranged from 58.1 to 63.8 years, and mean time since diagnosis ranged from 20.5 to 44.6 months. Two generic PBMs were found, the EQ-5D-3L (n&#x2009;=&#x2009;6) and the Quality of Well-Being Self-Administered (QWB-SA) scale (n&#x2009;=&#x2009;1). Convergent validity of the EQ-5D-3L was large against a global scale of self-perceived health (r&#x2009;=&#x2009;0.60) and small to large against ALS specific HRQL measures (r&#x2009;=&#x2009;0.19 to 0.75). For the QWB-SA scale, correlations were small against a generic measure (r&#x2009;=&#x2009;0.21) and large against ALS specific measures (r&#x2009;=&#x2009;0.55). The EQ-5D-3L discriminated across different disease severity; however, floor effects were reported.<br><br>CONCLUSION: This review highlights the need for more rigorously designed studies to assess the psychometric properties of generic PBMs in ALS and the development of an ALS specific PBM that adequately reflects the health concerns of individuals with ALS.}, }
@article {pmid33573368, year = {2021}, author = {Behl, T and Kaur, G and Sehgal, A and Bhardwaj, S and Singh, S and Buhas, C and Judea-Pusta, C and Uivarosan, D and Munteanu, MA and Bungau, S}, title = {Multifaceted Role of Matrix Metalloproteinases in Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {22}, number = {3}, pages = {}, pmid = {33573368}, issn = {1422-0067}, mesh = {Animals ; Apoptosis/drug effects/immunology ; Blood-Brain Barrier/drug effects/enzymology/immunology/*pathology ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Inflammation/drug therapy/immunology/pathology ; Matrix Metalloproteinase Inhibitors/pharmacology/*therapeutic use ; Matrix Metalloproteinases/*metabolism ; Microglia/immunology/metabolism/pathology ; Neurodegenerative Diseases/drug therapy/immunology/*pathology ; Neurons/immunology/pathology ; Treatment Outcome ; }, abstract = {Neurodegeneration is the pathological condition, in which the nervous system or neuron loses its structure, function, or both, leading to progressive degeneration or the death of neurons, and well-defined associations of tissue system, resulting in clinical manifestations. Neuroinflammation has been shown to precede neurodegeneration in several neurodegenerative diseases (NDs). No drug is yet known to delay or treat neurodegeneration. Although the etiology and potential causes of NDs remain widely indefinable, matrix metalloproteinases (MMPs) evidently have a crucial role in the progression of NDs. MMPs, a protein family of zinc (Zn[2+])-containing endopeptidases, are pivotal agents that are involved in various biological and pathological processes in the central nervous system (CNS). The current review delineates the several emerging evidence demonstrating the effects of MMPs in the progression of NDs, wherein they regulate several processes, such as (neuro)inflammation, microglial activation, amyloid peptide degradation, blood brain barrier (BBB) disruption, dopaminergic apoptosis, and α-synuclein modulation, leading to neurotoxicity and neuron death. Published papers to date were searched via PubMed, MEDLINE, etc., while using selective keywords highlighted in our manuscript. We also aim to shed a light on pathophysiological effect of MMPs in the CNS and focus our attention on its detrimental and beneficial effects in NDs, with a special focus on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), and Huntington's disease (HD), and discussed various therapeutic strategies targeting MMPs, which could serve as potential modulators in NDs. Over time, several agents have been developed in order to overcome challenges and open up the possibilities for making selective modulators of MMPs to decipher the multifaceted functions of MMPs in NDs. There is still a greater need to explore them in clinics.}, }
@article {pmid33571705, year = {2021}, author = {Calabrese, EJ and Calabrese, V and Giordano, J}, title = {Demonstrated hormetic mechanisms putatively subserve riluzole-induced effects in neuroprotection against amyotrophic lateral sclerosis (ALS): Implications for research and clinical practice.}, journal = {Ageing research reviews}, volume = {67}, number = {}, pages = {101273}, doi = {10.1016/j.arr.2021.101273}, pmid = {33571705}, issn = {1872-9649}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Neuroprotection ; *Neuroprotective Agents/pharmacology ; Riluzole/pharmacology ; }, abstract = {This paper provides evidence to support that riluzole, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), like many neuroprotective agents, displays and exerts hormetic biphasic dose responses. These findings have important implications for the experimental study and clinical treatment of ALS.}, }
@article {pmid33557726, year = {2021}, author = {Yadav, RK and Minz, E and Mehan, S}, title = {Understanding Abnormal c-JNK/p38MAPK Signaling in Amyotrophic Lateral Sclerosis: Potential Drug Targets and Influences on Neurological Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {20}, number = {5}, pages = {417-429}, doi = {10.2174/1871527320666210126113848}, pmid = {33557726}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System ; Motor Neurons/metabolism ; Nerve Degeneration/metabolism ; Phosphorylation ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to regulate neuronal signals. The abnormal activation of these cellular signals can cause glutamate excitotoxicity, disrupted protein homeostasis, defective axonal transport, and synaptic dysfunction. Various pre-clinical and clinical findings indicate that the up-regulation of c-JNK and p38MAPK signaling is associated with neurological disorders. Exceptionally, a significant amount of experimental data has recently shown that dysregulated c-JNK and p38MAPK are implicated in the damage to the central nervous system, including amyotrophic lateral sclerosis. Furthermore, currently available information has shown that c- JNK/p38MAPK signaling inhibitors may be a promising therapeutic alternative for improving histopathological, functional, and demyelination defects related to motor neuron disabilities. Understanding the abnormal activation of c-JNK/p38MAPK signaling and the prediction of motor neuron loss may help identify important therapeutic interventions that could prevent neurocomplications. Based on the involvement of c-JNK/p38MAPK signaling in the brain, we have assumed that the downregulation of the c-JNK/p38MAPK signaling pathway could trigger neuroprotection and neurotrophic effects towards clinicopathological presentations of ALS and other brain diseases. Thus, this research-based review also outlines the inhibition of c-JNK and p38MAPK signal downregulation in the pursuit of disease-modifying therapies for ALS.}, }
@article {pmid33557137, year = {2021}, author = {Bailes, J and Soloviev, M}, title = {Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports.}, journal = {Biomolecules}, volume = {11}, number = {2}, pages = {}, pmid = {33557137}, issn = {2218-273X}, mesh = {Animals ; *Apoptosis ; Biomarkers/metabolism ; Cell Differentiation ; Cell Proliferation ; Doping in Sports ; Growth Hormone/*metabolism ; Humans ; Insulin/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Intercellular Signaling Peptides and Proteins/metabolism ; Mice ; Neoplasms/metabolism ; Peptides/chemistry ; Performance-Enhancing Substances/pharmacology ; Protein Binding ; Receptor, IGF Type 1/metabolism ; Recombinant Proteins/chemistry ; Substance Abuse Detection/*methods ; }, abstract = {Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R). The six IGFBPs serve as carrier proteins and bind approximately 98% of all circulating IGF-1. Other proteins known to bind IGF-1 include ten IGFBP-related proteins (IGFBP-rPs), albeit with lower affinities than the IGFBPs. IGF-1 expression levels vary in a number of clinical conditions suggesting it has the potential to provide crucial information as to the state of an individual's health. IGF-1 is also a popular doping agent in sport and has featured in many high-profile doping cases in recent years. However, the existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicates interpretation of IGF-1 assay results. Here we provide an overview of the IGF network of growth factors, their receptors and the entirety of the extended family of IGFBPs, IGFBP-rPs, E peptides as well as recombinant IGF-1 and their derivatives. We also discuss issues related to the detection and quantification of bioavailable IGF-1.}, }
@article {pmid33556422, year = {2021}, author = {Kuzovlev, A and Monsieurs, KG and Gilfoyle, E and Finn, J and Greif, R and , }, title = {The effect of team and leadership training of advanced life support providers on patient outcomes: A systematic review.}, journal = {Resuscitation}, volume = {160}, number = {}, pages = {126-139}, doi = {10.1016/j.resuscitation.2021.01.020}, pmid = {33556422}, issn = {1873-1570}, mesh = {Adult ; Child ; Clinical Competence ; Health Personnel/education ; Humans ; *Leadership ; Randomized Controlled Trials as Topic ; *Resuscitation ; }, abstract = {AIM: To conduct a systematic review evaluating improvement in team and leadership performance and resuscitation outcomes after such a training of healthcare providers during advanced life support (ALS) courses.<br><br>METHODS: This systematic review asked the question of whether students taking structured and standardised ALS courses in an educational setting which include specific leadership or team training, compared to no such specific training in these courses, improves patient survival, skill performance in actual resuscitations, skill performance at 3-15 months (patient tasks, teamwork, leadership), skill performance at course conclusion (patient tasks, teamwork, leadership), or cognitive knowledge PubMed, Embase and the Cochrane database were searched until April 2020. Screening of articles, analysis of risk of bias, outcomes and quality assessment were performed according to the Grading of Recommendations Assessment, Development and Evaluation methodology. Only studies with abstracts in English were included.<br><br>RESULTS: 14 non-randomised studies and 17 randomised controlled trials, both in adults and children, and seven studies involving patients were included in this systematic review. No randomised controlled trials but three observational studies of team and leadership training showed improvement in the critical outcome of "patient survival". However, they suffered from risk of bias (indirectness and imprecision). The included studies reported many different methods to teach leadership skills and team behaviour.<br><br>CONCLUSION: This systematic review found very low certainty evidence that team and leadership training as part of ALS courses improved patient outcome. This supports the inclusion of team and leadership training in ALS courses for healthcare providers.}, }
@article {pmid33555628, year = {2021}, author = {Oh, J and An, J and Park, K}, title = {Coping in people with amyotrophic lateral sclerosis and motor neuron disease: Systematic review.}, journal = {Journal of clinical nursing}, volume = {30}, number = {13-14}, pages = {1838-1853}, doi = {10.1111/jocn.15692}, pmid = {33555628}, issn = {1365-2702}, support = {Dankook University in 2020//Dankook University/ ; }, mesh = {Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis ; Female ; Humans ; *Motor Neuron Disease ; Quality of Life ; Social Support ; }, abstract = {AIMS AND OBJECTIVES: To systematically review previous studies on the variables associated with coping strategies in people with amyotrophic lateral sclerosis and motor neuron disease (ALS/MND), such as demographics, clinical features and patient-reported outcomes.<br><br>BACKGROUND: Coping strategies are important factors for adjustment and quality of life (QOL) in patients with long-term conditions, and this topic in people with ALS/MND has not yet been the subject of a systematic review.<br><br>DESIGN: A systematic review was performed based on the PRISMA checklist.<br><br>METHODS: Electronic databases, including CINAHL, MEDLINE and EMBASE, were systemically searched from their inception to December 2019 for articles meeting the following inclusion criteria: (1) written in English, (2) published in peer-reviewed journals, (3) included subjects with ALS/MND and (4) used quantitative measurements of coping strategies in people with ALS/MND.<br><br>RESULTS: Twenty-one articles were included. Significant relationships between participants' demographics (age and sex) and any coping strategy aspect were shown in six studies. Eight studies found significant relationships between clinical characteristics (disease duration and physical functional status) and coping strategies, and ten studies reported coping strategies that were associated with patients' QOL and mental health outcomes.<br><br>CONCLUSION: Younger people used relatively more problem-focused, emotion-focused and social support coping strategies, and women used relatively more social support coping strategies. Problem-focused coping was generally related to better QOL and mental health, and emotion-focused coping was generally related to less depression.<br><br>As the pattern of coping strategies is related to demographic and clinical characteristics, this study could be used to inform the provision of patient-centred nursing in clinical care. Coping patterns are related to mental health and QOL; thus, in clinical care, it is recommended that people with ALS be encouraged to develop skills that enable them to cope more effectively and that their coping strategies be assessed.}, }
@article {pmid33546507, year = {2021}, author = {De-Bernardi-Ojuel, L and Torres-Collado, L and García-de-la-Hera, M}, title = {Occupational Therapy Interventions in Adults with Multiple Sclerosis or Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {International journal of environmental research and public health}, volume = {18}, number = {4}, pages = {}, pmid = {33546507}, issn = {1660-4601}, mesh = {Adolescent ; Adult ; *Amyotrophic Lateral Sclerosis/therapy ; Fatigue/etiology/therapy ; Humans ; *Multiple Sclerosis/therapy ; *Occupational Therapy ; Quality of Life ; }, abstract = {This scoping review aims to describe occupational therapy interventions carried out with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) patients in occupational therapy. A peer review of the literature was conducted in different databases: Pubmed, Scopus, Web of Science and Embase, and in some occupational therapy journals. A search of the literature published was carried out before December 2019. The inclusion criteria were as follows: (1) articles evaluating the intervention of occupational therapy in MS or ALS including experimental, randomized, nonrandomized and exploratory studies; (2) written in English or Spanish; (3) adult population (over 18 years old). The initial search identified 836 articles of which we included 32 divided into four areas of intervention: fatigue-targeted interventions, cognitive interventions, physical interventions and others. Only 16 studies were carried out exclusively by occupational therapists. Most occupational therapy interventions are aimed at fatigue and physical rehabilitation. The majority of the studies in our review included MS patients, with little representation from the ALS population. These interventions have shown an improvement in perceived fatigue, manual dexterity, falls prevention and improvement in cognitive aspects such as memory, communication, depression and quality of life in the MS and ALS populations.}, }
@article {pmid33546471, year = {2021}, author = {Woo, J and Cho, H and Seol, Y and Kim, SH and Park, C and Yousefian-Jazi, A and Hyeon, SJ and Lee, J and Ryu, H}, title = {Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33546471}, issn = {2076-3921}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; }, abstract = {The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5'-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration.}, }
@article {pmid33546386, year = {2021}, author = {Štětkářová, I and Ehler, E}, title = {Diagnostics of Amyotrophic Lateral Sclerosis: Up to Date.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {33546386}, issn = {2075-4418}, support = {Progres Q35//Univerzita Karlova v Praze/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by gradual loss of upper and lower motor neurons and their pathways, usually without affecting the extraocular and sphincter muscles. The cause of the disease is not yet known. It is a chain of subsequent events, ending in programmed cell death in selective neuronal subpopulations. The prognosis for survival is rather short with a median of 2 to 4 years. Survival may be prolonged based on prompt diagnosis, ALS subtype and proper management with supportive treatment (tracheostomy, gastrostomy, etc.). According to the clinical picture, the typical form of ALS with upper and lower motoneuron involvement and progressive bulbar paralysis with bulbar muscle involvement is observed. The ALS form with progressive muscle atrophy, where only the lower motoneuron is affected, and primary lateral sclerosis with only upper motoneuron damage are rare. Familiar forms of ALS (FALS) associated with specific genes (the most common is C9orf72) have been discovered. FALS is usually associated with dementia (frontotemporal lobar dementia, FTLD), behavioral disorders, cognitive dysfunction and impairment of executive functions. The diagnosis of ALS is determined by excluding other conditions and utilizing clinical examinations, laboratory and genetic tests and nerve conduction/needle electromyography studies (EMG). Needle EMG records abnormal activities at rest and looks for neurogenic patterns during muscle contraction. Motor evoked potentials after transcranial magnetic stimulation remain the test of choice to identify impairment of upper motor neurons. New biochemical, neurophysiological and morphological biomarkers are extensively studied as early diagnostic and prognostic factors and have implications for clinical trials, research and drug development.}, }
@article {pmid33545661, year = {2021}, author = {Tahir, MS and Almezgagi, M and Zhang, Y and Bashir, A and Abdullah, HM and Gamah, M and Wang, X and Zhu, Q and Shen, X and Ma, Q and Ali, M and Solangi, ZA and Malik, WS and Zhang, W}, title = {Mechanistic new insights of flavonols on neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {137}, number = {}, pages = {111253}, doi = {10.1016/j.biopha.2021.111253}, pmid = {33545661}, issn = {1950-6007}, mesh = {Animals ; Brain/*drug effects/metabolism/pathology ; Cognition/drug effects ; Drug Compounding ; Flavonols/adverse effects/*therapeutic use ; Humans ; Nanoparticles ; *Nerve Degeneration ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology/psychology ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/adverse effects/*therapeutic use ; }, abstract = {With a large and increasing elderly population, neurodegenerative diseases such as Parkinson's disease (PD), Huntington disease (HD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and Multiple sclerosis (MS) have become a major and growing health problem. During the past few decades, the elderly population has grown 2.5 % every year. Unfortunately, there are no specific therapeutic remedies available to slow the onset or development of these diseases. An aging brain causes many pathophysiological changes and is the major risk factor for most of the neurodegenerative disorders. Polyphenolic compounds such as flavonols have shown therapeutic potential and can contribute to the treatment of these diseases. In this review, evidence for the beneficial neuroprotective effect of multiple flavonols is discussed and their multifactorial cellular pathways for the progressions of age-associated brain changes are identified. Moreover, the animal models of these diseases support the neuroprotective effect and target the potential of flavonols in the treatment of neurodegenerative diseases.}, }
@article {pmid33544228, year = {2021}, author = {Vasta, R and D'Ovidio, F and Logroscino, G and Chiò, A}, title = {The links between diabetes mellitus and amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {4}, pages = {1377-1387}, pmid = {33544228}, issn = {1590-3478}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Body Mass Index ; *Cardiovascular Diseases ; *Diabetes Mellitus/epidemiology ; Humans ; Prognosis ; }, abstract = {ALS etiology and prognostic factors are mostly unknown. Metabolic diseases and especially diabetes mellitus (DM) have been variously related to ALS. However, pieces of evidence have been variegated and often conflicting so far. This review aims to give an overview of recent contributions focusing on the relationship between DM and ALS. DM seems to reduce the risk of developing ALS if diagnosed at a younger age; conversely, when diagnosed at an older age, DM seems protective against ALS. Such a relationship was not confirmed in Asian countries where DM increases the risk of ALS independently of the age of onset. Interestingly, DM does not affect ALS prognosis, possibly weakening the potential causal relationship between the two diseases. However, since most studies are observational, it is difficult to state the exact nature of such a relationship and several hypotheses have been made. A recent study using Mendelian randomization suggested that DM is indeed protective against ALS in the European population. However, these analyses are not without limits and further evidence is needed. DM is usually the core of a larger metabolic syndrome. Thus, other metabolic changes such as dyslipidemia, body mass index, and cardiovascular diseases should be collectively considered. Finally, hypermetabolism usually found in ALS patients should be considered too since all these metabolic changes could be compensation (or the cause) of the higher energy expenditure.}, }
@article {pmid33543942, year = {2021}, author = {Nguyen, PH and Ramamoorthy, A and Sahoo, BR and Zheng, J and Faller, P and Straub, JE and Dominguez, L and Shea, JE and Dokholyan, NV and De Simone, A and Ma, B and Nussinov, R and Najafi, S and Ngo, ST and Loquet, A and Chiricotto, M and Ganguly, P and McCarty, J and Li, MS and Hall, C and Wang, Y and Miller, Y and Melchionna, S and Habenstein, B and Timr, S and Chen, J and Hnath, B and Strodel, B and Kayed, R and Lesné, S and Wei, G and Sterpone, F and Doig, AJ and Derreumaux, P}, title = {Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.}, journal = {Chemical reviews}, volume = {121}, number = {4}, pages = {2545-2647}, pmid = {33543942}, issn = {1520-6890}, support = {R01 AG054025/AG/NIA NIH HHS/United States ; R56 NS113549/NS/NINDS NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; R35 GM134864/GM/NIGMS NIH HHS/United States ; R01 AG020135/AG/NIA NIH HHS/United States ; RF1 AG044342/AG/NIA NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; R01 NS094557/NS/NINDS NIH HHS/United States ; R01 GM107703/GM/NIGMS NIH HHS/United States ; R01 AG048934/AG/NIA NIH HHS/United States ; R01 NS092918/NS/NINDS NIH HHS/United States ; R21 AG065693/AG/NIA NIH HHS/United States ; R01 GM118560/GM/NIGMS NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid/*chemistry/*metabolism ; Amyloid beta-Peptides/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Diabetes Mellitus, Type 2/metabolism/pathology ; Humans ; Islet Amyloid Polypeptide/chemistry/metabolism ; Models, Molecular ; Neurodegenerative Diseases/*metabolism/pathology ; Parkinson Disease/metabolism/pathology ; Protein Aggregation, Pathological ; Proteostasis Deficiencies/metabolism ; Superoxide Dismutase-1/chemistry/metabolism ; alpha-Synuclein/chemistry/metabolism ; tau Proteins/chemistry/metabolism ; }, abstract = {Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.}, }
@article {pmid33538206, year = {2021}, author = {Jiang, Y and Jiao, B and Xiao, X and Shen, L}, title = {Genetics of frontotemporal dementia in China.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {5-6}, pages = {321-335}, doi = {10.1080/21678421.2021.1880596}, pmid = {33538206}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis ; China/epidemiology ; *Frontotemporal Dementia/epidemiology/genetics ; *Frontotemporal Lobar Degeneration ; Humans ; Mutation/genetics ; }, abstract = {Backgbround: Frontotemporal dementia (FTD) is the second most common presenile dementia, characterized by prominent behavioral, language, and cognitive impairment, which has a strong genetic component contributing to its pathogenesis. Due to geographical and ethnic variability, the prevalence of the causative genes of FTD may be different. Methods: To explore the genetics of FTD in the Chinese population, we reviewed 97 closely related studies that were searched in PubMed and Web of Science. In this review, we summarized the characteristics of each FTD gene. We also reassessed their pathogenicity and revised some mutations from pathogenic to uncertain significance according to the American College of Medical Genetics and Genomics (ACMG). Results: Thirty-two rare variants in genes of MAPT, GRN, C9orf72, CHCHD10, VCP, and TBK1 were identified in Chinese FTD populations, including 25 pathogenic mutations and seven variants of uncertain significance (VUS). Among them, the frequency of rare variants in the CHCHD10 gene was the highest. Surprisingly, twelve variants reported as pathogenic mutations were revised as VUS by ACMG. The correlations between genes and clinical manifestations were MAPT and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), GRN and frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), C9orf72/CHCHD10/TBK1 and amyotrophic lateral sclerosis (ALS)-FTD spectrum, and VCP corresponds inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). Conclusions: It is necessary to strictly interpret the contributions of genes to diseases by ACMG. MAPT is the most common pathogenic gene for FTD in China.}, }
@article {pmid33530383, year = {2021}, author = {Ortega-Hombrados, L and Molina-Torres, G and Galán-Mercant, A and Sánchez-Guerrero, E and González-Sánchez, M and Ruiz-Muñoz, M}, title = {Systematic Review of Therapeutic Physical Exercise in Patients with Amyotrophic Lateral Sclerosis over Time.}, journal = {International journal of environmental research and public health}, volume = {18}, number = {3}, pages = {}, pmid = {33530383}, issn = {1660-4601}, mesh = {Activities of Daily Living ; *Amyotrophic Lateral Sclerosis/therapy ; Exercise ; Exercise Therapy ; Humans ; Physical Therapy Modalities ; }, abstract = {BACKGROUND: the main objective of this study was to analyze the potential short-, medium- and long-term effects of a therapeutic physical exercise (TFE) programme on the functionality of amyotrophic lateral sclerosis (ALS) patients, measured with the Revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R) scale.<br><br>METHODS: a systematic review of the PubMed, SCOPUS, Cochrane, Scientific Electronic Library Online (Scielo), Physiotherapy Evidence Database (PEDro), Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Medical Literature Analysis and Retrieval System Online (MEDline) databases was carried out. The information was filtered using the following Medical Subjects Heading (MeSH) terms: "Amyotrophic lateral sclerosis", "Physical Therapy", and "Physical and Rehabilitation Medicine". The internal validity of the selected documents was evaluated using the PEDro scale. The study included clinical trials published in the last 5 years in which one of the interventions was therapeutic physical exercise in patients with ALS, using the ALSFRS-R as the main outcome variable and functional variables as secondary variables.<br><br>RESULTS: 10 clinical trials were analyzed, with an internal validity of 5-7 points. The TFE groups showed significant short-, medium- and long-term differences, obtaining a mean difference of 5.8 points compared to the 7.6 points obtained by the control groups, at six months, measured with ALSFRS-R. In addition, the participants showed significant improvements in functional abilities in the short, medium and long terms.<br><br>CONCLUSIONS: Therapeutic physical exercise could contribute to slowing down the deterioration of the musculature of patients with ALS, thus facilitating their performance in activities of daily living, based on the significant differences shown by these individuals in the short, medium and long term both in subjective perception, measured with ALSFRS-R, and functional capacities.}, }
@article {pmid33527218, year = {2021}, author = {Nguyen, H and Zerimech, S and Baltan, S}, title = {Astrocyte Mitochondria in White-Matter Injury.}, journal = {Neurochemical research}, volume = {46}, number = {10}, pages = {2696-2714}, pmid = {33527218}, issn = {1573-6903}, support = {R01 AG033720/AG/NIA NIH HHS/United States ; NS094881/NS/NINDS NIH HHS/United States ; AG033720/AG/NIA NIH HHS/United States ; AG033720/AG/NIA NIH HHS/United States ; NS094881/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*metabolism ; Brain Diseases/*metabolism ; Humans ; Mitochondria/*metabolism ; Neurons/metabolism ; White Matter/*metabolism ; }, abstract = {This review summarizes the diverse structure and function of astrocytes to describe the bioenergetic versatility required of astrocytes that are situated at different locations. The intercellular domain of astrocyte mitochondria defines their roles in supporting and regulating astrocyte-neuron coupling and survival against ischemia. The heterogeneity of astrocyte mitochondria, and how subpopulations of astrocyte mitochondria adapt to interact with other glia and regulate axon function, require further investigation. It has become clear that mitochondrial permeability transition pores play a key role in a wide variety of human diseases, whose common pathology may be based on mitochondrial dysfunction triggered by Ca[2+] and potentiated by oxidative stress. Reactive oxygen species cause axonal degeneration and a reduction in axonal transport, leading to axonal dystrophies and neurodegeneration including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Developing new tools to allow better investigation of mitochondrial structure and function in astrocytes, and techniques to specifically target astrocyte mitochondria, can help to unravel the role of mitochondrial health and dysfunction in a more inclusive context outside of neuronal cells. Overall, this review will assess the value of astrocyte mitochondria as a therapeutic target to mitigate acute and chronic injury in the CNS.}, }
@article {pmid33525344, year = {2021}, author = {Ghasemi, M and Keyhanian, K and Douthwright, C}, title = {Glial Cell Dysfunction in C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Cells}, volume = {10}, number = {2}, pages = {}, pmid = {33525344}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; C9orf72 Protein/*metabolism ; Frontotemporal Dementia/genetics/*pathology/therapy ; Humans ; Inflammation/pathology ; Mutation/genetics ; Neuroglia/metabolism/*pathology ; }, abstract = {Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested-(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.}, }
@article {pmid33516810, year = {2021}, author = {Acioglu, C and Li, L and Elkabes, S}, title = {Contribution of astrocytes to neuropathology of neurodegenerative diseases.}, journal = {Brain research}, volume = {1758}, number = {}, pages = {147291}, doi = {10.1016/j.brainres.2021.147291}, pmid = {33516810}, issn = {1872-6240}, mesh = {Animals ; Astrocytes/*pathology ; Humans ; Neurodegenerative Diseases/*pathology ; }, abstract = {Classically, the loss of vulnerable neuronal populations in neurodegenerative diseases was considered to be the consequence of cell autonomous degeneration of neurons. However, progress in the understanding of glial function, the availability of improved animal models recapitulating the features of the human diseases, and the development of new approaches to derive glia and neurons from induced pluripotent stem cells obtained from patients, provided novel information that altered this view. Current evidence strongly supports the notion that non-cell autonomous mechanisms contribute to the demise of neurons in neurodegenerative disorders, and glia causally participate in the pathogenesis and progression of these diseases. In addition to microglia, astrocytes have emerged as key players in neurodegenerative diseases and will be the focus of the present review. Under the influence of pathological stimuli present in the microenvironment of the diseased CNS, astrocytes undergo morphological, transcriptional, and functional changes and become reactive. Reactive astrocytes are heterogeneous and exhibit neurotoxic (A1) or neuroprotective (A2) phenotypes. In recent years, single-cell or single-nucleus transcriptome analyses unraveled new, disease-specific phenotypes beyond A1/A2. These investigations highlighted the complexity of the astrocytic responses to CNS pathology. The present review will discuss the contribution of astrocytes to neurodegenerative diseases with particular emphasis on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Some of the commonalties and differences in astrocyte-mediated mechanisms that possibly drive the pathogenesis or progression of the diseases will be summarized. The emerging view is that astrocytes are potential new targets for therapeutic interventions. A comprehensive understanding of astrocyte heterogeneity and disease-specific phenotypic complexity could facilitate the design of novel strategies to treat neurodegenerative disorders.}, }
@article {pmid33514916, year = {2021}, author = {Niesler, B and Kuerten, S and Demir, IE and Schäfer, KH}, title = {Disorders of the enteric nervous system - a holistic view.}, journal = {Nature reviews. Gastroenterology &amp; hepatology}, volume = {18}, number = {6}, pages = {393-410}, pmid = {33514916}, issn = {1759-5053}, mesh = {Colorectal Neoplasms/physiopathology ; Diabetes Mellitus/physiopathology ; Diet ; Enteric Nervous System/embryology/*physiopathology ; Esophageal Achalasia/genetics/physiopathology ; Gastric Mucosa/physiology ; Gastrointestinal Microbiome/physiology ; Hirschsprung Disease/genetics/physiopathology ; Humans ; Inflammatory Bowel Diseases/genetics/physiopathology ; Neurodegenerative Diseases/genetics/physiopathology ; }, abstract = {The enteric nervous system (ENS) is the largest division of the peripheral nervous system and closely resembles components and functions of the central nervous system. Although the central role of the ENS in congenital enteric neuropathic disorders, including Hirschsprung disease and inflammatory and functional bowel diseases, is well acknowledged, its role in systemic diseases is less understood. Evidence of a disordered ENS has accumulated in neurodegenerative diseases ranging from amyotrophic lateral sclerosis, Alzheimer disease and multiple sclerosis to Parkinson disease as well as neurodevelopmental disorders such as autism. The ENS is a key modulator of gut barrier function and a regulator of enteric homeostasis. A 'leaky gut' represents the gateway for bacterial and toxin translocation that might initiate downstream processes. Data indicate that changes in the gut microbiome acting in concert with the individual genetic background can modify the ENS, central nervous system and the immune system, impair barrier function, and contribute to various disorders such as irritable bowel syndrome, inflammatory bowel disease or neurodegeneration. Here, we summarize the current knowledge on the role of the ENS in gastrointestinal and systemic diseases, highlighting its interaction with various key players involved in shaping the phenotypes. Finally, current flaws and pitfalls related to ENS research in addition to future perspectives are also addressed.}, }
@article {pmid33513942, year = {2021}, author = {Fomicheva, A and Ross, ED}, title = {From Prions to Stress Granules: Defining the Compositional Features of Prion-Like Domains That Promote Different Types of Assemblies.}, journal = {International journal of molecular sciences}, volume = {22}, number = {3}, pages = {}, pmid = {33513942}, issn = {1422-0067}, support = {R35 GM130352/GM/NIGMS NIH HHS/United States ; R35GM130352/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Cytoplasmic Granules/*genetics/ultrastructure ; Frontotemporal Dementia/genetics/pathology ; Humans ; Neurodegenerative Diseases/genetics/pathology ; Organelles/*genetics/ultrastructure ; Prion Proteins/*genetics/ultrastructure ; Prions/*genetics/ultrastructure ; Protein Domains/genetics ; Proteome/genetics ; RNA-Binding Proteins ; Saccharomyces cerevisiae/genetics ; }, abstract = {Stress granules are ribonucleoprotein assemblies that form in response to cellular stress. Many of the RNA-binding proteins found in stress granule proteomes contain prion-like domains (PrLDs), which are low-complexity sequences that compositionally resemble yeast prion domains. Mutations in some of these PrLDs have been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia, and are associated with persistent stress granule accumulation. While both stress granules and prions are macromolecular assemblies, they differ in both their physical properties and complexity. Prion aggregates are highly stable homopolymeric solids, while stress granules are complex dynamic biomolecular condensates driven by multivalent homotypic and heterotypic interactions. Here, we use stress granules and yeast prions as a paradigm to examine how distinct sequence and compositional features of PrLDs contribute to different types of PrLD-containing assemblies.}, }
@article {pmid33512025, year = {2021}, author = {Ngo, ST and Wang, H and Henderson, RD and Bowers, C and Steyn, FJ}, title = {Ghrelin as a treatment for amyotrophic lateral sclerosis.}, journal = {Journal of neuroendocrinology}, volume = {33}, number = {7}, pages = {e12938}, doi = {10.1111/jne.12938}, pmid = {33512025}, issn = {1365-2826}, support = {//FightMND Mid-career Fellowship/ ; //Australian Institute for Bioengineering and Nanotechnology (AIBN) at the University of Queensland/ ; }, abstract = {Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider-ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin-mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide-ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease-relevant processes observed in ALS. Expanding on the well-known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin-mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin-like growth factor-1 (IGF-1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF-1 are associated with faster disease progression and worse disease outcome in patients with ALS.}, }
@article {pmid33510061, year = {2021}, author = {Xu, RS and Yuan, M}, title = {Considerations on the concept, definition, and diagnosis of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {16}, number = {9}, pages = {1723-1729}, pmid = {33510061}, issn = {1673-5374}, abstract = {The concept, definition, and diagnosis of amyotrophic lateral sclerosis (ALS) currently present some problems. This article systematically reviews the literature on the history, current concepts, definition, and diagnosis of ALS, and discloses the present problems based on the retrieved literature and the authors' clinical experience. The current concepts and definitions of ALS have not yet been unified or standardized in clinical practice, and are sometimes vague or inaccurate, which can cause difficulties for neurologists in the clinical treatment of ALS. The concept and definition of ALS need to be further ascertained, and the current diagnostic criteria for ALS require further development. The identification of effective and objective biomarkers may be a feasible method for the early and accurate diagnosis of ALS. Therefore, future research should focus on the identification of reliable biomarkers-especially neuroimaging biomarkers-through autopsy. Standardizing the concept and definition of ALS and formulating clear diagnostic criteria will largely avoid many uncertainties in the future clinical research and treatment of ALS, which will greatly benefit patients.}, }
@article {pmid33498503, year = {2021}, author = {Devi, S and Kumar, V and Singh, SK and Dubey, AK and Kim, JJ}, title = {Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {9}, number = {2}, pages = {}, pmid = {33498503}, issn = {2227-9059}, abstract = {Neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.}, }
@article {pmid33498186, year = {2021}, author = {Cihankaya, H and Theiss, C and Matschke, V}, title = {Little Helpers or Mean Rogue-Role of Microglia in Animal Models of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {3}, pages = {}, pmid = {33498186}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Disease Models, Animal ; Mice ; Microglia/*metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; Vesicular Transport Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, causing degeneration of both upper and lower motor neurons in the central nervous system (CNS). ALS patients suffer from hyperreflexia, spasticity, paralysis and muscle atrophy and typically die due to respiratory failure 1-5 years after disease onset. In addition to the degeneration of motor neurons on the cellular level, ALS has been associated with neuroinflammation, such as microgliosis. Microglial activation in ALS can either be protective or degenerative to the neurons. Among others, mutations in superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9Orf72), transactive response DNA binding protein (TDP) 43 and vacuolar protein sorting-associated protein 54 (VPS54) genes have been associated with ALS. Here, we describe the dual role and functionality of microglia in four different in vivo ALS models and search for the lowest common denominator with respect to the role of microglia in the highly heterogeneous disease of ALS.}, }
@article {pmid33495544, year = {2021}, author = {de Rus Jacquet, A and Denis, HL and Cicchetti, F and Alpaugh, M}, title = {Current and future applications of induced pluripotent stem cell-based models to study pathological proteins in neurodegenerative disorders.}, journal = {Molecular psychiatry}, volume = {26}, number = {7}, pages = {2685-2706}, pmid = {33495544}, issn = {1476-5578}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Huntington Disease ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Neurons ; *Prions ; }, abstract = {Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer's, Parkinson's, and Huntington's diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.}, }
@article {pmid33488352, year = {2020}, author = {Tran, M and Reddy, PH}, title = {Defective Autophagy and Mitophagy in Aging and Alzheimer's Disease.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {612757}, pmid = {33488352}, issn = {1662-4548}, abstract = {Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer's disease (AD), Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.}, }
@article {pmid33486755, year = {2021}, author = {Rodríguez-Cueto, C and García-Toscano, L and Santos-García, I and Gómez-Almería, M and Gonzalo-Consuegra, C and Espejo-Porras, F and Fernández-Ruiz, J and de Lago, E}, title = {Targeting the CB2 receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1373-1387}, doi = {10.1111/bph.15386}, pmid = {33486755}, issn = {1476-5381}, support = {ELA-Madrid (B2017/BMD-3813)//Comunidad de Madrid/ ; CB06/05/0089//CIBERNED, Instituto de Salud Carlos III/ ; RTI2018-098885-B-100//Ministerio de Ciencia e Innovaci&#xf3;n/ ; //GW Pharmaceuticals/ ; //Emerald Health Pharmaceuticals/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; *Cannabinoids/therapeutic use ; Disease Progression ; Endocannabinoids ; Humans ; Motor Neurons ; Receptor, Cannabinoid, CB1 ; Receptor, Cannabinoid, CB2 ; }, abstract = {Cannabinoids form a singular group of plant-derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic events that kill neurons in neurodegenerative disorders. In this review, we will address the potential of cannabinoids as neuroprotective agents in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder characterized by muscle denervation, atrophy and paralysis, and progressive deterioration in upper and/or lower motor neurons. The emphasis will be paid on the cannabinoid type 2 (CB2) receptor, whose activation limits glial reactivity, but the potential of additional endocannabinoid-related targets will be also addressed. The evidence accumulated so far at the preclinical level supports the need to soon move towards the patients and initiate clinical trials to confirm the potential of cannabinoid-based medicines as disease modifiers in ALS. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid33480168, year = {2021}, author = {Sharp, G and Steffens, D and Koh, CE}, title = {Evidence of negative pressure therapy for anastomotic leak: a systematic review.}, journal = {ANZ journal of surgery}, volume = {91}, number = {4}, pages = {537-545}, doi = {10.1111/ans.16581}, pmid = {33480168}, issn = {1445-2197}, mesh = {Anastomosis, Surgical/adverse effects ; *Anastomotic Leak/therapy ; Endoscopy ; Humans ; *Negative-Pressure Wound Therapy ; Rectum/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Anastomotic leak (AL) is a devastating complication. Several new treatment options are available, endoluminal negative pressure therapy is one. The aims of this systematic review are; to report success rates and stoma closure rates following endoluminal negative pressure therapy in colorectal AL patients.<br><br>METHODS: A systematic review of MEDLINE, PubMed, Cochrane and Embase databases from inception to June 2018. Search limits were; English language, humans, sample >5 and >18&#x2009;years. Search terms were Endospong* OR Endo-spong* OR Endo spong* OR Endoluminal negative pressure OR Endoluninal vac* OR Vacuum assisted OR negative pressure. Combined with colon OR rectum OR colorect* AND anastomotic leak OR leak*.<br><br>RESULTS: Twenty articles met inclusion criteria. There were 334 patients. Reported success rates ranged from 60% to 100%. However, success definition varied considerably. The most widely used definition was endoscopic assessment of residual cavity size, but this also varied from 0.5 cm to 3 cm. Stoma closure rates were only reported in 11 studies and ranged from 31% to 100%. Complication rates were reported in 13 studies (65%). The most common was on-going sepsis.<br><br>CONCLUSIONS: Included studies suggest that 60-100% of ALs heal with endoluminal negative pressure therapy. However, results from this review need to be interpreted with caution because of the variable definition of success. A more objective assessment of success may be stoma closure but this is only reported in 60% of studies. Further studies are needed to assess the benefit of negative pressure therapy in anastomotic leaks.}, }
@article {pmid33477509, year = {2021}, author = {Layalle, S and They, L and Ourghani, S and Raoul, C and Soustelle, L}, title = {Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33477509}, issn = {1422-0067}, support = {Inserm//Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale/ ; R19101FF//Association pour la Recherche sur la Scl&#xe9;rose Lat&#xe9;rale Amyotrophique et autres Maladies du Motoneurone/ ; MSCA-IF ADELE//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; C9orf72 Protein/*genetics ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/*genetics ; Humans ; Neurodegenerative Diseases/genetics/pathology ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.}, }
@article {pmid33476770, year = {2021}, author = {Mani, S and Swargiary, G and Chadha, R}, title = {Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.}, journal = {Mitochondrion}, volume = {57}, number = {}, pages = {270-293}, doi = {10.1016/j.mito.2021.01.001}, pmid = {33476770}, issn = {1872-8278}, mesh = {Biomarkers/*metabolism ; Gene Expression Regulation ; Humans ; Life Expectancy ; Mitochondria/*metabolism ; Mitophagy ; Neurodegenerative Diseases/metabolism/*pathology ; }, abstract = {Neurons are specialized cells, requiring a lot of energy for its proper functioning. Mitochondria are the key cellular organelles and produce most of the energy in the form of ATP, required for all the crucial functions of neurons. Hence, the regulation of mitochondrial biogenesis and quality control is important for maintaining neuronal health. As a part of mitochondrial quality control, the aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD). Various studies indicate that specific protein aggregates, the characteristics of different NDDs, affect this process of mitophagy, adding to the severity and progression of diseases. Though, the detailed process of this association is yet to be explored. In light of the significant role of impaired mitophagy in NDDs, further studies have also investigated a large number of therapeutic strategies to target mitophagy in these diseases. Our current review summarizes the abnormalities in different mitophagy pathways and their association with different NDDs. We have also elaborated upon various novel therapeutic strategies and their limitations to enhance mitophagy in NDDs that may help in the management of symptoms and increasing the life expectancy of NDD patients. Thus, our study provides an overview of mitophagy in NDDs and emphasizes the need to elucidate the mechanism of impaired mitophagy prevalent across different NDDs in future research. This will help designing better treatment options with high efficacy and specificity.}, }
@article {pmid33468103, year = {2021}, author = {Boddy, SL and Giovannelli, I and Sassani, M and Cooper-Knock, J and Snyder, MP and Segal, E and Elinav, E and Barker, LA and Shaw, PJ and McDermott, CJ}, title = {The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS).}, journal = {BMC medicine}, volume = {19}, number = {1}, pages = {13}, pmid = {33468103}, issn = {1741-7015}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*microbiology/*physiopathology ; Animals ; Disease Progression ; *Gastrointestinal Microbiome ; Gastrointestinal Tract/*microbiology/*physiopathology ; Humans ; Intestines/microbiology/physiopathology ; Microbiota ; Models, Animal ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS.<br><br>MAIN BODY: The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications.<br><br>CONCLUSION: Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.}, }
@article {pmid33467517, year = {2021}, author = {Silva-Hucha, S and Pastor, AM and Morcuende, S}, title = {Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33467517}, issn = {1422-0067}, support = {BFU2015-64515-P//Ministerio de Econom&#xed;a y Competitividad/ ; PGC2018-094654-B-100//Ministerio de Econom&#xed;a y Competitividad/ ; BIO-297//Consejer&#xed;a de Econom&#xed;a, Innovaci&#xf3;n, Ciencia y Empleo, Junta de Andaluc&#xed;a/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Brain Stem/*metabolism ; Humans ; Motor Neurons/*metabolism ; Neurodegenerative Diseases/metabolism ; Neuroprotective Agents/metabolism ; Oculomotor Nuclear Complex/*metabolism ; Vascular Endothelial Growth Factor A/*metabolism ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; }, abstract = {Vascular endothelial growth factor (VEGF) was initially characterized as a potent angiogenic factor based on its activity on the vascular system. However, it is now well established that VEGF also plays a crucial role as a neuroprotective factor in the nervous system. A deficit of VEGF has been related to motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). Strikingly, motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration in ALS compared to other motoneurons. These motoneurons presented higher amounts of VEGF and its receptor Flk-1 than other brainstem pools. That higher VEGF level could be due to an enhanced retrograde input from their target muscles, but it can also be produced by the motoneurons themselves and act in an autocrine way. By contrast, VEGF's paracrine supply from the vicinity cells, such as glial cells, seems to represent a minor source of VEGF for brainstem motoneurons. In addition, ocular motoneurons experiment an increase in VEGF and Flk-1 level in response to axotomy, not observed in facial or hypoglossal motoneurons. Therefore, in this review, we summarize the differences in VEGF availability that could contribute to the higher resistance of extraocular motoneurons to injury and neurodegenerative diseases.}, }
@article {pmid33467098, year = {2021}, author = {Gröger, V and Emmer, A and Staege, MS and Cynis, H}, title = {Endogenous Retroviruses in Nervous System Disorders.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {33467098}, issn = {1424-8247}, support = {ZS/2018/12/96228//European Regional Development Fund/ ; ZS/2018/12/96169//European Regional Development Fund/ ; }, abstract = {Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies.}, }
@article {pmid33466587, year = {2021}, author = {Azam, S and Haque, ME and Kim, IS and Choi, DK}, title = {Microglial Turnover in Ageing-Related Neurodegeneration: Therapeutic Avenue to Intervene in Disease Progression.}, journal = {Cells}, volume = {10}, number = {1}, pages = {}, pmid = {33466587}, issn = {2073-4409}, mesh = {Aging/*metabolism/pathology ; Brain/*metabolism/pathology ; Disease Progression ; Humans ; Inflammation/metabolism/pathology/therapy ; Microglia/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology/therapy ; Neurons/*metabolism/pathology ; *Signal Transduction ; }, abstract = {Microglia are brain-dwelling macrophages and major parts of the neuroimmune system that broadly contribute to brain development, homeostasis, ageing and injury repair in the central nervous system (CNS). Apart from other brain macrophages, they have the ability to constantly sense changes in the brain's microenvironment, functioning as housekeepers for neuronal well-being and providing neuroprotection in normal physiology. Microglia use a set of genes for these functions that involve proinflammatory cytokines. In response to specific stimuli, they release these proinflammatory cytokines, which can damage and kill neurons via neuroinflammation. However, alterations in microglial functioning are a common pathophysiology in age-related neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's and prion diseases, as well as amyotrophic lateral sclerosis, frontotemporal dementia and chronic traumatic encephalopathy. When their sentinel or housekeeping functions are severely disrupted, they aggravate neuropathological conditions by overstimulating their defensive function and through neuroinflammation. Several pathways are involved in microglial functioning, including the Trem2, Cx3cr1 and progranulin pathways, which keep the microglial inflammatory response under control and promote clearance of injurious stimuli. Over time, an imbalance in this system leads to protective microglia becoming detrimental, initiating or exacerbating neurodegeneration. Correcting such imbalances might be a potential mode of therapeutic intervention in neurodegenerative diseases.}, }
@article {pmid33465527, year = {2021}, author = {Choi, ES and Dokholyan, NV}, title = {SOD1 oligomers in amyotrophic lateral sclerosis.}, journal = {Current opinion in structural biology}, volume = {66}, number = {}, pages = {225-230}, pmid = {33465527}, issn = {1879-033X}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Mutation ; Superoxide Dismutase-1/genetics ; }, abstract = {Identifying nonnative, trimeric forms of SOD1 trimers as the toxic species, rather than large aggregates revolutionizes our understanding of ALS pathophysiology. Large protein aggregates, what was previously thought as the central cause of neurodegeneration, play protective role and are not responsible for neuronal death. SOD1 trimers are implicated at the molecular, cellular, and organismal level. Understanding the formation of the nonnative trimer and its role in the cell, leading to cell death, holds the key to developing a new standard of therapeutics for ALS and for other neurodegenerative diseases. This review highlights recent advances of knowledge for the role of SOD1 oligomers in ALS.}, }
@article {pmid33463907, year = {2021}, author = {Bączyk, M and Krutki, P and Zytnicki, D}, title = {Is there hope that transpinal direct current stimulation corrects motoneuron excitability and provides neuroprotection in amyotrophic lateral sclerosis?.}, journal = {Physiological reports}, volume = {9}, number = {2}, pages = {e14706}, pmid = {33463907}, issn = {2051-817X}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Electric Stimulation Therapy/*methods ; Humans ; Motor Neurons/physiology ; Spinal Cord/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of largely unknown pathophysiology, characterized by the progressive loss of motoneurons (MNs). We review data showing that in presymptomatic ALS mice, MNs display reduced intrinsic excitability and impaired level of excitatory inputs. The loss of repetitive firing specifically affects the large MNs innervating fast contracting muscle fibers, which are the most vulnerable MNs in ALS. Interventions that aimed at restoring either the intrinsic excitability or the synaptic excitation result in a decrease of disease markers in MNs and delayed neuromuscular junction denervation. We then focus on trans-spinal direct current stimulation (tsDCS), a noninvasive tool, since it modulates the activity of spinal neurons and networks. Effects of tsDCS depend on the polarity of applied current. Recent work shows that anodal tsDCS induces long-lasting enhancement of MN excitability and synaptic excitation of spinal MNs. Moreover, we show preliminary results indicating that anodal tsDCS enhances the excitatory synaptic inputs to MNs in ALS mice. In conclusion, we suggest that chronic application of anodal tsDCS might be useful as a complementary method in the management of ALS patients.}, }
@article {pmid33462636, year = {2021}, author = {Yao, L and He, X and Cui, B and Zhao, F and Zhou, C}, title = {NEK1 mutations and the risk of amyotrophic lateral sclerosis (ALS): a meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {4}, pages = {1277-1285}, pmid = {33462636}, issn = {1590-3478}, support = {ZR2014HM064//Natural Science Foundation of Shandong Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Asian People ; Case-Control Studies ; Humans ; Mutation ; NIMA-Related Kinase 1/genetics ; }, abstract = {Recently, NEK1 (NIMA-related kinase 1) mutations were identified as a cause of amyotrophic lateral sclerosis (ALS), but the relationship between them remains unclear owing to the small sample size and low mutation rate. We made a meta-analysis to make clear the relationship. Eight case-control studies involving 8603 cases and 18,695 controls were enrolled. Results demonstrated that the frequency of NEK1 mutations was 3.1% (95% CI 2.5-3.8%) in ALS patients, including the frequencies of loss of function (LoF) and missense mutations, which were 0.9% (95% CI 0.6-1.1%) and 2.3% (95% CI 1.7-2.8%) in ALS patients, respectively. NEK1 mutations (OR 2.14; 95% CI 1.81-2.52; p < 0.001), including LoF mutations (OR 6.93; 95% CI 4.38-10.96; p < 0.001) and missense mutations (OR 1.65; 95% CI 1.37-1.99; p < 0.001) were associated with a significantly increased risk for ALS. And the risk of NEK1 LoF mutations (OR 6.93) is more than four times of that of NEK1 missense mutations (OR 1.65). Subgroup analysis suggested that the frequency of LoF mutations was higher in European patients (1%) than that in Asian patients (0.7%). In conclusion, NEK1 LoF and missense mutations are low frequencies in ALS patients, but both of them are associated with the increased risk for ALS. Altogether, NEK1 mutations including LoF mutations and missense mutations are more associated with Asian patients than European patients.}, }
@article {pmid33458727, year = {2021}, author = {Song, Z and Zhou, Y and Han, X and Qin, J and Tang, X}, title = {Recent advances in enzymeless-based electrochemical sensors to diagnose neurodegenerative diseases.}, journal = {Journal of materials chemistry. B}, volume = {9}, number = {5}, pages = {1175-1188}, doi = {10.1039/d0tb02745f}, pmid = {33458727}, issn = {2050-7518}, mesh = {Biosensing Techniques/*methods ; Electrochemical Techniques/*methods ; Humans ; Neurodegenerative Diseases/*diagnosis ; }, abstract = {The use of sensitive electrochemical sensors to detect biomarkers is an effective method for the early diagnosis of several neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc. However, the commercialization of enzyme/aptamer-based sensors is still hampered owing to the historic drawbacks of biorecognition elements including high cost, poor stability, and complex integration technology. Non-enzymatic electrochemical sensors are more attractive compared to their traditional counterparts and can be widely harnessed owing to their low cost, high stability, sensitivity, and ease of miniaturization. This review summarizes recent research progress focusing on the construction of non-enzymatic electrochemical sensors and analyzes their present use in the early diagnosis of NDs. Additionally, this review addresses the limitations and challenges of the use of current non-enzymatic electrochemical sensor technologies for the diagnosis of NDs and highlights the possible directions for future research.}, }
@article {pmid33454337, year = {2021}, author = {Wang, XL and Feng, ST and Wang, ZZ and Chen, NH and Zhang, Y}, title = {Role of mitophagy in mitochondrial quality control: Mechanisms and potential implications for neurodegenerative diseases.}, journal = {Pharmacological research}, volume = {165}, number = {}, pages = {105433}, doi = {10.1016/j.phrs.2021.105433}, pmid = {33454337}, issn = {1096-1186}, mesh = {Animals ; Autophagy/physiology ; Humans ; Mitochondria/*metabolism/pathology ; Mitochondrial Dynamics/*physiology ; Mitophagy/*physiology ; Neurodegenerative Diseases/*metabolism/pathology ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) commonly characterized by the gradual loss of neurons have a seriously bad impact on motor and cognitive abilities of affected humans and bring great inconvenience to their lives. Mitochondrial dysfunction has been considered the key and common factor for the pathologies of neurodegenerative diseases for that neurons are extremely energy-intensive due to their unique properties in structures and functions. Thus, mitophagy, as a central role of mitochondrial quality control and currently believed to be the most effective pathway to clear dysfunctional or unwanted mitochondria, is rather crucial in the preservation of neuronal health. In addition, mitophagy establishes an intimated link with several other pathways of mitochondrial quality control (e.g., mitochondrial biogenesis and mitochondrial dynamics), and they work together to preserve mitochondrial health. Therefore, in this review, we summarized the recent process on the mechanisms of mitophagy pathways in mammals, it's linking to mitochondrial quality control, its role in several major neurodegenerative diseases, and possible therapeutic interventions focusing on mitophagy pathways. And we expect that it can provide us with more understanding of the mitophagy pathways and more promising approaches for the treatment of neurodegenerative diseases.}, }
@article {pmid33452054, year = {2021}, author = {van der Ende, EL and Jackson, JL and White, A and Seelaar, H and van Blitterswijk, M and Van Swieten, JC}, title = {Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {92}, number = {5}, pages = {502-509}, pmid = {33452054}, issn = {1468-330X}, support = {R21 NS110994/NS/NINDS NIH HHS/United States ; R21 NS099631/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; C9orf72 Protein/*genetics ; DNA Methylation ; *DNA Repeat Expansion ; Frontotemporal Dementia/diagnosis/*genetics ; Humans ; Phenotype ; }, abstract = {Since the discovery of the C9orf72 repeat expansion as the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis, it has increasingly been associated with a wider spectrum of phenotypes, including other types of dementia, movement disorders, psychiatric symptoms and slowly progressive FTD. Prompt recognition of patients with C9orf72-associated diseases is essential in light of upcoming clinical trials. The striking clinical heterogeneity associated with C9orf72 repeat expansions remains largely unexplained. In contrast to other repeat expansion disorders, evidence for an effect of repeat length on phenotype is inconclusive. Patients with C9orf72-associated diseases typically have very long repeat expansions, containing hundreds to thousands of GGGGCC-repeats, but smaller expansions might also have clinical significance. The exact threshold at which repeat expansions lead to neurodegeneration is unknown, and discordant cut-offs between laboratories pose a challenge for genetic counselling. Accurate and large-scale measurement of repeat expansions has been severely hindered by technical difficulties in sizing long expansions and by variable repeat lengths across and within tissues. Novel long-read sequencing approaches have produced promising results and open up avenues to further investigate this enthralling repeat expansion, elucidating whether its length, purity, and methylation pattern might modulate clinical features of C9orf72-related diseases.}, }
@article {pmid33450997, year = {2021}, author = {Madruga, E and Maestro, I and Martínez, A}, title = {Mitophagy Modulation, a New Player in the Race against ALS.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33450997}, issn = {1422-0067}, support = {H2020-MSCA-ITN-2017 (grant no. 765912)//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; BMD-3813 ELA_Madrid//CAM/ ; PID2019-105600RB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; CIBERNED (CB18/05/00040).//Instituto de Salud Carlos III/ ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/*metabolism ; Animals ; Autophagy/drug effects/genetics/immunology ; Disease Management ; Disease Models, Animal ; Disease Susceptibility ; Homeostasis ; Humans ; Mitochondria/*drug effects/genetics/immunology/metabolism ; Mitophagy/*drug effects/genetics/immunology ; Molecular Targeted Therapy/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.}, }
@article {pmid33446423, year = {2021}, author = {Portz, B and Lee, BL and Shorter, J}, title = {FUS and TDP-43 Phases in Health and Disease.}, journal = {Trends in biochemical sciences}, volume = {46}, number = {7}, pages = {550-563}, pmid = {33446423}, issn = {0968-0004}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 AG061784/AG/NIA NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics ; Humans ; *Neurodegenerative Diseases ; RNA-Binding Protein FUS ; }, abstract = {The distinct prion-like domains (PrLDs) of FUS and TDP-43, modulate phase transitions that result in condensates with a range of material states. These assemblies are implicated in both health and disease. In this review, we examine how sequence, structure, post-translational modifications, and RNA can affect the self-assembly of these RNA-binding proteins (RBPs). We discuss how our emerging understanding of FUS and TDP-43 liquid-liquid phase separation (LLPS) and aggregation, could be leveraged to design new therapies for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE).}, }
@article {pmid33446055, year = {2021}, author = {Vieira de Sá, R and Cañizares Luna, M and Pasterkamp, RJ}, title = {Advances in Central Nervous System Organoids: A Focus on Organoid-Based Models for Motor Neuron Disease.}, journal = {Tissue engineering. Part C, Methods}, volume = {27}, number = {3}, pages = {213-224}, doi = {10.1089/ten.TEC.2020.0337}, pmid = {33446055}, issn = {1937-3392}, mesh = {Animals ; Brain ; Central Nervous System ; Humans ; *Induced Pluripotent Stem Cells ; *Motor Neuron Disease/therapy ; Organoids ; }, abstract = {Despite their large societal burden, the development of therapeutic treatments for neurodegenerative diseases (NDDs) has been relatively unsuccessful. This is, in part, due to a lack of representative experimental models that reveal fundamental aspects of human brain pathology. Recently, assays for in vitro modeling of the human central nervous system (CNS) have significantly improved with the development of brain and spinal cord organoids. Coupled with induced-pluripotent stem cell and genome editing technologies, CNS organoids are a promising tool for studying neurodegeneration in a patient-specific manner. An extensive array of protocols for the generation of organoids for different brain regions has been developed and used for studying neurodegenerative and other brain diseases. However, their application in the field of motor neuron disease (MND) has been limited due to a lack of adequate organoid models. The development of protocols to derive spinal cord and trunk organoids and progress in the field of assembloids are providing new opportunities for modeling MND. In this study here we review recent advances in the development of CNS organoid models, their application in NDDs, and technical limitations. Finally, we discuss future perspectives for the development of organoid-based systems for MND and provide a framework for their development. Impact statement Animal models and two-dimensional cultures are currently the main platforms for studying neurodegenerative diseases (NDDs). However, central nervous system (CNS) organoid technology offers novel possibilities for studying these diseases. Organoid modeling in combination with emerging organ-on-a-chip approaches, induced-pluripotent stem cell technology, and genome editing render in vitro modeling of NDDs more robust and physiologically relevant. In this study, we review the principles underlying CNS organoid generation, their use in NDD research, and future perspectives in organoid technology. Finally, we discuss how advances in different fields could be combined to generate a multisystem organoid-on-a-chip model to investigate a specific class of NDDs, motor neuron diseases.}, }
@article {pmid33443670, year = {2021}, author = {de Almeida, FEO and do Carmo Santana, AK and de Carvalho, FO}, title = {Multidisciplinary care in Amyotrophic Lateral Sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {3}, pages = {911-923}, pmid = {33443670}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Interdisciplinary Studies ; Palliative Care ; *Quality of Life ; }, abstract = {Multidisciplinary care (MDC) has been the most recommended approach for symptom management in amyotrophic lateral sclerosis (ALS) but there is conflicting evidence about its effectiveness on survival and quality of life (QoL) of ALS patients. We conducted a systematic review to determine the effects of multidisciplinary care compared to general neurological care in survival and quality of life of ALS patients. A comprehensive literature search using Scopus, MEDLINE-PubMed, Cochrane, Web of Science, PEDro, and Science Direct was undertaken. Studies related to multidisciplinary care or general neurological care in ALS patients that assessed survival and quality of life and were published in the period up to and including January 2020 were included. A total of 1192 studies were initially identified, but only 6 were included. All studies that investigated survival showed and advantage of MDC over NC, and this benefit was even greater for bulbar onset patients. A meta-analysis was performed and showed a mean difference of 141.67 (CI 95%, 61.48 to 221.86), indicating that patients who received MDC had longer survival than those who underwent NC (p = 0.0005). Concerning QoL, only one study found better mental health scores related to QoL for patients under MDC. Multidisciplinary care is more effective than general neurology care at improving survival of patients with ALS, but only improves mental health outcomes related to quality of life of these patients.}, }
@article {pmid33441385, year = {2021}, author = {El-Wahsh, S and Finger, EC and Piguet, O and Mok, V and Rohrer, JD and Kiernan, MC and Ahmed, RM}, title = {Predictors of survival in frontotemporal lobar degeneration syndromes.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2020-324349}, pmid = {33441385}, issn = {1468-330X}, abstract = {After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies.}, }
@article {pmid33439410, year = {2021}, author = {Namusamba, M and Li, Z and Zhang, Q and Wang, C and Wang, T and Wang, B}, title = {Biological roles of the B cell receptor-associated protein 31: Functional Implication in Cancer.}, journal = {Molecular biology reports}, volume = {48}, number = {1}, pages = {773-786}, pmid = {33439410}, issn = {1573-4978}, support = {No. 31370784; No. 31972898; No. 31670770; Liaoning Revitalization Talents Program (XLYC1902063), Key Research and Development Plan of Liaoning Province (2020JH2/10300080).//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/genetics/metabolism/mortality/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/mortality/pathology ; Atlases as Topic ; B-Lymphocytes/metabolism/pathology ; Disease Progression ; Gene Expression Regulation ; Liver Diseases/genetics/metabolism/mortality/pathology ; *Membrane Proteins/genetics/metabolism ; Metabolic Networks and Pathways/genetics ; *Neoplasms/genetics/metabolism/mortality/pathology ; Protein Interaction Mapping ; Signal Transduction ; Survival Analysis ; }, abstract = {BAP31 is a ubiquitously expressed integral membrane protein of the endoplasmic reticulum. BAP31 is involved in various biological and molecular processes, including protein transport, viral processing, apoptosis signaling, MHC 1 antigen processing and presentation, mitochondria and ER calcium regulation, and proteasomal protein degradation. We employed a BAP31 interaction search using STRING and inBioMap™ protein-protein interaction networks, and the Metabolic Atlas, which revealed molecular and metabolic interactors involved in various pathways essential for cell growth, cell survival, and disease development. BAP31, as a chaperone and resident protein of the ER, was reported in the development of some central nervous system disorders and metabolic diseases about AD, ALS, and Liver disease. In addition, BAP31 is overexpressed in many cancers. Furthermore, research around BAP31 involvement in cancer has taken up a shape, focusing on its roles in cancer cell survival, disease prognosis, and targeted treatment. Here, we address published data on the Biological roles of BAP31 in both health and disease. We present an analytical description of BAP31 expression and functional implication in some human cancers and the impact of its expression and regulation while it models as a potential target in cancer therapy. Besides, a profound understanding of BAP31 is insightful of the gap between cancer development and neurodegeneration, thus generating novel ideas surrounding the link between the two different cell phenomena.}, }
@article {pmid33431046, year = {2021}, author = {Tefera, TW and Steyn, FJ and Ngo, ST and Borges, K}, title = {CNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target?.}, journal = {Cell &amp; bioscience}, volume = {11}, number = {1}, pages = {14}, pmid = {33431046}, issn = {2045-3701}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.}, }
@article {pmid33430731, year = {2021}, author = {Minj, E and Yadav, RK and Mehan, S}, title = {Targeting Abnormal Nrf2/HO-1 Signaling in Amyotrophic Lateral Sclerosis: Current Insights on Drug Targets and Influences on Neurological Disorders.}, journal = {Current molecular medicine}, volume = {21}, number = {8}, pages = {630-644}, doi = {10.2174/1566524021666210111104920}, pmid = {33430731}, issn = {1875-5666}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; *Drug Delivery Systems ; Heme Oxygenase-1/*metabolism ; Humans ; Motor Cortex/metabolism ; Motor Neurons/metabolism ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress ; *Signal Transduction ; }, abstract = {The nuclear erythroid 2-related-factor (Nrf2) transcription factor/hemoxygenase 1 (HO-1) is a key regulator of an important neuroprotection response by driving the interpretation of various cytoprotective gene to encode for anti-inflammatory, antioxidant, and detoxifying proteins. Various studies investigated that the upregulation of Nrf2/HO-1 has become the potential therapeutic approach in amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis is a motor neuron disease in which there is a progressive loss of upper motor neuron and lower motor neurons of the motor cortex, brain stem, and corticospinal tract. A result of this upregulation of Nrf2/HO-1 indicates that in the brain, anti-oxidant capacity is reinforced. Further, this shows a cytoprotective effect against oxidative stress in amyotrophic lateral sclerosis. A study reported functions associated with the Nrf2/HO-1 in the neuronal cell, oligodendrocytes, microglia, and astrocytes. Although ALS's pathogenesis is not yet clear, but it is compelling. The evidence shows any dysfunction in the brain such as mitochondrial dysfunction, protein aggregation, glial cell activation, excitotoxicity, and apoptosis which gives ALS-like symptoms. In this review, we have mainly focused on detailing the downregulation of Nrf2/HO-1, which may be the prime reason and may further serve as a pathological hallmark for ALS development. As surveyed, there are limited targetbased interventions that only provide symptomatic relief but do not cure the disease completely. Dysregulation of the Nrf2/HO-1 signaling pathway leads to many physiological changes contributing to neurological conditions, including ALS. Based on the above view, we summarized the combined role of Nrf2/HO-1 signaling in ALS and explored potential therapeutic strategies for disease improvement through pathway modulators.}, }
@article {pmid33427296, year = {2020}, author = {Clarke, BE and Patani, R}, title = {The microglial component of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {143}, number = {12}, pages = {3526-3539}, pmid = {33427296}, issn = {1460-2156}, support = {FC0101 10/CRUK_/Cancer Research UK/United Kingdom ; FC010110/WT_/Wellcome Trust/United Kingdom ; FC010110/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Microglia/*pathology ; }, abstract = {Microglia are the primary immune cells of the CNS, carrying out key homeostatic roles and undergoing context-dependent and temporally regulated changes in response to injury and neurodegenerative diseases. Microglia have been implicated in playing a role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by extensive motor neuron loss leading to paralysis and premature death. However, as the pathomechansims of ALS are increasingly recognized to involve a multitude of different cell types, it has been difficult to delineate the specific contribution of microglia to disease. Here, we review the literature of microglial involvement in ALS and discuss the evidence for the neurotoxic and neuroprotective pathways that have been attributed to microglia in this disease. We also discuss accumulating evidence for spatiotemporal regulation of microglial activation in this context. A deeper understanding of the role of microglia in the 'cellular phase' of ALS is crucial in the development of mechanistically rationalized therapies.}, }
@article {pmid33427209, year = {2021}, author = {Malik, AM and Barmada, SJ}, title = {Matrin 3 in neuromuscular disease: physiology and pathophysiology.}, journal = {JCI insight}, volume = {6}, number = {1}, pages = {}, pmid = {33427209}, issn = {2379-3708}, support = {F31 NS110119/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Animals ; Disease Models, Animal ; Distal Myopathies/genetics/physiopathology ; Frontotemporal Dementia/genetics/physiopathology ; Gene Expression Regulation ; Humans ; Mice, Knockout ; Mutation ; Neuromuscular Diseases/*genetics/*physiopathology ; Nuclear Matrix-Associated Proteins/chemistry/deficiency/*genetics/*physiology ; RNA-Binding Proteins/chemistry/*genetics/*physiology ; Mice ; }, abstract = {RNA-binding proteins (RBPs) are essential factors required for the physiological function of neurons, muscle, and other tissue types. In keeping with this, a growing body of genetic, clinical, and pathological evidence indicates that RBP dysfunction and/or gene mutation leads to neurodegeneration and myopathy. Here, we summarize the current understanding of matrin 3 (MATR3), a poorly understood RBP implicated not only in ALS and frontotemporal dementia but also in distal myopathy. We begin by reviewing MATR3's functions, its regulation, and how it may be involved in both sporadic and familial neuromuscular disease. We also discuss insights gleaned from cellular and animal models of MATR3 pathogenesis, the links between MATR3 and other disease-associated RBPs, and the mechanisms underlying RBP-mediated disorders.}, }
@article {pmid33422671, year = {2021}, author = {Rios, R and Jablonka-Shariff, A and Broberg, C and Snyder-Warwick, AK}, title = {Macrophage roles in peripheral nervous system injury and pathology: Allies in neuromuscular junction recovery.}, journal = {Molecular and cellular neurosciences}, volume = {111}, number = {}, pages = {103590}, pmid = {33422671}, issn = {1095-9327}, support = {K08 NS096232/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Macrophages/*immunology ; Motor Neuron Disease/*immunology/physiopathology ; Nerve Regeneration ; Neuromuscular Junction/*immunology/physiology/physiopathology ; Peripheral Nerve Injuries/*immunology/physiopathology ; }, abstract = {Peripheral nerve injuries remain challenging to treat despite extensive research on reparative processes at the injury site. Recent studies have emphasized the importance of immune cells, particularly macrophages, in recovery from nerve injury. Macrophage plasticity enables numerous functions at the injury site. At early time points, macrophages perform inflammatory functions, but at later time points, they adopt pro-regenerative phenotypes to support nerve regeneration. Research has largely been limited, however, to the injury site. The neuromuscular junction (NMJ), the synapse between the nerve terminal and end target muscle, has received comparatively less attention, despite the importance of NMJ reinnervation for motor recovery. Macrophages are present at the NMJ following nerve injury. Moreover, in denervating diseases, such as amyotrophic lateral sclerosis (ALS), macrophages may also play beneficial roles at the NMJ. Evidence of positive macrophages roles at the injury site after peripheral nerve injury and at the NMJ in denervating pathologies suggest that macrophages may promote NMJ reinnervation. In this review, we discuss the intersection of nerve injury and immunity, with a focus on macrophages.}, }
@article {pmid33419039, year = {2021}, author = {Yamaguchi, M and Omori, K and Asada, S and Yoshida, H}, title = {Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33419039}, issn = {1422-0067}, support = {Core-to-Core Program B, Asia-Africa Science Platforms, JP19K06659//Japan Society for the Promotion of Science/ ; Advance Insect Research Promotion Center Grant//Kyoto Institute of Technology/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Charcot-Marie-Tooth Disease/genetics/*pathology ; DNA Methylation ; Disease Models, Animal ; Drosophila ; *Epigenesis, Genetic ; Histones/metabolism ; Protein Processing, Post-Translational ; RNA, Long Noncoding/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the severity and progression of CMT symptoms markedly vary. The phenotypic heterogeneity of ALS and CMT suggests the existence of modifiers that determine disease characteristics. Epigenetic regulation of biological functions via gene expression without alterations in the DNA sequence may be an important factor. The methylation of DNA, noncoding RNA, and post-translational modification of histones are the major epigenetic mechanisms. Currently, Drosophila is emerging as a useful ALS and CMT model. In this review, we summarize recent studies linking ALS and CMT to epigenetic regulation with a strong emphasis on approaches using Drosophila models.}, }
@article {pmid33416892, year = {2021}, author = {Fontana, L and Ghezzi, L and Cross, AH and Piccio, L}, title = {Effects of dietary restriction on neuroinflammation in neurodegenerative diseases.}, journal = {The Journal of experimental medicine}, volume = {218}, number = {2}, pages = {}, pmid = {33416892}, issn = {1540-9538}, support = {R01 NS102633/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/physiology ; Animals ; Brain/*pathology ; Diet/methods ; Diet Therapy/methods ; Humans ; Inflammation/*pathology ; Neurodegenerative Diseases/*pathology ; }, abstract = {Recent and accumulating work in experimental animal models and humans shows that diet has a much more pervasive and prominent role than previously thought in modulating neuroinflammatory and neurodegenerative mechanisms leading to some of the most common chronic central nervous system (CNS) diseases. Chronic or intermittent food restriction has profound effects in shaping brain and peripheral metabolism, immunity, and gut microbiome biology. Interactions among calorie intake, meal frequency, diet quality, and the gut microbiome modulate specific metabolic and molecular pathways that regulate cellular, tissue, and organ homeostasis as well as inflammation during normal brain aging and CNS neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, among others. This review discusses these findings and their potential application to the prevention and treatment of CNS neuroinflammatory diseases and the promotion of healthy brain aging.}, }
@article {pmid33414510, year = {2021}, author = {Schmidt, MF and Gan, ZY and Komander, D and Dewson, G}, title = {Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities.}, journal = {Cell death and differentiation}, volume = {28}, number = {2}, pages = {570-590}, pmid = {33414510}, issn = {1476-5403}, mesh = {Amyloid beta-Peptides/metabolism ; Animals ; Autophagy/physiology ; Cell Death ; Humans ; Lysosomes/physiology ; Mitochondria/metabolism/*physiology ; Neurodegenerative Diseases/*metabolism/physiopathology ; Proteasome Endopeptidase Complex/*metabolism ; Signal Transduction ; Ubiquitin/*metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.}, }
@article {pmid33412145, year = {2021}, author = {Li, B and Xia, M and Zorec, R and Parpura, V and Verkhratsky, A}, title = {Astrocytes in heavy metal neurotoxicity and neurodegeneration.}, journal = {Brain research}, volume = {1752}, number = {}, pages = {147234}, pmid = {33412145}, issn = {1872-6240}, support = {R01 GM123971/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*metabolism/*pathology ; Brain/metabolism/pathology ; Environmental Exposure/adverse effects ; Humans ; Metals, Heavy/*toxicity ; Neurodegenerative Diseases/*metabolism/*pathology ; }, abstract = {With the industrial development and progressive increase in environmental pollution, the mankind overexposure to heavy metals emerges as a pressing public health issue. Excessive intake of heavy metals, such as arsenic (As), manganese (Mn), mercury (Hg), aluminium (Al), lead (Pb), nickel (Ni), bismuth (Bi), cadmium (Cd), copper (Cu), zinc (Zn), and iron (Fe), is neurotoxic and it promotes neurodegeneration. Astrocytes are primary homeostatic cells in the central nervous system. They protect neurons against all types of insults, in particular by accumulating heavy metals. However, this makes astrocytes the main target for heavy metals neurotoxicity. Intake of heavy metals affects astroglial homeostatic and neuroprotective cascades including glutamate/GABA-glutamine shuttle, antioxidative machinery and energy metabolism. Deficits in these astroglial pathways facilitate or even instigate neurodegeneration. In this review, we provide a concise outlook on heavy metal-induced astrogliopathies and their association with major neurodegenerative disorders. In particular, we focus on astroglial mechanisms of iron-induced neurotoxicity. Iron deposits in the brain are detected in main neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Accumulation of iron in the brain is associated with motor and cognitive impairments and iron-induced histopathological manifestations may be considered as the potential diagnostic biomarker of neurodegenerative diseases. Effective management of heavy metal neurotoxicity can be regarded as a potential strategy to prevent or retard neurodegenerative pathologies.}, }
@article {pmid33406777, year = {2021}, author = {Franić, D and Zubčić, K and Boban, M}, title = {Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance.}, journal = {Biomolecules}, volume = {11}, number = {1}, pages = {}, pmid = {33406777}, issn = {2218-273X}, support = {PZS-2019-02-3610//Croatian Science Foundation/ ; DOK-2018-01-9299//Croatian Science Foundation/ ; }, mesh = {Animals ; Cell Nucleus/*metabolism ; Humans ; Proteasome Endopeptidase Complex/*metabolism ; Protein Folding ; Proteolysis ; *Proteostasis ; Ubiquitin/*metabolism ; }, abstract = {Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.}, }
@article {pmid33400181, year = {2021}, author = {Rana, I and Rieswijk, L and Steinmaus, C and Zhang, L}, title = {Formaldehyde and Brain Disorders: A Meta-Analysis and Bioinformatics Approach.}, journal = {Neurotoxicity research}, volume = {39}, number = {3}, pages = {924-948}, pmid = {33400181}, issn = {1476-3524}, support = {P42 ES004705/ES/NIEHS NIH HHS/United States ; P42ES004705/ES/NIEHS NIH HHS/United States ; P42ES004705/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Brain/*drug effects/metabolism/pathology ; Brain Diseases/*chemically induced/epidemiology/metabolism ; Computational Biology/*methods ; Environmental Exposure/*adverse effects ; Formaldehyde/*adverse effects/toxicity ; Humans ; Neurodegenerative Diseases/chemically induced/epidemiology/metabolism ; Occupational Exposure/*adverse effects ; }, abstract = {While there is significant investigation and investment in brain and neurodegenerative disease research, current understanding of the etiologies of illnesses like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and brain cancer remains limited. Environmental exposure to the pollutant formaldehyde, an emerging neurotoxin widely used in industry, is suspected to play a critical role in mediating these disorders, although findings are limited and inconsistent. Focusing on highly exposed groups, we performed a meta-analysis of human epidemiological studies of formaldehyde and neurodegenerative disease (N = 19) or brain tumors (N = 12). To assess the biological plausibility of observed associations, we then conducted a bioinformatics analysis using WikiPathways and the Comparative Toxicogenomics Database and identified candidate genes and pathways that may be related to these interactions. We reported the meta-relative risk (meta-RR) of ALS following high exposures to formaldehyde was increased by 78% (meta-RR = 1.78, 95% confidence interval, CI 1.20-2.65). Similarly, the meta-RR for brain cancer was increased by 71% (meta-RR = 1.71; 95% CI 1.07-2.73) among highly exposed individuals. Multiple sensitivity analyses did not reveal sources of heterogeneity or bias. Our bioinformatics analysis revealed that the oxidative stress genes superoxide dismutase (SOD1, SOD2) and the pro-inflammatory marker tumor necrosis factor (TNF) were identified as the top relevant genes, and the folate metabolism, vitamin B12 metabolism, and the ALS pathways were highly affected by formaldehyde and related to the most brain diseases of interest. Further inquiry revealed the two metabolic pathways are also intimately tied with the formaldehyde cycle. Overall, our bioinformatics analysis supports the link of formaldehyde exposure to ALS or brain tumor reported from our meta-analysis. This new multifactorial approach enabled us to both interrogate the robustness of the epidemiological data and identify genes and pathways that may be involved in these interactions, ultimately lending strong evidence and potential biological plausibility for the association between formaldehyde exposure and brain disease.}, }
@article {pmid33398779, year = {2021}, author = {Li Hi Shing, S and McKenna, MC and Siah, WF and Chipika, RH and Hardiman, O and Bede, P}, title = {The imaging signature of C9orf72 hexanucleotide repeat expansions: implications for clinical trials and therapy development.}, journal = {Brain imaging and behavior}, volume = {15}, number = {5}, pages = {2693-2719}, pmid = {33398779}, issn = {1931-7565}, support = {HRB EIA 2017-019/HRBI_/Health Research Board/Ireland ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics ; Humans ; Magnetic Resonance Imaging ; Proteins/genetics ; }, abstract = {While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in young mutation carriers, considerable inconsistencies exist in the literature. Accordingly, a systematic review of C9orf72-imaging studies has been performed to identify consensus findings, stereotyped shortcomings, and unique contributions to outline future directions. A formal literature review was conducted according to the STROBE guidelines. All identified papers were individually reviewed for sample size, choice of controls, study design, imaging modalities, statistical models, clinical profiling, and identified genotype-associated pathological patterns. A total of 74 imaging papers were systematically reviewed. ALS patients with GGGGCC repeat expansions exhibit relatively limited motor cortex involvement and widespread extra-motor pathology. C9orf72 positive FTD patients often show preferential posterior involvement. Reports of thalamic involvement are relatively consistent across the various phenotypes. Asymptomatic hexanucleotide repeat carriers often exhibit structural and functional changes decades prior to symptom onset. Common shortcomings included sample size limitations, lack of disease-controls, limited clinical profiling, lack of genetic testing in healthy controls, and absence of post mortem validation. There is a striking paucity of longitudinal studies and existing presymptomatic studies have not evaluated the predictive value of radiological changes with regard to age of onset and phenoconversion. With the advent of antisense oligonucleotide therapies, the meticulous characterisation of C9orf72-associated changes has gained practical relevance. Neuroimaging offers non-invasive biomarkers for future clinical trials, presymptomatic ascertainment, diagnostic and prognostic applications.}, }
@article {pmid33397660, year = {2021}, author = {Erdmann, A and Spoden, C and Hirschberg, I and Neitzke, G}, title = {The wish to die and hastening death in amyotrophic lateral sclerosis: A scoping review.}, journal = {BMJ supportive &amp; palliative care}, volume = {11}, number = {3}, pages = {271-287}, pmid = {33397660}, issn = {2045-4368}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) develops into a life-threatening condition 2 to 4 years after the onset of symptoms. Although many people with the disease decide in favour of life-sustaining measures, thoughts about hastening death are not uncommon.<br><br>OBJECTIVES: Our aim was to examine the scope of literature on the wish to die in ALS and provide an insight into determinants and motives for different end-of-life options.<br><br>METHODS: We searched eight databases for English and German publications on death wishes in ALS for the period from 2008 to 2018 and updated the search up to May 2020. After the screening process, 213 full texts were included for the final analysis. We analysed the texts in MAXQDA, using deductively and inductively generated codes.<br><br>RESULTS: We identified end-of-life considerations, ranging from wishes to die without hastening death, to options with the possibility or intention of hastening death. Besides physical impairment, especially psychosocial factors, socio-demographic status and socio-cultural context have a great impact on decisions for life-shortening options. There is huge variation in the motives and determinants for end-of-life considerations between individuals, different societies, healthcare and legal systems.<br><br>CONCLUSIONS: For a variety of reasons, the information and counselling provided on different options for sustaining life or hastening death is often incomplete and insufficient. Since the motives and determinants for the wish to hasten death are extremely diverse, healthcare professionals should investigate the reasons, meaning and strength of the desire to die to detect unmet needs and examine which interventions are appropriate in each individual case.}, }
@article {pmid33396271, year = {2020}, author = {Cho, H and Shukla, S}, title = {Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {33396271}, issn = {1424-8247}, abstract = {Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive and fatal neurodegenerative disease that leads to a loss of muscle control due to nerve cells being affected in the brain and spinal cord. Some of the common clinical presentations of ALS include weakness of muscles, changes in behavior, dysfunction in speech, and cognitive difficulties. The cause of ALS is uncertain, but through several studies, it is known that mutations in SOD1 or C9orf72 genes could play a role as a factor of ALS. In addition, studies indicate that an excessive amount of free radicals, the reactive oxygen species (ROS), leads to neuronal damage by the peroxidation of unsaturated fatty acids in the neuronal cells. Edaravone, the newly approved antioxidant drug for ALS, halts the progression of ALS in the early stages through its cytoprotective effect and protects the nerves by reducing ROS. In this review, different aspects of ALS will be discussed, including its pathology, genetic aspect, and diagnosis. This review also focuses on edaravone as a treatment option for ALS, its mechanism of action, and its pharmacological properties. Clinical trials and adverse effects of edaravone and care for ALS patient are also discussed.}, }
@article {pmid33394258, year = {2021}, author = {Remiche, G and Vandernoot, I and Sadeghi-Meibodi, N and Desmyter, L}, title = {SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review.}, journal = {Neurogenetics}, volume = {22}, number = {1}, pages = {95-101}, pmid = {33394258}, issn = {1364-6753}, mesh = {Adolescent ; Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Brain/pathology ; Female ; *Heterozygote ; Humans ; Male ; Mitochondrial Proteins/*genetics ; Mutation/*genetics ; Phenotype ; }, abstract = {C19orf12 gene biallelic mutations lead mainly to neurodegeneration with brain iron accumulation-4. A 15-year-old male and his 17-year-old sister complained of cramps and exercise intolerance. Clinical examination of the boy mainly showed distal amyotrophy and mild weakness, while the sister predominantly had a tetrapyramidal syndrome. Widespread chronic neurogenic signs and hypointense signals on the striatum were present in both patients. Clinical exome sequencing identified, on both patients, the compound heterozygous pathogenic mutations c.204_214del p.(Gly69ArgfsTer10) and c.32C>T p.(Thr11Met). The description of these rare SPG43 and ALS-like phenotypes in the same family contributes to improve genotype-phenotype correlation in C19orf12-related diseases.}, }
@article {pmid33393416, year = {2021}, author = {Yang, Y and Okada, S and Sakurai, M}, title = {Adenosine-to-inosine RNA editing in neurological development and disease.}, journal = {RNA biology}, volume = {18}, number = {7}, pages = {999-1013}, pmid = {33393416}, issn = {1555-8584}, mesh = {Adenosine/genetics/metabolism ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Astrocytoma/*genetics/metabolism/pathology ; Bipolar Disorder/*genetics/metabolism/pathology ; Central Nervous System Neoplasms/*genetics/metabolism/pathology ; Epilepsy/*genetics/metabolism/pathology ; Humans ; Inosine/genetics/metabolism ; Kv1.1 Potassium Channel/genetics/metabolism ; MicroRNAs/genetics/metabolism ; *RNA Editing ; Receptor, Serotonin, 5-HT2C/genetics/metabolism ; Receptors, AMPA/genetics/metabolism ; Schizophrenia/*genetics/metabolism/pathology ; Spasms, Infantile/*genetics/metabolism/pathology ; }, abstract = {Adenosine-to-inosine (A-to-I) editing is one of the most prevalent post-transcriptional RNA modifications in metazoan. This reaction is catalysed by enzymes called adenosine deaminases acting on RNA (ADARs). RNA editing is involved in the regulation of protein function and gene expression. The numerous A-to-I editing sites have been identified in both coding and non-coding RNA transcripts. These editing sites are also found in various genes expressed in the central nervous system (CNS) and play an important role in neurological development and brain function. Aberrant regulation of RNA editing has been associated with the pathogenesis of neurological and psychiatric disorders, suggesting the physiological significance of RNA editing in the CNS. In this review, we discuss the current knowledge of editing on neurological disease and development.}, }
@article {pmid33390907, year = {2020}, author = {Giovedì, S and Ravanelli, MM and Parisi, B and Bettegazzi, B and Guarnieri, FC}, title = {Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {602116}, pmid = {33390907}, issn = {1662-5102}, abstract = {Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer's, Parkinson's, Huntington's and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.}, }
@article {pmid33390807, year = {2021}, author = {Xu, X and Su, Y and Zou, Z and Zhou, Y and Yan, J}, title = {Correlation between C9ORF72 mutation and neurodegenerative diseases: A comprehensive review of the literature.}, journal = {International journal of medical sciences}, volume = {18}, number = {2}, pages = {378-386}, pmid = {33390807}, issn = {1449-1907}, mesh = {Animals ; C9orf72 Protein/antagonists &amp; inhibitors/*genetics ; Disease Models, Animal ; Disease Progression ; Humans ; Mutation ; Neurodegenerative Diseases/diagnosis/drug therapy/*genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Chromosome 9 open reading frame 72 (C9ORF72) encodes a 54-kDa protein with unknown function that is expressed at high levels in the central nervous system. The C9ORF72 hexanucleotide amplification is one of the most recently discovered repetitive amplification diseases related to neurodegeneration. Its association with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum diseases has been fully established, although a causative role for C9ORF72 in Alzheimer's disease (AD) and Parkinson's disease (PD) remains to be established. Therefore, in this article, we will review the evidence for C9ORF72 as a causative factor in neurodegenerative diseases, the underlying mechanisms, and the potential for targeting C9ORF72 as a strategy to alleviate neurodegenerative disease progression.}, }
@article {pmid33390128, year = {2021}, author = {Waseem, R and Shamsi, A and Kazim, SN and Islam, A}, title = {An Insight Into Mitochondrial Dysfunction and its Implications in Neurological Diseases.}, journal = {Current drug targets}, volume = {22}, number = {14}, pages = {1585-1595}, doi = {10.2174/1389450121999201230204050}, pmid = {33390128}, issn = {1873-5592}, mesh = {Apoptosis ; Humans ; Mitochondria/metabolism/*pathology ; *Mitochondrial Diseases/physiopathology ; *Neurodegenerative Diseases/physiopathology ; Neurons/pathology ; Oxidative Stress ; }, abstract = {In the last few years, a massive increase in research has been observed that focuses on investigating the role of mitochondria in the pathogenesis of several neurodegenerative disorders. Mitochondria are vital cell organelles having important roles in different cellular processes, including energy production, calcium signaling, Reactive Oxygen Species (ROS) generation, apoptosis, etc. Therefore, healthy mitochondria are necessary for cell survival and functioning. It would seem feasible that mitochondrial dysfunction will have implications in various pathological conditions. A large body of evidence indicates the role of the mitochondrion as a potential key player in the loss or dysfunction of neurons in various neurodegenerative disorders. In this review, we provide an insight into mitochondrial dysfunction and its involvement in the pathology of several neurological diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Hypoxic- Ischemic Brain Injury, and many more.}, }
@article {pmid33387580, year = {2021}, author = {Thapa, K and Khan, H and Sharma, U and Grewal, AK and Singh, TG}, title = {Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases.}, journal = {Life sciences}, volume = {267}, number = {}, pages = {118975}, doi = {10.1016/j.lfs.2020.118975}, pmid = {33387580}, issn = {1879-0631}, mesh = {Animals ; Central Nervous System Diseases/drug therapy/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/*enzymology/metabolism ; Poly (ADP-Ribose) Polymerase-1/antagonists &amp; inhibitors/genetics/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; }, abstract = {AIMS: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors.<br><br>MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases.<br><br>KEY FINDINGS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated.<br><br>SIGNIFICANCE: In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases.}, }
@article {pmid33382092, year = {2021}, author = {de Jongh, R and Spijkers, XM and Pasteuning-Vuhman, S and Vulto, P and Pasterkamp, RJ}, title = {Neuromuscular junction-on-a-chip: ALS disease modeling and read-out development in microfluidic devices.}, journal = {Journal of neurochemistry}, volume = {157}, number = {3}, pages = {393-412}, doi = {10.1111/jnc.15289}, pmid = {33382092}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; *Computer Simulation ; Humans ; *Lab-On-A-Chip Devices ; Microfluidics/*methods ; Motor Neurons/pathology ; Neuromuscular Junction/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease affecting upper and lower motor neurons with no cure available. Clinical and animal studies reveal that the neuromuscular junction (NMJ), a synaptic connection between motor neurons and skeletal muscle fibers, is highly vulnerable in ALS and suggest that NMJ defects may occur at the early stages of the disease. However, mechanistic insight into how NMJ dysfunction relates to the onset and progression of ALS is incomplete, which hampers therapy development. This is, in part, caused by a lack of robust in vitro models. The ability to combine microfluidic and induced pluripotent stem cell (iPSC) technologies has opened up new avenues for studying molecular and cellular ALS phenotypes in vitro. Microfluidic devices offer several advantages over traditional culture approaches when modeling the NMJ, such as the spatial separation of different cell types and increased control over the cellular microenvironment. Moreover, they are compatible with 3D cell culture, which enhances NMJ functionality and maturity. Here, we review how microfluidic technology is currently being employed to develop more reliable in vitro NMJ models. To validate and phenotype such models, various morphological and functional read-outs have been developed. We describe and discuss the relevance of these read-outs and specifically illustrate how these read-outs have enhanced our understanding of NMJ pathology in ALS. Finally, we share our view on potential future directions and challenges.}, }
@article {pmid33374485, year = {2020}, author = {Stanga, S and Boido, M and Kienlen-Campard, P}, title = {How to Build and to Protect the Neuromuscular Junction: The Role of the Glial Cell Line-Derived Neurotrophic Factor.}, journal = {International journal of molecular sciences}, volume = {22}, number = {1}, pages = {}, pmid = {33374485}, issn = {1422-0067}, support = {"Dipartimenti di Eccellenza 2018-2022" to the Department of Neuroscience "Rita Levi Montalcini"//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Cells, Cultured ; Disease Models, Animal ; Dopaminergic Neurons/metabolism ; Glial Cell Line-Derived Neurotrophic Factor/metabolism/*physiology ; Humans ; Mice ; Motor Neurons ; Muscle, Skeletal/metabolism ; Muscular Atrophy, Spinal/metabolism/physiopathology ; Neurodegenerative Diseases/metabolism ; Neuromuscular Junction/*physiopathology ; Rats ; Substantia Nigra/metabolism ; Synapses/metabolism ; Synaptic Transmission ; }, abstract = {The neuromuscular junction (NMJ) is at the crossroad between the nervous system (NS) and the muscle. Following neurotransmitter release from the motor neurons (MNs), muscle contraction occurs and movement is generated. Besides eliciting muscle contraction, the NMJ represents a site of chemical bidirectional interplay between nerve and muscle with the active participation of Schwann cells. Indeed, signals originating from the muscle play an important role in synapse formation, stabilization, maintenance and function, both in development and adulthood. We focus here on the contribution of the Glial cell line-Derived Neurotrophic Factor (GDNF) to these processes and to its potential role in the protection of the NMJ during neurodegeneration. Historically related to the maintenance and survival of dopaminergic neurons of the substantia nigra, GDNF also plays a fundamental role in the peripheral NS (PNS). At this level, it promotes muscle trophism and it participates to the functionality of synapses. Moreover, compared to the other neurotrophic factors, GDNF shows unique peculiarities, which make its contribution essential in neurodegenerative disorders. While describing the known structural and functional changes occurring at the NMJ during neurodegeneration, we highlight the role of GDNF in the NMJ-muscle cross-talk and we review its therapeutic potential in counteracting the degenerative process occurring in the PNS in progressive and severe diseases such as Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). We also describe functional 3D neuromuscular co-culture systems that have been recently developed as a model for studying both NMJ formation in vitro and its involvement in neuromuscular disorders.}, }
@article {pmid33374313, year = {2020}, author = {Reichert, CO and Levy, D and Bydlowski, SP}, title = {Paraoxonase Role in Human Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {33374313}, issn = {2076-3921}, abstract = {The human body has biological redox systems capable of preventing or mitigating the damage caused by increased oxidative stress throughout life. One of them are the paraoxonase (PON) enzymes. The PONs genetic cluster is made up of three members (PON1, PON2, PON3) that share a structural homology, located adjacent to chromosome seven. The most studied enzyme is PON1, which is associated with high density lipoprotein (HDL), having paraoxonase, arylesterase and lactonase activities. Due to these characteristics, the enzyme PON1 has been associated with the development of neurodegenerative diseases. Here we update the knowledge about the association of PON enzymes and their polymorphisms and the development of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD).}, }
@article {pmid33359391, year = {2021}, author = {Sitruk-Ware, R and Bonsack, B and Brinton, R and Schumacher, M and Kumar, N and Lee, JY and Castelli, V and Corey, S and Coats, A and Sadanandan, N and Gonzales-Portillo, B and Heyck, M and Shear, A and Blaise, C and Zhang, H and Sheyner, M and García-Sánchez, J and Navarro, L and El-Etr, M and De Nicola, AF and Borlongan, CV}, title = {Progress in progestin-based therapies for neurological disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {122}, number = {}, pages = {38-65}, doi = {10.1016/j.neubiorev.2020.12.007}, pmid = {33359391}, issn = {1873-7528}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; R01 NS102395/NS/NINDS NIH HHS/United States ; R21 NS109575/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Progesterone ; *Progestins/therapeutic use ; Receptors, Progesterone ; Spinal Cord Injuries ; }, abstract = {Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.}, }
@article {pmid33358866, year = {2021}, author = {Ikawa, M and Okazawa, H and Yoneda, M}, title = {Molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1865}, number = {3}, pages = {129832}, doi = {10.1016/j.bbagen.2020.129832}, pmid = {33358866}, issn = {1872-8006}, mesh = {Acidosis, Lactic/*diagnostic imaging/metabolism/pathology ; Brain Diseases/*diagnostic imaging/metabolism/pathology ; Electron Transport/genetics ; Fatty Acids/metabolism ; Glucose/metabolism ; Humans ; Lactic Acid/metabolism ; MELAS Syndrome/*diagnostic imaging/metabolism/pathology ; Magnetic Resonance Imaging ; Mitochondria/genetics/*metabolism/pathology ; Mitochondrial Myopathies/*diagnostic imaging/metabolism/pathology ; Molecular Imaging ; Neurodegenerative Diseases/*diagnostic imaging/metabolism/pathology ; Oxidative Stress ; Positron-Emission Tomography ; Severity of Illness Index ; }, abstract = {BACKGROUND: Increasing evidence from pathological and biochemical investigations suggests that mitochondrial metabolic impairment and oxidative stress play a crucial role in the pathogenesis of mitochondrial diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and various neurodegenerative disorders. Recent advances in molecular imaging technology with positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have accomplished a direct and non-invasive evaluation of the pathophysiological changes in living patients.<br><br>SCOPE OF REVIEW: In this review, we focus on the latest achievements of molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders.<br><br>MAJOR CONCLUSIONS: Molecular imaging with PET and MRI exhibited mitochondrial metabolic changes, such as enhanced glucose utilization with lactic acid fermentation, suppressed fatty acid metabolism, decreased TCA-cycle metabolism, impaired respiratory chain activity, and increased oxidative stress, in patients with MELAS syndrome. In addition, PET imaging clearly demonstrated enhanced cerebral oxidative stress in patients with Parkinson's disease or amyotrophic lateral sclerosis. The magnitude of oxidative stress correlated well with clinical severity in patients, indicating that oxidative stress based on mitochondrial dysfunction is associated with the neurodegenerative changes in these diseases.<br><br>GENERAL SIGNIFICANCE: Molecular imaging is a promising tool to improve our knowledge regarding the pathogenesis of diseases associated with mitochondrial dysfunction and oxidative stress, and this would facilitate the development of potential antioxidants and mitochondrial therapies.}, }
@article {pmid33354940, year = {2021}, author = {Birkbeck, MG and Blamire, AM and Whittaker, RG and Sayer, AA and Dodds, RM}, title = {The role of novel motor unit magnetic resonance imaging to investigate motor unit activity in ageing skeletal muscle.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {12}, number = {1}, pages = {17-29}, pmid = {33354940}, issn = {2190-6009}, support = {MC_PC_15030/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Aged ; Aging ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Motor Neurons ; *Muscle, Skeletal/diagnostic imaging ; Sarcopenia/diagnostic imaging/pathology ; }, abstract = {Sarcopenia is a progressive and generalized disease, more common in older adults, which manifests as a loss of muscle strength and mass. The pathophysiology of sarcopenia is still poorly understood with many mechanisms suggested. Age associated changes to the neuromuscular architecture, including motor units and their constituent muscle fibres, represent one such mechanism. Electromyography can be used to distinguish between different myopathies and produce counts of motor units. Evidence from electromyography studies suggests that with age, there is a loss of motor units, increases to the sizes of remaining units, and changes to their activity patterns. However, electromyography is invasive, can be uncomfortable, does not reveal the exact spatial position of motor units within muscle and is difficult to perform in deep muscles. We present a novel diffusion-weighted magnetic resonance imaging technique called 'motor unit magnetic resonance imaging (MUMRI)'. MUMRI aims to improve our understanding of the changes to the neuromuscular system associated with ageing, sarcopenia and other neuromuscular diseases. To date, we have demonstrated that MUMRI can be used to detect statistically significant differences in fasciculation rate of motor units between (n = 4) patients with amyotrophic lateral sclerosis (mean age ± SD: 53 ± 15) and a group of (n = 4) healthy controls (38 ± 7). Patients had significantly higher rates of fasciculation compared with healthy controls (mean = 99.1/min, range = 25.7-161.0 in patients vs. 7.7/min, range = 4.3-9.7 in controls; P < 0.05. MUMRI has detected differences in size, shape, and distribution of single human motor units between (n = 5) young healthy volunteers (29 ± 2.2) and (n = 5) healthy older volunteers (65.6 ± 14.8). The maximum size of motor unit territories in the older group was 12.4 ± 3.3 mm and 9.7 ± 2.7 mm in the young group; P < 0.05. MUMRI is an entirely non-invasive tool, which can be used to detect physiological and pathological changes to motor units in neuromuscular diseases. MUMRI also has the potential to be used as an intermediate outcome measure in sarcopenia trials.}, }
@article {pmid33354328, year = {2020}, author = {Rocha, J and Borges, N and Pinho, O}, title = {Table olives and health: a review.}, journal = {Journal of nutritional science}, volume = {9}, number = {}, pages = {e57}, pmid = {33354328}, issn = {2048-6790}, mesh = {Diet, Mediterranean ; *Fruit ; Humans ; Nutritive Value ; *Olea ; }, abstract = {Table olives, a product of olive tree (Olea europaea L.), is an important fermented product of the Mediterranean Diet. Agronomical factors, particularly the cultivar, the ripening stage and the processing method employed are the main factors influencing the nutritional and non-nutritional composition of table olives and their organoleptic properties. The important nutritional value of this product is due to its richness in monounsaturated fat (MUFA), mainly oleic acid, fibre and vitamin E together with the presence of several phytochemicals. Among these, hydroxytyrosol (HT) is the major phenolic compound present in all types of table olives. There is a scarcity of in vitro, in vivo and human studies of table olives. This review focused comprehensively on the nutrients and bioactive compound content as well as the health benefits assigned to table olives. The possible health benefits associated with their consumption are thought to be primarily related to effects of MUFA on cardiovascular health, the antioxidant (AO) capacity of vitamin E and its role in protecting the body from oxidative damage and the anti-inflammatory and AO activities of HT. The influence of multiple factors on composition of the end product and the potential innovation in the production of table olives through the reduction of its final salt content was also discussed.}, }
@article {pmid33349931, year = {2021}, author = {Sidibé, H and Dubinski, A and Vande Velde, C}, title = {The multi-functional RNA-binding protein G3BP1 and its potential implication in neurodegenerative disease.}, journal = {Journal of neurochemistry}, volume = {157}, number = {4}, pages = {944-962}, pmid = {33349931}, issn = {1471-4159}, support = {//CIHR/Canada ; }, mesh = {Animals ; DNA Helicases/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Poly-ADP-Ribose Binding Proteins/*metabolism ; RNA Helicases/*metabolism ; RNA Recognition Motif Proteins/*metabolism ; }, abstract = {Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) is a multi-functional protein that is best known for its role in the assembly and dynamics of stress granules. Recent studies have highlighted that G3BP1 also has other functions related to RNA metabolism. In the context of disease, G3BP1 has been therapeutically targeted in cancers because its over-expression is correlated with proliferation of cancerous cells and metastasis. However, evidence suggests that G3BP1 is essential for neuronal development and possibly neuronal maintenance. In this review, we will examine the many functions that are carried out by G3BP1 in the context of neurons and speculate how these functions are critical to the progression of neurodegenerative diseases. Additionally, we will highlight the similarities and differences between G3BP1 and the closely related protein G3BP2, which is frequently overlooked. Although G3BP1 and G3BP2 have both been deemed important for stress granule assembly, their roles may differ in other cellular pathways, some of which are specific to the CNS, and presents an opportunity for further exploration.}, }
@article {pmid33348638, year = {2020}, author = {Steinke, A and Kopp, B}, title = {Toward a Computational Neuropsychology of Cognitive Flexibility.}, journal = {Brain sciences}, volume = {10}, number = {12}, pages = {}, pmid = {33348638}, issn = {2076-3425}, support = {n/a//Karlheinz-Hartmann Stiftung/ ; }, abstract = {Cognitive inflexibility is a well-documented, yet non-specific corollary of many neurological diseases. Computational modeling of covert cognitive processes supporting cognitive flexibility may provide progress toward nosologically specific aspects of cognitive inflexibility. We review computational models of the Wisconsin Card Sorting Test (WCST), which represents a gold standard for the clinical assessment of cognitive flexibility. A parallel reinforcement-learning (RL) model provides the best conceptualization of individual trial-by-trial WCST responses among all models considered. Clinical applications of the parallel RL model suggest that patients with Parkinson's disease (PD) and patients with amyotrophic lateral sclerosis (ALS) share a non-specific covert cognitive symptom: bradyphrenia. Impaired stimulus-response learning appears to occur specifically in patients with PD, whereas haphazard responding seems to occur specifically in patients with ALS. Computational modeling hence possesses the potential to reveal nosologically specific profiles of covert cognitive symptoms, which remain undetectable by traditionally applied behavioral methods. The present review exemplifies how computational neuropsychology may advance the assessment of cognitive flexibility. We discuss implications for neuropsychological assessment and directions for future research.}, }
@article {pmid33340024, year = {2021}, author = {Kiernan, MC and Vucic, S and Talbot, K and McDermott, CJ and Hardiman, O and Shefner, JM and Al-Chalabi, A and Huynh, W and Cudkowicz, M and Talman, P and Van den Berg, LH and Dharmadasa, T and Wicks, P and Reilly, C and Turner, MR}, title = {Improving clinical trial outcomes in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {17}, number = {2}, pages = {104-118}, pmid = {33340024}, issn = {1759-4766}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/*therapy ; Clinical Trials as Topic/*methods ; Disease Progression ; Genetic Therapy/methods/trends ; Humans ; Immunomodulating Agents/therapeutic use ; Precision Medicine/methods/trends ; Treatment Outcome ; }, abstract = {Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.}, }
@article {pmid33339180, year = {2020}, author = {Moreno-García, L and López-Royo, T and Calvo, AC and Toivonen, JM and de la Torre, M and Moreno-Martínez, L and Molina, N and Aparicio, P and Zaragoza, P and Manzano, R and Osta, R}, title = {Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {24}, pages = {}, pmid = {33339180}, issn = {1422-0067}, support = {PI17/00949//Instituto de Salud Carlos III/ ; CIBERNED-612-CB18/05/00037//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; }, mesh = {Animals ; Biomarkers/blood/cerebrospinal fluid/urine ; Cell-Free Nucleic Acids/*blood/cerebrospinal fluid/genetics/urine ; *Gene Regulatory Networks ; Humans ; Neurodegenerative Diseases/*blood/cerebrospinal fluid/genetics/urine ; }, abstract = {Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the human transcriptome and are particularly abundant in the central nervous system, where they have been proposed to be involved in the onset and development of NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs and pseudogenes) share a common functionality in their ability to regulate gene expression by modulating miRNAs in a phenomenon known as the competing endogenous RNA mechanism. Moreover, ncRNAs are found in body fluids where their presence and concentration could serve as potential non-invasive biomarkers of NDDs. In this review, we summarize the ceRNA networks described in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and spinocerebellar ataxia type 7, and discuss their potential as biomarkers of these NDDs. Although numerous studies have been carried out, further research is needed to validate these complex interactions between RNAs and the alterations in RNA editing that could provide specific ceRNET profiles for neurodegenerative disorders, paving the way to a better understanding of these diseases.}, }
@article {pmid33335475, year = {2020}, author = {Ulamec, SM and Brockwell, DJ and Radford, SE}, title = {Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {611285}, pmid = {33335475}, issn = {1662-4548}, support = {204963/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyloid proteins are involved in many neurodegenerative disorders such as Alzheimer's disease [Tau, Amyloid β (Aβ)], Parkinson's disease [alpha-synuclein (αSyn)], and amyotrophic lateral sclerosis (TDP-43). Driven by the early observation of the presence of ordered structure within amyloid fibrils and the potential to develop inhibitors of their formation, a major goal of the amyloid field has been to elucidate the structure of the amyloid fold at atomic resolution. This has now been achieved for a wide variety of sequences using solid-state NMR, microcrystallography, X-ray fiber diffraction and cryo-electron microscopy. These studies, together with in silico methods able to predict aggregation-prone regions (APRs) in protein sequences, have provided a wealth of information about the ordered fibril cores that comprise the amyloid fold. Structural and kinetic analyses have also shown that amyloidogenic proteins often contain less well-ordered sequences outside of the amyloid core (termed here as flanking regions) that modulate function, toxicity and/or aggregation rates. These flanking regions, which often form a dynamically disordered "fuzzy coat" around the fibril core, have been shown to play key parts in the physiological roles of functional amyloids, including the binding of RNA and in phase separation. They are also the mediators of chaperone binding and membrane binding/disruption in toxic amyloid assemblies. Here, we review the role of flanking regions in different proteins spanning both functional amyloid and amyloid in disease, in the context of their role in aggregation, toxicity and cellular (dys)function. Understanding the properties of these regions could provide new opportunities to target disease-related aggregation without disturbing critical biological functions.}, }
@article {pmid33335290, year = {2021}, author = {Wilson, EL and Metzakopian, E}, title = {ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms.}, journal = {Cell death and differentiation}, volume = {28}, number = {6}, pages = {1804-1821}, pmid = {33335290}, issn = {1476-5403}, mesh = {Animals ; Endoplasmic Reticulum/*metabolism ; Genetic Testing/*methods ; Humans ; Mice ; Mitochondria/*metabolism ; Neurodegenerative Diseases/*diagnosis/*genetics ; }, abstract = {Mitochondria-ER contact sites (MERCS) are known to underpin many important cellular homoeostatic functions, including mitochondrial quality control, lipid metabolism, calcium homoeostasis, the unfolded protein response and ER stress. These functions are known to be dysregulated in neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD) and amyloid lateral sclerosis (ALS), and the number of disease-related proteins and genes being associated with MERCS is increasing. However, many details regarding MERCS and their role in neurodegenerative diseases remain unknown. In this review, we aim to summarise the current knowledge regarding the structure and function of MERCS, and to update the field on current research in PD, AD and ALS. Furthermore, we will evaluate high-throughput screening techniques, including RNAi vs CRISPR/Cas9, pooled vs arrayed formats and how these could be combined with current techniques to visualise MERCS. We will consider the advantages and disadvantages of each technique and how it can be utilised to uncover novel protein pathways involved in MERCS dysfunction in neurodegenerative diseases.}, }
@article {pmid33333804, year = {2020}, author = {Yousefian-Jazi, A and Seol, Y and Kim, J and Ryu, HL and Lee, J and Ryu, H}, title = {Pathogenic Genome Signatures That Damage Motor Neurons in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {9}, number = {12}, pages = {}, pmid = {33333804}, issn = {2073-4409}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; R01 AG034156/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; DNA-Binding Proteins/chemistry/genetics ; *Genetic Predisposition to Disease ; *Genome, Human ; Humans ; Models, Biological ; Motor Neurons/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease and a neurodegenerative disorder, affecting the upper and/or lower motor neurons. Notably, it invariably leads to death within a few years of onset. Although most ALS cases are sporadic, familial amyotrophic lateral sclerosis (fALS) forms 10% of the cases. In 1993, the first causative gene (SOD1) of fALS was identified. With rapid advances in genetics, over fifty potentially causative or disease-modifying genes have been found in ALS so far. Accordingly, routine diagnostic tests should encompass the oldest and most frequently mutated ALS genes as well as several new important genetic variants in ALS. Herein, we discuss current literatures on the four newly identified ALS-associated genes (CYLD, S1R, GLT8D1, and KIF5A) and the previously well-known ALS genes including SOD1, TARDBP, FUS, and C9orf72. Moreover, we review the pathogenic implications and disease mechanisms of these genes. Elucidation of the cellular and molecular functions of the mutated genes will bring substantial insights for the development of therapeutic approaches to treat ALS.}, }
@article {pmid33329356, year = {2020}, author = {Strong, MJ and Donison, NS and Volkening, K}, title = {Alterations in Tau Metabolism in ALS and ALS-FTSD.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {598907}, pmid = {33329356}, issn = {1664-2295}, abstract = {There is increasing acceptance that amyotrophic lateral sclerosis (ALS), classically considered a neurodegenerative disease affecting almost exclusively motor neurons, is syndromic with both clinical and biological heterogeneity. This is most evident in its association with a broad range of neuropsychological, behavioral, speech and language deficits [collectively termed ALS frontotemporal spectrum disorder (ALS-FTSD)]. Although the most consistent pathology of ALS and ALS-FTSD is a disturbance in TAR DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein (tau) metabolism can also be observed in ALS-FTSD, most prominently as pathological phosphorylation at Thr[175] (pThr[175]tau). pThr[175] has been shown to promote exposure of the phosphatase activating domain (PAD) in the tau N-terminus with the consequent activation of GSK3β mediated phosphorylation at Thr[231] (pThr[231]tau) leading to pathological oligomer formation. This pathological cascade of tau phosphorylation has been observed in chronic traumatic encephalopathy with ALS (CTE-ALS) and in both in vivo and in vitro experimental paradigms, suggesting that it is of critical relevance to the pathobiology of ALS-FTSD. It is also evident that the co-existence of alterations in the metabolism of TDP-43 and tau acts synergistically in a rodent model to exacerbate the pathology of either.}, }
@article {pmid33328424, year = {2021}, author = {Yagishita, A}, title = {[Definitions and MR imaging of duropathies].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {61}, number = {1}, pages = {1-5}, doi = {10.5692/clinicalneurol.cn-001530}, pmid = {33328424}, issn = {1882-0654}, mesh = {Aged ; Cerebrospinal Fluid Leak/*diagnostic imaging/pathology ; Cervical Vertebrae ; Diffusion Tensor Imaging/*methods ; Dura Mater/*abnormalities/*diagnostic imaging/pathology ; Female ; Humans ; Male ; Middle Aged ; Muscular Atrophy, Spinal/*diagnostic imaging/pathology ; Siderosis/*diagnostic imaging/pathology ; Thoracic Vertebrae ; }, abstract = {Kumar defined duropathies as disorders with dural defects-related cerebrospinal fluid leaks, particularly of spinal anterior dura mater, Superficial (hemo) siderosis (SS) and multisegemental amyotrophy (MSAM) were included in duropathies. Dural defects of SS had two types; one was incomplete closure of the dura in the spinal and cranial operations, the other was a spontaneous defect in the spinal anterior dura mater. In a majority of SS patients, spontaneous dural defects were detected at the levels of C7/Th1 to Th2/Th3 on axial FIESTA (fast imaging employing steady state acquisition) images. Similarly, dural defects in our 6 cases with MSAM were showed at C7/Th1 to Th2/Th3. Axial FIESTA images were crucial on MR imaging. T2 weighted images demonstrated abnormal hyperintense lesions in both anterior horns at the level of C3 spinal cord in all of 7 patients with MSAM. A dural defect in one case was not found.}, }
@article {pmid33324162, year = {2020}, author = {Granzotto, A and Canzoniero, LMT and Sensi, SL}, title = {A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {600089}, pmid = {33324162}, issn = {1662-5099}, abstract = {Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer's, Parkinson's, and Huntington's diseases, and Amyotrophic Lateral Sclerosis. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.}, }
@article {pmid33323321, year = {2021}, author = {Gunay, A and Shin, HH and Gozutok, O and Gautam, M and Ozdinler, PH}, title = {Importance of lipids for upper motor neuron health and disease.}, journal = {Seminars in cell &amp; developmental biology}, volume = {112}, number = {}, pages = {92-104}, pmid = {33323321}, issn = {1096-3634}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Axons/metabolism/pathology ; Cerebral Cortex/metabolism/pathology ; Dendrites/genetics/metabolism/pathology ; Humans ; Lipid Metabolism/*genetics ; Lipids/genetics ; Motor Neuron Disease/genetics/*metabolism/pathology ; Motor Neurons/*metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Building evidence reveals the importance of maintaining lipid homeostasis for the health and function of neurons, and upper motor neurons (UMNs) are no exception. UMNs are critically important for the initiation and modulation of voluntary movement as they are responsible for conveying cerebral cortex' input to spinal cord targets. To maintain their unique cytoarchitecture with a prominent apical dendrite and a very long axon, UMNs require a stable cell membrane, a lipid bilayer. Lipids can act as building blocks for many biomolecules, and they also contribute to the production of energy. Therefore, UMNs require sustained control over the production, utilization and homeostasis of lipids. Perturbations of lipid homeostasis lead to UMN vulnerability and progressive degeneration in diseases such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Here, we discuss the importance of lipids, especially for UMNs.}, }
@article {pmid33310868, year = {2020}, author = {Vassileff, N and Cheng, L and Hill, AF}, title = {Extracellular vesicles - propagators of neuropathology and sources of potential biomarkers and therapeutics for neurodegenerative diseases.}, journal = {Journal of cell science}, volume = {133}, number = {23}, pages = {}, doi = {10.1242/jcs.243139}, pmid = {33310868}, issn = {1477-9137}, mesh = {*Alzheimer Disease ; Biomarkers ; *Extracellular Vesicles ; Humans ; *Neurodegenerative Diseases/therapy ; Neurons ; }, abstract = {Neurodegenerative diseases are characterised by the irreversible degeneration of neurons in the central or peripheral nervous systems. These include amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Small extracellular vesicles (sEVs), a type of EV involved in cellular communication, have been well documented as propagating neurodegenerative diseases. These sEVs carry cargo, such as proteins and RNA, to recipient cells but are also capable of promoting protein misfolding, thus actively contributing to the progression of these diseases. sEV secretion is also a compensatory process for lysosomal dysfunction in the affected cells, despite inadvertently propagating disease to recipient cells. Despite this, sEV miRNAs have biomarker potential for the early diagnosis of these diseases, while stem cell-derived sEVs and those generated through exogenous assistance demonstrate the greatest therapeutic potential. This Review will highlight novel advancements in the involvement of sEVs as propagators of neuropathology, biomarkers and potential therapeutics in neurodegenerative diseases.}, }
@article {pmid33307166, year = {2021}, author = {Coppedè, F}, title = {One-carbon epigenetics and redox biology of neurodegeneration.}, journal = {Free radical biology &amp; medicine}, volume = {170}, number = {}, pages = {19-33}, doi = {10.1016/j.freeradbiomed.2020.12.002}, pmid = {33307166}, issn = {1873-4596}, mesh = {Biology ; *Carbon ; DNA Methylation ; Epigenesis, Genetic ; Humans ; *Neurodegenerative Diseases/genetics ; Oxidation-Reduction ; }, abstract = {One-carbon metabolism provides the methyl groups for both DNA and histone tail methylation reactions, two of the main epigenetic processes that tightly regulate the chromatin structure and gene expression levels. Several enzymes involved in one-carbon metabolism, as well as several epigenetic enzymes, are regulated by intracellular metabolites and redox cofactors, but their expression levels are in turn regulated by epigenetic modifications, in such a way that metabolism and gene expression reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival, differentiation and response to environmental stimuli. Increasing evidence highlights the contribution of impaired one-carbon metabolism and epigenetic modifications in neurodegeneration. This article provides an overview of DNA and histone tail methylation changes in major neurodegenerative disorders, namely Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, discussing the contribution of oxidative stress and impaired one-carbon and redox metabolism to their onset and progression.}, }
@article {pmid33302404, year = {2020}, author = {Török, N and Tanaka, M and Vécsei, L}, title = {Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway.}, journal = {International journal of molecular sciences}, volume = {21}, number = {24}, pages = {}, pmid = {33302404}, issn = {1422-0067}, support = {2.3.2-15-2016-00034//GINOP/ ; 2.3.2-15-2016-00048 (Stay Alive)//GINOP/ ; 2020//T&#xe9;mater&#xfc;leti Kiv&#xe1;l&#xf3;s&#xe1;gi Program/ ; 2020//TKP2020 Thematic Excellence Programme/ ; Grant number 5070//University of Szeged Open Access Fund (FundRef)/ ; }, mesh = {Animals ; Biomarkers/metabolism ; Brain/metabolism ; Gastrointestinal Microbiome ; Humans ; Kynurenine/*metabolism ; Neurodegenerative Diseases/*metabolism/microbiology/pathology ; Tryptophan/*metabolism ; }, abstract = {Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to the abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes, which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of KP alterations observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota in the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.}, }
@article {pmid33299526, year = {2020}, author = {Silva, JM and Nobre, MSC and Albino, SL and Lócio, LL and Nascimento, APS and Scotti, L and Scotti, MT and Oshiro-Junior, JA and Lima, MCA and Mendonça-Junior, FJB and Moura, RO}, title = {Secondary Metabolites with Antioxidant Activities for the Putative Treatment of Amyotrophic Lateral Sclerosis (ALS): "Experimental Evidences".}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {5642029}, pmid = {33299526}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Antioxidants/*metabolism ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/*pathology ; Oxidative Stress/*physiology ; Secondary Metabolism/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that is characterized by progressive loss of the upper and lower motor neurons at the spinal or bulbar level. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain are factors that contribute to neurodegeneration and perform a potential role in the pathogenesis of ALS. Natural antioxidant molecules have been proposed as an alternative form of treatment for the prevention of age-related neurological diseases, in which ALS is included. Researches support that regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in this disease, and antioxidant drugs are aimed at a promising pathway to treatment. Among the strategies used for obtaining new drugs, we can highlight the isolation of secondary metabolite compounds from natural sources that, along with semisynthetic derivatives, correspond to approximately 40% of the drugs found on the market. Among these compounds, we emphasize oxygenated and nitrogenous compounds, such as flavonoids, coumarins, and alkaloids, in addition to the fatty acids, that already stand out in the literature for their antioxidant properties, consisting in a part of the diets of millions of people worldwide. Therefore, this review is aimed at presenting and summarizing the main articles published within the last years, which represent the therapeutic potential of antioxidant compounds of natural origin for the treatment of ALS.}, }
@article {pmid33292860, year = {2020}, author = {Otani, K and Shichita, T}, title = {Cerebral sterile inflammation in neurodegenerative diseases.}, journal = {Inflammation and regeneration}, volume = {40}, number = {1}, pages = {28}, pmid = {33292860}, issn = {1880-9693}, abstract = {Therapeutic strategies for regulating neuroinflammation are expected in the development of novel therapeutic agents to prevent the progression of central nervous system (CNS) pathologies. An understanding of the detailed molecular and cellular mechanisms of neuroinflammation in each CNS disease is necessary for the development of therapeutics. Since the brain is a sterile organ, neuroinflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) is triggered by cerebral cellular damage or the abnormal accumulation of inflammatogenic molecules in CNS tissue through the activation of innate and acquired immunity. Inflammation and CNS pathologies worsen each other through various cellular and molecular mechanisms, such as oxidative stress or the accumulation of inflammatogenic molecules induced in the damaged CNS tissue. In this review, we summarize the recent evidence regarding sterile immune responses in neurodegenerative diseases.}, }
@article {pmid33281563, year = {2020}, author = {Dudman, J and Qi, X}, title = {Stress Granule Dysregulation in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {598517}, pmid = {33281563}, issn = {1662-5102}, support = {R01 AG065240/AG/NIA NIH HHS/United States ; R01 NS115903/NS/NINDS NIH HHS/United States ; R21 NS107897/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no current cure. ALS causes degeneration of both upper and lower motor neurons leading to atrophy of the innervating muscles and progressive paralysis. The exact mechanism of the pathology of ALS is unknown. However, 147 genes have been identified that are causative, associated with, or modify disease progression. While the causative mechanism is unknown, a number of pathological processes have been associated with ALS. These include mitochondrial dysfunction, protein accumulation, and defects in RNA metabolism. RNA metabolism is a complicated process that is regulated by many different RNA-binding proteins (RBPs). A small defect in RNA metabolism can produce results as dramatic as determining cell survival. Stress granules (SGs) control RNA translation during stressed conditions. This is a protective reaction, but in conditions of chronic stress can become pathogenic. SGs are even hypothesized to act as a seeding mechanism for the pathological aggregation of proteins seen in many neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) in ALS. In this review, we will be summarizing the current findings of SG pathology in ALS. We also focus on the role of SG dysregulation in protein aggregate formation and mitochondrial dysfunction. In addition, we outline therapeutic strategies that target SG components in ALS.}, }
@article {pmid33281562, year = {2020}, author = {Castellanos-Montiel, MJ and Chaineau, M and Durcan, TM}, title = {The Neglected Genes of ALS: Cytoskeletal Dynamics Impact Synaptic Degeneration in ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {594975}, pmid = {33281562}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons (MNs) of the cortex, brainstem, and spinal cord. Several genes have been linked to both familial (fALS) and sporadic (sALS) cases of ALS. Among all the ALS-related genes, a group of genes known to directly affect cytoskeletal dynamics (ALS2, DCTN1, PFN1, KIF5A, NF-L, NF-H, PRPH, SPAST, and TUBA4A) is of high importance for MN health and survival, considering that MNs are large polarized cells with axons that can reach up to 1 m in length. In particular, cytoskeletal dynamics facilitate the transport of organelles and molecules across the long axonal distances within the cell, playing a key role in synapse maintenance. The majority of ALS-related genes affecting cytoskeletal dynamics were identified within the past two decades, making it a new area to explore for ALS. The purpose of this review is to provide insights into ALS-associated cytoskeletal genes and outline how recent studies have pointed towards novel pathways that might be impacted in ALS. Further studies making use of extensive analysis models to look for true hits, the newest technologies such as CRIPSR/Cas9, human induced pluripotent stem cells (iPSCs) and axon sequencing, as well as the development of more transgenic animal models could potentially help to: differentiate the variants that truly act as a primary cause of the disease from the ones that act as risk factors or disease modifiers, identify potential interactions between two or more ALS-related genes in disease onset and progression and increase our understanding of the molecular mechanisms leading to cytoskeletal defects. Altogether, this information will give us a hint on the real contribution of the cytoskeletal ALS-related genes during this lethal disease.}, }
@article {pmid33280374, year = {2020}, author = {Yeong, KY and Berdigaliyev, N and Chang, Y}, title = {Sirtuins and Their Implications in Neurodegenerative Diseases from a Drug Discovery Perspective.}, journal = {ACS chemical neuroscience}, volume = {11}, number = {24}, pages = {4073-4091}, doi = {10.1021/acschemneuro.0c00696}, pmid = {33280374}, issn = {1948-7193}, mesh = {*Alzheimer Disease/drug therapy ; Drug Discovery ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease ; *Sirtuins ; }, abstract = {Sirtuins are class III histone deacetylase (HDAC) enzymes that target both histone and non-histone substrates. They are linked to different brain functions and the regulation of different isoforms of these enzymes is touted to be an emerging therapy for the treatment of neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). The level of sirtuins affects brain health as many sirtuin-regulated pathways are responsible for the progression of NDs. Certain sirtuins are also implicated in aging, which is a risk factor for many NDs. In addition to SIRT1-3, it has been suggested that the less studied sirtuins (SIRT4-7) also play critical roles in brain health. This review delineates the role of each sirtuin isoform in NDs from a disease centric perspective and provides an up-to-date overview of sirtuin modulators and their potential use as therapeutics in these diseases. Furthermore, the future perspectives for sirtuin modulator development and their therapeutic application in neurodegeneration are outlined in detail, hence providing a research direction for future studies.}, }
@article {pmid33280067, year = {2021}, author = {Oggiano, R and Pisano, A and Sabalic, A and Farace, C and Fenu, G and Lintas, S and Forte, G and Bocca, B and Madeddu, R}, title = {An overview on amyotrophic lateral sclerosis and cadmium.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {2}, pages = {531-537}, pmid = {33280067}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; Animals ; Cadmium/toxicity ; *Neurodegenerative Diseases ; }, abstract = {The present review represents an update about the knowledge of the possible role of Cadmium (Cd) in amyotrophic lateral sclerosis (ALS) initiation and its progression. ALS is a neurodegenerative disease that occurs in adulthood; its etiology is unknown and leads to death within a few years from its appearance. Among the various possible causes that can favor the development of the disease, heavy metals cannot be excluded. Cadmium is a heavy metal that does not play a biological role, but its neurotoxicity is well known. Numerous in vitro studies on cell and animal models confirm the toxicity of the metal on the nervous system, but these data are not accompanied by an epidemiological evidence, and, thus, an unclear correlation between Cd and the onset of the disease can be pointed out. On the other hand, a possible multifactorial and synergic mechanism in which Cd may have a role can explain the ALS onset. More efforts in new clinical, biochemical, and epidemiological studies are necessary to better elucidate the involvement of Cd in this lethal disease.}, }
@article {pmid33276458, year = {2020}, author = {Hervás, R and Oroz, J}, title = {Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly.}, journal = {International journal of molecular sciences}, volume = {21}, number = {23}, pages = {}, pmid = {33276458}, issn = {1422-0067}, support = {BBM-TRA-0203//Fundaci&#xf3;n BBVA/ ; PID2019-109276RA-I00//Spanish AEI/EU-FEDER/ ; }, mesh = {Amyloid/metabolism ; Animals ; *Disease Susceptibility ; HSP70 Heat-Shock Proteins/chemistry/genetics/metabolism ; HSP90 Heat-Shock Proteins/chemistry/genetics/metabolism ; Humans ; Molecular Chaperones/*chemistry/genetics/isolation &amp; purification/*metabolism ; Protein Aggregation, Pathological ; Protein Binding ; Proteostasis Deficiencies/*etiology/*metabolism ; Structure-Activity Relationship ; }, abstract = {Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer's, Parkinson's, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.}, }
@article {pmid33274002, year = {2020}, author = {Cunha-Oliveira, T and Montezinho, L and Mendes, C and Firuzi, O and Saso, L and Oliveira, PJ and Silva, FSG}, title = {Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {5021694}, pmid = {33274002}, issn = {1942-0994}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Antioxidants/*therapeutic use ; Disease Models, Animal ; Humans ; *Motor Neurons/metabolism/pathology ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/*drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2-5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.}, }
@article {pmid33270954, year = {2021}, author = {Rõlova, T and Lehtonen, &#x160; and Goldsteins, G and Kettunen, P and Koistinaho, J}, title = {Metabolic and immune dysfunction of glia in neurodegenerative disorders: Focus on iPSC models.}, journal = {Stem cells (Dayton, Ohio)}, volume = {39}, number = {3}, pages = {256-265}, doi = {10.1002/stem.3309}, pmid = {33270954}, issn = {1549-4918}, mesh = {Animals ; Astrocytes/metabolism ; Brain/metabolism ; Humans ; Induced Pluripotent Stem Cells/*metabolism ; Neurodegenerative Diseases/*therapy ; Neuroglia/*metabolism ; Neurons/*metabolism ; }, abstract = {The research on neurodegenerative disorders has long focused on neuronal pathology and used transgenic mice as disease models. However, our understanding of the chronic neurodegenerative process in the human brain is still very limited. It is increasingly recognized that neuronal loss is not caused solely by intrinsic degenerative processes but rather via impaired interactions with surrounding glia and other brain cells. Dysfunctional astrocytes do not provide sufficient nutrients and antioxidants to the neurons, while dysfunctional microglia cannot efficiently clear pathogens and cell debris from extracellular space, thus resulting in chronic inflammatory processes in the brain. Importantly, human glia, especially the astrocytes, differ significantly in morphology and function from their mouse counterparts, and therefore more human-based disease models are needed. Recent advances in stem cell technology make it possible to reprogram human patients' somatic cells to induced pluripotent stem cells (iPSC) and differentiate them further into patient-specific glia and neurons, thus providing a virtually unlimited source of human brain cells. This review summarizes the recent studies using iPSC-derived glial models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discusses the applicability of these models to drug testing. This line of research has shown that targeting glial metabolism can improve the survival and function of cocultured neurons and thus provide a basis for future neuroprotective treatments.}, }
@article {pmid33265993, year = {2020}, author = {Szeliga, M}, title = {Peroxiredoxins in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {12}, pages = {}, pmid = {33265993}, issn = {2076-3921}, abstract = {Substantial evidence indicates that oxidative/nitrosative stress contributes to the neurodegenerative diseases. Peroxiredoxins (PRDXs) are one of the enzymatic antioxidant mechanisms neutralizing reactive oxygen/nitrogen species. Since mammalian PRDXs were identified 30 years ago, their significance was long overshadowed by the other well-studied ROS/RNS defense systems. An increasing number of studies suggests that these enzymes may be involved in the neurodegenerative process. This article reviews the current knowledge on the expression and putative roles of PRDXs in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies, multiple sclerosis, amyotrophic lateral sclerosis and Huntington's disease.}, }
@article {pmid33261024, year = {2020}, author = {Castro, AF and Loureiro, JR and Bessa, J and Silveira, I}, title = {Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries.}, journal = {Genes}, volume = {11}, number = {12}, pages = {}, pmid = {33261024}, issn = {2073-4425}, mesh = {Animals ; *DNA Repeat Expansion ; Disease Models, Animal ; Drosophila melanogaster/genetics ; Forecasting ; Gene Expression Regulation/genetics ; Humans ; Introns/genetics ; Mice ; Mice, Knockout ; Molecular Targeted Therapy ; Mutagenesis, Insertional ; Neurodegenerative Diseases/*genetics ; Neuromuscular Diseases/*genetics ; Peptides/genetics ; Poly A/genetics ; RNA Interference ; RNA Splicing/genetics ; RNA, Antisense/*biosynthesis/genetics ; Spinocerebellar Ataxias/genetics ; Transcription, Genetic ; Trinucleotide Repeat Expansion ; }, abstract = {Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype. Notably, antisense repeat RNAs from spinocerebellar ataxia type 7, myotonic dystrophy type 1, Huntington's disease and frontotemporal dementia/amyotrophic lateral sclerosis associated genes have been implicated in transcriptional regulation of sense gene expression, acting either at a transcriptional or posttranscriptional level. The recent evidence that antisense repeat RNAs could modulate gene expression broadens our understanding of the pathogenic pathways and adds more complexity to the development of therapeutic strategies for these disorders. In this review, we cover the amazing progress made in the understanding of the pathogenic mechanisms associated with repeat expansion neurodegenerative and neuromuscular diseases with a focus on the impact of antisense repeat transcription in the development of efficient therapies.}, }
@article {pmid33260927, year = {2020}, author = {Crabé, R and Aimond, F and Gosset, P and Scamps, F and Raoul, C}, title = {How Degeneration of Cells Surrounding Motoneurons Contributes to Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {9}, number = {12}, pages = {}, pmid = {33260927}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Astrocytes/pathology ; Humans ; Interneurons/pathology ; Motor Neurons/*pathology ; Neuroglia/pathology ; Oligodendroglia/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal cord accompanies and even precedes motoneuron elimination. In this review, we provide striking evidence that the degeneration of astrocytes and oligodendrocytes, in addition to inhibitory and modulatory interneurons, disrupt the functionally coherent environment of motoneurons. We discuss the extent to which the degeneration of glial cells and interneurons also contributes to the decline of the motor system. This pathogenic cellular network therefore represents a novel strategic field of therapeutic investigation.}, }
@article {pmid33259795, year = {2021}, author = {Eleutherio, ECA and Silva Magalhães, RS and de Araújo Brasil, A and Monteiro Neto, JR and de Holanda Paranhos, L}, title = {SOD1, more than just an antioxidant.}, journal = {Archives of biochemistry and biophysics}, volume = {697}, number = {}, pages = {108701}, doi = {10.1016/j.abb.2020.108701}, pmid = {33259795}, issn = {1096-0384}, mesh = {Amino Acid Sequence ; Animals ; Antioxidants/chemistry/*metabolism ; Health ; Humans ; Superoxide Dismutase-1/chemistry/*metabolism ; }, abstract = {During cellular respiration, radicals, such as superoxide, are produced, and in a large concentration, they may cause cell damage. To combat this threat, the cell employs the enzyme Cu/Zn Superoxide Dismutase (SOD1), which converts the radical superoxide into molecular oxygen and hydrogen peroxide, through redox reactions. Although this is its main function, recent studies have shown that the SOD1 has other functions that deviates from its original one including activation of nuclear gene transcription or as an RNA binding protein. This comprehensive review looks at the most important aspects of human SOD1 (hSOD1), including the structure, properties, and characteristics as well as transcriptional and post-translational modifications (PTM) that the enzyme can receive and their effects, and its many functions. We also discuss the strategies currently used to analyze it to better understand its participation in diseases linked to hSOD1 including Amyotrophic Lateral Sclerosis (ALS), cancer, and Parkinson.}, }
@article {pmid33259633, year = {2021}, author = {Pang, W and Hu, F}, title = {Cellular and physiological functions of C9ORF72 and implications for ALS/FTD.}, journal = {Journal of neurochemistry}, volume = {157}, number = {3}, pages = {334-350}, pmid = {33259633}, issn = {1471-4159}, support = {R01 NS088448/NS/NINDS NIH HHS/United States ; R01 NS095954/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Autophagy-Related Proteins/genetics ; C9orf72 Protein/*genetics ; Carrier Proteins/genetics ; Encephalitis/genetics/pathology ; Frontotemporal Dementia/*genetics ; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mutation/genetics ; Proteomics ; }, abstract = {The hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the main cause of two tightly linked neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). HRE leads to not only a gain of toxicity from RNA repeats and dipeptide repeats but also reduced levels of C9ORF72 protein. However, the cellular and physiological functions of C9ORF72 were unknown until recently. Through proteomic analysis, Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41) were identified as binding partners of C9ORF72. These three proteins have been shown to form a tight complex, but the exact functions of this complex remain to be characterized. Both C9ORF72 and SMCR8 contain a DENN domain, which has been shown to regulate the activities of small GTPases. The C9ORF72 complex has been implicated in many cellular processes, including vesicle trafficking, lysosome homeostasis, mTORC1 signaling , and autophagy. C9ORF72 deficiency in mice results in exaggerated inflammatory responses and human patients with C9ORF72 mutations have neuroinflammation phenotype. Recent studies indicate that C9ORF72 regulates trafficking and lysosomal degradation of inflammatory mediators, including toll-like receptors (TLRs) and STING, to affect inflammatory outputs. Further exploration of cellular and physiological functions of C9ORF72 will help dissect the pathological mechanism of ALS/FTD caused by C9ORF72 mutations.}, }
@article {pmid33257883, year = {2021}, author = {Patterson, V}, title = {Neurological telemedicine in the COVID-19 era.}, journal = {Nature reviews. Neurology}, volume = {17}, number = {2}, pages = {73-74}, pmid = {33257883}, issn = {1759-4766}, mesh = {COVID-19/epidemiology/*prevention &amp; control/transmission ; Humans ; Nervous System Diseases/*therapy ; Neurology/*organization &amp; administration ; Telemedicine/*organization &amp; administration ; }, abstract = {Many neurologists have used telemedicine during the COVID-19 pandemic. Studies have shown that videolinks in acute care can save personal protective equipment and protect staff. Furthermore, the telephone can provide supra-hospital care in Parkinson disease and manage patients with amyotrophic lateral sclerosis well. The primacy of face-to face care has been dented.}, }
@article {pmid33256133, year = {2020}, author = {Vasilopoulou, C and Morris, AP and Giannakopoulos, G and Duguez, S and Duddy, W}, title = {What Can Machine Learning Approaches in Genomics Tell Us about the Molecular Basis of Amyotrophic Lateral Sclerosis?.}, journal = {Journal of personalized medicine}, volume = {10}, number = {4}, pages = {}, pmid = {33256133}, issn = {2075-4426}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common late-onset motor neuron disorder, but our current knowledge of the molecular mechanisms and pathways underlying this disease remain elusive. This review (1) systematically identifies machine learning studies aimed at the understanding of the genetic architecture of ALS, (2) outlines the main challenges faced and compares the different approaches that have been used to confront them, and (3) compares the experimental designs and results produced by those approaches and describes their reproducibility in terms of biological results and the performances of the machine learning models. The majority of the collected studies incorporated prior knowledge of ALS into their feature selection approaches, and trained their machine learning models using genomic data combined with other types of mined knowledge including functional associations, protein-protein interactions, disease/tissue-specific information, epigenetic data, and known ALS phenotype-genotype associations. The importance of incorporating gene-gene interactions and cis-regulatory elements into the experimental design of future ALS machine learning studies is highlighted. Lastly, it is suggested that future advances in the genomic and machine learning fields will bring about a better understanding of ALS genetic architecture, and enable improved personalized approaches to this and other devastating and complex diseases.}, }
@article {pmid33255513, year = {2020}, author = {Bell, SM and Burgess, T and Lee, J and Blackburn, DJ and Allen, SP and Mortiboys, H}, title = {Peripheral Glycolysis in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {23}, pages = {}, pmid = {33255513}, issn = {1422-0067}, support = {na//Neuroscience Research Institute Foundation/ ; ARUK-PCRF2016A-1//Alzheimer's Research UK/ ; F-1301/PUK_/Parkinson's UK/United Kingdom ; NA//NIHR Sheffield Biomedical Research Center/ ; 216340/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; F1301/PUK_/Parkinson's UK/United Kingdom ; }, mesh = {Adenosine Triphosphate/*biosynthesis ; Alzheimer Disease/genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Brain/metabolism ; Glucose/*metabolism ; Glycolysis/*genetics ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Parkinson Disease/genetics/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients' needs to be accomplished first to meet this aim.}, }
@article {pmid33251731, year = {2020}, author = {Brüggen, MC and Stingl, G}, title = {[Not Available].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {18}, number = {11}, pages = {1225-1228}, doi = {10.1111/ddg.14335_g}, pmid = {33251731}, issn = {1610-0387}, abstract = {Die äußere Begrenzung des Körpers von Säugetieren, die Haut, besteht aus drei Schichten, Epidermis, Dermis und subkutanem weissem Fettgewebe (subcutaneous white adipose tissue, SWAT). Während die Epidermis und Dermis hinsichtlich ihrer Funktion als «Immunbarriere» eingehend charakterisiert sind, ist über das SWAT nur wenig bekannt. SWAT des Menschen setzt sich aus Läppchen zusammen, die vor allem aus Adipozyten bestehen und durch vaskularisierte Bindegewebssepten unterteilt und voneinander getrennt werden. Eine immun-phänotypische Untersuchung von durch Fettabsaugung gewonnenem SWAT zeigte, dass gesundes SWAT keine Entzündungszeichen aufweist, jedoch Immunzellen beherbergt. Im Unterschied zur restlichen Haut handelt es sich dabei hauptsächlich um Makrophagen und, in geringerem Maße, T- Lymphozyten, deren Phänotyp darauf hinweist, dass ihnen primär anti-inflammatorische und regulierende Funktionen zukommen. SWAT besitzt also nicht nur eine mechanische, sondern möglicherweise auch immunologische Schutzfunktion, die darin besteht, überschießende Immun- sowie Entzündungsreaktionen zu verhindern oder zumindest abzumildern.}, }
@article {pmid33244966, year = {2020}, author = {Alessenko, AV and Gutner, UA and Nebogatikov, VO and Shupik, MA and Ustyugov, AA}, title = {[The role of lipids in the pathogenesis of lateral amyotrophic sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {120}, number = {10}, pages = {108-117}, doi = {10.17116/jnevro2020120101108}, pmid = {33244966}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; C9orf72 Protein ; Humans ; Lipids ; *Motor Neuron Disease ; Mutation ; *Neurodegenerative Diseases ; RNA-Binding Protein FUS/genetics ; Sclerosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by selective degeneration of motor neurons of the motor cortex, brain stem and brain stem. Mutations in genes coding for SOD1, C9ORF72, TDP-43, FUS and others are associated with ALS and result in abnormal processing and transport of RNA as well as changes in the dynamics of cytoskeleton. In addition, a sharp change in the metabolism of various lipid classes, including phospholipids, fatty acids, sphingolipids, etc., was detected. This review describes changes in lipid content and activity of enzymes involved in their metabolism in ALS animal models as well as in patients. Changes in the metabolism of fatty acids, phospholipids, cholesterol and its derivatives are reviewed in detail. The prospects of searching for new drugs among modulators of lipid metabolism enzymes are discussed.}, }
@article {pmid33239064, year = {2020}, author = {Kwon, HS and Koh, SH}, title = {Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes.}, journal = {Translational neurodegeneration}, volume = {9}, number = {1}, pages = {42}, pmid = {33239064}, issn = {2047-9158}, support = {2018R1A2A2A15023219//Ministry of Science, ICT and Future Planning/International ; grant number: HI20C0253//Ministry of Health and Welfare/International ; 2017R1A5A2015395//Medical Research Centre/International ; }, mesh = {Animals ; Astrocytes/immunology/*metabolism/pathology ; Humans ; Inflammation/diagnosis/immunology/metabolism ; Inflammation Mediators/immunology/*metabolism ; Microglia/immunology/*metabolism/pathology ; Neurodegenerative Diseases/*diagnosis/immunology/*metabolism ; }, abstract = {Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.}, }
@article {pmid33229216, year = {2021}, author = {Evans, TA and Erwin, JA}, title = {Retroelement-derived RNA and its role in the brain.}, journal = {Seminars in cell &amp; developmental biology}, volume = {114}, number = {}, pages = {68-80}, doi = {10.1016/j.semcdb.2020.11.001}, pmid = {33229216}, issn = {1096-3634}, mesh = {Animals ; Brain/*physiology ; Humans ; RNA/*genetics ; Retroelements/*genetics ; }, abstract = {Comprising ~40% of the human genome, retroelements are mobile genetic elements which are transcribed into RNA, then reverse-transcribed into DNA and inserted into a new site in the genome. Retroelements are referred to as "genetic parasites", residing among host genes and relying on host machinery for transcription and evolutionary propagation. The healthy brain has the highest expression of retroelement-derived sequences compared to other somatic tissue, which leads to the question: how does retroelement-derived RNA influence human traits and cellular states? While the functional importance of upregulating retroelement expression in the brain is an active area of research, RNA species derived from retroelements influence both self- and host gene expression by contributing to chromatin remodeling, alternative splicing, somatic mosaicism and translational repression. Here, we review the emerging evidence that the functional importance of RNA derived from retroelements is multifaceted. Retroelements can influence organismal states through the seeding of epigenetic states in chromatin, the production of structured RNA and even catalytically active ribozymes, the generation of cytoplasmic ssDNA and RNA/DNA hybrids, the production of viral-like proteins, and the generation of somatic mutations. Comparative sequencing suggests that retroelements can contribute to intraspecies variation through these mechanisms to alter transcript identity and abundance. In humans, an increasing number of neurodevelopmental and neurodegenerative conditions are associated with dysregulated retroelements, including Aicardi-Goutieres syndrome (AGS), Rett syndrome (RTT), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), schizophrenia (SZ), and aging. Taken together, these concepts suggest a larger functional role for RNA derived from retroelements. This review aims to define retroelement-derived RNA, discuss how it impacts the mammalian genome, as well as summarize data supporting phenotypic consequences of this unique RNA subset in the brain.}, }
@article {pmid33228439, year = {2021}, author = {Pant, DC and Nazarko, TY}, title = {Selective autophagy: the rise of the zebrafish model.}, journal = {Autophagy}, volume = {17}, number = {11}, pages = {3297-3305}, pmid = {33228439}, issn = {1554-8635}, support = {R35 GM119571/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Autophagy/genetics/*physiology ; Host-Pathogen Interactions/genetics/physiology ; Humans ; Lipid Droplets/physiology ; Macroautophagy/genetics/physiology ; Mitophagy/genetics/physiology ; Models, Animal ; Models, Biological ; Protein Aggregates/genetics/physiology ; Zebrafish/genetics/*physiology ; }, abstract = {Selective autophagy is a specific elimination of certain intracellular substrates by autophagic pathways. The most studied macroautophagy pathway involves tagging and recognition of a specific cargo by the autophagic membrane (phagophore) followed by the complete sequestration of targeted cargo from the cytosol by the double-membrane vesicle, autophagosome. Until recently, the knowledge about selective macroautophagy was minimal, but now there is a panoply of links elucidating how phagophores engulf their substrates selectively. The studies of selective autophagy processes have further stressed the importance of using the in vivo models to validate new in vitro findings and discover the physiologically relevant mechanisms. However, dissecting how the selective autophagy occurs yet remains difficult in living organisms, because most of the organelles are relatively inaccessible to observation and experimental manipulation in mammals. In recent years, zebrafish (Danio rerio) is widely recognized as an excellent model for studying autophagic processes in vivo because of its optical accessibility, genetic manipulability and translational potential. Several selective autophagy pathways, such as mitophagy, xenophagy, lipophagy and aggrephagy, have been investigated using zebrafish and still need to be studied further, while other selective autophagy pathways, such as pexophagy or reticulophagy, could also benefit from the use of the zebrafish model. In this review, we shed light on how zebrafish contributed to our understanding of these selective autophagy processes by providing the in vivo platform to study them at the organismal level and highlighted the versatility of zebrafish model in the selective autophagy field.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CMA: chaperone-mediated autophagy; CQ: chloroquine; HsAMBRA1: human AMBRA1; KD: knockdown; KO: knockout; LD: lipid droplet; MMA: methylmalonic acidemia; PD: Parkinson disease; Tg: transgenic.}, }
@article {pmid33228235, year = {2020}, author = {Powell, CL and Davidson, AR and Brown, AM}, title = {Universal Glia to Neurone Lactate Transfer in the Nervous System: Physiological Functions and Pathological Consequences.}, journal = {Biosensors}, volume = {10}, number = {11}, pages = {}, pmid = {33228235}, issn = {2079-6374}, mesh = {Alzheimer Disease ; Animals ; Astrocytes ; Brain ; Glucose ; Glycogen ; Humans ; Lactic Acid/*metabolism ; Nervous System/*pathology ; Neuroglia/*physiology ; Neurons ; Signal Transduction ; }, abstract = {Whilst it is universally accepted that the energy support of the brain is glucose, the form in which the glucose is taken up by neurones is the topic of intense debate. In the last few decades, the concept of lactate shuttling between glial elements and neural elements has emerged in which the glial cells glycolytically metabolise glucose/glycogen to lactate, which is shuttled to the neural elements via the extracellular fluid. The process occurs during periods of compromised glucose availability where glycogen stored in astrocytes provides lactate to the neurones, and is an integral part of the formation of learning and memory where the energy intensive process of learning requires neuronal lactate uptake provided by astrocytes. More recently sleep, myelination and motor end plate integrity have been shown to involve lactate shuttling. The sequential aspect of lactate production in the astrocyte followed by transport to the neurones is vulnerable to interruption and it is reported that such disparate pathological conditions as Alzheimer's disease, amyotrophic lateral sclerosis, depression and schizophrenia show disrupted lactate signalling between glial cells and neurones.}, }
@article {pmid33224098, year = {2020}, author = {Rawji, V and Latorre, A and Sharma, N and Rothwell, JC and Rocchi, L}, title = {On the Use of TMS to Investigate the Pathophysiology of Neurodegenerative Diseases.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {584664}, pmid = {33224098}, issn = {1664-2295}, abstract = {Neurodegenerative diseases are a collection of disorders that result in the progressive degeneration and death of neurons. They are clinically heterogenous and can present as deficits in movement, cognition, executive function, memory, visuospatial awareness and language. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool that allows for the assessment of cortical function in vivo. We review how TMS has been used for the investigation of three neurodegenerative diseases that differ in their neuroanatomical axes: (1) Motor cortex-corticospinal tract (motor neuron diseases), (2) Non-motor cortical areas (dementias), and (3) Subcortical structures (parkinsonisms). We also make four recommendations that we hope will benefit the use of TMS in neurodegenerative diseases. Firstly, TMS has traditionally been limited by the lack of an objective output and so has been confined to stimulation of the motor cortex; this limitation can be overcome by the use of concurrent neuroimaging methods such as EEG. Given that neurodegenerative diseases progress over time, TMS measures should aim to track longitudinal changes, especially when the aim of the study is to look at disease progression and symptomatology. The lack of gold-standard diagnostic confirmation undermines the validity of findings in clinical populations. Consequently, diagnostic certainty should be maximized through a variety of methods including multiple, independent clinical assessments, imaging and fluids biomarkers, and post-mortem pathological confirmation where possible. There is great interest in understanding the mechanisms by which symptoms arise in neurodegenerative disorders. However, TMS assessments in patients are usually carried out during resting conditions, when the brain network engaged during these symptoms is not expressed. Rather, a context-appropriate form of TMS would be more suitable in probing the physiology driving clinical symptoms. In all, we hope that the recommendations made here will help to further understand the pathophysiology of neurodegenerative diseases.}, }
@article {pmid33223091, year = {2021}, author = {Roy, B and Griggs, R}, title = {Advances in Treatments in Muscular Dystrophies and Motor Neuron Disorders.}, journal = {Neurologic clinics}, volume = {39}, number = {1}, pages = {87-112}, doi = {10.1016/j.ncl.2020.09.005}, pmid = {33223091}, issn = {1557-9875}, mesh = {Genetic Therapy/methods ; Humans ; Motor Neuron Disease/*therapy ; Muscular Dystrophies/*therapy ; Neuroprotective Agents/therapeutic use ; }, abstract = {Increased understanding of disease pathophysiology and advances in gene therapies and drug technologies are revolutionizing treatment of muscular dystrophies and motor neuron disorders (MNDs). New drugs have been approved for Duchenne muscular dystrophy, spinal muscular atrophy, and amyotrophic lateral sclerosis. For other diseases, new targets have been identified, and new therapies are in clinical trials. The impact of such therapies will be fully understood only in the next decades. Cost burden and accessibility are major challenges in the wide application of new drugs. This article reviews advances in gene therapies, newly approved drugs, and therapeutic promises in muscular dystrophies and MNDs.}, }
@article {pmid33220280, year = {2021}, author = {Nakagawa, Y and Yamada, S}, title = {A novel hypothesis on metal dyshomeostasis and mitochondrial dysfunction in amyotrophic lateral sclerosis: Potential pathogenetic mechanism and therapeutic implications.}, journal = {European journal of pharmacology}, volume = {892}, number = {}, pages = {173737}, doi = {10.1016/j.ejphar.2020.173737}, pmid = {33220280}, issn = {1879-0712}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/physiopathology/therapy ; Animals ; Brain Stem/*metabolism/pathology/physiopathology ; Disease Progression ; Homeostasis ; Humans ; Lower Extremity/*innervation ; Metals/*metabolism ; Mitochondria/*metabolism/pathology ; Motor Neurons/*metabolism/pathology ; Sensory Receptor Cells/*metabolism/pathology ; Spinal Cord/*metabolism/pathology/physiopathology ; Upper Extremity/*innervation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunctions resulting from the loss of upper (UMNs) and lower (LMNs) motor neurons. While ALS symptoms are coincidental with pathological changes in LMNs and UMNs, the causal relationship between the two is unclear. For example, research on the extra-motor symptoms associated with this condition suggests that an imbalance of metals, including copper, zinc, iron, and manganese, is initially induced in the sensory ganglia due to a malfunction of metal binding proteins and transporters. It is proposed that the resultant metal dyshomeostasis may promote mitochondrial dysfunction in the satellite glial cells of these sensory ganglia, causing sensory neuron disturbances and sensory symptoms. Sensory neuron hyperactivation can result in LMN impairments, while metal dyshomeostasis in spinal cord and brain stem parenchyma induces mitochondrial dysfunction in LMNs and UMNs. These events could prompt intracellular calcium dyshomeostasis, pathological TDP-43 formation, and reactive microglia with neuroinflammation, which in turn activate the apoptosis signaling pathways within the LMNs and UMNs. Our model suggests that the degeneration of LMNs and UMNs is incidental to the metal-induced changes in the spinal cord and brain stem. Over time psychiatric symptoms may appear as the metal dyshomeostasis and mitochondrial dysfunction affect other brain regions, including the reticular formation, hippocampus, and prefrontal cortex. It is proposed that metal dyshomeostasis in combination with mitochondrial dysfunction could be the underlying mechanism responsible for the initiation and progression of the pathological changes associated with both the motor and extra-motor symptoms of ALS.}, }
@article {pmid33210961, year = {2020}, author = {Ijomone, OM and Ifenatuoha, CW and Aluko, OM and Ijomone, OK and Aschner, M}, title = {The aging brain: impact of heavy metal neurotoxicity.}, journal = {Critical reviews in toxicology}, volume = {50}, number = {9}, pages = {801-814}, doi = {10.1080/10408444.2020.1838441}, pmid = {33210961}, issn = {1547-6898}, mesh = {Aging/physiology ; Animals ; Brain/drug effects/*physiology ; Humans ; Metals, Heavy/*toxicity ; Nervous System/*drug effects ; Oxidative Stress ; }, abstract = {The aging process is accompanied by critical changes in cellular and molecular functions, which upset the homeostatic balance in the central nervous system. Accumulation of metals renders the brain susceptible to neurotoxic insults by mechanisms such as mitochondrial dysfunction, neuronal calcium-ion dyshomeostasis, buildup of damaged molecules, compromised DNA repair, reduction in neurogenesis, and impaired energy metabolism. These hallmarks have been identified to be responsible for neuronal injuries, resulting in several neurological disorders. Various studies have shown solid associations between metal accumulation, abnormal protein expressions, and pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic lateral sclerosis. This review highlights metals (such as manganese, zinc, iron, copper, and nickel) for their accumulation, and consequences in the development of neurological disorders, in relation to the aging brain.}, }
@article {pmid33205680, year = {2021}, author = {Lomov, N and Zerkalenkova, E and Lebedeva, S and Viushkov, V and Rubtsov, MA}, title = {Cytogenetic and molecular genetic methods for chromosomal translocations detection with reference to the KMT2A/MLL gene.}, journal = {Critical reviews in clinical laboratory sciences}, volume = {58}, number = {3}, pages = {180-206}, doi = {10.1080/10408363.2020.1844135}, pmid = {33205680}, issn = {1549-781X}, mesh = {Histone-Lysine N-Methyltransferase/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Molecular Biology ; *Myeloid-Lymphoid Leukemia Protein/genetics ; *Translocation, Genetic/genetics ; }, abstract = {Acute leukemias (ALs) are often associated with chromosomal translocations, in particular, KMT2A/MLL gene rearrangements. Identification or confirmation of these translocations is carried out by a number of genetic and molecular methods, some of which are routinely used in clinical practice, while others are primarily used for research purposes. In the clinic, these methods serve to clarify diagnoses and monitor the course of disease and therapy. On the other hand, the identification of new translocations and the confirmation of known translocations are of key importance in the study of disease mechanisms and further molecular classification. There are multiple methods for the detection of rearrangements that differ in their principle of operation, the type of problem being solved, and the cost-result ratio. This review is intended to help researchers and clinicians studying AL and related chromosomal translocations to navigate this variety of methods. All methods considered in the review are grouped by their principle of action and include karyotyping, fluorescence in situ hybridization (FISH) with probes for whole chromosomes or individual loci, PCR and reverse transcription-based methods, and high-throughput sequencing. Another characteristic of the described methods is the type of problem being solved. This can be the discovery of new rearrangements, the determination of unknown partner genes participating in the rearrangement, or the confirmation of the proposed rearrangement between the two genes. We consider the specifics of the application, the basic principle of each method, and its pros and cons. To illustrate the application, examples of studying the rearrangements of the KMT2A/MLL gene, one of the genes that are often rearranged in AL, are mentioned.}, }
@article {pmid33202952, year = {2020}, author = {Petrovic, S and Arsic, A and Ristic-Medic, D and Cvetkovic, Z and Vucic, V}, title = {Lipid Peroxidation and Antioxidant Supplementation in Neurodegenerative Diseases: A Review of Human Studies.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {33202952}, issn = {2076-3921}, abstract = {Being characterized by progressive and severe damage in neuronal cells, neurodegenerative diseases (NDDs) are the major cause of disability and morbidity in the elderly, imposing a significant economic and social burden. As major components of the central nervous system, lipids play important roles in neural health and pathology. Disturbed lipid metabolism, particularly lipid peroxidation (LPO), is associated with the development of many NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), all of which show elevated levels of LPO products and LPO-modified proteins. Thus, the inhibition of neuronal oxidation might slow the progression and reduce the severity of NDD; natural antioxidants, such as polyphenols and antioxidant vitamins, seem to be the most promising agents. Here, we summarize current literature data that were derived from human studies on the effect of natural polyphenols and vitamins A, C, and E supplementation in patients with AD, PD, and ALS. Although these compounds may reduce the severity and slow the progression of NDD, research gaps remain in antioxidants supplementation in AD, PD, and ALS patients, which indicates that further human studies applying antioxidant supplementation in different forms of NDDs are urgently needed.}, }
@article {pmid33200713, year = {2021}, author = {Mylvaganam, S and Earnshaw, R and Heymann, G and Kalia, SK and Kalia, LV}, title = {C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.}, journal = {Current neuropharmacology}, volume = {19}, number = {7}, pages = {1038-1068}, pmid = {33200713}, issn = {1875-6190}, mesh = {*Cerebellar Ataxia ; Humans ; *Huntington Disease ; Mutation ; *Spinocerebellar Ataxias ; *Ubiquitin-Protein Ligases/genetics ; }, abstract = {Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person's mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington's disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.}, }
@article {pmid33196974, year = {2022}, author = {Raeisossadati, R and Ferrari, MFR}, title = {Mitochondria-ER Tethering in Neurodegenerative Diseases.}, journal = {Cellular and molecular neurobiology}, volume = {42}, number = {4}, pages = {917-930}, pmid = {33196974}, issn = {1573-6830}, support = {#18/07592-4 and #19/01290-9//FAPESP/ ; }, mesh = {Cell Death ; Endoplasmic Reticulum/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Membranes ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Organelles juxtaposition has been detected for decades, although only recently gained importance due to a pivotal role in the regulation of cellular processes dependent on membrane contact sites. Endoplasmic reticulum (ER) and mitochondria interaction is a prime example of organelles contact sites. Mitochondria-associated membranes (MAM) are proposed to harbor ER-mitochondria tether complexes, mainly when these organelles are less than 30 nm apart. Dysfunctions of proteins located at the MAM are associated with neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, as well as neurodevelopmental disorders; hence any malfunction in MAM can potentially trigger cell death. This review will focus on the role of ER-mitochondria contact sites, regarding calcium homeostasis, lipid metabolism, autophagy, morphology and dynamics of mitochondria, mainly in the context of neurodegenerative diseases. Approaches that have been employed so far to study organelles contact sites, as well as methods that were not used in neurosciences yet, but are promising and accurate ways to unveil the functions of MAM during neurodegeneration, is also discussed in the present review.}, }
@article {pmid33196835, year = {2021}, author = {Takeuchi, T}, title = {Pathogenic and protective roles of extracellular vesicles in neurodegenerative diseases.}, journal = {Journal of biochemistry}, volume = {169}, number = {2}, pages = {181-186}, doi = {10.1093/jb/mvaa131}, pmid = {33196835}, issn = {1756-2651}, mesh = {Animals ; Brain/metabolism/pathology ; Extracellular Vesicles/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases are caused by aggregation and abnormal accumulation of the disease-causative proteins in brain and spinal cord. Recent studies have suggested that proteins associated with neurodegenerative diseases are secreted and transmitted intercellularly via extracellular vesicles (EVs), which may be involved in propagation of abnormal protein accumulation and progressive degeneration in patient brains. On the other hand, it has been also reported that EVs have neuroprotective roles in these diseases, which potentially contribute to preventing aggregation formation and aberrant accumulation of the disease-associated proteins. In this review, I summarize the current understanding of the roles of EVs in neurodegenerative diseases, especially focussing on the pathogenic and neuroprotective aspects. Elucidation of these two aspects of EVs would provide insight into not only potential therapeutic targets for treatment of neurodegenerative diseases but also development of EV-based biomarkers for disease diagnostics.}, }
@article {pmid33195025, year = {2020}, author = {Liu, X and Yang, W and Zhang, Q and Li, C and Wu, H}, title = {Current Approaches to Alkyl Levulinates via Efficient Valorization of Biomass Derivatives.}, journal = {Frontiers in chemistry}, volume = {8}, number = {}, pages = {794}, pmid = {33195025}, issn = {2296-2646}, abstract = {Biomass is a potential non-food, carbon-neutral, and abundant resource, which can be used as an alternative to fossil fuels during the sustainable preparation of various platform chemicals. Alkyl levulinates (ALs) have found widespread application as flavorings, plasticizing agents, and fuel additives, as well as synthetic precursors to various building blocks. Several processes have been investigated to transform biomass and its derivatives into ALs, which mainly include: (i) direct esterification of levulinic acid (LA) with alkyl alcohols and (ii) alcoholysis reactions of renewable biomass feedstocks and their derivatives, including furfuryl alcohol (FAL), chloromethyl furfural (CMF), and saccharides. This review focuses on illustrating the effects of the biomass pretreatment step, catalyst texture, possible mechanisms, acidities, and intermediates on the synthesis of ALs from sustainable resources covering a wide range of intermediates, including diethyl ether (DEE), 4,5,5-triethoxypentan-2-one (TEP), ethoxymethylfuran (EMF), ethyl-D-fructofuranoside (EDFF), and ethyl-D-glucopyranoside (EDGP).}, }
@article {pmid33193860, year = {2020}, author = {Stephen Inbaraj, B and Chen, BH}, title = {An overview on recent in vivo biological application of cerium oxide nanoparticles.}, journal = {Asian journal of pharmaceutical sciences}, volume = {15}, number = {5}, pages = {558-575}, pmid = {33193860}, issn = {2221-285X}, abstract = {Cerium oxide nanoparticles (CNPs) possess a great potential as therapeutic agents due to their ability to self-regenerate by reversibly switching between two valences +3 and +4. This article reviews recent articles dealing with in vivo studies of CNPs towards Alzheimer's disease, obesity, liver inflammation, cancer, sepsis, amyotrophic lateral sclerosis, acute kidney injury, radiation-induced tissue damage, hepatic ischemia reperfusion injury, retinal diseases and constipation. In vivo anti-cancer studies revealed the effectiveness of CNPs to reduce tumor growth and angiogenesis in melanoma, ovarian, breast and retinoblastoma cancer cell-induced mice, with their conjugation with folic acid, doxorubicin, CPM, or CXC receptor-4 antagonist ligand eliciting higher efficiency. After conjugation with triphenylphosphonium or magnetite nanoparticles, CNPs were shown to combat Alzheimer's disease by reducing amyloid-β, glial fibrillary acidic protein, inflammatory and oxidative stress markers in mice. By improving muscle function and longevity, the citrate/EDTA-stabilized CNPs could ameliorate amyotrophic lateral sclerosis. Also, they could effectively reduce obesity in mice by scavenging ROS and reducing adipogenesis, triglyceride synthesis, GAPDH enzyme activity, leptin and insulin levels. In CCl4-induced rats, stress signaling pathways due to inflammatory cytokines, liver enzymes, oxidative and endoplasmic reticulum messengers could be attenuated by CNPs. Commercial CNPs showed protective effects on rats with hepatic ischemia reperfusion and peritonitis-induced hepatic/cardiac injuries by decreasing oxidative stress and hepatic/cardiac inflammation. The same CNPs could improve kidney function by diminishing renal superoxide, hyperglycemia and tubular damage in peritonitis-induced acute kidney injury in rats. Radiation-induced lung and testicular tissue damage could be alleviated in mice, with the former showing improvement in pulmonary distress and bronchoconstriction and the latter exhibiting restoration in spermatogenesis rate and spermatid/spermatocyte number. Through enhancement of gastrointestinal motility, the CNPs could alleviate constipation in both young and old rats. They could also protect rat from light-induced retinal damage by slowing down neurodegenerative process and microglial activation.}, }
@article {pmid33192262, year = {2020}, author = {Morello, G and Salomone, S and D'Agata, V and Conforti, FL and Cavallaro, S}, title = {From Multi-Omics Approaches to Precision Medicine in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {577755}, pmid = {33192262}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disorder, caused by the degeneration of upper and lower motor neurons for which there is no truly effective cure. The lack of successful treatments can be well explained by the complex and heterogeneous nature of ALS, with patients displaying widely distinct clinical features and progression patterns, and distinct molecular mechanisms underlying the phenotypic heterogeneity. Thus, stratifying ALS patients into consistent and clinically relevant subgroups can be of great value for the development of new precision diagnostics and targeted therapeutics for ALS patients. In the last years, the use and integration of high-throughput "omics" approaches have dramatically changed our thinking about ALS, improving our understanding of the complex molecular architecture of ALS, distinguishing distinct patient subtypes and providing a rational foundation for the discovery of biomarkers and new individualized treatments. In this review, we discuss the most significant contributions of omics technologies in unraveling the biological heterogeneity of ALS, highlighting how these approaches are revealing diagnostic, prognostic and therapeutic targets for future personalized interventions.}, }
@article {pmid33190068, year = {2020}, author = {Spencer, PS and Palmer, VS and Kisby, GE}, title = {Western Pacific ALS-PDC: Evidence implicating cycad genotoxins.}, journal = {Journal of the neurological sciences}, volume = {419}, number = {}, pages = {117185}, doi = {10.1016/j.jns.2020.117185}, pmid = {33190068}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; Animals ; Guam ; Humans ; Indonesia ; Japan ; Mutagens ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) is a disappearing neurodegenerative disorder of apparent environmental origin formerly hyperendemic among Chamorros of Guam-USA, Japanese residents of the Kii Peninsula, Honshu Island, Japan and Auyu-Jakai linguistic groups of Papua-Indonesia on the island of New Guinea. The most plausible etiology is exposure to genotoxins in seed of neurotoxic cycad plants formerly used for food and/or medicine. Primary suspicion falls on methylazoxymethanol (MAM), the aglycone of cycasin and on the non-protein amino acid β-N-methylamino-L-alanine, both of which are metabolized to formaldehyde. Human and animal studies suggest: (a) exposures occurred early in life and sometimes during late fetal brain development, (b) clinical expression of neurodegenerative disease appeared years or decades later, and (c) pathological changes in various tissues indicate the disease was not confined to the CNS. Experimental evidence points to toxic molecular mechanisms involving DNA damage, epigenetic changes, transcriptional mutagenesis, neuronal cell-cycle reactivation and perturbation of the ubiquitin-proteasome system that led to polyproteinopathy and culminated in neuronal degeneration. Lessons learned from research on ALS-PDC include: (a) familial disease may reflect common toxic exposures across generations, (b) primary disease prevention follows cessation of exposure to culpable environmental triggers; and (c) disease latency provides a prolonged period during which to intervene therapeutically. Exposure to genotoxic chemicals ("slow toxins") in the early stages of life should be considered in the search for the etiology of ALS-PDC-related neurodegenerative disorders, including sporadic forms of ALS, progressive supranuclear palsy and Alzheimer's disease.}, }
@article {pmid33182806, year = {2020}, author = {Heise, C and Abou Ali, E and Hasenclever, D and Auriemma, F and Gulla, A and Regner, S and Gaujoux, S and Hollenbach, M}, title = {Systematic Review with Meta-Analysis: Endoscopic and Surgical Resection for Ampullary Lesions.}, journal = {Journal of clinical medicine}, volume = {9}, number = {11}, pages = {}, pmid = {33182806}, issn = {2077-0383}, support = {Open Access Funding//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Ampullary lesions (ALs) can be treated by endoscopic (EA) or surgical ampullectomy (SA) or pancreaticoduodenectomy (PD). However, EA carries significant risk of incomplete resection while surgical interventions can lead to substantial morbidity. We performed a systematic review and meta-analysis for R0, adverse-events (AEs) and recurrence between EA, SA and PD. Electronic databases were searched from 1990 to 2018. Outcomes were calculated as pooled means using fixed and random-effects models and the Freeman-Tukey-Double-Arcsine-Proportion-model. We identified 59 independent studies. The pooled R0 rate was 76.6% (71.8-81.4%, I[2] = 91.38%) for EA, 96.4% (93.6-99.2%, I[2] = 37.8%) for SA and 98.9% (98.0-99.7%, I[2] = 0%) for PD. AEs were 24.7% (19.8-29.6%, I[2] = 86.4%), 28.3% (19.0-37.7%, I[2] = 76.8%) and 44.7% (37.9-51.4%, I[2] = 0%), respectively. Recurrences were registered in 13.0% (10.2-15.6%, I[2] = 91.3%), 9.4% (4.8-14%, I[2] = 57.3%) and 14.2% (9.5-18.9%, I[2] = 0%). Differences between proportions were significant in R0 for EA compared to SA (p = 0.007) and PD (p = 0.022). AEs were statistically different only between EA and PD (p = 0.049) and recurrence showed no significance for EA/SA or EA/PD. Our data indicate an increased rate of complete resection in surgical interventions accompanied with a higher risk of complications. However, studies showed various sources of bias, limited quality of data and a significant heterogeneity, particularly in EA studies.}, }
@article {pmid33181336, year = {2021}, author = {Dash, R and Ali, MC and Jahan, I and Munni, YA and Mitra, S and Hannan, MA and Timalsina, B and Oktaviani, DF and Choi, HJ and Moon, IS}, title = {Emerging potential of cannabidiol in reversing proteinopathies.}, journal = {Ageing research reviews}, volume = {65}, number = {}, pages = {101209}, doi = {10.1016/j.arr.2020.101209}, pmid = {33181336}, issn = {1872-9649}, mesh = {Cannabidiol/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease ; Proteostasis ; *Proteostasis Deficiencies ; }, abstract = {The aberrant accumulation of disease-specific protein aggregates accompanying cognitive decline is a pathological hallmark of age-associated neurological disorders, also termed as proteinopathies, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. Along with oxidative stress and neuroinflammation, disruption in protein homeostasis (proteostasis), a network that constitutes protein surveillance system, plays a pivotal role in the pathobiology of these dementia disorders. Cannabidiol (CBD), a non-psychotropic phytocannabinoid of Cannabis sativa, is known for its pleiotropic neuropharmacological effects on the central nervous system, including the ability to abate oxidative stress, neuroinflammation, and protein misfolding. Over the past years, compelling evidence has documented disease-modifying role of CBD in various preclinical and clinical models of neurological disorders, suggesting the potential therapeutic implications of CBD in these disorders. Because of its putative role in the proteostasis network in particular, CBD could be a potent modulator for reversing not only age-associated neurodegeneration but also other protein misfolding disorders. However, the current understanding is insufficient to underpin this proposition. In this review, we discuss the potentiality of CBD as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing roles in the neurodegenerative disorders. We anticipate that the current effort will advance our knowledge on the implication of CBD in proteostasis network, opening up a new therapeutic window for aging proteinopathies.}, }
@article {pmid33180261, year = {2022}, author = {Venkataraman, L and Fair, SR and McElroy, CA and Hester, ME and Fu, H}, title = {Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer's disease.}, journal = {Stem cell reviews and reports}, volume = {18}, number = {2}, pages = {696-717}, pmid = {33180261}, issn = {2629-3277}, support = {K01 AG056673/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; Brain/metabolism ; Humans ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Organoids/pathology ; }, abstract = {Many neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington's disease, are characterized by the progressive accumulation of abnormal proteinaceous assemblies in specific cell types and regions of the brain, leading to cellular dysfunction and brain damage. Although animal- and in vitro-based studies of NDs have provided the field with an extensive understanding of some of the mechanisms underlying these diseases, findings from these studies have not yielded substantial progress in identifying treatment options for patient populations. This necessitates the development of complementary model systems that are better suited to recapitulate human-specific features of ND pathogenesis. Three-dimensional (3D) culture systems, such as cerebral organoids generated from human induced pluripotent stem cells, hold significant potential to model NDs in a complex, tissue-like environment. In this review, we discuss the advantages of 3D culture systems and 3D modeling of NDs, especially AD and FTD. We also provide an overview of the challenges and limitations of the current 3D culture systems. Finally, we propose a few potential future directions in applying state-of-the-art technologies in 3D culture systems to understand the mechanisms of NDs and to accelerate drug discovery. Graphical abstract.}, }
@article {pmid33180216, year = {2021}, author = {Goyal, S and Chaturvedi, RK}, title = {Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {58}, number = {4}, pages = {1418-1437}, pmid = {33180216}, issn = {1559-1182}, support = {BT/PR15819/MED/31/322/2015//Department of Biotechnology/ ; EMR/2016/001933//Science and Engineering Research Board/ ; BSC0111, BSC0115//Council of Scientific and Industrial Research/ ; }, mesh = {Animals ; Humans ; Mitochondrial Dynamics ; Mitochondrial Proteins/*metabolism ; Models, Biological ; Neurodegenerative Diseases/*metabolism ; Organelle Biogenesis ; Protein Transport ; }, abstract = {Mitochondria play an essential role in maintaining energy homeostasis and cellular survival. In the brain, higher ATP production is required by mature neurons for communication. Most of the mitochondrial proteins transcribe in the nucleus and import in mitochondria through different pathways of the mitochondrial protein import machinery. This machinery plays a crucial role in determining mitochondrial morphology and functions through mitochondrial biogenesis. Failure of this machinery and any alterations during mitochondrial biogenesis underlies neurodegeneration resulting in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) etc. Current knowledge has revealed the different pathways of mitochondrial protein import machinery such as translocase of the outer mitochondrial membrane complex, the presequence pathway, carrier pathway, β-barrel pathway, and mitochondrial import and assembly machinery etc. In this review, we have discussed the recent studies regarding protein import machinery, beyond the well-known effects of increased oxidative stress and bioenergetics dysfunctions. We have elucidated in detail how these types of machinery help to import and locate the precursor proteins to their specific location inside the mitochondria and play a major role in mitochondrial biogenesis. We further discuss their involvement in mitochondrial dysfunctioning and the induction of toxic aggregates in neurodegenerative diseases like AD and PD. The review supports the importance of import machinery in neuronal functions and its association with toxic aggregated proteins in mitochondrial impairment, suggesting a critical role in fostering and maintaining neurodegeneration and therapeutic response.}, }
@article {pmid33178687, year = {2020}, author = {Gharbi, T and Zhang, Z and Yang, GY}, title = {The Function of Astrocyte Mediated Extracellular Vesicles in Central Nervous System Diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {568889}, pmid = {33178687}, issn = {2296-634X}, abstract = {Astrocyte activation plays an important role during disease-induced inflammatory response in the brain. Exosomes in the brain could be released from bone marrow (BM)-derived stem cells, neuro stem cells (NSC), mesenchymal stem cells (MSC), etc. We summarized that exosomes release and transport signaling to the target cells, and then produce function. Furthermore, we discussed the pathological interactions between astrocytes and other brain cells, which are related to brain diseases such as stroke, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) disease, multiple sclerosis (MS), psychiatric, traumatic brain injury (TBI), etc. We provide up-to-date, comprehensive and valuable information on the involvement of exosomes in brain diseases, which is beneficial for basic researchers and clinical physicians.}, }
@article {pmid33177049, year = {2020}, author = {de Boer, EMJ and Orie, VK and Williams, T and Baker, MR and De Oliveira, HM and Polvikoski, T and Silsby, M and Menon, P and van den Bos, M and Halliday, GM and van den Berg, LH and Van Den Bosch, L and van Damme, P and Kiernan, MC and van Es, MA and Vucic, S}, title = {TDP-43 proteinopathies: a new wave of neurodegenerative diseases.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {92}, number = {1}, pages = {86-95}, pmid = {33177049}, issn = {1468-330X}, support = {G1100540/MRC_/Medical Research Council/United Kingdom ; MC_PC_13071/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; G0400074/MRC_/Medical Research Council/United Kingdom ; G0502157/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.}, }
@article {pmid33173626, year = {2020}, author = {Ortiz, JF and Khan, SA and Salem, A and Lin, Z and Iqbal, Z and Jahan, N}, title = {Post-Marketing Experience of Edaravone in Amyotrophic Lateral Sclerosis: A Clinical Perspective and Comparison With the Clinical Trials of the Drug.}, journal = {Cureus}, volume = {12}, number = {10}, pages = {e10818}, pmid = {33173626}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that affects the upper and lower motor neurons. Currently, the only treatment for ALS is riluzole, which only has a limited effect on increasing survival from 3 to 6 months. New therapies are needed in the clinical setting for ALS. We aim to compare and contrast the clinical trials of edaravone and the post-marketing experience of the drug during this study. For the method, a search strategy was made using PubMed with the search terms "Amyotrophic lateral sclerosis" (MeSH) and "Edaravone" (MeSH). For inclusion criteria, we used full papers, studies involving humans, and studies published in the English language. We exclude meta-analyses, literature reviews, systematic reviews, studies involving animals, and studies not published in English. After close examination, 20 papers were used for the discussion in this review. The clinical trials showed efficacy in patients in reducing the revised ALS functional rating scale (ALSFRS-R) in patients with early ALS with selective criteria. We documented edaravone's post-marketing experience in six countries: Kuwait, South Korea, Argentina, United States, Israel, and Italy. During the study we analyzed, the forced vital capacity (FVC) and ALSFRS-R scored, together with edaravone's safety in the clinical trials and post-marketing experience. Edaravone seems to be more effective in Asia, where the ALSFRS-R scores and the FVC decline were similar to the clinical trial results in Japan. Studies in Europe did not find the drug clinically useful. At the same time, studies in United States and Argentina were mainly descriptive, so more information is needed to evaluate the drug's efficacy in that part of the world. The drug was well-tolerated in all studies. In conclusion, more studies need to be done worldwide to carry out and clarify the effectiveness of edaravone in the clinical setting.}, }
@article {pmid33173502, year = {2020}, author = {Mayne, K and White, JA and McMurran, CE and Rivera, FJ and de la Fuente, AG}, title = {Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {572090}, pmid = {33173502}, issn = {1663-4365}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Neurodegenerative diseases of the central nervous system (CNS) are characterized by progressive neuronal death and neurological dysfunction, leading to increased disability and a loss of cognitive or motor functions. Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis have neurodegeneration as a primary feature. However, in other CNS diseases such as multiple sclerosis, stroke, traumatic brain injury, and spinal cord injury, neurodegeneration follows another insult, such as demyelination or ischaemia. Although there are different primary causes to these diseases, they all share a hallmark of neuroinflammation. Neuroinflammation can occur through the activation of resident immune cells such as microglia, cells of the innate and adaptive peripheral immune system, meningeal inflammation and autoantibodies directed toward components of the CNS. Despite chronic inflammation being pathogenic in these diseases, local inflammation after insult can also promote endogenous regenerative processes in the CNS, which are key to slowing disease progression. The normal aging process in the healthy brain is associated with a decline in physiological function, a steady increase in levels of neuroinflammation, brain shrinkage, and memory deficits. Likewise, aging is also a key contributor to the progression and exacerbation of neurodegenerative diseases. As there are associated co-morbidities within an aging population, pinpointing the precise relationship between aging and neurodegenerative disease progression can be a challenge. The CNS has historically been considered an isolated, "immune privileged" site, however, there is mounting evidence that adaptive immune cells are present in the CNS of both healthy individuals and diseased patients. Adaptive immune cells have also been implicated in both the degeneration and regeneration of the CNS. In this review, we will discuss the key role of the adaptive immune system in CNS degeneration and regeneration, with a focus on how aging influences this crosstalk.}, }
@article {pmid33172304, year = {2021}, author = {Schwartz, JL and Jones, KL and Yeo, GW}, title = {Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies.}, journal = {Critical reviews in biochemistry and molecular biology}, volume = {56}, number = {1}, pages = {31-53}, pmid = {33172304}, issn = {1549-7798}, support = {R01 EY029166/EY/NEI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; R56 AG069098/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics ; Animals ; Ataxia/drug therapy/*genetics ; Fragile X Syndrome/drug therapy/*genetics ; Frontotemporal Dementia/drug therapy/*genetics ; Humans ; Huntington Disease/drug therapy/*genetics ; Molecular Targeted Therapy/methods ; Muscular Atrophy, Spinal/drug therapy/*genetics ; Myotonic Dystrophy/drug therapy/*genetics ; Neurons/metabolism ; Protein Biosynthesis/genetics ; RNA Processing, Post-Transcriptional/*genetics ; RNA, Messenger/genetics/metabolism ; Transcription, Genetic/genetics ; Tremor/drug therapy/*genetics ; Trinucleotide Repeat Expansion/*genetics ; }, abstract = {Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG50-3,500 in DMPK; DM2, CCTG75-11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG50-200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG40-55 in AR), Huntington's disease (HD, CAG36-121 in HTT), C9ORF72- amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders - bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation - which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review.}, }
@article {pmid33169387, year = {2021}, author = {Tahamtan, A and Besteman, S and Samadizadeh, S and Rastegar, M and Bont, L and Salimi, V}, title = {Neutrophils in respiratory syncytial virus infection: From harmful effects to therapeutic opportunities.}, journal = {British journal of pharmacology}, volume = {178}, number = {3}, pages = {515-530}, doi = {10.1111/bph.15318}, pmid = {33169387}, issn = {1476-5381}, mesh = {Antiviral Agents/therapeutic use ; Child ; Child, Preschool ; Humans ; Lung ; Neutrophils ; *Respiratory Syncytial Virus Infections/drug therapy ; *Respiratory Syncytial Virus, Human ; }, abstract = {Respiratory syncytial virus (RSV) is an important infectious agent in infants and young children. In most cases, RSV infection only causes mild disease, but in some, it requires invasive ventilation. Although antiviral drugs are obvious candidates to treat viral illness, and some have shown antiviral effects in humans, antivirals such as GS-5806, ALX-0171 and ALS-8176 have not yet met their expectations. Since the inappropriate or dysregulated immune response against RSV leads to harmful immune pathology, a robust immune cascade is probably underway by the time patients reach the hospital. RSV infection is associated with a strong neutrophil influx into the airway. It not clear if these cells contribute to antiviral defence or to lung pathology. This article discusses the protective and harmful roles of neutrophils during RSV infection and provides an overview of mechanisms by which neutrophil function could be targeted to prevent tissue injury and preserve homeostasis.}, }
@article {pmid33168089, year = {2020}, author = {Quinn, PMJ and Moreira, PI and Ambrósio, AF and Alves, CH}, title = {PINK1/PARKIN signalling in neurodegeneration and neuroinflammation.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {189}, pmid = {33168089}, issn = {2051-5960}, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Gene Knock-In Techniques ; Glaucoma/genetics ; Humans ; Huntington Disease/genetics ; Inflammation/*genetics/metabolism ; Macular Degeneration/genetics ; Mice ; Mitochondria/*metabolism ; Mitophagy/genetics ; Neurodegenerative Diseases/*genetics/metabolism ; Parkinson Disease/genetics ; Protein Kinases/*genetics/metabolism ; Rats ; Signal Transduction ; Ubiquitin-Protein Ligases/*genetics/metabolism ; }, abstract = {Mutations in the PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) genes are associated with familial forms of Parkinson's disease (PD). PINK1, a protein kinase, and PARKIN, an E3 ubiquitin ligase, control the specific elimination of dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial network and preserving energy metabolism. PINK1 regulates PARKIN translocation in impaired mitochondria and drives their removal via selective autophagy, a process known as mitophagy. As knowledge obtained using different PINK1 and PARKIN transgenic animal models is being gathered, growing evidence supports the contribution of mitophagy impairment to several human pathologies, including PD and Alzheimer's diseases (AD). Therefore, therapeutic interventions aiming to modulate PINK1/PARKIN signalling might have the potential to treat these diseases. In this review, we will start by discussing how the interplay of PINK1 and PARKIN signalling helps mediate mitochondrial physiology. We will continue by debating the role of mitochondrial dysfunction in disorders such as amyotrophic lateral sclerosis, Alzheimer's, Huntington's and Parkinson's diseases, as well as eye diseases such as age-related macular degeneration and glaucoma, and the causative factors leading to PINK1/PARKIN-mediated neurodegeneration and neuroinflammation. Finally, we will discuss PINK1/PARKIN gene augmentation possibilities with a particular focus on AD, PD and glaucoma.}, }
@article {pmid33161136, year = {2020}, author = {Miranda-Lourenço, C and Ribeiro-Rodrigues, L and Fonseca-Gomes, J and Tanqueiro, SR and Belo, RF and Ferreira, CB and Rei, N and Ferreira-Manso, M and de Almeida-Borlido, C and Costa-Coelho, T and Freitas, CF and Zavalko, S and Mouro, FM and Sebastião, AM and Xapelli, S and Rodrigues, TM and Diógenes, MJ}, title = {Challenges of BDNF-based therapies: From common to rare diseases.}, journal = {Pharmacological research}, volume = {162}, number = {}, pages = {105281}, doi = {10.1016/j.phrs.2020.105281}, pmid = {33161136}, issn = {1096-1186}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/genetics/metabolism ; Humans ; Nervous System Diseases/metabolism/*therapy ; Rare Diseases/metabolism/*therapy ; Signal Transduction ; }, abstract = {Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75[NTR]). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.}, }
@article {pmid33160824, year = {2021}, author = {Bouscary, A and Quessada, C and René, F and Spedding, M and Turner, BJ and Henriques, A and Ngo, ST and Loeffler, JP}, title = {Sphingolipids metabolism alteration in the central nervous system: Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.}, journal = {Seminars in cell &amp; developmental biology}, volume = {112}, number = {}, pages = {82-91}, doi = {10.1016/j.semcdb.2020.10.008}, pmid = {33160824}, issn = {1096-3634}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Central Nervous System/metabolism/pathology ; Humans ; Lipid Metabolism/*genetics ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Sphingolipids/genetics/*metabolism ; }, abstract = {Sphingolipids are complex lipids. They play a structural role in neurons, but are also involved in regulating cellular communication, and neuronal differentiation and maturation. There is increasing evidence to suggest that dysregulated metabolism of sphingolipids is linked to neurodegenerative processes in amyotrophic lateral sclerosis (ALS), Parkinson's disease and Gaucher's disease. In this review, we provide an overview of the role of sphingolipids in the development and maintenance of the nervous system. We describe the implications of altered metabolism of sphingolipids in the pathophysiology of certain neurodegenerative diseases, with a primary focus on ALS. Finally, we provide an update of potential treatments that could be used to target the metabolism of sphingolipids in neurodegenerative diseases.}, }
@article {pmid33159700, year = {2021}, author = {Jmii, H and Fisson, S and Aouni, M and Jaidane, H}, title = {Type B coxsackieviruses and central nervous system disorders: critical review of reported associations.}, journal = {Reviews in medical virology}, volume = {31}, number = {4}, pages = {e2191}, doi = {10.1002/rmv.2191}, pmid = {33159700}, issn = {1099-1654}, mesh = {Antibodies, Viral ; Brain/*virology ; Central Nervous System Diseases/epidemiology/etiology/*virology ; Central Nervous System Infections/*virology ; Child ; Coxsackievirus Infections/*diagnosis/pathology ; Enterovirus B, Human/immunology/*isolation &amp; purification ; Humans ; Infant, Newborn ; }, abstract = {Type B coxsackieviruses (CV-B) frequently infect the central nervous system (CNS) causing neurological diseases notably meningitis and encephalitis. These infections occur principally among newborns and children. Epidemiological studies of patients with nervous system disorders demonstrate the presence of infectious virus, its components, or anti-CV-B antibodies. Some experimental studies conducted in vitro and in vivo support the potential association between CV-B and idiopathic neurodegenerative diseases such as amyotrophic lateral sclerosis and psychiatric illness such as schizophrenia. However, mechanisms explaining how CV-B infections may contribute to the genesis of CNS disorders remain unclear. The proposed mechanisms focus on the immune response following the viral infection as a contributor to pathogenesis. This review describes these epidemiological and experimental studies, the modes of transmission of CV-B with an emphasis on congenital transmission, the routes used by CV-B to reach the brain parenchyma, and plausible mechanisms by which CV-B may induce CNS diseases, with a focus on potential immunopathogenesis.}, }
@article {pmid33343018, year = {2019}, author = {Nay, MM and Souza, TLPO and Raatz, B and Mukankusi, CM and Gonçalves-Vidigal, MC and Abreu, AFB and Melo, LC and Pastor-Corrales, MA}, title = {A Review of Angular Leaf Spot Resistance in Common Bean.}, journal = {Crop science}, volume = {59}, number = {4}, pages = {1376-1391}, pmid = {33343018}, issn = {0011-183X}, abstract = {Angular leaf spot (ALS), caused by Pseudocercospora griseola, is one of the most devastating diseases of common bean (Phaseolus vulgaris L.) in tropical and subtropical production areas. Breeding for ALS resistance is difficult due to the extensive virulence diversity of P. griseola and the recurrent appearance of new virulent races. Five major loci, Phg-1 to Phg-5, conferring ALS resistance have been named, and markers tightly linked to these loci have been reported. Quantitative trait loci (QTLs) have also been described, but the validation of some QTLs is still pending. The Phg-1, Phg-4, and Phg-5 loci are from common bean cultivars of the Andean gene pool, whereas Phg-2 and Phg-3 are from beans of the Mesoamerican gene pool. The reference genome of common bean and high-throughput sequencing technologies are enabling the development of molecular markers closely linked to the Phg loci, more accurate mapping of the resistance loci, and the comparison of their genomic positions. The objective of this report is to provide a comprehensive review of ALS resistance in common bean. Furthermore, we are reporting three case studies of ALS resistance breeding in Latin America and Africa. This review will serve as a reference for future resistance mapping studies and as a guide for the selection of resistance loci in breeding programs aiming to develop common bean cultivars with durable ALS resistance.}, }
@article {pmid34644983, year = {1996}, author = {Saijonmaa-Koulumies, LE and Lloyd, DH}, title = {Colonization of the canine skin with bacteria.}, journal = {Veterinary dermatology}, volume = {7}, number = {3}, pages = {153-162}, doi = {10.1111/j.1365-3164.1996.tb00240.x}, pmid = {34644983}, issn = {1365-3164}, abstract = {Abstract Aspects of colonization of the canine skin with bacteria are reviewed. Owing to variability in sampling techniques, anatomical sites involved and lack of temporal studies, there is still controversy as to which bacteria are residents or transients on the canine skin. The establishment of the cutaneous flora is determined by the ability of bacteria to adhere to canine corneocytes, to use available nutrients from skin secretions and to resist challenge from competing bacteria. Variations in humidity and temperature due to environment, skin folds or differences in the haircoat are also likely to have an effect. Much research has focused around Staphylococcus intermedius, the main pathogen of the canine skin but its cutaneous residency status remains questionable. Pathological conditions such as atopy and seborrhoea favour the colonization of S. intermedius and predispose to infection. Recent studies indicate that bacterial interference as a method of preventing colonization of pathogenic staphylococci may be feasible. Résumé- Les aspects de la colonisation de la peau canine par des bactéries sont étudiées. A cause de la variabilité des techniques de prélèvements, des sites anatomiques, et du caratère ponctuel des études, le doute subsiste toujours quant à savoir quelle sont les bactéries résidentes ou transitoires sur la peau de chien. L'établissement d'une flore cutanée est déterminée par la capacité de la bactérie à adhérer aux cornéocytes canines, à utiliser les nutriments disponibles à partir des sécrétions cutanées et à résister aux autres bactéries qui concourent à l'occupation des memes sites. Les variations d'humidité et de température, dues à l'environnement, aux plis de peau et aux différences de pelage jouent probablement un role. La plupart des études concernent Staphylococcus intermedius, l'agent pathogène principal de la peau du chien, mais son statut de résident cutané est toujours débattu. Des conditions pathologiques telles que l'atopie et la séborrhée favorisent la colonisation par S. intermedius et prédisposent à l'infection. Des études récentes indiquent que l'interférence bactérienne peut être envisagée comme une méthode de prévention de la colonisation cutanée par un staphylocoque pathogène. [Saijonmaa-Koulumies, L. &amp; Lloyd, D. H. Colonization of the canine skin with bacteria (Colonisation de la peau canine par des bactéries). Veterinary Dermatology 1996; 7: 153-162.] Resumen Se revisan algunos aspectos de la colonización bacteriana en la piel canina. Existe aún controversia sobre qué bacterias son résidentes o transitorias en la piel del perro, debido a la variabilidad en las técnicas de recolección, localización y falta de estudios temporales. El establecimiento de la flora cutánea depende de su capacidad de adhesión a los corneocitos, de utilizar los nutrientes de las secreciones cutáneas y de resistir la competencia de otras bacterias. También es probable que tengan un papel los cambios de humedad y temperatura por los pliegues cutáneos o las diferencias en el pelaje. Se ha centrado mucha investigación en Staphylococcus intermedius, el principal patógeno de la piel canina, aunque se sigue cuestionando su existencia como residente cutáneo. Situaciones patológicas como la atopia o la seborrea favorecen la colonización por S. intermedius y predisponen a infección. Algunos estudios recientes indican que es factible la interferencia bacteriana como método de prevenir la colonización por estafilococos patógenos. [Saijonmaa-Koulumies, L. &amp; Lloyd, D. H. Colonization of the canine skin with bacteria (Colonizacion de la piel cannina con bacterias). Veterinary Dermatology 1996; 7: 153-162.] Zusammenfassung- Es werden Aspekte der Besiedelung der Hundehaut mit Bakterien dargestellt. Entsprechend der Variabilität in der Probenentnahme, verwendeten anatomischen Regionen und dem Mangel an temporären Studien exisitieren immer noch unterschiedliche Ansichten, ob Bakterien auf der Haut des Hundes als resident oder transient gelten. Die Aufstellung der kutanen Flora wird durch die Fähigkeit der Bakterien bestimmt, sich an die kaninen Korneozyten anzuheften, verfügbare Nährstoffe aus den Hautsekretionen zu verwenden und sich gegenüber konkurrierenden Keimen zu behaupten. Veränderungen in Feuchtigkeit und Temperatur in Abhängigkeit von Umgebung, Hautfalten oder Unterschieden im Haarkleid scheinen ebenfalls einen Effekt zu besitzen. Viele Untersuchungen konzentrierten sich auf Staphylococcus aureus, der hauptpathogene Keim auf der Hundehaut, aber sein Status als residenter Keim bleibt fraglich. Pathologische Zustände wie Atopie und Seborrhoe begünstigen die Besiedelung mit S. intermedius und prädisponieren für eine Infektion. Kürzliche Studien zeigen, daß bakterielle Interferenzen als Methode zur Verhinderung der Ansiedlung von pathogenen Staphylokokken möglich sein könnten. [Saijonmaa-Koulumies, L., Lloyd, D.H. Colonization of the canine skin with bacteria (Besiedelung der Haut des Hundes mit Bakterien). Veterinary Dermatology 1996; 7: 153-162.].}, }
@article {pmid33874112, year = {1993}, author = {}, title = {Reviews.}, journal = {The New phytologist}, volume = {123}, number = {3}, pages = {649}, doi = {10.1111/j.1469-8137.1993.tb03773.x}, pmid = {33874112}, issn = {1469-8137}, abstract = {Plant Membranes: a Biophysical Approach to Structure, Development and Senescence. By Y. Y. Leshem, with additional contributions by R. L. Shewfelt, C. M. Willmer and O. Pantoja. Methods in Plant Biochemistry (Series Eds. P. M. Dey and J. B. Harborne); Vol. 7: Terpenoids. Ed. by B. V. Charlwood and D. V. Banthorpe. CHCD Dictionary of Natural Products on CD-ROM. Plant Molecular Systematics. By D. J. Crawford. Physiology - Breeding of Winter Cereals for Stressed Mediterranean Environments. (Physiologie - Sélection des céréales d'hiver en conditions méditerranéennes). Ed. by E. Acevedo, A. P. Conesa, P. Monneveux and J. P. Srivastava. Plant Genetic Manipulation for Crop Protection. Ed. A. M. R. Gatehouse, V. A. Hilder and D. Boulter. In vitro Culture of Trees. By J. M. Bonga and P. von Aderkas. Flechten als Bioindikatoren. Integriertes biologisches Meβsystem der Luftverschmutzung für das Schweizer Mittelland. By Rolf Herzig and Martin Urech. Evolution and Function of Heterostyly. Ed. by S. C. H. Barrett. Wild Plants of Glasgow. By J. H. Dickson.}, }
@article {pmid34644823, year = {1992}, author = {Roudebush, P and Cowell, CS}, title = {Results of a Hypoallergenic Diet Survey of Veterinarians in North America with a Nutritional Evaluation of Homemade Diet Prescriptions.}, journal = {Veterinary dermatology}, volume = {3}, number = {1}, pages = {23-28}, doi = {10.1111/j.1365-3164.1992.tb00139.x}, pmid = {34644823}, issn = {1365-3164}, abstract = {Abstract- One hundred and sixteen veterinarians in North America completed a survey recording the use of specific commercial hypoallergenic diets in dogs and cats, ingredients recommended for homemade diets, and perceptions about problems with, or unacceptable ingredients in, current commercial pet foods. A wide variety of both commercial and homemade rations was recommended by the respondents for dogs and cats suspected of having adverse reactions to food. Homemade diets were recommended most often as the initial test diets for both dogs and cats with suspected food allergy. Ingredients recommended most often for homemade diets were lamb, lamb baby food, rice, potatoes, rabbit, fish, venison and tofu. Unacceptable ingredients in commercial pet foods mentioned multiple times included preservatives and dyes, wheat, beef, fish or fish meal, poultry/chicken, egg, soy and dairy products. Homemade diet recommendations of the respondents were evaluated for their nutritional adequacy. Most (90 per cent) of the homemade elimination diets were not nutritionally adequate for adult maintenance based on currently available recommendations. Résumé- 116 vétérinaires d'Amérique du Nord ont participéà une enquête sur l'utillsation d'aliments hypoallergéniques commerciaux pour chien et chats, les ingrédients recommandés dans les préparations ménagères et les recommandations concernat les problèmes rencontrés avec les aliments courrants industriels ou les ingrédients inacceptables dans leur composition. Un très large éventail de regimes ménagers ou industriels étaient recommandés par les participants pour les chiens et les chats suspects d'intolérance alimentaire. Des préparations ménagères étaient le plus souvant recommandées comme test d'exclusion, pour les chiens et les chats suspects d'allergie alimentaire. Les ingrédients les plus souvents recommandés étaient: viande d'agneau, viande d'agneau en pots pour bébés, riz, pommes de terre, lapin, poisson, gibler et pâte de soja. Les ingrédients mentionnés plusieurs fols comme étant à exclure des preparations industrielles étaient: conservateurs et colorants, bié, viande de boeuf, poisson, volaille, ouef, soja et produits laitiers. L'équilibre des preparations ménagères recommandées par les participantrs a étéétudié. La piupart (90 pour cent) de ces preparations étaient déséquilibrées par rapport aux recommendations courament admises pour l'entretien d'un chien adulte. Zusammenfassung- Einhundertsechzehn Tierärzte in Nordamerika nahmen an einer Umfrage teil, die folgende Punkte untersuchte: Einsatz von bestimmtem kommerziellen hypoallergenen Diätfutter für Hund und Katze, für hausgemachtes Diätfutter empfohlene Zutaten und Probleme mit gängiger kommerzieller Tiernahrung oder mit darin enthaltenen unannehmbare Inhaltsstoffen. Eine große Vielfalt sowohl von kommerziellen als auch hausgemachten Diäten wurde von den Befragten für Hunde und Katzen mit Verdacht auf adverse Reaktionen auf Futter empfohlen. Hausgemachte Diäten wurden am häufigsten als initialer Test für Hunde und Katzen mit Verdacht auf Futtermittelallergie empfohlen. Die am häufigsten empfohlenen Zutaten für hausgemachte Diäten bestanden in Lammfleisch, Lamm-Babynahrung, Reis, Kartoffeln, Kaninchen, Fisch, Wild und Tofu. Die als unannehmbar mehrfach genannten Inhaltsstoffe in kommerzieller Tiernahrung schließben Konservierungs-und Farbstoffe, Weizen, Rindfleisch, Fisch oder Fischmehl, Geflügel/Huhn, Ei, Soja und Milchprodukte mit ein. Die hausgemachten Diätemfehlungen der Befragten wurden auf ernährungsphysiologische Ausgewogenheit überpfrüft. Die meisten der hausgemachten Eliminationsdiäten [90%] waren nach den gängigen Ernährungsempfehlungen für den Erhaltungsbedarf erwachsener Tiere ernährungsphysiologische nicht ausgewogen. Resumen Cientosésis veterinarios en Norteamérica llevaron a cabo una estadística del uso de ciertas dietas comerciales hipoalergénicas en perros y gatos, ingredientes recomendados en dietas caseras e impresiones de los problemas causados por ingredientes inaceptables en la dietas comerciales de uso corriente. Los casos responsivos indicaban una gran variedad de comidas caseras y dietas comerciales para perros y gatos, en los que se sospecharon reacciones adversas a los alimentos. Dietas caseras se recomendaron mas frecuentamente como test inicial para ambos, perros y gatos sospechosos de algeria alimentaria. Los ingredientes más comunmente recomendados fueron cordero, alimento para bebé basado en cordero, arroz, patatas, conejo, pescado, venado y tofu. Ingredientes inaceptables en dietas comerciales mencionados en multiples ocasiones incluyeron preservativos y tintes, trigo, vacuno, pescado o harina de pescado, pollo/aves de corral, soja y productos lácticos. Las dietas caseras recomendadas de los casos responsivos se evaluaron por su eficacia nutricional. La mayoría de las dietas caseras de tests de eliminación, el 90%, no eran adecuadas desde el púnto de vista nutritivo papa la manutención de animales adultos, comparada con las corrientes recommendaciones.}, }
@article {pmid34644821, year = {1992}, author = {Guaguere, E and Hubert, B and Delabre, C}, title = {Feline Pododermatoses.}, journal = {Veterinary dermatology}, volume = {3}, number = {1}, pages = {1-12}, doi = {10.1111/j.1365-3164.1992.tb00137.x}, pmid = {34644821}, issn = {1365-3164}, abstract = {Abstract- Pododermatoses are uncommon in the cat. Diagnosis is based on a detailed and thorough history including progression of the disease, its response to previous therapy, involvement of other animals or people, and the cats' environment. Physical examination of both the skin and the body, as a whole, is essential because feline pododermatoses are often associated with systemic disease such as feline leukaemia virus (FeLV), feline immunodefiency virus (FIV) and diabetes mellitus. Laboratory tests include skin scrapings, Wood's light examination, fungal culture, lesion smears, and skin biopsy. The latter is often the key to the diagnosis of feline pododermatoses. Other tests may include the intradermal skin test, patch testing and evaluation of endocrine function. Successful therapy of feline pododermatoses is dependent upon obtaining a definitive diagnosis. Résumé- Les pododermatites sont peu fréquentes chez le chat. Le diagnostic repose sur une anamnèse soignée comprenant l'évolution de la maldie, sa réponse aux traitements antérieurs l'atteinte d'autres animaux on de personnes et l'environnement du chat. L'examen clinique, de la peau et de l'enseble du corps comme un tout, est essentiel, les pododermatites félines étant souvent associées à des maladies générales telles que le FeLV, le FIV ou le diabète sucré. Les examens complémentaires comportent des raclages cutanés, un examen à la lampe de Wood, une culture fongique, des caiques des lésions et des biopsies. Cette derrière est souvent la clef du diagnostic d'une pododermatite féline. Les autres examens complémentaires peuvent ètre des intradermopréactions, des tests épicutanés et des tests hormonaux. Le succès du traitement d'une pododermatite féline dépend de la possibilité d'établir un diagnostic définitif. Zusammenfassung- Pododermatitis bei Katzen ist selten. DieDiagnose beruht auf einer detaillierten und sorgfältig erhobenen Anamnèse einschließlich des Verlaufs der Erkrankung, ihrem Ansprechen auf bereits durchgeführte Therapien, die Erkrankung weiterer Tiere oder Menschen sowie Angaben über die Lebensumstände der Katze. Die klinische Untersuchungen von Haut und dem Körper als Ganzes ist ein wesentlicher Punkt, da feline Pododermatosen oft mit systemischen Erkrankungen wie FeLV, FIV und Diabetes mellitus vergesellschaftet sind. Laboruntersuchungen schließben Hautgeschabsel, Untersuchungen mit der Wood-Lampe, Pilzkultur, Abklatschpräparate, der Hautveränderungen und Hautbiopsien mit ein. Letztere sind oft der Schlüssel zur Diagnose der felinen Pododermatitis. Andere diagnostische Methoden können intradermale Hauttests, Patchtests und überprüfung endokriner Organfunktionene beinhalten. Die erfolgreiche Behandlung der felinen Pododermatitis hängt davon ab, ob eine definitive Diagnose erstellt werden kann. Resumen Pododermatosis es un hallazgo infrequente en el gato. El diagnóstico se basa en una historia detallada y completa incluyendo el curso de la enfermedad, respuesta a la terapia instaurada, si ha afectado a otros animales o personas, y el medio ambiente que rodea al gato. El examen fisico de ambos, piel y cuerpo, como si se tratase de una entidad única, és esencial, ya que las pododermatosis felinas se asocian frequentemente a enfermedades sistémicas como FeLV, FIV y diabetes mellitus. Los exámenes de laboratorio incluyen raspados cutáneos, investigación con la lámpara de wood, cultivos fungales, examinación microscópica directa del exudado, y biopsia cutánea. Esta última es frecuentemente la clave en el diagnóstico de la pododermatosis felina. Otros tests a llevar a cabo podrían ser pruebas cutáneas intradérmicas, tests de sensibilidad de contacto, y evalucación de la función endocrina. El éxito de la terapia depende de la obtención de un diagnóstico correcto.}, }
@article {pmid34644838, year = {1990}, author = {Paradis, M and Lemay, S and Scott, DW and Miller, WH and Wellington, J and Panich, R}, title = {Efficacy of Enrofloxacin in the Treatment of Canine Bacterial Pyoderma.}, journal = {Veterinary dermatology}, volume = {1}, number = {3}, pages = {123-127}, doi = {10.1111/j.1365-3164.1990.tb00090.x}, pmid = {34644838}, issn = {1365-3164}, abstract = {Abstract- Bacterial pyoderma was diagnosed in 30 dogs which were subsequently treated with enrofloxacin administered orally at 2.5 mg.kg[-1] of body weight every 12 h, for 2 to 14 weeks. Dogs were re-examined at the conclusion of antibiotic treatment and 28 (93.3 per cent) were found to have an excellent response. Relapses were seen in 25 per cent of these dogs after follow up periods of 1 to 4 months. Minor side effects were seen in only 1 dog. On the basis of this study, enrofloxacin is an excellent antibiotic for the treatment of canine bacterial pyoderma but must be administered well beyond the manufacturer's maximum recommendation for duration of therapy. Résumé- Une pyodermite bactérienne a été diagnostiquée chez 30 chiens qui furent traités avec de l'enrofloxacine administrée par voie orale à la dose de 2.5 mg/Kg toutes les 12 heures, pour une durée allant de 2.5 à 14 semaines. Les chiens furent réexaminés à la fin de l'antibiothérapie et 28 d'entre eux (93.3%) présentaient une excellente réponse au traitement. Des rechutes furent observées chez 25% des chiens lors de suivis portant sur des périodes de 1 à 4 mois. Des effets secondaires mineurs furent observés chez l'un des chiens. Cette étude montre que l'enrofloxacine est un excellent antibiotique pour le traitement des pyodermites canines mais, qu'il doit être administré pendant des délais beaucoup plus longs que ceux qui sont indiqués par le fabricant. Zusammenfassung- 30 Hunde mit bakteríellen Pyodermien wurden zweieinhalb bis vierzehn Wochen lang oral mit Enrofloxacin behandelt (2 täglich 2.5 mg/kg KGW). Nach Abschluß der Behandlung wurden die Tiere erneut untersucht. Bei 28 Patienten (93.3%) wurden hervorragende Ergebnisse erzielt. Bei 25% kam as nach 1 bis 4 Monaten zu Rezidiven. Geringe Nebenwirkungen wurden nur in einem Fall beobachtet. Die vorliegende Untersuchung zeigt, daß Enrofloxacin ein hervorragendes Antibiotikum für die Behandlung von Pyodermien ist, aber wesentlich länger als vom Hersteller angegeben verabreicht werden muß. Resumen Treinta perros, a los cuales se había diagnosticado una epiderma bacteriana, fueron tratado con Enrofloxacina via oral a una dosis de 2,5 mg/kg de peso corporal cada 12 horas durante un período de tiempo que oscíló entre las 2,5 semanas y las 14 semanas. Los perros se examinaron clínicamente de nuevo cuando acabó el tratamiento antibiótico y se observó en 28 (93,3%) una respuesta excelente. En un 25% de estos perros se observaron recidivas en un período comprendido entre uno y cuatro meses. Efectos colaterales de poca importancia se observaron úicamente en un animal. Según estos resultados puede concluirse que la Enrofloxacina es un antibiótico excelente para el tratamiento de las piodermas bacterianas del perro, aunque debe administrarse durante un período de tiempo superior al que recomiendan los productores.}, }
@article {pmid33158182, year = {2020}, author = {Nikseresht, S and Hilton, JBW and Kysenius, K and Liddell, JR and Crouch, PJ}, title = {Copper-ATSM as a Treatment for ALS: Support from Mutant SOD1 Models and Beyond.}, journal = {Life (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {33158182}, issn = {2075-1729}, support = {N/A//University of Melbourne/ ; 04_TRG_2017_Crouch//FightMND/ ; N/A//Motor Neurone Disease Australia/ ; }, abstract = {The blood-brain barrier permeant, copper-containing compound, Cu[II](atsm), has successfully progressed from fundamental research outcomes in the laboratory through to phase 2/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS). The most compelling outcomes to date to indicate potential for disease-modification have come from pre-clinical studies utilising mouse models that involve transgenic expression of mutated superoxide dismutase 1 (SOD1). Mutant SOD1 mice provide a very robust mammalian model of ALS with high validity, but mutations in SOD1 account for only a small percentage of ALS cases in the clinic, with the preponderant amount of cases being sporadic and of unknown aetiology. As per other putative drugs for ALS developed and tested primarily in mutant SOD1 mice, this raises important questions about the pertinence of Cu[II](atsm) to broader clinical translation. This review highlights some of the challenges associated with the clinical translation of new treatment options for ALS. It then provides a brief account of pre-clinical outcomes for Cu[II](atsm) in SOD1 mouse models of ALS, followed by an outline of additional studies which report positive outcomes for Cu[II](atsm) when assessed in cell and mouse models of neurodegeneration which do not involve mutant SOD1. Clinical evidence for Cu[II](atsm) selectively targeting affected regions of the CNS in patients is also presented. Overall, this review summarises the existing evidence which indicates why clinical relevance of Cu[II](atsm) likely extends beyond the context of cases of ALS caused by mutant SOD1.}, }
@article {pmid33158177, year = {2020}, author = {Amin, A and Perera, ND and Beart, PM and Turner, BJ and Shabanpoor, F}, title = {Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting.}, journal = {Cells}, volume = {9}, number = {11}, pages = {}, pmid = {33158177}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/*physiopathology ; Animals ; *Autophagy ; Caloric Restriction ; Genetic Predisposition to Disease ; Humans ; Models, Biological ; *Molecular Targeted Therapy ; }, abstract = {Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular "clearance" system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.}, }
@article {pmid33155830, year = {2020}, author = {Coppedè, F}, title = {Epigenetics of neuromuscular disorders.}, journal = {Epigenomics}, volume = {12}, number = {23}, pages = {2125-2139}, doi = {10.2217/epi-2020-0282}, pmid = {33155830}, issn = {1750-192X}, mesh = {Animals ; *Epigenesis, Genetic ; Epigenomics ; Humans ; Neuromuscular Diseases/*genetics ; }, abstract = {Neuromuscular disorders are a heterogeneous group of conditions affecting the neuromuscular system. The aim of this article is to review the major epigenetic findings in motor neuron diseases and major hereditary muscular dystrophies. DNA methylation changes are observed in both hereditary and sporadic forms, and combining DNA methylation analysis with mutational screening holds the potential for better diagnostic and prognostic accuracy. Novel, less toxic and more selective epigenetic drugs are designed and tested in animal and cell culture models of neuromuscular disorders, and non-coding RNAs are being investigated as either disease biomarkers or targets of therapeutic approaches to restore gene expression levels. Overall, neuromuscular disorder epigenetic biomarkers have a strong potential for clinical applications in the near future.}, }
@article {pmid33153757, year = {2021}, author = {Zhang, X and Zhou, J and Gu, Z and Zhang, H and Gong, Q and Luo, K}, title = {Advances in nanomedicines for diagnosis of central nervous system disorders.}, journal = {Biomaterials}, volume = {269}, number = {}, pages = {120492}, doi = {10.1016/j.biomaterials.2020.120492}, pmid = {33153757}, issn = {1878-5905}, mesh = {Blood-Brain Barrier ; *Central Nervous System Diseases/diagnosis/drug therapy ; Drug Delivery Systems ; Humans ; Nanomedicine ; *Nanoparticles ; Quality of Life ; }, abstract = {In spite of a great improvement in medical health services and an increase in lifespan, we have witnessed a skyrocket increase in the incidence of central nervous system (CNS) disorders including brain tumors, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease), ischemic stroke, and epilepsy, which have seriously undermined the quality of life and substantially increased economic and societal burdens. Development of diagnostic methods for CNS disorders is still in the early stage, and the clinical outcomes suggest these methods are not ready for the challenges associated with diagnosis of CNS disorders, such as early detection, specific binding, sharp contrast, and continuous monitoring of therapeutic interventions. Another challenge is to overcome various barrier structures during delivery of diagnostic agents, especially the blood-brain barrier (BBB). Fortunately, utilization of nanomaterials has been pursued as a potential and promising strategy to address these challenges. This review will discuss anatomical and functional structures of BBB and transport mechanisms of nanomaterials across the BBB, and special emphases will be placed on the state-of-the-art advances in the development of nanomedicines from a variety of nanomaterials for diagnosis of CNS disorders. Meanwhile, current challenges and future perspectives in this field are also highlighted.}, }
@article {pmid33151660, year = {2020}, author = {de Carvalho, M}, title = {Electrodiagnosis of Amyotrophic Lateral Sclerosis: A Review of Existing Guidelines.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {37}, number = {4}, pages = {294-298}, doi = {10.1097/WNP.0000000000000682}, pmid = {33151660}, issn = {1537-1603}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Electrodiagnosis/*methods ; Humans ; Neurophysiology/methods ; *Practice Guidelines as Topic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper motor neurons in the motor cortex and lower motor neurons (LMN) in the brainstem and spinal cord, resulting in a progressive functional impairment. Neurophysiology is a diagnostic tool to detect dysfunction of upper motor neurons and LMN, even when the changes are subclinical. Electromyography is the standard neurophysiological investigation to detect LMN changes, which is essential to exclude mimicking disorders and attain early diagnosis. Recently, Awaji criteria was proposed to support ALS diagnosis, in these criteria fasciculation potentials associated with neurogenic motor unit potentials represents a sufficient marker of LMN involvement, in each muscle. Many studies have confirmed that Awaji criteria are more sensitive, permitting earlier diagnosis without loss of specificity when compared with the revised El Escorial criteria. Fasciculations are easily detected by ultrasound; increasingly, this technique has been used to diagnose ALS, combined with electromyography. This combination can increase diagnostic accuracy. Many techniques for estimating the number of motor units have been proposed, they are useful to quantify LMN loss. Electrical impedance myography is an emerging technique with great potential to monitor ALS progression. Neurophysiological investigation of upper motor neuron dysfunction is difficult in ALS, detecting decreased cortical inhibition by threshold tracking cortical magnetic stimulation is a promising method, which needs to be validated in different centers.}, }
@article {pmid33145792, year = {2021}, author = {Korb, MK and Kimonis, VE and Mozaffar, T}, title = {Multisystem proteinopathy: Where myopathy and motor neuron disease converge.}, journal = {Muscle &amp; nerve}, volume = {63}, number = {4}, pages = {442-454}, doi = {10.1002/mus.27097}, pmid = {33145792}, issn = {1097-4598}, mesh = {Cell Cycle Proteins/*genetics/metabolism ; Humans ; Motor Neuron Disease/genetics/metabolism/*pathology ; Mutation/genetics ; Nuclear Matrix-Associated Proteins/genetics/metabolism ; RNA-Binding Proteins/*genetics/metabolism ; Valosin Containing Protein/genetics/*metabolism ; }, abstract = {Multisystem proteinopathy (MSP) is a pleiotropic group of inherited disorders that cause neurodegeneration, myopathy, and bone disease, and share common pathophysiology. Originally referred to as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), attributed to mutations in the gene encoding valosin-containing protein (VCP), it has more recently been discovered that there are several other genes responsible for similar clinical and pathological phenotypes with muscle, brain, nerve, and bone involvement, in various combinations. These include heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1, hnRNPA1), sequestosome 1 (SQSTM1), matrin 3 (MATR3), T-cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN), all of which share disruption of RNA stress granule function and autophagic degradation. This review will discuss each of the genes implicated in MSP, exploring the molecular pathogenesis, clinical features, current standards of care, and future directions for this diverse yet mechanistically linked spectrum of disorders.}, }
@article {pmid33144171, year = {2021}, author = {Ugbode, C and West, RJH}, title = {Lessons learned from CHMP2B, implications for frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {147}, number = {}, pages = {105144}, doi = {10.1016/j.nbd.2020.105144}, pmid = {33144171}, issn = {1095-953X}, support = {204829/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Endosomal Sorting Complexes Required for Transport/*genetics ; Frontotemporal Dementia/*genetics ; Humans ; Mutation ; }, abstract = {Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases with clinical, genetic and pathological overlap. As such, they are commonly regarded as a single spectrum disorder, with pure FTD and pure ALS representing distinct ends of a continuum. Dysfunctional endo-lysosomal and autophagic trafficking, leading to impaired proteostasis is common across the FTD-ALS spectrum. These pathways are, in part, mediated by CHMP2B, a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Here we review how ALS and FTD disease causing mutations in CHMP2B have greatly contributed to our understanding of how endosomal-lysosomal and autophagic dysfunction contribute to neurodegeneration, and how in vitro and in vivo models have helped elucidate novel candidates for potential therapeutic intervention with implications across the FTD-ALS spectrum.}, }
@article {pmid33134918, year = {2020}, author = {Béland, LC and Markovinovic, A and Jakovac, H and De Marchi, F and Bilic, E and Mazzini, L and Kriz, J and Munitic, I}, title = {Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses.}, journal = {Brain communications}, volume = {2}, number = {2}, pages = {fcaa124}, pmid = {33134918}, issn = {2632-1297}, abstract = {Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions-excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.}, }
@article {pmid33132902, year = {2020}, author = {Tittelmeier, J and Nachman, E and Nussbaum-Krammer, C}, title = {Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {581374}, pmid = {33132902}, issn = {1663-4365}, abstract = {Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.}, }
@article {pmid33132897, year = {2020}, author = {Chen, J and Liu, X and Zhong, Y}, title = {Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {566922}, pmid = {33132897}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are characterized by the loss of neurons and/or myelin sheath, which deteriorate over time and cause dysfunction. Interleukin 17A is the signature cytokine of a subset of CD4[+] helper T cells known as Th17 cells, and the IL-17 cytokine family contains six cytokines and five receptors. Recently, several studies have suggested a pivotal role for the interleukin-17A (IL-17A) cytokine family in human inflammatory or autoimmune diseases and neurodegenerative diseases, including psoriasis, rheumatoid arthritis (RA), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and glaucoma. Studies in recent years have shown that the mechanism of action of IL-17A is more subtle than simply causing inflammation. Although the specific mechanism of IL-17A in neurodegenerative diseases is still controversial, it is generally accepted now that IL-17A causes diseases by activating glial cells. In this review article, we will focus on the function of IL-17A, in particular the proposed roles of IL-17A, in the pathogenesis of neurodegenerative diseases.}, }
@article {pmid33131662, year = {2020}, author = {Cooksey, JA and Sergew, A}, title = {Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.}, journal = {Sleep medicine clinics}, volume = {15}, number = {4}, pages = {527-538}, doi = {10.1016/j.jsmc.2020.08.004}, pmid = {33131662}, issn = {1556-4088}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Humans ; *Noninvasive Ventilation/standards ; Respiratory Insufficiency/etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease involving upper and lower motor neurons and has limited treatment options. The weakness progresses to involve the diaphragms, resulting in respiratory failure and death. Home noninvasive ventilation has been shown to improve survival and quality of life, especially in those with intact bulbar function. Once initiated, close monitoring with nocturnal oximetry, remote downloads from the home noninvasive ventilation machine, and measurement of serum bicarbonate should be conducted. Additionally, transcutaneous CO2 monitoring can be considered if available. This article discusses the indications, timing, initiation, and management of noninvasive ventilation in amyotrophic lateral sclerosis.}, }
@article {pmid33130950, year = {2021}, author = {Chipika, RH and Siah, WF and McKenna, MC and Li Hi Shing, S and Hardiman, O and Bede, P}, title = {The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?.}, journal = {Journal of neurology}, volume = {268}, number = {12}, pages = {4607-4629}, pmid = {33130950}, issn = {1432-1459}, support = {HRB EIA-2017-019//Health Research Board Ireland/ ; SPF-2020//Spastic Paraplegia Foundation, Inc./ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Humans ; Sample Size ; }, abstract = {Presymptomatic studies in ALS have consistently captured considerable disease burden long before symptom manifestation and contributed important academic insights. With the emergence of genotype-specific therapies, however, there is a pressing need to address practical objectives such as the estimation of age of symptom onset, phenotypic prediction, informing the optimal timing of pharmacological intervention, and identifying a core panel of biomarkers which may detect response to therapy. Existing presymptomatic studies in ALS have adopted striking different study designs, relied on a variety of control groups, used divergent imaging and electrophysiology methods, and focused on different genotypes and demographic groups. We have performed a systematic review of existing presymptomatic studies in ALS to identify common themes, stereotyped shortcomings, and key learning points for future studies. Existing presymptomatic studies in ALS often suffer from sample size limitations, lack of disease controls and rarely follow their cohort until symptom manifestation. As the characterisation of presymptomatic processes in ALS serves a multitude of academic and clinical purposes, the careful review of existing studies offers important lessons for future initiatives.}, }
@article {pmid33130222, year = {2021}, author = {Shatunov, A and Al-Chalabi, A}, title = {The genetic architecture of ALS.}, journal = {Neurobiology of disease}, volume = {147}, number = {}, pages = {105156}, doi = {10.1016/j.nbd.2020.105156}, pmid = {33130222}, issn = {1095-953X}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; }, }
@article {pmid33127590, year = {2021}, author = {Panchal, K and Tiwari, AK}, title = {Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases.}, journal = {Mitochondrion}, volume = {56}, number = {}, pages = {118-135}, doi = {10.1016/j.mito.2020.10.005}, pmid = {33127590}, issn = {1872-8278}, mesh = {Apoptosis ; Axonal Transport ; Calcium/metabolism ; DNA, Mitochondrial/*genetics ; Humans ; Mitochondria/genetics/metabolism/*pathology ; Mitochondrial Dynamics ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress ; rho GTP-Binding Proteins/*metabolism ; }, abstract = {Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca[2+] homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.}, }
@article {pmid33127433, year = {2021}, author = {Hashimoto, M and Fukamizu, A and Nakagawa, T and Kizuka, Y}, title = {Roles of protein arginine methyltransferase 1 (PRMT1) in brain development and disease.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1865}, number = {1}, pages = {129776}, doi = {10.1016/j.bbagen.2020.129776}, pmid = {33127433}, issn = {1872-8006}, mesh = {Animals ; Arginine/analogs &amp; derivatives/genetics/*metabolism ; Brain/*growth &amp; development/metabolism/pathology ; Gene Expression Regulation, Developmental ; Humans ; Methylation ; Neural Stem Cells/metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Protein-Arginine N-Methyltransferases/genetics/*metabolism ; Repressor Proteins/genetics/*metabolism ; }, abstract = {BACKGROUND: Protein arginine methyltransferase 1 (PRMT1), a major type I arginine methyltransferase in mammals, methylates histone and non-histone proteins to regulate various cellular functions such as transcription, DNA damage response, and signal transduction.<br><br>SCOPE OF REVIEW: This review summarizes previous and recent studies on PRMT1 functions in major cell types of the central nervous system. We also discuss the potential involvement of PRMT1 in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. Also, we raise key questions that must be addressed in the future to more precisely understand the roles of PRMT1.<br><br>MAJOR CONCLUSIONS: Recent studies revealed that PRMT1 is essential for the development of neurons, astrocytes, and oligodendrocytes, although further investigation using cell type-specific PRMT1-deficient animals is required. In addition, the relevance of PRMT1 in neurodegenerative diseases will continue to be a hot topic.<br><br>GENERAL SIGNIFICANCE: PRMT1 is important for neural development and neurodegenerative diseases.}, }
@article {pmid33126923, year = {2020}, author = {Huang, C and Yan, S and Zhang, Z}, title = {Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {9}, number = {1}, pages = {40}, pmid = {33126923}, issn = {2047-9158}, support = {81922026//National Natural Science Foundation of China/International ; 91649115//National Natural Science Foundation of China/International ; 81872842//National Natural Science Foundation of China/International ; 82073821//National Natural Science Foundation of China/International ; 2017YFA0105104//National Key Research and Development Program of China Stem Cell and Translational Research/International ; 2017A020211019//Guang Dong Province science and technology plan project/International ; 2020A1515011061//Guang Dong Province science and technology plan project/International ; 21619104//Fundamental Research Funds for the Central Universities/International ; 202007030008//Guangzhou Key Research Program on Brain Science/International ; }, mesh = {Animals ; Autophagy/*physiology ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Mitochondria/genetics/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism/*therapy ; Neurons/metabolism ; Protein Binding/physiology ; }, abstract = {Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body. Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases. As mitochondria age in cells, they gradually become inefficient and potentially toxic. Acute injury can trigger the permeability of mitochondrial membranes, which can lead to apoptosis or necrosis. Transactive response DNA-binding protein 43 kDa (TDP-43) is a protein widely present in cells. It can bind to RNA, regulate a variety of RNA processes, and play a role in the formation of multi-protein/RNA complexes. Thus, the normal physiological functions of TDP-43 are particularly important for cell survival. Normal TDP-43 is located in various subcellular structures including mitochondria, mitochondrial-associated membrane, RNA particles and stress granules to regulate the endoplasmic reticulum-mitochondrial binding, mitochondrial protein translation, and mRNA transport and translation. Importantly, TDP-43 is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, which are characterized by abnormal phosphorylation, ubiquitination, lysis or nuclear depletion of TDP-43 in neurons and glial cells. Although the pathogenesis of TDP-43 proteinopathy remains unknown, the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology, transport, and function suggest that mitochondria are associated with TDP-43-related diseases. Autophagy is a basic physiological process that maintains the homeostasis of cells, including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm; therefore, it is considered protective against neurodegenerative diseases. However, the combination of abnormal TDP-43 aggregation, mitochondrial dysfunction, and insufficient autophagy can lead to a variety of aging-related pathologies. In this review, we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria. Finally, we discuss a novel approach for neurodegenerative treatment based on the knowledge.}, }
@article {pmid33125541, year = {2021}, author = {Li, W and Gao, H and Dong, X and Zheng, D}, title = {SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature.}, journal = {Journal of neurology}, volume = {268}, number = {4}, pages = {1351-1357}, pmid = {33125541}, issn = {1432-1459}, support = {2018225091//Natural Science Foundation of Liaoning Province/ ; }, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/complications/genetics ; *Frontotemporal Dementia/complications/diagnostic imaging/genetics ; Humans ; Male ; Middle Aged ; *Neurodegenerative Diseases ; Sequestosome-1 Protein/genetics ; }, abstract = {INTRODUCTION: Accumulating evidence shows that SQSTM1 plays a vital role in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which represent a neurodegenerative disease continuum. Here, we report a novel SQSTM1 variant in a patient presenting with progressive nonfluent aphasia (PNFA) and progressive bulbar palsy (PBP). Relevant literature about FTD and FTD-ALS caused by SQSTM1 mutation was reviewed to better understand its clinical features.<br><br>METHODS: We collected data from a 66-year-old male patient with a novel heterozygous variant (c.995C&#x2009;>&#x2009;G, p.S332X) in the SQSTM1 gene who was diagnosed with PNFA and PBP and performed a PubMed literature search using the advanced research criteria: [("frontotemporal lobar degeneration") OR ("frontotemporal dementia") OR ("amyotrophic lateral sclerosis") OR ("motor neuron disease")] AND ("SQSTM1"). The clinical features of FTD and FTD-ALS related to SQSTM1 mutation were summarized based on previous cases and our new case.<br><br>RESULTS: The initial symptom of the current patient was progressive verb finding difficulties and effortful speech output, which developed into dysarthria and dysphagia in subsequent months. The results, including tongue atrophy, fasciculations, neurogenic changes, and mild left dominant hypometabolism of 18F-fluorodeoxyglucose PET in the frontal cortex, suggest the possibility of PNFA and PBP. A novel likely pathogenic heterozygous variant (c.995C&#x2009;>&#x2009;G, p.S332X) in the SQSTM1 gene was identified. The literature search revealed a total of 33 FTD and FTD-ALS cases related to the SQSTM1 mutation with detailed clinical information. The mean age of onset (including our patient) was 63.5&#x2009;&#xb1;&#x2009;9.7&#xa0;years. bvFTD was the most common clinical phenotype. The missense mutation in the SQSTM1 gene coding region and the UBA domain involvement are its main genetic characteristics.<br><br>CONCLUSION: Although rare, mutations in SQSTM1 can lead to various clinical subtypes of FTD and FTD-ALS, including the rare combination of PNFA and PBP. Exon missense mutation is the main type of mutation, which is common in the UBA domain.}, }
@article {pmid33123310, year = {2020}, author = {Pichla, M and Bartosz, G and Sadowska-Bartosz, I}, title = {The Antiaggregative and Antiamyloidogenic Properties of Nanoparticles: A Promising Tool for the Treatment and Diagnostics of Neurodegenerative Diseases.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {3534570}, pmid = {33123310}, issn = {1942-0994}, mesh = {Amyloidogenic Proteins/antagonists &amp; inhibitors/metabolism ; Antioxidants/chemistry ; Dendrimers/chemistry ; Humans ; Nanoparticles/*chemistry/therapeutic use/toxicity ; Neurodegenerative Diseases/*diagnosis/drug therapy/genetics ; Protein Aggregates/drug effects ; Quantum Dots/chemistry/therapeutic use/toxicity ; Reactive Oxygen Species/metabolism ; alpha-Synuclein/antagonists &amp; inhibitors/metabolism ; }, abstract = {Due to the progressive aging of the society, the prevalence and socioeconomic burden of neurodegenerative diseases are predicted to rise. The most common neurodegenerative disorders nowadays, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, can be classified as proteinopathies. They can be either synucleinopathies, amyloidopathies, tauopathies, or TDP-43-related proteinopathies; thus, nanoparticles with a potential ability to inhibit pathological protein aggregation and/or degrade already existing aggregates can be a promising approach in the treatment of neurodegenerative diseases. As it turns out, nanoparticles can be a double-edged sword; they can either promote or inhibit protein aggregation, depending on coating, shape, size, surface charge, and concentration. In this review, we aim to emphasize the need of a breakthrough in the treatment of neurodegenerative disorders and draw attention to nanomaterials, as they can also serve as a diagnostic tool for protein aggregates or can be used in a high-throughput screening for novel antiaggregative compounds.}, }
@article {pmid33118626, year = {2021}, author = {Sodero, AO}, title = {24S-hydroxycholesterol: Cellular effects and variations in brain diseases.}, journal = {Journal of neurochemistry}, volume = {157}, number = {4}, pages = {899-918}, doi = {10.1111/jnc.15228}, pmid = {33118626}, issn = {1471-4159}, mesh = {Animals ; Brain/*metabolism ; Brain Diseases/*metabolism ; Humans ; Hydroxycholesterols/*metabolism ; }, abstract = {The adult brain exhibits a characteristic cholesterol homeostasis, with low synthesis rate and active catabolism. Brain cholesterol turnover is possible thanks to the action of the enzyme cytochrome P450 46A1 (CYP46A1) or 24-cholesterol hydroxylase, that transforms cholesterol into 24S-hydroxycholesterol (24S-HC). But before crossing the blood-brain barrier (BBB), this oxysterol, that is the most abundant in the brain, can act locally, affecting the functioning of neurons, astrocytes, oligodendrocytes, and vascular cells. The first part of this review addresses different aspects of 24S-HC production and elimination from the brain. The second part concentrates in the effects of 24S-HC at the cellular level, describing how this oxysterol affects cell viability, amyloid β production, neurotransmission, and transcriptional activity. Finally, the role of 24S-HC in Alzheimer, Huntington and Parkinson diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as the possibility of using this oxysterol as predictive and/or evolution biomarker in different brain disorders is discussed.}, }
@article {pmid33117120, year = {2020}, author = {Sipione, S and Monyror, J and Galleguillos, D and Steinberg, N and Kadam, V}, title = {Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {572965}, pmid = {33117120}, issn = {1662-4548}, abstract = {Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.}, }
@article {pmid33114553, year = {2020}, author = {Gavriilaki, M and Kimiskidis, VK and Gavriilaki, E}, title = {Precision Medicine in Neurology: The Inspirational Paradigm of Complement Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {33114553}, issn = {1424-8247}, abstract = {Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the innovative application of the first complement inhibitor in clinical practice as an approved treatment of myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) related with specific antibodies raised hope for the implementation of personalized therapies in detrimental neurological diseases. A thorough literature search was conducted through May 2020 at MEDLINE, EMBASE, Cochrane Library and ClinicalTrials.gov databases based on medical terms (MeSH)" complement system proteins" and "neurologic disease". Complement's role in pathophysiology, monitoring of disease activity and therapy has been investigated in MG, multiple sclerosis, NMOSD, spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson, Alzheimer, Huntington disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, stroke, and epilepsy. Given the complexity of complement diagnostics and therapeutics, this state-of-the-art review aims to provide a brief description of the complement system for the neurologist, an overview of novel complement inhibitors and updates of complement studies in a wide range of neurological disorders.}, }
@article {pmid33113845, year = {2020}, author = {Cipollina, G and Davari Serej, A and Di Nolfi, G and Gazzano, A and Marsala, A and Spatafora, MG and Peviani, M}, title = {Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?.}, journal = {International journal of molecular sciences}, volume = {21}, number = {21}, pages = {}, pmid = {33113845}, issn = {1422-0067}, support = {17-IIP-343//Amyotrophic Lateral Sclerosis Association/ ; 20-IIA-525//Amyotrophic Lateral Sclerosis Association/ ; W81XWH-17-1-0036//U.S. Department of Defense/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Biomarkers/metabolism ; Disease Models, Animal ; *Genetic Heterogeneity ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Inflammation/*genetics/metabolism ; Microglia/*metabolism ; Transcriptome/*genetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex pathology: (i) the neurodegeneration is chronic and progressive; it starts focally in specific central nervous system (CNS) areas and spreads to different districts; (ii) multiple cell types further than motor neurons (i.e., glial/immune system cells) are actively involved in the disease; (iii) both neurosupportive and neurotoxic neuroinflammatory responses were identified. Microglia cells (a key player of neuroinflammation in the CNS) attracted great interest as potential target cell population that could be modulated to counteract disease progression, at least in preclinical ALS models. However, the heterogeneous/multifaceted microglia cell responses occurring in different CNS districts during the disease represent a hurdle for clinical translation of single-drug therapies. To address this issue, over the past ten years, several studies attempted to dissect the complexity of microglia responses in ALS. In this review, we shall summarize these results highlighting how the heterogeneous signature displayed by ALS microglia reflects not only the extent of neuronal demise in different regions of the CNS, but also variable engagement in the attempts to cope with the neuronal damage. We shall discuss novel avenues opened by the advent of single-cell and spatial transcriptomics technologies, underlining the potential for discovery of novel therapeutic targets, as well as more specific diagnostic/prognostic not-invasive markers of neuroinflammation.}, }
@article {pmid33106318, year = {2020}, author = {Caldwell, KA and Willicott, CW and Caldwell, GA}, title = {Modeling neurodegeneration in Caenorhabditiselegans.}, journal = {Disease models &amp; mechanisms}, volume = {13}, number = {10}, pages = {}, pmid = {33106318}, issn = {1754-8411}, support = {R15 NS104857/NS/NINDS NIH HHS/United States ; R15 NS106460/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/pathology ; Animals ; Animals, Genetically Modified ; Behavior, Animal ; Caenorhabditis elegans ; Disease Models, Animal ; Humans ; Nerve Degeneration/genetics/*pathology ; }, abstract = {The global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The nematode Caenorhabditis elegans has served as the experimental subject for multiple transformative discoveries that have redefined our understanding of biology for ∼60 years. More recently, the considerable attributes of C. elegans have been applied to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. Transgenic nematodes with genes encoding normal and disease variants of proteins at the single- or multi-copy level under neuronal-specific promoters limits expression to select neuronal subtypes. The anatomical transparency of C. elegans affords the use of co-expressed fluorescent proteins to follow the progression of neurodegeneration as the animals age. Significantly, a completely defined connectome facilitates detailed understanding of the impact of neurodegeneration on organismal health and offers a unique capacity to accurately link cell death with behavioral dysfunction or phenotypic variation in vivo Moreover, chemical treatments, as well as forward and reverse genetic screening, hasten the identification of modifiers that alter neurodegeneration. When combined, these chemical-genetic analyses establish critical threshold states to enhance or reduce cellular stress for dissecting associated pathways. Furthermore, C. elegans can rapidly reveal whether lifespan or healthspan factor into neurodegenerative processes. Here, we outline the methodologies employed to investigate neurodegeneration in C. elegans and highlight numerous studies that exemplify its utility as a pre-clinical intermediary to expedite and inform mammalian translational research.}, }
@article {pmid33100967, year = {2020}, author = {Michalicova, A and Majerova, P and Kovac, A}, title = {Tau Protein and Its Role in Blood-Brain Barrier Dysfunction.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {570045}, pmid = {33100967}, issn = {1662-5099}, abstract = {The blood-brain barrier (BBB) plays a crucial role in maintaining the specialized microenvironment of the central nervous system (CNS). In aging, the stability of the BBB declines and the permeability increases. The list of CNS pathologies involving BBB dysfunction is growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic, neuronal dysfunction, and detrimental neuroinflammatory changes. Such processes have been implicated in different diseases, including vascular dementia, stroke, Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus. The BBB damage is also observed in tauopathies that lack amyloid-β overproduction, suggesting a role for tau in BBB damage. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of the MAPT in cells of the nervous system. Neuropathology of tauopathies is defined as intracellular accumulation of neurofibrillary tangles (NFTs) consisting of aggregated hyper- and abnormal phosphorylation of tau protein and neuroinflammation. Disruption of the BBB found in tauopathies is driven by chronic neuroinflammation. Production of pro-inflammatory signaling molecules such as cytokines, chemokines, and adhesion molecules by glial cells, neurons, and endothelial cells determine the integrity of the BBB and migration of immune cells into the brain. The inflammatory processes promote structural changes in capillaries such as fragmentation, thickening, atrophy of pericytes, accumulation of laminin in the basement membrane, and increased permeability of blood vessels to plasma proteins. Here, we summarize the knowledge about the role of tau protein in BBB structural and functional changes.}, }
@article {pmid33096681, year = {2020}, author = {Fortier, G and Butti, Z and Patten, SA}, title = {Modelling C9orf72-Related Amyotrophic Lateral Sclerosis in Zebrafish.}, journal = {Biomedicines}, volume = {8}, number = {10}, pages = {}, pmid = {33096681}, issn = {2227-9059}, abstract = {A hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and its discovery has revolutionized our understanding of this devastating disease. Model systems are a valuable tool for studying ALS pathobiology and potential therapies. The zebrafish (Danio rerio) has particularly become a useful model organism to study neurological diseases, including ALS, due to high genetic and physiological homology to mammals, and sensitivity to various genetic and pharmacological manipulations. In this review we summarize the zebrafish models that have been used to study the pathology of C9orf72-related ALS. We discuss their value in providing mechanistic insights and their potential use for drug discovery.}, }
@article {pmid33094283, year = {2020}, author = {Ng Kee Kwong, KC and Gregory, JM and Pal, S and Chandran, S and Mehta, AR}, title = {Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies.}, journal = {Brain communications}, volume = {2}, number = {2}, pages = {fcaa121}, pmid = {33094283}, issn = {2632-1297}, support = {MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Various studies have suggested that a neurotoxic cerebrospinal fluid profile could be implicated in amyotrophic lateral sclerosis. Here, we systematically review the evidence for cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and explore its clinical correlates. We searched the following databases with no restrictions on publication date: PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to cerebrospinal fluid from amyotrophic lateral sclerosis patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarized. Twenty-eight studies were included in our analysis. Both participant characteristics and study conditions including cerebrospinal fluid concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between cerebrospinal fluid cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that cerebrospinal fluid cytotoxicity is a feature of sporadic and possibly also of familial forms of amyotrophic lateral sclerosis. Further research is, however, required to better characterize its underlying mechanisms and to establish its possible contribution to amyotrophic lateral sclerosis pathophysiology.}, }
@article {pmid33094209, year = {2020}, author = {Bianchi, VE and Rizzi, L and Bresciani, E and Omeljaniuk, RJ and Torsello, A}, title = {Androgen Therapy in Neurodegenerative Diseases.}, journal = {Journal of the Endocrine Society}, volume = {4}, number = {11}, pages = {bvaa120}, pmid = {33094209}, issn = {2472-1972}, abstract = {Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.}, }
@article {pmid33083964, year = {2021}, author = {Fagiani, F and Govoni, S and Racchi, M and Lanni, C}, title = {The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {58}, number = {3}, pages = {1062-1073}, pmid = {33083964}, issn = {1559-1182}, mesh = {Aging/pathology ; Animals ; Humans ; NIMA-Interacting Peptidylprolyl Isomerase/*metabolism ; Nerve Degeneration/*enzymology/pathology ; Nervous System/*embryology ; Neurons/*enzymology/*pathology ; *Signal Transduction ; }, abstract = {The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts. While its implication in proliferating cells, and, in particular, in the field of cancer, has been widely characterized, less is known about Pin1 biological functions in terminally differentiated and post-mitotic neurons. Notably, Pin1 is widely expressed in the central and peripheral nervous system, where it regulates a variety of neuronal processes, including neuronal development, apoptosis, and synaptic activity. However, despite studies reporting the interaction of Pin1 with neuronal substrates or its involvement in specific signaling pathways, a more comprehensive understanding of its biological functions at neuronal level is still lacking. Besides its implication in physiological processes, a growing body of evidence suggests the crucial involvement of Pin1 in aging and age-related and neurodegenerative diseases, including Alzheimer's disease, Parkinson disease, frontotemporal dementias, Huntington disease, and amyotrophic lateral sclerosis, where it mediates profoundly different effects, ranging from neuroprotective to neurotoxic. Therefore, a more detailed understanding of Pin1 neuronal functions may provide relevant information on the consequences of Pin1 deregulation in age-related and neurodegenerative disorders.}, }
@article {pmid33078197, year = {2020}, author = {Sun, Y and Curle, AJ and Haider, AM and Balmus, G}, title = {The role of DNA damage response in amyotrophic lateral sclerosis.}, journal = {Essays in biochemistry}, volume = {64}, number = {5}, pages = {847-861}, pmid = {33078197}, issn = {1744-1358}, support = {/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; *DNA Damage ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.}, }
@article {pmid33074186, year = {2021}, author = {Cappella, M and Pradat, PF and Querin, G and Biferi, MG}, title = {Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy.}, journal = {Journal of neuromuscular diseases}, volume = {8}, number = {1}, pages = {25-38}, pmid = {33074186}, issn = {2214-3602}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; *Clinical Trials as Topic ; *Genetic Therapy ; Humans ; Oligonucleotides, Antisense/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease's pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.}, }
@article {pmid33072744, year = {2020}, author = {Stacchiotti, A and Corsetti, G}, title = {Natural Compounds and Autophagy: Allies Against Neurodegeneration.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {555409}, pmid = {33072744}, issn = {2296-634X}, abstract = {Prolonging the healthy life span and limiting neurological illness are imperative goals in gerontology. Age-related neurodegeneration is progressive and leads to severe diseases affecting motility, memory, cognitive function, and social life. To date, no effective treatments are available for neurodegeneration and irreversible neuronal loss. Bioactive phytochemicals could represent a natural alternative to ensure active aging and slow onset of neurodegenerative diseases in elderly patients. Autophagy or macroautophagy is an evolutionarily conserved clearing process that is needed to remove aggregate-prone proteins and organelles in neurons and glia. It also is crucial in synaptic plasticity. Aberrant autophagy has a key role in aging and neurodegeneration. Recent evidence indicates that polyphenols like resveratrol and curcumin, flavonoids, like quercetin, polyamine, like spermidine and sugars, like trehalose, limit brain damage in vitro and in vivo. Their common mechanism of action leads to restoration of efficient autophagy by dismantling misfolded proteins and dysfunctional mitochondria. This review focuses on the role of dietary phytochemicals as modulators of autophagy to fight Alzheimer's and Parkinson's diseases, fronto-temporal dementia, amyotrophic lateral sclerosis, and psychiatric disorders. Currently, most studies have involved in vitro or preclinical animal models, and the therapeutic use of phytochemicals in patients remains limited.}, }
@article {pmid33071748, year = {2020}, author = {Martier, R and Konstantinova, P}, title = {Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {580179}, pmid = {33071748}, issn = {1662-4548}, abstract = {Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.}, }
@article {pmid33071739, year = {2020}, author = {Rojas, P and Ramírez, AI and Fernández-Albarral, JA and López-Cuenca, I and Salobrar-García, E and Cadena, M and Elvira-Hurtado, L and Salazar, JJ and de Hoz, R and Ramírez, JM}, title = {Amyotrophic Lateral Sclerosis: A Neurodegenerative Motor Neuron Disease With Ocular Involvement.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {566858}, pmid = {33071739}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of the lower and upper motor neurons and is the most prevalent motor neuron disease. This disease is characterized by muscle weakness, stiffness, and hyperreflexia. Patients survive for a short period from the onset of the disease. Most cases are sporadic, with only 10% of the cases being genetic. Many genes are now known to be involved in familial ALS cases, including some of the sporadic cases. It has also been observed that, in addition to genetic factors, there are numerous molecular mechanisms involved in these pathologies, such as excitotoxicity, mitochondrial disorders, alterations in axonal transport, oxidative stress, accumulation of misfolded proteins, and neuroinflammation. This pathology affects the motor neurons, the spinal cord, the cerebellum, and the brain, but recently, it has been shown that it also affects the visual system. This impact occurs not only at the level of the oculomotor system but also at the retinal level, which is why the retina is being proposed as a possible biomarker of this pathology. The current review discusses the main aspects mentioned above related to ALS, such as the main genes involved, the most important molecular mechanisms that affect this pathology, its ocular involvement, and the possible usefulness of the retina as a biomarker.}, }
@article {pmid33070647, year = {2021}, author = {Maurice, T}, title = {Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders.}, journal = {Expert opinion on drug discovery}, volume = {16}, number = {4}, pages = {373-389}, doi = {10.1080/17460441.2021.1838483}, pmid = {33070647}, issn = {1746-045X}, mesh = {Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Development ; Humans ; Ligands ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*administration &amp; dosage/pharmacology ; Piperidines/administration &amp; dosage/pharmacology ; Receptors, sigma/*agonists/metabolism ; Sigma-1 Receptor ; }, abstract = {Introduction: The sigma-1 receptor (S1R) is attracting much attention for disease-modifying therapies in neurodegenerative diseases. It is a conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca2+ transfer and ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in diseases such as Alzheimer, Parkinson, Huntington or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases.Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the bi-phasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials.Expert opinion: S1R agonists modulate inter-organelles communication altered in neurodegenerative diseases and activate intracellular survival pathways. Research will continue growing in the future. The particular cellular nature of this chaperone protein must be better understood to facilitate the clinical developement of promising molecules.}, }
@article {pmid33070123, year = {2021}, author = {Rawat, K and Singh, N and Kumari, P and Saha, L}, title = {A review on preventive role of ketogenic diet (KD) in CNS disorders from the gut microbiota perspective.}, journal = {Reviews in the neurosciences}, volume = {32}, number = {2}, pages = {143-157}, doi = {10.1515/revneuro-2020-0078}, pmid = {33070123}, issn = {2191-0200}, mesh = {Animals ; Brain ; *Diet, Ketogenic ; *Epilepsy ; *Gastrointestinal Microbiome ; Humans ; *Probiotics/therapeutic use ; }, abstract = {The gut microbiota plays an important role in neurological diseases via the gut-brain axis. Many factors such as diet, antibiotic therapy, stress, metabolism, age, geography and genetics are known to play a critical role in regulating the colonization pattern of the microbiota. Recent studies have shown the role of the low carbohydrate, adequate protein, and high fat "ketogenic diet" in remodeling the composition of the gut microbiome and thereby facilitating protective effects in various central nervous system (CNS) disorders. Gut microbes are found to be involved in the pathogenesis of various CNS disorders like epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), autism spectrum disorders (ASDs), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and stress, anxiety and depression. In vivo studies have shown an intricate link between gut microbes and KD and specific microbes/probiotics proved useful in in vivo CNS disease models. In the present review, we discuss the gut-brain bidirectional axis and the underlying mechanism of KD-based therapy targeting gut microbiome in in vivo animal models and clinical studies in neurological diseases. Also, we tried to infer how KD by altering the microbiota composition contributes towards the protective role in various CNS disorders. This review helps to uncover the mechanisms that are utilized by the KD and gut microbiota to modulate gut-brain axis functions and may provide novel opportunities to target therapies to the gut to treat neurologic disorders.}, }
@article {pmid33069760, year = {2020}, author = {Khan, H and Tundis, R and Ullah, H and Aschner, M and Belwal, T and Mirzaei, H and Akkol, EK}, title = {Flavonoids targeting NRF2 in neurodegenerative disorders.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {146}, number = {}, pages = {111817}, doi = {10.1016/j.fct.2020.111817}, pmid = {33069760}, issn = {1873-6351}, mesh = {Animals ; Flavonoids/*pharmacology ; Humans ; NF-E2-Related Factor 2/*drug effects ; Neurodegenerative Diseases/*metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {Neurodegenerative disorders are characterized by progressive loss of neurons. To date, no efficacious therapies exist for these disorders, and current therapies provide only symptomatic relief. The neuroprotective effects of natural compounds have been reported in several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) amyotrophic lateral sclerosis (ALS), cerebral ischemia and brain tumors. Flavonoids are the most widely studied natural products for the prevention and treatment of neurodegenerative disorders. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) represents a complex gene regulated cytoprotective pathway. Several natural compounds have been identified as Nrf2 regulators in various chronic disorders, including carcinogenic, liver ailments, inflammatory conditions, neurodegeneration, diabetes and cardiotoxicities. The current review focuses on Nrf2 targeting by flavonoids in the prevention and treatment of neurodegenerative disorders, addressing the most contemporary information available on this timely subject.}, }
@article {pmid33068904, year = {2020}, author = {Sánchez-Torres, JL and Yescas-Gómez, P and Torres-Romero, J and Espinosa, OR and Canovas, LL and Tecalco-Cruz, &#xc1;C and Ponce-Regalado, MD and Alvarez-Sánchez, ME}, title = {Matrix metalloproteinases deregulation in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {419}, number = {}, pages = {117175}, doi = {10.1016/j.jns.2020.117175}, pmid = {33068904}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Matrix Metalloproteinases/genetics ; Motor Neurons ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons that results in progressive paralysis and muscular atrophy. There are many molecules and genes involved in neuromuscular degeneration in ALS; among these, matrix metalloproteinases (MMPs). MMPs play an important role in the pathology of ALS, and MMP-1, 2, 3, and 9 might serve as disease progression markers. Tissue inhibitors of metalloproteinases (TIMPS) might also function as progression markers in ALS because they participate in regulating the proteolytic activity of MMPs. Moreover, a diversity of genes also plays a role in the pathogenesis of ALS; most MMPs-coding genes present variants related to the pathological proteolytic activity. This short review, however, will focus on the role of matrix metalloproteinases in ALS.}, }
@article {pmid33068641, year = {2021}, author = {McLure, M and Eastwood, K and Parr, M and Bray, J}, title = {A rapid review of advanced life support guidelines for cardiac arrest associated with anaphylaxis.}, journal = {Resuscitation}, volume = {159}, number = {}, pages = {137-149}, doi = {10.1016/j.resuscitation.2020.10.001}, pmid = {33068641}, issn = {1873-1570}, mesh = {*Anaphylaxis/therapy ; Australia ; Canada ; Europe ; *Heart Arrest/therapy ; Humans ; Systematic Reviews as Topic ; United States ; }, abstract = {BACKGROUND: We conducted a rapid review of current international and Australian advanced life support (ALS) guidelines for cardiac arrest associated with anaphylaxis to (1) assess the variation and (2) determine if a systematic review update of ALS guideline recommendations is warranted.<br><br>METHOD: A search and comparison of key recommendations was conducted for major international and Australian clinical guidelines, including member societies and councils of the World Allergy Organisation and the International Liaison Committee on Resuscitation (ILCOR). Systematic database searches (Medline, Cochrane Database of Systematic Reviews, PROSPERO international register of systematic reviews and ClinicalTrials.gov databases) was conducted to identify existing and in-progress research published on the topic of anaphylaxis and cardiac arrest.<br><br>RESULTS: Eight international guidelines were identified from Australia/New Zealand, Europe, United States and Canada, and 5 national guidelines were identified for Australia. There was general consensus across all guidelines for the use of adrenaline, oxygen, patient positioning and glucagon. There was variation across international and Australian guidelines for adrenaline dosing and frequency, antihistamines and corticosteroid recommendations. Most recommendations were based on low-level evidence, and the review of published systematic reviews and clinical trials identified new evidence in the last decade.<br><br>CONCLUSIONS: We found significant variation between current ALS guideline recommendations for treating anaphylaxis. While there is no new evidence to suggest a systematic review of guideline recommendations is needed, there may be an opportunity to produce more consistent international guideline recommendations and educational materials.}, }
@article {pmid33068411, year = {2020}, author = {Louka, A and Zacco, E and Temussi, PA and Tartaglia, GG and Pastore, A}, title = {RNA as the stone guest of protein aggregation.}, journal = {Nucleic acids research}, volume = {48}, number = {21}, pages = {11880-11889}, pmid = {33068411}, issn = {1362-4962}, support = {MC_PC_13054/MRC_/Medical Research Council/United Kingdom ; PASTORE/APR15/840-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Binding Sites ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; Gene Expression ; Humans ; Models, Molecular ; Prions/chemistry/*genetics/metabolism ; Protein Aggregates ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; RNA/chemistry/*genetics/metabolism ; RNA-Binding Protein FUS/chemistry/*genetics/metabolism ; RNA-Binding Proteins/chemistry/*genetics/metabolism ; TATA-Binding Protein Associated Factors/chemistry/*genetics/metabolism ; }, abstract = {The study of prions as infectious aggregates dates several decades. From its original formulation, the definition of a prion has progressively changed to the point that many aggregation-prone proteins are now considered bona fide prions. RNA molecules, not included in the original 'protein-only hypothesis', are also being recognized as important factors contributing to the 'prion behaviour', that implies the transmissibility of an aberrant fold. In particular, an association has recently emerged between aggregation and the assembly of prion-like proteins in RNA-rich complexes, associated with both physiological and pathological events. Here, we discuss the historical rising of the concept of prion-like domains, their relation to RNA and their role in protein aggregation. As a paradigmatic example, we present the case study of TDP-43, an RNA-binding prion-like protein associated with amyotrophic lateral sclerosis. Through this example, we demonstrate how the current definition of prions has incorporated quite different concepts making the meaning of the term richer and more stimulating. An important message that emerges from our analysis is the dual role of RNA in protein aggregation, making RNA, that has been considered for many years a 'silent presence' or the 'stone guest' of protein aggregation, an important component of the process.}, }
@article {pmid33066585, year = {2020}, author = {Veenman, L}, title = {Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start.}, journal = {International journal of molecular sciences}, volume = {21}, number = {20}, pages = {}, pmid = {33066585}, issn = {1422-0067}, mesh = {Animals ; Brain Injuries/*drug therapy/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*therapeutic use ; Raloxifene Hydrochloride/*therapeutic use ; Selective Estrogen Receptor Modulators/*therapeutic use ; }, abstract = {Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects-fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson's disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health-on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer's disease, raloxifene may not cure diagnosed Alzheimer's disease. However, the onset of Alzheimer's disease may be delayed or arrested by raloxifene's capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer's disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer's disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.}, }
@article {pmid33061727, year = {2020}, author = {Taule, T and Søvik, M and Lein, RK and Wehling, E and Aßmus, J and Rekand, T}, title = {Psychometric Properties of Cognitive Assessment in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Patient related outcome measures}, volume = {11}, number = {}, pages = {181-194}, pmid = {33061727}, issn = {1179-271X}, abstract = {PURPOSE: We aimed to list all tests used to assess cognitive change in patients with amyotrophic lateral sclerosis (ALS) and to provide a descriptive synthesis of the psychometric properties of tests that were evaluated in a population of ALS patients.<br><br>MATERIALS AND METHODS: The protocol is registered in PROSPERO (ID: CRD42017055603). We systematically search for literature in 11 databases. Full-text articles, in any language, with original research were included. All included articles were scrutinised by two independent authors. Disagreement was resolved by consensus. The framework of Lezak informed conceptualises of the tests identified. To evaluate methodological quality, we used the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). Data were synthesised using criteria proposed by the Cochrane Back Review Group.<br><br>RESULTS: Of 319 included articles, 46 articles reported information on the psychometric properties of cognitive tests used in patients with ALS. We found that the highest level of evidence was supported for the Reading the Mind in the Eye Test (RME), Addenbrooke's Cognitive Evaluation (ACE) and Frontal Assessment Battery (FAB). Moderate level of evidence was found for the screening tests; Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the Montreal Cognitive Assessment (MoCA).<br><br>CONCLUSION: The screening test, ECAS and the social cognition test, RME, may have some advantages over other tests that have been used for assessing cognitive change in ALS patients. Recommendations of ALS-specific tests with sound psychometric properties are urgently needed.}, }
@article {pmid33059698, year = {2020}, author = {Zucchi, E and Bonetto, V and Sorarù, G and Martinelli, I and Parchi, P and Liguori, R and Mandrioli, J}, title = {Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {58}, pmid = {33059698}, issn = {1750-1326}, mesh = {Animals ; Biomarkers ; Humans ; *Intermediate Filaments ; *Motor Neuron Disease ; Prognosis ; }, abstract = {Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today's MND research agenda.In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood.In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.}, }
@article {pmid33058114, year = {2020}, author = {Barć, K and Kuźma-Kozakiewicz, M}, title = {Gastrostomy and mechanical ventilation in amyotrophic lateral sclerosis: how best to support the decision-making process?.}, journal = {Neurologia i neurochirurgia polska}, volume = {54}, number = {5}, pages = {366-377}, doi = {10.5603/PJNNS.a2020.0081}, pmid = {33058114}, issn = {0028-3843}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Disease Progression ; Gastrostomy ; Humans ; Quality of Life ; Respiration, Artificial ; }, abstract = {The unfavourable outcome of amyotrophic lateral sclerosis (ALS) confronts patients with challenging decisions regarding life-sustaining measures. The decision-making process is usually triggered by medical consultations and patient-dependent factors. This may largely depend on the physician's depth of knowledge and professional experience. This paper presents an overview of the life-sustaining methods used in ALS and their effects on disease progression, survival and quality of life of patients and their caregivers. It is intended to aid physicians in their discussions with patients. We interrogate all the positive and negative facets of life-sustaining measures that may allow for optimisation of the decision-making process and care provision.}, }
@article {pmid33053441, year = {2021}, author = {Li, X and Huang, L and Lan, J and Feng, X and Li, P and Wu, L and Peng, Y}, title = {Molecular mechanisms of mitophagy and its roles in neurodegenerative diseases.}, journal = {Pharmacological research}, volume = {163}, number = {}, pages = {105240}, doi = {10.1016/j.phrs.2020.105240}, pmid = {33053441}, issn = {1096-1186}, mesh = {Animals ; Humans ; Mitochondria/metabolism ; Mitochondrial Dynamics ; *Mitophagy ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Neurodegenerative diseases are the most common diseases of the nervous system in elderly people, which are currently incurable and cause great burden to families and societies. Mitochondria are the energy factory of the cell and have extremely important effects on neuronal function. The elimination of dysfunctional mitochondria is essential for the mitochondrial metabolic homeostasis, energy supply, and neuronal survival. Recent studies suggest that the impaired mitophagy may lead to the accumulation of damaged mitochondria and therefore contribute to the progression of neurodegenerative diseases. This review mainly focuses on mitophagy, mitochondrial dynamics, and their abnormal changes in neurodegenerative diseases, as well as the therapeutic strategies targeting mitophagy that have shown promise in recent preclinical and clinical studies.}, }
@article {pmid33051572, year = {2020}, author = {Jo, M and Lee, S and Jeon, YM and Kim, S and Kwon, Y and Kim, HJ}, title = {The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies.}, journal = {Experimental &amp; molecular medicine}, volume = {52}, number = {10}, pages = {1652-1662}, pmid = {33051572}, issn = {2092-6413}, support = {H I14C1135//Korea Health Industry Development Institute (KHIDI)/ ; 2020R1A2C4002366//National Research Foundation of Korea (NRF)/ ; }, mesh = {Animals ; DNA-Binding Proteins/chemistry/*genetics/*metabolism ; *Disease Susceptibility ; Gene Expression Regulation ; Humans ; Neurodegenerative Diseases/*etiology/*metabolism ; Protein Aggregation, Pathological ; Protein Binding ; Structure-Activity Relationship ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Accumulating evidence suggests that prion-like spreading of aberrant protein aggregates composed of tau, amyloid-β, and α-synuclein is involved in the progression of neurodegenerative diseases such as AD and PD. Similar to those of prion-like proteins, pathological aggregates of TDP-43 can be transferred from cell-to-cell in a seed-dependent and self-templating manner. Here, we review clinical and experimental studies supporting the prion-like spreading of misfolded TDP-43 and discuss the molecular mechanisms underlying the propagation of these pathological aggregated proteins. The idea that misfolded TDP-43 spreads in a prion-like manner between cells may guide novel therapeutic strategies for TDP-43-associated neurodegenerative diseases.}, }
@article {pmid33050475, year = {2020}, author = {Gentile, F and Doneddu, PE and Riva, N and Nobile-Orazio, E and Quattrini, A}, title = {Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {20}, pages = {}, pmid = {33050475}, issn = {1422-0067}, mesh = {Brain/*physiology ; *Diet ; Disease Susceptibility ; Energy Metabolism ; Health ; Homeostasis ; Humans ; Immune System ; *Microbiota ; Neurodegenerative Diseases/diagnosis/etiology/metabolism ; Nutrients ; Research ; }, abstract = {Increasing evidence gives support for the idea that extra-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer's and Parkinson's diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.}, }
@article {pmid33049674, year = {2021}, author = {Rebolledo-Solleiro, D and Castillo Flores, LY and Solleiro-Villavicencio, H}, title = {Impact of BPA on behavior, neurodevelopment and neurodegeneration.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {26}, number = {2}, pages = {363-400}, doi = {10.2741/4898}, pmid = {33049674}, issn = {2768-6698}, mesh = {Animals ; Benzhydryl Compounds/*adverse effects ; Endocrine Disruptors/*adverse effects ; Humans ; Neurodevelopmental Disorders/*chemically induced ; Phenols/*adverse effects ; }, abstract = {Bisphenol A (BPA), a compound used in the manufacturing of plastics and epoxy resins, is an endocrine disruptor with significant adverse impact on the human's health. Here, we review the animal models and clinical studies as well as the molecular and cellular mechanisms that show that BPA alters the normal function of the reproductive system, metabolism, brain function and behavior and contributes to the development of certain neurodevelopmental disorders including autism spectrum and attention-deficit and hyperactivity disorders. BPA also causes aberrant cognitive function, behavioral disturbances, and neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. It has recently been proposed that exposure to BPA may be associated with the development of certain neurodegenerative diseases and neurodevelopmental disorders; however, it is a line of research that is just emerging. This work aims to review the available information about the association between exposure to BPA and cognitive function, behavioral disturbances, neurodegenerative diseases (Parkinson�s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis), and neurodevelopmental disorders (Autism Spectrum and Attention-Deficit/Hyperactivity Disorders). Likewise, the molecular and cellular mechanisms that may be involved with these pathological conditions will be analyzed.}, }
@article {pmid33039660, year = {2021}, author = {Li, L and Acioglu, C and Heary, RF and Elkabes, S}, title = {Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases.}, journal = {Brain, behavior, and immunity}, volume = {91}, number = {}, pages = {740-755}, pmid = {33039660}, issn = {1090-2139}, mesh = {Animals ; Astrocytes/*metabolism/physiology ; Brain/metabolism ; Central Nervous System/immunology/metabolism ; Central Nervous System Diseases/immunology ; Central Nervous System Infections/pathology ; Encephalitis/immunology ; Humans ; Immunity, Innate/physiology ; Microglia/metabolism ; Neurodegenerative Diseases/metabolism/*physiopathology ; Neurons/metabolism ; Receptors, Pattern Recognition/immunology ; Signal Transduction ; Spinal Cord/pathology ; Spinal Cord Injuries/pathology ; Toll-Like Receptors/metabolism/*physiology ; }, abstract = {Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response. Toll-like receptors (TLRs) are a well-characterized family of PRRs. The contribution of microglial TLR signaling to CNS pathology has been extensively investigated. Even though astrocytes assume a wide variety of key functions, information about the role of astroglial TLRs in CNS disease and injuries is limited. Because astrocytes display heterogeneity and exhibit phenotypic plasticity depending on the effectors present in the local milieu, they can exert both detrimental and beneficial effects. TLRs are modulators of these paradoxical astroglial properties. The goal of the current review is to highlight the essential roles played by astroglial TLRs in CNS infections, injuries and diseases. We discuss the contribution of astroglial TLRs to host defense as well as the dissemination of viral and bacterial infections in the CNS. We examine the link between astroglial TLRs and the pathogenesis of neurodegenerative diseases and present evidence showing the pivotal influence of astroglial TLR signaling on sterile inflammation in CNS injury. Finally, we define the research questions and areas that warrant further investigations in the context of astrocytes, TLRs, and CNS dysfunction.}, }
@article {pmid33036763, year = {2021}, author = {Chen, L}, title = {FUS mutation is probably the most common pathogenic gene for JALS, especially sporadic JALS.}, journal = {Revue neurologique}, volume = {177}, number = {4}, pages = {333-340}, doi = {10.1016/j.neurol.2020.06.010}, pmid = {33036763}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Mutation ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe form of ALS. The development of gene sequencing methods has resulted in increased reports of JALS cases in recent years, and additional gene mutations in FUS have been identified. Fused in sarcoma (FUS) mutations, appeared rarely in classical ALS but indeed were the most frequent pathogenic mutations in JALS, especially in sporadic JALS. After studied the reports in the last 10 years about JALS cases, the case characteristics caused by FUS mutations and the commonality of the mutation sites were summarized in this review. FUS mutation associated with more than half of JALS and the very majority of sporadic JALS. It's worth noting that almost all of the mutations occur in nuclear localization signal (NLS) of FUS in sporadic JALS. This discovery emphasized a new perspective focus on NLS for the diagnosis and etiology of sporadic JALS as well as for further study about new treatment.}, }
@article {pmid33035446, year = {2021}, author = {Bennett, CF and Kordasiewicz, HB and Cleveland, DW}, title = {Antisense Drugs Make Sense for Neurological Diseases.}, journal = {Annual review of pharmacology and toxicology}, volume = {61}, number = {}, pages = {831-852}, pmid = {33035446}, issn = {1545-4304}, support = {R01 NS027036/NS/NINDS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Oligonucleotides, Antisense ; *Parkinson Disease ; *Pharmaceutical Preparations ; RNA ; }, abstract = {The genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of drugs-antisense oligonucleotides (ASOs)-show promise as a therapeutic platform for treating neurological diseases. ASOs are designed to bind to the RNAs either by promoting degradation of the targeted RNA or by elevating expression by RNA splicing. Intrathecal injection into the cerebral spinal fluid results in broad distribution of antisense drugs and long-term effects. Approval of nusinersen in 2016 demonstrated that effective treatments for neurodegenerative diseases can be identified and that treatments not only slow disease progression but also improve some symptoms. Antisense drugs are currently in development for amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and Angelman syndrome, and several drugs are in late-stage research for additional neurological diseases. This review highlights the advances in antisense technology as potential treatments for neurological diseases.}, }
@article {pmid33026644, year = {2021}, author = {Yiannopoulou, KG and Papagiannis, GI and Triantafyllou, AI and Koulouvaris, P and Anastasiou, AI and Kontoangelos, K and Anastasiou, IP}, title = {Neurological and neurourological complications of electrical injuries.}, journal = {Neurologia i neurochirurgia polska}, volume = {55}, number = {1}, pages = {12-23}, doi = {10.5603/JNNS.a2020.0076}, pmid = {33026644}, issn = {0028-3843}, mesh = {*Central Nervous System Diseases ; *Electric Injuries/complications ; Humans ; Retrospective Studies ; *Spinal Cord Injuries/complications ; }, abstract = {Electrical injury can affect any system and organ. Central nervous system (CNS) complications are especially well recognised, causing an increased risk of morbidity, while peripheral nervous system (PNS) complications, neurourological and cognitive and psychological abnormalities are less predictable after electrical injuries. PubMed was searched for English language clinical observational, retrospective, review and case studies published in the last 30 years using the key words: electrical injury, electrocution, complications, sequelae, neurological, cognitive, psychological, urological, neuropsychological, neurourological, neurogenic, and bladder. In this review, the broad spectrum of neurological, cognitive, psychological and neurourological consequences of electrical trauma are discussed, and clinical features characteristic of an underlying neurological, psychological or neurourological disorder are identified. The latest information about the most recently discovered forms of nervous system disorders secondary to electrical trauma, such as the presentation of neurological sequelae years after electrocution, in other words long-term sequelae, are presented. Unexpected central nervous system or muscular complications such as hydrocephalus, brain venous thrombosis, and amyotrophic lateral sclerosis are described. Common and uncommon neuropsychological syndromes after electrical trauma are defined. Neurourological sequelae secondary to spinal cord or brain trauma or as independent consequences of electrical shock are also highlighted.}, }
@article {pmid33025327, year = {2021}, author = {Bombaci, A and Abbadessa, G and Trojsi, F and Leocani, L and Bonavita, S and Lavorgna, L and , }, title = {Telemedicine for management of patients with amyotrophic lateral sclerosis through COVID-19 tail.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {1}, pages = {9-13}, pmid = {33025327}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; *COVID-19 ; Humans ; *Monitoring, Ambulatory ; *Severity of Illness Index ; *Telemedicine ; }, abstract = {Over the last months, due to coronavirus disease (COVID-19) pandemic, containment measures have led to important social restriction. Healthcare systems have faced a complete rearrangement of resources and spaces, with the creation of wards devoted to COVID-19 patients. In this context, patients affected by chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS), are at risk to be lost at follow-up, leading to a higher risk of morbidity and mortality. Telemedicine may allow meet the needs of these patients. In this commentary, we briefly discuss the digital tools to remotely monitor and manage ALS patients. Focusing on detecting disease progression and preventing life-threatening conditions, we propose a toolset able to improve ALS management during this unprecedented situation.}, }
@article {pmid33025162, year = {2020}, author = {Klein, B and Baumeister, A}, title = {[Robotic assistance in activities of daily living exemplified by food intake].}, journal = {Zeitschrift fur Gerontologie und Geriatrie}, volume = {53}, number = {7}, pages = {615-619}, pmid = {33025162}, issn = {1435-1269}, mesh = {Activities of Daily Living ; Eating ; Germany ; Humans ; Robotics ; *Self-Help Devices ; }, abstract = {Carrying out activities of daily living (ADL, also called basic activities) is limited or even no longer possible due to functional limitations and functional losses associated with aging, (chronic) illness and disabilities. Nowadays, there are a variety of assistive technologies/devices and even robotic products. The aim of this article is to give an exemplary overview of the existing products for the basic activity of food intake for people with tetraplegia caused by accidents or neurological disorders, such as multiple sclerosis or amyotrophic lateral sclerosis (ALS). The dissemination and implementation of these products seems to be relatively low in Germany. Inhibiting and promoting factors for the dissemination and utilization are discussed.}, }
@article {pmid33013859, year = {2020}, author = {Mallah, K and Couch, C and Borucki, DM and Toutonji, A and Alshareef, M and Tomlinson, S}, title = {Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {2021}, pmid = {33013859}, issn = {1664-3224}, support = {P30 DK123704/DK/NIDDK NIH HHS/United States ; I01 BX004256/BX/BLRD VA/United States ; I21 RX002363/RX/RRD VA/United States ; I01 RX001141/RX/RRD VA/United States ; TL1 TR001451/TR/NCATS NIH HHS/United States ; IK6 BX005235/BX/BLRD VA/United States ; T32 GM008716/GM/NIGMS NIH HHS/United States ; T32 AI132164/AI/NIAID NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Brain Injuries, Traumatic/*therapy ; Central Nervous System/*pathology ; Central Nervous System Diseases/*therapy ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Neurological disorders are major contributors to death and disability worldwide. The pathology of injuries and disease processes includes a cascade of events that often involve molecular and cellular components of the immune system and their interaction with cells and structures within the central nervous system. Because of this, there has been great interest in developing neuroprotective therapeutic approaches that target neuroinflammatory pathways. Several neuroprotective anti-inflammatory agents have been investigated in clinical trials for a variety of neurological diseases and injuries, but to date the results from the great majority of these trials has been disappointing. There nevertheless remains great interest in the development of neuroprotective strategies in this arena. With this in mind, the complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration. As we move forward in testing additional neuroprotective and immune-modulating agents, we believe it will be useful to review past trials and discuss potential factors that may have contributed to failure, which will assist with future agent selection and trial design, including for complement inhibitors. In this context, we also discuss inhibition of the complement system as a potential neuroprotective strategy for neuropathologies of the central nervous system.}, }
@article {pmid33013330, year = {2020}, author = {Schellino, R and Boido, M and Vercelli, A}, title = {The Dual Nature of Onuf's Nucleus: Neuroanatomical Features and Peculiarities, in Health and Disease.}, journal = {Frontiers in neuroanatomy}, volume = {14}, number = {}, pages = {572013}, pmid = {33013330}, issn = {1662-5129}, abstract = {Onuf's nucleus is a small group of neurons located in the ventral horns of the sacral spinal cord. The motor neurons (MNs) of Onuf's nucleus innervate striated voluntary muscles of the pelvic floor and are histologically and biochemically comparable to the other somatic spinal MNs. However, curiously, these neurons also show some autonomic-like features as, for instance, they receive a strong peptidergic innervation. The review provides an overview of the histological, biochemical, metabolic, and gene expression peculiarities of Onuf's nucleus. Moreover, it describes the aging-related pathologies as well as several traumatic and neurodegenerative disorders in which its neurons are involved: indeed, Onuf's nucleus is affected in Parkinson's disease (PD) and Shy-Drager Syndrome (SDS), whereas it is spared in Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Duchenne Muscular Dystrophy (DMD). We summarize here the milestone studies that have contributed to clarifying the nature of Onuf's neurons and in understanding what makes them either vulnerable or resistant to damage. Altogether, these works can offer the possibility to develop new therapeutic strategies for counteracting neurodegeneration.}, }
@article {pmid33007419, year = {2021}, author = {Jakaria, M and Azam, S and Go, EA and Uddin, MS and Jo, SH and Choi, DK}, title = {Biological evidence of gintonin efficacy in memory disorders.}, journal = {Pharmacological research}, volume = {163}, number = {}, pages = {105221}, doi = {10.1016/j.phrs.2020.105221}, pmid = {33007419}, issn = {1096-1186}, mesh = {Animals ; Humans ; Memory Disorders/*drug therapy/metabolism ; Neuroprotective Agents/pharmacology/*therapeutic use ; Plant Extracts/pharmacology/*therapeutic use ; }, abstract = {Gintonin is a novel glycolipoprotein, which has been abundantly found in the root of Korean ginseng. It holds lysophosphatidic acids (LPAs), primarily identified LPA C18:2, and is an exogenous agonist of LPA receptors (LPARs). Gintonin maintains blood-brain barrier integrity, and it has recently been studied in several models of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Gintonin demonstrated neuroprotective activity by providing action against neuroinflammation-, apoptosis- and oxidative stress-mediated neurodegeneration. Gintonin showed an emerging role as a modulator of synaptic transmission and neurogenesis and also potentially regulated autophagy in primary cortical astrocytes. It also ameliorated the toxic agent-induced and genetic models of cognitive deficits in experimental NDDs. As a novel agonist of LPARs, gintonin regulated several G protein-coupled receptors (GPCRs) including GPR40 and GPR55. However, further study needs to be investigated to understand the underlying mechanism of action of gintonin in memory disorders.}, }
@article {pmid33007294, year = {2021}, author = {Wieters, F and Weiss Lucas, C and Gruhn, M and Büschges, A and Fink, GR and Aswendt, M}, title = {Introduction to spasticity and related mouse models.}, journal = {Experimental neurology}, volume = {335}, number = {}, pages = {113491}, doi = {10.1016/j.expneurol.2020.113491}, pmid = {33007294}, issn = {1090-2430}, mesh = {Animals ; Cats ; Disease Models, Animal ; Humans ; Mice ; Muscle Hypotonia/physiopathology ; Muscle Spasticity/*physiopathology ; Rats ; Reflex, Abnormal ; }, abstract = {Although spasticity is one of the most common causes of motor disability worldwide, its precise definition and pathophysiology remain elusive, which to date renders its experimental targeting tricky. At least in part, this difficulty is caused by heterogeneous phenotypes of spasticity-causing neurological disorders, all causing spasticity by involving upper motor neurons. The most common clinical symptoms are a series of rapid muscle contractions (clonus), an increased muscle tone (hypertonia), and augmented tendon reflex activity (hyperreflexia). This muscle overactivity is due to disturbed inhibition of spinal reflexes following upper motor neuron dysfunction. Despite a range of physical and pharmacological therapies ameliorating the symptoms, their targeted application remains difficult. Therefore, to date, spasticity impacts rehabilitative therapy, and no therapy exists that reverses the pathology completely. In contrast to the incidence and importance of spasticity, only very little pre-clinical work in animal models exists, and this research is focused on the cat or the rat spastic tail model to decipher altered reflexes and excitability of the motor neurons in the spinal cord. Meanwhile, the characterization of spasticity in clinically more relevant mouse models of neurological disorders, such as stroke, remains understudied. Here, we provide a brief introduction into the clinical knowledge and therapy of spasticity and an in-depth review of pre-clinical studies of spasticity in mice including the current experimental challenges for clinical translation.}, }
@article {pmid33006054, year = {2020}, author = {Wang, L and Zhang, L}, title = {MicroRNAs in amyotrophic lateral sclerosis: from pathogenetic involvement to diagnostic biomarker and therapeutic agent development.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {41}, number = {12}, pages = {3569-3577}, pmid = {33006054}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Animals ; Biomarkers ; Humans ; *MicroRNAs/genetics ; Motor Neurons ; *Neurodegenerative Diseases ; }, abstract = {MicroRNAs (miRNAs) are a class of endogenous non-coding small single-stranded RNAs that are 21-25 nucleotides (NTs) in length and participate in post-transcriptional gene regulation. Studies have shown that miRNA dysfunction plays a critical role in the occurrence and development of a variety of nervous system diseases, including neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unclear etiology and is characterized by the selective invasion of motor neurons in the brain and spinal cord. Symptoms can range from mild spasms in the limbs or medulla oblongata muscles to paralysis in almost all skeletal muscles. The role of miRNAs in the pathogenesis, diagnosis, and treatment of ALS has become of greater importance to those studying ALS. In this review, we reviewed experimentally confirmed miRNAs shown to be involved in the pathogenesis of ALS and that are used as diagnostic biomarkers or therapeutic ALS agents. At present, there are at least 20-30 genes clearly related to the pathogenesis of ALS. Multiple miRNAs have been reported in different pathogenic gene models. MiRNAs could be used as biomarkers for the diagnosis of ALS; the differential expression of some miRNAs could be related to ALS prognosis. As therapeutic agents, miRNAs are still in the exploratory stage. Although encouraging results have been achieved using animal models, much research is still needed before clinical trials can ensue. However, with additional miRNA studies in ALS patients and animal models, the pathogenesis, early diagnosis, and therapy of ALS should be elucidated.}, }
@article {pmid33005040, year = {2020}, author = {Dalakas, MC and Alexopoulos, H and Spaeth, PJ}, title = {Complement in neurological disorders and emerging complement-targeted therapeutics.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {11}, pages = {601-617}, pmid = {33005040}, issn = {1759-4766}, mesh = {Animals ; Complement Inactivating Agents/*administration &amp; dosage ; Complement Inactivator Proteins/administration &amp; dosage/immunology ; Complement System Proteins/*immunology/metabolism ; Drug Delivery Systems/methods/*trends ; Humans ; Immunoglobulins, Intravenous/administration &amp; dosage/immunology ; Immunotherapy/methods/*trends ; Nervous System Diseases/*immunology/*therapy ; Signal Transduction/drug effects/immunology ; Synapses/drug effects/immunology ; }, abstract = {The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I-III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.}, }
@article {pmid33003004, year = {2020}, author = {Quinn, C and Elman, L}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {26}, number = {5}, pages = {1323-1347}, pmid = {33003004}, issn = {1538-6899}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics/physiopathology ; Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/drug therapy/genetics/physiopathology ; Young Adult ; }, abstract = {PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an update on the genetics and pathophysiology of ALS.<br><br>RECENT FINDINGS: ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress include a large expansion in the number of genes associated with familial and sporadic ALS. The discovery of these genes, along with other work, has provided a deeper understanding of the mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of transactive response DNA-binding protein 43 and other RNA-processing proteins in the development of disease.<br><br>SUMMARY: ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The current mainstay of treatment remains symptom management and palliation, particularly in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies based on an ever-evolving understanding of the pathophysiology of both familial and sporadic ALS.}, }
@article {pmid33000450, year = {2021}, author = {Low, YH and Asi, Y and Foti, SC and Lashley, T}, title = {Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases.}, journal = {Molecular neurobiology}, volume = {58}, number = {2}, pages = {631-646}, pmid = {33000450}, issn = {1559-1182}, mesh = {Alternative Splicing/genetics ; Animals ; Axonal Transport ; Heterogeneous-Nuclear Ribonucleoproteins/chemistry/genetics/*metabolism ; Humans ; Models, Biological ; Nervous System Diseases/*metabolism ; }, abstract = {Heterogenous nuclear ribonucleoproteins (hnRNPs) are a complex and functionally diverse family of RNA binding proteins with multifarious roles. They are involved, directly or indirectly, in alternative splicing, transcriptional and translational regulation, stress granule formation, cell cycle regulation, and axonal transport. It is unsurprising, given their heavy involvement in maintaining functional integrity of the cell, that their dysfunction has neurological implications. However, compared to their more established roles in cancer, the evidence of hnRNP implication in neurological diseases is still in its infancy. This review aims to consolidate the evidences for hnRNP involvement in neurological diseases, with a focus on spinal muscular atrophy (SMA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), congenital myasthenic syndrome (CMS), and fragile X-associated tremor/ataxia syndrome (FXTAS). Understanding more about hnRNP involvement in neurological diseases can further elucidate the pathomechanisms involved in these diseases and perhaps guide future therapeutic advances.}, }
@article {pmid32998479, year = {2020}, author = {Luo, F and Sandhu, AF and Rungratanawanich, W and Williams, GE and Akbar, M and Zhou, S and Song, BJ and Wang, X}, title = {Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {19}, pages = {}, pmid = {32998479}, issn = {1422-0067}, support = {NA//Brigham and Women's Hospital BRI Fund to Sustain Research Excellence (to X.W.)/ ; NA//the Gillian Reny Stepping Strong Center for Trauma Innovation (to S. Z.)./ ; }, mesh = {Aging/*genetics/metabolism ; Alzheimer Disease/genetics/metabolism/pathology/*prevention &amp; control ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/*prevention &amp; control ; Animals ; Antioxidants/metabolism/pharmacology ; Autophagy/drug effects/genetics ; Autophagy-Related Proteins/agonists/genetics/metabolism ; Circadian Rhythm/physiology ; Humans ; Huntington Disease/genetics/metabolism/pathology/*prevention &amp; control ; Melatonin/biosynthesis/*pharmacology ; Nervous System/drug effects/metabolism/pathology ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/metabolism/pharmacology ; Parkinson Disease/genetics/metabolism/pathology/*prevention &amp; control ; Pineal Gland/physiology ; }, abstract = {With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.}, }
@article {pmid32998318, year = {2020}, author = {Sonninen, TM and Goldsteins, G and Laham-Karam, N and Koistinaho, J and Lehtonen, &#x160;}, title = {Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases.}, journal = {Cells}, volume = {9}, number = {10}, pages = {}, pmid = {32998318}, issn = {2073-4409}, mesh = {Aging/genetics/pathology ; Alzheimer Disease/complications/*genetics/pathology ; Humans ; Inflammation ; Inflammation Mediators ; Neurodegenerative Diseases/complications/*genetics/pathology ; Parkinson Disease/complications/*genetics/pathology ; Protein Biosynthesis/genetics ; Protein Folding ; Proteostasis/*genetics ; Proteostasis Deficiencies/complications/genetics/pathology ; }, abstract = {Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.}, }
@article {pmid32998028, year = {2020}, author = {Shabir, O and Moll, TA and Matuszyk, MM and Eyre, B and Dake, MD and Berwick, J and Francis, SE}, title = {Preclinical models of disease and multimorbidity with focus upon cardiovascular disease and dementia.}, journal = {Mechanisms of ageing and development}, volume = {192}, number = {}, pages = {111361}, doi = {10.1016/j.mad.2020.111361}, pmid = {32998028}, issn = {1872-6216}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {Aging/*physiology ; Animals ; *Cardiovascular Diseases/drug therapy/metabolism/physiopathology ; *Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Humans ; *Metabolic Diseases/drug therapy/metabolism/physiopathology ; Multimorbidity ; *Neurodegenerative Diseases/drug therapy/metabolism/physiopathology ; }, abstract = {The use of animal models is fundamental to furthering our understanding of human disease mechanisms, as well as identifying potential therapeutic targets. Diseases of ageing often involve multiple body systems; however, multi-systemic features are not fully recapitulated in the many of the animal models available. Therefore, combining pre-clinical models to better reflect the multimorbidities observed at the clinical level is critical. This review will highlight some of the key pre-clinical experimental models associated with cardiovascular (atherosclerosis, coronary heart disease), cerebrovascular (stroke, vascular dementia), metabolic (obesity, type-2 diabetes mellitus) and neurological (amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's, epilepsy) diseases, and whether these models encompass known multimorbidities. In addition to this, we discuss established pre-clinical models that combine two or more conditions, within the context of dementia.}, }
@article {pmid32995749, year = {2020}, author = {Floare, ML and Allen, SP}, title = {Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience insights}, volume = {15}, number = {}, pages = {2633105520957302}, pmid = {32995749}, issn = {2633-1055}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein's pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS).}, }
@article {pmid32993098, year = {2020}, author = {Choi, HJ and Cha, SJ and Lee, JW and Kim, HJ and Kim, K}, title = {Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {10}, number = {10}, pages = {}, pmid = {32993098}, issn = {2076-3425}, support = {2019R1F1A1045639//Ministry of Science and ICT, South Korea/ ; 2020//Soonchunhyang University/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.}, }
@article {pmid32987654, year = {2020}, author = {Sukhanova, MV and Singatulina, AS and Pastré, D and Lavrik, OI}, title = {Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA.}, journal = {International journal of molecular sciences}, volume = {21}, number = {19}, pages = {}, pmid = {32987654}, issn = {1422-0067}, support = {20-14-00086//Russian Science Foundation/ ; }, mesh = {Animals ; *DNA Repair ; Humans ; Poly (ADP-Ribose) Polymerase-1/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; RNA-Binding Protein FUS/*physiology ; }, abstract = {The fused in sarcoma (FUS) protein combines prion-like properties with a multifunctional DNA/RNA-binding domain and has functions spanning the regulation of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and translation. In addition to its roles in RNA metabolism, FUS is implicated in the maintenance of DNA integrity. In this review, we examine the participation of FUS in major DNA repair pathways, focusing on DNA repair associated with poly(ADP-ribosyl)ation events and on how the interaction of FUS with poly(ADP-ribose) may orchestrate transient compartmentalisation of DNA strand breaks. Unravelling how prion-like RNA-binding proteins control DNA repair pathways will deepen our understanding of the pathogenesis of some neurological diseases and cancer as well as provide the basis for the development of relevant innovative therapeutic technologies. This knowledge may also extend the range of applications of poly(ADP-ribose) polymerase inhibitors to the treatment of neurodegenerative diseases related to RNA-binding proteins in the cell, e.g., amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, }
@article {pmid32986860, year = {2021}, author = {Manzano, R and Toivonen, JM and Moreno-Martínez, L and de la Torre, M and Moreno-García, L and López-Royo, T and Molina, N and Zaragoza, P and Calvo, AC and Osta, R}, title = {What skeletal muscle has to say in amyotrophic lateral sclerosis: Implications for therapy.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1279-1297}, doi = {10.1111/bph.15276}, pmid = {32986860}, issn = {1476-5381}, support = {752349//Horizon 2020 Framework Programme/ ; //Gobierno de Arag&#xf3;n/ ; CB18/05/00037//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red de Enfermedades Neurodegenerativas/ ; //European Regional Development Fund/ ; PI17/00949//Instituto de Salud Carlos III/ ; }, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Motor Neurons ; Muscle, Skeletal ; Neuromuscular Junction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset disorder characterized by progressive neuromuscular junction (NMJ) dismantling and degeneration of motor neurons leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. Except for a minority of patients harbouring genetic mutations, the origin of most ALS cases remains elusive. Peripheral tissues, and particularly skeletal muscle, have lately demonstrated an active contribution to disease pathology attracting a growing interest for these tissues as therapeutic targets in ALS. In this sense, molecular mechanisms essential for cell and tissue homeostasis have been shown to be deregulated in the disease. These include muscle metabolism and mitochondrial activity, RNA processing, tissue-resident stem cell function responsible for muscle regeneration, and proteostasis that regulates muscle mass in adulthood. This review aims to compile scientific evidence that demonstrates the role of skeletal muscle in ALS pathology and serves as reference for development of novel therapeutic strategies targeting this tissue to delay disease onset and progression. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32983232, year = {2020}, author = {Yang, Q and Jiao, B and Shen, L}, title = {The Development of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disorders.}, journal = {Frontiers in genetics}, volume = {11}, number = {}, pages = {562758}, pmid = {32983232}, issn = {1664-8021}, abstract = {The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There are three main disease mechanisms: loss of function of C9ORF72 protein, gain of function from the accumulation of sense and antisense (GGGGCC)n in RNA, and from the production of toxic dipeptides repeat proteins (DPRs) by non-AUG initiated translation. While many of the downstream mechanisms have been identified, the specific pathogenic pathway is still unclear. In this article, we provide an overview on the currently available literature and propose several hypotheses: (1) The pathogenesis of C9orf72-associated ALS/FTD, which cannot be explained by a single mechanism, involves a dual mechanism of both loss and gain of function. (2) The loss of function and gain of function can cause TDP-43 aggregation and damage nucleocytoplasmic transport. (3) Neurodegeneration can be caused by an accumulation of toxic substances in neurons themselves. In addition, we suggest that microglia may cause neurodegeneration by releasing inflammatory factors to neurons. Finally, we summarize several of the most promising treatment strategies.}, }
@article {pmid32982690, year = {2020}, author = {Castets, P and Ham, DJ and Rüegg, MA}, title = {The TOR Pathway at the Neuromuscular Junction: More Than a Metabolic Player?.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {162}, pmid = {32982690}, issn = {1662-5099}, abstract = {The neuromuscular junction (NMJ) is the chemical synapse connecting motor neurons and skeletal muscle fibers. NMJs allow all voluntary movements, and ensure vital functions like breathing. Changes in the structure and function of NMJs are hallmarks of numerous pathological conditions that affect muscle function including sarcopenia, the age-related loss of muscle mass and function. However, the molecular mechanisms leading to the morphological and functional perturbations in the pre- and post-synaptic compartments of the NMJ remain poorly understood. Here, we discuss the role of the metabolic pathway associated to the kinase TOR (Target of Rapamycin) in the development, maintenance and alterations of the NMJ. This is of particular interest as the TOR pathway has been implicated in aging, but its role at the NMJ is still ill-defined. We highlight the respective functions of the two TOR-associated complexes, TORC1 and TORC2, and discuss the role of localized protein synthesis and autophagy regulation in motor neuron terminals and sub-synaptic regions of muscle fibers and their possible effects on NMJ maintenance.}, }
@article {pmid32976566, year = {2021}, author = {Pakravan, D and Orlando, G and Bercier, V and Van Den Bosch, L}, title = {Role and therapeutic potential of liquid-liquid phase separation in amyotrophic lateral sclerosis.}, journal = {Journal of molecular cell biology}, volume = {13}, number = {1}, pages = {15-28}, pmid = {32976566}, issn = {1759-4685}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology ; Autophagy/drug effects ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Intrinsically Disordered Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Molecular Chaperones/pharmacology/therapeutic use ; Mutation ; Oligonucleotides, Antisense/pharmacology/therapeutic use ; Protein Aggregation, Pathological/drug therapy/genetics/*pathology ; Protein Folding/drug effects ; RNA-Binding Protein FUS/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess 'low-complexity domains' (LCDs) and are considered as 'intrinsically disordered proteins', which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional 'liquid-liquid phase separation' (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.}, }
@article {pmid32972341, year = {2020}, author = {Deeb, O and Nabulsi, M}, title = {Exploring Multiple Sclerosis (MS) and Amyotrophic Lateral Scler osis (ALS) as Neurodegenerative Diseases and their Treatments: A Review Study.}, journal = {Current topics in medicinal chemistry}, volume = {20}, number = {26}, pages = {2391-2403}, doi = {10.2174/1568026620666200924114827}, pmid = {32972341}, issn = {1873-4294}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*pathology ; Animals ; Blood-Brain Barrier/metabolism ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Discovery ; Humans ; Immunosuppressive Agents/*chemistry/pharmacology ; Magnetic Resonance Imaging ; Molecular Structure ; Motor Neurons/pathology ; Multiple Sclerosis/drug therapy/*pathology ; Neurodegenerative Diseases/drug therapy/*pathology ; Phenotype ; Quality of Life ; Spinal Cord/metabolism ; }, abstract = {Growing concern about neurodegenerative diseases is becoming a global issue. It is estimated that not only will their prevalence increase but also morbidity and health burden will be concerning. Scientists, researchers and clinicians share the responsibility of raising the awareness and knowledge about the restricting and handicapping health restrains related to these diseases. Multiple Sclerosis (MS), as one of the prevalent autoimmune diseases, is characterized by abnormal regulation of the immune system that periodically attacks parts of the nervous system; brain and spinal cord. Symptoms and impairments include weakness, numbness, visual problems, tingling pain that are quietly variable among patients. Amyotrophic Lateral Sclerosis (ALS) is another neurodegenerative disease that is characterized by the degeneration of motor neurons in the brain and spinal cord. Unlike MS, symptoms begin with muscle weakness and progress to affect speech, swallowing and finally breathing. Despite the major differences between MS and ALS, misdiagnosis is still influencing disease prognosis and patient's quality of life. Diagnosis depends on obtaining a careful history and neurological examination as well as the use of Magnetic Resonance Imaging (MRI), which are considered challenging and depend on the current disease status in individuals. Fortunately, a myriad of treatments is available now for MS. Most of the cases are steroid responsive. Disease modifying therapy is amongst the most important set of treatments. In ALS, few medications that slow down disease progression are present. The aim of this paper is to summarize what has been globally known and practiced about MS and ALS, as they are currently classified as important growing key players among autoimmune diseases. In terms of treatments, it is concluded that special efforts and input should be directed towards repurposing of older drugs and on stem cells trials. As for ALS, it is highlighted that supportive measurements and supplementary treatments remain essentially needed for ALS patients and their families. On the other hand, it is noteworthy to clarify that the patient-doctor communication is relatively a cornerstone in selecting the best treatment for each MS patient.}, }
@article {pmid32971909, year = {2020}, author = {Obrador, E and Salvador, R and López-Blanch, R and Jihad-Jebbar, A and Vallés, SL and Estrela, JM}, title = {Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32971909}, issn = {2076-3921}, support = {OTR2017-18255INVES and OTR2018-19337INVES//Universitat de Val&#xe8;ncia/ ; EH1 and EH2//Elysium Health Inc., USA/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.}, }
@article {pmid32971256, year = {2020}, author = {Gagliardi, D and Costamagna, G and Taiana, M and Andreoli, L and Biella, F and Bersani, M and Bresolin, N and Comi, GP and Corti, S}, title = {Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia.}, journal = {Ageing research reviews}, volume = {64}, number = {}, pages = {101172}, doi = {10.1016/j.arr.2020.101172}, pmid = {32971256}, issn = {1872-9649}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/therapy ; Humans ; Proteins/genetics ; }, abstract = {In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks. Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.}, }
@article {pmid32970857, year = {2021}, author = {Vangoor, VR and Gomes-Duarte, A and Pasterkamp, RJ}, title = {Long non-coding RNAs in motor neuron development and disease.}, journal = {Journal of neurochemistry}, volume = {156}, number = {6}, pages = {777-801}, pmid = {32970857}, issn = {1471-4159}, mesh = {Animals ; Humans ; Motor Neuron Disease/*genetics/physiopathology ; Motor Neurons/*physiology ; RNA, Long Noncoding/*genetics/*physiology ; }, abstract = {Long non-coding RNAs (lncRNAs) are RNAs that exceed 200 nucleotides in length and that are not translated into proteins. Thousands of lncRNAs have been identified with functions in processes such as transcription and translation regulation, RNA processing, and RNA and protein sponging. LncRNAs show prominent expression in the nervous system and have been implicated in neural development, function and disease. Recent work has begun to report on the expression and roles of lncRNAs in motor neurons (MNs). The cell bodies of MNs are located in cortex, brainstem or spinal cord and their axons project into the brainstem, spinal cord or towards peripheral muscles, thereby controlling important functions such as movement, breathing and swallowing. Degeneration of MNs is a pathological hallmark of diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. LncRNAs influence several aspects of MN development and disruptions in these lncRNA-mediated effects are proposed to contribute to the pathogenic mechanisms underlying MN diseases (MNDs). Accumulating evidence suggests that lncRNAs may comprise valuable therapeutic targets for different MNDs. In this review, we discuss the role of lncRNAs (including circular RNAs [circRNAs]) in the development of MNs, discuss how lncRNAs may contribute to MNDs and provide directions for future research.}, }
@article {pmid32965492, year = {2020}, author = {Zheng, T and Yang, Y and Castañeda, CA}, title = {Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery.}, journal = {The Biochemical journal}, volume = {477}, number = {18}, pages = {3471-3497}, pmid = {32965492}, issn = {1470-8728}, support = {R01 GM136946/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; *Autophagy ; *Autophagy-Related Proteins/chemistry/genetics/metabolism ; *DNA Repair ; *Endoplasmic Reticulum-Associated Degradation ; Frontotemporal Dementia/genetics/metabolism ; Humans ; Mutation ; Nuclear Proteins/chemistry/genetics/metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; Protein Domains ; Structure-Activity Relationship ; Ubiquitin/genetics/metabolism ; }, abstract = {Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through the ubiquitin-proteasome system (UPS), autophagy, and endoplasmic-reticulum-associated protein degradation (ERAD) pathways. In addition, UBQLNs engage with chaperones to sequester, degrade, or assist repair of misfolded client proteins. Furthermore, UBQLNs regulate DNA damage repair mechanisms, interact with RNA-binding proteins (RBPs), and engage with cytoskeletal elements to regulate cell differentiation and development. Important to the myriad functions of UBQLNs are its multidomain architecture and ability to self-associate. UBQLNs are linked to numerous types of cellular puncta, including stress-induced biomolecular condensates, autophagosomes, aggresomes, and aggregates. In this review, we focus on deciphering how UBQLNs function on a molecular level. We examine the properties of oligomerization-driven interactions among the structured and intrinsically disordered segments of UBQLNs. These interactions, together with the knowledge from studies of disease-linked mutations, provide significant insights to UBQLN structure, dynamics and function.}, }
@article {pmid32962914, year = {2021}, author = {Tracey, TJ and Kirk, SE and Steyn, FJ and Ngo, ST}, title = {The role of lipids in the central nervous system and their pathological implications in amyotrophic lateral sclerosis.}, journal = {Seminars in cell &amp; developmental biology}, volume = {112}, number = {}, pages = {69-81}, doi = {10.1016/j.semcdb.2020.08.012}, pmid = {32962914}, issn = {1096-3634}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Astrocytes/metabolism/pathology ; Central Nervous System/metabolism/*pathology ; Humans ; Lipids/*genetics ; Mitochondria/metabolism ; Neurons/*metabolism/pathology ; }, abstract = {Lipids play an important role in the central nervous system (CNS). They contribute to the structural integrity and physical characteristics of cell and organelle membranes, act as bioactive signalling molecules, and are utilised as fuel sources for mitochondrial metabolism. The intricate homeostatic mechanisms underpinning lipid handling and metabolism across two major CNS cell types; neurons and astrocytes, are integral for cellular health and maintenance. Here, we explore the various roles of lipids in these two cell types. Given that changes in lipid metabolism have been identified in a number of neurodegenerative diseases, we also discuss changes in lipid handling and utilisation in the context of amyotrophic lateral sclerosis (ALS), in order to identify key cellular processes affected by the disease, and inform future areas of research.}, }
@article {pmid32962866, year = {2021}, author = {Fernández-Cruz, I and Reynaud, E}, title = {Proteasome Subunits Involved in Neurodegenerative Diseases.}, journal = {Archives of medical research}, volume = {52}, number = {1}, pages = {1-14}, doi = {10.1016/j.arcmed.2020.09.007}, pmid = {32962866}, issn = {1873-5487}, mesh = {Animals ; Humans ; Huntingtin Protein/metabolism ; Neurodegenerative Diseases/*genetics/metabolism/pathology ; Proteasome Endopeptidase Complex/chemistry/metabolism/*physiology ; Protein Aggregation, Pathological/genetics/metabolism/pathology ; Protein Binding ; Protein Subunits/physiology ; Ubiquitin/metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {The ubiquitin-proteasome system is the major pathway for the maintenance of protein homeostasis. Its inhibition causes accumulation of ubiquitinated proteins; this accumulation has been associated with several of the most common neurodegenerative diseases. Several genetic factors have been identified for most neurodegenerative diseases, however, most cases are considered idiopathic, thus making the study of the mechanisms of protein accumulation a relevant field of research. It is often mentioned that the biggest risk factor for neurodegenerative diseases is aging, and several groups have reported an age-related alteration of the expression of some of the 26S proteasome subunits and a reduction of its activity. Proteasome subunits interact with proteins that are known to accumulate in neurodegenerative diseases such as α-synuclein in Parkinson's, tau in Alzheimer's, and huntingtin in Huntington's diseases. These interactions have been explored for several years, but only until recently, we are beginning to understand them. In this review, we discuss the known interactions, the underlying patterns, and the phenotypes associated with the 26S proteasome subunits in the etiology and progression of neurodegenerative diseases where there is evidence of proteasome involvement. Special emphasis is made in reviewing proteasome subunits that interact with proteins known to have an age-related altered expression or to be involved in neurodegenerative diseases to explore key effectors that may trigger or augment their progression. Interestingly, while the causes of age-related reduction of some of the proteasome subunits are not known, there are specific relationships between the observed neurodegenerative disease and the affected proteasome subunits.}, }
@article {pmid32958236, year = {2020}, author = {McAlary, L and Yerbury, JJ and Cashman, NR}, title = {The prion-like nature of amyotrophic lateral sclerosis.}, journal = {Progress in molecular biology and translational science}, volume = {175}, number = {}, pages = {261-296}, doi = {10.1016/bs.pmbts.2020.07.002}, pmid = {32958236}, issn = {1878-0814}, mesh = {Amyloid/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Humans ; Prions/*metabolism ; Protein Aggregates ; Protein Folding ; Superoxide Dismutase-1/metabolism ; }, abstract = {The misfolding, aggregation, and deposition of specific proteins is the key hallmark of most progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). ALS is characterized by the rapid and progressive degenerations of motor neurons in the spinal cord and motor cortex, resulting in paralysis of those who suffer from it. Pathologically, there are three major aggregating proteins associated with ALS, including TAR DNA-binding protein of 43kDa (TDP-43), superoxide dismutase-1 (SOD1), and fused in sarcoma (FUS). While there are ALS-associated mutations found in each of these proteins, the most prevalent aggregation pathology is that of wild-type TDP-43 (97% of cases), with the remaining split between mutant forms of SOD1 (~2%) and FUS (~1%). Considering the progressive nature of ALS and its association with the aggregation of specific proteins, a growing notion is that the spread of pathology and symptoms can be explained by a prion-like mechanism. Prion diseases are a group of highly infectious neurodegenerative disorders caused by the misfolding, aggregation, and spread of a transmissible conformer of prion protein (PrP). Pathogenic PrP is capable of converting healthy PrP into a toxic form through template-directed misfolding. Application of this finding to other neurodegenerative disorders, and in particular ALS, has revolutionized our understanding of cause and progression of these disorders. In this chapter, we first provide a background on ALS pathology and genetic origin. We then detail and discuss the evidence supporting a prion-like propagation of protein misfolding and aggregation in ALS with a particular focus on SOD1 and TDP-43 as these are the most well-established models in the field.}, }
@article {pmid32949726, year = {2021}, author = {Latsios, G and Synetos, A and Mastrokostopoulos, A and Vogiatzi, G and Bounas, P and Nikitas, G and Papanikolaou, A and Parisis, C and Kanakakis, I and Goudevenos, J}, title = {CardioPulmonary Resuscitation in patients with suspected or confirmed Covid-19. A consensus of the Working group on CardioPulmonary Resuscitation of the Hellenic Society of Cardiology.}, journal = {Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese}, volume = {62}, number = {1}, pages = {24-28}, pmid = {32949726}, issn = {2241-5955}, mesh = {*COVID-19/mortality/prevention &amp; control/transmission ; *Cardiopulmonary Resuscitation/ethics/methods/standards ; *Heart Arrest/therapy/virology ; Humans ; Occupational Exposure/prevention &amp; control ; *Occupational Health/ethics/standards ; SARS-CoV-2 ; }, abstract = {The unprecedented for modern medicine pandemic caused by the SARS-COV-2 virus ("coronavirus", Covid-19 disease) creates in turn new data on the management and survival of cardiac arrest victims, but mainly on the safety of CardioPulmonary Resuscitation (CPR) providers. The Covid-19 pandemic resulted in losses of thousands of lives, and many more people were hospitalized in simple or in intensive care unit beds, both globally and locally in Greece. More specifically, in victims of cardiac arrest, both in- and out- of hospital, the increased mortality and high contagiousness of the SARS-CoV-2 virus posed new questions, of both medical and moral nature/ to CPR providers. What we all know in resuscitation, that we cannot harm the victim and therefore do the most/best we can, is no longer the everyday reality. What we need to know and incorporate into decision-making in the resuscitation process is the distribution of limited human and material resources, the potentially very poor outcome of patients with Covid-19 and cardiac arrest, and especially that a potential infection of health professionals can lead in the lack of health professionals in the near future. This review tries to incorporate the added skills and precautions for CPR providers in terms of both in- and out- hospital CPR.}, }
@article {pmid32944919, year = {2021}, author = {Eyileten, C and Sharif, L and Wicik, Z and Jakubik, D and Jarosz-Popek, J and Soplinska, A and Postula, M and Czlonkowska, A and Kaplon-Cieslicka, A and Mirowska-Guzel, D}, title = {The Relation of the Brain-Derived Neurotrophic Factor with MicroRNAs in Neurodegenerative Diseases and Ischemic Stroke.}, journal = {Molecular neurobiology}, volume = {58}, number = {1}, pages = {329-347}, pmid = {32944919}, issn = {1559-1182}, support = {2017/25/N/NZ5/00545//Narodowe Centrum Nauki/ ; }, mesh = {Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Humans ; Ischemic Stroke/*genetics/therapy ; MicroRNAs/genetics/*metabolism ; Models, Biological ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*genetics/therapy ; }, abstract = {Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.}, }
@article {pmid32938372, year = {2020}, author = {Kitajima, Y and Yoshioka, K and Suzuki, N}, title = {The ubiquitin-proteasome system in regulation of the skeletal muscle homeostasis and atrophy: from basic science to disorders.}, journal = {The journal of physiological sciences : JPS}, volume = {70}, number = {1}, pages = {40}, pmid = {32938372}, issn = {1880-6562}, support = {15H05667//Grant-in-Aid for Scientific Research KAKENHI/ ; 16H05318//Grant-in-Aid for Scientific Research KAKENHI/ ; 18K07519//Grant-in-Aid for Scientific Research KAKENHI/ ; 18K17857//Grant-in-Aid for Scientific Research KAKENHI/ ; 20H04078//Grant-in-Aid for Scientific Research KAKENHI/ ; YK//Suzuken Memorial Foundation/ ; }, mesh = {Animals ; Homeostasis ; Humans ; Muscle Development ; Muscle Proteins/*metabolism ; Muscle, Skeletal/*enzymology/pathology/physiopathology ; Muscular Atrophy/*enzymology/pathology/physiopathology ; Proteasome Endopeptidase Complex/*metabolism ; Proteolysis ; Regeneration ; Satellite Cells, Skeletal Muscle/metabolism/pathology ; Ubiquitin/*metabolism ; Ubiquitination ; }, abstract = {Skeletal muscle is one of the most abundant and highly plastic tissues. The ubiquitin-proteasome system (UPS) is recognised as a major intracellular protein degradation system, and its function is important for muscle homeostasis and health. Although UPS plays an essential role in protein degradation during muscle atrophy, leading to the loss of muscle mass and strength, its deficit negatively impacts muscle homeostasis and leads to the occurrence of several pathological phenotypes. A growing number of studies have linked UPS impairment not only to matured muscle fibre degeneration and weakness, but also to muscle stem cells and deficiency in regeneration. Emerging evidence suggests possible links between abnormal UPS regulation and several types of muscle diseases. Therefore, understanding of the role of UPS in skeletal muscle may provide novel therapeutic insights to counteract muscle wasting, and various muscle diseases. In this review, we focussed on the role of proteasomes in skeletal muscle and its regeneration, including a brief explanation of the structure of proteasomes. In addition, we summarised the recent findings on several diseases and elaborated on how the UPS is related to their pathological states.}, }
@article {pmid32937849, year = {2020}, author = {Ikawa, M and Okazawa, H and Nakamoto, Y and Yoneda, M}, title = {PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32937849}, issn = {2076-3921}, support = {18H02763//Japan Society for the Promotion of Science/ ; 20K07900//Japan Society for the Promotion of Science/ ; }, abstract = {Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with [62]Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. [62]Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.}, }
@article {pmid32931756, year = {2020}, author = {Kim, G and Gautier, O and Tassoni-Tsuchida, E and Ma, XR and Gitler, AD}, title = {ALS Genetics: Gains, Losses, and Implications for Future Therapies.}, journal = {Neuron}, volume = {108}, number = {5}, pages = {822-842}, pmid = {32931756}, issn = {1097-4199}, support = {R35 NS097263/NS/NINDS NIH HHS/United States ; RF1 AG064690/AG/NIA NIH HHS/United States ; T32 HG000044/HG/NHGRI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; C9orf72 Protein/genetics ; Forecasting ; Gain of Function Mutation/*genetics ; Genetic Therapy/*trends ; Humans ; Loss of Function Mutation/*genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the loss of motor neurons from the brain and spinal cord. The ALS community has made remarkable strides over three decades by identifying novel familial mutations, generating animal models, elucidating molecular mechanisms, and ultimately developing promising new therapeutic approaches. Some of these approaches reduce the expression of mutant genes and are in human clinical trials, highlighting the need to carefully consider the normal functions of these genes and potential contribution of gene loss-of-function to ALS. Here, we highlight known loss-of-function mechanisms underlying ALS, potential consequences of lowering levels of gene products, and the need to consider both gain and loss of function to develop safe and effective therapeutic strategies.}, }
@article {pmid32930869, year = {2021}, author = {Ayers, JI and Borchelt, DR}, title = {Phenotypic diversity in ALS and the role of poly-conformational protein misfolding.}, journal = {Acta neuropathologica}, volume = {142}, number = {1}, pages = {41-55}, pmid = {32930869}, issn = {1432-0533}, support = {R01 NS092788/NS/NINDS NIH HHS/United States ; R21 NS088839/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; DNA-Binding Proteins/chemistry/genetics ; Humans ; Prion Proteins/chemistry ; Protein Conformation ; Proteostasis Deficiencies/genetics/*pathology ; Superoxide Dismutase-1/chemistry/genetics ; }, abstract = {In many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct conformations that ALS-linked proteins can adopt to produce the equivalent of prion strains. In this review, we discuss the in vitro and in vivo evidence that has been generated to better understand the characteristics of these proteins and how their tertiary structure may impact the disease phenotype.}, }
@article {pmid32927676, year = {2020}, author = {Marrero-Winkens, C and Sankaran, C and Schätzl, HM}, title = {From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins.}, journal = {Biomolecules}, volume = {10}, number = {9}, pages = {}, pmid = {32927676}, issn = {2218-273X}, support = {G2019000542//Alberta Innovates/International ; 201600010//Alberta Innovates/International ; }, mesh = {Alzheimer Disease/genetics/*metabolism/pathology ; Amyloid/chemistry/genetics/metabolism ; Amyloidogenic Proteins/*chemistry/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Autophagy/genetics ; Gene Expression Regulation ; HSP110 Heat-Shock Proteins/genetics/metabolism ; HSP40 Heat-Shock Proteins/genetics/metabolism ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Humans ; Huntington Disease/genetics/*metabolism/pathology ; Parkinson Disease/genetics/*metabolism/pathology ; Prion Diseases/genetics/*metabolism/pathology ; Prion Proteins/*chemistry/genetics/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Aggregates ; Protein Folding ; }, abstract = {Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases form self-templating oligomeric assemblies that recruit further correctly folded protein and induce their conversion. Over time, this leads to the formation of high molecular and mostly fibrillar aggregates that are increasingly inefficient at converting normal protein. Evidence from a multitude of in vitro models suggests that fibrils are fragmented to form new seeds, which can convert further normal protein and also spread to neighboring cells as observed in vivo. While fragmentation and seed generation were suggested as crucial steps in aggregate formation decades ago, the biological pathways involved remain largely unknown. Here, we show that mechanisms of aggregate clearance-namely the mammalian Hsp70-Hsp40-Hsp110 tri-chaperone system, macro-autophagy, and the proteasome system-may not only be protective, but also play a role in fragmentation. We further review the challenges that exist in determining the precise contribution of these mechanisms to protein misfolding diseases and suggest future directions to resolve these issues.}, }
@article {pmid32927603, year = {2020}, author = {Damiano, S and Sozio, C and La Rosa, G and Guida, B and Faraonio, R and Santillo, M and Mondola, P}, title = {Metabolism Regulation and Redox State: Insight into the Role of Superoxide Dismutase 1.}, journal = {International journal of molecular sciences}, volume = {21}, number = {18}, pages = {}, pmid = {32927603}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Antioxidants/metabolism ; Cell Respiration ; Cholesterol/metabolism ; Diet ; *Energy Metabolism ; Humans ; Lymphocyte Activation ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Energy metabolism and redox state are strictly linked; energy metabolism is a source of reactive oxygen species (ROS) that, in turn, regulate the flux of metabolic pathways. Moreover, to assure redox homeostasis, metabolic pathways and antioxidant systems are often coordinately regulated. Several findings show that superoxide dismutase 1 (SOD1) enzyme has effects that go beyond its superoxide dismutase activity and that its functions are not limited to the intracellular compartment. Indeed, SOD1 is secreted through unconventional secretory pathways, carries out paracrine functions and circulates in the blood bound to lipoproteins. Striking experimental evidence links SOD1 to the redox regulation of metabolism. Important clues are provided by the systemic effects on energy metabolism observed in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). The purpose of this review is to analyze in detail the involvement of SOD1 in redox regulation of metabolism, nutrient sensing, cholesterol metabolism and regulation of mitochondrial respiration. The scientific literature on the relationship between ALS, mutated SOD1 and metabolism will also be explored, in order to highlight the metabolic functions of SOD1 whose biological role still presents numerous unexplored aspects that deserve further investigation.}, }
@article {pmid32927063, year = {2020}, author = {Kwok, JB and Loy, CT and Dobson-Stone, C and Halliday, GM}, title = {The complex relationship between genotype, pathology and phenotype in familial dementia.}, journal = {Neurobiology of disease}, volume = {145}, number = {}, pages = {105082}, doi = {10.1016/j.nbd.2020.105082}, pmid = {32927063}, issn = {1095-953X}, mesh = {Dementia/*genetics/*pathology ; *Genetic Association Studies ; Humans ; }, abstract = {Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.}, }
@article {pmid32923185, year = {2020}, author = {Wasim, S and Kukkar, V and Awad, VM and Sakhamuru, S and Malik, BH}, title = {Neuroprotective and Neurodegenerative Aspects of Coffee and Its Active Ingredients in View of Scientific Literature.}, journal = {Cureus}, volume = {12}, number = {8}, pages = {e9578}, pmid = {32923185}, issn = {2168-8184}, abstract = {Coffee and its components have several neuroprotective properties that lower the risk of cognitive decline and other neurodegenerative diseases. This study reviews the mechanisms by which coffee and its respective compounds affect the brain and its pathologies. Many epidemiological studies in this literature review have shown coffee to reduce the risk of developing dementia, stroke, and Alzheimer's disease. It may also have a positive impact on the disease course of amyotrophic lateral sclerosis, Parkinson's disease, and depression. The optimal benefits achieved from coffee in these pathologies rely on higher daily doses. Most of its effects are attributed to caffeine by the antagonism of adenosine receptors in the central nervous system; however, other coffee constituents like chlorogenic acids have also shown much promise in therapeutic value. Existing research considers coffee to have great potential, but additional studies are still needed to clarify the mechanisms and actual causal relationships in certain neuropathologies.}, }
@article {pmid32922384, year = {2020}, author = {D'Ambrosi, N and Apolloni, S}, title = {Fibrotic Scar in Neurodegenerative Diseases.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {1394}, pmid = {32922384}, issn = {1664-3224}, mesh = {Animals ; Central Nervous System Diseases/*pathology ; Fibrosis/*pathology ; Humans ; Neurodegenerative Diseases/*pathology ; }, abstract = {The process of uncontrolled internal scarring, called fibrosis, is now emerging as a pathological feature shared by both peripheral and central nervous system diseases. In the CNS, damaged neurons are not replaced by tissue regeneration, and scar-forming cells such as endothelial cells, inflammatory immune cells, stromal fibroblasts, and astrocytes can persist chronically in brain and spinal cord lesions. Although this process was extensively described in acute CNS damages, novel evidence indicates the involvement of a fibrotic reaction in chronic CNS injuries as those occurring during neurodegenerative diseases, where inflammation and fibrosis fuel degeneration. In this mini review, we discuss recent advances around the role of fibrotic scar formation and function in different neurodegenerative conditions, particularly focusing on the rising role of scarring in the pathogenesis of amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease and highlighting the therapeutic relevance of targeting fibrotic scarring to slow and reverse neurodegeneration.}, }
@article {pmid32911810, year = {2020}, author = {Sidorova, YA and Saarma, M}, title = {Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {18}, pages = {}, pmid = {32911810}, issn = {1422-0067}, support = {1325555//Academy of Finland/ ; }, mesh = {Animals ; Cells, Cultured ; Drug Delivery Systems/*methods ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Glial Cell Line-Derived Neurotrophic Factor Receptors/*drug effects/metabolism ; Humans ; Ligands ; Neuralgia/metabolism ; Neurites/metabolism ; Neurodegenerative Diseases/drug therapy ; Neuroglia/drug effects/metabolism ; Neurons/metabolism ; Peptides/*pharmacology ; Receptors, Nerve Growth Factor/drug effects/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/pharmacology ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson's disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer's disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients' selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.}, }
@article {pmid32911219, year = {2020}, author = {Silva-Moraes, MH and Bispo-Torres, AC and Barouh, JL and Lucena, PH and Armani-Franceschi, G and Dorea-Bandeira, I and Vieira, F and Miranda-Scippa, &#xc2; and Quarantini, LC and Lucena, R and Bandeira, ID}, title = {Suicidal behavior in individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {Journal of affective disorders}, volume = {277}, number = {}, pages = {688-696}, doi = {10.1016/j.jad.2020.08.066}, pmid = {32911219}, issn = {1573-2517}, mesh = {*Amyotrophic Lateral Sclerosis ; Case-Control Studies ; Cross-Sectional Studies ; *Depressive Disorder, Major ; Humans ; Meta-Analysis as Topic ; Quality of Life ; Suicidal Ideation ; Suicide, Attempted ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) leads to a drastic reduction in quality of life, generating intense psychological distress and predisposing those affected to mental illness and, in more severe cases, suicidal behavior.<br><br>OBJECTIVE: This is a systematic review aiming to estimate the frequency of wish to die, suicide ideation and suicide in individuals with ALS using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P).<br><br>METHODS: The following databases were used: Pubmed/MEDLINE, PsycINFO, Embase, SciELO, Biblioteca Virtual de Sa&#xfa;de (BVS), and Cochrane Library. The choice of appropriate descriptors, or their equivalents, to define the search terms was based on the technical and scientific vocabulary of each database.<br><br>RESULTS: 13 articles were included in the present systematic review, of which three were cross-sectional studies, nine were cohort-type and there was one case-control study. The studies show that individuals with ALS have a higher risk of suicide in relation to the general population, and there is evidence that this risk is even higher in the early stages of the disease. Major Depressive Disorder was the most prevalent mental disorder in the studies included. This mental health concern is often undertreated, leading to the increased susceptibility of this population to suicide.<br><br>LIMITATIONS: In general, the study samples represent a highly heterogeneous population while many instruments used in the data collection were not uniform.<br><br>CONCLUSIONS: The high degree of psychological vulnerability of this population, associated with a greater predisposition to suicidal behavior, should be minimized through public health measures.}, }
@article {pmid32910255, year = {2021}, author = {Beswick, E and Park, E and Wong, C and Mehta, AR and Dakin, R and Chandran, S and Newton, J and Carson, A and Abrahams, S and Pal, S}, title = {A systematic review of neuropsychiatric and cognitive assessments used in clinical trials for amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {268}, number = {12}, pages = {4510-4521}, pmid = {32910255}, issn = {1432-1459}, support = {MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy ; Cognition ; Humans ; *Motor Neuron Disease ; Quality of Life ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Up to 50% of people with amyotrophic lateral sclerosis (ALS) experience cognitive dysfunction, whilst depression and anxiety are reported in up to 44% and 33%, respectively. These symptoms impact on quality of life, and are associated with a poorer prognosis. Historically, outcomes in clinical trials have focused on the effect of candidate drugs on physical functioning.<br><br>METHODS: We reviewed the past 25&#xa0;years of clinical trials of investigative medicinal products in people with ALS, since the licensing of riluzole, and extracted data on frequency and type of assessment for neuropsychiatric symptoms and cognitive impairment. Trial registry databases, including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed, were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 31/10/2019. No language restrictions were applied. Outcome measures, exclusion criteria and assessment tool used were extracted.<br><br>RESULTS: 216 trials, investigating 26,326 people with ALS, were reviewed. 35% assessed neuropsychiatric symptoms, and 22% assessed cognition, as Exclusion Criteria or Outcome Measures. 3% (n&#x2009;=&#x2009;6) of trials assessed neuropsychiatric symptoms as a Secondary Outcome Measure, and 4% (n&#x2009;=&#x2009;8) assessed cognition as Outcome Measures; only one trial included assessments for both cognition and neuropsychiatric symptoms as Outcome Measures. Three ALS-specific assessments were used in six trials.<br><br>CONCLUSIONS: Trials for people with ALS have neglected the importance of neuropsychiatric symptoms and cognitive impairment. Evaluation of these extra-motor features is essential to understanding the impact of candidate drugs on all symptoms of ALS.<br><br>PROPSERO REGISTRATION: CRD42020175612.}, }
@article {pmid32909132, year = {2020}, author = {Narayanan, SE and Rehuman, NA and Harilal, S and Vincent, A and Rajamma, RG and Behl, T and Uddin, MS and Ashraf, GM and Mathew, B}, title = {Molecular mechanism of zinc neurotoxicity in Alzheimer's disease.}, journal = {Environmental science and pollution research international}, volume = {27}, number = {35}, pages = {43542-43552}, doi = {10.1007/s11356-020-10477-w}, pmid = {32909132}, issn = {1614-7499}, mesh = {*Alzheimer Disease ; Cognition ; Humans ; Memory ; *Neurotoxicity Syndromes ; Zinc ; }, abstract = {Zinc (Zn) is an essential trace element for most organisms, including human beings. It plays a crucial role in several physiological processes such as catalytic reaction of enzymes, cellular growth, differentiation and metabolism, intracellular signaling, and modulation of nucleic acid structure. Zn containing above 50 metalloenzymes is responsible for proteins, receptors, and hormones synthesis and has a critical role in neurodevelopment. Zn also regulates excitatory and inhibitory neurotransmitters such as glutamate and GABA and is found in high concentration in the synaptic terminals of hippocampal mossy fibers that maintains cognitive function. It regulates LTP and LTD by regulation of AMPA and NMDA receptors. But an excess or deficiency of Zn becomes neurotoxic or cause impairment in growth or sexual maturation. There is mounting evidence that supports this idea of Zn becoming neurotoxic and being involved in the pathogenesis of AD. Zn dyshomeostasis in AD is an area that needs attention as moderate concentration of Zn is involved in the memory regulation via regulation of amyloid plaque. Dyshomeostasis of Zn is involved in the pathogenesis of diseases like AD, ALS, depression, PD, and schizophrenia.}, }
@article {pmid32903629, year = {2020}, author = {Park, D and Kwak, SG and Park, JS and Choo, YJ and Chang, MC}, title = {Can Therapeutic Exercise Slow Down Progressive Functional Decline in Patients With Amyotrophic Lateral Sclerosis? A Meta-Analysis.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {853}, pmid = {32903629}, issn = {1664-2295}, abstract = {Background: Despite the high incidence of muscle weakness in patients with amyotrophic lateral sclerosis (ALS), the effects of therapeutic exercise on these individuals have not been clearly determined. Methods: A comprehensive database search was conducted on PubMed, Embase, Cochrane Library, and SCOPUS. We included studies published up to December 31, 2019 that fulfilled our inclusion and exclusion criteria. Functional status was determined as the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score (previous and revised versions) before and after a therapeutic exercise program for the meta-analysis. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used for the methodological quality assessments of included studies. The meta-analysis was performed using the RevMan v.5.3. Results: A total of 94 patients in the experimental group (who received therapeutic exercise) and 159 patients in the control group (who received conventional exercise or therapy) were included from five randomized controlled trials. The decrement of ALSFRS (previous version), ALSFRS-R (revised version), and ALSFRS-R-Respiratory scores at the 6-month evaluation were less for the therapeutic exercise group as compared to the control group. However, at the 6-month evaluation, the ALSFRS-R-Limb scores did not significantly differ between the two groups. Conclusions: Therapeutic exercise appears beneficial for patients with ALS. Further, it appears to exert more of a cardiopulmonary benefit, as opposed to preventing the progression of limb weakness. However, as the therapeutic exercises applied in each included study were not uniform, the result of our meta-analysis should be considered cautiously.}, }
@article {pmid32900825, year = {2020}, author = {Prabhat, N and Ray, S and Chakravarty, K and Kathuria, H and Saravana, S and Singh, D and Rebello, A and Lakhanpal, V and Goyal, MK and Lal, V}, title = {Atypical neurological manifestations of dengue fever: a case series and mini review.}, journal = {Postgraduate medical journal}, volume = {96}, number = {1142}, pages = {759-765}, doi = {10.1136/postgradmedj-2020-137533}, pmid = {32900825}, issn = {1469-0756}, mesh = {*Dengue/diagnosis/physiopathology ; Dengue Virus/*pathogenicity ; Diagnosis, Differential ; Humans ; *Nervous System Diseases/diagnosis/virology ; Neurologic Examination/methods ; }, abstract = {BACKGROUND: In this mini review, we discuss some of the atypical neurological manifestations of dengue virus and attempt to bring them to attention to highlight the neurotropic property of the dengue virus.<br><br>METHODS: Cases were chosen from retrospective hospital and outpatient records of all patients seropositive for dengue who attended the neurology referral. Seven patients have been chosen as illustrative examples of dengue-associated neurological involvement. We discuss the various central and peripheral nervous system involvement of patients and discuss the relevant findings in them.<br><br>CONCLUSION: Through this case series, we wish to highlight that the dengue virus can affect the nervous system at various targets, using multiple mechanisms of pathogenesis to generate a plethora of presentations. Hence, it is vital to be aware of its presentations to be able to diagnose dengue and treat it accordingly.}, }
@article {pmid32897420, year = {2020}, author = {Cintrón-Colón, AF and Almeida-Alves, G and Boynton, AM and Spitsbergen, JM}, title = {GDNF synthesis, signaling, and retrograde transport in motor neurons.}, journal = {Cell and tissue research}, volume = {382}, number = {1}, pages = {47-56}, pmid = {32897420}, issn = {1432-0878}, support = {1R15AG022908-01A2/AG/NIA NIH HHS/United States ; 1R15AG022908-01A2/AG/NIA NIH HHS/United States ; }, mesh = {Biological Transport/*physiology ; Glial Cell Line-Derived Neurotrophic Factor/*immunology ; Humans ; Motor Neurons/*metabolism ; Signal Transduction ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial cell lines and identified as a neurotrophic factor with the ability to promote dopamine uptake within midbrain dopaminergic neurons. Since its discovery, the potential neuroprotective effects of GDNF have been researched extensively, and the effect of GDNF on motor neurons will be discussed herein. Similar to other members of the TGF-β superfamily, GDNF is first synthesized as a precursor protein (pro-GDNF). After a series of protein cleavage and processing, the 211 amino acid pro-GDNF is finally converted into the active and mature form of GDNF. GDNF has the ability to trigger receptor tyrosine kinase RET phosphorylation, whose downstream effects have been found to promote neuronal health and survival. The binding of GDNF to its receptors triggers several intracellular signaling pathways which play roles in promoting the development, survival, and maintenance of neuron-neuron and neuron-target tissue interactions. The synthesis and regulation of GDNF have been shown to be altered in many diseases, aging, exercise, and addiction. The neuroprotective effects of GDNF may be used to develop treatments and therapies to ameliorate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this review, we provide a detailed discussion of the general roles of GDNF and its production, delivery, secretion, and neuroprotective effects on motor neurons within the mammalian neuromuscular system.}, }
@article {pmid32894661, year = {2020}, author = {Saleem, U and Sabir, S and Niazi, SG and Naeem, M and Ahmad, B}, title = {Role of Oxidative Stress and Antioxidant Defense Biomarkers in Neurodegenerative Diseases.}, journal = {Critical reviews in eukaryotic gene expression}, volume = {30}, number = {4}, pages = {311-322}, doi = {10.1615/CritRevEukaryotGeneExpr.2020029202}, pmid = {32894661}, issn = {1045-4403}, mesh = {Antioxidants/*metabolism ; Biomarkers/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; *Oxidative Stress ; }, abstract = {Oxidative stress is caused by an imbalance in a redox system. It may involve either excessive production of reactive oxygen species or dysfunction of the antioxidant defense system. Unlike other viscera, the brain is especially highly susceptible to oxidative damage because of it requires a high oxygen level and contains an abundance of peroxida-tion-susceptible lipid cells. Oxidative stress is among the common etiological factors involved in neurodegeneration. To measure The extent of oxidative stress is measured with several indicators or biomarkers that are known to arise from oxidation of major biomolecules, including lipids, proteins, carbohydrates, and nucleic acids. In this review, we will discuss oxidative stress biomarkers associated with neurodegenerative diseases, for instance, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We will also highlight the biomarkers of antioxidant defense mechanisms that are impaired in these diseases.}, }
@article {pmid32890771, year = {2020}, author = {Häkkinen, S and Chu, SA and Lee, SE}, title = {Neuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {145}, number = {}, pages = {105063}, pmid = {32890771}, issn = {1095-953X}, support = {R01 AG058233/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/genetics ; Frontotemporal Dementia/*diagnostic imaging/genetics ; Humans ; Neuroimaging/*methods ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have a strong clinical, genetic and pathological overlap. This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS. We overview quantitative neuroimaging studies on the most common genes associated with FTD (MAPT, GRN), ALS (SOD1), and both (C9orf72), and summarize visual observations of images reported in the rarer genes (CHMP2B, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, TREM2, CHCHD10, TBK1).}, }
@article {pmid32885763, year = {2021}, author = {Shafi, S and Singh, A and Gupta, P and Chawla, PA and Fayaz, F and Sharma, A and Pottoo, FH}, title = {Deciphering the Role of Aberrant Protein Post-Translational Modification in the Pathology of Neurodegeneration.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {20}, number = {1}, pages = {54-67}, doi = {10.2174/1871527319666200903162200}, pmid = {32885763}, issn = {1996-3181}, mesh = {Acetylation ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Huntington Disease/metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; Phosphorylation ; Protein Processing, Post-Translational/*physiology ; Ubiquitination ; }, abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD), are characterized by progressive neuronal dysfunction and death. Recent studies have established detrimental modifications in the structure and function of brain proteins, which stimulate their aggregation, misfolding and deposition in and around the neurons an important hallmark of neurodegenerative diseases. Post-Translational Modification (PTM) of proteins, including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination, are important regulators of protein characteristics, including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid are associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease-associated proteins can prove to be a significant step in evaluating the functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins is linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.}, }
@article {pmid32882437, year = {2020}, author = {Pinto, S and Quintarelli, S and Silani, V}, title = {New technologies and Amyotrophic Lateral Sclerosis - Which step forward rushed by the COVID-19 pandemic?.}, journal = {Journal of the neurological sciences}, volume = {418}, number = {}, pages = {117081}, pmid = {32882437}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *COVID-19/epidemiology ; Health Services Accessibility ; Humans ; Inventions/legislation &amp; jurisprudence ; Pandemics ; Telemedicine/*methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fast-progressive neurodegenerative disease leading to progressive physical immobility with usually normal or mild cognitive and/or behavioural involvement. Many patients are relatively young, instructed, sensitive to new technologies, and professionally active when developing the first symptoms. Older patients usually require more time, encouragement, reinforcement and a closer support but, nevertheless, selecting user-friendly devices, provided earlier in the course of the disease, and engaging motivated carers may overcome many technological barriers. ALS may be considered a model for neurodegenerative diseases to further develop and test new technologies. From multidisciplinary teleconsults to telemonitoring of the respiratory function, telemedicine has the potentiality to embrace other fields, including nutrition, physical mobility, and the interaction with the environment. Brain-computer interfaces and eye tracking expanded the field of augmentative and alternative communication in ALS but their potentialities go beyond communication, to cognition and robotics. Virtual reality and different forms of artificial intelligence present further interesting possibilities that deserve to be investigated. COVID-19 pandemic is an unprecedented opportunity to speed up the development and implementation of new technologies in clinical practice, improving the daily living of both ALS patients and carers. The present work reviews the current technologies for ALS patients already in place or being under evaluation with published publications, prompted by the COVID-19 pandemic.}, }
@article {pmid32876811, year = {2020}, author = {Braems, E and Swinnen, B and Van Den Bosch, L}, title = {C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?.}, journal = {Acta neuropathologica}, volume = {140}, number = {5}, pages = {625-643}, pmid = {32876811}, issn = {1432-0533}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein/*genetics ; Frontotemporal Dementia/*genetics ; Humans ; }, abstract = {A repeat expansion in C9orf72 is responsible for the characteristic neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in a still unresolved manner. Proposed mechanisms involve gain-of-functions, comprising RNA and protein toxicity, and loss-of-function of the C9orf72 gene. Their exact contribution is still inconclusive and reports regarding loss-of-function are rather inconsistent. Here, we review the function of the C9orf72 protein and its relevance in disease. We explore the potential link between reduced C9orf72 levels and disease phenotypes in postmortem, in vitro, and in vivo models. Moreover, the significance of loss-of-function in other non-coding repeat expansion diseases is used to clarify its contribution in C9orf72 ALS/FTD. In conclusion, with evidence pointing to a multiple-hit model, loss-of-function on itself seems to be insufficient to cause neurodegeneration in C9orf72 ALS/FTD.}, }
@article {pmid32868602, year = {2020}, author = {Norris, SP and Likanje, MN and Andrews, JA}, title = {Amyotrophic lateral sclerosis: update on clinical management.}, journal = {Current opinion in neurology}, volume = {33}, number = {5}, pages = {641-648}, pmid = {32868602}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; COVID-19 ; Coronavirus Infections ; Humans ; Pandemics ; Pneumonia, Viral ; *Telemedicine ; }, abstract = {PURPOSE OF REVIEW: The current review will provide recent updates in the clinical management of amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: Although there is no cure for ALS, there are new treatments, growing knowledge of genetics, development of clinical staging systems, and the recent coronavirus disease 2019 pandemic that have recently impacted the clinical management of ALS. Increased understanding of genetics has helped provide insights into pathophysiology, the staging systems and clinical measures help to provide tools for monitoring disease clinically, and the recent coronavirus disease 2019 pandemic has provided opportunities to develop telemedicine and remote monitoring of disease thereby increasing accessibility to care and reducing burden of travel to centers for people living with the disease and their caregivers.<br><br>SUMMARY: ALS is a progressive neurodegenerative disease that causes degeneration of the motor neurons which leads to paralysis and respiratory failure. Despite the lack of a cure, multidisciplinary care, proactive respiratory management, nutritional care and management of symptoms as well as pharmacological interventions that can improve quality of life and survival.}, }
@article {pmid32861700, year = {2020}, author = {Domené, S and Domené, HM}, title = {The role of acid-labile subunit (ALS) in the modulation of GH-IGF-I action.}, journal = {Molecular and cellular endocrinology}, volume = {518}, number = {}, pages = {111006}, doi = {10.1016/j.mce.2020.111006}, pmid = {32861700}, issn = {1872-8057}, mesh = {Body Height/drug effects/genetics ; Carrier Proteins/genetics/pharmacology/*physiology ; Child ; Female ; Glycoproteins/deficiency/genetics/pharmacology/*physiology ; Growth Disorders/genetics/metabolism ; Human Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Male ; Puberty, Delayed/genetics/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Acid-labile subunit (ALS) deficiency (ACLSD) constitutes the first monogenic defect involving a member of the Insulin-like Growth Factor (IGF) binding protein system. The lack of ALS completely disrupts the circulating IGF system. Autocrine/paracrine action of local produced IGF-I could explain the mild effect on growth. In the present work we have revised the more relevant clinical and biochemical consequences of complete ACLSD in 61 reported subjects from 31 families. Low birth weight and/or length, reduced head circumference, height between -2 and -3 SD, pubertal delay and insulin resistance are commonly observed. Partial ACLSD could be present in children initially labeled as idiopathic short stature, presenting low IGF-I levels, suggesting that one functional IGFALS allele is insufficient to stabilize ternary complexes. Dysfunction of the GH-IGF axis observed in ACLSD may eventually result in increased risk for type-2 diabetes and tumor progression. Consequently, long term surveillance is recommended in these patients.}, }
@article {pmid32860626, year = {2020}, author = {Hao, Z and Wang, R and Ren, H and Wang, G}, title = {Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Neuroscience bulletin}, volume = {36}, number = {9}, pages = {1057-1070}, pmid = {32860626}, issn = {1995-8218}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; *C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics ; Humans ; Mice ; Mice, Transgenic ; Proteins ; }, abstract = {Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features of C9ORF72 patients have been well mimicked via several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated in C9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.}, }
@article {pmid32855905, year = {2020}, author = {Szczepanek, J}, title = {Role of microRNA dysregulation in childhood acute leukemias: Diagnostics, monitoring and therapeutics: A comprehensive review.}, journal = {World journal of clinical oncology}, volume = {11}, number = {6}, pages = {348-369}, pmid = {32855905}, issn = {2218-4333}, abstract = {MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation; they can also act as tumor suppressors (e.g., let-7b, miR-29a, miR-99, mir-100, miR-155, and miR-181) and/or oncogenes (e.g., miR-29a, miR-125b, miR-143-p3, mir-155, miR-181, miR-183, miR-196b, and miR-223) in childhood acute leukemia (AL). Differentially expressed miRNAs are important factors associated with the initiation and progression of AL. As shown in many studies, they can be used as noninvasive diagnostic and prognostic biomarkers, which are useful in monitoring early stages of AL development or during therapy (e.g., miR-125b, miR-146b, miR-181c, and miR-4786), accurate classification of different cellular or molecular AL subgroups (e.g., let-7b, miR-98, miR-100, miR-128b, and miR-223), and identification and development of new therapeutic agents (e.g., mir-10, miR-125b, miR-203, miR-210, miR-335). Specific miRNA patterns have also been described for commonly used AL therapy drugs (e.g., miR-125b and miR-223 for doxorubicin, miR-335 and miR-1208 for prednisolone, and miR-203 for imatinib), uncovering miRNAs that are associated with treatment response. In the current review, the role of miRNAs in the development, progression, and therapy monitoring of pediatric ALs will be presented and discussed.}, }
@article {pmid32854854, year = {2020}, author = {Aman, Y and Ryan, B and Torsetnes, SB and Knapskog, AB and Watne, LO and McEwan, WA and Fang, EF}, title = {Enhancing mitophagy as a therapeutic approach for neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {155}, number = {}, pages = {169-202}, doi = {10.1016/bs.irn.2020.02.008}, pmid = {32854854}, issn = {2162-5514}, support = {MR/N029453/1/MRC_/Medical Research Council/United Kingdom ; MR/P007058/1/MRC_/Medical Research Council/United Kingdom ; 206248/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; MR/L023784/1/MRC_/Medical Research Council/United Kingdom ; J-0901/PUK_/Parkinson's UK/United Kingdom ; MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Autophagy ; Humans ; Immunity, Innate ; *Mitophagy ; Neurodegenerative Diseases/immunology/*therapy ; Signal Transduction ; }, abstract = {Neurodegenerative diseases are highly debilitating illnesses and a growing cause of morbidity and mortality worldwide. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes underlying neurodegeneration. Defective mitophagy has been highlighted as the cause of the accumulation of damaged mitochondria, which consequently leads to cellular dysfunction and/or death in neurodegenerative diseases. Here, we highlight the recent advances in the molecular mechanisms of mitochondrial homeostasis and mitophagy in neurodegenerative diseases. In particular, we evaluate how mitophagy is altered in Alzheimer's, Parkinson's, and Huntington's diseases, as well as in amyotrophic lateral sclerosis, and the potential of restoring mitophagy as a therapeutic intervention. We also discuss the interlinked connections between mitophagy and innate immunity (e.g., the involvement of Parkin, interferons and TRIM21) as well as the opportunity these pathways provide to develop combinational therapeutic strategies targeting them and related molecular mechanisms in such neurodegenerative diseases.}, }
@article {pmid32854418, year = {2020}, author = {Ghemrawi, R and Khair, M}, title = {Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {17}, pages = {}, pmid = {32854418}, issn = {1422-0067}, mesh = {Activating Transcription Factor 6/metabolism ; Animals ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Stress ; Endoribonucleases/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Protein Serine-Threonine Kinases/metabolism ; *Signal Transduction ; Unfolded Protein Response ; eIF-2 Kinase/metabolism ; }, abstract = {The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.}, }
@article {pmid32854276, year = {2020}, author = {Le Gall, L and Anakor, E and Connolly, O and Vijayakumar, UG and Duddy, WJ and Duguez, S}, title = {Molecular and Cellular Mechanisms Affected in ALS.}, journal = {Journal of personalized medicine}, volume = {10}, number = {3}, pages = {}, pmid = {32854276}, issn = {2075-4426}, support = {EU Sustainable Competitiveness Programme for N. Ireland//European Union Regional Development Fund/ ; LLeGall fellowship//Association pour la Recherche sur la Scl&#xe9;rose Lat&#xe9;rale Amyotrophique et autres Maladies du Motoneurone/ ; ViTAL//Target ALS/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.}, }
@article {pmid32852645, year = {2021}, author = {Duarte, P and Cuadrado, A and León, R}, title = {Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches.}, journal = {Handbook of experimental pharmacology}, volume = {264}, number = {}, pages = {229-259}, pmid = {32852645}, issn = {0171-2004}, mesh = {Antidepressive Agents ; Humans ; Hydrogen Peroxide ; Monoamine Oxidase ; *Monoamine Oxidase Inhibitors/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; }, abstract = {Monoamine oxidases (MAOs) are involved in the oxidative deamination of different amines and neurotransmitters. This pointed them as potential targets for several disorders and along the last 70 years a wide variety of MAO inhibitors have been developed as successful drugs for the treatment of complex diseases, being the first drugs approved for depression in the late 1950s. The discovery of two MAO isozymes (MAO-A and B) with different substrate selectivity and tissue expression patterns led to novel therapeutic approaches and to the development of new classes of inhibitors, such as selective irreversible and reversible MAO-B inhibitors and reversible MAO-A inhibitors. Significantly, MAO-B inhibitors constitute a widely studied group of compounds, some of them approved for the treatment of Parkinson's disease. Further applications are under development for the treatment of Alzheimer's disease, amyotrophic lateral sclerosis, and cardiovascular diseases, among others. This review summarizes the most important aspects regarding the development and clinical use of MAO inhibitors, going through mechanistic and structural details, new indications, and future perspectives. Monoamine oxidases (MAOs) catalyze the oxidative deamination of different amines and neurotransmitters. The two different isozymes, MAO-A and MAO-B, are located at the outer mitochondrial membrane in different tissues. The enzymatic reaction involves formation of the corresponding aldehyde and releasing hydrogen peroxide (H2O2) and ammonia or a substituted amine depending on the substrate. MAO's role in neurotransmitter metabolism made them targets for major depression and Parkinson's disease, among other neurodegenerative diseases. Currently, these compounds are being studied for other diseases such as cardiovascular ones.}, }
@article {pmid32848579, year = {2020}, author = {Izrael, M and Slutsky, SG and Revel, M}, title = {Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {824}, pmid = {32848579}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.}, }
@article {pmid32848572, year = {2020}, author = {Maugeri, G and D'Amico, AG and Morello, G and Reglodi, D and Cavallaro, S and D'Agata, V}, title = {Differential Vulnerability of Oculomotor Versus Hypoglossal Nucleus During ALS: Involvement of PACAP.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {805}, pmid = {32848572}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive multifactorial disease characterized by the loss of motor neurons (MNs). Not all MNs undergo degeneration: neurons of the oculomotor nucleus, which regulate eye movements, are less vulnerable compared to hypoglossal nucleus MNs. Several molecular studies have been performed to understand the different vulnerability of these MNs. By analyzing postmortem samples from ALS patients to other unrelated decedents, the differential genomic pattern between the two nuclei has been profiled. Among identified genes, adenylate cyclase activating polypeptide 1 (ADCYAP1) gene, encoding for pituitary adenylate cyclase-activating polypeptide (PACAP), was found significantly up-regulated in the oculomotor versus hypoglossal nucleus suggesting that it could play a trophic effect on MNs in ALS. In the present review, some aspects regarding the different vulnerability of oculomotor and hypoglossal nucleus to degeneration will be summarized. The distribution and potential role of PACAP on these MNs as studied largely in an animal model of ALS compared to controls, will be discussed.}, }
@article {pmid32846148, year = {2020}, author = {Gromova, A and La Spada, AR}, title = {Harmony Lost: Cell-Cell Communication at the Neuromuscular Junction in Motor Neuron Disease.}, journal = {Trends in neurosciences}, volume = {43}, number = {9}, pages = {709-724}, doi = {10.1016/j.tins.2020.07.002}, pmid = {32846148}, issn = {1878-108X}, mesh = {*Amyotrophic Lateral Sclerosis ; Cell Communication ; Humans ; *Motor Neuron Disease ; Motor Neurons ; Neuromuscular Junction ; }, abstract = {The neuromuscular junction (NMJ) is a specialized synapse that is the point of connection between motor neurons and skeletal muscle. Although developmental studies have established the importance of cell-cell communication at the NMJ for the integrity and full functionality of this synapse, the contribution of this structure as a primary driver in motor neuron disease pathogenesis remains uncertain. Here, we consider the biology of the NMJ and review emerging lines of investigation that are highlighting the importance of cell-cell interaction at the NMJ in spinal muscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy (SBMA), and amyotrophic lateral sclerosis (ALS). Ongoing research may reveal NMJ targets and pathways whose therapeutic modulation will help slow the progression of motor neuron disease, offering a novel treatment paradigm for ALS, SBMA, SMA, and related disorders.}, }
@article {pmid32839928, year = {2020}, author = {Malek, EG and Salameh, JS and Makki, A}, title = {Kennedy's disease: an under-recognized motor neuron disorder.}, journal = {Acta neurologica Belgica}, volume = {120}, number = {6}, pages = {1289-1295}, pmid = {32839928}, issn = {2240-2993}, mesh = {*Bulbo-Spinal Atrophy, X-Linked ; Humans ; }, abstract = {Kennedy's disease or spinal bulbar muscular atrophy is a rare, inherited and slowly progressive multisystem disease mostly manifesting with a motor neuron disease phenotype leading to disability. The slow progression, partial androgen insensitivity, electrophysiological evidence of sensory neuronopathy, and relatively spared central nervous system pathways help differentiate it from amyotrophic lateral sclerosis. To date, there is no treatment or cure with clinical care mainly focused on accurate diagnosis, symptom management, patient education, and genetic counselling.}, }
@article {pmid32833751, year = {2020}, author = {Pender, N and Pinto-Grau, M and Hardiman, O}, title = {Cognitive and behavioural impairment in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {33}, number = {5}, pages = {649-654}, doi = {10.1097/WCO.0000000000000862}, pmid = {32833751}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/complications/*psychology ; Apathy ; Cognition/*physiology ; Cognitive Dysfunction/etiology/*psychology ; Disease Progression ; Humans ; Neuropsychological Tests ; }, abstract = {PURPOSE OF REVIEW: The current review provides an up to date overview of the nature and progression of the cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS). Understanding these symptoms has implications for the management of the disease and the design of clinical trials, in addition to the support of patient and caregiver regarding mental capacity and end of life decision-making.<br><br>RECENT FINDINGS: Cognitive and behavioural change in ALS are best characterized as the consequence of extensive network dysfunction. 35-45% of ALS patients present with mild-moderate cognitive impairment and comorbid dementia occurs in approximately 14% of patients, the majority of these meeting diagnostic criteria for frontotemporal dementia (FTD). Cognitive change in ALS manifests most commonly as executive dysfunction and language impairment. Behavioural change in the form of apathy, disinhibition, loss of sympathy and empathy, stereotyped behaviours and dietary changes occur.<br><br>SUMMARY: Cognitive and behavioural impairment is an important feature of ALS, and reflects broad network dysfunction of frontostriatal and frontotemporal systems. Cognition and behaviour should be assessed early in the diagnostic process, and data driven approaches should be developed to enable reliable quantitative outcome assessment suitable for clinical trials.}, }
@article {pmid32829028, year = {2020}, author = {McEachin, ZT and Parameswaran, J and Raj, N and Bassell, GJ and Jiang, J}, title = {RNA-mediated toxicity in C9orf72 ALS and FTD.}, journal = {Neurobiology of disease}, volume = {145}, number = {}, pages = {105055}, pmid = {32829028}, issn = {1095-953X}, support = {R21 NS114908/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; C9orf72 Protein/*genetics ; DNA Repeat Expansion ; Frontotemporal Dementia/*pathology ; Humans ; RNA/*toxicity ; }, abstract = {A GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Compelling evidence suggests that gain of toxicity from the bidirectionally transcribed repeat expanded RNAs plays a central role in disease pathogenesis. Two potential mechanisms have been proposed including RNA-mediated toxicity and/or the production of toxic dipeptide repeat proteins. In this review, we focus on the role of RNA mediated toxicity in ALS/FTD caused by the C9orf72 mutation and discuss arguments for and against this mechanism. In addition, we summarize how G4C2 repeat RNAs can elicit toxicity and potential therapeutic strategies to mitigate RNA-mediated toxicity.}, }
@article {pmid32828466, year = {2020}, author = {Webber, CJ and Lei, SE and Wolozin, B}, title = {The pathophysiology of neurodegenerative disease: Disturbing the balance between phase separation and irreversible aggregation.}, journal = {Progress in molecular biology and translational science}, volume = {174}, number = {}, pages = {187-223}, pmid = {32828466}, issn = {1878-0814}, support = {R01 AG064932/AG/NIA NIH HHS/United States ; RF1 AG056318/AG/NIA NIH HHS/United States ; R01 AG050471/AG/NIA NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; RF1 AG061706/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Biophysical Phenomena ; Cytoplasmic Granules/metabolism ; Humans ; Mutation/genetics ; Neurodegenerative Diseases/genetics/pathology/*physiopathology ; *Protein Aggregates ; RNA/metabolism ; }, abstract = {Liquid-liquid phase separation (LLPS) brings together functionally related proteins through the intrinsic biophysics of proteins in a process that is driven by reducing free energy and maximizing entropy. The process of LLPS allows proteins to form structures, termed membrane-less organelles. These diverse, dynamic organelles are active in a wide range of processes in the nucleus, cytoplasm, mitochondria and synapse, and ranging from bacteria to plants to eukaryotes. RNA and DNA present long chained charged polymers that promote LLPS. Consequently, many RNA binding proteins (RBPs) and DNA binding proteins form membrane-less organelles. However, the highly concentrated phase separated state creates conditions that also promote formation of irreversible protein aggregates. Mutations in RNA and DNA binding proteins that increase the stability of irreversible aggregates also increase the accumulation of irreversible aggregates directly and from membrane-less organelles. Many of the RBPs that exhibit disease-linked mutations carry out cytoplasmic actions through stress granules, which are a pleiotropic type of RNA granule that regulates the translational response to stress. Phosphorylation and oligomerization of tau facilitates its interactions with RBPs and ribosomal proteins, affecting RNA translation; we propose that this is a major reason that tau becomes phosphorylated with stress. Persistent stress leads to the accumulation of irreversible aggregates composed of RBPs or tau, which then cause toxicity and form many of the hallmark pathologies of major neurodegenerative diseases. This pathophysiology ultimately leads to multiple forms of neurodegenerative diseases, the specific type of which reflects the temporal and spatial accumulation of different aggregating proteins.}, }
@article {pmid32825423, year = {2020}, author = {Illes, P}, title = {P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {17}, pages = {}, pmid = {32825423}, issn = {1422-0067}, support = {CZYHW1901//Chengdu University of Traditional Chinese Medicine/ ; SZD201731, SZD201846//Sichuan Provincial Administration of Foreign Affairs/ ; }, mesh = {Animals ; Brain Ischemia/metabolism/pathology ; Central Nervous System Diseases/drug therapy/metabolism/*pathology ; Chronic Pain/metabolism/physiopathology ; Epilepsy/metabolism/physiopathology ; Humans ; Mice, Transgenic ; Neuralgia/metabolism/pathology ; Neurodegenerative Diseases/drug therapy/*metabolism/*pathology ; Purinergic P2X Receptor Antagonists/pharmacology ; Receptors, Purinergic P2X7/deficiency/*metabolism ; }, abstract = {ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na[+], Ca[2+], and K[+], but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca[2+] influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.}, }
@article {pmid32824215, year = {2020}, author = {Sandhof, CA and Hoppe, SO and Tittelmeier, J and Nussbaum-Krammer, C}, title = {C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins.}, journal = {Biomolecules}, volume = {10}, number = {8}, pages = {}, pmid = {32824215}, issn = {2218-273X}, support = {201348542//Deutsche Forschungsgemeinschaft/International ; 01ED1807B//Bundesministerium f&#xfc;r Bildung und Forschung/International ; }, mesh = {Animals ; *Caenorhabditis elegans ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Prions/*toxicity ; Protein Aggregates ; }, abstract = {A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients' families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.}, }
@article {pmid32820492, year = {2020}, author = {Lesman-Segev, OH and Edwards, L and Rabinovici, GD}, title = {Chronic Traumatic Encephalopathy: A Comparison with Alzheimer's Disease and Frontotemporal Dementia.}, journal = {Seminars in neurology}, volume = {40}, number = {4}, pages = {394-410}, doi = {10.1055/s-0040-1715134}, pmid = {32820492}, issn = {1098-9021}, support = {P30 AG062422/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*diagnosis/genetics/metabolism/pathology ; Chronic Traumatic Encephalopathy/*diagnosis/genetics/metabolism/pathology ; Frontotemporal Dementia/*diagnosis/genetics/metabolism/pathology ; Humans ; }, abstract = {The clinical diagnosis of chronic traumatic encephalopathy (CTE) is challenging due to heterogeneous clinical presentations and overlap with other neurodegenerative dementias. Depending on the clinical presentation, the differential diagnosis of CTE includes Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), Parkinson's disease, amyotrophic lateral sclerosis, primary mood disorders, posttraumatic stress disorder, and psychotic disorders. The aim of this article is to compare the clinical aspects, genetics, fluid biomarkers, imaging, treatment, and pathology of CTE to those of AD and bvFTD. A detailed clinical evaluation, neurocognitive assessment, and structural brain imaging can inform the differential diagnosis, while molecular biomarkers can help exclude underlying AD pathology. Prospective studies that include clinicopathological correlations are needed to establish tools that can more accurately determine the cause of neuropsychiatric decline in patients at risk for CTE.}, }
@article {pmid32819825, year = {2021}, author = {Cummings, J}, title = {The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {29}, number = {4}, pages = {375-383}, pmid = {32819825}, issn = {1545-7214}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; }, mesh = {Cognitive Dysfunction/diagnosis/physiopathology/psychology ; Dementia/diagnosis/physiopathology/psychology ; Humans ; Neurodegenerative Diseases/*diagnosis/physiopathology/*psychology ; Neuropsychological Tests ; Parkinson Disease/diagnosis/physiopathology/psychology ; Tauopathies/diagnosis/physiopathology/psychology ; }, abstract = {Neuropsychiatric syndromes and symptoms play increasingly important roles in research diagnostic criteria for neurodegenerative disorders. Diagnostic criteria were reviewed including those for dementia, Alzheimer's disease, mild cognitive impairment, mild behavioral impairment, prodromal Alzheimer's disease, dementia with Lewy bodies, prodromal dementia with Lewy bodies, Parkinson's disease, multiple system atrophy, frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy, corticobasal degeneration, traumatic encephalopathy syndrome, Huntington' disease, amyotrophic lateral sclerorsis. All contemporary research diagnostic criteria for neurodegenerative disorders expect those for Parkinson's disease, primary progressive aphasia, multisystem atrophy and amyotrophic lateral sclerosis include neuropsychiatric phenomena as core diagnostic criteria. There are no disease-specific neuropsychiatric symptoms; apathy and disinhibition are common in tauopathies, and rapid-eye-movement sleep behavioral disorder occurs almost exclusively in synucleinopathies. Neuropsychiatric symptoms and syndromes are increasingly integrated into research diagnostic criteria for neurodegenerative disorders; they require clinician skills for recognition; their biology is better understood as their relationships to cognitive, motor, and autonomic symptoms of neurodegenerative disorders are studied.}, }
@article {pmid32819425, year = {2020}, author = {Ng Kee Kwong, KC and Mehta, AR and Nedergaard, M and Chandran, S}, title = {Defining novel functions for cerebrospinal fluid in ALS pathophysiology.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {140}, pmid = {32819425}, issn = {2051-5960}, support = {MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; RF1 NS110049/NS/NINDS NIH HHS/United States ; MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS100366/NS/NINDS NIH HHS/United States ; RF1 AG057575/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/*physiopathology ; Animals ; Humans ; }, abstract = {Despite the considerable progress made towards understanding ALS pathophysiology, several key features of ALS remain unexplained, from its aetiology to its epidemiological aspects. The glymphatic system, which has recently been recognised as a major clearance pathway for the brain, has received considerable attention in several neurological conditions, particularly Alzheimer's disease. Its significance in ALS has, however, been little addressed. This perspective article therefore aims to assess the possibility of CSF contribution in ALS by considering various lines of evidence, including the abnormal composition of ALS-CSF, its toxicity and the evidence for impaired CSF dynamics in ALS patients. We also describe a potential role for CSF circulation in determining disease spread as well as the importance of CSF dynamics in ALS neurotherapeutics. We propose that a CSF model could potentially offer additional avenues to explore currently unexplained features of ALS, ultimately leading to new treatment options for people with ALS.}, }
@article {pmid32817118, year = {2020}, author = {Santoso, JW and McCain, ML}, title = {Neuromuscular disease modeling on a chip.}, journal = {Disease models &amp; mechanisms}, volume = {13}, number = {7}, pages = {}, pmid = {32817118}, issn = {1754-8411}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Cell Culture Techniques ; Cells, Cultured ; Humans ; Induced Pluripotent Stem Cells/*metabolism/pathology ; *Lab-On-A-Chip Devices ; Microfluidic Analytical Techniques/*instrumentation ; Motor Neurons/*metabolism/pathology ; Muscle, Skeletal/*innervation ; Neural Stem Cells/*metabolism/pathology ; *Tissue Engineering ; }, abstract = {Organs-on-chips are broadly defined as microfabricated surfaces or devices designed to engineer cells into microscale tissues with native-like features and then extract physiologically relevant readouts at scale. Because they are generally compatible with patient-derived cells, these technologies can address many of the human relevance limitations of animal models. As a result, organs-on-chips have emerged as a promising new paradigm for patient-specific disease modeling and drug development. Because neuromuscular diseases span a broad range of rare conditions with diverse etiology and complex pathophysiology, they have been especially challenging to model in animals and thus are well suited for organ-on-chip approaches. In this Review, we first briefly summarize the challenges in neuromuscular disease modeling with animal models. Next, we describe a variety of existing organ-on-chip approaches for neuromuscular tissues, including a survey of cell sources for both muscle and nerve, and two- and three-dimensional neuromuscular tissue-engineering techniques. Although researchers have made tremendous advances in modeling neuromuscular diseases on a chip, the remaining challenges in cell sourcing, cell maturity, tissue assembly and readout capabilities limit their integration into the drug development pipeline today. However, as the field advances, models of healthy and diseased neuromuscular tissues on a chip, coupled with animal models, have vast potential as complementary tools for modeling multiple aspects of neuromuscular diseases and identifying new therapeutic strategies.}, }
@article {pmid32815157, year = {2021}, author = {Kukharsky, MS and Skvortsova, VI and Bachurin, SO and Buchman, VL}, title = {In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches.}, journal = {Medicinal research reviews}, volume = {41}, number = {5}, pages = {2804-2822}, doi = {10.1002/med.21725}, pmid = {32815157}, issn = {1098-1128}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Pharmaceutical Preparations ; }, abstract = {Recent progress in understanding the pathological changes in the nervous system and in certain other body systems (e.g., immune system) that lead to the development and progression of amyotrophic lateral sclerosis (ALS) revealed a number of molecular and cellular processes that can potentially be used as therapeutic targets. Many of these processes are compromised not only in ALS but also in other diseases and a repertoire of drugs able to restore, at least partially, their functionality has been developed. In this review, we briefly describe current approaches to the repurposing of such "old" drugs for treatment of patients with ALS.}, }
@article {pmid32814257, year = {2020}, author = {Jamerlan, A and An, SSA}, title = {The influence of Aβ-dependent and independent pathways on TDP-43 proteinopathy in Alzheimer's disease: a possible connection to LATE-NC.}, journal = {Neurobiology of aging}, volume = {95}, number = {}, pages = {161-167}, doi = {10.1016/j.neurobiolaging.2020.06.020}, pmid = {32814257}, issn = {1558-1497}, mesh = {Alzheimer Disease/*etiology ; Amyloid beta-Peptides/*metabolism ; Amyotrophic Lateral Sclerosis/etiology ; Animals ; Brain Diseases/*etiology ; Comorbidity ; DNA-Binding Proteins/*metabolism ; Disease Progression ; Humans ; Mice ; Peptide Fragments/*metabolism ; Phosphorylation ; TDP-43 Proteinopathies/*etiology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results from the accumulation of plaques by cleaved Aβ42 peptides as well as neurofibrillary tangles of tau proteins. This accumulation triggers a complex cascade of cytotoxic, neuroinflammatory, and oxidative stresses that lead to neuronal death throughout the progression of the disease. Much of research in AD focused on the 2 pathologic proteins. Interestingly, another form of dementia with similar clinical manifestations of AD, but preferentially affected much older individuals, was termed as limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) and involved the cytotoxic intraneuronal deposition of phosphorylated TDP-43. TDP-43 proteinopathy was also found to be involved in AD pathology leading to the possibility that AD and LATE may share a common upstream etiology. This paper discusses the roles molecular pathways known in AD may have on influencing TDP-43 proteinopathy and the development of AD, LATE, or the 2 being comorbid with each other.}, }
@article {pmid32811540, year = {2020}, author = {Furukawa, Y and Tokuda, E}, title = {Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?.}, journal = {Translational neurodegeneration}, volume = {9}, number = {1}, pages = {33}, pmid = {32811540}, issn = {2047-9158}, support = {16H04768//Japan Society for the Promotion of Science/International ; 19H05765//Japan Society for the Promotion of Science/International ; Not applicable//Pharmacological Research Foundation (JP)/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/*pathology ; Animals ; Extracellular Fluid/enzymology ; Humans ; Motor Neurons/enzymology/pathology ; *Protein Folding ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.}, }
@article {pmid32806490, year = {2020}, author = {Khan, A and Jahan, S and Imtiyaz, Z and Alshahrani, S and Antar Makeen, H and Mohammed Alshehri, B and Kumar, A and Arafah, A and Rehman, MU}, title = {Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals.}, journal = {Biomedicines}, volume = {8}, number = {8}, pages = {}, pmid = {32806490}, issn = {2227-9059}, abstract = {With the increase in the expectancy of the life span of humans, neurodegenerative diseases (NDs) have imposed a considerable burden on the family, society, and nation. In defiance of the breakthroughs in the knowledge of the pathogenesis and underlying mechanisms of various NDs, very little success has been achieved in developing effective therapies. This review draws a bead on the availability of the nutraceuticals to date for various NDs (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, vascular cognitive impairment, Prion disease, Spinocerebellar ataxia, Spinal muscular atrophy, Frontotemporal dementia, and Pick's disease) focusing on their various mechanisms of action in various in vivo and in vitro models of NDs. This review is distinctive in its compilation to critically review preclinical and clinical studies of the maximum phytochemicals in amelioration and prevention of almost all kinds of neurodegenerative diseases and address their possible mechanism of action. PubMed, Embase, and Cochrane Library searches were used for preclinical studies, while ClinicalTrials.gov and PubMed were searched for clinical updates. The results from preclinical studies demonstrate the efficacious effects of the phytochemicals in various NDs while clinical reports showing mixed results with promise for phytochemical use as an adjunct to the conventional treatment in various NDs. These studies together suggest that phytochemicals can significantly act upon different mechanisms of disease such as oxidative stress, inflammation, apoptotic pathways, and gene regulation. However, further clinical studies are needed that should include the appropriate biomarkers of NDs and the effect of phytochemicals on them as well as targeting the appropriate population.}, }
@article {pmid32805742, year = {2021}, author = {Özdinler, PH}, title = {Expanded access: opening doors to personalized medicine for rare disease patients and patients with neurodegenerative diseases.}, journal = {The FEBS journal}, volume = {288}, number = {5}, pages = {1457-1461}, pmid = {32805742}, issn = {1742-4658}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Autophagy/drug effects ; Cerebral Cortex/drug effects/metabolism/pathology ; Drug Repositioning/methods ; Drugs, Investigational/*therapeutic use ; Health Services Accessibility/organization &amp; administration ; Humans ; Inflammation ; Mitochondria/drug effects/metabolism/pathology ; Neurons/drug effects/metabolism/pathology ; Parkinson Disease/*drug therapy/metabolism/pathology ; Precision Medicine/*trends ; Rare Diseases/*drug therapy/metabolism/pathology ; Unfolded Protein Response/drug effects ; }, abstract = {In neurodegenerative diseases, a select set of neuron population displays early vulnerability and undergoes progressive degeneration. The heterogeneity of the cerebral cortex and the heterogeneity of patient populations diagnosed with the same disease offer many challenges for developing effective and long-term treatment options. Currently, patients who are considered to have a 'rare' disease are left with no hopes for cure, and many of the neurodegenerative diseases progress fast without any effective solutions. However, as our understanding of disease mechanisms evolve, we begin to realize that the boundaries between diseases are not as sharp as once believed. There are many patients who develop disease due to common underlying causes and mechanisms. As we move forward with drug discovery effort, it becomes obvious that we will have to shift our focus from finding a cure for a disease, to finding solutions to the disease-causing cellular mechanisms so that patients can be treated by mechanism-based strategies. This paradigm shift will lay the foundation for personalized medicine approaches for neurodegenerative disease patients and patients diagnosed with a rare disease.}, }
@article {pmid32803397, year = {2021}, author = {Gagliardi, D and Bresolin, N and Comi, GP and Corti, S}, title = {Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {78}, number = {2}, pages = {561-572}, pmid = {32803397}, issn = {1420-9071}, support = {RF-2018-12366357//Italian Ministry of Health/ ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/metabolism/*pathology ; Animals ; Biomarkers/metabolism ; Extracellular Vesicles/metabolism/*pathology ; Humans ; Protein Folding ; Proteins/metabolism ; RNA/metabolism ; }, abstract = {Extracellular vesicles (EVs) are small reservoirs of different molecules and important mediators of cell-to-cell communication. As putative vehicles of misfolded protein propagation between cells, they have drawn substantial attention in the field of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Moreover, exosome-mediated non-coding RNA delivery may play a crucial role in ALS, given the relevance of RNA homeostasis in disease pathogenesis. Since EVs can enter the systemic circulation and are easily detectable in patients' biological fluids, they have generated broad interest both as diagnostic and prognostic biomarkers and as valuable tools in understanding disease pathogenesis. Here, after a brief introduction on biogenesis and functions of EVs, we aim to investigate their role in neurodegenerative disorders, especially ALS. Specifically, we focus on the main findings supporting EV-mediated protein and RNA transmission in ALS in vitro and in vivo models. Then, we provide an overview of clinical applications of EVs, summarizing the most relevant studies able to detect EVs in blood and cerebrospinal fluid (CSF) of ALS patients, underlying their potential use in aiding diagnosis and prognosis. Finally, we explore the therapeutic applications of EVs in ALS, either as targets or as vehicles of proteins, nucleic acids and molecular drugs.}, }
@article {pmid32800276, year = {2020}, author = {Shariati, A and Nemati, R and Sadeghipour, Y and Yaghoubi, Y and Baghbani, R and Javidi, K and Zamani, M and Hassanzadeh, A}, title = {Mesenchymal stromal cells (MSCs) for neurodegenerative disease: A promising frontier.}, journal = {European journal of cell biology}, volume = {99}, number = {6}, pages = {151097}, doi = {10.1016/j.ejcb.2020.151097}, pmid = {32800276}, issn = {1618-1298}, mesh = {Cell- and Tissue-Based Therapy/*methods ; Humans ; Mesenchymal Stem Cells/*metabolism ; Neurodegenerative Diseases/physiopathology/*therapy ; }, abstract = {Neurodegenerative disorders are a variety of diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) along with some other less common diseases generally described by the advanced deterioration of central or peripheral nervous system, structurally or functionally. In the last two decades, mesenchymal stromal cells (MSCs) due to their unique assets encompassing self-renewal, multipotency and accessibility in association with low ethical concern open new frontiers in the context of neurodegenerative diseases therapy. Interestingly, MSCs can be differentiated into endodermal and ectodermal lineages (e.g., neurons, oligodendrocyte, and astrocyte), and thus could be employed to advance cell-based therapeutic strategy. Additionally, as inflammation ordinarily ensues as a local response provoked by microglia in the neurodegenerative diseases, MSCs therapy because of their pronounced immunomodulatory properties is noticed as a rational approach for their treatment. Recently, varied types of studies have been mostly carried out in vitro and rodent models using MSCs upon their procurement from various sources and expansion. The promising results of the studies in rodent models have motivated researchers to design and perform several clinical trials, with a speedily rising number. In the current review, we aim to deliver a brief overview of MSCs sources, expansion strategies, and their immunosuppressive characteristics and discuss credible functional mechanisms exerted by MSCs to treat neurodegenerative disorders, covering AD, PD, ALS, MS, and HD.}, }
@article {pmid32799899, year = {2020}, author = {Suk, TR and Rousseaux, MWC}, title = {The role of TDP-43 mislocalization in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {45}, pmid = {32799899}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; DNA-Binding Proteins/*metabolism ; Humans ; TDP-43 Proteinopathies/*pathology ; }, abstract = {Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gain- and loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclear-to-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain- and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain- and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.}, }
@article {pmid32799578, year = {2020}, author = {Martins, AC and Gubert, P and Villas Boas, GR and Meirelles Paes, M and Santamaría, A and Lee, E and Tinkov, AA and Bowman, AB and Aschner, M}, title = {Manganese-induced neurodegenerative diseases and possible therapeutic approaches.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {11}, pages = {1109-1121}, pmid = {32799578}, issn = {1744-8360}, support = {R01 ES007331/ES/NIEHS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; R01 ES024756/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Manganese/*toxicity ; Neurodegenerative Diseases/*chemically induced/*drug therapy ; }, abstract = {INTRODUCTION: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion disease represent important public health concerns. Exposure to high levels of heavy metals such as manganese (Mn) may contribute to their development.<br><br>AREAS COVERED: In this critical review, we address the role of Mn in the etiology of neurodegenerative diseases and discuss emerging treatments of Mn overload, such as chelation therapy. In addition, we discuss natural and synthetic compounds under development as prospective therapeutics. Moreover, bioinformatic approaches to identify new potential targets and therapeutic substances to reverse the neurodegenerative diseases are discussed.<br><br>EXPERT OPINION: Here, the authors highlight the importance of better understanding the molecular mechanisms of toxicity associated with neurodegenerative diseases, and the role of Mn in these diseases. Additional emphasis should be directed to the discovery of new agents to treat Mn-induced diseases, since present day chelator therapies have limited bioavailability. Furthermore, the authors encourage the scientific community to develop research using libraries of compounds to screen those compounds that show efficacy in regulating brain Mn levels. In addition, bioinformatics may provide novel insight for pathways and clinical treatments associated with Mn-induced neurodegeneration, leading to a new direction in Mn toxicological research.}, }
@article {pmid32799572, year = {2020}, author = {Clark, JN and Whiting, A and McCaffery, P}, title = {Retinoic acid receptor-targeted drugs in neurodegenerative disease.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {16}, number = {11}, pages = {1097-1108}, doi = {10.1080/17425255.2020.1811232}, pmid = {32799572}, issn = {1744-7607}, mesh = {Animals ; Brain/drug effects/physiopathology ; Humans ; Ligands ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Protein Binding ; Receptors, Retinoic Acid/*drug effects/metabolism ; Retinoids/administration &amp; dosage/*pharmacology ; Signal Transduction/drug effects ; }, abstract = {INTRODUCTION: Neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by progressive neuronal loss and currently lack effective treatments that block the degenerative process. It has been suggested that retinoids, a class of vitamin A-derived compounds, may hold potential as future therapeutics for these disorders.<br><br>AREAS COVERED: In this review, we explore the role of retinoids in modulating various signaling pathways in the brain which influence pathologically relevant processes such as cellular differentiation, immune and antioxidant response, neurite outgrowth and neurite regeneration. These actions are predominantly mediated by the retinoic acid receptors and we discuss the developmental history of ligands for these receptors, assessing how refinements in receptor binding specificity and improved pharmacokinetic properties may influence the management of off-target effects.<br><br>EXPERT OPINION: New approaches to understanding retinoid's mechanisms of action, including non-genomic pathways, and how these mechanisms interact may prove vital in the development of future retinoid-based neurodegenerative disease treatments.}, }
@article {pmid32797289, year = {2021}, author = {Romero-Gangonells, E and Virgili-Casas, MN and Dominguez-Rubio, R and Povedano, M and Pérez-Saborit, N and Calvo-Malvar, N and Barceló, MA}, title = {Evaluation of Dysphagia in Motor Neuron Disease. Review of Available Diagnostic Tools and New Perspectives.}, journal = {Dysphagia}, volume = {36}, number = {4}, pages = {558-573}, pmid = {32797289}, issn = {1432-0460}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *Deglutition Disorders/diagnosis/etiology ; Humans ; *Motor Neuron Disease/complications/diagnosis ; Sensitivity and Specificity ; Surveys and Questionnaires ; }, abstract = {Oropharyngeal dysphagia (OD) is highly prevalent (up to 80%) in patients with motor neuron disease (MND), influencing the prognosis of the disease. The clinical assessment of dysphagia is complex. There are assessment scales and screening questionnaires, but they have not been tested in patients with MND. In a sample of 46 patients with MND, the sensitivity and specificity of the EAT-10 and SwalQoL questionnaires, as well as the ALS-SS and FOIS scales, were tested and compared to the gold standard technique (videofluoroscopy, VFS). The patients were stratified using the DOSSc variable according to the video fluoroscopic examination with (n = 37) or without (n = 8) signs of dysphagia, and the results were compared with the scores obtained in the dysphagia questionnaires. None of the studied questionnaires was more sensitive than the others, but one stood out for its high specificity (= 1): the SwalQoL revised FS. The symptom frequency section of the SwalQoL questionnaire with some modifications, (SwalQoL revised FS) may be a useful tool in the clinical assessment of dysphagia because it's capable to detect the patients that really don't have dysphagia. The ALS-SS showed the greatest validity as a severity scale of dysphagia among the sample studied. A specific questionnaire for screening for dysphagia in MND needs to be developed. Until that time, the proposal is to use a combination of the existing questionnaires for other pathologies (EAT-10 and SwalQoL) and the specific scale for MND, the ALS-SS, to make an accurately clinical assessment of OD in MND patients before to perform a videofluoroscopy.}, }
@article {pmid32795164, year = {2020}, author = {Vasques, JF and Mendez-Otero, R and Gubert, F}, title = {Modeling ALS using iPSCs: is it possible to reproduce the phenotypic variations observed in patients in vitro?.}, journal = {Regenerative medicine}, volume = {15}, number = {7}, pages = {1919-1933}, doi = {10.2217/rme-2020-0067}, pmid = {32795164}, issn = {1746-076X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; *Biological Variation, Population ; Cell- and Tissue-Based Therapy/*methods ; DNA-Binding Proteins/*genetics ; Humans ; In Vitro Techniques ; Induced Pluripotent Stem Cells/*cytology ; Models, Biological ; *Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that leads to progressive degeneration of motoneurons. Mutations in the C9ORF72, SOD1, TARDBP and FUS genes, among others, have been associated with ALS. Although motoneuron degeneration is the common outcome of ALS, different pathological mechanisms seem to be involved in this process, depending on the genotypic background of the patient. The advent of induced pluripotent stem cell (iPSC) technology enabled the development of patient-specific cell lines, from which it is possible to generate different cell types and search for phenotypic alterations. In this review, we summarize the pathophysiological markers detected in cells differentiated from iPSCs of ALS patients. In a translational perspective, iPSCs from ALS patients could be useful for drug screening, through stratifying patients according to their genetic background.}, }
@article {pmid32794552, year = {2020}, author = {Wright, GSA}, title = {Molecular and pharmacological chaperones for SOD1.}, journal = {Biochemical Society transactions}, volume = {48}, number = {4}, pages = {1795-1806}, pmid = {32794552}, issn = {1470-8752}, mesh = {Animals ; Copper/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Macrophage Migration-Inhibitory Factors/metabolism ; Molecular Chaperones/*metabolism ; Mutation ; Protein Folding ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.}, }
@article {pmid32792920, year = {2020}, author = {Guan, Y and Han, F}, title = {Key Mechanisms and Potential Targets of the NLRP3 Inflammasome in Neurodegenerative Diseases.}, journal = {Frontiers in integrative neuroscience}, volume = {14}, number = {}, pages = {37}, pmid = {32792920}, issn = {1662-5145}, abstract = {Neurodegenerative diseases are neuronal disorders characterized by the loss of a large number of neurons in the human brain. Innate immunity-mediated neuroinflammation actively contributes to the onset and progression of neurodegenerative diseases. Inflammasomes are involved in the progression of the innate immune response and are responsible for the maturation of caspase-1 and inflammatory cytokines during neuroinflammation. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is one of the most intensively investigated inflammasomes, has been reported to play a key role in neurodegenerative diseases. Here, we reviewed the mechanisms, role, and latest developments regarding the NLRP3 inflammasome with respect to three neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Patient and animal model studies have found that abnormal protein aggregation of Aβ, synuclein, or copper-zinc superoxide dismutase-1 (SOD1), which are the main proteins expressed in the three diseases, respectively, can activate microglial cells, induce increased interleukin-1β (IL-1β) release, and activate the NLRP3 pathway, leading to neurodegeneration. In contrast, a deficiency of the components of the NLRP3 pathway may inhibit Aβ, synuclein, or SOD1-induced microglial activation. These studies indicate a positive correlation between NLRP3 levels and abnormal protein aggregation. However, in the case of ALS, not only microglia but also astrocytes express increased NLRP3 levels and contribute to activation of the NLRP3 pathway. In addition, in this review article, we also focus on the therapeutic implications of targeting novel inhibitors of the NLRP3 inflammasome or of novel drugs that mediate the NLRP3 pathway, which could play a role via NLRP3 in the treatment of neurodegenerative diseases.}, }
@article {pmid32791113, year = {2020}, author = {Fang, P and Kazmi, SA and Jameson, KG and Hsiao, EY}, title = {The Microbiome as a Modifier of Neurodegenerative Disease Risk.}, journal = {Cell host &amp; microbe}, volume = {28}, number = {2}, pages = {201-222}, pmid = {32791113}, issn = {1934-6069}, support = {DP5 OD017924/OD/NIH HHS/United States ; F31 MH090749/MH/NIMH NIH HHS/United States ; R01 NS115537/NS/NINDS NIH HHS/United States ; T32 GM007185/GM/NIGMS NIH HHS/United States ; }, mesh = {Aging/*physiology ; Alzheimer Disease/microbiology ; Amyotrophic Lateral Sclerosis/microbiology ; Animals ; Central Nervous System/pathology ; Cognitive Dysfunction/*pathology ; Disease Models, Animal ; Gastrointestinal Microbiome/*physiology ; Humans ; Huntington Disease/microbiology ; Mice ; Neurodegenerative Diseases/*microbiology/*pathology ; Parkinson Disease/microbiology ; Peripheral Nervous System/pathology ; }, abstract = {The gut microbiome is increasingly implicated in modifying susceptibility to and progression of neurodegenerative diseases (NDs). In this review, we discuss roles for the microbiome in aging and in NDs. In particular, we summarize findings from human studies on microbiome alterations in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We assess animal studies of genetic and environmental models for NDs that investigate how manipulations of the microbiome causally impact the development of behavioral and neuropathological endophenotypes of disease. We additionally evaluate the likely immunological, neuronal, and metabolic mechanisms for how the gut microbiota may modulate risk for NDs. Finally, we speculate on cross-cutting features for microbial influences across multiple NDs and consider the potential for microbiome-targeted interventions for NDs.}, }
@article {pmid32787753, year = {2021}, author = {Shakkour, Z and Issa, H and Ismail, H and Ashekyan, O and Habashy, KJ and Nasrallah, L and Jourdi, H and Hamade, E and Mondello, S and Sabra, M and Zibara, K and Kobeissy, F}, title = {Drug Repurposing: Promises of Edaravone Target Drug in Traumatic Brain Injury.}, journal = {Current medicinal chemistry}, volume = {28}, number = {12}, pages = {2369-2391}, doi = {10.2174/0929867327666200812221022}, pmid = {32787753}, issn = {1875-533X}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Brain Injuries, Traumatic ; Drug Repositioning ; Edaravone ; Free Radical Scavengers/therapeutic use ; Humans ; *Neuroprotective Agents/therapeutic use ; *Pharmaceutical Preparations ; }, abstract = {Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on proinflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.}, }
@article {pmid32784556, year = {2020}, author = {Chen, D and Zhang, T and Lee, TH}, title = {Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {10}, number = {8}, pages = {}, pmid = {32784556}, issn = {2218-273X}, support = {81901071//National Natural Science Foundation of China/International ; 81970993//National Natural Science Foundation of China/International ; 2019J01297//Natural Science Foundation of Fujian Province/International ; 2019J05072//Natural Science Foundation of Fujian Province/International ; 2019-CX-36//Medical Innovation Grant of Fujian Province/International ; XRCZX2017007//Fujian Medical University/International ; XRCZX2017019//Fujian Medical University/International ; }, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; *Circadian Rhythm/drug effects ; Dementia, Vascular/metabolism ; Humans ; Huntington Disease/metabolism ; Melatonin/*physiology/therapeutic use ; Multiple Sclerosis/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; *Oxidative Stress/drug effects ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.}, }
@article {pmid32781742, year = {2020}, author = {Ruz, C and Alcantud, JL and Vives Montero, F and Duran, R and Bandres-Ciga, S}, title = {Proteotoxicity and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {16}, pages = {}, pmid = {32781742}, issn = {1422-0067}, support = {FPU14/03473//Spanish Ministry of Education and Science/ ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/drug therapy/*pathology ; Protein Aggregates ; Proteins/*toxicity ; }, abstract = {Neurodegenerative diseases are a major burden for our society, affecting millions of people worldwide. A main goal of past and current research is to enhance our understanding of the mechanisms underlying proteotoxicity, a common theme among these incurable and debilitating conditions. Cell proteome alteration is considered to be one of the main driving forces that triggers neurodegeneration, and unraveling the biological complexity behind the affected molecular pathways constitutes a daunting challenge. This review summarizes the current state on key processes that lead to cellular proteotoxicity in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, providing a comprehensive landscape of recent literature. A foundational understanding of how proteotoxicity affects disease etiology and progression may provide essential insight towards potential targets amenable of therapeutic intervention.}, }
@article {pmid32772223, year = {2020}, author = {Palermo, G and Mazzucchi, S and Della Vecchia, A and Siciliano, G and Bonuccelli, U and Azuar, C and Ceravolo, R and Lista, S and Hampel, H and Baldacci, F}, title = {Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {57}, number = {11}, pages = {4667-4691}, doi = {10.1007/s12035-020-02035-9}, pmid = {32772223}, issn = {1559-1182}, mesh = {Animals ; Biomarkers/blood ; Humans ; Mass Screening ; Neurodegenerative Diseases/*blood/diagnosis ; Neurofilament Proteins/*blood ; Prognosis ; Risk Factors ; }, abstract = {One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).}, }
@article {pmid32768089, year = {2020}, author = {Weimer, LH}, title = {Neuromuscular disorders in pregnancy.}, journal = {Handbook of clinical neurology}, volume = {172}, number = {}, pages = {201-218}, pmid = {32768089}, issn = {0072-9752}, mesh = {Animals ; Cesarean Section ; Female ; Humans ; *Muscular Diseases ; *Myasthenia Gravis ; *Neuromuscular Diseases/epidemiology/therapy ; Pregnancy ; *Pregnancy Complications/epidemiology/therapy ; Retrospective Studies ; }, abstract = {Many neuromuscular disorders preexist or occur during pregnancy. In some cases, pregnancy unmasks a latent hereditary disorder. Most available information is based on case reports or series or retrospective clinical experience or patient surveys. Of special interest are pregnancy-induced changes in disease course or severity and likelihood for baseline recovery of function postpartum. Labor and delivery present special challenges in many conditions that affect skeletal but not smooth (uterine) muscle; so labor complications must be anticipated. Anesthesia for cesarean section surgery requires special precautions in many disorders. The types of conditions reviewed are broad and include examples of autoimmune, hereditary, and compressive/mechanical processes. Disorders include carpal tunnel syndrome and other focal neuropathies, Bell palsy, myasthenia gravis, and other neuromuscular junction disorders, acute and chronic inflammatory neuropathy, hereditary and acquired muscle diseases, spinal muscular atrophy, amyotrophic lateral sclerosis, channelopathies, autonomic neuropathy, and dysautonomia. Many commonly used therapies have fetal animal but no proven human toxicity concerns, complicating treatment and risk decisions. Weaning off effective therapeutic agents or preemptive aggressive treatment or surgery prior to planned pregnancy is an option in some conditions.}, }
@article {pmid32765151, year = {2020}, author = {Spencer, PS}, title = {Etiology of Retinal and Cerebellar Pathology in Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex.}, journal = {Eye and brain}, volume = {12}, number = {}, pages = {97-104}, pmid = {32765151}, issn = {1179-2744}, abstract = {PURPOSE: To reexamine the etiology of a unique retinal pathology (linear and vermiform sub-retinal tubular structures) described among subjects with and without neurodegenerative disease in former high-incidence foci of Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in Guam (USA) and the Kii peninsula of Honshu island (Japan).<br><br>METHODS: Analysis of published and unpublished reports of 1) ALS/PDC and the retinal and cerebellar pathology associated therewith and 2) exogenous neurotoxic factors associated with ALS/PDC and the developing retina and cerebellum.<br><br>RESULTS: ALS/PDC retinal and cerebellar pathology matches persistent retinal and cerebellar dysplasia found in laboratory animals given single in utero or postnatal systemic treatment with cycasin, the principal neurotoxic component in the seed of cycad plants traditionally used for food (Guam) or oral medicine (Kii-Japan), both of which have been linked to the human neurodegenerative disease.<br><br>CONCLUSION: ALS/PDC-associated retinal and cerebellar dysplasia could arise from in utero exposure to methylazoxymethanol, the genotoxic metabolite of cycasin that results from maternal ingestion of this azoxyglucoside. These results support the environmental toxic etiology of retinal and brain pathology in ALS/PDC.}, }
@article {pmid32765149, year = {2020}, author = {Tsokolas, G and Tsaousis, KT and Diakonis, VF and Matsou, A and Tyradellis, S}, title = {Optical Coherence Tomography Angiography in Neurodegenerative Diseases: A Review.}, journal = {Eye and brain}, volume = {12}, number = {}, pages = {73-87}, pmid = {32765149}, issn = {1179-2744}, abstract = {BACKGROUND: Optical coherence tomography angiography (OCT-A) has emerged as a novel, fast, safe and non-invasive imaging technique of analyzing the retinal and choroidal microvasculature in vivo. OCT-A captures multiple sequential B-scans performed repeatedly over a specific retinal area at high speed, thus enabling the composition of a vascular map with areas of contrast change (high flow zones) and areas of steady contrast (slow or no flow zones). It therefore provides unique insight into the exact retinal or choroidal layer and location at which abnormal blood flow develops. OCTA has evolved into a useful tool for understanding a number of retinal pathologies such as diabetic retinopathy, age-related macular degeneration, central serous chorioretinopathy, vascular occlusions, macular telangiectasia and choroidal neovascular membranes of other causes. OCT-A technology is also increasingly being used in the evaluation of optic disc perfusion and has been suggested as a valuable tool in the early detection of glaucomatous damage and monitoring progression.<br><br>OBJECTIVE: To review the existing literature on the applications of optical coherence tomography angiography in neurodegenerative diseases.<br><br>SUMMARY: A meticulous literature was performed until the present day. Google Scholar, PubMed, Mendeley search engines were used for this purpose. We used 123 published manuscripts as our references. OCT-A has been utilized so far to describe abnormalities in multiple sclerosis (MS), Alzheimer's disease, arteritic and non-arteritic optic neuropathy (AION and NAION), Leber's hereditary optic neuropathy (LHON) papilloedema, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Wolfram syndrome, migraines, lesions of the visual pathway and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). It appears that OCT-A findings correlate quite well with the severity of the aforementioned diseases. However, OCT-A has its own limitations, namely its lack of wide-field view of the peripheral retina and the inaccurate interpretation due to motion artifacts in uncooperative groups of patients (e.g. children). Larger prospective longitudinal studies will need to be conducted in order to eliminate the aforementioned limitations.}, }
@article {pmid32763509, year = {2020}, author = {Richards, D and Morren, JA and Pioro, EP}, title = {Time to diagnosis and factors affecting diagnostic delay in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {417}, number = {}, pages = {117054}, doi = {10.1016/j.jns.2020.117054}, pmid = {32763509}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Canada ; *Delayed Diagnosis ; Egypt ; Europe ; Humans ; Japan ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease with limited treatment options. The diagnosis of ALS can be challenging for numerous reasons, resulting in delays that may compromise optimal management and enrollment into clinical trials. Several studies have examined the process and challenges regarding the clinical diagnosis of ALS. Twenty-one studies that were almost exclusively from the English literature published between 1990 and 2020 were identified via PubMed using relevant search terms and included patient populations from the United States, Canada, Japan, Egypt, and several countries in South America and Europe. Probable or definitive ALS patients were identified using El Escorial or revised El Escorial/Airlie House Criteria. Time to diagnosis or diagnostic delay was defined as mean or median time from patient-reported first symptom onset to formal diagnosis by a physician, as recorded in medical records. The typical time to diagnosis was 10-16 months from symptom onset. Several points of delay in the diagnosis course were identified, including specialist referrals and misdiagnoses, often resulting in unnecessary procedures and surgeries. Bulbar onset was noted to significantly reduce time to ALS diagnosis. Future interventions and potential research opportunities were reviewed.}, }
@article {pmid32763254, year = {2020}, author = {Desai, P and Bandopadhyay, R}, title = {Pathophysiological implications of RNP granules in frontotemporal dementia and ALS.}, journal = {Neurochemistry international}, volume = {140}, number = {}, pages = {104819}, doi = {10.1016/j.neuint.2020.104819}, pmid = {32763254}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*physiopathology ; Animals ; Brain/metabolism/physiopathology ; Frontotemporal Dementia/*metabolism/*physiopathology ; Humans ; Oxidative Stress/physiology ; Ribonucleoproteins/*metabolism ; }, abstract = {Neurodegenerative diseases are a group of chronic, progressive, age-related disorders that are becoming increasingly prevalent in the ageing population. Despite the variety of clinical features observed, neurodegenerative diseases are characterised by protein aggregation and deposition at the molecular level. The nature of such intracellular protein aggregates is dependent on disease type and specific to disease subtype. Frontotemporal dementia and amyotrophic lateral sclerosis (ALS) are two overlapping neurodegenerative diseases, exhibiting pathological aggregates commonly composed of the proteins: Fused in Sarcoma (FUS) or Transactive Response DNA Binding Protein of 43 KDa (TDP-43). The presence of these protein aggregates in late disease stages is suggestive of a converging underlying mechanism of pathology across diseases involving disrupted proteostasis. Despite this, at present there are no effective therapeutics for the diseases, with current treatment strategies generally tending to be only for symptom management. An area of research that has gained increased interest in recent years is the formation and maintenance of ribonucleoprotein (RNP) granules. These are membraneless organelles that consist of RNA and protein elements, which can be either constitutively expressed (such as nuclear paraspeckles) or upregulated under conditions of cellular stress as an adaptive response (such as cytoplasmic stress granules). RNA-binding proteins are a key component of RNP granules, and crucially some of which, for example FUS and TDP-43, are also neurodegenerative disease-associated proteins. Therefore, a better understanding of RNA-binding proteins in RNP granule formation and the regulation and maintenance of RNP granule biophysical properties and dynamics may provide insights into mechanisms contributing to disrupted proteostasis in neurodegenerative pathology; and thus open up new avenues for therapeutic discovery and development. This review will focus on stress granule and paraspeckle RNP granules, and discuss their possible contribution to pathology in cases of frontotemporal dementia and ALS.}, }
@article {pmid32761823, year = {2021}, author = {Herrando-Grabulosa, M and Gaja-Capdevila, N and Vela, JM and Navarro, X}, title = {Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1336-1352}, doi = {10.1111/bph.15224}, pmid = {32761823}, issn = {1476-5381}, support = {TERCEL (RD16/0011/0014)//Instituto de Salud Carlos III of Spain/ ; CIBERNED (CB06/05/1105)//Instituto de Salud Carlos III of Spain/ ; RTI2018-096386-B-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades of Spain/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; Humans ; Mitochondria ; Motor Neurons/metabolism ; *Receptors, sigma/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult disease causing a progressive loss of upper and lower motoneurons, muscle paralysis and early death. ALS has a poor prognosis of 3-5 years after diagnosis with no effective cure. The aetiopathogenic mechanisms involved include glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial alterations, disrupted axonal transport and inflammation. Sigma non-opioid intracellular receptor 1 (sigma 1 receptor) is a protein expressed in motoneurons, mainly found in the endoplasmic reticulum (ER) on the mitochondria-associated ER membrane (MAM) or in close contact with cholinergic postsynaptic sites. MAMs are sites that allow the assembly of several complexes implicated in essential survival cell functions. The sigma 1 receptor modulates essential mechanisms for motoneuron survival including excitotoxicity, calcium homeostasis, ER stress and mitochondrial dysfunction. This review updates sigma 1 receptor mechanisms and its alterations in ALS, focusing on MAM modulation, which may constitute a novel target for therapeutic strategies. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32761605, year = {2020}, author = {Ni, J and Wang, J}, title = {[Mitochondrial genome variants and neurodegenerative diseases].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {37}, number = {8}, pages = {898-902}, doi = {10.3760/cma.j.issn.1003-9406.2020.08.023}, pmid = {32761605}, issn = {1003-9406}, mesh = {*Alzheimer Disease/genetics ; DNA Copy Number Variations ; *Genome, Mitochondrial ; Humans ; *Neurodegenerative Diseases/genetics ; *Parkinson Disease/genetics ; }, abstract = {Neurodegenerative diseases are a group of diseases characterized by chronic progressive damage to tissues of central nervous system and peripheral nervous system, which include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, etc. The etiology is mainly related to factors such as aging, genetics and environment. More and more evidence indicate that mitochondrial dysfunction plays a vital role in the pathogenesis of neurodegenerative diseases. Variants of mitochondrial genes, including point variants, deletions, and copy number variations, have been recognized as important factors modulating genetic susceptibility to such diseases. This paper has reviewed recent studies for the influence of mitochondrial variants on the pathogenesis of neurodegenerative diseases, in order to provide clues for the pathogenesis, diagnosis and development of new drugs for such disorders.}, }
@article {pmid32760239, year = {2020}, author = {Calió, ML and Henriques, E and Siena, A and Bertoncini, CRA and Gil-Mohapel, J and Rosenstock, TR}, title = {Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {679}, pmid = {32760239}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.}, }
@article {pmid32758633, year = {2020}, author = {Aksoy, YA and Deng, W and Stoddart, J and Chung, R and Guillemin, G and Cole, NJ and Neely, GG and Hesselson, D}, title = {"STRESSED OUT": The role of FUS and TDP-43 in amyotrophic lateral sclerosis.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {126}, number = {}, pages = {105821}, doi = {10.1016/j.biocel.2020.105821}, pmid = {32758633}, issn = {1878-5875}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Cytosol/metabolism ; DNA-Binding Proteins/*genetics ; Humans ; *Mutation ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Mutations in fused-in-sarcoma (FUS) and TAR DNA binding protein-43 (TDP-43; TARDBP) are known to cause the severe adult-onset neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Proteinopathy caused by cellular stresses such as endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial stress and proteasomal stress and the formation of stress granules (SGs), cytoplasmic aggregates and inclusions is a hallmark of ALS. FUS and TDP-43, which are DNA/RNA binding proteins that regulate transcription, RNA homeostasis and protein translation are implicated in ALS proteinopathy. Disease-causing mutations in FUS and TDP-43 cause sequestration of these proteins and their interacting partners in the cytoplasm, which leads to aggregation. This mislocalization and formation of aggregates and SGs is cytotoxic and a contributor to neuronal death. We explore how loss-of-nuclear-function and gain-of-cytoplasmic function mechanisms that affect FUS and TPD-43 localization can generate a 'stressed out' neuronal pathology and proteinopathy that drives ALS progression.}, }
@article {pmid32751277, year = {2020}, author = {Lagrange, E and Vernoux, JP}, title = {Warning on False or True Morels and Button Mushrooms with Potential Toxicity Linked to Hydrazinic Toxins: An Update.}, journal = {Toxins}, volume = {12}, number = {8}, pages = {}, pmid = {32751277}, issn = {2072-6651}, mesh = {*Agaricales ; Animals ; Humans ; Hydrazines/*toxicity ; *Mushroom Poisoning ; Mycotoxins/*toxicity ; }, abstract = {Recently, consumption of the gyromitrin-containing neurotoxic mushroom Gyromitra sp. (false morel), as gourmet food was hypothesized to play a role in sporadic amyotrophic lateral sclerosis genesis. The present review analyses recent data on edibility and toxicity of false and true morels and Agaricus spp. Controversy about the toxic status of Gyromitra esculenta was due to variable toxin susceptibility within consumers. We suggest that Verpa bohemica, another false morel, is also inedible. We found a temporary neurological syndrome (NS) with cerebellar signs associated with high consumption of fresh or dried true morels Morchella sp. After ingestion of crude or poorly cooked fresh or dried morels, a gastrointestinal "haemolytic" syndrome was also observed. Agaritine, a water soluble hydrazinic toxin closely related to gyromitrin is present along with metabolites including diazonium ions and free radicals, in Agaricus spp. and A. bisporus, the button mushroom, and in mice after ingestion. It is a potential weak carcinogen in mice, but although no data are available for humans, a lifetime low cumulative extra cancer risk in humans can be estimated to be about 10[-5]. To conclude, a safety measure is to avoid consuming any true morels or button mushrooms when crude or poorly cooked, fresh or dried.}, }
@article {pmid32749157, year = {2020}, author = {van Es, MA and Goedee, HS and Westeneng, HJ and Nijboer, TCW and van den Berg, LH}, title = {Is it accurate to classify ALS as a neuromuscular disorder?.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {9}, pages = {895-906}, doi = {10.1080/14737175.2020.1806061}, pmid = {32749157}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*classification ; Humans ; Neurodegenerative Diseases/*classification ; Neuromuscular Diseases/*classification ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder.<br><br>AREAS COVERED: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies.<br><br>EXPERT OPINION: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.}, }
@article {pmid32748079, year = {2020}, author = {Bampton, A and Gittings, LM and Fratta, P and Lashley, T and Gatt, A}, title = {The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {140}, number = {5}, pages = {599-623}, pmid = {32748079}, issn = {1432-0533}, support = {FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Frontotemporal Dementia/*metabolism/pathology ; Heterogeneous-Nuclear Ribonucleoproteins/*metabolism ; Humans ; }, abstract = {Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U.}, }
@article {pmid32746659, year = {2020}, author = {Wang, Y and Patani, R}, title = {Novel therapeutic targets for amyotrophic lateral sclerosis: ribonucleoproteins and cellular autonomy.}, journal = {Expert opinion on therapeutic targets}, volume = {24}, number = {10}, pages = {971-984}, doi = {10.1080/14728222.2020.1805734}, pmid = {32746659}, issn = {1744-7631}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; FC010110/MRC_/Medical Research Council/United Kingdom ; FC010110/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Humans ; *Molecular Targeted Therapy ; Neuroglia/pathology ; Proteostasis ; RNA/*metabolism ; Ribonucleoproteins/metabolism ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating disease with a lifetime risk of approximately 1:400. It is incurable and invariably fatal. Average survival is between 3 and 5 years and patients become increasingly paralyzed, losing the ability to speak, eat, and breathe. Therapies in development either (i) target specific familial forms of ALS (comprising a minority of around 10% of cases) or ii) emanate from (over)reliance on animal models or non-human/non-neuronal cell models. There is a desperate and unmet clinical need for effective treatments. Deciphering the primacy and relative contributions of defective protein homeostasis and RNA metabolism in ALS across different model systems will facilitate the identification of putative therapeutic targets.<br><br>AREAS COVERED: This review examines the putative common primary molecular events that lead to ALS pathogenesis. We focus on deregulated RNA metabolism, protein mislocalization/pathological aggregation and the role of glia in ALS-related motor neuron degeneration. Finally, we describe promising targets for therapeutic evaluation.<br><br>EXPERT OPINION: Moving forward, an effective strategy could be achieved by a poly-therapeutic approach which targets both deregulated RNA metabolism and protein dyshomeostasis in the relevant cell types, at the appropriate phase of disease.}, }
@article {pmid32746649, year = {2020}, author = {Brimson, JM and Brimson, S and Chomchoei, C and Tencomnao, T}, title = {Using sigma-ligands as part of a multi-receptor approach to target diseases of the brain.}, journal = {Expert opinion on therapeutic targets}, volume = {24}, number = {10}, pages = {1009-1028}, doi = {10.1080/14728222.2020.1805435}, pmid = {32746649}, issn = {1744-7631}, mesh = {Animals ; Brain Diseases/*drug therapy/physiopathology ; Humans ; Ligands ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/administration &amp; dosage/pharmacology ; Receptors, sigma/*agonists/metabolism ; }, abstract = {INTRODUCTION: The sigma receptors are found abundantly in the central nervous system and are targets for the treatment of various diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), depression, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). However, for many of these diseases, other receptors and targets have been the focus of the most, such as acetylcholine esterase inhibitors in Alzheimer's and dopamine replacement in Parkinson's. The currently available drugs for these diseases have limited success resulting in the requirement of an alternative approach to their treatment.<br><br>AREAS COVERED: In this review, we discuss the potential role of the sigma receptors and their ligands as part of a multi receptor approach in the treatment of the diseases mentioned above. The literature reviewed was obtained through searches in databases, including PubMed, Web of Science, Google Scholar, and Scopus.<br><br>EXPERT OPINION: Given sigma receptor agonists provide neuroprotection along with other benefits such as potentiating the effects of other receptors, further development of multi-receptor targeting ligands, and or the development of multi-drug combinations to target multiple receptors may prove beneficial in the future treatment of degenerative diseases of the CNS, especially when coupled with better diagnostic techniques.}, }
@article {pmid32739295, year = {2020}, author = {Fujimoto, M and Andrew, M and Dauber, A}, title = {Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects.}, journal = {Molecular and cellular endocrinology}, volume = {518}, number = {}, pages = {110967}, pmid = {32739295}, issn = {1872-8057}, support = {R01 HD093622/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Female ; Genetic Diseases, Inborn/*genetics/metabolism ; Growth and Development/*genetics ; Human Growth Hormone/metabolism/physiology ; Humans ; Insulin-Like Growth Factor I/genetics/metabolism ; Male ; Mice ; Mutation ; Pregnancy-Associated Plasma Protein-A/*genetics/physiology ; Signal Transduction/genetics ; }, abstract = {Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), have long been recognized as central to human growth physiology. IGF-1 is known to complex with IGF binding proteins as well as with the acid labile subunit (ALS) in order to prolong its half-life in circulation. Factors regulating the bioavailability of IGF-1 (i.e. the balance between free and bound IGF-1) were less well understood. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) was discovered as a protease which specifically cleaves IGF-binding protein (IGFBP)-3 and -5. PAPP-A2 deficient patients present with characteristic findings including growth failure, elevated total IGF-1 and -2, IGFBPs, and ALS, but decreased percentage of free to total IGF-1. Additionally, patients with PAPP-A2 deficiency have impairments in glucose metabolism and bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) improved height SD scores, growth velocity, body composition, and dysglycemia. Mouse models recapitulate many of the human findings of PAPP-A2 deficiency. This review summarizes the function of PAPP-A2 and its contribution to the GH-IGF axis through an examination of PAPP-A2 deficient patients and mouse models, thereby emphasizing the importance of the regulation of IGF-1 bioavailability in human growth.}, }
@article {pmid32739173, year = {2020}, author = {Bouscary, A and Quessada, C and René, F and Spedding, M and Henriques, A and Ngo, S and Loeffler, JP}, title = {Drug repositioning in neurodegeneration: An overview of the use of ambroxol in neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {884}, number = {}, pages = {173446}, doi = {10.1016/j.ejphar.2020.173446}, pmid = {32739173}, issn = {1879-0712}, mesh = {Ambroxol/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; *Drug Repositioning ; Enzyme Inhibitors/*pharmacology ; Glucosylceramidase/antagonists &amp; inhibitors/metabolism ; Humans ; Mutation ; *Nerve Degeneration ; Neuroprotective Agents/*pharmacology ; Spinal Cord/*drug effects/enzymology/pathology ; Superoxide Dismutase-1/genetics ; beta-Glucosidase/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. While it is primarily characterized by the death of upper and lower motor neurons, there is a significant metabolic component involved in the progression of the disease. Two-thirds of ALS patients have metabolic alterations that are associated with the severity of symptoms. In ALS, as in other neurodegenerative diseases, the metabolism of glycosphingolipids, a class of complex lipids, is strongly dysregulated. We therefore assume that this pathway constitutes an interesting avenue for therapeutic approaches. We have shown that the glucosylceramide degrading enzyme, glucocerebrosidase (GBA) 2 is abnormally increased in the spinal cord of the SOD1[G86R] mouse model of ALS. Ambroxol, a chaperone molecule that inhibits GBA2, has been shown to have beneficial effects by slowing the development of the disease in SOD1[G86R] mice. Currently used in clinical trials for Parkinson's and Gaucher disease, ambroxol could be considered as a promising therapeutic treatment for ALS.}, }
@article {pmid32738903, year = {2020}, author = {Taheri, Y and Suleria, HAR and Martins, N and Sytar, O and Beyatli, A and Yeskaliyeva, B and Seitimova, G and Salehi, B and Semwal, P and Painuli, S and Kumar, A and Azzini, E and Martorell, M and Setzer, WN and Maroyi, A and Sharifi-Rad, J}, title = {Myricetin bioactive effects: moving from preclinical evidence to potential clinical applications.}, journal = {BMC complementary medicine and therapies}, volume = {20}, number = {1}, pages = {241}, pmid = {32738903}, issn = {2662-7671}, mesh = {Anti-Infective Agents/chemistry/pharmacology ; Antineoplastic Agents/chemistry/pharmacology ; Antioxidants/chemistry/pharmacology ; *Dietary Supplements ; Flavonoids/*chemistry/*pharmacology ; Humans ; Hypoglycemic Agents/chemistry/pharmacology ; Molecular Structure ; Neuroprotective Agents/chemistry/pharmacology ; }, abstract = {Several flavonoids have been recognized as nutraceuticals, and myricetin is a good example. Myricetin is commonly found in plants and their antimicrobial and antioxidant activities is well demonstrated. One of its beneficial biological effects is the neuroprotective activity, showing preclinical activities on Alzheimer, Parkinson, and Huntington diseases, and even in amyotrophic lateral sclerosis. Also, myricetin has revealed other biological activities, among them as antidiabetic, anticancer, immunomodulatory, cardiovascular, analgesic and antihypertensive. However, few clinical trials have been performed using myricetin as nutraceutical. Thus, this review provides new insights on myricetin preclinical pharmacological activities, and role in selected clinical trials.}, }
@article {pmid32737989, year = {2021}, author = {Palomo, V and Nozal, V and Rojas-Prats, E and Gil, C and Martinez, A}, title = {Protein kinase inhibitors for amyotrophic lateral sclerosis therapy.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1316-1335}, doi = {10.1111/bph.15221}, pmid = {32737989}, issn = {1476-5381}, support = {B2017/BMD3813//Comunidad de Madrid/ ; LCF/BQ/PR18/11640007//La Caixa Banking Foundation/ ; FPU14-00204//MECD/ ; FPU16/04466//MECD/ ; CIBERNED, CB18/05/00040//ISCiii/ ; //FEDER/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; Protein Kinase Inhibitors/therapeutic use ; Ubiquitin ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes the progressive loss of motoneurons and, unfortunately, there is no effective treatment for this disease. Interconnecting multiple pathological mechanisms are involved in the neuropathology of this disease, including abnormal aggregation of proteins, neuroinflammation and dysregulation of the ubiquitin proteasome system. Such complex mechanisms, together with the lack of reliable animal models of the disease have hampered the development of drugs for this disease. Protein kinases, a key pharmacological target in several diseases, have been linked to ALS as they play a central role in the pathology of many diseases. Therefore several inhibitors are being currently trailed for clinical proof of concept in ALS patients. In this review, we examine the recent literature on protein kinase inhibitors currently in pharmaceutical development for this diseaseas future therapy for AS together with their involvement in the pathobiology of ALS. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32733193, year = {2020}, author = {Ranganathan, R and Haque, S and Coley, K and Shepheard, S and Cooper-Knock, J and Kirby, J}, title = {Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {684}, pmid = {32733193}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.}, }
@article {pmid32729088, year = {2021}, author = {Costa Cruz, PH and Kawahara, Y}, title = {RNA Editing in Neurological and Neurodegenerative Disorders.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2181}, number = {}, pages = {309-330}, doi = {10.1007/978-1-0716-0787-9_18}, pmid = {32729088}, issn = {1940-6029}, mesh = {Adenosine/chemistry/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Epilepsy/genetics ; Humans ; Inosine/chemistry/genetics ; Nervous System Diseases/*genetics ; Neurodegenerative Diseases/*genetics ; Phenotype ; RNA Editing/*physiology ; }, abstract = {The brain is one of the organs that are preferentially targeted by adenosine-to-inosine (A-to-I) RNA editing, a posttranscriptional modification. This chemical modification affects neuronal development and functions at multiple levels, leading to normal brain homeostasis by increasing the complexity of the transcriptome. This includes modulation of the properties of ion channel and neurotransmitter receptors by recoding, redirection of miRNA targets by changing sequence complementarity, and suppression of immune response by altering RNA structure. Therefore, from another perspective, it appears that the brain is highly vulnerable to dysregulation of A-to-I RNA editing. Here, we focus on how aberrant A-to-I RNA editing is involved in neurological and neurodegenerative diseases of humans including epilepsy, amyotrophic lateral sclerosis, psychiatric disorders, developmental disorders, brain tumors, and encephalopathy caused by autoimmunity. In addition, we provide information regarding animal models to better understand the mechanisms behind disease phenotype.}, }
@article {pmid32726472, year = {2021}, author = {Klingl, YE and Pakravan, D and Van Den Bosch, L}, title = {Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1353-1372}, pmid = {32726472}, issn = {1476-5381}, support = {FWO/1S50320N//Fonds Wetenschappelijk Onderzoek/ ; //Amyotrophic Lateral Sclerosis Association/ ; //Target ALS/ ; //ALS Liga Belgi&#xeb; (A Cure for ALS)/ ; //Muscular Dystrophy Association/ ; //Association Belge contre les Maladies neuro-Musculaires/ ; //Fondation Thierry Latran/ ; //KU Leuven/ ; //Vlaams Instituut voor Biotechnologie/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Epigenomics ; Histone Deacetylases ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. ALS patients suffer from a progressive loss of motor neurons, leading to respiratory failure within 3 to 5 years after diagnosis. Available therapies only slow down the disease progression moderately or extend the lifespan by a few months. Epigenetic hallmarks have been linked to the disease, creating an avenue for potential therapeutic approaches. Interference with one class of epigenetic enzymes, histone deacetylases, has been shown to affect neurodegeneration in many preclinical models. Consequently, it is crucial to improve our understanding about histone deacetylases and their inhibitors in (pre)clinical models of ALS. We conclude that selective inhibitors with high tolerability and safety and sufficient blood-brain barrier permeability will be needed to interfere with both epigenetic and non-epigenetic targets of these enzymes. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32725516, year = {2020}, author = {Ahmad, A and Patel, V and Xiao, J and Khan, MM}, title = {The Role of Neurovascular System in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {57}, number = {11}, pages = {4373-4393}, doi = {10.1007/s12035-020-02023-z}, pmid = {32725516}, issn = {1559-1182}, mesh = {Animals ; Blood-Brain Barrier/pathology/physiopathology ; Cerebrovascular Circulation ; Humans ; Models, Neurological ; Nervous System/*blood supply/physiopathology ; Neurodegenerative Diseases/*pathology/physiopathology/therapy ; }, abstract = {The neurovascular system (NVS), which consisted of neurons, glia, and vascular cells, is a functional and structural unit of the brain. The NVS regulates blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), thereby maintaining the brain's microenvironment for normal functioning, neuronal survival, and information processing. Recent studies have highlighted the role of vascular dysfunction in several neurodegenerative diseases. This is not unexpected since both nervous and vascular systems are functionally interdependent and show close anatomical apposition, as well as similar molecular pathways. However, despite extensive research, the precise mechanism by which neurovascular dysfunction contributes to neurodegeneration remains incomplete. Therefore, understanding the mechanisms of neurovascular dysfunction in disease conditions may allow us to develop potent and effective therapies for prevention and treatment of neurodegenerative diseases. This review article summarizes the current research in the context of neurovascular signaling associated with neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss the potential implication of neurovascular factor as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions. Graphical Abstract.}, }
@article {pmid32725282, year = {2020}, author = {Ghasemzadeh Rahbardar, M and Hosseinzadeh, H}, title = {Effects of rosmarinic acid on nervous system disorders: an updated review.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {393}, number = {10}, pages = {1779-1795}, pmid = {32725282}, issn = {1432-1912}, mesh = {Animals ; Antioxidants/chemistry/isolation &amp; purification/*therapeutic use ; Cinnamates/chemistry/isolation &amp; purification/*therapeutic use ; Depsides/chemistry/isolation &amp; purification/*therapeutic use ; Humans ; Mental Disorders/*drug therapy/metabolism ; Nervous System Diseases/*drug therapy/metabolism ; Neuroprotective Agents/chemistry/isolation &amp; purification/*therapeutic use ; Prospective Studies ; *Rosmarinus ; Treatment Outcome ; Rosmarinic Acid ; }, abstract = {Nowadays, the worldwide interest is growing to use medicinal plants and their active constituents to develop new potent medicines with fewer side effects. Precise dietary compounds have prospective beneficial applications for various neurodegenerative ailments. Rosmarinic acid is a polyphenol and is detectable most primarily in many Lamiaceae families, for instance, Rosmarinus officinalis also called rosemary. This review prepared a broad and updated literature review on rosmarinic acid elucidating its biological activities on some nervous system disorders. Rosmarinic acid has significant antinociceptive, neuroprotective, and neuroregenerative effects. In this regard, we classified and discussed our findings in different nervous system disorders including Alzheimer's disease, epilepsy, depression, Huntington's disease, familial amyotrophic lateral sclerosis, Parkinson's disease, cerebral ischemia/reperfusion injury, spinal cord injury, stress, anxiety, and pain.}, }
@article {pmid32718499, year = {2020}, author = {Roggenbuck, J and Fong, JC}, title = {Genetic Testing for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Impact on Clinical Management.}, journal = {Clinics in laboratory medicine}, volume = {40}, number = {3}, pages = {271-287}, doi = {10.1016/j.cll.2020.05.002}, pmid = {32718499}, issn = {1557-9832}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; Genetic Counseling ; *Genetic Testing ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders that share clinical, pathologic, and genetic features. Persons and families affected by these conditions frequently question why they developed the disease, the expected disease course, treatment options, and the likelihood that family members will be affected. Genetic testing has the potential to answers these important questions. Despite the progress in gene discovery, the offer of genetic testing is not yet "standard of care" in ALS and FTD clinics. The authors review the current genetic landscape and present recommendations for the laboratory genetic evaluation of persons with these conditions.}, }
@article {pmid32714567, year = {2020}, author = {Papp, Z and Agostoni, P and Alvarez, J and Bettex, D and Bouchez, S and Brito, D and Černý, V and Comin-Colet, J and Crespo-Leiro, MG and Delgado, JF and Édes, I and Eremenko, AA and Farmakis, D and Fedele, F and Fonseca, C and Fruhwald, S and Girardis, M and Guarracino, F and Harjola, VP and Heringlake, M and Herpain, A and Heunks, LM and Husebye, T and Ivancan, V and Karason, K and Kaul, S and Kivikko, M and Kubica, J and Masip, J and Matskeplishvili, S and Mebazaa, A and Nieminen, MS and Oliva, F and Papp, JG and Parissis, J and Parkhomenko, A and Põder, P and Pölzl, G and Reinecke, A and Ricksten, SE and Riha, H and Rudiger, A and Sarapohja, T and Schwinger, RH and Toller, W and Tritapepe, L and Tschöpe, C and Wikström, G and von Lewinski, D and Vrtovec, B and Pollesello, P}, title = {Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.}, journal = {Cardiac failure review}, volume = {6}, number = {}, pages = {e19}, pmid = {32714567}, issn = {2057-7540}, abstract = {Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.}, }
@article {pmid32712267, year = {2020}, author = {Proukakis, C}, title = {Somatic mutations in neurodegeneration: An update.}, journal = {Neurobiology of disease}, volume = {144}, number = {}, pages = {105021}, doi = {10.1016/j.nbd.2020.105021}, pmid = {32712267}, issn = {1095-953X}, mesh = {Alzheimer Disease/genetics ; Amyloid beta-Protein Precursor/genetics ; Amyotrophic Lateral Sclerosis/genetics ; DNA Copy Number Variations ; DNA Repair-Deficiency Disorders/genetics ; DNA Repeat Expansion ; Humans ; Huntington Disease/genetics ; Mosaicism ; Multiple System Atrophy/genetics ; Mutagenesis, Insertional ; *Mutation ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/genetics ; Phosphorylation/genetics ; Polymorphism, Single Nucleotide ; Retroelements ; Synucleinopathies/genetics ; alpha-Synuclein/genetics ; tau Proteins ; }, abstract = {Mosaicism, the presence of genomic differences between cells due to post-zygotic somatic mutations, is widespread in the human body, including within the brain. A role for this in neurodegenerative diseases has long been hypothesised, and technical developments are now allowing the question to be addressed in detail. The rapidly accumulating evidence is discussed in this review, with a focus on recent developments. Somatic mutations of numerous types may occur, including single nucleotide variants (SNVs), copy number variants (CNVs), and retrotransposon insertions. They could act as initiators or risk factors, especially if they arise in development, although they could also result from the disease process, potentially contributing to progression. In common sporadic neurodegenerative disorders, relevant mutations have been reported in synucleinopathies, comprising somatic gains of SNCA in Parkinson's disease and multiple system atrophy, and in Alzheimer's disease, where a novel recombination mechanism leading to somatic variants of APP, as well as an excess of somatic SNVs affecting tau phosphorylation, have been reported. In Mendelian repeat expansion disorders, mosaicism due to somatic instability, first detected 25 years ago, has come to the forefront. Brain somatic SNVs occur in DNA repair disorders, and there is evidence for a role of several ALS genes in DNA repair. While numerous challenges, and need for further validation, remain, this new, or perhaps rediscovered, area of research has the potential to transform our understanding of neurodegeneration.}, }
@article {pmid32708926, year = {2020}, author = {Scuderi, SA and Ardizzone, A and Paterniti, I and Esposito, E and Campolo, M}, title = {Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {7}, pages = {}, pmid = {32708926}, issn = {2076-3921}, abstract = {Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.}, }
@article {pmid32708667, year = {2020}, author = {Liu, Z and Chen, X and Li, Z and Ye, W and Ding, H and Li, P and Aung, LHH}, title = {Role of RNA Oxidation in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {14}, pages = {}, pmid = {32708667}, issn = {1422-0067}, support = {91849209; 81850410551//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Cell Death ; Humans ; Neurodegenerative Diseases/*metabolism ; Oxidation-Reduction ; *Oxidative Stress ; RNA/*metabolism ; }, abstract = {In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases.}, }
@article {pmid32707914, year = {2020}, author = {Mignani, S and Majoral, JP and Desaphy, JF and Lentini, G}, title = {From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {15}, pages = {}, pmid = {32707914}, issn = {1420-3049}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Benzothiazoles/*chemical synthesis/chemistry/pharmacology ; Clinical Trials as Topic ; Drug Approval ; Drug Evaluation, Preclinical ; Humans ; Neuroprotective Agents/*chemical synthesis/pharmacology ; Pramipexole/*chemistry ; Riluzole/*chemistry ; Small Molecule Libraries/chemical synthesis/pharmacology ; Toluene/analogs &amp; derivatives/chemistry ; Treatment Outcome ; }, abstract = {The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.}, }
@article {pmid32707231, year = {2020}, author = {Ahmed, T and Zulfiqar, A and Arguelles, S and Rasekhian, M and Nabavi, SF and Silva, AS and Nabavi, SM}, title = {Map kinase signaling as therapeutic target for neurodegeneration.}, journal = {Pharmacological research}, volume = {160}, number = {}, pages = {105090}, doi = {10.1016/j.phrs.2020.105090}, pmid = {32707231}, issn = {1096-1186}, mesh = {Animals ; Anti-Inflammatory Agents/adverse effects/*therapeutic use ; Central Nervous System/*drug effects/enzymology/pathology/physiopathology ; Humans ; Inflammation Mediators/*antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Molecular Targeted Therapy ; *Nerve Degeneration ; Neurodegenerative Diseases/*drug therapy/enzymology/pathology/physiopathology ; Protein Kinase Inhibitors/adverse effects/*therapeutic use ; Signal Transduction ; }, abstract = {Aging is known to be one of the major risk factors in many neurodegenerative diseases (ND) whose prevalence is estimated to rise in the coming years due to the increase in life expectancy. Examples of neurodegenerative diseases include Huntington's, Parkinson's, and Alzheimer's diseases, along with Amyotrophic Lateral Sclerosis, Spinocerebellar ataxias and Frontotemporal Dementia. Given that so far these ND do not have effective pharmacological therapies, a better understanding of the molecular and cellular mechanisms can contribute to development of effective treatments. During the previous decade, the data indicated that dysregulation of MAP kinases [which included c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38] are associated with several stages of the inflammatory process which in turn contributes to age-related neurodegenerative diseases. This evidence suggests that control of inflammation through regulation of MAP kinase could be a worthwhile approach against neurodegenerative diseases. In this review we summarize the pathways of MAP kinase signal transduction and different pharmacological inhibitors that can be used in its modulation against ND.}, }
@article {pmid32703476, year = {2020}, author = {Katzberg, HD}, title = {Case Studies in Management of Muscle Cramps.}, journal = {Neurologic clinics}, volume = {38}, number = {3}, pages = {679-696}, doi = {10.1016/j.ncl.2020.03.011}, pmid = {32703476}, issn = {1557-9875}, mesh = {Adult ; *Disease Management ; Female ; Humans ; Male ; Mexiletine/therapeutic use ; Middle Aged ; Muscle Cramp/*diagnosis/physiopathology/*therapy ; Pregnancy ; Voltage-Gated Sodium Channel Blockers/therapeutic use ; Young Adult ; }, abstract = {Muscle cramps, defined as a painful contraction of a muscle or muscle group, are a common symptom most people have experienced throughout their lifespan. In some cases cramps can be frequent, severe, and disabling, thus requiring medical assessment and intervention. Physiologic states such as pregnancy and exercise are associated with excessive muscle cramps, as are numerous medical and neurologic conditions, medications such as diuretics and statins, and peripheral nerve hyperexcitability syndromes. Treatment options for muscle cramps are limited, although recent studies have shown that mexiletine could be a safe and efficient alternative for patients with amyotrophic lateral sclerosis.}, }
@article {pmid32703469, year = {2020}, author = {Brent, JR and Franz, CK and Coleman, JM and Ajroud-Driss, S}, title = {ALS: Management Problems.}, journal = {Neurologic clinics}, volume = {38}, number = {3}, pages = {565-575}, pmid = {32703469}, issn = {1557-9875}, support = {R25 NS070695/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*physiopathology/*therapy ; *Disease Management ; Female ; Humans ; Male ; Middle Aged ; Quality of Life ; Respiratory Insufficiency/etiology/*physiopathology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure; however, symptomatic management has an impact on quality of life and survival. Symptom management is best performed in a multidisciplinary care setting, where patients are evaluated by multiple health care professionals. Respiratory failure is a significant cause of morbidity and mortality in patients with ALS. Early initiation of noninvasive ventilation can prolong survival, and adequate use of airway clearance techniques can prevent respiratory infections. Preventing and treating weight loss caused by dysphagia may slow down disease progression, and expert management of spasticity from upper motor neuron dysfunction enhances patient well-being.}, }
@article {pmid32698402, year = {2020}, author = {Pineau, H and Sim, V}, title = {POSCAbilities: The Application of the Prion Organotypic Slice Culture Assay to Neurodegenerative Disease Research.}, journal = {Biomolecules}, volume = {10}, number = {7}, pages = {}, pmid = {32698402}, issn = {2218-273X}, mesh = {Animals ; Biomedical Research/methods ; Brain/drug effects/metabolism/pathology ; Drug Evaluation, Preclinical/methods ; Humans ; Neurodegenerative Diseases/drug therapy/metabolism/*pathology ; Organ Culture Techniques/*methods ; Prion Diseases/drug therapy/metabolism/*pathology ; Prions/*analysis/metabolism ; Protein Aggregation, Pathological/drug therapy/metabolism/pathology ; }, abstract = {Prion diseases are fatal, transmissible neurodegenerative disorders whose pathogenesis is driven by the misfolding, self-templating and cell-to-cell spread of the prion protein. Other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, share some of these prion-like features, with different aggregation-prone proteins. Consequently, researchers have begun to apply prion-specific techniques, like the prion organotypic slice culture assay (POSCA), to these disorders. In this review we explore the ways in which the prion phenomenon has been used in organotypic cultures to study neurodegenerative diseases from the perspective of protein aggregation and spreading, strain propagation, the role of glia in pathogenesis, and efficacy of drug treatments. We also present an overview of the advantages and disadvantages of this culture system compared to in vivo and in vitro models and provide suggestions for new directions.}, }
@article {pmid32687832, year = {2020}, author = {Guo, Q and Wang, J and Weng, Q}, title = {The diverse role of optineurin in pathogenesis of disease.}, journal = {Biochemical pharmacology}, volume = {180}, number = {}, pages = {114157}, doi = {10.1016/j.bcp.2020.114157}, pmid = {32687832}, issn = {1873-2968}, mesh = {Animals ; Cell Cycle Proteins/genetics/*metabolism ; Communicable Diseases/genetics/*metabolism ; Humans ; Membrane Transport Proteins/genetics/*metabolism ; Neoplasms/genetics/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Protein Binding/physiology ; Protein Transport/physiology ; Signal Transduction/*physiology ; }, abstract = {Optineurin is a widely expressed protein that possesses multiple functions. Growing evidence suggests that mutation or dysregulation of optineurin can cause several neurodegenerative diseases, including amyotrophic lateral sclerosis, primary open-angle glaucoma, and Huntington's disease, as well as inflammatory digestive disorders such as Crohn's disease. Optineurin engages in vesicular trafficking, receptor regulation, immune reactions, autophagy, and distinct signaling pathways including nuclear factor kappa beta, by which optineurin contributes to cellular death and related diseases, indicating its potential as a therapeutic target. In this review, we discuss the major functions and signaling pathways of optineurin. Furthermore, we illustrate the influence of optineurin mutation or dysregulation to region-specific pathogenesis as well as potential applications of optineurin in therapeutic strategies.}, }
@article {pmid32679881, year = {2020}, author = {Paul, S and Bravo Vázquez, LA and Pérez Uribe, S and Roxana Reyes-Pérez, P and Sharma, A}, title = {Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders.}, journal = {Cells}, volume = {9}, number = {7}, pages = {}, pmid = {32679881}, issn = {2073-4409}, mesh = {Animals ; Gene Transfer Techniques ; Humans ; MicroRNAs/biosynthesis/genetics/*therapeutic use ; Models, Biological ; Neurodegenerative Diseases/*therapy ; }, abstract = {MicroRNAs (miRNAs) are a key gene regulator and play essential roles in several biological and pathological mechanisms in the human system. In recent years, plenty of miRNAs have been identified to be involved in the development of neurodegenerative disorders (NDDs), thus making them an attractive option for therapeutic approaches. Hence, in this review, we provide an overview of the current research of miRNA-based therapeutics for a selected set of NDDs, either for their high prevalence or lethality, such as Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, Friedreich's Ataxia, Spinal Muscular Atrophy, and Frontotemporal Dementia. We also discuss the relevant delivery techniques, pertinent outcomes, their limitations, and their potential to become a new generation of human therapeutic drugs in the near future.}, }
@article {pmid32677086, year = {2020}, author = {Calzaferri, F and Ruiz-Ruiz, C and de Diego, AMG and de Pascual, R and Méndez-López, I and Cano-Abad, MF and Maneu, V and de Los Ríos, C and Gandía, L and García, AG}, title = {The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases.}, journal = {Medicinal research reviews}, volume = {40}, number = {6}, pages = {2427-2465}, doi = {10.1002/med.21710}, pmid = {32677086}, issn = {1098-1128}, mesh = {*Alzheimer Disease ; Animals ; Humans ; Mice ; *Neurodegenerative Diseases/drug therapy ; *Pharmaceutical Preparations ; Purinergic P2X Receptor Antagonists/pharmacology ; Receptors, Purinergic P2X7 ; }, abstract = {Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.}, }
@article {pmid32674730, year = {2020}, author = {Iqubal, A and Iqubal, MK and Khan, A and Ali, J and Baboota, S and Haque, SE}, title = {Gene Therapy, A Novel Therapeutic Tool for Neurological Disorders: Current Progress, Challenges and Future Prospective.}, journal = {Current gene therapy}, volume = {20}, number = {3}, pages = {184-194}, doi = {10.2174/1566523220999200716111502}, pmid = {32674730}, issn = {1875-5631}, mesh = {Alzheimer Disease/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Brain/pathology ; CRISPR-Cas Systems/*genetics ; Gene Transfer Techniques/*trends ; *Genetic Therapy ; Humans ; Huntington Disease/genetics/therapy ; Lysosomal Storage Diseases/genetics/therapy ; Nervous System Diseases/genetics/pathology/*therapy ; Parkinson Disease/genetics/therapy ; }, abstract = {Neurological disorders are one of the major threat for health care system as they put enormous socioeconomic burden. All aged populations are susceptible to one or other neurological problems with symptoms of neuroinflammation, neurodegeneration and cognitive dysfunction. At present, available pharmacotherapeutics are insufficient to treat these diseased conditions and in most cases, they provide only palliative effect. It was also found that the molecular etiology of neurological disorders is directly linked with the alteration in genetic makeup, which can be inherited or triggered by the injury, environmental toxins and by some existing disease. Therefore, to take care of this situation, gene therapy has emerged as an advanced modality that claims to permanently cure the disease by deletion, silencing or edition of faulty genes and by insertion of healthier genes. In this modality, vectors (viral and non-viral) are used to deliver targeted gene into a specific region of the brain via various routes. At present, gene therapy has shown positive outcomes in complex neurological disorders, such as Parkinson's disease, Alzheimer's disease, Huntington disease, Multiple sclerosis, Amyotrophic lateral sclerosis and in lysosomal storage disease. However, there are some limitations such as immunogenic reactions non-specificity of viral vectors and a lack of effective biomarkers to understand the efficacy of therapy. Considerable progress has been made to improve vector design, gene selection and targeted delivery. This review article deals with the current status of gene therapy in neurological disorders along with its clinical relevance, challenges and future prospective.}, }
@article {pmid32673410, year = {2021}, author = {Riancho, J and Paz-Fajardo, L and López de Munaín, A}, title = {Clinical and preclinical evidence of somatosensory involvement in amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1257-1268}, doi = {10.1111/bph.15202}, pmid = {32673410}, issn = {1476-5381}, support = {NVAL 16/21//Institute of Research Valdecilla (IDIVAL)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; *Peripheral Nervous System Diseases ; Somatosensory Cortex ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron neurodegenerative disease. Although it has been classically considered as a disease limited to the motor system, there is increasing evidence for the involvement of other neural and non-neuronal systems. In this review, we will discuss currently existing literature regarding the involvement of the sensory system in ALS. Human studies have reported intradermic small fibre loss, sensory axonal predominant neuropathy, as well as somatosensory cortex hyperexcitability. In line with this, ALS animal studies have demonstrated the involvement of several sensory components. Specifically, they have highlighted the impairment of sensory-motor networks as a potential mechanism for the disease. The elucidation of these "non-motor" systems involvement, which might also be part of the degeneration process, should prompt the scientific community to re-consider ALS as a pure motor neuron disease, which may in turn result in more holistic research approaches. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32671738, year = {2020}, author = {Zhang, X and Yang, K and Le, W}, title = {Autophagy and Motor Neuron Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1207}, number = {}, pages = {53-74}, doi = {10.1007/978-981-15-4272-5_3}, pmid = {32671738}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis ; *Autophagy ; Humans ; *Motor Neuron Disease ; Motor Neurons ; Spinal Cord ; }, abstract = {Motor neuron diseases (MND) are a group of fatal progressive neurodegenerative diseases, which selectively affect the motor system in the anterior horn of spinal cord, brainstem, cortex and pyramidal tract. Motor neurons could be divided into two groups, which are upper groups in the motor cortex and lower groups in the brain stem and spinal cord. Loss of lower motor neurons leads to muscle weakness, wasting and cramps. Loss of upper motor neurons leads to brisk reflexes and functional limits. There are several types of motor neuron disease: amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS). Now, the studies of autophagy in MND focus on the type of ALS, so this chapter will summarize the alteration of autophagy in motor neurons, and how that knowledge contributes to our understanding of the pathogenesis of ALS.}, }
@article {pmid32664395, year = {2020}, author = {Khan, A and Ikram, M and Hahm, JR and Kim, MO}, title = {Antioxidant and Anti-Inflammatory Effects of Citrus Flavonoid Hesperetin: Special Focus on Neurological Disorders.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {7}, pages = {}, pmid = {32664395}, issn = {2076-3921}, abstract = {Neurodegenerative disorders have emerged as a serious health issue in the current era. The most common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). These diseases involve progressive impairment of neurodegeneration and memory impairment. A wide range of compounds have been identified as potential neuroprotective agents against different models of neurodegeneration both in vivo and in vitro. Hesperetin, a flavanone class of citrus flavonoid, is a derivative of hesperidin found in citrus fruits such as oranges, grapes, and lemons. It has been extensively reported that hesperetin exerts neuroprotective effects in experimental models of neurodegenerative diseases. In this systematic review, we have compiled all the studies conducted on hesperetin in both in vivo and in vitro models of neurodegeneration. Here, we have used an approach to lessen the bias in each study, providing a least biased, broad understanding of findings and impartial conclusions of the strength of evidence and the reliability of findings. In this review, we collected different papers from a wide range of journals describing the beneficial effects of hesperetin on animal models of neurodegeneration. Our results demonstrated consistent neuroprotective effects of hesperetin against different models of neurodegeneration. In addition, we have summarized its underlying mechanisms. This study provides the foundations for future studies and recommendations of further mechanistic approaches to conduct preclinical studies on hesperetin in different models.}, }
@article {pmid32663608, year = {2020}, author = {Li, Q and Haney, MS}, title = {The role of glia in protein aggregation.}, journal = {Neurobiology of disease}, volume = {143}, number = {}, pages = {105015}, doi = {10.1016/j.nbd.2020.105015}, pmid = {32663608}, issn = {1095-953X}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*pathology ; Neuroglia/*pathology ; Protein Aggregates ; Protein Aggregation, Pathological/*pathology ; }, abstract = {Protein aggregation diseases involve intracellular accumulation or extracellular deposition of certain protein species in neuronal or glial cells, leading to neurodegeneration and shortened lifespan. Prime examples include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), which are affected by overlapping or specific aggregation-prone proteins. Mounting evidence suggests that dysfunctional glial cells may be major drivers for some diseases, and when they are not causal factors, they could still significantly exacerbate or alleviate disease progression by playing a plethora of detrimental or beneficial roles. Here we review the diverse functions performed by glial cells in a variety of protein aggregation diseases, highlighting the complexity of the issue and the interconnected relationships between these multifaceted effects.}, }
@article {pmid32660395, year = {2021}, author = {Li, SS and Dong, YH and Liu, ZP}, title = {Recent Advances in the Development of Casein Kinase 1 Inhibitors.}, journal = {Current medicinal chemistry}, volume = {28}, number = {8}, pages = {1585-1604}, doi = {10.2174/0929867327666200713185413}, pmid = {32660395}, issn = {1875-533X}, mesh = {Apoptosis ; *Casein Kinase I/metabolism ; Humans ; *Neoplasms/drug therapy ; Protein Isoforms ; Structure-Activity Relationship ; }, abstract = {BACKGROUND: The casein kinase 1 (CK1) family is involved in regulating many cellular processes, including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms, especially CK1δ and CK1ε have emerged as important therapeutic targets for severe disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors.<br><br>METHODS: Using SciFinder&#xae; as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion of those published as patents.<br><br>RESULTS: This review presents the current state of knowledge on the development of CK1 inhibitors, including both synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships.<br><br>CONCLUSION: Through physicochemical characterization and biological investigations, it is possible to understand the structure-activity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.}, }
@article {pmid32659950, year = {2020}, author = {Porro, C and Cianciulli, A and Panaro, MA}, title = {The Regulatory Role of IL-10 in Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {10}, number = {7}, pages = {}, pmid = {32659950}, issn = {2218-273X}, mesh = {Animals ; Humans ; Interleukin-10/*metabolism ; Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*immunology ; Signal Transduction ; }, abstract = {IL-10, an immunosuppressive cytokine, is considered an important anti-inflammatory modulator of glial activation, preventing inflammation-mediated neuronal degeneration under pathological conditions. In this narrative review, we summarize recent insights about the role of IL-10 in the neurodegeneration associated with neuroinflammation, in diseases such as Multiple Sclerosis, Traumatic Brain Injury, Amyotrophic lateral sclerosis, Alzheimer's Disease, and Parkinson's Disease, focusing on the contribution of this cytokine not only in terms of protective action, but also as possibly responsible for clinical worsening. The knowledge of this double face of the same coin, regarding the biological role of the IL-10, could aid the development of targeted therapies useful for limiting neurodegenerative processes.}, }
@article {pmid32659845, year = {2021}, author = {Kaczmarek, JM and Graczykowska, KA and Szymkuć-Bukowska, I and Łoś-Rycharska, E and Krogulska, A}, title = {Chubby Infant - Should One Worry? An Infant with Primary lymphedema - Mini Review and Case Report.}, journal = {Klinische Padiatrie}, volume = {233}, number = {2}, pages = {47-52}, doi = {10.1055/a-1200-1721}, pmid = {32659845}, issn = {1439-3824}, mesh = {Child ; Humans ; Infant ; *Lymphedema/diagnosis/therapy ; }, abstract = {Lymphedema is a localized form of tissue swelling, characterized by a progressive accumulation of a tissue fluid in the interstitial compartment as a result of the lymphatic system dysfunction. It is a rare disease in the pediatric population and in the majority of cases it is a consequence of an abnormal formation of the lymphatic system, which is called primary lymphedema. Although its epidemiology is not precise, it is assumed that 1:100 000 children suffer from primary lymphedema. The diagnosis can be made by a proper clinical examination after ruling out secondary causes of lymphedema, particularly in cases with a more asymmetric swelling of the extremities. In this very article we present a case report of an 8-months-old infant with primary lymphedema, who had presented swelling of the extremities from birth and yet no pathology was suspected before. The purpose of this article is to draw attention to the fact that a baby with excessive subcutaneous tissue is not always a healthy, chubby infant with considerable amount of fat tissue.Das Lymphödem ist eine lokalisierte Form des Gewebeödems, die durch eine fortschreitende Ansammlung von Gewebeflüssigkeit im Interstitialraum infolge einer Funktionsstörung des Lymphsystems gekennzeichnet ist. Dies ist eine seltene Erkrankung in der pädiatrischen Bevölkerung und in den meisten Fällen eine Folge der fehlerhaften Bildung des Lymphsystems, das als primäres Lymphödem bezeichnet wird. Obwohl die Epidemiologie nicht genau ist, wird angenommen, dass 1: 100 000 Kinder an einem primären Lymphödem leiden. Die Diagnose kann auf der Grundlage einer geeigneten klinischen Untersuchung gestellt werden, nachdem sekundäre Ursachen für Lymphödeme ausgeschlossen wurden, insbesondere bei asymmetrischeren Ödemen der Gliedmaßen. In diesem Artikel präsentieren wir den Fallbericht eines 8 Monate alten Kindes mit primärem Lymphödem, dessen Ödem der Gliedmaßen seit der Geburt aufgetreten ist, bei dem aber keine Pathologien vermutet wurde. Der Zweck dieses Artikels ist es, die Aufmerksamkeit auf die Tatsache zu lenken, dass ein Kind mit übermäßigem Unterhautgewebe nicht immer ein gesundes, molliges Kind mit übermäßigem Körperfett bedeutet.}, }
@article {pmid32657152, year = {2021}, author = {Zarotti, N and Mayberry, E and Ovaska-Stafford, N and Eccles, F and Simpson, J}, title = {Psychological interventions for people with motor neuron disease: a scoping review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {1-2}, pages = {1-11}, doi = {10.1080/21678421.2020.1788094}, pmid = {32657152}, issn = {2167-9223}, mesh = {Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis ; *Cognitive Behavioral Therapy ; Humans ; *Motor Neuron Disease/therapy ; Psychosocial Intervention ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive neurodegenerative condition with no known cure. MND can affect every aspect of a person's life and has been associated with a wide range of psychological difficulties, which can occur from pre-diagnosis through to the condition's later stages. However, very little research has been conducted on psychological interventions for people with MND (pwMND). This paper aimed to provide the first review specifically targeting psychological interventions in MND and offer potential directions for future research. Methods: A scoping review was carried out across five major databases (PubMed, PsycINFO, CINAHL, Academic Search Ultimate, and Cochrane Library) until 1st of March 2020. Results: From an initial return of 1278 citations, 10 papers were included in the review. These included three randomized controlled trials (RCTs), two quasi-experiments, three uncontrolled pretest-post-test designs, one single case study, and one qualitative secondary analysis. The existing studies focused on a limited number of psychological outcomes and did not take into account site of MND onset or level of depression/anxiety before intervention. Implications for clinical practice are discussed and suggestions for future research are provided. Conclusions: The literature on psychological interventions is still extremely sparse. Mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT) based on the stress-coping model show promise in RCTs, but require further evaluation. The need for further development and evaluation of psychological interventions to improve the well-being of pwMND cannot be overstated, particularly as the struggle toward the discovery of an effective treatment for MND continues.}, }
@article {pmid32656815, year = {2021}, author = {Angelova, PR and Esteras, N and Abramov, AY}, title = {Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention.}, journal = {Medicinal research reviews}, volume = {41}, number = {2}, pages = {770-784}, doi = {10.1002/med.21712}, pmid = {32656815}, issn = {1098-1128}, mesh = {Humans ; Lipid Peroxidation ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {The world's population aging progression renders age-related neurodegenerative diseases to be one of the biggest unsolved problems of modern society. Despite the progress in studying the development of pathology, finding ways for modifying neurodegenerative disorders remains a high priority. One common feature of neurodegenerative diseases is mitochondrial dysfunction and overproduction of reactive oxygen species, resulting in oxidative stress. Although lipid peroxidation is one of the markers for oxidative stress, it also plays an important role in cell physiology, including activation of phospholipases and stimulation of signaling cascades. Excessive lipid peroxidation is a hallmark for most neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and many other neurological conditions. The products of lipid peroxidation have been shown to be the trigger for necrotic, apoptotic, and more specifically for oxidative stress-related, that is, ferroptosis and neuronal cell death. Here we discuss the involvement of lipid peroxidation in the mechanism of neuronal loss and some novel therapeutic directions to oppose it.}, }
@article {pmid32655708, year = {2020}, author = {Yao, D and Zhang, Y and Liu, T and Xu, P and Gong, D and Lu, J and Xia, Y and Luo, C and Guo, D and Dong, L and Lai, Y and Chen, K and Li, J}, title = {Bacomics: a comprehensive cross area originating in the studies of various brain-apparatus conversations.}, journal = {Cognitive neurodynamics}, volume = {14}, number = {4}, pages = {425-442}, pmid = {32655708}, issn = {1871-4080}, abstract = {The brain is the most important organ of the human body, and the conversations between the brain and an apparatus can not only reveal a normally functioning or a dysfunctional brain but also can modulate the brain. Here, the apparatus may be a nonbiological instrument, such as a computer, and the consequent brain-computer interface is now a very popular research area with various applications. The apparatus may also be a biological organ or system, such as the gut and muscle, and their efficient conversations with the brain are vital for a healthy life. Are there any common bases that bind these different scenarios? Here, we propose a new comprehensive cross area: Bacomics, which comes from brain-apparatus conversations (BAC) + omics. We take Bacomics to cover at least three situations: (1) The brain is normal, but the conversation channel is disabled, as in amyotrophic lateral sclerosis. The task is to reconstruct or open up new channels to reactivate the brain function. (2) The brain is in disorder, such as in Parkinson's disease, and the work is to utilize existing or open up new channels to intervene, repair and modulate the brain by medications or stimulation. (3) Both the brain and channels are in order, and the goal is to enhance coordinated development between the brain and apparatus. In this paper, we elaborate the connotation of BAC into three aspects according to the information flow: the issue of output to the outside (BAC-1), the issue of input to the brain (BAC-2) and the issue of unity of brain and apparatus (BAC-3). More importantly, there are no less than five principles that may be taken as the cornerstones of Bacomics, such as feedforward and feedback control, brain plasticity, harmony, the unity of opposites and systems principles. Clearly, Bacomics integrates these seemingly disparate domains, but more importantly, opens a much wider door for the research and development of the brain, and the principles further provide the general framework in which to realize or optimize these various conversations.}, }
@article {pmid32655368, year = {2020}, author = {Yan, X and Wang, B and Hu, Y and Wang, S and Zhang, X}, title = {Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {138}, pmid = {32655368}, issn = {1662-5102}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are characterized by a progressive loss of selective neuron subtypes in the central nervous system (CNS). Although various factors account for the initiation and development of these diseases, accumulating evidence shows that impaired mitochondrial function is a prominent and common mechanism. Mitochondria play a critical role in neurons and are involved in energy production, cellular metabolism regulation, intracellular calcium homeostasis, immune responses, and cell fate. Thus, cells in the CNS heavily rely on mitochondrial integrity. Many aspects of mitochondrial dysfunction are manifested in neurodegenerative diseases, including aberrant mitochondrial quality control (mitoQC), mitochondrial-driven inflammation, and bioenergetic defects. Herein, we briefly summarize the molecular basis of mitoQC, including mitochondrial proteostasis, biogenesis, dynamics, and organelle degradation. We also focus on the research, to date, regarding aberrant mitoQC and mitochondrial-driven inflammation in several common neurodegenerative diseases. In addition, we outline novel therapeutic strategies that target aberrant mitoQC in neurodegenerative diseases.}, }
@article {pmid32654761, year = {2020}, author = {Kim, Y and Connor, JR}, title = {The roles of iron and HFE genotype in neurological diseases.}, journal = {Molecular aspects of medicine}, volume = {75}, number = {}, pages = {100867}, doi = {10.1016/j.mam.2020.100867}, pmid = {32654761}, issn = {1872-9452}, mesh = {Alzheimer Disease ; Genotype ; Hemochromatosis Protein/*genetics/metabolism ; Humans ; Iron ; *Nervous System Diseases/genetics ; Oxidative Stress ; }, abstract = {Iron accumulation is a recurring pathological phenomenon in many neurological diseases including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and others. Iron is essential for normal development and functions of the brain; however, excess redox-active iron can also lead to oxidative damage and cell death. Especially for terminally differentiated cells like neurons, regulation of reactive oxygen species is critical for cell viability. As a result, cellular iron level is tightly regulated. Although iron accumulation related to neurological diseases has been well documented, the pathoetiological contributions of the homeostatic iron regulator (HFE), which controls cellular iron uptake, is less understood. Furthermore, a common HFE variant, H63D HFE, has been identified as a modifier of multiple neurological diseases. This review will discuss the roles of iron and HFE in the brain as well as their impact on various disease processes.}, }
@article {pmid32654149, year = {2021}, author = {Clark, CM and Clark, RM and Hoyle, JA and Dickson, TC}, title = {Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {156}, number = {3}, pages = {273-289}, doi = {10.1111/jnc.15125}, pmid = {32654149}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Neuropeptide Y/*metabolism ; Receptors, Neuropeptide Y/metabolism ; }, abstract = {Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterized by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end stages of the disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a diverse range of neuroprotective roles in other neurodegenerative diseases; through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signalling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY-receptor signalling in the ALS disease context, as determining NPY's contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease.}, }
@article {pmid32653439, year = {2020}, author = {Volonté, C and Morello, G and Spampinato, AG and Amadio, S and Apolloni, S and D'Agata, V and Cavallaro, S}, title = {Omics-based exploration and functional validation of neurotrophic factors and histamine as therapeutic targets in ALS.}, journal = {Ageing research reviews}, volume = {62}, number = {}, pages = {101121}, doi = {10.1016/j.arr.2020.101121}, pmid = {32653439}, issn = {1872-9649}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Biomarkers ; Histamine ; Humans ; Nerve Growth Factors ; Prognosis ; }, abstract = {A plethora of genetic and molecular mechanisms have been implicated in the pathophysiology of the heterogeneous and multifactorial amyotrophic lateral sclerosis (ALS) disease, and hence the conventional "one target-one drug" paradigm has failed so far to provide effective therapeutic solutions, precisely because of the complex nature of ALS. This review intends to highlight how the integration of emerging "omics" approaches may provide a rational foundation for the comprehensive exploration of molecular pathways and dynamic interactions involved in ALS, for the identification of candidate targets and biomarkers that will assist in the rapid diagnosis and prognosis, lastly for the stratification of patients into different subgroups with the aim of personalized therapeutic strategies. To this purpose, particular emphasis will be placed on some potential therapeutic targets, including neurotrophic factors and histamine signaling that both have emerged as dysregulated at different omics levels in specific subgroups of ALS patients, and have already shown promising results in in vitro and in vivo models of ALS. To conclude, we will discuss about the utility of using integrated omics coupled with network-based approaches to provide additional guidance for personalization of medicine applications in ALS.}, }
@article {pmid32645824, year = {2020}, author = {Wang, T and Zhang, J and Xu, Y}, title = {Epigenetic Basis of Lead-Induced Neurological Disorders.}, journal = {International journal of environmental research and public health}, volume = {17}, number = {13}, pages = {}, pmid = {32645824}, issn = {1660-4601}, mesh = {*Alzheimer Disease ; Animals ; DNA/*genetics ; DNA Methylation/drug effects ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors ; Lead/*adverse effects ; Nervous System Diseases/*chemically induced/genetics ; Neurodegenerative Diseases/genetics ; }, abstract = {Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.}, }
@article {pmid32639325, year = {2020}, author = {Papp, Z and Agostoni, P and Alvarez, J and Bettex, D and Bouchez, S and Brito, D and Černý, V and Comin-Colet, J and Crespo-Leiro, MG and Delgado, JF and Édes, I and Eremenko, AA and Farmakis, D and Fedele, F and Fonseca, C and Fruhwald, S and Girardis, M and Guarracino, F and Harjola, VP and Heringlake, M and Herpain, A and Heunks, LMA and Husebye, T and Ivancan, V and Karason, K and Kaul, S and Kivikko, M and Kubica, J and Masip, J and Matskeplishvili, S and Mebazaa, A and Nieminen, MS and Oliva, F and Papp, JG and Parissis, J and Parkhomenko, A and Põder, P and Pölzl, G and Reinecke, A and Ricksten, SE and Riha, H and Rudiger, A and Sarapohja, T and Schwinger, RHG and Toller, W and Tritapepe, L and Tschöpe, C and Wikström, G and Lewinski, DV and Vrtovec, B and Pollesello, P}, title = {Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.}, journal = {Journal of cardiovascular pharmacology}, volume = {76}, number = {1}, pages = {4-22}, pmid = {32639325}, issn = {1533-4023}, mesh = {Cardiotonic Agents/adverse effects/*therapeutic use ; Heart Failure/diagnosis/*drug therapy/mortality/physiopathology ; Humans ; Myocardial Contraction/*drug effects ; Patient Safety ; Simendan/adverse effects/*therapeutic use ; Treatment Outcome ; Vasodilation/*drug effects ; Vasodilator Agents/adverse effects/*therapeutic use ; }, abstract = {Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.}, }
@article {pmid32639008, year = {2020}, author = {Odeh, HM and Shorter, J}, title = {Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD.}, journal = {Emerging topics in life sciences}, volume = {4}, number = {3}, pages = {293-305}, pmid = {32639008}, issn = {2397-8554}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R21 NS090205/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Arginine ; C9orf72 Protein/genetics ; *DNA Repeat Expansion ; Dipeptides/genetics ; *Frontotemporal Dementia/genetics ; Humans ; Proteomics ; }, abstract = {A hexanucleotide repeat expansion GGGGCC (G4C2) within chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). This seminal realization has rapidly focused our attention to the non-canonical translation (RAN translation) of the repeat expansion, which yields dipeptide-repeat protein products (DPRs). The mechanisms by which DPRs might contribute to C9-ALS/FTD are widely studied. Arginine-rich DPRs (R-DPRs) are the most toxic of the five different DPRs produced in neurons, but how do R-DPRs promote C9-ALS/FTD pathogenesis? Proteomic analyses have uncovered potential pathways to explore. For example, the vast majority of the R-DPR interactome is comprised of disease-linked RNA-binding proteins (RBPs) with low-complexity domains (LCDs), strongly suggesting a link between R-DPRs and aberrations in liquid-liquid phase separation (LLPS). In this review, we showcase several potential mechanisms by which R-DPRs disrupt various phase-separated compartments to elicit deleterious neurodegeneration. We also discuss potential therapeutic strategies to counter R-DPR toxicity in C9-ALS/FTD.}, }
@article {pmid32638429, year = {2021}, author = {Zakharova, M}, title = {Modern approaches in gene therapy of motor neuron diseases.}, journal = {Medicinal research reviews}, volume = {41}, number = {5}, pages = {2634-2655}, doi = {10.1002/med.21705}, pmid = {32638429}, issn = {1098-1128}, mesh = {*Amyotrophic Lateral Sclerosis ; Genetic Therapy ; Genetic Vectors ; Humans ; Infant ; *Muscular Atrophy, Spinal/genetics/therapy ; *Neurodegenerative Diseases ; }, abstract = {Motor neuron disorders are a group of neurodegenerative diseases characterized by muscle weakness, loss of ambulation, respiratory insufficiency, leading to an early death. Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis are the most common and fatal motor neuron diseases. The last 3 years became very successful for novel gene therapy approaches in SMA in infants. Two innovative drugs-nusinersen (Spinraza) and onasemnogene abeparvovec (Zolgensma) have been approved by health authorities. The numerous molecular and genetic overlaps between different neurodegenerative diseases are of great importance in the development of innovative therapeutic strategies, including viral vector therapy and RNA modulating approaches.}, }
@article {pmid32638230, year = {2020}, author = {Termsinsuk, P and Chantarojanasiri, T and Pausawasdi, N}, title = {Diagnosis and treatment of the afferent loop syndrome.}, journal = {Clinical journal of gastroenterology}, volume = {13}, number = {5}, pages = {660-668}, doi = {10.1007/s12328-020-01170-z}, pmid = {32638230}, issn = {1865-7265}, mesh = {*Afferent Loop Syndrome/diagnostic imaging/etiology ; Dilatation ; Gastrectomy ; *Gastric Bypass ; Humans ; }, abstract = {Afferent loop syndrome (ALS) is a mechanical complication that arises after gastric surgery with gastrojejunostomy reconstruction. This condition was first described in 1950 by Roux, Pedoussaut, and Marchal to post-gastrectomy patients with bilious vomiting. Acute ALS is associated with complete obstruction and considered a surgical emergency, whereas chronic ALS is mostly related to partial obstruction of the afferent loop. The delay in diagnosis may lead to intestinal ischemia, perforation and can be associated with a high mortality rate up to 60%. Surgery is usually the mainstay treatment of ALS, but endoscopic therapy, including stent placement in malignancy-related, anastomotic stricture dilation, has been evolving over the past recent years.}, }
@article {pmid32635451, year = {2020}, author = {Mészáros, &#xc1; and Molnár, K and Nógrádi, B and Hernádi, Z and Nyúl-Tóth, &#xc1; and Wilhelm, I and Krizbai, IA}, title = {Neurovascular Inflammaging in Health and Disease.}, journal = {Cells}, volume = {9}, number = {7}, pages = {}, pmid = {32635451}, issn = {2073-4409}, mesh = {Aging/*metabolism/pathology ; Animals ; Humans ; Inflammasomes/*metabolism ; Neurodegenerative Diseases/*metabolism/pathology ; Signal Transduction ; Stroke/*metabolism/pathology ; }, abstract = {Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.}, }
@article {pmid32629520, year = {2020}, author = {Stein, TD and Crary, JF}, title = {Chronic Traumatic Encephalopathy and Neuropathological Comorbidities.}, journal = {Seminars in neurology}, volume = {40}, number = {4}, pages = {384-393}, pmid = {32629520}, issn = {1098-9021}, support = {RF1 AG057768/AG/NIA NIH HHS/United States ; National Institute of Aging//R01NS095252/ ; U01 NS086659/NS/NINDS NIH HHS/United States ; National Institute of Neurological Disorders and Stroke//U01NS086659/ ; I01 CX001038/CX/CSRD VA/United States ; National Institute of Aging//RF1AG054156/ ; National Institute of Aging//R01AG054008/ ; National Institute of Aging Boston University AD Center//P30AG13846/ ; R56 AG057768/AG/NIA NIH HHS/United States ; National Institute of Aging//RF1AG060961/ ; Department of Defense//W81XWH-14-1-0399/ ; R01 AG062348/AG/NIA NIH HHS/United States ; Alzheimer's Association//NIRG-15-363188/ ; P30 AG013846/AG/NIA NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; National Institute of Aging//R01AG057768/ ; R01 NS095252/NS/NINDS NIH HHS/United States ; National Institute of Aging//R56AG057768/ ; Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award//I01-CX001038/ ; RF1 AG060961/AG/NIA NIH HHS/United States ; Veterans Affairs Biorepository//BX002466/ ; National Institute of Aging Boston University AD Center//supplement 0572063345-5/ ; R01 AG054008/AG/NIA NIH HHS/United States ; RF1 AG054156/AG/NIA NIH HHS/United States ; National Institute of Aging//R01AG062348/ ; }, mesh = {*Alzheimer Disease/epidemiology/pathology ; *Amyotrophic Lateral Sclerosis/epidemiology/pathology ; *Chronic Traumatic Encephalopathy/epidemiology/pathology ; Comorbidity ; Humans ; *Lewy Body Disease/epidemiology/pathology ; *Tauopathies/epidemiology/pathology ; }, abstract = {With age, the presence of multiple neuropathologies in a single individual becomes increasingly common. Given that traumatic brain injury and the repetitive head impacts (RHIs) that occur in contact sports have been associated with the development of many neurodegenerative diseases, including chronic traumatic encephalopathy (CTE), Alzheimer's disease, Lewy body disease, and amyotrophic lateral sclerosis, it is becoming critical to understand the relationship and interactions between these pathologies. In fact, comorbid pathology is common in CTE and likely influenced by both age and the severity and type of exposure to RHI as well as underlying genetic predisposition. Here, we review the major comorbid pathologies seen with CTE and in former contact sports athletes and discuss what is known about the associations between RHI, age, and the development of neuropathologies. In addition, we examine the distinction between CTE and age-related pathology including primary age-related tauopathy and age-related tau astrogliopathy.}, }
@article {pmid32629110, year = {2020}, author = {Karagiannis, P and Inoue, H}, title = {ALS, a cellular whodunit on motor neuron degeneration.}, journal = {Molecular and cellular neurosciences}, volume = {107}, number = {}, pages = {103524}, doi = {10.1016/j.mcn.2020.103524}, pmid = {32629110}, issn = {1095-9327}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Astrocytes/metabolism/pathology ; Cell Differentiation/physiology ; Humans ; Induced Pluripotent Stem Cells/*metabolism/pathology ; Motor Neurons/*metabolism/pathology ; Neurodegenerative Diseases/metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets motor neurons. Motor neurons from ALS patients show cytoplasmic inclusions that are reflective of an altered RNA metabolism and protein degradation. Causal gene mutations are found in all cell types even though patient motor neurons are by far the most susceptible to the degeneration. Using induced pluripotent stem cell (iPSC) technology, researchers have generated motor neurons with the same genotype as the patient including sporadic ones. They have also generated other cell types associated with the disease such as astrocytes, microglia and oligodendrocytes. These cells provide not only new insights on the mechanisms of the disease from the early stage, but also a platform for drug screening that has led to several clinical trials. This review examines the knowledge gained from iPSC studies using patient cells on the gene mutations and cellular networks in ALS and relevant experimental therapies.}, }
@article {pmid32628351, year = {2021}, author = {Jeon, JH and Thoudam, T and Choi, EJ and Kim, MJ and Harris, RA and Lee, IK}, title = {Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases.}, journal = {Journal of diabetes investigation}, volume = {12}, number = {1}, pages = {21-31}, pmid = {32628351}, issn = {2040-1124}, support = {NRF-2016M3A9B6902872//National Research Foundation/ ; NRF-2017R1A2B3006406//National Research Foundation/ ; NRF-2020R1C1C1012729//National Research Foundation/ ; HI16C1501//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {Animals ; Humans ; Immune System/*enzymology ; Liver/*enzymology ; Metabolic Diseases/*drug therapy/enzymology/pathology ; Molecular Targeted Therapy ; Muscles/*enzymology ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/*metabolism ; }, abstract = {Good health depends on the maintenance of metabolic flexibility, which in turn is dependent on the maintenance of regulatory flexibility of a large number of regulatory enzymes, but especially the pyruvate dehydrogenase complex (PDC), because of its central role in carbohydrate metabolism. Flexibility in regulation of PDC is dependent on rapid changes in the phosphorylation state of PDC determined by the relative activities of the pyruvate dehydrogenase kinases (PDKs) and the pyruvate dehydrogenase phosphatases. Inactivation of the PDC by overexpression of PDK4 contributes to hyperglycemia, and therefore the serious health problems associated with diabetes. Loss of regulatory flexibility of PDC occurs in other disease states and pathological conditions that have received less attention than diabetes. These include cancers, non-alcoholic fatty liver disease, cancer-induced cachexia, diabetes-induced nephropathy, sepsis and amyotrophic lateral sclerosis. Overexpression of PDK4, and in some situations, the other PDKs, as well as under expression of the pyruvate dehydrogenase phosphatases, leads to inactivation of the PDC, mitochondrial dysfunction and deleterious effects with health consequences. The possible basis for this phenomenon, along with evidence that overexpression of PDK4 results in phosphorylation of "off-target" proteins and promotes excessive transport of Ca[2+] into mitochondria through mitochondria-associated endoplasmic reticulum membranes are discussed. Recent efforts to find small molecule PDK inhibitors with therapeutic potential are also reviewed.}, }
@article {pmid32626703, year = {2020}, author = {Xu, L and Wang, X and Tong, C}, title = {Endoplasmic Reticulum-Mitochondria Contact Sites and Neurodegeneration.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {428}, pmid = {32626703}, issn = {2296-634X}, abstract = {Endoplasmic reticulum-mitochondria contact sites (ERMCSs) are dynamic contact regions with a distance of 10-30 nm between the endoplasmic reticulum and mitochondria. Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, including lipid transfer, calcium homeostasis, autophagy, and mitochondrial dynamics. The dysfunction of ERMCS is closely associated with various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In this review, we will summarize the current knowledge of the components and organization of ERMCSs, the methods for monitoring ERMCSs, and the physiological functions of ERMCSs in different model systems. Additionally, we will emphasize the current understanding of the malfunction of ERMCSs and their potential roles in neurodegenerative diseases.}, }
@article {pmid32625051, year = {2020}, author = {Gunes, ZI and Kan, VWY and Ye, X and Liebscher, S}, title = {Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {573}, pmid = {32625051}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.}, }
@article {pmid32622867, year = {2020}, author = {Bernstein, HG and Keilhoff, G and Dobrowolny, H and Lendeckel, U and Steiner, J}, title = {From putative brain tumor marker to high cognitive abilities: Emerging roles of a disintegrin and metalloprotease (ADAM) 12 in the brain.}, journal = {Journal of chemical neuroanatomy}, volume = {109}, number = {}, pages = {101846}, doi = {10.1016/j.jchemneu.2020.101846}, pmid = {32622867}, issn = {1873-6300}, mesh = {ADAM12 Protein/*metabolism ; Animals ; Biomarkers, Tumor/metabolism ; Brain/*metabolism ; Brain Neoplasms/*diagnosis/metabolism ; Cognition/*physiology ; Humans ; Oligodendroglia/metabolism ; Rats ; }, abstract = {ADAM (a disintergin and metalloprotease) 12 is a member of the large family of multidomain metalloprotease-disintegrins, which possess cell-binding and metalloprotease properties. The enzyme is responsible for the shedding of a number of membrane-bound proteins (heparin-binding-EGF, insulin-like growth factor 2-binding proteins 3 and 5, oxytocinase, glycoprotein non-metastatic melanoma protein B and basigin). In rat and human CNS, ADAM12 is predominantly localized in white and gray matter oligodendrocytes. In addition it can be detected in astrocytes, neurons and endothelial cells. Its function in healthy brain is not well established yet, but prominent roles in CNS development, myelination and high cognitive abilities are discussed. There is increasing evidence that ADAM12 is involved in numerous major diseases of the CNS, which are summarized in the present review (brain tumors, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer´s disease, stroke, schizophrenia, autism and bipolar disorder).}, }
@article {pmid32621411, year = {2020}, author = {Wang, Y and Lu, Y}, title = {[Poly adenosine diphosphate-ribosylation and neurodegenerative diseases].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {49}, number = {1}, pages = {100-106}, pmid = {32621411}, issn = {1008-9292}, mesh = {*ADP-Ribosylation ; Humans ; *Neurodegenerative Diseases/physiopathology ; *Poly Adenosine Diphosphate Ribose ; Poly(ADP-ribose) Polymerases/metabolism ; }, abstract = {The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.}, }
@article {pmid32620242, year = {2020}, author = {Rodríguez-Muela, N}, title = {Autophagy in motor neuron diseases.}, journal = {Progress in molecular biology and translational science}, volume = {172}, number = {}, pages = {157-202}, doi = {10.1016/bs.pmbts.2020.03.009}, pmid = {32620242}, issn = {1878-0814}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; *Autophagy/drug effects/physiology ; Autophagy-Related Proteins/genetics/physiology ; C9orf72 Protein/deficiency/genetics/physiology ; DNA Repeat Expansion ; Disease Models, Animal ; Endocytosis ; Humans ; Mice, Transgenic ; Motor Neuron Disease/genetics/*pathology ; Muscular Atrophy, Spinal/genetics/pathology ; Mutation ; Neurodegenerative Diseases/genetics/pathology ; Organelles ; RNA-Binding Protein FUS/deficiency/genetics/physiology ; TDP-43 Proteinopathies/genetics/pathology ; }, abstract = {Motor neuron diseases (MNDs) are a wide group of neurodegenerative disorders characterized by the degeneration of a specific neuronal type located in the central nervous system, the motor neuron (MN). There are two main types of MNs, spinal and cortical MNs and depending on the type of MND, one or both types are affected. Cortical MNs innervate spinal MNs and these control a variety of cellular targets, being skeletal muscle their main one which is also affected in MNDs. A correct functionality of autophagy is necessary for the survival of all cellular types and it is particularly crucial for neurons, given their postmitotic and highly specialized nature. Numerous studies have identified alterations of autophagy activity in multiple MNDs. The scientific community has been particularly prolific in reporting the role that autophagy plays in the most common adult MND, amyotrophic lateral sclerosis, although many studies have started to identify physiological and pathological functions of this catabolic system in other MNDs, such as spinal muscular atrophy and spinal and bulbar muscular atrophy. The degradation of selective cargo by autophagy and how this process is altered upon the presence of MND-causing mutations is currently also a matter of intense investigation, particularly regarding the selective autophagic clearance of mitochondria. Thorough reviews on this field have been recently published. This chapter will cover the current knowledge on the functionality of autophagy and lysosomal homeostasis in the main MNDs and other autophagy-related topics in the MND field that have risen special interest in the research community.}, }
@article {pmid32612503, year = {2020}, author = {Liu, Z and Cheng, X and Zhong, S and Zhang, X and Liu, C and Liu, F and Zhao, C}, title = {Peripheral and Central Nervous System Immune Response Crosstalk in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {575}, pmid = {32612503}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by muscle weakness due to the degeneration of the upper and lower motor neurons. Neuroinflammation is known as a prominent pathological feature of ALS. Although neuroinflammation cannot trigger ALS, activated central nervous system (CNS) microglia and astrocytes, proinflammatory periphery monocytes/macrophages and T lymphocytes, and infiltrated monocytes/macrophages and T lymphocytes, as well as the immunoreactive molecules they release, are closely related to disease progression. The crosstalk between the peripheral and CNS immune components mentioned above significantly correlates with survival in patients with ALS. This review provides an update on the role of this crosstalk between the CNS and peripheral immune responses in ALS. Additionally, we discuss changes in the composition of gut microbiota because these can directly or indirectly influence this crosstalk. These recent advances may well provide innovative ways for targeting the molecules associated with this crosstalk and breaking the current treatment impasse in ALS.}, }
@article {pmid32612045, year = {2020}, author = {Kimura, M}, title = {[Consideration of Advanced Pharmaceutical Control Functions through Pharmacy-provided Home Pharmaceutical Care].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {140}, number = {7}, pages = {841-850}, doi = {10.1248/yakushi.19-00237-1}, pmid = {32612045}, issn = {1347-5231}, mesh = {*Community Pharmacy Services ; *Delivery of Health Care ; *Home Care Services ; Humans ; Japan ; *Pharmacy ; }, abstract = {In October 2015, the Ministry of Health, Labour and Welfare of Japan newly included "health support functions" and "advanced pharmaceutical control functions" as part of "primary-care pharmacy" in the pharmacy vision for patients. "Health support functions" were defined as recommending that patients seek medical consultations, introducing them to relevant medical institutions, and contributing to disease prevention and health support among local residents, apart from health counseling and the consolidation of a framework for the appropriate selection and supply of and advice on pharmacist-only over-the-counter medications, etc. On the other hand, the term "advanced pharmaceutical control functions" is presumed to imply meeting the needs for advanced pharmaceutical control, e.g., cooperation with specialized medical institutions in addressing adverse reactions caused by anticancer drugs and support of the selection of anti-HIV drugs. However, the details remain unknown. Since the opening of the Akebono pharmacy group 22 years ago, our staff members have visited home-care patients, controlled and guided the use of pharmaceuticals, and supported all types of home-care patients including those with end-stage cancer and amyotrophic lateral sclerosis, undergoing home parenteral nutrition, and pediatric home-care patients. We have experienced many cases requiring sophisticated pharmaceutical control, e.g., pain control with opioids, sterile preparation of transfusions, and supply of special medical devices. We would like to consider the requirements for pharmacy-provided home healthcare that depends heavily on medical treatment as one advanced pharmaceutical control function.}, }
@article {pmid32610599, year = {2020}, author = {Connolly, O and Le Gall, L and McCluskey, G and Donaghy, CG and Duddy, WJ and Duguez, S}, title = {A Systematic Review of Genotype-Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS.}, journal = {Journal of personalized medicine}, volume = {10}, number = {3}, pages = {}, pmid = {32610599}, issn = {2075-4426}, support = {EU Sustainable Competitiveness Programme for N. Ireland//European Regional Development Fund/ ; HSC//Northern Ireland Public Health Agency/ ; Ph.D Fellowship//ArSLA/ ; DELL fellowship//Ulster University/ ; 2019//IICN/ ; }, abstract = {Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease's genotype-phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.}, }
@article {pmid32610099, year = {2020}, author = {Soo, SK and Rudich, PD and Traa, A and Harris-Gauthier, N and Shields, HJ and Van Raamsdonk, JM}, title = {Compounds that extend longevity are protective in neurodegenerative diseases and provide a novel treatment strategy for these devastating disorders.}, journal = {Mechanisms of ageing and development}, volume = {190}, number = {}, pages = {111297}, pmid = {32610099}, issn = {1872-6216}, support = {R01 GM121756/GM/NIGMS NIH HHS/United States ; //CIHR/Canada ; }, mesh = {Aged ; Humans ; *Longevity/drug effects/physiology ; *Neurodegenerative Diseases/classification/genetics/prevention &amp; control ; Protective Agents/*pharmacology ; }, abstract = {While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. In the inherited forms of these diseases, the disease-causing mutation is present from birth but symptoms appear decades later. This indicates that these mutations are well tolerated in younger individuals but not in older adults. Based on this observation, we hypothesized that changes taking place during normal aging make the cells in the brain (and elsewhere) susceptible to the disease-causing mutations. If so, then delaying some of these age-related changes may be beneficial in the treatment of neurodegenerative disease. In this review, we examine the effects of five compounds that have been shown to extend longevity (metformin, rapamycin, resveratrol, N-acetyl-l-cysteine, curcumin) in four of the most common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis). While not all investigations observe a beneficial effect of these compounds, there are multiple studies that show a protective effect of each of these lifespan-extending compounds in animal models of neurodegenerative disease. Combined with genetic studies, this suggests the possibility that targeting the aging process may be an effective strategy to treat neurodegenerative disease.}, }
@article {pmid32598273, year = {2021}, author = {Ebrahimi, T and Abasi, M and Seifar, F and Eyvazi, S and Hejazi, MS and Tarhriz, V and Montazersaheb, S}, title = {Transplantation of Stem Cells as a Potential Therapeutic Strategy in Neurodegenerative Disorders.}, journal = {Current stem cell research &amp; therapy}, volume = {16}, number = {2}, pages = {133-144}, doi = {10.2174/1574888X15666200628141314}, pmid = {32598273}, issn = {2212-3946}, mesh = {Animals ; Humans ; Huntington Disease ; *Neural Stem Cells ; *Neurodegenerative Diseases/therapy ; Parkinson Disease ; *Stem Cell Transplantation ; }, abstract = {Stem cells are considered to have significant capacity to differentiate into various cell types in humans and animals. Unlike specialized cells, these cells can proliferate several times to produce millions of cells. Nowadays, pluripotent stem cells are important candidates to provide a renewable source for the replacement of cells in tissues of interest. The damage to neurons and glial cells in the brain or spinal cord is present in neurological disorders such as Amyotrophic lateral sclerosis, stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, Huntington's disease, spinal cord injury, lysosomal storage disorder, epilepsy, and glioblastoma. Therefore, stem cell transplantation can be used as a novel therapeutic approach in cases of brain and spinal cord damage. Recently, researchers have generated neuron-like cells and glial-like cells from embryonic stem cells, mesenchymal stem cells, and neural stem cells. In addition, several experimental studies have been performed for developing stem cell transplantation in brain tissue. Herein, we focus on stem cell therapy to regenerate injured tissue resulting from neurological diseases and then discuss possible differentiation pathways of stem cells to the renewal of neurons.}, }
@article {pmid32595451, year = {2020}, author = {Ruiz-Ruiz, C and Calzaferri, F and García, AG}, title = {P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {93}, pmid = {32595451}, issn = {1662-5099}, abstract = {This review focuses on the purinergic ionotropic receptor P2X7 (P2X7R) as a potential target for developing drugs that delay the onset and/or disease progression in patients with amyotrophic lateral sclerosis (ALS). Description of clinical and genetic ALS features is followed by an analysis of advantages and drawbacks of transgenic mouse models of disease based on mutations in a bunch of proteins, particularly Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein-43 (TDP-43), Fused in Sarcoma/Translocated in Sarcoma (FUS), and Chromosome 9 open reading frame 72 (C9orf72). Though of limited value, these models are however critical to study the proof of concept of new compounds, before reaching clinical trials. The authors also provide a description of ALS pathogenesis including protein aggregation, calcium-dependent excitotoxicity, dysfunction of calcium-binding proteins, ultrastructural mitochondrial alterations, disruption of mitochondrial calcium handling, and overproduction of reactive oxygen species (ROS). Understanding disease pathogenic pathways may ease the identification of new drug targets. Subsequently, neuroinflammation linked with P2X7Rs in ALS pathogenesis is described in order to understand the rationale of placing the use of P2X7R antagonists as a new therapeutic pharmacological approach to ALS. This is the basis for the hypothesis that a P2X7R blocker could mitigate the neuroinflammatory state, indirectly leading to neuroprotection and higher motoneuron survival in ALS patients.}, }
@article {pmid32594029, year = {2020}, author = {Foster, AD and Rea, SL}, title = {The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis.}, journal = {Neural regeneration research}, volume = {15}, number = {12}, pages = {2186-2194}, pmid = {32594029}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic, pathological and clinical overlap. One such overlap is the presence of SQSTM1/p62 mutations. While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget's disease of bone, mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system, and also regulates cell survival via the Nrf2 antioxidant response pathway, the nuclear factor-kappa B signaling pathway and apoptosis. Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis. In this review we discuss the role of p62 in these pathways, the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1, in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.}, }
@article {pmid32586697, year = {2020}, author = {Alejos, M and Vázquez-Bourgon, J and Santurtún, M and Riancho, J and Santurtún, A}, title = {Do patients diagnosed with a neurological disease present increased risk of suicide?.}, journal = {Neurologia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.nrl.2020.03.003}, pmid = {32586697}, issn = {2173-5808}, abstract = {INTRODUCTION: Neurological diseases are the leading cause of disability and the second leading cause of death worldwide. Physical and psychological pain, despair, and disconnection with the environment are observed after the diagnosis of numerous neurological processes, particularly neurodegenerative diseases.<br><br>DEVELOPMENT: A higher risk of suicide is observed in patients with such common neurological diseases as epilepsy, migraine, and multiple sclerosis, as well as in those with such degenerative disorders as Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and Parkinson's disease. In most cases, suicidal ideation appears in the early stages after diagnosis, in the presence of disabling symptoms, and/or in patients with psychiatric comorbidities (often associated with these neurological diseases).<br><br>CONCLUSIONS: Effective suicide prevention in this population group requires assessment of the risk of suicide mainly in newly diagnosed patients, in patients showing unmistakable despair or disabling symptoms, and in patients presenting psychiatric comorbidities (especially depressive symptoms). It is essential to train specialists to detect warning signs in order that they may adopt a suitable approach and determine when psychiatric assessment is required.}, }
@article {pmid32586047, year = {2020}, author = {Albert-Gascó, H and Ros-Bernal, F and Castillo-Gómez, E and Olucha-Bordonau, FE}, title = {MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes.}, journal = {International journal of molecular sciences}, volume = {21}, number = {12}, pages = {}, pmid = {32586047}, issn = {1422-0067}, support = {19I436//Fundaci&#xf3;n Alicia Koplowitz/ ; RTI2018-095698-B-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; UJI-B2019-54//Universitat Jaume I/ ; UJI-A2017-17//Universitat Jaume I/ ; }, mesh = {Animals ; *Cognition ; *Emotions ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; *Memory ; Mitogen-Activated Protein Kinases/*metabolism ; Neurodegenerative Diseases/etiology/metabolism/*pathology ; }, abstract = {The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes.}, }
@article {pmid32583696, year = {2020}, author = {Blasco, H and Lanznaster, D and Veyrat-Durebex, C and Hergesheimer, R and Vourch, P and Maillot, F and Andres, CR and Pradat, PF and Corcia, P}, title = {Understanding and managing metabolic dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {9}, pages = {907-919}, doi = {10.1080/14737175.2020.1788389}, pmid = {32583696}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Metabolic Diseases/*etiology/*therapy ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease that leads to death after a median survival of 36 months. The development of an effective treatment has proven to be extremely difficult due to the inadequate understanding of the pathogenesis of ALS. Energy metabolism is thoroughly involved in the disease based on the discoveries of hypermetabolism, lipid/glucose metabolism, the tricarboxylic acid (TCA) cycle, and mitochondrial impairment.<br><br>AREA COVERED: Many perturbed metabolites within these processes have been identified as promising therapeutic targets. However, the therapeutic strategies targeting these pathways have failed to produce clinically significant results. The authors present in this review the metabolic disturbances observed in ALS and the derived-therapeutics.<br><br>EXPERT OPINION: The authors suggest that this is due to the insufficient knowledge of the relationship between the metabolic targets and the type of ALS of the patient, depending on genetic and environmental factors. We must improve our understanding of the pathological mechanisms and pay attention to the subtle hidden effects of changing diet, for example, and to use this strategy in addition to other drugs or to use metabolism status to determine subgroups of patients.}, }
@article {pmid32581709, year = {2020}, author = {Malik, R and Wiedau, M}, title = {Therapeutic Approaches Targeting Protein Aggregation in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {98}, pmid = {32581709}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease that targets motor neurons (MNs) in the brain and spinal cord. It leads to gradual loss of motor signals to muscles leading to atrophy and weakness. Most patients do not survive for more than 3-5 years after disease onset. Current ALS treatments provide only a small delay of disease progression. Therefore, it is of utmost importance to explore new therapeutic approaches. One of the major hindrances in achieving this goal is poor understanding of causes of the disease. ALS has complex pathophysiological mechanisms in its genetic and sporadic forms. Protein aggregates are a common hallmark of ALS regardless of cause making protein pathways attractive therapeutic targets in ALS. Here, we provide an overview of compounds in different stages of pharmacological development and their protein pathway targets.}, }
@article {pmid32576616, year = {2020}, author = {Kiernan, MC and Shefner, JM and Kaji, R and Burke, D}, title = {Amyotrophic lateral sclerosis: a new diagnostic paradigm.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {91}, number = {9}, pages = {903-904}, doi = {10.1136/jnnp-2020-324006}, pmid = {32576616}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Australia ; Consensus ; Humans ; }, }
@article {pmid32569484, year = {2020}, author = {McCombe, PA and Garton, FC and Katz, M and Wray, NR and Henderson, RD}, title = {What do we know about the variability in survival of patients with amyotrophic lateral sclerosis?.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {9}, pages = {921-941}, doi = {10.1080/14737175.2020.1785873}, pmid = {32569484}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*mortality ; Humans ; }, abstract = {INTRODUCTION: ALS is a fatal neurodegenerative disease. However, patients show variability in the length of survival after symptom onset. Understanding the mechanisms of long survival could lead to possible avenues for therapy.<br><br>AREAS COVERED: This review surveys the reported length of survival in ALS, the clinical features that predict survival in individual patients, and possible factors, particularly genetic factors, that could cause short or long survival. The authors also speculate on possible mechanisms.<br><br>EXPERT OPINION: a small number of known factors can explain some variability in ALS survival. However, other disease-modifying factors likely exist. Factors that alter motor neurone vulnerability and immune, metabolic, and muscle function could affect survival by modulating the disease process. Knowing these factors could lead to interventions to change the course of the disease. The authors suggest a broad approach is needed to quantify the proportion of variation survival attributable to genetic and non-genetic factors and to identify and estimate the effect size of specific factors. Studies of this nature could not only identify novel avenues for therapeutic research but also play an important role in clinical trial design and personalized medicine.}, }
@article {pmid32568450, year = {2020}, author = {Chang, Y and Kim, J and Park, H and Choi, H and Kim, J}, title = {Modelling neurodegenerative diseases with 3D brain organoids.}, journal = {Biological reviews of the Cambridge Philosophical Society}, volume = {95}, number = {5}, pages = {1497-1509}, doi = {10.1111/brv.12626}, pmid = {32568450}, issn = {1469-185X}, support = {NRF-2016H1A2A1909149//National Research Foundation of Korea/International ; NRF-2017M3A9C6029306//National Research Foundation of Korea/International ; NRF-2020R1A2C3007378//National Research Foundation of Korea/International ; }, mesh = {*Alzheimer Disease ; Animals ; Brain ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Organoids ; }, abstract = {Neurodegenerative diseases are incurable and debilitating conditions characterized by the deterioration of brain function. Most brain disease models rely on human post-mortem brain tissue, non-human primate tissue, or in vitro two-dimensional (2D) experiments. Resource limitations and the complexity of the human brain are some of the reasons that make suitable human neurodegenerative disease models inaccessible. However, recently developed three-dimensional (3D) brain organoids derived from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs, may provide suitable models for the study of the pathological features of neurodegenerative diseases. In this review, we provide an overview of existing 3D brain organoid models and discuss recent advances in organoid technology that have increased our understanding of brain development. Moreover, we explain how 3D organoid models recapitulate aspects of specific neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and explore the utility of these models, for therapeutic applications.}, }
@article {pmid32564745, year = {2020}, author = {Miller, JH and Das, V}, title = {Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules.}, journal = {Current pharmaceutical design}, volume = {26}, number = {35}, pages = {4362-4372}, doi = {10.2174/1381612826666200621171302}, pmid = {32564745}, issn = {1873-4286}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Biological Products/pharmacology ; Humans ; Microtubules ; *Neurodegenerative Diseases/drug therapy ; *Tauopathies ; tau Proteins ; }, abstract = {No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick's disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.}, }
@article {pmid32563294, year = {2020}, author = {Mariani, LL and Corvol, JC}, title = {Maximizing placebo response in neurological clinical practice.}, journal = {International review of neurobiology}, volume = {153}, number = {}, pages = {71-101}, doi = {10.1016/bs.irn.2020.04.003}, pmid = {32563294}, issn = {2162-5514}, mesh = {Humans ; Nervous System Diseases/*therapy ; Personality/*physiology ; *Placebo Effect ; Placebos/*therapeutic use ; }, abstract = {The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its positive potential to increase known drug effects has been neglected for too long. The placebo and nocebo responses have been described in many neurologic disorders such as Parkinson's, Huntington's and Alzheimer's diseases, restless leg syndrome, tics, essential tremor, dystonia, functional movement disorders, neuropathic pain, headaches, migraine, amyotrophic lateral sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis and epilepsy. Knowledge regarding placebo mechanisms and their consequences on clinical outcome have greatly improved over the last two decades. This evolution has led to reconsiderations of the importance of placebo response in the clinic and has given several clues on how to improve it in daily practice. In this chapter, we first illustrate "why," e.g. the reasons (relevance to clinical practice, help in differential diagnosis/treatment of psychogenic movements, clinical impact, proven neurobiological grounds, health economic potential), and "how," e.g. the means (increase patients' knowledge, increase learning, improve patient-doctor relationship, increase Hawthorne effect, increase positive/decrease negative expectations (the Rosenthal effect), personalize placebo response), the placebo should be maximized (and nocebo avoided) in neurological clinical practice. Future studies regarding more specific neurobiological mechanisms will allow a finer tuning of placebo response in clinical practice. The use of placebo in clinical practice raises ethical issues, and a recent expert consensus regarding placebo use in the clinic is a first step to future guidelines necessary to this field.}, }
@article {pmid32560789, year = {2020}, author = {Chernoff, YO and Grizel, AV and Rubel, AA and Zelinsky, AA and Chandramowlishwaran, P and Chernova, TA}, title = {Application of yeast to studying amyloid and prion diseases.}, journal = {Advances in genetics}, volume = {105}, number = {}, pages = {293-380}, pmid = {32560789}, issn = {0065-2660}, support = {P50 AG025688/AG/NIA NIH HHS/United States ; P51 OD011132/OD/NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism ; Amyloid beta-Peptides/chemistry/genetics/*metabolism ; Amyloidosis/genetics/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Humans ; Parkinson Disease/genetics/metabolism ; Prion Diseases/genetics/*metabolism ; Prions/*metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*metabolism ; alpha-Synuclein/*metabolism ; tau Proteins/genetics/*metabolism ; }, abstract = {Amyloids are fibrous cross-β protein aggregates that are capable of proliferation via nucleated polymerization. Amyloid conformation likely represents an ancient protein fold and is linked to various biological or pathological manifestations. Self-perpetuating amyloid-based protein conformers provide a molecular basis for transmissible (infectious or heritable) protein isoforms, termed prions. Amyloids and prions, as well as other types of misfolded aggregated proteins are associated with a variety of devastating mammalian and human diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, transmissible spongiform encephalopathies (TSEs), amyotrophic lateral sclerosis (ALS) and transthyretinopathies. In yeast and fungi, amyloid-based prions control phenotypically detectable heritable traits. Simplicity of cultivation requirements and availability of powerful genetic approaches makes yeast Saccharomyces cerevisiae an excellent model system for studying molecular and cellular mechanisms governing amyloid formation and propagation. Genetic techniques allowing for the expression of mammalian or human amyloidogenic and prionogenic proteins in yeast enable researchers to capitalize on yeast advantages for characterization of the properties of disease-related proteins. Chimeric constructs employing mammalian and human aggregation-prone proteins or domains, fused to fluorophores or to endogenous yeast proteins allow for cytological or phenotypic detection of disease-related protein aggregation in yeast cells. Yeast systems are amenable to high-throughput screening for antagonists of amyloid formation, propagation and/or toxicity. This review summarizes up to date achievements of yeast assays in application to studying mammalian and human disease-related aggregating proteins, and discusses both limitations and further perspectives of yeast-based strategies.}, }
@article {pmid32560258, year = {2020}, author = {Galbiati, M and Crippa, V and Rusmini, P and Cristofani, R and Messi, E and Piccolella, M and Tedesco, B and Ferrari, V and Casarotto, E and Chierichetti, M and Poletti, A}, title = {Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {21}, number = {12}, pages = {}, pmid = {32560258}, issn = {1422-0067}, support = {GGP14039//Fondazione Telethon/ ; GGP19128//Fondazione Telethon/ ; 2018 grant//Kennedy's Disease Association/ ; 2014-0686//Fondazione Cariplo/ ; 2017-0747//Fondazione Cariplo/ ; ALS_HSPB8//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; ALS_Granulopathy//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Target_RAN//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 16406//Association Fran&#xe7;aise contre les Myopathies/ ; Piano di sviluppo UNIMI - linea B//Universit&#xe0; degli Studi di Milano/ ; Bando SEED 2019: #TDP-43-iPSC//Universit&#xe0; degli Studi di Milano/ ; PRIN 2015LFPNMN//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; 2018//Fondo per il Finanziamento delle Attivit&#xe0; Base di Ricerca/ ; Co_ALS//Agenzia Italiana del Farmaco, Ministero della Salute/ ; TRANS_ALS//Fondazione Regionale per la Ricerca Biomedica/ ; 01ED1601A, CureALS//EU Joint Programme - Neurodegenerative Disease Research/ ; Progetto Dipartimenti di Eccellenza//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; PRIN 2017F2AC5//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Gene Expression Regulation ; Glutamic Acid/*metabolism ; Humans ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/metabolism ; Neuroglia/metabolism ; Signal Transduction ; Transforming Growth Factor beta/*metabolism ; }, abstract = {Transforming growth factor beta (TGFB) is a pleiotropic cytokine known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial cells, and the target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed, in order to foster new approaches to treat ALS.}, }
@article {pmid32558493, year = {2020}, author = {Thakur, K and Tiwari, A and Sharma, K and Modgil, S and Khosla, R and Anand, A}, title = {Angiogenesis-Centered Molecular Cross-Talk in Amyotrophic Lateral Sclerosis Survival: Mechanistic Insights.}, journal = {Critical reviews in eukaryotic gene expression}, volume = {30}, number = {2}, pages = {137-151}, doi = {10.1615/CritRevEukaryotGeneExpr.2020031020}, pmid = {32558493}, issn = {1045-4403}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Carrier Proteins/*genetics ; Cell Cycle Proteins/genetics ; Cytoplasm/genetics ; DNA-Binding Proteins/*genetics ; Humans ; Membrane Transport Proteins/genetics ; Mutation/genetics ; Neovascularization, Pathologic/*genetics/pathology ; Nuclear Proteins/*genetics ; Progranulins/genetics ; Ribonuclease, Pancreatic/genetics ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized with progressive muscle atrophy. We have attempted to establish the link between angiogenesis and cellular survival in the pathogenesis of ALS by compiling evidence described in various scientific reports. The phenotypes of human ALS have earlier been captured in the mutant SOD1 mice as well as by targeted deletion of the hypoxia response element (HRE) from the promoter of the mouse gene for vascular endothelial growth factor (VEGF). Indirect evidence shows that angiogenesis can help prevent oxidative stress, and hence, enhance cell survival. VEGF and angiogenin chiefly regulate the process of angiogenesis. Transactive response DNA-binding protein 43 (TDP-43) is usually found inside the nucleus, but in large number of cases of ALS, it accumulates in the cytoplasm (TDP-43 proteinopathy). Interestingly, TDP-43 proteinopathy is found to be aggravated in the presence of the OPTN mutation, which is the genetic factor that is responsible for such accumulation. Interaction of TDP-43 with progranulin can further affect the angiogenesis in ALS patients by regulating activity of VEGF receptors, but conclusive evidence is needed to establish its role in pathogenesis of ALS. Certain mutations in UBQLN2 and UBQLN4 indicate that ubiquitination has a role in ALS pathobiology, but its link to angiogenesis has not been adequately studied. Recent studies have shown that several mutations in RNA-binding proteins (RBPs) can also cause ALS. Conclusively, in this review, we have attempted to argue the role of angiogenesis in enhanced ALS survival rate is probably regulated with the activation of NF-κβ. Additionally, interaction between OPTN and TDP-43 can also impact the transcription of various angiogenic molecules. Whether targeting angiogenic substances or TDP-43 can provide clues about extending ALS survival rate, in combination with current treatments, can only be evaluated after additional studies.}, }
@article {pmid32552649, year = {2020}, author = {Kabir, MT and Uddin, MS and Abdeen, A and Ashraf, GM and Perveen, A and Hafeez, A and Bin-Jumah, MN and Abdel-Daim, MM}, title = {Evidence Linking Protein Misfolding to Quality Control in Progressive Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {20}, number = {23}, pages = {2025-2043}, doi = {10.2174/1568026620666200618114924}, pmid = {32552649}, issn = {1873-4294}, mesh = {Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Protein Folding ; Proteins/genetics/*metabolism ; Quality Control ; }, abstract = {Several proteolytic systems including ubiquitin (Ub)-proteasome system (UPS), chaperonemediated autophagy (CMA), and macroautophagy are used by the mammalian cells to remove misfolded proteins (MPs). UPS mediates degradation of most of the MPs, where Ub-conjugated substrates are deubiquitinated, unfolded, and passed through the proteasome's narrow chamber, and eventually break into smaller peptides. It has been observed that the substrates that show a specific degradation signal, the KFERQ sequence motif, can be delivered to and go through CMA-mediated degradation in lysosomes. Macroautophagy can help in the degradation of substrates that are prone to aggregation and resistant to both the CMA and UPS. In the aforesaid case, cargoes are separated into autophagosomes before lysosomal hydrolase-mediated degradation. Even though the majority of the aggregated and MPs in the human proteome can be removed via cellular protein quality control (PQC), some mutant and native proteins tend to aggregate into β-sheet-rich oligomers that exhibit resistance to all identified proteolytic processes and can, therefore, grow into extracellular plaques or inclusion bodies. Indeed, the buildup of protease-resistant aggregated and MPs is a usual process underlying various protein misfolding disorders, including neurodegenerative diseases (NDs) for example Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In this article, we have focused on the contribution of PQC in the degradation of pathogenic proteins in NDs.}, }
@article {pmid32547681, year = {2020}, author = {Wang, J and Hu, WW and Jiang, Z and Feng, MJ}, title = {Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors.}, journal = {World journal of stem cells}, volume = {12}, number = {5}, pages = {323-338}, pmid = {32547681}, issn = {1948-0210}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.}, }
@article {pmid32545788, year = {2020}, author = {Fusco, R and Siracusa, R and Genovese, T and Cuzzocrea, S and Di Paola, R}, title = {Focus on the Role of NLRP3 Inflammasome in Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {12}, pages = {}, pmid = {32545788}, issn = {1422-0067}, mesh = {Animals ; Caspase 1/metabolism ; Humans ; Immunity, Innate ; Inflammasomes/*metabolism ; Inflammation/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; }, abstract = {Inflammation is a protective reaction activated in response to detrimental stimuli, such as dead cells, irritants or pathogens, by the evolutionarily conserved immune system and is regulated by the host. The inflammasomes are recognized as innate immune system sensors and receptors that manage the activation of caspase-1 and stimulate inflammation response. They have been associated with several inflammatory disorders. The NLRP3 inflammasome is the most well characterized. It is so called because NLRP3 belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent evidence has greatly improved our understanding of the mechanisms by which the NLRP3 inflammasome is activated. Additionally, increasing data in animal models, supported by human studies, strongly implicate the involvement of the inflammasome in the initiation or progression of disorders with a high impact on public health, such as metabolic pathologies (obesity, type 2 diabetes, atherosclerosis), cardiovascular diseases (ischemic and non-ischemic heart disease), inflammatory issues (liver diseases, inflammatory bowel diseases, gut microbiome, rheumatoid arthritis) and neurologic disorders (Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurological disorders), compared to other molecular platforms. This review will provide a focus on the available knowledge about the NLRP3 inflammasome role in these pathologies and describe the balance between the activation of the harmful and beneficial inflammasome so that new therapies can be created for patients with these diseases.}, }
@article {pmid32538885, year = {2020}, author = {Ceravolo, MG}, title = {Is cell-based therapy more efficacious for people with amyotrophic lateral sclerosis/motor neuron disease than placebo or no treatment? - A Cochrane review summary with commentary.}, journal = {NeuroRehabilitation}, volume = {46}, number = {4}, pages = {613-615}, doi = {10.3233/NRE-209004}, pmid = {32538885}, issn = {1878-6448}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Mesenchymal Stem Cell Transplantation/*adverse effects/methods ; Placebo Effect ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Even if there is sparse evidence of efficacy of stem cell administration for amyotrophic lateral sclerosis (ALS) in preclinical studies, the clinical use of cell-based therapy is yet to be defined.<br><br>OBJECTIVE: To assess the efficacy, feasibility and safety of cell-based therapy in people with ALS/MND, compared with placebo or no treatment.<br><br>METHODS: A Cochrane Review on the topic was summarized with comments.<br><br>RESULTS: Two randomized controlled trials met the selection criteria, but only one provided data useful for the analysis. It compared autologous bone marrow-mesenchymal stem cells, combined with riluzole, to riluzole only, in 64 people with ALS. The ALS Functional Rating Scale-Revised score slightly improved 6 months after the intervention, though the change was not clinically meaningful. Respiratory function, overall survival and the risk of total adverse events or serious adverse events were not different in the two groups.<br><br>CONCLUSIONS: The available evidence does not support the use of bone marrow-mesenchymal stem cells to treat people with ALS/MND.}, }
@article {pmid32536900, year = {2020}, author = {Gaur, N and Perner, C and Witte, OW and Grosskreutz, J}, title = {The Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis: Signals From the CNS and Beyond.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {377}, pmid = {32536900}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative condition, most widely characterized by the selective vulnerability of motor neurons and the poor life expectancy of afflicted patients. Limited disease-modifying therapies currently exist, which only further attests to the substantial heterogeneity associated with this disease. In addition to established prognostic factors like genetic background, site of onset, and age at onset, wide consensus on the role of neuroinflammation as a disease exacerbator and driver has been established. In lieu of this, the emerging literature on chitinases in ALS is particularly intriguing. Individual groups have reported substantially elevated chitotriosidase (CHIT1), chitinase-3-like-1 (CHI3L1), and chitinase-3-like-2 (CHI3L2) levels in the cerebrospinal, motor cortex, and spinal cord of ALS patients with multiple-and often conflicting-lines of evidence hinting at possible links to disease severity and progression. This mini-review, while not exhaustive, will aim to discuss current evidence on the involvement of key chitinases in ALS within the wider framework of other neurodegenerative conditions. Implications for understanding disease etiology, developing immunomodulatory therapies and biomarkers, and other translational opportunities will be considered.}, }
@article {pmid32529183, year = {2020}, author = {Wang, GY and Rayner, SL and Chung, R and Shi, BY and Liang, XJ}, title = {Advances in nanotechnology-based strategies for the treatments of amyotrophic lateral sclerosis.}, journal = {Materials today. Bio}, volume = {6}, number = {}, pages = {100055}, pmid = {32529183}, issn = {2590-0064}, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease that affects both upper and lower motor neurons, which results in loss of muscle control and eventual paralysis [1]. Currently, there are as yet unresolved challenges regarding efficient drug delivery into the central nervous system (CNS). These challenges can be attributed to multiple factors including the presence of the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), as well as the inherent characteristics of the drugs themselves (e.g. low solubility, insufficient bioavailability/bio-stability, 'off-target' effects) etc. As a result, conventional drug delivery systems may not facilitate adequate dosage of the required drugs for functional recovery in ALS patients. Nanotechnology-based strategies, however, employ engineered nanostructures that show great potential in delivering single or combined therapeutic agents to overcome the biological barriers, enhance interaction with targeted sites, improve drug bioavailability/bio-stability and achieve real-time tracking while minimizing the systemic side-effects. This review provides a concise discussion of recent advances in nanotechnology-based strategies in relation to combating specific pathophysiology relevant to ALS disease progression and investigates the future scope of using nanotechnology to develop innovative treatments for ALS patients.}, }
@article {pmid32528400, year = {2020}, author = {Alessenko, AV and Albi, E}, title = {Exploring Sphingolipid Implications in Neurodegeneration.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {437}, pmid = {32528400}, issn = {1664-2295}, abstract = {Over the past decade, it was found that relatively simple sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate, and glucosylceramide play important roles in neuronal functions by regulating rates of neuronal growth and differentiation. Homeostasis of membrane sphingolipids in neurons and myelin is essential to prevent the loss of synaptic plasticity, cell death and neurodegeneration. In our review we summarize data about significant brain cell alterations of sphingolipids in different neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Amyotrophic Lateral Sclerosis, Gaucher's, Farber's diseases, etc. We reported results obtained in brain tissue from both animals in which diseases were induced and humans in autopsy samples. Moreover, attention was paid on sphingolipids in biofluids, liquor and blood, from patients. In Alzheimer's disease sphingolipids are involved in the processing and aggregation of β-amyloid and in the transmission of the cytotoxic signal β-amyloid and TNFα-induced. Recently, the gangliosides metabolism in transgenic animals and the relationship between blood sphingolipids changes and cognitive impairment in Alzheimer's disease patients have been intensively studied. Numerous experiments have highlighted the involvement of ceramide and monohexosylceramide metabolism in the pathophysiology of the sporadic forms of Parkinson's disease. Moreover, gene mutations of the glucocerebrosidase enzyme were considered as responsible for Parkinson's disease via transition of the monomeric form of α-synuclein to an oligomeric, aggregated toxic form. Disturbances in the metabolism of ceramides were also associated with the appearance of Lewy's bodies. Changes in sphingolipid metabolism were found as a manifestation of Amyotrophic Lateral Sclerosis, both sporadic and family forms, and affected the rate of disease development. Currently, fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator, is the only drug undergoing clinical trials of phase II safety for the treatment of Amyotrophic Lateral Sclerosis. The use of sphingolipids as new diagnostic markers and as targets for innovative therapeutic strategies in different neurodegenerative disorders has been included.}, }
@article {pmid32528241, year = {2020}, author = {Kuraszkiewicz, B and Goszczyńska, H and Podsiadły-Marczykowska, T and Piotrkiewicz, M and Andersen, P and Gromicho, M and Grosskreutz, J and Kuźma-Kozakiewicz, M and Petri, S and Stubbendorf, B and Szacka, K and Uysal, H and de Carvalho, M}, title = {Potential Preventive Strategies for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {428}, pmid = {32528241}, issn = {1662-4548}, abstract = {It may seem useless to propose preventive measures for a disease without established pathogenesis and successful therapy, such as amyotrophic lateral sclerosis (ALS). However, we will show that ALS shares essential molecular mechanisms with aging and that established anti-aging strategies, such as healthy diet or individually adjusted exercise, may be successfully applied to ameliorate the condition of ALS patients. These strategies might be applied for prevention if persons at ALS risk could be identified early enough. Recent research advances indicate that this may happen soon.}, }
@article {pmid32526057, year = {2020}, author = {Masrori, P and Van Damme, P}, title = {Amyotrophic lateral sclerosis: a clinical review.}, journal = {European journal of neurology}, volume = {27}, number = {10}, pages = {1918-1929}, pmid = {32526057}, issn = {1468-1331}, support = {C1-C14-17-107//KU Leuven/International ; //Opening the Future Fund (KU Leuven)/International ; //the Fund for Scientific Research Flanders (FWO-Flanders)/International ; //the ALS Liga Belgium/International ; //Een Hart voor ALS/International ; //'/International ; //Laeversfonds voor ALS Onderzoek/International ; //Val&#xe9;ry Perrier Race against ALS Fund/International ; SAO-FRA 2017/023//the Alzheimer Research Foundation/International ; VIND 135043//the Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research/International ; //Flanders Innovation and Enterpreneurship (IWT grants Project MinE and iPSCAF)/International ; //the Belgian National Lottery/International ; //the Latran Foundation/International ; 755094//the European Union's Horizon 2020 research and innovation programme/International ; //the European Union's ERA-Net for Research Programmes on Rare Diseases (INTEGRALS)/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; C9orf72 Protein/genetics ; DNA-Binding Proteins ; *Frontotemporal Dementia/epidemiology/genetics/therapy ; Humans ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.}, }
@article {pmid32523513, year = {2020}, author = {Falgairolle, M and O'Donovan, MJ}, title = {Motoneuronal Spinal Circuits in Degenerative Motoneuron Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {74}, pmid = {32523513}, issn = {1662-5099}, abstract = {The most evident phenotype of degenerative motoneuron disease is the loss of motor function which accompanies motoneuron death. In both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), it is now clear that dysfunction is not restricted to motoneurons but is manifest in the spinal circuits in which motoneurons are embedded. As mounting evidence shows that motoneurons possess more elaborate and extensive connections within the spinal cord than previously realized, it is necessary to consider the role of this circuitry and its dysfunction in the disease process. In this review article, we ask if the selective vulnerability of the different motoneuron types and the relative disease resistance of distinct motoneuron groups can be understood in terms of their intraspinal connections.}, }
@article {pmid32520676, year = {2021}, author = {Liu, YD and Tang, G and Qian, F and Liu, L and Huang, JR and Tang, FR}, title = {Astroglial Connexins in Neurological and Neuropsychological Disorders and Radiation Exposure.}, journal = {Current medicinal chemistry}, volume = {28}, number = {10}, pages = {1970-1986}, doi = {10.2174/0929867327666200610175037}, pmid = {32520676}, issn = {1875-533X}, mesh = {*Astrocytes ; *Connexins ; Endothelial Cells ; Humans ; *Nervous System Diseases ; *Radiation Exposure ; }, abstract = {Radiotherapy is a common treatment for brain and spinal cord tumors and also a risk factor for neuropathological changes in the brain leading to different neurological and neuropsychological disorders. Astroglial connexins are involved in brain inflammation, development of Alzheimer's Disease (AD), depressive, epilepsy, and amyotrophic lateral sclerosis, and are affected by radiation exposure. Therefore, it is speculated that radiation-induced changes of astroglial connexins may be related to the brain neuropathology and development of neurological and neuropsychological disorders. In this paper, we review the functional expression and regulation of astroglial connexins expressed between astrocytes and different types of brain cells (including oligodendrocytes, microglia, neurons and endothelial cells). The roles of these connexins in the development of AD, depressive, epilepsy, amyotrophic lateral sclerosis and brain inflammation have also been summarized. The radiation-induced astroglial connexins changes and development of different neurological and neuropsychological disorders are then discussed. Based on currently available data, we propose that radiation-induced astroglial connexins changes may be involved in the genesis of different neurological and neuropsychological disorders which depends on the age, brain regions, and radiation doses/dose rates. The abnormal astroglial connexins may be novel therapeutic targets for the prevention of radiation-induced cognitive impairment, neurological and neuropsychological disorders.}, }
@article {pmid32516966, year = {2020}, author = {Tilocca, B and Pieroni, L and Soggiu, A and Britti, D and Bonizzi, L and Roncada, P and Greco, V}, title = {Gut-Brain Axis and Neurodegeneration: State-of-the-Art of Meta-Omics Sciences for Microbiota Characterization.}, journal = {International journal of molecular sciences}, volume = {21}, number = {11}, pages = {}, pmid = {32516966}, issn = {1422-0067}, mesh = {Animals ; Brain/*physiology ; *Disease Susceptibility ; *Feedback, Physiological ; Gastrointestinal Tract/*physiology ; Genomics/methods ; Humans ; Metabolomics/methods ; Metagenomics/methods ; Microbiota ; Neurodegenerative Diseases/*etiology/*metabolism ; Proteomics/methods ; }, abstract = {Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in a finely tuned network of interconnections with the host, orchestrating a wide variety of physiological processes. These includes the bi-directional crosstalk between the central nervous system, the enteric nervous system, and the gastrointestinal tract (i.e., gut-brain axis). The increasing accumulation of evidence suggest a pivotal role of the composition and activity of the gut microbiota in neurodegeneration. In the present review we aim to provide an overview of the state-of-the-art of meta-omics sciences including metagenomics for the study of microbial genomes and taxa strains, metatranscriptomics for gene expression, metaproteomics and metabolomics to identify and/or quantify microbial proteins and metabolites, respectively. The potential and limitations of each discipline were highlighted, as well as the advantages of an integrated approach (multi-omics) to predict microbial functions and molecular mechanisms related to human diseases. Particular emphasis is given to the latest results obtained with these approaches in an attempt to elucidate the link between the gut microbiota and the most common neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid32513219, year = {2020}, author = {Tang, X and Toro, A and T G, S and Gao, J and Chalk, J and Oskarsson, B and Zhang, K}, title = {Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {34}, pmid = {32513219}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein/*genetics ; Cytological Techniques/methods ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/*genetics ; Humans ; Mutation/*genetics ; }, abstract = {Ever since a GGGGCC hexanucleotide repeat expansion mutation in C9ORF72 was identified as the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), three competing but nonexclusive hypotheses to explain how this mutation causes diseases have been proposed and are still under debate. Recent studies in the field have tried to understand how the repeat expansion disrupts cellular physiology, which has suggested interesting convergence of these hypotheses on downstream, functional defects in cells, such as nucleocytoplasmic transport disruption, membrane-less organelle defects, and DNA damage. These studies have not only provided an integrated view of the disease mechanism but also revealed novel cell biology implicated in neurodegeneration. Furthermore, some of the discoveries have given rise to new ideas for therapeutic development. Here, we review the research progress on cellular pathophysiology of C9ORF72-mediated ALS and FTD and its therapeutic implication. We suggest that the repeat expansion drives pathogenesis through a combination of downstream defects, of which some can be therapeutic targets.}, }
@article {pmid32512809, year = {2020}, author = {Limanaqi, F and Busceti, CL and Biagioni, F and Cantini, F and Lenzi, P and Fornai, F}, title = {Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA.}, journal = {International journal of molecular sciences}, volume = {21}, number = {11}, pages = {}, pmid = {32512809}, issn = {1422-0067}, support = {Ricerca Corrente 2020//Ministero della Salute/ ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; Autophagy ; Biomarkers ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; Disease Susceptibility ; Genetic Predisposition to Disease ; Humans ; Muscular Atrophy, Spinal/etiology/*metabolism ; Neuromuscular Junction/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Signal Transduction ; }, abstract = {The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. The findings here discussed may contribute to disclosing overlapping molecular mechanisms which are associated with a failure in cell-clearing systems in ALS and SBMA.}, }
@article {pmid32512150, year = {2020}, author = {Gleichman, AJ and Carmichael, ST}, title = {Glia in neurodegeneration: Drivers of disease or along for the ride?.}, journal = {Neurobiology of disease}, volume = {142}, number = {}, pages = {104957}, doi = {10.1016/j.nbd.2020.104957}, pmid = {32512150}, issn = {1095-953X}, mesh = {Animals ; Astrocytes/pathology ; Brain/*pathology ; Humans ; Neurodegenerative Diseases/*pathology ; Neuroglia/*pathology ; Neurons/*pathology ; }, abstract = {While much of the research on neurodegenerative diseases has focused on neurons, non-neuronal cells are also affected. The extent to which glia and other non-neuronal cells are causally involved in disease pathogenesis versus more passively responding to disease is an area of active research. This is complicated by the fact that there is rarely one known cause of neurodegenerative diseases; rather, these disorders likely involve feedback loops that perpetuate dysfunction. Here, we will review genetic as well as experimental evidence that suggest that non-neuronal cells are at least partially driving disease pathogenesis in numerous neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and Parkinson's disease.}, }
@article {pmid32505190, year = {2020}, author = {Schram, S and Loeb, JA and Song, F}, title = {Disease propagation in amyotrophic lateral sclerosis (ALS): an interplay between genetics and environment.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {175}, pmid = {32505190}, issn = {1742-2094}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; *Disease Progression ; *Gene-Environment Interaction ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease affecting the neuromuscular system. While there have been a number of important genetic discoveries, there are no therapeutics capable of stopping its insidious progression. Lessons from clinical histories reveal that ALS can start focally at a single limb, but then segmentally spread up and down the spinal cord as well as in the motor cortex and cortex of frontal and temporal lobes until respiratory muscles fail. With or without a clear genetic etiology, often there is no explanation as to why it starts in one region of the body versus another. Similarly, once the disease starts the mechanisms by which the neurodegenerative process spreads are not known. Here, we summarize recent work in animal models that support the hypothesis that critical environmental contributions, such as a nerve injury, can initiate the disease process. We also propose that pathological axoglial signaling by the glial growth factor neuregulin-1 leads to the slow propagation of neuroinflammation resulting in neurodegeneration up and down the spinal cord and that locally applied drugs that block neuregulin-1 signaling could slow or halt the spread of disease.}, }
@article {pmid32503641, year = {2020}, author = {Machhi, J and Kevadiya, BD and Muhammad, IK and Herskovitz, J and Olson, KE and Mosley, RL and Gendelman, HE}, title = {Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {32}, pmid = {32503641}, issn = {1750-1326}, support = {P01 DA028555/DA/NIDA NIH HHS/United States ; P30 MH062261/MH/NIMH NIH HHS/United States ; R01 AG043540/AG/NIA NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; R01 MH115860/MH/NIMH NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/immunology/metabolism/*therapy ; Animals ; Humans ; Inflammation/metabolism ; Neurodegenerative Diseases/immunology/*therapy ; *Neuroprotection ; Parkinson Disease/immunology/metabolism ; T-Lymphocytes, Regulatory/*immunology ; }, abstract = {Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities.}, }
@article {pmid32501768, year = {2020}, author = {Gotkine, M and Kviatcovsky, D and Elinav, E}, title = {Amyotrophic lateral sclerosis and intestinal microbiota-toward establishing cause and effect.}, journal = {Gut microbes}, volume = {11}, number = {6}, pages = {1833-1841}, pmid = {32501768}, issn = {1949-0984}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*microbiology ; Animals ; Bacteria/classification/genetics/isolation &amp; purification ; Disease Models, Animal ; Dysbiosis/microbiology ; *Gastrointestinal Microbiome ; Humans ; }, abstract = {The intestinal microbiota may be involved, through metabolic gut-brain interactions, in a variety of neurological conditions. In this addendum, we summarize the findings of our recent study investigating the potentially modulatory influence of the microbiome in a transgenic ALS mouse model, and the possible application to human disease. We found that transgenic mice show evidence of dysbiosis, even at the pre-symptomatic stage, and have a more severe disease course under germ-free conditions or after receiving broad-spectrum antibiotics. We demonstrated that Akkermansia muciniphila ameliorated the disease in mice and that this may be due to the production of nicotinamide. We then conducted a preliminary study in human ALS and identified functionally similar alterations within the metagenome. Furthermore, we found that patients with ALS had lower systemic and CSF levels of nicotinamide, suggesting that the changes observed in the mouse model may be relevant to human disease.}, }
@article {pmid32500266, year = {2020}, author = {Advani, VM and Ivanov, P}, title = {Stress granule subtypes: an emerging link to neurodegeneration.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {77}, number = {23}, pages = {4827-4845}, pmid = {32500266}, issn = {1420-9071}, support = {R01 GM126150/GM/NIGMS NIH HHS/United States ; R01 GM126150/NH/NIH HHS/United States ; }, mesh = {Animals ; Cell Compartmentation ; Cytoplasmic Granules/*metabolism ; Humans ; Nerve Degeneration/*metabolism/*pathology ; RNA/metabolism ; RNA-Binding Proteins/metabolism ; Transcriptome/genetics ; }, abstract = {Stress Granules (SGs) are membraneless cytoplasmic RNA granules, which contain translationally stalled mRNAs, associated translation initiation factors and multiple RNA-binding proteins (RBPs). They are formed in response to various stresses and contribute to reprogramming of cellular metabolism to aid cell survival. Because of their cytoprotective nature, association with translation regulation and cell signaling, SGs are an essential component of the integrated stress response pathway, a complex adaptive program central to stress management. Recent advances in SG biology unambiguously demonstrate that SGs are heterogeneous in their RNA and protein content leading to the idea that various SG subtypes exist. These SG variants are formed in cell type- and stress-specific manners and differ in their composition, dynamics of assembly and disassembly, and contribution to cell viability. As aberrant SG dynamics contribute to the formation of pathological persistent SGs that are implicated in neurodegenerative diseases, the biology of different SG subtypes may be directly implicated in neurodegeneration. Here, we will discuss mechanisms of SG formation, their subtypes, and potential contribution to health and disease.}, }
@article {pmid32500222, year = {2020}, author = {Geser, F and Fellner, L and Haybaeck, J and Wenning, GK}, title = {Development of neurodegeneration in amyotrophic lateral sclerosis: from up or down?.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {127}, number = {8}, pages = {1097-1105}, doi = {10.1007/s00702-020-02213-y}, pmid = {32500222}, issn = {1435-1463}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; DNA-Binding Proteins ; Humans ; Inclusion Bodies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease associated with neurodegeneration and intracellular pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) positive inclusions. The various clinical symptoms, such as motor disorders and cognitive impairment, reflect the degeneration of certain areas of the nervous system. Since the discovery of the significance of pathological TDP-43 for human disease including ALS, there has been an increasing number of studies reporting on the distribution and severity of neurodegeneration. These have rekindled the old debate about whether the first or second motor neuron is the primary site of degeneration in ALS. To shed light on this question, the following is a review of the relevant neuropathological studies.}, }
@article {pmid32497448, year = {2020}, author = {Perrone, B and Conforti, FL}, title = {Common mutations of interest in the diagnosis of amyotrophic lateral sclerosis: how common are common mutations in ALS genes?.}, journal = {Expert review of molecular diagnostics}, volume = {20}, number = {7}, pages = {703-714}, doi = {10.1080/14737159.2020.1779060}, pmid = {32497448}, issn = {1744-8352}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/ethnology/*genetics ; C9orf72 Protein/genetics ; DNA Mutational Analysis/methods ; DNA Repeat Expansion ; DNA-Binding Proteins/genetics ; Ethnicity/genetics ; Gene Frequency ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; Humans ; Molecular Diagnostic Techniques ; *Mutation ; Mutation, Missense ; Protein Aggregation, Pathological/genetics ; RNA-Binding Protein FUS/genetics ; Sequence Analysis, DNA/methods ; Superoxide Dismutase-1/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease predominantly affecting upper and lower motor neurons. Diagnosis of this devastating pathology is very difficult because the high degree of clinical heterogeneity with which it occurs and until now, no truly effective treatment exists.<br><br>AREAS COVERED: Molecular diagnosis may be a valuable tool for dissecting out ALS complex heterogeneity and for identifying new molecular mechanisms underlying the characteristic selective degeneration and death of motor neurons. To date, pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases and can be associated with risks for ALS only or risks for other neurodegenerative diseases. This paper shows the procedure currently used in diagnostic laboratories to investigate most frequent mutations in ALS and evaluating the utility of involved molecular techniques as potential tools to discriminate 'common mutations' in ALS patients.<br><br>EXPERT OPINION: Genetic testing may allow for establishing an accurate pathological diagnosis and a more precise stratification of patient groups in future drug trials.}, }
@article {pmid32497246, year = {2021}, author = {Riancho, J and Delgado-Alvarado, M and Andreu, MD and Paz-Fajardo, L and Arozamena, S and Gil-Bea, FJ and López de Munaín, A}, title = {Amyotrophic lateral sclerosis (ALS), cancer, autoimmunity and metabolic disorders: An unsolved tantalizing challenge.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1269-1278}, doi = {10.1111/bph.15151}, pmid = {32497246}, issn = {1476-5381}, mesh = {*Amyotrophic Lateral Sclerosis ; Autoimmunity ; Humans ; *Neoplasms ; *Neurodegenerative Diseases ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) commonly referred to as motor neurone disease, is a neurodegenerative disease of unknown pathogenesis that progresses rapidly and has attracted an increased amount of scholarly interest in recent years. The current conception of amyotrophic lateral sclerosis has transitioned into a more complex theory in which individual genetic risk, ageing and environmental factors interact, leading to disease onset in subjects in whom the sum of these factors reach a determined threshold. Based on this conceptualization, the environmental conditions, particularly those that are potentially modifiable, are becoming increasingly relevant. In this review, the current integrative model of the disease is discussed. In addition, we explore the role of cancer, autoimmunity and metabolic diseases as examples of novel, non-genetic and environmental factors. Together with the potential triggers or perpetuating pathogenic mechanisms along with new insights into potential lines of future research are provided. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32492924, year = {2020}, author = {Filipek, A and Leśniak, W}, title = {S100A6 and Its Brain Ligands in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {21}, number = {11}, pages = {}, pmid = {32492924}, issn = {1422-0067}, support = {2018/29/B/NZ4/01384//Narodowe Centrum Nauki/ ; Statutory funds//Nencki Institute of Experimental Biology/ ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Astrocytes/*metabolism ; Brain/*metabolism ; Calcium/chemistry ; Calcium-Binding Proteins/metabolism ; Cell Cycle Proteins/*metabolism ; Epilepsy/metabolism ; Gene Expression Regulation ; Humans ; Huntington Disease/metabolism ; Ligands ; Mice ; Neurodegenerative Diseases/*metabolism ; Neurons/*metabolism ; Parkinson Disease/metabolism ; Protein Conformation ; S100 Calcium Binding Protein A6/*metabolism ; Signal Transduction ; Spinal Cord/*metabolism ; }, abstract = {The S100A6 protein is present in different mammalian cells and tissues including the brain. It binds Ca[2+] and Zn[2+] and interacts with many target proteins/ligands. The best characterized ligands of S100A6, expressed at high level in the brain, include CacyBP/SIP and Sgt1. Research concerning the functional role of S100A6 and these two ligands indicates that they are involved in various signaling pathways that regulate cell proliferation, differentiation, cytoskeletal organization, and others. In this review, we focused on the expression/localization of these proteins in the brain and on their possible role in neurodegenerative diseases. Published results demonstrate that S100A6, CacyBP/SIP, and Sgt1 are expressed in various brain structures and in the spinal cord and can be found in different cell types including neurons and astrocytes. When it comes to their possible involvement in nervous system pathology, it is evident that their expression/level and/or subcellular localization is changed when compared to normal conditions. Among diseases in which such changes have been observed are Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), epileptogenesis, Parkinson's disease (PD), Huntington's disease (HD), and others.}, }
@article {pmid32487123, year = {2020}, author = {Liscic, RM and Alberici, A and Cairns, NJ and Romano, M and Buratti, E}, title = {From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {31}, pmid = {32487123}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Atrophy/genetics ; Frontotemporal Dementia/genetics/*therapy ; Humans ; Mutation/genetics ; Neurodegenerative Diseases/*therapy ; *Therapies, Investigational/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) are neurodegenerative disorders, related by deterioration of motor and cognitive functions and short survival. Aside from cases with an inherited pathogenic mutation, the causes of the disorders are still largely unknown and no effective treatment currently exists. It has been shown that FTD may coexist with ALS and this overlap occurs at clinical, genetic, and molecular levels. In this work, we review the main pathological aspects of these complex diseases and discuss how the integration of the novel pathogenic molecular insights and the analysis of molecular interaction networks among all the genetic players represents a critical step to shed light on discovering novel therapeutic strategies and possibly tailoring personalized medicine approaches to specific ALS and FTD patients.}, }
@article {pmid32486962, year = {2020}, author = {Deolankar, SC and Modi, PK and Subbannayya, Y and Pervaje, R and Prasad, TSK}, title = {Molecular Targets from Traditional Medicines for Neuroprotection in Human Neurodegenerative Diseases.}, journal = {Omics : a journal of integrative biology}, volume = {24}, number = {7}, pages = {394-403}, doi = {10.1089/omi.2020.0033}, pmid = {32486962}, issn = {1557-8100}, mesh = {Animals ; Behavior/drug effects ; *Biomarkers ; *Disease Susceptibility ; Genomics/methods ; Humans ; *Medicine, Traditional/methods ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; *Neuroprotection/drug effects ; Neuropsychological Tests ; Proteomics/methods ; }, abstract = {Neurodegeneration is one of the greatest threats to global public health. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the major causes of chronic neurological conditions in the elderly populations. Hence, neuroprotection is at the epicenter of the current 21st-century research agenda in biomedicine. Yet, novel molecular targets are limited and solely needed for neuroprotection. Marked person-to-person variations in outcomes require a deeper understanding of drug targets in neurology and clinical neurosciences. In this context, traditional medicines offer untapped potentials for discovery and translation of novel molecular targets to human neurodegenerative disease research and clinical neurology. This expert review offers a synthesis of the prospects and challenges of harnessing new molecular targets from traditional medicines, with a view to applications for neuroprotection in human neurodegenerative diseases.}, }
@article {pmid32485268, year = {2020}, author = {Smaga, I and Fierro, D and Mesa, J and Filip, M and Knackstedt, LA}, title = {Molecular changes evoked by the beta-lactam antibiotic ceftriaxone across rodent models of substance use disorder and neurological disease.}, journal = {Neuroscience and biobehavioral reviews}, volume = {115}, number = {}, pages = {116-130}, pmid = {32485268}, issn = {1873-7528}, support = {R01 DA033436/DA/NIDA NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides ; Animals ; Anti-Bacterial Agents ; *Ceftriaxone ; Excitatory Amino Acid Transporter 2 ; Glutamic Acid ; Rodentia ; *Substance-Related Disorders ; }, abstract = {Ceftriaxone is a beta-lactam antibiotic that increases the expression of the major glutamate transporter, GLT-1. As such, ceftriaxone ameliorates symptoms across multiple rodent models of neurological diseases and substance use disorders. However, the mechanism behind GLT-1 upregulation is unknown. The present review synthesizes this literature in order to identify commonalities in molecular changes. We find that ceftriaxone (200 mg/kg for at least two days) consistently restores GLT-1 expression in multiple rodent models of neurological disease, especially when GLT-1 is decreased in the disease model. The same dose given to healthy/drug-naive rodents does not reliably upregulate GLT-1 in any brain region except the hippocampus. Increased GLT-1 expression does not consistently arise from transcriptional regulation, and is likely to be due to trafficking changes. In addition to altered transporter expression, ceftriaxone ameliorates neuropathologies (e.g. tau, amyloid beta, cell death) and aberrant protein expression associated with a number of neurological disease models. Taken together, these results indicate that ceftriaxone remains a strong candidate for treatment of multiple disorders in the clinic.}, }
@article {pmid32484719, year = {2020}, author = {Giovannelli, I and Heath, P and Shaw, PJ and Kirby, J}, title = {The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {5-6}, pages = {435-444}, doi = {10.1080/21678421.2020.1752246}, pmid = {32484719}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; T-Lymphocytes, Regulatory ; }, abstract = {Neuroinflammation, meaning the establishment of a diffuse inflammatory condition in the CNS, is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, a crucial role of regulatory T cells (Tregs) in this disease has been outlined. Tregs are a T cell subpopulation with immunomodulatory properties. In this review, we discuss the physiology of Tregs and their role in ALS disease onset and progression. Evidence has demonstrated that in ALS patients Tregs are dramatically and progressively reduced in number and are less effective in promoting immune suppression. In addition, Tregs levels correlate with the rate of disease progression and patient survival. For this reason, Tregs are now considered a promising therapeutic target for neuroprotection in ALS. In this review, the clinical impact of these cells will be discussed and an overview of the current clinical trials targeting Tregs is also provided.}, }
@article {pmid32483988, year = {2020}, author = {Inglet, S and Winter, B and Yost, SE and Entringer, S and Lian, A and Biksacky, M and Pitt, RD and Mortensen, W}, title = {Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.}, journal = {The Annals of pharmacotherapy}, volume = {54}, number = {11}, pages = {1109-1143}, doi = {10.1177/1060028020930189}, pmid = {32483988}, issn = {1542-6270}, mesh = {Clinical Trials as Topic ; Drug Utilization Review/*trends ; Humans ; Medical Marijuana/administration &amp; dosage/adverse effects/*therapeutic use ; Multiple Sclerosis/drug therapy ; Nausea/drug therapy ; Pain/drug therapy ; Practice Guidelines as Topic ; Vomiting/drug therapy ; }, abstract = {OBJECTIVE: To compile and synthesize the available literature describing medical cannabis use across various disease states.<br><br>DATA SOURCES: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords.<br><br>Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019.<br><br>DATA SYNTHESIS: Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care.<br><br>Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria.<br><br>CONCLUSIONS: As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.}, }
@article {pmid32479211, year = {2020}, author = {Reyhani, S and Abbaspanah, B and Mousavi, SH}, title = {Umbilical cord-derived mesenchymal stem cells in neurodegenerative disorders: from literature to clinical practice.}, journal = {Regenerative medicine}, volume = {15}, number = {4}, pages = {1561-1578}, doi = {10.2217/rme-2019-0119}, pmid = {32479211}, issn = {1746-076X}, mesh = {Animals ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*cytology ; Neurodegenerative Diseases/*therapy ; Umbilical Cord/*cytology ; }, abstract = {Mesenchymal stem cells (MSCs) have provided a promising tool for cell therapy. Umbilical cord (UC) is one of the best sources of MSCs since its collection is noninvasive, and effortless, and the cells from this source are more capable and prolific. It has been proven that the differentiation, migration and protective properties of UC-MSCs are superior compared with other kinds of stem cells. Moreover, incurable neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and Huntington, encourage scientists to apply UC-MSCs transplantation in order to find a definite treatment. This review will focus on the preclinical and clinical use of mesenchymal stem cells derived from human umbilical cord in the treatment of neurodegenerative disorders.}, }
@article {pmid32471232, year = {2020}, author = {Yun, Y and Ha, Y}, title = {CRISPR/Cas9-Mediated Gene Correction to Understand ALS.}, journal = {International journal of molecular sciences}, volume = {21}, number = {11}, pages = {}, pmid = {32471232}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; C9orf72 Protein/genetics ; *CRISPR-Cas Systems ; DNA-Binding Proteins/genetics ; Humans ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Targeted Gene Repair/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the death of motor neurons in the spinal cord and brainstem. ALS has a diverse genetic origin; at least 20 genes have been shown to be related to ALS. Most familial and sporadic cases of ALS are caused by variants of the SOD1, C9orf72, FUS, and TARDBP genes. Genome editing using clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) can provide insights into the underlying genetics and pathophysiology of ALS. By correcting common mutations associated with ALS in animal models and patient-derived induced pluripotent stem cells (iPSCs), CRISPR/Cas9 has been used to verify the effects of ALS-associated mutations and observe phenotype differences between patient-derived and gene-corrected iPSCs. This technology has also been used to create mutations to investigate the pathophysiology of ALS. Here, we review recent studies that have used CRISPR/Cas9 to understand the genetic underpinnings of ALS.}, }
@article {pmid32469420, year = {2021}, author = {Buratti, E}, title = {Targeting TDP-43 proteinopathy with drugs and drug-like small molecules.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1298-1315}, doi = {10.1111/bph.15148}, pmid = {32469420}, issn = {1476-5381}, support = {PathensTDP//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; DNA-Binding Proteins ; *Frontotemporal Lobar Degeneration/drug therapy ; Humans ; *Pharmaceutical Preparations ; *TDP-43 Proteinopathies ; }, abstract = {Following the discovery of the involvement of the ribonucleoprotein TDP-43 in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), a major research focus has been to develop treatments that can prevent or alleviate these disease conditions. One pharmacological approach has been to use TDP-43-based disease models to test small molecules and drugs already known to have some therapeutic effect in a variety of neurodegenerative conditions. In parallel, various disease models have been used to perform high-throughput screens of drugs and small compound libraries. The aim of this review will be to provide a general overview of the compounds that have been described to alter pathological characteristics of TDP-43. These include expression levels, cytoplasmic mis-localization, post-translational modifications, cleavage, stress granule recruitment and aggregation. In parallel, this review will also address the use of compounds that modify the autophagic/proteasome systems that are known to target TDP-43 misfolding and aggregation. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32468479, year = {2020}, author = {Krokidis, MG}, title = {Transcriptomics and Metabolomics in Amyotrophic Lateral Sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {1195}, number = {}, pages = {205-212}, pmid = {32468479}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Gene Expression Profiling ; Humans ; *Metabolomics ; *Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive and selective loss of motor neurons, muscle weakness, paralysis and death. The pathogenesis of ALS is not clearly understood, while reliable prognostic markers have not been identified to detect symptoms at earlier time points. The rapid development of microarray technology offers great potential for simultaneous analysis of the transcriptional expression of thousands of genes, aiming to determine novel candidate targets for efficient treatment. Additionally, metabolomics, as a high-throughput approach, is gaining significant attention in ALS research providing an opportunity to develop predictive biomarkers that may be utilized as indicators of clinical symptoms of ALS. In this review, recent evidences from gene expression profiling studies in ALS are illustrated in order to examine molecular signatures related to the disease's pathogenesis and potential discovery of therapeutic targets. Moreover, potent challenges are presented regarding the utilization of the metabolomics approach as a diagnostic tool in context with distinctive biomarkers' identification.}, }
@article {pmid32468476, year = {2020}, author = {Kadena, K and Vlamos, P}, title = {Amyotrophic Lateral Sclerosis: Current Status in Diagnostic Biomarkers.}, journal = {Advances in experimental medicine and biology}, volume = {1195}, number = {}, pages = {179-187}, pmid = {32468476}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*metabolism ; Biomarkers/*analysis/metabolism ; Humans ; Incidence ; Racial Groups/statistics &amp; numerical data ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease that affects the human motor system. ALS is a highly heterogeneous disease, depending on several causative factors. The heterogeneity of the disease is also reflected in the variation of the symptoms in ALS patients. The worldwide annual incidence of ALS is about 2.08 per 100,000 with uniform rates in Caucasian populations and lower rates in African, Asian, and Hispanic populations, while the number of individuals with ALS is expected to grow significantly between 2015 and 2040 with an estimated increase of 69% (Chio et al. 2013a; Arthur et al. 2016).}, }
@article {pmid32466216, year = {2020}, author = {Stanga, S and Caretto, A and Boido, M and Vercelli, A}, title = {Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32466216}, issn = {1422-0067}, support = {"Dipartimenti di Eccellenza 2018-2022" to Department of Neuroscience "Rita Levi Montalcini//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; RF 2017.2052//Fondazione CRT/ ; }, mesh = {Alzheimer Disease/drug therapy/*metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Antioxidants/therapeutic use ; Humans ; Mitochondria/*metabolism/pathology ; Muscular Atrophy, Spinal/drug therapy/*metabolism ; Neuroprotective Agents/therapeutic use ; Organelle Biogenesis ; Parkinson Disease/drug therapy/*metabolism ; }, abstract = {Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the "mitochondrial switch" which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases.}, }
@article {pmid32464743, year = {2020}, author = {Uddin, MS and Hossain, MF and Mamun, AA and Shah, MA and Hasana, S and Bulbul, IJ and Sarwar, MS and Mansouri, RA and Ashraf, GM and Rauf, A and Abdel-Daim, MM and Bin-Jumah, MN}, title = {Exploring the multimodal role of phytochemicals in the modulation of cellular signaling pathways to combat age-related neurodegeneration.}, journal = {The Science of the total environment}, volume = {725}, number = {}, pages = {138313}, doi = {10.1016/j.scitotenv.2020.138313}, pmid = {32464743}, issn = {1879-1026}, mesh = {Humans ; Mitochondria ; *Neurodegenerative Diseases ; *Neuroprotective Agents ; Oxidative Stress ; Phytochemicals ; }, abstract = {Neurodegeneration is the progressive loss of neuronal structures and functions that lead to copious disorders like Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS), and other less recurring diseases. Aging is the prime culprit for most neurodegenerative events. Moreover, the shared pathogenic factors of many neurodegenerative processes are inflammatory responses and oxidative stress (OS). Unfortunately, it is very complicated to treat neurodegeneration and there is no effective remedy. The rapid progression of the neurodegenerative diseases that exacerbate the burden and the concurrent absence of effective treatment strategies force the researchers to investigate more therapeutic approaches that ultimately target the causative factors of the neurodegeneration. Phytochemicals have great potential to exert their neuroprotective effects by targeting various mechanisms, such as OS, neuroinflammation, abnormal protein aggregation, neurotrophic factor deficiency, disruption in mitochondrial function, and apoptosis. Therefore, this review represents the molecular mechanisms of neuroprotection by multifunctional phytochemicals to combat age-linked neurodegenerative disorders.}, }
@article {pmid32464049, year = {2020}, author = {Krahn, AI and Wells, C and Drewry, DH and Beitel, LK and Durcan, TM and Axtman, AD}, title = {Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases.}, journal = {ACS chemical neuroscience}, volume = {11}, number = {13}, pages = {1871-1886}, doi = {10.1021/acschemneuro.0c00176}, pmid = {32464049}, issn = {1948-7193}, support = {U24 DK116204/DK/NIDDK NIH HHS/United States ; U54 AG065187/AG/NIA NIH HHS/United States ; 106169/ZZ14/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Central Nervous System Diseases ; Drug Discovery ; Humans ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Kinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anticancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for the development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases. This Review highlights the imminent need for new therapeutics to treat the most prevalent neurodegenerative diseases as well as the promise of kinase inhibitors to address this need. With a focus on kinases that remain largely unexplored after decades of dedicated research in the kinase field, we offer specific examples of understudied kinases that are supported by patient-derived data as linked to Alzheimer's disease, Parkinson's disease, and/or amyotrophic lateral sclerosis. Finally, we show literature-reported high-quality inhibitors for several understudied kinases and suggest other kinases that merit additional medicinal chemistry efforts to elucidate their therapeutic potential.}, }
@article {pmid32462331, year = {2020}, author = {Boentert, M}, title = {Sleep and Sleep Disruption in Amyotrophic Lateral Sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {20}, number = {7}, pages = {25}, pmid = {32462331}, issn = {1534-6293}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology/therapy ; Humans ; Polysomnography ; Quality of Life ; *Respiratory Insufficiency ; Sleep ; }, abstract = {PURPOSE OF REVIEW: In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge on causes, pathophysiology, and treatment of sleep disturbances in ALS.<br><br>RECENT FINDINGS: Motor neuron degeneration and muscle weakness may lead to muscle cramps, pain, spasticity, immobilization, restless legs, sleep-disordered breathing, and difficulties to clear secretions. Furthermore, existential fears and depression may promote insomnia. Sleep-disordered breathing, and nocturnal hypoventilation in particular, requires ventilatory support which meaningfully prolongs survival and improves health-related quality of life albeit respiratory failure is inevitable. Early indication for non-invasive ventilation can be achieved by inclusion of capnometry in diagnostic sleep studies. Sleep disruption is extremely common in ALS and may arise from different etiologies. The absence of causative therapeutic options for ALS underlines the importance of symptomatic and palliative treatment strategies that acknowledge sleep-related complaints.}, }
@article {pmid32459513, year = {2020}, author = {Raval, U and Harary, JM and Zeng, E and Pasinetti, GM}, title = {The dichotomous role of the gut microbiome in exacerbating and ameliorating neurodegenerative disorders.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {7}, pages = {673-686}, pmid = {32459513}, issn = {1744-8360}, support = {IK6 BX003785/BX/BLRD VA/United States ; P50 AT008661/AT/NCCIH NIH HHS/United States ; }, mesh = {*Dysbiosis/complications/diet therapy/microbiology ; *Gastrointestinal Microbiome ; Humans ; *Neurodegenerative Diseases/diet therapy/etiology/microbiology ; Probiotics/*therapeutic use ; }, abstract = {INTRODUCTION: Age related neurodegenerative disorders affect millions of people around the world. The role of the gut microbiome (GM) in neurodegenerative disorders has been elucidated over the past few years. Dysbiosis of the gut microbiome ultimately results in neurodegeneration. However, the gut microbiome can be modulated to promote neuro-resilience.<br><br>AREAS COVERED: This review is focused on demonstrating the role of the gut microbiome in host physiology in Parkinson's disease (PD) and other neurodegenerative disorders. We will discuss how the microbiome will impact neurodegeneration in PD, Alzheimer's Disease (AD), Multiple sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and finally discuss how the gut microbiome can be influenced through diet and lifestyle.<br><br>EXPERT OPINION: Currently, much of the focus has been to study the mechanisms by which the microbiome induces neuroinflammation and neurodegeneration in PD, AD, MS, ALS. In particular, the role of certain dietary flavonoids in regulation of gut microbiome to promote neuro-resilience. Polyphenol prebiotics delivered in combination with probiotics (synbiotics) present an exciting new avenue to harness the microbiome to attenuate immune inflammatory responses which ultimately may influence brain cascades associated with promotion of neurodegeneration across the lifespan.}, }
@article {pmid32457568, year = {2020}, author = {Ueda, T and Inden, M and Ito, T and Kurita, H and Hozumi, I}, title = {Characteristics and Therapeutic Potential of Dental Pulp Stem Cells on Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {407}, pmid = {32457568}, issn = {1662-4548}, abstract = {To evaluate the therapeutic potential of stem cells for neurodegenerative diseases, emphasis should be placed on clarifying the characteristics of the various types of stem cells. Among stem cells, dental pulp stem cells (DPSCs) are a cell population that is rich in cell proliferation and multipotency. It has been reported that transplantation of DPSCs has protective effects against models of neurodegenerative diseases. The protective effects are not only through differentiation into the target cell type for the disease but are also related to trophic factors released from DPSCs. Recently, it has been reported that serum-free culture supernatant of dental pulp stem cell-conditioned medium (DPCM) contains various trophic factors and cytokines and that DPCM is effective for models of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Moreover, the use of stem cells from human exfoliated deciduous teeth (SHEDs) has been considered. SHEDs are derived from deciduous teeth that have been disposed of as medical waste. SHEDs have higher differentiation capacity and proliferation ability than DPSCs. In addition, the serum-free culture supernatant of SHEDs (SHED-CM) contains more trophic factors, cytokines, and biometals than DPCM and also promotes neuroprotection. The neuroprotective effect of DPSCs, including those from deciduous teeth, will be used as the seeds of therapeutic drugs for neurodegenerative diseases. SHEDs will be used for further cell therapy of neurodegenerative diseases in the future. In this paper, we focused on the characteristics of DPSCs and their potential for neurodegenerative diseases.}, }
@article {pmid32456491, year = {2020}, author = {Barp, A and Gerardi, F and Lizio, A and Sansone, VA and Lunetta, C}, title = {Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials.}, journal = {Expert opinion on emerging drugs}, volume = {25}, number = {2}, pages = {145-164}, doi = {10.1080/14728214.2020.1769067}, pmid = {32456491}, issn = {1744-7623}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Disease Progression ; *Drug Development ; Drug Discovery ; Edaravone/administration &amp; dosage/pharmacology ; Humans ; Neuroprotective Agents/*administration &amp; dosage/pharmacology ; Oxidative Stress/drug effects ; Riluzole/administration &amp; dosage/pharmacology ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing disability and death 3-5 years after onset of symptoms. Over 40 large clinical trials for ALS have been negative, except for Riluzole that offers a modest survival benefit, and Edaravone that modestly reduces disease progression in patients with specific characteristics. Thus, the discovery of efficient disease modifying therapy is an urgent need.<br><br>AREAS COVERED: Although the cause of ALS remains unclear, many studies have demonstrated that neuroinflammation, proteinopathies, glutamate-induced excitotoxicity, microglial activation, oxidative stress, and mitochondrial dysfunction may play a key role in the pathogenesis. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of therapy. Ongoing phase 2 clinical trials aimed to interfere with these pathophysiological mechanisms are discussed.<br><br>EXPERT OPINION: This review describes the challenges that the discovery of an efficient drug therapy faces and how these issues may be addressed. With the continuous advances coming from basic research, we provided possible suggestions that may be considered to improve performance of clinical trials and turn ALS research into a 'fertile ground' for drug development for this devastating disease.}, }
@article {pmid32456229, year = {2020}, author = {Obrenovich, M and Jaworski, H and Tadimalla, T and Mistry, A and Sykes, L and Perry, G and Bonomo, RA}, title = {The Role of the Microbiota-Gut-Brain Axis and Antibiotics in ALS and Neurodegenerative Diseases.}, journal = {Microorganisms}, volume = {8}, number = {5}, pages = {}, pmid = {32456229}, issn = {2076-2607}, abstract = {: The human gut hosts a wide and diverse ecosystem of microorganisms termed the microbiota, which line the walls of the digestive tract and colon where they co-metabolize digestible and indigestible food to contribute a plethora of biochemical compounds with diverse biological functions. The influence gut microbes have on neurological processes is largely yet unexplored. However, recent data regarding the so-called leaky gut, leaky brain syndrome suggests a potential link between the gut microbiota, inflammation and host co-metabolism that may affect neuropathology both locally and distally from sites where microorganisms are found. The focus of this manuscript is to draw connection between the microbiota-gut-brain (MGB) axis, antibiotics and the use of "BUGS AS DRUGS" for neurodegenerative diseases, their treatment, diagnoses and management and to compare the effect of current and past pharmaceuticals and antibiotics for alternative mechanisms of action for brain and neuronal disorders, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), mood disorders, schizophrenia, autism spectrum disorders and others. It is a paradigm shift to suggest these diseases can be largely affected by unknown aspects of the microbiota. Therefore, a future exists for applying microbial, chemobiotic and chemotherapeutic approaches to enhance translational and personalized medical outcomes. Microbial modifying applications, such as CRISPR technology and recombinant DNA technology, among others, echo a theme in shifting paradigms, which involve the gut microbiota (GM) and mycobiota and will lead to potential gut-driven treatments for refractory neurologic diseases.}, }
@article {pmid32455692, year = {2020}, author = {Trojsi, F and D'Alvano, G and Bonavita, S and Tedeschi, G}, title = {Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32455692}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics ; Animals ; C9orf72 Protein/genetics ; Humans ; Multifactorial Inheritance ; Sex Determination Processes/*genetics ; Sex Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5-10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.}, }
@article {pmid32455165, year = {2020}, author = {Theocharopoulou, G}, title = {The ubiquitous role of mitochondria in Parkinson and other neurodegenerative diseases.}, journal = {AIMS neuroscience}, volume = {7}, number = {1}, pages = {43-65}, pmid = {32455165}, issn = {2373-7972}, abstract = {Orderly mitochondrial life cycle, plays a key role in the pathology of neurodegenerative diseases. Mitochondria are ubiquitous in neurons as they respond to an ever-changing demand for energy supply. Mitochondria constantly change in shape and location, feature of their dynamic nature, which facilitates a quality control mechanism. Biological studies in mitochondria dynamics are unveiling the mechanisms of fission and fusion, which essentially arrange morphology and motility of these organelles. Control of mitochondrial network homeostasis is a critical factor for the proper function of neurons. Disease-related genes have been reported to be implicated in mitochondrial dysfunction. Increasing evidence implicate mitochondrial perturbation in neuronal diseases, such as AD, PD, HD, and ALS. The intricacy involved in neurodegenerative diseases and the dynamic nature of mitochondria point to the idea that, despite progress toward detecting the biology underlying mitochondrial disorders, its link to these diseases is difficult to be identified in the laboratory. Considering the need to model signaling pathways, both in spatial and temporal level, there is a challenge to use a multiscale modeling framework, which is essential for understanding the dynamics of a complex biological system. The use of computational models in order to represent both a qualitative and a quantitative structure of mitochondrial homeostasis, allows to perform simulation experiments so as to monitor the conformational changes, as well as the intersection of form and function.}, }
@article {pmid32449677, year = {2020}, author = {Douglas, A and Baborie, A}, title = {Inappropriate antidiuretic hormone secretion in amyotrophic lateral sclerosis.}, journal = {Clinical neuropathology}, volume = {39}, number = {6}, pages = {275-281}, doi = {10.5414/NP301280}, pmid = {32449677}, issn = {0722-5091}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*pathology ; Bodily Secretions/*metabolism ; Brain/pathology ; Humans ; Hyponatremia/complications/drug therapy/*pathology ; Inappropriate ADH Syndrome/complications/diagnosis/*pathology ; Male ; Vasopressins/therapeutic use ; }, abstract = {Only a few cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the setting of amyotrophic lateral sclerosis (ALS) have been described in the literature. We present the case of an 81-year-old male who developed severe hyponatremia following elective total hip replacement. His past medical history included prostate cancer, which was under surveillance, and ischemic heart disease. He reported recent weight loss, worsening shortness of breath, and lethargy. SIADH was diagnosed on the basis of hyponatremia, elevated urinary sodium, and decreased serum osmolality, presumed secondary to surgery. Investigations revealed no occult malignancy and no other cause for hyponatremia. He was discharged when sodium levels had normalized, however, he then had several further admissions for hyponatremia, general fatigue, and breathlessness. His condition continued to decline, and he developed dysphagia, weakness, and tongue fasciculations. Neurological examination showed globally decreased power, increased tone, and fasciculations. MRI of the brain was normal. He did not respond to neostigmine treatment, and a presumed diagnosis of motor neuron disease was made. The patient passed away shortly after this, and a post-mortem confirmed the diagnosis of ALS. Drug, post-operative, and cancer-related causes were precluded by the timing of onset of hyponatremia. We present this case and an analysis of previously published cases alongside a discussion on the potential causative mechanisms.}, }
@article {pmid32443527, year = {2020}, author = {Quinet, G and Gonzalez-Santamarta, M and Louche, C and Rodriguez, MS}, title = {Mechanisms Regulating the UPS-ALS Crosstalk: The Role of Proteaphagy.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {10}, pages = {}, pmid = {32443527}, issn = {1420-3049}, support = {765445//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; PLBIO16-251//Institut National Du Cancer/ ; 0280365//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; REPERE and Pre-maturation programs//R&#xe9;gion Occitanie Pyr&#xe9;n&#xe9;es-M&#xe9;diterran&#xe9;e/ ; }, mesh = {Autophagy/*genetics ; Cell Physiological Phenomena/genetics ; Humans ; Lysosomes/*genetics ; Macroautophagy/genetics ; Proteasome Endopeptidase Complex/*genetics ; Proteolysis ; Ubiquitin/*genetics ; Ubiquitination/genetics ; }, abstract = {Protein degradation is tightly regulated inside cells because of its utmost importance for protein homeostasis (proteostasis). The two major intracellular proteolytic pathways are the ubiquitin-proteasome and the autophagy-lysosome systems which ensure the fate of proteins when modified by various members of the ubiquitin family. These pathways are tightly interconnected by receptors and cofactors that recognize distinct chain architectures to connect with either the proteasome or autophagy under distinct physiologic and pathologic situations. The degradation of proteasome by autophagy, known as proteaphagy, plays an important role in this crosstalk since it favours the activity of autophagy in the absence of fully active proteasomes. Recently described in several biological models, proteaphagy appears to help the cell to survive when proteostasis is broken by the absence of nutrients or the excess of proteins accumulated under various stress conditions. Emerging evidence indicates that proteaphagy could be permanently activated in some types of cancer or when chemoresistance is observed in patients.}, }
@article {pmid32441415, year = {2020}, author = {Yuan, S and Roos, PM and Larsson, SC}, title = {Interleukin-1 receptor antagonist, interleukin-2 receptor alpha subunit and amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {27}, number = {10}, pages = {1913-1917}, doi = {10.1111/ene.14338}, pmid = {32441415}, issn = {1468-1331}, support = {2018-00123//Forskningsr&#xe5;det om H&#xe4;lsa, Arbetsliv och V&#xe4;lf&#xe4;rd/International ; 2019-00977//Vetenskapsr&#xe5;det/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Interleukin 1 Receptor Antagonist Protein/chemistry/*genetics ; Interleukin-2 Receptor alpha Subunit ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Receptors, Interleukin-1/chemistry/immunology ; }, abstract = {BACKGROUND AND PURPOSE: To clarify the causal associations of interleukin-1 receptor antagonist (IL-1ra) and interleukin-2 receptor alpha subunit (IL-2rα) with the risk of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A two-sample Mendelian randomization study design was employed. Single-nucleotide polymorphisms associated with IL-1ra (n&#xa0;=&#xa0;2) and IL-2r&#x3b1; (n&#xa0;=&#xa0;1) at the genome-wide significance level were used as unbiased instrumental variables. Summary-level data for ALS were obtained from Project MinE, an international collaboration consortium with 12&#xa0;577 ALS cases and 23&#xa0;475 controls of European descent.<br><br>RESULTS: Genetic predisposition to higher levels of IL-1ra was significantly associated with lower odds of ALS. For a 1-SD increase of circulating IL-1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46-0.88; P&#xa0;=&#xa0;0.005). There was a borderline inverse association between IL-2r&#x3b1; levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83-1.00; P&#xa0;=&#xa0;0.058).<br><br>CONCLUSIONS: Interleukin-1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin-1 inhibitors may lower the risk of this always fatal disease. The role of IL-2r&#x3b1; levels in ALS needs further verification in causal inference studies with larger sample sizes.}, }
@article {pmid32440312, year = {2020}, author = {Rajabian, A and Sadeghnia, H and Fanoudi, S and Hosseini, A}, title = {Genus Boswellia as a new candidate for neurodegenerative disorders.}, journal = {Iranian journal of basic medical sciences}, volume = {23}, number = {3}, pages = {277-286}, pmid = {32440312}, issn = {2008-3866}, abstract = {Neurodegenerative diseases, characterized by progressive loss of neurons, share common mechanisms such as apoptotic cell death, mitochondrial dysfunction, inflammation, and oxidative stress. Genus Boswellia is a genus in the Burseraceae family. It comprises several species traditionally used for treatment of chronic inflammatory diseases, cerebral edema, chronic pain syndrome, gastrointestinal diseases, tumors, as well as enhancing intelligence. Many studies have been carried out to discover therapeutic approaches for neurodegenerative diseases such as Alzheimer's diseases, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, stroke, and concomitant cognitive deficits. However, no curative treatment has been developed. This paper provides an overview of evidence about the potential of the Boswellia species and their main constituents, boswellic acids, as modulators of several mechanisms involved in the pathology of the neurodegenerative diseases. In vitro, animal, and clinical studies have confirmed that Boswellia species contain bioactive components that may enhance cognitive activity and protect against neurodegeneration. They exert the beneficial effects via targeting multiple pathological causes by antioxidative, anti-inflammatory, antiamyloidogenic, and anti-apoptotic properties. The Boswellia species, having neuroprotective potential, makes them a promising candidate to cure or prevent the neurodegenerative disorders.}, }
@article {pmid32437029, year = {2020}, author = {Yousefi, N and Abdollahii, S and Kouhbanani, MAJ and Hassanzadeh, A}, title = {Induced pluripotent stem cells (iPSCs) as game-changing tools in the treatment of neurodegenerative disease: Mirage or reality?.}, journal = {Journal of cellular physiology}, volume = {235}, number = {12}, pages = {9166-9184}, doi = {10.1002/jcp.29800}, pmid = {32437029}, issn = {1097-4652}, mesh = {Cell Differentiation/physiology ; *Cell- and Tissue-Based Therapy/methods ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Motor Neurons/pathology ; Neurodegenerative Diseases/pathology/*therapy ; Pluripotent Stem Cells/*cytology ; }, abstract = {Based on investigations, there exist tight correlations between neurodegenerative diseases' incidence and progression and aberrant protein aggregreferates in nervous tissue. However, the pathology of these diseases is not well known, leading to an inability to find an appropriate therapeutic approach to delay occurrence or slow many neurodegenerative diseases' development. The accessibility of induced pluripotent stem cells (iPSCs) in mimicking the phenotypes of various late-onset neurodegenerative diseases presents a novel strategy for in vitro disease modeling. The iPSCs provide a valuable and well-identified resource to clarify neurodegenerative disease mechanisms, as well as prepare a promising human stem cell platform for drug screening. Undoubtedly, neurodegenerative disease modeling using iPSCs has established innovative opportunities for both mechanistic types of research and recognition of novel disease treatments. Most important, the iPSCs have been considered as a novel autologous cell origin for cell-based therapy of neurodegenerative diseases following differentiation to varied types of neural lineage cells (e.g. GABAergic neurons, dopamine neurons, cortical neurons, and motor neurons). In this review, we summarize iPSC-based disease modeling in neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Moreover, we discuss the efficacy of cell-replacement therapies for neurodegenerative disease.}, }
@article {pmid32422969, year = {2020}, author = {Pham, J and Keon, M and Brennan, S and Saksena, N}, title = {Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32422969}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; DNA-Binding Proteins/*genetics ; Humans ; MicroRNAs/genetics ; Mutation ; RNA Splicing/genetics ; RNA-Binding Protein FUS/*genetics ; RNA-Binding Proteins/genetics ; Superoxide Dismutase-1/*genetics ; }, abstract = {Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)-including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)-have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1-a non-RBP commonly associated with familial ALS (fALS)-exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research.}, }
@article {pmid32417703, year = {2020}, author = {Hallett, M and de Haan, W and Deco, G and Dengler, R and Di Iorio, R and Gallea, C and Gerloff, C and Grefkes, C and Helmich, RC and Kringelbach, ML and Miraglia, F and Rektor, I and Strýček, O and Vecchio, F and Volz, LJ and Wu, T and Rossini, PM}, title = {Human brain connectivity: Clinical applications for clinical neurophysiology.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {131}, number = {7}, pages = {1621-1651}, doi = {10.1016/j.clinph.2020.03.031}, pmid = {32417703}, issn = {1872-8952}, mesh = {Brain/diagnostic imaging/physiology/physiopathology ; Brain Diseases/*diagnosis ; *Connectome ; Electroencephalography/methods ; Humans ; Magnetic Resonance Imaging/*methods ; Magnetoencephalography/methods ; Mental Disorders/*diagnosis ; }, abstract = {This manuscript is the second part of a two-part description of the current status of understanding of the network function of the brain in health and disease. We start with the concept that brain function can be understood only by understanding its networks, how and why information flows in the brain. The first manuscript dealt with methods for network analysis, and the current manuscript focuses on the use of these methods to understand a wide variety of neurological and psychiatric disorders. Disorders considered are neurodegenerative disorders, such as Alzheimer disease and amyotrophic lateral sclerosis, stroke, movement disorders, including essential tremor, Parkinson disease, dystonia and apraxia, epilepsy, psychiatric disorders such as schizophrenia, and phantom limb pain. This state-of-the-art review makes clear the value of networks and brain models for understanding symptoms and signs of disease and can serve as a foundation for further work.}, }
@article {pmid32415876, year = {2020}, author = {Govindarajan, R and Berry, JD and Paganoni, S and Pulley, MT and Simmons, Z}, title = {Optimizing telemedicine to facilitate amyotrophic lateral sclerosis clinical trials.}, journal = {Muscle &amp; nerve}, volume = {62}, number = {3}, pages = {321-326}, doi = {10.1002/mus.26921}, pmid = {32415876}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis ; *Betacoronavirus ; COVID-19 ; Clinical Trials as Topic ; Coronavirus Infections/*complications/epidemiology ; Humans ; *Pandemics ; Pneumonia, Viral/*complications/epidemiology ; *Quality of Life ; SARS-CoV-2 ; Telemedicine/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has the largest drug pipeline among neuromuscular diseases, with over 160 companies actively involved in ALS research. There is a growing need to recruit trial participants, but ALS patients often have limited mobility and most ALS trials are conducted in a small number of major centers. These factors effectively limit patient participation, particularly for those in rural areas. The current coronavirus disease 2019 (COVID-19) pandemic has necessitated the more widespread use of telemedicine technology for clinical care, and has prompted consideration of its increased use for clinical trials. In this opinion piece, we describe the current state of telemedicine for recruitment, consenting, and screening of participants for clinical trials. We also summarize the available data on remote administration of outcome measures. Current challenges include validation of outcome measures for remote assessment, as well as technological, regulatory, and licensure barriers.}, }
@article {pmid32415434, year = {2020}, author = {Srinivasan, E and Rajasekaran, R}, title = {A Systematic and Comprehensive Review on Disease-Causing Genes in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {70}, number = {11}, pages = {1742-1770}, pmid = {32415434}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein/genetics/metabolism ; *Genetic Predisposition to Disease ; Humans ; Profilins/chemistry/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/chemistry/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and is characterized by degeneration and axon loss from the upper motor neuron, that descends from the lower motor neuron in the brain. Over the period, assorted outcomes from medical findings, molecular pathogenesis, and structural and biophysical studies have abetted in providing thoughtful insights underlying the importance of disease-causing genes in ALS. Consequently, numerous mechanisms were proposed for the pathogenesis of ALS, considering protein mutations, aggregation, and misfolding. Besides, the answers to the majority of ALS cases that happen to be sporadic still remain obscure. The application in discovering susceptibility factors in ALS contemplating the genetic factors is to be further dissevered in the future years with innovation in research studies. Hence, this review targets in revisiting the breakthroughs on the disease-causing genes related with ALS.}, }
@article {pmid32410944, year = {2020}, author = {Brunet, A and Stuart-Lopez, G and Burg, T and Scekic-Zahirovic, J and Rouaux, C}, title = {Cortical Circuit Dysfunction as a Potential Driver of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {363}, pmid = {32410944}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects selected cortical and spinal neuronal populations, leading to progressive paralysis and death. A growing body of evidences suggests that the disease may originate in the cerebral cortex and propagate in a corticofugal manner. In particular, transcranial magnetic stimulation studies revealed that ALS patients present with early cortical hyperexcitability arising from a combination of increased excitability and decreased inhibition. Here, we discuss the possibility that initial cortical circuit dysfunction might act as the main driver of ALS onset and progression, and review recent functional, imaging and transcriptomic studies conducted on ALS patients, along with electrophysiological, pathological and transcriptomic studies on animal and cellular models of the disease, in order to evaluate the potential cellular and molecular origins of cortical hyperexcitability in ALS.}, }
@article {pmid32410936, year = {2020}, author = {Yu, X and Ji, C and Shao, A}, title = {Neurovascular Unit Dysfunction and Neurodegenerative Disorders.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {334}, pmid = {32410936}, issn = {1662-4548}, abstract = {The neurovascular unit (NVU), composed of vascular cells, glial cells, and neurons, is the minimal functional unit of the brain. The NVU maintains integrity of the blood-brain barrier (BBB) and regulates supply of the cerebral blood flow (CBF), both of which are keys to maintaining normal brain function. BBB dysfunction and a decreased CBF are early pathophysiological changes in neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In this review, we primarily focus on the NVU in AD as much research has been performed on the connection between NVU dysfunction and AD. We also discuss the role of NVU dysfunction in the pathophysiological mechanisms of PD and ALS. As most neurodegenerative diseases are difficult to treat, we discuss several potential drug targets that focus on the NVU that may inform novel vascular-targeted therapies for AD, PD, and ALS.}, }
@article {pmid32407951, year = {2020}, author = {Kumar, D and Ambasta, RK and Kumar, P}, title = {Ubiquitin biology in neurodegenerative disorders: From impairment to therapeutic strategies.}, journal = {Ageing research reviews}, volume = {61}, number = {}, pages = {101078}, doi = {10.1016/j.arr.2020.101078}, pmid = {32407951}, issn = {1872-9649}, mesh = {Alzheimer Disease/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Signal Transduction ; Ubiquitin/metabolism/*physiology ; alpha-Synuclein ; }, abstract = {The abnormal accumulation of neurotoxic proteins is the typical hallmark of various age-related neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis and Multiple sclerosis. The anomalous proteins, such as Aβ, Tau in Alzheimer's disease and α-synuclein in Parkinson's disease, perturb the neuronal physiology and cellular homeostasis in the brain thereby affecting the millions of human lives across the globe. Here, ubiquitin proteasome system (UPS) plays a decisive role in clearing the toxic metabolites in cells, where any aberrancy is widely reported to exaggerate the neurodegenerative pathologies. In spite of well-advancement in the ubiquitination research, their molecular markers and mechanisms for target-specific protein ubiquitination and clearance remained elusive. Therefore, this review substantiates the role of UPS in the brain signaling and neuronal physiology with their mechanistic role in the NDD's specific pathogenic protein clearance. Moreover, current and future promising therapies are discussed to target UPS-mediated neurodegeneration for better public health.}, }
@article {pmid32403313, year = {2020}, author = {Lanznaster, D and Veyrat-Durebex, C and Vourc'h, P and Andres, CR and Blasco, H and Corcia, P}, title = {Metabolomics: A Tool to Understand the Impact of Genetic Mutations in Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {11}, number = {5}, pages = {}, pmid = {32403313}, issn = {2073-4425}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein/genetics ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Genome-Wide Association Study ; High-Throughput Nucleotide Sequencing ; Humans ; Induced Pluripotent Stem Cells/metabolism/pathology ; *Metabolomics ; *Mutation ; Precision Medicine ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Metabolomics studies performed in patients with amyotrophic lateral sclerosis (ALS) reveal a set of distinct metabolites that can shed light on the pathological alterations taking place in each individual. Metabolites levels are influenced by disease status, and genetics play an important role both in familial and sporadic ALS cases. Metabolomics analysis helps to unravel the differential impact of the most common ALS-linked genetic mutations (as C9ORF72, SOD1, TARDBP, and FUS) in specific signaling pathways. Further, studies performed in genetic models of ALS reinforce the role of TDP-43 pathology in the vast majority of ALS cases. Studies performed in differentiated cells from ALS-iPSC (induced Pluripotent Stem Cells) reveal alterations in the cell metabolism that are also found in ALS models and ultimately in ALS patients. The development of metabolomics approaches in iPSC derived from ALS patients allow addressing and ultimately understanding the pathological mechanisms taking place in any patient. Lately, the creation of a "patient in a dish" will help to identify patients that may benefit from specific treatments and allow the implementation of personalized medicine.}, }
@article {pmid32394958, year = {2020}, author = {Riancho, J and Arozamena, S and López de Munaín, A}, title = {Dermic-derived fibroblasts for the study of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {15}, number = {11}, pages = {2043-2044}, pmid = {32394958}, issn = {1673-5374}, }
@article {pmid32393395, year = {2020}, author = {Song, Q and Meng, B and Xu, H and Mao, Z}, title = {The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {9}, number = {1}, pages = {17}, pmid = {32393395}, issn = {2047-9158}, support = {R01NS107505/NH/NIH HHS/United States ; R01NS095269/NH/NIH HHS/United States ; }, mesh = {Humans ; Hydrogen-Ion Concentration ; Lysosomal Storage Diseases/*metabolism/therapy ; Lysosomes/*metabolism ; Neurodegenerative Diseases/*metabolism/therapy ; Vacuolar Proton-Translocating ATPases/chemistry/*metabolism ; Vacuoles/chemistry/*metabolism ; }, abstract = {BACKGROUND: Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway. This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen. Lysosome pH gradients are mainly maintained by the vacuolar (H[+]) ATPase (or V-ATPase), which pumps protons into lysosomal lumen by consuming ATP. Dysfunction of V-ATPase affects lysosomal acidification, which disrupts the clearance of substrates and leads to many disorders, including neurodegenerative diseases.<br><br>MAIN BODY: As a large multi-subunit complex, the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis. The canonical functions of V-ATPase rely on its H[+]-pumping ability in multiple vesicle organelles to regulate endocytic traffic, protein processing and degradation, synaptic vesicle loading, and coupled transport. The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion, pH sensing, amino-acid-induced activation of mTORC1, and scaffolding for protein-protein interaction. In response to various stimuli, V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport. Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases, including neurodegenerative disorders such as Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders.<br><br>CONCLUSION: V-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells. Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases, further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.}, }
@article {pmid32392722, year = {2020}, author = {Angeloni, C and Gatti, M and Prata, C and Hrelia, S and Maraldi, T}, title = {Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress-Related Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32392722}, issn = {1422-0067}, mesh = {Animals ; Biomarkers/*metabolism ; Humans ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*metabolism ; Neurodegenerative Diseases/*metabolism/therapy ; Oxidation-Reduction ; Signal Transduction ; }, abstract = {Neurodegenerative diseases include a variety of pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer's and Parkinson's diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.}, }
@article {pmid32390802, year = {2020}, author = {Armada-Moreira, A and Gomes, JI and Pina, CC and Savchak, OK and Gonçalves-Ribeiro, J and Rei, N and Pinto, S and Morais, TP and Martins, RS and Ribeiro, FF and Sebastião, AM and Crunelli, V and Vaz, SH}, title = {Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {90}, pmid = {32390802}, issn = {1662-5102}, abstract = {Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.}, }
@article {pmid32389547, year = {2020}, author = {Maresca, G and Maggio, MG and Latella, D and Naro, A and Portaro, S and Calabrò, RS}, title = {Understanding the role of social cognition in neurodegenerative Disease: A scoping review on an overlooked problem.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {77}, number = {}, pages = {17-24}, doi = {10.1016/j.jocn.2020.05.013}, pmid = {32389547}, issn = {1532-2653}, mesh = {Amyotrophic Lateral Sclerosis/complications/diagnosis/psychology ; Cognition/*physiology ; Empathy/physiology ; Female ; Humans ; Male ; Multiple Sclerosis/complications/diagnosis/psychology ; Neurodegenerative Diseases/complications/diagnosis/*psychology ; Neuropsychological Tests ; Self Concept ; *Social Behavior ; Theory of Mind/*physiology ; }, abstract = {Social cognition (SC) is the set of socio-cognitive processes that guide automatic and voluntary behaviors by modulating behavioral responses, it includes both cognitive (Theory of the mind - ToM) and affective aspects (Empathy). SC also includes representations of internal somatic states, self-knowledge, perception of others, communication with others and interpersonal motivations. SC is relevant in daily life and reflects the neural complexity of social processing. The purpose of this scoping review is to evaluate the role of SC in neurological disorders, also considering the pathophysiological mechanisms underlying SC and potential assessment tools. The included studies were carried out between 2010 and 2019 and were found on PubMed, Scopus, Cochrane, and Web of Sciences databases, using the combined terms "social cognition"; "dementia"; "multiple sclerosis"; "parkinson", "amyotrophic lateral sclerosis", "neurodegenerative disease". Our review has shown that different SC domains are affected by several neurological conditions, with regards to dementia and amyotrophic lateral sclerosis. Further studies are needed to investigate the association between cognitive and social deficits, for a better management of patients with neurological disorders.}, }
@article {pmid32383122, year = {2020}, author = {Ustyantseva, EI and Medvedev, SP and Zakian, SM}, title = {Studying ALS: Current Approaches, Effect on Potential Treatment Strategy.}, journal = {Advances in experimental medicine and biology}, volume = {1241}, number = {}, pages = {195-217}, doi = {10.1007/978-3-030-41283-8_11}, pmid = {32383122}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Biomedical Research ; Disease Progression ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, characterized by inevitable progressive paralysis. To date, only two disease modifying therapeutic options are available for the patients with ALS, although they show very modest effect on disease course. The main reason of failure in the field of pharmacological correction of ALS is inability to untangle complex relationships taking place during ALS initiation and progression. Traditional methods of research, based on morphology or transgenic animal models studying provided lots of information about ALS throughout the years. However, translation of these results to humans was unsuccessful due to incomplete recapitulation of molecular pathology and overall inadequacy of the models used in the research.In this review we summarize current knowledge regarding ALS molecular pathology with depiction of novel methods applied recently for the studies. Furthermore we describe present and potential treatment strategies that are based on the recent findings in ALS disease mechanisms.}, }
@article {pmid32381174, year = {2020}, author = {Park, H and Kam, TI and Dawson, TM and Dawson, VL}, title = {Poly (ADP-ribose) (PAR)-dependent cell death in neurodegenerative diseases.}, journal = {International review of cell and molecular biology}, volume = {353}, number = {}, pages = {1-29}, doi = {10.1016/bs.ircmb.2019.12.009}, pmid = {32381174}, issn = {1937-6448}, mesh = {Animals ; *Cell Death ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Poly Adenosine Diphosphate Ribose/*metabolism ; }, abstract = {Disruption of cellular functions with aging-induced accumulation of neuronal stressors causes cell death which is a common feature of neurodegenerative diseases. Studies in a variety of neurodegenerative disease models demonstrate that poly (ADP-ribose) (PAR)-dependent cell death, also named parthanatos, is responsible for neuronal loss in neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Parthanatos has distinct features that differ from caspase-dependent apoptosis, necrosis or autophagic cell death. Parthanatos can be triggered by the accumulation of PAR due to overactivation of PAR polymerase-1 (PARP-1). Excess PAR, induces the mitochondrial release apoptosis-inducing factor (AIF), which binds to macrophage migration inhibitory factor (MIF) carrying MIF into the nucleus where it cleaves genomic DNA into large fragments. In this review, we will discuss the molecular mechanisms of parthanatos and their role in neurodegenerative diseases. Furthermore, we will discuss promising therapeutic interventions within the pathological PAR signaling cascade that could be designed to halt the progression of neurodegeneration.}, }
@article {pmid32375302, year = {2020}, author = {Bordoni, M and Scarian, E and Rey, F and Gagliardi, S and Carelli, S and Pansarasa, O and Cereda, C}, title = {Biomaterials in Neurodegenerative Disorders: A Promising Therapeutic Approach.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32375302}, issn = {1422-0067}, support = {RC2019-2020//Ministero della Salute/ ; }, mesh = {Animals ; *Biocompatible Materials/chemistry ; Humans ; Nanostructures ; Nanotechnology/methods ; Nerve Regeneration ; Neurodegenerative Diseases/etiology/metabolism/pathology/*therapy ; *Regenerative Medicine ; Theranostic Nanomedicine ; }, abstract = {Neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinal cord injury) represent a great problem worldwide and are becoming prevalent because of the increasing average age of the population. Despite many studies having focused on their etiopathology, the exact cause of these diseases is still unknown and until now, there are only symptomatic treatments. Biomaterials have become important not only for the study of disease pathogenesis, but also for their application in regenerative medicine. The great advantages provided by biomaterials are their ability to mimic the environment of the extracellular matrix and to allow the growth of different types of cells. Biomaterials can be used as supporting material for cell proliferation to be transplanted and as vectors to deliver many active molecules for the treatments of neurodegenerative disorders. In this review, we aim to report the potentiality of biomaterials (i.e., hydrogels, nanoparticles, self-assembling peptides, nanofibers and carbon-based nanomaterials) by analyzing their use in the regeneration of neural and glial cells their role in axon outgrowth. Although further studies are needed for their use in humans, the promising results obtained by several groups leads us to suppose that biomaterials represent a potential therapeutic approach for the treatments of neurodegenerative disorders.}, }
@article {pmid32374065, year = {2020}, author = {Lai, A and Valdez-Sinon, AN and Bassell, GJ}, title = {Regulation of RNA granules by FMRP and implications for neurological diseases.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {21}, number = {7}, pages = {454-462}, pmid = {32374065}, issn = {1600-0854}, support = {F31 NS101932/NS/NINDS NIH HHS/United States ; R01 MH109026/MH/NIMH NIH HHS/United States ; T32 GM008169/GM/NIGMS NIH HHS/United States ; 1R01MH109026, NIH F31NS101932 (ANV)//National Institute of Health/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Cytoplasmic Granules ; *Fragile X Mental Retardation Protein/genetics ; Humans ; RNA ; }, abstract = {RNA granule formation, which can be regulated by RNA-binding proteins (RBPs) such as fragile X mental retardation protein (FMRP), acts as a mechanism to control both the repression and subcellular localization of translation. Dysregulated assembly of RNA granules has been implicated in multiple neurological disorders, such as amyotrophic lateral sclerosis. Thus, it is crucial to understand the cellular pathways impinging upon granule assembly or disassembly. The goal of this review is to summarize recent advances in our understanding of the role of the RBP, FMRP, in translational repression underlying RNA granule dynamics, mRNA transport and localized. We summarize the known mechanisms of translational regulation by FMRP, the role of FMRP in RNA transport granules, fragile X granules and stress granules. Focusing on the emerging link between FMRP and stress granules, we propose a model for how hyperassembly and hypoassembly of RNA granules may contribute to neurological diseases.}, }
@article {pmid32373487, year = {2020}, author = {Unsal, V and Dalkıran, T and Çiçek, M and Kölükçü, E}, title = {The Role of Natural Antioxidants Against Reactive Oxygen Species Produced by Cadmium Toxicity: A Review.}, journal = {Advanced pharmaceutical bulletin}, volume = {10}, number = {2}, pages = {184-202}, pmid = {32373487}, issn = {2228-5881}, abstract = {Cadmium (Cd) is a significant ecotoxic heavy metal that adversely affects all biological processes of humans, animals and plants. Exposure to acute and chronic Cd damages many organs in humans and animals (e.g. lung, liver, brain, kidney, and testes). In humans, the Cd concentration at birth is zero, but because the biological half-life is long (about 30 years in humans), the concentration increases with age. The industrial developments of the last century have significantly increased the use of this metal. Especially in developing countries, this consumption is higher. Oxidative stress is the imbalance between antioxidants and oxidants. Cd increases reactive oxygen species (ROS) production and causes oxidative stress. Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles. This damage has been associated with various diseases. These include cancer, hypertension, ischemia/perfusion, cardiovascular diseases, chronic obstructive pulmonary disease, diabetes, insulin resistance, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, asthma, skin diseases, chronic kidney disease, eye diseases, neurodegenerative diseases (amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington disease). Natural antioxidants are popular drugs that are used by the majority of people and have few side effects. Natural antioxidants play an important role in reducing free radicals caused by Cd toxicity. Our goal in this review is to establish the relationship between Cd and oxidative stress and to discuss the role of natural antioxidants in reducing Cd toxicity.}, }
@article {pmid32373052, year = {2020}, author = {McCombe, PA and Lee, JD and Woodruff, TM and Henderson, RD}, title = {The Peripheral Immune System and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {279}, pmid = {32373052}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.}, }
@article {pmid32370112, year = {2020}, author = {Crespo-Castrillo, A and Arevalo, MA}, title = {Microglial and Astrocytic Function in Physiological and Pathological Conditions: Estrogenic Modulation.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32370112}, issn = {1422-0067}, support = {BFU2017-82754-R//Agencia Estatal de Investigaci&#xf3;n/ ; CB16/10/00383//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red Fragilidad y Envejecimiento Saludable/ ; }, mesh = {Alzheimer Disease/metabolism/*pathology ; Astrocytes/*pathology ; Depressive Disorder, Major/metabolism/*pathology ; Estrogens/metabolism ; Female ; Humans ; Male ; Microglia/*pathology ; Multiple Sclerosis/metabolism/*pathology ; Sex Factors ; }, abstract = {There are sexual differences in the onset, prevalence, and outcome of numerous neurological diseases. Thus, in Alzheimer's disease, multiple sclerosis, and major depression disorder, the incidence in women is higher than in men. In contrast, men are more likely to present other pathologies, such as amyotrophic lateral sclerosis, Parkinson's disease, and autism spectrum. Although the neurological contribution to these diseases has classically always been studied, the truth is that neurons are not the only cells to be affected, and there are other cells, such as glial cells, that are also involved and could be key to understanding the development of these pathologies. Sexual differences exist not only in pathology but also in physiological processes, which shows how cells are differentially regulated in males and females. One of the reasons these sexual differences may occur could be due to the different action of sex hormones. Many studies have shown an increase in aromatase levels in the brain, which could indicate the main role of estrogens in modulating proinflammatory processes. This review will highlight data about sex differences in glial physiology and how estrogenic compounds, such as estradiol and tibolone, could be used as treatment in neurological diseases due to their anti-inflammatory effects and the ability to modulate glial cell functions.}, }
@article {pmid32365642, year = {2020}, author = {Illes, P and Rubini, P and Ulrich, H and Zhao, Y and Tang, Y}, title = {Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS.}, journal = {Cells}, volume = {9}, number = {5}, pages = {}, pmid = {32365642}, issn = {2073-4409}, mesh = {Adenosine/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Central Nervous System/*metabolism/physiology/physiopathology ; Humans ; Macrophages/*metabolism ; Microglia/*metabolism ; Neurons/*metabolism ; }, abstract = {Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer's Disease, Parkinson's Disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, and A3, as targets of endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5'-nucleotidase enzymes to the almost inactive inosine as an end product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.}, }
@article {pmid32364065, year = {2021}, author = {Catalano, A and Franchini, C and Carocci, A}, title = {Voltage-Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues.}, journal = {Current medicinal chemistry}, volume = {28}, number = {8}, pages = {1535-1548}, doi = {10.2174/0929867327666200504080530}, pmid = {32364065}, issn = {1875-533X}, mesh = {Anti-Arrhythmia Agents/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Humans ; *Mexiletine/therapeutic use ; Sodium Channel Blockers/pharmacology/therapeutic use ; *Voltage-Gated Sodium Channel Blockers/pharmacology/therapeutic use ; }, abstract = {Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (-)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.}, }
@article {pmid32362075, year = {2020}, author = {Frydrýšková, K and Mašek, T and Pospíšek, M}, title = {Changing faces of stress: Impact of heat and arsenite treatment on the composition of stress granules.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {11}, number = {6}, pages = {e1596}, doi = {10.1002/wrna.1596}, pmid = {32362075}, issn = {1757-7012}, mesh = {Animals ; Arsenites/*metabolism ; Cytoplasmic Granules/*metabolism ; *Hot Temperature ; Humans ; Protein Processing, Post-Translational ; Stress, Physiological ; }, abstract = {Stress granules (SGs), hallmarks of the cellular adaptation to stress, promote survival, conserve cellular energy, and are fully dissolved upon the cessation of stress treatment. Different stresses can initiate the assembly of SGs, but arsenite and heat are the best studied of these stresses. The composition of SGs and posttranslational modifications of SG proteins differ depending on the type and severity of the stress insult, methodology used, cell line, and presence of overexpressed and tagged proteins. A group of 18 proteins showing differential localization to SGs in heat- and arsenite-stressed mammalian cell lines is described. Upon severe and prolonged stress, physiological SGs transform into more solid protein aggregates that are no longer reversible and do not contain mRNA. Similar pathological inclusions are hallmarks of neurodegenerative diseases. SGs induced by heat stress are less dynamic than SGs induced by arsenite and contain a set of unique proteins and linkage-specific polyubiquitinated proteins. The same types of ubiquitin linkages have been found to contribute to the development of neurodegenerative disorders such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). We propose heat stress-induced SGs as a possible model of an intermediate stage along the transition from dynamic, fully reversible arsenite stress-induced SGs toward aberrant SGs, the hallmark of neurodegenerative diseases. Stress- and methodology-specific differences in the compositions of SGs and the transition of SGs to aberrant protein aggregates are discussed. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.}, }
@article {pmid32357532, year = {2020}, author = {Bolus, H and Crocker, K and Boekhoff-Falk, G and Chtarbanova, S}, title = {Modeling Neurodegenerative Disorders in Drosophila melanogaster.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32357532}, issn = {1422-0067}, support = {R21 NS102698/NS/NINDS NIH HHS/United States ; T32 GM007133/GM/NIGMS NIH HHS/United States ; GM007133/NH/NIH HHS/United States ; NS102698/NH/NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Drosophila Proteins/*genetics ; Drosophila melanogaster ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation ; Nerve Regeneration ; Neurodegenerative Diseases/genetics/*pathology ; }, abstract = {Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using Drosophila models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders.}, }
@article {pmid32353380, year = {2020}, author = {Fish, LA and Fallon, JR}, title = {Multiple MuSK signaling pathways and the aging neuromuscular junction.}, journal = {Neuroscience letters}, volume = {731}, number = {}, pages = {135014}, pmid = {32353380}, issn = {1872-7972}, support = {T32 MH020068/MH/NIMH NIH HHS/United States ; R01 HD023924/HD/NICHD NIH HHS/United States ; U01 NS064295/NS/NINDS NIH HHS/United States ; R21 NS112743/NS/NINDS NIH HHS/United States ; R21 AR055878/AR/NIAMS NIH HHS/United States ; }, mesh = {Aging/physiology ; Agrin/*metabolism ; Animals ; Humans ; Motor Neurons/*metabolism ; Neuromuscular Junction/*physiology ; Receptor Protein-Tyrosine Kinases/*metabolism ; Receptors, Cholinergic/*metabolism ; }, abstract = {The neuromuscular junction (NMJ) is the vehicle for fast, reliable and robust communication between motor neuron and muscle. The unparalleled accessibility of this synapse to morphological, electrophysiological and genetic analysis has yielded an in depth understanding of many molecular components mediating its formation, maturation and stability. However, key questions surrounding the signaling pathways mediating these events and how they play out across the lifetime of the synapse remain unanswered. Such information is critical since the NMJ is necessary for normal movement and is compromised in several settings including myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), muscular dystrophy, sarcopenia and aging. Muscle specific kinase (MuSK) is a central player in most if not all contexts of NMJ formation and stability. However, elucidating the function of this receptor in this range of settings is challenging since MuSK participates in at least three signaling pathways: as a tyrosine kinase-dependent receptor for agrin-LRP4 and Wnts; and, as a kinase-independent BMP co-receptor. Here we focus on NMJ stability during aging and discuss open questions regarding the molecular mechanisms that govern active maintenance of the NMJ, with emphasis on MuSK and the potential role of its multiple signaling contexts.}, }
@article {pmid32353332, year = {2020}, author = {Yerbury, JJ and Farrawell, NE and McAlary, L}, title = {Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis.}, journal = {Trends in neurosciences}, volume = {43}, number = {5}, pages = {274-284}, doi = {10.1016/j.tins.2020.03.002}, pmid = {32353332}, issn = {1878-108X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Proteome/metabolism ; Motor Neurons ; Proteostasis ; Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease but currently has no effective treatment. Growing evidence suggests that proteome homeostasis underlies ALS pathogenesis. Protein production, trafficking, and degradation all shape the proteome. We present a hypothesis that proposes all genetic lesions associated with ALS (including in mRNA-binding proteins) cause widespread imbalance to an already metastable proteome. The impact of such dysfunction is felt across the entire proteome and is not restricted to a small subset of proteins. Proteome imbalance may cause functional defects, such as excitability alterations, and eventually cell death. While this idea is a unifying principle for all of ALS, we propose that stratification will appear that might dictate the efficacy of therapeutics based on the proteostasis network.}, }
@article {pmid32351395, year = {2020}, author = {Hong, C and Jeong, B and Park, HJ and Chung, JY and Lee, JE and Kim, J and Shin, YC and So, I}, title = {TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {238}, pmid = {32351395}, issn = {1664-042X}, abstract = {The development of treatment for neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is facing medical challenges due to the increasingly aging population. However, some pharmaceutical companies have ceased the development of therapeutics for NDs, and no new treatments for NDs have been established during the last decade. The relationship between ND pathogenesis and risk factors has not been completely elucidated. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where oxidative stress and disrupted Ca[2+] homeostasis consequently lead to neuronal apoptosis. Reactive oxygen species (ROS) -sensitive TRP channels can be key risk factors as polymodal sensors, since progressive late onset with secondary pathological damage after initial toxic insult is one of the typical characteristics of NDs. Recent evidence indicates that the dysregulation of TRP channels is a missing link between disruption of Ca[2+] homeostasis and neuronal loss in NDs. In this review, we discuss the latest findings regarding TRP channels to provide insights into the research and quests for alternative therapeutic candidates for NDs. As the structures of TRP channels have recently been revealed by cryo-electron microscopy, it is necessary to develop new TRP channel antagonists and reevaluate existing drugs.}, }
@article {pmid32351363, year = {2020}, author = {Wang, L and Zhang, L}, title = {Circulating Exosomal miRNA as Diagnostic Biomarkers of Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {53}, pmid = {32351363}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDDs) are a group of diseases caused by chronic and progressive degeneration of neural tissue. The main pathological manifestations are neuronal degeneration and loss in the brain and/or spinal cord. Common NDDs include Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS). The complicated pathological characteristics and different clinical manifestations of NDDs result in a lack of sensitive and efficient diagnostic methods. In addition, no sensitive biomarkers are available to monitor the course of NDDs, predict their prognosis, and monitor the therapeutic response. Despite extensive research in recent years, analysis of amyloid β (Aβ) and α-synuclein has failed to effectively improve NDD diagnosis. Although recent studies have indicated circulating miRNAs as promising diagnostic biomarkers of NDDs, the miRNA in the peripheral circulation is susceptible to interference by other components, making circulating miRNA results less consistent. Exosomes are small membrane vesicles with a diameter of approximately 30-100 nm that transport proteins, lipids, mRNA, and miRNA. Because recent studies have shown that exosomes have a double-membrane structure that can resist ribonuclease in the blood, giving exosomal miRNA high stability and making them resistant to degradation, they may become an ideal biomarker of circulating fluids. In this review, we discuss the applicability of circulating exosomal miRNAs as biomarkers, highlight the technical aspects of exosomal miRNA analysis, and review studies that have used circulating exosomal miRNAs as candidate diagnostic biomarkers of NDDs.}, }
@article {pmid32351353, year = {2020}, author = {Lenahan, C and Sanghavi, R and Huang, L and Zhang, JH}, title = {Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {326}, pmid = {32351353}, issn = {1662-4548}, abstract = {Retinal alterations have recently been associated with numerous neurodegenerative diseases. Rhodopsin is a G-protein coupled receptor found in the rod cells of the retina. As a biomarker associated with retinal thinning and degeneration, it bears potential in the early detection and monitoring of several neurodegenerative diseases. In this review article, we summarize the findings of correlations between rhodopsin and several neurodegenerative disorders as well as the potential of a novel technique, cSLO, in the quantification of rhodopsin.}, }
@article {pmid32350120, year = {2020}, author = {Tavassoly, O and Sato, T and Tavassoly, I}, title = {Inhibition of Brain Epidermal Growth Factor Receptor Activation: A Novel Target in Neurodegenerative Diseases and Brain Injuries.}, journal = {Molecular pharmacology}, volume = {98}, number = {1}, pages = {13-22}, doi = {10.1124/mol.120.119909}, pmid = {32350120}, issn = {1521-0111}, mesh = {Adult ; Animals ; Blood-Brain Barrier/drug effects ; Brain Injuries/drug therapy/*metabolism ; Central Nervous System/*growth &amp; development/metabolism ; Child ; Drug Repositioning ; ErbB Receptors/antagonists &amp; inhibitors/metabolism ; Gene Expression Regulation, Developmental ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*metabolism ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Spinal Cord Injuries/drug therapy/*metabolism ; Up-Regulation/drug effects ; }, abstract = {Several reports have been published recently demonstrating a beneficial effect of epidermal growth factor receptor (EGFR) inhibitors in improving pathologic and behavioral conditions in neurodegenerative diseases (NDDs) such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) as well as the brain and spinal cord injuries (SCI). Despite successful therapeutic effects of EGFR inhibition in these pathologic conditions, there is still no report of proof-of-concept studies in well-characterized animal models using recently developed blood-brain barrier (BBB)-penetrating EGFR inhibitors, which is due to previous conflicting reports concerning the level of EGFR or activated EGFR in normal and pathologic conditions that caused target engagement to be a concern in any future EGFR inhibition therapy. In this review, the level of EGFR expression and activation in the developing central nervous system (CNS) compared with the adult CNS will be explained as well as how neuronal injury or pathologic conditions, especially inflammation and amyloid fibrils, induce reactive astrocytes leading to an increase in the expression and activation of EGFR and, finally, neurodegeneration. Furthermore, in this review, we will discuss two main molecular mechanisms that can be proposed as the neuroprotective effects of EGFR inhibition in these pathologic conditions. We will also review the recent advances in the development of BBB-penetrating EGFR inhibitors in cancer therapy, which may eventually be repositioned for NDDs and SCI therapy in the future. SIGNIFICANCE STATEMENT: Based on the lessons from the applications of EGFR inhibitors in oncology, it is concluded that EGFR inhibitors can be beneficial in treatment of neurodegenerative diseases and spinal cord injuries. They carry their therapeutic potentials through induction of autophagy and attenuation of reactive astrocytes.}, }
@article {pmid32345319, year = {2020}, author = {Christoforidou, E and Joilin, G and Hafezparast, M}, title = {Potential of activated microglia as a source of dysregulated extracellular microRNAs contributing to neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {135}, pmid = {32345319}, issn = {1742-2094}, support = {HAFEZPARAST/APR15/836-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; HAFEZPARAST/APR18/861-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; Hafezparast/Apr15/836-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; Hafezparast/Apr18/861-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Cell Communication/*physiology ; Extracellular Vesicles/metabolism ; Humans ; MicroRNAs/*metabolism ; Microglia/*metabolism/pathology ; Nerve Degeneration/*metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron degeneration in adults, and several mechanisms underlying the disease pathology have been proposed. It has been shown that glia communicate with other cells by releasing extracellular vesicles containing proteins and nucleic acids, including microRNAs (miRNAs), which play a role in the post-transcriptional regulation of gene expression. Dysregulation of miRNAs is commonly observed in ALS patients, together with inflammation and an altered microglial phenotype. However, the role of miRNA-containing vesicles in microglia-to-neuron communication in the context of ALS has not been explored in depth. This review summarises the evidence for the presence of inflammation, pro-inflammatory microglia and dysregulated miRNAs in ALS, then explores how microglia may potentially be responsible for this miRNA dysregulation. The possibility of pro-inflammatory ALS microglia releasing miRNAs which may then enter neuronal cells to contribute to degeneration is also explored. Based on the literature reviewed here, microglia are a likely source of dysregulated miRNAs and potential mediators of neurodegenerative processes. Therefore, dysregulated miRNAs may be promising candidates for the development of therapeutic strategies.}, }
@article {pmid32344747, year = {2020}, author = {Basile, MS and Battaglia, G and Bruno, V and Mangano, K and Fagone, P and Petralia, MC and Nicoletti, F and Cavalli, E}, title = {The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {8}, pages = {}, pmid = {32344747}, issn = {1422-0067}, mesh = {Animals ; Biomarkers ; Central Nervous System/metabolism/pathology ; Clinical Studies as Topic ; Disease Management ; Disease Models, Animal ; *Disease Susceptibility ; Humans ; Intramolecular Oxidoreductases/*genetics/*metabolism ; Macrophage Migration-Inhibitory Factors/*genetics/*metabolism ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; }, abstract = {Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.}, }
@article {pmid32344665, year = {2020}, author = {Kodavati, M and Wang, H and Hegde, ML}, title = {Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective.}, journal = {Cells}, volume = {9}, number = {4}, pages = {}, pmid = {32344665}, issn = {2073-4409}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/pathology ; Genome, Mitochondrial ; Genomic Instability ; Humans ; *Mitochondrial Dynamics ; Motor Neuron Disease/genetics/*pathology ; Nerve Degeneration/pathology ; }, abstract = {Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Studies in MND rodent models also indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting a causal role of mitochondrial dysfunction. Our recent studies, which demonstrated the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS, raised a key question of its potential implication in mitochondrial DNA transactions because LIG3 is essential for both mitochondrial DNA replication and repair. This question, as well as how wild-type and mutant MND-associated factors affect mitochondria, remain to be elucidated. These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions.}, }
@article {pmid32344649, year = {2020}, author = {Chang, CY and Ting, HC and Liu, CA and Su, HL and Chiou, TW and Lin, SZ and Harn, HJ and Ho, TJ}, title = {Induced Pluripotent Stem Cell (iPSC)-Based Neurodegenerative Disease Models for Phenotype Recapitulation and Drug Screening.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {8}, pages = {}, pmid = {32344649}, issn = {1420-3049}, mesh = {Animals ; Cell Differentiation ; Disease Susceptibility ; *Drug Discovery/methods ; *Drug Evaluation, Preclinical/methods ; Humans ; Induced Pluripotent Stem Cells/cytology/*drug effects/*metabolism ; Neurodegenerative Diseases/drug therapy/etiology/metabolism ; Neuroglia/drug effects/metabolism ; Neurons/drug effects/metabolism ; Phenotype ; }, abstract = {Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.}, }
@article {pmid32342825, year = {2021}, author = {Alam, M and Yadav, RK and Minj, E and Tiwari, A and Mehan, S}, title = {Exploring Molecular Approaches in Amyotrophic Lateral Sclerosis: Drug Targets from Clinical and Pre-Clinical Findings.}, journal = {Current molecular pharmacology}, volume = {14}, number = {3}, pages = {263-280}, doi = {10.2174/1566524020666200427214356}, pmid = {32342825}, issn = {1874-4702}, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy/pathology ; Humans ; Mitochondria/pathology ; *Motor Neuron Disease/complications/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age, which include impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity, and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% of the patients live for more than 10 years. The limited intervention of pharmacologically active compounds, that are used clinically, is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models, where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB, is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, this current review specially targeted the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with the up-regulation of intracellular adenyl cyclase/cAMP/ CREB and activation of mitochondrial-ETC coenzyme-Q10 as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.}, }
@article {pmid32342435, year = {2020}, author = {Ahmadian-Moghadam, H and Sadat-Shirazi, MS and Zarrindast, MR}, title = {Therapeutic potential of stem cells for treatment of neurodegenerative diseases.}, journal = {Biotechnology letters}, volume = {42}, number = {7}, pages = {1073-1101}, doi = {10.1007/s10529-020-02886-1}, pmid = {32342435}, issn = {1573-6776}, support = {36034-159-03-96//Iran's National Elites Foundation/ ; }, mesh = {Animals ; Humans ; Induced Pluripotent Stem Cells/transplantation ; Mice ; Neural Stem Cells/transplantation ; Neurodegenerative Diseases/*surgery ; *Stem Cell Transplantation ; }, abstract = {Neurodegenerative diseases are caused by a loss of neurons within the peripheral or central nervous system. Inadequate repairability in the central nervous system and failure of treatments are the significant hurdles for several neurological diseases. The regenerative potential of stem cells drew the attention of researchers to cell-based therapy for treating neurodegenerative diseases. The clinical application of stem cells may help to substitute new cells and overcome the inability of the endogenous repairing system to repair the damaged brain. However, the clinical application induced pluripotent stem cells are restricted due to the risk of tumor formation by residual undifferentiated upon transplantation. In this focused review, we briefly discussed different stem cells currently being studied for therapeutic development. Moreover, we present supporting evidence for the utilization of stem cell therapy for the treatment of neurodegenerative diseases. Also, we described the key issues that should be considered to transplantation of stem cells for different neurodegenerative diseases. In our conclusion, stem cell therapy probably would be the only treatment strategy that offers a cure for neurodegenerative disease. Although, further study is required to identify ideal stem cells candidate, dosing and the ideal method of cell transplantation. We suggest that all grafted cells would be transgenically armed with a molecular kill-switch that could be activated by the event of adverse side effects.}, }
@article {pmid32341983, year = {2019}, author = {Nguyen, KV}, title = {β-Amyloid precursor protein (APP) and the human diseases.}, journal = {AIMS neuroscience}, volume = {6}, number = {4}, pages = {273-281}, pmid = {32341983}, issn = {2373-7972}, abstract = {Several pathophysiological functions of the human β-amyloid precursor protein (APP) have been recently proposed in different human diseases such as neurodevelopmental and neurodegenerative disorders including rare diseases such as autism, fragile X syndrome, amyotrophic lateral sclerosis, multiple sclerosis, Lesch-Nyhan disease; common and complex disorders such as Alzheimer's disease; metabolic disorders such as diabetes; and also cancer. APP as well as all of its proteolytic fragments including the amyloid-β (Aβ) peptide, are part of normal physiology. The targeting of the components of APP proteolytic processing as a pharmacologic strategy will not be without consequences. Recent research results highlight the impact of alternative splicing (AS) process on human disease, and may provide new directions for the research on the impact of the human APP on human diseases. The identification of molecules capable of correcting and/or inhibiting pathological splicing events is therefore an important issue for future therapeutic approaches. To this end, the defective APP-mRNA isoform responsible for the disease in cells and tissues appears as an ideal target for epigenetic therapeutic intervention and antisense drugs are potential treatment.}, }
@article {pmid32340815, year = {2020}, author = {Schreiber, S and Vielhaber, S and Schreiber, F and Cartwright, MS}, title = {Peripheral nerve imaging in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {131}, number = {9}, pages = {2315-2326}, doi = {10.1016/j.clinph.2020.03.026}, pmid = {32340815}, issn = {1872-8952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Humans ; Magnetic Resonance Imaging/*methods ; Peripheral Nerves/*diagnostic imaging ; Ultrasonography/*methods ; }, abstract = {We systematically identified and reviewed 29 studies of peripheral nerve ultrasound or magnetic resonance imaging (MRN) in amyotrophic lateral sclerosis (ALS). The majority of the ultrasound studies reported smaller nerves and nerve roots in ALS compared to healthy controls, but there was a large overlap of the cross-sectional nerve area between ALS and controls. Most of the MRN studies confirmed nerve abnormalities demonstrating slight T2 hyperintensities and, sometimes, mild enlargement of more proximal nerve segments (plexus, roots) in ALS. The size of the proximal nerve segments, i.e. nerve roots, is thus somewhat incongruent between nerve ultrasound and MRN in ALS. Peripheral nerve ultrasound has the potential to differentiate between ALS and multifocal motor neuropathy (MMN) in that patients with MMN have significantly larger nerves. Conversely, there is an overlap of MRN abnormalities in ALS and MMN, restricting the techniques' utility in the clinical setting. A subgroup of patients with ALS seems to reveal a sonographic nerve pattern suggesting peripheral nerve inflammation. In the future, combined imaging with nerve ultrasound and MRN assessing parameters such as blood flow or textural markers may aid in the understanding of the deep nerve microstructure down to the fascicle level, and thus, in the classification of the nerve state as more degenerative or more inflammatory in ALS. This systematic review provides evidence that nerve imaging abnormalities are common in ALS.}, }
@article {pmid32336828, year = {2020}, author = {Duarte, ML and Iared, W and Oliveira, ASB and Dos Santos, LR and Peccin, MS}, title = {Ultrasound versus electromyography for the detection of fasciculation in amyotrophic lateral sclerosis: systematic review and meta-analysis.}, journal = {Radiologia brasileira}, volume = {53}, number = {2}, pages = {116-121}, pmid = {32336828}, issn = {0100-3984}, abstract = {The objective of this study was to determine the diagnostic accuracy of ultrasound and electromyography for the detection of fasciculation in patients with amyotrophic lateral sclerosis and to compare detection rates between the two methods. By searching the Cochrane Library, MEDLINE, Excerpta Medica, and Latin-American and Caribbean Health Sciences Literature databases, we identified studies evaluating the diagnostic accuracy and fasciculation detection rates of ultrasound and electromyography. The Quality Assessment of Diagnostic Accuracy Studies, version 2, and RTI item bank tools were used for the evaluation of methodological quality. Ultrasound, for 10 s or 30 s, had a higher detection rate than did electromyography in all muscles evaluated. The overall detection rate (in patients) did not differ significantly between ultrasound for 10 s and ultrasound for 30 s. The accuracy of ultrasound for 10 s was 70% in muscles and 85% in patients. The accuracy of ultrasound for 30 s was 82% in patients. Ultrasound provided detection rates superior to those achieved with electromyography, independent of the examination time and muscles evaluated.}, }
@article {pmid32330468, year = {2020}, author = {Schiavi, A and Strappazzon, F and Ventura, N}, title = {Mitophagy and iron: two actors sharing the stage in age-associated neuronal pathologies.}, journal = {Mechanisms of ageing and development}, volume = {188}, number = {}, pages = {111252}, doi = {10.1016/j.mad.2020.111252}, pmid = {32330468}, issn = {1872-6216}, mesh = {*Aging ; Alzheimer Disease/metabolism ; Animals ; Autophagy/physiology ; Cardiovascular Diseases/*metabolism ; Heart Failure/*metabolism ; Homeostasis ; Humans ; Iron/*metabolism ; Lysosomes/*metabolism ; Mitochondria/*metabolism ; Mitophagy/*physiology ; Neurons/*metabolism ; Oxygen/metabolism ; Parkinson Disease/metabolism ; Phosphorylation ; }, abstract = {Aging is characterized by the deterioration of different cellular and organismal structures and functions. A typical hallmark of the aging process is the accumulation of dysfunctional mitochondria and excess iron, leading to a vicious cycle that promotes cell and tissue damage, which ultimately contribute to organismal aging. Accordingly, altered mitochondrial quality control pathways such as mitochondrial autophagy (mitophagy) as well as altered iron homeostasis, with consequent iron overload, can accelerate the aging process and the development and progression of different age-associated disorders. In this review we first briefly introduce the aging process and summarize molecular mechanisms regulating mitophagy and iron homeostasis. We then provide an overview on how dysfunction of these two processes impact on aging and age-associated neurodegenerative disorders with a focus on Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Finally, we summarize some recent evidence showing mechanistic links between iron metabolism and mitophagy and speculate on how regulating the crosstalk between the two processes may provide protective effects against aging and age-associated neuronal pathologies.}, }
@article {pmid32329299, year = {2020}, author = {Ayka, A and Şehirli, A&#xd6;}, title = {The Role of the SLC Transporters Protein in the Neurodegenerative Disorders.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {18}, number = {2}, pages = {174-187}, pmid = {32329299}, issn = {1738-1088}, abstract = {The solute carrier (SLC) superfamily is one of the major sub-groups of membrane proteins in mammalian cells. The solute carrier proteins include more than 400 different membrane-spanning solute carriers organized with 65 families in the human. In solute carrier family neurons, neurotransmitter is considered to be a pharmacological target of neuropsychiatric drugs because of their important role in the recovery of neurotransmitters such as GABA, glutamate, serotonin, dopamine and noradrenaline and regulation of their concentration in synaptic regions. Therefore, solute carrier transporters play vital and different roles in neurodegenerative disorders. In this article, the role of solute carrier transporters in neurodegenerative disorders such as Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Parkinson's diseases, depression, post-traumatic stress disorder, dementia, schizophrenia, and Epilepsy reviewed and discussed to see how defects or absences in SLC transporter cause neurodegenerative disorders. In this review, we try to summarize what is known about solute carriers with respect to brain distribution and expression. The review summarizes current knowledge on the roles of solute carrier transporters in neurodegenerative disorders.}, }
@article {pmid32326227, year = {2020}, author = {Schepici, G and Silvestro, S and Trubiani, O and Bramanti, P and Mazzon, E}, title = {Salivary Biomarkers: Future Approaches for Early Diagnosis of Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {10}, number = {4}, pages = {}, pmid = {32326227}, issn = {2076-3425}, support = {-//Ministero della Salute/ ; }, abstract = {Many neurological diseases are characterized by progressive neuronal degeneration. Early diagnosis and new markers are necessary for prompt therapeutic intervention. Several studies have aimed to identify biomarkers in different biological liquids. Furthermore, it is being considered whether saliva could be a potential biological sample for the investigation of neurodegenerative diseases. This work aims to provide an overview of the literature concerning biomarkers identified in saliva for the diagnosis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Specifically, the studies have revealed that is possible to quantify beta-amyloid1-42 and TAU protein from the saliva of AD patients. Instead, alpha-synuclein and protein deglycase (DJ-1) have been identified as new potential salivary biomarkers for the diagnosis of PD. Nevertheless, future studies will be needed to validate these salivary biomarkers in the diagnosis of neurological diseases.}, }
@article {pmid32320731, year = {2020}, author = {Gil-Martins, E and Barbosa, DJ and Silva, V and Remião, F and Silva, R}, title = {Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {213}, number = {}, pages = {107554}, doi = {10.1016/j.pharmthera.2020.107554}, pmid = {32320731}, issn = {1879-016X}, mesh = {ATP-Binding Cassette Transporters/*metabolism ; Animals ; Blood-Brain Barrier/*metabolism ; Brain/metabolism ; Central Nervous System Agents/pharmacokinetics/pharmacology ; Drug Resistance ; Humans ; Nervous System Diseases/drug therapy/*physiopathology ; }, abstract = {ABC (ATP-binding cassette) transporters represent one of the largest and most diverse superfamily of proteins in living species, playing an important role in many biological processes such as cell homeostasis, cell signaling, drug metabolism and nutrient uptake. Moreover, using the energy generated from ATP hydrolysis, they mediate the efflux of endogenous and exogenous substrates from inside the cells, thereby reducing their intracellular accumulation. At present, 48 ABC transporters have been identified in humans, which were classified into 7 different subfamilies (A to G) according to their phylogenetic analysis. Nevertheless, the most studied members with importance in drug therapeutic efficacy and toxicity include P-glycoprotein (P-gp), a member of the ABCB subfamily, the multidrug-associated proteins (MPRs), members of the ABCC subfamily, and breast cancer resistance protein (BCRP), a member of the ABCG subfamily. They exhibit ubiquitous expression throughout the human body, with a special relevance in barrier tissues like the blood-brain barrier (BBB). At this level, they play a physiological function in tissue protection by reducing or limiting the brain accumulation of neurotoxins. Furthermore, dysfunction of ABC transporters, at expression and/or activity level, has been associated with many neurological diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. Additionally, these transporters are strikingly associated with the pharmacoresistance to central nervous system (CNS) acting drugs, because they contribute to the decrease in drug bioavailability. This article reviews the signaling pathways that regulate the expression and activity of P-gp, BCRP and MRPs subfamilies of transporters, with particular attention at the BBB level, and their mis-regulation in neurological disorders.}, }
@article {pmid32315731, year = {2020}, author = {Harilal, S and Jose, J and Parambi, DGT and Kumar, R and Unnikrishnan, MK and Uddin, MS and Mathew, GE and Pratap, R and Marathakam, A and Mathew, B}, title = {Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules.}, journal = {Brain research bulletin}, volume = {160}, number = {}, pages = {121-140}, doi = {10.1016/j.brainresbull.2020.03.018}, pmid = {32315731}, issn = {1873-2747}, mesh = {Animals ; Biological Transport/drug effects/physiology ; Blood-Brain Barrier/drug effects/*metabolism ; Brain/drug effects/*metabolism ; Humans ; Membrane Proteins/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism ; Pharmaceutical Preparations/administration &amp; dosage/*metabolism ; Tight Junctions/drug effects/metabolism ; }, abstract = {Barriers are the hallmark of a healthy physiology, blood-brain barrier (BBB) being a tough nut to crack for most of the antigens and chemical substances. The presence of tight junctions plays a remarkable role in defending the brain from antigenic and pathogenic attacks. BBB constitutes a diverse assemblage of multiple physical and chemical barriers that judiciously restrict the flux of blood solutes into and out of the brain. Restrictions through the paracellular pathway and the tight junctions between intercellular clefts, together create well regulated metabolic and transport barricades, critical to brain pathophysiology. The brain being impermeable to many essential metabolites and nutrients regulates transportation via specialized transport systems across the endothelial abluminal and luminal membranes. The epithelial cells enveloping capillaries of the choroid plexus regulates the transport of complement, growth factors, hormones, microelements, peptides and trace elements into ventricles. Nerve terminals, microglia, and pericytes associated with the endothelium support barrier induction and function, ensuring an optimally stable ionic microenvironment that facilitates neurotransmission, orchestrated by multiple ion channels (Na[+], K[+] Mg[2+], Ca[2+]) and transporters. Brain pathology which can develop due to genetic mutations or secondary to other cerebrovascular, neurodegenerative diseases can cause aberration in the microvasculature of CNS which is the uniqueness of BBB. This can also alter BBB permeation and result in BBB breakdown and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The concluding section outlines contemporary trends in drug discovery, focusing on molecular determinants of BBB permeation and novel drug-delivery systems, such as dendrimers, liposomes, nanoparticles, nanogels, etc.}, }
@article {pmid32315694, year = {2020}, author = {Berhe, DF and Gebre, AK and Assefa, BT}, title = {Orexins role in neurodegenerative diseases: From pathogenesis to treatment.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {194}, number = {}, pages = {172929}, doi = {10.1016/j.pbb.2020.172929}, pmid = {32315694}, issn = {1873-5177}, mesh = {Alzheimer Disease/pathology/therapy ; Animals ; Epilepsy/pathology/therapy ; Humans ; Narcolepsy/pathology/therapy ; Neurodegenerative Diseases/metabolism/*pathology/*therapy ; Neurotransmitter Agents/metabolism ; Orexins/adverse effects/*metabolism ; Parkinson Disease/pathology/therapy ; Sleep ; Wakefulness ; }, abstract = {Orexin is a neurotransmitter that mainly regulates sleep/wake cycle. In addition to its sleep cycle regulatory role, it is involved in regulation of attention, energy homeostasis, neurogenesis and cognition. Several evidences has shown the involvement of orexin in narcolepsy, but there are also growing evidences that shows the disturbance in orexin system in neurodegenerative diseases including Alzheimer's, Parkinson's, Epilepsy, Huntington's diseases and Amyotrophic lateral sclerosis. Pathogenesis and clinical symptoms of these disorders can be partly attributed from orexin system imbalance. However, there are controversial reports on the exact relationship between orexin and these neurodegenerative diseases. Therefore, the aim of this review is to summarize the current evidences regarding the role of orexin in these neurodegenerative diseases.}, }
@article {pmid32312500, year = {2020}, author = {Sellami, L and Saracino, D and Le Ber, I}, title = {Genetic forms of frontotemporal lobar degeneration: Current diagnostic approach and new directions in therapeutic strategies.}, journal = {Revue neurologique}, volume = {176}, number = {7-8}, pages = {571-581}, doi = {10.1016/j.neurol.2020.02.008}, pmid = {32312500}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis ; *Frontotemporal Lobar Degeneration ; Humans ; Intercellular Signaling Peptides and Proteins ; Mutation ; Progranulins ; }, abstract = {Recent advances in the genetics of neurodegenerative diseases have substantially improved our knowledge about the genetic causes of frontotemporal lobar degeneration (FTLD). Three major genes, namely progranulin (GRN), C9orf72 and MAPT, as well as several less common genes, are responsible for the majority of familial cases and for a significant proportion of sporadic forms, including FTLD with or without associated amyotrophic lateral sclerosis and some rarer clinical presentations. Plasma progranulin dosage and next-generation sequencing are currently available tools which allow the detection of a genetic cause in a more rapid and efficient way. This has important consequences for clinical practice and genetic counseling for patients and families. The ongoing investigations on some therapeutic candidates targeting different biological pathways involved in the most frequent genetic forms of FTLD, as well as a better understanding of the early pathophysiological modifications occurring during the presymptomatic phase of the disease could hopefully contribute to develop effective disease-modifying therapies. The identification of a causal mutation in a family is of outmost importance indeed to propose to presymptomatic carriers their inclusion in clinical trials with the aim to prevent or delay the onset of disease.}, }
@article {pmid32311648, year = {2020}, author = {Figley, MD and DiAntonio, A}, title = {The SARM1 axon degeneration pathway: control of the NAD[+] metabolome regulates axon survival in health and disease.}, journal = {Current opinion in neurobiology}, volume = {63}, number = {}, pages = {59-66}, pmid = {32311648}, issn = {1873-6882}, support = {R01 CA219866/CA/NCI NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; }, mesh = {*Armadillo Domain Proteins/genetics/metabolism/physiology ; Axons/metabolism ; Cytoskeletal Proteins/metabolism/physiology ; Humans ; Metabolome ; *NAD/metabolism ; Nicotinamide-Nucleotide Adenylyltransferase/physiology ; Wallerian Degeneration/pathology ; }, abstract = {Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half after the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. The balance between axon survival and self-destruction is intimately tied to axonal NAD[+] metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson's.}, }
@article {pmid32308803, year = {2020}, author = {Höhn, A and Tramutola, A and Cascella, R}, title = {Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {5497046}, pmid = {32308803}, issn = {1942-0994}, mesh = {Humans ; Neurodegenerative Diseases/*genetics ; Oxidative Stress/*genetics ; Proteostasis/*genetics ; }, abstract = {Protein homeostasis or proteostasis is an essential balance of cellular protein levels mediated through an extensive network of biochemical pathways that regulate different steps of the protein quality control, from the synthesis to the degradation. All proteins in a cell continuously turn over, contributing to development, differentiation, and aging. Due to the multiple interactions and connections of proteostasis pathways, exposure to stress conditions may cause various types of protein damage, altering cellular homeostasis and disrupting the entire network with additional cellular stress. Furthermore, protein misfolding and/or alterations during protein synthesis results in inactive or toxic proteins, which may overload the degradation mechanisms. The maintenance of a balanced proteome, preventing the formation of impaired proteins, is accomplished by two major catabolic routes: the ubiquitin proteasomal system (UPS) and the autophagy-lysosomal system. The proteostasis network is particularly important in nondividing, long-lived cells, such as neurons, as its failure is implicated with the development of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These neurological disorders share common risk factors such as aging, oxidative stress, environmental stress, and protein dysfunction, all of which alter cellular proteostasis, suggesting that general mechanisms controlling proteostasis may underlay the etiology of these diseases. In this review, we describe the major pathways of cellular proteostasis and discuss how their disruption contributes to the onset and progression of neurodegenerative diseases, focusing on the role of oxidative stress.}, }
@article {pmid32307753, year = {2020}, author = {McDonald, TS and McCombe, PA and Woodruff, TM and Lee, JD}, title = {The potential interplay between energy metabolism and innate complement activation in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {6}, pages = {7225-7233}, doi = {10.1096/fj.201901781}, pmid = {32307753}, issn = {1530-6860}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Complement Activation/*immunology ; Complement System Proteins/*immunology ; Disease Progression ; Energy Metabolism/*immunology ; Humans ; Immunity, Innate/*immunology ; Motor Neurons/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating the defective energy metabolism and components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the mechanisms by which the energy metabolism and the complement system are altered during the disease progression of ALS and how it can contribute to disease. Furthermore, it will also examine how complement activation can modify the energy metabolism in metabolic disorders, in order to highlight how the complement system and energy metabolism may be linked in ALS.}, }
@article {pmid32305638, year = {2020}, author = {Zahiruddin, S and Basist, P and Parveen, A and Parveen, R and Khan, W and Gaurav,  and Ahmad, S}, title = {Ashwagandha in brain disorders: A review of recent developments.}, journal = {Journal of ethnopharmacology}, volume = {257}, number = {}, pages = {112876}, doi = {10.1016/j.jep.2020.112876}, pmid = {32305638}, issn = {1872-7573}, mesh = {Animals ; Brain/*drug effects/metabolism/pathology/physiopathology ; Brain Diseases/*drug therapy/metabolism/pathology/physiopathology ; Drug Development/legislation &amp; jurisprudence ; Drug Discovery/legislation &amp; jurisprudence ; Humans ; Neuroprotective Agents/adverse effects/isolation &amp; purification/*therapeutic use ; Patents as Topic ; *Phytotherapy ; Plant Extracts/adverse effects/chemistry/isolation &amp; purification/*therapeutic use ; Plant Roots ; Signal Transduction ; }, abstract = {Withania somnifera (Family: Solanaceae), commonly known as Ashwagandha or Indian ginseng is distributed widely in India, Nepal, China and Yemen. The roots of plant consist of active phytoconstituents mainly withanolides, alkaloids and sitoindosides and are conventionally used for the treatment of multiple brain disorders.<br><br>AIM OF THE REVIEW: This review aims to critically assess and summarize the current state and implication of Ashwagandha in brain disorders. We have mainly focussed on the reported neuroactive phytoconstituents, available marketed products, pharmacological studies, mechanism of action and recent patents published related to neuroprotective effects of Ashwagandha in brain disorders.<br><br>MATERIALS AND METHODS: All the information and data was collected on Ashwagandha using keywords "Ashwagandha" along with "Phytoconstituents", "Ayurvedic, Unani and Homeopathy marketed formulation", "Brain disorders", "Mechanism" and "Patents". Following sources were searched for data collection: electronic scientific databases such as Science Direct, Google Scholar, Elsevier, PubMed, Wiley On-line Library, Taylor and Francis, Springer; books such as AYUSH Pharmacopoeia; authentic textbooks and formularies.<br><br>RESULTS: Identified neuroprotective phytoconstituents of Ashwagandha are sitoindosides VII-X, withaferin A, withanosides IV, withanols, withanolide A, withanolide B, anaferine, beta-sitosterol, withanolide D with key pharmacological effects in brain disorders mainly anxiety, Alzheimer's, Parkinson's, Schizophrenia, Huntington's disease, dyslexia, depression, autism, addiction, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder and bipolar disorders. The literature survey does not highlight any toxic effects of Ashwagandha. Further, multiple available marketed products and patents recognized its beneficial role in various brain disorders; however, very few data is available on mechanistic pathway and clinical studies of Ashwagandha for various brain disorders is scarce and not promising.<br><br>CONCLUSION: The review concludes the results of recent studies on Ashwagandha suggesting its extensive potential as neuroprotective in various brain disorders as supported by preclinical studies, clinical trials and published patents. However vague understanding of the mechanistic pathways involved in imparting the neuroprotective effect of Ashwagandha warrants further study to promote it as a promising drug candidate.}, }
@article {pmid32299642, year = {2020}, author = {Anestis, E and Eccles, F and Fletcher, I and French, M and Simpson, J}, title = {Giving and receiving a diagnosis of a progressive neurological condition: A scoping review of doctors' and patients' perspectives.}, journal = {Patient education and counseling}, volume = {103}, number = {9}, pages = {1709-1723}, doi = {10.1016/j.pec.2020.03.023}, pmid = {32299642}, issn = {1873-5134}, mesh = {Attitude of Health Personnel ; Communication ; Emotions ; Empathy ; Health Communication/*methods ; Humans ; Motor Neuron Disease/diagnosis/psychology ; Multiple Sclerosis/diagnosis/psychology ; Neurodegenerative Diseases/*diagnosis/psychology ; Parkinson Disease/diagnosis/psychology ; *Physician-Patient Relations ; Physicians/*psychology ; Referral and Consultation/*statistics &amp; numerical data ; *Truth Disclosure ; }, abstract = {OBJECTIVE: Delivering a life changing diagnosis can be a distressing experience for patients and a challenging task for professionals. Diagnosis delivery can be especially difficult for individuals with neurodegenerative diseases such as motor neurone disease (MND), multiple sclerosis (MS) and Parkinson's disease (PD). This review aims to scope the literature on doctors' and patients' perspectives on diagnosis delivery for these conditions in order to enhance our understanding in this area and identify potential research gaps.<br><br>METHODS: A scoping review methodology was used, and data were summarised using content analysis.<br><br>RESULTS: 47 studies fulfilled the inclusion criteria. Studies showed that although patients were generally satisfied with diagnosis delivery, a considerable proportion was still dissatisfied with aspects of the consultation, especially the information and time provided and the doctor's approach. Only six studies addressed doctors' perspectives, which focused more on doctors' practice.<br><br>CONCLUSION: There was a significant research gap in professionals' perspectives. The review also found that although basic standards of good practice were being met, a significant proportion of patients were dissatisfied with diagnosis communication.<br><br>PRACTICE IMPLICATIONS: Professionals delivering such diagnoses need to assess and respond to patients' information needs, provide time for questions and maintain an empathic attitude.}, }
@article {pmid32297678, year = {2020}, author = {Haulman, A and Geronimo, A and Chahwala, A and Simmons, Z}, title = {The Use of Telehealth to Enhance Care in ALS and other Neuromuscular Disorders.}, journal = {Muscle &amp; nerve}, volume = {61}, number = {6}, pages = {682-691}, pmid = {32297678}, issn = {1097-4598}, support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Ambulatory Care/methods/psychology/*trends ; Amyotrophic Lateral Sclerosis/diagnosis/psychology/*therapy ; Humans ; Neuromuscular Diseases/diagnosis/psychology/therapy ; *Patient Acceptance of Health Care/psychology ; Patient Satisfaction ; Telemedicine/methods/*trends ; }, abstract = {Telehealth has the potential to improve the efficiency of healthcare while reducing the burden on patients and caregivers. Encounters can be synchronous or asynchronous. When used for care of those with amyotrophic lateral sclerosis (ALS) by individual health care providers or by a multidisciplinary team, synchronous telehealth is feasible, acceptable, may produce outcomes comparable to those of in-person care, and is cost effective. Individuals with ALS who use telehealth tend to have lower physical and respiratory function and to live farther from an ALS clinic than those who exclusively attend in-person clinic visits. Asynchronous telehealth can be used as a substitute full multidisciplinary visits, or for remote monitoring of pulmonary function, gait/falls, and speech. Barriers to implementing telehealth on a wider scale include disparities in access to technology and challenges surrounding medical licensure and billing, but these are being addressed.}, }
@article {pmid32297211, year = {2020}, author = {Sinnige, T and Yu, A and Morimoto, RI}, title = {Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease.}, journal = {Advances in experimental medicine and biology}, volume = {1243}, number = {}, pages = {53-68}, pmid = {32297211}, issn = {0065-2598}, support = {P01 AG054407/AG/NIA NIH HHS/United States ; R37 AG026647/AG/NIA NIH HHS/United States ; R56 AG059579/AG/NIA NIH HHS/United States ; RF1 AG057296/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Molecular Chaperones/*metabolism ; Neurodegenerative Diseases/*metabolism/*pathology/prevention &amp; control ; Protein Aggregation, Pathological/*prevention &amp; control ; *Proteostasis ; }, abstract = {Protein homeostasis (Proteostasis) is essential for correct and efficient protein function within the living cell. Among the critical components of the Proteostasis Network (PN) are molecular chaperones that serve widely in protein biogenesis under physiological conditions, and prevent protein misfolding and aggregation enhanced by conditions of cellular stress. For Alzheimer's, Parkinson's, Huntington's diseases and ALS, multiple classes of molecular chaperones interact with the highly aggregation-prone proteins amyloid-β, tau, α-synuclein, huntingtin and SOD1 to influence the course of proteotoxicity associated with these neurodegenerative diseases. Accordingly, overexpression of molecular chaperones and induction of the heat shock response have been shown to be protective in a wide range of animal models of these diseases. In contrast, for cancer cells the upregulation of chaperones has the undesirable effect of promoting cellular survival and tumor growth by stabilizing mutant oncoproteins. In both situations, physiological levels of molecular chaperones eventually become functionally compromised by the persistence of misfolded substrates, leading to a decline in global protein homeostasis and the dysregulation of diverse cellular pathways. The phenomenon of chaperone competition may underlie the broad pathology observed in aging and neurodegenerative diseases, and restoration of physiological protein homeostasis may be a suitable therapeutic avenue for neurodegeneration as well as for cancer.}, }
@article {pmid32296305, year = {2020}, author = {Wang, P and Kou, D and Le, W}, title = {Roles of VMP1 in Autophagy and ER-Membrane Contact: Potential Implications in Neurodegenerative Disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {42}, pmid = {32296305}, issn = {1662-5099}, abstract = {Cellular communication processes are highly dynamic and mediated, at least in part, by contacts between various membrane structures. The endoplasmic reticulum (ER), the major biosynthetic organelle of the cell, establishes an extensive network with other membrane structures to regulate the transport of intracellular molecules. Vacuole membrane protein 1 (VMP1), an ER-localized metazoan-specific protein, plays important roles in the formation of autophagosomes and communication between the ER and other organelles, including mitochondria, autophagosome precursor membranes, Golgi, lipid droplets, and endosomes. Increasing evidence has indicated that autophagy and ER-membrane communication at membrane contact sites are closely related to neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In this review, we summarize the roles of VMP1 in autophagy and ER-membrane contacts and discuss their potential implications in neurodegenerative disorders.}, }
@article {pmid32296300, year = {2020}, author = {Muddapu, VR and Dharshini, SAP and Chakravarthy, VS and Gromiha, MM}, title = {Neurodegenerative Diseases - Is Metabolic Deficiency the Root Cause?.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {213}, pmid = {32296300}, issn = {1662-4548}, abstract = {Neurodegenerative diseases, including Alzheimer, Parkinson, Huntington, and amyotrophic lateral sclerosis, are a prominent class of neurological diseases currently without a cure. They are characterized by an inexorable loss of a specific type of neurons. The selective vulnerability of specific neuronal clusters (typically a subcortical cluster) in the early stages, followed by the spread of the disease to higher cortical areas, is a typical pattern of disease progression. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, which contribute to neuronal death. Efforts to treat these diseases are often limited by the fact that they tend to address any one of the above pathological changes while ignoring others. Lack of clarity regarding a possible root cause that underlies all the above pathologies poses a significant challenge. In search of an integrative theory for neurodegenerative pathology, we hypothesize that metabolic deficiency in certain vulnerable neuronal clusters is the common underlying thread that links many dimensions of the disease. The current review aims to present an outline of such an integrative theory. We present a new perspective of neurodegenerative diseases as metabolic disorders at molecular, cellular, and systems levels. This helps to understand a common underlying mechanism of the many facets of the disease and may lead to more promising disease-modifying therapeutic interventions. Here, we briefly discuss the selective metabolic vulnerability of specific neuronal clusters and also the involvement of glia and vascular dysfunctions. Any failure in satisfaction of the metabolic demand by the neurons triggers a chain of events that precipitate various manifestations of neurodegenerative pathology.}, }
@article {pmid32292882, year = {2020}, author = {Picchiarelli, G and Dupuis, L}, title = {Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases.}, journal = {Cell stress}, volume = {4}, number = {4}, pages = {76-91}, pmid = {32292882}, issn = {2523-0204}, abstract = {A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.}, }
@article {pmid32290481, year = {2020}, author = {Schaffert, LN and Carter, WG}, title = {Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review.}, journal = {Brain sciences}, volume = {10}, number = {4}, pages = {}, pmid = {32290481}, issn = {2076-3425}, abstract = {The accumulation of abnormal protein aggregates represents a universal hallmark of neurodegenerative diseases (NDDs). Post-translational modifications (PTMs) regulate protein structure and function. Dysregulated PTMs may influence the propensity for protein aggregation in NDD-proteinopathies. To investigate this, we systematically reviewed the literature to evaluate effects of PTMs on aggregation propensity for major proteins linked to the pathogenesis and/or progression of NDDs. A search of PubMed, MEDLINE, EMBASE, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between PTMs and protein aggregation in seven NDDs: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, transmissible spongiform encephalopathy, and multiple sclerosis. Together, 1222 studies were identified, of which 69 met eligibility criteria. We identified that the following PTMs, in isolation or combination, potentially act as modulators of proteinopathy in NDDs: isoaspartate formation in Aβ, phosphorylation of Aβ or tau in AD; acetylation, 4-hydroxy-2-neonal modification, O-GlcNAcylation or phosphorylation of α-synuclein in PD; acetylation or phosphorylation of TAR DNA-binding protein-43 in ALS, and SUMOylation of superoxide dismutase-1 in ALS; and phosphorylation of huntingtin in HD. The potential pharmacological manipulation of these aggregation-modulating PTMs represents an as-yet untapped source of therapy to treat NDDs.}, }
@article {pmid32289328, year = {2020}, author = {Upadhya, R and Zingg, W and Shetty, S and Shetty, AK}, title = {Astrocyte-derived extracellular vesicles: Neuroreparative properties and role in the pathogenesis of neurodegenerative disorders.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {323}, number = {}, pages = {225-239}, pmid = {32289328}, issn = {1873-4995}, support = {R01 NS106907/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease ; Astrocytes ; *Extracellular Vesicles ; Humans ; *Neurodegenerative Diseases ; Vascular Endothelial Growth Factor A ; }, abstract = {Extracellular vesicles (EVs) released by neural cells play an essential role in brain homeostasis and the crosstalk between neural cells and the periphery. EVs are diverse, nano-sized vesicles, which transport proteins, nucleic acids, and lipids between cells over short and long expanses and hence are proficient for modulating the target cells. EVs released from neural cells are implicated in synaptic plasticity, neuron-glia interface, neuroprotection, neuroregeneration, and the dissemination of neuropathological molecules. This review confers the various properties of EVs secreted by astrocytes and their potential role in health and disease with a focus on evolving concepts. Naïve astrocytes shed EVs containing a host of neuroprotective compounds, which include fibroblast growth factor-2, vascular endothelial growth factor, and apolipoprotein-D. Stimulated astrocytes secrete EVs with neuroprotective molecules including heat shock proteins, synapsin 1, unique microRNAs, and glutamate transporters. Well-characterized astrocyte-derived EVs (ADEVs) generated in specific culture conditions and ADEVs that are engineered to carry the desired miRNAs or proteins are likely useful for treating brain injury and neurogenerative diseases. On the other hand, in conditions such as Alzheimer's disease (AD), stroke, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), and other neuroinflammatory conditions, EVs released by activated astrocytes appear to mediate or exacerbate the pathological processes. The examples include ADEVs spreading the dysregulated complement system in AD, mediating motoneuron toxicity in ALS, and stimulating peripheral leukocyte migration into the brain in inflammatory conditions. Strategies restraining the release of EVs by activated astrocytes or modulating the composition of ADEVs are likely beneficial for treating neurodegenerative diseases. Also, periodic analyses of ADEVs in the blood is useful for detecting astrocyte-specific biomarkers in different neurological conditions and for monitoring disease progression and remission with distinct therapeutic approaches.}, }
@article {pmid32283224, year = {2020}, author = {Singh, T and Yadav, S}, title = {Role of microRNAs in neurodegeneration induced by environmental neurotoxicants and aging.}, journal = {Ageing research reviews}, volume = {60}, number = {}, pages = {101068}, doi = {10.1016/j.arr.2020.101068}, pmid = {32283224}, issn = {1872-9649}, mesh = {*Aging/genetics ; *Alzheimer Disease/genetics ; Humans ; *MicroRNAs/genetics ; Neurodegenerative Diseases/chemically induced/genetics ; *Parkinson Disease/genetics ; }, abstract = {The progressive loss of neuronal structure and functions resulting in the death of neurons is considered as neurodegeneration. Environmental toxicants induced degeneration of neurons is accelerated with aging. In adult brains, most of the neurons are post-mitotic, and their loss results in the development of diseases like amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Neurodegenerative diseases have several similarities at the sub-cellular and molecular levels, such as synaptic degeneration, oxidative stress, inflammation, and cognitive decline, which are also known in brain aging. Identification of these similarities at the molecular level offers hope for the development of new therapeutics to ameliorate all neurodegenerative diseases simultaneously. Aging is known as the most strongly associated additive factor in the pathogenesis of neurodegenerative diseases. Studies carried out so far identified several genes, which are responsible for selective degeneration of neurons in different neurodegenerative diseases. Countless efforts have been made in identifying therapeutics for neurodegenerative diseases; however, the discovery of effective therapy remains elusive. Findings made in the last two decades identified microRNAs (miRNAs) as the most potent post-transcription regulatory RNA molecule, which can condition protein levels in the cell and tissue-specific manner. Identification of miRNAs, which regulate both neurotoxicant and aging-associated degeneration of brain cells, raises the possibility that roads leading to aging and neurotoxicant induced neurodegeneration cross at some point. Identification of miRNAs, which are common to aging and neurotoxicant induced neurodegeneration, will help in understanding the complex mechanism of neurodegenerative disease development. In the future, the use of natural miRNAs in vivo in therapy will be able to tackle several issues of aging and neurodegeneration. In the present review, we have provided a summary of findings made on the role of miRNAs in neurodegeneration and explored the common link made by miRNAs between aging and neurotoxicants induced neurodegeneration.}, }
@article {pmid32282307, year = {2020}, author = {Fayaz, F and Pottoo, FH and Shafi, S and Wani, MA and Wakode, S and Sharma, A}, title = {Denouement of Chemicals on Amyotrophic Lateral Sclerosis: Is Green Chemistry the Answer.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {16}, number = {8}, pages = {1058-1068}, doi = {10.2174/1573406416666200413111330}, pmid = {32282307}, issn = {1875-6638}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Chemistry, Pharmaceutical ; *Green Chemistry Technology ; Humans ; Neuroprotective Agents/chemical synthesis/chemistry/*therapeutic use ; }, abstract = {Medicinal Chemistry has played a critical role in evolving new products, resources and processes which inexorably correspond to our high standards of living. Unfortunately, this has also caused deterioration of human health and threats to the global environment, even deaths when highly exposed to certain chemicals, whether due to improper use, mishandling or disposal. There are chemicals, which apart from being carcinogens, endocrine disruptors or neurotoxins, are also responsible for climate change and ozone depletion. Certain chemicals are known to cause neurotoxicity and are having tendencies to damage the central and peripheral nervous system or brain by damaging neurons or cells which are responsible for transmitting and processing of signals. This has raised serious concerns for the use and handling of such chemicals and has given growth to a relatively new emerging field known as Green Chemistry that strives to achieve sustainability at the molecular level and has an ability to harness chemicals to meet environmental and economic goals. It has been reported in the literature that apart from family history in the aetiology of Amyotrophic lateral Sclerosis (ALS), also termed as "Lou Gehrig's disease", a neurological disorder, environmental factors, heavy metals, particularly selenium, lead, mercury, cadmium, formaldehyde, pesticides and certain herbicides are known to cause ALS. ALS, a progressive neurodegenerative disease affects the motor cortex, brain stem and spinal cord, causing muscular weakness, spasticity, and hyperreflexia. In this article we are aiming to discuss and summarize the various corroborations and findings supporting the undesirable role of chemical substance/herbicides/pesticides in ALS aetiology and its mitigation by adopting green chemistry.}, }
@article {pmid32282304, year = {2020}, author = {Chandra, S and Alam, MT and Dey, J and Sasidharan, BCP and Ray, U and Srivastava, AK and Gandhi, S and Tripathi, PP}, title = {Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders.}, journal = {Current topics in medicinal chemistry}, volume = {20}, number = {13}, pages = {1142-1153}, doi = {10.2174/1568026620666200413091101}, pmid = {32282304}, issn = {1873-4294}, mesh = {Animals ; Brain/drug effects/pathology/*physiology ; Gastrointestinal Microbiome/drug effects/*physiology ; Humans ; Neurodegenerative Diseases/drug therapy/*microbiology/pathology ; Neuroprotective Agents/chemistry/pharmacology ; }, abstract = {BACKGROUND: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD).<br><br>OBJECTIVE: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD.<br><br>METHODS: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them.<br><br>RESULTS: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction.<br><br>CONCLUSION: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.}, }
@article {pmid32281455, year = {2020}, author = {Picher-Martel, V and Brunet, F and Dupré, N and Chrestian, N}, title = {The Occurrence of FUS Mutations in Pediatric Amyotrophic Lateral Sclerosis: A Case Report and Review of the Literature.}, journal = {Journal of child neurology}, volume = {35}, number = {8}, pages = {556-562}, doi = {10.1177/0883073820915099}, pmid = {32281455}, issn = {1708-8283}, mesh = {Adolescent ; Amyotrophic Lateral Sclerosis/*genetics ; DNA Helicases/genetics ; Humans ; Male ; Multifunctional Enzymes/genetics ; *Mutation ; RNA Helicases/genetics ; RNA-Binding Protein FUS/*genetics ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease affecting both upper and lower motor neurons and leading to progressive paralysis. Most cases are sporadic, and the symptoms generally begin in the sixth or seventh decade. Juvenile ALS appears in a rare subgroup of patients with onset before the age of 25 years old. Contrary to the classical adult phenotype where 90% of cases are sporadic, most cases of juvenile ALS are caused by a genetic mutation in either SOD1 (superoxide dismutase one), SETX (senataxin), or FUS (fused in sarcoma). In the pediatric population, ALS is more infrequent and rarely considered in the differential diagnosis. There are few reports of ALS in children. Here, we describe a 14-year-old boy with a very fast progressing classical ALS phenotype and tremor caused by a c.1554_1557delACAG mutation in FUS. Our review of the literature advocates that pediatric ALS is highly suggestive of FUS mutations and that gene should be tested in children presenting with symptoms of ALS. The children with FUS-related ALS may have no family history and present initially with learning disabilities, tremor, and mild motor developmental delay.}, }
@article {pmid32281421, year = {2020}, author = {Serafino, A and Giovannini, D and Rossi, S and Cozzolino, M}, title = {Targeting the Wnt/β-catenin pathway in neurodegenerative diseases: recent approaches and current challenges.}, journal = {Expert opinion on drug discovery}, volume = {15}, number = {7}, pages = {803-822}, doi = {10.1080/17460441.2020.1746266}, pmid = {32281421}, issn = {1746-045X}, mesh = {Animals ; Brain/physiopathology ; Drug Development ; Humans ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Tissue Distribution ; Wnt Signaling Pathway/*physiology ; }, abstract = {INTRODUCTION: Wnt/β-catenin signaling is an evolutionarily conserved pathway having a crucial role in embryonic and adult life. Specifically, the Wnt/β-catenin axis is pivotal to the development and homeostasis of the nervous system, and its dysregulation has been associated with various neurological disorders, including neurodegenerative diseases. Therefore, this signaling pathway has been proposed as a potential therapeutic target against neurodegeneration.<br><br>AREAS COVERED: This review focuses on the role of Wnt/&#x3b2;-catenin pathway in the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's Diseases and Amyotrophic Lateral Sclerosis. The evidence showing that defects in the signaling might be involved in the development of these diseases, and the pharmacological approaches tested so far, are discussed. The possibilities that this pathway offers in terms of new therapeutic opportunities are also considered.<br><br>EXPERT OPINION: The increasing interest paid to the role of Wnt/&#x3b2;-catenin pathway in the onset of neurodegenerative diseases demonstrates how targeting this signaling for therapeutic purposes could be a great opportunity for both neuroprotection and neurorepair. Without overlooking some licit concerns about drug safety and delivery to the brain, there is growing and more convincing evidence that restoring this signaling in neurodegenerative diseases may strongly increase the chance to develop disease-modifying treatments for these brain pathologies.}, }
@article {pmid32278516, year = {2020}, author = {Chakraborty, A and Brauer, S and Diwan, A}, title = {A review of possible therapies for Parkinson's disease.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {76}, number = {}, pages = {1-4}, doi = {10.1016/j.jocn.2020.03.047}, pmid = {32278516}, issn = {1532-2653}, mesh = {Disease Progression ; Humans ; Parkinson Disease/*therapy ; }, abstract = {Parkinson's disease (PD) is a complex condition with a wide range of symptoms, like impaired movement, tremors, apathy and depression, and many other symptoms. The disease results from degeneration of dopaminergic neural cells. No cure at present but symptomatic some palliative treatments are available to slow down the disease progression. According to the Parkinson's Foundation every year in U.S., approximately 60,000 Americans diagnosed with PD. Nearly one million will be living with PD in the U.S. by 2020, which is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Amyotrophic Lateral Sclerosis (ALS). There is no diagnostic test for PD, yet, but this article will review all kinds symptomatic and disease-modifying therapy.}, }
@article {pmid32278047, year = {2020}, author = {Paudel, YN and Angelopoulou, E and Piperi, C and Othman, I and Shaikh, MF}, title = {Implication of HMGB1 signaling pathways in Amyotrophic lateral sclerosis (ALS): From molecular mechanisms to pre-clinical results.}, journal = {Pharmacological research}, volume = {156}, number = {}, pages = {104792}, doi = {10.1016/j.phrs.2020.104792}, pmid = {32278047}, issn = {1096-1186}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*metabolism/pathology ; Animals ; Brain/immunology/*metabolism/pathology ; HMGB1 Protein/*metabolism ; Humans ; Immunity, Innate ; Ligands ; Motor Neurons/immunology/*metabolism/pathology ; Receptor for Advanced Glycation End Products/*metabolism ; Signal Transduction ; Spinal Cord/immunology/*metabolism/pathology ; Toll-Like Receptor 4/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressing neurodegenerative disorder with no effective disease-modifying treatment up to date. The underlying molecular mechanisms of ALS are not yet completely understood. However, the critical role of the innate immune system and neuroinflammation in ALS pathogenesis has gained increased attention. High mobility group box 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, acting as a pro-inflammatory cytokine mainly through activation of its principal receptors, the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) which are crucial components of the innate immune system. HMGB1 is an endogenous ligand for both RAGE and TLR4 that mediate its biological effects. Herein, on the ground of pre-clinical findings we unravel the underlying mechanisms behind the plausible contribution of HMGB1 and its receptors (RAGE and TLR4) in the ALS pathogenesis. Furthermore, we provide an account of the therapeutic outcomes associated with inhibition/blocking of HMGB1 receptor signalling in preventing motor neuron's death and delaying disease progression in ALS experimental models. There is strong evidence that HMGB1, RAGE and TLR4 signaling axes might present potential targets against ALS, opening a novel headway in ALS research that could plausibly bridge the current treatment gap.}, }
@article {pmid32269505, year = {2020}, author = {Suzuki, N and Akiyama, T and Warita, H and Aoki, M}, title = {Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {194}, pmid = {32269505}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.}, }
@article {pmid32266160, year = {2020}, author = {Vendrik, KEW and Ooijevaar, RE and de Jong, PRC and Laman, JD and van Oosten, BW and van Hilten, JJ and Ducarmon, QR and Keller, JJ and Kuijper, EJ and Contarino, MF}, title = {Fecal Microbiota Transplantation in Neurological Disorders.}, journal = {Frontiers in cellular and infection microbiology}, volume = {10}, number = {}, pages = {98}, pmid = {32266160}, issn = {2235-2988}, mesh = {Animals ; *Autism Spectrum Disorder ; *Clostridium Infections/therapy ; Fecal Microbiota Transplantation ; Feces ; *Gastrointestinal Microbiome ; Humans ; *Nervous System Diseases/therapy ; Treatment Outcome ; }, abstract = {Background: Several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a treatment strategy. Fecal microbiota transplantation (FMT) is currently the most effective gut microbiota intervention and an accepted treatment for recurrent Clostridioides difficile infections. To evaluate indications of FMT for patients with neurological disorders, we summarized the available literature on FMT. In addition, we provide suggestions for future directions. Methods: In July 2019, five main databases were searched for studies and case descriptions on FMT in neurological disorders in humans or animal models. In addition, the ClinicalTrials.gov website was consulted for registered planned and ongoing trials. Results: Of 541 identified studies, 34 were included in the analysis. Clinical trials with FMT have been performed in patients with autism spectrum disorder and showed beneficial effects on neurological symptoms. For multiple sclerosis and Parkinson's disease, several animal studies suggested a positive effect of FMT, supported by some human case reports. For epilepsy, Tourette syndrome, and diabetic neuropathy some studies suggested a beneficial effect of FMT, but evidence was restricted to case reports and limited numbers of animal studies. For stroke, Alzheimer's disease and Guillain-Barré syndrome only studies with animal models were identified. These studies suggested a potential beneficial effect of healthy donor FMT. In contrast, one study with an animal model for stroke showed increased mortality after FMT. For Guillain-Barré only one study was identified. Whether positive findings from animal studies can be confirmed in the treatment of human diseases awaits to be seen. Several trials with FMT as treatment for the above mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis. Conclusions: Preliminary literature suggests that FMT may be a promising treatment option for several neurological disorders. However, available evidence is still scanty and some contrasting results were observed. A limited number of studies in humans have been performed or are ongoing, while for some disorders only animal experiments have been conducted. Large double-blinded randomized controlled trials are needed to further elucidate the effect of FMT in neurological disorders.}, }
@article {pmid32265650, year = {2020}, author = {Hornung, S and Dutta, S and Bitan, G}, title = {CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {38}, pmid = {32265650}, issn = {1662-5099}, abstract = {Eukaryotic cells release different types of extracellular vesicles (EVs) including exosomes, ectosomes, and microvesicles. Exosomes are nanovesicles, 30-200 nm in diameter, that carry cell- and cell-state-specific cargo of proteins, lipids, and nucleic acids, including mRNA and miRNA. Recent studies have shown that central nervous system (CNS)-derived exosomes may carry amyloidogenic proteins and facilitate their cell-to-cell transfer, thus playing a critical role in the progression of neurodegenerative diseases, such as tauopathies and synucleinopathies. CNS-derived exosomes also have been shown to cross the blood-brain-barrier into the bloodstream and therefore have drawn substantial attention as a source of biomarkers for various neurodegenerative diseases as they can be isolated via a minimally invasive blood draw and report on the biochemical status of the CNS. However, although isolating specific brain-cell-derived exosomes from the blood is theoretically simple and the approach has great promise, practical details are of crucial importance and may compromise the reproducibility and utility of this approach, especially when different laboratories use different protocols. In this review we discuss the role of exosomes in neurodegenerative diseases, the usefulness of CNS-derived blood exosomes as a source of biomarkers for these diseases, and practical challenges associated with the methodology of CNS-derived blood exosomes and subsequent biomarker analysis.}, }
@article {pmid32257625, year = {2020}, author = {Moos, WH and Faller, DV and Glavas, IP and Harpp, DN and Kanara, I and Mavrakis, AN and Pernokas, J and Pernokas, M and Pinkert, CA and Powers, WR and Sampani, K and Steliou, K and Vavvas, DG and Zamboni, RJ and Kodukula, K and Chen, X}, title = {Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs.}, journal = {BioResearch open access}, volume = {9}, number = {1}, pages = {94-105}, pmid = {32257625}, issn = {2164-7844}, support = {R01 EY025362/EY/NEI NIH HHS/United States ; R13 EY027184/EY/NEI NIH HHS/United States ; R13 EY029551/EY/NEI NIH HHS/United States ; }, abstract = {In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.}, }
@article {pmid32257544, year = {2020}, author = {Zhang, F and Niu, L and Liu, X and Liu, Y and Li, S and Yu, H and Le, W}, title = {Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: An Update.}, journal = {Aging and disease}, volume = {11}, number = {2}, pages = {315-326}, pmid = {32257544}, issn = {2152-5250}, abstract = {Rapid eye movement sleep behavior disorder (RBD) is a sleep behavior disorder characterized by abnormal behaviors and loss of muscle atonia during rapid eye movement (REM) sleep. RBD is generally considered to be associated with synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and usually precedes years before the first symptom of these diseases. It is believed that RBD predicts the neurodegeneration in synucleinopathy. However, increasing evidences have shown that RBD is also found in non-synucleinopathy neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc. Sleep disturbance such as RBD may be an early sign of neurodegeneration in these diseases, and also serve as an assessment of cognitive impairments. In this review, we updated the clinical characteristics, diagnosis, and possible mechanisms of RBD in neurogenerative diseases. A better understanding of RBD in these neurogenerative diseases will provide biomarkers and novel therapeutics for the early diagnosis and treatment of the diseases.}, }
@article {pmid32253536, year = {2020}, author = {de Munter, JPJM and Mey, J and Strekalova, T and Kramer, BW and Wolters, EC}, title = {Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {127}, number = {5}, pages = {715-727}, pmid = {32253536}, issn = {1435-1463}, mesh = {Animals ; *Mesenchymal Stem Cell Transplantation ; *Mesenchymal Stem Cells ; Mice ; Neurodegenerative Diseases/*therapy ; Rats ; }, abstract = {Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non)steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3β level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.}, }
@article {pmid32247802, year = {2020}, author = {Gois, AM and Mendonça, DMF and Freire, MAM and Santos, JR}, title = {IN VITRO AND IN VIVO MODELS OF AMYOTROPHIC LATERAL SCLEROSIS: AN UPDATED OVERVIEW.}, journal = {Brain research bulletin}, volume = {159}, number = {}, pages = {32-43}, doi = {10.1016/j.brainresbull.2020.03.012}, pmid = {32247802}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; *Disease Models, Animal ; Humans ; Motor Neurons/*metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease affects people all over the world and is more prevalent in men. Patients with ALS develop extensive muscle wasting, paralysis and ultimately death, with a median survival of usually fewer than five years after disease onset. ALS may be sporadic (sALS, 90%) or familial (fALS, 10%). The large majority of fALS cases are associated with genetic alterations, which are mainly related to the genes SOD1, TDP-43, FUS, and C9ORF72. In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis, as well as its molecular, cellular, and physiological mechanisms. Many studies in cell cultures and animal models, such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and non-human primates have been performed to clarify the relationship of these genes to ALS disease. However, there are inherent limitations to consider when using experimental models. In this review, we provide an updated overview of the most used in vitro and in vivo studies that have contributed to a better understanding of the different ALS pathogenic mechanisms.}, }
@article {pmid32247740, year = {2020}, author = {Chakraborty, A and Brauer, S and Diwan, A}, title = {Possible therapies of Parkinson's disease: A review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {75}, number = {}, pages = {1-4}, doi = {10.1016/j.jocn.2020.03.024}, pmid = {32247740}, issn = {1532-2653}, mesh = {Humans ; Neurology/*trends ; Parkinson Disease/*therapy ; }, abstract = {Parkinson's disease (PD) is a complex condition with a wide range of symptoms, like impaired movement, tremors, apathy and depression, and many other symptoms. The disease results from degeneration of dopaminergic neural cells. No cure at present but symptomatic some palliative treatments are available to slow down the disease progression. According to the Parkinson's Foundation every year in U.S., approximately 60,000 Americans diagnosed with PD. Nearly one million will be living with PD in the U.S. by 2020, which is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Amyotrophic Lateral Sclerosis (ALS). There is no diagnostic test for PD, yet, but this article will review all kinds symptomatic and disease-modifying therapy.}, }
@article {pmid32244957, year = {2020}, author = {De Nicola, AF and Meyer, M and Guennoun, R and Schumacher, M and Hunt, H and Belanoff, J and de Kloet, ER and Gonzalez Deniselle, MC}, title = {Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {6}, pages = {}, pmid = {32244957}, issn = {1422-0067}, support = {Salaries for argentine researchers//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; Ubacyt # 20020170100224BA//Universidad de Buenos Aires/ ; purchase of reagents//Corcept Therapeutics, California, USA/ ; }, mesh = {Animals ; Corticosterone/blood/chemistry ; Disease Models, Animal ; Humans ; Inflammation/blood/complications ; Models, Biological ; Neurodegenerative Diseases/blood/*drug therapy ; Receptors, Glucocorticoid/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic-pituitary-adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine-threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.}, }
@article {pmid32243913, year = {2020}, author = {Memon, AA and Coleman, JJ and Amara, AW}, title = {Effects of exercise on sleep in neurodegenerative disease.}, journal = {Neurobiology of disease}, volume = {140}, number = {}, pages = {104859}, pmid = {32243913}, issn = {1095-953X}, support = {R25 NS079188/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Disease Progression ; *Exercise Therapy ; Humans ; Huntington Disease/therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; Quality of Life ; Sleep/*physiology ; Sleep Wake Disorders/*therapy ; }, abstract = {As the population ages, the incidence and prevalence of neurodegenerative disorders will continue to increase. Persons with neurodegenerative disease frequently experience sleep disorders, which not only affect quality of life, but potentially accelerate progression of the disease. Unfortunately, pharmacological interventions are often futile or have adverse effects. Therefore, investigation of non-pharmacological interventions has the potential to expand the treatment landscape for these disorders. The last decade has observed increasing recognition of the beneficial role of exercise in brain diseases, and neurodegenerative disorders in particular. In this review, we will focus on the therapeutic role of exercise for sleep dysfunction in four neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Available data suggest that exercise may have the potential to improve sleep disorders and attenuate neurodegeneration, particularly in Alzheimer's disease and Parkinson's disease. However, additional research is required in order to understand the most effective exercise therapy for these indications; the best way to monitor the response to interventions; the influence of exercise on sleep dysfunction in Huntington's disease and amyotrophic lateral sclerosis; and the mechanisms underlying exercise-induced sleep modifications.}, }
@article {pmid32242755, year = {2020}, author = {Hergesheimer, R and Lanznaster, D and Vourc'h, P and Andres, C and Bakkouche, S and Beltran, S and Blasco, H and Corcia, P and Couratier, P}, title = {Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on pharmacotherapy}, volume = {21}, number = {9}, pages = {1103-1110}, doi = {10.1080/14656566.2020.1746270}, pmid = {32242755}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {INTRODUCTION: To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy.<br><br>AREAS COVERED: The authors discuss the two approved drugs, as well as several examples of drug candidates whose clinical trials did not demonstrate efficacy in phase III. Post-hoc analyses reveal that future clinical trials should include disease-staging procedures, longer-term trials to correctly assess survival, genetic studies of participants to aid in stratification, and more similarity between the protocols on preclinical models and clinical trials. Finally, they discuss the trials in process that demonstrate some of these suggestions and improvements.<br><br>EXPERT OPINION: The approval of riluzole and edaravone was essentially a desperate attempt to provide urgent pharmacotherapy to the ALS community. To evolve toward more efficient therapies, we must conduct clinical trials with optimal stratification based on rapid/slow progressors and cognitive decline. Pharmaco-metabolomics should allow for the identification of biomarkers that are adapted for a given drug.}, }
@article {pmid32241621, year = {2020}, author = {Bailly, C and Hecquet, PE and Kouach, M and Thuru, X and Goossens, JF}, title = {Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {28}, number = {10}, pages = {115463}, doi = {10.1016/j.bmc.2020.115463}, pmid = {32241621}, issn = {1464-3391}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/chemical synthesis/chemistry/*therapeutic use ; Humans ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*therapeutic use ; Stroke/*drug therapy ; }, abstract = {1-Phenyl-3-methyl-5-pyrazolone is a reagent, known as PMP, used to derivatize monosaccharides for the study of polysaccharides composition and structure, and for the dosage of carbohydrates in complex media. The same molecule is also known as edaravone, a drug approved for the treatment of stroke and amyotrophic lateral sclerosis. It is also a reactive molecule susceptible to form stable adducts with aromatic aldehydes, such as formylpterin and vanillin. In addition, the molecule serves as a scaffold to design of edaravone analogs and drug conjugates, with various pharmacological properties (antioxidant, anticancer, antiviral). We have analyzed the multiple usages of PMP/edaravone to highlight the reactivity of the molecule and its wide range of applications. This phenyl-pyrazolone compound, considered by many as a biochemical reagent and by other as a clinically useful drug, has not yet revealed the full extent of its capacities and benefits.}, }
@article {pmid32239718, year = {2020}, author = {Tang, BL}, title = {Glucose, glycolysis, and neurodegenerative diseases.}, journal = {Journal of cellular physiology}, volume = {235}, number = {11}, pages = {7653-7662}, doi = {10.1002/jcp.29682}, pmid = {32239718}, issn = {1097-4652}, mesh = {Animals ; Brain/*metabolism ; Energy Metabolism/physiology ; Glucose/*metabolism ; Glycolysis/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Neurons/*metabolism ; }, abstract = {Prolonged survival of a typical postmitotic neuron hinges on a balance between multiple processes, among these are a sustenance of ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both a drop in ATP levels, as well as increase reactive oxygen species production from inefficient electron transport processes and NADPH-oxidases activities. The former often resulted in the phenomenon of compensatory aerobic glycolysis. The latter stretches the capacity of the cell's redox buffering capacity, and may lead to damages of key enzymes involved in energy metabolism. Several recent reports have indicated that enhancing glucose availability and uptake, as well as increasing glycolytic flux via pharmacological or genetic manipulation of glycolytic enzymes, could be protective in animal models of several major neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Activation of canonical Wnt signaling, which improves disease symptoms in mouse models of Alzheimer's disease also appears to work via an elevation of glycolytic enzymes and enhance glucose metabolism. Here, I discuss these findings and the possible underlying mechanisms of how an increase in glucose uptake and glycolysis could be neuroprotective. Increased glycolytic production of ATP would help alleviate energy deficiency, and ATP's hydrotropic effect may enhance solubility and clearance of toxic aggregates prevalent in many neurodegenerative diseases. Furthermore, channeling of glucose into the Pentose Phosphate Pathway would increase the redox buffering capacity of the cell.}, }
@article {pmid32230811, year = {2020}, author = {Peng, B and Yang, Q and B Joshi, R and Liu, Y and Akbar, M and Song, BJ and Zhou, S and Wang, X}, title = {Role of Alcohol Drinking in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {21}, number = {7}, pages = {}, pmid = {32230811}, issn = {1422-0067}, mesh = {Alcohol Drinking/*adverse effects ; Alzheimer Disease/chemically induced/*metabolism ; Amyloid beta-Peptides/toxicity ; Amyotrophic Lateral Sclerosis/chemically induced/*metabolism ; Animals ; Brain/drug effects/metabolism ; Cell Line ; Disease Progression ; Ethanol/adverse effects/toxicity ; Humans ; Neurodegenerative Diseases/chemically induced ; Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Parkinson Disease/*metabolism ; Risk Factors ; alpha-Synuclein ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against β-amyloid (Aβ) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of Aβ and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (CYP2E1) and an increase in the amount of α-Synuclein (αSYN) relevant to PD. The findings on the association between alcohol consumption and ALS are inconsistent; a recent population-based study suggests that alcohol drinking seems to not influence the risk of developing ALS. Additional research is needed to clarify the potential etiological involvement of alcohol intake in causing or resulting in major neurodegenerative diseases, which will eventually lead to potential therapeutics against these alcoholic neurodegenerative diseases.}, }
@article {pmid32229686, year = {2020}, author = {Khosravi, S and Harner, ME}, title = {The MICOS complex, a structural element of mitochondria with versatile functions.}, journal = {Biological chemistry}, volume = {401}, number = {6-7}, pages = {765-778}, doi = {10.1515/hsz-2020-0103}, pmid = {32229686}, issn = {1437-4315}, mesh = {Animals ; Humans ; Mitochondria/*chemistry/metabolism ; Mitochondrial Membranes/*metabolism ; }, abstract = {Mitochondria perform a plethora of functions in various cells of different tissues. Their architecture differs remarkably, for instance in neurons versus steroidogenic cells. Furthermore, aberrant mitochondrial architecture results in mitochondrial dysfunction. This indicates strongly that mitochondrial architecture and function are intimately linked. Therefore, a deep knowledge about the determinants of mitochondrial architecture and their function on a molecular level is of utmost importance. In the past decades, various proteins and protein complexes essential for formation of mitochondrial architecture have been identified. Here we will review the current knowledge of the MICOS complex, one of the major structural elements of mitochondria. MICOS is a multi-subunit complex present in the inner mitochondrial membrane. Multiple interaction partners in the inner and outer mitochondrial membrane point to participation in a multitude of important processes, such as generation of mitochondrial architecture, lipid metabolism, and protein import into mitochondria. Since the MICOS complex is highly conserved in form and function throughout evolution, we will highlight the importance of MICOS for mammals. We will emphasize in particular the current knowledge of the association of MICOS with severe human diseases, including Charcot-Marie-Tooth disease type 2, Alzheimer's disease, Parkinson's disease, Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.}, }
@article {pmid32217663, year = {2020}, author = {Turner, MR and Talbot, K}, title = {Primary lateral sclerosis: diagnosis and management.}, journal = {Practical neurology}, volume = {20}, number = {4}, pages = {262-269}, doi = {10.1136/practneurol-2019-002300}, pmid = {32217663}, issn = {1474-7766}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/therapy ; Diagnosis, Differential ; *Disease Management ; Humans ; Motor Neuron Disease/*diagnostic imaging/genetics/*therapy ; Motor Neurons/pathology ; }, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder at the upper motor neurone extreme of the spectrum of motor neurone disease. The diagnosis is clinical and based on the characteristic features of slowly progressive spasticity beginning in the lower limbs, or more rarely with spastic dysarthria, typically presenting around 50 years of age. The absence of lower motor neurone involvement is considered to be a defining feature, but confident distinction of PLS from upper motor neurone-predominant forms of amyotrophic lateral sclerosis may be difficult in the first few years. Corticobulbar involvement in PLS is frequently accompanied by emotionality. While there may be dysphagia, gastrostomy is rarely required to maintain nutrition. Cognitive dysfunction is recognised, though dementia is rarely a prominent management issue. PLS is not necessarily life shortening. Specialised multidisciplinary care is recommended. Increasing international research cooperation is required if the aspiration of dedicated therapeutic trials for PLS is to be achieved.}, }
@article {pmid32209757, year = {2020}, author = {Gonzalez-Fernandez, C and González, P and Rodríguez, FJ}, title = {New insights into Wnt signaling alterations in amyotrophic lateral sclerosis: a potential therapeutic target?.}, journal = {Neural regeneration research}, volume = {15}, number = {9}, pages = {1580-1589}, pmid = {32209757}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by upper and lower motor neuron degeneration, which leads to progressive paralysis of skeletal muscles and, ultimately, respiratory failure between 2-5 years after symptom onset. Unfortunately, currently accepted treatments for amyotrophic lateral sclerosis are extremely scarce and only provide modest benefit. As a consequence, a great effort is being done by the scientific community in order to achieve a better understanding of the different molecular and cellular processes that influence the progression and/or outcome of this neuropathological condition and, therefore, unravel new potential targets for therapeutic intervention. Interestingly, a growing number of experimental evidences have recently shown that, besides its well-known physiological roles in the developing and adult central nervous system, the Wnt family of proteins is involved in different neuropathological conditions, including amyotrophic lateral sclerosis. These proteins are able to modulate, at least, three different signaling pathways, usually known as canonical (β-catenin dependent) and non-canonical (β-catenin independent) signaling pathways. In the present review, we aim to provide a general overview of the current knowledge that supports the relationship between the Wnt family of proteins and its associated signaling pathways and amyotrophic lateral sclerosis pathology, as well as their possible mechanisms of action. Altogether, the currently available knowledge suggests that Wnt signaling modulation might be a promising therapeutic approach to ameliorate the histopathological and functional deficits associated to amyotrophic lateral sclerosis , and thus improve the progression and outcome of this neuropathology.}, }
@article {pmid32207340, year = {2020}, author = {Garbuzova-Davis, S and Shell, R and Mustafa, H and Hailu, S and Willing, AE and Sanberg, PR and Borlongan, CV}, title = {Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis.}, journal = {Cell transplantation}, volume = {29}, number = {}, pages = {963689720913494}, pmid = {32207340}, issn = {1555-3892}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Lung/pathology ; Microvessels/*pathology ; Motor Neurons/*metabolism ; Spinal Cord/pathology ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.}, }
@article {pmid32206784, year = {2020}, author = {Guo, W and Vandoorne, T and Steyaert, J and Staats, KA and Van Den Bosch, L}, title = {The multifaceted role of kinases in amyotrophic lateral sclerosis: genetic, pathological and therapeutic implications.}, journal = {Brain : a journal of neurology}, volume = {143}, number = {6}, pages = {1651-1673}, pmid = {32206784}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology/*therapy ; Female ; Humans ; Male ; Motor Neurons/metabolism/pathology ; Phosphorylation ; Protein Kinases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is the most common degenerative disorder of motor neurons in adults. As there is no cure, thousands of individuals who are alive at present will succumb to the disease. In recent years, numerous causative genes and risk factors for amyotrophic lateral sclerosis have been identified. Several of the recently identified genes encode kinases. In addition, the hypothesis that (de)phosphorylation processes drive the disease process resulting in selective motor neuron degeneration in different disease variants has been postulated. We re-evaluate the evidence for this hypothesis based on recent findings and discuss the multiple roles of kinases in amyotrophic lateral sclerosis pathogenesis. We propose that kinases could represent promising therapeutic targets. Mainly due to the comprehensive regulation of kinases, however, a better understanding of the disturbances in the kinome network in amyotrophic lateral sclerosis is needed to properly target specific kinases in the clinic.}, }
@article {pmid32203399, year = {2020}, author = {Peng, C and Trojanowski, JQ and Lee, VM}, title = {Protein transmission in neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {4}, pages = {199-212}, pmid = {32203399}, issn = {1759-4766}, support = {U19 AG062418/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Axonal Transport ; Brain/*metabolism/pathology ; Cell Communication ; DNA-Binding Proteins/metabolism ; Endocytosis ; Exosomes/metabolism ; Genetic Predisposition to Disease ; Humans ; Huntingtin Protein/metabolism ; Huntington Disease/metabolism/pathology ; Membrane Fusion ; Nanotubes ; Neurodegenerative Diseases/*metabolism/pathology ; Neuroglia/metabolism ; Neurons/metabolism ; Parkinson Disease/metabolism/pathology ; Protein Aggregation, Pathological/*metabolism/pathology ; *Protein Transport ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.}, }
@article {pmid32200394, year = {2020}, author = {Rocha, II and Narasimhalu, K and De Silva, DA}, title = {Impact of Air Pollution and Seasonal Haze on Neurological Conditions.}, journal = {Annals of the Academy of Medicine, Singapore}, volume = {49}, number = {1}, pages = {26-36}, pmid = {32200394}, issn = {2972-4066}, mesh = {Air Pollutants/*toxicity ; Air Pollution/*adverse effects ; Asia, Southeastern ; Brain Ischemia/*epidemiology ; Humans ; Nervous System Diseases/*epidemiology ; Seasons ; Stroke/*epidemiology ; }, abstract = {INTRODUCTION: Air pollution is a global problem and seasonal haze from forest clearing and peat land burning in Indonesia is an annual phenomenon in Southeast Asia. As neurological disorders comprise 6.3% of the burden of disease globally, we reviewed evidence of the association between common neurological conditions and air pollution exposure, and summarised existing data on the impact of the haze phenomenon in Southeast Asia.<br><br>MATERIALS AND METHODS: A PubMed search for relevant studies on air pollution, Alzheimer's disease (AD), dementia, epilepsy, haze, headache, migraine, stroke, Parkinson's disease (PD) and neuromuscular conditions was performed. There were 52 articles which were relevant and were reviewed.<br><br>RESULTS: There were associations between short-term air pollution exposure with AD, epilepsy, ischaemic stroke and migraine. Long-term air pollution exposure was associated with AD, amyotrophic lateral sclerosis, dementia and ischaemic stroke. Evidence on the link between air pollution and PD was inconsistent. Currently, there is no specific data on the effects haze has on neurological conditions in Southeast Asia.<br><br>CONCLUSION: Air pollution is associated with increased risk of certain common neurological disorders. More specific studies are needed to investigate the impact of seasonal haze on neurological conditions in Southeast Asia.}, }
@article {pmid32199101, year = {2020}, author = {Luh, LM and Bertolotti, A}, title = {Potential benefit of manipulating protein quality control systems in neurodegenerative diseases.}, journal = {Current opinion in neurobiology}, volume = {61}, number = {}, pages = {125-132}, doi = {10.1016/j.conb.2020.02.009}, pmid = {32199101}, issn = {1873-6882}, support = {MC_U105185860/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis ; Humans ; *Neurodegenerative Diseases ; Proteins ; }, abstract = {The deposition of proteins of abnormal conformation is one of the major hallmarks of the common neurodegenerative diseases including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, frontotemporal dementia, and prion diseases. Protein quality control systems have evolved to protect cells and organisms against the harmful consequences of abnormally folded proteins that are constantly produced in small amounts. Mutations in rare inherited forms of neurodegenerative diseases have provided compelling evidence that failure of protein quality control systems can drive neurodegeneration. With extensive knowledge of these systems, and the notion that protein quality control may decline with age, many laboratories are now focussing on manipulating these evolutionarily optimized defence mechanisms to reduce the protein misfolding burden for therapeutic benefit.}, }
@article {pmid32198562, year = {2021}, author = {Riancho, J and Sanchez de la Torre, JR and Paz-Fajardo, L and Limia, C and Santurtun, A and Cifra, M and Kourtidis, K and Fdez-Arroyabe, P}, title = {The role of magnetic fields in neurodegenerative diseases.}, journal = {International journal of biometeorology}, volume = {65}, number = {1}, pages = {107-117}, doi = {10.1007/s00484-020-01896-y}, pmid = {32198562}, issn = {1432-1254}, mesh = {*Alzheimer Disease/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology ; Electromagnetic Fields ; Humans ; *Neurodegenerative Diseases/epidemiology ; *Parkinson Disease ; }, abstract = {The term neurodegenerative diseases include a long list of diseases affecting the nervous system that are characterized by the degeneration of different neurological structures. Among them, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) are the most representative ones. The vast majority of cases are sporadic and results from the interaction of genes and environmental factors in genetically predisposed individuals. Among environmental conditions, electromagnetic field exposure has begun to be assessed as a potential risk factor for neurodegeneration. In this review, we discuss the existing literature regarding electromagnetic fields and neurodegenerative diseases. Epidemiological studies in AD, PD, and ALS have shown discordant results; thus, a clear correlation between electromagnetic exposure and neurodegeneration has not been demonstrated. In addition, we discuss the role of electromagnetic radiation as a potential non-invasive therapeutic strategy for some neurodegenerative diseases, particularly for PD and AD.}, }
@article {pmid32194074, year = {2020}, author = {Sehgal, PB and Westley, J and Lerea, KM and DiSenso-Browne, S and Etlinger, JD}, title = {Biomolecular condensates in cell biology and virology: Phase-separated membraneless organelles (MLOs).}, journal = {Analytical biochemistry}, volume = {597}, number = {}, pages = {113691}, doi = {10.1016/j.ab.2020.113691}, pmid = {32194074}, issn = {1096-0309}, mesh = {Cell Biology ; Cell Nucleus/*chemistry/virology ; Cytoplasm/*chemistry/virology ; Humans ; Myxovirus Resistance Proteins/chemistry/*isolation &amp; purification ; Organelles/*chemistry/virology ; }, abstract = {Membraneless organelles (MLOs) in the cytoplasm and nucleus in the form of 2D and 3D phase-separated biomolecular condensates are increasingly viewed as critical in regulating diverse cellular functions. These functions include cell signaling, immune synapse function, nuclear transcription, RNA splicing and processing, mRNA storage and translation, virus replication and maturation, antiviral mechanisms, DNA sensing, synaptic transmission, protein turnover and mitosis. Components comprising MLOs often associate with low affinity; thus cell integrity can be critical to the maintenance of the full complement of respective MLO components. Phase-separated condensates are typically metastable (shape-changing) and can undergo dramatic, rapid and reversible assembly and disassembly in response to cell signaling events, cell stress, during mitosis, and after changes in cytoplasmic "crowding" (as observed with condensates of the human myxovirus resistance protein MxA). Increasing evidence suggests that neuron-specific aberrations in phase-separation properties of RNA-binding proteins (e.g. FUS and TDP-43) and others (such as the microtubule-binding protein tau) contribute to the development of degenerative neurological diseases (e.g. amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer's disease). Thus, studies of liquid-like phase separation (LLPS) and the formation, structure and function of MLOs are of considerable importance in understanding basic cell biology and the pathogenesis of human diseases.}, }
@article {pmid32184709, year = {2020}, author = {Luo, S and Ma, C and Zhu, MQ and Ju, WN and Yang, Y and Wang, X}, title = {Application of Iron Oxide Nanoparticles in the Diagnosis and Treatment of Neurodegenerative Diseases With Emphasis on Alzheimer's Disease.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {21}, pmid = {32184709}, issn = {1662-5102}, abstract = {Neurodegenerative diseases are characterized by chronic progressive degeneration of the structure and function of the nervous system, which brings an enormous burden on patients, their families, and society. It is difficult to make early diagnosis, resulting from the insidious onset and progressive development of neurodegenerative diseases. The drugs on the market cannot cross the blood-brain barrier (BBB) effectively, which leads to unfavorable prognosis and less effective treatments. Therefore, there is an urgent demand to develop a novel detection method and therapeutic strategies. Recently, nanomedicine has aroused considerable attention for diagnosis and therapy of central nervous system (CNS) diseases. Nanoparticles integrate targeting, imaging, and therapy in one system and facilitate the entry of drug molecules across the blood-brain barrier, offering new hope to patients. In this review, we summarize the application of iron oxide nanoparticles (IONPs) in the diagnosis and treatment of neurodegenerative disease, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We focus on IONPs as magnetic resonance imaging (MRI) contrast agents (CAs) and drug carriers in AD. What most neurodegenerative diseases have in common is that hall marker lesions are represented by protein aggregates (Soto and Pritzkow, 2018). These diseases are of unknown etiology and unfavorable prognosis, and the treatments toward them are less effective (Soto and Pritzkow, 2018). Such diseases usually develop in aged people, and early clinical manifestations are atypical, resulting in difficulty in early diagnosis. Recently, nanomedicine has aroused considerable attention for therapy and diagnosis of CNS diseases because it integrates targeting, imaging, and therapy in one system (Gupta et al., 2019). In this review article, we first introduce the neurodegenerative diseases and commonly used MRI CAs. Then we review the application of IONPs in the diagnosis and treatment of neurodegenerative diseases with the purpose of assisting early theranostics (therapy and diagnosis).}, }
@article {pmid32179176, year = {2020}, author = {Fallini, C and Khalil, B and Smith, CL and Rossoll, W}, title = {Traffic jam at the nuclear pore: All roads lead to nucleocytoplasmic transport defects in ALS/FTD.}, journal = {Neurobiology of disease}, volume = {140}, number = {}, pages = {104835}, pmid = {32179176}, issn = {1095-953X}, support = {R01 NS091749/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; C9orf72 Protein/metabolism ; Cell Nucleus/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/*pathology ; Humans ; Nuclear Pore/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that specifically affects the function and survival of spinal and cortical motor neurons. ALS shares many genetic, clinical, and pathological characteristics with frontotemporal dementia (FTD), and these diseases are now recognized as presentations of a disease spectrum known as ALS/FTD. The molecular determinants of neuronal loss in ALS/FTD are still debated, but the recent discovery of nucleocytoplasmic transport defects as a common denominator of most if not all forms of ALS/FTD has dramatically changed our understanding of the pathogenic mechanisms of this disease. Loss of nuclear pores and nucleoporin aggregation, altered nuclear morphology, and impaired nuclear transport are some of the most prominent features that have been identified using a variety of animal, cellular, and human models of disease. Here, we review the experimental evidence linking nucleocytoplasmic transport defects to the pathogenesis of ALS/FTD and propose a unifying view on how these defects may lead to a vicious cycle that eventually causes neuronal death.}, }
@article {pmid32178443, year = {2020}, author = {de Diego, AMG and Ortega-Cruz, D and García, AG}, title = {Disruption of Exocytosis in Sympathoadrenal Chromaffin Cells from Mouse Models of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {6}, pages = {}, pmid = {32178443}, issn = {1422-0067}, support = {SAF2016-78892R//Ministerio de Ciencia y Tecnolog&#xed;a/ ; 766124//Horizon 2020 Framework Programme/ ; }, mesh = {Animals ; Chromaffin Cells/*physiology ; Exocytosis/*physiology ; Mice ; Neurodegenerative Diseases/*physiopathology ; Secretory Vesicles/physiology ; Synaptic Transmission/physiology ; }, abstract = {Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a few studies done in adrenal medullary chromaffin cells (CCs), that are considered as the amplifying arm of the sympathetic nervous system; the sudden fast exocytotic release of their catecholamines-stored in noradrenergic and adrenergic cells-plays a fundamental role in the stress fight-or-flight response. Bulk exocytosis and the fine kinetics of single-vesicle exocytotic events have been studied in mouse models carrying a mutation linked to NDDs. For instance, in R6/1 mouse models of Huntington's disease (HD), mutated huntingtin is overexpressed in CCs; this causes decreased quantal secretion, smaller quantal size and faster kinetics of the exocytotic fusion pore, pore expansion, and closure. This was accompanied by decreased sodium current, decreased acetylcholine-evoked action potentials, and attenuated [Ca[2+]]c transients with faster Ca[2+] clearance. In the SOD1[G93A] mouse model of amyotrophic lateral sclerosis (ALS), CCs exhibited secretory single-vesicle spikes with a slower release rate but higher exocytosis. Finally, in the APP/PS1 mouse model of Alzheimer's disease (AD), the stabilization, expansion, and closure of the fusion pore was faster, but the secretion was attenuated. Additionally, α-synuclein that is associated with Parkinson's disease (PD) decreases exocytosis and promotes fusion pore dilation in adrenal CCs. Furthermore, Huntington-associated protein 1 (HAP1) interacts with the huntingtin that, when mutated, causes Huntington's disease (HD); HAP1 reduces full fusion exocytosis by affecting vesicle docking and controlling fusion pore stabilization. The alterations described here are consistent with the hypothesis that central alterations undergone in various NDDs are also manifested at the peripheral sympathoadrenal axis to impair the stress fight-or-flight response in patients suffering from those diseases. Such alterations may occur: (i) primarily by the expression of mutated disease proteins in CCs; (ii) secondarily to stress adaptation imposed by disease progression and the limitations of patient autonomy.}, }
@article {pmid32175837, year = {2020}, author = {Morello, M and Pieri, M and Zenobi, R and Talamo, A and Stephan, D and Landel, V and Féron, F and Millet, P}, title = {The Influence of Vitamin D on Neurodegeneration and Neurological Disorders: A Rationale for its Physio-pathological Actions.}, journal = {Current pharmaceutical design}, volume = {26}, number = {21}, pages = {2475-2491}, doi = {10.2174/1381612826666200316145725}, pmid = {32175837}, issn = {1873-4286}, mesh = {*Alzheimer Disease ; Humans ; *Multiple Sclerosis ; Vitamin D ; Vitamins ; }, abstract = {Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this "neuroactive" steroid can help to optimize the prevention and treatment of several neurological diseases.}, }
@article {pmid32169484, year = {2020}, author = {Babinchak, WM and Surewicz, WK}, title = {Liquid-Liquid Phase Separation and Its Mechanistic Role in Pathological Protein Aggregation.}, journal = {Journal of molecular biology}, volume = {432}, number = {7}, pages = {1910-1925}, pmid = {32169484}, issn = {1089-8638}, support = {F30 AG059350/AG/NIA NIH HHS/United States ; R01 NS083687/NS/NINDS NIH HHS/United States ; RF1 AG061797/AG/NIA NIH HHS/United States ; R01 GM094357/GM/NIGMS NIH HHS/United States ; P01 AI106705/AI/NIAID NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; R01 NS103848/NS/NINDS NIH HHS/United States ; }, mesh = {Amyloid/*chemistry/metabolism ; Animals ; Humans ; *Phase Transition ; *Protein Aggregation, Pathological ; Protein Binding ; Protein Domains ; *Protein Folding ; }, abstract = {Liquid-liquid phase separation (LLPS) of proteins underlies the formation of membrane-less organelles. While it has been recognized for some time that these organelles are of key importance for normal cellular functions, a growing number of recent observations indicate that LLPS may also play a role in disease. In particular, numerous proteins that form toxic aggregates in neurodegenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer's disease, were found to be highly prone to phase separation, suggesting that there might be a strong link between LLPS and the pathogenic process in these disorders. This review aims to assess the molecular basis of this link through exploration of the intermolecular interactions that underlie LLPS and aggregation and the underlying mechanisms facilitating maturation of liquid droplets into more stable assemblies, including so-called labile fibrils, hydrogels, and pathological amyloids. Recent insights into the structural basis of labile fibrils and potential mechanisms by which these relatively unstable structures could transition into more stable pathogenic amyloids are also discussed. Finally, this review explores how the environment of liquid droplets could modulate protein aggregation by altering kinetics of protein self-association, affecting folding of protein monomers, or changing aggregation pathways.}, }
@article {pmid32165170, year = {2020}, author = {de Araújo Boleti, AP and de Oliveira Flores, TM and Moreno, SE and Anjos, LD and Mortari, MR and Migliolo, L}, title = {Neuroinflammation: An overview of neurodegenerative and metabolic diseases and of biotechnological studies.}, journal = {Neurochemistry international}, volume = {136}, number = {}, pages = {104714}, doi = {10.1016/j.neuint.2020.104714}, pmid = {32165170}, issn = {1872-9754}, mesh = {Animals ; Brain/*metabolism ; Humans ; Macrophages/metabolism ; Metabolic Diseases/*metabolism ; Microglia/*metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; }, abstract = {Neuroinflammation is an important factor contributing to cognitive impairment and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), ischemic injury, and multiple sclerosis (MS). These diseases are characterized by inexorable progressive injury of neuron cells, and loss of motor or cognitive functions. Microglia, which are the resident macrophages in the brain, play an important role in both physiological and pathological conditions. In this review, we provide an updated discussion on the role of ROS and metabolic disease in the pathological mechanisms of activation of the microglial cells and release of cytotoxins, leading to the neurodegenerative process. In addition, we also discuss in vivo models, such as zebrafish and Caenorhabditis elegans, and provide new insights into therapeutics bioinspired by neuropeptides from venomous animals, supporting high throughput drug screening in the near future, searching for a complementary approach to elucidating crucial mechanisms associated with neurodegenerative disorders.}, }
@article {pmid32164864, year = {2020}, author = {Vaughan, TM}, title = {Brain-computer interfaces for people with amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {168}, number = {}, pages = {33-38}, doi = {10.1016/B978-0-444-63934-9.00004-4}, pmid = {32164864}, issn = {0072-9752}, support = {P41 EB018783/EB/NIBIB NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; *Brain-Computer Interfaces ; Communication ; *Electroencephalography/methods ; Humans ; Nerve Net/*physiopathology ; }, abstract = {A brain-computer interface (BCI) records and extracts features from brain signals, and translates these features into commands that can replace, restore, enhance, supplement, or improve natural CNS outputs. As demonstrated in the other chapters of this book, the focus of the work of the last three decades of BCI research has been the replacement, restoration, or improvement of diminished or lost function in people with CNS disease or injury including those with amyotrophic lateral sclerosis (ALS). Due in part to the desire to conduct controlled studies, and, in part, to the complexity of BCI technology, most of this work has been carried out in laboratories with healthy controls or with limited numbers of potential consumers with a variety of diagnoses under supervised conditions. The intention of this chapter is to describe the growing body of BCI research that has included people with amyotrophic lateral sclerosis (ALS). People in the late stages of ALS can lose all voluntary control, including the ability to communicate; and while recent research has provided new insights into underlying mechanisms, ALS remains a disease with no cure. As a result, people with ALS and their families, caregivers, and advocates have an active interest in both the current and potential capabilities of BCI technology. The focus of BCI research for people with ALS is on communication, and this topic is well covered elsewhere in this volume. This chapter focuses on the efforts dedicated to make BCI technology useful to people with ALS in their daily lives with a discussion of how researchers, clinicians, and patients must become partners in that process.}, }
@article {pmid32163386, year = {2020}, author = {Shpilyukova, YA and Fedotova, EY and Illarioshkin, SN}, title = {[Genetic Diversity in Frontotemporal Dementia].}, journal = {Molekuliarnaia biologiia}, volume = {54}, number = {1}, pages = {17-28}, doi = {10.31857/S0026898420010139}, pmid = {32163386}, issn = {0026-8984}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics ; Frontotemporal Dementia/complications/*genetics ; Humans ; *Mutation ; Phenotype ; }, abstract = {Frontotemporal dementia is a progressive neurodegenerative disorder with high clinical, genetic, and pathomorphological diversity It is the third most common cause of dementia in all ages and the most common cause of early onset dementia (below 65). Despite its multifactorial nature, up to 40% of patients have a family history where the autosomal dominant inheritance type is seen in a quarter of cases. In this review, we describe key genes whose mutations can result in the development of frontotemporal dementia, the possible pathogenic mechanisms of the degenerative process, and provide information on the clinical features of the disease for different genetic variants. Special emphasis is placed on the frontotemporal dementia phenotype that is associated with amyotrophic lateral sclerosis.}, }
@article {pmid32157757, year = {2020}, author = {Riku, Y}, title = {Reappraisal of the anatomical spreading and propagation hypothesis about TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {40}, number = {5}, pages = {426-435}, doi = {10.1111/neup.12644}, pmid = {32157757}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; DNA-Binding Proteins/*metabolism ; Disease Progression ; Frontotemporal Lobar Degeneration/metabolism/*pathology ; Humans ; Neurons/metabolism/*pathology ; Protein Aggregation, Pathological/metabolism/*pathology ; }, abstract = {Neuronal inclusion of transactivation response DNA-binding protein 43 kDa (TDP-43) is known to be a pathologic hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43, which is physiologically a nuclear protein, is mislocalized from the nucleus and aggregated within the cytoplasm of affected neurons in ALS and FTLD patients. Neuropathologic or experimental studies have addressed mechanisms underlying spreading of TDP-43 inclusions in the central nervous system of ALS and FTLD patients. On the basis of postmortem observations, it is hypothesized that TDP-43 inclusions spread along the neural projections. A centrifugal gradient of TDP-43 pathology in certain anatomical systems and axonal or synaptic aggregation of TDP-43 may support the hypothesis. Experimental studies have revealed cell-to-cell propagation of aggregated or truncated TDP-43, which indicates a direct transmission of TDP-43 inclusions to contiguous cells. However, discrepancies remain between the cell-to-cell propagation suggested in the experimental models and the anatomical spreading of TDP-43 aggregations based on postmortem observations. Trans-synaptic transmission, rather than the direct cell-to-cell transmission, may be consistent with the anatomical spreading of TDP-43 aggregations, but cellular mechanisms of trans-synaptic transmission of aggregated proteins remain to be elucidated. Moreover, the spreading of TDP-43 inclusions varies among patients and genetic backgrounds, which indicates host-dependent factors for spreading of TDP-43 aggregations. Perturbation of cellular TDP-43 clearance may be a possible factor modifying the aggregation and spreading. This review discusses postmortem and experimental evidence that address mechanisms of spreading of TDP-43 pathology in the central nervous system of ALS and FTLD patients.}, }
@article {pmid32152523, year = {2020}, author = {Coleman, MP and Höke, A}, title = {Programmed axon degeneration: from mouse to mechanism to medicine.}, journal = {Nature reviews. Neuroscience}, volume = {21}, number = {4}, pages = {183-196}, pmid = {32152523}, issn = {1471-0048}, support = {G1000702/MRC_/Medical Research Council/United Kingdom ; MR/N004582/1/MRC_/Medical Research Council/United Kingdom ; R01 NS091260/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Armadillo Domain Proteins/metabolism ; Cytoskeletal Proteins/metabolism ; Disease Models, Animal ; Drosophila melanogaster ; Humans ; Mice ; Mice, Transgenic ; NAD/metabolism ; Nicotinamide-Nucleotide Adenylyltransferase/metabolism ; Signal Transduction ; Translational Research, Biomedical ; Wallerian Degeneration/*metabolism ; }, abstract = {Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (Wld[S]) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.}, }
@article {pmid32148547, year = {2020}, author = {Mohd Sairazi, NS and Sirajudeen, KNS}, title = {Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2020}, number = {}, pages = {6565396}, pmid = {32148547}, issn = {1741-427X}, abstract = {In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.}, }
@article {pmid32147204, year = {2020}, author = {Pape, JA and Grose, JH}, title = {The effects of diet and sex in amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {176}, number = {5}, pages = {301-315}, pmid = {32147204}, issn = {0035-3787}, support = {R15 GM100376/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology/pathology ; Animals ; Body Mass Index ; *Diet ; Disease Models, Animal ; Disease Progression ; Female ; Gonadal Steroid Hormones/blood/physiology ; Humans ; Male ; Mice ; *Sex Characteristics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are multiple contributing factors that influence the disease risk, onset, and progression. Diet and sex are two factors that have been reported to alter ALS risk, onset and progression in humans and in animal models, providing potential modifiers of disease. Several epidemiological studies have identified diets that positively affect ALS patients, including various high-calorie fat or sugar-based diets, while animal models have been developed to test how these diets are working on a molecular level. These diets may offset the metabolic alterations that occur in ALS, such as hypermetabolism, lowered body mass index(BMI), and hyperlipidemia. Sex-dependent differences have also come forth from large-scale epidemiological studies as well as mouse-model studies. In addition, sex hormones have been shown to affect disease risk or progression. Herein, studies on the effects of diet and sex on ALS risk, onset, and progression will be reviewed. Understanding these diet- and sex-dependent outcomes may lead to optimized patient-specific therapies for ALS.}, }
@article {pmid32144338, year = {2020}, author = {Prehn, JHM and Jirström, E}, title = {Angiogenin and tRNA fragments in Parkinson's disease and neurodegeneration.}, journal = {Acta pharmacologica Sinica}, volume = {41}, number = {4}, pages = {442-446}, pmid = {32144338}, issn = {1745-7254}, mesh = {Animals ; Humans ; Parkinson Disease/*metabolism/pathology ; RNA, Transfer/*metabolism ; Ribonuclease, Pancreatic/*metabolism ; }, abstract = {In this review, we summarise the evidence for a role of the ribonuclease angiogenin in the pathophysiology of neurodegenerative disorders, with a specific focus on Parkinson's disease (PD). Angiogenin is a stress-induced, secreted ribonuclease with both nuclear and cytosolic activities. Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer's disease. Delivery of angiogenin protein reduces neurodegeneration and delays disease progression in in vitro and in vivo models of ALS and in vitro models of PD. In the nucleus, angiogenin promotes ribosomal RNA transcription. Under stress conditions, angiogenin also translocates to the cytosol where it cleaves non-coding RNA into RNA fragments, in particular transfer RNAs (tRNAs). Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. We will discuss recent evidence of tRNA fragment accumulation in PD, as well as their potential neuroprotective activities.}, }
@article {pmid32138249, year = {2020}, author = {Ravnik-Glavač, M and Glavač, D}, title = {Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {21}, number = {5}, pages = {}, pmid = {32138249}, issn = {1422-0067}, support = {P3-0054//Javna Agencija za Raziskovalno Dejavnost RS/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Animals ; Biomarkers/*blood ; Cell-Free Nucleic Acids/*blood ; Humans ; MicroRNAs/blood ; RNA, Messenger/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex multi-system neurodegenerative disorder with currently limited diagnostic and no therapeutic options. Despite the intense efforts no clinically applicable biomarkers for ALS are yet established. Most current research is thus focused, in particular, in identifying potential non-invasive circulating biomarkers for more rapid and accurate diagnosis and monitoring of the disease. In this review, we have focused on messenger RNA (mRNA), non-coding RNAs (lncRNAs), micro RNAs (miRNAs) and circular RNA (circRNAs) as potential biomarkers for ALS in peripheral blood serum, plasma and cells. The most promising miRNAs include miR-206, miR-133b, miR-27a, mi-338-3p, miR-183, miR-451, let-7 and miR-125b. To test clinical potential of this miRNA panel, a useful approach may be to perform such analysis on larger multi-center scale using similar experimental design. However, other types of RNAs (lncRNAs, circRNAs and mRNAs) that, together with miRNAs, represent RNA networks, have not been yet extensively studied in blood samples of patients with ALS. Additional research has to be done in order to find robust circulating biomarkers and therapeutic targets that will distinguish key RNA interactions in specific ALS-types to facilitate diagnosis, predict progression and design therapy.}, }
@article {pmid32131674, year = {2020}, author = {Evans, CS and Holzbaur, ELF}, title = {Lysosomal degradation of depolarized mitochondria is rate-limiting in OPTN-dependent neuronal mitophagy.}, journal = {Autophagy}, volume = {16}, number = {5}, pages = {962-964}, pmid = {32131674}, issn = {1554-8635}, support = {R37 NS060698/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagy/genetics/*physiology ; Cell Cycle Proteins/metabolism ; Humans ; Lysosomes/*metabolism ; Mitochondria/*metabolism ; Mitophagy/genetics/*physiology ; Neurons/*metabolism ; }, abstract = {Damaged mitochondria are selectively removed from the cell in a process termed mitophagy. This mitochondrial quality control mechanism is important for neuronal homeostasis, and mutations in pathway components are causative for Parkinson disease and amyotrophic lateral sclerosis (ALS). Here, we discuss our recent work using a novel mild induction paradigm to investigate the spatiotemporal dynamics of mitophagy in primary neurons. Using live-cell imaging, we find that mitophagy-associated proteins translocate to depolarized mitochondrial fragments. These mitophagic events were primarily localized to somatodendritic compartments, suggesting neuronal mitophagy is primarily a somal quality control mechanism. Damaged mitochondria were efficiently sequestered within autophagosomes, but lysosomal fusion or acidification was significantly delayed. Surprisingly, engulfed mitochondria persisted in non-acidified vesicular compartments for hours to days after initial damage. Expression of an ALS-associated mutation disrupted the membrane potential of the mitochondrial network, and oxidative stress exacerbated this effect. Importantly, our results highlight the slow kinetics of mitophagy and suggest that slow turnover of damaged mitochondria may increase neuronal susceptibility to neurodegeneration.}, }
@article {pmid32125907, year = {2020}, author = {Abati, E and Bresolin, N and Comi, G and Corti, S}, title = {Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on therapeutic targets}, volume = {24}, number = {4}, pages = {295-310}, doi = {10.1080/14728222.2020.1738390}, pmid = {32125907}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; CRISPR-Cas Systems/genetics ; Gene Expression Regulation ; *Gene Silencing ; Humans ; Molecular Targeted Therapy ; Mutation ; Oligonucleotides, Antisense/administration &amp; dosage ; RNA Interference ; Superoxide Dismutase-1/*genetics ; }, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disorder that targets upper and lower motor neurons and leads to fatal muscle paralysis. Mutations in the superoxide dismutase 1 (SOD1) gene are responsible for 15% of familial ALS cases, but several studies have indicated that SOD1 dysfunction may also play a pathogenic role in sporadic ALS. SOD1 induces numerous toxic effects through the pathological misfolding and aggregation of mutant SOD1 species, hence a reduction of the levels of toxic variants appears to be a promising therapeutic strategy for SOD1-related ALS. Several methods are used to modulate gene expression in vivo; these include RNA interference, antisense oligonucleotides (ASOs) and CRISPR/Cas9 technology.Areas covered: This paper examines the current approaches for gene silencing and the progress made in silencing SOD1 in vivo. It progresses to shed light on the key results and pitfalls of these studies and highlights the future challenges and new perspectives for this exciting research field.Expert opinion: Gene silencing strategies targeting SOD1 may represent effective approaches for familial and sporadic ALS-related neurodegeneration; however, the risk of off-target effects must be minimized, and effective and minimally invasive delivery strategies should be fine-tuned.}, }
@article {pmid32125540, year = {2020}, author = {Tao, L and Wang, Q and Liu, D and Wang, J and Zhu, Z and Feng, L}, title = {Eye tracking metrics to screen and assess cognitive impairment in patients with neurological disorders.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {41}, number = {7}, pages = {1697-1704}, doi = {10.1007/s10072-020-04310-y}, pmid = {32125540}, issn = {1590-3478}, support = {grant nos. 81771407//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Benchmarking ; *Cognition Disorders/diagnosis/etiology ; *Cognitive Dysfunction/diagnosis ; Eye-Tracking Technology ; Humans ; Neuropsychological Tests ; }, abstract = {PURPOSE OF REVIEW: Eye tracking is a powerful method to investigate the relationship between behavior and neural mechanisms. In recent years, eye movement analysis has been used in patients with neurological disorders to assess cognitive function. In this review, we explore the latest eye tracking researches in neurological disorders that are commonly associated with cognitive deficits, specifically, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and epilepsy. We focus on the application of ocular measures in these disorders, with the goal of understanding how eye tracking technology can be used in the clinical setting.<br><br>FINDINGS: Eye tracking tasks (especially saccadic tasks) are often used as an adjunct to traditional scales for cognitive assessment. Eye tracking data confirmed that executive dysfunction is common in PD and ALS, whereas AD and MS are characterized by attention deficits. Research in evaluating cognitive function in epilepsy using eye tracking is still in its early stages, but this approach has shown advantages as a sensitive quantitative method with high temporal and spatial resolution. Eye tracking technology can facilitate the assessment of cognitive impairment with higher temporal resolution and finer granularity than traditional cognitive assessment. Oculomotor data collected during cognitive tasks can provide insight into biological processes. Eye tracking provides a nonverbal and less cognitively demanding method of measuring disease progression in cognitively impaired patients.}, }
@article {pmid32121302, year = {2020}, author = {Pogačnik, L and Ota, A and Ulrih, NP}, title = {An Overview of Crucial Dietary Substances and Their Modes of Action for Prevention of Neurodegenerative Diseases.}, journal = {Cells}, volume = {9}, number = {3}, pages = {}, pmid = {32121302}, issn = {2073-4409}, mesh = {Dietary Supplements/*standards ; Humans ; Neurodegenerative Diseases/*prevention &amp; control ; Ubiquinone/*analogs &amp; derivatives/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases, namely Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis are becoming one of the main health concerns due to the increasing aging of the world's population. These diseases often share the same biological mechanisms, including neuroinflammation, oxidative stress, and/or protein fibrillation. Recently, there have been many studies published pointing out the possibilities to reduce and postpone the clinical manifestation of these deadly diseases through lifelong consumption of some crucial dietary substances, among which phytochemicals (e.g., polyphenols) and endogenous substances (e.g., acetyl-L-carnitine, coenzyme Q10, n-3 poysaturated fatty acids) showed the most promising results. Another important issue that has been pointed out recently is the availability of these substances to the central nervous system, where they have to be present in high enough concentrations in order to exhibit their neuroprotective properties. As so, such the aim of this review is to summarize the recent findings regarding neuroprotective substances, their mechanisms of action, as well as to point out therapeutic considerations, including their bioavailability and safety for humans.}, }
@article {pmid32119873, year = {2020}, author = {Casterton, RL and Hunt, RJ and Fanto, M}, title = {Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy.}, journal = {Journal of molecular biology}, volume = {432}, number = {8}, pages = {2692-2713}, doi = {10.1016/j.jmb.2020.02.018}, pmid = {32119873}, issn = {1089-8638}, support = {FANTO/APR17/855-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; *Autophagy ; Frontotemporal Dementia/*pathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) constitute aggressive neurodegenerative pathologies that lead to the progressive degeneration of upper and lower motor neurons and of neocortical areas, respectively. In the past decade, the identification of several genes that cause these disorders indicated that the two diseases overlap in a multifaceted spectrum of conditions. The autophagy-lysosome system has been identified as a main intersection for the onset and progression of neurodegeneration in ALS/FTD. Genetic evidence has revealed that several genes with a mechanistic role at different stages of the autophagy process are mutated in patients with ALS/FTD. Moreover, the three main proteins aggregating in ALS/FTD, including in sporadic cases, are also targeted by autophagy and affect this process. Here, we examine the varied dysfunctions and degrees of involvement of the autophagy-lysosome system that have been discovered in ALS/FTD. We argue that these findings shed light on the pathological mechanisms in the ALS/FTD spectrum and conclude that they have important consequences both for treatment options and for the basic biomolecular understanding of how this process intersects with RNA metabolism, the other major cellular process reported to be dysfunctional in part of the ALS/FTD spectrum.}, }
@article {pmid32116773, year = {2020}, author = {Carrera-Juliá, S and Moreno, ML and Barrios, C and de la Rubia Ortí, JE and Drehmer, E}, title = {Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {63}, pmid = {32116773}, issn = {1664-042X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD[+]) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.}, }
@article {pmid32116499, year = {2020}, author = {Abramzon, YA and Fratta, P and Traynor, BJ and Chia, R}, title = {The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {42}, pmid = {32116499}, issn = {1662-4548}, support = {FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.}, }
@article {pmid32107050, year = {2020}, author = {Krauss, R and Bosanac, T and Devraj, R and Engber, T and Hughes, RO}, title = {Axons Matter: The Promise of Treating Neurodegenerative Disorders by Targeting SARM1-Mediated Axonal Degeneration.}, journal = {Trends in pharmacological sciences}, volume = {41}, number = {4}, pages = {281-293}, doi = {10.1016/j.tips.2020.01.006}, pmid = {32107050}, issn = {1873-3735}, mesh = {Animals ; Armadillo Domain Proteins/*antagonists &amp; inhibitors/metabolism ; Axons/drug effects/enzymology/*pathology ; Cytoskeletal Proteins/*antagonists &amp; inhibitors/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/enzymology/*pathology ; }, abstract = {Attempts to develop neuroprotective treatments for neurodegenerative disorders have not yet been clinically successful. Axonal degeneration has been recognized as a predominant driver of disability and disease progression in central nervous system (CNS) diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Parkinson's disease, peripheral nervous system (PNS) disorders such as chemotherapy-induced, diabetic, and inherited neuropathies, and ocular disorders, such as glaucoma. In recent years, sterile alpha and TIR motif containing 1 (SARM1) has emerged as the first compelling axonal-specific target for therapeutic intervention. In this review, we discuss the role of axonal degeneration in neurodegenerative disorders, with a focus on SARM1 and the discovery of its intrinsic enzymatic function. Establishment of neurofilament light chain (NfL) as a reliable biomarker of axonal damage, and the availability of an ultrasensitive method for measuring NfL in plasma or serum, provide translational tools to make development of axonal protective, SARM1 inhibitors a viable approach to treat multiple neurodegenerative disorders.}, }
@article {pmid32106022, year = {2020}, author = {Annunziato, L and Secondo, A and Pignataro, G and Scorziello, A and Molinaro, P}, title = {New perspectives for selective NCX activators in neurodegenerative diseases.}, journal = {Cell calcium}, volume = {87}, number = {}, pages = {102170}, doi = {10.1016/j.ceca.2020.102170}, pmid = {32106022}, issn = {1532-1991}, mesh = {Animals ; Cell-Penetrating Peptides/metabolism ; Epigenesis, Genetic ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/physiopathology ; Protein Isoforms/metabolism ; Sodium-Calcium Exchanger/*metabolism ; }, abstract = {The Na[+]/Ca[2+] exchanger plays a relevant role in several neurological disorders, thus the pharmacological modulation of its isoforms might represent a promising strategy to ameliorate the course of some neurological pathologies including stroke, neonatal hypoxia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer Disease (AD), and spinal muscular atrophy (SMA). This review will summarize heterocyclic, peptidergic, genetic and epigenetic compounds activating or inhibiting the expression/activity of each NCX isoform. In addition, we will focus our attention on the development of new strategies aimed to ameliorate the pathophysiological conditions in which NCX isoform changes are found.}, }
@article {pmid32105239, year = {2020}, author = {Brodell, JD and Sulovari, A and Bernstein, DN and Mongiovi, PC and Ciafaloni, E and Rubery, PT and Mesfin, A}, title = {Dropped Head Syndrome: An Update on Etiology and Surgical Management.}, journal = {JBJS reviews}, volume = {8}, number = {1}, pages = {e0068}, doi = {10.2106/JBJS.RVW.19.00068}, pmid = {32105239}, issn = {2329-9185}, mesh = {*Cervical Vertebrae ; Humans ; Kyphosis/*etiology/rehabilitation/surgery ; *Neck Muscles ; Neuromuscular Diseases/complications ; Orthotic Devices ; }, abstract = {» Dropped head syndrome is a group of disorders with diverse etiologies involving different anatomical components of the neck, ultimately resulting in a debilitating, flexible, anterior curvature of the cervical spine. » Causes of dropped head syndrome include myasthenia gravis, amyotrophic lateral sclerosis, Parkinson disease, radiation therapy, and cumulative age-related changes. Idiopathic cases have also been reported. » Nonoperative treatment of dropped head syndrome includes orthotic bracing and physical therapy. » Surgical treatment of dropped head syndrome consists of cervical spine fusion to correct the deformity. » The limited data available examining the clinical and radiographic outcomes of surgical intervention indicate a higher rate of complications with the majority having favorable outcomes in the long term.}, }
@article {pmid32104476, year = {2019}, author = {Niu, X and Chen, J and Gao, J}, title = {Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances.}, journal = {Asian journal of pharmaceutical sciences}, volume = {14}, number = {5}, pages = {480-496}, pmid = {32104476}, issn = {2221-285X}, abstract = {Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington disease and amyotrophic lateral sclerosis throw a heavy burden on families and society. Related scientific researches make tardy progress. One reason is that the known pathogeny is just the tip of the iceberg. Another reason is that various physiological barriers, especially blood-brain barrier (BBB), hamper effective therapeutic substances from reaching site of action. Drugs in clinical treatment of neurodegenerative diseases are basically administered orally. And generally speaking, the brain targeting efficiency is pretty low. Nano-delivery technology brings hope for neurodegenerative diseases. The use of nanocarriers encapsulating molecules such as peptides and genomic medicine may enhance drug transport through the BBB in neurodegenerative disease and target relevant regions in the brain for regenerative processes. In this review, we discuss BBB composition and applications of nanocarriers -liposomes, nanoparticles, nanomicelles and new emerging exosomes in neurodegenerative diseases. Furthermore, the disadvantages and the potential neurotoxicity of nanocarriers according pharmacokinetics theory are also discussed.}, }
@article {pmid32100717, year = {2019}, author = {Kwapisz, A and Mollison, S and Cholewiński, J and MacDonald, P and Synder, M and Herman, K}, title = {Lateral Extra-articular Tenodesis with Iliotibial Band Strip - a Solution for Anterolateral Instability?.}, journal = {Ortopedia, traumatologia, rehabilitacja}, volume = {21}, number = {6}, pages = {397-406}, doi = {10.5604/01.3001.0013.7397}, pmid = {32100717}, issn = {2084-4336}, mesh = {Adult ; Aged ; Aged, 80 and over ; Anterior Cruciate Ligament Injuries/*surgery ; Anterior Cruciate Ligament Reconstruction/*methods ; Biomechanical Phenomena ; Female ; Humans ; Joint Instability/*surgery ; Ligaments, Articular/*surgery ; Male ; Middle Aged ; Range of Motion, Articular ; Tenodesis/*methods ; }, abstract = {It is widely acknowledged that anterior cruciate ligament (ACL) injury is the cause of anterolateral insta-bility, but in some cases not only the ACL ruptures, but also anterolateral structures (ALS), including the antero-lateral ligament. Their insufficiency may be the cause of residual instability after ACL reconstruction, which significantly increases the risk of graft rupture. In the past, anterolateral instability caused by ACL injury was treat-ed with extra-articular reconstructions, including lateral extra-articular tenodesis. Nowadays those techni-ques are used simultaneously in cases of complex anterolateral and rotational instability. This article briefly describes historical methods of lateral tenodesis and presents step-by-step two techniques used in our depart-ments involving two alternative graft femoral fixation methods.}, }
@article {pmid32100068, year = {2020}, author = {Heinrich, K and Pumberger, P and Schwaiger, K and Schaffler, G and Hladik, M and Wechselberger, G}, title = {[Surgical decompression of the peroneal nerve at the level of the fibular head].}, journal = {Operative Orthopadie und Traumatologie}, volume = {32}, number = {5}, pages = {467-474}, doi = {10.1007/s00064-020-00648-w}, pmid = {32100068}, issn = {1439-0981}, mesh = {Decompression, Surgical ; Fibula/diagnostic imaging/surgery ; Humans ; *Peroneal Nerve/surgery ; Peroneal Neuropathies/diagnosis/surgery ; Treatment Outcome ; }, abstract = {OBJECTIVE: Functional and sensible regeneration of deficits related to common peroneal nerve palsy.<br><br>INDICATIONS: Functional deficits like foot drop, malfunctioning pronation, foot in supination and sensible deficits located at the anterior and lateral lower leg, the dorsum of the foot, the extension side of toes&#xa0;1-4 and the interdigital space between toe&#xa0;1 and&#xa0;2, for positive Hoffmann-Tinel sign located at the fibular head and steppage gait.<br><br>CONTRAINDICATIONS: Infection, spinal cord damage and spinal cord tumors with related sensitivity disorders and paralysis, advanced multiple sclerosis, amyotrophic lateral sclerosis, pAVK&#xa0;IV, reinnervation refractory muscles with denervation >15-18 months, polyneuropathy, previous nerve lesions by direct trauma.<br><br>SURGICAL TECHNIQUE: Surgery in lateral position and thigh tourniquet. L&#x2011;Shaped incision made in accordance with the marking. Nerve release by fasciotomy first proximal, then distal up to the branching. Opening of the thigh tourniquet, careful coagulation. Insertion of a Mini Redovac Drainage, subcutaneous and skin sutures. Compression bandage.<br><br>POSTOPERATIVE MANAGEMENT: Full mobilization on postoperative day&#xa0;1. An electric stimulation therapy can be considered after drainage removal. After suture removal physio- and ergotherapy indicated. Check ups should be performed every 3&#xa0;months with clinical exams, photo and video documentation. Four months after surgery an electroneurographic exam should be done. Follow-up should be performed for 24&#xa0;months.<br><br>RESULTS: From 2010-2018 15&#xa0;patients received decompression of the common peroneal nerve. Sensibility, functionality and subjective feeling were evaluated. In 12&#xa0;patients (80%) a&#xa0;full recovery, in one case (6.67%) a&#xa0;partial recovery and in 2&#xa0;cases (13.33%) no recovery was observed.}, }
@article {pmid32096049, year = {2019}, author = {Cruz, A and Verma, M and Wolozin, B}, title = {The Pathophysiology of Tau and Stress Granules in Disease.}, journal = {Advances in experimental medicine and biology}, volume = {1184}, number = {}, pages = {359-372}, pmid = {32096049}, issn = {0065-2598}, support = {R01 AG064932/AG/NIA NIH HHS/United States ; RF1 AG056318/AG/NIA NIH HHS/United States ; R01 AG050471/AG/NIA NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; R21 AG059925/AG/NIA NIH HHS/United States ; RF1 AG061706/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Cytoplasmic Granules/*metabolism/pathology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; RNA-Binding Proteins/metabolism ; Tauopathies/metabolism/pathology ; tau Proteins/*metabolism ; }, abstract = {This chapter discusses the relationship between tau, RNA binding proteins and stress granules, which exhibit an intimate bidirectional relationship affecting the functions of both tau and the translational stress response. We describe how tau becomes hyperphosphorylated and oligomerized as part of an endogenous mechanism to promote the translational stress response through interaction with RNA binding proteins. Prior studies demonstrate that dysfunction of RNA binding proteins biology is sufficient to cause neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Emerging evidence indicates that tau-mediated neurodegeneration also occurs through a mechanism that is mediated by RNA binding proteins and the translational stress response. Discovery of the role of RNA metabolism in tauopathy opens a wide variety of novel therapeutic approaches. Multiple studies have already shown that approaches reducing the levels of selected RNA binding proteins or inhibiting the translational stress response can intervene in the pathophysiology of motoneuron diseases. Emerging studies show that reducing the levels of selected RNA binding proteins or inhibiting the translational stress response also reduces neurodegeneration in models of tauopathy and Aβ mediated degeneration. The combined impact of these studies indicate that RNA binding proteins and RNA metabolism represent a valuable new frontier for the investigation and treatment tauopathies.}, }
@article {pmid32096040, year = {2019}, author = {Fernandez-Gomez, F and Tran, H and Dhaenens, CM and Caillet-Boudin, ML and Schraen-Maschke, S and Blum, D and Sablonnière, B and Buée-Scherrer, V and Buee, L and Sergeant, N}, title = {Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy?.}, journal = {Advances in experimental medicine and biology}, volume = {1184}, number = {}, pages = {207-216}, doi = {10.1007/978-981-32-9358-8_17}, pmid = {32096040}, issn = {0065-2598}, mesh = {*Gain of Function Mutation ; Humans ; Myotonic Dystrophy/*genetics/*metabolism ; Protein Isoforms/chemistry/genetics/metabolism ; RNA/*metabolism ; Tauopathies/*genetics/*metabolism ; tau Proteins/chemistry/genetics/metabolism ; }, abstract = {Myotonic dystrophies (DM) are rare inherited neuromuscular disorders linked to microsatellite unstable expansions in non-coding regions of ubiquitously expressed genes. The DMPK and ZNF9/CNBP genes which mutations are responsible for DM1 and DM2 respectively. DM are multisystemic disorders with brain affection and cognitive deficits. Brain lesions consisting of neurofibrillary tangles are often observed in DM1 and DM2 brain. Neurofibrillary tangles (NFT) made of aggregates of hyper and abnormally phosphorylated isoforms of Tau proteins are neuropathological lesions common to more than 20 neurological disorders globally referred to as Tauopathies. Although NFT are observed in DM1 and DM2 brain, the question of whether DM1 and DM2 are Tauopathies remains a matter of debate. In the present review, several pathophysiological processes including, missplicing, nucleocytoplasmic transport disruption, RAN translation which are common mechanisms implicated in neurodegenerative diseases will be described. Together, these processes including the missplicing of Tau are providing evidence that DM1 and DM2 are not solely muscular diseases but that their brain affection component share many similarities with Tauopathies and other neurodegenerative diseases. Understanding DM1 and DM2 pathophysiology is therefore valuable to more globally understand other neurodegenerative diseases such as Tauopathies but also frontotemporal lobar neurodegeneration and amyotrophic lateral sclerosis.}, }
@article {pmid32093746, year = {2020}, author = {Chen, KW and Chen, JA}, title = {Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease.}, journal = {Journal of biomedical science}, volume = {27}, number = {1}, pages = {38}, pmid = {32093746}, issn = {1423-0127}, support = {NHRI-EX108-10831NI//National Health Research Institutes/ ; CDA-107-L05//Academia Sinica/ ; 108-2311-B-001-011//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; Mice ; Motor Neurons/*physiology ; Muscular Atrophy, Spinal/*genetics ; Neurodegenerative Diseases/genetics ; RNA, Long Noncoding/*genetics ; }, abstract = {Long non-coding RNAs (lncRNAs) have gained increasing attention as they exhibit highly tissue- and cell-type specific expression patterns. LncRNAs are highly expressed in the central nervous system and their roles in the brain have been studied intensively in recent years, but their roles in the spinal motor neurons (MNs) are largely unexplored. Spinal MN development is controlled by precise expression of a gene regulatory network mediated spatiotemporally by transcription factors, representing an elegant paradigm for deciphering the roles of lncRNAs during development. Moreover, many MN-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are associated with RNA metabolism, yet the link between MN-related diseases and lncRNAs remains obscure. In this review, we summarize lncRNAs known to be involved in MN development and disease, and discuss their potential future therapeutic applications.}, }
@article {pmid32091028, year = {2019}, author = {Cervantes-Aragón, I and Ramírez-García, SA and Baltazar-Rodríguez, LM and García-Cruz, D and Castañeda-Cisneros, G}, title = {Genetic approach in amyotrophic lateral sclerosis.}, journal = {Gaceta medica de Mexico}, volume = {155}, number = {5}, pages = {475-482}, doi = {10.24875/GMM.M20000335}, pmid = {32091028}, issn = {0016-3813}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Humans ; Ischemia/complications ; Mexico ; Oxidative Stress ; Point Mutation ; Superoxide Dismutase-1/*genetics ; }, abstract = {The superoxide dismutase type 1 (SOD1) gene is the first responsible gene mapped in amyotrophic lateral sclerosis type 1 (ALS1), and it codes for the enzyme SOD1, the function of which is to protect against damage mediated by free radicals deriving from oxygen. Its pathophysiological mechanism in ALS1 is related to ischemia. Several molecular studies of the SOD1 gene show that point mutations are the most frequent. The most common mutations in familial cases are p.A4V, p.I113Y, p.G37R, p.D90A and p.E100G, which account for more than 80% of cases, although intronic mutations have also been described as responsible for ALS1. Sporadic cases are explained by mutations in other genes such as SETX and C9orf72. ALS1 is a complex disease with genetic heterogeneity. On the other hand, familial and sporadic cases have a different etiology, which is explained by molecular heterogeneity and multiple pathogenic mechanisms that lead to ALS1; oxidative stress and ischemia are not the only cause. In Mexico, ALS molecular genetics studies are scarce. Clinical studies show an increase in cytokines such as adipsin in cerebrospinal fluid.}, }
@article {pmid32086712, year = {2020}, author = {Moore, S and Rabichow, BE and Sattler, R}, title = {The Hitchhiker's Guide to Nucleocytoplasmic Trafficking in Neurodegeneration.}, journal = {Neurochemical research}, volume = {45}, number = {6}, pages = {1306-1327}, doi = {10.1007/s11064-020-02989-1}, pmid = {32086712}, issn = {1573-6903}, mesh = {Active Transport, Cell Nucleus/*physiology ; Animals ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism ; Nuclear Pore Complex Proteins/*genetics/*metabolism ; Protein Transport/physiology ; }, abstract = {The widespread nature of nucleocytoplasmic trafficking defects and protein accumulation suggests distinct yet overlapping mechanisms in a variety of neurodegenerative diseases. Detailed understanding of the cellular pathways involved in nucleocytoplasmic transport and its dysregulation are essential for elucidating neurodegenerative pathogenesis and pinpointing potential areas for therapeutic intervention. The transport of cargos from the nucleus to the cytoplasm is generally regulated by the structure and function of the nuclear pore as well as the karyopherin α/β, importin, exportin, and mRNA export mechanisms. The disruption of these crucial transport mechanisms has been extensively described in the context of neurodegenerative diseases. One common theme in neurodegeneration is the cytoplasmic aggregation of proteins, including nuclear RNA binding proteins, repeat expansion associated gene products, and tau. These cytoplasmic aggregations are partly a consequence of failed nucleocytoplasmic transport machinery, but can also further disrupt transport, creating cyclical feed-forward mechanisms that exacerbate neurodegeneration. Here we describe the canonical mechanisms that regulate nucleocytoplasmic trafficking as well as how these mechanisms falter in neurodegenerative diseases.}, }
@article {pmid32085567, year = {2020}, author = {Guerreiro, S and Privat, AL and Bressac, L and Toulorge, D}, title = {CD38 in Neurodegeneration and Neuroinflammation.}, journal = {Cells}, volume = {9}, number = {2}, pages = {}, pmid = {32085567}, issn = {2073-4409}, mesh = {ADP-ribosyl Cyclase 1/genetics/*metabolism ; Aging/metabolism ; Animals ; Astrocytes/enzymology ; Brain/enzymology ; Humans ; Membrane Glycoproteins/genetics/*metabolism ; Mice ; Mice, Knockout ; Microglia/enzymology ; NAD/metabolism/pharmacology ; Nerve Degeneration/*enzymology/pathology ; Neurodegenerative Diseases/*enzymology/pathology ; Neurons/enzymology ; Neuroprotective Agents/metabolism/pharmacology ; }, abstract = {Neurodegenerative diseases are characterized by neuronal degeneration as well as neuroinflammation. While CD38 is strongly expressed in brain cells including neurons, astrocytes as well as microglial cells, the role played by CD38 in neurodegeneration and neuroinflammation remains elusive. Yet, CD38 expression increases as a consequence of aging which is otherwise the primary risk associated with neurodegenerative diseases, and several experimental data demonstrated that CD38 knockout mice are protected from neurodegenerative and neuroinflammatory insults. Moreover, nicotinamide adenine dinucleotide, whose levels are tightly controlled by CD38, is a recognized and potent neuroprotective agent, and NAD supplementation was found to be beneficial against neurodegenerative diseases. The aims of this review are to summarize the physiological role played by CD38 in the brain, present the arguments indicating the involvement of CD38 in neurodegeneration and neuroinflammation, and to discuss these observations in light of CD38 complex biology.}, }
@article {pmid32082970, year = {2020}, author = {Xiang, C and Zhang, Y and Guo, W and Liang, XJ}, title = {Biomimetic carbon nanotubes for neurological disease therapeutics as inherent medication.}, journal = {Acta pharmaceutica Sinica. B}, volume = {10}, number = {2}, pages = {239-248}, pmid = {32082970}, issn = {2211-3835}, abstract = {Nowadays, nanotechnology is revolutionizing the approaches to different fields from manufacture to health. Carbon nanotubes (CNTs) as promising candidates in nanomedicine have great potentials in developing novel entities for central nervous system pathologies, due to their excellent physicochemical properties and ability to interface with neurons and neuronal circuits. However, most of the studies mainly focused on the drug delivery and bioimaging applications of CNTs, while neglect their application prospects as therapeutic drugs themselves. At present, the relevant reviews are not available yet. Herein we summarized the latest advances on the biomedical and therapeutic applications of CNTs in vitro and in vivo for neurological diseases treatments as inherent therapeutic drugs. The biological mechanisms of CNTs-mediated bio-medical effects and potential toxicity of CNTs were also intensely discussed. It is expected that CNTs will exploit further neurological applications on disease therapy in the near future.}, }
@article {pmid32077821, year = {2020}, author = {Spasić, S and Nikolić-Kokić, A and Miletić, S and Oreščanin-Dušić, Z and Spasić, MB and Blagojević, D and Stević, Z}, title = {Edaravone May Prevent Ferroptosis in ALS.}, journal = {Current drug targets}, volume = {21}, number = {8}, pages = {776-780}, doi = {10.2174/1389450121666200220123305}, pmid = {32077821}, issn = {1873-5592}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Drug Therapy, Combination ; Edaravone/*pharmacology/therapeutic use ; Ferroptosis/*drug effects ; Humans ; Motor Neurons/drug effects/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.}, }
@article {pmid32076756, year = {2020}, author = {Brenner, D and Freischmidt, A and Ludolph, AC and Weishaupt, JH}, title = {[Gene-specific treatment approaches in amyotrophic lateral sclerosis in the present and future].}, journal = {Der Nervenarzt}, volume = {91}, number = {4}, pages = {287-293}, pmid = {32076756}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Animals ; C9orf72 Protein/genetics ; Disease Models, Animal ; *Genetic Therapy/trends ; Germany ; Mice ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is monogenic in up to 10% of cases. Various mutation types result in a loss of function, a gain of toxicity or a combination of both. Due to the continuous development of gene-specific approaches, the treatment of the various ALS forms is no longer a dream. Depending on the underlying mutation type and pathomechanism, different antisense oligonucleotide (ASO)-based or viral strategies are available. The SOD1 and C9ORF72 genes are the most frequently mutated ALS genes in Germany and their mutations most likely predominantly lead to a gain of toxicity. For both genes, specific ASOs were developed binding to the respective mRNAs and leading to their degradation and are now being tested in clinical trials after excellent efficacy in the related ALS mouse models, with promising interim results. For the sporadic form of ALS there are also gene-specific approaches that compensate pathomechanisms and are a promising therapeutic option. In this article, gene-specific therapeutic developments in ALS as well as possible pitfalls and challenges are discussed in detail.}, }
@article {pmid32066283, year = {2020}, author = {Baldacci, F and Mazzucchi, S and Della Vecchia, A and Giampietri, L and Giannini, N and Koronyo-Hamaoui, M and Ceravolo, R and Siciliano, G and Bonuccelli, U and Elahi, FM and Vergallo, A and Lista, S and Giorgi, FS and Hampel, H}, title = {The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.}, journal = {Expert review of molecular diagnostics}, volume = {20}, number = {4}, pages = {421-441}, pmid = {32066283}, issn = {1744-8352}, support = {K24 AG045333/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG056478/AG/NIA NIH HHS/United States ; R01 AG055865/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; }, mesh = {*Biomarkers ; Critical Pathways ; Disease Management ; Disease Susceptibility ; Humans ; Molecular Diagnostic Techniques/methods/standards ; Neurodegenerative Diseases/*diagnosis/*etiology/metabolism ; Organ Specificity ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {Introduction: The postmortem examination still represents the reference standard for detecting the pathological nature of chronic neurodegenerative diseases (NDD). This approach displays intrinsic conceptual limitations since NDD represent a dynamic spectrum of partially overlapping phenotypes, shared pathomechanistic alterations that often give rise to mixed pathologies.Areas covered: We scrutinized the international clinical diagnostic criteria of NDD and the literature to provide a roadmap toward a biomarker-based classification of the NDD spectrum. A few pathophysiological biomarkers have been established for NDD. These are time-consuming, invasive, and not suitable for preclinical detection. Candidate screening biomarkers are gaining momentum. Blood neurofilament light-chain represents a robust first-line tool to detect neurodegeneration tout court and serum progranulin helps detect genetic frontotemporal dementia. Ultrasensitive assays and retinal scans may identify Aβ pathology early, in blood and the eye, respectively. Ultrasound also represents a minimally invasive option to investigate the substantia nigra. Protein misfolding amplification assays may accurately detect α-synuclein in biofluids.Expert opinion: Data-driven strategies using quantitative rather than categorical variables may be more reliable for quantification of contributions from pathophysiological mechanisms and their spatial-temporal evolution. A systems biology approach is suitable to untangle the dynamics triggering loss of proteostasis, driving neurodegeneration and clinical evolution.}, }
@article {pmid32065105, year = {2020}, author = {Estrada, JA and Contreras, I}, title = {Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders.}, journal = {Current neuropharmacology}, volume = {18}, number = {8}, pages = {769-787}, pmid = {32065105}, issn = {1875-6190}, mesh = {Animals ; Brain/drug effects/metabolism/physiopathology ; Cannabinoid Receptor Agonists/pharmacology ; Cannabinoid Receptor Antagonists/pharmacology ; Cannabinoid Receptor Modulators/physiology ; Endocannabinoids ; Humans ; Inflammation/metabolism ; Mental Disorders/*drug therapy/physiopathology/*prevention &amp; control ; Nervous System Diseases/*drug therapy/physiopathology/*prevention &amp; control ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Receptors, Cannabinoid/*drug effects/*physiology ; }, abstract = {The endocannabinoid system participates in the regulation of CNS homeostasis and functions, including neurotransmission, cell signaling, inflammation and oxidative stress, as well as neuronal and glial cell proliferation, differentiation, migration and survival. Endocannabinoids are produced by multiple cell types within the CNS and their main receptors, CB1 and CB2, are expressed in both neurons and glia. Signaling through these receptors is implicated in the modulation of neuronal and glial alterations in neuroinflammatory, neurodegenerative and psychiatric conditions, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, epilepsy, anxiety and depression. The therapeutic potential of endocannabinoid receptors in neurological disease has been hindered by unwelcome side effects of current drugs used to target them; however, due to their extensive expression within the CNS and their involvement in physiological and pathological process in nervous tissue, they are attractive targets for drug development. The present review highlights the potential applications of the endocannabinoid system for the prevention and treatment of neurologic and psychiatric disorders.}, }
@article {pmid32062193, year = {2020}, author = {Chiò, A and Mazzini, L and Mora, G}, title = {Disease-modifying therapies in amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {167}, number = {}, pages = {107986}, doi = {10.1016/j.neuropharm.2020.107986}, pmid = {32062193}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*metabolism/*therapy ; Animals ; Clinical Trials as Topic/*methods ; Humans ; Motor Neurons/drug effects/metabolism ; Neuroprotective Agents/pharmacology/*therapeutic use ; Nitriles ; Pyridones/pharmacology/therapeutic use ; Riluzole/pharmacology/therapeutic use ; Stem Cell Transplantation/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of adult life, causing weakness and wasting of voluntary muscles, associated in about 50% of cases with a cognitive impairment. Pathologically, the disease is characterized by a degeneration of upper and lower motor neurons. A hallmark of the pathological process is the aggregation of the protein TDP43 in the cytoplasm of affected neurons detected in almost 97% of cases. About 15% of cases has a family history. Currently, only two drugs have been demonstrated to be effective in ALS, riluzole and edaravone, which show only modest effects on disease progression. The quest for disease-modifying therapies in ALS has several obstacles, the most important being the sub-optimal quality of the design of clinical trials, and the clinical and pathological heterogeneity of the disease. In this paper the pathological mechanisms relevant to ALS and current and future pharmacological and non-pharmacological trials, including gene and stem cells therapies, will be presented. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.}, }
@article {pmid32060097, year = {2020}, author = {Khristich, AN and Mirkin, SM}, title = {On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {13}, pages = {4134-4170}, pmid = {32060097}, issn = {1083-351X}, support = {R35 GM130322/GM/NIGMS NIH HHS/United States ; }, mesh = {Chromatin/genetics ; DNA Repair/genetics ; DNA Repeat Expansion/*genetics ; DNA Replication/genetics ; Genetic Diseases, Inborn/genetics/pathology ; Genome, Human/*genetics ; Genomic Instability/genetics ; Humans ; Microsatellite Repeats/*genetics ; *Nucleic Acid Conformation ; }, abstract = {Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?}, }
@article {pmid32052202, year = {2020}, author = {Patel, A and Lynch, F and Shepherd, SA}, title = {Newer Immunotherapies for the Treatment of Acute Neuromuscular Disease in the Critical Care Unit.}, journal = {Current treatment options in neurology}, volume = {22}, number = {3}, pages = {7}, pmid = {32052202}, issn = {1092-8480}, abstract = {OPINION STATEMENT: PURPOSE OF REVIEW: In this review, we discuss current treatment options for commonly encountered neuromuscular disorders in intensive care units. We will discuss epidemiology, pathophysiology, and acute and chronic treatment options for myasthenia gravis, Guillain-Barré syndrome, West Nile virus, Botulism, and amyotrophic lateral sclerosis.<br><br>RECENT FINDINGS: Eculizumab is the newest immunomodulator therapy approved by the Food and Drug Administration in treatment of myasthenia gravis, shown to improve long-term functional outcomes. Edaravone is the newest therapy in management of amyotrophic lateral sclerosis, shown to slow functional deterioration. Efgartigimod showed great promise in a phase 2 safety and efficacy trial in the treatment of stable generalized myasthenia gravis. Eculizumab was found to be safe in a small phase 2 trial for use in Guillain-Barr&#xe9; syndrome. Currently, therapies such as plasma exchange, intravenous immunoglobulins, and steroids remain the mainstay of treatment in the ICU for many neuromuscular disorders. While there are some newer immunotherapies available, few have been studied in the acute setting. However, with the advent of new immunotherapies and biologics, changes in these approaches may be on the horizon.}, }
@article {pmid32048886, year = {2021}, author = {Yao, RQ and Ren, C and Xia, ZF and Yao, YM}, title = {Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles.}, journal = {Autophagy}, volume = {17}, number = {2}, pages = {385-401}, pmid = {32048886}, issn = {1554-8635}, mesh = {Autophagy/*physiology ; Endoribonucleases/*metabolism ; Humans ; Inflammation/*metabolism ; Mitophagy/physiology ; Organelles/*metabolism ; Prohibitins ; Quality Control ; }, abstract = {The structural integrity and functional stability of organelles are prerequisites for the viability and responsiveness of cells. Dysfunction of multiple organelles is critically involved in the pathogenesis and progression of various diseases, such as chronic obstructive pulmonary disease, cardiovascular diseases, infection, and neurodegenerative diseases. In fact, those organelles synchronously present with evident structural derangement and aberrant function under exposure to different stimuli, which might accelerate the corruption of cells. Therefore, the quality control of multiple organelles is of great importance in maintaining the survival and function of cells and could be a potential therapeutic target for human diseases. Organelle-specific autophagy is one of the major subtypes of autophagy, selectively targeting different organelles for quality control. This type of autophagy includes mitophagy, pexophagy, reticulophagy (endoplasmic reticulum), ribophagy, lysophagy, and nucleophagy. These kinds of organelle-specific autophagy are reported to be beneficial for inflammatory disorders by eliminating damaged organelles and maintaining homeostasis. In this review, we summarized the recent findings and mechanisms covering different kinds of organelle-specific autophagy, as well as their involvement in various diseases, aiming to arouse concern about the significance of the quality control of multiple organelles in the treatment of inflammatory diseases.Abbreviations: ABCD3: ATP binding cassette subfamily D member 3; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATF: activating transcription factor; ATG: autophagy related; ATM: ATM serine/threonine kinase; BCL2: BCL2 apoptosis regulator; BCL2L11/BIM: BCL2 like 11; BCL2L13: BCL2 like 13; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CANX: calnexin; CAT: catalase; CCPG1: cell cycle progression 1; CHDH: choline dehydrogenase; COPD: chronic obstructive pulmonary disease; CSE: cigarette smoke exposure; CTSD: cathepsin D; DDIT3/CHOP: DNA-damage inducible transcript 3; DISC1: DISC1 scaffold protein; DNM1L/DRP1: dynamin 1 like; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 alpha kinase 3; EMD: emerin; EPAS1/HIF-2α: endothelial PAS domain protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FBXO27: F-box protein 27; FKBP8: FKBP prolyl isomerase 8; FTD: frontotemporal dementia; FUNDC1: FUN14 domain containing 1; G3BP1: G3BP stress granule assembly factor 1; GBA: glucocerebrosidase beta; HIF1A/HIF1: hypoxia inducible factor 1 subunit alpha; IMM: inner mitochondrial membrane; LCLAT1/ALCAT1: lysocardiolipin acyltransferase 1; LGALS3/Gal3: galectin 3; LIR: LC3-interacting region; LMNA: lamin A/C; LMNB1: lamin B1; LPS: lipopolysaccharide; MAPK8/JNK: mitogen-activated protein kinase 8; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MOD: multiple organelles dysfunction; MTPAP: mitochondrial poly(A) polymerase; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; NLRP3: NLR family pyrin domain containing 3; NUFIP1: nuclear FMR1 interacting protein 1; OMM: outer mitochondrial membrane; OPTN: optineurin; PD: Parkinson disease; PARL: presenilin associated rhomboid like; PEX3: peroxisomal biogenesis factor 3; PGAM5: PGAM family member 5; PHB2: prohibitin 2; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RETREG1/FAM134B: reticulophagy regulator 1; RHOT1/MIRO1: ras homolog family member T1; RIPK3/RIP3: receptor interacting serine/threonine kinase 3; ROS: reactive oxygen species; RTN3: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SESN2: sestrin2; SIAH1: siah E3 ubiquitin protein ligase 1; SNCA: synuclein alpha; SNCAIP: synuclein alpha interacting protein; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TICAM1/TRIF: toll-like receptor adaptor molecule 1; TIMM23: translocase of inner mitochondrial membrane 23; TNKS: tankyrase; TOMM: translocase of the outer mitochondrial membrane; TRIM: tripartite motif containing; UCP2: uncoupling protein 2; ULK1: unc-51 like autophagy activating kinase; UPR: unfolded protein response; USP10: ubiquitin specific peptidase 10; VCP/p97: valosin containing protein; VDAC: voltage dependent anion channels; XIAP: X-linked inhibitor of apoptosis; ZNHIT3: zinc finger HIT-type containing 3.}, }
@article {pmid32046139, year = {2020}, author = {Novellino, F and Saccà, V and Donato, A and Zaffino, P and Spadea, MF and Vismara, M and Arcidiacono, B and Malara, N and Presta, I and Donato, G}, title = {Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {3}, pages = {}, pmid = {32046139}, issn = {1422-0067}, mesh = {Animals ; Humans ; *Immunity, Innate ; Mental Disorders/*immunology ; Neurodegenerative Diseases/*immunology ; }, abstract = {The intricate relationships between innate immunity and brain diseases raise increased interest across the wide spectrum of neurodegenerative and neuropsychiatric disorders. Barriers, such as the blood-brain barrier, and innate immunity cells such as microglia, astrocytes, macrophages, and mast cells are involved in triggering disease events in these groups, through the action of many different cytokines. Chronic inflammation can lead to dysfunctions in large-scale brain networks. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are associated with a substrate of dysregulated immune responses that impair the central nervous system balance. Recent evidence suggests that similar phenomena are involved in psychiatric diseases, such as depression, schizophrenia, autism spectrum disorders, and post-traumatic stress disorder. The present review summarizes and discusses the main evidence linking the innate immunological response in neurodegenerative and psychiatric diseases, thus providing insights into how the responses of innate immunity represent a common denominator between diseases belonging to the neurological and psychiatric sphere. Improved knowledge of such immunological aspects could provide the framework for the future development of new diagnostic and therapeutic approaches.}, }
@article {pmid32046060, year = {2020}, author = {Vicencio, E and Beltrán, S and Labrador, L and Manque, P and Nassif, M and Woehlbier, U}, title = {Implications of Selective Autophagy Dysfunction for ALS Pathology.}, journal = {Cells}, volume = {9}, number = {2}, pages = {}, pmid = {32046060}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology/therapy ; Animals ; *Autophagy ; Humans ; Models, Biological ; Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.}, }
@article {pmid32043626, year = {2020}, author = {Wobst, HJ and Mack, KL and Brown, DG and Brandon, NJ and Shorter, J}, title = {The clinical trial landscape in amyotrophic lateral sclerosis-Past, present, and future.}, journal = {Medicinal research reviews}, volume = {40}, number = {4}, pages = {1352-1384}, pmid = {32043626}, issn = {1098-1128}, support = {R21 NS090205/NS/NINDS NIH HHS/United States ; R21 AG061784/AG/NIA NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R21 NS102687/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Anti-Inflammatory Agents/chemistry/pharmacology/therapeutic use ; Autophagy/drug effects ; *Clinical Trials as Topic ; Drug Approval ; Humans ; Immunologic Factors/chemistry/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult-onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small-molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.}, }
@article {pmid32034787, year = {2020}, author = {McFarland, DJ}, title = {Brain-computer interfaces for amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {61}, number = {6}, pages = {702-707}, pmid = {32034787}, issn = {1097-4598}, support = {P41 EB018783/EB/NIBIB NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*rehabilitation ; Brain/*physiology ; Brain-Computer Interfaces/*trends ; Electroencephalography/methods ; Event-Related Potentials, P300/physiology ; Humans ; }, abstract = {A brain-computer interface (BCI) is a device that detects signals from the brain and transforms them into useful commands. Researchers have developed BCIs that utilize different kinds of brain signals. These different BCI systems have differing characteristics, such as the amount of training required and the degree to which they are or are not invasive. Much of the research on BCIs to date has involved healthy individuals and evaluation of classification algorithms. Some BCIs have been shown to have potential benefit for users with minimal muscular function as a result of amyotrophic lateral sclerosis. However, there are still several challenges that need to be successfully addressed before BCIs can be clinically useful.}, }
@article {pmid32031423, year = {2020}, author = {Huynh, W and Ahmed, R and Mahoney, CJ and Nguyen, C and Tu, S and Caga, J and Loh, P and Lin, CS and Kiernan, MC}, title = {The impact of cognitive and behavioral impairment in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {3}, pages = {281-293}, doi = {10.1080/14737175.2020.1727740}, pmid = {32031423}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; *Behavioral Symptoms/diagnosis/etiology/physiopathology ; *Cognitive Dysfunction/diagnosis/etiology/physiopathology ; *Frontotemporal Dementia/diagnosis/etiology/physiopathology ; Humans ; }, abstract = {Introduction: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%.Areas covered: The present review explores the current understanding of cognitive and behavioral changes in ALS with a particular emphasis on its implications on prognosis and survival.Expert commentary: Further longitudinal studies are needed to clarify the evolution of cognitive impairment in ALS and how this may ultimately influence survival. Improving understanding of cognitive changes has important implications toward the capacity of patients in making critical medical decisions. There is a need to develop a universally accepted and validated cognitive assessment tool to be administered in a multidisciplinary clinic that is efficient and sensitive, as well as being integrated into the design and analysis of future ALS drug trials. In addition, revision of the ALS diagnostic criteria is critically needed that should accommodate cognitive and behavioral symptoms in addition to motor manifestations.}, }
@article {pmid32030995, year = {2021}, author = {Yeung, AWK and Tzvetkov, NT and Georgieva, MG and Ognyanov, IV and Kordos, K and Jóźwik, A and Kühl, T and Perry, G and Petralia, MC and Mazzon, E and Atanasov, AG}, title = {Reactive Oxygen Species and Their Impact in Neurodegenerative Diseases: Literature Landscape Analysis.}, journal = {Antioxidants &amp; redox signaling}, volume = {34}, number = {5}, pages = {402-420}, doi = {10.1089/ars.2019.7952}, pmid = {32030995}, issn = {1557-7716}, mesh = {Animals ; *Disease Susceptibility ; Humans ; Medicine in Literature ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {Significance: The excessive production of reactive oxygen species (ROS) has been linked to neurodegenerative diseases (NDs), and, therefore, many scientific works were published on the impact of ROS on the development of prevalent NDs, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Since quantitative and qualitative bibliometric analyses in this research area have not yet been done, the aim of this work is to explore the scientific literature implying ROS in NDs and to identify the major contributors, mainstream research themes, and topics on the rise. Recent Advances: Overall, 22,885 publications were identified and analyzed within the Web of Science (WoS) Core Collection electronic database (Clarivate Analytics, Philadelphia, PA). Most of the manuscripts were published in the 21st century. The publications were mainly related to the WoS categories Neurosciences and Biochemistry molecular biology. The United States is the major contributor, harboring the most productive authors and institutions. China, South Korea, and India have emerged as upcoming major contributors in the 2010s. Two most productive journals were Journal of Neurochemistry and Free Radical Biology and Medicine. Critical Issues: AD, PD, and amyotrophic lateral sclerosis were much more investigated than multiple sclerosis and Huntington's disease. Vitamin E and curcumin were frequently mentioned as potential antioxidant therapeutics, but their efficacy in treating NDs requires more clinical studies, since the existing evidence was mainly from in vitro experiments and in vivo animal studies. Future Directions: Mitochondrial dysfunction, autophagy, and nuclear factor erythroid 2-related factor 2 were among the author keywords with rising prevalence. Further research in these directions should advance our understanding of the mechanism and treatment of NDs. Antioxid. Redox Signal. 34, 402-420.}, }
@article {pmid32029967, year = {2019}, author = {Batra, G and Jain, M and Singh, RS and Sharma, AR and Singh, A and Prakash, A and Medhi, B}, title = {Novel therapeutic targets for amyotrophic lateral sclerosis.}, journal = {Indian journal of pharmacology}, volume = {51}, number = {6}, pages = {418-425}, pmid = {32029967}, issn = {1998-3751}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Axons/metabolism ; Glutamic Acid/metabolism ; Humans ; Mitochondria/metabolism ; Mutation ; Neuromuscular Junction/metabolism ; Neuroprotective Agents/therapeutic use ; Oxidative Stress ; Protein Aggregates ; RNA/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an untreatable and fatal neurodegenerative disease that is identified by the loss of motor neurons in the spinal cord, brain stem, and motor cortex which theatrically reduces life expectancy. Although the primary cause of ALS remains unclear, its heterogeneity put forward for consideration of association with various factors, including endogenous and/or environmental ones, which may be involved in progressive motor neuron stress that causes activation of different cell death pathways. It is hypothesized that this disease is triggered by factors related to genetic, environmental, and age-dependent risk. In spite of large neurobiological, molecular and genetic research, at the beginning of the 21[st] century, ALS still remains one of the most devastating neurodegenerative diseases because of the lack of effective therapeutic targets. It is a challenge for the clinical and scientific community. A better understanding of the etiology of ALS is necessary to develop specific targets of this progressive neurodegenerative disease. This review states about the current knowledge of targets in ALS research. This review provides an overview of the contribution of different targets like mitochondrial dysfunction, glutamate transport and excitotoxicity, protein accumulation, Oxidative stress, neuromuscular junction, microglia, and other molecular targets in the pathogenesis of ALS.}, }
@article {pmid32012713, year = {2020}, author = {Hindeya Gebreyesus, H and Gebrehiwot Gebremichael, T}, title = {The Potential Role of Astrocytes in Parkinson's Disease (PD).}, journal = {Medical sciences (Basel, Switzerland)}, volume = {8}, number = {1}, pages = {}, pmid = {32012713}, issn = {2076-3271}, abstract = {Astrocytes are multi-functional cells, now recognized as critical participants in many brain functions. They play a critical physiological role in the clearance of neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA), and in the regulation of K[+] from the space of synaptic clefts. Astrocytes also express the excitatory amino acid transporters (EAATs) and aquaporin-4 (AQP4) water channel, which are involved in both physiological functions and neurodegenerative diseases (ND). Some of the ND are the Alzheimer's (AD), Huntington's (HD), Parkinson's diseases (PD), Cerebral edema, amyotrophic lateral sclerosis (ALS), and epilepsy pathological conditions in specific regions of the CNS. Parkinson's disease is the second most common age-related neurodegenerative disorder, characterized by degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc). These project to the striatum, forming an important pathway within the basal ganglia. Mostly, PD has no clear etiology, and the mechanism of dopaminergic (DA) neuron loss is not well illustrated. The results of various studies suggest that astrocytes are involved in the pathophysiology of PD. Evidence has shown that the down-regulation of EAAT-2/GLT-1 and AQP4 expression is associated with PD pathogenesis. However, controversial results were reported in different experimental studies about the expression and function of EAAT-2/GLT-1 and AQP4, as well as their colocalization in different brain regions, and their involvement in PD development. Therefore, under neurological disorders, Parkinson's disease is related to the genetic and phenotypic change of astrocytes' biology. In this review, the authors summarized recent their research findings, which revealed the involvement of EAAT-2/GLT-1 and AQP4 expression, the physical interaction between EAAT-2/GLT-1 and AQP4 in astrocyte function, and their potential role in the development of PD in SNpc and Subthalamic nucleus (STN) of the basal ganglia nuclei.}, }
@article {pmid32010708, year = {2019}, author = {Thelen, MP and Kye, MJ}, title = {The Role of RNA Binding Proteins for Local mRNA Translation: Implications in Neurological Disorders.}, journal = {Frontiers in molecular biosciences}, volume = {6}, number = {}, pages = {161}, pmid = {32010708}, issn = {2296-889X}, abstract = {As neurons are one of the most highly polarized cells in our body, they require sophisticated cellular mechanisms to maintain protein homeostasis in their subcellular compartments such as axons and dendrites. When neuronal protein homeostasis is disturbed due to genetic mutations or deletions, this often results in degeneration of neurons leading to devastating outcome such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and fragile X syndrome (FXS). Ribonucleoprotein (RNP) complexes are macromolecular complexes composed of RNA binding proteins (RBPs) and their target RNAs. RBPs contain RNA binding domains and bind to RNA molecules via specific sequence motifs. RNP complexes have various functions in gene expression including messenger RNA (mRNA) trafficking, RNA processing and silencing. In neurons, RBPs deliver specific sets of mRNAs to subcellular compartments such as axons and dendrites to be locally translated. Mutations or deletions in genes coding for RNPs have been reported as causes for neurological disorders such as SMA, ALS, and FXS. As RBPs determine axonal or dendritic mRNA repertoires as well as proteomes by trafficking selective mRNAs and regulating local protein synthesis, they play a crucial role for neuronal function. In this review, we summarize the role of well-known RBPs, SMN, TDP-43, FUS, and FMRP, and review their function for local protein synthesis in neurons. Furthermore, we discuss their pathological contribution to the neurological disorders.}, }
@article {pmid32010340, year = {2020}, author = {Kosuge, Y}, title = {Neuroprotective mechanisms of S-allyl-L-cysteine in neurological disease.}, journal = {Experimental and therapeutic medicine}, volume = {19}, number = {2}, pages = {1565-1569}, pmid = {32010340}, issn = {1792-0981}, abstract = {S-allyl-L-cysteine (SAC) is a sulfur-containing amino acid present in garlic and exhibits a wide range of biological activities such as antioxidant, anti-inflammatory, and anticancer agent. An earlier study demonstrated that SAC ameliorates oxidative damage in a model of experimental stroke. However, the antioxidant property of SAC does not suffice to explain its beneficial effects in terms of the underlying mechanisms. Endoplasmic reticulum (ER) stress and ER stress-induced cell death have been shown to be involved in various neurological diseases such as brain ischemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. We have previously demonstrated that SAC exerts significant protective effects against ER stress-induced neurotoxicity in cultured rat hippocampal neurons and organotypic hippocampal slice cultures. Recently, we demonstrated that these results are due to the direct suppression of calpain activity via the binding of SAC to this enzyme's Ca[2+]-binding domain. We also found that the protective effects of the side-chain-modified SAC derivatives, S-ethyl-L-cysteine (SEC) and S-propyl-L-cysteine (SPC), against ER stress-induced neurotoxicity were more potent than those of SAC in cultured rat hippocampal neurons. In addition, SAC, SEC and SPC have been shown to decrease the production of amyloid-β peptide in the brains of mice with D-galactose-induced aging. These three hydrophilic cysteine-containing compounds have also been shown to exert neuroprotective effects against dopaminergic neuron injury in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this review, we aim to provide a current overview of the protective actions of SAC and the SAC-related compounds, SEC and SPC, in neurodegenerative disease and discuss the promise of SAC as a prototype for developing novel therapeutic drugs for neurological diseases.}, }
@article {pmid32006533, year = {2020}, author = {Pennuto, M and Pandey, UB and Polanco, MJ}, title = {Insulin-like growth factor 1 signaling in motor neuron and polyglutamine diseases: From molecular pathogenesis to therapeutic perspectives.}, journal = {Frontiers in neuroendocrinology}, volume = {57}, number = {}, pages = {100821}, doi = {10.1016/j.yfrne.2020.100821}, pmid = {32006533}, issn = {1095-6808}, support = {R21 NS111768/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Glutamine/genetics ; Humans ; Insulin-Like Growth Factor I/genetics/*physiology ; MAP Kinase Signaling System/physiology ; Motor Neurons/*metabolism ; Muscular Atrophy, Spinal/physiopathology ; Neurodegenerative Diseases/drug therapy/*physiopathology ; *Peptides ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/*physiology ; ras Proteins/metabolism ; }, abstract = {The pleiotropic peptide insulin-like growth factor 1 (IGF-I) regulates human body homeostasis and cell growth. IGF-I activates two major signaling pathways, namely phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt) and Ras/extracellular signal-regulated kinase (ERK), which contribute to brain development, metabolism and function as well as to neuronal maintenance and survival. In this review, we discuss the general and tissue-specific effects of the IGF-I pathways. In addition, we present a comprehensive overview examining the role of IGF-I in neurodegenerative diseases, such as spinal and muscular atrophy, amyotrophic lateral sclerosis, and polyglutamine diseases. In each disease, we analyze the disturbances of the IGF-I pathway, the modification of the disease protein by IGF-I signaling, and the therapeutic strategies based on the use of IGF-I developed to date. Lastly, we highlight present and future considerations in the use of IGF-I for the treatment of these disorders.}, }
@article {pmid31998750, year = {2019}, author = {Loganathan, S and Lehmkuhl, EM and Eck, RJ and Zarnescu, DC}, title = {To Be or Not To Be…Toxic-Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?.}, journal = {Frontiers in molecular biosciences}, volume = {6}, number = {}, pages = {154}, pmid = {31998750}, issn = {2296-889X}, abstract = {TAR DNA binding protein (TDP-43) is a nucleic acid binding protein associated with insoluble cytoplasmic aggregates in several neurodegenerative disorders, including 97% of the ALS cases. In healthy individuals, TDP-43 is primarily localized to the nucleus; it can shuttle between the nucleus and the cytoplasm, and is involved in several aspects of RNA processing including transcription, splicing, RNA stability, transport, localization, stress granule (SG) formation, and translation. Upon stress, TDP-43 aggregates in the cytoplasm and associates with several types of RNA and protein assemblies, resulting in nuclear depletion of TDP-43. Under conditions of prolonged stress, cytoplasmic TDP-43 undergoes liquid-liquid phase separation (LLPS) and becomes less mobile. Evidence exists to support a scenario in which insoluble TDP-43 complexes sequester RNA and/or proteins causing disturbances in both ribostasis and proteostasis, which in turn contribute to neurodegeneration. However, the relationship between RNA binding and TDP-43 toxicity remains unclear. Recent studies provide conflicting views on the role of RNA in TDP-43 toxicity, with some finding RNA as a toxic factor whereby RNA binding contributes to TDP-43 toxicity, while others find RNA to be a protective factor that inhibits TDP-43 aggregation. Here we review and discuss these recent reports, which ultimately highlight the importance of understanding the heterogeneity of TDP-43 assemblies and collectively point to solubilizing TDP-43 as a potential therapeutic strategy.}, }
@article {pmid31993129, year = {2020}, author = {Caplliure-Llopis, J and Peralta-Chamba, T and Carrera-Juliá, S and Cuerda-Ballester, M and Drehmer-Rieger, E and López-Rodriguez, MM and de la Rubia Ortí, JE}, title = {Therapeutic alternative of the ketogenic Mediterranean diet to improve mitochondrial activity in Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Food science &amp; nutrition}, volume = {8}, number = {1}, pages = {23-35}, pmid = {31993129}, issn = {2048-7177}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease which is pathogenically based on the mitochondrial alteration of motor neurons, causing progressive neuron death. While ALS is characterized by enormous oxidative stress, the Mediterranean diet has been seen to have high antioxidant power. Therefore, the aim of this study is to determine how the Mediterranean diet can improve mitochondrial activity, establishing the specific nutrients and, in addition, observing the pathogenic mechanisms related to the disease that would achieve this improvement. To this end, a comprehensive review of the literature was performed using PubMed. KBs have been observed to have a neuroprotective effect to improve energy balance, increasing survival and the number of motor neurons. This ketogenesis can be achieved after following a Mediterranean diet which is associated with great benefits in other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS. These benefits are due to the high antioxidant power especially based on polyphenols contained mainly in olive oil, wine, nuts, or berries. In short, KBs could be considered as a promising option to treat ALS, representing an alternative source to glucose in motor neurons by providing neuroprotection. In addition, treatment results can be improved as ketogenesis can be achieved (increase in KBs) by following a Mediterranean diet, thanks to the high antioxidant properties which, at the same time, would improve the high oxidative stress that characterizes the disease.}, }
@article {pmid31986926, year = {2020}, author = {Zilocchi, M and Moutaoufik, MT and Jessulat, M and Phanse, S and Aly, KA and Babu, M}, title = {Misconnecting the dots: altered mitochondrial protein-protein interactions and their role in neurodegenerative disorders.}, journal = {Expert review of proteomics}, volume = {17}, number = {2}, pages = {119-136}, doi = {10.1080/14789450.2020.1723419}, pmid = {31986926}, issn = {1744-8387}, support = {R01 GM106019/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mitochondrial Proteins/chemistry/*metabolism ; Neurodegenerative Diseases/*metabolism ; Protein Interaction Mapping/*methods ; *Protein Interaction Maps ; Proteomics/*methods ; }, abstract = {Introduction: Mitochondria (mt) are protein-protein interaction (PPI) hubs in the cell where mt-localized and associated proteins interact in a fashion critical for cell fitness. Altered mtPPIs are linked to neurodegenerative disorders (NDs) and drivers of pathological associations to mediate ND progression. Mapping altered mtPPIs will reveal how mt dysfunction is linked to NDs.Areas covered: This review discusses how database sources reflect on the number of mt protein or interaction predictions, and serves as an update on mtPPIs in mt dynamics and homeostasis. Emphasis is given to mRNA expression profiles for mt proteins in human tissues, cellular models relevant to NDs, and altered mtPPIs in NDs such as Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD).Expert opinion: We highlight the scarcity of biomarkers to improve diagnostic accuracy and tracking of ND progression, obstacles in recapitulating NDs using human cellular models to underpin the pathophysiological mechanisms of disease, and the shortage of mt protein interactome reference database(s) of neuronal cells. These bottlenecks are addressed by improvements in induced pluripotent stem cell creation and culturing, patient-derived 3D brain organoids to recapitulate structural arrangements of the brain, and cell sorting to elucidate mt proteome disparities between cell types.}, }
@article {pmid31984859, year = {2020}, author = {Varghese, M}, title = {Prehospital trauma care evolution, practice and controversies: need for a review.}, journal = {International journal of injury control and safety promotion}, volume = {27}, number = {1}, pages = {69-82}, doi = {10.1080/17457300.2019.1708409}, pmid = {31984859}, issn = {1745-7319}, mesh = {Accidents/*mortality ; Adolescent ; Emergency Medical Services/*organization &amp; administration ; Female ; Humans ; }, abstract = {Modern medicine and surgery is historically very recent, and most interventions that are so commonly done in a hospital now are only 60 to 70 years old. Understanding of emergency care of the injured is more recent; however, for the sake of temporal convenience trauma care has become compartmentalized into phases: first aid, bystander care, prehospital care, emergency care, definitive levels of care and rehabilitation. The injured patient's body physiology is changing continuously from the time of the impact at the injury site.. The outcome of trauma is dependent not only on what is done in the prehospital phase but also on hospital care and rehabilitation. Our understanding of the changes and the response to interventions in a trauma patient has been evolving over the years. This paper discusses the need to review recent advances in our understanding of the care process and how we need to improve it and how there is a pressing need to generate valid evidence on what we do in emergency care.}, }
@article {pmid31983009, year = {2020}, author = {Planas-Fontánez, TM and Dreyfus, CF and Saitta, KS}, title = {Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors.}, journal = {Neurochemical research}, volume = {45}, number = {3}, pages = {541-550}, pmid = {31983009}, issn = {1573-6903}, support = {R01 NS036647/NS/NINDS NIH HHS/United States ; R56 NS036647/NS/NINDS NIH HHS/United States ; T32 ES007148/ES/NIEHS NIH HHS/United States ; RG 4257B4/1//National Multiple Sclerosis Society/ ; }, mesh = {Animals ; Astrocytes/*metabolism ; Humans ; Neurodegenerative Diseases/metabolism/pathology/*therapy ; Receptors, Metabotropic Glutamate/*metabolism ; }, abstract = {Astrocytes are well known to play critical roles in the development and maintenance of the central nervous system (CNS). Moreover, recent reports indicate that these cells are heterogeneous with respect to the molecules they express and the functions they exhibit in the quiescent or activated state. Because astrocytes also contribute to pathology, promising new results raise the possibility of manipulating specific astroglial populations for therapeutic roles. In this mini-review, we highlight the function of metabotropic glutamate receptors (mGluRs), in particular mGluR3 and mGluR5, in reactive astrocytes and relate these to three degenerative CNS diseases: multiple sclerosis, Alzheimer's disease and Amyotrophic Lateral Sclerosis. Previous studies demonstrate that effects of these receptors may be beneficial, but this varies depending on the subtype of receptor, the state of the astrocytes, and the specific disease to which they are exposed. Elucidating the role of mGluRs on astrocytes at specific times during development and disease will provide novel insights in understanding how to best use these to serve as therapeutic targets.}, }
@article {pmid31982574, year = {2020}, author = {Teixeira, MI and Lopes, CM and Amaral, MH and Costa, PC}, title = {Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseases.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {149}, number = {}, pages = {192-217}, doi = {10.1016/j.ejpb.2020.01.005}, pmid = {31982574}, issn = {1873-3441}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism/physiopathology ; Drug Carriers/chemistry ; *Drug Delivery Systems ; Humans ; Lipids/chemistry ; *Nanoparticles ; Nanotechnology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Tissue Distribution ; }, abstract = {The central nervous system (CNS) is vulnerable to pathologic processes that lead to the development of neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's diseases, Multiple sclerosis or Amyotrophic lateral sclerosis. These are chronic and progressive pathologies characterized by the loss of neurons and the formation of misfolded proteins. Additionally, neurodegenerative diseases are accompanied by a structural and functional dysfunction of the blood-brain barrier (BBB). Although serving as a protection for the CNS, the existence of physiological barriers, especially the BBB, limits the access of several therapeutic agents to the brain, constituting a major hindrance in neurotherapeutics advancement. In this regard, nanotechnology-based approaches have arisen as a promising strategy to not only improve drug targeting to the brain, but also to increase bioavailability. Lipid nanocarriers such as liposomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), microemulsions and nanoemulsions, have already proven their potential for enhancing brain transport, crossing more easily into the CNS and allowing the administration of medicines that could benefit the treatment of neurological pathologies. Given the socioeconomic impact of such conditions and the advent of nanotechnology that inevitably leads to more effective and superior therapeutics for their management, it is imperative to constantly update on the current knowledge of these topics. Herein, we provide insight on the BBB and the pathophysiology of the main neurodegenerative disorders. Moreover, this review seeks to highlight the several approaches that can be used to improve the delivery of therapeutic agents to the CNS, while also offering an extensive overview of the latest efforts regarding the use of lipid-based nanocarriers in the management of neurodegenerative diseases.}, }
@article {pmid31980177, year = {2020}, author = {Asamitsu, S and Yabuki, Y and Ikenoshita, S and Wada, T and Shioda, N}, title = {Pharmacological prospects of G-quadruplexes for neurological diseases using porphyrins.}, journal = {Biochemical and biophysical research communications}, volume = {531}, number = {1}, pages = {51-55}, doi = {10.1016/j.bbrc.2020.01.054}, pmid = {31980177}, issn = {1090-2104}, mesh = {Animals ; Drug Discovery/methods ; G-Quadruplexes/*drug effects ; Humans ; Mental Retardation, X-Linked/*drug therapy/genetics ; Molecular Targeted Therapy/methods ; Porphyrins/chemistry/*pharmacology ; alpha-Thalassemia/*drug therapy/genetics ; }, abstract = {Genomic regions with guanine (G)-rich sequences make non-Watson-Crick base pairs, which result in the formation of unique nucleic acid structures called G-quadruplexes (G4s) in cells. Studies have suggested that abnormal G4s are involved in neurological diseases. For example, the formation of G4s caused by expansion of G-rich sequences is implicated in C9orf72-mediated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), and fragile X-related tremor/ataxia syndrome (FXTAS). In addition, the disruption and/or mutation of G4 binding proteins (G4BPs), such as heterogeneous nuclear ribonucleoproteins (hnRNPs) and DNA/RNA helicases, is related to neurological diseases. For instance, mutations in a G4BP called ATRX lead to a neurodevelopmental disorder, ATR-X syndrome, which is associated with intellectual disability. We found that porphyrins are potential candidate drugs for treating ATR-X syndrome through their G4 binding ability. Importantly, intracellular porphyrins are produced from 5-aminolevulinic acid (5-ALA) in vivo. Oral administration of 5-ALA improved cognitive dysfunction in an ATR-X syndrome model mouse, and language ability in an ATR-X syndrome patient. In this review, we suggest a novel therapeutic strategy targeting G4s using porphyrins in neurological diseases.}, }
@article {pmid31975553, year = {2020}, author = {Farina, E and Borgnis, F and Pozzo, T}, title = {Mirror neurons and their relationship with neurodegenerative disorders.}, journal = {Journal of neuroscience research}, volume = {98}, number = {6}, pages = {1070-1094}, doi = {10.1002/jnr.24579}, pmid = {31975553}, issn = {1097-4547}, mesh = {Animals ; Brain/*pathology ; Humans ; Mirror Neurons/*pathology ; Neurodegenerative Diseases/*pathology ; }, abstract = {The finding of mirror neurons (MNs) has provided a biological substrate to a new concept of cognition, relating data on actions and perceptions not only to integrate perception in action planning and execution but also as a neural mechanism supporting a wide range of cognitive functions. Here we first summarize data on MN localization and role in primates, then we report findings in normal human subjects: functional magnetic resonance imaging and neurophysiological studies sustain that MNs have a role in motor learning and recognizing actions and intentions of others, and they also support an embodied view of language, empathy, and memory. Then, we detail the results of literature searching on MNs and embodied cognition in Parkinson's disease (PD), frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS), and in mild cognitive impairment (MCI)/Alzheimer's disease (AD). In PD the network of MN could be altered, but its hyperactivation might support motor and cognitive performances at least in early stages. In the ALS/FTD continuum, preliminary evidence points out to an involvement of the MN network, which could explain language and inter-subjectivity deficits shown in patients affected by these clinical entities. In the MCI/AD spectrum, a few recent studies suggest a possible progressive involvement from posterior to anterior areas of the MN network, with the brain putting in place compensatory mechanisms in early stages. Reinterpreting neurodegenerative diseases at the light of the new views about brain organization stemming from the discovery of MN could help to better comprehend clinical manifestations and open new pathways to rehabilitation.}, }
@article {pmid31974302, year = {2020}, author = {Baker, MR and Williams, TL}, title = {Twitchy about fasciculation.}, journal = {Practical neurology}, volume = {20}, number = {3}, pages = {260-261}, doi = {10.1136/practneurol-2019-002469}, pmid = {31974302}, issn = {1474-7766}, mesh = {Fasciculation/*classification/diagnosis ; Humans ; Neurology/*classification ; Teaching Rounds/*classification ; *Terminology as Topic ; }, }
@article {pmid31969897, year = {2019}, author = {Terry, DM and Devine, SE}, title = {Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders.}, journal = {Frontiers in genetics}, volume = {10}, number = {}, pages = {1244}, pmid = {31969897}, issn = {1664-8021}, support = {R01 HG002898/HG/NHGRI NIH HHS/United States ; }, abstract = {Retrotransposable elements (RTEs) have actively multiplied over the past 80 million years of primate evolution, and as a consequence, such elements collectively occupy ∼ 40% of the human genome. As RTE activity can have detrimental effects on the human genome and transcriptome, silencing mechanisms have evolved to restrict retrotransposition. The brain is the only known somatic tissue where RTEs are de-repressed throughout the life of a healthy human and each neuron in specific brain regions accumulates up to ∼13.7 new somatic L1 insertions (and perhaps more). However, even higher levels of somatic RTE expression and retrotransposition have been found in a number of human neurological disorders. This review is focused on how RTE expression and retrotransposition in neuronal tissues might contribute to the initiation and progression of these disorders. These disorders are discussed in three broad and sometimes overlapping categories: 1) disorders such as Rett syndrome, Aicardi-Goutières syndrome, and ataxia-telangiectasia, where expression/retrotransposition is increased due to mutations in genes that play a role in regulating RTEs in healthy cells, 2) disorders such as autism spectrum disorder, schizophrenia, and substance abuse disorders, which are thought to be caused by a combination of genetic and environmental stress factors, and 3) disorders associated with age, such as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and normal aging, where there is a time-dependent accumulation of neurological degeneration, RTE copy number, and phenotypes. Research has revealed increased levels of RTE activity in many neurological disorders, but in most cases, a clear causal link between RTE activity and these disorders has not been well established. At the same time, even if increased RTE activity is a passenger and not a driver of disease, a detrimental effect is more likely than a beneficial one. Thus, a better understanding of the role of RTEs in neuronal tissues likely is an important part of understanding, preventing, and treating these disorders.}, }
@article {pmid31963681, year = {2020}, author = {Filipi, T and Hermanova, Z and Tureckova, J and Vanatko, O and Anderova, AM}, title = {Glial Cells-The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Journal of clinical medicine}, volume = {9}, number = {1}, pages = {}, pmid = {31963681}, issn = {2077-0383}, support = {19-02046S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.}, }
@article {pmid31956195, year = {2020}, author = {Kasahara, S and Ishihara, T and Koike, Y and Sugai, A and Onodera, O}, title = {[Molecular mechanism of amyotrophic lateral sclerosis (ALS) from the viewpoint of the formation and degeneration of transactive response DNA-binding protein 43 kDa (TDP-43) inclusions].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {60}, number = {2}, pages = {109-116}, doi = {10.5692/clinicalneurol.cn-001362}, pmid = {31956195}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Autophagy ; C9orf72 Protein ; *DNA-Binding Proteins/metabolism ; Humans ; Proteasome Endopeptidase Complex ; Protein Aggregation, Pathological ; RNA-Binding Protein FUS ; Ubiquitin ; }, abstract = {Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.}, }
@article {pmid31952509, year = {2020}, author = {Zhu, S and Jiang, Y and Xu, K and Cui, M and Ye, W and Zhao, G and Jin, L and Chen, X}, title = {The progress of gut microbiome research related to brain disorders.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {25}, pmid = {31952509}, issn = {1742-2094}, support = {2017YFC0907002, 2017YFC0907501//National Key Research and Development program of China/ ; 81502870, 31521003//National Natural Science Foundation of China/ ; 2014DFA32830//International Science and Technology Cooperation Programme/ ; 16JC1400500//the Key Basic Research Grants from Science and Technology Commission of Shanghai Municipality, China/ ; 2017SHZDZX01//Science and Technology Commission of Shanghai Municipality/ ; }, mesh = {Animals ; Brain Diseases/*microbiology ; Gastrointestinal Microbiome/*physiology ; Humans ; Neuroimmunomodulation/*physiology ; }, abstract = {There is increasing evidence showing that the dynamic changes in the gut microbiota can alter brain physiology and behavior. Cognition was originally thought to be regulated only by the central nervous system. However, it is now becoming clear that many non-nervous system factors, including the gut-resident bacteria of the gastrointestinal tract, regulate and influence cognitive dysfunction as well as the process of neurodegeneration and cerebrovascular diseases. Extrinsic and intrinsic factors including dietary habits can regulate the composition of the microbiota. Microbes release metabolites and microbiota-derived molecules to further trigger host-derived cytokines and inflammation in the central nervous system, which contribute greatly to the pathogenesis of host brain disorders such as pain, depression, anxiety, autism, Alzheimer's diseases, Parkinson's disease, and stroke. Change of blood-brain barrier permeability, brain vascular physiology, and brain structure are among the most critical causes of the development of downstream neurological dysfunction. In this review, we will discuss the following parts: Overview of technical approaches used in gut microbiome studiesMicrobiota and immunityGut microbiota and metabolitesMicrobiota-induced blood-brain barrier dysfunctionNeuropsychiatric diseases ■ Stress and depression■ Pain and migraine■ Autism spectrum disordersNeurodegenerative diseases ■ Parkinson's disease■ Alzheimer's disease■ Amyotrophic lateral sclerosis■ Multiple sclerosisCerebrovascular disease ■ Atherosclerosis■ Stroke■ Arteriovenous malformationConclusions and perspectives.}, }
@article {pmid31949944, year = {2019}, author = {Tsai, YY and Chen, WT}, title = {Management of anastomotic leakage after rectal surgery: a review article.}, journal = {Journal of gastrointestinal oncology}, volume = {10}, number = {6}, pages = {1229-1237}, pmid = {31949944}, issn = {2078-6891}, abstract = {Anastomotic leaks (ALs) are associated with increased perioperative morbidity and mortality, prolonged length of stay, higher readmission rates, the potential need for further operative interventions, and unintended permanent stomas; resulting in increased hospital costs and resource use, and decreased quality of life. This review article is to present definition, diagnosis and management strategies for AL after rectal surgery.}, }
@article {pmid31943276, year = {2020}, author = {Ghasemi, M and Rajabally, YA}, title = {Small fiber neuropathy in unexpected clinical settings: a review.}, journal = {Muscle &amp; nerve}, volume = {62}, number = {2}, pages = {167-175}, doi = {10.1002/mus.26808}, pmid = {31943276}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Biopsy ; Cornea/innervation/pathology ; Ehlers-Danlos Syndrome/complications ; Epidermis/innervation/pathology ; Evoked Potentials ; Fibromyalgia/*complications ; Guillain-Barre Syndrome/*complications ; Humans ; Lewy Body Disease/complications ; Microscopy, Confocal ; Nerve Fibers, Unmyelinated/pathology ; Papillomavirus Vaccines/adverse effects ; Parkinson Disease/*complications ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/*complications ; Psychophysics ; REM Sleep Behavior Disorder/complications ; Small Fiber Neuropathy/chemically induced/*complications/diagnosis/pathology ; }, abstract = {Small fiber neuropathy (SFN) is being recognized with increasing frequency in neuromuscular practice due to improved diagnostic techniques. Although there are some common etiologies, up to one-third of cases are considered idiopathic. In recent years, several disorders have unexpectedly been reported in association with SFN, on clinical grounds and complementary investigations, including quantitative sensory testing, intraepidermal nerve fiber density and confocal corneal microscopy. Knowledge of these disorders is important in clinical practice as increased awareness enables prompt diagnosis of SFN in these settings and early optimal therapeutic management of affected patients. Furthermore, these new developments may lead to a better understanding of the pathophysiologic mechanisms underlying SFN in these different disorders as well as, in some cases, an expanded spectrum of affected organs and systems. This article reviews these reported associations, their possible pathophysiologic bases, and the potential resulting management implications.}, }
@article {pmid31939642, year = {2020}, author = {Larson, ST and Wilbur, J}, title = {Muscle Weakness in Adults: Evaluation and Differential Diagnosis.}, journal = {American family physician}, volume = {101}, number = {2}, pages = {95-108}, pmid = {31939642}, issn = {1532-0650}, mesh = {Adult ; Aged ; Aged, 80 and over ; Diagnosis, Differential ; Humans ; Muscle Weakness/*diagnosis/*physiopathology ; Muscles/physiopathology ; Muscular Diseases/diagnosis ; Neurologic Examination/methods/*standards ; Neurology/standards ; }, abstract = {Although the prevalence of muscle weakness in the general population is uncertain, it occurs in about 5% of U.S. adults 60 years and older. Determining the cause of muscle weakness can be challenging. True muscle weakness must first be differentiated from subjective fatigue or pain-related motor impairment with normal motor strength. Muscle weakness should then be graded objectively using a formal tool such as the Medical Research Council Manual Muscle Testing scale. The differential diagnosis of true muscle weakness is extensive, including neurologic, rheumatologic, endocrine, genetic, medication- or toxin-related, and infectious etiologies. A stepwise approach to narrowing this differential diagnosis relies on the history and physical examination combined with knowledge of the potential etiologies. Frailty and sarcopenia are clinical syndromes occurring in older people that can present with generalized weakness. Asymmetric weakness is more common in neurologic conditions, whereas pain is more common in neuropathies or radiculopathies. Identifying abnormal findings, such as Chvostek sign, Babinski reflex, hoarse voice, and muscle atrophy, will narrow the possible diagnoses. Laboratory testing, including electrolyte, thyroid-stimulating hormone, and creatine kinase measurements, may also be helpful. Magnetic resonance imaging is indicated if there is concern for acute neurologic conditions, such as stroke or cauda equina syndrome, and may also guide muscle biopsy. Electromyography is indicated when certain diagnoses are being considered, such as amyotrophic lateral sclerosis, myasthenia gravis, neuropathy, and radiculopathy, and may also guide biopsy. If the etiology remains unclear, specialist consultation or muscle biopsy may be necessary to reach a diagnosis.}, }
@article {pmid31939487, year = {2019}, author = {Schilbach, K and Bidlingmaier, M}, title = {Laboratory investigations in the diagnosis and follow-up of GH-related disorders.}, journal = {Archives of endocrinology and metabolism}, volume = {63}, number = {6}, pages = {618-629}, pmid = {31939487}, issn = {2359-4292}, mesh = {Biomarkers/blood ; Follow-Up Studies ; Growth Disorders/*diagnosis ; Human Growth Hormone/*blood ; Humans ; Insulin-Like Growth Factor I/*analysis ; Reference Values ; Sensitivity and Specificity ; }, abstract = {In addition to auxiological, clinical and metabolic features measurements of growth hormone (GH) and insulin-like growth factor I (IGF-I) complement our tools in diagnosis and follow-up of GH-related disorders. While comparably robust during the pre-analytical phase, measurement and interpretation of concentrations of both hormones can be challenging due to analytical issues and biological confounders. Assay methods differ in terms of antibody specificity, interference from binding proteins, reference preparations and sensitivity. GH assays have different specificity towards different GH-isoforms (e.g. 20 kDa GH, placental GH) and interference from the GH antagonist Pegvisomant. The efficacy to prevent binding protein interference is most important in IGF-I assays. Methodological differences between assays require that reference intervals and diagnostic cut-offs are assay-specific. Among biological variables, pubertal development and age are most relevant for IGF-I, making detailed reference intervals mandatory for interpretation. GH has pulsatile secretion and short half-life. Its concentration is modified by acute factors such as stress, exercise and sleep, but also by intake of oral estrogens and anthropometric factors (e.g. BMI). Other GH dependent biomarkers such as free IGF-I, IGF binding protein 3 (IGFBP 3) and acid labile subunit (ALS) have been proposed. Their concentrations largely mirror the information obtained through measurement of IGF-I, but their measurement can be helpful in particular situations. In this review, we describe the evolution of analytical methods to measure biomarkers of GH action, the impact of the methodological changes on laboratory results and the need to include biological variables in their interpretation. Arch Endocrinol Metab. 2019;63(6):618-29.}, }
@article {pmid31937156, year = {2020}, author = {Kassubek, J and Müller, HP}, title = {Advanced neuroimaging approaches in amyotrophic lateral sclerosis: refining the clinical diagnosis.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {3}, pages = {237-249}, doi = {10.1080/14737175.2020.1715798}, pmid = {31937156}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/trends ; *Neuroimaging/trends ; }, abstract = {Introduction: In the last decade, multiparametric magnetic resonance imaging (MRI) has achieved tremendous advances in applications to amyotrophic lateral sclerosis (ALS) to increase the understanding of the associated pathophysiology. The aim of this review is to summarize recent progress in the development of MRI-based techniques aiming to support the clinical diagnosis in ALS.Areas covered: The review of structural and functional MRI applications to ALS and its variants (restricted phenotypes) is focused on the potential of MRI techniques which contribute to the diagnostic work-up of patients with the clinical presentation of a motor neuron disease. The potential of specific MRI methods for patient diagnosis and monitoring is discussed, and the future design of clinical MRI applications to ALS is conceptualized.Expert opinion: Current multiparametric MRI allows for the use as a clinical biological marker and a technical instrument in the clinical diagnosis of patients with ALS and also of patients with ALS variants. Composite neuroimaging indices of specific anatomical areas derived from different MRI techniques might guide in the diagnostic applications to ALS. Such a development of ALS-specific MRI-based composite scores with sufficient discriminative power versus ALS mimics at an individual level requires standardized advanced protocols and comprehensive analysis approaches.}, }
@article {pmid31936292, year = {2020}, author = {Cai, Q and Jeong, YY}, title = {Mitophagy in Alzheimer's Disease and Other Age-Related Neurodegenerative Diseases.}, journal = {Cells}, volume = {9}, number = {1}, pages = {}, pmid = {31936292}, issn = {2073-4409}, support = {R01 NS089737/NS/NINDS NIH HHS/United States ; R21 NS102780/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/*pathology ; Alzheimer Disease/*pathology ; Humans ; Mitochondria/*pathology ; *Mitophagy ; Neurodegenerative Diseases/*pathology ; }, abstract = {Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer's disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders.}, }
@article {pmid31932096, year = {2020}, author = {Diaz-Ortiz, ME and Chen-Plotkin, AS}, title = {Omics in Neurodegenerative Disease: Hope or Hype?.}, journal = {Trends in genetics : TIG}, volume = {36}, number = {3}, pages = {152-159}, pmid = {31932096}, issn = {0168-9525}, support = {T32 AG000255/AG/NIA NIH HHS/United States ; R01 NS115139/NS/NINDS NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; U01 NS082134/NS/NINDS NIH HHS/United States ; U01 NS097056/NS/NINDS NIH HHS/United States ; R01 NS082265/NS/NINDS NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Epigenome/*genetics ; Frontotemporal Lobar Degeneration/genetics ; Genome/*genetics ; Humans ; Multifactorial Inheritance/genetics ; Neurodegenerative Diseases/*genetics/pathology ; Parkinson Disease/genetics ; Transcriptome/*genetics ; }, abstract = {The past 15 years have seen a boom in the use and integration of 'omic' approaches (limited here to genomic, transcriptomic, and epigenomic techniques) to study neurodegenerative disease in an unprecedented way. We first highlight advances in and the limitations of using such approaches in the neurodegenerative disease literature, with a focus on Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). We next discuss how these studies can advance human health in the form of generating leads for downstream mechanistic investigation or yielding polygenic risk scores (PRSs) for prognostication. However, we argue that these approaches constitute a new form of molecular description, analogous to clinical or pathological description, that alone does not hold the key to solving these complex diseases.}, }
@article {pmid31931694, year = {2020}, author = {Binvignat, O and Olloquequi, J}, title = {Excitotoxicity as a Target Against Neurodegenerative Processes.}, journal = {Current pharmaceutical design}, volume = {26}, number = {12}, pages = {1251-1262}, doi = {10.2174/1381612826666200113162641}, pmid = {31931694}, issn = {1873-4286}, mesh = {*Alzheimer Disease ; *Glutamic Acid ; Humans ; Memantine/pharmacology ; Neurons/physiology ; }, abstract = {The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Huntington's disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.}, }
@article {pmid31926785, year = {2020}, author = {Brown, DG and Shorter, J and Wobst, HJ}, title = {Emerging small-molecule therapeutic approaches for amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {30}, number = {4}, pages = {126942}, doi = {10.1016/j.bmcl.2019.126942}, pmid = {31926785}, issn = {1464-3405}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Autophagy/drug effects ; C9orf72 Protein/antagonists &amp; inhibitors/metabolism ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Frontotemporal Dementia/*drug therapy/genetics/pathology ; Humans ; Poly(ADP-ribose) Polymerase Inhibitors/chemistry/metabolism/pharmacology/therapeutic use ; Poly(ADP-ribose) Polymerases/chemistry/metabolism ; Protein Kinase Inhibitors/chemistry/metabolism/pharmacology/therapeutic use ; Small Molecule Libraries/chemistry/pharmacology/*therapeutic use ; }, abstract = {Novel treatments are desperately needed for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review article, a survey of emerging small-molecule approaches for ALS and FTD therapies is provided. These approaches include targeting aberrant liquid-liquid phase separation and stress granule assembly, modulation of RNA-protein interactions, inhibition of TDP-43 phosphorylation, inhibition of poly(ADP-ribose) polymerases (PARP), RNA-targeting approaches to reduce RAN translation of dipeptide repeat proteins from repeat expansions of C9ORF72, and novel autophagy activation pathways. This review details the emerging small-molecule tools and leads in these areas, along with a critical perspective on the key challenges facing these opportunities.}, }
@article {pmid31926602, year = {2020}, author = {Okano, H and Yasuda, D and Fujimori, K and Morimoto, S and Takahashi, S}, title = {Ropinirole, a New ALS Drug Candidate Developed Using iPSCs.}, journal = {Trends in pharmacological sciences}, volume = {41}, number = {2}, pages = {99-109}, doi = {10.1016/j.tips.2019.12.002}, pmid = {31926602}, issn = {1873-3735}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Indoles/pharmacology ; *Induced Pluripotent Stem Cells ; *Pharmaceutical Preparations ; }, abstract = {Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs - ropinirole (ROPI), retigabine, and bosutinib - have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.}, }
@article {pmid31924312, year = {2020}, author = {Walusinski, O}, title = {Armand Trousseau (1801-1867), a neurologist before neurology.}, journal = {Revue neurologique}, volume = {176}, number = {7-8}, pages = {531-542}, doi = {10.1016/j.neurol.2019.12.002}, pmid = {31924312}, issn = {0035-3787}, mesh = {History, 19th Century ; Humans ; *Nervous System Diseases ; Neurologists ; Neurology/*history ; Paris ; *Physicians ; }, abstract = {Armand Trousseau is the emblematic figure of the prominent mid-19th century clinician, owing to the quality of his teaching and the influence of French medicine, which during his time brought students from around the world to Paris. A student of Pierre Bretonneau (1778-1862), the famous physician from the western French city of Tours, Trousseau carried forward Bretonneau's clinical description of infectious diseases, developing the notion of their contagion and paving the way toward the discovery of their microbial aetiology by Louis Pasteur (1822-1895) at the end of the century. His teachings, Les Leçons cliniques de l'Hôtel-Dieu, transcribed by his students, played a role in training young physicians for half a century. In this work, Trousseau covered several neurological diseases such as apoplexy, epilepsy, chorea, Parkinson's disease, and amyotrophic lateral sclerosis. The rich, Balzac-like detail of his clinical pictures would be unthinkable today. While he cannot be credited with any seminal descriptions in particular, some of his observations contain significant nuggets, such as a case of Gilles de la Tourette syndrome, twenty years before the seminal publication. After a biographical account, we will present the main lessons given by Trousseau on neurological subjects. One of Trousseau's little-known contributions is to have invited Guillaume Duchenne de Boulogne (1806-1875) to his department at the Hôtel-Dieu hospital, setting Duchenne on the path to becoming a pioneer of Parisian neurology.}, }
@article {pmid31920679, year = {2019}, author = {Alam, MA and Datta, PK}, title = {Epigenetic Regulation of Excitatory Amino Acid Transporter 2 in Neurological Disorders.}, journal = {Frontiers in pharmacology}, volume = {10}, number = {}, pages = {1510}, pmid = {31920679}, issn = {1663-9812}, support = {P01 DA037830/DA/NIDA NIH HHS/United States ; R01 DA033213/DA/NIDA NIH HHS/United States ; }, abstract = {Excitatory amino acid transporter 2 (EAAT2) is the predominant astrocyte glutamate transporter involved in the reuptake of the majority of the synaptic glutamate in the mammalian central nervous system (CNS). Gene expression can be altered without changing DNA sequences through epigenetic mechanisms. Mechanisms of epigenetic regulation, include DNA methylation, post-translational modifications of histones, chromatin remodeling, and small non-coding RNAs. This review is focused on neurological disorders, such as glioblastoma multiforme (GBM), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), bipolar disorder (BD), and neuroHIV where there is evidence that epigenetics plays a role in the reduction of EAAT2 expression. The emerging field of pharmaco-epigenetics provides a novel avenue for epigenetics-based drug therapy. This review highlights findings on the role of epigenetics in the regulation of EAAT2 in different neurological disorders and discusses the current pharmacological approaches used and the potential use of novel therapeutic approaches to induce EAAT2 expression in neurological disorders using CRISPR/Cas9 technology.}, }
@article {pmid31920478, year = {2019}, author = {Trageser, KJ and Smith, C and Herman, FJ and Ono, K and Pasinetti, GM}, title = {Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1298}, pmid = {31920478}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G4C2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G4C2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G4C2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular stress. A further understanding of the intricate, reciprocal relationship between the cellular and molecular pathologies resulting from C9orf72 HREs and immune activation may yield novel therapeutics for ALS/FTD, which currently have limited treatment strategies.}, }
@article {pmid31918850, year = {2020}, author = {Newhouse, A and Chemali, Z}, title = {Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review.}, journal = {Psychosomatics}, volume = {61}, number = {2}, pages = {105-115}, doi = {10.1016/j.psym.2019.11.002}, pmid = {31918850}, issn = {1545-7206}, mesh = {Alzheimer Disease/diagnosis/physiopathology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Endocrine System Diseases/*diagnosis/physiopathology ; Frontotemporal Dementia/diagnosis/physiopathology ; Homeostasis/physiology ; Humans ; Huntington Disease/diagnosis/physiopathology ; Neurodegenerative Diseases/*diagnosis/physiopathology ; Neurosecretory Systems/*physiopathology ; Parkinson Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Neurodegenerative diseases cause progressive irreversible neuronal loss that has broad downstream effects. The neuroendocrine system regulates homeostasis of circuits that control critical functions such as the stress response, metabolism, reproduction, fluid balance, and glucose control. These systems are frequently disrupted in neurodegenerative disorders yet often overlooked in clinical practice.<br><br>OBJECTIVE: This review aims to gather the available data regarding these disturbances in Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease and also to demonstrate the volume of literature in these individual arenas.<br><br>METHODS: Using the scoping review framework, a literature search was&#xa0;performed in PubMed to identify relevant articles&#xa0;published within the past 30&#xa0;years (January 1988 to November 2018). The search criteria produced a total of 2022 articles, 328 of which were identified as&#xa0;relevant to this review.<br><br>RESULTS: Several major themes emerged from this review. These neuroendocrine disturbances may be a precursor to the illness, a&#xa0;part of the primary pathophysiology, or a direct consequence of the disease or independent of it. They have the potential to further understanding of the disease, exacerbate the underlying pathology, or provide therapeutic benefit.<br><br>CONCLUSIONS: By synthesizing the data from a systems' perspective, we aim to broaden how clinicians think about these illnesses and provide care.}, }
@article {pmid31916190, year = {2020}, author = {Zhao, A and Pan, Y and Cai, S}, title = {Patient-Specific Cells for Modeling and Decoding Amyotrophic Lateral Sclerosis: Advances and Challenges.}, journal = {Stem cell reviews and reports}, volume = {16}, number = {3}, pages = {482-502}, doi = {10.1007/s12015-019-09946-8}, pmid = {31916190}, issn = {2629-3277}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Cellular Reprogramming ; Drug Discovery ; Humans ; *Models, Biological ; Motor Neurons/pathology ; Mutation/genetics ; }, abstract = {Motor neuron loss or degeneration is the typical characteristic of amyotrophic lateral sclerosis (ALS), which often leads to weakness, paralysis, or even death. The underlying mechanisms of motor neuron degeneration and ALS progression remain elusive, and there is no effective treatment for ALS. The advances of stem cells and reprogramming techniques has made it possible to generate patient-specific motor neurons as cell models for studying disease mechanisms and drug discovery. This review comprehensively discusses recent approaches to generate motor neurons from stem cells and somatic cells and highlights the application of induced motor neurons to modeling ALS diseases, dissecting the pathogenesis, and screening new drugs. New perspectives are also discussed on generating patient-specific motor neuron subtypes that are affected by ALS or creating 3D spinal cord organoid models for better recapitulating and understanding ALS.}, }
@article {pmid31914905, year = {2020}, author = {Bakir, S and Catalkaya, G and Ceylan, FD and Khan, H and Guldiken, B and Capanoglu, E and Kamal, MA}, title = {Role of Dietary Antioxidants in Neurodegenerative Diseases: Where are We Standing?.}, journal = {Current pharmaceutical design}, volume = {26}, number = {7}, pages = {714-729}, doi = {10.2174/1381612826666200107143619}, pmid = {31914905}, issn = {1873-4286}, mesh = {Antioxidants/*therapeutic use ; *Diet ; Humans ; *Neurodegenerative Diseases/therapy ; Oxidative Stress ; }, abstract = {This review presents the potential effects of dietary antioxidants on neurodegenerative diseases. The relationship between autoimmunity and antioxidants, and their preventive effect on neurodegenerative diseases are evaluated. The driven factors of neurodegeneration and the potential effects of natural antioxidants are summarized for Alzheimer's disease, Parkinson's disease, multiple sclerosis, spongiform encephalopathy, Huntington's disease, and amyotrophic lateral sclerosis. The effect of oxidative stress on neurodegenerative diseases and regulative effect of antioxidants on oxidative balance is discussed. This review provides beneficial information for the possible cure of neurodegenerative diseases with dietary intake of antioxidants.}, }
@article {pmid31914904, year = {2020}, author = {Rahman, MA and Rahman, MR and Zaman, T and Uddin, MS and Islam, R and Abdel-Daim, MM and Rhim, H}, title = {Emerging Potential of Naturally Occurring Autophagy Modulators Against Neurodegeneration.}, journal = {Current pharmaceutical design}, volume = {26}, number = {7}, pages = {772-779}, doi = {10.2174/1381612826666200107142541}, pmid = {31914904}, issn = {1873-4286}, mesh = {Animals ; *Autophagy ; Biological Products/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Signal Transduction ; }, abstract = {BACKGROUND: Naturally-occurring products derived from living organisms have been shown to modulate various pharmacological and biological activities. Natural products protect against various diseases, which could be used for therapeutic assistance. Autophagy, a lysosome-mediated self-digestion pathway, has been implicated in a range of pathophysiological conditions and has recently gained attention for its role in several neurodegenerative diseases.<br><br>METHODS: In this current review, we emphasized the recent progress made in our understanding of the molecular mechanism of autophagy in different cellular and mouse models using naturally-occurring autophagy modulators for the management of several neurodegenerative diseases.<br><br>RESULTS: Accumulating evidence has revealed that a wide variety of natural compounds such as alkaloids, polyphenols, terpenoids, xanthonoids, flavonoids, lignans, disaccharides, glycolipoproteins, and saponins are involved in the modulation of the autophagy signaling pathway. These natural products have been used to treat various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, neuroblastoma, and glioblastoma. Although a number of synthetic autophagy regulators have been recognized as encouraging neurodegenerative therapeutic candidates, natural autophagy- regulating compounds have been of further interest as potential disease therapeutics, as they cause insignificant side effects.<br><br>CONCLUSION: Existing in vitro and in vivo data are promising and highlight that naturally-occurring autophagyregulating compounds play an important role in the prevention and treatment of neurodegenerative disorders.}, }
@article {pmid31914903, year = {2020}, author = {Gulla, S and Lomada, D and Lade, A and Pallu, R and Reddy, MC}, title = {Role of Prostaglandins in Multiple Sclerosis.}, journal = {Current pharmaceutical design}, volume = {26}, number = {7}, pages = {730-742}, doi = {10.2174/1381612826666200107141328}, pmid = {31914903}, issn = {1873-4286}, mesh = {Central Nervous System/physiopathology ; Humans ; Inflammation ; Multiple Sclerosis/*physiopathology ; Prostaglandins/*physiology ; }, abstract = {Multiple sclerosis (MS) is an autoimmune demyelinating disorder with chronic inflammation in the central nervous system, manifested by both physical and cognitive disability. Neuroinflammation and neurodegeneration are the phenomena that appear in the central nervous system associated with various neurodegenerative disorders, including MS, Alzheimer's diseases, amyotrophic lateral sclerosis and Parkinson's disease. Prostaglandins are one of the major mediators of inflammation that exhibit an important function in enhancing neuroinflammatory and neurodegenerative processes. These mediators would help understand the pathophysiology of MS as the combination of antagonists or agonists of prostaglandins receptors could be beneficial during the treatment of MS. The present review focuses on the role played by different prostaglandins and the enzymes which produced them in the etiopathogenesis of MS.}, }
@article {pmid31914343, year = {2020}, author = {Bandookwala, M and Sengupta, P}, title = {3-Nitrotyrosine: a versatile oxidative stress biomarker for major neurodegenerative diseases.}, journal = {The International journal of neuroscience}, volume = {130}, number = {10}, pages = {1047-1062}, doi = {10.1080/00207454.2020.1713776}, pmid = {31914343}, issn = {1563-5279}, mesh = {*Alzheimer Disease/diagnosis/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/pathology ; Biomarkers/*metabolism ; Humans ; *Huntington Disease/diagnosis/metabolism/pathology ; *Parkinson Disease/diagnosis/metabolism/pathology ; *Prion Diseases/diagnosis/metabolism/pathology ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Reactive oxygen species are generated as a by-product of routine biochemical reactions. However, dysfunction of the antioxidant system or mutations in gene function may result in the elevated production of the pro-oxidant species. Modified endogenous molecules due to chemical interactions with increased levels of reactive oxygen and nitrogen species in the cellular microenvironment can be termed as biomarkers of oxidative stress. 3-Nitrotyrosine is one such promising biomarker of oxidative stress formed due to nitration of protein-bound and free tyrosine residues by reactive peroxynitrite molecules. Nitration of proteins at the subcellular level results in conformational alterations that damage the cytoskeleton and result in neurodegeneration. In this review, we summarized the role of oxidative/nitrosative processes as a contributing factor for progressive neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease and Prion disease. The selective tyrosine protein nitration of the major marker proteins in related pathologies has been discussed. The alteration in 3-Nitrotyrosine profile occurs well before any symptoms appear and can be considered as a potential target for early diagnosis of neurodegenerative diseases. Furthermore, the reduction in 3-Nitrotyrosine levels in response to treatment with neuroprotective has been highlighted which is indicative of the importance of this particular marker in oxidative stress-related brain and central nervous system pathologies.}, }
@article {pmid31912279, year = {2020}, author = {Devos, D and Cabantchik, ZI and Moreau, C and Danel, V and Mahoney-Sanchez, L and Bouchaoui, H and Gouel, F and Rolland, AS and Duce, JA and Devedjian, JC and , }, title = {Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {127}, number = {2}, pages = {189-203}, pmid = {31912279}, issn = {1435-1463}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; *Chelation Therapy/methods/standards ; Deferiprone/*pharmacology ; Humans ; Iron/*metabolism ; Iron Chelating Agents/*pharmacology ; Parkinson Disease/*drug therapy/metabolism ; }, abstract = {Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.}, }
@article {pmid31909174, year = {2019}, author = {Forgrave, LM and Ma, M and Best, JR and DeMarco, ML}, title = {The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)}, volume = {11}, number = {}, pages = {730-743}, pmid = {31909174}, issn = {2352-8729}, abstract = {INTRODUCTION: A systematic review and meta-analysis was performed regarding the diagnostic performance of neurofilament light chain (NfL) in CSF and blood.<br><br>METHODS: A database search was conducted for NfL biomarker studies in the context of Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) compared with controls (i.e., cognitively unimpaired, mild cognitive impairment, or disease mimics).<br><br>RESULTS: In groups with a sufficient number of studies, the performance of NfL in blood and CSF was similar. Compared with disease mimics, we observed that CSF NfL had strong discriminatory power for ALS, modest discriminatory power for FTD, and no discriminatory power for AD. NfL provided the greatest separation between ALS and cognitively unimpaired controls in both the blood and CSF, followed by FTD (CSF and blood), then AD (blood and CSF).<br><br>DISCUSSION: Comparable performance of CSF and blood NfL in many groups demonstrates the promise of NfL as a noninvasive biomarker of neurodegeneration; however, its utility in clinically meaningful scenarios requires greater scrutiny. Toward clinical implementation, a more comprehensive understanding of NfL concentrations in disease subtypes with overlapping phenotypes and at defined stages of disease, and the development of a harmonization program, are warranted.}, }
@article {pmid31907329, year = {2020}, author = {Urushitani, M}, title = {[Current Therapies for Amyotrophic Lateral Sclerosis in Japan].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {72}, number = {1}, pages = {13-22}, doi = {10.11477/mf.1416201474}, pmid = {31907329}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis ; Disease Progression ; Humans ; Japan ; *Muscular Atrophy, Spinal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness. Riluzole was the sole drug available for treating ALS until 2015, when edaravone was approved as a new anti-ALS drug. Recent discoveries of the disease-causal genes and proteins, as well as the rapid advancement of induced pluripotent stem (iPS) cell manipulations, drug deliveries, and molecular modifications have provided diverse and promising drug candidates. In particular, antisense-oligonucleotide therapy appears to significantly prevent disease progression when introduced early. Moreover, the in vitro modeling of ALS using patients' own iPS cells enables effective screening of approved drugs. Drug repositioning is a robust short-cut to bedside use in patients with ALS, due to the availability of data for safety concerns. Currently, five investigator-initiated drug trials are underway in Japan. These include trials of hepatocyte growth factor, perampanel, ultra-high-dose methylcobalamin, ropinirole, and bosutinib. This is a review of new ALS drugs that are either currently available or in on-going trials. We additionally review the pathogenic pathways that these drugs target.}, }
@article {pmid31903792, year = {2020}, author = {Motataianu, A and Barcutean, L and Balasa, R}, title = {Neuroimmunity in amyotrophic lateral sclerosis: focus on microglia.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {3-4}, pages = {159-166}, doi = {10.1080/21678421.2019.1708949}, pmid = {31903792}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/metabolism ; Animals ; Humans ; Immunity, Cellular/immunology ; Microglia/*immunology/metabolism ; Neuroimmunomodulation/*immunology ; T-Lymphocytes/*immunology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), an incurable, devastating condition of the central nervous system, is characterized by selective destruction of motoneurons with an important contribution of innate and adaptative immunity. Microglia and immune cells are key players in neuroinflammation and active participants in ALS pathogenesis. Recent experiments in animal models have shown that microglia display both neuroprotective and neurotoxic properties, depending on the stage of disease progression and cytokine secretion. A better knowledge of the interactions between T cells and microglia in the immunopathogenesis of ALS is desirable for the development of ALS therapeutic strategies.}, }
@article {pmid31901592, year = {2020}, author = {Saitoh, Y and Aoshima, Y and Mukai, T and Abe, H and Ariga, H and Mori-Yoshimura, M and Okamoto, T and Takahashi, Y}, title = {Riluzole-induced interstitial lung disease is a rare and potentially life-threatening adverse event successfully treated with high-dose steroid therapy: Case reports and review of the literature.}, journal = {Journal of the neurological sciences}, volume = {410}, number = {}, pages = {116650}, doi = {10.1016/j.jns.2019.116650}, pmid = {31901592}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Lung Diseases, Interstitial/chemically induced/drug therapy ; Riluzole/adverse effects ; }, abstract = {Riluzole (RZ)-induced interstitial lung disease (RZ-ILD) is a rare and potentially life-threatening adverse event in amyotrophic lateral sclerosis (ALS) patients, which is rarely reported. Therefore, the optimal treatment for RZ-ILD is unclear. We describe herein three Japanese cases of ALS complicated with RZ-ILD, of which two were successfully treated with high-dose steroid therapy. In our all ALS cases with RZ-ILD, the duration of RZ exposure until RZ-ILD onset was within 2 months. All three cases showed respiratory symptoms, dorsal predominant ground-glass opacities by imaging analysis, and abnormal laboratory findings associated with interstitial lung diseases, such as Krebs von den Lungen-6 and surfactant protein-D. Intravenous high-dose steroid therapy together with the discontinuation of RZ in two cases with respiratory symptoms markedly ameliorated their symptoms and abnormal findings of RZ-ILD. One case showed mild respiratory symptoms compared with the others and recovered after the withdrawal of RZ only. According to previous case reports and our cases, RZ-ILD may develop 2 months after initiating RZ and exacerbate respiratory symptoms rapidly in ALS patients with severe respiratory muscle involvement or complicating aspiration pneumonia. Transient high-dose steroid therapy in addition to discontinuation of RZ might be a good therapeutic option for RZ-ILD.}, }
@article {pmid31899540, year = {2020}, author = {Goyal, NA and Berry, JD and Windebank, A and Staff, NP and Maragakis, NJ and van den Berg, LH and Genge, A and Miller, R and Baloh, RH and Kern, R and Gothelf, Y and Lebovits, C and Cudkowicz, M}, title = {Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS.}, journal = {Muscle &amp; nerve}, volume = {62}, number = {2}, pages = {156-166}, pmid = {31899540}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/physiopathology ; *Biological Variation, Population ; *Biomarkers ; Clinical Trials as Topic/*methods ; Disease Progression ; Drug Development ; Humans ; Muscle Strength ; *Outcome Assessment, Health Care ; Physical Functional Performance ; Precision Medicine ; Prognosis ; Reproducibility of Results ; Respiratory Function Tests ; Risk Assessment ; Speech ; Transcranial Magnetic Stimulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.}, }
@article {pmid31889605, year = {2020}, author = {Swalley, SE}, title = {Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {28}, number = {3}, pages = {115239}, doi = {10.1016/j.bmc.2019.115239}, pmid = {31889605}, issn = {1464-3391}, mesh = {Drug Evaluation, Preclinical ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/*therapeutic use ; Phenotype ; Small Molecule Libraries/chemistry/*therapeutic use ; }, abstract = {Over the last 20 years, there have been remarkably few FDA-approved first-in-class drugs for neurodegenerative diseases. Debilitating conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have no effective disease-modifying therapeutics on the market, signifying an area of high unmet medical need where novel approaches are needed. Using a phenotypic screening approach, two separate groups discovered small molecule non-antisense oligonucleotide splice modulators for spinal muscular atrophy, a severe monogenetic disease that causes the degeneration ofalpha motor neuronsin the spinal cord. These compounds function by a novel mechanism: selective stabilization of the interaction of U1 small nuclear ribonucleic protein (snRNP), a core component of the spliceosome, with the 5' splice site of a pre-mRNA. The ability of the phenotypic screening approach to uncover a previously unknown mechanism and reveal a new druggable target class has broader implications for other neurodegenerative diseases.}, }
@article {pmid31888221, year = {2019}, author = {Wang, W and Gopal, S and Pocock, R and Xiao, Z}, title = {Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {24}, pages = {}, pmid = {31888221}, issn = {1420-3049}, mesh = {Animals ; *Biological Mimicry ; Biological Products/*chemistry ; *Biomimetics/methods ; Drug Discovery/methods ; Glycosylation ; Humans ; Molecular Structure ; Neurodegenerative Diseases/drug therapy ; Polysaccharides/biosynthesis/*chemistry/*pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.}, }
@article {pmid31887367, year = {2020}, author = {Nas, J and Kleinnibbelink, G and Hannink, G and Navarese, EP and van Royen, N and de Boer, MJ and Wik, L and Bonnes, JL and Brouwer, MA}, title = {Diagnostic performance of the basic and advanced life support termination of resuscitation rules: A systematic review and diagnostic meta-analysis.}, journal = {Resuscitation}, volume = {148}, number = {}, pages = {3-13}, doi = {10.1016/j.resuscitation.2019.12.016}, pmid = {31887367}, issn = {1873-1570}, mesh = {*Cardiopulmonary Resuscitation ; Decision Support Techniques ; *Emergency Medical Services ; Humans ; *Out-of-Hospital Cardiac Arrest ; Registries ; Resuscitation Orders ; }, abstract = {AIM: To minimize termination of resuscitation (TOR) in potential survivors, the desired positive predictive value (PPV) for mortality and specificity of universal TOR-rules are ≥99%. In lack of a quantitative summary of the collective evidence, we performed a diagnostic meta-analysis to provide an overall estimate of the performance of the basic and advanced life support (BLS and ALS) termination rules.<br><br>DATA SOURCES: We searched PubMed/EMBASE/Web-of-Science/CINAHL and Cochrane (until September 2019) for studies on either or both TOR-rules in non-traumatic, adult cardiac arrest. PRISMA-DTA-guidelines were followed.<br><br>RESULTS: There were 19 studies: 16 reported on the BLS-rule (205.073 patients, TOR-advice in 57%), 11 on the ALS-rule (161.850 patients, TOR-advice in 24%). Pooled specificities were 0.95 (0.89-0.98) and 0.98 (0.95-1.00) respectively, with a PPV of 0.99 (0.99-1.00) and 1.00 (0.99-1.00). Specificities were significantly lower in non-Western than Western regions: 0.84 (0.73-0.92) vs. 0.99 (0.97-0.99), p&#x202f;<&#x202f;0.001 for the BLS rule. For the ALS-rule, specificities were 0.94 (0.87-0.97) vs. 1.00 (0.99-1.00), p&#x202f;<&#x202f;0.001. For non-Western regions, 16 (BLS) or 6 (ALS) out of 100 potential survivors met the TOR-criteria. Meta-regression demonstrated decreasing performance in settings with lower rates of in-field shocks.<br><br>CONCLUSIONS: Despite an overall high PPV, this meta-analysis highlights a clinically important variation in diagnostic performance of the BLS and ALS TOR-rules. Lower specificity and PPV were seen in non-Western regions, and populations with lower rates of in-field defibrillation. Improved insight in the varying diagnostic performance is highly needed, and local validation of the rules is warranted to prevent in-field termination of potential survivors.}, }
@article {pmid31887286, year = {2020}, author = {Djajadikerta, A and Keshri, S and Pavel, M and Prestil, R and Ryan, L and Rubinsztein, DC}, title = {Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {Journal of molecular biology}, volume = {432}, number = {8}, pages = {2799-2821}, doi = {10.1016/j.jmb.2019.12.035}, pmid = {31887286}, issn = {1089-8638}, support = {UKDRI-2002/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Autophagy ; Autophagy-Related Proteins/*metabolism ; Humans ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/*pathology/*therapy ; Signal Transduction ; }, abstract = {Autophagy is a major, conserved cellular pathway by which cells deliver cytoplasmic contents to lysosomes for degradation. Genetic studies have revealed extensive links between autophagy and neurodegenerative disease, and disruptions to autophagy may contribute to pathology in some cases. Autophagy degrades many of the toxic, aggregate-prone proteins responsible for such diseases, including mutant huntingtin (mHTT), alpha-synuclein (α-syn), tau, and others, raising the possibility that autophagy upregulation may help to reduce levels of toxic protein species, and thereby alleviate disease. This review examines autophagy induction as a potential therapy in several neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, polyglutamine diseases, and amyotrophic lateral sclerosis (ALS). Evidence in cells and in vivo demonstrates promising results in many disease models, in which autophagy upregulation is able to reduce the levels of toxic proteins, ameliorate signs of disease, and delay disease progression. However, the effective therapeutic use of autophagy induction requires detailed knowledge of how the disease affects the autophagy-lysosome pathway, as activating autophagy when the pathway cannot go to completion (e.g., when lysosomal degradation is impaired) may instead exacerbate disease in some cases. Investigating the interactions between autophagy and disease pathogenesis is thus a critical area for further research.}, }
@article {pmid31881709, year = {2019}, author = {Lee, IS and Kang, KS and Kim, SY}, title = {Panax ginseng Pharmacopuncture: Current Status of the Research and Future Challenges.}, journal = {Biomolecules}, volume = {10}, number = {1}, pages = {}, pmid = {31881709}, issn = {2218-273X}, mesh = {Acupuncture Therapy/*methods ; Animals ; Humans ; Medicine, East Asian Traditional/*methods ; Panax/*chemistry ; *Research ; }, abstract = {Despite the increasing use of ginseng pharmacopuncture in clinical practice, evidence of its physiological effects, safety, and clinical outcomes is insufficient. The purpose of this review is to summarize previous studies and suggest future challenges for the clinical use of ginseng pharmacopuncture. We systematically searched clinical and animal studies that applied ginseng pharmacopuncture and reviewed the manufacturing processes of ginseng pharmacopuncture solution, safety, physiological responses, and clinical effects. Intravenous or point injection of the ginseng pharmacopuncture solution made by distillation extraction has been commonly used in studies. Ginseng pharmacopuncture does not show any toxicity in animals and humans, while it influenced the heart rate variability, pulse wave velocity, and protein synthesis in human subjects. In 25 case reports, patients with cancer, amyotrophic lateral sclerosis, skin wrinkles, and allergic rhinitis showed significant improvement of clinical outcomes. We found that more evidence is necessary to conclude that ginseng pharmacopuncture is safe and effective. First, the pharmacopuncture manufacturing process should be standardized on the basis of the safety and efficacy tests. Moreover, studies on the quantitative quality of the components of the solution and on the clinical comparison of various injection methods are required to improve clinical outcomes in the future.}, }
@article {pmid31877540, year = {2020}, author = {Qiao, Y and Maiti, K and Sultana, Z and Fu, L and Smith, R}, title = {Inhibition of vertebrate aldehyde oxidase as a therapeutic treatment for cancer, obesity, aging and amyotrophic lateral sclerosis.}, journal = {European journal of medicinal chemistry}, volume = {187}, number = {}, pages = {111948}, doi = {10.1016/j.ejmech.2019.111948}, pmid = {31877540}, issn = {1768-3254}, mesh = {Aldehyde Oxidase/*antagonists &amp; inhibitors/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; Neoplasms/*drug therapy/metabolism ; Neuroprotective Agents/chemistry/*pharmacology ; Obesity/*drug therapy/metabolism ; }, abstract = {The aldehyde oxidases (AOXs) are a small sub-family of cytosolic molybdo-flavoenzymes, which are structurally conserved proteins and broadly distributed from plants to animals. AOXs play multiple roles in both physiological and pathological processes and AOX inhibition is of increasing significance in the development of novel drugs and therapeutic strategies. This review provides an overview of the evolution and the action mechanism of AOX and the role of each domain. The review provides an update of the polymorphisms in the human AOX. This review also summarises the physiology of AOX in different organs and its role in drug metabolism. The inhibition of AOX is a promising therapeutic treatment for cancer, obesity, aging and amyotrophic lateral sclerosis.}, }
@article {pmid31868945, year = {2020}, author = {Jaunmuktane, Z and Brandner, S}, title = {Invited Review: The role of prion-like mechanisms in neurodegenerative diseases.}, journal = {Neuropathology and applied neurobiology}, volume = {46}, number = {6}, pages = {522-545}, pmid = {31868945}, issn = {1365-2990}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; Neurodegenerative Diseases/genetics/*pathology ; Prion Diseases/genetics/*pathology ; Prion Proteins/*genetics ; Proteostasis Deficiencies/genetics/pathology ; }, abstract = {The prototype of transmissible neurodegenerative proteinopathies is prion diseases, characterized by aggregation of abnormally folded conformers of the native prion protein. A wealth of mechanisms has been proposed to explain the conformational conversion from physiological protein into misfolded, pathological form, mode of toxicity, propagation from cell-to-cell and regional spread. There is increasing evidence that other neurodegenerative diseases, most notably Alzheimer's disease (Aβ and tau), Parkinson's disease (α-synuclein), frontotemporal dementia (TDP43, tau or FUS) and motor neurone disease (TDP43), exhibit at least some of the misfolded prion protein properties. In this review, we will discuss to what extent each of the properties of misfolded prion protein is known to occur for Aβ, tau, α-synuclein and TDP43, with particular focus on self-propagation through seeding, conformational strains, selective cellular and regional vulnerability, stability and resistance to inactivation, oligomers, toxicity and summarize the most recent literature on transmissibility of neurodegenerative disorders.}, }
@article {pmid31866818, year = {2019}, author = {Mejzini, R and Flynn, LL and Pitout, IL and Fletcher, S and Wilton, SD and Akkari, PA}, title = {ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1310}, pmid = {31866818}, issn = {1662-4548}, abstract = {The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined.}, }
@article {pmid31866784, year = {2019}, author = {Subramaniam, S}, title = {Selective Neuronal Death in Neurodegenerative Diseases: The Ongoing Mystery.}, journal = {The Yale journal of biology and medicine}, volume = {92}, number = {4}, pages = {695-705}, pmid = {31866784}, issn = {1551-4056}, support = {R01 NS087019/NS/NINDS NIH HHS/United States ; R01 NS094577/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; GTP-Binding Proteins/metabolism ; Humans ; Neurodegenerative Diseases/*pathology ; Neurons/*pathology ; }, abstract = {A major unresolved problem in neurodegenerative disease is why and how a specific set of neurons in the brain are highly vulnerable to neuronal death. Multiple pathways and mechanisms have been proposed to play a role in Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington disease (HD), yet how they contribute to neuronal vulnerability remains far from clear. In this review, various mechanisms ascribed in AD, PD, ALS, and HD will be briefly summarized. Particular focus will be placed on Rhes-mediated intercellular transport of the HD protein and its role in mitophagy, in which I will discuss some intriguing observations that I apply to model striatal vulnerability in HD. I may have unintentionally missed referring some studies in this review, and I extend my apologies to the authors in those circumstances.}, }
@article {pmid31862112, year = {2021}, author = {Murfield, J and Moyle, W and O'Donovan, A}, title = {Mindfulness- and compassion-based interventions for family carers of older adults: A scoping review.}, journal = {International journal of nursing studies}, volume = {116}, number = {}, pages = {103495}, doi = {10.1016/j.ijnurstu.2019.103495}, pmid = {31862112}, issn = {1873-491X}, mesh = {*Acceptance and Commitment Therapy ; Aged ; Caregivers ; Empathy ; Humans ; *Mindfulness ; Quality of Life ; }, abstract = {OBJECTIVES: To provide an overview of the current use of mindfulness- and compassion-based interventions with family carers of older adults, to aid primary healthcare practitioners in their decision-making around referral to wider healthcare services. The study was guided by four research questions: what interventions are currently used; whom they are used with; why they are used; and their evidence-base in terms of acceptability and effectiveness.<br><br>DESIGN: A scoping study using the methodological frameworks of Arksey and O'Malley and Levac et&#xa0;al.<br><br>DATA SOURCES: Searches of electronic databases (MEDLINE, CINHAL, PsycINFO), reference lists of relevant articles, and journal websites were conducted in June 2019. Search terms were developed via an iterative process, and included medical subject headings and keywords relating to mindfulness and compassion, interventions, and family carers.<br><br>REVIEW METHODS: Articles were included if: written in English; published in a peer-reviewed journal; employed quantitative, qualitative, or mixed-method research designs; and described a mindfulness- and/or compassion-based intervention for adults identified as a family carer of an older adult. Data from included studies were charted (using a purposively-designed template), and descriptively analysed in relation to the study's research questions.<br><br>RESULTS: From 2005 unique records, 32 primary studies were included. Seven types of mindfulness- or compassion-based interventions were broadly described within studies, including: mindfulness-based stress reduction (n&#xa0;=&#xa0;13), mindfulness-based cognitive therapy (n&#xa0;=&#xa0;3), meditation interventions (n&#xa0;=&#xa0;9), acceptance and commitment therapy (n&#xa0;=&#xa0;1), dialectical behaviour therapy (n&#xa0;=&#xa0;1), compassion-focused therapy (n&#xa0;=&#xa0;1), and study-specific interventions involving a combination of mindfulness and/or compassion (n&#xa0;=&#xa0;4). Studies sampled a total of n&#xa0;=&#xa0;991 participants and targeted six family carer sub-groups: dementia (n&#xa0;=&#xa0;23), cancer (n&#xa0;=&#xa0;5), amyotrophic lateral sclerosis (n&#xa0;=&#xa0;1), chronic conditions (n&#xa0;=&#xa0;1), cirrhosis (n&#xa0;=&#xa0;1), and Parkinson's disease (n&#xa0;=&#xa0;1). A variety of health outcomes were assessed across interventions, with the most common being depression (n&#xa0;=&#xa0;26), anxiety (n&#xa0;=&#xa0;15), burden (n&#xa0;=&#xa0;15), quality of life (n&#xa0;=&#xa0;14), and stress (n&#xa0;=&#xa0;11). The evidence-base for each intervention was insufficient and too heterogeneous to make clear statements regarding effectiveness. However, based on these findings, interventions show some potential utility in supporting family carers in their role and, given a collective rate of attrition (18%), may do so in a way that is acceptable to carers.<br><br>CONCLUSIONS: This scoping study highlighted the nascent use of mindfulness- and compassion-based interventions with family carers of older adults, and provided important substantive detail about what each intervention entails. Based on current evidence, a number of implications for research and practice are presented.}, }
@article {pmid31851317, year = {2020}, author = {Pandya, VA and Patani, R}, title = {Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective.}, journal = {Brain : a journal of neurology}, volume = {143}, number = {4}, pages = {1057-1072}, pmid = {31851317}, issn = {1460-2156}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging/*pathology ; Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Cellular Senescence/physiology ; Humans ; Motor Neurons/*pathology ; }, abstract = {With an ageing population comes an inevitable increase in the prevalence of age-associated neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease characterized by the degeneration of upper and lower motor neurons within the brain and spinal cord. Indeed, the physiological process of ageing causes a variety of molecular and cellular phenotypes. With dysfunction at the neuromuscular junction implicated as a key pathological mechanism in ALS, and each lower motor unit cell type vulnerable to its own set of age-related phenotypes, the effects of ageing might in fact prove a prerequisite to ALS, rendering the cells susceptible to disease-specific mechanisms. Moreover, we discuss evidence for overlap between age and ALS-associated hallmarks, potentially implicating cell type-specific ageing as a key contributor to this multifactorial and complex disease. With a dearth of disease-modifying therapy currently available for ALS patients and a substantial failure in bench to bedside translation of other potential therapies, the unification of research in ageing and ALS requires high fidelity models to better recapitulate age-related human disease and will ultimately yield more reliable candidate therapeutics for patients, with the aim of enhancing healthspan and life expectancy.}, }
@article {pmid31846136, year = {2020}, author = {Bagheri, H and Ghasemi, F and Barreto, GE and Sathyapalan, T and Jamialahmadi, T and Sahebkar, A}, title = {The effects of statins on microglial cells to protect against neurodegenerative disorders: A mechanistic review.}, journal = {BioFactors (Oxford, England)}, volume = {46}, number = {3}, pages = {309-325}, doi = {10.1002/biof.1597}, pmid = {31846136}, issn = {1872-8081}, mesh = {Animals ; Disease Models, Animal ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Mice ; Microglia/*drug effects ; Neurodegenerative Diseases/*prevention &amp; control ; Neuroprotective Agents/*pharmacology ; Rats ; }, abstract = {Microglia are the primary innate immune system cells in the central nervous system (CNS). They are crucial for the immunity, neurogenesis, synaptogenesis, neurotrophic support, phagocytosis of cellular debris, and maintaining the CNS integrity and homeostasis. Invasion by pathogens as well as in CNS injuries and damages results in activation of microglia known as microgliosis. The activated microglia have the capacity to release proinflammatory mediators leading to neuroinflammation. However, uncontrolled neuroinflammation can give rise to various neurological disorders (NDs), especially the neurodegenerative diseases including Parkinson's disease (PD) and related disorders, Alzheimer's disease (AD) and other dementias, multiple sclerosis (MS), Huntington's disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and stroke. Statins (HMG-CoA reductase inhibitors) are among the most widely prescribed medications for the management of hypercholesterolemia worldwide. It can be used for primary prevention in healthy individuals who are at higher risk of cardiovascular and coronary heart diseases as well as the secondary prevention in patients with cardiovascular and coronary heart diseases disease. A growing body of evidence has indicated that statins have the potential to attenuate the proinflammatory mediators and subsequent NDs by controlling the microglial activation and consequent reduction in neuroinflammatory mediators. In this review, we have discussed the recent studies on the effects of statins on microglia activation and neuroinflammation.}, }
@article {pmid31837826, year = {2020}, author = {Goodman, LD and Bonini, NM}, title = {New Roles for Canonical Transcription Factors in Repeat Expansion Diseases.}, journal = {Trends in genetics : TIG}, volume = {36}, number = {2}, pages = {81-92}, pmid = {31837826}, issn = {0168-9525}, support = {F32 NS009727/NS/NINDS NIH HHS/United States ; R01 NS078283/NS/NINDS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; T32 GM007517/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/genetics/pathology ; GC Rich Sequence/genetics ; Humans ; Microsatellite Repeats/genetics ; Neurons/metabolism/pathology ; Peptides/genetics ; RNA/biosynthesis/genetics ; RNA Polymerase II/genetics ; Transcription Factors/*genetics ; *Transcription, Genetic ; }, abstract = {The presence of microsatellite repeat expansions within genes is associated with >30 neurological diseases. Of interest, (GGGGCC)>30-repeats within C9orf72 are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These expansions can be 100s to 1000s of units long. Thus, it is perplexing how RNA-polymerase II (RNAPII) can successfully transcribe them. Recent investigations focusing on GGGGCC-transcription have identified specific, canonical complexes that may promote RNAPII-transcription at these GC-rich microsatellites: the DSIF complex and PAF1C. These complexes may be important for resolving the unique secondary structures formed by GGGGCC-DNA during transcription. Importantly, this process can produce potentially toxic repeat-containing RNA that can encode potentially toxic peptides, impacting neuron function and health. Understanding how transcription of these repeats occurs has implications for therapeutics in multiple diseases.}, }
@article {pmid31837086, year = {2020}, author = {Andica, C and Kamagata, K and Hatano, T and Saito, Y and Ogaki, K and Hattori, N and Aoki, S}, title = {MR Biomarkers of Degenerative Brain Disorders Derived From Diffusion Imaging.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {52}, number = {6}, pages = {1620-1636}, pmid = {31837086}, issn = {1522-2586}, support = {JP19dm0307024//Brain/MINDS Beyond program from the Japan Agency for Medical Research and Development (AMED)/International ; JP19dm0307101//Brain/MINDS Beyond program from the Japan Agency for Medical Research and Development (AMED)/International ; JP19K17244//JSPS KAKENHI/International ; JP16H06280//JSPS KAKENHI/International ; //MEXT-Supported Program for the Private University Research Branding Project/International ; }, mesh = {Biomarkers ; Brain/diagnostic imaging ; *Brain Diseases ; Diffusion Magnetic Resonance Imaging ; *Diffusion Tensor Imaging ; Humans ; Neurites ; }, abstract = {The incidence of neurodegenerative diseases has shown an increasing trend. These conditions typically cause progressive functional disability. Identification of robust biomarkers of neurodegenerative diseases is a key imperative to facilitate early identification of the pathological features and to foster a better understanding of the pathogenetic mechanisms of individual diseases. Diffusion tensor imaging (DTI) is the most widely used diffusion MRI technique for assessment of neurodegenerative diseases. The DTI parameters are promising biomarkers for evaluation of microstructural changes; however, some limitations of DTI restrict its wider clinical use. New diffusion MRI techniques, such as diffusion kurtosis imaging (DKI), bi-tensor DTI, and neurite orientation density and dispersion imaging (NODDI) have been demonstrated to provide value addition to DTI for evaluation of neurodegenerative diseases. In this review article, we summarize the key technical aspects and provide an overview of the current state of knowledge regarding the role of DKI, bi-tensor DTI, and NODDI as biomarkers of microstructural changes in representative neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 2 J. MAGN. RESON. IMAGING 2020;52:1620-1636.}, }
@article {pmid31834313, year = {2019}, author = {Araujo, AQC and Wedemann, D}, title = {HTLV-1 Associated Neurological Complex. What is Hidden below the Water?.}, journal = {AIDS reviews}, volume = {21}, number = {4}, pages = {211-217}, doi = {10.24875/AIDSRev.19000108}, pmid = {31834313}, issn = {1698-6997}, mesh = {HTLV-I Infections/*complications ; Humans ; Nervous System Diseases/*epidemiology/*pathology ; }, abstract = {The human T-cell lymphotropic virus type 1 (HTLV-1) infects 5-10 million people worldwide and causes fatal and disabling diseases in a significant proportion of them. A chronic myelitis named HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the typical neurological manifestation of HTLV-1. However, other neurological syndromes can be either associated with HAM/TSP or occur in isolation in the HTLV-1 infected individual. Although this fact has been widely described over the years, it has been somewhat neglected by the mainstream literature, which has been largely focused on HAM/TSP. Cognitive dysfunction, encephalopathy, neurogenic bladder, motor neuron disease, inflammatory myopathies, polyneuropathy, and dysautonomia can also occur in the HTLV-1 infected patient and may remain unnoticed to the unsuspecting physician. In the present review, we intend to draw attention, primarily to the infectious disease specialist and to the general practitioner, to the fact that HTLV-1 has a broader neurological spectrum than the designation HAM/TSP suggests and that infected individuals may harbor other neurological syndromes in addition to HAM/TSP.}, }
@article {pmid31833636, year = {2020}, author = {Tsuneda, T}, title = {Density Functional Theory as a Data Science.}, journal = {Chemical record (New York, N.Y.)}, volume = {20}, number = {7}, pages = {618-639}, doi = {10.1002/tcr.201900081}, pmid = {31833636}, issn = {1528-0691}, support = {17H01188//Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 16KT0047//Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; }, abstract = {The development of density functional theory (DFT) functionals and physical corrections are reviewed focusing on the physical meanings and the semiempirical parameters from the viewpoint of data science. This review shows that DFT exchange-correlation functionals have been developed under many strict physical conditions with minimizing the number of the semiempirical parameters, except for some recent functionals. Major physical corrections for exchange-correlation function- als are also shown to have clear physical meanings independent of the functionals, though they inevitably require minimum semiempirical parameters dependent on the functionals combined. We, therefore, interpret that DFT functionals with physical corrections are the most sophisticated target functions that are physically legitimated, even from the viewpoint of data science.}, }
@article {pmid31832125, year = {2019}, author = {Yap, TE and Balendra, SI and Almonte, MT and Cordeiro, MF}, title = {Retinal correlates of neurological disorders.}, journal = {Therapeutic advances in chronic disease}, volume = {10}, number = {}, pages = {2040622319882205}, pmid = {31832125}, issn = {2040-6223}, abstract = {Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research.}, }
@article {pmid31831863, year = {2020}, author = {Cristino, L and Bisogno, T and Di Marzo, V}, title = {Cannabinoids and the expanded endocannabinoid system in neurological disorders.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {1}, pages = {9-29}, pmid = {31831863}, issn = {1759-4766}, mesh = {Analgesics/metabolism/therapeutic use ; Animals ; Cannabidiol/metabolism/therapeutic use ; Cannabinoids/*metabolism/therapeutic use ; Dronabinol/metabolism/therapeutic use ; Drug Combinations ; Endocannabinoids/*metabolism/therapeutic use ; Humans ; Nervous System Diseases/*drug therapy/*metabolism ; Receptor, Cannabinoid, CB1/metabolism ; Receptor, Cannabinoid, CB2/metabolism ; }, abstract = {Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ[9]-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system - known as the endocannabinoidome - that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.}, }
@article {pmid31823882, year = {2020}, author = {Bose, P}, title = {Novel small molecule TRVA242 targets neuromuscular junction in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {15}, number = {6}, pages = {1041-1042}, pmid = {31823882}, issn = {1673-5374}, }
@article {pmid31823868, year = {2020}, author = {Calvo, AC and Moreno, L and Moreno, L and Toivonen, JM and Manzano, R and Molina, N and de la Torre, M and López, T and Miana-Mena, FJ and Muñoz, MJ and Zaragoza, P and Larrodé, P and García-Redondo, A and Osta, R}, title = {Type XIX collagen: a promising biomarker from the basement membranes.}, journal = {Neural regeneration research}, volume = {15}, number = {6}, pages = {988-995}, pmid = {31823868}, issn = {1673-5374}, abstract = {Among collagen members in the collagen superfamily, type XIX collagen has raised increasing interest in relation to its structural and biological roles. Type XIX collagen is a Fibril-Associated Collagen with Interrupted Triple helices member, one main subclass of collagens in this superfamily. This collagen contains a triple helix composed of three polypeptide segments aligned in parallel and it is associated with the basement membrane zone in different tissues. The molecular structure of type XIX collagen consists of five collagenous domains, COL1 to COL5, interrupted by six non-collagenous domains, NC1 to NC6. The most relevant domain by which this collagen exerts its biological roles is NC1 domain that can be cleavage enzymatically to release matricryptins, exerting anti-tumor and anti-angiogenic effect in murine and human models of cancer. Under physiological conditions, type XIX collagen expression decreases after birth in different tissues although it is necessary to keep its basal levels, mainly in skeletal muscle and hippocampal and telencephalic interneurons in brain. Notwithstanding, in amyotrophic lateral sclerosis, altered transcript expression levels show a novel biological effect of this collagen beyond its structural role in basement membranes and its anti-tumor and anti-angiogenic properties. Type XIX collagen can exert a compensatory effect to ameliorate the disease progression under neurodegenerative conditions specific to amyotrophic lateral sclerosis in transgenic SOD1G93A mice and amyotrophic lateral sclerosis patients. This novel biological role highlights its nature as prognostic biomarker of disease progression in and as promising therapeutic target, paving the way to a more precise prognosis of amyotrophic lateral sclerosis.}, }
@article {pmid31820696, year = {2020}, author = {Lee, Y and Lee, BH and Yip, W and Chou, P and Yip, BS}, title = {Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders.}, journal = {Current pharmaceutical design}, volume = {25}, number = {43}, pages = {4560-4569}, doi = {10.2174/1381612825666191210154535}, pmid = {31820696}, issn = {1873-4286}, mesh = {Biomarkers/blood ; Humans ; Neurodegenerative Diseases/*diagnosis ; Neurofilament Proteins/*blood ; Prognosis ; }, abstract = {Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.}, }
@article {pmid31817487, year = {2019}, author = {Lanuza, MA and Just-Borràs, L and Hurtado, E and Cilleros-Mañé, V and Tomàs, M and Garcia, N and Tomàs, J}, title = {The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling.}, journal = {Cells}, volume = {8}, number = {12}, pages = {}, pmid = {31817487}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Exercise ; Gene Expression ; Humans ; Membrane Glycoproteins/*metabolism ; Motor Neurons/metabolism ; Muscle, Skeletal/metabolism/physiopathology ; Neuromuscular Junction/*metabolism ; Protein Kinase C/*metabolism ; Receptor, trkB/*metabolism ; *Signal Transduction ; }, abstract = {Brain-derived neurotrophic factor (BDNF) promotes neuron survival in adulthood in the central nervous system. In the peripheral nervous system, BDNF is a contraction-inducible protein that, through its binding to tropomyosin-related kinase B receptor (TrkB), contributes to the retrograde neuroprotective control done by muscles, which is necessary for motor neuron function. BDNF/TrkB triggers downstream presynaptic pathways, involving protein kinase C, essential for synaptic function and maintenance. Undeniably, this reciprocally regulated system exemplifies the tight communication between nerve terminals and myocytes to promote synaptic function and reveals a new view about the complementary and essential role of pre and postsynaptic interplay in keeping the synapse healthy and strong. This signaling at the neuromuscular junction (NMJ) could establish new intervention targets across neuromuscular diseases characterized by deficits in presynaptic activity and muscle contractility and by the interruption of the connection between nervous and muscular tissues, such as amyotrophic lateral sclerosis (ALS). Indeed, exercise and other therapies that modulate kinases are effective at delaying ALS progression, preserving NMJs and maintaining motor function to increase the life quality of patients. Altogether, we review synaptic activity modulation of the BDNF/TrkB/PKC signaling to sustain NMJ function, its and other kinases' disturbances in ALS and physical and molecular mechanisms to delay disease progression.}, }
@article {pmid31817379, year = {2019}, author = {Schellino, R and Boido, M and Vercelli, A}, title = {JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death.}, journal = {Cells}, volume = {8}, number = {12}, pages = {}, pmid = {31817379}, issn = {2073-4409}, mesh = {Animals ; Cell Death ; Cell Differentiation ; Central Nervous System/embryology/metabolism ; Disease Susceptibility ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; *MAP Kinase Signaling System ; Neurodegenerative Diseases/etiology/metabolism/pathology ; Neurogenesis ; Neurons/*metabolism ; Organogenesis ; Spinal Cord/embryology/*metabolism ; }, abstract = {The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3. In the developing spinal cord, JNK proteins control neuronal polarity, axon growth/pathfinding, and programmed cell death; in adulthood they can drive degeneration and regeneration, after pathological insults. Indeed, recent studies have highlighted a role for JNK in motor neuron (MN) diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophy. In this review we discuss how JNK-dependent signaling regulates apparently contradictory functions in the spinal cord, in both the developmental and adult stages. In addition, we examine the evidence that the specific targeting of JNK signaling pathway may represent a promising therapeutic strategy for the treatment of MN diseases.}, }
@article {pmid31817338, year = {2019}, author = {Germeys, C and Vandoorne, T and Bercier, V and Van Den Bosch, L}, title = {Existing and Emerging Metabolomic Tools for ALS Research.}, journal = {Genes}, volume = {10}, number = {12}, pages = {}, pmid = {31817338}, issn = {2073-4425}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; *Energy Metabolism ; Humans ; *Metabolomics ; Motor Neurons/*metabolism/pathology ; }, abstract = {Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new possibilities for ALS research. Here, we review existing and emerging metabolomic tools that could be used to further investigate the role of metabolism in ALS. A better understanding of the metabolic state of motor neurons and their surrounding cells could hopefully result in novel therapeutic strategies.}, }
@article {pmid31816444, year = {2020}, author = {Ji, T and Zhang, X and Xin, Z and Xu, B and Jin, Z and Wu, J and Hu, W and Yang, Y}, title = {Does perturbation in the mitochondrial protein folding pave the way for neurodegeneration diseases?.}, journal = {Ageing research reviews}, volume = {57}, number = {}, pages = {100997}, doi = {10.1016/j.arr.2019.100997}, pmid = {31816444}, issn = {1872-9649}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Caenorhabditis elegans/metabolism ; Humans ; Mammals/metabolism ; Mitochondria/*metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; *Protein Folding ; Signal Transduction ; *Unfolded Protein Response ; }, abstract = {Mitochondria, which are cell compartments that are widely present in eukaryotic cells, have been shown to be involved in a variety of synthetic, metabolic, and signaling processes, thereby playing a vital role in cells. The mitochondrial unfolded protein response (mtUPR) is a response in which mitochondria reverse the signal to the nucleus and maintain mitochondrial protein homeostasis when unfolded and misfolded proteins continue to accumulate. Multiple neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and familial amyotrophic lateral sclerosis (fALS), are public health challenges. Every year, countless efforts are expended trying to clarify the pathogenesis and treatment of neurological disorders, which are associated with mitochondrial dysfunction to some extent. Numerous studies have shown that mtUPR is involved in and plays an important role in the pathogenesis of neurological disorders, but the exact mechanism of the disorders is still unclear. Further study of the process of mtUPR in neurological disorders can help us more accurately understand their pathogenesis in order to provide new therapeutic targets. In this paper, we briefly review mtUPR signaling in Caenorhabditis elegans (C. elegans) and mammals and summarize the role of mtUPR in neurodegeneration diseases, including AD, PD and fALS.}, }
@article {pmid31815123, year = {2019}, author = {Abg Abd Wahab, DY and Gau, CH and Zakaria, R and Muthu Karuppan, MK and A-Rahbi, BS and Abdullah, Z and Alrafiah, A and Abdullah, JM and Muthuraju, S}, title = {Review on Cross Talk between Neurotransmitters and Neuroinflammation in Striatum and Cerebellum in the Mediation of Motor Behaviour.}, journal = {BioMed research international}, volume = {2019}, number = {}, pages = {1767203}, pmid = {31815123}, issn = {2314-6141}, mesh = {Animals ; Astrocytes/metabolism ; Central Nervous System/drug effects ; Cerebellum/*drug effects ; Corpus Striatum/*drug effects ; Cytokines/metabolism ; Disease Models, Animal ; Dopamine/pharmacology ; Glutamic Acid/pharmacology ; Humans ; *Inflammation ; Interleukin-1beta ; Lipopolysaccharides/adverse effects ; Mice ; Microglia/metabolism ; Motor Neurons/*drug effects ; Neurotransmitter Agents/*pharmacology ; Serotonin/pharmacology ; Toll-Like Receptor 4 ; Toll-Like Receptors ; gamma-Aminobutyric Acid/pharmacology ; }, abstract = {Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1β, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour.}, }
@article {pmid31812811, year = {2020}, author = {Zhang, Y and Whalen, JK}, title = {Production of the neurotoxin beta-N-methylamino-l-alanine may be triggered by agricultural nutrients: An emerging public health issue.}, journal = {Water research}, volume = {170}, number = {}, pages = {115335}, doi = {10.1016/j.watres.2019.115335}, pmid = {31812811}, issn = {1879-2448}, mesh = {*Amino Acids, Diamino ; Animals ; Cyanobacteria Toxins ; Humans ; Neurotoxins ; Nutrients ; *Public Health ; }, abstract = {Diverse taxa of cyanobacteria, dinoflagellates and diatoms produce β-N-methylamino-l-alanine (BMAA), a non-lipophilic, non-protein amino acid. BMAA is a neurotoxin in mammals. Its ingestion may be linked to human neurodegenerative diseases, namely the Amyotrophic lateral sclerosis/Parkinsonism dementia complex, based on epidemiological evidence from regions where cyanobacterial harmful algal blooms occur frequently. In controlled environments, cyanobacteria produce BMAA in response to ecophysiological cues such as nutrient availability, which may explain the elevated BMAA concentrations in freshwater environments that receive nutrient-rich agricultural runoff. This critical review paper summarizes what is known about how BMAA supports ecophysiological functions like nitrogen metabolism, photosyntheis and provides a competitive advantage to cyanobacteria in controlled and natural environments. We explain how BMAA production affected competitive interactions among the N2-fixing and non-N2-fixing populations in a freshwater cyanobacterial bloom that was stimulated by nutrient loading from the surrounding agricultural landscape. Better control of nutrients in agricultural fields is an excellent strategy to avoid the negative environmental consequences and public health concerns related to BMAA production.}, }
@article {pmid31812544, year = {2020}, author = {Zhang, Y and Anoopkumar-Dukie, S and Arora, D and Davey, AK}, title = {Review of the anti-inflammatory effect of SIRT1 and SIRT2 modulators on neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {867}, number = {}, pages = {172847}, doi = {10.1016/j.ejphar.2019.172847}, pmid = {31812544}, issn = {1879-0712}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Brain/drug effects/immunology/pathology ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*drug therapy/genetics/immunology/pathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Polymorphism, Single Nucleotide ; Sirtuin 1/*antagonists &amp; inhibitors/genetics/immunology/metabolism ; Sirtuin 2/*antagonists &amp; inhibitors/genetics/immunology/metabolism ; Treatment Outcome ; }, abstract = {Neurodegenerative disease refers to a range of chronic and progressive disorders that are characterized by dysfunction and loss of neurons. Neurodegeneration involves protein misfolding, oxidative injury, impaired mitochondrial function, neurotrophin deficiency and may also involve neuroinflammation. The sirtuin family of proteins plays a key role in this process suggesting that modulation of sirtuin can modify disease progression. This review examines experimental and clinical evidence relating to the potential role of SIRT1 and SIRT2, and their modulators in neurodegenerative diseases. Both neuroprotective effects and negative effects of SIRT1 activators, SIRT1 inhibitors and SIRT2 activators are discussed in a range of different disease models, including in vitro and in vivo Alzheimer's disease (AD), Parkinson's disease (PD), Huntingdon's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). This highlights the potential of SIRT1 and SIRT 2 modulators as potential therapeutic agents. However, there is a paucity of clinical trials related to the effects of selective SIRT1 modulators, selective SIRT2 modulators or dual SIRT1/2 modulators on neuroinflammation and subsequent neurodegeneration.}, }
@article {pmid31811636, year = {2019}, author = {Sidibé, H and Vande Velde, C}, title = {RNA Granules and Their Role in Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1203}, number = {}, pages = {195-245}, doi = {10.1007/978-3-030-31434-7_8}, pmid = {31811636}, issn = {0065-2598}, mesh = {Cytoplasmic Granules/metabolism ; Humans ; *Neurodegenerative Diseases/physiopathology ; *RNA, Messenger/metabolism ; }, abstract = {In recent years, cytoplasmic RNA granules, which are micron-sized membrane-less entities formed by phase separation, have progressively gained recognition as essential constituents of neuronal RNA metabolism. Stress granules form under adverse growth conditions in order to protect nontranslating mRNA, shift translation toward the production of prosurvival factors, as well as potentially serve as hubs for intracellular signaling. In contrast, processing bodies play a role in RNA degradation in both stressed and homeostatic conditions. Lastly, transport granules permit, as their name indicates, the transport of mRNA within neurons. All of these granule subtypes are required for proper neuronal function; thus, impairments in their regulation and/or composition are expected to be deleterious. Here, we review these cytoplasmic RNA granule subtypes and discuss how they have been implicated in some neurodegenerative diseases.}, }
@article {pmid31802540, year = {2020}, author = {Takeda, T and Kitagawa, K and Arai, K}, title = {Phenotypic variability and its pathological basis in amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {40}, number = {1}, pages = {40-56}, doi = {10.1111/neup.12606}, pmid = {31802540}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Biological Variation, Population/*physiology ; Brain/pathology ; Disease Progression ; Frontotemporal Lobar Degeneration/*pathology ; Humans ; Motor Neurons/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by its inherent clinicopathological variability. The concurrence of upper and lower motor neuron signs is a common feature in the majority of patients with ALS. However, some patients manifest an atypical clinical course, with only upper or lower motor neuron signs, or various extra-motor symptoms including cognitive dysfunction, parkinsonism, autonomic dysfunction, or ophthalmoparesis. This variability indicates different manifestations of ALS and is reflected by ALS pathology spreading into the central nervous system. The presence of cytoplasmic inclusions positive for transactivation response DNA-binding protein 43 kDa (TDP-43) is a key feature in ALS. Loss of TDP-43 from the nucleus and its subsequent aggregation in the cytoplasm may occur in susceptible regions and may be associated with neuronal loss. However, in some regions, there is no apparent neuronal loss while TDP-43 accumulation is evident; in contrast, in other regions, neuronal loss is apparent without any evidence of TDP-43 accumulation. Therefore, in addition to TDP-43 dysfunction, underlying region-specific cellular vulnerability may exist in the upper and lower motor neurons and frontotemporal system in patients with ALS. The microscopic discrepancy and selective vulnerability may be linked to the macroscopic propensities of the sites of onset, and may also determine the direction and rate of progression of the lesions. Thus, there may be multicentric sites of onset, region-oriented disease development, and different speeds of disease progression across patients with ALS. ALS lesions occur in motor-related areas but may spread to neighboring areas. However, since lesions may spread in a discontinuous manner, and the dynamics of disease propagation have not been able to be identified, it remains controversial whether the stepwise appearance of TDP-43-positive inclusions is based on direct cell-to-cell protein propagation. Further understanding of the phenotypic variability of ALS and its pathological basis may serve as a guide for investigating the underlying pathogenesis of ALS.}, }
@article {pmid31801298, year = {2019}, author = {Konovalova, J and Gerasymchuk, D and Parkkinen, I and Chmielarz, P and Domanskyi, A}, title = {Interplay between MicroRNAs and Oxidative Stress in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {23}, pages = {}, pmid = {31801298}, issn = {1422-0067}, support = {293392, 319195//Academy of Finland/ ; }, mesh = {Alzheimer Disease/genetics/*metabolism/pathology ; Amyloid beta-Peptides/chemistry/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Gene Expression Regulation ; Humans ; Huntington Disease/genetics/*metabolism/pathology ; MicroRNAs/classification/*genetics/metabolism ; Mitochondria/metabolism ; Nerve Tissue Proteins/classification/genetics/metabolism ; Neurons/metabolism/pathology ; Oxidation-Reduction ; Oxidative Stress/*genetics ; Parkinson Disease/genetics/*metabolism/pathology ; Signal Transduction ; }, abstract = {MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.}, }
@article {pmid31792674, year = {2021}, author = {Cerveró, A and Casado, A and Riancho, J}, title = {Retinal changes in amyotrophic lateral sclerosis: looking at the disease through a new window.}, journal = {Journal of neurology}, volume = {268}, number = {6}, pages = {2083-2089}, pmid = {31792674}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; Retina/diagnostic imaging ; Retinal Vessels ; Tomography, Optical Coherence ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent degenerative disease affecting motor neurons (MN). ALS has been traditionally considered as a pure motor system disease; however, there are currently sufficient evidences supporting the involvement of other non-motor systems. Recently, the development and the implementation of the optical coherence tomography (OCT) have provided new data regarding the ocular involvement in the disease. In this sense, alterations in retinal nerve fiber layer thickness (RNFL), other retinal layers thicknesses such as outer nuclear layer (ONL) and inner nuclear layer (INL) and changes in the retinal blood vessels have been described in ALS patients. Interestingly, the study of ocular alterations in ALS appears not only as new biomarker tool, but also as a new opportunity to deep into the pathogenesis of the disease. In this article we will review and standardize published studies regarding OCT and ALS, emphasizing both their strengths and weaknesses.}, }
@article {pmid31785300, year = {2020}, author = {Simanaviciute, U and Ahmed, J and Brown, RE and Connor-Robson, N and Farr, TD and Fertan, E and Gambles, N and Garland, H and Morton, AJ and Staiger, JF and Skillings, EA and Trueman, RC and Wade-Martins, R and Wood, NI and Wong, AA and Grant, RA}, title = {Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.}, journal = {Journal of neuroscience methods}, volume = {331}, number = {}, pages = {108532}, doi = {10.1016/j.jneumeth.2019.108532}, pmid = {31785300}, issn = {1872-678X}, support = {J-0901/PUK_/Parkinson's UK/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; NC/M001598/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {Animals ; Cognition ; Locomotion ; Mice ; *Neurodegenerative Diseases ; Reproducibility of Results ; Somatosensory Cortex ; *Vibrissae ; }, abstract = {BACKGROUND: Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains.<br><br>NEW METHOD: We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke.<br><br>RESULTS: Sex, background strain, source breeder and genotype all affected whisker movements. All mouse models, apart from Parkinson's disease, revealed differences in whisker movements during locomotion. R6/2 CAG250 Huntington's disease mice had the strongest behavioural phenotype. Robo3R[3-5]-CKO and RIM-DKOSert mouse models have abnormal somatosensory cortex development and revealed significant changes in whisker movements during object exploration.<br><br>Our results have good agreement with past studies, which indicates the robustness and reliability of measuring whisking. We recommend that differences in whisker movements of mice with motor deficits can be captured in open field arenas, but that mice with impairments to sensory or cognitive functioning should also be filmed investigating objects. Scoring clips qualitatively before tracking will help to structure later analyses.<br><br>CONCLUSIONS: Studying whisker movements provides a quantitative measure of sensing, motor control and exploration. However, the effect of background strain, sex and age on whisker movements needs to be better understood.}, }
@article {pmid31783880, year = {2019}, author = {Malik, BR and Maddison, DC and Smith, GA and Peters, OM}, title = {Autophagic and endo-lysosomal dysfunction in neurodegenerative disease.}, journal = {Molecular brain}, volume = {12}, number = {1}, pages = {100}, pmid = {31783880}, issn = {1756-6606}, support = {MC_PC_16030/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_16030/2/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Autophagy ; Endosomes/metabolism ; Humans ; Lysosomes/*pathology ; Molecular Chaperones/metabolism ; Neurodegenerative Diseases/*pathology ; Signal Transduction ; }, abstract = {Due to their post-mitotic state, metabolic demands and often large polarised morphology, the function and survival of neurons is dependent on an efficient cellular waste clearance system both for generation of materials for metabolic processes and removal of toxic components. It is not surprising therefore that deficits in protein clearance can tip the balance between neuronal health and death. Here we discuss how autophagy and lysosome-mediated degradation pathways are disrupted in several neurological disorders. Both genetic and cell biological evidence show the diversity and complexity of vesicular clearance dysregulation in cells, and together may ultimately suggest a unified mechanism for neuronal demise in degenerative conditions. Causative and risk-associated mutations in Alzheimer's disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease and others have given the field a unique mechanistic insight into protein clearance processes in neurons. Through their broad implication in neurodegenerative diseases, molecules involved in these genetic pathways, in particular those involved in autophagy, are emerging as appealing therapeutic targets for intervention in neurodegeneration.}, }
@article {pmid31782056, year = {2019}, author = {Pahan, K}, title = {A Broad Application of CRISPR Cas9 in Infectious, Inflammatory and Neurodegenerative Diseases.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {14}, number = {4}, pages = {534-536}, pmid = {31782056}, issn = {1557-1904}, support = {I01 BX003033/BX/BLRD VA/United States ; R01 AG050431/AG/NIA NIH HHS/United States ; I01 BX005002/BX/BLRD VA/United States ; R21 NS108025/NS/NINDS NIH HHS/United States ; IK6 BX004982/BX/BLRD VA/United States ; }, mesh = {Animals ; CRISPR-Associated Protein 9/*genetics/immunology ; CRISPR-Cas Systems/*genetics/immunology ; Gene Editing/*methods/trends ; HIV Infections/*genetics/immunology/therapy ; Humans ; Inflammation/*genetics/immunology/therapy ; Neurodegenerative Diseases/*genetics/immunology/therapy ; }, abstract = {Being the most important immune-responsive cell type of the CNS, microglia always glorify the so-called crossroad of Neurology, Immunology and Pharmacology. As microglial activation is a hallmark of different neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), HIV-associated neurocognitive disorders (HAND), Amyotrophic lateral sclerosis (ALS), etc., selective targeting of microglial cell signaling may be a valid option to control these neurodegenerative disorders with lesser side effects. This is particularly important as no effective therapies are available against these diseases and available neuroimmune modulators are known to target multiple cell types in a non-cell-specific manner. How we can achieve such specificity? A newly-developed cutting-edge molecular biology tool is rocking biomedical research in recent years so much so that it has already come under major lawsuits between the University of California Berkeley and the MIT-Harvard Broad Institute regarding its ownership rights, probably halting the Nobel committee to announce the most coveted prize to its owners. It is none other than Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). In nutshell, the Cas9 enzyme has been paired with the bacterial immune system, CRISPR, to ultimately turn CRISPR/Cas9 as an effective genome editor. Therefore, this special issue has been devoted to highlight some of the recent discoveries on CRISPR/Cas9 in neurodegenerative disorders and explain these discoveries in the light of neuroimmune pharmacology.}, }
@article {pmid31780895, year = {2019}, author = {Wells, C and Brennan, SE and Keon, M and Saksena, NK}, title = {Prionoid Proteins in the Pathogenesis of Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {271}, pmid = {31780895}, issn = {1662-5099}, abstract = {There is a growing body of evidence that prionoid protein behaviors are a core element of neurodegenerative diseases (NDs) that afflict humans. Common elements in pathogenesis, pathological effects and protein-level behaviors exist between Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). These extend beyond the affected neurons to glial cells and processes. This results in a complicated system of disease progression, which often takes advantage of protective processes to promote the propagation of pathological protein aggregates. This review article provides a current snapshot of knowledge on these proteins and their intrinsic role in the pathogenesis and disease progression seen across NDs.}, }
@article {pmid31779815, year = {2019}, author = {Rowe, JB}, title = {Parkinsonism in frontotemporal dementias.}, journal = {International review of neurobiology}, volume = {149}, number = {}, pages = {249-275}, doi = {10.1016/bs.irn.2019.10.012}, pmid = {31779815}, issn = {2162-5514}, support = {MC_U105597119/MRC_/Medical Research Council/United Kingdom ; MC_UU_00005/12/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Frontotemporal Dementia/complications/drug therapy/genetics/*physiopathology ; Humans ; Motor Neuron Disease/complications/drug therapy/genetics/*physiopathology ; Parkinsonian Disorders/drug therapy/etiology/genetics/*physiopathology ; Primary Progressive Nonfluent Aphasia/complications/drug therapy/genetics/*physiopathology ; }, abstract = {Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders, with progressive impairment of behavior and language. They can be closely related to amyotrophic lateral sclerosis, clinically and through shared genetics and similar pathology. Approximately 40% of people with frontotemporal dementia report a family history of dementia, motor neuron disease or parkinsonism, and half of these familial cases are attributed to mutations in three genes (C9orf72, MAPT and PGRN). Akinetic-rigidity is a common feature in several types of frontotemporal dementia, particularly the behavioral variant and the non-fluent agrammatic variant of primary progressive aphasia, and the familial dementias. The majority of patients develop a degree of parkinsonism during the course of the illness, and signs may be present at the time of initial diagnosis. However, the parkinsonism of frontotemporal dementia is very different from that observed in idiopathic Parkinson's disease: it may be symmetric, axial, and poorly responsive to levodopa. Tremor is uncommon, and may be postural, action or occasionally rest tremor. The emergence of parkinsonism is often part of an evolving phenotype, in which frontotemporal dementia comes to resemble corticobasal syndrome or progressive supranuclear palsy. This chapter describes the prevalence and phenomenology of parkinsonism in each of the major syndromes, and according to the common genetic forms of frontotemporal dementia. We discuss the changing nosology and terminology surrounding the diagnoses, and the significance of parkinsonism as a core feature of frontotemporal dementia, relevant to clinical management and the design of future clinical trials.}, }
@article {pmid31776989, year = {2019}, author = {Wang, R and Wang, G}, title = {Protein Modification and Autophagy Activation.}, journal = {Advances in experimental medicine and biology}, volume = {1206}, number = {}, pages = {237-259}, doi = {10.1007/978-981-15-0602-4_12}, pmid = {31776989}, issn = {0065-2598}, mesh = {Acetylation ; *Autophagy ; Phosphorylation ; *Protein Processing, Post-Translational ; Sumoylation ; Ubiquitination ; }, abstract = {Protein modification refers to the chemical modification of proteins after their biosynthesis, which is also called posttranslational modification (PTM). PTM causes changes in protein properties and functions. PTM includes an attachment of addition of functional groups, such as methylation, acetylation, glycosylation and phosphorylation; a covalent coupling of small peptides or proteins, such as ubiquitination and SUMOylation; or chemical changes in amino acids, such as citrullination (conversion of arginine to citrulline). Protein modification plays an important role in cellular processes. Since a protein can be modified in different ways, such as acetylation, methylation and phosphorylation, the functions of proteins are different under different modification states. Moreover, the same modification at different sites may have completely different effects on protein function. For example, phosphorylation at some sites in a protein may lead to a functional activation, while phosphorylation at other sites may cause an inhibition of the functions. Thus, different modifications, combinations and sites changes lead to different functional regulations of a protein, resulting in different effects in the cells. In autophagy, PTMs are widely involved in the regulation of autophagy, including ubiquitination, phosphorylation and acetylation. Ubiquitination is the covalent conjugation of ubiquitin to the substrates through a series of enzymes. Phosphorylation refers to an attachment of a phosphoryl group into a protein, primarily on serine, threonine and tyrosine, which is catalyzed by the kinases. Phosphorylation, a common modification, regulates protein function and localization. Phosphorylation in autophagy regulates the activity of autophagy-associated proteins and the initiation and progression of autophagy by regulating signaling pathways. Acetylation means the addition of acetyl groups onto lysine or N-terminal segment of target proteins through acetyltransferases. Acetylation and deacetylation are both involved in the regulation of autophagy initiation and selective autophagy by controlling the acetylation level of important proteins in the autophagy process. In this chapter, we will focus on the regulation of ubiquitination and phosphorylation in autophagy.}, }
@article {pmid31773397, year = {2019}, author = {Silverman, HE and Goldman, JS and Huey, ED}, title = {Links Between the C9orf72 Repeat Expansion and Psychiatric Symptoms.}, journal = {Current neurology and neuroscience reports}, volume = {19}, number = {12}, pages = {93}, pmid = {31773397}, issn = {1534-6293}, mesh = {C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Genetic Linkage/*genetics ; Heterozygote ; Humans ; Mental Disorders/*diagnosis/*genetics/psychology ; Phenotype ; }, abstract = {PURPOSE OF REVIEW: To present recent findings on the links between the C9orf72 expansion and psychiatric impairment.<br><br>RECENT FINDINGS: Repeat hexanucleotide expansions in the C9orf72 gene are a cause of familial frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and the mixed phenotype, FTD-ALS. Symptomatic expansion carriers display higher rates of psychotic and other psychiatric symptoms than non-carriers. Neuroanatomical associations of these symptoms have been found in cortical and subcortical areas. Family members of symptomatic carriers have higher rates of primary neuropsychiatric disorders than control populations, and the C9orf72 expansion may contribute to this association. However, the expansion does not appear to directly cause primary psychiatric disorders. While there is strong evidence associating the C9orf72 expansion with psychotic symptoms in carriers and psychiatric disorders in their kindreds, the link between these two phenomena, if any, remains unclear.}, }
@article {pmid31770357, year = {2019}, author = {}, title = {Cannabis and cannabinoids.}, journal = {The Medical letter on drugs and therapeutics}, volume = {61}, number = {1585}, pages = {179-182}, pmid = {31770357}, issn = {1523-2859}, mesh = {Adult ; Cannabinoids/adverse effects/*therapeutic use ; Drug Interactions ; Drug Prescriptions ; Female ; Humans ; Legislation, Drug ; Medical Marijuana/adverse effects/*therapeutic use ; Pregnancy ; }, }
@article {pmid31767352, year = {2020}, author = {Boyman, L and Karbowski, M and Lederer, WJ}, title = {Regulation of Mitochondrial ATP Production: Ca[2+] Signaling and Quality Control.}, journal = {Trends in molecular medicine}, volume = {26}, number = {1}, pages = {21-39}, pmid = {31767352}, issn = {1471-499X}, support = {U01 HL116321/HL/NHLBI NIH HHS/United States ; R01 HL142290/HL/NHLBI NIH HHS/United States ; R01 AR071618/AR/NIAMS NIH HHS/United States ; R01 GM129584/GM/NIGMS NIH HHS/United States ; R01 HL140934/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Calcium Signaling/*physiology ; Humans ; Mitochondria/*metabolism ; Mitochondrial Membranes/metabolism ; Signal Transduction/*physiology ; }, abstract = {Cardiac ATP production primarily depends on oxidative phosphorylation in mitochondria and is dynamically regulated by Ca[2+] levels in the mitochondrial matrix as well as by cytosolic ADP. We discuss mitochondrial Ca[2+] signaling and its dysfunction which has recently been linked to cardiac pathologies including arrhythmia and heart failure. Similar dysfunction in other excitable and long-lived cells including neurons is associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Central to this new understanding is crucial Ca[2+] regulation of both mitochondrial quality control and ATP production. Mitochondria-associated membrane (MAM) signaling from the sarcoplasmic reticulum (SR) and the endoplasmic reticulum (ER) to mitochondria is discussed. We propose future research directions that emphasize a need to define quantitatively the physiological roles of MAMs, as well as mitochondrial quality control and ATP production.}, }
@article {pmid31760962, year = {2019}, author = {Wright, GSA and Antonyuk, SV and Hasnain, SS}, title = {The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis.}, journal = {Quarterly reviews of biophysics}, volume = {52}, number = {}, pages = {e12}, doi = {10.1017/S003358351900012X}, pmid = {31760962}, issn = {1469-8994}, support = {HASNAIN/APR15/833-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MRF_MRF-060-0002-RG-HASNA(60)/MRF/MRF/United Kingdom ; WRIGHT/OCT18/969-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Biophysical Phenomena ; Humans ; Superoxide Dismutase-1/*chemistry/*metabolism ; }, abstract = {Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in the sod1 gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.}, }
@article {pmid31759615, year = {2019}, author = {Alegret, N and Serra, P and Pessas, JP and Curià, X and Vidal, J and Valero, R}, title = {Anesthetic management of the diaphragmatic pacemaker placement surgery. Our experience in the Institut Guttmann.}, journal = {Revista espanola de anestesiologia y reanimacion}, volume = {66}, number = {10}, pages = {497-505}, doi = {10.1016/j.redar.2019.10.005}, pmid = {31759615}, issn = {2341-1929}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications ; Anesthesia, General/*methods ; Autonomic Dysreflexia/etiology ; Child ; Child, Preschool ; Chronic Disease ; *Diaphragm ; Female ; Humans ; Hypotension/etiology ; Implantable Neurostimulators ; Intraoperative Complications/etiology ; Laparoscopy/adverse effects ; Male ; Middle Aged ; *Pacemaker, Artificial ; Phrenic Nerve/injuries ; Pneumothorax/etiology ; Quadriplegia/*complications ; Respiration Disorders/etiology/*therapy ; Respiration, Artificial/adverse effects ; Retrospective Studies ; Spinal Cord Injuries/*complications ; Tracheostomy/statistics &amp; numerical data ; }, abstract = {BACKGROUND: The diaphragm pacemaker (DP) has proven its utility in replacing mechanical ventilation in patients with chronic spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). The DP improves patient quality of life and reduces morbidity and mortality and their associated health care costs. The anesthetic management of these patients and the particularities of the surgical procedure are challenging. The aim of our study is to analyze anesthetic management and intraoperative complications in patients undergoing DP placement in our hospital.<br><br>METHODS: We performed a chart review of patients treated between December 2007 and July 2017, recording the patients' preoperative status, anesthetic management and intraoperative complications.<br><br>RESULTS: The study included 16 patients (5 pediatric) undergoing DP implantation for chronic SCI (63%), ALS (25%) and other neurologic conditions (12%). Abdominal laparoscopy was performed under general anesthesia, with intravenous (87%) or inhalational (13%) induction and maintenance using total intravenous (50%) or balanced (50%) anesthesia. Rocuronium was administered in one case to permit airway management. Complications included: hypotension (50%), difficulties in mechanical ventilation during laparoscopy (31%), pneumothorax (12.5%) and autonomic dysreflexia (6%).<br><br>CONCLUSIONS: DP placement under general anesthesia is a safe intervention in both adult and pediatric patients. Complications derived from both the underlying disease and the surgical technique may appear, and must be rapidly identified and treated to obtain a satisfactory surgical outcome.}, }
@article {pmid31759135, year = {2020}, author = {Hawrot, J and Imhof, S and Wainger, BJ}, title = {Modeling cell-autonomous motor neuron phenotypes in ALS using iPSCs.}, journal = {Neurobiology of disease}, volume = {134}, number = {}, pages = {104680}, pmid = {31759135}, issn = {1095-953X}, support = {DP2 NS106664/NS/NINDS NIH HHS/United States ; K08 NS082364/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Animals ; Brain/physiopathology ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/*physiology ; *Models, Neurological ; Motor Neurons/*physiology ; Phenotype ; Spinal Cord/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an aggressive and uniformly fatal degenerative disease of the motor nervous system. In order to understand underlying disease mechanisms, researchers leverage a host of in vivo and in vitro models, including yeast, worms, flies, zebrafish, mice, and more recently, human induced pluripotent stem cells (iPSCs) derived from ALS patients. While mouse models have been the main workhorse of preclinical ALS research, the development of iPSCs provides a new opportunity to explore molecular phenotypes of ALS within human cells. Importantly, this technology enables modeling of both familial and sporadic ALS in the relevant human genetic backgrounds, as well as a personalized or targeted approach to therapy development. Harnessing these powerful tools requires addressing numerous challenges, including different variance components associated with iPSCs and motor neurons as well as concomitant limits of reductionist approaches. In order to overcome these obstacles, optimization of protocols and assays, confirmation of phenotype robustness at scale, and validation of findings in human tissue and genetics will cement the role for iPSC models as a valuable complement to animal models in ALS and more broadly among neurodegenerative diseases.}, }
@article {pmid31758537, year = {2019}, author = {Kivisäkk, P and Khoury, SJ}, title = {Co-signaling Molecules in Neurological Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1189}, number = {}, pages = {233-265}, doi = {10.1007/978-981-32-9717-3_9}, pmid = {31758537}, issn = {0065-2598}, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Animals ; Brain Ischemia ; Multiple Sclerosis ; *Nervous System Diseases ; Parkinson Disease ; *Signal Transduction ; }, abstract = {Inflammation plays an important role in the onset and progression of many neurological diseases. As the central nervous system (CNS) constitutes a highly specialized environment where immune activation can be detrimental, it is crucial to understand mechanisms by which the immune system is regulated during neurological diseases. The system of co-signaling pathways provides the immune system with the means to fine-tune immune responses by turning on and off immune cell activation. Studies of co-signaling molecules in neurological diseases and their animal models have highlighted the complexities of immune regulation within the CNS and the intricacies of the interplay between the different cells of the immune system and how they interact with the resident cells of the CNS. This complexity poses challenges when targeting co-signaling pathway to treat neurological diseases and may explain why no drugs targeting these pathways have been successfully developed this far. Here, we will review the current literature on some important co-signaling pathways in multiple sclerosis (MS), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and ischemic stroke to understand these pathways in mediating and controlling neuroinflammation.}, }
@article {pmid31753134, year = {2019}, author = {Risacher, SL and Saykin, AJ}, title = {Neuroimaging in aging and neurologic diseases.}, journal = {Handbook of clinical neurology}, volume = {167}, number = {}, pages = {191-227}, pmid = {31753134}, issn = {0072-9752}, support = {K01 AG049050/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG061788/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Aging/*pathology ; Brain Diseases/*diagnostic imaging ; Female ; Humans ; Male ; Neurodegenerative Diseases/*diagnostic imaging ; Neuroimaging/*methods/trends ; }, abstract = {Neuroimaging biomarkers for neurologic diseases are important tools, both for understanding pathology associated with cognitive and clinical symptoms and for differential diagnosis. This chapter explores neuroimaging measures, including structural and functional measures from magnetic resonance imaging (MRI) and molecular measures primarily from positron emission tomography (PET), in healthy aging adults and in a number of neurologic diseases. The spectrum covers neuroimaging measures from normal aging to a variety of dementias: late-onset Alzheimer's disease [AD; including mild cognitive impairment (MCI)], familial and nonfamilial early-onset AD, atypical AD syndromes, posterior cortical atrophy (PCA), logopenic aphasia (lvPPA), cerebral amyloid angiopathy (CAA), vascular dementia (VaD), sporadic and familial behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA), frontotemporal dementia with motor neuron disease (FTD-MND), frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), Parkinson's disease (PD) with and without dementia, and multiple systems atrophy (MSA). We also include a discussion of the appropriate use criteria (AUC) for amyloid imaging and conclude with a discussion of differential diagnosis of neurologic dementia disorders in the context of neuroimaging.}, }
@article {pmid31749933, year = {2019}, author = {Fathi, D and Nafissi, S and Attarian, S and Neuwirth, C and Fatehi, F}, title = {An overview of motor unit number index reproducibility in amyotrophic lateral sclerosis.}, journal = {Iranian journal of neurology}, volume = {18}, number = {3}, pages = {119-126}, pmid = {31749933}, issn = {2008-384X}, abstract = {Motor unit number index (MUNIX) is an electrophysiological technique to give an estimate of functioning motor neurons in a muscle. For any given neurophysiological technique for the use in clinical or research studies, reproducibility between different operators and in a single operator in different times is one of the most important qualities, which must be evaluated and approved by different examiners and centers. After its introduction, testing the reproducibility of MUNIX was the aim of many studies to show this quality of the technique. In this review, we aimed to summarize all the studies, which have been performed up to now to approve MUNIX reproducibility in amyotrophic lateral sclerosis comparing healthy individuals.}, }
@article {pmid31747384, year = {2020}, author = {Isaev, NK and Stelmashook, EV and Genrikhs, EE}, title = {Role of zinc and copper ions in the pathogenetic mechanisms of traumatic brain injury and Alzheimer's disease.}, journal = {Reviews in the neurosciences}, volume = {31}, number = {3}, pages = {233-243}, doi = {10.1515/revneuro-2019-0052}, pmid = {31747384}, issn = {2191-0200}, mesh = {Alzheimer Disease/*metabolism ; Animals ; Apoptosis ; Brain Injuries, Traumatic/*metabolism ; Copper/*metabolism/toxicity ; Humans ; Neurons/metabolism ; Zinc/*metabolism/toxicity ; }, abstract = {The disruption of homeostasis of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Wilson's, Creutzfeldt-Jakob, Parkinson's, and Alzheimer's diseases (AD), and traumatic brain injury (TBI). The last two pathological conditions of the brain are the most common; moreover, it is possible that TBI is a risk factor for the development of AD. Disruptions of Zn2+ and Cu2+ homeostasis play an important role in the mechanisms of pathogenesis of both TBI and AD. This review attempts to summarize and systematize the currently available research data on this issue. The neurocytotoxicity of Cu2+ and Zn2+, the synergism of the toxic effect of calcium and Zn2+ ions on the mitochondria of neurons, and the interaction of Zn2+ and Cu2+ with β-amyloid (Abeta) and tau protein are considered.}, }
@article {pmid31743251, year = {2019}, author = {Bromberg, MB}, title = {What Is in the Literature.}, journal = {Journal of clinical neuromuscular disease}, volume = {21}, number = {2}, pages = {84-89}, doi = {10.1097/CND.0000000000000249}, pmid = {31743251}, issn = {1537-1611}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*physiopathology/therapy ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents ; Stem Cell Transplantation ; }, abstract = {This installment of what is in the literature is on amyotrophic lateral sclerosis (ALS). The pathophysiology of ALS remains open and the role of genes, a foothold into pathophysiology, but there are >22 genes identified, and the mechanisms are not known for any. Despite the lack of a firm understanding of pathophysiology, drug trials continue based on possible mechanisms, but no new drugs beyond riluzole and edaravone have been positive in phase 3 trials. There are a number of formal stem cell trials underway, and the results of a phase 2 trial are described. Major efforts to make trials more sensitive are being considered. There are a number of articles with helpful and practical findings for the diagnosis and management of ALS.}, }
@article {pmid31736701, year = {2019}, author = {Werner, CT and Williams, CJ and Fermelia, MR and Lin, DT and Li, Y}, title = {Circuit Mechanisms of Neurodegenerative Diseases: A New Frontier With Miniature Fluorescence Microscopy.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1174}, pmid = {31736701}, issn = {1662-4548}, support = {P20 GM121310/GM/NIGMS NIH HHS/United States ; }, abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), are devastating age-associated brain disorders. Significant efforts have been made to uncover the molecular and cellular pathogenic mechanisms that underlie NDDs. However, our understanding of the neural circuit mechanisms that mediate NDDs and associated symptomatic features have been hindered by technological limitations. Our inability to identify and track individual neurons longitudinally in subcortical brain regions that are preferentially targeted in NDDs has left gaping holes in our knowledge of NDDs. Recent development and advancement of the miniature fluorescence microscope (miniscope) has opened up new avenues for examining spatially and temporally coordinated activity from hundreds of cells in deep brain structures in freely moving rodents. In the present mini-review, we examine the capabilities of current and future miniscope tools and discuss the innovative applications of miniscope imaging techniques that can push the boundaries of our understanding of neural circuit mechanisms of NDDs into new territories.}, }
@article {pmid31730560, year = {2019}, author = {Al-Chalabi, A and Heunks, LMA and Papp, Z and Pollesello, P}, title = {Potential of the Cardiovascular Drug Levosimendan in the Management of Amyotrophic Lateral Sclerosis: An Overview of a Working Hypothesis.}, journal = {Journal of cardiovascular pharmacology}, volume = {74}, number = {5}, pages = {389-399}, doi = {10.1097/FJC.0000000000000728}, pmid = {31730560}, issn = {1533-4023}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Diaphragm/*innervation ; Disease Progression ; Humans ; Motor Neurons/*drug effects/pathology ; Muscle Strength/*drug effects ; Neuromuscular Agents/*therapeutic use ; Recovery of Function ; Respiration/*drug effects ; Respiratory Insufficiency/*drug therapy/pathology/physiopathology ; Simendan/*therapeutic use ; Treatment Outcome ; }, abstract = {Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterized by progressive weakness, and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of the diaphragm muscle fibers of non-ALS patients and to improve in vivo diaphragm neuromuscular efficiency in healthy subjects. Possible positive effects on respiratory function in people with ALS were seen in an exploratory phase 2 study, and a phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here, we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS.}, }
@article {pmid31727215, year = {2019}, author = {Nguyen, L and Matsumoto, RR}, title = {The psychopharmacology of pseudobulbar affect.}, journal = {Handbook of clinical neurology}, volume = {165}, number = {}, pages = {243-251}, doi = {10.1016/B978-0-444-64012-3.00014-9}, pmid = {31727215}, issn = {0072-9752}, mesh = {Affective Symptoms/*drug therapy/*physiopathology/psychology ; Brain Stem/drug effects/physiopathology ; Clinical Trials as Topic/methods ; Humans ; Mood Disorders/*drug therapy/*physiopathology/psychology ; Motor Cortex/drug effects/physiopathology ; Pseudobulbar Palsy/*drug therapy/*physiopathology/psychology ; Psychopharmacology ; Psychotropic Drugs/pharmacology/therapeutic use ; }, abstract = {Pseudobulbar affect (PBA) is characterized by uncontrollable emotional episodes disconnected or disproportionate with mood, in association with an array of neurologic conditions. PBA is associated with disruption of descending control of brainstem motor circuitry and dysregulation of serotonergic and glutamatergic function. PBA has been historically under recognized, though advances resulting in more specific diagnostic criteria, validated rating scales, and an approved pharmacotherapy offer opportunities for improved treatment outcomes.}, }
@article {pmid31726793, year = {2019}, author = {Malik, AR and Willnow, TE}, title = {Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System.}, journal = {International journal of molecular sciences}, volume = {20}, number = {22}, pages = {}, pmid = {31726793}, issn = {1422-0067}, support = {POIR.04.04.00 00 5CEF/18 00//Fundacja na rzecz Nauki Polskiej/ ; 335692/ERC_/European Research Council/International ; AMPro//Helmholtz Association/ ; 18003//Alzheimer Forschung Initiative/ ; }, mesh = {Animals ; Biological Transport ; Brain Diseases/*metabolism/pathology/*physiopathology ; Central Nervous System/*metabolism/pathology/*physiopathology ; Glutamate Plasma Membrane Transport Proteins/*metabolism ; Humans ; Neurons/metabolism/pathology ; *Synaptic Transmission ; }, abstract = {Excitatory amino acid transporters (EAATs) encompass a class of five transporters with distinct expression in neurons and glia of the central nervous system (CNS). EAATs are mainly recognized for their role in uptake of the amino acid glutamate, the major excitatory neurotransmitter. EAATs-mediated clearance of glutamate released by neurons is vital to maintain proper glutamatergic signalling and to prevent toxic accumulation of this amino acid in the extracellular space. In addition, some EAATs also act as chloride channels or mediate the uptake of cysteine, required to produce the reactive oxygen speciesscavenger glutathione. Given their central role in glutamate homeostasis in the brain, as well as their additional activities, it comes as no surprise that EAAT dysfunctions have been implicated in numerous acute or chronic diseases of the CNS, including ischemic stroke and epilepsy, cerebellar ataxias, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Here we review the studies in cellular and animal models, as well as in humans that highlight the roles of EAATs in the pathogenesis of these devastating disorders. We also discuss the mechanisms regulating EAATs expression and intracellular trafficking and new exciting possibilities to modulate EAATs and to provide neuroprotection in course of pathologies affecting the CNS.}, }
@article {pmid31726381, year = {2020}, author = {Wanleenuwat, P and Iwanowski, P and Kozubski, W}, title = {Antiganglioside antibodies in neurological diseases.}, journal = {Journal of the neurological sciences}, volume = {408}, number = {}, pages = {116576}, doi = {10.1016/j.jns.2019.116576}, pmid = {31726381}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/blood/diagnosis ; Autoantibodies/*blood ; Biomarkers/blood ; Gangliosides/*blood ; Guillain-Barre Syndrome/blood/diagnosis ; Humans ; Nervous System Diseases/*blood/*diagnosis ; Polyneuropathies/blood/diagnosis ; }, abstract = {Gangliosides are sialylated glycosphingolipids, highly abundant in our nervous system. Antibodies targeting gangliosides are usually developed as a consequence of molecular mimicry following infections. Antiganglioside antibodies are implicated in many neurological disorders such as acute and chronic polyradiculoneuropathies which includes different variants of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy. Presence of such antibodies in paraneoplastic peripheral neuropathy, neurodegenerative disorders, multiple sclerosis, myasthenia gravis and amyotrophic lateral sclerosis have also been reported. Recent evidence supports a role of antiganglioside antibodies in the pathogenesis of acute vestibular syndrome. Binding of antibodies to gangliosides on axonal membranes, nodes of Ranvier, myelin sheath components, Schwann cells, neuromuscular junctions or other neural cell surfaces may elicit inflammatory damage through complement-dependent and independent mechanisms, resulting in nerve conduction blocks and subsequent axonal degeneration. Gangliosides are essential for proper cell signaling, transduction and influences neuroplasticity, all of which are affected by autoimmune mediated damage. Better insight into the pathophysiological role of antiganglioside antibodies in different neurological diseases may improve their utility as diagnostic and prognostic biomarkers.}, }
@article {pmid31726180, year = {2020}, author = {St Martin, JL and Wang, L and Kaprielian, Z}, title = {Toxicity in ALS: TDP-43 modifiers and C9orf72.}, journal = {Neuroscience letters}, volume = {716}, number = {}, pages = {134621}, doi = {10.1016/j.neulet.2019.134621}, pmid = {31726180}, issn = {1872-7972}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *C9orf72 Protein ; *DNA-Binding Proteins ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease affecting approximately 30,000 individuals in the United States. The average age of onset is 55 years and progression of the disease is rapid with most patients dying of respiratory failure within 3-5 years. Currently available therapeutics have modest effects on patient survival, underscoring the immediate need for more effective medicines. Recent technological advances in next generation sequencing have led to a substantial uptick in the discovery of genes linked to ALS. Since 90 % of ALS cases are sporadic, risk genes identified in familial cases provide invaluable insights into the molecular pathogenesis of the disease. Most notably, TDP-43-expressing neuronal inclusions and C9orf72 mutations have emerged as the key pathological and genetic hallmarks, respectively, of ALS. In this review, we will discuss recent advances in modifiers of TDP-43 toxicity, with an emphasis on Ataxin-2, one of the most well-characterized TDP-43 modifiers. An understanding of Ataxin-2 function and related biological pathways could provide a framework for the discovery of other novel modifiers of TDP-43. We will also describe the pathogenic mechanisms underlying C9orf72 toxicity and how these impact the disease process. Finally, we will explore emerging therapeutic strategies for dampening TDP-43 and C9orf72 toxicity and, ultimately, slowing or halting the progression of ALS.}, }
@article {pmid31724708, year = {2020}, author = {Moll, T and Shaw, PJ and Cooper-Knock, J}, title = {Disrupted glycosylation of lipids and proteins is a cause of neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {143}, number = {5}, pages = {1332-1340}, pmid = {31724708}, issn = {1460-2156}, mesh = {Animals ; Glycosylation ; Glycosyltransferases/*genetics/*metabolism ; Humans ; Lipid Metabolism/*physiology ; Lipids ; Mutation ; Nerve Degeneration/*enzymology ; Proteins/*metabolism ; }, abstract = {Glycosyltransferases represent a large family of enzymes that catalyse the biosynthesis of oligosaccharides, polysaccharides, and glycoconjugates. A number of studies have implicated glycosyltransferases in the pathogenesis of neurodegenerative diseases but differentiating cause from effect has been difficult. We have recently discovered that mutations proximal to the substrate binding site of glycosyltransferase 8 domain containing 1 (GLT8D1) are associated with familial amyotrophic lateral sclerosis (ALS). We demonstrated that ALS-associated mutations reduce activity of the enzyme suggesting a loss-of-function mechanism that is an attractive therapeutic target. Our work is the first evidence that isolated dysfunction of a glycosyltransferase is sufficient to cause a neurodegenerative disease, but connection between neurodegeneration and genetic variation within glycosyltransferases is not new. Previous studies have identified associations between mutations in UGT8 and sporadic ALS, and between ST6GAL1 mutations and conversion of mild cognitive impairment into clinical Alzheimer's disease. In this review we consider potential mechanisms connecting glycosyltransferase dysfunction to neurodegeneration. The most prominent candidates are ganglioside synthesis and impaired addition of O-linked β-N-acetylglucosamine (O-GlcNAc) groups to proteins important for axonal and synaptic function. Special consideration is given to examples where genetic mutations within glycosyltransferases are associated with neurodegeneration in recognition of the fact that these changes are likely to be upstream causes present from birth.}, }
@article {pmid31723121, year = {2019}, author = {Hernandez-Gerez, E and Fleming, IN and Parson, SH}, title = {A role for spinal cord hypoxia in neurodegeneration.}, journal = {Cell death &amp; disease}, volume = {10}, number = {11}, pages = {861}, pmid = {31723121}, issn = {2041-4889}, mesh = {Humans ; Hypoxia/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; *Regional Blood Flow/physiology ; Spinal Cord/*blood supply/metabolism/pathology ; Spinal Cord Injuries/metabolism/pathology ; }, abstract = {The vascular system of the spinal cord is particularly complex and vulnerable. Damage to the main vessels or alterations to the regulation of blood flow will result in a reduction or temporary cessation of blood supply. The resulting tissue hypoxia may be brief: acute, or long lasting: chronic. Damage to the vascular system of the spinal cord will develop after a traumatic event or as a result of pathology. Traumatic events such as road traffic accidents, serious falls and surgical procedures, including aortic cross-clamping, will lead to an immediate cessation of perfusion, the result of which may not be evident for several days, but may have long-term consequences including neurodegeneration. Pathological events such as arterial sclerosis, venous occlusion and spinal cord compression will result in a progressive reduction of blood flow, leading to chronic hypoxia. While in some situations the initial pathology is exclusively vascular, recent research in neurodegenerative disease has drawn attention to concomitant vascular anomalies in disorders, including amyotrophic lateral sclerosis, spinal muscular atrophy and muscular sclerosis. Understanding the role of, and tissue response to, chronic hypoxia is particularly important in these cases, where inherent neural damage exacerbates the vulnerability of the nervous system to stressors including hypoxia.}, }
@article {pmid31722309, year = {2019}, author = {Kokubo, Y}, title = {[The Current State of Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan, 2019].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {11}, pages = {1236-1244}, doi = {10.11477/mf.1416201433}, pmid = {31722309}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Dementia/*epidemiology ; Humans ; Japan/epidemiology ; Parkinsonian Disorders/*epidemiology ; }, abstract = {Recent papers of amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula, Japan (Kii ALS/PDC), published since 2015, were reviewed The studies included transition element of scalp hair analysis, dopaminergic PET study, review of life style changes in the high incident area, neurotoxic BMAA analysis, a clinical report of a migration case, comprehensive neuropathological study, cerebellar tau pathology, nitrative stress in the central nervous system study, optinurin pathology in the spinal cord, and tau PET study. Tau PET was advocated to be a new useful tool for diagnosis, even in the early stage of ALS/PDC with tauopathy. The etiology of Kii ALS/PDC remainds unknown. There are patients and healthy residents within the same environment in the high incidence foci, therefore it is difficult to explain this result by exposure to environmental factors alone. From the genetic viewpoint, rare-disease and rare-variant model may be applied to Kii ALS/PDC. Because there was an immigrant who was diagnosed neuropathologically, and a drastic decrease of the prevalence in the past several decades in the high incident area, it is feasible that Kii ALS/PDC is a multifactorial disease caused by both risk genes and environmental factors. Identifying risk genes and environmental factors for Kii ALS/PDC may contribute to the prevention of neurodegenerative diseases.}, }
@article {pmid31722303, year = {2019}, author = {Suzuki, N and Nishiyama, A and Kato, M and Warita, H and Aoki, M}, title = {[Familial Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {11}, pages = {1169-1181}, doi = {10.11477/mf.1416201427}, pmid = {31722303}, issn = {1881-6096}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Axons/pathology ; C9orf72 Protein/genetics ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells ; Japan ; Motor Neurons/pathology ; Mutation ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. Riluzole and edaravone are the only approved drugs available in Japan to date. Approximately 10% of ALS cases are familial in rature, defined as the existence of disease-causing mutation. SOD1 is the most frequent causative gene for ALS among Japanese individuals, while C9orf72 mutation is more prevalent in Western countries. Genotype-phenotype correlation described in the literature of familial ALS enables to establish models of the disease. This review article describes the clinical characteristics of familial ALS based on each disease-causing mutation. The pathomechanism of ALS including proteostasis, RNA metabolism, and axonal pathology are discussed in detail. We also reviewed the status of development of therapeutic strategies for familial ALS based on analysis of animal models and induced pluripotent stem cells.}, }
@article {pmid31722299, year = {2019}, author = {Narita, Y}, title = {[A Brief Review on Recent Epidemiologic Literature and Risk Factors of Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {11}, pages = {1129-1137}, doi = {10.11477/mf.1416201422}, pmid = {31722299}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Humans ; Incidence ; Japan ; Prevalence ; Risk Factors ; }, abstract = {This brief review of recent epidemiologic literature and risk factors of sporadic ALS found that the incidence and prevalence of the condition is higher among Caucasians and lower in East Asians, with the Japanese in the middle. The review also found that worldwide, the prevalence increases with age and the condition is 1.3 to 1.6 times higher in males than in females. The number of patients with ALS was calculated based on official diagnostic certificates from fiscal 1997 to 2015 obtained from a registry managed by Japan's Ministry of Health, Labor and Welfare. The data matched with those reported in the guidelines of the Japanese Society of Neurology (2013), with an incidence of 1.1-2.5, and prevalence 7.0-8.5/100,000 people. Smoking has been considered an established risk factor for sporadic ALS. The following possible risk factors have been speculated but are to be confirmed: excessive physical activity, head trauma, farming, environmental pollutants, pesticides, exposure to certain metals/heavy metals, electromagnetic fields, alcohol, low BMI, and low-density lipoprotein. Bandres-Ciga et al. applied linkage disequilibrium score regression and Mendelian randomization to a large data set and concluded that elevated low-density lipoprotein cholesterol is a causal risk factor for ALS.}, }
@article {pmid31721251, year = {2020}, author = {Swinnen, B and Robberecht, W and Van Den Bosch, L}, title = {RNA toxicity in non-coding repeat expansion disorders.}, journal = {The EMBO journal}, volume = {39}, number = {1}, pages = {e101112}, pmid = {31721251}, issn = {1460-2075}, support = {259867//EC|FP7|FP7 Ideas: European Research Council (FP7 Ideas)/International ; 340429//EC|FP7|FP7 Ideas: European Research Council (FP7 Ideas)/International ; G.0983.14N//Fonds Wetenschappelijk Onderzoek (FWO)/International ; GOA/11/014//KU Leuven (Katholieke Universiteit Leuven)/International ; C14/17/107//KU Leuven (Katholieke Universiteit Leuven)/International ; P7/16//Interuniversity Attraction Poles Program/International ; //Association Belge contre les Maladies Neuro-Musculaires (ABMM)/International ; //ALS liga Belgium/International ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Ataxia/genetics/*pathology ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Fragile X Syndrome/genetics/*pathology ; Frontotemporal Dementia/genetics/*pathology ; Humans ; Mutation ; Myotonic Dystrophy/genetics/*pathology ; Neurodegenerative Diseases/genetics/*pathology ; RNA/genetics/*toxicity ; Tremor/genetics/*pathology ; }, abstract = {Several neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are caused by non-coding nucleotide repeat expansions. Different pathogenic mechanisms may underlie these non-coding repeat expansion disorders. While gain-of-function mechanisms, such as toxicity associated with expression of repeat RNA or toxicity associated with repeat-associated non-ATG (RAN) products, are most frequently connected with these disorders, loss-of-function mechanisms have also been implicated. We review the different pathways that have been linked to non-coding repeat expansion disorders such as C9ORF72-linked ALS/frontotemporal dementia (FTD), myotonic dystrophy, fragile X tremor/ataxia syndrome (FXTAS), SCA, and Huntington's disease-like 2. We discuss modes of RNA toxicity focusing on the identity and the interacting partners of the toxic RNA species. Using the C9ORF72 ALS/FTD paradigm, we further explore the efforts and different methods used to disentangle RNA vs. RAN toxicity. Overall, we conclude that there is ample evidence for a role of RNA toxicity in non-coding repeat expansion diseases.}, }
@article {pmid31718830, year = {2020}, author = {Gunata, M and Parlakpinar, H and Acet, HA}, title = {Melatonin: A review of its potential functions and effects on neurological diseases.}, journal = {Revue neurologique}, volume = {176}, number = {3}, pages = {148-165}, doi = {10.1016/j.neurol.2019.07.025}, pmid = {31718830}, issn = {0035-3787}, mesh = {Aging/physiology ; Animals ; History, 20th Century ; History, 21st Century ; Humans ; Melatonin/pharmacology/*physiology/therapeutic use ; Nervous System Diseases/drug therapy/epidemiology/*etiology ; Neurology/history/trends ; }, abstract = {BACKGROUND: The aging process is not univocal, both body and brain age. Neurological disorders are a major cause of disability and death worldwide. According to the Global Burden of Disease Study 2015, neurological diseases are the second most common cause of death and 16.8% of total deaths are caused by neurological diseases worldwide. Neurological disease deaths have risen 36% worldwide in 25 years. Melatonin is a neuroregulator hormone that has free radical scavenger, strong antioxidant, anti-inflammatory, and immunosuppressive actions. These major properties of melatonin can play an important role in the pathophysiological mechanisms of neurological diseases. In addition, melatonin is necessary for circadian rhythm. Studies have shown that melatonin levels are low in people with neurological diseases. Both preventive and therapeutic effects of melatonin are known for many diseases, including neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headache, etc.). Based on all these reasons, clinical trials of melatonin were performed and successful results were declared.<br><br>CONCLUSIONS: In this review, biological and chemical knowledge of melatonin, its experimental effects, and the clinical impact on patients with neurological disorders were described. According to all of the beneficial results obtained from experimental and clinical trials, melatonin may have a prophylactic and therapeutic effect on neurological diseases. Strong collaboration between neurologists and health service policy makers is needed to encourage use of melatonin in the patients suffering from neurological diseases. Melatonin may be the solution we have been looking for.}, }
@article {pmid31717475, year = {2019}, author = {Riccio, P and Rossano, R}, title = {Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity.}, journal = {Nutrients}, volume = {11}, number = {11}, pages = {}, pmid = {31717475}, issn = {2072-6643}, mesh = {Animals ; Autistic Disorder/immunology/microbiology/physiopathology ; *Diet ; *Dysbiosis/immunology/microbiology/physiopathology ; *Gastrointestinal Microbiome ; Humans ; *Inflammation/immunology/microbiology/physiopathology ; Mice ; *Neurodegenerative Diseases/immunology/microbiology/physiopathology ; Organ Specificity/*immunology ; }, abstract = {As food is an active subject and may have anti-inflammatory or pro-inflammatory effects, dietary habits may modulate the low-grade neuroinflammation associated with chronic neurodegenerative diseases. Food is living matter different from us, but made of our own nature. Therefore, it is at the same time foreign to us (non-self), if not yet digested, and like us (self), after its complete digestion. To avoid the efflux of undigested food from the lumen, the intestinal barrier must remain intact. What and how much we eat shape the composition of gut microbiota. Gut dysbiosis, as a consequence of Western diets, leads to intestinal inflammation and a leaky intestinal barrier. The efflux of undigested food, microbes, endotoxins, as well as immune-competent cells and molecules, causes chronic systemic inflammation. Opening of the blood-brain barrier may trigger microglia and astrocytes and set up neuroinflammation. We suggest that what determines the organ specificity of the autoimmune-inflammatory process may depend on food antigens resembling proteins of the organ being attacked. This applies to the brain and neuroinflammatory diseases, as to other organs and other diseases, including cancer. Understanding the cooperation between microbiota and undigested food in inflammatory diseases may clarify organ specificity, allow the setting up of adequate experimental models of disease and develop targeted dietary interventions.}, }
@article {pmid31708347, year = {2019}, author = {Lee, JD and Coulthard, LG and Woodruff, TM}, title = {Complement dysregulation in the central nervous system during development and disease.}, journal = {Seminars in immunology}, volume = {45}, number = {}, pages = {101340}, doi = {10.1016/j.smim.2019.101340}, pmid = {31708347}, issn = {1096-3618}, mesh = {Animals ; Central Nervous System/*immunology/*metabolism ; Complement System Proteins/*immunology/metabolism ; *Disease Susceptibility ; Humans ; Neurodegenerative Diseases/etiology/metabolism/pathology ; *Neurogenesis/genetics/immunology ; }, abstract = {The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal death, but also neuroprotection and regeneration. In diseases of the aging CNS including dementias and motor neuron disease, chronic complement activation is associated with glial activation, and synapse and neuron loss. Proper regulation of complement is thus essential to allow for an appropriately developed CNS and prevention of excessive damage following neurotrauma or during neurodegeneration. This review provides a comprehensive overview of the evidence for functional roles of complement in brain formation, and its dysregulation during acute and chronic disease. We also provide working models for how complement can lead to neurodevelopmental disorders such as schizophrenia and autism, and either protect, or propagate neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid31707536, year = {2019}, author = {Thadathil, N and Hori, R and Xiao, J and Khan, MM}, title = {DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases.}, journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology}, volume = {27}, number = {4}, pages = {345-364}, pmid = {31707536}, issn = {1573-6849}, support = {R03 NS101485/NS/NINDS NIH HHS/United States ; R03 NS101485/NH/NIH HHS/United States ; W81XWH-17-1-0062//Department of Defense/International ; R21 GM118962/NH/NIH HHS/United States ; R21 GM118962/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Biomarkers ; *DNA Breaks, Double-Stranded ; DNA Damage ; DNA End-Joining Repair ; DNA Repair ; Diagnosis, Differential ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genetic Testing ; Homologous Recombination ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/diagnosis/*genetics/metabolism/therapy ; }, abstract = {The complexity of neurodegeneration restricts the ability to understand and treat the neurological disorders affecting millions of people worldwide. Therefore, there is an unmet need to develop new and more effective therapeutic strategies to combat these devastating conditions and that will only be achieved with a better understanding of the biological mechanism associated with disease conditions. Recent studies highlight the role of DNA damage, particularly, DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases. This is not unexpected because neurons are prone to DNA damage due to their non-proliferative nature and high metabolic activity. However, it is not clear if DSBs is a primary driver of neuronal loss in disease conditions or simply occurs concomitant with disease progression. Here, we provide evidence that supports a critical role of DSBs in the pathogenesis of the neurodegenerative diseases. Among different kinds of DNA damages, DSBs are the most harmful and perilous type of DNA damage and can lead to cell death if left unrepaired or repaired with error. In this review, we explore the current state of knowledge regarding the role of DSBs repair mechanisms in preserving neuronal function and survival and describe how DSBs could drive the molecular mechanisms resulting in neuronal death in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also discuss the potential implications of DSBs as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.}, }
@article {pmid31704179, year = {2019}, author = {Wallings, RL and Humble, SW and Ward, ME and Wade-Martins, R}, title = {Lysosomal Dysfunction at the Centre of Parkinson's Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.}, journal = {Trends in neurosciences}, volume = {42}, number = {12}, pages = {899-912}, pmid = {31704179}, issn = {1878-108X}, support = {MR/L023784/1/MRC_/Medical Research Council/United Kingdom ; H-1102/PUK_/Parkinson's UK/United Kingdom ; MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; J-0901/PUK_/Parkinson's UK/United Kingdom ; ZIA NS003155/ImNIH/Intramural NIH HHS/United States ; MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; Z99 NS999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Autophagy ; Brain/*metabolism ; Frontotemporal Dementia/genetics/*metabolism ; Humans ; Lysosomes/genetics/*metabolism ; Mitochondria/metabolism ; Neurons/*metabolism ; Parkinson Disease/genetics/*metabolism ; }, abstract = {Parkinson's disease (PD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) are insidious and incurable neurodegenerative diseases that represent a significant burden to affected individuals, caregivers, and an ageing population. Both PD and FTD/ALS are defined at post mortem by the presence of protein aggregates and the loss of specific subsets of neurons. We examine here the crucial role of lysosome dysfunction in these diseases and discuss recent evidence for converging mechanisms. This review draws upon multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells (iPSCs), and animal models to argue that lysosomal failure is a primary mechanism of disease, rather than merely reflecting association with protein aggregate end-points. This review provides compelling rationale for targeting lysosomes in future therapeutics for both PD and FTD/ALS.}, }
@article {pmid31698548, year = {2019}, author = {Jin, U and Park, SJ and Park, SM}, title = {Cholesterol Metabolism in the Brain and Its Association with Parkinson's Disease.}, journal = {Experimental neurobiology}, volume = {28}, number = {5}, pages = {554-567}, pmid = {31698548}, issn = {1226-2560}, abstract = {Parkinson's disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer's disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.}, }
@article {pmid31693760, year = {2020}, author = {Cogo, S and Manzoni, C and Lewis, PA and Greggio, E}, title = {Leucine-rich repeat kinase 2 and lysosomal dyshomeostasis in Parkinson disease.}, journal = {Journal of neurochemistry}, volume = {152}, number = {3}, pages = {273-283}, doi = {10.1111/jnc.14908}, pmid = {31693760}, issn = {1471-4159}, support = {MR/K01417X/1/MRC_/Medical Research Council/United Kingdom ; G-0907/PUK_/Parkinson's UK/United Kingdom ; MR/N026004/1/MRC_/Medical Research Council/United Kingdom ; G0701075/MRC_/Medical Research Council/United Kingdom ; MR/L010933/1/MRC_/Medical Research Council/United Kingdom ; G0901254/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Homeostasis/physiology ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/*metabolism ; Lysosomes/*metabolism/*pathology ; Parkinson Disease/*metabolism/*pathology ; }, abstract = {Over the last two decades, a number of studies have underlined the importance of lysosomal-based degradative pathways in maintaining the homeostasis of post-mitotic cells, and revealed the remarkable contribution of a functional autophagic machinery in the promotion of longevity. In contrast, defects in the clearance of organelles and aberrant protein aggregates have been linked to accelerated neuronal loss and neurological dysfunction. Several neurodegenerative disorders, among which Alzheimer disease (AD), Frontotemporal dementia, and Amyotrophic Lateral Sclerosis to name a few, are associated with alterations of the autophagy and endo-lysosomal pathways. In Parkinson disease (PD), the most prevalent genetic determinant, Leucine-rich repeat kinase 2 (LRRK2), is believed to be involved in the regulation of intracellular vesicle traffic, autophagy and lysosomal function. Here, we review the current understanding of the mechanisms by which LRRK2 regulates lysosomal-based degradative pathways in neuronal and non-neuronal cells and discuss the impact of pathogenic PD mutations in contributing to lysosomal dyshomeostasis.}, }
@article {pmid31692944, year = {2019}, author = {Tabassum, R and Jeong, NY}, title = {Potential for therapeutic use of hydrogen sulfide in oxidative stress-induced neurodegenerative diseases.}, journal = {International journal of medical sciences}, volume = {16}, number = {10}, pages = {1386-1396}, pmid = {31692944}, issn = {1449-1907}, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Brain/cytology/*drug effects/pathology ; Calcium Channels/drug effects/metabolism ; Clinical Trials, Phase III as Topic ; Disease Models, Animal ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Hydrogen Sulfide/*adverse effects ; Lipid Peroxidation/drug effects ; Mitochondria/*drug effects/metabolism/pathology ; Mitochondrial Dynamics/drug effects ; Neurodegenerative Diseases/*drug therapy/etiology/pathology ; Neurons/cytology/drug effects/pathology ; Oxidative Stress/drug effects ; Potassium Channels/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Treatment Outcome ; }, abstract = {Oxidative phosphorylation is a source of energy production by which many cells satisfy their energy requirements. Endogenous reactive oxygen species (ROS) are by-products of oxidative phosphorylation. ROS are formed due to the inefficiency of oxidative phosphorylation, and lead to oxidative stress that affects mitochondrial metabolism. Chronic oxidative stress contributes to the onset of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The immediate consequences of oxidative stress include lipid peroxidation, protein oxidation, and mitochondrial deoxyribonucleic acid (mtDNA) mutation, which induce neuronal cell death. Mitochondrial binding of amyloid-β (Aβ) protein has been identified as a contributing factor in AD. In PD and HD, respectively, α-synuclein (α-syn) and huntingtin (Htt) gene mutations have been reported to exacerbate the effects of oxidative stress. Similarly, abnormalities in mitochondrial dynamics and the respiratory chain occur in ALS due to dysregulation of mitochondrial complexes II and IV. However, oxidative stress-induced dysfunctions in neurodegenerative diseases can be mitigated by the antioxidant function of hydrogen sulfide (H2S), which also acts through the potassium (KATP/K[+]) ion channel and calcium (Ca[2+]) ion channels to increase glutathione (GSH) levels. The pharmacological activity of H2S is exerted by both inorganic and organic compounds. GSH, glutathione peroxidase (Gpx), and superoxide dismutase (SOD) neutralize H2O2-induced oxidative damage in mitochondria. The main purpose of this review is to discuss specific causes and effects of mitochondrial oxidative stress in neurodegenerative diseases, and how these are impacted by the antioxidant functions of H2S to support the development of advancements in neurodegenerative disease treatment.}, }
@article {pmid31692669, year = {2019}, author = {Cai, M and Yang, EJ}, title = {Complementary and alternative medicine for treating amyotrophic lateral sclerosis: A narrative review.}, journal = {Integrative medicine research}, volume = {8}, number = {4}, pages = {234-239}, pmid = {31692669}, issn = {2213-4220}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that is characterized by selective motor neuron cell death in the motor cortex, brainstem, and spinal cord. Two drugs for ALS, riluzole and edaravone, have been approved by FDA for the treatment of ALS patients. However, they have many side effects, and riluzole extends the patient's life by only 2-3 months. Therefore, ALS patients seek an effective therapy for treating the symptoms or delaying the progression of ALS. Based on this, we review the effects of complementary and alternative medicine (CAM) in ALS animals or patients to verify the efficacy of CAM in incurable diseases. For this review, we searched published papers focusing on the effect of CAM in pre-clinical and clinical study in ALS.<br><br>METHODS: The search keywords included amyotrophic lateral sclerosis, acupuncture, herbal medicine, Traditional Chinese medicine, CAM, animals, and clinical study through electronic databases PubMed and Google Scholar from their inception until March 2019.<br><br>RESULTS: In the ALS animal model, CAM modulated the immune system to increase motor function by reducing the expression levels of neuroinflammatory proteins in the spinal cord. Besides this, ALS patients treated with herbal medicine showed improved disease symptoms, but clinical trials with larger sample sizes are needed to develop a treatment with this herbal medicine.<br><br>CONCLUSION: This review shows that CAM may be useful for ALS treatment, but more evidence regarding the efficacy and molecular mechanisms is required to establish CAM as a good therapy for the treatment of ALS patients.}, }
@article {pmid31689888, year = {2019}, author = {D'Ambra, E and Capauto, D and Morlando, M}, title = {Exploring the Regulatory Role of Circular RNAs in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {20}, number = {21}, pages = {}, pmid = {31689888}, issn = {1422-0067}, support = {Pilot grant 2017 (circRNALS)//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Animals ; Biomarkers/metabolism ; Humans ; Nervous System/embryology/pathology ; Neurodegenerative Diseases/*genetics/pathology ; RNA Processing, Post-Transcriptional ; RNA, Circular/*genetics/metabolism ; }, abstract = {Circular RNAs (circRNAs) are a distinctive class of regulatory non-coding RNAs characterised by the presence of covalently closed ends. They are evolutionary conserved molecules, and although detected in different tissues, circRNAs resulted specifically enriched in the nervous system. Recent studies have shown that circRNAs are dynamically modulated during neuronal development and aging, that circRNAs are enriched at synaptic levels and resulted modulated after synaptic plasticity induction. This has suggested that circRNAs might play an important role in neuronal specification and activity. Despite the exact function of circRNAs is still poorly understood, emerging evidence indicates that circRNAs have important regulatory functions that might extensively contribute to the dynamic modulation of gene expression that supports neuronal pathways. More interestingly, deregulation of circRNAs expression has been linked with various pathological conditions. In this review, we describe current advances in the field of circRNA biogenesis and function in the nervous system both in physiological and in pathological conditions, and we specifically lay out their association with neurodegenerative diseases. Furthermore, we discuss the opportunity to exploit circRNAs for innovative therapeutic approaches and, due to their high stability, to use circRNAs as suitable biomarkers for diagnosis and disease progression.}, }
@article {pmid31680867, year = {2019}, author = {Limanaqi, F and Biagioni, F and Ryskalin, L and Busceti, CL and Fornai, F}, title = {Molecular Mechanisms Linking ALS/FTD and Psychiatric Disorders, the Potential Effects of Lithium.}, journal = {Frontiers in cellular neuroscience}, volume = {13}, number = {}, pages = {450}, pmid = {31680867}, issn = {1662-5102}, abstract = {Altered proteostasis, endoplasmic reticulum (ER) stress, abnormal unfolded protein response (UPR), mitochondrial dysfunction and autophagy impairment are interconnected events, which contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). In recent years, the mood stabilizer lithium was shown to potentially modify ALS/FTD beyond mood disorder-related pathology. The effects of lithium are significant in ALS patients carrying genetic variations in the UNC13 presynaptic protein, which occur in ALS/FTD and psychiatric disorders as well. In the brain, lithium modulates a number of biochemical pathways involved in synaptic plasticity, proteostasis, and neuronal survival. By targeting UPR-related events, namely ER stress, excitotoxicity and autophagy dysfunction, lithium produces plastic effects. These are likely to relate to neuroprotection, which was postulated for mood and motor neuron disorders. In the present manuscript, we try to identify and discuss potential mechanisms through which lithium copes concomitantly with ER stress, UPR and autophagy dysfunctions related to UNC13 synaptic alterations and aberrant RNA and protein processing. This may serve as a paradigm to provide novel insights into the neurobiology of ALS/FTD featuring early psychiatric disturbances.}, }
@article {pmid31678567, year = {2019}, author = {McAvoy, K and Kawamata, H}, title = {Glial mitochondrial function and dysfunction in health and neurodegeneration.}, journal = {Molecular and cellular neurosciences}, volume = {101}, number = {}, pages = {103417}, doi = {10.1016/j.mcn.2019.103417}, pmid = {31678567}, issn = {1095-9327}, support = {R21 NS104520/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*metabolism/pathology ; Electron Transport Complex I/genetics/metabolism ; Humans ; Mitochondria/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Oxidative Phosphorylation ; }, abstract = {Mitochondria play essential metabolic roles in neural cells. Mitochondrial dysfunction has profound effects on the brain. In primary mitochondrial diseases, mutations that impair specific oxidative phosphorylation (OXPHOS) proteins or OXPHOS assembly factors lead to isolated biochemical defects and a heterogeneous group of clinical phenotypes, including mitochondrial encephalopathies. A broader defect of OXPHOS function, due to mutations in proteins involved in mitochondrial DNA maintenance, mitochondrial biogenesis, or mitochondrial tRNAs can also underlie severe mitochondrial encephalopathies. While primary mitochondrial dysfunction causes rare genetic forms of neurological disorders, secondary mitochondrial dysfunction is involved in the pathophysiology of some of the most common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Many studies have investigated mitochondrial function and dysfunction in bulk central nervous system (CNS) tissue. However, the interpretation of these studies has been often complicated by the extreme cellular heterogeneity of the CNS, which includes many different types of neurons and glial cells. Because neurons are especially dependent on OXPHOS for ATP generation, mitochondrial dysfunction is thought to be directly involved in cell autonomous neuronal demise. Despite being metabolically more flexible than neurons, glial mitochondria also play an essential role in the function of the CNS, and have adapted specific metabolic and mitochondrial features to support their diversity of functions. This review analyzes our current understanding and the gaps in knowledge of mitochondrial properties of glia and how they affect neuronal functions, in health and disease.}, }
@article {pmid31676908, year = {2020}, author = {Czarny, P and Bialek, K and Ziolkowska, S and Strycharz, J and Sliwinski, T}, title = {DNA damage and repair in neuropsychiatric disorders. What do we know and what are the future perspectives?.}, journal = {Mutagenesis}, volume = {35}, number = {1}, pages = {79-106}, doi = {10.1093/mutage/gez035}, pmid = {31676908}, issn = {1464-3804}, mesh = {Alzheimer Disease/genetics/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Biomarkers ; Bipolar Disorder/genetics/physiopathology ; DNA/metabolism ; *DNA Damage ; *DNA Repair ; DNA, Mitochondrial/metabolism ; Depressive Disorder, Major/genetics/physiopathology ; Humans ; Mental Disorders/*genetics ; Neurodegenerative Diseases/*genetics ; Oxidative Stress/physiology ; Parkinson Disease/genetics/physiopathology ; RNA/metabolism ; Schizophrenia/genetics/physiopathology ; }, abstract = {Over the past two decades, extensive research has been done to elucidate the molecular etiology and pathophysiology of neuropsychiatric disorders. In majority of them, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), bipolar disorder (BD), schizophrenia and major depressive disorder, increased oxidative and nitrosative stress was found. This stress is known to induce oxidative damage to biomolecules, including DNA. Accordingly, increased mitochondrial and nuclear DNA, as well as RNA damage, were observed in patients suffering from these diseases. However, recent findings indicate that the patients are characterised by impaired DNA repair pathways, which may suggest that these DNA lesions could be also a result of their insufficient repair. In the current systematic, critical review, we aim to sum up, using available literature, the knowledge about the involvement of nuclear and mitochondrial DNA damage and repair, as well as about damage to RNA in pathoetiology of neuropsychiatric disorders, i.e., AD, PD, ALS, BD, schizophrenia and major depressive disorder, as well as the usefulness of the discussed factors as being diagnostic markers and targets for new therapies. Moreover, we also underline the new directions to which future studies should head to elucidate these phenomena.}, }
@article {pmid31674217, year = {2020}, author = {Zeng, SL and Sudlow, LC and Berezin, MY}, title = {Using Xenopus oocytes in neurological disease drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {15}, number = {1}, pages = {39-52}, pmid = {31674217}, issn = {1746-045X}, support = {R01 CA208623/CA/NCI NIH HHS/United States ; R21 CA269099/CA/NCI NIH HHS/United States ; U54 CA199092/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Agents/*pharmacology ; Central Nervous System Diseases/*drug therapy ; Drug Discovery/*methods ; Drug Evaluation, Preclinical/*methods ; Oocytes/*drug effects ; Xenopus ; }, abstract = {Introduction: Neurological diseases present a difficult challenge in drug discovery. Many of the current treatments have limited efficiency or result in a variety of debilitating side effects. The search of new therapies is of a paramount importance, since the number of patients that require a better treatment is growing rapidly. As an in vitro model, Xenopus oocytes provide the drug developer with many distinct advantages, including size, durability, and efficiency in exogenous protein expression. However, there is an increasing need to refine the recent breakthroughs.Areas covered: This review covers the usage and recent advancements of Xenopus oocytes for drug discovery in neurological diseases from expression and functional measurement techniques to current applications in Alzheimer's disease, painful neuropathies, and amyotrophic lateral sclerosis (ALS). The existing limitations of Xenopus oocytes in drug discovery are also discussed.Expert opinion: With the rise of aging population and neurological disorders, Xenopus oocytes, will continue to play an important role in understanding the mechanism of the disease, identification and validation of novel molecular targets, and drug screening, providing high-quality data despite the technical limitations. With further advances in oocytes-related techniques toward an accurate modeling of the disease, the diagnostics and treatment of neuropathologies will be becoming increasing personalized.}, }
@article {pmid31673239, year = {2019}, author = {Valles, SL and Iradi, A and Aldasoro, M and Vila, JM and Aldasoro, C and de la Torre, J and Campos-Campos, J and Jorda, A}, title = {Function of Glia in Aging and the Brain Diseases.}, journal = {International journal of medical sciences}, volume = {16}, number = {11}, pages = {1473-1479}, pmid = {31673239}, issn = {1449-1907}, mesh = {Aging/*genetics ; Blood-Brain Barrier/metabolism/pathology ; Brain/metabolism/pathology ; Brain Diseases/*genetics/pathology ; Gene Expression Regulation/genetics ; Humans ; Microglia/*metabolism/pathology ; Neuroglia/*metabolism/pathology ; }, abstract = {Microglia cells during aging, neurodegeneration and neuroinflammation show different morphological and transcriptional profiles (related to axonal direction and cell adhesion). Furthermore, expressions of the receptors on the surface and actin formation compared to young are also different. This review delves into the role of glia during aging and the development of the diseases. The susceptibility of different regions of the brain to disease are linked to the overstimulation of signals related to the immune system during aging, as well as the damaging impact of these cascades on the functionality of different populations of microglia present in each region of the brain. Furthermore, a decrease in microglial phagocytosis has been related to many diseases and also has been detected during aging. In this paper we also describe the role of glia in different illness, such as AD, ALS, pain related disorders, cancer, developmental disorders and the problems produced by opening of the blood brain barrier. Future studies will clarify many points planted by this review.}, }
@article {pmid31670780, year = {2019}, author = {Iverson, GL and Gardner, AJ and Shultz, SR and Solomon, GS and McCrory, P and Zafonte, R and Perry, G and Hazrati, LN and Keene, CD and Castellani, RJ}, title = {Chronic traumatic encephalopathy neuropathology might not be inexorably progressive or unique to repetitive neurotrauma.}, journal = {Brain : a journal of neurology}, volume = {142}, number = {12}, pages = {3672-3693}, pmid = {31670780}, issn = {1460-2156}, mesh = {Brain Injuries/complications/*pathology ; Chronic Traumatic Encephalopathy/etiology/*pathology ; Disease Progression ; Humans ; }, abstract = {In the 20th century, chronic traumatic encephalopathy (CTE) was conceptualized as a neurological disorder affecting some active and retired boxers who had tremendous exposure to neurotrauma. In recent years, the two research groups in the USA who have led the field have asserted definitively that CTE is a delayed-onset and progressive neurodegenerative disease, with symptoms appearing in midlife or decades after exposure. Between 2005 and 2012 autopsy cases of former boxers and American football players described neuropathology attributed to CTE that was broad and diverse. This pathology, resulting from multiple causes, was aggregated and referred to, in toto, as the pathology 'characteristic' of CTE. Preliminary consensus criteria for defining the neuropathology of CTE were forged in 2015 and published in 2016. Most of the macroscopic and microscopic neuropathological findings described as characteristic of CTE, in studies published before 2016, were not included in the new criteria for defining the pathology. In the past few years, there has been steadily emerging evidence that the neuropathology described as unique to CTE may not be unique. CTE pathology has been described in individuals with no known participation in collision or contact sports and no known exposure to repetitive neurotrauma. This pathology has been reported in individuals with substance abuse, temporal lobe epilepsy, amyotrophic lateral sclerosis, multiple system atrophy, and other neurodegenerative diseases. Moreover, throughout history, some clinical cases have been described as not being progressive, and there is now evidence that CTE neuropathology might not be progressive in some individuals. Considering the current state of knowledge, including the absence of a series of validated sensitive and specific biomarkers, CTE pathology might not be inexorably progressive or specific to those who have experienced repetitive neurotrauma.}, }
@article {pmid31670091, year = {2019}, author = {Bailly, C}, title = {Potential use of edaravone to reduce specific side effects of chemo-, radio- and immuno-therapy of cancers.}, journal = {International immunopharmacology}, volume = {77}, number = {}, pages = {105967}, doi = {10.1016/j.intimp.2019.105967}, pmid = {31670091}, issn = {1878-1705}, mesh = {Animals ; Antioxidants/metabolism ; Edaravone/*adverse effects/*therapeutic use ; Free Radical Scavengers/adverse effects/therapeutic use ; Humans ; Inflammation/metabolism ; Neoplasms/*drug therapy/metabolism ; Oxidative Stress/drug effects ; }, abstract = {The drug edaravone (EDA) is prescribed for the treatment of patients with amyotrophic lateral sclerosis or after an acute cerebral infarction. This synthetic pyrazolone derivative is a potent scavenger of oxygen free radicals and also functions as a modulator of transcription factors, repressing NFκB and activating Nrf2, to regulate oxidative stress. EDA displays complementary anti-oxidative and anti-inflammatory effects. The injectable small molecule is currently investigated for the treatment of several non-neurological diseases. The potential interest of EDA in oncology is reviewed here. EDA is a mild antiproliferative agent but has been found to enhance significantly the anticancer and antimetastatic activities of irinotecan in a colon cancer model. Anticancer derivatives of EDA have been designed but they generally display a limited antiproliferative activity. The antioxidant and anti-inflammatory activity of EDA can be best exploited to protect non-tumor cells from damages induced by chemotherapeutic drugs and radiations. Notably EDA can reduce the renal dysfunction induced by cisplatin, the neurotoxicity of cyclophosphamide and the cardiotoxicity of doxorubicin. Upon treatment with EDA, a significant improvement in neurologic symptoms has been observed in patients with nasopharyngeal carcinoma after radiotherapy. The drug could be used to limit radiation-induced brain injury or oral mucositis. EDA was found to ameliorate autoimmune thyroiditis (Hashimoto thyroiditis), which is a frequent side effect observed after treatment of cancer patients with monoclonal antibodies targeting the immune checkpoint PD-1. Therefore, EDA could also be useful to reduce specific side effects of immuno-therapy. Collectively, the information suggests that the medical use of EDA, a drug with a proven safety after 18 years of use in brain-related Human diseases, could be extended to cancer-related conditions.}, }
@article {pmid31669671, year = {2020}, author = {Messer, A and Butler, DC}, title = {Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders.}, journal = {Neurobiology of disease}, volume = {134}, number = {}, pages = {104619}, doi = {10.1016/j.nbd.2019.104619}, pmid = {31669671}, issn = {1095-953X}, mesh = {Animals ; Genetic Therapy/*methods ; Humans ; Immunotherapy/*methods ; *Neurodegenerative Diseases ; *Single-Domain Antibodies ; }, abstract = {Intrabodies (both single-chain Fv and single-domain VH, VHH, and VL nanobodies) offer unique solutions to some of the challenges of delivery and target engagement posed by immunotherapeutics for the brain and other areas of the nervous system. The specificity, which includes the recognition of post-translational modifications, and capacity for engineering that characterize these antibody fragments can be especially well-focused when the genes encoding only the binding sites of the antibody are expressed intracellularly. Multifunctional constructs use fusions with peptides that can re-target antigen-antibody complexes to enhance both pharmacodynamic activity and intracellular solubility simultaneously. Fusions with proteolytic targeting signals, such as the PEST degron, greatly enhance potency in some cases. Stem cell transplants can be protected from exogenous misfolded proteins by stable transfection with intrabodies. Tandem expression to target two or more misfolding proteins in one treatment may be especially valuable for proteostatic disruptions due to genetic, aging, or toxic triggers. Advances in bioinformatics, screening protocols, and especially gene therapy are showing great promise for intrabody/ nanobody treatments of a full range of neurological disorders, including Alzheimer's disease and related tau dementias, Parkinson's disease and Lewy body diseases, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, among others.}, }
@article {pmid31667754, year = {2019}, author = {Jiang, J and Ravits, J}, title = {Pathogenic Mechanisms and Therapy Development for C9orf72 Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {16}, number = {4}, pages = {1115-1132}, pmid = {31667754}, issn = {1878-7479}, support = {P30 NS047101/NS/NINDS NIH HHS/United States ; R01 NS088578/NS/NINDS NIH HHS/United States ; R01NS088578/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/*genetics/pathology/*therapy ; Genetic Therapy/methods/trends ; Humans ; Immunotherapy/methods/trends ; RNA Interference/physiology ; }, abstract = {In 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of evidence favors gain of toxicity as the main pathogenic mechanism for C9orf72 repeat expansions. Alterations in several downstream cellular functions, such as nucleocytoplasmic transport and autophagy, are implicated. Exciting progress has also been made in therapy development targeting this mutation, such as by antisense oligonucleotide therapies targeting sense transcripts and small molecules targeting nucleocytoplasmic transport, and these are now in phase 1 clinical trials.}, }
@article {pmid31654670, year = {2020}, author = {Conway, O and Akpinar, HA and Rogov, VV and Kirkin, V}, title = {Selective Autophagy Receptors in Neuronal Health and Disease.}, journal = {Journal of molecular biology}, volume = {432}, number = {8}, pages = {2483-2509}, doi = {10.1016/j.jmb.2019.10.013}, pmid = {31654670}, issn = {1089-8638}, support = {C2739/A2289/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Animals ; *Autophagy ; Autophagy-Related Proteins/*metabolism ; Humans ; Microtubule-Associated Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurons/cytology/*metabolism ; Signal Transduction ; }, abstract = {Neurons are electrically excitable, postmitotic cells that perform sensory, relaying, and motor functions. Because of their unique morphological and functional specialization, cells of this type are sensitive to the stress caused by accumulation of misfolded proteins or damaged organelles. Autophagy is the fundamental mechanism that ensures sequestration of cytosolic material and its subsequent degradation in lysosomes of eukaryotic cells, thereby providing cell-autonomous nutrients and removing harmful cargos. Strikingly, mice and flies lacking functional autophagy develop early onset progressive neurodegeneration. Like in human neurodegenerative diseases (NDDs)-Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, and amyotrophic lateral sclerosis-characteristic protein aggregates observed in autophagy-deficient neurons in the animal models are indicators of the ongoing neuronal pathology. A number of selective autophagy receptors (SARs) have been characterized that interact both with the cargo and components of the autophagic machinery, thus providing the molecular basis for selective degradation of sizable cytosolic components. Interference with autophagy in experimental models, but also during the pathological vagaries in neurons, will thus have far-reaching consequences for a range of selective autophagy pathways critical for the normal functioning of the nervous system. Here, we review the key principles behind the selective autophagy and discuss how the SARs may be involved in the pathogenesis of NDDs. Using recently published examples, we also examine the emerging role of less well studied selective autophagy pathways in neuronal health and disease. We conclude by discussing targeting selective autophagy as an emerging therapeutic modality in NDDs.}, }
@article {pmid31650248, year = {2019}, author = {Acevedo, K and Masaldan, S and Opazo, CM and Bush, AI}, title = {Redox active metals in neurodegenerative diseases.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {24}, number = {8}, pages = {1141-1157}, doi = {10.1007/s00775-019-01731-9}, pmid = {31650248}, issn = {1432-1327}, mesh = {Alzheimer Disease/drug therapy/*physiopathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Brain/metabolism ; Copper/*metabolism ; Humans ; Iron/*metabolism ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy/*physiopathology ; alpha-Synuclein/metabolism ; }, abstract = {Copper (Cu) and iron (Fe) are redox active metals essential for the regulation of cellular pathways that are fundamental for brain function, including neurotransmitter synthesis and release, neurotransmission, and protein turnover. Cu and Fe are tightly regulated by sophisticated homeostatic systems that tune the levels and localization of these redox active metals. The regulation of Cu and Fe necessitates their coordination to small organic molecules and metal chaperone proteins that restrict their reactions to specific protein centres, where Cu and Fe cycle between reduced (Fe[2+], Cu[+]) and oxidised states (Fe[3+], Cu[2+]). Perturbation of this regulation is evident in the brain affected by neurodegeneration. Here we review the evidence that links Cu and Fe dyshomeostasis to neurodegeneration as well as the promising preclinical and clinical studies reporting pharmacological intervention to remedy Cu and Fe abnormalities in the treatment of Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS).}, }
@article {pmid31646531, year = {2020}, author = {Delprat, B and Crouzier, L and Su, TP and Maurice, T}, title = {At the Crossing of ER Stress and MAMs: A Key Role of Sigma-1 Receptor?.}, journal = {Advances in experimental medicine and biology}, volume = {1131}, number = {}, pages = {699-718}, doi = {10.1007/978-3-030-12457-1_28}, pmid = {31646531}, issn = {0065-2598}, mesh = {*Cell Membrane/metabolism/pathology ; *Endoplasmic Reticulum Stress ; Humans ; Mitochondria/metabolism ; *Neurodegenerative Diseases/physiopathology ; *Receptors, sigma/metabolism ; Sigma-1 Receptor ; }, abstract = {Calcium exchanges and homeostasis are finely regulated between cellular organelles and in response to physiological signals. Besides ionophores, including voltage-gated Ca[2+] channels, ionotropic neurotransmitter receptors, or Store-operated Ca[2+] entry, activity of regulatory intracellular proteins finely tune Calcium homeostasis. One of the most intriguing, by its unique nature but also most promising by the therapeutic opportunities it bears, is the sigma-1 receptor (Sig-1R). The Sig-1R is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it interacts with several partners involved in ER stress response, or in Ca[2+] exchange between the ER and mitochondria. Small molecules have been identified that specifically and selectively activate Sig-1R (Sig-1R agonists or positive modulators) at the cellular level and that also allow effective pharmacological actions in several pre-clinical models of pathologies. The present review will summarize the recent data on the mechanism of action of Sig-1R in regulating Ca[2+] exchanges and protein interactions at MAMs and the ER. As MAMs alterations and ER stress now appear as a common track in most neurodegenerative diseases, the intracellular action of Sig-1R will be discussed in the context of the recently reported efficacy of Sig-1R drugs in pathologies like Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis.}, }
@article {pmid31631821, year = {2020}, author = {Gontijo, VS and Viegas, FPD and Ortiz, CJC and de Freitas Silva, M and Damasio, CM and Rosa, MC and Campos, TG and Couto, DS and Tranches Dias, KS and Viegas, C}, title = {Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {18}, number = {5}, pages = {348-407}, pmid = {31631821}, issn = {1875-6190}, mesh = {Animals ; *Drug Design ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*chemistry/*therapeutic use ; }, abstract = {Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.}, }
@article {pmid31630771, year = {2020}, author = {Cabral-Costa, JV and Kowaltowski, AJ}, title = {Neurological disorders and mitochondria.}, journal = {Molecular aspects of medicine}, volume = {71}, number = {}, pages = {100826}, doi = {10.1016/j.mam.2019.10.003}, pmid = {31630771}, issn = {1872-9452}, mesh = {Calcium Signaling ; Energy Metabolism ; Humans ; Mitochondria/*metabolism ; Mitochondrial Dynamics ; Neurodegenerative Diseases/*metabolism/pathology ; Oxidative Phosphorylation ; Oxidative Stress ; Proteostasis ; Reactive Oxygen Species/metabolism ; }, abstract = {The brain is highly dependent on mitochondrial energy metabolism. As a result, mitochondrial dysfunction is a central aspect of many adult-onset neurological diseases, including stroke, ALS, Alzheimer's, Huntington's, and Parkinson's diseases. We review here how different mitochondrial functions, including oxidative phosphorylation, mitochondrial dynamics, oxidant generation, cell death regulation, Ca[2+] homeostasis, and proteostasis are involved in these disorders.}, }
@article {pmid31626953, year = {2020}, author = {Baradaran-Heravi, Y and Van Broeckhoven, C and van der Zee, J}, title = {Stress granule mediated protein aggregation and underlying gene defects in the FTD-ALS spectrum.}, journal = {Neurobiology of disease}, volume = {134}, number = {}, pages = {104639}, doi = {10.1016/j.nbd.2019.104639}, pmid = {31626953}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Animals ; Frontotemporal Dementia/*genetics/*pathology ; Humans ; Inclusion Bodies/pathology ; *Protein Aggregates ; Protein Aggregation, Pathological/*genetics/*pathology ; }, abstract = {Stress granules (SGs) are dynamic membraneless compartments composed out of RNA-binding proteins (RBPs) and RNA molecules that assemble temporarily to allow the cell to cope with cellular stress by stalling mRNA translation and moving synthesis towards cytoprotective proteins. Aberrant SGs have become prime suspects in the nucleation of toxic protein aggregation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Perturbed SG dynamics appears to be mediated by alterations in RNA binding proteins (RBP). Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, EWSR1, TAF15, hnRNPA1, hnRNPA2B1, ATXN2, TIA1) have been identified to interfere with SG formation through mutation of their low-complexity domain (LCD), and thereby cause or influence disease. Interestingly, disease pathways associated to the C9orf72 repeat expansion, the leading genetic cause of the FTD-ALS spectrum, intersect with SG-mediated protein aggregate formation. In this review, we provide a comprehensive overview of known SG proteins and their genetic contribution to the FTD-ALS spectrum. Importantly, multiple LCD-baring RBPs have already been identified in FTD-ALS that have not yet been genetically linked to disease. These should be considered candidate genes and offer opportunities for gene prioritization when mining sequencing data of unresolved FTD and ALS. Further, we zoom into the current understanding of the molecular processes of perturbed RBP function leading to disturbed SG dynamics, RNA metabolism, and pathological inclusions. Finally, we indicate how these gained insights open new avenues for therapeutic strategies targeting phase separation and SG dynamics to reverse pathological protein aggregation and protect against toxicity.}, }
@article {pmid31619490, year = {2019}, author = {Bartoletti, M and Bosco, DA and Da Cruz, S and Lagier-Tourenne, C and Liachko, N and Markmiller, S and Webster, KM and Wharton, KA}, title = {Phenotypic Suppression of ALS/FTD-Associated Neurodegeneration Highlights Mechanisms of Dysfunction.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {39}, number = {42}, pages = {8217-8224}, pmid = {31619490}, issn = {1529-2401}, support = {R01 NS087227/NS/NINDS NIH HHS/United States ; R01 NS108769/NS/NINDS NIH HHS/United States ; /MRC_/Medical Research Council/United Kingdom ; I01 BX004044/BX/BLRD VA/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Disease Progression ; Frontotemporal Dementia/*genetics ; Humans ; Mutation ; }, abstract = {A fundamental question regarding the etiology of amyotrophic lateral sclerosis (ALS) is whether the various gene mutations associated with the disease converge on a single molecular pathway or act through multiple pathways to trigger neurodegeneration. Notably, several of the genes and cellular processes implicated in ALS have also been linked to frontotemporal dementia (FTD), suggesting these two diseases share common origins with varied clinical presentations. Scientists are rapidly identifying ALS/FTD suppressors that act on conserved pathways from invertebrates to vertebrates to alleviate degeneration. The elucidation of such genetic modifiers provides insight into the molecular pathways underlying this rapidly progressing neurodegenerative disease, while also revealing new targets for therapeutic development.}, }
@article {pmid31616242, year = {2019}, author = {Tan, VX and Guillemin, GJ}, title = {Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1013}, pmid = {31616242}, issn = {1662-4548}, abstract = {Amyotrophic Lateral Sclerosis (ALS) currently lacks a robust and well-defined biomarker that can 1) assess the progression of the disease, 2) predict and/or delineate the various clinical subtypes, and 3) evaluate or predict a patient's response to treatments. The kynurenine Pathway (KP) of tryptophan degradation represent a promising candidate as it is involved with several neuropathological features present in ALS including neuroinflammation, excitotoxicity, oxidative stress, immune system activation and dysregulation of energy metabolism. Some of the KP metabolites (KPMs) can cross the blood brain barrier, and many studies have shown their levels are dysregulated in major neurodegenerative diseases including ALS. The KPMs can be easily analyzed in body fluids and tissue and as they are small molecules, and are stable. KPMs have a Janus face action, they can be either or both neurotoxic and/or neuroprotective depending of their levels. This mini review examines and presents evidence supporting the use of KPMs as a relevant set of biomarkers for ALS, and highlights the criteria required to achieve a valid biomarker set for ALS.}, }
@article {pmid31610856, year = {2019}, author = {VanItallie, TB}, title = {Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE).}, journal = {Metabolism: clinical and experimental}, volume = {100S}, number = {}, pages = {153943}, doi = {10.1016/j.metabol.2019.07.007}, pmid = {31610856}, issn = {1532-8600}, mesh = {Animals ; Brain Injuries, Traumatic/*complications ; Chronic Traumatic Encephalopathy/*etiology ; Humans ; Neurodegenerative Diseases/etiology ; Neuropathology ; *Sports ; }, abstract = {Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to ~30% of all injury-related deaths in the US. TBI occurs when a force transmitted to the head causes neuropathologic damage and impairment of brain function. TBI doubles risk of suicide and is the major determinant of acquired seizure disorders. TBI arising from closed head trauma (CHT) significantly increases the risk of developing Alzheimer's disease (AD), Parkinson's disease (PD) and chronic traumatic encephalopathy (CTE). Evidence for a possible role of TBI as a risk factor for sporadic amyotrophic lateral sclerosis (sALS) has been provided by studies of professional players of European football. Depending on age, genetic make-up (in particular, being a carrier of one or two ApoE4 alleles), the number of TBIs sustained, their severity, the time periods involved, and many other factors that affect vulnerability, decades may pass after occurrence of one or more TBIs before sequelae such as AD, PD, sALS or CTE become clinically evident. Among college and professional football players who experience repeated concussions and sub-concussive blows to the head, the risk of developing CTE increases with the number of years actively devoted to the sport, and the degree of exposure to physical impacts inherent in the position played. Following a moderate or severe concussion, or a series of mild blows to the head, the brain may undergo subtle pathophysiological changes that are unlikely to be detected with confidence using available diagnostic methods. Biomarkers are being sought that can help the attending physician infer the likely presence of an ongoing occult neurodegenerative process. One example of the adverse effect of collision on the brain is "heading" the soccer ball-a feat that, repeated over years of competition, has been found to produce severe brain damage in veteran players. CTE has attracted increasing national attention because of its devastating effects in a high proportion of retired professional players of American football. In a study of brains from deceased former football players, contributed mostly by family members, CTE was neuropathologically diagnosed in 110 of 111 of National Football League (NFL) veterans. In the CTE-positive subjects, the authors observed extensive brain atrophy, astrogliosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. CTE's neuropathology has been formally defined as a tauopathy characterized by a distinct perivascular accumulation of hyperphosphorylated tau in neurons and astrocytes within cerebral sulci. Although the mechanism that underlies the unforeseen emergence of CTE long after the occurrence of one or more closed head traumas is unknown, an explanation proposed by Albayram and associates is persuasive. They discovered TBI-induced neuronal production of the toxic compound cis P-tau, an abnormal and destructive isomer of the normal and benign trans P-tau, in mouse models of CTE. Cis P-tau produced a CTE-like syndrome via a process they termed cistauosis. Cistauosis can be blocked in laboratory animals by cis P-tau monoclonal antibody, which prevents later development of tau tangles, brain atrophy and virtual CTE. In a subsequent study, the same group found in human samples obtained post-TBI from a variety of causes, that cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Thus, cis P-tau appears to contribute to short-term and long-term sequelae after TBI, but may be subject to neutralization by cis-antibody treatment.}, }
@article {pmid31597311, year = {2019}, author = {Tedeschi, V and Petrozziello, T and Secondo, A}, title = {Calcium Dyshomeostasis and Lysosomal Ca[2+] Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {8}, number = {10}, pages = {}, pmid = {31597311}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Calcium/*metabolism ; Endoplasmic Reticulum/metabolism ; Homeostasis ; Humans ; Lysosomes/*metabolism/pathology/physiology ; Mitochondria/metabolism ; Motor Neurons/*metabolism/pathology/physiology ; Neurodegenerative Diseases/metabolism/physiopathology ; }, abstract = {Recent findings in the understanding of amyotrophic lateral sclerosis (ALS) revealed that alteration in calcium (Ca[2+]) homeostasis may largely contribute to motor neuron demise. A large part of these alterations is due to dysfunctional Ca[2+]-storing organelles, including the endoplasmic reticulum (ER) and mitochondria. Very recently, lysosomal Ca[2+] dysfunction has emerged as an important pathological change leading to neuronal loss in ALS. Remarkably, the Ca[2+]-storing organelles are interacting with each other at specialized domains controlling mitochondrial dynamics, ER/lysosomal function, and autophagy. This occurs as a result of interaction between specific ionic channels and Ca[2+]-dependent proteins located in each structure. Therefore, the dysregulation of these ionic mechanisms could be considered as a key element in the neurodegenerative process. This review will focus on the possible role of lysosomal Ca[2+] dysfunction in the pathogenesis of several neurodegenerative diseases, including ALS and shed light on the possibility that specific lysosomal Ca[2+] channels might represent new promising targets for preventing or at least delaying neurodegeneration in ALS.}, }
@article {pmid31595953, year = {2019}, author = {Fernandopulle, M and Wang, G and Nixon-Abell, J and Qamar, S and Balaji, V and Morihara, R and St George-Hyslop, PH}, title = {Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins.}, journal = {Human molecular genetics}, volume = {28}, number = {R2}, pages = {R187-R196}, pmid = {31595953}, issn = {1460-2083}, support = {/WT_/Wellcome Trust/United Kingdom ; 203249/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /CAPMC/CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Annexins/chemistry/*genetics/metabolism ; Biological Transport/genetics ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics ; Humans ; Intracellular Membranes/chemistry/metabolism ; Mutation, Missense ; Neurodegenerative Diseases/physiopathology ; Neurons/chemistry/metabolism ; Protein Processing, Post-Translational/genetics ; RNA-Binding Protein FUS/*chemistry/genetics/metabolism ; Temporal Lobe/*physiopathology ; }, abstract = {Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).}, }
@article {pmid31587851, year = {2019}, author = {Chazot-Balcon, M and Dumazeaud, M and Bouchard, JP}, title = {[Neuropsychopathology of amyotrophic lateral sclerosis].}, journal = {Revue de l'infirmiere}, volume = {68}, number = {254}, pages = {36-38}, doi = {10.1016/j.revinf.2019.08.009}, pmid = {31587851}, issn = {1293-8505}, mesh = {Amyotrophic Lateral Sclerosis/nursing/physiopathology/*psychology ; Disease Progression ; Humans ; }, abstract = {Amyotrophic lateral sclerosis is a serious neuro-degenerative disease related to involvement of central motor neurons (cerebral cortex) and peripheral neurons (anterior horn of the spinal cord and motor nuclei of the medulla). Clinical progression is marked by extensive paralysis leading to death, most frequently by respiratory failure. Specific nursing care is required at each stage of the illness.}, }
@article {pmid31583591, year = {2019}, author = {Valori, CF and Guidotti, G and Brambilla, L and Rossi, D}, title = {Astrocytes in Motor Neuron Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1175}, number = {}, pages = {227-272}, doi = {10.1007/978-981-13-9913-8_10}, pmid = {31583591}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Astrocytes/*cytology ; Humans ; Motor Neurons/*pathology ; Muscular Atrophy, Spinal/*physiopathology ; Mutation ; }, abstract = {Motor neuron disorders are highly debilitating and mostly fatal conditions for which only limited therapeutic options are available. To overcome this limitation and develop more effective therapeutic strategies, it is critical to discover the pathogenic mechanisms that trigger and sustain motor neuron degeneration with the greatest accuracy and detail. In the case of Amyotrophic Lateral Sclerosis (ALS), several genes have been associated with familial forms of the disease, whilst the vast majority of cases develop sporadically and no defined cause can be held responsible. On the contrary, the huge majority of Spinal Muscular Atrophy (SMA) occurrences are caused by loss-of-function mutations in a single gene, SMN1. Although the typical hallmark of both diseases is the loss of motor neurons, there is increasing awareness that pathological lesions are also present in the neighbouring glia, whose dysfunction clearly contributes to generating a toxic environment in the central nervous system. Here, ALS and SMA are sequentially presented, each disease section having a brief introduction, followed by a focussed discussion on the role of the astrocytes in the disease pathogenesis. Such a dissertation is substantiated by the findings that built awareness on the glial involvement and how the glial-neuronal interplay is perturbed, along with the appraisal of this new cellular site for possible therapeutic intervention.}, }
@article {pmid31582840, year = {2019}, author = {Wolozin, B and Ivanov, P}, title = {Stress granules and neurodegeneration.}, journal = {Nature reviews. Neuroscience}, volume = {20}, number = {11}, pages = {649-666}, pmid = {31582840}, issn = {1471-0048}, support = {R01 AG064932/AG/NIA NIH HHS/United States ; RF1 AG056318/AG/NIA NIH HHS/United States ; R01 AG050471/AG/NIA NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; R01 GM126150/GM/NIGMS NIH HHS/United States ; R21 AG059925/AG/NIA NIH HHS/United States ; RF1 AG061706/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Organelles/*metabolism/pathology ; RNA-Binding Proteins/genetics/metabolism ; Signal Transduction/physiology ; Stress, Physiological/*physiology ; }, abstract = {Recent advances suggest that the response of RNA metabolism to stress has an important role in the pathophysiology of neurodegenerative diseases, particularly amyotrophic lateral sclerosis, frontotemporal dementias and Alzheimer disease. RNA-binding proteins (RBPs) control the utilization of mRNA during stress, in part through the formation of membraneless organelles termed stress granules (SGs). These structures form through a process of liquid-liquid phase separation. Multiple biochemical pathways regulate SG biology. The major signalling pathways regulating SG formation include the mammalian target of rapamycin (mTOR)-eukaryotic translation initiation factor 4F (eIF4F) and eIF2α pathways, whereas the pathways regulating SG dispersion and removal are mediated by valosin-containing protein and the autolysosomal cascade. Post-translational modifications of RBPs also strongly contribute to the regulation of SGs. Evidence indicates that SGs are supposed to be transient structures, but the chronic stresses associated with ageing lead to chronic, persistent SGs that appear to act as a nidus for the aggregation of disease-related proteins. We suggest a model describing how intrinsic vulnerabilities within the cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent. This process might accelerate the pathophysiology of many neurodegenerative diseases and myopathies, and it suggests new targets for disease intervention.}, }
@article {pmid31577933, year = {2019}, author = {Lautrup, S and Sinclair, DA and Mattson, MP and Fang, EF}, title = {NAD[+] in Brain Aging and Neurodegenerative Disorders.}, journal = {Cell metabolism}, volume = {30}, number = {4}, pages = {630-655}, pmid = {31577933}, issn = {1932-7420}, support = {R21 DE027490/DE/NIDCR NIH HHS/United States ; R37 AG028730/AG/NIA NIH HHS/United States ; DP1 AG058605/AG/NIA NIH HHS/United States ; R01 DK100263/DK/NIDDK NIH HHS/United States ; R01 AG019719/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Animals ; Brain/*metabolism ; Cell Line ; Humans ; Mice ; NAD/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neurons/cytology/*metabolism/pathology ; Rats ; }, abstract = {NAD[+] is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD[+]-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD[+] and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD[+]-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.}, }
@article {pmid31572381, year = {2019}, author = {Evans, FL and Dittmer, M and de la Fuente, AG and Fitzgerald, DC}, title = {Protective and Regenerative Roles of T Cells in Central Nervous System Disorders.}, journal = {Frontiers in immunology}, volume = {10}, number = {}, pages = {2171}, pmid = {31572381}, issn = {1664-3224}, support = {110138/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Adaptive Immunity ; Animals ; Behavior ; Brain/growth &amp; development/immunology ; Central Nervous System Diseases/*immunology ; Homeostasis ; Humans ; T-Lymphocytes/*immunology ; }, abstract = {Pathogenic mechanisms of T cells in several central nervous system (CNS) disorders are well-established. However, more recent studies have uncovered compelling beneficial roles of T cells in neurological diseases, ranging from tissue protection to regeneration. These divergent functions arise due to the diversity of T cell subsets, particularly CD4[+] T cells. Here, we review the beneficial impact of T cell subsets in a range of neuroinflammatory and neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and CNS trauma. Both T cell-secreted mediators and direct cell contact-dependent mechanisms deliver neuroprotective, neuroregenerative and immunomodulatory signals in these settings. Understanding the molecular details of these beneficial T cell mechanisms will provide novel targets for therapeutic exploitation that can be applied to a range of neurological disorders.}, }
@article {pmid31571171, year = {2019}, author = {Liu, L and Liu, X}, title = {Contributions of Drug Transporters to Blood-Brain Barriers.}, journal = {Advances in experimental medicine and biology}, volume = {1141}, number = {}, pages = {407-466}, doi = {10.1007/978-981-13-7647-4_9}, pmid = {31571171}, issn = {0065-2598}, mesh = {Biological Transport ; *Blood-Brain Barrier/metabolism ; Brain/metabolism ; Humans ; *Membrane Transport Proteins/metabolism ; *Pharmaceutical Preparations/administration &amp; dosage/metabolism ; }, abstract = {Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.}, }
@article {pmid31568865, year = {2019}, author = {Lai, JD and Ichida, JK}, title = {C9ORF72 protein function and immune dysregulation in amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {713}, number = {}, pages = {134523}, doi = {10.1016/j.neulet.2019.134523}, pmid = {31568865}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*physiopathology ; Animals ; C9orf72 Protein/genetics/*immunology/*physiology ; DNA Repeat Expansion ; Humans ; Nerve Degeneration/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing disease that affects upper and lower motor neurons eventually leading to paralysis and death by respiratory dysfunction. The most common genetic variant among ALS patients is a hexanucleotide repeat expansion within the first intron of the gene C9ORF72. This expansion elicits a complex cascade of events as a result of both gain- and loss-of-function mechanisms that contribute to neurodegeneration. Increasing evidence suggests that this repeat expansion in C9ORF72 also influences the immune homeostasis. In this review, we consolidate the current understanding of C9ORF72-mediated pathogenesis in both the central nervous system and peripheral immune system and propose mechanisms by which the immune system contributes to ALS.}, }
@article {pmid31562633, year = {2019}, author = {Trostchansky, A}, title = {Overview of Lipid Biomarkers in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Advances in experimental medicine and biology}, volume = {1161}, number = {}, pages = {233-241}, doi = {10.1007/978-3-030-21735-8_18}, pmid = {31562633}, issn = {0065-2598}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis ; Animals ; *Biomarkers/blood ; Disease Progression ; Humans ; Lipid Metabolism ; *Lipids/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease involving motor neuron (MN) degeneration in the spinal cord, brain stem and primary motor cortex. The existence of inflammatory processes around MN and axonal degeneration in ALS has been shown. Unfortunately, none of the successful therapies in ALS animal models has improved clinical outcomes in patients with ALS. Therefore, the detection of blood biomarkers to be used as screening tools for disease onset and progression has been an expanding research area with few advances in the development of drugs for the treatment of ALS. In this review, we will address the available data analyzing regarding the relationship of lipid metabolism and lipid derived- products with ALS. We will address the advances on the studies about the role that lipids plays at the onset, progression and lifespan extension of ALS patients.}, }
@article {pmid31555895, year = {2019}, author = {Kawakami, I and Arai, T and Hasegawa, M}, title = {The basis of clinicopathological heterogeneity in TDP-43 proteinopathy.}, journal = {Acta neuropathologica}, volume = {138}, number = {5}, pages = {751-770}, pmid = {31555895}, issn = {1432-0533}, support = {JP26117005//Ministry of Education, Culture, Sports, Science, and Technology Grants-in-Aid for Scientific Research Grants/International ; JP23228004//Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant/International ; JP14533254//Japan Agency for Medical Research and Development/International ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Brain/*pathology ; Frontotemporal Lobar Degeneration/*genetics/pathology ; Humans ; Inclusion Bodies/pathology ; Neurons/pathology ; TDP-43 Proteinopathies/*genetics/pathology ; }, abstract = {Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. Recent studies support the idea that pathological protein spreads from neuron to neuron via axonal transport in a hierarchical manner. However, little is known to date about the basis of the selective cellular and regional vulnerability, although the information would have important implications for the development of targeted and personalized therapies. Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research.}, }
@article {pmid31551714, year = {2019}, author = {Kanellopoulos, JM and Delarasse, C}, title = {Pleiotropic Roles of P2X7 in the Central Nervous System.}, journal = {Frontiers in cellular neuroscience}, volume = {13}, number = {}, pages = {401}, pmid = {31551714}, issn = {1662-5102}, abstract = {The purinergic receptor P2X7 is expressed in neural and immune cells known to be involved in neurological diseases. Its ligand, ATP, is a signaling molecule that can act as a neurotransmitter in physiological conditions or as a danger signal when released in high amount by damaged/dying cells or activated glial cells. Thus, ATP is a danger-associated molecular pattern. Binding of ATP by P2X7 leads to the activation of different biochemical pathways, depending on the physiological or pathological environment. The aim of this review is to discuss various functions of P2X7 in the immune and central nervous systems. We present evidence that P2X7 may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies: epilepsy, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration and cerebral artery occlusion.}, }
@article {pmid31551700, year = {2019}, author = {Benbrika, S and Desgranges, B and Eustache, F and Viader, F}, title = {Cognitive, Emotional and Psychological Manifestations in Amyotrophic Lateral Sclerosis at Baseline and Overtime: A Review.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {951}, pmid = {31551700}, issn = {1662-4548}, abstract = {It is now well recognized that, in addition to motor impairment, amyotrophic lateral sclerosis (ALS) may cause extra-motor clinical signs and symptoms. These can include the alteration of certain cognitive functions, impaired social cognition, and changes in the perception and processing of emotions. Where these extra-motor manifestations occur in ALS, they usually do so from disease onset. In about 10% of cases, the cognitive and behavioral changes meet the diagnostic criteria for frontotemporal dementia. The timecourse of behavioral and cognitive involvement in ALS is unclear. Whereas longitudinal studies have failed to show cognitive decline over time, some cross-sectional studies have demonstrated poorer cognitive performances in the advanced stages of the disease. Neuroimaging studies show that in ALS, extra-motor signs and symptoms are associated with specific brain lesions, but little is known about how they change over time. Finally, patients with ALS appear less depressed than might be expected, given the prognosis. Moreover, many patients achieve satisfactory psychosocial adjustment throughout the course of the disease, regardless of their degree of motor disability. There are scant longitudinal data on extra-motor impairment in ALS, and to our knowledge, no systematic review on this subject has yet been published. Even so, a better understanding of patients' clinical trajectory is essential if they are to be provided with tailored care and given the best possible support. We therefore undertook to review the evidence for extra-motor changes and their time course in ALS, in both the cognitive, emotional and psychological domains, with a view to identifying mechanisms that may help these patients cope with their disease.}, }
@article {pmid31551669, year = {2019}, author = {Ryskamp, DA and Korban, S and Zhemkov, V and Kraskovskaya, N and Bezprozvanny, I}, title = {Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {862}, pmid = {31551669}, issn = {1662-4548}, support = {F32 NS093786/NS/NINDS NIH HHS/United States ; R01 NS056224/NS/NINDS NIH HHS/United States ; RF1 AG055577/AG/NIA NIH HHS/United States ; }, abstract = {Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer's (AD) and Huntington's diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type- and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.}, }
@article {pmid31550516, year = {2019}, author = {Goodman, LD and Bonini, NM}, title = {Repeat-associated non-AUG (RAN) translation mechanisms are running into focus for GGGGCC-repeat associated ALS/FTD.}, journal = {Progress in neurobiology}, volume = {183}, number = {}, pages = {101697}, pmid = {31550516}, issn = {1873-5118}, support = {F32 NS009727/NS/NINDS NIH HHS/United States ; R01 NS078283/NS/NINDS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; T32 GM007517/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein/*genetics ; Frontotemporal Dementia/*genetics ; Humans ; Protein Biosynthesis/genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; }, abstract = {Many human diseases are associated with the expansion of repeat sequences within the genes. It has become clear that expressed disease transcripts bearing such long repeats can undergo translation, even in the absence of a canonical AUG start codon. Termed "RAN translation" for repeat associated non-AUG translation, this process is becoming increasingly prominent as a contributor to these disorders. Here we discuss mechanisms and variables that impact translation of the repeat sequences associated with the C9orf72 gene. Expansions of a G4C2 repeat within intron 1 of this gene are associated with the motor neuron disease ALS and dementia FTD, which comprise a clinical and pathological spectrum. RAN translation of G4C2 repeat expansions has been studied in cells in culture (ex vivo) and in the fly in vivo. Cellular states that lead to RAN translation, like stress, may be critical contributors to disease progression. Greater elucidation of the mechanisms that impact this process and the factors contributing will lead to greater understanding of the repeat expansion diseases, to the potential development of novel approaches to therapeutics, and to a greater understanding of how these players impact biological processes in the absence of disease.}, }
@article {pmid31548223, year = {2020}, author = {Goldman, JS}, title = {Predictive Genetic Counseling for Neurodegenerative Diseases: Past, Present, and Future.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {10}, number = {7}, pages = {}, pmid = {31548223}, issn = {2157-1422}, mesh = {Alzheimer Disease/*genetics ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Genetic Counseling/ethics/*methods/trends ; Genetic Testing/*methods ; Humans ; Huntington Disease/diagnosis/*genetics ; Parkinson Disease/genetics ; }, abstract = {Predictive genetic counseling for neurodegenerative diseases commenced with Huntington's disease (HD). Because the psychological issues and outcomes have been best studied in HD, the HD genetic counseling and testing protocol is still accepted as the gold standard for genetic counseling for these diseases. Yet, advances in genomic technology have produced an abundance of new information about the genetics of diseases such as Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. The resulting expansion of genetic tests together with the availability of direct-to-consumer testing and clinical trials for treatment of these diseases present new ethical and practical issues requiring modifications to the protocol for HD counseling and new demands on both physicians and genetic counselors. This work reviews the history of genetic counseling for neurodegenerative diseases, its current practice, and the future direction of genetic counseling for these conditions.}, }
@article {pmid31548044, year = {2020}, author = {Marsli, S and Mouni, F and Araqi, A and Elmoutawakil, B and Elotmani, H and Rafai, MA}, title = {Can pregnancy decompensate an amyotrophic lateral sclerosis (ALS)? Case report and review of literature.}, journal = {Revue neurologique}, volume = {176}, number = {3}, pages = {216-217}, doi = {10.1016/j.neurol.2019.07.021}, pmid = {31548044}, issn = {0035-3787}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/*etiology/pathology ; Disease Progression ; Female ; Gait Disorders, Neurologic/diagnosis/etiology ; Humans ; Muscle Cramp/*pathology ; Parturition/physiology ; Pregnancy ; Pregnancy Complications/diagnosis/*pathology ; Puerperal Disorders/*diagnosis/etiology/pathology ; }, }
@article {pmid31547555, year = {2019}, author = {Fuke, N and Nagata, N and Suganuma, H and Ota, T}, title = {Regulation of Gut Microbiota and Metabolic Endotoxemia with Dietary Factors.}, journal = {Nutrients}, volume = {11}, number = {10}, pages = {}, pmid = {31547555}, issn = {2072-6643}, mesh = {Animals ; Diet, High-Fat/adverse effects ; Dietary Fats/*adverse effects ; Dysbiosis/blood/etiology/*microbiology ; Endotoxemia/blood/etiology/*microbiology ; Gastrointestinal Microbiome/*physiology ; Humans ; Lipopolysaccharides/*blood ; Mice ; }, abstract = {Metabolic endotoxemia is a condition in which blood lipopolysaccharide (LPS) levels are elevated, regardless of the presence of obvious infection. It has been suggested to lead to chronic inflammation-related diseases such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), pancreatitis, amyotrophic lateral sclerosis, and Alzheimer's disease. In addition, it has attracted attention as a target for the prevention and treatment of these chronic diseases. As metabolic endotoxemia was first reported in mice that were fed a high-fat diet, research regarding its relationship with diets has been actively conducted in humans and animals. In this review, we summarize the relationship between fat intake and induction of metabolic endotoxemia, focusing on gut dysbiosis and the influx, kinetics, and metabolism of LPS. We also summarize the recent findings about dietary factors that attenuate metabolic endotoxemia, focusing on the regulation of gut microbiota. We hope that in the future, control of metabolic endotoxemia using dietary factors will help maintain human health.}, }
@article {pmid31547425, year = {2019}, author = {Bastings, JJAJ and van Eijk, HM and Olde Damink, SW and Rensen, SS}, title = {d-amino Acids in Health and Disease: A Focus on Cancer.}, journal = {Nutrients}, volume = {11}, number = {9}, pages = {}, pmid = {31547425}, issn = {2072-6643}, mesh = {Amino Acids/*physiology ; Humans ; Neoplasms/*metabolism ; Synaptic Transmission/*physiology ; }, abstract = {d-amino acids, the enantiomeric counterparts of l-amino acids, were long considered to be non-functional or not even present in living organisms. Nowadays, d-amino acids are acknowledged to play important roles in numerous physiological processes in the human body. The most commonly studied link between d-amino acids and human physiology concerns the contribution of d-serine and d-aspartate to neurotransmission. These d-amino acids and several others have also been implicated in regulating innate immunity and gut barrier function. Importantly, the presence of certain d-amino acids in the human body has been linked to several diseases including schizophrenia, amyotrophic lateral sclerosis, and age-related disorders such as cataract and atherosclerosis. Furthermore, increasing evidence supports a role for d-amino acids in the development, pathophysiology, and treatment of cancer. In this review, we aim to provide an overview of the various sources of d-amino acids, their metabolism, as well as their contribution to physiological processes and diseases in man, with a focus on cancer.}, }
@article {pmid31546015, year = {2019}, author = {Bawari, S and Tewari, D and Argüelles, S and Sah, AN and Nabavi, SF and Xu, S and Vacca, RA and Nabavi, SM and Shirooie, S}, title = {Targeting BDNF signaling by natural products: Novel synaptic repair therapeutics for neurodegeneration and behavior disorders.}, journal = {Pharmacological research}, volume = {148}, number = {}, pages = {104458}, doi = {10.1016/j.phrs.2019.104458}, pmid = {31546015}, issn = {1096-1186}, mesh = {Animals ; Biological Products/*pharmacology/*therapeutic use ; Brain-Derived Neurotrophic Factor/*metabolism ; Humans ; Mental Disorders/*drug therapy/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Neurodegenerative disorders like Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich's ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spectrum disorders are closely associated with neurobiological deficits. Brain derived neurotrophic factor (BDNF) is an extensively studied neurotrophin. BDNF is essential for neuronal genesis, differentiation, survival, growth, plasticity, synaptic viability and transmission. BDNF has emerged as a promising target for regulating synaptic activity and plasticity. An overview of effects and mechanisms of the natural products targeting BDNF is described. This review is an attempt to enumerate the effects of various natural products on BDNF as a novel therapeutic approach for neurodegenerative and neuropsychiatric disorders.}, }
@article {pmid31544208, year = {2020}, author = {Vegeto, E and Villa, A and Della Torre, S and Crippa, V and Rusmini, P and Cristofani, R and Galbiati, M and Maggi, A and Poletti, A}, title = {The Role of Sex and Sex Hormones in Neurodegenerative Diseases.}, journal = {Endocrine reviews}, volume = {41}, number = {2}, pages = {273-319}, pmid = {31544208}, issn = {1945-7189}, support = {R01 AG027713/AG/NIA NIH HHS/United States ; }, mesh = {Female ; Gonadal Steroid Hormones/*metabolism ; Humans ; Male ; Neurodegenerative Diseases/drug therapy/*metabolism ; Receptors, Steroid/*metabolism ; *Sex Characteristics ; }, abstract = {Neurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities. The response of the CNS to sex steroids is a complex and integrated process that depends on (i) the type and amount of the cognate steroid receptor and (ii) the target cell type-either neurons, glia, or microglia. Moreover, the levels of sex steroids in the CNS fluctuate due to gonadal activities and to local metabolism and synthesis. Importantly, biochemical processes involved in the pathogenesis of NDs are increasingly being recognized as different between the two sexes and as influenced by sex steroids. The aim of this review is to present current state-of-the-art understanding on the potential role of sex steroids and their receptors on the onset and progression of major neurodegenerative disorders, namely, Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis, and the peculiar motoneuron disease spinal and bulbar muscular atrophy, in which hormonal therapy is potentially useful as disease modifier.}, }
@article {pmid31542222, year = {2020}, author = {Guo, W and Stoklund Dittlau, K and Van Den Bosch, L}, title = {Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications.}, journal = {Seminars in cell &amp; developmental biology}, volume = {99}, number = {}, pages = {133-150}, doi = {10.1016/j.semcdb.2019.07.010}, pmid = {31542222}, issn = {1096-3634}, mesh = {Animals ; Axonal Transport/*drug effects/*genetics ; Humans ; Mutation ; Neurodegenerative Diseases/*drug therapy/*genetics/metabolism ; }, abstract = {Because of the extremely polarized morphology, the proper functioning of neurons largely relies on the efficient cargo transport along the axon. Axonal transport defects have been reported in multiple neurodegenerative diseases as an early pathological feature. The discovery of mutations in human genes involved in the transport machinery provide a direct causative relationship between axonal transport defects and neurodegeneration. Here, we summarize the current genetic findings related to axonal transport in neurodegenerative diseases, and we discuss the relationship between axonal transport defects and other pathological changes observed in neurodegeneration. In addition, we summarize the therapeutic approaches targeting the axonal transport machinery in studies of neurodegenerative diseases. Finally, we review the technical advances in tracking axonal transport both in vivo and in vitro.}, }
@article {pmid31519175, year = {2019}, author = {Brown, GC}, title = {The endotoxin hypothesis of neurodegeneration.}, journal = {Journal of neuroinflammation}, volume = {16}, number = {1}, pages = {180}, pmid = {31519175}, issn = {1742-2094}, support = {MR/L010593/MRC_/Medical Research Council/United Kingdom ; MR/L010593/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; RG50995/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Endotoxins/*adverse effects/*toxicity ; Humans ; Nerve Degeneration/*chemically induced ; Neurodegenerative Diseases/*etiology ; }, abstract = {The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer's disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer's disease. Intestinal permeability increases early in Parkinson's disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson's disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.}, }
@article {pmid31507117, year = {2019}, author = {Ralli, M and Lambiase, A and Artico, M and de Vincentiis, M and Greco, A}, title = {Amyotrophic Lateral Sclerosis: Autoimmune Pathogenic Mechanisms, Clinical Features, and Therapeutic Perspectives.}, journal = {The Israel Medical Association journal : IMAJ}, volume = {21}, number = {7}, pages = {438-443}, pmid = {31507117}, issn = {1565-1088}, mesh = {Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/*physiopathology ; Diagnosis, Differential ; Disease Progression ; Female ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Motor Neurons/*pathology ; *Quality of Life ; Riluzole/therapeutic use ; Risk Factors ; Sex Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive death of motor neurons leading to fatal paralysis. The causes of ALS remain unknown; however, evidence supports the presence of autoimmune mechanisms contributing to pathogenesis. Although several environmental factors have been proposed, the only established risk factors are older age, male gender, and a family history of ALS. To date, there are no diagnostic test for ALS, and clinicians rely on the combination of upper motor neuron and lower motor neuron signs in the same body region. The aim of this paper was to provide a comprehensive review of current clinical literature with special focus on the role of autoimmunity in ALS, differential diagnosis, and available therapeutic approaches. Current evidence suggests a contribution of the innate immune system in ALS, with a role of microglial cell activation at the sites of neurodegeneration. The median time from symptom onset to diagnosis of ALS is 14 months, and this time estimate is mainly based on specific clinical signs and exclusion of ALS-like conditions. Several therapeutic approaches have been proposed, including immunosuppressive drugs, to reduce disease progression. Riluzole has been established as the only, although modestly effective, disease modifying therapy, extending mean patient survival by 3to 6 months. Recent advances in understanding the pathophysiology mechanisms of ALS encourage realistic hope for new treatment approaches. To date, the cornerstones of the management of patients with ALS are focused on symptom control, maintaining quality of life and improving survival.}, }
@article {pmid31502763, year = {2020}, author = {Ho, DM and Artavanis-Tsakonas, S and Louvi, A}, title = {The Notch pathway in CNS homeostasis and neurodegeneration.}, journal = {Wiley interdisciplinary reviews. Developmental biology}, volume = {9}, number = {1}, pages = {e358}, doi = {10.1002/wdev.358}, pmid = {31502763}, issn = {1759-7692}, support = {R01NS111935/NH/NIH HHS/United States ; R21NS105001/NH/NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/*metabolism ; Homeostasis/*physiology ; Humans ; Mutation/physiology ; Neurodegenerative Diseases/*metabolism ; Receptors, Notch/*metabolism ; Signal Transduction/*physiology ; }, abstract = {The role of the Notch signaling pathway in neural development has been well established over many years. More recent studies, however, have demonstrated that Notch continues to be expressed and active throughout adulthood in many areas of the central nervous system. Notch signals have been implicated in adult neurogenesis, memory formation, and synaptic plasticity in the adult organism, as well as linked to acute brain trauma and chronic neurodegenerative conditions. NOTCH3 mutations are responsible for the most common form of hereditary stroke, the progressive disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Notch has also been associated with several progressive neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Although numerous studies link Notch activity with CNS homeostasis and neurodegenerative diseases, the data thus far are primarily correlative, rather than functional. Nevertheless, the evidence for Notch pathway activity in specific neural cellular contexts is strong, and certainly intriguing, and points to the possibility that the pathway carries therapeutic promise. This article is categorized under: Nervous System Development > Flies Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: General Principles.}, }
@article {pmid31500113, year = {2019}, author = {Cappella, M and Ciotti, C and Cohen-Tannoudji, M and Biferi, MG}, title = {Gene Therapy for ALS-A Perspective.}, journal = {International journal of molecular sciences}, volume = {20}, number = {18}, pages = {}, pmid = {31500113}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*therapy ; Animals ; C9orf72 Protein/genetics ; Disease Models, Animal ; Gene Editing ; Gene Expression ; Gene Transfer Techniques ; Genetic Predisposition to Disease ; *Genetic Therapy/adverse effects/methods ; Genetic Vectors/administration &amp; dosage/genetics ; Humans ; Molecular Targeted Therapy ; Motor Neurons/metabolism ; Mutation ; Superoxide Dismutase-1/genetics ; Transgenes ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder-particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the central nervous system (CNS) are being tested in clinical trials for patients with mutations in SOD1 or C9orf72 genes. Viral vectors can be used to deliver therapeutic sequences to stably transduce motor neurons in the CNS. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma, an AAV-mediated treatment for another MND-the infant form of spinal muscular atrophy. Given the accelerated progress in gene therapy, it is potentially a promising avenue to develop an efficient and safe cure for ALS.}, }
@article {pmid31493230, year = {2019}, author = {Kounakis, K and Tavernarakis, N}, title = {The Cytoskeleton as a Modulator of Aging and Neurodegeneration.}, journal = {Advances in experimental medicine and biology}, volume = {1178}, number = {}, pages = {227-245}, doi = {10.1007/978-3-030-25650-0_12}, pmid = {31493230}, issn = {0065-2598}, mesh = {*Aging/pathology ; *Cytoskeleton/chemistry/metabolism ; Humans ; *Neurodegenerative Diseases/pathology ; }, abstract = {The cytoskeleton consists of filamentous protein polymers that form organized structures, contributing to a multitude of cell life aspects. It includes three types of polymers: the actin microfilaments, the microtubules and the intermediate filaments. Decades of research have implicated the cytoskeleton in processes that regulate cellular and organismal aging, as well as neurodegeneration associated with injury or neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, or Charcot Marie Tooth disease. Here, we provide a brief overview of cytoskeletal structure and function, and discuss experimental evidence linking cytoskeletal function and dynamics with aging and neurodegeneration.}, }
@article {pmid31479821, year = {2019}, author = {Loughlin, FE and Wilce, JA}, title = {TDP-43 and FUS-structural insights into RNA recognition and self-association.}, journal = {Current opinion in structural biology}, volume = {59}, number = {}, pages = {134-142}, doi = {10.1016/j.sbi.2019.07.012}, pmid = {31479821}, issn = {1879-033X}, mesh = {DNA-Binding Proteins/*chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Conformation ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; RNA/*chemistry/metabolism ; RNA-Binding Protein FUS/*chemistry/metabolism ; RNA-Binding Proteins/chemistry/metabolism ; }, abstract = {RNA-binding proteins TDP-43 and FUS play essential roles in pre-mRNA splicing, localization, granule formation and other aspects of RNA metabolism. Both proteins are implicated in neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite their apparent similarities, each protein has unique structural characteristics. Here we present the current structural understanding of RNA-binding and self-association mechanisms. Both globular and intrinsically disordered domains contribute to RNA binding, each with different specificities, affinities and kinetics. Self-associating Prion-like domains in each protein form multivalent interactions and labile cross-β structures. These interactions are modulated by distinctive additional domains including a globular oligomerization domain in TDP-43 and synergistic interactions with intrinsically disordered Arginine-Glycine rich domains in FUS. These insights contribute to a better understanding of native biological functions of TDP-43 and FUS and potential molecular pathways in neurodegenerative diseases.}, }
@article {pmid31476356, year = {2019}, author = {Lyon, MS and Milligan, C}, title = {Extracellular heat shock proteins in neurodegenerative diseases: New perspectives.}, journal = {Neuroscience letters}, volume = {711}, number = {}, pages = {134462}, doi = {10.1016/j.neulet.2019.134462}, pmid = {31476356}, issn = {1872-7972}, mesh = {Animals ; Heat-Shock Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; }, abstract = {One pathological hallmark of neurodegenerative diseases and CNS trauma is accumulation of insoluble, hydrophobic molecules and protein aggregations found both within and outside cells. These may be the consequences of an inadequate or overburdened cellular response to stresses resulting from potentially toxic changes in extra- and intracellular environments. The upregulated expression of heat shock proteins (HSPs) is one example of a highly conserved cellular response to both internal and external stress. Intracellularly these proteins act as chaperones, playing vital roles in the folding of nascent polypeptides, the translocation of proteins between subcellular locations, and the disaggregation of misfolded or aggregated proteins in an attempt to maintain cellular proteostasis during both homeostatic and stressful conditions. While the predominant study of the HSPs has focused on their intracellular chaperone functions, it remains unclear if all neuronal populations can mount a complete stress response. Alternately, it is now well established that some members of this family of proteins can be secreted by nearby, non-neuronal cells to act in the extracellular environment. This review addresses the current literature detailing the use of exogenous and extracellular HSPs in the treatment of cellular and animal models of neurodegenerative disease. These findings offer a new measure of therapeutic potential to the HSPs, but obstacles must be overcome before they can be efficiently used in a clinical setting.}, }
@article {pmid31471331, year = {2019}, author = {McCully, KS}, title = {Chemical Pathology of Homocysteine VII. Cholesterol, Thioretinaco Ozonide, Mitochondrial Dysfunction, and Prevention of Mortality.}, journal = {Annals of clinical and laboratory science}, volume = {49}, number = {4}, pages = {425-438}, pmid = {31471331}, issn = {1550-8080}, mesh = {Cholesterol/*toxicity ; Homocysteine/*analogs &amp; derivatives/*toxicity ; Humans ; Mitochondria/drug effects/*pathology ; *Mortality ; Oxidative Phosphorylation/drug effects ; Vitamin B 12/*analogs &amp; derivatives/toxicity ; }, abstract = {The purpose of this review is to elucidate how low blood cholesterol promotes mitochondrial dysfunction and mortality by the loss of thioretinaco ozonide from opening of the mitochondrial permeability transition pore (mPTP). Mortality from infections and cancer are both inversely associated with blood cholesterol, as determined by multiple cohort studies from 10 to 30 years earlier. Moreover, low-density lipoprotein (LDL) is inversely related to all-cause and/or cardiovascular mortality, as determined by followup study of elderly cohorts. LDL adheres to and inactivates most microorganisms and their toxins, causing aggregation of LDL and homocysteinylated autoantibodies which obstruct vasa vasorum and produce intimal microabscesses, the vulnerable atherosclerotic plaques. The active site of mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis is proposed to consist of thioretinaco, a complex of two molecules of thioretinamide with cobalamin, oxidized to the disulfonium thioretinaco ozonide and complexed with oxygen, nicotinamide adenine dinucleotide (NAD[+]), phosphate, and ATP. Loss of the active site complex from mitochondria results from the opening of the mPTP and from decomposition of the disulfonium active site by electrophilic carcinogens, oncogenic viruses, microbes, and by reactive oxygen radicals from ionizing and non-ionizing radiation. Suppression of innate immunity is caused by the depletion of adenosyl methionine because of increased polyamine biosynthesis, resulting in inhibition of nitric oxide and peroxynitrite biosynthesis. Opening of the mPTP produces a loss of thioretinaco ozonide from mitochondria. This loss impairs ATP biosynthesis and causes the mitochondrial dysfunction observed in carcinogenesis, atherosclerosis, aging and dementia. Cholesterol inhibits the opening of the mPTP by preventing integration of the pro-apoptotic Bcl-2-associated X protein (BAX) in the outer mitochondrial membrane. This inhibition explains how elevated LDL reduces mitochondrial dysfunction by preventing loss of the active site of oxidative phosphorylation from mitochondria.}, }
@article {pmid31470787, year = {2019}, author = {Trujillo-Estrada, L and Gomez-Arboledas, A and Forner, S and Martini, AC and Gutierrez, A and Baglietto-Vargas, D and LaFerla, FM}, title = {Astrocytes: From the Physiology to the Disease.}, journal = {Current Alzheimer research}, volume = {16}, number = {8}, pages = {675-698}, doi = {10.2174/1567205016666190830110152}, pmid = {31470787}, issn = {1875-5828}, mesh = {Animals ; Astrocytes/pathology/*physiology ; Brain/pathology/physiology/physiopathology ; Humans ; Neurodegenerative Diseases/pathology/physiopathology ; }, abstract = {Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.}, }
@article {pmid31463415, year = {2019}, author = {Barua, S and Kim, JY and Yenari, MA and Lee, JE}, title = {The role of NOX inhibitors in neurodegenerative diseases.}, journal = {IBRO reports}, volume = {7}, number = {}, pages = {59-69}, pmid = {31463415}, issn = {2451-8301}, abstract = {Oxidative stress is a key player in both chronic and acute brain disease due to the higher metabolic demand of the brain. Among the producers of free radicals, NADPH-oxidase (NOX) is a major contributor to oxidative stress in neurological disorders. In the brain, the superoxide produced by NOX is mainly found in leukocytes. However, recent studies have reported that it can be found in several other cell types. NOX has been reported to regulate neuronal signaling, memory processing, and central cardiovascular homeostasis. However, overproduction of NOX can contribute to neurotoxicity, CNS degeneration, and cardiovascular disorders. Regarding the above functions, NOX has been shown to play a crucial role in chronic CNS diseases like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and in acute CNS disorders such as stroke, spinal cord injury, traumatic brain injury (TBI), and related cerebrovascular diseases. NOX is a multi-subunit complex consisting of two membrane-associated and four cytosolic subunits. Thus, in recent years, inhibition of NOX activity has drawn a great deal of attention from researchers in the field of treating chronic and acute CNS disorders and preventing secondary complications. Mounting evidence has shown that NOX inhibition is neuroprotective and that inhibiting NOX in circulating immune cells can improve neurological disease conditions. This review summarizes recent studies on the therapeutic effects and pharmacological strategies regarding NOX inhibitors in chronic and acute brain diseases and focuses on the hurdles that should be overcome before their clinical implementation.}, }
@article {pmid31460675, year = {2019}, author = {Veeresh, P and Kaur, H and Sarmah, D and Mounica, L and Verma, G and Kotian, V and Kesharwani, R and Kalia, K and Borah, A and Wang, X and Dave, KR and Rodriguez, AM and Yavagal, DR and Bhattacharya, P}, title = {Endoplasmic reticulum-mitochondria crosstalk: from junction to function across neurological disorders.}, journal = {Annals of the New York Academy of Sciences}, volume = {1457}, number = {1}, pages = {41-60}, doi = {10.1111/nyas.14212}, pmid = {31460675}, issn = {1749-6632}, support = {SB/YS/LS-196/2014//Department of Science and Technology (DST), Government of India/International ; //Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Government of India/International ; //National Institute of Pharmaceutical Education and Research/International ; //International Society for Neurochemistry/International ; }, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Autophagy ; Brain Ischemia/metabolism ; Calcium/metabolism ; Calcium Signaling ; Cell Line, Tumor ; Disease Progression ; Endoplasmic Reticulum/*physiology ; Endoplasmic Reticulum Stress ; GTP Phosphohydrolases/metabolism ; Homeostasis ; Humans ; Huntington Disease/metabolism ; Inflammation ; Lipids/chemistry ; Mice ; Mitochondria/*physiology ; Mitochondrial Dynamics ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Membranes/metabolism ; Nervous System Diseases/*physiopathology ; Parkinson Disease/metabolism ; Presenilins/metabolism ; Rats ; Vesicular Transport Proteins/metabolism ; }, abstract = {The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER-mitochondrial interconnections form specific microdomains, called mitochondria-associated ER membranes, that have been found to play important roles in calcium signaling and lipid homeostasis, and more recently in mitochondrial dynamics, inflammation, and autophagy. It is not surprising that perturbations in ER-mitochondria connections can result in the progression of disease, especially neurological disorders; hence, their architecture and regulation are crucial in determining the fate of cells and disease. The molecular identity of the specialized proteins regulating ER-mitochondrial crosstalk remains unclear. Our discussion here describes the physical and functional crosstalk between these two dynamic organelles and emphasizes the outcome of altered ER-mitochondrial interconnections in neurological disorders.}, }
@article {pmid31456666, year = {2019}, author = {Pradhan, J and Noakes, PG and Bellingham, MC}, title = {The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {13}, number = {}, pages = {368}, pmid = {31456666}, issn = {1662-5102}, abstract = {Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A2 a Rs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A2 a Rs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A2 a Rs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A2 a Rs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A2 a Rs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.}, }
@article {pmid31456211, year = {2019}, author = {Xiong, H and Tuo, QZ and Guo, YJ and Lei, P}, title = {Diagnostics and Treatments of Iron-Related CNS Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1173}, number = {}, pages = {179-194}, doi = {10.1007/978-981-13-9589-5_10}, pmid = {31456211}, issn = {0065-2598}, mesh = {Homeostasis ; Humans ; Iron ; Iron Metabolism Disorders/*diagnosis/*therapy ; Neurodegenerative Diseases/*diagnosis/*therapy ; }, abstract = {Iron has been proposed to be responsible for neuronal loss in several diseases of the central nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Friedreich's ataxia (FRDA), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). In many diseases, abnormal accumulation of brain iron in disease-affected area has been observed, without clear knowledge of the contribution of iron overload to pathogenesis. Recent evidences implicate that key proteins involved in the disease pathogenesis may also participate in cellular iron metabolism, suggesting that the imbalance of brain iron homeostasis is associated with the diseases. Considering the complicated regulation of iron homeostasis within the brain, a thorough understanding of the molecular events leading to this phenotype is still to be investigated. However, current understanding has already provided the basis for the diagnosis and treatment of iron-related CNS diseases, which will be reviewed here.}, }
@article {pmid31456209, year = {2019}, author = {Bu, XL and Xiang, Y and Guo, Y}, title = {The Role of Iron in Amyotrophic Lateral Sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {1173}, number = {}, pages = {145-152}, doi = {10.1007/978-981-13-9589-5_8}, pmid = {31456209}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Brain/*metabolism ; Homeostasis ; Humans ; Iron/*metabolism ; Motor Neurons/pathology ; Nerve Degeneration ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. The etiology and pathogenesis of this devastating disease remain largely unknown. Increasing evidence suggests that iron accumulation is involved in the onset and progression of ALS. In this review, we discuss the regulation of iron homoeostasis in the brain, the misregulation of iron homeostasis in ALS, and its possible roles in the mechanism of the disease. Finally, we summarize the recent progress and problems with respect to iron chelator therapies on ALS, aiming to propose a new therapeutic strategy to ameliorate the progression of the disease.}, }
@article {pmid31450955, year = {2019}, author = {Rey, F and Balsari, A and Giallongo, T and Ottolenghi, S and Di Giulio, AM and Samaja, M and Carelli, S}, title = {Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases.}, journal = {ASN neuro}, volume = {11}, number = {}, pages = {1759091419871420}, pmid = {31450955}, issn = {1759-0914}, mesh = {Animals ; Erythropoietin/*pharmacology ; Humans ; *Neurodegenerative Diseases ; Neuroprotection/*physiology ; Neuroprotective Agents/*pharmacology ; }, abstract = {Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlighting its secondary functions, with a crucial focus on its role in the central nervous system. Here, EPO may interact with up to four distinct isoforms of its receptor (erythropoietin receptor [EPOR]), activating different signaling cascades with roles in neuroprotection and neurogenesis. Indeed, the EPO/EPOR axis has been widely studied in the neurodegenerative diseases field. Its potential therapeutic effects have been evaluated in multiple disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, as well as brain ischemia, hypoxia, and hyperoxia. EPO is showing great promise by counteracting secondary neuroinflammatory processes, reactive oxygen species imbalance, and cell death in these diseases. Multiple studies have been performed both in vitro and in vivo, characterizing the mechanisms through which EPO exerts its neurotrophic action. In some cases, clinical trials involving EPO have been performed, highlighting its therapeutic potential. Together, all these works indicate the potential beneficial effects of EPO.}, }
@article {pmid31450774, year = {2019}, author = {Oliver, D and Reddy, PH}, title = {Dynamics of Dynamin-Related Protein 1 in Alzheimer's Disease and Other Neurodegenerative Diseases.}, journal = {Cells}, volume = {8}, number = {9}, pages = {}, pmid = {31450774}, issn = {2073-4409}, mesh = {Animals ; Dynamins/*metabolism ; Humans ; Mice ; Mitochondria/metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer's disease (AD) and other neurological diseases, including Parkinson's, Huntington's, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases.}, }
@article {pmid31450699, year = {2019}, author = {Gagliardi, D and Meneri, M and Saccomanno, D and Bresolin, N and Comi, GP and Corti, S}, title = {Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature.}, journal = {International journal of molecular sciences}, volume = {20}, number = {17}, pages = {}, pmid = {31450699}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism ; Biomarkers/*blood/*cerebrospinal fluid ; Humans ; Intermediate Filaments/*metabolism ; Neurofilament Proteins/blood/cerebrospinal fluid ; Phosphorylation ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity.}, }
@article {pmid31445085, year = {2019}, author = {Gao, J and Wang, L and Yan, T and Perry, G and Wang, X}, title = {TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration.}, journal = {Molecular and cellular neurosciences}, volume = {100}, number = {}, pages = {103396}, pmid = {31445085}, issn = {1095-9327}, support = {R01 AG056320/AG/NIA NIH HHS/United States ; R01 NS089604/NS/NINDS NIH HHS/United States ; RF1 AG056320/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Mitochondria/*metabolism/pathology ; Mitochondrial Turnover ; Neurons/metabolism/pathology ; TDP-43 Proteinopathies/genetics/*metabolism/pathology ; }, abstract = {Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer's disease (AD). Although the pathomechanisms underlying TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.}, }
@article {pmid31443476, year = {2019}, author = {Winter, AN and Bickford, PC}, title = {Anthocyanins and Their Metabolites as Therapeutic Agents for Neurodegenerative Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {9}, pages = {}, pmid = {31443476}, issn = {2076-3921}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), are characterized by the death of neurons within specific regions of the brain or spinal cord. While the etiology of many neurodegenerative diseases remains elusive, several factors are thought to contribute to the neurodegenerative process, such as oxidative and nitrosative stress, excitotoxicity, endoplasmic reticulum stress, protein aggregation, and neuroinflammation. These processes culminate in the death of vulnerable neuronal populations, which manifests symptomatically as cognitive and/or motor impairments. Until recently, most treatments for these disorders have targeted single aspects of disease pathology; however, this strategy has proved largely ineffective, and focus has now turned towards therapeutics which target multiple aspects underlying neurodegeneration. Anthocyanins are unique flavonoid compounds that have been shown to modulate several of the factors contributing to neuronal death, and interest in their use as therapeutics for neurodegeneration has grown in recent years. Additionally, due to observations that the bioavailability of anthocyanins is low relative to that of their metabolites, it has been proposed that anthocyanin metabolites may play a significant part in mediating the beneficial effects of an anthocyanin-rich diet. Thus, in this review, we will explore the evidence evaluating the neuroprotective and therapeutic potential of anthocyanins and their common metabolites for treating neurodegenerative diseases.}, }
@article {pmid31441732, year = {2020}, author = {Kolagar, TA and Farzaneh, M and Nikkar, N and Khoshnam, SE}, title = {Human Pluripotent Stem Cells in Neurodegenerative Diseases: Potentials, Advances and Limitations.}, journal = {Current stem cell research &amp; therapy}, volume = {15}, number = {2}, pages = {102-110}, doi = {10.2174/1574888X14666190823142911}, pmid = {31441732}, issn = {2212-3946}, mesh = {Animals ; Humans ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/pathology/*therapy ; Pluripotent Stem Cells/*cytology/*physiology/transplantation ; *Stem Cell Transplantation/methods/trends ; Tissue Engineering/methods/trends ; }, abstract = {Neurodegenerative diseases are progressive and uncontrolled gradual loss of motor neurons function or death of neuron cells in the central nervous system (CNS) and the mechanisms underlying their progressive nature remain elusive. There is urgent need to investigate therapeutic strategies and novel treatments for neural regeneration in disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Currently, the development and identification of pluripotent stem cells enabling the acquisition of a large number of neural cells in order to improve cell recovery after neurodegenerative disorders. Pluripotent stem cells which consist of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their ability to indefinitely self-renew and the capacity to differentiate into different types of cells. The first human ESC lines were established from donated human embryos; while, because of a limited supply of donor embryos, human ESCs derivation remains ethically and politically controversial. Hence, hiPSCs-based therapies have been shown as an effective replacement for human ESCs without embryo destruction. Compared to the invasive methods for derivation of human ESCs, human iPSCs has opened possible to reprogram patient-specific cells by defined factors and with minimally invasive procedures. Human pluripotent stem cells are a good source for cell-based research, cell replacement therapies and disease modeling. To date, hundreds of human ESC and human iPSC lines have been generated with the aim of treating various neurodegenerative diseases. In this review, we have highlighted the recent potentials, advances, and limitations of human pluripotent stem cells for the treatment of neurodegenerative disorders.}, }
@article {pmid31430861, year = {2019}, author = {Wehbe, R and Frangieh, J and Rima, M and El Obeid, D and Sabatier, JM and Fajloun, Z}, title = {Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {16}, pages = {}, pmid = {31430861}, issn = {1420-3049}, mesh = {Animals ; Bee Venoms/*chemistry/*pharmacology ; Bees/*chemistry ; Central Nervous System Diseases/drug therapy ; Humans ; Inflammation/drug therapy ; }, abstract = {Apitherapy is an alternate therapy that relies on the usage of honeybee products, most importantly bee venom for the treatment of many human diseases. The venom can be introduced into the human body by manual injection or by direct bee stings. Bee venom contains several active molecules such as peptides and enzymes that have advantageous potential in treating inflammation and central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Moreover, bee venom has shown promising benefits against different types of cancer as well as anti-viral activity, even against the challenging human immunodeficiency virus (HIV). Many studies described biological activities of bee venom components and launched preclinical trials to improve the potential use of apitoxin and its constituents as the next generation of drugs. The aim of this review is to summarize the main compounds of bee venom, their primary biological properties, mechanisms of action, and their therapeutic values in alternative therapy strategies.}, }
@article {pmid31429341, year = {2019}, author = {Vinaiphat, A and Sze, SK}, title = {Clinical implications of extracellular vesicles in neurodegenerative diseases.}, journal = {Expert review of molecular diagnostics}, volume = {19}, number = {9}, pages = {813-824}, doi = {10.1080/14737159.2019.1657407}, pmid = {31429341}, issn = {1744-8352}, mesh = {Biomarkers/metabolism ; Exosomes/*metabolism ; Extracellular Vesicles/*metabolism ; Humans ; Neurodegenerative Diseases/diagnosis/*pathology ; Neurons/physiology ; Neuroprotection/*physiology ; Prions/physiology ; Proteostasis Deficiencies/pathology ; }, abstract = {Introduction: Extracellular vesicles (EVs) released by neural cells play a crucial role in intracellular communication in both physiological and pathological states. Recent studies have shown that the neuropathogenic manifestation of many progressive nervous system diseases including Parkinson's disease (PD), Alzheimer's diseases (AD), and amyotrophic lateral sclerosis (ALS). These diseases are frequently found to be associated with the accumulation of misfolded proteins, exploit EVs for the spread of aggregates to naive cells in a prion-like mechanism. Therefore, characterization of EVs and understanding their mechanism of action could open a window of opportunity to discover biomarkers and therapeutic targets in a disease-specific manner. Areas covered: In this review, we discuss the role of neural cells-derived EVs in normal and disease states. We also highlight their biomedical potential in modern medicine, including the use of circulating EVs as biomarkers for diagnosis with a special focus on newly-identified potential biomarkers in neurodegenerative disease, and novel methodologies in EVs isolation. Expert opinion: Systematic and comprehensive analysis of EVs in different biofluid sources is needed. Considering the potential for tremendous clinical benefits of EVs research in neurodegenerative disease, there is also an urgent need to standardize neural cells-derived EV enrichment protocols for consensus results.}, }
@article {pmid31428042, year = {2019}, author = {Gouel, F and Rolland, AS and Devedjian, JC and Burnouf, T and Devos, D}, title = {Past and Future of Neurotrophic Growth Factors Therapies in ALS: From Single Neurotrophic Growth Factor to Stem Cells and Human Platelet Lysates.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {835}, pmid = {31428042}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that typically results in death within 3-5 years after diagnosis. To date, there is no curative treatment and therefore an urgent unmet need of neuroprotective and/or neurorestorative treatments. Due to their spectrum of capacities in the central nervous system-e.g., development, plasticity, maintenance, neurogenesis-neurotrophic growth factors (NTF) have been exploited for therapeutic strategies in ALS for decades. In this review we present the initial strategy of using single NTF by different routes of administration to the use of stem cells transplantation to express a multiple NTFs-rich secretome to finally focus on a new biotherapy based on the human platelet lysates, the natural healing system containing a mix of pleitropic NTF and having immunomodulatory function. This review highlights that this latter treatment may be crucial to power the neuroprotection and/or neurorestoration therapy requested in this devastating disease.}, }
@article {pmid31427919, year = {2019}, author = {Cristofani, R and Rusmini, P and Galbiati, M and Cicardi, ME and Ferrari, V and Tedesco, B and Casarotto, E and Chierichetti, M and Messi, E and Piccolella, M and Carra, S and Crippa, V and Poletti, A}, title = {The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {796}, pmid = {31427919}, issn = {1662-4548}, abstract = {Misfolding protein diseases are a wide class of disorders in which the aberrantly folded protein aggregates accumulate in affected cells. In the brain and in the skeletal muscle, misfolded protein accumulation induces a variety of cell dysfunctions that frequently lead to cell death. In motoneuron diseases (MNDs), misfolded proteins accumulate primarily in motoneurons, glial cells and/or skeletal muscle cells, altering motor function. The deleterious effects of misfolded proteins can be counteracted by the activity of the protein quality control (PQC) system, composed of chaperone proteins and degradative systems. Here, we focus on a PQC system component: heat shock protein family B (small) member 8 (HSPB8), a chaperone induced by harmful stressful events, including proteotoxicity. In motoneuron and muscle cells, misfolded proteins activate HSPB8 transcription and enhance HSPB8 levels, which contributes to prevent aggregate formation and their harmful effects. HSPB8 acts not only as a chaperone, but also facilitates the autophagy process, to enable the efficient clearance of the misfolded proteins. HSPB8 acts as a dimer bound to the HSP70 co-chaperone BAG3, a scaffold protein that is also capable of binding to HSP70 (associated with the E3-ligase CHIP) and dynein. When this complex is formed, it is transported by dynein to the microtubule organization center (MTOC), where aggresomes are formed. Here, misfolded proteins are engulfed into nascent autophagosomes to be degraded via the chaperone-assisted selective autophagy (CASA). When CASA is insufficient or impaired, HSP70 and CHIP associate with an alternative co-chaperone, BAG1, which routes misfolded proteins to the proteasome for degradation. The finely tuned equilibrium between proteasome and CASA activity is thought to be crucial for maintaining the functional cell homeostasis during proteotoxic stresses, which in turn is essential for cell survival. This fine equilibrium seems to be altered in MNDs, like Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), contributing to the onset and the progression of disease. Here, we will review how misfolded proteins may affect the PQC system and how the proper activity of this system can be restored by boosting or regulating HSPB8 activity, with the aim to ameliorate disease progression in these two fatal MNDs.}, }
@article {pmid31427374, year = {2020}, author = {Newton, K}, title = {Multitasking Kinase RIPK1 Regulates Cell Death and Inflammation.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {12}, number = {3}, pages = {}, pmid = {31427374}, issn = {1943-0264}, mesh = {Animals ; Apoptosis ; Caspase 8/metabolism ; *Cell Death ; Cell Survival ; Clinical Trials as Topic ; *Gene Expression Regulation ; *Gene Expression Regulation, Enzymologic ; Humans ; Inflammation/*enzymology ; Intestines ; Mice ; Neoplasms/*metabolism ; Phosphorylation ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; Signal Transduction ; Toll-Like Receptor 3/metabolism ; Toll-Like Receptor 4/metabolism ; }, abstract = {Receptor-interacting serine threonine kinase 1 (RIPK1) is a widely expressed kinase that is essential for limiting inflammation in both mice and humans. Mice lacking RIPK1 die at birth from multiorgan inflammation and aberrant cell death, whereas humans lacking RIPK1 are immunodeficient and develop very early-onset inflammatory bowel disease. In contrast to complete loss of RIPK1, inhibiting the kinase activity of RIPK1 genetically or pharmacologically prevents cell death and inflammation in several mouse disease models. Indeed, small molecule inhibitors of RIPK1 are in phase I clinical trials for amyotrophic lateral sclerosis, and phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. This review focuses on which signaling pathways use RIPK1, how activation of RIPK1 is regulated, and when activation of RIPK1 appears to be an important driver of inflammation.}, }
@article {pmid31426366, year = {2019}, author = {Lepore, E and Casola, I and Dobrowolny, G and Musarò, A}, title = {Neuromuscular Junction as an Entity of Nerve-Muscle Communication.}, journal = {Cells}, volume = {8}, number = {8}, pages = {}, pmid = {31426366}, issn = {2073-4409}, mesh = {Aging/*pathology ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Neuromuscular Junction/*pathology ; Protein Kinase C/*metabolism ; *Schwann Cells/metabolism/pathology ; Superoxide Dismutase-1/*metabolism ; }, abstract = {One of the crucial systems severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, leading to a pathological non-communication between the two tissues. The neuromuscular junction (NMJ) represents the critical region at the level of which muscle and nerve communicate. Defects in signal transmission between terminal nerve endings and muscle membrane is a common feature of several physio-pathologic conditions including aging and Amyotrophic Lateral Sclerosis (ALS). Nevertheless, controversy exists on whether pathological events beginning at the NMJ precede or follow loss of motor units. In this review, the role of NMJ in the physio-pathologic interplay between muscle and nerve is discussed.}, }
@article {pmid31417253, year = {2019}, author = {Yavarpour-Bali, H and Ghasemi-Kasman, M and Pirzadeh, M}, title = {Curcumin-loaded nanoparticles: a novel therapeutic strategy in treatment of central nervous system disorders.}, journal = {International journal of nanomedicine}, volume = {14}, number = {}, pages = {4449-4460}, pmid = {31417253}, issn = {1178-2013}, mesh = {Central Nervous System Diseases/*drug therapy ; Clinical Trials as Topic ; Curcumin/administration &amp; dosage/pharmacology/*therapeutic use ; Drug Delivery Systems ; Humans ; Nanoparticles/*chemistry ; Neuroprotective Agents/therapeutic use ; }, abstract = {Curcumin as a hydrophobic polyphenol is extracted from the rhizome of Curcuma longa. Curcumin is widely used as a dietary spice and a topical medication for the treatment of inflammatory disorders in Asia. This compound also possesses remarkable anti-inflammatory and neuroprotective effects with the ability to pass from the blood brain barrier. Based on several pharmacological activities of curcumin, it has been introduced as an ideal candidate for different neurological disorders. Despite the pleiotropic activities of curcumin, poor solubility, rapid clearance and low stability have limited its clinical application. In recent years, nano-based drug delivery system has effectively improved the aqueous solubility and bioavailability of curcumin. In this review article, the effects of curcumin nanoparticles and their possible mechanism/s of action has been elucidated in various central nervous system (CNS)-related diseases including Parkinson's disease, Huntington disease, Alzheimer's disease, Multiple sclerosis, epilepsy and Amyotrophic Lateral Sclerosis. Furthermore, recent evidences about administration of nano-curcumin in the clinical trial phase have been described in the present review article.}, }
@article {pmid31413155, year = {2019}, author = {Volpatti, JR and Al-Maawali, A and Smith, L and Al-Hashim, A and Brill, JA and Dowling, JJ}, title = {The expanding spectrum of neurological disorders of phosphoinositide metabolism.}, journal = {Disease models &amp; mechanisms}, volume = {12}, number = {8}, pages = {}, pmid = {31413155}, issn = {1754-8411}, support = {R21 AR074006/AR/NIAMS NIH HHS/United States ; 324830//CIHR/Canada ; }, mesh = {Animals ; Humans ; Minor Histocompatibility Antigens/metabolism ; Models, Biological ; Motor Neurons/pathology ; Nervous System Diseases/genetics/*metabolism/pathology ; Phosphatidylinositols/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Signal Transduction ; }, abstract = {Phosphoinositides (PIPs) are a ubiquitous group of seven low-abundance phospholipids that play a crucial role in defining localized membrane properties and that regulate myriad cellular processes, including cytoskeletal remodeling, cell signaling cascades, ion channel activity and membrane traffic. PIP homeostasis is tightly regulated by numerous inositol kinases and phosphatases, which phosphorylate and dephosphorylate distinct PIP species. The importance of these phospholipids, and of the enzymes that regulate them, is increasingly being recognized, with the identification of human neurological disorders that are caused by mutations in PIP-modulating enzymes. Genetic disorders of PIP metabolism include forms of epilepsy, neurodegenerative disease, brain malformation syndromes, peripheral neuropathy and congenital myopathy. In this Review, we provide an overview of PIP function and regulation, delineate the disorders associated with mutations in genes that modulate or utilize PIPs, and discuss what is understood about gene function and disease pathogenesis as established through animal models of these diseases.}, }
@article {pmid31403480, year = {2019}, author = {Verde, F and Silani, V and Otto, M}, title = {Neurochemical biomarkers in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {32}, number = {5}, pages = {747-757}, doi = {10.1097/WCO.0000000000000744}, pmid = {31403480}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/metabolism ; Biomarkers/metabolism ; Diagnosis, Differential ; Humans ; Neurofilament Proteins/*metabolism ; Phosphorylation ; Prognosis ; }, abstract = {PURPOSE OF REVIEW: The diagnosis of amyotrophic lateral sclerosis (ALS) still relies mainly on clinical criteria. In present review we will provide an overview of neurochemical ALS biomarkers, which are in the most advanced position on the way towards inclusion into the clinical work-up.<br><br>RECENT FINDINGS: The field of ALS neurology still lacks a neurochemical marker for routine clinical use. However, this is urgently needed, because it would help in diagnosis, prognostic stratification, and monitoring of drug response. Despite this lack of a routinely used biomarker, in the last decade significant progress has been made in the field. In particular, two molecules have been extensively studied - the light chain and the phosphorylated form of the heavy chain of neurofilaments, NFL and pNFH, respectively - which have demonstrated a high diagnostic performance and promising prognostic value and are therefore ready to be introduced into the clinical scenario. On the other hand, we still lack a neurochemical cerebrospinal fluid or blood biomarker reflecting TDP-43 pathology.<br><br>SUMMARY: Neurofilaments seem to be ready for clinical use in the early and differential diagnosis of ALS. We also highlight still unresolved issues which deserve further investigation.}, }
@article {pmid31398791, year = {2019}, author = {Mouzat, K and Chudinova, A and Polge, A and Kantar, J and Camu, W and Raoul, C and Lumbroso, S}, title = {Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?.}, journal = {International journal of molecular sciences}, volume = {20}, number = {16}, pages = {}, pmid = {31398791}, issn = {1422-0067}, mesh = {Animals ; Brain/*metabolism ; Cholesterol/*metabolism ; Disease Susceptibility ; Homeostasis ; Humans ; Ligands ; *Lipid Metabolism ; Liver X Receptors/chemistry/metabolism ; Neurodegenerative Diseases/etiology/metabolism/pathology ; Oxysterols/metabolism ; Structure-Activity Relationship ; }, abstract = {Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.}, }
@article {pmid31394733, year = {2019}, author = {Genc, B and Gozutok, O and Ozdinler, PH}, title = {Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons.}, journal = {International journal of molecular sciences}, volume = {20}, number = {16}, pages = {}, pmid = {31394733}, issn = {1422-0067}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; NIHR21NS093557/NH/NIH HHS/United States ; 1/CX/CSRD VA/United States ; }, mesh = {Animals ; Disease Models, Animal ; Disease Susceptibility ; Genetic Linkage ; Genetic Predisposition to Disease ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/etiology/metabolism/physiopathology ; Motor Neurons/cytology/*physiology/ultrastructure ; *Neural Conduction ; *Neuronal Plasticity ; }, abstract = {Motor neuron circuitry is one of the most elaborate circuitries in our body, which ensures voluntary and skilled movement that requires cognitive input. Therefore, both the cortex and the spinal cord are involved. The cortex has special importance for motor neuron diseases, in which initiation and modulation of voluntary movement is affected. Amyotrophic lateral sclerosis (ALS) is defined by the progressive degeneration of both the upper and lower motor neurons, whereas hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are characterized mainly by the loss of upper motor neurons. In an effort to reveal the cellular and molecular basis of neuronal degeneration, numerous model systems are generated, and mouse models are no exception. However, there are many different levels of complexities that need to be considered when developing mouse models. Here, we focus our attention to the upper motor neurons, which are one of the most challenging neuron populations to study. Since mice and human differ greatly at a species level, but the cells/neurons in mice and human share many common aspects of cell biology, we offer a solution by focusing our attention to the affected neurons to reveal the complexities of diseases at a cellular level and to improve translational efforts.}, }
@article {pmid31392677, year = {2019}, author = {Tejera, D and Heneka, MT}, title = {Microglia in Neurodegenerative Disorders.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2034}, number = {}, pages = {57-67}, doi = {10.1007/978-1-4939-9658-2_5}, pmid = {31392677}, issn = {1940-6029}, mesh = {Animals ; *Brain/immunology/pathology ; Cell Death/immunology ; Humans ; *Microglia/immunology/pathology ; *Neurodegenerative Diseases/immunology/pathology ; }, abstract = {Microglia are the brain's resident immune cells. Under physiological conditions, they participate in a myriad of processes mainly involved in housekeeping functions that promote tissue homeostasis. However, the triggering of an immune response is a common feature in neurodegenerative disorders. This shift in microglia cells toward a chronically activated phenotype contributing to neuronal dysfunction and cell death is of great interest nowadays. In this chapter, we review the implications of microglia activation in different neurodegenerative disorders.}, }
@article {pmid31387243, year = {2019}, author = {Jones, CL and Tepe, JJ}, title = {Proteasome Activation to Combat Proteotoxicity.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {15}, pages = {}, pmid = {31387243}, issn = {1420-3049}, mesh = {Animals ; Humans ; Intrinsically Disordered Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Proteasome Endopeptidase Complex/*metabolism ; Protein Aggregates ; Protein Aggregation, Pathological ; Proteostasis ; Structure-Activity Relationship ; }, abstract = {Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called "intrinsically disordered proteins" (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.}, }
@article {pmid31385134, year = {2020}, author = {Perrone, B and La Cognata, V and Sprovieri, T and Ungaro, C and Conforti, FL and Andò, S and Cavallaro, S}, title = {Alternative Splicing of ALS Genes: Misregulation and Potential Therapies.}, journal = {Cellular and molecular neurobiology}, volume = {40}, number = {1}, pages = {1-14}, pmid = {31385134}, issn = {1573-6830}, support = {DSB.AD009.001//Progetto Invecchiamento/ ; CIP 2014.IT.05.SFOP.014/3/10.4/9.2.10/0008//European Social Fund (Rafforzare l'Occupabilit&#xe0; nel sistema R&amp;S e la nascita di spin off di ricerca in Sicilia)/ ; CUP G67B17000170009//European Social Fund (Rafforzare l'Occupabilit&#xe0; nel sistema R&amp;S e la nascita di spin off di ricerca in Sicilia)/ ; DSB.AD008.456//Ministero dello Sviluppo Economico/ ; }, mesh = {Alternative Splicing/*genetics ; Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; Genome-Wide Association Study ; Humans ; Nerve Tissue Proteins/*genetics/metabolism ; }, abstract = {Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Parkinson's, Alzheimer's, and Huntington's disease affect a rapidly increasing population worldwide. Although common pathogenic mechanisms have been identified (e.g., protein aggregation or dysfunction, immune response alteration and axonal degeneration), the molecular events underlying timing, dosage, expression, and location of RNA molecules are still not fully elucidated. In particular, the alternative splicing (AS) mechanism is a crucial player in RNA processing and represents a fundamental determinant for brain development, as well as for the physiological functions of neuronal circuits. Although in recent years our knowledge of AS events has increased substantially, deciphering the molecular interconnections between splicing and ALS remains a complex task and still requires considerable efforts. In the present review, we will summarize the current scientific evidence outlining the involvement of AS in the pathogenic processes of ALS. We will also focus on recent insights concerning the tuning of splicing mechanisms by epigenomic and epi-transcriptomic regulation, providing an overview of the available genomic technologies to investigate AS drivers on a genome-wide scale, even at a single-cell level resolution. In the future, gene therapy strategies and RNA-based technologies may be utilized to intercept or modulate the splicing mechanism and produce beneficial effects against ALS.}, }
@article {pmid31381978, year = {2019}, author = {Halpern, M and Brennand, KJ and Gregory, J}, title = {Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs.}, journal = {Neurobiology of disease}, volume = {132}, number = {}, pages = {104562}, pmid = {31381978}, issn = {1095-953X}, support = {R56 MH101454/MH/NIMH NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Astrocytes/pathology/*physiology ; Coculture Techniques ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and fatal neurodegenerative disease for which the causes of disease onset and progression remain unclear. Recent advances in human induced pluripotent stem cell (hiPSC)-based models permit the study of the genetic factors associated with ALS in patient-derived neural cell types, including motor neurons and glia. While astrocyte dysfunction has traditionally been thought to exacerbate disease progression, astrocytic dysfunction may play a more direct role in disease initiation and progression. Such non-cell autonomous mechanisms expand the potential targets of therapeutic intervention, but only a handful of ALS risk-associated genes have been examined for their impact on astrocyte dysfunction and neurodegeneration. This review summarizes what is currently known about astrocyte function in ALS and suggests ways in which hiPSC-based models can be used to more effectively study the role of astrocytes in neurodegenerative disease.}, }
@article {pmid31380411, year = {2019}, author = {Kakaroubas, N and Brennan, S and Keon, M and Saksena, NK}, title = {Pathomechanisms of Blood-Brain Barrier Disruption in ALS.}, journal = {Neuroscience journal}, volume = {2019}, number = {}, pages = {2537698}, pmid = {31380411}, issn = {2314-4262}, abstract = {The blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are responsible for controlling the microenvironment within neural tissues in humans. These barriers are fundamental to all neurological processes as they provide the extreme nutritional demands of neural tissue, remove wastes, and maintain immune privileged status. Being a semipermeable membrane, both the BBB and BSCB allow the diffusion of certain molecules, whilst restricting others. In amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, these barriers become hyperpermeable, allowing a wider variety of molecules to pass through leading to more severe and more rapidly progressing disease. The intention of this review is to discuss evidence that BBB hyperpermeability is potentially a disease driving feature in ALS and other neurodegenerative diseases. The various biochemical, physiological, and genomic factors that can influence BBB permeability in ALS and other neurodegenerative diseases are also discussed, in addition to novel therapeutic strategies centred upon the BBB.}, }
@article {pmid31379732, year = {2019}, author = {Tsitkanou, S and Della Gatta, P and Foletta, V and Russell, A}, title = {The Role of Exercise as a Non-pharmacological Therapeutic Approach for Amyotrophic Lateral Sclerosis: Beneficial or Detrimental?.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {783}, pmid = {31379732}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, involves the rapid deterioration of motor neurons resulting in severe muscle atrophy and respiratory insufficiency. It is considered a "multisystemic" disease with many potential mechanisms responsible for its pathology. Currently, there is no cure for ALS. Exercise training is suggested as a potential approach to reduce ALS pathology, but its beneficial role remains controversial. This review provides an overview of the effects of exercise training in ALS-affected mice and patients. It will compare the intensity, duration, and type of exercise on the health of SOD1[G93A] mice, a mouse model of familial ALS, and review clinical studies involving ALS patients undergoing both endurance and resistance training. In summary, mild-to-moderate swimming-based endurance training appears the most advantageous mode of exercise in SOD1[G93A] mice, improving animal survival, and delaying the onset and progression of disease. Furthermore, clinical studies show that both endurance and resistance training have an advantageous impact on the quality of life of ALS patients without extending life expectancy. However, small sample sizes, non-representative control populations, heterogeneous disease stage of patients, and the presence of confounders often exist in the exercise studies conducted with ALS patients. This raises concerns about the interpretation of these findings and, therefore, these results should be considered with caution. While promising, more pre-clinical and clinical studies with improved experimental design and fewer limitations are still necessary to confirm the impact of exercise training on the health of ALS patients.}, }
@article {pmid31377995, year = {2019}, author = {Dunlop, RA and Guillemin, GJ}, title = {The Cyanotoxin and Non-protein Amino Acid β-Methylamino-L-Alanine (L-BMAA) in the Food Chain: Incorporation into Proteins and Its Impact on Human Health.}, journal = {Neurotoxicity research}, volume = {36}, number = {3}, pages = {602-611}, pmid = {31377995}, issn = {1476-3524}, mesh = {Amino Acids, Diamino/*toxicity ; Cyanobacteria ; Cyanobacteria Toxins ; Food Chain ; *Food Contamination ; Foodborne Diseases/epidemiology/*etiology ; Harmful Algal Bloom ; Humans ; Neurotoxins/*toxicity ; }, abstract = {The size and frequency of cyanobacterial blooms are increasing concomitantly with rising global temperatures and increased eutrophication, and this has implications for human health. Cyanotoxins, including L-BMAA, have been implicated in triggering neurodegenerative diseases such as ALS/PDC and Alzheimer's disease. L-BMAA is a water-soluble non-protein amino acid that can bioaccumulate up the food chain, in a free- and protein-bound form. While some data exists on the degree of environmental enrichment of L-BMAA in water bodies, cyanobacteria-derived supplements, fruit bats, and seafood, virtually nothing is known about the presence of L-BMAA in other foodstuffs. It has now been shown several times in laboratory settings that plants can absorb L-BMAA into their leaves and stems, but data from wild-grown plants is nascent. One of the mechanisms implicated in L-BMAA bioaccumulation is misincorporation into proteins in the place of the canonical amino acid L-serine. We first identified this as a mechanism of action of L-BMAA in 2013, and since then, several groups have replicated these findings, but others have not. Here, we discuss in detail the experimental approaches, why they may have produced negative findings and propose several ways forward for developing consistency within the field. We emphasize the need to standardize cell culture methods, using L-serine-free medium to study misincorporation of BMAA, and urge accurate reporting of the components present in cell culture media.}, }
@article {pmid31375365, year = {2020}, author = {Lou, G and Palikaras, K and Lautrup, S and Scheibye-Knudsen, M and Tavernarakis, N and Fang, EF}, title = {Mitophagy and Neuroprotection.}, journal = {Trends in molecular medicine}, volume = {26}, number = {1}, pages = {8-20}, doi = {10.1016/j.molmed.2019.07.002}, pmid = {31375365}, issn = {1471-499X}, mesh = {Aging/physiology ; Animals ; Homeostasis/physiology ; Humans ; Mitochondria/physiology ; Mitophagy/*physiology ; Neurodegenerative Diseases/*physiopathology ; Neurons/physiology ; Neuroprotection/*physiology ; }, abstract = {Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new aetiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival, and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.}, }
@article {pmid31372185, year = {2019}, author = {Tam, OH and Ostrow, LW and Gale Hammell, M}, title = {Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease.}, journal = {Mobile DNA}, volume = {10}, number = {}, pages = {32}, pmid = {31372185}, issn = {1759-8753}, abstract = {Transposable Elements (TEs) are mobile genetic elements whose sequences constitute nearly half of the human genome. Each TE copy can be present in hundreds to thousands of locations within the genome, complicating the genetic and genomic studies of these highly repetitive sequences. The recent development of better tools for evaluating TE derived sequences in genomic studies has enabled an increasing appreciation for the contribution of TEs to human development and disease. While some TEs have contributed novel and beneficial host functions, this review will summarize the evidence for detrimental TE activity in neurodegenerative disorders. Much of the evidence for pathogenicity implicates endogenous retroviruses (ERVs), a subset of TEs that entered the genome by retroviral infections of germline cells in our evolutionary ancestors and have since been passed down as a substantial fraction of the human genome. Human specific ERVs (HERVs) represent some of the youngest ERVs in the genome, and thus are presumed to retain greater function and resultant pathogenic potential.}, }
@article {pmid31362659, year = {2019}, author = {Zhu, LS and Wang, DQ and Cui, K and Liu, D and Zhu, LQ}, title = {Emerging Perspectives on DNA Double-strand Breaks in Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {17}, number = {12}, pages = {1146-1157}, pmid = {31362659}, issn = {1875-6190}, mesh = {Animals ; *DNA Breaks, Double-Stranded ; Humans ; Neurodegenerative Diseases/*genetics/metabolism ; }, abstract = {DNA double-strand breaks (DSBs) are common events that were recognized as one of the most toxic lesions in eukaryotic cells. DSBs are widely involved in many physiological processes such as V(D)J recombination, meiotic recombination, DNA replication and transcription. Deregulation of DSBs has been reported in multiple diseases in human beings, such as the neurodegenerative diseases, with which the underlying mechanisms are needed to be illustrated. Here, we reviewed the recent insights into the dysfunction of DSB formation and repair, contributing to the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and ataxia telangiectasia (A-T).}, }
@article {pmid31362360, year = {2019}, author = {Dolei, A and Ibba, G and Piu, C and Serra, C}, title = {Expression of HERV Genes as Possible Biomarker and Target in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {15}, pages = {}, pmid = {31362360}, issn = {1422-0067}, mesh = {*Biomarkers ; Endogenous Retroviruses/*genetics ; *Gene Expression ; Gene Expression Regulation ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/diagnosis/drug therapy/*etiology/metabolism ; Prognosis ; }, abstract = {Human endogenous retroviruses (HERVs) are genetic parasites, in-between genetics and environment. Few HERVs retain some coding capability. Sometimes, the host has the advantage of some HERV genes; conversely, HERVs may contribute to pathogenesis. The expression of HERVs depends on several factors, and is regulated epigenetically by stimuli such as inflammation, viral and microbial infections, etc. Increased expression of HERVs occurs in physiological and pathological conditions, in one or more body sites. Several diseases have been attributed to one or more HERVs, particularly neurological diseases. The key problem is to differentiate the expression of a HERV as cause or effect of a disease. To be used as a biomarker, a correlation between the expression of a certain HERV and the disease onset and/or behavior must be found. The greater challenge is to establish a pathogenic role. The criteria defining causal connections between HERVs and diseases include the development of animal models, and disease modulation in humans, by anti-HERV therapeutic antibody. So far, statistically significant correlations between HERVs and diseases have been achieved for HERV-W and multiple sclerosis; disease reproduction in transgenic animals was achieved for HERV-W and multiple sclerosis, and for HERV-K and amyotrophic lateral sclerosis. Clinical trials for both diseases are in progress.}, }
@article {pmid31361627, year = {2019}, author = {Longinetti, E and Fang, F}, title = {Epidemiology of amyotrophic lateral sclerosis: an update of recent literature.}, journal = {Current opinion in neurology}, volume = {32}, number = {5}, pages = {771-776}, pmid = {31361627}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Europe ; Humans ; Incidence ; Prevalence ; Risk Factors ; }, abstract = {PURPOSE OF REVIEW: The cause of amyotrophic lateral sclerosis (ALS) remains unknown for most of the patients with the disease. Epidemiologic studies can help describe disease burden and examine its potential risk factors, providing thereby evidence base for future mechanistic studies. With this review, we aimed to provide a summary of epidemiologic studies published during the past 18 months, which studied the incidence and risk factors for ALS.<br><br>RECENT FINDINGS: An increasing incidence and prevalence of ALS continue to be reported from different parts of the world. Several previously studied risk factors are confirmed as causally related to ALS by Mendelian randomization analysis. The previously known prognostic indicators for ALS appear to be the same across populations.<br><br>SUMMARY: Provided with the increasing number of patients diagnosed with ALS and the improved societal awareness of the disease, more resources should be allocated to the research and care of ALS. Population-based studies, especially population-based disease registers, should be the priorities in ALS research, and more data from outside Europe are needed in gaining a better global perspective of the disease.}, }
@article {pmid31354794, year = {2019}, author = {Gruchot, J and Kremer, D and Küry, P}, title = {Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses.}, journal = {Frontiers in genetics}, volume = {10}, number = {}, pages = {655}, pmid = {31354794}, issn = {1664-8021}, abstract = {Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.}, }
@article {pmid31354413, year = {2019}, author = {Rajagopalan, V and Pioro, EP}, title = {Unbiased MRI Analyses Identify Micropathologic Differences Between Upper Motor Neuron-Predominant ALS Phenotypes.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {704}, pmid = {31354413}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable and progressively fatal neurodegenerative disease that manifests with distinct clinical phenotypes, which are seen in neuroimaging, and clinical studies. T2- and proton density (PD)-weighted magnetic resonance imaging (MRI) displays hyperintense signal along the corticospinal tract (CST) in some ALS patients with upper motor neuron (UMN)-predominant signs. These patients tend to be younger and have significantly faster disease progression. We hypothesize that such ALS patients with CST hyperintensity (ALS-CST+) comprise a clinical subtype distinct from other ALS subtypes, namely patients with UMN-predominant ALS without CST hyperintensity, classic ALS, and ALS with frontotemporal dementia (FTD). Novel approaches such as fractal dimension analysis on conventional MRI (cMRI) and advanced MR techniques such as diffusion tensor imaging (DTI) reveal significant differences between ALS-CST+ and the aforementioned ALS subtypes. Our unbiased neuroimaging studies demonstrate that the ALS-CST+ group, which can be initially identified by T2-, PD-, and FLAIR-weighted cMRI, is distinctive and distinguishable from other ALS subtypes with possible differences in disease pathogenesis.}, }
@article {pmid31347256, year = {2019}, author = {Yudhistira, T and Mulay, SV and Kim, Y and Halle, MB and Churchill, DG}, title = {Imaging of Hypochlorous Acid by Fluorescence and Applications in Biological Systems.}, journal = {Chemistry, an Asian journal}, volume = {14}, number = {18}, pages = {3048-3084}, doi = {10.1002/asia.201900672}, pmid = {31347256}, issn = {1861-471X}, support = {2014R1A2A1A11052980//National Research Foundation/ ; }, mesh = {Cardiovascular Diseases/*diagnostic imaging ; Diabetes Mellitus/*diagnostic imaging ; Fluorescence ; Fluorescent Dyes/*chemistry ; Humans ; Hypochlorous Acid/*chemistry ; Microscopy, Confocal ; Neurodegenerative Diseases/*diagnostic imaging ; *Optical Imaging ; }, abstract = {In recent decades, HOCl research has attracted a lot of scientists from around the world. This chemical species is well known as an important player in the biological systems of eukaryotic organisms including humans. In the human body, HOCl is produced by the myeloperoxidase enzyme from superoxide in very low concentrations (20 to 400 μm); this species is secreted by neutrophils and monocytes to help fight pathogens. However, in the condition called "oxidative stress", HOCl has the capability to attack many important biomolecules such as amino acids, proteins, nucleotides, nucleic acids, carbohydrates, and lipids; these reactions could ultimately contribute to a number of diseases such as neurodegenerative diseases (AD, PD, and ALS), cardiovascular diseases, and diabetes. In this review, we discuss recent efforts by scientists to synthesize various fluorophores which are attached to receptors to detect HOCl such as: chalcogen-based oxidation, oxidation of 4-methoxyphenol, oxime/imine, lactone ring opening, and hydrazine. These synthetic molecules, involving rational synthetic pathways, allow us to chemoselectively target HOCl and to study the level of HOCl selectivity through emission responses. Virtually all the reports here deal with well-defined and small synthetic molecular systems. A large number of published compounds have been reported over the past years; this growing field has given scientists new insights regarding the design of the chemosensors. Reversibility, for example is considered important from the stand point of chemosensor reuse within the biological system; facile regenerability using secondary analytes to obtain the initial probe is a very promising avenue. Another aspect which is also important is the energy of the emission wavelength of the sensor; near-infrared (NIR) emission is favorable to prevent autofluorescence and harmful irradiation of tissue; thus, extended applicability of such sensors can be made to the mouse model or animal model to help image internal organs. In this review, we describe several well-known types of receptors that are covalently attached to the fluorophore to detect HOCl. We also discuss the common fluorophores which are used by chemist to detect HOCl, Apart from the chemical aspects, we also discuss the capabilities of the compounds to detect HOCl in living cells as measured through confocal imaging. The growing insight from HOCl probing suggests that there is still much room for improvement regarding the available molecular designs, knowledge of interplay between analytes, biological applicability, biological targeting, and chemical switching, which can also serve to further sensor and theurapeutic agent development alike.}, }
@article {pmid31344643, year = {2019}, author = {Banks, CJ and Andersen, JL}, title = {Mechanisms of SOD1 regulation by post-translational modifications.}, journal = {Redox biology}, volume = {26}, number = {}, pages = {101270}, pmid = {31344643}, issn = {2213-2317}, mesh = {Acylation ; Animals ; Humans ; Lysine/metabolism ; Oxidation-Reduction ; Phosphorylation ; Protein Binding ; *Protein Processing, Post-Translational ; Structure-Activity Relationship ; Superoxide Dismutase-1/chemistry/*metabolism ; Ubiquitination ; }, abstract = {SOD1 is commonly known for its ROS scavenging activity, but recent work has uncovered additional roles in modulating metabolism, maintaining redox balance, and regulating transcription. This new paradigm of expanded SOD1 function raises questions regarding the regulation of SOD1 and the cellular partitioning of its biological roles. Despite decades of research on SOD1, much of which focuses on its pathogenic role in amyotrophic lateral sclerosis, relatively little is known about its regulation by post-translational modifications (PTMs). However, over the last decade, advancements in mass spectrometry have led to a boom in PTM discovery across the proteome, which has also revealed new mechanisms of SOD1 regulation by PTMs and an array of SOD1 PTMs with high likelihood of biological function. In this review, we address emerging mechanisms of SOD1 regulation by post-translational modifications, many of which begin to shed light on how the various functions of SOD1 are regulated within the cell.}, }
@article {pmid31340904, year = {2022}, author = {Castillo-Álvarez, F and Marzo-Sola, ME}, title = {Role of the gut microbiota in the development of various neurological diseases.}, journal = {Neurologia}, volume = {37}, number = {6}, pages = {492-498}, doi = {10.1016/j.nrl.2019.03.017}, pmid = {31340904}, issn = {2173-5808}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Parkinson Disease/pathology ; *Alzheimer Disease ; *Neuromyelitis Optica ; *Amyotrophic Lateral Sclerosis ; *Multiple Sclerosis ; }, abstract = {INTRODUCTION: In recent years, the scientific evidence supporting a relationship between the microbiota and various diseases has increased significantly; this trend has also been observed for neurological diseases. This has given rise to the concept of the gut-brain axis and the idea of a relationship between the gut microbiota and several neurological diseases whose aetiopathogenesis is yet to be clearly defined.<br><br>DEVELOPMENT: We review the role of the gut microbiota in the gut-brain axis and analyse those neurological diseases in which alterations in the gut microbiota have been described as a result of human studies: specifically, Parkinson's disease, Alzheimer disease, amyotrophic lateral sclerosis, neuromyelitis optica, and multiple sclerosis.<br><br>CONCLUSIONS: The body of evidence linking the gut microbiota to various neurological diseases has grown considerably. Several interesting studies show a relationship between the gut microbiota and Parkinson's disease, Alzheimer disease, neuromyelitis optica, and multiple sclerosis, whereas other controversial studies implicate it in amyotrophic lateral sclerosis. Many of these studies place considerable emphasis on modulation of inflammation, particularly by bacteria capable of producing short-chain fatty acids. Despite these encouraging results, many questions remain, and there is a need to demonstrate causality, determine the role of fungi or viruses, and research possible treatment through diet, probiotics, or faecal microbiota transplantation.}, }
@article {pmid31339079, year = {2020}, author = {Liu, C and Li, J and Shi, W and Zhang, L and Liu, S and Lian, Y and Liang, S and Wang, H}, title = {Progranulin Regulates Inflammation and Tumor.}, journal = {Anti-inflammatory &amp; anti-allergy agents in medicinal chemistry}, volume = {19}, number = {2}, pages = {88-102}, pmid = {31339079}, issn = {1875-614X}, mesh = {Animals ; Carcinogenesis ; Cell Cycle ; Cell Movement ; Cell Proliferation ; Cell Transformation, Neoplastic ; Cytokines/metabolism ; Humans ; Inflammation/*metabolism ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; Progranulins/genetics/*metabolism ; }, abstract = {Progranulin (PGRN) mediates cell cycle progression and cell motility as a pleiotropic growth factor and acts as a universal regulator of cell growth, migration and transformation, cell cycle, wound healing, tumorigenesis, and cytotoxic drug resistance as a secreted glycoprotein. PGRN overexpression can induce the secretion of many inflammatory cytokines, such as IL-8, -6,-10, TNF-α. At the same time, this protein can promote tumor proliferation and the occurrence and development of many related diseases such as gastric cancer, breast cancer, cervical cancer, colorectal cancer, renal injury, neurodegeneration, neuroinflammatory, human atherosclerotic plaque, hepatocarcinoma, acute kidney injury, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. In short, PGRN plays a very critical role in injury repair and tumorigenesis, it provides a new direction for succeeding research and serves as a target for clinical diagnosis and treatment, thus warranting further investigation. Here, we discuss the potential therapeutic utility and the effect of PGRN on the relationship between inflammation and cancer.}, }
@article {pmid31338020, year = {2019}, author = {Peterson, AR and Binder, DK}, title = {Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {164}, pmid = {31338020}, issn = {1662-5099}, abstract = {Glutamate transporter-1 (GLT-1) is a Na[+]-dependent transporter that plays a key role in glutamate homeostasis by removing excess glutamate in the central nervous system (CNS). GLT-1 dysregulation occurs in various neurological diseases including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and epilepsy. Downregulation or dysfunction of GLT-1 has been a common finding across these diseases but how this occurs is still under investigation. This review aims to highlight post-translational regulation of GLT-1 which leads to its downregulation including sumoylation, palmitoylation, nitrosylation, ubiquitination, and subcellular localization. Various therapeutic interventions to restore GLT-1, their proposed mechanism of action and functional effects will be examined as potential treatments to attenuate the neurological symptoms associated with loss or downregulation of GLT-1.}, }
@article {pmid31336872, year = {2019}, author = {Sivandzade, F and Bhalerao, A and Cucullo, L}, title = {Cerebrovascular and Neurological Disorders: Protective Role of NRF2.}, journal = {International journal of molecular sciences}, volume = {20}, number = {14}, pages = {}, pmid = {31336872}, issn = {1422-0067}, support = {R01 DA029121/DA/NIDA NIH HHS/United States ; 2R01-DA029121/DA/NIDA NIH HHS/United States ; }, mesh = {Aging/genetics/metabolism ; Animals ; Biomarkers ; Cerebrovascular Disorders/diagnosis/*etiology/*genetics ; Comorbidity ; *Disease Susceptibility ; Humans ; NF-E2-Related Factor 2/*genetics/*metabolism ; Nervous System Diseases/diagnosis/*etiology/*metabolism ; Oxidative Stress ; Protein Binding ; Risk Factors ; Signal Transduction ; Smoking/adverse effects ; }, abstract = {Cellular defense mechanisms, intracellular signaling, and physiological functions are regulated by electrophiles and reactive oxygen species (ROS). Recent works strongly considered imbalanced ROS and electrophile overabundance as the leading cause of cellular and tissue damage, whereas oxidative stress (OS) plays a crucial role for the onset and progression of major cerebrovascular and neurodegenerative pathologies. These include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aging. Nuclear factor erythroid 2-related factor (NRF2) is the major modulator of the xenobiotic-activated receptor (XAR) and is accountable for activating the antioxidative response elements (ARE)-pathway modulating the detoxification and antioxidative responses of the cells. NRF2 activity, however, is also implicated in carcinogenesis protection, stem cells regulation, anti-inflammation, anti-aging, and so forth. Herein, we briefly describe the NRF2-ARE pathway and provide a review analysis of its functioning and system integration as well as its role in major CNS disorders. We also discuss NRF2-based therapeutic approaches for the treatment of neurodegenerative and cerebrovascular disorders.}, }
@article {pmid31335339, year = {2019}, author = {Brenner, D and Weishaupt, JH}, title = {Update on amyotrophic lateral sclerosis genetics.}, journal = {Current opinion in neurology}, volume = {32}, number = {5}, pages = {735-739}, doi = {10.1097/WCO.0000000000000737}, pmid = {31335339}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Frontotemporal Dementia/*genetics ; Genetic Association Studies ; Humans ; *Mutation ; *Phenotype ; }, abstract = {PURPOSE OF REVIEW: The fatal motoneuron disease amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a high contribution of genetic factors to pathogenesis, in probably both familial and sporadic ALS cases. State-of-the art sequencing techniques continue to reveal novel monogenic causes for ALS, risk factors and modifiers. This leads to an improved genotype/phenotype correlation and is becoming increasingly relevant for genetic diagnosis, counseling and therapy. The first gene-specific therapies are being tested in ongoing clinical trials. Consequently, this review aims to summarize the most important aspects of ALS genetics of the past 2 years.<br><br>RECENT FINDINGS: Most recent disease gene discoveries in the field of ALS constitute the genes KIF5A, ANXA11, GLT8D1 and TIA1, as well as an array of novel risk factors and modifiers. Increasing evidence suggests that even ALS mutations with high penetrance can co-occur with additional mutations in other known ALS genes, suggesting a relevant role of digenetic or polygenetic modes of inheritance. Genotype/phenotype correlation reveals clinical pleiotropy for several ALS genes, which can be linked, for example, to ataxia or Parkinsonian syndromes beyond classical ALS and frontotemporal dementia (FTD) phenotypes.<br><br>SUMMARY: The field of ALS continues to develop rapidly with multiple disease gene discoveries per year. The relevance of these findings for genetic counseling and diagnosis is obvious. With gene-specific therapies being tested in a clinical setting, the relevance of genetic aspects of ALS is increasing and likely to be linked to therapeutic consequences in the near future.}, }
@article {pmid31335338, year = {2019}, author = {McDermott, CJ}, title = {Clinical trials in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {32}, number = {5}, pages = {758-763}, doi = {10.1097/WCO.0000000000000731}, pmid = {31335338}, issn = {1473-6551}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; *Clinical Trials as Topic ; Edaravone/*therapeutic use ; Humans ; Hydroxylamines/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; Research Design ; Treatment Outcome ; }, abstract = {PURPOSE OF REVIEW: To review new developments in the field of amyotrophic lateral sclerosis (ALS) clinical trial design and to review the implications of the latest ALS clinical trials.<br><br>RECENT FINDINGS: There has been substantial reflection on how clinical trials in ALS are best conducted. The revised Airlie House recommendations are an important milestone and should guide trial design. In addition, innovations using individualized risk-based eligibility criteria, adaptive designs, joint modelling, patient-centred approaches, and remote collection of data show real promise. Edaravone was shown to have benefit on function in a well defined subset of patients with ALS, although there are concerns about the generalizability of the findings. Studies of arimoclomol, inosine, and cellular therapies have demonstrated promising signals in early phase work and are being taken forward into larger studies. Well conducted studies of rasagaline did not show an effect on primary outcome measures.<br><br>SUMMARY: For many decades there has been regular disappointment with the results of clinical trials. With the innovations in trial design and advances in our basic understanding of the biology of ALS, the prospects for a step change in treatments for people affected by ALS are strong.}, }
@article {pmid31335337, year = {2019}, author = {Kassubek, J and Pagani, M}, title = {Imaging in amyotrophic lateral sclerosis: MRI and PET.}, journal = {Current opinion in neurology}, volume = {32}, number = {5}, pages = {740-746}, doi = {10.1097/WCO.0000000000000728}, pmid = {31335337}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Brain/*diagnostic imaging ; Humans ; *Magnetic Resonance Imaging ; Neuroimaging/*methods ; *Positron-Emission Tomography ; }, abstract = {PURPOSE OF REVIEW: Neuroimaging with MRI and PET has become a well-established technical tool for amyotrophic lateral sclerosis (ALS). This review summarizes current developments in the advanced neuroimaging assessment of ALS and explores their potential in a clinical and neuroscientific setting.<br><br>RECENT FINDINGS: With a focus on diffusion-weighted imaging, MRI-based neuroimaging has shown to provide reliable measures for monitoring disease progression and should be included in the clinical workup of ALS. There have been efforts to improve the clinical utility of fluorodesoxyglucose (FDG)-PET, and multivariate analysis has made advances in discriminating patients from controls and for prognostic assessment. Beyond FDG-PET, promising investigations have been carried out implementing novel radiotracers.<br><br>SUMMARY: MRI and PET studies in ALS have consistently shown patterns of functional and structural changes considered to be the pathological signature of the disease. The constant advance of neuroimaging techniques encourages to investigate the cascade of ALS neurodegeneration and symptoms at finer and more specific level. Multicenter studies and the implementation of novel methodologies might confer a pivotal role to neuroimaging in the clinical setting in the near future, accelerating ALS diagnosis and allowing a prompt prognosis about disease progression.}, }
@article {pmid31331820, year = {2019}, author = {Abugable, AA and Morris, JLM and Palminha, NM and Zaksauskaite, R and Ray, S and El-Khamisy, SF}, title = {DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms.}, journal = {DNA repair}, volume = {81}, number = {}, pages = {102669}, doi = {10.1016/j.dnarep.2019.102669}, pmid = {31331820}, issn = {1568-7856}, support = {103844/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Alzheimer Disease/genetics/metabolism ; *DNA Repair ; Dementia/genetics/metabolism ; Humans ; Huntington Disease/genetics/metabolism ; Nervous System Diseases/*genetics/metabolism ; Neurons/metabolism ; Parkinson Disease/genetics/metabolism ; Trinucleotide Repeat Expansion ; }, abstract = {In both replicating and non-replicating cells, the maintenance of genomic stability is of utmost importance. Dividing cells can repair DNA damage during cell division, tolerate the damage by employing potentially mutagenic DNA polymerases or die via apoptosis. However, the options for accurate DNA repair are more limited in non-replicating neuronal cells. If DNA damage is left unresolved, neuronal cells die causing neurodegenerative disorders. A number of pathogenic variants of DNA repair proteins have been linked to multiple neurological diseases. The current challenge is to harness our knowledge of fundamental properties of DNA repair to improve diagnosis, prognosis and treatment of such debilitating disorders. In this perspective, we will focus on recent efforts in identifying novel DNA repair biomarkers for the diagnosis of neurological disorders and their use in monitoring the patient response to therapy. These efforts are greatly facilitated by the development of model organisms such as zebrafish, which will also be summarised.}, }
@article {pmid31331075, year = {2019}, author = {Martínez-Menárguez, J&#xc1; and Tomás, M and Martínez-Martínez, N and Martínez-Alonso, E}, title = {Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause?.}, journal = {Cells}, volume = {8}, number = {7}, pages = {}, pmid = {31331075}, issn = {2073-4409}, mesh = {Animals ; Cytoskeleton/*pathology ; *Golgi Apparatus/metabolism/pathology ; Humans ; Mice ; *Neurodegenerative Diseases/metabolism/pathology ; *Neurons/metabolism/pathology ; Protein Aggregation, Pathological ; }, abstract = {In most mammalian cells, the Golgi complex forms a continuous ribbon. In neurodegenerative diseases, the Golgi ribbon of a specific group of neurons is typically broken into isolated elements, a very early event which happens before clinical and other pathological symptoms become evident. It is not known whether this phenomenon is caused by mechanisms associated with cell death or if, conversely, it triggers apoptosis. When the phenomenon was studied in diseases such as Parkinson's and Alzheimer's or amyotrophic lateral sclerosis, it was attributed to a variety of causes, including the presence of cytoplasmatic protein aggregates, malfunctioning of intracellular traffic and/or alterations in the cytoskeleton. In the present review, we summarize the current findings related to these and other neurodegenerative diseases and try to search for clues on putative common causes.}, }
@article {pmid31324037, year = {2019}, author = {Tosato, M and Di Marco, V}, title = {Metal Chelation Therapy and Parkinson's Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs.}, journal = {Biomolecules}, volume = {9}, number = {7}, pages = {}, pmid = {31324037}, issn = {2218-273X}, mesh = {Chelating Agents/chemical synthesis/chemistry/*therapeutic use ; *Chelation Therapy ; Coordination Complexes/chemical synthesis/chemistry/*therapeutic use ; Humans ; Ligands ; Metals, Heavy/chemical synthesis/chemistry/*therapeutic use ; Neuroprotective Agents/chemical synthesis/chemistry/*therapeutic use ; Parkinson Disease/*drug therapy ; Thermodynamics ; }, abstract = {The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson's disease (PD) therapy in the year range 2014-2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant Kd (both computed at pH = 7.4 and at total metal and ligand concentrations of 10[-6] and 10[-5] mol/L, respectively), charge and stoichiometry of the most abundant metal-ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal-ligand speciation of PD drugs is underlined.}, }
@article {pmid31323950, year = {2019}, author = {Sznajder, &#x141;J and Swanson, MS}, title = {Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy.}, journal = {International journal of molecular sciences}, volume = {20}, number = {13}, pages = {}, pmid = {31323950}, issn = {1422-0067}, support = {MDA546770//Muscular Dystrophy Association/ ; NS058901//National Institute of Neurological Disorders and Stroke/ ; NS098819//National Institute of Neurological Disorders and Stroke/ ; P01 NS058901/NS/NINDS NIH HHS/United States ; MDA480539//Muscular Dystrophy Association/ ; }, mesh = {Alternative Splicing/*genetics ; Animals ; Cell Nucleus/genetics/metabolism ; Humans ; Microsatellite Repeats/*genetics ; Muscle, Skeletal/metabolism ; Myotonic Dystrophy/*genetics ; RNA/*genetics ; Ribonucleoproteins/genetics/metabolism ; Trinucleotide Repeat Expansion/*genetics ; }, abstract = {Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUG[exp], CCUG[exp]) RNAs, respectively. These CUG[exp] and CCUG[exp] RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly.}, }
@article {pmid31319884, year = {2019}, author = {Renaud, L and Picher-Martel, V and Codron, P and Julien, JP}, title = {Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Acta neuropathologica communications}, volume = {7}, number = {1}, pages = {103}, pmid = {31319884}, issn = {2051-5960}, support = {/CAPMC/CIHR/Canada ; }, mesh = {Adaptor Proteins, Signal Transducing/chemistry/genetics/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Autophagy-Related Proteins/chemistry/genetics/*metabolism ; DNA-Binding Proteins/chemistry/genetics/metabolism ; Frontotemporal Dementia/genetics/*metabolism/*pathology ; Humans ; Inclusion Bodies/chemistry/genetics/metabolism ; }, abstract = {Ubiquilin-2 (UBQLN2) is a member of the ubiquilin family, actively implicated in the degradation of misfolded and redundant proteins through the ubiquitin-proteasome system and macroautophagy. UBQLN2 received much attention after the discovery of gene mutations in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The abnormal presence of positive UBQLN2 inclusion in the cytosol of degenerating motor neurons of familial and sporadic forms of ALS patients has been newly related to neurodegeneration. Only recently, data have emerged on its role in liquid-liquid phase separation, in stress granule development and in the formation of secondary amyloid structures. Furthermore, several animal models are available to investigate its involvement in TDP-43 pathology and neuroinflammation in ALS. This review addresses the molecular pathogenetic pathways involving UBQLN2 abnormalities which are converging toward defects in clearance mechanisms. UBQLN2.}, }
@article {pmid31316455, year = {2019}, author = {Heyburn, L and Sajja, VSSS and Long, JB}, title = {The Role of TDP-43 in Military-Relevant TBI and Chronic Neurodegeneration.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {680}, pmid = {31316455}, issn = {1664-2295}, abstract = {Due largely to the use of improvised explosive devices (IEDs) and other explosives in recent military conflicts, blast-related TBI has emerged as a prominent injury sustained by warfighters. In the recent wars in Iraq and Afghanistan, traumatic brain injury (TBI) has been one of the most common types of injury sustained by soldiers and military personnel; of the ~380,000 TBIs reported in service members from 2000 to 2017, 82.3% were classified as mild (mTBI). While mTBI is associated with normal structural imaging, brief or no loss of consciousness, and rapid recovery of mental state, mTBI can nevertheless lead to persistent behavioral and cognitive effects. As in other cases of mTBI, exposure to low-level blast often does not cause immediate overt neurological effects, but may similarly lead to persistent behavioral and cognitive deficits. These effects are likely to be compounded when multiple exposures to blast and/or impact are sustained, since there is increasing evidence that multiple mTBIs can lead to chronic neurodegeneration. One common form of this deleterious outcome is frontotemporal lobar degeneration (FTLD), which is a progressive neurodegenerative process marked by atrophy of the frontal and temporal lobes, leading to frontotemporal dementia, a common form of dementia affecting behavior, cognition and language. About half of all cases of FTLD are marked by TAR-DNA binding protein (TDP-43)-positive protein inclusions. TDP-43, a DNA/RNA binding protein, controls the expression of thousands of genes and is associated with several neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, and chronic traumatic encephalopathy. TDP-43 abnormalities have also been associated with traumatic brain injury in both pre-clinical and clinical studies. The role of TDP-43 in the manifestation of FTLD pathology in military TBI cases is currently unclear, and to date there has been only a limited number of pre-clinical studies addressing the effects of repeated blast-related mild TBI (rbTBI) in relation to FTLD and TDP-43. This review will summarize some of these findings and address the concerns and critical knowledge gaps associated with FTLD manifestation with military populations, as well as clinical findings on other forms of mTBI.}, }
@article {pmid31316328, year = {2019}, author = {Ragagnin, AMG and Shadfar, S and Vidal, M and Jamali, MS and Atkin, JD}, title = {Motor Neuron Susceptibility in ALS/FTD.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {532}, pmid = {31316328}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of both upper and lower motor neurons (MNs) in the brain, brainstem and spinal cord. The neurodegenerative mechanisms leading to MN loss in ALS are not fully understood. Importantly, the reasons why MNs are specifically targeted in this disorder are unclear, when the proteins associated genetically or pathologically with ALS are expressed ubiquitously. Furthermore, MNs themselves are not affected equally; specific MNs subpopulations are more susceptible than others in both animal models and human patients. Corticospinal MNs and lower somatic MNs, which innervate voluntary muscles, degenerate more readily than specific subgroups of lower MNs, which remain resistant to degeneration, reflecting the clinical manifestations of ALS. In this review, we discuss the possible factors intrinsic to MNs that render them uniquely susceptible to neurodegeneration in ALS. We also speculate why some MN subpopulations are more vulnerable than others, focusing on both their molecular and physiological properties. Finally, we review the anatomical network and neuronal microenvironment as determinants of MN subtype vulnerability and hence the progression of ALS.}, }
@article {pmid31312134, year = {2019}, author = {Espinosa-Parrilla, Y and Gonzalez-Billault, C and Fuentes, E and Palomo, I and Alarcón, M}, title = {Decoding the Role of Platelets and Related MicroRNAs in Aging and Neurodegenerative Disorders.}, journal = {Frontiers in aging neuroscience}, volume = {11}, number = {}, pages = {151}, pmid = {31312134}, issn = {1663-4365}, abstract = {Platelets are anucleate cells that circulate in blood and are essential components of the hemostatic system. During aging, platelet numbers decrease and their aggregation capacity is reduced. Platelet dysfunctions associated with aging can be linked to molecular alterations affecting several cellular systems that include cytoskeleton rearrangements, signal transduction, vesicular trafficking, and protein degradation. Age platelets may adopt a phenotype characterized by robust secretion of extracellular vesicles that could in turn account for about 70-90% of blood circulating vesicles. Interestingly these extracellular vesicles are loaded with messenger RNAs and microRNAs that may have a profound impact on protein physiology at the systems level. Age platelet dysfunction is also associated with accumulation of reactive oxygen species. Thereby understanding the mechanisms of aging in platelets as well as their age-dependent dysfunctions may be of interest when evaluating the contribution of aging to the onset of age-dependent pathologies, such as those affecting the nervous system. In this review we summarize the findings that link platelet dysfunctions to neurodegenerative diseases including Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Huntington's Disease, and Amyotrophic Lateral Sclerosis. We discuss the role of platelets as drivers of protein dysfunctions observed in these pathologies, their association with aging and the potential clinical significance of platelets, and related miRNAs, as peripheral biomarkers for diagnosis and prognosis of neurodegenerative diseases.}, }
@article {pmid31307610, year = {2019}, author = {Andrews, JA and Shefner, JM}, title = {Clinical neurophysiology of anterior horn cell disorders.}, journal = {Handbook of clinical neurology}, volume = {161}, number = {}, pages = {317-326}, doi = {10.1016/B978-0-444-64142-7.00057-6}, pmid = {31307610}, issn = {0072-9752}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Electromyography ; Humans ; Muscular Atrophy, Spinal/*physiopathology ; }, abstract = {The development of neurophysiological techniques for clinical assessment in the 20th century is closely related to the study of anterior horn cell diseases. The effects of motor axon loss on nerve conduction velocity and compound motor amplitude were elucidated first in amyotrophic lateral sclerosis (ALS), as was the characterization of reinnervation as detected by needle electromyography. The same changes noted in early studies still play a major role in the diagnosis of anterior horn cell diseases. In addition, much of modern neurophysiological assessment of motor axon quantitation, ion channel changes in neurogenic disease, and cortical physiology studies to assess both network and excitability abnormalities have all been applied to ALS. In this chapter, we summarize the clinical attributes of ALS and Spinal Muscular Atrophy, and review how clinical neurophysiology is employed in the clinical and the research setting.}, }
@article {pmid31306211, year = {2019}, author = {Chiot, A and Lobsiger, CS and Boillée, S}, title = {New insights on the disease contribution of neuroinflammation in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {32}, number = {5}, pages = {764-770}, doi = {10.1097/WCO.0000000000000729}, pmid = {31306211}, issn = {1473-6551}, mesh = {Animals ; Humans ; *Myasthenic Syndromes, Congenital/drug therapy/genetics/pathology/physiopathology ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease with a strong neuroinflammatory component. This review summarizes how the connection between neurodegeneration and the immune system is strengthened by new discoveries from ALS genetics and the analysis of subpopulations of immune cells in ALS.<br><br>RECENT FINDINGS: Recent genes identified in ALS encode for proteins with direct immune roles, which when mutated lead to deregulation of immune functions, potentially influencing the disease. Although neuroinflammation in the central nervous system (CNS) of ALS patients has been well documented, new evidence suggests also direct malfunctions of immune cells in the CNS and at the periphery. Although CD4+ T-regulatory lymphocytes are protective in ALS, their number and function are altered over the disease course. CD8+ T cells are detrimental for motor neurons in the CNS but show some protective roles at the periphery. Similarly, the presence of mast cells in muscles of ALS models and patients and impairments of monocyte functions reveal potential new players in ALS disease progression.<br><br>SUMMARY: Although motor neuron degeneration is considered the prime event in ALS, dysfunctions in immune processes can impact the disease, highlighting that targeting specific immune components is a strategy for developing biomarkers and ultimately new drugs.}, }
@article {pmid31301281, year = {2019}, author = {Roy, J and Saucier, D and O'Connell, C and Morin, PJ}, title = {Extracellular vesicles and their diagnostic potential in amyotrophic lateral sclerosis.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {497}, number = {}, pages = {27-34}, doi = {10.1016/j.cca.2019.07.012}, pmid = {31301281}, issn = {1873-3492}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism ; Extracellular Vesicles/*metabolism ; Humans ; }, abstract = {Extracellular vesicles, small reservoirs that carry various biomolecules, have gained significant interest from the clinical field in recent years based on the diagnostic, therapeutic and prognostic possibilities they offer. While information abound regarding the clinical potential of such vesicles in diverse conditions, the information demonstrating their likely importance in amyotrophic lateral sclerosis (ALS) is more limited. This review will thus provide a brief introduction to extracellular vesicles, highlight their diagnostic significance in various diseases with a focus on ALS and explore additional applications of extracellular vesicles in the medical field. Overall, this work sheds further light on the clinical importance of extracellular vesicles in diagnostic applications as well as supports the need to better characterize their roles and signatures in patients diagnosed with ALS.}, }
@article {pmid31295847, year = {2019}, author = {Chen, K and Baluya, D and Tosun, M and Li, F and Maletic-Savatic, M}, title = {Imaging Mass Spectrometry: A New Tool to Assess Molecular Underpinnings of Neurodegeneration.}, journal = {Metabolites}, volume = {9}, number = {7}, pages = {}, pmid = {31295847}, issn = {2218-1989}, support = {GM120033//National Institutes of Health/ ; }, abstract = {Neurodegenerative diseases are prevalent and devastating. While extensive research has been done over the past decades, we are still far from comprehensively understanding what causes neurodegeneration and how we can prevent it or reverse it. Recently, systems biology approaches have led to a holistic examination of the interactions between genome, metabolome, and the environment, in order to shed new light on neurodegenerative pathogenesis. One of the new technologies that has emerged to facilitate such studies is imaging mass spectrometry (IMS). With its ability to map a wide range of small molecules with high spatial resolution, coupled with the ability to quantify them at once, without the need for a priori labeling, IMS has taken center stage in current research efforts in elucidating the role of the metabolome in driving neurodegeneration. IMS has already proven to be effective in investigating the lipidome and the proteome of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Here, we review the IMS platform for capturing biological snapshots of the metabolic state to shed more light on the molecular mechanisms of the diseased brain.}, }
@article {pmid31295455, year = {2020}, author = {Evans, CS and Holzbaur, ELF}, title = {Quality Control in Neurons: Mitophagy and Other Selective Autophagy Mechanisms.}, journal = {Journal of molecular biology}, volume = {432}, number = {1}, pages = {240-260}, pmid = {31295455}, issn = {1089-8638}, support = {R37 NS060698/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Autophagy/*genetics ; Endoplasmic Reticulum/*genetics ; Homeostasis/genetics ; Humans ; Mitophagy/*genetics ; Neurons/*metabolism ; Parkinson Disease/genetics ; Protein Aggregates/genetics ; Signal Transduction/genetics ; }, abstract = {The cargo-specific removal of organelles via selective autophagy is important to maintain neuronal homeostasis. Genetic studies indicate that deficits in these pathways are implicated in neurodegenerative diseases, including Parkinson's and amyotrophic lateral sclerosis. Here, we review our current understanding of the pathways that regulate mitochondrial quality control, and compare these mechanisms to those regulating turnover of the endoplasmic reticulum and the clearance of protein aggregates. Research suggests that there are multiple mechanisms regulating the degradation of specific cargos, such as dysfunctional organelles and protein aggregates. These mechanisms are critical for neuronal health, as neurons are uniquely vulnerable to impairment in organelle quality control pathways due to their morphology, size, polarity, and postmitotic nature. We highlight the consequences of dysregulation of selective autophagy in neurons and discuss current challenges in correlating noncongruent findings from in vitro and in vivo systems.}, }
@article {pmid31293369, year = {2019}, author = {Gentile, F and Scarlino, S and Falzone, YM and Lunetta, C and Tremolizzo, L and Quattrini, A and Riva, N}, title = {The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {601}, pmid = {31293369}, issn = {1662-4548}, abstract = {Although amyotrophic lateral sclerosis (ALS) has been considered as a disorder of the motor neuron (MN) cell body, recent evidences show the non-cell-autonomous pathogenic nature of the disease. Axonal degeneration, loss of peripheral axons and destruction of nerve terminals are early events in the disease pathogenic cascade, anticipating MN degeneration, and the onset of clinical symptoms. Therefore, although ALS and peripheral axonal neuropathies should be differentiated in clinical practice, they also share damage to common molecular pathways, including axonal transport, RNA metabolism and proteostasis. Thus, an extensive evaluation of the molecular events occurring in the peripheral nervous system (PNS) could be fundamental to understand the pathogenic mechanisms of ALS, favoring the discovery of potential disease biomarkers, and new therapeutic targets.}, }
@article {pmid31288090, year = {2019}, author = {Wu, Y and Chen, M and Jiang, J}, title = {Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling.}, journal = {Mitochondrion}, volume = {49}, number = {}, pages = {35-45}, doi = {10.1016/j.mito.2019.07.003}, pmid = {31288090}, issn = {1872-8278}, mesh = {Animals ; *Apoptosis ; Humans ; Mitochondria/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; *Oxidative Stress ; *Signal Transduction ; }, abstract = {Mitochondrial dysfunction is becoming one of the most emerging pathological process in the etiology of neurological disorders. Other common etiologies of the neurological disorders are aging and oxidative stress. Neurodegenerative disorders for instance Huntington's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Epilepsy, Schizophrenia, Multiple sclerosis, Neuropathic pain and Alzheimer's disease involves mitochondrial dysfunction and is regarded as the core of their pathological processes. Most central pathological feature of the neurodegenerative diseases is apoptosis which is regulated by mitochondria. Altered signaling of the apoptotic mechanisms are involved in neurodegeneration. Abnormal levels of these molecular apoptotic proteins promotes the pathogenesis of neurological disorders. Mitochondria are also implicated in the production of reactive oxygen species (ROS). Raised ROS levels initiates the cascade leading to the non-apoptotic death of cells. ROS produced in cells acts as signaling molecules, but when produced in abundance will result in cellular consequences to deoxyribonucleic acid, proteins and lipids, decreased effectiveness of cellular mechanisms, initiation of inflammatory pathways, excitotoxicity, protein agglomeration and apoptosis. Protecting mitochondrial function has been identified as the most effective therapeutic approach to attenuate the pathogenesis of neurodegenerative diseases. This review aims to provide an insight into the mitochondrial dysfunction in the pathogenesis of neurological disorders, alteration in signaling cascades of apoptosis in mitochondrial dysfunction and the therapeutic strategies (both natural and synthetic drugs) targeting these mitochondrial apoptotic pathways and oxidative stress that holds great promise.}, }
@article {pmid31283931, year = {2019}, author = {Weber, JJ and Clemensson, LE and Schiöth, HB and Nguyen, HP}, title = {Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate.}, journal = {Biochemical pharmacology}, volume = {168}, number = {}, pages = {305-318}, doi = {10.1016/j.bcp.2019.07.002}, pmid = {31283931}, issn = {1873-2968}, mesh = {Animals ; Calcium/metabolism ; Calpain/metabolism ; Cholestenones/chemistry/*pharmacology/*therapeutic use ; Cholesterol/metabolism ; Homeostasis/drug effects ; Humans ; Mice ; Mitochondria/drug effects/metabolism ; Mitochondrial Transmembrane Permeability-Driven Necrosis/drug effects ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/*pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Rats ; }, abstract = {Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.}, }
@article {pmid31283897, year = {2019}, author = {Bennett, CF and Krainer, AR and Cleveland, DW}, title = {Antisense Oligonucleotide Therapies for Neurodegenerative Diseases.}, journal = {Annual review of neuroscience}, volume = {42}, number = {}, pages = {385-406}, pmid = {31283897}, issn = {1545-4126}, support = {R37 GM042699/GM/NIGMS NIH HHS/United States ; R01 NS027036/NS/NINDS NIH HHS/United States ; R01 GM042699/GM/NIGMS NIH HHS/United States ; P01 CA013106/CA/NCI NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism/pathology ; Humans ; Muscular Atrophy, Spinal/*drug therapy ; Neurodegenerative Diseases/*drug therapy/genetics ; Oligonucleotides/*pharmacology ; Oligonucleotides, Antisense/*therapeutic use ; Tissue Distribution/*genetics ; }, abstract = {Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.}, }
@article {pmid31279830, year = {2019}, author = {Masi, A and Narducci, R and Mannaioni, G}, title = {Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders.}, journal = {Pharmacological research}, volume = {147}, number = {}, pages = {104343}, doi = {10.1016/j.phrs.2019.104343}, pmid = {31279830}, issn = {1096-1186}, mesh = {Animals ; Cell Death ; Humans ; *Neurodegenerative Diseases ; Neurons/pathology ; *Retinal Diseases ; }, abstract = {Progressive neuronal death is the key pathogenic event leading to clinical symptoms in neurodegenerative disorders (NDDs). Neuroprotective treatments are virtually unavailable, partly because of the marked internal heterogeneity of the mechanisms underlying pathology. Targeted neuroprotection would require deep mechanistic knowledge across the entire aetiological spectrum of each NDD and the development of tailored treatments. Although ideal, this strategy appears challenging, as it would require a degree of characterization of both the disease and the patient that is currently unavailable. The alternate strategy is to search for commonalities across molecularly distinct NDD forms and exploit these for the development of drugs with broad-spectrum efficacy. In this view, mounting evidence points to ionic mechanisms (IMs) as targets with potential therapeutic efficacy across distinct NDD subtypes. The scope of this review is to present clinical and preclinical evidence supporting the link between disruption of IMs and neuronal death in specific NDDs and to critically revise past and ongoing attempts of harnessing IMs for the development of neuroprotective treatments.}, }
@article {pmid31275093, year = {2019}, author = {Ma, J and Gao, J and Wang, J and Xie, A}, title = {Prion-Like Mechanisms in Parkinson's Disease.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {552}, pmid = {31275093}, issn = {1662-4548}, abstract = {Formation and aggregation of misfolded proteins in the central nervous system (CNS) is a key hallmark of several age-related neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). These diseases share key biophysical and biochemical characteristics with prion diseases. It is believed that PD is characterized by abnormal protein aggregation, mainly that of α-synuclein (α-syn). Of particular importance, there is growing evidence indicating that abnormal α-syn can spread to neighboring brain regions and cause aggregation of endogenous α-syn in these regions as seeds, in a "prion-like" manner. Abundant studies in vitro and in vivo have shown that α-syn goes through a templated conformational change, propagates from the original region to neighboring regions, and eventually cause neuron degeneration in the substantia nigra and striatum. The objective of this review is to summarize the mechanisms involved in the aggregation of abnormal intracellular α-syn and its subsequent cell-to-cell transmission. According to these findings, we look forward to effective therapeutic perspectives that can block the progression of neurodegenerative diseases.}, }
@article {pmid31273080, year = {2019}, author = {Turner, MR and Faull, C and McDermott, CJ and Nickol, AH and Palmer, J and Talbot, K}, title = {Tracheostomy in motor neurone disease.}, journal = {Practical neurology}, volume = {19}, number = {6}, pages = {467-475}, doi = {10.1136/practneurol-2018-002109}, pmid = {31273080}, issn = {1474-7766}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Motor Neuron Disease/*complications ; Respiratory Insufficiency/*etiology/*surgery ; Tracheostomy/*methods ; }, abstract = {Tracheostomy-associated ventilation for the respiratory insufficiency caused by amyotrophic lateral sclerosis (motor neurone disease (MND)) is a complex issue with practical, ethical and economic dimensions. This article considers the current prevalence of tracheostomy in MND, the evidence for its benefit both for survival and quality of life, and the practicalities of its implementation. The decision to request invasive ventilatory support is among the most challenging for those living with MND. Neurologists should be prepared to discuss this option openly and objectively: we suggest a framework for discussion, including withdrawal of therapy.}, }
@article {pmid31272349, year = {2019}, author = {Lushington, GH and Barnes, AC}, title = {Protein Glycation: An Old Villain is Shedding Secrets.}, journal = {Combinatorial chemistry &amp; high throughput screening}, volume = {22}, number = {6}, pages = {362-369}, doi = {10.2174/1386207322666190704094356}, pmid = {31272349}, issn = {1875-5402}, mesh = {Glycosylation ; Humans ; Proteins/chemistry/*metabolism ; }, abstract = {The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. This 'current frontier' article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.}, }
@article {pmid31264031, year = {2019}, author = {Howard, I and Potts, A}, title = {Interprofessional Care for Neuromuscular Disease.}, journal = {Current treatment options in neurology}, volume = {21}, number = {8}, pages = {35}, pmid = {31264031}, issn = {1092-8480}, abstract = {PURPOSE OF REVIEW: This review aims to delineate interprofessional care models for neuromuscular disease. Evidence regarding both the benefits and barriers to interprofessional neuromuscular care in both inpatient and outpatient settings is presented. Finally, opportunities to improve both access to and quality of care provided by interprofessional team clinics will be discussed.<br><br>RECENT FINDINGS: Although the term "multidisciplinary" is often misapplied to denote any interprofessional team-based care setting, there are important differences in team structure and dynamics in each of the three most common models: multidisciplinary, interdisciplinary, and transdisciplinary care. Evidence favors the more integrated interdisciplinary and transdisciplinary models for better patient outcomes and decreased staff burnout. Coordinated interprofessional care results in improved health outcomes, resource utilization, and patient satisfaction for persons with adult and pediatric neuromuscular disease. Distance remains the greatest barrier to specialized team-based care for this population; telehealth technologies may make interprofessional care more accessible to these persons. Despite limited evidence for the broader population of persons with neuromuscular disease, consensus guidelines increasingly support this model of care delivery. Further work may help determine effectiveness for other populations of persons with neuromuscular disease and best practices within these team-based models of care.}, }
@article {pmid31258624, year = {2019}, author = {Dorst, J and Ludolph, AC}, title = {Non-invasive ventilation in amyotrophic lateral sclerosis.}, journal = {Therapeutic advances in neurological disorders}, volume = {12}, number = {}, pages = {1756286419857040}, pmid = {31258624}, issn = {1756-2856}, abstract = {Non-invasive ventilation (NIV) has become an important cornerstone of symptomatic treatment in amyotrophic lateral sclerosis (ALS), improving survival and quality of life. In this review, we summarize the most important recent developments and insights, including evidence of efficacy, indication criteria and time of initiation, ventilation parameters and adaptation strategies, treatment of complicating factors, transition from NIV to invasive ventilation, termination of NIV and end-of-life management. Recent publications have questioned former conventions and guideline recommendations, especially with regard to timing and prognostic factors; therefore, a fresh look and re-evaluation of current evidence is needed.}, }
@article {pmid31258331, year = {2019}, author = {Dehhaghi, M and Kazemi Shariat Panahi, H and Guillemin, GJ}, title = {Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status.}, journal = {International journal of tryptophan research : IJTR}, volume = {12}, number = {}, pages = {1178646919852996}, pmid = {31258331}, issn = {1178-6469}, abstract = {The kynurenine pathway is important in cellular energy generation and limiting cellular ageing as it degrades about 90% of dietary tryptophan into the essential co-factor NAD[+] (nicotinamide adenine dinucleotide). Prior to the production of NAD[+], various intermediate compounds with neuroactivity (kynurenic acid, quinolinic acid) or antioxidant activity (3-hydroxykynurenine, picolinic acid) are synthesized. The kynurenine metabolites can participate in numerous neurodegenerative disorders (Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease) or other diseases such as AIDS, cancer, cardiovascular diseases, inflammation, and irritable bowel syndrome. Recently, the role of gut in affecting the emotional and cognitive centres of the brain has attracted a great deal of attention. In this review, we focus on the bidirectional communication between the gut and the brain, known as the gut-brain axis. The interaction of components of this axis, namely, the gut, its microbiota, and gut pathogens; tryptophan; the kynurenine pathway on tryptophan availability; the regulation of kynurenine metabolite concentration; and diversity and population of gut microbiota, has been considered.}, }
@article {pmid31257248, year = {2019}, author = {Tokuda, E and Marklund, SL and Furukawa, Y}, title = {[Prion-like Properties of Misfolded Cu/Zn-superoxide Dismutase in Amyotrophic Lateral Sclerosis: Update and Perspectives].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {139}, number = {7}, pages = {1015-1019}, doi = {10.1248/yakushi.18-00165-5}, pmid = {31257248}, issn = {1347-5231}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; Motor Neurons/metabolism ; Mutation ; Prions ; Protein Aggregation, Pathological ; Protein Folding ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that is characterized by the loss of motor neurons, which results in progressive muscle atrophy. The pathology spreads from the initial site of onset to contiguous anatomic regions. Mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) have been identified in a dominantly inherited form of ALS (ALS-SOD1). A major hallmark of ALS-SOD1 is the abnormal accumulation of conformationally aberrant SOD1 protein (i.e., misfolded SOD1) within motor neurons. Emerging experimental evidence has suggested that misfolded proteins associated with neurodegenerative diseases exhibit prion-like properties, i.e., misfolded proteins act as conformational templates that convert normal proteins into a pathogenic form. Possibly as a result of this prion-like self-propagation property, misfolded forms of pathological proteins are considered to accumulate in the central nervous system and cause neurodegeneration. In this article, we review recent evidence for the role of prion-like mechanisms in ALS-SOD1. In particular, we discuss the propensity of misfolded SOD1 to act as a pathological seed, spread between cells, and propagate neuroanatomically.}, }
@article {pmid31254610, year = {2020}, author = {Mandrioli, J and Mediani, L and Alberti, S and Carra, S}, title = {ALS and FTD: Where RNA metabolism meets protein quality control.}, journal = {Seminars in cell &amp; developmental biology}, volume = {99}, number = {}, pages = {183-192}, doi = {10.1016/j.semcdb.2019.06.003}, pmid = {31254610}, issn = {1096-3634}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Humans ; RNA/genetics/*metabolism ; RNA-Binding Proteins/genetics/*metabolism ; }, abstract = {Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade. In this review, we summarize key principles underlying ALS and FTD, and we discuss how mutations in genes involved in RNA metabolism, protein quality control and protein degradation meet mechanistically to impair the functionality and dynamics of RNP granules, and how this leads to cellular toxicity and death. Finally, we describe recent advances in understanding signaling pathways that become dysfunctional in ALS/FTD, partly due to altered RNP granule dynamics, but also with stress granule-independent mechanisms and, thus could be promising targets for future therapeutic intervention.}, }
@article {pmid31252669, year = {2019}, author = {Hosaka, T and Yamashita, T and Tamaoka, A and Kwak, S}, title = {Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {13}, pages = {}, pmid = {31252669}, issn = {1422-0067}, support = {16jm0310026h0004//Strategic International Collaborative Research Program/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/genetics ; Animals ; Biomarkers/blood ; Cell-Free Nucleic Acids/*blood/genetics ; Humans ; RNA Editing ; }, abstract = {Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell-cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.}, }
@article {pmid31251338, year = {2019}, author = {Nainu, F and Salim, E and Asri, RM and Hori, A and Kuraishi, T}, title = {Neurodegenerative disorders and sterile inflammation: lessons from a Drosophila model.}, journal = {Journal of biochemistry}, volume = {166}, number = {3}, pages = {213-221}, doi = {10.1093/jb/mvz053}, pmid = {31251338}, issn = {1756-2651}, mesh = {Animals ; *Disease Models, Animal ; *Drosophila/immunology ; Inflammation/drug therapy/immunology/*metabolism ; Neurodegenerative Diseases/drug therapy/immunology/*metabolism ; }, abstract = {Central nervous system (CNS)-related disorders, including neurodegenerative diseases, are common but difficult to treat. As effective medical interventions are limited, those diseases will likely continue adversely affecting people's health. There is evidence that the hyperactivation of innate immunity is a hallmark of most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases. In mammalian and fly CNS, the presence of noninfectious ligands, including danger-associated molecular patterns, is recognized by (micro)glial cells, inducing the expression of proinflammatory cytokines. Such inflammation may contribute to the onset and progression of neurodegenerative states. Studies using fruit flies have shed light on the types of signals, receptors and cells responsible for inducing the inflammation that leads to neurodegeneration. Researchers are using fly models to assess the mechanisms of sterile inflammation in the brain and its link to progressive neurodegeneration. Given the similarity of its physiological system and biochemical function to those of mammals, especially in activating and regulating innate immune signalling, Drosophila can be a versatile model system for studying the mechanisms and biological significance of sterile inflammatory responses in the pathogenesis of neurodegenerative diseases. Such knowledge would greatly facilitate the quest for a novel effective treatment for neurodegenerative diseases.}, }
@article {pmid31244752, year = {2019}, author = {Foggin, S and Mesquita-Ribeiro, R and Dajas-Bailador, F and Layfield, R}, title = {Biological Significance of microRNA Biomarkers in ALS-Innocent Bystanders or Disease Culprits?.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {578}, pmid = {31244752}, issn = {1664-2295}, support = {LAYFIELD/OCT16/887-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {MicroRNAs (miRNAs) represent potential biomarkers for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). However, whether expression changes of individual miRNAs are simply an indication of cellular dysfunction and degeneration, or actually promote functional changes in target gene expression relevant to disease pathogenesis, is unclear. Here we used bioinformatics to test the hypothesis that ALS-associated miRNAs exert their effects through targeting genes implicated in disease etiology. We documented deregulated miRNAs identified in studies of ALS patients, noting variations in participants, tissue samples, miRNA detection or quantification methods used, and functional or bioinformatic assessments (if performed). Despite lack of experimental standardization, overlap of many deregulated miRNAs between studies was noted; however, direction of reported expression changes did not always concur. The use of in silico predictions of target genes for the most commonly deregulated miRNAs, cross-referenced to a selection of previously identified ALS genes, did not support our hypothesis. Specifically, although deregulated miRNAs were predicted to commonly target ALS genes, random miRNAs gave similar predictions. To further investigate biological patterns in the deregulated miRNAs, we grouped them by tissue source in which they were identified, indicating that for a core of frequently detected miRNAs, blood/plasma/serum may be useful for future profiling experiments. We conclude that in silico predictions of gene targets of deregulated ALS miRNAs, at least using currently available algorithms, are unlikely to be sufficient in informing disease pathomechanisms. We advocate experimental functional testing of candidate miRNAs and their predicted targets, propose miRNAs to prioritise, and suggest a concerted move towards protocol standardization for biomarker identification.}, }
@article {pmid31244593, year = {2019}, author = {Hedl, TJ and San Gil, R and Cheng, F and Rayner, SL and Davidson, JM and De Luca, A and Villalva, MD and Ecroyd, H and Walker, AK and Lee, A}, title = {Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {548}, pmid = {31244593}, issn = {1662-4548}, abstract = {Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing in prevalence but lack targeted therapeutics. Although the pathological mechanisms behind these diseases remain unclear, both ALS and FTD are characterized pathologically by aberrant protein aggregation and inclusion formation within neurons, which correlates with neurodegeneration. Notably, aggregation of several key proteins, including TAR DNA binding protein of 43 kDa (TDP-43), superoxide dismutase 1 (SOD1), and tau, have been implicated in these diseases. Proteomics methods are being increasingly applied to better understand disease-related mechanisms and to identify biomarkers of disease, using model systems as well as human samples. Proteomics-based approaches offer unbiased, high-throughput, and quantitative results with numerous applications for investigating proteins of interest. Here, we review recent advances in the understanding of ALS and FTD pathophysiology obtained using proteomics approaches, and we assess technical and experimental limitations. We compare findings from various mass spectrometry (MS) approaches including quantitative proteomics methods such as stable isotope labeling by amino acids in cell culture (SILAC) and tandem mass tagging (TMT) to approaches such as label-free quantitation (LFQ) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) in studies of ALS and FTD. Similarly, we describe disease-related protein-protein interaction (PPI) studies using approaches including immunoprecipitation mass spectrometry (IP-MS) and proximity-dependent biotin identification (BioID) and discuss future application of new techniques including proximity-dependent ascorbic acid peroxidase labeling (APEX), and biotinylation by antibody recognition (BAR). Furthermore, we explore the use of MS to detect post-translational modifications (PTMs), such as ubiquitination and phosphorylation, of disease-relevant proteins in ALS and FTD. We also discuss upstream technologies that enable enrichment of proteins of interest, highlighting the contributions of new techniques to isolate disease-relevant protein inclusions including flow cytometric analysis of inclusions and trafficking (FloIT). These recently developed approaches, as well as related advances yet to be applied to studies of these neurodegenerative diseases, offer numerous opportunities for discovery of potential therapeutic targets and biomarkers for ALS and FTD.}, }
@article {pmid31234550, year = {2019}, author = {Maher, P}, title = {The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {12}, pages = {}, pmid = {31234550}, issn = {1422-0067}, support = {AG046153, AI104034 and NS106305//National Institutes of Health/ ; }, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Apoptosis ; Brain/drug effects/metabolism/physiopathology ; Flavonoids/pharmacology/*therapeutic use ; Humans ; Huntington Disease/drug therapy ; Inflammation ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Oxidative Stress ; Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.}, }
@article {pmid31233766, year = {2019}, author = {Volonté, C and Apolloni, S and Sabatelli, M}, title = {Histamine beyond its effects on allergy: Potential therapeutic benefits for the treatment of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Pharmacology &amp; therapeutics}, volume = {202}, number = {}, pages = {120-131}, doi = {10.1016/j.pharmthera.2019.06.006}, pmid = {31233766}, issn = {1879-016X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Histamine/*pharmacology/*therapeutic use ; Humans ; Hypersensitivity/*drug therapy ; Immunologic Factors/pharmacology/therapeutic use ; Motor Neurons/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {ALS currently remains a challenge despite many efforts in performing successful clinical trials and formulating therapeutic solutions. By learning from current failures and striving for success, scientists and clinicians are checking every possibility to search for missing hints and efficacious treatments. Because the disease is very complex and heterogeneous and, moreover, targeting not only motor neurons but also several different cell types including muscle, glial, and immune cells, the right answer to ALS is conceivably a multidrug strategy or the use of broad-spectrum molecules. The aim of the present work is to gather evidence about novel perspectives on ALS pathogenesis and to present recent and innovative paradigms for therapy. In particular, we describe how an old molecule possessing immunomodulatory and neuroprotective functions beyond its recognized effects on allergy, histamine, might have a renewed and far-reaching momentum in ALS.}, }
@article {pmid31233613, year = {2019}, author = {Kiernan, MC and Ziemann, U and Eisen, A}, title = {Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period.}, journal = {Muscle &amp; nerve}, volume = {60}, number = {3}, pages = {232-235}, doi = {10.1002/mus.26617}, pmid = {31233613}, issn = {1097-4598}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Animals ; Brain/*growth &amp; development/physiopathology ; Humans ; Infant, Newborn ; Motor Activity/physiology ; Neural Inhibition/*physiology ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset disease but with an increasingly recognized preclinical prodrome. A wide spectrum of investigative approaches has identified loss of inhibitory function at the heart of ALS. In developing an explanation for the onset of ALS, it remains a consideration that ALS has its origins in neonatal derangement of the γ-aminobutyric acid (GABA)-ergic system, with delayed conversion from excitatory to mature inhibitory GABA and impaired excitation/inhibition balance. If this is so, the resulting chronic excitotoxicity could marginalize cortical network functioning very early in life, laying the path for neurodegeneration. The possibility that adult-onset neurodegenerative conditions might have their roots in early developmental derangements is worthy of consideration, particularly in relation to current models of disease pathogenesis. Unraveling the very early molecular events will be crucial in developing a better understanding of ALS and other adult neurodegenerative disorders. Muscle Nerve, 2019.}, }
@article {pmid31231190, year = {2019}, author = {Chang, X and Wang, J and Jiang, H and Shi, L and Xie, J}, title = {Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {141}, pmid = {31231190}, issn = {1662-5099}, abstract = {Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) are chronic, progressive, and age-associated neurological disorders characterized by neuronal deterioration in specific brain regions. Although the specific pathological mechanisms underlying these disorders have remained elusive, ion channel dysfunction has become increasingly accepted as a potential mechanism for neurodegenerative diseases. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by the HCN1-4 gene family and conduct the hyperpolarization-activated current (I h). These channels play important roles in modulating cellular excitability, rhythmic activity, dendritic integration, and synaptic transmission. In the present review, we first provide a comprehensive picture of the role of HCN channels in PD by summarizing their role in the regulation of neuronal activity in PD-related brain regions. Dysfunction of I h may participate in 1-methyl-4-phenylpyridinium (MPP[+])-induced toxicity and represent a pathogenic mechanism in PD. Given current reports of the critical role of HCN channels in neuroinflammation and depression, we also discussed the putative contribution of HCN channels in inflammatory processes and non-motor symptoms in PD. In the second section, we summarize how HCN channels regulate the formation of β-amyloid peptide in AD and the role of these channels in learning and memory. Finally, we briefly discuss the effects of HCN channels in ALS and SMA based on existing discoveries.}, }
@article {pmid31230725, year = {2019}, author = {Spencer, PS and Lagrange, E and Camu, W}, title = {ALS and environment: Clues from spatial clustering?.}, journal = {Revue neurologique}, volume = {175}, number = {10}, pages = {652-663}, doi = {10.1016/j.neurol.2019.04.007}, pmid = {31230725}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Cluster Analysis ; Demography ; Environment ; Environmental Illness/chemically induced/epidemiology ; Environmental Pollutants/toxicity ; Humans ; Neurotoxins/toxicity ; Risk Factors ; }, abstract = {A role for environmental factors in the etiology of amyotrophic lateral sclerocis (ALS) has been suspected for many years. A large body of work has implicated common exposures, conjugal cases, at-risk activities, heavy metals, organic solvents, and electric shocks, among others. One of the most demonstrative relationships between ALS and the environment is spatial clustering. We reviewed the most important and recent spatial clusters in a given area, whatever the geographical size, with either substantial epidemiological approaches or with highly significant associations, and with precise hypotheses. We present a broad, albeit incomplete overview of investigations in different areas, including examples of the difficulties and contradictions of some approaches. Most of the time, the implication of neurotoxins is suspected and, although not always strictly identified, some candidates are emerging: cycasin, MAM, L-BMAA, hydrazine, for example. One other important point is the possibility of interaction among risk/causal factors that increase the complexity of investigation. Additionally, with the exception of Western Pacific ALS, studies of spatial clustering are lacking a major methodological approach, namely a large cohort analysis extended over a long period of time, and probably for decades. Nevertheless, any spatial cluster needs to be identified, described and studied as deeply as possible to illuminate knowledge of the origin of this devastating disorder and to promote primary or secondary disease prevention.}, }
@article {pmid31229686, year = {2019}, author = {Rodriguez, CM and Todd, PK}, title = {New pathologic mechanisms in nucleotide repeat expansion disorders.}, journal = {Neurobiology of disease}, volume = {130}, number = {}, pages = {104515}, pmid = {31229686}, issn = {1095-953X}, support = {I01 BX003231/BX/BLRD VA/United States ; I21 BX001841/BX/BLRD VA/United States ; R01 NS086810/NS/NINDS NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; }, mesh = {Brain/*pathology ; *DNA Repeat Expansion ; Humans ; *Microsatellite Repeats ; Neurodegenerative Diseases/genetics/*pathology ; }, abstract = {Tandem microsatellite repeats are common throughout the human genome and intrinsically unstable, exhibiting expansions and contractions both somatically and across generations. Instability in a small subset of these repeats are currently linked to human disease, although recent findings suggest more disease-causing repeats await discovery. These nucleotide repeat expansion disorders (NREDs) primarily affect the nervous system and commonly lead to neurodegeneration through toxic protein gain-of-function, protein loss-of-function, and toxic RNA gain-of-function mechanisms. However, the lines between these categories have blurred with recent findings of unconventional Repeat Associated Non-AUG (RAN) translation from putatively non-coding regions of the genome. Here we review two emerging topics in NREDs: 1) The mechanisms by which RAN translation occurs and its role in disease pathogenesis and 2) How nucleotide repeats as RNA and translated proteins influence liquid-liquid phase separation, membraneless organelle dynamics, and nucleocytoplasmic transport. We examine these topics with a particular eye on two repeats: the CGG repeat expansion responsible for Fragile X syndrome and Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and the intronic GGGGCC repeat expansion in C9orf72, the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Our thesis is that these emerging disease mechanisms can inform a broader understanding of the native roles of microsatellites in cellular function and that aberrations in these native processes provide clues to novel therapeutic strategies for these currently untreatable disorders.}, }
@article {pmid31229177, year = {2019}, author = {Cortés, A and Casadó-Anguera, V and Moreno, E and Casadó, V}, title = {The heterotetrameric structure of the adenosine A1-dopamine D1 receptor complex: Pharmacological implication for restless legs syndrome.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {84}, number = {}, pages = {37-78}, doi = {10.1016/bs.apha.2019.01.001}, pmid = {31229177}, issn = {1557-8925}, mesh = {Adenosine/metabolism ; Animals ; Dopamine/metabolism ; Humans ; *Protein Multimerization ; Receptor, Adenosine A1/*chemistry/metabolism ; Receptors, Dopamine/*chemistry/metabolism ; Restless Legs Syndrome/*drug therapy ; }, abstract = {Dopaminergic and purinergic signaling play a pivotal role in neurological diseases associated with motor symptoms, including Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS), spinal cord injury (SCI), and ataxias. Extracellular dopamine and adenosine exert their functions interacting with specific dopamine (DR) or adenosine (AR) receptors, respectively, expressed on the surface of target cells. These receptors are members of the family A of G protein-coupled receptors (GPCRs), which is the largest protein superfamily in mammalian genomes. GPCRs are target of about 40% of all current marketed drugs, highlighting their importance in clinical medicine. The striatum receives the densest dopamine innervations and contains the highest density of dopamine receptors. The modulatory role of adenosine on dopaminergic transmission depends largely on the existence of antagonistic interactions mediated by specific subtypes of DRs and ARs, the so-called A2AR-D2R and A1R-D1R interactions. Due to the dopamine/adenosine antagonism in the CNS, it was proposed that ARs and DRs could form heteromers in the neuronal cell surface. Therefore, adenosine can affect dopaminergic signaling through receptor-receptor interactions and by modulations in their shared intracellular pathways in the striatum and spinal cord. In this work we describe the allosteric modulations between GPCR protomers, focusing in those of adenosine and dopamine within the A1R-D1R heteromeric complex, which is involved in RLS. We also propose that the knowledge about the intricate allosteric interactions within the A1R-D1R heterotetramer, may facilitate the treatment of motor alterations, not only when the dopamine pathway is hyperactivated (RLS, chorea, etc.) but also when motor function is decreased (SCI, aging, PD, etc.).}, }
@article {pmid31229078, year = {2019}, author = {Jiménez-Carvelo, AM and González-Casado, A and Bagur-González, MG and Cuadros-Rodríguez, L}, title = {Alternative data mining/machine learning methods for the analytical evaluation of food quality and authenticity - A review.}, journal = {Food research international (Ottawa, Ont.)}, volume = {122}, number = {}, pages = {25-39}, doi = {10.1016/j.foodres.2019.03.063}, pmid = {31229078}, issn = {1873-7145}, mesh = {Data Mining/*methods ; Decision Trees ; Food Analysis/*methods ; *Food Quality ; *Machine Learning ; Statistics as Topic ; }, abstract = {In recent years, the variety and volume of data acquired by modern analytical instruments in order to conduct a better authentication of food has dramatically increased. Several pattern recognition tools have been developed to deal with the large volume and complexity of available trial data. The most widely used methods are principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), soft independent modelling by class analogy (SIMCA), k-nearest neighbours (kNN), parallel factor analysis (PARAFAC), and multivariate curve resolution-alternating least squares (MCR-ALS). Nevertheless, there are alternative data treatment methods, such as support vector machine (SVM), classification and regression tree (CART) and random forest (RF), that show a great potential and more advantages compared to conventional ones. In this paper, we explain the background of these methods and review and discuss the reported studies in which these three methods have been applied in the area of food quality and authenticity. In addition, we clarify the technical terminology used in this particular area of research.}, }
@article {pmid31225510, year = {2019}, author = {Meng, T and Lin, S and Zhuang, H and Huang, H and He, Z and Hu, Y and Gong, Q and Feng, D}, title = {Recent progress in the role of autophagy in neurological diseases.}, journal = {Cell stress}, volume = {3}, number = {5}, pages = {141-161}, pmid = {31225510}, issn = {2523-0204}, abstract = {Autophagy (here refers to macroautophagy) is a catabolic pathway by which large protein aggregates and damaged organelles are first sequestered into a double-membraned structure called autophago-some and then delivered to lysosome for destruction. Recently, tremen-dous progress has been made to elucidate the molecular mechanism and functions of this essential cellular metabolic process. In addition to being either a rubbish clearing system or a cellular surviving program in response to different stresses, autophagy plays important roles in a large number of pathophysiological conditions, such as cancer, diabetes, and especially neurodegenerative disorders. Here we review recent progress in the role of autophagy in neurological diseases and discuss how dysregulation of autophagy initiation, autophagosome formation, maturation, and/or au-tophagosome-lysosomal fusion step contributes to the pathogenesis of these disorders in the nervous system.}, }
@article {pmid31220841, year = {2019}, author = {Sakurai, Y}, title = {Kanji (Morphogram) and Kana (Phonogram) Problem in Japanese Alexia and Agraphia.}, journal = {Frontiers of neurology and neuroscience}, volume = {44}, number = {}, pages = {53-63}, doi = {10.1159/000494952}, pmid = {31220841}, issn = {1662-2804}, mesh = {Agraphia/*diagnosis/history ; Brain Mapping/*history ; Diagnosis, Differential ; Dyslexia/*diagnosis/history ; History, 20th Century ; Humans ; Japan ; Occipital Lobe/physiopathology ; Reading ; Writing ; }, abstract = {The kanji and kana (or kanji vs. kana) problem in the Japanese language denotes the dissociation between kanji (morphograms) and kana (phonograms) in reading/comprehension and writing. Since paragraphia of kana in a patient with amyotrophic lateral sclerosis was first reported in 1893, kanji-kana dissociation has been the central topic in Japanese aphasiology. Recent advancements in lesion-to-symptom analyses and functional imaging studies have identified some areas whose damage causes dissociative disturbances of reading or writing between kanji and kana. That is, (1) angular alexia with agraphia causes kanji agraphia; alexia of kana with an angular gyrus lesion is the result of a damage to the middle occipital gyrus; (2) alexia with agraphia for kanji is caused by a posterior inferior temporal cortex (mid-fusiform/inferior temporal gyri; visual word form area) lesion, whereas pure agraphia for kanji is caused by a posterior middle temporal gyrus lesion; and (3) pure alexia, particularly for kanji, results from a mid-fusiform gyrus lesion (Brodmann's Area [BA] 37), whereas pure alexia for kana results from a posterior fusiform/inferior occipital gyri lesion (BA 18/19).}, }
@article {pmid31217264, year = {2020}, author = {Weiss, N and Zamponi, GW}, title = {Genetic T-type calcium channelopathies.}, journal = {Journal of medical genetics}, volume = {57}, number = {1}, pages = {1-10}, pmid = {31217264}, issn = {1468-6244}, mesh = {Animals ; Calcium Channels/*genetics ; Channelopathies/genetics/*metabolism ; Humans ; Mutation ; }, abstract = {T-type channels are low-voltage-activated calcium channels that contribute to a variety of cellular and physiological functions, including neuronal excitability, hormone and neurotransmitter release as well as developmental aspects. Several human conditions including epilepsy, autism spectrum disorders, schizophrenia, motor neuron disorders and aldosteronism have been traced to variations in genes encoding T-type channels. In this short review, we present the genetics of T-type channels with an emphasis on structure-function relationships and associated channelopathies.}, }
@article {pmid31213978, year = {2019}, author = {Qu, L and Pan, C and He, SM and Lang, B and Gao, GD and Wang, XL and Wang, Y}, title = {The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {121}, pmid = {31213978}, issn = {1662-5099}, abstract = {The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), intellectual disability, epilepsy, drug addiction, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility.}, }
@article {pmid31210837, year = {2019}, author = {Cenini, G and Lloret, A and Cascella, R}, title = {Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {2105607}, pmid = {31210837}, issn = {1942-0994}, mesh = {Alzheimer Disease/*metabolism/pathology ; Antioxidants/*metabolism ; Humans ; Mitochondria/*metabolism/pathology ; Mitochondrial Diseases/*metabolism/pathology ; *Oxidative Stress ; Parkinson Disease/*metabolism/pathology ; }, abstract = {Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, particularly in organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidant defenses, and high content of polyunsaturated fats very prone to be oxidized. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. Here, we review the role of mitochondrial oxidative stress in the aging process, with a specific focus on neurodegenerative diseases. Understanding the molecular mechanisms involving mitochondria and oxidative stress in the aging and neurodegeneration may help to identify new strategies for improving the health and extending lifespan.}, }
@article {pmid31208099, year = {2019}, author = {Kiriyama, Y and Nochi, H}, title = {The Biosynthesis, Signaling, and Neurological Functions of Bile Acids.}, journal = {Biomolecules}, volume = {9}, number = {6}, pages = {}, pmid = {31208099}, issn = {2218-273X}, mesh = {Animals ; Bile Acids and Salts/*biosynthesis/*metabolism ; Brain/cytology/metabolism ; Humans ; *Neurology ; *Signal Transduction ; }, abstract = {Bile acids (BA) are amphipathic steroid acids synthesized from cholesterol in the liver. They act as detergents to expedite the digestion and absorption of dietary lipids and lipophilic vitamins. BA are also considered to be signaling molecules, being ligands of nuclear and cell-surface receptors, including farnesoid X receptor and Takeda G-protein receptor 5. Moreover, BA also activate ion channels, including the bile acid-sensitive ion channel and epithelial Na[+] channel. BA regulate glucose and lipid metabolism by activating these receptors in peripheral tissues, such as the liver and brown and white adipose tissue. Recently, 20 different BA have been identified in the central nervous system. Furthermore, BA affect the function of neurotransmitter receptors, such as the muscarinic acetylcholine receptor and γ-aminobutyric acid receptor. BA are also known to be protective against neurodegeneration. Here, we review recent findings regarding the biosynthesis, signaling, and neurological functions of BA.}, }
@article {pmid31207949, year = {2019}, author = {Chang, WD}, title = {Electrooculograms for Human-Computer Interaction: A Review.}, journal = {Sensors (Basel, Switzerland)}, volume = {19}, number = {12}, pages = {}, pmid = {31207949}, issn = {1424-8220}, support = {2017A005-1//Tongmyong University Research Grants 2017/ ; NRF-2017R1D1A1A09000774//Basic Science Research Program through the National Research Foundation of Korea/ ; }, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; *Communication Aids for Disabled ; Electrooculography/*trends ; Eye Movements/*physiology ; Humans ; Pattern Recognition, Automated/*methods ; Signal Processing, Computer-Assisted ; User-Computer Interface ; }, abstract = {Eye movements generate electric signals, which a user can employ to control his/her environment and communicate with others. This paper presents a review of previous studies on such electric signals, that is, electrooculograms (EOGs), from the perspective of human-computer interaction (HCI). EOGs represent one of the easiest means to estimate eye movements by using a low-cost device, and have been often considered and utilized for HCI applications, such as to facilitate typing on a virtual keyboard, moving a mouse, or controlling a wheelchair. The objective of this study is to summarize the experimental procedures of previous studies and provide a guide for researchers interested in this field. In this work the basic characteristics of EOGs, associated measurements, and signal processing and pattern recognition algorithms are briefly reviewed, and various applications reported in the existing literature are listed. It is expected that EOGs will be a useful source of communication in virtual reality environments, and can act as a valuable communication tools for people with amyotrophic lateral sclerosis.}, }
@article {pmid31206166, year = {2019}, author = {Gaweł, M}, title = {Electrodiagnostics: MUNE and MUNIX as methods of estimating the number of motor units - biomarkers in lower motor neurone disease.}, journal = {Neurologia i neurochirurgia polska}, volume = {53}, number = {4}, pages = {251-257}, doi = {10.5603/PJNNS.a2019.0026}, pmid = {31206166}, issn = {0028-3843}, mesh = {Action Potentials ; *Amyotrophic Lateral Sclerosis ; Electromyography ; Humans ; *Motor Neuron Disease ; Muscle, Skeletal ; }, abstract = {Routine quantitative electromyography is used for the assessment of the presence of lower motor neurone involvement and its consequences, including primary denervation and compensatory reinnervation of muscle fibres. However, it is not useful for the assessment of the motor unit number reserve. The need for a valid biomarker to evaluate lower motor neurone disease progression in such diseases as amyotrophic lateral sclerosis, and for use in clinical trials, has led to a number of studies of the methods that allow assessment of the number of motor units. In this review, motor unit number estimation (MUNE) methods with incremental stimulation and the recently developed motor unit number index (MUNIX) method, along with their technical and clinical aspects, are presented as methods which reflect motor unit loss in neurogenic processes. These electrodiagnostic tests may allow a valuable assessment of disease progression and the efficacy of new therapeutic methods in clinical trials in diseases with lower motor neurone degeneration.}, }
@article {pmid31205106, year = {2019}, author = {Chen, XQ and Qiu, K and Liu, H and He, Q and Bai, JH and Lu, W}, title = {Application and prospects of butylphthalide for the treatment of neurologic diseases.}, journal = {Chinese medical journal}, volume = {132}, number = {12}, pages = {1467-1477}, pmid = {31205106}, issn = {2542-5641}, mesh = {Animals ; Benzofurans/*therapeutic use ; Humans ; Nervous System Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {OBJECTIVE: The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized.<br><br>DATA SOURCES: Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including "3-N-butylphthalide," "microcirculation," "mitochondria," "ischemic stroke," "Alzheimer disease," "vascular dementia," "Parkinson disease," "brain edema," "CO poisoning," "traumatic central nervous system injury," "autoimmune disease," "amyotrophic lateral sclerosis," "seizures," "diabetes," "diabetic cataract," and "atherosclerosis."<br><br>STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files.<br><br>RESULTS: NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects.<br><br>CONCLUSIONS: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study.}, }
@article {pmid31200447, year = {2019}, author = {Pellegrini, C and Fornai, M and Antonioli, L and Blandizzi, C and Calderone, V}, title = {Phytochemicals as Novel Therapeutic Strategies for NLRP3 Inflammasome-Related Neurological, Metabolic, and Inflammatory Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {12}, pages = {}, pmid = {31200447}, issn = {1422-0067}, support = {PRA_2018_31//Universit&#xe0; di Pisa/ ; }, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Central Nervous System Diseases/*drug therapy ; Humans ; Inflammasomes/antagonists &amp; inhibitors/*metabolism ; Metabolic Diseases/*drug therapy ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists &amp; inhibitors/*metabolism ; Phytochemicals/*pharmacology/therapeutic use ; }, abstract = {Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in the pathophysiology of several neurological and psychiatric diseases (i.e., Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and major depressive disorder), metabolic disorders (i.e., obesity and type 2 diabetes) and chronic inflammatory diseases (i.e., intestinal inflammation, arthritis, and gout). Intensive research efforts are being made to achieve an integrated view about the pathophysiological role of NLRP3 inflammasome pathways in such disorders. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome by phytochemicals could represent a promising molecular target for the therapeutic management of neurological, psychiatric, metabolic, and inflammatory diseases. The present review article has been intended to provide an integrated and critical overview of the available clinical and experimental evidence about the role of NLRP3 inflammasome in the pathophysiology of neurological, psychiatric, metabolic, and inflammatory diseases, including PD, AD, MS, depression, obesity, type 2 diabetes, arthritis, and intestinal inflammation. Special attention has been paid to highlight and critically discuss current scientific evidence on the effects of phytochemicals on NLRP3 inflammasome pathways and their potential in counteracting central neuroinflammation, metabolic alterations, and immune/inflammatory responses in such diseases.}, }
@article {pmid31197405, year = {2019}, author = {Rivera, S and García-González, L and Khrestchatisky, M and Baranger, K}, title = {Metalloproteinases and their tissue inhibitors in Alzheimer's disease and other neurodegenerative disorders.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {76}, number = {16}, pages = {3167-3191}, pmid = {31197405}, issn = {1420-9071}, mesh = {ADAM Proteins/metabolism ; Alzheimer Disease/metabolism/*pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Humans ; Huntington Disease/metabolism/pathology ; Matrix Metalloproteinases/*metabolism ; Neurodegenerative Diseases/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; Tissue Inhibitor of Metalloproteinases/*metabolism ; }, abstract = {As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood-brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.}, }
@article {pmid31195846, year = {2019}, author = {Baldacci, F and Lista, S and Palermo, G and Giorgi, FS and Vergallo, A and Hampel, H}, title = {The neuroinflammatory biomarker YKL-40 for neurodegenerative diseases: advances in development.}, journal = {Expert review of proteomics}, volume = {16}, number = {7}, pages = {593-600}, doi = {10.1080/14789450.2019.1628643}, pmid = {31195846}, issn = {1744-8387}, mesh = {Alzheimer Disease/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Chitinase-3-Like Protein 1/*cerebrospinal fluid ; Humans ; Neurodegenerative Diseases/*cerebrospinal fluid/physiopathology ; Precision Medicine/methods ; }, abstract = {Introduction: Neuroinflammation is a common pathophysiological mechanism in neurodegenerative diseases (ND). Cerebrospinal fluid (CSF) YKL-40 has recently been candidated as a neuroinflammatory biomarker of ND. Areas covered: We provide an update on the role of CSF YKL-40 as a pathophysiological biomarker of ND. YKL-40 may discriminate Alzheimer's disease (AD) from controls and may predict the progression from the early preclinical to the late dementia stage. In genetic AD, YKL-40 increases decades before the clinical onset. It does not seem a specific biomarker of a certain ND although sporadic Creutzfeldt-Jacob disease shows the highest YKL-40 concentrations. YKL-40 may discriminate between amyotrophic lateral sclerosis (ALS) and ALS-mimics. YKL-40 is potentially associated with the rate of ALS progression. YKL-40 correlates with biomarkers of neuronal injury, large axonal damage and synaptic disruption in various ND. It is not associated with the presence of the APOE-ε4 allele whereas possibly linked to aging, female sex, Hispanic ethnicity and some genetic variants of the chitinase-3-like 1 locus. Expert opinion: There is growing evidence expanding the relevance of CSF YKL-40 as a pathophysiological biomarker for ND. Patients showing high YKL-40 levels might benefit from targeted clinical trials that use compounds acting against neuroinflammatory mechanisms, independently of the initial clinical diagnosis of ND.}, }
@article {pmid31195838, year = {2020}, author = {Pena, SA and Iyengar, R and Eshraghi, RS and Bencie, N and Mittal, J and Aljohani, A and Mittal, R and Eshraghi, AA}, title = {Gene therapy for neurological disorders: challenges and recent advancements.}, journal = {Journal of drug targeting}, volume = {28}, number = {2}, pages = {111-128}, doi = {10.1080/1061186X.2019.1630415}, pmid = {31195838}, issn = {1029-2330}, mesh = {Animals ; CRISPR-Cas Systems/genetics ; *Gene Transfer Techniques ; Genetic Therapy/*methods ; Genetic Vectors ; Humans ; Nanoparticles ; Nervous System Diseases/genetics/physiopathology/*therapy ; Polymers/chemistry ; }, abstract = {Major advancements in targeted gene therapy have opened up avenues for the treatment of major neurological disorders through a range of versatile modalities varying from expression of exogenous to suppression of endogenous genes. Recent technological innovations for improved gene sequence delivery have focussed on highly specific viral vector designs, plasmid transfection, nanoparticles, polymer-mediated gene delivery, engineered microRNA and in vivo clustered regulatory interspaced short palindromic repeats (CRISPR)-based therapeutics. These advanced techniques have profound applications in treating highly prevalent neurological diseases and neurodevelopmental disorders including Parkinson's disease, Alzheimer's disease and autism spectrum disorder, as well as rarer diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, lysosomal storage diseases, X-linked adrenoleukodystrophy and oncological diseases. In this article, we present an overview of the latest advances in targeted gene delivery and discuss the challenges and future direction of gene therapy in the treatment of neurological disorders.}, }
@article {pmid31195629, year = {2019}, author = {Moreno-Martinez, L and Calvo, AC and Muñoz, MJ and Osta, R}, title = {Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis?.}, journal = {International journal of molecular sciences}, volume = {20}, number = {11}, pages = {}, pmid = {31195629}, issn = {1422-0067}, support = {PI17/00949//Instituto de Salud Carlos III/ ; PI17/00949//European Regional Development Fund/ ; 612//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; A19_17R//Consolidated Groups from Gobierno de Arag&#xf3;n/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/immunology/therapy ; Animals ; Biomarkers/*blood ; Body Fluids/metabolism ; Cytokines/*blood ; Humans ; Immune System/metabolism ; Inflammation/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. The lack of any specific biomarker that can help in the diagnosis or prognosis of ALS has made the identification of biomarkers an urgent challenge. Multiple panels have shown alterations in levels of numerous cytokines in ALS, supporting the contribution of neuroinflammation to the progressive motor neuron loss. However, none of them is fully sensitive and specific enough to become a universal biomarker for ALS. This review gathers the numerous circulating cytokines that have been found dysregulated in both ALS animal models and patients. Particularly, it highlights the opposing results found in the literature to date, and points out another potential application of inflammatory cytokines as therapeutic targets.}, }
@article {pmid31189354, year = {2019}, author = {Goutman, SA and Savelieff, MG and Sakowski, SA and Feldman, EL}, title = {Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials.}, journal = {Expert opinion on investigational drugs}, volume = {28}, number = {6}, pages = {525-543}, pmid = {31189354}, issn = {1744-7658}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Clinical Trials as Topic/methods ; Humans ; Motor Neurons ; Research Design ; Stem Cell Transplantation/*methods ; Stem Cells/*cytology ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of cortical, brainstem, and spinal motor neurons; it causes progressive muscle weakness and atrophy, respiratory failure, and death. No currently available treatment either stops or reverses this disease. Therapeutics to slow, stop, and reverse ALS are needed. Stem cells may be a viable solution to sustain and nurture diseased motor neurons. Several early-stage clinical trials have been launched to assess the potential of stem cells for ALS treatment. Areas covered: Expert opinion:<br><br>AREAS COVERED: This review covers the key advances from early phase clinical trials of stem cell therapy for ALS and identifies promising avenues and key challenges.<br><br>EXPERT OPINION: Clinical trials in humans are still in the nascent stages of development. It will be critical to ensure that powered, well-controlled trials are conducted, that optimal treatment windows are identified, and that the ideal cell type, cell dose, and delivery site and method are determined. Several trials have used more invasive procedures, and ethical concerns of sham procedures on patients in the control arm and on their safety should be considered.}, }
@article {pmid31187709, year = {2019}, author = {Yadav, K and Yadav, A and Vashistha, P and Pandey, VP and Dwivedi, UN}, title = {Protein Misfolding Diseases and Therapeutic Approaches.}, journal = {Current protein &amp; peptide science}, volume = {20}, number = {12}, pages = {1226-1245}, doi = {10.2174/1389203720666190610092840}, pmid = {31187709}, issn = {1875-5550}, mesh = {Acyl-CoA Dehydrogenases/metabolism ; Animals ; Endoplasmic Reticulum/metabolism ; High-Throughput Screening Assays/methods ; Humans ; Mitochondria/metabolism ; Molecular Chaperones/*chemistry/pharmacology ; Protein Conformation ; Protein Folding/drug effects ; Proteostasis Deficiencies/*drug therapy ; Signal Transduction ; Small Molecule Libraries/chemistry ; Structure-Activity Relationship ; }, abstract = {Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.}, }
@article {pmid31185581, year = {2019}, author = {van den Bos, MAJ and Geevasinga, N and Higashihara, M and Menon, P and Vucic, S}, title = {Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques.}, journal = {International journal of molecular sciences}, volume = {20}, number = {11}, pages = {}, pmid = {31185581}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/etiology/physiopathology ; *Cortical Excitability ; Electroencephalography/methods ; Humans ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis.}, }
@article {pmid31185140, year = {2019}, author = {Bhat, A and Mahalakshmi, AM and Ray, B and Tuladhar, S and Hediyal, TA and Manthiannem, E and Padamati, J and Chandra, R and Chidambaram, SB and Sakharkar, MK}, title = {Benefits of curcumin in brain disorders.}, journal = {BioFactors (Oxford, England)}, volume = {45}, number = {5}, pages = {666-689}, doi = {10.1002/biof.1533}, pmid = {31185140}, issn = {1872-8081}, mesh = {Alzheimer Disease/*drug therapy/metabolism/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Animals ; Anxiety/drug therapy/metabolism/physiopathology ; Autistic Disorder/drug therapy/metabolism/physiopathology ; Biological Availability ; Curcuma/chemistry ; Curcumin/isolation &amp; purification/*pharmacology ; Dementia/*drug therapy/metabolism/physiopathology ; Depression/drug therapy/metabolism/physiopathology ; Drug Delivery Systems/*methods ; Glioma/drug therapy/metabolism/physiopathology ; Humans ; Huntington Disease/drug therapy/metabolism/physiopathology ; Multiple Sclerosis/drug therapy/metabolism/physiopathology ; Muscular Atrophy, Spinal/drug therapy/metabolism/physiopathology ; Neuroprotective Agents/isolation &amp; purification/*pharmacology ; Parkinson Disease/*drug therapy/metabolism/physiopathology ; Patents as Topic ; Prion Diseases/drug therapy/metabolism/physiopathology ; Stroke/drug therapy/metabolism/physiopathology ; }, abstract = {Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.}, }
@article {pmid31184206, year = {2019}, author = {Sanberg, PR and Ehrhart, J}, title = {A Hallmark Clinical Study of Cord Blood Therapy in Adults with Ischemic Stroke.}, journal = {Cell transplantation}, volume = {28}, number = {9-10}, pages = {1329-1332}, pmid = {31184206}, issn = {1555-3892}, mesh = {Adult ; Allografts ; *Brain Ischemia/metabolism/pathology/therapy ; *Cord Blood Stem Cell Transplantation ; Humans ; Neurodegenerative Diseases/metabolism/pathology/therapy ; *Stroke/metabolism/pathology/therapy ; }, abstract = {The therapeutic application of human umbilical cord blood cells has been an area of great interest for at least the last 25 years. Currently, cord blood cells are approved for reconstitution of the bone marrow following myeloablation in both young and old patients with myeloid malignancies and other blood cancers. Translational studies investigating alternative uses of cord blood have also shown that these cells not only stimulate neurogenesis in the aged brain but are also potentially therapeutic in the treatment of adult neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer's disease, ischemic stroke, traumatic brain injury, and Parkinson's disease. Recent advances in the clinical application of cord blood cells by Dr. Joanne Kurtzberg and colleagues have found that non-HLA matched allogeneic banked cord blood units in immunocompetent patients with ischemic stroke are safe and well tolerated. Although the exact mechanism(s) of action that provide the beneficial effects observed from a cord blood cell-based therapy are currently unknown, several studies using models of neurodegenerative disease have shown these cells are immune-modulatory and anti-inflammatory. Thus, any future clinical studies investigating the efficacy of this cord blood cell therapeutic would strongly benefit from the inclusion of methodologies to determine changes in both markers of inflammation and the response of immune tissues, such as the spleen, in subjects receiving cell infusion.}, }
@article {pmid31183763, year = {2019}, author = {Peng, W and Minakaki, G and Nguyen, M and Krainc, D}, title = {Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {16}, number = {3}, pages = {611-634}, pmid = {31183763}, issn = {1878-7479}, support = {R01 NS076054/NS/NINDS NIH HHS/United States ; R37 NS096241/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/*metabolism/physiology ; Amyotrophic Lateral Sclerosis/metabolism ; Brain/*metabolism/physiology ; Frontotemporal Dementia/metabolism ; Humans ; Huntington Disease/metabolism ; Lysosomes/*physiology ; Mitochondria/metabolism ; Neurodegenerative Diseases/*metabolism/prevention &amp; control ; Parkinson Disease/metabolism ; }, abstract = {Lysosomes are acidic, membrane-bound organelles that serve as the primary catabolic compartment of the cell. They are crucial to a variety of cellular processes from nutrient storage to autophagy. Given the diversity of lysosomal functions, it is unsurprising that lysosomes are also emerging as important players in aging. Lysosomal dysfunction is implicated in several aging-related neurodegenerative diseases including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington's. Although the precise role of lysosomes in the aging brain is not well-elucidated, some insight into their function has been gained from our understanding of the pathophysiology of age-dependent neurodegenerative diseases. Therapeutic strategies targeting lysosomes and autophagic machinery have already been tested in several of these diseases with promising results, suggesting that improving lysosomal function could be similarly beneficial in preserving function in the aging brain.}, }
@article {pmid31182245, year = {2019}, author = {McGurk, L and Rifai, OM and Bonini, NM}, title = {Poly(ADP-Ribosylation) in Age-Related Neurological Disease.}, journal = {Trends in genetics : TIG}, volume = {35}, number = {8}, pages = {601-613}, pmid = {31182245}, issn = {0168-9525}, support = {R35 NS097275/NS/NINDS NIH HHS/United States ; }, mesh = {ADP-Ribosylation/*drug effects ; Aging ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Brain/pathology ; Cells, Cultured ; Drosophila ; Frontotemporal Lobar Degeneration/*genetics/pathology ; Humans ; Neurodegenerative Diseases/*genetics/pathology ; Neurons/pathology ; Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/*pharmacology ; Protein Aggregation, Pathological ; Protein Processing, Post-Translational ; }, abstract = {A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment, regulatory pathways that modulate these aggregation-prone proteins must be defined. One such pathway is post-translational modification by the addition of poly(ADP-ribose) (PAR), which promotes protein recruitment and localization in several cellular contexts. Mounting evidence implicates PAR in seeding the abnormal localization and accumulation of proteins that are causative of neurodegenerative disease. Inhibitors of PAR polymerase (PARP) activity have been developed as cancer therapeutics, raising the possibility that they could be used to treat neurodegenerative disease. We focus on pathways regulated by PAR in neurodegenerative disease, with emphasis on amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).}, }
@article {pmid31171646, year = {2019}, author = {Andrews, JA and Bruijn, LI and Shefner, JM}, title = {ALS drug development guidances and trial guidelines: Consensus and opportunities for alignment.}, journal = {Neurology}, volume = {93}, number = {2}, pages = {66-71}, pmid = {31171646}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; *Clinical Trials as Topic ; *Drug Development ; *Guidelines as Topic ; Humans ; *Stakeholder Participation ; United States ; United States Food and Drug Administration ; }, abstract = {The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community's views on key topics. In parallel to this effort, there was an independent effort to revise and update the ALS Clinical Trial Guidelines. We discuss the areas of agreement of these 3 documents and the areas that provide opportunities to improve the efficiency of drug development in ALS. It is likely that further research into biomarkers, efficacy endpoints, and predictive algorithms will provide greater alignment among community stakeholders and increase clarity on drug development efforts going forward. Continued patient engagement and inclusion of patient experience data in every aspect of the drug development process will further facilitate the approval of new treatments.}, }
@article {pmid31169327, year = {2019}, author = {Nemr, MTM and Yousif, MNM and Barciszewski, J}, title = {Interaction of small molecules with polynucleotide repeats and frameshift site RNA.}, journal = {Archiv der Pharmazie}, volume = {352}, number = {8}, pages = {e1900062}, doi = {10.1002/ardp.201900062}, pmid = {31169327}, issn = {1521-4184}, mesh = {Aptamers, Nucleotide/chemical synthesis/chemistry ; Hormones/analysis ; Pharmaceutical Preparations/analysis ; Polynucleotides/*chemistry ; RNA/*chemistry ; Small Molecule Libraries/*chemistry ; Toxins, Biological/analysis ; }, abstract = {This mini-review describes the interaction between small molecules and RNA, in addition to its application either in treating RNA-associated diseases or detecting target molecules. In the case of RNA-associated disease treatment, the designed small molecules interact with RNA sites, forming adducts and providing successful therapeutic strategies over oligonucleotides. On the other hand, synthetically designed RNA moieties (aptamers) interact with target molecules like toxins, drugs, hormones; these interactions are useful in the detection, quantification or separation of these target moieties.}, }
@article {pmid31165208, year = {2019}, author = {Pulst, SM}, title = {[Antisense therapies for neurological diseases].}, journal = {Der Nervenarzt}, volume = {90}, number = {8}, pages = {781-786}, pmid = {31165208}, issn = {1433-0407}, support = {R01 NS097903/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; U01 NS103883/NS/NINDS NIH HHS/United States ; }, mesh = {Genetic Therapy ; Humans ; Muscular Atrophy, Spinal ; Muscular Dystrophy, Duchenne ; *Neurodegenerative Diseases/therapy ; *Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy, Duchenne muscular dystrophy and transthyretin amyloidosis predict a robust future for ASOs in medicine. Perhaps the most significant advantage of ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of possible complementary oligonucleotide therapeutics. This review article describes the various types of ASOs, their therapeutic use and the current preclinical efforts to develop new ASO treatments.}, }
@article {pmid31164862, year = {2019}, author = {Huai, J and Zhang, Z}, title = {Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {527}, pmid = {31164862}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degenerative disease in adults and has also been proven to be a type of conformational disease associated with protein misfolding and dysfunction. To date, more than 150 distinct genes have been found to be associated with ALS, among which Superoxide Dismutase 1 (SOD1) is the first and the most extensively studied gene. It has been well-established that SOD1 mutants-mediated toxicity is caused by a gain-of-function rather than the loss of the detoxifying activity of SOD1. Compared with the clear autosomal dominant inheritance of SOD1 mutants in ALS, the potential toxic mechanisms of SOD1 mutants in motor neurons remain incompletely understood. A large body of evidence has shown that SOD1 mutants may adopt a complex profile of conformations and interact with a wide range of client proteins. Here, in this review, we summarize the fundamental conformational properties and the gained interaction partners of the soluble forms of the SOD1 mutants which have been published in the past decades. Our goal is to find clues to the possible internal links between structural and functional anomalies of SOD1 mutants, as well as the relationships between their exposed epitopes and interaction partners, in order to help reveal and determine potential diagnostic and therapeutic targets.}, }
@article {pmid31164803, year = {2019}, author = {Barton, SK and Gregory, JM and Chandran, S and Turner, BJ}, title = {Could an Impairment in Local Translation of mRNAs in Glia be Contributing to Pathogenesis in ALS?.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {124}, pmid = {31164803}, issn = {1662-5099}, support = {MR/L023784/1/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; }, abstract = {One of the key pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis is abnormal RNA processing. Studies to date have focussed on defects in RNA stability, splicing, and translation, but this review article will focus on the largely overlooked RNA processing mechanism of RNA trafficking, with particular emphasis on the importance of glia. In the central nervous system (CNS), oligodendrocytes can extend processes to myelinate and metabolically support up to 50 axons and astrocytes can extend processes to cover up to 100,000 synapses, all with differing local functional requirements. Furthermore, many of the proteins required in these processes are large, aggregation-prone proteins which would be difficult to transport in their fully translated, terminally-folded state. This, therefore, highlights a critical requirement in these cells for local control of protein translation, which is achieved through specific trafficking of mRNAs to each process and local translation therein. Given that a large number of RNA-binding proteins have been implicated in ALS, and RNA-binding proteins are essential for trafficking mRNAs from the nucleus to glial processes for local translation, RNA misprocessing in glial cells is a likely source of cellular dysfunction in ALS. To date, neurons have been the focus of ALS research, but an intrinsic deficit in glia, namely astrocytes and oligodendrocytes, could have an additive effect on declining neuronal function in ALS. This review article aims to highlight the key evidence that supports the contention that RNA trafficking deficits in astrocytes and oligodendrocytes may contribute to in ALS.}, }
@article {pmid31161803, year = {2019}, author = {Garcia-Leon, JA and Vitorica, J and Gutierrez, A}, title = {Use of human pluripotent stem cell-derived cells for neurodegenerative disease modeling and drug screening platform.}, journal = {Future medicinal chemistry}, volume = {11}, number = {11}, pages = {1305-1322}, doi = {10.4155/fmc-2018-0520}, pmid = {31161803}, issn = {1756-8927}, mesh = {Animals ; CRISPR-Cas Systems ; Drug Evaluation, Preclinical/*methods ; Gene Editing/methods ; Humans ; Neurodegenerative Diseases/*drug therapy/genetics/pathology ; Neurogenesis/drug effects ; Neurons/*cytology/drug effects/metabolism/pathology ; Pluripotent Stem Cells/*cytology/metabolism/pathology ; }, abstract = {Most neurodegenerative diseases are characterized by a complex and mostly still unresolved pathology. This fact, together with the lack of reliable disease models, has precluded the development of effective therapies counteracting the disease progression. The advent of human pluripotent stem cells has revolutionized the field allowing the generation of disease-relevant neural cell types that can be used for disease modeling, drug screening and, possibly, cell transplantation purposes. In this Review, we discuss the applications of human pluripotent stem cells, the development of efficient protocols for the derivation of the different neural cells and their applicability for robust in vitro disease modeling and drug screening platforms for most common neurodegenerative conditions.}, }
@article {pmid31156371, year = {2019}, author = {Rostalski, H and Leskelä, S and Huber, N and Katisko, K and Cajanus, A and Solje, E and Marttinen, M and Natunen, T and Remes, AM and Hiltunen, M and Haapasalo, A}, title = {Astrocytes and Microglia as Potential Contributors to the Pathogenesis of C9orf72 Repeat Expansion-Associated FTLD and ALS.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {486}, pmid = {31156371}, issn = {1662-4548}, abstract = {Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with a complex, but often overlapping, genetic and pathobiological background and thus they are considered to form a disease spectrum. Although neurons are the principal cells affected in FTLD and ALS, increasing amount of evidence has recently proposed that other central nervous system-resident cells, including microglia and astrocytes, may also play roles in neurodegeneration in these diseases. Therefore, deciphering the mechanisms underlying the disease pathogenesis in different types of brain cells is fundamental in order to understand the etiology of these disorders. The major genetic cause of FTLD and ALS is a hexanucleotide repeat expansion (HRE) in the intronic region of the C9orf72 gene. In neurons, specific pathological hallmarks, including decreased expression of the C9orf72 RNA and proteins and generation of toxic RNA and protein species, and their downstream effects have been linked to C9orf72 HRE-associated FTLD and ALS. In contrast, it is still poorly known to which extent these pathological changes are presented in other brain cells. Here, we summarize the current literature on the potential role of astrocytes and microglia in C9orf72 HRE-linked FTLD and ALS and discuss their possible phenotypic alterations and neurotoxic mechanisms that may contribute to neurodegeneration in these diseases.}, }
@article {pmid31152789, year = {2020}, author = {Hutten, S and Dormann, D}, title = {Nucleocytoplasmic transport defects in neurodegeneration - Cause or consequence?.}, journal = {Seminars in cell &amp; developmental biology}, volume = {99}, number = {}, pages = {151-162}, doi = {10.1016/j.semcdb.2019.05.020}, pmid = {31152789}, issn = {1096-3634}, mesh = {*Active Transport, Cell Nucleus ; Humans ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Defects in nucleocytoplasmic transport have been associated with several neurodegenerative disorders and, in particular, the formation of pathological protein aggregates characteristic for the respective disease. However, whether impaired nucleocytoplasmic transport is a consequence of such aggregates or rather contributes to their formation is still mostly unclear. In this review, we summarize recent findings how both soluble and stationary components of the nucleocytoplasmic transport machinery are altered in neurodegenerative diseases, in particular amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD) and Huntington's disease (HD). We discuss the functional significance of the observed defects for nucleocytoplasmic transport of proteins and mRNAs. Moreover, we highlight interesting parallels observed in physiological ageing and the premature ageing syndrome progeria and propose that they that might provide mechanistic insights also for neurodegenerative processes.}, }
@article {pmid31141951, year = {2019}, author = {Nowicka, N and Juranek, J and Juranek, JK and Wojtkiewicz, J}, title = {Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {20}, number = {11}, pages = {}, pmid = {31141951}, issn = {1422-0067}, support = {OPUS/2017/25/B/NZ4/00435//Narodowym Centrum Nauki/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/therapy ; Animals ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Genetic Predisposition to Disease ; Genetic Therapy ; Humans ; Molecular Targeted Therapy ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to understand this heterogeneity to find effective treatments. In this review, we focus on selected environmental and genetic risk factors predisposing to ALS and highlight emerging treatments in ALS therapy. Of numerous defective genes associated with ALS, we focus on four principal genes that have been identified as definite causes of ALS: the SOD1 gene, C9orf72, TDP-43, as well as the recently identified TBK1. We also provide up-to-date information on selected environmental factors that have historically been considered as key players in ALS development and pathogenesis. In parallel to our survey of known risk factors, we also discuss emerging ALS stem cell therapies and experimental medicines currently undergoing phase II and III clinical trials.}, }
@article {pmid31139131, year = {2019}, author = {Vijayakumar, UG and Milla, V and Cynthia Stafford, MY and Bjourson, AJ and Duddy, W and Duguez, SM}, title = {A Systematic Review of Suggested Molecular Strata, Biomarkers and Their Tissue Sources in ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {400}, pmid = {31139131}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is an incurable neurodegenerative condition, characterized by the loss of upper and lower motor neurons. It affects 1-1.8/100,000 individuals worldwide, and the number of cases is projected to increase as the population ages. Thus, there is an urgent need to identify both therapeutic targets and disease-specific biomarkers-biomarkers that would be useful to diagnose and stratify patients into different sub-groups for therapeutic strategies, as well as biomarkers to follow the efficacy of any treatment tested during clinical trials. There is a lack of knowledge about pathogenesis and many hypotheses. Numerous "omics" studies have been conducted on ALS in the past decade to identify a disease-signature in tissues and circulating biomarkers. The first goal of the present review was to group the molecular pathways that have been implicated in monogenic forms of ALS, to enable the description of patient strata corresponding to each pathway grouping. This strategy allowed us to suggest 14 strata, each potentially targetable by different pharmacological strategies. The second goal of this review was to identify diagnostic/prognostic biomarker candidates consistently observed across the literature. For this purpose, we explore previous biomarker-relevant "omics" studies of ALS and summarize their findings, focusing on potential circulating biomarker candidates. We systematically review 118 papers on biomarkers published during the last decade. Several candidate markers were consistently shared across the results of different studies in either cerebrospinal fluid (CSF) or blood (leukocyte or serum/plasma). Although these candidates still need to be validated in a systematic manner, we suggest the use of combinations of biomarkers that would likely reflect the "health status" of different tissues, including motor neuron health (e.g., pNFH and NF-L, cystatin C, Transthyretin), inflammation status (e.g., MCP-1, miR451), muscle health (miR-338-3p, miR-206) and metabolism (homocysteine, glutamate, cholesterol). In light of these studies and because ALS is increasingly perceived as a multi-system disease, the identification of a panel of biomarkers that accurately reflect features of pathology is a priority, not only for diagnostic purposes but also for prognostic or predictive applications.}, }
@article {pmid31136989, year = {2019}, author = {Wakisaka, KT and Imai, Y}, title = {The dawn of pirna research in various neuronal disorders.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {24}, number = {8}, pages = {1440-1451}, doi = {10.2741/4789}, pmid = {31136989}, issn = {2768-6698}, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Humans ; Neurodegenerative Diseases/*genetics/metabolism ; Neurons/*metabolism/pathology ; Parkinson Disease/genetics/metabolism ; *RNA Interference ; RNA, Small Interfering/*genetics ; }, abstract = {Small non-coding PIWI-interacting RNAs (piRNAs) silence the expression of transposable elementsof eukaryotic genomes in germline cells. Additionally, piRNAs regulate chromatin modifications, such as trimethylation of histone H3 lysine 9 (H3K9me3) or DNA methylation. In the past decade, the roles of piRNAs have been characterized in somatic cells, including post-mitotic neurons. More recently, piRNAs have been shown to play important roles in brain functions and various neuronal diseases, including neurodegenerative disorders. In this review, we introduce recent findings showing the potential involvement of piRNAs in the etiology of different neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). These pioneering studies on disease-associated small RNAs will contribute to improving our understanding of the pathogenesis of these neurodegenerative diseases and the development of novel therapeutic strategies.}, }
@article {pmid31136977, year = {2019}, author = {Yamamoto, I and Azuma, Y and Yamaguchi, M}, title = {Cancer-related genes and ALS.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {24}, number = {7}, pages = {1241-1258}, doi = {10.2741/4777}, pmid = {31136977}, issn = {2768-6698}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Disease Models, Animal ; Drosophila Proteins/genetics ; Frontotemporal Lobar Degeneration/*genetics/pathology ; Hippo Signaling Pathway ; Humans ; Motor Neurons/*metabolism/pathology ; Neoplasms/*genetics/pathology ; Protein Serine-Threonine Kinases/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is characterized by the progressive degeneration of both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. Recent advances in human genetics have identified more than 30 ALS-causing genes or genetic loci that include the fused in sarcoma (FUS) gene. In addition, a set of studies suggested a mutual relationship between cancer and ALS. The hpo gene, Drosophila MST was newly identified as a novel genetic modifier of the cabeza (caz), Drosophila FUS. The Hippo pathway negatively regulates the control of organ growth and tumor suppression. Moreover, the p53 tumor suppressor was found to genetically interact with caz. Frontotemporal lobar degeneration (FTLD) is characterized by the degeneration of neurons in the frontal and temporal lobes, and consists of a spectrum with ALS. Fusion protein nucleophosmin-human myeloid leukemia factor 1 (NPM-hMLF1), which is associated with the pathologies of myelodysplastic syndrome and acute myeloid leukemia, was recently shown to suppress defects in the Drosophila FTLD model expressing the human FUS gene. Further studies in the field are expected to elucidate epidemiological, genetic, and histopathological links between cancer and ALS/FTLD, and will lead to the development of therapeutic strategies. We herein summarize previous and current findings that support mutual links between cancer and ALS/FTLD.}, }
@article {pmid31134873, year = {2019}, author = {Horrocks, P and Hobbs, L and Tippett, V and Aitken, P}, title = {Paramedic Disaster Health Management Competencies: A Scoping Review.}, journal = {Prehospital and disaster medicine}, volume = {34}, number = {3}, pages = {322-329}, doi = {10.1017/S1049023X19004357}, pmid = {31134873}, issn = {1945-1938}, mesh = {Allied Health Personnel/*education ; Clinical Competence ; Competency-Based Education/*methods ; Disaster Planning/*organization &amp; administration ; Disasters/statistics &amp; numerical data ; Emergency Medical Services/*organization &amp; administration ; Female ; Humans ; Male ; *Professional Competence ; Task Performance and Analysis ; United States ; }, abstract = {INTRODUCTION: Paramedics are tasked with providing 24/7 prehospital emergency care to the community. As part of this role, they are also responsible for providing emergency care in the event of a major incident or disaster. They play a major role in the response stage of such events, both domestic and international. Despite this, specific standardized training in disaster management appears to be variable and inconsistent throughout the profession. A suggested method of building disaster response capacities is through competency-based education (CBE). Core competencies can provide the fundamental basis of collective learning and help ensure consistent application and translation of knowledge into practice. These competencies are often organized into domains, or categories of learning outcomes, as defined by Blooms taxonomy of learning domains. It is these domains of competency, as they relate to paramedic disaster response, that are the subject of this review.<br><br>METHODS: The methodology for this paper to identify existing paramedic disaster response competency domains was adapted from the guidance for the development of systematic scoping reviews, using a methodology developed by members of the Joanna Briggs Institute (JBI; Adelaide, South Australia) and members of five Joanna Briggs Collaborating Centres.<br><br>RESULTS: The literature search identified six articles for review that reported on paramedic disaster response competency domains. The results were divided into two groups: (1) General Core Competency Domains, which are suitable for all paramedics (both Advanced Life Support [ALS] and Basic Life Support [BLS]) who respond to any disaster or major incident; and (2) Specialist Core Competencies, which are deemed necessary competencies to enable a response to certain types of disaster. Further review then showed that three separate and discrete types of competency domains exits in the literature: (1) Core Competencies, (2) Technical/Clinical Competencies, and (3) Specialist Technical/Clinical Competencies.<br><br>CONCLUSIONS: The most common domains of core competencies for paramedic first responders to manage major incidents and disasters described in the literature were identified. If it's accepted that training paramedics in disaster response is an essential part of preparedness within the disaster management cycle, then by including these competency domains into the curriculum development of localized disaster training programs, it will better prepare the paramedic workforce's competence and ability to effectively respond to disasters and major incidents.}, }
@article {pmid31133975, year = {2019}, author = {Kalra, S}, title = {Magnetic Resonance Spectroscopy in ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {482}, pmid = {31133975}, issn = {1664-2295}, abstract = {Proton magnetic resonance spectroscopy (MRS) provides a means of measuring cerebral metabolites relevant to neurodegeneration in vivo. In amyotrophic lateral sclerosis (ALS), neurochemical changes reflecting neuronal loss or dysfunction (decreased N-actylaspartate [NAA]) is most significant in the motor cortex and corticospinal tracts. Other neurochemical changes observed include increased myo-inositol (mIns), a putative marker of gliosis. MRS confirmation of involvement of non-motor regions such as the frontal lobes, thalamus, basal ganglia, and cingulum are consistent with the multi-system facet of motor neuron disease with ALS being part of a MND-FTD spectrum. MRS-derived markers exhibit an encouraging discriminatory ability to identify patients from healthy controls, however more data is needed to determine its ability to assist with the diagnosis in early stages when upper motor neuron signs are limited, and in distinguishing from disease mimics. Longitudinal change of NAA and mIns do not appear to be reliable in monitoring disease progression. Technological advances in hardware and high field scanning are increasing the number of accessible metabolites available for interrogation.}, }
@article {pmid31133802, year = {2019}, author = {Guo, Y and Hong, W and Wang, X and Zhang, P and Körner, H and Tu, J and Wei, W}, title = {MicroRNAs in Microglia: How do MicroRNAs Affect Activation, Inflammation, Polarization of Microglia and Mediate the Interaction Between Microglia and Glioma?.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {125}, pmid = {31133802}, issn = {1662-5099}, abstract = {The essential roles of microglia in maintaining homeostasis in the healthy brain and contributing to neuropathology are well documented. Emerging evidence suggests that epigenetic modulation regulates microglial behavior in both physiological and pathological conditions. MicroRNAs (miRNAs) are short, non-coding epigenetic regulators that repress target gene expression mostly via binding to 3'-untranslated region (3'-UTR) of mRNA in a Dicer-dependent manner. Dysregulation of certain miRNAs can contribute to microglial hyper-activation, persistent neuroinflammation, and abnormal macrophage polarization in the brain. These abnormal conditions can support the pathogenesis of neurological disorders such as glioma, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), stroke, ischemia, and spinal cord injury (SCI). However, the roles of miRNAs in microglia in health and neurological disease have not been systematically summarized. This review will first report the role of Dicer, a key endoribonulease that is responsible for most miRNA biogenesis in microglia. Second, we will focus on recent research about the function of miRNAs in activation, inflammation and polarization of microglia, respectively. In addition, potential crosstalk between microglia and glioma cells via miRNAs will be discussed in this part. Finally, the role of two essential miRNAs, miR-124, and miR-155, in microglia will be highlighted.}, }
@article {pmid31132469, year = {2020}, author = {Strohm, L and Behrends, C}, title = {Glia-specific autophagy dysfunction in ALS.}, journal = {Seminars in cell &amp; developmental biology}, volume = {99}, number = {}, pages = {172-182}, doi = {10.1016/j.semcdb.2019.05.024}, pmid = {31132469}, issn = {1096-3634}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; *Autophagy ; Central Nervous System/metabolism/pathology ; Humans ; Neuroglia/*metabolism/pathology ; }, abstract = {Neuronal cell death is the main pathological feature of chronic neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As age is strongly linked to NDs, these diseases are one of the leading medical and societal challenges faced by the rapidly aging western societies. Despite the increasing prevalence, the causes and mechanisms behind most NDs are still vague. A common hallmark of several NDs is the accumulation and aggregation of proteins. Prominent examples are amyloid beta and tau in Alzheimer's disease, α-synuclein in Parkinson's disease and transactive response DNA binding protein 43 kDa (TDP-43) in ALS and FTD. Under physiological conditions, protein quality control systems, namely the ubiquitin proteasome system and the autophagy machinery, eliminate such aberrant protein forms and thereby prevent proteotoxic stress. However, as proteins must unfold to undergo proteasomal degradation, aggregated proteins are poor substrates for the proteasome. Such proteins are thought to be primarily turned over by autophagy. Therefore, autophagy is considered a critical ND-protective pathway, which opens up potential new therapeutic interventions. One drawback is that the majority of research in NDs has been focused on elucidating the underlying pathomechanisms in neurons. However, neurons make up only about half of the brain cells with neuroglia being the other major central nervous system (CNS) cell type. Due to the ubiquitous presence of disease-causing mutations in all cells of the CNS, it is likely that non-neuronal cells contribute to the disease onset and/or progression. While our understanding of the roles of autophagy and its contribution to neurodegeneration in neurons deepened considerably over the last years, still comparatively little is known about the functions and disease contribution of the autophagy machinery in glia cells.}, }
@article {pmid31132467, year = {2020}, author = {Birsa, N and Bentham, MP and Fratta, P}, title = {Cytoplasmic functions of TDP-43 and FUS and their role in ALS.}, journal = {Seminars in cell &amp; developmental biology}, volume = {99}, number = {}, pages = {193-201}, doi = {10.1016/j.semcdb.2019.05.023}, pmid = {31132467}, issn = {1096-3634}, support = {FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; G1000287/MRC_/Medical Research Council/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Cytoplasm/*metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; RNA-Binding Protein FUS/*metabolism ; }, abstract = {TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA binding proteins (RBPs) primarily located in the nucleus, and involved in numerous aspects of RNA metabolism. Both proteins can be found to be depleted from the nucleus and accumulated in cytoplasmic inclusions in two major neurodegenerative conditions, amyotrophic lateral sclerosis and frontotemporal dementia. Recent evidences suggest that, in addition to their nuclear functions, both TDP-43 and FUS are involved in multiple processes in the cytoplasm, including mRNA stability and transport, translation, the stress response, mitochondrial function and autophagy regulation. Here, we review the most recent advances in understanding their functions in the cytoplasm and how these are affected in disease.}, }
@article {pmid31131478, year = {2020}, author = {Benvegnù, S}, title = {Nucleus-cytoplasm cross-talk in the aging brain.}, journal = {Journal of neuroscience research}, volume = {98}, number = {2}, pages = {247-261}, doi = {10.1002/jnr.24446}, pmid = {31131478}, issn = {1097-4547}, mesh = {Aging/*metabolism/pathology ; Animals ; Brain/*metabolism/pathology ; Cell Nucleus/*metabolism/pathology ; Cytoplasm/*metabolism/pathology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Aging is a primary risk factor for fatal neurodegenerative disorders, yet the mechanisms underlying physiological healthy aging and pathological aging, and how these mechanisms can divert one scenario to the other, are not completely understood. In recent years, reports indicate that alterations in nucleocytoplasmic transport may be a hallmark of both healthy and pathological aging. In this review, I summarize recent evidence supporting this information, specifically focusing on the association between the nucleocytoplasmic transport and aging of the brain, indicating both common and case-specific mechanisms and their interplay, and pointing out alterations of these mechanisms as regulatory "switches" for the fate of the aging brain. Importantly, some of these alterations are intervenable druggable targets, paving the way to a future pharmacotherapeutic intervention.}, }
@article {pmid31122082, year = {2019}, author = {McCombe, PA and Henderson, RD and Lee, A and Lee, JD and Woodruff, TM and Restuadi, R and McRae, A and Wray, NR and Ngo, S and Steyn, FJ}, title = {Gut microbiota in ALS: possible role in pathogenesis?.}, journal = {Expert review of neurotherapeutics}, volume = {19}, number = {9}, pages = {785-805}, doi = {10.1080/14737175.2019.1623026}, pmid = {31122082}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*microbiology ; Animals ; Dysbiosis/*complications ; *Gastrointestinal Microbiome ; Humans ; }, abstract = {Introduction: The gut microbiota has important roles in maintaining human health. The microbiota and its metabolic byproducts could play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Areas covered: The authors evaluate the methods of assessing the gut microbiota, and also review how the gut microbiota affects the various physiological functions of the gut. The authors then consider how gut dysbiosis could theoretically affect the pathogenesis of ALS. They present the current evidence regarding the composition of the gut microbiota in ALS and in rodent models of ALS. Finally, the authors review therapies that could improve gut dysbiosis in the context of ALS. Expert opinion: Currently reported studies suggest some instances of gut dysbiosis in ALS patients and mouse models; however, these studies are limited, and more information with well-controlled larger datasets is required to make a definitive judgment about the role of the gut microbiota in ALS pathogenesis. Overall this is an emerging field that is worthy of further investigation. The authors advocate for larger studies using modern metagenomic techniques to address the current knowledge gaps.}, }
@article {pmid31121863, year = {2019}, author = {Hsu, SK and Chiu, CC and Dahms, HU and Chou, CK and Cheng, CM and Chang, WT and Cheng, KC and Wang, HD and Lin, IL}, title = {Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {20}, number = {10}, pages = {}, pmid = {31121863}, issn = {1422-0067}, mesh = {Animals ; Cell Survival ; Disease Progression ; Humans ; Immune Tolerance ; Neoplasm Metastasis/immunology/pathology/therapy ; Neoplasms/immunology/metabolism/*pathology/therapy ; Neovascularization, Pathologic/immunology/metabolism/pathology/therapy ; *Unfolded Protein Response ; }, abstract = {The endoplasmic reticulum (ER) has diverse functions, and especially misfolded protein modification is in the focus of this review paper. With a highly regulatory mechanism, called unfolded protein response (UPR), it protects cells from the accumulation of misfolded proteins. Nevertheless, not only does UPR modify improper proteins, but it also degrades proteins that are unable to recover. Three pathways of UPR, namely PERK, IRE-1, and ATF6, have a significant role in regulating stress-induced physiological responses in cells. The dysregulated UPR may be involved in diseases, such as atherosclerosis, heart diseases, amyotrophic lateral sclerosis (ALS), and cancer. Here, we discuss the relation between UPR and cancer, considering several aspects including survival, dormancy, immunosuppression, angiogenesis, and metastasis of cancer cells. Although several moderate adversities can subject cancer cells to a hostile environment, UPR can ensure their survival. Excessive unfavorable conditions, such as overloading with misfolded proteins and nutrient deprivation, tend to trigger cancer cell death signaling. Regarding dormancy and immunosuppression, cancer cells can survive chemotherapies and acquire drug resistance through dormancy and immunosuppression. Cancer cells can also regulate the downstream of UPR to modulate angiogenesis and promote metastasis. In the end, regulating UPR through different molecular mechanisms may provide promising anticancer treatment options by suppressing cancer proliferation and progression.}, }
@article {pmid31119452, year = {2019}, author = {Greaves, CV and Rohrer, JD}, title = {An update on genetic frontotemporal dementia.}, journal = {Journal of neurology}, volume = {266}, number = {8}, pages = {2075-2086}, pmid = {31119452}, issn = {1432-1459}, support = {MR/J009482/1/MRC_/Medical Research Council/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Biomarkers/blood/cerebrospinal fluid ; C9orf72 Protein/blood/cerebrospinal fluid/genetics ; Frontotemporal Dementia/*diagnosis/*genetics/metabolism ; Genetic Predisposition to Disease/*genetics ; Humans ; Membrane Proteins/blood/cerebrospinal fluid/genetics ; Mutation/*genetics ; Nerve Tissue Proteins/blood/cerebrospinal fluid/genetics ; }, abstract = {Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.}, }
@article {pmid31119194, year = {2019}, author = {Scoles, DR and Minikel, EV and Pulst, SM}, title = {Antisense oligonucleotides: A primer.}, journal = {Neurology. Genetics}, volume = {5}, number = {2}, pages = {e323}, pmid = {31119194}, issn = {2376-7839}, support = {R01 NS097903/NS/NINDS NIH HHS/United States ; }, abstract = {There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.}, }
@article {pmid31118120, year = {2019}, author = {Afroz, T and Pérez-Berlanga, M and Polymenidou, M}, title = {Structural Transition, Function and Dysfunction of TDP-43 in Neurodegenerative Diseases.}, journal = {Chimia}, volume = {73}, number = {5}, pages = {380-390}, doi = {10.2533/chimia.2019.380}, pmid = {31118120}, issn = {0009-4293}, mesh = {Humans ; *Neurodegenerative Diseases ; TDP-43 Proteinopathies ; }, abstract = {Altered cellular localization and pathologic aggregation of RNA binding proteins (RPBs) containing low complexity regions (LCRs) is a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the importance of RBPs in maintaining a healthy RNA homeostasis, a common mechanism in disease progression is the loss of RNA-related cellular functions. In this review, we summarize and discuss the knowledge gained in the recent years on the molecular mechanisms of TDP-43 proteinopathies that comprise a set of neurodegenerative diseases characterized by the mislocalization and aggregation of the RNA-binding protein TDP-43. Based on biophysical, biochemical and in vivo data, we highlight pathways that are misregulated early in disease and contribute to its progression, thereby representing attractive therapeutic targets.}, }
@article {pmid31116639, year = {2019}, author = {Franz, CK and Joshi, D and Daley, EL and Grant, RA and Dalamagkas, K and Leung, A and Finan, JD and Kiskinis, E}, title = {Impact of traumatic brain injury on amyotrophic lateral sclerosis: from bedside to bench.}, journal = {Journal of neurophysiology}, volume = {122}, number = {3}, pages = {1174-1185}, pmid = {31116639}, issn = {1522-1598}, support = {R21 NS098129/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; R21 NS111248/NS/NINDS NIH HHS/United States ; R21 NS107761/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/etiology/metabolism/physiopathology ; Animals ; *Brain Concussion/complications/metabolism/physiopathology ; *DNA-Binding Proteins ; Humans ; *Induced Pluripotent Stem Cells ; *Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, which manifests clinically as progressive weakness. Although several epidemiological studies have found an association between traumatic brain injury (TBI) and ALS, there is not a consensus on whether TBI is an ALS risk factor. It may be that it can cause ALS in a subset of susceptible patients, based on a history of repetitive mild TBI and genetic predisposition. This cannot be determined based on clinical observational studies alone. Better preclinical models are necessary to evaluate the effects of TBI on ALS onset and progression. To date, only a small number of preclinical studies have been performed, mainly in the superoxide dismutase 1 transgenic rodents, which, taken together, have mixed results and notable methodological limitations. The more recent incorporation of additional animal models such as Drosophila flies, as well as patient-induced pluripotent stem cell-derived neurons, should facilitate a better understanding of a potential functional interaction between TBI and ALS.}, }
@article {pmid31110036, year = {2019}, author = {Benditt, JO}, title = {Respiratory Care of Patients With Neuromuscular Disease.}, journal = {Respiratory care}, volume = {64}, number = {6}, pages = {679-688}, doi = {10.4187/respcare.06827}, pmid = {31110036}, issn = {1943-3654}, mesh = {Cough ; Deglutition ; Humans ; Hypoventilation/physiopathology/therapy ; Insufflation/methods ; Laryngeal Masks ; Neuromuscular Diseases/*physiopathology ; Noninvasive Ventilation/methods ; Oxygen Inhalation Therapy ; Respiratory Therapy/*methods ; Sleep Apnea Syndromes/physiopathology/therapy ; }, abstract = {Neuromuscular diseases are a heterogeneous group of neurologic diseases that affect a number of neural structures including the motor nerves, neuromuscular junctions, or the muscles themselves. Although many of the diseases are rare, the total number of individuals who present to a pulmonologist or respiratory care provider is significant. Approaches to care include regular and careful clinical follow-up of symptoms of sleep-disordered breathing, daytime hypoventilation, as well as cough and swallowing effectiveness. Noninvasive support with nocturnal mask ventilation and a pressure support device can be extraordinarily helpful and delay daytime ventilatory failure. When daytime ventilatory failure develops, other noninvasive methods are available for portable assistance. Support of cough function with manual assistance, a resuscitator bag, and/or mechanical insufflation-exsufflation can help prevent and treat infection. Referral for swallowing evaluation and treatment is very important for those with impaired bulbar function. This comprehensive respiratory care approach to individuals with neuromuscular disease and respiratory system involvement is essential to maintaining the health and longevity of these individuals.}, }
@article {pmid31097008, year = {2019}, author = {Didonna, A and Opal, P}, title = {The role of neurofilament aggregation in neurodegeneration: lessons from rare inherited neurological disorders.}, journal = {Molecular neurodegeneration}, volume = {14}, number = {1}, pages = {19}, pmid = {31097008}, issn = {1750-1326}, support = {R56 NS108639/NS/NINDS NIH HHS/United States ; R01 NS082351/NS/NINDS NIH HHS/United States ; R01 NS062051/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Cytoskeletal Proteins/*metabolism ; Cytoskeleton/*metabolism ; Humans ; Intermediate Filaments/genetics/*metabolism ; Mutation/genetics ; Neurodegenerative Diseases/genetics/*metabolism ; }, abstract = {Many neurodegenerative disorders, including Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis, are well known to involve the accumulation of disease-specific proteins. Less well known are the accumulations of another set of proteins, neuronal intermediate filaments (NFs), which have been observed in these diseases for decades. NFs belong to the family of cytoskeletal intermediate filament proteins (IFs) that give cells their shape; they determine axonal caliber, which controls signal conduction; and they regulate the transport of synaptic vesicles and modulate synaptic plasticity by binding to neurotransmitter receptors. In the last two decades, a number of rare disorders caused by mutations in genes that encode NFs or regulate their metabolism have been discovered. These less prevalent disorders are providing novel insights into the role of NF aggregation in the more common neurological disorders.}, }
@article {pmid31095511, year = {2019}, author = {Sasmita, AO}, title = {Modification of the gut microbiome to combat neurodegeneration.}, journal = {Reviews in the neurosciences}, volume = {30}, number = {8}, pages = {795-805}, doi = {10.1515/revneuro-2019-0005}, pmid = {31095511}, issn = {2191-0200}, mesh = {Alzheimer Disease/etiology/*microbiology/therapy ; Amyotrophic Lateral Sclerosis/etiology/*microbiology/therapy ; Animals ; *Gastrointestinal Microbiome ; Humans ; Multiple Sclerosis/etiology/*microbiology/therapy ; Parkinson Disease/etiology/*microbiology/therapy ; Probiotics/*therapeutic use ; }, abstract = {The gut microbiome was extensively researched for its biological variety and its potential role in propagating diseases outside of the gastrointestinal (GI) tract. Recently, a lot of effort was focused on comprehending the gut-brain axis and the bizarre communication between the GI system and the nervous system. Ample amount of studies being carried out also revealed the involvement of the gut microbiome in enhancing the degree of many neurological disorders, including neurodegenerative diseases. It was widely observed that there were distinct microbiome profiles and dysbiosis within patients suffering from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Various approaches to re-establish the balance of the gut microbiome, from antibiotic therapy, fecal microbiota transplant, or ingestion of psychobiotics, are discussed within this review within the specific context of combating neurodegenerative diseases. Present studies and clinical trials indicate that although there is an immense potential of gut microbiome modification to be preventive or therapeutic, there are still many intercalated components of the gut-brain axis at play and thus, more research needs to be carried out to delineate microbiome factors that may potentially alleviate symptoms of neurodegeneration.}, }
@article {pmid31095406, year = {2020}, author = {Sharlow, ER and Koseoglu, MM and Bloom, GS and Lazo, JS}, title = {The Promise and Perils of Compound Discovery Screening with Inducible Pluripotent Cell-Derived Neurons.}, journal = {Assay and drug development technologies}, volume = {18}, number = {2}, pages = {97-103}, pmid = {31095406}, issn = {1557-8127}, support = {R01 AG063400/AG/NIA NIH HHS/United States ; }, mesh = {*Drug Discovery ; Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells/*drug effects/metabolism/pathology ; Nervous System Diseases/*drug therapy/metabolism/pathology ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; }, abstract = {Neurological diseases comprise more than a thousand ailments that adversely affect the brain and nervous system. When grouped together, these neurological conditions impact an estimated 100 million individuals in the United States and up to a billion people worldwide, making drug discovery efforts imperative. However, recent research and development efforts for these neurological diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, have been exceedingly disappointing and typify the challenges associated with translating in vitro and cell-based discoveries to successful preclinical models and subsequent human clinical trials. Our viewpoint is that neuronal progenitor cells and neurons derived from inducible pluripotent stem cells afford an innovative translational bridge, with higher pathological relevancy than previous cellular models. We outline some of the opportunities and challenges associated with their evolving usage in drug discovery and development.}, }
@article {pmid31089037, year = {2019}, author = {French, PW and Ludowyke, RI and Guillemin, GJ}, title = {Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {14}, number = {9}, pages = {1490-1493}, pmid = {31089037}, issn = {1673-5374}, abstract = {Fungi are important infectious disease-causing agents, but are often overlooked as environmental factors in disease. We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease. Approximately 90% cases of ALS are sporadic, and the aetiology of sporadic ALS is still unknown. We have previously postulated that grass or soil-associated fungal infections may be a leading cause of sporadic ALS. Herein we extend this proposal to water-associated fungi. A wide variety of fungi have been reported in drinking water including Acremonium, Alternaria, Aspergillus, Cladosporium, Fusarium, Penicillium and Trichoderma. Some of these are known to produce neurotoxic mycotoxins. Despite this, drinking water is not routinely monitored for fungal contamination. Fungal contamination could explain the close correlation between distribution of well water and cases of sporadic ALS in the United States. We propose several mechanisms by which an opportunistic fungal infection from environmental exposure (to water, soil or plants) can lead to long term neuronal degradation resulting in the hallmarks of ALS. If confirmed, the association between fungal infection and sporadic ALS could lead to novel treatment strategies for this progressive and fatal disease.}, }
@article {pmid31084461, year = {2019}, author = {Howard, I}, title = {Cannabis Hyperemesis Syndrome in Palliative Care: A Case Study and Narrative Review.}, journal = {Journal of palliative medicine}, volume = {22}, number = {10}, pages = {1227-1231}, doi = {10.1089/jpm.2018.0531}, pmid = {31084461}, issn = {1557-7740}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/therapy ; Humans ; Male ; Medical Marijuana/*adverse effects ; *Palliative Care ; Syndrome ; Vomiting/*chemically induced ; }, abstract = {Background: Cannabis is increasingly used by persons at end of life to ameliorate symptoms such as pain, spasticity, anorexia, or anxiety. Cannabis hyperemesis is a distressing adverse effect of chronic use and may cause significant morbidity. Unfortunately, the clinical presentation of this syndrome may be subtle in a person with complex medical issues or disability. Providers must remain vigilant for possible variations in presentation in these populations. Aim: To assess literature on cannabis hyperemesis and present unique considerations for clinical assessment and treatment for patients at end of life. Design: Initial literature scoping yielded limited evidence on the subject in the setting of chronic disease and disability. A case of cannabis hyperemesis in a person with advanced amyotrophic lateral sclerosis is presented to illustrate challenges in diagnosis and management in this setting. A narrative synthesis of current literature on assessment and management and special considerations for evaluation and treatment for patients under palliative care was performed. Results: Several unique considerations for the diagnosis and management of cannabis hyperemesis in palliative care patients are highlighted in the case presented, including: (1) Symptoms may possibly be abolished through decrease rather than complete abstinence from cannabis, (2) Frequent hot baths may not be present in patients with physical impairments in activities of daily living, and (3) Management of primary symptoms (pain, spasticity, nausea, and anxiety) in the end-of-life care patient must be considered to maximize comfort. Conclusion: The presentation of cannabis hyperemesis may be atypical in palliative care patients due to disability. More work is needed to improve risk stratification for patients using cannabis for palliative care.}, }
@article {pmid31083575, year = {2019}, author = {Granatiero, V and Manfredi, G}, title = {Mitochondrial Transport and Turnover in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Biology}, volume = {8}, number = {2}, pages = {}, pmid = {31083575}, issn = {2079-7737}, support = {R01NS062055//National Institute of Neurological Disorders and Stroke/ ; }, abstract = {Neurons are high-energy consuming cells, heavily dependent on mitochondria for ATP generation and calcium buffering. These mitochondrial functions are particularly critical at specific cellular sites, where ionic currents impose a large energetic burden, such as at synapses. The highly polarized nature of neurons, with extremely large axoplasm relative to the cell body, requires mitochondria to be efficiently transported along microtubules to reach distant sites. Furthermore, neurons are post-mitotic cells that need to maintain pools of healthy mitochondria throughout their lifespan. Hence, mitochondrial transport and turnover are essential processes for neuronal survival and function. In neurodegenerative diseases, the maintenance of a healthy mitochondrial network is often compromised. Numerous lines of evidence indicate that mitochondrial impairment contributes to neuronal demise in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), where degeneration of motor neurons causes a fatal muscle paralysis. Dysfunctional mitochondria accumulate in motor neurons affected by genetic or sporadic forms of ALS, strongly suggesting that the inability to maintain a healthy pool of mitochondria plays a pathophysiological role in the disease. This article critically reviews current hypotheses on mitochondrial involvement in the pathogenesis of ALS, focusing on the alterations of mitochondrial axonal transport and turnover in motor neurons.}, }
@article {pmid31077796, year = {2019}, author = {Subhramanyam, CS and Wang, C and Hu, Q and Dheen, ST}, title = {Microglia-mediated neuroinflammation in neurodegenerative diseases.}, journal = {Seminars in cell &amp; developmental biology}, volume = {94}, number = {}, pages = {112-120}, doi = {10.1016/j.semcdb.2019.05.004}, pmid = {31077796}, issn = {1096-3634}, mesh = {Animals ; Humans ; Inflammation/*metabolism/pathology ; Microglia/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Microglia, being the resident immune cells of the central nervous system, play an important role in maintaining tissue homeostasis and contributes towards brain development under normal conditions. However, when there is a neuronal injury or other insult, depending on the type and magnitude of stimuli, microglia will be activated to secrete either proinflammatory factors that enhance cytotoxicity or anti-inflammatory neuroprotective factors that assist in wound healing and tissue repair. Excessive microglial activation damages the surrounding healthy neural tissue, and the factors secreted by the dead or dying neurons in turn exacerbate the chronic activation of microglia, causing progressive loss of neurons. It is the case observed in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review gives a detailed account of the microglia-mediated neuroinflammation in various neurodegenerative diseases. Hence, resolving chronic inflammation mediated by microglia bears great promise as a novel treatment strategy to reduce neuronal damage and to foster a permissive environment for further regeneration effort.}, }
@article {pmid31075861, year = {2019}, author = {Batista, CRA and Gomes, GF and Candelario-Jalil, E and Fiebich, BL and de Oliveira, ACP}, title = {Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {20}, number = {9}, pages = {}, pmid = {31075861}, issn = {1422-0067}, support = {CNPq - 424588/2016-1//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; CNPq - 309718/2015-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; CBB-APQ-02044-15//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; }, mesh = {Animals ; Disease Models, Animal ; Humans ; Inflammation/*pathology ; Lipopolysaccharides ; Nerve Degeneration/*pathology ; Nervous System/*pathology ; Neurodegenerative Diseases/pathology ; }, abstract = {A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neuroinflammation associated with neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter the expression of a plethora of inflammatory mediators. These factors, in turn, initiate or contribute to the development of neurodegenerative processes. Therefore, LPS is an important tool for the study of neuroinflammation associated with neurodegenerative diseases. However, the serotype, route of administration, and number of injections of this toxin induce varied pathological responses. Thus, here, we review the use of LPS in various models of neurodegeneration as well as discuss the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the neurodegenerative process.}, }
@article {pmid31072957, year = {2019}, author = {Edmond, EC and Stagg, CJ and Turner, MR}, title = {Therapeutic non-invasive brain stimulation in amyotrophic lateral sclerosis: rationale, methods and experience.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {90}, number = {10}, pages = {1131-1138}, doi = {10.1136/jnnp-2018-320213}, pmid = {31072957}, issn = {1468-330X}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Brain/*physiopathology ; Humans ; Transcranial Direct Current Stimulation/*methods ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {The neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) is characterised by increased cortical excitability, thought to reflect pathological changes in the balance of local excitatory and inhibitory neuronal influences. Non-invasive brain stimulation (NIBS) has been shown to modulate cortical activity, with some protocols showing effects that outlast the stimulation by months. NIBS has been suggested as a potential therapeutic approach for disorders associated with changes in cortical neurophysiology, including ALS. This article reviews NIBS methodology, rationale for its application to ALS and progress to date.}, }
@article {pmid31059788, year = {2019}, author = {Jin, X and Liu, MY and Zhang, DF and Zhong, X and Du, K and Qian, P and Gao, H and Wei, MJ}, title = {Natural products as a potential modulator of microglial polarization in neurodegenerative diseases.}, journal = {Pharmacological research}, volume = {145}, number = {}, pages = {104253}, doi = {10.1016/j.phrs.2019.104253}, pmid = {31059788}, issn = {1096-1186}, mesh = {Animals ; Biological Products/*therapeutic use ; Humans ; Microglia/*drug effects/physiology ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Phenotype ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by the progressive loss of structure and function of neurons most common in elderly population, mainly including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Neuroinflammation caused by microglia as the resident macrophages of the central nervous system (CNS) plays a contributory role in the onset and progression of NDs. Activated microglia, as in macrophages, to be heterogeneous, can polarize into M1 (pro-inflammatory) and M2 (anti-inflammatory) functional phenotypes. The former elaborate pro-inflammatory mediators promoting neuroinflammation and neuronal damage. In contrast, the latter generate anti-inflammatory mediators and neurotrophins that inhibit neuroinflammation and promote neuronal healing. Consistently, the regulation of microglial polarization from M1 to M2 phenotype appears as an outstanding therapeutic and preventive approach for NDs treatment. Although non-steroidal anti-inflammatory drugs (NSAIDs) currently used to alleviate M1 microglia-associated neuroinflammation responsible for the development of NDs, these drugs have different degrees of adverse effects and limited efficacy. As the advantages of novel structure, multi-target, high efficiency and low toxicity, natural products as the modulators of microglial polarization have attracted considerable concerns in the therapeutic areas of NDs. In this review, we mainly summarized the therapeutic potential of natural products and their various molecular mechanisms for NDs treatment through modulating microglial polarization. The aim of the current review is expected to be useful to develop innovative modulators of microglial polarization from natural products for the amelioration and treatment of NDs.}, }
@article {pmid31057691, year = {2019}, author = {Huang, ML and Chiang, S and Kalinowski, DS and Bae, DH and Sahni, S and Richardson, DR}, title = {The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {6392763}, pmid = {31057691}, issn = {1942-0994}, mesh = {Antioxidants/*metabolism ; *Apoptosis ; *Autophagy ; *Energy Metabolism ; Heredodegenerative Disorders, Nervous System/*metabolism/pathology ; Humans ; Mitochondria/*metabolism/pathology ; Neurons/metabolism/pathology ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and Friedreich's ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.}, }
@article {pmid31054608, year = {2019}, author = {Staff, NP and Jones, DT and Singer, W}, title = {Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases.}, journal = {Mayo Clinic proceedings}, volume = {94}, number = {5}, pages = {892-905}, pmid = {31054608}, issn = {1942-5546}, support = {R01 CA211887/CA/NCI NIH HHS/United States ; R01 FD004789/FD/FDA HHS/United States ; R01 NS092625/NS/NINDS NIH HHS/United States ; U54 NS065736/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*therapy ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic ; Humans ; Mesenchymal Stem Cell Transplantation/adverse effects ; Mesenchymal Stem Cells/*physiology ; Multiple System Atrophy/*therapy ; Parkinson Disease/*therapy ; }, abstract = {Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson disease, and Alzheimer disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward effects.}, }
@article {pmid31048504, year = {2019}, author = {Degterev, A and Ofengeim, D and Yuan, J}, title = {Targeting RIPK1 for the treatment of human diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, number = {20}, pages = {9714-9722}, pmid = {31048504}, issn = {1091-6490}, support = {R21 AG059073/AG/NIA NIH HHS/United States ; R01 CA190542/CA/NCI NIH HHS/United States ; RF1 AG055521/AG/NIA NIH HHS/United States ; R21 AI124049/AI/NIAID NIH HHS/United States ; R56 AG058642/AG/NIA NIH HHS/United States ; R01 AG047231/AG/NIA NIH HHS/United States ; }, mesh = {Apoptosis ; Central Nervous System Diseases/*drug therapy ; Drug Development ; Gene Expression ; Humans ; Inflammation/metabolism ; *Molecular Targeted Therapy ; Necroptosis ; Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood-brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer's disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central nervous systems.}, }
@article {pmid31044582, year = {2019}, author = {Ban, J and Sámano, C and Mladinic, M and Munitic, I}, title = {Glia in amyotrophic lateral sclerosis and spinal cord injury: common therapeutic targets.}, journal = {Croatian medical journal}, volume = {60}, number = {2}, pages = {109-120}, pmid = {31044582}, issn = {1332-8166}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/therapy ; Animals ; Astrocytes/*physiology ; Blood-Brain Barrier ; Disease Models, Animal ; Humans ; Microglia/*physiology ; Neuroglia ; Neurons ; Spinal Cord Injuries/*etiology/therapy ; Stem Cells ; }, abstract = {The toolkit for repairing damaged neurons in amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI) is extremely limited. Here, we reviewed the in vitro and in vivo studies and clinical trials on nonneuronal cells in the neurodegenerative processes common to both these conditions. Special focus was directed to microglia and astrocytes, because their activation and proliferation, also known as neuroinflammation, is a key driver of neurodegeneration. Neuroinflammation is a multifaceted process that evolves during the disease course, and can be either beneficial or toxic to neurons. Given the fundamental regulatory functions of glia, pathogenic mechanisms in neuroinflammation represent promising therapeutic targets. We also discussed neuroprotective, immunosuppressive, and stem-cell based approaches applicable to both ALS and SCI.}, }
@article {pmid31034795, year = {2019}, author = {Liu, C and Fang, Y}, title = {New insights of poly(ADP-ribosylation) in neurodegenerative diseases: A focus on protein phase separation and pathologic aggregation.}, journal = {Biochemical pharmacology}, volume = {167}, number = {}, pages = {58-63}, doi = {10.1016/j.bcp.2019.04.028}, pmid = {31034795}, issn = {1873-2968}, mesh = {Animals ; DNA Damage/physiology ; Humans ; Neurodegenerative Diseases/drug therapy/*metabolism/pathology ; Poly ADP Ribosylation/drug effects/*physiology ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/*therapeutic use ; Protein Aggregation, Pathological/drug therapy/*metabolism/pathology ; }, abstract = {Abnormal protein aggregation is a common pathological feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Protein posttranslational modifications (PTMs) play a crucial regulatory role in the formation of pathologic aggregation. Among the known PTMs involved in neurodegeneration, poly(ADP-ribosylation) (PARylation) has emerged with promising therapeutic potentials of the use of poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors. In this review, we describe the mounting evidence that abnormal PARP activation is involved in various neurodegenerative diseases, and discuss the underpinning mechanisms with a focus on the recent findings that PARylation affects liquid-liquid phase separation and aggregation of amyloid proteins. We hope this review will stimulate further investigation of the unknown functions of PARylation and promote the development of more effective therapeutic agents in treating neurodegeneration.}, }
@article {pmid31034749, year = {2019}, author = {Taylor, LM and McMillan, PJ and Kraemer, BC and Liachko, NF}, title = {Tau tubulin kinases in proteinopathy.}, journal = {The FEBS journal}, volume = {286}, number = {13}, pages = {2434-2446}, pmid = {31034749}, issn = {1742-4658}, support = {I01 BX003755/BX/BLRD VA/United States ; I01 BX002619/BX/BLRD VA/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; T32 AG000057/AG/NIA NIH HHS/United States ; I01 BX004044/BX/BLRD VA/United States ; }, mesh = {Animals ; Brain/metabolism/pathology ; Humans ; Protein Serine-Threonine Kinases/chemistry/genetics/*metabolism ; TDP-43 Proteinopathies/*metabolism/pathology ; }, abstract = {A number of neurodegenerative diseases are characterized by deposition of abnormally phosphorylated tau or TDP-43 in disease-affected neurons. These diseases include Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. No disease-modifying therapeutics is available to treat these disorders, and we have a limited understanding of the cellular and molecular factors integral to disease initiation or progression. Phosphorylated tau and TDP-43 are important markers of pathology in dementia disorders and directly contribute to tau- and TDP-43-related neurotoxicity and neurodegeneration. Here, we review the scope of tau and TDP-43 phosphorylation in neurodegenerative disease and discuss recent work demonstrating the kinases TTBK1 and TTBK2 phosphorylate both tau and TDP-43, promoting neurodegeneration.}, }
@article {pmid31031688, year = {2019}, author = {El Mendili, MM and Querin, G and Bede, P and Pradat, PF}, title = {Spinal Cord Imaging in Amyotrophic Lateral Sclerosis: Historical Concepts-Novel Techniques.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {350}, pmid = {31031688}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease with no effective disease modifying therapies at present. Spinal cord degeneration is a hallmark feature of ALS, highlighted in the earliest descriptions of the disease by Lockhart Clarke and Jean-Martin Charcot. The anterior horns and corticospinal tracts are invariably affected in ALS, but up to recently it has been notoriously challenging to detect and characterize spinal pathology in vivo. With recent technological advances, spinal imaging now offers unique opportunities to appraise lower motor neuron degeneration, sensory involvement, metabolic alterations, and interneuron pathology in ALS. Quantitative spinal imaging in ALS has now been used in cross-sectional and longitudinal study designs, applied to presymptomatic mutation carriers, and utilized in machine learning applications. Despite its enormous clinical and academic potential, a number of physiological, technological, and methodological challenges limit the routine use of computational spinal imaging in ALS. In this review, we provide a comprehensive overview of emerging spinal cord imaging methods and discuss their advantages, drawbacks, and biomarker potential in clinical applications, clinical trial settings, monitoring, and prognostic roles.}, }
@article {pmid31031586, year = {2019}, author = {Faye, PA and Poumeaud, F and Miressi, F and Lia, AS and Demiot, C and Magy, L and Favreau, F and Sturtz, FG}, title = {Focus on 1,25-Dihydroxyvitamin D3 in the Peripheral Nervous System.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {348}, pmid = {31031586}, issn = {1662-4548}, abstract = {In this review, we draw attention to the roles of calcitriol (1,25-dihydroxyvitamin D3) in the trophicity of the peripheral nervous system. Calcitriol has long been known to be crucial in phosphocalcium homeostasis. However, recent discoveries concerning its involvement in the immune system, anti-cancer defenses, and central nervous system development suggest a more pleiotropic role than previously thought. Several studies have highlighted the impact of calcitriol deficiency as a promoting factor of various central neurological diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Based on these findings and recent publications, a greater role for calcitriol may be envisioned in the peripheral nervous system. Indeed, calcitriol is involved in myelination, axonal homogeneity of peripheral nerves, and neuronal-cell differentiation. This may have useful clinical consequences, as calcitriol supplementation may be a simple means to avoid the onset and/or development of peripheral nervous-system disorders.}, }
@article {pmid31031584, year = {2019}, author = {Berning, BA and Walker, AK}, title = {The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {335}, pmid = {31031584}, issn = {1662-4548}, abstract = {During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated in vivo models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD.}, }
@article {pmid31031583, year = {2019}, author = {Walters, R and Manion, J and Neely, GG}, title = {Dissecting Motor Neuron Disease With Drosophila melanogaster.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {331}, pmid = {31031583}, issn = {1662-4548}, abstract = {Motor Neuron Disease (MND) typically affects patients during the later stages of life, and thus, MND is having an increasingly devastating impact on diagnosed individuals, their families and society. The umbrella term MND refers to diseases which cause the progressive loss of upper and/or lower motor neurons and a subsequent decrease in motor ability such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The study of these diseases is complex and has recently involved the use of genome-wide association studies (GWAS). However, in the case of MND, it has been difficult to identify the complex genetics involved in subtypes, and functional investigation of new candidate disease genes is warranted. Drosophila is a powerful model for addressing these complex diseases. The UAS/Gal4/Gal80 system allows for the upregulation of Drosophila genes, the "knockdown" of genes and the ectopic expression of human genes or mutations in a tissue-specific manner; often resulting in Drosophila models which exhibit typical MND disease pathologies. These can then be further interrogated to identify disease-modifying genes or mutations and disease pathways. This review will discuss two common MNDs and the current Drosophila models which are being used to research their genetic basis and the different pathologies of MND.}, }
@article {pmid31028834, year = {2019}, author = {Gomez, M and Germain, D}, title = {Cross talk between SOD1 and the mitochondrial UPR in cancer and neurodegeneration.}, journal = {Molecular and cellular neurosciences}, volume = {98}, number = {}, pages = {12-18}, pmid = {31028834}, issn = {1095-9327}, support = {R01 CA172046/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cell Nucleus/metabolism ; Humans ; Mitochondria/*metabolism ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress ; Signal Transduction ; Superoxide Dismutase-1/*metabolism ; *Unfolded Protein Response ; }, abstract = {The mitochondrial unfolded protein response (UPR[mt]) is rapidly gaining attention. While the CHOP (ATF4/5) axis of the UPR[mt] was the first to be described, other axes have subsequently been reported. Validation of this complex pathway in C. elegans has been extensively studied. However, validation of the UPR[mt] in mouse models of disease known to implicate mitochondrial reprogramming or dysfunction, such as cancer and neurodegeneration, respectively, is only beginning to emerge. This review summarizes recent findings and highlights the major role of the superoxide dismutase SOD1 in the communication between the mitochondria and the nucleus in these settings. While SOD1 has mostly been studied in the context of familial amyotrophic lateral sclerosis (fALS), recent studies suggest that SOD1 may be a potentially important mediator of the UPR[mt] and converge to emphasize an increasingly vital role of SOD1 as a therapeutic target in cancer.}, }
@article {pmid31022909, year = {2019}, author = {Chen, C and Ding, X and Akram, N and Xue, S and Luo, SZ}, title = {Fused in Sarcoma: Properties, Self-Assembly and Correlation with Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {8}, pages = {}, pmid = {31022909}, issn = {1420-3049}, support = {Grant No. 91853116&#xff0c;21672019,21372026,21402006//National Natural Science Foundation of China/ ; Grand No.PYBZ1711, PT1613-08, 20130801//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Asparagine/chemistry/genetics ; Frontotemporal Lobar Degeneration/genetics/pathology ; GPI-Linked Proteins/chemistry/genetics ; Humans ; Neurodegenerative Diseases/*genetics/pathology ; Peptides/chemistry/genetics ; Prions/chemistry/genetics ; Protein Aggregation, Pathological/*genetics/pathology ; Protein Domains/genetics ; RNA-Binding Protein FUS/*chemistry/genetics ; }, abstract = {Fused in sarcoma (FUS) is a DNA/RNA binding protein that is involved in RNA metabolism and DNA repair. Numerous reports have demonstrated by pathological and genetic analysis that FUS is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and polyglutamine diseases. Traditionally, the fibrillar aggregation of FUS was considered to be the cause of those diseases, especially via its prion-like domains (PrLDs), which are rich in glutamine and asparagine residues. Lately, a nonfibrillar self-assembling phenomenon, liquid-liquid phase separation (LLPS), was observed in FUS, and studies of its functions, mechanism, and mutual transformation with pathogenic amyloid have been emerging. This review summarizes recent studies on FUS self-assembling, including both aggregation and LLPS as well as their relationship with the pathology of ALS, FTLD, and other neurodegenerative diseases.}, }
@article {pmid31019485, year = {2019}, author = {González De Aguilar, JL}, title = {Lipid Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {284}, pmid = {31019485}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease primarily characterized by the selective loss of upper and lower motor neurons. To date, there is still an unmet need for robust and practical biomarkers that could estimate the risk of the disease and its progression. Based on metabolic modifications observed at the level of the whole body, different classes of lipids have been proposed as potential biomarkers. This review summarizes investigations carried out over the last decade that focused on changes in three major lipid species, namely cholesterol, triglycerides and fatty acids. Despite some contradictory findings, it is becoming increasingly accepted that dyslipidemia, and related aberrant energy homeostasis, must be considered as essential components of the pathological process. Therefore, it is tempting to envisage dietary interventions as a means to counterbalance the metabolic disturbances and ameliorate the patient's quality of life.}, }
@article {pmid31016348, year = {2019}, author = {Oksanen, M and Lehtonen, S and Jaronen, M and Goldsteins, G and Hämäläinen, RH and Koistinaho, J}, title = {Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {76}, number = {14}, pages = {2739-2760}, pmid = {31016348}, issn = {1420-9071}, support = {278343//Academy of Finland/ ; }, mesh = {Astrocytes/metabolism/*pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/metabolism/*pathology ; }, abstract = {Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease. Moreover, human astrocytes have been found to be much more complex than their rodent counterparts, and to date, astrocytes are known to actively participate in a multitude of processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, maintenance of the blood-brain barrier, and many other crucial functions of the brain. This review focuses on the role of astrocytes in human neurodegenerative disease and the potential of the novel stem cell-based platforms in modeling astrocytic functions in health and in disease.}, }
@article {pmid31013638, year = {2019}, author = {Singh, A and Kukreti, R and Saso, L and Kukreti, S}, title = {Oxidative Stress: A Key Modulator in Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {8}, pages = {}, pmid = {31013638}, issn = {1420-3049}, support = {CD/2016/1761, RC/2015/9677-882//DU/DST PURSE and R&amp;D/ ; }, mesh = {Animals ; Humans ; Mitochondria/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Oxidation-Reduction ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Oxidative stress is proposed as a regulatory element in ageing and various neurological disorders. The excess of oxidants causes a reduction of antioxidants, which in turn produce an oxidation-reduction imbalance in organisms. Paucity of the antioxidant system generates oxidative-stress, characterized by elevated levels of reactive species (oxygen, hydroxyl free radical, and so on). Mitochondria play a key role in ATP supply to cells via oxidative phosphorylation, as well as synthesis of essential biological molecules. Various redox reactions catalyzed by enzymes take place in the oxidative phosphorylation process. An inefficient oxidative phosphorylation may generate reactive oxygen species (ROS), leading to mitochondrial dysfunction. Mitochondrial redox metabolism, phospholipid metabolism, and proteolytic pathways are found to be the major and potential source of free radicals. A lower concentration of ROS is essential for normal cellular signaling, whereas the higher concentration and long-time exposure of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, ultimately resulting in necrosis and apoptotic cell death. Normal and proper functioning of the central nervous system (CNS) is entirely dependent on the chemical integrity of brain. It is well established that the brain consumes a large amount of oxygen and is highly rich in lipid content, becoming prone to oxidative stress. A high consumption of oxygen leads to excessive production of ROS. Apart from this, the neuronal membranes are found to be rich in polyunsaturated fatty acids, which are highly susceptible to ROS. Various neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others, can be the result of biochemical alteration (due to oxidative stress) in bimolecular components. There is a need to understand the processes and role of oxidative stress in neurodegenerative diseases. This review is an effort towards improving our understanding of the pivotal role played by OS in neurodegenerative disorders.}, }
@article {pmid31011884, year = {2019}, author = {Raikwar, SP and Kikkeri, NS and Sakuru, R and Saeed, D and Zahoor, H and Premkumar, K and Mentor, S and Thangavel, R and Dubova, I and Ahmed, ME and Selvakumar, GP and Kempuraj, D and Zaheer, S and Iyer, SS and Zaheer, A}, title = {Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {14}, number = {4}, pages = {608-641}, pmid = {31011884}, issn = {1557-1904}, support = {I01 BX002477/BX/BLRD VA/United States ; R01 AG048205/AG/NIA NIH HHS/United States ; RO1 AG048205/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; CRISPR-Associated Protein 9/*genetics ; CRISPR-Cas Systems/*genetics ; Gene Editing/methods/*trends ; Genetic Therapy/methods/trends ; Humans ; Neurodegenerative Diseases/*genetics/*therapy ; Precision Medicine/methods/*trends ; Treatment Outcome ; }, abstract = {Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etc. Here, we review the latest developments in the field of CRISPR-mediated genome editing and provide unbiased futuristic insights regarding its translational potential to improve the treatment outcomes and minimize financial burden. However, despite significant advancements, we would caution the scientific community that since the CRISPR field is still evolving, currently we do not know the full spectrum of CRISPR-mediated side effects. In the wake of the recent news regarding CRISPR-edited human babies being born in China, we urge the scientific community to maintain high scientific and ethical standards and utilize CRISPR for developing in vitro disease in a dish model, in vivo testing in nonhuman primates and lower vertebrates and for the development of neurotherapeutics for the currently incurable neurodegenerative disorders. Graphical Abstract.}, }
@article {pmid31009755, year = {2019}, author = {Volonté, C and Amadio, S and Fabbrizio, P and Apolloni, S}, title = {Functional microglia neurotransmitters in amyotrophic lateral sclerosis.}, journal = {Seminars in cell &amp; developmental biology}, volume = {94}, number = {}, pages = {121-128}, doi = {10.1016/j.semcdb.2019.04.014}, pmid = {31009755}, issn = {1096-3634}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Humans ; Microglia/*drug effects/metabolism/pathology ; Neurotransmitter Agents/*pharmacology ; }, abstract = {Today neuroscience is dominated by the perspective that microglia are essential elements in any integrated view of the nervous system. A number of different neuroinflammatory conditions affect the CNS where microglia involvement, and particularly microgliosis, is not only a prominent feature, but also a pathogenic key mechanism of disease. On the other side, microglia can also constitute an important trigger of neuronal protection during neurodegenerative disorders. For instance in ALS and other motor neuron diseases, available evidence suggests the coexistence of quite different roles for microglia, characterized by neuroprotective functions at early stages, and neurotoxic actions during disease progression. The scope of this review is a brief discussion about microglia being activated and functioning during ALS, and particularly about neurotransmitters participating to the pathological signature of ALS microglia. We will discuss that ALS microglia can express a variety of classical neurotransmitter receptors comprising those for extracellular ATP, glutamate and histamine. We will review data indicating that the modulation of these transmitter receptors may induce beneficial effects in ALS models, so that the protective properties of microglia can be emphasized at the expenses of their toxicity.}, }
@article {pmid31001186, year = {2019}, author = {Verber, NS and Shepheard, SR and Sassani, M and McDonough, HE and Moore, SA and Alix, JJP and Wilkinson, ID and Jenkins, TM and Shaw, PJ}, title = {Biomarkers in Motor Neuron Disease: A State of the Art Review.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {291}, pmid = {31001186}, issn = {1664-2295}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; MR/S004920/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data.}, }
@article {pmid31000441, year = {2019}, author = {Conde, B and Martins, N and Brandão, M and Pimenta, AC and Winck, JC}, title = {Upper Airway Video Endoscopy: Assessment of the response to positive pressure ventilation and mechanical in-exsufflation.}, journal = {Pulmonology}, volume = {25}, number = {5}, pages = {299-304}, doi = {10.1016/j.pulmoe.2019.02.008}, pmid = {31000441}, issn = {2531-0437}, mesh = {Airway Obstruction/*diagnostic imaging ; Deep Sedation ; Endoscopy ; Humans ; *Insufflation ; Larynx/diagnostic imaging ; Nasal Cavity/diagnostic imaging ; Noninvasive Ventilation ; Pharynx/diagnostic imaging ; *Positive-Pressure Respiration ; Sleep ; Vocal Cord Dysfunction/*diagnostic imaging/etiology ; }, abstract = {Upper airways (UA) include the nasal cavities, pharynx, and larynx, and its main function is to warm and filter the inspired air. UA dysfunction is in the pathogenesis of various disorders, such as obstructive sleep apnea syndrome (OSAS) and vocal cord dysfunction. In addition, in some neurodegenerative diseases (e.g. Amyotrophic Lateral Sclerosis - ALS), UA dysfunction may also compromise the effective use of ventilatory support (VS). In this context, the endoscopic evaluation of UA may be useful in understanding the OSAS mechanisms, in determining the causes for treatment-induced airway obstruction and even in helping to titrate noninvasive ventilation (NIV) in ALS patients with bulbar or pseudo-bulbar (spastic) dysfunction. Specifically, in OSAS patients, when residual obstructive events persist, although an optimal ventilatory mode has been apparently achieved, along with interface and equipment, the endoscopic evaluation of UA seems to be a valuable tool in understanding its mechanisms, even assisting adjustments to NIV parameters. In addition, it has also been described as being useful in laryngeal response to mechanical in-exsufflation (MI-E) and Exercise-Induced Laryngeal Obstruction (EILO). However, no protocol has yet been published or validated for this. For this reason, a literature review was conducted on UA function and its response to positive pressure and MI-E. Special emphasis has also been given to the current indication for video endoscopy in chronically ventilated patients.}, }
@article {pmid30999379, year = {2019}, author = {Haensch, CA and Hilz, M and Jost, W and Kaufmann, A and Kessler, T and Lahrmann, H}, title = {[S1-Guideline for Diagnosis and Treatment of Erectile Dysfunction].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {87}, number = {4}, pages = {225-233}, doi = {10.1055/a-0747-5892}, pmid = {30999379}, issn = {1439-3522}, mesh = {Erectile Dysfunction/*diagnosis/*therapy ; Humans ; Male ; Practice Guidelines as Topic ; }, abstract = {Die S1-Leitlinie "Diagnostik und Therapie der erektilen Dysfunktion" (AWMF-Registernummer 030 / 112) steht in einer vollständig überarbeiteten Neufassung zur Verfügung. Erektile Dysfunktion ist definiert als die fortwährende Unfähigkeit, eine penile Erektion, die für einen befriedigenden Geschlechtsverkehr ausreicht, zu erreichen oder aufrechtzuerhalten. Betroffen sind Millionen Bundesbürger: Bei Männern mit regelmäßiger sexueller Aktivität nimmt die erektile Dysfunktion von 2,3 Prozent in der dritten Lebensdekade auf 53,4 Prozent in der siebten Lebensdekade zu. Die Leitlinie gibt dezidierte Empfehlungen zur adäquaten Diagnose und zur Therapie der erektilen Dysfunktion, die seit der Einführung der Phosphodiesterase-5-(PDE-5-)Hemmer häufig unkritisch erfolgt.}, }
@article {pmid30998900, year = {2019}, author = {Nussbacher, JK and Tabet, R and Yeo, GW and Lagier-Tourenne, C}, title = {Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.}, journal = {Neuron}, volume = {102}, number = {2}, pages = {294-320}, pmid = {30998900}, issn = {1097-4199}, support = {R01 EY029166/EY/NEI NIH HHS/United States ; R01 NS087227/NS/NINDS NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; U19 MH107367/MH/NIMH NIH HHS/United States ; T32 CA067754/CA/NCI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagy ; CRISPR-Cas Systems ; Genetic Therapy ; Genetic Vectors ; Homeostasis ; Humans ; Molecular Targeted Therapy ; Nervous System Diseases/genetics/*metabolism/therapy ; Oligoribonucleotides, Antisense/therapeutic use ; Paraneoplastic Syndromes, Nervous System/genetics/metabolism/therapy ; RNA/*metabolism ; RNA Processing, Post-Transcriptional ; RNA Splicing ; RNA Stability ; RNA Transport ; RNA-Binding Proteins/*metabolism ; }, abstract = {RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.}, }
@article {pmid30989697, year = {2019}, author = {Hobson-Webb, LD and Simmons, Z}, title = {ULTRASOUND IN THE DIAGNOSIS AND MONITORING OF AMYOTROPHIC LATERAL SCLEROSIS: A REVIEW.}, journal = {Muscle &amp; nerve}, volume = {60}, number = {2}, pages = {114-123}, doi = {10.1002/mus.26487}, pmid = {30989697}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/physiopathology ; Diaphragm/diagnostic imaging/physiopathology ; Disease Progression ; Fasciculation/*diagnostic imaging ; Humans ; Muscle, Skeletal/*diagnostic imaging/pathology ; Organ Size ; Peripheral Nerves/*diagnostic imaging/pathology ; Sensitivity and Specificity ; Ultrasonography ; }, abstract = {Neuromuscular ultrasound is complementary to electrodiagnostic (EDx) testing and is useful in enhancing the diagnosis of mononeuropathies, peripheral nerve trauma, and demyelinating polyneuropathies. There is increasing interest in using ultrasound both to aid in the diagnosis of amyotrophic lateral sclerosis (ALS) and to monitor its progression. In this article we review the relevant literature on ultrasound in ALS. Ultrasound is more sensitive than EDx in identifying fasciculations in patients with ALS. It can detect decreased muscle thickness, increased muscle echointensity and echovariance, and reduced peripheral nerve size in these patients. Ultrasound is also a helpful tool in assessment of diaphragm function. Although additional studies are required to define the exact role of ultrasound in the evaluation and monitoring of ALS, it can improve the diagnostic yield in patients when ALS is suspected, but insufficiently supported, by clinical and EDx examinations. Muscle Nerve 60: 114-123, 2019.}, }
@article {pmid30980198, year = {2019}, author = {Zou, S and Lan, YL and Wang, H and Zhang, B and Sun, YG}, title = {The potential roles of aquaporin 4 in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {40}, number = {8}, pages = {1541-1549}, pmid = {30980198}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Aquaporin 4/*metabolism ; Humans ; }, abstract = {Aquaporin 4 (AQP4) is a primary water channel found on astrocytes in the central nervous system (CNS). Besides its function in water and ion homeostasis, AQP4 has also been documented to be involved in a myriad of acute and chronic cerebral pathologies, including autoimmune neurodegenerative diseases. AQP4 has been postulated to be associated with the incidence of a progressive neurodegenerative disorder known as amyotrophic lateral sclerosis (ALS), a disease that targets the motor neurons, causing muscle weakness and eventually paralysis. Raised AQP4 levels were noted in association with vessels surrounded with swollen astrocytic processes as well as in the brainstem, cortex, and gray matter in patients with terminal ALS. AQP4 depolarization may lead to motor neuron degeneration in ALS via GLT-1. Besides, alterations in AQP4 expression in ALS may result in the loss of blood-brain barrier (BBB) integrity. Changes in AQP4 function may also disrupt K[+] homeostasis and cause connexin dysregulation, the latter of which is associated to ALS disease progression. Furthermore, AQP4 suppression augments recovery in motor function in ALS, a phenomenon thought to be associated to NGF. No therapeutic drug targeting AQP4 has been developed to date. Nevertheless, the plethora of suggestive experimental results underscores the significance of further exploration into this area.}, }
@article {pmid30980111, year = {2019}, author = {Nahalka, J}, title = {The role of the protein-RNA recognition code in neurodegeneration.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {76}, number = {11}, pages = {2043-2058}, pmid = {30980111}, issn = {1420-9071}, support = {ITMS 26220120054//Research and Development Operational Programme/ ; VEGA 2/0058/17//VEGA/ ; }, mesh = {Alzheimer Disease/genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Binding Sites ; *Genetic Code ; Genome, Human ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/genetics/metabolism ; Humans ; Huntington Disease/genetics/metabolism/pathology ; MicroRNAs/genetics/*metabolism ; *Microsatellite Repeats ; Myotonic Dystrophy/genetics/metabolism/pathology ; PTB-Associated Splicing Factor/genetics/metabolism ; Parkinson Disease/genetics/metabolism/pathology ; Prion Diseases/genetics/metabolism/pathology ; Protein Binding ; *Protein Processing, Post-Translational ; RNA, Messenger/genetics/*metabolism ; }, abstract = {MicroRNAs are small endogenous RNAs that pair and bind to sites on mRNAs to direct post-transcriptional repression. However, there is a possibility that microRNAs directly influence protein structure and activity, and this influence can be termed post-translational riboregulation. This conceptual review explores the literature on neurodegenerative disorders. Research on the association between neurodegeneration and RNA-repeat toxicity provides data that support a protein-RNA recognition code. For example, this code explains why hnRNP H and SFPQ proteins, which are involved in amyotrophic lateral sclerosis, are sequestered by the (GGGGCC)n repeat sequence. Similarly, it explains why MNBL proteins and (CTG)n repeats in RNA, which are involved in myotonic dystrophy, are sequestered into RNA foci. Using this code, proteins involved in diseases can be identified. A simple protein BLAST search of the human genome for amino acid repeats that correspond to the nucleotide repeats reveals new proteins among already known proteins that are involved in diseases. For example, the (CAG)n repeat sequence, when transcribed into possible peptide sequences, leads to the identification of PTCD3, Rem2, MESP2, SYPL2, WDR33, COL23A1, and others. After confirming this approach on RNA repeats, in the next step, the code was used in the opposite manner. Proteins that are involved in diseases were compared with microRNAs involved in those diseases. For example, a reasonable correspondence of microRNA 9 and 107 with amyloid-β-peptide (Aβ42) was identified. In the last step, a miRBase search for micro-nucleotides, obtained by transcription of a prion amino acid sequence, revealed new microRNAs and microRNAs that have previously been identified as involved in prion diseases. This concept provides a useful key for designing RNA or peptide probes.}, }
@article {pmid30974127, year = {2019}, author = {Beigel, JH and Nam, HH and Adams, PL and Krafft, A and Ince, WL and El-Kamary, SS and Sims, AC}, title = {Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference.}, journal = {Antiviral research}, volume = {167}, number = {}, pages = {45-67}, pmid = {30974127}, issn = {1872-9096}, support = {T32 AI095207/AI/NIAID NIH HHS/United States ; }, mesh = {Adenosine Monophosphate/analogs &amp; derivatives/pharmacology ; Alanine/analogs &amp; derivatives/pharmacology ; Antiviral Agents/*pharmacology ; Coronavirus Infections/diagnosis/drug therapy/transmission ; Humans ; Influenza, Human/diagnosis/drug therapy/transmission ; Pandemics ; Respiratory Syncytial Virus, Human/drug effects/genetics/pathogenicity ; Respiratory Tract Infections/*therapy/*virology ; }, abstract = {The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13-15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.}, }
@article {pmid30971875, year = {2019}, author = {Yimer, EM and Hishe, HZ and Tuem, KB}, title = {Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {236}, pmid = {30971875}, issn = {1662-4548}, abstract = {To date, there is no cure or disease-modifying agents available for most well-known neurological disorders. Current therapy is typically focused on relieving symptoms and supportive care in improving the quality of life of affected patients. Furthermore, the traditional de novo drug discovery technique is more challenging, particularly for neurological disorders. Therefore, the repurposing of existing drugs for these conditions is believed to be an efficient and dynamic approach that can substantially reduce the investments spent on drug development. Currently, there is emerging evidence that suggests the potential effect of a beta-lactam antibiotic, ceftriaxone (CEF), to alleviate the symptoms of different experimentally-induced neurological disorders: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epileptic-seizure, brain ischemia, traumatic brain injuries, and neuropathic pain. CEF also affects the markers of oxidative status and neuroinflammation, glutamatergic systems as well as various aggregated toxic proteins involved in the pathogenesis of different neurological disorders. Moreover, it was found that CEF administration to drug dependent animal models improved the withdrawal symptoms upon drug discontinuation. Thus, this review aimed to describe the effects of CEF against multiple models of neurological illnesses, drug dependency, and withdrawal. It also emphasizes the possible mechanisms of neuroprotective actions of CEF with respective neurological maladies.}, }
@article {pmid30967892, year = {2019}, author = {Verdile, V and De Paola, E and Paronetto, MP}, title = {Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease.}, journal = {Frontiers in genetics}, volume = {10}, number = {}, pages = {173}, pmid = {30967892}, issn = {1664-8021}, abstract = {Phase separation is a physiological process occurring spontaneously when single-phase molecular complexes separate in two phases, a concentrated phase and a more diluted one. Eukaryotic cells employ phase transition strategies to promote the formation of intracellular territories not delimited by membranes with increased local RNA concentration, such as nucleolus, paraspeckles, P granules, Cajal bodies, P-bodies, and stress granules. These organelles contain both proteins and coding and non-coding RNAs and play important roles in different steps of the regulation of gene expression and in cellular signaling. Recently, it has been shown that most human RNA-binding proteins (RBPs) contain at least one low-complexity domain, called prion-like domain (PrLD), because proteins harboring them display aggregation properties like prion proteins. PrLDs support RBP function and contribute to liquid-liquid phase transitions that drive ribonucleoprotein granule assembly, but also render RBPs prone to misfolding by promoting the formation of pathological aggregates that lead to toxicity in specific cell types. Protein-protein and protein-RNA interactions within the separated phase can enhance the transition of RBPs into solid aberrant aggregates, thus causing diseases. In this review, we highlight the role of phase transition in human disease such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and in cancer. Moreover, we discuss novel therapeutic strategies focused to control phase transitions by preventing the conversion into aberrant aggregates. In this regard, the stimulation of chaperone machinery to disassemble membrane-less organelles, the induction of pathways that could inhibit aberrant phase separation, and the development of antisense oligonucleotides (ASOs) to knockdown RNAs could be evaluated as novel therapeutic strategies for the treatment of those human diseases characterized by aberrant phase transition aggregates.}, }
@article {pmid30967833, year = {2019}, author = {Lulé, D and Kübler, A and Ludolph, AC}, title = {Ethical Principles in Patient-Centered Medical Care to Support Quality of Life in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {259}, pmid = {30967833}, issn = {1664-2295}, abstract = {It is one of the primary goals of medical care to secure good quality of life (QoL) while prolonging survival. This is a major challenge in severe medical conditions with a prognosis such as amyotrophic lateral sclerosis (ALS). Further, the definition of QoL and the question whether survival in this severe condition is compatible with a good QoL is a matter of subjective and culture-specific debate. Some people without neurodegenerative conditions believe that physical decline is incompatible with satisfactory QoL. Current data provide extensive evidence that psychosocial adaptation in ALS is possible, indicated by a satisfactory QoL. Thus, there is no fatalistic link of loss of QoL when physical health declines. There are intrinsic and extrinsic factors that have been shown to successfully facilitate and secure QoL in ALS which will be reviewed in the following article following the four ethical principles (1) Beneficence, (2) Non-maleficence, (3) Autonomy and (4) Justice, which are regarded as key elements of patient centered medical care according to Beauchamp and Childress. This is a JPND-funded work to summarize findings of the project NEEDSinALS (www.NEEDSinALS.com) which highlights subjective perspectives and preferences in medical decision making in ALS.}, }
@article {pmid30964958, year = {2020}, author = {Angelbello, AJ and Chen, JL and Disney, MD}, title = {Small molecule targeting of RNA structures in neurological disorders.}, journal = {Annals of the New York Academy of Sciences}, volume = {1471}, number = {1}, pages = {57-71}, pmid = {30964958}, issn = {1749-6632}, support = {DP1 NS096898/NS/NINDS NIH HHS/United States ; P01 NS099114/NS/NINDS NIH HHS/United States ; R01 GM097455/GM/NIGMS NIH HHS/United States ; R33 NS096032/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; Huntington Disease/drug therapy/genetics ; Nervous System Diseases/*drug therapy/genetics/pathology ; Nucleic Acid Conformation/*drug effects ; Oligonucleotides/genetics/therapeutic use ; RNA/antagonists &amp; inhibitors/*genetics ; RNA Precursors/genetics ; RNA Splicing/drug effects ; Small Molecule Libraries/*therapeutic use ; }, abstract = {Aberrant RNA structure and function operate in neurological disease progression and severity. As RNA contributes to disease pathology in a complex fashion, that is, via various mechanisms, it has become an attractive therapeutic target for small molecules and oligonucleotides. In this review, we discuss the identification of RNA structures that cause or contribute to neurological diseases as well as recent progress toward the development of small molecules that target them, including small molecule modulators of pre-mRNA splicing and RNA repeat expansions that cause microsatellite disorders such as Huntington's disease and amyotrophic lateral sclerosis. The use of oligonucleotide-based modalities is also discussed. There are key differences between small molecule and oligonucleotide targeting of RNA. The former targets RNA structure, while the latter prefers unstructured regions. Thus, some targets will be preferentially targeted by oligonucleotides and others by small molecules.}, }
@article {pmid30963986, year = {2019}, author = {Li, L and Liu, J and She, H}, title = {Targeting Macrophage for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {18}, number = {5}, pages = {366-371}, doi = {10.2174/1871527318666190409103831}, pmid = {30963986}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drug Delivery Systems/*methods ; Humans ; Macrophages/*drug effects ; Neuromuscular Junction/drug effects ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that specifically affects motor neurons in the brain and in the spinal cord. Patients with amyotrophic lateral sclerosis usually die from respiratory failure within 3 to 5 years from when the symptoms first appear. Currently, there is no cure for amyotrophic lateral sclerosis. Accumulating evidence suggests that dismantling of neuromuscular junction is an early event in the pathogenesis of amyotrophic lateral sclerosis.<br><br>CONCLUSION: It is starting to realized that macrophage malfunction contributes to the disruption of neuromuscular junction. Modulation of macrophage activation states may stabilize neuromuscular junction and provide protection against motor neuron degeneration in amyotrophic lateral sclerosis.}, }
@article {pmid30956667, year = {2019}, author = {Gugliandolo, A and Bramanti, P and Mazzon, E}, title = {Mesenchymal Stem Cells: A Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis?.}, journal = {Stem cells international}, volume = {2019}, number = {}, pages = {3675627}, pmid = {30956667}, issn = {1687-966X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Patients show both motor and extra-motor symptoms. A cure is not available at this time, and the disease leads to death within 3-5 years, mainly due to respiratory failure. Stem cell therapy is arising as a new promising approach for the treatment of neurodegenerative disorders. In particular, mesenchymal stem cells (MSCs) seem the most suitable type of stem cells, thanks to their demonstrated beneficial effects in different experimental models, to the easy availability, and to the lack of ethical problems. In this review, we focused on the studies involving ALS rodent models and clinical trials in order to understand the potential beneficial effects of MSC transplantation. In different ALS rodent models, the administration of MSCs induced a delay in disease progression and at least a partial recovery of the motor function. In addition, clinical trials evidenced the feasibility and safety of MSC transplantation in ALS patients, given that no major adverse events were recorded. However, only partial improvements were shown. For this reason, more studies and trials are needed to clarify the real effectiveness of MSC-based therapy in ALS.}, }
@article {pmid30949950, year = {2019}, author = {Ghasemi, F and Bagheri, H and Barreto, GE and Read, MI and Sahebkar, A}, title = {Effects of Curcumin on Microglial Cells.}, journal = {Neurotoxicity research}, volume = {36}, number = {1}, pages = {12-26}, pmid = {30949950}, issn = {1476-3524}, mesh = {Animals ; Anti-Inflammatory Agents/administration &amp; dosage/immunology ; Brain/*drug effects/*immunology ; Curcumin/*administration &amp; dosage ; Encephalitis/immunology/prevention &amp; control ; Humans ; Microglia/*drug effects/*immunology ; Neurons/drug effects/immunology ; }, abstract = {Microglia are innate immune system cells which reside in the central nervous system (CNS). Resting microglia regulate the homeostasis of the CNS via phagocytic activity to clear pathogens and cell debris. Sometimes, however, to protect neurons and fight invading pathogens, resting microglia transform to an activated-form, producing inflammatory mediators, such as cytokines, chemokines, iNOS/NO and cyclooxygenase-2 (COX-2). Excessive inflammation, however, leads to damaged neurons and neurodegenerative diseases (NDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Curcumin is a phytochemical isolated from Curcuma longa. It is widely used in Asia and has many therapeutic properties, including antioxidant, anti-viral, anti-bacterial, anti-mutagenic, anti-amyloidogenic and anti-inflammatory, especially with respect to neuroinflammation and neurological disorders (NDs). Curcumin is a pleiotropic molecule that inhibits microglia transformation, inflammatory mediators and subsequent NDs. In this mini-review, we discuss the effects of curcumin on microglia and explore the underlying mechanisms.}, }
@article {pmid30949121, year = {2019}, author = {Finegan, E and Chipika, RH and Li Hi Shing, S and Hardiman, O and Bede, P}, title = {Pathological Crying and Laughing in Motor Neuron Disease: Pathobiology, Screening, Intervention.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {260}, pmid = {30949121}, issn = {1664-2295}, abstract = {Pathological crying and laughing (PCL) has significant quality-of-life implications in amyotrophic lateral sclerosis (ALS); it can provoke restrictive life-style modifications and lead to social isolation. Despite its high prevalence and quality of life implications, it remains surprisingly understudied. Divergent pathophysiological models have been proposed, centered on corticobulbar tract degeneration, prefrontal cortex pathology, sensory deafferentation, and impaired cerebellar gate-control mechanisms. Quantitative MRI techniques and symptom-specific clinical instruments offer unprecedented opportunities to elucidate the anatomical underpinnings of PCL pathogenesis. Emerging neuroimaging studies of ALS support the role of cortico-pontine-cerebellar network dysfunction in context-inappropriate emotional responses. The characterization of PCL-associated pathophysiological processes is indispensable for the development of effective pharmacological therapies.}, }
@article {pmid30949015, year = {2019}, author = {Halon-Golabek, M and Borkowska, A and Herman-Antosiewicz, A and Antosiewicz, J}, title = {Iron Metabolism of the Skeletal Muscle and Neurodegeneration.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {165}, pmid = {30949015}, issn = {1662-4548}, abstract = {Recent studies clearly indicate that the endocrine function of the skeletal muscle is essential for a long and healthy life. Regular exercise, which has been shown to stimulate the release of myokines, lowers the risk of many diseases, including Alzheimer's and Parkinson's disease, emphasizing the role of skeletal muscle in proper functioning of other tissues. In addition, exercise increases insulin sensitivity, which may also impact iron metabolism. Even though the role of iron in neurodegeneration is well established, the exact mechanisms of iron toxicity are not known. Interestingly, exercise has been shown to modulate iron metabolism, mainly by reducing body iron stores. Insulin signaling and iron metabolism are interconnected, as high tissue iron stores are associated with insulin resistance, and conversely, impaired insulin signaling may lead to iron accumulation in an affected tissue. Excess iron accumulation in tissue triggers iron-dependent oxidative stress. Further, iron overload in the skeletal muscle not only negatively affects muscle contractility but also might impact its endocrine function, thus possibly affecting the clinical outcome of diseases, including neurodegenerative diseases. In this review, we discuss possible mechanisms of iron dependent oxidative stress in skeletal muscle, its impact on muscle mass and endocrine function, as well as on neurodegeneration processes.}, }
@article {pmid30948513, year = {2019}, author = {Shorter, J}, title = {Phase separation of RNA-binding proteins in physiology and disease: An introduction to the JBC Reviews thematic series.}, journal = {The Journal of biological chemistry}, volume = {294}, number = {18}, pages = {7113-7114}, pmid = {30948513}, issn = {1083-351X}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Chromatography, Liquid/*methods ; Frontotemporal Dementia/metabolism ; Humans ; Neurodegenerative Diseases/metabolism ; RNA-Binding Proteins/*isolation &amp; purification ; }, abstract = {In recent years, there has been a jarring awakening that liquid-liquid phase separation (LLPS) of key protein and nucleic acid scaffolds underpins the biogenesis of diverse membraneless organelles, including P granules and stress granules in the cytoplasm and nucleoli and paraspeckles in the nucleus. These biomolecular condensates are proposed to be critical organizers of subcellular biochemistry and to control the flow of information from genotype to phenotype. Despite clear biological utility, LLPS can also have deleterious outcomes. Phase-separated compartments can concentrate specific RNA-binding proteins (RBPs), such as TDP-43 and fused in sarcoma (FUS), that through low-complexity, prion-like domains have an intrinsic tendency to form self-templating fibrils that are closely tied to fatal neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This series of reviews illuminates the molecular language underlying membraneless organelle biogenesis, how prion-like domains and post-translational modifications regulate phase behavior, how cells exploit the phase-separation process for adaptive modalities, and how phase separation is corrupted in neurodegenerative diseases. Collectively, these pieces provide a cutting-edge view of our functional and mechanistic understanding of phase separation in physiology and disease.}, }
@article {pmid30941088, year = {2019}, author = {Chipika, RH and Finegan, E and Li Hi Shing, S and Hardiman, O and Bede, P}, title = {Tracking a Fast-Moving Disease: Longitudinal Markers, Monitoring, and Clinical Trial Endpoints in ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {229}, pmid = {30941088}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) encompasses a heterogeneous group of phenotypes with different progression rates, varying degree of extra-motor involvement and divergent progression patterns. The natural history of ALS is increasingly evaluated by large, multi-time point longitudinal studies, many of which now incorporate presymptomatic and post-mortem assessments. These studies not only have the potential to characterize patterns of anatomical propagation, molecular mechanisms of disease spread, but also to identify pragmatic monitoring markers. Sensitive markers of progressive neurodegenerative change are indispensable for clinical trials and individualized patient care. Biofluid markers, neuroimaging indices, electrophysiological markers, rating scales, questionnaires, and other disease-specific instruments have divergent sensitivity profiles. The discussion of candidate monitoring markers in ALS has a dual academic and clinical relevance, and is particularly timely given the increasing number of pharmacological trials. The objective of this paper is to provide a comprehensive and critical review of longitudinal studies in ALS, focusing on the sensitivity profile of established and emerging monitoring markers.}, }
@article {pmid30938443, year = {2019}, author = {Hergesheimer, RC and Chami, AA and de Assis, DR and Vourc'h, P and Andres, CR and Corcia, P and Lanznaster, D and Blasco, H}, title = {The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight?.}, journal = {Brain : a journal of neurology}, volume = {142}, number = {5}, pages = {1176-1194}, pmid = {30938443}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Autophagy/*physiology ; Cell Death/physiology ; Cytoplasm/metabolism/pathology ; DNA-Binding Proteins/*metabolism/*toxicity ; Humans ; Protein Aggregates/*physiology ; }, abstract = {Transactive response DNA-binding protein-43 (TDP-43) is an RNA/DNA binding protein that forms phosphorylated and ubiquitinated aggregates in the cytoplasm of motor neurons in amyotrophic lateral sclerosis, which is a hallmark of this disease. Amyotrophic lateral sclerosis is a neurodegenerative condition affecting the upper and lower motor neurons. Even though the aggregative property of TDP-43 is considered a cornerstone of amyotrophic lateral sclerosis, there has been major controversy regarding the functional link between TDP-43 aggregates and cell death. In this review, we attempt to reconcile the current literature surrounding this debate by discussing the results and limitations of the published data relating TDP-43 aggregates to cytotoxicity, as well as therapeutic perspectives of TDP-43 aggregate clearance. We point out key data suggesting that the formation of TDP-43 aggregates and the capacity to self-template and propagate among cells as a 'prion-like' protein, another pathological property of TDP-43 aggregates, are a significant cause of motor neuronal death. We discuss the disparities among the various studies, particularly with respect to the type of models and the different forms of TDP-43 used to evaluate cellular toxicity. We also examine how these disparities can interfere with the interpretation of the results pertaining to a direct toxic effect of TDP-43 aggregates. Furthermore, we present perspectives for improving models in order to better uncover the toxic role of aggregated TDP-43. Finally, we review the recent studies on the enhancement of the cellular clearance mechanisms of autophagy, the ubiquitin proteasome system, and endocytosis in an attempt to counteract TDP-43 aggregation-induced toxicity. Altogether, the data available so far encourage us to suggest that the cytoplasmic aggregation of TDP-43 is key for the neurodegeneration observed in motor neurons in patients with amyotrophic lateral sclerosis. The corresponding findings provide novel avenues toward early therapeutic interventions and clinical outcomes for amyotrophic lateral sclerosis management.}, }
@article {pmid30936848, year = {2019}, author = {Kirk, SE and Tracey, TJ and Steyn, FJ and Ngo, ST}, title = {Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {191}, pmid = {30936848}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators.}, }
@article {pmid30930396, year = {2019}, author = {Kusama-Eguchi, K}, title = {[Research in Motor Neuron Diseases Caused by Natural Substances: Focus on Pathological Mechanisms of Neurolathyrism].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {139}, number = {4}, pages = {609-615}, doi = {10.1248/yakushi.18-00202}, pmid = {30930396}, issn = {1347-5231}, mesh = {Animals ; Cell Death/drug effects ; Disease Models, Animal ; Fabaceae/*adverse effects/chemistry ; Humans ; Lathyrism/*etiology/pathology ; Lathyrus/*adverse effects/chemistry ; Motor Neuron Disease/etiology/pathology ; Motor Neurons/pathology ; Rats ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; beta-Alanine/*analogs &amp; derivatives/isolation &amp; purification/toxicity ; }, abstract = {Diseases of the motor-conducting system that cause moving disability affect socio-economic activity as well as human dignity. Neurolathyrism, konzo, and amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) have attracted researchers to study the pathology of motor neuron (MN) diseases such as ALS. I have been studying neurolathyrism, which is caused by overconsumption of a legume grass pea (Lathyrys sativus L.). Among people who consume the legume as a food staple, many developed life-long paraparesis in their legs. β-N-oxalyl-l-α,β- diaminopropionic (l-β-ODAP; BOAA), contained in this plant, is a neurotoxic analog of l-glutamic acid. We have clarified that in addition to the causal involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamatergic receptor in MN death, a toxic role of group I metabotropic glutamate receptors as well as transient receptor potential channels were involved in the MN insult by l-β-ODAP using primary MN culture. We have also established a neurolathyrism rat model by repeated, peripheral l-β-ODAP treatment to newborn rats under mild stress. Rats showing hind-leg paraparesis with an incidence rate of around 25% were useful to study the in vivo pathology of MN disease. MNs of these rats were greatly decreased at their lumbo/sacral segments at various ages. Intra-parenchymal hemorrhage was consistently observed in paraparetic rats but not in cripple-free, treated rats. MN were depleted even at an acute period around bleeding spots, suggesting catastrophic neuro-vascular-glial interaction in this MN disease. Summaries of konzo and ALS-PDCs studies are also introduced.}, }
@article {pmid30915018, year = {2019}, author = {Caga, J and Hsieh, S and Lillo, P and Dudley, K and Mioshi, E}, title = {The Impact of Cognitive and Behavioral Symptoms on ALS Patients and Their Caregivers.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {192}, pmid = {30915018}, issn = {1664-2295}, support = {MIOSHI/MAY16/934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Previously thought to be a pure motor disease, amyotrophic lateral sclerosis (ALS) is now established as multisystem neurodegenerative disorder that lies on a continuum with frontotemporal dementia (FTD). Cognitive and behavioral symptoms primarily extend to executive function, personality, social conduct, and emotion processing. The assessment and management of cognitive and behavioral symptoms is complicated as they must be differentiated from psychological responses to a terminal diagnosis and progressive physical impairment. This is made more difficult by the limited number of studies investigating how these symptoms specifically affect patients and caregivers well-being. The current review focuses on the impact of cognitive and behavioral symptoms on patient and caregiver well-being and their implications for future research and interventions in ALS. This is an important area of research that could form the basis for more tailored, and potentially more successful, non-pharmacological interventions to improve psychological well-being among patients with ALS and their caregivers.}, }
@article {pmid30914912, year = {2019}, author = {Zucchi, E and Ticozzi, N and Mandrioli, J}, title = {Psychiatric Symptoms in Amyotrophic Lateral Sclerosis: Beyond a Motor Neuron Disorder.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {175}, pmid = {30914912}, issn = {1662-4548}, abstract = {The historical view that Amyotrophic Lateral Sclerosis (ALS) as a pure motor disorder has been increasingly challenged by the discovery of cognitive and behavioral changes in the spectrum of Frontotemporal Dementia (FTD). Less recognized and still significant comorbidities that ALS patients may present are prior or concomitant psychiatric illness, such as psychosis and schizophrenia, or mood disorders. These non-motor symptoms disturbances have a close time relationship with disease onset, may constitute part of a larger framework of network disruption in motor neuron disorders, and may impact ALS patients and families, with regards to ethical choices and end-of-life decisions. This review aims at identifying the most common psychiatric alterations related to ALS and its prognosis, looking at a common genetic background and shared structural brain pathology.}, }
@article {pmid30914480, year = {2019}, author = {Elbaum-Garfinkle, S}, title = {Matter over mind: Liquid phase separation and neurodegeneration.}, journal = {The Journal of biological chemistry}, volume = {294}, number = {18}, pages = {7160-7168}, pmid = {30914480}, issn = {1083-351X}, support = {R00 NS096217/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Molecular Dynamics Simulation ; Neurodegenerative Diseases/*metabolism ; *Phase Transition ; Proteins/metabolism ; }, abstract = {Phase separation of biomolecules leading to the formation of assemblies with distinct material properties has recently emerged as a new paradigm underlying subcellular organization. The discovery that disordered proteins, long associated with aggregation in neurodegenerative disease, are also implicated in driving liquid phase separation has galvanized significant interest in exploring the relationship between misregulated phase transitions and disease. This review summarizes recent work linking liquid phase separation to neurodegeneration, highlighting a pathological role for altered phase behavior and material properties of proteins assembled via liquid phase separation. The techniques that recent and current work in this area have deployed are also discussed, as is the potential for these discoveries to promote new research directions for investigating the molecular etiologies of neurodegenerative diseases.}, }
@article {pmid30912216, year = {2019}, author = {Morelot-Panzini, C and Bruneteau, G and Gonzalez-Bermejo, J}, title = {NIV in amyotrophic lateral sclerosis: The 'when' and 'how' of the matter.}, journal = {Respirology (Carlton, Vic.)}, volume = {24}, number = {6}, pages = {521-530}, doi = {10.1111/resp.13525}, pmid = {30912216}, issn = {1440-1843}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; Cognition ; Humans ; Noninvasive Ventilation/*methods ; Prognosis ; *Quality of Life ; }, abstract = {Non-invasive ventilation (NIV) has become an essential part of the treatment of amyotrophic lateral sclerosis (ALS) since 2006. NIV very significantly improves survival, quality of life and cognitive performances. The initial NIV settings are simple, but progression of the disease, ventilator dependence and upper airway involvement sometimes make long-term adjustment of NIV more difficult, with a major impact on survival. Unique data concerning the long-term adjustment of NIV in ALS show that correction of leaks, management of obstructive apnoea and adaptation to the patient's degree of ventilator dependence improve the prognosis. Non-ventilatory factors also impact the efficacy of NIV and various solutions have been described and must be applied, including cough assist techniques, control of excess salivation and renutrition. NIV in ALS has been considerably improved as a result of application of all of these measures, avoiding the need for tracheostomy in the very great majority of cases. More advanced use of NIV also requires pulmonologists to master the associated end-of-life palliative care, as well as the modalities of discontinuing ventilation when it becomes unreasonable.}, }
@article {pmid30911936, year = {2019}, author = {Abati, E and Bresolin, N and Comi, G and Corti, S}, title = {Advances, Challenges, and Perspectives in Translational Stem Cell Therapy for Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {56}, number = {10}, pages = {6703-6715}, pmid = {30911936}, issn = {1559-1182}, support = {778003//Ministero della Salute/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic ; Humans ; Research Design ; *Stem Cell Transplantation ; *Translational Research, Biomedical ; }, abstract = {Finding an effective therapeutic approach is a primary goal for current and future research for amyotrophic lateral sclerosis (ALS), a fatal neurological disease characterized by degeneration and loss of upper and lower motor neurons. Transplantation approaches based on stem cells have been attempted in virtue of their potential to contrast simultaneously different ALS pathogenic aspects including either the replacement of lost cells or the protection of motor neurons from degeneration and toxic microenvironment. Here, we critically review the recent translational research aimed at the assessment of stem cell transplantation safety and feasibility in the treatment of ALS. Most of these efforts aim to exert a neuroprotective action rather than cell replacement. Critical aspects that emerge in these studies are the need for the identification of the most effective therapeutic cell source (mesenchymal stem cells, immune, or neural stem cells), the definition of the optimal injection site (cortical area, spinal cord, or muscles) with a suitable administration protocol (local or systemic injection), and the analysis of therapeutic mechanisms, which are necessary steps in order to overcome the hurdles posed by previous in vivo human studies. New perspectives will also be offered by the increasing number of induced pluripotent stem cell-based therapies that are now being tested in clinical trials. A thorough analysis of recently completed trials is the foundation for continued progress in cellular therapy for ALS and other neurodegenerative disorders.}, }
@article {pmid30909602, year = {2019}, author = {Geisler, JG}, title = {2,4 Dinitrophenol as Medicine.}, journal = {Cells}, volume = {8}, number = {3}, pages = {}, pmid = {30909602}, issn = {2073-4409}, mesh = {2,4-Dinitrophenol/*metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Calcium/metabolism ; Cognition ; Humans ; *Medicine ; Reactive Oxygen Species/metabolism ; }, abstract = {In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950's to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin[®] and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and "morning sickness" anti-nausea medication targeting pregnant women in the 1950's. The "thalidomide babies" became the case-in-point for the need of strict guidelines by the U.S. Food &amp; Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of "social responsibility" allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle's physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca[2+]) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca[2+] overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer's Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for "metabesity", an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP's induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80's years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).}, }
@article {pmid30907153, year = {2019}, author = {Crook, A and McEwen, A and Fifita, JA and Zhang, K and Kwok, JB and Halliday, G and Blair, IP and Rowe, DB}, title = {The C9orf72 hexanucleotide repeat expansion presents a challenge for testing laboratories and genetic counseling.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {5-6}, pages = {310-316}, doi = {10.1080/21678421.2019.1588904}, pmid = {30907153}, issn = {2167-9223}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Female ; Genetic Counseling/methods/*standards ; Genetic Testing/methods/*standards ; Humans ; Pedigree ; }, abstract = {C9orf72 hexanucleotide repeat expansions are the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Genetic testing for C9orf72 expansions in patients with ALS and/or FTD and their relatives has become increasingly available since hexanucleotide repeat expansions were first reported in 2011. The repeat number is highly variable and the threshold at which repeat size leads to neurodegeneration remains unknown. We present the case of an ALS patient who underwent genetic testing through our Motor Neurone Disease Clinic. We highlight current limitations to analysing and interpreting C9orf72 expansion test results and describe how this resulted in discordant reports of pathogenicity between testing laboratories that confounded the genetic counselling process. We conclude that patients with ALS or FTD and their at-risk family members, need to be adequately counselled about the limitations of current knowledge to ensure they are making informed decisions about genetic testing for C9orf72. Greater collaboration between clinicians, testing laboratories and researchers is required to ensure risks to patients and their families are minimised.}, }
@article {pmid30906528, year = {2019}, author = {Lemon, R}, title = {Recent advances in our understanding of the primate corticospinal system.}, journal = {F1000Research}, volume = {8}, number = {}, pages = {}, pmid = {30906528}, issn = {2046-1402}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Motor Cortex ; *Primates/physiology ; *Pyramidal Tracts/physiology ; Species Specificity ; }, abstract = {The last few years have seen major advances in our understanding of the organisation and function of the corticospinal tract (CST). These have included studies highlighting important species-specific variations in the different functions mediated by the CST. In the primate, the most characteristic feature is direct cortico-motoneuronal (CM) control of muscles, particularly of hand and finger muscles. This system, which is unique to dexterous primates, is probably at its most advanced level in humans. We now know much more about the origin of the CM system within the cortical motor network, and its connectivity within the spinal cord has been quantified. We have learnt much more about how the CM system works in parallel with other spinal circuits receiving input from the CST and how the CST functions alongside other brainstem motor pathways. New work in the mouse has provided fascinating insights into the contribution of the CM system to dexterity. Finally, accumulating evidence for the involvement of CM projections in motor neuron disease has highlighted the importance of advances in basic neuroscience for our understanding and possible treatment of a devastating neurological disease.}, }
@article {pmid30904737, year = {2019}, author = {Klim, JR and Vance, C and Scotter, EL}, title = {Antisense oligonucleotide therapies for Amyotrophic Lateral Sclerosis: Existing and emerging targets.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {110}, number = {}, pages = {149-153}, doi = {10.1016/j.biocel.2019.03.009}, pmid = {30904737}, issn = {1878-5875}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Drug Delivery Systems ; Humans ; Molecular Targeted Therapy/*methods ; Oligonucleotides, Antisense/chemistry/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease with highly heterogenous causes, most of which remain unknown, a multitude of possible disease mechanisms, and no therapy currently available that can halt disease progression. However, recent advances in antisense oligonucleotides have made them a viable option for targeted therapeutics for patients. These molecules offer a method of targeting RNA that is highly specific, adaptable, and does not require viral delivery. Antisense oligonucleotides are therefore being developed for several genetic causes of ALS. Furthermore, biological pathways involved in the pathogenesis of disease also offer tantalizing targets for intervention using antisense oligonucleotides. Here we detail existing and potential targets for antisense oligonucleotides in ALS and briefly examine the requirements for these drugs to reach and be effective in clinic.}, }
@article {pmid30899244, year = {2019}, author = {Joilin, G and Leigh, PN and Newbury, SF and Hafezparast, M}, title = {An Overview of MicroRNAs as Biomarkers of ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {186}, pmid = {30899244}, issn = {1664-2295}, support = {HAFEZPARAST/APR15/836-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; HAFEZPARAST/APR18/861-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS; MND, motor neuron disease) is a debilitating neurodegenerative disease affecting 4.5 per 100,000 people per year around the world. There is currently no cure for this disease, and its causes are relatively unknown. Diagnosis is based on a battery of clinical tests up to a year after symptom onset, with no robust markers of diagnosis or disease progression currently identified. A major thrust of current research is to identify potential non-invasive markers ("biomarkers") in body fluids such as blood and/or cerebrospinal fluid (CSF) to use for diagnostic or prognostic purposes. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are found at detectable and stable levels in blood and other bodily fluids. Specific ncRNAs can vary in levels between ALS patients and non-ALS controls without the disease. In this review, we will provide an overview of early findings, demonstrate the potential of this new class as biomarkers, and discuss future challenges and opportunities taking this forward to help patients with ALS.}, }
@article {pmid30898538, year = {2020}, author = {Zhang, X and Hu, D and Shang, Y and Qi, X}, title = {Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1866}, number = {4}, pages = {165431}, pmid = {30898538}, issn = {1879-260X}, support = {R01 AG065240/AG/NIA NIH HHS/United States ; R01 NS088192/NS/NINDS NIH HHS/United States ; R21 NS107897/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Induced Pluripotent Stem Cells/*metabolism/pathology ; *Models, Neurological ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Current application of human induced pluripotent stem cells (hiPSCs) technology in patient-specific models of neurodegenerative disorders recapitulate some of key phenotypes of diseases, representing disease-specific cellular modeling and providing a unique platform for therapeutics development. We review recent efforts toward advancing hiPSCs-derived neuronal cell types and highlight their potential use for the development of more complex in vitro models of neurodegenerative diseases by focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. We present evidence from previous works on the important phenotypic changes of various neuronal types in these neurological diseases. We also summarize efforts on conducting low- and high-throughput screening experiments with hiPSCs toward developing potential therapeutics for treatment of neurodegenerative diseases. Lastly, we discuss the limitations of hiPSCs culture system in studying neurodegenerative diseases and alternative strategies to overcome these hurdles.}, }
@article {pmid30897357, year = {2019}, author = {Cook, C and Petrucelli, L}, title = {Genetic Convergence Brings Clarity to the Enigmatic Red Line in ALS.}, journal = {Neuron}, volume = {101}, number = {6}, pages = {1057-1069}, doi = {10.1016/j.neuron.2019.02.032}, pmid = {30897357}, issn = {1097-4199}, support = {U54 NS100693/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; C9orf72 Protein/*genetics ; Cell Cycle Proteins ; Cytoplasmic Granules/metabolism ; Cytoskeleton/*metabolism ; DNA Repeat Expansion ; DNA-Binding Proteins/*genetics/metabolism ; Humans ; Membrane Transport Proteins ; Mitochondria/*metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Transport/genetics ; RNA/*metabolism ; RNA-Binding Protein FUS/genetics ; Stress, Physiological ; Superoxide Dismutase-1/*genetics/metabolism ; Transcription Factor TFIIIA/genetics/metabolism ; Unfolded Protein Response ; Valosin Containing Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder that orchestrates an attack on the motor nervous system that is unrelenting. Recent discoveries into the pathogenic consequences of repeat expansions in C9ORF72, which are the most common genetic cause of ALS, combined with the identification of new genetic mutations are providing novel insight into the underlying mechanism(s) that cause ALS. In particular, the myriad of functions linked to ALS-associated genes have collectively implicated four main pathways in disease pathogenesis, including RNA metabolism and translational biology; protein quality control; cytoskeletal integrity and trafficking; and mitochondrial function and transport. Through the identification of common disease mechanisms on which multiple ALS genes converge, key targets for potential therapeutic intervention are highlighted.}, }
@article {pmid30892087, year = {2019}, author = {Benatar, M and Turner, MR and Wuu, J}, title = {Defining pre-symptomatic amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {5-6}, pages = {303-309}, pmid = {30892087}, issn = {2167-9223}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/*diagnosis/epidemiology ; Animals ; *Asymptomatic Diseases/epidemiology ; Biomarkers/blood ; Humans ; }, abstract = {Successful treatment of neurodegenerative disease may hinge on early therapeutic intervention. This requires an understanding of early/pre-symptomatic disease, a need that is underscored by advances in antisense oligonucleotide, and viral-vector-based gene therapies. In amyotrophic lateral sclerosis (ALS), the study of pre-symptomatic disease requires a cohesive conceptual framework for describing this phase of disease. Informed by the literature in other neurodegenerative diseases and extensive personal experience, a model is proposed that distinguishes ALS as a clinical syndrome from ALS as a disease, and characterizes pre-symptomatic ALS as having two identifiable stages: pre-manifest and prodromal. The unique and critical importance of biomarker development is articulated and an operational definition of phenoconversion is provided. It is hoped that this framework will accelerate collective efforts to study pre-symptomatic ALS, and aid in the design and implementation of an early intervention- or disease-prevention trial.}, }
@article {pmid30891444, year = {2019}, author = {Grochowski, C and Blicharska, E and Krukow, P and Jonak, K and Maciejewski, M and Szczepanek, D and Jonak, K and Flieger, J and Maciejewski, R}, title = {Analysis of Trace Elements in Human Brain: Its Aim, Methods, and Concentration Levels.}, journal = {Frontiers in chemistry}, volume = {7}, number = {}, pages = {115}, pmid = {30891444}, issn = {2296-2646}, abstract = {Trace elements play a crucial role in many biochemical processes, mainly as components of vitamins and enzymes. Although small amounts of metal ions have protective properties, excess metal levels result in oxidative injury, which is why metal ion homeostasis is crucial for the proper functioning of the brain. The changes of their level in the brain have been proven to be a risk factor for Alzheimer's, Parkinson's, and Huntington's diseases, as well as amyotrophic lateral sclerosis. Therefore, it is currently an important application of various analytical methods. This review covers the most important of them: inductively coupled ground mass spectrometry (ICP-MS), flame-induced atomic absorption spectrometry (FAAS), electrothermal atomic absorption spectrometry (GFAAS), optical emission spectrometry with excitation in inductively coupled plasma (ICP-OES), X-ray fluorescence spectrometry (XRF), and neutron activation analysis (NAA). Additionally, we present a summary of concentration values found by different research groups.}, }
@article {pmid30891004, year = {2019}, author = {Basaia, S and Filippi, M and Spinelli, EG and Agosta, F}, title = {White Matter Microstructure Breakdown in the Motor Neuron Disease Spectrum: Recent Advances Using Diffusion Magnetic Resonance Imaging.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {193}, pmid = {30891004}, issn = {1664-2295}, abstract = {Motor neuron disease (MND) is a fatal progressive neurodegenerative disorder characterized by the breakdown of the motor system. The clinical spectrum of MND encompasses different phenotypes classified according to the relative involvement of the upper or lower motor neurons (LMN) and the presence of genetic or cognitive alterations, with clear prognostic implications. However, the pathophysiological differences of these phenotypes remain largely unknown. Recently, magnetic resonance imaging (MRI) has been recognized as a helpful in-vivo MND biomarker. An increasing number of studies is applying advanced neuroimaging techniques in order to elucidate the pathophysiological processes and to identify quantitative outcomes to be used in clinical trials. Diffusion tensor imaging (DTI) is a non-invasive method to detect white matter alterations involving the upper motor neuron and extra-motor white matter tracts. According to this background, the aim of this review is to highlight the key role of MRI and especially DTI, summarizing cross-sectional and longitudinal results of different approaches applied in MND. Current literature suggests that DTI is a promising tool in order to define anatomical "signatures" of the different phenotypes of MND and to track in vivo the progressive spread of pathological proteins aggregates.}, }
@article {pmid30890895, year = {2018}, author = {Bello-Haas, VD}, title = {Physical therapy for individuals with amyotrophic lateral sclerosis: current insights.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {8}, number = {}, pages = {45-54}, pmid = {30890895}, issn = {1179-9900}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative, and inevitably fatal disease. There is no cure for ALS and life expectancy is typically 2-5 years after symptom onset. Despite the lack of a cure and the rapidly progressive nature of the disease, ALS is considered a "treatable disease" and rehabilitation is integral to optimal, comprehensive care. In addition to the other health care professions making up the health care team, physical therapy provides a critical role in the overall management in individuals with ALS. Physical therapy that is tailored to the individual's needs and goals and focused on addressing symptoms and maximizing function and participation enables people with ALS to live their lives to the fullest and with quality. The purpose of this paper is to review some of the recent ALS research findings that have implications for physical therapy practice.}, }
@article {pmid30890779, year = {2019}, author = {Nedelsky, NB and Taylor, JP}, title = {Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {15}, number = {5}, pages = {272-286}, doi = {10.1038/s41582-019-0157-5}, pmid = {30890779}, issn = {1759-4766}, mesh = {Biophysics ; Brain/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Phase Transition ; Ribonucleoproteins/metabolism ; }, abstract = {Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases - specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.}, }
@article {pmid30886620, year = {2019}, author = {Carpanini, SM and Torvell, M and Morgan, BP}, title = {Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System.}, journal = {Frontiers in immunology}, volume = {10}, number = {}, pages = {362}, pmid = {30886620}, issn = {1664-3224}, support = {MC_PC_13060/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Antibodies, Monoclonal/immunology/therapeutic use ; *Blood-Brain Barrier/immunology/pathology ; Complement Activation/*drug effects ; *Complement C5/antagonists &amp; inhibitors/immunology ; Disease Models, Animal ; Humans ; *Neurodegenerative Diseases/drug therapy/immunology/pathology ; }, abstract = {The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Given this body of evidence implicating complement in diverse brain diseases, manipulating complement in the brain is an attractive prospect; however, the blood-brain barrier (BBB), critical to protect the brain from potentially harmful agents in the circulation, is also impermeable to current complement-targeting therapeutics, making drug design much more challenging. For example, antibody therapeutics administered systemically are essentially excluded from the brain. Recent protocols have utilized "Trojan horse" techniques to transport therapeutics across the BBB or used osmotic shock or ultrasound to temporarily disrupt the BBB. Most research to date exploring the impact of complement inhibition on CNS diseases has been in animal models, and some of these studies have generated convincing data; for example, in models of MS, NMO, and stroke. There have been a few recent clinical trials of available anti-complement drugs in CNS diseases associated with BBB impairment, for example the use of the anti-C5 monoclonal antibody (mAb) eculizumab in NMO, but for most CNS diseases there have been no human trials of anti-complement therapies. Here we will review the evidence implicating complement in diverse CNS disorders, from acute, such as traumatic brain or spine injury, to chronic, including demyelinating, neuroinflammatory, and neurodegenerative diseases. We will discuss the particular problems of drug access into the CNS and explore ways in which anti-complement therapies might be tailored for CNS disease.}, }
@article {pmid30881332, year = {2019}, author = {Chew, S and Atassi, N}, title = {Positron Emission Tomography Molecular Imaging Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {135}, pmid = {30881332}, issn = {1664-2295}, support = {K23 NS083715/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited treatment options. Despite decades of therapeutic development, only two modestly efficacious disease-modifying drugs-riluzole and edaravone-are available to ALS patients. Biomarkers that can facilitate ALS diagnosis, aid in prognosis, and measure drug pharmacodynamics are needed to accelerate therapeutic development for patients with ALS. Positron emission tomography (PET) imaging has promise as a biomarker for ALS because it permits visualization of central nervous system (CNS) pathology in individuals living with ALS. The availability of PET radioligands that target a variety of potential pathophysiological mechanisms-including cerebral metabolism, neuroinflammation, neuronal dysfunction, and oxidative stress-has enabled dynamic interrogation of molecular changes in ALS, in both natural history studies and human clinical trials. PET imaging has potential as a diagnostic biomarker that can establish upper motor neuron (UMN) pathology in ALS patients without overt UMN symptoms, as a prognostic biomarker that might help stratify patients for clinical trials, and as a pharmacodynamic biomarker that measures the biological effect of investigational drugs in the brain and spinal cord. In this Review, we discuss progress made with 30 years of PET imaging studies in ALS and consider future research needed to establish PET imaging biomarkers for ALS therapeutic development.}, }
@article {pmid30877731, year = {2019}, author = {Kiousi, V and Arnaoutoglou, M and Printza, A}, title = {Speech and language intervention for language impairment in patients in the FTD-ALS spectrum.}, journal = {Hellenic journal of nuclear medicine}, volume = {22 Suppl}, number = {}, pages = {133-146}, pmid = {30877731}, issn = {1790-5427}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Frontotemporal Dementia/*physiopathology ; Humans ; *Speech ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease that belongs to the group of motor neuron diseases. Motor deficits like reduce in tongue strength, may coexist with cognitive deficits compatible with frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD). FTD is a neurodegenerative syndrome with two main clinical variants: behavioral (bvFTD) and language or Primary Progressive Aphasia (PPA). ALS and FTD have significant clinical and neuropathological overlapping so that for some researchers they are "the ends of the same disease spectrum". A key intervention in this patient population is the speech language therapy (SLT), a specific form of cognitive intervention, which evaluates communication skills and designs a personalized intervention plan to improve communication abilities. It has been used in patients with aphasia of different etiologies and has been shown to be effective. There is limited research in SLT interventions in patients in FTD-ALS spectrum, and the initial findings indicate success to some extent. Due to progressive neurodegeneration in FTD-ALS spectrum, the main goal of the intervention is not the complete rehabilitation of linguistic deficits but the reduction and, if possible, the delay of language decline in order to improve patient's communication and the quality of his/her life. In this paper, we critically review the reported approaches of speech language therapy (SLT) for monitoring language impairments and the impact of interventions in patients with FTD-ALS spectrum. Initial findings are supporting more systematic treatment of speech and language impairment in patients in the FTD-ALS spectrum.}, }
@article {pmid30877611, year = {2019}, author = {Amin Lari, A and Ghavanini, AA and Bokaee, HR}, title = {A review of electrophysiological studies of lower motor neuron involvement in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {40}, number = {6}, pages = {1125-1136}, pmid = {30877611}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*pathology ; Electrodiagnosis/*methods ; Humans ; Motor Neurons/*pathology ; Sensitivity and Specificity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both the upper and lower motor neuron diseases. In this review, we studied and compared different articles regarding the electrodiagnostic criteria for diagnosis of lower motor neuron pathology in ALS. We reviewed the most recent articles and metaanalysis regarding various lower motor neuron electrodiagnostic methods for ALS and their sensitivities. We concluded that Awaji Shima criteria is by far the most sensitive criteria for diagnosis of ALS.}, }
@article {pmid30873213, year = {2019}, author = {Cankaya, S and Cankaya, B and Kilic, U and Kilic, E and Yulug, B}, title = {The therapeutic role of minocycline in Parkinson's disease.}, journal = {Drugs in context}, volume = {8}, number = {}, pages = {212553}, pmid = {30873213}, issn = {1745-1981}, abstract = {Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease (PD), Huntington's disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD.}, }
@article {pmid30872992, year = {2019}, author = {Grollemund, V and Pradat, PF and Querin, G and Delbot, F and Le Chat, G and Pradat-Peyre, JF and Bede, P}, title = {Machine Learning in Amyotrophic Lateral Sclerosis: Achievements, Pitfalls, and Future Directions.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {135}, pmid = {30872992}, issn = {1662-4548}, abstract = {Background: Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive neurodegenerative condition with limited therapeutic options at present. Survival from symptom onset ranges from 3 to 5 years depending on genetic, demographic, and phenotypic factors. Despite tireless research efforts, the core etiology of the disease remains elusive and drug development efforts are confounded by the lack of accurate monitoring markers. Disease heterogeneity, late-stage recruitment into pharmaceutical trials, and inclusion of phenotypically admixed patient cohorts are some of the key barriers to successful clinical trials. Machine Learning (ML) models and large international data sets offer unprecedented opportunities to appraise candidate diagnostic, monitoring, and prognostic markers. Accurate patient stratification into well-defined prognostic categories is another aspiration of emerging classification and staging systems. Methods: The objective of this paper is the comprehensive, systematic, and critical review of ML initiatives in ALS to date and their potential in research, clinical, and pharmacological applications. The focus of this review is to provide a dual, clinical-mathematical perspective on recent advances and future directions of the field. Another objective of the paper is the frank discussion of the pitfalls and drawbacks of specific models, highlighting the shortcomings of existing studies and to provide methodological recommendations for future study designs. Results: Despite considerable sample size limitations, ML techniques have already been successfully applied to ALS data sets and a number of promising diagnosis models have been proposed. Prognostic models have been tested using core clinical variables, biological, and neuroimaging data. These models also offer patient stratification opportunities for future clinical trials. Despite the enormous potential of ML in ALS research, statistical assumptions are often violated, the choice of specific statistical models is seldom justified, and the constraints of ML models are rarely enunciated. Conclusions: From a mathematical perspective, the main barrier to the development of validated diagnostic, prognostic, and monitoring indicators stem from limited sample sizes. The combination of multiple clinical, biofluid, and imaging biomarkers is likely to increase the accuracy of mathematical modeling and contribute to optimized clinical trial designs.}, }
@article {pmid30870681, year = {2019}, author = {Mathis, S and Goizet, C and Soulages, A and Vallat, JM and Masson, GL}, title = {Genetics of amyotrophic lateral sclerosis: A review.}, journal = {Journal of the neurological sciences}, volume = {399}, number = {}, pages = {217-226}, doi = {10.1016/j.jns.2019.02.030}, pmid = {30870681}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein/*genetics ; DNA-Binding Proteins/*genetics ; Humans ; RNA-Binding Protein FUS/*genetics ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor pathways, invariably leading to death within a few years of onset. Most cases of ALS are sporadic, but familial forms of the disease (FALS) constitute 10% of the cases. Since the first identification of a causative gene in the 1990s and with recent advances in genetics, more than twenty genes have now been linked to FALS. This increased number of genes led to a tremendous amount of research, clearly contributed to a better understanding of the pathophysiology of this disorder, and paved the way for the development of new therapeutics and new hope for this fatal disease.}, }
@article {pmid30866990, year = {2019}, author = {Koh, JY and Kim, HN and Hwang, JJ and Kim, YH and Park, SE}, title = {Lysosomal dysfunction in proteinopathic neurodegenerative disorders: possible therapeutic roles of cAMP and zinc.}, journal = {Molecular brain}, volume = {12}, number = {1}, pages = {18}, pmid = {30866990}, issn = {1756-6606}, mesh = {Animals ; Cyclic AMP/*metabolism ; Humans ; Hydrogen-Ion Concentration ; Lysosomes/*metabolism ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Zinc/*metabolism ; }, abstract = {A number of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, share intra- and/or extracellular deposition of protein aggregates as a common core pathology. While the species of accumulating proteins are distinct in each disease, an increasing body of evidence indicates that defects in the protein clearance system play a crucial role in the gradual accumulation of protein aggregates. Among protein degradation systems, the endosome-autophagosome-lysosome pathway (EALP) is the main degradation machinery, especially for large protein aggregates. Lysosomal dysfunction or defects in fusion with vesicles containing cargo are commonly observed abnormalities in proteinopathic neurodegenerative diseases. In this review, we discuss the available evidence for a mechanistic connection between components of the EALP-especially lysosomes-and neurodegenerative diseases. We also focus on lysosomal pH regulation and its significance in maintaining flux through the EALP. Finally, we suggest that raising cAMP and free zinc levels in brain cells may be beneficial in normalizing lysosomal pH and EALP flux.}, }
@article {pmid30855105, year = {2019}, author = {Ward, RJ and Crichton, RR}, title = {Ironing out the Brain.}, journal = {Metal ions in life sciences}, volume = {19}, number = {}, pages = {}, doi = {10.1515/9783110527872-010}, pmid = {30855105}, issn = {1559-0836}, mesh = {Aging ; Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Animals ; Brain/*physiology/physiopathology ; *Chelation Therapy ; Friedreich Ataxia ; Homeostasis ; Humans ; Huntington Disease ; Iron/*physiology/toxicity ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease ; }, abstract = {Our understanding of the broad principles of cellular and systemic iron homeostasis in man are well established with the exception of the brain. Most of the proteins involved in mammalian iron metabolism are present in the brain, although their distribution and precise roles in iron uptake, intracellular metabolism and export are still uncertain, as is the way in which systemic iron is transferred across the blood-brain barrier. We briefly review current concepts concerning the uptake and distribution of iron in the brain, before turning to the ways in which brain iron homeostasis might be regulated. The distribution of iron between different brain regions is then discussed as is the increase in brain iron with normal aging, and the different forms in which iron is present. The increased levels of iron found in specific brain regions and their potential contribution to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease and other polyglutamine expansion diseases, amyotrophic lateral sclerosis, Friedreich's ataxia, as well as a number of neurodegenerative diseases with iron accumulation, are discussed. The interactions between neuroinflammation and iron are presented, and the chapter concludes with a review of current clinical studies and discussion of the potential and efficacy of iron chelation therapy in the treatment of neurodegenerative diseases.}, }
@article {pmid30851357, year = {2019}, author = {Chen, R and Lee, C and Lin, X and Zhao, C and Li, X}, title = {Novel function of VEGF-B as an antioxidant and therapeutic implications.}, journal = {Pharmacological research}, volume = {143}, number = {}, pages = {33-39}, doi = {10.1016/j.phrs.2019.03.002}, pmid = {30851357}, issn = {1096-1186}, mesh = {Animals ; Antioxidants/pharmacology/*therapeutic use ; Eye Diseases/*drug therapy/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Vascular Endothelial Growth Factor B/metabolism/pharmacology/*therapeutic use ; }, abstract = {Oxidative stress, due to insufficiency of antioxidants or over-production of oxidants, can lead to severe cell and tissue damage. Oxidative stress occurs constantly and has been shown to be involved in innumerable diseases, such as degenerative, cardiovascular, neurological, and metabolic disorders, cancer, and aging, thus highlighting the vital need of antioxidant defense mechanisms. Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago, and is abundantly expressed in most types of cells and tissues. VEGF-B remained functionally mysterious for many years and later on has been shown to be minimally angiogenic. Recently, VEGF-B is reported to be a potent antioxidant by boosting the expression of key antioxidant enzymes. Thus, one major role of VEGF-B lies in safeguarding tissues and cells from oxidative stress-induced damage. VEGF-B may therefore have promising therapeutic utilities in treating oxidative stress-related diseases. In this review, we discuss the current knowledge on the newly discovered antioxidant function of VEGF-B and the related molecular mechanisms, particularly, in relationship to some oxidative stress-related diseases, such as retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, glaucoma, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease.}, }
@article {pmid30851309, year = {2019}, author = {Pajarillo, E and Rizor, A and Lee, J and Aschner, M and Lee, E}, title = {The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics.}, journal = {Neuropharmacology}, volume = {161}, number = {}, pages = {107559}, pmid = {30851309}, issn = {1873-7064}, support = {R01 ES020852/ES/NIEHS NIH HHS/United States ; R01 ES024756/ES/NIEHS NIH HHS/United States ; R01 ES031282/ES/NIEHS NIH HHS/United States ; R01 ES007331/ES/NIEHS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/drug effects/*metabolism ; Excitatory Amino Acid Transporter 1/drug effects/*genetics/*metabolism ; Excitatory Amino Acid Transporter 2/drug effects/*genetics/*metabolism ; Gene Expression Regulation ; Humans ; Nervous System Diseases/*drug therapy/*genetics/metabolism ; }, abstract = {Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.}, }
@article {pmid30850440, year = {2019}, author = {van den Berg, LH and Sorenson, E and Gronseth, G and Macklin, EA and Andrews, J and Baloh, RH and Benatar, M and Berry, JD and Chio, A and Corcia, P and Genge, A and Gubitz, AK and Lomen-Hoerth, C and McDermott, CJ and Pioro, EP and Rosenfeld, J and Silani, V and Turner, MR and Weber, M and Brooks, BR and Miller, RG and Mitsumoto, H and , }, title = {Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials.}, journal = {Neurology}, volume = {92}, number = {14}, pages = {e1610-e1623}, pmid = {30850440}, issn = {1526-632X}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; U13 NS093847/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; *Clinical Trials as Topic ; Delphi Technique ; *Guidelines as Topic ; Humans ; Outcome Assessment, Health Care ; Patient Selection ; *Research Design ; Statistics as Topic ; }, abstract = {OBJECTIVE: To revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry, and regulatory agencies) addressed 9 areas of need within ALS research: (1) preclinical studies; (2) biological and phenotypic heterogeneity; (3) outcome measures; (4) disease-modifying and symptomatic interventions; (5) recruitment and retention; (6) biomarkers; (7) clinical trial phases; (8) beyond traditional trial designs; and (9) statistical considerations. Assigned to 1 of 8 sections, committee members generated a draft set of guidelines based on a "background" of developing a (pre)clinical question and a "rationale" outlining the evidence and expert opinion. Following a 2-day, face-to-face workshop at the Airlie House Conference Center, a modified Delphi process was used to develop draft consensus research guidelines, which were subsequently reviewed and modified based on comments from the public. Statistical experts drafted a separate document of statistical considerations (section 9).<br><br>RESULTS: In this report, we summarize 112 guidelines and their associated backgrounds and rationales. The full list of guidelines, the statistical considerations, and a glossary of terms can be found in data available from Dryad (appendices e-3-e-5, doi.org/10.5061/dryad.32q9q5d). The authors prioritized 15 guidelines with the greatest potential to improve ALS clinical research.<br><br>CONCLUSION: The revised Airlie House ALS Clinical Trials Consensus Guidelines should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS.}, }
@article {pmid30849511, year = {2019}, author = {Parker, SE and Hanton, AM and Stefanou, SN and Noakes, PG and Woodruff, TM and Lee, JD}, title = {Revisiting the role of the innate immune complement system in ALS.}, journal = {Neurobiology of disease}, volume = {127}, number = {}, pages = {223-232}, doi = {10.1016/j.nbd.2019.03.003}, pmid = {30849511}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/metabolism ; Animals ; Complement System Proteins/*metabolism ; Humans ; Immunity, Innate/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.}, }
@article {pmid30846968, year = {2019}, author = {de Carvalho, M and Swash, M and Pinto, S}, title = {Diaphragmatic Neurophysiology and Respiratory Markers in ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {143}, pmid = {30846968}, issn = {1664-2295}, abstract = {The main reason for short survival in amyotrophic lateral sclerosis (ALS) is involvement of respiratory muscles. Severe compromise of diaphragmatic function due to marked loss of motor units causes poor inspiratory strength leading to symptomatic respiratory fatigue, and hypercapnia and hypoxemia, often firstly detected while sleeping supine. Weakness of expiratory muscles leads to cough weakness and poor bronchial clearance, increasing the risk of respiratory infection. Respiratory tests should therefore encompass inspiratory and expiratory function, and include measurements of blood gases during sleep. Non-volitional tests, such as phrenic nerve stimulation, are particularly convenient for investigating respiratory function in patients unable to perform standard respiratory function tests due to poor cooperation or facial weakness. However, SNIP is a sensitive test when patients with bulbar involvement are able to perform the necessary maneuvers. It is likely that central respiratory regulation is disturbed in some ALS patients, but its evaluation is more complex and not regularly implemented. Practical tests should incorporate tolerability, sensitivity, easy application for regular monitoring, and prognostic value. Impending respiratory failure can cause increased circulating inflammatory markers, but molecular assessment of respiratory distress requires further study. In future, home-monitoring of patients with accessible devices should be developed.}, }
@article {pmid30846210, year = {2019}, author = {Pinto, WBVR and Debona, R and Nunes, PP and Assis, ACD and Lopes, CG and Bortholin, T and Dias, RB and Naylor, FGM and Chieia, MAT and Souza, PVS and Oliveira, ASB}, title = {Atypical Motor Neuron Disease variants: Still a diagnostic challenge in Neurology.}, journal = {Revue neurologique}, volume = {175}, number = {4}, pages = {221-232}, doi = {10.1016/j.neurol.2018.04.016}, pmid = {30846210}, issn = {0035-3787}, mesh = {Humans ; Motor Neuron Disease/*diagnosis/physiopathology/therapy ; *Neurology ; }, abstract = {Motor neuron disease (MND) represents a wide and heterogeneous expanding group of disorders involving the upper or lower motor neurons, mainly represented by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy. Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Despite its well-known natural history, pathophysiological and clinical characteristics for the most common MND, atypical clinical presentation and neurodegenerative mechanisms are commonly observed in rare clinical entities, so-called atypical variants of MND-ALS, including flail-leg syndrome, flail-arm syndrome, facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus (FEWDON-MND) and long-lasting and juvenile MND-ALS. Herein, we provide a review article presenting clinical, genetic, pathophysiological and neuroimaging findings of atypical variants of MND-ALS in clinical practice.}, }
@article {pmid30843138, year = {2020}, author = {Hoch-Kraft, P and Trotter, J and Gonsior, C}, title = {Missing in Action: Dysfunctional RNA Metabolism in Oligodendroglial Cells as a Contributor to Neurodegenerative Diseases?.}, journal = {Neurochemical research}, volume = {45}, number = {3}, pages = {566-579}, pmid = {30843138}, issn = {1573-6903}, support = {SFB CRC TR 128, B7//Deutsche Forschungsgemeinschaft/ ; SPP 1757//Deutsche Forschungsgemeinschaft/ ; ELA 2011-004C2//Association Europ&#xe9;enne contre les Leucodystrophies/ ; ELA 2017-018C4B//Association Europ&#xe9;enne contre les Leucodystrophies/ ; }, mesh = {Animals ; Cell Differentiation ; Humans ; Neurodegenerative Diseases/*etiology/metabolism/pathology ; Neuroglia/metabolism/*pathology ; Oligodendroglia/metabolism/*pathology ; RNA/*genetics ; }, abstract = {The formation of myelin around axons by oligodendrocytes (OL) poses an enormous synthetic and energy challenge for the glial cell. Local translation of transcripts, including the mRNA for the essential myelin protein Myelin Basic Protein (MBP) at the site of myelin deposition has been recognised as an efficient mechanism to assure proper myelin sheath assembly. Oligodendroglial precursor cells (OPCs) form synapses with neurons and may localise many additional mRNAs in a similar fashion to synapses between neurons. In some diseases in which demyelination occurs, an abundance of OPCs is present but there is a failure to efficiently remyelinate and to synthesise MBP. This compromises axonal survival and function. OPCs are especially sensitive to cellular stress as occurring in neurodegenerative diseases, which can impinge on their ability to translate mRNAs into protein. Stress causes the build up of cytoplasmic stress granules (SG) in which many RNAs are sequestered and translationally stalled until the stress ceases. Chronic stress in particular could convert this initially protective reaction of the cell into damage, as persistence of SG may lead to pathological aggregate formation or long-term translation block of SG-associated RNAs. The recent recognition that many neurodegenerative diseases often exhibit an early white matter pathology with a proliferation of surviving OPCs, renders a study of the stress-associated processes in oligodendrocytes and OPCs especially relevant. Here, we discuss a potential dysfunction of RNA regulation in myelin diseases such as Multiple Sclerosis (MS) and Vanishing white matter disease (VWM) and potential contributions of OL dysfunction to neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Fragile X syndrome (FXS).}, }
@article {pmid30839376, year = {2019}, author = {Cimpoesu, D and Corlade-Andrei, M and Popa, TO and Grigorasi, G and Bouros, C and Rotaru, L and Nedelea, PL}, title = {Cardiac Arrest in Special Circumstances-Recent Advances in Resuscitation.}, journal = {American journal of therapeutics}, volume = {26}, number = {2}, pages = {e276-e283}, doi = {10.1097/MJT.0000000000000927}, pmid = {30839376}, issn = {1536-3686}, mesh = {Cardiopulmonary Resuscitation/*methods/trends ; Extracorporeal Membrane Oxygenation/methods ; Heart Arrest/*therapy ; Humans ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) in special circumstances includes the emergency intervention for special causes, special environments, and special patients. Special causes cover the potential reversible causes of cardiac arrest that must be identified or excluded during any resuscitation act. The special environments section includes recommendations for the treatment of cardiac arrest occurring in specific locations: cardiac surgery, catheterization laboratory, dialysis unit, dental surgery, commercial airplanes or air ambulances, playing field, difficult environment (eg, drowning, high altitude, avalanche, and electrical injuries) or mass casualty incident. CPR for special patients gives guidance for the patients with severe comorbidities (asthma, heart failure with ventricular assist devices, neurological disease, and obesity) and pregnant women or older people.<br><br>AREAS OF UNCERTAINTY: There are no generally worldwide accepted resuscitation guidelines for special circumstance, and there are still few studies investigating the safety and outcome of cardiac arrest in special circumstances. Applying standard advanced life support (ALS) guidelines in this situation is not enough to obtain better results from CPR, for example, cardiac arrest caused by electrolyte abnormalities require also the treatment of that electrolyte disturbance, not only standard CPR, or in the case of severe hypothermia, when standard ALS approach is not recommended until a temperature threshold is reached after warming measures. Data sources for this article are scientific articles describing retrospective studies conducted in CPR performed in special circumstances, experts' consensus, and related published opinion of experts in CPR.<br><br>THERAPEUTIC ADVANCES: The newest advance in therapeutics applied to resuscitation field for these particular situations is the use of extracorporeal life support/extracorporeal membrane oxygenation devices during CPR.<br><br>CONCLUSIONS: In special circumstances, ALS guidelines require modification and special attention for causes, environment, and patient particularities, with specific therapeutic intervention concomitant with standard ALS.}, }
@article {pmid30837953, year = {2019}, author = {Coppedè, F and Stoccoro, A}, title = {Mitoepigenetics and Neurodegenerative Diseases.}, journal = {Frontiers in endocrinology}, volume = {10}, number = {}, pages = {86}, pmid = {30837953}, issn = {1664-2392}, abstract = {Mitochondrial impairment and increased oxidative stress are common features in neurodegenerative disorders, leading researchers to speculate that epigenetic changes in the mitochondrial DNA (mitoepigenetics) could contribute to neurodegeneration. The few studies performed so far to address this issue revealed impaired methylation levels of the mitochondrial regulatory region (D-loop region) in both animal models, postmortem brain regions, or circulating blood cells of patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Those studies also revealed that mtDNA D-loop methylation levels are subjected to a dynamic regulation within the progression of the neurodegenerative process, could be affected by certain neurodegenerative disease-causative mutations, and are inversely correlated with the mtDNA copy number. The methylation levels of other mtDNA regions than the D-loop have been scarcely investigated in human specimens from patients with neurodegenerative disorders or in animal models of the disease, and evidence of impaired methylation levels is often limited to a single study, making it difficult to clarify their correlation with mitochondrial dynamics and gene expression levels in these disorders. Overall, the preliminary results of the studies performed so far are encouraging making mitoepigenetics a timely and attractive field of investigation, but additional research is warranted to clarify the connections among epigenetic changes occurring in the mitochondrial genome, mitochondrial DNA dynamics and gene expression, and the neurodegenerative process.}, }
@article {pmid30837936, year = {2019}, author = {Yunusova, Y and Plowman, EK and Green, JR and Barnett, C and Bede, P}, title = {Clinical Measures of Bulbar Dysfunction in ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {106}, pmid = {30837936}, issn = {1664-2295}, support = {R01 DC017291/DC/NIDCD NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; }, abstract = {Bulbar impairment represents a hallmark feature of Amyotrophic Lateral Sclerosis (ALS) that significantly impacts survival and quality of life. Speech and swallowing dysfunction are key contributors to the clinical heterogeneity of ALS and require well-timed and carefully coordinated interventions. The accurate clinical, radiological and electrophysiological assessment of bulbar dysfunction in ALS is one of the most multidisciplinary aspects of ALS care, requiring expert input from speech-language pathologists (SLPs), neurologists, otolaryngologists, augmentative alternative communication (AAC) specialists, dieticians, and electrophysiologists-each with their own evaluation strategies and assessment tools. The need to systematically evaluate the comparative advantages and drawbacks of various bulbar assessment instruments and to develop integrated assessment protocols is increasingly recognized. In this review, we provide a comprehensive appraisal of the most commonly utilized clinical tools for assessing and monitoring bulbar dysfunction in ALS based on the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) evaluation framework. Despite a plethora of assessment tools, considerable geographical differences exist in bulbar assessment practices and individual instruments exhibit considerable limitations. The gaps identified in the literature offer unique opportunities for the optimization of existing and development of new tools both for clinical and research applications. The multicenter validation and standardization of these instruments will be essential for guideline development and best practice recommendations.}, }
@article {pmid30837838, year = {2019}, author = {Prasad, A and Bharathi, V and Sivalingam, V and Girdhar, A and Patel, BK}, title = {Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {25}, pmid = {30837838}, issn = {1662-5099}, abstract = {TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90-95%) are sporadic (sALS), among familial ALS cases 5-10% involve the inheritance of mutations in the TARDBP gene and the remaining (90-95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS, and NEK1 etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.}, }
@article {pmid30832535, year = {2019}, author = {Liu, M and Lin, X and Wang, L and He, Y and Chen, M and Mao, R}, title = {Thalidomide-induced sinus bradycardia in Crohn's disease: case report and literature review.}, journal = {The Journal of international medical research}, volume = {47}, number = {5}, pages = {2228-2233}, pmid = {30832535}, issn = {1473-2300}, mesh = {Adult ; Bradycardia/*chemically induced/*complications/physiopathology ; Coronary Sinus/*pathology ; Crohn Disease/*complications/*drug therapy ; Heart Rate ; Humans ; Intestinal Mucosa/pathology ; Male ; Thalidomide/*adverse effects/*therapeutic use ; }, abstract = {Thalidomide is effective in inducing and maintaining clinical remission, as well as mucosal healing, in patients with refractory Crohn's disease (CD). However, long-term use of thalidomide has raised concern because of the high incidence of adverse events. Cardiovascular events induced by thalidomide have been reported in patients with multiple myeloma, amyotrophic lateral sclerosis, and transfusion-dependent refractory anemia. We report here an extremely rare case of sinus bradycardia induced by thalidomide in an adult patient with CD. This patient's heart rate converted back to a normal sinus rhythm after withdrawal of thalidomide, but recurred after restarting of thalidomide. Cardiac toxicity should be closely monitored when using thalidomide in patients with CD.}, }
@article {pmid30828191, year = {2019}, author = {Kumar, M and Bhoi, S and Sharma, K}, title = {Human-induced pluripotent stem cells derived hematopoietic progenitor cells for treatment of hematopoietic failure among trauma hemorrhagic shock patients.}, journal = {Journal of clinical orthopaedics and trauma}, volume = {10}, number = {2}, pages = {269-273}, pmid = {30828191}, issn = {0976-5662}, abstract = {Hematopoietic failure (HF) has been observed in trauma hemorrhagic shock (T/HS) patients. Multiple factors are involved. Elevated serum levels of cytokines, catecholamine, granulocyte colony stimulating factor, peripheral blood hematopoietic progenitor cells (HPCs) and decreased expression of erythropoietin receptor are associated with HF among T/HS. HF leads to anaemia, susceptibility to infection, sepsis and multi-organ failure. There is a lack of molecular understanding of HF and its potential therapeutic strategies. Cell-based therapy has ability to modulate the production of inflammatory cytokines, vascular dysfunction, tissue damage and apoptosis. Human-induced pluripotent stem cells (iPSC) derived HPCs may have the ability to restore HF in T/HS. Autologous cell-based iPSC have great promises for various diseases such as Alzheimer's disease, Parkinson's disease, cardiovascular disease, diabetes, amyotrophic lateral sclerosis, and spinal cord injury without ethical concerns. Similarly, treatment with iPSC derived hematopoietic stem cells can used for the treatment of HF among T/HS and may also improve the outcome. Here, we review the potential of human iPSC derived HSC to reversed HF following T/HS.}, }
@article {pmid30810406, year = {2019}, author = {Yoshino, H}, title = {Edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {19}, number = {3}, pages = {185-193}, doi = {10.1080/14737175.2019.1581610}, pmid = {30810406}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Cognitive Dysfunction/drug therapy/etiology ; Edaravone/pharmacokinetics/pharmacology/*therapeutic use ; Free Radical Scavengers/pharmacokinetics/pharmacology/*therapeutic use ; Humans ; Neuroprotective Agents/pharmacokinetics/pharmacology/*therapeutic use ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder that affects all skeletal muscles, leading to death, mostly within 2-4 years from onset. To date, the anti-glutamatergic drug riluzole is the only drug that has been approved for the treatment of this disease; however, its efficacy is modest. Oxidative stress is considered to be involved in the pathology of ALS, and in this regard, the free radical scavenger edaravone, which was originally developed for the treatment of acute ischemic stroke, has also been developed for the treatment of ALS. Areas covered: This review describes the pharmacological properties of edaravone and the progress of clinical trials conducted to evaluate the efficacy of this drug in the treatment of ALS. Expert commentary: Edaravone is the first drug to show effective inhibition of the motor function deterioration experienced by ALS patients with early-stage probable and definite types. In order to effectively prolong the quality of motor function, edaravone treatment should be initiated as soon as the diagnosis has been confirmed; however, the respiratory function should be carefully monitored when a deterioration in breathing capacity is detected.}, }
@article {pmid30804878, year = {2019}, author = {Festoff, BW and Citron, BA}, title = {Thrombin and the Coag-Inflammatory Nexus in Neurotrauma, ALS, and Other Neurodegenerative Disorders.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {59}, pmid = {30804878}, issn = {1664-2295}, support = {I01 RX001520/RX/RRD VA/United States ; }, abstract = {This review details our current understanding of thrombin signaling in neurodegeneration, with a focus on amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) as well as future directions to be pursued. The key factors are multifunctional and involved in regulatory pathways, namely innate immune and the coagulation cascade activation, that are essential for normal nervous system function and health. These two major host defense systems have a long history in evolution and include elements and regulators of the coagulation pathway that have significant impacts on both the peripheral and central nervous system in health and disease. The clotting cascade responds to a variety of insults to the CNS including injury and infection. The blood brain barrier is affected by these responses and its compromise also contributes to these detrimental effects. Important molecules in signaling that contribute to or protect against neurodegeneration include thrombin, thrombomodulin (TM), protease activated receptor 1 (PAR1), damage associated molecular patterns (DAMPs), such as high mobility group box protein 1 (HMGB1) and those released from mitochondria (mtDAMPs). Each of these molecules are entangled in choices dependent upon specific signaling pathways in play. For example, the particular cleavage of PAR1 by thrombin vs. activated protein C (APC) will have downstream effects through coupled factors to result in toxicity or neuroprotection. Furthermore, numerous interactions influence these choices such as the interplay between HMGB1, thrombin, and TM. Our hope is that improved understanding of the ways that components of the coagulation cascade affect innate immune inflammatory responses and influence the course of neurodegeneration, especially after injury, will lead to effective therapeutic approaches for ALS, traumatic brain injury, and other neurodegenerative disorders.}, }
@article {pmid30801863, year = {2019}, author = {Haenseler, W and Rajendran, L}, title = {Concise Review: Modeling Neurodegenerative Diseases with Human Pluripotent Stem Cell-Derived Microglia.}, journal = {Stem cells (Dayton, Ohio)}, volume = {37}, number = {6}, pages = {724-730}, pmid = {30801863}, issn = {1549-4918}, mesh = {Alzheimer Disease/genetics/metabolism/pathology/*therapy ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/*therapy ; Cell- and Tissue-Based Therapy/methods ; Coculture Techniques ; Frontotemporal Dementia/genetics/metabolism/pathology/*therapy ; Gene Knockout Techniques ; Genetic Engineering/methods ; High-Throughput Screening Assays ; Humans ; Induced Pluripotent Stem Cells/drug effects/metabolism/pathology ; Inflammation ; Microglia/drug effects/*metabolism/pathology ; Models, Biological ; Neurons/drug effects/*metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Nootropic Agents/therapeutic use ; Parkinson Disease/genetics/metabolism/pathology/*therapy ; }, abstract = {Inflammation of the brain and the consequential immunological responses play pivotal roles in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia (FTD). Microglia, the resident macrophage cells of the brain, have also emerged as key players in neuroinflammation. As primary human microglia from living subjects are normally not accessible to researchers, there is a pressing need for an alternative source of authentic human microglia which allows modeling of neurodegeneration in vitro. Several protocols for induced pluripotent stem cell (iPSC)-derived microglia have recently been developed and provide unlimited access to patient-derived material. In this present study, we give an overview of iPSC-derived microglia models in monoculture and coculture systems, their advantages and limitations, and how they have already been used for disease phenotyping. Furthermore, we outline some of the gene engineering tools to generate isogenic controls, the creation of gene knockout iPSC lines, as well as covering reporter cell lines, which could help to elucidate complex cell interaction mechanisms in the microglia/neuron coculture system, for example, microglia-induced synapse loss. Finally, we deliberate on how said cocultures could aid in personalized drug screening to identify patient-specific therapies against neurodegeneration. Stem Cells 2019;37:724-730.}, }
@article {pmid30797953, year = {2019}, author = {Vissers, C and Ming, GL and Song, H}, title = {Nanoparticle technology and stem cell therapy team up against neurodegenerative disorders.}, journal = {Advanced drug delivery reviews}, volume = {148}, number = {}, pages = {239-251}, pmid = {30797953}, issn = {1872-8294}, support = {R01 AG057497/AG/NIA NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; R37 NS047344/NS/NINDS NIH HHS/United States ; U19 MH106434/MH/NIMH NIH HHS/United States ; U19 AI131130/AI/NIAID NIH HHS/United States ; P01 NS097206/NS/NINDS NIH HHS/United States ; R35 NS097370/NS/NINDS NIH HHS/United States ; R35 NS116843/NS/NINDS NIH HHS/United States ; R01 MH105128/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Drug Delivery Systems ; Humans ; Nanostructures/*chemistry ; *Nanotechnology ; Neurodegenerative Diseases/*therapy ; Neuroprotective Agents/chemistry/*therapeutic use ; *Stem Cell Transplantation ; }, abstract = {The convergence of nanoparticles and stem cell therapy holds great promise for the study, diagnosis, and treatment of neurodegenerative disorders. Researchers aim to harness the power of nanoparticles to regulate cellular microenvironment, improve the efficiency of cell and drug delivery to the brain, and enhance the survival of stem cell transplants. Understanding the various properties of different nanoparticles is key to applying them to clinical therapies; the many distinct types of nanoparticles offer unique capacities for medical imaging, diagnosis, and treatment of neurodegeneration disorders. In this review we introduce the biology of Alzheimer's, Parkinson's Disease, and amyotrophic lateral sclerosis, and discuss the potentials and shortcomings of metal, silica, lipid-based, polymeric, and hydrogel nanoparticles for diagnosis and treatment of neurodegenerative disorders. We then provide an overview of current strategies in stem cell therapies and how they can be combined with nanotechnology to improve clinical outcomes.}, }
@article {pmid30792577, year = {2019}, author = {Saldi, TK and Gonzales, PK and LaRocca, TJ and Link, CD}, title = {Neurodegeneration, Heterochromatin, and Double-Stranded RNA.}, journal = {Journal of experimental neuroscience}, volume = {13}, number = {}, pages = {1179069519830697}, pmid = {30792577}, issn = {1179-0695}, support = {R01 NS063964/NS/NINDS NIH HHS/United States ; }, abstract = {Changes in chromatin and epigenetic modifications have been associated with aging and aging-associated neurodegenerative diseases, although the causal relationship between these changes and disease-related pathology has been unclear. Recent studies have now made direct connections between neurodegeneration-associated proteins and derepression of repetitive element transcription due to changes in heterochromatin. We suggest that this derepression leads to an increased accumulation of intracellular double-stranded RNA (dsRNA), with an attendant induction of innate immune responses that contribute to the neuroinflammation found in essentially all age-associated neurodegenerative diseases.}, }
@article {pmid30791515, year = {2019}, author = {Imai, Y and Meng, H and Shiba-Fukushima, K and Hattori, N}, title = {Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.}, journal = {International journal of molecular sciences}, volume = {20}, number = {4}, pages = {}, pmid = {30791515}, issn = {1422-0067}, support = {17H04049//Japan Society for the Promotion of Science/ ; 16K19525//Japan Society for the Promotion of Science/ ; 18H04043//Japan Society for the Promotion of Science/ ; N/A//Otsuka Pharmaceutical/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism ; Animals ; DNA-Binding Proteins ; Disease Susceptibility ; Frontotemporal Dementia/*etiology/metabolism ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Humans ; Mitochondria/genetics/metabolism ; Mitochondrial Proteins/chemistry/*genetics/metabolism ; Mutation ; Parkinson Disease/*etiology/metabolism ; Protein Binding ; Protein Transport ; Signal Transduction ; Structure-Activity Relationship ; Transcription Factors/chemistry/*genetics/metabolism ; }, abstract = {Mutations of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) have been found to be linked to Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and/or frontotemporal lobe dementia (FTD). CHCHD2 and CHCHD10 proteins, which are homologous proteins with 54% identity in amino acid sequence, belong to the mitochondrial coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family. A series of studies reveals that these twin proteins form a multimodal complex, producing a variety of pathophysiology by the disease-causing variants of these proteins. In this review, we summarize the present knowledge about the physiological and pathological roles of twin proteins, CHCHD2 and CHCHD10, in neurodegenerative diseases.}, }
@article {pmid30787905, year = {2019}, author = {Campanari, ML and Bourefis, AR and Kabashi, E}, title = {Diagnostic Challenge and Neuromuscular Junction Contribution to ALS Pathogenesis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {68}, pmid = {30787905}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) represents the major adult-onset motor neuron disease. Both human and animal studies reveal the critical implication of muscle and neuromuscular junctions (NMJs) in the initial phase of this disease. Despite the common efforts, ALS diagnosis remains particularly challenging since many other disorders can overlap yielding similar clinical phenotypic features. A combination of further research on the NMJ parameters that are specific for this disease and laboratory tests are crucial for the early determination of specific changes in the muscle, as well as in motor neuron and the prediction of ALS progression. Also, it could provide a powerful tool in the discrimination of particular ALS and ALS-mimic cases and increase the efficacy of therapeutic treatments.}, }
@article {pmid30785719, year = {2019}, author = {Palomo, V and Tosat-Bitrian, C and Nozal, V and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {TDP-43: A Key Therapeutic Target beyond Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {10}, number = {3}, pages = {1183-1196}, doi = {10.1021/acschemneuro.9b00026}, pmid = {30785719}, issn = {1948-7193}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Dementia/genetics/metabolism/therapy ; Humans ; Neuroprotective Agents/pharmacology ; }, abstract = {Accumulation of TDP-43 in the cytoplasm of diseased neurons is the pathological hallmark of frontotemporal dementia-TDP (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), two diseases that lack efficacious medicine to prevent or to stop disease progression. The discovery of mutations in the TARDBP gene (encoding the nuclear protein known as TDP-43) in both FTLD and ALS patients provided evidence for a link between TDP-43 alterations and neurodegeneration. Our understanding of TDP-43 function has advanced profoundly in the past several years; however, its complete role and the molecular mechanisms that lead to disease are not fully understood. Here we summarize the recent studies of this protein, its relation to neurodegenerative diseases, and the therapeutic strategies for restoring its homeostasis with small molecules. Finally, we briefly discuss the available cellular and animal models that help to shed light on TDP-43 pathology and could serve as tools for the discovery of pharmacological agents for the treatment of TDP-43-related diseases.}, }
@article {pmid30774737, year = {2019}, author = {Babić Leko, M and Župunski, V and Kirincich, J and Smilović, D and Hortobágyi, T and Hof, PR and Šimić, G}, title = {Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion.}, journal = {Behavioural neurology}, volume = {2019}, number = {}, pages = {2909168}, pmid = {30774737}, issn = {1875-8584}, support = {P50 AG005138/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Dipeptides/genetics ; Frontotemporal Dementia/*genetics ; Humans ; Neurodegenerative Diseases/genetics ; Pick Disease of the Brain/*genetics ; }, abstract = {Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.}, }
@article {pmid30771410, year = {2019}, author = {Sarkar, T and Patro, N and Patro, IK}, title = {Cumulative multiple early life hits- a potent threat leading to neurological disorders.}, journal = {Brain research bulletin}, volume = {147}, number = {}, pages = {58-68}, doi = {10.1016/j.brainresbull.2019.02.005}, pmid = {30771410}, issn = {1873-2747}, mesh = {Adverse Childhood Experiences/*ethics ; Animals ; Autistic Disorder ; Female ; Humans ; Maternal Deprivation ; Mental Disorders ; Nervous System Diseases/*etiology ; Neuroglia/physiology ; Neurons/physiology ; Oxidative Stress/physiology ; Parkinson Disease ; Pregnancy ; Prenatal Exposure Delayed Effects/physiopathology ; Risk Factors ; Schizophrenia ; Stress, Psychological/*physiopathology ; }, abstract = {Early life Stress is a worldwide concern linked with development of later life neurological disorders. Early developmental age is sensitive to many prominent environmental insults like malnourishment, immune inflammation, abuse, maternal separation, alcohol and drugs. Hence, an individual during an early age encounters more than one simultaneous stressor that leads to impairment of cognitive and behavioral abilities, a symptom common to most of the neurological disorders. Stressors like malnourishment and immune inflammation are common and encountered by a huge number of populations, contributing enormously to a damaged CNS and in most of the cases they act synergistically in dependency to each other, giving rise to the concept of multi-hit. Multi perinatal hit acts by mimicking the mechanism of ageing in CNS and increasing the risk for later life neurological disorders. Multi stress exposure is also responsible for disrupting the cellular homeostasis of the brain by inducing glial activation, neurotoxicity and oxidative stress, which is the major reason of cell death and circuitry damage in brain. Multi perinatal hit thus increases the risk of neurological disorders by many folds through interfering with ongoing developmental cascades and eventually modulating the fate of cellular components in brain. Thus, a stress induced architecturally and chemically altered CNS is vulnerable and prone to neurological disorders like Alzheimer's, Schizophrenia, ALS, Autism and Parkinson's disease. This review compiles the information available regarding the effects of early life stressors on different components of brain, primarily focusing on the connection between perinatally encountered multi hit and development of later life neurological disorders.}, }
@article {pmid30763568, year = {2019}, author = {Haukedal, H and Freude, K}, title = {Implications of Microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Journal of molecular biology}, volume = {431}, number = {9}, pages = {1818-1829}, doi = {10.1016/j.jmb.2019.02.004}, pmid = {30763568}, issn = {1089-8638}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/pathology ; Animals ; Autophagy/genetics/*immunology ; C9orf72 Protein/genetics/immunology ; DNA-Binding Proteins/genetics/immunology ; Disease Models, Animal ; Disease Progression ; Frontotemporal Dementia/genetics/*immunology/pathology ; Gene Expression Regulation/*immunology ; Humans ; Immunity, Innate ; Membrane Glycoproteins/genetics/immunology ; Mice ; Microglia/*immunology/pathology ; RNA-Binding Protein FUS/genetics/immunology ; Receptors, Immunologic/genetics/immunology ; Superoxide Dismutase-1/genetics/immunology ; tau Proteins/genetics/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes that correlated with ALS and FTD are implicated in the same molecular pathways. Strikingly, many of these genes are not exclusively expressed in neurons, but also in glial cells, suggesting a multicellular pathogenesis. Moreover, chronic inflammation is a common feature observed in ALS and FTD, indicating an essential role of microglia, the resident immune cells of the central nervous system, in disease development and progression. In this review, we will provide a comprehensive overview of the implications of microglia in ALS and FTD. Specifically, we will focus on the role of impaired phagocytosis and increased inflammatory responses and their impact on microglial function. Several genes associated with the disorders can directly be linked to microglial activation, phagocytosis and neuroinflammation. Other genes associated with the disorders are implicated in biological pathways involved in protein degradation and autophagy. In general such mutations have been shown to cause abnormal protein accumulation and impaired autophagy. These impairments have previously been linked to affect the innate immune system in the central nervous system through inappropriate activation of microglia and neuroinflammation, highlighted in this review. Although it has been well established that microglia play essential roles in neurodegenerative disorders, the precise underlying mechanisms remain to be elucidated.}, }
@article {pmid30762000, year = {2019}, author = {Carreras, FJ}, title = {Lessons from glaucoma: rethinking the fluid-brain barriers in common neurodegenerative disorders.}, journal = {Neural regeneration research}, volume = {14}, number = {6}, pages = {962-966}, pmid = {30762000}, issn = {1673-5374}, abstract = {Glaucoma has been recently characterized as a member of the group of anoikis-related diseases. Anoikis, a form of apoptosis, can be triggered by the unfastening of adherent junctions present in astrocytes. In those areas of the central nervous system in which the soma of the neurons or their axons and dendrites are metabolically dependent on the activity of astrocytes, a derangement of the lactate shuttle caused by a separation between the plasma membranes of neurons and astrocytes would result in metabolic impairment of the neurons themselves. In glaucoma, the triggering event has been attributed to the posterior deviation of aqueous humor towards the astrocyte-rich prelaminar tissue of the optic nerve head. The mean calcium content in the aqueous is able to interfere with calcium-dependent adherent junctions and induce anoikis of the astrocytes. As the cerebrospinal fluid has a similar base calcium concentration, a shunt of cerebrospinal fluid through the cerebral parenchyma would be able to interfere in the astrocytic architecture with dire consequences to the metabolically dependent neurons. Here the similitude between glaucoma, amyotrophic lateral sclerosis and Alzheimer's disease are discussed and the concept of the break in the fluid-brain barrier, as an event separated from the blood-brain barrier, is stressed.}, }
@article {pmid30761996, year = {2019}, author = {Qu, Y and Liu, Y and Noor, AF and Tran, J and Li, R}, title = {Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {14}, number = {6}, pages = {931-938}, pmid = {30761996}, issn = {1673-5374}, abstract = {Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.}, }
@article {pmid30760643, year = {2019}, author = {McMackin, R and Muthuraman, M and Groppa, S and Babiloni, C and Taylor, JP and Kiernan, MC and Nasseroleslami, B and Hardiman, O}, title = {Measuring network disruption in neurodegenerative diseases: New approaches using signal analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {90}, number = {9}, pages = {1011-1020}, pmid = {30760643}, issn = {1468-330X}, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Electroencephalography ; Frontotemporal Dementia/physiopathology ; Humans ; Lewy Body Disease/physiopathology ; Magnetoencephalography ; Nerve Net/*physiopathology ; Neurodegenerative Diseases/*physiopathology ; Parkinson Disease/physiopathology ; Transcranial Magnetic Stimulation ; }, abstract = {Advanced neuroimaging has increased understanding of the pathogenesis and spread of disease, and offered new therapeutic targets. MRI and positron emission tomography have shown that neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are associated with changes in brain networks. However, the underlying neurophysiological pathways driving pathological processes are poorly defined. The gap between what imaging can discern and underlying pathophysiology can now be addressed by advanced techniques that explore the cortical neural synchronisation, excitability and functional connectivity that underpin cognitive, motor, sensory and other functions. Transcranial magnetic stimulation can show changes in focal excitability in cortical and transcortical motor circuits, while electroencephalography and magnetoencephalography can now record cortical neural synchronisation and connectivity with good temporal and spatial resolution.Here we reflect on the most promising new approaches to measuring network disruption in AD, LBD, PD, FTD, MS, and ALS. We consider the most groundbreaking and clinically promising studies in this field. We outline the limitations of these techniques and how they can be tackled and discuss how these novel approaches can assist in clinical trials by predicting and monitoring progression of neurophysiological changes underpinning clinical symptomatology.}, }
@article {pmid30753166, year = {2019}, author = {Amanzadeh, E and Esmaeili, A and Rahgozar, S and Nourbakhshnia, M}, title = {Application of quercetin in neurological disorders: from nutrition to nanomedicine.}, journal = {Reviews in the neurosciences}, volume = {30}, number = {5}, pages = {555-572}, doi = {10.1515/revneuro-2018-0080}, pmid = {30753166}, issn = {2191-0200}, mesh = {Animals ; Antioxidants/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Humans ; Nanoparticles/chemistry ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Quercetin/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Tissue Distribution ; }, abstract = {Quercetin is a polyphenolic flavonoid, which is frequently found in fruits and vegetables. The antioxidant potential of quercetin has been studied from subcellular compartments, that is, mitochondria to tissue levels in the brain. The neurodegeneration process initiates alongside aging of the neurons. It appears in different parts of the brain as Aβ plaques, neurofibrillary tangles, Lewy bodies, Pick bodies, and others, which leads to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other diseases. So far, no specific treatment has been identified for these diseases. Despite common treatments that help to prevent the development of disease, the condition of patients with progressive neurodegenerative diseases usually do not completely improve. Currently, the use of flavonoids, especially quercetin for the treatment of neurodegenerative diseases, has been expanded in animal models. It has also been used to treat animal models of neurodegenerative diseases. In addition, improvements in behavioral levels, as well as in cellular and molecular levels, decreased activity of antioxidant and apoptotic proteins, and increased levels of antiapoptotic proteins have been observed. Low bioavailability of quercetin has also led researchers to construct various quercetin-involved nanoparticles. The treatment of animal models of neurodegeneration using quercetin-involved nanoparticles has shown that improvements are observed in shorter periods and with use of lower concentrations. Indeed, intranasal administration of quercetin-involved nanoparticles, constructing superparamagnetic nanoparticles, and combinational treatment using nanoparticles such as quercetin and other drugs are suggested for future studies.}, }
@article {pmid30742586, year = {2019}, author = {Gandhi, J and Antonelli, AC and Afridi, A and Vatsia, S and Joshi, G and Romanov, V and Murray, IVJ and Khan, SA}, title = {Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics.}, journal = {Reviews in the neurosciences}, volume = {30}, number = {4}, pages = {339-358}, doi = {10.1515/revneuro-2016-0035}, pmid = {30742586}, issn = {2191-0200}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy/pathology ; Proteasome Endopeptidase Complex/metabolism ; *Protein Folding ; Proteolysis ; *Proteostasis Deficiencies/diagnosis/drug therapy/pathology ; Treatment Outcome ; }, abstract = {Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.}, }
@article {pmid30742233, year = {2019}, author = {Ferreira, PA}, title = {The coming-of-age of nucleocytoplasmic transport in motor neuron disease and neurodegeneration.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {76}, number = {12}, pages = {2247-2273}, pmid = {30742233}, issn = {1420-9071}, support = {GM083165//National Institute of General Medical Sciences/ ; EY019492//National Eye Institute/ ; R01 EY011993/EY/NEI NIH HHS/United States ; R01 GM083165/GM/NIGMS NIH HHS/United States ; R01 EY019492/EY/NEI NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Cell Nucleus/metabolism/pathology ; Cytoplasm/metabolism/pathology ; Humans ; Motor Neuron Disease/*metabolism/pathology ; Motor Neurons/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {The nuclear pore is the gatekeeper of nucleocytoplasmic transport and signaling through which a vast flux of information is continuously exchanged between the nuclear and cytoplasmic compartments to maintain cellular homeostasis. A unifying and organizing principle has recently emerged that cements the notion that several forms of amyotrophic lateral sclerosis (ALS), and growing number of other neurodegenerative diseases, co-opt the dysregulation of nucleocytoplasmic transport and that this impairment is a pathogenic driver of neurodegeneration. The understanding of shared pathomechanisms that underpin neurodegenerative diseases with impairments in nucleocytoplasmic transport and how these interface with current concepts of nucleocytoplasmic transport is bound to illuminate this fundamental biological process in a yet more physiological context. Here, I summarize unresolved questions and evidence and extend basic and critical concepts and challenges of nucleocytoplasmic transport and its role in the pathogenesis of neurodegenerative diseases, such as ALS. These principles will help to appreciate the roles of nucleocytoplasmic transport in the pathogenesis of ALS and other neurodegenerative diseases, and generate a framework for new ideas of the susceptibility of motoneurons, and possibly other neurons, to degeneration by dysregulation of nucleocytoplasmic transport.}, }
@article {pmid30742063, year = {2019}, author = {Chornenkyy, Y and Fardo, DW and Nelson, PT}, title = {Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {99}, number = {7}, pages = {993-1007}, pmid = {30742063}, issn = {1530-0307}, support = {R56 AG057191/AG/NIA NIH HHS/United States ; R01 AG028303/AG/NIA NIH HHS/United States ; R01 AG061111/AG/NIA NIH HHS/United States ; R01 AG042475/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; R21 AG050146/AG/NIA NIH HHS/United States ; R01 AG057187/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Genetic Pleiotropy ; Humans ; TDP-43 Proteinopathies/*etiology ; Tauopathies/*etiology ; }, abstract = {We review the literature on Tau and TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in Alzheimer's disease and related dementias (ADRD), wherein multiple proteins tend to misfold in a manner that is "reactive," but, subsequently, each proteinopathy may contribute strongly to the clinical symptoms. Tau proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions-e.g., developmental, traumatic, and inflammatory/infectious diseases. TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although TDP-43 proteinopathy was first described in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) and in subtypes of frontotemporal dementia (FTD/FTLD), TDP-43 proteinopathy is also present in chronic traumatic encephalopathy, cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington's disease, and other diseases. We list known Tau and TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded proteins, suggesting common pathways or protein interactions facilitating misfolding in one protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects.}, }
@article {pmid30741580, year = {2018}, author = {Parakh, S and Perri, ER and Jagaraj, CJ and Ragagnin, AMG and Atkin, JD}, title = {Rab-dependent cellular trafficking and amyotrophic lateral sclerosis.}, journal = {Critical reviews in biochemistry and molecular biology}, volume = {53}, number = {6}, pages = {623-651}, doi = {10.1080/10409238.2018.1553926}, pmid = {30741580}, issn = {1549-7798}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; Biological Transport, Active ; C9orf72 Protein/genetics/*metabolism ; Cell Membrane/genetics/*metabolism/pathology ; Humans ; rab GTP-Binding Proteins/genetics/*metabolism ; }, abstract = {Rab GTPases are becoming increasingly implicated in neurodegenerative disorders, although their role in amyotrophic lateral sclerosis (ALS) has been somewhat overlooked. However, dysfunction of intracellular transport is gaining increasing attention as a pathogenic mechanism in ALS. Many previous studies have focused axonal trafficking, and the extreme length of axons in motor neurons may contribute to their unique susceptibility in this disorder. In contrast, the role of transport defects within the cell body has been relatively neglected. Similarly, whilst Rab GTPases control all intracellular membrane trafficking events, their role in ALS is poorly understood. Emerging evidence now highlights this family of proteins in ALS, particularly the discovery that C9orf72 functions in intra transport in conjunction with several Rab GTPases. Here, we summarize recent updates on cellular transport defects in ALS, with a focus on Rab GTPases and how their dysfunction may specifically target neurons and contribute to pathophysiology. We discuss the molecular mechanisms associated with dysfunction of Rab proteins in ALS. Finally, we also discuss dysfunction in other modes of transport recently implicated in ALS, including nucleocytoplasmic transport and the ER-mitochondrial contact regions (MAM compartment), and speculate whether these may also involve Rab GTPases.}, }
@article {pmid30733955, year = {2019}, author = {Grova, N and Schroeder, H and Olivier, JL and Turner, JD}, title = {Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants.}, journal = {International journal of genomics}, volume = {2019}, number = {}, pages = {2085496}, pmid = {30733955}, issn = {2314-436X}, abstract = {The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical "Developmental Origins of Health and Disease" paradigm to include exposure to pollutants. This model has been refined over the years to give the current "three-hit" model that considers the individual's genetic factors as a first "hit." It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second "hit." Together, these first two "hits" produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental "hit" in later life. It is only after the third "hit" that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.}, }
@article {pmid30731512, year = {2019}, author = {Esser, P and Metelmann, M and Hartung, T and Claßen, J and Mehnert, A and Koranyi, S}, title = {[Psychosocial Care For Patients With Amyotrophic Lateral Sclerosis: A Narrative Review].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {69}, number = {9-10}, pages = {372-381}, doi = {10.1055/a-0806-7862}, pmid = {30731512}, issn = {1439-1058}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; Health Services ; Humans ; *Psychosocial Support Systems ; Quality of Life ; }, abstract = {This narrative review gives a broad summary of the psychosocial strain in patients with amyotrophic lateral sclerosis (ALS) and psychotherapeutic interventions addressing these issues. ALS is a fatal, rapidly progressing neurodegenerative disease, which leads to weakness and atrophy in almost all muscles of the body, resulting in impairment and finally inability in all domains of daily life including mobility, food intake, respiration or communication. In addition to these mainly motor impairments, most patients are also affected by severe cognitive-emotional and behavioral alterations and deficits which may lead to additional distress. Due to the severe symptomatology and poor diagnosis, ALS can lead to significant psychosocial strain including heightened levels of depressive and anxious symptomatology, hopelessness and even the wish for hastened death. A large body of research demonstrates the strong effect of psychosocial aspects on quality of life (QoL) in ALS patients. Nevertheless, research on psychotherapeutic interventions for patients with ALS is very sparse to date. Besides the general lack of interventions and the methodological limitations in testing their efficacy, few of these therapeutic concepts incorporate the palliative character and the specific symptomatology of the disease such as impaired communication or problems with emotion control. Further research on psychosocial interventions in this patient group is therefore urgently needed. Future research could aim to adapt therapy programs that already have been proven to be effective in other populations with advanced diseases. Such research should also test the applicability of the therapy models using alternative communication including computer with a voice synthesizer or brain-computer-interfaces.}, }
@article {pmid30729795, year = {2020}, author = {Craenen, K and Verslegers, M and Baatout, S and Abderrafi Benotmane, M}, title = {An appraisal of folates as key factors in cognition and ageing-related diseases.}, journal = {Critical reviews in food science and nutrition}, volume = {60}, number = {5}, pages = {722-739}, doi = {10.1080/10408398.2018.1549017}, pmid = {30729795}, issn = {1549-7852}, mesh = {Aging/drug effects/*metabolism ; *Cognition/drug effects ; Dietary Supplements ; Folic Acid/*metabolism/therapeutic use ; Folic Acid Deficiency/complications/diet therapy/drug therapy/metabolism ; Humans ; Neurodegenerative Diseases/complications/drug therapy/*metabolism ; }, abstract = {Folic acid (FA) is often consumed as a food supplement and can be found in fortified staple foods in various western countries. Even though FA supplementation during pregnancy is known to prevent severe congenital anomalies in the developing child (e.g., neural tube defects), much less is known about its influence on cognition and neurological functioning. In this review, we address the advances in this field and situate how folate intake during pregnancy, postnatal life, adulthood and in the elderly affects cognition. In addition, an association between folate status and ageing, dementia and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis is discussed. While its role in the incidence and severity of these diseases is becoming apparent, the underlying action of folates and related metabolites remains elusive. Finally, the potential of FA as a nutraceutical has been proposed, although the efficacy will highly depend on the interplay with other micronutrients, the disease stage and the duration of supplementation. Hence, the lack of consistent data urges for more animal studies and (pre)clinical trials in humans to ascertain a potential beneficial role for folates in the treatment or amelioration of cognitive decline and ageing-related disorders.}, }
@article {pmid30728931, year = {2019}, author = {Audag, N and Goubau, C and Toussaint, M and Reychler, G}, title = {Screening and evaluation tools of dysphagia in adults with neuromuscular diseases: a systematic review.}, journal = {Therapeutic advances in chronic disease}, volume = {10}, number = {}, pages = {2040622318821622}, pmid = {30728931}, issn = {2040-6223}, abstract = {BACKGROUND: The purpose of this systematic review was to summarize the different dysphagia screening and evaluation tools, and to identify their measurement properties in adults with neuromuscular diseases (NMDs).<br><br>METHODS: A systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was conducted across three databases (PubMed, CINAHL and ScienceDirect). Measurement properties of each tools and the Quality Index, developed by Downs and Black, were considered for the different investigated studies.<br><br>RESULTS: The search strategy produced 2221 articles. After removal of duplicates and full-text analysis, 19 studies were included. Most of the publications focused on amyotrophic lateral sclerosis (ALS; n = 10) and Duchenne muscular dystrophy (DMD; n = 4). A total of 12 tools, listed as instrumental and noninstrumental examinations, were retrieved. A total of five of them used videofluoroscopic swallow study (VFSS). Measurement properties of the tools are not completely described in detail in many studies. The neuromuscular disease swallowing status scale, a noninstrumental tool, is the only one that assessed all measurement properties in ALS patients. The median score reported for the Quality Index was 16.<br><br>CONCLUSIONS: This systematic review identified 12 different tools for the screening and evaluation of dysphagia in adults with NMD. Majority of the studies presented VFSS as a valid and reliable examination to assess dysphagia in ALS and DMD. Other tools were mainly evaluated in ALS patients, but further studies are needed to complete their measurement properties. In other NMDs, no firm conclusion can be made because of insufficient data and heterogeneity of NMDs.}, }
@article {pmid30726905, year = {2019}, author = {Kamemura, K and Chihara, T}, title = {Multiple functions of the ER-resident VAP and its extracellular role in neural development and disease.}, journal = {Journal of biochemistry}, volume = {165}, number = {5}, pages = {391-400}, doi = {10.1093/jb/mvz011}, pmid = {30726905}, issn = {1756-2651}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Biological Transport ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism ; Cytosol/metabolism ; Endoplasmic Reticulum/*metabolism ; Humans ; Lipid Metabolism ; Membrane Proteins/chemistry/genetics/*metabolism/physiology ; Microtubules/metabolism ; Point Mutation ; Sequence Homology, Amino Acid ; Unfolded Protein Response ; }, abstract = {VAP (VAMP-associated protein) is a type II integral membrane protein of the endoplasmic reticulum (ER), and its N-terminal major sperm protein (MSP) domain faces the cytoplasmic side. VAP functions as a tethering molecule at the membrane contact sites between the ER and intracellular organelles and regulates a wide variety of cellular functions, including lipid transport, membrane trafficking, microtubule reorganization and unfolded protein response. VAP-point mutations in human vapb are strongly associated with amyotrophic lateral sclerosis. Importantly, the MSP domain of VAP is cleaved, secreted and interacts with the axon growth cone guidance receptors (Eph, Robo, Lar), suggesting that VAP could function as a circulating hormone similar to the Caenorhabditis elegans MSP protein. In this review, we discuss not only the intracellular functions of VAP but also the recently discovered extracellular functions and their implications for neurodegenerative disease.}, }
@article {pmid30723494, year = {2018}, author = {Butti, Z and Patten, SA}, title = {RNA Dysregulation in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in genetics}, volume = {9}, number = {}, pages = {712}, pmid = {30723494}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease and is characterized by the degeneration of upper and lower motor neurons. It has become increasingly clear that RNA dysregulation is a key contributor to ALS pathogenesis. The major ALS genes SOD1, TARDBP, FUS, and C9orf72 are involved in aspects of RNA metabolism processes such as mRNA transcription, alternative splicing, RNA transport, mRNA stabilization, and miRNA biogenesis. In this review, we highlight the current understanding of RNA dysregulation in ALS pathogenesis involving these major ALS genes and discuss the potential of therapeutic strategies targeting disease RNAs for treating ALS.}, }
@article {pmid30721407, year = {2019}, author = {Burk, K and Pasterkamp, RJ}, title = {Disrupted neuronal trafficking in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {137}, number = {6}, pages = {859-877}, pmid = {30721407}, issn = {1432-0533}, support = {-//Dutch ALS Foundation/International ; -//Prinses Beatrix Spierfonds/International ; -//Center for Nanoscale Microscopy and Molecular Physiology/International ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Autophagy ; Axonal Transport ; Biological Transport/*physiology ; C9orf72 Protein/deficiency/genetics/physiology ; DNA Repeat Expansion ; Endoplasmic Reticulum/metabolism ; Endosomes/metabolism ; Flavoproteins/genetics ; Golgi Apparatus/metabolism ; Humans ; Lysosomes/metabolism ; Motor Neurons/*metabolism ; Mutation ; Nerve Degeneration/physiopathology ; Nerve Tissue Proteins/genetics/*physiology ; Phosphoric Monoester Hydrolases/genetics ; Protein Transport ; Receptors, Glutamate/physiology ; Receptors, N-Methyl-D-Aspartate/physiology ; TDP-43 Proteinopathies/genetics ; Valosin Containing Protein/genetics ; rab GTP-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3-5 years and no effective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Different ALS disease mechanisms have been identified and recent evidence supports a prominent role for defects in intracellular transport. Several different ALS-causing gene mutations (e.g., in FUS, TDP-43, or C9ORF72) have been linked to defects in neuronal trafficking and a picture is emerging on how these defects may trigger disease. This review summarizes and discusses these recent findings. An overview of how endosomal and receptor trafficking are affected in ALS is followed by a description on dysregulated autophagy and ER/Golgi trafficking. Finally, changes in axonal transport and nucleocytoplasmic transport are discussed. Further insight into intracellular trafficking defects in ALS will deepen our understanding of ALS pathogenesis and will provide novel avenues for therapeutic intervention.}, }
@article {pmid30718958, year = {2019}, author = {Oliver, DJ}, title = {Palliative care in motor neurone disease: where are we now?.}, journal = {Palliative care}, volume = {12}, number = {}, pages = {1178224218813914}, pmid = {30718958}, issn = {1178-2242}, abstract = {Palliative care has a very important role in the care of patients with motor neurone disease and their families. There is increasing emphasis on the multidisciplinary assessment and support of patients within guidelines, supported by research. This includes the telling of the diagnosis, the assessment and management of symptoms, consideration of interventions, such as gastrostomy and ventilatory support, and care at the end of life. The aim of palliative care is to enable patients, and their families, to maintain as good a quality of life as possible and helping to ensure a peaceful death.}, }
@article {pmid30713520, year = {2018}, author = {Poesen, K and Van Damme, P}, title = {Diagnostic and Prognostic Performance of Neurofilaments in ALS.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1167}, pmid = {30713520}, issn = {1664-2295}, abstract = {There is a need for biomarkers for amyotrophic lateral sclerosis (ALS), to support the diagnosis of the disease, to predict disease progression and to track disease activity and treatment responses. Over the last decade multiple studies have investigated the potential of neurofilament levels, both in cerebrospinal fluid and blood, as biomarker for ALS. The most widely studied neurofilament subunits are neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH). Neurofilament levels are reflecting neuronal injury and therefore potentially of value in ALS and other neurological disorders. In this mini-review, we summarize and discuss the available evidence about neurofilaments as diagnostic and prognostic biomarker for human ALS.}, }
@article {pmid30697143, year = {2018}, author = {Petillon, C and Hergesheimer, R and Puy, H and Corcia, P and Vourc'h, P and Andres, C and Karim, Z and Blasco, H}, title = {The Relevancy of Data Regarding the Metabolism of Iron to Our Understanding of Deregulated Mechanisms in ALS; Hypotheses and Pitfalls.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {1031}, pmid = {30697143}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons. Its etiology remains unknown, but several pathophysiological mechanisms are beginning to explain motor neuronal death, as well as oxidative stress. Iron accumulation has been observed in both sporadic and familial forms of ALS, including mouse models. Therefore, the dysregulation of iron metabolism could play a role in the pathological oxidative stress in ALS. Several studies have been undertaken to describe iron-related metabolic markers, in most cases focusing on metabolites in the bloodstream due to few available data in the central nervous system. Reports of accumulation of iron, high serum ferritin, and low serum transferrin levels in ALS patients have encouraged researchers to consider dysregulated iron metabolism as an integral part of ALS pathophysiology. However, it appears complicated to suggest a general mechanism due to the diversity of models and iron markers studied, including the lack of consensus among all of the studies. Regarding clinical study reports, most of them do not take into account confusion biases such as inflammation, renal dysfunction, and nutritional status. Furthermore, the iron regulatory pathways, particularly involving hepcidin, have not been thoroughly explored yet within the pathogenesis of iron overload in ALS. In this sense, it is also essential to explore the relation between iron overload and other ALS-related events, such as neuro-inflammation, protein aggregation, and iron-driven cell death, termed ferroptosis. In this review, we point out limits of the designs of certain studies that may prevent the understanding of the role of iron in ALS and discuss the relevance of the published data regarding the pathogenic impact of iron metabolism deregulation in this disease and the therapeutics targeting this pathway.}, }
@article {pmid30689195, year = {2019}, author = {Gonzalez, D and Brandan, E}, title = {CTGF/CCN2 from Skeletal Muscle to Nervous System: Impact on Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {56}, number = {8}, pages = {5911-5916}, pmid = {30689195}, issn = {1559-1182}, support = {AFB170005//Basal CARE UC CHILE/ ; 1150106//FONDECYT/ ; 1//Beca de Doctorado/ ; }, mesh = {Animals ; Connective Tissue Growth Factor/*metabolism ; Humans ; Models, Biological ; Muscle, Skeletal/*metabolism ; Nervous System/*metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that belongs to the CCN family of proteins. Since its discovery, it has been linked to cellular processes such as cell proliferation, differentiation, adhesion, migration, and synthesis of extracellular matrix (ECM) components, among others. The pro-fibrotic role of CTGF/CCN2 has been well-studied in several pathologies characterized by the development of fibrosis. Reduction of CTGF/CCN2 levels in mdx mice, a murine model for Duchenne muscular dystrophy (DMD), decreases fibrosis and improves skeletal muscle phenotype and function. Recently, it has been shown that skeletal muscle of symptomatic hSOD1[G93A] mice, a model for Amyotrophic lateral sclerosis (ALS), shows up-regulation of CTGF/CCN2 accompanied by excessive deposition ECM molecules. Elevated levels of CTGF/CCN2 in spinal cord from ALS patients have been previously reported. However, there is no evidence regarding the role of CTGF/CCN2 in neurodegenerative diseases such as ALS, in which alterations in skeletal muscle seem to be the consequence of early pathological denervation. In this regard, the emerging evidence shows that CTGF/CCN2 also exerts non-fibrotic roles in the central nervous system (CNS), specifically impairing oligodendrocyte maturation and regeneration, and inhibiting axon myelination. Despite these striking observations, there is no evidence showing the role of CTGF/CCN2 in peripheral nerves. Therefore, even though more studies are needed to elucidate its precise role, CTGF/CCN2 is starting to emerge as a novel therapeutic target for the treatment of neurodegenerative diseases where demyelination and axonal degeneration occurs.}, }
@article {pmid30688256, year = {2019}, author = {Shefa, U and Jeong, NY and Song, IO and Chung, HJ and Kim, D and Jung, J and Huh, Y}, title = {Mitophagy links oxidative stress conditions and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {14}, number = {5}, pages = {749-756}, pmid = {30688256}, issn = {1673-5374}, abstract = {Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative diseases. Proper regulation of mitophagy is crucial for maintaining homeostasis; conversely, inadequate removal of mitochondria through mitophagy leads to the generation of oxidative species, including reactive oxygen species and reactive nitrogen species, resulting in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These diseases are most prevalent in older adults whose bodies fail to maintain proper mitophagic functions to combat oxidative species. As mitophagy is essential for normal body function, by targeting mitophagic pathways we can improve these disease conditions. The search for effective remedies to treat these disease conditions is an ongoing process, which is why more studies are needed. Additionally, more relevant studies could help establish therapeutic conditions, which are currently in high demand. In this review, we discuss how mitophagy plays a significant role in homeostasis and how its dysregulation causes neurodegeneration. We also discuss how combating oxidative species and targeting mitophagy can help treat these neurodegenerative diseases.}, }
@article {pmid30687254, year = {2018}, author = {Forbes, JD and Bernstein, CN and Tremlett, H and Van Domselaar, G and Knox, NC}, title = {A Fungal World: Could the Gut Mycobiome Be Involved in Neurological Disease?.}, journal = {Frontiers in microbiology}, volume = {9}, number = {}, pages = {3249}, pmid = {30687254}, issn = {1664-302X}, abstract = {The human microbiome has received decades of attention from scientific and medical research communities. The human gastrointestinal tract is host to immense populations of microorganisms including bacteria, viruses, archaea, and fungi (the gut microbiota). High-throughput sequencing and computational advancements provide unprecedented ability to investigate the structure and function of microbial communities associated with the human body in health and disease. Most research to date has largely focused on elucidating the bacterial component of the human gut microbiota. Study of the gut "mycobiota," which refers to the diverse array of fungal species, is a relatively new and rapidly progressing field. Though omnipresent, the number and abundance of fungi occupying the human gut is orders of magnitude smaller than that of bacteria. Recent insights however, have suggested that the gut mycobiota may be intricately linked to health and disease. Evaluation of the gut mycobiota has shown that not only are the fungal communities altered in disease, but they also play a role in maintaining intestinal homeostasis and influencing systemic immunity. In addition, it is now widely accepted that host-fungi and bacteria-fungi associations are critical to host health. While research of the gut mycobiota in health and disease is on the rise, little research has been performed in the context of neuroimmune and neurodegenerative conditions. Gut microbiota dysbiosis (specifically bacteria and archaea) have been reported in neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's, among others. Given the widely accepted bacteria-fungi associations and paucity of mycobiota-specific studies in neurological disease, this review discusses the potential role fungi may play in multiple sclerosis and other neurological diseases. Herein, we provide an overview of recent advances in gut mycobiome research and discuss the plausible role of both intestinal and non-intestinal fungi in the context of neuroimmune and neurodegenerative conditions.}, }
@article {pmid30682329, year = {2019}, author = {Zhou, J and Li, A and Li, X and Yi, J}, title = {Dysregulated mitochondrial Ca[2+] and ROS signaling in skeletal muscle of ALS mouse model.}, journal = {Archives of biochemistry and biophysics}, volume = {663}, number = {}, pages = {249-258}, pmid = {30682329}, issn = {1096-0384}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Autophagy ; *Calcium Signaling ; Disease Models, Animal ; Membrane Potential, Mitochondrial ; Mice ; Mitochondria, Muscle/*metabolism ; Mitochondrial Dynamics ; Muscle, Skeletal/metabolism ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by motor neuron loss and prominent skeletal muscle wasting. Despite more than one hundred years of research efforts, the pathogenic mechanisms underlying neuromuscular degeneration in ALS remain elusive. While the death of motor neuron is a defining hallmark of ALS, accumulated evidences suggested that in addition to being a victim of motor neuron axonal withdrawal, the intrinsic skeletal muscle degeneration may also actively contribute to ALS disease pathogenesis and progression. Examination of spinal cord and muscle autopsy/biopsy samples of ALS patients revealed similar mitochondrial abnormalities in morphology, quantity and disposition, which are accompanied by defective mitochondrial respiratory chain complex and elevated oxidative stress. Detailing the molecular/cellular mechanisms and the role of mitochondrial dysfunction in ALS relies on ALS animal model studies. This review article discusses the dysregulated mitochondrial Ca[2+] and reactive oxygen species (ROS) signaling revealed in live skeletal muscle derived from ALS mouse models, and a potential role of the vicious cycle formed between the dysregulated mitochondrial Ca[2+] signaling and excessive ROS production in promoting muscle wasting during ALS progression.}, }
@article {pmid30677752, year = {2019}, author = {Crimi, C and Pierucci, P and Carlucci, A and Cortegiani, A and Gregoretti, C}, title = {Long-Term Ventilation in Neuromuscular Patients: Review of Concerns, Beliefs, and Ethical Dilemmas.}, journal = {Respiration; international review of thoracic diseases}, volume = {97}, number = {3}, pages = {185-196}, doi = {10.1159/000495941}, pmid = {30677752}, issn = {1423-0356}, mesh = {Follow-Up Studies ; Humans ; Neuromuscular Diseases/*therapy ; *Quality of Life ; Respiration, Artificial/*ethics ; Respiratory Insufficiency/etiology/therapy ; Respiratory Therapy/*ethics/methods ; Time Factors ; }, abstract = {BACKGROUND: Noninvasive mechanical ventilation (NIV) is an effective treatment in patients with neuromuscular diseases (NMD) to improve symptoms, quality of life, and survival.<br><br>SUMMARY: NIV should be used early in the course of respiratory muscle involvement in NMD patients and its requirements may increase over time. Therefore, training on technical equipment at home and advice on problem solving are warranted. Remote monitoring of ventilator parameters using built-in ventilator software is recommended. Telemedicine may be helpful in reducing hospital admissions. Anticipatory planning and palliative care should be carried out to lessen the burden of care, to maintain or withdraw from NIV, and to guarantee the most respectful management in the last days of NMD patients' life. Key Message: Long-term NIV is effective but challenging in NMD patients. Efforts should be made by health care providers in arranging a planned transition to home and end-of-life discussions for ventilator-assisted individuals and their families.}, }
@article {pmid30672142, year = {2019}, author = {Yu, H and Yu, W and Luo, SS and Yang, YJ and Liu, FT and Zhang, Y and Chen, Y and Sun, YM and Wu, JJ}, title = {Association of the TBK1 mutation p.Ile334Thr with frontotemporal dementia and literature review.}, journal = {Molecular genetics &amp; genomic medicine}, volume = {7}, number = {3}, pages = {e547}, pmid = {30672142}, issn = {2324-9269}, mesh = {Adult ; Autophagy ; Cell Cycle Proteins ; Cells, Cultured ; Female ; Frontotemporal Dementia/*genetics/pathology ; HEK293 Cells ; Humans ; Loss of Function Mutation ; Membrane Transport Proteins ; *Mutation, Missense ; Protein Binding ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Transcription Factor TFIIIA/metabolism ; }, abstract = {BACKGROUND: The mutation of TANK-binding kinase 1 (TBK1) gene has been regarded as a causative gene of frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum disease in recent years. So far, more than 70 TBK1 variants have been identified in patients with FTD-ALS spectrum.<br><br>METHODS: We reported a Chinese FTD patient carrying TBK1 p.Ile334Thr variant detected by target sequencing and Sanger sequencing. The patient's clinical materials were collected. The transcription and translation levels of TBK1 mutant were investigated in fibroblast by qPCR and western blot. The effects of TBK1 mutant in inflammation pathway and autophagy were detected by luciferase reporter assay and GST pull-down assay.<br><br>RESULTS: The patient was diagnosed as behavioral variant FTD (bvFTD) and displayed progressively severe cognitive impairment especially in executive function. A pattern of frontotemporal atrophy and hypometabolism was shown through MRI and PET-CT. In vitro functional experiments of TBK1 p.Ile334Thr variant demonstrated reduced transcription and translation levels, decreased kinase activity but maintenance of interaction with optineurin. The variant was classified as likely pathogenic according to American College of Medical Genetics and Genomics guideline.<br><br>CONCLUSION: We proposed the TBK1 mutation p.Ile334Thr as a likely pathogenic variant in bvFTD which also expanded the clinical spectrum of this variant. It can partially abrogate TBK1 functions and be responsible for FTD-ALS spectrum diseases through neuroinflammatory pathway.}, }
@article {pmid30671016, year = {2018}, author = {Proudfoot, M and Bede, P and Turner, MR}, title = {Imaging Cerebral Activity in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1148}, pmid = {30671016}, issn = {1664-2295}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Advances in neuroimaging, complementing histopathological insights, have established a multi-system involvement of cerebral networks beyond the traditional neuromuscular pathological view of amyotrophic lateral sclerosis (ALS). The development of effective disease-modifying therapy remains a priority and this will be facilitated by improved biomarkers of motor system integrity against which to assess the efficacy of candidate drugs. Functional MRI (FMRI) is an established measure of both cerebral activity and connectivity, but there is an increasing recognition of neuronal oscillations in facilitating long-distance communication across the cortical surface. Such dynamic synchronization vastly expands the connectivity foundations defined by traditional neuronal architecture. This review considers the unique pathogenic insights afforded by the capture of cerebral disease activity in ALS using FMRI and encephalography.}, }
@article {pmid30666190, year = {2018}, author = {Saar, G and Koretsky, AP}, title = {Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases.}, journal = {Frontiers in neural circuits}, volume = {12}, number = {}, pages = {114}, pmid = {30666190}, issn = {1662-5110}, mesh = {Animals ; Brain/diagnostic imaging ; *Contrast Media ; Humans ; *Magnetic Resonance Imaging ; *Manganese Compounds ; Neurodegenerative Diseases/*diagnostic imaging ; }, abstract = {MRI has been extensively used in neurodegenerative disorders, such as Alzheimer's disease (AD), frontal-temporal dementia (FTD), mild cognitive impairment (MCI), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). MRI is important for monitoring the neurodegenerative components in other diseases such as epilepsy, stroke and multiple sclerosis (MS). Manganese enhanced MRI (MEMRI) has been used in many preclinical studies to image anatomy and cytoarchitecture, to obtain functional information in areas of the brain and to study neuronal connections. This is due to Mn[2+] ability to enter excitable cells through voltage gated calcium channels and be actively transported in an anterograde manner along axons and across synapses. The broad range of information obtained from MEMRI has led to the use of Mn[2+] in many animal models of neurodegeneration which has supplied important insight into brain degeneration in preclinical studies. Here we provide a brief review of MEMRI use in neurodegenerative diseases and in diseases with neurodegenerative components in animal studies and discuss the potential translation of MEMRI to clinical use in the future.}, }
@article {pmid30663610, year = {2019}, author = {Beers, DR and Appel, SH}, title = {Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies.}, journal = {The Lancet. Neurology}, volume = {18}, number = {2}, pages = {211-220}, doi = {10.1016/S1474-4422(18)30394-6}, pmid = {30663610}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*pathology ; Animals ; Humans ; }, abstract = {Neuroinflammation is a common pathological feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and is characterised by activated CNS microglia and astroglia, proinflammatory peripheral lymphocytes, and macrophages. Data from clinical studies show that multiple genetic mutations linked to ALS (eg, mutations in SOD1, TARDBP, and C9orf72) enhance this neuroinflammation, which provides compelling evidence for immune dysregulation in the pathogenesis of ALS. Transgenic rodent models expressing these mutations induce an ALS-like disease with accompanying inflammatory responses, confirming the immune system's involvement in disease progression. Even in the absence of known genetic alterations, immune dysregulation has been shown to lead to dysfunctional regulatory T lymphocytes and increased proinflammatory macrophages in clinical studies. Therefore, an improved understanding of the biological processes that induce this immune dysregulation will help to identify therapeutic strategies that circumvent or ameliorate the pathogenesis of ALS. Emerging cell-based therapies hold the promise of accomplishing this goal and, therefore, improving quality of life and extending survival in patients with ALS.}, }
@article {pmid30662429, year = {2018}, author = {Huynh, W and Dharmadasa, T and Vucic, S and Kiernan, MC}, title = {Functional Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1141}, pmid = {30662429}, issn = {1664-2295}, abstract = {The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on determination of progressive dysfunction of both cortical as well as spinal and bulbar motor neurons. However, the variable mix of upper and lower motor neuron signs result in the clinical heterogeneity of patients with ALS, resulting frequently in delay of diagnosis as well as difficulty in monitoring disease progression and treatment outcomes particularly in a clinical trial setting. As such, the present review provides an overview of recently developed novel non-invasive electrophysiological techniques that may serve as biomarkers to assess UMN and LMN dysfunction in ALS patients.}, }
@article {pmid30660504, year = {2019}, author = {Guo, L and Fare, CM and Shorter, J}, title = {Therapeutic Dissolution of Aberrant Phases by Nuclear-Import Receptors.}, journal = {Trends in cell biology}, volume = {29}, number = {4}, pages = {308-322}, pmid = {30660504}, issn = {1879-3088}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 NS090205/NS/NINDS NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/*drug effects ; Cell Nucleus/*drug effects/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; RNA-Binding Proteins/antagonists &amp; inhibitors/metabolism ; Receptors, Cytoplasmic and Nuclear/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Nuclear-import receptors (NIRs) bind nuclear-localization signals (NLSs) of protein cargo in the cytoplasm and transport them into the nucleus. Here, we review advances establishing that NIRs also function in the cytoplasm to prevent and reverse functional and aberrant phase transitions of their cargo, including neurodegenerative disease-linked RNA-binding proteins (RBPs) with prion-like domains, such as TDP-43, FUS, hnRNPA1, and hnRNPA2. NIRs selectively extract cargo from condensed liquid phases thereby regulating functional phase separation. Consequently, NIRs sculpt cytoplasmic membraneless organelles and regulate cellular organization beyond their canonical role in nuclear import. Elevating NIR expression dissolves cytoplasmic RBP aggregates, restores functional RBPs to the nucleus, and rescues disease-linked RBP toxicity. Thus, NIRs could be leveraged therapeutically to restore RBP homeostasis and mitigate neurodegeneration.}, }
@article {pmid30658292, year = {2019}, author = {Roy Sarkar, S and Banerjee, S}, title = {Gut microbiota in neurodegenerative disorders.}, journal = {Journal of neuroimmunology}, volume = {328}, number = {}, pages = {98-104}, doi = {10.1016/j.jneuroim.2019.01.004}, pmid = {30658292}, issn = {1872-8421}, mesh = {Animals ; Gastrointestinal Microbiome/*physiology ; Humans ; Neurodegenerative Diseases/*microbiology ; }, abstract = {Gut dysbiosis, a primary factor behind various gastrointestinal disorders may also augment lipopolysaccharides, pro-inflammatory cytokines, T helper cells and monocytes causing increased intestinal and BBB permeability via microbiota-gut-brain axis. Consequentially, accumulation of misfolded proteins, axonal damage and neuronal demyelination sets in, thus facilitating the pathogenesis of neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Studies revealed that intake of probiotics may help in the integrity of intestinal and BBB thus ameliorating the above neurodegenerative disorders. This review summarizes the current understanding of the role of gut microbiota in neurodegenerative disorders and possible intervention strategies.}, }
@article {pmid30657305, year = {2019}, author = {Ma, S and Attarwala, IY and Xie, XQ}, title = {SQSTM1/p62: A Potential Target for Neurodegenerative Disease.}, journal = {ACS chemical neuroscience}, volume = {10}, number = {5}, pages = {2094-2114}, pmid = {30657305}, issn = {1948-7193}, support = {P30 DA035778/DA/NIDA NIH HHS/United States ; R56 AG074951/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Brain/*metabolism/pathology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Sequestosome-1 Protein/*metabolism ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.}, }
@article {pmid30656911, year = {2018}, author = {Węgrzyn, G and Pierzynowska, K and Podlacha, M and Brokowska, J and Gaffke, L and Mantej, J and Cyske, Z and Rintz, E and Osiadły, M and Bartkowski, M and Puchalski, M and Grabski, M and Pierzynowski, M and Pankanin, D and Piotrowska, E and Tukaj, S}, title = {[Molecular mechanisms of genistein action in the light of therapies for genetic and immunological diseases].}, journal = {Postepy biochemii}, volume = {64}, number = {4}, pages = {262-276}, doi = {10.18388/pb.2018_140}, pmid = {30656911}, issn = {0032-5422}, mesh = {Alzheimer Disease/drug therapy/genetics ; Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Genistein/*pharmacology/*therapeutic use ; Humans ; Huntington Disease/drug therapy/genetics ; Immune System Diseases/*drug therapy ; Mucopolysaccharidosis III/drug therapy ; Parkinson Disease/drug therapy/genetics ; }, abstract = {Genetic and immunological diseases, despite many attempts to develop effective treatments, still remain a great challenge for medicine. Current therapies of these diseases consist of pharmacological alleviation of symptoms, rehabilitation and psychological help which, although very important, are not sufficient. Therefore, searching for new therapeutics which could remove the major causes of these diseases is of particular importance for the society. Natural compounds reveal many biological activities which makes them candidates for drugs in such diseases. One of them is genistein, a compound from the group of flavonoids. As it affects multiple processes, genistein has become in the center of interest of many scientists working on diseases of various etiology, course and inheritance. It was used in experimental therapies of some genetic diseases (Huntington's disease, amyotrophic lateral sclerosis Parkinson disease, cystic fibrosis), as well as autoimmunological diseases and allergies. Clinical trials with the use of genistein in treatment of patients suffering from Alzheimer's diseases and mucopolysaccharidosis type III are ongoing. The employment of differential properties of genistein in attempts to treat each of these diseases is of special interest. In this review, detailed molecular mechanisms of genistein action are summarized in the light of therapies of the above mentioned genetic and immunological diseases, including description of therapeutic potentials of each activity of this isoflavone, efficiency of its action, and its potential use as a drug in the future.}, }
@article {pmid30656405, year = {2019}, author = {Hoeper, AM and Barbara, DW and Watson, JC and Sprung, J and Weingarten, TN}, title = {Amyotrophic lateral sclerosis and anesthesia: a case series and review of the literature.}, journal = {Journal of anesthesia}, volume = {33}, number = {2}, pages = {257-265}, pmid = {30656405}, issn = {1438-8359}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*surgery ; Anesthesia/*methods ; Female ; Gastrostomy/methods ; Humans ; *Intubation, Intratracheal ; Male ; Middle Aged ; Pneumoperitoneum/etiology ; Retrospective Studies ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to death due to respiratory failure. This report describes the perioperative characteristics of ALS patients who underwent procedures with anesthesia at our institution.<br><br>METHODS: We reviewed perioperative records of ALS patients who underwent procedures with anesthesia from January 1, 2014, through December 31, 2015.<br><br>RESULTS: Seventy-eight patients underwent 89 procedures (71 procedures with monitored anesthesia care and 18 with general anesthesia), including 45 gastrostomy tube placements and 18 bone marrow biopsies. Three patients had prolonged duration of postoperative intubation related to preexisting respiratory muscle weakness, and one patient with bilateral pneumothorax required tracheal reintubation for respiratory distress. Four patients had prolonged duration of hospitalization. Three patients were hospitalized for ALS-related complications, and one patient was hospitalized for respiratory distress when pneumoperitoneum developed after gastrostomy tube placement. Three of these patients died of complications attributable to ALS within 30&#xa0;days of the procedure. Twenty-nine (32.6%) procedures required minimal sedation (e.g., bone marrow biopsy, cataract surgery) and were performed on an ambulatory basis.<br><br>CONCLUSION: When caring for patients with ALS, the perioperative team must be prepared to treat potentially complex medical conditions that may not be directly related to the procedure and anesthetic management. However, minor procedures performed with minimal sedation may be safely performed on an ambulatory basis.}, }
@article {pmid30654671, year = {2019}, author = {Finegan, E and Chipika, RH and Shing, SLH and Hardiman, O and Bede, P}, title = {Primary lateral sclerosis: a distinct entity or part of the ALS spectrum?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {3-4}, pages = {133-145}, doi = {10.1080/21678421.2018.1550518}, pmid = {30654671}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/classification/diagnostic imaging/*pathology ; Humans ; Motor Neuron Disease/classification/diagnostic imaging/*pathology ; Neuroimaging ; }, abstract = {Primary lateral sclerosis (PLS) has been traditionally viewed as a distinct upper motor neuron condition (UMN) but is increasingly regarded as a sub-phenotype within the amyotrophic lateral sclerosis (ALS) spectrum. Despite established diagnostic criteria, formal diagnosis can be challenging and the protracted diagnostic journey and uncertainty about longer-term prognosis cause considerable distress to patients and caregivers. PLS patients are invariably excluded from ALS clinical trials, while PLS pharmacological trials are lacking. There remains an unmet need for diagnostic biomarkers for upper motor neuron predominant conditions and prognostic indicators regarding prognosis, survival, and risk of conversion to ALS. Validated biomarkers will not only have implications for individualized patient care but also serve as outcome measures in pharmaceutical trials. Given the paucity of post-mortem studies in PLS, novel pathological insights are generally inferred from state-of-the-art imaging studies. Computational neuroimaging has already contributed significantly to the characterization of PLS-associated pathology in vivo and has underscored the role of neuro-inflammation, the presence of extra-motor changes, and confirmed pathological patterns similar to ALS. This systematic review assesses the current state of PLS research across clinical, neuroimaging and neuropathological domains from a combined clinical and academic perspective. We discuss patterns of pathological overlap with other ALS phenotypes, examine if the biological processes of PLS warrant therapeutic strategies distinct from ALS, and evaluate the evidence that classes PLS as a distinct clinico-pathological entity.}, }
@article {pmid30652056, year = {2018}, author = {Yedavalli, VS and Patil, A and Shah, P}, title = {Amyotrophic Lateral Sclerosis and its Mimics/Variants: A Comprehensive Review.}, journal = {Journal of clinical imaging science}, volume = {8}, number = {}, pages = {53}, pmid = {30652056}, issn = {2156-7514}, abstract = {Motor neuron diseases (MNDs) are a debilitating subset of diseases, which result in progressive neuronal destruction and eventual loss of voluntary muscular function. These entities are often challenging to distinguish and accurately diagnose given overlapping clinical pictures and overall rarity. This group of diseases has a high morbidity and mortality rate overall and delineating each type of disease can help guide appropriate clinical management and improve quality of life for patients. Of all MNDs, amyotrophic lateral sclerosis (ALS) is by far the most common comprising 80%-90% of cases. However, other mimics and variants of ALS can appear similar both clinically and radiographically. In this review, we delve into the epidemiological, physiological, neuroimaging, and prognostic characteristics and management of ALS and its most common MND mimics/variants. In doing so, we hope to improve accuracy in diagnosis and potential management for this rare group of diseases.}, }
@article {pmid30646937, year = {2019}, author = {Walker, OS and Holloway, AC and Raha, S}, title = {The role of the endocannabinoid system in female reproductive tissues.}, journal = {Journal of ovarian research}, volume = {12}, number = {1}, pages = {3}, pmid = {30646937}, issn = {1757-2215}, mesh = {Animals ; Endocannabinoids/*metabolism ; Female ; Humans ; Hypothalamo-Hypophyseal System ; Ovarian Diseases/*metabolism ; Ovary/*metabolism ; Reproduction ; }, abstract = {There has been increasing interest in the role of endocannabinoids as critical modulators of the female reproductive processes. Endocannabinoids are natural ligands of cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. Together with their receptors, enzymes and downstream signaling targets, they form the endocannabinoid system (ECS). While the ECS is known to modulate pain and neurodevelopment, it is also known to impact the female reproductive system where it affects folliculogenesis, oocyte maturation, and ovarian endocrine secretion. In addition, the ECS affects oviductal embryo transport, implantation, uterine decidualization and placentation. There is a complex interplay between the ECS and the hypothalamic-pituitary-ovarian axis, and an intricate crosstalk between the ECS and steroid hormone production and secretion. Exogenous cannabinoids, derived from plants such as Cannabis sativa, are also ligands for cannabinoid receptors. These have been shown to have clinical outcomes related to ECS dysregulation, including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, along with adverse effects on female reproduction. The aim of this review is to describe and discuss data from human, animal, and in vitro studies that support the important role of the endocannabinoid system in female reproductive tissues and processes. In particular, we will discuss some of the mechanisms by which endocannabinoid signaling can affect ovarian function in both physiological and pathophysiological states.}, }
@article {pmid30642145, year = {2018}, author = {Sferrazza Papa, GF and Pellegrino, GM and Shaikh, H and Lax, A and Lorini, L and Corbo, M}, title = {Respiratory muscle testing in amyotrophic lateral sclerosis: a practical approach.}, journal = {Minerva medica}, volume = {109}, number = {6 Suppl 1}, pages = {11-19}, doi = {10.23736/S0026-4806.18.05920-7}, pmid = {30642145}, issn = {1827-1669}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Humans ; Noninvasive Ventilation/*methods ; Positive-Pressure Respiration/*methods ; Respiratory Function Tests/methods ; Respiratory Insufficiency/etiology/*prevention &amp; control ; Respiratory Muscles/*physiopathology ; Spirometry ; }, abstract = {In amyotrophic lateral sclerosis (ALS), respiratory muscle weakness leads to respiratory failure and death. Non-invasive positive pressure ventilation (NIPPV) appears to reduce lung function decline, thus improving survival and quality-of-life of patients affected by the disease. Unfortunately, clinical features and timing to start NIPPV are not well defined. Starting from recent findings, we examine established and novel tests of respiratory muscle function that could help clinicians decide whether and when to start NIPPV in ALS. Non-invasive tests estimate the function of inspiratory, expiratory, and bulbar muscles, whereas clinical examination allows to assess the overall neurologic and respiratory symptoms and general conditions. Most of the studies recommend that together with a thorough clinical evaluation of the patient according to current guidelines, vital capacity, maximal static and sniff nasal inspiratory pressures, maximal static expiratory pressures and peak cough expiratory flow, and nocturnal pulse oximetry be measured. A sound understanding of physiology can guide the physician also through the current armamentarium for additional supportive treatments for ALS, such as symptomatic drugs and new treatments to manage sialorrhea and thickened saliva, cough assistance, air stacking, and physiotherapy. In conclusion, careful clinical and functional evaluation of respiratory function and patient's preference are key determinants to decide "when" and "to whom" respiratory treatments can be provided.}, }
@article {pmid30637277, year = {2018}, author = {Bourinaris, T and Houlden, H}, title = {C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature.}, journal = {Movement disorders clinical practice}, volume = {5}, number = {6}, pages = {575-585}, pmid = {30637277}, issn = {2330-1619}, abstract = {BACKGROUND: The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined.<br><br>METHODS: A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed.<br><br>RESULTS AND DISCUSSION: In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD-phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72-related neurodegeneration that could explain the wide phenotypic variation.}, }
@article {pmid30635082, year = {2019}, author = {Mesika, R and Reichmann, D}, title = {When safeguarding goes wrong: Impact of oxidative stress on protein homeostasis in health and neurodegenerative disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {114}, number = {}, pages = {221-264}, doi = {10.1016/bs.apcsb.2018.11.001}, pmid = {30635082}, issn = {1876-1631}, mesh = {Animals ; *Health ; Heat Shock Transcription Factors/*metabolism ; Heat-Shock Response ; *Homeostasis ; Humans ; NF-E2-Related Factor 2/metabolism ; Neurodegenerative Diseases/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Cellular redox status is an established player in many different cellular functions. The buildup of oxidants within the cell is tightly regulated to maintain a balance between the positive and negative outcomes of cellular oxidants. Proteins are highly sensitive to oxidation, since modification can cause widespread unfolding and the formation of toxic aggregates. In response, cells have developed highly regulated systems that contribute to the maintenance of both the global redox status and protein homeostasis at large. Changes to these systems have been found to correlate with aging and age-related disorders, such as neurodegenerative pathologies. This raises intriguing questions as to the source of the imbalance in the redox and protein homeostasis systems, their interconnectivity, and their role in disease progression. Here we focus on the crosstalk between the redox and protein homeostasis systems in neurodegenerative diseases, specifically in Alzheimer's, Parkinson's, and ALS. We elaborate on some of the main players of the stress response systems, including the master regulators of oxidative stress and the heat shock response, Nrf2 and Hsf1, which are essential features of protein folding, and mediators of protein turnover. We illustrate the elegant mechanisms used by these components to provide an immediate response, including protein plasticity controlled by redox-sensing cysteines and the recruitment of naive proteins to the redox homeostasis array that act as chaperons in an ATP-independent manner.}, }
@article {pmid30633870, year = {2019}, author = {Carty, M and Bowie, AG}, title = {SARM: From immune regulator to cell executioner.}, journal = {Biochemical pharmacology}, volume = {161}, number = {}, pages = {52-62}, doi = {10.1016/j.bcp.2019.01.005}, pmid = {30633870}, issn = {1873-2968}, mesh = {Animals ; Armadillo Domain Proteins/*immunology/*metabolism ; Cell Death/*physiology ; Cytoskeletal Proteins/*immunology/*metabolism ; Humans ; Immunity, Innate/*physiology ; }, abstract = {SARM is the fifth and most conserved member of the Toll/Il-1 Receptor (TIR) adaptor family. However, unlike the other TIR adaptors, MyD88, Mal, TRIF and TRAM, SARM does not participate in transducing signals downstream of TLRs. By contrast SARM inhibits TLR signalling by interacting with the adaptors TRIF and MyD88. In addition, SARM also has positive roles in innate immunity by activating specific transcriptional programs following immune challenge. SARM has a pivotal role in activating different forms of cell death following cellular stress and viral infection. Many of these functions of mammalian SARM are also reflected in SARM orthologues in lower organisms such as C. elegans and Drosophila. SARM expression is particularly enriched in neurons of the CNS and SARM has a critical role in neuronal death and in axon degeneration. Recent fascinating molecular insights have been revealed as to the molecular mechanism of SARM mediated axon degeneration. SARM has been shown to deplete NAD+ by possessing intrinsic NADase activity in the TIR domain of the protein. This activity can be activated experimentally by forced dimerization of the TIR domain. It is thought that this activity of SARM is normally switched off by the axo-protective activities of NMNAT2 which maintain low levels of the NAD+ precursor NMN. Therefore, there is now great excitement in the field of SARM research as targeting this enzymatic activity of SARM may lead to the development of new therapies for neurodegenerative diseases such as multiple sclerosis and motor neuron disease.}, }
@article {pmid30631918, year = {2019}, author = {Jaiser, SR and Mitra, D and Williams, TL and Baker, MR}, title = {Mills' syndrome revisited.}, journal = {Journal of neurology}, volume = {266}, number = {3}, pages = {667-679}, pmid = {30631918}, issn = {1432-1459}, support = {MC_PC_13071/MRC_/Medical Research Council/United Kingdom ; WT089893MA/WT_/Wellcome Trust/United Kingdom ; ACLNEUR03//National Institute for Health Research/ ; }, mesh = {Aged ; Electromyography ; Evoked Potentials, Motor/*physiology ; Female ; Hemiplegia/etiology/pathology/*physiopathology ; Humans ; Magnetic Resonance Imaging ; Male ; Motor Neuron Disease/complications/pathology/*physiopathology ; }, abstract = {Mills' syndrome is an idiopathic, slowly progressive, spastic hemiparesis. We describe three cases that have been under review for a minimum of 11 years (range 11-19). In all patients, symptoms started in a leg, with a mean age of onset of 59 years (range 53-63). The only abnormality on laboratory investigations was a mildly elevated CSF protein in one case. MRI demonstrated focal T2 hyper-intensity located eccentrically in the cervical cord ipsilateral to the symptomatic side. No cerebral abnormality was demonstrated. Whilst visual and somatosensory evoked potentials were unremarkable, motor evoked potentials were abnormal in all patients: central motor conduction times were significantly prolonged unilaterally in two patients and bilaterally but asymmetrically in the third. Beta-band (15-30 Hz) intermuscular coherence, a potentially more sensitive method of assessing upper motor neuron integrity, was absent unilaterally in one patient and bilaterally in the other two. One patient developed amyotrophy and thus a picture of amyotrophic lateral sclerosis after 16 years, suggesting that Mills' syndrome is part of the motor neuron disease spectrum. Both amyotrophy and subclinical contralateral upper motor neuron disease can therefore be features of Mills' syndrome. However, even with the most sensitive electrodiagnostic techniques, unilateral upper motor neuron disease can remain the only abnormality for as long as 10 years. We conclude that whilst Mills' syndrome should be classified as a motor neuron disorder, it is a distinct nosological entity which can be distinguished from amyotrophic lateral sclerosis, upper motor neuron-dominant amyotrophic lateral sclerosis and primary lateral sclerosis. We propose diagnostic criteria for Mills' syndrome, and estimate a point prevalence of at least 1.2:1,000,000 based on our well-defined referral population in the North of England.}, }
@article {pmid30626575, year = {2019}, author = {De Giorgio, F and Maduro, C and Fisher, EMC and Acevedo-Arozena, A}, title = {Transgenic and physiological mouse models give insights into different aspects of amyotrophic lateral sclerosis.}, journal = {Disease models &amp; mechanisms}, volume = {12}, number = {1}, pages = {}, pmid = {30626575}, issn = {1754-8411}, support = {MR/L021056/1/MRC_/Medical Research Council/United Kingdom ; MR/R005184/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; FISHER/APR14/874-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; FISHER/OCT14/876-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K018523/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Animals ; *Disease Models, Animal ; Gene Targeting ; Mice, Transgenic ; Mutagenesis/genetics ; Mutation/genetics ; }, abstract = {A wide range of genetic mouse models is available to help researchers dissect human disease mechanisms. Each type of model has its own distinctive characteristics arising from the nature of the introduced mutation, as well as from the specific changes to the gene of interest. Here, we review the current range of mouse models with mutations in genes causative for the human neurodegenerative disease amyotrophic lateral sclerosis. We focus on the two main types of available mutants: transgenic mice and those that express mutant genes at physiological levels from gene targeting or from chemical mutagenesis. We compare the phenotypes for genes in which the two classes of model exist, to illustrate what they can teach us about different aspects of the disease, noting that informative models may not necessarily mimic the full trajectory of the human condition. Transgenic models can greatly overexpress mutant or wild-type proteins, giving us insight into protein deposition mechanisms, whereas models expressing mutant genes at physiological levels may develop slowly progressing phenotypes but illustrate early-stage disease processes. Although no mouse models fully recapitulate the human condition, almost all help researchers to understand normal and abnormal biological processes, providing that the individual characteristics of each model type, and how these may affect the interpretation of the data generated from each model, are considered and appreciated.}, }
@article {pmid30619076, year = {2018}, author = {Lanznaster, D and de Assis, DR and Corcia, P and Pradat, PF and Blasco, H}, title = {Metabolomics Biomarkers: A Strategy Toward Therapeutics Improvement in ALS.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1126}, pmid = {30619076}, issn = {1664-2295}, abstract = {Biomarkers research in amyotrophic lateral sclerosis (ALS) holds the promise of improving ALS diagnosis, follow-up of patients, and clinical trials outcomes. Metabolomics have a big impact on biomarkers identification. In this mini-review, we provide the main findings of metabolomics studies in ALS and discuss the most relevant therapeutics attempts that targeted some prominent alterations found in ALS, like glutamate excitotoxicity, oxidative stress, alterations in energetic metabolism, and creatinine levels. Metabolomics studies have reported putative diagnosis or prognosis biomarkers, but discrepancies among these studies did not allow validation of metabolic biomarkers for clinical use in ALS. In this context, we wonder whether metabolomics knowledge could improve ALS therapeutics. As metabolomics identify specific metabolic pathways modified by disease progression and/or treatment, we support that adjuvant or combined treatment should be used to rescue these pathways, creating a new perspective for ALS treatment. Some ongoing clinical trials are already trying to target these pathways. As clinical trials in ALS have been disappointing and considering the heterogeneity of the disease presentation, we support the application of a pharmacometabolomic approach to evaluate the individual response to drug treatments and their side effects, enabling the development of personalized treatments for ALS. We suggest that the best strategy to apply metabolomics for ALS therapeutics progress is to establish a metabolic signature for ALS patients in order to improve the knowledge of patient metabotypes, to choose the most adequate pharmacological treatment, and to follow the drug response and side effects, based on metabolomics biomarkers.}, }
@article {pmid30618605, year = {2018}, author = {Monahan, ZT and Rhoads, SN and Yee, DS and Shewmaker, FP}, title = {Yeast Models of Prion-Like Proteins That Cause Amyotrophic Lateral Sclerosis Reveal Pathogenic Mechanisms.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {453}, pmid = {30618605}, issn = {1662-5099}, support = {R01 GM118530/GM/NIGMS NIH HHS/United States ; R35 GM119790/GM/NIGMS NIH HHS/United States ; }, abstract = {Many proteins involved in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) are remarkably similar to proteins that form prions in the yeast Saccharomyces cerevisiae. These ALS-associated proteins are not orthologs of yeast prion proteins, but are similar in having long, intrinsically disordered domains that are rich in hydrophilic amino acids. These so-called prion-like domains are particularly aggregation-prone and are hypothesized to participate in the mislocalization and misfolding processes that occur in the motor neurons of ALS patients. Methods developed for characterizing yeast prions have been adapted to studying ALS-linked proteins containing prion-like domains. These yeast models have yielded major discoveries, including identification of new ALS genetic risk factors, new ALS-causing gene mutations and insights into how disease mutations enhance protein aggregation.}, }
@article {pmid30617737, year = {2019}, author = {Bahn, G and Jo, DG}, title = {Therapeutic Approaches to Alzheimer's Disease Through Modulation of NRF2.}, journal = {Neuromolecular medicine}, volume = {21}, number = {1}, pages = {1-11}, pmid = {30617737}, issn = {1559-1174}, mesh = {Aging/genetics/metabolism ; Alzheimer Disease/*drug therapy/genetics/therapy ; Amyloid beta-Peptides/metabolism ; Animals ; Antioxidant Response Elements ; Basic-Leucine Zipper Transcription Factors/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Genetic Therapy ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Molecular Targeted Therapy/*methods ; NF-E2-Related Factor 2/*agonists/chemistry/deficiency/physiology ; Nerve Tissue Proteins/*agonists/chemistry/genetics/physiology ; Oxidative Stress/drug effects ; Protein Domains ; Signal Transduction/drug effects ; Tauopathies/drug therapy/genetics ; Transcription, Genetic/drug effects ; Up-Regulation/drug effects ; tau Proteins/metabolism ; }, abstract = {The nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/NRF2) is a master transcription factor that regulates oxidative stress-related genes containing the antioxidant response element (ARE) in their promoters. The damaged function and altered localization of NRF2 are found in most neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis. These neurodegenerative diseases developed from various risk factors such as accumulated oxidative stress and genetic and environmental elements. NRF2 activation protects our bodies from detrimental stress by upregulating antioxidative defense pathway, inhibiting inflammation, and maintaining protein homeostasis. NRF2 has emerged as a new therapeutic target in AD. Indeed, recent studies revealed that NRF2 activators have therapeutic effects in AD animal models and in cultured human cells that express AD pathology. This review will focus on the NRF2 pathway and the role of NRF2 in AD and suggest some NRF2 inducers as therapeutic agents for AD.}, }
@article {pmid30614179, year = {2019}, author = {Gagliardi, D and Comi, GP and Bresolin, N and Corti, S}, title = {MicroRNAs as regulators of cell death mechanisms in amyotrophic lateral sclerosis.}, journal = {Journal of cellular and molecular medicine}, volume = {23}, number = {3}, pages = {1647-1656}, pmid = {30614179}, issn = {1582-4934}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; *Apoptosis ; Humans ; MicroRNAs/*genetics ; Motor Neurons/*pathology ; *Necrosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons (MNs), resulting in paralysis and precocious death from respiratory failure. Although the causes of ALS are incompletely understood, the role of alterations in RNA metabolism seems central. MicroRNAs (miRNAs) are noncoding RNAs implicated in the regulation of gene expression of many relevant physiological processes, including cell death. The recent model of programmed cell death (PCD) encompasses different mechanisms, from apoptosis to regulated necrosis (RN), in particular necroptosis. Both apoptosis and necroptosis play a significant role in the progressive death of MNs in ALS. In this review, we present key research related to miRNAs that modulate apoptosis and RN pathways in ALS. We also discuss whether these miRNAs represent potential targets for therapeutic development in patients.}, }
@article {pmid30612333, year = {2019}, author = {Czubowicz, K and Jęśko, H and Wencel, P and Lukiw, WJ and Strosznajder, RP}, title = {The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer's Disease and Other Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {56}, number = {8}, pages = {5436-5455}, pmid = {30612333}, issn = {1559-1182}, support = {2013/11/N/NZ4/02233//Narodowym Centrum Nauki/ ; NIA AG038834//National Institutes of Health/ ; T. No 7//Instytut Medycyny Doswiadczalnej i Klinicznej im. M. Mossakowskiego, Polskiej Akademii Nauk/ ; }, mesh = {Alzheimer Disease/*metabolism ; Animals ; Ceramides/*metabolism ; Humans ; Lysophospholipids/*metabolism ; MicroRNAs/genetics/metabolism ; Nerve Degeneration/*metabolism ; Signal Transduction ; Sphingosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Bioactive sphingolipids-ceramide, sphingosine, and their respective 1-phosphates (C1P and S1P)-are signaling molecules serving as intracellular second messengers. Moreover, S1P acts through G protein-coupled receptors in the plasma membrane. Accumulating evidence points to sphingolipids' engagement in brain aging and in neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. Metabolic alterations observed in the course of neurodegeneration favor ceramide-dependent pro-apoptotic signaling, while the levels of the neuroprotective S1P are reduced. These trends are observed early in the diseases' development, suggesting causal relationship. Mechanistic evidence has shown links between altered ceramide/S1P rheostat and the production, secretion, and aggregation of amyloid β/α-synuclein as well as signaling pathways of critical importance for the pathomechanism of protein conformation diseases. Sphingolipids influence multiple aspects of Akt/protein kinase B signaling, a pathway that regulates metabolism, stress response, and Bcl-2 family proteins. The cross-talk between sphingolipids and transcription factors including NF-κB, FOXOs, and AP-1 may be also important for immune regulation and cell survival/death. Sphingolipids regulate exosomes and other secretion mechanisms that can contribute to either the spread of neurotoxic proteins between brain cells, or their clearance. Recent discoveries also suggest the importance of intracellular and exosomal pools of small regulatory RNAs in the creation of disturbed signaling environment in the diseased brain. The identified interactions of bioactive sphingolipids urge for their evaluation as potential therapeutic targets. Moreover, the early disturbances in sphingolipid metabolism may deliver easily accessible biomarkers of neurodegenerative disorders.}, }
@article {pmid30610461, year = {2019}, author = {Wei, X and Liu, X and Tan, C and Mo, L and Wang, H and Peng, X and Deng, F and Chen, L}, title = {Expression and Function of Zinc-α2-Glycoprotein.}, journal = {Neuroscience bulletin}, volume = {35}, number = {3}, pages = {540-550}, pmid = {30610461}, issn = {1995-8218}, mesh = {Adipocytes/metabolism ; Adipokines ; Animals ; Brain/*metabolism ; Carrier Proteins/*metabolism ; Epilepsy/metabolism ; Glucose/*metabolism ; Glycoproteins/*metabolism ; Humans ; *Insulin Resistance ; *Lipid Metabolism ; Neurons/metabolism ; Signal Transduction ; }, abstract = {Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.}, }
@article {pmid30606512, year = {2019}, author = {Corcia, P and Beltran, S and Lautrette, G and Bakkouche, S and Couratier, P}, title = {Staging amyotrophic lateral sclerosis: A new focus on progression.}, journal = {Revue neurologique}, volume = {175}, number = {5}, pages = {277-282}, doi = {10.1016/j.neurol.2018.09.017}, pmid = {30606512}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Disease Progression ; Forms as Topic ; Humans ; Symptom Assessment/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogenous motoneuronal neurodegenerative condition with a panel of phenotypes exhibiting different clinical patterns. Two compounds are currently available for the treatment of ALS but the majority of trials have failed to show a positive effect on prognosis. One of the explanations which could be put forward involves the way efficacy is evaluated: clinicians agree that the ALSFRS-revised scale used in all trials does not fit with highlighting a positive effect. So, the development and validation of new tools allowing a reliable assessment of ALS has become a key issue in clinical research. Over the last three years, two functional scales (the King's College and MiToS staging systems) have been proposed. These scales rely on two different approaches to ALS: an anatomical and prognostic concept, and loss of autonomy. Both scales propose five stages. We will discuss below the contribution of these two scales to clinical evaluation and the questions which remain to be resolved in the future.}, }
@article {pmid30602169, year = {2019}, author = {Logroscino, G and Piccininni, M}, title = {Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference.}, journal = {Neuroepidemiology}, volume = {52}, number = {1-2}, pages = {93-103}, doi = {10.1159/000493386}, pmid = {30602169}, issn = {1423-0208}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; *Global Burden of Disease ; Humans ; Incidence ; Registries ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) epidemiology has rapidly developed in the last 30 years alongside the evolving changes in concepts in the field of clinical ALS and also due to the recent proposals of new classification system for motor neuron diseases. Many of these changes in the clinical scenario have been determined through the results of ALS population-based studies conducted in the last 20 years primarily in Europe. All the evidences converge to show that ALS risk is different across continents and ethnicities. In a European registry consortium named EURALS, ALS incident cases were drawn from a source population comprising almost 24 million people across Europe (ALS cases: 1028) and the estimated incidence was 2.2 per 100,000 person-years (py) for the general population. In contrast, other population-based studies have measured the lowest incidence in East Asia to be 0.89 per 100,000 py and in South Asia to be 0.79 per 100,000 py. A large part of Africa, Latin America and Asia does not have any population-based studies. The origin of geographic difference in ALS incidence is a matter of debate. Probably, this is partly due to genes (C9ORF72) and partly due to environmental risk factors. The rapid disappearance of ALS Foci in Guam, Kii, and West Guinea underline the importance of changes in lifestyle and environmental factors. The Global Burden of Disease, a project aiming to describe the burden of all diseases and injuries across all the countries of the world with a standardized protocol, has collected heterogeneous sources of data to estimate the burden of motor neuron diseases. The demographic changes related to increased expectation of life and the growth of the world population indicate that the load of motor neuron disease is rapidly moving toward 400 thousand prevalent cases. The burden is expected to shift toward Asia and Africa in the next decades for the rapid increase of expectation of life of countries with high demographic impact.}, }
@article {pmid32478990, year = {2019}, author = {Manoli, A and Ploumidou, K and Georgopapadakos, N and Stratzias, P and Skandalakis, PN and Angelis, S and Apostolopoulos, AP and Filippou, DK}, title = {Hypoglossal Nerve: Anatomy, Anatomical Variations Comorbidities and Clinical Significance.}, journal = {Journal of long-term effects of medical implants}, volume = {29}, number = {3}, pages = {197-203}, doi = {10.1615/JLongTermEffMedImplants.2020033230}, pmid = {32478990}, issn = {1940-4379}, mesh = {Anatomic Landmarks ; Anatomic Variation ; Head and Neck Neoplasms/*complications ; Humans ; Hypoglossal Nerve/*anatomy &amp; histology ; Hypoglossal Nerve Diseases/complications/*etiology ; Hypoglossal Nerve Injuries/etiology ; Nerve Compression Syndromes/etiology ; Paresis/etiology ; }, abstract = {We review the anatomical variations of the hypoglossal nerve and their surgical and clinical significance, and we report multiple diseases that affect function of the nerve leading to paresis, either unilateral or bilateral. The hypoglossal nerve is the 12th cranial nerve, and knowledge of the detailed anatomy and relationship with critical structures is of paramount importance in neurosurgery, head and neck surgery, and vascular surgery. Numerous studies have depicted conventional landmarks in the cervical part of the hypoglossal nerve, but their findings have not been consistent reliable. We analyze and review these critical landmarks used to identify and preserve the hypoglossal nerve during surgery and to minimize iatrogenic complications in head and neck, neurosurgical, and vascular procedures. We performed an online database search during January and February 2019 to pinpoint the diseases that affect function of the nerve. According to this literature review, apart from iatrogenic injury during surgery, the most frequently observed cause of paresis is pressure due to the presence of tumours and head injury. Furthermore, motor neuron degenerative conditions, such as amyotrophic lateral sclerosis, multiple sclerosis or tooth infection and presence of an aberrant vessel in the hypoglossal canal can affect the function of the nerve.}, }
@article {pmid32270973, year = {2019}, author = {Korpysz, A and Szalecki, M}, title = {What's new in IUGR from the endocrinological point of view?.}, journal = {Pediatric endocrinology, diabetes, and metabolism}, volume = {25}, number = {4}, pages = {188-193}, doi = {10.5114/pedm.2019.91547}, pmid = {32270973}, issn = {2083-8441}, mesh = {Epigenesis, Genetic ; Fetal Growth Retardation/etiology/*genetics/metabolism ; Humans ; *Insulin Resistance ; Insulin-Like Growth Factor II ; *Mutation ; }, abstract = {Genetic causes of IUGR: The IGF 2 gene encoding IGF2 synthesis contributes to growth of the foetus. The maternal genes PHLDA2, GRB10, and placental ALS also play a role in the regulation of foetal growth. CDKN1C mutation can lead to IUGR. In SRS syndrome, apart from epimutation 11p15 and disomy 7, the cause may be a mutation of HMAGA2-PLAG1-IGF2 genes. Growth deficiency: in 10% of children with IUGR with growth deficiency, ACAN gene mutation (aggrecan gene) was described. Children with IUGR and with dynamic evolution of puberty can achieve better final growth through combined therapy with GH and GnRH analogues. Insulin resistance: In light of new reports, oxidative stress during pregnancy, epigenetic regulation in the foetal period in children with IUGR, and insulin resistance both peripheral and central during catch up growth" are observed.}, }
@article {pmid30595837, year = {2018}, author = {Takamatsu, Y and Fujita, M and Ho, GJ and Wada, R and Sugama, S and Takenouchi, T and Waragai, M and Masliah, E and Hashimoto, M}, title = {Motor and Nonmotor Symptoms of Parkinson's Disease: Antagonistic Pleiotropy Phenomena Derived from α-Synuclein Evolvability?.}, journal = {Parkinson's disease}, volume = {2018}, number = {}, pages = {5789424}, pmid = {30595837}, issn = {2090-8083}, abstract = {Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-β (Aβ) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.}, }
@article {pmid30594990, year = {2018}, author = {Bosisio, F and Jox, RJ and Jones, L and Rubli Truchard, E}, title = {Planning ahead with dementia: what role can advance care planning play? A review on opportunities and challenges.}, journal = {Swiss medical weekly}, volume = {148}, number = {}, pages = {w14706}, doi = {10.4414/smw.2018.14706}, pmid = {30594990}, issn = {1424-3997}, mesh = {*Advance Care Planning ; *Attitude to Death ; *Communication ; *Decision Making ; Dementia/*nursing/psychology ; Health Personnel ; Humans ; Palliative Care/methods ; Switzerland ; }, abstract = {Advance directives emerged in the 1960s with the goal of empowering people to exert control over their future medical decisions. However, it has become apparent, over recent years, that advance directives do not sufficiently capture the temporal and relational aspects of planning treatment and care. Advance care planning (ACP) has been suggested as a way to emphasise communication between the patient, their surrogate decision maker and healthcare professional(s) in order to anticipate healthcare decisions in the event that the patient loses decision-making capacity, either temporarily or permanently. In more and more countries, ACP has become common practice in planning the treatment of terminal diseases such as cancer or amyotrophic lateral sclerosis. However, even though neurodegenerative dementia results in the gradual loss of decision-making capacity, ACP is still extremely rare. There are several reasons for this. Firstly, some people have difficulties talking about illness and death, especially when this involves anticipation. Secondly, lay people and professionals alike struggle to consider Alzheimer’s disease and similar forms of dementia as terminal diseases. Thirdly, although patient decision-making capacity gradually decreases with the progression of dementia, the patient retains the ability to communicate and interact with surrogates and professionals until the later stages of the disease. Therefore, surrogates and professionals may feel unsure or even ambivalent when enforcing advance directives, in particular when those decisions may shorten a patient’s life expectancy. Finally, to be effective, existing ACP interventions should be adapted to patient’s cognitive impairments and lay out dementia-specific scenarios. Current WHO estimates indicate that by 2050 one out of four people will potentially have to take care of a relative with cognitive and communication impairments for several years. In Switzerland, the Federal Office of Public Health and the regional states have established national strategies on dementia and palliative care. These strategies emphasise the need for ACP as a means to prepare patients and their relatives for future decisions, as soon as someone is diagnosed with dementia. This moment is thus especially conducive to develop appropriate processes to prompt the elderly and people diagnosed with dementia to engage in ACP. Therefore, the aim of the present paper is to identify the benefits and challenges of ACP in dementia care, outline strategies to design appropriate procedures and tools, and provide professionals, patients and their relatives with opportunities to engage in ACP.}, }
@article {pmid30582889, year = {2019}, author = {Convery, R and Mead, S and Rohrer, JD}, title = {Review: Clinical, genetic and neuroimaging features of frontotemporal dementia.}, journal = {Neuropathology and applied neurobiology}, volume = {45}, number = {1}, pages = {6-18}, doi = {10.1111/nan.12535}, pmid = {30582889}, issn = {1365-2990}, support = {MC_UU_00024/1/MRC_/Medical Research Council/United Kingdom ; MR/J009482/1/MRC_/Medical Research Council/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Aphasia, Primary Progressive/diagnostic imaging/genetics/physiopathology ; *Frontotemporal Dementia/diagnostic imaging/genetics/physiopathology ; Humans ; }, abstract = {Frontotemporal dementia (FTD) is a heterogeneous group of disorders causing neurodegeneration within a network of areas centred on the frontal and temporal lobes. Clinically, patients present with behavioural symptoms (behavioural variant FTD) or language disturbance (primary progressive aphasia), although there is an overlap with motor neurone disease and atypical parkinsonian disorders. Whilst neuroimaging commonly reveals abnormalities in the frontal and temporal lobes, a closer review identifies a more complex picture with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy. An autosomal-dominant genetic disorder is found in around a third of people with mutations in progranulin, C9orf72 and the microtubule-associated protein tau being the commonest causes. In the other two-thirds, the disorder is sporadic, although recent genome-wide association studies have started to identify genetic risk factors within this group. Much of this knowledge has been understood only in the past 10 years and so this review will discuss the current knowledge about the clinical, genetic and neuroimaging features of FTD.}, }
@article {pmid30582188, year = {2019}, author = {Solomon, DA and Mitchell, JC and Salcher-Konrad, MT and Vance, CA and Mizielinska, S}, title = {Review: Modelling the pathology and behaviour of frontotemporal dementia.}, journal = {Neuropathology and applied neurobiology}, volume = {45}, number = {1}, pages = {58-80}, doi = {10.1111/nan.12536}, pmid = {30582188}, issn = {1365-2990}, mesh = {Animals ; *Disease Models, Animal ; Frontotemporal Dementia/*genetics/*pathology/*physiopathology ; Humans ; }, abstract = {Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease-causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP-43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide-ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease-relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease-relevance of findings and thus better inform therapeutic development.}, }
@article {pmid30578866, year = {2019}, author = {Elfawy, HA and Das, B}, title = {Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: Etiologies and therapeutic strategies.}, journal = {Life sciences}, volume = {218}, number = {}, pages = {165-184}, doi = {10.1016/j.lfs.2018.12.029}, pmid = {30578866}, issn = {1879-0631}, mesh = {Age Factors ; Animals ; Humans ; Mitochondria/metabolism/*pathology ; Neurodegenerative Diseases/etiology/metabolism/*therapy ; *Oxidative Stress ; Signal Transduction ; }, abstract = {Mitochondrial function is vital for normal cellular processes. Mitochondrial damage and oxidative stress have been greatly implicated in the progression of aging, along with the pathogenesis of age-related neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Although antioxidant therapy has been proposed for the prevention and treatment of age-related NDs, unraveling the molecular mechanisms of mitochondrial dysfunction can lead to significant progress in the development of effective treatments against such diseases. Aging is associated with the generation and accumulation of reactive oxygen species (ROS) that are the major contributors to oxidative stress. Oxidative stress is caused because of the imbalance between the production of ROS and their oxidation, which can affect the mitochondrial respiratory chain function, thereby altering the membrane permeability and calcium homeostasis, along with increasing the heteroplasmic mtDNA and weakening the mitochondrial defense systems. Mitochondrial dysfunction mainly affects mitochondrial biogenesis and dynamics that are prominent in several age-related NDs. Mitochondrial dysfunction has a crucial role in the pathophysiology of age-related NDs. Several mitochondria targeted strategies, such as enhancing the antioxidant bioavailability via novel delivery systems, identifying unique mitochondrial proteins as specific drug targets, investigating the signaling pathways of mitochondrial biogenesis and dynamics, and identifying effective natural products are potentially effective to counteract mitochondrial dysfunction-related NDs.}, }
@article {pmid30577465, year = {2018}, author = {Iridoy, MO and Zubiri, I and Zelaya, MV and Martinez, L and Ausín, K and Lachen-Montes, M and Santamaría, E and Fernandez-Irigoyen, J and Jericó, I}, title = {Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).}, journal = {International journal of molecular sciences}, volume = {20}, number = {1}, pages = {}, pmid = {30577465}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Biomarkers ; Female ; Frontotemporal Dementia/*metabolism/pathology ; Humans ; Male ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Organ Specificity ; Prohibitins ; *Proteome ; *Proteomics/methods ; Signal Transduction ; Spinal Cord/metabolism/pathology ; }, abstract = {(1) Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with an overlap in clinical presentation and neuropathology. Common and differential mechanisms leading to protein expression changes and neurodegeneration in ALS and FTD were studied trough a deep neuroproteome mapping of the spinal cord. (2) Methods: A liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the spinal cord from ALS-TAR DNA-binding protein 43 (TDP-43) subjects, ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) subjects and controls without neurodegenerative disease was performed. (3) Results: 281 differentially expressed proteins were detected among ALS versus controls, while 52 proteins were dysregulated among FTLD-U versus controls. Thirty-three differential proteins were shared between both syndromes. The resulting data was subjected to network-driven proteomics analysis, revealing mitochondrial dysfunction and metabolic impairment, both for ALS and FTLD-U that could be validated through the confirmation of expression levels changes of the Prohibitin (PHB) complex. (4) Conclusions: ALS-TDP-43 and FTLD-U share molecular and functional alterations, although part of the proteostatic impairment is region- and disease-specific. We have confirmed the involvement of specific proteins previously associated with ALS (Galectin 2 (LGALS3), Transthyretin (TTR), Protein S100-A6 (S100A6), and Protein S100-A11 (S100A11)) and have shown the involvement of proteins not previously described in the ALS context (Methanethiol oxidase (SELENBP1), Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN-1), Calcyclin-binding protein (CACYBP) and Rho-associated protein kinase 2 (ROCK2)).}, }
@article {pmid30576920, year = {2019}, author = {Sivandzade, F and Prasad, S and Bhalerao, A and Cucullo, L}, title = {NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches.}, journal = {Redox biology}, volume = {21}, number = {}, pages = {101059}, pmid = {30576920}, issn = {2213-2317}, support = {R01 DA029121/DA/NIDA NIH HHS/United States ; }, mesh = {Aging/metabolism ; Animals ; Cerebrovascular Disorders/drug therapy/*etiology/*metabolism ; *Disease Susceptibility ; Humans ; Hyperglycemia/complications/etiology/metabolism ; Inflammation/etiology/metabolism ; Molecular Targeted Therapy ; NF-E2-Related Factor 2/agonists/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Neurodegenerative Diseases/drug therapy/*etiology/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Smoking/adverse effects ; }, abstract = {Electrophiles and reactive oxygen species (ROS) play a major role in modulating cellular defense mechanisms as well as physiological functions, and intracellular signaling. However, excessive ROS generation (endogenous and exogenous) can create a state of redox imbalance leading to cellular and tissue damage (Ma and He, 2012) [1]. A growing body of research data strongly suggests that imbalanced ROS and electrophile overproduction are among the major prodromal factors in the onset and progression of several cerebrovascular and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and aging (Ma and He, 2012; Ramsey et al., 2017; Salminen et al., 2012; Sandberg et al., 2014; Sarlette et al., 2008; Tanji et al., 2013) [1-6]. Cells offset oxidative stress by the action of housekeeping antioxidative enzymes (such as superoxide dismutase, catalase, glutathione peroxidase) as well direct and indirect antioxidants (Dinkova-Kostova and Talalay, 2010) [7]. The DNA sequence responsible for modulating the antioxidative and cytoprotective responses of the cells has been identified as the antioxidant response element (ARE), while the nuclear factor erythroid 2-related factor (NRF2) is the major regulator of the xenobiotic-activated receptor (XAR) responsible for activating the ARE-pathway, thus defined as the NRF2-ARE system (Ma and He, 2012) [1]. In addition, the interplay between the NRF2-ARE system and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB, a protein complex that controls cytokine production and cell survival), has been further investigated in relation to neurodegenerative and neuroinflammatory disorders. On these premises, we provide a review analysis of current understanding of the NRF2-NF-ĸB interplay, their specific role in major CNS disorders, and consequent therapeutic implication for the treatment of neurodegenerative and cerebrovascular diseases.}, }
@article {pmid30568632, year = {2018}, author = {Floeter, MK and Gendron, TF}, title = {Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Associated With Hexanucleotide Expansion Mutations in C9orf72.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1063}, pmid = {30568632}, issn = {1664-2295}, abstract = {Now that genetic testing can identify persons at risk for developing amyotrophic lateral sclerosis (ALS) many decades before symptoms begin, there is a critical need for biomarkers that signal the onset and progression of degeneration. The search for candidate disease biomarkers in patients with mutations in the gene C9orf72 has included imaging, physiology, and biofluid measurements. In cross-sectional imaging studies, C9+ ALS patients display diffuse reductions of gray and white matter integrity compared to ALS patients without mutations. This structural imaging signature overlaps with frontotemporal dementia (FTD), reflecting the frequent co-occurrence of cognitive impairment, even frank FTD, in C9+ ALS patients. Changes in functional connectivity occur as critical components of the networks associated with cognition and behavior degenerate. In presymptomatic C9+carriers, subtle differences in volumes of subcortical structures and functional connectivity can be detected, often decades before the typical family age of symptom onset. Dipeptide repeat proteins produced by the repeat expansion mutation are also measurable in the cerebrospinal fluid (CSF) of presymptomatic gene carriers, possibly throughout their lives. In contrast, a rise in the level of neurofilament proteins in the CSF appears to presage the onset of degeneration in presymptomatic carriers in one longitudinal study. Cross-sectional studies indicate that neurofilament protein levels may provide prognostic information for survival in C9+ ALS patients. Longitudinal studies will be needed to validate the candidate biomarkers discussed here. Understanding how these candidate biomarkers change over time is critical if they are to be used in future therapeutic decisions.}, }
@article {pmid30568577, year = {2018}, author = {Lee, SH and Suk, K}, title = {Kinase-Based Taming of Brain Microglia Toward Disease-Modifying Therapy.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {474}, pmid = {30568577}, issn = {1662-5102}, abstract = {Microglia are the primary immune cells residing in the central nervous system (CNS), where they play essential roles in the health and disease. Depending on the CNS inflammatory milieu, they exist in either resting or activated states. Chronic neuroinflammation mediated by activated microglia is now considered to be a common characteristic shared by many neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, which currently pose a significant socioeconomic burden to the global healthcare system. Accumulating evidence has indicated protein kinases (PKs) as important drug targets for therapeutic interventions of these detrimental diseases. Here, we review recent findings suggesting that selected PKs potentially participate in microglia-mediated neuroinflammation. Taming microglial phenotypes by modulating the activity of these PKs holds great promise for the development of disease-modifying therapies for many neurodegenerative diseases.}, }
@article {pmid30565851, year = {2019}, author = {Ziff, OJ and Patani, R}, title = {Harnessing cellular aging in human stem cell models of amyotrophic lateral sclerosis.}, journal = {Aging cell}, volume = {18}, number = {1}, pages = {e12862}, pmid = {30565851}, issn = {1474-9726}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; 101149/Z/13/A/WT_/Wellcome Trust/United Kingdom ; //National Institute of Health Research (NIHR)/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; *Cellular Senescence ; Humans ; Induced Pluripotent Stem Cells/pathology ; *Models, Biological ; Motor Neurons/pathology ; Stem Cells/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The etiology of ALS remains unresolved and no effective treatments exist. There is therefore a desperate and unmet need for discovery of disease mechanisms to guide novel therapeutic strategies. The single major risk factor for ALS is aging, yet the molecular consequences of cell type-specific aging remain understudied in this context. Induced pluripotent stem cells (iPSCs) have transformed the standard approach of examining human disease, generating unlimited numbers of disease-relevant cells from patients, enabling analysis of disease mechanisms and drug screening. However, reprogramming patient cells to iPSCs reverses key hallmarks of cellular age. Therefore, although iPSC models recapitulate some disease hallmarks, a crucial challenge is to address the disparity between the advanced age of onset of neurodegenerative diseases and the fetal-equivalent maturational state of iPSC-derivatives. Increasing recognition of cell type-specific aging paradigms underscores the importance of heterogeneity in ultimately tipping the balance from a state of compensated dysfunction (clinically pre-symptomatic) to decompensation and progression (irreversible loss of neurological functions). In order to realize the true promise of iPSC technology in ALS, efforts need to prioritize faithfully recapitulating the clinical pathophysiological state, with proportionate emphasis on capturing the molecular sequelae of both cellular age and non-cell-autonomous disease mechanisms within this context.}, }
@article {pmid30564498, year = {2018}, author = {Dardiotis, E and Siokas, V and Sokratous, M and Tsouris, Z and Aloizou, AM and Florou, D and Dastamani, M and Mentis, AA and Brotis, AG}, title = {Body mass index and survival from amyotrophic lateral sclerosis: A meta-analysis.}, journal = {Neurology. Clinical practice}, volume = {8}, number = {5}, pages = {437-444}, pmid = {30564498}, issn = {2163-0402}, abstract = {BACKGROUND: Several studies have examined the relationship between body mass index (BMI) and survival from amyotrophic lateral sclerosis (ALS). Many indicate that low BMI at diagnosis or during follow-up may be associated with accelerated progression and shortened survival. This study systematically evaluated the relationship between BMI and survival in patients with ALS.<br><br>METHODS: The PubMed database was searched to identify all available studies reporting time-to-event data. Eight studies with 6,098 patients fulfilled the eligibility criteria. BMI was considered a continuous and ordered variable. Interstudy heterogeneity was assessed by the Cochran Q test and quantified by the I[2] metric. Fixed- or random-effects odds ratios summarized pooled effects after taking interstudy variability into account. Significance was set at p < 0.05.<br><br>RESULTS: The ALS survival hazard ratio (HR) decreased approximately by 3% (95% confidence interval [CI]: 2%-5%) for each additional BMI unit when BMI was considered a continuous variable. When BMI was considered a categorical variable, the HRs for "normal" BMI vs "overweight" BMI and "obese" BMI were estimated to be as high as 0.91 (95% CI: 0.79-1.04) and 0.78 (95% CI: 0.60-1.01), respectively. The HR for the comparison of the "normal" BMI vs "underweight" BMI was estimated to be as high as 1.94 (95% CI: 1.42-2.65).<br><br>CONCLUSIONS: BMI is significantly and inversely associated with ALS survival.}, }
@article {pmid30564192, year = {2018}, author = {Barritt, AW and Gabel, MC and Cercignani, M and Leigh, PN}, title = {Emerging Magnetic Resonance Imaging Techniques and Analysis Methods in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1065}, pmid = {30564192}, issn = {1664-2295}, support = {CERCIGNANI/OCT12/865-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; LEIGH/APR14/824-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Objective markers of disease sensitive to the clinical activity, symptomatic progression, and underlying substrates of neurodegeneration are highly coveted in amyotrophic lateral sclerosis in order to more eloquently stratify the highly heterogeneous phenotype and facilitate the discovery of effective disease modifying treatments for patients. Magnetic resonance imaging (MRI) is a promising, non-invasive biomarker candidate whose acquisition techniques and analysis methods are undergoing constant evolution in the pursuit of parameters which more closely represent biologically-applicable tissue changes. Neurite Orientation Dispersion and Density Imaging (NODDI; a form of diffusion imaging), and quantitative Magnetization Transfer Imaging (qMTi) are two such emerging modalities which have each broadened the understanding of other neurological disorders and have the potential to provide new insights into structural alterations initiated by the disease process in ALS. Furthermore, novel neuroimaging data analysis approaches such as Event-Based Modeling (EBM) may be able to circumvent the requirement for longitudinal scanning as a means to comprehend the dynamic stages of neurodegeneration in vivo. Combining these and other innovative imaging protocols with more sophisticated techniques to analyse ever-increasing datasets holds the exciting prospect of transforming understanding of the biological processes and temporal evolution of the ALS syndrome, and can only benefit from multicentre collaboration across the entire ALS research community.}, }
@article {pmid30564187, year = {2018}, author = {Steinbach, R and Gaur, N and Stubendorff, B and Witte, OW and Grosskreutz, J}, title = {Developing a Neuroimaging Biomarker for Amyotrophic Lateral Sclerosis: Multi-Center Data Sharing and the Road to a "Global Cohort".}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1055}, pmid = {30564187}, issn = {1664-2295}, abstract = {Neuroimaging in Amyotrophic Lateral Sclerosis (ALS) has steadily evolved from an academic exercise to a powerful clinical tool for detecting and following pathological change. Nevertheless, significant challenges need to be addressed for the translation of neuroimaging as a robust outcome-metric and biomarker in quality-of-care assessments and pharmaceutical trials. Studies have been limited by small sample sizes, poor replication, incomplete patient characterization, and substantial differences in data collection and processing. This has been further exacerbated by the substantial heterogeneity associated with ALS. Multi-center transnational collaborations are needed to address these methodological limitations and achieve representation of rare phenotypes. This review will use the example of the Neuroimaging Society in ALS (NiSALS) to discuss the set-up of a multi-center data sharing ecosystem and the flow of information between various stakeholders. NiSALS' founding objective was to establish best practices for the acquisition and processing of MRI data and establish a structure that allows continuous data sharing and therefore augments the ability to fully describe patients. The practical challenges associated with such a system, including quality control, legal, ethical, and logistical constraints, will be discussed, as will be recommendations for future collaborative endeavors. We posit that "global cohorts" of well-characterized sub-populations within the disease spectrum are needed to fully understand the complex interplay between neuroimaging and other clinical metrics used to study ALS.}, }
@article {pmid30560220, year = {2018}, author = {Vucic, S and van den Bos, M and Menon, P and Howells, J and Dharmadasa, T and Kiernan, MC}, title = {Utility of threshold tracking transcranial magnetic stimulation in ALS.}, journal = {Clinical neurophysiology practice}, volume = {3}, number = {}, pages = {164-172}, pmid = {30560220}, issn = {2467-981X}, abstract = {Upper motor neuron [UMN] and lower motor neuron [LMN] dysfunction, in the absence of sensory features, is a pathognomonic feature of amyotrophic lateral sclerosis [ALS]. Although the precise mechanisms have yet to be elucidated, one leading hypothesis is that UMN precede LMN dysfunction, which is induced by anterograde glutamatergic excitotoxicity. Transcranial magnetic stimulation (TMS) is a neurophysiological tool that provides a non-invasive and painless assessment of cortical function. Threshold tracking methodologies have been recently adopted for TMS, whereby changes in threshold rather than motor evoked potential (MEP) amplitude serve as outcome measures. This technique is reliable and provides a rapid assessment of cortical function in ALS. Utilisng the threshold tracking TMS technique, cortical hyperexcitability was demonstrated as an early feature in sporadic ALS preceding the onset of LMN dysfunction and possibly contributing to disease spread. Separately, cortical hyperexcitability was reported to precede the clinical onset of familial ALS. Of further relevance, the threshold tracking TMS technique was proven to reliably distinguish ALS from mimicking disorders, even in the presence of a comparable degree of LMN dysfunction, suggesting a diagnostic utility of TMS. Taken in total, threshold tracking TMS has provided support for a cortical involvement at the earliest detectable stages of ALS, underscoring the utility of the technique for probing the underlying pathophysiology. The present review will discuss the physiological processes underlying TMS parameters, while further evaluating the pathophysiological and diagnostic utility of threshold tracking TMS in ALS.}, }
@article {pmid30559272, year = {2019}, author = {Iqbal, S and Ghanimi Fard, M and Everest-Dass, A and Packer, NH and Parker, LM}, title = {Understanding cellular glycan surfaces in the central nervous system.}, journal = {Biochemical Society transactions}, volume = {47}, number = {1}, pages = {89-100}, doi = {10.1042/BST20180330}, pmid = {30559272}, issn = {1470-8752}, mesh = {Animals ; Central Nervous System/*metabolism ; Glycolipids/chemistry/metabolism ; Glycosylation ; Humans ; Lectins/chemistry/metabolism ; Polysaccharides/*chemistry/*metabolism ; }, abstract = {Glycosylation, the enzymatic process by which glycans are attached to proteins and lipids, is the most abundant and functionally important type of post-translational modification associated with brain development, neurodegenerative disorders, psychopathologies and brain cancers. Glycan structures are diverse and complex; however, they have been detected and targeted in the central nervous system (CNS) by various immunohistochemical detection methods using glycan-binding proteins such as anti-glycan antibodies or lectins and/or characterized with analytical techniques such as chromatography and mass spectrometry. The glycan structures on glycoproteins and glycolipids expressed in neural stem cells play key roles in neural development, biological processes and CNS maintenance, such as cell adhesion, signal transduction, molecular trafficking and differentiation. This brief review will highlight some of the important findings on differential glycan expression across stages of CNS cell differentiation and in pathological disorders and diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia and brain cancer.}, }
@article {pmid30556231, year = {2019}, author = {Pampalakis, G and Mitropoulos, K and Xiromerisiou, G and Dardiotis, E and Deretzi, G and Anagnostouli, M and Katsila, T and Rentzos, M and Patrinos, GP}, title = {New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis.}, journal = {Human mutation}, volume = {40}, number = {4}, pages = {361-373}, doi = {10.1002/humu.23697}, pmid = {30556231}, issn = {1098-1004}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*etiology/metabolism ; *Biomarkers ; *Disease Susceptibility ; Genes, Modifier ; Genetic Predisposition to Disease ; Humans ; *Molecular Diagnostic Techniques/methods/trends ; Mutation ; Proteomics/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.}, }
@article {pmid30555832, year = {2018}, author = {Billard, JM}, title = {Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging.}, journal = {Frontiers in molecular biosciences}, volume = {5}, number = {}, pages = {106}, pmid = {30555832}, issn = {2296-889X}, abstract = {The N-methyl-D-Aspartate glutamate receptors (NMDARs) are pivotal for the functional and morphological plasticity that are required in neuronal networks for efficient brain activities and notably for cognitive-related abilities. Because NMDARs are heterogeneous in subunit composition and associated with multiple functional regulatory sites, their efficacy is under the tonic influence of numerous allosteric modulations, whose dysfunction generally represents the first step generating pathological states. Among the enzymatic candidates, serine racemase (SR) has recently gathered an increasing interest considering that it tightly regulates the production of d-serine, an amino acid now viewed as the main endogenous co-agonist necessary for NMDAR activation. Nowadays, SR deregulation is associated with a wide range of neurological and psychiatric diseases including schizophrenia, amyotrophic lateral sclerosis, and depression. This review aims at compelling the most recent experimental evidences indicating that changes in SR-related modulation of NMDARs also govern opposite functional dysfunctions in physiological and pathological (Alzheimer's disease) aging that finally results in memory disabilities in both cases. It also highlights SR as a relevant alternative target for new pharmacological strategies aimed at preventing functional alterations and cognitive impairments linked to the aging process.}, }
@article {pmid30555538, year = {2018}, author = {Trias, E and Barbeito, L and Yamanaka, K}, title = {Phenotypic heterogeneity of astrocytes in motor neuron disease.}, journal = {Clinical &amp; experimental neuroimmunology}, volume = {9}, number = {4}, pages = {225-234}, pmid = {30555538}, issn = {1759-1961}, abstract = {Accumulating evidence has shown that astrocytes do not just support the function of neurons, but play key roles in maintaining the brain environment in health and disease. Contrary to the traditional understanding of astrocytes as static cells, reactive astrocytes possess more diverse functions and phenotypes than previously predicted. In the present focused review, we summarize the evidence showing that astrocytes are playing profound roles in the disease process of amyotrophic lateral sclerosis. Aberrantly activated astrocytes in amyotrophic lateral sclerosis rodents express microglial molecular markers and provoke toxicities to accelerate disease progression. In addition, TIR domain-containing adapter protein-inducing interferon-β-dependent innate immune pathway in astrocytes also has a novel function in terminating glial activation and neuroinflammation. Furthermore, heterogeneity in phenotypes and functions of astrocytes are also observed in various disease conditions, such as other neurodegenerative diseases, ischemia, aging and acute lesions in the central nervous system. Through accumulating knowledge of the phenotypic and functional diversity of astrocytes, these cells will become more attractive therapeutic targets for neurological diseases.}, }
@article {pmid30551677, year = {2018}, author = {Morgan, S and Duguez, S and Duddy, W}, title = {Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge.}, journal = {Journal of personalized medicine}, volume = {8}, number = {4}, pages = {}, pmid = {30551677}, issn = {2075-4426}, abstract = {Multiple genes and mechanisms of pathophysiology have been implicated in amyotrophic lateral sclerosis (ALS), suggesting it is a complex systemic disease. With this in mind, applying personalized medicine (PM) approaches to tailor treatment pipelines for ALS patients may be necessary. The modelling and analysis of molecular interaction networks could represent valuable resources in defining ALS-associated pathways and discovering novel therapeutic targets. Here we review existing omics datasets and analytical approaches, in order to consider how molecular interaction networks could improve our understanding of the molecular pathophysiology of this fatal neuromuscular disorder.}, }
@article {pmid30551598, year = {2018}, author = {García, JC and Bustos, RH}, title = {The Genetic Diagnosis of Neurodegenerative Diseases and Therapeutic Perspectives.}, journal = {Brain sciences}, volume = {8}, number = {12}, pages = {}, pmid = {30551598}, issn = {2076-3425}, abstract = {Genetics has led to a new focus regarding approaches to the most prevalent diseases today. Ascertaining the molecular secrets of neurodegenerative diseases will lead to developing drugs that will change natural history, thereby affecting the quality of life and mortality of patients. The sequencing of candidate genes in patients suffering neurodegenerative pathologies is faster, more accurate, and has a lower cost, thereby enabling algorithms to be proposed regarding the risk of neurodegeneration onset in healthy persons including the year of onset and neurodegeneration severity. Next generation sequencing has resulted in an explosion of articles regarding the diagnosis of neurodegenerative diseases involving exome sequencing or sequencing a whole gene for correlating phenotypical expression with genetic mutations in proteins having key functions. Many of them occur in neuronal glia, which can trigger a proinflammatory effect leading to defective proteins causing sporadic or familial mutations. This article reviews the genetic diagnosis techniques and the importance of bioinformatics in interpreting results from neurodegenerative diseases. Risk scores must be established in the near future regarding diseases with a high incidence in healthy people for defining prevention strategies or an early start for giving drugs in the absence of symptoms.}, }
@article {pmid30524366, year = {2018}, author = {Christidi, F and Karavasilis, E and Rentzos, M and Kelekis, N and Evdokimidis, I and Bede, P}, title = {Clinical and Radiological Markers of Extra-Motor Deficits in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1005}, pmid = {30524366}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is now universally recognized as a complex multisystem disorder with considerable extra-motor involvement. The neuropsychological manifestations of frontotemporal, parietal, and basal ganglia involvement in ALS have important implications for compliance with assistive devices, survival, participation in clinical trials, caregiver burden, and the management of individual care needs. Recent advances in neuroimaging have been instrumental in characterizing the biological substrate of heterogeneous cognitive and behavioral deficits in ALS. In this review we discuss the clinical and radiological aspects of cognitive and behavioral impairment in ALS focusing on the recognition, assessment, and monitoring of these symptoms.}, }
@article {pmid30538761, year = {2018}, author = {Kim, SJ and Park, YC and Baek, YH and Seo, BK}, title = {Traditional Korean Medicine Treatment for Patients with Wilting Disorder: A Literature Review of In Vivo Studies.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2018}, number = {}, pages = {5601846}, pmid = {30538761}, issn = {1741-427X}, abstract = {Wilting disorder is an abnormal condition characterized by weakness and paralysis of the upper and lower extremities. Pathogenesis and treatment target of the disorder are unclear; hence, allopathic treatment is generally used to relieve the symptoms. To investigate the treatment mechanism and effect of Traditional Korean Medicine (TKM) in patients with wilting disorder, we reviewed in vivo studies that focused on the effect of TKM on the main symptoms of wilting disorder and treatment of the diseases that can cause these symptoms. We electronically searched the PubMed, Cochrane, and CNKI (China National Knowledge Infrastructure) databases using the following search terms: (weakness OR motor function disorder) (myasthenia gravis OR Guillain-Barre syndrome OR amyotrophic lateral sclerosis OR paralysis OR polymyositis OR muscular dystrophy) AND (herbal medicine OR acupuncture OR bee-venom OR pharmacoacupuncture OR electro-acupuncture OR moxibustion). We selected 11 studies that demonstrated the effect of TKM treatment on the main symptoms of wilting disorder. In these studies, inducted models of amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular atrophy, polymyositis, and Guillain-Barre syndrome were used. With regard to treatment, herbal medicine was used in five studies, and acupuncture and bee-venom pharmacoacupuncture were used in three studies each. Future research is needed to determine the effectiveness of TKM treatment in patients with diseases that can cause the main symptoms of wilting disorder.}, }
@article {pmid30533572, year = {2018}, author = {An, H and Williams, NG and Shelkovnikova, TA}, title = {NEAT1 and paraspeckles in neurodegenerative diseases: A missing lnc found?.}, journal = {Non-coding RNA research}, volume = {3}, number = {4}, pages = {243-252}, pmid = {30533572}, issn = {2468-0540}, support = {MRF_MRF-060-0001-RG-SHELK/MRF/MRF/United Kingdom ; SHELKOVNIKOVA/OCT17/968-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Neurodegenerative diseases are among the most common causes of disability worldwide. Although neurodegenerative diseases are heterogeneous in both their clinical features and the underlying physiology, they are all characterised by progressive loss of specific neuronal populations. Recent experimental evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the CNS in health and disease. Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is an abundant, ubiquitously expressed lncRNA, which forms a scaffold for a specific RNA granule in the nucleus, or nuclear body, the paraspeckle. Paraspeckles act as molecular hubs for cellular processes commonly affected by neurodegeneration. Transcriptomic analyses of the diseased human tissue have revealed altered NEAT1 levels in the CNS in major neurodegenerative disorders as well as in some disease models. Although it is clear that changes in NEAT1 expression (and in some cases, paraspeckle assembly) accompany neuronal damage, our understanding of NEAT1 contribution to the disease pathogenesis is still rudimentary. In this review, we have summarised the available knowledge on NEAT1 involvement in the molecular processes linked to neurodegeneration and on NEAT1 dysregulation in this type of disease, with a special focus on amyotrophic lateral sclerosis. The goal of this review is to attract the attention of researchers in the field of neurodegeneration to NEAT1 and paraspeckles.}, }
@article {pmid30533570, year = {2018}, author = {Gagliardi, S and Pandini, C and Garofalo, M and Bordoni, M and Pansarasa, O and Cereda, C}, title = {Long non coding RNAs and ALS: Still much to do.}, journal = {Non-coding RNA research}, volume = {3}, number = {4}, pages = {226-231}, pmid = {30533570}, issn = {2468-0540}, abstract = {Alterations in RNA metabolism play an important role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. The literature has described, so far, a small number of long non coding RNAs (lncRNAs) associated to ALS demonstrating that how there is still much to do to identify and understand their role in ALS. This class of RNAs may offer numerous starting points for new investigations about pathogenic mechanism involved in ALS disease. In this review, we have collected all the presented data about lncRNAs and ALS to offer an overview about this class of non-coding RNAs and their possible role in ALS disease.}, }
@article {pmid30533567, year = {2018}, author = {Douglas, AGL}, title = {Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction.}, journal = {Non-coding RNA research}, volume = {3}, number = {4}, pages = {178-187}, pmid = {30533567}, issn = {2468-0540}, abstract = {A hexanucleotide repeat expansion in the first intron/promoter region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the C9orf72 locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of C9orf72-related ALS/FTD, not only through direct sequestration of important RNA binding proteins but also indirectly through non-ATG dependent translation into dipeptide repeats. Formation of RNA/DNA hybrid R-loops may also play a key role in the pathogenesis of this condition and this mechanism could provide a link between the repeat expansion, DNA damage, repeat instability and deficiency of RNA binding proteins. Non-coding C9orf72 antisense transcripts could also act to epigenetically regulate gene expression at the locus. The potential effects of such non-coding RNAs should be considered in the design of antisense oligonucleotide therapeutics for C9orf72-related ALS/FTD. Furthermore, the mechanisms of RNA dysregulation exemplified by C9orf72-related disease may help illustrate more broadly how a "perfect storm" of dysfunction occurs in ALS/FTD and how targeting these factors could lead to corrective or preventative therapies.}, }
@article {pmid30531003, year = {2019}, author = {Matschke, V and Theiss, C and Matschke, J}, title = {Oxidative stress: the lowest common denominator of multiple diseases.}, journal = {Neural regeneration research}, volume = {14}, number = {2}, pages = {238-241}, pmid = {30531003}, issn = {1673-5374}, abstract = {Oxygen is essential to the human life and life of all aerobic organisms. The complete oxidation of nutrients for the biological energy supply is one of the most important prerequisites for the formation of higher life forms. However, cells that benefit from oxidative respiration also suffer from reactive oxygen species because they adapted to oxygen as an energy source. Healthy cells balance the formation and elimination of reactive oxygen species thereby creating and keeping reactive oxygen species-homeostasis. When the concentration of free radicals exceeds a critical level and homeostasis is disturbed, oxidative stress occurs leading to damage of multiple cellular molecules and compartments. Therefore, oxidative stress plays an important role in the physiology and pathology of various diseases. Often, the antioxidant protection system becomes pathologically unbalanced in the genesis of several diseases, leading to functional losses of the organism, as in the case of amyotrophic lateral sclerosis, or cells develop metabolic mechanisms to use this system as protection against external influences, such as in the case of glioblastoma cells. Either way, understanding the underlying deregulated mechanisms of the oxidative protection system would allow the development of novel treatment strategies for various diseases. Thus, regardless of the direction in which the reactive oxygen species-homeostasis disequilibrate, the focus should be on the oxidative protection system.}, }
@article {pmid30530996, year = {2019}, author = {Riancho, J and Gil-Bea, FJ and Santurtun, A and López de Munaín, A}, title = {Amyotrophic lateral sclerosis: a complex syndrome that needs an integrated research approach.}, journal = {Neural regeneration research}, volume = {14}, number = {2}, pages = {193-196}, pmid = {30530996}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related to mutations in causative genes, while the vast majority of amyotrophic lateral sclerosis cases are considered to be sporadic, resulting from the interaction between genes and environmental factors in predisposed individuals. During the past few years, dozens of drugs have been postulated as promising strategies for the disease after showing some beneficial effects in preclinical cellular and murine models. However, the translation into clinical practice has been largely unsuccessful and the compounds failed when were tested in clinical trials. This might be explained, at least partially, by the enormous complexity of the disease both from clinico-epidemiological and a pathogenic points of view. In this review, we will briefly comment on the complexity of the disease focusing on some recent findings, and we will suggest how amyotrophic lateral sclerosis research might be reoriented to foster the advance in the diagnostic and therapeutic questions.}, }
@article {pmid30530995, year = {2019}, author = {Fogarty, MJ}, title = {Amyotrophic lateral sclerosis as a synaptopathy.}, journal = {Neural regeneration research}, volume = {14}, number = {2}, pages = {189-192}, pmid = {30530995}, issn = {1673-5374}, abstract = {The synapse is an incredibly specialized structure that allows for the coordinated communication of information from one neuron to another. When assembled into circuits, steady streams of excitatory and inhibitory synaptic activity shape neural outputs. At the organismal level, ensembles of neural networks underlie behavior, emotion and memory. Disorder or dysfunctions of synapses, a synaptopathy, may underlie a host of developmental and degenerative neurological conditions. There is a possibility that amyotrophic lateral sclerosis may be a result of a synaptopathy within the neuromotor system. To this end, particular attention has been trained on the excitatory glutamatergic synapses and their morphological proxy, the dendritic spine. The extensive detailing of these dysfunctions in vulnerable neuronal populations, including corticospinal neurons and motor neurons, has recently been the subject of original research in rodents and humans. If amyotrophic lateral sclerosis is indeed a synaptopathy, it is entirely consistent with other proposed pathogenic mechanisms - including glutamate excitotoxicity, accumulation of misfolded proteins and mitochondrial dysfunction at distal axon terminals (cortico-motor neuron and neuromuscular). Further, although the exact mechanism of disease spread from region to region is unknown, the synaptopathy hypothesis is consistent with emerging die-forward evidence and the prion-like propagation of misfolded protein aggregates to distant neuronal populations. Here in this mini-review, we focus on the timeline of synaptic observations in both cortical and spinal neurons from different rodent models, and provide a conceptual framework for assessing the synaptopathy hypothesis in amyotrophic lateral sclerosis.}, }
@article {pmid30528837, year = {2019}, author = {Porto, LB and Berndl, AML}, title = {Pregnancy 5 Years After Onset of Amyotrophic Lateral Sclerosis Symptoms: A Case Report and Review of the Literature.}, journal = {Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC}, volume = {41}, number = {7}, pages = {974-980}, doi = {10.1016/j.jogc.2018.09.015}, pmid = {30528837}, issn = {1701-2163}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis ; Cesarean Section ; Female ; Humans ; Infant, Newborn ; Pregnancy ; *Pregnancy Complications ; Pregnancy Outcome ; *Prenatal Care ; }, abstract = {BACKGROUND: Pregnancy in patients with amyotrophic lateral sclerosis (ALS) is extremely rare and often results in delivery of a healthy baby when patients are in the early stages of the disease.<br><br>CASE: This report describes the case of a successful pregnancy 5 years after ALS onset. Significant worsening of weakness, unsteady balance, and dysphagia were noticed around the third trimester. A healthy child was delivered at term by planned Caesarean section. After delivery the patient developed remarkable weakness, dysphagia, and dysarthria.<br><br>CONCLUSION: A literature search found 22 cases through PubMed and Ovid, with key words "amyotrophic lateral sclerosis" and "pregnancy." Both slow progression and rapid progression of ALS during pregnancy have been reported. Worsening of symptoms seems to be common, but little is still known about the influence of pregnancy on ALS onset and progression.}, }
@article {pmid30507302, year = {2019}, author = {Jones, RM and Hynynen, K}, title = {Advances in acoustic monitoring and control of focused ultrasound-mediated increases in blood-brain barrier permeability.}, journal = {The British journal of radiology}, volume = {92}, number = {1096}, pages = {20180601}, pmid = {30507302}, issn = {1748-880X}, support = {R01 EB003268/EB/NIBIB NIH HHS/United States ; }, mesh = {Blood-Brain Barrier/*metabolism ; Humans ; *Microbubbles ; Monitoring, Physiologic/*methods ; Permeability ; *Ultrasonic Waves ; }, abstract = {Transcranial focused ultrasound (FUS) combined with intravenously circulating microbubbles can transiently and selectively increase blood-brain barrier permeability to enable targeted drug delivery to the central nervous system, and is a technique that has the potential to revolutionize the way neurological diseases are managed in medical practice. Clinical testing of this approach is currently underway in patients with brain tumors, early Alzheimer's disease, and amyotrophic lateral sclerosis. A major challenge that needs to be addressed in order for widespread clinical adoption of FUS-mediated blood-brain barrier permeabilization to occur is the development of systems and methods for real-time treatment monitoring and control, to ensure that safe and effective acoustic exposure levels are maintained throughout the procedures. This review gives a basic overview of the oscillation dynamics, acoustic emissions, and biological effects associated with ultrasound-stimulated microbubbles in vivo, and provides a summary of recent advances in acoustic-based strategies for detecting, controlling, and mapping microbubble activity in the brain. Further development of next-generation clinical FUS brain devices tailored towards microbubble-mediated applications is warranted and required for translation of this potentially disruptive technology into routine clinical practice.}, }
@article {pmid30517945, year = {2018}, author = {Liberman, AC and Trias, E and da Silva Chagas, L and Trindade, P and Dos Santos Pereira, M and Refojo, D and Hedin-Pereira, C and Serfaty, CA}, title = {Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System.}, journal = {Neuroimmunomodulation}, volume = {25}, number = {5-6}, pages = {246-270}, doi = {10.1159/000494761}, pmid = {30517945}, issn = {1423-0216}, mesh = {Central Nervous System Diseases/*immunology/*physiopathology ; Humans ; Inflammation/*immunology/*physiopathology ; Neuroimmunomodulation/*physiology ; }, abstract = {An extensive microglial-astrocyte-monocyte-neuronal cross talk seems to be crucial for normal brain function, development, and recovery. However, under certain conditions neuroinflammatory interactions between brain cells and neuroimmune cells influence disease outcome and brain pathology. Microglial cells express a range of functional states with dynamically pleomorphic profiles from a surveilling status of synaptic transmission to an active player in major events of development such as synaptic elimination, regeneration, and repair. Also, inflammation mediates a series of neurotoxic roles in neuropsychiatric conditions and neurodegenerative diseases. The present review discusses data on the involvement of neuroinflammatory conditions that alter neuroimmune interactions in four different pathologies. In the first section of this review, we discuss the ability of the early developing brain to respond to a focal lesion with a rapid compensatory plasticity of intact axons and the role of microglial activation and proinflammatory cytokines in brain repair. In the second section, we present data of neuroinflammation and neurodegenerative disorders and discuss the role of reactive astrocytes in motor neuron toxicity and the progression of amyotrophic lateral sclerosis. In the third section, we discuss major depressive disorders as the consequence of dysfunctional interactions between neural and immune signals that result in increased peripheral immune responses and increase proinflammatory cytokines. In the last section, we discuss autism spectrum disorders and altered brain circuitries that emerge from abnormal long-term responses of innate inflammatory cytokines and microglial phenotypic dysfunctions.}, }
@article {pmid30517413, year = {2018}, author = {Severo, AH and Carvalho, ZMF and Lopes, MVO and Brasileiro, RSF and Braga, DCO}, title = {Impaired Verbal Communication: diagnosis review in patients with Amyotrophic Lateral Sclerosis.}, journal = {Revista brasileira de enfermagem}, volume = {71}, number = {6}, pages = {3063-3073}, doi = {10.1590/0034-7167-2017-0763}, pmid = {30517413}, issn = {1984-0446}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*diagnosis ; Clinical Competence/*standards ; *Communication ; Humans ; Nursing Diagnosis/methods/*standards ; Risk Factors ; }, abstract = {OBJECTIVE: To review the contents of the nursing diagnosis of Impaired Verbal Communication in patients with Amyotrophic Lateral Sclerosis.<br><br>METHOD: For the review of this diagnosis we used the integrative review. The 21 selected articles were submitted to a careful concept analysis for the definition of the diagnostic concept and review of its elements.<br><br>RESULTS: It is recommended, in addition to a new definition for the diagnosis of Impaired Verbal Communication, the incorporation of twelve Risk Factors, the maintenance of three others and the relocation of a Defining Characteristic for Risk Factor. It is also recommended the incorporation of nine Defining Characteristics and the modification of the nomenclature of the other three that already make up the NANDA-I.<br><br>CONCLUSION: The content review process subsidized a clarification of the chosen concept, contributing to a future refinement and improvement of the study diagnosis and its components present in NANDA-I.}, }
@article {pmid30515821, year = {2019}, author = {Qi, Z and Huang, Z and Xie, F and Chen, L}, title = {Dynamin-related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases.}, journal = {Journal of cellular physiology}, volume = {234}, number = {7}, pages = {10032-10046}, doi = {10.1002/jcp.27866}, pmid = {30515821}, issn = {1097-4652}, mesh = {Amyloid beta-Peptides/metabolism ; Animals ; Dynamins/*metabolism ; Humans ; Huntingtin Protein/metabolism ; Mitochondria/metabolism/pathology ; Mitochondrial Dynamics ; *Nerve Degeneration ; Nervous System/*metabolism/pathology/physiopathology ; Neurodegenerative Diseases/*metabolism/pathology/physiopathology ; Protein Processing, Post-Translational ; Signal Transduction ; tau Proteins/metabolism ; }, abstract = {Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin-related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1-dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid β (Aβ) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1-associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with Aβ, phosphorylated τ, and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.}, }
@article {pmid30515715, year = {2019}, author = {French, PW and Ludowyke, R and Guillemin, GJ}, title = {Fungal Neurotoxins and Sporadic Amyotrophic Lateral Sclerosis.}, journal = {Neurotoxicity research}, volume = {35}, number = {4}, pages = {969-980}, pmid = {30515715}, issn = {1476-3524}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*metabolism/*microbiology ; Animals ; Brain/metabolism/*microbiology ; DNA-Binding Proteins/metabolism ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/drug effects/metabolism ; Mycoses/*complications ; Mycotoxins/*metabolism ; Neurotoxins/*metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS). ALS is the most common form of motor neuron disease (MND) in adults. It is a progressive and fatal disease. Approximately 90% cases of ALS are sporadic, and 5-10% are due to genetic mutations (familial). About 25 genes implicated in familial ALS have been identified so far, including SOD1 and TARDBP, the gene encoding 43 kDa transactive response (TAR) DNA-binding protein (TDP-43). Despite intensive research over many decades, the aetiology of sporadic ALS is still unknown. An environmental cause, including grass or soil-associated fungal infections, is suggested from a range of widely diverse lines of evidence. Clusters of ALS have been reported in soccer players, natives of Guam and farmers. Grass-associated fungi are known to produce a range of neurotoxins and, in symbiotic associations, high levels of fungal SOD1. Exposure of neurons to fungal neurotoxins elicits a significant increase in glutamate production. High levels of glutamate stimulate TDP-43 translocation and modification, providing a link between fungal infection and one of the molecular and histologic hallmarks of sporadic ALS. A recent study provided evidence of a variety of fungi in the cerebrospinal fluid and brain tissue of ALS patients. This review provides a rational explanation for this observation. If a fungal infection could be confirmed as a potential cause of ALS, this could provide a straightforward treatment strategy for this fatal and incurable disease.}, }
@article {pmid30513656, year = {2018}, author = {Tarafdar, A and Pula, G}, title = {The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {19}, number = {12}, pages = {}, pmid = {30513656}, issn = {1422-0067}, support = {3858//Alzheimer's Research UK/ ; }, mesh = {Amyloid beta-Peptides/metabolism ; Animals ; Humans ; NADPH Oxidases/*metabolism ; Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91[phox] and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation-primarily superoxide anion (O2[●-]), although hydrogen peroxide (H2O2) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.}, }
@article {pmid30509290, year = {2018}, author = {Jawaid, A and Khan, R and Polymenidou, M and Schulz, PE}, title = {Disease-modifying effects of metabolic perturbations in ALS/FTLD.}, journal = {Molecular neurodegeneration}, volume = {13}, number = {1}, pages = {63}, pmid = {30509290}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Diabetes Mellitus, Type 2/*genetics/metabolism ; Frontotemporal Dementia/*genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics ; Humans ; Inclusion Bodies/metabolism ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions.}, }
@article {pmid30487362, year = {2018}, author = {Mitsumoto, H and Saito, T}, title = {[A prognostic biomarker in amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {58}, number = {12}, pages = {729-736}, doi = {10.5692/clinicalneurol.cn-001220}, pmid = {30487362}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/diagnostic imaging/*drug therapy ; Biomarkers/blood/cerebrospinal fluid/urine ; Brain/*diagnostic imaging ; Creatinine/*blood ; Disease Progression ; Electric Impedance ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Myography ; Neurofilament Proteins/*blood/cerebrospinal fluid ; *Neuroimaging ; Positron-Emission Tomography ; Prognosis ; Transcranial Magnetic Stimulation ; Uric Acid/*blood ; }, abstract = {Although we currently have two, approved, disease-modifying drugs for the treatment of amyotrophic lateral sclerosis (ALS), we are in disperate need for more efficacious treatment. To aggressively test for newer therapies, we must develop reliable objective biomarkers to supplement clinical outcome measures. Many biomarker candidates have been actively and vigorously investigated. Among neurophysiological biomarkers, transcranial magnetic stimulation (TMS)-based biomarkers show potential in exploring disease mechanisms. Neuroimaging biomarkers have high specificity in diagnosing ALS but are an expensive endeavor and are not sensitive enough to detect changes over time of the disease. Among fluid-based biochemical biomarkers, creatinine (Crn) and uric acids (UA), which have been known for decades, may prove to be highly promising biomarkers that can predict disease progression. They can be easily tested in any clinical trials because the costs are minimal. Although known for some time, neurofilaments (NF), either phosphorylated-NF heavy subunit (pNFH) or NF light subunit (NFL), have emerged as "new" biomarkers using specific antibodies. They appear to be highly specific and sensitive in diagnosing ALS, yet they may be insensitive to assess changes in disease over time. These two NF biomarkers along with Crn and UA should be explored extensively in future clinical trials and any other clinical studies in ALS. Yet, we still need newer, more innovative, and reliable biomarkers for future ALS research. Fortunatley, aggressive investigations appear to be currently underway.}, }
@article {pmid30484397, year = {2019}, author = {Bohon, J}, title = {Development of Synchrotron Footprinting at NSLS and NSLS-II.}, journal = {Protein and peptide letters}, volume = {26}, number = {1}, pages = {55-60}, doi = {10.2174/0929866526666181128125125}, pmid = {30484397}, issn = {1875-5305}, mesh = {Crystallography, X-Ray ; Equipment Design ; Protein Footprinting/*instrumentation/*methods ; Proteins/analysis/chemistry ; Synchrotrons/*instrumentation ; }, abstract = {BACKGROUND: First developed in the 1990's at the National Synchrotron Light Source, xray synchrotron footprinting is an ideal technique for the analysis of solution-state structure and dynamics of macromolecules. Hydroxyl radicals generated in aqueous samples by intense x-ray beams serve as fine probes of solvent accessibility, rapidly and irreversibly reacting with solvent exposed residues to provide a "snapshot" of the sample state at the time of exposure. Over the last few decades, improvements in instrumentation to expand the technology have continuously pushed the boundaries of biological systems that can be studied using the technique.<br><br>CONCLUSION: Dedicated synchrotron beamlines provide important resources for examining fundamental biological mechanisms of folding, ligand binding, catalysis, transcription, translation, and macromolecular assembly. The legacy of synchrotron footprinting at NSLS has led to significant improvement in our understanding of many biological systems, from identifying key structural components in enzymes and transporters to in vivo studies of ribosome assembly. This work continues at the XFP (17-BM) beamline at NSLS-II and facilities at ALS, which are currently accepting proposals for use.}, }
@article {pmid30482326, year = {2018}, author = {Dharmadasa, T and Matamala, JM and Huynh, W and Zoing, MC and Kiernan, MC}, title = {Motor neurone disease.}, journal = {Handbook of clinical neurology}, volume = {159}, number = {}, pages = {345-357}, doi = {10.1016/B978-0-444-63916-5.00022-7}, pmid = {30482326}, issn = {0072-9752}, mesh = {Humans ; *Motor Neuron Disease/physiopathology ; }, abstract = {Motor neurone disease (MND) patients exhibit poor gait, balance, and postural control, all of which significantly increases their risk of falling. Falls are frequent in the MND population, and are associated with an increased burden of disease. The complex interplay of both motor and extramotor manifestations in this disease contributes to the heterogeneous and multifactorial causes of such dysfunction. This review highlights the pathophysiologic influence of motor degeneration in gait disturbance, but also the additional influence on postural instability from other inputs such as cognitive impairment, autonomic dysregulation, cerebellar dysfunction, sensory impairment, and extrapyramidal involvement. In various combinations, these impairments are responsible for reduced gait speed and alteration in gait cycle, as well as structurally more variable and disorganized gait patterns. Based on these features, this chapter will also provide disease-specific interventions to assess, manage, and prevent falls in the MND cohort.}, }
@article {pmid30481590, year = {2019}, author = {Lee, J and Nguyen, PT and Shim, HS and Hyeon, SJ and Im, H and Choi, MH and Chung, S and Kowall, NW and Lee, SB and Ryu, H}, title = {EWSR1, a multifunctional protein, regulates cellular function and aging via genetic and epigenetic pathways.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1865}, number = {7}, pages = {1938-1945}, pmid = {30481590}, issn = {1879-260X}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; RF1 AG054156/AG/NIA NIH HHS/United States ; }, mesh = {*Aging ; Animals ; Autophagy ; Brain Diseases/*genetics ; *Epigenesis, Genetic ; Humans ; MicroRNAs/genetics ; *Mutation ; RNA-Binding Protein EWS/*genetics ; }, abstract = {Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.}, }
@article {pmid30479815, year = {2018}, author = {Eelen, P and Depreeuw, E and Van Den Bergh, O}, title = {The Therapist as Conditioned Stimulus.}, journal = {Psychologica Belgica}, volume = {58}, number = {1}, pages = {172-183}, pmid = {30479815}, issn = {0033-2879}, abstract = {This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. This manuscript was originally published in 1989 as part of an edited book on the therapeutic relation. In this chapter, Paul Eelen takes a critical position against the dominance of the client-centered approach. He presents the therapeutic relation as a behavioural interaction between the patient and his therapist which is subject to laws of learning. This is exemplified by an in-depth analysis of the therapist as a conditioned stimulus. First published as: Eelen, P., Depreeuw, E., &amp; Van den Bergh, O. (1989). De therapeut als geconditioneerde stimulus. In H. Vertommen, G. Cluckers, &amp; G. Lietaer (Eds.), De relatie in therapie (pp. 147-165). Leuven: Universitaire Pers Leuven.}, }
@article {pmid30477087, year = {2018}, author = {Rakotoarisoa, M and Angelova, A}, title = {Amphiphilic Nanocarrier Systems for Curcumin Delivery in Neurodegenerative Disorders.}, journal = {Medicines (Basel, Switzerland)}, volume = {5}, number = {4}, pages = {}, pmid = {30477087}, issn = {2305-6320}, abstract = {Neurodegenerative diseases have become a major challenge for public health because of their incurable status. Soft nanotechnology provides potential for slowing down the progression of neurodegenerative disorders by using innovative formulations of neuroprotective antioxidants like curcumin, resveratrol, vitamin E, rosmarinic acid, 7,8-dihydroxyflavone, coenzyme Q10, and fish oil. Curcumin is a natural, liposoluble compound, which is of considerable interest for nanomedicine development in combination therapies. The neuroprotective effects of combination treatments can involve restorative mechanisms against oxidative stress, mitochondrial dysfunction, inflammation, and protein aggregation. Despite the anti-amyloid and anti-tau potential of curcumin and its neurogenesis-stimulating properties, the utilization of this antioxidant as a drug in neuroregenerative therapies has huge limitations due to its poor water solubility, physico-chemical instability, and low oral bioavailability. We highlight the developments of soft lipid- and polymer-based delivery carriers of curcumin, which help improve the drug solubility and stability. We specifically focus on amphiphilic liquid crystalline nanocarriers (cubosome, hexosome, spongosome, and liposome particles) for the encapsulation of curcumin with the purpose of halting the progressive neuronal loss in Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid30473407, year = {2019}, author = {Walker, KL and Rodrigues, MJ and Watson, B and Reilly, C and Scotter, EL and Brunton, H and Turnbull, J and Roxburgh, RH}, title = {Establishment and 12-month progress of the New Zealand Motor Neurone Disease Registry.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {60}, number = {}, pages = {7-11}, doi = {10.1016/j.jocn.2018.11.034}, pmid = {30473407}, issn = {1532-2653}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease/epidemiology ; New Zealand/epidemiology ; *Registries ; }, abstract = {There are only limited treatments currently available for Motor Neurone Disease, each with modest benefits. However, there is a large amount of research and drug discovery currently underway worldwide. The New Zealand Motor Neurone Disease Registry was established in 2017 to facilitate participation in research and clinical trials, and to aid researchers in planning and recruitment. The NZ MND Registry is an opt in patient registry which collects demographic, contact and clinical data for those who choose to enrol. We report anonymised aggregated data from the first year's enrolment. 12th July 2018, there were 142 participants enrolled in the NZ MND Registry. Participant sex distribution reflects the demographics reported worldwide, but ethnicity is divergent from what is seen in New Zealand overall, with an over-representation of people who identify as New Zealand European. 85.5% of participants are diagnosed with sporadic MND and 6.1% with familial MND. The remainder were participants who have not been diagnosed but have a family history, or positive genetic test for a MND-causing mutation. Levels of disability are reported using ALSFRS-R scores, and show that the majority of participants are within the higher range of the scale. The registry has facilitated entry of patients into three studies to date. The establishment of the NZ MND Registry illustrates a swift launch of a rare disease patient registry. The role of patient registries is an ever changing one, but with clear utility at every point of along the pathway to drug discovery.}, }
@article {pmid30467385, year = {2019}, author = {Yuan, J and Amin, P and Ofengeim, D}, title = {Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases.}, journal = {Nature reviews. Neuroscience}, volume = {20}, number = {1}, pages = {19-33}, pmid = {30467385}, issn = {1471-0048}, support = {R01 AG047231/AG/NIA NIH HHS/United States ; R01 NS082257/NS/NINDS NIH HHS/United States ; R21 AG059073/AG/NIA NIH HHS/United States ; RF1 AG055521/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/*metabolism/pathology ; Humans ; Inflammation/*metabolism/pathology ; Necroptosis/*physiology ; Neurodegenerative Diseases/*metabolism/pathology ; Neurons/*metabolism/pathology ; Phosphorylation ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; }, abstract = {Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.}, }
@article {pmid30465257, year = {2019}, author = {McCauley, ME and Baloh, RH}, title = {Inflammation in ALS/FTD pathogenesis.}, journal = {Acta neuropathologica}, volume = {137}, number = {5}, pages = {715-730}, pmid = {30465257}, issn = {1432-0533}, support = {R01 NS097545/NS/NINDS NIH HHS/United States ; T32 GM118288/GM/NIGMS NIH HHS/United States ; 352536//Muscular Dystrophy Association/International ; R01 NS069669/NS/NINDS NIH HHS/United States ; NS097545/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/therapy ; Animals ; Frontotemporal Dementia/genetics/*immunology/therapy ; Humans ; Inflammation/genetics/*immunology/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence for an autoinflammatory state. However, despite the prominent role of neuro- and systemic inflammation in ALS/FTD, and experimental evidence in rodents that altering microglial function can mitigate pathology, therapeutic approaches to decrease inflammation have thus far failed to alter disease course in humans. Here, we review the characteristics of inflammation in ALS/FTD in both the nervous and peripheral immune systems. We further discuss evidence for direct influence on immune cell function by mutations in ALS/FTD genes including C9orf72, TBK1 and OPTN, and how this could lead to the altered innate immune system "tone" observed in these patients.}, }
@article {pmid30463376, year = {2018}, author = {Ricci, C and Marzocchi, C and Battistini, S}, title = {MicroRNAs as Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {7}, number = {11}, pages = {}, pmid = {30463376}, issn = {2073-4409}, support = {FFARB 2017//Italian Ministry for Instruction, University and Research/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable and fatal disorder characterized by the progressive loss of motor neurons in the cerebral cortex, brain stem, and spinal cord. Sporadic ALS form accounts for the majority of patients, but in 1[-]13.5% of cases the disease is inherited. The diagnosis of ALS is mainly based on clinical assessment and electrophysiological examinations with a history of symptom progression and is then made with a significant delay from symptom onset. Thus, the identification of biomarkers specific for ALS could be of a fundamental importance in the clinical practice. An ideal biomarker should display high specificity and sensitivity for discriminating ALS from control subjects and from ALS-mimics and other neurological diseases, and should then monitor disease progression within individual patients. microRNAs (miRNAs) are considered promising biomarkers for neurodegenerative diseases, since they are remarkably stable in human body fluids and can reflect physiological and pathological processes relevant for ALS. Here, we review the state of the art of miRNA biomarker identification for ALS in cerebrospinal fluid (CSF), blood and muscle tissue; we discuss advantages and disadvantages of different approaches, and underline the limits but also the great potential of this research for future practical applications.}, }
@article {pmid30459038, year = {2018}, author = {Dupuis, L and Petersen, &#xc5; and Weydt, P}, title = {Thermoregulation in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {157}, number = {}, pages = {749-760}, doi = {10.1016/B978-0-444-64074-1.00046-X}, pmid = {30459038}, issn = {0072-9752}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Body Temperature Regulation/*physiology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the major adult-onset motor neuron disease, and is clinically, pathologically, and genetically associated with frontotemporal dementia, the second cause of dementia in the elderly. Here, we review the evidence linking thermoregulation and ALS. Indeed, while ALS is not classically associated with defective thermoregulatory function, its progression severely affects key brain regions controlling body temperature and impacts multiple sensors and effectors of this homeostatic function. Furthermore, animal models of ALS display disturbed thermoregulation as a consequence of disrupted energy homeostasis. All these lines of indirect evidence call for studies directly addressing the body temperature regulatory system, both as a potential biomarker and as a possible modifier of disease progression in ALS.}, }
@article {pmid30458564, year = {2018}, author = {Papadopoulou, A and Oertel, FC and Zimmermann, H and Zeitz, O and Brandt, AU and Paul, F}, title = {[Optical Coherence Tomography in Disorders of the Central Nervous System].}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {235}, number = {11}, pages = {1242-1258}, doi = {10.1055/a-0715-7961}, pmid = {30458564}, issn = {1439-3999}, mesh = {Central Nervous System Diseases/*diagnostic imaging ; Humans ; Optic Nerve ; *Optic Neuritis ; Retina ; Retinal Ganglion Cells ; *Tomography, Optical Coherence/methods ; }, abstract = {Retinal changes and visual symptoms are present in several inflammatory, degenerative and tumorous disorders of the central nervous system (CNS). Optical coherence tomography (OCT) is a method that can be used in clinical practice to detect and quantify the structural correlates of these visual symptoms in neurological disorders. OCT is a non-invasive imaging technique, based on interferometry, which can create high-resolution images of the retina and measure the thickness and volume of the different retinal layers. The combined ganglion cell- and inner plexiform layer (GCIPL) and the peripapillary retinal nerve fibre layer (pRNFL) are of particular interest in the field of neurological disorders, since they contain the neuronal bodies (ganglion cells) and their axons that form the optic nerve. In acute optic neuritis (ON), initial swelling of the pRNFL can be detected by OCT and this may contribute to the diagnosis and differential diagnosis of ON; moreover, the extent of the GCIPL-thinning within the first 4 weeks after an acute ON can contribute to the prediction of the long-term visual recovery. However, the role of OCT in the field of multiple sclerosis (MS) is not restricted in patients with ON, since even eyes without an ON-history show mild thinning of the pRNFL and GCIPL. This thinning seems to be associated with neurodegenerative processes in the entire CNS. Several studies showed correlations between these OCT-parameters and a higher risk of clinical deterioration (disability progression), cognitive deficits and disease activity in patients with MS. However, it is often still unclear how these correlations can be useful in the management of the individual patient. In recent years, OCT has been applied to a greater extent to neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS) and various forms of dementia. However, routine clinical use is still further away than for inflammatory CNS diseases, since the role of OCT in the diagnosis, differential diagnosis and prediction of the clinical course of neurodegenerative diseases is still unclear. This review article offers a summary of the available study results on OCT parameters and their role in inflammatory, degenerative and tumorous diseases of the central nervous system (CNS).}, }
@article {pmid30430964, year = {2018}, author = {Mah, JK and van Alfen, N}, title = {Neuromuscular Ultrasound: Clinical Applications and Diagnostic Values.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {45}, number = {6}, pages = {605-619}, doi = {10.1017/cjn.2018.314}, pmid = {30430964}, issn = {0317-1671}, mesh = {Humans ; Muscle, Skeletal/pathology ; Muscular Diseases/*diagnosis/pathology ; Muscular Dystrophies/diagnosis/pathology ; Neuromuscular Diseases/*diagnosis/therapy ; Peripheral Nervous System Diseases/*diagnosis/pathology ; *Ultrasonography ; }, abstract = {Advances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented.}, }
@article {pmid30430356, year = {2019}, author = {Cieślak, M and Roszek, K and Wujak, M}, title = {Purinergic implication in amyotrophic lateral sclerosis-from pathological mechanisms to therapeutic perspectives.}, journal = {Purinergic signalling}, volume = {15}, number = {1}, pages = {1-15}, pmid = {30430356}, issn = {1573-9546}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology/*physiopathology ; Animals ; Humans ; Motor Neurons/metabolism/pathology ; Purines/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by degeneration of upper motor neurons in the brainstem and lower motor neurons in the spinal cord. Multiple mechanisms of motor neuron injury have been implicated, including more than 20 different genetic factors. The pathogenesis of ALS consists of two stages: an early neuroprotective stage and a later neurotoxic. During early phases of disease progression, the immune system through glial and T cell activities provides anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a rapidly succeeding neurotoxic phase develops. A well-orchestrated purine-mediated dialog among motor neurons, surrounding glia and immune cells control the beneficial and detrimental activities occurring in the nervous system. In general, low adenosine triphosphate (ATP) concentrations protect cells against excitotoxic stimuli through purinergic P2X4 receptor, whereas high concentrations of ATP trigger toxic P2X7 receptor activation. Finally, adenosine is also involved in ALS progression since A2A receptor antagonists prevent motor neuron death. Given the complex cellular cross-talk occurring in ALS and the recognized function of extracellular nucleotides and adenosine in neuroglia communication, the comprehensive understanding of purinome dynamics might provide new research perspectives to decipher ALS and help to design more efficient and targeted drugs. This review will focus on the purinergic players involved in ALS etiology and disease progression and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity.}, }
@article {pmid30425620, year = {2018}, author = {Di Gregorio, SE and Duennwald, ML}, title = {ALS Yeast Models-Past Success Stories and New Opportunities.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {394}, pmid = {30425620}, issn = {1662-5099}, abstract = {In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS). Expressing ALS-associated proteins, such as superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-43) and Fused in sarcoma (FUS), in yeast recapitulates major hallmarks of ALS pathology, including protein aggregation, mislocalization and cellular toxicity. Results from yeast have consistently been recapitulated in other model systems and even specimens from human patients, thus providing evidence for the power and validity of ALS yeast models. Focusing on impaired ribonucleic acid (RNA) metabolism and protein misfolding and their cytotoxic consequences in ALS, we summarize exemplary discoveries that originated from work in yeast. We also propose previously unexplored experimental strategies to modernize ALS yeast models, which will help to decipher the basic pathomechanisms underlying ALS and thus, possibly contribute to finding a cure.}, }
@article {pmid30422919, year = {2019}, author = {Long, R and Havics, B and Zembillas, M and Kelly, J and Amundson, M}, title = {Elucidating the End-of-Life Experience of Persons With Amyotrophic Lateral Sclerosis.}, journal = {Holistic nursing practice}, volume = {33}, number = {1}, pages = {3-8}, doi = {10.1097/HNP.0000000000000301}, pmid = {30422919}, issn = {1550-5138}, mesh = {Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/complications/*psychology ; Humans ; Qualitative Research ; Quality of Life/psychology ; Terminal Care/methods/*standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that occurs in 4 among 100 000 people in the United States. Individuals with ALS gradually lose their ability to control voluntary muscles, diminishing their ability to communicate. A comprehensive multidatabase search retrieved 31 qualitative research articles that addressed persons with end-of-life experiences with ALS. Inclusion/exclusion criteria were applied and a critical appraisal was applied for the final 8 included articles. First-person data extraction from the final articles represented emergence of 3 themes significant to persons with ALS: decisions for life-sustaining support, coping and fear of what is to come, and communication with providers. Tracheostomy and ventilation as a means of prolonging life were important considerations for individuals with ALS. Persons with ALS struggled emotionally with their sudden loss of control and facing their demise. Some facets in which they did exert control, such as living wills, were hindered by patient and health care provider communication. Effective communication in end-of-life circumstances is paramount to preserving patient autonomy and dignity. This can be achieved by the patients conveying their preferences with respect to end-of-life care in advance, as well the nurses and other health care providers supporting the patients emotionally as they cope with terminal illness. Understanding patients' views regarding end-of-life circumstances is pertinent to nurses and other health care providers as they plan for palliative care.}, }
@article {pmid30422329, year = {2019}, author = {Zetterberg, H and van Swieten, JC and Boxer, AL and Rohrer, JD}, title = {Review: Fluid biomarkers for frontotemporal dementias.}, journal = {Neuropathology and applied neurobiology}, volume = {45}, number = {1}, pages = {81-87}, doi = {10.1111/nan.12530}, pmid = {30422329}, issn = {1365-2990}, support = {MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; R01AG038791/GF/NIH HHS/United States ; }, mesh = {Biomarkers/*metabolism ; Frontotemporal Dementia/*diagnosis/*metabolism ; Humans ; }, abstract = {Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.}, }
@article {pmid30414815, year = {2018}, author = {Fitzgerald, DA and Doumit, M and Abel, F}, title = {Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1.}, journal = {Paediatric respiratory reviews}, volume = {28}, number = {}, pages = {11-17}, doi = {10.1016/j.prrv.2018.07.002}, pmid = {30414815}, issn = {1526-0550}, mesh = {Early Medical Intervention ; Humans ; Hypoventilation/etiology/physiopathology/*therapy ; Life Expectancy ; Oligonucleotides/*therapeutic use ; Phenotype ; *Physical Therapy Modalities ; Pneumonia/etiology/physiopathology ; *Respiration, Artificial ; Respiratory Aspiration/etiology/physiopathology ; Respiratory Insufficiency/etiology/physiopathology/*therapy ; *Respiratory Therapy ; Spinal Muscular Atrophies of Childhood/complications/physiopathology/*therapy ; }, abstract = {Spinal muscular atrophy [SMA] is the most common genetic cause of childhood mortality, primarily from the most severe form SMA type 1. It is a severe, progressive motor neurone disease, affecting the lower brainstem nuclei and the spinal cord. There is a graded level of severity with SMA children from a practical viewpoint described as "Non-sitters", "Sitters" and less commonly, "Ambulant" correlating with SMA Type 0/Type 1, Type 2 and Type 3 respectively. Children with SMA Type 0 have a severe neonatal form whilst those with SMA Type 1 develop hypoventilation, pulmonary aspiration, recurrent lower respiratory tract infections, dysphagia and failure to thrive before usually succumbing to respiratory failure and death before the age of 2 years. The recent introduction of the antisense oligonucleotide nusinersen into clinical practice in certain countries, following limited trials of less than two years duration, has altered the treatment landscape and improved the outlook considerably for SMN1 related SMA. Approximately 70% of infants appear to have a clinically significant response to nusinersen with improved motor function. It appears the earlier the treatment is initiated the better the response. There are other rarer genetic forms of SMA that are not treated with nusinersen. Clinical expectations will change although it is unclear as yet what the extent of response will mean in terms of screening initiatives [e.g., newborn screening], "preventative strategies" to maintain respiratory wellbeing, timing of introduction of respiratory supports, and prolonged life expectancy for the subcategory of children with treated SMA type 1. This article provides a review of the strategies available for supporting children with respiratory complications of SMA, with a particular emphasis on SMA Type 1.}, }
@article {pmid30410433, year = {2018}, author = {Mazón, M and Vázquez Costa, JF and Ten-Esteve, A and Martí-Bonmatí, L}, title = {Imaging Biomarkers for the Diagnosis and Prognosis of Neurodegenerative Diseases. The Example of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {784}, pmid = {30410433}, issn = {1662-4548}, abstract = {The term amyotrophic lateral sclerosis (ALS) comprises a heterogeneous group of fatal neurodegenerative disorders of largely unknown etiology characterized by the upper motor neurons (UMN) and/or lower motor neurons (LMN) degeneration. The development of brain imaging biomarkers is essential to advance in the diagnosis, stratification and monitoring of ALS, both in the clinical practice and clinical trials. In this review, the characteristics of an optimal imaging biomarker and common pitfalls in biomarkers evaluation will be discussed. Moreover, the development and application of the most promising brain magnetic resonance (MR) imaging biomarkers will be reviewed. Finally, the integration of both qualitative and quantitative multimodal brain MR biomarkers in a structured report will be proposed as a support tool for ALS diagnosis and stratification.}, }
@article {pmid30410025, year = {2018}, author = {Jaffrey, SR and Wilkinson, MF}, title = {Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease.}, journal = {Nature reviews. Neuroscience}, volume = {19}, number = {12}, pages = {715-728}, pmid = {30410025}, issn = {1471-0048}, support = {R01 GM111838/GM/NIGMS NIH HHS/United States ; R01 HD093846/HD/NICHD NIH HHS/United States ; R01 NS056306/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autism Spectrum Disorder/*pathology ; Brain/*metabolism ; Cell Differentiation ; Humans ; Neurogenesis/*physiology ; Nonsense Mediated mRNA Decay/*physiology ; Schizophrenia/*pathology ; }, abstract = {Steady-state RNA levels are controlled by the balance between RNA synthesis and RNA turnover. A selective RNA turnover mechanism that has received recent attention in neurons is nonsense-mediated RNA decay (NMD). NMD has been shown to influence neural development, neural stem cell differentiation decisions, axon guidance and synaptic plasticity. In humans, NMD factor gene mutations cause some forms of intellectual disability and are associated with neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Impairments in NMD are linked to neurodegenerative disorders, including amyotrophic lateral sclerosis. We discuss these findings, their clinical implications and challenges for the future.}, }
@article {pmid30408594, year = {2019}, author = {Panchal, K and Tiwari, AK}, title = {Mitochondrial dynamics, a key executioner in neurodegenerative diseases.}, journal = {Mitochondrion}, volume = {47}, number = {}, pages = {151-173}, doi = {10.1016/j.mito.2018.11.002}, pmid = {30408594}, issn = {1872-8278}, mesh = {Animals ; Humans ; Lipid Peroxidation ; Mitochondria/*metabolism/pathology ; *Mitochondrial Dynamics ; Neurodegenerative Diseases/*metabolism/pathology/therapy ; Neurons/metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well-studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions.}, }
@article {pmid30408527, year = {2019}, author = {Saraf, J and Kalia, K and Bhattacharya, P and Tekade, RK}, title = {Growing synergy of nanodiamonds in neurodegenerative interventions.}, journal = {Drug discovery today}, volume = {24}, number = {2}, pages = {584-594}, doi = {10.1016/j.drudis.2018.10.012}, pmid = {30408527}, issn = {1878-5832}, mesh = {Animals ; Humans ; Nanodiamonds/*therapeutic use ; Neurodegenerative Diseases/*diagnosis/*drug therapy ; Neurons/drug effects ; }, abstract = {Neurodegenerative diseases are complex in both their nature and prognosis. The difficulties associated with penetrating the blood-brain barrier (BBB), achieving site-specific targeting to the brain, and identifying the genetic etiologies responsible make treating neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and stroke, challenging. The aim to treat disease at the molecular level has galvanized nanotechnology research. Among the forms of nanoparticles (NPs) explored thus far, nanodiamonds (NDs) have shown great potential. Their unique physicochemical properties, such as a nanometer size range, stable and inert core, tunable surface, intrinsic fluorescence without photobleaching, negligible toxicity, and the ability to form complexes with drugs, highlight their theranostic potential. The ability of NDs to penetrate the BBB and target specific affected areas of the brain could take research one step closer to understanding the underlying disease etiology and unlocking more efficient methods of delivering neuromedicine to specific areas of the brain. Here, we explore interactions between NDs and the neuronal circuitry with a focus on the therapeutic potential of NDs as treatments for neurodegenerative diseases.}, }
@article {pmid30401437, year = {2018}, author = {Oskarsson, B and Gendron, TF and Staff, NP}, title = {Amyotrophic Lateral Sclerosis: An Update for 2018.}, journal = {Mayo Clinic proceedings}, volume = {93}, number = {11}, pages = {1617-1628}, doi = {10.1016/j.mayocp.2018.04.007}, pmid = {30401437}, issn = {1942-5546}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/physiopathology/therapy ; C9orf72 Protein ; Diagnosis, Differential ; Edaravone/therapeutic use ; Female ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental. Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common known genetic cause of ALS and are seen in approximately 40% of patients with a family history and approximately 10% of those without. No environmental risk factors are proved to be causative, but many have been proposed, including military service. The diagnosis of ALS rests on a history of painless progressive weakness coupled with examination findings of upper and lower motor dysfunction. No diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for patients is best provided by a multidisciplinary team, and most interventions are directed at managing symptoms. Two medications with modest benefits have Food and Drug Administration approval for the treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein we review stem cell and antisense oligonucleotide gene therapies.}, }
@article {pmid30399416, year = {2019}, author = {Steinacker, P and Barschke, P and Otto, M}, title = {Biomarkers for diseases with TDP-43 pathology.}, journal = {Molecular and cellular neurosciences}, volume = {97}, number = {}, pages = {43-59}, doi = {10.1016/j.mcn.2018.10.003}, pmid = {30399416}, issn = {1095-9327}, mesh = {Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Animals ; Biomarkers/metabolism ; Brain/*diagnostic imaging/*metabolism ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/diagnostic imaging/metabolism ; Humans ; Neuroimaging/methods ; TDP-43 Proteinopathies/*diagnostic imaging/*metabolism ; }, abstract = {The discovery that aggregated transactive response DNA-binding protein 43 kDa (TDP-43) is the major component of pathological ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) caused seminal progress in the unveiling of the genetic bases and molecular characteristics of these now so-called TDP-43 proteinopathies. Substantial increase in the knowledge of clinic-pathological coherencies, especially for FTLD variants, could be made in the last decade, but also revealed a considerable complexity of TDP-43 pathology and often a poor correlation of clinical and molecular disease characteristics. To date, an underlying TDP-43 pathology can be predicted only for patients with mutations in the genes C9orf72 and GRN, but is dependent on neuropathological verification in patients without family history, which represent the majority of cases. As etiology-specific therapies for neurodegenerative proteinopathies are emerging, methods to forecast TDP-43 pathology at patients' lifetime are highly required. Here, we review the current status of research pursued to identify specific indicators to predict or exclude TDP-43 pathology in the ALS-FTLD spectrum disorders and findings on candidates for prognosis and monitoring of disease progression in TDP-43 proteinopathies with a focus on TDP-43 with its pathological forms, neurochemical and imaging biomarkers.}, }
@article {pmid30396776, year = {2018}, author = {Janssens, R and Struyf, S and Proost, P}, title = {Pathological roles of the homeostatic chemokine CXCL12.}, journal = {Cytokine &amp; growth factor reviews}, volume = {44}, number = {}, pages = {51-68}, doi = {10.1016/j.cytogfr.2018.10.004}, pmid = {30396776}, issn = {1879-0305}, mesh = {Animals ; Central Nervous System Diseases/metabolism ; Chemokine CXCL12/*metabolism ; Eye Diseases/metabolism ; Humans ; Inflammatory Bowel Diseases/metabolism ; Neoplasms ; Receptors, CXCR4/metabolism ; Respiratory Tract Diseases/metabolism ; Rheumatic Diseases/metabolism ; Virus Diseases/metabolism ; }, abstract = {CXCL12 is a CXC chemokine that traditionally has been classified as a homeostatic chemokine. It contributes to physiological processes such as embryogenesis, hematopoiesis and angiogenesis. In contrast to these homeostatic functions, increased expression of CXCL12 in general, or of a specific CXCL12 splicing variant has been demonstrated in various pathologies. In addition to this increased or differential transcription of CXCL12, also upregulation of its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) contributes to the onset or progression of diseases. Moreover, posttranslational modification of CXCL12 during disease progression, through interaction with locally produced molecules or enzymes, also affects CXCL12 activity, adding further complexity. As CXCL12, CXCR4 and ACKR3 are broadly expressed, the number of pathologies wherein CXCL12 is involved is growing. In this review, the role of the CXCL12/CXCR4/ACKR3 axis will be discussed for the most prevalent pathologies. Administration of CXCL12-neutralizing antibodies or small-molecule antagonists of CXCR4 or ACKR3 delays disease onset or prevents disease progression in cancer, viral infections, inflammatory bowel diseases, rheumatoid arthritis and osteoarthritis, asthma and acute lung injury, amyotrophic lateral sclerosis and WHIM syndrome. On the other hand, CXCL12 has protective properties in Alzheimer's disease and multiple sclerosis, has a beneficial role in wound healing and has crucial homeostatic properties in general.}, }
@article {pmid30395851, year = {2019}, author = {Auffret, M and Drapier, S and Vérin, M}, title = {New tricks for an old dog: A repurposing approach of apomorphine.}, journal = {European journal of pharmacology}, volume = {843}, number = {}, pages = {66-79}, doi = {10.1016/j.ejphar.2018.10.052}, pmid = {30395851}, issn = {1879-0712}, mesh = {Animals ; Apomorphine/pharmacology/*therapeutic use ; Dopamine Agonists/pharmacology/*therapeutic use ; Drug Repositioning ; Humans ; Neoplasms/drug therapy ; Nervous System Diseases/drug therapy ; Sexual Dysfunction, Physiological/drug therapy ; }, abstract = {Apomorphine is a 150-year old nonspecific dopaminergic agonist, currently indicated for treating motor fluctuations in Parkinson's disease. At the era of drug repurposing, its pleiotropic biological functions suggest other possible uses. To further explore new therapeutic and diagnostic applications, the available literature up to July 2018 was reviewed using the PubMed and Google Scholar databases. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn, to give a broad overview of the potential of apomorphine. Apomorphine may play a role in neurological diseases like restless legs syndrome, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease and disorders of consciousness, but also in sexual disorders, neuroleptic malignant(-like) syndrome and cancer. Further work is needed in both basic and clinical research; current developments in novel delivery strategies and apomorphine derivatives are expected to open the way.}, }
@article {pmid30395400, year = {2018}, author = {Bleuel, R and Eberlein, B}, title = {Therapeutisches Management bei Vitiligo.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {16}, number = {11}, pages = {1309-1314}, doi = {10.1111/ddg.13680_g}, pmid = {30395400}, issn = {1610-0387}, abstract = {Vitiligo ist eine erworbene Hauterkrankung, an der weltweit 0,5 % der Bevölkerung erkranken und die eine große Herausforderung in der dermatologischen Versorgung darstellt. Die Erkrankung geht für Betroffene oftmals aufgrund der fleckigen Depigmentierung mit einer kosmetischen Entstellung und großem Leidensdruck einher. Pathophysiologisch werden als Hauptursachen für den Verlust funktionierender Melanozyten eine genetische Prädisposition, autoimmune Mechanismen und oxidativer Stress angesehen. Vorgestellt werden die Therapieempfehlungen der europäischen Leitlinie in Ergänzung mit Empfehlungen aus aktuellen Übersichtsarbeiten zu Vitiligo. Bisherige therapeutische Optionen greifen auf drei Wegen: (1.) Regulation der Autoimmunantwort mit topischen und systemischen immunmodulierenden Pharmaka (Kortikosteroide und Calcineurininhibitoren), (2.) Reduktion des melanozytären, oxidativen Stress mittels topischer und systemischer Antioxidantien sowie (3.) Aktivierung der Melanozytenregeneration durch Phototherapie (v. a. UVB) und Transplantation von pigmentierten Zellen. Darüber hinaus sollten dem Patienten Techniken zur Camouflage angeboten werden. Nach erfolgreicher Repigmentierung ist eine Rezidivprophylaxe mit Calcineurininhibitoren sinnvoll. Kombinationstherapien oben genannter Therapieansätze werden generell als erfolgreicher angesehen als Monotherapien. Auch ist ein möglichst früher Therapiebeginn prognostisch günstig. Mit Hilfe der genannten Therapieansätze kann es gelingen das Fortschreiten der Erkrankung aufzuhalten, depigmentierte Herde zu stabilisieren und eine Repigmentierung zu erreichen. Nur in Ausnahmefällen kommt eine dauerhafte Depigmentierung in Frage. Weiterreichende Erkenntnisse zur Pathogenese der Erkrankung lassen auf neue Therapieansätze hoffen.}, }
@article {pmid30391475, year = {2019}, author = {Bennett, SA and Tanaz, R and Cobos, SN and Torrente, MP}, title = {Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {204}, number = {}, pages = {19-30}, pmid = {30391475}, issn = {1878-1810}, support = {K22 NS091314/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/etiology/*genetics ; Animals ; Chromatin Assembly and Disassembly ; DNA Methylation ; *Epigenesis, Genetic ; Histones/*metabolism ; Humans ; MicroRNAs/physiology ; *Protein Processing, Post-Translational ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most common adult onset neurodegenerative disorder worldwide. It is generally characterized by progressive paralysis starting at the limbs ultimately leading to death caused by respiratory failure. There is no cure and current treatments fail to slow the progression of the disease. As such, new treatment options are desperately needed. Epigenetic targets are an attractive possibility because they are reversible. Epigenetics refers to heritable changes in gene expression unrelated to changes in DNA sequence. Three main epigenetic mechanisms include the methylation of DNA, microRNAs and the post-translational modification of histone proteins. Histone modifications occur in many amino acid residues and include phosphorylation, acetylation, methylation as well as other chemical moieties. Recent evidence points to a possible role for epigenetic mechanisms in the etiology of ALS. Here, we review recent advances linking ALS and epigenetics, with a strong focus on histone modifications. Both local and global changes in histone modification profiles are associated with ALS drawing attention to potential targets for future diagnostic and treatment approaches.}, }
@article {pmid30375034, year = {2019}, author = {Borrego-Écija, S and Cortés-Vicente, E and Cervera-Carles, L and Clarimón, J and Gámez, J and Batlle, J and Ricken, G and Molina-Porcel, L and Aldecoa, I and Sánchez-Valle, R and Rojas-García, R and Gelpi, E}, title = {Does ALS-FUS without FUS mutation represent ALS-FET? Report of three cases.}, journal = {Neuropathology and applied neurobiology}, volume = {45}, number = {4}, pages = {421-426}, pmid = {30375034}, issn = {1365-2990}, mesh = {Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Mutation/*genetics ; RNA-Binding Protein FUS/*genetics ; }, }
@article {pmid30373267, year = {2018}, author = {Willaert, RG}, title = {Adhesins of Yeasts: Protein Structure and Interactions.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {4}, number = {4}, pages = {}, pmid = {30373267}, issn = {2309-608X}, support = {ESA grant//Federaal Wetenschapsbeleid/ ; }, abstract = {The ability of yeast cells to adhere to other cells or substrates is crucial for many yeasts. The budding yeast Saccharomyces cerevisiae can switch from a unicellular lifestyle to a multicellular one. A crucial step in multicellular lifestyle adaptation is self-recognition, self-interaction, and adhesion to abiotic surfaces. Infectious yeast diseases such as candidiasis are initiated by the adhesion of the yeast cells to host cells. Adhesion is accomplished by adhesin proteins that are attached to the cell wall and stick out to interact with other cells or substrates. Protein structures give detailed insights into the molecular mechanism of adhesin-ligand interaction. Currently, only the structures of a very limited number of N-terminal adhesion domains of adhesins have been solved. Therefore, this review focuses on these adhesin protein families. The protein architectures, protein structures, and ligand interactions of the flocculation protein family of S. cerevisiae; the epithelial adhesion family of C. glabrata; and the agglutinin-like sequence protein family of C. albicans are reviewed and discussed.}, }
@article {pmid30368547, year = {2019}, author = {Vatsavayai, SC and Nana, AL and Yokoyama, JS and Seeley, WW}, title = {C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies.}, journal = {Acta neuropathologica}, volume = {137}, number = {1}, pages = {1-26}, pmid = {30368547}, issn = {1432-0533}, support = {R01 NS104437/NS/NINDS NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; K01 AG049152/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG033017/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/*genetics/*pathology ; Humans ; Inclusion Bodies/pathology ; }, abstract = {What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.}, }
@article {pmid30356682, year = {2018}, author = {Nötzel, M and Rosso, G and Möllmert, S and Seifert, A and Schlüßler, R and Kim, K and Hermann, A and Guck, J}, title = {Axonal Transport, Phase-Separated Compartments, and Neuron Mechanics - A New Approach to Investigate Neurodegenerative Diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {358}, pmid = {30356682}, issn = {1662-5102}, abstract = {Many molecular and cellular pathogenic mechanisms of neurodegenerative diseases have been revealed. However, it is unclear what role a putatively impaired neuronal transport with respect to altered mechanical properties of neurons play in the initiation and progression of such diseases. The biochemical aspects of intracellular axonal transport, which is important for molecular movements through the cytoplasm, e.g., mitochondrial movement, has already been studied. Interestingly, transport deficiencies are associated with the emergence of the affliction and potentially linked to disease transmission. Transport along the axon depends on the normal function of the neuronal cytoskeleton, which is also a major contributor to neuronal mechanical properties. By contrast, little attention has been paid to the mechanical properties of neurons and axons impaired by neurodegeneration, and of membraneless, phase-separated organelles such as stress granules (SGs) within neurons. Mechanical changes may indicate cytoskeleton reorganization and function, and thus give information about the transport and other system impairment. Nowadays, several techniques to investigate cellular mechanical properties are available. In this review, we discuss how select biophysical methods to probe material properties could contribute to the general understanding of mechanisms underlying neurodegenerative diseases.}, }
@article {pmid30355151, year = {2019}, author = {Hofmann, JW and Seeley, WW and Huang, EJ}, title = {RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration.}, journal = {Annual review of pathology}, volume = {14}, number = {}, pages = {469-495}, pmid = {30355151}, issn = {1553-4014}, support = {R01 AA027074/AA/NIAAA NIH HHS/United States ; R01 AG057462/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; I01 BX002978/BX/BLRD VA/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 NS098516/NS/NINDS NIH HHS/United States ; I01 BX001108/BX/BLRD VA/United States ; }, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; DNA-Binding Proteins/*genetics/metabolism ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration/etiology/genetics/*metabolism ; Humans ; *Mutation ; RNA-Binding Protein FUS/*genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; TDP-43 Proteinopathies ; tau Proteins ; }, abstract = {Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.}, }
@article {pmid30352259, year = {2019}, author = {Cobos, SN and Bennett, SA and Torrente, MP}, title = {The impact of histone post-translational modifications in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1865}, number = {8}, pages = {1982-1991}, pmid = {30352259}, issn = {1879-260X}, support = {K22 NS091314/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Ataxia/genetics ; *Epigenesis, Genetic ; Frontotemporal Dementia/genetics ; *Histone Code ; Histones/analysis/genetics ; Humans ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/genetics ; *Protein Processing, Post-Translational ; }, abstract = {Every year, neurodegenerative disorders take more than 5000 lives in the US alone. Cures have not yet been found for many of the multitude of neuropathies. The majority of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) cases have no known genetic basis. Thus, it is evident that contemporary genetic approaches have failed to explain the etiology or etiologies of ALS/FTD and PD. Recent investigations have explored the potential role of epigenetic mechanisms in disease development. Epigenetics comprises heritable changes in gene utilization that are not derived from changes in the genome. A main epigenetic mechanism involves the post-translational modification of histones. Increased knowledge of the epigenomic landscape of neurodegenerative diseases would not only further our understanding of the disease pathologies, but also lead to the development of treatments able to halt their progress. Here, we review recent advances on the association of histone post-translational modifications with ALS, FTD, PD and several ataxias.}, }
@article {pmid30342424, year = {2019}, author = {Nozal, V and Martinez, A}, title = {Tau Tubulin Kinase 1 (TTBK1), a new player in the fight against neurodegenerative diseases.}, journal = {European journal of medicinal chemistry}, volume = {161}, number = {}, pages = {39-47}, doi = {10.1016/j.ejmech.2018.10.030}, pmid = {30342424}, issn = {1768-3254}, mesh = {Dose-Response Relationship, Drug ; Humans ; Models, Molecular ; Molecular Structure ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/chemistry/*pharmacology ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; }, abstract = {Tau-tubuline kinases (TTBK) are a family of serine/threonine and tyrosine kinases recently discovered and implicated in the phosphorylation of important substrates such as tau, tubuline or TDP-43. Its two homologs, TTBK1 and TTBK2, show different expression patterns and different involvements in physiological mechanisms of great importance such as mitosis, ciliogenesis and neurotransmission. Their phosphorylation activity has also linked them to the development of neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis or spinocerebellar ataxia type 11. There are currently only three inhibitors of these kinases described in the literature. This review intends to give an overview of the structure, expression, physiological and pathological mechanisms of both kinases as well as an extended analysis on the molecules that can inhibit them. The final analysis of all this information led us to propose TTBK1 as a new target for the treatment of neurodegenerative diseases and its selective inhibitors as potential effective drugs for the treatment of these severe unmet disorders.}, }
@article {pmid30336221, year = {2019}, author = {Barnabas, W}, title = {Drug targeting strategies into the brain for treating neurological diseases.}, journal = {Journal of neuroscience methods}, volume = {311}, number = {}, pages = {133-146}, doi = {10.1016/j.jneumeth.2018.10.015}, pmid = {30336221}, issn = {1872-678X}, mesh = {Animals ; Blood-Brain Barrier/physiology ; Brain/*drug effects/physiopathology ; Drug Delivery Systems/*instrumentation/*methods ; Humans ; Nervous System Diseases/*drug therapy/physiopathology ; Treatment Outcome ; }, abstract = {Brain specific drug delivery is one of the most interesting and challenging areas of research. The blood-brain barrier separates the brain from blood and acts as a barrier to protect the brain from microorganisms, neurotoxins and chemical substances. But, the same mechanism poses an obstacle for the entry of many drugs into the brain. Worldwide, approximately 1.5 billion people are suffering from CNS disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, HIV-dementia and others. This number indicates the importance of delivering drugs effectively into the brain for treating various brain diseases. The recent advancements in drug targeting, a concept was introduced by Dr. Paul Ehrlich as 'magic bullet' give lot of hopes for delivering drugs specifically to the brain regions to treat brain diseases. This review discusses about the various targeting strategies to deliver drugs into the brain for treating neurological diseases.}, }
@article {pmid30328519, year = {2018}, author = {Garcia-Santibanez, R and Burford, M and Bucelli, RC}, title = {Hereditary Motor Neuropathies and Amyotrophic Lateral Sclerosis: a Molecular and Clinical Update.}, journal = {Current neurology and neuroscience reports}, volume = {18}, number = {12}, pages = {93}, pmid = {30328519}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/metabolism ; Animals ; Biomarkers/metabolism ; Humans ; Motor Neuron Disease/*drug therapy/*genetics/metabolism ; Randomized Controlled Trials as Topic ; }, abstract = {PURPOSE OF REVIEW: This article provides an overview of recent advancements in the fields of hereditary motor neuropathies and ALS.<br><br>RECENT FINDINGS: There has been a robust growth in our knowledge and understanding of hereditary and degenerative motor neuronopathies/neuropathies over the last decade. Many breakthroughs in the field of hereditary motor neuropathies (HMN) have been associated with identification and characterization of the genes and molecular mechanisms underlying these disorders. Similar recent breakthroughs on the genetic and molecular underpinnings of the degenerative motor neuronopathy, amyotrophic lateral sclerosis (ALS), have been accompanied by advancements in biomarker research and the development and FDA approval of novel therapies. There is a reasonable hope that the marked and continued growth in our understanding of the molecular pathophysiology of the HMNs will translate into novel therapeutic approaches in the decade to come. Such breakthroughs have already begun in ALS, where novel biomarkers and treatment strategies have translated into a new FDA-approved therapy with a number of promising agents in development and/or in definitive phase 2/3 trials.}, }
@article {pmid30323119, year = {2018}, author = {Morrice, JR and Gregory-Evans, CY and Shaw, CA}, title = {Animal models of amyotrophic lateral sclerosis: A comparison of model validity.}, journal = {Neural regeneration research}, volume = {13}, number = {12}, pages = {2050-2054}, pmid = {30323119}, issn = {1673-5374}, abstract = {Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis (ALS). Measures of model validity allow for a critical interpretation of results from each model and caution from over-interpretation of experimental models. Face and construct validity refer to the similarity in phenotype and the proposed causal factor to the human disease, respectively. More recently developed models are restricted by limited phenotype characterization, yet new models hold promise for novel disease insights, thus highlighting their importance. In this article, we evaluate the features of face and construct validity of our new zebrafish model of environmentally-induced motor neuron degeneration and discuss this in the context of current environmental and genetic ALS models, including C9orf72, mutant Cu/Zn superoxide dismutase 1 and TAR DNA-binding protein 43 mouse and zebrafish models. In this mini-review, we discuss the pros and cons to validity criteria in each model. Our zebrafish model of environmentally-induced motor neuron degeneration displays convincing features of face validity with many hallmarks of ALS-like features, and weakness in construct validity. However, the value of this model may lie in its potential to be more representative of the pathogenic features underlying sporadic ALS cases, where environmental factors may be more likely to be involved in disease etiology than single dominant gene mutations. It may be necessary to compare findings between different strains and species modeling specific genes or environmental factors to confirm findings from ALS animal models and tease out arbitrary strain- and overexpression-specific effects.}, }
@article {pmid30322030, year = {2018}, author = {Konopka, A and Atkin, JD}, title = {The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {19}, number = {10}, pages = {}, pmid = {30322030}, issn = {1422-0067}, support = {10305133, 1086887, 1095215//National Health and Medical Research Council/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein/*genetics ; DNA/chemistry/genetics ; *DNA Damage ; *DNA Repeat Expansion ; Genetic Predisposition to Disease ; Humans ; Nucleic Acid Conformation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.}, }
@article {pmid30321601, year = {2020}, author = {Fournier, CN and Houser, M and Tansey, MG and Glass, JD and Hertzberg, VS}, title = {The gut microbiome and neuroinflammation in amyotrophic lateral sclerosis? Emerging clinical evidence.}, journal = {Neurobiology of disease}, volume = {135}, number = {}, pages = {104300}, doi = {10.1016/j.nbd.2018.10.007}, pmid = {30321601}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*microbiology/physiopathology ; Animals ; Brain/physiopathology ; Disease Models, Animal ; Gastrointestinal Microbiome/*physiology ; Humans ; Inflammation/metabolism/*microbiology ; Neurodegenerative Diseases/microbiology/physiopathology ; }, }
@article {pmid30318978, year = {2018}, author = {Garcia-Montojo, M and Doucet-O'Hare, T and Henderson, L and Nath, A}, title = {Human endogenous retrovirus-K (HML-2): a comprehensive review.}, journal = {Critical reviews in microbiology}, volume = {44}, number = {6}, pages = {715-738}, pmid = {30318978}, issn = {1549-7828}, support = {ZIA NS003130-08//Intramural NIH HHS/United States ; }, mesh = {Animals ; Endogenous Retroviruses/classification/genetics/*isolation &amp; purification/physiology ; Genome, Human ; Humans ; Retroviridae/classification/genetics/*isolation &amp; purification/physiology ; Retroviridae Infections/*virology ; Virus Replication ; }, abstract = {The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered "junk DNA" and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.}, }
@article {pmid30317895, year = {2018}, author = {McGown, A and Stopford, MJ}, title = {High-throughput drug screens for amyotrophic lateral sclerosis drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {11}, pages = {1015-1025}, doi = {10.1080/17460441.2018.1533953}, pmid = {30317895}, issn = {1746-045X}, support = {MR/P027989/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Artificial Intelligence ; Computer Simulation ; Disease Models, Animal ; Drug Discovery/*methods ; High-Throughput Screening Assays/*methods ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapid adult-onset neurodegenerative disorder characterised by the progressive loss of upper and lower motor neurons. Current treatment options are limited for ALS, with very modest effects on survival. Therefore, there is a unmet need for novel therapeutics to treat ALS. Areas covered: This review highlights the many diverse high-throughput screening platforms that have been implemented in ALS drug discovery. The authors discuss cell free assays including in silico and protein interaction models. The review also covers classical in vitro cell studies and new cell technologies, such as patient derived cell lines. Finally, the review looks at novel in vivo models and their use in high-throughput ALS drug discovery Expert opinion: Greater use of patient-derived in vitro cell models and development of better animal models of ALS will improve translation of lead compounds into clinic. Furthermore, AI technology is being developed to digest and interpret obtained data and to make 'hidden knowledge' usable to researchers. As a result, AI will improve target selection for high-throughput drug screening (HTDS) and aid lead compound optimisation. Furthermore, with greater genetic characterisation of ALS patients recruited to clinical trials, AI may help identify responsive genetic subtypes of patients from clinical trials.}, }
@article {pmid30307310, year = {2018}, author = {Del Olmo García, M&#xaa;D and Virgili Casas, N and Cantón Blanco, A and Lozano Fuster, FM and Wanden-Berghe, C and Avilés, V and Ashbaugh Enguídanos, R and Ferrero López, I and Molina Soria, JB and Montejo González, JC and Bretón Lesmes, I and Álvarez Hernández, J and Moreno Villares, JM and Senpe, GT&#xc9;S}, title = {[Nutritional management of amyotrophic lateral sclerosis: summary of recommendations].}, journal = {Nutricion hospitalaria}, volume = {35}, number = {5}, pages = {1243-1251}, doi = {10.20960/nh.2162}, pmid = {30307310}, issn = {1699-5198}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Guidelines as Topic ; Humans ; Nutrition Therapy/*methods ; Nutritional Requirements ; }, }
@article {pmid30305322, year = {2019}, author = {Savage, AL and Schumann, GG and Breen, G and Bubb, VJ and Al-Chalabi, A and Quinn, JP}, title = {Retrotransposons in the development and progression of amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {90}, number = {3}, pages = {284-293}, pmid = {30305322}, issn = {1468-330X}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; QUINN/APR15/843-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Humans ; Retroelements/*physiology ; }, abstract = {Endogenous retrotransposon sequences constitute approximately 42% of the human genome, and mobilisation of retrotransposons has resulted in rearrangements, duplications, deletions, novel transcripts and the introduction of new regulatory domains throughout the human genome. Both germline and somatic de novo retrotransposition events have been involved in a range of human diseases, and there is emerging evidence for the modulation of retrotransposon activity during the development of specific diseases. Particularly, there is unequivocal consensus that endogenous retrotransposition can occur in neuronal lineages. This review addresses our current knowledge of the different mechanisms through which retrotransposons might influence the development of and predisposition to amyotrophic lateral sclerosis.}, }
@article {pmid30298513, year = {2018}, author = {Gu, X and Chen, Y and Shang, H}, title = {[Roles of exosomes in Parkinson's disease and amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {35}, number = {5}, pages = {757-761}, doi = {10.3760/cma.j.issn.1003-9406.2018.05.032}, pmid = {30298513}, issn = {1003-9406}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Exosomes/genetics/*metabolism ; Humans ; Parkinson Disease/genetics/*metabolism ; }, abstract = {Exosomes, as a kind of extracellular vesicles generated by inward budding of the endosomes to form multi-vesicular bodies (MVBs), are secreted into the extracellular milieu and the systemic circulation thereafter. By endocytosis, direct fusion or receptor-ligand interactions, exosomes can interact with receptor cells and involve in various pathophysiological processes. Accumulating evidence have indicated that exosomes may play crucial roles in the pathogenesis of many neurodegenerative diseases including Parkinson's disease (PD), Huntington's disease (HD), Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS). In this paper, the roles of exosomes in the pathogenesis, diagnosis and treatment of PD and ALS are reviewed.}, }
@article {pmid30293622, year = {2018}, author = {Howard, IM and Rad, N}, title = {Electrodiagnostic Testing for the Diagnosis and Management of Amyotrophic Lateral Sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {29}, number = {4}, pages = {669-680}, doi = {10.1016/j.pmr.2018.06.003}, pmid = {30293622}, issn = {1558-1381}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Disease Management ; *Electrodiagnosis ; Humans ; }, abstract = {Electrodiagnostic testing provides insight into subclinical aspects of disease in amyotrophic lateral sclerosis and helps to diagnose and exclude other diagnoses. It may also help to manage or track disease progression. Mapping the extent of subclinical disease may guide the clinician to supportive interventions. There is considerable interest in establishing electrodiagnostic biomarkers to monitor disease progression. This article details the usefulness of electrodiagnostic testing across the disease spectrum. A review of clinical presentations and differential diagnoses, diagnostic evaluation, and emerging applications of electrodiagnostic studies to guide management and assess response to treatment interventions are presented with considerations for clinical practice.}, }
@article {pmid30291145, year = {2019}, author = {Rutkove, SB and Sanchez, B}, title = {Electrical Impedance Methods in Neuromuscular Assessment: An Overview.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {9}, number = {10}, pages = {}, pmid = {30291145}, issn = {2157-1422}, support = {K24 NS060951/NS/NINDS NIH HHS/United States ; R01 NS091159/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Electric Impedance ; Electromyography/*methods/*trends ; Humans ; Muscle, Skeletal/physiopathology ; Neuromuscular Diseases/*diagnosis/*physiopathology ; }, abstract = {Electrical impedance methods have been used as evaluation tools in biological and medical science for well over 100 years. However, only recently have these techniques been applied specifically to the evaluation of conditions affecting nerve and muscle. This specific application, termed electrical impedance myography (EIM), is finding wide application as it can provide a quantitative index of muscle condition that can assist with diagnosis, track disease progression, and assess the beneficial impact of therapy. Using noninvasive surface methods, EIM has been studied in a number of conditions ranging from amyotrophic lateral sclerosis to muscular dystrophy to disuse atrophy. Data support that the technique is sensitive to disease status and can offer the possibility of performing clinical trials with fewer subjects than would otherwise be possible. Recent advances in the field include improved approaches for using EIM as a "virtual biopsy" and the development of combined needle impedance-electromyography technology.}, }
@article {pmid30289976, year = {2019}, author = {Li, KW and Ganz, AB and Smit, AB}, title = {Proteomics of neurodegenerative diseases: analysis of human post-mortem brain.}, journal = {Journal of neurochemistry}, volume = {151}, number = {4}, pages = {435-445}, pmid = {30289976}, issn = {1471-4159}, mesh = {Alzheimer Disease/complications/metabolism ; Amyotrophic Lateral Sclerosis/complications/metabolism ; Biomarkers/metabolism ; Brain/*metabolism ; Dementia/complications/*metabolism ; Disease Progression ; Frontotemporal Dementia/complications/metabolism ; Humans ; Neurodegenerative Diseases/complications/*metabolism ; Parkinson Disease/complications/metabolism ; Proteome/*metabolism ; *Proteomics ; }, abstract = {Dementias are prevalent brain disorders in the aged population. Dementias pose major socio-medical burden, but currently there is no cure available. Novel proteomics approaches hold promise to identify alterations of the brain proteome that could provide clues on disease etiology, and identify candidate proteins to develop further as a biomarker. In this review, we focus on recent proteomics findings from brains affected with Alzheimer's Disease, Parkinson Disease Dementia, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis. These studies confirmed known cellular changes, and in addition identified novel proteins that may underlie distinct aspects of the diseases. This article is part of the special issue "Proteomics".}, }
@article {pmid30289827, year = {2018}, author = {Yin, Z and Romano, AJ and Manduca, A and Ehman, RL and Huston, J}, title = {Stiffness and Beyond: What MR Elastography Can Tell Us About Brain Structure and Function Under Physiologic and Pathologic Conditions.}, journal = {Topics in magnetic resonance imaging : TMRI}, volume = {27}, number = {5}, pages = {305-318}, pmid = {30289827}, issn = {1536-1004}, support = {R37 EB001981/EB/NIBIB NIH HHS/United States ; }, mesh = {Algorithms ; Brain/*diagnostic imaging/pathology/*physiology ; Brain Diseases/*diagnostic imaging/pathology/physiopathology ; Elasticity Imaging Techniques/*methods ; Humans ; Magnetic Resonance Imaging/*methods ; Viscosity ; }, abstract = {Brain magnetic resonance elastography (MRE) was developed on the basis of a desire to "palpate by imaging" and is becoming a powerful tool in the investigation of neurophysiological and neuropathological states. Measurements are acquired with a specialized MR phase-contrast pulse sequence that can detect tissue motion in response to an applied external or internal excitation. The tissue viscoelasticity is then reconstructed from the measured displacement. Quantitative characterization of brain viscoelastic behaviors provides us an insight into the brain structure and function by assessing the mechanical rigidity, viscosity, friction, and connectivity of brain tissues. Changes in these features are associated with inflammation, demyelination, and neurodegeneration that contribute to brain disease onset and progression. Here, we review the basic principles and limitations of brain MRE and summarize its current neuroanatomical studies and clinical applications to the most common neurosurgical and neurodegenerative disorders, including intracranial tumors, dementia, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury. Going forward, further improvement in acquisition techniques, stable inverse reconstruction algorithms, and advanced numerical, physical, and preclinical validation models is needed to increase the utility of brain MRE in both research and clinical applications.}, }
@article {pmid30289025, year = {2020}, author = {Çekici, H and Acar Tek, N}, title = {Determining energy requirement and evaluating energy expenditure in neurological diseases.}, journal = {Nutritional neuroscience}, volume = {23}, number = {7}, pages = {543-553}, doi = {10.1080/1028415X.2018.1530180}, pmid = {30289025}, issn = {1476-8305}, mesh = {*Energy Metabolism ; Exercise ; Humans ; Nervous System Diseases/diagnosis/*metabolism ; *Nutritional Physiological Phenomena ; Nutritional Requirements ; Nutritional Status ; }, abstract = {Objectives: It has been reported that in most neurological patients, resting energy expenditure due to hypermetabolism is increased. Physical activity, which is another component of energy expenditure, varies depending on the course of the disease. Different mechanisms are used to explain changes in energy expenditure in this population. Pathological problems of centers that regulate energy balance in the brain, endocrine and metabolic dysfunction, mitochondrial damage, autonomic dysfunction and inflammatory anomalies are thought to be at the root of this situation. In this review study, studies about energy expenditure and energy requirement in neurological diseases have been examined and suggested practices in this field have been presented. Methods: We reviewed articles regarding selected from PubMed, Science Direct, EBSCO, and databases about energy expenditure and neurological diseases. Results: Based on the type of neurological diseases; factors such as stage of the disease, disease complications, metabolic status, mechanical ventilation, body composition, movement restrictions or hyperactivity change energy expenditure and, as a result, nutrition requirement. Determination of the energy requirement is the basic variable for adjusting medical nutrition therapy. Despite an increase in resting energy expenditure as a result of metabolic processes in most neurological disorders, the daily energy expenditure is reported to change based on the restriction of physical activity due to the disorder. Discussion: Determining patient's energy expenditure and energy requirements is regarded as the right approach in terms of improving the patient's quality of life, regulating appropriate medical nutrition treatment and increasing the effectiveness of other treatments.}, }
@article {pmid30287192, year = {2018}, author = {Fatehi, F and Grapperon, AM and Fathi, D and Delmont, E and Attarian, S}, title = {The utility of motor unit number index: A systematic review.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {48}, number = {5}, pages = {251-259}, doi = {10.1016/j.neucli.2018.09.001}, pmid = {30287192}, issn = {1769-7131}, mesh = {Action Potentials/physiology ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/*physiopathology ; Humans ; Motor Neurons/*physiology ; Muscle, Skeletal/physiology/*physiopathology ; Nerve Degeneration/physiopathology ; Recruitment, Neurophysiological/*physiology ; }, abstract = {The need for a valid biomarker for assessing disease progression and for use in clinical trials on amyotrophic lateral sclerosis (ALS) has stimulated the study of methods that could measure the number of motor units. Motor unit number index (MUNIX) is a newly developed neurophysiological technique that was demonstrated to have a good correlation with the number of motor units in a given muscle, even though it does not necessarily accurately express the actual number of viable motor neurons. Several studies demonstrated the technique is reproducible and capable of following motor neuron loss in patients with ALS and peripheral polyneuropathies. The main goal of this review was to conduct an extensive review of the literature using MUNIX. We conducted a systematic search in English medical literature published in two databases (PubMed and SCOPUS). In this review, we aimed to answer the following queries: Comparison of MUNIX with other MUNE techniques; the reproducibility of MUNIX; the utility of MUNIX in ALS and preclinical muscles, peripheral neuropathies, and other neurological disorders.}, }
@article {pmid30280653, year = {2019}, author = {Sweeney, MD and Zhao, Z and Montagne, A and Nelson, AR and Zlokovic, BV}, title = {Blood-Brain Barrier: From Physiology to Disease and Back.}, journal = {Physiological reviews}, volume = {99}, number = {1}, pages = {21-78}, pmid = {30280653}, issn = {1522-1210}, support = {R01 AG039452/AG/NIA NIH HHS/United States ; R01 NS034467/NS/NINDS NIH HHS/United States ; R01 NS100459/NS/NINDS NIH HHS/United States ; P01 AG052350/AG/NIA NIH HHS/United States ; RF1 AG039452/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG023084/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Biological Transport/*physiology ; Blood-Brain Barrier/*pathology/*physiopathology ; Central Nervous System/pathology/*physiopathology ; Humans ; Membrane Transport Proteins/metabolism ; Neurodegenerative Diseases/*pathology/physiopathology ; Neurons/pathology ; }, abstract = {The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of the central nervous system (CNS), which maintains tightly controlled chemical composition of the neuronal milieu that is required for proper neuronal functioning. In this review, we first examine molecular and cellular mechanisms underlying the establishment of the BBB. Then, we focus on BBB transport physiology, endothelial and pericyte transporters, and perivascular and paravascular transport. Next, we discuss rare human monogenic neurological disorders with the primary genetic defect in BBB-associated cells demonstrating the link between BBB breakdown and neurodegeneration. Then, we review the effects of genes underlying inheritance and/or increased susceptibility for Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and amyotrophic lateral sclerosis (ALS) on BBB in relation to other pathologies and neurological deficits. We next examine how BBB dysfunction relates to neurological deficits and other pathologies in the majority of sporadic AD, PD, and ALS cases, multiple sclerosis, other neurodegenerative disorders, and acute CNS disorders such as stroke, traumatic brain injury, spinal cord injury, and epilepsy. Lastly, we discuss BBB-based therapeutic opportunities. We conclude with lessons learned and future directions, with emphasis on technological advances to investigate the BBB functions in the living human brain, and at the molecular and cellular level, and address key unanswered questions.}, }
@article {pmid30280317, year = {2018}, author = {Vinceti, M and Filippini, T and Wise, LA}, title = {Environmental Selenium and Human Health: an Update.}, journal = {Current environmental health reports}, volume = {5}, number = {4}, pages = {464-485}, pmid = {30280317}, issn = {2196-5412}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced ; Cardiomyopathies/chemically induced ; Cardiovascular Diseases/*chemically induced ; Chronic Disease/epidemiology ; Diabetes Mellitus, Type 2/chemically induced ; Endocrine System Diseases/*chemically induced ; Enterovirus Infections/chemically induced ; Environmental Exposure/*adverse effects ; Humans ; Male ; Neoplasms/chemically induced ; Nervous System Diseases/*chemically induced ; Parkinson Disease/etiology ; Risk Assessment ; Selenium/*adverse effects ; Trace Elements/*adverse effects ; }, abstract = {PURPOSE OF REVIEW: Selenium, a trace element, is ubiquitous in the environment. The main source of human exposure is diet. Despite its nutritional benefits, it is one of the most toxic naturally occurring elements. Selenium deficiency and overexposure have been associated with adverse health effects. Its level of toxicity may depend on its chemical form, as inorganic and organic species have distinct biological properties.<br><br>RECENT FINDINGS: Nonexperimental and experimental studies have generated insufficient evidence for a role of selenium deficiency in human disease, with the exception of Keshan disease, a cardiomyopathy. Conversely, recent randomized trials have indicated that selenium overexposure is positively associated with type 2 diabetes and high-grade prostate cancer. In addition, a natural experiment has suggested an association between overexposure to inorganic hexavalent selenium and two neurodegenerative diseases, amyotrophic lateral sclerosis and Parkinson's disease. Risk assessments should be revised to incorporate the results of studies demonstrating toxic effects of selenium. Additional observational studies and secondary analyses of completed randomized trials are needed to address the uncertainties regarding the health risks of selenium exposure.}, }
@article {pmid30269801, year = {2018}, author = {Watanabe, TK}, title = {A Review of Stem Cell Therapy for Acquired Brain Injuries and Neurodegenerative Central Nervous System Diseases.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {10}, number = {9 Suppl 2}, pages = {S151-S156}, doi = {10.1016/j.pmrj.2018.07.008}, pmid = {30269801}, issn = {1934-1563}, mesh = {Brain Injuries/*therapy ; Humans ; Neurodegenerative Diseases/*therapy ; *Recovery of Function ; Regenerative Medicine/*methods ; Stem Cell Transplantation/*methods ; }, abstract = {Cell-based therapies have been the subject of much discussion regarding their potential role in enhancing central nervous system function for a number of pathologic conditions. Much of the current research has been in preclinical trials, with clinical trials in the phase I or I/II stage. Nevertheless, there is considerable interest in the public about the potential regenerative role that stem cells may have in improving function for these neurologic conditions. This review will describe the different types of stem cells that are available, review their possible effects, and discuss some of the variables that investigators need to consider when designing their studies. Current clinical research in the areas of stroke, traumatic brain injury, and neurodegenerative diseases (amyotrophic lateral sclerosis and Parkinson disease) will be reviewed. As this article is aimed at a rehabilitation audience, outcome measures, and the role of concurrent rehabilitation therapies will also be mentioned.}, }
@article {pmid30268058, year = {2018}, author = {Low, XM and Horrigan, D and Brewster, DJ}, title = {The effects of team-training in intensive care medicine: A narrative review.}, journal = {Journal of critical care}, volume = {48}, number = {}, pages = {283-289}, doi = {10.1016/j.jcrc.2018.09.015}, pmid = {30268058}, issn = {1557-8615}, mesh = {Critical Care/*standards ; Curriculum ; Health Personnel/*education ; Humans ; Patient Care Team/organization &amp; administration/*standards ; *Simulation Training ; }, abstract = {PURPOSE: Research into team-training within healthcare is growing exponentially. We aim to evaluate the effects of team-training within intensive care medicine (ICM) through a review of the literature and a narrative synthesis of the results.<br><br>MATERIALS AND METHODS: A search of OVID Medline, EMBASE and Scopus databases was undertaken. Keywords and MESH headings included were "team-based learning", "team-training", "interdisciplinary training", "intensive care medicine", "ICU", "intensive care unit", "critical care teams" and "critical care". Relevant papers were then analysed for a narrative synthesis.<br><br>RESULTS: Our search identified 187 articles. A total of 27 papers were analysed and their outcomes were evaluated based on the Kirkpatrick four step model of evaluation.<br><br>CONCLUSIONS: Team-training has been studied in multiple ICU team types, with crew resource management (CRM) and TeamSTEPPS curricula commonly used to support teaching via simulation. Clinical skills taught have included ALS provision, ECMO initiation, advanced airway management, sepsis management and trauma response skills. Team-training in ICU is well received by staff, facilitates clinical learning, and can positively alter staff behaviors. Few clinical outcomes have been demonstrated and the duration of the behavioral effects is unclear.}, }
@article {pmid30266679, year = {2019}, author = {Masaldan, S and Bush, AI and Devos, D and Rolland, AS and Moreau, C}, title = {Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration.}, journal = {Free radical biology &amp; medicine}, volume = {133}, number = {}, pages = {221-233}, doi = {10.1016/j.freeradbiomed.2018.09.033}, pmid = {30266679}, issn = {1873-4596}, mesh = {Alzheimer Disease/drug therapy/*metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/pathology ; Brain/drug effects/metabolism/pathology ; Cognitive Dysfunction/drug therapy/metabolism/pathology ; Ferroptosis/drug effects ; Humans ; Iron/*metabolism ; Iron Chelating Agents/therapeutic use ; Lipid Peroxidation/drug effects ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy/*metabolism/pathology ; Small Molecule Libraries/therapeutic use ; }, abstract = {Perturbations in iron homeostasis and iron accumulation feature in several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Proteins such as α-synuclein, tau and amyloid precursor protein that are pathologically associated with neurodegeneration are involved in molecular crosstalk with iron homeostatic proteins. Quantitative susceptibility mapping, an MRI based non-invasive technique, offers proximal evaluations of iron load in regions of the brain and powerfully predicts cognitive decline. Further, small molecules that target elevated iron have shown promise against PD and AD in preclinical studies and clinical trials. Despite these strong links between altered iron homeostasis and neurodegeneration the molecular biology to describe the association between enhanced iron levels and neuron death, synaptic impairment and cognitive decline is ill defined. In this review we discuss the current understanding of brain iron homeostasis and how it may be perturbed under pathological conditions. Further, we explore the ramifications of a novel cell death pathway called ferroptosis that has provided a fresh impetus to the "metal hypothesis" of neurodegeneration. While lipid peroxidation plays a central role in the execution of this cell death modality the removal of iron through chelation or genetic modifications appears to extinguish the ferroptotic pathway. Conversely, tissues that harbour elevated iron may be predisposed to ferroptotic damage. These emerging findings are of relevance to neurodegeneration where ferroptotic signalling may offer new targets to mitigate cell death and dysfunction.}, }
@article {pmid30258923, year = {2017}, author = {Tiwari, M}, title = {Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities.}, journal = {Genes &amp; diseases}, volume = {4}, number = {4}, pages = {196-203}, pmid = {30258923}, issn = {2352-3042}, abstract = {Glucose 6 phosphate dehydrogenase (G6PD) is a key and rate limiting enzyme in the pentose phosphate pathway (PPP). The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). There are preponderance research findings that demonstrate the enzyme (G6PD) role in the energy balance, and it is associated with blood-related diseases and disorders, primarily the anemia resulted from G6PD deficiency. The X-linked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe. Recent advancement in biology, more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders. The neuroprotective role of the enzyme (G6PD) has also been established, as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS) produced in cerebral ischemia. Though G6PD deficiency remains a global health issue, however, a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics. Here, in this study, more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia, thus providing diagnostic and therapeutic opportunities.}, }
@article {pmid30258257, year = {2018}, author = {Singh, N and Ray, S and Srivastava, A}, title = {Clinical Mimickers of Amyotrophic Lateral Sclerosis-Conditions We Cannot Afford to Miss.}, journal = {Annals of Indian Academy of Neurology}, volume = {21}, number = {3}, pages = {173-178}, pmid = {30258257}, issn = {0972-2327}, abstract = {Giving a diagnosis of amyotrophic lateral sclerosis to a patient is akin to handing out a death certificate. However, not all patients presenting with the classical dysphagia, wasting, and weakness may have motor neuron diseases. In these cases, it is extremely important not to miss little cues which can suggest an alternative diagnosis and in many cases a lease of life in terms of a treatment option. In this review, we consider some clinical scenarios that can present with the same symptom complex as diseases involving motor neurons but have a different anatomical or etiopathological basis and in many cases even a therapeutic option.}, }
@article {pmid30258241, year = {2018}, author = {Jucker, M and Walker, LC}, title = {Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases.}, journal = {Nature neuroscience}, volume = {21}, number = {10}, pages = {1341-1349}, pmid = {30258241}, issn = {1546-1726}, support = {P50 AG025688/AG/NIA NIH HHS/United States ; P51 OD011132/OD/NIH HHS/United States ; }, mesh = {Animals ; Cell Communication ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; Prions/*metabolism/*pathogenicity ; }, abstract = {Many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by the progressive appearance of abnormal proteinaceous assemblies in the nervous system. Studies in experimental systems indicate that the assemblies originate from the prion-like seeded aggregation of specific misfolded proteins that proliferate and amass to form the intracellular and/or extracellular lesions typical of each disorder. The host in which the proteopathic seeds arise provides the biochemical and physiological environment that either supports or restricts their emergence, proliferation, self-assembly, and spread. Multiple mechanisms influence the spatiotemporal spread of seeds and the nature of the resulting lesions, one of which is the cellular uptake, release, and transport of seeds along neural pathways and networks. The characteristics of cells and regions in the affected network govern their vulnerability and thereby influence the neuropathological and clinical attributes of the disease. The propagation of pathogenic protein assemblies within the nervous system is thus determined by the interaction of the proteopathic agent and the host milieu.}, }
@article {pmid30258235, year = {2018}, author = {De Jager, PL and Yang, HS and Bennett, DA}, title = {Deconstructing and targeting the genomic architecture of human neurodegeneration.}, journal = {Nature neuroscience}, volume = {21}, number = {10}, pages = {1310-1317}, doi = {10.1038/s41593-018-0240-z}, pmid = {30258235}, issn = {1546-1726}, support = {RF1 AG036042/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG036042/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; }, mesh = {Genetic Predisposition to Disease/*genetics ; *Genomics ; Humans ; Neurodegenerative Diseases/*genetics ; }, abstract = {The field of neurodegenerative disease research has seen tremendous advances over the last two decades as new technologies and analytic methods have enabled well-powered human genomic studies. Driven first by genetic studies and more recently by transcriptomic and epigenomic studies of proper size, we have uncovered a large repertoire of loci, genes, and molecular features that are implicated in discrete, syndromically defined neurodegenerative conditions, such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Parkinson's disease. As we begin to understand the impact of these genomic features in each disease, we also appreciate that many aging individuals accumulate each of these pathologies without fulfilling criteria for syndromic diagnoses, that other pathologies are common in individuals with a given diagnosis, and that there may be shared protective factors against central nervous system injury. Thus, we now need to bring these disparate observations together into a person-centered approach that considers all neurodegenerative and protective processes simultaneously to modulate the trajectory of cognitive and functional decline that comes with brain aging.}, }
@article {pmid30258234, year = {2018}, author = {Hickman, S and Izzy, S and Sen, P and Morsett, L and El Khoury, J}, title = {Microglia in neurodegeneration.}, journal = {Nature neuroscience}, volume = {21}, number = {10}, pages = {1359-1369}, pmid = {30258234}, issn = {1546-1726}, support = {RF1 AG051506/AG/NIA NIH HHS/United States ; T32 AI007061/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Humans ; Inflammation/*etiology ; Microglia/pathology/*physiology ; *Neurodegenerative Diseases/complications/immunology/pathology ; }, abstract = {The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection. Microglia use a defined armamentarium of genes to perform these tasks. In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons. Injury to neurons in Alzheimer's, Parkinson's, Huntington's, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation. Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury. Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy.}, }
@article {pmid30257805, year = {2018}, author = {Lai, X and Gu, X and Yang, X and Sun, J and Jiang, M and Bu, B and Feng, G and Li, L}, title = {Motor neurone disease-associated neck pain misdiagnosed as cervical spondylosis: A case report and literature review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {55}, number = {}, pages = {112-115}, doi = {10.1016/j.jocn.2018.06.048}, pmid = {30257805}, issn = {1532-2653}, mesh = {*Diagnostic Errors ; Disease Progression ; Humans ; Intracranial Hypertension/etiology ; Male ; Middle Aged ; Motor Neuron Disease/complications/*diagnosis ; Neck Pain/*etiology ; Neurologic Examination ; Respiratory Insufficiency/etiology ; Spondylosis/complications/*diagnosis ; }, abstract = {BACKGROUND: Motor neurone disease (MND) is a chronic, progressive and currently incurable neurodegenerative disorder. Although pain as a symptom appears in many patients with MND, it is often misdiagnosed as other diseases when occurs before the onset of weakness. Patients are often assigned to non-neurological departments due to the atypical symptoms, which can lead to diagnostic delay and inappropriate treatment.<br><br>OBJECTIVE: To analyze the causes of misdiagnosis and improve the clinician's understanding of neck pain in patients with MND.<br><br>METHODS: We reviewed relevant literature and retrospectively reported a misdiagnosis case of MND-associated neck pain.<br><br>RESULTS: A case of MND presenting prominently as neck pain was suspected of suffering from cervical spondylosis and wrongly assigned to orthopedic clinic. When eventually being diagnosed as MND, his neck pain was found to be caused by intracranial hypertension (ICH) resulting from hypoxia via insidious respiratory failure through ventilator insufficiency.<br><br>CONCLUSION: Careful evaluation of the clinical progression of the symptoms, extensive EMG and nerve conduction study, as well as the establishment of better clinical approach to the diagnosis and higher public awareness allow a reduction of misdiagnosis.}, }
@article {pmid30250265, year = {2018}, author = {Dawson, TM and Golde, TE and Lagier-Tourenne, C}, title = {Animal models of neurodegenerative diseases.}, journal = {Nature neuroscience}, volume = {21}, number = {10}, pages = {1370-1379}, pmid = {30250265}, issn = {1546-1726}, support = {P01 CA166009/CA/NCI NIH HHS/United States ; R01 NS082205/NS/NINDS NIH HHS/United States ; R21 NS098006/NS/NINDS NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; R01 NS087227/NS/NINDS NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P50 NS038377/NS/NINDS NIH HHS/United States ; R01 AG018454/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Disease Models, Animal ; Humans ; *Neurodegenerative Diseases ; }, abstract = {Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.}, }
@article {pmid30250261, year = {2018}, author = {Sweeney, MD and Kisler, K and Montagne, A and Toga, AW and Zlokovic, BV}, title = {The role of brain vasculature in neurodegenerative disorders.}, journal = {Nature neuroscience}, volume = {21}, number = {10}, pages = {1318-1331}, pmid = {30250261}, issn = {1546-1726}, support = {R01 AG023084/AG/NIA NIH HHS/United States ; RF1 AG039452/AG/NIA NIH HHS/United States ; R01 NS034467/NS/NINDS NIH HHS/United States ; R01 NS090904/NS/NINDS NIH HHS/United States ; R01 NS100459/NS/NINDS NIH HHS/United States ; P01 AG052350/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG039452/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Blood Vessels/*pathology/*physiopathology ; Brain/*pathology ; Humans ; Neurodegenerative Diseases/*pathology ; }, abstract = {Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood-brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood-brain barrier integrity. Then we examine the role of cerebral blood flow and blood-brain barrier in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer's disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer's disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.}, }
@article {pmid30248676, year = {2018}, author = {Adams, J and Lee, M and Peng, W}, title = {Critical Review of Complementary and Alternative Medicine Use in Amyotrophic Lateral Sclerosis: Prevalence and Users' Profile, Decision-Making, Information Seeking, and Disclosure in the Face of a Lack of Efficacy.}, journal = {Neuro-degenerative diseases}, volume = {18}, number = {4}, pages = {225-232}, doi = {10.1159/000492946}, pmid = {30248676}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*therapy ; *Complementary Therapies ; Decision Making/*physiology ; *Disclosure ; Humans ; *Information Seeking Behavior ; Prevalence ; }, abstract = {BACKGROUND: Despite a lack of evidence of clinical efficacy for complementary and alternative medicine (CAM) use in amyotrophic lateral sclerosis (ALS), these medicines remain popular around the world.<br><br>OBJECTIVE: To examine the prevalence and cost of CAM use in ALS and CAM users' profile, decision-making, information seeking, and disclosure among ALS patients.<br><br>METHODS: A comprehensive literature search was conducted of MEDLINE, CINAHL/SCOPUS, and AMED databases from their inception to April 2018. This review followed PRISMA guidelines and employed a quality scoring system to assess the included papers.<br><br>RESULTS: Seven papers met the inclusion criteria and were thematically analysed. ALS patients utilized a range of CAM therapies and/or products, with acupuncture and vitamins being the most frequently reported. CAM modalities were often employed concurrently with conventional medications throughout the disease process. Although some ALS patients reported positive experience regarding CAM use, many were reluctant to disclose their CAM use to their clinicians. Research focusing on CAM use in ALS remains ad hoc and restricted to only a few countries. The rigour and quality of this research field to date has been varied, predominantly drawing upon regional/localized data and failing to report CAM users' characteristics.<br><br>CONCLUSION: A proportion of ALS patients report utilizing CAM concurrently with conventional treatments. Such use, set amidst a dearth of evidence for the efficacy of CAM in ALS, poses potential direct and indirect risks to patient care, and medical providers should be mindful of and enquire about CAM use when treating ALS patients.}, }
@article {pmid30242016, year = {2018}, author = {Benarroch, EE}, title = {Sigma-1 receptor and amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {91}, number = {16}, pages = {743-747}, doi = {10.1212/WNL.0000000000006347}, pmid = {30242016}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics ; Cell Membrane/metabolism ; Endoplasmic Reticulum/pathology ; Humans ; Receptors, sigma/*genetics ; Sigma-1 Receptor ; }, }
@article {pmid30233272, year = {2018}, author = {Fiorentino, G and Annunziata, A and Gaeta, AM and Lanza, M and Esquinas, A}, title = {Continuous noninvasive ventilation for respiratory failure in patients with amyotrophic lateral sclerosis: current perspectives.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {8}, number = {}, pages = {55-61}, pmid = {30233272}, issn = {1179-9900}, abstract = {Respiratory failure is a recognized late complication of amyotrophic lateral sclerosis. It is related to the neurological progression of the diseases with the impairment of the respiratory musculature. Survival and quality of life of amyotrophic lateral sclerosis patients is improved by using noninvasive mechanical ventilation. The rate of long-term mechanical ventilation is different within and between countries. Cultural factors, socioeconomic conditions, and physician attitude often influence the decision to start noninvasive ventilation. Technical elements, like the choice of the correct interface, solid caregivers support, and the communication between the patient and the physician are essential for achieving therapeutic goals, especially in the case of continuous treatment.}, }
@article {pmid30233056, year = {2018}, author = {Branca, JJV and Morucci, G and Pacini, A}, title = {Cadmium-induced neurotoxicity: still much ado.}, journal = {Neural regeneration research}, volume = {13}, number = {11}, pages = {1879-1882}, pmid = {30233056}, issn = {1673-5374}, abstract = {Cadmium (Cd) is a highly toxic heavy metal that accumulates in living system and as such is currently one of the most important occupational and environmental pollutants. Cd reaches into the environment by anthropogenic mobilization and it is absorbed from tobacco consumption or ingestion of contaminated substances. Its extremely long biological half-life (approximately 20-30 years in humans) and low rate of excretion from the body cause cadmium storage predominantly in soft tissues (primarily, liver and kidneys) with a diversity of toxic effects such as nephrotoxicity, hepatotoxicity, endocrine and reproductive toxicities. Moreover, a Cd-dependent neurotoxicity has been also related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and multiple sclerosis. At the cellular level, Cd affects cell proliferation, differentiation, apoptosis and other cellular activities. Among all these mechanisms, the Cd-dependent interference in DNA repair mechanisms as well as the generation of reactive oxygen species, seem to be the most important causes of its cellular toxicity. Nevertheless, there is still much to find out about its mechanisms of action and ways to reduce health risks. This article gives a brief review of the relevant mechanisms that it would be worth investigating in order to deep inside cadmium toxicity.}, }
@article {pmid30233055, year = {2018}, author = {Zhang, Z and Nie, S and Chen, L}, title = {Targeting prion-like protein spreading in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {13}, number = {11}, pages = {1875-1878}, pmid = {30233055}, issn = {1673-5374}, abstract = {The infectious template-mediated protein conversion is a unique mechanism for the onset of rare and fatal neurodegenerative disorders known as transmissible spongiform encephalopathies, or prion diseases, which affect humans and other animal species. However, emerging studies are now demonstrating prion-like mechanisms of self-propagation of protein misfolding in a number of common, non-infectious neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. It has been proposed that distinct and unrelated proteins (beta-amyloid, tau, α-synuclein, TAR DNA-binding protein 43 and huntingtin, etc.) associated with common neurodegenerative disorders can seed conversion and spread via cell-to-cell transfer, sustaining the transmission of neurotoxic agents along a stereotypic route, sharing features at the heart of the intrinsic nature of prions. Here we review the most recent development on both the molecular mechanisms underlying the pathogenesis of prion-like neurodegenerative diseases as well as innovative methods and strategies for potential therapeutic applications.}, }
@article {pmid30220791, year = {2018}, author = {Volk, AE and Weishaupt, JH and Andersen, PM and Ludolph, AC and Kubisch, C}, title = {Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis.}, journal = {Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V}, volume = {30}, number = {2}, pages = {252-258}, pmid = {30220791}, issn = {0936-5931}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5-8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2-3 years after onset. Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS. Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone. Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i. e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.}, }
@article {pmid30219376, year = {2019}, author = {Nguyen, H and Zarriello, S and Coats, A and Nelson, C and Kingsbury, C and Gorsky, A and Rajani, M and Neal, EG and Borlongan, CV}, title = {Stem cell therapy for neurological disorders: A focus on aging.}, journal = {Neurobiology of disease}, volume = {126}, number = {}, pages = {85-104}, pmid = {30219376}, issn = {1095-953X}, support = {R01 NS071956/NS/NINDS NIH HHS/United States ; R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS089851/NS/NINDS NIH HHS/United States ; R21 NS094087/NS/NINDS NIH HHS/United States ; }, mesh = {*Aging ; Animals ; Cell- and Tissue-Based Therapy/*methods/trends ; Humans ; Nervous System Diseases/*therapy ; Stem Cells ; }, abstract = {Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.}, }
@article {pmid30210294, year = {2018}, author = {Jakaria, M and Park, SY and Haque, ME and Karthivashan, G and Kim, IS and Ganesan, P and Choi, DK}, title = {Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {307}, pmid = {30210294}, issn = {1662-5099}, abstract = {Glutamate receptors play a crucial role in the central nervous system and are implicated in different brain disorders. They play a significant role in the pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although many studies on NDDs have been conducted, their exact pathophysiological characteristics are still not fully understood. In in vivo and in vitro models of neurotoxic-induced NDDs, neurotoxic agents are used to induce several neuronal injuries for the purpose of correlating them with the pathological characteristics of NDDs. Moreover, therapeutic drugs might be discovered based on the studies employing these models. In NDD models, different neurotoxic agents, namely, kainic acid, domoic acid, glutamate, β-N-Methylamino-L-alanine, amyloid beta, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, rotenone, 3-Nitropropionic acid and methamphetamine can potently impair both ionotropic and metabotropic glutamate receptors, leading to the progression of toxicity. Many other neurotoxic agents mainly affect the functions of ionotropic glutamate receptors. We discuss particular neurotoxic agents that can act upon glutamate receptors so as to effectively mimic NDDs. The correlation of neurotoxic agent-induced disease characteristics with glutamate receptors would aid the discovery and development of therapeutic drugs for NDDs.}, }
@article {pmid30208281, year = {2019}, author = {Moutinho, M and Codocedo, JF and Puntambekar, SS and Landreth, GE}, title = {Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation.}, journal = {Annual review of pharmacology and toxicology}, volume = {59}, number = {}, pages = {237-261}, pmid = {30208281}, issn = {1545-4304}, support = {RF1 AG050597/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/drug effects/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neurons/drug effects/metabolism ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Transcriptome/drug effects ; }, abstract = {Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.}, }
@article {pmid30207672, year = {2018}, author = {Santaniello, B}, title = {ALS managed care considerations.}, journal = {The American journal of managed care}, volume = {24}, number = {15 Suppl}, pages = {S336-S341}, pmid = {30207672}, issn = {1936-2692}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*economics/therapy ; Cost-Benefit Analysis ; Drug Costs ; Early Diagnosis ; Health Care Costs ; Humans ; *Managed Care Programs ; Prior Authorization/economics ; }, abstract = {As a chronic neurological disorder characterized by the progressive deterioration of neuromuscular function, amyotrophic lateral sclerosis (ALS) renders significant physical, psychological, and emotional tolls on patients, their families, and caregivers. Coupled with and contributing to the severe impact on quality of life are the substantial economic costs, which can be direct and indirect, and personal as well as societal. Understanding the magnitude and specifics of the costs accompanying ALS will provide useful perspectives to pharmacists who treat patients with ALS.}, }
@article {pmid30207671, year = {2018}, author = {Schultz, J}, title = {Disease-modifying treatment of amyotrophic lateral sclerosis.}, journal = {The American journal of managed care}, volume = {24}, number = {15 Suppl}, pages = {S327-S335}, pmid = {30207671}, issn = {1936-2692}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/therapeutic use ; Humans ; Neuroprotective Agents/therapeutic use ; Quality of Life ; Riluzole/therapeutic use ; }, abstract = {Currently, there is no cure for amyotrophic lateral sclerosis (ALS) and the foundation of ALS management revolves around symptomatic and palliative care. Early diagnosis offers the best prognosis for a longer, quality life while living with the disease. Many medications are used to relieve symptoms but there are only 2 pharmacologic agents indicated for the management of ALS. For 2 decades, riluzole had been the mainstay of disease-modifying therapy, but in 2017, edaravone became the second agent approved in the management of patients with ALS. The mechanism of either agent is not well known. Riluzole is thought to reduce damage to motor neurons through an inhibitory effect on glutamate release, while edaravone is thought to act as a neuroprotective agent that prevents oxidative stress damage as a free radical scavenger. With the lack of treatment options, it is imperative for healthcare professionals to understand the nuances of using these 2 agents to optimize therapy and quality of life for patients with ALS.}, }
@article {pmid30207670, year = {2018}, author = {Hulisz, D}, title = {Amyotrophic lateral sclerosis: disease state overview.}, journal = {The American journal of managed care}, volume = {24}, number = {15 Suppl}, pages = {S320-S326}, pmid = {30207670}, issn = {1936-2692}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/*therapy ; Disease Progression ; Early Diagnosis ; Genetic Markers ; Humans ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease that results in the progressive deterioration and loss of function of the motor neurons in the brain and spinal cord, leading to paralysis. ALS affects approximately 16,000 individuals, with a prognosis for survival of 2 to 5 years. There are 2 types of ALS differentiated by genetics: familial and sporadic (idiopathic). Diagnosis is determined by excluding other conditions and utilizing clinical examinations, laboratory tests, and nerve conduction/electromyography studies. Due to the collection of information from the participation of patients with ALS in registries, biomarkers and genes associated with ALS have been discovered. The best practices for the management of ALS include an interdisciplinary approach aimed at addressing the physical and psychological needs and desires of patients and their families and caregivers.}, }
@article {pmid30203797, year = {2018}, author = {Li, D and Li, YP and Li, YX and Zhu, XH and Du, XG and Zhou, M and Li, WB and Deng, HY}, title = {Effect of Regulatory Network of Exosomes and microRNAs on Neurodegenerative Diseases.}, journal = {Chinese medical journal}, volume = {131}, number = {18}, pages = {2216-2225}, pmid = {30203797}, issn = {2542-5641}, mesh = {Alzheimer Disease ; Amyloid beta-Peptides ; *Exosomes ; Humans ; *MicroRNAs ; Neurodegenerative Diseases/*genetics/metabolism ; }, abstract = {OBJECTIVE: A comprehensive review of the network regulation of exosomes and microRNAs (miRNAs) in neurodegenerative diseases was done, centering on the mechanism of the formation of exosomes and miRNAs and the sorting mechanism of exosomal miRNAs, with the aim to provide a theoretical basis in the search of biomarkers and the treatment of neurodegenerative diseases.<br><br>DATA SOURCES: The comprehensive search used online literature databases including NCBI PubMed, Web of Science, Google Scholar, and Baidu Scholar.<br><br>STUDY SELECTION: The study selection was based on the following keywords: exosomes, miRNAs, central nervous system (CNS), and neurodegenerative diseases. The time limit for literature retrieval was from the year 2000 to 2018, with language restriction in English. Relevant articles were carefully reviewed, with no exclusions applied to study design and publication type.<br><br>RESULTS: Exosomes are the smallest nanoscale membranous microvesicles secreted by cells and contain important miRNAs, among other rich contents. In the CNS, exosomes can transport amyloid &#x3b2;-protein, &#x3b1;-synuclein, Huntington-associated protein 1, and superoxide dismutase I to other cells. These events relieve the abnormal accumulation of proteins and aggravating neurological diseases. In some neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, miRNAs are pathologically altered as an inexorable course, suggesting that miRNAs may contribute neurodegeneration. Exosomes and miRNAs form a network to regulate the homeostasis of the CNS, both synergistically and individually.<br><br>CONCLUSION: The network of exosomes and miRNAs that regulates CNS homeostasis is a promising biomarker for the diagnosis and treatment of neurodegenerative diseases.}, }
@article {pmid30199918, year = {2019}, author = {Stangl, MK and Böcker, W and Chubanov, V and Ferrari, U and Fischereder, M and Gudermann, T and Hesse, E and Meinke, P and Reincke, M and Reisch, N and Saller, MM and Seissler, J and Schmidmaier, R and Schoser, B and Then, C and Thorand, B and Drey, M}, title = {Sarcopenia - Endocrinological and Neurological Aspects.}, journal = {Experimental and clinical endocrinology &amp; diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association}, volume = {127}, number = {1}, pages = {8-22}, doi = {10.1055/a-0672-1007}, pmid = {30199918}, issn = {1439-3646}, mesh = {*Amyotrophic Lateral Sclerosis/complications/metabolism ; Animals ; *Cushing Syndrome/complications/metabolism ; *Diabetes Mellitus, Type 2/complications/metabolism ; Humans ; *Klinefelter Syndrome/complications/metabolism ; *Renal Insufficiency, Chronic/complications/metabolism ; *Sarcopenia/diagnosis/drug therapy/etiology/metabolism ; }, abstract = {Sarcopenia in geriatric patients is often associated with or even caused by changes of the endocrine and nervous system. The multifactorial pathogenesis of sarcopenia and additional multimorbidity in geriatric patients makes it difficult to study distinct pathogenic pathways leading to sarcopenia. Patients suffering from diabetes, Cushing's syndrome, chronic kidney disease, Klinefelter's syndrome or motor neuron diseases, such as amyotrophic lateral sclerosis for example are known to have impaired muscle property and reduced physical performance. These patients are typically younger and suffer from conditions caused by a known molecular disease mechanism and a peculiar sarcopenic phenotype. Therefore, these sequelae can serve as prototypic disease models to study isolated endocrinological and neurodegenerative causes for sarcopenia. This review focuses on diseases whose etiopathogenesis of muscle impairment is known. The idea is to use these diseases as proof of principles to develop a classification algorithm of sarcopenia in the elderly to make a more mechanism-oriented therapy be possible.}, }
@article {pmid30194981, year = {2019}, author = {Fernando, R and Drescher, C and Nowotny, K and Grune, T and Castro, JP}, title = {Impaired proteostasis during skeletal muscle aging.}, journal = {Free radical biology &amp; medicine}, volume = {132}, number = {}, pages = {58-66}, doi = {10.1016/j.freeradbiomed.2018.08.037}, pmid = {30194981}, issn = {1873-4596}, mesh = {Aging/*physiology ; Animals ; Autophagy ; Humans ; Muscle, Skeletal/pathology/*physiology ; *Oxidation-Reduction ; Oxidative Stress ; Proteasome Endopeptidase Complex/*metabolism ; Protein Folding ; Proteostasis ; Reactive Oxygen Species/*isolation &amp; purification ; Ubiquitination ; }, abstract = {Aging is a complex phenomenon that has detrimental effects on tissue homeostasis. The skeletal muscle is one of the earliest tissues to be affected and to manifest age-related changes such as functional impairment and the loss of mass. Common to these alterations and to most of tissues during aging is the disruption of the proteostasis network by detrimental changes in the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal system (ALS). In fact, during aging the accumulation of protein aggregates, a process mainly driven by increased levels of oxidative stress, has been observed, clearly demonstrating UPS and ALS dysregulation. Since the UPS and ALS are the two most important pathways for the removal of misfolded and aggregated proteins and also of damaged organelles, we provide here an overview on the current knowledge regarding the connection between the loss of proteostasis and skeletal muscle functional impairment and also how redox regulation can play a role during aging. Therefore, this review serves for a better understanding of skeletal muscle aging in regard to the loss of proteostasis and how redox regulation can impact its function and maintenance.}, }
@article {pmid30182337, year = {2019}, author = {Kurtishi, A and Rosen, B and Patil, KS and Alves, GW and Møller, SG}, title = {Cellular Proteostasis in Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {56}, number = {5}, pages = {3676-3689}, pmid = {30182337}, issn = {1559-1182}, mesh = {Animals ; Endoplasmic Reticulum Stress ; Humans ; Mitochondria/pathology ; Nerve Degeneration/*metabolism/*pathology ; Protein Aggregates ; Protein Processing, Post-Translational ; *Proteostasis ; }, abstract = {The term proteostasis reflects the fine-tuned balance of cellular protein levels, mediated through a vast network of biochemical pathways. This requires the regulated control of protein folding, post-translational modification, and protein degradation. Due to the complex interactions and intersection of proteostasis pathways, exposure to stress conditions may lead to a disruption of the entire network. Incorrect protein folding and/or modifications during protein synthesis results in inactive or toxic proteins, which may overload degradation mechanisms. Further, a disruption of autophagy and the endoplasmic reticulum degradation pathway may result in additional cellular stress which could ultimately lead to cell death. Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis all share common risk factors such as oxidative stress, aging, environmental stress, and protein dysfunction; all of which alter cellular proteostasis. The differing pathologies observed in neurodegenerative diseases are determined by factors such as location-specific neuronal death, source of protein dysfunction, and the cell's ability to counter proteotoxicity. In this review, we discuss how the disruption in cellular proteostasis contributes to the onset and progression of neurodegenerative diseases.}, }
@article {pmid30174585, year = {2018}, author = {Ferrara, D and Pasetto, L and Bonetto, V and Basso, M}, title = {Role of Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {574}, pmid = {30174585}, issn = {1662-4548}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease in adults and primarily targets upper and lower motor neurons. The progression of the disease is mostly mediated by altered intercellular communication in the spinal cord between neurons and glial cells. One of the possible ways by which intercellular communication occurs is through extracellular vesicles (EVs) that are responsible for the horizontal transfer of proteins and RNAs to recipient cells. EVs are nanoparticles released by the plasma membrane and this review will describe all evidence connecting ALS, intercellular miscommunication and EVs. We mainly focus on mutant proteins causing ALS and their accumulation in EVs, along with the propensity of mutant proteins to misfold and propagate through EVs in prion-like behavior. EVs are a promising source of biomarkers and the state of the art in ALS will be discussed along with the gaps and challenges still present in this blooming field of investigation.}, }
@article {pmid30171200, year = {2018}, author = {Khalil, M and Teunissen, CE and Otto, M and Piehl, F and Sormani, MP and Gattringer, T and Barro, C and Kappos, L and Comabella, M and Fazekas, F and Petzold, A and Blennow, K and Zetterberg, H and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {10}, pages = {577-589}, doi = {10.1038/s41582-018-0058-z}, pmid = {30171200}, issn = {1759-4766}, mesh = {Aging/*metabolism ; Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Biomarkers/*metabolism ; Bipolar Disorder/diagnosis/*metabolism ; Brain Injuries, Traumatic/diagnosis/*metabolism ; Dementia/diagnosis/*metabolism ; Humans ; Huntington Disease/diagnosis/*metabolism ; Immunoassay/*methods ; Multiple Sclerosis/diagnosis/*metabolism ; Neurofilament Proteins/blood/cerebrospinal fluid/*metabolism ; Parkinson Disease/diagnosis/*metabolism ; Stroke/diagnosis/*metabolism ; }, abstract = {Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.}, }
@article {pmid30168894, year = {2019}, author = {Swash, M and Czesnik, D and de Carvalho, M}, title = {Muscular cramp: causes and management.}, journal = {European journal of neurology}, volume = {26}, number = {2}, pages = {214-221}, doi = {10.1111/ene.13799}, pmid = {30168894}, issn = {1468-1331}, mesh = {Adolescent ; Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Exercise/physiology ; Humans ; Motor Neurons/physiology ; Muscle Cramp/*etiology/physiopathology/*therapy ; }, abstract = {Muscular cramp is a common symptom in healthy people, especially among the elderly and in young people after vigorous or peak exercise. It is prominent in a number of benign neurological syndromes. It is a particular feature of chronic neurogenic disorders, especially amyotrophic lateral sclerosis. A literature review was undertaken to understand the diverse clinical associations of cramp and its neurophysiological basis, taking into account recent developments in membrane physiology and modulation of motor neuronal excitability. Many aspects of cramping remain incompletely understood and require further study. Current treatment options are correspondingly limited.}, }
@article {pmid30159171, year = {2018}, author = {Khairoalsindi, OA and Abuzinadah, AR}, title = {Maximizing the Survival of Amyotrophic Lateral Sclerosis Patients: Current Perspectives.}, journal = {Neurology research international}, volume = {2018}, number = {}, pages = {6534150}, pmid = {30159171}, issn = {2090-1852}, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that leads to loss of the upper and lower motor neurons. Almost 90% of all cases occur in the sporadic form, with the rest occurring in the familial form. The disease has a poor prognosis, with only two disease-modifying drugs approved by the United States Food and Drug Administration (FDA). The approved drugs for the disease have very limited survival benefits. Edaravone is a new FDA-approved medication that may slow the disease progression by 33% in a selected subgroup of ALS patients. This paper covers the various interventions that may provide survival benefits, such as early diagnosis, medications, gene therapy, stem cell therapy, diet, nutritional supplements, multidisciplinary clinics, and mechanical invasive and noninvasive ventilation. The recent data on masitinib, the role of enteral feeding, gene therapy, and stem cell therapy is discussed.}, }
@article {pmid30157547, year = {2018}, author = {Zhao, M and Kim, JR and van Bruggen, R and Park, J}, title = {RNA-Binding Proteins in Amyotrophic Lateral Sclerosis.}, journal = {Molecules and cells}, volume = {41}, number = {9}, pages = {818-829}, pmid = {30157547}, issn = {0219-1032}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; Animals, Genetically Modified ; Cytoplasmic Granules/metabolism ; Humans ; Models, Animal ; Mutation ; Neurons/metabolism ; RNA/metabolism ; RNA-Binding Proteins/*genetics/*metabolism ; }, abstract = {Significant research efforts are ongoing to elucidate the complex molecular mechanisms underlying amyotrophic lateral sclerosis (ALS), which may in turn pinpoint potential therapeutic targets for treatment. The ALS research field has evolved with recent discoveries of numerous genetic mutations in ALS patients, many of which are in genes encoding RNA binding proteins (RBPs), including TDP-43, FUS, ATXN2, TAF15, EWSR1, hnRNPA1, hnRNPA2/B1, MATR3 and TIA1. Accumulating evidence from studies on these ALS-linked RBPs suggests that dysregulation of RNA metabolism, cytoplasmic mislocalization of RBPs, dysfunction in stress granule dynamics of RBPs and increased propensity of mutant RBPs to aggregate may lead to ALS pathogenesis. Here, we review current knowledge of the biological function of these RBPs and the contributions of ALS-linked mutations to disease pathogenesis.}, }
@article {pmid30154300, year = {2018}, author = {Zhou, L and Ouyang, R and Chen, P and Luo, H and Wu, B and Liu, G}, title = {[Obstructive sleep apnea hypopnea syndrome and alveolar hypoventilation syndrome in motor neuron disease: A case report and literature review].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {43}, number = {1}, pages = {106-112}, doi = {10.11817/j.issn.1672-7347.2018.01.017}, pmid = {30154300}, issn = {1672-7347}, mesh = {Hemosiderosis/diagnosis/*etiology/physiopathology ; Humans ; Lung Diseases/diagnosis/*etiology/physiopathology ; Male ; Middle Aged ; Motor Neuron Disease/*complications/physiopathology ; Polysomnography ; Retrospective Studies ; Sleep Apnea, Obstructive/diagnosis/*etiology/physiopathology ; Hemosiderosis, Pulmonary ; }, abstract = {To investigate the clinical characteristics of a patient with motor neuron disease, which caused sleep-disordered breathing (SDB) and alveolar hypoventilation syndrome, and to improve the diagnosis rate for this disease. Methods: Retrospectively analyze the diagnosis and treatment process for a 52 year-old male patient, who was accepted by the Second Xiangya Hospital, Central South University because of dyspnea, shortness of breath and malaise for 4 months, and eventually was diagnosed as motor neuron disease associated with obstructive sleep apnea hypopnea syndrome and alveolar hypoventilation syndrome. In addition, we searched CNKI, Wanfang and PubMed databases to review relevant literature with keywords (motor neuron disease or amyotrophic lateral sclerosis or progressive bulbar palsy or progressive muscular atrophy or primary lateral sclerosis) AND (sleep apnea or sleep disordered breathing) from January 1990 to May 2017. Results: The major clinical manifestation of motor neuron disease included impaired upper and lower motor neuron displayed with proximal muscle weakness, muscle tremor, amyotrophy, bulbar symptoms and pyramidal sign. It was a chronic, progressive disease with worse prognosis, low survival and difficult in diagnosis. Electroneuromyography was a vital way for diagnosis. Furthermore, sleep disordered breathing was common in patients with motor neuron disease, which was featured as decreased rapid eye movement sleep, increased awaking time, apnea and hypopnea. The main mechanism for sleep disordered breathing in motor neuron disease might be due to the disturbed central nervous system and paralysis of diaphragm and respiratory muscle. Moreover, the patient suffered from restrictive ventilatory dysfunction, alveolar hypoventilation and subsequent partial pressure of carbon dioxide and hypoxemia. Therefore, respiratory failure was the most frequent cause of death for patients with motor neuron disease. Non-invasive positive pressure ventilation was suggested to apply to such patients, whose forced vital capability was less than 75 percent of predicted value. Conclusion: Sleep disordered breathing is common in patients with motor neuron disease. Hence, polysomnography is suggested as a routine examination to confirm the potential complications and give timely therapy. Treatment with non-invasive positive pressure ventilation is important for patients to improve life quality, survival rate and prognosis.}, }
@article {pmid30150420, year = {2018}, author = {Alrafiah, AR}, title = {From Mouse Models to Human Disease: An Approach for Amyotrophic Lateral Sclerosis.}, journal = {In vivo (Athens, Greece)}, volume = {32}, number = {5}, pages = {983-998}, pmid = {30150420}, issn = {1791-7549}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology/physiopathology ; Animals ; Biomarkers ; C9orf72 Protein/genetics/metabolism ; *Disease Models, Animal ; Gene Expression Regulation ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Mice ; Motor Neurons/metabolism ; Mutation ; Oxidative Stress ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; TNF Receptor-Associated Death Domain Protein/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There are several genetic mutations that lead to ALS development, such as chromosome 9 hexanucleotide repeat 72 (C9ORF72), transactive response DNA-binding protein (TARDBP), superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS). ALS is associated with disrupted gene homeostasis causing aberrant RNA processing or toxic pathology. Several animal models of ALS disease have been developed to understand whether TARDBP-mediated neurodegeneration results from a gain or a loss of function of the protein, however, none exactly mimic the pathophysiology and the phenotype of human ALS. Here, the pathophysiology of specific ALS-linked gene mutations is discussed. Furthermore, some of the generated mouse models, as well as the similarities and differences between these models, are comprehensively reviewed. Further refinement of mouse models will likely aid the development of a better form of model that mimics human ALS. However, disrupted gene homeostasis that causes mutation can result in an ALS-like syndrome, increasing concerns about whether neurodegeneration and other effects in these models are due to the mutation or to gene overexpression. Research on the pleiotropic role of different proteins present in motor neurons is also summarized. The development of better mouse models that closely mimic human ALS will help identify potential therapeutic targets for this disease.}, }
@article {pmid30149183, year = {2019}, author = {Croce, KR and Yamamoto, A}, title = {A role for autophagy in Huntington's disease.}, journal = {Neurobiology of disease}, volume = {122}, number = {}, pages = {16-22}, pmid = {30149183}, issn = {1095-953X}, support = {R01 NS063973/NS/NINDS NIH HHS/United States ; R01 NS077111/NS/NINDS NIH HHS/United States ; R01 NS101663/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Autophagy ; Humans ; Huntington Disease/genetics/*physiopathology/therapy ; }, abstract = {The lysosome-mediated degradation pathway known as macroautophagy is the most versatile means through which cells can eliminate and recycle unwanted materials. Through both selective and non-selective means, macroautophagy can degrade a wide range of cargoes from bulk cytosol to organelles and aggregated proteins. Although studies of disorders such as Parkinson's disease and Amyotrophic Lateral Sclerosis suggest that autophagic and lysosomal dysfunction directly contributes to disease, this had not been the case for the polyglutamine disorder Huntington's disease (HD), for which there was little indication of a disruption in the autophagic-lysosomal system. This supported the possibility of targeting autophagy as a much needed therapeutic approach to combat this disease. Possibly challenging this view, however, are a recent set of studies suggesting that the protein affected in Huntington's disease, huntingtin, might mechanistically contribute to macroautophagy. In this review, we will explore how autophagy might impact or be impacted by HD pathogenesis, and whether a therapeutic approach centering on autophagy may be possible for this yet incurable disease.}, }
@article {pmid30144068, year = {2019}, author = {Michetti, F and D'Ambrosi, N and Toesca, A and Puglisi, MA and Serrano, A and Marchese, E and Corvino, V and Geloso, MC}, title = {The S100B story: from biomarker to active factor in neural injury.}, journal = {Journal of neurochemistry}, volume = {148}, number = {2}, pages = {168-187}, doi = {10.1111/jnc.14574}, pmid = {30144068}, issn = {1471-4159}, support = {NaEPF 2016-033//Nando and Elsa Peretti Foundation/International ; D3-2 line 2015//Universit&#xe0; Cattolica del Sacro Cuore (UCSC)/International ; D1 line 2017//Universit&#xe0; Cattolica del Sacro Cuore (UCSC)/International ; }, mesh = {Animals ; *Biomarkers ; Humans ; *Nervous System Diseases ; *S100 Calcium Binding Protein beta Subunit ; }, abstract = {S100B is a Ca[2+] -binding protein mainly concentrated in astrocytes. Its levels in biological fluids (cerebrospinal fluid, peripheral and cord blood, urine, saliva, amniotic fluid) are recognized as a reliable biomarker of active neural distress. Although the wide spectrum of diseases in which the protein is involved (acute brain injury, neurodegenerative diseases, congenital/perinatal disorders, psychiatric disorders) reduces its specificity, its levels remain an important aid in monitoring the trend of the disorder. Mounting evidence now points to S100B as a Damage-Associated Molecular Pattern molecule which, when released at high concentration, through its Receptor for Advanced Glycation Endproducts, triggers tissue reaction to damage in a series of different neural disorders. This review addresses this novel scenario, presenting data indicating that S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease: acute brain injury (ischemic/hemorrhagic stroke, traumatic injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis), congenital/perinatal disorders (Down syndrome, spinocerebellar ataxia-1), psychiatric disorders (schizophrenia, mood disorders), inflammatory bowel disease. In many cases, over-expression/administration of the protein induces worsening of the disease, whereas its deletion/inactivation produces amelioration. This review points out that the pivotal role of the protein resulting from these data, opens the perspective that S100B may be regarded as a therapeutic target for these different diseases, which appear to share some common features reasonably attributable to neuroinflammation, regardless their origin.}, }
@article {pmid30140318, year = {2018}, author = {Antonescu, F and Adam, M and Popa, C and Tuţă, S}, title = {A review of cervical spine MRI in ALS patients.}, journal = {Journal of medicine and life}, volume = {11}, number = {2}, pages = {123-127}, pmid = {30140318}, issn = {1844-3117}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Cervical Vertebrae/*diagnostic imaging/pathology ; Diffusion Tensor Imaging ; Humans ; Magnetic Resonance Imaging/*methods/standards ; }, abstract = {Rationale. In recent years, significant advances have been made on the subject of MRI examination techniques, which have opened new avenues of research regarding the spinal involvement in amyotrophic lateral sclerosis (ALS). Objective. Our objective was to compile and analyze the available literature data, concerning the MRI of the cervical spine in ALS, detailing the metrics and their significance in diagnosis and follow-up. Methods and results. We have conducted an extensive search on the subject using literature data published over the last fifteen years, correlating it with our own experience. In ALS, there is a permanent interest in developing new biomarkers that might be sensitive to spatial and temporal patterns of neurodegeneration, which will permit early diagnosis and hopefully lead to new therapeutic approaches. Both diffusion tensor imaging (DTI) and spinal cord morphometry (especially spinal atrophy) reflect different aspects of the disease and correlate with clinical deterioration. Newer approaches like inhomogeneous magnetization transfer (ihMTR) and multiparametric analysis seem to have better sensitivity, are more appropriate for follow-up, and lend themselves to prognostic conclusions. Discussion. We conclude that MRI is a constantly expanding field, a unique non-invasive tool with immense potential in evaluating the in vivo evolution of the neurodegenerative ALS process, both structurally and functionally, with high hopes for the future. Abbreviations: ALS - amyotrophic lateral sclerosis, UMN - upper motor neuron, LMN - lower motor neuron, EMG - electromyography, CST - cortico-spinal tract, FLAIR - fluid-attenuated inversion recovery, MND - motor neuron disease, DTI - Diffusion tensor imaging, FA - fractional anisotropy, MD - mean diffusivity, ihMTR - inhomogeneous magnetization transfer, fMRI - functional MRI.}, }
@article {pmid30137990, year = {2018}, author = {Boersema, PJ and Melnik, A and Hazenberg, BPC and Rezeli, M and Marko-Varga, G and Kamiie, J and Portelius, E and Blennow, K and Zubarev, RA and Polymenidou, M and Picotti, P}, title = {Biology/Disease-Driven Initiative on Protein-Aggregation Diseases of the Human Proteome Project: Goals and Progress to Date.}, journal = {Journal of proteome research}, volume = {17}, number = {12}, pages = {4072-4084}, doi = {10.1021/acs.jproteome.8b00401}, pmid = {30137990}, issn = {1535-3907}, mesh = {Achievement ; Alzheimer Disease ; Amyloidosis ; *Goals ; Human Genome Project ; Humans ; Parkinson Disease ; *Protein Aggregation, Pathological ; Proteome/*chemistry ; Proteomics/*methods ; }, abstract = {The Biology/Disease-driven (B/D) working groups of the Human Proteome Project are alliances of research groups aimed at developing or improving proteomic tools to support specific biological or disease-related research areas. Here, we describe the activities and progress to date of the B/D working group focused on protein aggregation diseases (PADs). PADs are characterized by the intra- or extracellular accumulation of aggregated proteins and include devastating diseases such as Parkinson's and Alzheimer's disease and systemic amyloidosis. The PAD B/D working group aims for the development of proteomic assays for the quantification of aggregation-prone proteins involved in PADs to support basic and clinical research on PADs. Because the proteins in PADs undergo aberrant conformational changes, a goal is to quantitatively resolve altered protein structures and aggregation states in complex biological specimens. We have developed protein-extraction protocols and a set of mass spectrometric (MS) methods that enable the detection and quantification of proteins involved in the systemic and localized amyloidosis and the probing of aberrant protein conformational transitions in cell and tissue extracts. In several studies, we have demonstrated the potential of MS-based proteomics approaches for specific and sensitive clinical diagnoses and for the subtyping of PADs. The developed methods have been detailed in both protocol papers and manuscripts describing applications to facilitate implementation by nonspecialized laboratories, and assay coordinates are shared through public repositories and databases. Clinicians actively involved in the PAD working group support the transfer to clinical practice of the developed methods, such as assays to quantify specific disease-related proteins and their fragments in biofluids and multiplexed MS-based methods for the diagnosis and typing of systemic amyloidosis. We believe that the increasing availability of tools to precisely measure proteins involved in PADs will positively impact research on the molecular bases of these diseases and support early disease diagnosis and a more-confident subtyping.}, }
@article {pmid30135644, year = {2018}, author = {Varidaki, A and Hong, Y and Coffey, ET}, title = {Repositioning Microtubule Stabilizing Drugs for Brain Disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {226}, pmid = {30135644}, issn = {1662-5102}, abstract = {Microtubule stabilizing agents are among the most clinically useful chemotherapeutic drugs. Mostly, they act to stabilize microtubules and inhibit cell division. While not without side effects, new generations of these compounds display improved pharmacokinetic properties and brain penetrance. Neurological disorders are intrinsically associated with microtubule defects, and efforts to reposition microtubule-targeting chemotherapeutic agents for treatment of neurodegenerative and psychiatric illnesses are underway. Here we catalog microtubule regulators that are associated with Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia and mood disorders. We outline the classes of microtubule stabilizing agents used for cancer treatment, their brain penetrance properties and neuropathy side effects, and describe efforts to apply these agents for treatment of brain disorders. Finally, we summarize the current state of clinical trials for microtubule stabilizing agents under evaluation for central nervous system disorders.}, }
@article {pmid30131665, year = {2018}, author = {Sirabella, R and Valsecchi, V and Anzilotti, S and Cuomo, O and Vinciguerra, A and Cepparulo, P and Brancaccio, P and Guida, N and Blondeau, N and Canzoniero, LMT and Franco, C and Amoroso, S and Annunziato, L and Pignataro, G}, title = {Ionic Homeostasis Maintenance in ALS: Focus on New Therapeutic Targets.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {510}, pmid = {30131665}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most threatening neurodegenerative disease since it causes muscular paralysis for the loss of Motor Neurons in the spinal cord, brainstem and motor cortex. Up until now, no effective pharmacological treatment is available. Two forms of ALS have been described so far: 90% of the cases presents the sporadic form (sALS) whereas the remaining 10% of the cases displays the familiar form (fALS). Approximately 20% of fALS is associated with inherited mutations in the Cu, Zn-superoxide dismutase 1 (SOD1) gene. In the last decade, ionic homeostasis dysregulation has been proposed as the main trigger of the pathological cascade that brings to motor-neurons loss. In the light of these premises, the present review will analyze the involvement in ALS pathophysiology of the most well studied metal ions, i.e., calcium, sodium, iron, copper and zinc, with particular focus to the role of ionic channels and transporters able to contribute in the regulation of ionic homeostasis, in order to propose new putative molecular targets for future therapeutic strategies to ameliorate the progression of this devastating neurodegenerative disease.}, }
@article {pmid30131172, year = {2019}, author = {Delpont, B and Beauvais, K and Jacquin-Piques, A and Alavoine, V and Rault, P and Blanc-Labarre, C and Osseby, GV and Hervieu-Bègue, M and Giroud, M and Béjot, Y}, title = {Clinical features of pain in amyotrophic lateral sclerosis: A clinical challenge.}, journal = {Revue neurologique}, volume = {175}, number = {1-2}, pages = {11-15}, doi = {10.1016/j.neurol.2017.11.009}, pmid = {30131172}, issn = {0035-3787}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/*complications/pathology ; Disease Progression ; Humans ; Musculoskeletal Pain/etiology/pathology ; Neuralgia/etiology/pathology ; Pain/*etiology/pathology ; Quality of Life ; }, abstract = {Pain in amyotrophic lateral sclerosis (ALS) is paradoxical in this disease of the upper and lower motor neurons. As such, it remains an underestimated and neglected clinical problem because it is poorly identified by physicians, its mechanisms are numerous and its treatments are generally not effective. Pain may be primary in the form of cramps, spasticity and neuropathy, or secondary as nociceptive pain, and may arise before the first motor symptoms. It may also lead to depression and, in all cases, affect patients' daily activities and quality of life. Given the high frequency of pain in ALS, the use of analgesic or sedative drugs is necessary and should reduce the course of the disease. Nevertheless, it is important to understand the pathophysiological mechanisms of pain in ALS, and to train physicians how to detect ALS pain early on and provide dedicated treatments. In France, the implementation of ALS centers is a positive response to the public-health problem resulting from this disorder.}, }
@article {pmid30126171, year = {2018}, author = {Olesnicky, EC and Wright, EG}, title = {Drosophila as a Model for Assessing the Function of RNA-Binding Proteins during Neurogenesis and Neurological Disease.}, journal = {Journal of developmental biology}, volume = {6}, number = {3}, pages = {}, pmid = {30126171}, issn = {2221-3759}, abstract = {An outstanding question in developmental neurobiology is how RNA processing events contribute to the regulation of neurogenesis. RNA processing events are increasingly recognized as playing fundamental roles in regulating multiple developmental events during neurogenesis, from the asymmetric divisions of neural stem cells, to the generation of complex and diverse neurite morphologies. Indeed, both asymmetric cell division and neurite morphogenesis are often achieved by mechanisms that generate asymmetric protein distributions, including post-transcriptional gene regulatory mechanisms such as the transport of translationally silent messenger RNAs (mRNAs) and local translation of mRNAs within neurites. Additionally, defects in RNA splicing have emerged as a common theme in many neurodegenerative disorders, highlighting the importance of RNA processing in maintaining neuronal circuitry. RNA-binding proteins (RBPs) play an integral role in splicing and post-transcriptional gene regulation, and mutations in RBPs have been linked with multiple neurological disorders including autism, dementia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Fragile X syndrome (FXS), and X-linked intellectual disability disorder. Despite their widespread nature and roles in neurological disease, the molecular mechanisms and networks of regulated target RNAs have been defined for only a small number of specific RBPs. This review aims to highlight recent studies in Drosophila that have advanced our knowledge of how RBP dysfunction contributes to neurological disease.}, }
@article {pmid30121249, year = {2018}, author = {Aymerich, MS and Aso, E and Abellanas, MA and Tolon, RM and Ramos, JA and Ferrer, I and Romero, J and Fernández-Ruiz, J}, title = {Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.}, journal = {Biochemical pharmacology}, volume = {157}, number = {}, pages = {67-84}, doi = {10.1016/j.bcp.2018.08.016}, pmid = {30121249}, issn = {1873-2968}, mesh = {Alzheimer Disease/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Cannabinoids/pharmacology/*therapeutic use ; Chronic Disease ; Endocannabinoids/metabolism ; Humans ; Huntington Disease/drug therapy/metabolism ; Mice ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases. In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration. Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects. Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS. Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.}, }
@article {pmid30120734, year = {2019}, author = {Abati, E and Bresolin, N and Comi, GP and Corti, S}, title = {Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy.}, journal = {Molecular neurobiology}, volume = {56}, number = {5}, pages = {3356-3367}, pmid = {30120734}, issn = {1559-1182}, support = {02362317//Ministero della Salute/ ; Optimized Transplantation of hiPSC derived LeX+CXCR4+VLA4 neural stem cells as a therapy for SMARD1//AFM-T&#xe9;l&#xe9;thon/ ; 612578//FP7 People: Marie-Curie Actions/ ; }, mesh = {Cell Hypoxia ; Cell Survival ; Humans ; *Metabolic Engineering ; Motor Neuron Disease/*therapy ; Neural Stem Cells/*transplantation ; Neurogenesis ; Translational Research, Biomedical ; }, abstract = {Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders.}, }
@article {pmid30120348, year = {2018}, author = {Balendra, R and Isaacs, AM}, title = {C9orf72-mediated ALS and FTD: multiple pathways to disease.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {9}, pages = {544-558}, pmid = {30120348}, issn = {1759-4766}, support = {//Wellcome Trust/United Kingdom ; 107196//Wellcome Trust/United Kingdom ; 648716/ERC_/European Research Council/International ; ISAACS/APR15/834-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/therapy ; Animals ; *C9orf72 Protein/genetics ; *Disease Models, Animal ; *Frontotemporal Dementia/genetics/metabolism/pathology/therapy ; Humans ; }, abstract = {The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.}, }
@article {pmid30116173, year = {2018}, author = {Verma, M and Wills, Z and Chu, CT}, title = {Excitatory Dendritic Mitochondrial Calcium Toxicity: Implications for Parkinson's and Other Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {523}, pmid = {30116173}, issn = {1662-4548}, support = {R01 NS065789/NS/NINDS NIH HHS/United States ; R21 MH107966/MH/NIMH NIH HHS/United States ; R56 NS065789/NS/NINDS NIH HHS/United States ; R01 AG026389/AG/NIA NIH HHS/United States ; R01 NS101628/NS/NINDS NIH HHS/United States ; }, abstract = {Dysregulation of calcium homeostasis has been linked to multiple neurological diseases. In addition to excitotoxic neuronal cell death observed following stroke, a growing number of studies implicate excess excitatory neuronal activity in chronic neurodegenerative diseases. Mitochondria function to rapidly sequester large influxes of cytosolic calcium through the activity of the mitochondrial calcium uniporter (MCU) complex, followed by more gradual release via calcium antiporters, such as NCLX. Increased cytosolic calcium levels almost invariably result in increased mitochondrial calcium uptake. While this response may augment mitochondrial respiration, limiting classic excitotoxic injury in the short term, recent studies employing live calcium imaging and molecular manipulation of calcium transporter activities suggest that mitochondrial calcium overload plays a key role in Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and related dementias [PD with dementia (PDD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)]. Herein, we review the literature on increased excitatory input, mitochondrial calcium dysregulation, and the transcriptional or post-translational regulation of mitochondrial calcium transport proteins, with an emphasis on the PD-linked kinases LRRK2 and PINK1. The impact on pathological dendrite remodeling and neuroprotective effects of manipulating MCU, NCLX, and LETM1 are reviewed. We propose that shortening and simplification of the dendritic arbor observed in neurodegenerative diseases occur through a process of excitatory mitochondrial toxicity (EMT), which triggers mitophagy and perisynaptic mitochondrial depletion, mechanisms that are distinct from classic excitotoxicity.}, }
@article {pmid30116051, year = {2018}, author = {Boland, B and Yu, WH and Corti, O and Mollereau, B and Henriques, A and Bezard, E and Pastores, GM and Rubinsztein, DC and Nixon, RA and Duchen, MR and Mallucci, GR and Kroemer, G and Levine, B and Eskelinen, EL and Mochel, F and Spedding, M and Louis, C and Martin, OR and Millan, MJ}, title = {Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.}, journal = {Nature reviews. Drug discovery}, volume = {17}, number = {9}, pages = {660-688}, pmid = {30116051}, issn = {1474-1784}, support = {MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; P01 AG017617/AG/NIA NIH HHS/United States ; UKDRI-2002/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging/*metabolism ; Animals ; Autophagy/physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Neurotoxins/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; }, abstract = {Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.}, }
@article {pmid30114473, year = {2018}, author = {Spielman, LJ and Gibson, DL and Klegeris, A}, title = {Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {120}, number = {}, pages = {149-163}, doi = {10.1016/j.neuint.2018.08.005}, pmid = {30114473}, issn = {1872-9754}, mesh = {Animals ; Brain/*metabolism ; Gastrointestinal Microbiome/*physiology ; Gastrointestinal Tract/*metabolism ; Humans ; Inflammation/*metabolism ; Microbiota ; Neurodegenerative Diseases/*metabolism ; }, abstract = {The number of bacterial cells living within the human body is approximately equal to, or greater than, the total number of human cells. This dynamic population of microorganisms, termed the human microbiota, resides mainly within the gastrointestinal tract. It is widely accepted that highly diverse and stable microbiota promote overall human health. Colonization of the gut with maladaptive and pathogenic microbiota, a state also known as dysbiosis, is associated with a variety of peripheral diseases ranging from type 2 diabetes mellitus to cardiovascular and inflammatory bowel disease. More recently, microbial dysbiosis has been associated with a number of brain pathologies, including autism spectrum disorder, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), suggesting a direct or indirect communication between intestinal bacteria and the central nervous system (CNS). In this review, we illustrate two pathways implicated in the crosstalk between gut microbiota and CNS involving 1) the vagus nerve and 2) transmission of signaling molecules through the circulatory system and across the blood-brain barrier (BBB). We summarize the available evidence of the specific changes in the intestinal microbiota, as well as microorganism-induced modifications to intestinal and BBB permeability, which have been linked to several neurodegenerative disorders including ALS, AD, and PD. Even though each of these diseases arises from unique pathogenetic mechanisms, all are characterized, at least in part, by chronic neuroinflammation. We provide an interpretation for the substantial evidence that healthy intestinal microbiota have the ability to positively regulate the neuroimmune responses in the CNS. Even though the evidence is mainly associative, it has been suggested that bacterial dysbiosis could contribute to an adverse neuroinflammatory state leading to increased risk of neurodegenerative diseases. Thus, developing strategies for regulating and maintaining healthy intestinal microbiota could be a valid approach for lowering individual risk and prevalence of neurodegenerative diseases.}, }
@article {pmid31225466, year = {2018}, author = {Jutzi, D and Akinyi, MV and Mechtersheimer, J and Frilander, MJ and Ruepp, MD}, title = {The emerging role of minor intron splicing in neurological disorders.}, journal = {Cell stress}, volume = {2}, number = {3}, pages = {40-54}, pmid = {31225466}, issn = {2523-0204}, abstract = {Pre-mRNA splicing is an essential step in eukaryotic gene expression. Mutations in cis-acting sequence elements within pre-mRNA molecules or trans-acting factors involved in pre-mRNA processing have both been linked to splicing dysfunction that give rise to a large number of human diseases. These mutations typically affect the major splicing pathway, which excises more than 99% of all introns in humans. However, approximately 700-800 human introns feature divergent intron consensus sequences at their 5' and 3' ends and are recognized by a separate pre-mRNA processing machinery denoted as the minor spliceosome. This spliceosome has been studied less than its major counterpart, but has received increasing attention during the last few years as a novel pathomechanistic player on the stage in neurodevelopmental and neurodegenerative diseases. Here, we review the current knowledge on minor spliceosome function and discuss its potential pathomechanistic role and impact in neurodegeneration.}, }
@article {pmid30966253, year = {2018}, author = {Díez-Pascual, AM and Luceño Sánchez, JA and Peña Capilla, R and García Díaz, P}, title = {Recent Developments in Graphene/Polymer Nanocomposites for Application in Polymer Solar Cells.}, journal = {Polymers}, volume = {10}, number = {2}, pages = {}, pmid = {30966253}, issn = {2073-4360}, support = {//Fundaci&#xf3;n Iberdrola Espa&#xf1;a/ ; }, abstract = {Graphene (G) and its derivatives, graphene oxide (GO) and reduced graphene oxide (rGO) have enormous potential for energy applications owing to their 2D structure, large specific surface area, high electrical and thermal conductivity, optical transparency, and huge mechanical strength combined with inherent flexibility. The combination of G-based materials with polymers leads to new nanocomposites with enhanced structural and functional properties due to synergistic effects. This review briefly summarizes recent progress in the development of G/polymer nanocomposites for use in polymer solar cells (PSCs). These nanocomposites have been explored as transparent conducting electrodes (TCEs), active layers (ALs) and interfacial layers (IFLs) of PSCs. Photovoltaic parameters, such as the open-circuit voltage (Voc), short-circuit current density (Jsc), fill factor (FF) and power-conversion efficiency (PCE) are compared for different device structures. Finally, future perspectives are discussed.}, }
@article {pmid30603519, year = {2017}, author = {Lee, JY and Kim, HS}, title = {Extracellular Vesicles in Neurodegenerative Diseases: A Double-Edged Sword.}, journal = {Tissue engineering and regenerative medicine}, volume = {14}, number = {6}, pages = {667-678}, pmid = {30603519}, issn = {2212-5469}, abstract = {Extracellular vesicles (EVs), a heterogenous group of membrane-bound particles, are virtually secreted by all cells and play important roles in cell-cell communication. Loaded with proteins, mRNAs, non-coding RNAs and membrane lipids from their donor cells, these vesicles participate in normal physiological and pathogenic processes. In addition, these sub-cellular vesicles are implicated in the progression of neurodegenerative disorders. Accumulating evidence suggests that intercellular communication via EVs is responsible for the propagation of key pathogenic proteins involved in the pathogenesis of amyotrophic lateral sclerosis, Parkinson's diseases, Alzheimer's diseases and other neurodegenerative disorders. For therapeutic perspective, EVs present advantage over other synthetic drug delivery systems or cell therapy; ability to cross biological barriers including blood brain barrier (BBB), ability to modulate inflammation and immune responses, stability and longer biodistribution with lack of tumorigenicity. In this review, we summarized the current state of EV research in central nervous system in terms of their values in diagnosis, disease pathology and therapeutic applications.}, }
@article {pmid32309596, year = {2017}, author = {Wang, X and Noroozian, Z and Lynch, M and Armstrong, N and Schneider, R and Liu, M and Ghodrati, F and Zhang, AB and Yang, YJ and Hall, AC and Solarski, M and Killackey, SA and Watts, JC}, title = {Strains of Pathological Protein Aggregates in Neurodegenerative Diseases.}, journal = {Discoveries (Craiova, Romania)}, volume = {5}, number = {3}, pages = {e78}, pmid = {32309596}, issn = {2359-7232}, abstract = {The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.}, }
@article {pmid32095743, year = {2017}, author = {Dorsey, ER and Papapetropoulos, S and Xiong, M and Kieburtz, K}, title = {The First Frontier: Digital Biomarkers for Neurodegenerative Disorders.}, journal = {Digital biomarkers}, volume = {1}, number = {1}, pages = {6-13}, pmid = {32095743}, issn = {2504-110X}, abstract = {Current measures of neurodegenerative diseases are highly subjective and based on episodic visits. Consequently, drug development decisions rely on sparse, subjective data, which have led to the conduct of large-scale phase 3 trials of drugs that are likely not effective. Such failures are costly, deter future investment, and hinder the development of treatments. Given the lack of reliable physiological biomarkers, digital biomarkers may help to address current shortcomings. Objective, high-frequency data can guide critical decision-making in therapeutic development and allow for a more efficient evaluation of therapies of increasingly common disorders.}, }
@article {pmid30276283, year = {2016}, author = {Rosenberg, JT and Yuan, X and Grant, S and Ma, T}, title = {Tracking mesenchymal stem cells using magnetic resonance imaging.}, journal = {Brain circulation}, volume = {2}, number = {3}, pages = {108-113}, pmid = {30276283}, issn = {2455-4626}, abstract = {Recent translational studies in the fields of tissue regeneration and cell therapy have characterized mesenchymal stem cells (MSCs) as a potentially effective and accessible measure for treating ischemic cerebral and neurodegenerative disorders such as stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Developing more efficient cell tracking techniques bear the potential to optimize MSC transplantation therapies by providing a more accurate picture of the fate and area of effect of implanted cells. Currently, determining the location of transplanted MSCs involves a histological approach, but magnetic resonance imaging (MRI) presents a noninvasive paradigm that permits repeat evaluations. To visualize MSCs using MRI, the implanted cells must be treated with an intracellular contrast agent. These are commonly paramagnetic compounds, many of which are based on superparamagnetic iron oxide (SPIO) nanoparticles. Recent research has set out characterize the effects of SPIO-uptake on the cellular activity of in vitro human MSCs and the resultant influence that respective SPIO concentration has on MRI sensitivity. As these studies reveal, SPIO-uptake has no effect on the cellular processes of proliferation and differentiation while producing high contrast MRI signals. Moreover, transplantation of SPIO-labeled MSCs in animal models encouragingly showed no loss in MRI contrast, suggesting that SPIO labeling may be an appealing regime for lasting MRI detection. This study is a review article. Referred literature in this study has been listed in the reference part. The datasets supporting the conclusions of this article are available online by searching the PubMed. Some original points in this article come from the laboratory practice in our research centers and the authors' experiences.}, }
@article {pmid30214954, year = {2016}, author = {Burke, D}, title = {Clinical uses of H reflexes of upper and lower limb muscles.}, journal = {Clinical neurophysiology practice}, volume = {1}, number = {}, pages = {9-17}, pmid = {30214954}, issn = {2467-981X}, abstract = {H reflexes can be recorded from virtually all muscles that have muscle spindles, but reflex reinforcement may be required for the reflex response to be demonstrable. This can allow conduction across proximal nerve segments and most nerve root segments commonly involved by pathology. Stimulus rate is critical in subjects who are at rest. However the reflex attenuation with higher rates is greatly reduced during a background contraction of the test muscle, with only minor changes in latency if any. In addition the contraction ensures that the reflex response occurs in the desired muscle. Reflex latencies should be corrected for height (or limb length) and age. Because the reflex discharge requires a synchronised volley in group Ia afferents, large increases in reflex latency occur rarely with purely sensory lesions. If the H reflex of soleus, quadriceps femoris or flexor carpi radialis is absent at rest but appears during a voluntary contraction at near-normal latency, there is either low central excitability or a predominantly sensory abnormality. With the former H reflexes will be difficult to elicit throughout the body. If H reflexes can be recorded at rest from muscles for which no reflex can normally be demonstrated, there is good evidence for hyperreflexia. In the context of possible ALS, this is an important finding when there is EMG evidence of chronic partial denervation in that muscle.}, }
@article {pmid30713928, year = {2016}, author = {Schneider, SA and Bird, T}, title = {Huntington's Disease, Huntington's Disease Look-Alikes‎, and Benign Hereditary Chorea: What's New?.}, journal = {Movement disorders clinical practice}, volume = {3}, number = {4}, pages = {342-354}, pmid = {30713928}, issn = {2330-1619}, abstract = {BACKGROUND: The differential diagnosis of chorea syndromes is complex. It includes inherited forms, the most common of which is autosomal dominant Huntington's disease (HD). In addition, there are disorders mimicking HD, the so-called HD-like (HDL) syndromes.<br><br>METHODS AND RESULTS: Here we review main clinical, genetic, and pathophysiological characteristics of HD and the rare HD phenocopies in order to familiarize clinicians with them. Molecular studies have shown that HD phenocopies account for about 1% of suspected HD cases, most commonly due to mutations in C9orf72 (also the main cause of frontotemporal dementia and amyotrophic lateral sclerosis syndromes), TATA box-binding protein (spinocerebellar ataxia type 17 [SCA17]/HDL4), and JPH3 (HDL2). Systematic screening studies also revealed mutations in PRNP (prion disease), VPS13A (chorea-acanthocytosis), ATXN8OS-ATXN8 (SCA8), and FXN (late-onset Friedreich's Ataxia) in single cases. Further differential diagnoses to consider in patients presenting with a clinical diagnosis consistent with HD, but without the HD expansion, include dentatorubral-pallidoluysian atrophy and benign hereditary chorea (TITF1), as well as the recently described form of ADCY5-associated neurodegeneration. Lastly, biallelic mutations in RNF216 and FRRS1L have recently been reported as autosomal recessive phenocopies of HD.<br><br>CONCLUSION: There is a growing list of genes associated with chorea, yet a substantial percentage of patients remain undiagnosed. It is likely that more genes will be discovered in the future and that the clinical spectrum of the described disorders will broaden.}, }
@article {pmid32545936, year = {2014}, author = {Finke, G}, title = {[Constanze Mozarts Tätigkeiten als Nachlassverwalterin im Kontext der Wissenskulturen um 1800].}, journal = {Berichte zur Wissenschaftsgeschichte}, volume = {37}, number = {3}, pages = {201-215}, doi = {10.1002/bewi.201401681}, pmid = {32545936}, issn = {1522-2365}, abstract = {Constanze Mozart's Activities as Trustee of the Estate in the Context of Memorial Cultures around 1800. After Wolfgang Amadé Mozart's death in 1791, Constanze Mozart established memorial practices to bring her husband's name and his music into the musical canon. At first she organized concerts to promote his name and music. She continued by publishing his compositions with Breitkopf &amp; Härtel in Leipzig and Johann Anton André between 1798 and 1802. Many years later, in 1828, she published a biography with her second husband, Georg Nikolaus Nissen. Her actions gained importance with the occurrence of bourgeois musical memorial cultures around 1800. These started to be organized around the musical estates of composers. Thus, the material quality of music became a dominant factor for organizing musical culture, and historiography as a whole within the nineteenth century. However, the activities of Constanze Mozart, as of other widows, have been marginalized. Memory is intertwined with gender constructions and processes of professionalization of musical historiography in the nineteenth century. The theoretical framework of memory research offers a vocabulary to analyze activities of widows in musical cultures and requires the deconstruction of the narrative of the "composer's widow". It also offers a way to highlight the importance of individual commitment for processes of cultural memory.}, }
@article {pmid30101496, year = {2019}, author = {Jaiswal, MK}, title = {Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs.}, journal = {Medicinal research reviews}, volume = {39}, number = {2}, pages = {733-748}, doi = {10.1002/med.21528}, pmid = {30101496}, issn = {1098-1128}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Disease Models, Animal ; Disease Progression ; Drug Design ; Edaravone/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Riluzole/*therapeutic use ; }, abstract = {Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I-III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages. The newly approved drug edaravone is a force multiplier for ALS treatment. This short report provides an overview of the two drugs that have been approved for ALS treatment and highlights an update on the timeline of drug development, how clinical trials were done, the outcome of these trials, primary endpoint, mechanism of actions, dosing information, administration, side effects, and storage procedures. Moreover, we also discussed the pressing issues and challenges of ALS clinical trials and drug developments as well as future outlook.}, }
@article {pmid30100896, year = {2018}, author = {Linse, K and Aust, E and Joos, M and Hermann, A}, title = {Communication Matters-Pitfalls and Promise of Hightech Communication Devices in Palliative Care of Severely Physically Disabled Patients With Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {603}, pmid = {30100896}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, leading to progressive paralysis, dysarthria, dysphagia, and respiratory disabilities. Therapy is mostly focused on palliative interventions. During the course of the disease, verbal as well as nonverbal communicative abilities become more and more impaired. In this light, communication has been argued to be "the essence of human life" and crucial for patients' quality of life. High-tech augmentative and alternative communication (HT-AAC) technologies such as eyetracking based computer devices and brain-computer-interfaces provide the possibility to maintain caregiver-independent communication and environmental control even in the advanced disease state of ALS. Thus, they enable patients to preserve social participation and to independently communicate end-of-life-decisions. In accordance with these functions of HT-AAC, their use is reported to strengthen self-determination, increase patients' quality of life and reduce caregiver burden. Therefore, HT-AAC should be considered as standard of (palliative) care for people with ALS. On the other hand, the supply with individually tailored HT-AAC technologies is limited by external and patient-inherent variables. This review aims to provide an overview of the possibilities and limitations of HT-AAC technologies and discuss their role in the palliative care for patients with ALS.}, }
@article {pmid30097809, year = {2018}, author = {Siddiqi, KS and Husen, A and Sohrab, SS and Yassin, MO}, title = {Recent Status of Nanomaterial Fabrication and Their Potential Applications in Neurological Disease Management.}, journal = {Nanoscale research letters}, volume = {13}, number = {1}, pages = {231}, pmid = {30097809}, issn = {1931-7573}, abstract = {Nanomaterials (NMs) are receiving remarkable attention due to their unique properties and structure. They vary from atoms and molecules along with those of bulk materials. They can be engineered to act as drug delivery vehicles to cross blood-brain barriers (BBBs) and utilized with better efficacy and safety to deliver specific molecules into targeted cells as compared to conventional system for neurological disorders. Depending on their properties, various metal chelators, gold nanoparticles (NPs), micelles, quantum dots, polymeric NPs, liposomes, solid lipid NPs, microparticles, carbon nanotubes, and fullerenes have been utilized for various purposes including the improvement of drug delivery system, treatment response assessment, diagnosis at early stage, and management of neurological disorder by using neuro-engineering. BBB regulates micro- and macromolecule penetration/movement, thus protecting it from many kinds of illness. This phenomenon also prevents drug delivery for the neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, and primary brain tumors. For some neurological disorders (AD and PD), the environmental pollution was considered as a major cause, as observed that metal and/or metal oxide from different sources are inhaled and get deposited in the lungs/brain. Old age, obesity, diabetes, and cardiovascular disease are other factors for rapid deterioration of human health and onset of AD. In addition, gene mutations have also been examined to cause the early onset familial forms of AD. AD leads to cognitive impairment and plaque deposits in the brain leading to neuronal cell death. Based on these facts and considerations, this review elucidates the importance of frequently used metal chelators, NMs and/or NPs. The present review also discusses the current status and future challenges in terms of their application in drug delivery for neurological disease management.}, }
@article {pmid30097696, year = {2018}, author = {Cheng, J and Korte, N and Nortley, R and Sethi, H and Tang, Y and Attwell, D}, title = {Targeting pericytes for therapeutic approaches to neurological disorders.}, journal = {Acta neuropathologica}, volume = {136}, number = {4}, pages = {507-523}, pmid = {30097696}, issn = {1432-0533}, support = {A1188//Rosetrees Trust/International ; 099222/Z/12/Z//Wellcome Trust/United Kingdom ; 2017YFC1307500//National Key R&amp;D Program of China/International ; M153F2//Rosetrees Trust (GB) and Stoneygate Trust/International ; 2017YFC1307504//National Key R&amp;D Program of China/International ; 81622041//National Natural Science Foundation of China/International ; //Wellcome Trust/United Kingdom ; //Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Blood-Brain Barrier/pathology ; Capillaries/pathology ; Humans ; Nervous System Diseases/genetics/*pathology ; Pericytes/*pathology ; }, abstract = {Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood-brain barrier. Pericytes, an under-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood-brain barrier, capillary blood flow and the movement of immune cells into the brain. They also form part of the "glial" scar isolating damaged parts of the CNS, and may have stem cell-like properties. Recent studies have suggested that pericytes play a crucial role in neurological diseases, and are thus a therapeutic target in disorders as diverse as stroke, traumatic brain injury, migraine, epilepsy, spinal cord injury, diabetes, Huntington's disease, Alzheimer's disease, diabetes, multiple sclerosis, glioma, radiation necrosis and amyotrophic lateral sclerosis. Here we report recent advances in our understanding of pericyte biology and discuss how pericytes could be targeted to develop novel therapeutic approaches to neurological disorders, by increasing blood flow, preserving blood-brain barrier function, regulating immune cell entry to the CNS, and modulating formation of blood vessels in, and the glial scar around, damaged regions.}, }
@article {pmid30095897, year = {2019}, author = {Savelieff, MG and Nam, G and Kang, J and Lee, HJ and Lee, M and Lim, MH}, title = {Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the Last Decade.}, journal = {Chemical reviews}, volume = {119}, number = {2}, pages = {1221-1322}, doi = {10.1021/acs.chemrev.8b00138}, pmid = {30095897}, issn = {1520-6890}, mesh = {Alzheimer Disease/*drug therapy/pathology ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Biological Products/chemistry/therapeutic use ; Drug Discovery ; Humans ; Metals/chemistry/metabolism ; Nerve Tissue Proteins/chemistry/metabolism ; Oxidative Stress ; Parkinson Disease/*drug therapy/pathology ; Prodrugs/chemistry/*therapeutic use ; }, abstract = {Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.}, }
@article {pmid30089789, year = {2019}, author = {Bradshaw, NJ and Korth, C}, title = {Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness.}, journal = {Molecular psychiatry}, volume = {24}, number = {7}, pages = {936-951}, pmid = {30089789}, issn = {1476-5578}, mesh = {Animals ; Basic Helix-Loop-Helix Transcription Factors ; Brain/metabolism ; Disease Models, Animal ; Dysbindin ; Humans ; Mental Disorders/*physiopathology ; Mental Health ; Microfilament Proteins ; Nerve Tissue Proteins ; Protein Aggregation, Pathological/*physiopathology ; Proteostasis Deficiencies/*physiopathology ; }, abstract = {Chronic mental illnesses (CMI), such as schizophrenia or recurrent affective disorders, are complex conditions with both genetic and non-genetic elements. In many other chronic brain conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia, sporadic instances of the disease are more common than gene-driven familial cases. Yet, the pathology of these conditions can be characterized by the presence of aberrant protein homeostasis, proteostasis, resulting in misfolded or aggregated proteins in the brains of patients that predominantly do not derive from genetic mutations. While visible deposits of aggregated protein have not yet been detected in CMI patients, we propose the existence of more subtle protein misassembly in these conditions, which form a continuum with the psychiatric phenotypes found in the early stages of many neurodegenerative conditions. Such proteinopathies need not rely on genetic variation. In a similar manner to the established aberrant neurotransmitter homeostasis in CMI, aberrant homeostasis of proteins is a functional statement that can only partially be explained by, but is certainly complementary to, genetic approaches. Here, we review evidence for aberrant proteostasis signatures from post mortem human cases, in vivo animal work, and in vitro analysis of candidate proteins misassembled in CMI. The five best-characterized proteins in this respect are currently DISC1, dysbindin-1, CRMP1, TRIOBP-1, and NPAS3. Misassembly of these proteins with inherently unstructured domains is triggered by extracellular stressors and thus provides a converging point for non-genetic causes of CMI.}, }
@article {pmid30088630, year = {2018}, author = {Pinto, TDRC and Castro, DS and Bringuente, MEO and Sant'Anna, HC and Souza, TV and Primo, CC}, title = {Educational animation about home care with premature newborn infants.}, journal = {Revista brasileira de enfermagem}, volume = {71}, number = {suppl 4}, pages = {1604-1610}, doi = {10.1590/0034-7167-2017-0401}, pmid = {30088630}, issn = {1984-0446}, mesh = {*Cartoons as Topic ; Health Education/*methods/standards ; Home Care Services/*trends ; Humans ; Infant, Newborn ; *Infant, Premature ; Parents/*education ; }, abstract = {OBJECTIVE: to elaborate and validate animation on the care of premature newborn infants at home.<br><br>METHOD: Methodological study in three stages: integrative review on home care; animation design based on Roper, Logan and Tierney's Model named "Activities of Living" (ALs), and validation of content and appearance by neonatology specialists. The steps to develop the animation were: creation of storyboard; definition of objects; specification of keyframes; and frame generation among key frameworks.<br><br>RESULTS: Of the 53 articles selected in the review, care was extracted and grouped into the twelve activities of living. Three storyboards were created to embrace all care and validated by 22 experts. Most of the care had matches above 80%.<br><br>CONCLUSION: The validation of the storyboards made it possible to glimpse the changes in scenes and dialogues in a clearer and more detailed way. Animation is an innovative educational technology to support teaching and learning of parents and family.}, }
@article {pmid30081499, year = {2018}, author = {Ravanidis, S and Kattan, FG and Doxakis, E}, title = {Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors.}, journal = {International journal of molecular sciences}, volume = {19}, number = {8}, pages = {}, pmid = {30081499}, issn = {1422-0067}, mesh = {Animals ; Humans ; Models, Biological ; Neurodegenerative Diseases/genetics/*metabolism ; RNA-Binding Proteins/genetics/*metabolism ; Ribonucleoproteins/genetics/*metabolism ; }, abstract = {The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.}, }
@article {pmid30080719, year = {2018}, author = {Baloh, RH and Glass, JD and Svendsen, CN}, title = {Stem cell transplantation for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {31}, number = {5}, pages = {655-661}, doi = {10.1097/WCO.0000000000000598}, pmid = {30080719}, issn = {1473-6551}, support = {P50 AG025688/AG/NIA NIH HHS/United States ; UG3 NS105703/NS/NINDS NIH HHS/United States ; U54 NS091046/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mesenchymal Stem Cell Transplantation ; Neural Stem Cells ; Stem Cell Transplantation/*methods ; }, abstract = {PURPOSE OF REVIEW: This review analyses the recent efforts to develop therapeutics using transplantation of stem cells for amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: Stem cells are considered as a potential therapeutic for a variety of neurodegenerative diseases, in an effort to either replace cells that are lost, or to enhance the survival of the remaining cells. In ALS, meaningful attempts to verify the safety and feasibility of many cell transplantation approaches have only recently been completed or are underway. Due to the complexities of reconstructing complete motor neuron circuits in adult patients, current approaches aim rather to prolong the survival and function of existing motor neurons through paracrine effects or production of new interneurons or astrocytes. Recent trials showed that autologous mesenchymal stem cells can be safely injected intrathecally, transiently enhancing growth factor concentrations and anti-inflammatory cytokines into the cerebrospinal fluid. Likewise, a small pilot study investigating safety of autologous transplantation of regulatory T-cells for immunomodulation was recently completed. Finally, early phase trials demonstrated safety of direct surgical transplantation of heterologous fetal-derived neural progenitor cells into the spinal cord of ALS patients, as an attempt to provide a lasting source of local trophic support for motor neurons.<br><br>SUMMARY: With clinical trials recently demonstrating that stem cell transplantation can be safe and well tolerated in ALS, the field is positioned to complete pivotal controlled trials to determine efficacy.}, }
@article {pmid30080715, year = {2018}, author = {Vucic, S and Rutkove, SB}, title = {Neurophysiological biomarkers in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {31}, number = {5}, pages = {640-647}, doi = {10.1097/WCO.0000000000000593}, pmid = {30080715}, issn = {1473-6551}, support = {K24 NS060951/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; *Biomarkers ; Electrodiagnosis ; Electromyography ; Humans ; Transcranial Magnetic Stimulation ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons, characterized by upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction. There have been significant technological advances in the development of neurophysiological biomarkers of UMN and LMN dysfunction in ALS. In this review, we discuss major advances in development of neurophysiological biomarkers in ALS, critiquing their potential in diagnosis and prognosis of ALS, as well as utility in monitoring treatment effects.<br><br>RECENT FINDINGS: The threshold tracking transcranial magnetic stimulation (TMS) technique has established cortical hyperexcitability as an early and specific biomarker of UMN dysfunction in ALS, and associated with neurodegeneration. In addition to establishing cortical hyperexcitability as a pathophysiological mechanism, threshold tracking TMS has enabled an earlier diagnosis of ALS and provided a means of monitoring effects of therapeutic agents. Biomarkers of LMN dysfunction, including motor unit number estimation, the neurophysiological index, electrical impedance myography and axonal excitability techniques, have all exhibited utility in monitoring disease progression.<br><br>SUMMARY: In addition to enhancing ALS diagnosis, the development of novel neurophysiological biomarkers has implications for clinical trials research and drug development, enabling the assessment of biological efficacy of agents in early stages of drug development.}, }
@article {pmid30077775, year = {2018}, author = {Ferrer, I}, title = {Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner.}, journal = {Progress in neurobiology}, volume = {169}, number = {}, pages = {24-54}, doi = {10.1016/j.pneurobio.2018.07.004}, pmid = {30077775}, issn = {1873-5118}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*complications ; Oligodendroglia/*pathology ; Protein Aggregation, Pathological/*complications ; }, abstract = {Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following different insults to the central nervous system including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinating diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with abnormal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein deposits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus signaling their involvement in the disease. Emerging evidence suggests that such deposits in oligodendrocytes are not mere bystanders but rather are associated with functional alterations. Moreover, operative modifications in oligodendrocytes are also detected in the absence of oligodendroglial inclusions in certain diseases. The present review focuses first on general aspects of oligodendrocytes and precursors, and their development and functions, and then introduces and updates alterations and dysfunction of oligodendrocytes in selected neurodegenerative diseases with abnormal protein aggregates such as multiple system atrophy, Lewy body diseases, tauopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration with TDP-43 inclusions (TDP-43 proteinopathies), and Creutzfeldt-Jakob´s disease as a prototypical human prionopathy.}, }
@article {pmid30075105, year = {2019}, author = {Foster, LA and Salajegheh, MK}, title = {Motor Neuron Disease: Pathophysiology, Diagnosis, and Management.}, journal = {The American journal of medicine}, volume = {132}, number = {1}, pages = {32-37}, doi = {10.1016/j.amjmed.2018.07.012}, pmid = {30075105}, issn = {1555-7162}, mesh = {Diagnosis, Differential ; Disease Management ; Humans ; Motor Neuron Disease/*diagnosis/etiology/therapy ; }, abstract = {Patients with motor neuron diseases may present to primary care clinic or may be initially encountered in the inpatient setting. Timely diagnosis of these conditions is a key factor in early intervention and therapy, and accuracy of diagnosis is of extreme importance, in particular for amyotrophic lateral sclerosis with its poor prognosis. The aim of this review article is to provide a clinical and diagnostic framework for the diagnosis and evaluation of motor neuron disease for primary care physicians.}, }
@article {pmid30066799, year = {2018}, author = {Teive, HAG and Munhoz, RP and Camargo, CHF and Walusinski, O}, title = {Yawning in neurology: a review.}, journal = {Arquivos de neuro-psiquiatria}, volume = {76}, number = {7}, pages = {473-480}, doi = {10.1590/0004-282X20180057}, pmid = {30066799}, issn = {1678-4227}, mesh = {Humans ; Nervous System Diseases/*physiopathology ; *Yawning ; }, abstract = {Yawning is a stereotyped physiological behavior that can represent a sign or symptom of several conditions, such as stroke, parakinesia brachialis oscitans, parkinsonism, Parkinson's disease and epilepsy. More rarely, it can occur in patients with intracranial hypertension, brain tumor, multiple sclerosis, migraine, Chiari malformation type I, and amyotrophic lateral sclerosis. Drug-induced yawning is an uncommon clinical condition and yawning in patients with autism or schizophrenia is very rare. The aim of this review is to describe in detail the occurrence of the phenomenon in such conditions, and its' phenomenology and pathophysiology.}, }
@article {pmid30055149, year = {2018}, author = {Morales, P and Goya, P and Jagerovic, N}, title = {Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism.}, journal = {Biochemical pharmacology}, volume = {157}, number = {}, pages = {8-17}, doi = {10.1016/j.bcp.2018.07.031}, pmid = {30055149}, issn = {1873-2968}, mesh = {Allosteric Regulation ; Animals ; Humans ; Ligands ; Mice ; Receptor, Cannabinoid, CB2/*agonists/chemistry/metabolism ; Signal Transduction ; }, abstract = {During these last years, the CB2 cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB2 agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB2 receptor may offer new avenues for the development of improved CB2 receptor-targeted therapies. Although there has been some exploration of CB1 receptor activation by new CB1 allosteric or biased-signaling ligands, the CB2 receptor is still at initial stages in this domain. In an effort to understand the molecular basis behind these pharmacological approaches, we have analyzed and summarized the structural data reported so far at CB2 receptor.}, }
@article {pmid30053494, year = {2018}, author = {Mostafalou, S and Abdollahi, M}, title = {The link of organophosphorus pesticides with neurodegenerative and neurodevelopmental diseases based on evidence and mechanisms.}, journal = {Toxicology}, volume = {409}, number = {}, pages = {44-52}, doi = {10.1016/j.tox.2018.07.014}, pmid = {30053494}, issn = {1879-3185}, mesh = {Animals ; Environmental Exposure/*adverse effects ; Humans ; Neurodegenerative Diseases/chemically induced/*epidemiology ; Neurodevelopmental Disorders/chemically induced/*epidemiology ; Organophosphorus Compounds/*toxicity ; Pesticides/*toxicity ; Prevalence ; }, abstract = {Organophosphorus (OP) compounds have been known as the most widely used pesticides during the past half century and there have been a huge body of literature regarding their association with human chronic diseases. Neurodegenerative and neurodevelopmental disorders including Alzheimer, Parkinson, amyotrophic lateral sclerosis (ALS), attention deficit hyperactivity disorder (ADHD), and autism are among the afflicting neurological diseases which overshadow human life and their higher risk in relation to OP exposures have been uncovered by epidemiological studies. In addition, experimental studies exploring the underlying mechanisms have provided some evidence for involvement of cholinergic deficit, oxidative stress, neuro-inflammation, and epigenetic modifications as the processes which are common in the toxicity of the OP and pathophysiology of the mentioned diseases. In addition, genetic mutations and polymorphisms of different variants of some genes like paraoxonase have been shown to be implicated in both susceptibility to OPs toxicity and neurological diseases. In this article, we reviewed the epidemiological as well as experimental studies evidencing the association of exposure to OPs and incidence of neurodegenerative and neurodevelopmental diseases.}, }
@article {pmid30050404, year = {2018}, author = {Sobue, G and Ishigaki, S and Watanabe, H}, title = {Pathogenesis of Frontotemporal Lobar Degeneration: Insights From Loss of Function Theory and Early Involvement of the Caudate Nucleus.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {473}, pmid = {30050404}, issn = {1662-4548}, abstract = {Frontotemporal lobar degeneration (FTLD) is a group of clinically, pathologically and genetically heterogeneous neurodegenerative disorders that involve the frontal and temporal lobes. Behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA) are three major clinical syndromes. TDP-43, FUS, and tau are three major pathogenetic proteins. In this review, we first discuss the loss-of-function mechanism of FTLD. We focus on FUS-associated pathogenesis in which FUS is linked to tau by regulating its alternative splicing machinery. Moreover, FUS is associated with abnormalities in post-synaptic formation, which can be an early disease marker of FTLD. Second, we discuss clinical and pathological aspects of FTLD. Recently, FTLD and amyotrophic lateral sclerosis (ALS) have been recognized as the same disease entity; indeed, nearly all sporadic ALS cases show TDP-43 pathology irrespective of FTD phenotype. Thus, investigating early structural and network changes in the FTLD/ALS continuum can be useful for developing early diagnostic markers of FTLD. MRI studies have revealed the involvement of the caudate nucleus and its anatomical networks in association with the early phase of behavioral/cognitive decline in FTLD/ALS. In particular, even ALS patients with normal cognition have shown a significant decrease in structural connectivity between the caudate head networks. In pathological studies, FTLD/ALS has shown striatal involvement of both efferent system components and glutamatergic inputs from the cerebral cortices even in ALS patients. Thus, the caudate nucleus may be primarily associated with behavioral abnormality and cognitive involvement in FTLD/ALS. Although several clinical trials have been conducted, there is still no therapy that can change the disease course in patients with FTLD. Therefore, there is an urgent need to establish a strategy for predominant sporadic FTLD cases.}, }
@article {pmid30050381, year = {2017}, author = {Ngo, ST and Mi, JD and Henderson, RD and McCombe, PA and Steyn, FJ}, title = {Exploring targets and therapies for amyotrophic lateral sclerosis: current insights into dietary interventions.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {7}, number = {}, pages = {95-108}, pmid = {30050381}, issn = {1179-9900}, abstract = {A growing number of preclinical and human studies demonstrate a disease-modifying effect of nutritional state in amyotrophic lateral sclerosis (ALS). The management of optimal nutrition in ALS is complicated, as physiological, physical, and psychological effects of the disease need to be considered and addressed accordingly. In this regard, multidisciplinary care teams play an integral role in providing dietary guidance to ALS patients and their carers. However, with an increasing research focus on the use of dietary intervention strategies to manage disease symptoms and improve prognosis in ALS, many ALS patients are now seeking or are actively engaged in using complementary and alternative therapies that are dietary in nature. In this article, we review the aspects of appetite control, energy balance, and the physiological effects of ALS relative to their impact on overall nutrition. We then provide current insights into dietary interventions for ALS, considering the mechanisms of action of some of the common dietary interventions used in ALS, discussing their validity in the context of clinical trials.}, }
@article {pmid30048339, year = {2018}, author = {Thonhoff, JR and Simpson, EP and Appel, SH}, title = {Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis.}, journal = {Current opinion in neurology}, volume = {31}, number = {5}, pages = {635-639}, doi = {10.1097/WCO.0000000000000599}, pmid = {30048339}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/immunology/*pathology ; Animals ; Disease Models, Animal ; Humans ; Inflammation/*complications/immunology/*pathology ; Mice ; T-Lymphocytes, Regulatory/immunology ; }, abstract = {PURPOSE OF REVIEW: Neuroinflammation is increasingly recognized as an important mediator of disease progression in patients with amyotrophic lateral sclerosis (ALS), and is characterized by reactive central nervous system (CNS) microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. Anti-inflammatory and neuroprotective factors sustain the early phase of the disease whereas inflammation becomes proinflammatory and neurotoxic as disease progression accelerates. Initially, motor neurons sustain injuries through multiple mechanisms resulting from harmful mutations causing disruptions of critical intracellular pathways. Injured motor neurons release distress signal(s), which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. This review will focus on mechanisms of neuroinflammation and their essential contributions in ALS pathogenesis.<br><br>RECENT FINDINGS: Regulatory T lymphocytes (Tregs) are a subpopulation of immunosuppressive T lymphocytes that become reduced and dysfunctional as the disease progresses in ALS patients. Their degree of dysfunction correlates with the extent and rapidity of the disease. Treg numbers are boosted in transgenic mutant SOD1 (mSOD1) mice through the passive transfer of Tregs or through treatment with an interleukin-2/ interleukin-2 monoclonal antibody complex and rapamycin. Treating the transgenic mice with either of these modalities delays disease progression and prolongs survival. In addition, Treg function is restored when dysfunctional Tregs are isolated from ALS patients and expanded ex vivo in the presence of interleukin-2 and rapamycin. Based on these findings, a first-in-human phase 1 trial has been completed in which expanded autologous Tregs were infused back into ALS patients as a potential treatment. The infusions were safe and shown to 'hit target' by enhancing both Treg numbers and suppressive functions.<br><br>SUMMARY: A delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward the anti-inflammatory mediators shows promise in slowing the progression of this devastating disease.}, }
@article {pmid30047795, year = {2018}, author = {Gaipa, G and Buracchi, C and Biondi, A}, title = {Flow cytometry for minimal residual disease testing in acute leukemia: opportunities and challenges.}, journal = {Expert review of molecular diagnostics}, volume = {18}, number = {9}, pages = {775-787}, doi = {10.1080/14737159.2018.1504680}, pmid = {30047795}, issn = {1744-8352}, mesh = {Acute Disease ; Flow Cytometry/methods ; Humans ; Immunophenotyping/methods ; Leukemia, Myeloid, Acute/*pathology ; Neoplasm, Residual/*pathology ; }, abstract = {Flow cytometric quantification of minimal residual disease (MRD) in acute leukemia (AL) represents an indispensable tool to guide modern therapeutic protocols toward a precision medicine approach, being a powerful predictor of the overall response to treatment. This review covers the most challenging aspects and developments of this method, aiming at supporting further its implementation in clinical practices. Area covered: Flow cytometric MRD is based on the discrimination of leukemia cells from their physiological counterparts by the recognition of the leukemia-associated immunophenotypes. Technical and standardization advances along the last decades have been implemented allowing flow cytometric MRD to consolidate its role in modern therapeutic protocols for ALs. However, gaps in sensitivity and data interpretation are still present together with the need for further optimization of MRD-based clinical protocols. In this review, we critically analyze and discuss the most relevant and representative contributions in the field by accurate selection of the literature available in PubMed. Expert commentary: Further research in flow cytometric MRD can bring this technology toward wider and consistent applications in multiple acute leukemia settings rendering this tool a future golden standard and providing clinicians with more reliable and accurate tools for clinical decisions.}, }
@article {pmid30047099, year = {2019}, author = {Perego, MGL and Taiana, M and Bresolin, N and Comi, GP and Corti, S}, title = {R-Loops in Motor Neuron Diseases.}, journal = {Molecular neurobiology}, volume = {56}, number = {4}, pages = {2579-2589}, pmid = {30047099}, issn = {1559-1182}, mesh = {Animals ; Humans ; Models, Biological ; Motor Neuron Disease/*pathology/therapy ; *Nucleic Acid Conformation ; RNA-Binding Proteins/metabolism ; }, abstract = {R loops are transient three-stranded nucleic acid structures that form physiologically during transcription when a nascent RNA transcript hybridizes with the DNA template strand, leaving a single strand of displaced nontemplate DNA. However, aberrant persistence of R-loops can cause DNA damage by inducing genomic instability. Indeed, evidence has emerged that R-loops might represent a key element in the pathogenesis of human diseases, including cancer, neurodegeneration, and motor neuron disorders. Mutations in genes directly involved in R-loop biology, such as SETX (senataxin), or unstable DNA expansion eliciting R-loop generation, such as C9ORF72 HRE, can cause DNA damage and ultimately result in motor neuron cell death. In this review, we discuss current advancements in this field with a specific focus on motor neuron diseases associated with deregulation of R-loop structures. These mechanisms can represent novel therapeutic targets for these devastating, incurable diseases.}, }
@article {pmid30045872, year = {2019}, author = {Gomes, E and Shorter, J}, title = {The molecular language of membraneless organelles.}, journal = {The Journal of biological chemistry}, volume = {294}, number = {18}, pages = {7115-7127}, pmid = {30045872}, issn = {1083-351X}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 NS090205/NS/NINDS NIH HHS/United States ; R21 NS102687/NS/NINDS NIH HHS/United States ; }, mesh = {Cell Physiological Phenomena ; Cytoplasm/metabolism ; Humans ; Organelles/*metabolism ; }, abstract = {Eukaryotic cells organize their intracellular components into organelles that can be membrane-bound or membraneless. A large number of membraneless organelles, including nucleoli, Cajal bodies, P-bodies, and stress granules, exist as liquid droplets within the cell and arise from the condensation of cellular material in a process termed liquid-liquid phase separation (LLPS). Beyond a mere organizational tool, concentrating cellular components into membraneless organelles tunes biochemical reactions and improves cellular fitness during stress. In this review, we provide an overview of the molecular underpinnings of the formation and regulation of these membraneless organelles. This molecular understanding explains emergent properties of these membraneless organelles and shines new light on neurodegenerative diseases, which may originate from disturbances in LLPS and membraneless organelles.}, }
@article {pmid30033758, year = {2018}, author = {Lee, JH and Liu, JW and Lin, SZ and Harn, HJ and Chiou, TW}, title = {Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis.}, journal = {Cell transplantation}, volume = {27}, number = {9}, pages = {1301-1312}, pmid = {30033758}, issn = {1555-3892}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Drug Discovery/*methods ; Drug Evaluation, Preclinical/*methods ; Genotype ; Humans ; Induced Pluripotent Stem Cells/*cytology/drug effects/metabolism ; Motor Neurons/*cytology/drug effects/metabolism ; Neurogenesis/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Small Molecule Libraries/pharmacology/therapeutic use ; }, abstract = {Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.}, }
@article {pmid30030591, year = {2018}, author = {Dhouafli, Z and Cuanalo-Contreras, K and Hayouni, EA and Mays, CE and Soto, C and Moreno-Gonzalez, I}, title = {Inhibition of protein misfolding and aggregation by natural phenolic compounds.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {75}, number = {19}, pages = {3521-3538}, pmid = {30030591}, issn = {1420-9071}, mesh = {Amyloidosis/drug therapy/metabolism/pathology ; Animals ; Biological Products/*pharmacology/therapeutic use ; Diabetes Mellitus, Type 2/drug therapy/metabolism/pathology ; Humans ; Phenols/*pharmacology/therapeutic use ; Prion Diseases/drug therapy/metabolism/pathology ; Protein Aggregation, Pathological/*prevention &amp; control ; Protein Folding/*drug effects ; Proteostasis Deficiencies/drug therapy/*prevention &amp; control ; }, abstract = {Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer's and Parkinson's diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.}, }
@article {pmid30030024, year = {2019}, author = {Chu, CT}, title = {Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {122}, number = {}, pages = {23-34}, pmid = {30030024}, issn = {1095-953X}, support = {R01 AG026389/AG/NIA NIH HHS/United States ; R01 NS065789/NS/NINDS NIH HHS/United States ; R01 NS101628/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Humans ; Mitophagy/*physiology ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Over the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathological hallmarks shared by most neurodegenerative diseases. The landmark discovery in 2007 of p62/SQSTM1 as the first mammalian selective autophagy receptor defined a new family of autophagy-related proteins that serve to target protein aggregates, mitochondria, intracellular pathogens and other cargoes to the core autophagy machinery via an LC3-interacting region (LIR)-motif. Notably, mutations in the LIR-motif proteins p62 (SQSTM1) and optineurin (OPTN) contribute to familial forms of frontotemporal dementia and amyotrophic lateral sclerosis. Moreover, a subset of LIR-motif proteins is involved in selective mitochondrial degradation initiated by two recessive familial Parkinson's disease genes. PTEN-induced kinase 1 (PINK1) activates the E3 ubiquitin ligase Parkin (PARK2) to mark depolarized mitochondria for degradation. An extensive body of literature delineates key mechanisms in this pathway, based mostly on work in transformed cell lines. However, the potential role of PINK1-triggered mitophagy in neurodegeneration remains a conundrum, particularly in light of recent in vivo mitophagy studies. There are at least three major mechanisms by which mitochondria are targeted for mitophagy: transmembrane receptor-mediated, ubiquitin-mediated and cardiolipin-mediated. This review summarizes key features of the major cargo recognition pathways for selective autophagy and mitophagy, highlighting their potential impact in the pathogenesis or amelioration of neurodegenerative diseases.}, }
@article {pmid30028737, year = {2018}, author = {Ly, CV and Miller, TM}, title = {Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {31}, number = {5}, pages = {648-654}, pmid = {30028737}, issn = {1473-6551}, support = {R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Dependovirus ; Humans ; Muscular Atrophy, Spinal/therapy ; Oligonucleotides, Antisense/*therapeutic use ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS.<br><br>RECENT FINDINGS: The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental work to identify the genetic underpinnings of familial ALS and develop relevant disease models. Preclinical studies have also identified promising targets for sporadic ALS (sALS). Moreover, encouraging results in adeno-associated virus (AAV)-based therapies for spinal muscular atrophy (SMA) provide a roadmap for continued improvement in delivery and design of molecular therapies for ALS.<br><br>SUMMARY: Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.}, }
@article {pmid30027910, year = {2018}, author = {Arneson, D and Zhang, Y and Yang, X and Narayanan, M}, title = {Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks.}, journal = {Journal of genetics}, volume = {97}, number = {3}, pages = {795-806}, pmid = {30027910}, issn = {0973-7731}, support = {R01 DK104363/DK/NIDDK NIH HHS/United States ; R21 NS103088/NS/NINDS NIH HHS/United States ; }, mesh = {Gene Expression Profiling ; Gene Expression Regulation ; *Gene Regulatory Networks ; *Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*genetics ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are pressing health concerns in modern societies for which effective therapies are still lacking. Recent high-throughput genomic technologies have enabled genome-scale, multidimensional investigations to facilitate a better understanding of the underlying mechanisms and the identification of novel targets. Here we review the molecular insights gained through such studies, and compare the similarities and differences between neurodegenerative diseases revealed by systems genomics and gene network modelling approaches. We focus specifically on the shared mechanisms at multiple molecular scales ranging from genetic factors to gene expression to network-level features of gene regulation, and whenever possible also point out mechanisms that distinguish one disease from another. Our review sets the stage for similar genomewide inspection in the future on shared/distinct features of neurodegenerative diseases at the levels of cellular, proteomic or epigenomic signatures, and how these features may interact to determine the progression and treatment response of different diseases afflicting the same individual.}, }
@article {pmid30027900, year = {2018}, author = {Kumar, S and Yadav, N and Pandey, S and Thelma, BK}, title = {Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches, success, challenges and prospects.}, journal = {Journal of genetics}, volume = {97}, number = {3}, pages = {625-648}, pmid = {30027900}, issn = {0973-7731}, mesh = {*Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*genetics ; Risk Factors ; }, abstract = {Neurodegenerative diseases constitute a large proportion of disorders in elderly, majority being sporadic in occurrence with ∼5-10% familial. A strong genetic component underlies the Mendelian forms but nongenetic factors together with genetic vulnerability contributes to the complex sporadic forms. Several gene discoveries in the familial forms have provided novel insights into the pathogenesis of neurodegeneration with implications for treatment. Conversely, findings from genetic dissection of the sporadic forms, despite large genomewide association studies and more recently whole exome and whole genome sequencing, have been limited. This review provides a concise account of the genetics that we know, the pathways that they implicate, the challenges that are faced and the prospects that are envisaged for the sporadic, complex forms of neurodegenerative diseases, taking four most common conditions, namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington disease as examples. Poor replication across studies, inability to establish genotype-phenotype correlations and the overall failure to predict risk and/or prevent disease in this group poses a continuing challenge. Among others, clinical heterogeneity emerges as the most important impediment warranting newer approaches. Advanced computational and system biology tools to analyse the big data are being generated and the alternate strategy such as subgrouping of case-control cohorts based on deep phenotyping using the principles of Ayurveda to overcome current limitation of phenotype heterogeneity seem to hold promise. However, at this point, with advances in discovery genomics and functional analysis of putative determinants with translation potential for the complex forms being minimal, stem cell therapies are being attempted as potential interventions. In this context, the possibility to generate patient derived induced pluripotent stem cells, mutant/gene/genome correction through CRISPR/Cas9 technology and repopulating the specific brain regions with corrected neurons, which may fulfil the dream of personalized medicine have been mentioned briefly. Understanding disease pathways/biology using this technology, with implications for development of novel therapeutics are optimistic expectations in the near future.}, }
@article {pmid30025485, year = {2018}, author = {Mazzini, L and Ferrari, D and Andjus, PR and Buzanska, L and Cantello, R and De Marchi, F and Gelati, M and Giniatullin, R and Glover, JC and Grilli, M and Kozlova, EN and Maioli, M and Mitrečić, D and Pivoriunas, A and Sanchez-Pernaute, R and Sarnowska, A and Vescovi, AL and , }, title = {Advances in stem cell therapy for amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {18}, number = {8}, pages = {865-881}, doi = {10.1080/14712598.2018.1503248}, pmid = {30025485}, issn = {1744-7682}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cell- and Tissue-Based Therapy/methods/trends ; Humans ; Randomized Controlled Trials as Topic/methods ; Stem Cell Transplantation/methods/*trends ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies.<br><br>AREAS COVERED: This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies.<br><br>EXPERT OPINION: While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.}, }
@article {pmid30018591, year = {2018}, author = {Christidi, F and Karavasilis, E and Velonakis, G and Ferentinos, P and Rentzos, M and Kelekis, N and Evdokimidis, I and Bede, P}, title = {The Clinical and Radiological Spectrum of Hippocampal Pathology in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {523}, pmid = {30018591}, issn = {1664-2295}, abstract = {Hippocampal pathology in Amyotrophic Lateral Sclerosis (ALS) remains surprisingly under recognized despite compelling evidence from neuropsychology, neuroimaging and neuropathology studies. Hippocampal dysfunction contributes significantly to the clinical heterogeneity of ALS and requires structure-specific cognitive and neuroimaging tools for accurate in vivo evaluation. Recent imaging studies have generated unprecedented insights into the presymptomatic and longitudinal processes affecting this structure and have contributed to the characterisation of both focal and network-level changes. Emerging neuropsychology data suggest that memory deficits in ALS may be independent from executive dysfunction. In the era of precision medicine, where the development of individualized care strategies and patient stratification for clinical trials are key priorities, the comprehensive review of hippocampal dysfunction in ALS is particularly timely.}, }
@article {pmid30016687, year = {2018}, author = {Niranjan, R}, title = {Recent advances in the mechanisms of neuroinflammation and their roles in neurodegeneration.}, journal = {Neurochemistry international}, volume = {120}, number = {}, pages = {13-20}, doi = {10.1016/j.neuint.2018.07.003}, pmid = {30016687}, issn = {1872-9754}, mesh = {Animals ; Disease Progression ; Humans ; Inflammation/*metabolism ; MicroRNAs/*metabolism ; Microglia/metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/*metabolism/pathology ; }, abstract = {Neuroinflammation is associated with the pathogenesis of many neurological disorders including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis and Huntington disease. Current studies in this area have advanced the mechanism of neuroinflammation and its role in neurodegeneration. Studies from epidemiologic, clinical and animal models also contributed in the various new mechanisms of neuroinflammation. In this line, activation of monocytes is an important emerging mechanism that has a, profound role in neuroinflammation and neurodegeneration. Ion channels, matrix metalloproteases and microRNAs are also found to be the key players in the pathogenesis of neuroinflammation. In particular, microRNA-32 regulates microglia-mediated neuroinflammation and thus neurodegeneration. Notably, some important studies describe the role of Th17 cells in neuroinflammation, but, very little knowledge is available about their mechanism of action. Particularly, the role of autophagy gets emphasized, which plays a very critical role in protein aggregation and neurodegeneration. In this review, we highlight and discuss the mechanisms of these mediators of inflammation by which they contribute to the disease progression. In conclusion, we focus on the various newer molecular mechanisms that are associated with the basic understanding of neuroinflammation in neurodegeneration.}, }
@article {pmid30014355, year = {2018}, author = {Carocci, A and Catalano, A and Sinicropi, MS and Genchi, G}, title = {Oxidative stress and neurodegeneration: the involvement of iron.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {31}, number = {5}, pages = {715-735}, doi = {10.1007/s10534-018-0126-2}, pmid = {30014355}, issn = {1572-8773}, mesh = {Animals ; Humans ; Iron/adverse effects/*metabolism ; Iron Chelating Agents/adverse effects/metabolism ; Neurodegenerative Diseases/chemically induced/*metabolism ; *Oxidative Stress/drug effects ; }, abstract = {Many evidences indicate that oxidative stress plays a significant role in a variety of human disease states, including neurodegenerative diseases. Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing proteins and enzymes, though it could be also toxic. Actually, free iron excess generates oxidative stress, particularly in brain, where anti-oxidative defences are relatively low. Its accumulation in specific regions is associated with pathogenesis in a variety of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis and Neurodegeneration with Brain Iron Accumulation). Anyway, the extent of toxicity is dictated, in part, by the localization of the iron complex within the cell (cytosolic, lysosomal and mitochondrial), its biochemical form, i.e., ferritin or hemosiderin, as well as the ability of the cell to prevent the generation and propagation of free radical by the wide range of antioxidants and cytoprotective enzymes in the cell. Particularly, ferrous iron can act as a catalyst in the Fenton reaction that potentiates oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals (·OH). The observation that patients with neurodegenerative diseases show a dramatic increase in their brain iron content, correlated with the production of reactive oxigen species in these areas of the brain, conceivably suggests that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. The aim of this review is to describe the chemical features of iron in human beings and iron induced toxicity in neurodegenerative diseases. Furthermore, the attention is focused on metal chelating drugs therapeutic strategies.}, }
@article {pmid30005051, year = {2019}, author = {Sarnicola, C and Farooq, AV and Colby, K}, title = {Fuchs Endothelial Corneal Dystrophy: Update on Pathogenesis and Future Directions.}, journal = {Eye &amp; contact lens}, volume = {45}, number = {1}, pages = {1-10}, doi = {10.1097/ICL.0000000000000469}, pmid = {30005051}, issn = {1542-233X}, mesh = {*Corneal Transplantation ; Endothelium, Corneal/*pathology ; *Fuchs' Endothelial Dystrophy/diagnosis/epidemiology/surgery ; Global Health ; Humans ; Incidence ; }, abstract = {Fuchs endothelial corneal dystrophy (FECD) is the most common indication for corneal transplantation in the United States, accounting 36% of the almost 47,000 transplants performed in 2016. Although the surgical management of FECD has undergone a revolution over the past 20 years, its pathogenesis remains elusive, with multiple putative disease pathways and an ever increasing number of candidate genes thought to play a role. This review will summarize the recent advancements in our understanding of the biology of FECD, including potential parallels with neurodegenerative disease like amyotrophic lateral sclerosis and will highlight prospects for future treatment advances.}, }
@article {pmid30002616, year = {2018}, author = {Lindström, M and Liu, B}, title = {Yeast as a Model to Unravel Mechanisms Behind FUS Toxicity in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {218}, pmid = {30002616}, issn = {1662-5099}, abstract = {Fused in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein predominantly localized in the cell nucleus. However, FUS has been shown to accumulate and form aggregates in the cytoplasm when mislocalized there due to mutations. These FUS protein aggregates are known as pathological hallmarks in a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) cases. In this review, we discussed recent research developments on elucidating the molecular mechanisms behind FUS protein aggregation and toxicity. We mainly focus on studies using the budding yeast (Saccharomyces cerevisiae) as a model system, especially on results acquired from yeast genome-wide screens addressing FUS aggregation and toxicity. Human homologs of the FUS toxicity suppressors, identified from these studies, indicate a strong relevance and correlation to a human disease model. By using yeast as a FUS cytotoxicity model these studies provided valuable clues on potential novel targets for therapeutic intervention in ALS.}, }
@article {pmid29999461, year = {2020}, author = {Andersen, JA}, title = {Amyotrophic Lateral Sclerosis and a "Death With Dignity".}, journal = {Omega}, volume = {81}, number = {4}, pages = {567-576}, doi = {10.1177/0030222818788254}, pmid = {29999461}, issn = {1541-3764}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Oregon ; Right to Die/*legislation &amp; jurisprudence ; Suicide, Assisted/*legislation &amp; jurisprudence ; United States ; }, abstract = {The Oregon "Death With Dignity" Act (DWD Act) allows a terminally ill patient with 6 months to live to ask a physician for medication to end their life. To receive the medication, the DWD Act requires the patient to verbally request the prescription twice 2 weeks apart as well as in writing. Patients with amyotrophic lateral sclerosis have three main barriers to using DWD: (a) the ability to communicate their informed consent as the disease progresses further, (b) the possibility of dementia which may affect their decisional capacity, and (c) given the nature and speed of amyotrophic lateral sclerosis, limited time is available for patients to self-administer the prescription and may rush the time line for the death. This article reviews the current knowledge and addresses the need for adjustments to existing law and recommendations for states considering a DWD law.}, }
@article {pmid29998226, year = {2018}, author = {Bhandari, R and Kuhad, A and Kuhad, A}, title = {Edaravone: a new hope for deadly amyotrophic lateral sclerosis.}, journal = {Drugs of today (Barcelona, Spain : 1998)}, volume = {54}, number = {6}, pages = {349-360}, doi = {10.1358/dot.2018.54.6.2828189}, pmid = {29998226}, issn = {1699-3993}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antipyrine/adverse effects/*analogs &amp; derivatives/pharmacokinetics/pharmacology/therapeutic use ; Edaravone ; Free Radical Scavengers/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a fatal motor neuron degenerative disorder leading to paralysis and eventual death. At present, we do not have any specific cure for this deadly disorder. Current drug therapy can only reduce morbidity in ALS patients. In 1995, riluzole was the first drug approved by the U.S. Food and Drug Administration (FDA) for ALS. After a long gap of 22 years, Mitsubishi Tanabe Pharma America got U.S. FDA approval for edaravone (Radicava) in May 2017 for the management of ALS. Edaravone, a novel neuroprotective agent, is indicated to slow down progression of ALS. In 2015, Mitsubishi Tanabe Pharma launched edaravone (Radicut) for the treatment of stroke and ALS in Japan. The U.S. FDA approved edaravone following clinical evidence from three clinical trials conducted in 368 ALS patients in Japan. Edaravone is awaiting approval by the European Medicines Agency (EMA) in Europe. Edaravone (60 mg) is administered by very slow intravenous infusion (60 minutes) in 28-day cycles. It has been shown to slow down the loss of physical function in ALS patients by 33% as compared to placebo. Edaravone is a strong antioxidant that prevents oxidative stress from inducing motor neuron death in ALS patients. Being a potent free radical scavenger, it has been shown to inhibit nitration of tyrosine residues in the cerebrospinal fluid and improve motor functions in mouse models of ALS. The product has been patented and the FDA has not approved any generic version of edaravone. This article discusses the preclinical pharmacology, pharmacokinetics, safety profile, clinical studies and drug interactions of edaravone (Radicava) in ALS.}, }
@article {pmid29990625, year = {2018}, author = {Shirooie, S and Nabavi, SF and Dehpour, AR and Belwal, T and Habtemariam, S and Argüelles, S and Sureda, A and Daglia, M and Tomczyk, M and Sobarzo-Sanchez, E and Xu, S and Nabavi, SM}, title = {Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration?.}, journal = {Pharmacological research}, volume = {135}, number = {}, pages = {37-48}, doi = {10.1016/j.phrs.2018.07.004}, pmid = {29990625}, issn = {1096-1186}, mesh = {Animals ; Fatty Acids, Omega-3/*pharmacology/therapeutic use ; Humans ; Neurodegenerative Diseases/drug therapy/*metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed.}, }
@article {pmid29990478, year = {2019}, author = {Niedermeyer, S and Murn, M and Choi, PJ}, title = {Respiratory Failure in Amyotrophic Lateral Sclerosis.}, journal = {Chest}, volume = {155}, number = {2}, pages = {401-408}, doi = {10.1016/j.chest.2018.06.035}, pmid = {29990478}, issn = {1931-3543}, mesh = {Airway Management ; Amyotrophic Lateral Sclerosis/*complications/mortality/*therapy ; Humans ; Respiratory Insufficiency/*etiology/mortality/*therapy ; Respiratory Therapy ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neuromuscular disease characterized by both lower motor neuron and upper motor neuron dysfunction. Although clinical presentations can vary, there is no cure for ALS, and the disease is universally terminal, with most patients dying of respiratory complications. Patients die, on average, within 3 to 5 years of diagnosis, unless they choose to undergo tracheostomy, in which case, they may live, on average, 2 additional years. Up to 95% of patients with ALS in the United States choose not to undergo tracheostomy; management of respiratory failure is therefore aimed at both prolonging survival as well as improving quality of life. Standard of care for patients with ALS includes treatment from multidisciplinary teams, but many patients do not have consistent access to a pulmonary physician who regularly sees patients with this disease. The goal of this review was to serve as an overview of respiratory considerations in the management of ALS. This article discusses noninvasive ventilation in the management of respiratory muscle weakness, mechanical insufflation/exsufflation devices for airway clearance, and treatment of aspiration, including timing of placement of a percutaneous endoscopic gastrostomy tube, as well as secretion management. In addition, it is important for physicians to consider end-of-life issues such as advanced directives, hospice referral, and ventilator withdrawal.}, }
@article {pmid29986938, year = {2018}, author = {Briston, T and Hicks, AR}, title = {Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention.}, journal = {Biochemical Society transactions}, volume = {46}, number = {4}, pages = {829-842}, pmid = {29986938}, issn = {1470-8752}, mesh = {Adenosine Triphosphate/metabolism ; Amyloid beta-Peptides/*metabolism ; Animals ; Homeostasis ; Humans ; Mitochondria/metabolism/*physiology ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Mitophagy ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism/physiopathology ; Oxidative Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Reactive Oxygen Species/metabolism ; Ubiquitin/metabolism ; alpha-Synuclein/*metabolism ; tau Proteins/*metabolism ; }, abstract = {Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin-proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.}, }
@article {pmid29981842, year = {2019}, author = {Evans, CS and Holzbaur, ELF}, title = {Autophagy and mitophagy in ALS.}, journal = {Neurobiology of disease}, volume = {122}, number = {}, pages = {35-40}, pmid = {29981842}, issn = {1095-953X}, support = {R37 NS060698/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Autophagy/*physiology ; Humans ; Mitophagy/*physiology ; Neurons/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have implicated deficits in autophagy and/or mitophagy in the onset of the disease. Here we review recent progress in our understanding of the pathways for autophagy and mitophagy in neurons, and how these pathways may be affected by mutations in genes including DCTN1, OPTN, TBK1, VCP, and C9ORF72. We also discuss the implications of modulating autophagy in ALS, highlighting both the potential of the approach and the concerns raised by targeting this pathway as a therapeutic strategy in neurodegenerative disease.}, }
@article {pmid29981392, year = {2018}, author = {Ramalho, TC and de Castro, AA and Tavares, TS and Silva, MC and Silva, DR and Cesar, PH and Santos, LA and da Cunha, EFF and Nepovimova, E and Kuca, K}, title = {Insights into the pharmaceuticals and mechanisms of neurological orphan diseases: Current Status and future expectations.}, journal = {Progress in neurobiology}, volume = {169}, number = {}, pages = {135-157}, doi = {10.1016/j.pneurobio.2018.06.011}, pmid = {29981392}, issn = {1873-5118}, mesh = {Animals ; Humans ; *Nervous System Diseases/drug therapy/genetics/physiopathology ; *Pharmaceutical Preparations ; *Rare Diseases/drug therapy/genetics/physiopathology ; }, abstract = {Several rare or orphan diseases have been characterized that singly affect low numbers of people, but cumulatively reach ∼6%-10% of the population in Europe and in the United States. Human genetics has shown to be broadly effective when evaluating subjacent genetic defects such as orphan genetic diseases, but on the other hand, a modest progress has been achieved toward comprehending the molecular pathologies and designing new therapies. Chemical genetics, placed at the interface of chemistry and genetics, could be employed to understand the molecular mechanisms of subjacent illnesses and for the discovery of new remediation processes. This review debates current progress in chemical genetics, and how a variety of compounds and reaction mechanisms can be used to study and ultimately treat rare genetic diseases. We focus here on a study involving Amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Spinal muscular atrophy (SMA) and Familial Amyloid Polyneuropathy (FAP), approaching different treatment methods and the reaction mechanisms of several compounds, trying to elucidate new routes capable of assisting in the treatment profile.}, }
@article {pmid29979478, year = {2019}, author = {Wosiski-Kuhn, M and Lyon, MS and Caress, J and Milligan, C}, title = {Inflammation, immunity, and amyotrophic lateral sclerosis: II. immune-modulating therapies.}, journal = {Muscle &amp; nerve}, volume = {59}, number = {1}, pages = {23-33}, doi = {10.1002/mus.26288}, pmid = {29979478}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/immunology/therapy ; Animals ; Humans ; *Immunity ; *Immunomodulation ; }, abstract = {With the emerging popularity of immune-modulatory therapies to treat human diseases there is a need to step back from hypotheses aimed at assessing a condition in a single-system context and instead take into account the disease pathology as a whole. In complex diseases, such as amyotrophic lateral sclerosis (ALS), the use of these therapies to treat patients has been largely unsuccessful and likely premature given our lack of understanding of how the immune system influences disease progression and initiation. In addition, we still have an incomplete understanding of the role of these responses in our model systems and how this may translate clinically to human patients. In this review we discuss preclinical evidence and clinical trial results for a selection of recently conducted studies in ALS. We provide evidence-based reasoning for the failure of these trials and offer suggestions to improve the design of future investigations. Muscle Nerve 59:23-33, 2019.}, }
@article {pmid29979464, year = {2019}, author = {Lyon, MS and Wosiski-Kuhn, M and Gillespie, R and Caress, J and Milligan, C}, title = {Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology.}, journal = {Muscle &amp; nerve}, volume = {59}, number = {1}, pages = {10-22}, doi = {10.1002/mus.26289}, pmid = {29979464}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/etiology/immunology/pathology ; Animals ; Humans ; *Immunity ; Inflammation/*complications ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. Charcot first described ALS in 1869[1] ; however, its pathogenesis remains unknown, and effective treatments remain elusive. It is apparent that new paradigms must be investigated to understand the effectors of ALS, including inflammation, immune responses, and the body's response to stress and injury. Herein we discuss the potential role of the immune system in ALS pathogenesis and critically review evidence from patient and animal studies. Although immune system components may indeed play a role in ALS pathogenesis, studies implicating immune cells, antibodies, and cytokines in early disease pathology are limited. We propose more focused studies that examine the role of the immune system together with characterized pathogenesis to determine when, where, and if immune and inflammatory processes are critical to disease progression, and thus worthy targets of intervention. Muscle Nerve 59:10-22, 2019.}, }
@article {pmid29977189, year = {2018}, author = {Martin, S and Iturrate, I and Millán, JDR and Knight, RT and Pasley, BN}, title = {Decoding Inner Speech Using Electrocorticography: Progress and Challenges Toward a Speech Prosthesis.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {422}, pmid = {29977189}, issn = {1662-4548}, support = {R01 NS021135/NS/NINDS NIH HHS/United States ; R37 NS021135/NS/NINDS NIH HHS/United States ; }, abstract = {Certain brain disorders resulting from brainstem infarcts, traumatic brain injury, cerebral palsy, stroke, and amyotrophic lateral sclerosis, limit verbal communication despite the patient being fully aware. People that cannot communicate due to neurological disorders would benefit from a system that can infer internal speech directly from brain signals. In this review article, we describe the state of the art in decoding inner speech, ranging from early acoustic sound features, to higher order speech units. We focused on intracranial recordings, as this technique allows monitoring brain activity with high spatial, temporal, and spectral resolution, and therefore is a good candidate to investigate inner speech. Despite intense efforts, investigating how the human cortex encodes inner speech remains an elusive challenge, due to the lack of behavioral and observable measures. We emphasize various challenges commonly encountered when investigating inner speech decoding, and propose potential solutions in order to get closer to a natural speech assistive device.}, }
@article {pmid29972106, year = {2018}, author = {Baj, T and Seth, R}, title = {Role of Curcumin in Regulation of TNF-α Mediated Brain Inflammatory Responses.}, journal = {Recent patents on inflammation &amp; allergy drug discovery}, volume = {12}, number = {1}, pages = {69-77}, doi = {10.2174/1872213X12666180703163824}, pmid = {29972106}, issn = {1872-213X}, mesh = {Animals ; Curcumin/pharmacology/*therapeutic use ; Drug Development ; Encephalitis/*drug therapy/etiology ; Glutamic Acid/physiology ; Humans ; NF-kappa B/physiology ; Neurodegenerative Diseases/*drug therapy ; Tumor Necrosis Factor-alpha/*physiology ; }, abstract = {BACKGROUND: Inflammation is a protective response of the body system that protects the body from the various kinds of external and internal insults; however, it has been found that most chronic illnesses are caused by dysregulated and excessive inflammation. Inflammation plays a major role in developing neurological diseases. In the brain cytokines, TNF-α and TNF-β are known to mediate inflammation in many diseases. Functions of these cytokines are regulated by the activation of transcription factor NF-κb. Recent evidence suggest that curcumin has an immense therapeutic potential because of its anti-inflammatory and anti-oxidant properties. It has been tested for treating various chronic illnesses associated with the brain.<br><br>OBJECTIVE: The study aims to elucidate the role of curcumin in alleviating the inflammatory reactions initiated by TNF-&#x3b1; and NF-&#x3ba;b signaling.<br><br>METHODS: This study is a survey of literature from sources like PubMed central, science direct, medline and available scientific databases to determine how inflammation plays an important role in the development of neurodegenerative diseases and the role of curcumin as an anti-inflammatory agent. Looking into the importance of curcumin in alleviating inflammatory responses, several patents are filed and accepted which are referenced in this article.<br><br>RESULTS: Neuro-inflammation mediated by TNF-&#x3b1; plays a major role in the development of pathologies like Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis etc. Curcumin appears to subside or reduce the inflammatory responses. Thus, it appears to have therapeutic potential for treating various neuroinflammatory diseases.<br><br>CONCLUSION: Cytokines get upregulated during neurodegenerative diseases as a result of which inflammatory responses are initiated in the brain. Curcumin is reported to have anti-inflammatory properties and thereby its supplementation may help in reducing the inflammation. Future research on this area will further explain the mode of action of curcumin in alleviating neuroinflammation.}, }
@article {pmid29971646, year = {2018}, author = {Goldman, JS and Van Deerlin, VM}, title = {Alzheimer's Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing.}, journal = {Molecular diagnosis &amp; therapy}, volume = {22}, number = {5}, pages = {505-513}, pmid = {29971646}, issn = {1179-2000}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; C031425//New York State Department of Health/International ; P30 AG-010124/NH/NIH HHS/United States ; P50 AG-008702/NH/NIH HHS/United States ; P01 AG-017586/NH/NIH HHS/United States ; }, mesh = {Algorithms ; Alzheimer Disease/*diagnosis/*genetics ; Frontotemporal Dementia/*diagnosis/*genetics ; *Genetic Association Studies/methods ; Genetic Counseling ; *Genetic Predisposition to Disease ; *Genetic Testing/methods ; Genomics/methods ; Humans ; Practice Patterns, Physicians' ; }, abstract = {The advent of next-generation sequencing has changed genetic diagnostics, allowing clinicians to test concurrently for phenotypically overlapping conditions such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, to interpret genetic results, clinicians require an understanding of the benefits and limitations of different genetic technologies, such as the inability to detect large repeat expansions in such diseases as C9orf72-associated FTD and amyotrophic lateral sclerosis. Other types of mutations such as large deletions or duplications and triple repeat expansions may also go undetected. Additionally, the concurrent testing of multiple genes or the whole exome increases the likelihood of discovering variants of unknown significance. Our goal here is to review the current knowledge about the genetics of AD and FTD and suggest up-to-date guidelines for genetic testing for these dementias. Despite the improvements in diagnosis due to biomarkers testing, AD and FTD can have overlapping symptoms. When used appropriately, genetic testing can elucidate the diagnosis and specific etiology of the disease, as well as provide information for the family and determine eligibility for clinical trials. Prior to ordering genetic testing, clinicians must determine the appropriate genes to test, the types of mutations that occur in these genes, and the best type of genetic test to use. Without this analysis, interpretation of genetic results will be difficult. Patients should be counseled about the benefits and limitations of different types of genetic tests so they can make an informed decision about testing.}, }
@article {pmid29971063, year = {2018}, author = {Weil, R and Laplantine, E and Curic, S and Génin, P}, title = {Role of Optineurin in the Mitochondrial Dysfunction: Potential Implications in Neurodegenerative Diseases and Cancer.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {1243}, pmid = {29971063}, issn = {1664-3224}, mesh = {Animals ; Biomarkers ; Cell Cycle Proteins ; Disease Susceptibility ; Gene Expression Regulation ; Humans ; Membrane Transport Proteins ; Mitochondria/*genetics/*metabolism ; Mitophagy/genetics ; Neoplasms/*etiology/*metabolism/pathology ; Neurodegenerative Diseases/*etiology/*metabolism/pathology ; Signal Transduction ; Transcription Factor TFIIIA/*genetics/*metabolism ; }, abstract = {Optineurin (Optn) is a 577 aa protein encoded by the Optn gene. Mutations of Optn are associated with normal tension glaucoma and amyotrophic lateral sclerosis, and its gene has also been linked to the development of Paget's disease of bone and Crohn's disease. Optn is involved in diverse cellular functions, including NF-κB regulation, membrane trafficking, exocytosis, vesicle transport, reorganization of actin and microtubules, cell cycle control, and autophagy. Besides its role in xenophagy and autophagy of aggregates, Optn has been identified as a primary autophagy receptor, among the five adaptors that translocate to mitochondria during mitophagy. Mitophagy is a selective macroautophagy process during which irreparable mitochondria are degraded, preventing accumulation of defective mitochondria and limiting the release of reactive oxygen species and proapoptotic factors. Mitochondrial quality control via mitophagy is central to the health of cells. One of the important surveillance pathways of mitochondrial health is the recently defined signal transduction pathway involving the mitochondrial PTEN-induced putative kinase 1 (PINK1) protein and the cytosolic RING-between-RING ubiquitin ligase Parkin. Both of these proteins, when mutated, have been identified in certain forms of Parkinson's disease. By targeting ubiquitinated mitochondria to autophagosomes through its association with autophagy related proteins, Optn is responsible for a critical step in mitophagy. This review reports recent discoveries on the role of Optn in mitophagy and provides insight into its link with neurodegenerative diseases. We will also discuss the involvement of Optn in other pathologies in which mitophagy dysfunctions are involved including cancer.}, }
@article {pmid29969760, year = {2018}, author = {Paladino, S and Conte, A and Caggiano, R and Pierantoni, GM and Faraonio, R}, title = {Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {47}, number = {5}, pages = {1951-1976}, doi = {10.1159/000491465}, pmid = {29969760}, issn = {1421-9778}, mesh = {Aging/genetics/*metabolism/pathology ; Animals ; Humans ; MicroRNAs/genetics/*metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; *Oxidative Stress ; *Signal Transduction ; }, abstract = {A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.}, }
@article {pmid29962397, year = {2018}, author = {Nakamura, S and Shimazawa, M and Hara, H}, title = {Physiological Roles of Metallothioneins in Central Nervous System Diseases.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {41}, number = {7}, pages = {1006-1013}, doi = {10.1248/bpb.b17-00856}, pmid = {29962397}, issn = {1347-5215}, mesh = {Central Nervous System Diseases/diagnosis/drug therapy/*pathology ; Eye Diseases/diagnosis/drug therapy/*pathology ; Humans ; Metallothionein/*metabolism ; Molecular Targeted Therapy/methods ; Protein Isoforms/metabolism ; }, abstract = {Metallothioneins (MTs) are small-molecular weight metal-binding proteins involved in the maintenance of tissue structure, efficient metal metabolism, and metal detoxification and have an antioxidative effect. Moreover, MTs are expressed as four isoforms, and there are no known patterns in their localization with various effects. According to recent studies, MTs affect central nervous system (CNS) diseases, and many reports suggest that each isoform of MT has a protective effect against disease. Notably, MTs are involved in regions of diseases related to unmet medical needs, and MTs affect intractable neurological diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). This review specifically focuses on MT-related ocular diseases, cerebral ischemia, psychological disorders, ALS, and SMA. Each of these diseases has a separate cause, but the conditions are related to MTs. To understand the physiological roles of MTs in CNS diseases, we reviewed the current literature on the complex interactions between each MT, pathological conditions, and perspectives. We also discuss current evidence on the expression and function of MTs for diagnosis and new therapeutic strategies.}, }
@article {pmid29961357, year = {2018}, author = {Neal, EG and Liska, MG and Lippert, T and Lin, R and Gonzalez, M and Russo, E and Xu, K and Ji, X and Vale, FL and Van Loveren, H and Borlongan, CV}, title = {An update on intracerebral stem cell grafts.}, journal = {Expert review of neurotherapeutics}, volume = {18}, number = {7}, pages = {557-572}, doi = {10.1080/14737175.2018.1491309}, pmid = {29961357}, issn = {1744-8360}, support = {R01 NS071956/NS/NINDS NIH HHS/United States ; R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS089851/NS/NINDS NIH HHS/United States ; R21 NS094087/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier ; Central Nervous System Diseases/metabolism/*therapy ; Graft vs Host Reaction ; Humans ; Risk Factors ; Stem Cell Transplantation/adverse effects/*methods ; }, abstract = {Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.}, }
@article {pmid29954341, year = {2018}, author = {Majumder, V and Gregory, JM and Barria, MA and Green, A and Pal, S}, title = {TDP-43 as a potential biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {18}, number = {1}, pages = {90}, pmid = {29954341}, issn = {1471-2377}, support = {217ARF R43969, 3138//Future MND/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Biomarkers/*cerebrospinal fluid ; DNA-Binding Proteins/*cerebrospinal fluid ; Female ; Frontotemporal Dementia/*cerebrospinal fluid ; Humans ; }, abstract = {BACKGROUND: Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are incurable, progressive and fatal neurodegenerative diseases with patients variably affected clinically by motor, behavior, and cognitive deficits. The accumulation of an RNA-binding protein, TDP-43, is the most significant pathological finding in approximately 95% of ALS cases and 50% of FTD cases, and discovery of this common pathological signature, together with an increasing understanding of the shared genetic basis of these disorders, has led to FTD and ALS being considered as part of a single disease continuum. Given the widespread aggregation and accumulation of TDP-43 in FTD-ALS spectrum disorder, TDP-43 may have potential as a biomarker in these diseases.<br><br>METHODS: We therefore conducted a systematic review and meta-analysis to evaluate the diagnostic utility of TDP-43 detected in the cerebrospinal fluid (CSF) of patients with FTD-ALS spectrum disorder.<br><br>RESULTS: From seven studies, our results demonstrate that patients with ALS have a statistically significantly higher level of TDP-43 in CSF (effect size 0.64, 95% CI: 0.1-1.19, p&#x2009;=&#x2009;0.02).<br><br>CONCLUSIONS: These data suggest promise for the use of CSF TDP-43 as a biomarker for ALS.}, }
@article {pmid29951816, year = {2018}, author = {Azuma, Y and Mizuta, I and Tokuda, T and Mizuno, T}, title = {Amyotrophic Lateral Sclerosis Model.}, journal = {Advances in experimental medicine and biology}, volume = {1076}, number = {}, pages = {79-95}, doi = {10.1007/978-981-13-0529-0_6}, pmid = {29951816}, issn = {0065-2598}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Disease Models, Animal ; *Drosophila melanogaster ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects upper and lower motor neurons in the brain and the spinal cord. Due to the progressive neurodegeneration, ALS leads to paralysis and death caused by respiratory failure 2-5 years after the onset of symptoms. There is no effective cure available. Most ALS cases are sporadic, without family history, whereas 10% of the cases are familial. Identification of variants in more than 30 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. Studies of a Drosophila melanogaster model for each of the ALS genes can contribute to uncovering pathophysiological mechanism of ALS and finding targets of the disease-modifying therapy. In this review, we focus on three ALS-causing genes: TAR DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and chromosome 9 open reading frame 72 (C9orf72).}, }
@article {pmid29951815, year = {2018}, author = {Ueyama, M and Nagai, Y}, title = {Repeat Expansion Disease Models.}, journal = {Advances in experimental medicine and biology}, volume = {1076}, number = {}, pages = {63-78}, doi = {10.1007/978-981-13-0529-0_5}, pmid = {29951815}, issn = {0065-2598}, mesh = {Animals ; *Disease Models, Animal ; *Drosophila melanogaster ; Humans ; *Neuromuscular Diseases/genetics ; *Trinucleotide Repeat Expansion/genetics ; }, abstract = {Repeat expansion disorders are a group of inherited neuromuscular diseases, which are caused by expansion mutations of repeat sequences in the disease-causing genes. Repeat expansion disorders include a class of diseases caused by repeat expansions in the coding region of the genes, producing mutant proteins with amino acid repeats, mostly the polyglutamine (polyQ) diseases, and another class of diseases caused by repeat expansions in the noncoding regions, producing aberrant RNA with expanded repeats, which are called noncoding repeat expansion diseases. A variety of Drosophila disease models have been established for both types of diseases, and they have made significant contributions toward elucidating the molecular mechanisms of and developing therapies for these neuromuscular diseases.}, }
@article {pmid29951484, year = {2018}, author = {Esaki, M and Johjima-Murata, A and Islam, MT and Ogura, T}, title = {Biological and Pathological Implications of an Alternative ATP-Powered Proteasomal Assembly With Cdc48 and the 20S Peptidase.}, journal = {Frontiers in molecular biosciences}, volume = {5}, number = {}, pages = {56}, pmid = {29951484}, issn = {2296-889X}, abstract = {The ATP-powered protein degradation machinery plays essential roles in maintaining protein homeostasis in all organisms. Robust proteolytic activities are typically sequestered within protein complexes to avoid the fatal removal of essential proteins. Because the openings of proteolytic chambers are narrow, substrate proteins must undergo unfolding. AAA superfamily proteins (ATPases associated with diverse cellular activities) are mostly located at these openings and regulate protein degradation appropriately. The 26S proteasome, comprising 20S peptidase and 19S regulatory particles, is the major ATP-powered protein degradation machinery in eukaryotes. The 19S particles are composed of six AAA proteins and 13 regulatory proteins, and bind to both ends of a barrel-shaped proteolytic chamber formed by the 20S peptidase. Several recent studies have reported that another AAA protein, Cdc48, can replace the 19S particles to form an alternative ATP-powered proteasomal complex, i.e., the Cdc48-20S proteasome. This review focuses on our current knowledge of this alternative proteasome and its possible linkage to amyotrophic lateral sclerosis.}, }
@article {pmid29951055, year = {2018}, author = {Swarup, G and Sayyad, Z}, title = {Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {1287}, pmid = {29951055}, issn = {1664-3224}, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Autoimmunity ; Autophagy/genetics ; Cell Cycle Proteins ; Disease Models, Animal ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Glaucoma/*genetics/immunology/*metabolism ; Humans ; Membrane Transport Proteins ; *Mutation ; NF-kappa B/metabolism ; Protein Transport ; Retinal Ganglion Cells/metabolism ; Signal Transduction ; Transcription Factor TFIIIA/*genetics/*metabolism ; }, abstract = {Optineurin (OPTN) is an adaptor protein that is involved in mediating a variety of cellular processes such as signaling, vesicle trafficking, and autophagy. Certain mutations in OPTN (gene OPTN) are associated with primary open angle glaucoma, a leading cause of irreversible blindness, and amyotrophic lateral sclerosis, a fatal motor neuron disease. Glaucoma-associated mutations of OPTN are mostly missense mutations. OPTN mediates its functions by interacting with various proteins and altered interactions of OPTN mutants with various proteins primarily contribute to functional defects. It interacts with Rab8, myosin VI, Huntigtin, TBC1D17, and transferrin receptor to mediate various membrane vesicle trafficking pathways. It is an autophagy receptor that mediates cargo-selective as well as non-selective autophagy. Glaucoma-associated mutants of OPTN, E50K, and M98K, cause defective vesicle trafficking, autophagy, and signaling that contribute to death of retinal ganglion cells (RGCs). Transgenic mice expressing E50K-OPTN show loss of RGCs and persistent reactive gliosis. TBK1 protein kinase, which mediates E50K-OPTN and M98K-OPTN induced cell death, is emerging as a potential drug target. Autoimmunity has been implicated in glaucoma but involvement of OPTN or its mutants in autoimmnity has not been explored. In this review, we highlight the main functions of OPTN and how glaucoma-associated mutants alter these functions. We also discuss some of the controversies, such as the role of OPTN in signaling to transcription factor NF-κB, interferon signaling, and use of RGC-5 cell line as a cell culture model.}, }
@article {pmid29947927, year = {2018}, author = {Chung, CG and Lee, H and Lee, SB}, title = {Mechanisms of protein toxicity in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {75}, number = {17}, pages = {3159-3180}, pmid = {29947927}, issn = {1420-9071}, support = {18-BD-0402//Ministry of Science and ICT/ ; 18-BT-02//Ministry of Science and ICT/ ; 18-01-HRSS-02//Ministry of Science and ICT/ ; 18-BR-04-03//Ministry of Science and ICT/ ; 2017R1A2B4003351//Ministry of Science, ICT and Future Planning/ ; 2016M3C7A1947307//Ministry of Science, ICT and Future Planning/ ; 2016M3C7A1904148//Ministry of Science, ICT and Future Planning/ ; KRISS-2018-GP2018-0018//Korea Research Institute of Standards and Science/ ; }, mesh = {Animals ; Cell Nucleus/metabolism ; Disease Progression ; Humans ; Mitochondria/metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; Proteins/*metabolism ; }, abstract = {Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.}, }
@article {pmid29944911, year = {2019}, author = {Yamashita, T and Kwak, S}, title = {Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS.}, journal = {Neuroscience research}, volume = {144}, number = {}, pages = {4-13}, doi = {10.1016/j.neures.2018.06.004}, pmid = {29944911}, issn = {1872-8111}, mesh = {Adenosine Deaminase/*deficiency ; Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/*therapy ; Animals ; Calcium Signaling/physiology ; Cell Death/physiology ; DNA, Complementary/administration &amp; dosage ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Genetic Therapy/methods ; Humans ; Mice ; Mice, Knockout ; Motor Neurons/metabolism/*pathology ; RNA-Binding Proteins ; }, abstract = {TAR DNA-binding protein (TDP-43) pathology in the motor neurons is the most reliable pathological hallmark of amyotrophic lateral sclerosis (ALS), and motor neurons bearing TDP-43 pathology invariably exhibit failure in RNA editing at the GluA2 glutamine/arginine (Q/R) site due to down-regulation of adenosine deaminase acting on RNA 2 (ADAR2). Conditional ADAR2 knockout (AR2) mice display ALS-like phenotype, including progressive motor dysfunction due to loss of motor neurons. Motor neurons devoid of ADAR2 express Q/R site-unedited GluA2, and AMPA receptors with unedited GluA2 in their subunit assembly are abnormally permeable to Ca[2+], which results in progressive neuronal death. Moreover, analysis of AR2 mice has demonstrated that exaggerated Ca[2+] influx through the abnormal AMPA receptors overactivates calpain, a Ca[2+]-dependent protease, that cleaves TDP-43 into aggregation-prone fragments, which serve as seeds for TDP-43 pathology. Activated calpain also disrupts nucleo-cytoplasmic transport and gene expression by cleaving molecules involved in nucleocytoplasmic transport, including nucleoporins. These lines of evidence prompted us to develop molecular targeting therapy for ALS by normalization of disrupted intracellular environment due to ADAR2 down-regulation. In this review, we have summarized the work from our group on the cell death cascade in sporadic ALS and discussed a potential therapeutic strategy for ALS.}, }
@article {pmid29940147, year = {2018}, author = {Chang, KH and Cheng, ML and Chiang, MC and Chen, CM}, title = {Lipophilic antioxidants in neurodegenerative diseases.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {485}, number = {}, pages = {79-87}, doi = {10.1016/j.cca.2018.06.031}, pmid = {29940147}, issn = {1873-3492}, mesh = {Animals ; Antioxidants/*pharmacology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Neurodegenerative Diseases/*drug therapy/pathology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Oxidative stress is commonly involved in the pathogenesis of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Therefore, lipophilic antioxidants, such as vitamin A, carotinoids, vitamin E, coenzyme Q10, docosahexaenoic acid and eicosapentaenoic acid, have received increasing attention as therapeutic and preventive intervention for neurodegenerative diseases. Although difficulties exist with clinical studies due to the nature of the long-standing progression of neurodegenerative diseases, findings in cell and animal models, as well as biomarker studies have implied a relationship between lipophilic antioxidants and neurodegeneration. By reviewing current findings and their implication in neurodegenerative diseases, we conclude that although none of these lipophilic antioxidants have yet provided clear-cut clinical evidence toward beneficial effects in neurodegenerative diseases, they could demonstrate neuroprotection in cellular and/or animal studies. Results from future multidisciplinary studies with optimization of factors including drug dosage, delivery route and chemical structure may provide us with novel treatments for neurodegenerative diseases using lipophilic antioxidants.}, }
@article {pmid29935915, year = {2019}, author = {Fröhlich, E and Wahl, R}, title = {The forgotten effects of thyrotropin-releasing hormone: Metabolic functions and medical applications.}, journal = {Frontiers in neuroendocrinology}, volume = {52}, number = {}, pages = {29-43}, doi = {10.1016/j.yfrne.2018.06.006}, pmid = {29935915}, issn = {1095-6808}, mesh = {Animals ; Breast Neoplasms/*metabolism ; Humans ; Hypothalamus/*metabolism ; Pituitary Gland/*metabolism ; Prolactin/*metabolism ; Spinocerebellar Degenerations/*drug therapy ; Thyroid Diseases/diagnosis/*metabolism ; Thyroid Gland/*metabolism ; Thyrotropin-Releasing Hormone/*metabolism/*therapeutic use ; }, abstract = {Thyrotropin-releasing hormone (TRH) causes a variety of thyroidal and non-thyroidal effects, the best known being the feedback regulation of thyroid hormone levels. This was employed in the TRH stimulation test, which is currently little used. The role of TRH as a cancer biomarker is minor, but exaggerated responses to TSH and prolactin levels in breast cancer led to the hypothesis of a potential role for TRH in the pathogenesis of this disease. TRH is a rapidly degraded peptide with multiple targets, limiting its suitability as a biomarker and drug candidate. Although some studies reported efficacy in neural diseases (depression, spinal cord injury, amyotrophic lateral sclerosis, etc.), therapeutic use of TRH is presently restricted to spinocerebellar degenerative disease. Regulation of TRH production in the hypothalamus, patterns of expression of TRH and its receptor in the body, its role in energy metabolism and in prolactin secretion are addressed in this review.}, }
@article {pmid29933890, year = {2018}, author = {Kjældgaard, AL and Pilely, K and Olsen, KS and Pedersen, SW and Lauritsen, A&#xd8; and Møller, K and Garred, P}, title = {Amyotrophic lateral sclerosis: The complement and inflammatory hypothesis.}, journal = {Molecular immunology}, volume = {102}, number = {}, pages = {14-25}, doi = {10.1016/j.molimm.2018.06.007}, pmid = {29933890}, issn = {1872-9142}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*physiopathology ; Animals ; Complement System Proteins/*physiology ; Humans ; Immunity, Innate/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, neurodegenerative motor neuron disease. The aetiology of ALS remains an enigma which hinders the design of an effective treatment to prevent, postpone, or reverse the pathophysiological changes occurring during the aggressive progression of this disease. During the last decade, basic research within the innate immune system, and in particular the complement system, has revealed new, important roles of the innate immune system during development, homeostasis, and ageing within as well as outside the central nervous system. Several lines of evidence indicate that aberrant activation of the complement system locally in the central nervous system as well as systemically may be involved in the pathophysiology of ALS. This exciting new knowledge could point towards the innate immune system as a potential target of medical intervention in ALS. Recently, the historic perception of ALS as a central neurodegenerative disease has been challenged due to the significant amount of evidence of a dying-back mechanism causing the selective destruction of the motor neurons, indicating that disease onset occurs outside the borders of the blood-brain-barrier. This review addresses the function of the innate immune system during ALS. We emphasize the role of the complement system and specifically suggest the involvement of ficolin-3 from the lectin pathway in the pathophysiology of ALS.}, }
@article {pmid29921889, year = {2019}, author = {Ni, R and Mu, L and Ametamey, S}, title = {Positron emission tomography of type 2 cannabinoid receptors for detecting inflammation in the central nervous system.}, journal = {Acta pharmacologica Sinica}, volume = {40}, number = {3}, pages = {351-357}, pmid = {29921889}, issn = {1745-7254}, mesh = {Animals ; Brain/metabolism ; Central Nervous System Diseases/*diagnosis ; Humans ; Inflammation/*diagnosis ; Positron-Emission Tomography ; Radiopharmaceuticals/metabolism ; Receptor, Cannabinoid, CB2/*metabolism ; }, abstract = {Cannabinoid receptor CB2 (CB2R) is upregulated on activated microglia and astrocytes in the brain under inflammatory conditions and plays important roles in many neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. The advent of positron emission tomography (PET) using CB2R radiotracers has enabled the visualization of CB2R distribution in vivo in animal models of central nervous system inflammation, however translation to humans has been less successful. Several novel CB2R radiotracers have been developed and evaluated to quantify microglial activation. In this review, we summarize the recent preclinical and clinical imaging results of CB2R PET tracers and discuss the prospects of CB2R imaging using PET.}, }
@article {pmid29921193, year = {2018}, author = {Niazi, ZR and Khan, N and Khan, S and Alam, M and Kamal, MA}, title = {Potential Application of Venom Proteins in Designing of Medicines for Treating Human Neurodegenerative Disorders.}, journal = {Protein and peptide letters}, volume = {25}, number = {7}, pages = {633-642}, doi = {10.2174/0929866525666180614120407}, pmid = {29921193}, issn = {1875-5305}, mesh = {Animals ; *Bee Venoms/genetics/therapeutic use ; *Drug Design ; Humans ; Mice ; Neurodegenerative Diseases/*drug therapy ; Rats ; *Wasp Venoms/genetics/therapeutic use ; }, abstract = {BACKGROUND: Neurodegenerative disorder are persistently increasing and relentlessly affecting the individuals, families and society as whole. Regrettably these disorders are resistant to the available drugs, the outcomes are only palliative while the side effects of the therapy harm the patient compliance as well as treatment. Drugs from venomous source have been considered as an effective alternative for such types of disorders, particularly neurodegenerative diseases. Due to emerging advancement in the field of proteomics, genomics and molecular biology, characterization and screening of these novel compounds become more assessable.<br><br>CONCLUSION: In this reverence, the present study reviews the current consideration of the mode of action and the future prediction concerning the use of novel compounds isolated from arthropods and other venomous animals in the treatment of major neurodegenerative diseases such as Parkinson disease, Alzheimer disease, Multiple Sclerosis, Epilepsy and Amyotrophic Lateral Sclerosis.}, }
@article {pmid29916024, year = {2018}, author = {Lehmkuhl, EM and Zarnescu, DC}, title = {Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {283-301}, pmid = {29916024}, issn = {2190-5215}, support = {R01 NS091299/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Frontotemporal Dementia/*metabolism ; Humans ; Protein Biosynthesis/*physiology ; RNA-Binding Proteins/*metabolism ; Ribosomes/metabolism ; }, abstract = {Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease. Here, we review dysregulation of translation in the context of age-related neurodegeneration and discuss novel methods to interrogate translation. This review primarily focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum disorder heavily associated with RNA metabolism, while also analyzing translational inhibition in the context of related neurodegenerative disorders such as Alzheimer's disease and Huntington's disease and the translation-related pathomechanisms common in neurodegenerative disease.}, }
@article {pmid29916023, year = {2018}, author = {Bennett, CL and La Spada, AR}, title = {Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {265-281}, doi = {10.1007/978-3-319-89689-2_10}, pmid = {29916023}, issn = {2190-5215}, mesh = {Cerebellar Diseases/*metabolism/pathology ; Cerebellum/*metabolism/pathology ; DNA Helicases ; Humans ; Motor Neuron Disease/*metabolism/pathology ; Multifunctional Enzymes ; Neurodegenerative Diseases/*metabolism/pathology ; RNA ; RNA Helicases/*metabolism ; *Transcriptome ; }, abstract = {Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. SETX performs a number of RNA regulatory functions, including maintaining RNA transcriptome homeostasis. Over the last decade, altered RNA regulation and aberrant RNA-binding protein function have emerged as a central theme in motor neuron disease pathogenesis, with evidence suggesting that sporadic ALS disease pathology may overlap with the molecular pathology uncovered in familial ALS. Like other RNA processing proteins linked to ALS, the basis for SETX gain-of-function motor neuron toxicity remains ill-defined. Studies of yeast Sen1p and mammalian SETX protein have revealed a range of important RNA regulatory functions, including resolution of R-loops to permit transcription termination, and RNA splicing. Growing evidence suggests that SETX may represent an important genetic modifier locus for sporadic ALS. In cycling cells, SETX is found at nuclear foci during the S/G2 cell-cycle transition phase, and may function at sites of collision between components of the replisome and transcription machinery. While we do not yet know which SETX activities are most critical to neurodegeneration, our evolving understanding of SETX function will undoubtedly be crucial for not only understanding the role of SETX in ALS and ataxia disease pathogenesis, but also for delineating the mechanistic biology of fundamentally important molecular processes in the cell.}, }
@article {pmid29916022, year = {2018}, author = {Shenouda, M and Zhang, AB and Weichert, A and Robertson, J}, title = {Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {239-263}, doi = {10.1007/978-3-319-89689-2_9}, pmid = {29916022}, issn = {2190-5215}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Brain/*metabolism/pathology ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/*metabolism/pathology ; Humans ; Mutation ; }, abstract = {The discovery of TDP-43 as a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) was first made in 2006. Prior to 2006 there were only 11 publications related to TDP-43, now there are over 2000, indicating the importance of TDP-43 to unraveling the complex molecular mechanisms that underpin the pathogenesis of ALS/FTLD. Subsequent to this discovery, TDP-43 pathology was also found in other neurodegenerative diseases, including Alzheimer's disease, the significance of which is still in the early stages of exploration. TDP-43 is a predominantly nuclear DNA/RNA-binding protein, one of a number of RNA-binding proteins that are now known to be linked with ALS/FTLD, including Fused in Sarcoma (FUS), heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). However, what sets TDP-43 apart is the vast number of cases in which TDP-43 pathology is present, providing a point of convergence, the understanding of which could lead to broadly applicable therapeutics. Here we will focus on TDP-43 in ALS/FTLD, its nuclear and cytoplasmic functions, and consequences should these functions go awry.}, }
@article {pmid29916020, year = {2018}, author = {Fernandes, N and Eshleman, N and Buchan, JR}, title = {Stress Granules and ALS: A Case of Causation or Correlation?.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {173-212}, doi = {10.1007/978-3-319-89689-2_7}, pmid = {29916020}, issn = {2190-5215}, support = {R01 GM114564/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Autophagy/physiology ; Cytoplasmic Granules/*metabolism ; Humans ; Motor Neurons/*metabolism ; RNA-Binding Protein FUS/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by cytoplasmic protein aggregates within motor neurons. These aggregates are linked to ALS pathogenesis. Recent evidence has suggested that stress granules may aid the formation of ALS protein aggregates. Here, we summarize current understanding of stress granules, focusing on assembly and clearance. We also assess the evidence linking alterations in stress granule formation and dynamics to ALS protein aggregates and disease pathology.}, }
@article {pmid29916017, year = {2018}, author = {Boehringer, A and Bowser, R}, title = {RNA Nucleocytoplasmic Transport Defects in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {85-101}, doi = {10.1007/978-3-319-89689-2_4}, pmid = {29916017}, issn = {2190-5215}, mesh = {Humans ; Neurodegenerative Diseases/*metabolism ; Nuclear Envelope/metabolism ; Nuclear Pore/*metabolism ; Nuclear Pore Complex Proteins/metabolism ; RNA Transport/*physiology ; }, abstract = {In eukaryotic cells, transcription and translation are compartmentalized by the nuclear membrane, requiring an active transport of RNA from the nucleus into the cytoplasm. This is accomplished by a variety of transport complexes that contain either a member of the exportin family of proteins and translocation fueled by GTP hydrolysis or in the case of mRNA by complexes containing the export protein NXF1. Recent evidence indicates that RNA transport is altered in a number of different neurodegenerative diseases including Huntington's disease, Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Alterations in RNA transport predominately fall into three categories: Alterations in the nuclear membrane and mislocalization and aggregation of the nucleoporins that make up the nuclear pore; alterations in the Ran gradient and the proteins that control it which impacts exportin based nuclear export; and alterations of proteins that are required for the export of mRNA leading nuclear accumulation of mRNA.}, }
@article {pmid29916014, year = {2018}, author = {Ebbert, MTW and Lank, RJ and Belzil, VV}, title = {An Epigenetic Spin to ALS and FTD.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {1-29}, doi = {10.1007/978-3-319-89689-2_1}, pmid = {29916014}, issn = {2190-5215}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; DNA Methylation ; *Epigenesis, Genetic ; Frontotemporal Dementia/*genetics ; Humans ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and lethal neurodegenerative diseases seen comorbidly in up to 15% of patients. Despite several decades of research, no effective treatment or disease-modifying strategies have been developed. We now understand more than before about the genetics and biology behind ALS and FTD, but the genetic etiology for the majority of patients is still unknown and the phenotypic variability observed across patients, even those carrying the same mutation, is enigmatic. Additionally, susceptibility factors leading to neuronal vulnerability in specific central nervous system regions involved in disease are yet to be identified. As the inherited but dynamic epigenome acts as a cell-specific interface between the inherited fixed genome and both cell-intrinsic mechanisms and environmental input, adaptive epigenetic changes might contribute to the ALS/FTD aspects we still struggle to comprehend. This chapter summarizes our current understanding of basic epigenetic mechanisms, how they relate to ALS and FTD, and their potential as therapeutic targets. A clear understanding of the biological mechanisms driving these two currently incurable diseases is urgent-well-needed therapeutic strategies need to be developed soon. Disease-specific epigenetic changes have already been observed in patients and these might be central to this endeavor.}, }
@article {pmid29915483, year = {2018}, author = {An, V and Chandra, R and Lawrence, M}, title = {Anastomotic Failure in Colorectal Surgery: Where Are We at?.}, journal = {The Indian journal of surgery}, volume = {80}, number = {2}, pages = {163-170}, pmid = {29915483}, issn = {0972-2068}, abstract = {Anastomotic leak (AL) can be a devastating complication in colorectal surgery. While it is less frequent in the modern era, it still results in significant morbidity and mortality, prolonged hospital stays and increases the costs and demands on health services. There is inevitable interplay between patient physiology and technical factors that predispose a patient to AL. Obesity, preoperative total proteins, male gender, ongoing anticoagulant treatment, intraoperative complication and number of hospital beds have been identified as independent risk factors. This has led to an online risk calculator for AL. Non-steroidal anti-inflammatory drugs and neoadjuvant chemoradiotherapy have also been implicated, but no significant evidence has yet been found to support causation. In addition, technical factors such as type of anastomosis, mechanical bowel preparation, drains, omentoplasty and faecal diversion have failed to show significant differences in AL rates. Early diagnosis and intervention in AL is essential in reducing the rates of morbidity and mortality. Clinical assessment has high sensitivity but low specificity and should be used in combination with imaging techniques to get a diagnosis. C-reactive protein is also a useful marker. The management will depend on the grade of AL and the clinical state of the patient. Management options include conservative measures such as antibiotics and/or percutaneous drainage to more invasion procedures such as open drainage and/or Hartmann's procedure. In conclusion, ALs will forever pose challenges to the surgeon in diagnosis and management. It is often the yardstick by which each surgeon is measured and is the source of significant morbidity to patients and health care services worldwide. As a result, a low threshold for investigation and intervention is mandatory to ensure better outcomes and lower overall mortality and morbidity.}, }
@article {pmid29909186, year = {2018}, author = {Lorenzoni, PJ and Ducci, RD and Dalledone, GO and Kay, CSK and de Almeida, SM and Werneck, LC and Scola, RH}, title = {Motor neuron disease in patients with HIV infection: Report of two cases and brief review of the literature.}, journal = {Clinical neurology and neurosurgery}, volume = {171}, number = {}, pages = {139-142}, doi = {10.1016/j.clineuro.2018.06.006}, pmid = {29909186}, issn = {1872-6968}, mesh = {Amyotrophic Lateral Sclerosis/complications/diagnosis/*virology ; Brazil ; Diagnosis, Differential ; Female ; HIV/*pathogenicity ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/complications/diagnosis/*virology ; Motor Neurons/*virology ; }, abstract = {HIV-associated motor neuron disease (MND), or amyotrophic lateral sclerosis (ALS)-like syndrome associated with HIV infection, is a rare manifestation of HIV infection. HIV-associated MND has only been identified in few cases to date. We analysed two Brazilian patients with HIV infection who developed MND. The diagnosis of HIV infection was concomitant with diagnosis of MND in one patient and it occurred eight years before the MND symptoms in another patient. The manifestation of MND in our patients with HIV infection was similar to classic ALS. The antiretroviral therapy improves their HIV infection. However, slow progression of MND occurred in the two patients despite their antiretroviral therapy or HIV viral load (undetectable). We revised the international literature (PubMed database) of the patients reported with MND and HIV infection.}, }
@article {pmid29902695, year = {2018}, author = {Scannevin, RH}, title = {Therapeutic strategies for targeting neurodegenerative protein misfolding disorders.}, journal = {Current opinion in chemical biology}, volume = {44}, number = {}, pages = {66-74}, doi = {10.1016/j.cbpa.2018.05.018}, pmid = {29902695}, issn = {1879-0402}, mesh = {Animals ; Drug Discovery/*methods ; Humans ; Models, Molecular ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/*drug therapy/pathology ; Protein Aggregates/drug effects ; Protein Conformation/drug effects ; Proteostasis Deficiencies/*drug therapy/pathology ; }, abstract = {Neurodegenerative diseases can arise from a multitude of different pathological drivers, however protein misfolding appears to be a common molecular feature central to several disorders. Protein folding, and attainment of correct secondary and tertiary structure, is essential for proper protein function. Protein misfolding gives rise to structural perturbations that can result in loss of protein function or a gain of toxic function, such as through aggregation, either of which can initiate and propagate biological responses that are deleterious to cells. Several neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease, each have identified molecular components in which protein misfolding perturbs cellular systems that ultimately lead to cell death, and this predominately occurs in neurons. Current efforts focused on developing therapies for protein misfolding disorders have employed diverse strategies; inhibiting the production of disease-relevant proteins prone to misfolding, inhibiting the aggregation of misfolded proteins, removing and preventing spread of aggregated misfolded proteins and manipulating cellular systems to mitigate the toxic effects of misfolded proteins. Each of these strategies has yielded therapeutic agents that have transitioned from preclinical proof of concept studies into human clinical testing. These approaches and therapies are described herein.}, }
@article {pmid29898036, year = {2018}, author = {Vieira, AS and Dogini, DB and Lopes-Cendes, I}, title = {Role of non-coding RNAs in non-aging-related neurological disorders.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {51}, number = {8}, pages = {e7566}, pmid = {29898036}, issn = {1414-431X}, mesh = {Circulating MicroRNA ; Gene Expression Regulation ; Genetic Markers/physiology ; Humans ; MicroRNAs/*physiology ; Nervous System Diseases/*genetics ; Neurodegenerative Diseases/genetics ; Neuromuscular Diseases/genetics ; RNA, Long Noncoding/*physiology ; }, abstract = {Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.}, }
@article {pmid29887768, year = {2018}, author = {Dupont, AC and Largeau, B and Guilloteau, D and Santiago Ribeiro, MJ and Arlicot, N}, title = {The Place of PET to Assess New Therapeutic Effectiveness in Neurodegenerative Diseases.}, journal = {Contrast media &amp; molecular imaging}, volume = {2018}, number = {}, pages = {7043578}, pmid = {29887768}, issn = {1555-4317}, mesh = {Animals ; Drug Monitoring/*methods ; Humans ; Neurodegenerative Diseases/*therapy ; Positron-Emission Tomography/*methods ; Precision Medicine ; }, abstract = {In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. We also discuss opportunities for PET imaging to drive more personalized neuroprotective and therapeutic strategies, taking into account individual variability, within the growing framework of precision medicine.}, }
@article {pmid29887144, year = {2018}, author = {Ayers, JI and Cashman, NR}, title = {Prion-like mechanisms in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {153}, number = {}, pages = {337-354}, doi = {10.1016/B978-0-444-63945-5.00018-0}, pmid = {29887144}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Prions/genetics/*metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {The prion hypothesis - a protein conformation capable of replicating without a nucleic acid genome - was heretical at the time of its discovery. However, the characteristics of the disease-misfolded prion protein and its ability to transmit disease, replicate, and spread are now widely accepted throughout the scientific community. In fact, in the last decade a wealth of evidence has emerged supporting similar properties observed for many of the misfolded proteins implicated in other neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, tauopathies, and as described in this chapter, amyotrophic lateral sclerosis (ALS). Multiple studies have now demonstrated the ability for superoxide dismutase-1, 43-kDa transactive response (TAR) DNA-binding protein, fused-in sarcoma, and most recently, C9orf72-encoded polypeptides to display properties similar to those of prions. The majority of these are cell-free and in vitro assays, while superoxide dismutase-1 remains the only ALS-linked protein to demonstrate several prion-like properties in vivo. In this chapter, we provide an introduction to ALS and review the recent literature linking several proteins implicated in the familial forms of the disease to properties of the prion protein.}, }
@article {pmid29885742, year = {2018}, author = {Berson, A and Nativio, R and Berger, SL and Bonini, NM}, title = {Epigenetic Regulation in Neurodegenerative Diseases.}, journal = {Trends in neurosciences}, volume = {41}, number = {9}, pages = {587-598}, pmid = {29885742}, issn = {1878-108X}, support = {F32 NS084667/NS/NINDS NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 NS078283/NS/NINDS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/genetics ; Animals ; Chromatin/genetics ; Chromatin Assembly and Disassembly/*physiology ; Epigenesis, Genetic/*physiology ; Histones/*physiology ; Humans ; Models, Biological ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/*genetics/*physiopathology ; }, abstract = {Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.}, }
@article {pmid29875767, year = {2018}, author = {Toth, RP and Atkin, JD}, title = {Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {1017}, pmid = {29875767}, issn = {1664-3224}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Autophagy ; Cell Cycle Proteins ; Glaucoma/*genetics ; Humans ; Membrane Transport Proteins ; Mice ; *Mutation ; Transcription Factor TFIIIA/*genetics/physiology ; }, abstract = {Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and glaucoma, affect millions of people worldwide. ALS is caused by the loss of motor neurons in the spinal cord, brainstem, and brain, and genetic mutations are responsible for 10% of all ALS cases. Glaucoma is characterized by the loss of retinal ganglion cells and is the most common cause of irreversible blindness. Interestingly, mutations in OPTN, encoding optineurin, are associated with both ALS and glaucoma. Optineurin is a highly abundant protein involved in a wide range of cellular processes, including the inflammatory response, autophagy, Golgi maintenance, and vesicular transport. In this review, we summarize the role of optineurin in cellular mechanisms implicated in neurodegenerative disorders, including neuroinflammation, autophagy, and vesicular trafficking, focusing in particular on the consequences of expression of mutations associated with ALS and glaucoma. This review, therefore showcases the impact of optineurin dysfunction in ALS and glaucoma.}, }
@article {pmid29875629, year = {2018}, author = {Krestel, H and Meier, JC}, title = {RNA Editing and Retrotransposons in Neurology.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {163}, pmid = {29875629}, issn = {1662-5099}, abstract = {Compared to sites in protein-coding sequences many more targets undergoing adenosine to inosine (A-to-I) RNA editing were discovered in non-coding regions of human cerebral transcripts, particularly in genetic transposable elements called retrotransposons. We review here the interaction mechanisms of RNA editing and retrotransposons and their impact on normal function and human neurological diseases. Exemplarily, A-to-I editing of retrotransposons embedded in protein-coding mRNAs can contribute to protein abundance and function via circular RNA formation, alternative splicing, and exonization or silencing of retrotransposons. Interactions leading to disease are not very well understood. We describe human diseases with involvement of the central nervous system including inborn errors of metabolism, neurodevelopmental disorders, neuroinflammatory and neurodegenerative and paroxysmal diseases, in which retrotransposons (Alu and/or L1 elements) appear to be causally involved in genetic rearrangements. Sole binding of single-stranded retrotransposon transcripts by RNA editing enzymes rather than enzymatic deamination may have a homeostatic effect on retrotransposon turnover. We also review evidence in support of the emerging pathophysiological function of A-to-I editing of retrotransposons in inflammation and its implication for different neurological diseases including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's and Parkinson's disease, and epilepsy.}, }
@article {pmid29874196, year = {2018}, author = {Röösli, M and Jalilian, H}, title = {A meta-analysis on residential exposure to magnetic fields and the risk of amyotrophic lateral sclerosis.}, journal = {Reviews on environmental health}, volume = {33}, number = {3}, pages = {309-313}, doi = {10.1515/reveh-2018-0019}, pmid = {29874196}, issn = {2191-0308}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; *Environmental Exposure ; Humans ; Magnetic Fields/*adverse effects ; *Residence Characteristics ; Risk Factors ; }, }
@article {pmid29872373, year = {2018}, author = {Fujikake, N and Shin, M and Shimizu, S}, title = {Association Between Autophagy and Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {255}, pmid = {29872373}, issn = {1662-4548}, abstract = {Autophagy is a phylogenetically conserved mechanism that controls the degradation of subcellular constituents, including misfolded proteins, and damaged organelles. The progression of many neurodegenerative diseases is thought to be driven by the aggregation of misfolded proteins; therefore, autophagic activity is thought to affect disease severity to some extent. In some neurodegenerative diseases, the suppression of autophagic activity accelerates disease progression. Given that the induction of autophagy can potentially mitigate disease severity, various autophagy-inducing compounds have been developed and their efficacy has been evaluated in several rodent models of neurodegenerative diseases.}, }
@article {pmid29870780, year = {2018}, author = {Fogarty, MJ}, title = {Driven to decay: Excitability and synaptic abnormalities in amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {140}, number = {}, pages = {318-333}, doi = {10.1016/j.brainresbull.2018.05.023}, pmid = {29870780}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Humans ; Neurons/physiology ; Synapses/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease and is clinically characterised by the death of corticospinal motor neurons (CSMNs), spinal and brainstem MNs and the degeneration of the corticospinal tract. Degeneration of CSMNs and MNs leads inexorably to muscle wastage and weakness, progressing to eventual death within 3-5 years of diagnosis. The CSMNs, located within layer V of the primary motor cortex, project axons constituting the corticospinal tract, forming synaptic connections with brainstem and spinal cord interneurons and MNs. Clinical ALS may be divided into familial (∼10% of cases) or sporadic (∼90% of cases), based on apparent random incidence. The emergence of transgenic murine models, expressing different ALS-associated mutations has accelerated our understanding of ALS pathogenesis, although precise mechanisms remain elusive. Multiple avenues of investigation suggest that cortical electrical abnormalities have pre-eminence in the pathophysiology of ALS. In addition, glutamate-mediated functional and structural alterations in both CSMNs and MNs are present in both sporadic and familial forms of ALS. This review aims to promulgate debate in the field with regard to the common aetiology of sporadic and familial ALS. A specific focus on a nexus point in ALS pathogenesis, namely, the synaptic and intrinsic hyperexcitability of CSMNs and MNs and alterations to their structure are comprehensively detailed. The association of extramotor dysfunction with neuronal structural/functional alterations will be discussed. Finally, the implications of the latest research on the dying-forward and dying-back controversy are considered.}, }
@article {pmid29870639, year = {2017}, author = {Patai, R and Nógrádi, B and Meszlényi, V and Obál, I and Engelhardt, J and Siklós, L}, title = {[Calcium ion is a common denominator in the pathophysiological processes of amyotrophic lateral sclerosis].}, journal = {Ideggyogyaszati szemle}, volume = {70}, number = {7-8}, pages = {247-257}, doi = {10.18071/isz.70.0247}, pmid = {29870639}, issn = {0019-1442}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Calcium/*metabolism ; Humans ; Ions/metabolism ; Motor Neurons/metabolism ; Nerve Degeneration/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most frequent motor neuron disease is characterized by progressive muscle weakness caused by the degeneration of the motor neurons in the spinal cord and motor cortex. However, according to the recent observations, ALS is a rather complex syndrome which frequently involves symptoms of cognitive impairment. Therefore, ALS cases can be interpreted in a clinico-pathological spectrum spanning from the classical ALS involving only the motor system to the fronto-temporal dementia. The progression of the disease, however, manifested in the degeneration of the upper and lower motor neurons, is based on the same complex pathobiology. The main elements of the pathomechanism, such as oxidative stress, excitotoxicity, immune/inflammatory processes and mitochondrial dysfunction are well described already, which operate in orchestrated way and amplify the deleterious effect of each other. It is assumed that calcium ions act as a catalyst in this interaction, hence each of the individual mechanisms has strong, positive and reciprocal calcium dependence thus may combine the individual pathological processes into a unified escalating mechanism of neuronal destruction. This review provides an overview of the role of calcium in connecting and amplifying the major mechanisms which lead to degeneration of the motor neurons in ALS.}, }
@article {pmid29867991, year = {2018}, author = {Ryan, TA and Tumbarello, DA}, title = {Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {1024}, pmid = {29867991}, issn = {1664-3224}, support = {205909/Z/17/Z//Wellcome Trust/United Kingdom ; }, mesh = {Adaptor Proteins, Signal Transducing ; Animals ; Autophagy/*genetics ; Cell Cycle Proteins ; Gene Expression Regulation ; Glaucoma/genetics ; Humans ; Membrane Transport Proteins ; Mice ; Mitophagy/genetics ; Mutation ; Protein Binding ; Protein Transport ; Signal Transduction/*genetics ; Transcription Factor TFIIIA/chemistry/*genetics ; }, abstract = {Optineurin is a multifunctional adaptor protein intimately involved in various vesicular trafficking pathways. Through interactions with an array of proteins, such as myosin VI, huntingtin, Rab8, and Tank-binding kinase 1, as well as via its oligomerisation, optineurin has the ability to act as an adaptor, scaffold, or signal regulator to coordinate many cellular processes associated with the trafficking of membrane-delivered cargo. Due to its diverse interactions and its distinct functions, optineurin is an essential component in a number of homeostatic pathways, such as protein trafficking and organelle maintenance. Through the binding of polyubiquitinated cargoes via its ubiquitin-binding domain, optineurin also serves as a selective autophagic receptor for the removal of a wide range of substrates. Alternatively, it can act in an ubiquitin-independent manner to mediate the clearance of protein aggregates. Regarding its disease associations, mutations in the optineurin gene are associated with glaucoma and have more recently been found to correlate with Paget's disease of bone and amyotrophic lateral sclerosis (ALS). Indeed, ALS-associated mutations in optineurin result in defects in neuronal vesicular localisation, autophagosome-lysosome fusion, and secretory pathway function. More recent molecular and functional analysis has shown that it also plays a role in mitophagy, thus linking it to a number of other neurodegenerative conditions, such as Parkinson's. Here, we review the role of optineurin in intracellular membrane trafficking, with a focus on autophagy, and describe how upstream signalling cascades are critical to its regulation. Current data and contradicting reports would suggest that optineurin is an important and selective autophagy receptor under specific conditions, whereby interplay, synergy, and functional redundancy with other receptors occurs. We will also discuss how dysfunction in optineurin-mediated pathways may lead to perturbation of critical cellular processes, which can drive the pathologies of number of diseases. Therefore, further understanding of optineurin function, its target specificity, and its mechanism of action will be critical in fully delineating its role in human disease.}, }
@article {pmid29867335, year = {2018}, author = {Purice, MD and Taylor, JP}, title = {Linking hnRNP Function to ALS and FTD Pathology.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {326}, pmid = {29867335}, issn = {1662-4548}, support = {R35 NS097974/NS/NINDS NIH HHS/United States ; }, abstract = {Following years of rapid progress identifying the genetic underpinnings of amyotrophic lateral sclerosis (ALS) and related diseases such as frontotemporal dementia (FTD), remarkable consistencies have emerged pointing to perturbed biology of heterogeneous nuclear ribonucleoproteins (hnRNPs) as a central driver of pathobiology. To varying extents these RNA-binding proteins are deposited in pathological inclusions in affected tissues in ALS and FTD. Moreover, mutations in hnRNPs account for a significant number of familial cases of ALS and FTD. Here we review the normal function and potential pathogenic contribution of TDP-43, FUS, hnRNP A1, hnRNP A2B1, MATR3, and TIA1 to disease. We highlight recent evidence linking the low complexity sequence domains (LCDs) of these hnRNPs to the formation of membraneless organelles and discuss how alterations in the dynamics of these organelles could contribute to disease. In particular, we discuss the various roles of disease-associated hnRNPs in stress granule assembly and disassembly, and examine the emerging hypothesis that disease-causing mutations in these proteins lead to accumulation of persistent stress granules.}, }
@article {pmid29866706, year = {2019}, author = {Agarwal, S and Koch, G and Hillis, AE and Huynh, W and Ward, NS and Vucic, S and Kiernan, MC}, title = {Interrogating cortical function with transcranial magnetic stimulation: insights from neurodegenerative disease and stroke.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {90}, number = {1}, pages = {47-57}, doi = {10.1136/jnnp-2017-317371}, pmid = {29866706}, issn = {1468-330X}, support = {P50 DC014664/DC/NIDCD NIH HHS/United States ; R01 DC005375/DC/NIDCD NIH HHS/United States ; }, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Cerebral Cortex/*physiopathology ; Frontotemporal Dementia/physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Parkinson Disease/physiopathology ; Stroke/*physiopathology ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {Transcranial magnetic stimulation (TMS) is an accessible, non-invasive technique to study cortical function in vivo. TMS studies have provided important pathophysiological insights across a range of neurodegenerative disorders and enhanced our understanding of brain reorganisation after stroke. In neurodegenerative disease, TMS has provided novel insights into the function of cortical output cells and the related intracortical interneuronal networks. Characterisation of cortical hyperexcitability in amyotrophic lateral sclerosis and altered motor cortical function in frontotemporal dementia, demonstration of cholinergic deficits in Alzheimer's disease and Parkinson's disease are key examples where TMS has led to advances in understanding of disease pathophysiology and potential mechanisms of propagation, with the potential for diagnostic applications. In stroke, TMS methodology has facilitated the understanding of cortical reorganisation that underlie functional recovery. These insights are critical to the development of effective and targeted rehabilitation strategies in stroke. The present review will provide an overview of cortical function measures obtained using TMS and how such measures may provide insight into brain function. Through an improved understanding of cortical function across a range of neurodegenerative disorders, and identification of changes in neural structure and function associated with stroke that underlie clinical recovery, more targeted therapeutic approaches may now be developed in an evolving era of precision medicine.}, }
@article {pmid29863360, year = {2018}, author = {Siu, M and Sengupta Ghosh, A and Lewcock, JW}, title = {Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration.}, journal = {Journal of medicinal chemistry}, volume = {61}, number = {18}, pages = {8078-8087}, doi = {10.1021/acs.jmedchem.8b00370}, pmid = {29863360}, issn = {1520-4804}, mesh = {Animals ; Calcium-Binding Proteins ; Humans ; Intercellular Signaling Peptides and Proteins ; MAP Kinase Kinase Kinases/*antagonists &amp; inhibitors ; Membrane Proteins/*antagonists &amp; inhibitors ; Neurodegenerative Diseases/*drug therapy ; Protein Kinase Inhibitors/*therapeutic use ; }, abstract = {Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and describe selected small molecules that have been utilized to inhibit DLK kinase activity in vivo. These compounds represent valuable tools for understanding the role of DLK signaling and evaluating the potential for DLK inhibition as a therapeutic strategy to prevent neuronal degeneration.}, }
@article {pmid29861271, year = {2018}, author = {Trist, BG and Hare, DJ and Double, KL}, title = {A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress.}, journal = {Cell chemical biology}, volume = {25}, number = {7}, pages = {807-816}, doi = {10.1016/j.chembiol.2018.05.004}, pmid = {29861271}, issn = {2451-9448}, mesh = {Animals ; Homeostasis ; Humans ; Metals/*metabolism ; Movement Disorders/*metabolism ; Mutation ; *Oxidative Stress ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration.}, }
@article {pmid29857583, year = {2018}, author = {Gerhardt, S and Mohajeri, MH}, title = {Changes of Colonic Bacterial Composition in Parkinson's Disease and Other Neurodegenerative Diseases.}, journal = {Nutrients}, volume = {10}, number = {6}, pages = {}, pmid = {29857583}, issn = {2072-6643}, mesh = {Biomedical Research/methods ; Confounding Factors, Epidemiologic ; Disease Progression ; Dysbiosis/epidemiology/immunology/*microbiology/physiopathology ; Enteric Nervous System/immunology/*physiopathology ; *Evidence-Based Medicine ; *Gastrointestinal Microbiome/immunology ; Humans ; Intestinal Mucosa/immunology/innervation/*microbiology/physiopathology ; Neurodegenerative Diseases/epidemiology/immunology/microbiology/physiopathology ; *Neuroimmunomodulation ; Parkinson Disease/epidemiology/immunology/*microbiology/physiopathology ; Reproducibility of Results ; Research Design ; Severity of Illness Index ; }, abstract = {In recent years evidence has emerged that neurodegenerative diseases (NDs) are strongly associated with the microbiome composition in the gut. Parkinson's disease (PD) is the most intensively studied neurodegenerative disease in this context. In this review, we performed a systematic evaluation of the published literature comparing changes in colonic microbiome in PD to the ones observed in other NDs including Alzheimer's disease (AD), multiple system atrophy (MSA), multiple sclerosis (MS), neuromyelitis optica (NMO) and amyotrophic lateral sclerosis (ALS). To enhance the comparability of different studies, only human case-control studies were included. Several studies showed an increase of Lactobacillus, Bifidobacterium, Verrucomicrobiaceae and Akkermansia in PD. A decrease of Faecalibacterium spp., Coprococcus spp., Blautia spp., Prevotella spp. and Prevotellaceae was observed in PD. On a low taxonomic resolution, like the phylum level, the changes are not disease-specific and are inconsistent. However, on a higher taxonomic resolution like genus or species level, a minor overlap was observed between PD and MSA, both alpha synucleinopathies. We show that standardization of sample collection and analysis is necessary for ensuring the reproducibility and comparability of data. We also provide evidence that assessing the microbiota composition at high taxonomic resolution reveals changes in relative abundance that may be specific to or characteristic of one disease or disease group, and might evolve discriminative power. The interactions between bacterial species and strains and the co-abundances must be investigated before assumptions about the effects of specific bacteria on the host can be made with certainty.}, }
@article {pmid29854003, year = {2018}, author = {Wurster, CD and Ludolph, AC}, title = {Antisense oligonucleotides in neurological disorders.}, journal = {Therapeutic advances in neurological disorders}, volume = {11}, number = {}, pages = {1756286418776932}, pmid = {29854003}, issn = {1756-2856}, abstract = {The introduction of genetics revolutionized the field of neurodegenerative and neuromuscular diseases and has provided considerable insight into the underlying pathomechanisms. Nevertheless, effective treatment options have been limited. This changed recently when antisense oligonucleotides (ASOs) could be translated from in vitro and experimental animal studies into clinical practice. In 2016, two ASOs were approved by the United States US Food and Drug Administration (FDA) and demonstrated remarkable efficacy in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). ASOs are synthetic single-stranded strings of nucleic acids. They selectively bind to specific premessenger ribonucleic acid (pre-mRNA)/mRNA sequences and alter protein synthesis by several mechanisms of action. Thus, apart from gene replacement, ASOs may therefore provide the most direct therapeutic strategy for influencing gene expression. In this review, we shall discuss basic mechanisms of ASO action, the role of chemical modifications needed to improve the pharmacodynamic and pharmacokinetic properties of ASOs, and we shall then focus on several ASOs developed for the treatment of neurodegenerative and neuromuscular disorders, including SMA, DMD, myotonic dystrophies, Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease.}, }
@article {pmid29852219, year = {2019}, author = {Cortes, CJ and La Spada, AR}, title = {TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities.}, journal = {Neurobiology of disease}, volume = {122}, number = {}, pages = {83-93}, pmid = {29852219}, issn = {1095-953X}, support = {R01 AG033082/AG/NIA NIH HHS/United States ; R01 NS100023/NS/NINDS NIH HHS/United States ; R03 AG063215/AG/NIA NIH HHS/United States ; RF1 AG057264/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*therapy ; }, abstract = {Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7 years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal &amp; bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.}, }
@article {pmid29845377, year = {2019}, author = {Castanedo-Vazquez, D and Bosque-Varela, P and Sainz-Pelayo, A and Riancho, J}, title = {Infectious agents and amyotrophic lateral sclerosis: another piece of the puzzle of motor neuron degeneration.}, journal = {Journal of neurology}, volume = {266}, number = {1}, pages = {27-36}, pmid = {29845377}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*microbiology/virology ; Animals ; Bacterial Infections/*immunology ; Humans ; Motor Neurons/immunology/microbiology/parasitology/virology ; Virus Diseases/*immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscle wasting and lacks an effective treatment. ALS pathogenesis has not been elucidated yet. In a small proportion of ALS patients, the disease has a familial origin, related to mutations in specific genes, which directly result in MN degeneration. By contrast, the vast majority of cases are though to be sporadic, in which genes and environment interact leading to disease in genetically predisposed individuals. Lately, the role of the environment has gained relevance in this field and an extensive list of environmental conditions have been postulated to be involved in ALS. Among them, infectious agents, particularly viruses, have been suggested to play an important role in the pathogenesis of the disease. These agents could act by interacting with some crucial pathways in MN degeneration, such as gene processing, oxidative stress or neuroinflammation. In this article, we will review the main studies about the involvement of microorganisms in ALS, subsequently discussing their potential pathogenic effect and integrating them as another piece in the puzzle of ALS pathogenesis.}, }
@article {pmid29807753, year = {2018}, author = {Armon, C}, title = {From Snow to Hill to ALS: An epidemiological odyssey in search of ALS causation.}, journal = {Journal of the neurological sciences}, volume = {391}, number = {}, pages = {134-140}, doi = {10.1016/j.jns.2018.05.016}, pmid = {29807753}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/etiology/genetics/physiopathology ; DNA Damage ; Epidemiologic Research Design ; Humans ; Smoking/epidemiology ; }, abstract = {BACKGROUND: Establishing mechanisms of disease causation in neurodegenerative diseases has long seemed to be beyond the pale of traditional epidemiological tools. Establishing a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared a particularly elusive goal. This review shows that a likely mechanism for ALS initiation may be inferred by applying classical methods of epidemiological inference.<br><br>KEY POINTS: Advances in characterizing the biology of ALS suggest that most cases of ALS are cortically-generated, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor super-network. Evidence-based methods identified the most credible exogenous risk factor - smoking. AB Hill's nine viewpoints to inferring causation from association were invoked. The most likely mechanism consistent with smoking being a risk factor for ALS was inferred: cumulative DNA damage, akin to cumulative somatic mutations in carcinogenesis. Focal onset supports the concept that these changes, occurring in a single cell, may trigger the cascade leading to clinical ALS. The plausibility of this mechanism was affirmed by its coherence/consistency with other observations in sporadic, familial and western Pacific ALS.<br><br>CONCLUSION: Application of traditional epidemiological reasoning suggests that cumulative DNA damage may contribute to disease onset in ALS.}, }
@article {pmid29804302, year = {2018}, author = {Audano, M and Schneider, A and Mitro, N}, title = {Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {147}, number = {3}, pages = {291-309}, doi = {10.1111/jnc.14471}, pmid = {29804302}, issn = {1471-4159}, mesh = {Animals ; Humans ; Lysosomal Storage Diseases/*pathology ; Lysosomes/*pathology ; Mitochondria/*pathology ; Mitochondrial Diseases/*pathology ; Neurodegenerative Diseases/*pathology ; }, abstract = {In the last decades, lysosomes and mitochondria were considered distinct and physically separated organelles involved in different cellular functions. While lysosomes were thought to exclusively be the rubbish dump of the cell involved in the degradation of proteins and other cell compartments, mitochondria were considered solely involved in the oxidation of energy substrate to get ATP, together with other minor duties. Nowadays, our view of these organelles is profoundly changed since studies demonstrated that mitochondria and lysosome are mutually functional, maintaining proper cell homeostasis. Furthermore, the onset of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, lysosomal storage disorders, and amyotrophic lateral sclerosis) is tightly linked to mutations in mitochondrial and lysosomal regulators. In this context, mitochondrial dysfunction leads to lysosomal impairment and buildup of autophagy by-products, whereas lysosomal imperfections trigger functional and morphological mitochondrial defects. Here, we provide an updated overview covering recent findings about mitochondria and lysosomal interaction in physiology and pathophysiology, focusing the attention on the molecular mechanism that control their interdependence.}, }
@article {pmid29804042, year = {2018}, author = {de Carvalho, M and Barkhaus, PE and Nandedkar, SD and Swash, M}, title = {Motor unit number estimation (MUNE): Where are we now?.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {129}, number = {8}, pages = {1507-1516}, doi = {10.1016/j.clinph.2018.04.748}, pmid = {29804042}, issn = {1872-8952}, mesh = {Action Potentials/*physiology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Electromyography/methods/trends ; Humans ; Motor Neurons/*physiology ; Muscle, Skeletal/cytology/*physiology ; Recruitment, Neurophysiological/*physiology ; }, abstract = {Estimation of the number of motor units (MUNE) in specific muscles is important to monitor outcome in progressive neurogenic disorders, with potential application in clinical trials. However, in spite of recent developments to identify the most convenient technique for MUNE, all current methods have individual shortcomings. It is essential to understand the scientific concepts that support MUNE and the many methods already proposed. In particular, the core role of the compound muscle action potential (CMAP) size in the estimation process is undervalued. Operator-dependent variation in CMAP amplitude or area is the main factor underlying MUNE stability. At present, MUNIX, as standardized in many centers, is probably the best accepted method. Future developments should be based on full understanding of the neurophysiological concepts underlying the MUNE calculation, in order to find a quick, well-tolerated, operator-friendly and reliable method to apply more universally in clinical practice.}, }
@article {pmid29797112, year = {2018}, author = {Pellegrini, C and Antonioli, L and Colucci, R and Blandizzi, C and Fornai, M}, title = {Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?.}, journal = {Acta neuropathologica}, volume = {136}, number = {3}, pages = {345-361}, doi = {10.1007/s00401-018-1856-5}, pmid = {29797112}, issn = {1432-0533}, mesh = {Animals ; Enteric Nervous System/*microbiology/pathology ; Gastrointestinal Microbiome/*physiology ; Humans ; Intestinal Mucosa/*microbiology/pathology ; Neurodegenerative Diseases/*microbiology/pathology ; }, abstract = {Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.}, }
@article {pmid29793420, year = {2018}, author = {Conte, A and Pierantoni, GM}, title = {Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs.}, journal = {MicroRNA (Shariqah, United Arab Emirates)}, volume = {7}, number = {3}, pages = {178-186}, doi = {10.2174/2211536607666180525102330}, pmid = {29793420}, issn = {2211-5374}, mesh = {Biomarkers, Tumor/genetics ; Carrier Proteins/genetics/*metabolism ; *Gene Expression Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; MicroRNAs/*genetics ; Neoplasms/*genetics/metabolism/pathology ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Signal Transduction ; }, abstract = {UNLABELLED: The Homeodomain-Interacting Protein Kinases (HIPKs) HIPK1, HIPK2 and HIPK3 are Ser/Thr kinases which interact with homeobox proteins and other transcription factors, acting as transcriptional coactivators or corepressors. HIPKs contribute to regulate several biological processes, such as signal transduction, apoptosis, embryonic development, DNA-damage response, and cellular proliferation, in response to various extracellular stimuli. Recently it has emerged that, in addition to their role in cancer, fibrosis and diabetes, HIPKs may also be involved in other human diseases, including Amyotrophic Lateral Sclerosis (ALS), Rett syndrome, cerebellar diseases, and retinal vascular dysfunction.<br><br>METHODS: Here, we update our previous paper concerning the regulation of HIPK proteins expression by microRNAs (miRNAs), pointing out the most recent findings about new cellular mechanisms and diseases which are affected by the interplay between HIPKs and miRNAs.<br><br>CONCLUSION: Recently, it has emerged that HIPKs and their related miRNAs are involved in diabetic nephropathy, gastric cancer chemoresistance, cervical cancer progression, and recombinant protein expression in cultured cells. Interestingly, circular RNAs (circRNAs) deriving from HIPK2 and HIPK3 loci also modulate cellular proliferation and viability by sponging several miRNAs, thus emerging as new putative therapeutic targets for diabetes-associated retinal vascular dysfunction, astrogliosis and cancer.}, }
@article {pmid29791943, year = {2018}, author = {Julian, K and Yuhasz, N and Hollingsworth, E and Imitola, J}, title = {The "Growing" Reality of the Neurological Complications of Global "Stem Cell Tourism".}, journal = {Seminars in neurology}, volume = {38}, number = {2}, pages = {176-181}, doi = {10.1055/s-0038-1649338}, pmid = {29791943}, issn = {1098-9021}, mesh = {*Global Health ; Humans ; Nervous System Diseases/epidemiology/*surgery ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; }, abstract = {"Stem cell tourism" is defined as the unethical practice of offering unproven cellular preparations to patients suffering from various medical conditions. This phenomenon is rising in the field of neurology as patients are requesting information and opportunities for treatment with stem cells for incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, despite their clinical research and experimental designation. Here, we review the recent trends in "stem cell tourism" in both the United States and abroad, and discuss the recent reports of neurological complications from these activities. Finally, we frame critical questions for the field of neurology regarding training in the ethical, legal, and societal issues of the global "stem cell tourism," as well as suggest strategies to alleviate this problem. Although there are ongoing legitimate clinical trials with stem cells for neurological diseases, procedures offered by "stem cell clinics" cannot be defined as clinical research. They lack the experimental and state-of-the-art framework defined by peers and the FDA that focus on human research that safeguard the protection of human subjects against economical exploitation, unwanted side effects, and futility of unproven procedures. "Stem cell tourism" ultimately exploits therapeutic hope of patients and families with incurable neurological diseases and can put in danger the legitimacy of stem cell research as a whole. We posit that an improvement in education, regulation, legislation, and involvement of authorities in global health in neurology and neurosurgery is required.}, }
@article {pmid29788997, year = {2018}, author = {Centeno, EGZ and Cimarosti, H and Bithell, A}, title = {2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling.}, journal = {Molecular neurodegeneration}, volume = {13}, number = {1}, pages = {27}, pmid = {29788997}, issn = {1750-1326}, mesh = {Cell Culture Techniques/*methods ; Humans ; Induced Pluripotent Stem Cells/*cytology ; *Neurodegenerative Diseases ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field.}, }
@article {pmid29788868, year = {2019}, author = {Borghi, SM and Fattori, V and Hohmann, MSN and Verri, WA}, title = {Contribution of Spinal Cord Oligodendrocytes to Neuroinflammatory Diseases and Pain.}, journal = {Current medicinal chemistry}, volume = {26}, number = {31}, pages = {5781-5810}, doi = {10.2174/0929867325666180522112441}, pmid = {29788868}, issn = {1875-533X}, mesh = {Animals ; Central Nervous System/*metabolism/pathology ; Homeostasis ; Humans ; Inflammation/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Oligodendroglia/*metabolism/pathology ; Pain/*metabolism/pathology ; Spinal Cord/*metabolism/pathology ; }, abstract = {BACKGROUND: Neuroinflammatory diseases that affect spinal cord or associated spinal nerves represent challenging conditions for management in current medicine because of their complex pathology, poor prognosis, and high morbidity, which strikingly reduces the quality of life of patients. In this sense, a better understanding of the cellular and molecular mechanisms of spinal cord neuroinflammation might contribute to the development of novel therapies. Oligodendrocytes have unique and vital biological properties in central nervous system (CNS) homeostasis and physiology. A growing body of experimental evidence demonstrates that these glial cells are involved in the pathophysiological mechanisms underlying many chronic, neurodegenerative, and incapacitating CNS disorders. These cells also have important implications for the development and maintenance of neural plasticity and chronic pain states. On the other hand, evidence indicates that oligodendrocytes and their products may act in favor of CNS promoting beneficial effects orchestrating CNS tissue repair after injury.<br><br>OBJECTIVE: The present review aims to explore the multi-faceted actions of spinal cord oligodendrocyte progenitors cells (OPCs) and mature oligodendrocytes in CNS inflammation and pathology, addressing their roles in experimental and clinical settings. A major focus was given to spinal cord amyotrophic lateral sclerosis, multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), traumatic injury and pain processing.<br><br>METHODS: This review analyses and discusses published original research articles regarding the role of OPCs/oligodendrocytes in spinal cord inflammation and pain processing.<br><br>RESULTS AND CONCLUSION: Findings from a number of clinical and experimental paradigms suggest spinal cord OPCs/oligodendrocytes are a potential therapeutic target for the control of neuroinflammation.}, }
@article {pmid29786645, year = {2018}, author = {Di Pietro, L and Lattanzi, W and Bernardini, C}, title = {Skeletal Muscle MicroRNAs as Key Players in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {19}, number = {5}, pages = {}, pmid = {29786645}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Animals ; Humans ; MicroRNAs/*genetics/metabolism ; Muscle, Skeletal/*metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, for which, to date, no effective treatment to ameliorate the clinical manifestations is available. The long-standing view of ALS as affecting only motor neurons has been challenged by the finding that the skeletal muscle plays an active role in the disease pathogenesis and can be a valuable target for therapeutic strategies. In recent years, non-coding RNAs, including microRNAs, have emerged as important molecules that play key roles in several cellular mechanisms involved in the pathogenic mechanisms underlying various human conditions. In this review, we summarize how the expression of some microRNAs is dysregulated in the skeletal muscle of ALS mouse models and patients. Shedding light on the mechanisms underlying microRNAs dysregulation in the skeletal muscle could clarify some of the processes involved in the pathogenesis of ALS and especially identify new promising therapeutic targets in patients.}, }
@article {pmid29779602, year = {2018}, author = {Britton, D and Karam, C and Schindler, JS}, title = {Swallowing and Secretion Management in Neuromuscular Disease.}, journal = {Clinics in chest medicine}, volume = {39}, number = {2}, pages = {449-457}, doi = {10.1016/j.ccm.2018.01.007}, pmid = {29779602}, issn = {1557-8216}, mesh = {Deglutition Disorders/complications/physiopathology/*therapy ; Humans ; Neuromuscular Diseases/complications/*physiopathology ; }, abstract = {Neuromuscular disease frequently leads to dysphagia and difficulty managing secretions. Dysphagia may lead to medical complications, such as malnutrition, dehydration, aspiration pneumonia, and other pulmonary complications, as well as social isolation and reduced overall quality of life. This review provides an overview of dysphagia associated with neuromuscular disease in adults, along with a concise review of swallowing assessment and intervention options.}, }
@article {pmid29779597, year = {2018}, author = {Braun, AT and Caballero-Eraso, C and Lechtzin, N}, title = {Amyotrophic Lateral Sclerosis and the Respiratory System.}, journal = {Clinics in chest medicine}, volume = {39}, number = {2}, pages = {391-400}, doi = {10.1016/j.ccm.2018.01.003}, pmid = {29779597}, issn = {1557-8216}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that always affects the respiratory muscles. It is characterized by degeneration of motor neurons in the brain and spinal cord. Respiratory complications are the most common causes of death in ALS and typically occur within 3 to 5 years of diagnosis. Because ALS affects both upper and lower motor neurons, it causes hyperreflexia, spasticity, muscle fasciculations, muscle atrophy, and weakness. It ultimately progresses to functional quadriplegia. ALS most commonly begins in the limbs, but in about one-third of cases it begins in the bulbar muscles responsible for speech and swallowing.}, }
@article {pmid29779590, year = {2018}, author = {Benditt, JO}, title = {Pathophysiology of Neuromuscular Respiratory Diseases.}, journal = {Clinics in chest medicine}, volume = {39}, number = {2}, pages = {297-308}, doi = {10.1016/j.ccm.2018.01.011}, pmid = {29779590}, issn = {1557-8216}, mesh = {Humans ; Neuromuscular Diseases/*physiopathology ; Respiration Disorders/*physiopathology ; }, abstract = {Gas exchange between the atmosphere and the human body depends on the lungs and the function of the respiratory pump. The respiratory pump consists of the respiratory control center located in the brain, bony rib cage, diaphragm, and intercostal, accessory, and abdominal muscles. A variety of muscles serve to fine-tune adjustments of ventilation to metabolic demands. Appropriate evaluation and interventions can prevent respiratory complications and prolong life in individuals with neuromuscular diseases. This article discusses normal function of the respiratory pump, general pathophysiologic issues, and abnormalities in more common neuromuscular diseases.}, }
@article {pmid29777602, year = {2018}, author = {Silberberg, AA and Robetto, J and Achával, M}, title = {[Suspension of Respiratory Support in Patients with Amyotrophic Lateral Sclerosis].}, journal = {Cuadernos de bioetica : revista oficial de la Asociacion Espanola de Bioetica y Etica Medica}, volume = {29}, number = {96}, pages = {137-146}, pmid = {29777602}, issn = {1132-1989}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Respiration, Artificial/*ethics ; Withholding Treatment/*ethics ; }, abstract = {Decision making in advanced Amyotrophic Lateral Sclerosis (ALS) patients keeps on being a controversial issue. The aim of this work is to discuss ethical implications of withdrawing respiratory support treatment in patients with ALS. Through a bibliographic search on Pubmed database (2010-2016) we investigated whether or not the use of Non-Invasive Ventilation (NIV) and Mechanical Ventilation (MV) would increase survival and quality of life. We included 38 review articles. From these papers, results and ethical implications of initiating and mainly withdrawing respiratory support were analyzed. Survival time increased with NIV and with MV. Quality of life, above all according to physiological criteria, improved with NIV but regarding MV it remained controversial. Implementation and future withdrawal of MV seemed open to medical and ethical discussion. From a perspective of the intrinsic dignity of every human being, whatever its quality of life was, and knowing that no effective therapies for the underlying disease are available, the decision to remove MV in a patient with advanced ALS requires: knowledge of the will of the patient and, above all, evaluating whether this respiratory support measure is becoming objectively disproportionate.}, }
@article {pmid29777524, year = {2019}, author = {Cariccio, VL and Samà, A and Bramanti, P and Mazzon, E}, title = {Mercury Involvement in Neuronal Damage and in Neurodegenerative Diseases.}, journal = {Biological trace element research}, volume = {187}, number = {2}, pages = {341-356}, doi = {10.1007/s12011-018-1380-4}, pmid = {29777524}, issn = {1559-0720}, mesh = {Animals ; Apoptosis/drug effects ; Environmental Exposure/*analysis ; Humans ; Mercury Compounds/metabolism/*poisoning ; Methylmercury Compounds/metabolism/*poisoning ; Neurodegenerative Diseases/chemically induced/*metabolism/pathology ; Neurons/*metabolism/pathology ; Oxidative Stress/*drug effects ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis are characterized by a chronic and selective process of neuronal cell death. Although the causes of neurodegenerative diseases remain still unknown, it is now a well-established idea that more factors, such as genetic, endogenous, and environmental, are involved. Among environmental causes, the accumulation of mercury, a heavy metal considered a toxic agent, was largely studied as a probable factor involved in neurodegenerative disease course. Mercury exists in three main forms: elemental mercury, inorganic mercury, and organic mercury (methylmercury and ethylmercury). Sources of elemental mercury can be natural (volcanic emission) or anthropogenic (coal-fired electric utilities, waste combustion, hazardous-waste incinerators, and gold extraction). Moreover, mercury is still used as an antiseptic, as a medical preservative, and as a fungicide. Dental amalgam can emit mercury vapor. Mercury vapor, being highly volatile and lipid soluble, can cross the blood-brain barrier and the lipid cell membranes and can be accumulated into the cells in its inorganic forms. Also, methylmercury can pass through blood-brain and placental barriers, causing serious damage in the central nervous system. This review describes the toxic effects of mercury in cell cultures, in animal models, and in patients with neurodegenerative diseases. In vitro experiments showed that mercury exposure was principally involved in oxidative stress and apoptotic processes. Moreover, motor and cognitive impairment and neural loss have been confirmed in various studies performed in animal models. Finally, observational studies on patients with neurodegenerative diseases showed discordant data about a possible mercury involvement.}, }
@article {pmid29774215, year = {2018}, author = {Ishigaki, S and Sobue, G}, title = {Importance of Functional Loss of FUS in FTLD/ALS.}, journal = {Frontiers in molecular biosciences}, volume = {5}, number = {}, pages = {44}, pmid = {29774215}, issn = {2296-889X}, abstract = {Fused in sarcoma (FUS) is an RNA binding protein that regulates RNA metabolism including alternative splicing, transcription, and RNA transportation. FUS is genetically and pathologically involved in frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS). Multiple lines of evidence across diverse models suggest that functional loss of FUS can lead to neuronal dysfunction and/or neuronal cell death. Loss of FUS in the nucleus can impair alternative splicing and/or transcription, whereas dysfunction of FUS in the cytoplasm, especially in the dendritic spines of neurons, can cause mRNA destabilization. Alternative splicing of the MAPT gene at exon 10, which generates 4-repeat Tau (4R-Tau) and 3-repeat Tau (3R-Tau), is one of the most impactful targets regulated by FUS. Additionally, loss of FUS function can affect dendritic spine maturations by destabilizing mRNAs such as Glutamate receptor 1 (GluA1), a major AMPA receptor, and Synaptic Ras GTPase-activating protein 1 (SynGAP1). Moreover, FUS is involved in axonal transport and morphological maintenance of neurons. These findings indicate that a biological link between loss of FUS function, Tau isoform alteration, aberrant post-synaptic function, and phenotypic expression might lead to the sequential cascade culminating in FTLD. Thus, to facilitate development of early disease markers and/or therapeutic targets of FTLD/ALS it is critical that the functions of FUS and its downstream pathways are unraveled.}, }
@article {pmid29772957, year = {2019}, author = {Slutzky, MW}, title = {Brain-Machine Interfaces: Powerful Tools for Clinical Treatment and Neuroscientific Investigations.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {25}, number = {2}, pages = {139-154}, pmid = {29772957}, issn = {1089-4098}, support = {R01NS09474/NS/NINDS NIH HHS/United States ; R01 NS094748/NS/NINDS NIH HHS/United States ; F32 NS009474/NS/NINDS NIH HHS/United States ; UL1 RR025741/RR/NCRR NIH HHS/United States ; UL1 TR001422/TR/NCATS NIH HHS/United States ; K08 NS060223/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/*physiology/physiopathology ; *Brain-Computer Interfaces ; Humans ; Learning ; Membrane Potentials ; *Movement ; Nervous System Diseases/*rehabilitation ; }, abstract = {Brain-machine interfaces (BMIs) have exploded in popularity in the past decade. BMIs, also called brain-computer interfaces, provide a direct link between the brain and a computer, usually to control an external device. BMIs have a wide array of potential clinical applications, ranging from restoring communication to people unable to speak due to amyotrophic lateral sclerosis or a stroke, to restoring movement to people with paralysis from spinal cord injury or motor neuron disease, to restoring memory to people with cognitive impairment. Because BMIs are controlled directly by the activity of prespecified neurons or cortical areas, they also provide a powerful paradigm with which to investigate fundamental questions about brain physiology, including neuronal behavior, learning, and the role of oscillations. This article reviews the clinical and neuroscientific applications of BMIs, with a primary focus on motor BMIs.}, }
@article {pmid29767817, year = {2018}, author = {Regensburger, M and Weidner, N and Kohl, Z}, title = {[Motor neuron diseases : Clinical and genetic differential diagnostics].}, journal = {Der Nervenarzt}, volume = {89}, number = {6}, pages = {658-665}, pmid = {29767817}, issn = {1433-0407}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Diagnosis, Differential ; Humans ; *Motor Neuron Disease/diagnosis/genetics ; Motor Neurons/pathology ; Muscular Atrophy, Spinal/diagnosis/genetics ; }, abstract = {The causes of degenerative disease of the upper and lower motor neurons are incompletely understood. In this review the current concepts in the clinical and genetic differential diagnostics of motor neuron diseases are presented. Hereditary spastic paraplegia, primary lateral sclerosis, spinal muscular atrophy and amyotrophic lateral sclerosis are explained, structured according to the affection of the upper and/or lower motor neuron. The substantial variability in the presentation and course of motor neuron diseases as well as the lack of specific laboratory tests hinder an early diagnosis. The precise description of the clinical picture, thorough testing of possible differential diagnoses as well as monitoring of the clinical course are essential. Genetic analyses should be offered to patients with a positive family history. Early identification of clinical and genetic subentities of the individual motor neuron diseases is a prerequisite for future neuroprotective interventions.}, }
@article {pmid29760288, year = {2018}, author = {Tada, M and Kakita, A}, title = {[Neuropathologic Subtypes of Frontotemporal Lobar Degeneration].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {70}, number = {5}, pages = {501-516}, doi = {10.11477/mf.1416201033}, pmid = {29760288}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis ; C9orf72 Protein ; *Frontotemporal Lobar Degeneration ; Humans ; *Pick Disease of the Brain ; tau Proteins ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is a heterogeneous disease entity encompassing a wide variety of histopathological features and genetic backgrounds. The last two decades have seen the discovery of causative genes and the identification of relevant proteins. The current histopathological classification is based on the major types of protein deposition in the brain, and most FTLD cases can be placed into one of three pathological subgroups: FTLD-tau, FTLD-TDP, and FTLD-FUS. Further sub-classification within each subgroup is based on the morphology of neuronal and glial inclusions and lesion distribution. Affected patients, including some from the same subgroups, show considerable heterogeneity in their clinical presentations, suggesting that the subgroups represent a variety of well-defined clinical syndromes, including variants of frontotemporal dementia (behavioral variant frontotemporal dementia, progressive non-fluent aphasia, and semantic dementia) and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, and supranuclear palsy syndrome). On the other hand, patients with MAPT mutations always show the FTLD-tau phenotype, whereas patients with progranulin, C9orf72, VCP or TARDBP usually present the FTLD-TDP phenotype. In this review, we describe the histopathologic features of the main FTLD subtypes and summarize the clinical presentations and genetic characteristics of affected patients.}, }
@article {pmid29758300, year = {2019}, author = {Chung, KM and Hernández, N and Sproul, AA and Yu, WH}, title = {Alzheimer's disease and the autophagic-lysosomal system.}, journal = {Neuroscience letters}, volume = {697}, number = {}, pages = {49-58}, doi = {10.1016/j.neulet.2018.05.017}, pmid = {29758300}, issn = {1872-7972}, mesh = {Alzheimer Disease/metabolism/*pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Autophagy/physiology ; Biological Transport ; Humans ; Lysosomes/metabolism/*pathology ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/metabolism/pathology ; Proteasome Endopeptidase Complex/metabolism ; Protein Folding ; Proteolysis ; tau Proteins/metabolism ; }, abstract = {Age-related neurodegenerative diseases are of critical concern to the general population and research/medical community due to their health impact and socioeconomic consequences. A feature of most, if not all, neurodegenerative disorders is the presence of proteinopathies, in which misfolded or conformationally altered proteins drive disease progression and are often used as a primary neuropathological marker of disease. In particular, Alzheimer's disease (AD) is characterized by abnormal accumulation of protein aggregates, primarily extracellular plaques composed of the Aβ peptide and intracellular tangles comprised of the tau protein, both of which may indicate a primary defect in protein clearance. Protein degradation is a key cellular mechanism for protein homeostasis and is essential for cell survival but is disrupted in neurodegenerative diseases. Dysregulation in proteolytic pathways - mainly the autophagic-lysosomal system (A-LS) and the ubiquitin-proteasome system (UPS) - has been increasingly associated with proteinopathies in neurodegenerative diseases. Here we review the role of dysfunctional autophagy underlying AD-related proteinopathy and discuss how to model this aspect of disease, as well as summarize recent advances in translational strategies for targeted A-LS dysfunction in AD.}, }
@article {pmid29755516, year = {2018}, author = {Ling, SC}, title = {Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions.}, journal = {Neural plasticity}, volume = {2018}, number = {}, pages = {8413496}, pmid = {29755516}, issn = {1687-5443}, mesh = {DNA-Binding Proteins/*metabolism ; Humans ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/*metabolism ; RNA-Binding Protein FUS/*metabolism ; Synapses/*metabolism ; }, abstract = {TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules. Intriguingly, many of the RNA targets of TDP-43 and FUS are involved in synaptic transmission and plasticity, indicating that synaptic dysfunction could be an early event contributing to motor and cognitive deficits in ALS and FTD. Furthermore, the ability of the low-complexity prion-like domains of TDP-43 and FUS to form liquid droplets suggests a potential mechanism for mRNP assembly and conversion. This review will discuss the role of TDP-43 and FUS in RNA metabolism, with an emphasis on the involvement of this process in synaptic function and neuroprotection. This will be followed by a discussion of the potential phase separation mechanism for forming RNP granules and pathological inclusions.}, }
@article {pmid29752901, year = {2018}, author = {Zhang, K and Coyne, AN and Lloyd, TE}, title = {Drosophila models of amyotrophic lateral sclerosis with defects in RNA metabolism.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {109-120}, doi = {10.1016/j.brainres.2018.04.043}, pmid = {29752901}, issn = {1872-6240}, support = {R01 NS082563/NS/NINDS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Cytoplasmic Granules/genetics/metabolism ; Disease Models, Animal ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/metabolism ; Humans ; Mutation ; RNA/genetics/*metabolism ; }, abstract = {The fruit fly Drosophila Melanogaster has been widely used to study neurodegenerative diseases. The conservation of nervous system biology coupled with the rapid life cycle and powerful genetic tools in the fly have enabled the identification of novel therapeutic targets that have been validated in vertebrate model systems and human patients. A recent example is in the study of the devastating motor neuron degenerative disease amyotrophic lateral sclerosis (ALS). Mutations in genes that regulate RNA metabolism are a major cause of inherited ALS, and functional analysis of these genes in the fly nervous system has shed light on how mutations cause disease. Importantly, unbiased genetic screens have identified key pathways that contribute to ALS pathogenesis such as nucleocytoplasmic transport and stress granule assembly. In this review, we will discuss the utilization of Drosophila models of ALS with defects in RNA metabolism.}, }
@article {pmid29751602, year = {2018}, author = {Durães, F and Pinto, M and Sousa, E}, title = {Old Drugs as New Treatments for Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {29751602}, issn = {1424-8247}, abstract = {Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.}, }
@article {pmid29751510, year = {2018}, author = {Pansarasa, O and Bordoni, M and Diamanti, L and Sproviero, D and Gagliardi, S and Cereda, C}, title = {SOD1 in Amyotrophic Lateral Sclerosis: "Ambivalent" Behavior Connected to the Disease.}, journal = {International journal of molecular sciences}, volume = {19}, number = {5}, pages = {}, pmid = {29751510}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cell Nucleus/metabolism ; DNA Damage/genetics/physiology ; Humans ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {In 1993, Rosen and collaborators discovered that the gene encoding SOD1 has mutations in amyotrophic lateral sclerosis (ALS) patients; moreover, these mutations are found in the exon regions, suggesting that their toxic effects are the consequence of protein dysfunction with an increase of oxidative stress. While a clear genetic picture has been delineated, a more complex scenario has been ascribed to the SOD1 protein. On the one hand, some evidence sustains the hypothesis of an additionally toxic role for wild-type SOD1 (WT-SOD1) in the pathogenesis of sporadic ALS. On the other hand, our group identified a discrepancy among WT-SOD1 protein expression levels and mRNA in ALS sporadic patients, thus providing the hypothesis of a re-localization of the &amp;ldquo;missing&amp;rdquo; SOD1 in a different sub-cellular compartment, i.e., nucleus, or an aggregation/precipitation in the insoluble fraction. Moreover, our data also indicate an association between longer disease duration and higher amounts of soluble SOD1 within the nucleus, suggesting a possible defensive role of the protein in this compartment. Starting from this evidence, in this review we will attempt to resolve the &amp;ldquo;ambivalent&amp;rdquo; behavior of SOD1 in ALS disease and we will try to classify sporadic ALS patients according to a novel biological signature, i.e., SOD localization.}, }
@article {pmid29740948, year = {2018}, author = {Sase, S and Takanohashi, A and Vanderver, A and Almad, A}, title = {Astrocytes, an active player in Aicardi-Goutières syndrome.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {28}, number = {3}, pages = {399-407}, pmid = {29740948}, issn = {1750-3639}, mesh = {Animals ; Astrocytes/*metabolism ; Autoimmune Diseases of the Nervous System/complications/*genetics/*metabolism ; Encephalitis/complications/metabolism ; Homeostasis ; Humans ; Inflammation/complications/metabolism ; Interferon-alpha/metabolism ; Mutation ; Nervous System Malformations/complications/*genetics/*metabolism ; Signal Transduction ; }, abstract = {Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.}, }
@article {pmid29736227, year = {2017}, author = {Soveyd, N and Abdolahi, M and Bitarafan, S and Tafakhori, A and Sarraf, P and Togha, M and Okhovat, AA and Hatami, M and Sedighiyan, M and Djalali, M and Mohammadzadeh Honarvar, N}, title = {Molecular mechanisms of omega-3 fatty acids in the migraine headache.}, journal = {Iranian journal of neurology}, volume = {16}, number = {4}, pages = {210-217}, pmid = {29736227}, issn = {2008-384X}, abstract = {Migraine is a common chronic inflammatory neurological disease with the progressive and episodic course. Much evidence have shown a role of inflammation in the pathogenesis of migraine. Omega-3 fatty acids are an important components of cell membranes phospholipids. The intake of these fatty acids is related to decrease concentration of C-reactive protein (CRP), proinflammatory eicosanoids, cytokines, chemokines and other inflammation biomarkers. Many of clinical trials have shown the beneficial effect of dietary supplementation with omega-3 fatty acids in inflammatory and autoimmune diseases in human, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS) and migraine headaches. Therefore, omega-3 fatty acids as an alternative therapy can be potentially important. This review focuses on the pathogenesis of a migraine, with an emphasis on the role of omega-3 fatty acid and its molecular mechanisms.}, }
@article {pmid29734735, year = {2018}, author = {Metaxakis, A and Ploumi, C and Tavernarakis, N}, title = {Autophagy in Age-Associated Neurodegeneration.}, journal = {Cells}, volume = {7}, number = {5}, pages = {}, pmid = {29734735}, issn = {2073-4409}, abstract = {The elimination of abnormal and dysfunctional cellular constituents is an essential prerequisite for nerve cells to maintain their homeostasis and proper function. This is mainly achieved through autophagy, a process that eliminates abnormal and dysfunctional cellular components, including misfolded proteins and damaged organelles. Several studies suggest that age-related decline of autophagy impedes neuronal homeostasis and, subsequently, leads to the progression of neurodegenerative disorders due to the accumulation of toxic protein aggregates in neurons. Here, we discuss the involvement of autophagy perturbation in neurodegeneration and present evidence indicating that upregulation of autophagy holds potential for the development of therapeutic interventions towards confronting neurodegenerative diseases in humans.}, }
@article {pmid29732485, year = {2019}, author = {Esparza, JL and Gómez, M and Domingo, JL}, title = {Role of Melatonin in Aluminum-Related Neurodegenerative Disorders: a Review.}, journal = {Biological trace element research}, volume = {188}, number = {1}, pages = {60-67}, doi = {10.1007/s12011-018-1372-4}, pmid = {29732485}, issn = {1559-0720}, mesh = {Aluminum/metabolism/*toxicity ; Animals ; Antioxidants/*therapeutic use ; Humans ; Melatonin/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neurotoxicity Syndromes/drug therapy/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Aluminum (Al), a potentially neurotoxic element, provokes various adverse effects on human health such as dialysis dementia, osteomalacia, and microcytic anemia. It has been also associated with serious neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Parkinsonism dementia of Guam. The "aluminum hypothesis" of AD assumes that the metal complexes can potentiate the rate of aggregation of amyloid-β (Aβ), enhancing the toxicity of this peptide, and being able of contributing to the pathogenesis of AD. It has been supported by a number of analytical, epidemiological, and neurotoxicological studies. On the other hand, melatonin (Mel) is a potent direct free radical scavenger and indirect antioxidant, which acts increasing the activity of important related antioxidant enzymes, and preventing oxidative stress and cell death of neurons exposed to Aβ-induced neurotoxicity. Therefore, Mel might be useful in the treatment of AD by reducing the Aβ generation and by inhibiting mitochondrial cell death pathways. The present review on the role of Mel in Al-related neurodegenerative disorders concludes that the protective effects of this hormone, together with its low toxicity, support the administration of Mel as a potential supplement in the treatment of neurological disorders, in which oxidative stress is involved.}, }
@article {pmid29731706, year = {2018}, author = {Moszczynski, AJ and Hintermayer, MA and Strong, MJ}, title = {Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder (ALS-FTSD). A Review.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {259}, pmid = {29731706}, issn = {1662-4548}, abstract = {Approximately 50-60% of all patients with amyotrophic lateral sclerosis (ALS) will develop a deficit of frontotemporal function, ranging from frontotemporal dementia (FTD) to one or more deficits of neuropsychological, speech or language function which are collectively known as the frontotemporal spectrum disorders of ALS (ALS-FTSD). While the neuropathology underlying these disorders is most consistent with a widespread alteration in the metabolism of transactive response DNA-binding protein 43 (TDP-43), in both ALS with cognitive impairment (ALSci) and ALS with FTD (ALS-FTD; also known as MND-FTD) there is evidence for alterations in the metabolism of the microtubule associated protein tau. This alteration in tau metabolism is characterized by pathological phosphorylation at residue Thr[175] (pThr[175] tau) which in vitro is associated with activation of GSK3β (pTyr[216]GSK3β), phosphorylation of Thr[231]tau, and the formation of cytoplasmic inclusions with increased rates of cell death. This putative pathway of pThr[175] induction of pThr[231] and the formation of pathogenic tau inclusions has been recently shown to span a broad range of tauopathies, including chronic traumatic encephalopathy (CTE) and CTE in association with ALS (CTE-ALS). This pathway can be experimentally triggered through a moderate traumatic brain injury, suggesting that it is a primary neuropathological event and not secondary to a more widespread neuronal dysfunction. In this review, we discuss the neuropathological underpinnings of the postulate that ALS is associated with a tauopathy which manifests as a FTSD, and examine possible mechanisms by which phosphorylation at Thr[175]tau is induced. We hypothesize that this might lead to an unfolding of the hairpin structure of tau, activation of GSK3β and pathological tau fibril formation through the induction of cis-Thr[231] tau conformers. A potential role of TDP-43 acting synergistically with pathological tau metabolism is proposed.}, }
@article {pmid29729808, year = {2018}, author = {Yuva-Aydemir, Y and Almeida, S and Gao, FB}, title = {Insights into C9ORF72-Related ALS/FTD from Drosophila and iPSC Models.}, journal = {Trends in neurosciences}, volume = {41}, number = {7}, pages = {457-469}, pmid = {29729808}, issn = {1878-108X}, support = {R01 NS093097/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; C9orf72 Protein/genetics/*metabolism ; DNA Repeat Expansion ; Disease Models, Animal ; Drosophila ; Frontotemporal Dementia/genetics/*metabolism ; Humans ; Induced Pluripotent Stem Cells ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. An important issue is how repeat RNAs and their translation products, various dipeptide repeat (DPR) proteins, cause neurodegeneration. Drosophila has been widely used to model G4C2 repeat RNA and DPR protein toxicity. Overexpression of disease molecules in flies has revealed important molecular insights. These have been validated and further explored in human neurons differentiated from induced pluripotent stem cells (iPSCs), a disease-relevant model in which expanded G4C2 repeats are expressed in their native molecular context. Approaches that combine the genetic power of Drosophila and the disease relevance of iPSC-derived patient neurons will continue to unravel the underlying pathogenic mechanisms and help identify potential therapeutic targets in C9ORF72-ALS/FTD.}, }
@article {pmid29725842, year = {2018}, author = {Mélé, N and Berzero, G and Maisonobe, T and Salachas, F and Nicolas, G and Weiss, N and Beaudonnet, G and Ducray, F and Psimaras, D and Lenglet, T}, title = {Motor neuron disease of paraneoplastic origin: a rare but treatable condition.}, journal = {Journal of neurology}, volume = {265}, number = {7}, pages = {1590-1599}, pmid = {29725842}, issn = {1432-1459}, mesh = {Action Potentials/physiology ; Adult ; Aged ; Aged, 80 and over ; Cytokines/cerebrospinal fluid ; Electromyography ; Female ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Immunologic Factors/therapeutic use ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/*etiology/therapy ; Neurologic Examination ; Paraneoplastic Syndromes, Nervous System/*complications/therapy ; Retrospective Studies ; }, abstract = {Paraneoplastic motor neuron disorders (MND) are rare conditions; their exact clinical and electrophysiological phenotype have not been exhaustively described yet. The purpose of this study is to depict the main characteristics of paraneoplastic MND to highlight the features that may allow its diagnosis. Based on the description of eight original cases, and on the revision of 21 patients identified from a systematic review of the literature, the main features of paraneoplastic MND can be summarized as follows: (1) subacute; (2) lower motor neuron syndrome, associated or not with upper motor neuron involvement; (3) predominant asymmetric upper limb involvement; (4) presence of other non-motor neurological manifestations, including sensory neuronopathy; (5) signs of inflammation in the cerebrospinal fluid (CSF); (6) neurological improvement or stabilization after immunotherapy and tumor treatment. The diagnosis of paraneoplastic MND may be difficult because of its rarity, the absence of pathognomonic clinical features, and the frequent absence of prior tumor history. However, it is of capital importance to correctly identify patients with paraneoplastic MND, as this represents a potentially treatable condition. In the presence of subacute lower motor neuron impairment, especially when atypical clinical features for degenerative MND or other non-motor neurological manifestations are present, we recommend testing for onconeural antibodies. In the case, the search for onconeural antibodies is negative, but it exists a strong clinical suspicion for a paraneoplastic etiology; CSF analysis and total-body 18FDG-PET/CT imaging should be performed to circumstantiate diagnosis.}, }
@article {pmid29723523, year = {2018}, author = {St George-Hyslop, P and Lin, JQ and Miyashita, A and Phillips, EC and Qamar, S and Randle, SJ and Wang, G}, title = {The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {11-23}, pmid = {29723523}, issn = {1872-6240}, support = {/WT_/Wellcome Trust/United Kingdom ; 203249/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; //CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; Biophysics/methods ; Cytoplasmic Granules/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Lobar Degeneration/*genetics/*physiopathology ; Humans ; Mutation ; Neurodegenerative Diseases/pathology ; Protein Domains ; Protein Processing, Post-Translational ; RNA-Binding Protein FUS/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Temporal Lobe/metabolism ; }, abstract = {Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using FUS as an example, this review examines the biophysics of this physiological process, and reports on how mutations and changes in post-translational state alter phase behaviour, and lead to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, }
@article {pmid29717332, year = {2018}, author = {Agosta, F and Altomare, D and Festari, C and Orini, S and Gandolfo, F and Boccardi, M and Arbizu, J and Bouwman, F and Drzezga, A and Nestor, P and Nobili, F and Walker, Z and Pagani, M and , }, title = {Clinical utility of FDG-PET in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {45}, number = {9}, pages = {1546-1556}, pmid = {29717332}, issn = {1619-7089}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Brain ; Fluorodeoxyglucose F18 ; Humans ; Huntington Disease/*diagnostic imaging ; *Positron-Emission Tomography ; Radiopharmaceuticals ; }, abstract = {AIM: To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington's disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients.<br><br>METHODS: Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios.<br><br>RESULTS: The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios.<br><br>CONCLUSION: Relative to other neurodegenerative diseases, the clinical use of FDG-PET in ALS and HD is still in its infancy. Once validated by disease-control studies, FDG-PET might represent a potentially useful biomarker for ALS diagnosis. FDG-PET is presently not justified as a routine investigation to predict conversion to HD, nor to detect evidence of brain dysfunction justifying cognitive decline in ALS and HD.}, }
@article {pmid29715444, year = {2018}, author = {Ferro, D and Yao, S and Zarnescu, DC}, title = {Dynamic duo - FMRP and TDP-43: Regulating common targets, causing different diseases.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {37-42}, pmid = {29715444}, issn = {1872-6240}, support = {R01 NS091299/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/genetics/metabolism/*physiology ; Disease Models, Animal ; Fragile X Mental Retardation Protein/genetics/*physiology ; Fragile X Syndrome/*genetics/physiopathology ; Humans ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Protein Biosynthesis/genetics/physiology ; RNA, Messenger/metabolism ; Receptors, Metabotropic Glutamate/physiology ; Ribonucleoproteins/metabolism ; Signal Transduction ; }, abstract = {RNA binding proteins play essential roles during development and aging, and are also involved in disease pathomechanisms. RNA sequencing and omics analyses have provided a window into systems level alterations in neurological disease, and have identified RNA processing defects among notable disease mechanisms. This review focuses on two seemingly distinct neurological disorders, the RNA binding proteins they are linked to, and their newly discovered functional relationship. When deficient, Fragile X Mental Retardation Protein (FMRP) causes developmental deficits and autistic behaviors while TAR-DNA Binding Protein (TDP-43) dysregulation causes age dependent neuronal degeneration. Recent findings that FMRP and TDP-43 associate in ribonuclear protein particles and share mRNA targets in neurons highlight the critical importance of translation regulation in synaptic plasticity and provide new perspectives on neuronal vulnerability during lifespan.}, }
@article {pmid29713939, year = {2018}, author = {Ning, P and Yang, X and Yang, B and Zhao, Q and Huang, H and An, R and Chen, Y and Hu, F and Xu, Z and Xu, Y}, title = {Meta-analysis of the association between ZNF512B polymorphism rs2275294 and risk of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {39}, number = {7}, pages = {1261-1266}, pmid = {29713939}, issn = {1590-3478}, support = {2010SZ0086//the Sichuan Key Project of Science and Technology/ ; 17ZD011//the Major Clinical Disease Research Program from the Health and Family Planning Commission of Sichuan Province/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Carrier Proteins/*genetics ; *Genetic Predisposition to Disease ; Humans ; *Polymorphism, Single Nucleotide ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, appears to result from the combination of genetic and environmental factors. Whether the rs2275294 polymorphism in the ZNF512B gene influences ALS risk is controversial. We meta-analysed the association between rs2275294 and ALS risk based on evidence published in the PubMed database. Five case-control studies involving 2559 patients with sporadic ALS and 5740 controls were analysed. Based on random-effects meta-analysis, the polymorphism rs2275294 was associated with increased risk of ALS disease in an allele model (C vs. T: OR 1.222, 95%CI 1.057 to 1.414, p = 0.007). The available evidence suggests that the ZNF512B polymorphism rs2275294 is associated with ALS risk. These results should be validated in large, well-designed studies, especially in non-Asian populations.}, }
@article {pmid29713861, year = {2018}, author = {Riancho, J and Bosque-Varela, P and Perez-Pereda, S and Povedano, M and de Munaín, AL and Santurtun, A}, title = {The increasing importance of environmental conditions in amyotrophic lateral sclerosis.}, journal = {International journal of biometeorology}, volume = {62}, number = {8}, pages = {1361-1374}, pmid = {29713861}, issn = {1432-1254}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; *Environmental Exposure ; Environmental Pollutants/toxicity ; Humans ; Motor Neurons ; Risk ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Although a small percentage of ALS has a familial origin, the vast majority of cases are sporadic in which genetic factors and environment interact with each other leading to disease onset in genetically predisposed individuals. In the current model of the disease, each individual has a determined genetic load, some degree of cell degeneration related to age and several risky environmental exposures. In this scenario, MN degeneration would occur when the sum of these factors reach a certain threshold. To date, an extensive list of environmental factors has been associated to ALS, including different categories, such as exposure to heavy metals and other toxicants, cyanotoxins or infectious agents. In addition, in recent years, lifestyle and other demographic parameters are gaining relevance in the genesis of the disease. Among them, physical activity, nutrition, body mass index, cardiovascular risk factors, autoimmune diseases and cancer are some of the conditions which have been related to the disease. In this review, we will discuss the potential mechanisms of environmental conditions in motor neuron degeneration. Understanding the role of each one of these factors as well as their interactions appears as a crucial step in order to develop new preventive, diagnostic and therapeutic approaches for ALS patients.}, }
@article {pmid29713276, year = {2018}, author = {Sebastião, AM and Rei, N and Ribeiro, JA}, title = {Amyotrophic Lateral Sclerosis (ALS) and Adenosine Receptors.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {267}, pmid = {29713276}, issn = {1663-9812}, abstract = {In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS). Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A2A receptors (A2AR), most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A2AR antagonists. It may happen that there are time windows where A2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression.}, }
@article {pmid29709651, year = {2018}, author = {Tao, QQ and Wei, Q and Wu, ZY}, title = {Sensory nerve disturbance in amyotrophic lateral sclerosis.}, journal = {Life sciences}, volume = {203}, number = {}, pages = {242-245}, doi = {10.1016/j.lfs.2018.04.052}, pmid = {29709651}, issn = {1879-0631}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*pathology ; Animals ; *Disease Models, Animal ; Humans ; Sensory Receptor Cells/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder, characterized by the selective degeneration of upper and lower motor neurons. The common clinical symptoms of ALS are caused by the degeneration and dysfunction of motor neurons. With the progression of our understanding of the pathogenesis of the disease, an increasing number of extramotor phenotypes have been linked to ALS. It has long been believed that sensory neurons localized in the dorsal root ganglia are not involved in ALS. In addition, sensory nerve injury can clearly be considered as an important basis that does not support the diagnosis of ALS. However, accumulating evidence has revealed abnormalities in sensory neurons in both ALS patients and mouse models. This review summarizes the discoveries related to sensory nerve disturbance in ALS, which may provide insightful information that will help us better diagnose and understand the disease.}, }
@article {pmid29703376, year = {2018}, author = {Pattamatta, A and Cleary, JD and Ranum, LPW}, title = {All in the Family: Repeats and ALS/FTD.}, journal = {Trends in neurosciences}, volume = {41}, number = {5}, pages = {247-250}, pmid = {29703376}, issn = {1878-108X}, support = {P01 NS058901/NS/NINDS NIH HHS/United States ; R01 NS040389/NS/NINDS NIH HHS/United States ; R01 NS098819/NS/NINDS NIH HHS/United States ; R37 NS040389/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein/*genetics ; *DNA Repeat Expansion ; Frontotemporal Dementia/*genetics ; Humans ; }, abstract = {In 2011, an intronic (G4C2)•(G2C4) expansion was shown to cause the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This discovery linked ALS with a clinically distinct form of dementia and a larger group of microsatellite repeat diseases, and catalyzed basic and translational research.}, }
@article {pmid29693363, year = {2018}, author = {Brooks, BR and Jorgenson, JA and Newhouse, BJ and Shefner, JM and Agnese, W}, title = {Edaravone in the treatment of amyotrophic lateral sclerosis: efficacy and access to therapy - a roundtable discussion.}, journal = {The American journal of managed care}, volume = {24}, number = {9 Suppl}, pages = {S175-S186}, pmid = {29693363}, issn = {1936-2692}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Dose-Response Relationship, Drug ; Edaravone/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease affecting approximately 5 out of every 100,000 individuals living in the United States. ALS is associated with 50% mortality within 30 months of initial symptom onset. The rarity of the disease, along with the significant inter- and intra-patient variability in clinical course and a lack of reliable biomarkers, have rendered the development of effective agents to treat ALS a challenge. Because oxidative stress is considered a contributing factor to ALS onset and progression, drugs that eliminate free radicals may protect motor neurons from damage potentially caused by free-radical and oxidative stress. Edaravone is an antioxidant free-radical scavenger approved by the FDA in 2017 for the treatment of ALS. A review of the edaravone clinical development program offers a clearer view of the clinical utility of this agent. Broader treatment success is also influenced by factors such as limited patient access and the restrictive payer environment. Cooperation within the healthcare community, among clinicians, patient advocacy groups, pharmaceutical companies, and managed care payers, must occur to advance ALS management and treatment and improve patient access. Moreover, collaborative discussions are useful in identifying potential solutions to problems currently surrounding patient access.}, }
@article {pmid29692728, year = {2018}, author = {Oliveira-Giacomelli, &#xc1; and Naaldijk, Y and Sardá-Arroyo, L and Gonçalves, MCB and Corrêa-Velloso, J and Pillat, MM and de Souza, HDN and Ulrich, H}, title = {Purinergic Receptors in Neurological Diseases With Motor Symptoms: Targets for Therapy.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {325}, pmid = {29692728}, issn = {1663-9812}, abstract = {Since proving adenosine triphosphate (ATP) functions as a neurotransmitter in neuron/glia interactions, the purinergic system has been more intensely studied within the scope of the central nervous system. In neurological disorders with associated motor symptoms, including Parkinson's disease (PD), motor neuron diseases (MND), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's Disease (HD), restless leg syndrome (RLS), and ataxias, alterations in purinergic receptor expression and activity have been noted, indicating a potential role for this system in disease etiology and progression. In neurodegenerative conditions, neural cell death provokes extensive ATP release and alters calcium signaling through purinergic receptor modulation. Consequently, neuroinflammatory responses, excitotoxicity and apoptosis are directly or indirectly induced. This review analyzes currently available data, which suggests involvement of the purinergic system in neuro-associated motor dysfunctions and underlying mechanisms. Possible targets for pharmacological interventions are also discussed.}, }
@article {pmid29692352, year = {2018}, author = {Sahni, AS and Wolfe, L}, title = {Respiratory Care in Neuromuscular Diseases.}, journal = {Respiratory care}, volume = {63}, number = {5}, pages = {601-608}, doi = {10.4187/respcare.06210}, pmid = {29692352}, issn = {1943-3654}, mesh = {Humans ; Neuromuscular Diseases/*complications/physiopathology ; *Respiratory Insufficiency/etiology/physiopathology/therapy ; Respiratory Therapy/*methods ; Treatment Outcome ; }, abstract = {Caring for patients with neuromuscular disease (NMD) is challenging. Respiratory care is of the utmost importance because it is a major determinant of quality of life and survival. Noninvasive ventilation (NIV) is one of the few modalities that has shown survival benefit in the NMD patient population. Newer modes with smart technologies are being developed to assist in better ventilation. Some noninvasive methods have shown success in the management of sialorrhea, which is of paramount importance in the initiation of NIV. This review will summarize the management of respiratory symptomatology in patients with NMD with recent advances made in NIV.}, }
@article {pmid29684753, year = {2018}, author = {Celeste, DB and Miller, MS}, title = {Reviewing the evidence for viruses as environmental risk factors for ALS: A new perspective.}, journal = {Cytokine}, volume = {108}, number = {}, pages = {173-178}, doi = {10.1016/j.cyto.2018.04.010}, pmid = {29684753}, issn = {1096-0023}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*virology ; Animals ; *Environment ; Humans ; Mice ; Neurodegenerative Diseases/*virology ; Risk Factors ; Virus Diseases/*complications ; Viruses/pathogenicity ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease whose etiology remains poorly understood. Since the genetic basis of disease is known in only a small subset of cases, there has been substantial interest in determining whether environmental factors act as triggers of ALS. Viruses have received longstanding attention as potential ALS triggers. Yet, existing studies have not provided a compelling case for causation. This review summarizes the evidence supporting a link between viral infection and motor neuron disease, with a focus on ALS. Limitations of prior studies are discussed and contextualized, and recent work that has provided stronger mechanistic evidence for viruses in disease pathogenesis is highlighted. Finally, we offer a new perspective on the association of viruses with ALS, and underscore the need for multidisciplinary approaches bridging neurology and infectious diseases research to move the field forward in the future.}, }
@article {pmid29684335, year = {2018}, author = {Subramaniam, NS and Bawden, CS and Waldvogel, H and Faull, RML and Howarth, GS and Snell, RG}, title = {Emergence of breath testing as a new non-invasive diagnostic modality for neurodegenerative diseases.}, journal = {Brain research}, volume = {1691}, number = {}, pages = {75-86}, doi = {10.1016/j.brainres.2018.04.017}, pmid = {29684335}, issn = {1872-6240}, mesh = {Breath Tests/*methods ; Humans ; Neurodegenerative Diseases/*diagnosis/*physiopathology ; }, abstract = {Neurodegenerative diseases (NDDs) are incapacitating disorders that result in progressive motor and cognitive impairment. These diseases include Alzheimer's disease, the most common cause of dementia, frontotemporal dementia, amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson's, Huntington's, Friedreich's ataxia, and prion disease. Dementia causing NDDs impose a high social and economic burden on communities around the world. Rapid growth in knowledge regarding the pathogenic mechanisms and disease-associated biomarkers of these diseases in the past few decades have accelerated the development of new diagnostic methods and therapeutic opportunities. Continuous effort is being applied to the development of more advanced, easy-to-apply and reliable methods of diagnosis, that are able to identify disease manifestation at its earliest stages and before clinical symptoms become apparent. Development of these diagnostic tools are essential in aiding effective disease management through accurate monitoring of disease progression, timely application of therapeutics and evaluation of treatment efficacy. Recently, several studies have identified novel biomarkers based on compounds in exhaled breath associated with specific NDDs. The use of breath testing, as a means of monitoring neurodegenerative disease onset and progression, has the potential to have a significant impact on augmenting the diagnosis of NDDs as the approach is non-invasive, relatively cost effective and straight forward to implement. This review highlights key features of current diagnostic methods utilised to identify NDDs, and describes the potential application and limitations associated with the use of breath analysis for disease diagnosis and progression monitoring.}, }
@article {pmid29682695, year = {2018}, author = {Dash, RP and Babu, RJ and Srinivas, NR}, title = {Two Decades-Long Journey from Riluzole to Edaravone: Revisiting the Clinical Pharmacokinetics of the Only Two Amyotrophic Lateral Sclerosis Therapeutics.}, journal = {Clinical pharmacokinetics}, volume = {57}, number = {11}, pages = {1385-1398}, pmid = {29682695}, issn = {1179-1926}, mesh = {Administration, Intravenous ; Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy ; Brain/metabolism ; Edaravone/*pharmacokinetics/therapeutic use ; Humans ; Neuroprotective Agents/administration &amp; dosage/pharmacokinetics/therapeutic use ; Riluzole/administration &amp; dosage/*pharmacokinetics/therapeutic use ; }, abstract = {The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity. Based on this review, the following key highlights were deduced: (i) as a result of both presystemic metabolism and polymorphic hepatic cytochrome P450 (CYP) metabolism, the oral drug riluzole exhibited more inter-subject variability than that of intravenous edaravone; (ii) using various parameters for comparison, including the published intravenous data for riluzole, it was apparent that edaravone was achieving the desired systemic concentrations to possibly drive the local brain concentrations for its efficacy in ALS patients with lesser variability than riluzole; (iii) using scientific conjectures, it was deduced that the availability of intravenous riluzole may not be beneficial in therapy due to its fast systemic clearance; (iv) on the contrary, however, there appeared to be an opportunity for the development of an oral dosage form of edaravone, which may potentially benefit the therapy option for ALS patients by avoiding hospitalization costs; and (v) because of the existence of pharmaco-resistance for the brain entry in ALS patients, it appeared prudent to consider combination strategies of edaravone and/or riluzole with suitable P-glycoprotein efflux-blocking drugs to gain more favorable outcomes in ALS patients.}, }
@article {pmid29681010, year = {2018}, author = {Fang, X}, title = {Impaired tissue barriers as potential therapeutic targets for Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Metabolic brain disease}, volume = {33}, number = {4}, pages = {1031-1043}, pmid = {29681010}, issn = {1573-7365}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Blood-Brain Barrier/*pathology ; Humans ; Intestinal Mucosa/*pathology ; Parkinson Disease/*pathology ; }, abstract = {The blood-brain barrier and the intestinal barrier show signs of disruption in patients with idiopathic Parkinson's disease (PD) and animal models of nigrostriatal degeneration, and likewise in amyotrophic lateral sclerosis (ALS) models. A substantial body of evidence shows that defects in epithelial membrane barriers, both in the gut and within the cerebral vasculature, can result in increased vulnerability of tissues to external factors potentially participating in the pathogenesis of PD and ALS. As such, restoration of tissue barriers may prove to be a novel therapeutic target in neurodegenerative disease. In this review, we focus on the potential of new intervention strategies for rescuing and maintaining barrier functions in PD and ALS.}, }
@article {pmid29677557, year = {2018}, author = {Dardiotis, E and Siokas, V and Sokratous, M and Tsouris, Z and Michalopoulou, A and Andravizou, A and Dastamani, M and Ralli, S and Vinceti, M and Tsatsakis, A and Hadjigeorgiou, GM}, title = {Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants.}, journal = {Environment international}, volume = {116}, number = {}, pages = {122-135}, doi = {10.1016/j.envint.2018.04.008}, pmid = {29677557}, issn = {1873-6750}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; Inactivation, Metabolic/*genetics ; Polymorphism, Genetic/*genetics ; }, }
@article {pmid29676287, year = {2018}, author = {Kellmeyer, P and Grosse-Wentrup, M and Schulze-Bonhage, A and Ziemann, U and Ball, T}, title = {Electrophysiological correlates of neurodegeneration in motor and non-motor brain regions in amyotrophic lateral sclerosis-implications for brain-computer interfacing.}, journal = {Journal of neural engineering}, volume = {15}, number = {4}, pages = {041003}, doi = {10.1088/1741-2552/aabfa5}, pmid = {29676287}, issn = {1741-2552}, mesh = {Amyotrophic Lateral Sclerosis/diagnostic imaging/*physiopathology/*therapy ; *Brain-Computer Interfaces ; Electrocorticography/methods ; Electroencephalography/methods ; Evoked Potentials, Somatosensory/physiology ; Humans ; Motor Cortex/diagnostic imaging/*physiopathology ; Neurodegenerative Diseases/diagnostic imaging/physiopathology/therapy ; }, abstract = {OBJECTIVE: For patients with amyotrophic lateral sclerosis (ALS) who are suffering from severe communication or motor problems, brain-computer interfaces (BCIs) can improve the quality of life and patient autonomy. However, current BCI systems are not as widely used as their potential and patient demand would let assume. This underutilization is a result of technological as well as user-based limitations but also of the comparatively poor performance of currently existing BCIs in patients with late-stage ALS, particularly in the locked-in state.<br><br>APPROACH: Here we review a broad range of electrophysiological studies in ALS patients with the aim to identify electrophysiological correlates of ALS-related neurodegeneration in motor and non-motor brain regions in to better understand potential neurophysiological limitations of current BCI systems for ALS patients. To this end we analyze studies in ALS patients that investigated basic sensory evoked potentials, resting-state and task-based paradigms using electroencephalography or electrocorticography for basic research purposes as well as for brain-computer interfacing. Main results and significance. Our review underscores that, similarly to mounting evidence from neuroimaging and neuropathology, electrophysiological measures too indicate neurodegeneration in non-motor areas in ALS. Furthermore, we identify an unexpected gap of basic and advanced electrophysiological studies in late-stage ALS patients, particularly in the locked-in state. We propose a research strategy on how to fill this gap in order to improve the design and performance of future BCI systems for this patient group.}, }
@article {pmid29676181, year = {2018}, author = {Lee, SH and Suk, K}, title = {Identification of glia phenotype modulators based on select glial function regulatory signaling pathways.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {7}, pages = {627-641}, doi = {10.1080/17460441.2018.1465925}, pmid = {29676181}, issn = {1746-045X}, mesh = {Animals ; Humans ; Microglia/*metabolism ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroglia/metabolism ; Phenotype ; Severity of Illness Index ; Signal Transduction/drug effects ; }, abstract = {Despite the considerable social and economic burden on the healthcare system worldwide due to neurodegenerative diseases, there are currently few disease-altering treatment options for many of these conditions. Therefore, new approaches for both prevention and intervention for neurodegenerative diseases are urgently required. Microglia-mediated neurotoxicity is one of the pathologic hallmarks common to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Current therapeutic approaches to target microglia-mediated neurotoxicity are focused on the identification of glia phenotype modulators (GPMs), which can inhibit the 'classical' pro-inflammatory and neurotoxic phenotypes of microglia. Areas covered: This article reviews selected microglial molecular targets and pathways involved in either neurotoxicity or neuroprotection and how their identification. Expert opinion: Microglial activation and their signaling pathways have important implications in the neurotoxicity and brain disorders. Pharmacological modulation of microglial activation may serve as a potential therapeutic approach for targeting microglia-mediated neurotoxicity. However, given that microglia change their activation states depending on the timing, stage, and severity of disease, and even aging, the appropriate window should be considered for this approach to be clinically effective. In the future, the identification of unknown extracellular signals and intracellular molecular switches that control phenotypic shifts may facilitate the development of novel therapeutics targeting microglia-mediated neurotoxicity.}, }
@article {pmid29667443, year = {2018}, author = {Dharmadasa, T and Huynh, W and Tsugawa, J and Shimatani, Y and Ma, Y and Kiernan, MC}, title = {Implications of structural and functional brain changes in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {18}, number = {5}, pages = {407-419}, doi = {10.1080/14737175.2018.1464912}, pmid = {29667443}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Atrophy/pathology ; Brain/*pathology/*physiopathology ; Cerebral Cortex/diagnostic imaging/pathology ; Diffusion Tensor Imaging ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Neuroimaging ; Phenotype ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive muscle weakness and disability, eventually leading to death. Heterogeneity of disease has become a major barrier to understanding key clinical questions such as prognosis and disease spread, and has disadvantaged clinical trials in search of therapeutic intervention. Patterns of disease have been explored through recent advances in neuroimaging, elucidating structural, molecular and functional changes. Unique brain signatures have emerged that have lent a greater understanding of critical disease mechanisms, offering opportunities to improve diagnosis, guide prognosis, and establish candidate biomarkers to direct future therapeutic strategies. Areas covered: This review explores patterns of cortical and subcortical change in ALS through advanced neuroimaging techniques and discusses the implications of these findings. Expert commentary: Cortical and subcortical signatures and patterns of atrophy are now consistently recognised, providing important pathophysiological insight into this heterogenous disease. The spread of cortical change, particularly involving frontotemporal networks, correlates with cognitive impairment and poorer prognosis. Cortical differences are also evident between ALS phenotypes and genotypes, which may partly explain the heterogeneity of prognosis. Ultimately, multimodal approaches with larger cohorts will be needed to provide sensitive biomarkers of disease spread at the level of the individual patient.}, }
@article {pmid29663553, year = {2019}, author = {Pugh, JD and McCoy, K and Williams, AM and Bentley, B and Monterosso, L}, title = {Rapid evidence assessment of approaches to community neurological nursing care for people with neurological conditions post-discharge from acute care hospital.}, journal = {Health &amp; social care in the community}, volume = {27}, number = {1}, pages = {43-54}, doi = {10.1111/hsc.12576}, pmid = {29663553}, issn = {1365-2524}, support = {16672//Neurological Council of Western Australia/International ; }, mesh = {Brain Diseases/epidemiology/*nursing ; Continuity of Patient Care ; Dementia/nursing ; Depression/epidemiology ; Health Knowledge, Attitudes, Practice ; Humans ; Life Style ; Patient Discharge/*statistics &amp; numerical data ; Patient Satisfaction ; Self-Management ; Social Participation ; Stroke/nursing ; }, abstract = {Neurological conditions represent leading causes of non-fatal burden of disease that will consume a large proportion of projected healthcare expenditure. Inconsistent access to integrated healthcare and other services for people with long-term neurological conditions stresses acute care services. The purpose of this rapid evidence assessment, conducted February-June 2016, was to review the evidence supporting community neurological nursing approaches for patients with neurological conditions post-discharge from acute care hospitals. CINAHL Plus with Full Text and MEDLINE were searched for English-language studies published January 2000 to June 2016. Data were extracted using a purpose-designed protocol. Studies describing community neurological nursing care services post-discharge for adults with stroke, dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis or motor neurone disease were included and their quality was assessed. Two qualitative and three quantitative studies were reviewed. Two themes were identified in the narrative summary of findings: (i) continuity of care and self-management and (ii) variable impact on clinical or impairment outcomes. There was low quality evidence of patient satisfaction, improved patient social activity, depression scores, stroke knowledge and lifestyle modification associated with post-discharge care by neurological nurses as an intervention. There were few studies and weak evidence supporting the use of neurology-generalist nurses to promote continuity of care for people with long-term or progressive, long-term neurological conditions post-discharge from acute care hospital. Further research is needed to provide role clarity to facilitate comparative studies and evaluations of the effectiveness of community neurological nursing models of care.}, }
@article {pmid29658475, year = {2018}, author = {Vallée, A}, title = {[Aerobic glycolysis activation through canonical WNT/β-catenin pathway in ALS].}, journal = {Medecine sciences : M/S}, volume = {34}, number = {4}, pages = {326-330}, doi = {10.1051/medsci/20183404013}, pmid = {29658475}, issn = {1958-5381}, mesh = {Aerobiosis/physiology ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Glycolysis/genetics/*physiology ; Humans ; Wnt Signaling Pathway/genetics/*physiology ; beta Catenin/genetics/*metabolism ; }, abstract = {Energy is the major determinant of neuronal viability. We focus our synthesis on the hypothesis of the development of aerobic glycolysis by the stimulation of the canonical WNT/β-catenin pathway in amyotrophic lateral sclerosis (ALS). The stimulation of the canonical WNT/β-catenin pathway induces the activation of aerobic glycolysis, also called Warburg effect, via the stimulation of glycolytic enzymes such as Glut (glucose transporter), PKM2 (pyruvate kinase M2), PDK1 (pyruvate dehydrogenase kinase 1), LDH-A (lactate dehydrogenase A) and MCT-1 (monocarboxylate transporter 1). The aerobic glycolysis consists to a supply of a large part of glucose into lactate regardless of oxygen. Aerobic glycolysis is less efficient in terms of ATP production than oxidative phosphorylation due to the shunt of the TCA cycle. Dysregulation of cellular energy metabolism promotes cell death and participates to the progression of ALS. Controlling the expression of the canonical WNT/β-catenin signaling pathway is an attractive strategy to regulate aerobic glycolysis initiation and the progression of ALS.}, }
@article {pmid29656681, year = {2018}, author = {Vogt, M}, title = {Progress with modeling activity landscapes in drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {7}, pages = {605-615}, doi = {10.1080/17460441.2018.1465926}, pmid = {29656681}, issn = {1746-045X}, mesh = {*Drug Design ; Drug Discovery/*methods ; Humans ; Machine Learning ; *Models, Molecular ; Models, Statistical ; Models, Theoretical ; Quantitative Structure-Activity Relationship ; }, abstract = {Activity landscapes (ALs) are representations and models of compound data sets annotated with a target-specific activity. In contrast to quantitative structure-activity relationship (QSAR) models, ALs aim at characterizing structure-activity relationships (SARs) on a large-scale level encompassing all active compounds for specific targets. The popularity of AL modeling has grown substantially with the public availability of large activity-annotated compound data sets. AL modeling crucially depends on molecular representations and similarity metrics used to assess structural similarity. Areas covered: The concepts of AL modeling are introduced and its basis in quantitatively assessing molecular similarity is discussed. The different types of AL modeling approaches are introduced. AL designs can broadly be divided into three categories: compound-pair based, dimensionality reduction, and network approaches. Recent developments for each of these categories are discussed focusing on the application of mathematical, statistical, and machine learning tools for AL modeling. AL modeling using chemical space networks is covered in more detail. Expert opinion: AL modeling has remained a largely descriptive approach for the analysis of SARs. Beyond mere visualization, the application of analytical tools from statistics, machine learning and network theory has aided in the sophistication of AL designs and provides a step forward in transforming ALs from descriptive to predictive tools. To this end, optimizing representations that encode activity relevant features of molecules might prove to be a crucial step.}, }
@article {pmid29654868, year = {2018}, author = {Zhang, S and Liu, Y and Ye, Y and Wang, XR and Lin, LT and Xiao, LY and Zhou, P and Shi, GX and Liu, CZ}, title = {Bee venom therapy: Potential mechanisms and therapeutic applications.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {148}, number = {}, pages = {64-73}, doi = {10.1016/j.toxicon.2018.04.012}, pmid = {29654868}, issn = {1879-3150}, mesh = {Acupuncture Therapy ; Animals ; Bee Venoms/adverse effects/*pharmacology/*therapeutic use ; *Bees ; Humans ; Insect Bites and Stings ; }, abstract = {Bee venom is a very complex mixture of natural products extracted from honey bee which contains various pharmaceutical properties such as peptides, enzymes, biologically active amines and nonpeptide components. The use of bee venom into the specific points is so called bee venom therapy, which is widely used as a complementary and alternative therapy for 3000 years. A growing number of evidence has demonstrated the anti-inflammation, the anti-apoptosis, the anti-fibrosis and the anti-arthrosclerosis effects of bee venom therapy. With these pharmaceutical characteristics, bee venom therapy has also been used as the therapeutic method in treating rheumatoid arthritis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, liver fibrosis, atherosclerosis, pain and others. Although widely used, several cases still reported that bee venom therapy might cause some adverse effects, such as local itching or swelling. In this review, we summarize its potential mechanisms, therapeutic applications, and discuss its existing problems.}, }
@article {pmid29649521, year = {2018}, author = {Aquilina, B and Cauchi, RJ}, title = {Modelling motor neuron disease in fruit flies: Lessons from spinal muscular atrophy.}, journal = {Journal of neuroscience methods}, volume = {310}, number = {}, pages = {3-11}, doi = {10.1016/j.jneumeth.2018.04.003}, pmid = {29649521}, issn = {1872-678X}, mesh = {Animals ; *Disease Models, Animal ; *Drosophila melanogaster ; Humans ; *Motor Neuron Disease ; *Muscular Atrophy, Spinal ; }, abstract = {Motor neuron disease (MND) is characterised by muscle weakness and paralysis downstream of motor neuron degeneration. Genetic factors play a major role in disease pathogenesis and progression. This is best underscored by spinal muscular atrophy (SMA), the most common MND affecting children. Although SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene, partial compensation by the paralogous SMN2 gene and/or genetic modifiers influence age of onset and disease severity. SMA is also the first MND that is treatable thanks to the recent development of a molecular-based therapy. This key milestone was possible following an intense research campaign in which animal models had a starring role. In this review, we specifically focus on the fruit fly Drosophila melanogaster and highlight its sterling contributions aimed at furthering our understanding of SMA pathogenesis. Methods of gene disruption utilised to generate SMA fly models are discussed and ways through which neuromuscular defects have been characterised are elaborated on. A phenotypic overlap with patients and mammalian models, allowed the use of SMA fly models to identify genetic modifiers, hence spurring investigators to discover pathways that are perturbed in disease. Targeting these can potentially lead to complimentary therapies for SMA. The same output is expected from the use of SMA fly models to identify therapeutic compounds that have an ameliorative effect. We believe that lessons gained from SMA will allow researchers to eagerly exploit Drosophila to confirm novel genes linked to MND, reveal disease mechanisms and ultimately identify therapeutics.}, }
@article {pmid29645384, year = {2018}, author = {Gaiser, MR and von Bubnoff, N and Gebhardt, C and Utikal, JS}, title = {Liquid Biopsy zur Überwachung von Melanompatienten.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {16}, number = {4}, pages = {405-416}, doi = {10.1111/ddg.13461_g}, pmid = {29645384}, issn = {1610-0387}, abstract = {In den letzten sechs Jahren wurden verschiedene innovative systemische Therapien zur Behandlung des metastasierten malignen Melanoms (MM) entwickelt. Die konventionelle Chemotherapie wurde durch neuartige Primärtherapien abgelöst, darunter systemische Immuntherapien (Anti-CTLA4- und Anti-PD1-Antikörper; Zulassung von Anti-PDL1-Antikörpern erwartet) und Therapien, die gegen bestimmte Mutationen gerichtet sind (BRAF, NRAS und c-KIT). Daher stehen die behandelnden Ärzte neuen Herausforderungen gegenüber, beispielsweise der Stratifizierung von Patienten für geeignete Behandlungen und der Überwachung von Langzeit-Respondern auf Progression. Folglich werden zuverlässige Methoden zur Überwachung von Krankheitsprogression oder Behandlungsresistenz benötigt. Lokalisierte und fortgeschrittene Krebserkrankungen können zur Bildung zirkulierender Tumorzellen und Tumor-DNA (ctDNA) führen, die sich in Proben von peripherem Blut nachweisen und quantifizieren lassen (Liquid Biopsy). Im Fall von Melanompatienten können die Ergebnisse von Liquid Biopsy als neuartige prädiktive Biomarker bei therapeutischen Entscheidungen hilfreich sein, insbesondere im Zusammenhang mit mutationsbasierten zielgerichteten Therapien. Die Herausforderungen bei der Anwendung der Liquid Biopsy beinhalten strikte Kriterien für den Phänotyp der zirkulierenden MM-Zellen oder ihrer Fragmente und die Instabilität von ctDNA im Blut. In diesem Übersichtsartikel diskutieren wir die Beschränkungen der Liquid Biopsy hinsichtlich ihrer Anwendung in der Routinediagnostik.}, }
@article {pmid29631171, year = {2018}, author = {Bertolotti, A}, title = {Importance of the subcellular location of protein deposits in neurodegenerative diseases.}, journal = {Current opinion in neurobiology}, volume = {51}, number = {}, pages = {127-133}, doi = {10.1016/j.conb.2018.03.004}, pmid = {29631171}, issn = {1873-6882}, support = {MC_U105185860/MRC_/Medical Research Council/United Kingdom ; 206367/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Endoplasmic Reticulum/*metabolism ; Humans ; Neurodegenerative Diseases/*pathology ; Neurons/metabolism/*ultrastructure ; Proteins/*metabolism ; Proteostasis Deficiencies/pathology ; }, abstract = {Alzheimer's disease, Parkinson's, Huntington's, amyotrophic lateral sclerosis (ALS) and prion disorders are devastating neurodegenerative diseases of increasing prevalence in aging populations. Although clinically different, they share similar molecular features: the accumulation of one or two proteins in abnormal conformations inside or outside neurons. Enhancing protein quality control systems could be a useful strategy to neutralize the abnormal proteins causing neurodegenerative diseases. This review emphasizes the subcellular location of protein deposits in neurodegenerative diseases and the need to tailor strategies aimed at boosting protein quality control systems to the affected subcellular compartment. Inhibition of a protein phosphatase terminating the unfolded protein response will be discussed as a strategy to protect from diseases associated with misfolded proteins in the endoplasmic reticulum.}, }
@article {pmid29630421, year = {2018}, author = {Agosta, F and Spinelli, EG and Filippi, M}, title = {Neuroimaging in amyotrophic lateral sclerosis: current and emerging uses.}, journal = {Expert review of neurotherapeutics}, volume = {18}, number = {5}, pages = {395-406}, doi = {10.1080/14737175.2018.1463160}, pmid = {29630421}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology/physiopathology ; Brain/diagnostic imaging/pathology ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Motor Neurons/pathology ; Neuroimaging/*methods ; Positron-Emission Tomography ; Spinal Cord/diagnostic imaging/pathology ; }, abstract = {Several neuroimaging techniques have been used to define in vivo markers of pathological alterations underlying amyotrophic lateral sclerosis (ALS). Growing evidence supports the use of magnetic resonance imaging (MRI) and positron emission tomography (PET) for the non-invasive detection of central nervous system involvement in patients with ALS. Areas covered: A comprehensive overview of structural and functional neuroimaging applications in ALS is provided, focusing on motor and extra-motor involvement in the brain and the spinal cord. Implications for pathogenetic models, patient diagnosis, prognosis, monitoring, and the design of clinical trials are discussed. Expert commentary: State-of-the-art neuroimaging techniques provide fundamental instruments for the detection and quantification of upper motor neuron and extra-motor brain involvement in ALS, with relevance for both pathophysiologic investigation and clinical practice. Network-based analysis of structural and functional connectivity alterations and multimodal approaches combining several neuroimaging measures are promising tools for the development of novel diagnostic and prognostic markers to be used at the individual patient level.}, }
@article {pmid29626651, year = {2019}, author = {Nguyen, DKH and Thombre, R and Wang, J}, title = {Autophagy as a common pathway in amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {697}, number = {}, pages = {34-48}, pmid = {29626651}, issn = {1872-7972}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Animals ; Autophagy/genetics/physiology ; Biological Transport ; Humans ; Neurons/metabolism/pathology ; }, abstract = {Age-dependent neurodegenerative diseases are associated with a decline in protein quality control systems including autophagy. Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease of complex etiology with increasing connections to other neurodegenerative conditions such as frontotemporal dementia. Among the diverse genetic causes for ALS, a striking feature is the common connection to autophagy and its associated pathways. There is a recurring theme of protein misfolding as in other neurodegenerative diseases, but importantly there is a distinct common thread among ALS genes that connects them to the cascade of autophagy. However, the roles of autophagy in ALS remain enigmatic and it is still unclear whether activation or inhibition of autophagy would be a reliable avenue to ameliorate the disease. The main evidence that links autophagy to different genetic forms of ALS is discussed.}, }
@article {pmid29621594, year = {2018}, author = {Koch, JC and Tatenhorst, L and Roser, AE and Saal, KA and Tönges, L and Lingor, P}, title = {ROCK inhibition in models of neurodegeneration and its potential for clinical translation.}, journal = {Pharmacology &amp; therapeutics}, volume = {189}, number = {}, pages = {1-21}, doi = {10.1016/j.pharmthera.2018.03.008}, pmid = {29621594}, issn = {1879-016X}, mesh = {Animals ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neurons/drug effects/physiology ; Protein Kinase Inhibitors/pharmacology/*therapeutic use ; rho-Associated Kinases/*antagonists &amp; inhibitors/physiology ; }, abstract = {Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders.}, }
@article {pmid29605155, year = {2018}, author = {Nguyen, HP and Van Broeckhoven, C and van der Zee, J}, title = {ALS Genes in the Genomic Era and their Implications for FTD.}, journal = {Trends in genetics : TIG}, volume = {34}, number = {6}, pages = {404-423}, doi = {10.1016/j.tig.2018.03.001}, pmid = {29605155}, issn = {0168-9525}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics ; Frontotemporal Dementia/epidemiology/*genetics ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.}, }
@article {pmid29593492, year = {2018}, author = {Xue, YC and Feuer, R and Cashman, N and Luo, H}, title = {Enteroviral Infection: The Forgotten Link to Amyotrophic Lateral Sclerosis?.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {63}, pmid = {29593492}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily attacks motor neurons in the brain and spinal cord, leading to progressive paralysis and ultimately death. Currently there is no effective therapy. The majority of ALS cases are sporadic, with no known family history; unfortunately the etiology remains largely unknown. Contribution of Enteroviruses (EVs), a family of positive-stranded RNA viruses including poliovirus, coxsackievirus, echovirus, enterovirus-A71 and enterovirus-D68, to the development of ALS has been suspected as they can target motor neurons, and patients with prior poliomyelitis show a higher risk of motor neuron disease. Multiple efforts have been made to detect enteroviral genome in ALS patient tissues over the past two decades; however the clinical data are controversial and a causal relationship has not yet been established. Recent evidence from in vitro and animal studies suggests that enterovirus-induced pathology remarkably resembles the cellular and molecular phenotype of ALS, indicating a possible link between enteroviral infection and ALS pathogenesis. In this review, we summarize the nature of enteroviral infection, including route of infection, cells targeted, and viral persistence within the central nervous system (CNS). We review the molecular mechanisms underlying viral infection and highlight the similarity between viral pathogenesis and the molecular and pathological features of ALS, and finally, discuss the potential role of enteroviral infection in frontotemporal dementia (FTD), a disease that shares common clinical, genetic, and pathological features with ALS, and the significance of anti-viral therapy as an option for the treatment of ALS.}, }
@article {pmid29589534, year = {2018}, author = {Degan, D and Ornello, R and Tiseo, C and Carolei, A and Sacco, S and Pistoia, F}, title = {The Role of Inflammation in Neurological Disorders.}, journal = {Current pharmaceutical design}, volume = {24}, number = {14}, pages = {1485-1501}, doi = {10.2174/1381612824666180327170632}, pmid = {29589534}, issn = {1873-4286}, mesh = {Animals ; Humans ; Inflammation/drug therapy/*immunology ; Inflammation Mediators/*immunology/therapeutic use ; Nervous System Diseases/drug therapy/*immunology ; }, abstract = {Traditionally neurological diseases have been classified, on the basis of their pathogenesis, into vascular, degenerative, inflammatory and traumatic diseases. Examples of the main inflammatory neurological diseases include multiple sclerosis, which is characterized by an immune-mediated response against myelin proteins, and meningoencephalitis, where the inflammatory response is triggered by infectious agents. However, recent evidence suggests a potential role of inflammatory mechanisms also in neurological conditions not usually categorized as inflammatory, such as Alzheimer's disease, Parkinson's disease, Huntington' disease, amyotrophic lateral sclerosis, stroke and traumatic brain injuries. The activation of glial cells and of complement-mediated pathways, the synthesis of inflammation mediators, and the recruitment of leukocytes are the key elements of secondary inflammatory injury following a wide spectrum of primary brain injuries. A better understanding of the role that inflammatory processes play in the natural history of diseases is essential in order to identify potential therapeutic targets and to develop integrated pharmacological approaches acting at different levels and stages of the diseases.}, }
@article {pmid29584802, year = {2018}, author = {Walker, C and El-Khamisy, SF}, title = {Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia.}, journal = {Brain : a journal of neurology}, volume = {141}, number = {5}, pages = {1247-1262}, pmid = {29584802}, issn = {1460-2156}, support = {//Wellcome Trust/United Kingdom ; 103844//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; Autophagy/*physiology ; DNA Repair/*physiology ; Dementia/*complications ; Humans ; Nerve Degeneration/*etiology ; }, abstract = {Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration. Here, we discuss this emerging paradigm in the context of amyotrophic lateral sclerosis and frontotemporal dementia, and outline how this knowledge paves the way to novel therapeutic interventions.}, }
@article {pmid29580918, year = {2018}, author = {Lv, J and Jiang, S and Yang, Z and Hu, W and Wang, Z and Li, T and Yang, Y}, title = {PGC-1α sparks the fire of neuroprotection against neurodegenerative disorders.}, journal = {Ageing research reviews}, volume = {44}, number = {}, pages = {8-21}, doi = {10.1016/j.arr.2018.03.004}, pmid = {29580918}, issn = {1872-9649}, mesh = {Alzheimer Disease/diagnosis/genetics/metabolism ; Animals ; Gene Expression Regulation ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics/*metabolism ; Neuroprotection/*physiology ; Parkinson Disease/diagnosis/genetics/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*biosynthesis/*genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Transcription Factors/metabolism ; }, abstract = {Recently, growing evidence has demonstrated that peroxisome proliferator activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a superior transcriptional regulator that acts via controlling the expression of anti-oxidant enzymes and uncoupling proteins and inducing mitochondrial biogenesis, which plays a beneficial part in the central nervous system (CNS). Given the significance of PGC-1α, we summarize the current literature on the molecular mechanisms and roles of PGC-1α in the CNS. Thus, in this review, we first briefly introduce the basic characteristics regarding PGC-1α. We then depict some of its important cerebral functions and discuss upstream modulators, partners, and downstream effectors of the PGC-1α signaling pathway. Finally, we highlight recent progress in research on the involvement of PGC-1α in certain major neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Collectively, the data presented here may be useful for supporting the future potential of PGC-1α as a therapeutic target.}, }
@article {pmid29580826, year = {2019}, author = {Press, M and Jung, T and König, J and Grune, T and Höhn, A}, title = {Protein aggregates and proteostasis in aging: Amylin and β-cell function.}, journal = {Mechanisms of ageing and development}, volume = {177}, number = {}, pages = {46-54}, doi = {10.1016/j.mad.2018.03.010}, pmid = {29580826}, issn = {1872-6216}, mesh = {Aging/*metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Amyloid/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Diabetes Mellitus, Type 2/metabolism/pathology ; Humans ; Insulin-Secreting Cells/*metabolism/pathology ; Islet Amyloid Polypeptide/*metabolism ; Protein Aggregation, Pathological/*metabolism/pathology ; *Proteostasis ; }, abstract = {The ubiquitin-proteasomal-system (UPS) and the autophagy-lysosomal-system (ALS) are both highly susceptible for disturbances leading to the accumulation of cellular damage. A decline of protein degradation during aging results in the formation of oxidatively damaged and aggregated proteins finally resulting in failure of cellular functionality. Besides protein aggregation in response to oxidative damage, amyloids are a different type of protein aggregates able to distract proteostasis and interfere with cellular functionality. Amyloids are clearly linked to the pathogenesis of age-related degenerative diseases such as Alzheimer's disease. Human amylin is one of the peptides forming fibrils in β-sheet conformation finally leading to amyloid formation. In contrast to rodent amylin, human amylin is prone to form amyloidogenic aggregates, proposed to play a role in the pathogenesis of Type 2 Diabetes by impairing β-cell functionality. Since aggregates such as lipofuscin and β-amyloid are known to impair proteostasis, it is likely to assume similar effects for human amylin. In this review, we focus on the effects of IAPP on UPS and ALS and their role in amylin degradation, since both systems play a crucial role in maintaining proteome balance thereby influencing, at least in part, cellular fate and aging.}, }
@article {pmid29577886, year = {2018}, author = {Lutz, C}, title = {Mouse models of ALS: Past, present and future.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {1-10}, doi = {10.1016/j.brainres.2018.03.024}, pmid = {29577886}, issn = {1872-6240}, support = {U54 OD020351/OD/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; *Disease Models, Animal ; Humans ; Mice ; Mutation ; }, abstract = {Genome sequencing of both sporadic and familial patients of Amyotrophic Lateral Sclerosis (ALS) has led to the identification of new genes that are both contributing and causative in the disease. This gene discovery has come at an unprecedented rate, and much of it in recent years. Knowledge of these genetic mutations provides us with opportunities to uncover new and related mechanisms, increasing our understanding of the disease and bringing us closer to defined therapies for patients. Mouse models have played an important role in our current understanding of the pathophysiology of ALS and have served as important preclinical models in testing new therapeutics. With these new gene discoveries, new mouse models will follow. The information derived from these new models will depend on the careful construction and importantly, an understanding of the capabilities and limitations of each of the models. The genetic discovery in ALS comes at a time when genetic engineering technologies in mice are highly efficient through CRISPR/Cas9 and can be applied to a wide array of genetic backgrounds. New mouse resources in the forms of the Collaborative Cross and Diversity Outbred panels provide us with unique opportunities to study these mutations on diverse genetic backgrounds, and importantly in the context of a population. This review focuses on the mouse models of the past and present, and discusses exciting new opportunities for mouse models of the future.}, }
@article {pmid29572723, year = {2018}, author = {Vallée, A and Lecarpentier, Y and Guillevin, R and Vallée, JN}, title = {Thermodynamics in Neurodegenerative Diseases: Interplay Between Canonical WNT/Beta-Catenin Pathway-PPAR Gamma, Energy Metabolism and Circadian Rhythms.}, journal = {Neuromolecular medicine}, volume = {20}, number = {2}, pages = {174-204}, pmid = {29572723}, issn = {1559-1174}, mesh = {Adenosine Triphosphate/biosynthesis ; Aerobiosis ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Brain/metabolism ; *Circadian Rhythm ; *Energy Metabolism ; Glycolysis ; Humans ; Huntington Disease/metabolism/physiopathology ; Melatonin/metabolism ; Models, Biological ; Neurodegenerative Diseases/*metabolism/physiopathology ; Oxidative Stress ; PPAR gamma/agonists/biosynthesis/*physiology ; Parkinson Disease/metabolism/physiopathology ; *Thermodynamics ; *Wnt Signaling Pathway ; }, abstract = {Entropy production rate is increased by several metabolic and thermodynamics abnormalities in neurodegenerative diseases (NDs). Irreversible processes are quantified by changes in the entropy production rate. This review is focused on the opposing interactions observed in NDs between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In amyotrophic lateral sclerosis and Huntington's disease, WNT/beta-catenin pathway is upregulated, whereas PPAR gamma is downregulated. In Alzheimer's disease and Parkinson's disease, WNT/beta-catenin pathway is downregulated while PPAR gamma is upregulated. The dysregulation of the canonical WNT/beta-catenin pathway is responsible for the modification of thermodynamics behaviors of metabolic enzymes. Upregulation of WNT/beta-catenin pathway leads to aerobic glycolysis, named Warburg effect, through activated enzymes, such as glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1(PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactic dehydrogenase kinase-A (LDH-A) and inactivation of pyruvate dehydrogenase complex (PDH). Downregulation of WNT/beta-catenin pathway leads to oxidative stress and cell death through inactivation of Glut, PKM2, PDK1, MCT-1, LDH-A but activation of PDH. In addition, in NDs, PPAR gamma is dysregulated, whereas it contributes to the regulation of several key circadian genes. NDs show many dysregulation in the mediation of circadian clock genes and so of circadian rhythms. Thermodynamics rhythms operate far-from-equilibrium and partly regulate interactions between WNT/beta-catenin pathway and PPAR gamma. In NDs, metabolism, thermodynamics and circadian rhythms are tightly interrelated.}, }
@article {pmid29570669, year = {2018}, author = {Kitamura, A and Kinjo, M}, title = {State-of-the-Art Fluorescence Fluctuation-Based Spectroscopic Techniques for the Study of Protein Aggregation.}, journal = {International journal of molecular sciences}, volume = {19}, number = {4}, pages = {}, pmid = {29570669}, issn = {1422-0067}, mesh = {Amyloid/*chemistry ; Fluorescence ; Humans ; Protein Folding ; Proteins/*chemistry ; Spectrometry, Fluorescence ; }, abstract = {Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease, are devastating proteinopathies with misfolded protein aggregates accumulating in neuronal cells. Inclusion bodies of protein aggregates are frequently observed in the neuronal cells of patients. Investigation of the underlying causes of neurodegeneration requires the establishment and selection of appropriate methodologies for detailed investigation of the state and conformation of protein aggregates. In the current review, we present an overview of the principles and application of several methodologies used for the elucidation of protein aggregation, specifically ones based on determination of fluctuations of fluorescence. The discussed methods include fluorescence correlation spectroscopy (FCS), imaging FCS, image correlation spectroscopy (ICS), photobleaching ICS (pbICS), number and brightness (N&amp;B) analysis, super-resolution optical fluctuation imaging (SOFI), and transient state (TRAST) monitoring spectroscopy. Some of these methodologies are classical protein aggregation analyses, while others are not yet widely used. Collectively, the methods presented here should help the future development of research not only into protein aggregation but also neurodegenerative diseases.}, }
@article {pmid29569624, year = {2018}, author = {Ahmed, RM and Ke, YD and Vucic, S and Ittner, LM and Seeley, W and Hodges, JR and Piguet, O and Halliday, G and Kiernan, MC}, title = {Physiological changes in neurodegeneration - mechanistic insights and clinical utility.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {5}, pages = {259-271}, pmid = {29569624}, issn = {1759-4766}, mesh = {*Alzheimer Disease/metabolism/physiopathology ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; *Autonomic Nervous System/physiopathology ; *Frontotemporal Dementia/metabolism/physiopathology ; Humans ; *Hypothalamus/metabolism/physiopathology ; *Nerve Net/physiopathology ; *Parkinsonian Disorders/metabolism/physiopathology ; *Sleep Wake Disorders/physiopathology ; }, abstract = {The effects of neurodegenerative syndromes extend beyond cognitive function to involve key physiological processes, including eating and metabolism, autonomic nervous system function, sleep, and motor function. Changes in these physiological processes are present in several conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease and the parkinsonian plus conditions. Key neural structures that mediate physiological changes across these conditions include neuroendocrine and hypothalamic pathways, reward pathways, motor systems and the autonomic nervous system. In this Review, we highlight the key changes in physiological processing in neurodegenerative syndromes and the similarities in these changes between different progressive neurodegenerative brain conditions. The changes and similarities between disorders might provide novel insights into the human neural correlates of physiological functioning. Given the evidence that physiological changes can arise early in the neurodegenerative process, these changes could provide biomarkers to aid in the early diagnosis of neurodegenerative diseases and in treatment trials.}, }
@article {pmid29564907, year = {2018}, author = {Bužgová, R and Kozáková, R and Zeleníková, R and Sikorová, L}, title = {[The review of questionnaires and scales evaluating patients with amyotrophic lateral sclerosis].}, journal = {Casopis lekaru ceskych}, volume = {157}, number = {1}, pages = {41-45}, pmid = {29564907}, issn = {0008-7335}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), it is advisable to provide multidisciplinary care, due to rapid progression and specific disease symptoms, in order to maintain the best quality of life for the patient and their family. Abroad, questionnaires and scales are used to assess the patient´s health condition, to determine disease progression, followed by the provision of personalized care. The aim of this review article is to describe and analyze the scales used in evaluating ALS patients in both functional and psychosocial areas. Having searched in electronic databases, 14 scales for patients with ALS or motor neuron disease were found, and 4 scales for patients with chronic diseases, which are appropriate and used also in patients with ALS. The ALSFRS scale (The Amyotrophic Lateral Sclerosis Functional Rating Scale) is most often used for assessment of functional status. All areas of care are best covered in the ALSSQOL-R (Amyotrophic Lateral Sclerosis Specific Quality of life) questionnaire, designed for assessment of quality of life. The use of both scales is recommended in clinical practice and research.}, }
@article {pmid29562705, year = {2018}, author = {Kruminis-Kaszkiel, E and Juranek, J and Maksymowicz, W and Wojtkiewicz, J}, title = {CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS).}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29562705}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; CRISPR-Cas Systems/*genetics ; *Genetic Techniques ; Humans ; Models, Biological ; }, abstract = {The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed as an RNA-guided DNA editing tool. Unlike zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas9 takes advantage of an RNA-guided DNA endonuclease enzyme, Cas9, which is able to generate double-strand breaks (DSBs) at specific genomic locations. It triggers cellular endogenous DNA repair pathways, contributing to the generation of desired modifications in the genome. The ability of the system to precisely disrupt DNA sequences has opened up new avenues in our understanding of amyotrophic lateral sclerosis (ALS) pathogenesis and the development of new therapeutic approaches. In this review, we discuss the current knowledge of the principles and limitations of the CRISPR/Cas9 system, as well as strategies to improve these limitations. Furthermore, we summarize novel approaches of engaging the CRISPR/Cas9 system in establishing an adequate model of neurodegenerative disease and in the treatment of SOD1-linked forms of ALS. We also highlight possible applications of this system in the therapy of ALS, both the inherited type as well as ALS of sporadic origin.}, }
@article {pmid29560813, year = {2018}, author = {Scoles, DR and Pulst, SM}, title = {Oligonucleotide therapeutics in neurodegenerative diseases.}, journal = {RNA biology}, volume = {15}, number = {6}, pages = {707-714}, pmid = {29560813}, issn = {1555-8584}, support = {R01 NS097903/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; U01 NS103883/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Ataxin-2/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Mice ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *Oligonucleotides, Antisense/genetics/therapeutic use ; }, abstract = {Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.}, }
@article {pmid29557356, year = {2018}, author = {Penndorf, D and Witte, OW and Kretz, A}, title = {DNA plasticity and damage in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {13}, number = {2}, pages = {173-180}, pmid = {29557356}, issn = {1673-5374}, abstract = {The pathophysiology of amyotrophic lateral sclerosis (ALS) is particularly challenging due to the heterogeneity of its clinical presentation and the diversity of cellular, molecular and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic disease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autonomous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood. This mini review summarizes current knowledge on DNA alterations and counteracting DNA repair strategies in ALS pathology and discusses the putative role of unconventional DNA entities including transposable elements and extrachromosomal circular DNA in the disease process. Focus is set on SOD1-related pathophysiology, with extension to FUS, TDP-43 and C9ORF72 mutations. Advancing our knowledge in the field will contribute to an improved understanding of this relentless disease, for which therapeutic options others than symptomatic approaches are almost unavailable.}, }
@article {pmid29551251, year = {2018}, author = {Küry, P and Nath, A and Créange, A and Dolei, A and Marche, P and Gold, J and Giovannoni, G and Hartung, HP and Perron, H}, title = {Human Endogenous Retroviruses in Neurological Diseases.}, journal = {Trends in molecular medicine}, volume = {24}, number = {4}, pages = {379-394}, pmid = {29551251}, issn = {1471-499X}, mesh = {Animals ; Endogenous Retroviruses/*genetics ; Gene Products, env/genetics ; Humans ; Multiple Sclerosis/genetics/pathology/virology ; Nervous System Diseases/genetics/*pathology/*virology ; }, abstract = {The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.}, }
@article {pmid29549424, year = {2018}, author = {Vandoorne, T and De Bock, K and Van Den Bosch, L}, title = {Energy metabolism in ALS: an underappreciated opportunity?.}, journal = {Acta neuropathologica}, volume = {135}, number = {4}, pages = {489-509}, pmid = {29549424}, issn = {1432-0533}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Animals ; *Energy Metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder that primarily affects motor neurons. Despite our increased understanding of the genetic factors contributing to ALS, no effective treatment is available. A growing body of evidence shows disturbances in energy metabolism in ALS. Moreover, the remarkable vulnerability of motor neurons to ATP depletion has become increasingly clear. Here, we review metabolic alterations present in ALS patients and models, discuss the selective vulnerability of motor neurons to energetic stress, and provide an overview of tested and emerging metabolic approaches to treat ALS. We believe that a further understanding of the metabolic biology of ALS can lead to the identification of novel therapeutic targets.}, }
@article {pmid29548988, year = {2019}, author = {Stavoe, AKH and Holzbaur, ELF}, title = {Axonal autophagy: Mini-review for autophagy in the CNS.}, journal = {Neuroscience letters}, volume = {697}, number = {}, pages = {17-23}, pmid = {29548988}, issn = {1872-7972}, support = {F32 NS100348/NS/NINDS NIH HHS/United States ; K99 NS109286/NS/NINDS NIH HHS/United States ; R37 NS060698/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagosomes/metabolism/pathology/*physiology ; Autophagy/physiology ; Axons/metabolism/pathology/*physiology ; Central Nervous System/*cytology/metabolism ; Endosomes/metabolism/pathology ; Homeostasis ; Humans ; Lysosomes/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/cytology/metabolism ; Protein Transport ; }, abstract = {Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the distal axon occurs via a conserved pathway that is required to maintain functional synapses and prevent axon degeneration. Autophagosomes are formed de novo at the axon terminal in a stepwise assembly process, engulfing mitochondrial fragments, aggregated proteins, and bulk cytosol in what appears to be a nonselective uptake mechanism. Following formation, autophagosomes fuse with late endosomes/lysosomes and then are rapidly and efficiently transported along the axon toward the soma, driven by the microtubule motor cytoplasmic dynein. Motile autophagosomes mature to autolysosomes in transit by fusing with additional late endosomes/lysosomes, arriving at the soma as fully competent degradative organelles. Misregulation of neuronal autophagy leads to axonal degeneration and synaptic destabilization, and has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.}, }
@article {pmid29547565, year = {2018}, author = {Rhoads, SN and Monahan, ZT and Yee, DS and Shewmaker, FP}, title = {The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS.}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29547565}, issn = {1422-0067}, support = {R01 GM118530/GM/NIGMS NIH HHS/United States ; R35 GM119790/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Frontotemporal Dementia/metabolism ; Humans ; Inclusion Bodies/chemistry/metabolism ; Mutation ; Neurons/metabolism ; Prion Proteins/chemistry/*metabolism ; *Protein Aggregates ; Protein Aggregation, Pathological/*metabolism ; *Protein Processing, Post-Translational ; RNA-Binding Protein FUS/chemistry/*metabolism ; }, abstract = {Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. FUS is one of several RNA-binding proteins that can functionally self-associate into distinct liquid-phase droplet structures. It is postulated that aberrant interactions within the dense phase-separated state can potentiate FUS's transition into solid prion-like aggregates that cause disease. FUS is post-translationally modified at numerous positions, which affect both its localization and aggregation propensity. These modifications may influence FUS-linked pathology and serve as therapeutic targets.}, }
@article {pmid29545202, year = {2018}, author = {Dolinar, A and Ravnik-Glavač, M and Glavač, D}, title = {Epigenetic mechanisms in amyotrophic lateral sclerosis: A short review.}, journal = {Mechanisms of ageing and development}, volume = {174}, number = {}, pages = {103-110}, doi = {10.1016/j.mad.2018.03.005}, pmid = {29545202}, issn = {1872-6216}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; *DNA Methylation ; *Epigenesis, Genetic ; Humans ; MicroRNAs/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease. Decades of research show that the etiology of this disease is affected by genetic, epigenetic and environmental factors rather than limited by a patient's genotype. The interaction between these factors is complex, and research has only begun to unravel this issue. The main epigenetic mechanisms, DNA methylation, miRNA, and histone modifications, can explain a portion of the disease complexity. However, the interplay among the epigenetic mechanisms themselves and with genetic factors remains largely uncharacterized. Epigenetic changes affect numerous cell processes, from transcription and translation to protein metabolism and cell junctions. In this review, we briefly summarize the main epigenetic mechanisms and outline recent research on the role of these epigenetic mechanisms in amyotrophic lateral sclerosis.}, }
@article {pmid29542412, year = {2018}, author = {Sehgal, SA and Hammad, MA and Tahir, RA and Akram, HN and Ahmad, F}, title = {Current Therapeutic Molecules and Targets in Neurodegenerative Diseases Based on in silico Drug Design.}, journal = {Current neuropharmacology}, volume = {16}, number = {6}, pages = {649-663}, pmid = {29542412}, issn = {1875-6190}, mesh = {Animals ; *Computer Simulation ; Databases, Factual/statistics &amp; numerical data ; *Drug Design ; Humans ; Molecular Docking Simulation ; Neurodegenerative Diseases/*drug therapy/*genetics ; Neuroprotective Agents/*therapeutic use ; }, abstract = {BACKGROUND: As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of oldage neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease.<br><br>OBJECTIVE: To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases.<br><br>METHOD: Review of literature published since 1997 against neurodegenerative diseases, utilizing as keywords: in silico, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis ALS, and Huntington's disease was conducted.<br><br>RESULTS AND CONCLUSION: Due to the costs associated with experimentation and current ethical law, performing experiments directly on living organisms has become much more difficult. In this scenario, in silico techniques have been successful and have become powerful tools in the search to cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3- dimensional structures of target proteins through homology modeling 2) achieves stabilization through molecular dynamics simulation, and 3) exploits molecular docking through large compound libraries. Next generation sequencing is continually producing enormous amounts of raw sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing problems, these new tools and algorithms are required. This review elaborates precise in silico tools and techniques for drug targets, active molecules, and molecular docking studies, together with future prospects and challenges concerning possible breakthroughs in Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis, and Huntington's disease.}, }
@article {pmid29537145, year = {2018}, author = {Crisan, D and Scharffetter-Kochanek, K and Kastler, S and Crisan, M and Manea, A and Wagner, K and Schneider, LA}, title = {Dermatochirurgie bei Kindern: Gegenwärtiger Stand zu Indikation, Anästhesie, Analgesie und potentiellen perioperativen Komplikationen.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {16}, number = {3}, pages = {268-277}, doi = {10.1111/ddg.13451_g}, pmid = {29537145}, issn = {1610-0387}, abstract = {HINTERGRUND: Anders als Erwachsene benötigen Kinder bei dermatochirurgischen Eingriffen besondere Aufmerksamkeit; die Anwendung verschiedener Analgetika, Anästhetika oder Sedativa erfordert eine gründliche Kenntnis von Pharmakokinetik und -dynamik der Medikamente. Außerdem können Medikamente zur Sedierung/Allgemeinanästhesie bei operierten Kindern zu Anästhesie- oder Analgesie-bedingten Komplikationen einschließlich Störungen der geistigen Entwicklung führen. ZIEL: Auf Basis unserer klinischen Erfahrung und einer Literaturübersicht stellen wir die gängigsten in der pädiatrischen Dermatochirurgie verwendeten Analgetika, Anästhetika und Sedativa dar und diskutieren Risiken und Komplikationen nach dermatochirurgischen Eingriffen.<br><br>ERGEBNISSE: Topische An&#xe4;sthetika k&#xf6;nnen bei Kindern f&#xfc;r oberfl&#xe4;chliche dermatologische Eingriffe oder vor einer Infiltrationsan&#xe4;sthesie eingesetzt werden. Die Berechnung der empfohlenen Maximaldosen auf Basis des K&#xf6;rpergewichts ist erforderlich, um eine &#xdc;berdosierung von Lokalan&#xe4;sthetika zu vermeiden. Die Allgemeinan&#xe4;sthesie gilt bei der Dermatochirurgie als sicher und hat eine geringe Nebenwirkungsrate. Allerdings ist bei Kindern im ersten Lebensjahr aufgrund potentieller langfristiger neurologischer Nebenwirkungen Vorsicht angebracht. NSAR und Opioide spielen bei der Analgesie von Kindern eine bedeutende Rolle.<br><br>SCHLUSSFOLGERUNGEN: Dieser Artikel gibt eine &#xdc;bersicht &#xfc;ber die derzeit verf&#xfc;gbaren Daten zu Analgesie, An&#xe4;sthesie und Komplikationen, die im Rahmen der p&#xe4;diatrischen Dermatochirurgie auftreten k&#xf6;nnen. Diese Daten k&#xf6;nnen dabei helfen, die Sicherheit und Qualit&#xe4;t der Versorgung zu optimieren und die Beratung der Eltern zu verbessern.}, }
@article {pmid29536564, year = {2018}, author = {Santosa, KB and Keane, AM and Jablonka-Shariff, A and Vannucci, B and Snyder-Warwick, AK}, title = {Clinical relevance of terminal Schwann cells: An overlooked component of the neuromuscular junction.}, journal = {Journal of neuroscience research}, volume = {96}, number = {7}, pages = {1125-1135}, pmid = {29536564}, issn = {1097-4547}, support = {F32 NS098561/NS/NINDS NIH HHS/United States ; K08 NS096232/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Humans ; Miller Fisher Syndrome/pathology ; Muscular Atrophy, Spinal/pathology ; Neuromuscular Diseases/pathology ; Neuromuscular Junction/*physiology ; Schwann Cells/metabolism/pathology/*physiology ; }, abstract = {The terminal Schwann cell (tSC), a type of nonmyelinating Schwann cell, is a significant yet relatively understudied component of the neuromuscular junction. In addition to reviewing the role tSCs play on formation, maintenance, and remodeling of the synapse, we review studies that implicate tSCs in neuromuscular diseases including spinal muscular atrophy, Miller-Fisher syndrome, and amyotrophic lateral sclerosis, among others. We also discuss the importance of these cells on degeneration and regeneration after nerve injury. Knowledge of tSC biology may improve our understanding of disease pathogenesis and help us identify new and innovative therapeutic strategies for the many patients who suffer from neuromuscular disorders and nerve injuries.}, }
@article {pmid29533975, year = {2018}, author = {Mammana, S and Fagone, P and Cavalli, E and Basile, MS and Petralia, MC and Nicoletti, F and Bramanti, P and Mazzon, E}, title = {The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29533975}, issn = {1422-0067}, mesh = {Alzheimer Disease/drug therapy/etiology/*metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/*metabolism ; Animals ; Central Nervous System/metabolism/pathology ; Humans ; Macrophages/*metabolism ; Molecular Targeted Therapy ; Multiple Sclerosis/drug therapy/etiology/*metabolism ; }, abstract = {In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases.}, }
@article {pmid29529498, year = {2018}, author = {Battaglia, G and Bruno, V}, title = {Metabotropic glutamate receptor involvement in the pathophysiology of amyotrophic lateral sclerosis: new potential drug targets for therapeutic applications.}, journal = {Current opinion in pharmacology}, volume = {38}, number = {}, pages = {65-71}, doi = {10.1016/j.coph.2018.02.007}, pmid = {29529498}, issn = {1471-4973}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Humans ; Receptors, Metabotropic Glutamate/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex genetic, late age-onset, progressive neurodegenerative disorder leading to the death of upper and lower motor neurons. Life expectancy after diagnosis is short due to the ongoing degeneration and to the lack of effective treatments. Axonal alterations, mitochondrial deficits, RNA changes, protein misfolding and turnover, glial dysfunction and hyperexcitability are key players in molecular mechanisms involved in the degeneration of motor neurons. In the context of hyperexcitability, metabotropic glutamate (mGlu) receptors, which are widely distributed throughout the central nervous system and act through many intracellular signaling pathways, are emerging as novel potential drug targets for the therapeutic treatment of ALS, as they are able to counteract excitotoxicity by reducing glutamate release and inducing the production of neurotrophic factors.}, }
@article {pmid29527170, year = {2018}, author = {de Souza, JM and Goncalves, BDC and Gomez, MV and Vieira, LB and Ribeiro, FM}, title = {Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {145}, pmid = {29527170}, issn = {1663-9812}, abstract = {Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis.}, }
@article {pmid29523774, year = {2018}, author = {Curmi, F and Cauchi, RJ}, title = {The multiple lives of DEAD-box RNA helicase DP103/DDX20/Gemin3.}, journal = {Biochemical Society transactions}, volume = {46}, number = {2}, pages = {329-341}, doi = {10.1042/BST20180016}, pmid = {29523774}, issn = {1470-8752}, mesh = {Animals ; Carcinogenesis ; DEAD Box Protein 20/genetics/*metabolism ; DEAD-box RNA Helicases/genetics/*metabolism ; Gene Expression ; Gene Silencing ; Humans ; NF-kappa B/metabolism ; Ribonucleoproteins, Small Nuclear/metabolism ; Signal Transduction ; Structure-Activity Relationship ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Gemin3, also known as DDX20 or DP103, is a DEAD-box RNA helicase which is involved in more than one cellular process. Though RNA unwinding has been determined in vitro, it is surprisingly not required for all of its activities in cellular metabolism. Gemin3 is an essential gene, present in Amoeba and Metazoa. The highly conserved N-terminus hosts the helicase core, formed of the helicase- and DEAD-domains, which, based on crystal structure determination, have key roles in RNA binding. The C-terminus of Gemin3 is highly divergent between species and serves as the interaction site for several accessory factors that could recruit Gemin3 to its target substrates and/or modulate its function. This review article focuses on the known roles of Gemin3, first as a core member of the survival motor neuron (SMN) complex, in small nuclear ribonucleoprotein biogenesis. Although mechanistic details are lacking, a critical function for Gemin3 in this pathway is supported by numerous in vitro and in vivo studies. Gene expression activities of Gemin3 are next underscored, mainly messenger ribonucleoprotein trafficking, gene silencing via microRNA processing, and transcriptional regulation. The involvement of Gemin3 in abnormal cell signal transduction pathways involving p53 and NF-κB is also highlighted. Finally, the clinical implications of Gemin3 deregulation are discussed including links to spinal muscular atrophy, poliomyelitis, amyotrophic lateral sclerosis, and cancer. Impressive progress made over the past two decades since the discovery of Gemin3 bodes well for further work that refines the mechanism(s) underpinning its multiple activities.}, }
@article {pmid29515547, year = {2018}, author = {Gröger, V and Cynis, H}, title = {Human Endogenous Retroviruses and Their Putative Role in the Development of Autoimmune Disorders Such as Multiple Sclerosis.}, journal = {Frontiers in microbiology}, volume = {9}, number = {}, pages = {265}, pmid = {29515547}, issn = {1664-302X}, abstract = {Human endogenous retroviruses (HERVs) are remnants of retroviral germ line infections of human ancestors and make up ~8% of the human genome. Under physiological conditions, these elements are frequently inactive or non-functional due to deactivating mutations and epigenetic control. However, they can be reactivated under certain pathological conditions and produce viral transcripts and proteins. Several disorders, like multiple sclerosis or amyotrophic lateral sclerosis are associated with increased HERV expression. Although their detailed contribution to individual diseases has yet to be elucidated, an increasing number of studies in vitro and in vivo suggest HERVs as potent modulators of the immune system. They are able to affect the transcription of other immune-related genes, interact with pattern recognition receptors, and influence the positive and negative selection of developing thymocytes. Interestingly, HERV envelope proteins can both stimulate and suppress immune responses based on different mechanisms. In the light of HERV proteins becoming an emerging drug target for autoimmune-related disorders and cancer, we will provide an overview on recent findings of the complex interactions between HERVs and the human immune system with a focus on autoimmunity.}, }
@article {pmid29513402, year = {2018}, author = {Stephenson, J and Nutma, E and van der Valk, P and Amor, S}, title = {Inflammation in CNS neurodegenerative diseases.}, journal = {Immunology}, volume = {154}, number = {2}, pages = {204-219}, pmid = {29513402}, issn = {1365-2567}, mesh = {Adaptive Immunity ; Aging/immunology/metabolism ; Animals ; Blood-Brain Barrier/immunology/metabolism/pathology ; Central Nervous System/immunology/metabolism/pathology ; Environment ; Humans ; Immune Privilege ; Immunity, Innate ; Immunotherapy ; Inflammation/*complications ; Life Style ; Microbiota ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; Risk Factors ; }, abstract = {Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.}, }
@article {pmid29512448, year = {2018}, author = {Azhar, A and Ashraf, GM and Zia, Q and Ansari, SA and Perveen, A and Hafeez, A and Saeed, M and Kamal, MA and Alexiou, A and Ganash, M and Yarla, NS and Baeesa, SS and Alfiky, MM and Bajouh, OS}, title = {Frontier View on Nanotechnological Strategies for Neuro-therapy.}, journal = {Current drug metabolism}, volume = {19}, number = {7}, pages = {596-604}, doi = {10.2174/1389200219666180305144143}, pmid = {29512448}, issn = {1875-5453}, mesh = {Animals ; Brain/metabolism ; Humans ; Nanoparticles/*therapeutic use ; Nanotechnology ; Neurodegenerative Diseases/*drug therapy ; Transcytosis ; }, abstract = {BACKGROUND: Nanotechnology exploits materials and devices with a functional organization that has been engineered at the nanometre scale. The application of nanotechnology in neuroscience involves specific interactions with neurons and glial cells. This property is used for delivering drugs and other small molecules (such as genes, oligonucleotides and contrasting agents) across the blood brain barrier (BBB), an important requirement for delivering the drug successfully to the brain.<br><br>OBJECTIVE: Nanotechnology based approaches (NBA) favours transcytosis-mediated delivery of nanoparticles to the brain by crossing the BBB. The last five years have witnessed the successful applications of NBA to treat neurological disorders. It is expected that the development of novel NBA will result in important insights on the brain mechanisms, and eventually provide better medical care to patients suffering from neurological disorders.<br><br>CONCLUSION: This review introduces the emerging work in this area and summarizes the successful NBA used in recent past for treating various neurological disorders ike Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, meningitis and glioblastoma.}, }
@article {pmid29511163, year = {2018}, author = {Delprat, B and Maurice, T and Delettre, C}, title = {Wolfram syndrome: MAMs' connection?.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {364}, pmid = {29511163}, issn = {2041-4889}, mesh = {Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Stress ; Humans ; Intracellular Membranes/*metabolism ; Mitochondria/*metabolism ; Models, Biological ; Wolfram Syndrome/*metabolism/*pathology/physiopathology ; }, abstract = {Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca[2+] transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed "mitochondria-associated ER membranes" (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.}, }
@article {pmid29507650, year = {2018}, author = {Shefa, U and Kim, MS and Jeong, NY and Jung, J}, title = {Antioxidant and Cell-Signaling Functions of Hydrogen Sulfide in the Central Nervous System.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {1873962}, pmid = {29507650}, issn = {1942-0994}, mesh = {Animals ; Antioxidants/*metabolism ; Central Nervous System/*metabolism ; Humans ; Hydrogen Sulfide/*metabolism ; Oxidative Stress/*physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Hydrogen sulfide (H2S), a toxic gaseous molecule, plays a physiological role in regulating homeostasis and cell signaling. H2S is produced from cysteine by enzymes, such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (3MST). These enzymes regulate the overall production of H2S in the body. H2S has a cell-signaling function in the CNS and plays important roles in combating oxidative species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body. H2S is crucial for maintaining balanced amounts of antioxidants to protect the body from oxidative stress, and appropriate amounts of H2S are required to protect the CNS in particular. The body regulates CBS, 3MST, and CSE levels in the CNS, and higher or lower levels of these enzymes cause various neurodegenerative diseases. This review discusses how H2S protects the CNS by acting as an antioxidant that reduces excessive amounts of ROS and RNS. Additionally, H2S regulates cell signaling to combat neuroinflammation and protect against central neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid29504729, year = {2018}, author = {Holecek, V and Rokyta, R}, title = {Possible etiology and treatment of amyotrophic lateral sclerosis.}, journal = {Neuro endocrinology letters}, volume = {38}, number = {8}, pages = {528-531}, pmid = {29504729}, issn = {0172-780X}, mesh = {Amyotrophic Lateral Sclerosis/classification/*etiology/*therapy ; Animals ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is one of the most dangerous and least understood diseases with a pathophysiology that is still largely unknown. In this article we try to provide a pathophysiological explanation of the etiological, pathogenetic, and clinical aspects of ALS. After a description of the rather complicated classification of the disease, we continue with an evaluation of its clinical presentation. The bibliography reveals several suspect etiological factors including atherosclerosis, inflammation, tumors, cataracts, diabetes mellitus type 2, aging, and degeneration of the nervous system. One of the more intriguing factors involves changes associated with oxidative damage to both neurons and glial cells. It is known that astrocytes support the development of motor neurons. Oxidative damage is known to lead to the expression of stress sensitive genes, proteins, as well as inflammation of glial cells. Chronic inflammation could be a key factor in ALS since it has been linked to the death of motor neurons. Pathophysiological research has confirmed the influence of certains proteins on the prognosis of ALS. ALS is typically a proteinopathy in which proteins aggregate in motoneurons. Additionally, glutamate excitotoxicity has also been linked to ALS, with mutated superoxide dismutase (SOD1) having been shown to be responsible for familial ALS. As concerns the pathogenesis of ALS, we discussed several phenomenon such as increased levels of specific serum compounds, reduced concentrations of myelin, and changes in 5-hydroxytryptamine that could represent key indicators of the pathogenesis, prognosis, and therapy of ALS. Concerning ALS therapy; treatment with antioxidatives is potentially very important. Exposure to heavy metals is also thought to negatively influence ALS. Evidence also suggests that good nutrition is a very important factor in the treatment of ALS. From a pharmacological perspective, serotonin treatment appears to be a useful therapeutic agent.}, }
@article {pmid29504292, year = {2018}, author = {Tae, WS and Ham, BJ and Pyun, SB and Kang, SH and Kim, BJ}, title = {Current Clinical Applications of Diffusion-Tensor Imaging in Neurological Disorders.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {14}, number = {2}, pages = {129-140}, pmid = {29504292}, issn = {1738-6586}, abstract = {Diffusion-tensor imaging (DTI) is a noninvasive medical imaging tool used to investigate the structure of white matter. The signal contrast in DTI is generated by differences in the Brownian motion of the water molecules in brain tissue. Postprocessed DTI scalars can be used to evaluate changes in the brain tissue caused by disease, disease progression, and treatment responses, which has led to an enormous amount of interest in DTI in clinical research. This review article provides insights into DTI scalars and the biological background of DTI as a relatively new neuroimaging modality. Further, it summarizes the clinical role of DTI in various disease processes such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's dementia, epilepsy, ischemic stroke, stroke with motor or language impairment, traumatic brain injury, spinal cord injury, and depression. Valuable DTI postprocessing tools for clinical research are also introduced.}, }
@article {pmid29502862, year = {2018}, author = {Nierenberg, AA and Ghaznavi, SA and Sande Mathias, I and Ellard, KK and Janos, JA and Sylvia, LG}, title = {Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha as a Novel Target for Bipolar Disorder and Other Neuropsychiatric Disorders.}, journal = {Biological psychiatry}, volume = {83}, number = {9}, pages = {761-769}, doi = {10.1016/j.biopsych.2017.12.014}, pmid = {29502862}, issn = {1873-2402}, mesh = {Bipolar Disorder/drug therapy/*metabolism ; Humans ; Neurodegenerative Diseases/drug therapy/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/drug effects/*metabolism ; Peroxisome Proliferator-Activated Receptors/agonists/drug effects/*metabolism ; }, abstract = {Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of peroxisome proliferator-activated receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be regulated in part by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this article is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed antidiabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder and warrant future clinical trials.}, }
@article {pmid29501653, year = {2018}, author = {Liu, X and He, J and Gao, FB and Gitler, AD and Fan, D}, title = {The epidemiology and genetics of Amyotrophic lateral sclerosis in China.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {121-126}, pmid = {29501653}, issn = {1872-6240}, support = {R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; Asian People/genetics ; C9orf72 Protein/genetics/physiology ; China/epidemiology ; DNA Repeat Expansion/genetics ; Genetic Association Studies ; Humans ; Superoxide Dismutase-1/genetics/physiology ; White People/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population. Additionally, we highlight potential genetic differences between Chinese and Caucasian ALS patients. Most notably, the frequency of GGGGCC repeat expansions in C9ORF72 in Chinese ALS is significantly lower than in Caucasians. Since some conclusions might not be consistent across all of the studies around China to date, we suggest that it is necessary to carry out a prospective population-based study and large-scale gene sequencing around to better define epidemiological and genetic features of Chinese ALS patients.}, }
@article {pmid29497049, year = {2018}, author = {Sheykhansari, S and Kozielski, K and Bill, J and Sitti, M and Gemmati, D and Zamboni, P and Singh, AV}, title = {Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: a review.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {348}, pmid = {29497049}, issn = {2041-4889}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cadmium/*metabolism ; Copper/*metabolism ; Gene Expression ; Homeostasis ; Humans ; Iron/*metabolism ; Multiple Sclerosis/genetics/*metabolism ; Oxidation-Reduction ; }, abstract = {The effect of redox metals such as iron and copper on multiple sclerosis and amyotrophic lateral sclerosis has been intensively studied. However, the origin of these disorders remains uncertain. This review article critically describes the physiology of redox metals that produce oxidative stress, which in turn leads to cascades of immunomodulatory alteration of neurons in multiple sclerosis and amyotrophic lateral sclerosis. Iron and copper overload has been well established in motor neurons of these diseases' lesions. On the other hand, the role of other metals like cadmium participating indirectly in the redox cascade of neurobiological mechanism is less studied. In the second part of this review, we focus on this less conspicuous correlation between cadmium as an inactive-redox metal and multiple sclerosis and amyotrophic lateral sclerosis, providing novel treatment modalities and approaches as future prospects.}, }
@article {pmid29493463, year = {2018}, author = {Feitosa, CM and da Silva Oliveira, GL and do Nascimento Cavalcante, A and Morais Chaves, SK and Rai, M}, title = {Determination of Parameters of Oxidative Stress in vitro Models of Neurodegenerative Diseases-A Review.}, journal = {Current clinical pharmacology}, volume = {13}, number = {2}, pages = {100-109}, doi = {10.2174/1574884713666180301091612}, pmid = {29493463}, issn = {2212-3938}, mesh = {Animals ; Antioxidants/pharmacology/*therapeutic use ; Humans ; *Models, Neurological ; Neurodegenerative Diseases/drug therapy/*metabolism ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Oxidative stress is a major mechanism underlying the development of various neurodegenerative diseases (Alzheimer, Parkinson, Huntington and amyotrophic lateral sclerosis). Excessive formation of reactive oxygen species (ROS) and nitrogen (RNSs) can overburden the ability of the enzymatic antioxidant defense mechanisms (superoxide dismutase, catalase and glutathione reductase) and non-enzymatic (uric acid, ascorbic acid, α-tocopherol and reduced glutathione), causing the development of oxidative stress, and consequently, impairing the neuronal system cells by means of oxidative damage to a variety of important biological molecules such as lipids, DNA and proteins. Considering the importance of oxidative stress in neurodegenerative diseases, the present review aims to address the main parameters evaluated in in vitro studies on oxidative stress in different models of neurodegenerative diseases.The literary review was conducted through Pubmed, Science Direct, LILACS, Scielo and Google using following keywords: oxidative stress, neurodegenerative diseases and parameters of oxidative stress. We selected articles published between 2002 and 2017.The in vitro evaluation of the oxidative stress related parameters has provided a preliminary view about the pathogenesis of many neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis). In this way, it has demonstrated the mechanism of action of ROS/RNSs in these diseases by direct or indirect detection through several experimental procedures in vitro.}, }
@article {pmid29491392, year = {2018}, author = {Lau, DHW and Hartopp, N and Welsh, NJ and Mueller, S and Glennon, EB and Mórotz, GM and Annibali, A and Gomez-Suaga, P and Stoica, R and Paillusson, S and Miller, CCJ}, title = {Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {327}, pmid = {29491392}, issn = {2041-4889}, support = {G0501573/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G-1308/PUK_/Parkinson's UK/United Kingdom ; MILLER/OCT12/863-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Dementia/genetics/*metabolism ; Endoplasmic Reticulum/genetics/*metabolism ; Humans ; Mitochondria/genetics/*metabolism ; Signal Transduction ; }, abstract = {Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic.}, }
@article {pmid29491385, year = {2018}, author = {Janikiewicz, J and Szymański, J and Malinska, D and Patalas-Krawczyk, P and Michalska, B and Duszyński, J and Giorgi, C and Bonora, M and Dobrzyn, A and Wieckowski, MR}, title = {Mitochondria-associated membranes in aging and senescence: structure, function, and dynamics.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {332}, pmid = {29491385}, issn = {2041-4889}, mesh = {Aging/*metabolism ; Animals ; Cellular Senescence ; Endoplasmic Reticulum/*metabolism ; Humans ; Mitochondria/*metabolism ; Mitochondrial Membranes/*metabolism ; }, abstract = {Sites of close contact between mitochondria and the endoplasmic reticulum (ER) are known as mitochondria-associated membranes (MAM) or mitochondria-ER contacts (MERCs), and play an important role in both cell physiology and pathology. A growing body of evidence indicates that changes observed in the molecular composition of MAM and in the number of MERCs predisposes MAM to be considered a dynamic structure. Its involvement in processes such as lipid biosynthesis and trafficking, calcium homeostasis, reactive oxygen species production, and autophagy has been experimentally confirmed. Recently, MAM have also been studied in the context of different pathologies, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, type 2 diabetes mellitus and GM1-gangliosidosis. An underappreciated amount of data links MAM with aging or senescence processes. In the present review, we summarize the current knowledge of basic MAM biology, composition and action, and discuss the potential connections supporting the idea that MAM are significant players in longevity.}, }
@article {pmid29491369, year = {2018}, author = {Bernard-Marissal, N and Chrast, R and Schneider, BL}, title = {Endoplasmic reticulum and mitochondria in diseases of motor and sensory neurons: a broken relationship?.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {333}, pmid = {29491369}, issn = {2041-4889}, mesh = {Animals ; Endoplasmic Reticulum/genetics/*metabolism ; Humans ; Mitochondria/genetics/*metabolism ; Mitochondrial Membranes/*metabolism ; Motor Neurons/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Sensory Receptor Cells/*metabolism ; }, abstract = {Recent progress in the understanding of neurodegenerative diseases revealed that multiple molecular mechanisms contribute to pathological changes in neurons. A large fraction of these alterations can be linked to dysfunction in the endoplasmic reticulum (ER) and mitochondria, affecting metabolism and secretion of lipids and proteins, calcium homeostasis, and energy production. Remarkably, these organelles are interacting with each other at specialized domains on the ER called mitochondria-associated membranes (MAMs). These membrane structures rely on the interaction of several complexes of proteins localized either at the mitochondria or at the ER interface and serve as an exchange platform of calcium, metabolites, and lipids, which are critical for the function of both organelles. In addition, recent evidence indicates that MAMs also play a role in the control of mitochondria dynamics and autophagy. MAMs thus start to emerge as a key element connecting many changes observed in neurodegenerative diseases. This review will focus on the role of MAMs in amyotrophic lateral sclerosis (ALS) and hereditary motor and sensory neuropathy, two neurodegenerative diseases particularly affecting neurons with long projecting axons. We will discuss how defects in MAM signaling may impair neuronal calcium homeostasis, mitochondrial dynamics, ER function, and autophagy, leading eventually to axonal degeneration. The possible impact of MAM dysfunction in glial cells, which may affect the capacity to support neurons and/or axons, will also be described. Finally, the possible role of MAMs as an interesting target for development of therapeutic interventions aiming at delaying or preventing neurodegeneration will be highlighted.}, }
@article {pmid29491329, year = {2018}, author = {Abe, K}, title = {[An early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {58}, number = {3}, pages = {141-165}, doi = {10.5692/clinicalneurol.cn-001095}, pmid = {29491329}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*history/physiopathology ; Asian People ; *Bibliographies as Topic ; History, 19th Century ; History, 20th Century ; History, 21st Century ; Humans ; Japan ; Research/*trends ; }, abstract = {The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development. In relation to foreign previous reports, five topics are introduced and discussed on ALS with dementia, ALS/Parkinsonism dementia complex (ALS/PDC), familial ALS (FALS), spinal bulbar muscular atrophy (SBMA), and multisystem involvement especially in cerebellar system of ALS including ALS/SCA (spinocerebellar ataxia) crossroad mutation Asidan. This review found the great contribution of Japanese reports on the above five topics, and confirmed the great development of ALS-related diseases over the past 120 years.}, }
@article {pmid29487852, year = {2018}, author = {Kondori, NR and Paul, P and Robbins, JP and Liu, K and Hildyard, JCW and Wells, DJ and de Belleroche, JS}, title = {Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS).}, journal = {Frontiers in molecular biosciences}, volume = {5}, number = {}, pages = {8}, pmid = {29487852}, issn = {2296-889X}, abstract = {We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), DAO[R199W], associated with familial Amyotrophic Lateral Sclerosis (ALS) that impairs D-serine metabolism and causes protein aggregation, autophagy and cell death in motor neuron cell lines. These features are consistent with the pathogenic processes occurring in ALS but most importantly, we have demonstrated that activation of the formation of ubiquitinated protein inclusions, increased autophagosome production and apoptotic cell death caused by the mutation in cell lines are attenuated by 5,7-dichlorokynurenic acid (DCKA), a selective inhibitor of the glycine/D-serine binding site of the NMDA receptor. D-serine is an essential co-agonist at this glutamate receptor. This data provides insight into potential upstream mechanisms that involve the action of D-serine at the NMDA receptor and might contribute to neurodegeneration. This is highly relevant to sporadic ALS (SALS), familial ALS, as well as ALS models, where elevated levels of D-serine have been reported and hence has broader clinical therapeutic implications. In order to investigate this further, we have generated a transgenic line expressing the pathogenic mutation, in order to determine whether mice expressing DAO[R199W] develop a motor phenotype and whether crossing the SOD1[G93A] model of ALS with mice expressing DAO[R199W] affects disease progression. We found that heterozygous expression of DAO[R199W] led to a significant loss of spinal cord motor neurons at 14 months, which is similar to that found in homozygous mice expressing DAO[G181R]. We hypothesize that DAO has potential for development as a therapeutic agent in ALS.}, }
@article {pmid29486281, year = {2018}, author = {van Eijk, RPA and Nikolakopoulos, S and Ferguson, TA and Liu, D and Eijkemans, MJC and van den Berg, LH}, title = {Increasing the efficiency of clinical trials in neurodegenerative disorders using group sequential trial designs.}, journal = {Journal of clinical epidemiology}, volume = {98}, number = {}, pages = {80-88}, doi = {10.1016/j.jclinepi.2018.02.013}, pmid = {29486281}, issn = {1878-5921}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Central Nervous System Agents/therapeutic use ; Confidence Intervals ; *Early Termination of Clinical Trials ; Equivalence Trials as Topic ; Humans ; *Medical Futility ; Neurodegenerative Diseases/drug therapy ; Placebos/therapeutic use ; Pramipexole/therapeutic use ; Randomized Controlled Trials as Topic/*methods ; Research Design ; Time Factors ; }, abstract = {OBJECTIVES: Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e., designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis.<br><br>STUDY DESIGN AND SETTING: We reviewed the literature to identify sequentially conducted trials. Subsequently, we reanalyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects.<br><br>RESULTS: Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential reanalysis of the EMPOWER study reduced the total trial duration with 140&#xa0;days (23.4%, 95% confidence interval [CI] 13.2-34.4%), the number of follow-ups with 2,688 visits (23.6%, 95% CI 11.3-38.6%), and the total drug exposure time with 73,377&#xa0;days (20.6%, 95% CI 9.8-35.9%). The functional questionnaire considerably increased the heterogeneity in the test statistics, which may negatively affect sequential monitoring.<br><br>CONCLUSION: Group sequential trials can result in important reductions in the trial duration, which could make clinical trials more ethical by reducing the patients' exposure to noneffective treatments or by limiting their time on placebo.}, }
@article {pmid29486049, year = {2018}, author = {Gao, J and Wang, L and Huntley, ML and Perry, G and Wang, X}, title = {Pathomechanisms of TDP-43 in neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, pmid = {29486049}, issn = {1471-4159}, support = {R01 NS089604/NS/NINDS NIH HHS/United States ; }, abstract = {Neurodegeneration, a term that refers to the progressive loss of structure and function of neurons, is a feature of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models. As such, the investigation of TDP-43 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP-43 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP-43 as a common therapeutic approach to treat neurodegenerative diseases.}, }
@article {pmid29479303, year = {2018}, author = {Ghaffari, LT and Starr, A and Nelson, AT and Sattler, R}, title = {Representing Diversity in the Dish: Using Patient-Derived in Vitro Models to Recreate the Heterogeneity of Neurological Disease.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {56}, pmid = {29479303}, issn = {1662-4548}, support = {R01 NS085207/NS/NINDS NIH HHS/United States ; }, abstract = {Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells. Distinct differentiation techniques for both models result in a variety of neuronal and glial cell types, which have been successful in displaying unique hallmarks of a variety of neurological diseases. Yield, length of differentiation, ease of genetic manipulation, expression of cell-specific markers, and recapitulation of disease pathogenesis are presented as determining factors in how these methods may be used separately or together to ascertain mechanisms of disease and identify therapeutics for distinct patient populations or for specific individuals in personalized medicine projects.}, }
@article {pmid29478603, year = {2018}, author = {Goutman, SA and Chen, KS and Paez-Colasante, X and Feldman, EL}, title = {Emerging understanding of the genotype-phenotype relationship in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {148}, number = {}, pages = {603-623}, doi = {10.1016/B978-0-444-64076-5.00039-9}, pmid = {29478603}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Autophagy/genetics ; DNA-Binding Proteins/genetics ; *Genetic Association Studies ; Genetic Counseling ; Genotype ; Humans ; Motor Neurons/*pathology ; Mutation/*genetics ; Proteins/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, noncurable neurodegenerative disorder of the upper and lower motor neurons causing weakness and death within a few years of symptom onset. About 10% of patients with ALS have a family history of the disease; however, ALS-associated genetic mutations are also found in sporadic cases. There are over 100 ALS-associated mutations, and importantly, several genetic mutations, including C9ORF72, SOD1, and TARDBP, have led to mechanistic insight into this complex disease. In the clinical realm, knowledge of ALS genetics can also help explain phenotypic heterogeneity, aid in genetic counseling, and in the future may help direct treatment efforts.}, }
@article {pmid29478591, year = {2018}, author = {Deleon, J and Miller, BL}, title = {Frontotemporal dementia.}, journal = {Handbook of clinical neurology}, volume = {148}, number = {}, pages = {409-430}, doi = {10.1016/B978-0-444-64076-5.00027-2}, pmid = {29478591}, issn = {0072-9752}, support = {K24 AG045333/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; }, mesh = {C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics ; Genetic Association Studies ; Genetic Predisposition to Disease/*genetics ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Membrane Glycoproteins/genetics ; Mitochondrial Proteins/genetics ; Progranulins ; Receptors, Immunologic/genetics ; Sequestosome-1 Protein/genetics ; Valosin Containing Protein/genetics ; tau Proteins/genetics ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive changes in behavior, personality, and language with involvement of the frontal and temporal regions of the brain. About 40% of FTD cases have a positive family history, and about 10% of these cases are inherited in an autosomal-dominant pattern. These gene defects present with distinct clinical phenotypes. As the diagnosis of FTD becomes more recognizable, it will become increasingly important to keep these gene mutations in mind. In this chapter, we review the genes with known associations to FTD. We discuss protein functions, mutation frequencies, clinical phenotypes, imaging characteristics, and pathology associated with these genes.}, }
@article {pmid29475576, year = {2018}, author = {Sridharan, K and Sivaramakrishnan, G}, title = {Pharmacological interventions for treating sialorrhea associated with neurological disorders: A mixed treatment network meta-analysis of randomized controlled trials.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {51}, number = {}, pages = {12-17}, doi = {10.1016/j.jocn.2018.02.011}, pmid = {29475576}, issn = {1532-2653}, mesh = {Benztropine/therapeutic use ; Botulinum Toxins, Type A/therapeutic use ; Child ; Child, Preschool ; Female ; Glycopyrrolate/therapeutic use ; Humans ; Muscarinic Antagonists/therapeutic use ; Nervous System Diseases/*complications/*drug therapy ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Scopolamine/therapeutic use ; Sialorrhea/*drug therapy/*etiology ; }, abstract = {Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders.}, }
@article {pmid29473876, year = {2018}, author = {Iyer, AK and Jones, KJ and Sanders, VM and Walker, CL}, title = {Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {19}, number = {2}, pages = {}, pmid = {29473876}, issn = {1422-0067}, support = {R01 NS040433/NS/NINDS NIH HHS/United States ; T32 HL079995/HL/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Humans ; Muscle, Skeletal/immunology/pathology ; Neuromuscular Junction/immunology/pathology ; Schwann Cells/immunology/pathology ; *Spatio-Temporal Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.}, }
@article {pmid29467610, year = {2018}, author = {Han, C and Chaineau, M and Chen, CX and Beitel, LK and Durcan, TM}, title = {Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {47}, pmid = {29467610}, issn = {1662-4548}, abstract = {Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.}, }
@article {pmid29462608, year = {2018}, author = {Khalil, B and Morderer, D and Price, PL and Liu, F and Rossoll, W}, title = {mRNP assembly, axonal transport, and local translation in neurodegenerative diseases.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {75-91}, pmid = {29462608}, issn = {1872-6240}, support = {R01 NS091749/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Axonal Transport ; Axons/*metabolism/pathology ; Cytoplasmic Granules/metabolism ; Dendrites/metabolism/pathology ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Neurons/metabolism/pathology ; Protein Biosynthesis ; RNA Transport/physiology ; RNA, Messenger/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Ribonucleoproteins/genetics/*metabolism ; Transcriptome ; }, abstract = {The development, maturation, and maintenance of the mammalian nervous system rely on complex spatiotemporal patterns of gene expression. In neurons, this is achieved by the expression of differentially localized isoforms and specific sets of mRNA-binding proteins (mRBPs) that regulate RNA processing, mRNA trafficking, and local protein synthesis at remote sites within dendrites and axons. There is growing evidence that axons contain a specialized transcriptome and are endowed with the machinery that allows them to rapidly alter their local proteome via local translation and protein degradation. This enables axons to quickly respond to changes in their environment during development, and to facilitate axon regeneration and maintenance in adult organisms. Aside from providing autonomy to neuronal processes, local translation allows axons to send retrograde injury signals to the cell soma. In this review, we discuss evidence that disturbances in mRNP transport, granule assembly, axonal localization, and local translation contribute to pathology in various neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD).}, }
@article {pmid29460270, year = {2018}, author = {Feneberg, E and Gray, E and Ansorge, O and Talbot, K and Turner, MR}, title = {Towards a TDP-43-Based Biomarker for ALS and FTLD.}, journal = {Molecular neurobiology}, volume = {55}, number = {10}, pages = {7789-7801}, pmid = {29460270}, issn = {1559-1182}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/R000743/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; FENEBERG/AUG17/949-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Biomarkers/*metabolism ; Brain/pathology ; DNA-Binding Proteins/blood/cerebrospinal fluid/chemistry/*metabolism ; Frontotemporal Lobar Degeneration/*metabolism ; Humans ; Models, Biological ; }, abstract = {TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD). There is currently no biochemical test or marker of disease activity for ALS or FTLD, and the clinical diagnosis depends on the opinion of an experienced neurologist. TDP-43 has a key role in the pathogenesis of ALS/FTLD. Measuring TDP-43 in easily accessible biofluids, such as blood or cerebrospinal fluid, might reduce diagnostic delay and offer a readout for use in future drug trials. However, attempts at measuring disease-specific forms of TDP-43 in peripheral biofluids of ALS and FTLD patients have not yielded consistent results, and only some of the pathological biochemical features of TDP-43 found in human brain tissue have been detected in clinical biofluids to date. Reflecting on the molecular pathology of TDP-43, this review provides a critical overview on biofluid studies and future directions to develop a TDP-43-based clinical biomarker for ALS and FTLD.}, }
@article {pmid29459769, year = {2018}, author = {Chen, H and Kankel, MW and Su, SC and Han, SWS and Ofengeim, D}, title = {Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD.}, journal = {Cell death and differentiation}, volume = {25}, number = {4}, pages = {648-662}, pmid = {29459769}, issn = {1476-5403}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Mutation ; }, abstract = {Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia normally act to mitigate neurodegeneration in ALS/FTLD? To what extent do cellular signaling pathways mediate non-cell autonomous communications between distinct central nervous system (CNS) cell types during disease? Is it possible to therapeutically target specific cell types in the CNS?}, }
@article {pmid29453960, year = {2018}, author = {Starr, A and Sattler, R}, title = {Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {98-108}, pmid = {29453960}, issn = {1872-6240}, support = {R01 NS085207/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; C9orf72 Protein/*genetics/metabolism ; Frontotemporal Dementia/*genetics/metabolism/pathology ; Humans ; Motor Neurons/metabolism ; Mutation ; RNA/genetics/metabolism ; RNA-Binding Proteins/genetics/physiology ; Synapses/metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping, putative toxic mechanisms have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.}, }
@article {pmid29450726, year = {2018}, author = {Herrmann, D and Parlato, R}, title = {C9orf72-associated neurodegeneration in ALS-FTD: breaking new ground in ribosomal RNA and nucleolar dysfunction.}, journal = {Cell and tissue research}, volume = {373}, number = {2}, pages = {351-360}, doi = {10.1007/s00441-018-2806-1}, pmid = {29450726}, issn = {1432-0878}, support = {DFG PA 1529/2-1//DFG-Deutsche Forschungsgemeinschaft/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; C9orf72 Protein/genetics/*metabolism ; Cell Nucleolus/*pathology ; Frontotemporal Dementia/*pathology ; Humans ; Nerve Degeneration/*pathology ; RNA, Ribosomal/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are neurodegenerative diseases with distinct clinical appearance. However, both share as major genetic risk factor a C9orf72 locus intronic hexanucleotide expansion. The pathogenic pathways associated with the expansion-dependent neuronal toxicity are still poorly understood. Recent efforts to identify common threads of neuronal dysfunction have pointed towards deficits of ribosomal RNA (rRNA) biogenesis and loss of nucleolar integrity, a condition known as nucleolar stress that is an emerging shared feature among neurodegenerative diseases. Intriguingly, the C9orf72 mutation in ALS-FTD interferes with the function of the nucleolus by transcripts and dipeptide repeats (DPRs) produced by the hexanucleotide expansion. Experimental discrepancies have given rise to different hypotheses with regard to the connection of C9orf72 and nucleolar activity. In this review, we present and discuss emerging concepts concerning the impact of C9orf72 expansion on nucleolar biology. Moreover, we discuss the "nucleolar stress hypothesis," according to which nucleolar malfunction accompanies, exacerbates, or potentially triggers a degenerative phenotype. Upcoming awareness of the involvement of nucleolar stress in C9orf72 ALS-FTD could shed light into its pathogenesis, enabling potential treatment options aimed at shielding an "Achilles' heel" of neurons.}, }
@article {pmid29448993, year = {2018}, author = {Farah, K and Graillon, T and Dufour, H and Fuentes, S}, title = {Adjacent level spondylodiscitis in a patient with thoracic spondylodiscitis: A case report and review of the literature.}, journal = {Neuro-Chirurgie}, volume = {64}, number = {1}, pages = {53-56}, doi = {10.1016/j.neuchi.2017.09.003}, pmid = {29448993}, issn = {1773-0619}, mesh = {Aged ; Discitis/diagnostic imaging/etiology/*surgery ; Humans ; Male ; Recurrence ; Spinal Fusion/*adverse effects ; Thoracic Vertebrae/diagnostic imaging/*surgery ; }, abstract = {INTRODUCTION: Adjacent level spondylodiscitis (ALS) after primary surgery for thoracic spondylodiscitis is a very rare condition.<br><br>CASE REPORT: We report the case of a 76-year-old man with this pathology. A first posterior minimally invasive approach combined with anterior approach to the thoracic spine was safely performed for thoracic spondylodiscitis. More than a year later, exploration of recurrent symptoms with [18]FDG PET scan helped to diagnose ALS. Further surgery was performed. At 3-year follow-up examination showed no recurrence of the infection.<br><br>DISCUSSION: ALS should be suspected during recurrent symptoms after spinal fusion surgery. Evaluation should be based on the results of [18]FDG PET scan and surgery.<br><br>CONCLUSION: Bacterial and histopathological analyses combined with an increase of spine fixation and adapted antimicrobial therapy are a safe management for ALS.}, }
@article {pmid29447051, year = {2018}, author = {Singh, N and Vijayanti, S and Saha, L}, title = {Targeting crosstalk between Nuclear factor (erythroid-derived 2)-like 2 and Nuclear factor kappa beta pathway by Nrf2 activator dimethyl fumarate in epileptogenesis.}, journal = {The International journal of neuroscience}, volume = {128}, number = {10}, pages = {987-994}, doi = {10.1080/00207454.2018.1441149}, pmid = {29447051}, issn = {1563-5279}, mesh = {Animals ; Dimethyl Fumarate/*pharmacology/therapeutic use ; Epilepsy/*drug therapy/*metabolism ; Humans ; Immunologic Factors/*pharmacology/therapeutic use ; Inflammation/*drug therapy ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/*metabolism ; Oxidative Stress/*drug effects ; *Signal Transduction/drug effects ; }, abstract = {UNLABELLED: Purpose/Aim: Epilepsy is a complex, chronic neurological disorder characterized by increased and abnormal synchronization of neuronal electrical activity, which is manifested as seizures. It is associated with many comorbid conditions such as depression, anxiety, sleep disorder, psychiatric disorder etc., which consequently causes higher mortality rate. The understanding of its cellular and molecular mechanism is partial, because of which it remains an ongoing health problem, despite the increasing availability of newer antiepileptic drugs. Although recurrent seizures are the clinical indication of epilepsy, the disease process (epileptogenesis) begins before the onset of the first seizure. This dormant phase before the onset of first seizure provides an opportune time window for modifying the epileptogenic process by intervening in its progression with an appropriate treatment.<br><br>MATERIAL AND METHODS: Studies have shown that in epilepsy, there is a chronic state of oxidative stress and inflammation, which plays a key role in epileptic pathogenesis. Various antioxidant mechanisms maintain the redox balance in the body by either scavenging or regulating the generation of free radicals. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is a well-established antioxidant pathway in various diseases such as diabetes, renal disease, various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, etc. Results: It has been observed that single-target therapies are inefficient in providing anticonvulsant and disease-modifying effects in epilepsy.<br><br>CONCLUSIONS: So, preventing the progression of epilepsy by targeting Nrf2-activated antioxidant pathway along with the other established antiepileptic pathways can prove beneficial in epilepsy treatment.}, }
@article {pmid29445532, year = {2018}, author = {D'Cruz, RF and Murphy, PB and Kaltsakas, G}, title = {Sleep disordered breathing in motor neurone disease.}, journal = {Journal of thoracic disease}, volume = {10}, number = {Suppl 1}, pages = {S86-S93}, pmid = {29445532}, issn = {2072-1439}, abstract = {Motor neurone disease (MND) is a neurodegenerative disease defined by axonal loss and gliosis of upper and lower motor neurones in the motor cortex, lower brainstem nuclei and ventral horn of the spinal cord. MND is currently incurable and has a poor prognosis, with death typically occurring 3 to 5 years after disease onset. The disease is characterised by rapidly progressive weakness leading to paralysis, fasciculations, bulbar symptoms (including dysarthria and dysphagia) and respiratory compromise. Respiratory complications arise as a result of weakness of upper airway (pharyngeal and laryngeal) muscles and respiratory muscles (diaphragm, intercostal and accessory muscles) leading to respiratory failure. Due to early involvement of respiratory muscles in MND, sleep disordered breathing (SDB) occurs at a higher frequency than compared to the general population. SDB usually precedes daytime respiratory symptoms and chronic respiratory failure. It significantly impacts upon patients' quality of life and survival and its presence may predict prognosis. Managing SDB in MND with non-invasive ventilation (NIV) improves quality of life and survival. Early identification and management of SDB in MND patients is therefore crucial. This update will review assessments of respiratory muscle function, types of SDB and the effects of NIV in patients with MND.}, }
@article {pmid29445325, year = {2018}, author = {Vejux, A and Namsi, A and Nury, T and Moreau, T and Lizard, G}, title = {Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {12}, pmid = {29445325}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases) and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer's disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology.}, }
@article {pmid29434537, year = {2018}, author = {Veyrat-Durebex, C and Reynier, P and Procaccio, V and Hergesheimer, R and Corcia, P and Andres, CR and Blasco, H}, title = {How Can a Ketogenic Diet Improve Motor Function?.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {15}, pmid = {29434537}, issn = {1662-5099}, abstract = {A ketogenic diet (KD) is a normocaloric diet composed by high fat (80-90%), low carbohydrate, and low protein consumption that induces fasting-like effects. KD increases ketone body (KBs) production and its concentration in the blood, providing the brain an alternative energy supply that enhances oxidative mitochondrial metabolism. In addition to its profound impact on neuro-metabolism and bioenergetics, the neuroprotective effect of specific polyunsaturated fatty acids and KBs involves pleiotropic mechanisms, such as the modulation of neuronal membrane excitability, inflammation, or reactive oxygen species production. KD is a therapy that has been used for almost a century to treat medically intractable epilepsy and has been increasingly explored in a number of neurological diseases. Motor function has also been shown to be improved by KD and/or medium-chain triglyceride diets in rodent models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinal cord injury. These studies have proposed that KD may induce a modification in synaptic morphology and function, involving ionic channels, glutamatergic transmission, or synaptic vesicular cycling machinery. However, little is understood about the molecular mechanisms underlying the impact of KD on motor function and the perspectives of its use to acquire the neuromuscular effects. The aim of this review is to explore the conditions through which KD might improve motor function. First, we will describe the main consequences of KD exposure in tissues involved in motor function. Second, we will report and discuss the relevance of KD in pre-clinical and clinical trials in the major diseases presenting motor dysfunction.}, }
@article {pmid29433734, year = {2018}, author = {Santo, EE and Paik, J}, title = {FOXO in Neural Cells and Diseases of the Nervous System.}, journal = {Current topics in developmental biology}, volume = {127}, number = {}, pages = {105-118}, pmid = {29433734}, issn = {1557-8933}, support = {R01 AG048284/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/genetics ; Forkhead Transcription Factors/genetics/*metabolism ; Gene Expression Regulation ; Humans ; Mice ; Nervous System/cytology/*metabolism ; Neural Stem Cells/metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Neurons/*metabolism ; }, abstract = {The evolutionarily conserved FOXO family of transcription factors has emerged as a significant arbiter of neural cell fate and function in mammals. From the neural stem cell (NSC) state through mature neurons under both physiological and pathological conditions, they have been found to modulate neural cell survival, stress responses, lineage commitment, and neuronal signaling. Lineage-specific FOXO knockout mice have provided an invaluable tool for the dissection of FOXO biology in the nervous system. Within the NSC compartments of the brain, FOXOs are required for the maintenance of NSC quiescence and for the clearance of reactive oxygen species. Within mature neurons, FOXO transcriptional activity is essential for the prevention of age-dependent axonal degeneration. Acutely, FOXO3 has been found to cause axonal degeneration upon withdrawal of neurotrophic factors. In more active neural signaling, FOXO6 promotes increased dendritic spine density of hippocampal neurons and is required for the consolidation of memories. In addition to the central nervous system (CNS), FOXOs also influence the functionality of the peripheral nervous system (PNS). FOXO1 knockout within the PNS results in a reduction of sympathetic tone and decreased levels of brain-derived norepinephrine and lower energy expenditure. FOXO3 knockout mice have impaired hearing which may be due to defects in synapse localization within the ear. Given the scope of FOXO activities in both the CNS and PNS, it will be of interest to study FOXOs within the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. From within the nervous system, FOXOs may also regulate important parameters such as whole-body metabolism, motor function, and catecholamine production, making FOXOs key players in physiologic homeostasis.}, }
@article {pmid29431050, year = {2018}, author = {Buratti, E}, title = {TDP-43 post-translational modifications in health and disease.}, journal = {Expert opinion on therapeutic targets}, volume = {22}, number = {3}, pages = {279-293}, doi = {10.1080/14728222.2018.1439923}, pmid = {29431050}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/therapy ; Animals ; DNA-Binding Proteins/*genetics ; Down-Regulation ; Frontotemporal Lobar Degeneration/genetics/physiopathology/therapy ; Gene Expression Regulation ; Humans ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/genetics/physiopathology/*therapy ; Protein Processing, Post-Translational ; }, abstract = {Nuclear factor TDP-43 is a ubiquitously expressed RNA binding protein that plays a key causative role in several neurodegenerative diseases, especially in the ALS/FTD spectrum. In addition, its aberrant aggregation and expression has been recently observed in other type of diseases, such as myopathies and Niemann-Pick C, a lysosomal storage disease. Areas covered: This review aims to specifically cover the post-translational modifications (PTMs) that can affect TDP-43 function and cellular status both in health and disease. To this date, these include phosphorylation, formation of C-terminal fragments, disulfide bridge formation, ubiquitination, acetylation, and sumoylation. Recently published articles on these subjects have been reviewed in this manuscript. Expert opinion: Targeting aberrant TDP-43 expression in neurodegenerative diseases is a very challenging task due to the fact that both its overexpression and downregulation are considerably toxic to cells. This characteristic makes it difficult to therapeutically target this protein in a generalized manner. An alternative approach could be the identification of specific aberrant PTMs that promote its aggregation or toxicity, and developing novel therapeutic approaches toward their selective modification.}, }
@article {pmid29425965, year = {2018}, author = {Zhu, Z and Reiser, G}, title = {The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {115}, number = {}, pages = {69-79}, doi = {10.1016/j.neuint.2018.02.006}, pmid = {29425965}, issn = {1872-9754}, mesh = {Animals ; Brain/metabolism ; HSP27 Heat-Shock Proteins ; Heat-Shock Proteins/*drug effects/metabolism ; Heat-Shock Proteins, Small/metabolism ; Mice ; Neurodegenerative Diseases/*physiopathology ; Peptides/pharmacology ; alpha-Crystallin B Chain/*genetics ; }, abstract = {Small heat shock proteins (sHsps) are a group of proteins with molecular mass between 12 and 43 kDa. Currently, 11 members of this family have been classified, namely HspB1 to HspB11. HspB1, HspB2, HspB5, HspB6, HspB7, and HspB8, which are expressed in brain have been observed to be related to the pathology of neurodegenerative diseases, including Parkinson's, Alzheimer's, Alexander's disease, multiple sclerosis, and human immunodeficiency virus-associated dementia. Specifically, sHsps interact with misfolding and damaging protein aggregates, like Glial fibrillary acidic protein in AxD, β-amyloid peptides aggregates in Alzheimer's disease, Superoxide dismutase 1 in Amyotrophic lateral sclerosis and cytosine-adenine-guanine/polyglutamine (CAG/PolyQ) in Huntington's disease, Spinocerebellar ataxia type 3, Spinal-bulbar muscular atrophy, to reduce the toxicity or increase the clearance of these protein aggregates. The degree of HspB4 expression in brain is still debated. For neuroprotective mechanisms, sHsps attenuate mitochondrial dysfunctions, reduce accumulation of misfolded proteins, block oxidative/nitrosative stress, and minimize neuronal apoptosis and neuroinflammation, which are molecular mechanisms commonly accepted to mirror the progression and development of neurodegenerative diseases. The increasing incidence of the neurodegenerative diseases enhanced search for effective approaches to rescue neural tissue from degeneration with minimal side effects. sHsps have been found to exert neuroprotective functions. HspB5 has been emphasized to reduce the paralysis in a mouse model of experimental autoimmune encephalomyelitis, providing a therapeutic basis for the disease. In this review, we discuss the current understanding of the properties and the mechanisms of protection orchestrated by sHsps in the nervous system, highlighting the promising therapeutic role of sHsps in neurodegenerative diseases.}, }
@article {pmid29418100, year = {2018}, author = {Sunderkötter, C and Becker, K and Kutzner, H and Meyer, T and Blödorn-Schlicht, N and Reischl, U and Nenoff, P and Geißdörfer, W and Gräser, Y and Herrmann, M and Kühn, J and Bogdan, C}, title = {Molekulare Diagnostik von Hautinfektionen am Paraffinmaterial - Übersicht und interdisziplinärer Konsensus.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {16}, number = {2}, pages = {139-148}, doi = {10.1111/ddg.13438_g}, pmid = {29418100}, issn = {1610-0387}, abstract = {Nukleinsäure-Amplifikations-Techniken (NAT), wie die PCR, sind hochsensitiv sowie selektiv und stellen in der mikrobiologischen Diagnostik wertvolle Ergänzungen zur kulturellen Anzucht und Serologie dar. Sie bergen aber gerade bei formalinfixiertem und in Paraffin eingebettetem Gewebe ein Risiko für sowohl falsch negative als auch falsch positive Resultate, welches nicht immer richtig eingeschätzt wird. Daher haben Vertreter der Deutschen Gesellschaft für Hygiene und Mikrobiologie (DGHM) und der Deutschen Dermatologischen Gesellschaft (DDG) einen Konsensus in Form einer Übersichtsarbeit erarbeitet, wann eine NAT am Paraffinschnitt angezeigt und sinnvoll ist und welche Punkte dabei in der Präanalytik und Befundinterpretation beachtet werden müssen. Da bei Verdacht auf eine Infektion grundsätzlich Nativgewebe genutzt werden soll, ist die PCR am Paraffinschnitt ein Sonderfall, wenn beispielsweise bei erst nachträglichaufgekommenem Verdacht auf eine Infektion kein Nativmaterial zur Verfügung steht und nicht mehr gewonnen werden kann. Mögliche Indikationen sind der histologisch erhobene Verdacht auf eine Leishmaniose, eine Infektion durch Bartonellen oder Rickettsien, oder ein Ecthyma contagiosum. Nicht sinnvoll ist oder kritisch gesehen wird eine NAT am Paraffinschnitt zum Beispiel bei Infektionen mit Mykobakterien oder RNA-Viren. Die Konstellation für eine NAT aus Paraffingewebe sollte jeweils benannt werden, die erforderliche Prä-Analytik, die jeweiligen Grenzen des Verfahrens und die diagnostischen Alternativen bekannt sein. Der PCR-Befund sollte entsprechend kommentiert werden, um Fehleinschätzungen zu vermeiden.}, }
@article {pmid29417336, year = {2018}, author = {Bräuer, S and Zimyanin, V and Hermann, A}, title = {Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {125}, number = {4}, pages = {591-613}, pmid = {29417336}, issn = {1435-1463}, support = {VH-VI-510//Helmholtz-Gemeinschaft/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; DNA-Binding Proteins/*metabolism ; Humans ; *Protein Folding ; }, abstract = {The hallmark of age-related neurodegenerative diseases is the appearance of cellular protein deposits and spreading of this pathology throughout the central nervous system. Growing evidence has shown the involvement and critical role of proteins with prion-like properties in the formation of these characteristic cellular aggregates. Prion-like domains of such proteins with their proposed function in the organization of membraneless organelles are prone for misfolding and promoting further aggregation. Spreading of these toxic aggregates between cells and across tissues can explain the progression of clinical phenotypes and pathology in a stereotypical manner, characteristic for almost every neurodegenerative disease. Here, we want to review the current evidence for the role of prion-like mechanisms in classical neurodegenerative diseases and ALS in particular. We will also discuss an intriguingly central role of the protein TDP-43 in the majority of cases of this devastating disease.}, }
@article {pmid29415504, year = {2018}, author = {Burden, SJ and Huijbers, MG and Remedio, L}, title = {Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses.}, journal = {International journal of molecular sciences}, volume = {19}, number = {2}, pages = {}, pmid = {29415504}, issn = {1422-0067}, support = {R01 AG051490/AG/NIA NIH HHS/United States ; R01 NS036193/NS/NINDS NIH HHS/United States ; R01 NS075124/NS/NINDS NIH HHS/United States ; R37 NS036193/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biomarkers ; Humans ; LDL-Receptor Related Proteins/metabolism ; Muscle Proteins/metabolism ; Neuromuscular Junction/*pathology ; Receptors, Cholinergic/metabolism ; *Synaptic Transmission ; }, abstract = {The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance.}, }
@article {pmid29411264, year = {2018}, author = {Kay, L and Pienaar, IS and Cooray, R and Black, G and Soundararajan, M}, title = {Understanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {55}, number = {9}, pages = {7352-7365}, pmid = {29411264}, issn = {1559-1182}, mesh = {Animals ; Disease Models, Animal ; GTP Phosphohydrolases/chemistry/*metabolism ; Homeostasis ; Humans ; Mitochondria/metabolism ; Mitochondrial Dynamics ; Neurodegenerative Diseases/*enzymology/*therapy ; }, abstract = {The Miro GTPases represent an unusual subgroup of the Ras superfamily and have recently emerged as important mediators of mitochondrial dynamics and for maintaining neuronal health. It is now well-established that these enzymes act as essential components of a Ca[2+]-sensitive motor complex, facilitating the transport of mitochondria along microtubules in several cell types, including dopaminergic neurons. The Miros appear to be critical for both anterograde and retrograde mitochondrial transport in axons and dendrites, both of which are considered essential for neuronal health. Furthermore, the Miros may be significantly involved in the development of several serious pathological processes, including the development of neurodegenerative and psychiatric disorders. In this review, we discuss the molecular structure and known mitochondrial functions of the Miro GTPases in humans and other organisms, in the context of neurodegenerative disease. Finally, we consider the potential human Miros hold as novel therapeutic targets for the treatment of such disease.}, }
@article {pmid29410613, year = {2018}, author = {Tracey, TJ and Steyn, FJ and Wolvetang, EJ and Ngo, ST}, title = {Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {10}, pmid = {29410613}, issn = {1662-5099}, abstract = {Lipids are a fundamental class of organic molecules implicated in a wide range of biological processes related to their structural diversity, and based on this can be broadly classified into five categories; fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids and sphingolipids. Different lipid classes play major roles in neuronal cell populations; they can be used as energy substrates, act as building blocks for cellular structural machinery, serve as bioactive molecules, or a combination of each. In amyotrophic lateral sclerosis (ALS), dysfunctions in lipid metabolism and function have been identified as potential drivers of pathogenesis. In particular, aberrant lipid metabolism is proposed to underlie denervation of neuromuscular junctions, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation and reduced neurotransmitter release. Here we review current knowledge of the roles of lipid metabolism and function in the CNS and discuss how modulating these pathways may offer novel therapeutic options for treating ALS.}, }
@article {pmid29410157, year = {2018}, author = {Arnerić, SP and Kern, VD and Stephenson, DT}, title = {Regulatory-accepted drug development tools are needed to accelerate innovative CNS disease treatments.}, journal = {Biochemical pharmacology}, volume = {151}, number = {}, pages = {291-306}, doi = {10.1016/j.bcp.2018.01.043}, pmid = {29410157}, issn = {1873-2968}, support = {U18 FD005320/FD/FDA HHS/United States ; }, mesh = {Biomarkers/*analysis ; Central Nervous System Diseases/*drug therapy/metabolism ; *Drug Development/legislation &amp; jurisprudence/methods ; *Drug Discovery/legislation &amp; jurisprudence/methods ; Guidelines as Topic ; Humans ; United States ; United States Food and Drug Administration ; }, abstract = {Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics.}, }
@article {pmid29409855, year = {2018}, author = {Sil, S and Periyasamy, P and Thangaraj, A and Chivero, ET and Buch, S}, title = {PDGF/PDGFR axis in the neural systems.}, journal = {Molecular aspects of medicine}, volume = {62}, number = {}, pages = {63-74}, pmid = {29409855}, issn = {1872-9452}, support = {R01 MH112848/MH/NIMH NIH HHS/United States ; R01 DA035203/DA/NIDA NIH HHS/United States ; R01 DA027729/DA/NIDA NIH HHS/United States ; R01 MH106425/MH/NIMH NIH HHS/United States ; R01 DA033150/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/metabolism ; Gene Expression Regulation/drug effects ; Humans ; Molecular Targeted Therapy ; Nervous System/*metabolism ; Neurodegenerative Diseases/*metabolism ; Platelet-Derived Growth Factor/*metabolism ; Receptors, Platelet-Derived Growth Factor/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are expressed in several cell types including the brain cells such as neuronal progenitors, neurons, astrocytes, and oligodendrocytes. Emerging evidence shows that PDGF-mediated signaling regulates diverse functions in the central nervous system (CNS) such as neurogenesis, cell survival, synaptogenesis, modulation of ligand-gated ion channels, and development of specific types of neurons. Interestingly, PDGF/PDFGR signaling can elicit paradoxical roles in the CNS, depending on the cell type and the activation stimuli and is implicated in the pathogenesis of various neurodegenerative diseases. This review summarizes the role of PDGFs/PDGFRs in several neurodegenerative diseases such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, brain cancer, cerebral ischemia, HIV-1 and drug abuse. Understanding PDGF/PDGFR signaling may lead to novel approaches for the future development of therapeutic strategies for combating CNS pathologies.}, }
@article {pmid29405034, year = {2017}, author = {Limanaqi, F and Gambardella, S and Lazzeri, G and Ferrucci, M and Ruggieri, S and Fornai, F}, title = {Revisiting the gamma loop in ALS.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {118-130}, doi = {10.12871/00039829201748}, pmid = {29405034}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Humans ; Motor Neurons/*pathology ; Neurons, Afferent/*pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fast progressive neurodegenerative disease characterized by muscle denervation, weakening and atrophy, which eventually culminates into death, mainly due to respiratory failure. The traditional view of ALS as a disorder affecting selectively motor neurons throughout the central nervous system has been progressively dispelled by innumerous lines of evidence indicating that other cells but motor neurons may be affected as well. Remarkably, this disorder is not limited to the motor system but rather configures as a systemic disease yielding a plethora of clinical signs. Among this broad clinical spectrum, sensory neuropathy occurring parallel to motor dysfunction is a quite frequent feature within ALS patients, which has spurred the interest of many investigators during the years. In line with this, morphological studies have confirmed that sensory neurons and axons' degeneration may occur in both ALS- experimental models and -patients. Noteworthy, this may have a nonetheless negligible role in ALS -related motor decline, as highlighted by recent studies showing that, degeneration of type I/II proprioceptive fibers is a primary source of alpha-motor neurons' death. These latter in fact, differently from gamma motor neurons, are a direct monosynaptic target of proprioceptive fibers. The present findings contribute to define a novel scenario of sensorimotor ALS pathophysiology where the gamma loop's fine connectivity may play a key role. In support to this view, in the present manuscript we provide a reappraisal on the role of single gamma loop's components in ALS.}, }
@article {pmid29405033, year = {2017}, author = {Silani, V}, title = {Therapy in Amyotrophic Lateral Sclerosis (ALS): an unexpected evolving scenario.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {118-130}, doi = {10.12871/00039829201747}, pmid = {29405033}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Molecular Targeted Therapy/methods ; Neuroprotective Agents/*therapeutic use ; Precision Medicine/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease resulting in increasing disability, being uniformly fatal. Since its approval in the 1990s, riluzole remained for long time the unique treatment, offering modest survival benefit. Most recently a second drug has been approved by the US Food and Drug Administration for treatment of ALS: edaravone. Significant advances have been made in the symptomatic management of the disease but more effective drug therapy targeting disease progression is still dreadfully needed, the success appearing almost a miracle. Recent discoveries related to genetics indicate divergent mechanisms of disease encouraging precision medicine leading to molecularly tailored interventions. The search for effective therapy still faces important challenges in the areas of both basic science and animal research, adequate translation of results into human clinical trials, inherent bias in human studies, and issues related to delays in clinical diagnosis. It is interesting to point out that ALS research may speed up drug development not only for this disease, but also for other more prevalent neurodegenerative diseases: the reverse is also conceivable.}, }
@article {pmid29405032, year = {2017}, author = {Verde, F and Del Tredici, K and Braak, H and Ludolph, A}, title = {The multisystem degeneration amyotrophic lateral sclerosis - neuropathological staging and clinical translation.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {118-130}, doi = {10.12871/00039829201746}, pmid = {29405032}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Brain/*pathology/physiopathology ; Disease Progression ; Humans ; Nerve Degeneration/*pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons. However, much evidence points towards additional involvement of brain systems other than the motor. As much as half of ALS patients display cognitive-behavioral disturbances. ALS shares with a considerable proportion of FTD cases the same neuropathological substrate, namely, inclusions of abnormally phosphorylated protein TDP-43 (pTDP-43). In analogy with pathological staging systems elaborated in the past decades for Alzheimer's disease (AD) and Parkinson's disease (PD), a model of staging of pTDP-43 pathology in sporadic ALS (sALS) has been recently proposed. According to it, 4 stages can be recognized, where pTDP-43 inclusions are found in the agranular motor cortex and α-motor neurons of the brain stem and spinal cord (stage 1), in prefrontal neocortex (middle frontal gyrus), reticular formation, and precerebellar nuclei (stage 2), in further areas of the prefrontal neocortex (gyrus rectus and orbitofrontal gyri), postcentrally located sensory cortex, and basal ganglia (stage 3), and in the anteromedial temporal lobe including the hippocampus (stage 4). Based on this staging effort, a corticofugal axonal model for spreading of pathology can be hypothesized, whereby pathology starts in the primary motor cortex and spreads from there via axonal projections to lower motor neurons and to subcortical structures. Recent neuroradiological evidence seems to support the proposed staging system. From the clinical standpoint, a proportion of ALS patients display extramotor deficits (namely cognitive-behavioural disturbances, impaired ocular movements, and extrapyramidal alterations), which seem to correspond to the pathological involvement of the relevant cerebral structures. This review describes neuropathological sALS staging and addresses clinical evidence corresponding to this staging, pointing towards the concept of ALS as a multisystem brain degeneration disorder instead of a disease confined to motor neurons.}, }
@article {pmid29405031, year = {2017}, author = {Zaccagna, F and Lucignani, G and Raz, E and Colonnese, C}, title = {Imaging techniques in ALS.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {142-151}, doi = {10.12871/00039829201745}, pmid = {29405031}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Humans ; Image Interpretation, Computer-Assisted/*methods ; Magnetic Resonance Imaging/methods ; Neuroimaging/*methods ; Pyramidal Tracts/*diagnostic imaging ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration of both upper and lower motor neuron located in the spinal cord and brainstem. Diagnosis of ALS is predominantly clinical, nevertheless, electromyography and Magnetic Resonance Imaging (MRI) may provide support. Several advanced MRI techniques have been proven useful for ALS diagnosis and, indeed, the combination of different MRI techniques demonstrated an improvement in sensitivity and specificity as far as 90%. This review focus on the imaging techniques currently used in the diagnosis and management of ALS with brief considerations on future applications.}, }
@article {pmid29405030, year = {2017}, author = {Chico, L and Modena, M and Lo Gerfo, A and Ricci, G and Caldarazzo Ienco, E and Ryskalin, L and Fornai, F and Siciliano, G}, title = {Cross-talk between pathogenic mechanisms in neurodegeneration: the role of oxidative stress in Amyotrophic Lateral Sclerosis.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {131-141}, doi = {10.12871/00039829201744}, pmid = {29405030}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Nerve Degeneration/*physiopathology ; Oxidative Stress/*physiology ; Signal Transduction/*physiology ; }, abstract = {The mechanisms underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that affects the motor system with progressive paralysis, are complex and not yet fully understood. It is generally agreed that ALS is a multifactorial and multisystem disease due not only possibly to genetic causes but also to other factors like oxidative stress, mitochondrial dysfunction, protein aggregation, RNA dysmetabolism, autophagy, and excitotoxicity glutamate-mediate. Altered oxidative stress biomarker profile has been repeatedly reported in ALS patients, which may suggest that abnormal free radical production is relevant in the ALS pathogenesis. This review aims to investigate how oxidative stress can affect other proposed mechanisms of neurodegeneration in ALS.}, }
@article {pmid29405029, year = {2017}, author = {Ferrucci, M and Ryskalin, L and Busceti, CL and Gaglione, A and Biagioni, F and Fornai, F}, title = {Are there endogenous stem cells in the spinal cord?.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {118-130}, doi = {10.12871/00039829201743}, pmid = {29405029}, issn = {0003-9829}, mesh = {Adult Stem Cells/*cytology ; Animals ; Humans ; Neural Stem Cells/*cytology ; Neurogenesis/*physiology ; Spinal Cord/*cytology ; }, abstract = {Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche.}, }
@article {pmid29405028, year = {2017}, author = {Campopiano, R and Ryskalin, L and Giardina, E and Zampatti, S and Busceti, CL and Biagioni, F and Ferese, R and Storto, M and Gambardella, S and Fornai, F}, title = {Next Generation Sequencing and ALS: known genes, different phenotyphes.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {110-117}, doi = {10.12871/00039829201742}, pmid = {29405028}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genotype ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease clinically characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. Most cases appear to be sporadic, but 5-10 % of cases have a family history of the disease, and over the last decade, identification of mutations in about 20 genes predisposing to these disorders has provided the means to better understand their pathogenesis. Next Generation sequencing (NGS) is an advanced high-throughput DNA sequencing technology which have rapidly contributed to an acceleration in the discovery of genetic risk factors for both familial and sporadic neurological and neurodegenerative diseases. These strategies allowed to rapidly identify disease-associated variants and genetic risk factors for both familial (fALS) and sporadic ALS (sALS), strongly contributing to the knowledge of the genetic architecture of ALS. Moreover, as the number of ALS genes grows, many of the proteins they encode are in intracellular processes shared with other known diseases, suggesting an overlapping of clinical and phatological features between different diseases. To emphasize this concept, the review focuses on genes coding for Valosin-containing protein (VPC) and two Heterogeneous nuclear RNA-binding proteins (HNRNPA1 and hnRNPA2B1), recently idefied through NGS, where different mutations have been associated in both ALS and other neurological and neurodegenerative diseases.}, }
@article {pmid29405027, year = {2017}, author = {Silani, V and Ludolph, A and Fornai, F}, title = {The emerging picture of ALS: a multisystem, not only a "motor neuron disease.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {99-109}, doi = {10.12871/00039829201741}, pmid = {29405027}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Motor Neuron Disease/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons: compelling evidence points now towards additional involvement of extramotor functions. Beside the cognitive-behavioural disturbances, many ALS patients express extrapyramidal deficits: neuropathological findings fully support the multisystem brain degeneration. The therapeutical option to treat the multisystemic character of ALS represents an additional difficult task in absence of sensitive biomarkers or better understanding of the pathophysiological mechanisms of the disease. Future clinical trials need to identify subgroups of patients, representing the post-hoc analysis after a trial the extreme effort to define sensitive ALS patients to new treatments, as the edaravone story seems to demonstrate.}, }
@article {pmid29403354, year = {2018}, author = {Vercruysse, P and Vieau, D and Blum, D and Petersén, &#xc5; and Dupuis, L}, title = {Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {2}, pmid = {29403354}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDDs) are disorders characterized by progressive deterioration of brain structure and function. Selective neuronal populations are affected leading to symptoms which are prominently motor in amyotrophic lateral sclerosis (ALS) or Huntington's disease (HD), or cognitive in Alzheimer's disease (AD) and fronto-temporal dementia (FTD). Besides the common existence of neuronal loss, NDDs are also associated with metabolic changes such as weight gain, weight loss, loss of fat mass, as well as with altered feeding behavior. Importantly, preclinical research as well as clinical studies have demonstrated that altered energy homeostasis influences disease progression in ALS, AD and HD, suggesting that identification of the pathways leading to perturbed energy balance might provide valuable therapeutic targets Signals from both the periphery and central inputs are integrated in the hypothalamus, a major hub for the control of energy balance. Recent research identified major hypothalamic changes in multiple NDDs. Here, we review these hypothalamic alterations and seek to identify commonalities and differences in hypothalamic involvement between the different NDDs. These hypothalamic defects could be key in the development of perturbations in energy homeostasis in NDDs and further understanding of the underlying mechanisms might open up new avenues to not only treat weight loss but also to ameliorate overall neurological symptoms.}, }
@article {pmid29400298, year = {2018}, author = {Morlet, &#xc9; and Hozer, F and Costemale-Lacoste, JF}, title = {Neuroprotective effects of lithium: what are the implications in humans with neurodegenerative disorders?.}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {16}, number = {1}, pages = {78-86}, doi = {10.1684/pnv.2017.0718}, pmid = {29400298}, issn = {2115-7863}, mesh = {Aged ; Aged, 80 and over ; Aging ; Humans ; Lithium/*therapeutic use ; Neurodegenerative Diseases/*prevention &amp; control ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Lithium is used as a first line treatment in bipolar disorder. The neuroprotective effects of lithium in this indication tend to be well known and are mediated by its action on two enzymes: glycogen synthase kinase-3 and inositol monophosphatase-1. Preclinical and clinical studies seek to evaluate the neuroprotective effect of lithium in neurodegenerative disorders. The aims of this literature review is to gather clinical studies that investigated the efficacy of lithium in neurodegenerative diseases, using a systematic method based on PubMed data. Results were found concerning Alzheimer's disease and related dementias, Huntington's disease, amyotrophic lateral sclerosis and spino-cerebellar ataxia. Lithium exposure showed a potential neuroprotective effect in studies on psychiatric populations with a lower prevalence of Alzheimer's disease in exposed patients. In patients with mild cognitive impairment, lithium would be associated with clinical improvement and a lower level of cerebrospinal phosphorylated tau protein. Lithium would allow at least a partial improvement in symptoms, including suicidal thoughts, in Huntington's disease. Despite several positive case reports and short studies, further controlled researches have failed to substantiate any positive effects of lithium exposure in amyotrophic lateral sclerosis. In spinocerebellar ataxia, introduction of lithium may be of benefits in terms of improvement of cerebellar symptoms. Large randomized controlled trials are required to asses the effect of early exposure lithium in these indications, based on reliable biological markers of disease.}, }
@article {pmid29399045, year = {2018}, author = {Dorst, J and Ludolph, AC and Huebers, A}, title = {Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis.}, journal = {Therapeutic advances in neurological disorders}, volume = {11}, number = {}, pages = {1756285617734734}, pmid = {29399045}, issn = {1756-2856}, abstract = {In this review, we summarize the most important recent developments in the treatment of amyotrophic lateral sclerosis (ALS). In terms of disease-modifying treatment options, several drugs such as dexpramipexole, pioglitazone, lithium, and many others have been tested in large multicenter trials, albeit with disappointing results. Therefore, riluzole remains the only directly disease-modifying drug. In addition, we discuss antisense oligonucleotides (ASOs) as a new and potentially causal treatment option. Progress in symptomatic treatments has been more important. Nutrition and ventilation are now an important focus of ALS therapy. Several studies have firmly established that noninvasive ventilation improves patients' quality of life and prolongs survival. On the other hand, there is still no consensus regarding best nutritional management, but big multicenter trials addressing this issue are currently ongoing. Evidence regarding secondary symptoms like spasticity, muscle cramps or sialorrhea remains generally scarce, but some new insights will also be discussed. Growing evidence suggests that multidisciplinary care in specialized clinics improves survival.}, }
@article {pmid29395044, year = {2018}, author = {Weskamp, K and Barmada, SJ}, title = {TDP43 and RNA instability in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1693}, number = {Pt A}, pages = {67-74}, pmid = {29395044}, issn = {1872-6240}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; }, mesh = {Alternative Splicing ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Cytoplasm/metabolism ; DNA-Binding Proteins/*genetics/metabolism ; Fragile X Mental Retardation Protein/genetics ; Humans ; Motor Neurons/metabolism ; RNA/genetics/metabolism ; *RNA Stability ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in RNA processing. In accord with this central function, TDP43 levels are tightly regulated through a negative feedback loop, in which TDP43 recognizes its own RNA transcript, destabilizes it, and reduces new TDP43 protein production. In the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), cytoplasmic mislocalization and accumulation of TDP43 disrupt autoregulation; conversely, inefficient TDP43 autoregulation can lead to cytoplasmic TDP43 deposition and subsequent neurodegeneration. Because TDP43 plays a multifaceted role in maintaining RNA metabolism, its mislocalization and accumulation interrupt several RNA processing pathways that in turn affect RNA stability and gene expression. TDP43-mediated disruption of these pathways-including alternative mRNA splicing, non-coding RNA processing, and RNA granule dynamics-may directly or indirectly contribute to ALS pathogenesis. Therefore, strategies that restore effective TDP43 autoregulation may ultimately prevent neurodegeneration in ALS and related disorders.}, }
@article {pmid29394876, year = {2018}, author = {Qosa, H and Volpe, DA}, title = {The development of biological therapies for neurological diseases: moving on from previous failures.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {4}, pages = {283-293}, doi = {10.1080/17460441.2018.1437142}, pmid = {29394876}, issn = {1746-045X}, mesh = {Animals ; Biological Products/adverse effects/*therapeutic use ; Biological Therapy/*methods ; Disease Progression ; Drug Design ; Humans ; Nervous System Diseases/*drug therapy/physiopathology ; }, abstract = {Although years of research have expanded the use of biologics for several clinical conditions, such development has not yet occurred in the treatment of neurological diseases. With the advancement of biologic technologies, there is promise for these therapeutics as novel therapeutic approaches for neurological diseases. Areas covered: In this article, the authors review the therapeutic potential of different types of biologics for the treatment of neurological diseases. Preclinical and clinical studies that investigate the efficacy and safety of biologics in the treatment of neurological diseases, namely Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke, were reviewed. Moreover, the authors describe the key challenges in the development of therapeutically safe and effective biologics for the treatment of neurological diseases. Expert opinion: Several biologics have shown promise in the treatment of neurological diseases. However, the complexity of the CNS, as well as a limited understanding of disease progression, and restricted access of biologics to the CNS has limited successful development. Therefore, more research needs to be conducted to overcome these hurdles before developing effective and safe biologics for neurological diseases. The emergence of new technologies for the design, production and delivery of biologics will accelerate translating biologics to the clinic.}, }
@article {pmid29394035, year = {2018}, author = {Denoyer, D and Clatworthy, SAS and Cater, MA}, title = {Copper Complexes in Cancer Therapy.}, journal = {Metal ions in life sciences}, volume = {18}, number = {}, pages = {}, doi = {10.1515/9783110470734-022}, pmid = {29394035}, issn = {1559-0836}, mesh = {Animals ; Antineoplastic Agents/adverse effects/chemistry/metabolism/*therapeutic use ; Coordination Complexes ; Copper/adverse effects/chemistry/metabolism/*therapeutic use ; Drug Design ; Drug Repositioning ; Humans ; Molecular Structure ; Neoplasms/*drug therapy/metabolism/pathology ; Organometallic Compounds/adverse effects/chemistry/metabolism/*therapeutic use ; Structure-Activity Relationship ; }, abstract = {Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials.}, }
@article {pmid29393026, year = {2018}, author = {Rudolph, SS and Isbye, DL and Pfeiffer, P and Kjærgaard, J}, title = {[Advanced life support for cardiac arrest beyond the algorithm].}, journal = {Ugeskrift for laeger}, volume = {180}, number = {5}, pages = {}, pmid = {29393026}, issn = {1603-6824}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Adrenergic beta-1 Receptor Antagonists/therapeutic use ; Advanced Cardiac Life Support/*methods ; Algorithms ; Cardiopulmonary Resuscitation/methods ; Electric Countershock/methods ; Extracorporeal Membrane Oxygenation ; *Heart Arrest/drug therapy/surgery/therapy ; Humans ; Methylene Blue/therapeutic use ; Percutaneous Coronary Intervention ; Propanolamines/therapeutic use ; Vasoconstrictor Agents/therapeutic use ; }, abstract = {In an advanced emergency medical service all parts of the advanced life support (ALS) algorithm can be provided. This evidence-based algorithm outlines resuscitative efforts for the first 10-15 minutes after cardiac arrest, whereafter the algorithm repeats itself. Restoration of spontaneous circulation fails in most cases, but in some circumstances the patient may benefit from additional interventional approaches, in which case transport to hospital with ongoing cardiopulmonary resuscitation is indicated. This paper has summarized treatments outside the ALS algorithm, which may be beneficial, but are not supported by firm scientific evidence.}, }
@article {pmid29388464, year = {2018}, author = {Valenzuela, V and Nassif, M and Hetz, C}, title = {Unraveling the role of motoneuron autophagy in ALS.}, journal = {Autophagy}, volume = {14}, number = {4}, pages = {733-737}, pmid = {29388464}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Autophagy/genetics/*physiology ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/*pathology ; Neuromuscular Junction/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {In recent years, the role of autophagy in the pathogenesis of most neurodegenerative diseases has transitioned into a limbo of protective or detrimental effects. Genetic evidence indicates that mutations in autophagy-regulatory genes can result in the occurrence of amyotrophic lateral sclerosis (ALS), suggesting a physiological role of the pathway to motoneuron function. However, experimental manipulation of autophagy in ALS models led to conflicting results depending on the intervention strategy and the disease model used. A recent work by the Maniatis group systematically explored the role of cell-specific autophagy in motoneurons at different disease stages, revealing surprising and unexpected findings. Autophagy activity at early stages may contribute to maintaining the structure and function of neuromuscular junctions, whereas at later steps of the disease it has a pathogenic activity possibly involving cell-nonautonomous mechanisms related to glial activation. This new study adds a new layer of complexity in the field, suggesting an intricate interplay between proteostasis alterations, the time-differential function of autophagy in neurons, and muscle innervation in ALS.}, }
@article {pmid29385710, year = {2018}, author = {Azadmanesh, J and Borgstahl, GEO}, title = {A Review of the Catalytic Mechanism of Human Manganese Superoxide Dismutase.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {7}, number = {2}, pages = {}, pmid = {29385710}, issn = {2076-3921}, support = {P30 CA036727/CA/NCI NIH HHS/United States ; }, abstract = {Superoxide dismutases (SODs) are necessary antioxidant enzymes that protect cells from reactive oxygen species (ROS). Decreased levels of SODs or mutations that affect their catalytic activity have serious phenotypic consequences. SODs perform their bio-protective role by converting superoxide into oxygen and hydrogen peroxide by cyclic oxidation and reduction reactions with the active site metal. Mutations of SODs can cause cancer of the lung, colon, and lymphatic system, as well as neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis. While SODs have proven to be of significant biological importance since their discovery in 1968, the mechanistic nature of their catalytic function remains elusive. Extensive investigations with a multitude of approaches have tried to unveil the catalytic workings of SODs, but experimental limitations have impeded direct observations of the mechanism. Here, we focus on human MnSOD, the most significant enzyme in protecting against ROS in the human body. Human MnSOD resides in the mitochondrial matrix, the location of up to 90% of cellular ROS generation. We review the current knowledge of the MnSOD enzymatic mechanism and ongoing studies into solving the remaining mysteries.}, }
@article {pmid29385088, year = {2018}, author = {Garbuzova-Davis, S and Ehrhart, J and Sanberg, PR and Borlongan, CV}, title = {Potential Role of Humoral IL-6 Cytokine in Mediating Pro-Inflammatory Endothelial Cell Response in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {19}, number = {2}, pages = {}, pmid = {29385088}, issn = {1422-0067}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Endothelial Cells/*metabolism/pathology ; Female ; Humans ; *Inflammation ; Interleukin-6/metabolism/*physiology ; Male ; Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial disease with limited therapeutic options. Numerous intrinsic and extrinsic factors are involved in ALS motor neuron degeneration. One possible effector accelerating motor neuron death in ALS is damage to the blood-Central Nervous System barrier (B-CNS-B), mainly due to endothelial cell (EC) degeneration. Although mechanisms of EC damage in ALS are still unknown, vascular impairment may be initiated by various humoral inflammatory factors and other mediators. Systemic IL-6-mediated inflammation is a possible early extrinsic effector leading to the EC death causing central nervous system (CNS) barrier damage. In this review, we discuss the potential role of humoral factors in triggering EC alterations in ALS. A specific focus was on humoral IL-6 cytokine mediating EC inflammation via the trans-signaling pathway. Our preliminary in vitro studies demonstrated a proof of principle that short term exposure of human bone marrow endothelial cells to plasma from ALS patient leads to cell morphological changes, significantly upregulated IL-6R immunoexpression, and pro-inflammatory cell response. Our in-depth understanding of specific molecular mechanisms of this humoral cytokine in EC degeneration may facilitate an endothelial-IL-6-targeting therapy for restoring cell homeostasis and eventually reestablishing B-CNS-B integrity in ALS.}, }
@article {pmid29384454, year = {2018}, author = {Brownstone, RM and Lancelin, C}, title = {Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {119}, number = {5}, pages = {1782-1794}, pmid = {29384454}, issn = {1522-1598}, support = {110193/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Afferent Pathways/*pathology ; Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; *Disease Progression ; Humans ; Motor Neurons/*pathology ; Muscle Spindles/*pathology ; Proprioception/*physiology ; Renshaw Cells/*pathology ; }, abstract = {In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS.}, }
@article {pmid29377176, year = {2018}, author = {Yan, M and Xing, GL and Xiong, WC and Mei, L}, title = {Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1413}, number = {1}, pages = {126-135}, doi = {10.1111/nyas.13573}, pmid = {29377176}, issn = {1749-6632}, mesh = {Agrin/genetics/*immunology ; Animals ; Autoantibodies/*immunology ; Humans ; LDL-Receptor Related Proteins/genetics/*immunology ; Mice ; Myasthenia Gravis/*immunology ; Neuromuscular Junction/immunology/*pathology ; Receptor Protein-Tyrosine Kinases/genetics/*immunology ; Receptors, Cholinergic/genetics/*immunology ; }, abstract = {Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.}, }
@article {pmid29377008, year = {2018}, author = {Sweeney, MD and Sagare, AP and Zlokovic, BV}, title = {Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {3}, pages = {133-150}, pmid = {29377008}, issn = {1759-4766}, support = {R01 AG039452/AG/NIA NIH HHS/United States ; R01 NS034467/NS/NINDS NIH HHS/United States ; R01 NS100459/NS/NINDS NIH HHS/United States ; P01 AG052350/AG/NIA NIH HHS/United States ; RF1 AG039452/AG/NIA NIH HHS/United States ; R01 NS090904/NS/NINDS NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG023084/AG/NIA NIH HHS/United States ; F31 AG044997/AG/NIA NIH HHS/United States ; }, mesh = {*Blood-Brain Barrier/metabolism/pathology/physiopathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; }, abstract = {The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.}, }
@article {pmid29375039, year = {2017}, author = {Csobonyeiova, M and Polak, S and Nicodemou, A and Danisovic, L}, title = {Induced pluripotent stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {68}, number = {5}, pages = {649-657}, pmid = {29375039}, issn = {1899-1505}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Cell Differentiation/physiology ; Cell- and Tissue-Based Therapy/*methods/trends ; *Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/physiology/*transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by neuromuscular degeneration and the progressive loss of upper and lower motor neurons (MNs), causing weakness and paralysis. However, the underlying mechanisms of this disease are still unknown and there is no cure, or even treatment to stop or reverse its pathology. Consequently, most ALS patients die within 3 - 5 years after disease onset. While considerable progress has been made in studying animal models of ALS, they lack clinical suitability due to genetic differences. However, the recent development of induced pluripotent stem cells (iPSCs) has made it possible to study human disease-specific neuronal and glial cells to identify disease mechanisms and develop phenotypic screens for drug discovery. iPSCs provide researchers with a model of naturally occurring pathology under the human genetic background and MNs differentiated from human iPSCs bearing ALS-associated mutations offer a powerful model to study disease pathology. This paper reviews recent methods of differentiating iPSCs into neuronal cells and suggests further applications of these iPSCs-derived cells for ALS disease modeling, drug screening, and possible cell-based therapy.}, }
@article {pmid29371752, year = {2018}, author = {Watanabe, K and Tanaka, M and Yuki, S and Hirai, M and Yamamoto, Y}, title = {How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {62}, number = {1}, pages = {20-38}, pmid = {29371752}, issn = {0912-0009}, abstract = {Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.}, }
@article {pmid29369391, year = {2018}, author = {Leija-Salazar, M and Piette, C and Proukakis, C}, title = {Review: Somatic mutations in neurodegeneration.}, journal = {Neuropathology and applied neurobiology}, volume = {44}, number = {3}, pages = {267-285}, doi = {10.1111/nan.12465}, pmid = {29369391}, issn = {1365-2990}, mesh = {Alzheimer Disease/*genetics/pathology ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Brain/*pathology ; Humans ; Mosaicism ; *Mutation ; Neurodegenerative Diseases/*genetics/pathology ; Parkinson Disease/*genetics/pathology ; }, abstract = {Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single-cell sequencing, which can still be error-prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late-onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.}, }
@article {pmid29361800, year = {2018}, author = {Penke, B and Bogár, F and Crul, T and Sántha, M and Tóth, ME and Vígh, L}, title = {Heat Shock Proteins and Autophagy Pathways in Neuroprotection: from Molecular Bases to Pharmacological Interventions.}, journal = {International journal of molecular sciences}, volume = {19}, number = {1}, pages = {}, pmid = {29361800}, issn = {1422-0067}, mesh = {Animals ; Autophagy/*genetics ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; Endosomes/metabolism ; Heat-Shock Proteins/*genetics/*metabolism ; Humans ; Lysosomes/metabolism ; Neurodegenerative Diseases/genetics/metabolism/prevention &amp; control/therapy ; Neurons/metabolism ; Neuroprotection/*genetics ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; *Signal Transduction ; Ubiquitin/metabolism ; Unfolded Protein Response ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease and Huntington's disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy). The role of heat shock proteins (Hsps) in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed.}, }
@article {pmid29357791, year = {2017}, author = {Ridolfi, B and Abdel-Haq, H}, title = {Neurodegenerative Disorders Treatment: The MicroRNA Role.}, journal = {Current gene therapy}, volume = {17}, number = {5}, pages = {327-363}, doi = {10.2174/1566523218666180119120726}, pmid = {29357791}, issn = {1875-5631}, mesh = {Alzheimer Disease/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Exosomes/*genetics ; Gene Expression Regulation ; Genetic Therapy/*methods/trends ; Humans ; MicroRNAs/*genetics ; Neurodegenerative Diseases/genetics/*therapy ; Parkinson Disease/genetics/therapy ; RNA Interference ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and prion disease are not timely and effectively treated using conventional therapies. This emphasizes the need for alternative therapeutic approaches. In this respect, gene-based therapies have been adopted as potentially feasible alternative therapies, where the microRNA (miRNA) approach has experienced a great explosion in recent years. Because miRNAs have been shown to be implicated in the pathogenesis of several diseases including neurodegenerative diseases, they are intensely studied as candidates for diagnostic and prognostic biomarkers, as predictors of drug response and as therapeutic agents. In this review, we evaluate the feasibility of both direct and indirect miRNA mimics and inhibitors toward the regulation of neurodegenerative-related genes both in vivo and in vitro models, highlight the advantages and drawbacks associated with miRNA-based therapy, and summarize the relevant techniques and approaches attempted to deliver miRNAs to the central nervous system for therapeutic purposes, with particular regard to the exosomes. Additionally, we describe a new approach that holds great promise for the treatment of a wide range of diseases including neurodegenerative disorders. This approach is based on addressing the incorporation of miRNAs into exosomes to increase the quantity and quality of miRNA packed and delivered to the central nervous system and other sites of action.}, }
@article {pmid29356625, year = {2018}, author = {Mitropoulos, K and Katsila, T and Patrinos, GP and Pampalakis, G}, title = {Multi-Omics for Biomarker Discovery and Target Validation in Biofluids for Amyotrophic Lateral Sclerosis Diagnosis.}, journal = {Omics : a journal of integrative biology}, volume = {22}, number = {1}, pages = {52-64}, doi = {10.1089/omi.2017.0183}, pmid = {29356625}, issn = {1557-8100}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/*metabolism ; *Biomarkers ; Body Fluids/metabolism ; *Genomics/methods ; Humans ; *Metabolomics/methods ; *Proteomics/methods ; Reproducibility of Results ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare but usually fatal neurodegenerative disease characterized by motor neuron degeneration in the brain and the spinal cord. Two forms are recognized, the familial that accounts for 5-10% and the sporadic that accounts for the rest. New studies suggest that ALS is a highly heterogeneous disease, and this diversity is a major reason for the lack of successful therapeutic treatments. Indeed, only two drugs (riluzole and edaravone) have been approved that provide a limited improvement in the quality of life. Presently, the diagnosis of ALS is based on clinical examination and lag period from the onset of symptoms to the final diagnosis is ∼12 months. Therefore, the discovery of robust molecular biomarkers that can assist in the diagnosis is of major importance. DNA sequencing to identify pathogenic gene variants can be applied in the cases of familial ALS. However, it is not a routinely used diagnostic procedure and most importantly, it cannot be applied in the diagnosis of sporadic ALS. In this expert review, the current approaches in identification of new ALS biomarkers are discussed. The advent of various multi-omics biotechnology platforms, including miRNomics, proteomics, metabolomics, metallomics, volatolomics, and viromics, has assisted in the identification of new biomarkers. The biofluids are the most preferable material for the analysis of potential biomarkers (such as proteins and cell-free miRNAs), since they are easily obtained. In the near future, the biofluid-based biomarkers will be indispensable to classify different ALS subtypes and understand the molecular heterogeneity of the disease.}, }
@article {pmid29355955, year = {2018}, author = {Thomas, EA and D'Mello, SR}, title = {Complex neuroprotective and neurotoxic effects of histone deacetylases.}, journal = {Journal of neurochemistry}, volume = {145}, number = {2}, pages = {96-110}, pmid = {29355955}, issn = {1471-4159}, support = {R01 NS040408/NS/NINDS NIH HHS/United States ; R21 NS087986/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Histone Deacetylases/*metabolism ; Humans ; Neurodegenerative Diseases/*enzymology ; }, abstract = {By their ability to shatter quality of life for both patients and caregivers, neurodegenerative diseases are the most devastating of human disorders. Unfortunately, there are no effective or long-terms treatments capable of slowing down the relentless loss of neurons in any of these diseases. One impediment is the lack of detailed knowledge of the molecular mechanisms underlying the processes of neurodegeneration. While some neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are mostly sporadic in nature, driven by both environment and genetic susceptibility, many others, including Huntington's disease, spinocerebellar ataxias, and spinal-bulbar muscular atrophy, are genetically inherited disorders. Surprisingly, given their different roots and etiologies, both sporadic and genetic neurodegenerative disorders have been linked to disease mechanisms involving histone deacetylase (HDAC) proteins, which consists of 18 family members with diverse functions. While most studies have implicated certain HDAC subtypes in promoting neurodegeneration, a substantial body of literature suggests that other HDAC proteins can preserve neuronal viability. Of particular interest, however, is the recent realization that a single HDAC subtype can have both neuroprotective and neurotoxic effects. Diverse mechanisms, beyond transcriptional regulation have been linked to these effects, including deacetylation of non-histone proteins, protein-protein interactions, post-translational modifications of the HDAC proteins themselves and direct interactions with disease proteins. The roles of these HDACs in both sporadic and genetic neurodegenerative diseases will be discussed in the current review.}, }
@article {pmid29350907, year = {2018}, author = {Ramírez-Jarquín, UN and Tapia, R}, title = {Excitatory and Inhibitory Neuronal Circuits in the Spinal Cord and Their Role in the Control of Motor Neuron Function and Degeneration.}, journal = {ACS chemical neuroscience}, volume = {9}, number = {2}, pages = {211-216}, doi = {10.1021/acschemneuro.7b00503}, pmid = {29350907}, issn = {1948-7193}, mesh = {Animals ; Humans ; Motor Neurons/*physiology ; Nerve Degeneration/physiopathology ; Neural Inhibition/*physiology ; Neural Pathways/physiology/physiopathology ; Spinal Cord/*physiology/*physiopathology ; }, abstract = {The complex neuronal networks of the spinal cord coordinate a wide variety of motor functions, including walking, running, and voluntary and involuntary movements. This is accomplished by different groups of neurons, called center pattern generators, which control left-right alternation and flexor-extensor patterns. These spinal circuits, located in the ventral horns, are formed by several neuronal types, and the specific function of most of them has been identified by means of studies in vivo and in the isolated spinal cord of mice harboring genetically induced ablation of specific neuronal populations. These studies have shown that the coordinated activity of several interneuron types, mainly GABAergic and glycinergic inhibitory neurons, have a crucial role in the modulation of motor neurons activity that finally excites the corresponding muscles. A pharmacological experimental approach by administering in the spinal cord agonists and antagonists of glutamate, GABA, glycine, and acetylcholine receptors to alter their synaptic action has also produced important results, linking the deficits in the synaptic function with the resulting motor alterations. These results have also increased the knowledge of the mechanisms of motor neuron degeneration, which is characteristic of diseases such as amyotrophic lateral sclerosis, and therefore open the possibility of designing new strategies for the prevention and treatment of these diseases.}, }
@article {pmid29350413, year = {2018}, author = {Huss, A and Peters, S and Vermeulen, R}, title = {Occupational exposure to extremely low-frequency magnetic fields and the risk of ALS: A systematic review and meta-analysis.}, journal = {Bioelectromagnetics}, volume = {39}, number = {2}, pages = {156-163}, doi = {10.1002/bem.22104}, pmid = {29350413}, issn = {1521-186X}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Humans ; Magnetic Fields/*adverse effects ; Occupational Exposure/*adverse effects ; Risk ; }, abstract = {We performed a meta-analysis to examine associations of occupational exposure to extremely-low frequency magnetic fields (ELF-MF) with amyotrophic lateral sclerosis (ALS). Epidemiologic studies were identified in EMBASE and MEDLINE, in reference lists and a specialist database. We included studies that reported risk estimates of ALS in association with occupational ELF-MF exposure. Summary relative risks (RR) or odds ratios (OR) were obtained with random effect meta-analysis, and analyses were stratified by type of exposure assessment. This was done to evaluate whether observed heterogeneity between studies could be explained with differences in the way the exposure had been determined. We included 20 studies in our meta-analysis. Overall, studies reported a slightly increased risk of ALS in those exposed to higher levels of ELF-MF compared to lower levels with a summary RR (sRR) of 1.14 (95% Confidence Interval [CI] 1.00-1.30) and for workers in electrical occupations (sRR 1.41, CI 1.05-1.92), but with large heterogeneity between studies (I[2] > 70%). Self-reported exposure or occupations determined from death certificates did not show increased risks. Highest-longest types of exposure translated into increased risks of ALS if the studies had evaluated the whole occupational history, in contrast to evaluating only few points in time (e.g., from census records); sRR were 1.89 (CI 1.31-2.73, I[2] 0%) and 1.06 (CI 0.75-1.57, I[2] 76%), respectively. In this meta-analysis, we observed an increased risk of ALS in workers occupationally exposed to ELF-MF. Results of studies depended on the quality of the exposure assessment. Bioelectromagnetics. 39:156-163, 2018. © 2018 Wiley Periodicals, Inc.}, }
@article {pmid29349657, year = {2018}, author = {Cui, R and Tuo, M and Li, P and Zhou, C}, title = {Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {39}, number = {5}, pages = {811-820}, doi = {10.1007/s10072-018-3246-0}, pmid = {29349657}, issn = {1590-3478}, support = {ZR2014HM064//the Natural Science Foundation of Shandong Province/ ; 2017YFC0909100//National Key R&amp;D Program of China/ ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Frontotemporal Dementia/enzymology/*genetics ; Genetic Predisposition to Disease ; Humans ; Mutation ; Protein Serine-Threonine Kinases/*genetics ; }, abstract = {Recently, mutations in TBK1 (TANK-binding kinase 1) have been reported to be a cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum, but the relationship between them remains unclear owing to the small sample size and low mutation rate. Therefore, we performed a two-stage meta-analysis to investigate the frequency of TBK1 mutations in ALS/FTD patients and the association between the mutations and risk of ALS/FTD spectrum. In the first stage, 12 studies involving 4173 ALS/FTD patients were included. The frequencies of loss of function (LoF) and missense mutations were 1.0% (95% CI 0.6-1.7%) and 1.8% (95% CI 0.9-3.4%) in ALS/FTD patients respectively. Subgroup analysis suggested a higher prevalence of TBK1 mutations in European patients than that in Asian patients. In the second stage, 7 studies involving 3146 cases and 4856 controls were enrolled. Results showed that TBK1 LoF mutations were associated with a significant increased risk for ALS/FTD spectrum (OR 11.78; 95% CI 4.21-33.00; p < 0.0001), while TBK1 missense mutations were associated with a moderately increased susceptibility for ALS/FTD spectrum (OR 1.62; 95% CI 1.19-2.19; p = 0.002). In conclusion, TBK1 LoF and missense mutations are not frequently found in ALS/FTD patients, and both of them are associated with an increased risk for ALS/FTD spectrum.}, }
@article {pmid29342921, year = {2018}, author = {Mathis, S and Le Masson, G}, title = {RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {6}, number = {1}, pages = {}, pmid = {29342921}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.}, }
@article {pmid29338427, year = {2018}, author = {Battaglia, L and Panciani, PP and Muntoni, E and Capucchio, MT and Biasibetti, E and De Bonis, P and Mioletti, S and Fontanella, M and Swaminathan, S}, title = {Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery.}, journal = {Expert opinion on drug delivery}, volume = {15}, number = {4}, pages = {369-378}, doi = {10.1080/17425247.2018.1429401}, pmid = {29338427}, issn = {1744-7593}, mesh = {Administration, Intranasal ; Animals ; Biological Transport ; Blood-Brain Barrier ; Brain/*metabolism ; Central Nervous System Agents/*administration &amp; dosage ; Drug Delivery Systems/*methods ; Humans ; Lipids/chemistry ; Nanoparticles/*administration &amp; dosage ; Nasal Mucosa/*drug effects/metabolism ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {INTRODUCTION: The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal.<br><br>AREAS COVERED: This review focuses on key brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems.<br><br>EXPERT OPINION: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.}, }
@article {pmid29333317, year = {2017}, author = {Castillo-Gonzalez, JA and Loera-Arias, MJ and Saucedo-Cardenas, O and Montes-de-Oca-Luna, R and Garcia-Garcia, A and Rodriguez-Rocha, H}, title = {Phosphorylated α-Synuclein-Copper Complex Formation in the Pathogenesis of Parkinson's Disease.}, journal = {Parkinson's disease}, volume = {2017}, number = {}, pages = {9164754}, pmid = {29333317}, issn = {2090-8083}, abstract = {Parkinson's disease is the second most important neurodegenerative disorder worldwide. It is characterized by the presence of Lewy bodies, which are mainly composed of α-synuclein and ubiquitin-bound proteins. Both the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway (ALS) are altered in Parkinson's disease, leading to aggregation of proteins, particularly α-synuclein. Interestingly, it has been observed that copper promotes the protein aggregation process. Additionally, phosphorylation of α-synuclein along with copper also affects the protein aggregation process. The interrelation among α-synuclein phosphorylation and its capability to interact with copper, with the subsequent disruption of the protein degradation systems in the neurodegenerative process of Parkinson's disease, will be analyzed in detail in this review.}, }
@article {pmid29331501, year = {2018}, author = {Dervishi, I and Ozdinler, PH}, title = {Incorporating upper motor neuron health in ALS drug discovery.}, journal = {Drug discovery today}, volume = {23}, number = {3}, pages = {696-703}, pmid = {29331501}, issn = {1878-5832}, support = {R21 NS085750/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Drug Discovery/methods ; Humans ; Motor Neurons/*drug effects ; Pharmaceutical Preparations/*administration &amp; dosage/*chemistry ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease, that affects the motor neuron circuitry. After consecutive failures in clinical trials for the past 20 years, edaravone was recently approved as the second drug for ALS. This generated excitement in the field revealed the need to improve preclinical assays for continued success. Here, we focus on the importance and relevance of upper motor neuron (UMN) pathology in ALS, and discuss how incorporation of UMN survival in preclinical assays will improve inclusion criteria for clinical trials and expedite the drug discovery effort in ALS and related motor neuron diseases.}, }
@article {pmid29326544, year = {2017}, author = {Kumar, V and Hasan, GM and Hassan, MI}, title = {Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {711}, pmid = {29326544}, issn = {1662-4548}, abstract = {The most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is intronic hexanucleotide (G4C2) repeat expansions (HRE) in the C9orf72 gene. The non-exclusive pathogenic mechanisms by which C9orf72 repeat expansions contribute to these neurological disorders include loss of C9orf72 function and gain-of-function determined by toxic RNA molecules and dipeptides repeats protein toxicity. The expanded repeats are transcribed bidirectionally and forms RNA foci in the central nervous system, and sequester key RNA-binding proteins (RBPs) leading to impairment in RNA processing events. Many studies report widespread transcriptome changes in ALS carrying a C9orf72 repeat expansion. Here we review the contribution of RNA foci interaction with RBPs as well as transcriptome changes involved in the pathogenesis of C9orf72- associated FTD/ALS. These informations are essential to elucidate the pathology and therapeutic intervention of ALS and/or FTD.}, }
@article {pmid29326542, year = {2017}, author = {Guo, W and Fumagalli, L and Prior, R and Van Den Bosch, L}, title = {Current Advances and Limitations in Modeling ALS/FTD in a Dish Using Induced Pluripotent Stem Cells.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {671}, pmid = {29326542}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs) from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these in vitro models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.}, }
@article {pmid29325606, year = {2018}, author = {Paulson, H}, title = {Repeat expansion diseases.}, journal = {Handbook of clinical neurology}, volume = {147}, number = {}, pages = {105-123}, pmid = {29325606}, issn = {0072-9752}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; R01 NS038712/NS/NINDS NIH HHS/United States ; U01 NS104326/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Nervous System Diseases/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; }, abstract = {More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.}, }
@article {pmid29323772, year = {2018}, author = {Dinkova-Kostova, AT and Kostov, RV and Kazantsev, AG}, title = {The role of Nrf2 signaling in counteracting neurodegenerative diseases.}, journal = {The FEBS journal}, volume = {285}, number = {19}, pages = {3576-3590}, pmid = {29323772}, issn = {1742-4658}, support = {18644/CRUK_/Cancer Research UK/United Kingdom ; C20953/A18644/CRUK_/Cancer Research UK/United Kingdom ; BB/L01923X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; *Molecular Targeted Therapy ; NF-E2-Related Factor 2/antagonists &amp; inhibitors/*metabolism ; Neurodegenerative Diseases/*metabolism/*prevention &amp; control ; Oxidative Stress ; Signal Transduction ; }, abstract = {The transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.}, }
@article {pmid29323501, year = {2018}, author = {Giampietro, R and Spinelli, F and Contino, M and Colabufo, NA}, title = {The Pivotal Role of Copper in Neurodegeneration: A New Strategy for the Therapy of Neurodegenerative Disorders.}, journal = {Molecular pharmaceutics}, volume = {15}, number = {3}, pages = {808-820}, doi = {10.1021/acs.molpharmaceut.7b00841}, pmid = {29323501}, issn = {1543-8392}, mesh = {Animals ; Brain Chemistry/*drug effects ; Chelating Agents/pharmacology/*therapeutic use ; Copper/metabolism/*toxicity ; Copper-Transporting ATPases/genetics/metabolism ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*drug therapy/genetics/metabolism/pathology ; Oxidative Stress/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Copper is an essential trace element for the human body since it is a cofactor of several enzymes and proteins and plays a pivotal role in several biological functions (e.g., respiration, protection from oxidative damage, iron metabolism, etc.), also including the central nervous system development and functioning (e.g., synthesis of neurotransmitters, myelination, activation of neuropeptides, etc.). Therefore, copper dysmetabolism is associated with different toxic effects, mainly represented by oxidative stress, and it has been reported in many neurodegenerative disorders, such as Wilson's disease, Menkes disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This paper shows a detailed report of how copper is involved in the pathophysiology of these diseases. Moreover, a hint on novel therapeutic approaches based on restoring copper homeostasis through metal chelators will be pointed out.}, }
@article {pmid29322304, year = {2018}, author = {Maurel, C and Dangoumau, A and Marouillat, S and Brulard, C and Chami, A and Hergesheimer, R and Corcia, P and Blasco, H and Andres, CR and Vourc'h, P}, title = {Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {55}, number = {8}, pages = {6480-6499}, pmid = {29322304}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Autophagy/genetics ; *Genetic Predisposition to Disease ; Humans ; Nerve Degeneration/*genetics ; *Proteolysis ; Proteostasis/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease caused by the degeneration of motor neurons (MNs) leading to progressive muscle weakness and atrophy. Several molecular pathways have been implicated, such as glutamate-mediated excitotoxicity, defects in cytoskeletal dynamics and axonal transport, disruption of RNA metabolism, and impairments in proteostasis. ALS is associated with protein accumulation in the cytoplasm of cells undergoing neurodegeneration, which is a hallmark of the disease. In this review, we focus on mechanisms of proteostasis, particularly protein degradation, and discuss how they are related to the genetics of ALS. Indeed, the genetic bases of the disease with the implication of more than 30 genes associated with familial ALS to date, together with the important increase in understanding of endoplasmic reticulum (ER) stress, proteasomal degradation, and autophagy, allow researchers to better understand the mechanisms underlying the selective death of motor neurons in ALS. It is clear that defects in proteostasis are involved in this type of cellular degeneration, but whether or not these mechanisms are primary causes or merely consequential remains to be clearly demonstrated. Novel cellular and animal models allowing chronic expression of mutant proteins, for example, are required. Further studies linking genetic discoveries in ALS to mechanisms of protein clearance will certainly be crucial in order to accelerate translational and clinical research towards new therapeutic targets and strategies.}, }
@article {pmid29318974, year = {2018}, author = {Merelli, A and Rodríguez, JCG and Folch, J and Regueiro, MR and Camins, A and Lazarowski, A}, title = {Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities.}, journal = {Current neuropharmacology}, volume = {16}, number = {10}, pages = {1484-1498}, pmid = {29318974}, issn = {1875-6190}, mesh = {Animals ; Brain/metabolism ; Cell Hypoxia/physiology ; *Drug Discovery ; Erythropoietin/pharmacology/therapeutic use ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*physiology ; Iron/metabolism ; Iron Chelating Agents/*pharmacology/therapeutic use ; Neurodegenerative Diseases/*drug therapy/*physiopathology ; }, abstract = {Neurodegeneration (NDG) is linked with the progressive loss of neural function with intellectual and/or motor impairment. Several diseases affecting older individuals, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, stroke, Multiple Sclerosis and many others, are the most relevant disorders associated with NDG. Since other pathologies such as refractory epilepsy, brain infections, or hereditary diseases such as "neurodegeneration with brain iron accumulation", also lead to chronic brain inflammation with loss of neural cells, NDG can be said to affect all ages. Owing to an energy and/or oxygen supply imbalance, different signaling mechanisms including MAPK/PI3K-Akt signaling pathways, glutamatergic synapse formation, and/or translocation of phosphatidylserine, might activate some central executing mechanism common to all these pathologies and also related to oxidative stress. Hypoxia inducible factor 1-α (HIF-1α) plays a twofold role through gene activation, in the sense that this factor has to "choose" whether to protect or to kill the affected cells. Most of the afore-mentioned processes follow a protracted course and are accompanied by progressive iron accumulation in the brain. We hypothesize that the neuroprotective effects of iron chelators are acting against the generation of free radicals derived from iron, and also induce sufficient -but not excessive- activation of HIF-1α, so that only the hypoxia-rescue genes will be activated. In this regard, the expression of the erythropoietin receptor in hypoxic/inflammatory neurons could be the cellular "sign" to act upon by the nasal administration of pharmacological doses of Neuro-EPO, inducing not only neuroprotection, but eventually, neurorepair as well.}, }
@article {pmid29317338, year = {2018}, author = {Gorshkov, K and Aguisanda, F and Thorne, N and Zheng, W}, title = {Astrocytes as targets for drug discovery.}, journal = {Drug discovery today}, volume = {23}, number = {3}, pages = {673-680}, pmid = {29317338}, issn = {1878-5832}, support = {ZIA TR000018-02//Intramural NIH HHS/United States ; ZIA TR000269-01//Intramural NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*drug effects ; Drug Discovery/methods ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neurons/drug effects ; Pharmaceutical Preparations/*administration &amp; dosage ; }, abstract = {Recent studies have illuminated the crucial role of astrocytes in maintaining proper neuronal health and function. Abnormalities in astrocytic functions have now been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Historically, drug development programs for neurodegenerative diseases generally target only neurons, overlooking the contributions of astrocytes. Therefore, targeting both disease neurons and astrocytes offers a new approach for drug development for the treatment of neurological diseases. Looking forward, the co-culturing of human neurons with astrocytes could be the next evolutionary step in drug discovery for neurodegenerative diseases.}, }
@article {pmid29316850, year = {2018}, author = {Ramanathan, RS and Rana, S}, title = {Demographics and clinical characteristics of primary lateral sclerosis: case series and a review of literature.}, journal = {Neurodegenerative disease management}, volume = {8}, number = {1}, pages = {17-23}, doi = {10.2217/nmt-2017-0051}, pmid = {29316850}, issn = {1758-2032}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/classification/diagnosis/*epidemiology/therapy ; Retrospective Studies ; }, abstract = {AIM: Primary lateral sclerosis (PLS) is a form of motor neuron disease involving only upper motor neurons. In some patients presenting as PLS, the disease progresses to involve lower motor neurons and thereby converting to amyotrophic lateral sclerosis (ALS). However, pure forms of PLS do exist. Our aim was to study epidemiological and clinical characteristics of pure PLS patients treated at our neuromuscular clinic.<br><br>METHODS: We retrospectively reviewed 15 patients from July 2011 to October 2014 with PLS treated at the neuromuscular disorder clinic at our hospital. Data collection included patient demographics, age and site of onset, duration of symptoms and&#xa0;duration of follow-up. We also studied clinical features such as bulbar involvement; pseudobulbar affect; depression; spasms/pain; bladder involvement; diagnostic work up, in other words, MRI; brain/electromyography&#xa0;findings;&#xa0;clinical course, namely years to wheelchair; and need for gastrostomy tube requirement baclofen pump placement. We also tried to find a correlation between PLS and environmental factors such as urban/suburban/rural living, consumption of well water, socioeconomic status/occupation and history of trauma.<br><br>RESULTS: Male-to-female ratio was 1:2, mean age at onset of symptoms was&#xa0;58.6&#xa0;years, with the oldest patient being an 84-year-old female at the time of onset of symptoms. Mean duration of follow-up was 51&#xa0;months. Mean duration of symptoms was 77.4&#xa0;months. About eight (53%) patients presented with bulbar symptoms in the form of spastic speech and dysphagia, pseudobulbar affect, developed depression&#xa0;and had bladder involvement. Seven (47%) patients presented with symmetric spasticity in the extremities. A third of the&#xa0;patients required baclofen for spasticity and a third required gastrostomy tube placement for dysphagia. None of them had abnormal neuroimaging or electrodiagnostic testing. Only one patient had history of trauma. About half of the patients were from lower socioeconomic status as well as middle class. One of the patients had consumed well water during younger years and three (20%) patients lived in the rural area.<br><br>CONCLUSION: Though on review of literature there is no clear consensus about the existence of PLS as a distinct disease entity, we believe that there are rare cases of motor neuron disease with progressive upper motor neuron symptoms that throughout their course never convert to ALS. Our series highlights the demographic and&#xa0;clinical features of these patients and underscores the longer survival of these patients when compared with ALS.}, }
@article {pmid29316798, year = {2018}, author = {Desai, S and Juncker, M and Kim, C}, title = {Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {243}, number = {6}, pages = {554-562}, pmid = {29316798}, issn = {1535-3699}, support = {R21 NS060960/NS/NINDS NIH HHS/United States ; }, mesh = {Cytokines/metabolism ; Humans ; *Mitophagy ; Neurodegenerative Diseases/*physiopathology ; Proteasome Endopeptidase Complex/*metabolism ; Protein Aggregation, Pathological ; Ubiquitin/*metabolism ; Ubiquitins/metabolism ; }, abstract = {Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.}, }
@article {pmid29314683, year = {2018}, author = {Wilk, M and Zelger, BG and Hauser, U and Höpfl, R and Zelger, B}, title = {Erosive pustulöse Dermatose der Kopfhaut: Neubewertung einer zu wenig beachteten Entität.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {16}, number = {1}, pages = {15-20}, doi = {10.1111/ddg.13387_g}, pmid = {29314683}, issn = {1610-0387}, abstract = {Die erosive pustulöse Dermatose der Kopfhaut (EPDK) ist eine entzündliche Erkrankung unbekannter Ätiologie. Wir besprechen die EPDK und präsentieren unsere eigene klinische und histopathologische Erfahrung von elf Patienten. Die EPDK neigt dazu, spontan die kahle Kopfhaut älterer Patienten zu befallen. Anamnestisch wird häufig - so auch bei vier unserer Patienten - eine vorausgegangene Operation an selbiger Stelle angegeben. Koronare Herzerkrankung, cerebraler Insult, arterieller Hypertonus, Diabetes mellitus und ernste Krebserkrankungen wurden ebenfalls häufig als Komorbidität diagnostiziert. Die meisten Patienten zeigen trotz antiinflammatorischer Lokaltherapie einen schwankenden klinischen Verlauf, bei einigen heilt die Läsion unter Narbenbildung ab. Histopathologisch findet sich eine Kruste oder Erosion mit Granulationsgewebe-ähnlichen Veränderungen im Korium mit späterer Entstehung einer Narbe. Neben einer lokalen und aktinischen Schädigung könnten eine eingeschränkte Immunität und Mikrozirkulation prädisponierende Faktoren der Erkrankung sein. Analog zum Pyoderma gangraenosum muss die EPDK bei nichtheilenden Wunden älterer Patienten bedacht werden, nachdem die Differenzialdiagnosen, die diese Erkrankung simulieren, ausgeschlossen wurden. Da vorausgegangene oder benachbarte Basalzell- und insbesondere Plattenepithelkarzinome häufig sind und infiltrative Varianten jenseits des klinisch sichtbaren Krankheitsprozesses vorkommen, kann im Zweifelsfall eine sogenannte histologische Kartierung der umgebenden Haut ratsam sein.}, }
@article {pmid29313812, year = {2018}, author = {Bowerman, M and Murray, LM and Scamps, F and Schneider, BL and Kothary, R and Raoul, C}, title = {Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development.}, journal = {European journal of medical genetics}, volume = {61}, number = {11}, pages = {685-698}, doi = {10.1016/j.ejmg.2017.12.001}, pmid = {29313812}, issn = {1878-0849}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/therapy ; Animals ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Humans ; Mice ; Motor Neurons/*pathology ; Muscular Atrophy, Spinal/*genetics/pathology/therapy ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Survival of Motor Neuron 1 Protein/*genetics ; }, abstract = {Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72). However, it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadic ALS. Beyond genetic interactions, accumulating evidence further suggests that both diseases share common pathological identities such as intrinsic muscle defects, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuron excitability and selective motoneuron vulnerability. Identifying common molecular effectors that mediate shared pathologies in SMA and ALS would allow for the development of therapeutic strategies and targeted gene therapies that could potentially alleviate symptoms and be equally beneficial in both disorders. In the present review, we will examine our current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases.}, }
@article {pmid29312938, year = {2017}, author = {Gonzalez, DM and Gregory, J and Brennand, KJ}, title = {The Importance of Non-neuronal Cell Types in hiPSC-Based Disease Modeling and Drug Screening.}, journal = {Frontiers in cell and developmental biology}, volume = {5}, number = {}, pages = {117}, pmid = {29312938}, issn = {2296-634X}, support = {R01 MH101454/MH/NIMH NIH HHS/United States ; T32 GM007280/GM/NIGMS NIH HHS/United States ; }, abstract = {Current applications of human induced pluripotent stem cell (hiPSC) technologies in patient-specific models of neurodegenerative and neuropsychiatric disorders tend to focus on neuronal phenotypes. Here, we review recent efforts toward advancing hiPSCs toward non-neuronal cell types of the central nervous system (CNS) and highlight their potential use for the development of more complex in vitro models of neurodevelopment and disease. We present evidence from previous works in both rodents and humans of the importance of these cell types (oligodendrocytes, microglia, astrocytes) in neurological disease and highlight new hiPSC-based models that have sought to explore these relationships in vitro. Lastly, we summarize efforts toward conducting high-throughput screening experiments with hiPSCs and propose methods by which new screening platforms could be designed to better capture complex relationships between neural cell populations in health and disease.}, }
@article {pmid29312526, year = {2017}, author = {Maguire, G}, title = {Amyotrophic lateral sclerosis as a protein level, non-genomic disease: Therapy with S2RM exosome released molecules.}, journal = {World journal of stem cells}, volume = {9}, number = {11}, pages = {187-202}, pmid = {29312526}, issn = {1948-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that leads to death. No effective treatments are currently available. Based on data from epidemiological, etiological, laboratory, and clinical studies, I offer a new way of thinking about ALS and its treatment. This paper describes a host of extrinsic factors, including the exposome, that disrupt the extracellular matrix and protein function such that a spreading, prion-like disease leads to neurodegeneration in the motor tracts. A treatment regimen is described using the stem cell released molecules from a number of types of adult stem cells to provide tissue dependent molecules that restore homeostasis, including proteostasis, in the ALS patient. Because stem cells themselves as a therapeutic are cumbersome and expensive, and when implanted in a host cause aging of the host tissue and often fail to engraft or remain viable, only the S2RM molecules are used. Rebuilding of the extracellular matrix and repair of the dysfunctional proteins in the ALS patient ensues.}, }
@article {pmid29310658, year = {2018}, author = {Shih, YT and Hsueh, YP}, title = {The involvement of endoplasmic reticulum formation and protein synthesis efficiency in VCP- and ATL1-related neurological disorders.}, journal = {Journal of biomedical science}, volume = {25}, number = {1}, pages = {2}, pmid = {29310658}, issn = {1423-0127}, support = {MOST 106-2321-B-001-019//Ministry of Science and Technology, Taiwan/ ; MOST 105-2311-B-001-061-MY3//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Endoplasmic Reticulum/*metabolism ; GTP-Binding Proteins/*genetics/metabolism ; Humans ; Membrane Proteins/*genetics/metabolism ; Nervous System Diseases/*genetics/physiopathology ; Protein Biosynthesis ; Valosin Containing Protein/*genetics/metabolism ; }, abstract = {The endoplasmic reticulum (ER) is the biggest organelle in cells and is involved in versatile cellular processes. Formation and maintenance of ER morphology are regulated by a series of proteins controlling membrane fusion and curvature. At least six different ER morphology regulators have been demonstrated to be involved in neurological disorders-including Valosin-containing protein (VCP), Atlastin-1 (ATL1), Spastin (SPAST), Reticulon 2 (RTN2), Receptor expression enhancing protein 1 (REEP1) and RAB10-suggesting a critical role of ER formation in neuronal activity and function. Among these genes, mutations in VCP gene involve in inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), familial amyotrophic lateral sclerosis (ALS), autism spectrum disorders (ASD), and hereditary spastic paraplegia (HSP). ATL1 is also one of causative genes of HSP. RAB10 is associated with Parkinson's disease (PD). A recent study showed that VCP and ATL1 work together to regulate dendritic spine formation by controlling ER formation and consequent protein synthesis efficiency. RAB10 shares the same function with VCP and ATL1 to control ER formation and protein synthesis efficiency but acts independently. Increased protein synthesis by adding extra leucine to cultured neurons ameliorated dendritic spine deficits caused by VCP and ATL1 deficiencies, strengthening the significance of protein synthesis in VCP- and ATL1-regulated dendritic spine formation. These findings provide new insight into the roles of ER and protein synthesis in controlling dendritic spine formation and suggest a potential etiology of neurodegenerative disorders caused by mutations in VCP, ATL1 and other genes encoding proteins regulating ER formation and morphogenesis.}, }
@article {pmid29305855, year = {2018}, author = {Trotta, T and Panaro, MA and Cianciulli, A and Mori, G and Di Benedetto, A and Porro, C}, title = {Microglia-derived extracellular vesicles in Alzheimer's Disease: A double-edged sword.}, journal = {Biochemical pharmacology}, volume = {148}, number = {}, pages = {184-192}, doi = {10.1016/j.bcp.2017.12.020}, pmid = {29305855}, issn = {1873-2968}, mesh = {Alzheimer Disease/*pathology ; Brain/pathology ; Extracellular Vesicles/*pathology ; Humans ; Microglia/*pathology ; }, abstract = {Extracellular vesicles (EVs), based on their origin or size, can be classified as apoptotic bodies, microvesicles (MVs)/microparticles (MPs), and exosomes. EVs are one of the new emerging modes of communication between cells that are providing new insights into the pathophysiology of several diseases. EVs released from activated or apoptotic cells contain specific proteins (signaling molecules, receptors, integrins, cytokines), bioactive lipids, nucleic acids (mRNA, miRNA, small non coding RNAs, DNA) from their progenitor cells. In the brain, EVs contribute to intercellular communication through their basal release and uptake by surrounding cells, or release into the cerebrospinal fluid (CSF) and blood. In the central nervous system (CNS), EVs have been suggested as potential carriers in the intercellular delivery of misfolded proteins associated to neurodegenerative disorders, such as tau and amyloid β in Alzheimer's Disease (AD), α-synuclein in Parkinson's Disease (PD), superoxide dismutase (SOD)1 in amyotrophic lateral sclerosis and huntingtin in Huntington's Disease. Multiple studies indicate that EVs are involved in the pathogenesis of AD, although their role has not been completely elucidated. The focus of this review is to analyze the new emerging role of EVs in AD progression, paying particular attention to microglia EVs. Recent data show that microglia are the first myeloid cells to be activated during neuroinflammation. Microglial EVs in fact, could have both a beneficial and a detrimental action in AD. The study of EVs may provide specific, precise information regarding the AD transition stage that may offer possibilities to intervene in order to retain cognition. In chronic neurodegenerative diseases EVs could be a novel biomarker to monitor the progression of the pathology and also represent a new therapeutical approach to CNS diseases.}, }
@article {pmid29303786, year = {2018}, author = {Vallée, A and Lecarpentier, Y and Guillevin, R and Vallée, JN}, title = {Aerobic glycolysis in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {Reviews in the neurosciences}, volume = {29}, number = {5}, pages = {547-555}, doi = {10.1515/revneuro-2017-0075}, pmid = {29303786}, issn = {2191-0200}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Cell Death/*physiology ; Glucose/metabolism ; Glycolysis/*physiology ; Humans ; Huntington Disease/*therapy ; Monocarboxylic Acid Transporters/metabolism ; }, abstract = {Neurodegenerative cells are the sites of numerous metabolic and energetic abnormalities with abnormalities in energy production. Energy is the primary determinant of neuronal viability. In neurodegenerative cells, metabolic enzymes are modified by the dysregulation of the canonical WNT/β-catenin pathway. In amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), WNT/β-catenin pathway is upregulated. We focused this review on the hypothesis of aerobic glycolysis stimulated by the upregulation of WNT/β-catenin pathway in ALS and HD. Upregulation of WNT/β-catenin pathway induces aerobic glycolysis, named Warburg effect, through activation of glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactate dehydrogenase kinase-A (LDH-A), and inactivation of pyruvate dehydrogenase complex (PDH). Aerobic glycolysis consists of a supply of a large part of glucose into lactate regardless of oxygen. Aerobic glycolysis is less efficient in terms of ATP production compared with oxidative phosphorylation because of the shunt of the TCA cycle. Dysregulation of energetic metabolism promotes cell death and disease progression in ALD and HD. Aerobic glycolysis regulation is an attractive mechanism for developing therapeutic interventions.}, }
@article {pmid29303785, year = {2018}, author = {Taalab, YM and Ibrahim, N and Maher, A and Hassan, M and Mohamed, W and Moustafa, AA and Salama, M and Johar, D and Bernstein, L}, title = {Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK).}, journal = {Reviews in the neurosciences}, volume = {29}, number = {4}, pages = {387-415}, doi = {10.1515/revneuro-2017-0071}, pmid = {29303785}, issn = {2191-0200}, mesh = {Animals ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Signal Transduction ; Ubiquitination/*physiology ; Unfolded Protein Response ; eIF-2 Kinase/*metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences from in vitro and in vivo disease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.}, }
@article {pmid29297656, year = {2017}, author = {Demler, TL}, title = {Introduction to pseudobulbar affect: setting the stage for recognition and familiarity with this challenging disorder.}, journal = {The American journal of managed care}, volume = {23}, number = {18 Suppl}, pages = {S339-S344}, pmid = {29297656}, issn = {1936-2692}, mesh = {Alzheimer Disease/*complications/diagnosis/therapy ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/therapy ; Female ; Humans ; Male ; Middle Aged ; Nervous System Diseases/complications/epidemiology ; Parkinson Disease/*complications/diagnosis/therapy ; Prevalence ; Pseudobulbar Palsy/*diagnosis/etiology/psychology/*therapy ; Quality of Life ; Risk Assessment ; Severity of Illness Index ; United States ; }, abstract = {Pseudobulbar affect (PBA), despite its prevalence and distinctive symptoms, is widely underrecognized and undertreated. It is characterized by uncontrollable laughing or crying that can occur in an exaggerated manner or inappropriately to a given situation or stimuli. PBA is thought to center around preexisting neurological conditions, which include Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer disease, traumatic brain injury, and stroke. The PBA Registry Series trial was created to measure the prevalence of PBA among patients with these underlying neurological conditions. Through greater awareness, recognition, and diagnosis, treatment for patients with PBA can be improved.}, }
@article {pmid29293261, year = {2018}, author = {Gibbons, C and Pagnini, F and Friede, T and Young, CA}, title = {Treatment of fatigue in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {1}, pages = {CD011005}, pmid = {29293261}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Benzhydryl Compounds/*therapeutic use ; Breathing Exercises/*methods ; Fatigue/etiology/*therapy ; Humans ; Modafinil ; Randomized Controlled Trials as Topic ; Resistance Training/*methods ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is terminal, progressive neurological condition for which there are no curative treatments. Among people with ALS/MND, fatigue is a common and debilitating symptom, which is characterised by reversible motor weakness and whole-body tiredness that is only partially relieved by rest. The effectiveness of pharmacological or non-pharmacological treatments for fatigue in ALS/MND is not yet established.<br><br>OBJECTIVES: To assess the effects of pharmacological and non-pharmacological interventions for fatigue in ALS/MND.<br><br>SEARCH METHODS: We searched the following databases on 5 September 2017: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL Plus, and ERIC. We also searched two clinical trials registries.<br><br>SELECTION CRITERIA: We selected randomised and quasi-randomised controlled trials of any intervention which sought to reduce fatigue for people with ALS/MND. We included studies if reduction in fatigue was a primary or secondary outcome of the trial.<br><br>DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane.<br><br>MAIN RESULTS: We included one pharmacological (modafinil) study and three non-pharmacological studies (resistance exercise, respiratory exercise, and repetitive transcranial magnetic stimulation (rTMS)), involving a total of 86 participants with ALS/MND. None of the included studies were free from risk of bias. Since there was only one trial for each intervention, no meta-analysis was possible. All studies assessed fatigue using the Fatigue Severity Scale (FSS; scale from 9 to 63, higher scores indicate more fatigue). Information for assessing bias was often lacking in study reports, making the risk of bias unclear across several domains in all trials. Blinding of participants was not possible in exercise trials, but the outcome assessment was blinded.We found very low-quality evidence suggesting possible improvements in fatigue for modafinil treatment versus placebo (MD -11.00, 95% CI -23.08 to 1.08), respiratory exercise versus a sham intervention (MD -9.65, 95% CI -22.04 to 2.73), and rTMS versus sham rTMS (data not provided), which warrant further investigation to clarify the efficacy of these treatments for fatigue in ALS/MND. We found no clear improvements in fatigue for resistance exercise versus usual care (MD 0.20, 95% CI -10.98 to 11.38; very low-quality evidence).Three participants in the modafinil group dropped out of the modafinil study, two citing issues with headache and one with chest tightness; other adverse effects were anxiety, nausea, dizziness, and sialorrhoea (probably ALS-related). The trials reported no adverse effects of exercise or rTMS.We cannot be certain about the effects of any of the interventions studied because of imprecision (small numbers of participants, wide CI), and possible study limitations.<br><br>AUTHORS' CONCLUSIONS: It is impossible to draw firm conclusions about the effectiveness of interventions to improve fatigue for people with ALS/MND as there are few randomised studies, and the quality of available evidence is very low.}, }
@article {pmid29282133, year = {2017}, author = {Deng, Z and Sheehan, P and Chen, S and Yue, Z}, title = {Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease?.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {90}, pmid = {29282133}, issn = {1750-1326}, support = {P50 NS094733/NS/NINDS NIH HHS/United States ; R01 NS060123/NS/NINDS NIH HHS/United States ; R01NS060123/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/*genetics/*metabolism ; Animals ; *Autophagy ; Cell Cycle Proteins ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/etiology/*genetics/*metabolism ; Humans ; Membrane Transport Proteins ; Mutation ; Protein Serine-Threonine Kinases/metabolism ; Sequestosome-1 Protein/metabolism ; Transcription Factor TFIIIA/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that share genetic risk factors and pathological hallmarks. Intriguingly, these shared factors result in a high rate of comorbidity of these diseases in patients. Intracellular protein aggregates are a common pathological hallmark of both diseases. Emerging evidence suggests that impaired RNA processing and disrupted protein homeostasis are two major pathogenic pathways for these diseases. Indeed, recent evidence from genetic and cellular studies of the etiology and pathogenesis of ALS-FTD has suggested that defects in autophagy may underlie various aspects of these diseases. In this review, we discuss the link between genetic mutations, autophagy dysfunction, and the pathogenesis of ALS-FTD. Although dysfunction in a variety of cellular pathways can lead to these diseases, we provide evidence that ALS-FTD is, in many cases, an autophagy disease.}, }
@article {pmid29280739, year = {2017}, author = {Fujimoto, M and Hwa, V and Dauber, A}, title = {Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2.}, journal = {Journal of clinical research in pediatric endocrinology}, volume = {9}, number = {Suppl 2}, pages = {1-8}, pmid = {29280739}, issn = {1308-5735}, support = {R01 HD078592/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Body Height/*physiology ; Glycoproteins/*metabolism ; Human Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor I/*metabolism ; Intercellular Signaling Peptides and Proteins/*metabolism ; Pregnancy-Associated Plasma Protein-A/*metabolism ; }, abstract = {Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease.}, }
@article {pmid29271898, year = {2017}, author = {Delcourt, N and Claudepierre, T and Maignien, T and Arnich, N and Mattei, C}, title = {Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy.}, journal = {Toxins}, volume = {10}, number = {1}, pages = {}, pmid = {29271898}, issn = {2072-6651}, mesh = {Amino Acids, Diamino/*metabolism ; Animals ; Cyanobacteria Toxins ; Humans ; Melanins/metabolism ; Neurodegenerative Diseases/*metabolism ; Receptors, Glutamate/metabolism ; }, abstract = {The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA) in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS) and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA-induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes.}, }
@article {pmid29270111, year = {2017}, author = {Tosolini, AP and Sleigh, JN}, title = {Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {405}, pmid = {29270111}, issn = {1662-5099}, support = {//Wellcome Trust/United Kingdom ; }, abstract = {Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.}, }
@article {pmid29269170, year = {2018}, author = {Gspörer, I and Schrems, BM}, title = {[Transparency and replicability of nursing intervention studies in long-term care: A selective literature review].}, journal = {Zeitschrift fur Evidenz, Fortbildung und Qualitat im Gesundheitswesen}, volume = {133}, number = {}, pages = {1-8}, doi = {10.1016/j.zefq.2017.11.006}, pmid = {29269170}, issn = {2212-0289}, mesh = {*Biomedical Research ; Checklist ; Clinical Trials as Topic/standards ; *Delivery of Health Care ; Germany ; Humans ; *Long-Term Care/standards ; Reproducibility of Results ; Research Design/standards ; Research Report/standards ; }, abstract = {BACKGROUND AND OBJECTIVE: The development and evaluation of interventions in long-term care is time-consuming and expensive due to their complexity. To ensure reproducibility and successful implementation, these interventions must be described and published in a comprehensible and qualitative manner. The aim of this study is to analyze intervention studies from the inpatient long-term care setting with regard to their completeness, reporting quality, transparency and thus reproducibility.<br><br>METHOD: The completeness and the reporting quality of the interventions described in the publications were examined in the context of a selective literature review by means of intervention studies from the long-term care setting (n=22). To this end, the Template for Intervention Description and Replication (TIDieR) checklist and the Criteria for Reporting the Development and Evaluation of Complex Interventions in Healthcare 2 (CReDECI2-DE) list were used. Transparency criteria included study registration and access to study protocols.<br><br>RESULTS: The TIDieR checklist examination revealed that only three studies contained all the information necessary; the CReDECI2 test provided a complete description for only one study. Frequent shortcomings were observed concerning the information on modifications and titrations for the study participants and the location. Protocols were available for eight studies, 14 studies were registered.<br><br>CONCLUSIONS: In terms of science, this means that the reproducibility of scientific findings is limited, which is why they cannot provide secure knowledge. As a result, the practical benefit to be derived from published studies that are accessible to decision-makers is limited as well. As far as publishers are concerned they should pay more attention to the completeness, registration and availability of materials.}, }
@article {pmid29261511, year = {2018}, author = {Yusuf, M and Khan, M and Robaian, MA and Khan, RA}, title = {Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders.}, journal = {Biological chemistry}, volume = {399}, number = {4}, pages = {305-319}, doi = {10.1515/hsz-2017-0250}, pmid = {29261511}, issn = {1437-4315}, mesh = {Animals ; Apoptosis ; Brain/metabolism/pathology ; Humans ; Mitochondria/metabolism ; Nervous System Diseases/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurological diseases like Alzheimer's disease, epilepsy, parkinsonism, depression, Huntington's disease and amyotrophic lateral sclerosis prevailing globally are considered to be deeply influenced by oxidative stress-based changes in the biochemical settings of the organs. The excess oxygen concentration triggers the production of reactive oxygen species, and even the intrinsic antioxidant enzyme system, i.e. SOD, CAT and GSHPx, fails to manage their levels and keep them under desirable limits. This consequently leads to oxidation of protein, lipids and nucleic acids in the brain resulting in apoptosis, proteopathy, proteasomes and mitochondrion dysfunction, glial cell activation as well as neuroinflammation. The present exploration deals with the evidence-based mechanism of oxidative stress towards development of key neurological diseases along with the involved biomechanistics and biomaterials.}, }
@article {pmid29249625, year = {2018}, author = {Domené, HM and Fierro-Carrión, G}, title = {Genetic disorders of GH action pathway.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {38}, number = {}, pages = {19-23}, doi = {10.1016/j.ghir.2017.12.004}, pmid = {29249625}, issn = {1532-2238}, mesh = {*Genetic Markers ; Growth Disorders/*diagnosis/*genetics/metabolism ; Human Growth Hormone/*deficiency ; Humans ; *Signal Transduction ; }, abstract = {While insensitivity to GH (GHI) is characterized by low IGF-I levels, normal or elevated GH levels, and lack of IGF-I response to GH treatment, IGF-I resistance is characterized by elevated IGF-I levels with normal/high GH levels. Several genetic defects are responsible for impairment of GH and IGF-I actions resulting in short stature that could affect intrauterine growth or be present in the postnatal period. The genetic defects affecting GH and/or IGF-I action can be divided into five different groups: GH insensitivity by defects affecting the GH receptor (GHR), the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), the synthesis of insulin-like growth factors (IGF1, IGF2), the transport/bioavailability of IGFs (IGFALS, PAPPA2), and defects affecting IGF-I sensitivity (IGF1R). Complete GH insensitivity (GHI) was first reported by Zvi Laron and his colleagues in patients with classical appearance of GH deficiency, but presenting elevated levels of GH. The association of GH insensitivity with several clinical sings of immune-dysfunction and autoimmune dysregulation are characteristic of molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1). Gene mutations in the IGF1 and IGF2 genes have been described in patients presenting intrauterine growth retardation and postnatal short stature. Molecular defects have also been reported in the IGFALS gene, that encodes the acid-labile subunit (ALS), responsible to stabilize circulating IGF-I in ternary complexes, and more recently in the PAPPA2 gen that encodes the pregnancy-associated plasma protein-A2, a protease that specifically cleaves IGFBP-3 and IGFBP-5 regulating the accessibility of IGFs to their target tissues. Mutations in the IGF1R gene resulted in IGF-I insensitivity in patients with impaired intrauterine and postnatal growth. These studies have revealed novel molecular mechanisms of GH insensitivity/primary IGF-I deficiency beyond the GH receptor gene. In addition, they have also underlined the importance of several players of the GH-IGF axis in the complex system that promotes human growth.}, }
@article {pmid29249183, year = {2018}, author = {Hardcastle, N and Boulis, NM and Federici, T}, title = {AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials.}, journal = {Expert opinion on biological therapy}, volume = {18}, number = {3}, pages = {293-307}, doi = {10.1080/14712598.2018.1416089}, pmid = {29249183}, issn = {1744-7682}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/genetics ; Dependovirus/*genetics ; Genetic Therapy/methods ; Genetic Vectors/genetics/metabolism ; Giant Axonal Neuropathy/*therapy ; Humans ; Muscular Atrophy, Spinal/*therapy ; RNA, Small Interfering/genetics ; Spinal Cord/*metabolism ; }, abstract = {INTRODUCTION: Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway.<br><br>AREAS COVERED: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed.<br><br>EXPERT OPINION: Intravenous (IV) and intrathecal (IT) deliveries seem to undoubtedly be the preferred routes of administration for diffuse spinal cord delivery of therapeutic AAV vectors that can cross the blood-brain barrier (BBB) and correct inherited genetic disorders. Conversely, intraparenchymal delivery is still an undervalued but very viable approach for segmental therapy in afflictions such as ALS or Pompe Disease as a means to prevent respiratory dysfunction.}, }
@article {pmid29241710, year = {2018}, author = {Recabarren-Leiva, D and Alarcón, M}, title = {New insights into the gene expression associated to amyotrophic lateral sclerosis.}, journal = {Life sciences}, volume = {193}, number = {}, pages = {110-123}, doi = {10.1016/j.lfs.2017.12.016}, pmid = {29241710}, issn = {1879-0631}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*metabolism ; Biomarkers ; Disease Progression ; Gene Expression/genetics ; Gene Expression Profiling ; Gene Ontology ; Humans ; MicroRNAs/genetics ; Motor Cortex/physiology ; Neurodegenerative Diseases/genetics/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction ; Spinal Cord/physiology ; Transcriptome/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent neuromuscular disease worldwide. It is a lethal and progressive neurodegenerative disease, principally affecting motor neurons; patient clinical characteristics are muscle weakness, dysphagia and respiratory failure. The mean age is related to family history (40years, familial ALS or FALS) or with no family history (50years), but it is more common in people aged 60-69years. The cause of ALS is not known and it is not known yet why it affects some people and not others. However expert consensus is that molecular alterations in different cells are involved in the development and progression of the disease. For example, motor neuron death is caused by a variety of cellular defects, including the processing of RNA molecules, water channels, and calcium levels, increasing evidence that these alterations of cells in the nervous system play an important role in ALS. Here we will systematically examine different genes (AQP1, SLC14A1, MT1X, DSCR1L1, PCP4, UCHL1, GABRA1, EGR1, OLFM1 and VSNL1) that are "up or down" regulated in the motor cortex and spinal cord and their association with ALS risk. These could be novel biomarkers associated with ALS risk. We built an interaction Network with Cytoscape, this was used to identify pathways, miRNA and drugs associated to ALS. The most important affected pathway is PI3K-Akt signaling. Thirteen microRNAs (miRNA-19B1, miRNA-107, miRNA-124-1, miRNA-124-2, miRNA-9-2, miRNA-29A, miRNA-9-3, miRNA-328, miRNA-19B2, miRNA-29B2, miRNA-124-3, miRNA-15A and miRNA-9-1) and four drugs (Estradiol, Acetaminophen, Progesterone and resveratrol) for new possible treatments were identified.}, }
@article {pmid29238946, year = {2017}, author = {Banaszak-Ziemska, M and Niedziela, M}, title = {PAPP-A2 a new key regulator of growth.}, journal = {Endokrynologia Polska}, volume = {68}, number = {6}, pages = {682-691}, doi = {10.5603/EP.a2017.0060}, pmid = {29238946}, issn = {2299-8306}, mesh = {Animals ; Female ; Growth/*genetics ; Growth Hormone ; Humans ; Insulin-Like Growth Factor I ; Male ; Mice ; *Mutation ; Pregnancy-Associated Plasma Protein-A/metabolism/*physiology ; }, abstract = {Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this is still one of the most common causes of reports to the endocrine clinic and hospitalisation in the endocrine department. A properly functioning growth hormone/insulin-like growth factor (GH/IGF) axis is one of the most important factors in proper growth. A lot of genetic defects in this axis lead to syndromes marked by impaired growth, like Laron syndrome, muta-tions in the STAT5B, insulin-like growth factor 1 (IGF1), and insulin-like growth factor 1 receptor (IGF1R) and mutations in the acid labile subunit (ALS). Two proteases important for the proper functioning of the GH/IGF axis: pregnancy-associated plasma protein-A (PAPP-A) and pregnancy-associated plasma protein-A2 (PAPP-A2), have been described. The first description of the new syndrome of growth failure associated with mutation in the PAPP-A2 gene was given by Andrew Dauber et al. This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth.}, }
@article {pmid29238910, year = {2018}, author = {Saifee, TA and Macerollo, A}, title = {Jaw clonus in motor neuron disease: an interesting case and review of literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {39}, number = {5}, pages = {949-950}, doi = {10.1007/s10072-017-3216-y}, pmid = {29238910}, issn = {1590-3478}, mesh = {Aged ; Female ; Humans ; Jaw Diseases/*etiology ; Motor Neuron Disease/*complications ; Reflex, Abnormal/*physiology ; }, }
@article {pmid29235200, year = {2018}, author = {Serio, A and Patani, R}, title = {Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis.}, journal = {Stem cells (Dayton, Ohio)}, volume = {36}, number = {3}, pages = {293-303}, doi = {10.1002/stem.2758}, pmid = {29235200}, issn = {1549-4918}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is incurable and devastating. A dearth of therapies has galvanized experimental focus onto the cellular and molecular mechanisms that both initiate and subsequently drive motor neuron degeneration. A traditional view of ALS pathogenesis posits that disease-specific injury to a subtype of neurons is mechanistically cell-autonomous. This "neuron-centric" view has biased past research efforts. However, a wealth of accumulating evidence now strongly implicates non-neuronal cells as being major determinants of ALS. Although animal models have proven invaluable in basic neuroscience research, a growing number of studies confirm fundamental interspecies differences between popular model organisms and the human condition. This may in part explain the failure of therapeutic translation from rodent preclinical models. It follows that integration of a human experimental model using patient-specific induced pluripotent stem cells may be necessary to capture the complexity of human neurodegeneration with fidelity. Integration of enriched human neuronal and glial experimental platforms into the existing repertoire of preclinical models might prove transformational for clinical trial outcomes in ALS. Such reductionist and integrated cross-modal approaches allow systematic elucidation of cell-autonomous and non-cell-autonomous mechanisms of disease, which may then provide novel cellular targets for therapeutic intervention. Stem Cells 2018;36:293-303.}, }
@article {pmid29226728, year = {2018}, author = {Liu, J and Wang, LN}, title = {The efficacy and safety of riluzole for neurodegenerative movement disorders: a systematic review with meta-analysis.}, journal = {Drug delivery}, volume = {25}, number = {1}, pages = {43-48}, pmid = {29226728}, issn = {1521-0464}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*adverse effects/*therapeutic use ; }, abstract = {Neurodegenerative movement disorders mainly include Parkinson's disease, atypical parkinsonisms, Huntington disease, and hereditary ataxia. Riluzole is the only drug approved by the US Food and Drug Administration for amyotrophic lateral sclerosis. The neuroprotective effects of riluzole have been observed in experimental models of neurodegenerative movement disorders. In this paper, we aimed to systematically analyze the efficacy and safety of riluzole for patients with neurodegenerative movement disorder. We searched the electronic databases such as PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure until June 2017 for the eligible randomized controlled trials, as well as the unpublished and ongoing trials. For continuous data, we calculated standardized mean differences with 95% confidence intervals if studies did not use the same scales to measure outcomes. For dichotomous data, we calculated risk differences if a trial reported no adverse events or dropouts. We pooled the results using a random-effects model. We included nine studies with 1320 patients with neurodegenerative movement disorders, which compared riluzole with placebo. No significant difference was found in the number of participants with adverse events but with motor improvement in hereditary ataxia. There were only two studies focusing on neuroprotective effect. Riluzole is well-tolerated in the patients with neurodegenerative movement disorders. Riluzole seems to be promising for patients with hereditary ataxia in symptomatic effect, which needs to be further confirmed by well-designed studies in the future. Moreover, it makes sense to design long-term study focusing on neuroprotective effect of riluzole in disease-modifying.}, }
@article {pmid29221753, year = {2018}, author = {Daniel, DC and Johnson, EM}, title = {PURA, the gene encoding Pur-alpha, member of an ancient nucleic acid-binding protein family with mammalian neurological functions.}, journal = {Gene}, volume = {643}, number = {}, pages = {133-143}, pmid = {29221753}, issn = {1879-0038}, support = {R01 GM089820/GM/NIGMS NIH HHS/United States ; R01 NS035000/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Sequence/genetics ; Animals ; Base Sequence ; Cell Cycle ; Cell Cycle Proteins/genetics ; Conserved Sequence/genetics ; DNA Replication ; DNA-Binding Proteins/*genetics/*metabolism ; Dendritic Cells/metabolism ; HIV-1/genetics ; Humans ; Leukemia, Myeloid, Acute/genetics ; Myelodysplastic Syndromes/genetics ; Neuroglia/metabolism ; Neurons/metabolism ; RNA Recognition Motif Proteins/genetics/metabolism ; RNA, Messenger/metabolism ; Transcription Factors/*genetics/*metabolism ; }, abstract = {The PURA gene encodes Pur-alpha, a 322 amino acid protein with repeated nucleic acid binding domains that are highly conserved from bacteria through humans. PUR genes with a single copy of this domain have been detected so far in spirochetes and bacteroides. Lower eukaryotes possess one copy of the PUR gene, whereas chordates possess 1 to 4 PUR family members. Human PUR genes encode Pur-alpha (Pura), Pur-beta (Purb) and two forms of Pur-gamma (Purg). Pur-alpha is a protein that binds specific DNA and RNA sequence elements. Human PURA, located at chromosome band 5q31, is under complex control of three promoters. The entire protein coding sequence of PURA is contiguous within a single exon. Several studies have found that overexpression or microinjection of Pura inhibits anchorage-independent growth of oncogenically transformed cells and blocks proliferation at either G1-S or G2-M checkpoints. Effects on the cell cycle may be mediated by interaction of Pura with cellular proteins including Cyclin/Cdk complexes and the Rb tumor suppressor protein. PURA knockout mice die shortly after birth with effects on brain and hematopoietic development. In humans environmentally induced heterozygous deletions of PURA have been implicated in forms of myelodysplastic syndrome and progression to acute myelogenous leukemia. Pura plays a role in AIDS through association with the HIV-1 protein, Tat. In the brain Tat and Pura association in glial cells activates transcription and replication of JC polyomavirus, the agent causing the demyelination disease, progressive multifocal leukoencephalopathy. Tat and Pura also act to stimulate replication of the HIV-1 RNA genome. In neurons Pura accompanies mRNA transcripts to sites of translation in dendrites. Microdeletions in the PURA locus have been implicated in several neurological disorders. De novo PURA mutations have been related to a spectrum of phenotypes indicating a potential PURA syndrome. The nucleic acid, G-rich Pura binding element is amplified as expanded polynucleotide repeats in several brain diseases including fragile X syndrome and a familial form of amyotrophic lateral sclerosis/fronto-temporal dementia. Throughout evolution the Pura protein plays a critical role in survival, based on conservation of its nucleic acid binding properties. These Pura properties have been adapted in higher organisms to the as yet unfathomable development of the human brain.}, }
@article {pmid29214587, year = {2017}, author = {Matilla-Dueñas, A and Corral-Juan, M and Rodríguez-Palmero Seuma, A and Vilas, D and Ispierto, L and Morais, S and Sequeiros, J and Alonso, I and Volpini, V and Serrano-Munuera, C and Pintos-Morell, G and Álvarez, R and Sánchez, I}, title = {Rare Neurodegenerative Diseases: Clinical and Genetic Update.}, journal = {Advances in experimental medicine and biology}, volume = {1031}, number = {}, pages = {443-496}, doi = {10.1007/978-3-319-67144-4_25}, pmid = {29214587}, issn = {0065-2598}, support = {P01AG000001S/AG/NIA NIH HHS/United States ; }, mesh = {DNA Mutational Analysis ; Genetic Markers ; Genetic Predisposition to Disease ; Genomics/*methods ; Heredity ; Humans ; *Mutation ; Neurodegenerative Diseases/diagnosis/epidemiology/*genetics/therapy ; Phenotype ; Predictive Value of Tests ; Prognosis ; Rare Diseases/diagnosis/epidemiology/*genetics/therapy ; Risk Factors ; }, abstract = {More than 600 human disorders afflict the nervous system. Of these, neurodegenerative diseases are usually characterised by onset in late adulthood, progressive clinical course, and neuronal loss with regional specificity in the central nervous system. They include Alzheimer's disease and other less frequent dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and Prion diseases, among others. Neurodegeneration usually affects, but is not limited to, the cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum. Although the majority of neurodegenerative diseases are sporadic, Mendelian inheritance is well documented. Intriguingly, the clinical presentations and neuropathological findings in inherited neurodegenerative forms are often indistinguishable from those of sporadic cases, suggesting that converging genomic signatures and pathophysiologic mechanisms underlie both hereditary and sporadic neurodegenerative diseases. Unfortunately, effective therapies for these diseases are scarce to non-existent. In this chapter, we highlight the clinical and genetic features associated with the rare inherited forms of neurodegenerative diseases, including ataxias, multiple system atrophy, spastic paraplegias, Parkinson's disease, dementias, motor neuron diseases, and rare metabolic disorders.}, }
@article {pmid29208474, year = {2018}, author = {Ma, L and Zhao, Y and Chen, Y and Cheng, B and Peng, A and Huang, K}, title = {Caenorhabditis elegans as a model system for target identification and drug screening against neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {819}, number = {}, pages = {169-180}, doi = {10.1016/j.ejphar.2017.11.051}, pmid = {29208474}, issn = {1879-0712}, mesh = {Animals ; *Caenorhabditis elegans ; Disease Models, Animal ; Drug Evaluation, Preclinical/*methods ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Over the past decades, Caenorhabditis elegans (C. elegans) has been widely used as a model system because of its small size, transparent body, short generation time and lifespan (~3 days and 3 weeks, respectively), completely sequenced genome and tractability to genetic manipulation. Protein misfolding and aggregation are key pathological features in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Animal models, including C. elegans, have been extensively used to discover and validate new drugs against neurodegenerative diseases. The well-defined and genetically tractable nervous system of C. elegans offers an effective model to explore basic mechanistic pathways of neurodegenerative diseases. Recent progress in high-throughput drug screening also provides a powerful approach for identifying chemical modulators of biological processes. Here, we summarize the latest progress of using C. elegans as a model system for target identification and drug screening in neurodegenerative diseases.}, }
@article {pmid29204881, year = {2018}, author = {Song, J}, title = {Environment-transformable sequence-structure relationship: a general mechanism for proteotoxicity.}, journal = {Biophysical reviews}, volume = {10}, number = {2}, pages = {503-516}, pmid = {29204881}, issn = {1867-2450}, support = {MOE2015-T2-1-111//Ministry of Education - Singapore/ ; }, abstract = {In his Nobel Lecture, Anfinsen stated "the native conformation is determined by the totality of interatomic interactions and hence by the amino acid sequence, in a given environment." As aqueous solutions and membrane systems co-exist in cells, proteins are classified into membrane and non-membrane proteins, but whether one can transform one into the other remains unknown. Intriguingly, many well-folded non-membrane proteins are converted into "insoluble" and toxic forms by aging- or disease-associated factors, but the underlying mechanisms remain elusive. In 2005, we discovered a previously unknown regime of proteins seemingly inconsistent with the classic "Salting-in" dogma: "insoluble" proteins including the integral membrane fragments could be solubilized in the ion-minimized water. We have thus successfully studied "insoluble" forms of ALS-causing P56S-MSP, L126Z-SOD1, nascent SOD1 and C71G-Profilin1, as well as E. coli S1 fragments. The results revealed that these "insoluble" forms are either unfolded or co-exist with their unfolded states. Most unexpectedly, these unfolded states acquire a novel capacity of interacting with membranes energetically driven by the formation of helices/loops over amphiphilic/hydrophobic regions which universally exit in proteins but are normally locked away in their folded native states. Our studies suggest that most, if not all, proteins contain segments which have the dual ability to fold into distinctive structures in aqueous and membrane environments. The abnormal membrane interaction might initiate disease and/or aging processes; and its further coupling with protein aggregation could result in radical proteotoxicity by forming inclusions composed of damaged membranous organelles and protein aggregates. Therefore, environment-transformable sequence-structure relationship may represent a general mechanism for proteotoxicity.}, }
@article {pmid29204783, year = {2018}, author = {Soofi, AY and Bello-Haas, VD and Kho, ME and Letts, L}, title = {The impact of rehabilitative interventions on quality of life: a qualitative evidence synthesis of personal experiences of individuals with amyotrophic lateral sclerosis.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {27}, number = {4}, pages = {845-856}, pmid = {29204783}, issn = {1573-2649}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*rehabilitation ; Female ; Humans ; Male ; Qualitative Research ; Quality of Life/*psychology ; }, abstract = {BACKGROUND: The nature of amyotrophic lateral sclerosis (ALS) is progressive and degenerative, thus influencing individuals physically, emotionally, and socially. A broad review of qualitative studies that describe the personal experiences of people with ALS with physiotherapy, occupational therapy and speech and language pathology interventions, and how those affect QoL is warranted.<br><br>PURPOSE: This study synthesizes qualitative research regarding the potential that rehabilitation interventions have to maintain and/or improve QoL from the perspective of people with ALS.<br><br>METHODS: The SPIDER search strategy was applied and five articles met inclusion criteria addressing the perceived impact of rehabilitation on QoL for individuals with ALS.<br><br>RESULTS: Four themes emerged: the concept of control; adapting interventions to disease stage; struggles with interventions; and barriers between healthcare providers and patients.<br><br>CONCLUSIONS: Rehabilitation interventions were perceived to have potential to support QoL by people with ALS. Advantages and limitations of rehabilitation services within this population were identified.}, }
@article {pmid29203718, year = {2018}, author = {Zarouchlioti, C and Parfitt, DA and Li, W and Gittings, LM and Cheetham, ME}, title = {DNAJ Proteins in neurodegeneration: essential and protective factors.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {373}, number = {1738}, pages = {}, pmid = {29203718}, issn = {1471-2970}, support = {/WT_/Wellcome Trust/United Kingdom ; 205041/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; CHEETHAM/OCT15/881-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/N004434/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Fetal Proteins/*genetics/metabolism ; HSP40 Heat-Shock Proteins/*genetics/metabolism ; Humans ; Mice ; Molecular Chaperones/*genetics/metabolism ; Neurodegenerative Diseases/*genetics ; Protein Folding ; Rats ; }, abstract = {Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion disorders-like Huntington's disease or spinocerebellar ataxia (SCA), Alzheimer's disease, fronto-temporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease-are often characterized by the presence of inclusions of aggregated protein. Neurons contain complex protein networks dedicated to protein quality control and maintaining protein homeostasis, or proteostasis. Molecular chaperones are a class of proteins with prominent roles in maintaining proteostasis, which act to bind and shield hydrophobic regions of nascent or misfolded proteins while allowing correct folding, conformational changes and enabling quality control. There are many different families of molecular chaperones with multiple functions in proteostasis. The DNAJ family of molecular chaperones is the largest chaperone family and is defined by the J-domain, which regulates the function of HSP70 chaperones. DNAJ proteins can also have multiple other protein domains such as ubiquitin-interacting motifs or clathrin-binding domains leading to diverse and specific roles in the cell, including targeting client proteins for degradation via the proteasome, chaperone-mediated autophagy and uncoating clathrin-coated vesicles. DNAJ proteins can also contain ER-signal peptides or mitochondrial leader sequences, targeting them to specific organelles in the cell. In this review, we discuss the multiple roles of DNAJ proteins and in particular focus on the role of DNAJ proteins in protecting against neurodegenerative diseases caused by misfolded proteins. We also discuss the role of DNAJ proteins as direct causes of inherited neurodegeneration via mutations in DNAJ family genes.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.}, }
@article {pmid29195055, year = {2018}, author = {Li, L and Xiong, WC and Mei, L}, title = {Neuromuscular Junction Formation, Aging, and Disorders.}, journal = {Annual review of physiology}, volume = {80}, number = {}, pages = {159-188}, doi = {10.1146/annurev-physiol-022516-034255}, pmid = {29195055}, issn = {1545-1585}, mesh = {Aging/*physiology ; Animals ; Humans ; Motor Neurons/*physiology ; Muscle Fibers, Skeletal/physiology ; Neuromuscular Diseases/*physiopathology ; Neuromuscular Junction/*physiology ; }, abstract = {Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. NMJ formation requires intimate interactions among motoneurons, muscles, and SCs. Deficits in NMJ formation and maintenance cause neuromuscular disorders, including congenital myasthenic syndrome and myasthenia gravis. NMJ decline occurs in aged animals and may appear before clinical presentation of motoneuron disorders such as amyotrophic lateral sclerosis. We review recent findings in NMJ formation, maintenance, neuromuscular disorders, and aging of the NMJ, focusing on communications among motoneurons, muscles and SCs, and underlying mechanisms.}, }
@article {pmid29187847, year = {2017}, author = {Ottesen, EW and Seo, J and Singh, NN and Singh, RN}, title = {A Multilayered Control of the Human Survival Motor Neuron Gene Expression by Alu Elements.}, journal = {Frontiers in microbiology}, volume = {8}, number = {}, pages = {2252}, pmid = {29187847}, issn = {1664-302X}, support = {R01 NS055925/NS/NINDS NIH HHS/United States ; R21 NS101312/NS/NINDS NIH HHS/United States ; }, abstract = {Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Mutations or deletions of SMN1, which codes for SMN, cause spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Aberrant expression or localization of SMN has been also implicated in other pathological conditions, including male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. SMN2 fails to compensate for the loss of SMN1 due to skipping of exon 7, leading to the production of SMNΔ7, an unstable protein. In addition, SMNΔ7 is less functional due to the lack of a critical C-terminus of the full-length SMN, a multifunctional protein. Alu elements are specific to primates and are generally found within protein coding genes. About 41% of the human SMN gene including promoter region is occupied by more than 60 Alu-like sequences. Here we discuss how such an abundance of Alu-like sequences may contribute toward SMA pathogenesis. We describe the likely impact of Alu elements on expression of SMN. We have recently identified a novel exon 6B, created by exonization of an Alu-element located within SMN intron 6. Irrespective of the exon 7 inclusion or skipping, transcripts harboring exon 6B code for the same SMN6B protein that has altered C-terminus compared to the full-length SMN. We have demonstrated that SMN6B is more stable than SMNΔ7 and likely functions similarly to the full-length SMN. We discuss the possible mechanism(s) of regulation of SMN exon 6B splicing and potential consequences of the generation of exon 6B-containing transcripts.}, }
@article {pmid29187283, year = {2018}, author = {Min, B and Chung, KC}, title = {New insight into transglutaminase 2 and link to neurodegenerative diseases.}, journal = {BMB reports}, volume = {51}, number = {1}, pages = {5-13}, pmid = {29187283}, issn = {1976-670X}, mesh = {Animals ; GTP-Binding Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/*enzymology ; Protein Aggregation, Pathological ; Protein Glutamine gamma Glutamyltransferase 2 ; Transglutaminases/*metabolism ; }, abstract = {Formation of toxic protein aggregates is a common feature and mainly contributes to the pathogenesis of neurodegenerative diseases (NDDs), which include amyotrophic lateral sclerosis (ALS), Alzheimer's, Parkinson's, Huntington's, and prion diseases. The transglutaminase 2 (TG2) gene encodes a multifunctional enzyme, displaying four types of activity, such as transamidation, GTPase, protein disulfide isomerase, and protein kinase activities. Many studies demonstrated that the calcium-dependent transamidation activity of TG2 affects the formation of insoluble and toxic amyloid aggregates that mainly consisted of NDD-related proteins. So far, many important and NDD-related substrates of TG2 have been identified, including amlyoid-β, tau, α-synuclein, mutant huntingtin, and ALS-linked trans-activation response (TAR) DNA-binding protein 43. Recently, the formation of toxic inclusions mediated by several TG2 substrates were efficiently inhibited by TG2 inhibitors. Therefore, the development of highly specific TG2 inhibitors would be an important tool in alleviating the progression of TG2-related brain disorders. In this review, the authors discuss recent advances in TG2 biochemistry, several mechanisms of molecular regulation and pleotropic signaling functions, and the presumed role of TG2 in the progression of many NDDs. [BMB Reports 2018; 51(1): 5-13].}, }
@article {pmid29182055, year = {2019}, author = {Hwang, WJ and Huang, K and Huang, JS}, title = {Amyotrophic lateral sclerosis presenting as the temporomandibular disorder: A case report and literature review.}, journal = {Cranio : the journal of craniomandibular practice}, volume = {37}, number = {3}, pages = {196-200}, doi = {10.1080/08869634.2017.1407117}, pmid = {29182055}, issn = {2151-0903}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Masticatory Muscles ; Quality of Life ; *Temporomandibular Joint Disorders ; }, abstract = {BACKGROUND: Spasticity and pain in the masticatory muscles or mouth opening limitation have been reported as early signs and symptoms of amyotrophic lateral sclerosis (ALS). These signs and symptoms are also frequently seen in, and thus mistaken for, temporomandibular disorders (TMD).<br><br>CLINICAL PRESENTATION: The authors report a case of ALS initially presenting with signs and symptoms of TMD. The TMD was followed by dysarthria of insidious onset, leading to the diagnosis of ALS. This case highlights the importance of considering TMD as a potential early form of presentation of ALS, requiring multidisciplinary treatment, especially by dental professionals.<br><br>CONCLUSION: A review of the literature was conducted to elucidate the oral and facial signs and symptoms of ALS and to identify ways of improving the quality of life of patients through a multidisciplinary approach.}, }
@article {pmid29165027, year = {2017}, author = {Hogden, A and Crook, A}, title = {Patient-centered decision making in amyotrophic lateral sclerosis: where are we?.}, journal = {Neurodegenerative disease management}, volume = {7}, number = {6}, pages = {377-386}, doi = {10.2217/nmt-2017-0026}, pmid = {29165027}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; *Clinical Decision-Making/methods ; Decision Support Systems, Clinical ; Humans ; *Patient-Centered Care/methods ; }, abstract = {Developments in amyotrophic lateral sclerosis research and care delivery have created new arenas, and new dilemmas, for patients' decision making. This review explores three aspects of amyotrophic lateral sclerosis patient-centered care and decision making: patient-centered service delivery through the expanding multidisciplinary team; decision making for genetic testing and the implications of undergoing testing; and development of user-designed decision support tools to help patients and families make decisions as their choices become more complex. Until a cure is found, well-timed and effective decision making will rely on patient and family preferences to guide them through an increasingly complicated disease landscape.}, }
@article {pmid29163212, year = {2017}, author = {Stouth, DW and vanLieshout, TL and Shen, NY and Ljubicic, V}, title = {Regulation of Skeletal Muscle Plasticity by Protein Arginine Methyltransferases and Their Potential Roles in Neuromuscular Disorders.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {870}, pmid = {29163212}, issn = {1664-042X}, abstract = {Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Indeed, full-body knockouts of specific PRMTs are lethal and PRMT dysregulation has been implicated in the most prevalent chronic disorders, such as cancers and cardiovascular disease (CVD). PRMTs are now emerging as important mediators of skeletal muscle phenotype and plasticity. Since their first description in muscle in 2002, a number of studies employing wide varieties of experimental models support the hypothesis that PRMTs regulate multiple aspects of skeletal muscle biology, including development and regeneration, glucose metabolism, as well as oxidative metabolism. Furthermore, investigations in non-muscle cell types strongly suggest that proteins, such as peroxisome proliferator-activated receptor-γ coactivator-1α, E2F transcription factor 1, receptor interacting protein 140, and the tumor suppressor protein p53, are putative downstream targets of PRMTs that regulate muscle phenotype determination and remodeling. Recent studies demonstrating that PRMT function is dysregulated in Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) suggests that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders (NMDs). This review summarizes our understanding of PRMT biology in skeletal muscle, and identifies uncharted areas that warrant further investigation in this rapidly expanding field of research.}, }
@article {pmid29163032, year = {2017}, author = {Dodge, JC}, title = {Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {356}, pmid = {29163032}, issn = {1662-5099}, abstract = {Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot-Marie-Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.}, }
@article {pmid29159928, year = {2018}, author = {Misra, MK and Damotte, V and Hollenbach, JA}, title = {The immunogenetics of neurological disease.}, journal = {Immunology}, volume = {153}, number = {4}, pages = {399-414}, pmid = {29159928}, issn = {1365-2567}, support = {R01 AI128775/AI/NIAID NIH HHS/United States ; R01 NS102153/NS/NINDS NIH HHS/United States ; U19 NS095774/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Genetic Variation/genetics/immunology ; Humans ; *Immunogenetics ; Nervous System Diseases/*genetics/*immunology ; }, abstract = {Genes encoding antigen-presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin-like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non-coding variation in immunogenetic loci using high-throughput high-resolution next-generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.}, }
@article {pmid29156920, year = {2018}, author = {Cheng, HWB and Chan, KY and Chung, YKJ and Choi, CW and Chan, CH and Cheng, SC and Chan, WH and Fung, KS and Wong, KY and Chan, OMI and Man, CW}, title = {Supportive &amp; palliative interventions in motor neurone disease: what we know from current literature?.}, journal = {Annals of palliative medicine}, volume = {7}, number = {3}, pages = {320-331}, doi = {10.21037/apm.2017.10.01}, pmid = {29156920}, issn = {2224-5839}, mesh = {Cost-Benefit Analysis ; Hospitalization ; Humans ; Motor Neuron Disease/economics/physiopathology/*therapy ; Nutritional Support ; *Palliative Care/methods ; Patient Care Team ; Quality of Life ; Respiratory Therapy ; Social Support ; Survival Analysis ; }, abstract = {Although there is no cure for motor neurone disease (MND), the advent of supportive interventions including multidisciplinary care (MDC) has improved treatment interventions and enhanced quality of life (QOL) for MND patients and their carers. Our integrative review showed evidence-based MDC, respiratory management and disease-modifying therapy that have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the QOL for MND patients. Notwithstanding improvement to care and QOL, survival benefit has become evident with the advent of a MDC framework, early treatment with non-invasive ventilation (NIV). In addition, weight maintenance remains critical, as weight loss is associated with more rapid disease progression. The endof- life phase is poorly defined in MND patients and treatment remains challenging, yet effective symptom control through palliative care (PC) is achievable and essential.}, }
@article {pmid29154141, year = {2018}, author = {Chia, R and Chiò, A and Traynor, BJ}, title = {Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.}, journal = {The Lancet. Neurology}, volume = {17}, number = {1}, pages = {94-102}, pmid = {29154141}, issn = {1474-4465}, support = {Z99 AG999999//Intramural NIH HHS/United States ; ZIA AG000933-03//Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/metabolism/therapy ; Humans ; }, abstract = {BACKGROUND: The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS.<br><br>RECENT DEVELOPMENTS: Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.}, }
@article {pmid29153601, year = {2017}, author = {Molteni, M and Rossetti, C}, title = {Neurodegenerative diseases: The immunological perspective.}, journal = {Journal of neuroimmunology}, volume = {313}, number = {}, pages = {109-115}, doi = {10.1016/j.jneuroim.2017.11.002}, pmid = {29153601}, issn = {1872-8421}, mesh = {Animals ; Central Nervous System/*immunology ; Humans ; Neurodegenerative Diseases/*immunology/*pathology ; }, abstract = {Increasing evidence supports the notion that the neurodegenerative process occurring in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) does not only imply the neuronal compartment but also involves a strong interaction with the immunological cells of the Central Nervous System (CNS), primarily microglia. Starting from the observation that the neurodegenerative disorders are frequent in elderly individuals, who have an immunological background that possibly favors this process, it is evident that a dysregulation of innate immune response triggered by misfolded and aggregated proteins, or by endogenous molecules released by injured neurons, directly contributes to disease pathogenesis and progression. There are important differences in the immunological processes occurring in AD, PD, ALS involving microglial function. Furthermore, although the contribution of adaptive immune cells in AD seems to be modest, in PD and especially in ALS models, T cells can influence microglial phenotype, inducing neuroprotection. A better understanding of the immunological mechanisms involved in the different phases of the neurodegenerative processes observed in AD, PD, ALS could effectively contribute to the development of new preventive and therapeutic strategies for such diseases.}, }
@article {pmid29149058, year = {2017}, author = {Bianchi, VE and Locatelli, V and Rizzi, L}, title = {Neurotrophic and Neuroregenerative Effects of GH/IGF1.}, journal = {International journal of molecular sciences}, volume = {18}, number = {11}, pages = {}, pmid = {29149058}, issn = {1422-0067}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Brain Injuries/*therapy ; Drug Evaluation ; Growth Hormone/*therapeutic use ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Mice ; Middle Aged ; Models, Animal ; Neurons/metabolism ; Neuroprotective Agents/*therapeutic use ; Rats ; Treatment Outcome ; }, abstract = {INTRODUCTION: Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects.<br><br>METHODS: In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: "GH/IGF-1" associated with "neuroregeneration", "amyotrophic lateral sclerosis", "Alzheimer disease", "Parkinson's disease", "brain", and "neuron".<br><br>RESULTS: Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results.<br><br>CONCLUSIONS: Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.}, }
@article {pmid29147901, year = {2017}, author = {Antipova, D and Bandopadhyay, R}, title = {Expression of DJ-1 in Neurodegenerative Disorders.}, journal = {Advances in experimental medicine and biology}, volume = {1037}, number = {}, pages = {25-43}, doi = {10.1007/978-981-10-6583-5_3}, pmid = {29147901}, issn = {0065-2598}, support = {WT089698//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Brain/*metabolism/pathology ; *Gene Expression ; Humans ; Mitochondria/metabolism ; Neurodegenerative Diseases/*genetics/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Protein Deglycase DJ-1/*genetics/metabolism ; Protein Processing, Post-Translational ; }, abstract = {In 2003, autosomal recessive loss-of-function mutations were identified in PARK7 gene that caused early-onset Parkinson's disease (PD). The PARK7 gene encodes a conserved protein termed DJ-1. DJ-1 is a ubiquitous protein, and within the brain, it is present in the nucleus and cytoplasm of both neuronal and glial cells. DJ-1 is a multifunctional protein, and numerous studies have ascribed various roles, including antioxidative properties, chaperone function, protease activities, mitochondrial functions and regulation of transcription to the protein. The DJ-1 protein undergoes oxidation and post-translational modifications that are important for its function. Not only is DJ-1 linked to familial PD, but it is also associated with the pathogenic mechanisms of sporadic PD and other neurodegenerative disorders where oxidative stress is implicated. In this chapter we provide an overview on the expression of DJ-1 mRNA and protein in different neurodegenerative disorders and discuss some of its main functions together with DJ-1's potential for neuroprotection.}, }
@article {pmid29145182, year = {2018}, author = {Walusinski, O}, title = {Pathological Yawning, Laughing and Crying.}, journal = {Frontiers of neurology and neuroscience}, volume = {41}, number = {}, pages = {40-49}, doi = {10.1159/000475691}, pmid = {29145182}, issn = {1662-2804}, mesh = {Brain/*physiopathology ; *Crying ; Humans ; *Laughter ; Nervous System Diseases/*physiopathology ; *Yawning ; }, abstract = {Yawning, laughing, and crying are normal physiological behaviors of humans in good health. As with all physiological behaviors, their deregulation can reveal disorders. Pathological yawning occurs in salvos of 10-20 successive yawns, and the number of yawns per day can exceed one hundred. After listing the functional etiologies, we will give the clinical keys for differentiating the most serious causes: iatrogenic, tumors, strokes, amyotrophic lateral sclerosis, and intracranial hypertension. Sudden, uncontrollable episodes of emotional display involving pathological laughing and crying (PLC) may be encountered in various neurological diseases: amyotrophic lateral sclerosis, multiple system atrophy (cerebellar), cerebrovascular disease, traumatic brain injuries, mass lesions in the cerebellopontine junction, and epilepsy. After describing the pathophysiology of PLC and the use of diagnostic scales for PLC, we will discuss the current treatments.}, }
@article {pmid29137922, year = {2018}, author = {Croese, T and Furlan, R}, title = {Extracellular vesicles in neurodegenerative diseases.}, journal = {Molecular aspects of medicine}, volume = {60}, number = {}, pages = {52-61}, doi = {10.1016/j.mam.2017.11.006}, pmid = {29137922}, issn = {1872-9452}, mesh = {Animals ; Biomarkers ; Disease Progression ; Extracellular Vesicles/*metabolism ; Humans ; Neurodegenerative Diseases/*diagnosis/genetics/*metabolism/physiopathology ; }, abstract = {Extracellular vesicles (EVs) are released by all neural cells, including neurons, oligodendrocytes, astrocytes, and microglia. The lack of adequate technology has not halted neuroscientists from investigating EVs as a mean to decipher neurodegenerative disorders, still in search of comprehensible pathogenic mechanisms and efficient treatment. EVs are thought to be one of ways neurodegenerative pathologies spread in the brain, but also one of the ways the brain tries to displace toxic proteins, making their meaning in pathogenesis uncertain. EVs, however do reach biological fluids where they can be analyzed, and might therefore constitute clinically decisive biomarkers for neurodegenerative diseases in the future. Finally, if they constitute a physiological inter-cell communication system, they may represent also a very specific drug delivery tool for a difficult target such as the brain. We try to resume here available information on the role of EVs in neurodegeneration, with a special focus on Alzheimer's disease, progressive multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid29133694, year = {2017}, author = {Proudfoot, O}, title = {Manganese in manganism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease: A narrative review.}, journal = {Neurology India}, volume = {65}, number = {6}, pages = {1241-1247}, doi = {10.4103/0028-3886.217949}, pmid = {29133694}, issn = {0028-3886}, mesh = {Amyotrophic Lateral Sclerosis/*chemically induced ; Humans ; Huntington Disease/*chemically induced ; Manganese/*toxicity ; *Manganese Poisoning ; Neuronal Ceroid-Lipofuscinoses/*chemically induced ; Parkinson Disease, Secondary/*chemically induced ; }, abstract = {The collective evidence to date suggests that environmental exposure to excessive amounts of manganese (Mn) can cause a neurodegenerative condition known as manganism. It is now also relatively clear that Mn is involved in the pathogenesis of Alzheimer's disease and at least some prion diseases. The potential involvement of Mn in a panel of other neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease has been suggested and investigated, but the results to date are somewhat inconclusive. Herein, previously reported experimental studies investigating the involvement of Mn in the pathogenesis of these conditions are narratively reviewed.}, }
@article {pmid29132389, year = {2017}, author = {Ciervo, Y and Ning, K and Jun, X and Shaw, PJ and Mead, RJ}, title = {Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {85}, pmid = {29132389}, issn = {1750-1326}, support = {MR/K008943/1/MRC_/Medical Research Council/United Kingdom ; MR/M010864/1/MRC_/Medical Research Council/United Kingdom ; SITRAN/APR13/983-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; 983-797//MND Association/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3-5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1[G93A] mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed.}, }
@article {pmid29128155, year = {2018}, author = {de Souza, PVS and Bortholin, T and Naylor, FGM and Chieia, MAT and de Rezende Pinto, WBV and Oliveira, ASB}, title = {Motor neuron disease in inherited neurometabolic disorders.}, journal = {Revue neurologique}, volume = {174}, number = {3}, pages = {115-124}, doi = {10.1016/j.neurol.2017.06.020}, pmid = {29128155}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Brain Diseases, Metabolic, Inborn/*complications/*genetics ; Humans ; Motor Neuron Disease/*etiology/*genetics ; }, abstract = {Inherited neurometabolic disorders represent a growing group of inborn errors of metabolism that present with major neurological symptoms or a complex spectrum of symptoms dominated by central or peripheral nervous system dysfunction. Many neurological presentations may arise from the same metabolic defect, especially in autosomal-recessive inherited disorders. Motor neuron disease (MND), mainly represented by amyotrophic lateral sclerosis, may also result from various inborn errors of metabolism, some of which may represent potentially treatable conditions, thereby emphasizing the importance of recognizing such diseases. The present review discusses the most important neurometabolic disorders presenting with motor neuron (lower and/or upper) dysfunction as the key clinical and neuropathological feature.}, }
@article {pmid29125194, year = {2018}, author = {Ratner, MH and Jabre, JF and Ewing, WM and Abou-Donia, M and Oliver, LC}, title = {Amyotrophic lateral sclerosis-A case report and mechanistic review of the association with toluene and other volatile organic compounds.}, journal = {American journal of industrial medicine}, volume = {61}, number = {3}, pages = {251-260}, doi = {10.1002/ajim.22791}, pmid = {29125194}, issn = {1097-0274}, mesh = {Age of Onset ; *Amyotrophic Lateral Sclerosis ; Humans ; Male ; Middle Aged ; *Occupational Exposure ; Oxidative Stress ; *Solvents ; *Toluene ; *Volatile Organic Compounds ; }, abstract = {Unmasking of latent neurodegenerative disease has been reported following exposure to chemicals that share one or more mechanisms of action in common with those implicated in the specific disease. For example, unmasking of latent Parkinson's disease (PD) has been associated with exposure to anti-dopaminergic agents, while the progression of pre-existing mild cognitive impairment and unmasking of latent Alzheimer's disease has been associated with exposure to general anesthetic agents which promote Aβ protein aggregation. This literature review and clinical case report about a 45-year-old man with no family history of motor neuron disease who developed overt symptoms of a neuromuscular disorder in close temporal association with his unwitting occupational exposure to volatile organic compounds (VOCs) puts forth the hypothesis that exposure to VOCs such as toluene, which disrupt motor function and increase oxidative stress, can unmask latent ALS type neuromuscular disorder in susceptible individuals.}, }
@article {pmid29121942, year = {2017}, author = {Burwell, S and Sample, M and Racine, E}, title = {Ethical aspects of brain computer interfaces: a scoping review.}, journal = {BMC medical ethics}, volume = {18}, number = {1}, pages = {60}, pmid = {29121942}, issn = {1472-6939}, mesh = {Biomedical Research/*ethics ; Brain Diseases/rehabilitation ; Brain-Computer Interfaces/*ethics/trends ; Communication Aids for Disabled/*ethics/trends ; Electroencephalography ; Ethics, Research ; Humans ; Neurosciences/*ethics/*trends ; Personhood ; User-Computer Interface ; }, abstract = {BACKGROUND: Brain-Computer Interface (BCI) is a set of technologies that are of increasing interest to researchers. BCI has been proposed as assistive technology for individuals who are non-communicative or paralyzed, such as those with amyotrophic lateral sclerosis or spinal cord injury. The technology has also been suggested for enhancement and entertainment uses, and there are companies currently marketing BCI devices for those purposes (e.g., gaming) as well as health-related purposes (e.g., communication). The unprecedented direct connection created by BCI between human brains and computer hardware raises various ethical, social, and legal challenges that merit further examination and discussion.<br><br>METHODS: To identify and characterize the key issues associated with BCI use, we performed a scoping review of biomedical ethics literature, analyzing the ethics concerns cited across multiple disciplines, including philosophy and medicine.<br><br>RESULTS: Based on this investigation, we report that BCI research and its potential translation to therapeutic intervention generate significant ethical, legal, and social concerns, notably with regards to personhood, stigma, autonomy, privacy, research ethics, safety, responsibility, and justice. Our review of the literature determined, furthermore, that while these issues have been enumerated extensively, few concrete recommendations have been expressed.<br><br>CONCLUSIONS: We conclude that future research should focus on remedying a lack of practical solutions to the ethical challenges of BCI, alongside the collection of empirical data on the perspectives of the public, BCI users, and BCI researchers.}, }
@article {pmid29118263, year = {2017}, author = {Ito, D and Hatano, M and Suzuki, N}, title = {RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration.}, journal = {Science translational medicine}, volume = {9}, number = {415}, pages = {}, doi = {10.1126/scitranslmed.aah5436}, pmid = {29118263}, issn = {1946-6242}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Cytoplasmic Granules/metabolism ; Frontotemporal Dementia/*metabolism/*pathology ; Humans ; Mutation/genetics ; Prions/metabolism ; RNA-Binding Proteins/chemistry/*metabolism ; }, abstract = {Advanced genetic approaches have accelerated the identification of causative genes linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the disease-related proteins encoded by these genes form aggregates in the cellular machineries that regulate RNA and protein quality control in cells. Cross-talk among the signaling pathways governing these machineries leads to pathological cascades mediated by the accumulation of mutant RNA binding proteins. We outline the molecular basis of ALS and FTD pathogenesis and discuss the prospects for therapeutic strategies to treat these diseases.}, }
@article {pmid29115051, year = {2018}, author = {Costa, CJ and Willis, DE}, title = {To the end of the line: Axonal mRNA transport and local translation in health and neurodegenerative disease.}, journal = {Developmental neurobiology}, volume = {78}, number = {3}, pages = {209-220}, pmid = {29115051}, issn = {1932-846X}, support = {R56 NS097568/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport/*physiology ; Axons/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; RNA, Messenger/*metabolism ; }, abstract = {Axons and growth cones, by their very nature far removed from the cell body, encounter unique environments and require distinct populations of proteins. It seems only natural, then, that they have developed mechanisms to locally synthesize a host of proteins required to perform their specialized functions. Acceptance of this ability has taken decades; however, there is now consensus that axons do indeed have the capacity for local translation, and that this capacity is even retained into adulthood. Accumulating evidence supports the role of locally synthesized proteins in the proper development, maintenance, and function of neurons, and newly emerging studies also suggest that disruption in this process has implications in a number of neurodevelopmental and neurodegenerative diseases. Here, we briefly review the long history of axonal mRNA localization and local translation, and the role that these locally synthesized proteins play in normal neuronal function. Additionally, we highlight the emerging evidence that dysregulation in these processes contributes to a wide range of pathophysiology, including neuropsychiatric disorders, Alzheimer's, and motor neuron diseases such as spinal muscular atrophy and Amyotrophic Lateral Sclerosis. © 2017 Wiley Periodicals, Inc. Develop. Neurobiol 78: 209-220, 2018.}, }
@article {pmid29114200, year = {2017}, author = {Forostyak, S and Sykova, E}, title = {Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {591}, pmid = {29114200}, issn = {1662-4548}, abstract = {Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular.}, }
@article {pmid29106805, year = {2018}, author = {Labzin, LI and Heneka, MT and Latz, E}, title = {Innate Immunity and Neurodegeneration.}, journal = {Annual review of medicine}, volume = {69}, number = {}, pages = {437-449}, doi = {10.1146/annurev-med-050715-104343}, pmid = {29106805}, issn = {1545-326X}, support = {MC_U105181010/MRC_/Medical Research Council/United Kingdom ; R01 HL112661/HL/NHLBI NIH HHS/United States ; }, mesh = {Alzheimer Disease/immunology ; Amyotrophic Lateral Sclerosis/immunology ; Humans ; Huntington Disease/immunology ; Immunity, Innate/*immunology ; Inflammation/immunology ; Microglia/*immunology ; Neurodegenerative Diseases/*immunology ; Parkinson Disease/immunology ; }, abstract = {The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.}, }
@article {pmid29105153, year = {2018}, author = {Goyal, N and Narayanaswami, P}, title = {Making sense of antisense oligonucleotides: A narrative review.}, journal = {Muscle &amp; nerve}, volume = {57}, number = {3}, pages = {356-370}, doi = {10.1002/mus.26001}, pmid = {29105153}, issn = {1097-4598}, mesh = {Genetic Therapy ; Humans ; Neuromuscular Diseases/*genetics ; *Oligonucleotides, Antisense ; Research ; }, abstract = {Synthetic nucleic acid sequences that bind to ribonucleic acid (RNA) through Watson-Crick base pairing are known as antisense oligonucleotides (ASOs) because they are complementary to "sense strand" nucleic acids. ASOs bind to selected sequences of RNA and regulate the expression of genes by several mechanisms depending on their chemical properties and targets. They can be used to restore deficient protein expression, reduce the expression of a toxic protein, modify functional effects of proteins, or reduce toxicity of mutant proteins. Two ASOs were approved by the U.S. Food and Drug Administration in 2016: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy. Clinical trials in amyotrophic lateral sclerosis and familial amyloid polyneuropathy are ongoing. We review the chemistry, pharmacology, and mechanisms of action of ASOs, preclinical data, and clinical trials in neuromuscular diseases and discuss some ethical, regulatory, and policy considerations in the clinical development and use of ASOs. Muscle Nerve 57: 356-370, 2018.}, }
@article {pmid29104236, year = {2017}, author = {Chiarotto, GB and Nardo, G and Trolese, MC and França, MC and Bendotti, C and Rodrigues de Oliveira, AL}, title = {The Emerging Role of the Major Histocompatibility Complex Class I in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {18}, number = {11}, pages = {}, pmid = {29104236}, issn = {1422-0067}, mesh = {Adaptive Immunity ; Amyotrophic Lateral Sclerosis/*immunology/pathology/physiopathology ; Animals ; Histocompatibility Antigens Class I/analysis/*immunology ; Humans ; Microglia/immunology/pathology ; Neuroglia/immunology/pathology ; Neuronal Plasticity ; Neuroprotection ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motoneurons (MNs). The etiology of the disease is still unknown for most patients with sporadic ALS, while in 5-10% of the familial cases, several gene mutations have been linked to the disease. Mutations in the gene encoding Cu, Zn superoxide dismutase (SOD1), reproducing in animal models a pathological scenario similar to that found in ALS patients, have allowed for the identification of mechanisms relevant to the ALS pathogenesis. Among them, neuroinflammation mediated by glial cells and systemic immune activation play a key role in the progression of the disease, through mechanisms that can be either neuroprotective or neurodetrimental depending on the type of cells and the MN compartment involved. In this review, we will examine and discuss the involvement of major histocompatibility complex class I (MHCI) in ALS concerning its function in the adaptive immunity and its role in modulating the neural plasticity in the central and peripheral nervous system. The evidence indicates that the overexpression of MHCI into MNs protect them from astrocytes' toxicity in the central nervous system (CNS) and promote the removal of degenerating motor axons accelerating collateral reinnervation of muscles.}, }
@article {pmid29095723, year = {2017}, author = {Brendish, NJ and Clark, TW}, title = {Antiviral treatment of severe non-influenza respiratory virus infection.}, journal = {Current opinion in infectious diseases}, volume = {30}, number = {6}, pages = {573-578}, doi = {10.1097/QCO.0000000000000410}, pmid = {29095723}, issn = {1473-6527}, support = {PDF-2016-09-061/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Aged ; Antiviral Agents/*therapeutic use ; Child ; Hospitalization ; Humans ; Infant ; *Respiratory Tract Infections/drug therapy/virology ; *Virus Diseases/drug therapy/virology ; *Viruses ; }, abstract = {PURPOSE OF REVIEW: Non-influenza respiratory virus infections are a frequent cause of severe acute respiratory infections, especially in infants, the elderly, and the immunocompromised. We review here the current treatment options for non-influenza respiratory viruses and promising candidate antiviral agents currently in development.<br><br>RECENT FINDINGS: Small molecule antiviral agents active against respiratory syncytial virus (RSV), such as ALS-8176 and GS-5806, show considerable promise in challenge studies and are undergoing late-phase clinical trials in hospitalised adults and children. Monoclonal antibodies (mAbs) active against non-influenza respiratory viruses are broadly at a preclinical stage. Broad-spectrum antivirals, such as favipiravir and nitrazoxanide, have potential utility in treating illness caused by non-influenza respiratory viruses but further definitive clinical trials are needed.<br><br>SUMMARY: Severe non-influenza respiratory virus infection is common and current treatment is largely supportive. Ribavirin is used in immunocompromised patients but its use is limited by toxicity and the evidence for its efficacy is weak. Effective antiviral treatment for RSV may shortly become available, pending the results of ongoing clinical trials. For other non-influenza viruses, effective treatments may become available in the medium term. Early detection of respiratory viruses with rapid molecular test platforms will be crucial in differentiating virus types and directing the prompt initiation of novel treatments when available.}, }
@article {pmid29084431, year = {2018}, author = {Towner, RA and Smith, N}, title = {In Vivo and In Situ Detection of Macromolecular Free Radicals Using Immuno-Spin Trapping and Molecular Magnetic Resonance Imaging.}, journal = {Antioxidants &amp; redox signaling}, volume = {28}, number = {15}, pages = {1404-1415}, doi = {10.1089/ars.2017.7390}, pmid = {29084431}, issn = {1557-7716}, mesh = {Animals ; Antibodies/chemistry ; Cyclic N-Oxides/chemistry ; Electron Spin Resonance Spectroscopy/methods ; Free Radicals/*chemistry ; Macromolecular Substances/*chemistry ; Magnetic Resonance Imaging/methods ; Oxidation-Reduction ; Spin Labels ; Spin Trapping/methods ; }, abstract = {SIGNIFICANCE: In vivo free radical imaging in preclinical models of disease has become a reality. Free radicals have traditionally been characterized by electron spin resonance (ESR) or electron paramagnetic resonance (EPR) spectroscopy coupled with spin trapping. The disadvantage of the ESR/EPR approach is that spin adducts are short-lived due to biological reductive and/or oxidative processes. Immuno-spin trapping (IST) involves the use of an antibody that recognizes macromolecular 5,5-dimethyl-pyrroline-N-oxide (DMPO) spin adducts (anti-DMPO antibody), regardless of the oxidative/reductive state of trapped radical adducts. Recent Advances: The IST approach has been extended to an in vivo application that combines IST with molecular magnetic resonance imaging (mMRI). This combined IST-mMRI approach involves the use of a spin-trapping agent, DMPO, to trap free radicals in disease models, and administration of an mMRI probe, an anti-DMPO probe, which combines an antibody against DMPO-radical adducts and an MRI contrast agent, resulting in targeted free radical adduct detection.<br><br>CRITICAL ISSUES: The combined IST-mMRI approach has been used in several rodent disease models, including diabetes, amyotrophic lateral sclerosis (ALS), gliomas, and septic encephalopathy. The advantage of this approach is that heterogeneous levels of trapped free radicals can be detected directly in vivo and in situ to pin point where free radicals are formed in different tissues.<br><br>FUTURE DIRECTIONS: The approach can also be used to assess therapeutic agents that are either free radical scavengers or generate free radicals. Smaller probe constructs and radical identification approaches are being considered. The focus of this review is on the different applications that have been studied, advantages and limitations, and future directions. Antioxid. Redox Signal. 28, 1404-1415.}, }
@article {pmid29081604, year = {2017}, author = {Ferri, A and Coccurello, R}, title = {What is "Hyper" in the ALS Hypermetabolism?.}, journal = {Mediators of inflammation}, volume = {2017}, number = {}, pages = {7821672}, pmid = {29081604}, issn = {1466-1861}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Disease Models, Animal ; Energy Metabolism/physiology ; Humans ; }, abstract = {The progressive and fatal loss of upper (brain) and lower (spinal cord) motor neurons and muscle denervation concisely condenses the clinical picture of amyotrophic lateral sclerosis (ALS). Despite the multiple mechanisms believed to underlie the selective loss of motor neurons, ALS aetiology remains elusive and obscure. Likewise, there is also a cluster of alterations in ALS patients in which muscle wasting, body weight loss, eating dysfunction, and abnormal energy dissipation coexist. Defective energy metabolism characterizes the ALS progression, and such paradox of energy balance stands as a challenge for the understanding of ALS pathogenesis. The hypermetabolism in ALS will be examined from tissue-specific energy imbalance (e.g., skeletal muscle) to major energetic pathways (e.g., AMP-activated protein kinase) and whole-body energy alterations including glucose and lipid metabolism, nutrition, and potential involvement of interorgan communication. From the point of view here expressed, the hypermetabolism in ALS should be evaluated as a magnifying glass through which looking at the ALS pathogenesis is from a different perspective in which defective metabolism can disclose novel mechanistic interpretations and lines of intervention.}, }
@article {pmid29081600, year = {2017}, author = {Tortarolo, M and Lo Coco, D and Veglianese, P and Vallarola, A and Giordana, MT and Marcon, G and Beghi, E and Poloni, M and Strong, MJ and Iyer, AM and Aronica, E and Bendotti, C}, title = {Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα.}, journal = {Mediators of inflammation}, volume = {2017}, number = {}, pages = {2985051}, pmid = {29081600}, issn = {1466-1861}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*metabolism/pathology ; Animals ; Humans ; Motor Neurons/metabolism/pathology ; T-Lymphocytes, Regulatory/immunology/*metabolism ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.}, }
@article {pmid29078263, year = {2017}, author = {Zhu, J and Shen, L and Lin, X and Hong, Y and Feng, Y}, title = {Clinical Research on Traditional Chinese Medicine compounds and their preparations for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {96}, number = {}, pages = {854-864}, doi = {10.1016/j.biopha.2017.09.135}, pmid = {29078263}, issn = {1950-6007}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drugs, Chinese Herbal/*pharmacology/*therapeutic use ; Humans ; Medicine, Chinese Traditional/methods ; Phytotherapy/methods ; Plant Extracts/*therapeutic use ; Plants, Medicinal/chemistry ; Riluzole/pharmacology/therapeutic use ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disease which leads to progressive muscle atrophy and paralysis. In order to summarize the characteristics of Traditional Chinese Medicine compounds and their preparations in the prevention and treatment of ALS through analyzing the mechanism, action site, and symptoms according to effective clinical research.<br><br>METHODS: We searched ALS, motor neuron disease, chemical drugs, herbal medicine, Chinese medicine, Traditional Chinese Medicine (TCM), and various combinations of these terms in databases including the PudMed, Springer, Ovid, Google, China National Knowledge Infrastructure, and Wanfang databases.<br><br>RESULT: It was found that the chemical drugs almost had not sufficient evidence to show their effectiveness in the treatment of ALS, except RILUZOLE. According to the characteristics of clinical symptoms of ALS, Chinese medicine practitioners believe that this disease belongs to the category of "atrophic disease". In clinical research, many Chinese herbal formulas had good clinical efficacies in the treatment of ALS with multiple targets, multiple links, and few side effects. And four kinds of dialectical treatment had been developed based on Clinical data analysis and the use of dialectical therapy: Benefiting the kidney; Declaring the lungs; Enhancing the Qi; and Dredging the meridian.<br><br>CONCLUSION: In this review, we provide an overview of chemical drugs and Traditional Chinese Medicine compound and its preparations in therapy of ALS as well as how they may contribute to the ALS pathogenesis, thereby offering some clues for further studies.}, }
@article {pmid29076800, year = {2018}, author = {Trojsi, F and Sorrentino, P and Sorrentino, G and Tedeschi, G}, title = {Neurodegeneration of brain networks in the amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTLD) continuum: evidence from MRI and MEG studies.}, journal = {CNS spectrums}, volume = {23}, number = {6}, pages = {378-387}, doi = {10.1017/S109285291700075X}, pmid = {29076800}, issn = {1092-8529}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnostic imaging/physiopathology ; *Connectome ; Frontotemporal Lobar Degeneration/*diagnostic imaging/etiology/physiopathology ; Humans ; Magnetic Resonance Imaging ; Magnetoencephalography ; }, abstract = {Brain imaging techniques, especially those based on magnetic resonance imaging (MRI) and magnetoencephalography (MEG), have been increasingly applied to study multiple large-scale distributed brain networks in healthy people and neurological patients. With regard to neurodegenerative disorders, amyotrophic lateral sclerosis (ALS), clinically characterized by the predominant loss of motor neurons and progressive weakness of voluntary muscles, and frontotemporal lobar degeneration (FTLD), the second most common early-onset dementia, have been proven to share several clinical, neuropathological, genetic, and neuroimaging features. Specifically, overlapping or mildly diverging brain structural and functional connectivity patterns, mostly evaluated by advanced MRI techniques-such as diffusion tensor and resting-state functional MRI (DT-MRI, RS-fMRI)-have been described comparing several ALS and FTLD populations. Moreover, though only pioneering, promising clues on connectivity patterns in the ALS-FTLD continuum may derive from MEG investigations. We will herein overview the current state of knowledge concerning the most advanced neuroimaging findings associated with clinical and genetic patterns of neurodegeneration across the ALS-FTLD continuum, underlying the possibility that network-based approaches may be useful to develop novel biomarkers of disease for adequately designing and monitoring more appropriate treatment strategies.}, }
@article {pmid29073741, year = {2017}, author = {Lim, K and See, YM and Lee, J}, title = {A Systematic Review of the Effectiveness of Medical Cannabis for Psychiatric, Movement and Neurodegenerative Disorders.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {15}, number = {4}, pages = {301-312}, pmid = {29073741}, issn = {1738-1088}, abstract = {The discovery of endocannabinoid's role within the central nervous system and its potential therapeutic benefits have brought forth rising interest in the use of cannabis for medical purposes. The present review aimed to synthesize and evaluate the available evidences on the efficacy of cannabis and its derivatives for psychiatric, neurodegenerative and movement disorders. A systematic search of randomized controlled trials of cannabis and its derivatives were conducted via databases (PubMed, Embase and the Cochrane Central Register of Controlled Trials). A total of 24 reports that evaluated the use of medical cannabis for Alzheimer's disease, anorexia nervosa, anxiety, dementia, dystonia, Huntington's disease, Parkinson's disease, post-traumatic stress disorder (PTSD), psychosis and Tourette syndrome were included in this review. Trial quality was assessed with the Cochrane risk of bias tool. There is a lack of evidence on the therapeutic effects of cannabinoids for amyotrophic lateral sclerosis and dystonia. Although trials with positive findings were identified for anorexia nervosa, anxiety, PTSD, psychotic symptoms, agitation in Alzheimer's disease and dementia, Huntington's disease, and Tourette syndrome, and dyskinesia in Parkinson's disease, definitive conclusion on its efficacy could not be drawn. Evaluation of these low-quality trials, as rated on the Cochrane risk of bias tools, was challenged by methodological issues such as inadequate description of allocation concealment, blinding and underpowered sample size. More adequately powered controlled trials that examine the long and short term efficacy, safety and tolerability of cannabis for medical use, and the mechanisms underpinning the therapeutic potential are warranted.}, }
@article {pmid29069183, year = {2017}, author = {Souza, GDS and Costa, LCAD and Maciel, AC and Reis, FDV and Pamplona, YAP}, title = {Presence of pesticides in atmosphere and risk to human health: a discussion for the Environmental Surveillance.}, journal = {Ciencia &amp; saude coletiva}, volume = {22}, number = {10}, pages = {3269-3280}, doi = {10.1590/1413-812320172210.18342017}, pmid = {29069183}, issn = {1678-4561}, mesh = {Air Pollutants/analysis/*toxicity ; Air Pollution/adverse effects/analysis ; Brazil ; Environmental Exposure/adverse effects ; Environmental Health ; Environmental Monitoring/*methods ; Humans ; National Health Programs/organization &amp; administration ; Pesticides/analysis/*toxicity ; Public Health ; }, abstract = {Brazil is the main consumer of pesticides in the world. Large-scale use of these products is likely to contaminate major environmental compartments and expose more people to their toxic effects. Therefore, this literature review was carried out to seek supporting elements for a qualified discussion about the performance of Environmental Surveillance (HS) within the Brazilian Unified Health System (SUS) related to air contamination by pesticides and health risks. Twelve papers were selected and analyzed in this literature review. Of these, only one was published in a specialized public health journal. Notwithstanding this, two epidemiological studies published in the field of environmental sciences investigated the association between air contaminated by pesticides and specific outcomes such as non-Hodgkin's lymphoma (NHL) and amyotrophic lateral sclerosis (ALS). Our findings reflect the lack of studies addressing such issue by public health. The discussion on air contamination by pesticides and potential risks to human health should be expanded by Brazilian science in order to further increase knowledge on the subject and support the HS performance capacity.}, }
@article {pmid29064456, year = {2017}, author = {Allison, WT and DuVal, MG and Nguyen-Phuoc, K and Leighton, PLA}, title = {Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology.}, journal = {International journal of molecular sciences}, volume = {18}, number = {10}, pages = {}, pmid = {29064456}, issn = {1422-0067}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Humans ; Prion Diseases/metabolism/*pathology ; Prion Proteins/chemistry/*metabolism ; Protein Folding ; Superoxide Dismutase-1/chemistry/metabolism ; tau Proteins/chemistry/metabolism ; }, abstract = {Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis (ALS), including amyloid-β precursor protein, Tau and superoxide dismutase 1 (SOD1), spread to adjacent cells in their misfolded aggregated forms and exhibit template-directed misfolding to induce further misfolding, disruptions to proteostasis and toxicity. Here we invert this comparison to ask what these prion-like diseases can teach us about the broad prion disease class, especially regarding the loss of these key proteins' function(s) as they misfold and aggregate. We also consider whether functional amyloids might reveal a role for subverted protein function in neurodegenerative disease. Our synthesis identifies SOD1 as an exemplar of protein functions being lost during prion-like protein misfolding, because SOD1 is inherently unstable and loses function in its misfolded disease-associated form. This has under-appreciated parallels amongst the canonical prion diseases, wherein the normally folded prion protein, PrP[C], is reduced in abundance in fatal familial insomnia patients and during the preclinical phase in animal models, apparently via proteostatic mechanisms. Thus while template-directed misfolding and infectious properties represent gain-of-function that fascinates proteostasis researchers and defines (is required for) the prion(-like) diseases, loss and subversion of the functions attributed to hallmark proteins in neurodegenerative disease needs to be integrated into design towards effective therapeutics. We propose experiments to uniquely test these ideas.}, }
@article {pmid29063415, year = {2017}, author = {Comfort, N and Re, DB}, title = {Sex-Specific Neurotoxic Effects of Organophosphate Pesticides Across the Life Course.}, journal = {Current environmental health reports}, volume = {4}, number = {4}, pages = {392-404}, pmid = {29063415}, issn = {2196-5412}, support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; T32 ES007322/ES/NIEHS NIH HHS/United States ; }, mesh = {Environmental Exposure/adverse effects ; Humans ; Neurodegenerative Diseases/*chemically induced ; Neurotoxicity Syndromes/*etiology ; Occupational Exposure/adverse effects ; Organophosphates/*toxicity ; Pesticides/*toxicity ; *Sex Characteristics ; }, abstract = {PURPOSE OF REVIEW: This review discusses the sex-specific effects of exposure to various organophosphate (OP) pesticides throughout the life course and potential reasons for the differential vulnerabilities observed across sexes.<br><br>RECENT FINDINGS: Sex is a crucial factor in the response to toxicants, yet the sex-specific effects of OP exposure, particularly in juveniles and adults, remain unresolved. This is largely due to study design and inconsistencies in exposure and outcome assessments. Exposure to OPs results in multiple adverse outcomes influenced by many factors including sex. Reported sex-specific effects suggest that males are more susceptible to OPs, which reflects the sex-dependent prevalence of various neurodevelopmental and neurodegenerative disorders such as autism and amyotrophic lateral sclerosis (ALS), in which males are at greater risk. Thus, this review proposes that the biological sex-specific effects elicited by OP exposure may in part underlie the dimorphic susceptibilities observed in neurological disorders. Understanding the immediate and long-term effects of OP exposure across sexes will be critical in advancing our understanding of OP-induced neurotoxicity and disease.}, }
@article {pmid29063348, year = {2018}, author = {Baufeld, C and O'Loughlin, E and Calcagno, N and Madore, C and Butovsky, O}, title = {Differential contribution of microglia and monocytes in neurodegenerative diseases.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {125}, number = {5}, pages = {809-826}, pmid = {29063348}, issn = {1435-1463}, support = {R01AG054672/AG/NIA NIH HHS/United States ; R01 NS088137/NS/NINDS NIH HHS/United States ; R01AG051812/AG/NIA NIH HHS/United States ; R01 AG054672/AG/NIA NIH HHS/United States ; 5092A1/MSS_/Multiple Sclerosis Society/United Kingdom ; 1R01NS088137/NS/NINDS NIH HHS/United States ; R01 AG051812/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Microglia/*immunology/pathology ; Monocytes/*immunology/pathology ; Neurodegenerative Diseases/*immunology/pathology ; }, abstract = {Neuroinflammation is a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Microglia, the innate immune cells of the CNS, are the first to react to pathological insults. However, multiple studies have also demonstrated an involvement of peripheral monocytes in several neurodegenerative diseases. Due to the different origins of these two cell types, it is important to distinguish their role and function in the development and progression of these diseases. In this review, we will summarize and discuss the current knowledge of the differential contributions of microglia and monocytes in the common neurodegenerative diseases AD, PD, and ALS, as well as multiple sclerosis, which is now regarded as a combination of inflammatory processes and neurodegeneration. Until recently, it has been challenging to differentiate microglia from monocytes, as there were no specific markers. Therefore, the recent identification of specific molecular signatures of both cell types will help to advance our understanding of their differential contribution in neurodegenerative diseases.}, }
@article {pmid29054467, year = {2018}, author = {Yamanaka, K and Komine, O}, title = {The multi-dimensional roles of astrocytes in ALS.}, journal = {Neuroscience research}, volume = {126}, number = {}, pages = {31-38}, doi = {10.1016/j.neures.2017.09.011}, pmid = {29054467}, issn = {1872-8111}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Animals ; Astrocytes/*metabolism ; Brain/metabolism/physiopathology ; Humans ; Motor Neurons/*metabolism ; }, abstract = {Despite significant progress in understanding the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, the precise and comprehensive pathomechanisms remain largely unknown. In addition to motor neuron involvement, recent studies using cellular and animal models of ALS indicate that there is a complex interplay between motor neurons and neighboring non-neuronal cells, such as astrocytes, in non-cell autonomous neurodegeneration. Astrocytes are key homeostatic cells that play numerous supportive roles in maintaining the brain environment. In neurodegenerative diseases such as ALS, astrocytes change their shape and molecular expression patterns and are referred to as reactive or activated astrocytes. Reactive astrocytes in ALS lose their beneficial functions and gain detrimental roles. In addition, interactions between motor neurons and astrocytes are impaired in ALS. In this review, we summarize growing evidence that astrocytes are critically involved in the survival and demise of motor neurons through several key molecules and cascades in astrocytes in both sporadic and inherited ALS. These observations strongly suggest that astrocytes have multi-dimensional roles in disease and are a viable therapeutic target for ALS.}, }
@article {pmid29046784, year = {2017}, author = {Pang, SY and Teo, KC and Hsu, JS and Chang, RS and Li, M and Sham, PC and Ho, SL}, title = {The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review.}, journal = {Translational neurodegeneration}, volume = {6}, number = {}, pages = {27}, pmid = {29046784}, issn = {2047-9158}, abstract = {The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.}, }
@article {pmid29033893, year = {2017}, author = {Katyal, N and Govindarajan, R}, title = {Shortcomings in the Current Amyotrophic Lateral Sclerosis Trials and Potential Solutions for Improvement.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {521}, pmid = {29033893}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically progressive neurodegenerative syndrome predominantly affecting motor neurons and their associated tracts. Riluzole and edaravone are the only FDA certified drugs for treating ALS. Over the past two decades, almost all clinical trials aiming to develop a successful therapeutic strategy for this disease have failed. Genetic complexity, inadequate animal models, poor clinical trial design, lack of sensitive biomarkers, and diagnostic delays are some of the potential reasons limiting any significant development in ALS clinical trials. In this review, we have outlined the possible reasons for failure of ALS clinical trials, addressed the factors limiting timely diagnosis, and suggested possible solutions for future considerations for each of the shortcomings.}, }
@article {pmid29028904, year = {2017}, author = {Woolley, SC and Rush, BK}, title = {Considerations for Clinical Neuropsychological Evaluation in Amyotrophic Lateral Sclerosis.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {32}, number = {7}, pages = {906-916}, doi = {10.1093/arclin/acx089}, pmid = {29028904}, issn = {1873-5843}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*psychology ; Humans ; Neuropsychological Tests ; }, abstract = {The clinical neuropsychologist has the opportunity to be uniquely involved in the evaluation and treatment of individuals with amyotrophic lateral sclerosis (ALS). We review the current literature that defines cognitive and behavioral symptoms in ALS, including current knowledge of the neuropathological and genetic underpinning for these symptoms. There are unique considerations for clinical neuropsychological evaluation and clinical research in ALS and we highlight these in this review. Specifically, we shed light on special factors that contribute to our understanding of cognitive and behavioral impairment in ALS, including co-morbid symptoms, differential diagnosis, and considerations for longitudinal tracking of phenotypes. We discuss the rationale for proposing a specific approach to such as cognitive screening, test selection, response modality consideration, and test-retest intervals. With this didactic overview, the clinical neuropsychologist has the potential to learn more about the heterogeneous presentation of motor and neuropsychological symptoms in ALS. Furthermore, the reader has the opportunity to understand what it takes to develop a valid assessment approach particularly when the phenotype of ALS remains undefined in some regards. This clinical practice review sets the stage for the clinical neuropsychologist to further contribute to our clinical and scientific understanding of ALS and cognition.}, }
@article {pmid29027011, year = {2018}, author = {Guillot-Sestier, MV and Town, T}, title = {Let's make microglia great again in neurodegenerative disorders.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {125}, number = {5}, pages = {751-770}, pmid = {29027011}, issn = {1435-1463}, support = {RF1 AG053982/AG/NIA NIH HHS/United States ; R21 AG053884/AG/NIA NIH HHS/United States ; ZEN-10-174633/ALZ/Alzheimer''s Association/United States ; R01 NS076794/NS/NINDS NIH HHS/United States ; 1R01NS076794-01/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Microglia/*immunology/pathology ; Neurodegenerative Diseases/*immunology/pathology ; }, abstract = {All of the common neurodegenerative disorders-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion diseases-are characterized by accumulation of misfolded proteins that trigger activation of microglia; brain-resident mononuclear phagocytes. This chronic form of neuroinflammation is earmarked by increased release of myriad cytokines and chemokines in patient brains and biofluids. Microglial phagocytosis is compromised early in the disease process, obfuscating clearance of abnormal proteins. This review identifies immune pathologies shared by the major neurodegenerative disorders. The overarching concept is that aberrant innate immune pathways can be targeted for return to homeostasis in hopes of coaxing microglia into clearing neurotoxic misfolded proteins.}, }
@article {pmid29024655, year = {2017}, author = {Kim, HJ and Taylor, JP}, title = {Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases.}, journal = {Neuron}, volume = {96}, number = {2}, pages = {285-297}, pmid = {29024655}, issn = {1097-4199}, support = {/HHMI/Howard Hughes Medical Institute/United States ; R35 NS097974/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/*physiology ; Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; C9orf72 Protein ; DNA-Binding Proteins/*genetics/*metabolism ; Humans ; Mutation/genetics ; Neurodegenerative Diseases/genetics ; Protein Transport/physiology ; Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord. The hallmark pathological feature in most cases of ALS is nuclear depletion and cytoplasmic accumulation of the protein TDP-43 in degenerating neurons. Consistent with this pattern of intracellular protein redistribution, impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to ALS pathology. Dysfunction in nucleocytoplasmic transport is also an emerging theme in physiological aging and other related neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. Here we review transport through the nuclear pore complex, pointing out vulnerabilities that may underlie ALS and potentially contribute to this and other age-related neurodegenerative diseases.}, }
@article {pmid29023416, year = {2017}, author = {De Luca, C and Virtuoso, A and Maggio, N and Papa, M}, title = {Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases.}, journal = {International journal of molecular sciences}, volume = {18}, number = {10}, pages = {}, pmid = {29023416}, issn = {1422-0067}, mesh = {Animals ; Astrocytes/metabolism ; *Blood Coagulation ; *Blood Coagulation Factors/metabolism ; Blood-Brain Barrier/metabolism ; Central Nervous System Diseases/*blood/diagnosis/etiology/therapy ; Humans ; Microglia/metabolism ; Neurons/metabolism ; Proteolysis ; Signal Transduction ; }, abstract = {Blood coagulation factors and other proteins, with modulatory effects or modulated by the coagulation cascade have been reported to affect the pathophysiology of the central nervous system (CNS). The protease-activated receptors (PARs) pathway can be considered the central hub of this regulatory network, mainly through thrombin or activated protein C (aPC). These proteins, in fact, showed peculiar properties, being able to interfere with synaptic homeostasis other than coagulation itself. These specific functions modulate neuronal networks, acting both on resident (neurons, astrocytes, and microglia) as well as circulating immune system cells and the extracellular matrix. The pleiotropy of these effects is produced through different receptors, expressed in various cell types, in a dose- and time-dependent pattern. We reviewed how these pathways may be involved in neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases), multiple sclerosis, ischemic stroke and post-ischemic epilepsy, CNS cancer, addiction, and mental health. These data open up a new path for the potential therapeutic use of the agonist/antagonist of these proteins in the management of several central nervous system diseases.}, }
@article {pmid28993751, year = {2017}, author = {Khalid, SI and Ampie, L and Kelly, R and Ladha, SS and Dardis, C}, title = {Immune Modulation in the Treatment of Amyotrophic Lateral Sclerosis: A Review of Clinical Trials.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {486}, pmid = {28993751}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing.}, }
@article {pmid28990513, year = {2019}, author = {Tellone, E and Galtieri, A and Russo, A and Ficarra, S}, title = {Protective Effects of the Caffeine Against Neurodegenerative Diseases.}, journal = {Current medicinal chemistry}, volume = {26}, number = {27}, pages = {5137-5151}, doi = {10.2174/0929867324666171009104040}, pmid = {28990513}, issn = {1875-533X}, mesh = {Animals ; Caffeine/chemistry/*pharmacology/*therapeutic use ; Humans ; Molecular Structure ; Neurodegenerative Diseases/*prevention &amp; control ; Neuroprotective Agents/chemistry/*pharmacology/*therapeutic use ; }, abstract = {BACKGROUND: Recent studies and increased interest of the scientific community helped to clarify the neurological health property of caffeine, one of the pharmacologically active substances most consumed in the world.<br><br>METHODS: This article is a review search to provide an overview on the current state of understanding neurobiochemical impact of caffeine, focusing on the ability of the drug to effectively counteract several neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's diseases, Multiple sclerosis and Amyotrophic lateral sclerosis.<br><br>RESULTS: Data collection shown in this review provide a significant therapeutic and prophylactic potentiality of caffeine which acts on human brain through several pathways because of its antioxidant activity combined with multiple molecular targets. However, the need to adjust the CF dosage to individuals, because some people are more sensitive to drugs than others, may constituted a limit to the CF effectiveness.<br><br>CONCLUSION: What emerges from the complex of clinical and epidemiological studies is a significant CF potential impact against all neurological disorders. Although, further studies are needed to fully elucidate the several mechanisms of drug action which in part are still elusive.}, }
@article {pmid28987183, year = {2017}, author = {Hortobágyi, T and Cairns, NJ}, title = {Amyotrophic lateral sclerosis and non-tau frontotemporal lobar degeneration.}, journal = {Handbook of clinical neurology}, volume = {145}, number = {}, pages = {369-381}, doi = {10.1016/B978-0-12-802395-2.00026-2}, pmid = {28987183}, issn = {0072-9752}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; C9orf72 Protein/genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/*metabolism ; Humans ; Mutation/genetics ; RNA-Binding Protein FUS/metabolism ; Superoxide Dismutase-1/metabolism ; tau Proteins/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the major motor neuron disorder. The hallmark features are progressive, irreversible motor neuron loss leading to denervation atrophy of muscles and death, usually within 5 years of disease onset. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43, or FUS; rarely the disease is caused by mutation of the respective genes. Frontotemporal lobar degeneration (FTLD) is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively. The characteristic aggregate-forming protein in non-tau FTLD is either TDP-43 or FUS. It has been known for several years that frontotemporal dementia (or less severe forms of cognitive impairment) may coexist with ALS. Recent discoveries in genetics (e.g., C9orf72 mutation) and the subsequent neuropathologic characterization have revealed remarkable overlap between ALS and non-tau FTLD also at a molecular level, indicating common molecular pathways in pathogenesis. After a historic overview we demonstrate and compare the macroscopic and microscopic appearances and molecular characteristics with emphasis on genetic background, neuroanatomic distribution, and morphology of abnormal protein aggregates and their possible association with specific mutations. The clinicopathologic classifications and correlations are also discussed.}, }
@article {pmid28982489, year = {2017}, author = {Robinson, MT and Holloway, RG}, title = {Palliative Care in Neurology.}, journal = {Mayo Clinic proceedings}, volume = {92}, number = {10}, pages = {1592-1601}, doi = {10.1016/j.mayocp.2017.08.003}, pmid = {28982489}, issn = {1942-5546}, mesh = {*Central Nervous System Diseases/diagnosis/physiopathology/psychology/therapy ; Humans ; *Palliative Care/ethics/methods/psychology ; Patient Care Planning/ethics/organization &amp; administration ; Prognosis ; *Quality of Life ; }, abstract = {Palliative medicine is a specialty that focuses on improving the quality of life for patients with serious or advanced medical conditions, and it is appropriate at any stage of disease, including at the time of diagnosis. Neurologic conditions tend to have high symptom burdens, variable disease courses, and poor prognoses that affect not only patients but also their families and caregivers. Patients with a variety of neurologic conditions such as Parkinson disease, dementia, amyotrophic lateral sclerosis, brain tumors, stroke, and acute neurologic illnesses have substantial unmet needs that can be addressed through a combination of primary and specialty palliative care. The complex needs of these patients are ideally managed with a comprehensive approach to care that addresses the physical, psychological, social, and spiritual aspects of care in an effort to reduce suffering. Early discussions about prognosis, goals of care, and advance care planning are critical as they can provide guidance for treatment decisions and allow patients to retain a sense of autonomy despite progressive cognitive or functional decline. With the rapid growth in palliative care across the United States, there are opportunities to improve the palliative care knowledge of neurology trainees, the delivery of palliative care to patients with neurologic disease by both neurologists and nonneurologists, and the research agenda for neuropalliative care.}, }
@article {pmid28982219, year = {2017}, author = {Radunovic, A and Annane, D and Rafiq, MK and Brassington, R and Mustfa, N}, title = {Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {10}, number = {10}, pages = {CD004427}, pmid = {28982219}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*mortality ; Disease Progression ; Humans ; Motor Neuron Disease/mortality ; *Quality of Life ; Randomized Controlled Trials as Topic ; Respiration, Artificial/methods/*mortality ; Respiratory Insufficiency/etiology/*mortality/therapy ; Survival Analysis ; Time Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009.<br><br>OBJECTIVES: To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies.<br><br>SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care.<br><br>DATA COLLECTION AND ANALYSIS: For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies.<br><br>MAIN RESULTS: For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of NIV (13 participants). We contacted the trial authors, who were not able to provide the missing data. The conclusions of the review were therefore based on a single study of 41 participants comparing NIV with standard care. Lack of (or uncertain) blinding represented a risk of bias for participant- and clinician-assessed outcomes such as quality of life, but it was otherwise a well-conducted study with a low risk of bias.The study provided moderate-quality evidence that overall median survival was significantly different between the group treated with NIV and the standard care group. The median survival in the NIV group was 48 days longer (219 days compared to 171 days for the standard care group (estimated 95% confidence interval 12 to 91 days, P = 0.0062)). This survival benefit was accompanied by an enhanced quality of life. On subgroup analysis, in the subgroup with normal to moderately impaired bulbar function (20 participants), median survival was 205 days longer (216 days in the NIV group versus 11 days in the standard care group, P = 0.0059), and quality of life measures were better than with standard care (low-quality evidence). In the participants with poor bulbar function (21 participants), NIV did not prolong survival or improve quality of life, although there was significant improvement in the mean symptoms domain of the Sleep Apnea Quality of Life Index by some measures. Neither trial reported clinical data on intervention-related adverse effects.<br><br>AUTHORS' CONCLUSIONS: Moderate-quality evidence from a single RCT of NIV in 41 participants suggests that it significantly prolongs survival, and low-quality evidence indicates that it improves or maintains quality of life in people with ALS. Survival and quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment. Adverse effects related to NIV should be systematically reported, as at present there is little information on this subject. More RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable. Future studies should examine the benefits of early intervention with NIV and establish the most appropriate timing for initiating NIV in order to obtain its maximum benefit. The effect of adding cough augmentation techniques to NIV also needs to be investigated in an RCT. Future studies should examine the health economics of NIV. Access to NIV remains restricted in many parts of the world, including Europe and North America. We need to understand the factors, personal and socioeconomic, that determine access to NIV.}, }
@article {pmid28980860, year = {2017}, author = {Uversky, VN}, title = {The roles of intrinsic disorder-based liquid-liquid phase transitions in the "Dr. Jekyll-Mr. Hyde" behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Autophagy}, volume = {13}, number = {12}, pages = {2115-2162}, pmid = {28980860}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Autophagy ; Cytoplasmic Granules/metabolism ; Frontotemporal Lobar Degeneration/*metabolism/pathology ; Humans ; *Phase Transition ; Proteins/*metabolism ; }, abstract = {Pathological developments leading to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are associated with misbehavior of several key proteins, such as SOD1 (superoxide dismutase 1), TARDBP/TDP-43, FUS, C9orf72, and dipeptide repeat proteins generated as a result of the translation of the intronic hexanucleotide expansions in the C9orf72 gene, PFN1 (profilin 1), GLE1 (GLE1, RNA export mediator), PURA (purine rich element binding protein A), FLCN (folliculin), RBM45 (RNA binding motif protein 45), SS18L1/CREST, HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), ATXN2 (ataxin 2), MAPT (microtubule associated protein tau), and TIA1 (TIA1 cytotoxic granule associated RNA binding protein). Although these proteins are structurally and functionally different and have rather different pathological functions, they all possess some levels of intrinsic disorder and are either directly engaged in or are at least related to the physiological liquid-liquid phase transitions (LLPTs) leading to the formation of various proteinaceous membrane-less organelles (PMLOs), both normal and pathological. This review describes the normal and pathological functions of these ALS- and FTLD-related proteins, describes their major structural properties, glances at their intrinsic disorder status, and analyzes the involvement of these proteins in the formation of normal and pathological PMLOs, with the ultimate goal of better understanding the roles of LLPTs and intrinsic disorder in the "Dr. Jekyll-Mr. Hyde" behavior of those proteins.}, }
@article {pmid28980624, year = {2017}, author = {Hardiman, O and Al-Chalabi, A and Chio, A and Corr, EM and Logroscino, G and Robberecht, W and Shaw, PJ and Simmons, Z and van den Berg, LH}, title = {Amyotrophic lateral sclerosis.}, journal = {Nature reviews. Disease primers}, volume = {3}, number = {}, pages = {17071}, doi = {10.1038/nrdp.2017.71}, pmid = {28980624}, issn = {2056-676X}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/physiopathology/therapy ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Until recently, ALS was classified primarily within the neuromuscular domain, although new imaging and neuropathological data have indicated the involvement of the non-motor neuraxis in disease pathology. In most patients, the mechanisms underlying the development of ALS are poorly understood, although a subset of patients have familial disease and harbour mutations in genes that have various roles in neuronal function. Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.}, }
@article {pmid28980404, year = {2017}, author = {Moretti, M and Fraga, DB and Rodrigues, ALS}, title = {Preventive and therapeutic potential of ascorbic acid in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {23}, number = {12}, pages = {921-929}, pmid = {28980404}, issn = {1755-5949}, mesh = {Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/*prevention &amp; control ; }, abstract = {In this review, we summarize the involvement of ascorbic acid in neurodegenerative diseases by presenting available evidence on the behavioral and biochemical effects of this compound in animal models of neurodegeneration as well as the use of ascorbic acid as a therapeutic approach to alleviate neurodegenerative progression in clinical studies. Ascorbate, a reduced form of vitamin C, has gained interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. In the brain, ascorbate exerts neuromodulatory functions and scavenges reactive oxygen species generated during synaptic activity and neuronal metabolism. These are important properties as redox imbalance and abnormal protein aggregation constitute central mechanisms implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Indeed, several studies have indicated an association between low serum ascorbate concentrations and neurodegeneration. Moreover, ascorbic acid is a suitable candidate for supplying either antioxidant defense or modulation of neuronal and astrocytic metabolism under neurodegenerative conditions. Ascorbic acid acts mainly by decreasing oxidative stress and reducing the formation of protein aggregates, which may contribute to the reduction of cognitive and/or motor impairments observed in neurodegenerative processes. Although several studies support a possible role of ascorbic acid administration against neurodegeneration, more researches are essential to substantiate the existing results and accelerate the knowledge in this field.}, }
@article {pmid28978660, year = {2017}, author = {van Eijk, RPA and Jones, AR and Sproviero, W and Shatunov, A and Shaw, PJ and Leigh, PN and Young, CA and Shaw, CE and Mora, G and Mandrioli, J and Borghero, G and Volanti, P and Diekstra, FP and van Rheenen, W and Verstraete, E and Eijkemans, MJC and Veldink, JH and Chio, A and Al-Chalabi, A and van den Berg, LH and van Es, MA and , }, title = {Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.}, journal = {Neurology}, volume = {89}, number = {18}, pages = {1915-1922}, pmid = {28978660}, issn = {1526-632X}, support = {AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; JONES/OCT15/958-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0300329/MRC_/Medical Research Council/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; C9orf72 Protein ; Genotype ; Lithium Carbonate/therapeutic use ; Nerve Tissue Proteins/genetics ; Neuroprotective Agents/*therapeutic use ; *Pharmacogenetics ; Proportional Hazards Models ; Proteins/genetics ; *Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.<br><br>METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.<br><br>RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).<br><br>CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.}, }
@article {pmid28977445, year = {2017}, author = {Medinas, DB and Valenzuela, V and Hetz, C}, title = {Proteostasis disturbance in amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {26}, number = {R2}, pages = {R91-R104}, doi = {10.1093/hmg/ddx274}, pmid = {28977445}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Animals ; Autophagy/physiology ; Humans ; Motor Neurons/metabolism ; Protein Aggregation, Pathological/physiopathology ; Protein Folding ; Protein Transport/physiology ; Proteostasis/*physiology ; Risk Factors ; Spinal Cord/metabolism ; Ubiquitination ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motoneurons in the brain and spinal cord leading to paralysis and death. Although the etiology of ALS remains poorly understood, abnormal protein aggregation and altered proteostasis are common features of sporadic and familial ALS forms. The proteostasis network is decomposed into different modules highly conserved across species and comprehends a collection of mechanisms related to protein synthesis, folding, trafficking, secretion and degradation that is distributed in different compartments inside the cell. Functional studies in various ALS models are revealing a complex scenario where distinct and even opposite effects in disease progression are observed depending on the targeted component of the proteostasis network. Importantly, alteration of the folding capacity of the endoplasmic reticulum (ER) is becoming a common pathological alteration in ALS, representing one of the earliest defects observed in disease models, contributing to denervation and motoneuron dysfunction. Strategies to target-specific components of the proteostasis network using small molecules and gene therapy are under development, and promise interesting avenues for future interventions to delay or stop ALS progression.}, }
@article {pmid28977441, year = {2017}, author = {Niccoli, T and Partridge, L and Isaacs, AM}, title = {Ageing as a risk factor for ALS/FTD.}, journal = {Human molecular genetics}, volume = {26}, number = {R2}, pages = {R105-R113}, doi = {10.1093/hmg/ddx247}, pmid = {28977441}, issn = {1460-2083}, mesh = {Active Transport, Cell Nucleus/genetics ; Aging/genetics/physiology ; Amyotrophic Lateral Sclerosis/complications/*genetics/physiopathology ; Autophagy/genetics ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics/*physiopathology ; Humans ; Inflammation/metabolism ; Lysosomes/metabolism ; Mutation ; RNA Splicing/genetics ; Risk Factors ; }, abstract = {Like many other neurodegenerative diseases, age is a major risk factor in the development of ALS/FTD. But why is this the case? Recent genetic advances have highlighted some of pathways involved in the development of disease, and, strikingly, they appear to substantially overlap with those known to directly modulate the ageing process. Many ALS/FTD linked genes play a direct role in autophagy/lysosomal degradation, one of the most important pathways linked to ageing. However, systemic processes such as inflammation, as well as cellular maintenance pathways, including RNA splicing and nuclear-cytoplasmic transport have been increasingly linked both to disease and ageing. We highlight some of the shared mechanisms between the ageing process itself and emerging pathogenic mechanisms in ALS/FTD.}, }
@article {pmid28972545, year = {2017}, author = {Cappello, V and Francolini, M}, title = {Neuromuscular Junction Dismantling in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {18}, number = {10}, pages = {}, pmid = {28972545}, issn = {1422-0067}, mesh = {Aging ; Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Humans ; Motor Neurons/pathology ; Muscle, Skeletal/innervation/pathology/physiopathology ; Neuroglia/pathology ; Neuromuscular Junction/*pathology/physiopathology ; Schwann Cells/pathology ; Synapses/pathology ; }, abstract = {Neuromuscular junction assembly and plasticity during embryonic, postnatal, and adult life are tightly regulated by the continuous cross-talk among motor nerve endings, muscle fibers, and glial cells. Altered communications among these components is thought to be responsible for the physiological age-related changes at this synapse and possibly for its destruction in pathological states. Neuromuscular junction dismantling plays a crucial role in the onset of Amyotrophic Lateral Sclerosis (ALS). ALS is characterized by the degeneration and death of motor neurons leading to skeletal muscle denervation, atrophy and, most often, death of the patient within five years from diagnosis. ALS is a non-cell autonomous disease as, besides motor neuron degeneration, glial cells, and possibly muscle fibers, play a role in its onset and progression. Here, we will review the recent literature regarding the mechanisms leading to neuromuscular junction disassembly and muscle denervation focusing on the role of the three players of this peripheral tripartite synapse.}, }
@article {pmid28971036, year = {2017}, author = {Bach, JR}, title = {Noninvasive Respiratory Management of Patients With Neuromuscular Disease.}, journal = {Annals of rehabilitation medicine}, volume = {41}, number = {4}, pages = {519-538}, pmid = {28971036}, issn = {2234-0645}, abstract = {This review article describes definitive noninvasive respiratory management of respiratory muscle dysfunction to eliminate need to resort to tracheotomy. In 2010 clinicians from 22 centers in 18 countries reported 1,623 spinal muscular atrophy type 1 (SMA1), Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis users of noninvasive ventilatory support (NVS) of whom 760 required it continuously (CNVS). The CNVS sustained their lives by over 3,000 patient-years without resort to indwelling tracheostomy tubes. These centers have now extubated at least 74 consecutive ventilator unweanable patients with DMD, over 95% of CNVS-dependent patients with SMA1, and hundreds of others with advanced neuromuscular disorders (NMDs) without resort to tracheotomy. Two centers reported a 99% success rate at extubating 258 ventilator unweanable patients without resort to tracheotomy. Patients with myopathic or lower motor neuron disorders can be managed noninvasively by up to CNVS, indefinitely, despite having little or no measurable vital capacity, with the use of physical medicine respiratory muscle aids. Ventilator-dependent patients can be decannulated of their tracheostomy tubes.}, }
@article {pmid28968371, year = {2017}, author = {Simmons, Z}, title = {Right-to-Try Investigational Therapies for Incurable Disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {23}, number = {5, Peripheral Nerve and Motor Neuron Disorders}, pages = {1451-1457}, doi = {10.1212/CON.0000000000000515}, pmid = {28968371}, issn = {1538-6899}, mesh = {Compassionate Use Trials/*ethics/*legislation &amp; jurisprudence ; Humans ; Therapies, Investigational/*ethics ; United States ; }, abstract = {Patients with life-threatening disorders such as amyotrophic lateral sclerosis, for which only minimally effective medical therapies currently exist, often seek treatments not proven to be effective and not approved by regulatory agencies for use outside of experimental treatment trials. The expanded access (compassionate use) provisions of the US Food and Drug Administration (FDA) for access to such therapies are often perceived as being inadequate. In response, states have passed right-to-try laws designed to improve access to experimental therapies for patients willing to assume the risks associated with such treatments. This situation has resulted in conflicts between those who perceive access to such treatments as their right as autonomous individuals and those who believe that the principles of beneficence and nonmaleficence justify actions of physicians and regulators in controlling access to such treatments. A variety of factors also contribute to the inequitable distribution of such treatments. Better systems are needed to improve access to promising new treatments while protecting these vulnerable patients from the abuses associated with human research in the preregulatory era.}, }
@article {pmid28968365, year = {2017}, author = {Goutman, SA}, title = {Diagnosis and Clinical Management of Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {23}, number = {5, Peripheral Nerve and Motor Neuron Disorders}, pages = {1332-1359}, doi = {10.1212/CON.0000000000000535}, pmid = {28968365}, issn = {1538-6899}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Humans ; *Motor Neuron Disease/diagnosis/genetics/therapy ; }, abstract = {PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic pathway, therapies, and current understanding of the pathophysiology of amyotrophic lateral sclerosis (ALS). The spectrum of motor neuron diseases is reviewed, and the clinical heterogeneity of ALS is described.<br><br>RECENT FINDINGS: ALS is increasingly recognized as a clinical spectrum disorder with pure upper and pure lower motor neuron presentations, supported by genetic links. The phenotypic variability is broad. Identification of ALS-related genes provides insights into disease mechanisms.<br><br>SUMMARY: ALS is a progressive fatal multisystem neurodegenerative disease primarily affecting motor neurons. Clinical recognition of suspicious symptoms and the appropriate laboratory evaluation are essential to limit diagnostic delay and avoid unnecessary testing and procedures. ALS has broad genetic and hypothesized environmental causes and phenotypic variability. Recognizing related motor neuron diseases will prevent misdiagnosis while allowing proper disease counseling. Although ALS cannot be cured, implementation of appropriate symptomatic treatment is valuable.}, }
@article {pmid28965171, year = {2018}, author = {Longhena, F and Spano, P and Bellucci, A}, title = {Targeting of Disordered Proteins by Small Molecules in Neurodegenerative Diseases.}, journal = {Handbook of experimental pharmacology}, volume = {245}, number = {}, pages = {85-110}, doi = {10.1007/164_2017_60}, pmid = {28965171}, issn = {0171-2004}, mesh = {Amyloid beta-Peptides/antagonists &amp; inhibitors/chemistry ; Humans ; Neurodegenerative Diseases/*drug therapy/etiology ; Prion Proteins/antagonists &amp; inhibitors/chemistry ; Protein Aggregation, Pathological/*drug therapy ; Superoxide Dismutase-1/antagonists &amp; inhibitors/chemistry ; alpha-Synuclein/antagonists &amp; inhibitors/chemistry ; }, abstract = {The formation of protein aggregates and inclusions in the brain and spinal cord is a common neuropathological feature of a number of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and many others. These are commonly referred as neurodegenerative proteinopathies or protein-misfolding diseases. The main characteristic of protein aggregates in these disorders is the fact that they are enriched in amyloid fibrils. Since protein aggregation is considered to play a central role for the onset of neurodegenerative proteinopathies, research is ongoing to develop strategies aimed at preventing or removing protein aggregation in the brain of affected patients. Numerous studies have shown that small molecule-based approaches may be potentially the most promising for halting protein aggregation in neurodegenerative diseases. Indeed, several of these compounds have been found to interact with intrinsically disordered proteins and promote their clearing in experimental models. This notwithstanding, at present small molecule inhibitors still awaits achievements for clinical translation. Hopefully, if we determine whether the formation of insoluble inclusions is effectively neurotoxic and find a valid biomarker to assess their protein aggregation-inhibitory activity in the human central nervous system, the use of small molecule inhibitors will be considered as a cure for neurodegenerative protein-misfolding diseases.}, }
@article {pmid28960544, year = {2018}, author = {Takeda, T}, title = {Possible concurrence of TDP-43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {38}, number = {1}, pages = {72-81}, doi = {10.1111/neup.12428}, pmid = {28960544}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Brain/pathology ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/metabolism/*pathology ; Humans ; Inclusion Bodies/metabolism/pathology ; tau Proteins/*metabolism ; }, abstract = {Transactivation response DNA-binding protein 43 kDa (TDP-43) has been regarded as a major component of ubiquitin-positive/tau-negative inclusions of motor neurons and the frontotemporal cortices in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Neurofibrillary tangles (NFT), an example of tau-positive inclusions, are biochemically and morphologically distinguished from TDP-43-positive inclusions, and are one of the pathological core features of Alzheimer disease (AD). Although ALS/FTLD and AD are distinct clinical entities, they can coexist in an individual patient. Whether concurrence of ALS/FTLD-TDP-43 and AD-tau is incidental is still controversial, because aging is a common risk factor for ALS/FTLD and AD development. Indeed, it remains unclear whether the pathogenesis of ALS/FTLD is a direct causal link to tau accumulation. Recent studies suggested that AD pathogenesis could cause the accumulation of TDP-43, while abnormal TDP-43 accumulation could also lead to abnormal tau expression. Overlapping presence of TDP-43 and tau, when observed in a brain during autopsy, should attract attention, and should initiate the search for the pathological substrate for this abnormal protein accumulation. In addition to tau, other proteins including α-synuclein and amyloid β should be also taken into account as candidates for an interaction with TDP-43. Awareness of a possible comorbidity between TDP-43, tau and other proteins in patients with ALS/FTLD will be useful for our understanding of the influence of these proteins on the disease development and its clinical manifestation.}, }
@article {pmid28955296, year = {2017}, author = {Velázquez-Pérez, LC and Rodríguez-Labrada, R and Fernandez-Ruiz, J}, title = {Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {472}, pmid = {28955296}, issn = {1664-2295}, abstract = {Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits.}, }
@article {pmid28952628, year = {2017}, author = {Lacerda, S and Morfin, JF and Geraldes, CFGC and Tóth, &#xc9;}, title = {Metal complexes for multimodal imaging of misfolded protein-related diseases.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {46}, number = {42}, pages = {14461-14474}, doi = {10.1039/c7dt02371e}, pmid = {28952628}, issn = {1477-9234}, mesh = {Amyloid beta-Peptides/chemistry ; Animals ; *Coordination Complexes/chemistry ; Humans ; Multimodal Imaging/*methods ; Protein Aggregates ; Proteostasis Deficiencies/*diagnostic imaging/metabolism ; }, abstract = {Aggregation of misfolded proteins and progressive polymerization of otherwise soluble proteins is a common hallmark of a wide range of highly debilitating and increasingly prevalent diseases, including amyotrophic lateral sclerosis, cerebral amyloid angiopathy, type II diabetes and Parkinson's, Huntington's and Alzheimer's diseases. There is a growing interest in creating imaging agents to detect such aggregates in various imaging modalities, including PET, SPECT and MRI. We present here an overview of recent efforts from the perspective of early diagnosis of amyloid diseases, with a major focus on Aβ detection and metal complexes bearing PiB units.}, }
@article {pmid28951720, year = {2017}, author = {Galieva, LR and Mukhamedshina, YO and Arkhipova, SS and Rizvanov, AA}, title = {Human Umbilical Cord Blood Cell Transplantation in Neuroregenerative Strategies.}, journal = {Frontiers in pharmacology}, volume = {8}, number = {}, pages = {628}, pmid = {28951720}, issn = {1663-9812}, abstract = {At present there is no effective treatment of pathologies associated with the death of neurons and glial cells which take place as a result of physical trauma or ischemic lesions of the nervous system. Thus, researchers have high hopes for a treatment based on the use of stem cells (SC), which are potentially able to replace dead cells and synthesize neurotrophic factors and other molecules that stimulate neuroregeneration. We are often faced with ethical issues when selecting a source of SC. In addition to precluding these, human umbilical cord blood (hUCB) presents a number of advantages when compared with other sources of SC. In this review, we consider the key characteristics of hUCB, the results of various studies focused on the treatment of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), ischemic (stroke) and traumatic injuries of the nervous system and the molecular mechanisms of hUCB-derived mononuclear and stem cells.}, }
@article {pmid28943839, year = {2017}, author = {Kalmar, B and Greensmith, L}, title = {Cellular Chaperones As Therapeutic Targets in ALS to Restore Protein Homeostasis and Improve Cellular Function.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {251}, pmid = {28943839}, issn = {1662-5099}, abstract = {Heat shock proteins (Hsps) are ubiquitously expressed chaperone proteins that enable cells to cope with environmental stresses that cause misfolding and denaturation of proteins. With aging this protein quality control machinery becomes less effective, reducing the ability of cells to cope with damaging environmental stresses and disease-causing mutations. In neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), such mutations are known to result in protein misfolding, which in turn results in the formation of intracellular aggregates cellular dysfunction and eventual neuronal death. The exact cellular pathology of ALS and other neurodegenerative diseases has been elusive and thus, hindering the development of effective therapies. However, a common scheme has emerged across these "protein misfolding" disorders, in that the mechanism of disease involves one or more aspects of proteostasis; from DNA transcription, RNA translation, to protein folding, transport and degradation via proteosomal and autophagic pathways. Interestingly, members of the Hsp family are involved in each of these steps facilitating normal protein folding, regulating the rate of protein synthesis and degradation. In this short review we summarize the evidence that suggests that ALS is a disease of protein dyshomeostasis in which Hsps may play a key role. Overwhelming evidence now indicates that enabling protein homeostasis to cope with disease-causing mutations might be a successful therapeutic strategy in ALS, as well as other neurodegenerative diseases. Novel small molecule co-inducers of Hsps appear to be able to achieve this aim. Arimoclomol, a hydroxylamine derivative, has shown promising results in cellular and animal models of ALS, as well as other protein misfolding diseases such as Inclusion Body Myositis (IBM). Initial clinical investigations of Arimoclomol have shown promising results. Therefore, it is possible that the long series of unsuccessful clinical trials for ALS may soon be reversed, as optimal targeting of proteostasis in ALS may now be possible, and may deliver clinical benefit to patients.}, }
@article {pmid28939972, year = {2018}, author = {Farinato, A and Altamura, C and Desaphy, JF}, title = {Effects of Benzothiazolamines on Voltage-Gated Sodium Channels.}, journal = {Handbook of experimental pharmacology}, volume = {246}, number = {}, pages = {233-250}, doi = {10.1007/164_2017_46}, pmid = {28939972}, issn = {0171-2004}, mesh = {Animals ; Humans ; Myotonia/drug therapy ; Piperidines/*pharmacology/therapeutic use ; Riluzole/*pharmacology/therapeutic use ; Thiazoles/*pharmacology/therapeutic use ; Voltage-Gated Sodium Channels/*drug effects ; }, abstract = {Benzothiazole is a versatile fused heterocycle that aroused much interest in drug discovery as anticonvulsant, neuroprotective, analgesic, anti-inflammatory, antimicrobial, and anticancer. Two benzothiazolamines, riluzole and lubeluzole, are known blockers of voltage-gated sodium (Nav) channels. Riluzole is clinically used as a neuroprotectant in amyotrophic lateral sclerosis. Inhibition of Nav channels by riluzole is voltage-dependent due to preferential binding to inactivated sodium channels. Yet the drug exerts little use-dependent block, probably because it lacks protonable amine. One important property is riluzole ability to inhibit persistent Na[+] currents, which likely contributes to its neuroprotective activity. Lubeluzole showed promising neuroprotective effects in animal stroke models, but failed to show benefits in acute ischemic stroke in humans. One important concern is its propensity to prolong the cardiac QT interval, due to hERG K[+] channel block. Lubeluzole very potently inhibits Nav channels in a voltage- and use-dependent manner, due to its great preferential affinity for inactivated channels and the presence of a protonable amine group. Patch-clamp experiments suggest that the binding sites of both drugs overlap the local anesthetic receptor within the ion-conducting pathway. Riluzole and lubeluzole displayed very potent antimyotonic activity in a rat model of myotonia, a pathological skeletal muscle condition characterized by high-frequency runs of action potentials. Such results well support the repurposing of riluzole as an antimyotonic drug, allowing the launch of a pilot study in myotonic patients. Riluzole, lubeluzole, and new Nav channel blockers built on the benzothiazolamine scaffold will certainly continue to be investigated for possible clinical applications.}, }
@article {pmid28933017, year = {2017}, author = {Sanchez, B and Rutkove, SB}, title = {Present Uses, Future Applications, and Technical Underpinnings of Electrical Impedance Myography.}, journal = {Current neurology and neuroscience reports}, volume = {17}, number = {11}, pages = {86}, doi = {10.1007/s11910-017-0793-3}, pmid = {28933017}, issn = {1534-6293}, mesh = {*Electric Impedance ; Electromyography/*methods/*trends ; Humans ; Muscle, Skeletal/physiopathology ; Neuromuscular Diseases/*diagnosis/*physiopathology ; }, abstract = {PURPOSE OF REVIEW: In this article, we provide an overview of electrical impedance myography (EIM), including its technical and theoretical basis, a summary of its varied applications, and ongoing developments.<br><br>RECENT FINDINGS: EIM has been used as a disease severity biomarker in a variety of disorders affecting the muscle, ranging from amyotrophic lateral sclerosis (ALS) to muscular dystrophies to disuse atrophy due to the weightlessness of space. In ALS, studies have demonstrated that major reductions in sample size in clinical trials can be achieved. Similarly, in the Duchenne muscular dystrophy, the technique tracks disease progression and is sensitive to the beneficial effect of steroids. More basic work has demonstrated that EIM can provide a non-invasive means of tracking muscle fiber size. Ongoing innovations include the development of techniques for assessing muscle contraction. EIM is gradually being adopted as a useful, practical, and convenient tool for the assessment of neuromuscular conditions.}, }
@article {pmid28931454, year = {2018}, author = {Holkham, L and Soundy, A}, title = {The experience of informal caregivers of patients with motor neurone disease: A thematic synthesis.}, journal = {Palliative &amp; supportive care}, volume = {16}, number = {4}, pages = {487-496}, doi = {10.1017/S1478951517000852}, pmid = {28931454}, issn = {1478-9523}, mesh = {Caregivers/*psychology ; Cost of Illness ; Humans ; Motor Neuron Disease/*complications/psychology ; Patient Care/methods/*psychology ; Qualitative Research ; Quality of Life/psychology ; }, abstract = {UNLABELLED: ABSTRACTObjective:Research is required in order to illustrate and detail the experiences of informal caregivers of patients with motor neurone disease (pwMND) to further advance the research base and to inform the development of future support structures and services. Due to the heterogeneous nature of caregiving for pwMND, one way in which this can be achieved is through a qualitative review. A qualitative thematic analysis of existing qualitative studies has not, to the best of the authors' knowledge, been previously undertaken. Thus, the present synthesis aims to identify caregivers' experiences and to suggest factors that contribute to these experiences in order to fulfill the required research needs.<br><br>METHOD: A thematic synthesis of qualitative literature was conducted. AMED, Medline, SPORTDiscus, CINAHL, and PubMed were electronically searched from inception until September of 2015. Studies were eligible if they included qualitative literature reporting on firsthand experience of informal caregivers of patients with MND, were published in English, and contained verbatim quotations. Critical appraisal was undertaken using a 13-item consolidated criteria for reporting qualitative studies (COREQ) checklist.<br><br>RESULTS: A total of 10 studies met the inclusion criteria, with 148 (50 male) current or previous informal caregivers of pwMND identified. Critical appraisal demonstrated that study design and reflexivity were underreported. The synthesis derived three themes: (1) loss of control, (2) inability to choose, and (3) isolation.<br><br>SIGNIFICANCE OF RESULTS: The synthesis highlighted the factors that contribute to both positive and negative caregiving experiences. Through these experiences, such suggestions for service provision as improving communication with healthcare professionals and having a single point of contact emerged. However, the outcome of such suggestions on the experience of caregivers is beyond the scope of our synthesis, so that further research is required.}, }
@article {pmid28930607, year = {2018}, author = {Krokidis, MG and Vlamos, P}, title = {Transcriptomics in amyotrophic lateral sclerosis.}, journal = {Frontiers in bioscience (Elite edition)}, volume = {10}, number = {1}, pages = {103-121}, doi = {10.2741/e811}, pmid = {28930607}, issn = {1945-0508}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Disease Progression ; Gene Expression Regulation ; Humans ; Oligonucleotide Array Sequence Analysis ; RNA Processing, Post-Transcriptional ; *Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, incurable neurodegenerative disease characterized by the selective death of upper and lowers motor neurons in the spinal cord, brainstem and motor cortex, which ultimately leads to paralysis and death within 2-3 years of onset. ALS is poorly understood, although multiple studies have been proposed to explain the pathophysiological mechanisms of the disorder. The development of microarray technology, for simultaneous analysis of the transcriptional expression of thousands of genes, has provided new possibilities to get better insights into the pathogenesis of ALS, and most important, potential new candidate targets for novel treatments. The present review illustrates current evidences from transcriptomic studies in animal models and human samples, related to ALS pathogenesis in parallel to molecular targets associated with the disease progression. Additionally, alteration of RNA metabolism was identified as a major dysregulated pathway in ALS and via this study, new insights into the contribution of altered transcriptional profiles of microRNAs and ALS-associated ribosomal binding proteins have been investigated, in an effort to understand the functional consequences of widespread RNA dysregulation in the disease's pathological mechanism.}, }
@article {pmid28929385, year = {2018}, author = {Metcalf, JS and Dunlop, RA and Powell, JT and Banack, SA and Cox, PA}, title = {L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {213-221}, pmid = {28929385}, issn = {1476-3524}, mesh = {Animals ; Humans ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Serine/*therapeutic use ; }, abstract = {In human neuroblastoma cell cultures, non-human primates and human beings, L-serine is neuroprotective, acting through a variety of biochemical and molecular mechanisms. Although L-serine is generally classified as a non-essential amino acid, it is probably more appropriate to term it as a "conditional non-essential amino acid" since, under certain circumstances, vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine. Physiologically, it has a variety of roles, perhaps most importantly as a phosphorylation site in proteins. Mutations in the metabolic enzymes that synthesize L-serine have been implicated in various human diseases. Dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine support the FDA's determination that L-serine is generally regarded as safe (GRAS); it also appears to be neuroprotective. We here consider the role of L-serine in neurological disorders and its potential as a therapeutic agent.}, }
@article {pmid28928628, year = {2017}, author = {Salvadores, N and Sanhueza, M and Manque, P and Court, FA}, title = {Axonal Degeneration during Aging and Its Functional Role in Neurodegenerative Disorders.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {451}, pmid = {28928628}, issn = {1662-4548}, abstract = {Aging constitutes the main risk factor for the development of neurodegenerative diseases. This represents a major health issue worldwide that is only expected to escalate due to the ever-increasing life expectancy of the population. Interestingly, axonal degeneration, which occurs at early stages of neurodegenerative disorders (ND) such as Alzheimer's disease, Amyotrophic lateral sclerosis, and Parkinson's disease, also takes place as a consequence of normal aging. Moreover, the alteration of several cellular processes such as proteostasis, response to cellular stress and mitochondrial homeostasis, which have been described to occur in the aging brain, can also contribute to axonal pathology. Compelling evidence indicate that the degeneration of axons precedes clinical symptoms in NDs and occurs before cell body loss, constituting an early event in the pathological process and providing a potential therapeutic target to treat neurodegeneration before neuronal cell death. Although, normal aging and the development of neurodegeneration are two processes that are closely linked, the molecular basis of the switch that triggers the transition from healthy aging to neurodegeneration remains unrevealed. In this review we discuss the potential role of axonal degeneration in this transition and provide a detailed overview of the literature and current advances in the molecular understanding of the cellular changes that occur during aging that promote axonal degeneration and then discuss this in the context of ND.}, }
@article {pmid28926091, year = {2018}, author = {Lo Furno, D and Mannino, G and Giuffrida, R}, title = {Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases.}, journal = {Journal of cellular physiology}, volume = {233}, number = {5}, pages = {3982-3999}, doi = {10.1002/jcp.26192}, pmid = {28926091}, issn = {1097-4652}, mesh = {Alzheimer Disease/physiopathology/therapy ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; *Cell- and Tissue-Based Therapy ; Humans ; Huntington Disease/pathology/therapy ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/physiology ; Neurodegenerative Diseases/physiopathology/*therapy ; Neurogenesis/*physiology ; Neurons/transplantation ; Parkinson Disease/physiopathology/therapy ; Umbilical Cord/transplantation ; }, abstract = {Mesenchymal stem cells (MSCs) can differentiate into not only cells of mesodermal lineages, but also into endodermal and ectodermal derived elements, including neurons and glial cells. For this reason, MSCs have been extensively investigated to develop cell-based therapeutic strategies, especially in pathologies whose pharmacological treatments give poor results, if any. As in the case of irreversible neurological disorders characterized by progressive neuronal death, in which behavioral and cognitive functions of patients inexorably decline as the disease progresses. In this review, we focus on the possible functional role exerted by MSCs in the treatment of some disabling neurodegenerative disorders such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Parkinson's Disease. Investigations have been mainly performed in vitro and in animal models by using MSCs generally originated from umbilical cord, bone marrow, or adipose tissue. Positive results obtained have prompted several clinical trials, the number of which is progressively increasing worldwide. To date, many of them have been primarily addressed to verify the safety of the procedures but some improvements have already been reported, fortunately. Although the exact mechanisms of MSC-induced beneficial activities are not entirely defined, they include neurogenesis and angiogenesis stimulation, antiapoptotic, immunomodulatory, and anti-inflammatory actions. Most effects would be exerted through their paracrine expression of neurotrophic factors and cytokines, mainly delivered at damaged regions, given the innate propensity of MSCs to home to injured sites. Hopefully, in the near future more efficacious cell-replacement therapies will be developed to substantially restore disease-disrupted brain circuitry.}, }
@article {pmid28923363, year = {2018}, author = {Spagnuolo, C and Moccia, S and Russo, GL}, title = {Anti-inflammatory effects of flavonoids in neurodegenerative disorders.}, journal = {European journal of medicinal chemistry}, volume = {153}, number = {}, pages = {105-115}, doi = {10.1016/j.ejmech.2017.09.001}, pmid = {28923363}, issn = {1768-3254}, mesh = {Animals ; Anti-Inflammatory Agents/chemistry/pharmacology/*therapeutic use ; Flavonoids/chemistry/pharmacology/*therapeutic use ; Humans ; Inflammation/complications/*drug therapy/immunology/pathology ; MAP Kinase Signaling System/drug effects ; Microglia/drug effects/immunology/pathology ; NF-kappa B/immunology ; Neurodegenerative Diseases/complications/*drug therapy/immunology/pathology ; Neuroprotective Agents/chemistry/pharmacology/*therapeutic use ; Signal Transduction/drug effects ; }, abstract = {Neuroinflammation is one of the main mechanisms involved in the progression of several neurodegenerative diseases, such as Parkinson, Alzheimer, multiple sclerosis, amyotrophic lateral sclerosis and others. The activation of microglia is the main feature of neuroinflammation, promoting the release of pro-inflammatory cytokines and resulting in the progressive neuronal cell death. Natural compounds, such as flavonoids, possess neuroprotective potential probably related to their ability to modulate the inflammatory responses involved in neurodegenerative diseases. In fact, pure flavonoids (e.g., quercetin, genistein, hesperetin, epigallocatechin-3-gallate) or enriched-extracts, can reduce the expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2), down-regulate inflammatory markers and prevent neural damage. This anti-inflammatory activity is primarily related to the regulation of microglial cells, mediated by their effects on MAPKs and NF-κB signalling pathways, as demonstrated by in vivo and in vitro data. The present work reviews the role of inflammation in neurodegenerative diseases, highlighting the potential therapeutic effects of flavonoids as a promising approach to develop innovative neuroprotective strategy.}, }
@article {pmid28923312, year = {2017}, author = {Moloudizargari, M and Asghari, MH and Ghobadi, E and Fallah, M and Rasouli, S and Abdollahi, M}, title = {Autophagy, its mechanisms and regulation: Implications in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {40}, number = {}, pages = {64-74}, doi = {10.1016/j.arr.2017.09.005}, pmid = {28923312}, issn = {1872-9649}, mesh = {Alzheimer Disease/genetics/metabolism/pathology ; Animals ; Autophagy/*physiology ; Clinical Trials as Topic/methods ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/*pathology ; Parkinson Disease/genetics/metabolism/pathology ; }, abstract = {Autophagy is a major regulatory cellular mechanism which gives the cell an ability to cope with some of the destructive events that normally occur within a metabolically living cell. This is done by maintaining the cellular homeostasis, clearance of damaged organelles and proteins and recycling necessary molecules like amino acids and fatty acids. There is a wide array of factors that influence autophagy in the state of health and disease. Disruption of these mechanisms may not only give rise to several autophagy-related disease, but also it can occur as the result of intracellular changes induced during disease pathogenesis causing exacerbation of the disease. Our knowledge is increasing regarding the role of autophagy and its mechanisms in the pathogenesis of various neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis. Indeed, getting to know about the pathways of autophagy and its regulation can provide the basis for designing therapeutic interventions. In the present paper, we review the pathways of autophagy, its regulation and the possible autophagy-targeting interventions for the treatment of neurodegenerative disorders.}, }
@article {pmid28923065, year = {2017}, author = {San Gil, R and Ooi, L and Yerbury, JJ and Ecroyd, H}, title = {The heat shock response in neurons and astroglia and its role in neurodegenerative diseases.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {65}, pmid = {28923065}, issn = {1750-1326}, mesh = {Animals ; Astrocytes/*metabolism/pathology ; Heat-Shock Response/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Neurons/*metabolism/pathology ; }, abstract = {Protein inclusions are a predominant molecular pathology found in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease. Protein inclusions form in discrete areas of the brain characteristic to the type of neurodegenerative disease, and coincide with the death of neurons in that region (e.g. spinal cord motor neurons in amyotrophic lateral sclerosis). This suggests that the process of protein misfolding leading to inclusion formation is neurotoxic, and that cell-autonomous and non-cell autonomous mechanisms that maintain protein homeostasis (proteostasis) can, at times, be insufficient to prevent protein inclusion formation in the central nervous system. The heat shock response is a pro-survival pathway induced under conditions of cellular stress that acts to maintain proteostasis through the up-regulation of heat shock proteins, a superfamily of molecular chaperones, other co-chaperones and mitotic regulators. The kinetics and magnitude of the heat shock response varies in a stress- and cell-type dependent manner. It remains to be determined if and/or how the heat shock response is activated in the different cell-types that comprise the central nervous system (e.g. neurons and astroglia) in response to protein misfolding events that precede cellular dysfunctions in neurodegenerative diseases. This is particularly relevant considering emerging evidence demonstrating the non-cell autonomous nature of amyotrophic lateral sclerosis and Huntington's disease (and other neurodegenerative diseases) and the destructive role of astroglia in disease progression. This review highlights the complexity of heat shock response activation and addresses whether neurons and glia sense and respond to protein misfolding and aggregation associated with neurodegenerative diseases, in particular Huntington's disease and amyotrophic lateral sclerosis, by inducing a pro-survival heat shock response.}, }
@article {pmid28923025, year = {2017}, author = {Lin, HC and Lin, CH and Chen, PL and Cheng, SJ and Chen, PH}, title = {Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review.}, journal = {BMC neurology}, volume = {17}, number = {1}, pages = {186}, pmid = {28923025}, issn = {1471-2377}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Asian People ; Atrophy/pathology ; Frontotemporal Dementia/*pathology ; High-Throughput Nucleotide Sequencing ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Neuron Disease/pathology ; Mutation ; Parkinsonian Disorders/pathology ; Temporal Lobe/pathology ; Tomography, Emission-Computed, Single-Photon ; tau Proteins/*genetics ; }, abstract = {BACKGROUND: Frontotemporal degeneration (FTD) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by deficits in executive function that frequently overlaps with parkinsonism and motor neuron disorders. Several genes have been identified to cause autosomal dominant forms of FTD, including the gene coding for the protein associated with microtubule tau (MAPT). While most reported pathogenic mutations in MAPT occur in exons 9-13, few families have been reported with mutations outside of this region. Herein, we report a first Taiwanese family having the exon 1 p.Arg5His mutation in MAPT with intrafamilial phenotype heterogeneity.<br><br>CASE PRESENTATION: A 63-year-old man presented with progressive non-fluent speech and impaired memory for 3&#xa0;years. He then developed apraxia, myoclonus and parkinsonism feature at his right hand. Extensive neurologic and neurocognitive examination lead to a diagnosis of FTD mixed with corticobasal syndrome. Magnetic resonance imaging revealed asymmetric atrophy in the left frontal and temporal lobes and single-photon emission computed tomography indicated decreased metabolism in the same areas as well as the left basal ganglia. The patient's mother had been diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 60 and was deceased 10&#xa0;years later due to respiratory failure. The patient's younger sister had persistent depressive disorder in her early forties and did not have any prominent cognitive or motor dysfunctions. We performed genetic analysis applying a targeted next generation sequencing (NGS) panel covering MAPT, GRN, VCP, FUS, CHMP2B, and TARDBP on the proband, followed by Sanger sequencing of candidate genes in eight family members. Hexanucleotide repeat expansion of C9Orf72 was determined by repeat-primed PCR. We identified a missense mutation in exon 1 of MAPT gene, c.14G&#xa0;>&#xa0;A (p.R5H), which was previously reported in only two Japanese patients in a literature review. This substitution co-segregated with the disease phenotypes in the family.<br><br>CONCLUSIONS: This is the first report of the occurrence of the MAPT p.R5H mutation in the Taiwanese population. Our findings extend the current knowledge of phenotypic heterogeneity among family members carrying the MAPT p.R5H mutation.}, }
@article {pmid28917260, year = {2017}, author = {Weng, TY and Tsai, SA and Su, TP}, title = {Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases.}, journal = {Journal of biomedical science}, volume = {24}, number = {1}, pages = {74}, pmid = {28917260}, issn = {1423-0127}, support = {Z01 DA000206-22//Intramural NIH HHS/United States ; Z01 DA000206-23//Intramural NIH HHS/United States ; ZIA DA000549-08//Intramural NIH HHS/United States ; }, mesh = {Humans ; Ligands ; Mitochondria/*physiology ; Molecular Chaperones/*genetics/metabolism ; Neurodegenerative Diseases/*genetics/physiopathology ; Receptors, sigma/*genetics/metabolism ; Sigma-1 Receptor ; }, abstract = {The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca[2+] signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca[2+] transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.}, }
@article {pmid28916614, year = {2017}, author = {Gao, FB and Almeida, S and Lopez-Gonzalez, R}, title = {Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder.}, journal = {The EMBO journal}, volume = {36}, number = {20}, pages = {2931-2950}, pmid = {28916614}, issn = {1460-2075}, support = {R01 NS057553/NS/NINDS NIH HHS/United States ; R01 NS079725/NS/NINDS NIH HHS/United States ; R01 NS093097/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology/therapy ; Animals ; Cell Physiological Phenomena ; Frontotemporal Dementia/*physiopathology/therapy ; Humans ; }, abstract = {Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of C9ORF72 As shown by recent intensive studies, some key cellular pathways are dysregulated in the ALS-FTD spectrum disorder, including autophagy, nucleocytoplasmic transport, DNA damage repair, pre-mRNA splicing, stress granule dynamics, and others. These exciting advances reveal the complexity of the pathogenic mechanisms of FTD and ALS and suggest promising molecular targets for future therapeutic interventions in these devastating disorders.}, }
@article {pmid28916533, year = {2017}, author = {Curtis, AF and Masellis, M and Hsiung, GR and Moineddin, R and Zhang, K and Au, B and Millett, G and Mackenzie, I and Rogaeva, E and Tierney, MC}, title = {Sex differences in the prevalence of genetic mutations in FTD and ALS: A meta-analysis.}, journal = {Neurology}, volume = {89}, number = {15}, pages = {1633-1642}, pmid = {28916533}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; C9orf72 Protein ; Databases, Bibliographic/statistics &amp; numerical data ; Female ; Frontotemporal Dementia/*epidemiology/genetics ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Male ; Microtubule-Associated Proteins/genetics ; Mutation/*genetics ; Progranulins ; Proteins/genetics ; Sex Factors ; }, abstract = {OBJECTIVE: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)-in patients clinically diagnosed with these conditions.<br><br>METHODS: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models.<br><br>RESULTS: Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04-1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81-1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRN mutation carriers) revealed a higher prevalence of female patients with GRN-related FTD (RR 1.33, 95% CI 1.09-1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95-1.55).<br><br>CONCLUSIONS: Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression.}, }
@article {pmid28914735, year = {2017}, author = {de Visser, M and Oliver, DJ}, title = {Palliative care in neuromuscular diseases.}, journal = {Current opinion in neurology}, volume = {30}, number = {6}, pages = {686-691}, doi = {10.1097/WCO.0000000000000493}, pmid = {28914735}, issn = {1473-6551}, mesh = {Humans ; Neuromuscular Diseases/*therapy ; Palliative Care/*methods ; }, abstract = {PURPOSE OF REVIEW: Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness. Neuromuscular disorders (NMDs) are characterized by progressive muscle weakness, leading to pronounced and incapacitating physical disabilities. Most NMDs are not amenable to curative treatment and would thus qualify for palliative care. Amyotrophic lateral sclerosis is a relentlessly progressive disease, which leads to death about 2 years after onset due to respiratory muscle weakness. Increasingly, neurologists caring for these patients learn to apply the principles of palliative care. However, this does not yet apply to other well known and frequently occurring NMDs.<br><br>RECENT FINDINGS: There is sparse literature on palliative care in NMDs such as Duchenne muscular dystrophy, spinal muscular atrophy, muscular dystrophies, some congenital myopathies, Pompe's disease and myotonic dystrophy type 1. These NMDs are often associated with imminent respiratory insufficiency and/or heart failure leading to a reduced life expectancy. Reasons for underutilization may include misconceptions about palliative care amongst patients, family carers and healthcare professionals or lack of awareness of the usefulness of this approach in these severely affected patients and the possibilities of integration of palliative principles into care for children and adults with NMDs.<br><br>SUMMARY: There is an urgent need for increased attention to the development of palliative care in chronic progressive neuromuscular diseases associated with increasing functional incapacities and premature death. This will require education and training of the healthcare professionals, involvement of patient associations and funding to perform research.}, }
@article {pmid28914734, year = {2017}, author = {Strong, MJ}, title = {Revisiting the concept of amyotrophic lateral sclerosis as a multisystems disorder of limited phenotypic expression.}, journal = {Current opinion in neurology}, volume = {30}, number = {6}, pages = {599-607}, doi = {10.1097/WCO.0000000000000488}, pmid = {28914734}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism/*physiopathology ; Humans ; }, abstract = {PURPOSE OF REVIEW: The current review will examine the contemporary evidence that amyotrophic lateral sclerosis (ALS) is a syndrome in which the unifying feature is a progressive loss of upper and lower motor neuron function.<br><br>RECENT FINDINGS: Although ALS is traditionally viewed as a neurodegenerative disorder affecting the motor neurons, there is considerable phenotypic heterogeneity and widespread involvement of the central nervous system. A broad range of both causative and disease modifying genetic variants are associated with both sporadic and familial forms of ALS. A significant proportion of ALS patients have an associated frontotemporal dysfunction which can be a harbinger of a significantly shorter survival and for which there is increasing evidence of a fundamental disruption of tau metabolism in those affected individuals. Although the traditional neuropathology of the degenerating motor neurons in ALS is that of neuronal cytoplasmic inclusions composed neuronal intermediate filaments, the presence of neuronal cytoplasmic inclusions composed of RNA binding proteins suggests a key role for RNA dysmetabolism in the pathogenesis of ALS.<br><br>SUMMARY: ALS is a complex multisystem neurodegenerative syndrome with marked heterogeneity at not only the level of clinical expression, but also etiologically.}, }
@article {pmid28913566, year = {2017}, author = {Gallo, A and Vukic, D and Michalík, D and O'Connell, MA and Keegan, LP}, title = {ADAR RNA editing in human disease; more to it than meets the I.}, journal = {Human genetics}, volume = {136}, number = {9}, pages = {1265-1278}, pmid = {28913566}, issn = {1432-1203}, support = {621368//EU/International ; 17615//AIRC IG/International ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Animals ; Humans ; *Mental Disorders/genetics/metabolism ; Mice ; Mice, Mutant Strains ; *Mutation ; *Nervous System Diseases/genetics/metabolism ; RNA Editing/*genetics ; *RNA, Double-Stranded/genetics/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; }, abstract = {We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi-Goutières Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction. On the other hand, upregulation of ADAR1 with widespread promiscuous RNA editing is a prominent feature of many cancers and particular site-specific RNA editing events are also affected. ADAR2 is most highly expressed in brain and is primarily required for site-specific editing of CNS transcripts; recent findings indicate that ADAR2 editing is regulated by neuronal excitation for synaptic scaling of glutamate receptors. ADAR2 is also linked to the circadian clock and to sleep. Mutations in ADAR2 could contribute to excitability syndromes such as epilepsy, to seizures, to diseases involving neuronal plasticity defects, such as autism and Fragile-X Syndrome, to neurodegenerations such as ALS, or to astrocytomas or glioblastomas in which reduced ADAR2 activity is required for oncogenic cell behavior. The range of human disease associated with ADAR1 mutations may extend further to include other inflammatory conditions while ADAR2 mutations may affect psychiatric conditions.}, }
@article {pmid28913349, year = {2017}, author = {Carelli, L and Solca, F and Faini, A and Meriggi, P and Sangalli, D and Cipresso, P and Riva, G and Ticozzi, N and Ciammola, A and Silani, V and Poletti, B}, title = {Brain-Computer Interface for Clinical Purposes: Cognitive Assessment and Rehabilitation.}, journal = {BioMed research international}, volume = {2017}, number = {}, pages = {1695290}, pmid = {28913349}, issn = {2314-6141}, mesh = {Brain/*physiopathology ; Brain-Computer Interfaces ; Cognition/*physiology ; Humans ; Nervous System Diseases/*physiopathology/*rehabilitation ; Neurofeedback/physiology ; Neuronal Plasticity/physiology ; }, abstract = {Alongside the best-known applications of brain-computer interface (BCI) technology for restoring communication abilities and controlling external devices, we present the state of the art of BCI use for cognitive assessment and training purposes. We first describe some preliminary attempts to develop verbal-motor free BCI-based tests for evaluating specific or multiple cognitive domains in patients with Amyotrophic Lateral Sclerosis, disorders of consciousness, and other neurological diseases. Then we present the more heterogeneous and advanced field of BCI-based cognitive training, which has its roots in the context of neurofeedback therapy and addresses patients with neurological developmental disorders (autism spectrum disorder and attention-deficit/hyperactivity disorder), stroke patients, and elderly subjects. We discuss some advantages of BCI for both assessment and training purposes, the former concerning the possibility of longitudinally and reliably evaluating cognitive functions in patients with severe motor disabilities, the latter regarding the possibility of enhancing patients' motivation and engagement for improving neural plasticity. Finally, we discuss some present and future challenges in the BCI use for the described purposes.}, }
@article {pmid28912682, year = {2017}, author = {Ciregia, F and Urbani, A and Palmisano, G}, title = {Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {276}, pmid = {28912682}, issn = {1662-5099}, abstract = {Extracellular vesicles (EVs) can be classified into apoptotic bodies, microvesicles (MVs), and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM), neuroblastoma (NB), medulloblastoma (MB), and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis.}, }
@article {pmid28911903, year = {2017}, author = {Sui, X and Yan, L and Jiang, YY}, title = {The vaccines and antibodies associated with Als3p for treatment of Candida albicans infections.}, journal = {Vaccine}, volume = {35}, number = {43}, pages = {5786-5793}, doi = {10.1016/j.vaccine.2017.08.082}, pmid = {28911903}, issn = {1873-2518}, mesh = {Animals ; Antibodies, Fungal/*immunology ; Antibodies, Monoclonal/*immunology ; Antigens, Fungal/immunology ; Candida albicans/*immunology ; Candidiasis/*immunology ; Humans ; Vaccines/*immunology ; }, abstract = {Candida albicans is the most common fungal microorganism in healthy individuals, as well as the cause of high mortality infections in high-risk hosts such as immunocompromised patients. Antifungal vaccines and monoclonal antibodies useful for active or passive immunizations have recently generated considerable excitement for the treatment of fungal infections. The cell wall proteins of C. albicans, which are crucial for virulence and pathogenicity, are attractive target antigens. Als3p, a member of the C. albicans agglutinin-like sequence (ALS) family, is a hyphal-specific glycophosphatidylinositol cell wall protein that plays a key role in the interaction with host cells. The abundance of Als3p on the hyphal surface makes it an attractive target. For example, the NDV-3 vaccine, targeted at the N-terminus of Als3p, has entered a preparation of Phase 2 clinical trial. The Als3p-specific antibodies include monoclonal antibodies (MAbs) 3-A5, MAb 113, and scFv3. In addition, MAb C7, MAb 3D9.3 and MAb 2G8, which were supposed to be identifying other targets, have also provided good protection by recognizing Als3p. In this review, we summarize the functions of Als3p and highlight the development of the vaccines and the antibodies that are associated, directly or indirectly, with this protein.}, }
@article {pmid28904990, year = {2017}, author = {Antenora, A and Rinaldi, C and Roca, A and Pane, C and Lieto, M and Saccà, F and Peluso, S and De Michele, G and Filla, A}, title = {The Multiple Faces of Spinocerebellar Ataxia type 2.}, journal = {Annals of clinical and translational neurology}, volume = {4}, number = {9}, pages = {687-695}, pmid = {28904990}, issn = {2328-9503}, abstract = {Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin-2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin-2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin-2 plays a fundamental role in maintenance of neuronal homeostasis.}, }
@article {pmid28903059, year = {2017}, author = {Lange, F and Seer, C and Kopp, B}, title = {Cognitive flexibility in neurological disorders: Cognitive components and event-related potentials.}, journal = {Neuroscience and biobehavioral reviews}, volume = {83}, number = {}, pages = {496-507}, doi = {10.1016/j.neubiorev.2017.09.011}, pmid = {28903059}, issn = {1873-7528}, mesh = {Cognition Disorders/*etiology ; Electroencephalography ; Evoked Potentials/*physiology ; Humans ; Nervous System Diseases/*complications ; Neuropsychological Tests ; }, abstract = {Performance deficits on the Wisconsin Card Sorting Test (WCST) in patients with prefrontal cortex (PFC) lesions are traditionally interpreted as evidence for a role of the PFC in cognitive flexibility. However, WCST deficits do not occur exclusively after PFC lesions, but also in various neurological and psychiatric disorders. We propose a multi-component approach that can accommodate this pattern of omnipresent WCST deficits: the WCST is not a pure test of cognitive flexibility, but relies on the effective functioning of multiple dissociable cognitive components. Our review of recent efforts to decompose WCST performance deficits supports this view by revealing that WCST deficits in different neurological disorders can be attributed to alterations in different components. Frontoparietal changes underlying impaired set shifting seem to give rise to WCST deficits in patients with amyotrophic lateral sclerosis, whereas the WCST deficits associated with primary dystonia and Parkinson's disease are rather related to frontostriatal changes underlying deficient rule inference. Clinical implications of these findings and of a multi-component view of WCST performance are discussed.}, }
@article {pmid28895473, year = {2018}, author = {D'Ambrosi, N and Cozzolino, M and Carrì, MT}, title = {Neuroinflammation in Amyotrophic Lateral Sclerosis: Role of Redox (dys)Regulation.}, journal = {Antioxidants &amp; redox signaling}, volume = {29}, number = {1}, pages = {15-36}, doi = {10.1089/ars.2017.7271}, pmid = {28895473}, issn = {1557-7716}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Humans ; Inflammation/genetics/*metabolism ; Oxidation-Reduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is due to degeneration of upper and lower motor neurons in the anterior horn of the spinal cord and in the motor cortex. Mechanisms leading to motor neuron death are complex and currently the disease is untreatable. Recent Advances: Work in genetic models of ALS indicates that an imbalance in the cross talk that physiologically exists between motor neurons and the surrounding cells is eventually detrimental to motor neurons. In particular, the cascade of events collectively known as neuroinflammation and mainly characterized by a reactive phenotype of astrocytes and microglia, moderate infiltration of peripheral immune cells, and elevated levels of inflammatory mediators has been consistently observed in motor regions of the central nervous system (CNS) in sporadic and familial ALS, constituting a hallmark of the disease. Resident glial cells and infiltrated immune cells are considered among the major producers of reactive species of oxygen and nitrogen in pathological conditions of the CNS, including motor neuron diseases.<br><br>CRITICAL ISSUES: The timing and exact role of oxidative stress-mediated neuroinflammation and damage to motor neurons in ALS are still not fully elucidated.<br><br>FUTURE DIRECTIONS: It is clear that a major challenge in the next future will be to envisage effective strategies to modulate the neuroinflammatory response in the symptomatic stage of disease, to prevent progression of neurodegeneration through the propagation of oxidative damage. Antioxid. Redox Signal. 29, 15-36.}, }
@article {pmid28887079, year = {2017}, author = {Hu, F and Jin, J and Jia, R and Xiang, L and Qi, H and Zhao, X and Dang, J}, title = {Measuring the validation of assessing the non-dominant-hand function by ALSFRS-r in Chinese ALS patients.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {46}, number = {}, pages = {17-20}, doi = {10.1016/j.jocn.2017.08.036}, pmid = {28887079}, issn = {1532-2653}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/diagnosis ; Asian People ; Disease Progression ; Female ; Humans ; Middle Aged ; *Severity of Illness Index ; }, abstract = {ALSFRS-r is a widely accepted rating scale for measuring the global function of Amyotrophic Lateral Sclerosis (ALS) patients, but we found some limitations of ALSFRS-r in assessing the function of non-dominant hand in Chinese ALS patients. We reviewed 95 ALS patients who expressed upper-limb symptoms at first visit and analyzed the ALSFRS-r score and subscale. In both upper limb involved patients, the ALSFRS-r had no difference between dominant-hand and non-dominant-hand onset groups (39.15±5.55 vs 38.0±5.91, p=0.477). But in only one upper limb involved patients, the ALSFRS-r score in non-dominant-hand onset patients was higher than dominant-hand onset patients (43.94±3.44 vs 40.87±4.42, p<0.05), especially in item of handwriting, cutting food and handing utensils (3.56±0.89 vs 2.2±1.27 p=0.001, 3.44±1.03 vs 1.8±1.21 p=0.000). When the item of cutting food and handing utensils was replaced by using food bowl and chopsticks to assess the function of non-dominant-hand, the modified ALSFRS-r score was significantly lower than original ALSFRS-r (43.94±3.44 vs 42.88±3.07 p=0.001), the progression rate was slower (0.81±0.63 vs 0.64±0.63, p=0.001). So, for Chinese ALS patients, using food bowl and chopsticks should replace the item of cutting food and handling utensils to assess the non-dominant-hand function, especially in non-dominant-hand onset patients.}, }
@article {pmid28882588, year = {2017}, author = {Guo, X and Namekata, K and Kimura, A and Harada, C and Harada, T}, title = {ASK1 in neurodegeneration.}, journal = {Advances in biological regulation}, volume = {66}, number = {}, pages = {63-71}, doi = {10.1016/j.jbior.2017.08.003}, pmid = {28882588}, issn = {2212-4934}, mesh = {Alzheimer Disease/genetics/metabolism ; Animals ; Humans ; MAP Kinase Kinase Kinase 5/genetics/metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Oxidative Stress/genetics/*physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases (NDDs) such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are characterized by the progressive loss of neurons, causing irreversible damage to patients. Longer lifespans may be leading to an increase in the number of people affected by NDDs worldwide. Among the pathways strongly impacting the pathogenesis of NDDs, oxidative stress, a condition that occurs because of an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs. One of the molecules activated by oxidative stress is apoptosis signal-regulating kinase 1 (ASK1), which has been shown to play a role in NDDs. ASK1 activation is regulated by multiple steps, including oligomerization, phosphorylation, and protein-protein interactions. In the oxidative stress state, reactive oxygen species (ROS) induce the dissociation of thioredoxin, a protein regulating cellular reduction and oxidation (redox), from the N-terminal region of ASK1, and ASK1 is subsequently activated by the oligomerization and phosphorylation of a critical threonine residue, leading to cell death. Here, we review experimental evidence that links ASK1 signaling with the pathogenesis of several NDDs. We propose that ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs.}, }
@article {pmid28881425, year = {2018}, author = {Osaki, T and Shin, Y and Sivathanu, V and Campisi, M and Kamm, RD}, title = {In Vitro Microfluidic Models for Neurodegenerative Disorders.}, journal = {Advanced healthcare materials}, volume = {7}, number = {2}, pages = {}, doi = {10.1002/adhm.201700489}, pmid = {28881425}, issn = {2192-2659}, mesh = {Animals ; Biomimetics ; Humans ; *Lab-On-A-Chip Devices ; Microfluidic Analytical Techniques/*methods ; *Neurodegenerative Diseases ; Tissue Engineering/*methods ; }, abstract = {Microfluidic devices enable novel means of emulating neurodegenerative disease pathophysiology in vitro. These organ-on-a-chip systems can potentially reduce animal testing and substitute (or augment) simple 2D culture systems. Reconstituting critical features of neurodegenerative diseases in a biomimetic system using microfluidics can thereby accelerate drug discovery and improve our understanding of the mechanisms of several currently incurable diseases. This review describes latest advances in modeling neurodegenerative diseases in the central nervous system and the peripheral nervous system. First, this study summarizes fundamental advantages of microfluidic devices in the creation of compartmentalized cell culture microenvironments for the co-culture of neurons, glial cells, endothelial cells, and skeletal muscle cells and in their recapitulation of spatiotemporal chemical gradients and mechanical microenvironments. Then, this reviews neurodegenerative-disease-on-a-chip models focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Finally, this study discusses about current drawbacks of these models and strategies that may overcome them. These organ-on-chip technologies can be useful to be the first line of testing line in drug development and toxicology studies, which can contribute significantly to minimize the phase of animal testing steps.}, }
@article {pmid28879883, year = {2017}, author = {Li, DC and Malcolm, JG and Rindler, RS and Baum, GR and Rao, A and Khurpad, SN and Ahmad, FU}, title = {The role of diffusion tensor imaging in spinal pathology: A review.}, journal = {Neurology India}, volume = {65}, number = {5}, pages = {982-992}, doi = {10.4103/neuroindia.NI_198_17}, pmid = {28879883}, issn = {0028-3886}, mesh = {Diffusion Tensor Imaging/*methods ; Humans ; Neuroimaging/*methods ; Spinal Cord/*diagnostic imaging ; Spinal Cord Diseases/*diagnostic imaging ; }, abstract = {Diffusion tensor imaging (DTI) allows for noninvasive, in vivo visualization of white matter fiber tracts in the central nervous system by measuring the diffusion of water molecules. It provides both quantitative and qualitative (i.e., tractography) means to describe a region-of-interest. While protocols for the use of DTI are better established in the brain, the efficacy and potential applications of DTI in spinal cord pathology are less understood. In this review, we examine the current literature regarding the use of DTI in the spinal cord pathology, and in particular its diagnostic and prognostic value in traumatic injury, spinal tumors, cervical myelopathies, amyotrophic lateral sclerosis, and multiple sclerosis. Although structural magnetic resonance imaging (MRI) has long been the gold standard for noninvasive imaging of soft tissues, DTI provides additional tissue characteristics not found in the conventional MRI. We place emphasis on the unique characteristics of DTI, its potential value as an adjunct imaging modality, and its impact on clinical practice.}, }
@article {pmid28878620, year = {2017}, author = {Ramesh, N and Pandey, UB}, title = {Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {263}, pmid = {28878620}, issn = {1662-5099}, support = {R21 NS094921/NS/NINDS NIH HHS/United States ; R21 NS100055/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results from the loss of upper and lower motor neurons. One of the key pathological hallmarks in diseased neurons is the mislocalization of disease-associated proteins and the formation of cytoplasmic aggregates of these proteins and their interactors due to defective protein quality control. This apparent imbalance in the cellular protein homeostasis could be a crucial factor in causing motor neuron death in the later stages of the disease in patients. Autophagy is a major protein degradation pathway that is involved in the clearance of protein aggregates and damaged organelles. Abnormalities in autophagy have been observed in numerous neurodegenerative disorders, including ALS. In this review, we discuss the contribution of autophagy dysfunction in various in vitro and in vivo models of ALS. Furthermore, we examine the crosstalk between autophagy and other cellular stresses implicated in ALS pathogenesis and the therapeutic implications of regulating autophagy in ALS.}, }
@article {pmid28872912, year = {2017}, author = {Takei, K and Tsuda, K and Takahashi, F and Hirai, M and Palumbo, J}, title = {An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {88-97}, doi = {10.1080/21678421.2017.1361445}, pmid = {28872912}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/*epidemiology ; Clinical Trials as Topic/methods/standards ; Demography/methods/*standards ; *Disease Progression ; Europe/epidemiology ; Female ; Humans ; Japan/epidemiology ; Male ; Neuroprotective Agents/therapeutic use ; Practice Guidelines as Topic/*standards ; United States/epidemiology ; }, abstract = {BACKGROUND: There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions.<br><br>OBJECTIVE: To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe.<br><br>METHODS: We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies.<br><br>RESULTS: Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month).<br><br>CONCLUSION: There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.}, }
@article {pmid28872911, year = {2017}, author = {Maragakis, NJ}, title = {What can we learn from the edaravone development program for ALS?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {98-103}, doi = {10.1080/21678421.2017.1361446}, pmid = {28872911}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*drug therapy ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Clinical Trials as Topic/methods/standards ; Edaravone ; Free Radical Scavengers/*therapeutic use ; Humans ; Program Development/*methods/standards ; }, abstract = {Edaravone's development into an ALS therapeutic has been a process which began with preclinical studies regarding its potential in targeting ALS. Despite edaravone's inability to show benefit in a general ALS population, an important post-hoc analysis showed that a clinical subset of patients had benefit. Most importantly, a subsequent study examining the capacity of edaravone to have benefit in this specific subset of ALS patients was successful in meeting its primary outcome measures. Questions regarding whether the dosing regimen could be simplified or improved, the duration of the effects, and the timing of the potential treatment to different stages of disease remain to be answered. However, the benefit of this compound in delivering a meaningful therapy to ALS patients and the lessons learned with regard to its development should widen interest in clinical research so that additional strategies for treating ALS may become available to patients.}, }
@article {pmid28872907, year = {2017}, author = {Takei, K and Watanabe, K and Yuki, S and Akimoto, M and Sakata, T and Palumbo, J}, title = {Edaravone and its clinical development for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {5-10}, doi = {10.1080/21678421.2017.1353101}, pmid = {28872907}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*metabolism ; Antipyrine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Clinical Trials as Topic/methods ; Edaravone ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Oxidative Stress/*drug effects/physiology ; }, abstract = {The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.}, }
@article {pmid28872247, year = {2017}, author = {Cosgarea, I and Ritter, C and Becker, JC and Schadendorf, D and Ugurel, S}, title = {Update zum klinischen Einsatz von Inhibitoren mutierter Phosphokinasen beim Melanom.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {15}, number = {9}, pages = {887-894}, doi = {10.1111/ddg.13321_g}, pmid = {28872247}, issn = {1610-0387}, mesh = {Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Drug Resistance, Neoplasm/genetics ; Humans ; MAP Kinase Kinase 1/antagonists &amp; inhibitors/genetics ; Melanoma/*drug therapy/enzymology/genetics ; *Molecular Targeted Therapy ; Protein Kinase Inhibitors/adverse effects/*therapeutic use ; Proto-Oncogene Proteins B-raf/antagonists &amp; inhibitors/genetics ; Signal Transduction/*drug effects/genetics ; Skin Neoplasms/*drug therapy/enzymology/genetics ; }, abstract = {Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellulärer Signalwege radikal geändert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekülen, den Phosphokinasen, angreifen, können diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der für die Schaltmoleküle kodierenden Gene konstitutiv aktiviert sind. Aktuell ist diese therapeutische Strategie insbesondere für Patienten bedeutsam, deren Melanome eine Mutation im BRAF-Gen aufweisen. Diese Patienten können durch eine Kombinationstherapie aus Inhibitoren der Phosphokinasen BRAF und MEK langfristig mit sehr guter Krankheitskontrolle behandelt werden. Unter dieser Kombinationstherapie wird aktuell ein progressionsfreies Überleben von über zehn Monaten und ein Gesamtüberleben von mehr als zwei Jahren bei guter Lebensqualität erzielt. Da unter längerfristiger Therapie mit Kinaseinhibitoren jedoch bei einem Großteil der Patienten eine Resistenzbildung auftritt, sind aktuelle klinische Therapiestudien auf die Suche nach geeigneten Kombinationspartnern unter Blockierung anderer Signalwege oder unter Aktivierung der T-Zell-vermittelten Immunantwort ausgerichtet. Der vorliegende Übersichtsartikel stellt sowohl die aktuell verfügbaren als auch die in der klinischen Testung befindlichen zukünftigen Optionen der zielgerichteten Therapie des Melanoms dar.}, }
@article {pmid28871262, year = {2017}, author = {Liu, J and Wang, F}, title = {Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications.}, journal = {Frontiers in immunology}, volume = {8}, number = {}, pages = {1005}, pmid = {28871262}, issn = {1664-3224}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.}, }
@article {pmid28862491, year = {2018}, author = {Karlsson, P and Allsop, A and Dee-Price, BJ and Wallen, M}, title = {Eye-gaze control technology for children, adolescents and adults with cerebral palsy with significant physical disability: Findings from a systematic review.}, journal = {Developmental neurorehabilitation}, volume = {21}, number = {8}, pages = {497-505}, doi = {10.1080/17518423.2017.1362057}, pmid = {28862491}, issn = {1751-8431}, mesh = {Adolescent ; Adult ; *Cerebral Palsy ; Child ; *Communication ; Disabled Persons ; *Eye Movements ; Humans ; *Quality of Life ; *Technology ; }, abstract = {PURPOSE: The primary objective of this systematic review was to examine the effectiveness of eye-gaze control technology for facilitating communication across different social contexts for people with cerebral palsy and significant physical disability.<br><br>METHODS: Systematic review.<br><br>RESULTS: The search identified 756 potentially eligible articles, of which two, low level articles were eligible. One study reported positive results for achieving communication goals for children with cerebral palsy. The second concluded that eye-gaze control technology resulted in greater quality of life and less depression for adults with late stage amyotrophic lateral sclerosis when compared to non-users.<br><br>DISCUSSION: Research regarding the effectiveness of eye-gaze control technology used to access a laptop, tablet or computer on communication outcomes, participation, quality of life and self-esteem in children, adolescents and adults with cerebral palsy and significant physical disability is sparse. A scoping review to fully identify issues to inform clinical practice and future research is required.}, }
@article {pmid28860970, year = {2017}, author = {Coyne, AN and Zaepfel, BL and Zarnescu, DC}, title = {Failure to Deliver and Translate-New Insights into RNA Dysregulation in ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {243}, pmid = {28860970}, issn = {1662-5102}, support = {R01 NS091299/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease. With wild-type TDP-43 pathology being found in ~97% of ALS cases and the identification of disease causing mutations within its sequence, TDP-43 has emerged as a prominent player in ALS. More recently, studies of the newly discovered C9orf72 repeat expansion are lending further support to the notion of defects in RNA metabolism as a key factor underlying ALS. RNA binding proteins are involved in all aspects of RNA metabolism ranging from splicing, transcription, transport, storage into RNA/protein granules, and translation. How these processes are affected by disease-associated mutations is just beginning to be understood. Considerable work has gone into the identification of splicing and transcription defects resulting from mutations in RNA binding proteins associated with disease. More recently, defects in RNA transport and translation have been shown to be involved in the pathomechanism of ALS. A central hypothesis in the field is that disease causing mutations lead to the persistence of RNA/protein complexes known as stress granules. Under times of prolonged cellular stress these granules sequester specific mRNAs preventing them from translation, and are thought to evolve into pathological aggregates. Here we will review recent efforts directed at understanding how altered RNA metabolism contributes to ALS pathogenesis.}, }
@article {pmid28856541, year = {2018}, author = {Budge, KM and Neal, ML and Richardson, JR and Safadi, FF}, title = {Glycoprotein NMB: an Emerging Role in Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {55}, number = {6}, pages = {5167-5176}, pmid = {28856541}, issn = {1559-1182}, mesh = {Animals ; Humans ; Immune System/metabolism ; Membrane Glycoproteins/chemistry/*metabolism ; Nerve Degeneration/pathology ; Neurodegenerative Diseases/*metabolism/therapy ; }, abstract = {Neurodegeneration is characterized by severe neuronal loss leading to the cognitive and physical impairments that define various neurodegenerative diseases. Neuroinflammation is one hallmark of neurodegenerative diseases and can ultimately contribute to disease progression. Increased inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1 β), and tumor necrosis factor-α (TNF-α) are associated with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Unfortunately, current therapeutic options lack ability to stop or effectively slow progression of these diseases and are primarily aimed at alleviating symptoms. Thus, it is crucial to discover novel treatment candidates for neurodegenerative diseases. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type-I transmembrane glycoprotein first identified in a melanoma cell line. GPNMB augments bone mineral deposition by stimulating osteoblast differentiation. Aside from its anabolic function in the bone, emerging evidence suggests that GPNMB has anti-inflammatory and reparative functions. GPNMB has also been demonstrated to be neuroprotective in an animal model of ALS, cerebral ischemia, and other disease models. Given these discoveries, GPNMB should be investigated as a potential therapeutic option for multiple neurodegenerative diseases.}, }
@article {pmid28852477, year = {2017}, author = {Liu, Y and Zhu, X}, title = {Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {6}, number = {}, pages = {21}, pmid = {28852477}, issn = {2047-9158}, support = {R01 NS083385/NS/NINDS NIH HHS/United States ; RF1 AG049479/AG/NIA NIH HHS/United States ; }, abstract = {Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic "network structure" that facilitates the formation of inter-organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. This review will focus on the architecture and function of MAMs and its involvement in the neurodegenerative diseases.}, }
@article {pmid28852382, year = {2017}, author = {Khalil, B and Liévens, JC}, title = {Mitochondrial quality control in amyotrophic lateral sclerosis: towards a common pathway?.}, journal = {Neural regeneration research}, volume = {12}, number = {7}, pages = {1052-1061}, pmid = {28852382}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons. Different mechanisms contribute to the disease initiation and progression, including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis. Indeed, while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants, it is now well established that mitochondria become also dysfunctional in other ALS conditions. In such context, the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death, by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy. Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system. This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.}, }
@article {pmid28851463, year = {2017}, author = {Rohilla, KJ and Gagnon, KT}, title = {RNA biology of disease-associated microsatellite repeat expansions.}, journal = {Acta neuropathologica communications}, volume = {5}, number = {1}, pages = {63}, pmid = {28851463}, issn = {2051-5960}, mesh = {Animals ; DNA Repeat Expansion/*physiology ; Humans ; *Microsatellite Repeats ; RNA/*metabolism ; RNA Splicing ; Transcription, Genetic ; }, abstract = {Microsatellites, or simple tandem repeat sequences, occur naturally in the human genome and have important roles in genome evolution and function. However, the expansion of microsatellites is associated with over two dozen neurological diseases. A common denominator among the majority of these disorders is the expression of expanded tandem repeat-containing RNA, referred to as xtrRNA in this review, which can mediate molecular disease pathology in multiple ways. This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development.}, }
@article {pmid28850080, year = {2017}, author = {Sirangelo, I and Iannuzzi, C}, title = {The Role of Metal Binding in the Amyotrophic Lateral Sclerosis-Related Aggregation of Copper-Zinc Superoxide Dismutase.}, journal = {Molecules (Basel, Switzerland)}, volume = {22}, number = {9}, pages = {}, pmid = {28850080}, issn = {1420-3049}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; Models, Molecular ; Protein Aggregates ; Protein Folding ; Protein Stability ; Superoxide Dismutase-1/*chemistry/metabolism ; Zinc/chemistry/*metabolism ; }, abstract = {Protein misfolding and conformational changes are common hallmarks in many neurodegenerative diseases involving formation and deposition of toxic protein aggregates. Although many players are involved in the in vivo protein aggregation, physiological factors such as labile metal ions within the cellular environment are likely to play a key role. In this review, we elucidate the role of metal binding in the aggregation process of copper-zinc superoxide dismutase (SOD1) associated to amyotrophic lateral sclerosis (ALS). SOD1 is an extremely stable Cu-Zn metalloprotein in which metal binding is crucial for folding, enzymatic activity and maintenance of the native conformation. Indeed, demetalation in SOD1 is known to induce misfolding and aggregation in physiological conditions in vitro suggesting that metal binding could play a key role in the pathological aggregation of SOD1. In addition, this study includes recent advances on the role of aberrant metal coordination in promoting SOD1 aggregation, highlighting the influence of metal ion homeostasis in pathologic aggregation processes.}, }
@article {pmid28845922, year = {2018}, author = {Jorfi, M and D'Avanzo, C and Kim, DY and Irimia, D}, title = {Three-Dimensional Models of the Human Brain Development and Diseases.}, journal = {Advanced healthcare materials}, volume = {7}, number = {1}, pages = {}, pmid = {28845922}, issn = {2192-2659}, support = {RF1 AG048080/AG/NIA NIH HHS/United States ; P01 AG015379/AG/NIA NIH HHS/United States ; P30 NS045776/NS/NINDS NIH HHS/United States ; R01 AG014713/AG/NIA NIH HHS/United States ; R21 AG051082/AG/NIA NIH HHS/United States ; P41 EB002503/EB/NIBIB NIH HHS/United States ; }, mesh = {Alzheimer Disease/*pathology/*therapy ; Biocompatible Materials/chemistry ; Brain/*cytology/pathology ; Cell Culture Techniques ; Humans ; Microfluidics/methods ; Organoids/*cytology/physiology ; }, abstract = {Deciphering the human brain pathophysiology remains one of the greatest challenges of the 21[st] century. Neurological disorders represent a significant proportion of diseases burden; however, the complexity of the brain physiology makes it challenging to model its diseases. Simple in vitro models have been very useful for precise measurements in controled conditions. However, existing models are limited in their ability to replicate complex interactions between various cells in the brain. Studying human brain requires sophisticated models to reconstitute the tangled architecture and functions of brain cells. Recently, advances in the development of three-dimensional (3D) brain cell culture models have begun to recapitulate various aspects of the human brain physiology in vitro and replicate basic disease processes of Alzheimer's disease, amyotrophic lateral sclerosis, and microcephaly. In this review, we discuss the progress, advantages, limitations, and future directions of 3D cell culture systems for modeling the human brain development and diseases.}, }
@article {pmid28844606, year = {2017}, author = {Peixoto, CA and Oliveira, WH and Araújo, SMDR and Nunes, AKS}, title = {AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration.}, journal = {Experimental neurology}, volume = {298}, number = {Pt A}, pages = {31-41}, doi = {10.1016/j.expneurol.2017.08.013}, pmid = {28844606}, issn = {1090-2430}, mesh = {AMP-Activated Protein Kinases/chemistry/*metabolism ; Animals ; Enzyme Activation/physiology ; Humans ; Inflammation/metabolism/pathology ; Inflammation Mediators/*metabolism ; Neurodegenerative Diseases/*metabolism/pathology ; Protein Structure, Secondary ; Signal Transduction/*physiology ; }, abstract = {Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status and has been reported to be involved in chronic inflammatory disorders. AMPK is expressed in immune cells, such as dendritic cells, macrophages, lymphocytes and neutrophils, and is an important regulator of inflammatory responses through the regulation of complex signaling networks in part by inhibiting downstream cascade pathways, such as nuclear factor kB, which is a key regulator of innate immunity and inflammation, as well as acting as a negative regulator of toll-like receptors. Recent data suggest that AMPK dysregulation may participate in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and neuropathies. However, there are conflicting reports on the benefits or detrimental effects of AMPK in distinct pathological conditions. This paper offers a review of the recent literature on the pharmacological modulation of the AMPK system as a potential molecular target in the management of neurodegenerative diseases.}, }
@article {pmid28841058, year = {2017}, author = {Milette, I and Martel, MJ and Ribeiro da Silva, M and Coughlin McNeil, M}, title = {Guidelines for the Institutional Implementation of Developmental Neuroprotective Care in the Neonatal Intensive Care Unit. Part A: Background and Rationale. A Joint Position Statement From the CANN, CAPWHN, NANN, and COINN.}, journal = {The Canadian journal of nursing research = Revue canadienne de recherche en sciences infirmieres}, volume = {49}, number = {2}, pages = {46-62}, doi = {10.1177/0844562117706882}, pmid = {28841058}, issn = {0844-5621}, mesh = {Canada ; Humans ; Infant, Newborn ; Intensive Care Units, Neonatal/*organization &amp; administration ; Intensive Care, Neonatal/*standards ; Neonatal Nursing/*standards ; Societies, Nursing ; }, abstract = {The use of age-appropriate care as an organized framework for care delivery in the neonatal intensive care unit is founded on the work of Heidelise Als, PhD, and her synactive theory of development. This theoretical construct has recently been advanced by the work of Gibbins and colleagues with the "universe of developmental care" conceptual model and developmental care core measures which were endorsed by the National Association of Neonatal Nurses in their age-appropriate care of premature infant guidelines as best-practice standards for the provision of high-quality care in the neonatal intensive care unit. These guidelines were recently revised and expanded. In alignment with the Joint Commission's requirement for health-care professionals to provide age-specific care across the lifespan, the core measures for developmental care suggest the necessary competencies for those caring for the premature and critically ill hospitalized infant. Further supported by the Primer Standards of Accreditation and Health Canada, the institutional implementation of theses core measures requires a strong framework for institutional operationalization, presented in these guidelines. Part A of this article will present the background and rationale behind the present guidelines and their condensed table of recommendations.}, }
@article {pmid28841057, year = {2017}, author = {Milette, I and Martel, MJ and da Silva, MR and Coughlin McNeil, M}, title = {Guidelines for the Institutional Implementation of Developmental Neuroprotective Care in the NICU. Part B: Recommendations and Justification. A Joint Position Statement From the CANN, CAPWHN, NANN, and COINN.}, journal = {The Canadian journal of nursing research = Revue canadienne de recherche en sciences infirmieres}, volume = {49}, number = {2}, pages = {63-74}, doi = {10.1177/0844562117708126}, pmid = {28841057}, issn = {0844-5621}, mesh = {Canada ; Humans ; Infant, Newborn ; Intensive Care Units, Neonatal/*organization &amp; administration ; Intensive Care, Neonatal/*standards ; Neonatal Nursing/*standards ; Societies, Nursing ; }, abstract = {The use of age-appropriate care as an organized framework for care delivery in the NICU is founded on the work of Heidelise Als, PhD, and her synactive theory of development. This theoretical construct has recently been advanced by the work of Gibbins and colleagues with the "universe of developmental care" conceptual model and developmental care core measures which were endorsed by the National Association of Neonatal Nurses in their age-appropriate care of premature infant guidelines as best-practice standards for the provision of high-quality care in the NICU. These guidelines were recently revised and expanded. In alignment with the Joint Commission's requirement for healthcare professionals to provide age-specific care across the lifespan, the core measures for developmental care suggest the necessary competencies for those caring for the premature and critically ill hospitalized infant. Further supported by the Primer Standards of Accreditation and Health Canada, the institutional implementation of these core measures require a strong framework for institutional operationalization presented in these guidelines. Part B will present the recommendations and justification of each steps behind the present guidelines to facilitate their implementation.}, }
@article {pmid28840555, year = {2017}, author = {Allen, CF and Shaw, PJ and Ferraiuolo, L}, title = {Can Astrocytes Be a Target for Precision Medicine?.}, journal = {Advances in experimental medicine and biology}, volume = {1007}, number = {}, pages = {111-128}, doi = {10.1007/978-3-319-60733-7_7}, pmid = {28840555}, issn = {0065-2598}, support = {K-1506/PUK_/Parkinson's UK/United Kingdom ; }, mesh = {Animals ; Astrocytes/*metabolism ; Blood-Brain Barrier/*metabolism ; Brain/*metabolism ; Humans ; Inflammation/metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; *Precision Medicine ; Transcriptome ; }, abstract = {Astrocytes are the most abundant non-neural cell type residing within the central nervous system (CNS) displaying tremendous heterogeneity depending on their location. Once believed to be 'passive support cells for electrically active neurons', astrocytes are now recognised to play an active role in brain homeostasis by forming connections with the surrounding neurons, microglia and endothelial cells. Most importantly, they provide an optimum microenvironment for functional neurons through regulation of the blood brain barrier, energy supply and removal of debris and toxic waste.Their dysfunction has been identified as a potential contributing factor for several neurodegenerative disorders, from Alzheimer's Disease to Amyotrophic Lateral Sclerosis.In this chapter, we will explore the implications of astrocyte dysfunction in neurodegenerative diseases and how these cells can be used as therapeutic targets in precision medicine.}, }
@article {pmid28840457, year = {2017}, author = {Friedman, MJ and Huber, BR and Brady, CB and Ursano, RJ and Benedek, DM and Kowall, NW and McKee, AC and , }, title = {VA's National PTSD Brain Bank: a National Resource for Research.}, journal = {Current psychiatry reports}, volume = {19}, number = {10}, pages = {73}, pmid = {28840457}, issn = {1535-1645}, mesh = {Biomedical Research/*organization &amp; administration ; Brain/*pathology ; Humans ; Stress Disorders, Post-Traumatic/*pathology ; Tissue Banks/*organization &amp; administration ; United States ; *United States Department of Veterans Affairs ; }, abstract = {The National PTSD Brain Bank (NPBB) is a brain tissue biorepository established to support research on the causes, progression, and treatment of PTSD. It is a six-part consortium led by VA's National Center for PTSD with participating sites at VA medical centers in Boston, MA; Durham, NC; Miami, FL; West Haven, CT; and White River Junction, VT along with the Uniformed Services University of Health Sciences. It is also well integrated with VA's Boston-based brain banks that focus on Alzheimer's disease, ALS, chronic traumatic encephalopathy, and other neurological disorders. This article describes the organization and operations of NPBB with specific attention to: tissue acquisition, tissue processing, diagnostic assessment, maintenance of a confidential data biorepository, adherence to ethical standards, governance, accomplishments to date, and future challenges. Established in 2014, NPBB has already acquired and distributed brain tissue to support research on how PTSD affects brain structure and function.}, }
@article {pmid28831926, year = {2017}, author = {Mulder, JGH and Sonneveld, JPC}, title = {[Organ donation following physician-hastened death at home].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {161}, number = {}, pages = {D1779}, pmid = {28831926}, issn = {1876-8784}, mesh = {Adaptation, Psychological ; Adult ; Amyotrophic Lateral Sclerosis/*psychology ; *Attitude to Death ; Disease Progression ; Humans ; Male ; Netherlands ; Patient Rights ; Physicians/*psychology ; Suicide, Assisted/*psychology ; *Tissue and Organ Procurement ; }, abstract = {Patients considering physician-hastened death (PHD) increasingly express a wish to donate organs after death. This fairly unique proposition stems from patients' desire to do something good with (parts of) the same diseased body that has prompted them to request physician-hastened death. In this article we describe a patient with amyotrophic lateral sclerosis (ALS) who expressed this wish. In March 2017 a national guideline on 'Organ donation following physician-hastened death' (ODP) was presented to the Minister of Health, Welfare and Sport of the Netherlands. From the development of this guideline it emerged that, for PHD patients, being forced to experience their final conscious moments in hospital - in order to facilitate organ donation - was a key reason for not choosing ODP. Together with an anaesthesiologist-intensivist, the GP of the ALS patient developed a domestic ODP, thereby overcoming the hurdle of experiencing death in hospital and maintaining the possible option of organ donation. The applied solution is an 'anaesthesia bridge' which separates the experience of farewells, and losing consciousness under pre-medication at home, from biological death and organ donation in hospital.}, }
@article {pmid28831921, year = {2018}, author = {Makhouri, FR and Ghasemi, JB}, title = {In Silico Studies in Drug Research Against Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {16}, number = {6}, pages = {664-725}, pmid = {28831921}, issn = {1875-6190}, mesh = {Animals ; Central Nervous System Agents/*chemistry/*therapeutic use ; *Drug Design ; Humans ; *Models, Molecular ; Neurodegenerative Diseases/*drug therapy ; Quantitative Structure-Activity Relationship ; }, abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computeraided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays.<br><br>METHODS: In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches.<br><br>RESULTS: Detailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach.<br><br>CONCLUSION: Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future.}, }
@article {pmid28828608, year = {2017}, author = {Rosenblum, LT and Trotti, D}, title = {EAAT2 and the Molecular Signature of Amyotrophic Lateral Sclerosis.}, journal = {Advances in neurobiology}, volume = {16}, number = {}, pages = {117-136}, pmid = {28828608}, issn = {2190-5215}, support = {R01 NS044292/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*physiopathology ; Excitatory Amino Acid Transporter 2 ; Excitatory Amino Acids/metabolism/toxicity ; Glutamate Plasma Membrane Transport Proteins/*metabolism ; Glutamic Acid/*metabolism/toxicity ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapid and fatal neurodegenerative disease, primarily affecting upper and lower motor neurons. It is an extremely heterogeneous disease in both cause and symptom development, and its mechanisms of pathogenesis remain largely unknown. Excitotoxicity, a process caused by excessive glutamate signaling, is believed to play a substantial role, however. Excessive glutamate release, changes in postsynaptic glutamate receptors, and reduction of functional astrocytic glutamate transporters contribute to excitotoxicity in ALS. Here, we explore the roles of each, with a particular emphasis on glutamate transporters and attempts to increase them as therapy for ALS. Screening strategies have been employed to find compounds that increase the functional excitatory amino acid transporter EAAT2 (GLT1), which is responsible for the vast majority of glutamate clearance. One such compound, ceftriaxone, was recently tested in clinical trials but unfortunately did not modify disease course, though its effect on EAAT2 expression in patients was not measured.}, }
@article {pmid28828603, year = {2017}, author = {Lee, E and Karki, P and Johnson, J and Hong, P and Aschner, M}, title = {Manganese Control of Glutamate Transporters' Gene Expression.}, journal = {Advances in neurobiology}, volume = {16}, number = {}, pages = {1-12}, pmid = {28828603}, issn = {2190-5215}, support = {G12 MD007586/MD/NIMHD NIH HHS/United States ; SC1 GM089630/GM/NIGMS NIH HHS/United States ; R01 ES020852/ES/NIEHS NIH HHS/United States ; R01 ES024756/ES/NIEHS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; R01 ES 003771/NH/NIH HHS/United States ; }, mesh = {Amino Acid Transport System X-AG/*metabolism ; Animals ; Astrocytes/metabolism ; Brain/*metabolism ; Gene Expression Regulation ; Humans ; Manganese/*metabolism/*toxicity ; Manganese Poisoning/metabolism/physiopathology ; Neurotoxicity Syndromes/*metabolism/physiopathology ; }, abstract = {Manganese (Mn) is an essential trace element, serving as a cofactor for several enzymes involved in various cellular and biochemical reactions in human body. However, chronic overexposure to Mn from occupational or environmental sources induces a neurological disorder, characterized by psychiatric, cognitive, and motor abnormalities, referred to as manganism. Mn-induced neurotoxicity is known to target astrocytes since these cells preferentially accumulate Mn. Astrocytes are the most abundant non-neuronal glial cells in the brain, and they play a critical role in maintaining the optimal glutamate levels to prevent excitotoxic death. The fine regulation of glutamate in the brain is accomplished by two major glutamate transporters - glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST) that are predominantly expressed in astrocytes. Excitotoxic neuronal injury has been demonstrated as a critical mechanism involved in Mn neurotoxicity and implicated in the pathological signs of multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recent evidences also establish that Mn directly deregulates the expression and function of both astrocytic glutamate transporters by decreasing mRNA and protein levels of GLT-1 and GLAST. Herein, we will review the mechanisms of Mn-induced gene regulation of glutamate transporters at the transcriptional level and their role in Mn toxicity.}, }
@article {pmid28825343, year = {2017}, author = {Ohno, K and Ohkawara, B and Ito, M}, title = {Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders.}, journal = {Expert opinion on therapeutic targets}, volume = {21}, number = {10}, pages = {949-958}, doi = {10.1080/14728222.2017.1369960}, pmid = {28825343}, issn = {1744-7631}, mesh = {Agrin/metabolism ; Animals ; Cholinesterase Inhibitors/pharmacology ; Drug Design ; Germ-Line Mutation ; Humans ; LDL-Receptor Related Proteins/metabolism ; *Molecular Targeted Therapy ; Myasthenia Gravis/*drug therapy/genetics/physiopathology ; Neuromuscular Diseases/*drug therapy/genetics/physiopathology ; Neuromuscular Junction/drug effects/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, Cholinergic/metabolism ; Signal Transduction/drug effects ; }, abstract = {Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, α-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few. Areas covered: This review covers the agrin-LRP4-MuSK signaling pathway, which drives clustering of acetylcholine receptors (AChRs) and ensures efficient signal transduction at the NMJ. We also address diseases caused by autoantibodies against the NMJ molecules and by germline mutations in genes encoding the NMJ molecules. Expert opinion: Representative small compounds to treat the defective NMJ signal transduction are cholinesterase inhibitors, which exert their effects by increasing the amount of acetylcholine at the synaptic space. Another possible therapeutic strategy to enhance the NMJ signal transduction is to increase the number of AChRs, but no currently available drug has this functionality.}, }
@article {pmid28824365, year = {2017}, author = {Nassif, M and Woehlbier, U and Manque, PA}, title = {The Enigmatic Role of C9ORF72 in Autophagy.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {442}, pmid = {28824365}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of motor neurons resulting in a progressive and irreversible muscular paralysis. Advances in large-scale genetics and genomics have revealed intronic hexanucleotide repeat expansions in the gene encoding C9ORF72 as a main genetic cause of ALS and frontotemporal dementia (FTD), the second most common cause of early-onset dementia after Alzheimer's disease. Novel insights regarding the underlying pathogenic mechanisms of C9ORF72 seem to suggest a synergy of loss and gain of toxic function during disease. C9ORF72, thus far, has been found to be involved in homeostatic cellular pathways, such as actin dynamics, regulation of membrane trafficking, and macroautophagy. All these pathways have been found compromised in the pathogenesis of ALS. In this review, we aim to summarize recent findings on the function of C9ORF72, particularly in the macroautophagy pathway, hinting at a requirement to maintain the fine balance of macroautophagy to prevent neurodegeneration.}, }
@article {pmid28820437, year = {2017}, author = {Liddell, JR}, title = {Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {6}, number = {3}, pages = {}, pmid = {28820437}, issn = {2076-3921}, abstract = {Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates hundreds of antioxidant genes, and is activated in response to oxidative stress. Given that many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis are characterised by oxidative stress, Nrf2 is commonly activated in these diseases. Evidence demonstrates that Nrf2 activity is repressed in neurons in vitro, and only cultured astrocytes respond strongly to Nrf2 inducers, leading to the interpretation that Nrf2 signalling is largely restricted to astrocytes. However, Nrf2 activity can be observed in neurons in post-mortem brain tissue and animal models of disease. Thus this interpretation may be false, and a detailed analysis of the cell type expression of Nrf2 in neurodegenerative diseases is required. This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.}, }
@article {pmid28816094, year = {2018}, author = {Kim, K and Heinze, K and Xu, J and Kurtz, M and Park, H and Foradori, M and Nolan, MT}, title = {Theories of Health Care Decision Making at the End of Life: A Meta-Ethnography.}, journal = {Western journal of nursing research}, volume = {40}, number = {12}, pages = {1861-1884}, pmid = {28816094}, issn = {1552-8456}, support = {T32 NR013456/NR/NINR NIH HHS/United States ; R01 NR010733/NR/NINR NIH HHS/United States ; R24 HS022140/HS/AHRQ HHS/United States ; }, mesh = {*Anthropology, Cultural ; Caregivers ; *Communication ; *Decision Making ; Humans ; Terminal Care/*psychology ; }, abstract = {The aim of this meta-ethnography is to appraise the types and uses of theories relative to end-of-life decision making and to develop a conceptual framework to describe end-of-life decision making among patients with advanced cancers, heart failure, and amyotrophic lateral sclerosis (ALS) and their caregivers or providers. We used PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases to extract English-language articles published between January 2002 and April 2015. Forty-three articles were included. The most common theories included decision-making models (n = 14) followed by family-centered (n = 11) and behavioral change models (n = 7). A conceptual framework was developed using themes including context of decision making, communication and negotiation of decision making, characteristics of decision makers, goals of decision making, options and alternatives, and outcomes. Future research should enhance and apply these theories to guide research to develop patient-centered decision-making programs that facilitate informed and shared decision making at the end of life among patients with advanced illness and their caregivers.}, }
@article {pmid28811143, year = {2017}, author = {Sorce, S and Stocker, R and Seredenina, T and Holmdahl, R and Aguzzi, A and Chio, A and Depaulis, A and Heitz, F and Olofsson, P and Olsson, T and Duveau, V and Sanoudou, D and Skosgater, S and Vlahou, A and Wasquel, D and Krause, KH and Jaquet, V}, title = {NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence?.}, journal = {Free radical biology &amp; medicine}, volume = {112}, number = {}, pages = {387-396}, doi = {10.1016/j.freeradbiomed.2017.08.006}, pmid = {28811143}, issn = {1873-4596}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/*enzymology/pathology ; Animals ; Antioxidants/therapeutic use ; Biomarkers/blood ; Central Nervous System/drug effects/enzymology/pathology ; Creutzfeldt-Jakob Syndrome/diagnosis/drug therapy/*enzymology/pathology ; Disease Models, Animal ; Europe ; Gene Expression ; Humans ; Hydrogen Peroxide/metabolism ; International Cooperation ; Microglia/drug effects/enzymology/pathology ; Multiple Sclerosis/diagnosis/drug therapy/*enzymology/pathology ; NADPH Oxidase 2/antagonists &amp; inhibitors/blood/*genetics ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis/drug therapy/*enzymology/pathology ; Superoxides/metabolism ; }, abstract = {Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O2[•-]) and hydrogen peroxide (H2O2). However in the context of neuroinflammation, they present paradoxical features since O2[•-]/H2O2 generated by NOX and/or secondary reactive oxygen species (ROS) derived from O2[•-]/H2O2 can either lead to neuronal oxidative damage or resolution of inflammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological approaches. In the present review we provide a critical assessment of recent findings related to the role of NOX in the CNS as well as how the field has advanced over the last 5 years. In particular, we focus on the data derived from the work of a consortium (Neurinox) funded by the European Commission's Programme 7 (FP7). We discuss the evidence gathered from animal models and human samples linking NOX expression/activity with neuroinflammation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease as well as autoimmune demyelinating diseases like multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We address the possibility to use measurement of the activity of the NOX2 isoform in blood samples as biomarker of disease severity and treatment efficacy in neurodegenerative disease. Finally we clarify key controversial aspects in the field of NOX, such as NOX cellular expression in the brain, measurement of NOX activity, impact of genetic deletion of NOX in animal models of neurodegeneration and specificity of NOX inhibitors.}, }
@article {pmid28807987, year = {2017}, author = {Banfi, P and Volpato, E and Valota, C and D'Ascenzo, S and Alunno, CB and Lax, A and Nicolini, A and Ticozzi, N and Silani, V and Bach, JR}, title = {Use of Noninvasive Ventilation During Feeding Tube Placement.}, journal = {Respiratory care}, volume = {62}, number = {11}, pages = {1474-1484}, doi = {10.4187/respcare.05031}, pmid = {28807987}, issn = {1943-3654}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Enteral Nutrition/*instrumentation/methods ; Gastrostomy/*methods ; Humans ; Intubation, Gastrointestinal/adverse effects/*methods ; Noninvasive Ventilation/*methods ; Treatment Outcome ; Vital Capacity ; }, abstract = {Parenteral nutrition is indicated in amyotrophic lateral sclerosis (ALS) when dysphagia, loss of appetite, and difficulty protecting the airways cause malnutrition, severe weight loss, dehydration, and increased risk of aspiration pneumonia. The aim of this review is to compare percutaneous endoscopic gastrostomy (PEG), radiologically inserted G-tube (RIG), and percutaneous radiologic gastrostomy (PRG) in patients with ALS, performed with or without noninvasive ventilation (NIV). We searched PubMed, MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the EBSCO Online Research Database, and Scopus up to December 2015. A priori selection included all randomized controlled trials (RCTs), quasi-randomized trials, and prospective and retrospective studies. The primary outcome was 30-d survival. We found no RCTs or quasi-RCTs. Seven studies about the implementation of the PEG/RIG procedure during the use of NIV and 5 studies without NIV were included. In another study of 59 subjects undergoing open gastrostomy, all with vital capacity < 30% of normal, 18 of whom were dependent on continuous NIV at full ventilatory support settings, there were no respiratory complications. Thus, the use of NIV during the implementation of these procedures, especially when used at full ventilatory support settings of pressure preset 18-25 cm H2O, can support alveolar ventilation before, during, and after the procedures and prevent respiratory complications. The procedures investigated appear equivalent, but the methodological quality of the studies could be improved. Possible benefits with regard to nutrition parameters, quality of life, and psychological features need to be further investigated.}, }
@article {pmid28805578, year = {2017}, author = {Fang, T and Jozsa, F and Al-Chalabi, A}, title = {Nonmotor Symptoms in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International review of neurobiology}, volume = {134}, number = {}, pages = {1409-1441}, doi = {10.1016/bs.irn.2017.04.009}, pmid = {28805578}, issn = {2162-5514}, support = {MR/L501529/1//Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology/therapy ; Autonomic Nervous System Diseases/diagnosis/physiopathology/therapy ; Gastrointestinal Diseases/diagnosis/physiopathology/therapy ; Humans ; Mental Disorders/diagnosis/physiopathology/therapy ; Prospective Studies ; Randomized Controlled Trials as Topic/*methods ; Retrospective Studies ; }, abstract = {BACKGROUND: ALS is a progressive neurodegenerative disease with no curative treatment. Nonmotor symptoms presenting in ALS may cause significant distress, worsen prognosis, and affect survival.<br><br>OBJECTIVE: To systematically review evidence for the prevalence of nonmotor ALS symptoms, and treatment options.<br><br>METHODS: Multiple medical literature databases were searched and studies screened using predefined inclusion criteria. Of 4580 studies, 44 were eligible for inclusion with 25 relating to treatment and 19 to the prevalence of nonmotor symptoms in ALS.<br><br>RESULTS: Nonmotor symptoms involve neuropsychiatric, autonomic, gastrointestinal, and vascular systems, and affect between 5% and 80% of people with ALS. Screening tools for individual nonmotor symptoms are useful in classifying symptom severity and to compare between treatment options. Several methods to relieve nonmotor symptoms have been trialed with varying success rates.<br><br>CONCLUSIONS: Many of the current studies of nonmotor symptoms in ALS have small sample sizes, requiring more evidence to increase precision in prevalence estimates. Further research is needed to assess the efficacy of current treatments and to find new therapies. Symptom relief or treatment of these nonmotor symptoms should therefore be considered during the clinical management of ALS.}, }
@article {pmid28799854, year = {2017}, author = {Barschke, P and Oeckl, P and Steinacker, P and Ludolph, A and Otto, M}, title = {Proteomic studies in the discovery of cerebrospinal fluid biomarkers for amyotrophic lateral sclerosis.}, journal = {Expert review of proteomics}, volume = {14}, number = {9}, pages = {769-777}, doi = {10.1080/14789450.2017.1365602}, pmid = {28799854}, issn = {1744-8387}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/pathology ; Biomarkers/*cerebrospinal fluid ; Brain/metabolism/pathology ; Cerebrospinal Fluid Proteins/*genetics ; Gene Expression Regulation/genetics ; Humans ; Mass Spectrometry ; Proteome/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive degenerative motor neuron disease, which usually leads to death within a few years. The diagnosis is mainly based on clinical symptoms and there is a need for ALS-specific biomarkers to make an early and precise diagnosis, for development of disease-modifying drugs and to gain new insights into pathophysiology. Areas covered: In the present review, we summarize studies using mass spectrometric (MS) approaches to identify protein alterations in the cerebrospinal fluid (CSF) of ALS patients. In total, we identified 11 studies fulfilling our criteria by searching in the PubMed database using the keywords 'ALS' and 'CSF' combined with 'proteome', 'proteomic', 'mass spectrometry' or 'protein biomarker'. Ten proteins were differently regulated in ALS CSF compared to controls in at least 2 studies. We will discuss the relevance of the identified proteins regarding the frequency of identification, extent of alteration and brain-specificity. Expert commentary: Most of the identified CSF biomarker candidates are irreproducible or mainly blood-derived. We assign the missing success of CSF proteomic studies in biomarker discovery to a lack of sensitivity, unsuitable normalization, low quality assurance and variations originating from sample preparation. These issues must be improved in future proteomic studies in CSF.}, }
@article {pmid28799808, year = {2018}, author = {Foley, G and Hynes, G}, title = {Decision-making among patients and their family in ALS care: a review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {3-4}, pages = {173-193}, doi = {10.1080/21678421.2017.1353099}, pmid = {28799808}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Caregivers/*psychology ; Databases, Factual ; Decision Making/*physiology ; Humans ; }, abstract = {OBJECTIVES: Practice guidelines in ALS care emphasise the role of the patient and their family in the decision-making process. We aimed to examine the ALS patient/family relationship in the decision-making process and to ascertain how patients and their family can shape one another's decisions pertaining to care.<br><br>METHODS: We conducted a review of peer-reviewed empirical research, published in full and in English between January 2007 and January 2017, relating to care decision-making among ALS patients and their family. Database sources included: Medline; CINAHL; AMED; PsycINFO; PsycARTICLES; and Social Sciences Full Text. A narrative synthesis was undertaken.<br><br>RESULTS: Forty-seven studies from the empirical literature were extracted. The family viewpoint was captured primarily from family members with direct care-giving duties. Patients' cognitive status was not routinely assessed. The findings revealed that the decision-making process in ALS care can be contoured by patients' and family caregivers' perceived responsibilities to one another and to the wider family.<br><br>CONCLUSIONS: Greater attention to family member roles beyond the primary caregiver role is needed. Strategies that integrate cognitively-impaired patients into the family decision-making process require investigation. Identification of the domains in which ALS patients and their family members support one another in the decision-making process could facilitate the development of patient/family decision-making tools in ALS care.}, }
@article {pmid28799488, year = {2017}, author = {Ferrante, M and Conti, GO}, title = {Environment and Neurodegenerative Diseases: An Update on miRNA Role.}, journal = {MicroRNA (Shariqah, United Arab Emirates)}, volume = {6}, number = {3}, pages = {157-165}, doi = {10.2174/2211536606666170811151503}, pmid = {28799488}, issn = {2211-5374}, mesh = {Animals ; *Epigenesis, Genetic ; *Gene-Environment Interaction ; Humans ; MicroRNAs/genetics/*metabolism ; Neurodegenerative Diseases/*genetics/*pathology ; }, abstract = {INTRODUCTION: The importance of neurodegenerative diseases on the management of public health is growing and the real role of the environment and miRNA in their occurrence is still unclear. miRNA can significantly affect the regulatory network. The complex variety and gene-regulatory capacity of miRNAs are particularly valuable in the brain, being a very complex organ with a functional specialization of neurons highly adaptable to environmental stimuli. In particular, an miRNAs role is demonstrated in neurological diseases as an effect to toxic and mutagenic substances exposure by the environment.<br><br>OBJECTIVE: The focus was on the three most important neurodegenerative diseases: Alzheimer, Parkinson and Amyotrophic lateral sclerosis.<br><br>MATERIALS AND METHODS: A brief critical review on scientific papers of the last ten years using PuBMED, Scopus, Web of Science and Cochrane databases was carried out.<br><br>RESULTS: Several studies have shown that miRNAs may contribute to neurodegeneration process in response to environmental risks. The miRNAs are known to play a dynamic role in many biochemical pathways of mammalian's brain, including neuroplasticity, stress responses, cellular signaling, etc. miRNAs have a role in neurodegenerative phenotype of AD, PD and ALS. The environmental chemicals such as metals and pesticides and then behavior can cause miRNA alterations via increasing oxidative stress and/or triggering inflammatory responses.<br><br>CONCLUSION: A discussion with theoretical and possible future research directions is provided and it is clear that the need is not only of longitudinal population studies and of better knowledge of epigenetics markers but, especially, of environmental policy interventions based on the green economy.}, }
@article {pmid28798902, year = {2017}, author = {Kenny, TC and Manfredi, G and Germain, D}, title = {The Mitochondrial Unfolded Protein Response as a Non-Oncogene Addiction to Support Adaptation to Stress during Transformation in Cancer and Beyond.}, journal = {Frontiers in oncology}, volume = {7}, number = {}, pages = {159}, pmid = {28798902}, issn = {2234-943X}, support = {R01 CA172046/CA/NCI NIH HHS/United States ; R01 NS084486/NS/NINDS NIH HHS/United States ; T32 CA078207/CA/NCI NIH HHS/United States ; }, abstract = {Upon accumulation of misfolded proteins in the mitochondria, the mitochondrial unfolded protein response (UPR[mt]) is activated. This review focuses on the role of this response in cancer. We discuss evidence that during transformation, the UPR[mt] may play an essential role in the maintenance of the integrity of the mitochondria in the face of increased oxidative stress. However, the role of the UPR[mt] in other diseases is also emerging and is therefore also briefly discussed.}, }
@article {pmid28797885, year = {2018}, author = {Rodolfo, C and Campello, S and Cecconi, F}, title = {Mitophagy in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {117}, number = {}, pages = {156-166}, doi = {10.1016/j.neuint.2017.08.004}, pmid = {28797885}, issn = {1872-9754}, mesh = {Alzheimer Disease/metabolism/pathology ; Animals ; Autophagy/*physiology ; Humans ; Huntington Disease/metabolism/pathology ; Mitophagy/*physiology ; Neurodegenerative Diseases/*metabolism/pathology ; Parkinson Disease/metabolism/pathology ; }, abstract = {Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are a complex "family" of pathologies, characterised by the progressive loss of neurons and/or neuronal functions, leading to severe physical and cognitive inabilities in affected patients. These syndromes, despite differences in the causative events, the onset, and the progression of the disease, share as common features the presence of aggregate-prone neuro-toxic proteins, in the form of aggresomes and/or inclusion bodies, perturbing cellular homeostasis and neuronal function (Popovic et al., 2014), and the presence of dysfunctional mitochondria. The removal of protein aggregates and of damaged organelles, through the ubiquitin-proteasome system (UPS) and/or the autophagy/lysosome machinery, is a crucial step for the maintenance of neuronal homeostasis. Indeed, their impairment has been reported as associated with the development of these diseases. In this review, we focus on the role played by mitophagy, a specialised form of autophagy, in the onset and progression of major neurodegenerative diseases, as well as on possible therapeutic approaches involving mitophagy modulation.}, }
@article {pmid28791401, year = {2017}, author = {Zhou, T and Ahmad, TK and Gozda, K and Truong, J and Kong, J and Namaka, M}, title = {Implications of white matter damage in amyotrophic lateral sclerosis (Review).}, journal = {Molecular medicine reports}, volume = {16}, number = {4}, pages = {4379-4392}, pmid = {28791401}, issn = {1791-3004}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology ; Animals ; Disease Progression ; Humans ; Models, Biological ; White Matter/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a disease of the grey matter; however, pathological alterations of the white matter (WM), including axonal loss, axonal demyelination and oligodendrocyte death, have been reported in patients with ALS. The present review examined motor neuron death as the primary cause of ALS and evaluated the associated WM damage that is guided by neuronal‑glial interactions. Previous studies have suggested that WM damage may occur prior to the death of motor neurons, and thus may be considered an early indicator for the diagnosis and prognosis of ALS. However, the exact molecular mechanisms underlying early‑onset WM damage in ALS have yet to be elucidated. The present review explored the detailed anatomy of WM and identified several pathological mechanisms that may be implicated in WM damage in ALS. In addition, it associated the pathophysiological alterations of WM, which may contribute to motor neuron death in ALS, with similar mechanisms of WM damage that are involved in multiple sclerosis (MS). Furthermore, the early detection of WM damage in ALS, using neuroimaging techniques, may lead to earlier therapeutic intervention, using immunomodulatory treatment strategies similar to those used in relapsing‑remitting MS, aimed at delaying WM damage in ALS. Early therapeutic approaches may have the potential to delay motor neuron damage and thus prolong the survival of patients with ALS. The therapeutic interventions that are currently available for ALS are only marginally effective. However, early intervention with immunomodulatory drugs may slow the progression of WM damage in the early stages of ALS, thus delaying motor neuron death and increasing the life expectancy of patients with ALS.}, }
@article {pmid28790913, year = {2017}, author = {Geloso, MC and Corvino, V and Marchese, E and Serrano, A and Michetti, F and D'Ambrosi, N}, title = {The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches.}, journal = {Frontiers in aging neuroscience}, volume = {9}, number = {}, pages = {242}, pmid = {28790913}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss. While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease. On these grounds, many treatments have been tested on ALS animals with the aim of inhibiting or reducing the pro-inflammatory action of microglia and astrocytes and counteract the progression of the disease. Unfortunately, these anti-inflammatory therapies have been only modestly successful. The non-univocal role played by microglia during stress and injuries might explain this failure. Indeed, it is now well recognized that, during ALS, microglia displays different phenotypes, from surveillant in early stages, to activated states, M1 and M2, characterized by the expression of respectively harmful and protective genes in later phases of the disease. Consistently, the inhibition of microglial function seems to be a valid strategy only if the different stages of microglia polarization are taken into account, interfering with the reactivity of microglia specifically targeting only the harmful pathways and/or potentiating the trophic ones. In this review article, we will analyze the features and timing of microglia activation in the light of M1/M2 phenotypes in the main mice models of ALS. Moreover, we will also revise the results obtained by different anti-inflammatory therapies aimed to unbalance the M1/M2 ratio, shifting it towards a protective outcome.}, }
@article {pmid28785371, year = {2017}, author = {Liu, Z and Zhou, T and Ziegler, AC and Dimitrion, P and Zuo, L}, title = {Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {2525967}, pmid = {28785371}, issn = {1942-0994}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*genetics/*pathology ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {Increasing numbers of individuals, particularly the elderly, suffer from neurodegenerative disorders. These diseases are normally characterized by progressive loss of neuron cells and compromised motor or cognitive function. Previous studies have proposed that the overproduction of reactive oxygen species (ROS) may have complex roles in promoting the disease development. Research has shown that neuron cells are particularly vulnerable to oxidative damage due to their high polyunsaturated fatty acid content in membranes, high oxygen consumption, and weak antioxidant defense. However, the exact molecular pathogenesis of neurodegeneration related to the disturbance of redox balance remains unclear. Novel antioxidants have shown great potential in mediating disease phenotypes and could be an area of interest for further research. In this review, we provide an updated discussion on the roles of ROS in the pathological mechanisms of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, as well as a highlight on the antioxidant-based therapies for alleviating disease severity.}, }
@article {pmid28785215, year = {2017}, author = {E Hirbec, H and Noristani, HN and Perrin, FE}, title = {Microglia Responses in Acute and Chronic Neurological Diseases: What Microglia-Specific Transcriptomic Studies Taught (and did Not Teach) Us.}, journal = {Frontiers in aging neuroscience}, volume = {9}, number = {}, pages = {227}, pmid = {28785215}, issn = {1663-4365}, abstract = {Over the last decade, microglia have been acknowledged to be key players in central nervous system (CNS) under both physiological and pathological conditions. They constantly survey the CNS environment and as immune cells, in pathological contexts, they provide the first host defense and orchestrate the immune response. It is well recognized that under pathological conditions microglia have both sequential and simultaneous, beneficial and detrimental effects. Cell-specific transcriptomics recently became popular in Neuroscience field allowing concurrent monitoring of the expression of numerous genes in a given cell population. Moreover, by comparing two or more conditions, these approaches permit to unbiasedly identify deregulated genes and pathways. A growing number of studies have thus investigated microglial transcriptome remodeling over the course of neuropathological conditions and highlighted the molecular diversity of microglial response to different diseases. In the present work, we restrict our review to microglia obtained directly from in vivo samples and not cell culture, and to studies using whole-genome strategies. We first critically review the different methods developed to decipher microglia transcriptome. In particular, we compare advantages and drawbacks of flow cytometry and laser microdissection to isolate pure microglia population as well as identification of deregulated microglial genes obtained via RNA sequencing (RNA-Seq) vs. microarrays approaches. Second, we summarize insights obtained from microglia transcriptomes in traumatic brain and spinal cord injuries, pain and more chronic neurological conditions including Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD) and Multiple sclerosis (MS). Transcriptomic responses of microglia in other non-neurodegenerative CNS disorders such as gliomas and sepsis are also addressed. Third, we present a comparison of the most activated pathways in each neuropathological condition using Gene ontology (GO) classification and highlight the diversity of microglia response to insults focusing on their pro- and anti-inflammatory signatures. Finally, we discuss the potential of the latest technological advances, in particular, single cell RNA-Seq to unravel the individual microglial response diversity in neuropathological contexts.}, }
@article {pmid28785203, year = {2017}, author = {Yuan, S and Zhang, ZW and Li, ZL}, title = {Cell Death-Autophagy Loop and Glutamate-Glutamine Cycle in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {231}, pmid = {28785203}, issn = {1662-5099}, abstract = {Although we know that amyotrophic lateral sclerosis (ALS) is correlated with the glutamate-mediated corticomotor neuronal hyperexcitability, detailed ALS pathology remains largely unexplained. While a number of drugs have been developed, no cure exists so far. Here, we propose a hypothesis of neuronal cell death-incomplete autophagy positive-feedback loop-and summarize the role of the neuron-astrocyte glutamate-glutamine cycle in ALS. The disruption of these two cycles might ideally retard ALS progression. Cerebrovascular injuries (such as multiple embolization sessions and strokes) induce neuronal cell death and the subsequent autophagy. ALS impairs autophagosome-lysosome fusion and leads to magnified cell death. Trehalose rescues this impaired fusion step, significantly delaying the onset of the disease, although it does not affect the duration of the disease. Therefore, trehalose might be a prophylactic drug for ALS. Given that a major part of neuronal glutamate is converted from glutamine through neuronal glutaminase (GA), GA inhibitors may decrease the neuronal glutamate accumulation, and, therefore, might be therapeutic ALS drugs. Of these, Ebselen is the most promising one with strong antioxidant properties.}, }
@article {pmid28782538, year = {2017}, author = {Shimizu, M and Dickhoff, WW}, title = {Circulating insulin-like growth factor binding proteins in fish: Their identities and physiological regulation.}, journal = {General and comparative endocrinology}, volume = {252}, number = {}, pages = {150-161}, doi = {10.1016/j.ygcen.2017.08.002}, pmid = {28782538}, issn = {1095-6840}, mesh = {Amino Acid Sequence ; Animals ; Environment ; Fishes/*blood ; Hormones/metabolism ; Insulin-Like Growth Factor Binding Proteins/*blood/chemistry/genetics/isolation &amp; purification ; Insulin-Like Growth Factor I/metabolism ; }, abstract = {Insulin-like growth factor binding proteins (IGFBPs) play crucial roles in regulating the availability of IGFs to receptors and prolong the half-lives of IGFs. There are six IGFBPs present in the mammalian circulation with IGFBP-3 being most abundant. In mammals IGFBP-3 is the major carrier of circulating IGFs, facilitated by forming a ternary complex with IGF and an acid-labile subunit (ALS). IGFBP-1 is generally inhibitory to IGF action by preventing it from interacting with its receptors. In teleosts, the third-round of vertebrate whole genome duplication created paralogs of each IGFBP, except IGFBP-4. In the fish circulation, three major IGFBPs are typically detected at molecular ranges of 20-25, 28-32 and 40-50kDa. However, their identities are not well established. Three major circulating IGFBPs in Chinook salmon have been identified through protein purification and cDNA cloning. Salmon 28- and 22-kDa IGFBPs are co-orthologs of IGFBP-1, termed IGFBP-1a and -1b, respectively. They are induced under catabolic conditions such as stress and fasting but their responses are somewhat different, with IGFBP-1b being the most sensitive of the two. Cortisol stimulates production and secretion of these IGFBP-1 subtypes while, unlike in mammals, insulin may not be a primary suppressor. Salmon 41-kDa IGFBP, a major carrier of IGF-I, is not IGFBP-3, as might be expected extrapolating from mammals, but is in fact IGFBP-2b. Salmon IGFBP-2b levels in plasma are high when fish are fed, and GH treatment increases its circulating levels similar to mammalian IGFBP-3. These findings suggest that salmon IGFBP-2b acquired the role and regulation similar to mammalian IGFBP-3. Multiple replications of fish IGFBPs offer a unique opportunity to investigate molecular evolution of IGFBPs.}, }
@article {pmid28779378, year = {2017}, author = {Mohamed, LA and Markandaiah, S and Bonanno, S and Pasinelli, P and Trotti, D}, title = {Blood-Brain Barrier Driven Pharmacoresistance in Amyotrophic Lateral Sclerosis and Challenges for Effective Drug Therapies.}, journal = {The AAPS journal}, volume = {19}, number = {6}, pages = {1600-1614}, pmid = {28779378}, issn = {1550-7416}, support = {R01 NS074886/NS/NINDS NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists &amp; inhibitors/physiology ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; *Blood-Brain Barrier ; Brain/blood supply ; Clinical Trials as Topic ; Drug Resistance ; Humans ; }, abstract = {The blood-brain barrier (BBB) is essential for proper neuronal function, homeostasis, and protection of the central nervous system (CNS) microenvironment from blood-borne pathogens and neurotoxins. The BBB is also an impediment for CNS penetration of drugs. In some neurologic conditions, such as epilepsy and brain tumors, overexpression of P-glycoprotein, an efflux transporter whose physiological function is to expel catabolites and xenobiotics from the CNS into the blood stream, has been reported. Recent studies reported that overexpression of P-glycoprotein and increase in its activity at the BBB drives a progressive resistance to CNS penetration and persistence of riluzole, the only drug approved thus far for treatment of amyotrophic lateral sclerosis (ALS), rapidly progressive and mostly fatal neurologic disease. This review will discuss the impact of transporter-mediated pharmacoresistance for ALS drug therapy and the potential therapeutic strategies to improve the outcome of ALS clinical trials and efficacy of current and future drug treatments.}, }
@article {pmid28777965, year = {2017}, author = {Cicero, CE and Mostile, G and Vasta, R and Rapisarda, V and Signorelli, SS and Ferrante, M and Zappia, M and Nicoletti, A}, title = {Metals and neurodegenerative diseases. A systematic review.}, journal = {Environmental research}, volume = {159}, number = {}, pages = {82-94}, doi = {10.1016/j.envres.2017.07.048}, pmid = {28777965}, issn = {1096-0953}, mesh = {Alzheimer Disease/chemically induced/*epidemiology ; Amyotrophic Lateral Sclerosis/chemically induced/*epidemiology ; Environmental Pollutants/*toxicity ; Humans ; Metals/*toxicity ; Parkinson Disease, Secondary/chemically induced/*epidemiology ; }, abstract = {Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical presentation such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease (AD) and Parkinson's disease (PD). Genetic mutations have a known causative role, but the majority of cases are likely to be probably caused by a complex gene-environment interaction. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies and it is likely that each metal could be toxic through specific pathways. The possible pathogenic role of different metals has been supported by some epidemiological evidences coming from occupational and ecological studies. In order to assess the possible association between metals and neurodegenerative disorders, several case-control studies have also been carried out evaluating the metals concentration in different biological specimens such as blood/serum/plasma, cerebrospinal fluid (CSF), nail and hair, often reporting conflicting results. This review provides an overview of our current knowledge on the possible association between metals and ALS, AD and PD as main neurodegenerative disorders.}, }
@article {pmid28777179, year = {2017}, author = {Ju, YS and Videnovic, A and Vaughn, BV}, title = {Comorbid Sleep Disturbances in Neurologic Disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {23}, number = {4, Sleep Neurology}, pages = {1117-1131}, doi = {10.1212/CON.0000000000000501}, pmid = {28777179}, issn = {1538-6899}, mesh = {Comorbidity ; Humans ; Nervous System Diseases/complications/diagnosis/*therapy ; Restless Legs Syndrome/diagnosis/*therapy ; Sleep/*physiology ; Sleep Apnea Syndromes/complications/therapy ; Sleep Wake Disorders/complications/diagnosis/*therapy ; }, abstract = {PURPOSE OF REVIEW: This article provides a review of disturbances of sleep comorbid with common neurologic disorders.<br><br>RECENT FINDINGS: A wide variety of neurologic disorders are frequently complicated by comorbid sleep disturbances. In many cases, a bidirectional relationship appears to occur between sleep function and the neurologic disease, such that treatment of comorbid sleep disturbances may improve the symptoms of the neurologic disease.<br><br>SUMMARY: Neurologic disorders are often associated with abnormalities of sleep. Sleep influences the severity of both epilepsy and headache, and treatment of comorbid sleep disorders may improve seizure and headache frequency. Alzheimer disease is characterized by circadian phase delay and poor nighttime sleep and is strongly associated with obstructive sleep apnea. Parkinson disease is associated with several sleep disorders, including insomnia, restless legs syndrome, rapid eye movement (REM) sleep behavior disorder, daytime hypersomnia, and sleep-disordered breathing. Hypoventilation in amyotrophic lateral sclerosis and other neuromuscular disorders often presents initially with sleep problems, and treatment with noninvasive ventilation improves survival and quality of life.}, }
@article {pmid28762306, year = {2018}, author = {Fatima, MT and Islam, Z and Ahmad, E and Salahuddin, P}, title = {Emerging Targets and Latest Proteomics Based Therapeutic Approaches in Neurodegenerative Diseases.}, journal = {Current protein &amp; peptide science}, volume = {19}, number = {9}, pages = {858-875}, doi = {10.2174/1389203718666170731114757}, pmid = {28762306}, issn = {1875-5550}, mesh = {Drug Design ; Humans ; Molecular Chaperones/metabolism ; Molecular Targeted Therapy ; Neurodegenerative Diseases/etiology/metabolism/*therapy ; Protein Folding ; Protein Multimerization ; Proteins/antagonists &amp; inhibitors/*metabolism ; Proteolysis ; Proteomics/*methods ; Proteostasis ; }, abstract = {Protein homeostasis (proteostasis) is achieved by the interplay among various components and pathways inside a cell. Dysfunction in proteostasis leads to protein misfolding and aggregation which is ubiquitously associated with many neurodegenerative disorders, although the exact role of these aggregate in the pathogenesis remains unknown. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others are characterized by the conversion of specific protein aggregates into protein inclusions and/or plaques in degenerating brains. Apart from the conventional disease specific proteins, such as amyloid-β, α - synuclein, huntingtin protein, and prions that are known to aggregate, a number of other proteins play a vital role in aggravating the disease condition. In this review, we discuss the disease etiology, mechanism, the role of various pathways, molecular machinery including molecular chaperones, protein degradation pathways, and the active formation of inclusions in various neurodegenerative diseases. We also highlight the approaches, strategies, and methods that have been used for the treatment of these complex diseases over the years and the efforts that have potential in the near future.}, }
@article {pmid28762175, year = {2017}, author = {Kapeli, K and Martinez, FJ and Yeo, GW}, title = {Genetic mutations in RNA-binding proteins and their roles in ALS.}, journal = {Human genetics}, volume = {136}, number = {9}, pages = {1193-1214}, pmid = {28762175}, issn = {1432-1203}, support = {HG007005/NH/NIH HHS/United States ; U54 HG007005/HG/NHGRI NIH HHS/United States ; NS075449/NH/NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; T32GM008666//National Institutes of Health (US)/International ; T32 GM008666/GM/NIGMS NIH HHS/United States ; HG004659/NH/NIH HHS/United States ; R01 NS075449/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Humans ; *Mutation ; Neurons/*metabolism ; RNA-Binding Proteins/*genetics/*metabolism ; }, abstract = {Mutations in genes that encode RNA-binding proteins (RBPs) have emerged as critical determinants of neurological diseases, especially motor neuron disorders such as amyotrophic lateral sclerosis (ALS). RBPs are involved in all aspects of RNA processing, controlling the life cycle of RNAs from synthesis to degradation. Hallmark features of RBPs in neuron dysfunction include misregulation of RNA processing, mislocalization of RBPs to the cytoplasm, and abnormal aggregation of RBPs. Much progress has been made in understanding how ALS-associated mutations in RBPs drive pathogenesis. Here, we focus on several key RBPs involved in ALS-TDP-43, HNRNP A2/B1, HNRNP A1, FUS, EWSR1, and TAF15-and review our current understanding of how mutations in these proteins cause disease.}, }
@article {pmid28761418, year = {2017}, author = {Sher, RB}, title = {The interaction of genetics and environmental toxicants in amyotrophic lateral sclerosis: results from animal models.}, journal = {Neural regeneration research}, volume = {12}, number = {6}, pages = {902-905}, pmid = {28761418}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in the progressive death of motor neurons, leading to paralysis and eventual death. There is presently no cure for ALS, and only two drugs are available, neither of which provide significant extension of life. The wide variation in onset and progression of the disease, both in sporadic and even in strongly penetrant monogenic familial forms of ALS, indicate that in addition to background genetic variation impacting the disease process, environmental exposures are likely contributors. Epidemiological evidence worldwide implicates exposures to bacterial toxins, heavy metals, pesticides, and trauma as probable environmental factors. Here, we review current advances in gene-environment interactions in ALS animal models. We report our recent discoveries in a zebrafish model of ALS in relation to exposure to the cyanobacterial toxin BMAA, and discuss several results from mouse models that show interactions with exposure to mercury and statin drugs, both leading to acceleration of the disease process. The increasing research into this combinatorial gene-environment process is just starting, but shows early promise to uncover the underlying biochemical pathways that instigate the initial motor neuron defects and lead to their rapidly progressive dysfunction.}, }
@article {pmid28760593, year = {2018}, author = {Artusi, CA and Mishra, M and Latimer, P and Vizcarra, JA and Lopiano, L and Maetzler, W and Merola, A and Espay, AJ}, title = {Integration of technology-based outcome measures in clinical trials of Parkinson and other neurodegenerative diseases.}, journal = {Parkinsonism &amp; related disorders}, volume = {46 Suppl 1}, number = {Suppl 1}, pages = {S53-S56}, pmid = {28760593}, issn = {1873-5126}, support = {K23 MH092735/MH/NIMH NIH HHS/United States ; KL2 TR001426/TR/NCATS NIH HHS/United States ; }, mesh = {Clinical Trials as Topic/*methods ; Databases, Bibliographic/statistics &amp; numerical data ; Humans ; Neurodegenerative Diseases/*drug therapy ; Outcome Assessment, Health Care/*methods ; Parkinson Disease/*drug therapy ; }, abstract = {INTRODUCTION: We sought to review the landscape of past, present, and future use of technology-based outcome measures (TOMs) in clinical trials of neurodegenerative disorders.<br><br>METHODS: We systematically reviewed PubMed and ClinicalTrials.gov for published and ongoing clinical trials in neurodegenerative disorders employing TOMs. In addition, medical directors of selected pharmaceutical companies were surveyed on their companies' ongoing efforts and future plans to integrate TOMs in clinical trials as primary, secondary, or exploratory endpoints.<br><br>RESULTS: We identified 164 published clinical trials indexed in PubMed that used TOMs as outcome measures in Parkinson disease (n&#xa0;=&#xa0;132) or other neurodegenerative disorders (n&#xa0;=&#xa0;32). The ClinicalTrials.gov search yielded 42 clinical trials using TOMs, representing 2.7% of ongoing trials. Sensor-based technology accounted for over 75% of TOMs applied. Gait and physical activity were the most common targeted domains. Within the next 5 years, 83% of surveyed pharmaceutical companies engaged in neurodegenerative disorders plan to deploy TOMs in clinical trials.<br><br>CONCLUSION: Although promising, TOMs are underutilized in clinical trials of neurodegenerative disorders. Validating relevant endpoints, standardizing measures and procedures, establishing a single platform for integration of data and algorithms from different devices, and facilitating regulatory approvals should advance TOMs integration into clinical trials.}, }
@article {pmid28752333, year = {2017}, author = {Zárate, R and El Jaber-Vazdekis, N and Tejera, N and Pérez, JA and Rodríguez, C}, title = {Significance of long chain polyunsaturated fatty acids in human health.}, journal = {Clinical and translational medicine}, volume = {6}, number = {1}, pages = {25}, pmid = {28752333}, issn = {2001-1326}, abstract = {In the last decades, the development of new technologies applied to lipidomics has revitalized the analysis of lipid profile alterations and the understanding of the underlying molecular mechanisms of lipid metabolism, together with their involvement in the occurrence of human disease. Of particular interest is the study of omega-3 and omega-6 long chain polyunsaturated fatty acids (LC-PUFAs), notably EPA (eicosapentaenoic acid, 20:5n-3), DHA (docosahexaenoic acid, 22:6n-3), and ARA (arachidonic acid, 20:4n-6), and their transformation into bioactive lipid mediators. In this sense, new families of PUFA-derived lipid mediators, including resolvins derived from EPA and DHA, and protectins and maresins derived from DHA, are being increasingly investigated because of their active role in the "return to homeostasis" process and resolution of inflammation. Recent findings reviewed in the present study highlight that the omega-6 fatty acid ARA appears increased, and omega-3 EPA and DHA decreased in most cancer tissues compared to normal ones, and that increments in omega-3 LC-PUFAs consumption and an omega-6/omega-3 ratio of 2-4:1, are associated with a reduced risk of breast, prostate, colon and renal cancers. Along with their lipid-lowering properties, omega-3 LC-PUFAs also exert cardioprotective functions, such as reducing platelet aggregation and inflammation, and controlling the presence of DHA in our body, especially in our liver and brain, which is crucial for optimal brain functionality. Considering that DHA is the principal omega-3 FA in cortical gray matter, the importance of DHA intake and its derived lipid mediators have been recently reported in patients with major depressive and bipolar disorders, Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. The present study reviews the relationships between major diseases occurring today in the Western world and LC-PUFAs. More specifically this review focuses on the dietary omega-3 LC-PUFAs and the omega-6/omega-3 balance, in a wide range of inflammation disorders, including autoimmune diseases. This review suggests that the current recommendations of consumption and/or supplementation of omega-3 FAs are specific to particular groups of age and physiological status, and still need more fine tuning for overall human health and well being.}, }
@article {pmid28750498, year = {2017}, author = {Arbizu, J and Giuliani, A and Gállego Perez-Larraya, J and Riverol, M and Jonsson, C and García-García, B and Morales, M and Imaz, L and Pagani, M}, title = {Emerging clinical issues and multivariate analyses in PET investigations.}, journal = {The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...}, volume = {61}, number = {4}, pages = {386-404}, doi = {10.23736/S1824-4785.17.03024-2}, pmid = {28750498}, issn = {1827-1936}, mesh = {Brain/diagnostic imaging ; Fluorodeoxyglucose F18/chemistry ; Humans ; Magnetic Resonance Imaging/*methods ; Multimodal Imaging/*methods ; Multivariate Analysis ; Nervous System Diseases/*diagnostic imaging/metabolism ; Positron-Emission Tomography/*methods ; Radiopharmaceuticals/chemistry ; }, abstract = {PET using 18F-2-fluoro-2-deoxy-D-glucose (FDG-PET) has been gradually introduced in the diagnostic clinical criteria of the most prevalent neurodegenerative diseases. Moreover, an increasing amount of literature has shown that the information provided by FDG-PET enhances the sensitivity of standard imaging biomarkers in less frequent disorders in which an early differential diagnosis can be of paramount relevance for patient management and outcome. Therefore emerging uses of FDG-PET may be important in prion diseases, autoimmune encephalitis (AE) and amyotrophic lateral sclerosis. Interestingly, FDG-PET findings can also be observed in the early phases of these conditions, even in the presence of normal magnetic resonance imaging scans. Thalamic hypometabolism is a common finding in sporadic Creutzfeldt-Jacob disease and fatal familiar insomnia patients, with further cortical synaptic dysfunction in the former. Limbic and extra-limbic metabolic abnormalities (more often hypermetabolism) can be observed in AE, although specific patterns may be seen within different syndromes associated with antibodies that target neuronal surface or synaptic antigens. FDG-PET shows its usefulness by discriminating patients with amyotrophic lateral sclerosis associated to upper motor neuron onset that evolve to frontotemporal dementia. Besides visual and voxel based image analysis, multivariate analysis as interregional correlation analysis and independent/principal component analysis have been successfully implemented to PET images increasing the accuracy of the discrimination of neurodegenerative diseases. The clinical presentation and current diagnostic criteria of these neurologic disorders as well as the emerging usefulness of FDG-PET in the diagnostic workup are presented and discussed in this review.}, }
@article {pmid28745069, year = {2017}, author = {de Vries, BS and Rustemeijer, LMM and van der Kooi, AJ and Raaphorst, J and Schröder, CD and Nijboer, TCW and Hendrikse, J and Veldink, JH and van den Berg, LH and van Es, MA}, title = {A case series of PLS patients with frontotemporal dementia and overview of the literature.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {7-8}, pages = {534-548}, doi = {10.1080/21678421.2017.1354996}, pmid = {28745069}, issn = {2167-9223}, mesh = {Aged ; Diagnosis, Differential ; Female ; Frontotemporal Dementia/classification/complications/*diagnosis ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/classification/complications/*diagnosis ; Risk Factors ; Symptom Assessment/*methods ; }, abstract = {OBJECTIVE: Primary lateral sclerosis (PLS) is a rare form of motor neuron disease characterised by UMN degeneration leading to slowly progressive spasticity. Whether it is a separate disease or a subtype of ALS has been debated. In ALS comorbid frontotemporal dementia (FTD) is frequently seen (±15%). However, cognitive and behavioural changes are generally not considered to be a part of PLS.<br><br>METHODS: To report the clinical findings and frequency of PLS patients that developed FTD in a referral-based cohort and provide an overview of the literature.<br><br>RESULTS: In our cohort six out of 181 (3.3%) PLS patients developed FTD. In the literature a few cases of PLS with FTD have been reported and only a limited number of small studies have investigated cognition in PLS. However, when these studies are summarised a pattern emerges with FTD diagnoses in&#x2009;&#xb1;2% and frontotemporal impairment in 22% of patients.<br><br>CONCLUSIONS: These findings suggest that PLS is part of the FTD-MND continuum and would favour viewing it as a subtype of ALS. It is, however, not a restricted (isolated UMN involvement) phenotype.}, }
@article {pmid28744202, year = {2017}, author = {Barker, HV and Niblock, M and Lee, YB and Shaw, CE and Gallo, JM}, title = {RNA Misprocessing in C9orf72-Linked Neurodegeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {195}, pmid = {28744202}, issn = {1662-5102}, support = {G0501573/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0300329/MRC_/Medical Research Council/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; GALLO/APR14/827-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {A large GGGGCC hexanucleotide repeat expansion in the first intron or promoter region of the C9orf72 gene is the most common genetic cause of familial and sporadic Amyotrophic lateral sclerosis (ALS), a devastating degenerative disease of motor neurons, and of Frontotemporal Dementia (FTD), the second most common form of presenile dementia after Alzheimer's disease. C9orf72-associated ALS/FTD is a multifaceted disease both in terms of its clinical presentation and the misregulated cellular pathways contributing to disease progression. Among the numerous pathways misregulated in C9orf72-associated ALS/FTD, altered RNA processing has consistently appeared at the forefront of C9orf72 research. This includes bidirectional transcription of the repeat sequence, accumulation of repeat RNA into nuclear foci sequestering specific RNA-binding proteins (RBPs) and translation of RNA repeats into dipeptide repeat proteins (DPRs) by repeat-associated non-AUG (RAN)-initiated translation. Over the past few years the true extent of RNA misprocessing in C9orf72-associated ALS/FTD has begun to emerge and disruptions have been identified in almost all aspects of the life of an RNA molecule, including release from RNA polymerase II, translation in the cytoplasm and degradation. Furthermore, several alterations have been identified in the processing of the C9orf72 RNA itself, in terms of its transcription, splicing and localization. This review article aims to consolidate our current knowledge on the consequence of the C9orf72 repeat expansion on RNA processing and draws attention to the mechanisms by which several aspects of C9orf72 molecular pathology converge to perturb every stage of RNA metabolism.}, }
@article {pmid28737870, year = {2017}, author = {Zaidman, VE}, title = {Analysis of acid-labile subunit and its usefulness in pediatrics.}, journal = {Archivos argentinos de pediatria}, volume = {115}, number = {4}, pages = {391-398}, doi = {10.5546/aap.2017.eng.391}, pmid = {28737870}, issn = {1668-3501}, mesh = {Carrier Proteins/*blood ; Child ; Deficiency Diseases/blood ; Glycoproteins/*blood/*deficiency ; Humans ; }, abstract = {The acid-labile subunit (ALS) is an 85 kDa glycoprotein that belongs to the leucine-rich repeat superfamily. It mainly circulates in serum bound to a high molecular weight ternary complex. The main and most widely studied function of ALS is to prolong the half-life of the binary complex formed by insulin-like growth factors type 1 and 2 and its transport proteins 3 and 5. ALS serum levels are lower in neonates, reach a peak in late puberty, and then slowly decrease throughout adulthood. ALS deficiency has consequences on growth, hydrocarbon and bone metabolism, and, in some cases, it affects pubertal development. To date, 25 patients with complete ALS deficiency due to IGFALS gene mutations have been found.}, }
@article {pmid28737506, year = {2017}, author = {Lall, D and Baloh, RH}, title = {Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia.}, journal = {The Journal of clinical investigation}, volume = {127}, number = {9}, pages = {3250-3258}, pmid = {28737506}, issn = {1558-8238}, support = {R01 NS069669/NS/NINDS NIH HHS/United States ; R01 NS097545/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Autoimmunity ; C9orf72 Protein ; DNA-Binding Proteins/metabolism ; Disease Progression ; Frontotemporal Dementia/*metabolism/pathology ; Genetic Predisposition to Disease ; Humans ; Inflammation ; Mice ; Microglia/metabolism/*pathology ; Motor Neurons/metabolism ; Mutation ; Myeloid Cells/metabolism ; Phenotype ; Proteins/*metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.}, }
@article {pmid28729824, year = {2017}, author = {Batra, R and Lee, CW}, title = {Mouse Models of C9orf72 Hexanucleotide Repeat Expansion in Amyotrophic Lateral Sclerosis/ Frontotemporal Dementia.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {196}, pmid = {28729824}, issn = {1662-5102}, abstract = {The presence of hexanucleotide repeat expansion (HRE) in the first intron of the human C9orf72 gene is the most common genetic cause underlying both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies aimed at elucidating the pathogenic mechanisms associated of C9orf72 FTD and ALS (C9FTD/ALS) have focused on the hypothesis of RNA and protein toxic gain-of-function models, including formation of nuclear RNA foci containing GGGGCC (G4C2) HRE, inclusions containing dipeptide repeat proteins through a non-canonical repeat associated non-ATG (RAN) translation mechanism, and on loss-of-function of the C9orf72 protein. Immense effort to elucidate these mechanisms has been put forth and toxic gain-of-function models have especially gained attention. Various mouse models that recapitulate distinct disease-related pathological, functional, and behavioral phenotypes have been generated and characterized. Although these models express the C9orf72 HRE mutation, there are numerous differences among them, including the transgenesis approach to introduce G4C2-repeat DNA, genomic coverage of C9orf72 features in the transgene, G4C2-repeat length after genomic stabilization, spatiotemporal expression profiles of RNA foci and RAN protein aggregates, neuropathological features, and neurodegeneration-related clinical symptoms. This review aims to (1) provide an overview of the key characteristics; (2) provide insights into potential pathological factors contributing to neurotoxicity and clinical phenotypes through systematic comparison of these models.}, }
@article {pmid28721826, year = {2017}, author = {Sanchez-Barcelo, EJ and Rueda, N and Mediavilla, MD and Martinez-Cue, C and Reiter, RJ}, title = {Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders.}, journal = {Current medicinal chemistry}, volume = {24}, number = {35}, pages = {3851-3878}, doi = {10.2174/0929867324666170718105557}, pmid = {28721826}, issn = {1875-533X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Melatonin/pharmacology/*therapeutic use ; Mental Disorders/*drug therapy ; Nervous System Diseases/*drug therapy ; Oxidative Stress/drug effects ; Receptors, Melatonin/agonists/metabolism ; }, abstract = {BACKGROUND: Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory "bench" are not always applicable to the patient's "bedside".<br><br>OBJECTIVE: In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology.<br><br>CONCLUSION: Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases.}, }
@article {pmid28718185, year = {2017}, author = {Yuan, SM}, title = {Congenital Pulmonary Lymphangiectasia: A Disorder not only of Fetoneonates.}, journal = {Klinische Padiatrie}, volume = {229}, number = {4}, pages = {205-208}, doi = {10.1055/s-0043-112500}, pmid = {28718185}, issn = {1439-3824}, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Cross-Sectional Studies ; DNA Mutational Analysis ; Female ; Fetal Diseases/*diagnosis/genetics/pathology/therapy ; Forkhead Transcription Factors/genetics ; Humans ; Infant ; Infant, Newborn ; Infant, Newborn, Diseases/*diagnosis/genetics/pathology/therapy ; Integrins/genetics ; Longitudinal Studies ; Lung Diseases/*congenital/diagnosis/genetics/pathology/therapy ; Lymphangiectasis/*congenital/diagnosis/genetics/pathology/therapy ; Pregnancy ; Prognosis ; Stillbirth/genetics ; Treatment Outcome ; Vascular Endothelial Growth Factor Receptor-3/genetics ; Young Adult ; }, abstract = {Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder of the lung, characterized by dilation of pulmonary subpleural, interlobar, perivascular and peribronchial lymphatics. The incidence of CPL among stillborn and neonates was estimated to be <1%. The etiology of CPL is unknown. However, it has been suspected to be of a genetic background. Recent basic studies revealed that it might be caused by the FOXC2, Vegfr-3 and integrin α9β1gene mutations. A clinical diagnosis of CPL can be made much easier in full-term neonates who present with respiratory distress, pleural (especially chylous) effusions with or without generalized edema. In infancy, the diagnosis seems to be more difficult due to the nonspecific respiratory symptoms like persistent tachypnea, cough and wheeze. Lung biopsy with subsequent histological and immunohistochemical studies is the golden diagnostic method of CPL. Immunohistochemical staining for endothelial cell markers CD31, CD34 and D2-40 confirms lymphatic origin. Therapeutic strategies include supportive, nutritional, investigational, aggressively interventional and surgical regimens, most of which have shown promising outcomes. Although CPL was once regarded as a disorder of very poor prognosis in neonatal onset cases, teenager and adult patients have shown good outcomes upon long-term follow-up.Die angeborene pulmonale Lymphangiektasie (CPL) ist eine seltene Entwicklungsstörung der Lunge, die durch eine Dilatation der pulmonalen subpleuralen, interlobären, perivaskulären und peribronchialen Lymphgefäße charakterisiert ist. Die Inzidenz der CPL bei Totgeburten und Neugeborenen wird <1% geschätzt. Die Ätiologie der CPL ist unbekannt. Allerdings wird ein genetischer Hintergrund vermutet. Neuere Grundlagenstudien zeigten, dass die CPL durch FOXC2, Vegfr-3 und Integrin α9β1-Genmutationen verursacht sein könnte. Die klinische Diagnose der CPL ist sehr viel einfacher in Reifgeborenen zu stellen, die Atemnot, Pleuraergüsse (vor allem chylöse) mit und ohne generalisiertem Ödem aufweisen. In der frühen Kindheit ist die Diagnose aufgrund der unspezifischen respiratorischen Symptomatik wie persistierende Tachypnoen, Husten oder Röcheln schwerer zu stellen. Die Lungenbiopsie mit anschließenden histologischen und immunhistochemischen Untersuchungen ist der Goldstandard für die Diagnose der CPL. Die immunhistochemische Färbung der Endothelzellmarker CD31, CD34 und D2-40 bestätigt den lymphatischen Ursprung. Die Behandlungsstrategien umfassen unterstützende, alimentäre, in Erprobung befindliche, aggressiv-interventionelle und chirurgische Behandlungspläne, von denen die meisten ermutigende Ergebnisse zeigten. Obwohl die CPL einst bei Fällen mit Ausbruch im Neugeborenenalter als Erkrankung mit sehr schlechter Prognose galt, zeigen Teenager und erwachsene Patienten in der Langzeit-Nachbeobachtung gute Verläufe.}, }
@article {pmid28717872, year = {2018}, author = {Olejniczak, M and Kotowska-Zimmer, A and Krzyzosiak, W}, title = {Stress-induced changes in miRNA biogenesis and functioning.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {75}, number = {2}, pages = {177-191}, pmid = {28717872}, issn = {1420-9071}, support = {N N302 633240//NSC/International ; 2015/18/E/NZ2/00678//NSC/International ; KNOW//NSC/International ; }, mesh = {Animals ; DNA Damage ; *Gene Expression Regulation ; Humans ; MicroRNAs/*genetics/metabolism ; Models, Genetic ; Protein Binding ; RNA Processing, Post-Transcriptional ; Signal Transduction/*genetics ; Transcription Factors/*genetics/metabolism ; }, abstract = {MicroRNAs (miRNAs) are small, noncoding RNAs that play key roles in the regulation of cellular homeostasis in eukaryotic organisms. There is emerging evidence that some of these processes are influenced by various forms of cellular stresses, including DNA damage, pathogen invasion or chronic stress associated with diseases. Many reports over the last decade demonstrate examples of stress-induced miRNA deregulation at the level of transcription, processing, subcellular localization and functioning. Moreover, core miRNA biogenesis proteins and their interactions with partners can be selectively regulated in response to stress signaling. However, little is known about the role of isomiRs and the interactions of miRNA with non-canonical targets in the context of the stress response. In this review, we summarize the current knowledge on miRNA functions under various stresses, including chronic stress and miRNA deregulation in the pathogenesis of age-associated neurodegenerative disorders.}, }
@article {pmid28714393, year = {2017}, author = {Caballero-Villarraso, J and Galvan, A and Escribano, BM and Tunez, I}, title = {Interrelationships Among Gut Microbiota and Host: Paradigms, Role in Neurodegenerative Diseases and Future Prospects.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {8}, pages = {945-964}, doi = {10.2174/1871527316666170714120118}, pmid = {28714393}, issn = {1996-3181}, mesh = {Animals ; Gastrointestinal Microbiome/*physiology ; Host Microbial Interactions/*physiology ; Humans ; Neurodegenerative Diseases/*microbiology/*physiopathology ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Advances in the knowledge of the microbiota and concepts related to it have triggered a wake-up call in biomedicine. The development in various scientific areas has enabled a better and broader approach to everything concerning the set of families of microorganisms that coexist with an individual and are able to function as one or more organs in its body. Among the aforementioned scientific areas, those worth mentioning are the advances/progress in biotechnological resources and, in particular, molecular biology and related areas. This has given rise to the era of "omics", marking a turning point in the understanding of numerous physiologic and pathophysiologic processes of the organism. The current theory is that the microbiota and the host maintain an intimate relationship that is of a markedly bilateral nature. This continuous feedback has different connotations between one individual and another, but also within the same individual throughout its life span, which is determined by its own conditioning factors (such as its genetic profile), and environmental ones (mainly diet and lifestyles). Both elements (microbiota and host) coexist harmoniously, maintaining a balance, which can be altered and give rise to different morbid entities. Among these is its relation to chronic processes, and especially those of an autoimmune origin. Such may be neurological diseases situations and, specifically, those of a neurodegenerative nature. In disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and Alzheimer's disease, among others, it has been found that a disharmonic coexistence between microbiota and host may have implications in their etiology and pathogenesis. A better understanding of those implications has led to the development of actions on the gut microbiota as a target to slow down the advancement or establishment of neurodegeneration.<br><br>CONCLUSION: In this scenario, several treatment strategies have emerged, such as probiotic food intake and stool transplantation. Their real potentialities remain to be elucidated, although current scientific evidence infers that the development of those therapeutic approaches could offer a ray of hope in the prospects of tackling neurodegenerative diseases.}, }
@article {pmid28713244, year = {2017}, author = {Quan, Z and Zheng, D and Qing, H}, title = {Regulatory Roles of Long Non-Coding RNAs in the Central Nervous System and Associated Neurodegenerative Diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {175}, pmid = {28713244}, issn = {1662-5102}, abstract = {Accumulating studies have revealed that the human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), which participate in multiple biological networks modulating gene expression via transcriptional, post-transcriptional and epigenetic regulation. Strikingly, a large fraction of tissue-specific lncRNAs are expressed in the Central Nervous System (CNS) with precisely regulated temporal and spatial expression patterns. These brain-specific lncRNAs are also featured with the cell-type specificity, the highest signals of evolutionary conservation, and their preferential location adjacent to brain-expressed protein-coding genes. Mounting evidence has indicated dysregulation or mutations in lncRNA gene loci are associated with a variety of CNS-associated neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's diseases, Amyotrophic Lateral Sclerosis and others. However, how lncRNAs contribute to these disorders remains to be further explored and studied. In this review article, we systematically and comprehensively summarize the current studies of lncRNAs, demonstrate the specificity of lncRNAs expressed in the brain, their functions during neural development and expression profiles in major cell types of the CNS, highlight the regulatory mechanisms of several studied lncRNAs that may play essential roles in the pathophysiology of neurodegenerative diseases, and discuss the current challenges and future perspectives of lncRNA studies involved in neurodegenerative and other diseases.}, }
@article {pmid28712499, year = {2017}, author = {Chilcoat, D and Liu, ZB and Sander, J}, title = {Use of CRISPR/Cas9 for Crop Improvement in Maize and Soybean.}, journal = {Progress in molecular biology and translational science}, volume = {149}, number = {}, pages = {27-46}, doi = {10.1016/bs.pmbts.2017.04.005}, pmid = {28712499}, issn = {1878-0814}, mesh = {Base Sequence ; CRISPR-Cas Systems/*genetics ; Crops, Agricultural/*genetics ; Genetic Engineering/*methods ; Glycine max/*genetics ; Zea mays/*genetics ; }, abstract = {CRISPR/Cas enables precise improvement of commercially relevant crop species by transgenic and nontransgenic methodologies. We have used CRISPR/Cas with or without DNA repair template in both corn and soybean for a range of applications including enhancing drought tolerance, improving seed oil composition, and endowing herbicide tolerance. Importantly, by pairing CRISPR/Cas technology with recent advances in plant tissue culture, these changes can be introduced directly into commercially relevant genotypes. This powerful combination of technologies enables advanced breeding techniques for introducing natural genetic variations directly into product relevant lines with improved speed and quality compared with traditional breeding methods. Variation generated through such CRISPR/Cas enabled advanced breeding approaches can be indistinguishable from naturally occurring variation and therefore should be readily accessible for commercialization. The precision, reach, and flexibility afforded by CRISPR/Cas promise an important role for genome editing in future crop improvement efforts.}, }
@article {pmid28711596, year = {2017}, author = {Hanspal, MA and Dobson, CM and Yerbury, JJ and Kumita, JR}, title = {The relevance of contact-independent cell-to-cell transfer of TDP-43 and SOD1 in amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1863}, number = {11}, pages = {2762-2771}, pmid = {28711596}, issn = {0925-4439}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Cell Communication ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Protein Aggregation, Pathological/genetics/*metabolism/pathology ; Proteostasis Deficiencies/genetics/*metabolism/pathology ; Superoxide Dismutase-1/genetics/*metabolism ; alpha-Synuclein/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the formation of cytoplasmic aggregates by proteins including TDP-43 and SOD1, in affected cells in the central nervous system (CNS). Pathology spreads from an initial site of onset to contiguous anatomical regions. There is evidence that for disease-associated proteins, including TDP-43 and SOD1, non-native protein conformers can promote misfolding of the natively folded counterparts, and cell-to-cell transfer of pathological aggregates may underlie the spread of the disease throughout the CNS. A variety of studies have demonstrated that SOD1 is released by neuron-like cells into the surrounding culture medium, either in their free state or encapsulated in extracellular vesicles such as exosomes. Extracellular SOD1 can then be internalised by naïve cells incubated in this conditioned medium, leading to the misfolding and aggregation of endogenous intracellular SOD1; an effect that propagates over serial passages. A similar phenomenon has also been observed with other proteins associated with protein misfolding and progressive neurological disorders, including tau, α-synuclein and both mammalian and yeast prions. Conditioned media experiments using TDP-43 have been less conclusive, with evidence for this protein undergoing intercellular transfer being less straightforward. In this review, we describe the properties of TDP-43 and SOD1 and look at the evidence for their respective abilities to participate in cell-to-cell transfer via conditioned medium, and discuss how variations in the nature of cell-to-cell transfer suggests that a number of different mechanisms are involved in the spreading of pathology in ALS.}, }
@article {pmid28710326, year = {2017}, author = {Eisen, A and Braak, H and Del Tredici, K and Lemon, R and Ludolph, AC and Kiernan, MC}, title = {Cortical influences drive amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {88}, number = {11}, pages = {917-924}, doi = {10.1136/jnnp-2017-315573}, pmid = {28710326}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/pathology/*physiopathology ; Axons/pathology/physiology ; Cerebral Cortex/pathology/*physiopathology ; Disease Progression ; Early Diagnosis ; Frontotemporal Dementia/diagnosis/pathology/physiopathology ; Humans ; Neural Inhibition/physiology ; Neural Pathways/physiopathology ; Neuroanatomical Tract-Tracing Techniques ; Neuroimaging ; Presynaptic Terminals/pathology/physiology ; TDP-43 Proteinopathies/diagnosis/*physiopathology ; Transcranial Magnetic Stimulation ; }, abstract = {The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia.}, }
@article {pmid28709951, year = {2017}, author = {Saraiva, C and Esteves, M and Bernardino, L}, title = {MicroRNA: Basic concepts and implications for regeneration and repair of neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {141}, number = {}, pages = {118-131}, doi = {10.1016/j.bcp.2017.07.008}, pmid = {28709951}, issn = {1873-2968}, mesh = {Animals ; Brain/pathology/*physiology ; Humans ; MicroRNAs/genetics/*metabolism ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Neurogenesis/*physiology ; }, abstract = {MicroRNAs (miRNA) are small non-coding molecules that revolutionized our knowledge about the regulation of gene expression. Capable to target a large number of mRNA, miRNA are thought to regulate around 30% of the entire human genome. Therefore, these molecules are able to regulate several biological processes, including neuronal survival, differentiation and regeneration. Additionally, miRNA might act as valuable clinical agents in brain pathological conditions. Their specific expression patterns in the brain parenchyma and/or in circulating fluids have been highlighted as potential biomarkers, while the modulation of their activity may have therapeutic value for several neurodegenerative diseases. In this review, we describe miRNA biogenesis, signaling and regulation as well as the role of miR-9, miR-124, miR-132 and miR-137 in both adult neurogenesis and neurodegeneration, namely in Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The relationship between miRNA, neurodegeneration and neurogenesis will be highlighted. Moreover, the benefits, outcomes and limitations of therapies using miRNA technology for neurodegenerative disorders will also be discussed.}, }
@article {pmid28707655, year = {2017}, author = {Efimova, AD and Ovchinnikov, RK and Roman, AY and Maltsev, AV and Grigoriev, VV and Kovrazhkina, EA and Skvortsova, VI}, title = {[The FUS protein: Physiological functions and a role in amyotrophic lateral sclerosis].}, journal = {Molekuliarnaia biologiia}, volume = {51}, number = {3}, pages = {387-399}, doi = {10.7868/S0026898417020094}, pmid = {28707655}, issn = {0026-8984}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; DNA Repair/genetics ; Humans ; Motor Neurons/*metabolism/pathology ; Protein Aggregation, Pathological/*genetics ; RNA Splicing/genetics ; RNA-Binding Protein FUS/*genetics/metabolism ; }, abstract = {Certain forms of amyotrophic lateral sclerosis (ALS) are associated with an altered compartmentalization of FUS and its aggregation in the cytoplasm of motoneurons. FUS is a DNA/RNA-binding protein that is involved in DNA repair and the regulation of transcription, splicing, RNA transport, and local translation. Two theories have been proposed to explain the mechanism of the pathophysiological process in ALS. The theories attribute degeneration of motor neurons to either loss or gain of FUS function. The review describes the main physiological functions of FUS and considers evidence for each of the theories of ALS pathogenesis.}, }
@article {pmid28703923, year = {2018}, author = {Guo, F and Liu, X and Cai, H and Le, W}, title = {Autophagy in neurodegenerative diseases: pathogenesis and therapy.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {28}, number = {1}, pages = {3-13}, pmid = {28703923}, issn = {1750-3639}, support = {Z01 AG000941-01//Intramural NIH HHS/United States ; Z01 AG000942-01//Intramural NIH HHS/United States ; Z01 AG000944-01//Intramural NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Humans ; Neurodegenerative Diseases/*physiopathology ; }, abstract = {The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy-related pathways as therapeutic targets for the treatment of these diseases.}, }
@article {pmid28703543, year = {2017}, author = {Maulucci, F and Benninger, D and Démonet, JF and Du Pasquier, RA and Hirt, L and Hottinger, A and Kuntzer, T and Michel, P and Nater, B and Novy, J and Rossetti, AO and Schluep, M and Vingerhoets, FJG}, title = {[Neurology].}, journal = {Revue medicale suisse}, volume = {13}, number = {544-545}, pages = {79-83}, pmid = {28703543}, issn = {1660-9379}, mesh = {Brain Neoplasms/therapy ; Cerebrovascular Disorders/therapy ; Epilepsy/therapy ; Humans ; Migraine Disorders/etiology/therapy ; Multiple Sclerosis/therapy ; Neurology/methods/*trends ; Parkinson Disease/therapy ; Peripheral Nervous System Neoplasms/therapy ; Tremor/therapy ; }, abstract = {Aducanumab reduces the burden of amyloid plaques in Alzheimer's disease, with significant improvement of clinical scores. Endovascular thrombectomy is recommended in patients with acute stroke with proximal occlusion of the anterior circulation. CGRP antagonists and botulinum toxin are effective in migraine. ZIKA virus infection has been linked to the Guillain-Barré syndrome. Edaravone has been approved for amyotrophic lateral sclerosis. Two monoclonal antibodies (ocrelizumab and daclizumab) and siponimod show positive results in multiple sclerosis. Thalamotomy of ventral intermediate nucleus (by gamma-knife or by magnetic resonance-guided focused ultrasound) is effective in drug-resistant essential tremor. The dose-dependent risk of foetal malformations associated with valproate and topiramate is confirmed.}, }
@article {pmid28702179, year = {2017}, author = {Cruz-Haces, M and Tang, J and Acosta, G and Fernandez, J and Shi, R}, title = {Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {6}, number = {}, pages = {20}, pmid = {28702179}, issn = {2047-9158}, abstract = {Traumatic brain injury is among the most common causes of death and disability in youth and young adults. In addition to the acute risk of morbidity with moderate to severe injuries, traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration, the causative factors linking these processes have not yet been fully elucidated. Apart from removal from activity, few, if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist. Therefore, it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes. Oxidative stress, neuroinflammation, and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration. In particular, reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity. As such, it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration. Consequently, reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage. Furthermore, these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury.}, }
@article {pmid28700839, year = {2017}, author = {Brown, RH and Al-Chalabi, A}, title = {Amyotrophic Lateral Sclerosis.}, journal = {The New England journal of medicine}, volume = {377}, number = {2}, pages = {162-172}, doi = {10.1056/NEJMra1603471}, pmid = {28700839}, issn = {1533-4406}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/physiopathology/therapy ; Genetic Variation ; Humans ; Survival Analysis ; }, }
@article {pmid28697282, year = {2018}, author = {Bansal, R and Singh, R}, title = {Exploring the potential of natural and synthetic neuroprotective steroids against neurodegenerative disorders: A literature review.}, journal = {Medicinal research reviews}, volume = {38}, number = {4}, pages = {1126-1158}, doi = {10.1002/med.21458}, pmid = {28697282}, issn = {1098-1128}, mesh = {Alzheimer Disease/*drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Antioxidants/chemistry ; Apoptosis ; Brain Injuries/*drug therapy ; Brain Injuries, Traumatic/drug therapy ; Diabetic Neuropathies/drug therapy ; Drug Discovery ; Humans ; Huntington Disease/drug therapy ; Inflammation ; Multiple Sclerosis/drug therapy ; *Neuroprotection ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; Parkinson Disease/drug therapy ; Steroids/pharmacology/*physiology ; Stroke/drug therapy ; }, abstract = {Neurodegeneration is a complex process, which leads to progressive brain damage due to loss of neurons. Despite exhaustive research, the cause of neuronal loss in various degenerative disorders is not entirely understood. Neuroprotective steroids constitute an important line of attack, which could play a major role against the common mechanisms associated with various neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Natural endogenous steroids induce the neuroprotection by protecting the nerve cells from neuronal injury through multiple mechanisms, therefore the structural modifications of the endogenous steroids could be helpful in the generation of new therapeutically useful neuroprotective agents. The review article will keep the readers apprised of the detailed description of natural as well as synthetic neuroprotective steroids from the medicinal chemistry point of view, which would be helpful in drug discovery efforts aimed toward neurodegenerative diseases.}, }
@article {pmid28696821, year = {2020}, author = {Jung, J and Behrends, C}, title = {Multifaceted role of SMCR8 as autophagy regulator.}, journal = {Small GTPases}, volume = {11}, number = {1}, pages = {53-61}, pmid = {28696821}, issn = {2154-1256}, mesh = {Animals ; *Autophagy ; Carrier Proteins/*metabolism ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Protein Processing, Post-Translational ; }, abstract = {Through autophagy intracellular material is engulfed by double membrane vesicles and delivered to lysosomes for degradation. This process requires Rab GTPases, Rab GAPs and Rab GEFs for proper membrane trafficking, since they control vesicle budding, targeting and fusion. Deregulation of autophagy contributes to several human diseases including cancer, bacterial or viral infections and neurodegeneration. This review focuses on the complex roles of the newly identified protein SMCR8 and its interaction partners during formation and maturation of autophagosomes as well as regulation of lysosomal function and further discusses their implication in neurodegenerative diseases such as ALS and FTD.}, }
@article {pmid28689190, year = {2017}, author = {Ng, ASL and Tan, EK}, title = {Intermediate C9orf72 alleles in neurological disorders: does size really matter?.}, journal = {Journal of medical genetics}, volume = {54}, number = {9}, pages = {591-597}, pmid = {28689190}, issn = {1468-6244}, mesh = {Alleles ; C9orf72 Protein/*genetics ; *DNA Repeat Expansion ; Ethnicity ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Mental Disorders/*genetics ; Neurodegenerative Diseases/ethnology/*genetics ; }, abstract = {C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson's disease (PD), atypical parkinsonism, Alzheimer's disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the 'risk' haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the 'critical' repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.}, }
@article {pmid28684305, year = {2017}, author = {Lee, SH and Suk, K}, title = {Emerging roles of protein kinases in microglia-mediated neuroinflammation.}, journal = {Biochemical pharmacology}, volume = {146}, number = {}, pages = {1-9}, doi = {10.1016/j.bcp.2017.06.137}, pmid = {28684305}, issn = {1873-2968}, mesh = {Central Nervous System Diseases/*enzymology/*pathology ; Gene Expression Regulation, Enzymologic ; Humans ; Inflammation/*enzymology/*pathology ; Microglia/*enzymology ; Protein Kinases/genetics/*metabolism ; }, abstract = {Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation. To date, 32 small-molecule protein kinase inhibitors have been approved by the United States Food and Drug Administration for the treatment of cancer and inflammation. However, there is no drug effectively targeting neuroinflammation and/or neurodegenerative diseases. Recent studies have advanced several protein kinases as important drug targets in neuroinflammation and/or neurodegenerative diseases. Here, we review emerging protein kinases potentially involved in neuroinflammation and subsequent neurodegenerative diseases.}, }
@article {pmid28684172, year = {2017}, author = {Auburger, G and Sen, NE and Meierhofer, D and Başak, AN and Gitler, AD}, title = {Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2.}, journal = {Trends in neurosciences}, volume = {40}, number = {8}, pages = {507-516}, doi = {10.1016/j.tins.2017.06.004}, pmid = {28684172}, issn = {1878-108X}, mesh = {Animals ; Ataxin-2/*deficiency ; Humans ; Neurodegenerative Diseases/*metabolism/*prevention &amp; control ; }, abstract = {Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast.}, }
@article {pmid28681543, year = {2017}, author = {Oh, J and Kim, JA}, title = {Supportive care needs of patients with amyotrophic lateral sclerosis/motor neuron disease and their caregivers: A scoping review.}, journal = {Journal of clinical nursing}, volume = {26}, number = {23-24}, pages = {4129-4152}, doi = {10.1111/jocn.13945}, pmid = {28681543}, issn = {1365-2702}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*therapy ; Caregivers/*psychology ; Cross-Sectional Studies ; Female ; *Health Services Needs and Demand ; Humans ; Longitudinal Studies ; Male ; Qualitative Research ; Social Support ; }, abstract = {AIMS AND OBJECTIVES: To identify the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, categorise and summarise them into a Supportive Care Needs Framework and identify gaps in literature.<br><br>BACKGROUND: Little is known about the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, and this subject has not previously been systemically reviewed.<br><br>DESIGN: Scoping review.<br><br>METHODS: We conducted a scoping review from the MEDLINE, EMBASE, CINAHL and Cochrane databases for the period January 2000-July 2016, using the following inclusion criteria: (i) written in English only, (ii) published in peer-reviewed journals, (iii) at least part of the research considered the supportive care needs perspective of amyotrophic lateral sclerosis/motor neuron disease patients or their caregivers and (iv) the population sample included patients of amyotrophic lateral sclerosis/motor neuron disease or their caregivers.<br><br>RESULTS: Thirty-seven articles were included. Our review shows that amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers' supportive care needs were mentioned across all seven domains of the Supportive Care Needs Framework. Most common were practical needs (n&#xa0;=&#xa0;24), followed by Informational needs (n&#xa0;=&#xa0;19), Social needs (n&#xa0;=&#xa0;18), Psychological needs (n&#xa0;=&#xa0;16), Physical needs (n&#xa0;=&#xa0;15), Emotional needs (n&#xa0;=&#xa0;13) and Spiritual needs (n&#xa0;=&#xa0;8).<br><br>CONCLUSION: From the perspectives of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, there is a significant need for more practical, social, informational, psychological, physical, emotional and spiritual support.<br><br>The Supportive Care Needs Framework has potential utility in the development of patient-centred support services or healthcare policies and serves as an important base for further studies; especially, specific examples of each supportive care needs domain can guide in clinical settings when healthcare professionals provide multidisciplinary care to amyotrophic lateral sclerosis/motor neuron disease patients and individualised care.}, }
@article {pmid28680391, year = {2017}, author = {Stürner, E and Behl, C}, title = {The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {177}, pmid = {28680391}, issn = {1662-5099}, abstract = {In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3). Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer's disease (tau-protein), Huntington's disease (mutated huntingtin/polyQ proteins), and amyotrophic lateral sclerosis (mutated SOD1). In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate.}, }
@article {pmid28680390, year = {2017}, author = {Rusmini, P and Cristofani, R and Galbiati, M and Cicardi, ME and Meroni, M and Ferrari, V and Vezzoli, G and Tedesco, B and Messi, E and Piccolella, M and Carra, S and Crippa, V and Poletti, A}, title = {The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {176}, pmid = {28680390}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are two motoneuron diseases (MNDs) characterized by aberrant protein behavior in affected cells. In familial ALS (fALS) and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which then accumulate in form of aggregates. Notably, some of these proteins accumulate into aggregates also in sporadic ALS (sALS) even if not mutated. To prevent proteotoxic stresses detrimental to cells, misfolded and/or aggregated proteins must be rapidly removed by the protein quality control (PQC) system. The small heat shock protein B8 (HSPB8) is a chaperone induced by harmful events, like proteasome inhibition. HSPB8 is expressed both in motoneuron and muscle cells, which are both targets of misfolded protein toxicity in MNDs. In ALS mice models, in presence of the mutant proteins, HSPB8 is upregulated both in spinal cord and muscle. HSPB8 interacts with the HSP70 co-chaperone BAG3 and enhances the degradation of misfolded proteins linked to sALS, or causative of fALS and of SBMA. HSPB8 acts by facilitating autophagy, thereby preventing misfolded protein accumulation in affected cells. BAG3 and BAG1 compete for HSP70-bound clients and target them for disposal to the autophagy or proteasome, respectively. Enhancing the selective targeting of misfolded proteins by HSPB8-BAG3-HSP70 to autophagy may also decrease their delivery to the proteasome by the BAG1-HSP70 complex, thereby limiting possible proteasome overwhelming. Thus, approaches aimed at potentiating HSPB8-BAG3 may contribute to the maintenance of proteostasis and may delay MNDs progression.}, }
@article {pmid28679106, year = {2018}, author = {Leyton-Jaimes, MF and Kahn, J and Israelson, A}, title = {Macrophage migration inhibitory factor: A multifaceted cytokine implicated in multiple neurological diseases.}, journal = {Experimental neurology}, volume = {301}, number = {Pt B}, pages = {83-91}, doi = {10.1016/j.expneurol.2017.06.021}, pmid = {28679106}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Cytokines/*metabolism/physiology ; Humans ; Macrophage Migration-Inhibitory Factors/*metabolism/physiology ; Mental Disorders/metabolism/pathology ; Nervous System Diseases/*metabolism/pathology ; }, abstract = {Macrophage migration inhibitory factor (MIF) is a conserved cytokine found as a homotrimer protein. It is found in a wide spectrum of cell types in the body including neuronal and non-neuronal cells. MIF is implicated in several biological processes; chemo-attraction, cytokine activity, and receptor binding, among other functions. More recently, a chaperone-like activity has been added to its repertoire. In this review, we focus on the implication of MIF in the central nervous system and peripheries, its role in neurological disorders, and the mechanisms by which MIF is regulated. Numerous studies have associated MIF with various disease settings. MIF plays an important role in advocating tumorigenic processes, Alzheimer's disease, and is also upregulated in autism-spectrum disorders and spinal cord injury where it contributes to the severity of the injured area. The protective effect of MIF has been reported in amyotrophic lateral sclerosis by its reduction of aggregated misfolded SOD1, subsequently reducing the severity of this disease. Interestingly, a protective as well as pathological role for MIF has been implicated in stroke and cerebral ischemia, as well as depression. Thus, the role of MIF in neurological disorders appears to be diverse with both beneficial and adversary effects. Furthermore, its modulation is rather complex and it is regulated by different proteins, either on a molecular or protein level. This complexity might be dependent on the pathophysiological context and/or cellular microenvironment. Hence, further clarification of its diverse roles in neurological pathologies is warranted to provide new mechanistic insights which may lead in the future to the development of therapeutic strategies based on MIF, to fight some of these neurological disorders.}, }
@article {pmid28676349, year = {2017}, author = {Girolamo, F and Coppola, C and Ribatti, D}, title = {Immunoregulatory effect of mast cells influenced by microbes in neurodegenerative diseases.}, journal = {Brain, behavior, and immunity}, volume = {65}, number = {}, pages = {68-89}, doi = {10.1016/j.bbi.2017.06.017}, pmid = {28676349}, issn = {1090-2139}, mesh = {Blood-Brain Barrier/immunology/microbiology/physiology ; Brain/immunology ; Cell Communication ; Cell Membrane Permeability/immunology ; Central Nervous System/immunology ; Gastrointestinal Microbiome/immunology/physiology ; Gastrointestinal Motility/immunology ; Humans ; Intestines/microbiology ; Mast Cells/*immunology/microbiology/*physiology ; Microbiota ; Neurodegenerative Diseases/*immunology/microbiology ; Neuroglia/immunology ; }, abstract = {When related to central nervous system (CNS) health and disease, brain mast cells (MCs) can be a source of either beneficial or deleterious signals acting on neural cells. We review the current state of knowledge about molecular interactions between MCs and glia in neurodegenerative diseases such as Multiple Sclerosis, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Epilepsy. We also discuss the influence on MC actions evoked by the host microbiota, which has a profound effect on the host immune system, inducing important consequences in neurodegenerative disorders. Gut dysbiosis, reduced intestinal motility and increased intestinal permeability, that allow bacterial products to circulate and pass through the blood-brain barrier, are associated with neurodegenerative disease. There are differences between the microbiota of neurologic patients and healthy controls. Distinguishing between cause and effect is a challenging task, and the molecular mechanisms whereby remote gut microbiota can alter the brain have not been fully elucidated. Nevertheless, modulation of the microbiota and MC activation have been shown to promote neuroprotection. We review this new information contributing to a greater understanding of MC-microbiota-neural cells interactions modulating the brain, behavior and neurodegenerative processes.}, }
@article {pmid28674995, year = {2017}, author = {Jeromin, A and Bowser, R}, title = {Biomarkers in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {15}, number = {}, pages = {491-528}, doi = {10.1007/978-3-319-57193-5_20}, pmid = {28674995}, issn = {2190-5215}, support = {NS061867/NS/NINDS NIH HHS/United States ; NS068179/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/diagnostic imaging/genetics/metabolism ; Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/metabolism ; Biomarkers/blood/cerebrospinal fluid/*metabolism ; Brain/diagnostic imaging/*metabolism ; DNA/genetics ; Humans ; Neurodegenerative Diseases/diagnostic imaging/genetics/*metabolism ; Parkinson Disease/diagnostic imaging/genetics/metabolism ; Prognosis ; RNA/genetics ; }, abstract = {The past decade has seen tremendous efforts in biomarker discovery and validation for neurodegenerative diseases. The source and type of biomarkers has continued to grow for central nervous system diseases, from biofluid-based biomarkers (blood or cerebrospinal fluid (CSF)), to nucleic acids, tissue, and imaging. While DNA remains a predominant biomarker used to identify familial forms of neurodegenerative diseases, various types of RNA have more recently been linked to familial and sporadic forms of neurodegenerative diseases during the past few years. Imaging approaches continue to evolve and are making major contributions to target engagement and early diagnostic biomarkers. Incorporation of biomarkers into drug development and clinical trials for neurodegenerative diseases promises to aid in the development and demonstration of target engagement and drug efficacy for neurologic disorders. This review will focus on recent advancements in developing biomarkers for clinical utility in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid28674994, year = {2017}, author = {Cookson, MR}, title = {Gene Linkage and Systems Biology.}, journal = {Advances in neurobiology}, volume = {15}, number = {}, pages = {479-489}, doi = {10.1007/978-3-319-57193-5_19}, pmid = {28674994}, issn = {2190-5215}, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; *Genetic Linkage ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/genetics ; *Systems Biology ; }, abstract = {In the past two decades it has become increasingly clear that the risk for many neurodegenerative disorders is at least partially genetic. Assignment of causality for a given gene depends on showing that a particular variant shows either segregation within a family or association with disease across a population. In terms of lifetime risk of disease, the former generally show strong effects compared to the latter. In rare, but interesting, circumstances there are genetic loci that contain different variants that encode either highly penetrant Mendelian disease but also that contribute to risk of sporadic disease. Here, we will discuss the current efforts to complete our understanding of the genetic architecture of neurodegenerative diseases of aging with a particular focus on Parkinson's disease. We will also briefly outline attempts to use systematic approaches to infer relationships between genes associated with the same diseases, which likely demonstrate that in each case there are a relatively small number of underlying biological pathways or processes that may explain pathogenesis.}, }
@article {pmid28674992, year = {2017}, author = {Verkhratsky, A and Zorec, R and Rodriguez, JJ and Parpura, V}, title = {Neuroglia: Functional Paralysis and Reactivity in Alzheimer's Disease and Other Neurodegenerative Pathologies.}, journal = {Advances in neurobiology}, volume = {15}, number = {}, pages = {427-449}, doi = {10.1007/978-3-319-57193-5_17}, pmid = {28674992}, issn = {2190-5215}, support = {HD078678/NH/NIH HHS/United States ; }, mesh = {Alzheimer Disease/*pathology/physiopathology ; Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Asthenia/*pathology/physiopathology ; Astrocytes/pathology ; Brain/*pathology/physiopathology ; Disease Models, Animal ; Disease Progression ; Humans ; Huntington Disease/pathology/physiopathology ; Mice, Transgenic ; Microglia/pathology ; Neurodegenerative Diseases/pathology/physiopathology ; Neuroglia/*pathology ; Neurons/pathology ; Oligodendroglia/pathology ; Paralysis/*pathology/physiopathology ; }, abstract = {The most notable finding in neurodegenerative diseases is the progressive death of neurones cells. Yet, neuroglial changes can precede and facilitate neuronal loss. This is perhaps expected because astroglial cells maintain the brain homoeostasis, and are responsible for defence and regeneration, so that their malfunction manifested as degeneration or asthenia together with reactivity contribute to pathophysiology. Neuroglia may represent a novel target for therapeutic intervention, be that prevention, slowing progression of or possibly curing neurodegenerative diseases.}, }
@article {pmid28674982, year = {2017}, author = {Ilieva, H and Maragakis, NJ}, title = {Motoneuron Disease: Clinical.}, journal = {Advances in neurobiology}, volume = {15}, number = {}, pages = {191-210}, doi = {10.1007/978-3-319-57193-5_7}, pmid = {28674982}, issn = {2190-5215}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Disease Progression ; Exercise Therapy ; Frontotemporal Dementia/physiopathology/*therapy ; *Genetic Therapy ; Humans ; Motor Neuron Disease/physiopathology/therapy ; Neuroprotective Agents/*therapeutic use ; Noninvasive Ventilation ; Nutritional Support ; Oligonucleotides, Antisense/*therapeutic use ; Phenotype ; Riluzole/*therapeutic use ; *Stem Cell Transplantation ; }, abstract = {ALS is a neurodegenerative disease in which the primary symptoms result in progressive neuromuscular weakness. Recent studies have highlighted that there is significant heterogeneity with regard to anatomical and temporal disease progression. Importantly, more recent advances in genetics have revealed new causative genes to the disease. New efforts have focused on the development of biomarkers that could aid in diagnosis, prognosis, and serve as pharmacodynamics markers. Although traditional pharmaceuticals continue to undergo trials for ALS, new therapeutic strategies including stem cell transplantation studies, gene therapies, and antisense therapies targeting some of the familial forms of ALS are gaining momentum.}, }
@article {pmid28674981, year = {2017}, author = {Ilieva, H and Maragakis, NJ}, title = {Motoneuron Disease: Basic Science.}, journal = {Advances in neurobiology}, volume = {15}, number = {}, pages = {163-190}, doi = {10.1007/978-3-319-57193-5_6}, pmid = {28674981}, issn = {2190-5215}, mesh = {Adaptor Proteins, Signal Transducing ; Amyotrophic Lateral Sclerosis/epidemiology/*genetics/physiopathology ; Animals ; Autophagy-Related Proteins ; C9orf72 Protein/*genetics ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; Frontotemporal Dementia/epidemiology/*genetics/physiopathology ; Genes, Modifier/genetics ; Humans ; Induced Pluripotent Stem Cells ; Motor Neuron Disease/epidemiology/genetics/physiopathology ; RNA-Binding Protein FUS/*genetics ; Superoxide Dismutase-1/*genetics ; Translational Research, Biomedical ; Ubiquitins/genetics ; }, abstract = {ALS is a relentless neurodegenerative disease in which motor neurons are the susceptible neuronal population. Their death results in progressive paresis of voluntary and respiratory muscles. The unprecedented rate of discoveries over the last two decades have broadened our knowledge of genetic causes and helped delineate molecular pathways. Here we critically review ALS epidemiology, genetics, pathogenic mechanisms, available animal models, and iPS cell technologies with a focus on their translational therapeutic potential. Despite limited clinical success in treatments to date, the new discoveries detailed here offer new models for uncovering disease mechanisms as well as novel strategies for intervention.}, }
@article {pmid28673891, year = {2017}, author = {Lagman, C and Chung, LK and Chitale, RV and Yang, I}, title = {Dural Arteriovenous Fistula and Foix-Alajouanine Syndrome: Assessment of Functional Scores with Review of Pathogenesis.}, journal = {World neurosurgery}, volume = {106}, number = {}, pages = {206-210}, doi = {10.1016/j.wneu.2017.06.141}, pmid = {28673891}, issn = {1878-8769}, mesh = {Central Nervous System Vascular Malformations/complications/physiopathology/*therapy ; *Embolization, Therapeutic ; Gait Disorders, Neurologic/etiology/physiopathology ; Humans ; *Neurosurgical Procedures ; Paraplegia/etiology/physiopathology ; Spinal Cord Diseases/etiology/physiopathology/*therapy ; Syndrome ; Treatment Outcome ; Urination/physiology ; }, abstract = {OBJECTIVE: To assess the use of functional scores in the evaluation of patients with dural arteriovenous fistula and Foix-Alajouanine syndrome.<br><br>METHODS: We systematically surveyed the literature to identify relevant patients. Aminoff-Logue Scale (ALS) and modified Rankin Scale (mRS) scores were ascertained and combined to form a novel functional score, the Aminoff-Rankin Composite (ARC) score. We compared functional scores between surgery and embolization groups and ran one-sided point-biserial analyses to test our expectation that positive correlations exist between functional scores and treatment outcomes. Finally, we reviewed the pathogenesis of dural arteriovenous fistula formation.<br><br>RESULTS: The quantitative synthesis included 18 patients. Surgery alone was performed in 11 patients (61.11%); 7&#xa0;patients&#xa0;underwent embolization alone (38.89%). There were no significant differences in functional scores or symptom outcomes when we compared surgery to embolization. The pre-intervention ALS gait, mRS, and ARC scores were correlated with improved symptoms (rpb = 0.43, P = 0.04; rpb = 0.47, P = 0.02; rpb = 0.48, P = 0.04, respectively). In patients whose symptoms were improved, post-intervention ALS gait and micturition scores (2.55 vs. 4.43, P = 0.02 and 1.09 vs. 2.71, P = 0.01, respectively) and post-intervention ARC scores (6.66 vs. 11.57, P = 0.01) were on average lower than in patients whose symptoms were unimproved.<br><br>CONCLUSIONS: We believe that patients with dAVF and Foix-Alajouanine syndrome present with worse function (higher functional scores) as a result of an acute myelopathic episode, and that if diagnosed and treated appropriately, will experience some level of symptom improvement that is evidenced by reduced post-intervention functional scores.}, }
@article {pmid28670265, year = {2017}, author = {Remondelli, P and Renna, M}, title = {The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {187}, pmid = {28670265}, issn = {1662-5099}, abstract = {In eukaryotic cells, the endoplasmic reticulum (ER) is the cell compartment involved in secretory protein translocation and quality control of secretory protein folding. Different conditions can alter ER function, resulting in the accumulation of unfolded or misfolded proteins within the ER lumen. Such a condition, known as ER stress, elicits an integrated adaptive response known as the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway. Conversely, in prolonged cell stress or insufficient adaptive response, UPR signaling causes cell death. ER dysfunctions are involved and contribute to neuronal degeneration in several human diseases, including Alzheimer, Parkinson and Huntington disease and amyotrophic lateral sclerosis. The correlations between ER stress and its signal transduction pathway known as the UPR with neuropathological changes are well established. In addition, much evidence suggests that genetic or pharmacological modulation of UPR could represent an effective strategy for minimizing the progressive neuronal loss in neurodegenerative diseases. Here, we review recent results describing the main cellular mechanisms linking ER stress and UPR to neurodegeneration. Furthermore, we provide an up-to-date panoramic view of the currently pursued strategies for ameliorating the toxic effects of protein unfolding in disease by targeting the ER UPR pathway.}, }
@article {pmid28669745, year = {2019}, author = {Smith, EF and Shaw, PJ and De Vos, KJ}, title = {The role of mitochondria in amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {710}, number = {}, pages = {132933}, doi = {10.1016/j.neulet.2017.06.052}, pmid = {28669745}, issn = {1872-7972}, support = {DEVOS/OCT13/870-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K005146/1/MRC_/Medical Research Council/United Kingdom ; MR/M013251/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*pathology ; Animals ; Apoptosis ; Axonal Transport ; Calcium/metabolism ; Energy Metabolism ; Humans ; Mitochondria/*pathology ; Mitophagy ; Oxidative Stress ; Signal Transduction ; Superoxide Dismutase-1/metabolism ; }, abstract = {Mitochondria are unique organelles that are essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is a prevalent feature of many neurodegenerative diseases including motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption of mitochondrial structure, dynamics, bioenergetics and calcium buffering has been extensively reported in ALS patients and model systems and has been suggested to be directly involved in disease pathogenesis. Here we review the alterations in mitochondrial parameters in ALS and examine the common pathways to dysfunction.}, }
@article {pmid28668295, year = {2018}, author = {Calvo, NL and Maggio, RM and Kaufman, TS}, title = {Chemometrics-assisted solid-state characterization of pharmaceutically relevant materials. Polymorphic substances.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {147}, number = {}, pages = {518-537}, doi = {10.1016/j.jpba.2017.06.018}, pmid = {28668295}, issn = {1873-264X}, mesh = {Chemistry, Pharmaceutical/*methods ; Crystallization/*methods ; Magnetic Resonance Spectroscopy/*methods ; Pharmaceutical Preparations/*analysis/chemistry ; Spectrum Analysis, Raman/*methods ; X-Ray Diffraction/methods ; }, abstract = {Current regulations command to properly characterize pharmaceutically relevant solid systems. Chemometrics comprise a range of valuable tools, suitable to process large amounts of data and extract valuable information hidden in their structure. This review aims to detail the results of the fruitful association between analytical techniques and chemometrics methods, focusing on those which help to gain insight into the characteristics of drug polymorphism as an important aspect of the solid state of bulk drugs and drug products. Hence, the combination of Raman, terahertz, mid- and near- infrared spectroscopies, as well as instrumental signals resulting from X-ray powder diffraction, [13]C solid state nuclear magnetic resonance spectroscopy and thermal methods with quali-and quantitative chemometrics methodologies are examined. The main issues reviewed, concerning pharmaceutical drug polymorphism, include the use of chemometrics-based approaches to perform polymorph classification and assignment of polymorphic identity, as well as the determination of given polymorphs in simple mixtures and complex systems. Aspects such as the solvation/desolvation of solids, phase transformation, crystallinity and the recrystallization from the amorphous state are also discussed. A brief perspective of the field for the next future is provided, based on the developments of the last decade and the current state of the art of analytical instrumentation and chemometrics methodologies.}, }
@article {pmid28667575, year = {2017}, author = {Lefcort, F and Mergy, M and Ohlen, SB and Ueki, Y and George, L}, title = {Animal and cellular models of familial dysautonomia.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {27}, number = {4}, pages = {235-243}, pmid = {28667575}, issn = {1619-1560}, support = {R01 NS035714/NS/NINDS NIH HHS/United States ; R01 NS086796/NS/NINDS NIH HHS/United States ; R15 NS090384/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Disease Models, Animal ; Dysautonomia, Familial/genetics/*pathology/therapy ; Humans ; Mice ; Stem Cells/*physiology ; }, abstract = {Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60 years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders.}, }
@article {pmid28664472, year = {2017}, author = {Waito, AA and Valenzano, TJ and Peladeau-Pigeon, M and Steele, CM}, title = {Trends in Research Literature Describing Dysphagia in Motor Neuron Diseases (MND): A Scoping Review.}, journal = {Dysphagia}, volume = {32}, number = {6}, pages = {734-747}, pmid = {28664472}, issn = {1432-0460}, support = {R01 DC011020/DC/NIDCD NIH HHS/United States ; }, mesh = {Deglutition/*physiology ; Deglutition Disorders/epidemiology/*etiology/therapy ; Enteral Nutrition ; Humans ; Motor Neuron Disease/*physiopathology ; }, abstract = {Dysphagia in motor neuron diseases (MNDs) is highly complex, affecting all stages of swallowing and leading to impaired swallowing safety and efficiency. In order to explore the degree to which research is capturing the symptom of dysphagia in MND, we conducted a scoping review of the existing literature. The primary aims of this review were to identify common themes within the literature on dysphagia in MND, explore patterns and trends in research focus, and identify if any imbalances exist between the research themes related to dysphagia description and management. A comprehensive search strategy yielded 1690 unique articles for review. Following relevance screening, a total of 157 articles were included in the synthesis. Relevant data and keywords were extracted from each article and grouped into themes. Frequency estimates were calculated for each theme to identify trends across research literature. Swallowing impairment in MNDs is described in a variety of ways across current research. The most commonly reported theme was Aspiration/Penetration, mentioned in 73.2% of all included articles; a significant imbalance was identified between reports of swallowing safety and efficiency (p = 0.008). The most frequently reported theme related to dysphagia management was Enteral Nutrition, and very few studies have reported on the efficacy of Rehabilitation/Compensatory recommendations. It is suggested that researchers and clinicians remain mindful of imbalances and gaps in research, and aim to characterize dysphagia in MNDs in a comprehensive manner. Further research investigating discrete, measureable changes in swallowing pathophysiology would be beneficial to delineate the key factors contributing to impaired swallowing safety and efficiency.}, }
@article {pmid28652210, year = {2017}, author = {Galper, J and Rayner, SL and Hogan, AL and Fifita, JA and Lee, A and Chung, RS and Blair, IP and Yang, S}, title = {Cyclin F: A component of an E3 ubiquitin ligase complex with roles in neurodegeneration and cancer.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {89}, number = {}, pages = {216-220}, doi = {10.1016/j.biocel.2017.06.011}, pmid = {28652210}, issn = {1878-5875}, mesh = {Animals ; Cyclins/chemistry/genetics/*metabolism ; Gene Expression Regulation ; Humans ; Neoplasms/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {Cyclin F, encoded by CCNF, is the substrate recognition component of the Skp1-Cul1-F-box E3 ubiquitin ligase complex, SCF[cyclin F]. E3 ubiquitin ligases play a key role in ubiquitin-proteasome mediated protein degradation, an essential component of protein homeostatic mechanisms within the cell. By recognising and regulating the availability of several protein substrates, SCF[cyclin F] plays a role in regulating various cellular processes including replication and repair of DNA and cell cycle checkpoint control. Cyclin F dysfunction has been implicated in various forms of cancer and CCNF mutations were recently linked to familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia, offering a new lead to understanding the pathogenic mechanisms underlying neurodegeneration. In this review, we evaluate the current literature on the function of cyclin F with an emphasis on its roles in cancer and neurodegeneration.}, }
@article {pmid28642865, year = {2017}, author = {Lanfranco, M and Vassallo, N and Cauchi, RJ}, title = {Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction.}, journal = {Frontiers in molecular biosciences}, volume = {4}, number = {}, pages = {41}, pmid = {28642865}, issn = {2296-889X}, abstract = {Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a "housekeeping" activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.}, }
@article {pmid28641540, year = {2017}, author = {Ono, SI}, title = {Metallothionein is a Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {23}, number = {33}, pages = {5001-5009}, doi = {10.2174/1381612823666170622105513}, pmid = {28641540}, issn = {1873-4286}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Chelating Agents/metabolism/pharmacology/therapeutic use ; Humans ; Metallothionein/*metabolism/pharmacology/*therapeutic use ; Oxidative Stress/drug effects/physiology ; }, abstract = {Lou Gehrig's disease, a synonym of amyotrophic lateral sclerosis, is an adult-onset lethal neurodegenerative disorder. Irrespective of extensive efforts to elucidate the pathogenesis of the disease and searches for therapies, no favorable pharmacotherapeutic strategies have yet to be proposed. In a popular rodent model of ALS, G93A SOD1 strain of mouse, intracellular copper conditions were geared toward copper accumulation inside cells, resulting in an acceleration of oxidative stress and apoptotic process. Disruption of intracellular copper homeostasis was common to transgenic mice expressing human mutant SOD1s. In this review, the novel hypothesis that disruption of intracellular copper homeostasis could be involved in the development of the disease was introduced. Based upon the hypothesis, therapeutic outcomes of agents that are capable of correcting and/or modifying intracellular copper homeostasis are described. Administration of ammonium tetrathiomolybdate, a selective intracellular copper chelator, delayed onset, slowed progression, and prolonged survival of a rodent model of the disease (G93A SOD1 mice). Metallothionein is a low molecular weight, cysteine-rich, metal-binding cytoplasmic protein that has beneficial properties in detoxification of toxic heavy metals, homeostatic regulation of intracellular essential trace elements, including copper, antioxidant, and antiapoptotic roles. In animal experiments of the G93A SOD1 mice, an increase of metallothionein proteins by means of induction by exercise or dexamethasone, genetic overexpression, or intraperitoneal administration, all resulted in a preferable outcome. The therapeutic effects were not inferior to those of approved drugs for ALS in humans. These observations suggest that metallothionein could be worth investigating the therapeutic potential in clinical use.}, }
@article {pmid28641533, year = {2017}, author = {Pehar, M and Harlan, BA and Killoy, KM and Vargas, MR}, title = {Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {23}, number = {33}, pages = {5010-5021}, pmid = {28641533}, issn = {1873-4286}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/*therapy ; Animals ; Astrocytes/*metabolism/pathology ; Cells, Cultured ; Gliosis/diagnosis/metabolism/therapy ; Humans ; Motor Neurons/metabolism/pathology ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.}, }
@article {pmid28641519, year = {2017}, author = {De Filippis, L and Zalfa, C and Ferrari, D}, title = {Neural Stem Cells and Human Induced Pluripotent Stem Cells to Model Rare CNS Diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {8}, pages = {915-926}, doi = {10.2174/1871527316666170615121753}, pmid = {28641519}, issn = {1996-3181}, mesh = {Animals ; Central Nervous System Diseases/*surgery ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/*physiology/transplantation ; Neural Stem Cells/*physiology/transplantation ; Rare Diseases/*surgery ; Stem Cell Transplantation/*methods ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Despite the great effort spent over recent decades to unravel the pathological mechanisms underpinning the development of central nervous system disorders, most of them still remain unclear. In particular, the study of rare CNS diseases is hampered by the lack of postmortem samples and of reliable epidemiological studies, thus the setting of in vitro modeling systems appears essential to dissect the puzzle of genetic and environmental alterations affecting neural cells viability and functionality. The isolation and expansion in vitro of embryonic (ESC) and fetal neural stem cells (NSC) from human tissue have allowed the modeling of several neurological diseases "in a dish" and have also provided a novel platform to test potential therapeutic strategies in a pre-clinical setting. In recent years, the development of induced pluripotent stem cell (iPS) technology has added enormous value to the aforementioned approach, thanks to their capability for generating diseaserelevant cell phenotypes in vitro and to their perspective use in autologous transplantation. However, while the potentiality of ESC, NSC and iPS has been widely sponsored, the pitfalls related to the available protocols for differentiation and the heterogeneity of lines deriving from different individuals have been poorly discussed. Here we present pro and contra of using ESC, NSC or iPS for modeling rare diseases like Lysosomal Storage disorders and Motor Neuron Diseases.<br><br>CONCLUSION: In this view, the advent of gene editing technologies is a unique opportunity to standardize the data analysis in preclinical studies and to tailor clinical protocols for stem cell-mediated therapy.}, }
@article {pmid28638596, year = {2017}, author = {Yu, B and Pamphlett, R}, title = {Environmental insults: critical triggers for amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {6}, number = {}, pages = {15}, pmid = {28638596}, issn = {2047-9158}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases.<br><br>MAIN BODY: Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies, while environmental insults remain a suspected but largely unexplored source of risk. Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS, but none so far has proved conclusive. We propose a new ALS model which links the current knowledge of genetic factors, ageing and environmental insults. This model provides a mechanism as to how ALS is initiated, with environmental insults playing a critical role.<br><br>CONCLUSION: The available evidence has suggested that inherited defect(s) could cause mitochondrial dysfunction, which would establish the primary susceptibility to ALS. Further study of the underlying mechanism may shed light on ALS pathogenesis. Environmental insults are a critical trigger for ALS, particularly in the aged individuals with other toxicant susceptible genes. The identification of ALS triggers could lead to preventive strategies for those individuals at risk.}, }
@article {pmid28635376, year = {2017}, author = {Hosseinibarkooie, S and Schneider, S and Wirth, B}, title = {Advances in understanding the role of disease-associated proteins in spinal muscular atrophy.}, journal = {Expert review of proteomics}, volume = {14}, number = {7}, pages = {581-592}, doi = {10.1080/14789450.2017.1345631}, pmid = {28635376}, issn = {1744-8387}, mesh = {Animals ; Cytoskeleton/metabolism ; Humans ; Muscular Atrophy, Spinal/genetics/*metabolism ; Proteome/genetics/*metabolism ; Ribonucleoproteins, Small Nuclear/metabolism ; Ubiquitins/metabolism ; }, abstract = {Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by alpha motor neuron loss in the spinal cord due to reduced survival motor neuron (SMN) protein level. While the genetic basis of SMA is well described, the specific molecular pathway underlying SMA is still not fully understood. Areas covered: This review discusses the recent advancements in understanding the molecular pathways in SMA using different omics approaches and genetic modifiers identified in both vertebrate and invertebrate systems. The findings that are summarized in this article were deduced from original articles and reviews with a particular focus on the latest advancements in the field. Expert commentary: The identification of genetic modifiers such as PLS3 and NCALD in humans or of SMA modulators such as Elavl4 (HuD), Copa, Uba1, Mapk10 (Jnk3), Nrxn2 and Tmem41b (Stasimon) in various SMA animal models improved our knowledge of impaired cellular pathways in SMA. Inspiration from modifier genes and their functions in motor neuron and neuromuscular junctions may open a new avenue for future SMA combinatorial therapies.}, }
@article {pmid28632945, year = {2017}, author = {Paganoni, S and Nicholson, K and Leigh, F and Swoboda, K and Chad, D and Drake, K and Haley, K and Cudkowicz, M and Berry, JD}, title = {Developing multidisciplinary clinics for neuromuscular care and research.}, journal = {Muscle &amp; nerve}, volume = {56}, number = {5}, pages = {848-858}, pmid = {28632945}, issn = {1097-4598}, mesh = {Adult ; Child ; *Delivery of Health Care/economics ; Humans ; Neuromuscular Diseases/diagnosis/economics/psychology/*therapy ; Quality of Life ; *Research ; }, abstract = {Multidisciplinary care is considered the standard of care for both adult and pediatric neuromuscular disorders and has been associated with improved quality of life, resource utilization, and health outcomes. Multidisciplinary care is delivered in multidisciplinary clinics that coordinate care across multiple specialties by reducing travel burden and streamlining care. In addition, the multidisciplinary care setting facilitates the integration of clinical research, patient advocacy, and care innovation (e.g., telehealth). Yet, multidisciplinary care requires substantial commitment of staff time and resources. We calculated personnel costs in our ALS clinic in 2015 and found an average cost per patient visit of $580, of which only 45% was covered by insurance reimbursement. In this review, we will describe classic and emerging concepts in multidisciplinary care models for adult and pediatric neuromuscular disease. We will then explore the financial impact of multidisciplinary care with emphasis on sustainability and metrics to demonstrate quality and value. Muscle Nerve 56: 848-858, 2017.}, }
@article {pmid28623007, year = {2017}, author = {Recabarren, D and Alarcón, M}, title = {Gene networks in neurodegenerative disorders.}, journal = {Life sciences}, volume = {183}, number = {}, pages = {83-97}, doi = {10.1016/j.lfs.2017.06.009}, pmid = {28623007}, issn = {1879-0631}, mesh = {Alzheimer Disease/*genetics/physiopathology ; Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; Animals ; Biomarkers/metabolism ; Gene Expression Regulation ; Gene Regulatory Networks/genetics ; Humans ; MicroRNAs/genetics ; Parkinson Disease/*genetics/physiopathology ; Signal Transduction/genetics ; }, abstract = {Three neurodegenerative diseases [Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD)] have many characteristics like pathological mechanisms and genes. In this sense some researchers postulate that these diseases share the same alterations and that one alteration in a specific protein triggers one of these diseases. Analyses of gene expression may shed more light on how to discover pathways, pathologic mechanisms associated with the disease, biomarkers and potential therapeutic targets. In this review, we analyze four microarrays related to three neurodegenerative diseases. We will systematically examine seven genes (CHN1, MDH1, PCP4, RTN1, SLC14A1, SNAP25 and VSNL1) that are altered in the three neurodegenerative diseases. A network was built and used to identify pathways, miRNA and drugs associated with ALS, AD and PD using Cytoscape software an interaction network based on the protein interactions of these genes. The most important affected pathway is PI3K-Akt signalling. Thirteen microRNAs (miRNA-19B1, miRNA-107, miRNA-124-1, miRNA-124-2, miRNA-9-2, miRNA-29A, miRNA-9-3, miRNA-328, miRNA-19B2, miRNA-29B2, miRNA-124-3, miRNA-15A and miRNA-9-1) and four drugs (Estradiol, Acetaminophen, Resveratrol and Progesterone) for new possible treatments were identified.}, }
@article {pmid28622521, year = {2017}, author = {Frakes, AE and Dillin, A}, title = {The UPR[ER]: Sensor and Coordinator of Organismal Homeostasis.}, journal = {Molecular cell}, volume = {66}, number = {6}, pages = {761-771}, doi = {10.1016/j.molcel.2017.05.031}, pmid = {28622521}, issn = {1097-4164}, mesh = {Aging/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Endoplasmic Reticulum/*metabolism/pathology ; *Endoplasmic Reticulum Stress ; Homeostasis ; Humans ; Inflammation/metabolism/pathology ; Inflammation Mediators ; NF-kappa B/metabolism ; Protein Aggregates ; *Signal Transduction ; *Unfolded Protein Response ; }, abstract = {Life is stressful. Organisms are repeatedly exposed to stressors that disrupt protein homeostasis (proteostasis), resulting in protein misfolding and aggregation. To sense and respond to proteotoxic perturbations, cells have evolved compartment-specific stress responses, such as the unfolded protein response of the endoplasmic reticulum (UPR[ER]). However, UPR[ER] function is impaired with age, which, we propose, creates a permissive environment for protein aggregation, unresolved ER stress, and chronic inflammation. Understanding age-related changes to the UPR[ER] will provide new avenues for therapeutic intervention in metabolic disease, neurodegeneration, and aging.}, }
@article {pmid28619002, year = {2017}, author = {Peric, M and Mitrecic, D and Andjus, PR}, title = {Targeting Astrocytes for Treatment in Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {23}, number = {33}, pages = {5037-5044}, doi = {10.2174/1381612823666170615110446}, pmid = {28619002}, issn = {1873-4286}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/*therapy ; Animals ; Aquaporins/antagonists &amp; inhibitors/metabolism ; Astrocytes/drug effects/*metabolism/pathology ; Drug Delivery Systems/methods/*trends ; Humans ; Potassium Channel Blockers/administration &amp; dosage ; Potassium Channels, Inwardly Rectifying/antagonists &amp; inhibitors/metabolism ; Stem Cell Transplantation/methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting upper and lower motoneurons. The two types, sporadic and familial differ in the aetiopathogenesis but have a similar neuropathology characterized by oxidative stress, excitotoxicity and inflammation. The disease is also characterized by a non-cell autonomous mechanism with astrocytes playing a central role by affecting synaptic glutamate, the blood-brain barrier, and metabolic and trophic support. Two types of therapeutic approaches focusing on astrocytes are presented: a) emerging molecular targets (potassium inward rectifier channels and aquaporins at the astrocyte endfeet, and IP3 receptor signaling pathway), and b) cell therapy with stem cell - generated and transplanted astrocytes.}, }
@article {pmid28619000, year = {2017}, author = {Johann, S}, title = {Astrocytes Pathology in ALS: A Potential Therapeutic Target?.}, journal = {Current pharmaceutical design}, volume = {23}, number = {33}, pages = {5022-5036}, doi = {10.2174/1381612823666170615110856}, pmid = {28619000}, issn = {1873-4286}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*pathology ; Animals ; Astrocytes/drug effects/metabolism/*pathology ; Drug Delivery Systems/methods/*trends ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/administration &amp; dosage ; Oxidative Stress/drug effects/physiology ; }, abstract = {The mechanisms underlying neurodegeneration in amyotrophic lateral sclerosis (ALS) are multifactorial and include genetic and environmental factors. Nowadays, it is well accepted that neuronal loss is driven by non-cell autonomous toxicity. Non-neuronal cells, such as astrocytes, have been described to significantly contribute to motoneuron cell death and disease progression in cell culture experiments and animal models of ALS. Astrocytes are essential for neuronal survival and function by regulating neurotransmitter and ion homeostasis, immune response, blood flow and glucose uptake, antioxidant defence and growth factor release. Based on their significant functions in "housekeeping" the central nervous system (CNS), they are no longer thought to be passive bystanders but rather contributors to ALS pathogenesis. Findings from animal models have broadened our knowledge about different pathomechanisms in ALS, but therapeutic approaches to impede disease progression failed. So far, there is no cure for ALS and effective medication to slow down disease progression is limited. Targeting only a single aspect of this multifactorial disease may exhibit therapeutic limitations. Hence, novel cellular targets must be defined and new pharmaceutical strategies, such as combinatorial drug therapies are urgently needed. The present review discusses the physiological role of astrocytes and current hypotheses of astrocyte pathology in ALS. Furthermore, recent investigation of potential drug candidates in astrocyte cell culture systems and animal models, as well as data obtained from clinical trials, will be addressed. The central role of astrocytes in ALS pathogenesis makes them a promising target for pharmaceutical interventions.}, }
@article {pmid28616022, year = {2017}, author = {Jaiswal, MK}, title = {Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.}, journal = {Neural regeneration research}, volume = {12}, number = {5}, pages = {723-736}, pmid = {28616022}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro "disease in dish" and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.}, }
@article {pmid28612294, year = {2018}, author = {Caller, T and Henegan, P and Stommel, E}, title = {The Potential Role of BMAA in Neurodegeneration.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {222-226}, pmid = {28612294}, issn = {1476-3524}, mesh = {Amino Acids, Diamino/*toxicity ; Animals ; Cyanobacteria Toxins ; Gene-Environment Interaction ; Humans ; Neurodegenerative Diseases/*chemically induced/*genetics ; Neurotoxins/*toxicity ; Risk Factors ; }, abstract = {Neurodegenerative diseases are a major public health issue throughout the world with devastating effects on patients and families. Sporadic forms of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are generally thought to develop as a consequence of genetic susceptibility and environmental influences. A number of environmental triggers have been identified in association with amyotrophic lateral sclerosis and Parkinson's disease. We discuss the role of β-methylamino-L-alanine in the development of neurodegeneration and the potential importance of this neurotoxin as a risk for neurodegeneration.}, }
@article {pmid28611593, year = {2017}, author = {Budini, M and Buratti, E and Morselli, E and Criollo, A}, title = {Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {170}, pmid = {28611593}, issn = {1662-5099}, abstract = {Autophagy is a catabolic mechanism where intracellular material is degraded by vesicular structures called autophagolysosomes. Autophagy is necessary to maintain the normal function of the central nervous system (CNS), avoiding the accumulation of misfolded and aggregated proteins. Consistently, impaired autophagy has been associated with the pathogenesis of various neurodegenerative diseases. The proteins TAR DNA-binding protein-43 (TDP-43), which regulates RNA processing at different levels, and chromosome 9 open reading frame 72 (C9orf72), probably involved in membrane trafficking, are crucial in the development of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Additionally, recent studies have identified a role for these proteins in the control of autophagy. In this manuscript, we review what is known regarding the autophagic mechanism and discuss the involvement of TDP-43 and C9orf72 in autophagy and their impact on neurodegenerative diseases.}, }
@article {pmid28599400, year = {2017}, author = {Tang, BL}, title = {The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy - a perspective on cell biological mechanisms.}, journal = {Reviews in the neurosciences}, volume = {28}, number = {7}, pages = {725-738}, doi = {10.1515/revneuro-2017-0018}, pmid = {28599400}, issn = {2191-0200}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/physiopathology/*therapy ; Animals ; Extracellular Vesicles/transplantation ; Humans ; Mesenchymal Stem Cell Transplantation/adverse effects/*methods ; Neurogenesis ; Paracrine Communication ; }, abstract = {Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.}, }
@article {pmid28598725, year = {2017}, author = {Chernoff, N and Hill, DJ and Diggs, DL and Faison, BD and Francis, BM and Lang, JR and Larue, MM and Le, TT and Loftin, KA and Lugo, JN and Schmid, JE and Winnik, WM}, title = {A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans.}, journal = {Journal of toxicology and environmental health. Part B, Critical reviews}, volume = {20}, number = {4}, pages = {1-47}, pmid = {28598725}, issn = {1521-6950}, support = {R15 NS088776/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/etiology/physiopathology ; Amino Acids, Diamino/*toxicity ; Amyotrophic Lateral Sclerosis/etiology/physiopathology ; Animals ; Cyanobacteria/*metabolism ; Cyanobacteria Toxins ; Cycas/toxicity ; Flour/toxicity ; Humans ; Neurodegenerative Diseases/*etiology/physiopathology ; Neurotoxins/toxicity ; Parkinsonian Disorders/etiology/physiopathology ; }, abstract = {The compound BMAA (β-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer's disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.}, }
@article {pmid28597807, year = {2017}, author = {Gil-Bea, FJ and Aldanondo, G and Lasa-Fernández, H and López de Munain, A and Vallejo-Illarramendi, A}, title = {Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis.}, journal = {Expert reviews in molecular medicine}, volume = {19}, number = {}, pages = {e7}, doi = {10.1017/erm.2017.9}, pmid = {28597807}, issn = {1462-3994}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; Animals ; Biological Transport ; Central Nervous System/metabolism ; Copper/*metabolism ; Homeostasis ; Humans ; Mitochondria/genetics/metabolism ; Motor Neurons/metabolism ; Nervous System Diseases/etiology/metabolism ; Oxidation-Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neuromuscular disease characterised by a progressive loss of motor neurons that usually results in paralysis and death within 2 to 5 years after disease onset. The pathophysiological mechanisms involved in ALS remain largely unknown and to date there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of copper homeostasis in the central nervous system is a crucial underlying event in motor neuron degeneration and ALS pathophysiology. We also review and discuss novel approaches seeking to target copper delivery to treat ALS. These novel approaches may be clinically relevant not only for ALS but also for other neurological disorders with abnormal copper homeostasis, such as Parkinson's, Huntington's and Prion diseases.}, }
@article {pmid28587229, year = {2017}, author = {Ostrowski, LA and Hall, AC and Mekhail, K}, title = {Ataxin-2: From RNA Control to Human Health and Disease.}, journal = {Genes}, volume = {8}, number = {6}, pages = {}, pmid = {28587229}, issn = {2073-4425}, abstract = {RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases.}, }
@article {pmid28586775, year = {2017}, author = {Granitzer, E and Meier, B and Drexel, H and Saely, CH}, title = {[Auswirkungen von Flohsamen (Psyllium) auf Parameter des Glukosestoffwechsels: Eine Übersicht].}, journal = {Complementary medicine research}, volume = {24}, number = {3}, pages = {164-171}, doi = {10.1159/000477366}, pmid = {28586775}, issn = {2504-2106}, mesh = {Blood Glucose/analysis/*drug effects ; Humans ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/blood ; Psyllium/*pharmacology/therapeutic use ; }, abstract = {Ziel dieser Literaturübersicht war es, den klinischen Stellenwert von Flohsamen (Psyllium) und deren Auswirkungen auf Parameter des Glukosestoffwechsels zu bewerten. Hierzu wurde in den Datenbanken CAMbase, CAM-QUEST, Cochrane Library, EMBASE und PubMed die Literatur zur glukosesenkenden Wirkung von Flohsamen herangezogen und letztmalig am 16. September 2015 systematisch erfasst. Von ursprünglich 107 als potenziell relevant identifizierten Veröffentlichungen erwiesen sich 11 als randomisierte, kontrollierte klinische Studien, in denen 417 Testpersonen Psyllium eingenommen hatten. Das Phytotherapeutikum zeigte in 2 Studien signifikante Senkungen der Nüchternglukose. In 1 Studie konnte durch die Einnahme von Flohsamen der Hämoglobin-A1c (HbA1c)-Wert signifikant um 1,6% gesenkt werden. Signifikant Auswirkungen von Psyllium auf den postprandialen Glukosewert konnten in 4 Studien gemessen werden. Ebenfalls reduzierte Psyllium in 4 Studien den Insulinspiegel nach Nahrungsaufnahme signifikant. Der Jadad-Score für die ausgewerteten Publikationen lag im Durchschnitt bei 3 Punkten, das Minimum bei 1 Punkt, das Maximum bei 5 Punkten. Gegenwärtig ist die Evidenz aus publizierten, randomisierten Studien für eine glukosesenkende Wirkung von Flohsamen für eine behördliche Empfehlung oder eine Aufnahme in therapeutische Richtlinien ungenügend. Da aber in einigen, teilweise kleineren Studien positive Auswirkungen des pflanzlichen Arzneimittels auf Parameter des Glukosestoffwechsels beobachtet wurden, erscheint die Prüfung der glukosesenkenden Wirkung von Flohsamen in größeren, methodisch einwandfreien Studien sinnvoll.}, }
@article {pmid28585888, year = {2017}, author = {Crook, A and Williams, K and Adams, L and Blair, I and Rowe, DB}, title = {Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {7-8}, pages = {475-485}, doi = {10.1080/21678421.2017.1332079}, pmid = {28585888}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/*psychology ; Clinical Decision-Making/methods ; Evidence-Based Medicine ; Frontotemporal Dementia/diagnosis/*genetics/*psychology ; Genetic Counseling/methods/*psychology ; Genetic Testing/*methods ; Humans ; Patient Participation/methods/*psychology ; Physician-Patient Relations ; Prognosis ; Risk Assessment ; }, abstract = {Once a gene mutation that is causal of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) is identified in a family, relatives may decide to undergo predictive genetic testing to determine whether they are at risk of developing disease. Recent advances in gene discovery have led to a pressing need to better understand the implications of predictive genetic testing. Here we review the uptake of genetic counselling, predictive and reproductive testing, and the factors that impact the decision to undergo testing, for consideration in clinical practice. The literature suggests that the factors impacting the decision to undergo testing are complex due to the nature of these diseases, absence of available preventative medical treatment and variable age of onset in mutation carriers. Gaining further insight into the decision-making process and the impact of testing is critical as we seek to develop best-practice guidelines for predictive testing for familial ALS and FTD.}, }
@article {pmid28585384, year = {2017}, author = {Selvaraj, BT and Livesey, MR and Chandran, S}, title = {Modeling the C9ORF72 repeat expansion mutation using human induced pluripotent stem cells.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {27}, number = {4}, pages = {518-524}, pmid = {28585384}, issn = {1750-3639}, support = {MR/K017047/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; Humans ; Induced Pluripotent Stem Cells/*pathology ; }, abstract = {C9ORF72 repeat expansion is the most frequent causal genetic mutation giving rise to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). The relatively recent discovery of the C9ORF72 repeat expansion in 2011 and the complexity of the mutation have meant that animal models that successfully recapitulate human C9ORF72 repeat expansion-mediated disease are only now emerging. Concurrent advances in the use of patient-derived induced pluripotent stem cells (iPSCs) to model aspects of neurological disease offers an additional approach for the study of C9ORF72 mutation. This review focuses on the opportunities of human C9ORF72 iPSC platforms to model pathological aspects of disease and how findings compare with other existing models of disease and post mortem data.}, }
@article {pmid28579792, year = {2017}, author = {Hogden, A and Foley, G and Henderson, RD and James, N and Aoun, SM}, title = {Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach.}, journal = {Journal of multidisciplinary healthcare}, volume = {10}, number = {}, pages = {205-215}, pmid = {28579792}, issn = {1178-2390}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, leading to death within an average of 2-3 years. A cure is yet to be found, and a single disease-modifying treatment has had a modest effect in slowing disease progression. Specialized multidisciplinary ALS care has been shown to extend survival and improve patients' quality of life, by providing coordinated interprofessional care that seeks to address the complex needs of this patient group. This review examines the nature of specialized multidisciplinary care in ALS and draws on a broad range of evidence that has shaped current practice. The authors explain how multidisciplinary ALS care is delivered. The existing models of care, the role of palliative care within multidisciplinary ALS care, and the costs of formal and informal care are examined. Critical issues of ALS care are then discussed in the context of the support rendered by multidisciplinary-based care. The authors situate the patient and family as key stakeholders and decision makers in the multidisciplinary care network. Finally, the current challenges to the delivery of coordinated interprofessional care in ALS are explored, and the future of coordinated interprofessional care for people with ALS and their family caregivers is considered.}, }
@article {pmid28579383, year = {2017}, author = {Gazzina, S and Manes, MA and Padovani, A and Borroni, B}, title = {Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies.}, journal = {European journal of pharmacology}, volume = {817}, number = {}, pages = {76-85}, doi = {10.1016/j.ejphar.2017.05.056}, pmid = {28579383}, issn = {1879-0712}, mesh = {Animals ; Frontotemporal Dementia/*drug therapy/genetics/metabolism ; Humans ; Phenotype ; }, abstract = {Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies.}, }
@article {pmid28573364, year = {2017}, author = {Synofzik, M and Otto, M and Ludolph, A and Weishaupt, JH}, title = {[Genetic architecture of amyotrophic lateral sclerosis and frontotemporal dementia : Overlap and differences].}, journal = {Der Nervenarzt}, volume = {88}, number = {7}, pages = {728-735}, pmid = {28573364}, issn = {1433-0407}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; C9orf72 Protein/genetics ; Comorbidity ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics/therapy ; Gene Expression Regulation/genetics ; Genetic Association Studies ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Molecular Targeted Therapy ; Phenotype ; Progranulins ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; tau Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability. The recently identified genes are not only key to investigate the pathophysiology underlying ALS and FTD, but also the first step in the development of causal gene- or pathway-specific therapies. Mutations in these genes are also found in a substantial share of seemingly "sporadic" ALS and FTD patients. Given the large genetic heterogeneity with more than >25 genes having been identified for ALS and FTD, genetic diagnostics should - after exclusion of C9orf72 repeat expansions - no longer resort to single gene-diagnostics, but rather use next generation sequencing panels or whole exome sequencing.}, }
@article {pmid28572049, year = {2017}, author = {Muller, S and Brun, S and René, F and de Sèze, J and Loeffler, JP and Jeltsch-David, H}, title = {Autophagy in neuroinflammatory diseases.}, journal = {Autoimmunity reviews}, volume = {16}, number = {8}, pages = {856-874}, doi = {10.1016/j.autrev.2017.05.015}, pmid = {28572049}, issn = {1873-0183}, mesh = {Animals ; *Autophagy ; *Central Nervous System Diseases/immunology ; Humans ; Inflammation/immunology ; *Neurodegenerative Diseases/immunology ; Peptide Fragments/immunology ; *Peripheral Nervous System Diseases/immunology ; }, abstract = {Autophagy is a metabolically-central process that is crucial in diverse areas of cell physiology. It ensures a fair balance between life and death molecular and cellular flows, and any disruption in this vital intracellular pathway can have consequences leading to major diseases such as cancer, metabolic and neurodegenerative disorders, and cardiovascular and pulmonary diseases. Recent pharmacological studies have shown evidence that small molecules and peptides able to activate or inhibit autophagy might be valuable therapeutic agents by down- or up-regulating excessive or defective autophagy, or to modulate normal autophagy to allow other drugs to repair some cell alteration or destroy some cell subsets (e.g. in the case of cancer concurrent treatments). Here, we provide an overview of neuronal autophagy and of its potential implication in some inflammatory diseases of central and peripheral nervous systems. Based on our own studies centred on a peptide called P140 that targets autophagy, we highlight the validity of autophagy processes, and in particular of chaperone-mediated autophagy, as a particularly pertinent pathway for developing novel selective therapeutic approaches for treating some neuronal diseases. Our findings with the P140 peptide support a direct cross-talk between autophagy and certain central and peripheral neuronal diseases. They also illustrate the fact that autophagy alterations are not evenly distributed across all organs and tissues of the same individual, and can evolve in different stages along the disease course.}, }
@article {pmid28571556, year = {2017}, author = {Magri, A and Messina, A}, title = {Interactions of VDAC with Proteins Involved in Neurodegenerative Aggregation: An Opportunity for Advancement on Therapeutic Molecules.}, journal = {Current medicinal chemistry}, volume = {24}, number = {40}, pages = {4470-4487}, doi = {10.2174/0929867324666170601073920}, pmid = {28571556}, issn = {1875-533X}, mesh = {Alzheimer Disease/physiopathology ; Amyloid beta-Peptides/*metabolism ; Animals ; *Drug Delivery Systems ; Humans ; Parkinson Disease/physiopathology ; Protein Aggregation, Pathological/genetics/*physiopathology ; Protein Folding ; Protein Isoforms ; Voltage-Dependent Anion Channel 1/*metabolism ; }, abstract = {BACKGROUND: The Voltage Dependent Anion Channel (VDAC) proteins represent the most important pore-forming proteins of the mitochondrial outer membrane, directly involved in metabolism and apoptosis regulation. Literature has highlighted a key role of VDACs in mitochondrial dysfunction typical of many neurodegenerative disorders. In particular, the principal isoform VDAC1 represents the main mitochondrial docking site of many misfolded proteins, such as amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and several SOD1 mutants in Amyotrophic Lateral Sclerosis. The interaction of misfolded proteins with VDAC1 has a strong impact on both cellular bioenergetics and apoptosis' pathways alteration. Therefore, VDACs represent a promising therapeutic target in neurodegeneration.<br><br>OBJECTIVE: This review summarizes the roles of VDAC isoforms, and particularly of VDAC1, in the most common neurological disorders and analyzes in detail molecules and peptides available so far, able to interact and modulate VDAC1 in any considered pathological condition.<br><br>CONCLUSION: This review offers a description of the most promising therapeutic strategies acting on VDAC1, for the treatment of neurodegenerative diseases.}, }
@article {pmid28559789, year = {2017}, author = {Lackie, RE and Maciejewski, A and Ostapchenko, VG and Marques-Lopes, J and Choy, WY and Duennwald, ML and Prado, VF and Prado, MAM}, title = {The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {254}, pmid = {28559789}, issn = {1662-4548}, abstract = {The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide-either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrP[C]). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrP[C] and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD.}, }
@article {pmid28554311, year = {2018}, author = {Penke, B and Fulop, L and Szucs, M and Frecska, E}, title = {The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {16}, number = {1}, pages = {97-116}, pmid = {28554311}, issn = {1875-6190}, mesh = {Animals ; Endoplasmic Reticulum/pathology ; Humans ; Molecular Chaperones/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism/*pathology ; Receptors, sigma/agonists/*metabolism ; Sigma-1 Receptor ; }, abstract = {BACKGROUND: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death.<br><br>METHODS: Research articles on Sigma-1 receptor were reviewed.<br><br>RESULTS: ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins.<br><br>CONCLUSION: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity.}, }
@article {pmid28553327, year = {2017}, author = {Iyer, AK and Jones, KJ}, title = {A tale of motor neurons and CD4[+] T cells: moving forward by looking back.}, journal = {Neural regeneration research}, volume = {12}, number = {4}, pages = {562-565}, pmid = {28553327}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal progressive disorder characterized by the selective degeneration of motor neurons (MN). The impact of peripheral immune status on disease progression and MN survival is becoming increasingly recognized in the ALS research field. In this review, we briefly discuss findings from mouse models of peripheral nerve injury and immunodeficiency to understand how the immune system regulates MN survival. We extend these observations to similar studies in the widely used superoxide dismutase 1 (SOD1) mouse model of ALS. Last, we present future hypotheses to identify potential causative factors that lead to immune dysregulation in ALS. The lessons from preceding work in this area offer new exciting directions to bridge the gap in our current understanding of immune-mediated neuroprotection in ALS.}, }
@article {pmid28552366, year = {2017}, author = {van Es, MA and Hardiman, O and Chio, A and Al-Chalabi, A and Pasterkamp, RJ and Veldink, JH and van den Berg, LH}, title = {Amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {390}, number = {10107}, pages = {2084-2098}, doi = {10.1016/S0140-6736(17)31287-4}, pmid = {28552366}, issn = {1474-547X}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*genetics/therapy ; *Cause of Death ; Chronic Disease ; DNA-Binding Proteins/*genetics ; Disease Progression ; Female ; *Genetic Predisposition to Disease ; Humans ; Male ; Survival Rate ; TDP-43 Proteinopathies ; }, abstract = {Amyotrophic lateral sclerosis is characterised by the progressive loss of motor neurons in the brain and spinal cord. This neurodegenerative syndrome shares pathobiological features with frontotemporal dementia and, indeed, many patients show features of both diseases. Many different genes and pathophysiological processes contribute to the disease, and it will be necessary to understand this heterogeneity to find effective treatments. In this Seminar, we discuss clinical and diagnostic approaches as well as scientific advances in the research fields of genetics, disease modelling, biomarkers, and therapeutic strategies.}, }
@article {pmid28552237, year = {2017}, author = {Gowing, G and Svendsen, S and Svendsen, CN}, title = {Ex vivo gene therapy for the treatment of neurological disorders.}, journal = {Progress in brain research}, volume = {230}, number = {}, pages = {99-132}, doi = {10.1016/bs.pbr.2016.11.003}, pmid = {28552237}, issn = {1875-7855}, mesh = {Animals ; Cell- and Tissue-Based Therapy ; *Genetic Therapy ; Humans ; Mesenchymal Stem Cell Transplantation ; Nervous System Diseases/genetics/*therapy ; Neural Stem Cells ; Stem Cell Transplantation ; }, abstract = {Ex vivo gene therapy involves the genetic modification of cells outside of the body to produce therapeutic factors and their subsequent transplantation back into patients. Various cell types can be genetically engineered. However, with the explosion in stem cell technologies, neural stem/progenitor cells and mesenchymal stem cells are most often used. The synergy between the effect of the new cell and the additional engineered properties can often provide significant benefits to neurodegenerative changes in the brain. In this review, we cover both preclinical animal studies and clinical human trials that have used ex vivo gene therapy to treat neurological disorders with a focus on Parkinson's disease, Huntington's disease, Alzheimer's disease, ALS, and stroke. We highlight some of the major advances in this field including new autologous sources of pluripotent stem cells, safer ways to introduce therapeutic transgenes, and various methods of gene regulation. We also address some of the remaining hurdles including tunable gene regulation, in vivo cell tracking, and rigorous experimental design. Overall, given the current outcomes from researchers and clinical trials, along with exciting new developments in ex vivo gene and cell therapy, we anticipate that successful treatments for neurological diseases will arise in the near future.}, }
@article {pmid28552054, year = {2017}, author = {Cassereau, J and Ferré, M and Chevrollier, A and Codron, P and Verny, C and Homedan, C and Lenaers, G and Procaccio, V and May-Panloup, P and Reynier, P}, title = {Neurotoxicity of Insecticides.}, journal = {Current medicinal chemistry}, volume = {24}, number = {27}, pages = {2988-3001}, doi = {10.2174/0929867324666170526122654}, pmid = {28552054}, issn = {1875-533X}, mesh = {Animals ; Genetic Predisposition to Disease ; Humans ; Insecticides/chemistry/*toxicity ; Nervous System/*drug effects/metabolism ; Neurodegenerative Diseases/etiology ; Neurons/*drug effects/metabolism ; Organophosphates/chemistry/toxicity ; }, abstract = {BACKGROUND: Human exposure to insecticides raises serious public health concerns worldwide. Insecticides constitute a wide-ranging heterogeneous group of chemicals, most of which target the nervous system and disrupt neurometabolism and/or neurotransmission. Although the acute effects of insecticide poisoning in humans are well documented, the chronic and long-term effects remain difficult to investigate.<br><br>OBJECTIVES AND METHOD: We sought to review the present state-of-knowledge of acute, chronic, neurodevelopmental and neurological consequences of human exposure to insecticides.<br><br>RESULTS: Animal and epidemiologic studies indicate cognitive, behavioral and psychomotor alterations in mammals chronically exposed to insecticides. Parkinson's and Alzheimer's diseases, amyotrophic lateral sclerosis, and depression, have been regularly associated with insecticide exposure. Clinical studies, supported by experiments on animal models, demonstrate the neurotoxic impact of insecticide exposure during the period of cerebral development, the developing brain being particularly vulnerable to the action of insecticides. Moreover, detoxifying systems that are highly polymorph lead to great inter-individual variability in susceptibility to the neurotoxic effects of insecticides.<br><br>CONCLUSION: Studies on mild chronic exposure to insecticides suggest significant involvement in the pathogenesis of multifactorial neurological diseases. However, the tardive appearance of neurodegenerative disorders and the large variability of inter-individual susceptibility to neurotoxicants make it difficult to assess the relative contribution of insecticide exposure. Close vigilance should therefore be exercised with regard to possible exposure to insecticides, particularly during the period of cerebral development.}, }
@article {pmid30050378, year = {2017}, author = {Hinchcliffe, M and Smith, A}, title = {Riluzole: real-world evidence supports significant extension of median survival times in patients with amyotrophic lateral sclerosis.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {7}, number = {}, pages = {61-70}, pmid = {30050378}, issn = {1179-9900}, abstract = {Amyotrophic lateral sclerosis (ALS) is the commonest form of motor neuron disease and is a fatal, degenerative, multisystem disorder affecting upper and/or lower motor neurons in the motor cortex, brain stem, and spinal cord. ALS is characterized by progressive atrophy of associated bulbar, limb, thoracic, and abdominal muscles and supporting cells manifesting in a range of muscular symptoms such as weakness and wasting and eventual paralysis; the majority of patients will die from respiratory failure within 2-5 years of onset. Riluzole, a synthetic benzothiazole drug with glutamine antagonist activity, is indicated for the treatment of patients with ALS and is the only drug that has been shown to slow the course of the disease and extend survival in ALS patients. The original analyses, and subsequent meta-analyses, of data obtained from randomized controlled trials (RCTs) suggest that riluzole typically extends survival by 2-3 months and increases the chance of an additional year of survival by ~9%. However, published real-world evidence (RWE) from 10 clinical ALS databases indicates that riluzole therapy may afford much greater extension of survival, and improvements in median survival times of more than 19 months have been reported in the overall ALS patient population. This article will review the available data from RCTs and RWE on riluzole therapy.}, }
@article {pmid28545479, year = {2017}, author = {Sprenkle, NT and Sims, SG and Sánchez, CL and Meares, GP}, title = {Endoplasmic reticulum stress and inflammation in the central nervous system.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {42}, pmid = {28545479}, issn = {1750-1326}, support = {P20 GM109098/GM/NIGMS NIH HHS/United States ; T32 AG052375/AG/NIA NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/*immunology/pathology ; Endoplasmic Reticulum Stress/*immunology ; Humans ; Inflammation/immunology/*pathology ; Neurodegenerative Diseases/*immunology/pathology ; Neuroimmunomodulation/*immunology ; }, abstract = {Persistent endoplasmic reticulum (ER) stress is thought to drive the pathology of many chronic disorders due to its potential to elicit aberrant inflammatory signaling and facilitate cell death. In neurodegenerative diseases, the accumulation of misfolded proteins and concomitant induction of ER stress in neurons contributes to neuronal dysfunction. In addition, ER stress responses induced in the surrounding neuroglia may promote disease progression by coordinating damaging inflammatory responses, which help fuel a neurotoxic milieu. Nevertheless, there still remains a gap in knowledge regarding the cell-specific mechanisms by which ER stress mediates neuroinflammation. In this review, we will discuss recently uncovered inflammatory pathways linked to the ER stress response. Moreover, we will summarize the present literature delineating how ER stress is generated in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis, and highlight how ER stress and neuroinflammation intersect mechanistically within the central nervous system. The mechanisms by which stress-induced inflammation contributes to the pathogenesis and progression of neurodegenerative diseases remain poorly understood. Further examination of this interplay could present unappreciated insights into the development of neurodegenerative diseases, and reveal new therapeutic targets.}, }
@article {pmid28540663, year = {2018}, author = {Cox, PA and Kostrzewa, RM and Guillemin, GJ}, title = {BMAA and Neurodegenerative Illness.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {178-183}, pmid = {28540663}, issn = {1476-3524}, mesh = {Amino Acids, Diamino/chemistry/*toxicity ; Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Animals ; Cyanobacteria Toxins ; Excitatory Amino Acid Agonists/chemistry/*toxicity ; Humans ; Parkinsonian Disorders/*chemically induced/epidemiology ; }, abstract = {The cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) now appears to be a cause of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Its production by cyanobacteria throughout the world combined with multiple mechanisms of BMAA neurotoxicity, particularly to vulnerable subpopulations of motor neurons, has significantly increased interest in investigating exposure to this non-protein amino acid as a possible risk factor for other forms of neurodegenerative illness. We here provide a brief overview of BMAA studies and provide an introduction to this collection of scientific manuscripts in this special issue on BMAA.}, }
@article {pmid28534084, year = {2017}, author = {Ma, X and Li, H and He, Y and Hao, J}, title = {The emerging link between O-GlcNAcylation and neurological disorders.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {74}, number = {20}, pages = {3667-3686}, pmid = {28534084}, issn = {1420-9071}, support = {81571600//the National Natural Science Foundation of China/International ; 81322018//the National Natural Science Foundation of China/International ; 81273287//the National Natural Science Foundation of China/International ; 81401361//the National Natural Science Foundation of China/International ; }, mesh = {Acetylglucosamine/*metabolism ; Acetylglucosaminidase/metabolism ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Brain/*metabolism ; Humans ; N-Acetylglucosaminyltransferases/metabolism ; Nervous System Diseases/*metabolism ; Neurons/metabolism ; Parkinson Disease/metabolism ; *Protein Processing, Post-Translational ; Proteins/*metabolism ; }, abstract = {O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders. In neurodegenerative diseases, O-GlcNAcylation of the brain's key proteins, such as tau and amyloid-β, interacts with their phosphorylation, thereby triggering the formation of neurofibrillary tangles and amyloid plaques. An increase of O-GlcNAcylation by pharmacological intervention prevents neuronal loss. Additionally, O-GlcNAcylation is stress sensitive, and its elevation is cytoprotective. Increased O-GlcNAcylation ameliorated brain damage in victims of both trauma-hemorrhage and stroke. In this review, we summarize the current understanding of O-GlcNAcylation's physiological and pathological roles in the nervous system and provide a foundation for development of a therapeutic strategy for neurological disorders.}, }
@article {pmid28527504, year = {2017}, author = {Tenforde, AS and Hefner, JE and Kodish-Wachs, JE and Iaccarino, MA and Paganoni, S}, title = {Telehealth in Physical Medicine and Rehabilitation: A Narrative Review.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {9}, number = {5S}, pages = {S51-S58}, doi = {10.1016/j.pmrj.2017.02.013}, pmid = {28527504}, issn = {1934-1563}, mesh = {Humans ; *Physical and Rehabilitation Medicine ; *Telemedicine ; }, abstract = {Telehealth refers to health care interactions that leverage telecommunication devices to provide medical care outside the traditional face-to-face, in-person medical encounter. Technology advances and research have expanded use of telehealth in health care delivery. Physical medicine and rehabilitation providers may use telehealth to deliver care to populations with neurologic and musculoskeletal conditions, commonly treated in both acute care and outpatient settings. Patients with impaired mobility and those living in locations with reduced access to care may particularly benefit. Video-teleconferencing has been shown to be effective for management of burn patients during acute rehabilitation, including reduced health care use expenses and less disruptions to care. Telehealth can facilitate developing interprofessional care plans. Patients with neurologic conditions including stroke, spinal cord injury, traumatic brain injury, and amyotrophic lateral sclerosis may use telehealth to monitor symptoms and response to treatment. Telehealth also may facilitate occupational and physical therapy programs as well as improve weight management and skin care in patients with chronic conditions. Other applications include imaging review in sports medicine, symptom management and counseling in concussion, traumatic brain injury, and pain management programs. Limitations of telehealth include barriers in establishing relationship between medical provider and patient, ability to perform limited physical examination, and differences in payment models and liability coverage. The expansion of telehealth services is expected to grow and has potential to improve patient satisfaction by delivering high quality and value of care.}, }
@article {pmid28523551, year = {2017}, author = {Jimenez-Pacheco, A and Franco, JM and Lopez, S and Gomez-Zumaquero, JM and Magdalena Leal-Lasarte, M and Caballero-Hernandez, DE and Cejudo-Guillén, M and Pozo, D}, title = {Epigenetic Mechanisms of Gene Regulation in Amyotrophic Lateral Sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {978}, number = {}, pages = {255-275}, doi = {10.1007/978-3-319-53889-1_14}, pmid = {28523551}, issn = {0065-2598}, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/metabolism/pathology ; Animals ; DNA Methylation/genetics ; Disease Models, Animal ; Environmental Exposure ; Epigenesis, Genetic/*genetics ; Gene Expression Regulation/*genetics ; Gene-Environment Interaction ; Histone Code/genetics ; Histone Deacetylase Inhibitors/therapeutic use ; Histone Deacetylases/physiology ; Humans ; MicroRNAs/genetics ; Motor Neurons/metabolism/pathology ; Mutation ; Oxidative Stress ; Protein Processing, Post-Translational ; Riluzole/therapeutic use ; Superoxide Dismutase-1/deficiency/genetics ; }, abstract = {Despite being clinically described 150 years ago, the mechanisms underlying amyotrophic lateral sclerosis (ALS) pathogenesis have not yet been fully understood. Studies in both animal models of ALS and human patients reveal a plethora of alterations such as increased glutamate-mediated excitotoxicity, redox stress, increased apoptosis, defective axonal transport, protein-misfolding events, mitochondrial impairment and sustained unregulated immune responses. Regardless of being sporadic or familiar ALS, the final outcome at the cellular level is the death of upper and lower motor neurons, and once diagnosed, ALS is typically lethal within the next 5 years. There are neither clear biomarkers nor therapeutic or disease-modifying treatments for ALS.Accumulating evidence supports the concept that epigenetic-driven modifications, including altered chromatin remodelling events, RNA editing and non-coding RNA molecules, might shed light into the pathogenic mechanisms underlying sporadic/familiar ALS onset and/or severity to facilitate the identification of effective therapies, early diagnosis and potentially early-stage therapeutic interventions to increase the survival outcome of ALS patients.}, }
@article {pmid28522961, year = {2017}, author = {Liu, YJ and Tsai, PY and Chern, Y}, title = {Energy Homeostasis and Abnormal RNA Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {126}, pmid = {28522961}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that is clinically characterized by progressive muscle weakness and impaired voluntary movement due to the loss of motor neurons in the brain, brain stem and spinal cord. To date, no effective treatment is available. Ample evidence suggests that impaired RNA homeostasis and abnormal energy status are two major pathogenesis pathways in ALS. In the present review article, we focus on recent studies that report molecular insights of both pathways, and discuss the possibility that energy dysfunction might negatively regulate RNA homeostasis via the impairment of cytoplasmic-nuclear shuttling in motor neurons and subsequently contribute to the development of ALS.}, }
@article {pmid28522960, year = {2017}, author = {Hawley, ZCE and Campos-Melo, D and Droppelmann, CA and Strong, MJ}, title = {MotomiRs: miRNAs in Motor Neuron Function and Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {127}, pmid = {28522960}, issn = {1662-5099}, abstract = {MiRNAs are key regulators of the mammalian transcriptome that have been increasingly linked to degenerative diseases of the motor neurons. Although many of the miRNAs currently incriminated as participants in the pathogenesis of these diseases are also important to the normal development and function of motor neurons, at present there is no knowledge of the complete miRNA profile of motor neurons. In this review, we examine the current understanding with respect to miRNAs that are specifically required for motor neuron development, function and viability, and provide evidence that these should be considered as a functional network of miRNAs which we have collectively termed MotomiRs. We will also summarize those MotomiRs currently known to be associated with both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), and discuss their potential use as biomarkers.}, }
@article {pmid28515268, year = {2017}, author = {Rooney, JPK and Brayne, C and Tobin, K and Logroscino, G and Glymour, MM and Hardiman, O}, title = {Benefits, pitfalls, and future design of population-based registers in neurodegenerative disease.}, journal = {Neurology}, volume = {88}, number = {24}, pages = {2321-2329}, doi = {10.1212/WNL.0000000000004038}, pmid = {28515268}, issn = {1526-632X}, mesh = {Humans ; Neurodegenerative Diseases/economics/*epidemiology/therapy ; *Registries ; }, abstract = {Population-based disease registers identify and characterize all cases of disease, including those that might otherwise be neglected. Prospective population-based registers in neurodegeneration are necessary to provide comprehensive data on the whole phenotypic spectrum and can guide planning of health services. With the exception of the rare disease amyotrophic lateral sclerosis, few complete population-based registers exist for neurodegenerative conditions. Incomplete ascertainment, limitations and uncertainty in diagnostic categorization, and failure to recognize sources of bias reduce the accuracy and usefulness of many registers. Common biases include population stratification, the use of prevalent rather than incident cases in earlier years, changes in disease understanding and diagnostic criteria, and changing demographics over time. Future registers are at risk of funding shortfalls and changes to privacy legislation. Notwithstanding, as heterogeneities of clinical phenotype and disease pathogenesis are increasingly recognized in the neurodegenerations, well-designed longitudinal population-based disease registers will be an essential requirement to complete clinical understanding of neurodegenerative diseases.}, }
@article {pmid28512398, year = {2017}, author = {Webster, CP and Smith, EF and Shaw, PJ and De Vos, KJ}, title = {Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {123}, pmid = {28512398}, issn = {1662-5099}, support = {DEVOS/OCT13/870-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K005146/1/MRC_/Medical Research Council/United Kingdom ; MR/M013251/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Protein homeostasis (proteostasis), the correct balance between production and degradation of proteins, is essential for the health and survival of cells. Proteostasis requires an intricate network of protein quality control pathways (the proteostasis network) that work to prevent protein aggregation and maintain proteome health throughout the lifespan of the cell. Collapse of proteostasis has been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disorder. Here, we review the evidence linking dysfunctional proteostasis to the etiology of ALS and discuss how ALS-associated insults affect the proteostasis network. Finally, we discuss the potential therapeutic benefit of proteostasis network modulation in ALS.}, }
@article {pmid28502042, year = {2018}, author = {Shah, K and Rossie, S}, title = {Tale of the Good and the Bad Cdk5: Remodeling of the Actin Cytoskeleton in the Brain.}, journal = {Molecular neurobiology}, volume = {55}, number = {4}, pages = {3426-3438}, pmid = {28502042}, issn = {1559-1182}, support = {R21 AG047447/AG/NIA NIH HHS/United States ; NIAR21AG 47447//National Institute on Aging/ ; }, mesh = {Actin Cytoskeleton/*metabolism ; Animals ; Brain/*metabolism ; Cyclin-Dependent Kinase 5/*metabolism ; Humans ; Models, Biological ; Neurons/metabolism ; Presynaptic Terminals/metabolism ; }, abstract = {Cdk5 kinase, a cyclin-dependent kinase family member, is a key regulator of cytoskeletal remodeling in the brain. Cdk5 is essential for brain development during embryogenesis. After birth, it is essential for numerous neuronal processes such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity is deregulated in various brain disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration. This review focuses on the "good and bad" Cdk5 in the brain and its pleiotropic contribution in regulating neuronal actin cytoskeletal remodeling. A vast majority of physiological and pathological Cdk5 substrates are associated with the actin cytoskeleton. Thus, our special emphasis is on the numerous Cdk5 substrates identified in the past two decades such as ephexin1, p27, Mst3, CaMKv, kalirin-7, RasGRF2, Pak1, WAVE1, neurabin-1, TrkB, 5-HT6R, talin, drebrin, synapsin I, synapsin III, CRMP1, GKAP, SPAR, PSD-95, and LRRK2. These substrates have unraveled the molecular mechanisms by which Cdk5 plays divergent roles in regulating neuronal actin cytoskeletal dynamics both in healthy and diseased states.}, }
@article {pmid28501823, year = {2017}, author = {Gellersen, HM and Guo, CC and O'Callaghan, C and Tan, RH and Sami, S and Hornberger, M}, title = {Cerebellar atrophy in neurodegeneration-a meta-analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {88}, number = {9}, pages = {780-788}, doi = {10.1136/jnnp-2017-315607}, pmid = {28501823}, issn = {1468-330X}, mesh = {Atrophy/*pathology ; Cerebellar Ataxia ; *Cerebellum/pathology ; Gray Matter/*pathology ; Humans ; Neurodegenerative Diseases/*diagnosis ; }, abstract = {INTRODUCTION: The cerebellum has strong cortical and subcortical connectivity, but is rarely taken into account for clinical diagnosis in many neurodegenerative conditions, particularly in the absence of clinical ataxia. The current meta-analysis aims to assess patterns of cerebellar grey matter atrophy in seven neurodegenerative conditions (Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (MSP)).<br><br>METHODS: We carried out a systematic search in PubMed (any date: 14 July 2016) and a hand search of references from pertinent articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The authors were contacted to provide missing coordinate data. Peer-reviewed studies with direct comparison of patient and control groups, and availability of coordinate data of grey matter cerebellar atrophy in patients were included. These coordinates were used in an anatomical likelihood estimation meta-analysis.<br><br>RESULTS: Across 54 studies, clusters of cerebellar atrophy were found for AD, ALS, FTD, MSA, and PSP. Atrophy patterns were largely disease-specific, with overlap in certain areas of the cerebellar hemisphere, which showed marked atrophy in AD, ALS, FTD and PSP (Crus I/II), and MSA and PSP (lobules I-IV), respectively. Atrophy colocated with cerebellar areas implicated for motor (PSP, MSA) or cognitive symptoms (FTD, ALS, PSP) in the diseases.<br><br>DISCUSSION: Our findings suggest that cerebellar changes are largely disease-specific and correspond to cortical or subcortical changes in neurodegenerative conditions. High clinical variability in PD and HD samples may explain the absence of findings for consistent grey matter loss across studies. Our results have clinical implications for diagnosis and cerebellar neuroimaging referencing approaches.}, }
@article {pmid28497735, year = {2017}, author = {Medina, J and Charvet, B and Leblanc, P and Germi, R and Horvat, B and Marche, PN and Perron, H}, title = {[Endogenous retroviral sequences in the human genome can play a physiological or pathological role].}, journal = {Medecine sciences : M/S}, volume = {33}, number = {4}, pages = {397-403}, doi = {10.1051/medsci/20173304009}, pmid = {28497735}, issn = {1958-5381}, mesh = {Animals ; Cytomegalovirus/physiology ; DNA Methylation ; Endogenous Retroviruses/genetics/*pathogenicity/*physiology ; Gene Expression Regulation, Viral ; Genome, Human/*genetics ; Herpesviridae/pathogenicity/physiology ; Herpesviridae Infections/genetics/pathology/virology ; Herpesvirus 4, Human/physiology ; Humans ; Viral Envelope Proteins/genetics/physiology ; }, abstract = {Human endogenous retroviruses (HERV) represent a large part of our genome and the few elements that have retained a potential of expression still remain "dormant" in physiological conditions. In some instances, they can be awakened by environmental factors activating their expression. The best studied conditions of HERV activation are infections caused by microorganisms such as viruses of the Herpesvirus family. This activation can thus lead to the expression of pathogenic proteins such as envelope proteins belonging to the HERV-W and HERV-K families, respectively involved in Multiple Sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Endogenous retroviral proteins can also acquire a physiological function beneficial for humans. This is the case of Syncytin-1 from the HERV-W family, that is involved in placenta formation.}, }
@article {pmid28497222, year = {2017}, author = {Mistry, A and Savic, S and van der Hilst, JCH}, title = {Interleukin-1 Blockade: An Update on Emerging Indications.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {31}, number = {3}, pages = {207-221}, doi = {10.1007/s40259-017-0224-7}, pmid = {28497222}, issn = {1179-190X}, mesh = {Gout/drug therapy/metabolism ; Humans ; Inflammation/drug therapy/metabolism ; Interleukin-1/*antagonists &amp; inhibitors/*metabolism ; Schnitzler Syndrome/drug therapy/metabolism ; Still's Disease, Adult-Onset/drug therapy/metabolism ; }, abstract = {Interleukin (IL)-1 is a pro-inflammatory cytokine that induces local and systemic inflammation aimed to eliminate microorganisms and tissue damage. However, an increasing number of clinical conditions have been identified in which IL-1 production is considered inappropriate and IL-1 is part of the disease etiology. In autoinflammatory diseases, gout, Schnitzler's syndrome, and adult-onset Still's disease, high levels of inappropriate IL-1 production have been shown to be a key process in the etiology of the disease. In these conditions, blocking IL-1 has proven very effective in clinical studies. In other diseases, IL-1 has shown to be present in disease process but is not the central driving force of inflammation. In these conditions, including type 1 and 2 diabetes mellitus, acute coronary syndrome, amyotrophic lateral sclerosis, and several neoplastic diseases, the benefits of IL-1 blockade are minimal or absent.}, }
@article {pmid28495324, year = {2017}, author = {Rosenfeld, RG and Hwa, V}, title = {Biology of the somatotroph axis (after the pituitary).}, journal = {Annales d'endocrinologie}, volume = {78}, number = {2}, pages = {80-82}, pmid = {28495324}, issn = {2213-3941}, support = {R01 HD078592/HD/NICHD NIH HHS/United States ; }, mesh = {Human Growth Hormone/genetics/metabolism ; Humans ; Insulin-Like Growth Factor I/genetics/metabolism ; Pituitary Diseases/genetics/metabolism ; Receptor, IGF Type 1/genetics ; STAT Transcription Factors/genetics ; Somatotrophs/metabolism/*physiology ; }, abstract = {Normal growth requires that pituitary-secreted growth hormone (GH) bind to its specific receptor and activate a complex signaling cascade, leaving to production of insulin-like growth factor-I (IGF-I), which, in turn, activates its own receptor (IGF1R). The GH receptor (GHR) is preformed as a dimer and is transported in a nonligand bound state to the cell surface. Binding of GH to the GHR dimer, results in a conformational change of the dimer, activation of the intracellular Janus Kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 5B. Phosphorylated STAT5B dimers are then translocated to the nucleus, where they transcriptionally activate multiple genes, including those for IGF-I, IGF binding protein-3 and the acid-labile subunit (ALS).}, }
@article {pmid28494742, year = {2017}, author = {Bangde, P and Atale, S and Dey, A and Pandit, A and Dandekar, P and Jain, R}, title = {Potential Gene Therapy Towards Treating Neurodegenerative Disea ses Employing Polymeric Nanosystems.}, journal = {Current gene therapy}, volume = {17}, number = {2}, pages = {170-183}, doi = {10.2174/1566523217666170510153845}, pmid = {28494742}, issn = {1875-5631}, mesh = {Animals ; Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Humans ; Nanoparticles/*administration &amp; dosage/chemistry ; Nanotechnology/methods ; Neurodegenerative Diseases/genetics/*therapy ; Polymers/*administration &amp; dosage/chemistry ; }, abstract = {BACKGROUND: Recent integrated approaches involving nanotechnology and gene therapy have accelerated development of efficient drug delivery to the central nervous system (CNS). Neurodegenerative disorders are closely associated with genetic inheritance and mutation.<br><br>MATERIALS: Nanotechnology has allowed effective engineering of various such polymeric structures. Moreover, availability of a wide array of polymeric materials has enabled fabrication of biocompatible and biodegradable delivery vehicles. Our manuscript focuses on the ideal features and properties of polymeric nanoparticles that have enabled successful gene therapy for neurodegenerative disorders, as well as the challenges that are posing difficulties in their practical application. We have highlighted these aspects through examples of polymeric nanoparticles that have exhibited therapeutic promise in the treatment of neurological disorders and mutations.<br><br>METHODS: Complete cure of these diseases is a challenging task and gene therapy appears as a realistic approach for their treatment. Gene therapy allows effective replacement or suppression of faulty genes, thereby increasing chances for neuron survival and repair. However, successful delivery of naked genetic material to CNS faces severe obstacles due to possible degradation and restricted transportation of these biological entities across the blood brain barrier (BBB). Structurally, the BBB is composed of several tight junctions, making the membrane highly selective towards the entry of molecules.<br><br>CONCLUSION: In order to target BBB for treating neurodegenerative diseases, it is essential to develop a tailor-made system that may not only cross this barrier, but also effectively modulate the expression of disease-causing genes. Stabilization of therapeutic genes and their effective, targeted delivery may be possible using polymeric nanoparticles as carriers.}, }
@article {pmid28490504, year = {2017}, author = {de Carvalho, M and Kiernan, MC and Swash, M}, title = {Fasciculation in amyotrophic lateral sclerosis: origin and pathophysiological relevance.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {88}, number = {9}, pages = {773-779}, doi = {10.1136/jnnp-2017-315574}, pmid = {28490504}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Axons/physiology ; Electromyography ; Fasciculation/diagnosis/*physiopathology ; Humans ; Motor Neurons/physiology ; Muscle Fibers, Skeletal/*physiology ; }, abstract = {This review considers the origin and significance of fasciculations in neurological practice, with an emphasis on fasciculations in amyotrophic lateral sclerosis (ALS), and in benign fasciculation syndromes. Fasciculation represents a brief spontaneous contraction that affects a small number of muscle fibres, causing a flicker of movement under the skin. While an understanding of the role of fasciculation in ALS remains incomplete, fasciculations derive from ectopic activity generated in the motor system. A proximal origin seems likely to contribute to the generation of fasciculation in the early stages of ALS, while distal sites of origin become more prominent later in the disease, associated with distal motor axonal sprouting as part of the reinnervation response that develops secondary to loss of motor neurons. Fasciculations are distinct from the recurrent trains of axonal firing described in neuromyotonia. Fasciculation without weakness, muscle atrophy or increased tendon reflexes suggests a benign fasciculation syndrome, even when of sudden onset. Regardless of origin, fasciculations often present as the initial abnormality in ALS, an early harbinger of dysfunction and aberrant firing of motor neurons.}, }
@article {pmid28489058, year = {2017}, author = {Szwajgier, D and Borowiec, K and Pustelniak, K}, title = {The Neuroprotective Effects of Phenolic Acids: Molecular Mechanism of Action.}, journal = {Nutrients}, volume = {9}, number = {5}, pages = {}, pmid = {28489058}, issn = {2072-6643}, mesh = {Animals ; Central Nervous System Diseases/*prevention &amp; control ; Humans ; Molecular Structure ; Neuroprotective Agents/*pharmacology ; Phenols/chemistry/*pharmacology ; }, abstract = {The neuroprotective role of phenolic acids from food has previously been reported by many authors. In this review, the role of phenolic acids in ameliorating depression, ischemia/reperfusion injury, neuroinflammation, apoptosis, glutamate-induced toxicity, epilepsy, imbalance after traumatic brain injury, hyperinsulinemia-induced memory impairment, hearing and vision disturbances, Parkinson's disease, Huntington's disease, anti-amyotrophic lateral sclerosis, Chagas disease and other less distributed diseases is discussed. This review covers the in vitro, ex vivo and in vivo studies concerning the prevention and treatment of neurological disorders (on the biochemical and gene expression levels) by phenolic acids.}, }
@article {pmid28488363, year = {2018}, author = {Duffy, SS and Keating, BA and Perera, CJ and Moalem-Taylor, G}, title = {The role of regulatory T cells in nervous system pathologies.}, journal = {Journal of neuroscience research}, volume = {96}, number = {6}, pages = {951-968}, doi = {10.1002/jnr.24073}, pmid = {28488363}, issn = {1097-4547}, mesh = {Animals ; Central Nervous System Diseases/*immunology/pathology ; Humans ; Neurodegenerative Diseases/immunology/pathology ; T-Lymphocytes, Regulatory/*immunology/pathology ; }, abstract = {Regulatory T (Treg) cells are a special subpopulation of immunosuppressive T cells that are essential for sustaining immune homeostasis. They maintain self-tolerance, inhibit autoimmunity, and act as critical negative regulators of inflammation in various pathological states including autoimmunity, injury, and degeneration of the nervous system. Treg cells are known to convey both beneficial and detrimental influences in certain disease contexts, and accumulating research suggests that their action may be altered in a range of peripheral and central nervous system pathologies. In this review, we discuss emerging evidence for the dichotomous role of Treg cells in various neurological pathologies including multiple sclerosis, Guillain-Barré syndrome, neuropathic pain, traumatic central nervous system injury, stroke, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. We are in the early stages of uncovering the role of Treg cells in these conditions, and a better understanding of the ways in which these cells operate in the nervous system will enable us to develop novel therapeutic interventions.}, }
@article {pmid28484853, year = {2017}, author = {Morriss, GR and Cooper, TA}, title = {Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions.}, journal = {Human genetics}, volume = {136}, number = {9}, pages = {1247-1263}, pmid = {28484853}, issn = {1432-1203}, support = {K12 GM084897/GM/NIGMS NIH HHS/United States ; R01AR060733/AR/NIAMS NIH HHS/United States ; R01AR045653/AR/NIAMS NIH HHS/United States ; R01 AR045653/AR/NIAMS NIH HHS/United States ; R01 AR060733/AR/NIAMS NIH HHS/United States ; R01HL045565/HL/NHLBI NIH HHS/United States ; R01 HL045565/HL/NHLBI NIH HHS/United States ; }, mesh = {*DNA Repeat Expansion ; *Genetic Diseases, Inborn/genetics/metabolism ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; }, abstract = {An emerging class of long noncoding RNAs (lncRNAs) function as decoy molecules that bind and sequester proteins thereby inhibiting their normal functions. Titration of proteins by lncRNAs has wide-ranging effects affecting nearly all steps in gene expression. While decoy lncRNAs play a role in normal physiology, RNAs expressed from alleles containing nucleotide repeat expansions can be pathogenic due to protein sequestration resulting in disruption of normal functions. This review focuses on commonalities between decoy lncRNAs that regulate gene expression by competitive inhibition of protein function through sequestration and specific examples of nucleotide repeat expansion disorders mediated by toxic RNA that sequesters RNA-binding proteins and impedes their normal functions. Understanding how noncoding RNAs compete with various RNA and DNA molecules for binding of regulatory proteins will provide insight into how similar mechanisms contribute to disease pathogenesis.}, }
@article {pmid28479534, year = {2017}, author = {Shibuya, K}, title = {[Cortical Motor Neuron Hyperexcitability and Motor Neuron Death in ALS: Dying Forward Hypothesis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {69}, number = {5}, pages = {565-569}, doi = {10.11477/mf.1416200783}, pmid = {28479534}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Cell Death/*physiology ; Humans ; Motor Cortex/*pathology ; Motor Neurons/*pathology ; Nerve Net/pathology ; Spinal Cord/*pathology ; }, abstract = {In the late 19th century, Charcot examined patients with amyotrophic lateral sclerosis (ALS) and concluded that the sclerosis in the lateral columns of the spinal cord induced the loss of neurons in the anterior horns. The reason for this remains unknown. In contrast, hyperexcitability of motor neurons is believed to be one of the pathogenetic factors for motor neuron death in ALS. In this article, I have reviewed the relationship between motor neuron hyperexcitability and motor neuron death and considered the mechanism of ALS pathogenesis.}, }
@article {pmid28479121, year = {2017}, author = {Danel-Brunaud, V and Touzet, L and Chevalier, L and Moreau, C and Devos, D and Vandoolaeghe, S and Defebvre, L}, title = {Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {300-307}, doi = {10.1016/j.neurol.2017.03.032}, pmid = {28479121}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Caregivers ; Ethics, Medical ; Humans ; Palliative Care/*ethics ; Quality of Life ; Terminal Care ; Withholding Treatment ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is not a curable disease, but it is treatable. By definition, much of the care provided to ALS patients is palliative, even though active life-sustaining strategies are available to prolong survival. Healthcare professionals must develop communication skills that help patients cope with the inexorable progression of the disease and the inevitability of death. Symptomatic treatments as well as respiratory insufficiency and nutritional life-sustaining therapies must be regularly evaluated as the disease progresses, without losing sight of the burden placed on the patient's non-professional caregivers. The decision-making process regarding tracheostomy with invasive ventilation (TIV) is of greater complexity. Providing full information is crucial. Several long interviews are necessary to explain, discuss and allow assimilation of the information. Also, physicians should be careful not to focus exclusively on the biomedical aspects of disease, as ALS patients generally welcome the opportunity to discuss end-of-life issues with their physicians. Psychological factors, education level and cognitive status (especially the level of executive dysfunction) have a major influence on their decisions. However, as many patients do not complete advance directives with regard to TIV, advance care planning may instead be suggested in anticipation of emergency interventions. This should be discussed by healthcare professionals and the patient, and based on the wishes of the patient and caregiver(s), and communicated to all healthcare professionals. Many healthcare professionals are involved in the management of an ALS patient: they include not only those at ALS centers who provide diagnosis, follow-up and treatment initiation (particularly for respiratory and nutritional care), but also the medical and social care networks involved in disability support and home care. Specialist palliative care teams can work in partnership with ALS centers early in the course of the disease, with the center coordinating information-sharing and collaborative discussions.}, }
@article {pmid28477850, year = {2017}, author = {Tard, C and Defebvre, L and Moreau, C and Devos, D and Danel-Brunaud, V}, title = {Clinical features of amyotrophic lateral sclerosis and their prognostic value.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {263-272}, doi = {10.1016/j.neurol.2017.03.029}, pmid = {28477850}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/physiopathology/therapy ; Disease Progression ; Humans ; Prognosis ; }, abstract = {In classic amyotrophic lateral sclerosis (ALS), the relative degree of impairment of cortical vs spinal motor neurons serving the different body regions is highly variable. This means that an accurate, systematic assessment of the patient's clinical presentation is essential for both the diagnosis and prognosis. The patient's phenotype, rate of disease progression, time of onset (if early) of respiratory failure and nutritional status all have prognostic value, and should be specified in the nosological classification of the disease.}, }
@article {pmid28477849, year = {2017}, author = {Luna, J and Logroscino, G and Couratier, P and Marin, B}, title = {Current issues in ALS epidemiology: Variation of ALS occurrence between populations and physical activity as a risk factor.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {244-253}, doi = {10.1016/j.neurol.2017.03.035}, pmid = {28477849}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/mortality/physiopathology ; *Exercise ; Humans ; Incidence ; Prevalence ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a fatal outcome. This review aims to report key epidemiological features of ALS in relation to the hypothesis of variation between populations, to summarize environmental hypothesis and to highlight current issues that deserve much considerations. Epidemiological ALS studies have shown a variation of incidence, mortality and prevalence between geographical areas and different populations. These data could support the notion that genetic factors, especially populations' ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. To date, there is no strong evidence to confirm an association between a particular environmental factor and ALS. Physical activity (PA) has been extensively evaluated. Recent studies support with the best evidence level that PA in general population is not a risk factor for ALS. However, further research is needed to clarify the association of PA in some occupations and some athletic activities. Epidemiological research based on multicenter international collaboration is essential to provide new data on ALS especially in some regions of the world that are to date poorly represented in the ALS literature.}, }
@article {pmid28477436, year = {2018}, author = {Slowik, A and Lammerding, L and Hoffmann, S and Beyer, C}, title = {Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen.}, journal = {Journal of neuroendocrinology}, volume = {30}, number = {2}, pages = {}, doi = {10.1111/jne.12482}, pmid = {28477436}, issn = {1365-2826}, mesh = {Animals ; Brain/*metabolism/pathology ; Cell Death/physiology ; Cytokines/metabolism ; Depressive Disorder/*metabolism/pathology ; Estrogens/*metabolism ; Humans ; Inflammasomes/*metabolism ; Stroke/*metabolism/pathology ; }, abstract = {Neuroinflammation is a devastating pathophysiological process that results in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. Irrespective of the cause, inflammasomes are key intracellular multiprotein signalling platforms that sense neuropathological conditions. The activation of inflammasomes leads to the auto-proteolytic cleavage of caspase-1, resulting in the proteolysis of the pro-inflammatory cytokines interleukin (IL)1β and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders. Sex steroids, in particular oestrogens, are well-described neuroprotective agents in the central nervous system. Oestrogens improve the functional outcome after ischaemia and traumatic brain injury, reduce neuronal death in Parkinson's and Alzheimer's disease, as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and the formation of radical oxygen species, and lessen the spread of oedema after damage. Moreover, oestrogens alleviate menopause-related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signalling affects anxiety- and depressive-like behaviour and that oestrogen ameliorates depression-like behaviour through the suppression of inflammasomes. In the present review, we highlight the most recent findings demonstrating that oestrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Furthermore, we aim to describe putative regulatory signalling pathways involved in the control of inflammasomes. Finally, we consider that psychiatric disorders such as depression also contain an inflammatory component that could be modulated by oestrogen.}, }
@article {pmid28474174, year = {2018}, author = {Banack, SA and Murch, SJ}, title = {Methods for the Chemical Analysis of β-N-Methylamino-L-A lanine: What Is Known and What Remains to Be Determined.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {184-191}, pmid = {28474174}, issn = {1476-3524}, mesh = {Amino Acids, Diamino/*analysis/chemistry ; Animals ; Chromatography, Liquid ; Cyanobacteria Toxins ; Neurotoxins/*analysis/chemistry ; Reproducibility of Results ; Tandem Mass Spectrometry ; }, abstract = {β-N-Methylamino-L-alanine (BMAA) is a non-canonical amino acid implicated as a cause for amyotrophic lateral sclerosis/parkinsonism dementia complex and potentially other neurodegenerative diseases. As interest in this molecule has increased, there has been a proliferation of methods along with a plethora of opinions as to the superiority of some methods over others. We analyzed the literature with reference to BMAA and its naturally occurring isomers, N-(2-aminoethyl) glycine (AEG) and 2,4 diaminobutyric acid (DAB). A comparison of methods, results, and critiques reveal that a single method has been approved by the AOAC but several different methods provide comparable BMAA quantification concentrations in similar tissues. We also describe a productive way to move forward as technology improves and changes.}, }
@article {pmid28473940, year = {2017}, author = {Caballero, B and Sherman, SJ and Falk, T}, title = {Insights into the Mechanisms Involved in Protective Effects of VEGF-B in Dopaminergic Neurons.}, journal = {Parkinson's disease}, volume = {2017}, number = {}, pages = {4263795}, pmid = {28473940}, issn = {2090-8083}, abstract = {Vascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, vascular endothelial growth factor-A (VEGF-A). Studies demonstrated that VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about the mechanism of action of VEGF-B in pathological processes. We explore its potential as a homeostatic protective factor that improves mitochondrial function in the setting of cardiovascular and neurological disease, with a specific focus on dopaminergic neurons in Parkinson's disease.}, }
@article {pmid28469644, year = {2017}, author = {Kinghorn, KJ and Asghari, AM and Castillo-Quan, JI}, title = {The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease.}, journal = {Neural regeneration research}, volume = {12}, number = {3}, pages = {380-384}, pmid = {28469644}, issn = {1673-5374}, abstract = {Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the GBA1 gene. There is an established association between GBA1 mutations and Parkinson's disease (PD), and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and GBA1-PD. Indeed we have recently shown in a Drosophila model lacking neuronal GCase, that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration. In addition, we demonstrated alterations in mechanistic target of rapamycin complex 1 (mTORC1) signaling and functional rescue of the lifespan, locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mTOR inhibitor rapamycin. Moreover, a number of other recent studies have shown autophagy-lysosomal system (ALS) dysfunction, with specific defects in both chaperone-mediated autophagy (CMA), as well as macroautophagy, in GD and GBA1-PD model systems. Lastly we discuss the possible therapeutic benefits of inhibiting mTOR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.}, }
@article {pmid28468939, year = {2017}, author = {Van Damme, P and Robberecht, W and Van Den Bosch, L}, title = {Modelling amyotrophic lateral sclerosis: progress and possibilities.}, journal = {Disease models &amp; mechanisms}, volume = {10}, number = {5}, pages = {537-549}, pmid = {28468939}, issn = {1754-8411}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; *Disease Models, Animal ; Genetic Predisposition to Disease ; Humans ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects the motor system and presents with progressive muscle weakness. Most patients survive for only 2-5 years after disease onset, often due to failure of the respiratory muscles. ALS is a familial disease in ∼10% of patients, with the remaining 90% developing sporadic ALS. Over the past decade, major advances have been made in our understanding of the genetics and neuropathology of ALS. To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in SOD1, TARDBP, FUS and C9orf72 Advances in our understanding of the genetic basis of ALS have led to the creation of different models of this disease. The molecular pathways that have emerged from these systems are more heterogeneous than previously anticipated, ranging from protein aggregation and defects in multiple key cellular processes in neurons, to dysfunction of surrounding non-neuronal cells. Here, we review the different model systems used to study ALS and discuss how they have contributed to our current knowledge of ALS disease mechanisms. A better understanding of emerging disease pathways, the detrimental effects of the various gene mutations and the causes underlying motor neuron denegation in sporadic ALS will accelerate progress in the development of novel treatments.}, }
@article {pmid28466273, year = {2018}, author = {Oberstadt, M and Claßen, J and Arendt, T and Holzer, M}, title = {TDP-43 and Cytoskeletal Proteins in ALS.}, journal = {Molecular neurobiology}, volume = {55}, number = {4}, pages = {3143-3151}, pmid = {28466273}, issn = {1559-1182}, support = {100111005//EU funds (EFRE; SAB)/ ; ALS Young Investigator Research Scholarship//Deutsche Gesellschaft f&#xfc;r Muskelkranke/ ; }, mesh = {Actin Cytoskeleton/metabolism ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cytoskeletal Proteins/*metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; Motor Neurons/metabolism ; Protein Binding ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease and is characterized by a degeneration of motor neurons. Motor neurons are particularly susceptible to selective and early degeneration because of their extended axon length and their dependency on the cytoskeleton for its stability, signaling, and axonal transport. The motor neuron cytoskeleton comprises actin filaments, neurofilaments like peripherin, and microtubules. The Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) forms characteristic cytoplasmic aggregates in motor neurons of ALS patients, and at least in part, the pathogenesis of ALS seems to be driven by toxic pTDP-43 aggregates in cytoplasm, which lead to a diminished axon formation and reduced axon length. Diminished axon formation and reduced axon length suggest an interaction of TDP-43 with the cytoskeleton of motor neurons. TDP-43 interacts with several cytoskeletal components, e.g., the microtubule-associated protein 1B (MAP1B) or the neurofilament light chain (NFL) through direct binding to its RNA. From a clinical perspective, cytoskeletal biomarkers like phosphorylated neurofilament heavy chain (pNFH) and NFL are already clinically used in ALS patients to predict survival, disease progression, and duration. Thus, in this review, we focus on the interaction of TDP-43 with the different cytoskeleton components such as actin filaments, neurofilaments, and microtubules as well as their associated proteins as one aspect in the complex pathogenesis of ALS.}, }
@article {pmid28461025, year = {2017}, author = {Lenglet, T and Camdessanché, JP}, title = {Amyotrophic lateral sclerosis or not: Keys for the diagnosis.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {280-287}, doi = {10.1016/j.neurol.2017.04.003}, pmid = {28461025}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Electrodiagnosis ; Evoked Potentials, Motor ; Humans ; Motor Neuron Disease/*diagnosis ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease (MND) which prognosis is poor. Early diagnosis permit to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electrodiagnostic (EDX) tests are the key tools to identify peripheral motor neuron involvement. Needle examination records abnormal activities at rest, and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. In the absence of diagnostic biomarker of ALS and among essential investigations of suspected MND, a careful clinical and neurophysiological work-up is essential to rule out the differential diagnosis.}, }
@article {pmid28461024, year = {2017}, author = {Soriani, MH and Desnuelle, C}, title = {Care management in amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {288-299}, doi = {10.1016/j.neurol.2017.03.031}, pmid = {28461024}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/psychology/rehabilitation/*therapy ; Humans ; Nutritional Support ; Palliative Care ; *Patient Care Management ; Patient Care Team ; Respiration, Artificial ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disease characterized by progressive weakness of voluntary muscles of movement as well as those for swallowing, speech and respiration. In the absence of curative treatment, care can improve quality of life, prolong survival, and support ALS patients and their families, and also help them to anticipate and prepare for the end of life. Multidisciplinary management in tertiary centers is recommended in close collaboration with general practitioners, home carers and a dedicated health network. Patients' follow-up deals mainly with motor impairment and physical disability, adaptation, nutrition and respiratory function. Involvement of palliative care as part of the multidisciplinary team management offers patients the possibility of discussing their end of life issues. This review summarizes the different aspects of ALS care, from delivering the diagnosis to the end of life, and the organization of its management.}, }
@article {pmid28459188, year = {2018}, author = {Hensel, N and Claus, P}, title = {The Actin Cytoskeleton in SMA and ALS: How Does It Contribute to Motoneuron Degeneration?.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {24}, number = {1}, pages = {54-72}, doi = {10.1177/1073858417705059}, pmid = {28459188}, issn = {1089-4098}, mesh = {Actin Cytoskeleton/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Humans ; Motor Neurons/*metabolism ; Muscular Atrophy, Spinal/genetics/*metabolism ; Nerve Degeneration/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neurodegenerative diseases with overlapping clinical phenotypes based on impaired motoneuron function. However, the pathomechanisms of both diseases are largely unknown, and it is still unclear whether they converge on the molecular level. SMA is a monogenic disease caused by low levels of functional Survival of Motoneuron (SMN) protein, whereas ALS involves multiple genes as well as environmental factors. Recent evidence argues for involvement of actin regulation as a causative and dysregulated process in both diseases. ALS-causing mutations in the actin-binding protein profilin-1 as well as the ability of the SMN protein to directly bind to profilins argue in favor of a common molecular mechanism involving the actin cytoskeleton. Profilins are major regulat ors of actin-dynamics being involved in multiple neuronal motility and transport processes as well as modulation of synaptic functions that are impaired in models of both motoneuron diseases. In this article, we review the current literature in SMA and ALS research with a focus on the actin cytoskeleton. We propose a common molecular mechanism that explains the degeneration of motoneurons for SMA and some cases of ALS.}, }
@article {pmid28457490, year = {2017}, author = {Grapperon, AM and Attarian, S}, title = {Disorders of motor neurons manifested by hyperactivity.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {345-351}, doi = {10.1016/j.neurol.2017.04.002}, pmid = {28457490}, issn = {0035-3787}, mesh = {Electromyography ; Fasciculation/etiology/physiopathology ; Humans ; Motor Neuron Disease/complications/*physiopathology ; *Motor Neurons ; Muscle Cramp/etiology/physiopathology ; }, abstract = {Neuronal and/or axonal hyperactivity and hyperexcitability is an important feature of motor neuron diseases. It results clinically in cramps and fasciculations. It is not specific to motor neuron diseases, and can occur in healthy subjects, as well as in various pathologies of the peripheral nervous system, including nerve hyperexcitability syndromes. Hyperexcitability plays an important and debated role in the pathophysiology of motor neuron diseases, especially in amyotrophic lateral sclerosis (ALS). The mechanisms causing hyperexcitability are not yet clearly identified. While most studies favor a distal axonal origin site of fasciculations, some of the fasciculations could be of cortical origin. The consequences of hyperexcitability are also discussed, whether it is rather protective or deleterious in the disease course. Fasciculations are depicted both clinically and using electromyogram, and more recently the interest of ultrasound has been highlighted. The importance of fasciculation potentials in the diagnosis of ALS led to changes in electrophysiological criteria at Awaji consensus conference. The contribution of these modifications to ALS diagnosis has been the subject of several studies. In clinical practice, it is necessary to distinguish fasciculations potentials of motor neuron disease from benign fasciculations. In most studies of fasciculation potentials in ALS, the presence of complex fasciculation potentials appears to be relevant for the diagnosis and the prognosis of the disease.}, }
@article {pmid28456633, year = {2017}, author = {Markovinovic, A and Cimbro, R and Ljutic, T and Kriz, J and Rogelj, B and Munitic, I}, title = {Optineurin in amyotrophic lateral sclerosis: Multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms.}, journal = {Progress in neurobiology}, volume = {154}, number = {}, pages = {1-20}, doi = {10.1016/j.pneurobio.2017.04.005}, pmid = {28456633}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Cell Cycle Proteins ; Humans ; Membrane Transport Proteins ; Mutation ; Neuroprotection/*physiology ; Transcription Factor TFIIIA/*genetics/*metabolism ; }, abstract = {When optineurin mutations showed up on the amyotrophic lateral sclerosis (ALS) landscape in 2010, they differed from most other ALS-causing genes. They seemed to act by loss- rather than gain-of-function, and it was unclear how a polyubiquitin-binding adaptor protein, which was proposed to regulate a variety of cellular functions including cell signaling and vesicle trafficking, could mediate neuroprotection. This review discusses the considerable progress that has been made since then. A large number of mutations in optineurin and optineurin-interacting proteins TANK-binding kinase (TBK1) and p62/SQSTM-1 have been found in the ALS patients, suggesting a common neuroprotective pathway. Moreover, functional studies of the ALS-causing optineurin mutations and the recently established optineurin ubiquitin-binding deficient and knockout mouse models helped identify three major mechanisms likely to mediate neuroprotection: regulation of autophagy, mitigation of (chronic) inflammatory signaling, and blockade of necroptosis. These three processes crosstalk, and require multiple levels of control, many of which can be mediated by optineurin. Based on the role of optineurin in multiple processes and the unexpected finding that targeted optineurin deletion in microglia and oligodendrocytes ultimately leads to the same phenotype of axonal degeneration despite different initial defects, we propose that the failure of the weakest link in the optineurin neuroprotective network is sufficient to disturb homeostasis and set-off the domino effect that could ultimately lead to neurodegeneration.}, }
@article {pmid28456383, year = {2017}, author = {Juntas Morales, R and Pageot, N and Taieb, G and Camu, W}, title = {Adult-onset spinal muscular atrophy: An update.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {308-319}, doi = {10.1016/j.neurol.2017.03.015}, pmid = {28456383}, issn = {0035-3787}, mesh = {Adult ; Age of Onset ; Humans ; Motor Neuron Disease/genetics/psychology/therapy ; Muscular Atrophy, Spinal/genetics/psychology/*therapy ; Survival of Motor Neuron 1 Protein/genetics ; }, abstract = {Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials. This report provides a general overview of the clinical features and pathophysiological mechanisms in adult-onset genetic SMA disorders in which the causative gene has been identified (SMN1-related SMA, Kennedy disease, CHCHD10, TRPV4, DYNC1H1 and BICD2). Sporadic lower motor neuron disease, also known as progressive muscular atrophy (PMA), is also discussed. The finding of TDP-43 aggregates in immunohistochemical studies of PMA strongly supports the idea that it is a phenotypic variant of amyotrophic lateral sclerosis (ALS).}, }
@article {pmid28455693, year = {2018}, author = {Crisafulli, SG and Brajkovic, S and Cipolat Mis, MS and Parente, V and Corti, S}, title = {Therapeutic Strategies Under Development Targeting Inflammatory Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {55}, number = {4}, pages = {2789-2813}, pmid = {28455693}, issn = {1559-1182}, support = {smallRNALS grant//ARISLA/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Cytokines/metabolism ; Drug Delivery Systems ; Drug Evaluation, Preclinical ; Humans ; Inflammation/*pathology ; *Molecular Targeted Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes. The neuroimmune activation is not only a physiological reaction to cell-autonomous death but is an active component of nonautonomous cell death. Such injury-perpetuating phenomenon is now proved to be a common mechanism in many human disorders characterized by progressive neurodegeneration. Therefore, it represents an interesting therapeutic target. To date, no single cell population has been proved to play a major role. The existing evidence points to a complex cross talk between resident immune cells and nonresident cells, like monocytes and T lymphocytes, and to a dysregulation in cytokine profile and in phenotype commitment. After a summary of the most important mechanisms involved in the inflammatory reaction in ALS, this review will focus on novel therapeutic tools that rely on tackling inflammation to improve motor function and survival. Herein, completed, ongoing, or planned clinical trials, which aim to modify the rapidly fatal course of this disease, are discussed. Anti-inflammatory compounds that are currently undergoing preclinical study and novel suitable molecular targets are also mentioned.}, }
@article {pmid28449883, year = {2017}, author = {Parodi, L and Fenu, S and Stevanin, G and Durr, A}, title = {Hereditary spastic paraplegia: More than an upper motor neuron disease.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {352-360}, doi = {10.1016/j.neurol.2017.03.034}, pmid = {28449883}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Heat-Shock Proteins/genetics ; Humans ; Motor Neuron Disease/genetics/*physiopathology ; Mutation ; Spastic Paraplegia, Hereditary/genetics/*physiopathology ; }, abstract = {Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs. The genetic diagnosis is further complicated by the fact that causative mutations of HSP can be inherited through all possible modes of transmission (autosomal-dominant and -recessive, X-linked, maternal), with some genes showing multiple inheritance patterns. The pathogenic mutations of SPGs primarily lead to progressive degeneration of the upper motor neurons (UMNs) comprising corticospinal tracts. However, it is possible to observe lower-limb muscle atrophy and fasciculations on clinical examination that are clear signs of lower motor neuron (LMN) involvement. The purpose of this review is to classify HSPs based on their degree of motor neuron involvement, distinguishing forms in which only UMNs are affected from those involving both UMN and LMN degeneration, and to describe their differential diagnosis from diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid28449882, year = {2017}, author = {Couratier, P and Corcia, P and Lautrette, G and Nicol, M and Marin, B}, title = {ALS and frontotemporal dementia belong to a common disease spectrum.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {273-279}, doi = {10.1016/j.neurol.2017.04.001}, pmid = {28449882}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/classification/epidemiology/genetics/*psychology ; Frontotemporal Dementia/classification/epidemiology/genetics/*psychology ; Humans ; }, abstract = {ALS is now understood to be a complex multisystem neurodegenerative disease because areas other than the motor cortices of the brain undergo degeneration. Frontotemporal dementia (FTD) may be associated with motor neuron disease, and the transactive response DNA-binding protein 43 (TDP-43) is a major pathological substrate underlying both diseases. The recent discovery of a gene that can cause both FTD, ALS and FTD-ALS, C9ORF72, has modified the way for considering these two pathologies. These findings would allow the development of potential biomarkers and therapeutic targets for these devastating diseases. This review summarizes the key points leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS.}, }
@article {pmid28449881, year = {2017}, author = {Corcia, P and Couratier, P and Blasco, H and Andres, CR and Beltran, S and Meininger, V and Vourc'h, P}, title = {Genetics of amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {254-262}, doi = {10.1016/j.neurol.2017.03.030}, pmid = {28449881}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein/genetics ; Humans ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by upper and lower motor neuron damage in the bulbar and spinal territories. Although the pathophysiology of ALS is still unknown, the involvement of genetic factors is no longer a subject of debate. Familial ALS (fALS) accounts for 10-20% of cases. Since the identification of the SOD1 gene, more than 20 genes have been described, of which four can explain >50% of familial cases. This review is an update focused on major aspects of the field of ALS genetics concerning both causative and susceptibility factors.}, }
@article {pmid28449871, year = {2017}, author = {Salvatori, I and Valle, C and Ferri, A and Carrì, MT}, title = {SIRT3 and mitochondrial metabolism in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {109}, number = {}, pages = {184-192}, doi = {10.1016/j.neuint.2017.04.012}, pmid = {28449871}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Humans ; Mice ; Mitochondria/*metabolism ; Muscle, Skeletal/metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Sirtuin 3/*biosynthesis/genetics ; }, abstract = {The NAD[+]-dependent deacetylase protein Sirtuin 3 (SIRT3) is emerging among the factors playing a key role in the regulation of mitochondrial function and in the prevention of oxidative stress. This deacetylase activates protein substrates directly involved in the production and detoxification of ROS, such as superoxide dismutase 2 and catalase, but also enzymes in the lipid beta-oxidation pathway. In this paper we review existing evidence on the role of SIRT3 in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington disease, including data from new experiments in a model for amyotrophic lateral sclerosis linked to mutations in superoxide dismutase 1. Specifically, we report that expression of the mitochondrial isoform of SIRT3 is altered in muscle from the G93A-SOD1 mice during progression of disease; this alteration influences mitochondrial metabolism, which may be relevant for the well known energetic alterations taking place in ALS patients. These data reinforce the concept that SIRT3 may be a relevant therapeutic target is ALS as well as in other neurodegenerative diseases.}, }
@article {pmid28448871, year = {2017}, author = {Caprnda, M and Kubatka, P and Gazdikova, K and Gasparova, I and Valentova, V and Stollarova, N and La Rocca, G and Kobyliak, N and Dragasek, J and Mozos, I and Prosecky, R and Siniscalco, D and Büsselberg, D and Rodrigo, L and Kruzliak, P}, title = {Immunomodulatory effects of stem cells: Therapeutic option for neurodegenerative disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {91}, number = {}, pages = {60-69}, doi = {10.1016/j.biopha.2017.04.034}, pmid = {28448871}, issn = {1950-6007}, mesh = {Animals ; Humans ; Immunologic Factors/*metabolism ; Models, Biological ; Neurodegenerative Diseases/*therapy ; *Stem Cell Transplantation ; Stem Cells/*metabolism ; }, abstract = {Stem cells have the capability of self-renewal and can differentiate into different cell types that might be used in regenerative medicine. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) currently lack effective treatments. Although stem cell therapy is still on the way from bench to bedside, we consider that it might provide new hope for patients suffering with neurodegenerative diseases. In this article, we will give an overview of recent studies on the potential therapeutic use of mesenchymal stem cells (MSCs), neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and perinatal stem cells to neurodegenerative disorders and we will describe their immunomodulatory mechanisms of action in specific therapeutic modalities.}, }
@article {pmid28446118, year = {2017}, author = {Dharmadasa, T and Henderson, RD and Talman, PS and Macdonell, RA and Mathers, S and Schultz, DW and Needham, M and Zoing, M and Vucic, S and Kiernan, MC}, title = {Motor neurone disease: progress and challenges.}, journal = {The Medical journal of Australia}, volume = {206}, number = {8}, pages = {357-362}, doi = {10.5694/mja16.01063}, pmid = {28446118}, issn = {1326-5377}, mesh = {Australia ; Evidence-Based Practice ; Genetic Testing ; Genetic Therapy ; Humans ; *Interdisciplinary Communication ; Motor Neuron Disease/*therapy ; Neuroprotection ; Noninvasive Ventilation ; Nutritional Support ; Patient Acceptance of Health Care ; Quality of Life ; Randomized Controlled Trials as Topic ; *Standard of Care ; Stem Cell Transplantation ; }, abstract = {Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.}, }
@article {pmid28443372, year = {2017}, author = {Garbuzova-Davis, S and Ehrhart, J and Sanberg, PR}, title = {Cord blood as a potential therapeutic for amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {17}, number = {7}, pages = {837-851}, doi = {10.1080/14712598.2017.1323862}, pmid = {28443372}, issn = {1744-7682}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology/*therapy ; Animals ; Cell Differentiation ; Cell- and Tissue-Based Therapy ; Clinical Trials as Topic ; Disease Models, Animal ; Fetal Blood/cytology/metabolism/*transplantation ; Humans ; Neural Cell Adhesion Molecule L1/genetics/metabolism ; Tissue Distribution ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord. Treatment options are limited due to the complexity of underlying disease factors. Cell therapy, using human umbilical cord blood (hUCB) cells may be a promising new treatment for ALS, mainly by providing a protective microenvironment for motor neuron survival. Areas covered: Composition, in vitro and in vivo differentiation of hUCB cells, and the advantages of cord blood as a source of transplant cells are discussed. A brief history of hUCB in treatment of an ALS animal model and the feasibility of these cells in therapy for ALS patients is provided. Current ALS clinical trials are also deliberated. Expert opinion: Among multiple advantages, hUCB cells' production of various anti-inflammatory/growth/trophic factors makes them an attractive cell source for ALS therapy. Biodistribution and optimal hUCB cell dose for transplantation have been determined in preclinical studies. Repeated intravenous cell doses during disease progression may be the best approach for cell-based ALS treatment. Accumulated evidence shows the efficacy of naïve or genetically modified MNC hUCB cells in the treatment of ALS and provide a superior basis for the development of clinical trials in the near future.}, }
@article {pmid28442996, year = {2017}, author = {Ciesiolka, A and Jazurek, M and Drazkowska, K and Krzyzosiak, WJ}, title = {Structural Characteristics of Simple RNA Repeats Associated with Disease and their Deleterious Protein Interactions.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {97}, pmid = {28442996}, issn = {1662-5102}, abstract = {Short Tandem Repeats (STRs) are frequent entities in many transcripts, however, in some cases, pathological events occur when a critical repeat length is reached. This phenomenon is observed in various neurological disorders, such as myotonic dystrophy type 1 (DM1), fragile X-associated tremor/ataxia syndrome, C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), and polyglutamine diseases, such as Huntington's disease (HD) and spinocerebellar ataxias (SCA). The pathological effects of these repeats are triggered by mutant RNA transcripts and/or encoded mutant proteins, which depend on the localization of the expanded repeats in non-coding or coding regions. A growing body of recent evidence revealed that the RNA structures formed by these mutant RNA repeat tracts exhibit toxic effects on cells. Therefore, in this review article, we present existing knowledge on the structural aspects of different RNA repeat tracts as revealed mainly using well-established biochemical and biophysical methods. Furthermore, in several cases, it was shown that these expanded RNA structures are potent traps for a variety of RNA-binding proteins and that the sequestration of these proteins from their normal intracellular environment causes alternative splicing aberration, inhibition of nuclear transport and export, or alteration of a microRNA biogenesis pathway. Therefore, in this review article, we also present the most studied examples of abnormal interactions that occur between mutant RNAs and their associated proteins.}, }
@article {pmid28434507, year = {2017}, author = {Verschueren, A}, title = {Motor neuropathies and lower motor neuron syndromes.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {320-325}, doi = {10.1016/j.neurol.2017.03.018}, pmid = {28434507}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Motor Neuron Disease/immunology/pathology/*physiopathology ; Muscular Atrophy, Spinal/physiopathology ; Peroneal Neuropathies/immunology/pathology/*physiopathology ; }, abstract = {Motor or motor-predominant neuropathies may arise from disease processes affecting the motor axon and/or its surrounding myelin. Lower motor neuron syndrome (LMNS) arises from a disease process affecting the spinal motor neuron itself. The term LMNS is more generally used, rather than motor neuronopathy, although both entities are clinically similar. Common features are muscle weakness (distal or proximal) with atrophy and hyporeflexia, but no sensory involvement. They can be acquired or hereditary. Immune-mediated neuropathies (multifocal motor neuropathy, motor-predominant chronic inflammatory demyelinating polyneuropathy) are important to identify, as effective treatments are available. Other acquired neuropathies, such as infectious, paraneoplastic and radiation-induced neuropathies are also well known. Focal LMNS is an amyotrophic lateral sclerosis (ALS)-mimicking syndrome especially affecting young adults. The main hereditary LMNSs in adulthood are Kennedy's disease, late-onset spinal muscular atrophy and distal hereditary motor neuropathies. Motor neuropathies and LMNS are all clinical entities that should be better known, despite being rare diseases. They can sometimes be difficult to differentially diagnose from other diseases, particularly from the more frequent ALS in its pure LMN form. Nevertheless, correct identification of these syndromes is important because their treatment and prognoses are definitely different.}, }
@article {pmid28434044, year = {2017}, author = {Pagliarini, V and La Rosa, P and Sette, C}, title = {Faulty RNA splicing: consequences and therapeutic opportunities in brain and muscle disorders.}, journal = {Human genetics}, volume = {136}, number = {9}, pages = {1215-1235}, pmid = {28434044}, issn = {1432-1203}, support = {#12-0150//Association for International Cancer Research (AICR)/International ; #14581//Associazione Italiana Ricerca sul Cancro (AIRC)/International ; #18790//Associazione Italiana Ricerca sul Cancro (AIRC)/International ; GGP14095//Fondazione Telethon (IT)/International ; }, mesh = {Animals ; *Brain Diseases/genetics/metabolism ; Humans ; *Muscular Diseases/genetics/metabolism ; *RNA Splicing ; }, abstract = {Alternative splicing is a powerful mechanism that largely expands the coding potential of eukaryotic genomes. Indeed, its complex and flexible regulation is exploited by cells to adapt to various environmental conditions, through production of protein variants displaying different functions. Such flexibility, however, is accompanied by high risk of errors, and dysregulation of splicing is now recognized as an important factor in human diseases. Notably, the RNA-based nature of splicing, which involves high specificity through base pair recognition, offers a remarkable therapeutic opportunity by allowing design of tools with elevated target selectivity. Herein, we illustrate examples of how defective splicing, obtained by mutations affecting multiple layers of regulation, can result in pathology. In particular, we focus on splicing-related defects occurring in brain and muscle diseases and describe therapeutic approaches currently available for these pathologies.}, }
@article {pmid28428907, year = {2017}, author = {Tarolli, CG and Chesire, AM and Biglan, KM}, title = {Palliative Care in Huntington Disease: Personal Reflections and a Review of the Literature.}, journal = {Tremor and other hyperkinetic movements (New York, N.Y.)}, volume = {7}, number = {}, pages = {454}, pmid = {28428907}, issn = {2160-8288}, abstract = {BACKGROUND: Huntington disease is a fatal, autosomal dominant, neurodegenerative disorder manifest by the triad of a movement disorder, behavioral disturbances, and dementia. At present, no curative or disease modifying therapies exist for the condition and current treatments are symptomatic. Palliative care is an approach to care that focuses on symptom relief, patient and caregiver support, and end of life care. There is increasing evidence of the benefit of palliative care throughout the course of neurodegenerative conditions including Parkinson disease and amyotrophic lateral sclerosis. However, beyond its application at the end of life, little is known about the role of palliative care in Huntington disease.<br><br>METHODS: In this article, we discuss what is known about palliative care in Huntington disease, specifically related to early disease burden, caregiver burnout, advance care planning, and end of life care.<br><br>RESULTS: We provide a review of the current literature and discuss our own care practices.<br><br>DISCUSSION: We conclude by discussing questions that remain unanswered and positing ideas for future work in the field.}, }
@article {pmid28421535, year = {2018}, author = {Rinchetti, P and Rizzuti, M and Faravelli, I and Corti, S}, title = {MicroRNA Metabolism and Dysregulation in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {55}, number = {3}, pages = {2617-2630}, pmid = {28421535}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Humans ; MicroRNAs/genetics/*metabolism ; Motor Neurons/*metabolism/pathology ; Mutation/physiology ; }, abstract = {MicroRNAs (miRNAs) are a subset of endogenous, small, non-coding RNA molecules involved in the post-transcriptional regulation of eukaryotic gene expression. Dysregulation in miRNA-related pathways in the central nervous system (CNS) is associated with severe neuronal injury and cell death, which can lead to the development of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). ALS is a fatal adult onset disease characterized by the selective loss of upper and lower motor neurons. While the pathogenesis of ALS is still largely unknown, familial ALS forms linked to TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) gene mutations, as well as sporadic forms, display changes in several steps of RNA metabolism, including miRNA processing. Here, we review the current knowledge about miRNA metabolism and biological functions and their crucial role in ALS pathogenesis with an in-depth analysis on different pathways. A more precise understanding of miRNA involvement in ALS could be useful not only to elucidate their role in the disease etiopathogenesis but also to investigate their potential as disease biomarkers and novel therapeutic targets.}, }
@article {pmid28420986, year = {2017}, author = {Roser, AE and Tönges, L and Lingor, P}, title = {Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {9}, number = {}, pages = {94}, pmid = {28420986}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are characterized by the progressive degeneration of neurons in the central and peripheral nervous system (CNS, PNS), resulting in a reduced innervation of target structures and a loss of function. A shared characteristic of many neurodegenerative diseases is the infiltration of microglial cells into affected brain regions. During early disease stages microglial cells often display a rather neuroprotective phenotype, but switch to a more pro-inflammatory neurotoxic phenotype in later stages of the disease, contributing to the neurodegeneration. Activation of the Rho kinase (ROCK) pathway appears to be instrumental for the modulation of the microglial phenotype: increased ROCK activity in microglia mediates mechanisms of the inflammatory response and is associated with improved motility, increased production of reactive oxygen species (ROS) and release of inflammatory cytokines. Recently, several studies suggested inhibition of ROCK signaling as a promising treatment option for neurodegenerative diseases. In this review article, we discuss the contribution of microglial activity and phenotype switch to the pathophysiology of Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases without disease-modifying treatment options. Furthermore, we describe how ROCK inhibition can influence the microglial phenotype in disease models and explore ROCK inhibition as a future treatment option for PD and ALS.}, }
@article {pmid28420962, year = {2017}, author = {Maziuk, B and Ballance, HI and Wolozin, B}, title = {Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {89}, pmid = {28420962}, issn = {1662-5099}, support = {R01 AG050471/AG/NIA NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; }, abstract = {The unique biology of RNA binding proteins is altering our view of the genesis of protein misfolding diseases. These proteins use aggregation of low complexity domains (LCDs) as a means to regulate the localization and utilization of RNA by forming RNA granules, such as stress granules, transport granules and P-bodies. The reliance on reversible aggregation as a mechanism for biological regulation renders this family of proteins highly vulnerable to promoting diseases of protein misfolding. Mutations in RNA binding proteins are associated with many neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). The biology of RNA binding proteins also extends to microtubule associated protein tau. Tau is normally an axonal protein, but in stress it translocates to the somatodendritic arbor where it takes on a new function promoting formation of stress granules. The interaction of tau with stress granules also promotes tau aggregation, accelerating formation of the tau pathology that we associate with diseases such as Alzheimer's disease (AD).}, }
@article {pmid28412918, year = {2017}, author = {Mannucci, C and Navarra, M and Calapai, F and Spagnolo, EV and Busardò, FP and Cas, RD and Ippolito, FM and Calapai, G}, title = {Neurological Aspects of Medical Use of Cannabidiol.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {5}, pages = {541-553}, doi = {10.2174/1871527316666170413114210}, pmid = {28412918}, issn = {1996-3181}, mesh = {Animals ; Cannabidiol/chemistry/pharmacology/*therapeutic use ; Central Nervous System Diseases/*drug therapy ; Humans ; Neuroprotective Agents/chemistry/pharmacology/*therapeutic use ; }, abstract = {BACKGROUND: Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activities and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.<br><br>OBJECTIVE: The aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.<br><br>METHOD: Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclusion of studies on neuropsychiatric disorders.<br><br>RESULTS: Laboratory and clinical studies on the potential role of CBD in Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.<br><br>CONCLUSION: Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.}, }
@article {pmid28411118, year = {2017}, author = {Brady, ST and Morfini, GA}, title = {Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {105}, number = {}, pages = {273-282}, pmid = {28411118}, issn = {1095-953X}, support = {R01 NS023320/NS/NINDS NIH HHS/United States ; R01 NS082730/NS/NINDS NIH HHS/United States ; R01 NS041170/NS/NINDS NIH HHS/United States ; R21 NS096642/NS/NINDS NIH HHS/United States ; R01 NS023868/NS/NINDS NIH HHS/United States ; R01 NS066942/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport/*physiology ; Humans ; Microtubule-Associated Proteins/*metabolism ; Molecular Motor Proteins/*metabolism ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; Signal Transduction/physiology ; }, abstract = {Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a "dying back" pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.}, }
@article {pmid28410962, year = {2017}, author = {Krewski, D and Barakat-Haddad, C and Donnan, J and Martino, R and Pringsheim, T and Tremlett, H and van Lieshout, P and Walsh, SJ and Birkett, NJ and Gomes, J and Little, J and Bowen, S and Candundo, H and Chao, TK and Collins, K and Crispo, JAG and Duggan, T and El Sherif, R and Farhat, N and Fortin, Y and Gaskin, J and Gupta, P and Hersi, M and Hu, J and Irvine, B and Jahanfar, S and MacDonald, D and McKay, K and Morrissey, A and Quach, P and Rashid, R and Shin, S and Sikora, L and Tkachuk, S and Taher, MK and Wang, MD and Darshan, S and Cashman, NR}, title = {Determinants of neurological disease: Synthesis of systematic reviews.}, journal = {Neurotoxicology}, volume = {61}, number = {}, pages = {266-289}, doi = {10.1016/j.neuro.2017.04.002}, pmid = {28410962}, issn = {1872-9711}, mesh = {Disease Progression ; Humans ; Nervous System Diseases/epidemiology/*etiology/genetics ; Risk Factors ; }, abstract = {Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally.}, }
@article {pmid28410876, year = {2017}, author = {Lefaucheur, JP and Chalah, MA and Mhalla, A and Palm, U and Ayache, SS and Mylius, V}, title = {The treatment of fatigue by non-invasive brain stimulation.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {47}, number = {2}, pages = {173-184}, doi = {10.1016/j.neucli.2017.03.003}, pmid = {28410876}, issn = {1769-7131}, mesh = {Brain/physiology/*surgery ; Fatigue/complications/*therapy ; Humans ; Multiple Sclerosis/*complications/therapy ; *Pain Management ; *Transcranial Direct Current Stimulation/methods ; Treatment Outcome ; }, abstract = {The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson's disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.}, }
@article {pmid28409282, year = {2017}, author = {Nijssen, J and Comley, LH and Hedlund, E}, title = {Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {133}, number = {6}, pages = {863-885}, pmid = {28409282}, issn = {1432-0533}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Humans ; Motor Neurons/*physiology ; }, abstract = {In the fatal disease-amyotrophic lateral sclerosis (ALS)-upper (corticospinal) motor neurons (MNs) and lower somatic MNs, which innervate voluntary muscles, degenerate. Importantly, certain lower MN subgroups are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expressed. Ocular MNs (OMNs), including the oculomotor, trochlear and abducens nuclei (CNIII, IV and VI), which regulate eye movement, persist throughout the disease. Consequently, eye-tracking devices are used to enable paralysed ALS patients (who can no longer speak) to communicate. Additionally, there is a gradient of vulnerability among spinal MNs. Those innervating fast-twitch muscle are most severely affected and degenerate first. MNs innervating slow-twitch muscle can compensate temporarily for the loss of their neighbours by re-innervating denervated muscle until later in disease these too degenerate. The resistant OMNs and the associated extraocular muscles (EOMs) are anatomically and functionally very different from other motor units. The EOMs have a unique set of myosin heavy chains, placing them outside the classical characterization spectrum of all skeletal muscle. Moreover, EOMs have multiple neuromuscular innervation sites per single myofibre. Spinal fast and slow motor units show differences in their dendritic arborisations and the number of myofibres they innervate. These motor units also differ in their functionality and excitability. Identifying the molecular basis of cell-intrinsic pathways that are differentially activated between resistant and vulnerable MNs could reveal mechanisms of selective neuronal resistance, degeneration and regeneration and lead to therapies preventing progressive MN loss in ALS. Illustrating this, overexpression of OMN-enriched genes in spinal MNs, as well as suppression of fast spinal MN-enriched genes can increase the lifespan of ALS mice. Here, we discuss the pattern of lower MN degeneration in ALS and review the current literature on OMN resistance in ALS and differential spinal MN vulnerability. We also reflect upon the non-cell autonomous components that are involved in lower MN degeneration in ALS.}, }
@article {pmid28408982, year = {2017}, author = {Martin, S and Al Khleifat, A and Al-Chalabi, A}, title = {What causes amyotrophic lateral sclerosis?.}, journal = {F1000Research}, volume = {6}, number = {}, pages = {371}, pmid = {28408982}, issn = {2046-1402}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis.}, }
@article {pmid28408478, year = {2017}, author = {Dahal, A and Hinton, SD}, title = {Antagonistic roles for STYX pseudophosphatases in neurite outgrowth.}, journal = {Biochemical Society transactions}, volume = {45}, number = {2}, pages = {381-387}, doi = {10.1042/BST20160273}, pmid = {28408478}, issn = {1470-8752}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Animals ; Cell Differentiation ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase Phosphatases/*metabolism ; Mitogen-Activated Protein Kinases/metabolism ; *Neuronal Outgrowth ; Neurons/*metabolism ; Nuclear Proteins/metabolism ; }, abstract = {Mitogen-activated protein kinases (MAPKs) are essential players in important neuronal signaling pathways including neuronal development, plasticity, survival, learning, and memory. The inactivation of MAPKs is tightly controlled by MAPK phosphatases (MKPs), which also are important regulators of these neuronal processes. Considering that MAPKs and MKPs are major players in neuronal signaling, it follows that their misregulation is pivotal in neurodegenerative diseases such as Alzheimer's, Huntington's, Parkinson's, and amyotrophic lateral sclerosis. In contrast, the actions of their noncatalytic homologs, or pseudoenzymes, have received minimal attention as important regulators in neuronal signaling pathways and relevant diseases. There is compelling evidence, however, that pseudophosphatases, such as STYX (phospho-serine-threonine/tyrosine-binding protein) and MAPK-STYX (MK-STYX), are integral signaling molecules in regulating pathways involved in neuronal developmental processes such as neurite outgrowth. Here, we discuss how the dynamics of MK-STYX in the stress response pathway imply that this unique member of the MKP subfamily has the potential to have a major role in neuronal signaling. We further compare the actions of STYX in preventing neurite-like outgrowths and MK-STYX in inducing neurite outgrowths. The roles of these pseudophosphatases in neurite outgrowth highlight their emergence as important candidates to investigate in neurodegenerative disorders and diseases.}, }
@article {pmid28408340, year = {2017}, author = {Pernet, V}, title = {Nogo-A in the visual system development and in ocular diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1863}, number = {6}, pages = {1300-1311}, doi = {10.1016/j.bbadis.2017.04.008}, pmid = {28408340}, issn = {0925-4439}, mesh = {Animals ; Axons/*metabolism/pathology ; Humans ; Mice ; Nogo Proteins/*metabolism ; Optic Nerve Diseases/embryology/*metabolism/pathology ; Visual Cortex/embryology/*metabolism/pathology ; }, abstract = {Nogo-A is a potent myelin-associated inhibitor for neuronal growth and plasticity in the central nervous system (CNS). Its effects are mediated by the activation of specific receptors that intracellularly control cytoskeleton rearrangements, protein synthesis and gene expression. Moreover, Nogo-A has been involved in the development of the visual system and in a variety of neurodegenerative diseases and injury processes that can alter its function. For example, Nogo-A was shown to influence optic nerve myelinogenesis, the formation and maturation of retinal axon projections, and retinal angiogenesis. In adult animals, the inactivation of Nogo-A exerted remarkable effects on visual plasticity. Relieving Nogo-A-induced inhibition increased axonal sprouting after optic nerve lesion and axonal rewiring in the visual cortex of intact adult mice. This review aims at presenting our current knowledge on the role of Nogo-A in the visual system and to discuss how its therapeutic targeting may promote visual improvement in ophthalmic diseases.}, }
@article {pmid28406335, year = {2017}, author = {Sawada, H}, title = {Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on pharmacotherapy}, volume = {18}, number = {7}, pages = {735-738}, doi = {10.1080/14656566.2017.1319937}, pmid = {28406335}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Disease Models, Animal ; Edaravone ; Free Radical Scavengers/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Time Factors ; Treatment Outcome ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid. Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed. In all trials, the primary outcome measure was the changes in scores on the revised ALS functional rating scale (ALSFRS-R) to evaluate motor function of patients. Expert opinion: The phase II open label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the cerebrospinal fluid. One of the two randomized controlled trials showed beneficial effects in ALSFRS-R, although the differences were not significant. The last trial demonstrated that edaravone provided significant efficacy in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted. Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Therefore, combination therapy with edaravone and riluzole should be considered earlier.}, }
@article {pmid28402959, year = {2017}, author = {Zhang, CC and Zhu, JX and Wan, Y and Tan, L and Wang, HF and Yu, JT and Tan, L}, title = {Meta-analysis of the association between variants in MAPT and neurodegenerative diseases.}, journal = {Oncotarget}, volume = {8}, number = {27}, pages = {44994-45007}, pmid = {28402959}, issn = {1949-2553}, mesh = {Alzheimer Disease/genetics ; Gene Frequency ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; *Genetic Variation ; Haplotypes ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics ; Odds Ratio ; Polymorphism, Single Nucleotide ; tau Proteins/*genetics ; }, abstract = {Microtubule-associated protein tau (MAPT) gene is compelling among the susceptibility genes of neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Our meta-analysis aimed to find the association between MAPT and the risk of these diseases. Published literatures were retrieved from MEDLINE and other databases, and 82 case-control studies were recruited. Six haplotype tagging single-nucleotide polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9 and rs7521) and haplotypes (H2 and H1c) were significantly associated with the above diseases. The odds ratios (ORs) and 95 % confidence intervals (CIs) were evaluated by comparison in minor and major allele frequency using the R software. This study demonstrated that different variants in MAPT were associated with AD (rs2471738: OR= 1.04, 95%CI = 1.00 - 1.09; H2: OR = 0.94, 95% CI = 0.91 - 0.97), PD (H2: OR = 0.76, 95% CI = 0.74 - 0.79), PSP (rs242557: OR = 1. 96, 95% CI = 1. 71 - 2.25; rs2471738: OR = 1. 85, 95% CI = 1. 48 - 2.31; H2: OR = 0.20, 95% CI = 0.18 - 0.23), CBD (rs242557: OR = 2.51, 95%CI = 1. 66 -3.78; rs2471738: OR = 2.07, 95%CI = 1. 32 -3.23; H2: OR = OR = 0.30, 95% CI = 0.23 - 0.41) and ALS (H2: OR = 0.92, 95% CI = 0.86 - 0.98) instead of FTD (H2: OR = 1.02, 95% CI = 0.78 - 1.32). In conclusion, MAPT is associated with risk of neurodegenerative diseases, suggesting crucial roles of tau in neurodegenerative processes.}, }
@article {pmid28401350, year = {2017}, author = {Wright, EC and Connolly, P and Vella, M and Moug, S}, title = {Peritoneal fluid biomarkers in the detection of colorectal anastomotic leaks: a systematic review.}, journal = {International journal of colorectal disease}, volume = {32}, number = {7}, pages = {935-945}, pmid = {28401350}, issn = {1432-1262}, mesh = {Anastomotic Leak/*etiology/*metabolism ; Ascitic Fluid/*metabolism ; Biomarkers, Tumor/*metabolism ; Colorectal Neoplasms/*complications/*metabolism ; Cytokines/metabolism ; Humans ; Inflammation/pathology ; Ischemia/pathology ; }, abstract = {PURPOSE: Anastomotic leak (AL) in colorectal surgery leads to significant morbidity, mortality and poorer oncological outcomes. Diagnosis of AL is frequently delayed as current methods of detection are not 100% sensitive or specific. 'Biomarkers', such as cytokines and markers of ischaemia, from the milieu of the anastomosis may aid early detection. This paper aims to review the evidence for their role in AL detection, allowing identification of targets for future research.<br><br>METHODS: A systematic review was performed using PubMed, MEDLINE and Cochrane Library databases. Papers concerning detection or prediction of AL with biomarkers were identified. References within the papers were used to identify further relevant articles.<br><br>RESULTS: Research has taken place in small cohorts with varying definitions of AL. Lactate has consistently been shown to be elevated in patients with intra-abdominal complications and ALs. pH on post-operative day 3 showed excellent specificity. Despite mixed results, a meta-analysis found that the cytokines tumour necrosis factor-&#x3b1; and interleukin-6 were elevated early in AL. Detection of bacteria in drain fluid by RT-PCR has good specificity but a high rate of false positives.<br><br>CONCLUSIONS: Peritoneal cytokines, lactate and pH have the potential to identify AL early. The consistency of the results for lactate and pH, alongside the fact that they are easy, quick and inexpensive to test, makes them the most attractive targets. Studies in larger cohorts with standardized definitions of AL are required to clarify their usefulness. Emerging biosensor technology may facilitate the development of small, low-cost and degradable intra-abdominal devices to measure peritoneal fluid biomarkers.}, }
@article {pmid28401333, year = {2017}, author = {Spires-Jones, TL and Attems, J and Thal, DR}, title = {Interactions of pathological proteins in neurodegenerative diseases.}, journal = {Acta neuropathologica}, volume = {134}, number = {2}, pages = {187-205}, pmid = {28401333}, issn = {1432-0533}, support = {/WT_/Wellcome Trust/United Kingdom ; G0400074/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging/metabolism/pathology ; DNA-Binding Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; alpha-Synuclein/*metabolism ; tau Proteins/*metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations. They also occur in non-diseased individuals and can co-exist in the same brain without or with a clinical picture of a distinct dementing or movement disorder. In this review, we discuss the co-existence of these pathologies and potential additive effects in the human brain as well as related functional findings on cross-seeding and molecular interactions between these aggregates/proteins. We conclude that there is evidence for interactions at the molecular level as well as for additive effects on brain damage by multiple pathologies occurring in different functionally important neurons. Based upon this information, we hypothesize a cascade of events that may explain general mechanisms in the development of neurodegenerative disorders: (1) distinct lesions are a prerequisite for the development of a distinct disease (e.g., primary age-related tauopathy for AD), (2) disease-specific pathogenic events further trigger the development of a specific disease (e.g., Aβ aggregation in AD that exaggerate further Aβ and AD-related τ pathology), (3) the symptomatic disease manifests, and (4) neurodegenerative co-pathologies may be either purely coincidental or (more likely) have influence on the disease development and/or its clinical presentation.}, }
@article {pmid28400790, year = {2017}, author = {Mathis, S and Couratier, P and Julian, A and Corcia, P and Le Masson, G}, title = {Current view and perspectives in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {12}, number = {2}, pages = {181-184}, pmid = {28400790}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.}, }
@article {pmid28397197, year = {2017}, author = {Ruffoli, R and Biagioni, F and Busceti, CL and Gaglione, A and Ryskalin, L and Gambardella, S and Frati, A and Fornai, F}, title = {Neurons other than motor neurons in motor neuron disease.}, journal = {Histology and histopathology}, volume = {32}, number = {11}, pages = {1115-1123}, doi = {10.14670/HH-11-895}, pmid = {28397197}, issn = {1699-5848}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Humans ; Motor Neuron Disease/pathology ; Motor Neurons/*pathology ; Nerve Degeneration/*pathology ; Neurons/*pathology ; Spinal Cord/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.}, }
@article {pmid28397096, year = {2017}, author = {Bailey, JM and Colón-Rodríguez, A and Atchison, WD}, title = {Evaluating a Gene-Environment Interaction in Amyotrophic Lateral Sclerosis: Methylmercury Exposure and Mutated SOD1.}, journal = {Current environmental health reports}, volume = {4}, number = {2}, pages = {200-207}, pmid = {28397096}, issn = {2196-5412}, support = {R01 ES024064/ES/NIEHS NIH HHS/United States ; T32 ES007255/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*physiopathology ; Calcium ; Free Radical Scavengers ; *Gene-Environment Interaction ; Glutamic Acid ; Humans ; Methylmercury Compounds/*toxicity ; Receptors, AMPA ; Superoxide Dismutase/*toxicity ; }, abstract = {PURPOSE OF REVIEW: Gene-environment (GxE) interactions likely contribute to numerous diseases, but are often difficult to model in the laboratory. Such interactions have been widely hypothesized for amyotrophic lateral sclerosis (ALS); recent controlled laboratory studies are discussed here and hypotheses related to possible mechanisms of action are offered. Using methylmercury exposure and mutated SOD1 to model the impacts of such an interaction, we interpret evidence about their respective mechanisms of toxicity to interrogate the possibility of additive (or synergistic) effects when combined.<br><br>RECENT FINDINGS: Recent work has converged on mechanisms of calcium-mediated glutamate excitotoxicity as a likely contributor in one model of a gene-environment interaction affecting the onset and progression of ALS-like phenotype. The current experimental literature on mechanisms of metal-induced neuronal injury and their relevant interactions with genetic contributions in ALS is sparse, but we describe those studies here and offer several integrative hypotheses about the likely mechanisms involved.}, }
@article {pmid28396624, year = {2017}, author = {Alberti, S and Mateju, D and Mediani, L and Carra, S}, title = {Granulostasis: Protein Quality Control of RNP Granules.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {84}, pmid = {28396624}, issn = {1662-5099}, abstract = {Ribonucleoprotein (RNP) granules transport, store, or degrade messenger RNAs, thereby indirectly regulating protein synthesis. Normally, RNP granules are highly dynamic compartments. However, because of aging or severe environmental stress, RNP granules, in particular stress granules (SGs), convert into solid, aggregate-like inclusions. There is increasing evidence that such RNA-protein inclusions are associated with several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's disease (AD). Thus, understanding what triggers the conversion of RNP granules into aggregates and identifying the cellular players that control RNP granules will be critical to develop treatments for these diseases. In this review article, we discuss recent insight into RNP and SG formation. More specifically, we examine the evidence for liquid-liquid phase separation (LLPS) as an organizing principle of RNP granules and the role of aggregation-prone RNA-binding proteins (RBPs) in this process. We further discuss recent findings that liquid-like SGs can sequester misfolded proteins, which promote an aberrant conversion of liquid SGs into solid aggregates. Importantly, very recent studies show that a specific protein quality control (PQC) process prevents the accumulation of misfolding-prone proteins in SGs and, by doing so, maintains the dynamic state of SGs. This quality control process has been referred to as granulostasis and it relies on the specific action of the HSPB8-BAG3-HSP70 complex. Additional players such as p97/valosin containing protein (VCP) and other molecular chaperones (e.g., HSPB1) participate, directly or indirectly, in granulostasis, and ensure the timely elimination of defective ribosomal products and other misfolded proteins from SGs. Finally, we discuss recent findings that, in the stress recovery phase, SGs are preferentially disassembled with the assistance of chaperones, and we discuss evidence for a back-up system that targets aberrant SGs to the aggresome for autophagy-mediated clearance. Altogether the findings discussed here provide evidence for an intricate network of interactions between RNP granules and various components of the PQC machinery. Molecular chaperones in particular are emerging as key players that control the composition and dynamics of RNP granules, which may be important to protect against age-related diseases.}, }
@article {pmid28389532, year = {2017}, author = {Harrison, AF and Shorter, J}, title = {RNA-binding proteins with prion-like domains in health and disease.}, journal = {The Biochemical journal}, volume = {474}, number = {8}, pages = {1417-1438}, pmid = {28389532}, issn = {1470-8728}, support = {UC2 HL103010/HL/NHLBI NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; RC2 HL102924/HL/NHLBI NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; RC2 HL103010/HL/NHLBI NIH HHS/United States ; RC2 HL102923/HL/NHLBI NIH HHS/United States ; UC2 HL102926/HL/NHLBI NIH HHS/United States ; R21 NS090205/NS/NINDS NIH HHS/United States ; RC2 HL102926/HL/NHLBI NIH HHS/United States ; UC2 HL102923/HL/NHLBI NIH HHS/United States ; UC2 HL102924/HL/NHLBI NIH HHS/United States ; F31 NS087676/NS/NINDS NIH HHS/United States ; RC2 HL102925/HL/NHLBI NIH HHS/United States ; UC2 HL102925/HL/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Calmodulin-Binding Proteins/chemistry/genetics/metabolism ; Cytoplasmic Granules ; DNA-Binding Proteins/chemistry/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism/pathology ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/genetics/metabolism ; Humans ; Mutation ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Prion Proteins/chemistry/genetics/*metabolism ; Protein Domains ; Proteostasis Deficiencies/genetics/*metabolism/pathology ; RNA-Binding Protein EWS ; RNA-Binding Protein FUS/chemistry/genetics/metabolism ; RNA-Binding Proteins/chemistry/genetics/*metabolism ; TATA-Binding Protein Associated Factors/chemistry/genetics/metabolism ; TDP-43 Proteinopathies/genetics/metabolism/pathology ; }, abstract = {Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.}, }
@article {pmid28389271, year = {2017}, author = {Erpapazoglou, Z and Mouton-Liger, F and Corti, O}, title = {From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration.}, journal = {Neurochemistry international}, volume = {109}, number = {}, pages = {171-183}, doi = {10.1016/j.neuint.2017.03.021}, pmid = {28389271}, issn = {1872-9754}, mesh = {Animals ; Endoplasmic Reticulum/*metabolism/pathology ; Endoplasmic Reticulum Stress/physiology ; Humans ; Mitochondria/*metabolism/pathology ; Mitochondrial Dynamics/physiology ; Mitochondrial Membranes/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Over the last years, contact sites between the endoplasmic reticulum (ER) and mitochondria have attracted great attention in the study of cell homeostasis and dysfunction, especially in the context of neurodegenerative disorders. This is largely due to the critical involvement of this subcellular compartment in a plethora of vital cellular functions: Ca[2+] homeostasis, mitochondrial dynamics, transport, bioenergetics and turnover, ER stress, apoptotic signaling and inflammation. An increasing number of disease-associated proteins have been reported to physically associate with the ER-mitochondria interface, and cause structural and/or functional perturbations of this compartment. In the present review, we summarize current knowledge about the architecture and functions of the ER-mitochondria contact sites, and the consequences of their alteration in different neurodegenerative disorders. Special emphasis is placed on the caveats and difficulties in defining the nature and origin of the highlighted defects in ER-mitochondria communication, and their exact contribution to the neurodegenerative process.}, }
@article {pmid28387722, year = {2017}, author = {Dupont, AC and Largeau, B and Santiago Ribeiro, MJ and Guilloteau, D and Tronel, C and Arlicot, N}, title = {Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {18}, number = {4}, pages = {}, pmid = {28387722}, issn = {1422-0067}, mesh = {Biomarkers/metabolism ; Early Diagnosis ; Humans ; Microglia/metabolism ; Neurodegenerative Diseases/*diagnostic imaging/metabolism ; Positron-Emission Tomography/*methods ; Radiopharmaceuticals/*pharmacology ; Receptors, GABA/*metabolism ; Up-Regulation ; }, abstract = {In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease's stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia's role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.}, }
@article {pmid28387447, year = {2017}, author = {Payne, C and Wiffen, PJ and Martin, S}, title = {WITHDRAWN: Interventions for fatigue and weight loss in adults with advanced progressive illness.}, journal = {The Cochrane database of systematic reviews}, volume = {4}, number = {4}, pages = {CD008427}, doi = {10.1002/14651858.CD008427.pub3}, pmid = {28387447}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications ; Cystic Fibrosis/complications ; Disease Progression ; Emaciation/etiology/*therapy ; Fatigue/etiology/*therapy ; HIV Infections/complications ; Humans ; Multiple Sclerosis/complications ; Neoplasms/complications ; Pulmonary Disease, Chronic Obstructive/complications ; Review Literature as Topic ; *Weight Loss ; }, abstract = {BACKGROUND: Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress.<br><br>OBJECTIVES: To conduct an overview of the evidence available on the efficacy of&#xa0;interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews.<br><br>METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review.<br><br>MAIN RESULTS: We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies. Management of fatigueAmyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration. Management of weight lossALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness - we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition.<br><br>AUTHORS' CONCLUSIONS: There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures.}, }
@article {pmid28386218, year = {2017}, author = {Cestra, G and Rossi, S and Di Salvio, M and Cozzolino, M}, title = {Control of mRNA Translation in ALS Proteinopathy.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {85}, pmid = {28386218}, issn = {1662-5099}, abstract = {Cells robustly reprogram gene expression during stress generated by protein misfolding and aggregation. In this condition, cells assemble the bulk of mRNAs into translationally silent stress granules (SGs), while they sustain the translation of specific mRNAs coding for proteins that are needed to overcome cellular stress. Alterations of this process are deeply associated to neurodegeneration. This is the case of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by a selective loss of motor neurons. Indeed, impairment of protein homeostasis as well as alterations of RNA metabolism are now recognized as major players in the pathogenesis of ALS. In particular, evidence shows that defective mRNA transport and translation are implicated. Here, we provide a review of what is currently known about altered mRNA translation in ALS and how this impacts on the ability of affected cells to cope with proteotoxic stress.}, }
@article {pmid28382594, year = {2017}, author = {Shao, L and Yu, S and Ji, W and Li, H and Gao, Y}, title = {The Contribution of Necroptosis in Neurodegenerative Diseases.}, journal = {Neurochemical research}, volume = {42}, number = {8}, pages = {2117-2126}, pmid = {28382594}, issn = {1573-6903}, mesh = {Animals ; Apoptosis/*physiology ; Humans ; Necrosis/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/*pathology ; Signal Transduction/physiology ; }, abstract = {Over the past decades, cell apoptosis has been significantly reputed as an accidental, redundant and alternative manner of cell demise which partakes in homeostasis in the development of extensive diseases. Nevertheless, necroptosis, another novel manner of cell death through a caspase-independent way, especially in neurodegenerative diseases remains ambiguous. The cognition of this form of cell demise is helpful to understand other forms of morphological resemblance of necrosis. Additionally, the concrete signal mechanism in the regulation of necroptosis is beneficial to the diagnosis and treatment of neurodegenerative diseases. Recent studies have demonstrated that necroptotic inhibitor, 24(S)-Hydroxycholesterol and partial specific histone deacetylase inhibitors could alleviate pathogenetic conditions of neurodegenerative diseases via necroptosis pathway. In this review, we summarize recent researches about mechanisms and modulation of necroptotic signaling pathways and probe into the role of programmed necroptotic cell demise in neurodegenerative diseases such as Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis.}, }
@article {pmid28382000, year = {2017}, author = {Petrov, D and Mansfield, C and Moussy, A and Hermine, O}, title = {ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?.}, journal = {Frontiers in aging neuroscience}, volume = {9}, number = {}, pages = {68}, pmid = {28382000}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.}, }
@article {pmid28380257, year = {2017}, author = {Ederle, H and Dormann, D}, title = {TDP-43 and FUS en route from the nucleus to the cytoplasm.}, journal = {FEBS letters}, volume = {591}, number = {11}, pages = {1489-1507}, doi = {10.1002/1873-3468.12646}, pmid = {28380257}, issn = {1873-3468}, mesh = {Active Transport, Cell Nucleus/genetics/physiology ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cell Nucleus/*metabolism ; Cytoplasm/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; RNA-Binding Protein FUS/genetics/*metabolism ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {Misfolded or mislocalized RNA-binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS), which form pathological messenger ribonucleoprotein aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP-43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm. We discuss how TDP-43 and FUS may exit the nucleus and how defects in both nuclear and cytosolic mRNA processing events, and possibly nuclear export defects, may contribute to neurodegeneration and ALS/FTD pathogenesis.}, }
@article {pmid28379197, year = {2017}, author = {Gao, J and Wang, L and Liu, J and Xie, F and Su, B and Wang, X}, title = {Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {6}, number = {2}, pages = {}, pmid = {28379197}, issn = {2076-3921}, support = {R01 NS097679/NS/NINDS NIH HHS/United States ; }, abstract = {Neurodegenerative diseases are incurable and devastating neurological disorders characterized by the progressive loss of the structure and function of neurons in the central nervous system or peripheral nervous system. Mitochondria, organelles found in most eukaryotic cells, are essential for neuronal survival and are involved in a number of neuronal functions. Mitochondrial dysfunction has long been demonstrated as a common prominent early pathological feature of a variety of common neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Mitochondria are highly dynamic organelles that undergo continuous fusion, fission, and transport, the processes of which not only control mitochondrial morphology and number but also regulate mitochondrial function and location. The importance of mitochondrial dynamics in the pathogenesis of neurodegenerative diseases has been increasingly unraveled after the identification of several key fusion and fission regulators such as Drp1, OPA1, and mitofusins. In this review, after a brief discussion of molecular mechanisms regulating mitochondrial fusion, fission, distribution, and trafficking, as well as the important role of mitochondrial dynamics for neuronal function, we review previous and the most recent studies about mitochondrial dynamic abnormalities observed in various major neurodegenerative diseases and discuss the possibility of targeting mitochondrial dynamics as a likely novel therapeutic strategy for neurodegenerative diseases.}, }
@article {pmid28377696, year = {2017}, author = {Bonafede, R and Mariotti, R}, title = {ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {80}, pmid = {28377696}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.}, }
@article {pmid28377694, year = {2017}, author = {Koon, AC and Chan, HY}, title = {Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {70}, pmid = {28377694}, issn = {1662-5102}, abstract = {For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development.}, }
@article {pmid28365506, year = {2017}, author = {Cleary, JD and Ranum, LP}, title = {New developments in RAN translation: insights from multiple diseases.}, journal = {Current opinion in genetics &amp; development}, volume = {44}, number = {}, pages = {125-134}, pmid = {28365506}, issn = {1879-0380}, support = {R37 NS040389/NS/NINDS NIH HHS/United States ; R01 NS035870/NS/NINDS NIH HHS/United States ; R01 NS040389/NS/NINDS NIH HHS/United States ; P01 NS058901/NS/NINDS NIH HHS/United States ; R01 NS098819/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; C9orf72 Protein/genetics ; Codon, Initiator/genetics ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/*genetics/physiopathology ; Humans ; Mutant Proteins/*genetics ; Neurodegenerative Diseases/genetics/physiopathology ; Open Reading Frames/genetics ; *Protein Biosynthesis ; }, abstract = {Since the discovery of repeat-associated non-ATG (RAN) translation, and more recently its association with amyotrophic lateral sclerosis/frontotemporal dementia, there has been an intense focus to understand how this process works and the downstream effects of these novel proteins. RAN translation across several different types of repeat expansions mutations (CAG, CTG, CCG, GGGGCC, GGCCCC) results in the production of proteins in all three reading frames without an ATG initiation codon. The combination of bidirectional transcription and RAN translation has been shown to result in the accumulation of up to six mutant expansion proteins in a growing number of diseases. This process is complex mechanistically and also complex from the perspective of the downstream consequences in disease. Here we review recent developments in RAN translation and their implications on our basic understanding of neurodegenerative disease and gene expression.}, }
@article {pmid28364657, year = {2017}, author = {Moens, TG and Partridge, L and Isaacs, AM}, title = {Genetic models of C9orf72: what is toxic?.}, journal = {Current opinion in genetics &amp; development}, volume = {44}, number = {}, pages = {92-101}, doi = {10.1016/j.gde.2017.01.006}, pmid = {28364657}, issn = {1879-0380}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; C9orf72 Protein/*genetics ; Dipeptides/genetics ; Disease Models, Animal ; Frontotemporal Dementia/*genetics/pathology ; Humans ; Mice ; Mice, Knockout/genetics ; Nerve Degeneration/*genetics/pathology ; Repetitive Sequences, Amino Acid/genetics ; }, abstract = {A hexanucleotide repeat expansion in the gene C9orf72 is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems. Additionally, models have now been created to attempt to study the effects of repetitive RNA and dipeptide proteins in isolation and thus determine their relevance to disease.}, }
@article {pmid28356047, year = {2017}, author = {Echeverria, V and Barreto, GE and Avila-Rodriguezc, M and Tarasov, VV and Aliev, G}, title = {Is VEGF a Key Target of Cotinine and Other Potential Therapies Against Alzheimer Disease?.}, journal = {Current Alzheimer research}, volume = {14}, number = {11}, pages = {1155-1163}, doi = {10.2174/1567205014666170329113007}, pmid = {28356047}, issn = {1875-5828}, mesh = {Alzheimer Disease/*drug therapy/*metabolism ; Animals ; Cotinine/pharmacology/*therapeutic use ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {BACKGROUND: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions.<br><br>CONCLUSION: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.}, }
@article {pmid28344778, year = {2017}, author = {Sleigh, JN and Vagnoni, A and Twelvetrees, AE and Schiavo, G}, title = {Methodological advances in imaging intravital axonal transport.}, journal = {F1000Research}, volume = {6}, number = {}, pages = {200}, pmid = {28344778}, issn = {2046-1402}, support = {MC_U105178790/MRC_/Medical Research Council/United Kingdom ; NC/N001753/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, abstract = {Axonal transport is the active process whereby neurons transport cargoes such as organelles and proteins anterogradely from the cell body to the axon terminal and retrogradely in the opposite direction. Bi-directional transport in axons is absolutely essential for the functioning and survival of neurons and appears to be negatively impacted by both aging and diseases of the nervous system, such as Alzheimer's disease and amyotrophic lateral sclerosis. The movement of individual cargoes along axons has been studied in vitro in live neurons and tissue explants for a number of years; however, it is currently unclear as to whether these systems faithfully and consistently replicate the in vivo situation. A number of intravital techniques originally developed for studying diverse biological events have recently been adapted to monitor axonal transport in real-time in a range of live organisms and are providing novel insight into this dynamic process. Here, we highlight these methodological advances in intravital imaging of axonal transport, outlining key strengths and limitations while discussing findings, possible improvements, and outstanding questions.}, }
@article {pmid28343168, year = {2017}, author = {Paré, B and Gros-Louis, F}, title = {Potential skin involvement in ALS: revisiting Charcot's observation - a review of skin abnormalities in ALS.}, journal = {Reviews in the neurosciences}, volume = {28}, number = {5}, pages = {551-572}, doi = {10.1515/revneuro-2017-0004}, pmid = {28343168}, issn = {2191-0200}, mesh = {Actin Cytoskeleton/genetics/metabolism ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Biomarkers/metabolism ; Collagen/genetics/metabolism ; Extracellular Matrix/genetics/metabolism ; Humans ; Skin/metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons of the brain and spinal cord, leading to progressive paralysis and death. Interestingly, many skin changes have been reported in ALS patients, but never as yet fully explained. These observations could be due to the common embryonic origin of the skin and neural tissue known as the ectodermal germ layer. Following the first observation in ALS patients' skin by Dr Charcot in the 19th century, in the absence of bedsores unlike other bedridden patients, other morphological and molecular changes have been observed. Thus, the skin could be of interest in the study of ALS and other neurodegenerative diseases. This review summarizes skin changes reported in the literature over the years and discusses about a novel in vitro ALS tissue-engineered skin model, derived from patients, for the study of ALS.}, }
@article {pmid28341166, year = {2017}, author = {Gallini, A and Moisan, F and Maura, G and Carcaillon-Bentata, L and Leray, E and Haesebaert, J and Bruandet, A and Moutengou, E and Luciano, L and Weill, A and Marin, B and Gardette, V}, title = {[Identification of neurodegenerative diseases in administrative databases in France: A systematic review of the literature].}, journal = {Revue d'epidemiologie et de sante publique}, volume = {65 Suppl 4}, number = {}, pages = {S183-S197}, doi = {10.1016/j.respe.2017.01.115}, pmid = {28341166}, issn = {0398-7620}, mesh = {Algorithms ; Databases, Factual/*statistics &amp; numerical data ; France/epidemiology ; Humans ; Information Storage and Retrieval ; National Health Programs/statistics &amp; numerical data ; Neurodegenerative Diseases/*epidemiology ; }, abstract = {BACKGROUND: Given the health, social and economic burden of neurodegenerative diseases (ND), the development of epidemiologic studies is required. Administrative databases, such as the French national health insurance database (SNIIRAM) could represent an opportunity for researchers. ND could be presumed from drug reimbursement data, hospital stays or registration of a chronic condition. The aim of this study was to describe, in French administrative databases, algorithms used to identify Alzheimer's disease and associated disorders (ADAD), Parkinson's disease and associated disorders (PDAD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A systematic literature review was performed in Medline and gray literature through December&#xa0;31th, 2015. French studies focusing on ADAD, PDAD, MS or ALS as a primary health outcome, conducted among one of the SNIIRAM data sources (outpatient reimbursements, chronic condition registration, hospital discharge) were included.<br><br>RESULTS: Thirty-four studies were included (ADAD, n=18, PDAD, n=9, MS, n=4, ALS, n=3), leading to 36&#xa0;algorithms. For each studied ND, there was an important variability in the algorithms, concerning (i) the type of criteria used (administrative database versus multi-source systems); (ii) the number of criteria used; (iii) the definition used for each criteria. The extent and level of drug exposure highly varied. Identification through hospitalizations showed variations in terms of type of stay (short stay, long-term stay, psychiatric ward&#x2026;), extent of diagnosis codes used, diagnosis type (principal, related, associated diagnosis) and period used. A validation study was conducted for 2 out of 36&#xa0;algorithms (PDAD), and criteria completeness was estimated for 3&#xa0;algorithms (MS, ALS).<br><br>CONCLUSION: Despite the increase in ND identification among French administrative databases, few algorithms have been validated. Validation studies should be encouraged.}, }
@article {pmid28331770, year = {2017}, author = {Cox, PA and Metcalf, JS}, title = {Traditional Food Items in Ogimi, Okinawa: l-Serine Content and the Potential for Neuroprotection.}, journal = {Current nutrition reports}, volume = {6}, number = {1}, pages = {24-31}, pmid = {28331770}, issn = {2161-3311}, abstract = {PURPOSE OF REVIEW: Ogimi village is renowned for its aging population. We sought to determine if the l-serine content of their diet could account for their neurological health.<br><br>RECENT FINDINGS: The most frequently consumed food items, including tofu and seaweeds, are rich in the dietary amino acid l-serine. l-serine content of the Ogimi diet >8 grams/day for Ogimi women significantly exceeds the average American dietary intake of 2.5 grams/day for women >70&#xa0;years old.<br><br>SUMMARY: Our hypothesis that the high l-serine content of the Ogimi diet is related to the paucity of tangle diseases among villagers is buttressed by in vivo results with non-human primates where dietary l-serine slowed development of neurofibrillary tangles and &#x3b2;-amyloid plaques by up to 85% and a human clinical trial finding that l-serine at 15 grams/day twice daily slows functional decline in ALS patients. Analysis of the Ogimi diet suggests that l-serine should be evaluated for therapeutic potential as a neuroprotective agent.}, }
@article {pmid28326328, year = {2017}, author = {Brütting, C and Emmer, A and Kornhuber, ME and Staege, MS}, title = {Cooccurrences of Putative Endogenous Retrovirus-Associated Diseases.}, journal = {BioMed research international}, volume = {2017}, number = {}, pages = {7973165}, pmid = {28326328}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/genetics/therapy/*virology ; Antiretroviral Therapy, Highly Active ; Diabetes Mellitus, Type 1/genetics/therapy/*virology ; Endogenous Retroviruses/*genetics/pathogenicity ; HIV Infections/genetics/therapy/*virology ; Humans ; Multiple Sclerosis/genetics/therapy/*virology ; Schizophrenia/genetics/therapy/*virology ; }, abstract = {At least 8% of the human genome is composed of endogenous retrovirus (ERV) sequences. ERVs play a role in placental morphogenesis and can sometimes protect the host against exogenous viruses. On the other hand, ERV reactivation has been found to be associated with different diseases, for example, multiple sclerosis (MS), schizophrenia, type 1 diabetes mellitus (T1D), or amyotrophic lateral sclerosis (ALS). Little is known about the cooccurrence of these diseases. If all these diseases are caused by ERV, antiretroviral therapy should perhaps also show some effects in the other diseases. Here, we summarize literature demonstrating that some ERV-associated diseases seem to appear together more often than expected, for example, MS and ALS, MS and T1D, MS and schizophrenia, or ALS and T1D. In contrast, some ERV-associated diseases seem to appear together less frequently than expected, for example, schizophrenia and T1D. Besides, some reports demonstrate amelioration of MS, ALS, or schizophrenia under antiretroviral therapy in human immunodeficiency virus-infected patients. If such results could be confirmed in larger studies, alternative therapy strategies for ERV-associated diseases like MS and schizophrenia might be possible.}, }
@article {pmid28321196, year = {2017}, author = {Boschi, V and Catricalà, E and Consonni, M and Chesi, C and Moro, A and Cappa, SF}, title = {Connected Speech in Neurodegenerative Language Disorders: A Review.}, journal = {Frontiers in psychology}, volume = {8}, number = {}, pages = {269}, pmid = {28321196}, issn = {1664-1078}, abstract = {Language assessment has a crucial role in the clinical diagnosis of several neurodegenerative diseases. The analysis of extended speech production is a precious source of information encompassing the phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic levels of language organization. The knowledge about the distinctive linguistic variables identifying language deficits associated to different neurodegenerative diseases has progressively improved in the last years. However, the heterogeneity of such variables and of the way they are measured and classified limits any generalization and makes the comparison among studies difficult. Here we present an exhaustive review of the studies focusing on the linguistic variables derived from the analysis of connected speech samples, with the aim of characterizing the language disorders of the most prevalent neurodegenerative diseases, including primary progressive aphasia, Alzheimer's disease, movement disorders, and amyotrophic lateral sclerosis. A total of 61 studies have been included, considering only those reporting group analysis and comparisons with a group of healthy persons. This review first analyzes the differences in the tasks used to elicit connected speech, namely picture description, story narration, and interview, considering the possible different contributions to the assessment of different linguistic domains. This is followed by an analysis of the terminologies and of the methods of measurements of the variables, indicating the need for harmonization and standardization. The final section reviews the linguistic domains affected by each different neurodegenerative disease, indicating the variables most consistently impaired at each level and suggesting the key variables helping in the differential diagnosis among diseases. While a large amount of valuable information is already available, the review highlights the need of further work, including the development of automated methods, to take advantage of the richness of connected speech analysis for both research and clinical purposes.}, }
@article {pmid28317317, year = {2017}, author = {Kolahdouzan, M and Hamadeh, MJ}, title = {The neuroprotective effects of caffeine in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {23}, number = {4}, pages = {272-290}, pmid = {28317317}, issn = {1755-5949}, mesh = {Animals ; Caffeine/*therapeutic use ; Humans ; Neurodegenerative Diseases/*prevention &amp; control ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Caffeine is the most widely used psychostimulant in Western countries, with antioxidant, anti-inflammatory and anti-apoptotic properties. In Alzheimer's disease (AD), caffeine is beneficial in both men and women, in humans and animals. Similar effects of caffeine were observed in men with Parkinson's disease (PD); however, the effect of caffeine in female PD patients is controversial due to caffeine's competition with estrogen for the estrogen-metabolizing enzyme, CYP1A2. Studies conducted in animal models of amyotrophic lateral sclerosis (ALS) showed protective effects of A2A R antagonism. A study found caffeine to be associated with earlier age of onset of Huntington's disease (HD) at intakes >190 mg/d, but studies in animal models have found equivocal results. Caffeine is protective in AD and PD at dosages equivalent to 3-5 mg/kg. However, further research is needed to investigate the effects of caffeine on PD in women. As well, the effects of caffeine in ALS, HD and Machado-Joseph disease need to be further investigated. Caffeine's most salient mechanisms of action relevant to neurodegenerative diseases need to be further explored.}, }
@article {pmid28315276, year = {2017}, author = {Mavlyutov, TA and Baker, EM and Losenegger, TM and Kim, JR and Torres, B and Epstein, ML and Ruoho, AE}, title = {The Sigma-1 Receptor-A Therapeutic Target for the Treatment of ALS?.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {255-265}, doi = {10.1007/978-3-319-50174-1_17}, pmid = {28315276}, issn = {0065-2598}, support = {NS075820/NH/NIH HHS/United States ; DK081634/NH/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Cell Membrane/drug effects ; Endoplasmic Reticulum/drug effects/metabolism ; Humans ; Motor Neurons/drug effects/metabolism ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS). The S1R has an important role in regulating motor neuron function. High levels of the S1R are localized in postsynaptic endoplasmic reticulum (ER) subsurface cisternae within 10-20 nm of the plasma membrane that contain muscarinic type 2 acetylcholine receptors (M2AChR), calcium activated potassium channels (Kv2.1) and slow potassium (SK) channels. An increase in action potentials in the S1R KO mouse motor neurons indicates a critical role for the S1R as a "brake" on motor neuron function possibly via calcium dependent hyperpolarization mechanisms involving the aforementioned potassium channels. The longevity of SOD-1/S1R KO ALS mice is significantly reduced compared to SOD-1/WT ALS controls. The S1R colocalizes in C-terminals with Indole(ethyl)amine-N-methyl transferase (INMT), the enzyme that produces the S1R agonist , N,N'- dimethyltryptamine (DMT). INMT methylation can additionally neutralize endogenous toxic sulfur and selenium derivatives thus providing functional synergism with DMT to reduce oxidative stress in motor neurons . Small molecule activation of the S1R and INMT thus provides a possible therapeutic strategy to treat ALS .}, }
@article {pmid28315275, year = {2017}, author = {Mancuso, R and Navarro, X}, title = {Sigma-1 Receptor in Motoneuron Disease.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {235-254}, doi = {10.1007/978-3-319-50174-1_16}, pmid = {28315275}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Motor Neuron Disease/*metabolism ; Motor Neurons/*metabolism ; Neuroglia/metabolism ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord and brain motoneurons , leading to paralysis and early death. Multiple etiopathogenic mechanisms appear to contribute in the development of ALS , including glutamate excitotoxicity, oxidative stress , protein misfolding, mitochondrial defects, impaired axonal transport, inflammation and glial cell alterations. The Sigma-1 receptor is highly expressed in motoneurons of the spinal cord, particularly enriched in the endoplasmic reticulum (ER) at postsynaptic cisternae of cholinergic C-terminals. Several evidences point to participation of Sigma-1R alterations in motoneuron degeneration. Thus, mutations of the transmembrane domain of the Sigma-1R have been described in familial ALS cases. Interestingly, Sigma-1R KO mice display muscle weakness and motoneuron loss. On the other hand, Sigma-1R agonists promote neuroprotection and neurite elongation through activation of protein kinase C on motoneurons in vitro and in vivo after ventral root avulsion. Remarkably, treatment of SOD1 mice, the most usual animal model of ALS , with Sigma-1R agonists resulted in significantly enhanced motoneuron function and preservation, and increased animal survival. Sigma-1R activation also reduced microglial reactivity and increased the glial expression of neurotrophic factors. Two main interconnected mechanisms seem to underlie the effects of Sigma-1R manipulation on motoneurons: modulation of neuronal excitability and regulation of calcium homeostasis. In addition, Sigma-1R also contributes to regulating protein degradation, and reducing oxidative stress. Therefore, the multi-functional nature of the Sigma-1R represents an attractive target for treating aspects of ALS and other motoneuron diseases .}, }
@article {pmid28315271, year = {2017}, author = {Cai, Y and Yang, L and Niu, F and Liao, K and Buch, S}, title = {Role of Sigma-1 Receptor in Cocaine Abuse and Neurodegenerative Disease.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {163-175}, doi = {10.1007/978-3-319-50174-1_12}, pmid = {28315271}, issn = {0065-2598}, support = {P30 GM103509/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Cocaine/adverse effects ; Cocaine-Related Disorders/*metabolism ; Humans ; Ligands ; Neurodegenerative Diseases/*metabolism ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {Sigma-1 receptors (Sig-1R) are recognized as a unique class of non-G protein-coupled intracellular protein. Sig-1R binds to its ligand such as cocaine , resulting in dissociation of Sig-1R from mitochondrion-associated ER membrane (MAM) to the endoplasmic reticulum (ER), plasma membrane, and nuclear membrane, regulating function of various proteins. Sig-1R has diverse roles in both physiological as well as in pathogenic processes. The disruption of Sig-1R pathways has been implicated as causative mechanism(s) in the development of both neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington Disease (HD) . Additionally, the interaction of cocaine and Sig-1R has more recently been implicated in potentiating the pathogenesis of HIV-associated neurocognitive disorders (HAND) through impairment of blood-brain barrier (BBB), microglial activation and astrogliosis. On the other hand, restoration of Sig-1R homeostasis has been shown to exert neuroprotective effects. In this review, we provide an overview of how Sig-1R plays a role in the pathogenesis of neurodegenerative disorders and cocaine and implications for future development of therapeutic strategies.}, }
@article {pmid28315269, year = {2017}, author = {Nguyen, L and Lucke-Wold, BP and Mookerjee, S and Kaushal, N and Matsumoto, RR}, title = {Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {133-152}, pmid = {28315269}, issn = {0065-2598}, support = {U54 GM104942/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Brain/drug effects/metabolism ; Humans ; Ligands ; Molecular Chaperones/*pharmacology ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neuroprotection/drug effects ; Neuroprotective Agents/*pharmacology ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.}, }
@article {pmid28315265, year = {2017}, author = {Soriani, O and Rapetti-Mauss, R}, title = {Sigma 1 Receptor and Ion Channel Dynamics in Cancer.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {63-77}, doi = {10.1007/978-3-319-50174-1_6}, pmid = {28315265}, issn = {0065-2598}, mesh = {Animals ; Humans ; Ion Channels/*metabolism ; Neoplasms/*metabolism/*pathology ; Neurodegenerative Diseases/metabolism/pathology ; Receptors, sigma/*metabolism ; Tumor Microenvironment/physiology ; Sigma-1 Receptor ; }, abstract = {SigmaR1 is a multitasking chaperone protein which has mainly been studied in CNS physiological and pathophysiological processes such as pain, memory, neurodegenerative diseases (amyotrophic lateral sclerosis , Parkinson's and Alzheimer's diseases, retinal neurodegeneration), stroke and addiction . Strikingly, G-protein and ion channels are the main client protein fami lies of this atypical chaperone and the recent advances that have been performed for the last 10 years demonstrate that SigmaR1 is principally activated following tissue injury and disease development to promote cell survival. In this chapter, we synthesize the data enhancing our comprehension of the interaction between SigmaR1 and ion channels and the unexpected consequences of such functional coupling in cancer development. We also describe a model in which the pro-survival functions of SigmaR1 observed in CNS pathologies are hijacked by cancer cells to shape their electrical signature and behavior in response to the tumor microenvironment .}, }
@article {pmid28315260, year = {2017}, author = {Smith, SB}, title = {Introduction to Sigma Receptors: Their Role in Disease and as Therapeutic Targets.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {1-4}, doi = {10.1007/978-3-319-50174-1_1}, pmid = {28315260}, issn = {0065-2598}, support = {R01 EY014560/EY/NEI NIH HHS/United States ; R01 EY028103/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Depression/*metabolism ; Humans ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; Receptors, sigma/*metabolism ; Substance-Related Disorders/*metabolism ; Sigma-1 Receptor ; }, abstract = {This book highlights contributions from leaders in the field of sigma receptor research. Sigma receptors represent a promising, novel target for the treatment of neurodegenerative diseases, retinal degenerations, pain and substance abuse. Information is presented about tracers for molecular imaging these receptors, the newly determined crystal structure of human sigma 1 receptor and information about sigma 2 receptor. New discoveries about the role of sigma 1 receptors in cancer, pain, neuropsychiatric disorders, learning and memory, neuronal networks and depression are described. The compendium offers important insights about the direction unfolding for this exciting field of research.}, }
@article {pmid28302142, year = {2017}, author = {Schoser, B and Fong, E and Geberhiwot, T and Hughes, D and Kissel, JT and Madathil, SC and Orlikowski, D and Polkey, MI and Roberts, M and Tiddens, HA and Young, P}, title = {Maximum inspiratory pressure as a clinically meaningful trial endpoint for neuromuscular diseases: a comprehensive review of the literature.}, journal = {Orphanet journal of rare diseases}, volume = {12}, number = {1}, pages = {52}, pmid = {28302142}, issn = {1750-1172}, mesh = {Humans ; *Maximal Respiratory Pressures ; Neuromuscular Diseases/*physiopathology ; Respiratory Function Tests ; Respiratory Insufficiency/physiopathology ; Spirometry ; }, abstract = {Respiratory muscle strength is a proven predictor of long-term outcome of neuromuscular disease (NMD), including amyotrophic lateral sclerosis, Duchenne muscular dystrophy, and spinal muscular atrophy. Maximal inspiratory pressure (MIP), a sensitive measure of respiratory muscle strength, one of several useful tests of respiratory muscle strength, is gaining interest as a therapeutic clinical trial endpoint for NMD. In this comprehensive review we investigate the use of MIP as a measure of respiratory muscle strength in clinical trials of therapeutics targeting respiratory muscle, examine the correlation of MIP with survival, quality of life, and other measures of pulmonary function, and outline the role of MIP as a clinically significantly meaningful outcome measure. Our analysis supports the utility of MIP for the early evaluation of respiratory muscle strength, especially of the diaphragm, in patients with NMD and as a surrogate endpoint in clinical trials of therapies for NMD.}, }
@article {pmid28302022, year = {2017}, author = {Ahmed, S and Gull, A and Khuroo, T and Aqil, M and Sultana, Y}, title = {Glial Cell: A Potential Target for Cellular and Drug Based Therapy in Various CNS Diseases.}, journal = {Current pharmaceutical design}, volume = {23}, number = {16}, pages = {2389-2399}, doi = {10.2174/1381612823666170316124500}, pmid = {28302022}, issn = {1873-4286}, mesh = {Animals ; Blood-Brain Barrier/drug effects/pathology ; Central Nervous System Diseases/*drug therapy/pathology ; Humans ; Neuroglia/*drug effects/pathology ; }, abstract = {Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells. Multiple sclerosis is a prototype glia mediated disease that manifests demyelination. Fingolimod is already being marketed for this disease, while guanabenz and ibudilast are facing clinical trials. Many researches revealed the role of glial cells in Alzheimer's disease, in which riluzole (a glutamate modulator already in market for amyotrophic lateral sclerosis-ALS) was found to be effective. Q-cells® are glial cell-based therapeutic agent to treat ALS that only produce astrocytes and oligodendrocytes, when transplanted in vivo. hIL13-PE is a gene based therapeutic agent that has been smartly designed for the treatment of glioma. Although for CNS diseases, drugs are available, still it is not easy to extract satisfactory therapeutic effect of most of the drugs due to the presence of BBB. This barrier can be overcome by implanting a drug reservoir in brain parenchyma (wafer), by judicious selection of drug delivery system (nanoparticulate system), or by using an alternative route of administration (intranasal route). This review revolves around cellular and drug based modulation of glial cells to achieve maximum therapeutic benefit for some of the CNS diseases.}, }
@article {pmid28297055, year = {2017}, author = {Labriola, L and Pochet, JM}, title = {Any use for alternative lock solutions in the prevention of catheter-related blood stream infections?.}, journal = {The journal of vascular access}, volume = {18}, number = {Suppl. 1}, pages = {34-38}, doi = {10.5301/jva.5000681}, pmid = {28297055}, issn = {1724-6032}, mesh = {Anti-Infective Agents/adverse effects/*therapeutic use ; Anticoagulants/therapeutic use ; Bacteremia/diagnosis/microbiology/*prevention &amp; control ; Biofilms ; Catheter-Related Infections/diagnosis/microbiology/*prevention &amp; control ; Catheterization, Central Venous/adverse effects/*instrumentation ; *Catheters, Indwelling/adverse effects/microbiology ; *Central Venous Catheters/adverse effects/microbiology ; Equipment Design ; Humans ; *Renal Dialysis ; Risk Factors ; Treatment Outcome ; }, abstract = {The prevention of catheter-related blood stream infections (CRBSI) in hemodialysis (HD) patients remains a challenge because of high morbidity and mortality associated to CRBSI. Alternative locking solutions (ALS) containing an antithrombotic substance with additional antimicrobial or antibiofilm properties (citrate, ethylenediaminetetraacetic acid [EDTA], 70% ethanol, thrombolytics) with or without the addition of molecules with specific antimicrobial activity (antibiotics, taurolidine, paraben-methylene-blue) has been proposed with the aim to prevent or eradicate intraluminal biofilm colonization and subsequent CRBSI. In this review, we examine the available evidence concerning their efficacy and potential side effects, in order to determine whether ALS should be implemented widely or only in selected cases.}, }
@article {pmid28295262, year = {2017}, author = {Donlin-Asp, PG and Rossoll, W and Bassell, GJ}, title = {Spatially and temporally regulating translation via mRNA-binding proteins in cellular and neuronal function.}, journal = {FEBS letters}, volume = {591}, number = {11}, pages = {1508-1525}, doi = {10.1002/1873-3468.12621}, pmid = {28295262}, issn = {1873-3468}, mesh = {Animals ; Humans ; Models, Biological ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Protein Biosynthesis ; RNA, Messenger/*metabolism ; RNA-Binding Proteins/*metabolism ; }, abstract = {Coordinated regulation of mRNA localization and local translation are essential steps in cellular asymmetry and function. It is increasingly evident that mRNA-binding proteins play critical functions in controlling the fate of mRNA, including when and where translation occurs. In this review, we discuss the robust and complex roles that mRNA-binding proteins play in the regulation of local translation that impact cellular function in vertebrates. First, we discuss the role of local translation in cellular polarity and possible links to vertebrate development and patterning. Next, we discuss the expanding role for local protein synthesis in neuronal development and function, with special focus on how a number of neurological diseases have given us insight into the importance of translational regulation. Finally, we discuss the ever-increasing set of tools to study regulated translation and how these tools will be vital in pushing forward and addressing the outstanding questions in the field.}, }
@article {pmid28293919, year = {2017}, author = {Gerth, HU and Pohlen, M and Pavenstädt, H and Schmidt, H}, title = {[Extracorporeal liver support of liver failure].}, journal = {Zeitschrift fur Gastroenterologie}, volume = {55}, number = {4}, pages = {383-393}, doi = {10.1055/s-0043-100020}, pmid = {28293919}, issn = {1439-7803}, mesh = {*Extracorporeal Circulation ; Humans ; Liver Failure/physiopathology/*therapy ; *Liver, Artificial ; Plasmapheresis/methods ; *Randomized Controlled Trials as Topic ; Sorption Detoxification ; }, abstract = {Extracorporeal liver support can be classified into cell-free, artificial methods (artificial liver support, ALS) and cell-based bioartificial methods (bioartificial liver support, BLS). ALS improves biochemical parameters of liver failure by the simultaneous removal of protein-bound and water-soluble substances. Here, the MARS therapy belongs to the most studied methods with a proved beneficial effect on hepatic encephalopathy (HE), hepatorenal syndrome (HRS) or hyperbilirubinemia. However, a general survival advantage of any liver support for liver failure has not been shown yet and is restricted to meta-analyses or patient subgroups. There are no prospective randomized studies on the treatment of liver failure by intoxication. However, several case series report positive treatment effects using the MARS system, particularly in mushroom poisoning or acetaminophen intoxication. In acute liver failure (ALF) studies, the usage of BLS showed no survival advantage. Using ALS systems, a positive effect on mortality could be demonstrated in patient subgroups after several consecutive MARS therapies. The first randomized controlled trial demonstrating a survival benefit used large-volume plasmapheresis. Apparently, immunomodulatory and hemodynamic effects of the treatment play a crucial role in this context. In patients with acute-on-chronic liver failure (ACLF) accompanied by hyperbilirubinemia without any further organ failure (singular hepatic dysfunction), prognostic favorable effects by using a BLS system have been shown. However, once other extrahepatic organ systems are affected, indicating a progressive transition to multi-organ failure, a survival advantage could be achieved with the MARS and Prometheus system. Decisive for a successful therapy is the exact indication of the respective liver dialysis procedure for this very heterogeneous disease. Future studies are needed to define more accurate patient selection criteria for each liver support.}, }
@article {pmid28293168, year = {2017}, author = {Bahmad, H and Hadadeh, O and Chamaa, F and Cheaito, K and Darwish, B and Makkawi, AK and Abou-Kheir, W}, title = {Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {50}, pmid = {28293168}, issn = {1662-5099}, abstract = {With the help of several inducing factors, somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) lines. The success is in obtaining iPSCs almost identical to embryonic stem cells (ESCs), therefore various approaches have been tested and ultimately several ones have succeeded. The importance of these cells is in how they serve as models to unveil the molecular pathways and mechanisms underlying several human diseases, and also in its potential roles in the development of regenerative medicine. They further aid in the development of regenerative medicine, autologous cell therapy and drug or toxicity screening. Here, we provide a comprehensive overview of the recent development in the field of iPSCs research, specifically for modeling human neurological and neurodegenerative diseases, and its applications in neurotrauma. These are mainly characterized by progressive functional or structural neuronal loss rendering them extremely challenging to manage. Many of these diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) have been explored in vitro. The main purpose is to generate patient-specific iPS cell lines from the somatic cells that carry mutations or genetic instabilities for the aim of studying their differentiation potential and behavior. This new technology will pave the way for future development in the field of stem cell research anticipating its use in clinical settings and in regenerative medicine in order to treat various human diseases, including neurological and neurodegenerative diseases.}, }
@article {pmid28293166, year = {2017}, author = {Jackrel, ME and Shorter, J}, title = {Protein-Remodeling Factors As Potential Therapeutics for Neurodegenerative Disease.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {99}, pmid = {28293166}, issn = {1662-4548}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 NS090205/NS/NINDS NIH HHS/United States ; }, abstract = {Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function. Here, we describe the application of protein-remodeling factors to alleviate protein misfolding in neurodegenerative disease. We focus on Hsp104, Hsp110/Hsp70/Hsp40, NMNAT, and HtrA1, which can prevent and reverse protein aggregation. While many of these protein-remodeling systems are highly promising, their activity can be limited. Thus, engineering protein-remodeling factors to enhance their activity could be therapeutically valuable. Indeed, engineered Hsp104 variants suppress neurodegeneration in animal models, which opens the way to novel therapeutics and mechanistic probes to help understand neurodegenerative disease.}, }
@article {pmid28292200, year = {2017}, author = {Brusilow, WS and Peters, TJ}, title = {Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase.}, journal = {Expert opinion on therapeutic targets}, volume = {21}, number = {5}, pages = {461-469}, doi = {10.1080/14728222.2017.1303484}, pmid = {28292200}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Brain Edema/*drug therapy/physiopathology ; Disease Models, Animal ; Drug Design ; Glutamate-Ammonia Ligase/*metabolism ; Hepatic Encephalopathy/drug therapy/physiopathology ; Humans ; Methionine Sulfoximine/*pharmacology ; Molecular Targeted Therapy ; Stroke/drug therapy/physiopathology ; }, abstract = {Methionine sulfoximine (MSO), a well-characterized inhibitor of glutamine synthetase, displays significant therapeutic benefits in animal models for several human diseases. This amino acid might therefore be a viable candidate for drug development to treat diseases for which there are few effective therapies. Areas covered: We describe the effects of MSO on brain swelling occurring in overt hepatic encephalopathy resulting from liver failure, the effects of MSO on excitotoxic damage involved in amyotrophic lateral sclerosis (ALS) or resulting from stroke, and the effects of MSO on a model for an inflammatory immune response involved in a range of diseases. We conclude that these results imply the existence of another therapeutic target for MSO in addition to glutamine synthetase. Expert opinion: We summarize the various diseases for which MSO treatment might be a candidate for drug development. We discuss why MSO has limited enthusiasm in the scientific and medical communities for use in humans, with a rebuttal to those negative opinions. And we conclude that MSO should be considered a candidate drug to treat brain swelling involved in overt hepatic encephalopathy and diseases involving an inflammatory immune response.}, }
@article {pmid28285264, year = {2017}, author = {Hardiman, O and Al-Chalabi, A and Brayne, C and Beghi, E and van den Berg, LH and Chio, A and Martin, S and Logroscino, G and Rooney, J}, title = {The changing picture of amyotrophic lateral sclerosis: lessons from European registers.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {88}, number = {7}, pages = {557-563}, doi = {10.1136/jnnp-2016-314495}, pmid = {28285264}, issn = {1468-330X}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; Ethnicity ; Europe/epidemiology ; Humans ; Incidence ; Phenotype ; Population Surveillance ; Prevalence ; Prospective Studies ; Registries/*statistics &amp; numerical data ; Risk Factors ; }, abstract = {Prospective population based-registers of amyotrophic lateral sclerosis (ALS) have operated in Europe for over two decades, and have provided important insights into our understanding of ALS. Here, we review the benefits that population registers have brought to the understanding of the incidence, prevalence, phenotype and genetics of ALS and outline the core operating principles that underlie these registers and facilitate international collaboration. Going forward, we offer lessons learned from our collective experience of operating population-based ALS registers in Europe for over two decades, focusing on register design, maintenance, identification and management of bias and the value of cross-national harmonisation and integration.}, }
@article {pmid28282684, year = {2017}, author = {Labenz, J and Koop, H}, title = {[Gastro-Oesophageal Reflux Disease - How to Manage if PPI are not Sufficiently Effective, not Tolerated, or not Wished?].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {142}, number = {5}, pages = {356-366}, doi = {10.1055/s-0042-121021}, pmid = {28282684}, issn = {1439-4413}, mesh = {Alginates/*administration &amp; dosage ; Drug Therapy, Combination/methods ; Esophagitis, Peptic/diagnosis/etiology/*prevention &amp; control ; Evidence-Based Medicine ; Gastroesophageal Reflux/complications/diagnosis/*drug therapy ; Humans ; *Patient Satisfaction ; Proton Pump Inhibitors/*administration &amp; dosage/adverse effects ; Treatment Outcome ; Treatment Refusal ; }, abstract = {Die Standardtherapie der GERD mit PPI ist weniger wirksam als gedacht: Mindestens 30 % der Patienten haben persistierende Symptome und Läsionen (Therapielücke). Bei persistierender Symptomatik oder Wunsch einer alternativen Behandlung ist eine stratifizierte Diagnostik erforderlich. Alginate und neue Operationsverfahren erweitern die Therapieoptionen.}, }
@article {pmid28277881, year = {2017}, author = {Martinez, A and Palomo Ruiz, MD and Perez, DI and Gil, C}, title = {Drugs in clinical development for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {26}, number = {4}, pages = {403-414}, doi = {10.1080/13543784.2017.1302426}, pmid = {28277881}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Antipyrine/analogs &amp; derivatives/therapeutic use ; Biological Therapy/methods ; Biomarkers/metabolism ; Cell- and Tissue-Based Therapy/methods ; *Drug Design ; Drug Repositioning ; Drugs, Investigational/*therapeutic use ; Edaravone ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.}, }
@article {pmid28276873, year = {2017}, author = {Hendriksz, CJ and Anheim, M and Bauer, P and Bonnot, O and Chakrapani, A and Corvol, JC and de Koning, TJ and Degtyareva, A and Dionisi-Vici, C and Doss, S and Duning, T and Giunti, P and Iodice, R and Johnston, T and Kelly, D and Klünemann, HH and Lorenzl, S and Padovani, A and Pocovi, M and Synofzik, M and Terblanche, A and Then Bergh, F and Topçu, M and Tranchant, C and Walterfang, M and Velten, C and Kolb, SA}, title = {The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.}, journal = {Current medical research and opinion}, volume = {33}, number = {5}, pages = {877-890}, doi = {10.1080/03007995.2017.1294054}, pmid = {28276873}, issn = {1473-4877}, mesh = {Humans ; Niemann-Pick Disease, Type C/*epidemiology ; Prevalence ; Rare Diseases/*epidemiology ; }, abstract = {BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes.<br><br>METHODS: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included.<br><br>FINDINGS: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches.<br><br>CONCLUSIONS: Several clinical niches have been identified that harbor patients at increased risk of NP-C.}, }
@article {pmid28275911, year = {2017}, author = {Maurice, T and Goguadze, N}, title = {Sigma-1 (σ1) Receptor in Memory and Neurodegenerative Diseases.}, journal = {Handbook of experimental pharmacology}, volume = {244}, number = {}, pages = {81-108}, doi = {10.1007/164_2017_15}, pmid = {28275911}, issn = {0171-2004}, mesh = {Animals ; Humans ; Ligands ; *Memory/drug effects ; Memory Disorders/drug therapy/*metabolism/psychology ; *Nerve Degeneration ; Neurodegenerative Diseases/drug therapy/genetics/*metabolism/pathology ; Neurons/drug effects/*metabolism/pathology ; Neuroprotective Agents/pharmacology ; Nootropic Agents/pharmacology ; Receptors, sigma/drug effects/genetics/*metabolism ; Signal Transduction ; Sigma-1 Receptor ; }, abstract = {The sigma-1 (σ1) receptor has been associated with regulation of intracellular Ca[2+] homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ1 receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ1 receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism. Recent studies have highlighted the efficacy of drugs that act through the σ1 receptor to mitigate symptoms associated with neurodegenerative disorders with distinct mechanisms of pathogenesis. Here, we will review genetic and pharmacological evidence of σ1 receptor engagement in learning and memory disorders, cognitive impairment, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease.}, }
@article {pmid28274814, year = {2018}, author = {Hubbard, JA and Szu, JI and Binder, DK}, title = {The role of aquaporin-4 in synaptic plasticity, memory and disease.}, journal = {Brain research bulletin}, volume = {136}, number = {}, pages = {118-129}, doi = {10.1016/j.brainresbull.2017.02.011}, pmid = {28274814}, issn = {1873-2747}, mesh = {Animals ; Aquaporin 4/*metabolism ; Central Nervous System Diseases/*metabolism ; Humans ; Memory/*physiology ; Neuronal Plasticity/*physiology ; }, abstract = {Since the discovery of aquaporins, it has become clear that the various mammalian aquaporins play critical physiological roles in water and ion balance in multiple tissues. Aquaporin-4 (AQP4), the principal aquaporin expressed in the central nervous system (CNS, brain and spinal cord), has been shown to mediate CNS water homeostasis. In this review, we summarize new and exciting studies indicating that AQP4 also plays critical and unanticipated roles in synaptic plasticity and memory formation. Next, we consider the role of AQP4 in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), neuromyelitis optica (NMO), epilepsy, traumatic brain injury (TBI), and stroke. Each of these conditions involves changes in AQP4 expression and/or distribution that may be functionally relevant to disease physiology. Insofar as AQP4 is exclusively expressed on astrocytes, these data provide new evidence of "astrocytopathy" in the etiology of diverse neurological diseases.}, }
@article {pmid28270533, year = {2018}, author = {Ghasemi, M and Brown, RH}, title = {Genetics of Amyotrophic Lateral Sclerosis.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {8}, number = {5}, pages = {}, pmid = {28270533}, issn = {2157-1422}, support = {R56 NS073873/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; R01 NS065847/NS/NINDS NIH HHS/United States ; R01 NS079836/NS/NINDS NIH HHS/United States ; R01 FD004127/FD/FDA HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Frontotemporal Dementia/*genetics ; Genetic Association Studies ; Humans ; Intercellular Signaling Peptides and Proteins/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disorder of motor neurons that overlaps clinically with frontotemporal dementia (FTD). Investigations of the 10% of ALS cases that are transmitted as dominant traits have revealed numerous gene mutations and variants that either cause these disorders or influence their clinical phenotype. The evolving understanding of the genetic architecture of ALS has illuminated broad themes in the molecular pathophysiology of both familial and sporadic ALS and FTD. These central themes encompass disturbances of protein homeostasis, alterations in the biology of RNA binding proteins, and defects in cytoskeletal dynamics, as well as numerous downstream pathophysiological events. Together, these findings from ALS genetics provide new insight into therapies that target genetically distinct subsets of ALS and FTD.}, }
@article {pmid28270301, year = {2017}, author = {Bae, JR and Kim, SH}, title = {Synapses in neurodegenerative diseases.}, journal = {BMB reports}, volume = {50}, number = {5}, pages = {237-246}, pmid = {28270301}, issn = {1976-670X}, mesh = {Alzheimer Disease/metabolism/pathology ; Humans ; Huntington Disease/pathology ; Neurodegenerative Diseases/*metabolism/physiopathology ; Neuronal Plasticity ; Parkinson Disease/metabolism/pathology ; Synapses/*metabolism/*pathology ; Synaptic Transmission/physiology ; Synaptic Vesicles/metabolism/pathology ; }, abstract = {Synapse is the basic structural and functional component for neural communication in the brain. The presynaptic terminal is the structural and functionally essential area that initiates communication and maintains the continuous functional neural information flow. It contains synaptic vesicles (SV) filled with neurotransmitters, an active zone for release, and numerous proteins for SV fusion and retrieval. The structural and functional synaptic plasticity is a representative characteristic; however, it is highly vulnerable to various pathological conditions. In fact, synaptic alteration is thought to be central to neural disease processes. In particular, the alteration of the structural and functional phenotype of the presynaptic terminal is a highly significant evidence for neural diseases. In this review, we specifically describe structural and functional alteration of nerve terminals in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). [BMB Reports 2017; 50(5): 237-246].}, }
@article {pmid28267691, year = {2017}, author = {Serebruany, VL and Fortmann, SD and Hanley, DF and Kim, MH}, title = {Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?.}, journal = {American journal of therapeutics}, volume = {24}, number = {2}, pages = {e139-e143}, doi = {10.1097/MJT.0000000000000395}, pmid = {28267691}, issn = {1536-3686}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/metabolism ; Glutamic Acid/metabolism ; Humans ; Incidence ; Lactones/*therapeutic use ; Platelet Aggregation Inhibitors/*therapeutic use ; Pyridines/*therapeutic use ; Receptor, PAR-1/*antagonists &amp; inhibitors/metabolism ; Risk Factors ; Thrombin/metabolism ; United States ; United States Food and Drug Administration ; }, abstract = {BACKGROUND: Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The vorapaxar safety profile was acceptable. However, aside from heightened bleeding risks, excesses of solid cancers and diplopia, there were more amyotrophic lateral sclerosis (ALS) diagnoses after vorapaxar.<br><br>STUDY QUESTION: To assess the Food and Drug Administration (FDA) reviews on the potential association of vorapaxar with ALS.<br><br>STUDY DESIGN: The review the public FDA records on reported adverse events after vorapaxar.<br><br>MEASURES AND OUTCOMES: Incidence of ALS after vorapaxar and placebo.<br><br>RESULTS: The ALS risk appears very small, about 1 case per 10,000 treated subjects, but quite probable. Indeed, there were overall 2 placebo and 4 vorapaxar ALS incidences in the Phase III clinical trials.<br><br>CONCLUSIONS: Potential adverse association of vorapaxar with ALS risks may be related to off-target neuronal PAR receptor(s) blockade beyond platelet inhibition.}, }
@article {pmid28266105, year = {2017}, author = {Amick, J and Ferguson, SM}, title = {C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {18}, number = {5}, pages = {267-276}, pmid = {28266105}, issn = {1600-0854}, support = {F31 GM119249/GM/NIGMS NIH HHS/United States ; P50 AG047270/AG/NIA NIH HHS/United States ; R01 GM105718/GM/NIGMS NIH HHS/United States ; T32 GM007223/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Frontotemporal Dementia/metabolism/pathology ; Humans ; Lysosomes/*metabolism ; Neurodegenerative Diseases/*metabolism/*pathology ; Proteins/*metabolism ; TOR Serine-Threonine Kinases/metabolism ; rab GTP-Binding Proteins ; }, abstract = {The discovery that expansion of a hexanucleotide repeat within a noncoding region of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia raised questions about C9orf72 protein function and potential disease relevance. The major predicted structural feature of the C9orf72 protein is a DENN (differentially expressed in normal and neoplastic cells) domain. As DENN domains are best characterized for regulation of specific Rab GTPases, it has been proposed that C9orf72 may also act through regulation of a GTPase target. Recent genetic and cell biological studies furthermore indicate that the C9orf72 protein functions at lysosomes as part of a larger complex that also contains the Smith-Magenis chromosome region 8 (SMCR8) and WD repeat-containing protein 41 (WDR41) proteins. An important role for C9orf72 at lysosomes is supported by defects in lysosome morphology and mTOR complex 1 (mTORC1) signaling arising from C9orf72 KO in diverse model systems. Collectively, these new findings define a C9orf72-containing protein complex and a lysosomal site of action as central to C9orf72 function and provide a foundation for the elucidation of direct physiological targets for C9orf72. Further elucidation of mechanisms whereby C9orf72 regulates lysosome function will help to determine how the reductions in C9orf72 expression levels that accompany hexanucleotide repeat expansions contribute to disease pathology.}, }
@article {pmid28258384, year = {2017}, author = {Bausch, D and Keck, T}, title = {[Laparoscopic pancreatic resection].}, journal = {Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen}, volume = {88}, number = {6}, pages = {484-489}, pmid = {28258384}, issn = {1433-0385}, mesh = {Cohort Studies ; Germany ; Hospitals, High-Volume/statistics &amp; numerical data ; Hospitals, Low-Volume/statistics &amp; numerical data ; Laparoscopy/instrumentation/*methods ; Pancreatectomy/instrumentation/*methods ; Pancreatic Neoplasms/mortality/*surgery ; Retrospective Studies ; Survival Analysis ; }, abstract = {INTRODUCTION AND PURPOSE: Despite being technically challenging, laparoscopic surgical procedures are increasingly being used also in pancreatic surgery. This review attempts to evaluate these procedures based on the currently available literature against the background of the high mortality of pancreatic surgery observed nationwide and the as yet unclear oncological validation of these procedures.<br><br>MATERIAL AND METHODS: Recently published retrospective cohort and register trials have evaluated not only perioperative outcome but also long-term survival after laparoscopic pancreatic resection.<br><br>RESULTS AND CONCLUSION: Laparoscopic interventions are increasingly being used for treatment of malignant tumors of the pancreas. The advantages of laparoscopy, such as less intraoperative blood loss, reduced postoperative pain and a&#xa0;shorter duration of hospital stay, have all been demonstrated in retrospective trials. Equivalent long-term survival after oncological laparoscopic pancreatic surgery compared to open procedures was also observed in these trials; however, mortality even after laparoscopic pancreatic surgery was found to be significantly increased in low-volume centers. Prospective trials are still needed to prove adequate oncological treatment. Laparoskopische Verfahren haben sich in den letzten Jahren in fast allen Bereichen der Chirurgie quasi zum Standard entwickelt und werden von Patienten zunehmend nachgefragt. Die kosmetischen Ergebnisse sind deutlich besser als bei konventionellem Vorgehen und sie reduzieren unter anderem den postoperativen Schmerz, Schmerzmittelbedarf sowie den Krankenhausaufenthalt [29]. Daher ist es wenig &#xfc;berraschend, dass minimal-invasive Verfahren auch bei technisch hochkomplexen Eingriffen, wie z.&#x2009;B. am Pankreas, zunehmend eingesetzt werden. Allerdings wird ihr Einsatz hier noch immer kontrovers diskutiert.}, }
@article {pmid28253991, year = {2017}, author = {Kumar, S and Vijayan, M and Bhatti, JS and Reddy, PH}, title = {MicroRNAs as Peripheral Biomarkers in Aging and Age-Related Diseases.}, journal = {Progress in molecular biology and translational science}, volume = {146}, number = {}, pages = {47-94}, doi = {10.1016/bs.pmbts.2016.12.013}, pmid = {28253991}, issn = {1878-0814}, support = {R01 AG042178/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*genetics ; Animals ; Biomarkers/blood/metabolism ; *Disease ; Humans ; MicroRNAs/blood/*metabolism ; Models, Biological ; }, abstract = {MicroRNAs (miRNAs) are found in the circulatory biofluids considering the important molecules for biomarker study in aging and age-related diseases. Blood or blood components (serum/plasma) are primary sources of circulatory miRNAs and can release these in cell-free form either bound with some protein components or encapsulated with microvesicle particles, called exosomes. miRNAs are quite stable in the peripheral circulation and can be detected by high-throughput techniques like qRT-PCR, microarray, and sequencing. Intracellular miRNAs could modulate mRNA activity through target-specific binding and play a crucial role in intercellular communications. At a pathological level, changes in cellular homeostasis lead to the modulation of molecular function of cells; as a result, miRNA expression is deregulated. Deregulated miRNAs came out from cells and frequently circulate in extracellular body fluids as part of various human diseases. Most common aging-associated diseases are cardiovascular disease, cancer, arthritis, dementia, cataract, osteoporosis, diabetes, hypertension, and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Variation in the miRNA signature in a diseased peripheral circulatory system opens up a new avenue in the field of biomarker discovery. Here, we measure the biomarker potential of circulatory miRNAs in aging and various aging-related pathologies. However, further more confirmatory researches are needed to elaborate these findings at the translation level.}, }
@article {pmid28253983, year = {2017}, author = {Reddy, PH and Williams, J and Smith, F and Bhatti, JS and Kumar, S and Vijayan, M and Kandimalla, R and Kuruva, CS and Wang, R and Manczak, M and Yin, X and Reddy, AP}, title = {MicroRNAs, Aging, Cellular Senescence, and Alzheimer's Disease.}, journal = {Progress in molecular biology and translational science}, volume = {146}, number = {}, pages = {127-171}, doi = {10.1016/bs.pmbts.2016.12.009}, pmid = {28253983}, issn = {1878-0814}, support = {R01 AG042178/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*genetics ; Alzheimer Disease/*genetics ; Animals ; Cellular Senescence/*genetics ; Humans ; MicroRNAs/*metabolism ; Nerve Degeneration/genetics/pathology ; Signal Transduction/genetics ; }, abstract = {Aging is a normal process of living being. It has been reported that multiple cellular changes, including oxidative damage/mitochondrial dysfunction, telomere shortening, inflammation, may accelerate the aging process, leading to cellular senescence. These cellular changes induce age-related human diseases, including Alzheimer's, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, cardiovascular, cancer, and skin diseases. Changes in somatic and germ-line DNA and epigenetics are reported to play large roles in accelerating the onset of human diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent discoveries in molecular biology have revealed that microRNAs (miRNAs) are potential indicators of aging, cellular senescence, and Alzheimer's disease (AD). The purpose of our chapter is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging, cellular senescence, and AD. This chapter also critically evaluates miRNA-based therapeutic drug targets for aging and age-related diseases, particularly Alzheimer's.}, }
@article {pmid28253479, year = {2017}, author = {von Vopelius-Feldt, J and Brandling, J and Benger, J}, title = {Systematic review of the effectiveness of prehospital critical care following out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {114}, number = {}, pages = {40-46}, doi = {10.1016/j.resuscitation.2017.02.018}, pmid = {28253479}, issn = {1873-1570}, support = {DRF-2015-08-040/DH_/Department of Health/United Kingdom ; }, mesh = {Advanced Cardiac Life Support/*standards ; Critical Care/*standards ; Emergency Medical Services/*standards ; Female ; Humans ; Male ; Observational Studies as Topic ; Out-of-Hospital Cardiac Arrest/mortality/*therapy ; Outcome Assessment, Health Care ; Prospective Studies ; *Quality of Health Care ; }, abstract = {BACKGROUND: Improving survival after out-of-hospital cardiac arrest (OHCA) is a priority for modern emergency medical services (EMS) and prehospital research. Advanced life support (ALS) is now the standard of care in most EMS. In some EMS, prehospital critical care providers are also dispatched to attend OHCA. This systematic review presents the evidence for prehospital critical care for OHCA, when compared to standard ALS care.<br><br>METHODS: We searched the following electronic databases: PubMed, EmBASE, CINAHL Plus and AMED (via EBSCO), Cochrane Database of Systematic Reviews, DARE, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, NIHR Health Technology Assessment Database, Google Scholar and ClinicalTrials.gov. Search terms related to cardiac arrest and prehospital critical care. All studies that compared patient-centred outcomes between prehospital critical care and ALS for OHCA were included.<br><br>RESULTS: The review identified six full text publications that matched the inclusion criteria, all of which are observational studies. Three studies showed no benefit from prehospital critical care but were underpowered with sample sizes of 1028-1851. The other three publications showed benefit from prehospital critical care delivered by physicians. However, an imbalance of prognostic factors and hospital treatment in these studies systematically favoured the prehospital critical care group.<br><br>CONCLUSION: Current evidence to support prehospital critical care for OHCA is limited by the logistic difficulties of undertaking high quality research in this area. Further research needs an appropriate sample size with adjustments for confounding factors in observational research design.}, }
@article {pmid28250737, year = {2017}, author = {Braidy, N and Grant, R}, title = {Kynurenine pathway metabolism and neuroinflammatory disease.}, journal = {Neural regeneration research}, volume = {12}, number = {1}, pages = {39-42}, pmid = {28250737}, issn = {1673-5374}, abstract = {Immune-mediated activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP) is a consistent finding in all inflammatory disorders. Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites, including quinolinic acid (QUIN) in neuroinflammatory neurological disorders, including Alzheimer's disease (AD), multiple sclerosis, amylotropic lateral sclerosis (ALS), and AIDS related dementia complex (ADC). Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response. Under physiological conditions, QUIN is metabolized to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD[+]), which represents an important metabolic cofactor and electron transporter. NAD[+] also serves as a substrate for the DNA 'nick sensor' and putative nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP). Free radical initiated DNA damage, PARP activation and NAD[+] depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease.}, }
@article {pmid28248783, year = {2017}, author = {Bellomo, TL and Cichminski, L}, title = {Amyotrophic Lateral Sclerosis: What Nurses Need to Know.}, journal = {Home healthcare now}, volume = {35}, number = {3}, pages = {160-165}, doi = {10.1097/NHH.0000000000000532}, pmid = {28248783}, issn = {2374-4537}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*nursing ; Humans ; *Nursing Assessment ; }, abstract = {A MOTHER OF THREE teenage children, Mrs. S, 49, presented to her healthcare provider with bilateral leg twitching and weakness, difficulty swallowing, and fatigue that's worsened over the past few weeks. While she was on her daily morning walk, she tripped and fell. She experienced a small laceration to her leg, prompting her visit to the healthcare facility. Her husband said that she'd had periods of slurred speech over the past few months as well. She was alert and oriented, and her vital signs were all within normal limits.After an exam, her healthcare provider referred her to a neurologist who ordered magnetic resonance imaging (MRI), an electromyogram, and a full bloodwork panel. After multiple visits to rule out other causes, Mrs. S received the devastating diagnosis of amyotrophic lateral sclerosis (ALS).}, }
@article {pmid28245254, year = {2017}, author = {Horrocks, S and Wilkinson, T and Schnier, C and Ly, A and Woodfield, R and Rannikmäe, K and Quinn, TJ and Sudlow, CL}, title = {Accuracy of routinely-collected healthcare data for identifying motor neurone disease cases: A systematic review.}, journal = {PloS one}, volume = {12}, number = {2}, pages = {e0172639}, pmid = {28245254}, issn = {1932-6203}, support = {MC_U137686860/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/P001823/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Data Collection/*standards ; Databases, Factual/standards ; Delivery of Health Care ; Humans ; Motor Neuron Disease/*diagnosis ; }, abstract = {BACKGROUND: Motor neurone disease (MND) is a rare neurodegenerative condition, with poorly understood aetiology. Large, population-based, prospective cohorts will enable powerful studies of the determinants of MND, provided identification of disease cases is sufficiently accurate. Follow-up in many such studies relies on linkage to routinely-collected health datasets. We systematically evaluated the accuracy of such datasets in identifying MND cases.<br><br>METHODS: We performed an electronic search of MEDLINE, EMBASE, Cochrane Library and Web of Science for studies published between 01/01/1990-16/11/2015 that compared MND cases identified in routinely-collected, coded datasets to a reference standard. We recorded study characteristics and two key measures of diagnostic accuracy-positive predictive value (PPV) and sensitivity. We conducted descriptive analyses and quality assessments of included studies.<br><br>RESULTS: Thirteen eligible studies provided 13 estimates of PPV and five estimates of sensitivity. Twelve studies assessed hospital and/or death certificate-derived datasets; one evaluated a primary care dataset. All studies were from high income countries (UK, Europe, USA, Hong Kong). Study methods varied widely, but quality was generally good. PPV estimates ranged from 55-92% and sensitivities from 75-93%. The single (UK-based) study of primary care data reported a PPV of 85%.<br><br>CONCLUSIONS: Diagnostic accuracy of routinely-collected health datasets is likely to be sufficient for identifying cases of MND in large-scale prospective epidemiological studies in high income country settings. Primary care datasets, particularly from countries with a widely-accessible national healthcare system, are potentially valuable data sources warranting further investigation.}, }
@article {pmid28243191, year = {2017}, author = {Freibaum, BD and Taylor, JP}, title = {The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {35}, pmid = {28243191}, issn = {1662-5099}, support = {R35 NS097974/NS/NINDS NIH HHS/United States ; }, abstract = {Expansion of a hexanucleotide (GGGGCC) repeat in the gene chromosome 9 open reading frame 72 (C9ORF72) is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Three non-exclusive mechanisms have been proposed to contribute to the pathology initiated by this genetic insult. First, it was suggested that decreased expression of the C9orf72 protein product may contribute to disease. Second, the recognition that C9ORF72-related disease is associated with accumulation of GGGGCC repeat-containing RNA in nuclear foci led to the suggestion that toxic gain of RNA function, perhaps related to sequestration of RNA-binding proteins, might be an important driver of disease. Third, it was subsequently appreciated that GGGGCC repeat-containing RNA undergoes unconventional translation to produce unnatural dipeptide repeat (DPR) proteins that accumulate in patient brain early in disease. DPRs translated from all six reading frames in either the sense or antisense direction of the hexanucleotide repeat result in the expression of five DPRs: glycine-alanine (GA), glycine-arginine (GR), proline-alanine (PA), proline-arginine (PR) and glycine-proline (GP; GP is generated from both the sense and antisense reading frames). However, the relative contribution of each DPR to disease pathogenesis remains unclear. Here, we review evidence for the contribution of each specific DPR to pathogenesis and examine the probable mechanisms through which these DPRs induce neurodegeneration. We also consider the association of the toxic DPRs with impaired RNA metabolism and alterations to the liquid-like state of non-membrane-bound organelles.}, }
@article {pmid28240206, year = {2017}, author = {Medina, J and Perron, H}, title = {[DNA sequences from mobile genetic elements, a hidden half of the human genome].}, journal = {Medecine sciences : M/S}, volume = {33}, number = {2}, pages = {151-158}, doi = {10.1051/medsci/20173302010}, pmid = {28240206}, issn = {1958-5381}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; *Base Sequence ; Evolution, Molecular ; Genome, Human/*genetics ; Humans ; Interspersed Repetitive Sequences/*genetics ; Multiple Sclerosis/genetics ; Retroelements/genetics ; Sequence Analysis, DNA ; Terminal Repeat Sequences ; }, abstract = {Current data estimate that mobile genetic elements represent more than one-half of the human genome. The literature is constantly updating data following the evolution of sequencing techniques and of algorithms for genome analyses. This review aims to provide an overview of the topic showing the complexity given by the various designations and classifications found in scientific papers. A particular focus is made on retrotransposons, including Endogenous RetroViruses (ERV), to introduce a second article focusing on their activation and their involvement in physiological functions and/or pathological mechanisms associated with diseases like multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS).}, }
@article {pmid28235672, year = {2017}, author = {De Vos, KJ and Hafezparast, M}, title = {Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research?.}, journal = {Neurobiology of disease}, volume = {105}, number = {}, pages = {283-299}, pmid = {28235672}, issn = {1095-953X}, support = {BB/D012309/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0300854/MRC_/Medical Research Council/United Kingdom ; MR/K005146/1/MRC_/Medical Research Council/United Kingdom ; MR/M013251/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Axonal Transport/*physiology ; Humans ; Motor Neuron Disease/*physiopathology ; *Neurobiology ; Translational Research, Biomedical/*methods ; }, abstract = {Intracellular trafficking of cargoes is an essential process to maintain the structure and function of all mammalian cell types, but especially of neurons because of their extreme axon/dendrite polarisation. Axonal transport mediates the movement of cargoes such as proteins, mRNA, lipids, membrane-bound vesicles and organelles that are mostly synthesised in the cell body and in doing so is responsible for their correct spatiotemporal distribution in the axon, for example at specialised sites such as nodes of Ranvier and synaptic terminals. In addition, axonal transport maintains the essential long-distance communication between the cell body and synaptic terminals that allows neurons to react to their surroundings via trafficking of for example signalling endosomes. Axonal transport defects are a common observation in a variety of neurodegenerative diseases, and mutations in components of the axonal transport machinery have unequivocally shown that impaired axonal transport can cause neurodegeneration (reviewed in El-Kadi et al., 2007, De Vos et al., 2008; Millecamps and Julien, 2013). Here we review our current understanding of axonal transport defects and the role they play in motor neuron diseases (MNDs) with a specific focus on the most common form of MND, amyotrophic lateral sclerosis (ALS).}, }
@article {pmid28222570, year = {2017}, author = {Neto, LL and Constantini, AC and Chun, RYS}, title = {Communication vulnerable in patients with Amyotrophic Lateral Sclerosis: A systematic review.}, journal = {NeuroRehabilitation}, volume = {40}, number = {4}, pages = {561-568}, doi = {10.3233/NRE-171443}, pmid = {28222570}, issn = {1878-6448}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*rehabilitation ; Brain-Computer Interfaces/statistics &amp; numerical data ; Communication Aids for Disabled/*statistics &amp; numerical data ; Disabled Persons/rehabilitation/statistics &amp; numerical data ; Humans ; Nonverbal Communication ; Periodicals as Topic/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Individuals with Amyotrophic Lateral Sclerosis (ALS) exhibit speech disorders since the early stages that decrease the communication rate and interfere in social participation.<br><br>OBJECTIVE: To conduct a literature review on communication vulnerable and Augmentative and Alternative Communication (AAC) in Amyotrophic Lateral Sclerosis.<br><br>METHOD: Descriptors of the Health Sciences Descriptors (DeCS) were used: Amyotrophic Lateral Sclerosis, Health Vulnerability, Communication Barriers, Nonverbal Communication, and Communication Aids for Disabled. Articles in Portuguese and English from 2010 to 2015, fully available in the Virtual Health Library, PubMed, and Scopus were used. Duplicate articles and those not related to communication/language were excluded.<br><br>RESULTS: Of the 94 articles found, 37 met the criteria. All of them were published in the USA and Europe, none was Brazilian; 27% of 2012 to 2014; 40.5% descriptive studies and 24.3% case studies; 45.9% addressed ALS and 24.3%, other serious motor alterations, including ALS. A large proportion (89.2%) addressed AAC, 70.3% Brain-Computer Interface (BCI).<br><br>CONCLUSION: The results show that the researches recurrently addressed communication vulnerable, although not necessarily in these terms. The device which was most employed was the BCI, mainly in advanced stages of the disease.}, }
@article {pmid28220542, year = {2017}, author = {Tremlett, H and Bauer, KC and Appel-Cresswell, S and Finlay, BB and Waubant, E}, title = {The gut microbiome in human neurological disease: A review.}, journal = {Annals of neurology}, volume = {81}, number = {3}, pages = {369-382}, doi = {10.1002/ana.24901}, pmid = {28220542}, issn = {1531-8249}, mesh = {Animals ; *Demyelinating Autoimmune Diseases, CNS/etiology/immunology/microbiology ; Gastrointestinal Microbiome/*physiology ; Humans ; *Neurodegenerative Diseases/etiology/immunology/microbiology ; }, abstract = {Almost half the cells and 1% of the unique genes found in our bodies are human, the rest are from microbes, predominantly bacteria, archaea, fungi, and viruses. These microorganisms collectively form the human microbiota, with most colonizing the gut. Recent technological advances, open access data libraries, and application of high-throughput sequencing have allowed these microbes to be identified and their contribution to neurological health to be examined. Emerging evidence links perturbations in the gut microbiota to neurological disease, including disease risk, activity, and progression. This review provides an overview of the recent advances in microbiome research in relation to neuro(auto)immune and neurodegenerative conditions affecting humans, such as multiple sclerosis, neuromyelitis optica spectrum disorders, Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Study design and terminology used in this rapidly evolving, highly multidisciplinary field are summarized to empower and engage the neurology community in this "newly discovered organ." Ann Neurol 2017;81:369-382.}, }
@article {pmid28214306, year = {2017}, author = {Peckruhn, M and Tittelbach, J and Elsner, P}, title = {Update: Therapie der Necrobiosis lipoidica.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {15}, number = {2}, pages = {151-158}, doi = {10.1111/ddg.13186_g}, pmid = {28214306}, issn = {1610-0387}, abstract = {Die Necrobiosis lipoidica ist eine seltene granulomatöse Erkrankung von bisher unzureichend geklärter Ätiologie. Häufig stellt die bei Diabetikern gehäuft zu beobachtende und zur Ulzeration neigende Dermatose eine starke Belastung für die Patienten dar. Bezüglich der Therapie existieren aktuell keine deutschen oder europäischen Leitlinien. Gleichzeitig lässt sich unter der aktuellen Standardtherapie, der lokalen oder intraläsionalen Anwendung von Glukokortikoiden, nicht immer ein zufriedenstellendes Ansprechen beobachten. Daher wurde untersucht, ob seit dem Jahr 2000 publizierte Therapiemodalitäten das Therapiespektrum relevant und erfolgversprechend erweitern. Es erfolgte eine Betrachtung aller Arbeiten im oben genannten Zeitraum, bei denen mehr als ein Einzelfallbericht je Therapiemodalität publiziert wurde. Insgesamt wurden in einem systematischen Review die Daten von 16 verschiedenen, seit 2000 publizierten Therapieverfahren in 49 Publikationen analysiert. Im Ergebnis zeigte sich, dass die meisten Erfahrungen bezüglich der topischen PUVA-Therapie, der photodynamischen Therapie (PDT) und der systemischen Therapie mit Fumarsäureestern vorliegen. Allerdings ist auffällig, dass mit steigender Zahl der pro Behandlungsmodalität behandelten Patienten der Anteil der Patienten, bei denen eine Abheilung bzw. eine teilweise Abheilung berichtet wurde, sinkt. Wir interpretieren diese Beobachtung als Publikationsbias. Daher kann für keines der besprochenen Verfahren eine klare Empfehlung als Therapie der zweiten Wahl nach Versagen der lokalen bzw. intraläsionalen Steroidtherapie gegeben werden.}, }
@article {pmid28214109, year = {2017}, author = {Dardiotis, E and Siokas, V and Pantazi, E and Dardioti, M and Rikos, D and Xiromerisiou, G and Markou, A and Papadimitriou, D and Speletas, M and Hadjigeorgiou, GM}, title = {A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature.}, journal = {Neurobiology of aging}, volume = {53}, number = {}, pages = {194.e13-194.e22}, doi = {10.1016/j.neurobiolaging.2017.01.015}, pmid = {28214109}, issn = {1558-1497}, mesh = {Adaptor Proteins, Signal Transducing/genetics ; Adult ; Exons/genetics ; Female ; *Genetic Association Studies ; Heterozygote ; Humans ; Lipodystrophy/*genetics ; Membrane Glycoproteins/*genetics ; Membrane Proteins/genetics ; *Mutation ; Osteochondrodysplasias/*genetics ; Phenotype ; Receptors, Immunologic/*genetics ; Subacute Sclerosing Panencephalitis/*genetics ; }, abstract = {Nasu-hakola disease (NHD) is a rare disease characterized by bone cysts and fractures, frontal lobe syndrome, and progressive presenile dementia. NHD may be the prototype of primary microglial disorders of the CNS or, as they have been coined, "microgliopathies". Mutations in TREM2 and TYROBP genes are known to cause NHD. Interestingly, recent evidence-associated rare genetic variants of TREM2 gene with increased risk of Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we report a 33-year-old Greek female with phenotype suggestive of NHD. Full gene sequencing of the TREM2 and TYROBP genes revealed a novel mutation in exon 2 of TREM2 gene, namely c.244G>T (p.W50C) and heterozygosity in the parents and her brother. This report extends the range of TREM2 mutations that cause NHD phenotype. In addition, we provide a comprehensive review of all reported in the literature TREM2 gene mutations and the respective wide spectrum of clinical manifestations that highlights the importance of considering TREM2 gene mutations in a variety of neurodegenerative phenotypes.}, }
@article {pmid28210978, year = {2017}, author = {Masdeu, JC}, title = {Future Directions in Imaging Neurodegeneration.}, journal = {Current neurology and neuroscience reports}, volume = {17}, number = {1}, pages = {9}, pmid = {28210978}, issn = {1534-6293}, mesh = {Alzheimer Disease/*diagnosis/metabolism ; Amyloid/analysis/metabolism ; Animals ; Humans ; Magnetic Resonance Imaging ; Neuroimaging/*methods ; Positron-Emission Tomography ; tau Proteins/analysis/metabolism ; }, abstract = {Neuroimaging comprises a powerful set of instruments to diagnose various neurodegenerative disorders, clarifies their neurobiology, and monitors their treatment. Magnetic resonance imaging depicts volume changes, as well as abnormalities in functional and structural connectivity. Positron emission tomography (PET) allows for the quantification of regional cerebral metabolism, characteristically altered in Alzheimer's disease, amyotrophic lateral sclerosis, diffuse Lewy-body disease, and the frontotemporal dementias. PET is also used to measure several neurotransmitters, such as dopamine, which is abnormal in Parkinson's disease, and to determine the abnormal brain deposition of amyloid-β and tau, as well as brain inflammation. These instruments allow for the quantification in vivo and the longitudinal follow-up of key neurobiological events in neurodegeneration. For instance, amyloid imaging is being used not only to determine who has excess amyloid in the brain but also to investigate whether removing it may slow the deposition of tau and delay cognitive impairment in Alzheimer's disease.}, }
@article {pmid28209726, year = {2017}, author = {Bading, H}, title = {Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations.}, journal = {The Journal of experimental medicine}, volume = {214}, number = {3}, pages = {569-578}, pmid = {28209726}, issn = {1540-9538}, mesh = {Animals ; Calcium Signaling ; Cell Nucleus/metabolism ; Energy Metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/therapeutic use ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors/physiology ; Signal Transduction/drug effects/physiology ; }, abstract = {Activation of extrasynaptic N-methyl-d-aspartate (NMDA) receptors causes neurodegeneration and cell death. The disease mechanism involves a pathological triad consisting of mitochondrial dysfunction, loss of integrity of neuronal structures and connectivity, and disruption of excitation-transcription coupling caused by CREB (cyclic adenosine monophosphate-responsive element-binding protein) shut-off and nuclear accumulation of class IIa histone deacetylases. Interdependency within the triad fuels an accelerating disease progression that culminates in failure of mitochondrial energy production and cell loss. Both acute and slowly progressive neurodegenerative conditions, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease, share increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. Six areas of therapeutic objectives are defined, based on which a broadly applicable combination therapy is proposed to combat the pathological triad of extrasynaptic NMDA receptor signaling that is common to many neurodegenerative diseases.}, }
@article {pmid28208729, year = {2017}, author = {Yamashita, T and Akamatsu, M and Kwak, S}, title = {Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {8}, number = {2}, pages = {}, pmid = {28208729}, issn = {2073-4425}, abstract = {Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca[2+] influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model.}, }
@article {pmid28208059, year = {2017}, author = {Shorter, J}, title = {Designer protein disaggregases to counter neurodegenerative disease.}, journal = {Current opinion in genetics &amp; development}, volume = {44}, number = {}, pages = {1-8}, pmid = {28208059}, issn = {1879-0380}, support = {R21 NS090205/NS/NINDS NIH HHS/United States ; R21 HD074510/HD/NICHD NIH HHS/United States ; DP2 OD002177/OD/NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 NS067354/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Bacteriophages/genetics ; HSP110 Heat-Shock Proteins/*genetics ; HSP40 Heat-Shock Proteins/*genetics ; HSP72 Heat-Shock Proteins/*genetics ; Heat-Shock Proteins/*genetics ; Humans ; Parkinson Disease/genetics ; Protein Aggregation, Pathological/genetics ; Protein Folding ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; }, abstract = {Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, and apply protein disaggregases to mitigate deleterious protein misfolding and counter neurodegeneration. I focus on two exogenous protein disaggregases, Hsp104 from yeast and gene 3 protein from bacteriophages, as well as endogenous human protein disaggregases, including: (a) Hsp110, Hsp70, Hsp40, and small heat-shock proteins; (b) HtrA1; and (c) NMNAT2 and Hsp90. I suggest that protein-disaggregase modalities can be channeled to treat numerous fatal and presently incurable neurodegenerative diseases.}, }
@article {pmid28202372, year = {2017}, author = {Parashar, A and Udayabanu, M}, title = {Gut microbiota: Implications in Parkinson's disease.}, journal = {Parkinsonism &amp; related disorders}, volume = {38}, number = {}, pages = {1-7}, pmid = {28202372}, issn = {1873-5126}, mesh = {Animals ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Cognition/drug effects ; *Gastrointestinal Microbiome/drug effects ; Humans ; Parkinson Disease/*microbiology/*physiopathology ; Probiotics/therapeutic use ; }, abstract = {Gut microbiota (GM) can influence various neurological outcomes, like cognition, learning, and memory. Commensal GM modulates brain development and behavior and has been implicated in several neurological disorders like Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, anxiety, stress and much more. A recent study has shown that Parkinson's disease patients suffer from GM dysbiosis, but whether it is a cause or an effect is yet to be understood. In this review, we try to connect the dots between GM and PD pathology using direct and indirect evidence.}, }
@article {pmid28197918, year = {2017}, author = {Anderson, DB and Zanella, CA and Henley, JM and Cimarosti, H}, title = {Sumoylation: Implications for Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {963}, number = {}, pages = {261-281}, doi = {10.1007/978-3-319-50044-7_16}, pmid = {28197918}, issn = {0065-2598}, support = {G-1605/PUK_/Parkinson's UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/L003791/1/MRC_/Medical Research Council/United Kingdom ; 170/ALZS_/Alzheimer's Society/United Kingdom ; BB/F00723X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/K014358/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; *Nerve Degeneration ; Neurodegenerative Diseases/drug therapy/*metabolism/pathology/physiopathology ; Neurons/drug effects/*metabolism/pathology ; Neuroprotective Agents/therapeutic use ; *Signal Transduction/drug effects ; Small Ubiquitin-Related Modifier Proteins/*metabolism ; *Sumoylation ; Synaptic Transmission ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {The covalent posttranslational modifications of proteins are critical events in signaling cascades that enable cells to efficiently, rapidly and reversibly respond to extracellular stimuli. This is especially important in the CNS where the processes affecting synaptic communication between neurons are highly complex and very tightly regulated. Sumoylation regulates the function and fate of a diverse array of proteins and participates in the complex cell signaling pathways required for cell survival. One of the most complex signaling pathways is synaptic transmission.Correct synaptic function is critical to the working of the brain and its alteration through synaptic plasticity mediates learning, mental disorders and stroke. The investigation of neuronal sumoylation is a new and exciting field and the functional and pathophysiological implications are far-reaching. Sumoylation has already been implicated in a diverse array of neurological disorders. Here we provide an overview of current literature highlighting recent insights into the role of sumoylation in neurodegeneration. In addition we present a brief assessment of drug discovery in the analogous ubiquitin system and extrapolate on the potential for development of novel therapies that might target SUMO-associated mechanisms of neurodegenerative disease.}, }
@article {pmid28197175, year = {2016}, author = {Giacoppo, S and Mazzon, E}, title = {Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?.}, journal = {Neural regeneration research}, volume = {11}, number = {12}, pages = {1896-1899}, pmid = {28197175}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.}, }
@article {pmid28190398, year = {2017}, author = {Song, J}, title = {Transforming Cytosolic Proteins into "Insoluble" and Membrane-toxic Forms Triggering Diseases/Aging by Genetic, Pathological or Environmental Factors.}, journal = {Protein and peptide letters}, volume = {24}, number = {4}, pages = {294-306}, doi = {10.2174/0929866524666170209154001}, pmid = {28190398}, issn = {1875-5305}, mesh = {Cellular Senescence/*physiology ; *Cytosol/chemistry/metabolism ; Escherichia coli/chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; *Intrinsically Disordered Proteins/chemistry/metabolism ; *Models, Molecular ; Neurodegenerative Diseases/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Aggregates/*physiology ; }, abstract = {An increasing spectrum of diseases more than neurodegenerative diseases is characteristic of aggregation of specific proteins, while aggregation of a large number of non-specific proteins are associated with aging down to Escherichia coli. Triggered by disease-causing mutations and agingassociated damages, many well-folded cytosolic proteins become "completely insoluble" in vivo. As facilitated by our discovery in 2005 that "completely insoluble" proteins could be solubilized in unsalted water, we have deciphered that disease- and aging-associated factors act to eliminate the native folds of human VAPB-MSP and SOD1, as well as E. coli S1 ribosomal protein, consequently unlocking amphiphilic/hydrophobic regions universally existing in proteins. These disordered states with hydrophobic patches unavoidably exposed are only soluble in unsalted water but become "insoluble" in vivo with high salt concentrations. Most unexpectedly, we decoded that these disordered states acquire novel capacity to interact with membranes energetically driven by forming helices in membrane environments. Remarkably, the abnormal insertion of SOD1 mutants into ER membrane has been functionally established to trigger ER stress, an initial event of a cascade of cell specific damages in ALS pathogenesis. Together with previous results that all aggregation-prone proteins causing diseases contain "intrinsic" membrane-interacting regions, our results with "acquired" membrane- interacting capacity suggest that abnormal interactions with membranes represent a common mechanism for aggregation-prone proteins to trigger diseases and aging. Proteins, the most important functional players for all forms of life, can transform into membrane-toxic forms, if their hydrophobic/ amphiphilic regions are unlocked by genetic, pathological, or/and environmental factors, which is characteristic of aggregation.}, }
@article {pmid28181459, year = {2017}, author = {Naz, S and Beach, J and Heckert, B and Tummala, T and Pashchenko, O and Banerjee, T and Santra, S}, title = {Cerium oxide nanoparticles: a 'radical' approach to neurodegenerative disease treatment.}, journal = {Nanomedicine (London, England)}, volume = {12}, number = {5}, pages = {545-553}, doi = {10.2217/nnm-2016-0399}, pmid = {28181459}, issn = {1748-6963}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Blood-Brain Barrier/drug effects ; Cerium/chemistry/*therapeutic use ; Humans ; Multiple Sclerosis/drug therapy ; Nanomedicine/*trends ; Nanoparticles/chemistry/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress/drug effects ; Parkinson Disease/drug therapy ; }, abstract = {Despite advances in understanding the factors that cause many neurodegenerative diseases (NDs), no current therapies have yielded significant results. Cerium oxide nanoparticles (CeONPs) have recently emerged as therapeutics for the treatment of NDs due to their antioxidant properties. This report summarizes the recent findings regarding CeONPs in treatment of various NDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, ischemic stroke and amyotrophic lateral sclerosis. Interest in CeONPs as a potential nanomedicine for NDs has increased due to: their ability to alter signaling pathways, small diameter allowing passage through the blood-brain barrier and scavenging of reactive oxygen species. Due to these properties, CeONPs could eventually revolutionize existing treatments for NDs.}, }
@article {pmid28178902, year = {2017}, author = {Silva Adaya, D and Aguirre-Cruz, L and Guevara, J and Ortiz-Islas, E}, title = {Nanobiomaterials' applications in neurodegenerative diseases.}, journal = {Journal of biomaterials applications}, volume = {31}, number = {7}, pages = {953-984}, doi = {10.1177/0885328216659032}, pmid = {28178902}, issn = {1530-8022}, mesh = {Animals ; Biocompatible Materials/administration &amp; dosage/chemical synthesis ; Blood-Brain Barrier/*chemistry ; Diffusion ; Drug Compounding/methods ; Evidence-Based Medicine ; Humans ; Nanocapsules/*administration &amp; dosage/*chemistry/ultrastructure ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*administration &amp; dosage/*chemistry ; Particle Size ; Tissue Distribution ; }, abstract = {The blood-brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1-100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell-material interactions, and the current status of nanotechnology in treating Alzheimer's, Parkinson's diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.}, }
@article {pmid28176659, year = {2017}, author = {Mompean, M and Laurents, DV}, title = {Intrinsically Disordered Domains, Amyloids and Protein Liquid Phases: Evolving Concepts and Open Questions.}, journal = {Protein and peptide letters}, volume = {24}, number = {4}, pages = {281-293}, doi = {10.2174/0929866524666170206122106}, pmid = {28176659}, issn = {1875-5305}, mesh = {*Amyloid/chemistry/metabolism ; Crystallography, X-Ray ; Hydrogel, Polyethylene Glycol Dimethacrylate ; *Intrinsically Disordered Proteins/chemistry/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; *Protein Domains ; }, abstract = {Enzymes and structural proteins dominated thinking about protein structure and function for most of the twentieth century. In recent decades, however, we have begun to appreciate the significant physiological and pathological roles of nonglobular proteins. Amyloids first gained infamy from their implications in a score of human mortal diseases. However, they have recently been discovered to play vital physiological roles, such as memory consolidation in humans. This raises an important question: Can we inhibit pathological amyloids without affecting functional amyloids? Intrinsically disordered proteins (IDPs), many of which are prone to form amyloids, perform many essential functions, yet their importance has only been recognized in the last quarter century. A subclass of IDPs can form, under certain conditions, water immiscible liquid phases which serve to process, regulate, store or transport RNA. Perturbation of these remarkable liquid phases can lead to aggregates, such as those formed by the proteins TDP-43 and FUS, which are linked to ALS and other dementia. Here, we summarize our changing view of intrinsically disordered, liquid phase forming and amyloidogenic proteins and the uncertainties that will drive future research.}, }
@article {pmid28167899, year = {2017}, author = {Valle, C and Carrì, MT}, title = {Cysteine Modifications in the Pathogenesis of ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {5}, pmid = {28167899}, issn = {1662-5099}, abstract = {Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions. Consolidated studies have demonstrated a fundamental role of cysteine residues in the aggregation process of SOD1 and TDP43, but disturbance of protein thiols homeostatic factors such as protein disulfide isomerases (PDI), glutathione, cysteine oxidation or palmitoylation might contribute to a general aberration of cysteine residues proteostasis in ALS. In this article we review the evidence that cysteine modifications may have a central role in many, if not all, forms of this disease.}, }
@article {pmid28164774, year = {2017}, author = {Michalicova, A and Banks, WA and Legath, J and Kovac, A}, title = {Tauopathies - Focus on Changes at the Neurovascular Unit.}, journal = {Current Alzheimer research}, volume = {14}, number = {7}, pages = {790-801}, doi = {10.2174/1567205014666170203143336}, pmid = {28164774}, issn = {1875-5828}, mesh = {Animals ; Blood-Brain Barrier/pathology/*physiopathology ; Brain/*metabolism ; Cerebrovascular Circulation/*physiology ; Humans ; Tauopathies/*pathology ; }, abstract = {In the past, the blood-brain barrier (BBB) has been characterized mainly as a layer of endothelial cells forming the vessel/capillary wall of the brain. More recently, the BBB is considered to be a part of a highly dynamic and interactive system called the neurovascular unit (NVU), consisting of vascular cells, glial cells, and neurons. The list of central nervous system (CNS) pathologies involving BBB dysfunction is rapidly growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic and neuronal dysfunction and loss. Such processes have been implicated in different diseases, including vascular dementias, stroke, Alzheimer´s disease (AD), Parkinson´s disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau in cells of the nervous system. Increased microvascular permeability has been more typically related to cerebrovascular deposition of amyloid-β (Aβ), but in contrast very little is known about the connection between functional impairment of the BBB and the misfolded tau proteins. Here, we review what is known about tauopathies, the BBB, and the NVU.}, }
@article {pmid28164765, year = {2017}, author = {Ahmad, K and Baig, MH and Mushtaq, G and Kamal, MA and Greig, NH and Choi, I}, title = {Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview.}, journal = {Current Alzheimer research}, volume = {14}, number = {11}, pages = {1190-1197}, pmid = {28164765}, issn = {1875-5828}, support = {Z99 AG999999//Intramural NIH HHS/United States ; ZIA AG000311-16//Intramural NIH HHS/United States ; }, mesh = {Computer Simulation ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/therapy ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies.<br><br>METHOD: In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation.<br><br>CONCLUSION: The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.}, }
@article {pmid28163382, year = {2017}, author = {Yamamoto, Y}, title = {Plasma marker of tissue oxidative damage and edaravone as a scavenger drug against peroxyl radicals and peroxynitrite.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {60}, number = {1}, pages = {49-54}, pmid = {28163382}, issn = {0912-0009}, abstract = {The percentage of the plasma oxidized form of coenzyme Q10 in the total amount of coenzyme Q10 (%CoQ10) is a useful marker of oxidative stress in the circulation. Plasma free fatty acids and their composition can be used as markers of tissue oxidative damage, as demonstrated in patients suffering from a wide variety of diseases and in humans and rats under oxidative stress. Edaravone was approved for the treatment of stroke in Japan in 2001 and its mechanism of action is based on scavenging lipid peroxyl radicals. In 2015, edaravone was also approved for the treatment of ALS patients. Edaravone functions therapeutically as a scavenger of peroxynitrite, as demonstrated by the finding that its administration raises plasma uric acid levels and decreases 3-nitrotyrosine in cerebrospinal fluid.}, }
@article {pmid28163193, year = {2017}, author = {Shellikeri, S and Karthikeyan, V and Martino, R and Black, SE and Zinman, L and Keith, J and Yunusova, Y}, title = {The neuropathological signature of bulbar-onset ALS: A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {75}, number = {}, pages = {378-392}, pmid = {28163193}, issn = {1873-7528}, support = {R01 DC009890/DC/NIDCD NIH HHS/United States ; R01 DC013547/DC/NIDCD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis ; *Brain ; DNA-Binding Proteins ; Humans ; Inclusion Bodies ; Language Disorders ; }, abstract = {ALS is a multisystem disorder affecting motor and cognitive functions. Bulbar-onset ALS (bALS) may be preferentially associated with cognitive and language impairments, compared with spinal-onset ALS (sALS), stemming from a potentially unique neuropathology. The objective of this systematic review was to compare neuropathology findings reported for bALS and sALS subtypes in studies of cadaveric brains. Using Cochrane guidelines, we reviewed articles in MEDLINE, Embase, and PsycINFO databases using standardized search terms for ALS and neuropathology, from inception until July 16th 2016. 17 studies were accepted for analysis. The analysis revealed that both subtypes presented with involvement in motor and frontotemporal cortices, deep cortical structures, and cerebellum and were characterized by neuronal loss, spongiosis, myelin pallor, and ubiquitin+ and TDP43+ inclusion bodies. Changes in Broca and Wernicke areas - regions associated with speech and language processing - were noted exclusively in bALS. Further, some bALS cases presented with atypical pathology such as neurofibrillary tangles and basophilic inclusions, which were not found in sALS cases. Given the limited number of studies, all with methodological biases, further work is required to better understand neuropathology of ALS subtypes.}, }
@article {pmid28161391, year = {2017}, author = {Tu, WY and Simpson, JE and Highley, JR and Heath, PR}, title = {Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.}, journal = {Neurobiology of disease}, volume = {102}, number = {}, pages = {11-20}, doi = {10.1016/j.nbd.2017.01.011}, pmid = {28161391}, issn = {1095-953X}, mesh = {Animals ; Humans ; Motor Neurons/*physiology ; Muscular Atrophy, Spinal/*physiopathology ; }, abstract = {Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets.}, }
@article {pmid28160214, year = {2018}, author = {Do-Ha, D and Buskila, Y and Ooi, L}, title = {Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.}, journal = {Molecular neurobiology}, volume = {55}, number = {2}, pages = {1410-1418}, pmid = {28160214}, issn = {1559-1182}, support = {APP1095215//National Health and Medical Research Council/International ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Animals ; Astrocytes/*physiology ; Humans ; Interneurons/*physiology ; Ion Channels/metabolism ; Membrane Potentials/*physiology ; Motor Neurons/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K[+] concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.}, }
@article {pmid28159885, year = {2017}, author = {Vajda, A and McLaughlin, RL and Heverin, M and Thorpe, O and Abrahams, S and Al-Chalabi, A and Hardiman, O}, title = {Genetic testing in ALS: A survey of current practices.}, journal = {Neurology}, volume = {88}, number = {10}, pages = {991-999}, pmid = {28159885}, issn = {1526-632X}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MCLAUGHLIN/OCT15/957-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Testing ; Humans ; International Cooperation ; Mutation/*genetics ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: To determine the degree of consensus among clinicians on the clinical use of genetic testing in amyotrophic lateral sclerosis (ALS) and the factors that determine decision-making.<br><br>METHODS: ALS researchers worldwide were invited to participate in a detailed online survey to determine their attitudes and practices relating to genetic testing.<br><br>RESULTS: Responses from 167 clinicians from 21 different countries were analyzed. The majority of respondents (73.3%) do not consider that there is a consensus definition of familial ALS (FALS). Fifty-seven percent consider a family history of frontotemporal dementia and 48.5% the presence of a known ALS genetic mutation as sufficient for a diagnosis of FALS. Most respondents (90.2%) offer genetic testing to patients they define as having FALS and 49.4% to patients with sporadic ALS. Four main genes (SOD1, C9orf72, TARDBP, and FUS) are commonly tested. A total of 55.2% of respondents would seek genetic testing if they had personally received a diagnosis of ALS. Forty-two percent never offer presymptomatic testing to family members of patients with FALS. Responses varied between ALS specialists and nonspecialists and based on the number of new patients seen per year.<br><br>CONCLUSIONS: There is a lack of consensus among clinicians as to the definition of FALS. Substantial variation exists in attitude and practices related to genetic testing of patients and presymptomatic testing of their relatives across geographic regions and between experienced specialists in ALS and nonspecialists.}, }
@article {pmid28148298, year = {2017}, author = {Oakes, JA and Davies, MC and Collins, MO}, title = {TBK1: a new player in ALS linking autophagy and neuroinflammation.}, journal = {Molecular brain}, volume = {10}, number = {1}, pages = {5}, pmid = {28148298}, issn = {1756-6606}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; *Autophagy ; Humans ; Inflammation/*enzymology/*pathology ; Models, Biological ; Nervous System/*pathology ; Protein Serine-Threonine Kinases/chemistry/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage. Recently, eight independent human genetics studies have uncovered a link between TANK-binding kinase 1 (TBK1) mutations and ALS. TBK1 belongs to the IKK-kinase family of kinases that are involved in innate immunity signaling pathways; specifically, TBK1 is an inducer of type-1 interferons. TBK1 also has a major role in autophagy and mitophagy, chiefly the phosphorylation of autophagy adaptors. Several other ALS genes are also involved in autophagy, including p62 and OPTN. TBK1 is required for efficient cargo recruitment in autophagy; mutations in TBK1 may result in impaired autophagy and contribute to the accumulation of protein aggregates and ALS pathology. In this review, we focus on the role of TBK1 in autophagy and the contributions of this process to the pathophysiology of ALS.}, }
@article {pmid29624970, year = {2017}, author = {Fukunaga, K and Shinoda, Y}, title = {[Pathophysiological role of sigma-1 receptor in Amyotrophic lateral sclerosis].}, journal = {Seikagaku. The Journal of Japanese Biochemical Society}, volume = {89}, number = {1}, pages = {106-110}, pmid = {29624970}, issn = {0037-1017}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Calcium/metabolism ; Humans ; Mitochondria/metabolism ; Molecular Chaperones/metabolism ; Receptors, sigma/chemistry/genetics/*metabolism ; Sigma-1 Receptor ; }, }
@article {pmid28140542, year = {2017}, author = {Quist, SR and Kraas, L}, title = {Therapieoptionen beim Pyoderma gangraenosum.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {15}, number = {1}, pages = {34-41}, doi = {10.1111/ddg.13173_g}, pmid = {28140542}, issn = {1610-0387}, mesh = {Administration, Oral ; Administration, Topical ; Biological Products/adverse effects/therapeutic use ; Dermatologic Agents/adverse effects/*therapeutic use ; Drug Administration Schedule ; Drug Therapy, Combination ; Evidence-Based Medicine ; Humans ; Immunosuppressive Agents/adverse effects/therapeutic use ; Infusions, Intravenous ; Injections, Subcutaneous ; Pyoderma Gangrenosum/diagnosis/*drug therapy ; }, abstract = {Das Pyoderma gangraenosum (PG) gehört zu den orphan diseases, deren Erforschung sich lediglich auf einzelne, randomisierte, multizentrische sowie retrospektive Studien stützen kann und überwiegend auf Fallserien an kleinen Patientenkollektiven beruht. Die Therapie basiert neben topischen und lokal intraläsionalen Therapieoptionen, bei initialem und leichtem Krankheitsverlauf, insbesondere auf der Gabe von Systemtherapeutika. Diese beinhaltet neben den systemischen Glukokortikosteroiden und Ciclosporin A (CsA) auch Biologika wie intravenöses Immunglobulin G (IVIG), die TNFα-Inhibitoren Infliximab, Adalimumab und Etanercept, den IL-12/23-Antikörper Ustekinumab, den Interleukin-1-Rezeptorantagonist Anakinra und den Interleukin-1β-Antikörper Canakinumab. Die besten evidenzbasierten Studienergebnisse liegen zu CsA, Prednisolon und Infliximab vor, letzteres insbesondere bei gleichzeitigem Vorliegen einer Colitis ulcerosa oder eines Morbus Crohn. Kleinere Fallserien liegen für ein Ansprechen auf IVIG und Canakinumab vor. Obwohl die Erstbeschreibung durch Brocq fast 100 Jahren zurückliegt und die Behandlungsnotwendigkeit des PG früh erkannt wurde, bleibt die Therapie des PG bis heute eine klinische Herausforderung. Weitere klinische Studien, insbesondere an dringend erforderlichen größeren Patientenkollektiven, ein besseres Verständnis der Ätiopathogenese, der Einsatz moderner zielgerichteter Therapien mit höherer Effektivität und geringerer Nebenwirkungsrate als die konventionellen Immunsuppressiva Prednisolon und CsA lassen trotz des seltenen aber schwerwiegenden Krankheitsbildes eine Verbesserung der Therapieoptionen in Zukunft erwarten.}, }
@article {pmid28132491, year = {2016}, author = {Sangwan, S and Eisenberg, DS}, title = {Perspective on SOD1 mediated toxicity in Amyotrophic Lateral Sclerosis.}, journal = {Postepy biochemii}, volume = {62}, number = {3}, pages = {362-369}, pmid = {28132491}, issn = {0032-5422}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Humans ; Models, Molecular ; *Mutation ; Protein Conformation ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of spinal motor neurons. Although mutations in dozens of proteins have been associated with ALS, the enzyme, superoxide dismutase 1 (SOD1) was the first protein identified with the development of ALS and accounts for ~20% of familial cases. In experimental animals and patient samples, mutant SOD1 is found in cytoplasmic deposits implicating SOD1 aggregates as the toxic entities. Here we discuss the various biochemical and structure-based hypotheses proposed for mutant SOD1-associated ALS. Although much remains to be discovered about the molecular mechanism of SOD1 mediated toxicity, these hypotheses offer new avenues for therapeutic development.}, }
@article {pmid28130314, year = {2018}, author = {Gendron, TF and Petrucelli, L}, title = {Disease Mechanisms of C9ORF72 Repeat Expansions.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {8}, number = {4}, pages = {}, pmid = {28130314}, issn = {2157-1422}, support = {R21 NS089979/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/*genetics/metabolism ; Humans ; RNA Isoforms/metabolism ; RNA, Antisense/biosynthesis/genetics ; }, abstract = {G4C2 repeat expansions within the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense G4C2 and antisense G2C4 repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased C9ORF72 mRNA and protein expression. Consequently, there is ample opportunity for the C9ORF72 mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in behavior and cognition. It is thus somewhat surprising that investigations of these three seemingly disparate events often converge on similar putative pathological mechanisms. This review aims to summarize the findings and questions emerging from the field's quest to decipher how C9ORF72 repeat expansions cause the devastating diseases collectively referred to as "c9ALS/FTD."}, }
@article {pmid28130313, year = {2018}, author = {Gijselinck, I and Cruts, M and Van Broeckhoven, C}, title = {The Genetics of C9orf72 Expansions.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {8}, number = {4}, pages = {}, pmid = {28130313}, issn = {2157-1422}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein/*genetics/metabolism ; *DNA Repeat Expansion ; Frontotemporal Dementia/*genetics ; Genetic Variation ; Humans ; Phenotype ; Protein Isoforms/metabolism ; Risk Factors ; }, abstract = {Repeat expansions in the promoter region of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and related disorders of the ALS/frontotemporal lobar degeneration (FTLD) spectrum. Remarkable clinical heterogeneity among patients with a repeat expansion has been observed, and genetic anticipation over different generations has been suggested. Genetic factors modifying the clinical phenotype have been proposed, including genetic variation in other known disease genes, the genomic context of the C9orf72 repeat, and expanded repeat size, which has been estimated between 45 and several thousand units. The role of variability in normal and expanded repeat sizes for disease risk and clinical phenotype is under debate. Different pathogenic mechanisms have been proposed, including loss of function, RNA toxicity, and dipeptide repeat (DPR) protein toxicity resulting from abnormal translation of the expanded repeat, but the major mechanism is yet unclear.}, }
@article {pmid28126529, year = {2017}, author = {Danielsson, J and Oliveberg, M}, title = {Comparing protein behaviour in vitro and in vivo, what does the data really tell us?.}, journal = {Current opinion in structural biology}, volume = {42}, number = {}, pages = {129-135}, doi = {10.1016/j.sbi.2017.01.002}, pmid = {28126529}, issn = {1879-033X}, mesh = {Animals ; Humans ; Protein Stability ; *Proteins/chemistry/metabolism ; Superoxide Dismutase-1/chemistry/metabolism ; }, abstract = {The recent advancement in moving 'biophysical' analysis of proteins in vivo has finally brought us to a position where we can start to make quantitative comparisons with existing in-vitro data. A striking observation is that protein behaviour in live cells seems, after all, not that different from in test tubes, not even at the level of complex mechanisms like protein aggregation. The example examined in this review is the ALS associated protein SOD1 that apparently retains its in-vitro properties in vivo. Does this mean that the protocols for studying proteins in vivo are somehow oversimplified, or that the macromolecular properties and interplay - despite being intrinsically malleable - are evolutionary more 'streamlined' than previously anticipated? Whatever the answer may be the time is now right to put these data to critical biological test.}, }
@article {pmid28125293, year = {2017}, author = {Viswambharan, V and Thanseem, I and Vasu, MM and Poovathinal, SA and Anitha, A}, title = {miRNAs as biomarkers of neurodegenerative disorders.}, journal = {Biomarkers in medicine}, volume = {11}, number = {2}, pages = {151-167}, doi = {10.2217/bmm-2016-0242}, pmid = {28125293}, issn = {1752-0371}, mesh = {Alzheimer Disease/diagnosis/genetics/pathology ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; Biomarkers/*metabolism ; Friedreich Ataxia/diagnosis/genetics/pathology ; Humans ; Huntington Disease/diagnosis/genetics/pathology ; MicroRNAs/metabolism ; Multiple Sclerosis/diagnosis/genetics/pathology ; Muscular Atrophy, Spinal/diagnosis/genetics/pathology ; Neurodegenerative Diseases/*diagnosis/genetics/pathology ; Parkinson Disease/diagnosis/genetics/pathology ; Prion Diseases/diagnosis/genetics/pathology ; }, abstract = {Neurodegenerative diseases (NDDs) are the result of progressive deterioration of neurons, ultimately leading to disabilities. There is no effective cure for NDDs at present; ongoing therapies are mainly aimed at treating the most bothersome symptoms. Since early treatment is crucial in NDDs, there is an urgent need for specific and sensitive biomarkers that can aid in early diagnosis of these disorders. Recently, altered expression of miRNAs has been implicated in several neurological disorders, including NDDs. miRNA expression has been extensively investigated in the cells, tissues and body fluids of patients with different types of NDDs. The aim of this review is to provide a comprehensive overview of miRNAs as biomarkers and therapeutic targets for NDDs.}, }
@article {pmid28124594, year = {2017}, author = {Nguyen, KT and Pham, MN and Vo, TV and Duan, W and Tran, PH and Tran, TT}, title = {Strategies of Engineering Nanoparticles for Treating Neurodegenerative Disorders.}, journal = {Current drug metabolism}, volume = {18}, number = {9}, pages = {786-797}, doi = {10.2174/1389200218666170125114751}, pmid = {28124594}, issn = {1875-5453}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Humans ; Nanoparticles/*chemistry/*therapeutic use ; Nanotechnology ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {BACKGROUND: Neurodegenerative disorders (NDs) are typically referred to Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis and prion disease. These are commonly debilitating and, unfortunately, have few therapeutic options.<br><br>OBJECTIVE: In this review, we describe some emerging advances in nanoengineering strategies for the treatment of NDs. One of the main difficulties in fighting against NDs is to overcome the shielding of blood-brain barrier (BBB), which greatly limits the penetration of various therapeutic drugs, which sometimes leads to severe side effects. Nanotechnology, by engineering materials of a size scale usually within 1-100 nm, fortunately offers an alternative approach for novel, promising and innovative solutions. Nanoparticles are capable of not only penetrating the BBB but also releasing active ingredients at a specific site due to its surface functionalization. Therefore, nanoengineered delivery systems potentially facilitate the targeted delivery of neuronal therapeutic drugs and genes to the central nervous system. Furthermore, recently developed nanomaterials are considered as therapeutic agents themselves since they exhibit important roles in promoting the protection of healthy neurons or the regeneration of neurons to repair damaged tissues.<br><br>CONCLUSION: There have been a variety of innovative approaches to designing therapeutic nanoparticles for NDs, and each has been associated with certain pros and cons.}, }
@article {pmid28120152, year = {2018}, author = {Morello, G and Guarnaccia, M and Spampinato, AG and La Cognata, V and D'Agata, V and Cavallaro, S}, title = {Copy Number Variations in Amyotrophic Lateral Sclerosis: Piecing the Mosaic Tiles Together through a Systems Biology Approach.}, journal = {Molecular neurobiology}, volume = {55}, number = {2}, pages = {1299-1322}, pmid = {28120152}, issn = {1559-1182}, support = {CTN01_00177_817708//Italian Ministry of Education, Universities and Research/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; *DNA Copy Number Variations ; *Genetic Predisposition to Disease ; *Genome, Human ; Humans ; Polymorphism, Single Nucleotide ; Systems Biology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. Despite the molecular mechanisms underlying ALS pathogenesis that are still far from being understood, several studies have suggested the importance of a genetic contribution in both familial and sporadic forms of the disease. In addition to single-nucleotide polymorphisms (SNPs), which account for only a limited number of ALS cases, a consistent number of common and rare copy number variations (CNVs) have been associated to ALS. Most of the CNV-based association studies use a traditional candidate-gene approach that is inadequate for uncovering the genetic architectures of complex traits like ALS. The emergent paradigm of "systems biology" may offer a new perspective to better interpret the wide spectrum of CNVs in ALS, enabling the characterization of the complex network of gene products underlying ALS pathogenesis. In this review, we will explore the landscape of CNVs in ALS, putting specific emphasis on the functional impact of common CNV regions and genes consistently associated with increased risk of developing disease. In addition, we will discuss the potential contribution of multiple rare CNVs in ALS pathogenesis, focusing our attention on the complex mechanisms by which these proteins might impact, individually or in combination, the genetic susceptibility of ALS. The comprehensive detection and functional characterization of common and rare candidate risk CNVs in ALS susceptibility may bring new pieces into the intricate mosaic of ALS pathogenesis, providing interesting and important implications for a more precise molecular biomarker-assisted diagnosis and more effective and personalized treatments.}, }
@article {pmid28119559, year = {2016}, author = {Tefera, TW and Borges, K}, title = {Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments.}, journal = {Frontiers in neuroscience}, volume = {10}, number = {}, pages = {611}, pmid = {28119559}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily characterized by loss of motor neurons in brain and spinal cord. The death of motor neurons leads to denervation of muscle which in turn causes muscle weakness and paralysis, decreased respiratory function and eventually death. Growing evidence indicates disturbances in energy metabolism in patients with ALS and animal models of ALS, which are likely to contribute to disease progression. Particularly, defects in glucose metabolism and mitochondrial dysfunction limit the availability of ATP to CNS tissues and muscle. Several metabolic approaches improving mitochondrial function have been investigated in vitro and in vivo and showed varying effects in ALS. The effects of metabolic approaches in ALS models encompass delays in onset of motor symptoms, protection of motor neurons and extension of survival, which signifies an important role of metabolism in the pathogenesis of the disease. There is now an urgent need to test metabolic approaches in controlled clinical trials. In addition, more detailed studies to better characterize the abnormalities in energy metabolism in patients with ALS and ALS models are necessary to develop metabolically targeted effective therapies that can slow the progression of the disease and prolong life for patients with ALS.}, }
@article {pmid28112502, year = {2017}, author = {Sun, Y and Chakrabartty, A}, title = {Phase to Phase with TDP-43.}, journal = {Biochemistry}, volume = {56}, number = {6}, pages = {809-823}, doi = {10.1021/acs.biochem.6b01088}, pmid = {28112502}, issn = {1520-4995}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Frontotemporal Dementia/genetics/metabolism/pathology ; Humans ; *Models, Molecular ; Mutation ; Nerve Tissue Proteins/chemistry/genetics/metabolism ; Neurons/metabolism/pathology ; Phase Transition ; Protein Aggregation, Pathological/genetics/*metabolism/pathology ; Protein Conformation ; Protein Folding ; Protein Interaction Domains and Motifs ; RNA-Binding Proteins/chemistry/genetics/*metabolism ; }, abstract = {TDP-43 is a dimeric nuclear protein that plays a central role in RNA metabolism. In recent years, this protein has become a focal point of research in the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, as pathognomonic inclusions within affected neurons contain post-translationally modified TDP-43. A key question in TDP-43 research involves determining the mechanisms and triggers that cause TDP-43 to form pathological aggregates. This review gives a brief overview of the physiological and pathological roles of TDP-43 and focuses on the structural features of its protein domains and how they may contribute to normal protein function and to disease. A special emphasis is placed on the C-terminal prion-like region thought to be implicated in pathology, as it is where nearly all ALS/FTD-associated mutations reside. Recent structural studies of this domain revealed its crucial role in the formation of phase-separated liquid droplets through a partially populated α-helix. This new discovery provides further support for the theory that liquid droplets such as stress granules may be precursors to pathological aggregates, linking environmental effects such as stress to the potential etiology of the disease. The transition of TDP-43 among soluble, droplet, and aggregate phases and the implications of these transitions for pathological aggregation are summarized and discussed.}, }
@article {pmid28110595, year = {2017}, author = {Sami, N and Rahman, S and Kumar, V and Zaidi, S and Islam, A and Ali, S and Ahmad, F and Hassan, MI}, title = {Protein aggregation, misfolding and consequential human neurodegenerative diseases.}, journal = {The International journal of neuroscience}, volume = {127}, number = {11}, pages = {1047-1057}, doi = {10.1080/00207454.2017.1286339}, pmid = {28110595}, issn = {1563-5279}, mesh = {Animals ; Genetic Therapy/*methods ; Humans ; Immunotherapy/*methods ; *Molecular Chaperones ; Neurodegenerative Diseases/drug therapy/*etiology/*therapy ; Protein Aggregation, Pathological/*complications ; Proteostasis Deficiencies/*complications ; Stem Cell Transplantation/*methods ; }, abstract = {Proteins are major components of the biological functions in a cell. Biology demands that a protein must fold into its stable three-dimensional structure to become functional. In an unfavorable cellular environment, protein may get misfolded resulting in its aggregation. These conformational disorders are directly related to the tissue damage resulting in cellular dysfunction giving rise to different diseases. This way, several neurodegenerative diseases such as Alzheimer, Parkinson Huntington diseases and amyotrophic lateral sclerosis are caused. Misfolding of the protein is prevented by innate molecular chaperones of different classes. It is envisaged that work on this line is likely to translate the knowledge into the development of possible strategies for early diagnosis and efficient management of such related human diseases. The present review deals with the human neurodegenerative diseases caused due to the protein misfolding highlighting pathomechanisms and therapeutic intervention.}, }
@article {pmid28108532, year = {2018}, author = {Nonaka, T and Hasegawa, M}, title = {TDP-43 Prions.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {8}, number = {3}, pages = {}, pmid = {28108532}, issn = {2157-1422}, mesh = {Animals ; Brain/metabolism ; DNA-Binding Proteins/*chemistry ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/genetics/*pathology ; Neurons/metabolism ; Prion Proteins/*chemistry ; Protein Aggregation, Pathological/genetics/*pathology ; Proteostasis Deficiencies/genetics/*pathology ; }, abstract = {The most common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are all protein-misfolding diseases and are characterized by the presence of disease-specific protein aggregates in affected neuronal cells. Recent studies have shown that, like tau and α-synuclein, TAR-DNA binding protein of 43 kDa (TDP-43) can form aggregates in vitro in a seed-dependent, self-templating, prion-like manner. Insoluble TDP-43 prepared from the brains of patients has been classified into several strains, which can be transferred from cell to cell in vitro, suggesting the involvement of mechanisms reminiscent of those by which prions spread through the nervous system. The idea that aberrant TDP-43 aggregates propagate in a prion-like manner between cells presents the possibility of novel therapeutic strategies to block spreading of these aggregates throughout the brain.}, }
@article {pmid28105588, year = {2017}, author = {Ineichen, BV and Plattner, PS and Good, N and Martin, R and Linnebank, M and Schwab, ME}, title = {Nogo-A Antibodies for Progressive Multiple Sclerosis.}, journal = {CNS drugs}, volume = {31}, number = {3}, pages = {187-198}, pmid = {28105588}, issn = {1179-1934}, mesh = {Animals ; Antibodies/pharmacology/*therapeutic use ; Humans ; Immunologic Factors/pharmacology/*therapeutic use ; Multiple Sclerosis/*drug therapy/metabolism ; Nogo Proteins/*immunology ; }, abstract = {Most of the current therapies, as well as many of the clinical trials, for multiple sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injury. Data from spinal cord injury and amyotrophic lateral sclerosis (ALS) trials accredit a good safety profile of high doses of anti-Nogo-A antibodies administered intravenously or intrathecally. An antibody against a Nogo receptor subunit, leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1), was recently shown to improve outcome in patients with acute optic neuritis in a phase II study. Nogo-A-suppressing antibodies could be novel drug candidates for the relapsing as well as the progressive MS disease stage. In this review, we summarize the available pre-clinical and clinical evidence on Nogo-A and elucidate the potential of Nogo-A-antibodies as a therapy for progressive MS.}, }
@article {pmid28100023, year = {2017}, author = {Mann, DMA and Snowden, JS}, title = {Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {27}, number = {6}, pages = {723-736}, pmid = {28100023}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Aphasia/pathology ; Brain/pathology ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/pathology ; Frontotemporal Lobar Degeneration/*genetics/*pathology ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Mutation ; Phenotype ; Progranulins ; RNA-Binding Protein FUS/genetics ; TDP-43 Proteinopathies/genetics ; tau Proteins/genetics ; }, abstract = {Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.}, }
@article {pmid28096265, year = {2017}, author = {Sibilla, C and Bertolotti, A}, title = {Prion Properties of SOD1 in Amyotrophic Lateral Sclerosis and Potential Therapy.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {9}, number = {10}, pages = {}, pmid = {28096265}, issn = {1943-0264}, support = {BERTOLOTTI/APR11/807-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_U105185860/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Humans ; Prions/*metabolism ; Superoxide Dismutase-1/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressive neurodegenerative disease caused by the deterioration of motor neurons. The first symptoms of ALS always begin at a focal but variable site and consistently spread to neighboring regions, suggesting that neurodegeneration in ALS is an orderly and propagating process. Like other neurodegenerative diseases, misfolding of a specific protein is central to ALS. SOD1, the major constituent of the protein deposits in some familial and sporadic forms of ALS, propagates its misfolded conformation like prions, providing a plausible molecular basis for the focality and spreading of muscle weakness in ALS. Because protein misfolding is a common cause of diverse neurodegenerative diseases, strategies aimed at boosting a cell's ability to cope with misfolded proteins could lead to therapeutics to combat these devastating age-related proteinopathies.}, }
@article {pmid28096243, year = {2017}, author = {Mackenzie, IRA and Neumann, M}, title = {Fused in Sarcoma Neuropathology in Neurodegenerative Disease.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {7}, number = {12}, pages = {}, pmid = {28096243}, issn = {2157-1422}, mesh = {Humans ; *Mutation ; Neurodegenerative Diseases/*genetics/*pathology ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms.}, }
@article {pmid28095923, year = {2017}, author = {Ma, MW and Wang, J and Zhang, Q and Wang, R and Dhandapani, KM and Vadlamudi, RK and Brann, DW}, title = {NADPH oxidase in brain injury and neurodegenerative disorders.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {7}, pmid = {28095923}, issn = {1750-1326}, support = {R01 NS050730/NS/NINDS NIH HHS/United States ; R01 NS088058/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain Injuries/*enzymology ; Humans ; NADPH Oxidases/*metabolism ; Neurodegenerative Diseases/*enzymology ; }, abstract = {Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.}, }
@article {pmid28095679, year = {2017}, author = {Ballatore, C and Brunden, KR and Trojanowski, JQ and Lee, VM and Smith, AB}, title = {Non-Naturally Occurring Small Molecule Microtubule-Stabilizing Agents: A Potential Tactic for CNS-Directed Therapies.}, journal = {ACS chemical neuroscience}, volume = {8}, number = {1}, pages = {5-7}, pmid = {28095679}, issn = {1948-7193}, support = {P01 AG017586/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 NS053488/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/metabolism ; Animals ; Biological Products/administration &amp; dosage/*chemistry/*metabolism ; Central Nervous System/drug effects/metabolism ; Drug Delivery Systems/trends ; Humans ; Microtubules/drug effects/*metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Several independent studies indicate that microtubule (MT)-stabilizing agents hold considerable promise as candidate therapeutics for a wide spectrum of conditions of the central nervous system (CNS), from brain tumors to spinal cord injury, as well as a number of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease, and amyotrophic lateral sclerosis. Although the identification and development of candidate compounds for CNS-directed MT-stabilizing therapies has been a challenge in drug discovery for many years, a growing number of molecules have now been identified that exhibit both MT-stabilizing activity and brain penetration. In this Viewpoint, we will highlight the potential utility of MT-active triazolopyrimidines, phenylpyrimidines, and related classes of non-naturally occurring small molecules that exhibit favorable druglike properties, including brain penetration and oral bioavailability. The mode of action of these small molecules has not as yet been fully elucidated at the molecular level. However, based on all available data, compounds from these classes appear to act on MTs in a potentially unique manner. Further characterization of these molecules may have important ramifications for drug discovery, especially in the area of CNS diseases.}, }
@article {pmid28095296, year = {2017}, author = {Singh, RN and Howell, MD and Ottesen, EW and Singh, NN}, title = {Diverse role of survival motor neuron protein.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1860}, number = {3}, pages = {299-315}, pmid = {28095296}, issn = {1874-9399}, support = {R01 NS055925/NS/NINDS NIH HHS/United States ; R21 NS055149/NS/NINDS NIH HHS/United States ; R21 NS072259/NS/NINDS NIH HHS/United States ; R21 NS080294/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Coiled Bodies/genetics/metabolism ; Cytoskeleton/genetics/metabolism ; Female ; *Gene Expression Regulation ; Humans ; Infertility, Male/genetics/metabolism ; Male ; Myositis, Inclusion Body/genetics/metabolism ; RNA, Small Nuclear/genetics/metabolism ; Spinal Muscular Atrophies of Childhood/genetics/metabolism ; Survival of Motor Neuron 1 Protein/genetics/*metabolism ; }, abstract = {The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions.}, }
@article {pmid28090150, year = {2016}, author = {Parisi, C and Napoli, G and Pelegrin, P and Volonté, C}, title = {M1 and M2 Functional Imprinting of Primary Microglia: Role of P2X7 Activation and miR-125b.}, journal = {Mediators of inflammation}, volume = {2016}, number = {}, pages = {2989548}, pmid = {28090150}, issn = {1466-1861}, support = {614578/ERC_/European Research Council/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; Inflammation ; Macrophages/metabolism ; Mice ; MicroRNAs/genetics/*metabolism ; Microglia/*metabolism ; Motor Neurons/metabolism ; Mutation ; Phenotype ; Receptors, Purinergic P2X7/*metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a most frequently occurring and severe form of motor neuron disease, causing death within 3-5 years from diagnosis and with a worldwide incidence of about 2 per 100,000 person-years. Mutations in over twenty genes associated with familial forms of ALS have provided insights into the mechanisms leading to motor neuron death. Moreover, mutations in two RNA binding proteins, TAR DNA binding protein 43 and fused in sarcoma, have raised the intriguing possibility that perturbations of RNA metabolism, including that of the small endogenous RNA molecules that repress target genes at the posttranscriptional level, that is, microRNAs, may contribute to disease pathogenesis. At present, the mechanisms by which microglia actively participate to both toxic and neuroprotective actions in ALS constitute an important matter of research. Among the pathways involved in ALS-altered microglia responses, in previous works we have uncovered the hyperactivation of P2X7 receptor by extracellular ATP and the overexpression of miR-125b, both leading to uncontrolled toxic M1 reactions. In order to shed further light on the complexity of these processes, in this short review we will describe the M1/M2 functional imprinting of primary microglia and a role played by P2X7 and miR-125b in ALS microglia activation.}, }
@article {pmid28088537, year = {2017}, author = {Ahmed, RM and Irish, M and van Eersel, J and Ittner, A and Ke, YD and Volkerling, A and van der Hoven, J and Tanaka, K and Karl, T and Kassiou, M and Kril, JJ and Piguet, O and Götz, J and Kiernan, MC and Halliday, GM and Hodges, JR and Ittner, LM}, title = {Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology.}, journal = {Neuroscience and biobehavioral reviews}, volume = {74}, number = {Pt A}, pages = {126-138}, doi = {10.1016/j.neubiorev.2017.01.004}, pmid = {28088537}, issn = {1873-7528}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Disease Models, Animal ; *Frontotemporal Dementia ; Humans ; Mice ; Mutation ; Phenotype ; }, abstract = {Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.}, }
@article {pmid28088365, year = {2017}, author = {Czarzasta, J and Habich, A and Siwek, T and Czapliński, A and Maksymowicz, W and Wojtkiewicz, J}, title = {Stem cells for ALS: An overview of possible therapeutic approaches.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {57}, number = {}, pages = {46-55}, doi = {10.1016/j.ijdevneu.2017.01.003}, pmid = {28088365}, issn = {1873-474X}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Humans ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an unusual, fatal, neurodegenerative disorder leading to the loss of motor neurons. After diagnosis, the average lifespan ranges from 3 to 5 years, and death usually results from respiratory failure. Although the pathogenesis of ALS remains unclear, multiple factors are thought to contribute to the progression of ALS, such as network interactions between genes, environmental exposure, impaired molecular pathways and many others. The neuroprotective properties of neural stem cells (NSCs) and the paracrine signaling of mesenchymal stem cells (MSCs) have been examined in multiple pre-clinical trials of ALS with promising results. The data from these initial trials indicate a reduction in the rate of disease progression. The mechanism through which stem cells achieve this reduction is of major interest. Here, we review the to-date pre-clinical and clinical therapeutic approaches employing stem cells, and discuss the most promising ones.}, }
@article {pmid28087719, year = {2017}, author = {Ji, AL and Zhang, X and Chen, WW and Huang, WJ}, title = {Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum.}, journal = {Journal of medical genetics}, volume = {54}, number = {3}, pages = {145-154}, doi = {10.1136/jmedgenet-2016-104271}, pmid = {28087719}, issn = {1468-6244}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Brain/pathology ; C9orf72 Protein/*genetics ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics/pathology ; Humans ; Mutation ; }, abstract = {Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.}, }
@article {pmid28084617, year = {2017}, author = {Lemarchant, S and Wojciechowski, S and Vivien, D and Koistinaho, J}, title = {ADAMTS-4 in central nervous system pathologies.}, journal = {Journal of neuroscience research}, volume = {95}, number = {9}, pages = {1703-1711}, doi = {10.1002/jnr.24021}, pmid = {28084617}, issn = {1097-4547}, mesh = {*ADAMTS4 Protein ; Animals ; Central Nervous System Diseases/*metabolism ; Humans ; }, abstract = {ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloproteinase specialized in the degradation of chondroitin sulfate proteoglycans, contributing to cartilage breakdown during arthritis. In this review, we first focus on the modifications of ADAMTS-4 expression during CNS physiological and pathological conditions, including chronic diseases and injuries. Then, we discuss the contributions of ADAMTS-4 to mechanisms mediating neuroplasticity, neuroinflammation and neurodegeneration during spinal cord injury, ischemic stroke, amyotrophic lateral sclerosis and Alzheimer's disease. Here, we provide an overview of ADAMTS-4 functions and effects in the CNS, and we discuss directions for future studies and treatments. Overall, this review highlights that ADAMTS-4 is a unique multifaceted metalloproteinase which influences various CNS disease pathophysiologies. © 2017 Wiley Periodicals, Inc.}, }
@article {pmid28082868, year = {2016}, author = {Campanari, ML and García-Ayllón, MS and Ciura, S and Sáez-Valero, J and Kabashi, E}, title = {Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase.}, journal = {Frontiers in molecular neuroscience}, volume = {9}, number = {}, pages = {160}, pmid = {28082868}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a highly debilitating disease caused by progressive degeneration of motorneurons (MNs). Due to the wide variety of genes and mutations identified in ALS, a highly varied etiology could ultimately converge to produce similar clinical symptoms. A major hypothesis in ALS research is the "distal axonopathy" with pathological changes occurring at the neuromuscular junction (NMJ), at very early stages of the disease, prior to MNs degeneration and onset of clinical symptoms. The NMJ is a highly specialized cholinergic synapse, allowing signaling between muscle and nerve necessary for skeletal muscle function. This nerve-muscle contact is characterized by the clustering of the collagen-tailed form of acetylcholinesterase (ColQ-AChE), together with other components of the extracellular matrix (ECM) and specific key molecules in the NMJ formation. Interestingly, in addition to their cholinergic role AChE is thought to play several "non-classical" roles that do not require catalytic function, most prominent among these is the facilitation of neurite growth, NMJ formation and survival. In all this context, abnormalities of AChE content have been found in plasma of ALS patients, in which AChE changes may reflect the neuromuscular disruption. We review these findings and particularly the evidences of changes of AChE at neuromuscular synapse in the pre-symptomatic stages of ALS.}, }
@article {pmid28072907, year = {2017}, author = {Ng, L and Khan, F and Young, CA and Galea, M}, title = {Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {1}, pages = {CD011776}, pmid = {28072907}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Enteral Nutrition ; Exercise Therapy ; Humans ; Motor Neuron Disease/complications ; Muscle Cramp/*drug therapy/etiology ; Muscle Spasticity/etiology/*therapy ; Noninvasive Ventilation ; Pain/*drug therapy/etiology ; Respiratory Insufficiency/etiology/*therapy ; Review Literature as Topic ; Sialorrhea/etiology/*therapy ; Transcranial Magnetic Stimulation ; }, abstract = {BACKGROUND: Motor neuron disease (MND), which is also known as amyotrophic lateral sclerosis (ALS), causes a wide range of symptoms but the evidence base for the effectiveness of the symptomatic treatment therapies is limited.<br><br>OBJECTIVES: To summarise the evidence from Cochrane Systematic Reviews of all symptomatic treatments for MND.<br><br>METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) on 15 November 2016 for systematic reviews of symptomatic treatments for MND. We assessed the methodological quality of the included reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the GRADE approach. We followed standard Cochrane study (review) selection and data extraction procedures. We reported findings narratively and in tables.<br><br>MAIN RESULTS: We included nine Cochrane Systematic Reviews of interventions to treat symptoms in people with MND. Three were empty reviews with no included randomised controlled trials (RCTs); however, all three reported on non-RCT evidence and the remaining six included mostly one or two studies. We deemed all of the included reviews of high methodological quality. Drug therapy for painThere is no RCT evidence in a Cochrane Systematic Review exploring the efficacy of drug therapy for pain in MND. Treatment for crampsThere is evidence (13 RCTs, N = 4012) that for the treatment of cramps in MND, compared to placebo:- memantine and tetrahydrocannabinol (THC) are probably ineffective (moderate-quality evidence);- vitamin E may have little or no effect (low-quality evidence); and- the effects of L-threonine, gabapentin, xaliproden, riluzole, and baclofen are uncertain as the evidence is either very low quality or the trial specified the outcome but did not report numerical data.The review reported adverse effects of riluzole, but it is not clear whether other interventions had adverse effects. Treatment for spasticityIt is uncertain whether an endurance-based exercise programme improved spasticity or quality of life, measured at three months after the programme, as the quality of evidence is very low (1 RCT, comparison "usual activities", N = 25). The review did not evaluate other approaches, such as use of baclofen as no RCTs were available. Mechanical ventilation for supporting respiratory functionNon-invasive ventilation (NIV) probably improves median survival and quality of life in people with respiratory insufficiency and normal to moderately impaired bulbar function compared to standard care, and improves quality of life but not survival for people with poor bulbar function (1 RCT, N = 41, moderate-quality evidence; a second RCT did not provide data). The review did not evaluate other approaches such as tracheostomy-assisted ('invasive') ventilation, or assess timing of NIV initiation. Treatment for sialorrhoeaA single session of botulinum toxin type B injections to parotid and submandibular glands probably improves sialorrhoea and quality of life at up to 4 weeks compared to placebo injections, but not at 8 or 12 weeks after the injections (moderate-quality evidence from 1 placebo-controlled RCT, N = 20). The review authors found no trials of other approaches. Enteral tube feeding for supporting nutritionThere is no RCT evidence in a Cochrane Systematic Review to support benefit or harms of enteral tube feeding in supporting nutrition in MND. Repetitive transcranial magnetic stimulationIt is uncertain whether repetitive transcranial magnetic stimulation (rTMS) improves disability or limitation in activity in MND in comparison with sham rTMS (3 RCTs, very low quality evidence, N = 50). Therapeutic exerciseThere is evidence that exercise may improve disability in MND at three months after the exercise programme, but not quality of life, in comparison with "usual activities" or "usual care" including stretching (2 RCTs, low-quality evidence, N = 43). Multidisciplinary careThere is no RCT evidence in a Cochrane Systematic Review to demonstrate any benefit or harm for multidisciplinary care in MND.None of the reviews, other than the review of treatment for cramps, reported that adverse events occurred. However, the trials were too small for reliable adverse event reporting.<br><br>AUTHORS' CONCLUSIONS: This overview has highlighted the lack of robust evidence in Cochrane Systematic Reviews on interventions to manage symptoms resulting from MND. It is important to recognise that clinical trials may fail to demonstrate efficacy of an intervention for reasons other than a true lack of efficacy, for example because of insufficient statistical power, the wrong choice of dose, insensitive outcome measures or inappropriate participant eligibility. The trials were mostly too small to reliably assess adverse effects of the treatments. The nature of MND makes it difficult to research clinically accepted or recommended practice, regardless of the level of evidence supporting the practice. It would not be ethical, for example, to design a placebo-controlled trial for treatment of pain in MND or to withhold multidisciplinary care where such care is available. It is therefore highly unlikely that there will ever be classically designed placebo-controlled RCTs in these areas.We need more research with appropriate study designs, robust methodology, and of sufficient duration to address the changing needs-of people with MND and their caregivers-associated with MND disease progression and mortality. There is a significant gap in studies assessing the effectiveness of interventions for symptoms relating to MND, such as pseudobulbar emotional lability and cognitive and behavioural difficulties. Future studies should use appropriate outcome measures that are reliable, have internal and external validity, and are sensitive to change in what is being measured (such as quality of life).}, }
@article {pmid28070599, year = {2017}, author = {Merwin, SJ and Obis, T and Nunez, Y and Re, DB}, title = {Organophosphate neurotoxicity to the voluntary motor system on the trail of environment-caused amyotrophic lateral sclerosis: the known, the misknown, and the unknown.}, journal = {Archives of toxicology}, volume = {91}, number = {8}, pages = {2939-2952}, pmid = {28070599}, issn = {1432-0738}, support = {P30 ES009089/ES/NIEHS NIH HHS/United States ; R25 GM062454/GM/NIGMS NIH HHS/United States ; T32 ES007322/ES/NIEHS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/epidemiology/*etiology/physiopathology ; Animals ; Environmental Exposure/adverse effects ; Humans ; Incidence ; Neurotoxicity Syndromes/*physiopathology ; Organophosphates/*toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder. It is characterized by progressive degeneration of the motor neurons controlling voluntary movement. The underlying mechanisms remain elusive, a fact that has precluded development of effective treatments. ALS presents as a sporadic condition 90-95% of the time, i.e., without familial history or obvious genetic mutation. This suggests that ALS has a strong environmental component. Organophosphates (OPs) are prime candidate neurotoxicants in the etiology of ALS, as exposure to OPs was linked to higher ALS incidence among farmers, soccer players, and Gulf War veterans. In addition, polymorphisms in paraoxonase 1, an enzyme that detoxifies OPs, may increase individual vulnerability both to OP poisoning and to the risk of developing ALS. Furthermore, exposure to high doses of OPs can give rise to OP-induced delayed neuropathy (OPIDN), a debilitating condition akin to ALS characterized by similar motor impairment and paralysis. The question we pose in this review is: "what can we learn from acute exposure to high doses of neurotoxicants (OPIDN) that could help our understanding of chronic diseases resulting from potentially decades of silent exposure (ALS)?" The resemblances between OPIDN and ALS are striking at the clinical, etiological, neuropathological, cellular, and potentially molecular levels. Here, we critically present available evidence, discuss current limitations, and posit future research. In the search for the environmental origin of ALS, OPIDN offers an exciting trail to follow, which can hopefully lead to the development of novel strategies to prevent and cure these dreadful disorders.}, }
@article {pmid28067943, year = {2017}, author = {Diana, A and Pillai, R and Bongioanni, P and O'Keeffe, AG and Miller, RG and Moore, DH}, title = {Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {1}, pages = {CD006049}, pmid = {28067943}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Baclofen/therapeutic use ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; GABA Agents/adverse effects/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Time Factors ; gamma-Aminobutyric Acid/adverse effects/*therapeutic use ; }, abstract = {BACKGROUND: Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS.<br><br>OBJECTIVES: To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventions<br><br>SEARCH METHODS: On 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries.<br><br>SELECTION CRITERIA: Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.<br><br>DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.<br><br>MAIN RESULTS: We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low.<br><br>AUTHORS' CONCLUSIONS: According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.}, }
@article {pmid28063152, year = {2017}, author = {Howell, BN and Newman, DS}, title = {Dysfunction of central control of breathing in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {56}, number = {2}, pages = {197-201}, doi = {10.1002/mus.25564}, pmid = {28063152}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; Central Nervous System/*pathology ; Humans ; Respiration Disorders/*etiology/pathology ; }, abstract = {Dysfunction in central control of breathing in some amyotrophic lateral sclerosis (ALS) patients is not adequately detected with standard evaluation for respiratory dysfunction. Nocturnal oximetry reveals periodic desaturations despite normal respiratory muscle movements. Continuous diaphragmatic electromyography has provided in vivo data consistent with impaired central control of diaphragm motor units. Current understanding of central control of breathing identifies the pre-Botzinger complex as the inspiratory rhythm generator. Animal models of pre-Botzinger complex neurodegeneration demonstrate rapid eye movement-related central sleep apneas progressing to loss of rapid eye movement sleep, also apparent in some ALS patients. Evidence supports the hypothesis that dysfunction in central control of breathing in some ALS patients may be related to pre-Botzinger complex degeneration. As the impact dysfunction of central control of breathing has on ALS becomes better defined the current standard of evaluating respiratory dysfunction in ALS patients may need updating. Muscle Nerve 56: 197-201, 2017.}, }
@article {pmid28062558, year = {2017}, author = {Polymenidou, M and Cleveland, DW}, title = {Biological Spectrum of Amyotrophic Lateral Sclerosis Prions.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {7}, number = {11}, pages = {}, pmid = {28062558}, issn = {2157-1422}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; C9orf72 Protein/*genetics ; DNA-Binding Proteins/*genetics/metabolism ; Disease Models, Animal ; Frontotemporal Dementia/*genetics/metabolism ; Humans ; Inclusion Bodies/pathology ; Mice ; Mutation ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, these assemblies serve as the foci of protein misfolding and mature into insoluble structures, which further recruit native proteins, turning them into misfolded forms. This self-perpetuating mechanism is a twisted version of classical prion replication that leads to amplification of pathological protein complexes that spread throughout the neuraxis, offering a pathogenic principle that underlies the rapid disease progression that characterizes ALS and FTLD.}, }
@article {pmid28058507, year = {2017}, author = {Tan, RH and Ke, YD and Ittner, LM and Halliday, GM}, title = {ALS/FTLD: experimental models and reality.}, journal = {Acta neuropathologica}, volume = {133}, number = {2}, pages = {177-196}, doi = {10.1007/s00401-016-1666-6}, pmid = {28058507}, issn = {1432-0533}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Disease Models, Animal ; *Frontotemporal Dementia ; Humans ; }, abstract = {Amyotrophic lateral sclerosis is characterised by a loss of upper and lower motor neurons and characteristic muscle weakness and wasting, the most common form being sporadic disease with neuronal inclusions containing the tar DNA-binding protein 43 (TDP-43). Frontotemporal lobar degeneration is characterised by atrophy of the frontal and/or temporal lobes, the most common clinical form being the behavioural variant, in which neuronal inclusions containing either TDP-43 or 3-repeat tau are most prevalent. Although the genetic mutations associated with these diseases have allowed various experimental models to be developed, the initial genetic forms identified remain the most common models employed to date. It is now known that these first models faithfully recapitulate only some aspects of these diseases and do not represent the majority of cases or the most common overlapping pathologies. Newer models targeting the main molecular pathologies are still rare and in some instances, lack significant aspects of the molecular pathology. However, these diseases are complex and multigenic, indicating that experimental models may need to be targeted to different disease aspects. This would allow information to be gleaned from a variety of different yet relevant models, each of which has the capacity to capture a certain aspect of the disease, and together will enable a more complete understanding of these complex and multi-layered diseases.}, }
@article {pmid28057713, year = {2017}, author = {Zou, ZY and Zhou, ZR and Che, CH and Liu, CY and He, RL and Huang, HP}, title = {Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {88}, number = {7}, pages = {540-549}, doi = {10.1136/jnnp-2016-315018}, pmid = {28057713}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Asian People/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; Humans ; *Molecular Epidemiology ; Mutation/*genetics ; White People/genetics ; }, abstract = {BACKGROUND: Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS.<br><br>METHODS: We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis.<br><br>RESULTS: 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations.<br><br>CONCLUSIONS: These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS.}, }
@article {pmid28057298, year = {2017}, author = {Lin, G and Mao, D and Bellen, HJ}, title = {Amyotrophic Lateral Sclerosis Pathogenesis Converges on Defects in Protein Homeostasis Associated with TDP-43 Mislocalization and Proteasome-Mediated Degradation Overload.}, journal = {Current topics in developmental biology}, volume = {121}, number = {}, pages = {111-171}, doi = {10.1016/bs.ctdb.2016.07.004}, pmid = {28057298}, issn = {1557-8933}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; DNA-Binding Proteins/*metabolism ; *Homeostasis ; Humans ; Proteasome Endopeptidase Complex/*metabolism ; *Proteolysis ; RNA Processing, Post-Transcriptional ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS. We examine the biological functions of these genes to assess how these pathogenic variants contribute to ALS pathogenesis by integrating findings from studies in Drosophila melanogaster and mammals. Additionally, we highlight the functional and genetic connections between these loci. Altogether, this review reveals that the majority of biological studies converge on defects in proteostasis due to the mislocalization of TDP-43 and/or altering the function of specific proteins mediating or modulating proteasomal degradation.}, }
@article {pmid28054827, year = {2017}, author = {Strong, MJ and Abrahams, S and Goldstein, LH and Woolley, S and Mclaughlin, P and Snowden, J and Mioshi, E and Roberts-South, A and Benatar, M and HortobáGyi, T and Rosenfeld, J and Silani, V and Ince, PG and Turner, MR}, title = {Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {3-4}, pages = {153-174}, pmid = {28054827}, issn = {2167-9223}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/K026992/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Canada ; Diagnosis, Differential ; Frontotemporal Dementia/*diagnosis/*psychology ; Humans ; Language ; Neuroimaging ; Neuropsychological Tests ; Social Perception ; Survival Analysis ; }, abstract = {This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised - - including deficits in social cognition and language - but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).}, }
@article {pmid28054357, year = {2017}, author = {Gama-Carvalho, M and L Garcia-Vaquero, M and R Pinto, F and Besse, F and Weis, J and Voigt, A and Schulz, JB and De Las Rivas, J}, title = {Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA-transcriptome homeostasis: a genomics perspective.}, journal = {Journal of neurochemistry}, volume = {141}, number = {1}, pages = {12-30}, doi = {10.1111/jnc.13945}, pmid = {28054357}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Animals ; Databases, Genetic ; Genomics/*methods ; Homeostasis/*genetics ; Humans ; Muscular Atrophy, Spinal/diagnosis/*genetics ; RNA/*genetics ; Transcriptome/*genetics ; }, abstract = {In this review, we present our most recent understanding of key biomolecular processes that underlie two motor neuron degenerative disorders, amyotrophic lateral sclerosis, and spinal muscular atrophy. We focus on the role of four multifunctional proteins involved in RNA metabolism (TDP-43, FUS, SMN, and Senataxin) that play a causal role in these diseases. Recent results have led to a novel scenario of intricate connections between these four proteins, bringing transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration. We review reported functional and physical interactions between these four proteins, highlighting their common association with nuclear bodies and small nuclear ribonucleoprotein particle biogenesis and function. We discuss how these interactions are turning out to be particularly relevant for the control of transcription and chromatin homeostasis, including the recent identification of an association between SMN and Senataxin required to ensure the resolution of DNA-RNA hybrid formation and proper termination by RNA polymerase II. These connections strongly support the existence of common pathways underlying the spinal muscular atrophy and amyotrophic lateral sclerosis phenotype. We also discuss the potential of genome-wide expression profiling, in particular RNA sequencing derived data, to contribute to unravelling the underlying mechanisms. We provide a review of publicly available datasets that have addressed both diseases using these approaches, and highlight the value of investing in cross-disease studies to promote our understanding of the pathways leading to neurodegeneration.}, }
@article {pmid28053803, year = {2016}, author = {Kiriyama, Y and Nochi, H}, title = {D-Amino Acids in the Nervous and Endocrine Systems.}, journal = {Scientifica}, volume = {2016}, number = {}, pages = {6494621}, pmid = {28053803}, issn = {2090-908X}, abstract = {Amino acids are important components for peptides and proteins and act as signal transmitters. Only L-amino acids have been considered necessary in mammals, including humans. However, diverse D-amino acids, such as D-serine, D-aspartate, D-alanine, and D-cysteine, are found in mammals. Physiological roles of these D-amino acids not only in the nervous system but also in the endocrine system are being gradually revealed. N-Methyl-D-aspartate (NMDA) receptors are associated with learning and memory. D-Serine, D-aspartate, and D-alanine can all bind to NMDA receptors. H2S generated from D-cysteine reduces disulfide bonds in receptors and potentiates their activity. Aberrant receptor activity is related to diseases of the central nervous system (CNS), such as Alzheimer's disease, amyotrophic lateral sclerosis, and schizophrenia. Furthermore, D-amino acids are detected in parts of the endocrine system, such as the pineal gland, hypothalamus, pituitary gland, pancreas, adrenal gland, and testis. D-Aspartate is being investigated for the regulation of hormone release from various endocrine organs. Here we focused on recent findings regarding the synthesis and physiological functions of D-amino acids in the nervous and endocrine systems.}, }
@article {pmid28049644, year = {2017}, author = {Rayman, JB and Kandel, ER}, title = {Functional Prions in the Brain.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {9}, number = {1}, pages = {}, pmid = {28049644}, issn = {1943-0264}, mesh = {Animals ; Aplysia ; Brain/*metabolism ; Drosophila ; Humans ; Memory ; Models, Animal ; Prions/*metabolism ; Serotonin/metabolism ; Synapses/physiology ; Transcription Factors/chemistry/metabolism ; mRNA Cleavage and Polyadenylation Factors/chemistry/metabolism ; }, abstract = {Prions are proteins that can adopt self-perpetuating conformations and are traditionally regarded as etiological agents of infectious neurodegenerative diseases in humans, such as Creutzfeldt-Jakob disease, kuru, and transmissible encephalopathies. More recently, a growing consensus has emerged that prion-like, self-templating mechanisms also underlie a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, and Huntington's disease. Perhaps most surprising, not all prion-like aggregates are associated with pathological changes. There are now several examples of prion-like proteins in mammals that serve positive biological functions in their aggregated state. In this review, we discuss functional prions in the nervous system, with particular emphasis on the cytoplasmic polyadenylation element-binding protein (CPEB) and the role of its prion-like aggregates in synaptic plasticity and memory. We also mention a more recent example of a functional prion-like protein in the brain, TIA-1, and its role during stress. These studies of functional prion-like proteins have provided a number of generalizable insights on how prion-based protein switches may operate to serve physiological functions in higher eukaryotes.}, }
@article {pmid28049398, year = {2017}, author = {Alam, MZ and Alam, Q and Kamal, MA and Jiman-Fatani, AA and Azhar, EI and Khan, MA and Haque, A}, title = {Infectious Agents and Neurodegenerative Diseases: Exploring the Links.}, journal = {Current topics in medicinal chemistry}, volume = {17}, number = {12}, pages = {1390-1399}, doi = {10.2174/1568026617666170103164040}, pmid = {28049398}, issn = {1873-4294}, mesh = {Animals ; Anti-Infective Agents/chemistry/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Recent studies have shown that bacterial and viral infections are risk factors for various neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS), Alzheimer's disease (AD), and Lyme disease (LD). However, it is still controversial how the infections play a role in neurological diseases progression. Infections in central nervous system may lead multiple damages in infected and neighboring cells. The infection leads to the activation of inflammatory processes and host immune responses, which acts as defense mechanism and also causes damage to the host neuronal functions and viability. Several bacterial and viral pathogens have been reported for neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in combination with other factors, like aging, metabolic diseases and the genetic makeup of the host. We will focus in this review on the possible link between neurodegeneration and infections particularly Chlamydophila pneumoniae, Borrelia burgdorferi, Mycoplasma etc.}, }
@article {pmid28049396, year = {2017}, author = {Hassan, W and Noreen, H and Rehman, S and Gul, S and Kamal, MA and Kamdem, JP and Zaman, B and da Rocha, JBT}, title = {Oxidative Stress and Antioxidant Potential of One Hundred Medicinal Plants.}, journal = {Current topics in medicinal chemistry}, volume = {17}, number = {12}, pages = {1336-1370}, doi = {10.2174/1568026617666170102125648}, pmid = {28049396}, issn = {1873-4294}, mesh = {Antioxidants/chemistry/*pharmacology ; Humans ; Oxidative Stress/*drug effects ; Plants, Medicinal/*chemistry ; Reactive Nitrogen Species/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {Reactive species are produced in biological system because of redox reactions. The imbalance in pro-oxidant and antioxidant homeostasis leads to the production of toxic reactive oxygen and nitrogen species like hydrogen peroxide, organic peroxides, hydroxyl radicals, superoxide anion and nitric oxide. Inactivation of metabolic enzymes, oxidation of biomolecules and cellular damage are some of the prominent characteristics of reactive species. Similarly, oxidative stress has been associated with more than one hundred (100) pathologies such as atherosclerosis, diabetes, cardiovascular diseases, pancreatic and liver diseases, joint disorders, cardiac fibrosis, acute respiratory distress syndrome, neurological diseases (amyotrophic lateral sclerosis, Huntington's disorder, Parkinson's disease and Alzheimer's disease), ageing and cancer etc. The toxicity of reactive species is balanced by the integrated antioxidant systems, which include enzymatic and non-enzymatic antioxidants. Antioxidant therapies or defenses protect the biological sites by removing or quenching the free radicals (prooxidants). Medicinal plants can not only protect the oxidative damage, but also play a vital role in health maintenance and prevention of chronic degenerative diseases. This review will provide a valuable discussion of one hundred (100) well known medicinal plants, which may add to the optimization of antioxidants rank. Besides, some of the antioxidant evaluation techniques or mechanisms via which medicinal plants act as antioxidants are also described.}, }
@article {pmid28042779, year = {2017}, author = {Robert, MA and Gilbert, R and Gaillet, B}, title = {Antibody Delivery Mediated by Recombinant Adeno-associated Virus for the Treatment of Various Chronic and Infectious Diseases.}, journal = {Current gene therapy}, volume = {16}, number = {6}, pages = {363-374}, doi = {10.2174/1566523217666170102111251}, pmid = {28042779}, issn = {1875-5631}, mesh = {Antibodies/genetics/*therapeutic use ; Communicable Diseases/genetics/*therapy ; Dependovirus/*genetics ; *Genetic Therapy ; Genetic Vectors ; Humans ; Transduction, Genetic ; }, abstract = {Monoclonal antibodies (mAbs) based-therapies are currently one of the most successful strategies to treat immune disorders, cancer and infectious diseases. Vectors derived from adenoassociated virus (AAV) are very attractive to deliver the genes coding the mAbs because they allow long-term expression thus, reducing the number of administrations. They can also penetrate biological barriers such as the blood-brain-barrier to transduce cells localized in immunoprivileged organs. Recent animal studies with AAV have demonstrated the capacity of AAV to deliver sufficient quantity of antibodies to confer an efficient immunoprotection against chronic and infectious diseases for several months to years. The treatment was successfully applied either for prophylaxis or therapeutic use, depending on the disease and its progression. In this review, we discuss the advantages and the limitations of AAV for mAb and immunoadhesin delivery. Recent advances in vector design and antibody engineering are also presented. Optimization of the vector design can improve the kinetic and the level of mAbs expression whereas protein engineering can enhance transgene product properties. Furthermore, an exhaustive review of pre-clinical studies for chronic diseases including Alzheimer disease, amyotrophic lateral sclerosis and cancer is presented as well as for infectious diseases.}, }
@article {pmid28035620, year = {2017}, author = {Zhang, J and Wang, B and Li, R and Ge, L and Chen, KH and Tian, J}, title = {Does antimicrobial lock solution reduce catheter-related infections in hemodialysis patients with central venous catheters? A Bayesian network meta-analysis.}, journal = {International urology and nephrology}, volume = {49}, number = {4}, pages = {701-716}, pmid = {28035620}, issn = {1573-2584}, mesh = {Adult ; Anti-Infective Agents/*therapeutic use ; Anticoagulants/therapeutic use ; Bayes Theorem ; Catheter-Related Infections/*prevention &amp; control ; Central Venous Catheters/*adverse effects/microbiology ; Citric Acid/therapeutic use ; Gentamicins/*therapeutic use ; Heparin/therapeutic use ; Humans ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Renal Dialysis ; }, abstract = {PURPOSE: The purpose of our study is to carry out a Bayesian network meta-analysis comparing the efficacy of different antimicrobial lock solutions (ALS) for prevention of catheter-related infections (CRI) in patients with hemodialysis (HD) and ranking these ALS for practical consideration.<br><br>METHODS: We searched six electronic databases, earlier relevant meta-analysis and reference lists of included studies for randomized controlled trials (RCTs) that compared ALS for preventing episodes of CRI in patients with HD either head-to-head or against control interventions using non-ALS. Two authors independently assessed the methodological quality of included studies using the Cochrane risk of bias tool and extracted relevant information according to a predesigned extraction form. Data were analysed using the WinBUGS (V.1.4.3) and the Stata (V.13.0).<br><br>RESULTS: Finally, 18 studies involving 2395 patients and evaluating 9 ALS strategies were included. Network meta-analysis showed that gentamicin plus citrate (OR 0.07, 95% CrI 0.00-0.48) and gentamicin plus heparin (OR 0.04, 95% CrI 0.00-0.23) were statistically superior to heparin alone in terms of reducing CRBSI. For exit site infection and all-cause mortality, no significant difference in the intervention effect (p&#xa0;>&#xa0;0.05) was detected for all included ALS when compared to heparin. Moreover, all ALS were similar in efficacy (p&#xa0;>&#xa0;0.05) from each other for CRBSI, exit site infection and all-cause mortality.<br><br>CONCLUSIONS: Our findings indicated that gentamicin plus heparin may be selected for the prophylaxis of CRI in patients undergoing HD with CVCs. Whether this strategy will lead to antimicrobial resistance remains unclear in view of the relatively short duration of included studies. More attentions should be made regarding head-to-head comparisons of the most commonly used ALS in this field.}, }
@article {pmid28034792, year = {2017}, author = {Rae, CD and Williams, SR}, title = {Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy.}, journal = {Analytical biochemistry}, volume = {529}, number = {}, pages = {127-143}, doi = {10.1016/j.ab.2016.12.022}, pmid = {28034792}, issn = {1096-0309}, mesh = {Animals ; Brain/*metabolism ; Glutathione/*metabolism ; Humans ; Magnetic Resonance Imaging/*methods ; Magnetic Resonance Spectroscopy/*methods ; Models, Biological ; }, abstract = {We review the transport, synthesis and catabolism of glutathione in the brain as well as its compartmentation and biochemistry in different brain cells. The major reactions involving glutathione are reviewed and the factors limiting its availability in brain cells are discussed. We also describe and critique current methods for measuring glutathione in the human brain using magnetic resonance spectroscopy, and review the literature on glutathione measurements in healthy brains and in neurological, psychiatric, neurodegenerative and neurodevelopmental conditions In summary: Healthy human brain glutathione concentration is ∼1-2 mM, but it varies by brain region, with evidence of gender differences and age effects; in neurological disease glutathione appears reduced in multiple sclerosis, motor neurone disease and epilepsy, while being increased in meningiomas; in psychiatric disease the picture is complex and confounded by methodological differences, regional effects, length of disease and drug-treatment. Both increases and decreases in glutathione have been reported in depression and schizophrenia. In Alzheimer's disease and mild cognitive impairment there is evidence for a decrease in glutathione compared to age-matched healthy controls. Improved methods to measure glutathione in vivo will provide better precision in glutathione determination and help resolve the complex biochemistry of this molecule in health and disease.}, }
@article {pmid28034353, year = {2017}, author = {Wilkins, HM and Morris, JK}, title = {New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders.}, journal = {Current pharmaceutical design}, volume = {23}, number = {5}, pages = {731-752}, pmid = {28034353}, issn = {1873-4286}, support = {K99 AG050490/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Energy Metabolism/*drug effects ; Humans ; Mitochondria/*drug effects/*metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {BACKGROUND: Mitochondrial function and energy metabolism are impaired in neurodegenerative diseases. There is evidence for these functional declines both within the brain and systemically in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Due to these observations, therapeutics targeted to alter mitochondrial function and energy pathways are increasingly studied in pre-clinical and clinical settings.<br><br>METHODS: The goal of this article was to review therapies with specific implications on mitochondrial energy metabolism published through May 2016 that have been tested for treatment of neurodegenerative diseases.<br><br>RESULTS: We discuss implications for mitochondrial dysfunction in neurodegenerative diseases and how this drives new therapeutic initiatives.<br><br>CONCLUSION: Thus far, treatments have achieved varying degrees of success. Further investigation into the mechanisms driving mitochondrial dysfunction and bioenergetic failure in neurodegenerative diseases is warranted.}, }
@article {pmid28030361, year = {2017}, author = {Esposito, S and Masala, A and Sanna, S and Rassu, M and Pimxayvong, V and Iaccarino, C and Crosio, C}, title = {Redox-sensitive GFP to monitor oxidative stress in neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {28}, number = {2}, pages = {133-144}, doi = {10.1515/revneuro-2016-0041}, pmid = {28030361}, issn = {2191-0200}, mesh = {Alzheimer Disease/diagnosis/*metabolism ; Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Animals ; Brain/metabolism/physiopathology ; Humans ; *Oxidation-Reduction ; Oxidative Stress/*physiology ; Parkinson Disease/diagnosis/*metabolism ; }, abstract = {Redox processes are key events in the degenerative cascade of many adult-onset neurodegenerative diseases (NDs), but the biological relevance of a single redox change is often dependent on the redox couple involved and on its subcellular origin. The biosensors based on engineered fluorescent proteins (redox-sensitive GFP [roGFP]) offer a unique opportunity to monitor redox changes in both physiological and pathological contexts in living animals and plants. Here, we review the use of roGFPs to monitor oxidative stress in different three adult-onset NDs: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Despite the many differences spanning from incidence to onset, the hypotheses on biological processes underlying both sporadic and familiar ND forms in humans outline a model in which noncompeting mechanisms are likely to converge in various unsuccessful patterns to mediate the selective degeneration of a specific neuronal population. roGFPs, targeted to different cell compartments, are successfully used as specific markers of cell toxicity, induced by expression of causative genes linked to a determined ND. We also report the use of roGFP to monitor oxidative stress induced by the expression of the ALS-causative gene SOD1.}, }
@article {pmid28017151, year = {2017}, author = {Bhat, SA and Kamal, MA and Yarla, NS and Ashraf, GM}, title = {Synopsis on Managment Strategies for Neurodegenerative Disorders: Challenges from Bench to Bedside in Successful Drug Discovery and Development.}, journal = {Current topics in medicinal chemistry}, volume = {17}, number = {12}, pages = {1371-1378}, doi = {10.2174/1568026616666161222121229}, pmid = {28017151}, issn = {1873-4294}, mesh = {Biological Products/chemistry/*therapeutic use ; *Drug Discovery ; Humans ; Neurodegenerative Diseases/diagnosis/*drug therapy ; }, abstract = {The maintenance of health requires successful cell functioning, which in turn depends upon the proper and active conformation of proteins besides other biomolecules. However, occasionally these proteins may misfold and lead to the appearance and progression of protein conformational diseases. These diseases apart from others include several neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other lesser known diseases. Although much knowledge has been gained, these NDDs still warrant advance research in the elucidation of their mechanisms as well as effective therapeutic interventions and proper management. There is an ever-growing and urgent need to improve the diagnosis and management of NDDs due to their devastating nature, serious social impact and neuropsychiatric symptoms. It is also envisioned that we may be able to encourage, develop, and strengthen the cell defenses against amyloid toxicity and prevent neuronal destruction and consequently neurodegeneration. In this review, the implications of protein misfolding and aggregation in NDDs are discussed along with some of the most recent findings on the curative and beneficial effects of natural molecules such as polyphenols. This paper also reviews the anti-aggregation and protective effects of some organic and peptidic compounds duly supported experimentally, as prospective future therapeutics for NDDs. The synopses presented in this review shall prove helpful in further understanding of the causes, cures and management of lethal NDDs.}, }
@article {pmid28012891, year = {2017}, author = {Brunden, KR and Lee, VM and Smith, AB and Trojanowski, JQ and Ballatore, C}, title = {Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs.}, journal = {Neurobiology of disease}, volume = {105}, number = {}, pages = {328-335}, pmid = {28012891}, issn = {1095-953X}, support = {P01 AG017586/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; R01 AG044332/AG/NIA NIH HHS/United States ; R21 NS087059/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Microtubules/drug effects/*metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Tubulin Modulators/chemistry/pharmacology/*therapeutic use ; }, abstract = {Many neurodegenerative diseases are characterized by deficiencies in neuronal axonal transport, a process in which cellular cargo is shuttled with the aid of molecular motors from the cell body to axonal termini and back along microtubules (MTs). Proper axonal transport is critical to the normal functioning of neurons, and impairments in this process could contribute to the neuronal damage and death that is characteristic of neurodegenerative disease. Although the causes of axonal transport abnormalities may vary among the various neurodegenerative conditions, in many cases it appears that the transport deficiencies result from a diminution of axonal MT stability. Here we review the evidence of MT abnormalities in a number of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury, and highlight the potential benefit of MT-stabilizing agents in improving axonal transport and nerve function in these diseases. Moreover, we discuss the challenges associated with the utilization of MT-stabilizing drugs as therapeutic candidates for neurodegenerative conditions.}, }
@article {pmid28003278, year = {2017}, author = {Grad, LI and Rouleau, GA and Ravits, J and Cashman, NR}, title = {Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {7}, number = {8}, pages = {}, pmid = {28003278}, issn = {2157-1422}, mesh = {Amyotrophic Lateral Sclerosis/classification/*genetics/*pathology/physiopathology ; Disease Progression ; Extremities/physiopathology ; Frontotemporal Dementia/etiology ; Humans ; Motor Neurons/*pathology ; Mutation ; *Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology. Because the same phenotypes can have multiple causes, including different gene mutations, there may be multiple molecular mechanisms causing ALS, implying that the disease is a syndrome. Conversely, multiple phenotypes can be caused by a single gene mutation; thus, a single molecular mechanism could be compatible with clinical heterogeneity. The pathogenic mechanism(s) in ALS remain unknown, but active propagation of the pathology neuroanatomically is likely a primary component.}, }
@article {pmid27995822, year = {2017}, author = {Gluyas, C and Mathers, S and Hennessy Anderson, N and Ugalde, A}, title = {Factors to consider for motor neurone disease carer intervention research: A narrative literature review.}, journal = {Palliative &amp; supportive care}, volume = {15}, number = {5}, pages = {600-608}, doi = {10.1017/S1478951516000912}, pmid = {27995822}, issn = {1478-9523}, mesh = {Adaptation, Psychological ; Caregivers/*psychology ; *Cost of Illness ; Humans ; Motor Neuron Disease/complications/*psychology/*therapy ; Narration ; Quality of Life/*psychology ; Social Support ; }, abstract = {OBJECTIVE: The experience of caregiving in the context of motor neurone disease (MND) is extremely challenging. Over the past 15 years, quantitative and qualitative studies have delineated the psychosocial aspects of this experience, exploring its impact on caregivers' quality of life, rates of depression, distress, anxiety, and burden. Our paper aimed to provide an overview of the lived experience of MND caregivers, identifying the variables that can influence MND caregiver functioning that are relevant to the development of an intervention.<br><br>METHOD: A narrative review was conducted, synthesizing the findings of literature retrieved from 2000 to early 2016.<br><br>RESULTS: A total of 37 articles were included in the review. The articles varied considerably in terms of methodology and quality. The main influential aspects reported and identified were factors pertaining to the patient, factors intrinsic to the caregiver, relationship factors, and social support factors.<br><br>SIGNIFICANCE OF RESULTS: There is evidence to support the fact that caregivers have poorer outcomes when they care for patients with a more severe clinical profile, poorer emotional health or neurobehavioral concerns, or when the caregivers themselves struggle with adaptive problem-solving and coping skills. The availability and use of social support are also likely to be important for caregiver psychosocial outcomes. Further investigation is required to clarify the influence of changes in the relationship with the patient. Significant factors affecting the caregiver experience are considered in relation to their amenability to psychosocial intervention. Recommendations are made regarding the optimal features of future psychosocial intervention research.}, }
@article {pmid27995438, year = {2017}, author = {Paganoni, S and Schwarzschild, MA}, title = {Urate as a Marker of Risk and Progression of Neurodegenerative Disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {148-153}, pmid = {27995438}, issn = {1878-7479}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Biomarkers ; Clinical Trials as Topic ; *Disease Progression ; Humans ; Neurodegenerative Diseases/*diagnosis/*metabolism ; Parkinson Disease/diagnosis/metabolism ; Risk Factors ; Uric Acid/blood/cerebrospinal fluid/*metabolism ; }, abstract = {Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.}, }
@article {pmid27983884, year = {2017}, author = {McCombe, PA and Wray, NR and Henderson, RD}, title = {Extra-motor abnormalities in amyotrophic lateral sclerosis: another layer of heterogeneity.}, journal = {Expert review of neurotherapeutics}, volume = {17}, number = {6}, pages = {561-577}, doi = {10.1080/14737175.2017.1273772}, pmid = {27983884}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Disease Progression ; Humans ; *Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by the presence of muscle weakness. The motor features of disease are heterogeneous in site of onset and progression. There are also extra-motor features in some patients. The genetic basis for extra-motor features is uncertain. The heterogeneity of ALS is an issue for clinical trials. Areas covered: This paper reviews the range and prevalence of extra-motor features associated with ALS, and highlights the current information about genetic associations with extra-motor features. Expert commentary: There are extra-motor features of ALS, but these are not found in all patients. The most common is cognitive abnormality. More data is required to ascertain whether extra-motor features arise with progression of disease. Extra-motor features are reported in patients with a range of causative genetic mutations, but are not found in all patients with these mutations. Further studies are required of the heterogeneity of ALS, and genotype/phenotype correlations are required, taking note of extra-motor features.}, }
@article {pmid27983596, year = {2016}, author = {Preciados, M and Yoo, C and Roy, D}, title = {Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases.}, journal = {International journal of molecular sciences}, volume = {17}, number = {12}, pages = {}, pmid = {27983596}, issn = {1422-0067}, mesh = {Brain Diseases/epidemiology/*genetics ; Endocrine Disruptors/*toxicity ; Estrogens/*pharmacology ; Female ; Gene Regulatory Networks/*drug effects ; Humans ; Male ; Nuclear Respiratory Factor 1/*metabolism ; Sexism ; }, abstract = {During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer's Disease (AD), Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD-APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF-underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes-APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE-are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders.}, }
@article {pmid27982040, year = {2017}, author = {Al-Chalabi, A and van den Berg, LH and Veldink, J}, title = {Gene discovery in amyotrophic lateral sclerosis: implications for clinical management.}, journal = {Nature reviews. Neurology}, volume = {13}, number = {2}, pages = {96-104}, pmid = {27982040}, issn = {1759-4766}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, with death typically resulting from diaphragmatic failure within 2-5 years. Since the discovery of mutations in SOD1, which account for ∼2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS - including the relevance of family history - and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling.}, }
@article {pmid27981909, year = {2017}, author = {Bjelobaba, I and Savic, D and Lavrnja, I}, title = {Multiple Sclerosis and Neuroinflammation: The Overview of Current and Prospective Therapies.}, journal = {Current pharmaceutical design}, volume = {23}, number = {5}, pages = {693-730}, doi = {10.2174/1381612822666161214153108}, pmid = {27981909}, issn = {1873-4286}, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Humans ; Inflammation/*physiopathology ; Multiple Sclerosis/*drug therapy/etiology ; Neurodegenerative Diseases/*physiopathology ; Neuroimmunomodulation/*drug effects ; }, abstract = {Persistent neuroinflammation is now recognized as a chief pathological component of practically all neurodegenerative diseases. Neuroinflammation in the central nervous system (CNS), is accompanied with immune responses of glial cells. Glial cells respond to pathological stimuli through antigen presentation, and cytokine and chemokine signaling. Therefore, limiting CNS inflammation represents prospective therapeutic approach in diseases like Alzheimer's, amyotrophic lateral sclerosis, Parkinson's, ischemia, various psychiatric disorders and Multiple sclerosis (MS). As a complex disease, MS is characterized by neuroinflamation, demyelination and sequential axonal loss. Due to unknown etiology and the heterogeneous presentation of the disease, MS is hard to treat and the search for potential therapeutics is wide and meticulous. However, finding a proper antineuroinflammatory drug may bring an advance in selecting novel treatment regimens of ample of neurodegenerative diseases and neurological disorders. The present review gives the overview of the existing and potential therapies in MS, aimed to modulate neuroinflammation and ensure neuroprotection.}, }
@article {pmid27975196, year = {2017}, author = {Moore, A and Young, CA and Hughes, DA}, title = {Economic Studies in Motor Neurone Disease: A Systematic Methodological Review.}, journal = {PharmacoEconomics}, volume = {35}, number = {4}, pages = {397-413}, pmid = {27975196}, issn = {1179-2027}, support = {YOUNG/JAN15/929-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Costs and Cost Analysis/methods ; Disease Progression ; Humans ; Markov Chains ; Models, Economic ; Motor Neuron Disease/economics/physiopathology/*therapy ; Neuroprotective Agents/economics/therapeutic use ; *Quality of Life ; Research Design ; Riluzole/economics/therapeutic use ; Surveys and Questionnaires ; Technology Assessment, Biomedical/*methods ; }, abstract = {BACKGROUND: Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges.<br><br>OBJECTIVE: The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND.<br><br>METHODS: We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively.<br><br>RESULTS: A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n&#xa0;=&#xa0;9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location-specific characteristics. Few cost studies reported disease-stage-specific costs (n&#xa0;=&#xa0;3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers.<br><br>CONCLUSION: Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients.}, }
@article {pmid27965593, year = {2016}, author = {Mondola, P and Damiano, S and Sasso, A and Santillo, M}, title = {The Cu, Zn Superoxide Dismutase: Not Only a Dismutase Enzyme.}, journal = {Frontiers in physiology}, volume = {7}, number = {}, pages = {594}, pmid = {27965593}, issn = {1664-042X}, abstract = {The Cu,Zn superoxide dismutase (SOD1) is an ubiquitary cytosolic dimeric carbohydrate free molecule, belonging to a family of isoenzymes involved in the scavenger of superoxide anions. This effect certainly represents the main and well known function ascribed to this enzyme. Here we highlight new aspects of SOD1 physiology that point out some inedited effects of this enzyme in addition to the canonic role of oxygen radical enzymatic dismutation. In the last two decades our research group produced many data obtained in in vitro studies performed in many cellular lines, mainly neuroblastoma SK-N-BE cells, indicating that this enzyme is secreted either constitutively or after depolarization induced by high extracellular K[+] concentration. In addition, we gave many experimental evidences showing that SOD1 is able to stimulate, through muscarinic M1 receptor, pathways involving ERK1/2, and AKT activation. These effects are accompanied with an intracellular calcium increase. In the last part of this review we describe researches that link deficient extracellular secretion of mutant SOD1[G93A] to its intracellular accumulation and toxicity in NSC-34 cells. Alternatively, SOD1[G93A] toxicity has been attributed to a decrease of Km for H2O2 with consequent OH radical formation. Interestingly, this last inedited effect of SOD1[G93A] could represent a gain of function that could be involved in the pathogenesis of familial Amyotrophic Lateral Sclerosis (fALS).}, }
@article {pmid27965018, year = {2017}, author = {Rinaldi, F and Motti, D and Ferraiuolo, L and Kaspar, BK}, title = {High content analysis in amyotrophic lateral sclerosis.}, journal = {Molecular and cellular neurosciences}, volume = {80}, number = {}, pages = {180-191}, pmid = {27965018}, issn = {1095-9327}, support = {R01 NS064492/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the progressive loss of motor neurons. Neurons, astrocytes, oligodendrocytes and microglial cells all undergo pathological modifications in the onset and progression of ALS. A number of genes involved in the etiopathology of the disease have been identified, but a complete understanding of the molecular mechanisms of ALS has yet to be determined. Currently, people affected by ALS have a life expectancy of only two to five years from diagnosis. The search for a treatment has been slow and mostly unsuccessful, leaving patients in desperate need of better therapies. Until recently, most pre-clinical studies utilized the available ALS animal models. In the past years, the development of new protocols for isolation of patient cells and differentiation into relevant cell types has provided new tools to model ALS, potentially more relevant to the disease itself as they directly come from patients. The use of stem cells is showing promise to facilitate ALS research by expanding our understanding of the disease and help to identify potential new therapeutic targets and therapies to help patients. Advancements in high content analysis (HCA) have the power to contribute to move ALS research forward by combining automated image acquisition along with digital image analysis. With modern HCA machines it is possible, in a period of just a few hours, to observe changes in morphology and survival of cells, under the stimulation of hundreds, if not thousands of drugs and compounds. In this article, we will summarize the major molecular and cellular hallmarks of ALS, describe the advancements provided by the in vitro models developed in the last few years, and review the studies that have applied HCA to the ALS field to date.}, }
@article {pmid27964824, year = {2017}, author = {Chiò, A and Mora, G and Lauria, G}, title = {Pain in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {16}, number = {2}, pages = {144-157}, doi = {10.1016/S1474-4422(16)30358-1}, pmid = {27964824}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Muscle Cramp/drug therapy/*etiology ; Neuralgia/drug therapy/*etiology ; Nociceptive Pain/drug therapy/*etiology ; }, abstract = {Pain is a largely neglected symptom in patients with amyotrophic lateral sclerosis (ALS) although it is reported by most of these patients. It occurs at all stages of the disease and can be an onset symptom preceding motor dysfunction. Pain is correlated with a deterioration in patients' quality of life and increased prevalence of depression. In the later stages of ALS, pain can be severe enough to require increased use of sedative and analgesic drugs, and is among the events that predict clinical deterioration and death. The site of pain depends on the pain type or underlying mechanism (eg, painful cramps, nociceptive pain, or neuropathic pain). Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices. Further understanding of the pathophysiology is crucial to drive assessment in clinical trials of therapeutic strategies targeted at specific mechanisms and studies of individualised therapies.}, }
@article {pmid27957611, year = {2017}, author = {Reinhold, AK and Rittner, HL}, title = {Barrier function in the peripheral and central nervous system-a review.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {469}, number = {1}, pages = {123-134}, pmid = {27957611}, issn = {1432-2013}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System/*metabolism ; Humans ; Occludin/metabolism ; Peripheral Nervous System/*metabolism ; Spinal Cord/metabolism ; Tight Junction Proteins ; Tight Junctions/metabolism ; }, abstract = {The peripheral (PNS) and central nervous system (CNS) are delicate structures, highly sensitive to homeostatic changes-and crucial for basic vital functions. Thus, a selection of barriers ensures the protection of the nervous system from noxious blood-borne or surrounding stimuli. In this chapter, anatomy and functioning of the blood-nerve (BNB), the blood-brain (BBB), and the blood-spinal cord barriers (BSCB) are presented and the key tight junction (TJ) proteins described: claudin-1, claudin-3, claudin-5, claudin-11, claudin-12, claudin-19, occludin, Zona occludens-1 (ZO-1), and tricellulin are by now identified as relevant for nerval barriers. Different diseases can lead to or be accompanied by neural barrier disruption, and impairment of these barriers worsens pathology. Peripheral nerve injury and inflammatory polyneuropathy cause an increased permeability of BNB as well as BSCB, while, e.g., diseases of the CNS such as amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, or Alzheimer's disease can progress and worsen through barrier dysfunction. Moreover, the complex role and regulation of the BBB after ischemic stroke is described. On the other side, PNS and CNS barriers hamper the delivery of drugs in diseases when the barrier is intact, e.g., in certain neurodegenerative diseases or inflammatory pain. Understanding of the barrier - regulating processes has already lead to the discovery of new molecules as drug enhancers. In summary, the knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases.}, }
@article {pmid27956443, year = {2016}, author = {Turner, MR}, title = {Motor neuron disease: biomarker development for an expanding cerebral syndrome.}, journal = {Clinical medicine (London, England)}, volume = {16}, number = {Suppl 6}, pages = {s60-s65}, pmid = {27956443}, issn = {1473-4893}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Biomarkers/analysis/metabolism ; Frontotemporal Dementia ; Humans ; *Motor Neuron Disease/diagnosis/genetics/metabolism ; }, abstract = {Descriptions of motor neuron disease (MND) documented more than a century ago remain instantly recognisable to the physician. The muscle weakness, typically with signs of upper and lower motor neuron dysfunction, is uniquely relentless. Over the last 30 years, a wider cerebral pathology has emerged, despite the lack of overt cognitive impairment in the majority of patients. From the initial linkage of a small number of cases to mutations in SOD1, diverse cellular pathways have been implicated in pathogenesis. An increasingly complex clinical heterogeneity has emerged around a significant variability in survival. Defining a cellular signature of aggregated TDP-43 common to nearly all MND and a large proportion of frontotemporal dementia (FTD), has placed MND alongside more traditional cerebral neurodegeneration. With new genetic causes, most notably a hexanucleotide expansion in C9orf72 associated with both MND and FTD, the development of biomarkers against which to test therapeutic candidates is a priority.}, }
@article {pmid27942908, year = {2017}, author = {Tang, BL}, title = {Could Sirtuin Activities Modify ALS Onset and Progression?.}, journal = {Cellular and molecular neurobiology}, volume = {37}, number = {7}, pages = {1147-1160}, pmid = {27942908}, issn = {1573-6830}, support = {C-183-000-102-091//National University of Singapore/ ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/*pathology ; Animals ; *Disease Progression ; Humans ; Motor Neurons/drug effects/metabolism/pathology ; Sirtuins/*metabolism/*therapeutic use ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex etiology. Sirtuins have been implicated as disease-modifying factors in several neurological disorders, and in the past decade, attempts have been made to check if manipulating Sirtuin activities and levels could confer benefit in terms of neuroprotection and survival in ALS models. The efforts have largely focused on mutant SOD1, and while limited in scope, the results were largely positive. Here, the body of work linking Sirtuins with ALS is reviewed, with discussions on how Sirtuins and their activities may impact on the major etiological mechanisms of ALS. Moving forward, it is important that the potentially beneficial effect of Sirtuins in ALS disease onset and progression are assessed in ALS models with TDP-43, FUS, and C9orf72 mutations.}, }
@article {pmid27941618, year = {2016}, author = {Oklinski, MK and Skowronski, MT and Skowronska, A and Rützler, M and Nørgaard, K and Nieland, JD and Kwon, TH and Nielsen, S}, title = {Aquaporins in the Spinal Cord.}, journal = {International journal of molecular sciences}, volume = {17}, number = {12}, pages = {}, pmid = {27941618}, issn = {1422-0067}, mesh = {Animals ; Aquaporin 4/metabolism ; Aquaporins/*metabolism ; Astrocytes/metabolism ; Central Nervous System/metabolism ; Humans ; Spinal Cord/*metabolism ; }, abstract = {Aquaporins (AQPs) are water channel proteins robustly expressed in the central nervous system (CNS). A number of previous studies described the cellular expression sites and investigated their major roles and function in the brain and spinal cord. Among thirteen different mammalian AQPs, AQP1 and AQP4 have been mainly studied in the CNS and evidence has been presented that they play important roles in the pathogenesis of CNS injury, edema and multiple diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, amyotrophic lateral sclerosis, glioblastoma multiforme, Alzheimer's disease and Parkinson's disease. The objective of this review is to highlight the current knowledge about AQPs in the spinal cord and their proposed roles in pathophysiology and pathogenesis related to spinal cord lesions and injury.}, }
@article {pmid27933485, year = {2017}, author = {Vu, LT and Bowser, R}, title = {Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {119-134}, pmid = {27933485}, issn = {1878-7479}, support = {R01 NS061867/NS/NINDS NIH HHS/United States ; R56 NS061867/NS/NINDS NIH HHS/United States ; RC1 NS068179/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*diagnosis/urine ; *Biomarkers/blood/cerebrospinal fluid/urine ; *Disease Progression ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.}, }
@article {pmid27933416, year = {2017}, author = {Willekens, SM and Van Weehaeghe, D and Van Damme, P and Van Laere, K}, title = {Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {44}, number = {3}, pages = {533-547}, pmid = {27933416}, issn = {1619-7089}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Humans ; Positron-Emission Tomography/*methods/standards ; *Radiopharmaceuticals ; }, abstract = {During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [[18]F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression.}, }
@article {pmid27920668, year = {2016}, author = {Wen, MM}, title = {Getting miRNA Therapeutics into the Target Cells for Neurodegenerative Diseases: A Mini-Review.}, journal = {Frontiers in molecular neuroscience}, volume = {9}, number = {}, pages = {129}, pmid = {27920668}, issn = {1662-5099}, abstract = {miRNAs play important roles in modulating gene expression in varying cellular processes and disease pathogenesis, including neurodegenerative diseases. Several miRNAs are expressed in the brain, control brain development and are identified as important biomarkers in the pathogenesis of motor-and neuro-cognitive diseases such as Alzheimer's (AD), Huntington's and Parkinson's diseases (PD) and amyotrophic lateral sclerosis. These remarkable miRNAs could be used as diagnostic markers and therapeutic targeting potential for many stressful and untreatable progressive neurodegenerative diseases. To modulate these miRNA activities, there are currently two strategies involved; first one is to therapeutically restore the suppressed miRNA level by miRNA mimics (agonist), and the other one is to inhibit miRNA function by using anti-miR (antagonist) to repress overactive miRNA function. However, RNAi-based therapeutics often faces in vivo instability because naked nucleic acids are subject to enzyme degradation before reaching the target sites. Therefore, an effective, safe and stable bio-responsive delivery system is necessary to protect the nucleic acids from serum degradation and assist their entrance to the cells. Since neuronal cells are non-regenerating, to design engineered miRNAs to be delivered to the central nervous system (CNS) for long term gene expression and knockdown is representing an enormous challenge for scientists. This article provides an insight summary on some of the innovative strategies employed to deliver miRNA into target cells. These viral and non-viral carrier systems hold promise in RNA therapy delivery for neurodegenerative diseases.}, }
@article {pmid27920024, year = {2017}, author = {Guo, L and Shorter, J}, title = {Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {7}, number = {9}, pages = {}, pmid = {27920024}, issn = {2157-1422}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 NS067354/NS/NINDS NIH HHS/United States ; }, mesh = {DNA-Binding Proteins/*genetics ; Humans ; Mutation ; RNA-Binding Proteins/*genetics ; TDP-43 Proteinopathies/*genetics/pathology ; }, abstract = {Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases. Importantly, PrLDs enable RBP function and mediate phase transitions that partition functional ribonucleoprotein compartments. This PrLD activity, however, renders RBPs prone to populating deleterious oligomers or self-templating fibrils that might spread disease, and disease-linked PrLD mutations can exacerbate this risk. Several strategies have emerged to counter TDP-43 proteinopathies, including engineering enhanced protein disaggregases based on Hsp104.}, }
@article {pmid27916654, year = {2017}, author = {Hasegawa, M and Nonaka, T and Masuda-Suzukake, M}, title = {Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {172}, number = {}, pages = {22-33}, doi = {10.1016/j.pharmthera.2016.11.010}, pmid = {27916654}, issn = {1879-016X}, mesh = {Alzheimer Disease/physiopathology/therapy ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Animals ; DNA-Binding Proteins/metabolism ; Disease Progression ; Humans ; Neurodegenerative Diseases/*physiopathology/therapy ; Parkinson Disease/physiopathology/therapy ; Prions/*metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Prion-like propagation of abnormal intracytoplasmic proteins, which are the defining features of major neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), has been proposed. A growing body of evidence strongly suggests that abnormal tau, α-synuclein and TDP-43 have prion-like properties, convert the corresponding normal proteins into abnormal forms, and are transmitted from cell to cell, spreading throughout the brain. This idea is extremely important not only for understanding the pathogenesis and progression of these diseases, but also for the development of molecular therapies. Since the distributions and spreading of the abnormal proteins are closely associated with disease symptoms and progression, gain-of-toxic-function of these proteins may affect the neurons and glial cells either directly or indirectly, or both. It is essential to regulate the aggregation of abnormal intracellular proteins and their cell-to-cell transmission in order to stop, or at least slow, the progression of these diseases.}, }
@article {pmid27906525, year = {2017}, author = {Eskreis-Winkler, S and Zhang, Y and Zhang, J and Liu, Z and Dimov, A and Gupta, A and Wang, Y}, title = {The clinical utility of QSM: disease diagnosis, medical management, and surgical planning.}, journal = {NMR in biomedicine}, volume = {30}, number = {4}, pages = {}, doi = {10.1002/nbm.3668}, pmid = {27906525}, issn = {1099-1492}, mesh = {Biomarkers/metabolism ; Brain/*diagnostic imaging/metabolism ; Brain Diseases/*diagnostic imaging/metabolism/*surgery ; Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Image Enhancement/methods ; Molecular Imaging/*methods ; Preoperative Care/*methods ; Surgery, Computer-Assisted/*methods ; }, abstract = {Quantitative susceptibility mapping (QSM) is an MR technique that depicts and quantifies magnetic susceptibility sources. Mapping iron, the dominant susceptibility source in the brain, has many important clinical applications. Herein, we review QSM applications in the diagnosis, medical management, and surgical treatment of disease. To assist in early disease diagnosis, QSM can identify elevated iron levels in the motor cortex of amyotrophic lateral sclerosis patients, in the substantia nigra of Parkinson's disease (PD) patients, in the globus pallidus, putamen, and caudate of Huntington's disease patients, and in the basal ganglia of Wilson's disease patients. Additionally, QSM can distinguish between hemorrhage and calcification, which could prove useful in tumor subclassification, and can measure microbleeds in traumatic brain injury patients. In guiding medical management, QSM can be used to monitor iron chelation therapy in PD patients, to monitor smoldering inflammation of multiple sclerosis (MS) lesions after the blood-brain barrier (BBB) seals, to monitor active inflammation of MS lesions before the BBB seals without using gadolinium, and to monitor hematoma volume in intracerebral hemorrhage. QSM can also guide neurosurgical treatment. Neurosurgeons require accurate depiction of the subthalamic nucleus, a tiny deep gray matter nucleus, prior to inserting deep brain stimulation electrodes into the brains of PD patients. QSM is arguably the best imaging tool for depiction of the subthalamic nucleus. Finally, we discuss future directions, including bone QSM, cardiac QSM, and using QSM to map cerebral metabolic rate of oxygen. Copyright © 2016 John Wiley &amp; Sons, Ltd.}, }
@article {pmid27903442, year = {2017}, author = {Williams, J and Smith, F and Kumar, S and Vijayan, M and Reddy, PH}, title = {Are microRNAs true sensors of ageing and cellular senescence?.}, journal = {Ageing research reviews}, volume = {35}, number = {}, pages = {350-363}, pmid = {27903442}, issn = {1872-9649}, support = {R01 AG042178/AG/NIA NIH HHS/United States ; R01 AG047812/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*physiology ; *Alzheimer Disease/metabolism/physiopathology ; Animals ; Cellular Senescence/*physiology ; Epigenesis, Genetic ; Humans ; *MicroRNAs/biosynthesis/metabolism ; }, abstract = {All living beings are programmed to death due to aging and age-related processes. Aging is a normal process of every living species. While all cells are inevitably progressing towards death, many disease processes accelerate the aging process, leading to senescence. Pathologies such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, cardiovascular disease, cancer, and skin diseases have been associated with deregulated aging. Healthy aging can delay onset of all age-related diseases. Genetics and epigenetics are reported to play large roles in accelerating and/or delaying the onset of age-related diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent molecular biology discoveries have revealed that microRNAs (miRNAs) are potential sensors of aging and cellular senescence. Due to miRNAs capability to bind to the 3' untranslated region (UTR) of mRNA of specific genes, miRNAs can prevent the translation of specific genes. The purpose of our article is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging and senescence. Our article discusses the current understanding of cellular senescence, its interplay with miRNAs regulation, and how they both contribute to disease processes.}, }
@article {pmid27902929, year = {2017}, author = {Morrice, JR and Gregory-Evans, CY and Shaw, CA}, title = {Necroptosis in amyotrophic lateral sclerosis and other neurological disorders.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1863}, number = {2}, pages = {347-353}, doi = {10.1016/j.bbadis.2016.11.025}, pmid = {27902929}, issn = {0925-4439}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Death ; Humans ; Necrosis/metabolism/*pathology ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/metabolism/*pathology ; Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons. Cell death in ALS and in general was previously believed to exist as a dichotomy between apoptosis and necrosis. Most research investigating cell death mechanisms in ALS was conducted before the discovery of programmed necrosis thus did not use selective cell death pathway-specific markers. Recently, a new form of programmed cell death, termed "necroptosis", has been characterized and has been recently implicated in ALS as a primary mechanism driving motor neuron cell death in different forms of ALS. The present review is aimed at summarizing cell death pathways that are currently implicated in ALS and highlighting the emerging evidence on necroptosis as a major driver of motor neuron cell death.}, }
@article {pmid27898033, year = {2016}, author = {Bezdjian, A and Kraaijenga, VJ and Ramekers, D and Versnel, H and Thomeer, HG and Klis, SF and Grolman, W}, title = {Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans.}, journal = {International journal of molecular sciences}, volume = {17}, number = {12}, pages = {}, pmid = {27898033}, issn = {1422-0067}, mesh = {Animals ; Cochlear Nerve/*drug effects ; Humans ; Nerve Growth Factors/administration &amp; dosage/adverse effects/*therapeutic use ; Neurodegenerative Diseases/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.}, }
@article {pmid27892983, year = {2017}, author = {Freischmidt, A and Müller, K and Ludolph, AC and Weishaupt, JH and Andersen, PM}, title = {Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {JAMA neurology}, volume = {74}, number = {1}, pages = {110-113}, doi = {10.1001/jamaneurol.2016.3712}, pmid = {27892983}, issn = {2168-6157}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Frontotemporal Dementia/*genetics ; Genetic Association Studies ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation/*genetics ; Protein Serine-Threonine Kinases/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.}, }
@article {pmid27885636, year = {2016}, author = {Jayakumar, AR and Norenberg, MD}, title = {Glutamine Synthetase: Role in Neurological Disorders.}, journal = {Advances in neurobiology}, volume = {13}, number = {}, pages = {327-350}, doi = {10.1007/978-3-319-45096-4_13}, pmid = {27885636}, issn = {2190-5215}, support = {DK063311/NH/NIH HHS/United States ; }, mesh = {Ammonia/metabolism ; Astrocytes/*enzymology/metabolism/pathology ; Glutamate-Ammonia Ligase/*metabolism ; Glutamic Acid/metabolism ; Glutamine/biosynthesis ; Humans ; Nervous System Diseases/*enzymology/physiopathology/therapy ; }, abstract = {Glutamine synthetase (GS) is an ATP-dependent enzyme found in most species that synthesizes glutamine from glutamate and ammonia. In brain, GS is exclusively located in astrocytes where it serves to maintain the glutamate-glutamine cycle, as well as nitrogen metabolism. Changes in the activity of GS, as well as its gene expression, along with excitotoxicity, have been identified in a number of neurological conditions. The literature describing alterations in the activation and gene expression of GS, as well as its involvement in different neurological disorders, however, is incomplete. This review summarizes changes in GS gene expression/activity and its potential contribution to the pathogenesis of several neurological disorders, including hepatic encephalopathy, ischemia, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and astroglial neoplasms. This review also explores the possibility of targeting GS in the therapy of these conditions.}, }
@article {pmid27881068, year = {2016}, author = {Rodríguez, MJ and Mahy, N}, title = {Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited.}, journal = {Current medicinal chemistry}, volume = {23}, number = {42}, pages = {4753-4772}, doi = {10.2174/0929867324666161123091314}, pmid = {27881068}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/therapy ; Animals ; Energy Metabolism ; Humans ; Inflammation/pathology ; Microglia/*pathology ; Motor Neurons/*pathology ; Protein Folding ; }, abstract = {Research onto the pathogenesis of amyotrophic lateral sclerosis (ALS) has obtained notable gene discoveries, although, to date, only progress with regard to treatment has been very modest. Currently ALS is considered a multifactorial disease that presents diverse clinical presentations, ranging from a monogenic inherited disease to an autoimmune pathology, and develops with misfolded protein aggregation and neuroinflammation. An important factor related to ALS pathogenesis is the microglial activation associated with degenerative motor neurons. This activation leads to changes in the expression of a wide range of genes related to phagocytosis and inflammation, and to profound modifications in the dynamic interactions between neurons and glial cells. Overactivation and deregulation of microglial activity causes deleterious effects and leads to neuronal death. However, the involvement of microglia in non-inflammatory functions challenges our concept of neuroinflammation and opens up new possibilities for the study of the pathophysiological mechanisms of ALS. In this review we summarize the current knowledge on the adaptive interactions between neurons and microglia in ALS. We also discuss the hypothesis that controlling the extent of microglial activation and neuroinflammation may have clinical and therapeutic benefits for the condition.}, }
@article {pmid27878658, year = {2017}, author = {Jayakumar, AR and Apeksha, A and Norenberg, MD}, title = {Role of Matricellular Proteins in Disorders of the Central Nervous System.}, journal = {Neurochemical research}, volume = {42}, number = {3}, pages = {858-875}, pmid = {27878658}, issn = {1573-6903}, mesh = {Animals ; CCN Intercellular Signaling Proteins/metabolism ; Central Nervous System Diseases/drug therapy/*metabolism ; Extracellular Matrix Proteins/*metabolism ; Glypicans/metabolism ; Humans ; Osteonectin/metabolism ; Tenascin/metabolism ; Thrombospondins/metabolism ; }, abstract = {Matricellular proteins (MCPs) are actively expressed non-structural proteins present in the extracellular matrix, which rapidly turnover and possess regulatory roles, as well as mediate cell-cell interactions. MCPs characteristically contain binding sites for other extracellular proteins, cell surface receptors, growth factors, cytokines and proteases, that provide structural support for surrounding cells. MCPs are present in most organs, including brain, and play a major role in cell-cell interactions and tissue repair. Among the MCPs found in brain include thrombospondin-1/2, secreted protein acidic and rich in cysteine family (SPARC), including Hevin/SC1, Tenascin C and CYR61/Connective Tissue Growth Factor/Nov family of proteins, glypicans, galectins, plasminogen activator inhibitor (PAI-1), autotaxin, fibulin and perisostin. This review summarizes the potential role of MCPs in the pathogenesis of major neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, ischemia, trauma, hepatic encephalopathy, Down's syndrome, autism, multiple sclerosis, brain neoplasms, Parkinson's disease and epilepsy. Potential therapeutic opportunities of MCP's for these disorders are also considered in this review.}, }
@article {pmid27878516, year = {2017}, author = {Park, SB and Kiernan, MC and Vucic, S}, title = {Axonal Excitability in Amyotrophic Lateral Sclerosis : Axonal Excitability in ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {78-90}, pmid = {27878516}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Axons/*physiology ; Disease Progression ; Humans ; *Membrane Potentials ; Potassium Channels/physiology ; Sodium Channels/physiology ; }, abstract = {Axonal excitability testing provides in vivo assessment of axonal ion channel function and membrane potential. Excitability techniques have provided insights into the pathophysiological mechanisms underlying the development of neurodegeneration and clinical features of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Specifically, abnormalities of Na[+] and K[+] conductances contribute to development of membrane hyperexcitability in ALS, thereby leading to symptom generation of muscle cramps and fasciculations, in addition to promoting a neurodegenerative cascade via Ca[2+]-mediated processes. Modulation of axonal ion channel function in ALS has resulted in significant symptomatic improvement that has been accompanied by stabilization of axonal excitability parameters. Separately, axonal ion channel dysfunction evolves with disease progression and correlates with survival, thereby serving as a potential therapeutic biomarker in ALS. The present review provides an overview of axonal excitability techniques and the physiological mechanisms underlying membrane excitability, with a focus on the role of axonal ion channel dysfunction in motor neuron disease and related neuromuscular diseases.}, }
@article {pmid27873462, year = {2017}, author = {Golpich, M and Amini, E and Mohamed, Z and Azman Ali, R and Mohamed Ibrahim, N and Ahmadiani, A}, title = {Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {23}, number = {1}, pages = {5-22}, pmid = {27873462}, issn = {1755-5949}, mesh = {Animals ; Histocompatibility Antigens/genetics/metabolism ; Humans ; Mitochondrial Diseases/*etiology ; Neurodegenerative Diseases/*complications/*metabolism ; *Organelle Biogenesis ; }, abstract = {Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.}, }
@article {pmid27869378, year = {2016}, author = {Reinholz, M and Ruzicka, T and Steinhoff, M and Schaller, M and Gieler, U and Schöfer, H and Homey, B and Lehmann, P and Luger, TA}, title = {Pathogenese und Klinik der Rosazea als Schlüssel für eine symptomorientierte Therapie.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14 Suppl 6}, number = {}, pages = {4-16}, doi = {10.1111/ddg.13139_g}, pmid = {27869378}, issn = {1610-0387}, mesh = {Evidence-Based Medicine ; Facial Dermatoses/*diagnosis/genetics/*therapy ; Germany ; Humans ; Patient-Centered Care/*methods ; Rosacea/*diagnosis/genetics/*therapy ; Symptom Assessment/*methods ; Treatment Outcome ; }, abstract = {Rosazea ist eine häufige chronisch-entzündliche Hauterkrankung, die typischerweise bei Erwachsenen vorkommt und das Gesicht betrifft. Synonyme der Rosazea sind Acne rosacea, Kupferfinne, Rotfinne, Couperose und Rosacea. Die Erkrankung ist durch einen chronischen und schubartigen Verlauf gekennzeichnet und wird durch ein genetisch prädisponiertes, multifaktorielles Geschehen bedingt. Ein vermehrtes Auftreten wird bei hellem Hauttyp und positiver Familienanamnese verzeichnet. Die charakteristischen Rosazea-Symptome manifestieren sich vorwiegend, aber nicht ausschließlich zentrofazial, wobei Stirn, Nase, Kinn und die Wangen maßgeblich betroffen sind. Dabei werden unterschiedliche Hauptsymptome voneinander unterschieden, anhand derer eine Klassifikation der verschiedenen klinischen Bilder vorgenommen werden kann. Eine Klassifizierung wird oftmals jedoch nicht der klinischen Realität gerecht, da die verschiedenen Symptome häufig gemeinsam auftreten. Diese Übersichtarbeit führt in die Pathogenese und Klinik der Rosazea ein und plädiert für einen symptomorientierten Therapieansatz.}, }
@article {pmid27869375, year = {2016}, author = {Schaller, M and Schöfer, H and Homey, B and Gieler, U and Lehmann, P and Luger, TA and Ruzicka, T and Steinhoff, M}, title = {Aktueller Stand der systemischen Rosazea-Therapie.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14 Suppl 6}, number = {}, pages = {29-37}, doi = {10.1111/ddg.13141_g}, pmid = {27869375}, issn = {1610-0387}, mesh = {Administration, Cutaneous ; Administration, Topical ; Anti-Inflammatory Agents/*administration &amp; dosage ; Dermatologic Agents/administration &amp; dosage ; Evidence-Based Medicine ; Facial Dermatoses/*diagnosis/*drug therapy ; Germany ; Humans ; Immunologic Factors/*administration &amp; dosage ; Patient-Centered Care/methods ; Rosacea/*diagnosis/*drug therapy ; Symptom Assessment/methods ; Treatment Outcome ; }, abstract = {Basierend auf den Daten zahlreicher Studien sind orale Tetracycline - und hier insbesondere Doxycyclin als Tetracyclin der zweiten Generation - die Grundpfeiler der systemischen Rosazea-Therapie. Bisher ist dafür jedoch nur Doxycyclin 40 mg in antientzündlicher Dosierung mit veränderter Wirkstofffreisetzung zugelassen. Seit Einführung der Therapie mit Doxycyclin einmal täglich in nicht antibiotischer Dosierung wird die orale Therapie häufiger als Erstbehandlung bei mittelschwerer bis schwerer papulopustulöser Rosazea verschrieben. Oft wird diese Behandlung aufgrund der besseren Wirksamkeit im Vergleich zur Monotherapie auch mit einer topischen Behandlung kombiniert. Obwohl in der Systemtherapie weitere, nicht zugelassene Wirkstoffe wie Makrolide, Isotretinoin und Carvedilol mit viel versprechenden Ergebnissen untersucht wurden, ist die vorliegende Erfahrung bisher begrenzt, so dass diese Substanzen speziellen Situationen vorbehalten bleiben sollten.}, }
@article {pmid27869373, year = {2016}, author = {Schaller, M and Schöfer, H and Homey, B and Hofmann, M and Gieler, U and Lehmann, P and Luger, TA and Ruzicka, T and Steinhoff, M}, title = {Rosazea-Management: Update über allgemeine Maßnahmen und topische Therapieoptionen.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14 Suppl 6}, number = {}, pages = {17-28}, doi = {10.1111/ddg.13143_g}, pmid = {27869373}, issn = {1610-0387}, mesh = {Administration, Cutaneous ; Administration, Topical ; Anti-Inflammatory Agents/*administration &amp; dosage ; Dermatologic Agents/administration &amp; dosage ; Evidence-Based Medicine ; Facial Dermatoses/*diagnosis/*drug therapy ; Germany ; Humans ; Immunologic Factors/*administration &amp; dosage ; Patient-Centered Care/methods ; Rosacea/*diagnosis/*drug therapy ; Symptom Assessment/methods ; Treatment Outcome ; }, abstract = {Obwohl bislang für die Rosazea keine kurative Therapie besteht, können verschiedene Optionen zur Behandlung der Symptome und zur Vorbeugung von Exazerbationen empfohlen werden. Neben Selbsthilfemaßnahme wie der Vermeidung von Triggerfaktoren und einer geeigneten Hautpflege sollte das Rosazea-Management bei Patienten mit erythematöser und leichter bis schwerer papulopustulöser Rosazea die Anwendung topischer Präparate als First-Line-Therapie umfassen. Da Überlappungen der charakteristischen Rosazea-Symptome im klinischen Alltag die Regel sind, sollte die medikamentöse Therapie auf die individuellen Symptome zugeschnitten werden; auch eine Kombinationstherapie kann erforderlich sein. Zu den für die Behandlung der Hauptsymptome der Rosazea zugelassenen Wirkstoffen gehören Brimonidin gegen das Erythem sowie Ivermectin, Metronidazol oder Azelainsäure gegen entzündliche Läsionen. Ihre Wirksamkeit wurde in zahlreichen validen, gut kontrollierten Studien belegt. Darüber hinaus existieren verschiedene nicht zugelassene topische Behandlungsmöglichkeiten, deren Wirksamkeit und Sicherheit noch in größeren, kontrollierten Studien zu untersuchen ist.}, }
@article {pmid27868154, year = {2017}, author = {Tefera, TW and Tan, KN and McDonald, TS and Borges, K}, title = {Alternative Fuels in Epilepsy and Amyotrophic Lateral Sclerosis.}, journal = {Neurochemical research}, volume = {42}, number = {6}, pages = {1610-1620}, pmid = {27868154}, issn = {1573-6903}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/*metabolism ; Animals ; Brain/*metabolism ; Diet, Ketogenic/methods ; Epilepsy/*diet therapy/*metabolism ; Fatty Acids/administration &amp; dosage/metabolism ; Glycolysis/physiology ; Humans ; Triglycerides/administration &amp; dosage/metabolism ; }, abstract = {This review summarises the recent findings on metabolic treatments for epilepsy and Amyotrophic Lateral Sclerosis (ALS) in honour of Professor Ursula Sonnewald. The metabolic impairments in rodent models of these disorders as well as affected patients are being discussed. In both epilepsy and ALS, there are defects in glucose uptake and reduced tricarboxylic acid (TCA) cycling, at least in part due to reduced amounts of C4 TCA cycle intermediates. In addition there are impairments in glycolysis in ALS. A reduction in glucose uptake can be addressed by providing the brain with alternative fuels, such as ketones or medium-chain triglycerides. As anaplerotic fuels, such as the triglyceride of heptanoate, triheptanoin, refill the TCA cycle C4/C5 intermediate pool that is deficient, they are ideal to boost TCA cycling and thus the oxidative metabolism of all fuels.}, }
@article {pmid27866730, year = {2016}, author = {Stojkovic, T}, title = {Hereditary neuropathies: An update.}, journal = {Revue neurologique}, volume = {172}, number = {12}, pages = {775-778}, doi = {10.1016/j.neurol.2016.06.007}, pmid = {27866730}, issn = {0035-3787}, mesh = {Amyloid Neuropathies, Familial/epidemiology/genetics ; Charcot-Marie-Tooth Disease/epidemiology/genetics ; Humans ; Mutation ; Nervous System Diseases/epidemiology/*genetics ; Neuromuscular Diseases/epidemiology/*genetics ; Prealbumin/genetics ; Prevalence ; }, abstract = {Hereditary neuropathies are the most common inherited neuromuscular diseases. Charcot-Marie-Tooth (CMT) disease represents the most common form with an average prevalence ranging from 1/2500 to 1/1200, depending on the studies. To date and with the advances of the latest generation sequencing, more than 80 genes have been identified. Although the common clinical phenotype comprises a progressive distal muscle weakness and sensory loss, foot deformities and decreased or absent tendon reflexes, clinical and electrophysiological phenotypes exhibit great variability. Moreover, atypical phenotypes are arising, overlapping with spastic paraplegia, hereditary sensory neuropathies or amyotrophic lateral sclerosis. The causative genes are involved in various biological processes such as myelin development and maintenance, biosynthesis and degradation of proteins, neuronal structural maintenance, axonal transport, endocytosis, membrane dynamics, ion-channel function and the mitochondrial network. An accurate genetic diagnosis is important for appropriate genetic counselling and treatment options. Therapeutic advances, particularly small interfering RNA therapy, are encouraging in hereditary transthyretin amyloid neuropathy.}, }
@article {pmid30050373, year = {2016}, author = {Pfeffer, G and Povitz, M}, title = {Respiratory management of patients with neuromuscular disease: current perspectives.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {6}, number = {}, pages = {111-118}, pmid = {30050373}, issn = {1179-9900}, abstract = {Neuromuscular ventilatory weakness can be difficult to recognize because the symptoms can be nocturnal, nonspecific, or attributed to other conditions. The presence of respiratory muscle weakness suggests a number of possible heterogeneous conditions, including neurodegenerative, autoimmune, and genetic neuromuscular diseases. In some conditions, disease-modifying management exists, but in the absence of such intervention, supportive respiratory therapy can improve quality of life and survival. In this review, we discuss the differential diagnosis and diagnostic approach to chronic neuromuscular respiratory weakness. We also review the clinical assessment and management of respiratory failure in these conditions.}, }
@article {pmid27854227, year = {2016}, author = {Walklet, E and Muse, K and Meyrick, J and Moss, T}, title = {Do Psychosocial Interventions Improve Quality of Life and Wellbeing in Adults with Neuromuscular Disorders? A Systematic Review and Narrative Synthesis.}, journal = {Journal of neuromuscular diseases}, volume = {3}, number = {3}, pages = {347-362}, pmid = {27854227}, issn = {2214-3599}, mesh = {Amyotrophic Lateral Sclerosis/psychology/rehabilitation ; Charcot-Marie-Tooth Disease/psychology/rehabilitation ; *Cognitive Behavioral Therapy ; Disclosure ; Humans ; *Hypnosis ; *Mental Health ; Muscular Dystrophies/psychology/rehabilitation ; Myasthenia Gravis/psychology/rehabilitation ; Myotonic Dystrophy/psychology/rehabilitation ; Neuromuscular Diseases/psychology/*rehabilitation ; Patient Education as Topic ; Postpoliomyelitis Syndrome/psychology/rehabilitation ; *Quality of Life ; }, abstract = {Quality of life and well-being are frequently restricted in adults with neuromuscular disorders. As such, identification of appropriate interventions is imperative. The objective of this paper was to systematically review and critically appraise quantitative studies (RCTs, controlled trials and cohort studies) of psychosocial interventions designed to improve quality of life and well-being in adults with neuromuscular disorders. A systematic review of the published and unpublished literature was conducted. Studies meeting inclusion criteria were appraised using a validated quality assessment tool and results presented in a narrative synthesis. Out of 3,136 studies identified, ten studies met criteria for inclusion within the review. Included studies comprised a range of interventions including: cognitive behavioural therapy, dignity therapy, hypnosis, expressive disclosure, gratitude lists, group psychoeducation and psychologically informed rehabilitation. Five of the interventions were for patients with Amyotrophic Lateral Sclerosis (ALS). The remainder were for patients with post-polio syndrome, muscular dystrophies and mixed disorders, such as Charcot-Marie-Tooth disease, myasthenia gravis and myotonic dystrophy. Across varied interventions and neuromuscular disorders, seven studies reported a short-term beneficial effect of intervention on quality of life and well-being. Whilst such findings are encouraging, widespread issues with the methodological quality of these studies significantly compromised the results. There is no strong evidence that psychosocial interventions improve quality of life and well-being in adults with neuromuscular disorders, due to a paucity of high quality research in this field. Multi-site, randomised controlled trials with active controls, standardised outcome measurement and longer term follow-ups are urgently required.}, }
@article {pmid27847465, year = {2016}, author = {Kojic, M and Wainwright, B}, title = {The Many Faces of Elongator in Neurodevelopment and Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {9}, number = {}, pages = {115}, pmid = {27847465}, issn = {1662-5099}, abstract = {Development of the nervous system requires a variety of cellular activities, such as proliferation, migration, axonal outgrowth and guidance and synapse formation during the differentiation of neural precursors into mature neurons. Malfunction of these highly regulated and coordinated events results in various neurological diseases. The Elongator complex is a multi-subunit complex highly conserved in eukaryotes whose function has been implicated in the majority of cellular activities underlying neurodevelopment. These activities include cell motility, actin cytoskeleton organization, exocytosis, polarized secretion, intracellular trafficking and the maintenance of neural function. Several studies have associated mutations in Elongator subunits with the neurological disorders familial dysautonomia (FD), intellectual disability (ID), amyotrophic lateral sclerosis (ALS) and rolandic epilepsy (RE). Here, we review the various cellular activities assigned to this complex and discuss the implications for neural development and disease. Further research in this area has the potential to generate new diagnostic tools, better prevention strategies and more effective treatment options for a wide variety of neurological disorders.}, }
@article {pmid27830784, year = {2016}, author = {Taylor, JP and Brown, RH and Cleveland, DW}, title = {Decoding ALS: from genes to mechanism.}, journal = {Nature}, volume = {539}, number = {7628}, pages = {197-206}, pmid = {27830784}, issn = {1476-4687}, support = {R01 NS027036/NS/NINDS NIH HHS/United States ; R35 NS097974/NS/NINDS NIH HHS/United States ; /HHMI/HHMI/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*physiopathology/therapy ; Animals ; Biological Transport ; C9orf72 Protein ; Endoplasmic Reticulum Stress/genetics ; Frontotemporal Dementia/genetics ; Humans ; Nervous System/pathology/physiopathology ; Organelles/genetics/metabolism/pathology ; Prions/metabolism ; Proteins/genetics/metabolism ; Proteolysis ; RNA/biosynthesis/genetics/metabolism/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.}, }
@article {pmid27830583, year = {2017}, author = {Wu, Q and Luo, CL and Tao, LY}, title = {Dynamin-related protein 1 (Drp1) mediating mitophagy contributes to the pathophysiology of nervous system diseases and brain injury.}, journal = {Histology and histopathology}, volume = {32}, number = {6}, pages = {551-559}, doi = {10.14670/HH-11-841}, pmid = {27830583}, issn = {1699-5848}, mesh = {Animals ; Autophagy/physiology ; Brain Injuries/*metabolism/physiopathology ; Dynamins ; GTP Phosphohydrolases/*metabolism ; Humans ; Microtubule-Associated Proteins/*metabolism ; Mitochondrial Proteins/*metabolism ; Mitophagy/*physiology ; Neurodegenerative Diseases/*metabolism/physiopathology ; }, abstract = {As the main source of energy (celluar ATP) in eukaryotic cells, mitochondria are involved in cellular physiology and pathology. The balance of mitochondrial dynamic, fission and fusion regulated by quality control mechanisms, provides a guarantee for maintaining mitochondrial function, even celluar function. Worn out mitochondria would be removed through mitophagy which is regulated by autophagy related proteins and mitochondrial membrane proteins. Drp1, dynamic-related protein 1, is regarded as one of the most important proteins to evaluate mitochondrial fission mediating mitophagy in neurodegenerative diseases (eg. Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis) and heart failure. Recent studies have focused on the roles of Drp1 in ischemia-induced mitophagy in the hippocampal CA3 region, and traumatic brain injury (TBI)-induced cell death together with functional deficits. However, the exact mechanisms have not been well characterized. In this review, we will discuss and clarify the role of Drp1 and mitophagy in nervous system diseases and brain injury therein, with a special emphasis on their molecular mechanisms mediating mitochondrial dynamics and mitophagy.}, }
@article {pmid27830492, year = {2017}, author = {Vucic, S and Kiernan, MC}, title = {Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {91-106}, pmid = {27830492}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Animals ; Biomarkers ; *Cortical Excitability ; Evoked Potentials, Motor ; Humans ; Motor Cortex/physiopathology ; Motor Neurons/physiology ; Neurodegenerative Diseases/*diagnosis/*physiopathology ; Pyramidal Tracts/physiopathology ; Sensitivity and Specificity ; *Transcranial Magnetic Stimulation ; }, abstract = {Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motor-evoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.}, }
@article {pmid27822919, year = {2016}, author = {Abdul Wahid, SF and Law, ZK and Ismail, NA and Azman Ali, R and Lai, NM}, title = {Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {11}, number = {11}, pages = {CD011742}, pmid = {27822919}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cell- and Tissue-Based Therapy/*methods ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND.<br><br>OBJECTIVES: To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment.<br><br>SEARCH METHODS: On 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies.<br><br>SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally.<br><br>DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology.<br><br>MAIN RESULTS: No studies were eligible for inclusion in the review. We identified four ongoing trials.<br><br>AUTHORS' CONCLUSIONS: Currently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.}, }
@article {pmid27815720, year = {2017}, author = {Xiang, C and Wang, Y and Zhang, H and Han, F}, title = {The role of endoplasmic reticulum stress in neurodegenerative disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {22}, number = {1}, pages = {1-26}, doi = {10.1007/s10495-016-1296-4}, pmid = {27815720}, issn = {1573-675X}, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Apoptosis/*genetics ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum Stress/*genetics ; Humans ; Huntington Disease/genetics/pathology ; Parkinson Disease/genetics/pathology ; Unfolded Protein Response/*genetics ; }, abstract = {The endoplasmic reticulum (ER) is an important organelle involved in cellular homeostasis and control of protein quality. Unfolded protein response (UPR) is a cellular response to ER stress and promotes cell survival. Severe or prolonged stress activates apoptosis signaling to trigger cell death. In mammals, the UPR is initiated by three major ER stress sensors, including inositol-requiring transmembrane kinase 1, double-stranded RNA-activated protein kinase-like ER kinase and activating transcription factor 6. UPR dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, which is characterized by the accumulation and aggregation of misfolded proteins. ER stress mediates the pathogenesis of psychiatric diseases, such as depression, schizophrenia, sleep fragmentation and post-traumatic stress disorder. The role of UPR in the neuropathology of humans, cell lines and animal models, is established. Therefore, inhibition of specific ER mediators may contribute to the treatment and prevention of neurodegeneration. Preclinical studies have shed light on the potential therapeutic strategies. Here, we will review the evidence of UPR activation in neurodegenerative disorders and psychiatric diseases along with the methodology.}, }
@article {pmid27812980, year = {2016}, author = {Domise, M and Vingtdeux, V}, title = {AMPK in Neurodegenerative Diseases.}, journal = {Experientia supplementum (2012)}, volume = {107}, number = {}, pages = {153-177}, doi = {10.1007/978-3-319-43589-3_7}, pmid = {27812980}, issn = {1664-431X}, mesh = {AMP-Activated Protein Kinases/*genetics/metabolism ; Alzheimer Disease/*enzymology/genetics/pathology ; Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Brain/enzymology/pathology ; Dementia/*enzymology/genetics/pathology ; Energy Metabolism/genetics ; Gene Expression Regulation ; Humans ; Huntington Disease/*enzymology/genetics/pathology ; Neurons/enzymology/pathology ; Oxidative Stress ; Parkinson Disease/*enzymology/genetics/pathology ; Protein Subunits/genetics/metabolism ; Signal Transduction ; }, abstract = {Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are neurodegenerative disorders that are characterized by a progressive degeneration of nerve cells eventually leading to dementia. While these diseases affect different neuronal populations and present distinct clinical features, they share in common several features and signaling pathways. In particular, energy metabolism defects, oxidative stress, and excitotoxicity are commonly described and might be correlated with AMP-activated protein kinase (AMPK) deregulation. AMPK is a master energy sensor which was reported to be overactivated in the brain of patients affected by these neurodegenerative disorders. While the exact role played by AMPK in these diseases remains to be clearly established, several studies reported the implication of AMPK in various signaling pathways that are involved in these diseases' progression. In this chapter, we review the current literature regarding the involvement of AMPK in the development of these diseases and discuss the common pathways involved.}, }
@article {pmid27809706, year = {2017}, author = {Islam, MT}, title = {Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.}, journal = {Neurological research}, volume = {39}, number = {1}, pages = {73-82}, doi = {10.1080/01616412.2016.1251711}, pmid = {27809706}, issn = {1743-1328}, mesh = {Animals ; Humans ; Mitochondrial Diseases/*etiology ; Neurodegenerative Diseases/*complications ; Oxidative Stress/*physiology ; }, abstract = {Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.}, }
@article {pmid27807401, year = {2016}, author = {Vallée, A and Lecarpentier, Y}, title = {Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma.}, journal = {Frontiers in neuroscience}, volume = {10}, number = {}, pages = {459}, pmid = {27807401}, issn = {1662-4548}, abstract = {The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system (CNS). Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR alpha upregulates transcription of the alpha-secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR alpha signaling.}, }
@article {pmid27805903, year = {2016}, author = {Wang, SP and Wang, LH}, title = {Disease implication of hyper-Hippo signalling.}, journal = {Open biology}, volume = {6}, number = {10}, pages = {}, pmid = {27805903}, issn = {2046-2441}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Apoptosis ; Arrhythmias, Cardiac/metabolism ; Cell Differentiation ; Cell Proliferation ; Corneal Dystrophies, Hereditary/metabolism ; Diabetes Mellitus/metabolism ; Gene Expression Regulation ; Hippo Signaling Pathway ; Homeostasis ; Humans ; Protein Serine-Threonine Kinases/*metabolism ; Retinal Degeneration/metabolism ; *Signal Transduction ; *Up-Regulation ; }, abstract = {The Hippo signalling pathway regulates cellular proliferation, apoptosis and differentiation, thus exerting profound effects on cellular homeostasis. Inhibition of Hippo signalling has been frequently implicated in human cancers, indicating a well-known tumour suppressor function of the Hippo pathway. However, it is less certain whether and how hyperactivation of the Hippo pathway affects biological outcome in living cells. This review describes current knowledge of the regulatory mechanisms of the Hippo pathway, mainly focusing on hyperactivation of the Hippo signalling nexus. The disease implications of hyperactivated Hippo signalling have also been discussed, including arrhythmogenic cardiomyopathy, Sveinsson's chorioretinal atrophy, Alzheimer's disease, amyotrophic lateral sclerosis and diabetes. By highlighting the significance of disease-relevant Hippo signalling activation, this review can offer exciting prospects to address the onset and potential reversal of Hippo-related disorders.}, }
@article {pmid27804883, year = {2017}, author = {Suryadevara, U and Bruijnzeel, DM and Nuthi, M and Jagnarine, DA and Tandon, R and Bruijnzeel, AW}, title = {Pros and Cons of Medical Cannabis use by People with Chronic Brain Disorders.}, journal = {Current neuropharmacology}, volume = {15}, number = {6}, pages = {800-814}, pmid = {27804883}, issn = {1875-6190}, mesh = {Animals ; Brain Diseases/*drug therapy ; Chronic Disease ; Humans ; Medical Marijuana/*adverse effects/*therapeutic use ; Mental Disorders/*drug therapy ; Substance-Related Disorders ; }, abstract = {BACKGROUND: Cannabis is the most widely used illicit drug in the world and there is growing concern about the mental health effects of cannabis use. These concerns are at least partly due to the strong increase in recreational and medical cannabis use and the rise in tetrahydrocannabinol (THC) levels. Cannabis is widely used to self-medicate by older people and people with brain disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), bipolar disorder, and schizophrenia.<br><br>OBJECTIVE: This review provides an overview of the perceived benefits and adverse mental health effects of cannabis use in people with ALS, MS, AD, PD, bipolar disorder, and schizophrenia.<br><br>RESULTS: The reviewed studies indicate that cannabis use diminishes some symptoms associated with these disorders. Cannabis use decreases pain and spasticity in people with MS, decreases tremor, rigidity, and pain in people with PD, and improves the quality of life of ALS patients by improving appetite, and decreasing pain and spasticity. Cannabis use is more common among people with schizophrenia than healthy controls. Cannabis use is a risk factor for schizophrenia which increases positive symptoms in schizophrenia patients and diminishes negative symptoms. Cannabis use worsens bipolar disorder and there is no evidence that bipolar patients derive any benefit from cannabis. In late stage Alzheimer's patients, cannabis products may improve food intake, sleep quality, and diminish agitation.<br><br>CONCLUSION: Cannabis use diminishes some of the adverse effects of neurological and psychiatric disorders. However, chronic cannabis use may lead to cognitive impairments and dependence.}, }
@article {pmid27804858, year = {2017}, author = {van Noort, JM and Bugiani, M and Amor, S}, title = {Heat Shock Proteins: Old and Novel Roles in Neurodegenerative Diseases in the Central Nervous System.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {3}, pages = {244-256}, doi = {10.2174/1871527315666161031125317}, pmid = {27804858}, issn = {1996-3181}, mesh = {Animals ; Central Nervous System/*metabolism ; Heat-Shock Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; }, abstract = {Heat shock proteins (HSPs) are families of molecular chaperones that play important homeostatic functions in the central nervous system (CNS) by preventing protein misfolding, promoting degradation of improperly folded proteins, and protecting against apoptosis and inflammatory damage especially during hyperthermia, hypoxia, or oxidative stress. Under stress conditions, HSPs are upregulated to protect cells from damage that accumulates during ageing as well as pathological conditions. An important, yet frequently overlooked function of some HSPs is their ability to function as extracellular messengers (also termed chaperokines) that modulate immune responses within the CNS. Given the strong association between protein aggregation, innate immune cell activation and neurodegeneration, the expression and roles of HSPs in the CNS is attracting attention in many neurodegenerative disorders including inflammatory diseases such as multiple sclerosis, protein folding diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, and genetic white matter diseases. This is especially so since several studies show that HSPs act therapeutically by modulating innate immune activation and may thus serve as neuroprotective agents. Here we review the evidence linking HSPs with neurodegenerative disorders in humans and the experimental animal models of these disorders. We discuss the mechanisms by which HSPs protect cells, and how the knowledge of their endogenous functions can be exploited to treat disorders of the CNS.}, }
@article {pmid27764523, year = {2016}, author = {Simon, ST and Higginson, IJ and Booth, S and Harding, R and Weingärtner, V and Bausewein, C}, title = {Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults.}, journal = {The Cochrane database of systematic reviews}, volume = {10}, number = {10}, pages = {CD007354}, pmid = {27764523}, issn = {1469-493X}, support = {MCCC-RP-15-A18859/MCCC_/Marie Curie/United Kingdom ; PB-PG-0808-17311/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Benzodiazepines/adverse effects/*therapeutic use ; Dyspnea/*drug therapy/etiology ; Humans ; Lung Neoplasms/*complications ; Pulmonary Disease, Chronic Obstructive/*complications ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2010, on 'Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults'. Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. At the time of the previously published Cochrane review, there was no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in people with advanced cancer and chronic obstructive pulmonary disease (COPD).<br><br>OBJECTIVES: The primary objective of this review was to determine the efficacy of benzodiazepines for the relief of breathlessness in people with advanced disease. Secondary objectives were to determine the efficacy of different benzodiazepines, different doses of benzodiazepines, different routes of application, adverse effects of benzodiazepines, and the efficacy in different disease groups.<br><br>SEARCH METHODS: This is an update of a review published in 2010. We searched 14 electronic databases up to September 2009 for the original review. We checked the reference lists of all relevant studies, key textbooks, reviews, and websites. For the update, we searched CENTRAL, MEDLINE, and EMBASE and registers of clinical trials for further ongoing or unpublished studies, up to August 2016. We contacted study investigators and experts in the field of palliative care asking for further studies, unpublished data, or study details when necessary.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines compared with placebo or active control in relieving breathlessness in people with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary fibrosis (IPF).<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three review authors independently performed assessment of all potentially relevant studies (full text), data extraction, and assessment of methodological quality. We carried out meta-analysis where appropriate.<br><br>MAIN RESULTS: Overall, we identified eight studies for inclusion: seven in the previous review and an additional study for this update. We also identified two studies awaiting classification in this update. The studies were small (a maximum number of 101 participants) and comprised data from a total of 214 participants with advanced cancer or COPD, which we analysed. There was only one study of low risk of bias. Most of the studies had an unclear risk of bias due to lack of information on random sequence generation, concealment, and attrition. Analysis of all studies did not show a beneficial effect of benzodiazepines for the relief of breathlessness (the primary outcome) in people with advanced cancer and COPD (8 studies, 214 participants) compared to placebo, midazolam, morphine, or promethazine. Furthermore, we observed no statistically significant effect in the prevention of episodic breathlessness (breakthrough dyspnoea) in people with cancer (after 48 hours: risk ratio of 0.76 (95% CI 0.53 to 1.09; 2 studies, 108 participants)) compared to morphine. Sensitivity analyses demonstrated no statistically significant differences regarding type of benzodiazepine, dose, route and frequency of delivery, duration of treatment, or type of control. Benzodiazepines caused statistically significantly more adverse events, particularly drowsiness and somnolence, when compared to placebo (risk difference 0.74 (95% CI 0.37, 1.11); 3 studies, 38 participants). In contrast, two studies reported that morphine caused more adverse events than midazolam (RD -0.18 (95% CI -0.31, -0.04); 194 participants).<br><br>AUTHORS' CONCLUSIONS: Since the last version of this review, we have identified one new study for inclusion, but the conclusions remain unchanged. There is no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. Benzodiazepines may be considered as a second- or third-line treatment, when opioids and non-pharmacological measures have failed to control breathlessness. There is a need for well-conducted and adequately powered studies.}, }
@article {pmid27790057, year = {2016}, author = {Lee, J and Hyeon, SJ and Im, H and Ryu, H and Kim, Y and Ryu, H}, title = {Astrocytes and Microglia as Non-cell Autonomous Players in the Pathogenesis of ALS.}, journal = {Experimental neurobiology}, volume = {25}, number = {5}, pages = {233-240}, pmid = {27790057}, issn = {1226-2560}, support = {R01 NS052724/NS/NINDS NIH HHS/United States ; R01 NS067283/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that leads to a progressive muscle wasting and paralysis. The pathological phenotypes are featured by severe motor neuron death and glial activation in the lumbar spinal cord. Proposed ALS pathogenic mechanisms include glutamate cytotoxicity, inflammatory pathway, oxidative stress, and protein aggregation. However, the exact mechanisms of ALS pathogenesis are not fully understood yet. Recently, a growing body of evidence provides a novel insight on the importance of glial cells in relation to the motor neuronal damage via the non-cell autonomous pathway. Accordingly, the aim of the current paper is to overview the role of astrocytes and microglia in the pathogenesis of ALS and to better understand the disease mechanism of ALS.}, }
@article {pmid27789292, year = {2017}, author = {Di Domenico, F and Tramutola, A and Butterfield, DA}, title = {Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders.}, journal = {Free radical biology &amp; medicine}, volume = {111}, number = {}, pages = {253-261}, doi = {10.1016/j.freeradbiomed.2016.10.490}, pmid = {27789292}, issn = {1873-4596}, mesh = {Aging/*metabolism ; Aldehydes/*metabolism ; Alzheimer Disease/genetics/*metabolism/pathology ; Amyloid beta-Peptides/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Apolipoproteins E/genetics/metabolism ; Fatty Acids, Unsaturated/metabolism ; Glucose/metabolism ; Humans ; Huntington Disease/genetics/*metabolism/pathology ; Lipid Peroxidation ; Mitochondria/metabolism/pathology ; Nerve Tissue Proteins/genetics/metabolism ; Oxidative Stress ; Parkinson Disease/genetics/*metabolism/pathology ; *Protein Processing, Post-Translational ; }, abstract = {Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case.}, }
@article {pmid27415968, year = {2016}, author = {Svetoni, F and Frisone, P and Paronetto, MP}, title = {Role of FET proteins in neurodegenerative disorders.}, journal = {RNA biology}, volume = {13}, number = {11}, pages = {1089-1102}, pmid = {27415968}, issn = {1555-8584}, support = {14-0333/AICR_/Worldwide Cancer Research/United Kingdom ; }, mesh = {Animals ; Calmodulin-Binding Proteins/*genetics/metabolism ; Disease Models, Animal ; Disease Progression ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Humans ; Mutation ; Neurodegenerative Diseases/genetics/*metabolism ; RNA/metabolism ; RNA-Binding Protein EWS ; RNA-Binding Protein FUS/*genetics/metabolism ; RNA-Binding Proteins/*genetics/metabolism ; TATA-Binding Protein Associated Factors/*genetics/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) affect different neuronal cells, and have a variable age of onset, clinical symptoms, and pathological features. Despite the great progress in understanding the etiology of these disorders, the underlying mechanisms remain largely unclear. Among the processes affected in neurodegenerative diseases, alteration in RNA metabolism is emerging as a crucial player. RNA-binding proteins (RBPs) are involved at all stages of RNA metabolism and display a broad range of functions, including modulation of mRNA transcription, splicing, editing, export, stability, translation and localization and miRNA biogenesis, thus enormously impacting regulation of gene expression. On the other hand, aberrant regulation of RBP expression or activity can contribute to disease onset and progression. Recent reports identified mutations causative of neurological disorders in the genes encoding a family of RBPs named FET (FUS/TLS, EWS and TAF15). This review summarizes recent works documenting the involvement of FET proteins in the pathology of ALS, FTLD, essential tremor (ET) and other neurodegenerative diseases. Moreover, clinical implications of recent advances in FET research are critically discussed.}, }
@article {pmid27108096, year = {2016}, author = {Tognatta, R and Miller, RH}, title = {Contribution of the oligodendrocyte lineage to CNS repair and neurodegenerative pathologies.}, journal = {Neuropharmacology}, volume = {110}, number = {Pt B}, pages = {539-547}, pmid = {27108096}, issn = {1873-7064}, support = {R01 NS030800/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell Differentiation/physiology ; *Cell Lineage ; Central Nervous System/*pathology ; Humans ; Myelin Sheath/physiology ; Neurodegenerative Diseases/*physiopathology ; Oligodendroglia/*physiology ; Stem Cells/physiology ; }, abstract = {The concept of the oligodendrocyte lineage as simply a source of myelinating cells in the vertebrate CNS is undergoing radical revision. Elucidation of the origins of oligodendrocytes in the CNS has led to identification of important signaling pathways, the timing and mechanism of lineage commitments and overlapping as well as redundant functionality among oligodendrocytes. The realization that a significant proportion of the oligodendrocyte lineage cells remain in a proliferative and immature state suggests they have roles other than as a reservoir of myelinating cells. While early studies were focused on understanding the development of oligodendrocytes, more recent work has begun to define the role of oligodendrocyte lineage cells in CNS functionality and the identification of new avenues for neural repair. A relatively unexplored aspect of the oligodendrocyte lineage is their contribution either directly or indirectly to the pathology of neurodegenerative diseases such as ALS and Alzheimer's disease. Here we briefly consider the potential role of oligodendrocyte lineage cells as mediators of neural repair and neurodegeneration in the vertebrate CNS. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.}, }
@article {pmid27788555, year = {2016}, author = {Boentert, M and Young, P}, title = {[Ventilatory Support and Management of Secretions in Amyotrophic Lateral Sclerosis].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {84}, number = {10}, pages = {640-650}, doi = {10.1055/s-0042-117284}, pmid = {27788555}, issn = {1439-3522}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Humans ; Respiration, Artificial/*methods ; Respiratory Insufficiency/etiology/therapy ; Respiratory Muscles/physiopathology ; }, abstract = {The term amyotrophic lateral sclerosis (ALS) comprises a group of motor neuron diseases which are characterized by rapid disease progression and poor prognosis which is mostly due to severe respiratory muscle weakness and its sequelae. Since causative treatment options are limited it is crucial to offer comprehensive symptomatic therapies to affect patients. Symptoms of respiratory muscle weakness, sleep-disordered breathing and, subsequently, chronic hypercapnic respiratory failure are known to severely affect health-related quality of life and social functioning of patients with ALS. This review article delineates the clinical presentation of respiratory muscle weakness, diagnostic procedures to assess diaphragmatic function, and practical aspects of both mechanical ventilation and cough assistance, respectively. Various technical and electrophysiological methods allow for detection of diaphragmatic weakness and nocturnal hypoventilation. These include spiro-manometric tests of respiratory muscle strength, cardiorespiratory polygraphy and polysomnography, transcutaneous capnography, and blood gas analysis. Once the diagnosis of respiratory muscle weakness is established, non-invasive ventilation, tracheostomy-invasive ventilation (if the patient agrees to it), and management of secretions all become increasingly important in the course of the disease.}, }
@article {pmid27786579, year = {2017}, author = {Perri, E and Parakh, S and Atkin, J}, title = {Protein Disulphide Isomerases: emerging roles of PDI and ERp57 in the nervous system and as therapeutic targets for ALS.}, journal = {Expert opinion on therapeutic targets}, volume = {21}, number = {1}, pages = {37-49}, doi = {10.1080/14728222.2016.1254197}, pmid = {27786579}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Animals ; Drug Design ; Humans ; Molecular Targeted Therapy ; Protein Disulfide-Isomerases/*metabolism ; Proteostasis Deficiencies/physiopathology/therapy ; }, abstract = {There is increasing evidence that endoplasmic reticulum (ER) chaperones Protein Disulphide Isomerase (PDI) and ERp57 (endoplasmic reticulum protein 57) are protective against neurodegenerative diseases related to protein misfolding, including Amyotrophic Lateral Sclerosis (ALS). PDI and ERp57 also possess disulphide interchange activity, in which protein disulphide bonds are oxidized, reduced and isomerized, to form their native conformation. Recently, missense and intronic variants of PDI and ERp57 were associated with ALS, implying that PDI proteins are relevant to ALS pathology. Areas covered: Here, we discuss possible implications of the PDI and ERp57 variants, as well as recent studies describing previously unrecognized roles for PDI and ERp57 in the nervous system. Therapeutics based on PDI may therefore be attractive candidates for ALS. However, in addition to its protective functions, aberrant, toxic roles for PDI have recently been described. These functions need to be fully characterized before effective therapeutic strategies can be designed. Expert opinion: These disease-associated variants of PDI and ERp57 provide additional evidence for an important role for PDI proteins in ALS. However, there are many questions remaining unanswered that need to be addressed before the potential of the PDI family in relation to ALS can be fully realized.}, }
@article {pmid27658852, year = {2016}, author = {Geevasinga, N and Menon, P and Özdinler, PH and Kiernan, MC and Vucic, S}, title = {Pathophysiological and diagnostic implications of cortical dysfunction in ALS.}, journal = {Nature reviews. Neurology}, volume = {12}, number = {11}, pages = {651-661}, pmid = {27658852}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/physiopathology ; C9orf72 Protein/*genetics ; Cortical Excitability/*physiology ; Humans ; Motor Neurons/*pathology ; }, abstract = {Cortical dysfunction - specifically, the development of hyperexcitability - seems to be an early and intrinsic feature of sporadic and familial amyotrophic lateral sclerosis (ALS) phenotypes, preceding the onset of lower motor neuron dysfunction and correlating with ensuing lower motor neuron dysfunction and degeneration. In fact, cortical dysfunction could provide a pathogenic basis for ALS, with corticomotor neuronal hyperexcitability mediating motor neuron degeneration via a trans-synaptic, glutamate-mediated, excitotoxic mechanism. The recent identification of C9orf72 repeat expansion as an important genetic risk factor for both ALS and frontotemporal dementia has underscored the importance of cortical function in ALS pathogenesis, and has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. Changes in cortical function that develop in ALS could prove useful as diagnostic biomarkers, potentially enhancing the diagnosis of ALS at an early stage of the disease process. Pathophysiological and diagnostic biomarkers of cortical function might also provide insights to guide the development of future therapeutic approaches, including stem cell and genetic interventions, thereby providing potential for more-effective management of patients with ALS.}, }
@article {pmid27774051, year = {2016}, author = {Tang, BL}, title = {C9orf72's Interaction with Rab GTPases-Modulation of Membrane Traffic and Autophagy.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {228}, pmid = {27774051}, issn = {1662-5102}, abstract = {Hexanucleotide repeat expansion in an intron of Chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). While functional haploinsufficiency of C9orf72 resulting from the mutation may play a role in ALS/FTD, the actual cellular role of the protein has been unclear. Recent findings have now shown that C9orf72 physically and functionally interacts with multiple members of the Rab small GTPases family, consequently exerting important influences on cellular membrane traffic and the process of autophagy. Loss of C9orf72 impairs endocytosis in neuronal cell lines, and attenuated autophagosome formation. Interestingly, C9orf72 could influence autophagy both as part of a Guanine nucleotide exchange factor (GEF) complex, or as a Rab effector that facilitates transport of the Unc-51-like Autophagy Activating Kinase 1 (Ulk1) autophagy initiation complex. The cellular function of C9orf72 is discussed in the light of these recent findings.}, }
@article {pmid27771899, year = {2017}, author = {Takada, SH and Ikebara, JM and de Sousa, E and Cardoso, DS and Resende, RR and Ulrich, H and Rückl, M and Rüdiger, S and Kihara, AH}, title = {Determining the Roles of Inositol Trisphosphate Receptors in Neurodegeneration: Interdisciplinary Perspectives on a Complex Topic.}, journal = {Molecular neurobiology}, volume = {54}, number = {9}, pages = {6870-6884}, pmid = {27771899}, issn = {1559-1182}, support = {2014/16711-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2012/50880-4//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2013/07424-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2014/17343-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2014/15018-5//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 308608/2014-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; 2012/50880-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; 467465/2014-2//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/International ; RU1660/2-1//Deutsche Forschungsgemeinschaft/International ; IRTG 1740//Deutsche Forschungsgemeinschaft/International ; }, mesh = {Animals ; Calcium Signaling/*physiology ; Humans ; Inositol 1,4,5-Trisphosphate Receptors/physiology ; Lectins, C-Type/*physiology ; Membrane Proteins/*physiology ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {It is well known that calcium (Ca[2+]) is involved in the triggering of neuronal death. Ca[2+] cytosolic levels are regulated by Ca[2+] release from internal stores located in organelles, such as the endoplasmic reticulum. Indeed, Ca[2+] transit from distinct cell compartments follows complex dynamics that are mediated by specific receptors, notably inositol trisphosphate receptors (IP3Rs). Ca[2+] release by IP3Rs plays essential roles in several neurological disorders; however, details of these processes are poorly understood. Moreover, recent studies have shown that subcellular location, molecular identity, and density of IP3Rs profoundly affect Ca[2+] transit in neurons. Therefore, regulation of IP3R gene products in specific cellular vicinities seems to be crucial in a wide range of cellular processes from neuroprotection to neurodegeneration. In this regard, microRNAs seem to govern not only IP3Rs translation levels but also subcellular accumulation. Combining new data from molecular cell biology with mathematical modelling, we were able to summarize the state of the art on this topic. In addition to presenting how Ca[2+] dynamics mediated by IP3R activation follow a stochastic regimen, we integrated a theoretical approach in an easy-to-apply, cell biology-coherent fashion. Following the presented premises and in contrast to previously tested hypotheses, Ca[2+] released by IP3Rs may play different roles in specific neurological diseases, including Alzheimer's disease and Parkinson's disease.}, }
@article {pmid27771483, year = {2017}, author = {Groh, M and Albulescu, LO and Cristini, A and Gromak, N}, title = {Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration.}, journal = {Journal of molecular biology}, volume = {429}, number = {21}, pages = {3181-3195}, doi = {10.1016/j.jmb.2016.10.021}, pmid = {27771483}, issn = {1089-8638}, support = {GROMAK/JUN11/6278/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/J007870/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {DNA Helicases ; *Gene Expression Regulation ; Humans ; Multifunctional Enzymes ; Neurodegenerative Diseases/*genetics ; RNA Helicases/*genetics ; *Transcription, Genetic ; }, abstract = {R-loops comprise an RNA/DNA hybrid and a displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia and fragile X syndrome), and cancer. Currently, it is unclear which mechanisms cause R-loop structures to become pathogenic. The RNA/DNA helicase senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4). SETX is known to play a role in transcription, neurogenesis, and antiviral response. Here, we review the causes of R-loop dysregulation in neurodegenerative diseases and how these structures contribute to pathomechanisms. We will discuss the importance of SETX as a genome guardian in suppressing aberrant R-loop formation and analyse how SETX mutations can lead to neurodegeneration in AOA2/ALS4. Finally, we will discuss the implications for other R-loop-associated neurodegenerative diseases and point to future therapeutic approaches to treat these disorders.}, }
@article {pmid27490205, year = {2016}, author = {Kanduc, D and Shoenfeld, Y}, title = {From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide.}, journal = {Autoimmunity reviews}, volume = {15}, number = {11}, pages = {1054-1061}, doi = {10.1016/j.autrev.2016.07.030}, pmid = {27490205}, issn = {1873-0183}, mesh = {Amino Acid Sequence ; Antigens, Viral/chemistry/*immunology ; Capsid Proteins/chemistry/immunology ; Cross Reactions ; Epitopes/chemistry ; Hepatitis B Surface Antigens/chemistry/*immunology ; Hepatitis B Vaccines/adverse effects/chemistry/*immunology ; Humans ; Immunization Programs ; Oncogene Proteins, Viral/chemistry/immunology ; Papillomavirus Vaccines/adverse effects/chemistry/*immunology ; Vaccination ; Viral Envelope Proteins/chemistry/immunology ; }, abstract = {HBsAg and HPV L1 proteins - the HBV and HPV antigens utilized in current vaccines - share amino acid sequences with human proteins such as cardiomyopathy-associated protein 5, titin, protein-arginine deiminase, E3 ubiquitin-protein ligase RNF19A, bassoon, G-protein coupled receptor for fatty acids, insulin isoform 2, and mitogen-activated protein kinase kinase kinase 10, inter alia. Many shared peptides are also part of immunopositive epitopes. The data 1) support the possibility of crossreactions between the two viral antigens and human proteins that, when altered, may associate with neuropsychiatric, cardiovascular and metabolic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, diabetes, and sudden death; 2) confirm the concept that only vaccines based on sequences unique to pathogens might nullify potential crossreactivity risks in vaccination protocols.}, }
@article {pmid27479193, year = {2016}, author = {Maya, S and Prakash, T and Madhu, KD and Goli, D}, title = {Multifaceted effects of aluminium in neurodegenerative diseases: A review.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {83}, number = {}, pages = {746-754}, doi = {10.1016/j.biopha.2016.07.035}, pmid = {27479193}, issn = {1950-6007}, mesh = {Aluminum/*toxicity ; Animals ; Apoptosis/drug effects ; Calcium/metabolism ; Humans ; Neurodegenerative Diseases/genetics/*pathology ; Neurotoxins/toxicity ; Oxidative Stress/drug effects ; }, abstract = {Aluminium (Al) is the most common metal and widely distributed in our environment. Al was first isolated as an element in 1827, and its use began only after 1886. Al is widely used for industrial applications and consumer products. Apart from these it is also used in cooking utensils and in pharmacological agents, including antacids and antiperspirants from which the element usually enters into the human body. Evidence for the neurotoxicity of Al is described in various studies, but still the exact mechanism of Al toxicity is not known. However, the evidence suggests that the Al can potentiate oxidative stress and inflammatory events and finally leads to cell death. Al is considered as a well-established neurotoxin and have a link between the exposure and development of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), dementia, Gulf war syndrome and Parkinsonism. Here, we review the detailed possible pathogenesis of Al neurotoxicity. This review summarizes Al induced events likewise oxidative stress, cell mediated toxicity, apoptosis, inflammatory events in the brain, glutamate toxicity, effects on calcium homeostasis, gene expression and Al induced Neurofibrillary tangle (NFT) formation. Apart from these we also discussed animal models that are commonly used for Al induced neurotoxicity and neurodegeneration studies. These models help to find out a better way to treat and prevent the progression in Al induced neurodegenerative diseases.}, }
@article {pmid27693724, year = {2016}, author = {Minegishi, Y and Nakayama, M and Iejima, D and Kawase, K and Iwata, T}, title = {Significance of optineurin mutations in glaucoma and other diseases.}, journal = {Progress in retinal and eye research}, volume = {55}, number = {}, pages = {149-181}, doi = {10.1016/j.preteyeres.2016.08.002}, pmid = {27693724}, issn = {1873-1635}, mesh = {Animals ; Cell Cycle Proteins ; DNA/*genetics ; DNA Mutational Analysis ; Glaucoma/*genetics/metabolism ; Humans ; Membrane Transport Proteins ; *Mutation ; Transcription Factor TFIIIA/*genetics/metabolism ; }, abstract = {Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi et al. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport. Recently, OPTN mutations were found to cause amyotrophic lateral sclerosis (ALS). Surprisingly, a mutation in the OPTN interacting protein, i.e., the duplication of TANK binding protein 1 (TBK1) gene, also can cause both NTG and ALS. These phenotypically distinct neuronal diseases are now merging into one common pathological mechanism by these two genes. TBK1 inhibition has emerged as a potential therapy for NTG. In this manuscript, we focus on the OPTN E50K mutation, the most common mutation for NTG, to describe the molecular mechanism of NTG by expressing a mutant Optn gene in cells and genetically modified mice. Patient iPS cells were developed and differentiated into neural cells to observe abnormal behavior and the impact of the E50K mutation. These in vitro studies were further extended to identify the inhibitors BX795 and amlexanox, which have the potential to reverse the disease-causing phenomenon in patient's neural cells. Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice.}, }
@article {pmid27768524, year = {2018}, author = {Webster, CP and Smith, EF and Grierson, AJ and De Vos, KJ}, title = {C9orf72 plays a central role in Rab GTPase-dependent regulation of autophagy.}, journal = {Small GTPases}, volume = {9}, number = {5}, pages = {399-408}, pmid = {27768524}, issn = {2154-1256}, support = {DEVOS/OCT13/870-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M013251/1//Medical Research Council/United Kingdom ; MR/K005146/1//Medical Research Council/United Kingdom ; }, mesh = {*Autophagy ; C9orf72 Protein/*metabolism ; Humans ; rab GTP-Binding Proteins/*metabolism ; }, abstract = {A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients. In a recent study, we investigated this possibility by reducing expression of C9orf72 in cell lines and primary neurons and found that C9orf72 regulates the initiation of autophagy. C9orf72 interacts with Rab1a, preferentially in its GTP-bound state, as well as the ULK1 autophagy initiation complex. As an effector of Rab1a, C9orf72 controls the Rab1a-dependent trafficking of the ULK1 initiation complex prior to autophagosome formation. In line with this function, C9orf72 depletion in cell lines and primary neurons caused the accumulation of p62/sequestosome-1-positive inclusions. In support of a role in disease pathogenesis, C9ALS/FTD patient-derived iNeurons showed markedly reduced levels of autophagy. In this Commentary we summarise recent findings supporting the key role of C9orf72 in Rab GTPase-dependent regulation of autophagy and discuss autophagy dysregulation as a pathogenic mechanism in ALS/FTD.}, }
@article {pmid27767282, year = {2016}, author = {Weins, AB and Biedermann, T and Weiss, T and Weiss, JM}, title = {Wells-Syndrom.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14}, number = {10}, pages = {989-994}, doi = {10.1111/ddg.13132_g}, pmid = {27767282}, issn = {1610-0387}, abstract = {Das Wells-Syndrom, auch als eosinophile Zellulitis bezeichnet, ist eine seltene, sporadisch auftretende eosinophile Dermatose mit polymorphem klinischem Bild. Als typisch gelten entzündliche Erytheme oder Plaques an den Extremitäten, die initial als Erysipel imponieren können, unter antimikrobieller Behandlung aber persistieren. Die eosinophile Zellulitis ist eine Ausschlussdiagnose, die in Zusammenschau von klinischem Befund und charakteristischem histologischem Bild (Flammenfiguren) nur im Verlauf gestellt werden kann. Mit einer Vielzahl möglicher Triggerfaktoren ist die Ätiologie nicht geklärt. Die Beteiligung abnormer Th2-Zellen, des Zytokins IL-5 und aktivierter eosinophiler Granulozyten lässt eine unspezifische Hypersensitivitätsreaktion auf exo- und endogene Stimuli vermuten. Die häufiger vorkommenden chronisch- rezidivierenden Formen lassen sich durch Glukokortikoide günstig beeinflussen. Der Verlauf ist meist selbstlimitierend, ohne Residuen. Aufgrund von Übergängen in hämatoonkologische Erkrankungen sind Verlaufskontrollen angezeigt.}, }
@article {pmid27619540, year = {2017}, author = {Wen, X and Westergard, T and Pasinelli, P and Trotti, D}, title = {Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene.}, journal = {Neuroscience letters}, volume = {636}, number = {}, pages = {16-26}, pmid = {27619540}, issn = {1872-7972}, support = {R21 NS090912/NS/NINDS NIH HHS/United States ; R56 NS092572/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; C9orf72 Protein ; *DNA Repeat Expansion ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Haploinsufficiency ; Humans ; Mutation ; Protein Biosynthesis ; Proteins/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene C9orf72. Three hypotheses have been proposed to explain how this repeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded repeats interfere with transcription or translation of the gene, leading to decreased expression of the C9orf72 protein; 2) RNA gain of function-RNA foci formed by sense and antisense transcripts of expanded repeats interact and sequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat associated non-ATG initiated (RAN) translation of expanded sense GGGGCC and antisense CCCCGG repeats produces potential toxic dipeptide repeat protein (DPR). In this review, we assess current evidence supporting or arguing against each proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, controversial findings are also discussed. Lastly, we discuss the possibility that the three pathogenic mechanisms are not mutually exclusive and all three might be involved in disease.}, }
@article {pmid27597727, year = {2016}, author = {Khanam, H and Ali, A and Asif, M and Shamsuzzaman, }, title = {Neurodegenerative diseases linked to misfolded proteins and their therapeutic approaches: A review.}, journal = {European journal of medicinal chemistry}, volume = {124}, number = {}, pages = {1121-1141}, doi = {10.1016/j.ejmech.2016.08.006}, pmid = {27597727}, issn = {1768-3254}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*complications/drug therapy/metabolism/*therapy ; Proteostasis Deficiencies/*complications ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Huntington's diseases and amyotrophic lateral sclerosis, are mainly characterized by the massive deposition of misfolded protein aggregates consequent to aberrant production or overexpression of specific proteins. The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this review we examine recent progress in the area of neurodegenerative drug discovery, focusing on some of the most common targets.}, }
@article {pmid27759834, year = {2016}, author = {Oliveira, AF and Silva, GA and Almeida, DM}, title = {Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review.}, journal = {Einstein (Sao Paulo, Brazil)}, volume = {14}, number = {3}, pages = {431-434}, pmid = {27759834}, issn = {2317-6385}, support = {UL1 TR001425/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/*therapeutic use ; Humans ; Injections/methods ; Neuromuscular Agents/*therapeutic use ; Salivary Glands ; Sialorrhea/*drug therapy/etiology ; Treatment Outcome ; Ultrasonography, Interventional ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are the central nervous system cells that control voluntary muscle movements. The excessive salivation (sialorrhea) is present in approximately 50% of amyotrophic lateral sclerosis cases. Thus, some alternative therapeutic methods are sought, such as anticholinergic drugs and surgery. Recently the use of botulinum toxin applied at a midpoint of the salivary glands, often guided by ultrasound, have demonstrated positive results. The objective was to review the literature to demonstrate an alternative method to treatments of sialorrhea in patients with amyotrophic lateral sclerosis. In recent studies, the efficacy of botulinum toxin is confirmed, although new applications are required. Since the side effects are negligible, this is an alternative to treat amyotrophic lateral sclerosis, and other patients with diseases that present sialorrhea. RESUMO Esclerose lateral amiotrófica é uma doença neurodegenerativa progressiva e fatal, caracterizada pela degeneração dos neurônios motores, as células do sistema nervoso central que controlam os movimentos voluntários dos músculos. A salivação excessiva (sialorreia) está presente em cerca de 50% dos casos de esclerose lateral amiotrófica. Dessa forma, surgem medidas terapêuticas alternativas como drogas anticolinérgicas e cirurgia, e recentemente, o uso da toxina botulínica, aplicada em um ponto central das glândulas salivares, muitas vezes guiado por ultrassonografia, demostrou resultados positivos. Objetivou-se revisar a literatura no intuito de demonstrar um método alternativo aos tratamentos de sialorreia em pacientes com esclerose lateral amiotrófica. Em estudos recentes, a eficácia do tratamento com toxina botulínica foi confirmada e, mesmo requerendo novas aplicações, os efeitos colaterais são ínfimos. Ela surge então como alternativa não só ao tratamento de esclerose lateral amiotrófica, mas também para outros pacientes com doenças que apresentem a sialorreia.}, }
@article {pmid27759812, year = {2016}, author = {Souza, PV and Pinto, WB and Rezende, FM and Oliveira, AS}, title = {Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {74}, number = {10}, pages = {849-854}, doi = {10.1590/0004-282X20160117}, pmid = {27759812}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Glutamic Acid/physiology ; Humans ; Medical Illustration ; Motor Neurons/chemistry/*physiology ; Nerve Growth Factors/physiology ; Neuroglia/chemistry/*physiology ; }, abstract = {Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical data regarding its pathophysiological mechanisms, motor neuron disease develops under a complex network of mechanisms not restricted to the unique functions of the alpha motor neurons but which actually involve diverse functions of glial cell interaction. This review aims to expose some of the leading roles of glial cells in the physiological mechanisms of neuron-glial cell interactions and the mechanisms related to motor neuron survival linked to glial cell functions.}, }
@article {pmid27752938, year = {2017}, author = {Menke, RA and Agosta, F and Grosskreutz, J and Filippi, M and Turner, MR}, title = {Neuroimaging Endpoints in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {11-23}, pmid = {27752938}, issn = {1878-7479}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology/physiopathology ; Animals ; Biomarkers ; Brain/diagnostic imaging/pathology/physiopathology ; Brain Mapping ; Clinical Trials as Topic ; Diffusion Tensor Imaging ; Disease Models, Animal ; *Disease Progression ; *Endpoint Determination ; Humans ; Image Interpretation, Computer-Assisted/methods ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; *Neuroimaging ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative, clinically heterogeneous syndrome pathologically overlapping with frontotemporal dementia. To date, therapeutic trials in animal models have not been able to predict treatment response in humans, and the revised ALS Functional Rating Scale, which is based on coarse disability measures, remains the gold-standard measure of disease progression. Advances in neuroimaging have enabled mapping of functional, structural, and molecular aspects of ALS pathology, and these objective measures may be uniquely sensitive to the detection of propagation of pathology in vivo. Abnormalities are detectable before clinical symptoms develop, offering the potential for neuroprotective intervention in familial cases. Although promising neuroimaging biomarker candidates for diagnosis, prognosis, and disease progression have emerged, these have been from the study of necessarily select patient cohorts identified in specialized referral centers. Further multicenter research is now needed to establish their validity as therapeutic outcome measures.}, }
@article {pmid27744330, year = {2016}, author = {Bett, JS}, title = {Proteostasis regulation by the ubiquitin system.}, journal = {Essays in biochemistry}, volume = {60}, number = {2}, pages = {143-151}, doi = {10.1042/EBC20160001}, pmid = {27744330}, issn = {1744-1358}, mesh = {Animals ; Autophagy ; *Homeostasis ; Humans ; Protein Aggregates ; Proteins/*metabolism ; Ubiquitin/*metabolism ; Ubiquitination ; }, abstract = {Cells have developed an evolutionary obligation to survey and maintain proteome fidelity and avoid the possible toxic consequences of protein misfolding and aggregation. Disturbances to protein homoeostasis (proteostasis) can result in severe cellular phenotypes and are closely linked with the accumulation of microscopically visible deposits of aggregated proteins. These include inclusion bodies found in AD (Alzheimer's disease), HD (Huntington's disease) and ALS (amyotrophic lateral sclerosis) patient neurons. Protein aggregation is intimately linked with the ubiquitin and ubiquitin-like post-translational modifier system, which manages cellular protein folding stress and promotes the restoration of proteostasis. This is achieved in large part through the action of the UPS (ubiquitin-proteasome system), which is responsible for directing the proteasomal destruction of misfolded and damaged proteins tagged with ubiquitin chains. There are other less well understood ways in which ubiquitin family members can help to maintain proteostasis that complement, but are independent of, the UPS. This article discusses our current understanding of how the ubiquitin family regulates the protein misfolding pathways that threaten proteome fidelity, and how this is achieved by the key players in this process.}, }
@article {pmid27734164, year = {2016}, author = {Hrastelj, J and Robertson, NP}, title = {Ice bucket challenge bears fruit for amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {263}, number = {11}, pages = {2355-2357}, doi = {10.1007/s00415-016-8297-7}, pmid = {27734164}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Gene Expression Regulation/*genetics ; Genetic Association Studies ; Humans ; }, }
@article {pmid27732645, year = {2016}, author = {Xu, Z and Henderson, RD and David, M and McCombe, PA}, title = {Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {PloS one}, volume = {11}, number = {10}, pages = {e0164625}, pmid = {27732645}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*blood/*cerebrospinal fluid/diagnosis/pathology ; Biomarkers/blood/cerebrospinal fluid ; Disease Progression ; Humans ; Neurofilament Proteins/*blood/*cerebrospinal fluid ; }, abstract = {BACKGROUND: To allow early diagnosis and monitoring of disease progression, there is a need for biomarkers in amyotrophic lateral sclerosis (ALS). Neurofilaments (NF) are emerging protein biomarkers in other neurological diseases, and are of possible use in ALS.<br><br>OBJECTIVE: The aim of this study is to evaluate the utility of NF levels as blood or cerebrospinal fluid (CSF) biomarker in patients with ALS.<br><br>METHODS: A systematic search of Pubmed, Embase and Scopus was performed. Methodological quality assessment was applied to refine the final search results. Meta-analysis of the data was performed.<br><br>RESULTS: Level of NF heavy chain and light chains were significantly elevated in the CSF of ALS patients compared to healthy controls/controls without parenchymal central nervous system (CNS) involvement and ALS mimic disease patients. NF light chain level in CSF was higher in ALS patients than in neurological patients with CNS involvement (SMD = 1.352, P = 0.01). NF light chain concentration in blood was higher in ALS patients than healthy controls/controls without CNS involvement (SMD = 1.448, P<0.0001). NF heavy chain levels in CSF were negatively correlated disease duration and ALSFRS-R ((r = -0.447, P<0.0001; r = -0.486, P<0.0001). NF light chain levels in CSF were negatively correlated with disease duration (r = -0.273, P = 0.011).<br><br>CONCLUSION: NF heavy and light chain levels have potential use as a marker of neural degeneration in ALS, but are not specific for the disease, and are more likely to be used as measures of disease progression.}, }
@article {pmid27725795, year = {2016}, author = {Chandrasekaran, A and Avci, HX and Leist, M and Kobolák, J and Dinnyés, A}, title = {Astrocyte Differentiation of Human Pluripotent Stem Cells: New Tools for Neurological Disorder Research.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {215}, pmid = {27725795}, issn = {1662-5102}, abstract = {Astrocytes have a central role in brain development and function, and so have gained increasing attention over the past two decades. Consequently, our knowledge about their origin, differentiation and function has increased significantly, with new research showing that astrocytes cultured alone or co-cultured with neurons have the potential to improve our understanding of various central nervous system diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, or Alexander disease. The generation of astrocytes derived from pluripotent stem cells (PSCs) opens up a new area for studying neurologic diseases in vitro; these models could be exploited to identify and validate potential drugs by detecting adverse effects in the early stages of drug development. However, as it is now known that a range of astrocyte populations exist in the brain, it will be important in vitro to develop standardized protocols for the in vitro generation of astrocyte subsets with defined maturity status and phenotypic properties. This will then open new possibilities for co-cultures with neurons and the generation of neural organoids for research purposes. The aim of this review article is to compare and summarize the currently available protocols and their strategies to generate human astrocytes from PSCs. Furthermore, we discuss the potential role of human-induced PSCs derived astrocytes in disease modeling.}, }
@article {pmid27722929, year = {2017}, author = {Mostafalou, S and Abdollahi, M}, title = {Pesticides: an update of human exposure and toxicity.}, journal = {Archives of toxicology}, volume = {91}, number = {2}, pages = {549-599}, doi = {10.1007/s00204-016-1849-x}, pmid = {27722929}, issn = {1432-0738}, mesh = {Asthma/chemically induced ; Attention Deficit Disorder with Hyperactivity/chemically induced ; Carcinogens/toxicity ; Environmental Exposure/*adverse effects/analysis/statistics &amp; numerical data ; Female ; Humans ; Infertility/chemically induced ; Lung Diseases/chemically induced ; Male ; Neoplasms/*chemically induced ; Neurotoxicity Syndromes/*etiology ; Occupational Exposure/*adverse effects/analysis/statistics &amp; numerical data ; Pesticides/*toxicity ; }, abstract = {Pesticides are a family of compounds which have brought many benefits to mankind in the agricultural, industrial, and health areas, but their toxicities in both humans and animals have always been a concern. Regardless of acute poisonings which are common for some classes of pesticides like organophosphoruses, the association of chronic and sub-lethal exposure to pesticides with a prevalence of some persistent diseases is going to be a phenomenon to which global attention has been attracted. In this review, incidence of various malignant, neurodegenerative, respiratory, reproductive, developmental, and metabolic diseases in relation to different routes of human exposure to pesticides such as occupational, environmental, residential, parental, maternal, and paternal has been systematically criticized in different categories of pesticide toxicities like carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. A huge body of evidence exists on the possible role of pesticide exposures in the elevated incidence of human diseases such as cancers, Alzheimer, Parkinson, amyotrophic lateral sclerosis, asthma, bronchitis, infertility, birth defects, attention deficit hyperactivity disorder, autism, diabetes, and obesity. Most of the disorders are induced by insecticides and herbicides most notably organophosphorus, organochlorines, phenoxyacetic acids, and triazine compounds.}, }
@article {pmid27715256, year = {2016}, author = {Bergin, S and Mockford, C}, title = {Recommendations to support informal carers of people living with motor neurone disease.}, journal = {British journal of community nursing}, volume = {21}, number = {10}, pages = {518-524}, doi = {10.12968/bjcn.2016.21.10.518}, pmid = {27715256}, issn = {1462-4753}, mesh = {*Caregivers ; Health Services Needs and Demand ; *Home Nursing ; Humans ; Motor Neuron Disease/*nursing ; Quality of Life ; *Social Support ; }, abstract = {Informal carers are increasingly providing specialist care at home for people living with motor neurone disease. The carers may experience significant deterioration in their quality of life as a result of the physical and psychological burden they undertake. This systematic review seeks to provide evidence-based recommendations to enable healthcare professionals to support carers appropriately to maintain their wellbeing and to continue providing care at home. Inclusion criteria included articles focusing on the experience of informal carers of people with motor neurone disease, particularly when reporting on their perspective of professional services. Twenty-three studies were included and a thematic analysis was undertaken. Four key recommendations were identified: providing support, early access to palliative care, information regarding availability of services, and offering carers training for using specialist equipment. These recommendations offer healthcare professionals practical, cost-effective suggestions to improve existing services.}, }
@article {pmid27713094, year = {2017}, author = {Little, J and Barakat-Haddad, C and Martino, R and Pringsheim, T and Tremlett, H and McKay, KA and van Lieshout, P and Walsh, SJ and Gomes, J and Krewski, D}, title = {Genetic variation associated with the occurrence and progression of neurological disorders.}, journal = {Neurotoxicology}, volume = {61}, number = {}, pages = {243-264}, doi = {10.1016/j.neuro.2016.09.018}, pmid = {27713094}, issn = {1872-9711}, mesh = {C9orf72 Protein/genetics ; *Disease Progression ; Genetic Variation/*genetics ; Genome-Wide Association Study ; HLA-DRB5 Chains/genetics ; Humans ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics ; Nervous System Diseases/*epidemiology/*genetics ; }, abstract = {This paper presents an overview of genetic variation associated with the onset and progression of 14 neurological disorders, focusing primarily on association studies. The 14 disorders are heterogeneous in terms of their frequency, age of onset, etiology and progression. There is substantially less evidence on progression than onset. With regard to onset, the conditions are diverse in terms of their epidemiology and patterns of familial aggregation. While the muscular dystrophies and Huntington's disease are monogenic diseases, for the other 12 conditions only a small proportion of cases is associated with specific genetic syndromes or mutations. Excluding these, some familial aggregation remains for the majority of cases. There is considerable variation in the volume of evidence by condition, and by gene within condition. The volume of evidence is greatest for Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. As for common complex chronic diseases, genome wide association studies have found that validated genomic regions account for a low proportion of heritability. Apart from multiple sclerosis, which shares several susceptibility loci with other immune-related disorders, variation at HLA-DRB5 being associated both with Parkinson's disease and Alzheimer's disease, and the association of the C9orf72 repeat expansion with ALS and frontotemporal degeneration, there was little evidence of gene loci being consistently associated with more than one neurological condition or with other conditions. With the exception of spina bifida, for which maternal MTHFR genotype is associated with risk in the offspring, and corroborates other evidence of the importance of folate in etiology, there was little evidence that the pathways influenced by genetic variation are related to known lifestyle or environmental exposures.}, }
@article {pmid27704495, year = {2016}, author = {Morrison, BM}, title = {Neuromuscular Diseases.}, journal = {Seminars in neurology}, volume = {36}, number = {5}, pages = {409-418}, doi = {10.1055/s-0036-1586263}, pmid = {27704495}, issn = {1098-9021}, mesh = {Amyotrophic Lateral Sclerosis ; Electromyography ; Humans ; Lambert-Eaton Myasthenic Syndrome ; Myasthenia Gravis ; *Neuromuscular Diseases/diagnosis/therapy ; }, abstract = {Neuromuscular diseases are a broadly defined group of disorders that all involve injury or dysfunction of peripheral nerves or muscle. The site of injury can be in the cell bodies (i.e., amyotrophic lateral sclerosis [ALS] or sensory ganglionopathies), axons (i.e., axonal peripheral neuropathies or brachial plexopathies), Schwann cells (i.e., chronic inflammatory demyelinating polyradiculoneuropathy), neuromuscular junction (i.e., myasthenia gravis or Lambert-Eaton myasthenic syndrome), muscle (i.e., inflammatory myopathy or muscular dystrophy), or any combination of these sites. Some neuromuscular diseases are also associated with central nervous system disease, such as ALS, but most are restricted to the peripheral nervous system. The multitude of possible sites of injury can make neuromuscular diseases difficult to diagnose. Here the author reviews key features of the clinical presentation that help localize the site of injury and some basic tenets of electromyography. He then shares several pearls in diagnosing and treating patients with specific neuromuscular diseases.}, }
@article {pmid27697702, year = {2016}, author = {Lam, MM and Mapletoft, JP and Miller, MS}, title = {Abnormal regulation of the antiviral response in neurological/neurodegenerative diseases.}, journal = {Cytokine}, volume = {88}, number = {}, pages = {251-258}, doi = {10.1016/j.cyto.2016.09.002}, pmid = {27697702}, issn = {1096-0023}, support = {//CIHR/Canada ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*immunology/pathology ; Viruses/*immunology ; }, abstract = {Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis are a few examples of debilitating neurological/neurodegenerative diseases for which there are currently no curative treatments. Recent evidence has strongly suggested a role for neuroinflammation in both the onset and progression of these diseases. However, the mechanisms that initiate neuroinflammation are presently unclear. Mounting evidence suggests that environmental factors are likely involved. One proposed mechanism linking both genetic and environmental factors is dysregulation of the antiviral response. Indeed, many mutations that have been linked to neurological conditions occur in genes related to the antiviral response. Although the products of these genes may have potent antiviral activities - they can also have deleterious effects when their expression is not appropriately regulated. For that reason, expression of antiviral genes is a tightly controlled process. Herein, we review the various antiviral genes that have been linked to neurological conditions. We focus specifically on type I interferonopathies, the symptoms of which are often evident at birth, and neurodegenerative diseases, which frequently onset later in life.}, }
@article {pmid27693252, year = {2016}, author = {Guerrero, EN and Wang, H and Mitra, J and Hegde, PM and Stowell, SE and Liachko, NF and Kraemer, BC and Garruto, RM and Rao, KS and Hegde, ML}, title = {TDP-43/FUS in motor neuron disease: Complexity and challenges.}, journal = {Progress in neurobiology}, volume = {145-146}, number = {}, pages = {78-97}, pmid = {27693252}, issn = {1873-5118}, support = {I01 BX002619/BX/BLRD VA/United States ; IK2 BX002243/BX/BLRD VA/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; DNA-Binding Proteins/*genetics ; Humans ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.}, }
@article {pmid29624324, year = {2016}, author = {Yamashita, T and Kwak, S}, title = {[Abnormal RNA editing and treatment strategy in neurological diseases; towards cure for ALS].}, journal = {Seikagaku. The Journal of Japanese Biochemical Society}, volume = {88}, number = {5}, pages = {600-608}, pmid = {29624324}, issn = {0037-1017}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Cell Death ; Humans ; Motor Neurons ; *RNA Editing ; }, }
@article {pmid29441921, year = {2016}, author = {Zhuo, H and Zhou, L}, title = {Gpnmb/osteoactivin: an indicator and therapeutic target in tumor and nontumorous lesions.}, journal = {Die Pharmazie}, volume = {71}, number = {10}, pages = {555-561}, doi = {10.1691/ph.2016.6683}, pmid = {29441921}, issn = {0031-7144}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Biomarkers/*analysis ; Biomarkers, Tumor/*analysis ; Humans ; Membrane Glycoproteins/*drug effects/*metabolism ; }, abstract = {Non-metastatic melanoma glycoprotein B (Gpnmb), a type I transmembrane glycoprotein, was first cloned and described in low-metastatic human melanoma and xenografts in 1995. Up to now a growing number of studies have confirmed that Gpnmb is expressed not only in numerous normal tissues but also at pathological sites and malignant tissues and often connected with the invasive and metastatic phenotypes, including breast cancer. Nowadays, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential. Glembatumumabvedotin, also called CR011-vcMMAE, is a Mab-drug conjugate which was developed for the treatment of Gpnmb-expressing cancers. Several phase I/II studies have confirmed the safety and activity of glembatumumabvedotin in patients with advanced/metastatic breast cancer and unresectable cutaneous melanoma. Moreover, increasing numbers of studies have supported the potential roles of targeting Gpnmb with glembatumumabvedotin in patients with recurrent osteosarcoma, uveal melanoma, ALS, Gaucher disease, pancreatic ductal adenocarcinoma etc. This review will summarize the latest understanding of Gpnmb in the aspects of diagnosis, progression and prognosis of pathological disorders and neoplasms, emphasizing the clinical advances in targeting Gpnmb-expressing malignancies.}, }
@article {pmid27686535, year = {2017}, author = {Ansari, A and Rahman, MS and Saha, SK and Saikot, FK and Deep, A and Kim, KH}, title = {Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease.}, journal = {Aging cell}, volume = {16}, number = {1}, pages = {4-16}, pmid = {27686535}, issn = {1474-9726}, mesh = {Animals ; *Cell Physiological Phenomena ; Humans ; Mitochondria/*metabolism ; Models, Biological ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; Sirtuin 3/*metabolism ; }, abstract = {In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes. SIRT3 is well known for its ability to eliminate reactive oxygen species and to prevent the development of cancerous cells or apoptosis. This review article provides a comprehensive review on numerous (noteworthy) molecular functions of SIRT3 and its effect on cancer cells and various diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.}, }
@article {pmid27679854, year = {2016}, author = {Heath, CG and Viphakone, N and Wilson, SA}, title = {The role of TREX in gene expression and disease.}, journal = {The Biochemical journal}, volume = {473}, number = {19}, pages = {2911-2935}, pmid = {27679854}, issn = {1470-8728}, support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Biological Transport ; DNA Damage ; *Gene Expression ; Humans ; RNA Processing, Post-Transcriptional ; RNA, Messenger/genetics/metabolism ; Transcription Factors/*physiology ; }, abstract = {TRanscription and EXport (TREX) is a conserved multisubunit complex essential for embryogenesis, organogenesis and cellular differentiation throughout life. By linking transcription, mRNA processing and export together, it exerts a physiologically vital role in the gene expression pathway. In addition, this complex prevents DNA damage and regulates the cell cycle by ensuring optimal gene expression. As the extent of TREX activity in viral infections, amyotrophic lateral sclerosis and cancer emerges, the need for a greater understanding of TREX function becomes evident. A complete elucidation of the composition, function and interactions of the complex will provide the framework for understanding the molecular basis for a variety of diseases. This review details the known composition of TREX, how it is regulated and its cellular functions with an emphasis on mammalian systems.}, }
@article {pmid27679581, year = {2016}, author = {Tsitkanou, S and Della Gatta, PA and Russell, AP}, title = {Skeletal Muscle Satellite Cells, Mitochondria, and MicroRNAs: Their Involvement in the Pathogenesis of ALS.}, journal = {Frontiers in physiology}, volume = {7}, number = {}, pages = {403}, pmid = {27679581}, issn = {1664-042X}, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal motor neuron disorder. It results in progressive degeneration and death of upper and lower motor neurons, protein aggregation, severe muscle atrophy and respiratory insufficiency. Median survival with ALS is between 2 and 5 years from the onset of symptoms. ALS manifests as either familial ALS (FALS) (~10% of cases) or sporadic ALS (SALS), (~90% of cases). Mutations in the copper/zinc (CuZn) superoxide dismutase (SOD1) gene account for ~20% of FALS cases and the mutant SOD1 mouse model has been used extensively to help understand the ALS pathology. As the precise mechanisms causing ALS are not well understood there is presently no cure. Recent evidence suggests that motor neuron degradation may involve a cell non-autonomous phenomenon involving numerous cell types within various tissues. Skeletal muscle is now considered as an important tissue involved in the pathogenesis of ALS by activating a retrograde signaling cascade that degrades motor neurons. Skeletal muscle heath and function are regulated by numerous factors including satellite cells, mitochondria and microRNAs. Studies demonstrate that in ALS these factors show various levels of dysregulation within the skeletal muscle. This review provides an overview of their dysregulation in various ALS models as well as how they may contribute individually and/or synergistically to the ALS pathogenesis.}, }
@article {pmid27679561, year = {2016}, author = {Clark, JA and Yeaman, EJ and Blizzard, CA and Chuckowree, JA and Dickson, TC}, title = {A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {204}, pmid = {27679561}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is an aggressive multifactorial disease converging on a common pathology: the degeneration of motor neurons (MNs), their axons and neuromuscular synapses. This vulnerability and dysfunction of MNs highlights the dependency of these large cells on their intracellular machinery. Neuronal microtubules (MTs) are intracellular structures that facilitate a myriad of vital neuronal functions, including activity dependent axonal transport. In ALS, it is becoming increasingly apparent that MTs are likely to be a critical component of this disease. Not only are disruptions in this intracellular machinery present in the vast majority of seemingly sporadic cases, recent research has revealed that mutation to a microtubule protein, the tubulin isoform TUBA4A, is sufficient to cause a familial, albeit rare, form of disease. In both sporadic and familial disease, studies have provided evidence that microtubule mediated deficits in axonal transport are the tipping point for MN survivability. Axonal transport deficits would lead to abnormal mitochondrial recycling, decreased vesicle and mRNA transport and limited signaling of key survival factors from the neurons peripheral synapses, causing the characteristic peripheral "die back". This disruption to microtubule dependant transport in ALS has been shown to result from alterations in the phenomenon of microtubule dynamic instability: the rapid growth and shrinkage of microtubule polymers. This is accomplished primarily due to aberrant alterations to microtubule associated proteins (MAPs) that regulate microtubule stability. Indeed, the current literature would argue that microtubule stability, particularly alterations in their dynamics, may be the initial driving force behind many familial and sporadic insults in ALS. Pharmacological stabilization of the microtubule network offers an attractive therapeutic strategy in ALS; indeed it has shown promise in many neurological disorders, ALS included. However, the pathophysiological involvement of MTs and their functions is still poorly understood in ALS. Future investigations will hopefully uncover further therapeutic targets that may aid in combating this awful disease.}, }
@article {pmid27679556, year = {2016}, author = {Navarro, G and Morales, P and Rodríguez-Cueto, C and Fernández-Ruiz, J and Jagerovic, N and Franco, R}, title = {Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders.}, journal = {Frontiers in neuroscience}, volume = {10}, number = {}, pages = {406}, pmid = {27679556}, issn = {1662-4548}, abstract = {Endocannabinoids activate two types of specific G-protein-coupled receptors (GPCRs), namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases (Parkinson's disease, Huntington's chorea, cerebellar ataxia, amyotrohic lateral sclerosis). Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are keys to understand the therapeutic potential in inter alia diseases that imply progressive neurodegeneration. Medicinal chemistry approaches are now engaged to develop imaging tools to map receptors in the living human brain, to develop more efficacious agonists, and to investigate the possibility to develop allosteric modulators.}, }
@article {pmid27677549, year = {2016}, author = {Popova, AA and Koksharova, OA}, title = {Neurotoxic Non-proteinogenic Amino Acid β-N-Methylamino-L-alanine and Its Role in Biological Systems.}, journal = {Biochemistry. Biokhimiia}, volume = {81}, number = {8}, pages = {794-805}, doi = {10.1134/S0006297916080022}, pmid = {27677549}, issn = {1608-3040}, mesh = {*Alanine/analogs &amp; derivatives/metabolism/toxicity ; *Alzheimer Disease/chemically induced/metabolism ; *Amino Acids, Diamino/metabolism/toxicity ; *Amyotrophic Lateral Sclerosis/chemically induced/metabolism ; Animals ; Humans ; *Neurotoxins/metabolism/toxicity ; *Parkinson Disease, Secondary/chemically induced/metabolism ; }, abstract = {Secondary metabolites of photoautotrophic organisms have attracted considerable interest in recent years. In particular, molecules of non-proteinogenic amino acids participating in various physiological processes and capable of producing adverse ecological effects have been actively investigated. For example, the non-proteinogenic amino acid β-N-methylamino-L-alanine (BMAA) is neurotoxic to animals including humans. It is known that BMAA accumulation via the food chain can lead to development of neurodegenerative diseases in humans such as Alzheimer's and Parkinson's diseases as well as amyotrophic lateral sclerosis. Moreover, BMAA can be mistakenly incorporated into a protein molecule instead of serine. Natural sources of BMAA and methods for its detection are discussed in this review, as well as the role of BMAA in metabolism of its producers and possible mechanisms of toxicity of this amino acid in different living organisms.}, }
@article {pmid27669692, year = {2017}, author = {Alkam, D and Feldman, EZ and Singh, A and Kiaei, M}, title = {Profilin1 biology and its mutation, actin(g) in disease.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {74}, number = {6}, pages = {967-981}, pmid = {27669692}, issn = {1420-9071}, support = {P30 GM110702/GM/NIGMS NIH HHS/United States ; R21 NS088653/NS/NINDS NIH HHS/United States ; }, mesh = {Actins/*metabolism ; Animals ; Brain/embryology ; Disease/genetics ; Humans ; Mutation/*genetics ; Neuronal Plasticity ; Profilins/chemistry/*genetics/metabolism ; }, abstract = {Profilins were discovered in the 1970s and were extensively studied for their significant physiological roles. Profilin1 is the most prominent isoform and has drawn special attention due to its role in the cytoskeleton, cell signaling, and its link to conditions such as cancer and vascular hypertrophy. Recently, multiple mutations in the profilin1 gene were linked to amyotrophic lateral sclerosis (ALS). In this review, we will discuss the physiological and pathological roles of profilin1. We will further highlight the cytoskeletal function and dysfunction caused by profilin1 dysregulation. Finally, we will discuss the implications of mutant profilin1 in various diseases with an emphasis on its contribution to the pathogenesis of ALS.}, }
@article {pmid27668807, year = {2016}, author = {Long, C and Amoasii, L and Bassel-Duby, R and Olson, EN}, title = {Genome Editing of Monogenic Neuromuscular Diseases: A Systematic Review.}, journal = {JAMA neurology}, volume = {73}, number = {11}, pages = {1349-1355}, pmid = {27668807}, issn = {2168-6157}, support = {U54 HD087351/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; Gene Editing/*methods ; Genetic Therapy/*methods ; Humans ; Muscular Atrophy, Spinal/genetics/*therapy ; Muscular Dystrophy, Duchenne/genetics/*therapy ; Myotonic Dystrophy/genetics/*therapy ; }, abstract = {IMPORTANCE: Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1.<br><br>OBJECTIVES: To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing.<br><br>EVIDENCE REVIEW: PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9-mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed.<br><br>FINDINGS: Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing-meditated correction of monogenic neuromuscular diseases in cultured cells and animal models.<br><br>CONCLUSIONS AND RELEVANCE: Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies.}, }
@article {pmid27667492, year = {2016}, author = {Maruyama, H and Morino, H and Kawakami, H}, title = {[Causative Genes for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {68}, number = {9}, pages = {1081-1086}, doi = {10.11477/mf.1416200555}, pmid = {27667492}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Genetic Counseling ; High-Throughput Nucleotide Sequencing ; Humans ; Phenotype ; }, abstract = {About 20 causative genes were reported for amyotrophic lateral sclerosis. Using next generation sequencer, new genes have been sequentially reported. These genes' products are thought to be involved in the pathologic mechanism of ALS. The pathophysiology is investigated and disease characteristics are discussed according to the causative genes. In addition, genetic counseling is recommended when genetic diagnosis is attempted.}, }
@article {pmid27664933, year = {2018}, author = {Huber, AK and Giles, DA and Segal, BM and Irani, DN}, title = {An emerging role for eotaxins in neurodegenerative disease.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {189}, number = {}, pages = {29-33}, doi = {10.1016/j.clim.2016.09.010}, pmid = {27664933}, issn = {1521-7035}, mesh = {Aging/immunology ; Animals ; Chemokine CCL11/blood/cerebrospinal fluid/*immunology ; Chemokine CCL24/blood/cerebrospinal fluid/*immunology ; Chemokine CCL26/blood/cerebrospinal fluid/*immunology ; Humans ; Immunity, Innate/*immunology ; Neurodegenerative Diseases/blood/cerebrospinal fluid/*immunology ; Receptors, CCR3/immunology/metabolism ; }, abstract = {Eotaxins are C-C motif chemokines first identified as potent eosinophil chemoattractants. They facilitate eosinophil recruitment to sites of inflammation in response to parasitic infections as well as allergic and autoimmune diseases such as asthma, atopic dermatitis, and inflammatory bowel disease. The eotaxin family currently includes three members: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26). Despite having only ~30% sequence homology to one another, each was identified based on its ability to bind the chemokine receptor, CCR3. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid of both mice and humans as part of normal aging. In mice, these increases are associated with declining neurogenesis and impaired cognition and memory. In humans, elevated plasma levels of CCL11 have been observed in Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and secondary progressive multiple sclerosis when compared to age-matched, healthy controls. Since CCL11 is capable of crossing the blood-brain barrier of normal mice, it is plausible that eotaxins generated in the periphery may exert physiological and pathological actions in the CNS. Here, we briefly review known functions of eotaxin family members during innate immunity, and then focus on whether and how these molecules might participate in the progression of neurodegenerative diseases.}, }
@article {pmid27659705, year = {2017}, author = {Quek, C and Hill, AF}, title = {The role of extracellular vesicles in neurodegenerative diseases.}, journal = {Biochemical and biophysical research communications}, volume = {483}, number = {4}, pages = {1178-1186}, doi = {10.1016/j.bbrc.2016.09.090}, pmid = {27659705}, issn = {1090-2104}, mesh = {Animals ; Extracellular Vesicles/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Prion Diseases/metabolism ; }, abstract = {Extracellular vesicles, including exosomes, are small membranous vesicles released from many biotypes, contributing to the disease progression and spreading. These extracellular vesicles provide an important mode of cell-to-cell communication by delivering proteins, lipids and RNA to target cells. Exosomes are found associated with neurodegenerative diseases, which are characterised by progressive degeneration of neurons and often associated with misfolded protein. The common diseases include Parkinson's disease (PD), Alzheimer's diseases (AD), amyotrophic lateral sclerosis (ALS), and the prion diseases. Of all neurodegenerative diseases, prion diseases are classified as the distinctive group owing to its transmissible and infectious nature of misfolded prion protein. The infectious prion particles have been demonstrated to be present in exosomes to spread prion infectivity within cells. Similarly, misfolded proteins involved in other neurodegenerative diseases such as Amyloid-β and tau in AD, α-synuclein in PD, and superoxide dismutase 1 in ALS have been demonstrated to exploit exosomes for induced spreading of misfolded proteins in a prion-like mechanism. Furthermore, RNA molecules can be taken up by the recipient cells as cargo in exosomes. These RNAs can module the expression of the target genes by repressing or inhibiting protein translation. Here we review the role of exosomes in prion diseases and other common neurodegenerative diseases, and discuss the potential of these vesicles for disease pathogenesis.}, }
@article {pmid27659605, year = {2017}, author = {Cookson, MR}, title = {RNA-binding proteins implicated in neurodegenerative diseases.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {8}, number = {1}, pages = {}, pmid = {27659605}, issn = {1757-7012}, support = {ZIA AG000947-08//Intramural NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; RNA-Binding Proteins/*metabolism ; }, abstract = {Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor. The bulk of evidence from recent surveys of the types of RNA species that are affected in these disorders suggests a global deregulation of control rather than a very small number of RNA species, although why some groups of neurons are sensitive to these changes is not well understood. Overall, these data suggest that neurodegeneration can be initiated by mutations in RNA binding proteins and, as a corollary, that neurons are particularly sensitive to loss of control of gene expression at the post-transcriptional level. Such observations have implications not only for understanding the nature of neurodegenerative disorders but also how we might intervene therapeutically in these diseases. WIREs RNA 2017, 8:e1397. doi: 10.1002/wrna.1397 For further resources related to this article, please visit the WIREs website.}, }
@article {pmid27658510, year = {2017}, author = {Burnstock, G}, title = {Purinergic Signalling and Neurological Diseases: An Update.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {3}, pages = {257-265}, doi = {10.2174/1871527315666160922104848}, pmid = {27658510}, issn = {1996-3181}, mesh = {Animals ; Humans ; *Nervous System Diseases/drug therapy/metabolism/physiopathology ; Purinergic P2X Receptor Antagonists/*therapeutic use ; Receptors, Purinergic/*metabolism ; Signal Transduction/drug effects/*physiology ; }, abstract = {Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson's disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders.}, }
@article {pmid27652898, year = {2016}, author = {Porojan, C and Mitrovic, SM and Yeo, DC and Furey, A}, title = {Overview of the potent cyanobacterial neurotoxin β-methylamino-L-alanine (BMAA) and its analytical determination.}, journal = {Food additives &amp; contaminants. Part A, Chemistry, analysis, control, exposure &amp; risk assessment}, volume = {33}, number = {10}, pages = {1570-1586}, doi = {10.1080/19440049.2016.1217070}, pmid = {27652898}, issn = {1944-0057}, mesh = {Amino Acids, Diamino/*analysis ; Animals ; Cyanobacteria/*chemistry ; Cyanobacteria Toxins ; Humans ; Molecular Conformation ; Neurotoxins/*analysis ; }, abstract = {Blue-green algae are responsible for the production of different types of toxins which can be neurotoxic, hepatotoxic, cytotoxic and dermatotoxic and that can affect both aquatic and terrestrial life. Since its discovery the neurotoxin β-methylamino-L-alanine (BMAA) has been a cause for concern, being associated with the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). The initial focus was on Guam where it was observed that a high number of people were affected by the ALS/PDC complex. Subsequently, researchers were surprised to find levels of BMAA in post mortem brains from Canadian patients who also suffered from ALS/PDC. Recent research demonstrates that BMAA has been found at different levels in the aquatic food web in the brackish waters of the Baltic Sea. There is emerging evidence to suggest that sand-borne algae from Qatar can also contain BMAA. Furthermore, there is now concern because BMAA has been found not only in warmer regions of the world but also in temperate regions like Europe. The aim of this review is to focus on the methods of extraction and analysis of the neurotoxic non-protein amino acid BMAA. We also consider the neurotoxicity, aetiology, and diverse sources and routes of exposure to BMAA. In recent years, different methods have been developed for the analysis of BMAA. Some of these use HPLC-FD, UPLC-UV, UPLC-MS and LC-MS/MS using samples that have been derivatised or underivatised. To date the LC-MS/MS approach is the most widely used analytical technique as it is the most selective and sensitive method for BMAA determination.}, }
@article {pmid27651758, year = {2016}, author = {Gubert, F and Satiago, MF}, title = {Prospects for bone marrow cell therapy in amyotrophic lateral sclerosis: how far are we from a clinical treatment?.}, journal = {Neural regeneration research}, volume = {11}, number = {8}, pages = {1216-1219}, pmid = {27651758}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular atrophy and death within 3-5 years after its onset. Despite the significant advances in knowledge of ALS pathology, no effective treatment is available. Therefore, it is imperative to search for new alternatives to treat ALS. Cell therapy, especially using bone-marrow cells, has showed to be very useful to protect the neural tissue in different brain disease or traumatic lesions. In ALS, most published results show beneficial effects of the use bone marrow cells, especially mesenchymal stromal cells. However, until now, the best outcome extends animal's lifespan by only a few weeks. It is essential to continue the search for a really effective therapy, testing different cells, routes and time-windows of administration. Studying the mechanisms that initiate and spread the degenerative process is also important to find out an effective therapy. Therefore, we discussed here some progresses that have been made using bone-marrow cell therapy as a therapeutic tool for ALS.}, }
@article {pmid27651262, year = {2016}, author = {Ameer, K}, title = {Avocado as a Major Dietary Source of Antioxidants and Its Preventive Role in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {12}, number = {}, pages = {337-354}, doi = {10.1007/978-3-319-28383-8_18}, pmid = {27651262}, issn = {2190-5215}, mesh = {Antioxidants/chemistry/*pharmacology ; *Diet ; Humans ; Neurodegenerative Diseases/diet therapy/*prevention &amp; control ; Neurons/drug effects ; Oxidative Stress/*drug effects ; Persea/*chemistry ; }, abstract = {Avocados have a high content of phytochemicals especially antioxidants with potential neuroprotective effect. Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages and modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Thus, antioxidants have been used for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. The critical review results indicate that compounds in avocado are unique antioxidants, preferentially suppressing radical generation, and thus may be promising as effective neuropreventive agents. The diverse array of bioactive nutrients present in avocado plays a pivotal role in the prevention and cure of various neurodegenerative diseases.}, }
@article {pmid27647646, year = {2016}, author = {Al-Chalabi, A and Hardiman, O and Kiernan, MC and Chiò, A and Rix-Brooks, B and van den Berg, LH}, title = {Amyotrophic lateral sclerosis: moving towards a new classification system.}, journal = {The Lancet. Neurology}, volume = {15}, number = {11}, pages = {1182-1194}, doi = {10.1016/S1474-4422(16)30199-5}, pmid = {27647646}, issn = {1474-4465}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*classification/*diagnosis ; Humans ; }, abstract = {Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and other regions of the brain. The extent to which each neuronal population is affected varies between individuals. The subsequent patterns of disease progression form the basis of diagnostic criteria and phenotypic classification systems, with considerable overlap in the clinical terms used. This overlap can lead to confusion between diagnosis and phenotype. Formal classification systems such as the El Escorial criteria and the International Classification of Diseases are systematic approaches but they omit features that are important in clinical management, such as rate of progression, genetic basis, or functional effect. Therefore, many neurologists use informal classification approaches that might not be systematic, and could include, for example, anatomical descriptions such as flail-arm syndrome. A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice.}, }
@article {pmid27644548, year = {2017}, author = {Mathis, S and Couratier, P and Julian, A and Vallat, JM and Corcia, P and Le Masson, G}, title = {Management and therapeutic perspectives in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {17}, number = {3}, pages = {263-276}, doi = {10.1080/14737175.2016.1227705}, pmid = {27644548}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; Humans ; Nerve Degeneration ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. Areas covered: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life). Expert commentary: ALS is a complex neurodegenerative disease, these days considered as a multisystem disorder with predominant motor symptoms (and various clinical forms). Further comprehension of the pathophysiology of this disease is required, although pathophysiological mechanisms (such as TDP-43) show promise in the search for new therapies. There is still no curative treatment for ALS, but the emergence of multidisciplinary specialized ALS clinics has increased both the quality of life and the survival of these patients.}, }
@article {pmid27640217, year = {2016}, author = {Fraess-Phillips, AJ}, title = {Can Paramedics Safely Refuse Transport of Non-Urgent Patients?.}, journal = {Prehospital and disaster medicine}, volume = {31}, number = {6}, pages = {667-674}, doi = {10.1017/S1049023X16000935}, pmid = {27640217}, issn = {1945-1938}, mesh = {*Decision Making ; *Emergency Medical Technicians ; Humans ; *Transportation of Patients ; }, abstract = {OBJECTIVE: The goal of this search was to review the current literature regarding paramedic triage of primary care patients and the safety of paramedic-initiated non-transport of non-urgent patients.<br><br>METHODS: A narrative literature review was conducted using the Medline (Medline Industries, Inc.; Mundelein, Illinois USA) database and a manual search of Google Scholar (Google; Mountain View, California USA).<br><br>RESULTS: Only 11 studies were found investigating paramedic triage and safety of non-transport of non-urgent patients. It was found that triage agreement between paramedic and emergency department staff generally is poor and that paramedics are limited in their abilities to predict the ultimate admission location of their patients. However, these triage decisions and admission predictions are much more accurate when the patient's condition is the result of trauma and when the patient requires critical care services. Furthermore, the literature provides very limited support for the safety of paramedic triage in the refusal of non-urgent patient transport, especially without physician oversight. Though many non-transported patients are satisfied with the quality of non-urgent treatment that they receive from paramedics, the rates of under-triage and subsequent hospitalization reported in the literature are too high to suggest that this practice can be adopted widely.<br><br>CONCLUSION: There is insufficient evidence to suggest that non-urgent patients can safely be refused transport based on paramedic triage alone. Further attempts to implement paramedic-initiated non-transport of non-urgent patients should be approached with careful triage protocol development, paramedic training, and pilot studies. Future primary research and systematic reviews also are required to build on the currently limited literature. Fraess-Phillips AJ . Can paramedics safely refuse transport of non-urgent patients? Prehosp Disaster Med. 2016;31(6):667-674.}, }
@article {pmid27639947, year = {2017}, author = {Sakhri, L and Saint-Raymond, C and Quetant, S and Pison, C and Lagrange, E and Hamidfar Roy, R and Janssens, JP and Maindet-Dominici, C and Garrouste-Orgeas, M and Levy-Soussan, M and Terzi, N and Toffart, AC}, title = {[Limitations of active therapeutic and palliative care in chronic respiratory disease].}, journal = {Revue des maladies respiratoires}, volume = {34}, number = {2}, pages = {102-120}, doi = {10.1016/j.rmr.2016.06.005}, pmid = {27639947}, issn = {1776-2588}, mesh = {Chronic Disease ; Critical Care/*statistics &amp; numerical data ; Decision Making ; Humans ; Palliative Care/*methods ; Patient Comfort/methods ; Prognosis ; Respiration Disorders/*complications/diagnosis/*therapy ; }, abstract = {The issue of intensive and palliative care in patients with chronic disease frequently arises. This review aims to describe the prognostic factors of chronic respiratory diseases in stable and in acute situations in order to improve the management of these complex situations. The various laws on patients' rights provide a legal framework and define the concept of unreasonable obstinacy. For patients with chronic obstructive pulmonary disease, the most robust decision factors are good knowledge of the respiratory disease, the comorbidities, the history of previous exacerbations and patient preferences. In the case of idiopathic pulmonary fibrosis, it is necessary to know if there is a prospect of transplantation and to assess the reversibility of the respiratory distress. In the case of amyotrophic lateral sclerosis, treatment decisions depend on the presence of advance directives about the use of intubation and tracheostomy. For lung cancer patients, general condition, cancer history and the tumor treatment plan are important factors. A multidisciplinary discussion that takes into account the patient's medical history, wishes and the current state of knowledge permits the taking of a coherent decision.}, }
@article {pmid27637961, year = {2016}, author = {Talbott, EO and Malek, AM and Lacomis, D}, title = {The epidemiology of amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {138}, number = {}, pages = {225-238}, doi = {10.1016/B978-0-12-802973-2.00013-6}, pmid = {27637961}, issn = {0072-9752}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; Female ; Humans ; Male ; Middle Aged ; Prevalence ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults and is characterized by neurodegeneration of motor neurons in the brain and spinal cord. The incidence of ALS is approximately 1-2.6 cases per 100 000 persons annually, whereas the prevalence is approximately 6 cases per 100 000. The average age of onset of ALS is currently 58-60 years and the average survival from onset to death is 3-4 years. Between October 19, 2010 and December 31, 2011, there were an estimated 12 187 prevalent cases diagnosed with definite ALS in the USA alone. Sporadic ALS (90-95%) constitutes the large majority of cases, while the remaining 5-10% are hereditary and termed familial ALS. Sporadic ALS is suspected to involve genetic susceptibility to environmental risk factors. The purpose of this review is to present a clinical overview of ALS and provide an epidemiologic summary of personal and environmental risk factors shown to be related to the risk of disease. A discussion of the most recent research initiatives is also included.}, }
@article {pmid27633977, year = {2017}, author = {Arbour, D and Vande Velde, C and Robitaille, R}, title = {New perspectives on amyotrophic lateral sclerosis: the role of glial cells at the neuromuscular junction.}, journal = {The Journal of physiology}, volume = {595}, number = {3}, pages = {647-661}, pmid = {27633977}, issn = {1469-7793}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Humans ; Motor Neurons/physiology ; Neuroglia/*physiology ; Neuromuscular Junction/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease leading to the death of motor neurons (MNs). It is also recognized as a non-cell autonomous disease where glial cells in the CNS are involved in its pathogenesis and progression. However, although denervation of neuromuscular junctions (NMJs) represents an early and major event in ALS, the importance of glial cells at this synapse receives little attention. An interesting possibility is that altered relationships between glial cells and MNs in the spinal cord in ALS may also take place at the NMJ. Perisynaptic Schwann cells (PSCs), which are glial cells at the NMJ, show great morphological and functional adaptability to ensure NMJ stability, maintenance and repair. More specifically, PSCs change their properties according to the state of innervation. Hence, abnormal changes or lack of changes can have detrimental effects on NMJs in ALS. This review will provide an overview of known and hypothesized interactions between MN nerve terminals and PSCs at NMJs during development, aging and ALS-induced denervation. These neuron-PSC interactions may be crucial to the understanding of how degenerative changes begin and progress at NMJs in ALS, and represent a novel therapeutic target.}, }
@article {pmid27631878, year = {2017}, author = {Zhou, ZD and Saw, WT and Tan, EK}, title = {Mitochondrial CHCHD-Containing Proteins: Physiologic Functions and Link with Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {54}, number = {7}, pages = {5534-5546}, pmid = {27631878}, issn = {1559-1182}, mesh = {Animals ; DNA, Mitochondrial/*metabolism ; Humans ; Mitochondria/*metabolism ; Mitochondrial Diseases/*metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism/physiopathology ; }, abstract = {The coiled-coil-helix-coiled-coil-helix domain (CHCHD)-containing proteins are evolutionarily conserved nucleus-encoded small mitochondrial proteins with important functions. So far, nine members have been identified in this protein family. All CHCHD proteins have at least one functional coiled-coil-helix-coiled-coil-helix (CHCH) domain, which is stabilized by two pairs of disulfide bonds between two helices. CHCHD proteins have various important pathophysiological roles in mitochondria and other key cellular processes. Mutations of CHCHD proteins have been associated with various human neurodegenerative diseases. Mutations of CHCHD10 are associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobe dementia (FTD), motor neuron disease, and late-onset spinal muscular atrophy and autosomal dominant mitochondrial myopathy. CHCHD10 stabilizes mitochondrial crista ultrastructure and maintains its integrity. In patients with CHCHD10 mutations, there are abnormal mitochondrial crista structure, deficiencies of respiratory chain complexes, impaired mitochondrial respiration, and multiple mitochondrial DNA (mtDNA) deletions. Recently, CHCHD2 mutations are linked with autosomal dominant and sporadic Parkinson's disease (PD). The CHCHD2 is a multifunctional protein and plays roles in regulation of mitochondrial metabolism, synthesis of respiratory chain components, and modulation of cell apoptosis. With a better understanding of the pathophysiologic roles of CHCHD proteins, they may be potential novel therapeutic targets for human neurodegenerative diseases.}, }
@article {pmid27630777, year = {2016}, author = {Carvajal, FJ and Mattison, HA and Cerpa, W}, title = {Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies.}, journal = {Neural plasticity}, volume = {2016}, number = {}, pages = {2701526}, pmid = {27630777}, issn = {1687-5443}, mesh = {Animals ; Cell Death/physiology ; Humans ; Nervous System Diseases/*physiopathology ; Neurons/*physiology ; Receptors, N-Methyl-D-Aspartate/*physiology ; Signal Transduction/*physiology ; Synapses/*physiology ; }, abstract = {N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca(2+) influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca(2+) homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases.}, }
@article {pmid27627892, year = {2017}, author = {Lafarga, M and Tapia, O and Romero, AM and Berciano, MT}, title = {Cajal bodies in neurons.}, journal = {RNA biology}, volume = {14}, number = {6}, pages = {712-725}, pmid = {27627892}, issn = {1555-8584}, mesh = {Animals ; Cell Nucleolus/metabolism ; Coiled Bodies/*metabolism ; Disease Susceptibility ; Humans ; Nervous System Diseases/genetics/metabolism/pathology ; Neurons/*metabolism ; Nuclear Proteins/genetics/metabolism ; Protein Transport ; RNA Splicing ; RNA, Small Nuclear/genetics/metabolism ; Ribonucleoproteins, Small Nuclear/metabolism ; }, abstract = {Cajal is commonly regarded as the father of modern neuroscience in recognition of his fundamental work on the structure of the nervous system. But Cajal also made seminal contributions to the knowledge of nuclear structure in the early 1900s, including the discovery of the "accessory body" later renamed "Cajal body" (CB). This important nuclear structure has emerged as a center for the assembly of ribonucleoproteins (RNPs) required for splicing, ribosome biogenesis and telomere maintenance. The modern era of CB research started in the 1990s with the discovery of coilin, now known as a scaffold protein of CBs, and specific probes for small nuclear RNAs (snRNAs). In this review, we summarize what we have learned in the recent decades concerning CBs in post-mitotic neurons, thereby ruling out dynamic changes in CB functions during the cell cycle. We show that CBs are particularly prominent in neurons, where they frequently associate with the nucleolus. Neuronal CBs are transcription-dependent nuclear organelles. Indeed, their number dynamically accommodates to support the high neuronal demand for splicing and ribosome biogenesis required for sustaining metabolic and bioelectrical activity. Mature neurons have canonical CBs enriched in coilin, survival motor neuron protein and snRNPs. Disruption and loss of neuronal CBs associate with severe neuronal dysfunctions in several neurological disorders such as motor neuron diseases. In particular, CB depletion in motor neurons seems to reflect a perturbation of transcription and splicing in spinal muscular atrophy, the most common genetic cause of infant mortality.}, }
@article {pmid27625421, year = {2017}, author = {Wilcox, SR and Ries, M and Bouthiller, TA and Berry, ED and Dowdy, TL and DeGrace, S}, title = {The Importance of Ground Critical Care Transport.}, journal = {Journal of intensive care medicine}, volume = {32}, number = {2}, pages = {163-169}, doi = {10.1177/0885066616668484}, pmid = {27625421}, issn = {1525-1489}, mesh = {Adult ; Air Ambulances ; Critical Care ; Critical Illness/*therapy ; *Emergency Medical Services ; Extracorporeal Membrane Oxygenation/*methods ; Female ; Humans ; Hypoxia/etiology/therapy ; Influenza A Virus, H1N1 Subtype/*pathogenicity ; Influenza, Human/diagnosis/physiopathology/*therapy ; Male ; Respiratory Distress Syndrome/diagnosis/*therapy/virology ; *Transportation of Patients ; Vasodilator Agents/*administration &amp; dosage ; }, abstract = {Critical care transport (CCT) teams are specialized transport services, comprised of highly trained paramedics, nurses, and occasionally respiratory therapists, offering an expanded scope of practice beyond advanced life support (ALS) emergency medical service teams. We report 4 cases of patients with severe acute respiratory distress syndrome from influenza in need of extracorporeal membrane oxygenation evaluation at a tertiary care center, transported by ground. Our medical center did not previously have a ground CCT service, and therefore, in these cases, a physician and/or a respiratory therapist was sent with the paramedic team. In all 4 cases, the ground transport team enhanced the intensive care provided to these patients prior to arrival at the tertiary care center. In 2 of the cases, although limited by the profound hypoxemia, the team decreased the pressures and tidal volumes in an effort to approach evidence-based ventilator goals. In 3 cases, they stopped bicarbonate drips being used to treat mixed metabolic and respiratory acidosis, and in 1 case, they administered furosemide. In 1 case, they started cisatracurium, and in 3 others, they initiated inhaled epoprostenol. Existing literature supports the use of CCT teams over ALS teams for transport of the most critically ill patients, and helicopter CCT is not always available or practical. Therefore, offering comparable air and ground options, with similar staffing and resources, is a hallmark of a mature medical system with an integrated approach to CCT.}, }
@article {pmid27607029, year = {2016}, author = {Ockenfels, HM}, title = {Therapeutisches Management kutaner und genitaler Warzen.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14}, number = {9}, pages = {892-900}, doi = {10.1111/ddg.12838_g}, pmid = {27607029}, issn = {1610-0387}, abstract = {Mindestens 10 % der Bevölkerung erkranken während ihres Lebens an einer Infektion mit humanen Papillomaviren (HPV), welche sich klinisch anhand der Ausbildung kutaner oder genitaler Warzen manifestiert. Obwohl Warzen ubiquitär sind, existieren keine definierten Behandlungen. Warzen zeigen, insbesondere in den ersten sechs Monaten, eine erhöhte Selbstheilungsrate. Dieser Umstand erschwert die Interpretation von Studien, da häufig Patienten mit Neuinfektionen zusammen mit Patienten mit Altinfektionen behandelt werden. Lokalisationen, Größe und Dicke der Warzen sind ebenfalls in den meisten Fällen nicht berücksichtigt. Ziel dieses Übersichtsartikels ist eine Analyse des vorliegenden Studienmaterials, unter der für den klinischen Alltag so wichtigen Berücksichtigung von Subtypen und Lokalisationen. Insbesondere die Abgrenzung zwischen frischen und chronisch-therapieresistenten Verrucae vulgares spiegelt sich in einem Therapiealgorithmus wider. Bei genitalen Warzen wird der Therapiealgorithmus deutlicher durch das Ausmaß der infizierten Fläche als durch das Alter der Warzen bestimmt. Bei immunkompetenten Personen muss es mit den hier aufgezeigten therapeutischen Methoden immer das Ziel sein, eine komplette Abheilung zu erzielen.}, }
@article {pmid27600654, year = {2016}, author = {Nolan, M and Talbot, K and Ansorge, O}, title = {Pathogenesis of FUS-associated ALS and FTD: insights from rodent models.}, journal = {Acta neuropathologica communications}, volume = {4}, number = {1}, pages = {99}, pmid = {27600654}, issn = {2051-5960}, support = {ANSORGE/OCT14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L022656/1/MRC_/Medical Research Council/United Kingdom ; TALBOT/APR11/811-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Frontotemporal Dementia/genetics/*metabolism ; Humans ; RNA-Binding Protein FUS/genetics/*metabolism ; }, abstract = {Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases.}, }
@article {pmid27600518, year = {2017}, author = {Shefner, JM}, title = {Strength Testing in Motor Neuron Diseases.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {154-160}, pmid = {27600518}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/therapy ; Disease Progression ; Female ; Hand Strength ; Humans ; Male ; Motor Neuron Disease/*diagnosis/physiopathology/*therapy ; *Muscle Strength ; Muscle Strength Dynamometer ; Muscle, Skeletal/physiopathology ; }, abstract = {Loss of muscle strength is a cardinal feature of all motor neuron diseases. Functional loss over time, including respiratory dysfunction, inability to ambulate, loss of ability to perform activities of daily living, and others are due, in large part, to decline in strength. Thus, the accurate measurement of limb muscle strength is essential in therapeutic trials to best understand the impact of therapy on vital function. While qualitative strength measurements show declines over time, the lack of reproducibility and linearity of measurement make qualitative techniques inadequate. A variety of quantitative measures have been developed; all have both positive attributes and limitations. However, with careful training and reliability testing, quantitative measures have proven to be reliable and sensitive indicators of both disease progression and the impact of experimental therapy. Quantitative strength measurements have demonstrated potentially important therapeutic effects in both amyotrophic lateral sclerosis and spinobulbar muscular atrophy, and have been shown feasible in children with spinal muscular atrophy. The spectrum of both qualitative and quantitative strength measurements are reviewed and their utility examined in this review.}, }
@article {pmid27600517, year = {2017}, author = {Henderson, RD and McCombe, PA}, title = {Assessment of Motor Units in Neuromuscular Disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {69-77}, pmid = {27600517}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/diagnostic imaging/*physiopathology ; Anterior Horn Cells/*physiology ; Biomarkers ; Disease Progression ; Electric Stimulation ; Electromyography ; Humans ; Magnetic Resonance Imaging ; Muscle, Skeletal/*physiopathology ; Neural Conduction ; Neuromuscular Diseases/*diagnosis/diagnostic imaging/*physiopathology ; Ultrasonography ; }, abstract = {The motor unit comprises the anterior horn cell, its axon, and the muscle fibers that it innervates. Although the true number of motor units is unknown, the number of motor units appears to vary greatly between different muscles and between different individuals. Assessment of the number and function of motor units is needed in diseases of the anterior horn cell and other motor nerve disorders. Amyotrophic lateral sclerosis is the most important disease of anterior horn cells. The need for an effective biomarker for assessing disease progression and for use in clinical trials in amyotrophic lateral sclerosis has stimulated the study of methods to measure the number of motor units. Since 1970 a number of different methods, including the incremental, F-wave, multipoint, and statistical methods, have been developed but none has achieved widespread applicability. Two methods (MUNIX and the multipoint incremental method) are in current use across multiple centres and are discussed in detail in this review, together with other recently published methods. Imaging with magnetic resonance and ultrasound is increasingly being applied to this area. Motor unit number estimates have also been applied to other neuromuscular diseases such as spinal muscular atrophy, compression neuropathies, and prior poliomyelitis. The need for an objective measure for the assessment of motor units remains tantalizingly close but unfulfilled in 2016.}, }
@article {pmid27598689, year = {2017}, author = {Cohen, Y and Anaby, D and Morozov, D}, title = {Diffusion MRI of the spinal cord: from structural studies to pathology.}, journal = {NMR in biomedicine}, volume = {30}, number = {3}, pages = {}, doi = {10.1002/nbm.3592}, pmid = {27598689}, issn = {1099-1492}, mesh = {Animals ; Diffusion Magnetic Resonance Imaging/*methods ; Evidence-Based Medicine ; Humans ; Image Enhancement/methods ; Image Interpretation, Computer-Assisted/methods ; Reproducibility of Results ; Sensitivity and Specificity ; Spinal Cord/*diagnostic imaging/*pathology ; Spinal Cord Diseases/*diagnostic imaging/*pathology ; Spinal Cord Injuries/*diagnostic imaging/*pathology ; }, abstract = {Diffusion MRI is extensively used to study brain microarchitecture and pathologies, and water diffusion appears highly anisotropic in the white matter (WM) of the spinal cord (SC). Despite these facts, the use of diffusion MRI to study the SC, which has increased in recent years, is much less common than that in the brain. In the present review, after a brief outline of early studies of diffusion MRI (DWI) and diffusion tensor MRI (DTI) of the SC, we provide a short survey on DTI and on diffusion MRI methods beyond the tensor that have been used to study SC microstructure and pathologies. After introducing the porous view of WM and describing the q-space approach and q-space diffusion MRI (QSI), we describe other methodologies that can be applied to study the SC. Selected applications of the use of DTI, QSI, and other more advanced diffusion MRI methods to study SC microstructure and pathologies are presented, with some emphasis on the use of less conventional diffusion methodologies. Because of length constraints, we concentrate on structural studies and on a few selected pathologies. Examples of the use of diffusion MRI to study dysmyelination, demyelination as in experimental autoimmune encephalomyelitis and multiple sclerosis, amyotrophic lateral sclerosis, and traumatic SC injury are presented. We conclude with a brief summary and a discussion of challenges and future directions for diffusion MRI of the SC. Copyright © 2016 John Wiley &amp; Sons, Ltd.}, }
@article {pmid27590975, year = {2016}, author = {Riccio, A and Pichiorri, F and Schettini, F and Toppi, J and Risetti, M and Formisano, R and Molinari, M and Astolfi, L and Cincotti, F and Mattia, D}, title = {Interfacing brain with computer to improve communication and rehabilitation after brain damage.}, journal = {Progress in brain research}, volume = {228}, number = {}, pages = {357-387}, doi = {10.1016/bs.pbr.2016.04.018}, pmid = {27590975}, issn = {1875-7855}, mesh = {Brain/*physiology ; Brain Injuries/*complications/rehabilitation ; *Brain-Computer Interfaces ; Communicable Diseases/*etiology/*rehabilitation ; Electroencephalography ; Humans ; Neurofeedback/*physiology ; }, abstract = {Communication and control of the external environment can be provided via brain-computer interfaces (BCIs) to replace a lost function in persons with severe diseases and little or no chance of recovery of motor abilities (ie, amyotrophic lateral sclerosis, brainstem stroke). BCIs allow to intentionally modulate brain activity, to train specific brain functions, and to control prosthetic devices, and thus, this technology can also improve the outcome of rehabilitation programs in persons who have suffered from a central nervous system injury (ie, stroke leading to motor or cognitive impairment). Overall, the BCI researcher is challenged to interact with people with severe disabilities and professionals in the field of neurorehabilitation. This implies a deep understanding of the disabled condition on the one hand, and it requires extensive knowledge on the physiology and function of the human brain on the other. For these reasons, a multidisciplinary approach and the continuous involvement of BCI users in the design, development, and testing of new systems are desirable. In this chapter, we will focus on noninvasive EEG-based systems and their clinical applications, highlighting crucial issues to foster BCI translation outside laboratories to eventually become a technology usable in real-life realm.}, }
@article {pmid27590968, year = {2016}, author = {Chaudhary, U and Birbaumer, N and Ramos-Murguialday, A}, title = {Brain-computer interfaces in the completely locked-in state and chronic stroke.}, journal = {Progress in brain research}, volume = {228}, number = {}, pages = {131-161}, doi = {10.1016/bs.pbr.2016.04.019}, pmid = {27590968}, issn = {1875-7855}, mesh = {Brain/*physiology ; Brain Waves/physiology ; *Brain-Computer Interfaces ; Chronic Disease ; *Communication ; Conditioning, Classical/physiology ; Electroencephalography ; Female ; Humans ; Male ; Paralysis/*etiology/*rehabilitation ; Spectroscopy, Near-Infrared ; Stroke/*complications ; User-Computer Interface ; }, abstract = {Brain-computer interfaces (BCIs) use brain activity to control external devices, facilitating paralyzed patients to interact with the environment. In this chapter, we discuss the historical perspective of development of BCIs and the current advances of noninvasive BCIs for communication in patients with amyotrophic lateral sclerosis and for restoration of motor impairment after severe stroke. Distinct techniques have been explored to control a BCI in patient population especially electroencephalography (EEG) and more recently near-infrared spectroscopy (NIRS) because of their noninvasive nature and low cost. Previous studies demonstrated successful communication of patients with locked-in state (LIS) using EEG- and invasive electrocorticography-BCI and intracortical recordings when patients still showed residual eye control, but not with patients with complete LIS (ie, complete paralysis). Recently, a NIRS-BCI and classical conditioning procedure was introduced, allowing communication in patients in the complete locked-in state (CLIS). In severe chronic stroke without residual hand function first results indicate a possible superior motor rehabilitation to available treatment using BCI training. Here we present an overview of the available studies and recent results, which open new doors for communication, in the completely paralyzed and rehabilitation in severely affected stroke patients. We also reflect on and describe possible neuronal and learning mechanisms responsible for BCI control and perspective for future BMI research for communication in CLIS and stroke motor recovery.}, }
@article {pmid27590581, year = {2017}, author = {Eraña, H and Venegas, V and Moreno, J and Castilla, J}, title = {Prion-like disorders and Transmissible Spongiform Encephalopathies: An overview of the mechanistic features that are shared by the various disease-related misfolded proteins.}, journal = {Biochemical and biophysical research communications}, volume = {483}, number = {4}, pages = {1125-1136}, doi = {10.1016/j.bbrc.2016.08.166}, pmid = {27590581}, issn = {1090-2104}, mesh = {Alzheimer Disease/metabolism ; Amyloidosis/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Parkinson Disease/metabolism ; Prion Diseases/*metabolism ; Protein Folding ; }, abstract = {Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species. Its causative agent, disease-associated prion protein (PrP[d]), is a self-propagating β-sheet rich aberrant conformation of the cellular prion protein (PrP[C]) with neurotoxic and aggregation-prone properties, capable of inducing misfolding of PrP[C] molecules. PrP[d] is the major constituent of prions and, most importantly, is the first known example of a protein with infectious attributes. It has been suggested that similar molecular mechanisms could be shared by other proteins implicated in diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or systemic amyloidoses. Accordingly, several terms have been proposed to collectively group all these disorders. Through the stringent evaluation of those aspects that characterise TSE-causing prions, in particular propagation and spread, strain variability or transmissibility, we will discuss whether terms such as "prion", "prion-like", "prionoid" or "propagon" can be used when referring to the aetiological agents of the above other disorders. Moreover, it will also be discussed whether the term "infectious", which defines a prion essential trait, is currently misused when referring to the other misfolded proteins.}, }
@article {pmid27586258, year = {2016}, author = {East, DA and Campanella, M}, title = {Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {79}, number = {}, pages = {382-387}, doi = {10.1016/j.biocel.2016.08.019}, pmid = {27586258}, issn = {1878-5875}, support = {BB/M010384/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; G1100809/2//Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Mitochondria/drug effects/*metabolism ; *Mitophagy/drug effects ; Neurodegenerative Diseases/drug therapy/pathology ; *Neuroprotection ; }, abstract = {Mitochondria are the foremost producers of the cellular energy currency ATP. They are also a significant source of reactive oxygen species and an important buffer of intracellular calcium. Mitochondrial retrograde signals regulate energy homeostasis and pro-survival elements whereas anterograde stimuli can trigger programmed cell death. Maintenance of a healthy, functional mitochondria network is therefore essential, and several mechanisms of mitochondrial quality control have been described. Mitochondrial dysfunction is linked to several neurodegenerative conditions including Parkinson, and Huntingdon diseases as well as Amyotrophic lateral sclerosis. Understanding the mechanisms governing mitochondrial quality control may reveal novel strategies for pharmacological intervention and disease therapy.}, }
@article {pmid29116729, year = {2016}, author = {Orrell, RW}, title = {Diagnosis and management of motor neurone disease.}, journal = {The Practitioner}, volume = {260}, number = {1796}, pages = {17-21}, pmid = {29116729}, issn = {0032-6518}, mesh = {Humans ; Motor Neuron Disease/*diagnosis/*therapy ; }, abstract = {Motor neurone disease is a rapidly progressive and fatal neurodegenerative condition which causes progressive weakness, with normal sensation. It can occur at any age but is more frequent with increasing age. Key clinical presentations include bulbar (slurred or difficult speech, problems swallowing, tongue fasciculation), limb (typically in one limb with weakness and muscle wasting), respiratory (breathlessness, chest muscle fasciculation) and cognitive features (behavioural change, emotional lability, features of frontotemporal dementia). Although survival is typically three to five years from symptom onset, there is significant individual variation. Rarely, survival may be 20 years or longer. Favourable features include a limb rather than a bulbar presentation, preserved weight and respiratory function, younger age of onset and longer time from fist symptom to diagnosis. The patient should be linked to a multidisciplinary team able to provide support from the start with a designated individual as the point of contact, with regular, coordinated assessments, as the patient's needs change and their condition progresses. Gastrostomy is an important supportive intervention which maximizes nutrition, and minimizes aspiration and chest infection. Adequate nutrition and hydration is key to maximizing health and survival. It is possible for a patient to control a computer and speech by eye. movement alone. An important consideration is voice banking where the patient may store their voice before there is difficulty with speech so that it can be used at a later stage if they need a communication aid. Impaired cough and retention of respiratory secretions is frequent in the later stages, and may be managed with physiotherapy. The patient should be referred for expert respiratory assessment if needed.}, }
@article {pmid27579582, year = {2016}, author = {Bartolo, M and Chiò, A and Ferrari, S and Tassorelli, C and Tamburin, S and Avenali, M and Azicnuda, E and Calvo, A and Caraceni, AT and Defazio, G and DE Icco, R and Formisano, R and Franzoni, S and Greco, E and Jedrychowska, I and Magrinelli, F and Manera, U and Marchioni, E and Mariotto, S and Monaco, S and Pace, A and Saviola, D and Springhetti, I and Tinazzi, M and DE Tanti, A and , }, title = {Assessing and treating pain in movement disorders, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness, dementia, oncology and neuroinfectivology. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.}, journal = {European journal of physical and rehabilitation medicine}, volume = {52}, number = {6}, pages = {841-854}, pmid = {27579582}, issn = {1973-9095}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Brain Diseases/*complications/*microbiology ; Brain Injuries/*complications ; Combined Modality Therapy ; Consciousness Disorders/*complications ; Dementia/*complications ; Evidence-Based Medicine ; Humans ; Italy ; Movement Disorders/*complications ; Neoplasms/*complications ; Neurological Rehabilitation/*methods ; Outcome Assessment, Health Care ; Pain/*etiology/*rehabilitation ; Pain Management/*methods ; *Pain Measurement ; Translational Research, Biomedical ; }, abstract = {Pain is an important non-motor symptom in several neurological diseases, such as Parkinson's disease, cervical dystonia, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness and dementia, as well as in oncology and neuroinfectivology. To overcome the lack of evidence-based data on pain management in these diseases, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) has defined criteria for good clinical practice among Italian neurorehabilitation professionals. Here a review of the literature (PubMed, EMBASE and gray literature) on pain characteristics, treatment and impact of pain in a neurorehabilitation setting is provided. Despite the heterogeneity of data, a consensus was reached on pain management for patients with these diseases: it is an approach originating from an analysis of the available data on pain characteristics in each disease, the evolution of pain in relation to the natural course of the disease and the impact of pain on the overall process of rehabilitation. There was unanimous consensus regarding the utility of a multidisciplinary approach to pain therapy, combining the benefits of pharmacological therapy with the techniques of physiotherapy and neurorehabilitation for all the conditions considered. While some treatments could be different depending on pathology, a progressive approach to the pharmacological treatment of pain is advisable, starting with non-opioid analgesics (paracetamol) and nonsteroidal anti-inflammatory drugs as a first-line treatment, and opioid analgesics as a second-line treatment. In cases of pain secondary to spasticity, botulinum neurotoxin, and, in some cases, intrathecal baclofen infusion should be considered. Randomized controlled trials and prospective multicenter studies aimed at documenting the efficacy of pain treatment and their risk-benefit profile are recommended for these conditions.}, }
@article {pmid27577737, year = {2016}, author = {Gonçalves, ID and Rehorst, WA and Kye, MJ}, title = {Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {15}, number = {8}, pages = {887-895}, doi = {10.2174/1871527315666160815164808}, pmid = {27577737}, issn = {1996-3181}, mesh = {Animals ; Gene Expression Regulation/*physiology ; Humans ; Mitochondrial Diseases/etiology ; *Motor Neuron Disease/complications/genetics/metabolism/physiopathology ; Oxidative Stress/*physiology ; RNA-Binding Proteins/*metabolism ; }, abstract = {Recent findings indicate an important role for RNA-mediated gene expression in motor neuron diseases, including ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). ALS, also known as Lou Gehrig's disease, is an adult-onset progressive neurodegenerative disorder, whereby SMA or "children's Lou Gehrig's disease" is considered a pediatric neurodevelopmental disorder. Despite the difference in genetic causes, both ALS and SMA share common phenotypes; dysfunction/loss of motor neurons that eventually leads to muscle weakness and atrophy. With advanced techniques in molecular genetics and cell biology, current data suggest that these two distinct motor neuron diseases share more than phenotypes; ALS and SMA have similar cellular pathological mechanisms including mitochondrial dysfunction, oxidative stress and dysregulation in RNA-mediated gene expression. Here, we will discuss the current findings on these two diseases with specific focus on RNA-mediated gene regulation including miRNA expression, pre-mRNA processing and RNA binding proteins.}, }
@article {pmid27575793, year = {2016}, author = {Fearns, R and Deval, J}, title = {New antiviral approaches for respiratory syncytial virus and other mononegaviruses: Inhibiting the RNA polymerase.}, journal = {Antiviral research}, volume = {134}, number = {}, pages = {63-76}, doi = {10.1016/j.antiviral.2016.08.006}, pmid = {27575793}, issn = {1872-9096}, mesh = {Antiviral Agents/pharmacology/*therapeutic use ; Clinical Trials as Topic ; DNA-Directed RNA Polymerases/*antagonists &amp; inhibitors/drug effects/metabolism ; Deoxycytidine/analogs &amp; derivatives/therapeutic use ; Hemorrhagic Fever, Ebola/drug therapy ; Humans ; Measles/drug therapy ; Mononegavirales/*drug effects/enzymology/genetics ; Nucleosides/agonists ; RNA, Messenger ; RNA-Dependent RNA Polymerase/drug effects ; Respiratory Syncytial Virus Infections/drug therapy ; Respiratory Syncytial Virus, Human/*drug effects/enzymology/genetics ; Transcription, Genetic ; Virus Replication/drug effects ; }, abstract = {Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is available. RSV is a member of the non-segmented, negative-strand (NNS) group of RNA viruses and relies on its RNA-dependent RNA polymerase to transcribe and replicate its genome. Because of its essential nature and unique properties, the RSV polymerase has proven to be a good target for antiviral drugs, with one compound, ALS-8176, having already achieved clinical proof-of-concept efficacy in a human challenge study. In this article, we first provide an overview of the role of the RSV polymerase in viral mRNA transcription and genome replication. We then review past and current approaches to inhibiting the RSV polymerase, including use of nucleoside analogs and non-nucleoside inhibitors. Finally, we consider polymerase inhibitors that hold promise for treating infections with other NNS RNA viruses, including measles and Ebola.}, }
@article {pmid27567641, year = {2016}, author = {Grolez, G and Moreau, C and Danel-Brunaud, V and Delmaire, C and Lopes, R and Pradat, PF and El Mendili, MM and Defebvre, L and Devos, D}, title = {The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review.}, journal = {BMC neurology}, volume = {16}, number = {1}, pages = {155}, pmid = {27567641}, issn = {1471-2377}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology ; *Biomarkers ; Clinical Trials as Topic ; Humans ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug's clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers.<br><br>METHODS: The PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking.<br><br>RESULTS: A total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected.<br><br>CONCLUSION: Despite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.}, }
@article {pmid27560387, year = {2016}, author = {Simonds, AK}, title = {Home Mechanical Ventilation: An Overview.}, journal = {Annals of the American Thoracic Society}, volume = {13}, number = {11}, pages = {2035-2044}, doi = {10.1513/AnnalsATS.201606-454FR}, pmid = {27560387}, issn = {2325-6621}, mesh = {Heart Failure/mortality/*therapy ; Humans ; Neuromuscular Diseases/mortality/*therapy ; Noninvasive Ventilation/adverse effects/*trends ; Obesity Hypoventilation Syndrome/mortality/*therapy ; Pulmonary Disease, Chronic Obstructive/mortality/*therapy ; Randomized Controlled Trials as Topic ; Risk Management ; Self Care/trends ; Terminal Care/methods ; }, abstract = {Prevalence studies have shown heterogeneous use of home mechanical ventilation in different conditions, with a marked increase in uptake especially in users of noninvasive ventilation. Although randomized controlled trials have examined noninvasive ventilation in acute exacerbations of chronic obstructive pulmonary disease, for weaning from invasive ventilation and for postextubation respiratory failure, the evidence base for long-term noninvasive ventilation and comparisons with invasive ventilation are less well developed. The combination of noninvasive ventilation and cough-assist devices has reduced the indications for tracheotomy ventilation in some situations (e.g., Duchenne muscular dystrophy, spinal muscular atrophy, myopathies, and amyotrophic lateral sclerosis) and has also prolonged survival. Several excellent overviews have been written on the history of home mechanical ventilation and its evolution from negative pressure to positive pressure techniques, including a systematic review of outcomes. This review, instead, will cover recent trials, trends in the field, outcomes, and safety. Because the greatest growth has been in home noninvasive ventilation, this will be the main focus of this article.}, }
@article {pmid27556379, year = {2016}, author = {Sica, RE and Caccuri, R and Quarracino, C and Capani, F}, title = {Are astrocytes executive cells within the central nervous system?.}, journal = {Arquivos de neuro-psiquiatria}, volume = {74}, number = {8}, pages = {671-678}, doi = {10.1590/0004-282X20160101}, pmid = {27556379}, issn = {1678-4227}, mesh = {Astrocytes/*physiology ; Dementia/*physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Neurons/*physiology ; }, abstract = {Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson's disease, Alzheimer's dementia, Huntington's dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.}, }
@article {pmid27554449, year = {2016}, author = {Alberti, S and Hyman, AA}, title = {Are aberrant phase transitions a driver of cellular aging?.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {38}, number = {10}, pages = {959-968}, pmid = {27554449}, issn = {1521-1878}, mesh = {Animals ; *Cell Compartmentation ; *Cellular Senescence ; Humans ; Neurodegenerative Diseases/*physiopathology ; Neurons/*physiology ; *Phase Transition ; }, abstract = {Why do cells age? Recent advances show that the cytoplasm is organized into many membrane-less compartments via a process known as phase separation, which ensures spatiotemporal control over diffusion-limited biochemical reactions. Although phase separation is a powerful mechanism to organize biochemical reactions, it comes with the trade-off that it is extremely sensitive to changes in physical-chemical parameters, such as protein concentration, pH, or cellular energy levels. Here, we highlight recent findings showing that age-related neurodegenerative diseases are linked to aberrant phase transitions in neurons. We discuss how these aberrant phase transitions could be tied to a failure to maintain physiological physical-chemical conditions. We generalize this idea to suggest that the process of cellular aging involves a progressive loss of the organization of phase-separated compartments in the cytoplasm.}, }
@article {pmid27545602, year = {2017}, author = {Patai, R and Nógrádi, B and Engelhardt, JI and Siklós, L}, title = {Calcium in the pathomechanism of amyotrophic lateral sclerosis - Taking center stage?.}, journal = {Biochemical and biophysical research communications}, volume = {483}, number = {4}, pages = {1031-1039}, doi = {10.1016/j.bbrc.2016.08.089}, pmid = {27545602}, issn = {1090-2104}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Calcium/*metabolism ; Humans ; Motor Neurons/metabolism ; Oxidative Stress ; Receptors, AMPA/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is an incurable, relentlessly progressive disease primarily affecting motor neurons. The cause of the disease, except for the mutations identified in a small fraction of patients, is unknown. The major mechanisms contributing to the degeneration of motor neurons have already been disclosed and characterized, including excitotoxicity, oxidative stress, mitochondrial dysfunction, and immune/inflammatory processes. During the progression of the disease these toxic processes are not discrete, but each facilitates the deleterious effect of the other. However, due to their common reciprocal calcium dependence, calcium ions may act as a common denominator and through a positive feedback loop may combine the individual pathological processes into a unified escalating mechanism of neuronal destruction. This mini-review provides an overview of the mutual calcium dependence of the major toxic mechanisms associated with amyotrophic lateral sclerosis.}, }
@article {pmid27540379, year = {2016}, author = {Lovelace, MD and Varney, B and Sundaram, G and Franco, NF and Ng, ML and Pai, S and Lim, CK and Guillemin, GJ and Brew, BJ}, title = {Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis.}, journal = {Frontiers in immunology}, volume = {7}, number = {}, pages = {246}, pmid = {27540379}, issn = {1664-3224}, abstract = {The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson's disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington's disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood-brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.}, }
@article {pmid27540165, year = {2016}, author = {Ransohoff, RM}, title = {How neuroinflammation contributes to neurodegeneration.}, journal = {Science (New York, N.Y.)}, volume = {353}, number = {6301}, pages = {777-783}, doi = {10.1126/science.aag2590}, pmid = {27540165}, issn = {1095-9203}, mesh = {Blood-Brain Barrier/pathology/physiopathology ; CX3C Chemokine Receptor 1 ; Humans ; Inflammation/*complications/genetics/pathology ; Membrane Glycoproteins/genetics ; Microglia/*pathology/physiology ; Neurodegenerative Diseases/*etiology/*pathology/therapy ; Neurons/*pathology/physiology ; Protein Aggregates ; Receptors, Chemokine/genetics ; Receptors, Immunologic/genetics ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.}, }
@article {pmid27539655, year = {2016}, author = {Kumar, V and Kashav, T and Islam, A and Ahmad, F and Hassan, MI}, title = {Structural insight into C9orf72 hexanucleotide repeat expansions: Towards new therapeutic targets in FTD-ALS.}, journal = {Neurochemistry international}, volume = {100}, number = {}, pages = {11-20}, doi = {10.1016/j.neuint.2016.08.008}, pmid = {27539655}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; DNA/genetics ; Frontotemporal Dementia/*genetics/therapy ; G-Quadruplexes/*drug effects ; Humans ; *Models, Molecular ; RNA/genetics ; }, abstract = {Hexanucleotide repeat expansions, (G4C2) in the C9orf72 gene are considered as the single most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). (G4C2), either as DNA or the transcribed RNA, can folds into unusual secondary structures, including G-quadruplex, R-loop, I-motif and hairpin. These structural polymorphism at both DNA and RNA levels were proposed to initiate molecular cascade leading to ALS/FTD. G-quadruplexes are composed of stacked G4 tetrads, held by hydrophobic bonds, and is highly stable secondary structure. Here, we covers the structural and functional features of G-quadruplexes with an emphasis on C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS). We also highlighted tools and techniques used to study the G-quadruplexes. Current perspectives for molecules that target G-quadruplexes as potential therapeutic are discussed. Our extensive analysis of structural features of G-quadruplexes will be used for a better understanding of molecular mechanism of C9-FTD/ALS.}, }
@article {pmid27539560, year = {2016}, author = {Chaudhary, U and Birbaumer, N and Ramos-Murguialday, A}, title = {Brain-computer interfaces for communication and rehabilitation.}, journal = {Nature reviews. Neurology}, volume = {12}, number = {9}, pages = {513-525}, pmid = {27539560}, issn = {1759-4766}, mesh = {Brain-Computer Interfaces/*trends ; Communication Aids for Disabled/*trends ; Electroencephalography/trends ; Humans ; Nervous System Diseases/physiopathology/psychology/*rehabilitation ; }, abstract = {Brain-computer interfaces (BCIs) use brain activity to control external devices, thereby enabling severely disabled patients to interact with the environment. A variety of invasive and noninvasive techniques for controlling BCIs have been explored, most notably EEG, and more recently, near-infrared spectroscopy. Assistive BCIs are designed to enable paralyzed patients to communicate or control external robotic devices, such as prosthetics; rehabilitative BCIs are designed to facilitate recovery of neural function. In this Review, we provide an overview of the development of BCIs and the current technology available before discussing experimental and clinical studies of BCIs. We first consider the use of BCIs for communication in patients who are paralyzed, particularly those with locked-in syndrome or complete locked-in syndrome as a result of amyotrophic lateral sclerosis. We then discuss the use of BCIs for motor rehabilitation after severe stroke and spinal cord injury. We also describe the possible neurophysiological and learning mechanisms that underlie the clinical efficacy of BCIs.}, }
@article {pmid27538057, year = {2016}, author = {White, MA and Sreedharan, J}, title = {Amyotrophic lateral sclerosis: recent genetic highlights.}, journal = {Current opinion in neurology}, volume = {29}, number = {5}, pages = {557-564}, doi = {10.1097/WCO.0000000000000367}, pmid = {27538057}, issn = {1473-6551}, support = {MR/K010611/1/MRC_/Medical Research Council/United Kingdom ; SREEDHARAN/JAN13/943-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein/*genetics ; Exome ; *Genetic Therapy ; Humans ; Mitochondria/genetics ; Mutation ; RNA ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS), like other neurodegenerative diseases, remains incurable, but gene mutations linked to ALS are providing clues as to how to target therapies. It is important for researchers to keep abreast of the rapid influx of new data in ALS, and we aim to summarize the major genetic advances made in the field over the past 2 years.<br><br>RECENT FINDINGS: Significant variation in seven genes has recently been found in ALS: TBK1, CCNF, GLE1, MATR3, TUBA4A, CHCHD10 and NEK1. These have mostly been identified through large exome screening studies, though traditional linkage approaches and candidate gene screening remain important. We briefly update C9orf72 research, noting in particular the development of reagents to better understand the normal role of C9orf72 protein.<br><br>SUMMARY: Striking advances in our understanding of the genetic heterogeneity of ALS continue to be made, year on year. These implicate proteostasis, RNA export, nuclear transport, the cytoskeleton, mitochondrial function, the cell cycle and DNA repair. Functional studies to integrate these hits are needed. By building a web of knowledge with interlinked genes and mechanisms, it is hoped we can better understand ALS and work toward effective therapies.}, }
@article {pmid27537704, year = {2017}, author = {Roggenbuck, J and Quick, A and Kolb, SJ}, title = {Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {19}, number = {3}, pages = {267-274}, doi = {10.1038/gim.2016.107}, pmid = {27537704}, issn = {1530-0366}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Frontotemporal Dementia/genetics ; Genetic Counseling/methods ; Genetic Testing/methods ; High-Throughput Nucleotide Sequencing/methods ; Humans ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often have questions about why they developed the disease and the likelihood that family members will also be affected. In recent years, providing answers to these questions has become more complex with the identification of multiple novel genes, the newly recognized etiologic link between ALS and frontotemporal dementia (FTD), and the increased availability of commercial genetic testing. A genetic diagnosis is particularly important to establish in the era of emerging gene-based therapies, such as SOD1 antisense oligonucleotide trials. In the span of a few years, ALS genetic testing options have progressed from testing of a single gene to multigene next-generation sequencing panels and whole-exome sequencing. This article provides suggestions for genetic counseling and genetic testing for ALS in this new environment.Genet Med 19 3, 267-274.}, }
@article {pmid27531973, year = {2016}, author = {Stoica, L and Sena-Esteves, M}, title = {Adeno Associated Viral Vector Delivered RNAi for Gene Therapy of SOD1 Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {9}, number = {}, pages = {56}, pmid = {27531973}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of upper and lower motor neurons. Mutations in superoxide dismutase 1 (SOD1) are a leading cause of ALS, responsible for up to 20% of familial cases. Although the exact mechanism by which mutant SOD1 causes disease remains unknown, multiple studies have shown that reduction of the mutant species leads to delayed disease onset and extension of lifespan of animal models. This makes SOD1 an ideal target for gene therapy coupling adeno associated virus vector (AAV) gene delivery with RNAi molecules. In this review we summarize the studies done thus far attempting to decrease SOD1 gene expression, using AAV vectors as delivery tools, and RNAi as therapeutic molecules. Current hurdles to be overcome, such as the need for widespread gene delivery through the entire central nervous system (CNS), are discussed. Continued efforts to improve current AAV delivery methods and capsids will accelerate the application of these therapeutics to the clinic.}, }
@article {pmid27529240, year = {2016}, author = {Grottelli, S and Ferrari, I and Pietrini, G and Peirce, MJ and Minelli, A and Bellezza, I}, title = {The Role of Cyclo(His-Pro) in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {17}, number = {8}, pages = {}, pmid = {27529240}, issn = {1422-0067}, mesh = {Animals ; Endoplasmic Reticulum Stress/physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress/physiology ; Peptides, Cyclic/chemistry/*metabolism ; Signal Transduction ; }, abstract = {Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function.}, }
@article {pmid27528056, year = {2016}, author = {Karthikeyan, A and Patnala, R and Jadhav, SP and Eng-Ang, L and Dheen, ST}, title = {MicroRNAs: Key Players in Microglia and Astrocyte Mediated Inflammation in CNS Pathologies.}, journal = {Current medicinal chemistry}, volume = {23}, number = {30}, pages = {3528-3546}, doi = {10.2174/0929867323666160814001040}, pmid = {27528056}, issn = {1875-533X}, mesh = {Antagomirs/metabolism ; Astrocytes/cytology/*metabolism ; Drug Carriers/chemistry ; HIV Infections/diagnosis/genetics ; Humans ; Inflammation/prevention &amp; control ; Inflammation Mediators/*metabolism ; MicroRNAs/antagonists &amp; inhibitors/*metabolism/therapeutic use ; Microglia/cytology/*metabolism ; Neurodegenerative Diseases/diagnosis/*pathology/therapy ; }, abstract = {The significance of microglia and astrocytes in neural development, in maintaining synaptic connections and homeostasis in the healthy brain is well established. Microglia are dynamic immune cells of the brain that elicit an immune response during brain damage and also participate in tissue repair and regeneration, while astrocytes contribute to the local inflammatory response by producing proinflammatory cytokines and resolving neuronal damage through production of anti-inflammatory cytokines and neurotrophic factors. Recent efforts have focused on elucidating the epigenetic mechanisms which regulate glial cell behavior in normal and pathologic states. An important class of epigenetic regulators is microRNAs (miRNAs) which are small non-coding RNA molecules that regulate gene expression posttranscriptionally. Certain dysregulated miRNAs contribute to chronic microglial inflammation in the brain, thereby leading to progression of neurological diseases like Alzheimer's disease, traumatic injury, amyotrophic lateral sclerosis and stroke. Further, several miRNAs are differentially expressed in astrocytes after ischemia and spinal cord injury. Despite knowledge about miRNAs in neuroinflammation, little is known about effective delivery routes and pharmacokinetic data for miRNA based therapeutics. This review summarizes the current research on the role of miRNAs in promoting and inhibiting inflammatory response of microglia and astrocytes in a disease-specific manner. In addition, miRNA delivery as a therapeutic strategy to treat neuroinflammation is discussed.}, }
@article {pmid27526115, year = {2016}, author = {Evans, JC and Malhotra, M and Cryan, JF and O'Driscoll, CM}, title = {The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease.}, journal = {British journal of pharmacology}, volume = {173}, number = {21}, pages = {3041-3079}, pmid = {27526115}, issn = {1476-5381}, mesh = {Antigens, Surface/genetics/*metabolism ; Glutamate Carboxypeptidase II/antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Kallikreins/antagonists &amp; inhibitors/genetics/*metabolism ; Male ; Nervous System Diseases/*diagnosis/enzymology/*therapy ; Prostate-Specific Antigen/antagonists &amp; inhibitors/genetics/*metabolism ; Prostatic Neoplasms/*diagnosis/enzymology/*therapy ; }, abstract = {Prostate specific membrane antigen (PSMA) otherwise known as glutamate carboxypeptidase II (GCPII) is a membrane bound protein that is highly expressed in prostate cancer and in the neovasculature of a wide variety of tumours including glioblastomas, breast and bladder cancers. This protein is also involved in a variety of neurological diseases including schizophrenia and ALS. In recent years, there has been a surge in the development of both diagnostics and therapeutics that take advantage of the expression and activity of PSMA/GCPII. These include gene therapy, immunotherapy, chemotherapy and radiotherapy. In this review, we discuss the biological roles that PSMA/GCPII plays, both in normal and diseased tissues, and the current therapies exploiting its activity that are at the preclinical stage. We conclude by giving an expert opinion on the future direction of PSMA/GCPII based therapies and diagnostics and hurdles that need to be overcome to make them effective and viable.}, }
@article {pmid27524729, year = {2016}, author = {Lewandowski, SA and Fredriksson, L and Lawrence, DA and Eriksson, U}, title = {Pharmacological targeting of the PDGF-CC signaling pathway for blood-brain barrier restoration in neurological disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {167}, number = {}, pages = {108-119}, pmid = {27524729}, issn = {1879-016X}, support = {R01 HL055374/HL/NHLBI NIH HHS/United States ; R01 NS079639/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism/pathology ; Drug Design ; Humans ; Lymphokines/*metabolism ; Mice ; Molecular Targeted Therapy ; Nervous System Diseases/*drug therapy/etiology/physiopathology ; Neurodegenerative Diseases/*drug therapy/etiology/physiopathology ; Neuroprotective Agents/pharmacology ; Platelet-Derived Growth Factor/*metabolism ; Risk Factors ; Signal Transduction ; }, abstract = {Neurological disorders account for a majority of non-malignant disability in humans and are often associated with dysfunction of the blood-brain barrier (BBB). Recent evidence shows that despite apparent variation in the origin of neural damage, the central nervous system has a common injury response mechanism involving platelet-derived growth factor (PDGF)-CC activation in the neurovascular unit and subsequent dysfunction of BBB integrity. Inhibition of PDGF-CC signaling with imatinib in mice has been shown to prevent BBB dysfunction and have neuroprotective effects in acute damage conditions, including traumatic brain injury, seizures or stroke, as well as in neurodegenerative diseases that develop over time, including multiple sclerosis and amyotrophic lateral sclerosis. Stroke and traumatic injuries are major risk factors for age-associated neurodegenerative disorders and we speculate that restoring BBB properties through PDGF-CC inhibition might provide a common therapeutic opportunity for treatment of both acute and progressive neuropathology in humans. In this review we will summarize what is known about the role of PDGF-CC in neurovascular signaling events and the variety of seemingly different neuropathologies it is involved in. We will also discuss the pharmacological means of therapeutic interventions for anti-PDGF-CC therapy and ongoing clinical trials. In summary: inhibition of PDGF-CC signaling can be protective for immediate injury and decrease the long-term neurodegenerative consequences.}, }
@article {pmid27521200, year = {2016}, author = {Crespo, V and James, ML}, title = {Neuromuscular Disease in the Neurointensive Care Unit.}, journal = {Anesthesiology clinics}, volume = {34}, number = {3}, pages = {601-619}, doi = {10.1016/j.anclin.2016.04.010}, pmid = {27521200}, issn = {1932-2275}, mesh = {Airway Management ; Amyotrophic Lateral Sclerosis/therapy ; Anesthesia ; Demyelinating Diseases/therapy ; Humans ; Immunotherapy ; *Intensive Care Units ; Myasthenia Gravis/therapy ; Neuromuscular Diseases/*therapy ; Pain Management ; Polyneuropathies/therapy ; }, abstract = {Neuromuscular diseases are syndromic disorders that affect nerve, muscle, and/or neuromuscular junction. Knowledge about the management of these diseases is required for anesthesiologists, because these may frequently be encountered in the intensive care unit, operating room, and other settings. The challenges and advances in management for some of the neuromuscular diseases most commonly encountered in the operating room and neurointensive care unit are reviewed.}, }
@article {pmid27517509, year = {2016}, author = {Vadori, M and Denaro, L and D'Avella, D and Cozzi, E}, title = {Indications and prospects of neural transplantation for chronic neurological diseases.}, journal = {Current opinion in organ transplantation}, volume = {21}, number = {5}, pages = {490-496}, doi = {10.1097/MOT.0000000000000344}, pmid = {27517509}, issn = {1531-7013}, mesh = {Animals ; Cell- and Tissue-Based Therapy/*methods ; Chronic Disease ; Humans ; Nervous System Diseases/*therapy ; Neural Stem Cells/*transplantation ; }, abstract = {PURPOSE OF REVIEW: The replacement of damaged cells in the central nervous system (CNS) affected by degenerative disorders represents an attractive therapeutic strategy. The advent of stem cell technology may offer the possibility of generating a large number of renewable, specifically differentiated cells to potentially cure large cohorts of patients. In this review, we discuss current knowledge and issues involved in neural cell transplantation. The most important preclinical and clinical results of cellular transplantation applied to Parkinson's, Huntington's disease and amyotrophic lateral sclerosis will be summarized.<br><br>RECENT FINDINGS: Cellular transplantation is emerging as a possible therapy for a variety of incurable neurological disorders. The disorders that will primarily take advantage from neural stem cell grafting are those involving a well defined cell population in a restricted area of the CNS. Several clinical trials have been initiated to assess safety and efficacy of different stem cell-derived products, and promising results have been obtained for disorders such as Parkinson's disease. However, several scientific questions remain unanswered. Among these, the impact of the immunological interaction between host and graft in the particular environment of the CNS still requires additional investigations.<br><br>SUMMARY: Several chronic neurological disorders appear to be amenable to cell regenerative therapies. However, safety, efficacy and immunological issues will need to be carefully evaluated beforehand.}, }
@article {pmid27514452, year = {2017}, author = {Agarwal, S and Yadav, A and Chaturvedi, RK}, title = {Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {483}, number = {4}, pages = {1166-1177}, doi = {10.1016/j.bbrc.2016.08.043}, pmid = {27514452}, issn = {1090-2104}, mesh = {Animals ; Calcium/metabolism ; Homeostasis ; Humans ; Inflammation/metabolism ; Mitochondria/metabolism ; Neurodegenerative Diseases/metabolism/pathology/*therapy ; Oxidative Stress ; Peroxisome Proliferator-Activated Receptors/*drug effects/metabolism ; }, abstract = {Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models.}, }
@article {pmid27514291, year = {2016}, author = {Hobson, EV and McDermott, CJ}, title = {Supportive and symptomatic management of amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {12}, number = {9}, pages = {526-538}, pmid = {27514291}, issn = {1759-4766}, support = {DRF-2013-06-076/DH_/Department of Health/United Kingdom ; SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/physiopathology/*therapy ; *Disease Management ; *Disease Progression ; Humans ; *Outcome and Process Assessment, Health Care/organization &amp; administration/standards ; *Patient Care Team/organization &amp; administration/standards ; Respiratory Insufficiency/etiology/*therapy ; *Terminal Care/organization &amp; administration/standards ; }, abstract = {The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies.}, }
@article {pmid27510420, year = {2016}, author = {Mouzat, K and Raoul, C and Polge, A and Kantar, J and Camu, W and Lumbroso, S}, title = {Liver X receptors: from cholesterol regulation to neuroprotection-a new barrier against neurodegeneration in amyotrophic lateral sclerosis?.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {73}, number = {20}, pages = {3801-3808}, pmid = {27510420}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Cholesterol/*metabolism ; Humans ; Liver X Receptors/chemistry/*metabolism ; Models, Biological ; Nerve Degeneration/*metabolism/*pathology ; *Neuroprotection ; }, abstract = {Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3 years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy.}, }
@article {pmid27509413, year = {2016}, author = {Müller, CS and Burgard, B and Zimmerman, M and Vogt, T and Pföhler, C}, title = {Zum Stellenwert der Unterdruck-Instillationstherapie in der Dermatologie.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14}, number = {8}, pages = {786-796}, doi = {10.1111/ddg.13038_g}, pmid = {27509413}, issn = {1610-0387}, mesh = {Humans ; *Negative-Pressure Wound Therapy ; }, abstract = {Die Methoden zur Behandlung akuter und chronischer Wunden unterliegen einer steten Weiterentwicklung, Reevaluierung und Anwendung innovativer Therapieformen. Die Vakuumtherapie zur Wundbehandlung gehört zu den etablierten Behandlungsmodalitäten. Ein innovatives Verfahren kombiniert die Vakuumtherapie mit der automatisierten, kontrollierten Zufuhr und Drainage wirkstoffhaltiger Lösungen zur topischen Wundbehandlung im Wundbett und auch wirkstofffrei durch Instillation physiologischer Kochsalzlösung (Unterdruck-Instillationstherapie). Hierdurch können die Effekte der konventionellen Vakuumtherapie mit denen der lokalen Antisepsis kombiniert werden. Hierdurch kommt es zu einer Reduktion der Wundfläche, einer Induktion von Granulationsgewebe sowie einer Reduktion der Keimbesiedelung der Wunden. Bisher publizierte Studien konzentrieren sich auf die Anwendung dieses Therapieverfahrens zur Behandlung orthopädisch-chirurgischer Krankheiten. Die Datenlage bezüglich der Vakuum-Instillationstherapie in der Dermatochirurgie beschränkt sich derzeit auf Fallberichte und Einzelfallerfahrungen. Randomisierte, prospektive Studien zum Vergleich der Vakuum-Instillationstherapie zur Behandlung dermatologischer Krankheitsbilder existieren bislang nicht. Ziele des vorliegenden Artikels sind die Vorstellung der Vakuumtherapie mit Instillation einschließlich ihres Wirkprinzips, deren mögliche Komplikationen, die Diskussion erdenklicher Kontraindikationen sowie eine Übersicht über die aktuell verfügbare Datenlage. Zusammenfassend scheint sich die Evidenz zu verdichten, dass mittels Unterdruck-Instillationstherapie sowohl einfache als auch komplizierte Wunden effizient behandelt werden können, was sich in einer deutlichen Beschleunigung der Wundgranulation mit konsekutiv früher möglichem Defektverschluss äußert.}, }
@article {pmid27507699, year = {2017}, author = {van Zundert, B and Brown, RH}, title = {Silencing strategies for therapy of SOD1-mediated ALS.}, journal = {Neuroscience letters}, volume = {636}, number = {}, pages = {32-39}, doi = {10.1016/j.neulet.2016.07.059}, pmid = {27507699}, issn = {1872-7972}, support = {R01 NS050557/NS/NINDS NIH HHS/United States ; R01 NS065847/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*therapy ; Animals ; Gene Silencing ; Genetic Therapy ; Humans ; MicroRNAs/genetics ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; RNA Interference ; RNA, Small Interfering/genetics ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, lethal, paralytic disorder caused by the degeneration of motor neurons. Our understanding of this disease has been greatly facilitated by studies of familial ALS caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Evidence indicates that misfolded wild-type SOD1 may also be pathogenic in sporadic ALS. Mutant SOD1 is neurotoxic through multiple mechanisms. Because the pathogenicity of mutant SOD1 is proportional to the dose of the toxic protein, a rational approach to treating SOD1-related ALS is to reduce levels of the toxic SOD1 species. An advantage of this strategy is that it potentially obviates intervening in multiple, downstream pathological cascades. In recent years, several strategies to silence gene expression have been developed. The most clinically promising are predicated on approaches that enhance degradation of RNA, such as anti-sense oligonucleotides (ASO) and RNA interference (RNAi); the latter include small inhibitory RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miR). Agents such as shRNA and either native or synthetic miR are capable of permeating the central nervous system (CNS) and efficiently silencing genes in the brain and spinal cord. Here we review recent progress in silencing SOD1, focusing on studies using artificial shRNA or miRNA in combination with potent viral vector delivery systems to mediate SOD1 silencing within the CNS in transgenic SOD1[G93A] mice and non-human primates.}, }
@article {pmid27498188, year = {2016}, author = {Weishaupt, JH and Hyman, T and Dikic, I}, title = {Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Trends in molecular medicine}, volume = {22}, number = {9}, pages = {769-783}, doi = {10.1016/j.molmed.2016.07.005}, pmid = {27498188}, issn = {1471-499X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/therapy ; Animals ; Autophagy ; Frontotemporal Dementia/genetics/metabolism/*pathology/therapy ; Humans ; Protein Aggregates ; RNA/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism.}, }
@article {pmid27497493, year = {2017}, author = {Prpar Mihevc, S and Darovic, S and Kovanda, A and Bajc Česnik, A and Župunski, V and Rogelj, B}, title = {Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Brain : a journal of neurology}, volume = {140}, number = {1}, pages = {13-26}, doi = {10.1093/brain/aww197}, pmid = {27497493}, issn = {1460-2156}, mesh = {*Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/*metabolism ; C9orf72 Protein ; Cell Nucleus/*metabolism ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/*metabolism ; Humans ; Proteins/*metabolism ; RNA-Binding Protein FUS/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, }
@article {pmid27495204, year = {2016}, author = {Mestre, TA}, title = {Chorea.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {22}, number = {4 Movement Disorders}, pages = {1186-1207}, doi = {10.1212/CON.0000000000000349}, pmid = {27495204}, issn = {1538-6899}, mesh = {C9orf72 Protein/genetics ; Chorea/*diagnosis/genetics/physiopathology ; Humans ; Mutation/genetics ; }, abstract = {PURPOSE OF REVIEW: This article reviews the clinical approach to the diagnosis of adult patients presenting with chorea, using Huntington disease (HD) as a point of reference, and presents the clinical elements that help in the diagnostic workup. Principles of management for chorea and some of the associated features of other choreic syndromes are also described.<br><br>RECENT FINDINGS: Mutations in the C9orf72 gene, previously identified in families with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both, have been recognized as one of the most prevalent causes of HD phenocopies in the white population.<br><br>SUMMARY: The diagnosis of chorea in adult patients is challenging. A varied number of associated causes require a physician to prioritize the investigations, and a detailed history of chorea and associated findings will help. For chorea presenting as part of a neurodegenerative syndrome, the consideration of a mutation in the C9orf72 gene is a new recommendation after excluding HD. There are no new treatment options for chorea, aside from dopamine blockers and tetrabenazine. There are no disease-modifying treatments for HD or other neurodegenerative choreic syndromes.}, }
@article {pmid27494456, year = {2017}, author = {Corbier, C and Sellier, C}, title = {C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy.}, journal = {Small GTPases}, volume = {8}, number = {3}, pages = {181-186}, pmid = {27494456}, issn = {2154-1256}, support = {310659/ERC_/European Research Council/International ; }, mesh = {*Autophagy ; C9orf72 Protein/*metabolism ; Guanosine Diphosphate/*metabolism ; Guanosine Triphosphate/*metabolism ; Humans ; rab GTP-Binding Proteins/*metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) are devastating neurodegenerative disease affecting motoneurons from the spinal chord and neurons from the frontal and temporal cortex, respectively. The most common genetic cause for ALS-FTD is an expansion of GGGGCC repeats within the first intron of the C9ORF72 gene. However, little is known on the function of C9ORF72. Recently, other and we found that C9ORF72 forms a stable complex with the SMCR8 and WDR41 proteins. This complex acts as a GDP/GTP exchange factor for the small RAB GTPases Rab8a and Rab39b. Since Rab8 and Rab39 are involved in macroautophagy, we tested the role of C9ORF72 in this mechanism. Decrease expression of C9ORF72 in neuronal cultures leads to autophagy dysfunction characterized by accumulation of aggregates of p62/SQSTM1. However, loss of C9ORF72 expression does not cause major neuronal cell death, suggesting that a second stress may be required to promote cell toxicity. Intermediate size of polyglutamine repeats within Ataxin-2 (ATXN2) is an important genetic modifier of ALS-FTD. We found that decrease expression of C9ORF72 synergizes the toxicity and aggregation of ATXN2 with intermediate size of polyglutamine (30Q). Overall, our data suggest that reduce expression of C9ORF72 causes suboptimal autophagy that sensitizes neurons to a second stress. These data suggest that reduce expression of C9ORF72 may partly contribute to ALS-FTD pathogenesis.}, }
@article {pmid27494151, year = {2017}, author = {Lucchesi, C and Caldarazzo Ienco, E and Fabbrini, M and Pasquali, L and Lo Gerfo, A and Fogli, A and Siciliano, G}, title = {Amyotrophic lateral sclerosis with long lasting disease course and SOD1 and TARDBP mutations: Report of two cases and overview of the literature.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {1-2}, pages = {137-139}, doi = {10.1080/21678421.2016.1212896}, pmid = {27494151}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; DNA-Binding Proteins/*genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation/*genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/*genetics ; }, }
@article {pmid27492589, year = {2016}, author = {Malkki, H}, title = {Motor Neuron Disease: New insights into genetic risk factors for amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {12}, number = {9}, pages = {491}, pmid = {27492589}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*genetics ; Genetic Markers/*genetics ; Genetic Predisposition to Disease/epidemiology/*genetics ; Humans ; Motor Neuron Disease/diagnosis/epidemiology/genetics ; Risk Factors ; }, }
@article {pmid27480243, year = {2016}, author = {Slowicka, K and Vereecke, L and van Loo, G}, title = {Cellular Functions of Optineurin in Health and Disease.}, journal = {Trends in immunology}, volume = {37}, number = {9}, pages = {621-633}, doi = {10.1016/j.it.2016.07.002}, pmid = {27480243}, issn = {1471-4981}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology ; Animals ; Autophagy/*genetics ; Cell Cycle Proteins ; Glaucoma/genetics/*immunology ; Humans ; Immunity/genetics ; Interferons/metabolism ; Membrane Transport Proteins ; Mutation/genetics ; NF-kappa B/metabolism ; Osteitis Deformans/genetics/*immunology ; Signal Transduction ; Transcription Factor TFIIIA/genetics/*metabolism ; }, abstract = {Optineurin (OPTN) was initially identified as a regulator of NF-κB and interferon signaling, but attracted most attention because of its association with various human disorders such as glaucoma, Paget disease of bone, and amyotrophic lateral sclerosis. Importantly, OPTN has recently been identified as an autophagy receptor important for the autophagic removal of pathogens, damaged mitochondria, and protein aggregates. This activity is most likely compromised in patients carrying OPTN mutations, and contributes to the observed phenotypes. In this review we summarize recent studies describing the molecular mechanisms by which OPTN controls immunity and autophagy, and discuss these findings in the context of several diseases that have been associated with OPTN (mal)function.}, }
@article {pmid27477685, year = {2017}, author = {McBean, GJ and López, MG and Wallner, FK}, title = {Redox-based therapeutics in neurodegenerative disease.}, journal = {British journal of pharmacology}, volume = {174}, number = {12}, pages = {1750-1770}, pmid = {27477685}, issn = {1476-5381}, mesh = {Animals ; Enzyme Inhibitors/*pharmacology ; Humans ; Mitochondria/drug effects/metabolism ; NADPH Oxidases/*antagonists &amp; inhibitors/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; Nitrosative Stress/drug effects ; Oxidation-Reduction ; }, abstract = {UNLABELLED: This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research.<br><br>LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.}, }
@article {pmid27473942, year = {2017}, author = {Trias, E and Ibarburu, S and Barreto-Núñez, R and Barbeito, L}, title = {Significance of aberrant glial cell phenotypes in pathophysiology of amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {636}, number = {}, pages = {27-31}, doi = {10.1016/j.neulet.2016.07.052}, pmid = {27473942}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Astrocytes/pathology ; Brain/pathology ; Cellular Microenvironment ; Humans ; Microglia/pathology ; Motor Neurons/pathology ; Mutation ; Neuroglia/*pathology ; Phenotype ; Spinal Cord/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a paradigmatic neurodegenerative disease, characterized by progressive paralysis of skeletal muscles associated with motor neuron degeneration. It is well-established that glial cells play a key role in ALS pathogenesis. In transgenic rodent models for familial ALS reactive astrocytes, microglia and oligodendrocyte precursors accumulate in the degenerating spinal cord and appear to contribute to primary motor neuron death through a non-cell autonomous pathogenic mechanism. Furthermore in rats expressing the ALS-linked SOD1[G93A] mutation, rapid spread of paralysis coincides with emergence of neurotoxic and proliferating aberrant glia cells with an astrocyte-like phenotype (AbA cells) that are found surrounding damaged motor neurons. AbAs simultaneously express astrocytic markers GFAP, S100β and Connexin-43 along with microglial markers Iba-1, CD11b and CD163. Studies with cell cultures have shown that AbAs originate from inflammatory microglial cells that undergo phenotypic transition. Because AbAs appear only after paralysis onset and exponentially increase in parallel with disease progression, they appear to actively contribute to ALS progression. While several reviews have been published on the pathogenic role of glial cells in ALS, this review focuses on emergence and pro-inflammatory activity of AbAs as part of an increasingly complex neurodegenerative microenvironment during ALS disease development.}, }
@article {pmid27473302, year = {2016}, author = {Zheng, Q and Chu, L and Tan, L and Zhang, H}, title = {Facial onset sensory and motor neuronopathy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {37}, number = {12}, pages = {1905-1909}, pmid = {27473302}, issn = {1590-3478}, mesh = {Databases, Bibliographic ; Face/*innervation ; Humans ; Motor Neuron Disease/*complications/*pathology ; Trigeminal Nerve/*physiopathology ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) is a recently defined slowly progressive motor neuron disorder. It is characterized by facial onset sensory abnormalities which may spread to the scalp, neck, upper trunk and extremities, followed by lower motor neuron deficits. Bulbar symptoms, such as dysarthria and dysphagia, muscle weakness, cramps and fasciculations, can present later in the course of the disease. We search the PubMed database for articles published in English from 2006 to 2016 using the term of "Facial onset sensory and motor neuronopathy". Reference lists of the identified articles were selected and reviewed. Only 38 cases of FOSMN have been reported in the Pubmed database since it was first reported in 2006. Typically, FOSMN present with slowly evolving numbness of the face followed by neck and arm weakness. Reduced or absent of corneal reflexes and blink reflex is the main pathognomonic features of FOSMN. In this review, we summarize the epidemiology, clinical presentation, auxiliary examination, and treatment of all the reported cases of FOSMN. Moreover, we discuss the pathogenesis of this rare disorder. In addition, we propose diagnostic criteria for FOSMN.}, }
@article {pmid27464072, year = {2016}, author = {Tortelli, R and Seripa, D and Panza, F and Solfrizzi, V and Logroscino, G}, title = {Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.}, journal = {Frontiers of neurology and neuroscience}, volume = {39}, number = {}, pages = {124-135}, doi = {10.1159/000445453}, pmid = {27464072}, issn = {1662-2804}, mesh = {Cytochrome P-450 Enzyme System/*genetics ; Humans ; Neurodegenerative Diseases/*drug therapy/*therapy ; Neuroprotective Agents/*therapeutic use ; *Pharmacogenetics ; *Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases.<br><br>SUMMARY: Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted.<br><br>KEY MESSAGES: The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification.}, }
@article {pmid27463686, year = {2016}, author = {Beghi, E and Pupillo, E and Giussani, G}, title = {Peculiarities of Neurological Disorders and Study Designs.}, journal = {Frontiers of neurology and neuroscience}, volume = {39}, number = {}, pages = {8-23}, doi = {10.1159/000445409}, pmid = {27463686}, issn = {1662-2804}, mesh = {Clinical Trials as Topic/*methods ; Humans ; Nervous System Diseases/diagnosis/*therapy ; *Research Design ; }, abstract = {BACKGROUND: Neurological disorders are heterogeneous clinical conditions with variable course and outcome.<br><br>SUMMARY: The basic aspects of the commonest neurological disorders are addressed along with the proposed structure of randomized clinical trials (RCTs). Dementing disorders, including Alzheimer's disease (AD), are clinical conditions in which altered cognitive functions are associated with behavioral and personality changes. Parkinson's disease (PD) is a multisystem disorder characterized by motor dysfunction associated with dysautonomia, sleep and olfactory disturbances, cognitive changes, and depression. Amyotrophic lateral sclerosis (ALS) is an invariably fatal clinical condition involving motor neurons. The available treatments are purely symptomatic for PD but virtually ineffective for AD and ALS. Headache disorders, multiple sclerosis, and epilepsy, three diseases characterized by recurrent symptoms and chronic or episodic course, can be fairly easily controlled by current treatments, but cannot be prevented nor cured. The objectives of treatments of neurodegenerative disorders include primary prevention, slowing or arrest of disease progression, and control of symptoms. Stroke is an acute clinical condition causing frequent disability and death, with only one approved treatment. There are many challenges to acute stroke clinical trials; among them, the very short therapeutic window and the issue of stroke heterogeneity. In this chapter, only the core elements of the study designs are outlined.<br><br>KEY MESSAGES: The design of an RCT must be adapted to the basic characteristics of each clinical condition.}, }
@article {pmid27462978, year = {2016}, author = {Bruijn, LI and Kolb, S}, title = {The Right Therapy for Neurological Disorders: From Randomized Trials to Clinical Practice - Patients versus Investigator Expectations and Needs.}, journal = {Frontiers of neurology and neuroscience}, volume = {39}, number = {}, pages = {147-153}, doi = {10.1159/000445455}, pmid = {27462978}, issn = {1662-2804}, mesh = {Health Services Needs and Demand/*statistics &amp; numerical data ; Humans ; Nervous System Diseases/*psychology/*therapy ; *Randomized Controlled Trials as Topic ; Research Personnel/*psychology ; }, abstract = {BACKGROUND: People living with amyotrophic lateral sclerosis (ALS) are now more proactive in making decisions about their treatment options, in particular with increased awareness through social media and the Internet. Together with increased awareness about the disease comes increased frustration that there is still only one Food and Drug Administration (FDA)-approved drug that modestly improves survival.<br><br>SUMMARY: While efforts are underway to improve clinical trial design, patient involvement in trial design, clinical outcomes, and risk/benefit evaluations have become more recognized and will play a major role in the future success of clinical trials. This chapter addresses the perspective of people living with ALS and their perceptions of clinical trials. We describe various organizations and programs available that provide increased education and patient involvement.<br><br>KEY MESSAGE: Stronger partnerships between those living with ALS, clinicians, government, nonprofit organizations, and regulatory agencies will significantly impact treatment development.}, }
@article {pmid27459462, year = {2016}, author = {Hagan, KA and Munger, KL and Ascherio, A and Grodstein, F}, title = {Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses' Health Study.}, journal = {American journal of public health}, volume = {106}, number = {9}, pages = {1650-1655}, pmid = {27459462}, issn = {1541-0048}, support = {R01 NS089619/NS/NINDS NIH HHS/United States ; R01 NS061858/NS/NINDS NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; R01 ES012667/ES/NIEHS NIH HHS/United States ; R01 NS048517/NS/NINDS NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 NS045893/NS/NINDS NIH HHS/United States ; R01 NS047467/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Epidemiologic Studies ; Female ; Humans ; Longitudinal Studies ; Middle Aged ; Neurodegenerative Diseases/*epidemiology ; *Nurses ; Prospective Studies ; Risk Factors ; United States/epidemiology ; Women's Health ; }, abstract = {OBJECTIVES: To review the contribution of the Nurses' Health Study (NHS) to identifying the role of lifestyle, diet, and genetic or biological factors in several neurodegenerative diseases, including cognitive decline, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis.<br><br>METHODS: We completed a narrative review of the publications of the NHS and NHS II between 1976 and 2016.<br><br>RESULTS: In primary findings for cognitive function, higher intake of nuts, moderate alcohol consumption, and higher physical activity levels were associated with better cognitive function. Flavonoids, physical activity, and postmenopausal hormone therapy were related to cognitive decline over 2 to 6 years. The NHS also has been integral in establishing Epstein-Barr virus infection, inadequate vitamin D nutrition, cigarette smoking, and obesity as risk factors for multiple sclerosis and inverse associations between cigarette smoking and caffeine and risk of Parkinson's disease. Increased risk of amyotrophic lateral sclerosis has been associated with cigarette smoking and decreased risk associated with obesity.<br><br>CONCLUSIONS: The NHS has provided invaluable resources on neurodegenerative diseases and contributed to their etiological understanding. We anticipate that the NHS cohorts will continue to make important contributions to the field of neurodegenerative diseases.}, }
@article {pmid27458821, year = {2016}, author = {Boscia, F and Begum, G and Pignataro, G and Sirabella, R and Cuomo, O and Casamassa, A and Sun, D and Annunziato, L}, title = {Glial Na(+) -dependent ion transporters in pathophysiological conditions.}, journal = {Glia}, volume = {64}, number = {10}, pages = {1677-1697}, pmid = {27458821}, issn = {1098-1136}, support = {I01 BX002891/BX/BLRD VA/United States ; R01 NS038118/NS/NINDS NIH HHS/United States ; R01 NS048216/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Ion Transport/physiology ; Membrane Transport Proteins/*metabolism ; Nervous System Diseases/*pathology ; Neuroglia/*physiology ; Signal Transduction/physiology ; Sodium/*metabolism ; }, abstract = {Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na(+) signaling influences and regulates important glial activities, and plays a role in neuron-glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na(+) pumps and Na(+) -dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na(+) homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer's disease, epilepsy, Parkinson's disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na(+) -dependent ion transporters, including Na(+) /K(+) ATPase, Na(+) /Ca(2+) exchangers, Na(+) /H(+) exchangers, Na(+) -K(+) -Cl(-) cotransporters, and Na(+) - HCO3- cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na(+) -dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na(+) dynamics in different neurological disorders. GLIA 2016;64:1677-1697.}, }
@article {pmid27454577, year = {2016}, author = {Dharmadasa, T and Matamala, JM and Kiernan, MC}, title = {Treatment approaches in motor neurone disease.}, journal = {Current opinion in neurology}, volume = {29}, number = {5}, pages = {581-591}, doi = {10.1097/WCO.0000000000000369}, pmid = {27454577}, issn = {1473-6551}, mesh = {*Disease Management ; Disease Progression ; Evidence-Based Medicine ; Humans ; Motor Neuron Disease/diagnosis/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Noninvasive Ventilation ; *Quality of Life ; }, abstract = {PURPOSE OF REVIEW: Although there is no cure for motor neurone disease (MND), the advent of multidisciplinary care and neuroprotective agents has improved treatment interventions and enhanced quality of life for MND patients and their carers.<br><br>RECENT FINDINGS: Evidence-based multidisciplinary care, respiratory management and disease-modifying therapy have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the quality of life for MND patients.<br><br>SUMMARY: Recent progress in the understanding of the clinical, pathophysiological and genetic heterogeneity of MND has improved the approach of clinicians to treatment. Notwithstanding improvement to care and quality of life, survival benefit has become evident with the advent of a multidisciplinary care framework, early treatment with riluzole and noninvasive ventilation. Weight maintenance remains critical, with weight loss associated with more rapid disease progression. The end-of-life phase is poorly defined and treatment is challenging, but effective symptom control through palliative care is achievable and essential. Encouragingly, current progress of clinical trials continues to close the gap towards the successful development of curative treatment in MND.}, }
@article {pmid27450455, year = {2016}, author = {Morgan, S and Orrell, RW}, title = {Pathogenesis of amyotrophic lateral sclerosis.}, journal = {British medical bulletin}, volume = {119}, number = {1}, pages = {87-98}, doi = {10.1093/bmb/ldw026}, pmid = {27450455}, issn = {1471-8391}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/pathology/*physiopathology ; Anticonvulsants/therapeutic use ; C9orf72 Protein ; DNA-Binding Proteins ; Executive Function/drug effects ; Genome-Wide Association Study ; Humans ; Molecular Targeted Therapy/*trends ; Mutation/genetics ; Proteins ; RNA-Binding Protein FUS ; Riluzole/therapeutic use ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition.<br><br>SOURCES OF DATA: Peer-reviewed journal articles and reviews. PubMed.gov<br><br>AREAS OF AGREEMENT: The pathogenesis of ALS remains largely unknown. There are a wide range of potential mechanisms related to neurodegeneration. An increasing number of genetic factors are recognized.<br><br>AREAS OF CONTROVERSY: There remains controversy, or lack of knowledge, in explaining how cellular events manifest as the complex human disease. There is controversy as to how well cellular and animal models of disease relate to the human disease.<br><br>GROWING POINTS: Large-scale international collaborative genetic epidemiological studies are replacing local studies. Therapies related to pathogenesis remain elusive, with the greatest advances to date relating to provision of care (including multidisciplinary management) and supportive care (nutrition and respiratory support).<br><br>The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies.}, }
@article {pmid27445967, year = {2016}, author = {Lecarpentier, Y and Vallée, A}, title = {Opposite Interplay between PPAR Gamma and Canonical Wnt/Beta-Catenin Pathway in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {7}, number = {}, pages = {100}, pmid = {27445967}, issn = {1664-2295}, abstract = {The opposite interplay between peroxisome proliferator-activated receptor gamma (PPAR gamma) and Wnt/beta-catenin signaling has led to the categorization of neurodegenerative diseases (NDs) as either NDs in which PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated [amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, multiple sclerosis, Friedreich's ataxia] or NDs in which PPAR gamma is upregulated while the canonical Wnt/beta-catenin signaling is downregulated (bipolar disorder, schizophrenia, Alzheimer's disease). ALS, a common adult-onset debilitating ND, is characterized by a chronic and progressive degeneration of upper and lower motor neurons resulting in muscular atrophy, paralysis, and ultimately death. The intent of this review is to provide an analysis of the integration of these two opposed systems, i.e., canonical Wnt/beta-catenin and PPAR gamma, in ALS. Understanding this integration may aid in the development of novel ALS therapies. Although the canonical Wnt/beta-catenin pathway is upregulated in ALS, riluzole, an enhancer of the canonical Wnt signaling, is classically prescribed in this disease in humans. However, studies carried out on ALS transgenic mice have shown beneficial effects after treatment by PPAR gamma agonists partly due to their anti-inflammatory effects.}, }
@article {pmid27439463, year = {2016}, author = {van Groenestijn, AC and Kruitwagen-van Reenen, ET and Visser-Meily, JM and van den Berg, LH and Schröder, CD}, title = {Associations between psychological factors and health-related quality of life and global quality of life in patients with ALS: a systematic review.}, journal = {Health and quality of life outcomes}, volume = {14}, number = {1}, pages = {107}, pmid = {27439463}, issn = {1477-7525}, mesh = {Adaptation, Psychological ; Affect ; Amyotrophic Lateral Sclerosis/*psychology ; Anxiety ; Depression ; Humans ; Personality ; Quality of Life/*psychology ; Spirituality ; }, abstract = {OBJECTIVE: To systematically identify and appraise evidence on associations between psychological factors (moods, beliefs, personality) and Health-related QoL (HRQoL) and/or global QoL in patients with Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: A systematic review was conducted in several online databases (PsycINFO, EMBASE, PubMed and CINAHL) up to October 2015. Articles were included if they reported associations between psychological factors (moods, beliefs and personality) and HRQoL and/or global QoL in an ALS population. The search was limited to empirical studies, published in English, which provided quantitative data. The methodological quality of the included articles was assessed.<br><br>RESULTS: In total, 22 studies were included. Mood was investigated in 14 studies, beliefs in 11 studies and personality in one study. Fifteen different psychological factors were extracted and assessed using 24 different measures. Twelve different QoL measures were used in the selected studies, subdivided into seven different HRQoL measures and five different global QoL measures. Higher levels of anxiety and depression appeared to be related to a poorer HRQoL, whereas a higher level of religiosity seemed to be associated with better global QoL. No conclusive associations were found for confusion-bewilderment (mood), spirituality, mindfulness, coping styles, hopelessness, perception of burden, cognitive appraisal (beliefs), neuroticism, extraversion, openness, agreeableness and conscientiousness (personality), due to insufficient or inconsistent evidence. Religiosity and spirituality appeared to become more positively associated over time.<br><br>CONCLUSIONS: Our results suggest that higher levels of anxiety and depression are related to a poorer HRQoL, whereas higher levels of religiosity appeared to be related to better global QoL. Associations might change during the disease course. This review supports the importance of psychological factors with regard to ALS care. Further research is needed to supplement the available evidence and to investigate how psychological factors can be modified to improve QoL.<br><br>REVIEW REGISTRATION NUMBER: PROSPERO 2015:CRD42015027303.}, }
@article {pmid27435372, year = {2016}, author = {Rao, M and Gershon, MD}, title = {The bowel and beyond: the enteric nervous system in neurological disorders.}, journal = {Nature reviews. Gastroenterology &amp; hepatology}, volume = {13}, number = {9}, pages = {517-528}, pmid = {27435372}, issn = {1759-5053}, support = {R01 DK093094/DK/NIDDK NIH HHS/United States ; R01 NS015547/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Diseases/complications/etiology ; *Enteric Nervous System/physiology ; Gastrointestinal Diseases/etiology ; Humans ; *Nervous System Diseases/complications/etiology ; }, abstract = {The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut-brain alliance has raised consciousness as a contributor to health, but a gut-brain axis that contributes to disease merits equal attention.}, }
@article {pmid27430450, year = {2016}, author = {Klein, JP}, title = {Imaging of progressive weakness or numbness of central or peripheral origin.}, journal = {Handbook of clinical neurology}, volume = {136}, number = {}, pages = {923-937}, doi = {10.1016/B978-0-444-53486-6.00047-8}, pmid = {27430450}, issn = {0072-9752}, mesh = {Central Nervous System Diseases/*complications/diagnostic imaging ; Humans ; Hypesthesia/*diagnostic imaging/*etiology ; *Neuroimaging ; Peripheral Nerve Injuries/*complications/diagnostic imaging ; }, abstract = {Weakness and numbness occur in a variety of patterns that reflect injury to different parts of the central and peripheral nervous system. Progressive symptoms most often signify an underlying structural or degenerative problem. Familiarity with the major descending motor and ascending sensory tracts of the central nervous system, as well as radicular (dermatome and myotome) and peripheral nerve anatomy, is essential. Damage to these tracts and nerve fibers produces characteristic clinical symptoms and signs. Imaging, when used in a hypothesis-driven way, can be a valuable adjunct to the clinical history and physical examination. One of the most useful aspects of imaging is that it allows for differentiation of edema and inflammation from gliosis and atrophy, both of which can be associated with progressive weakness or numbness. Compression of nervous system structures by nonnervous system tissue can also be easily detected. The spectrum of diseases and imaging abnormalities associated with progressive weakness and numbness is highlighted in this review via a series of illustrative cases. In each case, anatomic localization and the key imaging findings are emphasized.}, }
@article {pmid27430445, year = {2016}, author = {Pillen, S and Boon, A and Van Alfen, N}, title = {Muscle ultrasound.}, journal = {Handbook of clinical neurology}, volume = {136}, number = {}, pages = {843-853}, doi = {10.1016/B978-0-444-53486-6.00042-9}, pmid = {27430445}, issn = {0072-9752}, mesh = {Animals ; Humans ; Muscles/*diagnostic imaging ; Muscular Diseases/*diagnostic imaging ; *Ultrasonography ; }, abstract = {Muscle ultrasound is an ideal imaging modality that allows for noninvasive, radiation-free point-of-care neuromuscular imaging. There are many potential applications of muscle ultrasound, including identification of abnormal muscle movements such as fasciculations, evaluation of muscle trauma, identification of physiologic parameters such as pennation angle, accurate performance of chemodenervation, and improved accuracy of challenging electrodiagnostic studies such as phrenic nerve conduction studies or needle electromyogram (EMG) of the diaphragm. Tissue Doppler imaging can be used to help identify inflammatory myopathies. With computer-assisted quantification, muscle ultrasound has high sensitivity and specificity in the diagnosis of pediatric neuromuscular disease and amyotrophic lateral sclerosis, and is a valuable addition to other diagnostic techniques for neuromuscular disease. When used as a first-line screening tool it can obviate the need for more invasive procedures such as EMG or muscle biopsy in certain patients. This chapter provides an overview of the fundamentals, clinical applications, and validation of muscle ultrasound for patients with neuromuscular disorders.}, }
@article {pmid27426933, year = {2016}, author = {Shakhbazau, A and Potapnev, M}, title = {Autologous mesenchymal stromal cells as a therapeutic in ALS and epilepsy patients: Treatment modalities and ex vivo neural differentiation.}, journal = {Cytotherapy}, volume = {18}, number = {10}, pages = {1245-1255}, doi = {10.1016/j.jcyt.2016.06.001}, pmid = {27426933}, issn = {1477-2566}, mesh = {Adult ; Adult Stem Cells/pathology/physiology/transplantation ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Cells, Cultured ; Epilepsy/physiopathology/*therapy ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/*physiology ; Neural Stem Cells/*physiology/transplantation ; Neurogenesis/*physiology ; Transplantation, Autologous ; }, abstract = {Stem cell therapy for incurable central nervous system disorders has long been viewed as a promising therapeutic option. In this review, we discuss the existing data and approaches on cell transplantation in the context of the neural differentiation potential of adult autologous stem cells, focusing on those of mesenchymal origin as easily accessible and well studied. Mesenchymal stromal cells (MSCs) are a heterogeneous cell population with a remarkable therapeutic plasticity, demonstrated by their ability to dampen inflammation, inhibit pathogenic immune responses and secrete neuroprotective factors. To demonstrate and discuss the broad therapeutic potential of MSCs, this review focuses on two examples of neurological conditions: amyotrophic lateral sclerosis and epilepsy. We review the lessons from animal models and clinical trials, and consider encouraging newly published clinical data on therapeutic applications of neurally induced MSCs.}, }
@article {pmid27416757, year = {2017}, author = {Carrì, MT and D'Ambrosi, N and Cozzolino, M}, title = {Pathways to mitochondrial dysfunction in ALS pathogenesis.}, journal = {Biochemical and biophysical research communications}, volume = {483}, number = {4}, pages = {1187-1193}, doi = {10.1016/j.bbrc.2016.07.055}, pmid = {27416757}, issn = {1090-2104}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*physiopathology ; Animals ; Humans ; Mitochondria/metabolism/*physiology ; Mutation ; }, abstract = {Alterations in the structure and functions of mitochondria are a typical trait of Amyotrophic Lateral Sclerosis, a neurodegenerative disease characterized by a prominent degeneration of upper and lower motor neurons. The known gene mutations that are responsible for a small fraction of ALS cases point to a complex interplay between different mechanisms in the disease pathogenesis. Here we will briefly overview the genetic and mechanistic evidence that make dysfunction of mitochondria a candidate major player in this process.}, }
@article {pmid27404258, year = {2016}, author = {Yaron, A and Schuldiner, O}, title = {Common and Divergent Mechanisms in Developmental Neuronal Remodeling and Dying Back Neurodegeneration.}, journal = {Current biology : CB}, volume = {26}, number = {13}, pages = {R628-R639}, pmid = {27404258}, issn = {1879-0445}, support = {615906/ERC_/European Research Council/International ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; *Apoptosis ; Humans ; Invertebrates/*physiology ; Neurodegenerative Diseases/*physiopathology ; Neurogenesis ; *Neuronal Plasticity ; Peripheral Nervous System Diseases/physiopathology ; Vertebrates/*physiology ; }, abstract = {Cell death is an inherent process that is required for the proper wiring of the nervous system. Studies over the last four decades have shown that, in a parallel developmental pathway, axons and dendrites are eliminated without the death of the neuron. This developmentally regulated 'axonal death' results in neuronal remodeling, which is an essential mechanism to sculpt neuronal networks in both vertebrates and invertebrates. Studies across various organisms have demonstrated that a conserved strategy in the formation of adult neuronal circuitry often involves generating too many connections, most of which are later eliminated with high temporal and spatial resolution. Can neuronal remodeling be regarded as developmentally and spatially regulated neurodegeneration? It has been previously speculated that injury-induced degeneration (Wallerian degeneration) shares some molecular features with 'dying back' neurodegenerative diseases. In this opinion piece, we examine the similarities and differences between the mechanisms regulating neuronal remodeling and those being perturbed in dying back neurodegenerative diseases. We focus primarily on amyotrophic lateral sclerosis and peripheral neuropathies and highlight possible shared pathways and mechanisms. While mechanistic data are only just beginning to emerge, and despite the inherent differences between disease-oriented and developmental processes, we believe that some of the similarities between these developmental and disease-initiated degeneration processes warrant closer collaborations and crosstalk between these different fields.}, }
@article {pmid27400686, year = {2016}, author = {Picher-Martel, V and Valdmanis, PN and Gould, PV and Julien, JP and Dupré, N}, title = {From animal models to human disease: a genetic approach for personalized medicine in ALS.}, journal = {Acta neuropathologica communications}, volume = {4}, number = {1}, pages = {70}, pmid = {27400686}, issn = {2051-5960}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology/*therapy ; Animals ; Genetic Therapy ; Humans ; *Precision Medicine/methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.}, }
@article {pmid27400329, year = {2017}, author = {de Tommaso, M and Kunz, M and Valeriani, M}, title = {Therapeutic approach to pain in neurodegenerative diseases: current evidence and perspectives.}, journal = {Expert review of neurotherapeutics}, volume = {17}, number = {2}, pages = {143-153}, doi = {10.1080/14737175.2016.1210512}, pmid = {27400329}, issn = {1744-8360}, mesh = {Alzheimer Disease/physiopathology/therapy ; Humans ; Neurodegenerative Diseases/*physiopathology ; *Pain/physiopathology ; *Pain Management ; Parkinson Disease/physiopathology/therapy ; }, abstract = {Neurodegenerative diseases are increasing in parallel to the lengthening of survival. The management of Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, and motor neuron diseases (MND), is mainly targeted to motor and cognitive impairment, with special care for vital functions such as breathing and feeding. Areas covered: The present review focuses on chronic pain in main neurodegenerative diseases, addressing current evidence on pain therapeutic management, pain frequency and clinical features, and possible pathophysiological mechanisms. The search on PubMed had no time limits and was performed by searching for the following key issues: pain, dementia, Alzheimer disease, Parkinson's disease, extrapyramidal disorders, motoneuronal disease, Amyotrophic lateral sclerosis, FXTAS, frequency, pathophysiology, treatments, therapy, efficacy, opioids, side effects. No controlled therapeutic trials and guidelines are currently available. The effects of current therapies such as L-Dopa or riluzole on pain symptoms are not clear. Emerging evidences on the possible anti-nociceptive effects of cannabis or botulinum toxin might be available soon. Expert commentary: Pain needs to be better evaluated and fully considered in the global management of neurodegenerative disease because a more focused treatment may have a positive impact on the global burden of these devastating disorders.}, }
@article {pmid27400276, year = {2016}, author = {Ioannides, ZA and Ngo, ST and Henderson, RD and McCombe, PA and Steyn, FJ}, title = {Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression.}, journal = {Neuro-degenerative diseases}, volume = {16}, number = {5-6}, pages = {382-397}, doi = {10.1159/000446502}, pmid = {27400276}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Brain/metabolism ; *Disease Progression ; Energy Metabolism ; *Homeostasis ; Humans ; Mitochondria/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.}, }
@article {pmid27397642, year = {2016}, author = {Greenough, MA and Ramírez Munoz, A and Bush, AI and Opazo, CM}, title = {Metallo-pathways to Alzheimer's disease: lessons from genetic disorders of copper trafficking.}, journal = {Metallomics : integrated biometal science}, volume = {8}, number = {9}, pages = {831-839}, doi = {10.1039/c6mt00095a}, pmid = {27397642}, issn = {1756-591X}, mesh = {Alzheimer Disease/*etiology/metabolism/pathology ; Copper/*metabolism ; *Genetic Predisposition to Disease ; Humans ; Menkes Kinky Hair Syndrome/complications/*genetics ; Mitochondria/metabolism/*pathology ; *Oxidative Stress ; Signal Transduction ; }, abstract = {Copper is an essential metal ion that provides catalytic function to numerous enzymes and also regulates neurotransmission and intracellular signaling. Conversely, a deficiency or excess of copper can cause chronic disease in humans. Menkes and Wilson disease are two rare heritable disorders of copper transport that are characterized by copper deficiency and copper overload, respectively. Changes to copper status are also a common feature of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). In the case of AD, which is characterized by brain copper depletion, changes in the distribution of copper has been linked with various aspects of the disease process; protein aggregation, defective protein degradation, oxidative stress, inflammation and mitochondrial dysfunction. Although AD is a multifactorial disease that is likely caused by a breakdown in multiple cellular pathways, copper and other metal ions such as iron and zinc play a central role in many of these cellular processes. Pioneering work by researchers who have studied relatively rare copper transport diseases has shed light on potential metal ion related disease mechanisms in other forms of neurodegeneration such as AD.}, }
@article {pmid27392869, year = {2016}, author = {Leighton, PL and Allison, WT}, title = {Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {54}, number = {1}, pages = {3-29}, doi = {10.3233/JAD-160361}, pmid = {27392869}, issn = {1875-8908}, mesh = {Alzheimer Disease/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Huntington Disease/*metabolism ; PrPC Proteins/*metabolism ; Prion Diseases/*metabolism ; Protein Folding ; }, abstract = {Prion disease research has contributed much toward understanding other neurodegenerative diseases, including recent demonstrations that Alzheimer's disease (AD) and other neurodegenerative diseases are prion-like. Prion-like diseases involve the spread of degeneration between individuals and/or among cells or tissues via template directed misfolding, wherein misfolded protein conformers propagate disease by causing normal proteins to misfold. Here we use the premise that AD, amyotrophic lateral sclerosis, Huntington's disease, and other similar diseases are prion-like and ask: Can we apply knowledge gained from studies of these prion-like diseases to resolve debates about classical prion diseases? We focus on controversies about what role(s) protein loss-of-function might have in prion diseases because this has therapeutic implications, including for AD. We examine which loss-of-function events are recognizable in prion-like diseases by considering the normal functions of the proteins before their misfolding and aggregation. We then delineate scenarios wherein gain-of-function and/or loss-of-function would be necessary or sufficient for neurodegeneration. We consider roles of PrPC loss-of-function in prion diseases and in AD, and conclude that the conventional wisdom that prion diseases are 'toxic gain-of-function diseases' has limitations. While prion diseases certainly have required gain-of-function components, we propose that disease phenotypes are predominantly caused by deficits in the normal physiology of PrPC and its interaction partners as PrPC converts to PrPSc. In this model, gain-of-function serves mainly to spread disease, and loss-of-function directly mediates neuron dysfunction. We propose experiments and predictions to assess our conclusion. Further study on the normal physiological roles of these key proteins is warranted.}, }
@article {pmid27379008, year = {2016}, author = {Nardo, G and Trolese, MC and Bendotti, C}, title = {Major Histocompatibility Complex I Expression by Motor Neurons and Its Implication in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {7}, number = {}, pages = {89}, pmid = {27379008}, issn = {1664-2295}, abstract = {Neuronal expression of major histocompatibility complex I (MHCI)-related molecules in adults and during CNS diseases is involved in the synaptic plasticity and axonal regeneration with mechanisms either dependent or independent of their immune functions. Motor neurons are highly responsive in triggering the expression of MHCI molecules during normal aging or following insults and diseases, and this has implications in the synaptic controls, axonal regeneration, and neuromuscular junction stability of these neurons. We recently reported that MHCI and immunoproteasome are strongly activated in spinal motor neurons and their peripheral motor axon in a mouse model of familial amyotrophic lateral sclerosis (ALS) during the course of the disease. This response was prominent in ALS mice with slower disease progression in which the axonal structure and function was better preserved than in fast-progressing mice. This review summarizes and discusses our observations in the light of knowledge about the possible role of MHCI in motor neurons providing additional insight into the pathophysiology of ALS.}, }
@article {pmid27377857, year = {2017}, author = {Wang, MD and Little, J and Gomes, J and Cashman, NR and Krewski, D}, title = {Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis.}, journal = {Neurotoxicology}, volume = {61}, number = {}, pages = {101-130}, doi = {10.1016/j.neuro.2016.06.015}, pmid = {27377857}, issn = {1872-9711}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*epidemiology/*etiology/genetics ; Databases, Bibliographic/statistics &amp; numerical data ; *Disease Progression ; Environmental Exposure/adverse effects ; Humans ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Nutritional Status ; Pesticides/toxicity ; Risk Factors ; Vitamin D Deficiency/epidemiology ; }, abstract = {Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain largely unknown. Monogenic mutations in over 30 genes are associated with about 10% of ALS cases. The age at onset of ALS and disease types has been found to influence ALS progression. The present study was designed to identify additional putative risk factors associated with the onset and progression of ALS using systematic review and meta-analysis of observational studies. Risk factors that may be associated with ALS include: 1) genetic mutations, including the intermediate CAG repeat expansion in ATXN2; 2) previous exposure to heavy metals such as lead and mercury; 3) previous exposure to organic chemicals, such as pesticides and solvents; 4) history of electric shock; 5) history of physical trauma/injury (including head trauma/injury); 6) smoking (a weak risk factor for ALS in women); and 6) other risk factors, such as participating in professional sports, lower body mass index, lower educational attainment, or occupations requiring repetitive/strenuous work, military service, exposure to Beta-N-methylamino-l-alanin and viral infections. Risk factors that may be associated with ALS progression rate include: 1) nutritional status, including vitamin D deficiency; 2) comorbidities; 3) ethnicity and genetic factors; 4) lack of supportive care; and 4) smoking. The extent to which these associations may be causal is discussed, with further research recommended to strengthen the evidence on which determinations of causality may be based.}, }
@article {pmid27377856, year = {2017}, author = {Hersi, M and Quach, P and Wang, MD and Gomes, J and Gaskin, J and Krewski, D}, title = {Systematic reviews of factors associated with the onset and progression of neurological conditions in humans: A methodological overview.}, journal = {Neurotoxicology}, volume = {61}, number = {}, pages = {12-18}, doi = {10.1016/j.neuro.2016.06.017}, pmid = {27377856}, issn = {1872-9711}, mesh = {Databases, Bibliographic/statistics &amp; numerical data ; *Disease Progression ; Humans ; Meta-Analysis as Topic ; Nervous System Diseases/*epidemiology/*etiology ; Risk Factors ; }, abstract = {As a component of the National Population Health Study of Neurological conditions, systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 priority neurological conditions. Between 2011 and 2013, electronic databases and grey literature sources were searched to identify systematic reviews and primary studies reporting on the onset and progression of each condition. Inclusion was restricted to studies of humans reported in English or French. Additional condition-specific eligibility criteria were also applied. Titles and abstracts were screened by one reviewer with excluded records verified by a second reviewer. Full-text reports were screened independently by two reviewers. Disagreements were resolved by consensus or third party adjudication. Systematic reviews were quality appraised using the AMSTAR criteria, with only moderate and high quality reviews considered for inclusion. Primary studies were also sought to ensure that evidence from existing systematic reviews was supplemented with recent primary study findings (i.e., those published after the most recent systematic review). Evidence from primary studies was also considered if a systematic review was unavailable or of poor quality. Data were extracted using standardized forms. Where feasible, data were extracted independently by two reviewers. Otherwise, data were extracted by a single reviewer and independent data extraction by a second reviewer was conducted for a randomly selected sample of studies. An updated search was conducted in 2016 to identify systematic reviews published since the initial search in 2011-2013. A summary of the methodology used to conduct the systematic reviews is described. Illustrative results are provided for the risk of amyotrophic lateral sclerosis in relation to occupational exposure to lead and other heavy metals.}, }
@article {pmid27373243, year = {2016}, author = {Wilden, SM and Lang, BM and Mohr, P and Grabbe, S}, title = {Checkpoint-Inhibitoren in der Immuntherapie: Ein Meilenstein in der Behandlung des malignen Melanoms.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14}, number = {7}, pages = {685-697}, doi = {10.1111/ddg.13012_g}, pmid = {27373243}, issn = {1610-0387}, mesh = {Humans ; *Immunotherapy ; Melanoma/*drug therapy ; Skin Neoplasms/*drug therapy ; }, abstract = {Seit Jahrzehnten ist bekannt, dass Tumoren vom Immunsystem erkannt und zerstört werden können. Diese, vor allem in Tierversuchen gewonnene Erkenntnis konnte jedoch in der Vergangenheit nicht zum Nutzen unserer Patienten umgesetzt werden, da immunonkologische Therapieansätze in den letzten Jahrzehnten in der Anwendung beim Menschen stets versagt haben. Daher hat, mit Ausnahme der adjuvanten Interferontherapie, keines dieser Verfahren den Einzug in die klinische Versorgung gefunden. Langzeitüberleben unter guter Lebensqualität war dabei sehr wenigen Patienten vorbehalten. Mit den neuen immunologischen Therapieansätzen wird jedoch sowohl das Langzeitüberleben als auch die Lebensqualität onkologischer Patienten neu definiert. Auf die neuen "Immun-Checkpoint-Inhibitoren" spricht erstmals ein relevanter Teil der behandelten Patienten an und diese zeigen in der Regel langandauernde Remissionen bis hin zur Heilung. Schon jetzt ist klar, dass die Immuntherapie in Zukunft eine der wesentlichen Therapiesäulen bei der Behandlung des metastasierten Melanoms und auch vieler anderer fortgeschrittener Tumoren bilden wird. In dieser Übersicht werden die wichtigsten neuen Therapiemodalitäten besprochen und sowohl deren Wirkprinzip als auch klinische Daten zum Therapieansprechen und zu erwartenden Nebenwirkungen der Therapie referiert.}, }
@article {pmid27372371, year = {2016}, author = {Kumar, V and Islam, A and Hassan, MI and Ahmad, F}, title = {Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning.}, journal = {European journal of medicinal chemistry}, volume = {121}, number = {}, pages = {903-917}, doi = {10.1016/j.ejmech.2016.06.017}, pmid = {27372371}, issn = {1768-3254}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/*therapy ; Animals ; Drug Evaluation, Preclinical ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle weakness, paralysis and finally death. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and proteasomal dysfunction. Although numerous pathological mechanisms have been explained, ALS remains incurable disease because of failure of clinical trials and lack of any effective therapy. The rapid advancement in genetic discoveries in ALS emphasizes the point that ALS is a multi-subtype syndrome rather than a single disease. This can be argued as one of the single reason why many previous therapeutic drug trials have failed. Efforts to develop novel ALS treatments which target specific pathomechanisms are currently being pursued. Herein, we review the recent discovery and preclinical characterization of neuroprotective compounds and compare their effects on disease onset, duration and survival. Furthermore, the structure-activity relationships of these agents are analyzed with the overall goal of developing a screening strategy for future clinical applications.}, }
@article {pmid27370940, year = {2016}, author = {Libro, R and Bramanti, P and Mazzon, E}, title = {The role of the Wnt canonical signaling in neurodegenerative diseases.}, journal = {Life sciences}, volume = {158}, number = {}, pages = {78-88}, doi = {10.1016/j.lfs.2016.06.024}, pmid = {27370940}, issn = {1879-0631}, mesh = {Humans ; Neurodegenerative Diseases/*metabolism ; *Signal Transduction ; Wnt Proteins/*metabolism ; }, abstract = {The Wnt/β-catenin or Wnt canonical pathway controls multiple biological processes throughout development and adult life. Growing evidences have suggested that deregulation of the Wnt canonical pathway could be involved in the pathogenesis of neurodegenerative diseases. The Wnt canonical signaling is a pathway tightly regulated, which activation results in the inhibition of the Glycogen Synthase Kinase 3β (GSK-3β) function and in increased β-catenin activity, that migrates into the nucleus, activating the transcription of the Wnt target genes. Conversely, when the Wnt canonical pathway is turned off, increased levels of GSK-3β promote β-catenin degradation. Hence, GSK-3β could be considered as a key regulator of the Wnt canonical pathway. Of note, GSK-3β has also been involved in the modulation of inflammation and apoptosis, determining the delicate balance between immune tolerance/inflammation and neuronal survival/neurodegeneration. In this review, we have summarized the current acknowledgements about the role of the Wnt canonical pathway in the pathogenesis of some neurodegenerative diseases including Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, with particular regard to the main in vitro and in vivo studies in this field, by reviewing 85 research articles about.}, }
@article {pmid27370938, year = {2016}, author = {Réus, GZ and Titus, SE and Abelaira, HM and Freitas, SM and Tuon, T and Quevedo, J and Budni, J}, title = {Neurochemical correlation between major depressive disorder and neurodegenerative diseases.}, journal = {Life sciences}, volume = {158}, number = {}, pages = {121-129}, doi = {10.1016/j.lfs.2016.06.027}, pmid = {27370938}, issn = {1879-0631}, mesh = {Aging/metabolism ; Depressive Disorder, Major/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Major depressive disorder (MDD) is one of the most prevalent and life-threatening forms of mental illnesses affecting elderly people and has been associated with poor cognitive function. Recent evidence suggests a strong relationship between MDD and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), as well as natural processes of aging. Changes in the neuroplasticity, morphology, and neurotransmission in the brain are seem to be associated to both, MDD and neurodegenerative diseases. In addition, there is evidence that psychological stress and MDD are associated with molecular and cellular signs of accelerated aging. This review will highlight the relationship between MDD, the aging process, and neurodegenerative diseases, emphasizing the neurochemical processes involved.}, }
@article {pmid27362330, year = {2016}, author = {Garbuzova-Davis, S and Thomson, A and Kurien, C and Shytle, RD and Sanberg, PR}, title = {Potential new complication in drug therapy development for amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {16}, number = {12}, pages = {1397-1405}, pmid = {27362330}, issn = {1744-8360}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Disease Models, Animal ; Humans ; Pharmaceutical Preparations ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the brain and spinal cord. Treatment development for ALS is complicated by complex underlying disease factors. Areas covered: Numerous tested drug compounds have shown no benefits in ALS patients, although effective in animal models. Discrepant results of pre-clinical animal studies and clinical trials for ALS have primarily been attributed to limitations of ALS animal models for drug-screening studies and methodological inconsistencies in human trials. Current status of pre-clinical and clinical trials in ALS is summarized. Specific blood-CNS barrier damage in ALS patients, as a novel potential reason for the clinical failures in drug therapies, is discussed. Expert commentary: Pathological perivascular collagen IV accumulation, one unique characteristic of barrier damage in ALS patients, could be hindering transport of therapeutics to the CNS. Restoration of B-CNS-B integrity would foster delivery of therapeutics to the CNS.}, }
@article {pmid27357569, year = {2016}, author = {Courchaine, EM and Lu, A and Neugebauer, KM}, title = {Droplet organelles?.}, journal = {The EMBO journal}, volume = {35}, number = {15}, pages = {1603-1612}, pmid = {27357569}, issn = {1460-2075}, support = {T32 GM007223/GM/NIGMS NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {*Cell Physiological Phenomena ; Cytosol/*chemistry ; Macromolecular Substances/*metabolism ; Multienzyme Complexes/*metabolism ; }, abstract = {Cells contain numerous, molecularly distinct cellular compartments that are not enclosed by lipid bilayers. These compartments are implicated in a wide range of cellular activities, and they have been variously described as bodies, granules, or organelles. Recent evidence suggests that a liquid-liquid phase separation (LLPS) process may drive their formation, possibly justifying the unifying term "droplet organelle". A veritable deluge of recent publications points to the importance of low-complexity proteins and RNA in determining the physical properties of phase-separated structures. Many of the proteins linked to such structures are implicated in human diseases, such as amyotrophic lateral sclerosis (ALS). We provide an overview of the organizational principles that characterize putative "droplet organelles" in healthy and diseased cells, connecting protein biochemistry with cell physiology.}, }
@article {pmid27357213, year = {2016}, author = {Leman, P and Morley, P}, title = {Review article: Updated resuscitation guidelines for 2016: A summary of the Australian and New Zealand Committee on Resuscitation recommendations.}, journal = {Emergency medicine Australasia : EMA}, volume = {28}, number = {4}, pages = {379-382}, doi = {10.1111/1742-6723.12638}, pmid = {27357213}, issn = {1742-6723}, mesh = {Australia ; Evidence-Based Medicine ; Humans ; New Zealand ; Resuscitation/*standards ; }, abstract = {This review paper summarises the key changes made to the resuscitation guidelines used in Australia and New Zealand. They were released by the Australian and New Zealand Committee on Resuscitation in January 2016. These are local adaptations of the evidence previously published in October 2015 by the International Liaison Committee on Resuscitation (ILCOR). They are presented across the main working groups in ILCOR: ALS, BLS, paediatrics, neonates, acute coronary syndromes, first aid and 'Education, Implementation and Teams'.}, }
@article {pmid27356602, year = {2016}, author = {Gajowiak, A and Styś, A and Starzyński, RR and Staroń, R and Lipiński, P}, title = {Misregulation of iron homeostasis in amyotrophic lateral sclerosis.}, journal = {Postepy higieny i medycyny doswiadczalnej (Online)}, volume = {70}, number = {0}, pages = {709-721}, doi = {10.5604/17322693.1208036}, pmid = {27356602}, issn = {1732-2693}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Cell Death ; Central Nervous System/metabolism/physiopathology ; *Homeostasis ; Humans ; Iron/*metabolism/physiology ; Motor Neurons/*metabolism/physiology ; Mutation ; Oxidative Stress ; Superoxide Dismutase/*genetics ; }, abstract = {Iron is essential for all mammalian cells, but it is toxic in excess. Our understanding of molecular mechanisms ensuring iron homeostasis at both cellular and systemic levels has dramatically increased over the past 15 years. However, despite major advances in this field, homeostatic regulation of iron in the central nervous system (CNS) requires elucidation. It is unclear how iron moves in the CNS and how its transfer to the CNS across the blood-brain and the blood-cerebrospinal fluid barriers, which separate the CNS from the systemic circulation, is regulated. Increasing evidence indicates the role of iron dysregulation in neuronal cell death observed in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder characterized by selective cortical czynand spinal motor neuron dysfunction that results from a complex interplay among various pathogenic factors including oxidative stress. The latter is known to strongly affect cellular iron balance, creating a vicious circle to exacerbate oxidative injury. The role of iron in the pathogenesis of ALS is confirmed by therapeutic effects of iron chelation in ALS mouse models. These models are of great importance for deciphering molecular mechanisms of iron accumulation in neurons. Most of them consist of transgenic rodents overexpressing the mutated human superoxide dismutase 1 (SOD1) gene. Mutations in the SOD1 gene constitute one of the most common genetic causes of the inherited form of ALS. However, it should be considered that overexpression of the SOD1 gene usually leads to increased SOD1 enzymatic activity, a condition which does not occur in human pathology and which may itself change the expression of iron metabolism genes.}, }
@article {pmid27356036, year = {2016}, author = {Blasco, H and Patin, F and Andres, CR and Corcia, P and Gordon, PH}, title = {Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection.}, journal = {Expert opinion on pharmacotherapy}, volume = {17}, number = {12}, pages = {1669-1682}, doi = {10.1080/14656566.2016.1202919}, pmid = {27356036}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/genetics ; Biomarkers/metabolism ; Clinical Trials as Topic ; Frontotemporal Dementia/diagnosis/drug therapy/genetics ; Humans ; Hydroxylamines/therapeutic use ; Memantine/therapeutic use ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics/metabolism ; Vitamin B 12/analogs &amp; derivatives/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials.<br><br>AREAS COVERED: In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS.<br><br>EXPERT OPINION: Age-related neurodegenerative disorders are fast becoming major public health problems for the world's aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.}, }
@article {pmid27352979, year = {2016}, author = {Corona, JC and Duchen, MR}, title = {PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease.}, journal = {Free radical biology &amp; medicine}, volume = {100}, number = {}, pages = {153-163}, pmid = {27352979}, issn = {1873-4596}, support = {G-1101/PUK_/Parkinson's UK/United Kingdom ; MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Disease Models, Animal ; Humans ; Huntington Disease/drug therapy/metabolism ; Mitochondria/*drug effects/metabolism/physiology ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; PPAR gamma/*pharmacology/therapeutic use ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {There is increasing evidence for the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of many of the major neurodegenerative and neuroinflammatory diseases, suggesting that mitochondrial and antioxidant pathways may represent potential novel therapeutic targets. Recent years have seen a rapidly growing interest in the use of therapeutic strategies that can limit the defects in, or even to restore, mitochondrial function while reducing free radical generation. The peroxisome proliferation-activated receptor gamma (PPARγ), a ligand-activated transcription factor, has a wide spectrum of biological functions, regulating mitochondrial function, mitochondrial turnover, energy metabolism, antioxidant defence and redox balance, immune responses and fatty acid oxidation. In this review, we explore the evidence for potential beneficial effects of PPARγ agonists in a number of neurological disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis and Huntington's disease, ischaemia, autoimmune encephalomyelitis and neuropathic pain. We discuss the mechanisms underlying those beneficial effects in particular in relation to mitochondrial function, antioxidant defence, cell death and inflammation, and suggest that the PPARγ agonists show significant promise as therapeutic agents in otherwise intractable neurological disease.}, }
@article {pmid29765840, year = {2016}, author = {Casas, C and Manzano, R and Vaz, R and Osta, R and Brites, D}, title = {Synaptic Failure: Focus in an Integrative View of ALS.}, journal = {Brain plasticity (Amsterdam, Netherlands)}, volume = {1}, number = {2}, pages = {159-175}, pmid = {29765840}, issn = {2213-6312}, abstract = {From early description by Charcot, the classification of the Amyotrophic Lateral Sclerosis (ALS) is evolving from a subtype of Motor Neuron (MN) Disease to be considered rather a multi-systemic, non-cell autonomous and complex neurodegenerative disease. In the last decade, the huge amount of knowledge acquired has shed new insights on the pathological mechanisms underlying ALS from different perspectives. However, a whole vision on the multiple dysfunctional pathways is needed with the inclusion of information often excluded in other published revisions. We propose an integrative view of ALS pathology, although centered on the synaptic failure as a converging and crucial player to the etiology of the disease. Homeostasis of input and output synaptic activity of MNs has been proved to be severely and early disrupted and to definitively contribute to microcircuitry alterations at the spinal cord. Several cells play roles in synaptic communication across the MNs network system such as interneurons, astrocytes, microglia, Schwann and skeletal muscle cells. Microglia are described as highly dynamic surveying cells of the nervous system but also as determinant contributors to the synaptic plasticity linked to neuronal activity. Several signaling axis such as TNFα/TNFR1 and CX3CR1/CX3CL1 that characterize MN-microglia cross talk contribute to synaptic scaling and maintenance, have been found altered in ALS. The presence of dystrophic and atypical microglia in late stages of ALS, with a decline in their dynamic motility and phagocytic ability, together with less synaptic and neuronal contacts disrupts the MN-microglia dialogue, decreases homeostatic regulation of neuronal activity, perturbs "on/off" signals and accelerates disease progression associated to impaired synaptic function and regeneration. Other hotspot in the ALS affected network system is the unstable neuromuscular junction (NMJ) leading to distal axonal degeneration. Reduced neuromuscular spontaneous synaptic activity in ALS mice models was also suggested to account for the selective vulnerability of MNs and decreased regenerative capability. Synaptic destabilization may as well derive from increased release of molecules by muscle cells (e.g. NogoA) and by terminal Schwann cells (e.g. semaphorin 3A) conceivably causing nerve terminal retraction and denervation, as well as inhibition of re-connection to muscle fibers. Indeed, we have overviewed the alterations on the metabolic pathways and self-regenerative capacity presented in skeletal muscle cells that contribute to muscle wasting in ALS. Finally, a detailed footpath of pathologic changes on MNs and associated dysfunctional and synaptic alterations is provided. The oriented motivation in future ALS studies as outlined in the present article will help in fruitful novel achievements on the mechanisms involved and in developing more target-driven therapies that will bring new hope in halting or delaying disease progression in ALS patients.}, }
@article {pmid27352114, year = {2017}, author = {Duong, MT and Bingham, BA and Aldana, PC and Chung, ST and Sumner, AE}, title = {Variation in the Calculation of Allostatic Load Score: 21 Examples from NHANES.}, journal = {Journal of racial and ethnic health disparities}, volume = {4}, number = {3}, pages = {455-461}, pmid = {27352114}, issn = {2196-8837}, support = {Z01 DK047023-07//Intramural NIH HHS/United States ; }, mesh = {Allostasis/immunology/*physiology ; Biomarkers/metabolism ; Blood Pressure/immunology/physiology ; C-Reactive Protein/immunology/metabolism ; Health Surveys/*methods ; Humans ; RNA-Binding Proteins/immunology/metabolism ; Stress, Psychological/immunology/metabolism ; United States ; }, abstract = {After decades of resistance, there is now a genuine consensus that disease cannot be prevented or even successfully treated unless the role of stress is addressed alongside traditionally recognized factors such as genes and the environment. Measurement of allostatic load, which is quantified by the allostatic load score (ALS), is one of the most frequently used methods to assess the physiologic response to stress. Even though there is universal agreement that in the calculation of ALS, biomarkers from three categories should be included (cardiovascular, metabolic and immune), enormous variation exists in how ALS is calculated. Specifically, there is no consensus on which biomarkers to include or the method which should be used to determine whether the value of a biomarker represents high risk. In this perspective, we outline the approach taken in 21 different NHANES studies.}, }
@article {pmid27352074, year = {2016}, author = {Li, W and Tong, HI and Gorantla, S and Poluektova, LY and Gendelman, HE and Lu, Y}, title = {Neuropharmacologic Approaches to Restore the Brain's Microenvironment.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {11}, number = {3}, pages = {484-494}, pmid = {27352074}, issn = {1557-1904}, support = {R01 NS036126/NS/NINDS NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; P30 MH062261/MH/NIMH NIH HHS/United States ; P01 NS031492/NS/NINDS NIH HHS/United States ; R13 DA035084/DA/NIDA NIH HHS/United States ; R01 MH079717/MH/NIMH NIH HHS/United States ; P01 MH064570/MH/NIMH NIH HHS/United States ; R01 AG043540/AG/NIA NIH HHS/United States ; P30 GM103509/GM/NIGMS NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; R24 OD018546/OD/NIH HHS/United States ; R21 DA041018/DA/NIDA NIH HHS/United States ; P01 DA028555/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Brain/*drug effects/*metabolism/pathology ; Cellular Microenvironment/*drug effects/physiology ; Central Nervous System Agents/pharmacology/therapeutic use ; Genetic Therapy/methods/trends ; Humans ; Immunotherapy/methods/trends ; Neurodegenerative Diseases/*drug therapy/*metabolism/pathology ; }, abstract = {Maintaining the central nervous system microenvironment after injury, infection, inflammatory and degenerative diseases is contingent upon adequate control of glial homeostatic functions. Disease is caused by microbial, environmental and endogenous factors that compromise ongoing nervous system functions. The final result is neuronal injury, dropout and nerve connection loss, and these underlie the pathobiology of Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, stroke, and bacterial, parasitic and viral infections. However, what promotes disease are homeostatic changes in the brain's microenvironment affected by innate glial immune pro-inflammatory and adaptive immune responses. These events disturb the brain's metabolic activities and communication abilities. How the process affects the brain's regulatory functions that can be harnessed for therapeutic gain is the subject at hand. Specific examples are provided that serve to modulate inflammation and improve disease outcomes specifically for HIV-associated neurocognitive disorders.}, }
@article {pmid27349438, year = {2017}, author = {Mis, MSC and Brajkovic, S and Tafuri, F and Bresolin, N and Comi, GP and Corti, S}, title = {Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders.}, journal = {Molecular neurobiology}, volume = {54}, number = {6}, pages = {4466-4476}, pmid = {27349438}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; C9orf72 Protein/*genetics ; Frontotemporal Dementia/genetics/*therapy ; Genetic Therapy ; Humans ; Oligonucleotides, Antisense/therapeutic use ; RNA Interference ; }, abstract = {The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we discuss the most promising progress that has been achieved to date in the field.}, }
@article {pmid27343997, year = {2016}, author = {Ray, RS and Katyal, A}, title = {Myeloperoxidase: Bridging the gap in neurodegeneration.}, journal = {Neuroscience and biobehavioral reviews}, volume = {68}, number = {}, pages = {611-620}, doi = {10.1016/j.neubiorev.2016.06.031}, pmid = {27343997}, issn = {1873-7528}, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Astrocytes ; *Neurodegenerative Diseases ; Peroxidase/*metabolism ; }, abstract = {Neurodegenerative conditions present a group of complex disease pathologies mostly due to unknown aetiology resulting in neuronal death and permanent neurological disability. Any undesirable stress to the brain, disrupts homeostatic balance, through a remarkable convergence of pathophysiological changes and immune dysregulation. The crosstalk between inflammatory and oxidative mechanisms results in the release of neurotoxic mediators apparently spearheaded by myeloperoxidase derived from activated microglia, astrocytes, neurons as well as peripheral inflammatory cells. These isolated entities combinedly have the potential to flare up and contribute significantly to neuropathology and disease progression. Recent, clinicopathological evidence support the association of myeloperoxidase and its cytotoxic product, hypochlorous acid in a plethora of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, Stroke, Epilepsy etc. But the biochemical and mechanistic insights into myeloperoxidase mediated neuroinflammation and neuronal death is still an uncharted territory. The current review outlines the emerging recognition of myeloperoxidase in neurodegeneration, which may offer novel therapeutic and diagnostic targets for neurodegenerative disorders.}, }
@article {pmid27338628, year = {2016}, author = {Riva, P and Ratti, A and Venturin, M}, title = {The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis.}, journal = {Current Alzheimer research}, volume = {13}, number = {11}, pages = {1219-1231}, doi = {10.2174/1567205013666160622112234}, pmid = {27338628}, issn = {1875-5828}, mesh = {Gene Expression Regulation/*genetics ; Humans ; Neurodegenerative Diseases/*genetics/*pathology ; Proteasome Endopeptidase Complex/*genetics ; RNA, Long Noncoding/*genetics ; }, abstract = {BACKGROUND: Long-non-coding RNAs (lncRNAs), RNA molecules longer than 200 nucleotides, have been involved in several biological processes and in a growing number of diseases, controlling gene transcription, pre-mRNA processing, the transport of mature mRNAs to specific cellular compartments, the regulation of mRNA stability, protein translation and turnover. The fundamental role of lncRNAs in central nervous system (CNS) is becoming increasingly evident. LncRNAs are abundantly expressed in mammalian CNS in a specific spatio-temporal manner allowing a quick response to environmental/molecular changes.<br><br>METHODS: This article reviews the biology and mechanisms of action of lncRNAs underlying their potential role in CNS and in some neurodegenerative diseases.<br><br>RESULTS: an increasing number of studies report on lncRNAs involvement in different molecular mechanisms of gene expression modulation in CNS, from neural stem cell differentiation mainly by chromatin remodeling, to control of neuronal activities. More recently, lncRNAs have been implicated in neurodegenerative diseases, including Alzheimer's Disease, where the role of BACE1-AS lncRNA has been widely defined. BACE1-AS levels are up-regulated in AD brains where BACE1-AS acts by stabilizing BACE1 mRNA thereby increasing BACE1 protein content and A&#x3b2;42 formation. In Frontotemporal dementia and Amyotrophic lateral sclerosis the lncRNAs NEAT1_2 and MALAT1 co-localize at nuclear paraspeckles with TDP-43 and FUS proteins and their binding to TDP-43 is markedly increased in affected brains. In Parkinson's Disease the lncRNA UCHL1-AS1 acts by directly promoting translation of UCHL1 protein leading to perturbation of the ubiquitin-proteasome system. Different lncRNAs, such as HTT-AS, BDNF-AS and HAR1, were found to be dysregulated in their expression also in Huntington's Disease. In Fragile X syndrome (FXS) and Fragile X tremor/ataxia syndrome (FXTAS) patients, the presence of CGG repeats expansion alters the expression of the lncRNAs FMR1-AS1 and FMR6. Interestingly, they are expressed in peripheral blood leukocytes, suggesting these lncRNAs may represent biomarkers for FXS/FXTAS early detection and therapy. Finally, the identification of the antisense RNAs SCAANT1-AS and ATXN8OS in spinocerebellar ataxia 7 and 8, respectively, suggests that very different mechanisms of action driven by lncRNAs may trigger neurodegeneration in these disorders.<br><br>CONCLUSION: The emerging role of lncRNAs in neurodegenerative diseases suggests that their dysregulation could trigger neuronal death via still unexplored RNA-based regulatory mechanisms which deserve further investigation. The evaluation of their diagnostic significance and therapeutic potential could also address the setting up of novel treatments in diseases where no cure is available to date.}, }
@article {pmid27335539, year = {2016}, author = {Deng, P and Torrest, A and Pollock, K and Dahlenburg, H and Annett, G and Nolta, JA and Fink, KD}, title = {Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells.}, journal = {Neural regeneration research}, volume = {11}, number = {5}, pages = {702-705}, pmid = {27335539}, issn = {1673-5374}, support = {F32 NS090722/NS/NINDS NIH HHS/United States ; R01 GM099688/GM/NIGMS NIH HHS/United States ; T32 GM099608/GM/NIGMS NIH HHS/United States ; }, abstract = {Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells (MSC) to secrete brain-derived neurotrophic factor (BDNF) supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington's disease (HD). There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease, and some forms of Parkinson's disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system.}, }
@article {pmid27333827, year = {2016}, author = {Mathews, PM and Levy, E}, title = {Cystatin C in aging and in Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {32}, number = {}, pages = {38-50}, pmid = {27333827}, issn = {1872-9649}, support = {P01 AG017617/AG/NIA NIH HHS/United States ; R01 AG037693/AG/NIA NIH HHS/United States ; R01 NS042029/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/*physiology ; *Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Autophagy/physiology ; Brain/*metabolism ; Cystatin C/*metabolism ; Humans ; Nerve Degeneration/*metabolism ; Protective Factors ; }, abstract = {Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer's disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.}, }
@article {pmid27333745, year = {2016}, author = {Hattori, Y and Ihara, M}, title = {[SIRT1].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {74}, number = {4}, pages = {589-594}, pmid = {27333745}, issn = {0047-1852}, mesh = {Acetylation ; Animals ; Anti-Inflammatory Agents ; Apoptosis/drug effects ; Cerebral Infarction/*genetics/*therapy ; Dementia, Vascular/genetics/therapy ; Drug Discovery ; Humans ; Mice ; *Molecular Targeted Therapy ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Sirtuin 1/metabolism/pharmacology/*physiology ; }, abstract = {Silent information regulator 2 homolog 1 (SIRT1), a product of the so called "longevity gene", is a protein deacetylase that has been reported to suppress cardiovascular pathologies such as myocardial infarction, and neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease via anti-apoptosis, anti-inflammation, or increasing mitochondrial biogenesis in model organisms. In addition, SIRT1 can counter cerebral hypoperfusion and ischemia through deacetylating anti-inflammatory and anti-apoptotic molecules and also through deacetylating endothelial nitric oxide synthase and inducing arterial dilation. Since cerebral hypoperfusion/ischemia, inflammation, and apoptosis can induce vascular cognitive impairment, SIRT1 potentiation may provide molecular targets for future therapeutic intervention of vascular cognitive impairment and cerebral infarction.}, }
@article {pmid27326363, year = {2016}, author = {Ghasemi, M}, title = {Amyotrophic lateral sclerosis mimic syndromes.}, journal = {Iranian journal of neurology}, volume = {15}, number = {2}, pages = {85-91}, pmid = {27326363}, issn = {2008-384X}, abstract = {Amyotrophic lateral sclerosis (ALS) misdiagnosis has many broad implications for the patient and the neurologist. Potentially curative treatments exist for certain ALS mimic syndromes, but delay in starting these therapies may have an unfavorable effect on outcome. Hence, it is important to exclude similar conditions. In this review, we discuss some of the important mimics of ALS.}, }
@article {pmid29546172, year = {2016}, author = {Sc, Y and Muralidhara, }, title = {Beneficial Role of Coffee and Caffeine in Neurodegenerative Diseases: A Minireview.}, journal = {AIMS public health}, volume = {3}, number = {2}, pages = {407-422}, pmid = {29546172}, issn = {2327-8994}, abstract = {Coffee is among the most widespread and healthiest beverages in the world. Coffee typically contains more caffeine than most other beverages, and is widely and frequently consumed. Thus, it contributes significantly to the overall caffeine consumption within the general population, particularly in adults. Controversies regarding its benefits and risks still exist as reliable evidence is becoming available supporting its health-promoting potential. Several lines of evidence have highlighted the beneficial effects towards several disease conditions including Type II diabetes, hepatitis C virus, hepatocellular carcinoma, nonalcoholic fatty liver disease and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The health-promoting properties of coffee are largely attributed to its rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, and hydroxy hydroquinone. In this minireview, an attempt has been made to discuss the various evidences which are mainly derived from animal and cell models. Various mechanisms chiefly responsible for the beneficial effects of caffeine have also been briefly outlined. A short note on the undesirable effects of excessive coffee intakes is also presented.}, }
@article {pmid27314534, year = {2016}, author = {Noto, Y and Shibuya, K and Vucic, S and Kiernan, MC}, title = {Novel therapies in development that inhibit motor neuron hyperexcitability in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {16}, number = {10}, pages = {1147-1154}, doi = {10.1080/14737175.2016.1197774}, pmid = {27314534}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Antipyrine/analogs &amp; derivatives/therapeutic use ; Edaravone ; Humans ; Motor Neurons/*drug effects ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron hyperexcitability appears linked to the process of neurodegeneration in amyotrophic lateral sclerosis (ALS). As such, therapies that inhibit neuronal hyperexcitability may prove effective in arresting the progression of ALS.<br><br>AREA COVERED: We searched MEDLINE and ClinicalTrials.gov and selected randomised controlled trials that covered neuroprotective therapy. Riluzole has been established to reduce neuronal hyperexcitability. More recently, initial studies of Na(+) channel blockers (mexiletine and flecainide) have been trialled. Separately, a trial of a K(+) channel activator (retigabine) is underway, while edaravone is currently being considered for licensing by drug approval agencies based on a hypothesis that the elimination of free radicals may lead to protection of motor neurones. Expert commentary: Initial clinical trials with Na(+) channel blockers have not yet established efficacy in ALS. Currently, retigabine is under evaluation as a potential therapy. Edaravone has recently been approved as a new therapeutic option for ALS in Japan.}, }
@article {pmid27311820, year = {2016}, author = {Karlsson, O and Lindquist, NG}, title = {Melanin and neuromelanin binding of drugs and chemicals: toxicological implications.}, journal = {Archives of toxicology}, volume = {90}, number = {8}, pages = {1883-1891}, doi = {10.1007/s00204-016-1757-0}, pmid = {27311820}, issn = {1432-0738}, mesh = {Animals ; Antipsychotic Agents/metabolism/*toxicity ; Environmental Pollutants/metabolism/*toxicity ; Humans ; Melanins/*metabolism ; Neurons/drug effects/metabolism/pathology ; Parkinson Disease, Secondary/*chemically induced/metabolism/pathology ; Protein Binding ; Retinal Pigment Epithelium/*drug effects/metabolism/pathology ; alpha-Synuclein/biosynthesis ; }, abstract = {Melanin is a polyanionic pigment that colors, e.g., the hair, skin and eyes. The pigment neuromelanin is closely related to melanin and is mainly produced in specific neurons of the substantia nigra. Certain drugs and chemicals bind to melanin/neuromelanin and are retained in pigment cells for long periods. This specific retention is thought to protect the cells but also to serve as a depot that slowly releases accumulated compounds and may cause toxicity in the eye and skin. Moreover, neuromelanin and compounds with high neuromelanin affinity have been suggested to be implicated in the development of adverse drug reactions in the central nervous system (CNS) as well as in the etiology of Parkinson's disease (PD). Epidemiologic studies implicate the exposure to pesticides, metals, solvents and other chemicals as risk factors for PD. Neuromelanin interacts with several of these toxicants which may play a significant part in both the initiation and the progression of neurodegeneration. MPTP/MPP(+) that has been casually linked with parkinsonism has high affinity for neuromelanin, and the induced dopaminergic denervation correlates with the neuromelanin content in the cells. Recent studies have also reported that neuromelanin may interact with α-synuclein as well as activate microglia and dendritic cells. This review aims to provide an overview of melanin binding of drugs and other compounds, and possible toxicological implications, with particular focus on the CNS and its potential involvement in neurodegenerative disorders.}, }
@article {pmid27311318, year = {2017}, author = {Furukawa, Y and Tokuda, E}, title = {Aggregation of FET Proteins as a Pathological Change in Amyotrophic Lateral Sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {925}, number = {}, pages = {1-12}, doi = {10.1007/5584_2016_32}, pmid = {27311318}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Calmodulin-Binding Proteins/*genetics/metabolism ; Cell Nucleus/metabolism ; Cytosol/metabolism ; Gene Expression Regulation ; Humans ; Inclusion Bodies/chemistry/pathology ; Mutation ; Neurons/metabolism/pathology ; Protein Aggregates/genetics ; Protein Aggregation, Pathological/*genetics/metabolism/pathology ; RNA-Binding Protein EWS ; RNA-Binding Protein FUS/*genetics/metabolism ; RNA-Binding Proteins/*genetics/metabolism ; Signal Transduction ; TATA-Binding Protein Associated Factors/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that is characterized by the formation of abnormal inclusions in neurons. While the pathomechanism of ALS remains obscure, a number of proteins have been identified in the inclusion bodies, and the pathological roles of RNA-binding proteins have been increasingly emphasized. Among those, the FET proteins (FUS, EWSR1, TAF15) were recently identified as RNA-binding proteins in pathological inclusions of ALS and other neurodegenerative diseases; moreover, mutations in the genes encoding the FET proteins were found to be associated with familial forms of ALS. FET proteins are normally localized in the nucleus, but the introduction of pathogenic mutations in FET proteins leads to their abnormal redistribution to the cytoplasm, where they form aggregates. While further investigation will be required to understand the intracellular factors controlling the aggregation propensities of FET proteins, they are thought to lose their physiological functions and become toxic through their misfolding/aggregation. Here, we will briefly review recent advances of our understanding of the physiological functions and aggregation behavior of FET proteins in vivo as well as in vitro.}, }
@article {pmid27302727, year = {2016}, author = {Huang, Z and Adachi, H}, title = {Natural Compounds Preventing Neurodegenerative Diseases Through Autophagic Activation.}, journal = {Journal of UOEH}, volume = {38}, number = {2}, pages = {139-148}, doi = {10.7888/juoeh.38.139}, pmid = {27302727}, issn = {0387-821X}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis ; Autophagy/*drug effects ; Humans ; Huntington Disease/pathology ; Machado-Joseph Disease/pathology ; Muscular Disorders, Atrophic/pathology ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/pathology ; Plant Extracts/*pharmacology ; }, abstract = {Neurodegenerative diseases (NDDs) are a group of intractable diseases that significantly affect human health. To date, the pathogenesis of NDDs is still poorly understood and effective disease-modifying therapies for NDDs have not been established. NDDs share the common morphological characteristic of the deposition of abnormal proteins in the nervous system, including neurons. Autophagy is one of the major processes by which damaged organelles and abnormal proteins are removed from cells. Impairment of autophagy has been found to be involved in the pathogenesis of NDDs, and the regulation of autophagy may become a therapeutic strategy for NDDs. In recent years, some active compounds from plants have been found to regulate autophagy and exert neuroprotection against NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia 3, and amyotrophic lateral sclerosis, via activating autophagy. In this paper, we review recent advances in the use of active ingredients from plants for the regulation of autophagy and treatment of NDDs.}, }
@article {pmid27298447, year = {2016}, author = {Pulst, SM}, title = {Degenerative ataxias, from genes to therapies: The 2015 Cotzias Lecture.}, journal = {Neurology}, volume = {86}, number = {24}, pages = {2284-2290}, pmid = {27298447}, issn = {1526-632X}, mesh = {Animals ; Humans ; Spinocerebellar Ataxias/*genetics/physiopathology/*therapy ; }, abstract = {OBJECTIVE: To review progress in spinocerebellar ataxias (SCAs) and novel approaches to treatment.<br><br>RESULTS AND CONCLUSIONS: Autosomal dominant ataxias are now referred to as SCAs, with polyglutamine expansion mutations constituting the most common cause of SCAs. Phenotypic variation in patients with SCA is remarkable even in patients with identical mutations. In patients with SCA2, cerebellar ataxia is typically associated with slowed saccadic eye movements. In addition to classic cerebellar and brainstem signs, however, SCA2 can also present as a parkinsonian syndrome or as amyotrophic lateral sclerosis. After identifying the SCA2 gene (gene symbol ATXN2) in 1996, we generated several mouse models that recapitulated salient features of the human disease. In these models, behavioral and physiologic changes preceded cell death. Modified antisense oligonucleotides (ASOs) provide a unique tool to target mRNA transcripts in vivo with extended stability of ASOs and better activation of RNAse H. We generated methoxyethyl group-gapmer ASOs that reduced ATXN2 expression >80% in vitro and then progressed the lead ASO to in vivo testing in an SCA2 mouse model. Compared to intraventricular injection of saline, treatment with ASO resulted in significant knockdown of endogenous mouse and human transgenic ATXN2. In addition, progression of the motor phenotype was slowed and Purkinje cell firing in the acute cerebellar slice normalized. ASO-based therapies are underway in humans providing hope that this approach will also be applicable to patients with cerebellar degenerations.}, }
@article {pmid27293325, year = {2016}, author = {Verma, A}, title = {Prions, prion-like prionoids, and neurodegenerative disorders.}, journal = {Annals of Indian Academy of Neurology}, volume = {19}, number = {2}, pages = {169-174}, pmid = {27293325}, issn = {0972-2327}, abstract = {Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn)-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like "prionoids" are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.}, }
@article {pmid27291884, year = {2016}, author = {Huynh, W and Simon, NG and Grosskreutz, J and Turner, MR and Vucic, S and Kiernan, MC}, title = {Assessment of the upper motor neuron in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {127}, number = {7}, pages = {2643-2660}, doi = {10.1016/j.clinph.2016.04.025}, pmid = {27291884}, issn = {1872-8952}, support = {SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/diagnostic imaging/*physiopathology ; Diffusion Tensor Imaging ; H-Reflex ; Humans ; Magnetic Resonance Imaging ; Motor Neurons/*physiology ; Positron-Emission Tomography ; Transcranial Magnetic Stimulation ; }, abstract = {Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS.}, }
@article {pmid27291591, year = {2016}, author = {Preza, E and Hardy, J and Warner, T and Wray, S}, title = {Review: Induced pluripotent stem cell models of frontotemporal dementia.}, journal = {Neuropathology and applied neurobiology}, volume = {42}, number = {6}, pages = {497-520}, doi = {10.1111/nan.12334}, pmid = {27291591}, issn = {1365-2990}, support = {//Medical Research Council/United Kingdom ; }, mesh = {*Frontotemporal Dementia ; Humans ; In Vitro Techniques ; *Induced Pluripotent Stem Cells ; *Models, Biological ; }, abstract = {The increasing prevalence of dementia in the ageing population combined with the lack of treatments and the burden on national health care systems globally make dementia a public health priority. Despite the plethora of important research findings published over the past two decades, the mechanisms underlying dementia are still poorly understood and the progress in pharmacological interventions is limited. Recent advances in cellular reprogramming and genome engineering technologies offer an unprecedented new paradigm in disease modeling. Induced pluripotent stem cells (iPSCs) have enabled the study of patient-derived neurons in vitro, a significant progress in the field of dementia research. The first studies using iPSCs to model dementia have recently emerged, holding promise for elucidating disease pathogenic mechanisms and accelerating drug discovery. In this review, we summarize the major findings of iPSC-based studies in frontotemporal dementia (FTD) and FTD overlapping with amyotrophic lateral sclerosis (FTD/ALS). We also discuss some of the main challenges in the use of iPSCs to model complex, late-onset neurodegenerative diseases such as dementias.}, }
@article {pmid27288080, year = {2016}, author = {Tsai, GE}, title = {Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {76}, number = {}, pages = {257-309}, doi = {10.1016/bs.apha.2016.03.003}, pmid = {27288080}, issn = {1557-8925}, mesh = {Alzheimer Disease/physiopathology ; Animals ; Central Nervous System Diseases/*physiopathology ; Cognition/physiology ; D-Amino-Acid Oxidase/metabolism ; Humans ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Schizophrenia/physiopathology ; Synaptic Transmission/physiology ; }, abstract = {N-Methyl-d-aspartate receptors (NMDARs) are broadly distributed in the central nervous system (CNS), where they mediate excitatory signaling. NMDAR-mediated neurotransmission (NMDARMN) is the molecular engine of learning, memory and cognition, which are the basis for high cortical function. NMDARMN is also critically involved in the development and plasticity of CNS. Due to its essential and critical role, either over- or under-activation of NMDARMN can contribute substantially to the development of CNS disorders. The involvement of NMDARMN has been demonstrated in a variety of CNS disorders, including schizophrenia, depression, posttraumatic stress disorder, aging, mild cognitive impairment and Alzheimer's dementia, amyotrophic lateral sclerosis, and anti-NMDAR encephalitis. Several targets to "correct" or "reset" the NMDARMN in these CNS disorders have been identified and confirmed. With analogy to aminergic treatments, these targets include the glycine/d-serine co-agonist site, channel ionophore, glycine transporter-1, and d-amino acid oxidase. It is still early days in terms of developing novel therapeutics targeting the NMDAR. However, agents modulating NMDARMN hold promise as the next generation of CNS therapeutics.}, }
@article {pmid27286578, year = {2016}, author = {Bohl, D}, title = {[Neuronal cells derived from induced pluripotent stem cells to model motoneuron diseases].}, journal = {Biologie aujourd'hui}, volume = {210}, number = {1}, pages = {27-36}, doi = {10.1051/jbio/2016004}, pmid = {27286578}, issn = {2105-0686}, mesh = {Amyotrophic Lateral Sclerosis/pathology/therapy ; *Cell Differentiation ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Models, Biological ; Motor Neuron Disease/*pathology/therapy ; Motor Neurons/*physiology ; Muscular Atrophy, Spinal/pathology/therapy ; Neural Stem Cells/physiology ; Neuroglia/physiology ; }, abstract = {Among motor neuron diseases, spinal muscular atrophy type 1 and amyotrophic lateral sclerosis are very aggressive diseases with no cure. With the breakthrough of human induced pluripotent stem cells, iPS, researchers have now at their disposal a powerful tool to generate human motor neurons in culture and study the pathological defects in patient cells. In this review, we will see which tools for the study of patients motoneurons were developed from iPS cells and the different cellular models that were generated. We will also see how these models were validated and current research to identify new therapeutic leads.}, }
@article {pmid27282474, year = {2016}, author = {Belzil, VV and Katzman, RB and Petrucelli, L}, title = {ALS and FTD: an epigenetic perspective.}, journal = {Acta neuropathologica}, volume = {132}, number = {4}, pages = {487-502}, pmid = {27282474}, issn = {1432-0533}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Epigenesis, Genetic/*genetics ; Frontotemporal Dementia/*genetics ; Gene Expression Regulation/*genetics ; *Genetic Predisposition to Disease ; Humans ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50 % of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate, or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanucleotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. Epigenetic processes regulate DNA replication and repair, RNA transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. Transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control DNA methylation, histone modifications, and RNA editing. While the alteration of DNA methylation and histone modification has recently been reported in ALS and FTD, the assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. As the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating ALS and FTD, especially for sporadic cases. Here, we provide a review of what is currently known about altered epigenetic processes in both ALS and FTD and discuss potential therapeutic strategies targeting epigenetic mechanisms. As approximately 85 % of ALS and FTD cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the field.}, }
@article {pmid27275785, year = {2016}, author = {Blasco, H and Vourc'h, P and Pradat, PF and Gordon, PH and Andres, CR and Corcia, P}, title = {Further development of biomarkers in amyotrophic lateral sclerosis.}, journal = {Expert review of molecular diagnostics}, volume = {16}, number = {8}, pages = {853-868}, doi = {10.1080/14737159.2016.1199277}, pmid = {27275785}, issn = {1744-8352}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*genetics/*metabolism ; *Biomarkers ; Biomedical Research ; Genome-Wide Association Study ; Genomics/methods ; Humans ; Metabolomics/methods ; Multimodal Imaging ; Neuroimaging/methods ; Proteomics/methods ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an idiopathic neurodegenerative disease usually fatal in less than three years. Even if standard guidelines are available to diagnose ALS, the mean diagnosis delay is more than one year. In this context, biomarker discovery is a priority. Research has to focus on new diagnostic tools, based on combined explorations.<br><br>AREAS COVERED: In this review, we specifically focus on biology and imaging markers. We detail the innovative field of 'omics' approach and imaging and explain their limits to be useful in routine practice. We describe the most relevant biomarkers and suggest some perspectives for biomarker research. Expert commentary: The successive failures of clinical trials in ALS underline the need for new strategy based on innovative tools to stratify patients and to evaluate their responses to treatment. Biomarker data may be useful to improve the designs of clinical trials. Biomarkers are also needed to better investigate disease pathophysiology, to identify new therapeutic targets, and to improve the performance of clinical assessments for diagnosis and prognosis in the clinical setting. A consensus on the best management of neuroimaging and 'omics' methods is necessary and a systematic independent validation of findings may add robustness to future studies.}, }
@article {pmid27271576, year = {2016}, author = {Boeynaems, S and Bogaert, E and Van Damme, P and Van Den Bosch, L}, title = {Inside out: the role of nucleocytoplasmic transport in ALS and FTLD.}, journal = {Acta neuropathologica}, volume = {132}, number = {2}, pages = {159-173}, pmid = {27271576}, issn = {1432-0533}, support = {R01 NS079183/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/genetics/*physiology ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/*pathology ; Humans ; Inclusion Bodies/*pathology ; RNA-Binding Proteins/*metabolism ; }, abstract = {Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.}, }
@article {pmid27265569, year = {2017}, author = {Lee, JM and Tan, V and Lovejoy, D and Braidy, N and Rowe, DB and Brew, BJ and Guillemin, GJ}, title = {Involvement of quinolinic acid in the neuropathogenesis of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {112}, number = {Pt B}, pages = {346-364}, doi = {10.1016/j.neuropharm.2016.05.011}, pmid = {27265569}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/*pathology ; Animals ; Humans ; Kynurenine/metabolism ; Metabolic Networks and Pathways/physiology ; Quinolinic Acid/*metabolism ; Tryptophan/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by a progressive degeneration of central and peripheral motor neurons, leading to the atrophy of voluntary muscles. It has been previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in ALS. In particular, the neuroactive intermediate, quinolinic acid (QUIN) has been shown to accumulate with a concomitant decrease in other neuroprotective and immunomodulatory KP metabolites. Furthermore, multiple biochemical phenomena associated with QUIN cytotoxicity are present in ALS, suggesting that QUIN may play a substantial role in the pathogenesis of ALS. This review highlights the potential roles of QUIN in ALS, and explores KP modulation as a therapeutic candidate in ALS. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.}, }
@article {pmid27261369, year = {2016}, author = {Jaworska, E and Kozlowska, E and Switonski, PM and Krzyzosiak, WJ}, title = {Modeling simple repeat expansion diseases with iPSC technology.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {73}, number = {21}, pages = {4085-4100}, pmid = {27261369}, issn = {1420-9071}, mesh = {Animals ; Humans ; Induced Pluripotent Stem Cells/*cytology ; *Models, Biological ; Nerve Degeneration/*pathology/*therapy ; Neurons/cytology ; Stem Cell Transplantation ; Trinucleotide Repeat Expansion/*genetics ; }, abstract = {A number of human genetic disorders, including Huntington's disease, myotonic dystrophy type 1, C9ORF72 form of amyotrophic lateral sclerosis and several spinocerebellar ataxias, are caused by the expansion of various microsatellite sequences in single implicated genes. The neurodegenerative and neuromuscular nature of the repeat expansion disorders considerably limits the access of researchers to appropriate cellular models of these diseases. This limitation, however, can be overcome by the application of induced pluripotent stem cell (iPSC) technology. In this paper, we review the current knowledge on the modeling of repeat expansion diseases with human iPSCs and iPSC-derived cells, focusing on the disease phenotypes recapitulated in these models. In subsequent sections, we provide basic practical knowledge regarding iPSC generation, characterization and differentiation into neurons. We also cover disease modeling in iPSCs, neuronal stem cells and specialized neuronal cultures. Furthermore, we also summarize the therapeutic potential of iPSC technology in repeat expansion diseases.}, }
@article {pmid27255695, year = {2016}, author = {Shorter, J}, title = {Engineering therapeutic protein disaggregases.}, journal = {Molecular biology of the cell}, volume = {27}, number = {10}, pages = {1556-1560}, pmid = {27255695}, issn = {1939-4586}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/metabolism ; Protein Aggregates/drug effects/*physiology ; Protein Engineering/methods ; Protein Folding/drug effects ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD.}, }
@article {pmid27249162, year = {2016}, author = {Patten, SA and Parker, JA and Wen, XY and Drapeau, P}, title = {Simple animal models for amyotrophic lateral sclerosis drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {11}, number = {8}, pages = {797-804}, doi = {10.1080/17460441.2016.1196183}, pmid = {27249162}, issn = {1746-045X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans ; Disease Models, Animal ; Drosophila ; *Drug Design ; Drug Discovery/*methods ; Humans ; Molecular Targeted Therapy ; Zebrafish ; }, abstract = {INTRODUCTION: Simple animal models have enabled great progress in uncovering the disease mechanisms of amyotrophic lateral sclerosis (ALS) and are helping in the selection of therapeutic compounds through chemical genetic approaches.<br><br>AREAS COVERED: Within this article, the authors provide a concise overview of simple model organisms, C. elegans, Drosophila and zebrafish, which have been employed to study ALS and discuss their value to ALS drug discovery. In particular, the authors focus on innovative chemical screens that have established simple organisms as important models for ALS drug discovery.<br><br>EXPERT OPINION: There are several advantages of using simple animal model organisms to accelerate drug discovery for ALS. It is the authors' particular belief that the amenability of simple animal models to various genetic manipulations, the availability of a wide range of transgenic strains for labelling motoneurons and other cell types, combined with live imaging and chemical screens should allow for new detailed studies elucidating early pathological processes in ALS and subsequent drug and target discovery.}, }
@article {pmid27242432, year = {2016}, author = {Li, J and Zhang, L and Chu, Y and Namaka, M and Deng, B and Kong, J and Bi, X}, title = {Astrocytes in Oligodendrocyte Lineage Development and White Matter Pathology.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {119}, pmid = {27242432}, issn = {1662-5102}, abstract = {White matter is primarily composed of myelin and myelinated axons. Structural and functional completeness of myelin is critical for the reliable and efficient transmission of information. White matter injury has been associated with the development of many demyelinating diseases. Despite a variety of scientific advances aimed at promoting re-myelination, their benefit has proven at best to be marginal. Research suggests that the failure of the re-myelination process may be the result of an unfavorable microenvironment. Astrocytes, are the most ample and diverse type of glial cells in central nervous system (CNS) which display multiple functions for the cells of the oligodendrocytes lineage. As such, much attention has recently been drawn to astrocyte function in terms of white matter myelin repair. They are different in white matter from those in gray matter in specific regards to development, morphology, location, protein expression and other supportive functions. During the process of demyelination and re-myelination, the functions of astrocytes are dynamic in that they are able to change functions in accordance to different time points, triggers or reactive pathways resulting in vastly different biologic effects. They have pivotal effects on oligodendrocytes and other cell types in the oligodendrocyte lineage by serving as an energy supplier, a participant of immunological and inflammatory functions, a source of trophic factors and iron and a sustainer of homeostasis. Astrocytic impairment has been shown to be directly linked to the development of neuromyelities optica (NMO). In addition, astroctyes have also been implicated in other white matter conditions such as psychiatric disorders and neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Inhibiting specifically detrimental signaling pathways in astrocytes while preserving their beneficial functions may be a promising approach for remyelination strategies. As such, the ability to manipulate astrocyte function represents a novel therapeutic approach that can repair the damaged myelin that is known to occur in a variety of white matter-related disorders.}, }
@article {pmid27240063, year = {2016}, author = {Crisan, D and Treiber, N and Kull, T and Widschwendter, P and Adolph, O and Schneider, LA}, title = {Chirurgische Behandlung von Melanomen in der Schwangerschaft: eine praktische Anleitung.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14}, number = {6}, pages = {585-594}, doi = {10.1111/ddg.12996_g}, pmid = {27240063}, issn = {1610-0387}, mesh = {Humans ; Melanoma/*surgery ; Skin Neoplasms/*surgery ; }, abstract = {Als ein Tumor, der primär eine chirurgische Behandlung erfordert, ist ein neu diagnostiziertes oder vorbestehendes Melanom in der Schwangerschaft eine klinische Rarität. In solchen Fällen steht der Chirurg vor der Herausforderung, ein geeignetes therapeutisches Vorgehen festlegen zu müssen. Auf der Grundlage unserer klinischen Erfahrung und einer Übersicht über die Literatur geben wir in der vorliegenden Arbeit eine Anleitung für das praktische Vorgehen bei dieser seltenen klinischen Konstellation. Unserer Erfahrung nach müssen schwangere Melanom-Patientinnen im Hinblick auf ihre therapeutischen Optionen ausführlich beraten werden. Naturgemäß setzen sie ihr ungeborenes Kind an die erste Stelle und zögern, der erforderlichen Operation zuzustimmen, obwohl bei ihnen eine möglicherweise lebensbedrohliche Erkrankung diagnostiziert worden ist. Daher ist es entscheidend, diese Patientinnen klar darüber zu informieren, dass, wie die vorliegenden medizinischen Erfahrungen zeigen, eine Schwangerschaft per se kein Grund ist, eine notwendige Melanom-Operation aufzuschieben. Jedoch müssen bei einigen Parametern wie den präoperativen Bildgebungsverfahren, der Positionierung auf dem Operationstisch, der Überwachung, Anästhesie und der perioperativen Medikation bestimmte Anpassungen vorgenommen werden, um der speziellen Situation Rechnung zu tragen.}, }
@article {pmid27240061, year = {2016}, author = {Stücker, M and Debus, ES and Hoffmann, J and Jünger, M and Kröger, K and Mumme, A and Ramelet, AA and Rabe, E}, title = {Konsensuspapier zur symptomorientierten Therapie der chronischen Venenerkrankungen.}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {14}, number = {6}, pages = {575-584}, doi = {10.1111/ddg.13006_g}, pmid = {27240061}, issn = {1610-0387}, mesh = {Animals ; Combined Modality Therapy ; Complementary Therapies ; *Evidence-Based Medicine ; Female ; Germany ; Humans ; Naturopathy ; Practice Guidelines as Topic ; }, abstract = {HINTERGRUND: Chronische Venenerkrankungen sind eine Volkskrankheit. Venöse Symptome wie Schwellungs- und Schweregefühl können bereits früh ohne sichtbaren Befund auftreten und werden als belastend erlebt. Ein Fortschreiten im Sinne einer objektivierbaren Varikose bzw. chronischen venösen Insuffizienz schränkt die Lebensqualität erheblich ein.<br><br>METHODIK: Pubmed-gelistete Publikationen sowie relevante Leitlinien zur Therapie chronischer Venenkrankheiten bilden die Basis der vorliegenden Konsensusempfehlungen. Inkludiert in die Bewertung wurden ausschlie&#xdf;lich aussagekr&#xe4;ftige randomisierte Studien (RCT) und &#xdc;bersichtsarbeiten (Reviews/Metaanalysen).<br><br>ERGEBNISSE: Die symptomorientierte Behandlung chronischer Venenerkrankungen st&#xfc;tzt sich auf drei S&#xe4;ulen mit nachgewiesener Wirksamkeit: invasive Therapie, Kompressionstherapie und orale medikament&#xf6;se Therapie. Gem&#xe4;&#xdf; Empfehlungen aktueller Leitlinien sollte zun&#xe4;chst eine Sanierung des ven&#xf6;sen Gef&#xe4;&#xdf;betts erwogen werden, um einen st&#xf6;rungsfreien ven&#xf6;sen Blutfluss wiederherzustellen und Symptome und pathologische Ver&#xe4;nderungen zu beseitigen oder zu bessern. Ist ein invasiver Eingriff nicht m&#xf6;glich bzw. nicht erw&#xfc;nscht oder bestehen nach einem Eingriff noch Restsymptome, gilt es, die symptomatischen Therapieoptionen optimal auszusch&#xf6;pfen. Kompressionstherapie und medikament&#xf6;se Therapie k&#xf6;nnen allein oder in Kombination angewendet werden. Welche Strategie den gr&#xf6;&#xdf;ten Erfolg verspricht, ist individuell zu entscheiden.<br><br>SCHLUSSFOLGERUNGEN: Chronische Venenerkrankungen sollten auf der Basis der individuellen pathophysiologischen St&#xf6;rung behandelt werden. Sie symptomorientierte Behandlung chronischer Venenerkrankungen fu&#xdf;t auf der invasiven Therapie, der Kompressionstherapie und der medikament&#xf6;sen Therapie. Bei der Indikationsstellung sind objektive Symptome ebenso wie subjektive Beschwerden zu ber&#xfc;cksichtigen.}, }
@article {pmid27236050, year = {2016}, author = {Zufiría, M and Gil-Bea, FJ and Fernández-Torrón, R and Poza, JJ and Muñoz-Blanco, JL and Rojas-García, R and Riancho, J and López de Munain, A}, title = {ALS: A bucket of genes, environment, metabolism and unknown ingredients.}, journal = {Progress in neurobiology}, volume = {142}, number = {}, pages = {104-129}, doi = {10.1016/j.pneurobio.2016.05.004}, pmid = {27236050}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*genetics/*metabolism ; Animals ; *Gene-Environment Interaction ; Humans ; }, abstract = {The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed. These discoveries have enlarged an extense list of genes implicated in different cellular processes such as RNA processing or autophagia among others and have broaden the putative molecular targets of the disease. Some of ALS-related genes such as TARDBP or SOD1 among others have important roles in the regulation of glucose and fatty acids metabolism, so that an impairment of fatty acids (FA) consumption and ketogenic deficits during exercise in ALS patients would connect the physiopathology with some of the more intriguing epidemiological traits of the disease. The current understanding of ALS as part of a continuum with other neurodegenerative diseases and a crossroads between genetic, neurometabolic and environmental factors represent a fascinating model of interaction that could be translated to other neurodegenerative diseases. In this review we summarize the most relevant data obtained in the ten last years and the key lines for future research in ALS.}, }
@article {pmid30050369, year = {2016}, author = {Oliver, DJ}, title = {Palliative care for patients with motor neurone disease: current challenges.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {6}, number = {}, pages = {65-72}, pmid = {30050369}, issn = {1179-9900}, abstract = {Motor neurone disease is a progressive disease, and the patient and his/her family face many challenges during the disease progression, with increasing weakness and multiple losses of function. The provision of care for these patients and their families is equally challenging, anticipating and responding to the person's needs. There are increasing challenges as more is understood about the disease and its management, including the genetic basis, cognitive change, the use of interventions such as ventilatory support, and gastrostomy. There is also an increasing need to ensure that the later stages are recognized so that all can be more prepared for the end of life, including recognition of deterioration and end of life, advance care planning, symptom management and psychosocial care at the end of life, and coping with requests for assisted dying. Careful assessment and good multidisciplinary team (MDT) work can enable patients and their families to have as good a quality of life as possible, and allow a peaceful death of the patient.}, }
@article {pmid27213408, year = {2016}, author = {White, JA and Banerjee, R and Gunawardena, S}, title = {Axonal Transport and Neurodegeneration: How Marine Drugs Can Be Used for the Development of Therapeutics.}, journal = {Marine drugs}, volume = {14}, number = {5}, pages = {}, pmid = {27213408}, issn = {1660-3397}, support = {R03 NS084386/NS/NINDS NIH HHS/United States ; R03 NS092024/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport/drug effects/*physiology ; Humans ; Microtubules/drug effects/*physiology ; Neurodegenerative Diseases/drug therapy/*physiopathology ; Oceans and Seas ; Tubulin Modulators/pharmacology/*therapeutic use ; }, abstract = {Unlike virtually any other cells in the human body, neurons are tasked with the unique problem of transporting important factors from sites of synthesis at the cell bodies, across enormous distances, along narrow-caliber projections, to distally located nerve terminals in order to maintain cell viability. As a result, axonal transport is a highly regulated process whereby necessary cargoes of all types are packaged and shipped from one end of the neuron to the other. Interruptions in this finely tuned transport have been linked to many neurodegenerative disorders including Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) suggesting that this pathway is likely perturbed early in disease progression. Therefore, developing therapeutics targeted at modifying transport defects could potentially avert disease progression. In this review, we examine a variety of potential compounds identified from marine aquatic species that affect the axonal transport pathway. These compounds have been shown to function in microtubule (MT) assembly and maintenance, motor protein control, and in the regulation of protein degradation pathways, such as the autophagy-lysosome processes, which are defective in many degenerative diseases. Therefore, marine compounds have great potential in developing effective treatment strategies aimed at early defects which, over time, will restore transport and prevent cell death.}, }
@article {pmid27211305, year = {2016}, author = {Ahmad, L and Zhang, SY and Casanova, JL and Sancho-Shimizu, V}, title = {Human TBK1: A Gatekeeper of Neuroinflammation.}, journal = {Trends in molecular medicine}, volume = {22}, number = {6}, pages = {511-527}, pmid = {27211305}, issn = {1471-499X}, support = {MRF_C0483/MRF/MRF/United Kingdom ; R01 AI088364/AI/NIAID NIH HHS/United States ; R01 NS072381/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/immunology/*metabolism ; Autophagy ; Central Nervous System/*metabolism ; Disease Progression ; Encephalitis, Herpes Simplex/genetics/immunology/*metabolism ; Frontotemporal Dementia/genetics/*metabolism ; Gene Expression ; Humans ; Inflammation/*metabolism ; Interferons/immunology/metabolism ; Low Tension Glaucoma/genetics/immunology/*metabolism ; Mutation ; Protein Serine-Threonine Kinases/genetics/*metabolism ; }, abstract = {The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases.}, }
@article {pmid27195135, year = {2016}, author = {Le Pimpec-Barthes, F and Legras, A and Arame, A and Pricopi, C and Boucherie, JC and Badia, A and Panzini, CM}, title = {Diaphragm pacing: the state of the art.}, journal = {Journal of thoracic disease}, volume = {8}, number = {Suppl 4}, pages = {S376-86}, pmid = {27195135}, issn = {2072-1439}, abstract = {Diaphragm pacing (DP) is an orphan surgical procedure that may be proposed in strictly selected ventilator-dependent patients to get an active diaphragm contraction. The goal is to wean from mechanical ventilation (MV) and restore permanent efficient breathing. The two validated indications, despite the lack of randomised control trials, concern patients with high-level spinal cord injuries (SCI) and central hypoventilation syndromes (CHS). To date, two different techniques exist. The first, intrathoracic diaphragm pacing (IT-DP), based on a radiofrequency method, in which the electrodes are directly placed around the phrenic nerve. The second, intraperitoneal diaphragm pacing (IP-DP) uses intradiaphragmatic electrodes implanted through laparoscopy. In both techniques, the phrenic nerves must be intact and diaphragm reconditioning is always required after implantation. No perioperative mortality has been reported and ventilator-weaning rate is about 72% to 96% in both techniques. Improvement of quality of life, by restoring a more physiological breathing, has been almost constant in patients that could be weaned. Failure or delay in recovery of effective diaphragm contractions could be due to irreversible amyotrophy or chest wall damage. Recent works have evaluated the interest of IP-DP in amyotrophic lateral sclerosis (ALS). After some short series were reported in the literature, the only multicentric randomized study including 74 ALS patients was prematurely stopped because of excessive mortality in paced patients. Then, another trial analysed the place of IP-DP in peripheral diaphragm dysfunction but, given the multiple biases, the published results cannot validate that indication. Reviewing all available literature as in our experience, shows that DP is an effective method to wean selected patients dependent on ventilator and improve their daily life. Other potential indications will have to be evaluated by randomised control trials.}, }
@article {pmid27194384, year = {2016}, author = {Benatar, M and Stanislaw, C and Reyes, E and Hussain, S and Cooley, A and Fernandez, MC and Dauphin, DD and Michon, SC and Andersen, PM and Wuu, J}, title = {Presymptomatic ALS genetic counseling and testing: Experience and recommendations.}, journal = {Neurology}, volume = {86}, number = {24}, pages = {2295-2302}, pmid = {27194384}, issn = {1526-632X}, support = {U01 NS084495/NS/NINDS NIH HHS/United States ; U10 NS077423/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; Genetic Counseling/*methods ; Genetic Testing/*methods ; Humans ; Practice Guidelines as Topic ; Prodromal Symptoms ; }, abstract = {Remarkable advances in our understanding of the genetic contributions to amyotrophic lateral sclerosis (ALS) have sparked discussion and debate about whether clinical genetic testing should routinely be offered to patients with ALS. A related, but distinct, question is whether presymptomatic genetic testing should be offered to family members who may be at risk for developing ALS. Existing guidelines for presymptomatic counseling and testing are mostly based on small number of individuals, clinical judgment, and experience from other neurodegenerative disorders. Over the course of the last 8 years, we have provided testing and 317 genetic counseling sessions (including predecision, pretest, posttest, and ad hoc counseling) to 161 first-degree family members participating in the Pre-Symptomatic Familial ALS Study (Pre-fALS), as well as testing and 75 posttest counseling sessions to 63 individuals with familial ALS. Based on this experience, and the real-world challenges we have had to overcome in the process, we recommend an updated set of guidelines for providing presymptomatic genetic counseling and testing to people at high genetic risk for developing ALS. These recommendations are especially timely and relevant given the growing interest in studying presymptomatic ALS.}, }
@article {pmid27191240, year = {2016}, author = {Teive, HA and Lima, PM and Germiniani, FM and Munhoz, RP}, title = {What's in a name? Problems, facts and controversies regarding neurological eponyms.}, journal = {Arquivos de neuro-psiquiatria}, volume = {74}, number = {5}, pages = {423-425}, doi = {10.1590/0004-282X20160040}, pmid = {27191240}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/history ; *Eponyms ; Guillain-Barre Syndrome/history ; History, 17th Century ; History, 18th Century ; History, 19th Century ; History, 20th Century ; History, 21st Century ; Humans ; Iron Metabolism Disorders/history ; Nervous System Diseases/*history ; Neuroaxonal Dystrophies/history ; Restless Legs Syndrome/history ; }, abstract = {The use of eponyms in neurology remains controversial, and important questions have been raised about their appropriateness. Different approaches have been taken, with some eponyms being excluded, others replaced, and new ones being created. An example is Hallervorden-Spatz syndrome, which has been replaced by neurodegeneration with brain iron accuulatium (NBIA). Amiothoplic lateral sclerosys (ALS), for which the eponym is Charcot's disease, has been replaced in the USA by Lou Gehrig's disease. Guillain-Barré syndrome (GBS) is an eponym that is still the subject of controversy, and various different names are associated with it. Finally,restless legs syndrome (RLS), which was for years known as Ekbom's syndrome, has been rechristened as RLS/Willis-Ekbom syndrome.}, }
@article {pmid27185810, year = {2017}, author = {Marin, B and Boumédiene, F and Logroscino, G and Couratier, P and Babron, MC and Leutenegger, AL and Copetti, M and Preux, PM and Beghi, E}, title = {Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis.}, journal = {International journal of epidemiology}, volume = {46}, number = {1}, pages = {57-74}, pmid = {27185810}, issn = {1464-3685}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*epidemiology ; Asia/epidemiology ; Europe/epidemiology ; Humans ; Incidence ; New Zealand/epidemiology ; North America/epidemiology ; Sex Factors ; }, abstract = {BACKGROUND: To assess the worldwide variation of amyotrophic lateral sclerosis (ALS) incidence, we performed a systematic review and meta-analysis of population-based data published to date.<br><br>METHODS: We reviewed Medline and Embase up to June 2015 and included all population-based studies of newly diagnosed ALS cases, using multiple sources for case ascertainment. ALS crude and standardized incidence (on age and sex using the US 2010 population) were calculated. Random effect meta-analysis and meta-regression were performed using the subcontinent as the main study level covariate. Sources of heterogeneity related to the characteristics of the study population and the study methodology were investigated.<br><br>RESULTS: Among 3216 records, 44 studies were selected, covering 45 geographical areas in 11 sub-continents. A total of 13 146 ALS cases and 825 million person-years of follow-up (PYFU) were co-nsidered. The overall pooled worldwide crude ALS incidence was at 1.75 (1.55-1.96)/100 000 PYFU; 1.68 (1.50-1.85)/100&#xa0;000 PYFU after standardization. Heterogeneity was identified in ALS standardized incidence between North Europe [1.89 (1.46-2.32)/100 000 PYFU] and East Asia [0.83 (0.42-1.24)/100 000 PYFU, China and Japan P = 0.001] or South Asia [0.73 (0.58-0.89)/100 000/PYFU Iran, P = 0.02]. Conversely, homogeneous rates have been reported in populations from Europe, North America and New Zealand [pooled ALS standardized incidence of 1.81 (1.66-1.97)/100 000 PYFU for those areas].<br><br>CONCLUSION: This review confirms a heterogeneous distribution worldwide of ALS, and sets the scene to sustain a collaborative study involving a wide international consortium to investigate the link between ancestry, environment and ALS incidence.}, }
@article {pmid27183983, year = {2016}, author = {Catalano, A and Carocci, A}, title = {Antiarrhythmic Mexiletine: A Review on Synthetic Routes to Racemic and Homochiral Mexiletine and its Enantioseparation.}, journal = {Current medicinal chemistry}, volume = {23}, number = {29}, pages = {3227-3244}, doi = {10.2174/0929867323666160517120234}, pmid = {27183983}, issn = {1875-533X}, mesh = {Anti-Arrhythmia Agents/blood/*chemical synthesis/metabolism/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Chromatography, High Pressure Liquid ; Diabetic Nephropathies/drug therapy ; Humans ; Mexiletine/blood/*chemistry/metabolism/therapeutic use ; Stereoisomerism ; }, abstract = {Mexiletine is an oral class IB antiarrhythmic agent. Although it was primarily studied for the treatment of ventricular arrhythmias, it has been demonstrated to be useful also for the treatment of chronic painful diabetic neuropathy, neuropathic pain, skeletal muscle channelopathies, and recently amyotrophic lateral sclerosis. This review presents a detailed report on the different synthetic routes to racemic and homochiral mexiletine developed in the last decades, as well as analytical studies regarding enantioseparation methods and enantiomeric excess determination. Finally, some analogues of mexiletine reported in the literature, most of which along with pharmacological studies, have been mentioned.}, }
@article {pmid27181519, year = {2016}, author = {Monahan, Z and Shewmaker, F and Pandey, UB}, title = {Stress granules at the intersection of autophagy and ALS.}, journal = {Brain research}, volume = {1649}, number = {Pt B}, pages = {189-200}, pmid = {27181519}, issn = {1872-6240}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; R21 NS094921/NS/NINDS NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing ; Adenosine Triphosphatases/metabolism ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; *Autophagy ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/metabolism ; Cytoplasmic Granules/*metabolism ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism ; Humans ; Membrane Transport Proteins ; Nuclear Matrix-Associated Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Proteins/metabolism ; RNA-Binding Protein FUS/metabolism ; RNA-Binding Proteins/*metabolism ; Transcription Factor TFIIIA/metabolism ; Ubiquitins/metabolism ; Valosin Containing Protein ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease caused by loss of upper and lower motor neurons. The majority of ALS cases are classified as sporadic (80-90%), with the remaining considered familial based on patient history. The last decade has seen a surge in the identification of ALS-causing genes - including TARDBP (TDP-43), FUS, MATR3 (Matrin-3), C9ORF72 and several others - providing important insights into the molecular pathways involved in pathogenesis. Most of the protein products of ALS-linked genes fall into two functional categories: RNA-binding/homeostasis and protein-quality control (i.e. autophagy and proteasome). The RNA-binding proteins tend to be aggregation-prone with low-complexity domains similar to the prion-forming domains of yeast. Many also incorporate into stress granules (SGs), which are cytoplasmic ribonucleoprotein complexes that form in response to cellular stress. Mutant forms of TDP-43 and FUS perturb SG dynamics, lengthening their cytoplasmic persistence. Recent evidence suggests that SGs are regulated by the autophagy pathway, suggesting a unifying connection between many of the ALS-linked genes. Persistent SGs may give rise to intractable aggregates that disrupt neuronal homeostasis, thus failure to clear SGs by autophagic processes may promote ALS pathogenesis. This article is part of a Special Issue entitled SI:Autophagy.}, }
@article {pmid30050368, year = {2016}, author = {Alsultan, AA and Waller, R and Heath, PR and Kirby, J}, title = {The genetics of amyotrophic lateral sclerosis: current insights.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {6}, number = {}, pages = {49-64}, pmid = {30050368}, issn = {1179-9900}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in loss of the upper and lower motor neurons from motor cortex, brainstem, and spinal cord. While the majority of cases are sporadic, approximately 10% show familial inheritance. ALS is usually inherited in an autosomal dominant manner, although autosomal recessive and X-linked inheritance do occur. To date, 24 of the genes at 26 loci have been identified; these include loci linked to ALS and to frontotemporal dementia-ALS, where family pedigrees contain individuals with frontotemporal dementia with/without ALS. The most commonly established genetic causes of familial ALS (FALS) to date are the presence of a hexanucleotide repeat expansion in the C9ORF72 gene (39.3% FALS) and mutation of SOD1, TARDBP, and FUS, with frequencies of 12%-23.5%, 5%, and 4.1%, respectively. However, with the increasing use of next-generation sequencing of small family pedigrees, this has led to an increasing number of genes being associated with ALS. This review provides a comprehensive review on the genetics of ALS and an update of the pathogenic mechanisms associated with these genes. Commonly implicated pathways have been established, including RNA processing, the protein degradation pathways of autophagy and ubiquitin-proteasome system, as well as protein trafficking and cytoskeletal function. Elucidating the role genetics plays in both FALS and sporadic ALS is essential for understanding the subsequent cellular dysregulation that leads to motor neuron loss, in order to develop future effective therapeutic strategies.}, }
@article {pmid27166223, year = {2016}, author = {Götzl, JK and Lang, CM and Haass, C and Capell, A}, title = {Impaired protein degradation in FTLD and related disorders.}, journal = {Ageing research reviews}, volume = {32}, number = {}, pages = {122-139}, doi = {10.1016/j.arr.2016.04.008}, pmid = {27166223}, issn = {1872-9649}, mesh = {Active Transport, Cell Nucleus/*physiology ; Adaptor Proteins, Signal Transducing ; Autophagy/physiology ; Autophagy-Related Proteins ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/*metabolism ; Frontotemporal Dementia/*metabolism ; Humans ; Lysosomes/*metabolism ; Membrane Transport Proteins ; Mutation ; Nerve Degeneration/metabolism ; Neuronal Ceroid-Lipofuscinoses/*metabolism ; Proteolysis ; Sequestosome-1 Protein/genetics ; Transcription Factor TFIIIA/genetics ; Ubiquitins/genetics ; }, abstract = {Impaired protein degradation has been discussed as a cause or consequence of various neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's disease. More recently, evidence accumulated that dysfunctional protein degradation may play a role in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Since in almost all neurodegenerative diseases, protein aggregates are disease-defining hallmarks, it is most likely that impaired protein degradation contributes to disease onset and progression. In the majority of FTD cases, the pathological protein aggregates contain either microtubuleassociated protein tau or TAR DNA-binding protein (TDP)-43. Aggregates are also positive for ubiquitin and p62/sequestosome 1 (SQSTM1) indicating that these aggregates are targeted for degradation. FTD-linked mutations in genes encoding three autophagy adaptor proteins, p62/SQSTM1, ubiquilin 2 and optineurin, indicate that impaired autophagy might cause FTD. Furthermore, the strongest evidence for lysosomal impairment in FTD is provided by the progranulin (GRN) gene, which is linked to FTD and neuronal ceroid lipofuscinosis. In this review, we summarize the observations that have been made during the last years linking the accumulation of disease-associated proteins in FTD to impaired protein degradation pathways. In addition, we take resent findings for nucleocytoplasmic transport defects of TDP-43, as discussed for hexanucleotide repeat expansions in C9orf72 into account and provide a hypothesis how the interplay of altered nuclear transport and protein degradation leads to the accumulation of protein deposits.}, }
@article {pmid27164308, year = {2016}, author = {Macpherson, CE and Bassile, CC}, title = {Pulmonary Physical Therapy Techniques to Enhance Survival in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Journal of neurologic physical therapy : JNPT}, volume = {40}, number = {3}, pages = {165-175}, doi = {10.1097/NPT.0000000000000136}, pmid = {27164308}, issn = {1557-0584}, mesh = {Amyotrophic Lateral Sclerosis/complications/mortality/*rehabilitation ; Humans ; *Physical Therapy Modalities ; Respiratory Insufficiency/etiology/*rehabilitation ; }, abstract = {BACKGROUND AND PURPOSE: Respiratory insufficiency is the primary cause of morbidity and mortality in individuals with amyotrophic lateral sclerosis (ALS). Although mechanical interventions are effective in prolonging survival through respiratory support, pulmonary physical therapy interventions are being investigated. The purpose of this systematic review was to examine the effectiveness of pulmonary physical therapy interventions across the progressive stages of ALS.<br><br>METHODS: Six databases were searched for articles from inception to December 2014 investigating pulmonary physical therapy interventions in the ALS population. The search strategy followed Cochrane Collaboration guidelines with replication per database. Effect sizes (ES) were calculated for primary outcome measures: forced vital capacity (FVC) and peak cough expiratory flow (PCEF).<br><br>RESULTS: Seven studies met inclusion criteria. Four studies used control groups whereas the remainder used repeated measures. With the exception of diaphragmatic breathing, pulmonary physical therapy interventions were effective in improving multiple respiratory outcome measures in this population. Inspiratory muscle training (IMT) was shown to prolong respiratory muscle strength with a strong effect size (ES = 1.48) for FVC. In addition, mean length of survival increased by 12 months. Lung volume recruitment training (LVRT) strongly enhanced immediate cough efficacy with improved FVC (ES = 1.02) and PCEF (ES = 1.82). Manually assisted cough (MAC) only improved PCEF by a small amount (ES = 0.15, bulbar ALS; ES = 0.16, classical ALS groups).<br><br>DISCUSSION AND CONCLUSIONS: Specific pulmonary physical therapy interventions (IMT, LVRT, and MAC) have effectiveness in improving respiratory outcome measures and increasing survival. These should be routinely incorporated into the comprehensive management of individuals with ALS. More rigorous methodological investigations should be performed to replicate these findings.Video abstract available with brief technique demonstration of IMT and LVRT (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A136).}, }
@article {pmid27160086, year = {2016}, author = {Keller, M and Müller, S}, title = {[Vegetarische und vegane Ernährung bei Kindern - Stand der Forschung und Forschungsbedarf].}, journal = {Forschende Komplementarmedizin (2006)}, volume = {23}, number = {2}, pages = {81-88}, doi = {10.1159/000445486}, pmid = {27160086}, issn = {1661-4127}, mesh = {Child ; *Diet, Vegan ; *Diet, Vegetarian ; Germany ; Humans ; Nutritional Requirements ; Nutritive Value ; Research ; }, abstract = {Die Praxis vegetarischer Ernährungsformen ist in Deutschland im letzten Jahrzehnt deutlich angestiegen. Allerdings ist der Anteil vegetarischer und veganer Kinder dabei unbekannt. Studien mit Erwachsenen zeigen das präventive Potenzial, aber auch potenzielle Schwachstellen pflanzenbasierter Kostformen. Die Vorteile und Risiken einer vegetarischen bzw. veganen Ernährung im Kindesalter wurden bisher jedoch relativ selten untersucht. Außerdem lassen das unterschiedliche Alter der Kinder, das heterogene Studiendesign sowie die teilweise geringe Probandenzahl der Studien keine verbindlichen Aussagen zu. In dieser Übersichtsarbeit werden die Ergebnisse der wenigen Studien zu vegetarisch und vegan ernährten Kindern (< 12 Jahren) in Nordamerika und Europa zusammengefasst. Demnach lag die Zufuhr von Nahrungsenergie und Makronährstoffen vegetarischer und veganer Kinder meist näher an den Empfehlungen der Fachgesellschaften als die Ernährung gleichaltriger Mischkostkinder. Ebenso wiesen vegetarisch und vegan ernährte Kinder eine höhere Zufuhr von und bessere Versorgung mit verschiedenen Vitaminen und Mineralstoffen auf. Häufiger zeigten sich jedoch Defizite bei Vitamin B12, Zink, Kalzium, Eisen und Vitamin D. Das Wachstum und die Entwicklung vegetarisch und vegan ernährter Kinder entsprachen weitgehend den Referenzstandards, wobei sie dazu tendierten, leichter, schlanker und (< 5 Jahren) auch kleiner zu sein. Aufgrund der unzureichenden Studienlage besteht erheblicher Forschungsbedarf zu den Auswirkungen einer vegetarischen und veganen Ernährung im Kindesalter.}, }
@article {pmid27155453, year = {2016}, author = {Sasaguri, H and Chew, J and Xu, YF and Gendron, TF and Garrett, A and Lee, CW and Jansen-West, K and Bauer, PO and Perkerson, EA and Tong, J and Stetler, C and Zhang, YJ}, title = {The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {57-64}, pmid = {27155453}, issn = {1872-6240}, support = {R21 NS079807/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Caspase 3/metabolism ; Cell Death ; Cells, Cultured ; Cerebral Cortex/*metabolism/pathology ; DNA-Binding Proteins/genetics/*metabolism ; Gliosis/metabolism ; Inclusion Bodies/metabolism ; Mice ; Motor Activity ; Neurons/*metabolism/pathology ; }, abstract = {Inclusions of Tar DNA- binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP). Pathological TDP-43 exhibits the disease-specific biochemical signatures, which include its ubiquitination, phosphorylation and truncation. Recently, we demonstrated that the extreme N-terminus of TDP-43 regulates formation of abnormal cytoplasmic TDP-43 aggregation in cultured cells and primary neurons. However, it remained unclear whether this N-terminal domain mediates TDP-43 aggregation and the associated toxicity in vivo. To investigate this, we expressed a GFP-tagged TDP-43 with a nuclear localization signal mutation (GFP-TDP-43NLSm) and a truncated form without the extreme N-terminus (GFP-TDP-4310-414-NLSm) by adeno-associated viral (AAV) vectors in mouse primary cortical neurons and murine central nervous system. Compared to neurons containing GFP alone, expression of GFP-TDP-43NLSm resulted in the formation of ubiquitin-positive cytoplasmic inclusions and activation of caspase-3, an indicator of cell death. Moreover, mice expressing GFP-TDP-43NLSm proteins show reactive gliosis and develop neurological abnormalities. However, by deletion of TDP-43's extreme N-terminus, these pathological alterations can be abrogated. Together, our study provides further evidence confirming the critical role of the extreme N-terminus of TDP-43 in regulating protein structure as well as mediating toxicity associated with its aggregation. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid27153565, year = {2016}, author = {Speier, W and Arnold, C and Pouratian, N}, title = {Integrating language models into classifiers for BCI communication: a review.}, journal = {Journal of neural engineering}, volume = {13}, number = {3}, pages = {031002}, pmid = {27153565}, issn = {1741-2552}, support = {K23 EB014326/EB/NIBIB NIH HHS/United States ; }, mesh = {Algorithms ; Brain-Computer Interfaces/*classification ; *Communication Aids for Disabled ; Electroencephalography ; Humans ; *Language ; Models, Theoretical ; Natural Language Processing ; }, abstract = {OBJECTIVE: The present review systematically examines the integration of language models to improve classifier performance in brain-computer interface (BCI) communication systems.<br><br>APPROACH: The domain of natural language has been studied extensively in linguistics and has been used in the natural language processing field in applications including information extraction, machine translation, and speech recognition. While these methods have been used for years in traditional augmentative and assistive communication devices, information about the output domain has largely been ignored in BCI communication systems. Over the last few years, BCI communication systems have started to leverage this information through the inclusion of language models.<br><br>MAIN RESULTS: Although this movement began only recently, studies have already shown the potential of language integration in BCI communication and it has become a growing field in BCI research. BCI communication systems using language models in their classifiers have progressed down several parallel paths, including: word completion; signal classification; integration of process models; dynamic stopping; unsupervised learning; error correction; and evaluation.<br><br>SIGNIFICANCE: Each of these methods have shown significant progress, but have largely been addressed separately. Combining these methods could use the full potential of language model, yielding further performance improvements. This integration should be a priority as the field works to create a BCI system that meets the needs of the amyotrophic lateral sclerosis population.}, }
@article {pmid27152026, year = {2016}, author = {Stavroulakis, T and McDermott, CJ}, title = {Enteral feeding in neurological disorders.}, journal = {Practical neurology}, volume = {16}, number = {5}, pages = {352-361}, doi = {10.1136/practneurol-2016-001408}, pmid = {27152026}, issn = {1474-7766}, support = {SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Dementia ; *Enteral Nutrition ; Humans ; Motor Neuron Disease ; *Neurodegenerative Diseases ; Stroke ; }, abstract = {Malnutrition and weight loss, due to suboptimal oral intake, are common in patients with neurological disorders and are associated with increased morbidity, disability and mortality. The nutritional management of neurological patients is crucial, and enteral feeding is commonly used to provide nutritional support. This review presents the different methods of enteral tube feeding and discusses its practice and efficacy in terms of clinical outcomes in the context of motor neurone disease, Parkinson's disease, Alzheimer's disease and other dementias, and stroke.}, }
@article {pmid27151634, year = {2016}, author = {Hayes, LR and Rothstein, JD}, title = {C9ORF72-ALS/FTD: Transgenic Mice Make a Come-BAC.}, journal = {Neuron}, volume = {90}, number = {3}, pages = {427-431}, pmid = {27151634}, issn = {1097-4199}, support = {R01 NS094239/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Disease Models, Animal ; Frontotemporal Dementia/*genetics ; Guanine Nucleotide Exchange Factors/*genetics ; Humans ; }, abstract = {For five years, since the landmark discovery of the C9ORF72 hexanucleotide repeat expansion in ALS/FTD, a transgenic mouse model has remained elusive. Now, two laboratories (Liu et al., 2016; Jiang et al., 2016) report the development of BAC transgenic mice that recapitulate features of the human disease.}, }
@article {pmid27150398, year = {2016}, author = {Haeusler, AR and Donnelly, CJ and Rothstein, JD}, title = {The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease.}, journal = {Nature reviews. Neuroscience}, volume = {17}, number = {6}, pages = {383-395}, pmid = {27150398}, issn = {1471-0048}, support = {K99 NS091486/NS/NINDS NIH HHS/United States ; R01 NS085207/NS/NINDS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Base Sequence/*physiology ; C9orf72 Protein ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/pathology ; Proteins/*genetics/*metabolism ; Trinucleotide Repeat Expansion/*physiology ; }, abstract = {A nucleotide repeat expansion (NRE) within the chromosome 9 open reading frame 72 (C9orf72) gene was the first of this type of mutation to be linked to multiple neurological conditions, including amyotrophic lateral sclerosis and frontotemporal dementia. The pathogenic mechanisms through which the C9orf72 NRE contributes to these disorders include loss of C9orf72 function and gain-of-function mechanisms of C9orf72 driven by toxic RNA and protein species encoded by the NRE. These mechanisms have been linked to several cellular defects - including nucleocytoplasmic trafficking deficits and nuclear stress - that have been observed in both patients and animal models.}, }
@article {pmid27150076, year = {2017}, author = {Rozas, P and Bargsted, L and Martínez, F and Hetz, C and Medinas, DB}, title = {The ER proteostasis network in ALS: Determining the differential motoneuron vulnerability.}, journal = {Neuroscience letters}, volume = {636}, number = {}, pages = {9-15}, doi = {10.1016/j.neulet.2016.04.066}, pmid = {27150076}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/pathology ; Animals ; Endoplasmic Reticulum/*metabolism ; *Endoplasmic Reticulum Stress ; Humans ; Molecular Chaperones/metabolism ; Motor Neurons/metabolism/*pathology ; Muscle, Skeletal/innervation ; Protein Aggregates ; Protein Folding ; Proteome/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease characterized by the selective loss of motoneurons. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting abnormal protein aggregation and altered mRNA metabolism as common phenomena. ALS involves the selective vulnerablility of a subpopulation of motoneurons, suggesting that intrinsic factors may determine ALS pathogenesis. Accumulating evidence indicates that alterations to endoplasmic reticulum (ER) proteostasis play a critical role on disease progression, representing one of the earliests pathological signatures of the disease. Here we discuss recent studies uncovering a fundamental role of ER stress as the driver of selective neuronal vulnerability in ALS and discuss the potential of targeting the unfolded protein response (UPR) as a therapeutic strategy to treat ALS.}, }
@article {pmid27150074, year = {2017}, author = {Bozzo, F and Mirra, A and Carrì, MT}, title = {Oxidative stress and mitochondrial damage in the pathogenesis of ALS: New perspectives.}, journal = {Neuroscience letters}, volume = {636}, number = {}, pages = {3-8}, doi = {10.1016/j.neulet.2016.04.065}, pmid = {27150074}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Iron/metabolism ; Mitochondria/*metabolism ; Mutation ; *Oxidative Stress ; Protein Aggregation, Pathological/metabolism ; Protein Folding ; RNA/metabolism ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {This review attempts to reconcile the present dual view of the mechanisms operating in Amyotrophic Lateral Sclerosis (ALS). On one side, oxidative stress, mitochondrial damage and protein aggregation are considered as causative of the disease, as strongly supported by evidence obtained in models based on the expression of ALS-typical mutant SOD1. On the other hand, evidence from models expressing ALS-typical mutations in RNA-binding proteins such as FUS and TDP43 indicate that mRNA (dys)metabolism is a major pathway in this disease. A critical analysis of existing literature suggests that there may be more than one point of intersection.}, }
@article {pmid27144467, year = {2016}, author = {Woollacott, IO and Rohrer, JD}, title = {The clinical spectrum of sporadic and familial forms of frontotemporal dementia.}, journal = {Journal of neurochemistry}, volume = {138 Suppl 1}, number = {}, pages = {6-31}, doi = {10.1111/jnc.13654}, pmid = {27144467}, issn = {1471-4159}, support = {MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; MR/M018288/1/MRC_/Medical Research Council/United Kingdom ; MR/J009482/1/MRC_/Medical Research Council/United Kingdom ; MR/M501724/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Frontotemporal Dementia/genetics/*psychology/therapy ; Humans ; tau Proteins/genetics ; }, abstract = {The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their 20s through to their 90s, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD). Less frequently patients present with language problems (primary progressive aphasia). Both of these groups of patients can develop motor features consistent with either motor neuron disease (usually the amyotrophic lateral sclerosis variant) or parkinsonism (most commonly a progressive supranuclear palsy or corticobasal syndrome). In about a third of cases FTD is familial, with mutations in the progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72 genes being the major causes. Mutations in a number of other genes including TANK-binding kinase 1 are rare causes of familial FTD. This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes. It will also discuss the current major challenges in FTD research and clinical practice, and potential areas for future research. This review clarifies the terminology of frontotemporal dementia (FTD) and summarizes the various clinical features and most recent diagnostic criteria of sporadic and familial FTD syndromes. It also discusses the current major challenges in FTD research and clinical practice, and highlights potential areas for future research.}, }
@article {pmid27142684, year = {2017}, author = {Rauskolb, S and Dombert, B and Sendtner, M}, title = {Insulin-like growth factor 1 in diabetic neuropathy and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {97}, number = {Pt B}, pages = {103-113}, doi = {10.1016/j.nbd.2016.04.007}, pmid = {27142684}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Diabetic Neuropathies/*metabolism ; Humans ; Insulin-Like Growth Factor I/*metabolism ; }, abstract = {Insulin-like growth factor 1 (IGF-1) is a pluripotent growth factor with multiple functions in the peripheral and central nervous system. It supports neuronal survival and axon growth, and also acts on myelinating Schwann cells and oligodendroglia. The biological functions of IGF-1 are modulated by IGF-binding proteins (IGFBPs). Expression of IGF-1 and its corresponding IGF-1 receptor (IGF-1R) are dysregulated in patients with diabetes and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). IGFBP5, an inhibitory binding protein for IGF-1, is also substantially increased in nerve biopsies of patients with sensorimotor diabetic neuropathy (DNP). We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which IGF-1R was conditionally depleted in motoneurons, indicating that reduced activity of IGF-1 on IGF-1R in motoneurons is responsible for the observed effect. The upregulation of IGFBP5 has possibly contributed to the lack of efficacy found in previous clinical trials with systemically administered IGF-1 in patients with other forms of motoneuron disease such as ALS. Thus, strategies aiming at circumventing these inhibitory effects could be of benefit for development of new therapies for ALS and DNP. However, these strategies have to be built on a better understanding of the metabolic processes that contribute to neurodegeneration, and on the role of IGF-1 in these metabolic processes that go beyond protection from axonal degeneration and cell death.}, }
@article {pmid27139021, year = {2016}, author = {Chi, S and Jiang, T and Tan, L and Yu, JT}, title = {Distinct neurological disorders with C9orf72 mutations: genetics, pathogenesis, and therapy.}, journal = {Neuroscience and biobehavioral reviews}, volume = {66}, number = {}, pages = {127-142}, doi = {10.1016/j.neubiorev.2016.03.033}, pmid = {27139021}, issn = {1873-7528}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; C9orf72 Protein ; Frontotemporal Dementia ; Humans ; *Mutation ; Phenotype ; Proteins/*genetics ; }, abstract = {The G4C2 repeat expansion within C9orf72 has been recently identified as the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. This mutation has also been detected in a variety of other neurological diseases with distinct clinical manifestations. The exact mechanisms of how this mutation leads to the wide spectrum of clinical syndromes remain unknown. A series of molecular changes together with some potential modifiers may play a key role. Nucleolar stress, nucleocytoplasmic transport defect, oxidative damage, inhibited stress granules assembly, activated endoplasmic reticulum stress, and inhibited proteasome activity are mechanisms that contribute to the pathogenesis of these diseases. Additional mutations, epigenetic modifiers, and repeat size are potential modifiers that modulate specific phenotypes on the basis of the molecular changes. Here, we summarize distinct C9orf72-related neurological disorders and their corresponding neuropathological changes. Then, we elucidate the existing molecular knowledge and the potential modifiers. Finally, we detail the main target of treatment aiming at controlling expanded RNA transcripts.}, }
@article {pmid27136532, year = {2016}, author = {Tokuda, E and Furukawa, Y}, title = {Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations.}, journal = {International journal of molecular sciences}, volume = {17}, number = {5}, pages = {}, pmid = {27136532}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/pathology ; Animals ; Chelating Agents/chemistry/metabolism/therapeutic use ; Copper/chemistry/*metabolism ; Disease Models, Animal ; Humans ; Polymorphism, Single Nucleotide ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.}, }
@article {pmid27134035, year = {2016}, author = {Xiao, S and MacNair, L and McLean, J and McGoldrick, P and McKeever, P and Soleimani, S and Keith, J and Zinman, L and Rogaeva, E and Robertson, J}, title = {C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {43-49}, doi = {10.1016/j.brainres.2016.04.062}, pmid = {27134035}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein ; DNA Repeat Expansion ; Frontotemporal Lobar Degeneration/*genetics ; Gene Expression ; Humans ; Motor Neurons/metabolism ; Protein Isoforms/genetics ; Proteins/*genetics ; Purkinje Cells/metabolism ; }, abstract = {A hexanucleotide (G4C2) repeat expansion in the 5' non-coding region C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Three modes of toxicity have been proposed: gain of function through formation of RNA foci and sequestration of RNA binding proteins; expression of dipeptide repeat proteins generated by repeat-associated non-ATG translation; and loss of function due to C9orf72 haploinsufficiency. Much is known about the proposed gain of function mechanisms, but there is little knowledge of the normal function of C9orf72 and the cellular consequences if its activity is perturbed. Here we will review what is known of C9orf72 at the transcript and protein levels and how changes in C9orf72 expression could contribute to disease pathogenesis. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid27132521, year = {2016}, author = {Hostenbach, S and D'haeseleer, M and Kooijman, R and De Keyser, J}, title = {The pathophysiological role of astrocytic endothelin-1.}, journal = {Progress in neurobiology}, volume = {144}, number = {}, pages = {88-102}, doi = {10.1016/j.pneurobio.2016.04.009}, pmid = {27132521}, issn = {1873-5118}, mesh = {Animals ; Astrocytes/*metabolism ; Central Nervous System Diseases/*metabolism ; Endothelin-1/*metabolism ; Humans ; Neuroprotection/*physiology ; }, abstract = {In the normal central nervous system, endothelin-1 (ET-1) is found in some types of neurons, epithelial cells of the choroid plexus, and endothelial cells of microvessels, but it is usually not detectable in glial cells. However, in different pathological conditions, astrocytes adapting a reactive phenotype express high levels of ET-1 and its receptors, mainly the ETB receptor. ET-1 released by reactive astrocytes appears mainly to have neurodeleterious effects by mechanisms that include constriction of cerebral arterioles leading to impairment of the cerebral microcirculation, increase of blood brain barrier permeability, inflammation, excitotoxicity, impairment of fast axonal transport, and astrogliosis. A few studies in rodents found that ET-1 increased the astrocytic expression of brain-derived neurotrophic factor, glial cell-line derived neurotrophic factor and neurotropin-3, and the production of endocannabinoids. However, whether this occurs in physiological or pathological conditions is unclear. This review summarizes current knowledge about the role of the astrocytic ET-1 system in acute and chronic neurological conditions, including multiple sclerosis, ischemic stroke and hypoxic/ischemic brain injury, traumatic brain injury, subarachnoid hemorrhage, Alzheimer's disease, Binswanger's disease and post-stroke dementia, amyotrophic lateral sclerosis, and CNS infections. Counteracting the harmful effects of astrocytic ET-1 may represent a promising therapeutic target for mitigating secondary brain damage in a variety of neurological diseases. We also briefly address the role of astrocytic ET-1 in astrocytic tumors and pain.}, }
@article {pmid27131987, year = {2016}, author = {Valenzuela, V and Martínez, G and Duran-Aniotz, C and Hetz, C}, title = {Gene therapy to target ER stress in brain diseases.}, journal = {Brain research}, volume = {1648}, number = {Pt B}, pages = {561-570}, doi = {10.1016/j.brainres.2016.04.064}, pmid = {27131987}, issn = {1872-6240}, mesh = {Animals ; Brain Diseases/genetics/*therapy ; Dependovirus/genetics/physiology ; Endoplasmic Reticulum Stress/*genetics ; Genetic Therapy/*methods ; Humans ; Unfolded Protein Response/genetics ; }, abstract = {Gene therapy based on the use of Adeno-associated viruses (AAVs) is emerging as a safe and stable strategy to target molecular pathways involved in a variety of brain diseases. Endoplasmic reticulum (ER) stress is proposed as a transversal feature of most animal models and clinical samples from patients affected with neurodegenerative diseases. Manipulation of the unfolded protein response (UPR), a major homeostatic reaction under ER stress conditions, had proved beneficial in diverse models of neurodegeneration. Although increasing number of drugs are available to target ER stress, the use of small molecules to treat chronic brain diseases is challenging because of poor blood brain barrier permeability and undesirable side effects due to the role of the UPR in the physiology of peripheral organs. Gene therapy is currently considered a possible future alternative to circumvent these problems by the delivery of therapeutic agents to selective regions and cell types of the nervous system. Here we discuss current efforts to design gene therapy strategies to alleviate ER stress on a disease context. This article is part of a Special Issue entitled SI:ER stress.}, }
@article {pmid27121507, year = {2016}, author = {Arnao, V and Di Raimondo, D and Tuttolomondo, A and Pinto, A}, title = {Neurotrophic and Neuroprotective Effects of Muscle Contraction.}, journal = {Current pharmaceutical design}, volume = {22}, number = {24}, pages = {3749-3763}, doi = {10.2174/1381612822666160428111234}, pmid = {27121507}, issn = {1873-4286}, mesh = {Brain-Derived Neurotrophic Factor/metabolism ; Cerebrovascular Circulation ; Dementia/physiopathology ; Endocannabinoids/metabolism ; Exercise ; Humans ; Life Style ; *Muscle Contraction ; Nervous System Diseases/physiopathology ; *Nervous System Physiological Phenomena ; Oxidative Stress ; Stroke/physiopathology ; }, abstract = {BACKGROUND: Physical activity has been shown to be associated with reduced risk of coronary heart disease but the same effect seems to be produced in neurological diseases.<br><br>OBJECTIVE: In this review, we focused on the interplay between physical activity and some neurological conditions (Stroke, dementia, epilepsy, headache, Parkinson' s disease, amyotrophic lateral sclerosis, multiple sclerosis, insomnia, depression and anxiety) with the aim of describing the potential role of physical activity in the prevention of such diseases and the physiological mechanisms involved in these processes.<br><br>RESULTS: Despite a growing body of evidence which reveals that physical activity is able to reduce the frequency of neurological diseases, directly or indirectly by enhancing cardiovascular conditions, further studies are necessary to better characterize which type of exercise is useful for each condition.<br><br>CONCLUSION: Physical activity could represent an additional approach to fight against such diseases.}, }
@article {pmid27117334, year = {2016}, author = {de Carvalho, M and Swash, M}, title = {Lower motor neuron dysfunction in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {127}, number = {7}, pages = {2670-2681}, doi = {10.1016/j.clinph.2016.03.024}, pmid = {27117334}, issn = {1872-8952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Electromyography/methods ; Humans ; Motor Neurons/pathology/*physiology ; Muscle, Skeletal/pathology/physiopathology ; Neural Conduction ; }, abstract = {In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN's, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future.}, }
@article {pmid27116041, year = {2016}, author = {Zhang, K and Grima, JC and Rothstein, JD and Lloyd, TE}, title = {Nucleocytoplasmic transport in C9orf72-mediated ALS/FTD.}, journal = {Nucleus (Austin, Tex.)}, volume = {7}, number = {2}, pages = {132-137}, pmid = {27116041}, issn = {1949-1042}, mesh = {Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis/*complications/*metabolism/pathology ; Animals ; C9orf72 Protein ; Cell Nucleus/*metabolism ; Frontotemporal Dementia/*complications ; Humans ; Protein Aggregates ; Proteins/*metabolism ; }, abstract = {A GGGGCC hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies indicate that disruption of nucleocytoplasmic transport pathways play a critical role in the pathogenesis of C9orf72-mediated ALS/FTD (C9-ALS). Here, we discuss mechanisms by which C9orf72 mutations cause nucleocytoplasmic transport deficits and contribute to disease pathogenesis. We review the current literature regarding nucleocytoplasmic transport disruption in C9-ALS, and discuss implications and directions for future research.}, }
@article {pmid27113253, year = {2016}, author = {Therrien, M and Dion, PA and Rouleau, GA}, title = {ALS: Recent Developments from Genetics Studies.}, journal = {Current neurology and neuroscience reports}, volume = {16}, number = {6}, pages = {59}, pmid = {27113253}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein ; Humans ; Mitochondrial Proteins/genetics ; Mutation ; Nuclear Matrix-Associated Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; Proteins/genetics ; RNA-Binding Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder that is characterized by a progressive degeneration of the upper and lower motor neurons. Most cases appear to be sporadic, but 5-10 % of cases have a family history of the disease. High-throughput DNA sequencing and related genomic capture tools are methodological advances which have rapidly contributed to an acceleration in the discovery of genetic risk factors for both familial and sporadic ALS. It is interesting to note that as the number of ALS genes grows, many of the proteins they encode are in shared intracellular processes. This review will summarize some of the recent advances and gene discovery made in ALS.}, }
@article {pmid27111119, year = {2015}, author = {Althari, S and Gloyn, AL}, title = {When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes.}, journal = {The review of diabetic studies : RDS}, volume = {12}, number = {3-4}, pages = {330-348}, pmid = {27111119}, issn = {1614-0575}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Diabetes Mellitus, Type 2/*genetics ; Humans ; *Mutation ; *Phenotype ; }, abstract = {The genomics revolution has raised more questions than it has provided answers. Big data from large population-scale resequencing studies are increasingly deconstructing classic notions of Mendelian disease genetics, which support a simplistic correlation between mutational severity and phenotypic outcome. The boundaries are being blurred as the body of evidence showing monogenic disease-causing alleles in healthy genomes, and in the genomes of individu-als with increased common complex disease risk, continues to grow. In this review, we focus on the newly emerging challenges which pertain to the interpretation of sequence variants in genes implicated in the pathogenesis of maturity-onset diabetes of the young (MODY), a presumed mono-genic form of diabetes characterized by Mendelian inheritance. These challenges highlight the complexities surrounding the assignments of pathogenicity, in particular to rare protein-alerting variants, and bring to the forefront some profound clinical diagnostic implications. As MODY is both genetically and clinically heterogeneous, an accurate molecular diagnosis and cautious extrapolation of sequence data are critical to effective disease management and treatment. The biological and translational value of sequence information can only be attained by adopting a multitude of confirmatory analyses, which interrogate variant implication in disease from every possible angle. Indeed, studies which have effectively detected rare damaging variants in known MODY genes in normoglycemic individuals question the existence of a sin-gle gene mutation scenario: does monogenic diabetes exist when the genetic culprits of MODY have been systematical-ly identified in individuals without MODY?}, }
@article {pmid27110325, year = {2016}, author = {Limongi, D and Baldelli, S}, title = {Redox Imbalance and Viral Infections in Neurodegenerative Diseases.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {6547248}, pmid = {27110325}, issn = {1942-0994}, mesh = {Animals ; Humans ; Inflammation/pathology ; Nerve Degeneration/pathology ; Neurodegenerative Diseases/*pathology/*virology ; Oxidation-Reduction ; Oxidative Stress ; Virus Diseases/*complications ; }, abstract = {Reactive oxygen species (ROS) are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid27108217, year = {2016}, author = {Lacorte, E and Ferrigno, L and Leoncini, E and Corbo, M and Boccia, S and Vanacore, N}, title = {Physical activity, and physical activity related to sports, leisure and occupational activity as risk factors for ALS: A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {66}, number = {}, pages = {61-79}, doi = {10.1016/j.neubiorev.2016.04.007}, pmid = {27108217}, issn = {1873-7528}, mesh = {*Amyotrophic Lateral Sclerosis ; Exercise ; Humans ; Leisure Activities ; Risk Factors ; Sports ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem neurodegenerative disease due to an interaction between environmental and genetic factors. This systematic review aims at gathering all available evidence on the association between physical activity (PA) and the risk of ALS.<br><br>METHODS: Relevant literature published up to January 2015 was gathered through structured searches on Medline, The Cochrane Library, and the ISI Web of Science databases. Studies considering any type of PA as the main exposure and a diagnosis of ALS or motor neuron disease were selected. Data were extracted in standardized forms, and the quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS).<br><br>RESULTS: Bibliographic searches yielded 3168 records. Nineteen case control studies and 7 cohort studies met the inclusion criteria, and were included in the analysis. Evidence on cumulative measures of PA as a risk factor for ALS remain inconclusive. However, cohort studies report a significantly higher number of cases of ALS in professional soccer and American football players, and a slightly increased risk of ALS in varsity athletes.}, }
@article {pmid27106072, year = {2016}, author = {Kampinga, HH and Bergink, S}, title = {Heat shock proteins as potential targets for protective strategies in neurodegeneration.}, journal = {The Lancet. Neurology}, volume = {15}, number = {7}, pages = {748-759}, doi = {10.1016/S1474-4422(16)00099-5}, pmid = {27106072}, issn = {1474-4465}, mesh = {Animals ; Heat-Shock Proteins/drug effects/*metabolism ; Humans ; Neurodegenerative Diseases/drug therapy/*metabolism ; }, abstract = {Protein aggregates are hallmarks of nearly all age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several polyglutamine diseases such as Huntington's disease and different forms of spinocerebellar ataxias (SCA; SCA1-3, SCA6, and SCA7). The collapse of cellular protein homoeostasis can be both a cause and a consequence of this protein aggregation. Boosting components of the cellular protein quality control system has been widely investigated as a strategy to counteract protein aggregates or their toxic consequences. Heat shock proteins (HSPs) play a central part in regulating protein quality control and contribute to protein aggregation and disaggregation. Therefore, HSPs are viable targets for the development of drugs aimed at reducing pathogenic protein aggregates that are thought to contribute to the development of so many neurodegenerative disorders.}, }
@article {pmid27103621, year = {2016}, author = {E, M and Yu, S and Dou, J and Jin, W and Cai, X and Mao, Y and Zhu, D and Yang, R}, title = {Association between alcohol consumption and amyotrophic lateral sclerosis: a meta-analysis of five observational studies.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {37}, number = {8}, pages = {1203-1208}, pmid = {27103621}, issn = {1590-3478}, mesh = {Alcohol Drinking/*epidemiology ; Amyotrophic Lateral Sclerosis/*epidemiology ; Databases, Bibliographic/statistics &amp; numerical data ; Humans ; *Observational Studies as Topic ; Risk Factors ; }, abstract = {The purpose of this study is to examine the association between alcohol consumption and amyotrophic lateral sclerosis. Published literature on the association between alcohol consumption and amyotrophic lateral sclerosis was retrieved from the PubMed and Embase databases. Two authors independently extracted the data. The quality of the identified studies was evaluated according to the Newcastle-Ottawa scale. Subgroup and sensitivity analyses were performed and publication bias was assessed. Five articles, including one cohort study and seven case-control studies, and a total of 431,943 participants, were identified. The odds ratio for the association between alcohol consumption and amyotrophic lateral sclerosis was 0.57 (95 % confidence interval 0.51-0.64). Subgroup and sensitivity analyses confirmed the result. Evidence for publication bias was detected. Alcohol consumption reduced the risk of developing amyotrophic lateral sclerosis compared with non-drinking. Alcohol, therefore, has a potentially neuroprotective effect on the development of amyotrophic lateral sclerosis.}, }
@article {pmid27100517, year = {2016}, author = {Rudolf, R and Khan, MM and Wild, F and Hashemolhosseini, S}, title = {The impact of autophagy on peripheral synapses in health and disease.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {21}, number = {7}, pages = {1474-1487}, doi = {10.2741/4467}, pmid = {27100517}, issn = {2768-6698}, mesh = {Animals ; Autophagy/*physiology ; Charcot-Marie-Tooth Disease/physiopathology ; Humans ; Peripheral Nerves/*physiology ; Peripheral Nervous System Diseases/*physiopathology/therapy ; Protein Aggregation, Pathological/physiopathology ; Synapses/*physiology ; }, abstract = {Alterations of autophagy have been linked to several peripheral nervous system diseases, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Modulation of autophagy by metabolic or pharmacological interventions has been increasingly recognized as a strategy to fight many of these disorders. Cellular processes that are aberrant in case of impaired autophagy and that might lead to these diseases belong to three different categories: (1) clearing of protein aggregates, (2) regulation of vesicle and cargo turnover, and (3) disposal of damaged mitochondria. This review summarizes the present literature that addresses both, the impact and mechanisms of autophagy on the health of the peripheral nervous system and treatment proposals for human disorders associated with impaired autophagy.}, }
@article {pmid27095262, year = {2016}, author = {Eira, J and Silva, CS and Sousa, MM and Liz, MA}, title = {The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.}, journal = {Progress in neurobiology}, volume = {141}, number = {}, pages = {61-82}, doi = {10.1016/j.pneurobio.2016.04.007}, pmid = {27095262}, issn = {1873-5118}, mesh = {*Aging ; Cytoskeleton/drug effects/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism/*therapy ; }, abstract = {Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease.}, }
@article {pmid27095229, year = {2016}, author = {Yamamoto, Y}, title = {Coenzyme Q10 redox balance and a free radical scavenger drug.}, journal = {Archives of biochemistry and biophysics}, volume = {595}, number = {}, pages = {132-135}, doi = {10.1016/j.abb.2015.11.026}, pmid = {27095229}, issn = {1096-0384}, mesh = {Free Radical Scavengers/*pharmacology ; Oxidation-Reduction ; Oxidative Stress ; Ubiquinone/*analogs &amp; derivatives/metabolism ; }, }
@article {pmid27094743, year = {2016}, author = {Gnanapragasam, S and Hopkins, CW and Moulton, CD}, title = {Can pharmacotherapy improve depressive symptoms in patients with amyotrophic lateral sclerosis? A systematic review of the literature.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {3-4}, pages = {289-291}, doi = {10.3109/21678421.2015.1111385}, pmid = {27094743}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Antidepressive Agents/*therapeutic use ; Databases, Bibliographic/statistics &amp; numerical data ; Depressive Disorder/*drug therapy/*etiology ; Humans ; }, }
@article {pmid27093948, year = {2016}, author = {Shahrizaila, N and Sobue, G and Kuwabara, S and Kim, SH and Birks, C and Fan, DS and Bae, JS and Hu, CJ and Gourie-Devi, M and Noto, Y and Shibuya, K and Goh, KJ and Kaji, R and Tsai, CP and Cui, L and Talman, P and Henderson, RD and Vucic, S and Kiernan, MC}, title = {Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {87}, number = {8}, pages = {821-830}, doi = {10.1136/jnnp-2015-312751}, pmid = {27093948}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*epidemiology/genetics/mortality ; Asia/epidemiology ; Disease Progression ; Humans ; Motor Neuron Disease/*complications/*epidemiology/genetics/mortality ; Phenotype ; Syndrome ; }, abstract = {While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.}, }
@article {pmid27089615, year = {2016}, author = {Tienari, P and Kiviharju, A and Valori, M and Lindholm, D and Laaksovirta, H}, title = {[The pathogenesis of amyotrophic lateral sclerosis and frontal lobe dementia is unraveling: pathology of the nucleus and glutamate sensitivity].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {132}, number = {5}, pages = {423-431}, pmid = {27089615}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/metabolism/*pathology ; C9orf72 Protein ; DNA Repeat Expansion/genetics ; Frontotemporal Dementia/epidemiology/*genetics/metabolism/*pathology ; Glutamic Acid/metabolism ; Humans ; Mutation ; Proteins/*genetics ; }, abstract = {The mechanisms of neurodegenerative diseases have begun to become unraveled, thanks to the progress in stem cell research. The repeat expansion in the C90RF72 gene was identified in 2011 as the most common genetic cause of both ALS and frontal lobe dementia. Only over a couple of years the disease mechanisms of this mutation have been revealed and treatment trials have already been conducted in nerve cell cultures differentiated from patients' stem cells. We discuss the role of the repeat expansion in the C90RF72 gene in the epidemiology of the diseases and the resulting disturbances in nerve cell function.}, }
@article {pmid27087014, year = {2016}, author = {Jovičić, A and Paul, JW and Gitler, AD}, title = {Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Journal of neurochemistry}, volume = {138 Suppl 1}, number = {}, pages = {134-144}, doi = {10.1111/jnc.13642}, pmid = {27087014}, issn = {1471-4159}, support = {R01 NS093865/NS/NINDS NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/*genetics ; Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics/*metabolism ; Humans ; RNA-Binding Protein FUS/genetics ; TDP-43 Proteinopathies/genetics/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.}, }
@article {pmid27078045, year = {2016}, author = {Janssens, AI and Ruytings, M and Al-Chalabi, A and Chio, A and Hardiman, O and Mcdermott, CJ and Meyer, T and Mora, G and Van Damme, P and Van Den Berg, LH and Vanhaecht, K and Winkler, AS and Sermeus, W and , }, title = {A mapping review of international guidance on the management and care of amyotrophic lateral sclerosis (ALS).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {5-6}, pages = {325-336}, doi = {10.3109/21678421.2016.1167911}, pmid = {27078045}, issn = {2167-9223}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Databases, Factual/statistics &amp; numerical data ; *Disease Management ; Humans ; International Cooperation ; *Practice Guidelines as Topic ; }, abstract = {Management of ALS is suboptimal. Consequently, quality improvement interventions are needed to improve ALS care. An evidence-based insight into how patients should be managed is essential when developing quality improvement interventions. Therefore, this study aimed to map, categorize and summarize international guidance on the management and care of ALS and to identify gaps in this guidance by means of a mapping review. Literature was searched for clinical practice guidelines, quality indicators and evidence-based clinical summaries. A content analysis and meta-synthesis of the included literature was performed. Interventions and outcomes used in the management and care of ALS were identified and categorized. Furthermore, the amount of guidance underpinning these interventions and outcomes was analysed. Six clinical practice guidelines, one set of quality indicators and three evidence-based clinical summaries were identified. The results demonstrated that certain domains in ALS care, mainly disease-specific domains such as breathing and swallowing, are extensively addressed in the literature whereas other subjects, such as care coordination, receive little attention. In conclusion, this mapping review provides a scientific basis for targeting and developing the clinical content of a quality improvement intervention for the management of ALS.}, }
@article {pmid27064956, year = {2016}, author = {Vega, IE}, title = {EFhd2, a Protein Linked to Alzheimer's Disease and Other Neurological Disorders.}, journal = {Frontiers in neuroscience}, volume = {10}, number = {}, pages = {150}, pmid = {27064956}, issn = {1662-4548}, support = {R25 GM061151/GM/NIGMS NIH HHS/United States ; R25 NS080687/NS/NINDS NIH HHS/United States ; SC1 NS066988/NS/NINDS NIH HHS/United States ; }, abstract = {EFhd2 is a conserved calcium binding protein linked to different neurological disorders and types of cancer. Although, EFhd2 is more abundant in neurons, it is also found in other cell types. The physiological function of this novel protein is still unclear, but it has been shown in vitro to play a role in calcium signaling, apoptosis, actin cytoskeleton, and regulation of synapse formation. Recently, EFhd2 was shown to promote cell motility by modulating the activity of Rac1, Cdc42, and RhoA. Although, EFhd2's role in promoting cell invasion and metastasis is of great interest in cancer biology, this review focusses on the evidence that links EFhd2 to Alzheimer's disease (AD) and other neurological disorders. Altered expression of EFhd2 has been documented in AD, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and schizophrenia, indicating that Efhd2 gene expression is regulated in response to neuropathological processes. However, the specific role that EFhd2 plays in the pathophysiology of neurological disorders is still poorly understood. Recent studies demonstrated that EFhd2 has structural characteristics similar to amyloid proteins found in neurological disorders. Moreover, EFhd2 co-aggregates and interacts with known neuropathological proteins, such as tau, C9orf72, and Lrrk2. These results suggest that EFhd2 may play an important role in the pathophysiology of neurodegenerative diseases. Therefore, the understanding of EFhd2's role in health and disease could lead to decipher molecular mechanisms that become activated in response to neuronal stress and degeneration.}, }
@article {pmid27064076, year = {2016}, author = {Parakh, S and Atkin, JD}, title = {Protein folding alterations in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1648}, number = {Pt B}, pages = {633-649}, doi = {10.1016/j.brainres.2016.04.010}, pmid = {27064076}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*physiopathology ; Animals ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Humans ; Molecular Chaperones/genetics ; Mutation/genetics ; *Protein Folding ; Proteostasis Deficiencies/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Protein misfolding leads to the formation of aggregated proteins and protein inclusions, which are associated with synaptic loss and neuronal death in neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that targets motor neurons in the brain, brainstem and spinal cord. Several proteins misfold and are associated either genetically or pathologically in ALS, including superoxide dismutase 1 (SOD1), Tar DNA binding protein-43 (TDP-43), Ubiquilin-2, p62, VCP, and dipeptide repeat proteins produced by unconventional repeat associated non-ATG translation of the repeat expansion in C9ORF72. Chaperone proteins, including heat shock proteins (Hsp׳s) and the protein disulphide isomerase (PDI) family, assist in protein folding and therefore can prevent protein misfolding, and have been implicated as being protective in ALS. In this review we provide an overview of the current literature regarding the molecular mechanisms of protein misfolding and aggregation in ALS, and the role of chaperones as potential targets for therapeutic intervention. This article is part of a Special Issue entitled SI:ER stress.}, }
@article {pmid27063798, year = {2017}, author = {Bartus, RT and Johnson, EM}, title = {Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 1: Where have we been and what have we learned?.}, journal = {Neurobiology of disease}, volume = {97}, number = {Pt B}, pages = {156-168}, doi = {10.1016/j.nbd.2016.03.027}, pmid = {27063798}, issn = {1095-953X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Nerve Growth Factors/*administration &amp; dosage/genetics ; Neurodegenerative Diseases/*therapy ; Neuroprotective Agents/*administration &amp; dosage ; }, abstract = {Over the past 25years, about 3 dozen clinical reports have been published regarding the safety and possible efficacy of neurotrophic factors in patients with various neurodegenerative diseases. This effort involved a half dozen different neurotrophic factors, using at least 5 different general delivery approaches for ALS (amyolateral sclerosis), peripheral neuropathies, PD (Parkinson's disease) and AD (Alzheimer's disease). While none of these efforts have yet produced efficacy data sufficiently robust or reliable to establish neurotrophic factors as treatments for any human disease, the obstacles encountered and novel information reported, when viewed collectively, provide important insight to help future efforts. Three consistent themes emerge from these publications: (1) unexpected and undesirable side effects, at times serious, have plagued many efforts to deliver neurotrophic factors to humans; (2) the magnitude and consistency of clinical benefit has been disappointing; (3) by far that most consistently proposed reason for the side effects and poor efficacy has been inadequate dosing and delivery. This paper reviews and attempts to synthesize the available data derived from clinical tests of neurotrophic factors for neurodegenerative diseases. The obstacles encountered, the solutions attempted, and the lessons learned are discussed. The vast majority of solutions have involved changes in dosing paradigms and dose levels, which has primarily led to improved safety outcomes. However, lack of adequate efficacy remains a significant issue. While current efforts continue to focus exclusively on still-further changes in dosing parameters, a review of available data argues that it may now be the time to ask whether other, non-dose-related variables should be given more serious consideration as being responsible for the great divide that exists between the robust effects seen in animal models and the relatively weak effects seen in human neurodegenerative patients. Foremost among these appears to be the severe degeneration seen in the majority of patients enrolled in past and current trials testing neurotrophic factors in humans. A companion paper (Bartus and Johnson, 2016), reviews the contemporary data and concludes that compelling empirical evidence already exists for enrolling earlier-stage subjects as likely essential to achieving more robust and reliable benefit.}, }
@article {pmid27063797, year = {2017}, author = {Bartus, RT and Johnson, EM}, title = {Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 2: Where do we stand and where must we go next?.}, journal = {Neurobiology of disease}, volume = {97}, number = {Pt B}, pages = {169-178}, doi = {10.1016/j.nbd.2016.03.026}, pmid = {27063797}, issn = {1095-953X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Nerve Growth Factors/*administration &amp; dosage/genetics ; Neurodegenerative Diseases/*therapy ; Neuroprotective Agents/*administration &amp; dosage ; }, abstract = {The therapeutic potential of neurotrophic factors has been recognized for decades, with clinical trials in human neurodegenerative diseases extending back at least 25years. While improvements in clinical dosing paradigms have reduced the side effects commonly seen in the earlier trials, efficacy has remained a serious disappointment (reviewed in Bartus and Johnson, 2016). This lengthy clinical effort stands in contrast to robust effects consistently achieved from different neurotrophic factors in a variety of animal models of neurodegeneration. This review discusses the prevailing assumption and supporting data that the major reason for the disappointing efficacy of past clinical trials is related to suboptimal dosing methods. It is concluded that while further improvements in dosing parameters might be useful, a much greater problem centers around a number of specific morphologic and functional changes in neurons in human neurodegenerative disease that mitigate the ability of neurotrophic factors to exert their effects. Moreover, the biological substrate which neurotrophic factors depend upon to exert their effects continues to erode as time progresses, due to the progressive nature of these diseases. For this reason, most of the empirically-supported reasons contributing to the weak neurotrophic responses in human patients can be mitigated by enrolling less severely advanced cases. It is further concluded that recent clinical trials of neurotrophic factors have generated important evidence that shifts risk: benefit assessments to support enrolling earlier-stage patients. While the Alzheimer's field has begun to shift attention toward much earlier-stage (even prodromal) patients in trials intended to modify disease progression, other neurodegenerative diseases (e.g., Parkinson's, ALS and possibly HD) must now consider similar changes in approach.}, }
@article {pmid27060770, year = {2016}, author = {Green, KM and Linsalata, AE and Todd, PK}, title = {RAN translation-What makes it run?.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {30-42}, pmid = {27060770}, issn = {1872-6240}, support = {I01 BX001689/BX/BLRD VA/United States ; R01 NS086810/NS/NINDS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; I21 BX001841/BX/BLRD VA/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; T32 GM007315/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Ataxia/genetics ; *DNA Repeat Expansion ; Dipeptides/genetics ; Fragile X Syndrome/genetics ; Frontotemporal Dementia/genetics ; Humans ; Huntington Disease/genetics ; Neurodegenerative Diseases/*genetics ; Open Reading Frames ; *Peptide Chain Initiation, Translational ; Tremor/genetics ; }, abstract = {Nucleotide-repeat expansions underlie a heterogeneous group of neurodegenerative and neuromuscular disorders for which there are currently no effective therapies. Recently, it was discovered that such repetitive RNA motifs can support translation initiation in the absence of an AUG start codon across a wide variety of sequence contexts, and that the products of these atypical translation initiation events contribute to neuronal toxicity. This review examines what we currently know and do not know about repeat associated non-AUG (RAN) translation in the context of established canonical and non-canonical mechanisms of translation initiation. We highlight recent findings related to RAN translation in three repeat expansion disorders: CGG repeats in fragile X-associated tremor ataxia syndrome (FXTAS), GGGGCC repeats in C9orf72 associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and CAG repeats in Huntington disease. These studies suggest that mechanistic differences may exist for RAN translation dependent on repeat type, repeat reading frame, and the surrounding sequence context, but that for at least some repeats, RAN translation retains a dependence on some of the canonical translational initiation machinery. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid27059391, year = {2016}, author = {Gitler, AD and Tsuiji, H}, title = {There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {19-29}, pmid = {27059391}, issn = {1872-6240}, support = {R01 NS065317/NS/NINDS NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; R01 NS093865/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; C9orf72 Protein ; DNA Repeat Expansion ; Dipeptides/genetics ; Frontotemporal Dementia/*genetics ; Humans ; Mice ; *Mutation ; Proteins/*genetics ; RNA/metabolism ; }, abstract = {The discovery of C9orf72 mutations as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has awakened a surge of interest in deciphering how mutations in this mysterious gene cause disease and what can be done to stop it. C9orf72 harbors a hexanucleotide repeat, GGGGCC, in a non-coding region of the gene and a massive expansion of this repeat causes ALS, FTD, or both (FTD/ALS). Many questions lie ahead. What does this gene normally do? What is the consequence of an enormous GGGGCC repeat expansion on that gene's function? Could that hexanucleotide repeat expansion have additional pathological actions unrelated to C9orf72 function? There has been tremendous progress on all fronts in the quest to define how C9orf72 mutations cause disease. Many new experimental models have been constructed and unleashed in powerful genetic screens. Studies in mouse and human patient samples, including iPS-derived neurons, have provided unprecedented insights into pathogenic mechanisms. Three major hypotheses have emerged and are still being hotly debated in the field. These include (1) loss of function owing to decrease in the abundance of C9orf72 protein and its ability to carryout its still unknown cellular role; (2) RNA toxicity from bidirectionally transcribed sense (GGGGCC) and antisense (GGCCCC) transcripts that accumulate in RNA foci and might sequester critical RNA-binding proteins; (3) proteotoxicity from dipeptide repeat proteins produced by an unconventional form of translation from the expanded nucleotide repeats. Here we review the evidence in favor and against each of these three hypotheses. We also suggest additional experiments and considerations that we propose will help clarify which mechanism(s) are most important for driving disease and therefore most critical for considering during the development of therapeutic interventions. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid27049459, year = {2016}, author = {Brennan, FH and Lee, JD and Ruitenberg, MJ and Woodruff, TM}, title = {Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions.}, journal = {Seminars in immunology}, volume = {28}, number = {3}, pages = {292-308}, doi = {10.1016/j.smim.2016.03.015}, pmid = {27049459}, issn = {1096-3618}, mesh = {Brain/*pathology ; Clinical Trials as Topic ; Complement Activation ; Complement Inactivating Agents/*therapeutic use ; Complement System Proteins/*metabolism ; Disease Progression ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/immunology/*therapy ; Neuroprotection ; Treatment Outcome ; Wounds and Injuries/immunology/*therapy ; }, abstract = {The recognition that complement proteins are abundantly present and can have pathological roles in neurological conditions offers broad scope for therapeutic intervention. Accordingly, an increasing number of experimental investigations have explored the potential of harnessing the unique activation pathways, proteases, receptors, complexes, and natural inhibitors of complement, to mitigate pathology in acute neurotrauma and chronic neurodegenerative diseases. Here, we review mechanisms of complement activation in the central nervous system (CNS), and explore the effects of complement inhibition in cerebral ischemic-reperfusion injury, traumatic brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. We consider the challenges and opportunities arising from these studies. As complement therapies approach clinical translation, we provide perspectives on how promising complement-targeted therapeutics could become part of novel and effective future treatment options to improve outcomes in the initiation and progression stages of these debilitating CNS disorders.}, }
@article {pmid27038103, year = {2016}, author = {Yasuda, K and Mili, S}, title = {Dysregulated axonal RNA translation in amyotrophic lateral sclerosis.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {7}, number = {5}, pages = {589-603}, pmid = {27038103}, issn = {1757-7012}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Axons/*metabolism ; Biological Transport ; Humans ; Mice ; Mutant Proteins/*metabolism ; *Protein Biosynthesis ; RNA, Messenger/*metabolism ; RNA-Binding Proteins/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease that has been associated with a diverse array of genetic changes. Prominent among these are mutations in RNA-binding proteins (RBPs) or repeat expansions that give rise to toxic RNA species. RBPs are additionally central components of pathologic aggregates that constitute a disease hallmark, suggesting that dysregulation of RNA metabolism underlies disease progression. In the context of neuronal physiology, transport of RNAs and localized RNA translation in axons are fundamental to neuronal survival and function. Several lines of evidence suggest that axonal RNA translation is a central process perturbed by various pathogenic events associated with ALS. Dysregulated translation of specific RNA groups could underlie feedback effects that connect and reinforce disease manifestations. Among such candidates are RNAs encoding proteins involved in the regulation of microtubule dynamics. Further understanding of axonally dysregulated RNA targets and of the feedback mechanisms they induce could provide useful therapeutic insights. WIREs RNA 2016, 7:589-603. doi: 10.1002/wrna.1352 For further resources related to this article, please visit the WIREs website.}, }
@article {pmid27034475, year = {2016}, author = {Sechi, G and Sechi, E and Fois, C and Kumar, N}, title = {Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults.}, journal = {Nutrition reviews}, volume = {74}, number = {5}, pages = {281-300}, doi = {10.1093/nutrit/nuv107}, pmid = {27034475}, issn = {1753-4887}, mesh = {Adult ; Alzheimer Disease/etiology/metabolism ; Amyotrophic Lateral Sclerosis/etiology/metabolism ; Central Nervous System/metabolism/*pathology ; Humans ; Nervous System Diseases/*etiology/metabolism ; Parkinson Disease/etiology/metabolism ; Vitamin B Complex/*metabolism ; Vitamin B Deficiency/*complications/metabolism ; }, abstract = {B vitamin deficiency is a leading cause of neurological impairment and disability throughout the world. Multiple B vitamin deficiencies often coexist, and thus an understanding of the complex relationships between the different biochemical pathways regulated in the brain by these vitamins may facilitate prompter diagnosis and improved treatment. Particular populations at risk for multiple B vitamin deficiencies include the elderly, people with alcoholism, patients with heart failure, patients with recent obesity surgery, and vegetarians/vegans. Recently, new clinical settings that predispose individuals to B vitamin deficiency have been highlighted. Moreover, other data indicate a possible pathogenetic role of subclinical chronic B vitamin deficiency in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In light of these findings, this review examines the clinical manifestations of B vitamin deficiency and the effect of B vitamin deficiency on the adult nervous system. The interrelationships of multiple B vitamin deficiencies are emphasized, along with the clinical phenotypes related to B vitamin deficiencies. Recent advances in the clinical determinants and diagnostic clues of B vitamin deficiency, as well as the suggested therapies for B vitamin disorders, are described.}, }
@article {pmid27033833, year = {2016}, author = {Ruegsegger, C and Saxena, S}, title = {Proteostasis impairment in ALS.}, journal = {Brain research}, volume = {1648}, number = {Pt B}, pages = {571-579}, doi = {10.1016/j.brainres.2016.03.032}, pmid = {27033833}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; Autophagy/physiology ; Endoplasmic Reticulum Stress/physiology ; Humans ; Proteostasis Deficiencies/*complications ; Signal Transduction/physiology ; }, abstract = {In physiological conditions the maintenance of the cellular proteome is a prerequisite for optimal cell functioning and cell survival. Additionally, cells need to constantly sense and adapt to their changing environment and associated stressors. Cells achieve this via a set of molecular chaperones, protein clearance pathways as well as stress-associated signaling networks which work together to prevent protein misfolding, its aggregation and accumulation in subcellular compartments. These processes together form the proteostasis network which helps in maintaining cellular proteostasis. Imbalance or impairment in this processes is directly linked to ageing associated disorders such as diabetes, cancer, stroke, metabolic disorders, pulmonary fibrosis, inflammation and neurodegenerative diseases. In this review, we provide insights into the proteostasis process and how its failure governs neurodegenerative disorders with a special focus on Amyotrophic lateral sclerosis (ALS). This article is part of a Special Issue entitled SI:ER stress.}, }
@article {pmid27033831, year = {2016}, author = {Shang, Y and Huang, EJ}, title = {Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {65-78}, pmid = {27033831}, issn = {1872-6240}, support = {I01 BX001108/BX/BLRD VA/United States ; R21 OD011915/OD/NIH HHS/United States ; I01 BX002213/BX/BLRD VA/United States ; I21 BX001625/BX/BLRD VA/United States ; R01 NS098516/NS/NINDS NIH HHS/United States ; I01 RX002133/RX/RRD VA/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Animals, Genetically Modified ; DNA Damage ; DNA Repair ; DNA-Binding Proteins/metabolism ; Dendrites/metabolism/pathology ; Disease Models, Animal ; Humans ; *Mutation ; Neurodegenerative Diseases/genetics ; RNA/metabolism ; RNA Splicing ; RNA-Binding Protein FUS/chemistry/*genetics ; Synapses/metabolism/pathology ; }, abstract = {Recent advances in the genetics of amyotrophic lateral sclerosis (ALS) have provided key mechanistic insights to the pathogenesis of this devastating neurodegenerative disease. Among many etiologies for ALS, the identification of mutations and proteinopathies in two RNA binding proteins, TDP-43 (TARDBP or TAR DNA binding protein 43) and its closely related RNA/DNA binding protein FUS (fused in sarcoma), raises the intriguing possibility that perturbations to the RNA homeostasis and metabolism in neurons may contribute to the pathogenesis of these diseases. Although the similarities between TDP-43 and FUS suggest that mutations and proteinopathy involving these two proteins may converge on the same mechanisms leading to neurodegeneration, there is increasing evidence that FUS mutations target distinct mechanisms to cause early disease onset and aggressive progression of disease. This review focuses on the recent advances on the molecular, cellular and genetic approaches to uncover the mechanisms of wild type and mutant FUS proteins during development and in neurodegeneration. These findings provide important insights to understand how FUS mutations may perturb the maintenance of dendrites through fundamental processes in RNA splicing, RNA transport and DNA damage response/repair. These results contribute to the understanding of phenotypic manifestations in neurodegeneration related to FUS mutations, and to identify important directions for future investigations. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid27033377, year = {2016}, author = {Scheperjans, F}, title = {Can microbiota research change our understanding of neurodegenerative diseases?.}, journal = {Neurodegenerative disease management}, volume = {6}, number = {2}, pages = {81-85}, doi = {10.2217/nmt-2015-0012}, pmid = {27033377}, issn = {1758-2032}, mesh = {Animals ; Biomedical Research/*trends ; Brain/*microbiology/physiology ; Gastrointestinal Microbiome/*genetics ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics/*microbiology ; }, }
@article {pmid27033240, year = {2016}, author = {Bourke, SC and Steer, J}, title = {Practical respiratory management in amyotrophic lateral sclerosis: evidence, controversies and recent advances.}, journal = {Neurodegenerative disease management}, volume = {6}, number = {2}, pages = {147-160}, doi = {10.2217/nmt-2015-0010}, pmid = {27033240}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*therapy ; *Disease Management ; Evidence-Based Medicine/*methods/trends ; Humans ; Muscle Weakness/diagnosis/epidemiology/therapy ; Respiratory Insufficiency/diagnosis/epidemiology/*therapy ; Respiratory Therapy/*methods/trends ; }, abstract = {In amyotrophic lateral sclerosis, the onset of respiratory muscle weakness is silent, but survival following symptom recognition may only be a few weeks. Consequently, respiratory function and symptoms should be assessed every 2-3 months. Noninvasive ventilation improves symptoms, quality of life and survival, without increasing carer burden. Lung volume recruitment helps to reverse and prevent atelectasis, improving gas exchange, while techniques to enhance sputum clearance reduce the risk of mucus plugging and lower respiratory tract infections. When noninvasive support fails, often due to severe bulbar impairment, tracheostomy ventilation prolongs life. Most patients receiving tracheostomy ventilation at home report satisfactory quality of life, but at the expense of high carer burden. Diaphragmatic pacing is associated with an increased risk of death.}, }
@article {pmid27033194, year = {2017}, author = {Chong, CM and Ai, N and Lee, SM}, title = {ROCK in CNS: Different Roles of Isoforms and Therapeutic Target for Neurodegenerative Disorders.}, journal = {Current drug targets}, volume = {18}, number = {4}, pages = {455-462}, doi = {10.2174/1389450117666160401123825}, pmid = {27033194}, issn = {1873-5592}, mesh = {Animals ; Central Nervous System/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*metabolism ; Signal Transduction ; rho-Associated Kinases/*metabolism ; }, abstract = {Rho-associated protein kinase (ROCK) is a serine-threonine kinase originally identified as a crucial regulator of actin cytoskeleton. Recent studies have defined new functions of ROCK as a critical component of diverse signaling pathways in neurons. In addition, inhibition of ROCK causes several biological events such as increase of neurite outgrowth, axonal regeneration, and activation of prosurvival Akt. Thus, it has attracted scientist's strong attentions and considered ROCK as a promising therapeutic target for the treatment of neurodegenerative disorders including Alzheimer disease, Parkinson's disease, Huntington';s disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, ROCK has two highly homologous isoforms, ROCK1 and ROCK2. Accumulated evidences indicate that ROCK1 and ROCK2 might involve in distinct cellular functions in central nervous system (CNS) and neurodegenerative processes. This review summarizes recent updates regarding ROCK isoformspecific functions in CNS and the progress of ROCK inhibitors in preclinical studies for neurodegenerative diseases.}, }
@article {pmid29377035, year = {2016}, author = {Walker, RH}, title = {The non-Huntington disease choreas: Five new things.}, journal = {Neurology. Clinical practice}, volume = {6}, number = {2}, pages = {150-156}, pmid = {29377035}, issn = {2163-0402}, abstract = {PURPOSE OF REVIEW: Chorea can be due to a wide variety of causes. In this review, I provide updates on several recently identified genetic and autoimmune causes of chorea, and review evidence supporting the use of deep brain stimulation in chorea.<br><br>RECENT FINDINGS: New genes that may cause chorea include ADCY5 (encoding for adenylate cyclase 5) C9ORF72 (in addition to amyotrophic lateral sclerosis and frontotemporal dementia), and those responsible for the neurodegeneration with brain iron accumulation disorders. Novel autoantibodies are increasingly being identified as associated with a variety of neurologic syndromes, including chorea, in both paraneoplastic and non-paraneoplastic settings. Deep brain stimulation can be a useful intervention in patients with chorea who do not respond to oral medications, whether due to neurodegenerative or nondegenerative causes.<br><br>SUMMARY: New causes of chorea continue to be identified. Correct diagnosis is essential for prognostication and treatment.}, }
@article {pmid28722839, year = {2016}, author = {Budinčević, H and Marčinko Budinčević, A and Kos, M and Vlašić, S and Bartolović, J and Benko, S and Ostojić, V and Soldo Butković, S}, title = {[Multidisciplinary Management and Neurorehabilitation of Patients with Amyotrophic Lateral Sclerosis].}, journal = {Acta medica Croatica : casopis Hravatske akademije medicinskih znanosti}, volume = {70}, number = {2}, pages = {111-116}, pmid = {28722839}, issn = {1330-0164}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Comprehensive Health Care/*organization &amp; administration ; Disease Management ; Disease Progression ; Humans ; Neurological Rehabilitation/*methods ; Pain Management/methods ; Patient Care Team/*organization &amp; administration ; Quality of Life ; }, abstract = {Patients with amyotrophic lateral sclerosis require comprehensive care with a multidisciplinary approach, which is individually adjusted to each patient. The goals of neurorehabilitation should be adjusted to the stage of disease. In early stages, physical therapy is focused on preserving and optimizing motor and respiratory function. At this stage, family should be involved to partake in desired activities and be informed regarding the natural course of the disease. In late stages, physical therapy is focused on preventing respiratory complications and contractures, and orthotics may also be recommended. The onset of dysarthria should trigger swallowing and pulmonary function testing. Swallowing maneuvers should be tried at the onset of symptoms, later feeding tubes or percutaneous gastrostomy tube is necessary. Noninvasive mechanical ventilation may delay the need of tracheostomy and invasive mechanical ventilation. The key objectives of multidisciplinary teams are to optimize medical care, facilitate communication, and thus to improve the quality of care and quality of life.}, }
@article {pmid27031290, year = {2016}, author = {Richard-Lepouriel, H and Etain, B and Hasler, R and Bellivier, F and Gard, S and Kahn, JP and Prada, P and Nicastro, R and Ardu, S and Dayer, A and Leboyer, M and Aubry, JM and Perroud, N and Henry, C}, title = {Similarities between emotional dysregulation in adults suffering from ADHD and bipolar patients.}, journal = {Journal of affective disorders}, volume = {198}, number = {}, pages = {230-236}, doi = {10.1016/j.jad.2016.03.047}, pmid = {27031290}, issn = {1573-2517}, mesh = {Adult ; Affective Symptoms/*epidemiology/*psychology ; Attention Deficit Disorder with Hyperactivity/*epidemiology/*psychology ; Bipolar Disorder/*epidemiology/*psychology ; Comorbidity ; Emotions ; Female ; Humans ; Male ; Retrospective Studies ; Severity of Illness Index ; Switzerland/epidemiology ; }, abstract = {BACKGROUND: Emotional dysregulation in subjects with attention deficit and hyperactivity disorder (ADHD) is a topic of growing interest among clinicians and researchers. The present study aims at investigating components of emotional dysregulation in adults ADHD compared to subjects suffering from bipolar disorder (BD).<br><br>METHODS: A total of 150 adults ADHD, 335 adults BD subjects and 48 controls were assessed using the Affective Lability Scale (ALS) and the Affect Intensity Measure (AIM), measuring respectively emotion lability and emotion responsiveness.<br><br>RESULTS: ADHD and BD subjects scored significantly higher on the ALS compared to controls (p=0.0001). BD subjects scored above ADHD ones (3.07 (SD=0.66) vs. 2.30 (SD=0.68); p<0.0001). The average total scores achieved on the AIM were significantly different for the three groups (p=0.0001) with significantly higher scores for ADHD subjects compared to BD ones (3.74 (SD=0.59) vs. 3.56 (SD=0.69); p<0.0001).<br><br>LIMITATIONS: Suspected cases of ADHD in the BD and control groups were derived from the Wender Utah Rating Scale (WURS). This study is a retrospective one.<br><br>CONCLUSION: Our study thus highlights the importance of emotional dysregulation in adults suffering from ADHD, showing that they display higher emotional intensity than bipolar disorder subjects and controls. Although the current diagnostic criteria of ADHD do not contain an emotional dimension, a better recognition of the significance of emotional responsiveness in ADHD patients can improve the care afforded to these patients, beyond the inattentive and hyperactive/impulsive components.}, }
@article {pmid27030902, year = {2016}, author = {Tams, R and Prangnell, SJ and Daisley, A}, title = {Helping families thrive in the face of uncertainty: Strengths based approaches to working with families affected by progressive neurological illness.}, journal = {NeuroRehabilitation}, volume = {38}, number = {3}, pages = {257-270}, doi = {10.3233/NRE-161317}, pmid = {27030902}, issn = {1878-6448}, mesh = {*Disease Progression ; *Family ; *Family Therapy ; Humans ; Nervous System Diseases/*nursing ; *Uncertainty ; }, abstract = {BACKGROUND: Management of the uncertainty inherent in a diagnosis of a progressive neurological illness is one of the major adjustment tasks facing those affected and their families. A causal relationship has been demonstrated between perceived illness uncertainty and negative psychological outcomes for individuals with progressive neurological illness. Whilst there is a small and promising intervention literature on the use of a range of individually focused strengths based psychological interventions there appears to be little guidance available how clinicians might help those family members of those affected.<br><br>OBJECTIVE: To undertake a systematic review of the evidence on the use of strengths based, family focused interventions that target illness uncertainty.<br><br>METHODS: A systematic literature search was undertaken using the National Library for Health abstract database.<br><br>RESULTS: Five papers were included in the review, only two of which were published in peer reviewed journals. All five reported on strengths based approaches that could be used with families but only two explicitly identified illness uncertainty as a target. Outcome measures were heterogeneous so data could not be aggregated for meta-analysis. The results suggested that these interventions showed promised but the review highlighted a number of methodological issues which mean that the results must be interpreted with caution.<br><br>CONCLUSIONS: There is very little evidence of the use of strengths based approaches to helping families manage the uncertainty associated with progressive neurological illness despite it having been identified as a key target for intervention. The review highlights the need for the development of an intervention framework to address this key clinical issue and suggests one model that might show promise.}, }
@article {pmid27028664, year = {2016}, author = {Gadhave, K and Bolshette, N and Ahire, A and Pardeshi, R and Thakur, K and Trandafir, C and Istrate, A and Ahmed, S and Lahkar, M and Muresanu, DF and Balea, M}, title = {The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.}, journal = {Journal of cellular and molecular medicine}, volume = {20}, number = {7}, pages = {1392-1407}, pmid = {27028664}, issn = {1582-4934}, mesh = {Alzheimer Disease/*metabolism ; Animals ; Humans ; Models, Biological ; *Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/*metabolism ; Ubiquitin/*metabolism ; }, abstract = {The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS-related therapies for AD.}, }
@article {pmid27027889, year = {2016}, author = {Bozzoni, V and Pansarasa, O and Diamanti, L and Nosari, G and Cereda, C and Ceroni, M}, title = {Amyotrophic lateral sclerosis and environmental factors.}, journal = {Functional neurology}, volume = {31}, number = {1}, pages = {7-19}, pmid = {27027889}, issn = {1971-3274}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Electromagnetic Fields/*adverse effects ; Environmental Exposure/*adverse effects ; Humans ; Metals, Heavy/*adverse effects ; Pesticides/*adverse effects ; Risk Factors ; *Sports ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects central and peripheral motor neuron cells. Its etiology is unknown, although a relationship between genetic background and environmental factors may play a major role in triggering the neurodegeneration. In this review, we analyze the role of environmental factors in ALS: heavy metals, electromagnetic fields and electric shocks, pesticides, β-N-methylamino-L-alanine, physical activity and the controversial role of sports. The literature on the single issues is analyzed in an attempt to clarify, as clearly as possible, whether each risk factor significantly contributes to the disease pathogenesis. After summarizing conflicting observations and data, the authors provide a final synthetic statement.}, }
@article {pmid27027466, year = {2016}, author = {Hobson, EV and Baird, WO and Cooper, CL and Mawson, S and Shaw, PJ and Mcdermott, CJ}, title = {Using technology to improve access to specialist care in amyotrophic lateral sclerosis: A systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {5-6}, pages = {313-324}, doi = {10.3109/21678421.2016.1165255}, pmid = {27027466}, issn = {2167-9223}, support = {DRF-2013-06-076/DH_/Department of Health/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Databases, Factual/statistics &amp; numerical data ; Delivery of Health Care/*methods ; Humans ; Quality of Life ; Randomized Controlled Trials as Topic ; Respiratory Insufficiency/etiology/*therapy ; Telemedicine/*methods ; }, abstract = {Our objective was to review the evidence for using technology to improve access to specialist care for patients with amyotrophic lateral sclerosis (ALS) and their carers. Medline, Google Scholar and the Cochrane library were searched for articles describing technology that enabled clinical care of patients with ALS or their carers where the patient/carer and clinician were not in the same location. Two applications were identified: telemedicine to facilitate video conferencing as an alternative to outpatient consultations and telehealth monitoring for patients with respiratory failure. One randomized controlled trial using telehealth in patients with respiratory failure including 22 patients with ALS was identified. While rates of hospitalization were reduced, overall mortality was unchanged and there were too few patients with ALS in the study to detect significant benefit. In conclusion, there is limited evidence to support the use of telemedicine or telehealth in the care of patients with ALS. Future research needs to develop an understanding of the key beneficial aspects of the traditional specialist ALS service and how these factors could be delivered using technology. Successful evaluation and implementation of technologies to facilitate access to specialist care will only be possible if all the relevant impacts of an intervention are understood and measured.}, }
@article {pmid27026167, year = {2016}, author = {Ferreira, GD and Costa, AC and Plentz, RD and Coronel, CC and Sbruzzi, G}, title = {Respiratory training improved ventilatory function and respiratory muscle strength in patients with multiple sclerosis and lateral amyotrophic sclerosis: systematic review and meta-analysis.}, journal = {Physiotherapy}, volume = {102}, number = {3}, pages = {221-228}, doi = {10.1016/j.physio.2016.01.002}, pmid = {27026167}, issn = {1873-1465}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*rehabilitation ; *Breathing Exercises ; Disability Evaluation ; Humans ; Multiple Sclerosis/*physiopathology/*rehabilitation ; Quality of Life ; Respiratory Function Tests ; }, abstract = {BACKGROUND: Among neurodegenerative diseases, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) have a high rate of respiratory disability.<br><br>OBJECTIVES: To analyze the effects of respiratory muscle training (RMT) on ventilatory function, muscle strength and functional capacity in patients with MS or ALS.<br><br>DATA SOURCES: A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed. The sources were MEDLINE, PEDro, Cochrane CENTRAL, EMBASE, and LILACS, from inception to January 2015.<br><br>The following were included: RCTs of patients with neurodegenerative diseases (MS or lateral ALS) who used the intervention as RMT (inspiratory/expiratory), comparison with controls who had not received RMT full time or were receiving training without load, and evaluations of ventilatory function (forced vital capacity - FVC, forced expiratory volume in one second - FEV1, maximum voluntary ventilation - MVV), respiratory muscle strength (maximal expiratory pressure/maximum inspiratory pressure - MEP/MIP) and functional capacity (6-minute walk test - 6MWT).<br><br>RESULTS: The review included nine papers, and a total of 194 patients. It was observed that RMT significantly increased at MIP (23.50cmH2O; 95% CI: 7.82 to 39.19), MEP (12.03cmH2O; 95% CI: 5.50 to 18.57) and FEV1 (0.27L; 95% CI: 0.12 to 0.42) compared to the control group, but did not differ in FVC (0.48L; 95% CI: -0.15 to 1.10) and distance in 6MWT (17.95m; 95% CI: -4.54 to 40.44).<br><br>CONCLUSION: RMT can be an adjunctive therapy in the rehabilitation of neurodegenerative diseases improving ventilatory function and respiratory strength.}, }
@article {pmid27025993, year = {2016}, author = {Kimura, F}, title = {[Tracheostomy and invasive mechanical ventilation in amyotrophic lateral sclerosis: decision-making factors and survival analysis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {56}, number = {4}, pages = {241-247}, doi = {10.5692/clinicalneurol.cn-000837}, pmid = {27025993}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/mortality/*therapy ; *Clinical Decision-Making ; Disease Progression ; Humans ; Noninvasive Ventilation/*statistics &amp; numerical data/trends ; Prognosis ; Respiration, Artificial/*statistics &amp; numerical data/trends ; Severity of Illness Index ; Survival Analysis ; Time Factors ; Tracheotomy/*statistics &amp; numerical data/trends ; }, abstract = {BACKGROUND: Invasive and/or non-invasive mechanical ventilation are most important options of respiratory management in amyotrophic lateral sclerosis.<br><br>METHODS: We evaluated the frequency, clinical characteristics, decision-making factors about ventilation and survival analysis of 190 people with amyotrophic lateral sclerosis patients from 1990 until 2013.<br><br>RESULTS: Thirty-one percentage of patients underwent tracheostomy invasive ventilation with the rate increasing more than the past 20 years. The ratio of tracheostomy invasive ventilation in patients >65 years old was significantly increased after 2000 (25%) as compared to before (10%). After 2010, the standard use of non-invasive ventilation showed a tendency to reduce the frequency of tracheostomy invasive ventilation. Mechanical ventilation prolonged median survival (75 months in tracheostomy invasive ventilation, 43 months in non-invasive ventilation vs natural course, 32 months). The life-extending effects by tracheostomy invasive ventilation were longer in younger patients &#x2264;65 years old at the time of ventilation support than in older patients. Presence of partners and care at home were associated with better survival. Following factors related to the decision to perform tracheostomy invasive ventilation: patients &#x2264;65 years old: greater use of non-invasive ventilation: presence of a spouse: faster tracheostomy: higher progression rate; and preserved motor functions. No patients who underwent tracheostomy invasive ventilation died from a decision to withdraw mechanical ventilation.<br><br>CONCLUSION: The present study provides factors related to decision-making process and survival after tracheostomy and help clinicians and family members to expand the knowledge about ventilation.}, }
@article {pmid27025851, year = {2016}, author = {Riva, N and Agosta, F and Lunetta, C and Filippi, M and Quattrini, A}, title = {Recent advances in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {263}, number = {6}, pages = {1241-1254}, pmid = {27025851}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*therapy ; Humans ; }, abstract = {ALS is a relentlessly progressive and fatal disease, with no curative therapies available to date. Symptomatic and palliative care, provided in a multidisciplinary context, still remains the cornerstone of ALS management. However, our understanding of the molecular mechanisms underlying the disease has advanced greatly over the past years, giving new hope for the development of novel diagnostic and therapeutic approaches. Here, we have reviewed the most recent studies that have contributed to improving both clinical management and our understanding of ALS pathogenesis.}, }
@article {pmid27023045, year = {2016}, author = {Moon, Y and Sung, J and An, R and Hernandez, ME and Sosnoff, JJ}, title = {Gait variability in people with neurological disorders: A systematic review and meta-analysis.}, journal = {Human movement science}, volume = {47}, number = {}, pages = {197-208}, doi = {10.1016/j.humov.2016.03.010}, pmid = {27023045}, issn = {1872-7646}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; }, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Central Nervous System Diseases/*physiopathology ; Cerebellar Ataxia/physiopathology ; *Gait ; Humans ; Huntington Disease/physiopathology ; Multiple Sclerosis/physiopathology ; Parkinson Disease/physiopathology ; }, abstract = {There has been growing evidence showing gait variability provides unique information about gait characteristics in neurological disorders. This study systemically reviewed and quantitatively synthesized (via meta-analysis) existing evidence on gait variability in various neurological diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), cerebellar ataxia (CA), Huntington's disease (HD), multiple sclerosis (MS), and Parkinson's disease (PD). Keyword search were conducted in PubMed, Web of science, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library. Meta-analysis was performed to estimate the pooled effect size for gait variability for each neurological group. Meta-regression was performed to compare gait variability across multiple groups with neurological diseases. Gait variability of 777 patients with AD, ALS, CA, HD, MS, or PD participating in 25 studies was included in meta-analysis. All pathological groups had increased amount of gait variability and loss of fractal structure of gait dynamics compared to healthy controls, and gait variability differentiated distinctive neurological conditions. The HD groups had the highest alterations in gait variability among all pathological groups, whereas the PD, AD and MS groups had the lowest. Interventions that aim to improve gait function in patients with neurological disorders should consider the heterogeneous relationship between gait variability and neurological conditions.}, }
@article {pmid27021939, year = {2016}, author = {Sances, S and Bruijn, LI and Chandran, S and Eggan, K and Ho, R and Klim, JR and Livesey, MR and Lowry, E and Macklis, JD and Rushton, D and Sadegh, C and Sareen, D and Wichterle, H and Zhang, SC and Svendsen, CN}, title = {Modeling ALS with motor neurons derived from human induced pluripotent stem cells.}, journal = {Nature neuroscience}, volume = {19}, number = {4}, pages = {542-553}, pmid = {27021939}, issn = {1546-1726}, support = {R01 NS049553/NS/NINDS NIH HHS/United States ; R37NS041590/NS/NINDS NIH HHS/United States ; R37 NS041590/NS/NINDS NIH HHS/United States ; R01 NS041590/NS/NINDS NIH HHS/United States ; R01NS045523/NS/NINDS NIH HHS/United States ; R01NS075672/NS/NINDS NIH HHS/United States ; T32 GM007753/GM/NIGMS NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 NS045523/NS/NINDS NIH HHS/United States ; R01NS049553/NS/NINDS NIH HHS/United States ; R01 NS075672/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; *Cell Differentiation/physiology ; Cells, Cultured ; Coculture Techniques/methods ; Humans ; Induced Pluripotent Stem Cells/*pathology/physiology ; Motor Neurons/*pathology/physiology ; }, abstract = {Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis (ALS). However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or coculture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.}, }
@article {pmid27019797, year = {2016}, author = {Balendra, R and Patani, R}, title = {Quo vadis motor neuron disease?.}, journal = {World journal of methodology}, volume = {6}, number = {1}, pages = {56-64}, pmid = {27019797}, issn = {2222-0682}, abstract = {Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The aetio-pathogenesis of MND remains unresolved and no effective treatments exist. The only Food and Drug Administration approved disease modifying therapy is riluzole, a glutamate antagonist, which prolongs survival by up to 3 mo. Current management is largely symptomatic/supportive. There is therefore a desperate and unmet clinical need for discovery of disease mechanisms to guide novel therapeutic strategy. In this review, we start by introducing the organizational anatomy of the motor system, before providing a clinical overview of its dysfunction specifically in MND. We then summarize insights gained from pathological, genetic and animal models and conclude by speculating on optimal strategies to drive the step change in discovery, which is so desperately needed in this arena.}, }
@article {pmid29858890, year = {2016}, author = {Yang, S and He, R and Zhang, FY and Xue, Q and Xu, XY}, title = {[Application of cell co-culture techniques in central nervous system diseases].}, journal = {Yao xue xue bao = Acta pharmaceutica Sinica}, volume = {51}, number = {3}, pages = {338-346}, pmid = {29858890}, issn = {0513-4870}, mesh = {Animals ; Astrocytes/*cytology ; Brain/cytology ; Cell Culture Techniques ; Central Nervous System ; *Central Nervous System Diseases ; *Coculture Techniques ; Endothelial Cells/*cytology ; Humans ; Neurons/*cytology ; }, abstract = {The study of central nervous system disease is dependent on in vitro culture of neuronal cells. However, it is hard to determine the interaction between cells in culture of single type of neuronal cells. The co-culture system is able to mimic the cell-cell interaction in the brain and to facilitate investigation into the interaction between different types of cells, as well as cell-environment interaction. The co-culture of neurocytes is more and more popular in the disease study of central nervous system in vitro, such as stroke, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, etc. Neurovascular unit(NVU), which is composed of neurons, brain microvascular endothelial cells and astrocytes, can reflect the structure and function of brain in state of the art. Establishment of NVU in vitro is important in the study of the brain diseases. In this paper, several co-culture models of the central nervous system are reviewed in techniques for two-dimensional and three-dimensional culturing. Cell contact and non-contact methods are compared. Moreover, their application in the relevant research and the future direction are explored.}, }
@article {pmid29461733, year = {2016}, author = {de Schoutheete, JC and Hachimi Idrissi, S and Watelet, JB}, title = {Pre-hospital interventions: introduction to life support systems.}, journal = {B-ENT}, volume = {Suppl 26}, number = {1}, pages = {41-54}, pmid = {29461733}, issn = {1781-782X}, mesh = {*Emergency Medical Services ; Humans ; *Life Support Care ; *Life Support Systems ; Mass Casualty Incidents ; Military Medicine ; Otolaryngology ; Patient Care Team ; Triage ; War-Related Injuries/diagnosis/*therapy ; }, abstract = {Pre-hospital interventions: introduction to life support systems. Crucial decisions in pre-hospital emergency care are often made; therefore, a tactical emergency medical support team (TEMS) should maintain the capacity to capture the situation instantaneously and in all circumstances. However, low exposure to severe trauma cases can be a weakness for emergency specialists, which makes pre-hospital assessment more difficult. Pre-hospital interventions (PHI) are usually classified in Western countries into BLS (basic life support) and ALS (ad- vanced life support) levels, according to the methods used. This review introduces tactical combat casualty care for medical personnel (TCCC) guidelines, designed for basic care management under fire or in a hostile environment. The phases of TCCC are: (1) care under fire (or in an unstable environment); (2) tactical field care; and (3) tactical evacuation care, and are mainly dependent on the different hazard zones (hot, warm or cold). In a mass casualty situation due to disaster or cataclysm, standardized protocol and triage are unquestionably required for identifying the environmental risks, for categorizing the casualties in accordance with medical care priorities, and for the initial management of casualty care. When considering conflict situations, or chemical, biological, radiological, or nuclear (CBRN) events, processes always start at the local level. Even before the detection and analysis of agents can be undertaken, zoning, triage, decontamination, and treatment should be initiated promptly. Otorhinolaryngologists should be aware of PHI procedures for completing preliminary assessment and management together with emergency specialists or TEMS.}, }
@article {pmid29213986, year = {2015}, author = {da Rocha, AJ and Nunes, RH and Maia, ACM}, title = {Dementia in motor neuron disease: Reviewing the role of MRI in diagnosis.}, journal = {Dementia &amp; neuropsychologia}, volume = {9}, number = {4}, pages = {369-379}, pmid = {29213986}, issn = {1980-5764}, abstract = {The superimposed clinical features of motor neuron disease (MND) and frontotemporal dementia (FTD) comprise a distinct, yet not fully understood, neurological overlap syndrome whose clinicopathological basis has recently been reviewed. Here, we present a review of the clinical, pathological and genetic basis of MND-FTD and the role of MRI in its diagnosis. In doing so, we discuss current techniques that depict the involvement of the selective corticospinal tract (CST) and temporal lobe in MND-FTD.}, }
@article {pmid28031870, year = {2015}, author = {Peffer, S and Cope, K and Morano, KA}, title = {Unraveling protein misfolding diseases using model systems.}, journal = {Future science OA}, volume = {1}, number = {2}, pages = {FSO41}, pmid = {28031870}, issn = {2056-5623}, support = {R01 GM074696/GM/NIGMS NIH HHS/United States ; }, abstract = {Experimental model systems have long been used to probe the causes, consequences and mechanisms of pathology leading to human disease. Ideally, such information can be exploited to inform the development of therapeutic strategies or treatments to combat disease progression. In the case of protein misfolding diseases, a wide range of model systems have been developed to investigate different aspects of disorders including Huntington's disease, Parkinson's disease, Alzheimer's disease as well as amyotrophic lateral sclerosis. Utility of these systems broadly correlates with evolutionary complexity: small animal models such as rodents and the fruit fly are appropriate for pharmacological modeling and cognitive/behavioral assessment, the roundworm Caenorhabditis elegans allows analysis of tissue-specific disease features, and unicellular organisms such as the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli are ideal for molecular studies. In this chapter, we highlight key advances in our understanding of protein misfolding/unfolding disease provided by model systems.}, }
@article {pmid29213965, year = {2015}, author = {Takada, LT}, title = {The Genetics of Monogenic Frontotemporal Dementia.}, journal = {Dementia &amp; neuropsychologia}, volume = {9}, number = {3}, pages = {219-229}, pmid = {29213965}, issn = {1980-5764}, abstract = {Around 10-15% of patients diagnosed with frontotemporal dementia (FTD) have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT (microtubule-associated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN (progranulin) and C9orf72 (chromosome 9 open reading frame 72) are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND) can be caused by mutations in C9orf72 and other genes, such as TARDBP (TAR DNA-binding protein), FUS (fused in sarcoma), UBQLN2 (ubiquilin 2). Multisystem proteinopathy is a complex phenotype that includes FTD, Paget disease of the bone, inclusion body myopathy and MND, and can be due to mutations in VCP (valosing containing protein) and other recently identified genes.}, }
@article {pmid28548072, year = {2014}, author = {Matsumoto, K and Funakoshi, H and Takahashi, H and Sakai, K}, title = {HGF-Met Pathway in Regeneration and Drug Discovery.}, journal = {Biomedicines}, volume = {2}, number = {4}, pages = {275-300}, pmid = {28548072}, issn = {2227-9059}, abstract = {Hepatocyte growth factor (HGF) is composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. Activation of the HGF-Met pathway evokes dynamic biological responses that support morphogenesis (e.g., epithelial tubulogenesis), regeneration, and the survival of cells and tissues. Characterizations of conditional Met knockout mice have indicated that the HGF-Met pathway plays important roles in regeneration, protection, and homeostasis in various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. The promotion of cell growth, survival, migration, and morphogenesis that is associated with extracellular matrix proteolysis are the biological activities that underlie the therapeutic actions of HGF. Recombinant HGF protein and the expression vectors for HGF are biological drug candidates for the treatment of patients with diseases and injuries that are associated with impaired tissue function. The intravenous/systemic administration of recombinant HGF protein has been well tolerated in phase I/II clinical trials. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing.}, }
@article {pmid27713255, year = {2010}, author = {Bordet, T and Berna, P and Abitbol, JL and Pruss, RM}, title = {Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {3}, number = {2}, pages = {345-368}, pmid = {27713255}, issn = {1424-8247}, abstract = {Olesoxime (TRO19622) is a novel mitochondrial-targeted neuroprotective compound undergoing a pivotal clinical efficacy study in Amyotrophic Lateral Sclerosis (ALS) and also in development for Spinal Muscular Atrophy (SMA). It belongs to a new family of cholesterol-oximes identified for its survival-promoting activity on purified motor neurons deprived of neurotrophic factors. Olesoxime targets proteins of the outer mitochondrial membrane, concentrates at the mitochondria and prevents permeability transition pore opening mediated by, among other things, oxidative stress. Olesoxime has been shown to exert a potent neuroprotective effect in various in vitro and in vivo models. In particular olesoxime provided significant protection in experimental animal models of motor neuron disorders and more particularly ALS. Olesoxime is orally active, crosses the blood brain barrier, and is well tolerated. Collectively, its pharmacological properties designate olesoxime as a promising drug candidate for motor neuron diseases.}, }
@article {pmid27713238, year = {2009}, author = {Cardoso, S and Santos, R and Correia, S and Carvalho, C and Zhu, X and Lee, HG and Casadesus, G and Smith, MA and Perry, G and Moreira, PI}, title = {Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {2}, number = {3}, pages = {250-286}, pmid = {27713238}, issn = {1424-8247}, abstract = {Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.}, }
@article {pmid27713230, year = {2009}, author = {Mancuso, M and Orsucci, D and Calsolaro, V and Choub, A and Siciliano, G}, title = {Coenzyme Q10 and Neurological Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {2}, number = {3}, pages = {134-149}, pmid = {27713230}, issn = {1424-8247}, abstract = {Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because of defective synthesis. Primary CoQ10 deficiency is a treatable condition, so heightened "clinical awareness" about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been widely used in the treatment of other neurodegenerative disorders. These compounds could potentially play a therapeutic role in Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological diseases, from primary CoQ10 deficiency to neurodegenerative disorders.}, }
@article {pmid29213532, year = {2008}, author = {Marcourakis, T and Camarini, R and Kawamoto, EM and Scorsi, LR and Scavone, C}, title = {Peripheral biomarkers of oxidative stress in aging and Alzheimer's disease.}, journal = {Dementia &amp; neuropsychologia}, volume = {2}, number = {1}, pages = {2-8}, pmid = {29213532}, issn = {1980-5764}, abstract = {Aging is associated with a greatly increased incidence of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). These conditions are associated with chronic inflammation, which generates oxygen reactive species, ultimately responsible for a process known as oxidative stress. It is well established that this process is the culprit of neurodegeneration, and there are also mounting evidences that it is not restricted to the central nervous system. Indeed, several studies, including some by our group, have demonstrated that increased peripheral oxidative stress markers are associated to aging and, more specifically, to AD. Therefore, it is very instigating to regard aging and AD as systemic conditions that might be determined by studying peripheral markers of oxidative stress.}, }
@article {pmid27016703, year = {2016}, author = {Bryson, JB and Machado, CB and Lieberam, I and Greensmith, L}, title = {Restoring motor function using optogenetics and neural engraftment.}, journal = {Current opinion in biotechnology}, volume = {40}, number = {}, pages = {75-81}, doi = {10.1016/j.copbio.2016.02.016}, pmid = {27016703}, issn = {1879-0429}, support = {G0900585/MRC_/Medical Research Council/United Kingdom ; GREENSMITH/APR14/825-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/N025865/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Motor Activity/*physiology ; Neural Stem Cells/*transplantation ; Optogenetics/*methods ; *Recovery of Function ; Spinal Cord Injuries/*therapy ; }, abstract = {Controlling muscle function is essential for human behaviour and survival, thus, impairment of motor function and muscle paralysis can severely impact quality of life and may be immediately life-threatening, as occurs in many cases of traumatic spinal cord injury (SCI) and in patients with amyotrophic lateral sclerosis (ALS). Repairing damaged spinal motor circuits, in either SCI or ALS, currently remains an elusive goal. Therefore alternative strategies are needed to artificially control muscle function and thereby enable essential motor tasks. This review focuses on recent advances towards restoring motor function, with a particular focus on stem cell-derived neuronal engraftment strategies, optogenetic control of motor function and the potential future translational application of these approaches.}, }
@article {pmid27016280, year = {2016}, author = {Todd, TW and Petrucelli, L}, title = {Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions.}, journal = {Journal of neurochemistry}, volume = {138 Suppl 1}, number = {}, pages = {145-162}, doi = {10.1111/jnc.13623}, pmid = {27016280}, issn = {1471-4159}, support = {R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein ; Chromosomes, Human, Pair 9/*genetics ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/genetics ; Humans ; Proteins/*genetics ; }, abstract = {The identification of a hexanucleotide repeat expansion in a non-coding region of C9orf72 as a major cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) drastically changed the field of research on both of these conditions. Yet, despite the vast amount of work aimed at elucidating the molecular mechanisms underlying the role of this repeat in disease, the exact pathomechanisms are still unclear. A reduction in the expression of the C9orf72 gene is observed in patients, but a gain-of-function model is now preferred. The hexanucleotide repeat expansion forms RNA foci in the central nervous system (CNS) of repeat-positive FTD and ALS patients, and these foci are believed to sequester RNA-binding proteins (RBPs) and impair their function in RNA processing. At the same time, the repeat undergoes repeat-associated non-ATG translation to produce dipeptide repeat proteins that also form inclusions in the patient CNS. Studies from cells and flies suggest that these proteins may also be an important factor in the disease. Finally, the hexanucleotide repeat also induces the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) through an as yet unknown mechanism. This review covers the different potential pathogenic factors that have been put forth for C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS), while highlighting some remaining questions. A repeat expansion in C9orf72 is a common cause of both frontal temporal dementia and amyotrophic lateral sclerosis. Although there is a decrease in C9orf72 expression in patients, this repeat is believed to induce disease primarily through an unknown gain-of-function mechanism involving the RNA, repeat-associated non-AUG translation, or both. This review summarizes and discusses current knowledge on C9orf72 repeat-associated pathophysiology. This article is part of the Frontotemporal Dementia special issue.}, }
@article {pmid27015757, year = {2016}, author = {Ratti, A and Buratti, E}, title = {Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins.}, journal = {Journal of neurochemistry}, volume = {138 Suppl 1}, number = {}, pages = {95-111}, doi = {10.1111/jnc.13625}, pmid = {27015757}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology ; DNA-Binding Proteins/*genetics/*physiology ; Frontotemporal Dementia/*genetics/physiopathology ; Frontotemporal Lobar Degeneration/metabolism ; Humans ; RNA-Binding Protein FUS/*genetics/*physiology ; TDP-43 Proteinopathies/*genetics/*pathology ; }, abstract = {The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue.}, }
@article {pmid27014702, year = {2016}, author = {Mack, KL and Shorter, J}, title = {Engineering and Evolution of Molecular Chaperones and Protein Disaggregases with Enhanced Activity.}, journal = {Frontiers in molecular biosciences}, volume = {3}, number = {}, pages = {8}, pmid = {27014702}, issn = {2296-889X}, support = {DP2 OD002177/OD/NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; }, abstract = {Cells have evolved a sophisticated proteostasis network to ensure that proteins acquire and retain their native structure and function. Critical components of this network include molecular chaperones and protein disaggregases, which function to prevent and reverse deleterious protein misfolding. Nevertheless, proteostasis networks have limits, which when exceeded can have fatal consequences as in various neurodegenerative disorders, including Parkinson's disease and amyotrophic lateral sclerosis. A promising strategy is to engineer proteostasis networks to counter challenges presented by specific diseases or specific proteins. Here, we review efforts to enhance the activity of individual molecular chaperones or protein disaggregases via engineering and directed evolution. Remarkably, enhanced global activity or altered substrate specificity of various molecular chaperones, including GroEL, Hsp70, ClpX, and Spy, can be achieved by minor changes in primary sequence and often a single missense mutation. Likewise, small changes in the primary sequence of Hsp104 yield potentiated protein disaggregases that reverse the aggregation and buffer toxicity of various neurodegenerative disease proteins, including α-synuclein, TDP-43, and FUS. Collectively, these advances have revealed key mechanistic and functional insights into chaperone and disaggregase biology. They also suggest that enhanced chaperones and disaggregases could have important applications in treating human disease as well as in the purification of valuable proteins in the pharmaceutical sector.}, }
@article {pmid27014701, year = {2016}, author = {Butchbach, ME}, title = {Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases.}, journal = {Frontiers in molecular biosciences}, volume = {3}, number = {}, pages = {7}, pmid = {27014701}, issn = {2296-889X}, support = {P20 GM103464/GM/NIGMS NIH HHS/United States ; }, abstract = {Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10-20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases.}, }
@article {pmid27014205, year = {2016}, author = {Hoyer, LL and Cota, E}, title = {Candida albicans Agglutinin-Like Sequence (Als) Family Vignettes: A Review of Als Protein Structure and Function.}, journal = {Frontiers in microbiology}, volume = {7}, number = {}, pages = {280}, pmid = {27014205}, issn = {1664-302X}, abstract = {Approximately two decades have passed since the description of the first gene in the Candida albicans ALS (agglutinin-like sequence) family. Since that time, much has been learned about the composition of the family and the function of its encoded cell-surface glycoproteins. Solution of the structure of the Als adhesive domain provides the opportunity to evaluate the molecular basis for protein function. This review article is formatted as a series of fundamental questions and explores the diversity of the Als proteins, as well as their role in ligand binding, aggregative effects, and attachment to abiotic surfaces. Interaction of Als proteins with each other, their functional equivalence, and the effects of protein abundance on phenotypic conclusions are also examined. Structural features of Als proteins that may facilitate invasive function are considered. Conclusions that are firmly supported by the literature are presented while highlighting areas that require additional investigation to reveal basic features of the Als proteins, their relatedness to each other, and their roles in C. albicans biology.}, }
@article {pmid27014182, year = {2016}, author = {Bourke, CA}, title = {Molybdenum Deficiency Produces Motor Nervous Effects That Are Consistent with Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {7}, number = {}, pages = {28}, pmid = {27014182}, issn = {1664-2295}, }
@article {pmid27012524, year = {2016}, author = {Browne, EC and Abbott, BM}, title = {Recent progress towards an effective treatment of amyotrophic lateral sclerosis using the SOD1 mouse model in a preclinical setting.}, journal = {European journal of medicinal chemistry}, volume = {121}, number = {}, pages = {918-925}, doi = {10.1016/j.ejmech.2016.02.048}, pmid = {27012524}, issn = {1768-3254}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Biological Products/therapeutic use ; Disease Models, Animal ; Drug Discovery ; Humans ; Mice ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal and incurable neurodegenerative disorder. Motor neurone degeneration can be caused by genetic mutation but the exact etiology of the disease, particularly for sporadic illness, still remains unclear. Therapeutics which target known pathogenic mechanisms involved in ALS, such as protein aggregation, oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and mitochondria dysfunction, are currently being pursued in order to provide neuroprotection which may be able to slow down, or perhaps even halt, disease progression. This present review focuses on the compounds which have been recently evaluated using the SOD1 mouse model, the most widely used preclinical model for ALS research.}, }
@article {pmid27011561, year = {2015}, author = {Michalopoulos, N and Laskou, S and Karayannopoulou, G and Pavlidis, L and Kanellos, I}, title = {Adrenal Gland Lymphangiomas.}, journal = {The Indian journal of surgery}, volume = {77}, number = {Suppl 3}, pages = {1334-1342}, pmid = {27011561}, issn = {0972-2068}, abstract = {Lymphangiomas of the adrenal glands (ALs) are benign vascular lesions. Approximately, 53 cases have been reported in the literature. The current study reviews and analyzes the clinical and pathologic features of all reported ALs and additionally illustrates a typical case of adrenal lymphangioma (AL). In order to perform the review analysis, a search of the international literature for ALs in adults was conducted. Thirty-eight related articles were found. Clinical and pathological information were obtained for all the reported cases and a database was created. ALs were detected more frequently in women than men. The mean age of occurrence was 39.5 years, while their mean size was 8.86 cm. Fifty-nine percent of ALs were right-sided. Size and localization were responsible for the presenting symptoms, though 30.4 % were asymptomatic. Diagnosis was made postoperatively in all cases by histological results. ALs are rare and benign lesions. They usually present as an incidental finding after abdominal imaging. The diagnosis is made after the surgical removal by histological and immunohistochemical examinations.}, }
@article {pmid27009575, year = {2016}, author = {Pottier, C and Ravenscroft, TA and Sanchez-Contreras, M and Rademakers, R}, title = {Genetics of FTLD: overview and what else we can expect from genetic studies.}, journal = {Journal of neurochemistry}, volume = {138 Suppl 1}, number = {}, pages = {32-53}, doi = {10.1111/jnc.13622}, pmid = {27009575}, issn = {1471-4159}, support = {P50 AG016574/AG/NIA NIH HHS/United States ; P50 NS072187/NS/NINDS NIH HHS/United States ; R01 NS080882/NS/NINDS NIH HHS/United States ; R01 NS076471/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein ; Frontotemporal Lobar Degeneration/*genetics/psychology ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Progranulins ; Proteins/genetics ; Risk Factors ; tau Proteins/genetics ; }, abstract = {Frontotemporal lobar degeneration (FTLD) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule-associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with the emerging use of next-generation sequencing. Common variants in the transmembrane protein 106 B were identified as a genetic risk factor of FTLD and disease modifier in patients with known mutations. This review summarizes for each FTLD gene what we know about the type and frequency of mutations, their associated clinical and pathological features, and potential disease mechanisms. We also provide an overview of emerging disease pathways encompassing multiple FTLD genes. We further discuss how FTLD specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of FTLD, can pose challenges for future FTLD gene identification and risk assessment of specific variants. Finally, we highlight emerging clinical, genetic, and translational research opportunities that lie ahead. Genetic research led to the identification of three common FTLD genes with rare variants (MAPT, GRN, and C9orf72) and a small number of rare genes. Efforts are now ongoing, which aimed at the identification of rare variants with high risk and/or low frequency variants with intermediate effect. Common risk variants have also been identified, such as TMEM106B. This review discusses the current knowledge on FTLD genes and the emerging disease pathways encompassing multiple FTLD genes.}, }
@article {pmid27007942, year = {2016}, author = {Carvalho, TL and de Almeida, LM and Lorega, CM and Barata, MF and Ferreira, ML and de Brito-Marques, PR and Correia, Cda C}, title = {Depression and anxiety in individuals with amyotrophic lateral sclerosis: a systematic review.}, journal = {Trends in psychiatry and psychotherapy}, volume = {38}, number = {1}, pages = {1-5}, doi = {10.1590/2237-6089-2015-0030}, pmid = {27007942}, issn = {2238-0019}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*psychology ; Anxiety/*epidemiology ; Depression/*epidemiology ; Humans ; }, abstract = {INTRODUCTION: Studies assessing symptoms of depression and anxiety in individuals with amyotrophic lateral sclerosis (ALS) have reported contradictory results. The objective of this systematic review is to identify the prevalence of these mood disorders in the literature.<br><br>METHODS: We searched the PubMed, HighWire, MEDLINE, SciELO, LILACS and ScienceDirect databases. Literature was selected for review in two stages, according to eligibility criteria. The first stage involved searching databases and checking titles and abstracts. The second step consisted of reading complete articles and excluding those that did not meet the inclusion criteria. The inclusion criteria were articles written in Portuguese, English or Spanish, published in the last five years and involving people with ALS diagnosed according to the El Escorial criteria.<br><br>RESULTS: The database searches returned a total of 1,135 titles and abstracts and then 1,117 of these were excluded. Eighteen articles were selected for review. The 12-item Amyotrophic Lateral Sclerosis Depression Inventory (ADI-12) was the only instrument designed specifically to assess depression in ALS, but it was only used in three studies. No instruments specifically designed for anxiety in ALS were used. A large number of studies found presence and slight increase of anxiety disorders. There was considerable large variation in the results related to depressive disorders, ranging from moderate depression to an absence of symptoms.<br><br>CONCLUSIONS: Patients with ALS may exhibit symptoms of depression and anxiety at different levels, but there is a need for studies using specific instruments with larger samples in order to ascertain the prevalence of symptoms in ALS and the factors associated with it.}, }
@article {pmid27006759, year = {2016}, author = {Chen, P and Miah, MR and Aschner, M}, title = {Metals and Neurodegeneration.}, journal = {F1000Research}, volume = {5}, number = {}, pages = {}, pmid = {27006759}, issn = {2046-1402}, support = {R01 ES020852/ES/NIEHS NIH HHS/United States ; }, abstract = {Metals play important roles in the human body, maintaining cell structure and regulating gene expression, neurotransmission, and antioxidant response, to name a few. However, excessive metal accumulation in the nervous system may be toxic, inducing oxidative stress, disrupting mitochondrial function, and impairing the activity of numerous enzymes. Damage caused by metal accumulation may result in permanent injuries, including severe neurological disorders. Epidemiological and clinical studies have shown a strong correlation between aberrant metal exposure and a number of neurological diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, autism spectrum disorders, Guillain-Barré disease, Gulf War syndrome, Huntington's disease, multiple sclerosis, Parkinson's disease, and Wilson's disease. Here, we briefly survey the literature relating to the role of metals in neurodegeneration.}, }
@article {pmid26998936, year = {2016}, author = {Mahringer, A and Fricker, G}, title = {ABC transporters at the blood-brain barrier.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {12}, number = {5}, pages = {499-508}, doi = {10.1517/17425255.2016.1168804}, pmid = {26998936}, issn = {1744-7607}, mesh = {ATP-Binding Cassette Transporters/*metabolism ; Animals ; Biological Transport/physiology ; Blood-Brain Barrier/*metabolism ; Brain/*metabolism/physiopathology ; Brain Diseases/physiopathology ; Central Nervous System Diseases/physiopathology ; Humans ; Signal Transduction/physiology ; Xenobiotics/pharmacokinetics/toxicity ; }, abstract = {INTRODUCTION: The blood-brain barrier (BBB) possesses an outstanding ability to protect the brain against xenobiotics and potentially poisonous metabolites. Owing to this, ATP binding cassette (ABC) export proteins have garnered significant interest in the research community. These transport proteins are predominantly localized to the luminal membrane of brain microvessels, where they recognize a wide range of different substrates and transport them back into the blood circulation.<br><br>AREAS COVERED: This review summarizes recent findings on these transport proteins, including their expression in the endothelial cell membrane and their substrate recognition. Signaling cascades underlying the expression and function of these proteins will be discussed as well as their role in diseases such as Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis and brain tumors.<br><br>EXPERT OPINION: ABC transporters represent an integral part of the human transportome and are of particular interest at the blood-brain barrier they as they significantly contribute to brain homeostasis. In addition, they appear to be involved in myriad CNS diseases. Therefore studying their mechanisms of action as well as their signaling cascades and responses to internal and external stimuli will help us understand the pathogenesis of these diseases.}, }
@article {pmid26996412, year = {2016}, author = {March, ZM and King, OD and Shorter, J}, title = {Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {9-18}, pmid = {26996412}, issn = {1872-6240}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; T32 GM071339/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Ataxin-1/metabolism ; Ataxin-2/metabolism ; Calmodulin-Binding Proteins/metabolism ; DNA-Binding Proteins/metabolism ; *Epigenesis, Genetic ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Organelles/metabolism ; Prion Proteins/genetics/*metabolism ; Protein Domains ; RNA-Binding Protein EWS ; RNA-Binding Protein FUS/metabolism ; RNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae ; TATA-Binding Protein Associated Factors/metabolism ; }, abstract = {Key challenges faced by all cells include how to spatiotemporally organize complex biochemistry and how to respond to environmental fluctuations. The budding yeast Saccharomyces cerevisiae harnesses alternative protein folding mediated by yeast prion domains (PrDs) for rapid evolution of new traits in response to environmental stress. Increasingly, it is appreciated that low complexity domains similar in amino acid composition to yeast PrDs (prion-like domains; PrLDs) found in metazoa have a prominent role in subcellular cytoplasmic organization, especially in relation to RNA homeostasis. In this review, we highlight recent advances in our understanding of the role of prions in enabling rapid adaptation to environmental stress in yeast. We also present the complete list of human proteins with PrLDs and discuss the prevalence of the PrLD in nucleic-acid binding proteins that are often connected to neurodegenerative disease, including: ataxin 1, ataxin 2, FUS, TDP-43, TAF15, EWSR1, hnRNPA1, and hnRNPA2. Recent paradigm-shifting advances establish that PrLDs undergo phase transitions to liquid states, which contribute to the structure and biophysics of diverse membraneless organelles. This structural functionality of PrLDs, however, simultaneously increases their propensity for deleterious protein-misfolding events that drive neurodegenerative disease. We suggest that even these PrLD-misfolding events are not irreversible and can be mitigated by natural or engineered protein disaggregases, which could have important therapeutic applications. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid26995730, year = {2017}, author = {Lovelace, MD and Varney, B and Sundaram, G and Lennon, MJ and Lim, CK and Jacobs, K and Guillemin, GJ and Brew, BJ}, title = {Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases.}, journal = {Neuropharmacology}, volume = {112}, number = {Pt B}, pages = {373-388}, doi = {10.1016/j.neuropharm.2016.03.024}, pmid = {26995730}, issn = {1873-7064}, mesh = {Animals ; Humans ; Kynurenine/*metabolism ; Metabolic Networks and Pathways/*physiology ; Nervous System Diseases/*metabolism ; Tryptophan/*metabolism ; }, abstract = {The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N-Methyl-d-Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component; hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other diseases such as HIV, Alzheimer's disease/dementia, infection, immune privilege and cardiovascular disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.}, }
@article {pmid26993125, year = {2016}, author = {Board, PG and Menon, D}, title = {Structure, function and disease relevance of Omega-class glutathione transferases.}, journal = {Archives of toxicology}, volume = {90}, number = {5}, pages = {1049-1067}, doi = {10.1007/s00204-016-1691-1}, pmid = {26993125}, issn = {1432-0738}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic ; Genetic Predisposition to Disease ; Glutathione/*metabolism ; Glutathione Transferase/antagonists &amp; inhibitors/chemistry/genetics/*metabolism ; Humans ; Inactivation, Metabolic ; Oxidation-Reduction ; Polymorphism, Genetic ; Protein Conformation ; Protein Processing, Post-Translational ; Structure-Activity Relationship ; Substrate Specificity ; }, abstract = {The Omega-class cytosolic glutathione transferases (GSTs) have distinct structural and functional attributes that allow them to perform novel roles unrelated to the functions of other GSTs. Mammalian GSTO1-1 has been found to play a previously unappreciated role in the glutathionylation cycle that is emerging as significant mechanism regulating protein function. GSTO1-1-catalyzed glutathionylation or deglutathionylation of a key signaling protein may explain the requirement for catalytically active GSTO1-1 in LPS-stimulated pro-inflammatory signaling through the TLR4 receptor. The observation that ML175 a specific GSTO1-1 inhibitor can block LPS-stimulated inflammatory signaling has opened a new avenue for the development of novel anti-inflammatory drugs that could be useful in the treatment of toxic shock and other inflammatory disorders. The role of GSTO2-2 remains unclear. As a dehydroascorbate reductase, it could contribute to the maintenance of cellular redox balance and it is interesting to note that the GSTO2 N142D polymorphism has been associated with multiple diseases including Alzheimer's disease, Parkinson's disease, familial amyotrophic lateral sclerosis, chronic obstructive pulmonary disease, age-related cataract and breast cancer.}, }
@article {pmid26988875, year = {2016}, author = {Garzillo, EM and Miraglia, N and Pedata, P and Feola, D and Lamberti, M}, title = {Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus.}, journal = {International journal of occupational medicine and environmental health}, volume = {29}, number = {3}, pages = {355-367}, doi = {10.13075/ijomeh.1896.00368}, pmid = {26988875}, issn = {1896-494X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Electromagnetic Fields/adverse effects ; Epigenesis, Genetic ; Humans ; Metals, Heavy/toxicity ; Occupational Exposure/*adverse effects ; Occupational Medicine ; Pesticides/toxicity ; Risk Factors ; Solvents/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons. In recent years, in addition to several studies about genetic mechanisms leading to motor neurons damage, various epigenetic theories have been developed, involving the study of the patients' work and lifestyle. The work aims at focusing the role of occupational exposure related to ALS by literature data analysis. Articles, selected on the basis of keywords, year of publication and topics, are related to occupational exposure, suggesting an impact on ALS onset. The literature review shows that there are still a lot of biases in the studies design, which actually do not allow to draw unequivocal conclusions.}, }
@article {pmid26985861, year = {2016}, author = {Albrecht, DS and Granziera, C and Hooker, JM and Loggia, ML}, title = {In Vivo Imaging of Human Neuroinflammation.}, journal = {ACS chemical neuroscience}, volume = {7}, number = {4}, pages = {470-483}, pmid = {26985861}, issn = {1948-7193}, support = {154508/SNSF_/Swiss National Science Foundation/Switzerland ; R21 NS087472/NS/NINDS NIH HHS/United States ; 5T32EB13180/EB/NIBIB NIH HHS/United States ; 1R21NS087472-01A1/NS/NINDS NIH HHS/United States ; T32 EB013180/EB/NIBIB NIH HHS/United States ; }, mesh = {*Brain Mapping ; Central Nervous System/*diagnostic imaging ; Humans ; Inflammation/diagnostic imaging/*pathology ; *Neuroimaging ; }, abstract = {Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.}, }
@article {pmid26979993, year = {2016}, author = {Li, Y and Collins, M and An, J and Geiser, R and Tegeler, T and Tsantilas, K and Garcia, K and Pirrotte, P and Bowser, R}, title = {Immunoprecipitation and mass spectrometry defines an extensive RBM45 protein-protein interaction network.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {79-93}, pmid = {26979993}, issn = {1872-6240}, support = {F31 NS080614/NS/NINDS NIH HHS/United States ; R01 NS061867/NS/NINDS NIH HHS/United States ; R56 NS061867/NS/NINDS NIH HHS/United States ; RC1 NS068179/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Eukaryotic Initiation Factor-2/metabolism ; Frontotemporal Lobar Degeneration/*metabolism ; HEK293 Cells ; Humans ; Immunoprecipitation ; Inclusion Bodies/metabolism ; Mass Spectrometry ; Nerve Tissue Proteins/*metabolism ; Peptide Initiation Factors/metabolism ; Protein Interaction Maps ; RNA Splicing ; RNA-Binding Proteins/*metabolism ; Signal Transduction ; }, abstract = {The pathological accumulation of RNA-binding proteins (RBPs) within inclusion bodies is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBP aggregation results in both toxic gain and loss of normal function. Determining the protein binding partners and normal functions of disease-associated RBPs is necessary to fully understand molecular mechanisms of RBPs in disease. Herein, we characterized the protein-protein interactions (PPIs) of RBM45, a RBP that localizes to inclusions in ALS/FTLD. Using immunoprecipitation coupled to mass spectrometry (IP-MS), we identified 132 proteins that specifically interact with RBM45 within HEK293 cells. Select PPIs were validated by immunoblot and immunocytochemistry, demonstrating that RBM45 associates with a number of other RBPs primarily via RNA-dependent interactions in the nucleus. Analysis of the biological processes and pathways associated with RBM45-interacting proteins indicates enrichment for nuclear RNA processing/splicing via association with hnRNP proteins and cytoplasmic RNA translation via eiF2 and eiF4 pathways. Moreover, several other ALS-linked RBPs, including TDP-43, FUS, Matrin-3, and hnRNP-A1, interact with RBM45, consistent with prior observations of these proteins within intracellular inclusions in ALS/FTLD. Taken together, our results define a PPI network for RBM45, suggest novel functions for this protein, and provide new insights into the contributions of RBM45 to neurodegeneration in ALS/FTLD. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid26976762, year = {2016}, author = {Weil, R and Laplantine, E and Génin, P}, title = {Regulation of TBK1 activity by Optineurin contributes to cell cycle-dependent expression of the interferon pathway.}, journal = {Cytokine &amp; growth factor reviews}, volume = {29}, number = {}, pages = {23-33}, doi = {10.1016/j.cytogfr.2016.03.001}, pmid = {26976762}, issn = {1879-0305}, mesh = {Amyotrophic Lateral Sclerosis/immunology/pathology ; Animals ; Bacterial Infections/immunology/pathology ; Cell Cycle/*immunology ; Cell Cycle Proteins ; Gene Expression Regulation/*immunology ; Glaucoma, Open-Angle/immunology/pathology ; Humans ; *Immunity, Innate ; Interferons/*immunology ; Membrane Transport Proteins ; Osteitis Deformans/immunology/pathology ; Protein Serine-Threonine Kinases/*immunology ; Transcription Factor TFIIIA/*immunology ; Virus Diseases/immunology/pathology ; }, abstract = {The innate immune system has evolved to detect and neutralize viral invasions. Triggering of this defense mechanism relies on the production and secretion of soluble factors that stimulate intracellular antiviral defense mechanisms. The Tank Binding Kinase 1 (TBK1) is a serine/threonine kinase in the innate immune signaling pathways including the antiviral response and the host defense against cytosolic infection by bacteries. Given the critical roles of TBK1, important regulatory mechanisms are required to regulate its activity. Among these, Optineurin (Optn) was shown to negatively regulate the interferon response, in addition to its important role in membrane trafficking, protein secretion, autophagy and cell division. As Optn does not carry any enzymatic activity, its functions depend on its precise subcellular localization and its interaction with other proteins, especially with components of the innate immune pathway. This review highlights advances in our understanding of Optn mechanisms of action with focus on the relationships between Optn and TBK1 and their implication in host defense against pathogens. Specifically, how the antiviral immune system is controlled during the cell cycle by the Optn/TBK1 axis and the physiological consequences of this regulatory mechanism are described. This review may serve to a better understanding of the relationships between the different functions of Optn, including those related to immune responses and its associated pathologies such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget's disease of bone.}, }
@article {pmid26973461, year = {2016}, author = {Edens, BM and Miller, N and Ma, YC}, title = {Impaired Autophagy and Defective Mitochondrial Function: Converging Paths on the Road to Motor Neuron Degeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {44}, pmid = {26973461}, issn = {1662-5102}, support = {R01 NS094564/NS/NINDS NIH HHS/United States ; R21 AG043970/AG/NIA NIH HHS/United States ; R21 NS106307/NS/NINDS NIH HHS/United States ; }, abstract = {Selective motor neuron degeneration is a hallmark of amyotrophic lateral sclerosis (ALS). Around 10% of all cases present as familial ALS (FALS), while sporadic ALS (SALS) accounts for the remaining 90%. Diverse genetic mutations leading to FALS have been identified, but the underlying causes of SALS remain largely unknown. Despite the heterogeneous and incompletely understood etiology, different types of ALS exhibit overlapping pathology and common phenotypes, including protein aggregation and mitochondrial deficiencies. Here, we review the current understanding of mechanisms leading to motor neuron degeneration in ALS as they pertain to disrupted cellular clearance pathways, ATP biogenesis, calcium buffering and mitochondrial dynamics. Through focusing on impaired autophagic and mitochondrial functions, we highlight how the convergence of diverse cellular processes and pathways contributes to common pathology in motor neuron degeneration.}, }
@article {pmid26972529, year = {2016}, author = {Krasniak, CS and Ahmad, ST}, title = {The role of CHMP2B[Intron5] in autophagy and frontotemporal dementia.}, journal = {Brain research}, volume = {1649}, number = {Pt B}, pages = {151-157}, pmid = {26972529}, issn = {1872-6240}, support = {P20 GM103423/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Autophagy/genetics ; Endosomal Sorting Complexes Required for Transport/chemistry/*genetics/*physiology ; Frontotemporal Dementia/genetics/*physiopathology ; Humans ; Mice ; Mutation ; Neurons/*physiology ; }, abstract = {Charged multivesicular body protein 2B (CHMP2B) - a component of the endosomal complex required for transport-III (ESCRT-III) - is responsible for the vital membrane deformation functions in autophagy and endolysosomal trafficking. A dominant mutation in CHMP2B (CHMP2B[Intron5]) is associated with a subset of heritable frontotemporal dementia - frontotemporal dementia linked to chromosome 3 (FTD-3). ESCRT-III recruits Vps4, an AAA-ATPase that abscises the membrane during various cellular processes including autophagy and intraluminal vesicle formation. CHMP2B[Intron5] results in a C-terminus truncation removing an important Vps4 binding site as well as eliminating the normal autoinhibitory resting state of CHMP2B. CHMP2B is expressed in most cell types but seems to be especially vital for proper neuronal function. CHMP2B[Intron5]-mediated phenotypes include misregulation of transmembrane receptors, accumulation of multilamellar structures, abnormal lysosomal morphology, down regulation of a brain-specific micro RNA (miRNA-124), abnormal dendritic spine morphology, decrease in dendritic arborization, and cell death. Currently, transgenic-fly,-mouse, and -human cell lines are being used to better understand the diverse phenotypes and develop therapeutic approaches for the CHMP2B[Intron5]-induced FTD-3. This article is part of a Special Issue entitled SI:Autophagy.}, }
@article {pmid26972033, year = {2016}, author = {Fermin, AM and Afzal, U and Culebras, A}, title = {Sleep in Neuromuscular Diseases.}, journal = {Sleep medicine clinics}, volume = {11}, number = {1}, pages = {53-64}, doi = {10.1016/j.jsmc.2015.10.005}, pmid = {26972033}, issn = {1556-4088}, mesh = {Humans ; Neuromuscular Diseases/*complications/diagnosis/physiopathology/therapy ; Sleep/physiology ; Sleep Wake Disorders/*complications/diagnosis/physiopathology/therapy ; }, abstract = {Sleep disorders in neuromuscular disorders are generally caused by respiratory dysfunction associated with these diseases. Hypoventilation in neuromuscular diseases results from both respiratory muscle weakness and reduced chemoreceptor sensitivity, which is required for ventilatory drive. This condition results in repeated arousals, sleep fragmentation, and nocturnal hypoxemia, manifesting most commonly as excessive daytime somnolence. Polysomnography can identify sleep disordered breathing in patients with neuromuscular disorders and treatment with noninvasive ventilation may improve quality of life.}, }
@article {pmid26971940, year = {2017}, author = {Bali, P and Lahiri, DK and Banik, A and Nehru, B and Anand, A}, title = {Potential for Stem Cells Therapy in Alzheimer's Disease: Do Neurotrophic Factors Play Critical Role?.}, journal = {Current Alzheimer research}, volume = {14}, number = {2}, pages = {208-220}, pmid = {26971940}, issn = {1875-5828}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; R01 AG051086/AG/NIA NIH HHS/United States ; //PHS HHS/International ; R41 AG053117/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*physiopathology/*therapy ; Animals ; Humans ; Nerve Growth Factors/*metabolism ; *Stem Cell Transplantation ; }, abstract = {Alzheimer's disease (AD) is one of the most common causes of dementia. Despite several decades of research in AD, there is no standard disease- modifying therapy available and currentlyapproved drugs provide only symptomatic relief. Stem cells hold immense potential to regenerate damaged tissues and are currently tested in some brain-related disorders, such as AD, amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). We review stem cell transplantation studies using preclinical and clinical tools. We describe different sources of stem cells used in various animal models and explaining the putative molecular mechanisms that can rescue neurodegenerative disorders. The clinical studies suggest safety, efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies, but no unifying hypothesis can convincingly explain the underlying mechanism. Some studies have reported paracrine effects exerted by these stem cells via the release of neurotrophic factors, while other studies describe the immunomodulatory effects exerted by the transplanted cells. There are also reports which indicate that stem cell transplantation might result in endogenous cell proliferation or replacement of diseased cells. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins.}, }
@article {pmid26970394, year = {2016}, author = {Li, YH and Zhang, N and Wang, YN and Shen, Y and Wang, Y}, title = {Multiple faces of protein interacting with C kinase 1 (PICK1): Structure, function, and diseases.}, journal = {Neurochemistry international}, volume = {98}, number = {}, pages = {115-121}, doi = {10.1016/j.neuint.2016.03.001}, pmid = {26970394}, issn = {1872-9754}, mesh = {Animals ; Carrier Proteins/chemistry/genetics/*metabolism/physiology ; Cell Cycle Proteins ; Humans ; Nervous System Diseases/*genetics/*metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism/physiology ; Protein Conformation ; Structure-Activity Relationship ; }, abstract = {Protein interacting with C-kinase 1 (PICK1) has received considerable attention because it is the only protein that contains both PSD-95/DlgA/ZO-1 (PDZ) domain and Bin-Amphiphysin-Rvs (BAR) domain. Through PDZ and BAR domains, PICK1 binds to a large number of membrane proteins and lipid molecules, and is thereby of multiple functions. PICK1 is widely expressed in various tissues, particularly abundant in the brain and testis. In the central nervous system (CNS), PICK1 interacts with numerous neurotransmitters receptors, transporters, ion channels, and enzymes, and controls their trafficking. The best characterized function of PICK1 is that it regulates trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit GluA2 during long-term depression and long-term potentiation. Recent evidence shows that PICK1 participates in various diseases including neurobiological disorders, such as chronic pain, epilepsy, oxidative stress, stroke, Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia, and non-neurological disorders, such as globozoospermia, breast cancer, and heart failure. In this review, we will summarize recent advances focusing on the structure and regulation of PICK1 and its functions in protein trafficking, neurological and non-neurological diseases.}, }
@article {pmid26966440, year = {2016}, author = {Hedges, EC and Mehler, VJ and Nishimura, AL}, title = {The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine.}, journal = {Stem cells international}, volume = {2016}, number = {}, pages = {9279516}, pmid = {26966440}, issn = {1687-966X}, abstract = {In recent years several genes have linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as a spectrum disease; however little is known about what triggers their onset. With the ability to generate patient specific stem cell lines from somatic cells, it is possible to model disease without the need to transfect cells with exogenous DNA. These pluripotent stem cells have opened new avenues for identification of disease phenotypes and their relation to specific molecular pathways. Thus, as never before, compounds with potential applications for regenerative medicine can be specifically tailored in patient derived cultures. In this review, we discuss how patient specific induced pluripotent stem cells (iPSCs) have been used to model ALS and FTD and the most recent drug screening targets for these diseases. We also discuss how an iPSC bank would improve the quality of the available cell lines and how it would increase knowledge about the ALS/FTD disease spectrum.}, }
@article {pmid26963158, year = {2016}, author = {Yerbury, JJ}, title = {Protein aggregates stimulate macropinocytosis facilitating their propagation.}, journal = {Prion}, volume = {10}, number = {2}, pages = {119-126}, pmid = {26963158}, issn = {1933-690X}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*pathology ; Neurons/*pathology ; *Pinocytosis ; Protein Aggregation, Pathological/*pathology ; Protein Folding ; }, abstract = {Temporal and spatial patterns of pathological changes such as loss of neurons and presence of pathological protein aggregates are characteristic of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Alzheimer's disease and Parkinson's disease. These patterns are consistent with the propagation of protein misfolding and aggregation reminiscent of the prion diseases. There is a surge of evidence that suggests that large protein aggregates of a range of proteins are able to enter cells via macropinocytosis. Our recent work suggests that this process is activated by the binding of aggregates to the neuron cell surface. The current review considers the potential role of cell surface receptors in the triggering of macropinocytosis by protein aggregates and the possibility of utilizing macropinocytosis pathways as a therapeutic target.}, }
@article {pmid26961251, year = {2016}, author = {Nwaobi, SE and Cuddapah, VA and Patterson, KC and Randolph, AC and Olsen, ML}, title = {The role of glial-specific Kir4.1 in normal and pathological states of the CNS.}, journal = {Acta neuropathologica}, volume = {132}, number = {1}, pages = {1-21}, pmid = {26961251}, issn = {1432-0533}, support = {R01 NS075062/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/*metabolism ; Central Nervous System Diseases/*metabolism ; Humans ; Potassium Channels, Inwardly Rectifying/*metabolism ; }, abstract = {Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.}, }
@article {pmid26957644, year = {2016}, author = {Davies, KM and Mercer, JF and Chen, N and Double, KL}, title = {Copper dyshomoeostasis in Parkinson's disease: implications for pathogenesis and indications for novel therapeutics.}, journal = {Clinical science (London, England : 1979)}, volume = {130}, number = {8}, pages = {565-574}, doi = {10.1042/CS20150153}, pmid = {26957644}, issn = {1470-8736}, mesh = {Animals ; Antiparkinson Agents/*therapeutic use ; Brain/*drug effects/metabolism/physiopathology ; Copper/*metabolism ; Homeostasis ; Humans ; Oxidative Stress/drug effects ; Parkinson Disease/*drug therapy/metabolism/physiopathology ; alpha-Synuclein/metabolism ; }, abstract = {Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well-characterized disorders of disrupted copper homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper-modulating strategies in in vitro and in vivo models of this disorder. Copper-modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease.}, }
@article {pmid26956112, year = {2016}, author = {Ferrara, P}, title = {The Unbiased Search of Biomarkers in Neurodegenerative Diseases.}, journal = {Current pharmaceutical biotechnology}, volume = {17}, number = {5}, pages = {471-479}, doi = {10.2174/138920101705160303165719}, pmid = {26956112}, issn = {1873-4316}, mesh = {Biomarkers/analysis/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Proteomics ; }, abstract = {A clear link exists between the extension of life expectancy throughout the world and the increased incidence of age-related neurodegenerative disorders. Diseases like Alzheimer's and Parkinson's are chronic diseases with devastating consequences for patients and their families. They also represent a major economic cost for society. Therapeutic progress has been made mainly by alleviating some of the symptoms of these diseases, but currently no cure is available. Attempts to develop new therapies have been hampered mainly because of gaps in our current knowledge about the pathogenic mechanism underlying neurodegeneration, making difficult the identification of targets for new drug development, and also because of the lack of biomarkers essential for early diagnosis, patient stratification and follow up of treatment. Taking advantage of the latest technical developments, proteomics and peptidomics based approaches are being used to identify new cellular pathophysiological pathways as well as biomarkers in biological fluids. Here we will review the results, mainly published in the last five years, of unbiased proteomics and peptidomics approaches for biomarker research using biological fluids of Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis patients.}, }
@article {pmid26938019, year = {2016}, author = {Bowden, HA and Dormann, D}, title = {Altered mRNP granule dynamics in FTLD pathogenesis.}, journal = {Journal of neurochemistry}, volume = {138 Suppl 1}, number = {}, pages = {112-133}, doi = {10.1111/jnc.13601}, pmid = {26938019}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Cytoplasmic Granules/*genetics/*pathology ; Frontotemporal Lobar Degeneration/*genetics/*pathology ; Humans ; RNA-Binding Protein FUS/genetics/metabolism ; TDP-43 Proteinopathies/genetics/metabolism ; Vault Ribonucleoprotein Particles/*genetics/metabolism ; }, abstract = {In neurons, RNA-binding proteins (RBPs) play a key role in post-transcriptional gene regulation, for example alternative splicing, mRNA localization in neurites and local translation upon synaptic stimulation. There is increasing evidence that defective or mislocalized RBPs - and consequently altered mRNA processing - lead to neuronal dysfunction and cause neurodegeneration, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Cytosolic RBP aggregates containing TAR DNA-binding protein of 43 kDa (TDP-43) or fused in sarcoma (FUS) are a common hallmark of both disorders. There is mounting evidence that translationally silent mRNP granules, such as stress granules or transport granules, play an important role in the formation of these RBP aggregates. These granules are thought to be 'catalytic convertors' of RBP aggregation by providing a high local concentration of RBPs. As recently shown in vitro, RBPs that contain a so-called low-complexity domain start to 'solidify' and eventually aggregate at high protein concentrations. The same may happen in mRNP granules in vivo, leading to 'solidified' granules that lose their dynamic properties and ability to fulfill their physiological functions. This may result in a disturbed stress response, altered mRNA transport and local translation, and formation of pathological TDP-43 or FUS aggregates, all of which may contribute to neuronal dysfunction and neurodegeneration. Here, we discuss the general functional properties of these mRNP granules, how their dynamics may be disrupted in frontotemporal lobar degeneration/amyotrophic lateral sclerosis, for example by loss or gain of function of TDP-43 and FUS, and how this may contribute to the development of RBP aggregates and neurotoxicity. In this review, we discuss how dynamic mRNP granules, such as stress granules or neuronal transport granules, may be converted into pathological aggregates containing misfolded RNA-binding proteins (RBPs), such as TDP-43 and FUS. Abnormal interactions between low-complexity domains in RBPs may cause dynamic mRNP granules to solidify and become dysfunctional. This may result in a disturbed stress response, altered mRNA transport and local translation, as well as RBP aggregation, all of which may contribute to neuronal dysfunction and neurodegeneration.}, }
@article {pmid26935478, year = {2016}, author = {Chen, WW and Zhang, X and Huang, WJ}, title = {Role of neuroinflammation in neurodegenerative diseases (Review).}, journal = {Molecular medicine reports}, volume = {13}, number = {4}, pages = {3391-3396}, pmid = {26935478}, issn = {1791-3004}, mesh = {Aging ; Amyotrophic Lateral Sclerosis/complications ; Cytokines/metabolism ; Humans ; Inflammation/*etiology ; Metabolic Diseases/complications ; Microglia/metabolism ; Neurodegenerative Diseases/metabolism/*pathology ; Virus Diseases/complications ; }, abstract = {Neurodegeneration is a phenomenon that occurs in the central nervous system through the hallmarks associating the loss of neuronal structure and function. Neurodegeneration is observed after viral insult and mostly in various so-called 'neurodegenerative diseases', generally observed in the elderly, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis that negatively affect mental and physical functioning. Causative agents of neurodegeneration have yet to be identified. However, recent data have identified the inflammatory process as being closely linked with multiple neurodegenerative pathways, which are associated with depression, a consequence of neurodegenerative disease. Accordingly, pro‑inflammatory cytokines are important in the pathophysiology of depression and dementia. These data suggest that the role of neuroinflammation in neurodegeneration must be fully elucidated, since pro‑inflammatory agents, which are the causative effects of neuroinflammation, occur widely, particularly in the elderly in whom inflammatory mechanisms are linked to the pathogenesis of functional and mental impairments. In this review, we investigated the role played by the inflammatory process in neurodegenerative diseases.}, }
@article {pmid26927092, year = {2016}, author = {Kai, M}, title = {Roles of RNA-Binding Proteins in DNA Damage Response.}, journal = {International journal of molecular sciences}, volume = {17}, number = {3}, pages = {310}, pmid = {26927092}, issn = {1422-0067}, mesh = {Animals ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/*genetics/metabolism ; Humans ; Signal Transduction ; }, abstract = {Living cells experience DNA damage as a result of replication errors and oxidative metabolism, exposure to environmental agents (e.g., ultraviolet light, ionizing radiation (IR)), and radiation therapies and chemotherapies for cancer treatments. Accumulation of DNA damage can lead to multiple diseases such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and also aging. Cells have evolved elaborate mechanisms to deal with DNA damage. Networks of DNA damage response (DDR) pathways are coordinated to detect and repair DNA damage, regulate cell cycle and transcription, and determine the cell fate. Upstream factors of DNA damage checkpoints and repair, "sensor" proteins, detect DNA damage and send the signals to downstream factors in order to maintain genomic integrity. Unexpectedly, we have discovered that an RNA-processing factor is involved in DNA repair processes. We have identified a gene that contributes to glioblastoma multiforme (GBM)'s treatment resistance and recurrence. This gene, RBM14, is known to function in transcription and RNA splicing. RBM14 is also required for maintaining the stem-like state of GBM spheres, and it controls the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway by interacting with KU80. RBM14 is a RNA-binding protein (RBP) with low complexity domains, called intrinsically disordered proteins (IDPs), and it also physically interacts with PARP1. Furthermore, RBM14 is recruited to DNA double-strand breaks (DSBs) in a poly(ADP-ribose) (PAR)-dependent manner (unpublished data). DNA-dependent PARP1 (poly-(ADP) ribose polymerase 1) makes key contributions in the DNA damage response (DDR) network. RBM14 therefore plays an important role in a PARP-dependent DSB repair process. Most recently, it was shown that the other RBPs with intrinsically disordered domains are recruited to DNA damage sites in a PAR-dependent manner, and that these RBPs form liquid compartments (also known as "liquid-demixing"). Among the PAR-associated IDPs are FUS/TLS (fused in sarcoma/translocated in sarcoma), EWS (Ewing sarcoma), TARF15 (TATA box-binding protein-associated factor 68 kDa) (also called FET proteins), a number of heterogeneous nuclear ribonucleoproteins (hnRNPs), and RBM14. Importantly, various point mutations within the FET genes have been implicated in pathological protein aggregation in neurodegenerative diseases, specifically with amyotrophic lateral sclerosis (ALS), and frontotemporal lobe degeneration (FTLD). The FET proteins also frequently exhibit gene translocation in human cancers, and emerging evidence shows their physical interactions with DDR proteins and thus implies their involvement in the maintenance of genome stability.}, }
@article {pmid26926900, year = {2016}, author = {Pinho, AC and Gonçalves, E}, title = {Are Amyotrophic Lateral Sclerosis Caregivers at Higher Risk for Health Problems?.}, journal = {Acta medica portuguesa}, volume = {29}, number = {1}, pages = {56-62}, doi = {10.20344/amp.6590}, pmid = {26926900}, issn = {1646-0758}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Anxiety/*complications ; Caregivers ; Depression/*complications ; Humans ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis is a rare neurodegenerative disease affecting motor neurons. Patients present with progressive physical impairment, respiratory failure being the main cause of death. A significant portion of patients presents neurobehavioral problems as well. As severe impairment occurs, patients become highly dependent and in general, their families assume the role of primary caregivers, exposing them to stress and other potential causes of disease like insomnia, physical strain from patients' mobilization and changes on eating habits. The aim of this work is to understand if taking care of patients with amyotrophic lateral sclerosis increases disease and health problems on caregivers.<br><br>MATERIAL AND METHODS: Comprehensive review of the literature published on the electronic databases PubMed and Scopus between 2010 and 2014.<br><br>RESULTS: Eighteen studies met the inclusion criteria. We found that amyotrophic lateral sclerosis caregivers have higher levels of burden, depression and anxiety with lower quality of life. This is associated to age and gender of caregivers, time spent caring, patients' disability and neurobehavioral changes. Higher sense of support and spirituality on family seem to promote wellbeing.<br><br>DISCUSSION: On our work, we were able to understand that several factors have influenced caregivers' quality of life and affect their health. Besides, we could understand that the outcomes studied are related between themselves and, as seen in some of the studies, related to patients' quality of life itself. Consequently, it has become essential to adopt a holistic approach of these patients and their families, fighting the deteriorating risk factors and investing on health promoters.<br><br>CONCLUSION: Despite the large body of research on family caregiving for amyotrophic lateral sclerosis patients, little has changed and the outcomes measured remain almost the same before and after 2010. The work indicates that caregivers have lower levels of health than the general population. Still additional research is required, in order to better understand and characterized the changes on caregivers' health. It is nevertheless clear that health care professionals cannot ignore these health changes and need an approach focused not only on patients but also on caregivers.}, }
@article {pmid26923414, year = {2016}, author = {Loureiro, JR and Oliveira, CL and Silveira, I}, title = {Unstable repeat expansions in neurodegenerative diseases: nucleocytoplasmic transport emerges on the scene.}, journal = {Neurobiology of aging}, volume = {39}, number = {}, pages = {174-183}, doi = {10.1016/j.neurobiolaging.2015.12.007}, pmid = {26923414}, issn = {1558-1497}, mesh = {Active Transport, Cell Nucleus/*genetics ; C9orf72 Protein ; *DNA Repeat Expansion ; Frontotemporal Dementia/genetics ; Humans ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*genetics ; Nuclear Proteins/genetics ; Proteins/genetics ; RNA/genetics ; RNA Splicing/genetics ; RNA-Binding Proteins ; Spinocerebellar Ataxias/genetics ; }, abstract = {An astonishing number of neurological diseases result from expansion of unstable repetitive sequences causing alterations in key neuronal processes. Some are progressive late-onset conditions related to aging, such as the spinocerebellar ataxias. In several of these pathologies, the expanded repeat is transcribed, producing an expanded RNA repeat that causes neurodegeneration by a complex mechanism, comprising 3 main pathways. These include (1) accumulation in the nucleus of RNA foci, resulting from sequestration of RNA-binding proteins functioning in important neuronal cascades; (2) decrease in availability of RNA-binding proteins, such as splicing factors, causing alternative splicing misregulation with imbalance in the expression ratio of neuronal isoforms; and (3) generation of neurotoxic peptides, produced from repeat-associated non-ATG-initiated translation across the RNA repeat, in all reading frames. Recently, 2 pathologies characterized by impaired motor function, cognitive decline, or/and degeneration of motor neurons have been found that have broaden our understanding of these diseases. Moreover, the finding of compromised nucleocytoplasmic transport opens new avenues for research. This review will cover the amazing progress regarding these conditions.}, }
@article {pmid26920688, year = {2016}, author = {Kumar, P and Kumar, D and Jha, SK and Jha, NK and Ambasta, RK}, title = {Ion Channels in Neurological Disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {103}, number = {}, pages = {97-136}, doi = {10.1016/bs.apcsb.2015.10.006}, pmid = {26920688}, issn = {1876-1623}, mesh = {Alzheimer Disease/genetics/*metabolism/pathology ; Brain/metabolism/pathology ; Humans ; Ion Channels/*genetics/metabolism ; Multiple Sclerosis ; Mutation ; Nervous System Diseases/genetics/*metabolism/pathology ; Parkinson Disease/genetics/*metabolism/pathology ; }, abstract = {The convergent endeavors of the neuroscientist to establish a link between clinical neurology, genetics, loss of function of an important protein, and channelopathies behind neurological disorders are quite intriguing. Growing evidence reveals the impact of ion channels dysfunctioning in neurodegenerative disorders (NDDs). Many neurological/neuromuscular disorders, viz, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and age-related disorders are caused due to altered function or mutation in ion channels. To maintain cell homeostasis, ion channels are playing a crucial role which is a large transmembrane protein. Further, these channels are important as it determines the membrane potential and playing critically in the secretion of neurotransmitter. Behind NDDs, losses of pathological proteins and defective ion channels have been reported and are found to aggravate the disease symptoms. Moreover, ion channel dysfunctions are eliciting a range of symptoms, including memory loss, movement disabilities, neuromuscular sprains, and strokes. Since the possible mechanistic role played by aberrant ion channels, their receptor and associated factors in neurodegeneration remained elusive; therefore, it is a challenging task for the neuroscientist to implement the therapeutics for targeting NDDs. This chapter reviews the potential role of the ion channels in membrane physiology and brain homeostasis, where ion channels and their associated factors have been characterized with their functional consequences in neurological diseases. Moreover, mechanistic role of perturbed ion channels has been identified in various NDDs, and finally, ion channel modulators have been investigated for their therapeutic intervention in treating common NDDs.}, }
@article {pmid26914914, year = {2016}, author = {Bahrani, E and Nunneley, CE and Hsu, S and Kass, JS}, title = {Cutaneous Adverse Effects of Neurologic Medications.}, journal = {CNS drugs}, volume = {30}, number = {3}, pages = {245-267}, pmid = {26914914}, issn = {1179-1934}, mesh = {Central Nervous System Agents/*adverse effects/therapeutic use ; Drug Eruptions/*etiology ; Drug-Related Side Effects and Adverse Reactions/*etiology ; Humans ; Nervous System Diseases/drug therapy ; United States ; United States Food and Drug Administration ; }, abstract = {Life-threatening and benign drug reactions occur frequently in the skin, affecting 8 % of the general population and 2-3 % of all hospitalized patients, emphasizing the need for physicians to effectively recognize and manage patients with drug-induced eruptions. Neurologic medications represent a vast array of drug classes with cutaneous side effects. Approximately 7 % of the United States (US) adult population is affected by adult-onset neurological disorders, reflecting a large number of patients on neurologic drug therapies. This review elucidates the cutaneous reactions associated with medications approved by the US Food and Drug Administration (FDA) to treat the following neurologic pathologies: Alzheimer disease, amyotrophic lateral sclerosis, epilepsy, Huntington disease, migraine, multiple sclerosis, Parkinson disease, and pseudobulbar affect. A search of the literature was performed using the specific FDA-approved drug or drug classes in combination with the terms 'dermatologic,' 'cutaneous,' 'skin,' or 'rash.' Both PubMed and the Cochrane Database of Systematic Reviews were utilized, with side effects ranging from those cited in randomized controlled trials to case reports. It behooves neurologists, dermatologists, and primary care physicians to be aware of the recorded cutaneous adverse reactions and their severity for proper management and potential need to withdraw the offending medication.}, }
@article {pmid26910817, year = {2017}, author = {Wan, P and Su, W and Zhuo, Y}, title = {The Role of Long Noncoding RNAs in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {54}, number = {3}, pages = {2012-2021}, pmid = {26910817}, issn = {1559-1182}, mesh = {Animals ; Brain/pathology/physiology ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/pathology ; Neurons/pathology/*physiology ; RNA, Long Noncoding/*physiology ; }, abstract = {Long noncoding RNAs (lncRNAs) are transcripts with low protein-coding potential but occupy a large part of transcriptional output. Their roles include regulating gene expression at the epigenetic, transcriptional, and post-transcriptional level in cellular homeostasis. However, lncRNA studies are still in their infancy and the functions of the vast majority of lncRNA transcripts remain unknown. It is generally known that the function of the human nervous system largely relies on the precise regulation of gene expression. Various studies have shown that lncRNAs have a significant impact on normal neural development and on the development and progression of neurodegenerative diseases. In this review, we focused on recent studies associated with lncRNAs in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), frontotemporal lobar degeneration (FTLD), and glaucoma. Glaucoma, caused by unexplained ganglion cell lesion and apoptosis, is now labeled as a chronic neurodegenerative disorder [1], and therefore, we discussed the association of lncRNAs with glaucoma as well. We illustrate the role of some specific lncRNAs, which may provide new insights into our understanding of the etiology and pathophysiology of the neurodegenerative diseases mentioned above.}, }
@article {pmid26908139, year = {2016}, author = {Silverman, JM and Fernando, SM and Grad, LI and Hill, AF and Turner, BJ and Yerbury, JJ and Cashman, NR}, title = {Disease Mechanisms in ALS: Misfolded SOD1 Transferred Through Exosome-Dependent and Exosome-Independent Pathways.}, journal = {Cellular and molecular neurobiology}, volume = {36}, number = {3}, pages = {377-381}, pmid = {26908139}, issn = {1573-6830}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*pathology ; Animals ; Exosomes/*metabolism ; Humans ; Protein Aggregation, Pathological/enzymology ; *Protein Folding ; *Signal Transduction ; Superoxide Dismutase-1/*chemistry/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neuromuscular degenerative disorder with a poorly defined etiology. ALS patients experience motor weakness, which starts focally and spreads throughout the nervous system, culminating in paralysis and death within a few years of diagnosis. While the vast majority of clinical ALS is sporadic with no known cause, mutations in human copper-zinc superoxide dismutase 1 (SOD1) cause about 20 % of inherited cases of ALS. ALS with SOD1 mutations is caused by a toxic gain of function associated with the propensity of mutant SOD1 to misfold, presenting a non-native structure. The mechanisms responsible for the progressive spreading of ALS pathology have been the focus of intense study. We have shown that misfolded SOD1 protein can seed misfolding and aggregation of endogenous wild-type SOD1 similar to amyloid-β and prion protein seeding. Our recent observations demonstrate a transfer of the misfolded SOD1 species from cell to cell, modeling the intercellular transmission of disease through the neuroaxis. We have shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell, either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or in association with vesicles which are released into the extracellular environment. Furthermore, once misfolding of wild-type SOD1 has been initiated in a human cell culture, it can induce misfolding in naïve cell cultures over multiple passages of media transfer long after the initial misfolding template is degraded. Herein we review the data on mechanisms of intercellular transmission of misfolded SOD1.}, }
@article {pmid26907528, year = {2016}, author = {Herms, J and Dorostkar, MM}, title = {Dendritic Spine Pathology in Neurodegenerative Diseases.}, journal = {Annual review of pathology}, volume = {11}, number = {}, pages = {221-250}, doi = {10.1146/annurev-pathol-012615-044216}, pmid = {26907528}, issn = {1553-4014}, mesh = {Animals ; Dendritic Spines/*pathology ; Humans ; Neurodegenerative Diseases/*pathology ; }, abstract = {Substantial progress has been made toward understanding the neuropathology, genetic origins, and epidemiology of neurodegenerative diseases, including Alzheimer's disease; tauopathies, such as frontotemporal dementia; α-synucleinopathies, such as Parkinson's disease or dementia with Lewy bodies; Huntington's disease; and amyotrophic lateral sclerosis with dementia, as well as prion diseases. Recent evidence has implicated dendritic spine dysfunction as an important substrate of the pathogenesis of dementia in these disorders. Dendritic spines are specialized structures, extending from the neuronal processes, on which excitatory synaptic contacts are formed, and the loss of dendritic spines correlates with the loss of synaptic function. We review the literature that has implicated direct or indirect structural alterations at dendritic spines in the pathogenesis of major neurodegenerative diseases, focusing on those that lead to dementias such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as frontotemporal dementia and prion diseases. We stress the importance of in vivo studies in animal models.}, }
@article {pmid26905828, year = {2016}, author = {Forostyak, O and Forostyak, S and Kortus, S and Sykova, E and Verkhratsky, A and Dayanithi, G}, title = {Physiology of Ca(2+) signalling in stem cells of different origins and differentiation stages.}, journal = {Cell calcium}, volume = {59}, number = {2-3}, pages = {57-66}, doi = {10.1016/j.ceca.2016.02.001}, pmid = {26905828}, issn = {1532-1991}, mesh = {Animals ; Calcium/*metabolism ; *Calcium Signaling ; *Cell Differentiation ; Humans ; Stem Cells/*cytology/*metabolism ; }, abstract = {Stem cells (SCs) of different origins have brought hope as potential tools for the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. Calcium signalling plays a key role in SC differentiation and proliferation, and dysregulation of Ca(2+) homeostasis may instigate pathological scenarios. Currently, the role of ion channels and receptors in SCs is not fully understood. In the recent years, we found that (i) the pre-differentiation of human embryonic SCs (hESCs) led to the activation of Ca(2+) signalling cascades and enhanced the functional activities of these cells, (ii) the Ca(2+) homeostasis and the physiological properties of hESC-derived neural precursors (NPs) changed during long term propagation in vitro, (iii) differentiation of NPs derived from human induced pluripotent SCs affects the expression of ion channels and receptors, (iv) these neuronal precursors exhibited spontaneous activity, indicating that their electrophysiological and Ca(2+) handling properties are similar to those of mature neurones, and (v) in mesenchymal SCs isolated from the adipose tissue and bone marrow of rats the expression profile of ion channels and receptors depends not only on the differentiation conditions but also on the source from which the cells were isolated, indicating that the fate and functional properties of the differentiated cells are driven by intrinsic mechanisms. Together, identification and assignment of a unique ion channel and a Ca(2+) handling footprint for each cell type would be necessary to qualify them as physiologically suitable for medical research, drug screening, and cell therapy.}, }
@article {pmid26904266, year = {2016}, author = {Hodgson, LE and Murphy, PB}, title = {Update on clinical trials in home mechanical ventilation.}, journal = {Journal of thoracic disease}, volume = {8}, number = {2}, pages = {255-267}, pmid = {26904266}, issn = {2072-1439}, abstract = {Home mechanical ventilation (HMV) is an increasingly common intervention and is initiated for a range of pathological processes, including neuromuscular disease (NMD), chronic obstructive pulmonary disease (COPD) and obesity related respiratory failure. There have been important recent data published in this area, which helps to guide practice by indicating which populations may benefit from this intervention and the optimum method of setting up and controlling sleep disordered breathing. Recent superficially conflicting data has been published regarding HMV in COPD, with a trial in post-exacerbation patients suggesting no benefit, but in stable chronic hypercapnic patients suggesting a clear and sustained mortality benefit. The two studies are critiqued and the potential reasons for the differing results are discussed. Early and small trial data is frequently contradicted with larger randomised controlled trials and this has been the case with diaphragm pacing being shown to be potentially harmful in the latest data, confirming the importance of non-invasive ventilation (NIV) in NMD such as motor neurone disease. Advances in ventilator technology have so far appeared quicker than the clinical data to support their use; although small and often unblinded, the current data suggests equivalence to standard modes of NIV, but with potential comfort benefits that may enhance adherence. The indications for NIV have expanded since its inception, with an effort to treat sleep disordered breathing as a result of chronic heart failure (HF). The SERVE-HF trial has recently demonstrated no clear advantage to this technology and furthermore detected a potentially deleterious effect, with a worsening of all cause and cardiovascular mortality in the treated group compared to controls. The review serves to provide the reader with a critical review of recent advances in the field of sleep disordered breathing and HMV.}, }
@article {pmid26903945, year = {2016}, author = {Leis, AA and Ross, MA and Verheijde, JL and Leis, JF}, title = {Immunoablation and Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: The Ultimate Test for the Autoimmune Pathogenesis Hypothesis.}, journal = {Frontiers in neurology}, volume = {7}, number = {}, pages = {12}, pmid = {26903945}, issn = {1664-2295}, }
@article {pmid26902584, year = {2016}, author = {Cai, Y and Arikkath, J and Yang, L and Guo, ML and Periyasamy, P and Buch, S}, title = {Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders.}, journal = {Autophagy}, volume = {12}, number = {2}, pages = {225-244}, pmid = {26902584}, issn = {1554-8635}, support = {DA036157/DA/NIDA NIH HHS/United States ; R01 DA035203/DA/NIDA NIH HHS/United States ; DA035203/DA/NIDA NIH HHS/United States ; R01 DA036157/DA/NIDA NIH HHS/United States ; P30 GM103509/GM/NIGMS NIH HHS/United States ; R25 MH080661/MH/NIMH NIH HHS/United States ; DA033150/DA/NIDA NIH HHS/United States ; R01 DA033150/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; *Autophagy ; *Endoplasmic Reticulum Stress ; Humans ; Models, Biological ; Neurodegenerative Diseases/*pathology ; Unfolded Protein Response ; }, abstract = {The common underlying feature of most neurodegenerative diseases such as Alzheimer disease (AD), prion diseases, Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) involves accumulation of misfolded proteins leading to initiation of endoplasmic reticulum (ER) stress and stimulation of the unfolded protein response (UPR). Additionally, ER stress more recently has been implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Autophagy plays an essential role in the clearance of aggregated toxic proteins and degradation of the damaged organelles. There is evidence that autophagy ameliorates ER stress by eliminating accumulated misfolded proteins. Both abnormal UPR and impaired autophagy have been implicated as a causative mechanism in the development of various neurodegenerative diseases. This review highlights recent advances in the field on the role of ER stress and autophagy in AD, prion diseases, PD, ALS and HAND with the involvement of key signaling pathways in these processes and implications for future development of therapeutic strategies.}, }
@article {pmid26899735, year = {2016}, author = {Paillusson, S and Stoica, R and Gomez-Suaga, P and Lau, DHW and Mueller, S and Miller, T and Miller, CCJ}, title = {There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases.}, journal = {Trends in neurosciences}, volume = {39}, number = {3}, pages = {146-157}, pmid = {26899735}, issn = {1878-108X}, support = {/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G-1308/PUK_/Parkinson's UK/United Kingdom ; MILLER/OCT08/6247/MNDA_/Motor Neurone Disease Association/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Endoplasmic Reticulum/*metabolism/ultrastructure ; Humans ; Mitochondria/*metabolism/ultrastructure ; Neurodegenerative Diseases/genetics/*metabolism/pathology/therapy ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.}, }
@article {pmid26899126, year = {2016}, author = {Watzlawik, JO and Wootla, B and Rodriguez, M}, title = {Tryptophan Catabolites and Their Impact on Multiple Sclerosis Progression.}, journal = {Current pharmaceutical design}, volume = {22}, number = {8}, pages = {1049-1059}, pmid = {26899126}, issn = {1873-4286}, support = {R01 GM092993/GM/NIGMS NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Disease Progression ; Humans ; Multiple Sclerosis/*physiopathology ; Tryptophan/*metabolism ; }, abstract = {Accumulating evidence demonstrates involvement of tryptophan metabolites and in particular activation of the kynurenine pathway (KP) in neurocognitive disorders under CNS inflammatory conditions. The KP is involved in several brain-associated disorders including Parkinson's disease, AIDS dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, and brain tumors. Our review is an attempt to address any relevant association between dysregulation of KP and multiple sclerosis (MS), an inflammatory CNS disorder that ultimately leads to demyelinated brain areas and severe neurological deficits. Modulation of KP is a new topic for the field of MS and warrants further research. The availability of potential KP modulators approved for MS may shed some light into the therapeutic potential of KP antagonists for the treatment of MS patients.}, }
@article {pmid26898182, year = {2016}, author = {Murphy, SE and Levine, TP}, title = {VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome.}, journal = {Biochimica et biophysica acta}, volume = {1861}, number = {8 Pt B}, pages = {952-961}, pmid = {26898182}, issn = {0006-3002}, support = {BB/M011801/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/L016028/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/M011801/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Endoplasmic Reticulum/*metabolism ; Humans ; Molecular Sequence Data ; Protein Binding ; Protein Interaction Domains and Motifs/*physiology ; *Protein Interaction Maps ; Vesicular Transport Proteins/*chemistry/metabolism/*physiology ; }, abstract = {Dysfunction of VAMP-associated protein (VAP) is associated with neurodegeneration, both Amyotrophic Lateral Sclerosis and Parkinson's disease. Here we summarize what is known about the intracellular interactions of VAP in humans and model organisms. VAP is a simple, small and highly conserved protein on the cytoplasmic face of the endoplasmic reticulum (ER). It is the sole protein on that large organelle that acts as a receptor for cytoplasmic proteins. This may explain the extremely wide range of interacting partners of VAP, with components of many cellular pathways binding it to access the ER. Many proteins that bind VAP also target other intracellular membranes, so VAP is a component of multiple molecular bridges at membrane contact sites between the ER and other organelles. So far approximately 100 proteins have been identified in the VAP interactome (VAPome), of which a small minority have a "two phenylalanines in an acidic tract" (FFAT) motif as it was originally defined. We have analyzed the entire VAPome in humans and yeast using a simple algorithm that identifies many more FFAT-like motifs. We show that approximately 50% of the VAPome binds directly or indirectly via the VAP-FFAT interaction. We also review evidence on pathogenesis in genetic disorders of VAP, which appear to arise from reduced overall VAP levels, leading to ER stress. It is not possible to identify one single interaction that underlies disease. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.}, }
@article {pmid26896755, year = {2017}, author = {Yu, LJ and Wall, BA and Wangari-Talbot, J and Chen, S}, title = {Metabotropic glutamate receptors in cancer.}, journal = {Neuropharmacology}, volume = {115}, number = {}, pages = {193-202}, pmid = {26896755}, issn = {1873-7064}, support = {R21 CA185835/CA/NCI NIH HHS/United States ; R25 ES020721/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*metabolism/pharmacology/*therapeutic use ; Excitatory Amino Acid Agonists/metabolism/pharmacology/therapeutic use ; Excitatory Amino Acid Antagonists/metabolism/pharmacology/therapeutic use ; Humans ; Neoplasms/*drug therapy/*metabolism ; Receptors, Metabotropic Glutamate/agonists/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Metabotropic glutamate receptors (mGluRs) are widely known for their roles in synaptic signaling. However, accumulating evidence suggests roles of mGluRs in human malignancies in addition to synaptic transmission. Somatic cell homeostasis presents intriguing possibilities of mGluRs and glutamate signaling as novel targets for human cancers. More recently, aberrant glutamate signaling has been shown to participate in the transformation and maintenance of various cancer types, including glioma, melanoma skin cancer, breast cancer, and prostate cancer, indicating that genes encoding mGluRs, GRMs, can function as oncogenes. Here, we provide a review on the interactions of mGluRs and their ligand, glutamate, in processes that promote the growth of tumors of neuronal and non-neuronal origins. Further, we discuss the evolution of riluzole, a glutamate release inhibitor approved for amyotrophic lateral sclerosis (ALS), but now fashioned as an mGluR1 inhibitor for melanoma therapy and as a radio-sensitizer for tumors that have metastasized to the brain. With the success of riluzole, it is not far-fetched to believe that other drugs that may act directly or indirectly on other mGluRs can be beneficial for multiple applications. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.}, }
@article {pmid26895253, year = {2016}, author = {Moujalled, D and White, AR}, title = {Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis.}, journal = {CNS drugs}, volume = {30}, number = {3}, pages = {227-243}, pmid = {26895253}, issn = {1179-1934}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Animals ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/*pharmacology/*therapeutic use ; Humans ; Mutation/genetics ; Riluzole/*pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset, neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Over recent years, numerous genes ha ve been identified that promote disease pathology, including SOD1, TARDBP, and the expanded hexanucleotide repeat (GGGGCC) within C9ORF72. However, despite these major advances in identifying genes contributing to ALS pathogenesis, there remains only one currently approved therapeutic: the glutamate antagonist, riluzole. Seminal breakthroughs in the pathomechanisms and genetic factors associated with ALS have heavily relied on the use of rodent models that recapitulate the ALS phenotype; however, while many therapeutics have proved to be significant in animal models by prolonging life and rescuing motor deficits, they have failed in human clinical trials. This may be due to fundamental differences between rodent models and human disease, the fact that animal models are based on overexpression of mutated genes, and confounding issues such as difficulties mimicking the dosing schedules and regimens implemented in mouse models to humans. Here, we review the major pathways associated with the pathology of ALS, the rodent models engineered to test efficacy of candidate drugs, the advancements being made in stem cell therapy for ALS, and what strategies may be important to circumvent the lack of successful translational studies in the clinic.}, }
@article {pmid26892289, year = {2016}, author = {Forlenza, OV and Aprahamian, I and de Paula, VJ and Hajek, T}, title = {Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders.}, journal = {Current Alzheimer research}, volume = {13}, number = {8}, pages = {879-886}, doi = {10.2174/1567205013666160219112854}, pmid = {26892289}, issn = {1875-5828}, mesh = {Alzheimer Disease/drug therapy ; Animals ; Clinical Trials as Topic ; Humans ; Lithium Compounds/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; }, abstract = {BACKGROUND: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer's disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects.<br><br>METHODS: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014.<br><br>RESULTS: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease.<br><br>CONCLUSION: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.}, }
@article {pmid26889480, year = {2016}, author = {Zou, ZY and Liu, CY and Che, CH and Huang, HP}, title = {Toward precision medicine in amyotrophic lateral sclerosis.}, journal = {Annals of translational medicine}, volume = {4}, number = {2}, pages = {27}, pmid = {26889480}, issn = {2305-5839}, abstract = {Precision medicine is an innovative approach that uses emerging biomedical technologies to deliver optimally targeted and timed interventions, customized to the molecular drivers of an individual's disease. This approach is only just beginning to be considered for treating amyotrophic lateral sclerosis (ALS). The clinical and biological complexities of ALS have hindered development of effective therapeutic strategies. In this review we consider applying the key elements of precision medicine to ALS: phenotypic classification, comprehensive risk assessment, presymptomatic period detection, potential molecular pathways, disease model development, biomarker discovery and molecularly tailored interventions. Together, these would embody a precision medicine approach, which may provide strategies for optimal targeting and timing of efforts to prevent, stop or slow progression of ALS.}, }
@article {pmid26881708, year = {2016}, author = {Mckenzie-Nickson, S and Bush, AI and Barnham, KJ}, title = {Bis(thiosemicarbazone) Metal Complexes as Therapeutics for Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {16}, number = {27}, pages = {3058-3068}, doi = {10.2174/1568026616666160216155746}, pmid = {26881708}, issn = {1873-4294}, mesh = {Animals ; Coordination Complexes/*therapeutic use ; Humans ; Metals/chemistry/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Thiosemicarbazones/chemistry/*therapeutic use ; }, abstract = {Pathological aggregation of endogenous proteins is a common feature of many neurodegenerative diseases. This is generally accompanied by elevated levels of oxidative stress associated with transition metal dyshomeostasis. As such, strategies targeted toward rectifying metal imbalance are increasingly becoming an attractive therapeutic option. One class of compound showing such therapeutic potential are the bis(thiosemicarbazone) metal complexes. These are small, orally bioavailable compounds capable of crossing the blood brain barrier and capable of delivering bioavailable metal intracellularly. Members of this family of compounds have been shown to successfully treat animal models of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Here we review the current evidence for the efficacy of bis(thiosemicarbazone) metal complexes in treating these diseases and discuss the implications for future development of these compounds.}, }
@article {pmid26881039, year = {2016}, author = {Chiurchiù, V and Orlacchio, A and Maccarrone, M}, title = {Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {7909380}, pmid = {26881039}, issn = {1942-0994}, mesh = {Aging ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Blood-Brain Barrier ; Brain/metabolism ; Central Nervous System ; Humans ; Inflammation ; Ions ; Metals/chemistry ; Neurodegenerative Diseases/*metabolism ; *Oxidation-Reduction ; *Oxidative Stress ; Oxygen/metabolism ; Oxygen Consumption ; Parkinson Disease/metabolism ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Spastic Paraplegia, Hereditary/metabolism ; }, abstract = {The central nervous system is particularly sensitive to oxidative stress due to many reasons, including its high oxygen consumption even under basal conditions, high production of reactive oxygen and nitrogen species from specific neurochemical reactions, and the increased deposition of metal ions in the brain with aging. For this reason, along with inflammation, oxidative stress seems to be one of the main inducers of neurodegeneration, causing excitotoxicity, neuronal loss, and axonal damage, ultimately being now considered a key element in the onset and progression of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and hereditary spastic paraplegia. Thus, the present paper reviews the role of oxidative stress and of its mechanistic insights underlying the pathogenesis of these neurodegenerative diseases, with particular focus on current studies on its modulation as a potential and promising therapeutic strategy.}, }
@article {pmid26876477, year = {2016}, author = {Devall, M and Roubroeks, J and Mill, J and Weedon, M and Lunnon, K}, title = {Epigenetic regulation of mitochondrial function in neurodegenerative disease: New insights from advances in genomic technologies.}, journal = {Neuroscience letters}, volume = {625}, number = {}, pages = {47-55}, pmid = {26876477}, issn = {1872-7972}, support = {R01 AG036039/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism ; *DNA Methylation ; DNA, Mitochondrial/*genetics ; *Epigenesis, Genetic ; Epigenomics/*methods ; Gene Expression Regulation ; Humans ; Neurodegenerative Diseases/*genetics ; Sequence Analysis, DNA ; }, abstract = {The field of mitochondrial epigenetics has received increased attention in recent years and changes in mitochondrial DNA (mtDNA) methylation has been implicated in a number of diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis. However, current publications have been limited by the use of global or targeted methods of measuring DNA methylation. In this review, we discuss current findings in mitochondrial epigenetics as well as its potential role as a regulator of mitochondria within the brain. Finally, we summarize the current technologies best suited to capturing mtDNA methylation, and how a move towards whole epigenome sequencing of mtDNA may help to advance our current understanding of the field.}, }
@article {pmid26872323, year = {2016}, author = {Rabinstein, AA}, title = {Noninvasive ventilation for neuromuscular respiratory failure: when to use and when to avoid.}, journal = {Current opinion in critical care}, volume = {22}, number = {2}, pages = {94-99}, doi = {10.1097/MCC.0000000000000284}, pmid = {26872323}, issn = {1531-7072}, mesh = {Contraindications ; Guillain-Barre Syndrome/complications/*therapy ; Humans ; Intubation, Intratracheal/*methods ; Myasthenia Gravis/complications/*therapy ; Noninvasive Ventilation/*methods ; Patient Selection ; Practice Guidelines as Topic ; Primary Dysautonomias/complications/*therapy ; Respiratory Insufficiency/diagnosis/etiology/*therapy ; }, abstract = {PURPOSE OF REVIEW: Neuromuscular respiratory failure can occur from a variety of diseases, both acute and chronic with acute exacerbation. There is often a misunderstanding about how the nature of the neuromuscular disease should affect the decision on how to ventilate the patient. This review provides an update on the value and relative contraindications for the use of noninvasive ventilation in patients with various causes of primary neuromuscular respiratory failure.<br><br>RECENT FINDINGS: Myasthenic crisis represents the paradigmatic example of the neuromuscular condition that can be best treated with noninvasive ventilation. Timely use of noninvasive ventilation can substantially reduce the duration of ventilatory assistance in these patients. Noninvasive ventilation can also be very helpful after extubation in patients recovering from an acute cause of neuromuscular respiratory failure who have persistent weakness. Noninvasive ventilation can improve quality of survival in patients with advanced motor neuron disorder (such as amyotrophic lateral sclerosis) and muscular dystrophies, and can avoid intubation when these patients present to the hospital with acute respiratory failure. Attempting noninvasive ventilation is not only typically unsuccessful in patients with Guillain-Barre syndrome, but can also be dangerous in these cases.<br><br>SUMMARY: Noninvasive ventilation can be very effective to treat acute respiratory failure caused by myasthenia gravis and to prevent reintubation in other neuromuscular patients, but should be used cautiously for other indications, particularly Guillain-Barre syndrome.}, }
@article {pmid26872075, year = {2016}, author = {Yerbury, JJ and Ooi, L and Dillin, A and Saunders, DN and Hatters, DM and Beart, PM and Cashman, NR and Wilson, MR and Ecroyd, H}, title = {Walking the tightrope: proteostasis and neurodegenerative disease.}, journal = {Journal of neurochemistry}, volume = {137}, number = {4}, pages = {489-505}, doi = {10.1111/jnc.13575}, pmid = {26872075}, issn = {1471-4159}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Protein Folding ; Protein Interaction Maps/physiology ; *Proteolysis ; Proteostasis Deficiencies/*metabolism/pathology ; Ubiquitin/metabolism ; }, abstract = {A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid-β, α-synuclein, or superoxide dismutase1 (SOD1), many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration, and location to be functional. In this review, we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degradation pathways, and the active formation of inclusions, in neurodegenerative diseases associated with protein aggregation. A characteristic of many neurodegenerative diseases is the aggregation of specific proteins, which alone provides strong evidence that protein homeostasis is disrupted in these disease states. Proteostasis is the maintenance of the proteome in the correct conformation, concentration, and location by functional pathways such as molecular chaperones and protein degradation machinery. Here, we discuss the potential roles of quality control pathways, both inside and outside cells, in the loss of proteostasis during aging and disease.}, }
@article {pmid26870889, year = {2016}, author = {Rudolf, R and Deschenes, MR and Sandri, M}, title = {Neuromuscular junction degeneration in muscle wasting.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {19}, number = {3}, pages = {177-181}, pmid = {26870889}, issn = {1473-6519}, support = {R15 AR060637/AR/NIAMS NIH HHS/United States ; R15 060 637//PHS HHS/United States ; }, mesh = {Animals ; Autophagy ; Gene Expression Regulation ; Humans ; *Models, Biological ; Muscle Proteins/agonists/genetics/metabolism ; Muscular Atrophy/*etiology ; Nerve Degeneration/*etiology ; Nerve Tissue Proteins/genetics/metabolism ; Neuromuscular Junction/metabolism/pathology/*physiopathology ; Neuromuscular Junction Diseases/*etiology ; Wasting Syndrome/metabolism/pathology/*physiopathology ; Wnt Signaling Pathway ; }, abstract = {PURPOSE OF REVIEW: Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and clinical relevance of maintaining the neuromuscular junction to counteract muscle wasting resulting from aging or neural disease/damage.<br><br>RECENT FINDINGS: Activity-dependent regulation of autophagy, the agrin-muscle specific kinase-Lrp4 signaling axis, and sympathetic modulation are principal mechanisms involved in stabilizing the neuromuscular junction. These findings are derived from several animal models and were largely confirmed by human gene expression analysis as well as insights from rare neuromuscular diseases such as amyotrophic lateral sclerosis and congenital myasthenic syndromes. Based on these insights, agrin-derived fragments are currently being evaluated as biomarkers for age-related muscle wasting. Tuning of autophagy, of the agrin pathway, and of sympathetic input are being studied as clinical treatment of muscle wasting disorders.<br><br>SUMMARY: Basic research has revealed that maintenance of neuromuscular junctions and a few signaling pathways are important in the context of age-dependent and other forms of muscle wasting. These findings have recently started to enter clinical practice, but further research needs to substantiate and refine our knowledge.}, }
@article {pmid26867662, year = {2016}, author = {Mpandzou, G and Aït Ben Haddou, E and Regragui, W and Benomar, A and Yahyaoui, M}, title = {Vitamin D deficiency and its role in neurological conditions: A review.}, journal = {Revue neurologique}, volume = {172}, number = {2}, pages = {109-122}, doi = {10.1016/j.neurol.2015.11.005}, pmid = {26867662}, issn = {0035-3787}, mesh = {Alzheimer Disease/blood/etiology ; Central Nervous System/drug effects/physiology ; Humans ; Multiple Sclerosis/blood/etiology ; Nervous System Diseases/blood/*etiology ; Neurodegenerative Diseases/blood/etiology ; Neuromuscular Junction/drug effects/physiology ; Parkinson Disease/blood/etiology ; Vitamin D/biosynthesis/pharmacology/physiology ; Vitamin D Deficiency/*complications/psychology ; }, abstract = {This review exposes recent advances on the role of vitamin D, cholecalciferol, a secosteroid, in the central nervous system. In humans, vitamin D arises from cutaneous transformation of 7-dehydrocholesterol under the effect of UVB exposure or from food intake. Vitamin D has an immunomodulatory role through its anti-inflammatory and anti-autoimmune actions. In the nervous system, vitamin D is involved in the regulation of calcium-mediated neuronal excitotoxicity, in the reduction of oxidative stress, and in the induction of synaptic structural proteins, neurotrophic factors and deficient neurotransmitters. Reduced exposure to sunlight and low food intake can lead to vitamin D deficiency. Increasing evidence highlights the impact of vitamin D deficiency as a favoring factor in various central or peripheral neurological diseases, especially multiple sclerosis and several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. Recently, several clinical trials on vitamin D supplementation stressed the role of vitamin D as a protective and/or prognostic factor in the onset and progress of such neurological conditions.}, }
@article {pmid26866492, year = {2016}, author = {Hosp, C and Naumann, MK and Hamm, H}, title = {Botulinum Toxin Treatment of Autonomic Disorders: Focal Hyperhidrosis and Sialorrhea.}, journal = {Seminars in neurology}, volume = {36}, number = {1}, pages = {20-28}, doi = {10.1055/s-0035-1571214}, pmid = {26866492}, issn = {1098-9021}, mesh = {Acetylcholine Release Inhibitors/therapeutic use ; Animals ; Autonomic Nervous System Diseases/diagnosis/*drug therapy/physiopathology ; Botulinum Toxins/*therapeutic use ; Humans ; Hyperhidrosis/diagnosis/*drug therapy/physiopathology ; Multicenter Studies as Topic ; Prospective Studies ; Sialorrhea/diagnosis/*drug therapy/physiopathology ; Treatment Outcome ; }, abstract = {Primary focal hyperhidrosis is a common autonomic disorder that significantly impacts quality of life. It is characterized by excessive sweating confined to circumscribed areas, such as the axillae, palms, soles, and face. Less frequent types of focal hyperhidrosis secondary to underlying causes include gustatory sweating in Frey's syndrome and compensatory sweating in Ross' syndrome and after sympathectomy. Approval of onabotulinumtoxinA for severe primary axillary hyperhidrosis in 2004 has revolutionized the treatment of this indication. Meanwhile further type A botulinum neurotoxins like abobotulinumtoxinA and incobotulinumtoxinA, as well as the type B botulinum neurotoxin rimabotulinumtoxinB are successfully used off-label for axillary and various other types of focal hyperhidrosis. For unexplained reasons, the duration of effect differs considerably at different sites. Beside hyperhidrosis, botulinum neurotoxin is also highly valued for the treatment of sialorrhea affecting patients with Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, motor neuron disease, and other neurologic conditions. With correct dosing and application, side effects are manageable and transient.}, }
@article {pmid26862478, year = {2016}, author = {Martin, AR and Aleksanderek, I and Cohen-Adad, J and Tarmohamed, Z and Tetreault, L and Smith, N and Cadotte, DW and Crawley, A and Ginsberg, H and Mikulis, DJ and Fehlings, MG}, title = {Translating state-of-the-art spinal cord MRI techniques to clinical use: A systematic review of clinical studies utilizing DTI, MT, MWF, MRS, and fMRI.}, journal = {NeuroImage. Clinical}, volume = {10}, number = {}, pages = {192-238}, pmid = {26862478}, issn = {2213-1582}, mesh = {Animals ; Brain Mapping ; Diffusion Tensor Imaging/*methods ; Humans ; Magnetic Phenomena ; Magnetic Resonance Imaging/*methods ; Magnetic Resonance Spectroscopy/*methods ; Myelin Sheath/metabolism ; Spinal Cord/*pathology ; Spinal Cord Injuries/*pathology ; Translational Research, Biomedical/*trends ; Water/metabolism ; }, abstract = {BACKGROUND: A recent meeting of international imaging experts sponsored by the International Spinal Research Trust (ISRT) and the Wings for Life Foundation identified 5 state-of-the-art MRI techniques with potential to transform the field of spinal cord imaging by elucidating elements of the microstructure and function: diffusion tensor imaging (DTI), magnetization transfer (MT), myelin water fraction (MWF), MR spectroscopy (MRS), and functional MRI (fMRI). However, the progress toward clinical translation of these techniques has not been established.<br><br>METHODS: A systematic review of the English literature was conducted using MEDLINE, MEDLINE-in-Progress, Embase, and Cochrane databases to identify all human studies that investigated utility, in terms of diagnosis, correlation with disability, and prediction of outcomes, of these promising techniques in pathologies affecting the spinal cord. Data regarding study design, subject characteristics, MRI methods, clinical measures of impairment, and analysis techniques were extracted and tabulated to identify trends and commonalities. The studies were assessed for risk of bias, and the overall quality of evidence was assessed for each specific finding using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.<br><br>RESULTS: A total of 6597 unique citations were identified in the database search, and after full-text review of 274 articles, a total of 104 relevant studies were identified for final inclusion (97% from the initial database search). Among these, 69 studies utilized DTI and 25 used MT, with both techniques showing an increased number of publications in recent years. The review also identified 1 MWF study, 11 MRS studies, and 8 fMRI studies. Most of the studies were exploratory in nature, lacking a priori hypotheses and showing a high (72%) or moderately high (20%) risk of bias, due to issues with study design, acquisition techniques, and analysis methods. The acquisitions for each technique varied widely across studies, rendering direct comparisons of metrics invalid. The DTI metric fractional anisotropy (FA) had the strongest evidence of utility, with moderate quality evidence for its use as a biomarker showing correlation with disability in several clinical pathologies, and a low level of evidence that it identifies tissue injury (in terms of group differences) compared with healthy controls. However, insufficient evidence exists to determine its utility as a sensitive and specific diagnostic test or as a tool to predict clinical outcomes. Very low quality evidence suggests that other metrics also show group differences compared with controls, including DTI metrics mean diffusivity (MD) and radial diffusivity (RD), the diffusional kurtosis imaging (DKI) metric mean kurtosis (MK), MT metrics MT ratio (MTR) and MT cerebrospinal fluid ratio (MTCSF), and the MRS metric of N-acetylaspartate (NAA) concentration, although these results were somewhat inconsistent.<br><br>CONCLUSIONS: State-of-the-art spinal cord MRI techniques are emerging with great potential to improve the diagnosis and management of various spinal pathologies, but the current body of evidence has only showed limited clinical utility to date. Among these imaging tools DTI is the most mature, but further work is necessary to standardize and validate its use before it will be adopted in the clinical realm. Large, well-designed studies with a priori hypotheses, standardized acquisition methods, detailed clinical data collection, and robust automated analysis techniques are needed to fully demonstrate the potential of these rapidly evolving techniques.}, }
@article {pmid26862206, year = {2016}, author = {Kim, YJ and Guzman-Hernandez, ML and Wisniewski, E and Echeverria, N and Balla, T}, title = {Phosphatidylinositol and phosphatidic acid transport between the ER and plasma membrane during PLC activation requires the Nir2 protein.}, journal = {Biochemical Society transactions}, volume = {44}, number = {1}, pages = {197-201}, pmid = {26862206}, issn = {1470-8752}, support = {Z01 HD000196-11//Intramural NIH HHS/United States ; }, mesh = {Animals ; Biological Transport ; Calcium-Binding Proteins/*metabolism ; Cell Membrane/*metabolism ; Endoplasmic Reticulum/*metabolism ; Humans ; Phosphatidic Acids/*metabolism ; Phosphatidylinositols/*metabolism ; Type C Phospholipases/*metabolism ; }, abstract = {Phospholipase C (PLC)-mediated hydrolysis of the limited pool of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] requires replenishment from a larger pool of phosphatidylinositol (PtdIns) via sequential phosphorylation by PtdIns 4-kinases and phosphatidylinositol 4-phosphate (PtdIns4P) 5-kinases. Since PtdIns is synthesized in the endoplasmic reticulum (ER) and PtdIns(4,5)P2 is generated in the PM, it has been postulated that PtdIns transfer proteins (PITPs) provide the means for this lipid transfer function. Recent studies identified the large PITP protein, Nir2 as important for PtdIns transfer from the ER to the PM. It was also found that Nir2 was required for the transfer of phosphatidic acid (PtdOH) from the PM to the ER. In Nir2-depleted cells, activation of PLC leads to PtdOH accumulation in the PM and PtdIns synthesis becomes severely impaired. In quiescent cells, Nir2 is localized to the ER via interaction of its FFAT domain with ER-bound VAMP-associated proteins VAP-A and-B. After PLC activation, Nir2 also binds to the PM via interaction of its C-terminal domains with diacylglycerol (DAG) and PtdOH. Through these interactions, Nir2 functions in ER-PM contact zones. Mutations in VAP-B that have been identified in familial forms of amyotrophic lateral sclerosis (ALS or Lou-Gehrig's disease) cause aggregation of the VAP-B protein, which then impairs its binding to several proteins, including Nir2. These findings have shed new lights on the importance of non-vesicular lipid transfer of PtdIns and PtdOH in ER-PM contact zones with a possible link to a devastating human disease.}, }
@article {pmid26861067, year = {2016}, author = {Clerc, P and Lipnick, S and Willett, C}, title = {A look into the future of ALS research.}, journal = {Drug discovery today}, volume = {21}, number = {6}, pages = {939-949}, doi = {10.1016/j.drudis.2016.02.002}, pmid = {26861067}, issn = {1878-5832}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Biomedical Research ; Disease Models, Animal ; Humans ; }, abstract = {Although amyotrophic lateral sclerosis (ALS), also referred as 'Lou Gehrig's Disease,' was first described in 1869 and the first disease-associated gene was discovered almost 20 years ago, the disease etiology is still not fully understood and treatment options are limited to one drug approved by the US Food and Drug Administration (FDA). The slow translational progress suggests that current research models are not ideal to study such a complicated disease and need to be re-examined. Progress will require greater insight into human genes and biology involved in ALS susceptibility, as well as a deeper understanding of disease phenotype at the histological and molecular levels. Improving human disease outcome will require directing focus toward improved assessment technologies and innovative approaches.}, }
@article {pmid26860749, year = {2016}, author = {van Es, MA and Kruitwagen-van Reenen, ET and Schröder, CD and Pasterkamp, RJ and Veldink, JH and van den Berg, LH}, title = {[Amyotrophic lateral sclerosis, a heterogeneous disorder].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {160}, number = {}, pages = {A9658}, pmid = {26860749}, issn = {1876-8784}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics/therapy ; Diagnosis, Differential ; Frontotemporal Dementia/diagnosis/genetics/therapy ; Humans ; Quality of Life ; }, abstract = {ALS is a disease characterized by the progressive loss of upper and lower motor neurons leading to weakness and spasticity. Diagnosis of ALS is based on exclusion. ALS and frontotemporal dementia (FTD) constitute the extremes of the spectrum of one disease. Many patients show signs of both ALS and FTD. ALS is a heterogeneous disease in which multiple genetic factors contribute. More than 20 genes are known to play a role in ALS pathogenesis. In approximately 5-10% of cases the disease is familial with autosomal dominant inheritance. There is no curative treatment for ALS. The treatment of ALS patients is symptomatic and is focused on achieving a high level of quality of life. New insights into the genetic fundamentals of ALS offer hope for new therapies. Gene-targeted treatment strategies using antisense oligonucleotides are a promising development.}, }
@article {pmid26858720, year = {2016}, author = {Nigro, A and Colombo, F and Casella, G and Finardi, A and Verderio, C and Furlan, R}, title = {Myeloid Extracellular Vesicles: Messengers from the Demented Brain.}, journal = {Frontiers in immunology}, volume = {7}, number = {}, pages = {17}, pmid = {26858720}, issn = {1664-3224}, abstract = {Blood-borne monocyte derived cells play a pivotal, initially unrecognized, role in most central nervous system disorders, including diseases initially classified as purely neurodegenerative (i.e., Alzheimer's disease, Parkinson's disease, and ALS). Their trafficking to the brain and spinal cord has been extensively studied in classical neuroinflammatory disorders such as multiple sclerosis. Central nervous system resident myeloid cells, namely microglia and perivascular macrophages, also are in the spotlight of investigations on neurological disorders. Myeloid cells, such as infiltrating macrophages and microglia, have been described as having both protective and destructive features in neurological disorders, thus identification of their functional phenotype during disease evolution would be of paramount importance. Extracellular vesicles, namely exosomes and shed vesicles, are released by virtually any cell type and can be detected and identified in terms of cell origin in biological fluids. They therefore constitute an ideal tool to access information on cells residing in an inaccessible site such as the brain. We will review here available information on extracellular vesicles detection in neurological disorders with special emphasis on neurodegenerative diseases.}, }
@article {pmid26858605, year = {2016}, author = {Krieger, C and Wang, SJ and Yoo, SH and Harden, N}, title = {Adducin at the Neuromuscular Junction in Amyotrophic Lateral Sclerosis: Hanging on for Dear Life.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {11}, pmid = {26858605}, issn = {1662-5102}, abstract = {The neurological dysfunction in amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND) is associated with defective nerve-muscle contacts early in the disease suggesting that perturbations of cell adhesion molecules (CAMs) linking the pre- and post-synaptic components of the neuromuscular junction (NMJ) are involved. To search for candidate proteins implicated in this degenerative process, researchers have studied the Drosophila larval NMJ and find that the cytoskeleton-associated protein, adducin, is ideally placed to regulate synaptic contacts. By controlling the levels of synaptic proteins, adducin can de-stabilize synaptic contacts. Interestingly, elevated levels of phosphorylated adducin have been reported in ALS patients and in a mouse model of the disease. Adducin is regulated by phosphorylation through protein kinase C (PKC), some isoforms of which exhibit Ca(2+)-dependence, raising the possibility that changes in intracellular Ca(2+) might alter PKC activation and secondarily influence adducin phosphorylation. Furthermore, adducin has interactions with the alpha subunit of the Na(+)/K(+)-ATPase. Thus, the phosphorylation of adducin may secondarily influence synaptic stability at the NMJ and so influence pre- and post-synaptic integrity at the NMJ in ALS.}, }
@article {pmid26854959, year = {2016}, author = {Prado, Lde G and Bicalho, IC and Vidigal-Lopes, M and Ferreira, CJ and Mageste Barbosa, LS and Gomez, RS and De Souza, LC and Teixeira, AL}, title = {Amyotrophic lateral sclerosis in Brazil: Case series and review of the Brazilian literature.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {3-4}, pages = {282-288}, doi = {10.3109/21678421.2016.1143011}, pmid = {26854959}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*epidemiology ; Brazil/epidemiology ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Statistics, Nonparametric ; }, abstract = {Our objective was to systematically analyse the first series of cases of amyotrophic lateral sclerosis (ALS) in Minas Gerais and to review the Brazilian literature about clinical studies in ALS. This was a cross-sectional and descriptive study of a consecutive series of patients with probable or defined sporadic ALS according to the Awaji criteria, followed at two referral centres of Belo Horizonte (South-east Brazil). Patients underwent full clinical assessment. Comparisons of patient subgroups according to disease duration and initial presentation were performed. A systematic review was performed about Brazilian clinical studies in ALS. Results showed that of the 61 enrolled patients the male/female ratio was 1.6:1. The mean age at onset of symptoms was 54.9 years (SD ± 11.4). Mean age at diagnosis was 56.3 years (SD ± 11.1). Regarding the initial form of presentation, 43 cases (70.5%) were spinal, 12 cases (19.7%) were generalized and six cases (9.8%) were bulbar. Eight studies were found in the systematic review. In conclusion, the profile of our sample was similar to other national and international series, except for fewer cases of bulbar ALS in our series. There are few clinical studies of ALS in Brazil. The national data of prevalence and incidence are still uncertain.}, }
@article {pmid26854827, year = {2016}, author = {Kansal, K and Mareddy, M and Sloane, KL and Minc, AA and Rabins, PV and McGready, JB and Onyike, CU}, title = {Survival in Frontotemporal Dementia Phenotypes: A Meta-Analysis.}, journal = {Dementia and geriatric cognitive disorders}, volume = {41}, number = {1-2}, pages = {109-122}, doi = {10.1159/000443205}, pmid = {26854827}, issn = {1421-9824}, support = {P50AG05146/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Alzheimer Disease/*mortality ; Amyotrophic Lateral Sclerosis/mortality ; Female ; Frontotemporal Dementia/*mortality ; Humans ; Male ; Phenotype ; Primary Progressive Nonfluent Aphasia/mortality ; Supranuclear Palsy, Progressive/mortality ; *Survival Rate ; }, abstract = {BACKGROUND: Survival in frontotemporal dementia (FTD) is not well understood. We conducted a mixed effects meta-analysis of survival in FTD to examine phenotype differences and contributory factors.<br><br>METHODS: The PubMed, Medline, EMBASE, CINAHL, PsycINFO and Cochrane databases were searched for studies describing survival or natural history of behavioral variant FTD (bvFTD), progressive non-fluent aphasia (PNFA), semantic dementia (SD), FTD with amyotrophic lateral sclerosis (FTD-ALS), progressive supranuclear palsy and corticobasal degeneration. There were no language restrictions.<br><br>RESULTS: We included 27 studies (2,462 subjects). Aggregate mean and median survival were derived for each phenotype and, for comparison, Alzheimer's disease (AD) (using data from the selected studies). Survival was shortest in FTD-ALS (2.5 years). Mean survival was longest in bvFTD and PNFA (8 years) and median survival in SD (12 years). AD was comparable in survival to all except FTD-ALS. Age and sex did not affect survival; the education effect was equivocal. Heterogeneity in FTD survival was largely, but not wholly, explained by phenotypes.<br><br>CONCLUSIONS: Survival differs for FTD phenotypes but, except for FTD-ALS, compares well to AD survival. Elucidating the potential causes of within-phenotype heterogeneity in survival (such as complicating features and comorbidities) may open up opportunities for tailored interventions.}, }
@article {pmid26853842, year = {2019}, author = {Riancho, J and Gonzalo, I and Ruiz-Soto, M and Berciano, J}, title = {Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {34}, number = {1}, pages = {27-37}, doi = {10.1016/j.nrl.2015.12.001}, pmid = {26853842}, issn = {2173-5808}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment.<br><br>DEVELOPMENT: This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration.<br><br>CONCLUSIONS: ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established.}, }
@article {pmid26852120, year = {2016}, author = {Nostramo, R and Herman, PK}, title = {Deubiquitination and the regulation of stress granule assembly.}, journal = {Current genetics}, volume = {62}, number = {3}, pages = {503-506}, pmid = {26852120}, issn = {1432-0983}, support = {R01 GM065227/GM/NIGMS NIH HHS/United States ; R01 GM101191/GM/NIGMS NIH HHS/United States ; }, mesh = {Cytoplasmic Granules/*metabolism ; Endopeptidases/metabolism ; Eukaryotic Cells/physiology ; Humans ; Protein Processing, Post-Translational ; *Stress, Physiological ; Ubiquitin Thiolesterase/metabolism ; *Ubiquitination ; Ubiquitins/metabolism ; Yeasts/physiology ; }, abstract = {Stress granules (SGs) are evolutionarily conserved ribonucleoprotein (RNP) structures that form in response to a variety of environmental and cellular cues. The presence of these RNP granules has been linked to a number of human diseases, including neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (Li et al., J Cell Biol 201:361-372, 2013; Nonhoff et al., Mol Biol Cell 18:1385-1396, 2007). Understanding how the assembly of these granules is controlled could, therefore, suggest possible routes of therapy for patients afflicted with these conditions. Interestingly, several reports have identified a potential role for protein deubiquitination in the assembly of these RNP granules. In particular, recent work has found that a specific deubiquitinase enzyme, Ubp3, is required for efficient SG formation in S. cerevisiae (Nostramo et al., Mol Cell Biol 36:173-183, 2016). This same enzyme has been linked to SGs in other organisms, including humans and the fission yeast, Schizosaccharomyces pombe (Takahashi et al., Mol Cell Biol 33:815-829, 2013; Wang et al., RNA 18:694-703, 2012). At first glance, these observations suggest that a striking degree of conservation exists for a ubiquitin-based mechanism controlling SG assembly. However, the devil is truly in the details here, as the precise nature of the involvement of this deubiquitinating enzyme seems to vary in each organism. Here, we briefly review these differences and attempt to provide an overarching model for the role of ubiquitin in SG formation.}, }
@article {pmid26844759, year = {2017}, author = {Smith, DK and He, M and Zhang, CL and Zheng, JC}, title = {The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders.}, journal = {Progress in neurobiology}, volume = {157}, number = {}, pages = {212-229}, pmid = {26844759}, issn = {1873-5118}, support = {R01 NS097195/NS/NINDS NIH HHS/United States ; R01 NS070981/NS/NINDS NIH HHS/United States ; R01 NS088095/NS/NINDS NIH HHS/United States ; R01 NS061642/NS/NINDS NIH HHS/United States ; R01 NS041858/NS/NINDS NIH HHS/United States ; R56 NS041858/NS/NINDS NIH HHS/United States ; P30 GM103509/GM/NIGMS NIH HHS/United States ; }, mesh = {*Aging/physiology ; Animals ; *Cellular Reprogramming/drug effects/physiology ; Humans ; Induced Pluripotent Stem Cells/drug effects/physiology/*transplantation ; Neurodegenerative Diseases/physiopathology/*therapy ; }, abstract = {Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.}, }
@article {pmid26843957, year = {2016}, author = {Li, HF and Wu, ZY}, title = {Genotype-phenotype correlations of amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {5}, number = {}, pages = {3}, pmid = {26843957}, issn = {2047-9158}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron (UMN) and lower motor neuron (LMN). The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS. Most cases are diagnosed based on symptoms, physical signs, progression, EMG, and tests to exclude the overlapping conditions. Familial ALS represents about 5 ~ 10 % of ALS cases, whereas the vast majority of patients are sporadic. To date, more than 20 causative genes have been identified in hereditary ALS. Detecting the pathogenic mutations or risk variants for each ALS individual is challenging. However, ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features. Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations. In this review, we will delineate the clinical features of ALS, outline the major ALS-related genes, and summarize the possible genotype-phenotype correlations of ALS.}, }
@article {pmid26837042, year = {2016}, author = {Cipolat Mis, MS and Brajkovic, S and Frattini, E and Di Fonzo, A and Corti, S}, title = {Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets.}, journal = {Molecular and cellular neurosciences}, volume = {72}, number = {}, pages = {84-90}, doi = {10.1016/j.mcn.2016.01.012}, pmid = {26837042}, issn = {1095-9327}, mesh = {Animals ; *Autophagy ; Drug Discovery ; Humans ; *Molecular Targeted Therapy ; Motor Neuron Disease/drug therapy/*metabolism ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Autophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases.}, }
@article {pmid26823667, year = {2016}, author = {Patani, R}, title = {Generating Diverse Spinal Motor Neuron Subtypes from Human Pluripotent Stem Cells.}, journal = {Stem cells international}, volume = {2016}, number = {}, pages = {1036974}, pmid = {26823667}, issn = {1687-966X}, abstract = {Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevant in vitro disease models. I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability using in vitro human disease models.}, }
@article {pmid26822748, year = {2016}, author = {Ahmed, RM and Irish, M and Piguet, O and Halliday, GM and Ittner, LM and Farooqi, S and Hodges, JR and Kiernan, MC}, title = {Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism.}, journal = {The Lancet. Neurology}, volume = {15}, number = {3}, pages = {332-342}, doi = {10.1016/S1474-4422(15)00380-4}, pmid = {26822748}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Feeding Behavior/*physiology ; Frontotemporal Dementia/*metabolism/physiopathology ; Humans ; }, abstract = {Metabolic changes incorporating fluctuations in weight, insulin resistance, and cholesterol concentrations have been identified in several neurodegenerative disorders. Whether these changes result from the neurodegenerative process affecting brain regions necessary for metabolic regulation or whether they drive the degenerative process is unknown. Emerging evidence from epidemiological, clinical, pathological, and experimental studies emphasises a range of changes in eating behaviours and metabolism in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS, metabolic changes have been linked to disease progression and prognosis. Furthermore, changes in eating behaviour that affect metabolism have been incorporated into the diagnostic criteria for FTD, which has some clinical and pathological overlap with ALS. Whether the distinct and shared metabolic and eating changes represent a component of the proposed spectrum of the two diseases is an intriguing possibility. Moreover, future research should aim to unravel the complex connections between eating, metabolism, and neurodegeneration in ALS and FTD, and aim to understand the potential for targeting modifiable risk factors in disease development and progression.}, }
@article {pmid26822316, year = {2016}, author = {Blasco, H and Patin, F and Madji Hounoum, B and Gordon, PH and Vourc'h, P and Andres, CR and Corcia, P}, title = {Metabolomics in amyotrophic lateral sclerosis: how far can it take us?.}, journal = {European journal of neurology}, volume = {23}, number = {3}, pages = {447-454}, doi = {10.1111/ene.12956}, pmid = {26822316}, issn = {1468-1331}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; Metabolomics/*methods/standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. Alongside identification of aetiologies, development of biomarkers is a foremost research priority. Metabolomics is one promising approach that is being utilized in the search for diagnosis and prognosis markers. Our aim is to provide an overview of the principal research in metabolomics applied to ALS. References were identified using PubMed with the terms 'metabolomics' or 'metabolomic' and 'ALS' or 'amyotrophic lateral sclerosis' or 'MND' or 'motor neuron disorders'. To date, nine articles have reported metabolomics research in patients and a few additional studies examined disease physiology and drug effects in patients or models. Metabolomics contribute to a better understanding of ALS pathophysiology but, to date, no biomarker has been validated for diagnosis, principally due to the heterogeneity of the disease and the absence of applied standardized methodology for biomarker discovery. A consensus on best metabolomics methodology as well as systematic independent validation will be an important accomplishment on the path to identifying the long-awaited biomarkers for ALS and to improve clinical trial designs.}, }
@article {pmid26822113, year = {2016}, author = {Masuda, A and Takeda, J and Ohno, K}, title = {FUS-mediated regulation of alternative RNA processing in neurons: insights from global transcriptome analysis.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {7}, number = {3}, pages = {330-340}, doi = {10.1002/wrna.1338}, pmid = {26822113}, issn = {1757-7012}, mesh = {Animals ; *Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Mice ; Neurons/*physiology ; *Polyadenylation ; *RNA Splicing ; RNA, Messenger/*metabolism ; RNA-Binding Protein FUS/*metabolism ; }, abstract = {Fused in sarcoma (FUS) is an RNA-binding protein that is causally associated with oncogenesis and neurodegeneration. Recently, the role of FUS in neurodegeneration has been extensively studied, because mutations in FUS are associated with amyotrophic lateral sclerosis (ALS), and the FUS protein has been identified as a major component of intracellular inclusions in neurodegenerative disorders including ALS and frontotemporal lobar degeneration. FUS is a key molecule in transcriptional regulation and RNA processing including processes such as pre-messenger RNA (mRNA) splicing and polyadenylation. Interaction of FUS with various components of the transcription machinery, spliceosome, and the 3'-end processing machinery has been identified. Furthermore, recent advances in high-throughput transcriptomic profiling approaches have enabled us to determine the mechanisms of FUS-dependent RNA processing networks at a cellular level. These analyses have revealed that depletion of FUS in neuronal cells affects alternative splicing and alternative polyadenylation of thousands of mRNAs. Gene ontology analysis has suggested that FUS-modulated genes are implicated in neuronal functions and development. CLIP-seq of FUS has shown that FUS is frequently clustered around these alternative sites of nascent RNA. ChIP-seq of RNA polymerase II (RNAP II) has demonstrated that an interaction between FUS and nascent RNA downregulates local transcriptional activity of RNAP II, which is critically involved in RNA processing. Both alternative splicing and alternative polyadenylation are fundamental processes by which cells expand their transcriptomic diversity, and are particularly essential in the nervous system. Dependence of transcriptomic diversity on FUS makes the nervous system vulnerable to neurodegeneration, when FUS is functionally compromised. WIREs RNA 2016, 7:330-340. doi: 10.1002/wrna.1338 For further resources related to this article, please visit the WIREs website.}, }
@article {pmid26818266, year = {2016}, author = {Christensen, T}, title = {Human endogenous retroviruses in neurologic disease.}, journal = {APMIS : acta pathologica, microbiologica, et immunologica Scandinavica}, volume = {124}, number = {1-2}, pages = {116-126}, doi = {10.1111/apm.12486}, pmid = {26818266}, issn = {1600-0463}, mesh = {Anti-Retroviral Agents/therapeutic use ; Endogenous Retroviruses/*genetics/pathogenicity/physiology ; Epigenomics ; *Gene Expression Regulation, Viral ; HIV Infections/therapy ; Humans ; Multiple Sclerosis/etiology/*physiopathology/therapy/*virology ; Nervous System Diseases/physiopathology/therapy/*virology ; Schizophrenia/etiology/physiopathology/therapy/virology ; *Viral Envelope Proteins/genetics ; Virus Activation ; }, abstract = {Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential.}, }
@article {pmid26812803, year = {2016}, author = {Yuyama, K and Igarashi, Y}, title = {Physiological and pathological roles of exosomes in the nervous system.}, journal = {Biomolecular concepts}, volume = {7}, number = {1}, pages = {53-68}, doi = {10.1515/bmc-2015-0033}, pmid = {26812803}, issn = {1868-503X}, mesh = {Animals ; Cell Communication ; Exosomes/metabolism/*pathology ; Humans ; Neurodegenerative Diseases/metabolism/*pathology ; Neuroglia/metabolism/*pathology ; Neurons/metabolism/*pathology ; }, abstract = {Exosomes represent a subtype of extracellular nanovesicles that are generated from the luminal budding of limiting endosomal membranes and subsequent exocytosis. They encapsulate or associate with obsolete molecules to eliminate or to transfer their cargos in intercellular communication. The exosomes are also released and transported between neurons and glia in the nervous system, having a broad impact on nerve development, activation and regeneration. Accumulating evidence suggests that the exosomes are attributed to the pathogenesis of several neurodegenerative diseases such as prion disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, as well as aging, in which the exosomes lack the capacity for cellular self-repair and spread their enclosed pathological agents among neurons. In this article, we review the current proposed functions of exosomes in physiological and pathological processes in the nervous system.}, }
@article {pmid26812787, year = {2016}, author = {Esteras, N and Dinkova-Kostova, AT and Abramov, AY}, title = {Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function.}, journal = {Biological chemistry}, volume = {397}, number = {5}, pages = {383-400}, doi = {10.1515/hsz-2015-0295}, pmid = {26812787}, issn = {1437-4315}, support = {18644/CRUK_/Cancer Research UK/United Kingdom ; BB/L01923X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; C20953/A18644/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Animals ; Brain/metabolism ; *Energy Metabolism ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors ; Humans ; Lipid Metabolism ; Membrane Transport Proteins/metabolism ; Mitochondria/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.}, }
@article {pmid26811420, year = {2016}, author = {Williams, ST and Sykes, MC and Boon Lim, P and Salciccioli, JD}, title = {The 2015 advanced life support guidelines: a summary and evidence for the updates.}, journal = {Emergency medicine journal : EMJ}, volume = {33}, number = {5}, pages = {357-360}, doi = {10.1136/emermed-2015-205571}, pmid = {26811420}, issn = {1472-0213}, mesh = {Cardiopulmonary Resuscitation/*methods/standards ; Emergency Medical Services/standards ; Heart Arrest/*therapy ; Humans ; Life Support Care/*methods/standards ; *Practice Guidelines as Topic ; }, abstract = {The International Liaison Committee on Resuscitation recently released updated 2015 recommendations for resuscitation. The guidelines form the basis for all levels of resuscitation training, now from first aid to advanced life support (ALS), and for trainees of varying medical skills, from schoolchildren to medical students and consultants. We highlight major updates relating to intra-arrest and postarrest care, and the evidence for their recommendation. We also summarise areas of uncertainty in the evidence for ALS, and highlight current discussions that will likely inform the next round of recommendations.}, }
@article {pmid26810719, year = {2016}, author = {Wilke, C and Pomper, JK and Biskup, S and Puskás, C and Berg, D and Synofzik, M}, title = {Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature.}, journal = {Journal of neurology}, volume = {263}, number = {3}, pages = {558-574}, pmid = {26810719}, issn = {1432-1459}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Brain/diagnostic imaging ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Electrooculography ; Family Health ; Female ; Fluorodeoxyglucose F18 ; Humans ; Male ; Middle Aged ; Parkinsonian Disorders/diagnostic imaging/*genetics ; Positron-Emission Tomography ; Proteins/*genetics ; PubMed/statistics &amp; numerical data ; Young Adult ; }, abstract = {While C9orf72 repeat expansions usually present with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS), an increasing number of reports suggests that the primary phenotype of C9orf72 patients may also include movement disorders. We here provide the first systematic clinical characterisation of C9orf72-associated parkinsonism. We report a C9orf72 expansion carrier presenting with a clinical syndrome of progressive supranuclear palsy (PSP), pronounced mesencephalic atrophy on MRI and PSP-characteristic electrooculography findings. Moreover, we systematically review all previous reports on C9orf72 patients with parkinsonian features. Review of 28 reports revealed 45 C9orf72-positive patients with hypokinesia, rigidity and/or resting tremor. C9orf72-associated parkinsonism predominantly consisted in a hypokinetic-rigid syndrome without resting tremor (61%), with both asymmetric (59%) and symmetric (41%) distributions. Additional features included upper motor neuron signs (60%), lower motor neuron signs (36%), cognitive dysfunction (85%), behaviour and/or personality change (55%) and psychiatric symptoms (29%). Vertical supranuclear gaze palsy was reported in three further cases and cerebellar dysfunction in four cases. Family history frequently yielded evidence of ALS (31%) and FTD (21%). Atypical parkinsonism is a recurrent phenotypic manifestation of C9orf72 expansions. It occurs as part of a broad spectrum of C9orf72-related multi-system neurodegeneration, which can include basal ganglia, mesencephalic and cerebellar dysfunction. C9orf72 genotyping should be considered in those patients with atypical parkinsonism who present with a family history of ALS or FTD, upper or lower motor neuron signs and/or cognitive dysfunction with pronounced frontotemporal impairment.}, }
@article {pmid26808361, year = {2016}, author = {, }, title = {ALS Untangled No.33 Endotherapia.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {5-6}, pages = {461-465}, doi = {10.3109/21678421.2015.1128668}, pmid = {26808361}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/immunology/microbiology ; Animals ; Antigen-Antibody Complex/blood ; Antioxidants/administration &amp; dosage/*therapeutic use ; Autoantibodies/blood ; Bacterial Translocation ; Clinical Trials as Topic ; *Complementary Therapies ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Enzyme-Linked Immunosorbent Assay ; Fatty Acids/administration &amp; dosage/*therapeutic use ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Immunoblotting ; Polylysine/administration &amp; dosage ; Rats ; }, }
@article {pmid26803559, year = {2016}, author = {Åkesson, E and Sundström, E}, title = {Human neural progenitor cells in central nervous system lesions.}, journal = {Best practice &amp; research. Clinical obstetrics &amp; gynaecology}, volume = {31}, number = {}, pages = {69-81}, doi = {10.1016/j.bpobgyn.2015.11.020}, pmid = {26803559}, issn = {1532-1932}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Central Nervous System Diseases/*therapy ; Humans ; Neural Stem Cells/*transplantation ; Parkinson Disease/therapy ; Spinal Cord Injuries/therapy ; Stem Cell Transplantation ; Stroke/therapy ; Time-to-Treatment ; }, abstract = {Various immature cells can be isolated from human embryonic and fetal central nervous system (CNS) residual tissue and potentially be used in cell therapy for a number of neurological diseases and CNS insults. Transplantation of neural stem and progenitor cells is essential for replacing lost cells, particularly in the CNS with very limited endogenous regenerative capacity. However, while dopamine released from transplanted cells can substitute the lost dopamine neurons in the experimental models of Parkinson's disease, stem and progenitor cells primarily have a neuroprotective effect, probably through the release of trophic factors. Understanding the therapeutic effects of transplanted cells is crucial to determine the design of clinical trials. During the last few years, a number of clinical trials for CNS diseases and insults such as amyotrophic lateral sclerosis (ALS), stroke, and spinal cord trauma using neural progenitor cells have been initiated. Data from these early studies will provide vital information on the safety of transplanting these cells, which still is a major concern. That the beneficial results observed in experimental models also can be repeated in the clinical setting is highly hoped for.}, }
@article {pmid26795196, year = {2016}, author = {Miyazaki, I and Asanuma, M}, title = {Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson's Disease.}, journal = {Current medicinal chemistry}, volume = {23}, number = {7}, pages = {686-700}, pmid = {26795196}, issn = {1875-533X}, mesh = {Animals ; Astrocytes/*drug effects/*metabolism/pathology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Humans ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Parkinson Disease/*drug therapy/metabolism/pathology ; Receptor, Serotonin, 5-HT1A/*metabolism ; }, abstract = {Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson's disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease- modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.}, }
@article {pmid26793099, year = {2015}, author = {Zhang, CW and Hang, L and Yao, TP and Lim, KL}, title = {Parkin Regulation and Neurodegenerative Disorders.}, journal = {Frontiers in aging neuroscience}, volume = {7}, number = {}, pages = {248}, pmid = {26793099}, issn = {1663-4365}, support = {R01 NS054022/NS/NINDS NIH HHS/United States ; }, abstract = {Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognition that Parkin dysfunction represents not only a predominant cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of Parkinson's disease (PD). Accordingly, keen research on Parkin over the past decade has led to an explosion of knowledge regarding its physiological roles and its relevance to PD. However, our understanding of Parkin is far from being complete. Indeed, surprises emerge from time to time that compel us to constantly update the paradigm of Parkin function. For example, we now know that Parkin's function is not confined to mere housekeeping protein quality control (QC) roles but also includes mitochondrial homeostasis and stress-related signaling. Furthermore, emerging evidence also suggest a role for Parkin in several other major neurodegenerative diseases including Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Yet, it remains truly amazing to note that a single enzyme could serve such multitude of functions and cellular roles. Clearly, its activity has to be tightly regulated. In this review, we shall discuss this and how dysregulated Parkin function may precipitate neuronal demise in various neurodegenerative disorders.}, }
@article {pmid26789431, year = {2016}, author = {Göhl, O and Walker, DJ and Walterspacher, S and Langer, D and Spengler, CM and Wanke, T and Petrovic, M and Zwick, RH and Stieglitz, S and Glöckl, R and Dellweg, D and Kabitz, HJ}, title = {[Respiratory Muscle Training: State of the Art].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {70}, number = {1}, pages = {37-48}, doi = {10.1055/s-0041-109312}, pmid = {26789431}, issn = {1438-8790}, mesh = {Breathing Exercises/*methods/trends ; Dyspnea/diagnosis/*rehabilitation ; Evidence-Based Medicine ; Humans ; Muscle Weakness/diagnosis/*rehabilitation ; Physical Conditioning, Human/*methods ; Respiratory Muscles ; Treatment Outcome ; }, abstract = {Specific respiratory muscle training (IMT) improves the function of the inspiratory muscles. According to literature and clinical experience, there are 3 established methods: 1.) resistive load 2.) threshold load and 3.) normocapnic hyperpnea. Each training method and the associated devices have specific characteristics. Setting up an IMT should start with specific diagnostics of respiratory muscle function and be followed by detailed individual introduction to training. The aim of this review is to take a closer look at the different training methods for the most relevant indications and to discuss these results in the context of current literature. The group of neuromuscular diseases includes muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, paralysis of the phrenic nerve, and injuries to the spinal cord. Furthermore, interstitial lung diseases, sarcoidosis, left ventricular heart failure, pulmonary arterial hypertension (PAH), kyphoscoliosis and obesity are also discussed in this context. COPD, asthma, cystic fibrosis (CF) and non-CF-bronchiectasis are among the group of obstructive lung diseases. Last but not least, we summarize current knowledge on weaning from respirator in the context of physical activity.}, }
@article {pmid26786249, year = {2016}, author = {Lu, H and Le, WD and Xie, YY and Wang, XP}, title = {Current Therapy of Drugs in Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {14}, number = {4}, pages = {314-321}, pmid = {26786249}, issn = {1875-6190}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Cholestenones/therapeutic use ; Dasatinib/therapeutic use ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mice ; Mitochondria/drug effects ; Nerve Growth Factors/therapeutic use ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase-1/genetics ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / antiinflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients.}, }
@article {pmid26780671, year = {2016}, author = {Sabatelli, M and Marangi, G and Conte, A and Tasca, G and Zollino, M and Lattante, S}, title = {New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {266-275}, pmid = {26780671}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/physiopathology/therapy ; Animals ; Humans ; Phenotype ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons. Clinical heterogeneity is a well-recognized feature of the disease as age of onset, site of onset and the duration of the disease can vary greatly among patients. A number of genes have been identified and associated to familial and sporadic forms of ALS but the majority of cases remains still unexplained. Recent breakthrough discoveries have demonstrated that clinical manifestations associated with ALS-related genes are not circumscribed to motor neurons involvement. In this view, ALS appears to be linked to different conditions over a continuum or spectrum in which overlapping phenotypes may be identified. In this review, we aim to examine the increasing number of spectra, including ALS/Frontotemporal Dementia and ALS/Myopathies spectra. Considering all these neurodegenerative disorders as different phenotypes of the same spectrum can help to identify common pathological pathways and consequently new therapeutic targets in these incurable diseases.}, }
@article {pmid26780562, year = {2016}, author = {Myszczynska, M and Ferraiuolo, L}, title = {New In Vitro Models to Study Amyotrophic Lateral Sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {258-265}, pmid = {26780562}, issn = {1750-3639}, support = {K-1506/PUK_/Parkinson's UK/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*physiopathology ; Animals ; Cellular Reprogramming Techniques/methods ; Drug Evaluation, Preclinical/methods ; Embryonic Stem Cells/drug effects/*physiology ; Humans ; Induced Pluripotent Stem Cells/drug effects/*physiology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex multifactorial disorder, characterized by motor neuron loss with involvement of several other cell types, including astrocytes, oligodendrocytes and microglia. Studies in vivo and in in vitro models have highlighted that the contribution of non-neuronal cells to the disease is a primary event and ALS pathogenesis is driven by both cell-autonomous and non-cell autonomous mechanisms. The advancements in genetics and in vitro modeling of the past 10 years have dramatically changed the way we investigate the pathogenic mechanisms involved in ALS. The identification of mutations in transactive response DNA-binding protein gene (TARDBP), fused in sarcoma (FUS) and, more recently, a GGGGCC-hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) and their link with familial ALS have provided new avenues of investigation and hypotheses on the pathophysiology of this devastating disease. In the same years, from 2007 to present, in vitro technologies to model neurological disorders have also undergone impressive developments. The advent of induced pluripotent stem cells (iPSCs) gave the field of ALS the opportunity to finally model in vitro not only familial, but also the larger part of ALS cases affected by sporadic disease. Since 2008, when the first human iPS-derived motor neurons from patients were cultured in a petri dish, several different techniques have been developed to produce iPSC lines through genetic reprogramming and multiple direct conversion methods have been optimised. In this review, we will give an overview of how human in vitro models have been used so far, what discoveries they have led to since 2007, and how the recent advances in technology combined with the genetic discoveries, have tremendously widened the horizon of ALS research.}, }
@article {pmid26780491, year = {2016}, author = {Puentes, F and Malaspina, A and van Noort, JM and Amor, S}, title = {Non-neuronal Cells in ALS: Role of Glial, Immune cells and Blood-CNS Barriers.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {248-257}, pmid = {26780491}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Blood-Brain Barrier/drug effects/*metabolism ; Humans ; Immune System/drug effects/*physiopathology ; Lymphocytes/drug effects/*physiology ; Neuroglia/drug effects/*physiology ; }, abstract = {Neurological dysfunction and motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is strongly associated with neuroinflammation reflected by activated microglia and astrocytes in the CNS. In ALS endogenous triggers in the CNS such as aggregated protein and misfolded proteins activate a pathogenic response by innate immune cells. However, there is also strong evidence for a neuroprotective immune response in ALS. Emerging evidence also reveals changes in the peripheral adaptive immune responses as well as alterations in the blood brain barrier that may aid traffic of lymphocytes and antibodies into the CNS. Understanding the triggers of neuroinflammation is key to controlling neuronal loss. Here, we review the current knowledge regarding the roles of non-neuronal cells as well as the innate and adaptive immune responses in ALS. Existing ALS animal models, in particular genetic rodent models, are very useful to study the underlying pathogenic mechanisms of motor neuron degeneration. We also discuss the approaches used to target the pathogenic immune responses and boost the neuroprotective immune pathways as novel immunotherapies for ALS.}, }
@article {pmid26780365, year = {2016}, author = {Nardo, G and Trolese, MC and Tortarolo, M and Vallarola, A and Freschi, M and Pasetto, L and Bonetto, V and Bendotti, C}, title = {New Insights on the Mechanisms of Disease Course Variability in ALS from Mutant SOD1 Mouse Models.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {237-247}, pmid = {26780365}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology/*physiopathology ; Animals ; *Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disease in terms of progression rate and survival. This is probably one of the reasons for the failure of many clinical trials and the lack of effective therapies. Similar variability is also seen in SOD1(G93A) mouse models based on their genetic background. For example, when the SOD1(G93A) transgene is expressed in C57BL6 background the phenotype is mild with slower disease progression than in the 129Sv mice expressing the same amount of transgene but showing faster progression and shorter lifespan. This review summarizes and discusses data obtained from the analysis of these two mouse models under different aspects such as the motor phenotype, neuropathological alterations in the central nervous system (CNS) and peripheral nervous system (PNS) and the motor neuron autonomous and non-cell autonomous mechanisms with the aim of finding elements to explain the different rates of disease progression. We also discuss the identification of promising prognostic biomarkers by comparative analysis of the two ALS mouse models. This analysis might possibly suggest new strategies for effective therapeutic intervention in ALS to slow significantly or even block the course of the disease.}, }
@article {pmid26780251, year = {2016}, author = {Loeffler, JP and Picchiarelli, G and Dupuis, L and Gonzalez De Aguilar, JL}, title = {The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {227-236}, pmid = {26780251}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology/physiopathology ; Animals ; Humans ; Muscle, Skeletal/*drug effects/*pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.}, }
@article {pmid26779612, year = {2016}, author = {Rossi, S and Cozzolino, M and Carrì, MT}, title = {Old versus New Mechanisms in the Pathogenesis of ALS.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {276-286}, pmid = {26779612}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology/therapy ; Animals ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is recognized as a very complex disease. As we have learned in the past 20 years from studies in patients and in models based on the expression of mutant SOD1, ALS is not a purely motor neuron disease as previously thought. While undoubtedly motor neurons are lost in patients, a number of alterations in those cell-types that interact functionally with motor neurons (astrocytes, microglia, muscle fibers, oligodendrocytes) take place even long before onset of symptoms. At the same time, disturbance of several, only partly inter-related physiological functions play some role in the onset and progression of the disease. Traditionally, mitochondrial damage and oxidative stress, excitotoxicity, neuroinflammation, altered axonal transport, ER stress, protein aggregation and defective removal of toxic proteins have been considered as key factors in the pathogenesis of ALS, with the relatively recent addition of disturbances in RNA metabolism. This complexity makes the search for an effective treatment extremely difficult and prompts further studies to reveal other possible, previously unappreciated aspects of the pathogenesis of ALS. In this review, we focus on previous knowledge on ALS mechanisms as well as new facets emerging from studies on genetic ALS patients and models that may both provide precious information for a novel therapeutic approach.}, }
@article {pmid26779479, year = {2015}, author = {Perri, ER and Thomas, CJ and Parakh, S and Spencer, DM and Atkin, JD}, title = {The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration.}, journal = {Frontiers in cell and developmental biology}, volume = {3}, number = {}, pages = {80}, pmid = {26779479}, issn = {2296-634X}, abstract = {The maintenance and regulation of proteostasis is a critical function for post-mitotic neurons and its dysregulation is increasingly implicated in neurodegenerative diseases. Despite having different clinical manifestations, these disorders share similar pathology; an accumulation of misfolded proteins in neurons and subsequent disruption to cellular proteostasis. The endoplasmic reticulum (ER) is an important component of proteostasis, and when the accumulation of misfolded proteins occurs within the ER, this disturbs ER homeostasis, giving rise to ER stress. This triggers the unfolded protein response (UPR), distinct signaling pathways that whilst initially protective, are pro-apoptotic if ER stress is prolonged. ER stress is increasingly implicated in neurodegenerative diseases, and emerging evidence highlights the complexity of the UPR in these disorders, with both protective and detrimental components being described. Protein Disulfide Isomerase (PDI) is an ER chaperone induced during ER stress that is responsible for the formation of disulfide bonds in proteins. Whilst initially considered to be protective, recent studies have revealed unconventional roles for PDI in neurodegenerative diseases, distinct from its normal function in the UPR and the ER, although these mechanisms remain poorly defined. However, specific aspects of PDI function may offer the potential to be exploited therapeutically in the future. This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.}, }
@article {pmid26778173, year = {2016}, author = {Eitan, C and Hornstein, E}, title = {Vulnerability of microRNA biogenesis in FTD-ALS.}, journal = {Brain research}, volume = {1647}, number = {}, pages = {105-111}, doi = {10.1016/j.brainres.2015.12.063}, pmid = {26778173}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; DEAD-box RNA Helicases/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/*metabolism ; Humans ; MicroRNAs/*biosynthesis/genetics ; Nuclear Pore/metabolism ; RNA Processing, Post-Transcriptional ; RNA-Binding Protein FUS/metabolism ; Ribonuclease III/metabolism ; }, abstract = {The genetics of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) turn our attention to RNA metabolism, primarily because many of the identified diseases-associated genes encode for RNA-binding proteins. microRNAs (miRNAs) are endogenous noncoding RNAs that play critical roles in maintaining brain integrity. The current review sheds light on miRNA dysregulation in neurodegenerative diseases, focusing on FTD-ALS. We propose that miRNAs are susceptible to fail when protein factors that are critical for miRNA biogenesis malfunction. Accordingly, potential insufficiencies of the 'microprocessor' complex, the nucleo-cytoplasmic export of miRNA precursors or their processing by Dicer were recently reported. Furthermore, specific miRNAs are involved in the regulation of pathways that are essential for neuronal survival or function. Any change in the expression of these specific miRNAs or in their ability to recognize their target sequences will have negative consequences. Taken together, recent reports strengthens the hypothesis that dysregulation of miRNAs might play an important role in the pathogenesis of neurodegenerative diseases, and highlights the miRNA biogenesis machinery as an interesting target for therapeutic interventions for ALS as well as FTD. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.}, }
@article {pmid26774696, year = {2016}, author = {Costa, J and de Carvalho, M}, title = {Emerging molecular biomarker targets for amyotrophic lateral sclerosis.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {455}, number = {}, pages = {7-14}, doi = {10.1016/j.cca.2016.01.011}, pmid = {26774696}, issn = {1873-3492}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/*metabolism ; Biomarkers/*metabolism ; Child ; Humans ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects upper (UMN) and lower motor (LMN) neurons. It is associated with a short survival and there is no effective treatment, in spite of a large number of clinical trials. Strong efforts have been made to identify novel disease biomarkers to support diagnosis, provide information on prognosis, to measure disease progression in trials and increase our knowledge on disease pathogenesis. Electromyography by testing the function of the LMN can be used as a biomarker of its dysfunction. A number of electrophysiological and neuroimaging methods have been explored to identify a reliable marker of UMN degeneration. Recently, strong evidence from independent groups, large cohorts of patients and multicenter studies indicate that neurofilaments are very promising diagnostic biomarkers, in particular cerebrospinal fluid and blood levels of phosphoneurofilament heavy chain and neurofilament light chain. Furthermore, their increased levels are associated with poor prognosis. Additional studies have been performed aiming to identify other biomarkers, which alone or in combination with neurofilaments could increase the sensitivity and the specificity of the assays. Emerging molecular marker targets are being discovered, but more studies with standardized methods are required in larger cohorts of ALS patients.}, }
@article {pmid26774442, year = {2016}, author = {Schmidt, MHM and Pearson, CE}, title = {Disease-associated repeat instability and mismatch repair.}, journal = {DNA repair}, volume = {38}, number = {}, pages = {117-126}, doi = {10.1016/j.dnarep.2015.11.008}, pmid = {26774442}, issn = {1568-7856}, mesh = {Animals ; Base Sequence ; DNA Mismatch Repair/*genetics ; Disease/*genetics ; *Genomic Instability ; Humans ; Molecular Sequence Data ; MutS Homolog 2 Protein/chemistry/metabolism ; Polymorphism, Genetic ; Trinucleotide Repeat Expansion/*genetics ; }, abstract = {Expanded tandem repeat sequences in DNA are associated with at least 40 human genetic neurological, neurodegenerative, and neuromuscular diseases. Repeat expansion can occur during parent-to-offspring transmission, and arise at variable rates in specific tissues throughout the life of an affected individual. Since the ongoing somatic repeat expansions can affect disease age-of-onset, severity, and progression, targeting somatic expansion holds potential as a therapeutic target. Thus, understanding the factors that regulate this mutation is crucial. DNA repair, in particular mismatch repair (MMR), is the major driving force of disease-associated repeat expansions. In contrast to its anti-mutagenic roles, mammalian MMR curiously drives the expansion mutations of disease-associated (CAG)·(CTG) repeats. Recent advances have broadened our knowledge of both the MMR proteins involved in disease repeat expansions, including: MSH2, MSH3, MSH6, MLH1, PMS2, and MLH3, as well as the types of repeats affected by MMR, now including: (CAG)·(CTG), (CGG)·(CCG), and (GAA)·(TTC) repeats. Mutagenic slipped-DNA structures have been detected in patient tissues, and the size of the slip-out and their junction conformation can determine the involvement of MMR. Furthermore, the formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential.}, }
@article {pmid26770824, year = {2015}, author = {Flanagan, MF}, title = {The Role of the Craniocervical Junction in Craniospinal Hydrodynamics and Neurodegenerative Conditions.}, journal = {Neurology research international}, volume = {2015}, number = {}, pages = {794829}, pmid = {26770824}, issn = {2090-1852}, abstract = {The craniocervical junction (CCJ) is a potential choke point for craniospinal hydrodynamics and may play a causative or contributory role in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, MS, and ALS, as well as many other neurological conditions including hydrocephalus, idiopathic intracranial hypertension, migraines, seizures, silent-strokes, affective disorders, schizophrenia, and psychosis. The purpose of this paper is to provide an overview of the critical role of the CCJ in craniospinal hydrodynamics and to stimulate further research that may lead to new approaches for the prevention and treatment of the above neurodegenerative and neurological conditions.}, }
@article {pmid26753798, year = {2016}, author = {Pan, LS and Deng, XB and Wang, Z and Leng, HL and Zhu, XP and Ding, D}, title = {Lack of association between the Angiogenin (ANG) rs11701 polymorphism and amyotrophic lateral sclerosis risk: a meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {37}, number = {5}, pages = {655-662}, pmid = {26753798}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; *Genetic Association Studies/statistics &amp; numerical data ; Humans ; Polymorphism, Single Nucleotide/*genetics ; Ribonuclease, Pancreatic/*genetics ; }, abstract = {To perform a meta-analysis to help resolve the controversy of whether the Angiogenin (ANG) rs11701 polymorphism is associated with amyotrophic lateral sclerosis (ALS) risk. A literature search of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and SinoMed was conducted for eligible studies published up to Jun 5, 2015. The strength of the association between the polymorphism and ALS susceptibility was estimated by odds ratio (OR) and associated 95 % confidence interval (CI). The pooled ORs were assessed for the dominant model (TG + GG vs. TT), recessive model (GG vs. TG + TT), heterozygote model (TG vs. TT), homozygote model (GG vs. TT) and allele model (G vs. T). Ten eligible articles were identified, which reported 14 case-control studies and a total of 5807 cases and 3861 controls. Analysis of pooled ORs and 95 % CIs suggested lack of association between the ANG rs11701 polymorphism and risk for ALS, Familial ALS or Sporadic ALS (all p value for z test >0.05). A stratified analysis according to Caucasian or Han Chinese origin further showed that the rs11701 polymorphism was not associated with the disease risk in Caucasians or Han Chinese. There is no difference in the polymorphism frequencies between patients with FALS or SALS. The ANG rs11701 polymorphism was not associated with risk for ALS, FALS or SALS. There is no difference between the polymorphism frequencies in patients with FALS or SALS. Further well-designed studies with larger populations are required to validate these results.}, }
@article {pmid26751860, year = {2015}, author = {Liščić, RM}, title = {Molecular basis of ALS and FTD: implications for translational studies.}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {66}, number = {4}, pages = {285-290}, doi = {10.1515/aiht-2015-66-2679}, pmid = {26751860}, issn = {1848-6312}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; DNA-Binding Proteins/*genetics ; Frontotemporal Dementia/*genetics ; Humans ; Hydroxylamines/*therapeutic use ; Mutation/*genetics ; Riluzole/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options.}, }
@article {pmid26748651, year = {2016}, author = {Bender, A and Klopstock, T}, title = {Creatine for neuroprotection in neurodegenerative disease: end of story?.}, journal = {Amino acids}, volume = {48}, number = {8}, pages = {1929-1940}, doi = {10.1007/s00726-015-2165-0}, pmid = {26748651}, issn = {1438-2199}, mesh = {Animals ; Creatine/*therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {Creatine (Cr) is a natural compound that plays an important role in cellular energy homeostasis. In addition, it ameliorates oxidative stress, glutamatergic excitotoxicity, and apoptosis in vitro as well as in vivo. Since these pathomechanisms are implicated to play a role in several neurodegenerative diseases, Cr supplementation as a neuroprotective strategy has received a lot of attention with several positive animal studies in models of Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This has led to a number of randomized clinical trials (RCT) with oral Cr supplementation, with durations up to 5 years. In this paper, we review the evidence and consequences stemming from these trials. In the case of PD, the initial phase II RCT was promising and led to a large and well-designed phase III trial, which, however, turned out to be negative for all outcome measures. None of the RCTs that have examined effects of Cr in ALS patients showed any clinical benefit. In HD, Cr in high doses (up to 30 g/day) was shown to slow down brain atrophy in premanifest Huntingtin mutation carriers. In spite of this, proof is still lacking that Cr can also have beneficial clinical effects in this group of patients, who will go on to develop HD symptoms. Taken together, the use of Cr supplementation has so far proved disappointing in clinical studies with a number of symptomatic neurodegenerative diseases.}, }
@article {pmid26744348, year = {2016}, author = {Krols, M and van Isterdael, G and Asselbergh, B and Kremer, A and Lippens, S and Timmerman, V and Janssens, S}, title = {Mitochondria-associated membranes as hubs for neurodegeneration.}, journal = {Acta neuropathologica}, volume = {131}, number = {4}, pages = {505-523}, pmid = {26744348}, issn = {1432-0533}, mesh = {Animals ; Charcot-Marie-Tooth Disease/metabolism/pathology ; Endoplasmic Reticulum/*metabolism ; Humans ; Mitochondrial Membranes/*metabolism ; Nerve Degeneration/metabolism/*pathology ; Neurons/*ultrastructure ; }, abstract = {There is a growing appreciation that membrane-bound organelles in eukaryotic cells communicate directly with one another through direct membrane contact sites. Mitochondria-associated membranes are specialized subdomains of the endoplasmic reticulum that function as membrane contact sites between the endoplasmic reticulum and mitochondria. These sites have emerged as major players in lipid metabolism and calcium signaling. More recently also autophagy and mitochondrial dynamics have been found to be regulated at ER-mitochondria contact sites. Neurons critically depend on mitochondria-associated membranes as a means to exchange metabolites and signaling molecules between these organelles. This is underscored by the fact that genes affecting mitochondrial and endoplasmic reticulum homeostasis are clearly overrepresented in several hereditary neurodegenerative disorders. Conversely, the processes affected by the contact sites between the endoplasmic reticulum and mitochondria are widely implicated in neurodegeneration. This review will focus on the most recent data addressing the structural composition and function of the mitochondria-associated membranes. In addition, the 3D morphology of the contact sites as observed using volume electron microscopy is discussed. Finally, it will highlight the role of several key proteins associated with these contact sites that are involved not only in dementias, amyotrophic lateral sclerosis and Parkinson's disease, but also in axonopathies such as hereditary spastic paraplegia and Charcot-Marie-Tooth disease.}, }
@article {pmid26733805, year = {2015}, author = {Brites, D and Fernandes, A}, title = {Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {476}, pmid = {26733805}, issn = {1662-5102}, abstract = {Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines. Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis. Rapid advances in the understanding of microglial and astrocytic neurobiology were obtained in the past 15-20 years. Indeed, recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions, besides their involvement in immune-response generating cytokines. The communication between microglia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), comprising ectosomes and exosomes with a size ranging from 0.1-1 μm, are key players in intercellular signaling. These EVs may carry specific proteins, mRNAs and microRNAs (miRNAs). Transfer of exosomes to neurons was shown to be mediated by oligodendrocytes, microglia and astrocytes that may either be supportive to neurons, or instead disseminate the disease. Interestingly, several recent reports have identified changes in miRNAs in depressed patients, which target not only crucial pathways associated with synaptic plasticity, learning and memory but also the production of neurotrophic factors and immune cell modulation. In this article, we discuss the role of neuroinflammation in the emergence of depression, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior. We will overview the involvement of miRNAs, exosomes, ectosomes and microglia in regulating critical pathways associated with depression and how they may contribute to other brain disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), which share several neuroinflammatory-associated processes. Specific reference will be made to EVs as potential biomarkers and disease monitoring approaches, focusing on their potentialities as drug delivery vehicles, and on putative therapeutic strategies using autologous exosome-based delivery systems to treat neurodegenerative and psychiatric disorders.}, }
@article {pmid26733784, year = {2015}, author = {Lewerenz, J and Maher, P}, title = {Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence?.}, journal = {Frontiers in neuroscience}, volume = {9}, number = {}, pages = {469}, pmid = {26733784}, issn = {1662-4548}, abstract = {Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.}, }
@article {pmid26733573, year = {2016}, author = {Zhang, J and Li, RK and Chen, KH and Ge, L and Tian, JH}, title = {Antimicrobial lock solutions for the prevention of catheter-related infection in patients undergoing haemodialysis: study protocol for network meta-analysis of randomised controlled trials.}, journal = {BMJ open}, volume = {6}, number = {1}, pages = {e010264}, pmid = {26733573}, issn = {2044-6055}, mesh = {Adolescent ; Adult ; Aged ; Anti-Infective Agents/*therapeutic use ; Catheter-Related Infections/*prevention &amp; control ; Catheterization, Central Venous/adverse effects ; Clinical Protocols ; Female ; Humans ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; *Renal Dialysis ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: Catheter-related infection (CRI) is a difficult clinical problem in renal medicine, with blood stream infections occurring in up to 40% of patients with haemodialysis (HD) catheters, conferring significant rates of morbidity and mortality. Several approaches have been assessed as a means to prevent CRI. Currently, an intervention that is the source of much discussion is the use of antimicrobial lock solutions (ALS). A number of past conventional meta-analyses have compared different ALS with heparin. However, there is no consensus recommendation regarding which type of ALS is best. The purpose of our study is to carry out a network meta-analysis comparing the efficacy of different ALS for prevention of CRI in patients with HD and ranking these ALS for practical consideration.<br><br>METHODS AND ANALYSIS: We will search six electronic databases, earlier relevant meta-analyses and reference lists of included studies for randomised controlled trials (RCTs) that compared ALS for preventing episodes of CRI in patients with HD either head-to-head or against control interventions using non-ALS. Study selection and data collection will be performed by two reviewers independently. The Cochrane Risk of Bias Tool will be used to assess the quality of included studies. The primary outcome of efficacy will be catheter-related bloodstream infection (CRBSI). We will perform a Bayesian network meta-analysis to compare the relative efficacy of different ALS by WinBUGS (V.1.4.3) and STATA (V.13.0). The quality of evidence will be assessed by GRADE.<br><br>ETHICS AND DISSEMINATION: Ethical approval is not required given that this study includes no confidential personal data and no data on interventions on patients. The results of this study will be submitted to a peer-review journal for publication.<br><br>TRIAL REGISTRATION NUMBER: CRD42015027010.}, }
@article {pmid26731747, year = {2016}, author = {Belbasis, L and Bellou, V and Evangelou, E}, title = {Environmental Risk Factors and Amyotrophic Lateral Sclerosis: An Umbrella Review and Critical Assessment of Current Evidence from Systematic Reviews and Meta-Analyses of Observational Studies.}, journal = {Neuroepidemiology}, volume = {46}, number = {2}, pages = {96-105}, doi = {10.1159/000443146}, pmid = {26731747}, issn = {1423-0208}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; *Environmental Exposure ; Female ; Humans ; Male ; Meta-Analysis as Topic ; Observational Studies as Topic ; Risk Factors ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both environmental and genetic factors. Our study aimed at summarising the environmental risk factors for ALS, assessing the evidence for diverse biases, and pinpointing risk factors with high epidemiological credibility.<br><br>METHODS: We searched PubMed from inception to August 20, 2015, to identify systematic reviews and meta-analyses of observational studies examining associations between environmental factors and ALS. For each meta-analysis, we estimated the summary effect size by the use of random-effects and fixed-effects models, the 95% CI, the 95% prediction interval (PI), and the between-study heterogeneity. We assessed the evidence of small-study effects and excess significance bias.<br><br>RESULTS: Sixteen unique meta-analyses of different risk factors and ALS were considered. Of them, 5 were statistically significant at p < 0.001 under the random-effects model. Only one factor presented robust evidence for a convincing association. This association pertained to chronic occupational exposure to lead (random-effects OR 1.81, 95% CI 1.39-2.35).<br><br>CONCLUSIONS: A small number of published meta-analyses on environmental factors and risk of ALS was identified, a phenomenon that could be attributed to the challenges in studying a rare neurological disease. More observational studies with adequate sample size and study design are needed to clarify the environmental component of ALS pathogenesis.}, }
@article {pmid26727307, year = {2016}, author = {Couratier, P and Corcia, P and Lautrette, G and Nicol, M and Preux, PM and Marin, B}, title = {Epidemiology of amyotrophic lateral sclerosis: A review of literature.}, journal = {Revue neurologique}, volume = {172}, number = {1}, pages = {37-45}, doi = {10.1016/j.neurol.2015.11.002}, pmid = {26727307}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Humans ; Incidence ; Prevalence ; Prognosis ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death occurs from respiratory failure. The incidence of ALS in European populations is two to three people per year per 100,000 of the general population. In Europe, crude prevalences range from 1.1/100,000 population in Yugoslavia to 8.2/100,000 in the Faroe Islands. Major advances have been made in our understanding of the genetic causes of ALS, whereas the contribution of environmental factors has been more difficult to assess and large-scale studies have not yet revealed a replicable, definitive environmental risk factor. The only established risk factors to date are older age, male gender and a family history of ALS. Median survival time from onset to death is usually 3 years from the first appearance of symptoms. Older age and bulbar onset are consistently reported to have poorer outcomes. However, there are conflicting data regarding gender, diagnostic delay and El Escorial criteria. The rate of symptom progression has been revealed to be an independent prognostic factor. Psychosocial factors and impaired cognitive function are negatively related to ALS outcome, while nutritional status and respiratory function are also related to ALS prognosis. The effect of enteral nutrition on survival is still unclear, although noninvasive positive pressure ventilation (NIPPV) has been found to improve survival. These findings have relevant implications for the design of future trials.}, }
@article {pmid26727306, year = {2016}, author = {Roses, AD and Akkari, PA and Chiba-Falek, O and Lutz, MW and Gottschalk, WK and Saunders, AM and Saul, B and Sundseth, S and Burns, D}, title = {Structural variants can be more informative for disease diagnostics, prognostics and translation than current SNP mapping and exon sequencing.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {12}, number = {2}, pages = {135-147}, doi = {10.1517/17425255.2016.1133586}, pmid = {26727306}, issn = {1744-7607}, mesh = {Alzheimer Disease/*genetics/physiopathology ; Animals ; Exons ; Gene Expression Regulation/genetics ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Lewy Body Disease/*genetics/physiopathology ; Microsatellite Repeats ; Parkinson Disease/*genetics/physiopathology ; Phylogeny ; Polymorphism, Single Nucleotide ; Prognosis ; }, abstract = {INTRODUCTION: In this article we discuss several human neurological diseases and their relationship to specific highly polymorphic small structural variants (SVs). Unlike genome-wide association analysis (GWAS), this methodology is not a genome screen to define new possibly associated genes, requiring statistical corrections for a million association tests. SVs provide local mapping information at a specific locus. Used with phylogenetic analysis, the specific association of length variants can be mapped and recognized.<br><br>AREAS COVERED: This experimental strategy provides identification of DNA variants, particularly variable length Simple Sequence Repeats (SSRs or STRs or microsatellites) that provide specific local association data at the SV locus. Phylogenetic analysis that includes the specific appearance of different length SV variations can differentiate specific phenotypic risks in a population such as age of onset related to variable length polymorphisms and risk of phenotypic variations associated with several adjacent structural variations (SVs). We focus on data for three recent examples associated with Alzheimer's disease, Levy Bodies, and Parkinson's disease.<br><br>EXPERT OPINION: SVs are understudied, but have led directly to mechanism of pathogenesis studies involving the regulation of gene expression. The identification of specific length polymorphisms associated with clinical disease has led to translational advances and new drug discovery.}, }
@article {pmid26725888, year = {2016}, author = {Dadhania, VP and Trivedi, PP and Vikram, A and Tripathi, DN}, title = {Nutraceuticals against Neurodegeneration: A Mechanistic Insight.}, journal = {Current neuropharmacology}, volume = {14}, number = {6}, pages = {627-640}, pmid = {26725888}, issn = {1875-6190}, mesh = {Animals ; *Dietary Supplements ; Humans ; Neurodegenerative Diseases/*diet therapy/*metabolism ; }, abstract = {The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.}, }
@article {pmid26724598, year = {2016}, author = {Ray, R and Juranek, JK and Rai, V}, title = {RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Neuroscience and biobehavioral reviews}, volume = {62}, number = {}, pages = {48-55}, doi = {10.1016/j.neubiorev.2015.12.006}, pmid = {26724598}, issn = {1873-7528}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Carrier Proteins/metabolism ; Humans ; Inflammation/*metabolism ; Neurodegenerative Diseases/immunology/*physiopathology ; Oxidative Stress/immunology/physiology ; Signal Transduction/*physiology ; }, abstract = {RAGE, the receptor of advanced glycation end-products, is thought to be one of the potential contributors to the neurodegeneration. It has been shown that RAGE activation triggers an increase in proinflammatory molecules, oxidative stressors and cytokines. RAGE involvement has been documented in the pathogenesis of a number of neurodegenerative diseases such amyotrophic lateral sclerosis (ALS), Alzheimer's, Parkinson's, Huntington's, Creutzfeld-Jakob' diseases and various neurodegenerative conditions such as diabetic neuropathy, familial amyloid polyneuropathy, Charcot neuroarthropathy and vasculitic neuropathy. Although the detailed mechanisms of RAGE contribution to the neurodegeneration remains unclear, studies indicate that RAGE detrimental actions are exerted via its binding to the pro-inflammatory ligands such as advanced glycation end-products, S100/calgranulin and amphoterin and subsequent activation of downstream regulatory pathways such as NF-κB, STAT and JKN pathways. Here, in this review we attempt to shed light onto molecular events and pathological pathways involved in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis (ALS)--a progressive and fatal neurodegenerative disorder, summarizing current knowledge and the prospect of RAGE in the pathogenesis of this disastrous disease.}, }
@article {pmid26723986, year = {2016}, author = {Riancho, J and Berciano, MT and Ruiz-Soto, M and Berciano, J and Landreth, G and Lafarga, M}, title = {Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {360}, number = {}, pages = {115-120}, pmid = {26723986}, issn = {1878-5883}, support = {R01 AG043522/AG/NIA NIH HHS/United States ; RF1 AG050597/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Humans ; Motor Neurons/*metabolism/pathology ; Retinoids/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscular atrophy and unfortunately it does not have an effective treatment. Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to have a sporadic origin. Although the pathogenesis of ALS has not been fully elucidated, various disorders in different cellular functions such as gene expression, protein metabolism, axonal transport and glial cell disorders have been linked to MN degeneration. Among them, proteostasis is one of the best studied. Retinoids are vitamin A-derived substances that play a crucial role in embryogenesis, development, programmed cell death and other cellular functions. Retinoid agonists behave as transcription factors throughout the activation of the nuclear retinoid receptors. Several reports in the literature suggest that retinoids are involved in proteostasis regulation, by modulating its two major pathways, the ubiquitin-proteasome system and the autophagy-lysosome response. Additionally, there are some evidences for a role of retinoids themselves, in ALS pathogenesis. In this review, we discuss the importance of proteostasis disruption as a trigger for MN degeneration and the capability of retinoids to modulate it, as well as the potential therapeutic role of retinoids as a new therapy in ALS.}, }
@article {pmid26722648, year = {2015}, author = {Russo, FB and Cugola, FR and Fernandes, IR and Pignatari, GC and Beltrão-Braga, PC}, title = {Induced pluripotent stem cells for modeling neurological disorders.}, journal = {World journal of transplantation}, volume = {5}, number = {4}, pages = {209-221}, pmid = {26722648}, issn = {2220-3230}, abstract = {Several diseases have been successfully modeled since the development of induced pluripotent stem cell (iPSC) technology in 2006. Since then, methods for increased reprogramming efficiency and cell culture maintenance have been optimized and many protocols for differentiating stem cell lines have been successfully developed, allowing the generation of several cellular subtypes in vitro. Gene editing technologies have also greatly advanced lately, enhancing disease-specific phenotypes by creating isogenic cell lines, allowing mutations to be corrected in affected samples or inserted in control lines. Neurological disorders have benefited the most from iPSC-disease modeling for its capability for generating disease-relevant cell types in vitro from the central nervous system, such as neurons and glial cells, otherwise only available from post-mortem samples. Patient-specific iPSC-derived neural cells can recapitulate the phenotypes of these diseases and therefore, considerably enrich our understanding of pathogenesis, disease mechanism and facilitate the development of drug screening platforms for novel therapeutic targets. Here, we review the accomplishments and the current progress in human neurological disorders by using iPSC modeling for Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy, amyotrophic lateral sclerosis, duchenne muscular dystrophy, schizophrenia and autism spectrum disorders, which include Timothy syndrome, Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome, Phelan-McDermid, Rett syndrome as well as Nonsyndromic Autism.}, }
@article {pmid26721251, year = {2016}, author = {Schreij, AM and Fon, EA and McPherson, PS}, title = {Endocytic membrane trafficking and neurodegenerative disease.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {73}, number = {8}, pages = {1529-1545}, pmid = {26721251}, issn = {1420-9071}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Autophagy/physiology ; Clathrin-Coated Vesicles/metabolism ; Endocytosis/genetics/physiology ; Humans ; Lysosomes/metabolism ; Multivesicular Bodies/*metabolism ; Parkinson Disease/*genetics ; Protein Transport/genetics/*physiology ; Spastic Paraplegia, Hereditary/*genetics ; }, abstract = {Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related genes with an enhanced appreciation of the key roles played by genetics in the etiology of these disorders. Importantly, pinpointing the normal function of disease gene proteins leads to new understanding of the cellular machineries and pathways that are altered in the disease process. One such emerging pathway is membrane trafficking in the endosomal system. This key cellular process controls the localization and levels of a myriad of proteins and is thus critical for normal cell function. In this review we will focus on three neurodegenerative diseases; Parkinson disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias, for which a large number of newly discovered disease genes encode proteins that function in endosomal membrane trafficking. We will describe how alterations in these proteins affect endosomal function and speculate on the contributions of these disruptions to disease pathophysiology.}, }
@article {pmid26713267, year = {2015}, author = {Siklos, M and BenAissa, M and Thatcher, GR}, title = {Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors.}, journal = {Acta pharmaceutica Sinica. B}, volume = {5}, number = {6}, pages = {506-519}, pmid = {26713267}, issn = {2211-3835}, abstract = {Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.}, }
@article {pmid26713266, year = {2015}, author = {Niu, L}, title = {Mechanism-based design of 2,3-benzodiazepine inhibitors for AMPA receptors.}, journal = {Acta pharmaceutica Sinica. B}, volume = {5}, number = {6}, pages = {500-505}, pmid = {26713266}, issn = {2211-3835}, support = {R01 NS060812/NS/NINDS NIH HHS/United States ; }, abstract = {2,3-Benzodiazepine (2,3-BDZ) compounds represent a group of structurally diverse, small-molecule antagonists of (R, S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors. Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy, stroke and amyotrophic lateral sclerosis (ALS). How to make better inhibitors, such as 2,3-BDZs, has been an enduring quest in drug discovery. Among a few available tools to address this specific question for making better 2,3-BDZs, perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists. Here I review recent work in this area, and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo.}, }
@article {pmid26713006, year = {2015}, author = {Ambesh, P and Angeli, DG}, title = {Nanotechnology in neurology: Genesis, current status, and future prospects.}, journal = {Annals of Indian Academy of Neurology}, volume = {18}, number = {4}, pages = {382-386}, pmid = {26713006}, issn = {0972-2327}, abstract = {Nanotechnology is a promising, novel field of technological development. There is great potential in research and clinical applications for neurological diseases. Here we chronicle the inception of nanotechnology, discuss its integration with neurology, and highlight the challenges in current application. Some of the problems involving practical use of neuronanotechnology are direct biological toxicity, visualization of the nanodevice, and the short life expectancy of nanomachinery. Neuron cell therapy is an upcoming field for the treatment of challenging problems in neurology. Peptide nanofibers based on amphiphilic molecules have been developed that can autoregulate their structure depending on the conditions of the surrounding milieu. Such frameworks are promising for serving as drug delivery systems or communication bridges between damaged neurons. For common disabling diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), recent developments have seen revolutionary nanotech-based novelties, which are discussed here in detail. Bioimaging integrated with nanoneuromedicine has opened up new doors for cancer and infection therapeutics.}, }
@article {pmid26696811, year = {2015}, author = {Haase, G and Rabouille, C}, title = {Golgi Fragmentation in ALS Motor Neurons. New Mechanisms Targeting Microtubules, Tethers, and Transport Vesicles.}, journal = {Frontiers in neuroscience}, volume = {9}, number = {}, pages = {448}, pmid = {26696811}, issn = {1662-4548}, abstract = {Pathological alterations of the Golgi apparatus, such as its fragmentation represent an early pre-clinical feature of many neurodegenerative diseases and have been widely studied in the motor neuron disease amyotrophic lateral sclerosis (ALS). Yet, the underlying molecular mechanisms have remained cryptic. In principle, Golgi fragmentation may result from defects in three major classes of proteins: structural Golgi proteins, cytoskeletal proteins and molecular motors, as well as proteins mediating transport to and through the Golgi. Here, we present the different mechanisms that may underlie Golgi fragmentation in animal and cellular models of ALS linked to mutations in SOD1, TARDBP (TDP-43), VAPB, and C9Orf72 and we propose a novel one based on findings in progressive motor neuronopathy (pmn) mice. These mice are mutated in the TBCE gene encoding the cis-Golgi localized tubulin-binding cofactor E, one of five chaperones that assist in tubulin folding and microtubule polymerization. Loss of TBCE leads to alterations in Golgi microtubules, which in turn impedes on the maintenance of the Golgi architecture. This is due to down-regulation of COPI coat components, dispersion of Golgi tethers and strong accumulation of ER-Golgi SNAREs. These effects are partially rescued by the GTPase ARF1 through recruitment of TBCE to the Golgi. We hypothesize that defects in COPI vesicles, microtubules and their interaction may also underlie Golgi fragmentation in human ALS linked to other mutations, spinal muscular atrophy (SMA), and related motor neuron diseases. We also discuss the functional relevance of pathological Golgi alterations, in particular their potential causative, contributory, or compensatory role in the degeneration of motor neuron cell bodies, axons and synapses.}, }
@article {pmid26696091, year = {2016}, author = {Chen, KS and Sakowski, SA and Feldman, EL}, title = {Intraspinal stem cell transplantation for amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {79}, number = {3}, pages = {342-353}, pmid = {26696091}, issn = {1531-8249}, support = {R25 NS089450/NS/NINDS NIH HHS/United States ; R25NS089450/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Evidence-Based Medicine ; Humans ; Injections, Spinal/*methods ; Neural Stem Cells/*transplantation ; Spinal Cord/*pathology ; Stem Cell Transplantation/*methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder in which the loss of upper and lower motor neurons produces progressive weakness and eventually death. In the decades since the approval of riluzole, the only US Food and Drug Administration-approved medication to moderately slow progression of ALS, no new therapeutics have arisen to alter the course of the disease. This is partly due to our incomplete understanding of the complex pathogenesis of motor neuron degeneration. Stem cells have emerged as an attractive option in treating ALS, because they come armed with equally complex cellular machinery and may modulate the local microenvironment in many ways to rescue diseased motor neurons. Various stem cell types are being evaluated in preclinical and early clinical applications; here, we review the preclinical strategies and advances supporting the recent clinical translation of neural progenitor cell therapy for ALS. Specifically, we focus on the use of spinal cord neural progenitor cells and the pipeline starting from preclinical studies to the designs of phase I and IIa clinical trials involving direct intraspinal transplantation in humans.}, }
@article {pmid26694727, year = {2016}, author = {Török, N and Majláth, Z and Fülöp, F and Toldi, J and Vécsei, L}, title = {Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism.}, journal = {Current drug metabolism}, volume = {17}, number = {5}, pages = {412-429}, doi = {10.2174/1389200217666151222155043}, pmid = {26694727}, issn = {1875-5453}, mesh = {Aging/immunology/*metabolism ; Animals ; Brain/metabolism ; Central Nervous System Diseases/*metabolism ; Humans ; Kynurenine/immunology/*metabolism ; Pharmaceutical Preparations/metabolism ; Signal Transduction ; }, abstract = {INTRODUCTION: The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission. Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia.<br><br>HIGHLIGHTS: This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.}, }
@article {pmid26691296, year = {2016}, author = {Caballero-Hernandez, D and Toscano, MG and Cejudo-Guillen, M and Garcia-Martin, ML and Lopez, S and Franco, JM and Quintana, FJ and Roodveldt, C and Pozo, D}, title = {The 'Omics' of Amyotrophic Lateral Sclerosis.}, journal = {Trends in molecular medicine}, volume = {22}, number = {1}, pages = {53-67}, doi = {10.1016/j.molmed.2015.11.001}, pmid = {26691296}, issn = {1471-499X}, support = {AI075285/AI/NIAID NIH HHS/United States ; AI093903/AI/NIAID NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Female ; Genomics ; Humans ; Male ; Precision Medicine ; Proteomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that primarily affects motor neurons and is accompanied by sustained unregulated immune responses, but without clear indications of the ultimate causative mechanisms. The identification of a diverse array of ALS phenotypes, a series of recently discovered mutations, and the links between ALS and frontotemporal degeneration have significantly increased our knowledge of the disease. In this review we discuss the main features involved in ALS pathophysiology in the context of recent advances in 'omics' approaches, including genomics, proteomics, and others. We emphasize the pressing need to combine clinical imaging with various different parameters taken from omics fields to facilitate early, accurate diagnosis and rational drug design in the treatment of ALS.}, }
@article {pmid26689011, year = {2015}, author = {Walczak, J and Szczepanowska, J}, title = {[Dysfunction of mitochondrial dynamic and distribution in Amyotrophic Lateral Sclerosis].}, journal = {Postepy biochemii}, volume = {61}, number = {2}, pages = {183-190}, pmid = {26689011}, issn = {0032-5422}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Mitochondrial Dynamics/*physiology ; Motor Neurons/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease leading to degradation of motor neurons. One of the early symptoms of many neurodegenerative disorders are mitochondrial dysfunctions. Since few decades mitochondrial morphology changes have been observed in tissues of patients with ALS. Mitochondria are highly dynamic organelles which constantly undergo continuous process of fusion and fission and are actively transported within the cell. Proper functioning of mitochondrial dynamics and distribution is crucial for cell survival, especially neuronal cells that have long axons. This article summarizes the current knowledge about the role of mitochondrial dynamics and distribution in pathophysiology of familial and sporadic form of ALS.}, }
@article {pmid26689008, year = {2015}, author = {Koza, P}, title = {[RNA processing TDP-43 protein has a main pathological role in FTLD and ALS].}, journal = {Postepy biochemii}, volume = {61}, number = {2}, pages = {159-167}, pmid = {26689008}, issn = {0032-5422}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; DNA-Binding Proteins/*physiology ; Frontotemporal Lobar Degeneration/*physiopathology ; Humans ; Neurons/*pathology ; RNA Processing, Post-Transcriptional/*physiology ; Transcription, Genetic/*physiology ; }, abstract = {TDP-43 is mainly a nuclear protein belonging to the heterogeneous ribonucleoproteins family. It plays a crucial role in the regulation of gene transcription and RNA processing. In 2006, TDP-43 was characterized as the main component of ubiquitin-positive inclusions observed in Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) cases. Since then, its central role in a number of neurodegenerative diseases was confirmed, originating the TDP-43 proteinopathies term. Pathological TDP-43 redistributes and accumulates in the cytoplasm forming toxic aggregates. Plethora of animal models recapitulating features typical for human TDP-43 proteinopathies has been generated. However, the mechanism involving TDP-43 and causing functional disturbances, like dementia and motoneurons degeneration, remains unknown. Loss and gain of function hypotheses are proposed, but they still need to be verified.}, }
@article {pmid26687930, year = {2016}, author = {Sánchez-Santed, F and Colomina, MT and Herrero Hernández, E}, title = {Organophosphate pesticide exposure and neurodegeneration.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {74}, number = {}, pages = {417-426}, doi = {10.1016/j.cortex.2015.10.003}, pmid = {26687930}, issn = {1973-8102}, mesh = {Brain/*pathology ; Environmental Exposure/adverse effects ; Humans ; Neurodegenerative Diseases/*chemically induced/pathology ; Occupational Exposure/adverse effects ; Organophosphate Poisoning/*complications/pathology ; Pesticides/*poisoning ; }, abstract = {Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.}, }
@article {pmid26686055, year = {2016}, author = {Berger, J and Dorninger, F and Forss-Petter, S and Kunze, M}, title = {Peroxisomes in brain development and function.}, journal = {Biochimica et biophysica acta}, volume = {1863}, number = {5}, pages = {934-955}, pmid = {26686055}, issn = {0006-3002}, support = {I 2738/FWF_/Austrian Science Fund FWF/Austria ; P 24843/FWF_/Austrian Science Fund FWF/Austria ; P 26112/FWF_/Austrian Science Fund FWF/Austria ; }, mesh = {ATPases Associated with Diverse Cellular Activities ; Animals ; Brain/*metabolism/pathology ; Disease Models, Animal ; Gene Expression Regulation ; Humans ; Membrane Proteins/chemistry/*deficiency/genetics ; Metabolic Networks and Pathways/genetics ; Mice ; Mutation ; Peroxisomal Disorders/genetics/*metabolism/pathology ; Peroxisomes/chemistry/*metabolism ; Protein Isoforms/chemistry/genetics/metabolism ; Protein Transport ; Synaptic Transmission ; }, abstract = {Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer's disease, autism and amyotrophic lateral sclerosis.}, }
@article {pmid26663933, year = {2015}, author = {Komine, O and Yamanaka, K}, title = {Neuroinflammation in motor neuron disease.}, journal = {Nagoya journal of medical science}, volume = {77}, number = {4}, pages = {537-549}, pmid = {26663933}, issn = {0027-7622}, abstract = {Increasing evidence suggests that the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) is not restricted to the neurons but attributed to the abnormal interactions of neurons and surrounding glial and lymphoid cells. These findings led to the concept of non-cell autonomous neurodegeneration. Neuroinflammation, which is mediated by activated glial cells and infiltrated lymphocytes and accompanied by the subsequent production of proinflammatory cytokines and neurotoxic or neuroprotective molecules, is characteristic to the pathology in ALS and is a key component for non-cell autonomous neurodegeneration. This review covers the involvement of microglia and astrocytes in the ALS mouse models and human ALS, and it also covers the deregulated pathways in motor neurons, which are involved in initiating the disease. Based on the cell-type specific pathomechanisms of motor neuron disease, targeting of neuroinflammation could lead to future therapeutic strategies for ALS and could be potentially applied to other neurodegenerative diseases.}, }
@article {pmid26663180, year = {2015}, author = {Qiu, L and Tan, EK and Zeng, L}, title = {microRNAs and Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {888}, number = {}, pages = {85-105}, doi = {10.1007/978-3-319-22671-2_6}, pmid = {26663180}, issn = {0065-2598}, mesh = {Alzheimer Disease/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; *Gene Expression Regulation ; Humans ; Huntington Disease/genetics/therapy ; MicroRNAs/*genetics ; Neurodegenerative Diseases/*genetics/therapy ; Parkinson Disease/genetics/therapy ; Signal Transduction/*genetics ; }, abstract = {microRNAs (miRNAs) are small, noncoding RNA molecules that through imperfect base-pairing with complementary sequences of target mRNA molecules, typically cleave target mRNA, causing subsequent degradation or translation inhibition. Although an increasing number of studies have identified misregulated miRNAs in the neurodegenerative diseases (NDDs) Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, which suggests that alterations in the miRNA regulatory pathway could contribute to disease pathogenesis, the molecular mechanisms underlying the pathological implications of misregulated miRNA expression and the regulation of the key genes involved in NDDs remain largely unknown. In this chapter, we provide evidence of the function and regulation of miRNAs and their association with the neurological events in NDDs. This will help improve our understanding of how miRNAs govern the biological functions of key pathogenic genes in these diseases, which potentially regulate several pathways involved in the progression of neurodegeneration. Additionally, given the growing interest in the therapeutic potential of miRNAs, we discuss current clinical challenges to developing miRNA-based therapeutics for NDDs.}, }
@article {pmid26659872, year = {2016}, author = {Xu, L and He, D and Bai, Y}, title = {Microglia-Mediated Inflammation and Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {53}, number = {10}, pages = {6709-6715}, pmid = {26659872}, issn = {1559-1182}, mesh = {Animals ; Humans ; Inflammation/*pathology ; Microglia/*pathology ; Neurodegenerative Diseases/*pathology ; }, abstract = {Microglia are the main effectors in the inflammatory process of the central nervous system. As the first line of defense, microglia play an important role in the inflammatory reaction. When there is pathogen invasion or cell debris, microglia will be activated rapidly and remove it, while releasing the inflammatory cytokines to mediate inflammatory reaction. Activated microglia were found surrounding lesions of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, muscular amyotrophic lateral sclerosis, and multiple sclerosis. Microglia, the effectors of neuronal degeneration and necrosis, are involved in the removal of necrotic neurons. But over activated microglia may accelerate the process of some neurodegenerative diseases. Activated microglia can release cytotoxic factor and cytokines. Some of them may cause further damage to neuron, and some of them can regulate inflammatory cells to gather to the lesion. Microglia-mediated inflammation was considered to be the possible mechanism for the occurrence or deterioration of neurodegenerative diseases. Therefore, inhibiting the activity of microglia appropriately may be an effective way for the treatment of neurodegenerative diseases.}, }
@article {pmid26657039, year = {2016}, author = {Kaur, SJ and McKeown, SR and Rashid, S}, title = {Mutant SOD1 mediated pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Gene}, volume = {577}, number = {2}, pages = {109-118}, doi = {10.1016/j.gene.2015.11.049}, pmid = {26657039}, issn = {1879-0038}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/therapy ; Animals ; Genetic Therapy ; Humans ; Molecular Sequence Data ; *Mutation ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/chemistry/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neural disorder that causes death of the motor neurons in the brain and spinal cord; this affects the voluntary muscles and gradually leads to paralysis of the whole body. Most ALS cases are sporadic, though about 5-10% are familial. ALS is caused by multiple factors including mutation in any one of a number of specific genes, one of the most frequently affected is superoxide dismutase (SOD) 1. Alterations in SOD 1 have been linked with several variants of familial ALS. SOD 1 is a powerful antioxidant enzyme that protects cells from the damaging effects of superoxide radicals. The enzyme binds both copper and zinc ions that are directly involved in the deactivation of toxic superoxide radicals. Mutated SOD1 gene can acquire both gain and loss of function mutations. The most commonly identified mutations in SOD1 that affect protein activity are D90A, A4V and G93A. Deleterious mutations have been shown to modify SOD1 activity, which leads to the accumulation of highly toxic hydroxyl radicals. Accumulation of these free radicals causes degradation of both nuclear and mitochondrial DNA and protein misfolding, features which can be used as pathological indicators associated with ALS. Numerous clinical trials have been carried out over last few years with limited success. In some patients advanced techniques like gene and stem cell therapy have been trialed. However no definitive treatment option can provide a cure and currently ALS is managed by drugs and other supportive therapies. Consequently there is a need to identify new approaches for treatment of this ultimately fatal disease.}, }
@article {pmid26653545, year = {2015}, author = {Shu, YH and Lu, XM and Wei, JX and Xiao, L and Wang, YT}, title = {Update on the role of p75NTR in neurological disorders: A novel therapeutic target.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {76}, number = {}, pages = {17-23}, doi = {10.1016/j.biopha.2015.10.010}, pmid = {26653545}, issn = {1950-6007}, mesh = {Animals ; Apoptosis/physiology ; Cell Cycle Checkpoints/physiology ; Cell Movement/physiology ; Cell Survival/physiology ; Humans ; Mental Disorders/*physiopathology ; Nervous System Diseases/*physiopathology ; Receptor, Nerve Growth Factor/*metabolism ; }, abstract = {As a low-affinity neurotrophins receptor, p75 neurotrophin receptor (p75NTR) is a transmembrane receptor involved in a diverse array of cellular responses, including apoptosis, survival, neurite outgrowth, migration, and cell cycle arrest, which may be related to some neurological disorders, such as Alzheimer's disease (AD), schizophrenia, major depressive disorder (MDD), posttraumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Indeed, a series of studies during the last decade has demonstrated that the p75NTR signaling plays key roles in most aspects of the neurological disorder diseases. In spite of the limited information available, this review still tried to summary the relationship between p75NTR and diverse neurological disorder diseases, and tried to further clarify the possible mechanism, which may provide a novel therapeutic target for the treatment of neurological disorders.}, }
@article {pmid26646927, year = {2015}, author = {Maiti, TK and Konar, S and Bir, S and Kalakoti, P and Bollam, P and Nanda, A}, title = {Role of apolipoprotein E polymorphism as a prognostic marker in traumatic brain injury and neurodegenerative disease: a critical review.}, journal = {Neurosurgical focus}, volume = {39}, number = {5}, pages = {E3}, doi = {10.3171/2015.8.FOCUS15329}, pmid = {26646927}, issn = {1092-0684}, mesh = {Animals ; Apolipoproteins E/*genetics ; Brain Injuries/diagnosis/*genetics ; Genetic Markers/*genetics ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics ; Polymorphism, Genetic/*genetics ; Prognosis ; }, abstract = {OBJECT The difference in course and outcome of several neurodegenerative conditions and traumatic injuries of the nervous system points toward a possible role of genetic and environmental factors as prognostic markers. Apolipoprotein E (Apo-E), a key player in lipid metabolism, is recognized as one of the most powerful genetic risk factors for dementia and other neurodegenerative diseases. In this article, the current understanding of APOE polymorphism in various neurological disorders is discussed. METHODS The English literature was searched for various studies describing the role of APOE polymorphism as a prognostic marker in neurodegenerative diseases and traumatic brain injury. The wide ethnic distribution of APOE polymorphism was discussed, and the recent meta-analyses of role of APOE polymorphism in multiple diseases were analyzed and summarized in tabular form. RESULTS Results from the review of literature revealed that the distribution of APOE is varied in different ethnic populations. APOE polymorphism plays a significant role in pathogenesis of neurodegeneration, particularly in Alzheimer's disease. APOE ε4 is considered a marker for poor prognosis in various diseases, but APOE ε2 rather than APOE ε4 has been associated with cerebral amyloid angiopathy-related bleeding and sporadic Parkinson's disease. The role of APOE polymorphism in various neurological diseases has not been conclusively elucidated. CONCLUSIONS Apo-E is a biomarker for various neurological and systemic diseases. Therefore, while analyzing the role of APOE polymorphism in neurological diseases, the interpretation should be done after adjusting all the confounding factors. A continuous quest to look for associations with various neurological diseases and wide knowledge of available literature are required to improve the understanding of the role of APOE polymorphism in these conditions and identify potential therapeutic targets.}, }
@article {pmid26646612, year = {2016}, author = {Hübers, A and Ludolph, AC and Rosenbohm, A and Pinkhardt, EH and Weishaupt, JH and Dorst, J}, title = {[Amyotrophic lateral sclerosis. Multisystem degeneration].}, journal = {Der Nervenarzt}, volume = {87}, number = {2}, pages = {179-188}, pmid = {26646612}, issn = {1433-0407}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Cognition Disorders/*diagnosis/*therapy ; Diagnosis, Differential ; Evidence-Based Medicine ; Humans ; Ocular Motility Disorders/*diagnosis/*therapy ; Symptom Assessment/methods ; }, abstract = {BACKGROUND: There is increasing evidence that amyotrophic lateral sclerosis (ALS) has to be regarded as multisystem degeneration rather than as purely a motor neuron disease, as it also includes various dnonmotor symptoms. This modern view has been confirmed by neuropathological and imaging findings.<br><br>OBJECTIVES: To review recent findings supporting the idea of multisystem degeneration and to describe the implications for diagnostics and therapy.<br><br>METHODS: A discussion of recent clinical, imaging, and neuropathological findings is presented.<br><br>RESULTS: Symptoms of ALS include not only motor symptoms but also cognitive impairment, oculomotor abnormalities, and extrapyramidal and sensory symptoms. As a neuropathological correlate, a systematic spreading of "transactive response DNA binding protein 43&#xa0;kDa" (TDP-43) over functionally connected cortical structures has been described.<br><br>CONCLUSIONS: Nonmotor symptoms are regularly seen in ALS, although they usually do not dominate the clinical picture. Recent neuropathological findings offer new perspectives for diagnostics and therapy in ALS.}, }
@article {pmid26642082, year = {2016}, author = {Choong, CJ and Baba, K and Mochizuki, H}, title = {Gene therapy for neurological disorders.}, journal = {Expert opinion on biological therapy}, volume = {16}, number = {2}, pages = {143-159}, doi = {10.1517/14712598.2016.1114096}, pmid = {26642082}, issn = {1744-7682}, mesh = {Alzheimer Disease/genetics/therapy ; Animals ; Clinical Trials as Topic/methods ; Gene Silencing/physiology ; Genetic Therapy/*methods/trends ; Genetic Vectors ; Humans ; Nervous System Diseases/*genetics/*therapy ; Parkinson Disease/genetics/therapy ; RNA Interference/physiology ; }, abstract = {INTRODUCTION: Many nervous system disorders are minimally responsive to existing treatments but they are potential candidates for gene therapy, an approach that can correct the genetic abnormalities contributing to its pathogenesis at molecular level. Gene therapy involves either the introduction of a replacement allele into cells to compensate for loss of gene function or the silencing of dominant mutant allele that is pathologic to cells.<br><br>AREAS COVERED: This review discusses the currently available gene therapy techniques, potential problems derived from gene therapy strategies and the recent development of gene therapy to treat neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and strokes.<br><br>EXPERT OPINION: Gene therapy may revolutionize the treatment of neurological disorders in the coming decades but there are still great challenges ahead. The strength of gene therapy has been emphasized in the overexpression of therapeutic genes. However, in a number of dominantly inherited nervous system diseases, the ideal therapeutic goal would be to inhibit the expression of disease-causing allele. Gene silencing strategies by single-stranded antisense oligonucleotides and RNA interference represent a major breakthrough. Clinical trials using these approaches for dominant diseases are likely to be implemented in the near future.}, }
@article {pmid26639457, year = {2016}, author = {Catorce, MN and Gevorkian, G}, title = {LPS-induced Murine Neuroinflammation Model: Main Features and Suitability for Pre-clinical Assessment of Nutraceuticals.}, journal = {Current neuropharmacology}, volume = {14}, number = {2}, pages = {155-164}, pmid = {26639457}, issn = {1875-6190}, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Astrocytes/metabolism ; Brain/drug effects/metabolism ; *Dietary Supplements ; *Disease Models, Animal ; Encephalitis/chemically induced/etiology/*metabolism/*prevention &amp; control ; Lipopolysaccharides/*administration &amp; dosage ; Mice ; Microglia/metabolism ; Neurodegenerative Diseases/*complications ; Reproducibility of Results ; }, abstract = {Neuroinflammation is an important feature in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer´s disease (AD), Parkinson´s disease (PD), frontotemporal dementia and amyotrophic lateral sclerosis. Based on current knowledge in the field, suggesting that targeting peripheral inflammation could be a promising additional treatment/prevention approach for neurodegenerative diseases, drugs and natural products with anti-inflammatory properties have been evaluated in animal models of neuroinflammation and neurodegeneration. In this review, we provide an extensive analysis of one of the most important and widely-used animal models of peripherally induced neuroinflammation and neurodegeneration - lipopolysaccharide (LPS)-treated mice, and address the data reproducibility in published research. We also summarize briefly basic features of various natural products, nutraceuticals, with known anti-inflammatory effects and present an overview of data on their therapeutic potential for reducing neuroinflammation in LPS-treated mice.}, }
@article {pmid26635528, year = {2015}, author = {Kaus, A and Sareen, D}, title = {ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {448}, pmid = {26635528}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood. Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients. Key associated molecular and neuropathological features include ubiquitinated TDP-43 inclusions, stress granules, aggregated dipeptide proteins from mutant C9orf72 transcripts, altered mitochondrial ultrastructure, dysregulated calcium homeostasis, oxidative and endoplasmic reticulum (ER) stress, and an unfolded protein response (UPR). Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable. Human induced pluripotent stem cells (iPSCs) are a valuable tool that could resolve this "chicken or egg" causality dilemma. Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described. Performing unbiased 'OMICS and high-throughput screening in relevant neural cells from a cohort of ALS patient iPSCs, and rescuing mitochondrial and ER stress impairments, can identify targeted therapeutics for increasing MN longevity in ALS.}, }
@article {pmid26630810, year = {2015}, author = {Morris, J}, title = {Amyotrophic Lateral Sclerosis (ALS) and Related Motor Neuron Diseases: An Overview.}, journal = {The Neurodiagnostic journal}, volume = {55}, number = {3}, pages = {180-194}, doi = {10.1080/21646821.2015.1075181}, pmid = {26630810}, issn = {2164-6821}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease ; Motor Neurons ; Neural Conduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease, resulting in the destruction and ultimate death of neurons that control muscles. ALS affects motor neurons in the brain, brainstem, and spinal cord (upper motor neurons, bulbar region of the brain, and lower motor neurons). ALS patients have an average life expectancy of 3-5 years, therefore, proper diagnosis, care, and treatment is essential in order to provide the best quality of life for these patients. A thorough understanding of the symptomatology, potential cause(s), progression, and treatment of ALS is essential to provide timely and high-quality patient care. Electrodiagnostic examination, specifically electromyography (EMG) and nerve conduction studies (NCS), is one of the key diagnostics of ALS.}, }
@article {pmid26629397, year = {2015}, author = {Zarei, S and Carr, K and Reiley, L and Diaz, K and Guerra, O and Altamirano, PF and Pagani, W and Lodin, D and Orozco, G and Chinea, A}, title = {A comprehensive review of amyotrophic lateral sclerosis.}, journal = {Surgical neurology international}, volume = {6}, number = {}, pages = {171}, pmid = {26629397}, issn = {2229-5097}, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5-10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease.}, }
@article {pmid26626189, year = {2016}, author = {Denzer, I and Münch, G and Friedland, K}, title = {Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds.}, journal = {Pharmacological research}, volume = {103}, number = {}, pages = {80-94}, doi = {10.1016/j.phrs.2015.11.019}, pmid = {26626189}, issn = {1096-1186}, mesh = {Animals ; *Food ; Humans ; Mitochondria/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress ; }, abstract = {Oxidative stress and mitochondrial dysfunction are early events in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Mitochondria are important key players in cellular function based on mitochondrial energy production and their major role in cell physiology. Since neurons are highly depending on mitochondrial energy production due to their high energy demand and their reduced glycolytic capacity mitochondrial dysfunction has fatal consequences for neuronal function and survival. The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) is the major regulator of cellular response to oxidative stress. Activation of Nrf2 induces the transcriptional regulation of antioxidant response element (ARE)-dependent expression of a battery of cytoprotective and antioxidant enzymes and proteins. Moreover, activation of Nrf2 protects mitochondria from dysfunction and promotes mitochondrial biogenesis. Therefore, the Nrf2/ARE pathway has become an attractive target for the prevention and treatment of oxidative stress-related neurodegenerative diseases. Small food-derived inducers of the Nrf2/ARE pathway including l-sulforaphane from broccoli and isoliquiritigenin from licorice displayed promising protection of mitochondrial function in models of oxidative stress and neurodegenerative diseases and represent a novel approach to prevent and treat aging-associated neurodegenerative diseases.}, }
@article {pmid26619150, year = {2015}, author = {Clark, R and Blizzard, C and Dickson, T}, title = {Inhibitory dysfunction in amyotrophic lateral sclerosis: future therapeutic opportunities.}, journal = {Neurodegenerative disease management}, volume = {5}, number = {6}, pages = {511-525}, doi = {10.2217/nmt.15.49}, pmid = {26619150}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Disease Progression ; Humans ; Interneurons/drug effects/physiology ; Neural Inhibition/*drug effects/*physiology ; }, abstract = {In amyotrophic lateral sclerosis, motor neuron hyperexcitability and inhibitory dysfunction is emerging as a potential causative link in the dysfunction and degeneration of the motoneuronal circuitry that characterizes the disease. Interneurons, as key regulators of excitability, may mediate much of this imbalance, yet we know little about the way in which inhibitory deficits perturb excitability. In this review, we explore inhibitory control of excitability and the potential contribution of altered inhibition to amyotrophic lateral sclerosis disease processes and vulnerabilities, identifying important windows of therapeutic opportunity and potential interventions, specifically targeting inhibitory control at key disease stages.}, }
@article {pmid26617668, year = {2015}, author = {Chen, X and Barclay, JW and Burgoyne, RD and Morgan, A}, title = {Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases.}, journal = {Chemistry Central journal}, volume = {9}, number = {}, pages = {65}, pmid = {26617668}, issn = {1752-153X}, abstract = {Age-associated neurodegenerative disorders such as Alzheimer's disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential.}, }
@article {pmid26617320, year = {2016}, author = {Lewis, O and Woolley, M and Johnson, D and Rosser, A and Barua, NU and Bienemann, AS and Gill, SS and Evans, S}, title = {Chronic, intermittent convection-enhanced delivery devices.}, journal = {Journal of neuroscience methods}, volume = {259}, number = {}, pages = {47-56}, doi = {10.1016/j.jneumeth.2015.11.008}, pmid = {26617320}, issn = {1872-678X}, support = {MR/J005134/1/MRC_/Medical Research Council/United Kingdom ; MR/L010305/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Brain ; *Catheters ; Convection ; Drug Delivery Systems/*methods ; Humans ; }, abstract = {BACKGROUND: Intraparenchymal convection-enhanced delivery (CED) of therapeutics directly into the brain has long been endorsed as a medium through which meaningful concentrations of drug can be administered to patients, bypassing the blood brain barrier. The translation of the technology to clinic has been hindered by poor distribution not previously observed in smaller pre-clinical models. In part this was due to the larger volumes of target structures found in humans but principally the poor outcome was linked to reflux (backflow) of infusate proximally along the catheter track. Over the past 10 years, improvements have been made to the technology in the field which has led to a small number of commercially available devices containing reflux inhibiting features.<br><br>NEW METHOD: While these devices are currently suitable for acute or short term use, several indications would benefit from longer term repeated, intermittent administration of therapeutics (Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Brain tumours such as Glioblastoma Multiforme (GBM) and Diffuse intrinsic Pontine Glioma (DIPG), etc.).<br><br>RESULTS: Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field.<br><br>At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists.<br><br>CONCLUSIONS: Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems.}, }
@article {pmid26604027, year = {2015}, author = {Cavaleri, F}, title = {Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define pathology of the novel paradigm for Alzheimer's with heavy metals as primary disease cause.}, journal = {Medical hypotheses}, volume = {85}, number = {6}, pages = {779-790}, doi = {10.1016/j.mehy.2015.10.009}, pmid = {26604027}, issn = {1532-2777}, mesh = {Brain/*drug effects/*physiopathology ; Disease Progression ; Evidence-Based Medicine ; Heavy Metal Poisoning, Nervous System/complications/*physiopathology ; Humans ; Metals/*poisoning ; *Models, Neurological ; Neurodegenerative Diseases/etiology/*physiopathology ; }, abstract = {Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) - and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult. One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease hallmarks that we often classify as absolute signatures of one disease. These new perspectives will be discussed in the context of a new paradigm for Alzheimer's disease that implicates heavy metals as a primary cause. Plausible links between these distinctly different pathologies are presented showing intersections of their distinct pathologies that hinge on metal interactions.}, }
@article {pmid26602023, year = {2016}, author = {Spalloni, A and Longone, P}, title = {Cognitive impairment in amyotrophic lateral sclerosis, clues from the SOD1 mouse.}, journal = {Neuroscience and biobehavioral reviews}, volume = {60}, number = {}, pages = {12-25}, doi = {10.1016/j.neubiorev.2015.11.006}, pmid = {26602023}, issn = {1873-7528}, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/*psychology ; Animals ; Cognition Disorders/*complications/genetics ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function.}, }
@article {pmid26601962, year = {2016}, author = {Mushtaq, G and Greig, NH and Anwar, F and Al-Abbasi, FA and Zamzami, MA and Al-Talhi, HA and Kamal, MA}, title = {Neuroprotective Mechanisms Mediated by CDK5 Inhibition.}, journal = {Current pharmaceutical design}, volume = {22}, number = {5}, pages = {527-534}, pmid = {26601962}, issn = {1873-4286}, support = {ZIA AG000311-16//Intramural NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/metabolism ; Animals ; Brain Ischemia/drug therapy/metabolism ; Cyclin-Dependent Kinase 5/*antagonists &amp; inhibitors/metabolism ; Humans ; Neuroprotective Agents/chemistry/*pharmacology ; Stroke/drug therapy/metabolism ; }, abstract = {Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke.}, }
@article {pmid26584004, year = {2016}, author = {King, AE and Woodhouse, A and Kirkcaldie, MT and Vickers, JC}, title = {Excitotoxicity in ALS: Overstimulation, or overreaction?.}, journal = {Experimental neurology}, volume = {275 Pt 1}, number = {}, pages = {162-171}, doi = {10.1016/j.expneurol.2015.09.019}, pmid = {26584004}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Cell Death/physiology ; Glutamic Acid/*metabolism ; Humans ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/*metabolism/pathology ; Spinal Cord/*metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS.}, }
@article {pmid26579223, year = {2015}, author = {Ni, Z and Chen, R}, title = {Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {4}, number = {}, pages = {22}, pmid = {26579223}, issn = {2047-9158}, abstract = {Common neurodegenerative diseases include Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Transcranial magnetic stimulation (TMS) is a noninvasive and painless method to stimulate the human brain. Single- and paired-pulse TMS paradigms are powerful ways to study the pathophysiological mechanisms of neurodegenerative diseases. Motor evoked potential studied with single-pulse TMS is increased in PD, AD and ALS, but is decreased in HD. Changes in motor cortical excitability in neurodegenerative diseases may be related to functional deficits in cortical circuits or to compensatory mechanisms. Reduction or even absence of short interval intracortical inhibition induced by paired-pulse TMS is common in neurodegenerative diseases, suggesting that there are functional impairments of inhibitory cortical circuits. Decreased short latency afferent inhibition in AD, PD and HD may be related to the cortical cholinergic deficits in these conditions. Cortical plasticity tested by paired associative stimulation or theta burst stimulation is impaired in PD, AD and HD. Repetitive TMS (rTMS) refers to the application of trains of regularly repeating TMS pulses. High-frequency facilitatory rTMS may improve motor symptoms in PD patients whereas low-frequency inhibitory stimulation is a potential treatment for levodopa induced dyskinesia. rTMS delivered both to the left and right dorsolateral prefrontal cortex improves memory in AD patients. Supplementary motor cortical stimulation in low frequency may be useful for HD patients. However, the effects of treatment with multiple sessions of rTMS for neurodegenerative diseases need to be tested in large, sham-controlled studies in the future before they can be adopted for routine clinical practice.}, }
@article {pmid26578880, year = {2015}, author = {Radford, RA and Morsch, M and Rayner, SL and Cole, NJ and Pountney, DL and Chung, RS}, title = {The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {414}, pmid = {26578880}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.}, }
@article {pmid26578862, year = {2015}, author = {Sundaramoorthy, V and Sultana, JM and Atkin, JD}, title = {Golgi fragmentation in amyotrophic lateral sclerosis, an overview of possible triggers and consequences.}, journal = {Frontiers in neuroscience}, volume = {9}, number = {}, pages = {400}, pmid = {26578862}, issn = {1662-4548}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an invariably fatal neurodegenerative disorder, which specifically targets motor neurons in the brain, brain stem and spinal cord. Whilst the etiology of ALS remains unknown, fragmentation of the Golgi apparatus is detected in ALS patient motor neurons and in animal/cellular disease models. The Golgi is a highly dynamic organelle that acts as a dispatching station for the vesicular transport of secretory/transmembrane proteins. It also mediates autophagy and maintains endoplasmic reticulum (ER) and axonal homeostasis. Both the trigger for Golgi fragmentation and the functional consequences of a fragmented Golgi apparatus in ALS remain unclear. However, recent evidence has highlighted defects in vesicular trafficking as a pathogenic mechanism in ALS. This review summarizes the evidence describing Golgi fragmentation in ALS, with possible links to other disease processes including cellular trafficking, ER stress, defective autophagy, and axonal degeneration.}, }
@article {pmid26574709, year = {2016}, author = {Benatar, M and Boylan, K and Jeromin, A and Rutkove, SB and Berry, J and Atassi, N and Bruijn, L}, title = {ALS biomarkers for therapy development: State of the field and future directions.}, journal = {Muscle &amp; nerve}, volume = {53}, number = {2}, pages = {169-182}, pmid = {26574709}, issn = {1097-4598}, support = {K23 NS083715/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; U54-NS-092091/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; *Biomarkers/metabolism ; *Drug Discovery/methods/standards/trends ; Humans ; United States ; }, abstract = {Biomarkers have become the focus of intense research in the field of amyotrophic lateral sclerosis (ALS), with the hope that they might aid therapy development efforts. Notwithstanding the discovery of many candidate biomarkers, none have yet emerged as validated tools for drug development. In this review we present a nuanced view of biomarkers based on the perspective of the Food and Drug Administration; highlight the distinction between discovery and validation; describe existing and emerging resources; review leading biological fluid-based, electrophysiological, and neuroimaging candidates relevant to therapy development efforts; discuss lessons learned from biomarker initiatives in related neurodegenerative diseases; and outline specific steps that we, as a field, might take to hasten the development and validation of biomarkers that will prove useful in enhancing efforts to develop effective treatments for ALS patients. Most important among these is the proposal to establish a federated ALS Biomarker Consortium in which all interested and willing stakeholders may participate with equal opportunity to contribute to the broader mission of biomarker development and validation.}, }
@article {pmid26573331, year = {2015}, author = {Hauw, JJ and Haïk, S and Duyckaerts, C}, title = {[Spreading of protein misfolding: A new paradigm in neurology].}, journal = {Revue neurologique}, volume = {171}, number = {12}, pages = {825-831}, doi = {10.1016/j.neurol.2015.09.010}, pmid = {26573331}, issn = {0035-3787}, mesh = {Humans ; Nervous System Diseases/etiology/*pathology ; Neurology ; Proteostasis Deficiencies/complications/*pathology ; }, abstract = {Protein misfolding and spreading ("transconformation") are being better understood. Described in Prions diseases, this new paradigm in the field of neurodegenerative disorders and brain aging also implies sporadic inclusion myositis, type 2 diabetes, some cancers, sickle cell disease... Misfolding is transmitted from a protein or peptide to a normally folded one. Often associated with a stress of the endoplasmic reticulum, it may spread along the neurites, following anterograde or retrograde axonal transport. In the central nervous system, it occurs in a few cells and there is invasion of adjacent cells by cell-to-cell spread. Three varieties of protein misfolding occur along neuroanatomical pathways. It can be a 'centripetal' process. The synucleinopathy of Parkinson disease has been carefully studied: the changes first occur in cardiac or enteric plexuses... and reach later on the mesencephalon and neocortex. Thus, skin biopsy might prove a diagnostic tool. Protein misfolding may also occur along 'centrifugal' pathways, from motor cortex to peripheral motor neurons. Examples are provided by SOD and pTDP-43 in Amyotrophic Lateral Sclerosis. Amyloid β peptide in cerebral aging and Alzheimer's disease also spread from occipital cortex to the brainstem. Lastly, the propagation may remain 'central' for TDP-43 in behavioral variant frontotemporal dementia, following only pathways of the encephalic neural network. This has to be confirmed, however, since the spreading of some proteins (such as tau or Aβ peptides) has been considered central for a long time and has proved today to involve extracerebral tissues. The complex mechanisms of protein misfolding, still in analysis, include the involvement of chaperone proteins, the formation of very toxic labile proteins molecules (oligomers?), and provide a number of new therapeutic perspectives.}, }
@article {pmid26569220, year = {2015}, author = {Kiriyama, Y and Nochi, H}, title = {The Function of Autophagy in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {16}, number = {11}, pages = {26797-26812}, pmid = {26569220}, issn = {1422-0067}, mesh = {AMP-Activated Protein Kinases/genetics/metabolism ; Alzheimer Disease/*genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Apoptosis Regulatory Proteins/genetics/metabolism ; Autophagy/*genetics ; Autophagy-Related Protein-1 Homolog ; Beclin-1 ; Gene Expression Regulation ; Humans ; Huntington Disease/*genetics/metabolism/pathology ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Membrane Proteins/genetics/metabolism ; Multiprotein Complexes/genetics/metabolism ; Neurons/metabolism/pathology ; Parkinson Disease/*genetics/metabolism/pathology ; Protein Serine-Threonine Kinases/genetics/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {Macroautophagy, hereafter referred to as autophagy, is a bulk degradation process performed by lysosomes in which aggregated and altered proteins as well as dysfunctional organelles are decomposed. Autophagy is a basic cellular process that maintains homeostasis and is crucial for postmitotic neurons. Thus, impaired autophagic processes in neurons lead to improper homeostasis and neurodegeneration. Recent studies have suggested that impairments of the autophagic process are associated with several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and static encephalopathy of childhood with neurodegeneration in adulthood. In this review, we focus on the recent findings regarding the autophagic process and the involvement of autophagy in neurodegenerative diseases.}, }
@article {pmid26568363, year = {2016}, author = {Peña-Altamira, E and Prati, F and Massenzio, F and Virgili, M and Contestabile, A and Bolognesi, ML and Monti, B}, title = {Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation.}, journal = {Expert opinion on therapeutic targets}, volume = {20}, number = {5}, pages = {627-640}, doi = {10.1517/14728222.2016.1121237}, pmid = {26568363}, issn = {1744-7631}, mesh = {Animals ; Anti-Inflammatory Agents/therapeutic use ; Humans ; Immunomodulation ; Microglia/*metabolism ; Neurodegenerative Diseases/metabolism/*therapy ; }, abstract = {INTRODUCTION: The importance of microglia in most neurodegenerative pathologies, from Parkinson's disease to amyotrophic lateral sclerosis and Alzheimer's disease, is increasingly recognized. Until few years ago, microglial activation in pathological conditions was considered dangerous to neurons due to its causing inflammation. Today we know that these glial cells also play a crucial physiological and neuroprotective role, which is altered in neurodegenerative conditions.<br><br>AREAS COVERED: The neuroinflammatory hypothesis for neurodegenerative diseases has led to the trial of anti-inflammatory agents as therapeutics with largely disappointing results. New information about the physiopathological role of microglia has highlighted the importance of immunomodulation as a potential new therapeutic approach. This review summarizes knowledge on microglia as a potential therapeutic target in the most common neurodegenerative diseases, with focus on compounds directed toward the modulation of microglial immune response through specific molecular pathways.<br><br>EXPERT OPINION: Here we support the innovative concept of targeting microglial cells by modulating their activity, rather than simply trying to counteract their inflammatory neurotoxicity, as a potential therapeutic approach for neurodegenerative diseases. The advantage of this therapeutic approach could be to reduce neuroinflammation and toxicity, while at the same time strengthening intrinsic neuroprotective properties of microglia and promoting neuroregeneration.}, }
@article {pmid26563995, year = {2016}, author = {Lennon, MJ and Jones, SP and Lovelace, MD and Guillemin, GJ and Brew, BJ}, title = {Bcl11b: A New Piece to the Complex Puzzle of Amyotrophic Lateral Sclerosis Neuropathogenesis?.}, journal = {Neurotoxicity research}, volume = {29}, number = {2}, pages = {201-207}, pmid = {26563995}, issn = {1476-3524}, mesh = {Amyotrophic Lateral Sclerosis/genetics/immunology/*metabolism/virology ; Animals ; Brain/growth &amp; development/*metabolism ; Encephalitis/genetics/metabolism ; Endogenous Retroviruses/metabolism ; Humans ; Mice ; Motor Neurons/metabolism ; Nerve Regeneration ; Neurons/metabolism ; Repressor Proteins/genetics/*metabolism ; T-Lymphocytes/metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, neurodegenerative disease of the human motor system. The pathogenesis of ALS is a topic of fascinating speculation and experimentation, with theories revolving around intracellular protein inclusions, mitochondrial structural issues, glutamate excitotoxicity and free radical formation. This review explores the rationale for the involvement of a novel protein, B-cell lymphoma/leukaemia 11b (Bcl11b) in ALS. Bcl11b is a multifunctional zinc finger protein transcription factor. It functions as both a transactivator and genetic suppressor, acting both directly, binding to promoter regions, and indirectly, binding to promoter-bound transcription factors. It has essential roles in the differentiation and growth of various cells in the central nervous system, immune system, integumentary system and cardiovascular system, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. It also has various roles in pathology including the suppression of latent retroviruses, thymic tumourigenesis and neurodegeneration. In particular its functions in neurodevelopment, viral latency and T-cell development suggest potential roles in ALS pathology.}, }
@article {pmid26563614, year = {2016}, author = {Hayashi, Y and Homma, K and Ichijo, H}, title = {SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS.}, journal = {Advances in biological regulation}, volume = {60}, number = {}, pages = {95-104}, doi = {10.1016/j.jbior.2015.10.006}, pmid = {26563614}, issn = {2212-4934}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Humans ; Mutation ; Protein Folding ; Superoxide Dismutase-1/chemistry/*genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder that is characterized by the selective death of motor neurons. While the fundamental cause of the disorder is still unclear, the first identified risk gene, Cu,Zn superoxide dismutase (SOD1), has led to the proposal of several mechanisms that are relevant to its pathogenesis. These include excitotoxicity, oxidative stress, ER stress, mitochondrial dysfunction, axonal transport disruption, prion-like propagation, and non-cell autonomous toxicity of neuroglia. Recent evidence suggests that the toxicity of the misfolded wild-type SOD1 (SOD1(WT)) is involved in the pathogenesis of sporadic cases. Yet to what extent SOD1 contributes to neurotoxicity in ALS cases generally is unknown. This review discusses the toxic mechanisms of mutant SOD1 (SOD1(mut)) and misfolded SOD1(WT) in the context of ALS as well as the potential implication of these mechanisms in SOD1 mutation-negative ALS.}, }
@article {pmid26561744, year = {2015}, author = {Properzi, F and Ferroni, E and Poleggi, A and Vinci, R}, title = {The regulation of exosome function in the CNS: implications for neurodegeneration.}, journal = {Swiss medical weekly}, volume = {145}, number = {}, pages = {w14204}, doi = {10.4414/smw.2015.14204}, pmid = {26561744}, issn = {1424-3997}, mesh = {Alzheimer Disease/genetics ; Central Nervous System/*physiopathology ; Exosomes/*genetics ; Humans ; MicroRNAs/*genetics ; Parkinson Disease/genetics ; RNA, Messenger/*genetics ; }, abstract = {Exosomes are nanovesicles, generally 50 to 90 nm in diameter, that correspond to the intraluminal vesicles of the endosomal multivesicular bodies and are secreted upon fusion of multivesicular bodies with the plasma membrane. Their molecular content is highly selected and includes not only specific proteins and lipids, but also RNA species, such as messenger RNAs (mRNAs) and microRNAs (miRNAs), which are delivered and active in target cells. As they are released in body fluids, exosomes can shuttle molecules for long distances. In the CNS they have been shown to regulate neuronal development and regeneration, and to modulate synaptic functions. In neurodegenerative diseases, they have an important role in propagating neurotoxic misfolded protein from one cell to another and, as recent data show, possibly other molecules contributing to neurotoxicity. Some exosomal lipids such as gangliosides GM1 and GM3 enhance the aggregation of alpha-synuclein, and RNA exosomal cargo is also altered during pathologies such as Alzheimer's disease, prion diseases and amyotrophic lateral sclerosis. The aim of this review is to focus on the regulation of CNS exosomal function and highlight pathways that might have a role in the neurodegenerative process. The identification of the novel exosomal molecules involved in neurodegenerative diseases could provide important insights into the pathogenesis and contribute to the finding of novel diagnostic biomarkers and therapeutic approaches.}, }
@article {pmid26558293, year = {2016}, author = {Mazzini, L and Vescovi, A and Cantello, R and Gelati, M and Vercelli, A}, title = {Stem cells therapy for ALS.}, journal = {Expert opinion on biological therapy}, volume = {16}, number = {2}, pages = {187-199}, doi = {10.1517/14712598.2016.1116516}, pmid = {26558293}, issn = {1744-7682}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism/*therapy ; Animals ; Clinical Trials as Topic/methods ; Genetic Therapy/methods/trends ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Neural Stem Cells/transplantation ; Quality of Life ; Stem Cell Transplantation/*methods/trends ; }, abstract = {INTRODUCTION: Despite knowledge on the molecular basis of amyotrophic lateral sclerosis (ALS) having quickly progressed over the last few years, such discoveries have not yet translated into new therapeutics. With the advancement of stem cell technologies there is hope for stem cell therapeutics as novel treatments for ALS.<br><br>AREAS COVERED: We discuss in detail the therapeutic potential of different types of stem cells in preclinical and clinical works. Moreover, we address many open questions in clinical translation.<br><br>EXPERT OPINION: SC therapy is a potentially promising new treatment for ALS and the need to better understand how to develop cell-based experimental treatments, and how to implement them in clinical trials, becomes more pressing. Mesenchymal stem cells and neural fetal stem cells have emerged as safe and potentially effective cell types, but there is a need to carry out appropriately designed experimental studies to verify their long-term safety and possibly efficacy. Moreover, the cost-benefit analysis of the results must take into account the quality of life of the patients as a major end point. It is our opinion that a multicenter international clinical program aime d at fine-tuning and coordinating transplantation procedures and protocols is mandatory.}, }
@article {pmid26557057, year = {2015}, author = {Aulas, A and Vande Velde, C}, title = {Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS?.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {423}, pmid = {26557057}, issn = {1662-5102}, abstract = {Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.}, }
@article {pmid26555807, year = {2016}, author = {Edbauer, D and Haass, C}, title = {An amyloid-like cascade hypothesis for C9orf72 ALS/FTD.}, journal = {Current opinion in neurobiology}, volume = {36}, number = {}, pages = {99-106}, doi = {10.1016/j.conb.2015.10.009}, pmid = {26555807}, issn = {1873-6882}, support = {321366/ERC_/European Research Council/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Atrophy ; Brain/*metabolism/pathology ; C9orf72 Protein ; Cognition Disorders/*genetics/metabolism/pathology ; DNA Repeat Expansion/genetics ; Dipeptides/metabolism ; Frontotemporal Dementia/*genetics/metabolism/pathology ; Humans ; Protein Aggregation, Pathological/*genetics/metabolism/pathology ; Proteins/*genetics ; RNA-Binding Proteins/metabolism ; TDP-43 Proteinopathies/*genetics/metabolism/pathology ; }, abstract = {Expansion of a GGGGCC repeat in C9orf72 causes amyotrophic lateral sclerosis, frontotemporal dementia, or a combination of both. Bidirectional repeat transcripts sequester RNA-binding proteins into nuclear RNA foci. The repeat is translated into dipeptide repeat (DPR) proteins that are crucial for repeat-induced toxicity. DPRs inhibit the proteasome and sequester other proteins. These changes are accompanied by widespread brain atrophy and subclinical cognitive impairment before disease onset. Both repeat RNA and DPRs impair nucleocytoplasmic transport and promote TDP-43 mislocalization and aggregation. Thus, repeat RNA and DPRs may gradually trigger TDP-43 pathology and subsequent region-specific neurodegeneration in a cascade similar to amyloid-β peptide in Alzheimer's disease. The key components of the C9orf72 cascade are promising therapeutic targets in different disease stages.}, }
@article {pmid26551884, year = {2016}, author = {Finsterer, J and Stöllberger, C and Maeztu, C}, title = {Sudden cardiac death in neuromuscular disorders.}, journal = {International journal of cardiology}, volume = {203}, number = {}, pages = {508-515}, doi = {10.1016/j.ijcard.2015.10.176}, pmid = {26551884}, issn = {1874-1754}, mesh = {Austria/epidemiology ; Death, Sudden, Cardiac/*epidemiology/etiology/*prevention &amp; control ; Humans ; Neuromuscular Diseases/*complications ; Risk Assessment ; Risk Factors ; Spain/epidemiology ; }, abstract = {OBJECTIVES: The heart is frequently affected in neuromuscular disorders (NMDs). Some of these patients even experience sudden cardiac death (SCD). In the following review, we summarize recent findings concerning epidemiology, risk stratification, and prevention of SCD in NMDs.<br><br>METHODS: Review of publications about SCD and NMDs by search of MEDLINE applying appropriate search terms.<br><br>RESULTS: NMDs in which SCD was most frequently reported include myotonic dystrophy type 1, mitochondrial disorders, laminopathy, desminopathy, Danon disease, and amyotrophic lateral sclerosis. Risk factors for developing SCD vary considerably between NMDs and include positive family history for SCD, palpitations, arterial hypertension, ECG-abnormalities (bundle branch block, bifascicular block, QT-prolongation, increased QT-variability, early repolarization, T-wave alternans, ventricular tachycardia), late gadolinium enhancement as an equivalent of myocardial fibrosis, and noncompaction. NMD patients at risk for SCD require a thorough history, long-term ECG recordings, and cardiac MRI with contrast medium. In case a propensity for ventricular arrhythmias is documented, implantation of an implantable cardioverter defibrillator should be considered.<br><br>CONCLUSIONS: SCD is the cause of death in various NMDs why these patients need to be thoroughly screened for risk factors of SCD. Verification of risk factors for SCD in NMDs requires appropriate management.}, }
@article {pmid26540641, year = {2015}, author = {Ishiura, H and Tsuji, S}, title = {Epidemiology and molecular mechanism of frontotemporal lobar degeneration/amyotrophic lateral sclerosis with repeat expansion mutation in C9orf72.}, journal = {Journal of neurogenetics}, volume = {29}, number = {2-3}, pages = {85-94}, doi = {10.3109/01677063.2015.1085980}, pmid = {26540641}, issn = {1563-5260}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics ; C9orf72 Protein ; Frontotemporal Lobar Degeneration/epidemiology/*genetics ; Humans ; *Mutation ; Prevalence ; Proteins/*genetics ; }, abstract = {GGGGCC hexanucleotide repeat expansions in C9orf72 were identified in 2011 as the genetic cause of frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS) linked to chromosome 9. Since then, a number of studies have been conducted to delineate the molecular epidemiology of the repeat expansions and the molecular pathophysiology of the disease. The frequency of the repeat expansions considerably varied among countries. The frequency of the repeat expansions was high in European populations and populations of European descent and a substantial proportion of sporadic FTLD or ALS patients also have the mutations in these populations. On the other hand, the frequency was extremely low in Asia or Oceania except for limited regions including Kii Peninsula of Japan. A founder effect seems to strongly influence the regional differences in the frequency, but there is no definitive evidence that supports the notion that the repeat expansions arose in a single founder or multiple founders. As a disease-causing mechanism, several molecular mechanisms have been proposed, including conformational changes of DNA (G-quadruplex formation and hypermethylation) or RNA (G-quadruplex formation) molecules, altered transcriptional levels of C9orf72, sequestration of RNA-binding proteins, bidirectional transcription, formation of RNA foci, and neurotoxicity of dipeptide repeat proteins generated by repeat-associated non-ATG-initiated translation. Further investigations on the molecular mechanisms of neurodegeneration are expected to lead to the development of therapeutic interventions for this disease as well as for other diseases associated with non-coding repeat expansions.}, }
@article {pmid26539077, year = {2015}, author = {Schmitt-John, T}, title = {VPS54 and the wobbler mouse.}, journal = {Frontiers in neuroscience}, volume = {9}, number = {}, pages = {381}, pmid = {26539077}, issn = {1662-4548}, abstract = {The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS). The spontaneous, recessive wobbler mutation causes degeneration of upper and lower motor neurons leading to progressive muscle weakness with striking similarities to the ALS pathology. The wobbler mutation is a point mutation affecting Vps54, a component of the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a ubiquitously expressed Golgi-localized vesicle tethering complex, tethering endosome-derived vesicles to the trans Golgi network. The wobbler point mutation leads to a destabilization of the Vps54 protein and thereby the whole GARP complex. This effectuates impairments of the retrograde vesicle transport, mis-sorting of Golgi- and endosome localized proteins and on the long run defects in Golgi morphology and function. It is currently largely unknown how the destabilization of the GARP complex interferes with the pathological hallmarks, reported for the wobbler motor neuron degeneration, like neurofilament aggregation, axonal transport defects, hyperexcitability, mitochondrial dysfunction, and how these finally lead to motor neuron death. However, the impairments of the retrograde vesicle transport and the Golgi-function appear to be critical phenomena in the molecular pathology of the wobbler motor neuron disease.}, }
@article {pmid26538832, year = {2015}, author = {Brkic, M and Balusu, S and Libert, C and Vandenbroucke, RE}, title = {Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases.}, journal = {Mediators of inflammation}, volume = {2015}, number = {}, pages = {620581}, pmid = {26538832}, issn = {1466-1861}, mesh = {Alzheimer Disease/enzymology ; Amyotrophic Lateral Sclerosis/enzymology ; Animals ; Biomarkers/metabolism ; *Gene Expression Regulation, Enzymologic ; Humans ; Huntington Disease/enzymology ; Inflammation/enzymology ; Matrix Metalloproteinases/*metabolism ; Multiple Sclerosis/enzymology ; Neurodegenerative Diseases/*enzymology ; Neurogenesis ; Parkinson Disease/enzymology ; }, abstract = {Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration of central nervous system (CNS) functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs), a protein family of zinc-containing endopeptidases, are essential in (neuro)inflammation and might be involved in neurodegeneration. Although MMPs are indispensable for physiological development and functioning of the organism, they are often referred to as double-edged swords due to their ability to also inflict substantial damage in various pathological conditions. MMP activity is strictly controlled, and its dysregulation leads to a variety of pathologies. Investigation of their potential use as therapeutic targets requires a better understanding of their contributions to the development of neurodegenerative diseases. Here, we review MMPs and their roles in neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). We also discuss MMP inhibition as a possible therapeutic strategy to treat neurodegenerative diseases.}, }
@article {pmid26538429, year = {2016}, author = {Deshpande, M and Rodal, AA}, title = {The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {17}, number = {2}, pages = {87-101}, doi = {10.1111/tra.12345}, pmid = {26538429}, issn = {1600-0854}, support = {DP2 NS082127/NS/NINDS NIH HHS/United States ; NS60947/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Drosophila/*physiology ; Humans ; Motor Neurons/pathology ; Nervous System Diseases/*physiopathology ; Neuromuscular Junction/physiology ; Protein Transport/*physiology ; Signal Transduction/*physiology ; Synapses/*physiology ; Synaptic Transmission/physiology ; }, abstract = {Neurons require target-derived autocrine and paracrine growth factors to maintain proper identity, innervation, homeostasis and survival. Neuronal growth factor signaling is highly dependent on membrane traffic, both for the packaging and release of the growth factors themselves, and for regulation of intracellular signaling by their transmembrane receptors. Here, we review recent findings from the Drosophila larval neuromuscular junction (NMJ) that illustrate how specific steps of intracellular traffic and inter-organelle interactions impinge on signaling, particularly in the bone morphogenic protein, Wingless and c-Jun-activated kinase pathways, regulating elaboration and stability of NMJ arbors, construction of synapses and synaptic transmission and homeostasis. These membrane trafficking and signaling pathways have been implicated in human motor neuron diseases including amyotrophic lateral sclerosis and hereditary spastic paraplegia, highlighting their importance for neuronal health and survival.}, }
@article {pmid26528186, year = {2015}, author = {Zeineddine, R and Yerbury, JJ}, title = {The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {6}, number = {}, pages = {277}, pmid = {26528186}, issn = {1664-042X}, abstract = {With the onset of the rapidly aging population, the impact of age related neurodegenerative diseases is becoming a predominant health and economic concern. Neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease (CJD), Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) result from the loss of a specific subsets of neurons, which is closely associated with accumulation and deposition of specific protein aggregates. Protein aggregation, or fibril formation, is a well-studied phenomenon that occurs in a nucleation-dependent growth reaction. Recently, there has been a swell of literature implicating protein aggregation and its ability to propagate cell-to-cell in the rapid progression of these diseases. In order for protein aggregation to be kindled in recipient cells it is a requisite that aggregates must be able to be released from one cell and then taken up by others. In this article we will explore the relationship between protein aggregates, their propagation and the role of macropinocytosis in their uptake. We highlight the ability of neurons to undergo stimulated macropinocytosis and identify potential therapeutic targets.}, }
@article {pmid26520433, year = {2015}, author = {Gendelman, HE and Mosley, RL}, title = {A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {10}, number = {4}, pages = {645-650}, pmid = {26520433}, issn = {1557-1904}, support = {R01 NS036126/NS/NINDS NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; P01 DA028555/DA/NIDA NIH HHS/United States ; P30 MH062261/MH/NIMH NIH HHS/United States ; P01 NS031492/NS/NINDS NIH HHS/United States ; P01 NS31492/NS/NINDS NIH HHS/United States ; 2R01 NS034239/NS/NINDS NIH HHS/United States ; P01 MH64570/MH/NIMH NIH HHS/United States ; P01 MH064570/MH/NIMH NIH HHS/United States ; R01 AG043540/AG/NIA NIH HHS/United States ; R01 NS070190/NS/NINDS NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; P01 NS43985/NS/NINDS NIH HHS/United States ; R01 NS36126/NS/NINDS NIH HHS/United States ; }, mesh = {Adaptive Immunity/*immunology ; Alzheimer Disease/*immunology ; Amyotrophic Lateral Sclerosis/*immunology ; Humans ; Immunity, Innate/*immunology ; Parkinson Disease/*immunology ; Stroke/*immunology ; }, abstract = {Aberrant innate and adaptive immune responses are neurodegenerative disease effectors. Disease is heralded by a generalized, but subtle immune activation orchestrated by the release of extracellular prion-like aggregated and oxidized or otherwise modified proteins. These are responsible for an inflammatory neurotoxic cascade. The perpetrators of such events include effector T cells and activated microglia. What ensues are Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis and stroke with changed frequencies of effector T cell and reduced numbers or function of regulatory lymphocytes. The control of such immune responses could lead to new therapeutic strategies and the means to effectively combat a composite of diseases that have quite limited therapeutic options.}, }
@article {pmid26515630, year = {2015}, author = {Katz, JS and Barohn, RJ and Dimachkie, MM and Mitsumoto, H}, title = {The Dilemma of the Clinical Trialist in Amyotrophic Lateral Sclerosis: The Hurdles to Finding a Cure.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {937-947}, doi = {10.1016/j.ncl.2015.07.014}, pmid = {26515630}, issn = {1557-9875}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; *Clinical Trials as Topic/methods ; Humans ; Research Personnel/*psychology ; }, abstract = {Amyotrophic lateral sclerosis can be described as a disease with a poorly understood pathophysiologic mechanism and no treatment that dramatically impacts the course of the disease. Clinical trialists are faced with finding small treatment effects against a background of multiple potential treatments, a past history of failed trials, and heterogenous clinical outcomes. This article summarizes this environment and provides a rationale for drug development going forward.}, }
@article {pmid26515629, year = {2015}, author = {Bedlack, RS and Joyce, N and Carter, GT and Paganoni, S and Karam, C}, title = {Complementary and Alternative Therapies in Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {909-936}, pmid = {26515629}, issn = {1557-9875}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; 2K12HD001097-16/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Complementary Therapies/*methods ; Decision Making ; Humans ; }, abstract = {Given the severity of their illness and lack of effective disease-modifying agents, it is not surprising that most patients with amyotrophic lateral sclerosis (ALS) consider trying complementary and alternative therapies. Some of the most commonly considered alternative therapies include special diets, nutritional supplements, cannabis, acupuncture, chelation, and energy healing. This article reviews these in detail. The authors also describe 3 models by which physicians may frame discussions about alternative therapies: paternalism, autonomy, and shared decision making. Finally, the authors review a program called ALSUntangled, which uses shared decision making to review alternative therapies for ALS.}, }
@article {pmid26515628, year = {2015}, author = {Jackson, CE and McVey, AL and Rudnicki, S and Dimachkie, MM and Barohn, RJ}, title = {Symptom Management and End-of-Life Care in Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {889-908}, pmid = {26515628}, issn = {1557-9875}, support = {UL1 TR000001/TR/NCATS NIH HHS/United States ; UL1TR000001/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*nursing/*therapy ; *Disease Management ; Humans ; Terminal Care ; }, abstract = {The number of available symptomatic treatments has markedly enhanced the care of patients with amyotrophic lateral sclerosis (ALS). Once thought to be untreatable, patients with ALS today clearly benefit from multidisciplinary care. The impact of such care on the disease course, including rate of progression and mortality, has surpassed the treatment effects commonly sought in clinical drug trials. Unfortunately, there are few randomized controlled trials of medications or interventions addressing symptom management. In this review, the authors provide the level of evidence, when available, for each intervention that is currently considered standard of care by consensus opinion.}, }
@article {pmid26515627, year = {2015}, author = {Oskarsson, B and Horton, DK and Mitsumoto, H}, title = {Potential Environmental Factors in Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {877-888}, pmid = {26515627}, issn = {1557-9875}, support = {UL1TR000002/TR/NCATS NIH HHS/United States ; KL2 TR000134/TR/NCATS NIH HHS/United States ; KL2 RR024144/RR/NCRR NIH HHS/United States ; UL1 TR000002/TR/NCATS NIH HHS/United States ; R01 ES 016848-01A2/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Environmental Exposure/*adverse effects ; Female ; Gene-Environment Interaction ; Humans ; Male ; Occupational Exposure/*adverse effects ; Risk Factors ; Sex Characteristics ; Smoking/*adverse effects ; }, abstract = {The causes of amyotrophic lateral sclerosis (ALS) are largely unknown, and may always be multiple, including environmental factors. Monogenetic determinants of ALS are involved in roughly 20% of all cases (including 10% familial cases). Less well understood multigenetic causes may contribute to another 20% to 80%. Environmental factors likely play a role in the development of ALS in susceptible individuals, but proved causation remains elusive. This article discusses the possible factors of male gender (males are selectively exposed to different influences, or genetically predisposed to be susceptible), smoking, military service, exercise, electrical exposure, heavy metals, agricultural chemicals, and geographic clusters.}, }
@article {pmid26515626, year = {2015}, author = {Saberi, S and Stauffer, JE and Schulte, DJ and Ravits, J}, title = {Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {855-876}, pmid = {26515626}, issn = {1557-9875}, support = {R01 NS088578/NS/NINDS NIH HHS/United States ; NS051738/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; C9orf72 Protein ; DNA-Binding Proteins/*genetics ; Genetic Variation/*genetics ; Humans ; Proteins/*genetics ; }, abstract = {The neuropathologic molecular signature common to almost all sporadic amyotrophic lateral sclerosis (ALS) and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathologic and molecular neuropathologic features of ALS variants, primarily lateral sclerosis and progressive muscular atrophy, are less certain but also seem to share the primary features of ALS. Genetic causes, including mutations in SOD1, TDP-43, FUS, and C9orf72, all have distinctive molecular neuropathologic signatures. Neuropathology will continue to play an increasingly key role in solving the puzzle of ALS pathogenesis.}, }
@article {pmid26515623, year = {2015}, author = {Boylan, K}, title = {Familial Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {807-830}, pmid = {26515623}, issn = {1557-9875}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; DNA-Binding Proteins/genetics ; *Family Health ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation/*genetics ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Genes linked to amyotrophic lateral sclerosis (ALS) susceptibility are being identified at an increasing rate owing to advances in molecular genetic technology. Genetic mechanisms in ALS pathogenesis seem to exert major effects in about 10% of patients, but genetic factors at some level may be important components of disease risk in most patients with ALS. Identification of gene variants associated with ALS has informed concepts of the pathogenesis of ALS, aided the identification of therapeutic targets, facilitated research to develop new ALS biomarkers, and supported the establishment of clinical diagnostic tests for ALS-linked genes.}, }
@article {pmid26515622, year = {2015}, author = {Woolley, SC and Strong, MJ}, title = {Frontotemporal Dysfunction and Dementia in Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {787-805}, doi = {10.1016/j.ncl.2015.07.011}, pmid = {26515622}, issn = {1557-9875}, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/*pathology ; Cognition Disorders/*etiology ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*etiology ; Frontotemporal Lobar Degeneration/*etiology ; Humans ; Language Disorders/etiology ; Male ; Middle Aged ; Neuropsychological Tests ; Severity of Illness Index ; tau Proteins/genetics ; }, abstract = {Although amyotrophic lateral sclerosis (ALS) is classically considered a disorder exclusively affecting motor neurons, there is substantial clinical, neuroimaging, and neuropathologic evidence that more than half of patients have an associated syndrome of frontotemporal dysfunction. These syndromes range from frontotemporal dementia to behavioral or cognitive syndromes. Neuroimaging and neuropathologic findings are consistent with frontotemporal lobar degeneration that underpins alterations in network connectivity. Future clinical trials need to be stratified based on the presence or absence of frontotemporal dysfunction on the disease course of ALS.}, }
@article {pmid26515621, year = {2015}, author = {Jawdat, O and Statland, JM and Barohn, RJ and Katz, JS and Dimachkie, MM}, title = {Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis).}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {775-785}, pmid = {26515621}, issn = {1557-9875}, support = {UL1TR000001/TR/NCATS NIH HHS/United States ; TL1 TR000120/TR/NCATS NIH HHS/United States ; T32 NS007338/NS/NINDS NIH HHS/United States ; KL2TR000119/TR/NCATS NIH HHS/United States ; UL1 TR000001/TR/NCATS NIH HHS/United States ; KL2 TR000119/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*classification/*pathology/physiopathology ; Disease Progression ; Humans ; Male ; Neuroimaging ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials.}, }
@article {pmid26515620, year = {2015}, author = {Liewluck, T and Saperstein, DS}, title = {Progressive Muscular Atrophy.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {761-773}, doi = {10.1016/j.ncl.2015.07.005}, pmid = {26515620}, issn = {1557-9875}, mesh = {Diagnosis, Differential ; Disease Management ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Motor Neuron Disease/classification/diagnosis/therapy ; Muscular Atrophy, Spinal/*diagnosis/epidemiology/physiopathology/*therapy ; Neuroimaging ; Severity of Illness Index ; }, abstract = {Progressive muscular atrophy (PMA) is a rare, sporadic, adult-onset motor neuron disease, clinically characterized by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. Subclinical upper motor neuron involvement is identified pathologically, radiologically, and neurophysiologically in a substantial number of patients with PMA. Patients with subclinical upper motor neuron involvement do not fulfill the revised El Escorial criteria to participate in amyotrophic lateral sclerosis clinical trials. Intravenous immunoglobulin therapy is only marginally beneficial in a small subgroup of patients with lower motor neuron syndrome without conduction block.}, }
@article {pmid26515618, year = {2015}, author = {Statland, JM and Barohn, RJ and McVey, AL and Katz, JS and Dimachkie, MM}, title = {Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {735-748}, pmid = {26515618}, issn = {1557-9875}, support = {UL1TR000001/TR/NCATS NIH HHS/United States ; TL1 TR000120/TR/NCATS NIH HHS/United States ; T32 NS007338/NS/NINDS NIH HHS/United States ; KL2TR000119/TR/NCATS NIH HHS/United States ; UL1 TR000001/TR/NCATS NIH HHS/United States ; KL2 TR000119/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/history ; Diagnosis, Differential ; History, 20th Century ; Humans ; Motor Neuron Disease/*classification/history/*physiopathology ; Severity of Illness Index ; }, abstract = {When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS.}, }
@article {pmid26515617, year = {2015}, author = {Katz, JS and Dimachkie, MM and Barohn, RJ}, title = {Amyotrophic Lateral Sclerosis: A Historical Perspective.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {727-734}, doi = {10.1016/j.ncl.2015.07.013}, pmid = {26515617}, issn = {1557-9875}, mesh = {Amyotrophic Lateral Sclerosis/*history/pathology/physiopathology ; History, 19th Century ; History, 20th Century ; Humans ; }, abstract = {This article looks back in time to see where the foundational basis for the understanding of amyotrophic lateral sclerosis originated. This foundation was created primarily in France by Jean-Martin Charcot and his fellow countrymen and disciples, along with key contributions from early clinicians in England and Germany. The early work on amyotrophic lateral sclerosis provides a useful foundation for today's clinicians with respect to tying together genetic and biologic aspects of the disorder that have been discovered over the past few decades.}, }
@article {pmid26514402, year = {2016}, author = {Volonté, C and Apolloni, S and Parisi, C and Amadio, S}, title = {Purinergic contribution to amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {104}, number = {}, pages = {180-193}, doi = {10.1016/j.neuropharm.2015.10.026}, pmid = {26514402}, issn = {1873-7064}, mesh = {Adenosine/metabolism ; Adenosine Triphosphate/metabolism ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Astrocytes/metabolism ; Biomarkers/metabolism ; Brain/metabolism ; Humans ; Microglia/metabolism ; Motor Neurons/metabolism ; Oligodendroglia/metabolism ; Receptors, Purinergic P1/*metabolism ; Receptors, Purinergic P2/*metabolism ; Schwann Cells/metabolism ; Signal Transduction ; }, abstract = {By signalling through purinergic receptors classified as ionotropic P2X (for ATP) and metabotropic P1 (for adenosine) and P2Y (mainly for ADP, UDP, UTP, ATP), the extracellular nucleotides and their metabolic derivatives originated by extracellular activity of several different ectonucleotidases, are involved in the functioning of the nervous system. Here they exert a central role during physiological processes, but also in the precarious balance between beneficial and noxious events. Indeed, in recent years, the dysregulation of extracellular purinergic homeostasis has been correlated to well-characterized acute and chronic neurodegenerative and neuroinflammatory diseases. Among these, we focus our attention on purinergic signalling occurring in amyotrophic lateral sclerosis (ALS), the most common late onset motoneuron disease, characterized by specific loss of motoneurons in brain stem and ventral horns of spinal cord. ALS is a progressive non-cell-autonomous and multifactorial neuroinflammatory disease, whose aetiology and pathological mechanisms are unidentified for most patients and initiate long before any sign or symptom becomes apparent. By combining purinergic with ALS knowledge, in this work we thus present and sustain a novel line of investigation on the purinergic contribution to ALS. In particular, here we recapitulate very early results about P2X4, P2X7 and P2Y6 receptor expression in tissues from ALS animal and cell models and patients, and more recent achievements about purinergic signalling mainly performed in vitro in microglia and lately in astrocytes and motoneurons. We finally highlight how purinergic signalling has progressively evolved up to preclinical trials, to the point of deserving now full consideration with reference to ALS. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.}, }
@article {pmid26505672, year = {2015}, author = {de Boer, AS and Eggan, K}, title = {A perspective on stem cell modeling of amyotrophic lateral sclerosis.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {14}, number = {23}, pages = {3679-3688}, pmid = {26505672}, issn = {1551-4005}, support = {R01NS089742/NS/NINDS NIH HHS/United States ; RC2NS069395/NS/NINDS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Astrocytes/physiology ; *Cell Culture Techniques ; Cell Differentiation ; DNA-Binding Proteins/genetics ; Humans ; Induced Pluripotent Stem Cells ; Microglia/physiology ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vesicular Transport Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis is a complex neurodegenerative disease. Limitations in animal models have impeded progress in studying disease pathology and potential drug discovery. Here, we will review recent advances in the development of stem cell models for the study of ALS. Additionally, we will discuss the progress toward therapeutic development derived from these stem cell based assays.}, }
@article {pmid26502769, year = {2015}, author = {Salameh, JS and Brown, RH and Berry, JD}, title = {Amyotrophic Lateral Sclerosis: Review.}, journal = {Seminars in neurology}, volume = {35}, number = {4}, pages = {469-476}, doi = {10.1055/s-0035-1558984}, pmid = {26502769}, issn = {1098-9021}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting the upper and lower motor neurons. The lifetime risk of developing ALS is estimated at 1:350 for men and 1:500 for women, higher for those who have served in the military. The diagnosis remains clinical with electrodiagnostic support. Alternative diagnoses can usually be ruled out by the use of neuroimaging studies and laboratory evaluation. Perhaps because ALS is a diagnosis of exclusion, there is a substantial delay in diagnosis, upward of 12 months after the onset of symptoms, and most patients see three or more providers in the course of the diagnostic process. Once diagnosed, patients are best medically managed in a multidisciplinary care setting, an approach that has been shown to prolong survival and improve quality of life. Riluzole is the only disease-modifying therapy approved by the Food and Drug Administration, but numerous symptomatic therapies exist. In the past 20 years, ALS has become the focus of intense investigation by a worldwide community of basic scientists, and for clinical investigators the disease is an active area of research, with stem cell therapies, gene therapies, and a host of small molecule agents under investigation at various stages of clinical and preclinical development.}, }
@article {pmid26499115, year = {2015}, author = {Majd, S and Power, JH and Grantham, HJ}, title = {Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways.}, journal = {BMC neuroscience}, volume = {16}, number = {}, pages = {69}, pmid = {26499115}, issn = {1471-2202}, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/*metabolism ; Humans ; Parkinson Disease/*metabolism ; *Protein Folding ; Signal Transduction/*physiology ; alpha-Synuclein/*metabolism ; }, abstract = {Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.}, }
@article {pmid26494454, year = {2016}, author = {Kandimalla, R and Vallamkondu, J and Corgiat, EB and Gill, KD}, title = {Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {139-154}, pmid = {26494454}, issn = {1750-3639}, mesh = {Aluminum/metabolism/*toxicity ; Alzheimer Disease/etiology/*metabolism ; Animals ; Hippocampus/metabolism ; Humans ; }, abstract = {Aluminum is a ubiquitously abundant nonessential element. Aluminum has been associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and dialysis encephalopathy. Many continue to regard aluminum as controversial although increasing evidence supports the implications of aluminum in the pathogenesis of AD. Aluminum causes the accumulation of tau protein and Aβ protein in the brain of experimental animals. Aluminum induces neuronal apoptosis in vivo and in vitro, either by endoplasmic stress from the unfolded protein response, by mitochondrial dysfunction, or a combination of them. Some, people who are exposed chronically to aluminum, either from through water and/or food, have not shown any AD pathology, apparently because their gastrointestinal barrier is more effective. This article is written keeping in mind mechanisms of action of aluminum neurotoxicity with respect to AD.}, }
@article {pmid26487927, year = {2015}, author = {Orsini, M and Oliveira, AB and Nascimento, OJ and Reis, CH and Leite, MA and de Souza, JA and Pupe, C and de Souza, OG and Bastos, VH and de Freitas, MR and Teixeira, S and Bruno, C and Davidovich, E and Smidt, B}, title = {Amyotrophic Lateral Sclerosis: New Perpectives and Update.}, journal = {Neurology international}, volume = {7}, number = {2}, pages = {5885}, pmid = {26487927}, issn = {2035-8385}, abstract = {Amyotrophic lateral sclerosis (ALS), Charcot's disease or Lou Gehrig's disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades - or even one decade - ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion.}, }
@article {pmid26478128, year = {2015}, author = {Veber, D and Scalabrino, G}, title = {Are PrP(C)s involved in some human myelin diseases? Relating experimental studies to human pathology.}, journal = {Journal of the neurological sciences}, volume = {359}, number = {1-2}, pages = {396-403}, doi = {10.1016/j.jns.2015.09.365}, pmid = {26478128}, issn = {1878-5883}, mesh = {Animals ; Humans ; *Leukoencephalopathies/complications/metabolism/pathology ; Myelin Sheath/*pathology ; PrPC Proteins/genetics/*metabolism ; Subacute Combined Degeneration/etiology ; Vitamin B 12/genetics/metabolism ; Vitamin B 12 Deficiency/complications/metabolism/pathology ; }, abstract = {We have experimentally demonstrated that cobalamin (Cbl) deficiency increases normal cellular prion (PrP(C)) levels in rat spinal cord (SC) and cerebrospinal fluid (CSF), and decreases PrP(C)-mRNA levels in rat SC. Repeated intracerebroventricular administrations of anti-octapeptide repeat-PrP(C)-region antibodies to Cbl-deficient (Cbl-D) rats prevent SC myelin lesions, and the administrations of PrP(C)s to otherwise normal rats cause SC white matter lesions similar to those induced by Cbl deficiency. Cbl positively regulates SC PrP(C) synthesis in rat by stimulating the local synthesis of epidermal growth factor (EGF), which also induces the local synthesis of PrP(C)-mRNAs, and downregulating the local synthesis of tumor necrosis factor(TNF)-α, thus preventing local PrP(C) overproduction. We have clinically demonstrated that PrP(C) levels are increased in the CSF of patients with subacute combined degeneration (SCD), unchanged in the CSF of patients with Alzheimer's disease and amyotrophic lateral sclerosis, and decreased in the CSF and SC of patients with multiple sclerosis (MS), regardless of its clinical course. We conclude that SCD (human and experimental) is a neurological disease due to excess PrP(C) without conformational change and aggregation, that the increase in PrP(C) levels in SCD and Cbl-D polyneuropathy and their decrease in MS CNS make them antipodian myelin diseases in terms of quantitative PrP(C) abnormalities, and that these abnormalities are related to myelin damage in the former, and impede myelin repair in the latter.}, }
@article {pmid26477803, year = {2015}, author = {Zhou, J and Sun, J}, title = {Does the gut drive amyotrophic lateral sclerosis progress?.}, journal = {Neurodegenerative disease management}, volume = {5}, number = {5}, pages = {375-378}, doi = {10.2217/nmt.15.38}, pmid = {26477803}, issn = {1758-2032}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; K01 DK075386/DK/NIDDK NIH HHS/United States ; R01DK105118/DK/NIDDK NIH HHS/United States ; R03DK089010/DK/NIDDK NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Animals ; *Disease Progression ; Dysbiosis/*complications ; Humans ; Intestines/*microbiology ; }, }
@article {pmid26473940, year = {2015}, author = {Yang, F and Luo, J}, title = {Endoplasmic Reticulum Stress and Ethanol Neurotoxicity.}, journal = {Biomolecules}, volume = {5}, number = {4}, pages = {2538-2553}, pmid = {26473940}, issn = {2218-273X}, support = {AA015407/AA/NIAAA NIH HHS/United States ; R01 AA015407/AA/NIAAA NIH HHS/United States ; R01 AA017226/AA/NIAAA NIH HHS/United States ; AA017226/AA/NIAAA NIH HHS/United States ; I01 BX001721/BX/BLRD VA/United States ; }, mesh = {Animals ; Endoplasmic Reticulum Stress/*drug effects ; Ethanol/*toxicity ; Humans ; Neurodegenerative Diseases/*chemically induced/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity.}, }
@article {pmid26468157, year = {2016}, author = {Biasiotto, G and Di Lorenzo, D and Archetti, S and Zanella, I}, title = {Iron and Neurodegeneration: Is Ferritinophagy the Link?.}, journal = {Molecular neurobiology}, volume = {53}, number = {8}, pages = {5542-5574}, pmid = {26468157}, issn = {1559-1182}, mesh = {Animals ; *Autophagy ; Brain/metabolism ; Ferritins/*metabolism ; Humans ; Iron/*metabolism ; Mammals/metabolism ; Nerve Degeneration/*metabolism/pathology ; }, abstract = {Mounting evidence indicates that the lysosome-autophagy pathway plays a critical role in iron release from ferritin, the main iron storage cellular protein, hence in the distribution of iron to the cells. The recent identification of nuclear receptor co-activator 4 as the receptor for ferritin delivery to selective autophagy sheds further light on the understanding of the mechanisms underlying this pathway. The emerging view is that iron release from ferritin through the lysosomes is a general mechanism in normal and tumour cells of different tissue origins, but it has not yet been investigated in brain cells. Defects in the lysosome-autophagy pathway are often involved in the pathogenesis of neurodegenerative disorders, and brain iron homeostasis disruption is a hallmark of many of these diseases. However, in most cases, it has not been established whether iron dysregulation is directly involved in the pathogenesis of the diseases or if it is a secondary effect derived from other pathogenic mechanisms. The recent evidence of the crucial involvement of autophagy in cellular iron handling offers new perspectives about the role of iron in neurodegeneration, suggesting that autophagy dysregulation could cause iron dyshomeostasis. In this review, we recapitulate our current knowledge on the routes through which iron is released from ferritin, focusing on the most recent advances. We summarise the current evidence concerning lysosome-autophagy pathway dysfunctions and those of iron metabolism and discuss their potential interconnections in several neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases; amyotrophic lateral sclerosis; and frontotemporal lobar dementia.}, }
@article {pmid26465287, year = {2015}, author = {Souza, PV and Pinto, WB and Chieia, MA and Oliveira, AS}, title = {Clinical and genetic basis of familial amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {73}, number = {12}, pages = {1026-1037}, doi = {10.1590/0004-282X20150161}, pmid = {26465287}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/classification/*genetics ; C9orf72 Protein ; Humans ; Mutation/*genetics ; Proteins/*genetics ; }, abstract = {Amyotrophic lateral sclerosis represents the most common neurodegenerative disease leading to upper and lower motor neuron compromise. Although the vast majority of cases are sporadic, substantial gain has been observed in the knowledge of the genetic forms of the disease, especially of familial forms. There is a direct correlation between the profile of the mutated genes in sporadic and familial forms, highlighting the main role of C9orf72 gene in the clinical forms associated with frontotemporal dementia spectrum. The different genes related to familial and sporadic forms represent an important advance on the pathophysiology of the disease and genetic therapeutic perspectives, such as antisense therapy. The objective of this review is to signal and summarize clinical and genetic data related to familial forms of amyotrophic lateral sclerosis.}, }
@article {pmid26462880, year = {2016}, author = {Murray, L and Butow, PN}, title = {Advance care planning in motor neuron disease: A systematic review.}, journal = {Palliative &amp; supportive care}, volume = {14}, number = {4}, pages = {411-432}, doi = {10.1017/S1478951515001066}, pmid = {26462880}, issn = {1478-9523}, mesh = {Adult ; Advance Care Planning/*organization &amp; administration ; Aged ; Aged, 80 and over ; Caregivers/*psychology ; Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease ; Patient Participation/*psychology ; Qualitative Research ; Terminal Care/*organization &amp; administration ; }, abstract = {OBJECTIVE: Motor neuron disease (MND) is an incurable progressive illness, characterized by incessant deterioration of neuromuscular function. Timely commencement of advance care planning (ACP) may enable patients to participate in future care choices. The present systematic review aimed to summarize what is known about the prevalence, content, patient/caregiver benefits, healthcare professional (HCP) awareness/support, and healthcare outcomes associated with ACP in the MND setting.<br><br>METHOD: Quantitative and qualitative studies were identified through database searches and eligibility assessed by one author and verified by her coauthor. Data extraction and quality assessments against standardized criteria were completed by the two authors.<br><br>RESULTS: Of the 422 studies identified, 16 were included. The research methods generally lacked rigor. Advance directive (AD) prevalence varied considerably across studies. Disease progression was the strongest predictor of AD completion. ACP processes may clarify patients' wishes and promote communication. HCP attitudes or lack of awareness may limit ACP processes. Varying patient preferences may make flexible approaches and timing necessary.<br><br>SIGNIFICANCE OF RESULTS: Important benefits may be associated with ACP in the context of a motor neuron disease (e.g., feelings of control/relief and refusal of unwanted treatments). However, further evidence is required to verify findings and identify optimal streamlined approaches (e.g., use of decision aids) consistent with patients' (and caregivers') needs over time.}, }
@article {pmid26462653, year = {2017}, author = {Lee, S and Huang, EJ}, title = {Modeling ALS and FTD with iPSC-derived neurons.}, journal = {Brain research}, volume = {1656}, number = {}, pages = {88-97}, pmid = {26462653}, issn = {1872-6240}, support = {I01 RX002133/RX/RRD VA/United States ; I21 BX001625/BX/BLRD VA/United States ; R21 OD011915/OD/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Frontotemporal Dementia/genetics/*physiopathology ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Neurons/*physiology ; }, abstract = {Recent advances in genetics and neuropathology support the idea that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD) are two ends of a disease spectrum. Although several animal models have been developed to investigate the pathogenesis and disease progression in ALS and FTD, there are significant limitations that hamper our ability to connect these models with the neurodegenerative processes in human diseases. With the technical breakthrough in reprogramming biology, it is now possible to generate patient-specific induced pluripotent stem cells (iPSCs) and disease-relevant neuron subtypes. This review provides a comprehensive summary of studies that use iPSC-derived neurons to model ALS and FTD. We discuss the unique capabilities of iPSC-derived neurons that capture some key features of ALS and FTD, and underscore their potential roles in drug discovery. There are, however, several critical caveats that require improvements before iPSC-derived neurons can become highly effective disease models. This article is part of a Special Issue entitled SI: Exploiting human neurons.}, }
@article {pmid26459114, year = {2016}, author = {Bartus, RT and Bétourné, A and Basile, A and Peterson, BL and Glass, J and Boulis, NM}, title = {β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS).}, journal = {Neurobiology of disease}, volume = {85}, number = {}, pages = {11-24}, doi = {10.1016/j.nbd.2015.10.006}, pmid = {26459114}, issn = {1095-953X}, mesh = {Administration, Oral ; Adrenergic beta-2 Receptor Agonists/*administration &amp; dosage/adverse effects ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Humans ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need.}, }
@article {pmid26458931, year = {2016}, author = {Marin, B and Logroscino, G and Boumédiene, F and Labrunie, A and Couratier, P and Babron, MC and Leutenegger, AL and Preux, PM and Beghi, E}, title = {Clinical and demographic factors and outcome of amyotrophic lateral sclerosis in relation to population ancestral origin.}, journal = {European journal of epidemiology}, volume = {31}, number = {3}, pages = {229-245}, pmid = {26458931}, issn = {1573-7284}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/ethnology/*genetics/mortality ; Disease Progression ; Ethnicity ; *Genetic Predisposition to Disease ; Humans ; Male ; Phenotype ; Prognosis ; *Racial Groups ; Registries ; Sex Factors ; Survival Rate ; Treatment Outcome ; }, abstract = {BACKGROUND: To review how the phenotype and outcome of amyotrophic lateral sclerosis (ALS) change with variations in population ancestral origin (PAO). Knowledge of how PAO modifies ALS phenotype may provide important insight into the risk factors and pathogenic mechanisms of the disease.<br><br>METHODS: We performed a systematic review and meta-analysis of the literature concerning differences in phenotype and outcome of ALS that relate to PAO.<br><br>RESULTS: A review of 3111 records identified 78 population-based studies. The 40 that were included covered 40 geographical areas in 10 subcontinents. Around 12,700 ALS cases were considered. The results highlight the phenotypic heterogeneity of ALS at time of onset [age, sex ratio (SR), bulbar onset], age at diagnosis, occurrence of comorbidities in the first year after diagnosis, and outcome (survival). Subcontinent is a major explanatory factor for the variability of the ALS phenotype in population-based studies. Some markers of ALS phenotype were homogeneously distributed in western countries (SR, mean age at onset/diagnosis) but their distributions in other subcontinents were remarkably different. Other markers presented variations in European subcontinents (familial ALS, bulbar onset) and in other continents. As a consequence, ALS outcome strongly varied, with a median survival time from onset ranging from 24 months (Northern Europe) to 48 months (Central Asia).<br><br>DISCUSSION: This review sets the scene for a collaborative study involving a wide international consortium to investigate, using a standard methodology, the link between ancestry, environment, and ALS phenotype.}, }
@article {pmid26455341, year = {2016}, author = {Böttcher, C and Priller, J}, title = {Myeloid cell-based therapies in neurological disorders: How far have we come?.}, journal = {Biochimica et biophysica acta}, volume = {1862}, number = {3}, pages = {323-328}, doi = {10.1016/j.bbadis.2015.10.003}, pmid = {26455341}, issn = {0006-3002}, mesh = {Alzheimer Disease/pathology/*therapy ; Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Cell- and Tissue-Based Therapy/methods ; Central Nervous System Diseases/pathology ; Humans ; Multiple Sclerosis/pathology/*therapy ; Myeloid Cells/*transplantation ; }, abstract = {The pathogenesis of neurological disorders such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) is multifactorial and incompletely understood. The development of therapies for these disorders of the central nervous system (CNS) is thus far very challenging. Neuroinflammation is one of the processes that contribute to the pathogenesis of CNS diseases, and therefore represents an important therapeutic target. Myeloid cells derived from the bone marrow are ideal candidates for cell therapy in the CNS as they are capable of targeting the brain and providing neuroprotective and anti-inflammatory effects. In this review, experimental and clinical evidence for the therapeutic potential of myeloid cells in neurological disorders will be discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.}, }
@article {pmid26454200, year = {2016}, author = {Kramerov, AA and Ljubimov, AV}, title = {Stem cell therapies in the treatment of diabetic retinopathy and keratopathy.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {241}, number = {6}, pages = {559-568}, pmid = {26454200}, issn = {1535-3699}, support = {R01 EY013431/EY/NEI NIH HHS/United States ; R01 EY023429/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Biomedical Research/trends ; Corneal Diseases/*therapy ; Diabetic Retinopathy/*therapy ; Disease Models, Animal ; Humans ; Stem Cell Transplantation/*methods ; }, abstract = {Nonproliferative diabetic retinopathy (DR) is characterized by multiple degenerative changes that could be potentially corrected by stem cell therapies. Most studies so far have attempted to alleviate typical abnormalities of early retinopathy, including vascular hyperpermeability, capillary closure and pericyte dropout. Success was reported with adult stem cells (vascular progenitors or adipose stem cells), as well as induced pluripotent stem cells from cord blood. The cells were able to associate with damaged vessels in both pericyte and endothelial lining positions in models of DR and ischemia-reperfusion. In some diabetic models, functional amelioration of vasculature and electroretinograms was noted. Another approach for endogenous progenitor cell therapy is to normalize dysfunctional diabetic bone marrow and residing endothelial progenitors using NO donors, PPAR-δ and -γ agonists, or inhibition of TGF-β. A potentially important strategy would be to reduce neuropathy by stem cell inoculations, either naïve (e.g., paracrine-acting adipose stem cells) or secreting specific neuroprotectants, such as ciliary neurotrophic factor or brain-derived neurotrophic factor that showed benefit in amyotrophic lateral sclerosis and Parkinson's disease. Recent advances in stem cell therapies for diabetic retinal microangiopathy may form the basis of first clinical trials in the near future. Additionally, stem cell therapies may prove beneficial for diabetic corneal disease (diabetic keratopathy) with pronounced epithelial stem cell dysfunction.}, }
@article {pmid26453964, year = {2016}, author = {Fumagalli, M and Lecca, D and Abbracchio, MP}, title = {CNS remyelination as a novel reparative approach to neurodegenerative diseases: The roles of purinergic signaling and the P2Y-like receptor GPR17.}, journal = {Neuropharmacology}, volume = {104}, number = {}, pages = {82-93}, doi = {10.1016/j.neuropharm.2015.10.005}, pmid = {26453964}, issn = {1873-7064}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Cell Differentiation ; Demyelinating Diseases/*metabolism ; Humans ; Myelin Sheath/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oligodendroglia/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Receptors, Purinergic P1/*metabolism ; Receptors, Purinergic P2/*metabolism ; Signal Transduction ; }, abstract = {Oligodendrocytes are the myelin-forming cells in the CNS. They enwrap axons, thus permitting fast impulse transmission and exerting trophic actions on neurons. Demyelination accompanied by neurological deficit is a rather frequent condition that is not only associated with multiple sclerosis but has been also recognized in several other neurodegenerative diseases, including brain trauma and stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Recently, alterations of myelin function have been also reported in neuropsychiatric diseases, like depression and autism. Highly relevant for therapeutic purposes, oligodendrocyte precursor cells (OPCs) still persist in the adult brain and spinal cord. These cells are normally rather quiescent, but under specific circumstances, they can be stimulated to undergo differentiation and generate mature myelinating oligodendrocytes. Thus, approaches aimed at restoring myelin integrity and at fostering a correct oligodendrocyte function are now viewed as novel therapeutic opportunities for both neurodegenerative and neuropsychiatric diseases. Both OPCs and mature oligodendrocytes express purinergic receptors. For some of these receptors, expression is restricted at specific differentiation stages, suggesting key roles in OPCs maturation and myelination. Some of these receptors are altered under demyelinating conditions, suggesting that their dysregulation may contribute to disease development and could represent adequate new targets for remyelinating therapies. Here, we shall describe the current literature available on all these receptors, with special emphasis on the P2Y-like GPR17 receptor, that represents one of the most studied receptor subtypes in these cells. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.}, }
@article {pmid26447127, year = {2015}, author = {McGurk, L and Berson, A and Bonini, NM}, title = {Drosophila as an In Vivo Model for Human Neurodegenerative Disease.}, journal = {Genetics}, volume = {201}, number = {2}, pages = {377-402}, pmid = {26447127}, issn = {1943-2631}, support = {R01 NS078283/NS/NINDS NIH HHS/United States ; R01-NS0736690/NS/NINDS NIH HHS/United States ; R21 NS088370/NS/NINDS NIH HHS/United States ; F32-NS084667/NS/NINDS NIH HHS/United States ; R01-NS078283/NS/NINDS NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; F32 NS084667/NS/NINDS NIH HHS/United States ; R21-NS088370/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Brain/growth &amp; development/*metabolism ; Disease Models, Animal ; Drosophila melanogaster/*genetics ; Humans ; Mice ; Neurodegenerative Diseases/*genetics/pathology ; Peptides/genetics/*metabolism ; }, abstract = {With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research.}, }
@article {pmid26446984, year = {2016}, author = {Holm, IE and Alstrup, AK and Luo, Y}, title = {Genetically modified pig models for neurodegenerative disorders.}, journal = {The Journal of pathology}, volume = {238}, number = {2}, pages = {267-287}, doi = {10.1002/path.4654}, pmid = {26446984}, issn = {1096-9896}, mesh = {Animals ; Animals, Genetically Modified/*genetics ; Behavior, Animal ; Brain/anatomy &amp; histology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; *Disease Models, Animal ; Forecasting ; Humans ; Magnetic Resonance Imaging ; Neurodegenerative Diseases/*genetics ; Nuclear Transfer Techniques ; Positron-Emission Tomography ; Swine/anatomy &amp; histology/*genetics ; Tomography, X-Ray Computed ; }, abstract = {Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions.}, }
@article {pmid26442764, year = {2015}, author = {Toker, L and Agam, G}, title = {Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects.}, journal = {Neuropsychiatric disease and treatment}, volume = {11}, number = {}, pages = {2441-2447}, pmid = {26442764}, issn = {1176-6328}, abstract = {Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson's, Alzheimer's, Huntington's, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, "mitochondrial dysfunction" became more of a cliché than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions.}, }
@article {pmid26442283, year = {2015}, author = {Agrawal, M and Biswas, A}, title = {Molecular diagnostics of neurodegenerative disorders.}, journal = {Frontiers in molecular biosciences}, volume = {2}, number = {}, pages = {54}, pmid = {26442283}, issn = {2296-889X}, abstract = {Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.}, }
@article {pmid26441662, year = {2015}, author = {Kumar, A and Singh, A}, title = {A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions.}, journal = {Frontiers in pharmacology}, volume = {6}, number = {}, pages = {206}, pmid = {26441662}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are intricate in nature because of the involvement of the multiple pathophysiological events including mitochondrial dysfunction, neuroinflammation and oxidative stress. Alzheimer's disease (AD) is a neurodegenerative disease explained by extracellular amyloid β deposits, intracellular neurofibrillary tangles and mitochondrial dysfunction. Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD. Mitochondrial dysfunction involves alterations in mitochondrial respiratory enzyme complex activities, oxidative stress, opening of permeability transition pore, and enhanced apoptosis. Various bioenergetics and antioxidants have been tried or under different investigational phase against AD and other neurodegenerative disorders (Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) because of their complex and multiple site of action. These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified. Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD.}, }
@article {pmid26441521, year = {2015}, author = {Dubey, J and Ratnakaran, N and Koushika, SP}, title = {Neurodegeneration and microtubule dynamics: death by a thousand cuts.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {343}, pmid = {26441521}, issn = {1662-5102}, abstract = {Microtubules form important cytoskeletal structures that play a role in establishing and maintaining neuronal polarity, regulating neuronal morphology, transporting cargo, and scaffolding signaling molecules to form signaling hubs. Within a neuronal cell, microtubules are found to have variable lengths and can be both stable and dynamic. Microtubule associated proteins, post-translational modifications of tubulin subunits, microtubule severing enzymes, and signaling molecules are all known to influence both stable and dynamic pools of microtubules. Microtubule dynamics, the process of interconversion between stable and dynamic pools, and the proportions of these two pools have the potential to influence a wide variety of cellular processes. Reduced microtubule stability has been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and tauopathies like Progressive Supranuclear Palsy. Hyperstable microtubules, as seen in Hereditary Spastic Paraplegia (HSP), also lead to neurodegeneration. Therefore, the ratio of stable and dynamic microtubules is likely to be important for neuronal function and perturbation in microtubule dynamics might contribute to disease progression.}, }
@article {pmid26438189, year = {2015}, author = {Cota, E and Hoyer, LL}, title = {The Candida albicans agglutinin-like sequence family of adhesins: functional insights gained from structural analysis.}, journal = {Future microbiology}, volume = {10}, number = {10}, pages = {1635-1548}, doi = {10.2217/fmb.15.79}, pmid = {26438189}, issn = {1746-0921}, support = {BB/K003887/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; R01 DE14158/DE/NIDCR NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Antigens, Fungal/*chemistry/genetics ; Candida albicans/genetics/*pathogenicity ; Candidiasis/pathology ; Cell Adhesion/*physiology ; Fungal Proteins/*chemistry/genetics ; Humans ; Mating Factor ; Molecular Sequence Data ; Peptides/*metabolism ; }, abstract = {Candida albicans colonizes many host sites suggesting its interaction with diverse ligands. Candida albicans adhesion is mediated by a number of proteins including those in the Als (agglutinin-like sequence) family, which have been studied intensively. The recent solution of the Als binding domain structure ended years of speculation regarding the molecular mechanism for Als adhesive function. Als adhesins bind flexible C termini from a broad collection of proteins, providing the basis for adhesion to various cell types and perhaps for C. albicans broad tissue tropism. Understanding adhesive functions at the molecular level will reveal the sequence of events in C. albicans pathogenesis, from host recognition to complex interactions such as development of polymicrobial biofilms or disseminated disease.}, }
@article {pmid26437251, year = {2015}, author = {Callaghan, BC and Price, RS and Chen, KS and Feldman, EL}, title = {The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.}, journal = {JAMA neurology}, volume = {72}, number = {12}, pages = {1510-1518}, pmid = {26437251}, issn = {2168-6157}, support = {K23 NS079417/NS/NINDS NIH HHS/United States ; DP3 DK094292/DK/NIDDK NIH HHS/United States ; R25 NS089450/NS/NINDS NIH HHS/United States ; R24 DK082841/DK/NIDDK NIH HHS/United States ; K23 NS079417-01/NS/NINDS NIH HHS/United States ; }, mesh = {*Disease Management ; Humans ; Peripheral Nervous System Diseases/*classification/*diagnosis ; *Treatment Outcome ; }, abstract = {IMPORTANCE: Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments.<br><br>OBJECTIVE: To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments.<br><br>EVIDENCE REVIEW: References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment.<br><br>FINDINGS: Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain-Barr&#xe9; syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barr&#xe9; syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking.<br><br>CONCLUSIONS AND RELEVANCE: Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the diagnostic evaluation and provide information on the localization and pathophysiology of nerve injury.}, }
@article {pmid26432396, year = {2016}, author = {Nardone, R and Höller, Y and Taylor, AC and Lochner, P and Tezzon, F and Golaszewski, S and Brigo, F and Trinka, E}, title = {Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis.}, journal = {Zoology (Jena, Germany)}, volume = {119}, number = {1}, pages = {64-73}, doi = {10.1016/j.zool.2015.09.003}, pmid = {26432396}, issn = {1873-2720}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*etiology/genetics/*pathology ; Animals ; *Disease Models, Animal ; *Dogs ; Humans ; Spinal Cord/pathology ; Spinal Cord Diseases/genetics/pathology/veterinary ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS.}, }
@article {pmid26429216, year = {2015}, author = {Simon, NG and Huynh, W and Vucic, S and Talbot, K and Kiernan, MC}, title = {Motor neuron disease: current management and future prospects.}, journal = {Internal medicine journal}, volume = {45}, number = {10}, pages = {1005-1013}, doi = {10.1111/imj.12874}, pmid = {26429216}, issn = {1445-5994}, mesh = {Biomarkers ; C9orf72 Protein ; Clinical Trials as Topic ; Disease Progression ; Exercise ; Humans ; Motor Neuron Disease/*diagnosis/*genetics/*therapy ; Nutritional Support ; Proteins/*genetics ; }, abstract = {Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments.}, }
@article {pmid26425392, year = {2015}, author = {Park, KH}, title = {Mechanisms of Muscle Denervation in Aging: Insights from a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {6}, number = {5}, pages = {380-389}, pmid = {26425392}, issn = {2152-5250}, abstract = {Muscle denervation at the neuromuscular junction (NMJ) is thought to be a contributing factor in age-related muscle weakness. Therefore, understanding the mechanisms that modulate NMJ innervation is a key to developing therapies to combat age-related muscle weakness affecting the elderly. Two mouse models, one lacking the Cu/Zn superoxide dismutase (SOD1) gene and another harboring the transgenic mutant human SOD1 gene, display progressive changes at the NMJ, including muscle endplate fragmentation, nerve terminal sprouting, and denervation. These changes at the NMJ share many of the common features observed in the NMJs of aged mice. In this review, research findings demonstrating the effects of PGC-1α, IGF-1, GDNF, MyoD, myogenin, and miR-206 on NMJ innervation patterns in the G93A SOD1 mice will be highlighted in the context of age-related muscle denervation.}, }
@article {pmid26425343, year = {2015}, author = {Chen, X and Shang, HF}, title = {New developments and future opportunities in biomarkers for amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {4}, number = {}, pages = {17}, pmid = {26425343}, issn = {2047-9158}, abstract = {Modern technology has improved the ability to probe effectively the underlying biology of ALS by examination of genomic, proteomic and physiological changes in patients with ALS, as well as to monitor functional and structural changes during the course of disease. While effective treatments for ALS are lacking, the discovery of sensitive biomarkers to disease activity offers clinicians tools for rapid diagnosis and insights into the pathophysiology of ALS. The ultimate aim is to lessen reliance on clinical measures and survival as trial endpoints and broaden the therapeutic options for patients with this disease.}, }
@article {pmid26423934, year = {2016}, author = {Liu, Y and Deng, W}, title = {Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.}, journal = {Brain research}, volume = {1638}, number = {Pt A}, pages = {30-41}, pmid = {26423934}, issn = {1872-6240}, support = {R01NS061983/NS/NINDS NIH HHS/United States ; R01 NS059043/NS/NINDS NIH HHS/United States ; R01 HD087566/HD/NICHD NIH HHS/United States ; R01 ES015988/ES/NIEHS NIH HHS/United States ; R01 HD091325/HD/NICHD NIH HHS/United States ; DR01ES015988/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/therapy ; Animals ; Cellular Reprogramming ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism/transplantation ; Motor Neurons/*pathology ; Neurodegenerative Diseases/*pathology/therapy ; Pluripotent Stem Cells/*cytology/metabolism/transplantation ; Stem Cell Transplantation/*methods ; }, abstract = {With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control and to complement the iPSC-based approach for ALS disease modeling studies. Much knowledge has been generated from the study of both ALS iPSCs and ESCs. As these methods have advantages and disadvantages that should be balanced on experimental design in order for them to complement one another, combining the diverse methods would help build an expanded knowledge of ALS pathophysiology. The goals are to reverse engineer the human disease using ESCs and iPSCs, generate lineage reporter lines and in vitro disease models, target disease related genes, in order to better understand the molecular and cellular mechanisms of differentiation regulation along neural (neuronal versus glial) lineages, to unravel the pathogenesis of the neurodegenerative disease, and to provide appropriate cell sources for replacement therapy. This article is part of a Special Issue entitled SI: PSC and the brain.}, }
@article {pmid26421849, year = {2015}, author = {Martić-Kehl, MI and Wernery, J and Folkers, G and Schubiger, PA}, title = {Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development--A Systematic Review.}, journal = {PloS one}, volume = {10}, number = {9}, pages = {e0137235}, pmid = {26421849}, issn = {1932-6203}, mesh = {Angiogenesis Inhibitors/*pharmacology/therapeutic use ; Animal Experimentation/*standards ; Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cluster Analysis ; *Drug Discovery ; Drug Evaluation, Preclinical ; Humans ; Neoplasms/drug therapy/pathology ; Neovascularization, Pathologic/drug therapy ; }, abstract = {Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti-angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill prevents publication or experimental license, can help to improve this situation.}, }
@article {pmid26418526, year = {2015}, author = {Tripodoro, VA and De Vito, EL}, title = {What does end stage in neuromuscular diseases mean? Key approach-based transitions.}, journal = {Current opinion in supportive and palliative care}, volume = {9}, number = {4}, pages = {361-368}, doi = {10.1097/SPC.0000000000000172}, pmid = {26418526}, issn = {1751-4266}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Dyspnea/therapy ; Hospice Care/organization &amp; administration ; Humans ; Life Support Care/organization &amp; administration ; Neuromuscular Diseases/classification/*therapy ; Nutritional Support ; Palliative Care/organization &amp; administration ; Patient Care Planning/organization &amp; administration ; Respiration, Artificial/methods ; Terminal Care/methods/*organization &amp; administration ; }, abstract = {PURPOSE OF REVIEW: To revise the definition of end stage in the setting of neuromuscular disease (NMD), to understand the implications for the patient, family and healthcare team, and to address the obstacles involved in the lack of definition.<br><br>RECENT FINDINGS: Unlike several conditions such as cancer, kidney or liver disease, the literature reveals no clear definition or categorization for NMD. Many articles mention end stage without defining it. Many years ago an expert consensus panel defined it based on functional criteria (forced vital capacity values and hypercapnic events). Only for amyotrophic lateral sclerosis/motoneurone disease has a wider criteria been proposed. As a consequence, the management of this heterogeneous group of disorders is often fragmented compared with the well organized palliative care program for cancer patients.<br><br>SUMMARY: Better end-stage NMD definitions should help to identify the goals of care, but a broad range in time and intensity of deterioration make a valid definition difficult for end-stage NMD. Respiratory care, life-prolonging therapies, and structured care planning should be seen as complementary rather than dichotomous. This article emphasized the relevance of an integrated approach through the whole trajectories of NMD patients considering key transitions.}, }
@article {pmid26415220, year = {2015}, author = {Wang, DW and Peng, ZJ and Ren, GF and Wang, GX}, title = {The different roles of selective autophagic protein degradation in mammalian cells.}, journal = {Oncotarget}, volume = {6}, number = {35}, pages = {37098-37116}, pmid = {26415220}, issn = {1949-2553}, mesh = {Animals ; *Autophagy ; Humans ; Molecular Chaperones/*metabolism ; *Protein Processing, Post-Translational ; *Proteolysis ; }, abstract = {Autophagy is an intracellular pathway for bulk protein degradation and the removal of damaged organelles by lysosomes. Autophagy was previously thought to be unselective; however, studies have increasingly confirmed that autophagy-mediated protein degradation is highly regulated. Abnormal autophagic protein degradation has been associated with multiple human diseases such as cancer, neurological disability and cardiovascular disease; therefore, further elucidation of protein degradation by autophagy may be beneficial for protein-based clinical therapies. Macroautophagy and chaperone-mediated autophagy (CMA) can both participate in selective protein degradation in mammalian cells, but the process is quite different in each case. Here, we summarize the various types of macroautophagy and CMA involved in determining protein degradation. For this summary, we divide the autophagic protein degradation pathways into four categories: the post-translational modification dependent and independent CMA pathways and the ubiquitin dependent and independent macroautophagy pathways, and describe how some non-canonical pathways and modifications such as phosphorylation, acetylation and arginylation can influence protein degradation by the autophagy lysosome system (ALS). Finally, we comment on why autophagy can serve as either diagnostics or therapeutic targets in different human diseases.}, }
@article {pmid26410029, year = {2015}, author = {Buratti, E}, title = {Functional Significance of TDP-43 Mutations in Disease.}, journal = {Advances in genetics}, volume = {91}, number = {}, pages = {1-53}, doi = {10.1016/bs.adgen.2015.07.001}, pmid = {26410029}, issn = {0065-2660}, mesh = {Animals ; DNA-Binding Proteins/chemistry/*genetics/*metabolism ; Humans ; *Mutation ; Neurodegenerative Diseases/*genetics/metabolism ; }, abstract = {At present, there are very few therapeutic options for patients affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, almost all patients affected by ALS or tau-negative FTD share in their brains the presence of aggregated TDP-43, a nuclear factor that plays an important role in regulating RNA metabolism. For this reason, this protein represents a very promising target to develop novel therapeutic options. Over the years, these options have mostly involved the search for new effectors capable of reducing aberrant aggregation or enhancing its clearance by UPS-dependent protein quality control or autophagy system. Targeting eventual mutations in the sequence of this protein might represent a parallel alternative therapeutic option. To this date, the study of various patient populations has allowed to find more than 50 mutations associated with disease. It is, therefore, important to better understand what the functional consequences of these mutations are. As discussed in this review, the emerging picture is that most TDP-43 mutations appear to directly relate to specific disease features such as increased aggregation, half-life, or altered cellular localization and protein-protein interactions.}, }
@article {pmid26409694, year = {2015}, author = {Fried-Oken, M and Mooney, A and Peters, B}, title = {Supporting communication for patients with neurodegenerative disease.}, journal = {NeuroRehabilitation}, volume = {37}, number = {1}, pages = {69-87}, pmid = {26409694}, issn = {1878-6448}, support = {R01 DC009834/DC/NIDCD NIH HHS/United States ; R21 DC014099/DC/NIDCD NIH HHS/United States ; }, mesh = {*Communication Aids for Disabled ; Humans ; Neurodegenerative Diseases/psychology/*rehabilitation ; Speech Therapy/instrumentation/*methods ; }, abstract = {BACKGROUND: Communication supports, referred to as augmentative and alternative communication (AAC), are an integral part of medical speech-language pathology practice, yet many providers remain unfamiliar with assessment and intervention principles. For patients with complex communication impairments secondary to neurodegenerative disease, AAC services differ depending on whether their condition primarily affects speech and motor skills (ALS), language (primary progressive aphasia) or cognition (Alzheimer's disease). This review discusses symptom management for these three conditions, identifying behavioral strategies, low- and high-tech solutions for implementation during the natural course of disease. These AAC principles apply to all neurodegenerative diseases in which common symptoms appear.<br><br>OBJECTIVES: To present AAC interventions for patients with neurodegenerative diseases affecting speech, motor, language and cognitive domains. Three themes emerge: (1) timing of intervention: early referral, regular re-evaluations and continual treatment are essential; (2) communication partners must be included from the onset to establish AAC acceptance and use; and (3) strategies will change over time and use multiple modalities to capitalize on patients' strengths.<br><br>CONCLUSIONS: AAC should be standard practice for adults with neurodegenerative disease. Patients can maintain effective, functional communication with AAC supports. Individualized communication systems can be implemented ensuring patients remain active participants in daily activities.}, }
@article {pmid26409693, year = {2015}, author = {Paganoni, S and Karam, C and Joyce, N and Bedlack, R and Carter, GT}, title = {Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis.}, journal = {NeuroRehabilitation}, volume = {37}, number = {1}, pages = {53-68}, pmid = {26409693}, issn = {1878-6448}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; }, mesh = {Activities of Daily Living ; Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/psychology/*rehabilitation/therapy ; Animals ; Humans ; Quality of Life ; Terminal Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a neurodegenerative disease that results in progressive muscle weakness and wasting. There is no known cure and the disease is uniformly fatal.<br><br>PURPOSE: This review discusses current concepts in ALS care, from breaking the diagnosis to end-of-life care. People with ALS have several multidisciplinary needs due to a complex and dynamic disease process. They benefit from rehabilitation interventions that are individualized and have the goal of optimizing independence, function, and safety. These strategies also help minimize symptomatic burden and maximize quality of life.<br><br>CONCLUSION: Patient-centered, multidisciplinary care has a significant impact on the life of people with ALS and is the current standard of care for this patient population.}, }
@article {pmid26408162, year = {2015}, author = {Pryce, G and Baker, D}, title = {Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.}, journal = {Handbook of experimental pharmacology}, volume = {231}, number = {}, pages = {213-231}, doi = {10.1007/978-3-319-20825-1_7}, pmid = {26408162}, issn = {0171-2004}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/physiopathology ; Animals ; Central Nervous System/drug effects/*metabolism/physiopathology ; Disability Evaluation ; Disease Models, Animal ; Endocannabinoids/*metabolism/therapeutic use ; Humans ; Multiple Sclerosis/drug therapy/*metabolism/physiopathology ; Prognosis ; Receptor, Cannabinoid, CB1/metabolism ; Receptor, Cannabinoid, CB2/metabolism ; Signal Transduction ; }, abstract = {There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.}, }
@article {pmid26402105, year = {2015}, author = {Karnati, HK and Panigrahi, MK and Gutti, RK and Greig, NH and Tamargo, IA}, title = {miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {48}, number = {3}, pages = {563-580}, pmid = {26402105}, issn = {1875-8908}, support = {ZIA AG000311-15//Intramural NIH HHS/United States ; }, mesh = {Animals ; Anticonvulsants/pharmacology/therapeutic use ; Epilepsy/drug therapy/*metabolism ; Humans ; MicroRNAs/agonists/antagonists &amp; inhibitors/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {MicroRNAs (miRNAs) are endogenous, ∼22 nucleotide, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. miRNA dysregulation has been observed in cancer and in neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and the neurological disorder, epilepsy. Neuronal degradation and death are important hallmarks of neurodegenerative disorders. Additionally, abnormalities in metabolism, synapsis and axonal transport have been associated with Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. A number of recently published studies have demonstrated the importance of miRNAs in the nervous system and have contributed to the growing body of evidence on miRNA dysregulation in neurological disorders. Knowledge of the expressions and activities of such miRNAs may aid in the development of novel therapeutics. In this review, we discuss the significance of miRNA dysregulation in the development of neurodegenerative disorders and the use of miRNAs as targets for therapeutic intervention.}, }
@article {pmid26398431, year = {2015}, author = {Solovyev, ND}, title = {Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signalling.}, journal = {Journal of inorganic biochemistry}, volume = {153}, number = {}, pages = {1-12}, doi = {10.1016/j.jinorgbio.2015.09.003}, pmid = {26398431}, issn = {1873-3344}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Antioxidants/*metabolism ; Brain/*metabolism/pathology ; Glutathione Peroxidase/metabolism ; Humans ; Huntington Disease/pathology ; Mice ; Neurons/*metabolism/pathology ; Neuroprotection ; Parkinson Disease/pathology ; Rats ; Schizophrenia/pathology ; Selenium/*metabolism ; Selenoproteins/*metabolism ; Synaptic Transmission ; }, abstract = {Multiple biological functions of selenium manifest themselves mainly via 25 selenoproteins that have selenocysteine at their active centre. Selenium is vital for the brain and seems to participate in the pathology of disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and epilepsy. Since selenium was shown to be involved in diverse functions of the central nervous system, such as motor performance, coordination, memory and cognition, a possible role of selenium and selenoproteins in brain signalling pathways may be assumed. The aim of the present review is to analyse possible relations between selenium and neurotransmission. Selenoproteins seem to be of special importance in the development and functioning of GABAergic (GABA, γ-aminobutyric acid) parvalbumin positive interneurons of the cerebral cortex and hippocampus. Dopamine pathway might be also selenium dependent as selenium shows neuroprotection in the nigrostriatal pathway and also exerts toxicity towards dopaminergic neurons under higher concentrations. Recent findings also point to acetylcholine neurotransmission involvement. The role of selenium and selenoproteins in neurotransmission might not only be limited to their antioxidant properties but also to inflammation, influencing protein phosphorylation and ion channels, alteration of calcium homeostasis and brain cholesterol metabolism. Moreover, a direct signalling function was proposed for selenoprotein P through interaction with post-synaptic apoliprotein E receptors 2 (ApoER2).}, }
@article {pmid26389734, year = {2015}, author = {Wootla, B and Watzlawik, JO and Warrington, AE and Wittenberg, NJ and Denic, A and Xu, X and Jordan, LR and Papke, LM and Zoecklein, LJ and Pierce, ML and Oh, SH and Kantarci, OH and Rodriguez, M}, title = {Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases.}, journal = {JAMA neurology}, volume = {72}, number = {11}, pages = {1346-1353}, doi = {10.1001/jamaneurol.2015.2188}, pmid = {26389734}, issn = {2168-6157}, support = {R01 GM092993/GM/NIGMS NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Monoclonal/*therapeutic use ; Humans ; Immunoglobulin Isotypes/*immunology ; Nervous System Diseases/*drug therapy/immunology ; Recombinant Proteins/*therapeutic use ; }, abstract = {IMPORTANCE: Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases.<br><br>OBJECTIVE: To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.<br><br>EVIDENCE REVIEW: Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis.<br><br>FINDINGS: Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis.<br><br>CONCLUSIONS AND RELEVANCE: Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.}, }
@article {pmid26388731, year = {2015}, author = {Ruffoli, R and Bartalucci, A and Frati, A and Fornai, F}, title = {Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {341}, pmid = {26388731}, issn = {1662-5102}, abstract = {The key role of mitochondria in patients affected by amyotrophic lateral sclerosis (ALS) is well documented by electron microscopy studies of motor neurons within spinal cord and brainstem. Nonetheless, recent studies challenged the role of mitochondria placed within the cell body of motor neuron. In fact, it was demonstrated that, despite preservation of mitochondria placed within this compartment, there is no increase in the lifespan of transgenic mouse models of ALS. Thus, the present mini-review comments on morphological findings of mitochondrial alterations in ALS patients in connection with novel findings about mitochondrial dynamics within various compartments of motor neurons. The latter issue was recently investigated in relationship with altered calcium homeostasis and autophagy, which affect mitochondria in ALS. In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons. This might explain why specific compartments of motor neurons possess different thresholds to mitochondrial damage. In particular, it appears that motor axons represent the most sensitive compartment which undergoes the earliest and most severe alterations in the course of ALS. It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis. On the other hand, mitochondrial homeostasis strongly relies on calcium handling, the removal of altered mitochondria through the autophagy flux (mitophagy) and the biogenesis of novel mitochondria (mitochondriogenesis). Thus, recent findings related to altered calcium storage and impaired autophagy flux in ALS may help to understand the occurrence of mitochondrial alterations as a hallmark in ALS patients. At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.}, }
@article {pmid26381230, year = {2016}, author = {Fang, X}, title = {Potential role of gut microbiota and tissue barriers in Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {The International journal of neuroscience}, volume = {126}, number = {9}, pages = {771-776}, doi = {10.3109/00207454.2015.1096271}, pmid = {26381230}, issn = {1563-5279}, mesh = {Amyotrophic Lateral Sclerosis/*microbiology ; *Gastrointestinal Microbiome ; Humans ; Parkinson Disease/*microbiology ; }, abstract = {Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with pathophysiology that may be related to the gastrointestinal tract. It is well established that tissue barriers maintain homeostasis and health. Furthermore, gut microbiota may have an impact on brain activity through the gut-microbiota-brain axis under both physiological and pathological conditions. In this review, we highlight the current knowledge regarding the role of gut microbiota and tissue barriers in PD and ALS. To our knowledge, this is the first review of the key issues involving both the altered gut microbiota and impaired tissue barriers in the pathophysiology of PD and ALS.}, }
@article {pmid26379505, year = {2015}, author = {Tafuri, F and Ronchi, D and Magri, F and Comi, GP and Corti, S}, title = {SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {336}, pmid = {26379505}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease presenting as sporadic (sALS) or familial (fALS) forms. Even if the list of the genes underlining ALS greatly expanded, defects in superoxide dismutase 1 (SOD1), encoding the copper/zinc SOD1, still remain a major cause of fALS and are likely involved also in apparently sporadic presentations. The pathogenesis of ALS is still unknown, but several lines of evidence indicate that the mitochondrial accumulation of mutant SOD1 is an important mechanism of mitochondrial dysfunction, leading to motor neuron pathology and death. The intramitochondrial localization of mutant SOD1 is debated. Mutant SOD1 might accumulate inside the intermembrane space (IMS), overriding the physiological retention regulated by the copper chaperone for superoxide dismutase (CCS). On the other hand, misfolded SOD1 might deposit onto the outer mitochondrial membrane (OMM), clumping the transport across mitochondrial membranes and engaging mitochondrial-dependent cell apoptosis. The elucidation of the mechanisms ruling SOD1 localization and misplacing might shed light on peculiar ALS features such as cell selectivity and late onset. More importantly, these studies might disclose novel targets for therapeutic intervention in familial ALS as well as non-genetic forms. Finally, pharmacological or genetic manipulation aimed to prevent or counteract the intracellular shifting of mutant SOD1 could be effective for other neurodegenerative disorders featuring the toxic accumulation of misfolded proteins.}, }
@article {pmid26373655, year = {2016}, author = {Schipper, LJ and Raaphorst, J and Aronica, E and Baas, F and de Haan, R and de Visser, M and Troost, D}, title = {Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review.}, journal = {Neuropathology and applied neurobiology}, volume = {42}, number = {6}, pages = {547-560}, doi = {10.1111/nan.12284}, pmid = {26373655}, issn = {1365-2990}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Brain/*pathology ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; DNA-Binding Proteins/metabolism ; Female ; Frontotemporal Dementia/genetics/*pathology ; Humans ; Inclusion Bodies/*pathology ; Male ; Middle Aged ; RNA-Binding Proteins/metabolism ; Spinal Cord/*pathology ; }, abstract = {AIM: The current literature shows no consensus on the localization and number of characteristic neuronal inclusions [p62 and dipeptide repeat proteins (DRPs) positive, TDP-43-negative and TDP-43 positive] in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small sample sizes. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists.<br><br>METHODS: We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD.<br><br>RESULTS: In the cerebellum and hippocampus, the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCIs; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared with p62 inclusion density in these regions. The pooled prevalence rate of TDP-43 NCI in the substantia nigra was high (94.4%).<br><br>DISCUSSION: The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.}, }
@article {pmid26365142, year = {2015}, author = {Gazulla, J and Ruiz-Gazulla, C and Tintore, M}, title = {GABAergic Pharmacotherapy in the Treatment of Motor Disorders of the Central Nervous System.}, journal = {Current pharmaceutical design}, volume = {21}, number = {34}, pages = {4989-4995}, doi = {10.2174/1381612821666150914120923}, pmid = {26365142}, issn = {1873-4286}, mesh = {Adult ; Animals ; Central Nervous System Diseases/*drug therapy/physiopathology ; Cerebellar Ataxia/drug therapy/physiopathology ; GABA Agents/pharmacology/therapeutic use ; Humans ; Motor Disorders/*drug therapy/physiopathology ; Neurotransmitter Agents/metabolism ; Purkinje Cells/metabolism ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and diseases that associate a deficiency in GABA might benefit from GABAergic drugs. Cerebellar Purkinje cells employ GABA as a neurotransmitter. Cortical cerebellar atrophy (CCA) shows Purkinje cell loss, and ataxia caused by it was alleviated by gabapentin and pregabalin. Thus, CCA is proposed as a model of selective deficiency in GABA in the cerebellum, which benefits clinically from administration of GABAergic drugs, in a manner similar in which levodopa improves motor manifestations in Parkinson's disease. Other ataxias also benefited clinically from GABAergic drugs, as adult-onset GM2 gangliosidosis, olivopontocerebellar atrophy, cerebellar ataxia with hypogonadism, spinocerebellar ataxias 1, 2 and 6, and adult-onset ataxia-telangiectasia. Complex neurochemical diseases, as multiple-system atrophy, had ataxia worsened by GABAergic drugs. Various disorders with a deficiency in GABA content had their manifestations relieved by admistration of GABAergic drugs, as one patient with progressive encephalomyelitis with rigidity, whose muscular spasms were suppressed by a combination of gabapentin and tiagabine, and another with diaphragmatic myoclonus, who required gabapentin and tiagabine for symptomatic control. On the contrary, GABAergic drugs were not effective in cervical dystonia, amyotrophic lateral sclerosis, Parkinson's disease and progressive supranuclear palsy, presumably because a deficiency in GABA is not an essential neurochemical abnormality in these diseases. Research aimed at identifying effective therapies to treat cerebellar ataxias and other motor disorders of the central nervous system is warranted. Meanwhile, therapeutic tests with GABAergic drugs might yield clinical improvement in these diseases.}, }
@article {pmid26358892, year = {2015}, author = {Ibáñez, C and Cifuentes, A and Simó, C}, title = {Recent advances and applications of metabolomics to investigate neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {122}, number = {}, pages = {95-132}, doi = {10.1016/bs.irn.2015.05.015}, pmid = {26358892}, issn = {2162-5514}, mesh = {Biomarkers/metabolism ; Humans ; *Metabolomics ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Metabolomics is gaining an important role in the investigation of neurological pathologies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis which are characterized by the absence of reliable diagnostic markers. The magnitude of emotional, physical, and financial burden related to these three devastating pathologies can be deduced considering that nearly 20 million people worldwide suffer from these three pathologies. In this chapter, an overview of the recent advances and applications of metabolomics to investigate these major neurodegenerative diseases will be presented. Metabolomics strategies are now being developed to map potential perturbations in biochemical pathways linked to neurodegeneration. Going further, there is more and more evidence supporting the concept that these pathologies can begin years or even decades before the onset of clinical symptoms, and thus, metabolomics is also increasingly being used to discover preclinical biomarkers of these neurological diseases.}, }
@article {pmid26358890, year = {2015}, author = {Botas, A and Campbell, HM and Han, X and Maletic-Savatic, M}, title = {Metabolomics of neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {122}, number = {}, pages = {53-80}, doi = {10.1016/bs.irn.2015.05.006}, pmid = {26358890}, issn = {2162-5514}, support = {P30HD024064/HD/NICHD NIH HHS/United States ; }, mesh = {Biomarkers/metabolism ; Brain/*metabolism/pathology ; Humans ; *Metabolomics ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Neurodegenerative diseases are progressive, devastating, and terminal, carrying both personal and societal burden. Currently, their diagnosis depends on their clinical presentation. No quantitative biomarkers exist to enable early verdict and commencement of therapy. The lack of diagnostic biomarkers stems from the unavailability of brain tissue, the complexity and heterogeneity of the brain and neurodegenerative pathology, and the fact that peripheral tissues such as blood, urine, and even cerebrospinal fluid might not reflect early stages of brain pathology. Moreover, accumulated evidence indicates the majority of these diseases are not genetically inherited; rather, the genes bring about the risk to develop them, but the trigger is not known. As metabolites are at the intersection between the genetic background of a cell or a tissue and the environmental effects on the same, metabolomics has emerged as a field with great promise to deliver new, biologically, and clinically relevant biomarkers for neurodegenerative disorders. Here, we review the basic principles of metabolomics and focus on studies performed in most common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, Multiple sclerosis, and Amyotrophic lateral sclerosis.}, }
@article {pmid26356410, year = {2015}, author = {Pradat, PF and Kabashi, E and Desnuelle, C}, title = {Deciphering spreading mechanisms in amyotrophic lateral sclerosis: clinical evidence and potential molecular processes.}, journal = {Current opinion in neurology}, volume = {28}, number = {5}, pages = {455-461}, doi = {10.1097/WCO.0000000000000239}, pmid = {26356410}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; Animals ; Humans ; }, abstract = {PURPOSE OF REVIEW: The aim of this review is to refer to recent arguments supporting the existence of specific propagation mechanisms associated with spreading of neuron injury in amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: Misfolded ALS-linked protein accumulation can induce aggregation of their native equivalent isoforms through a mechanism analogous to the infectious prion proteins initiation and its propagation.<br><br>SUMMARY: Although ALS is clinically heterogeneous, a shared characteristic is the focal onset and the progressive extension to all body regions. Being viewed until now as just summation of the increased number of affected neurons, dispersion is now rather considered as the result of a seeded self-propagating process. A sequential regional spreading pattern is supported by the distribution of TDP-43 aggregates in ALS autopsy cases. Electrophysiology and advanced neuroimaging methods also recently provided some evidence for propagation of lesions both in the brain and spinal cord, more longitudinal studies being still needed. Lesions are supposed to spread cell-to-cell regionally or through connected neuronal pathway. At the molecular level, the prion-like spreading is an emerging mechanism hypothesis, but other machineries such as those that are in charge of dealing with misfolded proteins and secretion of deleterious peptides may be involved in the propagation of neuron loss. Deciphering the mechanisms underlying spreading of ALS symptoms is of crucial importance to better understand this neurodegenerative disease, build new and appropriate animal models and to define novel therapeutic targets.}, }
@article {pmid26352357, year = {2015}, author = {Conway, ME and Lee, C}, title = {The redox switch that regulates molecular chaperones.}, journal = {Biomolecular concepts}, volume = {6}, number = {4}, pages = {269-284}, doi = {10.1515/bmc-2015-0015}, pmid = {26352357}, issn = {1868-503X}, mesh = {Animals ; Disulfides/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Molecular Chaperones/*metabolism ; Neurodegenerative Diseases/metabolism ; Oxidation-Reduction ; Peroxiredoxins/chemistry/*metabolism ; Protein Disulfide-Isomerases/*metabolism ; Protein Folding ; Transaminases/*metabolism ; }, abstract = {Modification of reactive cysteine residues plays an integral role in redox-regulated reactions. Oxidation of thiolate anions to sulphenic acid can result in disulphide bond formation, or overoxidation to sulphonic acid, representing reversible and irreversible endpoints of cysteine oxidation, respectively. The antioxidant systems of the cell, including the thioredoxin and glutaredoxin systems, aim to prevent these higher and irreversible oxidation states. This is important as these redox transitions have numerous roles in regulating the structure/function relationship of proteins. Proteins with redox-active switches as described for peroxiredoxin (Prx) and protein disulphide isomerase (PDI) can undergo dynamic structural rearrangement resulting in a gain of function. For Prx, transition from cysteine sulphenic acid to sulphinic acid is described as an adaptive response during increased cellular stress causing Prx to form higher molecular weight aggregates, switching its role from antioxidant to molecular chaperone. Evidence in support of PDI as a redox-regulated chaperone is also gaining impetus, where oxidation of the redox-active CXXC regions causes a structural change, exposing its hydrophobic region, facilitating polypeptide folding. In this review, we will focus on these two chaperones that are directly regulated through thiol-disulphide exchange and detail how these redox-induced switches allow for dual activity. Moreover, we will introduce a new role for a metabolic protein, the branched-chain aminotransferase, and discuss how it shares common mechanistic features with these well-documented chaperones. Together, the physiological importance of the redox regulation of these proteins under pathological conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis will be discussed to illustrate the impact and importance of correct folding and chaperone-mediated activity.}, }
@article {pmid26352199, year = {2016}, author = {Gupta, R and Sen, N}, title = {Traumatic brain injury: a risk factor for neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {27}, number = {1}, pages = {93-100}, doi = {10.1515/revneuro-2015-0017}, pmid = {26352199}, issn = {2191-0200}, support = {R01 EY025622/EY/NEI NIH HHS/United States ; R01 NS094516/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/epidemiology/*etiology/metabolism ; Amyotrophic Lateral Sclerosis/epidemiology/*etiology/metabolism ; Animals ; Brain Injuries/*complications/metabolism ; Humans ; }, abstract = {Traumatic brain injury (TBI), a major global health and socioeconomic problem, is now established as a chronic disease process with a broad spectrum of pathophysiological symptoms followed by long-term disabilities. It triggers multiple and multidirectional biochemical events that lead to neurodegeneration and cognitive impairment. Recent studies have presented strong evidence that patients with TBI history have a tendency to develop proteinopathy, which is the pathophysiological feature of neurodegenerative disorders such as Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). This review mainly focuses on mechanisms related to AD, CTE, and ALS that are induced after TBI and their relevance to the advancement of these neurodegenerative diseases. This review encompasses acute effects and chronic neurodegenerative consequences after TBI for a better understanding of TBI-induced neuronal death and to design therapies that will effectively treat patients in the primary or secondary progressive stages.}, }
@article {pmid26347879, year = {2015}, author = {Quansah, E and Karikari, TK}, title = {Motor Neuron Diseases in Sub-Saharan Africa: The Need for More Population-Based Studies.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {298409}, pmid = {26347879}, issn = {2314-6141}, mesh = {Animals ; *Disease Models, Animal ; Glaucoma/*metabolism/*pathology ; Humans ; }, abstract = {Motor neuron diseases (MNDs) are devastating neurological diseases that are characterised by gradual degeneration and death of motor neurons. Major types of MNDs include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). These diseases are incurable, with limited disease-modifying treatment options. In order to improve MND-based biomedical research, drug development, and clinical care, population-based studies will be important. These studies, especially among less-studied populations, might identify novel factors controlling disease susceptibility and resistance. To evaluate progress in MND research in Africa, we examined the published literature on MNDs in Sub-Saharan Africa to identify disease prevalence, genetic factors, and other risk factors. Our findings indicate that the amount of research evidence on MNDs in Sub-Saharan Africa is scanty; molecular and genetics-based studies are particularly lacking. While only a few genetic studies were identified, these studies strongly suggest that there appear to be population-specific causes of MNDs among Africans. MND genetic underpinnings vary among different African populations and also between African and non-African populations. Further studies, especially molecular, genetic and genomic studies, will be required to advance our understanding of MND biology among African populations. Insights from these studies would help to improve the timeliness and accuracy of clinical diagnosis and treatment.}, }
@article {pmid26344214, year = {2015}, author = {Philips, T and Rothstein, JD}, title = {Rodent Models of Amyotrophic Lateral Sclerosis.}, journal = {Current protocols in pharmacology}, volume = {69}, number = {}, pages = {5.67.1-5.67.21}, pmid = {26344214}, issn = {1934-8290}, support = {R01 NS033958/NS/NINDS NIH HHS/United States ; R01 NS085207/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/*physiopathology ; Animals ; Central Nervous System/drug effects/enzymology/*physiopathology ; DNA-Binding Proteins/agonists/antagonists &amp; inhibitors/genetics/metabolism ; *Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Mice ; Mice, Knockout ; Mice, Neurologic Mutants ; Mice, Transgenic ; Motor Neurons/drug effects/enzymology/*metabolism ; Mutation ; Nerve Tissue Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Promoter Regions, Genetic/drug effects ; RNA Processing, Post-Transcriptional/drug effects ; Rats ; Rats, Mutant Strains ; Rats, Transgenic ; Superoxide Dismutase/chemistry/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (∼ 40% to 50% of fALS and ∼ 10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disorder is mediated non-cell autonomously, i.e., not only motor neurons are involved, but glial cells including microglia, astrocytes, and oligodendrocytes, and other neuronal subpopulations are also implicated in the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models.}, }
@article {pmid26338060, year = {2015}, author = {Zhou, C and Ma, G and Li, X and Li, J and Yan, Y and Liu, P and He, J and Ren, Y}, title = {Is minimally invasive esophagectomy effective for preventing anastomotic leakages after esophagectomy for cancer? A systematic review and meta-analysis.}, journal = {World journal of surgical oncology}, volume = {13}, number = {}, pages = {269}, pmid = {26338060}, issn = {1477-7819}, mesh = {Anastomotic Leak/*prevention &amp; control ; Esophageal Neoplasms/*surgery ; *Esophagectomy ; Humans ; *Minimally Invasive Surgical Procedures ; Prognosis ; }, abstract = {BACKGROUND: Compared with open esophagectomy (OE), minimally invasive esophagectomy (MIE) proves to have clear benefits in reducing the risk of pulmonary complications for patients with resectable esophageal cancer. The objectives of our study were to explore the superiority of MIE in reducing the occurrence of anastomotic leakages (ALs) when compared to OE.<br><br>METHODS: A systematic review and meta-analysis was performed to assess the superiority of MIE on the occurrence of ALs over OE, by searching many sources (through December, 2014) such as Medline, Embase, Wiley Online Library, and Cochrane Library. Fixed-effects model was used to calculate summary odds ratios (ORs) to quantify associations between OE and MIE groups. Cochran's Q and I(2) statistics were used to evaluate heterogeneity among studies.<br><br>RESULTS: Among a total of 43 studies involving 5537 patients included in the meta-analysis, 2527 (45.6%) cases underwent MIE and 3010 (54.4%) cases underwent OE. Compared to patients undergoing OE, patients undergoing MIE did not have statistical significance in reduced occurrence of ALs (OR&#x2009;=&#x2009;0.97, 95% CI&#x2009;=&#x2009;0.80-1.17). Insignificant reduced occurrence of ALs was not associated with anastomotic location (OR&#x2009;=&#x2009;0.90, 95% CI&#x2009;=&#x2009;0.71-1.13) or anastomotic procedure (OR&#x2009;=&#x2009;1.02, 95% CI&#x2009;=&#x2009;0.79-1.30).<br><br>CONCLUSIONS: More proofs are needed to clarify the strengths or weaknesses of MIE in preventing anastomotic leakages after esophagectomy for cancer. A largely randomized, controlled trial should be undertaken to resolve this contentious issue urgently.}, }
@article {pmid26329483, year = {2016}, author = {Hajivalili, M and Pourgholi, F and Kafil, HS and Jadidi-Niaragh, F and Yousefi, M}, title = {Mesenchymal Stem Cells in the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Current stem cell research &amp; therapy}, volume = {11}, number = {1}, pages = {41-50}, doi = {10.2174/1574888x10666150902095031}, pmid = {26329483}, issn = {2212-3946}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS is a neurodegenerative disorder which is characterized by motor neuron (MN dysfunction, progressive paralysis, and death. Although several therapeutic approaches have been used for treatment of ALS, little success has been achieved. Natural vectors such as mesenchymal stem cells (MSCs can be a promising tool for overcoming therapeutic problems. MSCs have multipotential characteristics such as the ability to differentiate into variety of cell types, easy access, immunomodulation, tissue repair, exertion of trophic factors, exosome secretion and efficient homing. In this review, we will discuss the characteristics of MSCs and their possible therapeutic mechanisms in ALS patients.}, }
@article {pmid26329154, year = {2015}, author = {Nodera, H and Izumi, Y and Kaji, R}, title = {[Effects of Vitamin B12 in Patients with Amyotrophic Lateral Sclerosis and Peripheral Neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {67}, number = {9}, pages = {1133-1138}, doi = {10.11477/mf.1416200272}, pmid = {26329154}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/*therapeutic use ; Peripheral Nervous System Diseases/*drug therapy ; Treatment Outcome ; Vitamin B 12/*therapeutic use ; }, abstract = {Vitamin B(12)(vB(12)) deficient is regarded as iatrogenic in some cases. Although the recommended oral intake of vB(12) has been determined, administration of vB(12) exceeding the recommended dose could have multiple pharmacological effects. "Ultra-high dose" vB(12) therapy has been used for peripheral neuropathy and amyotrophic lateral sclerosis, suggesting its promising neuroprotective effects.}, }
@article {pmid26328537, year = {2016}, author = {Yagami, T and Koma, H and Yamamoto, Y}, title = {Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System.}, journal = {Molecular neurobiology}, volume = {53}, number = {7}, pages = {4754-4771}, pmid = {26328537}, issn = {1559-1182}, mesh = {Animals ; Cell Death/physiology ; Central Nervous System/*metabolism/*physiopathology ; Cyclooxygenase 2/*metabolism ; Humans ; Nervous System Diseases/metabolism/physiopathology ; Neurons/metabolism ; Prostaglandins/*metabolism ; }, abstract = {Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF2α, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF2α, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange via EP1, resulting in the excess Ca(2+) accumulation. Neither PGE2, PGF2α, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although PGD2 induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE2, PGD2 is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-Δ(12,14)-PGJ2, which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE2 attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system.}, }
@article {pmid26327120, year = {2015}, author = {Petracca, M and Guidubaldi, A and Ricciardi, L and Ialongo, T and Del Grande, A and Mulas, D and Di Stasio, E and Bentivoglio, AR}, title = {Botulinum Toxin A and B in sialorrhea: Long-term data and literature overview.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {107}, number = {Pt A}, pages = {129-140}, doi = {10.1016/j.toxicon.2015.08.014}, pmid = {26327120}, issn = {1879-3150}, mesh = {Botulinum Toxins, Type A/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Injections ; Salivary Glands/drug effects ; Sialorrhea/*drug therapy ; Treatment Outcome ; }, abstract = {INTRODUCTION AND OBJECTIVES: In recent years, Botulinum Toxin has been shown to be efficacious and safe in the treatment of sialorrhea, but scanty data are available on its long term use. The aim of this study was to investigate adverse events, discriminate differences in safety, and evaluate the efficacy of long-term use of both abobotulinumtoxinA and rimabotulinumtoxinB ultrasound-guided injections for sialorrhea in a retrospective trial. Moreover we review the literature on this topic.<br><br>PATIENTS AND METHODS: Consecutive patients with severe sialorrhea and receiving at least two ultrasound-guided intrasalivary glands abobotulinumtoxinA 250 U or rimabotulinumtoxinB 2500 U injections were included. Clinical and demographic data were collected. Safety and tolerability were assessed on the basis of patients' self-reports. Efficacy was assessed by recording the duration of benefit and by the Drooling Severity Scale and Drooling Frequency Scale 4 weeks after intervention. A review of literature was performed using 'Botulinum Toxin' and/or 'drooling' and/or 'sialorrhea' and/or 'hypersalivation' as keywords.<br><br>RESULTS: Sixty-five patients (32 Amyotrophic Lateral Sclerosis and 33 Parkinson's Disease) were treated in a total of 317 sessions (181 rimabotulinumtoxinB and 136 abobotulinumtoxinA). Both serotypes induced a clear-cut benefit in 89% of injections. Mean benefit duration was 87 days (range 30-240), similar for abobotulinumtoxinA and rimabotulinumtoxinB but significantly shorter in Amyotrophic Lateral Sclerosis group compared to Parkinson's Disease (p < 0.001). Older age was positively correlated to benefit duration (p = 0.003). Botulinum Toxin-related and injection-related side effects complicated respectively 8,2% and 1,5% of treatments. The only Botulinum Toxin-related adverse event was a change of saliva thickness, mostly rated mild to moderate and more frequent in Amyotrophic Lateral Sclerosis patients (p = NS).<br><br>CONCLUSIONS: Both 250 U abobotulinumtoxinA and 2500 U rimabotulinumtoxinB administered by ultrasound-guided intrasalivary gland injection are safe and effective in treating sialorrhea, even in long-term follow-up. Older age is significantly associated with longer benefit duration. Parkinson's Disease patients showed a more favorable safety-efficacy ratio than did Amyotrophic Lateral Sclerosis patients, due to lower adverse events (p = NS) and longer benefit duration (p < 0.001).}, }
@article {pmid26315764, year = {2015}, author = {Conti, A and Alessio, M}, title = {Comparative Proteomics for the Evaluation of Protein Expression and Modifications in Neurodegenerative Diseases.}, journal = {International review of neurobiology}, volume = {121}, number = {}, pages = {117-152}, doi = {10.1016/bs.irn.2015.05.004}, pmid = {26315764}, issn = {2162-5514}, mesh = {Animals ; Biomarkers/metabolism ; Ceruloplasmin/metabolism ; Cytoskeletal Proteins/metabolism ; Humans ; Models, Molecular ; Nervous System Diseases/metabolism ; Neurodegenerative Diseases/*metabolism/*physiopathology ; Protein Processing, Post-Translational/*physiology ; *Proteomics ; }, abstract = {Together with hypothesis-driven approaches, high-throughput differential proteomic analysis performed primarily not only in human cerebrospinal fluid and serum but also on protein content of other tissues (blood cells, muscles, peripheral nerves, etc.) has been used in the last years to investigate neurodegenerative diseases. Even if the goal for these analyses was mainly the discovery of neurodegenerative disorders biomarkers, the characterization of specific posttranslational modifications (PTMs) and the differential protein expression resulted in being very informative to better define the pathological mechanisms. In this chapter are presented and discussed the positive aspects and challenges of the outcomes of some of our investigations on neurological and neurodegenerative disease, in order to highlight the important role of protein PTMs studies in proteomics-based approaches.}, }
@article {pmid26315762, year = {2015}, author = {Nayak, A and Salt, G and Verma, SK and Kishore, U}, title = {Proteomics Approach to Identify Biomarkers in Neurodegenerative Diseases.}, journal = {International review of neurobiology}, volume = {121}, number = {}, pages = {59-86}, doi = {10.1016/bs.irn.2015.05.003}, pmid = {26315762}, issn = {2162-5514}, mesh = {Biomarkers/*metabolism ; Humans ; Neurodegenerative Diseases/*diagnosis/*metabolism ; Proteomics/*methods ; }, abstract = {This chapter examines the use of proteomics in understanding pathogenesis and identifying possible biomarkers in a range of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and prion diseases. We have attempted to look at the neuroproteomic approach from a biomarker discovery point of view. Novel biomarkers can pave the way for new therapeutic targets and lead us to a better understanding of the pathogenesis involved in the neurodegenerative diseases.}, }
@article {pmid26315761, year = {2015}, author = {Pal, R and Larsen, JP and Moller, SG}, title = {The Potential of Proteomics in Understanding Neurodegeneration.}, journal = {International review of neurobiology}, volume = {121}, number = {}, pages = {25-58}, doi = {10.1016/bs.irn.2015.05.002}, pmid = {26315761}, issn = {2162-5514}, mesh = {Animal Diseases ; Animals ; Humans ; Neurodegenerative Diseases/*diagnosis/*metabolism ; Protein Processing, Post-Translational/*physiology ; Proteomics/*methods ; }, abstract = {Neurodegenerative diseases are a major health concern worldwide. Diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as many other diseases affecting the neuromuscular system, are a leading cause of disability in the aging population. Presymptomatic diagnosis of neurodegenerative disorders is challenging due to the lack of robust biomarkers. Likewise, the design of effective intervention strategies is limited because most neurodegenerative disorders are heterogeneous in nature. Reliable noninvasive biomarkers are therefore urgently needed to allow presymptomatic and accurate diagnosis, to track disease progression, to evaluate the effectiveness of new treatment regimens, and to ultimately design new therapeutic intervention strategies. Recent biological and technological advances within the field of proteomic promises to provide insight into global proteome changes in neurodegeneration, thus allowing increased understanding of molecular pathways leading to neuronal cell death and the identification of biomarkers. The combination of gel-based techniques and mass spectrometry permits large-scale identification of peptide sequences in biological samples as well as the characterization of posttranslational protein modifications. The application of comparative high-throughput proteomic analyses in animal models and human tissues will aid in the identification of both diagnostic and prognostic biomarkers and will provide a platform for a future personalized medicine approach in neurodegeneration.}, }
@article {pmid26315003, year = {2016}, author = {Perry, DC and Sturm, VE and Peterson, MJ and Pieper, CF and Bullock, T and Boeve, BF and Miller, BL and Guskiewicz, KM and Berger, MS and Kramer, JH and Welsh-Bohmer, KA}, title = {Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis.}, journal = {Journal of neurosurgery}, volume = {124}, number = {2}, pages = {511-526}, pmid = {26315003}, issn = {1933-0693}, support = {K23 AG045289/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; K23 AG040127/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG28377/AG/NIA NIH HHS/United States ; P50AG023501/AG/NIA NIH HHS/United States ; KM1CA156687/CA/NCI NIH HHS/United States ; P50 AG1657303/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG032306/AG/NIA NIH HHS/United States ; 1K23AG040127/AG/NIA NIH HHS/United States ; R01 AG041797/AG/NIA NIH HHS/United States ; KM1 CA156687/CA/NCI NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P01AG019724/AG/NIA NIH HHS/United States ; }, mesh = {Brain Concussion/pathology ; Brain Injuries/*complications/*psychology ; Dementia/etiology ; Humans ; Mental Disorders/*etiology/*psychology ; Nervous System Diseases/*etiology/*psychology ; Risk Factors ; }, abstract = {OBJECTIVE: Mild traumatic brain injury (TBI) has been proposed as a risk factor for the development of Alzheimer's disease, Parkinson's disease, depression, and other illnesses. This study's objective was to determine the association of prior mild TBI with the subsequent diagnosis (that is, at least 1 year postinjury) of neurological or psychiatric disease.<br><br>METHODS: All studies from January 1995 to February 2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study designs and characteristics.<br><br>RESULTS: Fifty-seven studies met the inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurological and psychiatric diagnoses. The pooled odds ratio (OR) for the development of any illness subsequent to prior TBI was 1.67 (95% CI 1.44-1.93, p < 0.0001). Prior TBI was independently associated with both neurological (OR 1.55, 95% CI 1.31-1.83, p < 0.0001) and psychiatric (OR 2.00, 95% CI 1.50-2.66, p < 0.0001) outcomes. Analyses of individual diagnoses revealed higher odds of Alzheimer's disease, Parkinson's disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI as compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies demonstrated no evidence that multiple TBIs were associated with higher odds of disease than a single TBI.<br><br>CONCLUSIONS: History of TBI, including mild TBI, is associated with the development of neurological and psychiatric illness. This finding indicates that either TBI is a risk factor for heterogeneous pathological processes or that TBI may contribute to a common pathological mechanism.}, }
@article {pmid26307158, year = {2015}, author = {DeLoach, A and Cozart, M and Kiaei, A and Kiaei, M}, title = {A retrospective review of the progress in amyotrophic lateral sclerosis drug discovery over the last decade and a look at the latest strategies.}, journal = {Expert opinion on drug discovery}, volume = {10}, number = {10}, pages = {1099-1118}, doi = {10.1517/17460441.2015.1067197}, pmid = {26307158}, issn = {1746-045X}, support = {5P20RR020146-09/RR/NCRR NIH HHS/United States ; P30 GM110702/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Biomarkers ; Drug Delivery Systems ; *Drug Design ; Drug Discovery/*methods ; Humans ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: Drug discovery for amyotrophic lateral sclerosis (ALS) has experienced a surge in clinical studies and remarkable preclinical milestones utilizing a variety of mutant superoxide dismutase 1 model systems. Of the drugs that were tested and showed positive preclinical effects, none demonstrated therapeutic benefits to ALS patients in clinical settings.<br><br>AREAS COVERED: This review discusses the advances made in drug discovery for ALS and highlights why drug development is proving to be so difficult. It also discusses how a closer look at both preclinical and clinical studies could uncover the reasons why these preclinical successes have yet to result in the availability of an effective drug for clinical use.<br><br>EXPERT OPINION: Valuable lessons from the numerous preclinical and clinical studies supply the biggest advantage in the monumental task of finding a cure for ALS. Obviously, a single design type for ALS clinical trials has not yielded success. The authors suggest a two-pronged approach that may prove essential to achieve clinical efficacy in the identification of novel targets and preclinical testing in multiple models to identify biomarkers that can function in diagnostic, predictive and prognostic roles, and changes to clinical trial design and patient recruitment criteria. The advancement of technology and invention of more powerful tools will further enhance the above. This will give rise to more sophisticated clinical trials with consideration of a range of criteria from: optimum dose, route of delivery, specific biomarkers, pharmacokinetics, pharmacodynamics and toxicology to biomarkers, timing for trial and patients' clinical status.}, }
@article {pmid26302799, year = {2016}, author = {Muthuraman, A and Kaur, P}, title = {Renin-Angiotensin-Aldosterone System: A Current Drug Target for the Management of Neuropathic Pain.}, journal = {Current drug targets}, volume = {17}, number = {2}, pages = {178-195}, doi = {10.2174/1389450116666150825115658}, pmid = {26302799}, issn = {1873-5592}, mesh = {Aldosterone/*metabolism ; Angiotensin II Type 1 Receptor Blockers/pharmacology/therapeutic use ; Animals ; Humans ; Molecular Targeted Therapy ; Neuralgia/*drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism ; Renin-Angiotensin System/*drug effects ; }, abstract = {Renin-Angiotensin-Aldosterone System (RAAS) is well established in renovascular and cardiovascular functions. The modulators of this system are significantly used for regulating elevated blood pressure in human and animals. Recently, it has also been documented to produce neurological actions. The abnormalities of this system raise renin, angiotensin (AT), angiotensin converting enzyme (ACE) activity, and aldosterone in circulation and nerve tissues. In the nervous system, abundant rise of these components cause neuronal damage and neurodegeneration. ACE contributes to degradation of β-amyloid in the brain, that is responsible for Alzheimer disease (AD). But, angiotensin converting enzyme-2 (ACE-2) mediated release of angiotensin1-7 (AT1-7) peptide in nerve tissue has potential neuroprotective actions. This review focuses on the current perspectives of the RAAS in neurodegeneration along with possible cellular and molecular mechanisms. Also, we have discussed the current evidence of RAAS modulators in the management of neuropathic pain in human and animals. Thus, we believe that, in the future, RAAS modulators may play a great role in the management of neuropathic pain and other neurodegenerative disorders such as AD, Parkinson disease (PD) and amyotrophic lateral sclerosis. But, more extensive clinical research is required for utilizing RAAS modulators in neurodegenerative disorders.}, }
@article {pmid26301221, year = {2015}, author = {Wallner, S and Peters, S and Pitzer, C and Resch, H and Bogdahn, U and Schneider, A}, title = {The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity.}, journal = {Frontiers in cell and developmental biology}, volume = {3}, number = {}, pages = {48}, pmid = {26301221}, issn = {2296-634X}, abstract = {Granulocyte-colony stimulating factor (G-CSF) is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.}, }
@article {pmid26295717, year = {2015}, author = {Liddell, JR}, title = {Targeting mitochondrial metal dyshomeostasis for the treatment of neurodegeneration.}, journal = {Neurodegenerative disease management}, volume = {5}, number = {4}, pages = {345-364}, doi = {10.2217/nmt.15.19}, pmid = {26295717}, issn = {1758-2032}, mesh = {Brain/*metabolism ; *Brain Chemistry ; Clinical Trials as Topic ; *Homeostasis ; Humans ; Iron/metabolism ; Metalloproteins/*metabolism ; Mitochondrial Diseases/*metabolism ; Neurodegenerative Diseases/*metabolism/*therapy ; Oxyquinoline/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mitochondrial impairment and metal dyshomeostasis are suggested to be associated with many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Treatments aimed at restoring metal homeostasis are highly effective in models of these diseases, and clinical trials hold promise. However, in general, the effect of these treatments on mitochondrial metal homeostasis is unclear, and the contribution of mitochondrial metal dyshomeostasis to disease pathogenesis requires further investigation. This review describes the role of metals in mitochondria in health, how mitochondrial metals are disrupted in neurodegenerative diseases, and potential therapeutics aimed at restoring mitochondrial metal homeostasis and function.}, }
@article {pmid26295258, year = {2015}, author = {Silva, J and Monge-Fuentes, V and Gomes, F and Lopes, K and dos Anjos, L and Campos, G and Arenas, C and Biolchi, A and Gonçalves, J and Galante, P and Campos, L and Mortari, M}, title = {Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools.}, journal = {Toxins}, volume = {7}, number = {8}, pages = {3179-3209}, pmid = {26295258}, issn = {2072-6651}, mesh = {Animals ; Bee Venoms/pharmacology/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; Wasp Venoms/pharmacology/*therapeutic use ; }, abstract = {Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.}, }
@article {pmid26295035, year = {2015}, author = {de Paula, CZ and Gonçalves, BD and Vieira, LB}, title = {An Overview of Potential Targets for Treating Amyotrophic Lateral Sclerosis and Huntington's Disease.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {198612}, pmid = {26295035}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Disease Progression ; Humans ; Huntington Disease/pathology/*therapy ; Nerve Degeneration/pathology/*therapy ; Neurons/*pathology ; }, abstract = {Neurodegenerative diseases affect millions of people worldwide. Progressive damage or loss of neurons, neurodegeneration, has severe consequences on the mental and physical health of a patient. Despite all efforts by scientific community, there is currently no cure or manner to slow degeneration progression. We review some treatments that attempt to prevent the progress of some of major neurodegenerative diseases: Amyotrophic Lateral Sclerosis and Huntington's disease.}, }
@article {pmid26290961, year = {2015}, author = {Xie, Y and Zhou, B and Lin, MY and Sheng, ZH}, title = {Progressive endolysosomal deficits impair autophagic clearance beginning at early asymptomatic stages in fALS mice.}, journal = {Autophagy}, volume = {11}, number = {10}, pages = {1934-1936}, doi = {10.1080/15548627.2015.1084460}, pmid = {26290961}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Autophagy/*physiology ; Disease Models, Animal ; Humans ; Lysosomes/*metabolism ; Motor Neurons/*pathology ; Spinal Cord/*metabolism/pathology ; }, abstract = {Autophagy is an important homeostatic process that functions by eliminating defective organelles and aggregated proteins over a neuron's lifetime. One pathological hallmark in amyotrophic lateral sclerosis (ALS)-linked motor neurons (MNs) is axonal accumulation of autophagic vacuoles (AVs), thus raising a fundamental question as to whether reduced autophagic clearance due to an impaired lysosomal system contributes to autophagic stress and axonal degeneration. We recently revealed progressive lysosomal deficits in spinal MNs beginning at early asymptomatic stages in fALS-linked mice expressing the human (Hs) SOD1(G93A) protein. Such deficits impair the degradation of AVs engulfing damaged mitochondria from distal axons. These early pathological changes are attributable to mutant HsSOD1, which interferes with dynein-driven endolysosomal trafficking. Elucidation of this pathological mechanism is broadly relevant, because autophagy-lysosomal deficits are associated with several major neurodegenerative diseases. Therefore, enhancing autophagic clearance by rescuing endolysosomal trafficking may be a potential therapeutic strategy for ALS and perhaps other neurodegenerative diseases.}, }
@article {pmid26287246, year = {2015}, author = {Navone, F and Genevini, P and Borgese, N}, title = {Autophagy and Neurodegeneration: Insights from a Cultured Cell Model of ALS.}, journal = {Cells}, volume = {4}, number = {3}, pages = {354-386}, pmid = {26287246}, issn = {2073-4409}, abstract = {Autophagy plays a major role in the elimination of cellular waste components, the renewal of intracellular proteins and the prevention of the build-up of redundant or defective material. It is fundamental for the maintenance of homeostasis and especially important in post-mitotic neuronal cells, which, without competent autophagy, accumulate protein aggregates and degenerate. Many neurodegenerative diseases are associated with defective autophagy; however, whether altered protein turnover or accumulation of misfolded, aggregate-prone proteins is the primary insult in neurodegeneration has long been a matter of debate. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by selective degeneration of motor neurons. Most of the ALS cases occur in sporadic forms (SALS), while 10%-15% of the cases have a positive familial history (FALS). The accumulation in the cell of misfolded/abnormal proteins is a hallmark of both SALS and FALS, and altered protein degradation due to autophagy dysregulation has been proposed to contribute to ALS pathogenesis. In this review, we focus on the main molecular features of autophagy to provide a framework for discussion of our recent findings about the role in disease pathogenesis of the ALS-linked form of the VAPB gene product, a mutant protein that drives the generation of unusual cytoplasmic inclusions.}, }
@article {pmid26283915, year = {2015}, author = {Ben Haim, L and Carrillo-de Sauvage, MA and Ceyzériat, K and Escartin, C}, title = {Elusive roles for reactive astrocytes in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {278}, pmid = {26283915}, issn = {1662-5102}, abstract = {Astrocytes play crucial roles in the brain and are involved in the neuroinflammatory response. They become reactive in response to virtually all pathological situations in the brain such as axotomy, ischemia, infection, and neurodegenerative diseases (ND). Astrocyte reactivity was originally characterized by morphological changes (hypertrophy, remodeling of processes) and the overexpression of the intermediate filament glial fibrillary acidic protein (GFAP). However, it is unclear how the normal supportive functions of astrocytes are altered by their reactive state. In ND, in which neuronal dysfunction and astrocyte reactivity take place over several years or decades, the issue is even more complex and highly debated, with several conflicting reports published recently. In this review, we discuss studies addressing the contribution of reactive astrocytes to ND. We describe the molecular triggers leading to astrocyte reactivity during ND, examine how some key astrocyte functions may be enhanced or altered during the disease process, and discuss how astrocyte reactivity may globally affect ND progression. Finally we will consider the anticipated developments in this important field. With this review, we aim to show that the detailed study of reactive astrocytes may open new perspectives for ND.}, }
@article {pmid26283685, year = {2016}, author = {Beeldman, E and Raaphorst, J and Klein Twennaar, M and de Visser, M and Schmand, BA and de Haan, RJ}, title = {The cognitive profile of ALS: a systematic review and meta-analysis update.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {87}, number = {6}, pages = {611-619}, doi = {10.1136/jnnp-2015-310734}, pmid = {26283685}, issn = {1468-330X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; Cognition Disorders/*diagnosis ; Diagnosis, Differential ; Disability Evaluation ; Female ; Frontotemporal Dementia/diagnosis ; Humans ; Language Disorders/diagnosis ; Male ; Mental Status Schedule/statistics &amp; numerical data ; Middle Aged ; Neuropsychological Tests/statistics &amp; numerical data ; Point-of-Care Testing ; Psychometrics ; Reference Values ; }, abstract = {Cognitive impairment is present in approximately 30% of patients with amyotrophic lateral sclerosis (ALS) and, especially when severe, has a negative impact on survival and caregiver burden. Our 2010 meta-analysis of the cognitive profile of ALS showed impairment of fluency, executive function, language and memory. However, the limited number of studies resulted in large confidence intervals. To obtain a more valid assessment, we updated the meta-analysis and included methodological improvements (controlled data extraction, risk of bias analysis and effect size calculation of individual neuropsychological tests). Embase, Medline and PsycInfo were searched for neuropsychological studies of non-demented patients with ALS and age-matched and education-matched healthy controls. Neuropsychological tests were categorised in 13 cognitive domains and effect sizes (Hedges' g) were calculated for each domain and for individual tests administered in ≥5 studies. Subgroup analyses were performed to assess the influence of clinical and demographic variables. Forty-four studies were included comprising 1287 patients and 1130 healthy controls. All cognitive domains, except visuoperceptive functions, showed significant effect sizes compared to controls. Cognitive domains without bias due to motor impairment showed medium effect sizes (95% CI): fluency (0.56 (0.43 to 0.70)), language (0.56 (0.40 to 0.72)), social cognition (0.55 (0.34 to 0.76)), or small effect sizes: delayed verbal memory 0.47 (0.27 to 0.68)) and executive functions (0.41 (0.27 to 0.55)). Individual neuropsychological tests showed diverging effect sizes, which could be explained by bias due to motor impairment. Subgroup analyses showed no influence of bulbar disease onset and depression and anxiety on the cognitive outcomes. The cognitive profile of ALS consists of deficits in fluency, language, social cognition, executive functions and verbal memory. Social cognition is a new cognitive domain with a relatively large effect size, highlighting the overlap between ALS and frontotemporal dementia. The diverging effect sizes for individual neuropsychological tests show the importance of correction for motor impairment in patients with ALS. These findings have implications for bedside testing, the design of cognitive screening measures and full neuropsychological examinations.}, }
@article {pmid26282323, year = {2016}, author = {Manfredi, G and Kawamata, H}, title = {Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {90}, number = {}, pages = {35-42}, pmid = {26282323}, issn = {1095-953X}, support = {2R01NS051419-05/NS/NINDS NIH HHS/United States ; R01 NS093872/NS/NINDS NIH HHS/United States ; R01 NS051419/NS/NINDS NIH HHS/United States ; R01 NS084486/NS/NINDS NIH HHS/United States ; 1R01NS062055-01/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Endoplasmic Reticulum/*metabolism ; Humans ; Mitochondria/*metabolism ; }, abstract = {Physical and functional interactions between mitochondria and the endoplasmic reticulum (ER) are crucial for cell life. These two organelles are intimately connected and collaborate to essential processes, such as calcium homeostasis and phospholipid biosynthesis. The connections between mitochondria and endoplasmic reticulum occur through structures named mitochondria associated membranes (MAMs), which contain lipid rafts and a large number of proteins, many of which serve multiple functions at different cellular sites. Growing evidence strongly suggests that alterations of ER-mitochondria interactions are involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a devastating and rapidly fatal motor neuron disease. Mutations in proteins that participate in ER-mitochondria interactions and MAM functions are increasingly being associated with genetic forms of ALS and other neurodegenerative diseases. This evidence strongly suggests that, rather than considering the two organelles separately, a better understanding of the disease process can derive from studying the alterations in their crosstalk. In this review we discuss normal and pathological ER-mitochondria interactions and the evidence that link them to ALS.}, }
@article {pmid26281945, year = {2015}, author = {Johnson, DA and Johnson, JA}, title = {Nrf2--a therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Free radical biology &amp; medicine}, volume = {88}, number = {Pt B}, pages = {253-267}, pmid = {26281945}, issn = {1873-4596}, support = {P50AG033514/AG/NIA NIH HHS/United States ; R01 ES10042/ES/NIEHS NIH HHS/United States ; R01 ES008089/ES/NIEHS NIH HHS/United States ; R01 AG033493/AG/NIA NIH HHS/United States ; R01 ES08089/ES/NIEHS NIH HHS/United States ; R01 ES010042/ES/NIEHS NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism ; Humans ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Signal Transduction/*physiology ; }, abstract = {The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to attenuate disease progression.}, }
@article {pmid26268526, year = {2015}, author = {Herhaus, L and Dikic, I}, title = {Expanding the ubiquitin code through post-translational modification.}, journal = {EMBO reports}, volume = {16}, number = {9}, pages = {1071-1083}, pmid = {26268526}, issn = {1469-3178}, support = {250241/ERC_/European Research Council/International ; }, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/etiology/genetics ; Animals ; Autophagy/genetics ; Humans ; Mitophagy/genetics/physiology ; Parkinson Disease/etiology/genetics ; Phosphorylation/genetics ; Protein Kinases/metabolism ; Protein Processing, Post-Translational/*genetics ; Protein Structure, Tertiary ; Ubiquitin/chemistry/*genetics/*metabolism ; Ubiquitination/*genetics ; Yeasts/genetics/physiology ; }, abstract = {Ubiquitylation is among the most prevalent post-translational modifications (PTMs) and regulates numerous cellular functions. Interestingly, ubiquitin (Ub) can be itself modified by other PTMs, including acetylation and phosphorylation. Acetylation of Ub on K6 and K48 represses the formation and elongation of Ub chains. Phosphorylation of Ub happens on multiple sites, S57 and S65 being the most frequently modified in yeast and mammalian cells, respectively. In mammals, the PINK1 kinase activates ubiquitin ligase Parkin by phosphorylating S65 of Ub and of the Parkin Ubl domain, which in turn promotes the amplification of autophagy signals necessary for the removal of damaged mitochondria. Similarly, TBK1 phosphorylates the autophagy receptors OPTN and p62 to initiate feedback and feedforward programs for Ub-dependent removal of protein aggregates, mitochondria and pathogens (such as Salmonella and Mycobacterium tuberculosis). The impact of PINK1-mediated phosphorylation of Ub and TBK1-dependent phosphorylation of autophagy receptors (OPTN and p62) has been recently linked to the development of Parkinson's disease and amyotrophic lateral sclerosis, respectively. Hence, the post-translational modification of Ub and its receptors can efficiently expand the Ub code and modulate its functions in health and disease.}, }
@article {pmid26266872, year = {2015}, author = {Sui, YP and Zhang, XX and Lu, JL and Sui, F}, title = {New Insights into the Roles of Nogo-A in CNS Biology and Diseases.}, journal = {Neurochemical research}, volume = {40}, number = {9}, pages = {1767-1785}, pmid = {26266872}, issn = {1573-6903}, mesh = {Animals ; Animals, Genetically Modified ; Central Nervous System/*physiology ; Central Nervous System Diseases/*physiopathology ; Myelin Proteins/*physiology ; Neuronal Plasticity ; Nogo Proteins ; Rats ; Signal Transduction ; }, abstract = {Nogos have become a hot topic for its well-known number Nogo-A's big role in clinical matters. It has been recognized that the expression of Nogo-A and the receptor NgR1 inhibit the neuron's growth after CNS injuries or the onset of the MS. The piling evidence supports the notion that the Nogo-A is also involved in the synaptic plasticity, which was shown to negatively regulate the strength of synaptic transmission. The occurrence of significant schizophrenia-like behavioral phenotypes in Nogo-A KO rats also added strong proof to this conclusion. This review mainly focuses on the structure of Nogo-A and its corresponding receptor-NgR1, its intra- and extra-cellular signaling, together with its major physiological functions such as regulation of migration and distribution and its related diseases like stroke, AD, ALS and so on.}, }
@article {pmid26264610, year = {2015}, author = {Lee, JK and Shin, JH and Lee, JE and Choi, EJ}, title = {Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1852}, number = {11}, pages = {2517-2524}, doi = {10.1016/j.bbadis.2015.08.005}, pmid = {26264610}, issn = {0006-3002}, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons associated with the abnormal aggregation of ubiquitinated proteins. The molecular mechanisms underlying the pathogenesis of ALS remain unclear, however. Autophagy is a major pathway for the elimination of protein aggregates and damaged organelles and therefore contributes to cellular homeostasis. This catabolic process begins with the formation of the double membrane-bound autophagosome that engulfs portions of the cytoplasm and subsequently fuses with a lysosome to form an autolysosome, in which lysosomal enzymes digest autophagic substrates. Defects at various stages of autophagy have been associated with pathological mutations of several ALS-linked genes including SOD1, p62, TDP-43, and optineurin, suggesting that such defects may play a causative role in the pathogenesis of this condition. In this review, we summarize the dysregulation of autophagy associated with ALS as well as potential therapeutic strategies based on modulation of the autophagic process.}, }
@article {pmid26263977, year = {2015}, author = {Abdelhak, A and Junker, A and Brettschneider, J and Kassubek, J and Ludolph, AC and Otto, M and Tumani, H}, title = {Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?.}, journal = {International journal of molecular sciences}, volume = {16}, number = {8}, pages = {17565-17588}, pmid = {26263977}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/physiopathology ; Biomarkers/*cerebrospinal fluid ; Brain/pathology ; Brain Injuries/*genetics/pathology ; Cytoskeleton/pathology ; Humans ; Motor Neurons/metabolism/pathology ; Multiple Sclerosis, Chronic Progressive/*cerebrospinal fluid/physiopathology ; Tubulin/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; }, abstract = {Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.}, }
@article {pmid26260390, year = {2015}, author = {Fernández-Ruiz, J and Moro, MA and Martínez-Orgado, J}, title = {Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {4}, pages = {793-806}, pmid = {26260390}, issn = {1878-7479}, mesh = {Animals ; Brain Injuries/*drug therapy ; Cannabinoids/*therapeutic use ; Disease Models, Animal ; *Drug Evaluation, Preclinical ; Humans ; Neurodegenerative Diseases/*drug therapy ; Stroke/*drug therapy ; }, abstract = {Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.}, }
@article {pmid26255941, year = {2015}, author = {Coppedè, F and Migliore, L}, title = {DNA damage in neurodegenerative diseases.}, journal = {Mutation research}, volume = {776}, number = {}, pages = {84-97}, doi = {10.1016/j.mrfmmm.2014.11.010}, pmid = {26255941}, issn = {1873-135X}, mesh = {Animals ; Chromosome Segregation/*genetics ; *Chromosomes, Human, Pair 21/genetics/metabolism ; *DNA Damage ; *Epigenesis, Genetic ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Oxidation-Reduction ; Oxidative Stress/*genetics ; }, abstract = {Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans.}, }
@article {pmid26253783, year = {2015}, author = {Mancuso, R and Navarro, X}, title = {Amyotrophic lateral sclerosis: Current perspectives from basic research to the clinic.}, journal = {Progress in neurobiology}, volume = {133}, number = {}, pages = {1-26}, doi = {10.1016/j.pneurobio.2015.07.004}, pmid = {26253783}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology/*therapy ; Animals ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motoneurons, leading to muscle weakness and paralysis, and finally death. Considerable recent advances have been made in basic research and preclinical therapeutic attempts using experimental models, leading to increasing clinical and translational research in the context of this disease. In this review we aim to summarize the most relevant findings from a variety of aspects about ALS, including evaluation methods, animal models, pathophysiology, and clinical findings, with particular emphasis in understanding the role of every contributing mechanism to the disease for elucidating the causes underlying degeneration of motoneurons and the development of new therapeutic strategies.}, }
@article {pmid26252269, year = {2015}, author = {Menezes, R and Pantelyat, A and Izbudak, I and Birnbaum, J}, title = {Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases: A Case Series of 8 Patients and Review of the Literature.}, journal = {Medicine}, volume = {94}, number = {31}, pages = {e0971}, pmid = {26252269}, issn = {1536-5964}, mesh = {Aged ; Diagnosis, Differential ; Female ; Humans ; Male ; Middle Aged ; Movement Disorders/*diagnosis/etiology ; Neurodegenerative Diseases/*diagnosis/etiology ; Rheumatic Diseases/*complications ; Syndrome ; }, abstract = {Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjögren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien-limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ∼1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ∼1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury in a psoriatic arthritis patient who developed an amyotrophic lateral sclerosis (ALS)-plus syndrome after tumor necrosis factor (TNF)-inhibitor therapy.We have described a diverse spectrum of movement and other neurodegenerative disorders in our rheumatic disease patients. The widespread pattern of clinical injury, the propensity of our patients to present with co-occurring movement disorders, and the lack of MRI neuroimaging findings suggestive of a vasculopathy collectively suggest unique patterns of immune-mediated injury.}, }
@article {pmid26239912, year = {2016}, author = {Levy, M and Boulis, N and Rao, M and Svendsen, CN}, title = {Regenerative cellular therapies for neurologic diseases.}, journal = {Brain research}, volume = {1638}, number = {Pt A}, pages = {88-96}, pmid = {26239912}, issn = {1872-6240}, support = {K08 NS078555/NS/NINDS NIH HHS/United States ; NS078555/NS/NINDS NIH HHS/United States ; }, mesh = {Cell- and Tissue-Based Therapy/*methods ; Humans ; Neurodegenerative Diseases/*therapy ; Regenerative Medicine/methods ; Stem Cell Transplantation/methods ; }, abstract = {The promise of stem cell regeneration has been the hope of many neurologic patients with permanent damage to the central nervous system. There are hundreds of stem cell trials worldwide intending to test the regenerative capacity of stem cells in various neurological conditions from Parkinson's disease to multiple sclerosis. Although no stem cell therapy is clinically approved for use in any human disease indication, patients are seeking out trials and asking clinicians for guidance. This review summarizes the current state of regenerative stem cell transplantation divided into seven conditions for which trials are currently active: demyelinating diseases/spinal cord injury, amyotrophic lateral sclerosis, stroke, Parkinson's disease, Huntington's disease, macular degeneration and peripheral nerve diseases. This article is part of a Special Issue entitled SI: PSC and the brain.}, }
@article {pmid26237914, year = {2015}, author = {Siirala, W and Korpela, J and Vuori, A and Saaresranta, T and Olkkola, KT and Aantaa, R}, title = {[Amyotrophic lateral sclerosis and respiratory insufficiency].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {131}, number = {2}, pages = {127-135}, pmid = {26237914}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; *Noninvasive Ventilation ; Respiratory Insufficiency/*diagnosis/*etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease causing degeneration of motor neurons, without any curative treatment. The most common cause of death is respiratory arrest due to atrophy of the respiratory musculature. ALS-associated respiratory insufficiency differs in mechanism from the more common causes of dyspnea, such as diseases of pulmonary or cardiac origin. Recognizing the respiratory insufficiency can be challenging for a clinician. It should be possible to predict the development of respiratory insufficiency in order to avoid leaving the treatment decisions concerning respiratory insufficiency to emergency services. Noninvasive ventilatory support can be used to alleviate the patient's dyspnea. It is actually recommended as the first-line treatment of ALS-associated respiratory insufficiency.}, }
@article {pmid26227992, year = {2015}, author = {Bicchi, I and Emiliani, C and Vescovi, A and Martino, S}, title = {The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics.}, journal = {Neuro-degenerative diseases}, volume = {15}, number = {6}, pages = {313-321}, doi = {10.1159/000435917}, pmid = {26227992}, issn = {1660-2862}, mesh = {Alzheimer Disease/*diagnosis/therapy ; Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/*therapy ; Animals ; Diagnosis, Differential ; Diagnostic Errors/*prevention &amp; control ; Frontotemporal Dementia/*diagnosis/therapy ; Humans ; Muscular Atrophy, Spinal/diagnosis/metabolism ; }, abstract = {Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms.}, }
@article {pmid26223903, year = {2015}, author = {Zhou, J and Yi, J and Bonewald, L}, title = {Muscle-Bone Crosstalk in Amyotrophic Lateral Sclerosis.}, journal = {Current osteoporosis reports}, volume = {13}, number = {5}, pages = {274-279}, pmid = {26223903}, issn = {1544-2241}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology/physiopathology ; Animals ; Bone and Bones/*pathology/*physiopathology ; Disease Models, Animal ; Humans ; Muscle, Skeletal/pathology/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a fatal neuromuscular disorder characterized by degeneration of motor neurons and by skeletal muscle atrophy. Although the death of motor neurons is a pathological hallmark of ALS, the potential role of other organs in disease progression remains to be elucidated. Skeletal muscle and bone are the two largest organs in the human body. They are responsible not only for locomotion but also for maintaining whole body normal metabolism and homeostasis. Patients with ALS display severe muscle atrophy, which may reflect intrinsic defects in mitochondrial respiratory function and calcium (Ca) signaling in muscle fibers, in addition to the role of axonal withdrawal associated with ALS progression. Incidence of fractures is high in ALS patients, indicating there are potential bone defects in individuals with this condition. There is a lifelong interaction between skeletal muscle and bone. The severe muscle degeneration that occurs during ALS progression may potentially have a significant impact on bone function, and the defective bone may also contribute significantly to neuromuscular degeneration in the course of the disease. Due to the nature of the rapid and severe neuromuscular symptoms, a majority of studies on ALS have focused on neurodegeneration. Just a few studies have explored the possible contribution of muscle defects, even fewer on bone defects, and fewer still on possible muscle-bone crosstalk in ALS. This review article discusses current studies on bone defects and potential defects in muscle-bone crosstalk in ALS.}, }
@article {pmid26223806, year = {2016}, author = {Seitzer, F and Kahrass, H and Neitzke, G and Strech, D}, title = {The full spectrum of ethical issues in the care of patients with ALS: a systematic qualitative review.}, journal = {Journal of neurology}, volume = {263}, number = {2}, pages = {201-209}, pmid = {26223806}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis ; *Ethics, Medical ; Female ; Humans ; Male ; }, abstract = {Dealing systematically with ethical issues in amyotrophic lateral sclerosis (ALS) care requires an unbiased awareness of all the relevant ethical issues. The aim of the study was to determine systematically and transparently the full spectrum of ethical issues in ALS care. We conducted a systematic review in Medline and Google Books (restricted to English and German literature published between 1993 and 2014). We applied qualitative text analysis and normative analysis to categorise the spectrum of ethical issues in ALS care. The literature review retrieved 56 references that together mentioned a spectrum of 103 ethical issues in ALS care. The spectrum was structured into six major categories that consist of first and second-order categories of ethical issues. The systematically derived spectrum of ethical issues in ALS care presented in this paper raises awareness and understanding of the complexity of ethical issues in ALS care. It also offers a basis for the systematic development of informational and training materials for health professionals, patients and their relatives, and society as a whole. Finally, it supports a rational and fair selection of all those ethical issues that should be addressed in health policies, position papers and clinical practice guidelines. Further research is needed to identify ways to systematically select the most relevant ethical issues not only in the clinical environment, but also for the development of clinical practice guidelines.}, }
@article {pmid26221742, year = {2015}, author = {Opattova, A and Cente, M and Novak, M and Filipcik, P}, title = {The ubiquitin proteasome system as a potential therapeutic target for treatment of neurodegenerative diseases.}, journal = {General physiology and biophysics}, volume = {34}, number = {4}, pages = {337-352}, doi = {10.4149/gpb_2015024}, pmid = {26221742}, issn = {0231-5882}, mesh = {Animals ; Brain/*metabolism ; Humans ; Models, Neurological ; Molecular Targeted Therapy/methods ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism/therapy ; Neuroprotective Agents/therapeutic use ; Proteasome Endopeptidase Complex/*metabolism ; Ubiquitin-Protein Ligase Complexes/*metabolism ; Ubiquitins/*metabolism ; }, abstract = {Impairment of "protein quality control" in neurons is associated with etiopathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy. The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others. Although the primary events in etiopathogenesis of sporadic forms of these diseases are still unknown, it is clear that aging, in connection with decreased activity of ubiquitin proteasome system, is the most significant risk factor. In this review we discuss the pathogenic role and intracellular fate of the candidate molecules associated with onset and progression of AD and PD, the protein tau and α-synuclein in context with the function of ubiquitin proteasome system. We also discuss the possibility whether or not the strategies focused to re-establishment of neuroproteostasis via accelerated clearance of damaged proteins in proteasome could be a promising therapeutic approach for treatment of major neurodegenerative diseases.}, }
@article {pmid26220395, year = {2015}, author = {Lourenco, GF and Janitz, M and Huang, Y and Halliday, GM}, title = {Long noncoding RNAs in TDP-43 and FUS/TLS-related frontotemporal lobar degeneration (FTLD).}, journal = {Neurobiology of disease}, volume = {82}, number = {}, pages = {445-454}, doi = {10.1016/j.nbd.2015.07.011}, pmid = {26220395}, issn = {1095-953X}, mesh = {Animals ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/*metabolism ; Humans ; RNA, Long Noncoding/*metabolism ; RNA-Binding Protein FUS/genetics/*metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) defines a spectrum of heterogeneous neurodegenerative disorders characterized by the progressive deterioration of the frontal and anterior temporal lobes of the brain. FTLD is histopathologically classified according to the presence of neuropathological protein aggregates. Two of the major pathologies, FTLD-TDP and FTLD-FUS, are characterized by the abnormal accumulation in cytoplasmic inclusions of RNA-binding proteins (RBPs) - TDP-43 and FUS/TLS, respectively. That suggests that a crucial common downstream pathway leading to cell death might involve the disruption of RNA-based mechanisms. Long noncoding RNAs have emerged as key regulators in the different layers of gene regulation. Increasing evidence suggests that long non-coding RNAs (lncRNAs) may have pivotal biological functions in the brain and, not surprisingly, they have been implicated with neurodegenerative diseases, like Alzheimer's and Parkinson's diseases. Recent studies report that FTLD/ALS-related proteins TDP-43 and FUS/TLS bind lncRNAs, and that several lncRNAs have binding sites for TDP-43 and/or FUS/TLS. These findings raise important questions about how TDP-43 and FUS/TLS pathologies can affect lncRNA-based mechanisms. One alternative is that TDP-43 and FUS/TLS regulate lncRNA transcription or transcript stability. In fact, it has been demonstrated that lncRNAs are dysregulated upon either depletion or unavailability of functional TDP-43 or FUS/TLS in a range of different models and diseases, including post-mortem samples from subjects with FTLD-TDP. The second alternative is that the binding to TDP-43 or FUS/TLS would enable lncRNAs to perform their cellular function. In this case, the unavailability of these RBPs would disrupt functional properties of lncRNAs, without necessarily altering their cellular levels. It has been experimentally demonstrated that the cellular function of some lncRNAs is strictly dependent on the direct binding to TDP-43 or FUS/TLS.}, }
@article {pmid26219222, year = {2015}, author = {Yang, DJ and Zhu, L and Ren, J and Ma, RJ and Zhu, H and Xu, J}, title = {Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model.}, journal = {Neuroscience bulletin}, volume = {31}, number = {4}, pages = {445-451}, pmid = {26219222}, issn = {1995-8218}, mesh = {Animals ; *Autophagy ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Motor Neuron Disease/genetics/*metabolism/*physiopathology ; }, abstract = {Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.}, }
@article {pmid26210990, year = {2015}, author = {Scheper, W and Hoozemans, JJ}, title = {The unfolded protein response in neurodegenerative diseases: a neuropathological perspective.}, journal = {Acta neuropathologica}, volume = {130}, number = {3}, pages = {315-331}, pmid = {26210990}, issn = {1432-0533}, mesh = {Animals ; Brain/*pathology/*physiopathology ; Humans ; Neurodegenerative Diseases/*pathology/*physiopathology ; Unfolded Protein Response/*physiology ; }, abstract = {The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.}, }
@article {pmid26202426, year = {2016}, author = {Perera, ND and Turner, BJ}, title = {AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Neurochemical research}, volume = {41}, number = {3}, pages = {544-553}, pmid = {26202426}, issn = {1573-6903}, support = {G1002117//Medical Research Council/United Kingdom ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Brain/metabolism ; *Energy Metabolism ; Glycolysis ; Humans ; Lipid Metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Oxidative Phosphorylation ; Signal Transduction ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by selective loss of upper and lower motor neurons by complex mechanisms that are incompletely understood. Motor neurons are large, highly polarised and excitable cells with unusually high energetic demands to maintain resting membrane potential and propagate action potentials. This leads to higher ATP consumption and mitochondrial metabolism in motor neurons relative to other cells. Here, we review increasing evidence that defective energy metabolism and homeostasis contributes to selective vulnerability and degeneration of motor neurons in ALS. Firstly, we provide a brief overview of major energetic pathways in the CNS, including glycolysis, oxidative phosphorylation and the AMP-activated protein kinase (AMPK) signalling pathway, while highlighting critical metabolic interactions between neurons and astrocytes. Next, we review evidence from ALS patients and transgenic mutant SOD1 mice for weight loss, hypermetabolism, hyperlipidemia and mitochondrial dysfunction in disease onset and progression. Genetic and therapeutic modifiers of energy metabolism in mutant SOD1 mice will also be summarised. We also present evidence that additional ALS-linked proteins, TDP-43 and FUS, lead to energy disruption and mitochondrial defects in motor neurons. Lastly, we review emerging evidence including our own that dysregulation of the AMPK signalling cascade in motor neurons is an early and common event in ALS pathogenesis. We suggest that an imbalance in energy metabolism should be considered an important factor in both progression and potential treatment of ALS.}, }
@article {pmid26198888, year = {2015}, author = {Patel, AN and Sampson, JB}, title = {Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {15}, number = {9}, pages = {59}, pmid = {26198888}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/physiopathology ; Animals ; C9orf72 Protein ; *Cognition ; Frontotemporal Dementia/*enzymology/genetics/physiopathology ; Humans ; Mutation ; Phenotype ; Proteins/*genetics/metabolism ; }, abstract = {This review article focuses on the cognitive profile associated with the C9orf72 gene with GGGGCC (G4C2) hexanucleotide repeat expansions that is commonly found in both familial and sporadic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in order to aid clinicians in the screening process. In this growing clinical continuum between FTD and ALS, understanding and recognizing a neurocognitive profile is important for diagnosis. Key features of this profile include executive dysfunction with memory impairment and language deficits as the disease progresses. Behaviorally, patients are prone to disinhibition, apathy, and psychosis. With the discovery of this mutation, studies have begun to characterize the different phenotypes associated with this mutation in terms of epidemiology, clinical presentation, imaging, and pathology. Greater awareness and increased surveillance for this mutation will benefit patients and their families in terms of access to genetic counseling, research studies, and improved understanding of the disease process.}, }
@article {pmid26198567, year = {2016}, author = {Niedzielska, E and Smaga, I and Gawlik, M and Moniczewski, A and Stankowicz, P and Pera, J and Filip, M}, title = {Oxidative Stress in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {53}, number = {6}, pages = {4094-4125}, pmid = {26198567}, issn = {1559-1182}, mesh = {Animals ; Antioxidants/metabolism ; Biomarkers/metabolism ; Clinical Trials as Topic ; Humans ; Neurodegenerative Diseases/*pathology ; *Oxidative Stress ; }, abstract = {The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.}, }
@article {pmid26193736, year = {2015}, author = {Garzillo, EM and Miraglia, N and Pedata, P and Feola, D and Sannolo, N and Lamberti, M}, title = {[Amyotrophic lateral sclerosis and exposure to metals and other occupational/environmental hazardous materials: state of the art].}, journal = {Giornale italiano di medicina del lavoro ed ergonomia}, volume = {37}, number = {1}, pages = {8-19}, pmid = {26193736}, issn = {1592-7830}, mesh = {Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology/etiology ; Electromagnetic Fields/adverse effects ; Humans ; Italy/epidemiology ; Meta-Analysis as Topic ; Metals, Heavy/*toxicity ; Occupational Diseases/*chemically induced/epidemiology/etiology ; Occupational Exposure/*adverse effects ; Pesticides/*toxicity ; Risk Assessment ; Risk Factors ; Xenobiotics/*toxicity ; }, abstract = {In recent years, scientific literature has been giving more and more importance to the study of the occupational/environmental exposure to risk agents related to the onset of Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex. Aim of this work is to verify the state of art about the eventual role of occupational/environmental exposure to risk agents. Selected articles, on the basis of keywords, year of publication and topics, are related to occupational and environmental exposure to xenobiotics, and, in particular, to the exposure to heavy metals that could lead to neuronal damage mechanisms involved in ALS onset. The review shows that although the scientific production has increased the interest in the evaluation of extra-genetic causes of ALS onset, there are still few studies concerning the careful study of the work activities of the individual patient, and the inferences that can be drawn to date about the possible connection between occupational exposure to risk factors and the onset of ALS are still lacking.}, }
@article {pmid26190397, year = {2015}, author = {Bonaccini, L and Karioti, A and Bergonzi, MC and Bilia, AR}, title = {Effects of Salvia miltiorrhiza on CNS Neuronal Injury and Degeneration: A Plausible Complementary Role of Tanshinones and Depsides.}, journal = {Planta medica}, volume = {81}, number = {12-13}, pages = {1003-1016}, doi = {10.1055/s-0035-1546196}, pmid = {26190397}, issn = {1439-0221}, support = {R01 DK078602/DK/NIDDK NIH HHS/United States ; }, mesh = {Abietanes/*pharmacology ; Alkenes/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Apoptosis/drug effects ; Cyclooxygenase 2/drug effects ; Depsides/*pharmacology ; Humans ; Medicine, Chinese Traditional ; Nerve Degeneration/*drug therapy ; Nitric Oxide Synthase Type II/drug effects ; Polyphenols/pharmacology ; Salvia miltiorrhiza/*chemistry ; }, abstract = {Salvia miltiorrhiza is a very important herbal drug of traditional Chinese medicine. Bioactive constituents are represented by two main groups of secondary metabolites, the lipophilic diterpenic quinones known as tanshinones and the hydrophilic depsides known as salvianolic acids. S. miltiorrhiza extracts and single constituents have been shown to have positive effects in central nervous system neuronal injury and degeneration in several animal models by various biological mechanisms. Both tanshinones and depsides protect against β-amyloid-induced toxicity, but their mechanisms are complementary due to their different structure, the lipophilic tanshinones and the hydrophilic depsides. A number of anti-inflammatory mechanisms is also reported for both tanshinones and depsides. Common mechanisms are the effects on cytokines, inducible nitric oxide synthase, and glial fibrillary acidic protein. In addition, depsides are inhibitors of nitric oxide and cyclooxygenase-2, while tanshinones inhibit hypoxia-inducible factor-1α and nuclear factor kappa β. Both constituents can also modulate the protection of the central nervous system from oxidative stress with different but complementary mechanisms: tanshinones can enhance the activities of superoxide dismutase and glutathione peroxidase, while depsides can decrease reactive oxygen species.Furthermore, neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. Both classes of constituents can enhance the antiapoptotic B-cell leukemia protein-2 family members and decrease the translocation of cytochrome c, and, in addition, depsides decrease caspase-3 and intracellular Ca(2+). Again, both classes of constituents have an activity on vascular endothelial growth factor but it is opposite, whereas tanshinones are inhibitors of acetylcholinesterase.Besides the extensive studies reporting on the biological mechanisms of depsides and tanshinones, pharmacokinetics studies are still very limited and not conclusive, especially for brain distribution. Further research is warranted to address the mechanisms of the multitarget actions of S. miltiorrhiza constituents and to translate this knowledge into clinical practice.}, }
@article {pmid26187860, year = {2015}, author = {Pasquin, S and Sharma, M and Gauchat, JF}, title = {Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies.}, journal = {Cytokine &amp; growth factor reviews}, volume = {26}, number = {5}, pages = {507-515}, doi = {10.1016/j.cytogfr.2015.07.007}, pmid = {26187860}, issn = {1879-0305}, support = {MOP-57832//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Ciliary Neurotrophic Factor/genetics/immunology/*therapeutic use ; Ciliary Neurotrophic Factor Receptor alpha Subunit/genetics/immunology ; Cytokine Receptor gp130/genetics/immunology ; Humans ; Metabolic Syndrome/*drug therapy/genetics/immunology ; Neurodegenerative Diseases/*drug therapy/genetics/immunology ; Receptors, Interleukin-6/genetics/immunology ; }, abstract = {Ciliary neurotrophic factor (CNTF) is the most extensively studied member of the cytokine family that signal through intracellular chains of the gp130/LIFRβ receptor. The severe phenotype in patients suffering from mutations inactivating LIFRβ indicates that members of this cytokine family play key, non-redundant roles during development. Accordingly, three decades of research has revealed potent and promising trophic and regulatory activities of CNTF in neurons, oligodendrocytes, muscle cells, bone cells, adipocytes and retinal cells. These findings led to clinical trials to test the therapeutic potential of CNTF and CNTF derivatives for treating neurodegenerative and metabolic diseases. Promising results have encouraged continuation of studies for treating retinal degenerative diseases. Results of some clinical trials showed that side-effects may limit the systemically administrated doses of CNTF. Therefore, therapies being currently tested rely on local delivery of CNTF using encapsulated cytokine-secreting implants. Since the side effects of CNTF might be linked to its ability to activate the alternative IL6Rα-LIFRβ-gp130 receptor, CNTFR-specific mutants of CNTF have been developed that bind to the CNTFRα-LIFRβ-gp130 receptor. These developments may prove to be a breakthrough for therapeutic applications of systemically administered CNTF in pathologies such as multiple sclerosis or Alzheimer's disease. The "designer cytokine approach" offers future opportunities to further enhance specificity by conjugating mutant CNTF with modified soluble CNTFRα to target therapeutically relevant cells that express gp130-LIFRβ and a specific cell surface marker.}, }
@article {pmid26187754, year = {2015}, author = {Haidet-Phillips, AM and Maragakis, NJ}, title = {Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Brain research}, volume = {1628}, number = {Pt B}, pages = {343-350}, pmid = {26187754}, issn = {1872-6240}, support = {U01 NS062713/NS/NINDS NIH HHS/United States ; U01NS062713/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Humans ; Neuroglia/*physiology ; Neurons/*physiology ; Stem Cell Transplantation/*methods ; }, abstract = {ALS is a neurodegenerative disease with a prevalence rate of up to 7.4/100,000 and the overall risk of developing ALS over a lifetime is 1:400. Most patients die from respiratory failure following a course of progressive weakness. To date, only one traditional pharmaceutical agent-riluzole, has been shown to afford a benefit on survival but numerous pharmaceutical interventions have been studied in preclinical models of ALS without subsequent translation to patient efficacy. Despite the relative selectivity of motor neuron cell death, animal and tissue culture models of familial ALS suggest that non-neuronal cells significantly contribute to neuronal dysfunction and death. Early efforts to transplant stem cells had focused on motor neuron replacement. More practically for this aggressive neurodegenerative disease, recent studies, preclinical efforts, and early clinical trials have focused on the transplantation of neural stem cells, mesenchymal stem cells, or glial progenitors. Using transgenic mouse or rat models of ALS, a number of studies have shown neuroprotection through a variety of different mechanisms that have included neurotrophic factor secretion, glutamate transporter regulation, and modulation of neuroinflammation, among others. However, given that cell replacement could involve a number of biologically relevant factors, identifying the key pathway(s) that may contribute to neuroprotection remains a challenge. Nevertheless, given the abundant data supporting the interplay between non-neuronal cell types and motor neuron disease propagation, the replacement of disease-carrying host cells by normal cells may be sufficient to confer neuroprotection. Key preclinical issues that currently are being addressed include the most appropriate methods and routes for delivery of cells to disease-relevant regions of the neuraxis, cell survival and migration, and tracking the cells following transplantation. Central to the initial development of stem cell transplantation into patients with ALS is the demonstration that transplanted cells lack tumorigenicity and have the appropriate biodistribution to ensure the safety of ALS patients receiving these therapies. Here, we review preclinical and clinical studies focusing on the transplantation of neural and glial progenitor cells as a promising neuroprotective therapy for ALS. The rationale for stem cell transplantation for neuroprotection, proof-of-concept animal studies, and current challenges facing translation of these therapies to the clinic is presented. Lastly, we discuss advancements on the horizon including induced pluripotent stem cell technology and developments for cellular tracking and detection post-transplantation. With the safe completion of the first-in-human Phase I clinical trial for intraspinal stem cell transplantation for ALS in the United States, the time is ripe for stem cell therapies to be translated to the clinic and excitingly, evaluated for neuroprotection for ALS. This article is part of a Special Issue entitled SI: Neuroprotection.}, }
@article {pmid26180587, year = {2015}, author = {Tellone, E and Galtieri, A and Russo, A and Giardina, B and Ficarra, S}, title = {Resveratrol: A Focus on Several Neurodegenerative Diseases.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {392169}, pmid = {26180587}, issn = {1942-0994}, mesh = {Alzheimer Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; Huntington Disease/metabolism/pathology ; Mitochondria/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Parkinson Disease/drug therapy/metabolism/pathology ; Resveratrol ; Stilbenes/pharmacology/*therapeutic use ; }, abstract = {Molecules of the plant world are proving their effectiveness in countering, slowing down, and regressing many diseases. The resveratrol for its intrinsic properties related to its stilbene structure has been proven to be a universal panacea, especially for a wide range of neurodegenerative diseases. This paper evaluates (in vivo and in vitro) the various molecular targets of this peculiar polyphenol and its ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. What emerges is that, in the deep heterogeneity of the pathologies evaluated, resveratrol through a convergence on the protein targets is able to give therapeutic responses in neuronal cells deeply diversified not only in morphological structure but especially in their function performed in the anatomical district to which they belong.}, }
@article {pmid26174444, year = {2015}, author = {Gould, RL and Coulson, MC and Brown, RG and Goldstein, LH and Al-Chalabi, A and Howard, RJ}, title = {Psychotherapy and pharmacotherapy interventions to reduce distress or improve well-being in people with amyotrophic lateral sclerosis: A systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {5-6}, pages = {293-302}, doi = {10.3109/21678421.2015.1062515}, pmid = {26174444}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy/rehabilitation ; Databases, Bibliographic/statistics &amp; numerical data ; Humans ; Psychotherapy/*methods ; Randomized Controlled Trials as Topic ; Stress, Psychological/drug therapy/etiology/rehabilitation ; }, abstract = {Our objective was to systematically review and critically evaluate the evidence for psychotherapy and pharmacotherapy interventions for reducing distress or improving well-being in people with amyotrophic lateral sclerosis (pwALS). Online bibliographic databases and clinical trial registers were searched and an assessment of study quality was conducted. Seven thousand two hundred and twenty-three studies were identified, of which five met inclusion criteria (four completed and one in progress). All studies examined psychotherapeutic interventions, and no studies investigated pharmacotherapy. Two studies adopted a randomized controlled trial design, one a controlled trial design and two a cohort design. Sample sizes were small in all studies (overall n = 145). The quality of completed studies was generally poor, with evidence that all were at potential risk of bias in numerous areas. Improvements in well-being were found with expressive disclosure (compared to no disclosure), cognitive behavioural therapy/counselling (compared to non-randomized pharmacotherapy) and hypnosis in the short term only, while no improvements were seen with a life review intervention. In conclusion, there is currently insufficient evidence to recommend the use of specific psychotherapy interventions for reducing distress or improving well-being in pwALS, and no evidence to support pharmacotherapy interventions. Research is urgently needed to address these significant gaps in the literature.}, }
@article {pmid26171319, year = {2015}, author = {Maiese, K}, title = {FoxO proteins in the nervous system.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2015}, number = {}, pages = {569392}, pmid = {26171319}, issn = {2210-7185}, mesh = {Animals ; Epigenesis, Genetic ; Forkhead Transcription Factors/genetics/*metabolism ; Humans ; Nervous System/*metabolism ; Nervous System Diseases/metabolism/pathology ; Oxidative Stress ; Protein Processing, Post-Translational ; }, abstract = {Acute as well as chronic disorders of the nervous system lead to significant morbidity and mortality for millions of individuals globally. Given the ability to govern stem cell proliferation and differentiated cell survival, mammalian forkhead transcription factors of the forkhead box class O (FoxO) are increasingly being identified as potential targets for disorders of the nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and auditory neuronal disease. FoxO proteins are present throughout the body, but they are selectively expressed in the nervous system and have diverse biological functions. The forkhead O class transcription factors interface with an array of signal transduction pathways that include protein kinase B (Akt), serum- and glucocorticoid-inducible protein kinase (SgK), IκB kinase (IKK), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), growth factors, and Wnt signaling that can determine the activity and integrity of FoxO proteins. Ultimately, there exists a complex interplay between FoxO proteins and their signal transduction pathways that can significantly impact programmed cell death pathways of apoptosis and autophagy as well as the development of clinical strategies for the treatment of neurodegenerative disorders.}, }
@article {pmid26166612, year = {2015}, author = {Finsterwald, C and Magistretti, PJ and Lengacher, S}, title = {Astrocytes: New Targets for the Treatment of Neurodegenerative Diseases.}, journal = {Current pharmaceutical design}, volume = {21}, number = {25}, pages = {3570-3581}, doi = {10.2174/1381612821666150710144502}, pmid = {26166612}, issn = {1873-4286}, mesh = {Animals ; Astrocytes/drug effects/*metabolism ; Cerebral Cortex/drug effects/*metabolism ; Drug Discovery/*methods ; Energy Metabolism/*drug effects ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neurons/drug effects/metabolism ; }, abstract = {The causes of neurodegenerative disorders are multiple, and for most of them a mechanistic understanding is still lacking. However, neurodegenerative diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) all share common features that include elevated oxidative stress levels and impaired energy metabolism in the nervous system. Most of the current treatments are only successful at alleviating some of the pathological symptoms, but fail at preventing neurodegeneration. There is therefore an urgent need for innovative and more efficient treatments for neurodegenerative disorders. We review here the central role played by astrocytes in the regulation of brain homeostasis, protection and function by supporting neuronal health and activity. In particular, astrocytes are key partners of neuronal metabolism, notably through activation of the astrocyteneuron lactate shuttle (ANLS). They also control the levels of extracellular glutamate, production of antioxidant molecules, disposal of neuronal waste products, storage of energy in the form of glycogen, and expression of neurotrophic factors. These mechanisms, which are key for brain activity and cognition, also largely contribute to neuronal degeneration in pathological situations. Thus, as astrocytes appear to play a key role in the etiology of neurodegenerative disorders, a growing interest has arisen for astrocytemediated pathways as targets for drugs that aim at treating the root causes of the pathology. We present here the most recent and promising astrocyte-based therapeutic approaches - from fundamental discoveries to clinical trials - that intent to sustain neuronal health and function in neurodegenerative disorders.}, }
@article {pmid26166297, year = {2016}, author = {Ahmed, RM and Newcombe, RE and Piper, AJ and Lewis, SJ and Yee, BJ and Kiernan, MC and Grunstein, RR}, title = {Sleep disorders and respiratory function in amyotrophic lateral sclerosis.}, journal = {Sleep medicine reviews}, volume = {26}, number = {}, pages = {33-42}, doi = {10.1016/j.smrv.2015.05.007}, pmid = {26166297}, issn = {1532-2955}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Disease Progression ; Humans ; Respiratory Insufficiency/etiology/*physiopathology/therapy ; Sleep Wake Disorders/etiology/*physiopathology/therapy ; }, abstract = {Sleep disorders in amyotrophic lateral sclerosis (ALS) present a significant challenge to the management of patients. Issues include the maintenance of adequate ventilatory status through techniques such as non-invasive ventilation, which has the ability to modulate survival and improve patient quality of life. Here, a multidisciplinary approach to the management of these disorders is reviewed, from concepts about the underlying neurobiological basis, through to current management approaches and future directions for research.}, }
@article {pmid26162835, year = {2015}, author = {Kida, K and Ichinose, F}, title = {Hydrogen Sulfide and Neuroinflammation.}, journal = {Handbook of experimental pharmacology}, volume = {230}, number = {}, pages = {181-189}, doi = {10.1007/978-3-319-18144-8_9}, pmid = {26162835}, issn = {0171-2004}, mesh = {Animals ; Apoptosis ; Humans ; Hydrogen Sulfide/*metabolism ; Inflammation/*etiology ; Parkinson Disease/*etiology ; }, abstract = {The innate and adaptive immune system plays an important role in diverse forms of central nervous system (CNS) pathologies including neurodegenerative diseases and peripheral nerve injury. Evidence for an innate inflammatory response in Alzheimer's disease (AD) was described 20 years ago, and subsequent studies have documented roles of inflammation in Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and a growing number of other CNS pathologies. Although inflammation may not be the initiating factor for neurodegenerative pathologies, experimental data suggests that persistent inflammatory responses involving microglia and astrocytes, as well as blood monocyte-derived macrophages, clearly contribute to disease progression. High levels of hydrogen sulfide exert toxic effects to CNS. On the other hand, low and physiological levels of H2S may have beneficial effects on number of tissues including CNS. For example, a number of studies have reported that H2S exerts anti-inflammatory and anti-apoptotic effects in CNS. In this chapter, studies related to the role of H2S in neuroinflammation and neurodegeneration will be reviewed and discussed. In particular, we will focus on the role of H2S in neuroinflammation associated with PD.}, }
@article {pmid26160823, year = {2015}, author = {Kokubo, Y}, title = {[Diagnostic Criteria for Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {67}, number = {7}, pages = {961-966}, doi = {10.11477/mf.1416200238}, pmid = {26160823}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/epidemiology ; Dementia/complications/*diagnosis/epidemiology ; Humans ; Incidence ; Japan/epidemiology ; Parkinsonian Disorders/complications/*diagnosis/epidemiology ; Severity of Illness Index ; }, abstract = {The diagnostic criteria for amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula of Japan (Kii ALS/PDC) have been proposed. Muro disease has been considered an endemic neurodegenerative disease in the southern part of the Kii peninsula. Recent intensive and comprehensive research has revealed it to be a complex and genetically heterogeneous disease. At present, there are four subtypes of Muro disease: sporadic amyotrophic lateral sclerosis (ALS), Kii ALS/PDC with tauopathy, ALS with C9orf72 gene mutation, and ALS with optineurin gene mutation. The present criteria are applicable to only one of these subtypes, Kii ALS/PDC with tauopathy, which is quite similar to ALS/PDC in Guam.}, }
@article {pmid26157387, year = {2015}, author = {Foster, PP}, title = {Role of physical and mental training in brain network configuration.}, journal = {Frontiers in aging neuroscience}, volume = {7}, number = {}, pages = {117}, pmid = {26157387}, issn = {1663-4365}, abstract = {It is hypothesized that the topology of brain networks is constructed by connecting nodes which may be continuously remodeled by appropriate training. Efficiency of physical and/or mental training on the brain relies on the flexibility of networks' architecture molded by local remodeling of proteins and synapses of excitatory neurons producing transformations in network topology. Continuous remodeling of proteins of excitatory neurons is fine-tuning the scaling and strength of excitatory synapses up or down via regulation of intra-cellular metabolic and regulatory networks of the genome-transcriptome-proteome interface. Alzheimer's disease is a model of "energy cost-driven small-world network disorder" with dysfunction of high-energy cost wiring as the network global efficiency is impaired by the deposition of an informed agent, the amyloid-β, selectively targeting high-degree nodes. In schizophrenia, the interconnectivity and density of rich-club networks are significantly reduced. Training-induced homeostatic synaptogenesis-enhancement, presumably via reconfiguration of brain networks into greater small-worldness, appears essential in learning, memory, and executive functions. A macroscopic cartography of creation-removal of synaptic connections in a macro-network, and at the intra-cellular scale, micro-networks regulate the physiological mechanisms for the preferential attachment of synapses. The strongest molecular relationship of exercise and functional connectivity was identified for brain-derived neurotrophic factor (BDNF). The allele variant, rs7294919, also shows a powerful relationship with the hippocampal volume. How the brain achieves this unique quest of reconfiguration remains a puzzle. What are the underlying mechanisms of synaptogenesis promoting communications brain ↔ muscle and brain ↔ brain in such trainings? What is the respective role of independent mental, physical, or combined-mental-physical trainings? Physical practice seems to be playing an instrumental role in the cognitive enhancement (brain ↔ muscle com.). However, mental training, meditation or virtual reality (films, games) require only minimal motor activity and cardio-respiratory stimulation. Therefore, other potential paths (brain ↔ brain com.) molding brain networks are nonetheless essential. Patients with motor neuron disease/injury (e.g., amyotrophic lateral sclerosis, traumatism) also achieve successful cognitive enhancement albeit they may only elicit mental practice.}, }
@article {pmid26152655, year = {2016}, author = {Hawkey, NM and Zaorsky, NG and Galloway, TJ}, title = {The role of radiation therapy in the management of sialorrhea: A systematic review.}, journal = {The Laryngoscope}, volume = {126}, number = {1}, pages = {80-85}, doi = {10.1002/lary.25444}, pmid = {26152655}, issn = {1531-4995}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Parkinson Disease/*complications ; Salivary Glands/*radiation effects ; Sialorrhea/etiology/*radiotherapy ; }, abstract = {PURPOSE: Up to 80% of patients with Parkinson disease and 30% of patients with amyotrophic lateral sclerosis (ALS) suffer from sialorrhea. Patients who fail medical and surgical therapy should be considered for external beam radiation therapy (EBRT). In this study, we conduct a systematic review to determine the dose and techniques used that result in greatest efficacy and lowest toxicity for the administration of EBRT in patients with Parkinson disease or ALS-associated sialorrhea.<br><br>METHODS AND MATERIALS: This review included 216 patients from four prospective and six retrospective studies published from 1998 to 2014, with ALS or Parkinson disease who were treated with electron or photon EBRT for sialorrhea.<br><br>RESULTS: A total of 216 patients were treated with EBRT from 10 studies. The indication for EBRT was failure of alternative medical treatment in all ALS patients. For patients with Parkinson disease, EBRT was the primary mode of treatment in 68% of cases. Overall, 176 (81%) of 216 patients treated with EBRT for sialorrhea reported symptomatic improvement from baseline. The most common target was the inferior two-thirds of the bilateral parotid glands and the entire bilateral submandibular glands. The total number of patients who experienced short-term toxicity was 86 of 216 patients (40%). The total number of patients who experienced long-term toxicity was 24 of 207 (12%).<br><br>CONCLUSIONS: EBRT is an effective treatment for sialorrhea in patients suffering from ALS or Parkinson disease. Treatment to the bilateral submandibular glands and caudal parotid glands is the most common field arrangement.}, }
@article {pmid26150098, year = {2015}, author = {Maizels, N}, title = {G4-associated human diseases.}, journal = {EMBO reports}, volume = {16}, number = {8}, pages = {910-922}, pmid = {26150098}, issn = {1469-3178}, support = {P01 CA077852/CA/NCI NIH HHS/United States ; R01 GM065988/GM/NIGMS NIH HHS/United States ; P01 CA77852/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; DNA/genetics ; Disease/*genetics ; *G-Quadruplexes ; *Genome, Human ; Genomic Instability ; Humans ; Neoplasms/genetics ; Nervous System Diseases/*genetics ; }, abstract = {Recent research has established clear connections between G-quadruplexes and human disease. Features of quadruplex structures that promote genomic instability have been determined. Quadruplexes have been identified as transcriptional, translational and epigenetic regulatory targets of factors associated with human genetic disease. An expandable GGGGCC motif that can adopt a G4 structure, located in the previously obscure C9ORF72 locus, has been shown to contribute to two well-recognized neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review focuses on these advances, which further dispel the view that genomic biology is limited to the confines of the canonical B-form DNA duplex, and show how quadruplexes contribute spatial and temporal dimensionalities to linear sequence information. This recent progress also has clear practical ramifications, as prevention, diagnosis, and treatment of disease depend on understanding the underlying mechanisms.}, }
@article {pmid26148561, year = {2015}, author = {Jones, KJ and Lovett-Racke, AE and Walker, CL and Sanders, VM}, title = {CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {10}, number = {4}, pages = {587-594}, pmid = {26148561}, issn = {1557-1904}, support = {R01 NS040433/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; CD4-Positive T-Lymphocytes/*immunology ; Humans ; Motor Neurons/*immunology ; Nerve Regeneration/*immunology ; Neuroprotection/*immunology ; }, abstract = {We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1(G93A); abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.}, }
@article {pmid26144267, year = {2015}, author = {Morello, G and Cavallaro, S}, title = {Transcriptional analysis reveals distinct subtypes in amyotrophic lateral sclerosis: implications for personalized therapy.}, journal = {Future medicinal chemistry}, volume = {7}, number = {10}, pages = {1335-1359}, doi = {10.4155/fmc.15.60}, pmid = {26144267}, issn = {1756-8927}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/metabolism/*pathology ; Animals ; Drug Discovery/methods ; *Gene Expression Profiling ; Humans ; Molecular Targeted Therapy/*methods ; Motor Neurons/drug effects/metabolism/*pathology ; Precision Medicine/methods ; Signal Transduction/drug effects ; Transcriptome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable disease, caused by the loss of the upper and lower motor neurons. The lack of therapeutic progress is mainly due to the insufficient understanding of complexity and heterogeneity underlying the pathogenic mechanisms of ALS. Recently, we analyzed whole-genome expression profiles of motor cortex of sporadic ALS patients, classifying them into two subgroups characterized by differentially expressed genes and pathways. Some of the deregulated genes encode proteins, which are primary targets of drugs currently in preclinical or clinical studies for several clinical conditions, including neurodegenerative diseases. In this review, we discuss in-depth the potential role of these candidate targets in ALS pathogenesis, highlighting their possible relevance for personalized ALS treatments.}, }
@article {pmid26142952, year = {2016}, author = {Ying, H and Yue, BY}, title = {Optineurin: The autophagy connection.}, journal = {Experimental eye research}, volume = {144}, number = {}, pages = {73-80}, pmid = {26142952}, issn = {1096-0007}, support = {P30 EY001792/EY/NEI NIH HHS/United States ; R01 EY018828/EY/NEI NIH HHS/United States ; EY001792/EY/NEI NIH HHS/United States ; EY018828/EY/NEI NIH HHS/United States ; }, mesh = {Autophagy/*genetics ; Cell Cycle Proteins ; Humans ; Low Tension Glaucoma/*genetics ; Membrane Transport Proteins ; Transcription Factor TFIIIA/*genetics ; }, abstract = {Optineurin is a cytosolic protein encoded by the OPTN gene. Mutations of OPTN are associated with normal tension glaucoma and amyotrophic lateral sclerosis. Autophagy is an intracellular degradation system that delivers cytoplasmic components to the lysosomes. It plays a wide variety of physiological and pathophysiological roles. The optineurin protein is a selective autophagy receptor (or adaptor), containing an ubiquitin binding domain with the ability to bind polyubiquitinated cargoes and bring them to autophagosomes via its microtubule-associated protein 1 light chain 3-interacting domain. It is involved in xenophagy, mitophagy, aggrephagy, and tumor suppression. Optineurin can also mediate the removal of protein aggregates through an ubiquitin-independent mechanism. This protein in addition can induce autophagy upon overexpression or mutation. When overexpressed or mutated, the optineurin protein also serves as a substrate for autophagic degradation. In the present review, the multiple connections of optineurin to autophagy are highlighted.}, }
@article {pmid26136661, year = {2015}, author = {Leal, SS and Gomes, CM}, title = {Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {225}, pmid = {26136661}, issn = {1662-5102}, abstract = {More than 20 distinct gene loci have so far been implicated in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by progressive neurodegeneration of motor neurons (MN) and death. Most of this distinct set of ALS-related proteins undergoes toxic deposition specifically in MN for reasons which remain unclear. Here we overview a recent body of evidence indicative that mutations in ALS-related proteins can disrupt fundamental Ca(2+) signalling pathways in MN, and that Ca(2+) itself impacts both directly or indirectly in many ALS critical proteins and cellular processes that result in MN neurodegeneration. We argue that the inherent vulnerability of MN to dysregulation of intracellular Ca(2+) is deeply associated with discriminating pathogenicity and aberrant crosstalk of most of the critical proteins involved in ALS. Overall, Ca(2+) deregulation in MN is at the cornerstone of different ALS processes and is likely one of the factors contributing to the selective susceptibility of these cells to this particular neurodegenerative disease.}, }
@article {pmid26136395, year = {2015}, author = {Carreiro, AV and Mendonça, A and de Carvalho, M and Madeira, SC}, title = {Integrative biomarker discovery in neurodegenerative diseases.}, journal = {Wiley interdisciplinary reviews. Systems biology and medicine}, volume = {7}, number = {6}, pages = {357-379}, doi = {10.1002/wsbm.1310}, pmid = {26136395}, issn = {1939-005X}, mesh = {Biomarkers/*metabolism ; Genome-Wide Association Study ; Genomics ; Humans ; Models, Theoretical ; Neurodegenerative Diseases/metabolism/*pathology ; Proteomics ; }, abstract = {Data mining has been widely applied in biomarker discovery resulting in significant findings of different clinical and biological biomarkers. With developments in technology, from genomics to proteomics analysis, a deluge of data has become available, as well as standardized data repositories. Nonetheless, researchers are still facing important challenges in analyzing the data, especially when considering the complexity of pathways involved in biological processes and diseases. Data from single sources appear unable to explain complex processes, such as those involved in brain-related disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, thus raising the need for a more comprehensive perspective. A possible solution relies on data and model integration, where several data types are combined to provide complementary views. This in turn can result in the discovery of previously unknown biomarkers by unraveling otherwise hidden relationships between data from different sources, and/or validate such composite biomarkers in more powerful predictive models.}, }
@article {pmid26131313, year = {2015}, author = {Yanovsky-Dagan, S and Mor-Shaked, H and Eiges, R}, title = {Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells.}, journal = {World journal of stem cells}, volume = {7}, number = {5}, pages = {823-838}, pmid = {26131313}, issn = {1948-0210}, abstract = {Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences (mostly microsatellites) that become unstable beyond a critical length when transmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells (diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.}, }
@article {pmid26129625, year = {2015}, author = {Nakagawa, Y and Chiba, K}, title = {Diversity and plasticity of microglial cells in psychiatric and neurological disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {154}, number = {}, pages = {21-35}, doi = {10.1016/j.pharmthera.2015.06.010}, pmid = {26129625}, issn = {1879-016X}, mesh = {Adiponectin/immunology ; Bipolar Disorder/*immunology ; Brain/immunology ; Cytokines/immunology ; Endocannabinoids/immunology ; Feeding Behavior/physiology ; Ghrelin/immunology ; Humans ; Inflammation Mediators/immunology ; Lysophospholipids/immunology ; Macrophages/*immunology ; Mental Disorders/immunology ; Microglia/*immunology ; Nerve Net/immunology ; Nervous System Diseases/*immunology ; Obesity/*immunology ; Social Behavior ; Sphingosine/analogs &amp; derivatives/immunology ; }, abstract = {Recent advanced immunological analyses have revealed that the diversity and plasticity of macrophages lead to the identification of functional polarization states (classically activated M1 type and alternatively activated M2 type) which are dependent on the extracellular environment. M1 and M2 polarization states of macrophages play an important role in controlling the balance between pro-inflammatory and anti-inflammatory conditions. Microglial cells are resident mononuclear phagocytes in the central nervous system (CNS), express several macrophage-associated markers, and appear to display functional polarization states similar to macrophages. Like M1 macrophages, M1 polarized microglia can produce pro-inflammatory cytokines and mediators such as interleukin (IL) 1β, IL-6, tumor necrosis factor-α, CC-chemokine ligand 2, nitric oxide, and reactive oxygen species, suggesting that these molecules contribute to dysfunction of neural network in the CNS. On the other hand, M2 polarized microglia can produce anti-inflammatory cytokine, IL-10 and express several receptors that are implicated in inhibiting inflammation and restoring homeostasis. In this review, we summarize the diversity, plasticity, and immunoregulatory functions of M1 and M2 microglia in psychiatric and neurological disorders. Based on these aspects, we propose a contribution of imbalance between M1 and M2 polarization of microglia in bipolar disorder, obesity, amyotrophic lateral sclerosis, and Rett syndrome. Consequently, molecules that normalize the imbalance between M1 and M2 microglial polarization states may provide a beneficial therapeutic target for the treatment of these disorders.}, }
@article {pmid26122838, year = {2015}, author = {O'Connor, DM and Boulis, NM}, title = {Gene therapy for neurodegenerative diseases.}, journal = {Trends in molecular medicine}, volume = {21}, number = {8}, pages = {504-512}, doi = {10.1016/j.molmed.2015.06.001}, pmid = {26122838}, issn = {1471-499X}, mesh = {Animals ; Clinical Trials as Topic ; *Genetic Therapy/adverse effects/methods ; Humans ; Neurodegenerative Diseases/*genetics/*therapy ; Treatment Outcome ; }, abstract = {Gene therapy is, potentially, a powerful tool for treating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Parkinson's disease (PD) and Alzheimer's disease (AD). To date, clinical trials have failed to show any improvement in outcome beyond the placebo effect. Efforts to improve outcomes are focusing on three main areas: vector design and the identification of new vector serotypes, mode of delivery of gene therapies, and identification of new therapeutic targets. These advances are being tested both individually and together to improve efficacy. These improvements may finally make gene therapy successful for these disorders.}, }
@article {pmid26121273, year = {2015}, author = {Huang, R and Guo, X and Chen, X and Zheng, Z and Wei, Q and Cao, B and Zeng, Y and Shang, H}, title = {The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {5-6}, pages = {359-365}, doi = {10.3109/21678421.2015.1047454}, pmid = {26121273}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood/genetics ; C9orf72 Protein ; Case-Control Studies ; China/epidemiology ; Databases, Bibliographic/statistics &amp; numerical data ; Female ; Humans ; Lipids/*blood ; Male ; Middle Aged ; Neurologic Examination ; Proportional Hazards Models ; Proteins/genetics ; Regression Analysis ; Young Adult ; }, abstract = {Associations between the fasting levels of serum lipid and amyotrophic lateral sclerosis (ALS) in Chinese populations remain largely unknown. Our objective was to analyse data from a cohort of ALS patients to determine these associations. Four hundred and thirteen ALS patients and 400 age- and gender-matched healthy controls were included. Fasting serum lipid concentration of all subjects, including total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglyceride (TG), were measured at the time of first visit. The revised ALS Functional Rating Scale (ALSFRS-R) was used to assess the severity of ALS. Systems Analysis by Review Manager 5 was used to evaluate differences in dyslipidaemia between ALS patients and controls. Results showed that ALS patients with higher triglyceride levels had longer survival time compared to patients with lower triglyceride levels (p < 0.05). We found a median prolonged life expectancy of 5.8 months for patients with serum triglyceride levels above the median of 127.5 mg/dl. Cox regression analysis indicated that disease duration and age were positively correlated with death, and triglyceride was positively correlated with survival. A meta-analysis indicated that there were no significant differences in mean total cholesterol, TG, LDL or the LDL/HDL ratio between patients and controls. In conclusion, high serum TG might be a protective factor for the survival of patients with ALS.}, }
@article {pmid26119401, year = {2015}, author = {Liu, YJ and Chern, Y}, title = {AMPK-mediated regulation of neuronal metabolism and function in brain diseases.}, journal = {Journal of neurogenetics}, volume = {29}, number = {2-3}, pages = {50-58}, doi = {10.3109/01677063.2015.1067203}, pmid = {26119401}, issn = {1563-5260}, mesh = {Adenylate Kinase/*metabolism ; Brain/*metabolism/physiopathology ; Brain Diseases/*metabolism/physiopathology ; Humans ; Neurodegenerative Diseases/*metabolism/physiopathology ; Neurons/*metabolism ; }, abstract = {The AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a key energy sensor in a wide variety of tissues. This kinase has been a major drug target for metabolic diseases (e.g., type 2 diabetes) and cancers. For example, metformin (an activator of AMPK) is a first-line diabetes drug that protects against cancers. Abnormal regulation of AMPK has been implicated in several brain diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Given the emerging importance of neurodegenerative diseases in our aging societies, this review features the recent studies that have delineated the functions of AMPK in brain diseases and discusses their potential clinical implications or roles as drug targets in brain diseases.}, }
@article {pmid26096891, year = {2015}, author = {Fontana, AC}, title = {Current approaches to enhance glutamate transporter function and expression.}, journal = {Journal of neurochemistry}, volume = {134}, number = {6}, pages = {982-1007}, doi = {10.1111/jnc.13200}, pmid = {26096891}, issn = {1471-4159}, mesh = {Animals ; Brain/*metabolism ; Excitatory Amino Acid Transporter 2/*metabolism ; Homeostasis/*physiology ; Humans ; Synaptic Transmission/*physiology ; }, abstract = {L-glutamate is the predominant excitatory neurotransmitter in the CNS and has a central role in a variety of brain functions. The termination of glutamate neurotransmission by excitatory amino acid transporters (EAATs) is essential to maintain glutamate concentration low in extracellular space and avoid excitotoxicity. EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamate transmission. Dysfunction of EAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, amyotrophic lateral sclerosis, Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression of EAAT2/GLT-1 could serve as a potential therapy for these conditions. Translational activators of EAAT2/GLT-1, such as ceftriaxone and LDN/OSU-0212320, have been described to have significant protective effects in animal models of amyotrophic lateral sclerosis and epilepsy. In addition, pharmacological activators of the activity of EAAT2/GLT-1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators. This review describes the current status of the search for EAAT2/GLT-1 activators and addresses challenges and limitations that this approach might encounter. Termination of glutamate neurotransmission by glutamate transporter EAAT2 is essential to maintain homeostasis in the brain and to avoid excitotoxicity. Dysfunction of EAAT2 has been correlated with various neurological pathologies. Therefore, activators of the function or enhancers of the expression of EAAT2 (green arrows) could serve as a potential therapy for these conditions. This review describes the current status of the search for EAAT2 activators and addresses challenges and limitations of this approach.}, }
@article {pmid26091205, year = {2015}, author = {Plowman, EK}, title = {Is There a Role for Exercise in the Management of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis?.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {58}, number = {4}, pages = {1151-1166}, doi = {10.1044/2015_JSLHR-S-14-0270}, pmid = {26091205}, issn = {1558-9102}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Exercise Therapy/*methods ; Extremities/physiopathology ; Humans ; Respiration ; Speech/physiology ; }, abstract = {PURPOSE: The role of exercise in the management of people with amyotrophic lateral sclerosis (PALS) is controversial and currently unclear. The purpose of this review article is to review literature examining the impact of limb, respiratory, and oral motor exercise on function, disease progression, and survival in PALS and the transgenic ALS animal model.<br><br>METHOD: A literature review was conducted to examine relevant studies published in peer-reviewed journals between 1960 and 2014. All studies were appraised for quality of research and were assigned a level of evidence, and treatment outcomes were classified as either positive, negative, or neutral.<br><br>RESULTS: A total of 18 exercise-based intervention studies on limb (13), respiratory (3), or speech (2) function were identified. Of the human clinical trials, 6 were experimental and 4 were exploratory. No experimental studies were identified examining the impact of targeted exercise on speech or swallowing function. Mild to moderate intensity limb or respiratory exercise, applied early in the disease, was noted to have a beneficial impact on motor function and survival.<br><br>CONCLUSION: Insufficient data exist to support or refute the role of exercise in the management of bulbar dysfunction in PALS. This represents a critical area of future investigation.}, }
@article {pmid26088116, year = {2015}, author = {Hulse, G and Kelty, E and Hood, S and Norman, A and Basso, MR and Reece, AS}, title = {Novel Indications for Benzodiazepine Antagonist Flumazenil in GABA Mediated Pathological Conditions of the Central Nervous System.}, journal = {Current pharmaceutical design}, volume = {21}, number = {23}, pages = {3325-3342}, doi = {10.2174/1381612821666150619092720}, pmid = {26088116}, issn = {1873-4286}, mesh = {Animals ; Central Nervous System/*drug effects/metabolism/physiopathology ; Central Nervous System Diseases/diagnosis/*drug therapy/metabolism/physiopathology ; Flumazenil/adverse effects/*therapeutic use ; GABA Antagonists/adverse effects/*therapeutic use ; Humans ; Inappropriate Prescribing ; *Off-Label Use ; Patient Safety ; Practice Patterns, Physicians' ; Risk Assessment ; Risk Factors ; Treatment Outcome ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {This review paper discusses the central role of gamma-aminobutyric acid (GABA) in diverse physiological systems and functions and the therapeutic potential of the benzodiazepine antagonist flumazenil (Ro 15- 1788) for a wide range of disorders of the central nervous system (CNS). Our group and others have studied the potential of flumazenil as a treatment for benzodiazepine dependence. A small but growing body of research has indicated that flumazenil may also have clinical application in CNS disorders such as Parkinson's disease, idiopathic hypersomnia and amyotrophic lateral sclerosis. Despite this body of research the therapeutic potential of flumazenil remains poorly understood and largely unrealized. The purpose of this paper is not to provide an exhaustive review of all possible therapeutic applications for flumazenil but rather to stimulate research interest, and discussion of the exciting therapeutic potential of this drug for a range of chronic debilitating conditions.}, }
@article {pmid26087000, year = {2016}, author = {Ganie, SA and Dar, TA and Bhat, AH and Dar, KB and Anees, S and Zargar, MA and Masood, A}, title = {Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders.}, journal = {Rejuvenation research}, volume = {19}, number = {1}, pages = {21-40}, doi = {10.1089/rej.2015.1704}, pmid = {26087000}, issn = {1557-8577}, mesh = {Aging/drug effects/pathology ; Antioxidants/pharmacology/*therapeutic use ; Humans ; Melatonin/pharmacology/*therapeutic use ; Metabolome/drug effects ; Mitochondrial Diseases/*drug therapy/pathology ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed.}, }
@article {pmid26082680, year = {2015}, author = {Hensel, N and Rademacher, S and Claus, P}, title = {Chatting with the neighbors: crosstalk between Rho-kinase (ROCK) and other signaling pathways for treatment of neurological disorders.}, journal = {Frontiers in neuroscience}, volume = {9}, number = {}, pages = {198}, pmid = {26082680}, issn = {1662-4548}, abstract = {ROCK inhibition has been largely applied as a strategy to treat neurodegenerative diseases (NDDs) and promising results have been obtained in the recent years. However, the underlying molecular and cellular mechanisms are not fully understood and different models have been proposed for neurodegenerative disorders. Here, we aim to review the current knowledge obtained for NDDs identifying common mechanisms as well as disease-specific models. In addition to the role of ROCK in different cell types such as neurons and microglia, we focus on the molecular signaling-pathways which mediate the beneficial effects of ROCK. Besides canonical ROCK signaling, modulation of neighboring pathways by non-canonical ROCK-crosstalk is a recurrent pattern in many NDD-model systems and has been suggested to mediate beneficial effects of ROCK-inhibition.}, }
@article {pmid26081142, year = {2016}, author = {Chang, XL and Tan, MS and Tan, L and Yu, JT}, title = {The Role of TDP-43 in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {53}, number = {5}, pages = {3349-3359}, pmid = {26081142}, issn = {1559-1182}, mesh = {Alzheimer Disease/blood/cerebrospinal fluid/*metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; DNA-Binding Proteins/blood/cerebrospinal fluid/chemistry/*metabolism ; Humans ; Models, Biological ; Molecular Targeted Therapy ; }, abstract = {The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, also known as FTLD-TDP). Several studies have indicated TDP-43 deposits in Alzheimer's disease (AD) brains and have robust connection with AD clinical phenotype. FTLD-U, which was symptomatically connected with AD, may be predictable for the comprehension of the role TDP-43 in AD. TDP-43 may contribute to AD through both β-amyloid (Aβ)-dependent and Aβ-independent pathways. In this article, we summarize the latest studies concerning the role of TDP-43 in AD and explore TDP-43 modulation as a potential therapeutic strategy for AD. However, to date, little of pieces of the research on TDP-43 have been performed to investigate the role in AD; more investigations need to be confirmed in the future.}, }
@article {pmid26073858, year = {2016}, author = {Marinangeli, C and Didier, S and Vingtdeux, V}, title = {AMPK in Neurodegenerative Diseases: Implications and Therapeutic Perspectives.}, journal = {Current drug targets}, volume = {17}, number = {8}, pages = {890-907}, doi = {10.2174/1389450117666160201105645}, pmid = {26073858}, issn = {1873-5592}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Energy Metabolism ; Gene Expression Regulation ; Humans ; Hypothalamus/metabolism ; Neurodegenerative Diseases/*metabolism ; Neuronal Plasticity ; Neurons/*metabolism ; Signal Transduction ; }, abstract = {Maintaining proper energy levels in brain neurons is crucial for many cerebral functions such as synaptic transmission, vesicle recycling and axonal transport. AMP-activated protein kinase (AMPK) is the main energy sensor of all living cells. Beside its role as a crucial whole-body energy sensor in hypothalamic neurons, AMPK is also expressed in neurons throughout the brain where it might play additional fundamental roles. For instance, AMPK might be involved in brain development, neuronal polarization and neuronal activity. In addition, recent evidences suggest that AMPK deregulation might participate in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and ischemic stroke. Therefore, AMPK is emerging as a potential therapeutic target for these neurodegenerative diseases. Here, we will review the recent literature regarding the physiological and pathological role of AMPK in the brain and discuss the resulting potential therapeutic implications.}, }
@article {pmid26073124, year = {2015}, author = {Karademir, B and Corek, C and Ozer, NK}, title = {Endoplasmic reticulum stress and proteasomal system in amyotrophic lateral sclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {88}, number = {Pt A}, pages = {42-50}, doi = {10.1016/j.freeradbiomed.2015.05.038}, pmid = {26073124}, issn = {1873-4596}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Apoptosis ; Autophagy ; Endoplasmic Reticulum Stress/*physiology ; Humans ; Proteasome Endopeptidase Complex/*metabolism ; Unfolded Protein Response/*physiology ; }, abstract = {Protein processing including folding, unfolding and degradation is involved in the mechanisms of many diseases. Unfolded protein response and/or endoplasmic reticulum stress are accepted to be the first steps which should be completed via protein degradation. In this direction, proteasomal system and autophagy play important role as the degradation pathways and controlled via complex mechanisms. Amyotrophic lateral sclerosis is a multifactorial neurodegenerative disease which is also known as the most catastrophic one. Mutation of many different genes are involved in the pathogenesis such as superoxide dismutase 1, chromosome 9 open reading frame 72 and ubiquilin 2. These genes are mainly related to the antioxidant defense systems, endoplasmic reticulum stress related proteins and also protein aggregation, degradation pathways and therefore mutation of these genes cause related disorders.This review focused on the role of protein processing via endoplasmic reticulum and proteasomal system in amyotrophic lateral sclerosis which are the main players in the pathology. In this direction, dysfunction of endoplasmic reticulum associated degradation and related cell death mechanisms that are autophagy/apoptosis have been detailed.}, }
@article {pmid26071511, year = {2015}, author = {Khin Khin, E and Minor, D and Holloway, A and Pelleg, A}, title = {Decisional Capacity in Amyotrophic Lateral Sclerosis.}, journal = {The journal of the American Academy of Psychiatry and the Law}, volume = {43}, number = {2}, pages = {210-217}, pmid = {26071511}, issn = {1943-3662}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Behavior Observation Techniques ; Cognition Disorders/diagnosis/psychology ; *Decision Making ; Humans ; Mental Competency/*legislation &amp; jurisprudence ; Mental Disorders/diagnosis/psychology ; Patient Self-Determination Act ; United States ; }, abstract = {The cognitive and behavioral changes that can be observed in the neurodegenerative terminal disease amyotrophic lateral sclerosis (ALS), once characterized as purely a motor neuron disease, have become increasingly recognized over the past century. Detecting cognitive deficits earlier and identifying continued changes at regular intervals can lead to improved care, proactive treatments, and earlier discussions about end-of-life wishes. Although medical decisional capacity is required for every treatment decision made, its importance becomes paramount when making decisions on complex medical treatments that will invariably and significantly affect quality of life or life itself. In this review, we conducted a critical analysis of the evidence-based literature on the cognitive and behavioral impairments in ALS that can compromise medical decisional capacity. We review specific ALS-related clinical scenarios in which decisional capacity is of utmost importance and discuss a practical framework for cognitive and behavioral assessment that can be routinely and efficiently used, while being mindful of the confounding factors associated with ALS. Finally, we review models for preserving patient choices that can be used in patients with ALS to help safeguard autonomy and retain dignity toward the end of life.}, }
@article {pmid26059699, year = {2015}, author = {Liu, YT and Lee, YC and Soong, BW}, title = {What we have learned from the next-generation sequencing: Contributions to the genetic diagnoses and understanding of pathomechanisms of neurodegenerative diseases.}, journal = {Journal of neurogenetics}, volume = {29}, number = {2-3}, pages = {103-112}, doi = {10.3109/01677063.2015.1060972}, pmid = {26059699}, issn = {1563-5260}, mesh = {Exome ; Genotype ; *High-Throughput Nucleotide Sequencing ; Humans ; Neurodegenerative Diseases/*diagnosis/*genetics ; }, abstract = {Since its first availability in 2009, the next-generation sequencing (NGS) has been proved to be a powerful tool in identifying disease-associated variants in many neurological diseases, such as spinocerebellar ataxias, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Whole exome sequencing and whole genome sequencing are efficient for identifying variants in novel or unexpected genes responsible for inherited diseases, whereas targeted sequencing is useful in detecting variants in previously known disease-associated genes. The trove of genetic data yielded by NGS has made a significant impact on the clinical diagnoses while contributing hugely on the discovery of molecular pathomechanisms underlying these diseases. Nonetheless, elucidation of the pathogenic roles of the variants identified by NGS is challenging. Establishment of consensus guidelines and development of public genomic/phenotypic databases are thus vital to facilitate data sharing and validation.}, }
@article {pmid26056033, year = {2016}, author = {Burnstock, G}, title = {An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration.}, journal = {Neuropharmacology}, volume = {104}, number = {}, pages = {4-17}, doi = {10.1016/j.neuropharm.2015.05.031}, pmid = {26056033}, issn = {1873-7064}, mesh = {Adenosine/metabolism ; Animals ; Brain/metabolism ; Brain Ischemia/metabolism ; Humans ; *Nerve Regeneration ; Neural Stem Cells/metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; Purines/*metabolism ; Pyrimidines/metabolism ; Receptors, Purinergic/*metabolism ; Receptors, Purinergic P2X/metabolism ; Receptors, Purinergic P2Y/metabolism ; *Signal Transduction ; Stroke/metabolism ; }, abstract = {Purinergic signalling appears to play important roles in neurodegeneration, neuroprotection and neuroregeneration. Initially there is a brief summary of the background of purinergic signalling, including release of purines and pyrimidines from neural and non-neural cells and their ectoenzymatic degradation, and the current characterisation of P1 (adenosine), and P2X (ion channel) and P2Y (G protein-coupled) nucleotide receptor subtypes. There is also coverage of the localization and roles of purinoceptors in the healthy central nervous system. The focus is then on the roles of purinergic signalling in trauma, ischaemia, stroke and in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, as well as multiple sclerosis and amyotrophic lateral sclerosis. Neuroprotective mechanisms involving purinergic signalling are considered and its involvement in neuroregeneration, including the role of adult neural stem/progenitor cells. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.}, }
@article {pmid26052512, year = {2015}, author = {Parakh, S and Atkin, JD}, title = {Novel roles for protein disulphide isomerase in disease states: a double edged sword?.}, journal = {Frontiers in cell and developmental biology}, volume = {3}, number = {}, pages = {30}, pmid = {26052512}, issn = {2296-634X}, abstract = {Protein disulphide isomerase (PDI) is a multifunctional redox chaperone of the endoplasmic reticulum (ER). Since it was first discovered 40 years ago the functions ascribed to PDI have evolved significantly and recent studies have recognized its distinct functions, with adverse as well as protective effects in disease. Furthermore, post translational modifications of PDI abrogate its normal functional roles in specific disease states. This review focusses on recent studies that have identified novel functions for PDI relevant to specific diseases.}, }
@article {pmid26047658, year = {2015}, author = {Sephton, CF and Yu, G}, title = {The function of RNA-binding proteins at the synapse: implications for neurodegeneration.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {72}, number = {19}, pages = {3621-3635}, pmid = {26047658}, issn = {1420-9071}, mesh = {Gene Expression Regulation/*physiology ; Humans ; *Models, Biological ; Neurodegenerative Diseases/*physiopathology ; RNA-Binding Proteins/genetics/*metabolism ; Synapses/*metabolism ; }, abstract = {The loss of synapses is a central event in neurodegenerative diseases. Synaptic proteins are often associated with disease neuropathology, but their role in synaptic loss is not fully understood. Of the many processes involved in sustaining the integrity of synapses, local protein translation can directly impact synaptic formation, communication, and maintenance. RNA-binding proteins and their association with RNA granules serve to regulate mRNA transportation and translation at synapses and in turn regulate the synapse. Genetic mutations in RNA-binding proteins FUS and TDP-43 have been linked with causing neurodegenerative diseases: amyotrophic lateral sclerosis and frontotemporal dementia. The observation that mutations in FUS and TDP-43 coincide with changes in RNA granules provides evidence that dysfunction of RNA metabolism may underlie the mechanism of synaptic loss in these diseases. However, we do not know how mutations in RNA-binding proteins would affect RNA granule dynamics and local translation, or if these alterations would cause neurodegeneration. Further investigation into this area will lead to important insights into how disruption of RNA metabolism and local translation at synapses can cause neurodegenerative diseases.}, }
@article {pmid26041104, year = {2015}, author = {Lashley, T and Rohrer, JD and Mead, S and Revesz, T}, title = {Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations.}, journal = {Neuropathology and applied neurobiology}, volume = {41}, number = {7}, pages = {858-881}, doi = {10.1111/nan.12250}, pmid = {26041104}, issn = {1365-2990}, support = {MC_U123160651/MRC_/Medical Research Council/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Frontotemporal Dementia/genetics/*pathology ; Frontotemporal Lobar Degeneration/genetics/*pathology ; Humans ; Motor Neuron Disease/genetics/*pathology ; }, abstract = {The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided.}, }
@article {pmid26039159, year = {2015}, author = {Sabate, R and Rousseau, F and Schymkowitz, J and Batlle, C and Ventura, S}, title = {Amyloids or prions? That is the question.}, journal = {Prion}, volume = {9}, number = {3}, pages = {200-206}, pmid = {26039159}, issn = {1933-690X}, mesh = {Amino Acids/chemistry ; Amyloid/chemistry/*metabolism ; Models, Molecular ; Prions/chemistry/*metabolism ; }, abstract = {Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.}, }
@article {pmid26036964, year = {2016}, author = {Trépanier, MO and Hopperton, KE and Orr, SK and Bazinet, RP}, title = {N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update.}, journal = {European journal of pharmacology}, volume = {785}, number = {}, pages = {187-206}, doi = {10.1016/j.ejphar.2015.05.045}, pmid = {26036964}, issn = {1879-0712}, mesh = {Animals ; Disease Models, Animal ; Fatty Acids, Omega-3/*pharmacology/therapeutic use ; Humans ; Inflammation/complications/*drug therapy/metabolism ; Nervous System Diseases/complications/*drug therapy/metabolism ; }, abstract = {Neuroinflammation is a characteristic of a multitude of neurological and psychiatric disorders. Modulating inflammatory pathways offers a potential therapeutic target in these disorders. Omega-3 polyunsaturated fatty acids have anti-inflammatory and pro-resolving properties in the periphery, however, their effect on neuroinflammation is less studied. This review summarizes 61 animal studies that tested the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory outcomes in vivo in various models including stroke, spinal cord injury, aging, Alzheimer's disease, Parkinson's disease, lipopolysaccharide and IL-1β injections, diabetes, neuropathic pain, traumatic brain injury, depression, surgically induced cognitive decline, whole body irradiation, amyotrophic lateral sclerosis, N-methyl-D-aspartate-induced excitotoxicity and lupus. The evidence presented in this review suggests anti-neuroinflammatory properties of omega-3 polyunsaturated fatty acids, however, it is not clear by which mechanism omega-3 polyunsaturated fatty acids exert their effect. Future research should aim to isolate the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory signaling in vivo and elucidate the mechanisms underlying these effects.}, }
@article {pmid26033496, year = {2015}, author = {Takahashi, K and Foster, JB and Lin, CL}, title = {Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {72}, number = {18}, pages = {3489-3506}, pmid = {26033496}, issn = {1420-9071}, support = {R01NS064275/NS/NINDS NIH HHS/United States ; U01NS074601/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Glutamate Plasma Membrane Transport Proteins/*metabolism ; Humans ; Mental Disorders/*metabolism ; Nervous System Diseases/*metabolism ; }, abstract = {Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.}, }
@article {pmid26032484, year = {2015}, author = {Le Ber, I}, title = {Frontotemporal lobar dementia and amyotrophic lateral sclerosis associated with c9orf72 expansion.}, journal = {Revue neurologique}, volume = {171}, number = {6-7}, pages = {475-481}, doi = {10.1016/j.neurol.2015.04.004}, pmid = {26032484}, issn = {0035-3787}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; Frontotemporal Dementia/*genetics ; Humans ; Penetrance ; Proteins/*genetics ; TDP-43 Proteinopathies/genetics ; }, abstract = {An intronic GGGGCC repeat expansion in c9orf72 gene has been identified as the most common genetic cause of frontotemporal lobar dementia (FTLD), amyotrophic lateral sclerosis (ALS) and FTLD-ALS. The discovery of c9orf72 gene has led to important scientific progresses and has considerably changed our clinical practice over the last few years. This paper summarizes the common and less typical phenotypes associated with c9orf72 expansion, the complex pathological pattern characterized by p62/dipeptide repeat aggregates, as well as the pathological mechanisms by which the expansion might produce neurodegeneration implicating loss-of-function, RNA toxicity, RNA-binding protein sequestration and accumulation of dipeptide repeats. We also discuss the recommendations and limits for genetic testing and counseling in clinical practice.}, }
@article {pmid26018231, year = {2016}, author = {Bohl, D and Pochet, R and Mitrecic, D and Nicaise, C}, title = {Modelling and treating amyotrophic lateral sclerosis through induced-pluripotent stem cells technology.}, journal = {Current stem cell research &amp; therapy}, volume = {11}, number = {4}, pages = {301-312}, doi = {10.2174/1574888x10666150528144303}, pmid = {26018231}, issn = {2212-3946}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Cell Differentiation/genetics ; *Cellular Reprogramming ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/*transplantation ; Motor Neurons/transplantation ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease affecting primarily the population of motor neurons, even though a non-cell autonomous component, involving neighbouring non-neuronal cells, is more and more described. Despite 140 years of disease experience, still no efficient treatment exists against ALS. The inability to readily obtain the faulty cell types relevant to ALS has impeded progress in drug discovery for decades. However, the pioneer work of Shinya Yamanaka in 2007 in the stem cell field was a real breakthrough. Recent advances in cell reprogramming now grant access to significant quantities of CNS disease-affected cells. Induced pluripotent stem cells (iPSc) have been recently derived from patients carrying mutations linked to familial forms of ALS as well as from sporadic patients. Precise and mature protocols allow now their differentiation into ALS-relevant cell subtypes; sustainable and renewable sources of human motor neurons or glia are being available for ALS disease modelling, drug screening or for the development of cell therapies. In few years, the proof-of-concept was made that ALS disease-related phenotypes can be reproduced with iPSc and despite some remaining challenges, we are now not so far to provide platforms for the investigation of ALS therapeutics. This paper also reviews the pioneering studies regarding the applicability of iPSc technology in ALS animal models. From modest slowing down of ALS progression to no severe adverse effects, iPSc-based cell therapy resulted in promising premises in ALS preclinical paradigms, although long-term surveys are highly recommended.}, }
@article {pmid26008818, year = {2015}, author = {Klebe, S and Stevanin, G and Depienne, C}, title = {Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting.}, journal = {Revue neurologique}, volume = {171}, number = {6-7}, pages = {505-530}, doi = {10.1016/j.neurol.2015.02.017}, pmid = {26008818}, issn = {0035-3787}, mesh = {Diagnosis, Differential ; Genetic Association Studies ; Genetic Testing ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Spastic Paraplegia, Hereditary/diagnosis/*genetics ; }, abstract = {Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes. Autosomal recessive HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP; complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations. In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders.}, }
@article {pmid26008817, year = {2015}, author = {Turner, MR and Verstraete, E}, title = {What does imaging reveal about the pathology of amyotrophic lateral sclerosis?.}, journal = {Current neurology and neuroscience reports}, volume = {15}, number = {7}, pages = {45}, pmid = {26008817}, issn = {1534-6293}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Brain/pathology ; Humans ; Ligands ; Magnetic Resonance Imaging ; *Neuroimaging/methods ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape.}, }
@article {pmid26000221, year = {2014}, author = {Pioro, EP}, title = {Review of Dextromethorphan 20 mg/Quinidine 10 mg (NUEDEXTA(®)) for Pseudobulbar Affect.}, journal = {Neurology and therapy}, volume = {3}, number = {1}, pages = {15-28}, pmid = {26000221}, issn = {2193-8253}, abstract = {Pseudobulbar affect (PBA) is a dysfunction of emotional expression characterized by involuntary outbursts of crying or laughing disproportionate or unrelated to mood, occurring in patients with various underlying neurologic disorders. This review describes the clinical data supporting dextromethorphan (DM) hydrobromide combined with quinidine sulfate (Q) as treatment of PBA and briefly surveys the ongoing debates concerning the terminology for dysfunction of emotional expression, as well as the ongoing searches for its brain substrates. Until recently, pharmacologic intervention consisted chiefly of off-label antidepressants. In October 2010, however, DM/Q at 20/10 mg twice daily received approval from the United States Food and Drug Administration for PBA in any setting, and in June 2013, dosages of 20/10 and 30/10 mg twice daily (labeled as 15/9 and 23/9 mg, respectively, DM/Q base) received approval from the European Medicines Agency. DM is an uncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, a sigma-1 receptor agonist, and a serotonin and norepinephrine reuptake inhibitor. To block DM hepatic metabolism, thereby increasing DM bioavailability, Quinidine, a cytochrome P450 2D6 inhibitor, is coadministered at a dosage well below those for treating cardiac arrhythmia. Three large-scale DM/Q trials have utilized PBA-episode counts and the Center for Neurologic Study-Lability Scale (CNS-LS), a validated PBA rating scale, to measure efficacy. In a 4-week study of patients with PBA in amyotrophic lateral sclerosis (ALS), DM/Q 30/30 mg was superior to its component drugs. A 12-week, double-blind, placebo-controlled study of DM/Q 30/30 mg showed similar efficacy in patients with PBA in multiple sclerosis (MS). A subsequent 12-week study of patients with PBA and ALS or MS showed superiority to placebo for the 20/10 and 30/10 mg doses. Efficacy was maintained during a 12-week, open-label extension (30/10 mg dose), with further improvement of mean CNS-LS scores. Across these studies, DM/Q was generally safe and well tolerated, with no evidence of clinically relevant cardiac or respiratory effects. DM/Q is being studied (currently unapproved) for conditions including agitation in autism and in dementia.}, }
@article {pmid25998118, year = {2015}, author = {Kansal, K and Irwin, DJ}, title = {The use of cerebrospinal fluid and neuropathologic studies in neuropsychiatry practice and research.}, journal = {The Psychiatric clinics of North America}, volume = {38}, number = {2}, pages = {309-322}, pmid = {25998118}, issn = {1558-3147}, support = {K23 NS088341/NS/NINDS NIH HHS/United States ; K23NS088341-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides/*analysis ; Biomarkers/analysis ; Brain/*pathology ; *Cerebrospinal Fluid/metabolism/microbiology ; DNA-Binding Proteins/*analysis ; *Dementia/diagnosis/etiology ; Disease Progression ; Humans ; *Neurodegenerative Diseases/blood/cerebrospinal fluid/complications/diagnosis/microbiology ; Neuropsychiatry/methods ; alpha-Synuclein/*analysis ; }, abstract = {The gold standard for diagnosis of neurodegenerative diseases (ie, Alzheimer disease, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, amyotrophic lateral sclerosis) is neuropathologic examination at autopsy. As such, laboratory studies play a central role in antemortem diagnosis of these conditions and their differentiation from the neuroinflammatory, infectious, toxic, and other nondegenerative etiologies (eg, rapidly progressive dementias) that are encountered in neuropsychiatric practice. This article summarizes the use of cerebrospinal fluid (CSF) laboratory studies in the diagnostic evaluation of dementia syndromes and emerging CSF biomarkers specific for underlying neuropathology in neurodegenerative disease research.}, }
@article {pmid25998063, year = {2015}, author = {Kim, RB and Irvin, CW and Tilva, KR and Mitchell, CS}, title = {State of the field: An informatics-based systematic review of the SOD1-G93A amyotrophic lateral sclerosis transgenic mouse model.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {1-2}, pages = {1-14}, pmid = {25998063}, issn = {2167-9223}, support = {K01 NS069616/NS/NINDS NIH HHS/United States ; R21 NS081426/NS/NINDS NIH HHS/United States ; NS069616/NS/NINDS NIH HHS/United States ; NS081426/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/classification/pathology/*physiopathology ; Animals ; Axonal Transport ; *Disease Models, Animal ; Energy Metabolism ; Genetic Markers/genetics ; Genetic Predisposition to Disease/genetics ; Inflammation/pathology/*physiopathology ; Mice/*genetics ; Mice, Transgenic ; Movement ; Natural Language Processing ; Neurons/*metabolism ; Oxidative Stress ; Periodicals as Topic/statistics &amp; numerical data ; Polymorphism, Single Nucleotide/genetics ; Proteome/metabolism ; Superoxide Dismutase/*genetics ; }, abstract = {Numerous sub-cellular through system-level disturbances have been identified in over 1300 articles examining the superoxide dismutase-1 guanine 93 to alanine (SOD1-G93A) transgenic mouse amyotrophic lateral sclerosis (ALS) pathophysiology. Manual assessment of such a broad literature base is daunting. We performed a comprehensive informatics-based systematic review or 'field analysis' to agnostically compute and map the current state of the field. Text mining of recaptured articles was used to quantify published data topic breadth and frequency. We constructed a nine-category pathophysiological function-based ontology to systematically organize and quantify the field's primary data. Results demonstrated that the distribution of primary research belonging to each category is: systemic measures an motor function, 59%; inflammation, 46%; cellular energetics, 37%; proteomics, 31%; neural excitability, 22%; apoptosis, 20%; oxidative stress, 18%; aberrant cellular chemistry, 14%; axonal transport, 10%. We constructed a SOD1-G93A field map that visually illustrates and categorizes the 85% most frequently assessed sub-topics. Finally, we present the literature-cited significance of frequently published terms and uncover thinly investigated areas. In conclusion, most articles individually examine at least two categories, which is indicative of the numerous underlying pathophysiological interrelationships. An essential future path is examination of cross-category pathophysiological interrelationships and their co-correspondence to homeostatic regulation and disease progression.}, }
@article {pmid25979579, year = {2015}, author = {Valadi, N}, title = {Evaluation and management of amyotrophic lateral sclerosis.}, journal = {Primary care}, volume = {42}, number = {2}, pages = {177-187}, doi = {10.1016/j.pop.2015.01.009}, pmid = {25979579}, issn = {1558-299X}, mesh = {Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*therapy ; Diagnosis, Differential ; Electromyography ; Genetic Predisposition to Disease ; Humans ; Magnetic Resonance Imaging ; Primary Health Care/*methods ; Quality of Life ; Risk Factors ; }, abstract = {Motor neuron diseases can cause progressive impairment of voluntary muscles of movement, respiration, speech, and swallowing. This review discusses the most common motor neuron disease, amyotrophic lateral sclerosis (ALS). It reviews the evaluation, diagnosis, and management of ALS, and its epidemiology, pathophysiology, and management. A coordinated approach by the primary care physician and neurologist is necessary with a focus on treatment options, durable medical equipment needs, and end-of-life discussions.}, }
@article {pmid25979489, year = {2015}, author = {Boison, D and Aronica, E}, title = {Comorbidities in Neurology: Is adenosine the common link?.}, journal = {Neuropharmacology}, volume = {97}, number = {}, pages = {18-34}, pmid = {25979489}, issn = {1873-7064}, support = {R01 MH083973/MH/NIMH NIH HHS/United States ; R01 NS084920/NS/NINDS NIH HHS/United States ; R21 NS088024/NS/NINDS NIH HHS/United States ; R01MH83973/MH/NIMH NIH HHS/United States ; }, mesh = {Adenosine/*metabolism ; Animals ; Comorbidity ; Humans ; Nervous System Diseases/complications/epidemiology/*metabolism/therapy ; Neuroglia/metabolism ; Signal Transduction ; }, abstract = {Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the 'adenosine hypothesis of comorbidities' implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic 'comorbidity model', in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain co-morbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.}, }
@article {pmid25979174, year = {2015}, author = {Simone, R and Fratta, P and Neidle, S and Parkinson, GN and Isaacs, AM}, title = {G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome.}, journal = {FEBS letters}, volume = {589}, number = {14}, pages = {1653-1668}, doi = {10.1016/j.febslet.2015.05.003}, pmid = {25979174}, issn = {1873-3468}, support = {FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*G-Quadruplexes ; Humans ; Neurodegenerative Diseases/*genetics ; *Transcriptome ; }, abstract = {G-rich sequences in DNA and RNA have a propensity to fold into stable secondary structures termed G-quadruplexes. G-quadruplex forming sequences are widespread throughout the human genome, within both, protein coding and non-coding genes, and regulatory regions. G-quadruplexes have been implicated in multiple cellular functions including chromatin epigenetic regulation, DNA recombination, transcriptional regulation of gene promoters and enhancers, and translation. Here we will review the evidence for the occurrence of G-quadruplexes both in vitro and in vivo; their role in neurological diseases including G-quadruplex-forming repeat expansions in the C9orf72 gene in frontotemporal dementia and amyotrophic lateral sclerosis and loss of the G-quadruplex binding protein FMRP in the intellectual disability fragile X syndrome. We also review mounting evidence that supports a role for G-quadruplexes in regulating the processing or function of a range of non-coding RNAs. Finally we will highlight current perspectives for therapeutic interventions that target G-quadruplexes.}, }
@article {pmid25974624, year = {2015}, author = {McBean, GJ and Aslan, M and Griffiths, HR and Torrão, RC}, title = {Thiol redox homeostasis in neurodegenerative disease.}, journal = {Redox biology}, volume = {5}, number = {}, pages = {186-194}, pmid = {25974624}, issn = {2213-2317}, mesh = {Cysteine/chemistry/metabolism ; Glaucoma/metabolism/pathology ; Glutaredoxins/chemistry/metabolism ; Humans ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/metabolism ; Oxidation-Reduction ; Peroxiredoxins/chemistry/metabolism ; Sulfhydryl Compounds/*chemistry/metabolism ; Thioredoxins/chemistry/metabolism ; }, abstract = {This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc(-) cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed.}, }
@article {pmid25968934, year = {2015}, author = {Oweiss, KG and Badreldin, IS}, title = {Neuroplasticity subserving the operation of brain-machine interfaces.}, journal = {Neurobiology of disease}, volume = {83}, number = {}, pages = {161-171}, pmid = {25968934}, issn = {1095-953X}, support = {R01 NS062031/NS/NINDS NIH HHS/United States ; R01 NS093909/NS/NINDS NIH HHS/United States ; NS062031/NS/NINDS NIH HHS/United States ; }, mesh = {Adaptation, Physiological ; Animals ; Brain/*physiology ; *Brain-Computer Interfaces ; Homeostasis ; Humans ; Learning/*physiology ; *Models, Neurological ; Motor Skills ; *Neuronal Plasticity ; *Psychomotor Performance ; User-Computer Interface ; }, abstract = {Neuroplasticity is key to the operation of brain machine interfaces (BMIs)-a direct communication pathway between the brain and a man-made computing device. Whereas exogenous BMIs that associate volitional control of brain activity with neurofeedback have been shown to induce long lasting plasticity, endogenous BMIs that use prolonged activity-dependent stimulation--and thus may curtail the time scale that governs natural sensorimotor integration loops--have been shown to induce short lasting plasticity. Here we summarize recent findings from studies using both categories of BMIs, and discuss the fundamental principles that may underlie their operation and the longevity of the plasticity they induce. We draw comparison to plasticity mechanisms known to mediate natural sensorimotor skill learning and discuss principles of homeostatic regulation that may constrain endogenous BMI effects in the adult mammalian brain. We propose that BMIs could be designed to facilitate structural and functional plasticity for the purpose of re-organization of target brain regions and directed augmentation of sensorimotor maps, and suggest possible avenues for future work to maximize their efficacy and viability in clinical applications.}, }
@article {pmid25961436, year = {2015}, author = {Goutman, SA and Feldman, EL}, title = {Clinical Trials of Therapies for Amyotrophic Lateral Sclerosis: One Size Does Not Fit All.}, journal = {JAMA neurology}, volume = {72}, number = {7}, pages = {743-744}, pmid = {25961436}, issn = {2168-6157}, support = {R01 NS077982/NS/NINDS NIH HHS/United States ; R01 NS082304/NS/NINDS NIH HHS/United States ; 200-2013-56856//PHS HHS/United States ; R01 NS08230401A1/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/*therapy ; Animals ; Antioxidants/therapeutic use ; Clinical Trials as Topic/methods/*trends ; Genetic Therapy/methods/trends ; Humans ; }, }
@article {pmid25959569, year = {2015}, author = {Scarrott, JM and Herranz-Martín, S and Alrafiah, AR and Shaw, PJ and Azzouz, M}, title = {Current developments in gene therapy for amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {15}, number = {7}, pages = {935-947}, doi = {10.1517/14712598.2015.1044894}, pmid = {25959569}, issn = {1744-7682}, support = {G1001492/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; C9orf72 Protein ; Dependovirus/genetics ; Disease Models, Animal ; *Genetic Therapy ; Humans ; Motor Neurons/metabolism/pathology ; Nerve Degeneration ; Nerve Growth Factors/genetics/metabolism ; Proteins/genetics/metabolism ; RNA Interference ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating adult neurodegenerative disorder characterized by motor neuron degeneration and death around 3 years from onset. So far, riluzole is the only treatment available, although it only offers a slight increase in survival. The complex etiology of ALS, with several genes able to trigger the disease, makes its study difficult.<br><br>AREAS COVERED: RNA-mediated or protein-mediated toxic gain-of-function leading to motor neuron degeneration appears to be likely common pathogenic mechanisms in ALS. Consequently, gene therapy technologies to reduce toxic RNA and/or proteins and to protect motor neurons by modulating gene expression are at the forefront of the field. Here, we review the most promising scientific advances, paying special attention to the successful treatments tested in animal models as well as analyzing relevant gene therapy clinical trials.<br><br>EXPERT OPINION: Despite broad advances in target gene identification in ALS and advances in gene therapy technologies, a successful gene therapy for ALS continues to elude researchers. Multiple hurdles encompassing technical, biological, economical and clinical challenges must be overcome before a therapy for patients becomes available. Optimism remains due to positive results obtained in several in vivo studies demonstrating significant disease amelioration in animal models of ALS.}, }
@article {pmid25957927, year = {2015}, author = {Deepmala,  and Slattery, J and Kumar, N and Delhey, L and Berk, M and Dean, O and Spielholz, C and Frye, R}, title = {Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {55}, number = {}, pages = {294-321}, doi = {10.1016/j.neubiorev.2015.04.015}, pmid = {25957927}, issn = {1873-7528}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Clinical Trials as Topic ; Female ; Humans ; Male ; Mental Disorders/*drug therapy ; Nervous System Diseases/*drug therapy ; Neurology ; Psychiatry ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Young Adult ; }, abstract = {N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.}, }
@article {pmid25939274, year = {2015}, author = {Ittner, LM and Halliday, GM and Kril, JJ and Götz, J and Hodges, JR and Kiernan, MC}, title = {FTD and ALS--translating mouse studies into clinical trials.}, journal = {Nature reviews. Neurology}, volume = {11}, number = {6}, pages = {360-366}, pmid = {25939274}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Disease Models, Animal ; *Drug Evaluation, Preclinical ; Frontotemporal Dementia/*drug therapy/genetics ; Humans ; Mice ; *Translational Research, Biomedical ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are related neurodegenerative disorders, which are characterized by a rapid decline in cognitive and motor functions, and short survival. Although the clinical and neuropathological characterization of these diseases has progressed--in part--through animal studies of pathogenetic mechanisms, the translation of findings from rodent models to clinical practice has generally not been successful. This article discusses the gap between preclinical animal studies in mice and clinical trials in patients with FTD or ALS. We outline how to better design preclinical studies, and present strategies to improve mouse models to overcome the translational shortfall. This new approach could help identify drugs that are more likely to achieve a therapeutic benefit for patients.}, }
@article {pmid25939067, year = {2015}, author = {Nagoshi, N and Nakashima, H and Fehlings, MG}, title = {Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside.}, journal = {Molecules (Basel, Switzerland)}, volume = {20}, number = {5}, pages = {7775-7789}, pmid = {25939067}, issn = {1420-3049}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Rats ; Riluzole/pharmacology/*therapeutic use ; Sodium Channel Blockers/*therapeutic use ; Spinal Cord Injuries/*drug therapy ; Synaptic Transmission/*drug effects ; }, abstract = {Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI.}, }
@article {pmid25938971, year = {2015}, author = {Bohár, Z and Toldi, J and Fülöp, F and Vécsei, L}, title = {Changing the face of kynurenines and neurotoxicity: therapeutic considerations.}, journal = {International journal of molecular sciences}, volume = {16}, number = {5}, pages = {9772-9793}, pmid = {25938971}, issn = {1422-0067}, mesh = {Animals ; Humans ; Kynurenine/*toxicity ; Nerve Degeneration/pathology/therapy ; Neurotoxins/*toxicity ; }, abstract = {Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and their involvement in oxidative stress has also been suggested. Consequently, it is not surprising that kynurenines have been closely related to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. More information about the less-known metabolites, picolinic and cinnabarinic acid, evaluation of new receptorial targets, such as aryl-hydrocarbon receptors, and intensive research on the field of the immunomodulatory function of kynurenines delineated the high importance of this pathway in general homeostasis. Emerging knowledge about the kynurenine pathway provides new target points for the development of therapeutical solutions against neurodegenerative diseases.}, }
@article {pmid25938606, year = {2015}, author = {Jiménez García, I and Sala Moya, N and Riera Munt, M and Herrera Rodríguez, MV and Povedano Panadés, M and Virgili Casas, MN}, title = {[The patient's opinion matters: experience in the nutritional care in an ALS multidisciplinary team].}, journal = {Nutricion hospitalaria}, volume = {31 Suppl 5}, number = {}, pages = {56-66}, doi = {10.3305/nh.2015.31.sup5.9132}, pmid = {25938606}, issn = {1699-5198}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Family ; Humans ; Nutrition Therapy/*methods ; Patient Care Team/*organization &amp; administration ; Patient Satisfaction ; }, abstract = {UNLABELLED: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease which has no cure, so the treatment will be symptomatic in a Multidisciplinary Unit. It is composed of professionals, experts in patient care, with an interdisciplinary vision in order to act in a coordinated manner depending on the different situations which may arise over the course of the disease. There are several studies showing improved survival in patients treated within the framework of a multidisciplinary team compared to treatment by isolated specialties. An ALS Multidisciplinary Unit was created in 2004 in the University Hospital of Bellvitge (HUB). It is composed of a neurologist, pulmonologist, nutritionist, endocrinologist, rehabilitation, physical therapist, psychologist, social worker, nurse manager, speech therapist and an administrative worker. To assess the impact of the multidisciplinary care of our program 418 patients diagnosed with ALS were evaluated, 84 patients who had been treated by general neurology and 334 who had been treated under a model of multidisciplinary care. Patients who were treated in the unit of multidisciplinary care had a median survival of 1246 days (IC 1109-1382), 104 days above the median 1148 days of those followed by a general neurology consultation (CI 998-1297). This difference was statistically significant (log-rank 10,8; p= 0.008). This benefit was independent of having received treatment with riluzole, non-invasive mechanical ventilation or percutaneous gastrostomy. Nutritional assessment was performed on the first visit and all subsequent controls. It is important to do anthropometric measurements and detect unintentional weight loss and its possible precipitating causes in order to establish the appropriate nutritional treatment. The exploration of dysphagia allows a determination of the appropriate dietary advice, the introduction of thickeners to adjust the texture of food or nutritional supplementation with high-calorie formulas to prevent or correct weight loss. If these measures are not sufficient or there is the risk of failure of respiratory function, early gastrostomy placement will be indicated. The analysis of 140 ALS patients (92 controls and 48 with radiologic percutaneous gastrostomy) showed no difference in mean survival time between groups (32 vs 33.9 months, log Rank 1.86 p=0.39). Any patient had major complications. Despite not find changes in survival, the use of gastrostomy should be understood as a treatment to improve the quality of life and well-being of the patient. Psychosocial support of the person and the family environment is essential to integrate all the changes and situations that arise in the course of the disease. This should start from diagnosis as early intervention contributes to improved training, preventing situations of deterioration and helping coping with the dependency process. It is also possible to use technology and social media to complement the classic care model. In the case of the HUB ALS Multidisciplinary Unit, affected individuals and their families have the resources of the Aula Paciente and ALS blog, created with the objective of providing opportunities for dialogue between patients, families and caregivers. The satisfaction degree of the patients with the care provided by the ALS Multidisciplinary Unit on service accessibility, information received and the quality of care was assessed globally as good in 52.8% or very good in 29, 2% of patients.<br><br>CONCLUSION: Attention for the ALS affected person must be considered within the framework of a multidisciplinary team made up of all the professionals who go to intervene throughout the disease process in order to provide increased survival with the best care and quality of life.}, }
@article {pmid25937392, year = {2015}, author = {Ketha, H and Singh, RJ}, title = {Clinical assays for quantitation of insulin-like-growth-factor-1 (IGF1).}, journal = {Methods (San Diego, Calif.)}, volume = {81}, number = {}, pages = {93-98}, doi = {10.1016/j.ymeth.2015.04.029}, pmid = {25937392}, issn = {1095-9130}, mesh = {Chromatography, Liquid/*methods ; Humans ; Immunoassay/*methods ; Immunologic Tests ; Insulin-Like Growth Factor I/*analysis ; Tandem Mass Spectrometry/methods ; }, abstract = {Insulin-like growth factor 1 (IGF1), a 70 amino acid peptide hormone is the principal mediator of effects of growth hormone (GH). Since GH secretion is pulsatile in nature and is affected by many factors including sleep, feeding and exercise it is not a reliable marker for diagnosis of GH related disorders. On the other hand, IGF1 levels does not undergo short-term fluctuations in the manner that GH does making it the preferred IGF1 biomarker for the diagnosis of growth related disorders. There are several immunoassays available for IGF1 determination. Since majority (>90%) of IGF1 circulates as a ternary complex bound to its principal carrier/binding protein, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS), the assay methodology used to quantitate IGF1 has to dissociate IGF1 from IGFBPs prior to quantitation. IGFBPs are known to be a source of interference in immunoassays and many techniques have been employed to circumvent this issue. Immunoassays rely on antibody specificity towards IGF1 and differential cross reactivity towards IGFBPs. Mass spectrometry (MS) has also been employed for quantitation of IGF1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) assays for IGF1 rely on generating tryptic peptides followed by selective reaction monitoring (SRM) while LC high resolution accurate-mass mass spectrometry (LC-HRAMS) approaches for intact IGF1 rely on mass accuracy for reliable, robust and accurate quantitation. This review article will focus on the clinical assays available and the clinical utility of quantitative assessment of IGF1. IGF1 quantitation using diverse assay platforms including immunoassay, LC-MS/MS and LC-HRAMS are discussed in detail.}, }
@article {pmid25932674, year = {2015}, author = {Peters, OM and Ghasemi, M and Brown, RH}, title = {Emerging mechanisms of molecular pathology in ALS.}, journal = {The Journal of clinical investigation}, volume = {125}, number = {5}, pages = {1767-1779}, pmid = {25932674}, issn = {1558-8238}, support = {RC2 NS070342/NS/NINDS NIH HHS/United States ; 1RC1NS068391-01/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; R01 NS065847/NS/NINDS NIH HHS/United States ; RC1 NS068391/NS/NINDS NIH HHS/United States ; R01NS050557-05/NS/NINDS NIH HHS/United States ; R01 NS050557/NS/NINDS NIH HHS/United States ; 1RC2NS070342-01/NS/NINDS NIH HHS/United States ; R01NS065847-01A1/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology/therapy ; Animals ; Axonal Transport ; Axons/ultrastructure ; Cytoskeleton/ultrastructure ; DNA-Binding Proteins/genetics/metabolism ; Genetic Association Studies ; Genetic Therapy ; Humans ; Inflammation ; Mice ; Mice, Transgenic ; Molecular Targeted Therapy ; Motor Neurons/chemistry/pathology ; Nerve Tissue Proteins/chemistry/genetics/metabolism ; Neuroglia/immunology ; Oxidative Stress ; Protein Aggregation, Pathological ; Protein Processing, Post-Translational ; Proteolysis ; RNA-Binding Proteins/genetics/metabolism ; Superoxide Dismutase/deficiency/genetics ; Superoxide Dismutase-1 ; Ubiquitination ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable.}, }
@article {pmid25932462, year = {2015}, author = {Conway, ME and Harris, M}, title = {S-nitrosylation of the thioredoxin-like domains of protein disulfide isomerase and its role in neurodegenerative conditions.}, journal = {Frontiers in chemistry}, volume = {3}, number = {}, pages = {27}, pmid = {25932462}, issn = {2296-2646}, abstract = {Correct protein folding and inhibition of protein aggregation is facilitated by a cellular "quality control system" that engages a network of protein interactions including molecular chaperones and the ubiquitin proteasome system. Key chaperones involved in these regulatory mechanisms are the protein disulfide isomerases (PDI) and their homologs, predominantly expressed in the endoplasmic reticulum of most tissues. Redox changes that disrupt ER homeostasis can lead to modification of these enzymes or chaperones with the loss of their proposed neuroprotective role resulting in an increase in protein misfolding. Misfolded protein aggregates have been observed in several disease states and are considered to play a pivotal role in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral sclerosis. This review will focus on the importance of the thioredoxin-like CGHC active site of PDI and how our understanding of this structural motif will play a key role in unraveling the pathogenic mechanisms that underpin these neurodegenerative conditions.}, }
@article {pmid25930681, year = {2015}, author = {Rossi, D}, title = {Astrocyte physiopathology: At the crossroads of intercellular networking, inflammation and cell death.}, journal = {Progress in neurobiology}, volume = {130}, number = {}, pages = {86-120}, doi = {10.1016/j.pneurobio.2015.04.003}, pmid = {25930681}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Astrocytes/*cytology ; Cell Communication/*physiology ; Cell Death/*physiology ; Humans ; Inflammation/*metabolism/pathology ; Neurons/*cytology ; }, abstract = {Recent breakthroughs in neuroscience have led to the awareness that we should revise our traditional mode of thinking and studying the CNS, i.e. by isolating the privileged network of "intelligent" synaptic contacts. We may instead need to contemplate all the variegate communications occurring between the different neural cell types, and centrally involving the astrocytes. Basically, it appears that a single astrocyte should be considered as a core that receives and integrates information from thousands of synapses, other glial cells and the blood vessels. In turn, it generates complex outputs that control the neural circuitry and coordinate it with the local microcirculation. Astrocytes thus emerge as the possible fulcrum of the functional homeostasis of the healthy CNS. Yet, evidence indicates that the bridging properties of the astrocytes can change in parallel with, or as a result of, the morphological, biochemical and functional alterations these cells undergo upon injury or disease. As a consequence, they have the potential to transform from supportive friends and interactive partners for neurons into noxious foes. In this review, we summarize the currently available knowledge on the contribution of astrocytes to the functioning of the CNS and what goes wrong in various pathological conditions, with a particular focus on Amyotrophic Lateral Sclerosis, Alzheimer's Disease and ischemia. The observations described convincingly demonstrate that the development and progression of several neurological disorders involve the de-regulation of a finely tuned interplay between multiple cell populations. Thus, it seems that a better understanding of the mechanisms governing the integrated communication and detrimental responses of the astrocytes as well as their impact towards the homeostasis and performance of the CNS is fundamental to open novel therapeutic perspectives.}, }
@article {pmid25924979, year = {2015}, author = {Gladman, M and Zinman, L}, title = {The economic impact of amyotrophic lateral sclerosis: a systematic review.}, journal = {Expert review of pharmacoeconomics &amp; outcomes research}, volume = {15}, number = {3}, pages = {439-450}, doi = {10.1586/14737167.2015.1039941}, pmid = {25924979}, issn = {1744-8379}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*economics/physiopathology/therapy ; *Cost of Illness ; *Health Care Costs ; Health Services Needs and Demand ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease for which there is no cure, and the associated economic burden is considerable. In this review, the authors summarize the existing body of literature pertaining to the costs associated with ALS to demonstrate the scale and scope of the economic burden of this paralyzing disease. Twelve studies from eight countries published between January 2001 and January 2015 met the inclusion criteria and were included in this review. Direct and indirect costs varied significantly across countries. Standardized to the 2015 US$, the annual total cost per patient ranged from US$ 13,667 in Denmark to as high as US$ 69,475 in the USA, with the national economic burden of ALS estimated at US$ 279-472 million in the USA. Costs associated with ALS were greater than that of other neurological diseases, indicating a continued need for medical advances and financial support for patients and families. Regional cost analyses are necessary to determine how best to spend funds that have been raised globally from the ice bucket phenomenon.}, }
@article {pmid25921746, year = {2015}, author = {Placido, AI and Pereira, CM and Duarte, AI and Candeias, E and Correia, SC and Carvalho, C and Cardoso, S and Oliveira, CR and Moreira, PI}, title = {Modulation of endoplasmic reticulum stress: an opportunity to prevent neurodegeneration?.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {14}, number = {4}, pages = {518-533}, doi = {10.2174/1871527314666150429112353}, pmid = {25921746}, issn = {1996-3181}, mesh = {Animals ; Apoptosis/physiology ; Brain/*metabolism ; Endoplasmic Reticulum Stress/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism/prevention &amp; control ; Oxidative Stress/*physiology ; Protein Folding ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-related diseases) have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, accumulating evidence supports a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.}, }
@article {pmid25921543, year = {2015}, author = {Smith, GB and Welch, J and DeVita, MA and Hillman, KM and Jones, D}, title = {Education for cardiac arrest--Treatment or prevention?.}, journal = {Resuscitation}, volume = {92}, number = {}, pages = {59-62}, doi = {10.1016/j.resuscitation.2015.04.018}, pmid = {25921543}, issn = {1873-1570}, mesh = {Advanced Cardiac Life Support/*education ; Cardiopulmonary Resuscitation/*education ; *Emergency Medical Services ; Heart Arrest/*prevention &amp; control ; Humans ; Medical Staff, Hospital/*education ; }, abstract = {In-hospital cardiac arrests (IHCA) occur infrequently and individual staff members working on general wards may only rarely encounter one. Mortality following IHCA is high and the evidence for the benefits of many advanced life support (ALS) interventions is scarce. Nevertheless, regular, often frequent, ALS training is mandatory for many hospital medical staff and nurses. The incidence of pre-cardiac arrest deterioration is much higher than that of cardiac arrests, and there is evidence that intervention prior to cardiac arrest can reduce the incidence of IHCA. This article discusses a proposal to reduce the emphasis on widespread ALS training and to increase education in the recognition and response to pre-arrest clinical deterioration.}, }
@article {pmid25919670, year = {2015}, author = {Geisewall, K and Håkansson, S and Oddby, E and Ek, ME and Jakobsson, JG}, title = {[National respiration center support patients with tracheostomy tubes. Outpatient clinic for respiratory support in the home].}, journal = {Lakartidningen}, volume = {112}, number = {}, pages = {}, pmid = {25919670}, issn = {1652-7518}, mesh = {Ambulatory Care Facilities ; Home Health Nursing ; Humans ; Respiration, Artificial/*instrumentation ; Tracheostomy/*instrumentation ; Ventilators, Mechanical ; }, abstract = {It is now 60 years since the polio epidemic in Copenhagen and the first use of prolonged invasive positive pressure ventilation. After this pioneer work positive pressure ventilation rapidly became well established. Intubation/tracheostomy and mechanical ventilation are now standard in Intensive Care Units. In the late 1970 Gillis Andersson was the first in Sweden to discharge patients home with invasive mechanical ventilator support. His pioneer work included the development of a dedicated practical and technical support organization at National Respiration Centre at Danderyds Hospital. This unit developed skills in patient customized tracheostomy tube construction and home invasive ventilation supportive care. Tracheostomy tubes and home ventilators have since then developed rapidly. Some patients still need customized tracheostomy tubes, which the NRC supplies. The production is certified by the Swedish Medicinal Product Agency. Today invasive home ventilation is standard care. Invasive mechanical home ventilation when instituted as a life-saving therapy in, for example, progressive ALS patients is complex and resource-intensive. New aspects such as training and education in order to secure quality of care in the home environment is one of many challenges. When commencing invasive ventilation in patients with progressive neurological disease ethical considerations must also be acknowledged, e.g. aspects such as patients' perhaps changing wishes during the course of illness regarding cessation of life support.}, }
@article {pmid25917917, year = {2015}, author = {Goveas, J and O'Dwyer, L and Mascalchi, M and Cosottini, M and Diciotti, S and De Santis, S and Passamonti, L and Tessa, C and Toschi, N and Giannelli, M}, title = {Diffusion-MRI in neurodegenerative disorders.}, journal = {Magnetic resonance imaging}, volume = {33}, number = {7}, pages = {853-876}, doi = {10.1016/j.mri.2015.04.006}, pmid = {25917917}, issn = {1873-5894}, mesh = {*Algorithms ; Brain/*pathology ; *Contrast Media ; Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Image Enhancement/*methods ; Image Interpretation, Computer-Assisted/*methods ; Neurodegenerative Diseases/*pathology ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {The ability to image the whole brain through ever more subtle and specific methods/contrasts has come to play a key role in understanding the basis of brain abnormalities in several diseases. In magnetic resonance imaging (MRI), "diffusion" (i.e. the random, thermally-induced displacements of water molecules over time) represents an extraordinarily sensitive contrast mechanism, and the exquisite structural detail it affords has proven useful in a vast number of clinical as well as research applications. Since diffusion-MRI is a truly quantitative imaging technique, the indices it provides can serve as potential imaging biomarkers which could allow early detection of pathological alterations as well as tracking and possibly predicting subtle changes in follow-up examinations and clinical trials. Accordingly, diffusion-MRI has proven useful in obtaining information to better understand the microstructural changes and neurophysiological mechanisms underlying various neurodegenerative disorders. In this review article, we summarize and explore the main applications, findings, perspectives as well as challenges and future research of diffusion-MRI in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and degenerative ataxias.}, }
@article {pmid25917207, year = {2015}, author = {Matic, I and Strobbe, D and Frison, M and Campanella, M}, title = {Controlled and Impaired Mitochondrial Quality in Neurons: Molecular Physiology and Prospective Pharmacology.}, journal = {Pharmacological research}, volume = {99}, number = {}, pages = {410-424}, doi = {10.1016/j.phrs.2015.03.021}, pmid = {25917207}, issn = {1096-1186}, support = {G1100809/2//Medical Research Council/United Kingdom ; //Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Mitochondria/*pathology/*physiology ; Neurodegenerative Diseases/pathology ; Neurons/*pathology/*physiology ; }, abstract = {Tuned mitochondrial physiology is fundamental for qualitative cellular function. This is particularly relevant for neurons, whose pathology is frequently associated with mitochondrial deficiencies. Defects in mitochondria are indeed key features in most neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). When mitochondrial coupling impairs, so does cell metabolism, trafficking and the signaling depending on the homeostasis of the mitochondrial network. Moreover, the quality control of mitochondria - via the process of mitochondrial autophagy - results biased in neurodegeneration stemming major interest on the molecular determinants of this process among neuroscientists. In this review, we highlight the most notable and acknowledged deficiencies of mitochondrial function and their relationship with diseases occurring in neurons and their transmission. The physiological aspects of mitochondrial biology in relation to bio-energy, dynamics and quality control will be discussed with the finality to form a comprehensive picture of the mitochondrial contribution to the pathophysiology of neurodegenerative syndromes. In this way we aim to set the scene to conceive novel strategies to better diagnose and target these debilitative conditions.}, }
@article {pmid25911031, year = {2015}, author = {Modrzewska, B and Kurnatowski, P}, title = {Adherence of Candida sp. to host tissues and cells as one of its pathogenicity features.}, journal = {Annals of parasitology}, volume = {61}, number = {1}, pages = {3-9}, pmid = {25911031}, issn = {2299-0631}, mesh = {Animals ; Candida/*physiology ; *Cell Adhesion ; Epithelial Cells/*microbiology/physiology ; Fungal Proteins/genetics/*metabolism ; Gene Expression Regulation, Fungal ; Humans ; }, abstract = {The ability of Candida sp. cells to adhere to the mucosal surfaces of various host organs as well as synthetic materials is an important pathogenicity feature of those fungi which contributes to the development of infection. This property varies depending on the species of the fungus and is the greatest for C. albicans. The process of adhesion depends on plenty of factors related to the fungal and host cells as well as environmental conditions. The main adhesins present on the fungal cell wall are: Als, Epa, Hwp1, but also Eap1, Sun41, Csh1 and probably Hyr1; for adhesion significant are also secreted aspartyl proteases Sap. Various researchers specify a range of genes which contribute to adhesion, such as: CZF1, EFG1, TUP1, TPK1, TPK2, HGC1, RAS1, RIM101, VPS11, ECM1, CKA2, BCR1, BUD2, RSR1, IRS4, CHS2, SCS7, UBI4, UME6, TEC1 and GAT2. Influence for adherence have also heat shock proteins Hsp70, Mediator Middle domain subunit Med31 and morphological transition. Among factors affecting adhesion related to host cells it is necessary to mention fibronectins and integrins (receptors for Candida sp. adhesins), type of epithelial cells, their morphology and differentiation phase. To a lesser degree influence on adhesion have non-specific factors and environmental conditions.}, }
@article {pmid25907990, year = {2015}, author = {Fernández-Borges, N and Eraña, H and Venegas, V and Elezgarai, SR and Harrathi, C and Castilla, J}, title = {Animal models for prion-like diseases.}, journal = {Virus research}, volume = {207}, number = {}, pages = {5-24}, doi = {10.1016/j.virusres.2015.04.014}, pmid = {25907990}, issn = {1872-7492}, mesh = {Animals ; *Disease Models, Animal ; Humans ; Prion Diseases/genetics/*metabolism ; Protein Folding ; Proteins/chemistry/genetics/metabolism ; Proteostasis Deficiencies/genetics/*metabolism ; }, abstract = {Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease.}, }
@article {pmid25896576, year = {2015}, author = {Belendiuk, KA and Baldini, LL and Bonn-Miller, MO}, title = {Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders.}, journal = {Addiction science &amp; clinical practice}, volume = {10}, number = {}, pages = {10}, pmid = {25896576}, issn = {1940-0640}, support = {R01 MH40564/MH/NIMH NIH HHS/United States ; }, mesh = {Cachexia/drug therapy ; *Cannabis ; Central Nervous System Diseases/drug therapy ; Chronic Disease/*drug therapy ; Crohn Disease/drug therapy ; Glaucoma/drug therapy ; HIV Infections/drug therapy ; Humans ; Medical Marijuana/administration &amp; dosage/adverse effects/*therapeutic use ; Mental Disorders/*drug therapy ; Neoplasms/drug therapy ; }, abstract = {The present investigation aimed to provide an objective narrative review of the existing literature pertaining to the benefits and harms of marijuana use for the treatment of the most common medical and psychological conditions for which it has been allowed at the state level. Common medical conditions for which marijuana is allowed (i.e., those conditions shared by at least 80 percent of medical marijuana states) were identified as: Alzheimer's disease, amyotrophic lateral sclerosis, cachexia/wasting syndrome, cancer, Crohn's disease, epilepsy and seizures, glaucoma, hepatitis C virus, human immunodeficiency virus/acquired immunodeficiency syndrome, multiple sclerosis and muscle spasticity, severe and chronic pain, and severe nausea. Post-traumatic stress disorder was also included in the review, as it is the sole psychological disorder for which medical marijuana has been allowed. Studies for this narrative review were included based on a literature search in PsycINFO, MEDLINE, and Google Scholar. Findings indicate that, for the majority of these conditions, there is insufficient evidence to support the recommendation of medical marijuana at this time. A significant amount of rigorous research is needed to definitively ascertain the potential implications of marijuana for these conditions. It is important for such work to not only examine the effects of smoked marijuana preparations, but also to compare its safety, tolerability, and efficacy in relation to existing pharmacological treatments.}, }
@article {pmid25896254, year = {2015}, author = {Nah, J and Yuan, J and Jung, YK}, title = {Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach.}, journal = {Molecules and cells}, volume = {38}, number = {5}, pages = {381-389}, pmid = {25896254}, issn = {0219-1032}, mesh = {Animals ; *Autophagy ; Humans ; Lysosomes/metabolism ; Neurodegenerative Diseases/drug therapy/*pathology ; Protein Aggregates/drug effects ; }, abstract = {Autophagy is a lysosome-dependent intracellular degradation process that allows recycling of cytoplasmic constituents into bioenergetic and biosynthetic materials for maintenance of homeostasis. Since the function of autophagy is particularly important in various stress conditions, perturbation of autophagy can lead to cellular dysfunction and diseases. Accumulation of abnormal protein aggregates, a common cause of neurodegenerative diseases, can be reduced through autophagic degradation. Recent studies have revealed defects in autophagy in most cases of neurodegenerative disorders. Moreover, deregulated excessive autophagy can also cause neurodegeneration. Thus, healthy activation of autophagy is essential for therapeutic approaches in neurodegenerative diseases and many autophagy-regulating compounds are under development for therapeutic purposes. This review describes the overall role of autophagy in neurodegeneration, focusing on various therapeutic strategies for modulating specific stages of autophagy and on the current status of drug development.}, }
@article {pmid25896087, year = {2015}, author = {Paez-Colasante, X and Figueroa-Romero, C and Sakowski, SA and Goutman, SA and Feldman, EL}, title = {Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era.}, journal = {Nature reviews. Neurology}, volume = {11}, number = {5}, pages = {266-279}, pmid = {25896087}, issn = {1759-4766}, support = {R01 NS077982/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/therapy ; Chromatin Assembly and Disassembly/genetics ; DNA Methylation/genetics ; Early Diagnosis ; Epigenesis, Genetic/*genetics ; Epigenomics ; Gene-Environment Interaction ; Histones/genetics ; Humans ; MicroRNAs/antagonists &amp; inhibitors/*physiology ; Mutation/genetics ; Oligonucleotides, Antisense/therapeutic use ; RNA Editing/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neurons, which results in weakness and atrophy of voluntary skeletal muscles. Treatments do not modify the disease trajectory effectively, and only modestly improve survival. A complex interaction between genes, environmental exposure and impaired molecular pathways contributes to pathology in patients with ALS. Epigenetic mechanisms control the hereditary and reversible regulation of gene expression without altering the basic genetic code. Aberrant epigenetic patterns-including abnormal microRNA (miRNA) biogenesis and function, DNA modifications, histone remodeling, and RNA editing-are acquired throughout life and are influenced by environmental factors. Thus, understanding the molecular processes that lead to epigenetic dysregulation in patients with ALS might facilitate the discovery of novel therapeutic targets and biomarkers that could reduce diagnostic delay. These achievements could prove crucial for successful disease modification in patients with ALS. We review the latest findings regarding the role of miRNA modifications and other epigenetic mechanisms in ALS, and discuss their potential as therapeutic targets.}, }
@article {pmid25877220, year = {2015}, author = {Phatnani, H and Maniatis, T}, title = {Astrocytes in neurodegenerative disease.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {7}, number = {6}, pages = {}, pmid = {25877220}, issn = {1943-0264}, mesh = {Animals ; Astrocytes/*physiology ; Dementia/*physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Neurons/physiology ; }, abstract = {Astrocytes contribute to the maintenance of the health and function of the central nervous system (CNS). Thus, it is not surprising that these multifunctional cells have been implicated in the onset and progression of several neurodegenerative diseases. The involvement of astrocytes in the neuropathology of these diseases is likely a consequence of both the loss of normal homeostatic functions and gain of toxic functions. Intracellular aggregates in astrocytes are a common feature of various neurodegenerative diseases, and these aggregates perturb normal astrocytic functions in ways that can be harmful to neuronal viability. Here, we review the role of astrocytes in neurodegenerative diseases, focusing on their dysfunction in Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid25870959, year = {2015}, author = {Xiang, W and Chao, ZY and Feng, DY}, title = {Role of Toll-like receptor/MYD88 signaling in neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {26}, number = {4}, pages = {407-414}, doi = {10.1515/revneuro-2014-0067}, pmid = {25870959}, issn = {0334-1763}, mesh = {Animals ; Humans ; Myeloid Differentiation Factor 88/*metabolism ; Neurodegenerative Diseases/*metabolism ; Signal Transduction ; Toll-Like Receptors/*metabolism ; }, abstract = {Toll-like receptors (TLRs) are important innate immune proteins, and the activation of the TLRs results in the activation of intracellular signaling pathways, leading to the expression of proinflammatory cytokines that are essential to the identification and clearance of invading pathogens. TLR signaling occurs through adaptor proteins, most commonly myeloid differentiation primary response gene 88 (MyD88). It is now known that immune surveillance and inflammatory responses occur in neurodegenerative diseases and TLR/MYD88 signaling plays a critical role in these diseases. The included studies suggest a contribution for this signaling to the pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, and related disorders. In this review, a discussion of the recent findings in this field is presented.}, }
@article {pmid25869998, year = {2015}, author = {Lattante, S and Ciura, S and Rouleau, GA and Kabashi, E}, title = {Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD).}, journal = {Trends in genetics : TIG}, volume = {31}, number = {5}, pages = {263-273}, doi = {10.1016/j.tig.2015.03.005}, pmid = {25869998}, issn = {0168-9525}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Disease Models, Animal ; Frontotemporal Dementia/*genetics ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Inheritance Patterns ; Risk Factors ; Translational Research, Biomedical ; }, abstract = {Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the notion of an oligogenic model of disease. In this review we summarize major advances in the elucidation of novel genetic factors in these diseases which have led to a better understanding of the common pathogenic factors leading to neurodegeneration.}, }
@article {pmid25869332, year = {2015}, author = {Schubert, W}, title = {Advances in toponomics drug discovery: Imaging cycler microscopy correctly predicts a therapy method of amyotrophic lateral sclerosis.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {87}, number = {8}, pages = {696-703}, pmid = {25869332}, issn = {1552-4930}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Drug Discovery/methods ; Humans ; Microscopy, Fluorescence/methods ; Proteins/metabolism ; Proteome/metabolism ; }, abstract = {An imaging cycler microscope (ICM) is a fully automated (epi)fluorescence microscope which overcomes the spectral resolution limit resulting in parameter- and dimension-unlimited fluorescence imaging. This enables the spatial resolution of large molecular systems with their emergent topological properties (toponome) in morphologically intact cells and tissues displaying thousands of multi protein assemblies at a time. The resulting combinatorial geometry of these systems has been shown to be key for in-vivo/in-situ detection of lead proteins controlling protein network topology and (dys)function: If lead proteins are blocked or downregulated the corresponding disease protein network disassembles. Here, correct therapeutic predictions are exemplified for ALS. ICM drug target studies have discovered an 18-dimensional cell surface molecular system in ALS-PBMC with a lead drug target protein, whose therapeutic downregulation is now reported to show statistically significant effect with stop of disease progression in one third of the ALS patients. Together, this clinical and the earlier experimental validations of the ICM approach indicate that ICM readily discovers in vivo robustness nodes of disease with lead proteins controlling them. Breaking in vivo robustness nodes using drugs against their lead proteins is likely to overcome current high drug attrition rates.}, }
@article {pmid25866875, year = {2015}, author = {Picone, RP and Kendall, DA}, title = {Minireview: From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation.}, journal = {Molecular endocrinology (Baltimore, Md.)}, volume = {29}, number = {6}, pages = {801-813}, pmid = {25866875}, issn = {1944-9917}, support = {R01 DA020763/DA/NIDA NIH HHS/United States ; DA020763/DA/NIDA NIH HHS/United States ; }, mesh = {Cannabinoid Receptor Modulators/*therapeutic use ; Disease ; Humans ; Neuroprotection ; Receptor, Cannabinoid, CB1/chemistry/metabolism ; Receptor, Cannabinoid, CB2/chemistry/metabolism ; *Translational Research, Biomedical ; }, abstract = {The effects of cannabinoids have been known for centuries and over the past several decades two G protein-coupled receptors, CB1 and CB2, that are responsible for their activity have been identified. Endogenous lipid-derived cannabinergic agents have been found, biosynthetic and catabolic machinery has been characterized, and synthetic agents have been designed to modulate these receptors. Selective agents including agonists, antagonists, inverse agonists, and novel allosteric modulators targeting either CB1 or CB2 have been developed to inhibit or augment their basal tone. As a result, the role these receptors play in human physiology and their potential therapeutic applications in disease states are being elucidated. The CB1 receptor, although ubiquitous, is densely expressed in the brain, and CB2 is largely found on cells of immune origin. This minireview highlights the role of CB1 in excitotoxic assaults in the brain and its potential to limit addiction liability. In addition, it will examine the relationship between receptor activity and stimulation of insulin release from pancreatic β-cells, insulin resistance, and feeding behavior leading toward obesity. The roles of CB2 in the neuropathology of amyotrophic lateral sclerosis and in the central manifestations of chronic HIV infection potentially converge at inflammatory cell activation, thereby providing an opportunity for intervention. Last, CB2 modulation is discussed in the context of an experimental model of postmenopausal osteoporosis. Achieving exquisite receptor selectivity and elucidating the mechanisms underlying receptor inhibition and activation will be essential for the development of the next generation of cannabinergic-based therapeutic agents.}, }
@article {pmid25862375, year = {2016}, author = {Paschon, V and Takada, SH and Ikebara, JM and Sousa, E and Raeisossadati, R and Ulrich, H and Kihara, AH}, title = {Interplay Between Exosomes, microRNAs and Toll-Like Receptors in Brain Disorders.}, journal = {Molecular neurobiology}, volume = {53}, number = {3}, pages = {2016-2028}, pmid = {25862375}, issn = {1559-1182}, mesh = {Animals ; Brain Diseases/*metabolism ; Exosomes/*metabolism ; Extracellular Vesicles/metabolism ; Humans ; MicroRNAs/*metabolism ; RNA Transport ; Toll-Like Receptors/*metabolism ; }, abstract = {Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, participate in intercellular communication, and particularly, in paracrine and endocrine signalling. The EVs and their specific contents have been considered hallmarks of different diseases. It has been recently discovered that EVs can co-transport nucleic acids such as DNAs, ribosomal RNAs, circular RNAs (circRNAs), long noncoding RNAs (lnRNAs) and microRNAs (miRNAs). miRNAs are important regulators of gene expression at the post-transcriptional level, although they may also play other roles. Recent evidence supports the hypothesis that miRNAs can activate Toll-like receptors (TLRs) under certain circumstances. TLRs belong to a multigene family of immune system receptors and have been recently described in the nervous system. In the immune system, TLRs are important for the recognition of the invading microorganisms, whereas in the nervous system, they recognise endogenous ligands released by undifferentiated or necrotic/injured cells. In the neuronal disease field, TLRs activity has been associated with amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's and Parkinson's disease. Herein, we reviewed the current knowledge of the relationship between miRNA release by EVs and the inflammation signalling triggered by TLRs in neighbouring cells or during long-distance cell-to-cell communication. We highlight novel aspects of this communication mechanism, offering a valuable insight into such pathways in health and disease.}, }
@article {pmid25855473, year = {2015}, author = {Bansal, M and Swarup, G and Balasubramanian, D}, title = {Functional analysis of optineurin and some of its disease-associated mutants.}, journal = {IUBMB life}, volume = {67}, number = {2}, pages = {120-128}, doi = {10.1002/iub.1355}, pmid = {25855473}, issn = {1521-6551}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Autophagy/genetics ; Cell Cycle/genetics ; Cell Cycle Proteins ; Glaucoma/*genetics ; Humans ; Membrane Transport Proteins ; *Mutation ; NF-kappa B/metabolism ; Neurodegenerative Diseases/genetics ; Transcription Factor TFIIIA/*genetics/*metabolism ; }, abstract = {Optineurin is a multifunctional protein involved in a variety of cellular functions such as protein trafficking by vesicles, autophagy, and signal transduction. Certain mutations in optineurin (gene OPTN) are associated with neurodegenerative diseases like glaucoma and amyotrophic lateral sclerosis (ALS). Optineurin is also seen in pathological structures present in several other neurodegenerative diseases. In glaucoma, loss of vision occurs due to progressive degeneration of retinal ganglion cells, and perhaps loss of photoreceptor cone cells as well. Most of the glaucoma-associated mutations of optineurin are heterozygous missense mutations, whereas the ALS-associated mutations include deletion, truncation, and missense mutations. Optineurin mediates its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more proteins. Disease-causing mutations alter these interactions leading to functional defects in membrane vesicle trafficking, autophagy, signaling, aggregate formation, and other processes. Some of these functional defects, caused by glaucoma-associated mutants of optineurin, led to retinal cell death mediated by apoptosis and therefore may contribute to pathogenesis directly. Other mutations are likely to cause glaucoma by indirect mechanisms involving other cell types. Mechanisms of ALS pathogenesis by optineurin mutations are yet to be investigated in detail; however, some ALS-associated mutants cause defects in signaling, autophagy, and ubiquitin binding, which might contribute to pathogenesis.}, }
@article {pmid25850769, year = {2015}, author = {Morello, G and Conforti, FL and Parenti, R and D'Agata, V and Cavallaro, S}, title = {Selection of Potential Pharmacological Targets in ALS Based on Whole- Genome Expression Profiling.}, journal = {Current medicinal chemistry}, volume = {22}, number = {17}, pages = {2004-2021}, doi = {10.2174/0929867322666150408112135}, pmid = {25850769}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Animals ; Gene Expression Profiling ; Genome, Human ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by the gradual degeneration and death of upper and lower motor neurons. Despite continue efforts, the etiology and pathogenesis of ALS are not well understood yet. The lack of knowledge about molecular and cellular players involved in the neurodegenerative progression of ALS hinders effective therapy development. Several genomicbased studies have been conducted to identify genetic contributors to sporadic ALS (SALS) and new potential pharmacological targets, but these have resulted in short and non-overlapping lists of candidates. In the last few years, our research group has developed the largest whole-genome expression profile database of SALS human samples. We have identified several genes deregulated in the motor cortex of SALS patients and analyzed the role of these genes within deregulated pathways, providing a full molecular portrait of ALS pathogenesis. Some of deregulated genes encode for proteins that are direct or indirect targets of experimental or therapeutic drugs already applied to unrelated diseases. In this review, we focus on the potential role of candidate targets in ALS pathophysiology, highlighting their possible contribution to ALS therapy. The rational selection of the most promising drug targets and related modulatory drugs may provide a starting point for their preclinical or clinical validation and, hopefully, the development of more effective treatments for ALS patients.}, }
@article {pmid25846565, year = {2015}, author = {Ludolph, AC and Brettschneider, J}, title = {TDP-43 in amyotrophic lateral sclerosis - is it a prion disease?.}, journal = {European journal of neurology}, volume = {22}, number = {5}, pages = {753-761}, doi = {10.1111/ene.12706}, pmid = {25846565}, issn = {1468-1331}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; Prion Diseases/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating disease characterized by rapidly progressive paresis. The neuropathological hallmark of most amyotrophic lateral sclerosis cases are neuronal and glial aggregates of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43). The accumulation of similar proteins into insoluble aggregates is now recognized as a common pathological hallmark of neurodegenerative diseases in general. Importantly, many of these proteins such as tau and amyloid-β in Alzheimer's disease and α-synuclein in Parkinson's show a stereotypical sequential distribution pattern with progressing disease. In this review, we discuss recent evidence that TDP-43 in ALS may propagate similarly to other neurodegenerative disease proteins. We furthermore delineate similarities and important differences of TDP-43 proteinopathies to prion diseases.}, }
@article {pmid25845840, year = {2015}, author = {Volpe, CM and Nogueira-Machado, JA}, title = {Is Innate Immunity and Inflammasomes Involved in Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)?.}, journal = {Recent patents on endocrine, metabolic &amp; immune drug discovery}, volume = {9}, number = {1}, pages = {40-45}, doi = {10.2174/1872214809666150407111420}, pmid = {25845840}, issn = {2212-3334}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*immunology/metabolism ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Drug Design ; Genetic Predisposition to Disease ; Humans ; *Immunity, Innate/drug effects ; Inflammasomes/drug effects/*immunology/metabolism ; Mutation ; Neuroprotective Agents/therapeutic use ; Patents as Topic ; Phenotype ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease is an axonopathy with adultonset, progressive and irreversible degeneration of upper and lower motor neurons. Around 90% of ALS is considered as sporadic ALS (sALS) without apparent genetic cause while in the familial type of ALS (fALS) at least one affected blood relative needs to be identified. Both sALS and fALS show similar progression and pathological profile. Biochemical and immunological roles have been reported for both types of ALS. It has been suggested that mutation in SOD1 gene would be responsible for the oxidative stress and neurotoxicity. Besides, oxidative stress, protein aggregation, altered cholinergic synapse, neuro-inflammation and production of pro-inflammatory cytokines have also been reported. Thus, the focus of the present review was on biochemical and immunological biomarkers and pathogenic mechanism. Regulatory T cells, pro-inflammatory cytokines and activation of pro-inflammatory signaling pathway are discussed. The activation of NRL inflammasomes in ALS and the involvement of IL-18, IL-1β and caspases-1 are also suggested. The presence and importance of HMGB-1 (DAMP) and activation of Tolllike receptors and/or RAGE also are envisaged. The patents US20140212508, WO2014145776, WO2014145118, US20140255371, US20140194427, US20140243400, WO2014128254, WO2014076702, WO2014071449, WO2014043696, WO2014001742, and WO2013082299 are summarized. This review intends to evaluate the biochemical and immunological responses and the involvement of inflammasomes in the pathogenesis of ALS. In the present review, we suggest hypothetical model for ALS pathogenesis and we discuss some patents that suggest new treatment and/or therapeutic targets. Due to a large number of patents covering therapy and control of neurodegenerative diseases, our focus was restricted only to discuss the latest registered patents in 2014.}, }
@article {pmid25841277, year = {2015}, author = {Barthel, H and Schroeter, ML and Hoffmann, KT and Sabri, O}, title = {PET/MR in dementia and other neurodegenerative diseases.}, journal = {Seminars in nuclear medicine}, volume = {45}, number = {3}, pages = {224-233}, doi = {10.1053/j.semnuclmed.2014.12.003}, pmid = {25841277}, issn = {1558-4623}, mesh = {Dementia/*diagnosis/diagnostic imaging ; Humans ; Magnetic Resonance Imaging/*methods ; Multimodal Imaging ; Parkinsonian Disorders/diagnostic imaging ; Positron-Emission Tomography/*methods ; }, abstract = {The spectrum of neurodegenerative diseases covers the dementias, parkinsonian syndromes, Huntington disease, amyotrophic lateral sclerosis, and prion diseases. In these entities, brain MRI is often used in clinical routine to exclude other pathologies and to demonstrate specific atrophy patterns. [18F]FDG PET delivers early and sensitive readouts of neural tissue loss, and more specific PET tracers currently in use clinically target β-amyloid plaques or dopaminergic deficiency. The recent integration of PET into MR technology offers a new chance to improve early and differential diagnosis of many neurodegenerative diseases. Initial evidence in the literature is available to support this notion. New emerging PET tracers, such as tracers that bind to tau or α-synuclein aggregates, as well as MR techniques, like diffusion-tensor imaging, resting-state functional MRI, and arterial spin labeling, have the potential to broaden the diagnostic capabilities of combined PET/MRI to image dementias, Parkinson disease, and other neurodegenerative diseases. The ultimate goal is to establish combined PET/MRI as a first-line imaging technique to provide, in a one-stop-shop fashion with improved patient comfort, all biomarker information required to increase diagnostic confidence toward specific diagnoses. The technical challenge of accurate PET data attenuation correction within PET/MRI systems needs yet to be solved. Apart from the projected clinical routine applications, future research would need to answer the questions of whether combined brain PET/MRI is able to improve basic research of neurodegenerative diseases and antineurodegeneration drug testing.}, }
@article {pmid25834301, year = {2015}, author = {Indo, HP and Yen, HC and Nakanishi, I and Matsumoto, K and Tamura, M and Nagano, Y and Matsui, H and Gusev, O and Cornette, R and Okuda, T and Minamiyama, Y and Ichikawa, H and Suenaga, S and Oki, M and Sato, T and Ozawa, T and Clair, DK and Majima, HJ}, title = {A mitochondrial superoxide theory for oxidative stress diseases and aging.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {56}, number = {1}, pages = {1-7}, pmid = {25834301}, issn = {0912-0009}, support = {P30 CA177558/CA/NCI NIH HHS/United States ; }, abstract = {Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed "the Superoxide Theory," which postulates that superoxide (O2 (•-)) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q10) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich's seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.}, }
@article {pmid25832720, year = {2015}, author = {Farber, NM and Perez-Lloret, S and Gamzu, ER}, title = {Design and development of a novel supportive care product for the treatment of sialorrhea in Parkinson's disease.}, journal = {Current topics in medicinal chemistry}, volume = {15}, number = {10}, pages = {939-954}, doi = {10.2174/156802661510150328224130}, pmid = {25832720}, issn = {1873-4294}, mesh = {Animals ; *Drug Design ; *Drug Discovery ; Humans ; Muscarinic Antagonists/*therapeutic use ; Parkinson Disease/*complications ; Sialorrhea/*drug therapy/*etiology ; Tropicamide/*therapeutic use ; }, abstract = {Sialorrhea or excessive drooling is a significant medical issue in Parkinson's disease (PD) and neurodegenerative disorders, although it is often underreported by patients. Sialorrhea affects a large proportion of PD patients, ranging up to 78% in advanced stages, with many PD patients considering drooling as their worst non-motor symptom. Sialorrhea affects up to a million patients with diverse neurological impairments, including cerebral palsy, amyotrophic lateral sclerosis (ALS), Huntington's, survivors of stroke and severe traumatic brain injury. Numerous approaches have been attempted to treat sialorrhea in PD patients, including surgical procedures, prosthetic devices, botulinum injections, systemic anticholinergic drugs, and speech and behavioral therapy. A novel drug treatment (NH004) to control the symptoms of sialorrhea is under development. The active ingredient is the anticholinergic drug tropicamide. Anticholinergic drugs work by blocking acetylcholine muscarinic receptors and ultimately decreasing saliva secretion via the reduction of parasympathetic autonomic nervous system activity. The tropicamide is delivered in a thin film designed to adhere to the buccal mucosa and to slowly dissolve within the oral cavity, allowing the drug to reach the underlying salivary gland. A pilot study testing NH004 in PD patients has suggested a potentially useful sialorrhea-reducing effect with NH004 compared to placebo. The advantages of NH004 include local bioavailability with low systemic exposure, rapid onset of action and, importantly, convenience of use for patients. This review summarizes the current knowledge and impact of sialorrhea as a common non-motor symptom in PD, treatment options, the anticholinergic drug tropicamide, the design and development of the thin film drug delivery system, and NH004 for the treatment of sialorrhea.}, }
@article {pmid25832510, year = {2015}, author = {Grassi, L and Caruso, R and Costantini, A}, title = {Communication with patients suffering from serious physical illness.}, journal = {Advances in psychosomatic medicine}, volume = {34}, number = {}, pages = {10-23}, doi = {10.1159/000369050}, pmid = {25832510}, issn = {0065-3268}, mesh = {Chronic Disease/*psychology ; *Communication ; Education, Medical/*standards ; Humans ; Patients/*psychology ; *Physician-Patient Relations ; }, abstract = {Communication is the corner stone of the relationship with the patient in all medical settings with the main aims of creating a good inter-personal relationship, exchanging information, and making treatment-related decisions. In a rapidly changing cultural and social context, the paternalistic approach of doctors knowing the best and deciding what should be done for a patient has been replaced by a shared decision-making approach, with patients being advised to educate themselves, ask questions and influence the course of the discussion with their doctors. Thus, a need for an improvement in the communication skills of physicians is extremely important for patients affected by serious physical illness (e.g. cancer, HIV infection, multiple sclerosis, amyotrophic lateral sclerosis). Certain attitudes, behaviour and skills (e.g. capacity to impart confidence, being empathetic, providing a 'human touch', relating on a personal level, being forthright, being respectful, and being thorough) are part of effective communication. However, some specific aspects influencing doctor-patient communication and relationships, such as personality variables, coping and attachment styles, as well as cultural factors, should also be taken in to account. The development of training curricula to help doctors acquire proper skills in communication is mandatory, since research has shown that training in communication may facilitate the effectiveness of a doctor-patient relationship and the patient's satisfaction with care and give a general sense of humanity, which is easily lost in a biotechnologically oriented medicine.}, }
@article {pmid25829512, year = {2015}, author = {Wong, YC and Holzbaur, EL}, title = {Autophagosome dynamics in neurodegeneration at a glance.}, journal = {Journal of cell science}, volume = {128}, number = {7}, pages = {1259-1267}, pmid = {25829512}, issn = {1477-9137}, support = {R01 NS060698/NS/NINDS NIH HHS/United States ; R01NS060698/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Autophagy ; Humans ; Neurodegenerative Diseases/genetics/metabolism/*physiopathology ; Neurons/cytology/metabolism ; Phagosomes/genetics/*metabolism ; }, abstract = {Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.}, }
@article {pmid25827094, year = {2015}, author = {Bruce, ED and Konda, S and Dean, DD and Wang, EW and Huang, JH and Little, DM}, title = {Neuroimaging and traumatic brain injury: State of the field and voids in translational knowledge.}, journal = {Molecular and cellular neurosciences}, volume = {66}, number = {Pt B}, pages = {103-113}, doi = {10.1016/j.mcn.2015.03.017}, pmid = {25827094}, issn = {1095-9327}, mesh = {Animals ; Biomarkers/*blood ; Brain/metabolism/pathology ; Brain Injuries/*diagnosis/*pathology ; Humans ; Neurodegenerative Diseases/*diagnosis/*pathology ; *Neuroimaging ; Risk Factors ; }, abstract = {Traumatic brain injury (TBI) is a leading cause of death and disability in every developed country in the world and is believed to be a risk factor in the later development of depression, anxiety disorders and neurodegenerative diseases including chronic traumatic encephalopathy (CTE), Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). One challenge faced by those who conduct research into TBI is the lack of a verified and validated biomarker that can be used to diagnose TBI or for use as a prognostic variable which can identify those at risk for poor recovery following injury or at risk for neurodegeneration later in life. Neuroimaging continues to hold promise as a TBI biomarker but is limited by a lack of clear relationship between the neuropathology of injury/recovery and the quantitative and image based data that is obtained. Specifically lacking is the data on biochemical and biologic changes that lead to alterations in neuroimaging markers. There are multiple routes towards developing the knowledge required to more definitively link pathology to imaging but the most efficient approach is expanded leveraging of in vivo human blood, serum, and imaging biomarkers with both in vivo and ex vivo animal findings. This review describes the current use and limitations of imaging in TBI including a discussion of currently used animal injury models and the available animal imaging data and extracted markers that hold the greatest promise for helping translate alterations in imaging back to injury pathology. Further, it reviews both the human and animal TBI literature supporting current standards, identifies the remaining voids in the literature, and briefly highlights recent advances in molecular imaging. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.}, }
@article {pmid25825074, year = {2018}, author = {Camacho, A and Esteban, J and Paradas, C}, title = {Report by the Spanish Foundation for the Brain on the social impact of amyotrophic lateral sclerosis and other neuromuscular disorders.}, journal = {Neurologia}, volume = {33}, number = {1}, pages = {35-46}, doi = {10.1016/j.nrl.2015.02.003}, pmid = {25825074}, issn = {2173-5808}, mesh = {Amyotrophic Lateral Sclerosis/*economics/*epidemiology/mortality ; *Awareness ; Brain ; Cost of Illness ; Humans ; Incidence ; Prevalence ; *Socioeconomic Factors ; Spain/epidemiology ; }, abstract = {INTRODUCTION: A thorough knowledge of the socioeconomic scope of neuromuscular disease is essential for managing resources and raising social awareness.<br><br>DEVELOPMENT: Our group reviewed current data on the epidemiology, mortality and dependence rates, and socioeconomic impact of amyotrophic lateral sclerosis and neuromuscular diseases in Spain. We also recorded how neurological care for these patients is organised.<br><br>CONCLUSIONS: Neuromuscular disorders are a very heterogeneous group of diseases, and some are very rare. These disorders account for between 2.8% and 18% of the total motives for a neurological consultation. In Spain, prevalence and incidence figures for amyotrophic lateral sclerosis are similar to those in other countries; however, figures for patients with other neuromuscular diseases are not known. Since the diseases are chronic, progressive, and debilitating, they cause considerable disability and dependence, which in turn directly affects healthcare and social costs associated with the disease. The costs generated by one patient with amyotrophic lateral sclerosis or Duchenne disease have been calculated at about 50 000 euros per year. Neuromuscular disease shows aetiological, diagnostic, and prognostic complexity, and it requires multidisciplinary management. Follow-up for these patients should be entrusted to specialised units.}, }
@article {pmid25819934, year = {2015}, author = {Espejo-Porras, F and Piscitelli, F and Verde, R and Ramos, JA and Di Marzo, V and de Lago, E and Fernández-Ruiz, J}, title = {Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {10}, number = {2}, pages = {233-244}, pmid = {25819934}, issn = {1557-1904}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*metabolism ; Animals ; Central Nervous System/drug effects/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Endocannabinoids/genetics/*metabolism ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; Receptor, Cannabinoid, CB2/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Because of their neuroprotective properties, cannabinoids are being investigated in neurodegenerative disorders, mainly in preclinical studies. These disorders also include amyotrophic lateral sclerosis (ALS), a degenerative disease produced by the damage of the upper and lower motor neurons leading to muscle denervation, atrophy and paralysis. The studies with cannabinoids in ALS have been conducted exclusively in a transgenic mouse model bearing mutated forms of human superoxide dismutase-1, the first gene that was identified in relation with ALS. The present study represents the first attempt to investigate the endocannabinoid system in an alternative model, the transgenic mouse model of TAR-DNA binding protein-43 (TDP-43), a protein related to ALS and also to frontotemporal dementia. We used these mice for behavioral and histological characterization at an early symptomatic phase (70-80 days of age) and at a post-symptomatic stage (100-110 days of age). TDP-43 transgenic mice exhibited a worsened rotarod performance at both disease stages. This was accompanied by a loss of motor neurons in the spinal cord (measured by Nissl staining) and by reactive microgliosis (measured by Iba-1 immunostaining) at the post-symptomatic stage. We also detected elevated levels of the CB2 receptor (measured by qRT-PCR and western blotting) in the spinal cord of these animals. Double-staining studies confirmed that this up-regulation occurs in microglial cells in the post-symptomatic stage. Some trends towards an increase were noted also for the levels of endocannabinoids, which in part correlate with a small reduction of FAAH. Some of these parameters were also analyzed in the cerebral cortex of TDP-43 transgenic mice, but we did not observe any significant change, in agreement with the absence of anomalies in cognitive tests. In conclusion, our data support the idea that the endocannabinoid signaling system, in particular the CB2 receptor, may serve for the development of a neuroprotective therapy in TDP-43-related disorders. We are presently engaged in pharmacological experiments to investigate this possibility.}, }
@article {pmid25815256, year = {2015}, author = {Raglio, A and Attardo, L and Gontero, G and Rollino, S and Groppo, E and Granieri, E}, title = {Effects of music and music therapy on mood in neurological patients.}, journal = {World journal of psychiatry}, volume = {5}, number = {1}, pages = {68-78}, pmid = {25815256}, issn = {2220-3206}, abstract = {Mood disorder and depressive syndromes represent a common comorbid condition in neurological disorders with a prevalence rate that ranges between 20% and 50% of patients with stroke, epilepsy, multiple sclerosis, and Parkinson's disease. Notwithstanding, these conditions are often under-diagnosed and under-treated in the clinical practice and negatively affect the functional recovery, the adherence to treatment, the quality of life, and even the mortality risk. In addition, a bidirectional association between depression and neurological disorders may be possible being that depressive syndromes may be considered as a risk factor for certain neurological diseases. Despite the large amount of evidence regarding the effects of music therapy (MT) and other musical interventions on different aspects of neurological disorders, no updated article reviewing outcomes such as mood, emotions, depression, activity of daily living and so on is actually available; for this reason, little is known about the effectiveness of music and MT on these important outcomes in neurological patients. The aim of this article is to provide a narrative review of the current literature on musical interventions and their effects on mood and depression in patients with neurological disorders. Searching on PubMed and PsycInfo databases, 25 studies corresponding to the inclusion criteria have been selected; 11 of them assess the effects of music or MT in Dementia, 9 explore the efficacy on patients with Stroke, and 5 regard other neurological diseases like Multiple Sclerosis, Amyotrophic Lateral Sclerosis/motor neuron disease, Chronic quadriplegia, Parkinson's Disease, and Acquired Brain dysfunctions. Selected studies are based on relational and rehabilitative music therapy approaches or concern music listening interventions. Most of the studies support the efficacy of MT and other musical interventions on mood, depressive syndromes, and quality of life on neurological patients.}, }
@article {pmid25815122, year = {2015}, author = {Nicaise, C and Mitrecic, D and Falnikar, A and Lepore, AC}, title = {Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury.}, journal = {World journal of stem cells}, volume = {7}, number = {2}, pages = {380-398}, pmid = {25815122}, issn = {1948-0210}, support = {R01 NS079702/NS/NINDS NIH HHS/United States ; }, abstract = {Neglected for years, astrocytes are now recognized to fulfill and support many, if not all, homeostatic functions of the healthy central nervous system (CNS). During neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), astrocytes in the vicinity of degenerating areas undergo both morphological and functional changes that might compromise their intrinsic properties. Evidence from human and animal studies show that deficient astrocyte functions or loss-of-astrocytes largely contribute to increased susceptibility to cell death for neurons, oligodendrocytes and axons during ALS and SCI disease progression. Despite exciting advances in experimental CNS repair, most of current approaches that are translated into clinical trials focus on the replacement or support of spinal neurons through stem cell transplantation, while none focus on the specific replacement of astroglial populations. Knowing the important functions carried out by astrocytes in the CNS, astrocyte replacement-based therapies might be a promising approach to alleviate overall astrocyte dysfunction, deliver neurotrophic support to degenerating spinal tissue and stimulate endogenous CNS repair abilities. Enclosed in this review, we gathered experimental evidence that argue in favor of astrocyte transplantation during ALS and SCI. Based on their intrinsic properties and according to the cell type transplanted, astrocyte precursors or stem cell-derived astrocytes promote axonal growth, support mechanisms and cells involved in myelination, are able to modulate the host immune response, deliver neurotrophic factors and provide protective molecules against oxidative or excitotoxic insults, amongst many possible benefits. Embryonic or adult stem cells can even be genetically engineered in order to deliver missing gene products and therefore maximize the chance of neuroprotection and functional recovery. However, before broad clinical translation, further preclinical data on safety, reliability and therapeutic efficiency should be collected. Although several technical challenges need to be overcome, we discuss the major hurdles that have already been met or solved by targeting the astrocyte population in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology.}, }
@article {pmid25814255, year = {2015}, author = {Burns, TC and Verfaillie, CM}, title = {From mice to mind: Strategies and progress in translating neuroregeneration.}, journal = {European journal of pharmacology}, volume = {759}, number = {}, pages = {90-100}, doi = {10.1016/j.ejphar.2015.03.041}, pmid = {25814255}, issn = {1879-0712}, mesh = {Animals ; *Disease Models, Animal ; Humans ; Mice ; Neurodegenerative Diseases/genetics/pathology/*therapy ; Neurogenesis ; Species Specificity ; *Stem Cell Transplantation ; Treatment Outcome ; }, abstract = {Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer׳s disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man.}, }
@article {pmid25807946, year = {2015}, author = {Milenkovic, VM and Rupprecht, R and Wetzel, CH}, title = {The Translocator Protein 18 kDa (TSPO) and Its Role in Mitochondrial Biology and Psychiatric Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {15}, number = {5}, pages = {366-372}, doi = {10.2174/1389557515666150324122642}, pmid = {25807946}, issn = {1875-5607}, mesh = {Antipsychotic Agents/therapeutic use ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Isoquinolines/therapeutic use ; Ligands ; Mental Disorders/drug therapy/metabolism/*pathology ; Mitochondria/*metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Receptors, GABA/chemistry/genetics/*metabolism ; }, abstract = {The translocator protein 18 kDa (TSPO) is localized in the outer mitochondrial membrane of many cell types and its expression is found to be up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions, and neurological diseases, e.g. amyotrophic lateral sclerosis (ALS). Its primary function is to mediate the transport of cholesterol into the inner compartments of mitochondria. Moreover, TSPO is interacting and building up functional complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC), the adenine nucleotide transporter (ANT), hexokinase I and II and Glycogen synthase kinase 3 beta (GSK3β). This mini review will focus on the role of TSPO as a central regulator of mitochondrial function with regard to pathologic states and as a target for new therapeutic strategies for the treatment of psychiatric disorders.}, }
@article {pmid25807491, year = {2015}, author = {Vardjan, N and Verkhratsky, A and Zorec, R}, title = {Pathologic potential of astrocytic vesicle traffic: new targets to treat neurologic diseases?.}, journal = {Cell transplantation}, volume = {24}, number = {4}, pages = {599-612}, doi = {10.3727/096368915X687750}, pmid = {25807491}, issn = {1555-3892}, mesh = {Aquaporins/metabolism ; Astrocytes/*metabolism ; Histocompatibility Antigens Class II/metabolism ; Humans ; Nervous System Diseases/metabolism/*pathology ; Receptors, G-Protein-Coupled/metabolism ; Secretory Vesicles/*physiology ; Vesicular Glutamate Transport Protein 1/metabolism ; }, abstract = {Vesicles are small intracellular organelles that are fundamental for constitutive housekeeping of the plasmalemma, intercellular transport, and cell-to-cell communications. In astroglial cells, traffic of vesicles is associated with cell morphology, which determines the signaling potential and metabolic support for neighboring cells, including when these cells are considered to be used for cell transplantations or for regulating neurogenesis. Moreover, vesicles are used in astrocytes for the release of vesicle-laden chemical messengers. Here we review the properties of membrane-bound vesicles that store gliotransmitters, endolysosomes that are involved in the traffic of plasma membrane receptors, and membrane transporters. These vesicles are all linked to pathological states, including amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, trauma, edema, and states in which astrocytes contribute to developmental disorders. In multiple sclerosis, for example, fingolimod, a recently introduced drug, apparently affects vesicle traffic and gliotransmitter release from astrocytes, indicating that this process may well be used as a new pathophysiologic target for the development of new therapies.}, }
@article {pmid25797014, year = {2015}, author = {Evers, MM and Toonen, LJ and van Roon-Mom, WM}, title = {Antisense oligonucleotides in therapy for neurodegenerative disorders.}, journal = {Advanced drug delivery reviews}, volume = {87}, number = {}, pages = {90-103}, doi = {10.1016/j.addr.2015.03.008}, pmid = {25797014}, issn = {1872-8294}, mesh = {Alternative Splicing/drug effects/genetics ; Animals ; Blood-Brain Barrier/*metabolism ; Drug Delivery Systems ; Gene Targeting ; Humans ; Neurodegenerative Diseases/*drug therapy/genetics ; Oligonucleotides, Antisense/administration &amp; dosage/chemistry/pharmacokinetics/*therapeutic use ; Structure-Activity Relationship ; }, abstract = {Antisense oligonucleotides are synthetic single stranded strings of nucleic acids that bind to RNA and thereby alter or reduce expression of the target RNA. They can not only reduce expression of mutant proteins by breakdown of the targeted transcript, but also restore protein expression or modify proteins through interference with pre-mRNA splicing. There has been a recent revival of interest in the use of antisense oligonucleotides to treat several neurodegenerative disorders using different approaches to prevent disease onset or halt disease progression and the first clinical trials for spinal muscular atrophy and amyotrophic lateral sclerosis showing promising results. For these trials, intrathecal delivery is being used but direct infusion into the brain ventricles and several methods of passing the blood brain barrier after peripheral administration are also under investigation.}, }
@article {pmid25792864, year = {2015}, author = {Lee, S and Kim, HJ}, title = {Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?.}, journal = {Experimental neurobiology}, volume = {24}, number = {1}, pages = {1-7}, pmid = {25792864}, issn = {1226-2560}, abstract = {ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.}, }
@article {pmid25791072, year = {2015}, author = {Verstraete, E and Foerster, BR}, title = {Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {403-416}, pmid = {25791072}, issn = {1878-7479}, support = {R01 NS082304/NS/NINDS NIH HHS/United States ; R01 NS082301-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; Image Processing, Computer-Assisted ; Neuroimaging/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of upper and lower motor neurons, with variable involvement of extramotor brain regions. Currently, there are no established objective markers of upper motor neuron and extramotor involvement in ALS. Here, we review the potential diagnostic value of advanced neuroimaging techniques that are increasingly being used to study the brain in ALS. First, we discuss the role of different imaging modalities in our increasing understanding of ALS pathogenesis, and their potential to contribute to objective upper motor neuron biomarkers for the disease. Second, we discuss the challenges to be overcome and the required phases of diagnostic test development to translate imaging technology to clinical care. We also present examples of multidimensional imaging approaches to achieve high levels of diagnostic accuracy. Last, we address the role of neuroimaging in clinical therapeutic trials. Advanced neuroimaging techniques will continue to develop and offer significant opportunities to facilitate the development of new effective treatments for ALS.}, }
@article {pmid25785563, year = {2015}, author = {Kitamura, A and Nagata, K and Kinjo, M}, title = {Conformational analysis of misfolded protein aggregation by FRET and live-cell imaging techniques.}, journal = {International journal of molecular sciences}, volume = {16}, number = {3}, pages = {6076-6092}, pmid = {25785563}, issn = {1422-0067}, mesh = {Endoplasmic Reticulum/metabolism ; *Fluorescence Resonance Energy Transfer ; Humans ; Luminescent Proteins/chemistry/genetics/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Protein Folding ; Proteins/*chemistry/genetics/metabolism ; Recombinant Fusion Proteins/biosynthesis/genetics ; Superoxide Dismutase/chemistry/genetics/metabolism ; }, abstract = {Cellular homeostasis is maintained by several types of protein machinery, including molecular chaperones and proteolysis systems. Dysregulation of the proteome disrupts homeostasis in cells, tissues, and the organism as a whole, and has been hypothesized to cause neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). A hallmark of neurodegenerative disorders is formation of ubiquitin-positive inclusion bodies in neurons, suggesting that the aggregation process of misfolded proteins changes during disease progression. Hence, high-throughput determination of soluble oligomers during the aggregation process, as well as the conformation of sequestered proteins in inclusion bodies, is essential for elucidation of physiological regulation mechanism and drug discovery in this field. To elucidate the interaction, accumulation, and conformation of aggregation-prone proteins, in situ spectroscopic imaging techniques, such as Förster/fluorescence resonance energy transfer (FRET), fluorescence correlation spectroscopy (FCS), and bimolecular fluorescence complementation (BiFC) have been employed. Here, we summarize recent reports in which these techniques were applied to the analysis of aggregation-prone proteins (in particular their dimerization, interactions, and conformational changes), and describe several fluorescent indicators used for real-time observation of physiological states related to proteostasis.}, }
@article {pmid25776222, year = {2015}, author = {Goutman, SA and Chen, KS and Feldman, EL}, title = {Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {428-448}, pmid = {25776222}, issn = {1878-7479}, support = {R25 NS089450/NS/NINDS NIH HHS/United States ; R25NS089450/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Humans ; Pluripotent Stem Cells/*physiology ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor neurons without a known cure. Based on the possibility of cellular neuroprotection and early preclinical results, stem cells have gained widespread enthusiasm as a potential treatment strategy. Preclinical models demonstrate a protective role of engrafted stem cells and provided the basis for human trials carried out using various types of stem cells, as well as a range of cell delivery methods. To date, no trial has demonstrated a clear therapeutic benefit; however, results remain encouraging and are the basis for ongoing studies. In addition, stem cell technology continues to improve, and induced pluripotent stem cells may offer additional therapeutic options in the future. Improved disease models and clinical trials will be essential in order to validate stem cells as a beneficial therapy.}, }
@article {pmid25770121, year = {2015}, author = {Sakai, K and Aoki, S and Matsumoto, K}, title = {Hepatocyte growth factor and Met in drug discovery.}, journal = {Journal of biochemistry}, volume = {157}, number = {5}, pages = {271-284}, doi = {10.1093/jb/mvv027}, pmid = {25770121}, issn = {1756-2651}, mesh = {Animals ; *Drug Discovery ; Hepatocyte Growth Factor/*metabolism ; Homeostasis ; Humans ; Mice ; Mice, Knockout ; Models, Molecular ; Protein Binding ; Proto-Oncogene Proteins c-met/genetics/*metabolism ; }, abstract = {Activation of the hepatocyte growth factor (HGF)-Met pathway evokes dynamic biological responses that support the morphogenesis, regeneration and survival of cells and tissues. A characterization of conditional Met knockout mice indicates that the HGF-Met pathway plays important roles in the regeneration, protection and homeostasis of cells such as hepatocytes, renal tubular cells and neurons. Preclinical studies in disease models have indicated that recombinant HGF protein and expression plasmid for HGF are biological drug candidates for the treatment of patients with diseases or injuries that involve impaired tissue function. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing. Biological actions of HGF that promote the dynamic movement, morphogenesis and survival of cells also closely participate in invasion-metastasis and resistance to the molecular-targeted drugs in tumour cells. Different types of HGF-Met pathway inhibitors are now in clinical trials for treatment of malignant tumours. Basic research on HGF and Met has lead to drug discoveries in regenerative medicine and tumour biology.}, }
@article {pmid25766616, year = {2015}, author = {Ciechanover, A and Kwon, YT}, title = {Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.}, journal = {Experimental &amp; molecular medicine}, volume = {47}, number = {3}, pages = {e147}, pmid = {25766616}, issn = {2092-6413}, support = {R01 HL083365/HL/NHLBI NIH HHS/United States ; HL083365/HL/NHLBI NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Autophagy/drug effects ; DNA-Binding Proteins/metabolism ; Humans ; Huntingtin Protein ; Huntington Disease/drug therapy/genetics/metabolism ; Lysosomes/metabolism ; Molecular Targeted Therapy ; Mutation ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Parkinson Disease/drug therapy/metabolism ; PrPSc Proteins/metabolism ; Prion Diseases/drug therapy/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Proteostasis Deficiencies/metabolism ; Superoxide Dismutase/metabolism ; Ubiquitin/metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.}, }
@article {pmid25754173, year = {2015}, author = {Hilton, JB and White, AR and Crouch, PJ}, title = {Metal-deficient SOD1 in amyotrophic lateral sclerosis.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {93}, number = {5}, pages = {481-487}, pmid = {25754173}, issn = {1432-1440}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; Copper/deficiency ; Disease Models, Animal ; Humans ; Metals/*metabolism ; Protein Aggregates ; Rodentia ; Superoxide Dismutase/*genetics/*metabolism ; Superoxide Dismutase-1 ; Zinc/deficiency ; }, abstract = {Mutations to the ubiquitous antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) were the first established genetic cause of the fatal, adult-onset neurodegenerative disease amyotrophic lateral sclerosis (ALS). It is widely accepted that these mutations do not cause ALS via a loss of antioxidant function, but elucidating the alternate toxic gain of function has proven to be elusive. Under physiological conditions, SOD1 binds one copper ion and one zinc ion per monomer to form a highly stable and functional homodimer, but there is now ample evidence to indicate aberrant persistence of SOD1 in an intermediate metal-deficient state may contribute to the protein's involvement in ALS. This review briefly discusses some of the data to support a role for metal-deficient SOD1 in the development of ALS and some of the outcomes from drug development studies that have aimed to modify the symptoms of ALS by targeting the metal state of SOD1. The implications for the metal state of SOD1 in cases of sporadic ALS that do not involve mutant SOD1 are also discussed.}, }
@article {pmid25753730, year = {2015}, author = {Reddy, LV and Miller, TM}, title = {RNA-targeted Therapeutics for ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {424-427}, pmid = {25753730}, issn = {1878-7479}, support = {R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*therapy ; Animals ; Genetic Therapy/*methods ; Humans ; RNA/genetics/*metabolism ; RNA, Small Interfering/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to cell death of predominantly motor neurons. Despite extensive research in this disease, finding a way to slow the progress of the disease has been challenging. RNA-targeted therapeutic approaches, including small interfering RNA and antisense oligonucleotides are being developed for genetic forms of ALS. ALS provides an unique opportunity for the use of RNA inhibition strategies given a well-defined animal model, extensive available information regarding the causative genes, and recent experience in phase 1 clinical trial.}, }
@article {pmid25748121, year = {2015}, author = {Gardner, RC and Yaffe, K}, title = {Epidemiology of mild traumatic brain injury and neurodegenerative disease.}, journal = {Molecular and cellular neurosciences}, volume = {66}, number = {Pt B}, pages = {75-80}, pmid = {25748121}, issn = {1095-9327}, support = {K24 AG031155/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Autopsy ; Brain Injuries/*epidemiology ; Humans ; Neurodegenerative Diseases/*epidemiology ; Prevalence ; Risk ; Risk Factors ; }, abstract = {Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury.}, }
@article {pmid25747736, year = {2015}, author = {Frausin, S and Viventi, S and Verga Falzacappa, L and Quattromani, MJ and Leanza, G and Tommasini, A and Valencic, E}, title = {Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research.}, journal = {Acta histochemica}, volume = {117}, number = {4-5}, pages = {329-338}, doi = {10.1016/j.acthis.2015.02.005}, pmid = {25747736}, issn = {1618-0372}, mesh = {Adult ; Adult Stem Cells/*metabolism ; *Cell Differentiation ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*metabolism ; Neurodegenerative Diseases/metabolism/pathology/*therapy ; Neurons/*metabolism ; }, abstract = {Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.}, }
@article {pmid25741238, year = {2015}, author = {Carrì, MT and Valle, C and Bozzo, F and Cozzolino, M}, title = {Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {41}, pmid = {25741238}, issn = {1662-5102}, abstract = {It is well known that mitochondrial damage (MD) is both the major contributor to oxidative stress (OS) (the condition arising from unbalance between production and removal of reactive oxygen species) and one of the major consequences of OS, because of the high dependance of mitochondrial function on redox-sensitive targets such as intact membranes. Conditions in which neuronal cells are not able to cope with MD and OS seem to lead or contribute to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), at least in the most studied superoxide dismutase 1 (SOD1)-linked genetic variant. As summarized in this review, new evidence indicates that MD and OS play a role also in non-SOD1 ALS and thus they may represent a target for therapy despite previous failures in clinical trials.}, }
@article {pmid25738979, year = {2015}, author = {Jackrel, ME and Shorter, J}, title = {Engineering enhanced protein disaggregases for neurodegenerative disease.}, journal = {Prion}, volume = {9}, number = {2}, pages = {90-109}, pmid = {25738979}, issn = {1933-690X}, support = {R21HD074510/HD/NICHD NIH HHS/United States ; R01GM099836/GM/NIGMS NIH HHS/United States ; DP2OD002177/OD/NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R21NS067354/NS/NINDS NIH HHS/United States ; }, mesh = {Amyloid/*metabolism ; Calmodulin-Binding Proteins/metabolism ; Heat-Shock Proteins/*metabolism ; Humans ; Models, Molecular ; Neurodegenerative Diseases/*metabolism ; *Protein Engineering ; Protein Folding ; RNA-Binding Protein EWS ; RNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; }, abstract = {Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious α-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.}, }
@article {pmid25731823, year = {2015}, author = {Cooper-Knock, J and Kirby, J and Highley, R and Shaw, PJ}, title = {The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {326-339}, pmid = {25731823}, issn = {1878-7479}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; MR/K003771/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/therapy ; Animals ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Humans ; Nerve Degeneration/*genetics/metabolism ; Proteins/*genetics ; }, abstract = {The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date.}, }
@article {pmid25728958, year = {2015}, author = {Connolly, S and Galvin, M and Hardiman, O}, title = {End-of-life management in patients with amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {14}, number = {4}, pages = {435-442}, doi = {10.1016/S1474-4422(14)70221-2}, pmid = {25728958}, issn = {1474-4465}, mesh = {Advance Directives ; *Amyotrophic Lateral Sclerosis/psychology ; Attitude to Death ; Caregivers/psychology ; *Clinical Competence ; Cognition ; *Communication ; Decision Making/ethics ; Education, Medical/standards/*trends ; Empathy ; Europe/epidemiology ; *Health Personnel/education/ethics/psychology/standards ; Hospice Care/ethics/statistics &amp; numerical data ; Humans ; Mental Competency ; Palliative Care/ethics/statistics &amp; numerical data ; *Personal Autonomy ; *Quality of Life ; Stress, Psychological/etiology/*prevention &amp; control ; *Suicide, Assisted/ethics/statistics &amp; numerical data ; *Terminal Care/ethics/statistics &amp; numerical data ; United States/epidemiology ; }, abstract = {Most health-care professionals are trained to promote and maintain life and often have difficulty when faced with the often rapid decline and death of people with terminal illnesses such as amyotrophic lateral sclerosis (ALS). By contrast, data suggest that early and open discussion of end-of-life issues with patients and families allows time for reflection and planning, can obviate the introduction of unwanted interventions or procedures, can provide reassurance, and can alleviate fear. Patients' perspectives regarding end-of-life interventions and use of technologies might differ from those of the health professionals involved in their care, and health-care professionals should recognise this and respect the patient's autonomy. Advance care directives can preserve autonomy, but their legal validity and use varies between countries. Clinical management of the end of life should aim to maximise quality of life of both the patient and caregiver and, when possible, incorporate appropriate palliation of distressing physical, psychosocial, and existential distress. Training of health-care professionals should include the development of communication skills that help to sensitively manage the inevitability of death. The emotional burden for health-care professionals caring for people with terminal neurological disease should be recognised, with structures and procedures developed to address compassion, fatigue, and the moral and ethical challenges related to providing end-of-life care.}, }
@article {pmid25728552, year = {2015}, author = {Bateman, DK and Millhouse, PW and Shahi, N and Kadam, AB and Maltenfort, MG and Koerner, JD and Vaccaro, AR}, title = {Anterior lumbar spine surgery: a systematic review and meta-analysis of associated complications.}, journal = {The spine journal : official journal of the North American Spine Society}, volume = {15}, number = {5}, pages = {1118-1132}, doi = {10.1016/j.spinee.2015.02.040}, pmid = {25728552}, issn = {1878-1632}, mesh = {Adult ; Aged ; Female ; Humans ; Lumbar Vertebrae/*surgery ; Male ; Postoperative Complications/*epidemiology ; Spinal Fusion/*adverse effects/methods ; }, abstract = {BACKGROUND CONTEXT: The anterior approach to the lumbar spine is increasingly used to accomplish various surgical procedures. However, the incidence and risk factors for complications associated with anterior lumbar spine surgery (ALS) have not been fully elucidated.<br><br>PURPOSE: To identify and document types of complications and complication rates associated with ALS, determine risk factors for these events, and evaluate the effect of measures used to decrease complication rates.<br><br>STUDY DESIGN: Systematic review and meta-analysis.<br><br>METHODS: A systematic review of the English-language literature was conducted for articles published between January 1992 and December 2013. A MEDLINE search was conducted to identify articles reporting complications associated with ALS. For each complication, the data were combined using a generalized linear mixed model with a binomial probability distribution and a random effect based on the study. Predictors used were the type of procedure (open, minimally invasive, or laparoscopic), the approach used (transperitoneal vs. retroperitoneal), use of recombinant bone morphogenetic protein-2, use of preoperative computed tomography angiography (CTA), and the utilization of an access surgeon. Open surgery was used as a reference category.<br><br>RESULTS: Seventy-six articles met final inclusion criteria and reported complication rates in 11,410 patients who underwent arthrodesis and/or arthroplasty via laparoscopic, mini-open, and open techniques. The overall complication rate was 14.1%, with intraoperative and postoperative complication rates of 9.1% and 5.2%, respectively. Only 3% of patients required reoperation or revision procedures. The most common complications reported were venous injury (3.2%), retrograde ejaculation (2.7%), neurologic injury (2%), prosthesis related (2%), postoperative ileus (1.4%), superficial infection (1%), and others (1.3%). Laparoscopic and transperitoneal procedures were associated with higher complication rates, whereas lower complication rates were observed in patients receiving mini-open techniques. Our analysis indicated that the use of recombinant bone morphogenetic protein-2 was associated with increased rates of retrograde ejaculation; however, there may be limitations in interpreting these data. Data regarding the use of preoperative CTA and an access surgeon were limited and demonstrated mixed benefit.<br><br>CONCLUSIONS: Overall complication rates with ALS are relatively low, with the most common complications occurring at a rate of 1% to 3%. Complication rates are related to surgical technique, approach, and implant characteristics. Further randomized controlled trials are needed to validate the use of preventative measures including CTA and the use of an access surgeon.}, }
@article {pmid25727900, year = {2015}, author = {Eisen, A and Lemon, R and Kiernan, MC and Hornberger, M and Turner, MR}, title = {Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis?.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {126}, number = {7}, pages = {1288-1294}, doi = {10.1016/j.clinph.2015.02.003}, pmid = {25727900}, issn = {1872-8952}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Cognition/physiology ; Empathy/physiology ; Gait/physiology ; Humans ; Mirror Neurons/*physiology ; Motor Activity/physiology ; Pyramidal Tracts/*physiopathology ; Speech/physiology ; }, abstract = {There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy.}, }
@article {pmid25726748, year = {2015}, author = {Murdock, BJ and Bender, DE and Segal, BM and Feldman, EL}, title = {The dual roles of immunity in ALS: injury overrides protection.}, journal = {Neurobiology of disease}, volume = {77}, number = {}, pages = {1-12}, doi = {10.1016/j.nbd.2015.02.017}, pmid = {25726748}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology/*physiopathology ; Humans ; Immunity/*physiology ; Signal Transduction/physiology ; Toll-Like Receptors/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease affecting motor neurons. Disease progression is accompanied by a multi-phased immune response, and recent studies indicate that the immune system is not simply a bystander during disease, but plays an active role in shaping ALS pathology. The role of the immune system during ALS progression is highly complex, however, as it has been found to have a role in both enhancing neurodegeneration as well as protecting the central nervous system. Previous reports have established that the immune response can therefore be separated into two distinct phases: a protective Type 2 response followed by a neurotoxic Type 1 response. This review will address the two phases of the immune response in ALS and describe their roles during disease progression. More importantly, it will also examine the likely sources of immune polarization that are responsible for shifting immunity from the protective T2 phase to the neurotoxic T1 phase.}, }
@article {pmid25725943, year = {2015}, author = {Pearce, N and Gallo, V and McElvenny, D}, title = {Head trauma in sport and neurodegenerative disease: an issue whose time has come?.}, journal = {Neurobiology of aging}, volume = {36}, number = {3}, pages = {1383-1389}, doi = {10.1016/j.neurobiolaging.2014.12.024}, pmid = {25725943}, issn = {1558-1497}, mesh = {Amyotrophic Lateral Sclerosis ; Athletic Injuries/*complications ; Brain Concussion/*complications ; Craniocerebral Trauma/*complications ; Dementia/epidemiology/etiology ; Humans ; Neurodegenerative Diseases/epidemiology/*etiology ; Parkinson Disease/epidemiology/etiology ; Recurrence ; Risk ; Time Factors ; }, abstract = {A number of small studies and anecdotal reports have been suggested that sports involving repeated head trauma may have long-term risks of neurodegenerative disease. There are now plausible mechanisms for these effects, and a recognition that these problems do not just occur in former boxers, but in a variety of sports involving repeated concussions, and possibly also in sports in which low-level head trauma is common. These neurodegenerative effects potentially include increased risks of impaired cognitive function and dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Many would argue for taking a precautionary approach and immediately banning or restricting sports such as boxing. However, there are important public health issues in terms of how wide the net should be cast in terms of other sports, and what remedial measures could be taken? This in turn requires a major research effort involving both clinical and basic research to understand the underlying mechanisms, leading from head trauma to neurodegenerative disease and epidemiologic studies to assess the long-term consequences.}, }
@article {pmid25725227, year = {2015}, author = {Bennett, CL and La Spada, AR}, title = {Unwinding the role of senataxin in neurodegeneration.}, journal = {Discovery medicine}, volume = {19}, number = {103}, pages = {127-136}, pmid = {25725227}, issn = {1944-7930}, support = {R01 GM094384/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Ataxia/pathology ; Humans ; Models, Biological ; Motor Neurons/pathology ; Mutation ; Nerve Degeneration/*metabolism/pathology ; RNA Helicases/genetics/*metabolism ; }, abstract = {Interest in senataxin biology began in 2004 when mutations were first identified in what was then a novel protein. Dominantly inherited mutations were documented in rare juvenile-onset, motor neuron disease pedigrees in a familial form of amyotrophic lateral sclerosis (ALS4), while recessive mutations were found to cause a severe early-onset ataxia with oculomotor apraxia (AOA2) that is actually the second most common recessive ataxia after Freidreich's ataxia. From earlier studies of sen1p, the yeast ortholog of senataxin, a range of important RNA processing functions have been attributed to this protein. Like sen1p, senataxin contains a helicase domain to interact with RNA and an amino-terminal domain for critical protein interactions. Senataxin also joins a group of important proteins responsible for maintaining RNA transcriptome homeostasis, including FUS, TDP-43, and SMN that can all cause familial forms of motor neuron disease (MND). Independent of this association, senataxin is gaining attention for its role in maintaining genomic stability. Senataxin has been shown to resolve R-Loop structures, which form when nascent RNA hybridizes to DNA, displacing the non-transcribed strand. But in cycling cells, senataxin is also found at nuclear foci during the S/G2 cell-cycle phase, and may function at sites of specific collision between components of the replisome and transcription machinery. Which of these important processes is most critical to prevent neurodegeneration remains unknown, but our evolving understanding of these processes will be crucial not only for understanding senataxin's role in neurological disease, but also in a number of fundamentally important cellular functions.}, }
@article {pmid25720096, year = {2015}, author = {Harikrishnareddy, D and Misra, S and Upadhyay, S and Modi, M and Medhi, B}, title = {Roots to start research in amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future.}, journal = {Reviews in the neurosciences}, volume = {26}, number = {2}, pages = {161-181}, doi = {10.1515/revneuro-2014-0057}, pmid = {25720096}, issn = {2191-0200}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism/therapy ; Animals ; Clinical Trials as Topic ; Genetic Therapy ; Humans ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease that rapidly progresses from mild motor symptoms to severe motor paralysis and premature death. There is currently no cure for this devastating disease; most ALS patients die of respiratory failure generally within 3-5 years from the onset of signs and symptoms. Approximately 90% of ALS cases are sporadic in nature, with no clear associated risk factors. It is reported that ALS is a complex and multifaceted neurodegenerative disease. Less is known about the key factors involved in the sporadic form of the disease. The intricate pathogenic mechanisms that target motor neurons in ALS includes oxidative stress, glutamate excitotoxicity, mitochondrial damage, protein aggregation, glia and neuroinflammation pathology, defective axonal transport, and aberrant RNA metabolism. Despite aggressive research, no therapy has been yet proven to completely reverse the core symptoms of the disease. Riluzole is the only drug approved by the Food and Drug Administration and recommended by the National Institute for Clinical Excellence so far proven to be successful against ALS and may prevent progression and extend life for a few months or so. This article provides a novel understanding in key findings of pathogenesis and interventions currently under investigation to slow disease progression in ALS.}, }
@article {pmid25714967, year = {2015}, author = {Kamal, MA and Mushtaq, G and Greig, NH}, title = {Current Update on Synopsis of miRNA Dysregulation in Neurological Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {14}, number = {4}, pages = {492-501}, pmid = {25714967}, issn = {1996-3181}, support = {Z99 AG999999//Intramural NIH HHS/United States ; }, mesh = {Animals ; Brain/*metabolism/pathology ; Humans ; MicroRNAs/genetics/*metabolism ; Nervous System Diseases/genetics/*metabolism/pathology ; Oxidative Stress/*physiology ; }, abstract = {Aberrant expression of microRNAs (miRNAs) has been implicated in various neurological disorders (NDs) of the central nervous system such as Alzheimer disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia and autism. If dysregulated miRNAs are identified in patients suffering from NDs, this may serve as a biomarker for the earlier diagnosis and monitoring of disease progression. Identifying the role of miRNAs in normal cellular processes and understanding how dysregulated miRNA expression is responsible for their neurological effects is also critical in the development of new therapeutic strategies for NDs. miRNAs hold great promise from a therapeutic point of view especially if it can be proved that a single miRNA has the ability to influence several target genes, making it possible for the researchers to potentially modify a whole disease phenotype by modulating a single miRNA molecule. Hence, better understanding of the mechanisms by which miRNA play a role in the pathogenesis of NDs may provide novel targets to scientists and researchers for innovative therapies.}, }
@article {pmid25714965, year = {2015}, author = {Volonté, C and Parisi, C and Apolloni, S}, title = {New kid on the block: does histamine get along with inflammation in amyotrophic lateral sclerosis?.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {14}, number = {5}, pages = {677-686}, doi = {10.2174/1871527314666150225143921}, pmid = {25714965}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Cytokines/metabolism ; Histamine/metabolism/*therapeutic use ; Humans ; Inflammation/*drug therapy/etiology ; Microglia/drug effects ; Models, Biological ; }, abstract = {Results from amyotrophic lateral sclerosis (ALS) patients and pre-clinical studies strongly suggest that systemic and CNS-intrinsic immune activation plays a central role in ALS pathogenesis. Microglial cells are emerging in this context as master regulators with a bi-functional role in the progression of the pathological response. They foster a pro-inflammatory setting through the production of cytotoxic cytokines and chemokines (M1 phenotype), after an aborted effort to sustain an anti-inflammatory environment for motor neurons through the release of beneficial cytokines and growth factors (M2 phenotype). In this review, we gather information meant to propose that histamine and ATP, which are released from mast cells, microglia and damaged neurons at sites of injury where they function as transmitters, have to be considered as new players in the ALS neuroinflammatory arena. After all, abnormal histamine and ATP signalling in the brain are already documented in neurodegenerative/neuroinflammatory conditions such as multiple sclerosis, Alzheimer and Parkinson's disease and, at present, histamine- as well as ATP-related compounds are in clinical trial for these same pathologies. Concerning ALS, while emerging data are now available about purinergic mechanisms, the involvement of histamine is basically unexplored. The circumstantial evidence that we present here thus constitutes a solid background for formulating novel hypotheses, stimulating a scientific debate and, most of all, inspiring future research. We deem that a new potential role of histamine in the setting of ALS neuroinflammation might find a fertile ground where to thrive. ALS is still a disease without a cure: why not to play with a new kid on the block?}, }
@article {pmid25713513, year = {2015}, author = {Cozzolino, M and Rossi, S and Mirra, A and Carrì, MT}, title = {Mitochondrial dynamism and the pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {31}, pmid = {25713513}, issn = {1662-5102}, abstract = {Research on mitochondria in the last years has been characterized by the fundamental finding that the morphology of mitochondria is deeply connected to the regulation of a vast number of different processes, including oxidative phosphorylation and ATP production, calcium buffering, and apoptosis. This has immediately focused the attention of the neuroscience community to the possible involvement of mitochondrial dynamism, the process underlying morphological features of mitochondria, in neurodegeneration, where mitochondrial dysfunction is believed to represent an important contributing event, or even a primary causative factor. Amyotrophic Lateral Sclerosis (ALS), a disease of motor neurons and their neighboring cells, has long been considered as a neurodegenerative disease with an important mitochondrial issue. Yet, whether mitochondria have a causative, primary role in the pathogenic process has always been debated, and the specific defects which account for this role are elusive. Here we discuss recent genetic advances suggesting that defective mitochondrial dynamism is primarily involved in the pathogenic mechanisms of ALS, and that foster the longstanding concept that disruption of mitochondrial function is a vulnerable factor for motor neurons.}, }
@article {pmid25709501, year = {2015}, author = {Ingre, C and Roos, PM and Piehl, F and Kamel, F and Fang, F}, title = {Risk factors for amyotrophic lateral sclerosis.}, journal = {Clinical epidemiology}, volume = {7}, number = {}, pages = {181-193}, pmid = {25709501}, issn = {1179-1349}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2-5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS.}, }
@article {pmid25708461, year = {2015}, author = {Gershoni-Emek, N and Chein, M and Gluska, S and Perlson, E}, title = {Amyotrophic lateral sclerosis as a spatiotemporal mislocalization disease: location, location, location.}, journal = {International review of cell and molecular biology}, volume = {315}, number = {}, pages = {23-71}, doi = {10.1016/bs.ircmb.2014.11.003}, pmid = {25708461}, issn = {1937-6448}, mesh = {Amyloid beta-Protein Precursor/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Axonal Transport ; Humans ; RNA-Binding Proteins/metabolism ; Signal Transduction ; Time Factors ; }, abstract = {Spatiotemporal localization of signals is a fundamental feature impacting cell survival and proper function. The cell needs to respond in an accurate manner in both space and time to both intra- and intercellular environment cues. The regulation of this comprehensive process involves the cytoskeleton and the trafficking machinery, as well as local protein synthesis and ligand-receptor mechanisms. Alterations in such mechanisms can lead to cell dysfunction and disease. Motor neurons that can extend over tens of centimeters are a classic example for the importance of such events. Changes in spatiotemporal localization mechanisms are thought to play a role in motor neuron degeneration that occurs in amyotrophic lateral sclerosis (ALS). In this review we will discuss these mechanisms and argue that possible misregulated factors can lead to motor neuron degeneration in ALS.}, }
@article {pmid25704308, year = {2015}, author = {Coleman, BM and Hill, AF}, title = {Extracellular vesicles--Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases.}, journal = {Seminars in cell &amp; developmental biology}, volume = {40}, number = {}, pages = {89-96}, doi = {10.1016/j.semcdb.2015.02.007}, pmid = {25704308}, issn = {1096-3634}, mesh = {Animals ; Extracellular Vesicles/chemistry/*metabolism ; Humans ; MicroRNAs/analysis ; Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/*pathology ; Prions/metabolism ; *Protein Folding ; }, abstract = {Many cell types, including neurons, are known to release small membranous vesicles known as exosomes. In addition to their protein content these vesicles have recently been shown to contain messenger RNA (mRNA) and micro RNA (miRNA) species. Roles for these vesicles include cell-cell signalling, removal of unwanted proteins, and transfer of pathogens (including prion-like misfolded proteins) between cells, such as infectious prions. Prions are the infectious particles that are responsible for transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Exosomes are also involved in processing the amyloid precursor protein (APP), which is associated with Alzheimer's disease (AD). As exosomes can be isolated from circulating fluids such as serum, urine, and cerebrospinal fluid (CSF), they provide a potential source of biomarkers for neurological conditions. Here, we review the roles these vesicles play in neurodegenerative disease and highlight their potential in diagnosing these disorders through analysis of their RNA content.}, }
@article {pmid25704016, year = {2015}, author = {Fukunaga, K and Shinoda, Y and Tagashira, H}, title = {The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.}, journal = {Journal of pharmacological sciences}, volume = {127}, number = {1}, pages = {36-41}, doi = {10.1016/j.jphs.2014.12.012}, pmid = {25704016}, issn = {1347-8648}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/metabolism/*pathology ; Animals ; Humans ; Mitochondria/drug effects/*pathology ; Models, Biological ; Motor Neurons/metabolism ; *Mutation ; Neuroprotective Agents/agonists/therapeutic use ; Receptors, sigma/*genetics/metabolism ; Sigma-1 Receptor ; }, abstract = {Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials.}, }
@article {pmid25704013, year = {2015}, author = {Mavlyutov, TA and Guo, LW and Epstein, ML and Ruoho, AE}, title = {Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Journal of pharmacological sciences}, volume = {127}, number = {1}, pages = {10-16}, pmid = {25704013}, issn = {1347-8648}, support = {R21 NS075820/NS/NINDS NIH HHS/United States ; DK081634/DK/NIDDK NIH HHS/United States ; NS075820/NS/NINDS NIH HHS/United States ; R01EY022678/EY/NEI NIH HHS/United States ; R01 EY022678/EY/NEI NIH HHS/United States ; R01 DK081634/DK/NIDDK NIH HHS/United States ; }, mesh = {Action Potentials/physiology ; Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Humans ; Mice, Knockout ; Motor Neurons/physiology/ultrastructure ; Receptors, sigma/genetics/*physiology ; Sigma-1 Receptor ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a "brake" on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed.}, }
@article {pmid25703524, year = {2015}, author = {McDermott, FD and Heeney, A and Kelly, ME and Steele, RJ and Carlson, GL and Winter, DC}, title = {Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks.}, journal = {The British journal of surgery}, volume = {102}, number = {5}, pages = {462-479}, doi = {10.1002/bjs.9697}, pmid = {25703524}, issn = {1365-2168}, mesh = {Age Factors ; Aged ; Anastomotic Leak/*etiology ; Biomarkers/metabolism ; C-Reactive Protein/metabolism ; Colon/*surgery ; Colorectal Neoplasms/surgery ; Emergency Treatment/adverse effects ; Female ; Humans ; Male ; Middle Aged ; Operative Time ; Perioperative Care/*statistics &amp; numerical data ; Rectum/*surgery ; Risk Factors ; Sex Factors ; }, abstract = {BACKGROUND: Anastomotic leak (AL) represents a dreaded complication following colorectal surgery, with a prevalence of 1-19 per cent. There remains a lack of consensus regarding factors that may predispose to AL and the relative risks associated with them. The objective was to perform a systematic review of the literature, focusing on the role of preoperative, intraoperative and postoperative factors in the development of colorectal ALs.<br><br>METHODS: A systematic review was performed to identify adjustable and non-adjustable preoperative, intraoperative and postoperative factors in the pathogenesis of AL. Additionally, a severity grading system was proposed to guide treatment.<br><br>RESULTS: Of 1707 papers screened, 451 fulfilled the criteria for inclusion in the review. Significant preoperative risk factors were: male sex, American Society of Anesthesiologists fitness grade above II, renal disease, co-morbidity and history of radiotherapy. Tumour-related factors were: distal site, size larger than 3&#x2009;cm, advanced stage, emergency surgery and metastatic disease. Adjustable risk factors were: smoking, obesity, poor nutrition, alcohol excess, immunosuppressants and bevacizumab. Intraoperative risk factors were: blood loss/transfusion and duration of surgery more than 4&#x2009;h. Stomas lessen the consequences but not the prevalence of AL. In the postoperative period, CT is the most commonly used imaging tool, with or without rectal contrast, and a C-reactive protein level exceeding 150&#x2009;mg/l on day 3-5 is the most sensitive biochemical marker. A five-level classification system for AL severity and appropriate management is presented.<br><br>CONCLUSION: Specific risk factors and their potential correction or indications for stoma were identified. An AL severity score is proposed to aid clinical decision-making.}, }
@article {pmid25701498, year = {2015}, author = {Grad, LI and Fernando, SM and Cashman, NR}, title = {From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {77}, number = {}, pages = {257-265}, doi = {10.1016/j.nbd.2015.02.009}, pmid = {25701498}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; DNA-Binding Proteins/metabolism ; Humans ; Prions/*metabolism ; Protein Folding ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Prions, self-proliferating infectious agents consisting of misfolded protein, are most often associated with aggressive neurodegenerative diseases in animals and humans. Akin to the contiguous spread of a living pathogen, the prion paradigm provides a mechanism by which a mutant or wild-type misfolded protein can dominate pathogenesis through self-propagating protein misfolding, and subsequently spread from region to region through the central nervous system. The prion diseases, along with more common neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and the tauopathies belong to a larger group of protein misfolding disorders termed proteinopathies that feature aberrant misfolding and aggregation of specific proteins. Amyotrophic lateral sclerosis (ALS), a lethal disease characterized by progressive degeneration of motor neurons is currently understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within motor neurons that contribute to neurotoxicity. It is well established that misfolded/aggregated proteins such as SOD1 and TDP-43 contribute to the toxicity of motor neurons and play a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, and to a lesser extent TDP-43, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of proteins associated with ALS pathology as well as their possible mechanisms of transmission.}, }
@article {pmid25700798, year = {2015}, author = {Nicholson, KA and Cudkowicz, ME and Berry, JD}, title = {Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {376-383}, pmid = {25700798}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Biomedical Research/history/*methods ; *Clinical Trials as Topic/history ; History, 20th Century ; Humans ; }, abstract = {The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.}, }
@article {pmid25690731, year = {2015}, author = {Kim, EK and Choi, EJ}, title = {Compromised MAPK signaling in human diseases: an update.}, journal = {Archives of toxicology}, volume = {89}, number = {6}, pages = {867-882}, doi = {10.1007/s00204-015-1472-2}, pmid = {25690731}, issn = {1432-0738}, mesh = {Alzheimer Disease/*enzymology/immunology/pathology ; Amyotrophic Lateral Sclerosis/*enzymology/immunology/pathology ; Cell Proliferation ; Humans ; Immunity, Innate ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Neoplasms/*enzymology/immunology/pathology ; Oxidative Stress ; Parkinson Disease/*enzymology/immunology/pathology ; }, abstract = {The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.}, }
@article {pmid25690002, year = {2015}, author = {Numan, MS and Brown, JP and Michou, L}, title = {Impact of air pollutants on oxidative stress in common autophagy-mediated aging diseases.}, journal = {International journal of environmental research and public health}, volume = {12}, number = {2}, pages = {2289-2305}, pmid = {25690002}, issn = {1660-4601}, mesh = {Aging/*drug effects ; Air Pollutants/*adverse effects ; Autophagy/*drug effects/*physiology ; Humans ; Oxidative Stress/*drug effects ; }, abstract = {Atmospheric pollution-induced cellular oxidative stress is probably one of the pathogenic mechanisms involved in most of the common autophagy-mediated aging diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, disease, as well as Paget's disease of bone with or without frontotemporal dementia and inclusion body myopathy. Oxidative stress has serious damaging effects on the cellular contents: DNA, RNA, cellular proteins, and cellular organelles. Autophagy has a pivotal role in recycling these damaged non-functional organelles and misfolded or unfolded proteins. In this paper, we highlight, through a narrative review of the literature, that when autophagy processes are impaired during aging, in presence of cumulative air pollution-induced cellular oxidative stress and due to a direct effect on air pollutant, autophagy-mediated aging diseases may occur.}, }
@article {pmid25689976, year = {2015}, author = {Barmada, SJ}, title = {Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {340-351}, pmid = {25689976}, issn = {1878-7479}, support = {K08 NS072233/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*genetics ; Animals ; DNA-Binding Proteins/genetics ; Humans ; MicroRNAs/genetics ; Nerve Degeneration/etiology ; RNA/*genetics/*metabolism ; RNA Splicing/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.}, }
@article {pmid25687700, year = {2015}, author = {Hashioka, S and McGeer, EG and Miyaoka, T and Wake, R and Horiguchi, J and McGeer, PL}, title = {Interferon-γ-induced neurotoxicity of human astrocytes.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {14}, number = {2}, pages = {251-256}, doi = {10.2174/1871527314666150217122305}, pmid = {25687700}, issn = {1996-3181}, mesh = {Antiviral Agents/*adverse effects ; Astrocytes/*drug effects ; Humans ; Interferon-gamma/*adverse effects ; Neurotoxicity Syndromes/*etiology/*pathology ; }, abstract = {Activated astrocytes, which can also be referred to as reactive astrocytes or astrogliosis, have been identified in affected regions of common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Activated astrocytes may be beneficial, promoting neuronal survival due to their production of growth factors and neurotrophins. Activated astrocytes can also be detrimental to neighboring neurons in neuroinflammatory processes. Astrocytes exposed to certain inflammatory stimulants in vitro have been shown to release potentially neurotoxic molecules, including inflammatory cytokines, glutamate, nitric oxide and reactive oxygen species. It has recently been shown that adult human astrocytes stimulated with interferon-γ, a common inflammatory cytokine evidently present in neuropathological brains, exert potent neurotoxicity in vitro. This interferon- γ-induced astrocytic neurotoxicity is mediated by the activation of the Janus kinase-signal transducer and activator of transcription (STAT) 3 pathway in the astrocytes, and involves intracellular phosphorylation of STAT3 at tyrosine-705 residue. Therefore, control of STAT3 activation in human astrocytes may be a promising new therapeutic strategy for a broad spectrum of neurodegenerative and neuroinflammatory disorders where activated astrocytes may contribute to the pathology.}, }
@article {pmid25683489, year = {2015}, author = {Majcher, V and Goode, A and James, V and Layfield, R}, title = {Autophagy receptor defects and ALS-FTLD.}, journal = {Molecular and cellular neurosciences}, volume = {66}, number = {Pt A}, pages = {43-52}, doi = {10.1016/j.mcn.2015.01.002}, pmid = {25683489}, issn = {1095-9327}, support = {LAYFIELD/APR13/821-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Autophagy/*physiology ; Frontotemporal Lobar Degeneration/*physiopathology ; Humans ; Nerve Tissue Proteins/genetics/*metabolism ; Signal Transduction/*physiology ; }, abstract = {Various pathophysiological mechanisms have been implicated in the ALS-FTLD clinicopathological spectrum of neurodegenerative disorders. Here we focus on the role of autophagy, an intracellular catabolic pathway, in these conditions. Growing evidence suggests that the autophagic process can be disturbed in ALS-FTLD, including by genetic mutations affecting autophagy receptor proteins (ubiquilin-2, optineurin, SQSTM1/p62) and regulators (VCP). Such mutations may impair clearance of autophagy substrates with pathological consequences. Recent studies have also uncovered a direct connection between autophagy and RNA processing, supporting an integrated model connecting several ALS-FTLD associated gene products. This article is part of a Special Issue entitled 'Neuronal Protein'.}, }
@article {pmid25680928, year = {2015}, author = {Shevchenko, G and Konzer, A and Musunuri, S and Bergquist, J}, title = {Neuroproteomics tools in clinical practice.}, journal = {Biochimica et biophysica acta}, volume = {1854}, number = {7}, pages = {705-717}, doi = {10.1016/j.bbapap.2015.01.016}, pmid = {25680928}, issn = {0006-3002}, mesh = {Animals ; Biomarkers/metabolism ; Humans ; Mass Spectrometry/*methods ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/diagnosis/*metabolism ; Proteomics/*methods ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by neuronal impairment that leads to disease-specific changes in the neuronal proteins. The early diagnosis of these disorders is difficult, thus, the need for identifying, developing and using valid clinically applicable biomarkers that meet the criteria of precision, specificity and repeatability is very vital. The application of rapidly emerging technology such as mass spectrometry (MS) in proteomics has opened new avenues to accelerate biomarker discovery, both for diagnostic as well as for prognostic purposes. This review summarizes the most recent advances in the mass spectrometry-based neuroproteomics and analyses the current and future directions in the biomarker discovery for the neurodegenerative diseases. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology.}, }
@article {pmid25680510, year = {2015}, author = {Reith, S and Burgmaier, M}, title = {[Resuscitation].}, journal = {Medizinische Klinik, Intensivmedizin und Notfallmedizin}, volume = {110}, number = {1}, pages = {81-93; quiz 94-5}, doi = {10.1007/s00063-014-0460-2}, pmid = {25680510}, issn = {2193-6226}, mesh = {Advanced Cardiac Life Support/methods ; Cardiac Catheterization/methods ; Cardiopulmonary Resuscitation/*methods ; Electric Countershock/methods ; Guideline Adherence ; Humans ; Hypothermia, Induced/methods ; }, abstract = {The primary aim of cardiopulmonary resuscitation after cardiac arrest is to achieve the return of spontaneous circulation (ROSC). However, following ROSC the clinical and neurologic outcome is mainly influenced by adequate treatment in the postresuscitation period. There are several novel recommendations in the current 2010 guidelines of the European Resuscitation Council (ERC) concerning advanced life support (ALS). In addition to established standards for mechanical, electrical (defibrillation), and pharmacological resuscitation during the initial phase, the guidelines moreover deal with recommendations for standardized therapy in the postresuscitation period. Major aspects concerning the therapy of the postcardiac arrest syndrome include temperature management with therapeutic hypothermia, mechanical ventilation and the extent of oxygenation and blood glucose control. Thus, the initial cardiopulmonary resuscitation and the following postresuscitation treatment have to be considered as merging therapy concepts. Only a standardized therapeutic approach in these different phases of treatment will result in successful resuscitation with high rates of survival and good neurologic outcome.}, }
@article {pmid25680080, year = {2015}, author = {Kaur, P and Muthuraman, A and Kaur, M}, title = {The implications of angiotensin-converting enzymes and their modulators in neurodegenerative disorders: current and future perspectives.}, journal = {ACS chemical neuroscience}, volume = {6}, number = {4}, pages = {508-521}, doi = {10.1021/cn500363g}, pmid = {25680080}, issn = {1948-7193}, mesh = {Angiotensin-Converting Enzyme Inhibitors/adverse effects/pharmacokinetics/pharmacology/*therapeutic use ; Animals ; Humans ; Neurodegenerative Diseases/*drug therapy/enzymology ; Neuroprotective Agents/adverse effects/pharmacokinetics/pharmacology/*therapeutic use ; Peptidyl-Dipeptidase A/metabolism ; }, abstract = {Angiotensin converting enzyme (ACE) is a dipeptidyl peptidase transmembrane bound enzyme. Generally, ACE inhibitors are used for the cardiovascular disorders. ACE inhibitors are primary agents for the management of hypertension, so these cannot be avoided for further use. The present Review focuses on the implications of angiotensin converting enzyme inhibitors in neurodegenerative disorders such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and diabetic neuropathy. ACE inhibitors such as ramipril, captopril, perindopril, quinapril, lisinopril, enalapril, and trandolapril have been documented to ameliorate the above neurodegenerative disorders. Neurodegeneration occurs not only by angiotensin II, but also by other endogenous factors, such as the formation of free radicals, amyloid beta, immune reactions, and activation of calcium dependent enzymes. ACE inhibitors interact with the above cellular mechanisms. Thus, these may act as a promising factor for future medicine for neurological disorders beyond the cardiovascular actions. Central acting ACE inhibitors can be useful in the future for the management of neuropathic pain due to following actions: (i) ACE-2 converts angiotensinogen to angiotensin(1-7) (hepatapeptide) which produces neuroprotective action; (ii) ACE inhibitors downregulate kinin B1 receptors in the peripheral nervous system which is responsible for neuropathic pain. However, more extensive research is required in the field of neuropathic pain for the utilization of ACE inhibitors in human.}, }
@article {pmid25678853, year = {2015}, author = {Ma, G and Wang, Y and Li, Y and Cui, L and Zhao, Y and Zhao, B and Li, K}, title = {MiR-206, a key modulator of skeletal muscle development and disease.}, journal = {International journal of biological sciences}, volume = {11}, number = {3}, pages = {345-352}, pmid = {25678853}, issn = {1449-2288}, mesh = {Animals ; Cell Differentiation/genetics ; Cell Proliferation/genetics ; Humans ; Mice ; MicroRNAs/genetics/metabolism/*physiology ; *Models, Genetic ; Muscle, Skeletal/growth &amp; development/*metabolism/physiology ; Muscular Diseases/genetics ; Regeneration ; }, abstract = {MicroRNAs (miRNAs) have recently emerged as fundamental post-transcriptional regulators inhibit gene expression linked to various biological processes. MiR-206 is one of the most studied and best characterized miRNA to date, which specifically expressed in skeletal muscle. In this review, we summarized the results of studies of miR-206 with emphasis on its function in skeletal muscle development. Importantly, dysregulation of miR-206 has been linked to many disorders in skeletal muscle such as Duchenne muscular dystrophy (DMD) and amyotrophic lateral sclerosis (ALS), and circulating miR-206 has highlighted its potential as a diagnose biomarker. In addition, a mutation in the 3' untranslated region (3'-UTR) of the myostatin gene in the Texel sheep creating a target site for the miR-206 and miR-1 leads to inhibition of myostatin expression, which likely to cause the muscular hypertrophy phenotype of this breed of sheep. Therefore, miR-206 may become novel target for ameliorating skeletal muscle-related disorders and optimization of muscle quantity of domestic animals.}, }
@article {pmid25672733, year = {2014}, author = {Yamashita, T and Kwak, S}, title = {[Calpain plays a crucial role in TDP-43 pathology].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {54}, number = {12}, pages = {1151-1154}, doi = {10.5692/clinicalneurol.54.1151}, pmid = {25672733}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Calcium Signaling/genetics/physiology ; Calpain/*physiology ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Humans ; Mice ; Mice, Knockout ; Motor Neurons/metabolism ; RNA Editing ; Receptors, AMPA/physiology ; Spinal Cord/cytology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease affecting healthy middle-aged individuals. Mislocalization of TAR DNA binding protein of 43 kDa (TDP-43) or TDP-43 pathology observed in the spinal motor neurons is the pathological hallmark of ALS. The mechanism generating TDP-43 pathology remained uncertain. Several reports suggested that cleavage of TDP-43 into aggregation-prone fragments might be the earliest event. Therefore, elucidation of the protease(s) that is responsible for TDP-43 cleavage in the motor neurons is awaited. ALS-specific molecular abnormalities other than TDP-43 pathology in the motor neurons of sporadic ALS patients include inefficient RNA editing at the GluA2 glutamine/arginine (Q/R) site, which is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2). We have developed the conditional ADAR2 knockout (AR2) mice, in which the ADAR2 gene is targeted in motor neurons. We found that Ca(2+)-dependent cysteine protease calpain cleaved TDP-43 into aggregation-prone fragments, which initiated TDP-43 mislocalization in the motor neurons expressing abnormally abundant Ca(2+)-permeable AMPA receptors. Here we summarized the molecular cascade leading to TDP-43 pathology observed in the motor neurons of AR2 mice and discussed possible roles of dysregulation of calpain-dependent cleavage of TDP-43 in TDP-43 pathology observed in neurological diseases in general.}, }
@article {pmid25672713, year = {2014}, author = {Sonoo, M and Higashihara, M}, title = {[Fasciculation potential and ALS diagnosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {54}, number = {12}, pages = {1080-1082}, doi = {10.5692/clinicalneurol.54.1080}, pmid = {25672713}, issn = {1882-0654}, mesh = {Action Potentials ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Fasciculation/*physiopathology ; Humans ; }, abstract = {Fasciculations and fasciculation potentials (FPs) have been long known as a characteristic feature of amyotrophic lateral sclerosis (ALS). In this article, the history of the researches on fasciculation and FPs is first reviewed. The word and concept of fasciculation was first properly defined by Denny-Brown and Pennybacker (1938). It is noteworthy that they already stressed the necessity of strict discrimination of FPs from the "contraction fasciculation", a remnant of large voluntary motor unit potentials (MUPs), in this early milestone paper. FPs are rarely observed in neurogenic diseases other than ALS or disorders presenting with conduction block, i. e. they retain a high specificity in ALS diagnosis. Despite such usefulness, FPs were devaluated in the revised El-Escorial criteria. It is welcome that their value has been restored in the newer Awaji criteria. In the actual practice, correct identification of FPs would be a critical point. Remnant of voluntary MUPs is the greatest FP mimic to be differentiated. The key point for differentiation is the firing rhythm. FPs are characterized by a low-frequency and quite irregular firing, showing clustering of discharges. In contrast, voluntary MUPs are characterized by a semiregular firing.}, }
@article {pmid25671101, year = {2014}, author = {Anderson, KM and Olson, KE and Estes, KA and Flanagan, K and Gendelman, HE and Mosley, RL}, title = {Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders.}, journal = {Translational neurodegeneration}, volume = {3}, number = {1}, pages = {25}, pmid = {25671101}, issn = {2047-9158}, support = {R01 NS036126/NS/NINDS NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; P01 DA028555/DA/NIDA NIH HHS/United States ; P01 NS031492/NS/NINDS NIH HHS/United States ; P01 MH064570/MH/NIMH NIH HHS/United States ; R01 AG043540/AG/NIA NIH HHS/United States ; R01 NS070190/NS/NINDS NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, abstract = {Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of antigen-specific CD4+ T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal survival. The destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T cells. Temporally, immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the CNS. Immune responses with predominate T cell subtypes may differentially manifest migratory, regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific stimuli. The final result is altered glial and neuronal behaviors that influence the disease course. Thus, discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression.}, }
@article {pmid25666449, year = {2015}, author = {Bucchia, M and Ramirez, A and Parente, V and Simone, C and Nizzardo, M and Magri, F and Dametti, S and Corti, S}, title = {Therapeutic development in amyotrophic lateral sclerosis.}, journal = {Clinical therapeutics}, volume = {37}, number = {3}, pages = {668-680}, doi = {10.1016/j.clinthera.2014.12.020}, pmid = {25666449}, issn = {1879-114X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Disease Progression ; Humans ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. It is almost invariably lethal within a few years after the onset of symptoms. No effective treatment is currently available beyond supportive care and riluzole, a putative glutamate release blocker linked to modestly prolonged survival. This review provides a general overview of preclinical and clinical advances during recent years and summarizes the literature regarding emerging therapeutic approaches, focusing on their molecular targets.<br><br>METHODS: A systematic literature review of PubMed was performed, identifying key clinical trials involving molecular therapies for ALS. In addition, the ALS Therapy Development Institute website was carefully analyzed, and a selection of ALS clinical trials registered at ClinicalTrials.gov has been included.<br><br>FINDINGS: In the last several years, strategies have been developed to understand both the genetic and molecular mechanisms of ALS. Several therapeutic targets have been actively pursued, including kinases, inflammation inhibitors, silencing of key genes, and modulation or replacement of specific cell populations. The majority of ongoing clinical trials are investigating the safety profiles and tolerability of pharmacologic, gene, and cellular therapies, and have begun to assess their effects on ALS progression.<br><br>IMPLICATIONS: Currently, no therapeutic effort seems to be efficient, but recent findings in ALS could help accelerate the discovery of an effective treatment for this disease.}, }
@article {pmid25664170, year = {2014}, author = {Smith, RN and Agharkar, AS and Gonzales, EB}, title = {A review of creatine supplementation in age-related diseases: more than a supplement for athletes.}, journal = {F1000Research}, volume = {3}, number = {}, pages = {222}, pmid = {25664170}, issn = {2046-1402}, support = {T32 AG020494/AG/NIA NIH HHS/United States ; }, abstract = {Creatine is an endogenous compound synthesized from arginine, glycine and methionine. This dietary supplement can be acquired from food sources such as meat and fish, along with athlete supplement powders. Since the majority of creatine is stored in skeletal muscle, dietary creatine supplementation has traditionally been important for athletes and bodybuilders to increase the power, strength, and mass of the skeletal muscle. However, new uses for creatine have emerged suggesting that it may be important in preventing or delaying the onset of neurodegenerative diseases associated with aging. On average, 30% of muscle mass is lost by age 80, while muscular weakness remains a vital cause for loss of independence in the elderly population. In light of these new roles of creatine, the dietary supplement's usage has been studied to determine its efficacy in treating congestive heart failure, gyrate atrophy, insulin insensitivity, cancer, and high cholesterol. In relation to the brain, creatine has been shown to have antioxidant properties, reduce mental fatigue, protect the brain from neurotoxicity, and improve facets/components of neurological disorders like depression and bipolar disorder. The combination of these benefits has made creatine a leading candidate in the fight against age-related diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, long-term memory impairments associated with the progression of Alzheimer's disease, and stroke. In this review, we explore the normal mechanisms by which creatine is produced and its necessary physiology, while paying special attention to the importance of creatine supplementation in improving diseases and disorders associated with brain aging and outlining the clinical trials involving creatine to treat these diseases.}, }
@article {pmid25659970, year = {2015}, author = {Prakash, A and Bharti, K and Majeed, AB}, title = {Zinc: indications in brain disorders.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {29}, number = {2}, pages = {131-149}, doi = {10.1111/fcp.12110}, pmid = {25659970}, issn = {1472-8206}, mesh = {Animals ; Biological Transport/physiology ; Brain/*metabolism/pathology ; Brain Diseases/diagnosis/*metabolism ; Brain Injuries/diagnosis/metabolism ; Cation Transport Proteins/metabolism ; Homeostasis/physiology ; Humans ; Neurodegenerative Diseases/diagnosis/metabolism ; Stroke/diagnosis/metabolism ; Zinc/*metabolism ; }, abstract = {Zinc is the authoritative metal which is present in our body, and reactive zinc metal is crucial for neuronal signaling and is largely distributed within presynaptic vesicles. Zinc also plays an important role in synaptic function. At cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Different importers and transporters are involved in zinc homeostasis. ZnT-3 is a main transporter involved in zinc homeostasis in the brain. It has been found that alterations in brain zinc status have been implicated in a wide range of neurological disorders including impaired brain development and many neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Furthermore, zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.}, }
@article {pmid25656065, year = {2015}, author = {Maniecka, Z and Polymenidou, M}, title = {From nucleation to widespread propagation: A prion-like concept for ALS.}, journal = {Virus research}, volume = {207}, number = {}, pages = {94-105}, doi = {10.1016/j.virusres.2014.12.032}, pmid = {25656065}, issn = {1872-7492}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Humans ; Protein Aggregation, Pathological/genetics/*metabolism ; RNA-Binding Protein FUS/*chemistry/genetics/metabolism ; Superoxide Dismutase/*chemistry/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Propagation of pathological protein assemblies via a prion-like mechanism has been suggested to drive neurodegenerative diseases, such as Parkinson's and Alzheimer's. Recently, amyotrophic lateral sclerosis (ALS)-linked proteins, such as SOD1, TDP-43 and FUS were shown to follow self-perpetuating seeded aggregation, thereby adding ALS to the group of prion-like disorders. The cell-to-cell spread of these pathological protein assemblies and their pathogenic mechanism is poorly understood. However, as ALS is a non-cell autonomous disease and pathology in glial cells was shown to contribute to motor neuron damage, spreading mechanisms are likely to underlie disease progression via the interplay between affected neurons and their neighboring glial cells.}, }
@article {pmid25652700, year = {2015}, author = {Garofalo, T and Manganelli, V and Grasso, M and Mattei, V and Ferri, A and Misasi, R and Sorice, M}, title = {Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {20}, number = {5}, pages = {621-634}, doi = {10.1007/s10495-015-1100-x}, pmid = {25652700}, issn = {1573-675X}, mesh = {Animals ; *Apoptosis ; Biological Transport ; Gangliosides/metabolism ; Humans ; Mitochondria/*physiology ; Mitochondrial Membranes/*physiology ; Neurodegenerative Diseases/pathology ; }, abstract = {Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies.}, }
@article {pmid25652699, year = {2015}, author = {Scotter, EL and Chen, HJ and Shaw, CE}, title = {TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {352-363}, pmid = {25652699}, issn = {1878-7479}, support = {089701/WT_/Wellcome Trust/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Environment ; Gene Silencing/physiology ; Humans ; Mutation/genetics ; *TDP-43 Proteinopathies/genetics/metabolism/therapy ; }, abstract = {Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia.}, }
@article {pmid25647067, year = {2015}, author = {Yeh, DC and Chan, TM and Harn, HJ and Chiou, TW and Chen, HS and Lin, ZS and Lin, SZ}, title = {Adipose tissue-derived stem cells in neural regenerative medicine.}, journal = {Cell transplantation}, volume = {24}, number = {3}, pages = {487-492}, doi = {10.3727/096368915X686940}, pmid = {25647067}, issn = {1555-3892}, mesh = {Adipose Tissue/*cytology ; Amyotrophic Lateral Sclerosis/therapy ; Brain Injuries/therapy ; Central Nervous System Diseases/*therapy ; Humans ; Neurodegenerative Diseases/therapy ; *Regenerative Medicine ; *Stem Cell Transplantation ; Stem Cells/*cytology ; Stroke/therapy ; }, abstract = {Adipose tissue-derived stem cells (ADSCs) have two essential characteristics with regard to regenerative medicine: the convenient and efficient generation of large numbers of multipotent cells and in vitro proliferation without a loss of stemness. The implementation of clinical trials has prompted widespread concern regarding safety issues and has shifted research toward the therapeutic efficacy of stem cells in dealing with neural degeneration in cases such as stroke, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, cavernous nerve injury, and traumatic brain injury. Most existing studies have reported that cell therapies may be able to replenish lost cells and promote neuronal regeneration, protect neuronal survival, and play a role in overcoming permanent paralysis and loss of sensation and the recovery of neurological function. The mechanisms involved in determining therapeutic capacity remain largely unknown; however, this concept can still be classified in a methodical manner by citing current evidence. Possible mechanisms include the following: 1) the promotion of angiogenesis, 2) the induction of neuronal differentiation and neurogenesis, 3) reductions in reactive gliosis, 4) the inhibition of apoptosis, 5) the expression of neurotrophic factors, 6) immunomodulatory function, and 7) facilitating neuronal integration. In this study, several human clinical trials using ADSCs for neuronal disorders were investigated. It is suggested that ADSCs are one of the choices among various stem cells for translating into clinical application in the near future.}, }
@article {pmid25645594, year = {2015}, author = {Coatti, GC and Beccari, MS and Olávio, TR and Mitne-Neto, M and Okamoto, OK and Zatz, M}, title = {Stem cells for amyotrophic lateral sclerosis modeling and therapy: myth or fact?.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {87}, number = {3}, pages = {197-211}, doi = {10.1002/cyto.a.22630}, pmid = {25645594}, issn = {1552-4930}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Embryonic Stem Cells/*transplantation ; Humans ; Induced Pluripotent Stem Cells/*transplantation ; Neural Stem Cells/transplantation ; Stem Cell Transplantation/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy.}, }
@article {pmid25644224, year = {2015}, author = {Turner, MR and Swash, M}, title = {The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {86}, number = {6}, pages = {667-673}, pmid = {25644224}, issn = {1468-330X}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/classification/diagnosis/*genetics/*physiopathology ; Animals ; Humans ; Mice ; Mice, Transgenic ; Terminology as Topic ; }, abstract = {Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS.}, }
@article {pmid25638642, year = {2015}, author = {Rohrer, JD and Isaacs, AM and Mizielinska, S and Mead, S and Lashley, T and Wray, S and Sidle, K and Fratta, P and Orrell, RW and Hardy, J and Holton, J and Revesz, T and Rossor, MN and Warren, JD}, title = {C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {14}, number = {3}, pages = {291-301}, doi = {10.1016/S1474-4422(14)70233-9}, pmid = {25638642}, issn = {1474-4465}, support = {FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; 091673//Wellcome Trust/United Kingdom ; MR/J009482/1/MRC_/Medical Research Council/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; ISAACS/APR13/818-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Female ; Frontotemporal Dementia/diagnosis/*genetics ; Humans ; Male ; Middle Aged ; Proteins/*genetics ; }, abstract = {C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.}, }
@article {pmid25635910, year = {2015}, author = {Laser-Azogui, A and Kornreich, M and Malka-Gibor, E and Beck, R}, title = {Neurofilament assembly and function during neuronal development.}, journal = {Current opinion in cell biology}, volume = {32}, number = {}, pages = {92-101}, doi = {10.1016/j.ceb.2015.01.003}, pmid = {25635910}, issn = {1879-0410}, mesh = {Animals ; Axons/metabolism ; Humans ; Intermediate Filament Proteins/chemistry/metabolism ; Intermediate Filaments/*metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/*cytology/metabolism/pathology ; Protein Processing, Post-Translational ; }, abstract = {Studies on the assembly of neuronal intermediate filaments (IFs) date back to the early work of Alzheimer. Developing neurons express a series of IF proteins, sequentially, at distinct stages of mammalian cell differentiation. This correlates with altered morphologies during the neuronal development, including axon outgrowth, guidance and conductivity. Importantly, neuronal IFs that fail to properly assemble into a filamentous network are a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. Traditional structural methodologies fail to fully describe neuronal IF assembly, interactions and resulting function due to IFs structural plasticity, particularly in their C-terminal domains. We review here current progress in the field of neuronal-specific IFs, a dominant component affecting the cytoskeletal structure and function of neurons.}, }
@article {pmid25635517, year = {2015}, author = {Laferriere, F and Polymenidou, M}, title = {Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis.}, journal = {Swiss medical weekly}, volume = {145}, number = {}, pages = {w14054}, doi = {10.4414/smw.2015.14054}, pmid = {25635517}, issn = {1424-3997}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/etiology/*genetics/*physiopathology ; Animals ; DNA-Binding Proteins/*genetics/metabolism ; Disease Progression ; Humans ; Mice ; Middle Aged ; Mutation/genetics ; Nuclear Proteins/*genetics/metabolism ; RNA-Binding Protein FUS/*genetics/metabolism ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Transcription Factors/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, which primarily affects motor neurons leading to progressive paralysis and death within a few years from onset. The pathological hallmark of ALS is the presence of cytoplasmic ubiquitinated protein inclusions in motor neurons and glial cells primarily in the spinal cord. While the vast majority of ALS occurs sporadically (sALS), in ~10% of cases, called familial ALS (fALS), there is clear indication of genetic inheritance. In the last decade, enormous progress was made in unravelling the aetiology of the disease, with the identification of ALS-causing mutations in new genes, as well as key molecular players involved in the origin or progression of ALS. However, much more needs to be done, as the pathogenic mechanisms triggered by a genetic or sporadic event leading to cytotoxicity and neuronal cell death are still poorly understood. The recent discoveries offer new possibilities for devising experimental animal and cellular models, which will hopefully contribute to the development of new techniques for early diagnosis and the identification of therapeutic targets for ALS. Here we review the current understanding of the aetiology, genetics, and pathogenic factors and mechanisms of ALS. We also discuss the challenges in deciphering ALS pathogenesis that result from the high complexity and heterogeneity of the disease.}, }
@article {pmid25632606, year = {2014}, author = {Hübers, A and Weishaupt, JH and Ludolph, AC}, title = {[Amyotrophic lateral sclerosis].}, journal = {Medizinische Monatsschrift fur Pharmazeuten}, volume = {37}, number = {10}, pages = {356-64; quiz 365-6}, pmid = {25632606}, issn = {0342-9601}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Humans ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an aggressive degeneration of upper and lower motor neurons and thus affects both the central and the peripheral nervous system. Clinically, the disease is characterized by rapidly progressing atrophy and paresis of all muscle groups with a letal outcome after three to six years due to paresis of the respiratory muscles. So far, no causal treatment is known.}, }
@article {pmid25632156, year = {2015}, author = {Schuster, C and Elamin, M and Hardiman, O and Bede, P}, title = {Presymptomatic and longitudinal neuroimaging in neurodegeneration--from snapshots to motion picture: a systematic review.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {86}, number = {10}, pages = {1089-1096}, doi = {10.1136/jnnp-2014-309888}, pmid = {25632156}, issn = {1468-330X}, mesh = {Disease Progression ; Humans ; Longitudinal Studies ; Neurodegenerative Diseases/*pathology ; Neuroimaging/*methods ; Prospective Studies ; }, abstract = {BACKGROUND: Recent quantitative neuroimaging studies have been successful in capturing phenotype and genotype-specific changes in dementia syndromes, amyotrophic lateral sclerosis, Parkinson's disease and other neurodegenerative conditions. However, the majority of imaging studies are cross-sectional, despite the obvious superiority of longitudinal study designs in characterising disease trajectories, response to therapy, progression rates and evaluating the presymptomatic phase of neurodegenerative conditions.<br><br>OBJECTIVES: The aim of this work is to perform a systematic review of longitudinal imaging initiatives in neurodegeneration focusing on methodology, optimal statistical models, follow-up intervals, attrition rates, primary study outcomes and presymptomatic studies.<br><br>METHODS: Longitudinal imaging studies were identified from 'PubMed' and reviewed from 1990 to 2014. The search terms 'longitudinal', 'MRI', 'presymptomatic' and 'imaging' were utilised in combination with one of the following degenerative conditions; Alzheimer's disease, amyotrophic lateral sclerosis/motor neuron disease, frontotemporal dementia, Huntington's disease, multiple sclerosis, Parkinson's disease, ataxia, HIV, alcohol abuse/dependence.<br><br>RESULTS: A total of 423 longitudinal imaging papers and 103 genotype-based presymptomatic studies were identified and systematically reviewed. Imaging techniques, follow-up intervals and attrition rates showed significant variation depending on the primary diagnosis. Commonly used statistical models included analysis of annualised percentage change, mixed and random effect models, and non-linear cumulative models with acceleration-deceleration components.<br><br>DISCUSSION AND CONCLUSIONS: Although longitudinal imaging studies have the potential to provide crucial insights into the presymptomatic phase and natural trajectory of neurodegenerative processes a standardised design is required to enable meaningful data interpretation.}, }
@article {pmid25628533, year = {2014}, author = {Figueiredo-Pereira, ME and Rockwell, P and Schmidt-Glenewinkel, T and Serrano, P}, title = {Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {7}, number = {}, pages = {104}, pmid = {25628533}, issn = {1662-5099}, support = {R24 DA012136/DA/NIDA NIH HHS/United States ; SC3 GM086323/GM/NIGMS NIH HHS/United States ; UL1 RR024996/RR/NCRR NIH HHS/United States ; UL1 TR000457/TR/NCATS NIH HHS/United States ; }, abstract = {The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.}, }
@article {pmid25623279, year = {2015}, author = {Vanmierlo, T and Bogie, JF and Mailleux, J and Vanmol, J and Lütjohann, D and Mulder, M and Hendriks, JJ}, title = {Plant sterols: Friend or foe in CNS disorders?.}, journal = {Progress in lipid research}, volume = {58}, number = {}, pages = {26-39}, doi = {10.1016/j.plipres.2015.01.003}, pmid = {25623279}, issn = {1873-2194}, mesh = {Animals ; Central Nervous System Diseases/drug therapy/*metabolism/pathology ; Humans ; Multiple Sclerosis/drug therapy/metabolism ; Phytosterols/*metabolism/therapeutic use ; }, abstract = {In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders.}, }
@article {pmid25613506, year = {2015}, author = {Volonte, C and Apolloni, S and Parisi, C}, title = {MicroRNAs: newcomers into the ALS picture.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {14}, number = {2}, pages = {194-207}, doi = {10.2174/1871527314666150116125506}, pmid = {25613506}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; MicroRNAs/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) causes neurodegeneration of both upper and lower motor neurons and progressive muscle impairment, atrophy and death within approximately five years from diagnosis. The aetiology is still not clear but evidence obtained in animal models of the disease indicates a non-cell-autonomous mechanism with the active contribution of non-neuronal cells such as microglia, astrocytes, muscle and T cells, which differently participate to the diverse phases of the disease. Clinically indistinguishable forms of ALS occur as sporadic disease in the absence of known mutation, or can be initiated by genetic mutations. About two-third of familial cases are triggered by mutations of four genes that are chromosome 9 open reading frame 72 (C9ORF72), Cu/Zn superoxide dismutase (SOD1), fused in sarcoma/translocated in liposarcoma (FUS/TLS), TAR-DNA binding protein 43 (TDP43). There is at present no succesfull treatment against ALS and the identification of novel signalling pathways, molecular mechanisms and cellular mediators are still a major task in the search for effective therapies. MiRNAs are conserved, endogenous, non-coding RNAs that post-transcriptionally regulate protein expression. Produced as long primary transcripts, they are exported to the cytoplasm and further modified to obtain the mature miRNAs, with each step of their biogenesis being a potential step of regulation. There are more than 1000 different known human miRNA sequences, and more than 20-30% of all human protein-coding genes are likely controlled by miRNAs. This earns to miRNAs the definition of fine regulators of genetic networks. The discovery of the involvement of ALS mutated proteins TDP43 and FUS/TLS in miRNAs biogenesis strongly suggests a role of miRNA dysregulation also in ALS and many efforts are thus directed toward understanding the role of these small RNA molecules in the pathogenesis of ALS. The overall objective of this review is thus to highlight the emerging involvement of miRNAs in ALS. After a brief description of miRNA biogenesis and function, we discuss the effects of miRNA dysregulation in cellular and molecular pathways that lead to ALS neuroinflammation and neurodegeneration. In the last part, we focus on the mechanistic insights of miRNAs that might have implications for the development of novel neuroprotective agents against ALS, and on recent attempts to establish new molecular miRNA-based therapies. Paving the way for more comparative studies on neuroinflammatory and neurodegenerative mechanisms, this strategy indeed promises a broader impact on ALS.}, }
@article {pmid25613183, year = {2015}, author = {Zach, N and Ennist, DL and Taylor, AA and Alon, H and Sherman, A and Kueffner, R and Walker, J and Sinani, E and Katsovskiy, I and Cudkowicz, M and Leitner, ML}, title = {Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {417-423}, pmid = {25613183}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Clinical Trials as Topic/*methods/*statistics &amp; numerical data ; Databases, Factual/statistics &amp; numerical data ; Disease Progression ; Humans ; }, abstract = {Advancing research and clinical care, and conducting successful and cost-effective clinical trials requires characterizing a given patient population. To gather a sufficiently large cohort of patients in rare diseases such as amyotrophic lateral sclerosis (ALS), we developed the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) platform. The PRO-ACT database currently consists of >8600 ALS patient records from 17 completed clinical trials, and more trials are being incorporated. The database was launched in an open-access mode in December 2012; since then, >400 researchers from >40 countries have requested the data. This review gives an overview on the research enabled by this resource, through several examples of research already carried out with the goal of improving patient care and understanding the disease. These examples include predicting ALS progression, the simulation of future ALS clinical trials, the verification of previously proposed predictive features, the discovery of novel predictors of ALS progression and survival, the newly identified stratification of patients based on their disease progression profiles, and the development of tools for better clinical trial recruitment and monitoring. Results from these approaches clearly demonstrate the value of large datasets for developing a better understanding of ALS natural history, prognostic factors, patient stratification, and more. The increasing use by the community suggests that further analyses of the PRO-ACT database will continue to reveal more information about this disease that has for so long defied our understanding.}, }
@article {pmid25608779, year = {2015}, author = {Usdin, K and House, NC and Freudenreich, CH}, title = {Repeat instability during DNA repair: Insights from model systems.}, journal = {Critical reviews in biochemistry and molecular biology}, volume = {50}, number = {2}, pages = {142-167}, pmid = {25608779}, issn = {1549-7798}, support = {P01 GM105473/GM/NIGMS NIH HHS/United States ; Z01 DK057808/ImNIH/Intramural NIH HHS/United States ; P01GM105473/GM/NIGMS NIH HHS/United States ; }, mesh = {Chromosome Fragility/genetics ; DNA/chemistry/*genetics ; DNA Damage ; DNA Repair/*genetics ; DNA Replication/genetics ; Genetic Diseases, Inborn/classification/etiology ; Genomic Instability ; Humans ; *Nucleic Acid Conformation ; Recombination, Genetic ; Trinucleotide Repeat Expansion/*genetics ; }, abstract = {The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.}, }
@article {pmid25604957, year = {2015}, author = {Paul, P and de Belleroche, J}, title = {Experimental approaches for elucidating co-agonist regulation of NMDA receptor in motor neurons: Therapeutic implications for amyotrophic lateral sclerosis (ALS).}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {116}, number = {}, pages = {2-6}, doi = {10.1016/j.jpba.2014.12.040}, pmid = {25604957}, issn = {1873-264X}, support = {DEBELLEROCHE/MAR10/6064/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; D-Amino-Acid Oxidase/genetics/metabolism ; Excitatory Amino Acid Agonists/pharmacology/*therapeutic use ; Humans ; Motor Neurons/*drug effects/physiology ; Receptors, N-Methyl-D-Aspartate/*agonists/physiology ; Serine/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterised by selective loss of motor neurons leading to fatal paralysis. Although most cases are sporadic, approximately 10% of cases are familial and the identification of mutations in these kindred has greatly accelerated our understanding of disease mechanisms. To date, the causal genes in over 70% of these families have been identified. Recently, we reported a mutation (R199W) in the enzyme that degrades d-serine, D-amino acid oxidase (DAO) and co-segregates with disease in familial ALS. Moreover, D-serine and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated protein aggregates and promotes apoptosis, all of which processes are attenuated by a D-serine/glycine site antagonist of the N-methyl D-aspartate receptor (NMDAR). These findings suggest that the toxic effects of R199W-DAO are at least in part mediated via the NMDAR involving the D-serine/glycine site and that an excitotoxic mechanism may contribute to disease pathogenesis.}, }
@article {pmid25601726, year = {2015}, author = {Chiurchiù, V and Leuti, A and Maccarrone, M}, title = {Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {10}, number = {2}, pages = {268-280}, pmid = {25601726}, issn = {1557-1904}, mesh = {Alzheimer Disease/drug therapy/immunology ; Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Animals ; Brain/*drug effects/*immunology ; Cannabinoids/pharmacology/*therapeutic use ; Humans ; Immunity, Cellular/*drug effects/immunology ; Inflammation/drug therapy/immunology ; Multiple Sclerosis/drug therapy/immunology ; Receptors, Cannabinoid/immunology ; Signal Transduction/*drug effects/immunology ; }, abstract = {The concept of the central nervous system (CNS) as an immune-privileged site, essentially due to the presence of the blood brain barrier, appears to be overly simplistic. Indeed, within healthy CNS immune activities are permitted and are required for neuronal function and host defense, not only due to the presence of the resident innate immune cells of the brain, but also by virtue of a complex cross-talk of the CNS with peripheral immune cells. Nonetheless, long-standing and persisting neuroinflammatory responses are most often detrimental and characterize several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors. In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders.}, }
@article {pmid25601606, year = {2015}, author = {Nabavi, SF and Daglia, M and D'Antona, G and Sobarzo-Sánchez, E and Talas, ZS and Nabavi, SM}, title = {Natural compounds used as therapies targeting to amyotrophic lateral sclerosis.}, journal = {Current pharmaceutical biotechnology}, volume = {16}, number = {3}, pages = {211-218}, doi = {10.2174/1389201016666150118132224}, pmid = {25601606}, issn = {1873-4316}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*metabolism ; Animals ; Biological Products/*administration &amp; dosage ; Humans ; Neuroprotective Agents/administration &amp; dosage ; Oxidative Stress/drug effects/physiology ; Plant Extracts/*administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that occurs throughout the world with no racial, ethnic or socioeconomic boundaries. Despite its high morbidity and mortality, there are limited medications available for ALS that may increase survival in patients with amyotrophic lateral sclerosis by approximately 2-3 months. Inasmuch as negative effects of riluzole on muscle atrophy and wasting, weakness, muscle spasticity, dysarthria, dysphagia, and overall patient quality of life and its different adverse effects, much attention has been paid to natural products and herbal medicines. Overall scientific reports indicate that natural products have beneficial effects on patients with ALS low side effects and multiple targets. In the present paper, we review the scientific reports on beneficial role of natural polyphenolic compounds in treatment of ALS.}, }
@article {pmid25598354, year = {2016}, author = {Tang, Y and Le, W}, title = {Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {53}, number = {2}, pages = {1181-1194}, pmid = {25598354}, issn = {1559-1182}, mesh = {Animals ; Humans ; Microglia/*pathology ; Neurodegenerative Diseases/*pathology/*therapy ; Phenotype ; }, abstract = {One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease (AD), and amyotrophic lateral sclerosis, is microglia-mediated neuroinflammation. Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M1 phenotype and M2 phenotype. Depending on the phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects. In this review, we focus on the potential role of M1 and M2 microglia and the dynamic changes of M1/M2 phenotypes that are critically associated with the neurodegenerative diseases. Generally, M1 microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair process of M2 microglia are dampened. This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed β-amyloid (Aβ) plaque and tangles that are released into the extracellular space. The endogenous stimuli including aggregated α-synuclein, mutated superoxide dismutase, Aβ, and tau oligomers exist in the milieu that may persistently activate M1 pro-inflammatory responses and finally lead to irreversible neuron loss. The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.}, }
@article {pmid25593144, year = {2015}, author = {Solanki, I and Parihar, P and Mansuri, ML and Parihar, MS}, title = {Flavonoid-based therapies in the early management of neurodegenerative diseases.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {6}, number = {1}, pages = {64-72}, pmid = {25593144}, issn = {2156-5376}, mesh = {Alzheimer Disease/*drug therapy ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antioxidants/pharmacology/therapeutic use ; Brain/*drug effects ; Flavonoids/pharmacology/*therapeutic use ; Humans ; Huntington Disease/*drug therapy ; Multiple Sclerosis/*drug therapy ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/pharmacology/therapeutic use ; Parkinson Disease/*drug therapy ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there have been no therapies available that benefit patients who suffer from these diseases. Because most neurodegenerative diseases are late-onset and remain asymptomatic for most of the phases, the therapies initiated in advanced stages of the disease have limited value to patients. It may be possible to prevent or halt the disease progression to a great extent if therapies start at the initial stage of the disease. Such therapies may restore neuronal function by reducing or even eliminating the primary stressor. Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Regular consumption of flavonoids has been associated with a reduced risk of neurodegenerative diseases. In addition to their antioxidant properties, these polyphenolic compounds exhibit neuroprotective properties by their interaction with cellular signaling pathways followed by transcription and translation that mediate cell function under both normal and pathologic conditions. This review focuses on human intervention studies as well as animal studies on the role of various flavonoids in the prevention of neurodegenerative diseases.}, }
@article {pmid25592439, year = {2015}, author = {Mamo, JP}, title = {Motor neurone disease presenting with raised serum Troponin T.}, journal = {Scottish medical journal}, volume = {60}, number = {2}, pages = {e1-3}, doi = {10.1177/0036933014565064}, pmid = {25592439}, issn = {0036-9330}, mesh = {Aged ; Biomarkers/blood ; Chest Pain/*blood/etiology/physiopathology ; Electrocardiography ; Humans ; Male ; Motor Neuron Disease/*blood/complications/physiopathology ; Myocardial Infarction/blood ; Troponin T/*blood ; }, abstract = {Myocardial damage indicated by a rise in cardiac Troponin may not necessarily be due to a cardiac event. Many diseases such as sepsis, pulmonary embolism, heart and renal failure can also be associated with an elevated cardiac Troponin level. This brief report discusses the rare event of a patient with motor neurone disease, where the possible diagnosis of acute myocardial infarction arose due to an elevated cardiac Troponin. A 69-year-old gentleman presented with a history of a central chest ache of mild intensity, lasting a total of 2 h prior to complete resolution. Multiple cardiac Troponin assays were elevated, and echocardiography did not show any acute changes of myocardial damage. His electrocardiogram was also normal. This patient's raised cardiac Troponin was therefore explained on the basis of his active motor neurone disease. This rare case outlines the importance of considering motor neurone disease as a cause of elevated cardiac Troponin in the absence of clinical evidence of an acute coronary event.}, }
@article {pmid25590659, year = {2015}, author = {Moran, C and O'Mahony, S}, title = {When is feeding via a percutaneous endoscopic gastrostomy indicated?.}, journal = {Current opinion in gastroenterology}, volume = {31}, number = {2}, pages = {137-142}, doi = {10.1097/MOG.0000000000000152}, pmid = {25590659}, issn = {1531-7056}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Contraindications ; Deglutition Disorders/therapy ; Dementia/*therapy ; *Endoscopes, Gastrointestinal ; Enteral Nutrition/*instrumentation/methods ; *Gastrostomy/methods ; Humans ; Motor Neuron Disease/therapy ; Patient Selection ; Pneumonia, Aspiration/therapy ; Practice Guidelines as Topic ; Stroke/*therapy ; }, abstract = {PURPOSE OF REVIEW: This review addresses current controversies regarding appropriate indications for percutaneous endoscopic gastrostomy (PEG) insertion. We address specific indications, namely, dementia, stroke, aspiration, motor neurone disease/amyotrophic lateral sclerosis, and head and neck cancer. We recommend practical strategies for improving patient selection.<br><br>RECENT FINDINGS: There is now a general consensus in the United States that PEG feeding does not benefit patients with advanced dementia. 'Early' PEG insertion following stroke is similarly of no benefit. It is currently unclear whether patients with amyotrophic lateral sclerosis and head and neck tumors should have PEG or radiologically inserted gastrostomy.<br><br>SUMMARY: Decisions relating to PEG insertion remain difficult. The gastroenterologist, working as a member of a multidisciplinary nutrition team, needs to take a lead role in this regard, rather than functioning as a technician.}, }
@article {pmid25590632, year = {2015}, author = {Wang, J and Haeusler, AR and Simko, EA}, title = {Emerging role of RNA•DNA hybrids in C9orf72-linked neurodegeneration.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {14}, number = {4}, pages = {526-532}, pmid = {25590632}, issn = {1551-4005}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; NS07432/NS/NINDS NIH HHS/United States ; }, mesh = {C9orf72 Protein ; DNA/genetics/*metabolism ; DNA Methylation ; DNA Repeat Expansion/*genetics ; Gene Expression Regulation/*genetics ; Heredodegenerative Disorders, Nervous System/*genetics ; Humans ; *Models, Biological ; Proteins/*genetics ; RNA/genetics/*metabolism ; }, abstract = {RNA plays an active role in structural polymorphism of the genome through the formation of stable RNA•DNA hybrids (R-loops). R-loops can modulate normal physiological processes and are also associated with pathological conditions, such as those related to nucleotide repeat expansions. A guanine-rich hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) has been linked to a spectrum of neurological conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we discuss the possible roles, both locally and genome-wide, of R-loops that may arise from the C9orf72 hexanucleotide repeat. R-loops have the potential to influence the pathological processes identified in many repeat expansion diseases, such as repeat instability, transcriptional dysregulation, epigenetic modification, and antisense-mediated gene regulation. We propose that, given the wide-ranging consequences of R-loops in the cell, these structures could underlie multiple pathological processes in C9orf72-linked neurodegeneration.}, }
@article {pmid25587791, year = {2015}, author = {Salvi, JS and Mekhail, K}, title = {R-loops highlight the nucleus in ALS.}, journal = {Nucleus (Austin, Tex.)}, volume = {6}, number = {1}, pages = {23-29}, pmid = {25587791}, issn = {1949-1042}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Base Sequence ; Cell Nucleus/*genetics ; Cytoplasm/genetics ; DNA/*genetics ; Feedback, Physiological ; Humans ; RNA/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative disease linked to mutations in various genes implicated in cytoplasmic RNA metabolism. Recent studies from genetic models have also helped reveal connections between various ALS-linked factors and RNA-DNA hybrid (R-loop) regulation. Here, we examine how such hybrid-regulatory processes are pointing to a key role for the nucleus in ALS. We also present a potential molecular mechanism in which hybrids may represent at least one of the long sought after missing links between different ALS genes. Our opinion is that RNA-DNA hybrids will play a key role in deciphering ALS and other human diseases.}, }
@article {pmid25582382, year = {2015}, author = {Rutkove, SB}, title = {Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {384-393}, pmid = {25582382}, issn = {1878-7479}, support = {K24 NS060951/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/metabolism/*therapy ; Animals ; Biomarkers/blood/cerebrospinal fluid ; Disease Progression ; Hand Strength ; Humans ; Magnetic Resonance Imaging ; Nervous System/physiopathology ; Neural Conduction/physiology ; Outcome Assessment, Health Care/*methods ; Respiration Disorders/etiology ; Surveys and Questionnaires ; }, abstract = {Progressive weakness remains the clinical hallmark of amyotrophic lateral sclerosis (ALS). Accordingly, a variety of tools has been developed to capture this disease feature, including questionnaires, such as the ALS-functional rating scale, strength testing, pulmonary function tests, electrophysiologic measures, including motor unit number estimation, and imaging techniques. Despite this plethora of approaches, there is little agreement as to what measures to use in a given clinical trial or in the clinic during routine patient care. Part of the reason for this uncertainty is that ALS is a remarkably protean disease. Some individuals progress rapidly, others slowly; some patients have considerable upper motor neuron dysfunction, whereas others have little; and there is considerable variation in the sequence of body regions affected, in some the disease beginning in the bulbar musculature and in others in one arm or one leg. Here, I present a variety of basic and more complex clinical measures for potential use in therapeutic trials with the aim of offering a balanced and practical set of recommendations, as well as considerations for future studies.}, }
@article {pmid25574882, year = {2015}, author = {Lisle, S and Tennison, M}, title = {Amyotrophic lateral sclerosis: the role of exercise.}, journal = {Current sports medicine reports}, volume = {14}, number = {1}, pages = {45-46}, doi = {10.1249/JSR.0000000000000122}, pmid = {25574882}, issn = {1537-8918}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/*therapy ; *Exercise/physiology ; Exercise Therapy/*methods ; Humans ; Resistance Training/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease affecting both the upper and lower motor neurons. Given the deterioration of skeletal muscle function, historically there has been concern regarding exercise and its affect on ALS. This article reviews and explains current research, helping patients, caregivers, and providers be equipped better to make decisions regarding the treatment of ALS with exercise.}, }
@article {pmid25572957, year = {2015}, author = {Rosenfeld, J and Strong, MJ}, title = {Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {317-325}, pmid = {25572957}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*therapy ; Animals ; Biomarkers/metabolism ; Humans ; }, abstract = {With the acceleration in our understanding of ALS and the related motor neuron disease has come even greater challenges in reconciling all of the proposed pathogenic mechanisms and how this will translate into impactful treatments. Fundamental issues such as diagnostic definition(s) of the disease spectrum, relevant biomarkers, the impact of multiple novel genetic mutations and the significant effect of symptomatic treatments on disease progression are all areas of active investigation. In this review, we will focus on these key issues and highlight the challenges that confront both clinicians and basic science researchers.}, }
@article {pmid25568878, year = {2014}, author = {Jiang, T and Tan, MS and Tan, L and Yu, JT}, title = {Application of next-generation sequencing technologies in Neurology.}, journal = {Annals of translational medicine}, volume = {2}, number = {12}, pages = {125}, pmid = {25568878}, issn = {2305-5839}, abstract = {Genetic risk factors that underlie many rare and common neurological diseases remain poorly understood because of the multi-factorial and heterogeneous nature of these disorders. Although genome-wide association studies (GWAS) have successfully uncovered numerous susceptibility genes for these diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. These results implicated that there are rare (present in <5% of the population) but not causative variants exist in the pathogenesis of these diseases, which usually have large effect size and cannot be captured by GWAS. With the decreasing cost of next-generation sequencing (NGS) technologies, whole-genome sequencing (WGS) and whole-exome sequencing (WES) have enabled the rapid identification of rare variants with large effect size, which made huge progress in understanding the basis of many Mendelian neurological conditions as well as complex neurological diseases. In this article, recent NGS-based studies that aimed to investigate genetic causes for neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, stroke, amyotrophic lateral sclerosis and spinocerebellar ataxias, have been reviewed. In addition, we also discuss the future directions of NGS applications in this article.}, }
@article {pmid25568877, year = {2014}, author = {Tan, MS and Jiang, T and Tan, L and Yu, JT}, title = {Genome-wide association studies in neurology.}, journal = {Annals of translational medicine}, volume = {2}, number = {12}, pages = {124}, pmid = {25568877}, issn = {2305-5839}, abstract = {Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWAS in common neurological diseases, including Stroke, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, migraine, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, restless legs syndrome, intracranial aneurysm, human prion diseases and moyamoya disease. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of potential therapeutic agents.}, }
@article {pmid25567872, year = {2014}, author = {Chen, S and Wu, Z}, title = {[Advances in repeat-primed PCR assay for the genetic diagnosis of dynamic mutation diseases with large pathogenic expansions].}, journal = {Yi chuan = Hereditas}, volume = {36}, number = {11}, pages = {1145-1151}, pmid = {25567872}, issn = {0253-9772}, mesh = {Ataxin-10 ; C9orf72 Protein ; Genetic Diseases, Inborn/*diagnosis ; Humans ; *Mutation ; Nerve Tissue Proteins/genetics ; Polymerase Chain Reaction/*methods ; Proteins/genetics ; }, abstract = {Dynamic mutation diseases are genetic diseases caused by unstable repeat expansions in coding region or noncoding region. The unstable repeat expansions located in the noncoding region usually perform as large expansions which the standard PCR assay is difficult to amplify. Traditional detection methods, including Southern blot, are supposed to be time-consuming and labor-wasting. A new method called fluorescent repeat-primed PCR assay was brought into genetic diagnosis. Here, we reviewed the advances in repeat-primed PCR assay for the genetic diagnoses of myotonic dystrophy, Friedreich's ataxia, SCA10, and amyotrophic lateral sclerosis or frontotemporal dementia caused by C9 or f72 mutations.}, }
@article {pmid25567201, year = {2015}, author = {Hooten, KG and Beers, DR and Zhao, W and Appel, SH}, title = {Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {364-375}, pmid = {25567201}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*pathology ; Animals ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Cytokines/metabolism ; Disease Models, Animal ; Humans ; Inflammation/*etiology/*prevention &amp; control ; Mice ; Motor Neurons/metabolism/pathology ; Neuroglia/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.}, }
@article {pmid25567110, year = {2015}, author = {Gentil, BJ and Tibshirani, M and Durham, HD}, title = {Neurofilament dynamics and involvement in neurological disorders.}, journal = {Cell and tissue research}, volume = {360}, number = {3}, pages = {609-620}, doi = {10.1007/s00441-014-2082-7}, pmid = {25567110}, issn = {1432-0878}, mesh = {Animals ; Humans ; Intermediate Filaments/*metabolism ; Nervous System Diseases/*pathology ; Neurons/pathology ; Organ Specificity ; }, abstract = {Neurons are extremely polarised cells in which the cytoskeleton, composed of microtubules, microfilaments and neurofilaments, plays a crucial role in maintaining structure and function. Neurofilaments, the 10-nm intermediate filaments of neurons, provide structure and mechanoresistance but also provide a scaffolding for the organization of the nucleus and organelles such as mitochondria and ER. Disruption of neurofilament organization and expression or metabolism of neurofilament proteins is characteristic of certain neurological syndromes including Amyotrophic Lateral Sclerosis, Charcot-Marie-Tooth sensorimotor neuropathies and Giant Axonal Neuropathy. Microfluorometric live imaging techniques have been instrumental in revealing the dynamics of neurofilament assembly and transport and their functions in organizing intracellular organelle networks. The insolubility of neurofilament proteins has limited identifying interactors by conventional biochemical techniques but yeast two-hybrid experiments have revealed new roles for oligomeric, nonfilamentous structures including vesicular trafficking. Although having long half-lives, new evidence points to degradation of subunits by the ubiquitin-proteasome system as a mechanism of normal turnover. Although certain E3-ligases ubiquitinating neurofilament proteins have been identified, the overall process of neurofilament degradation is not well understood. We review these mechanisms of neurofilament homeostasis and abnormalities in motor neuron and peripheral nerve disorders. Much remains to discover about the disruption of processes that leads to their pathological aggregation and accumulation and the relevance to pathogenesis. Understanding these mechanisms is crucial for identifying novel therapeutic strategies.}, }
@article {pmid25565965, year = {2014}, author = {Chan, HY}, title = {RNA-mediated pathogenic mechanisms in polyglutamine diseases and amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {431}, pmid = {25565965}, issn = {1662-5102}, abstract = {Gene transcription produces a wide variety of ribonucleic acid (RNA) species in eukaryotes. Individual types of RNA, such as messenger, structural and regulatory RNA, are known to play distinct roles in the cell. Recently, researchers have identified a large number of RNA-mediated toxicity pathways that play significant pathogenic roles in numerous human disorders. In this article, we describe various common RNA toxicity pathways, namely epigenetic gene silencing, nucleolar stress, nucleocytoplasmic transport, bi-directional gene transcription, repeat-associated non-ATG translation, RNA foci formation and cellular protein sequestration. We emphasize RNA toxicity mechanisms that involve nucleotide repeat expansion, such as those related to polyglutamine (polyQ) disorders and frontotemporal lobar degeneration-amyotrophic lateral sclerosis.}, }
@article {pmid25559087, year = {2015}, author = {Mazibuko, Z and Choonara, YE and Kumar, P and Du Toit, LC and Modi, G and Naidoo, D and Pillay, V}, title = {A review of the potential role of nano-enabled drug delivery technologies in amyotrophic lateral sclerosis: lessons learned from other neurodegenerative disorders.}, journal = {Journal of pharmaceutical sciences}, volume = {104}, number = {4}, pages = {1213-1229}, doi = {10.1002/jps.24322}, pmid = {25559087}, issn = {1520-6017}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Biological Availability ; Blood-Brain Barrier/metabolism ; Capillary Permeability ; Central Nervous System Agents/*administration &amp; dosage/chemistry/pharmacokinetics ; Chemistry, Pharmaceutical ; *Drug Carriers ; Drug Delivery Systems/*methods ; Humans ; Nanomedicine/*methods ; Nerve Regeneration/drug effects ; Polymers/*chemistry ; Technology, Pharmaceutical/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has a multitude of factors implicated in its etiology. The complex neuro-etiology and the restrictive nature of the blood-brain barrier (BBB) have significantly hindered the drug therapy of ALS. Riluzole, a moderately performing drug, is the only agent approved for treating ALS. However, several promising nanocarrier approaches are surfacing that can provide more efficient drug delivery. In addition, biologicals such as stem cells are able to carry neurotrophic factors to their target site, providing motor neurons with the benefits of both, stem cells and neurotrophic factors. This review examines the current drug delivery strategies investigated for optimally treating ALS and related neurodegenerative disorders. Examples include cerium oxide nanoparticles in Alzheimer's disease, odorranalectin, and lactoferrin-coupled PEG-PLGA nanoparticles for urocortin transportation in Parkinson's disease that can also be employed in ALS to bypass the BBB and increase drug bioavailability. A concise incursion into the progress (and lack thereof) made in ALS clinical trials is also discussed. Nanocarriers can potentially eliminate the challenges of poor drug bioavailability in ALS as they have been proven to cross the BBB and reach target sites while minimizing systemic side-effects. Nanocarrier-based delivery of ALS drugs is an area that requires much needed investigation.}, }
@article {pmid25557955, year = {2015}, author = {Ng, AS and Rademakers, R and Miller, BL}, title = {Frontotemporal dementia: a bridge between dementia and neuromuscular disease.}, journal = {Annals of the New York Academy of Sciences}, volume = {1338}, number = {1}, pages = {71-93}, pmid = {25557955}, issn = {1749-6632}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; }, mesh = {Chromosomes, Human, Pair 9 ; Frontotemporal Dementia/*complications/genetics/pathology ; Humans ; Neuromuscular Diseases/*complications/genetics/pathology ; Open Reading Frames ; }, abstract = {The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.}, }
@article {pmid26934784, year = {2015}, author = {Shafirkin, AV}, title = {[BIOLOGICAL EFFECTIVENESS OF FISSION SPECTRUM NEUTRONS AND PROTONS WITH ENERGIES OF 60-126 MEV DURING ACUTE AND PROLONGED IRRADIATION].}, journal = {Aviakosmicheskaia i ekologicheskaia meditsina = Aerospace and environmental medicine}, volume = {49}, number = {6}, pages = {5-13}, pmid = {26934784}, issn = {0233-528X}, mesh = {Animals ; *Cosmic Radiation ; Dose-Response Relationship, Radiation ; *Gamma Rays ; Linear Energy Transfer ; *Neutrons ; *Protons ; Relative Biological Effectiveness ; }, abstract = {Neutrons of the fission spectrum are characterized by relatively high values of linear energy transfer (LET). Data about their effects on biological objects are used to evaluate the risk of delayed effects of accelerated ions within the same LET range that serve as an experimental model of the nuclei component of galactic cosmic rays (GCR). Additionally, risks of delayed consequences to cosmonaut's health and average lifetime from certain GCR fluxes and secondary neutrons can be also prognosticated. The article deals with comparative analysis of the literature on reduction of average lifespan (ALS) of animals exposed to neutron reactor spectrum, 60-126 MeV protons, and X- and γ-rays in a broad range of radiation intensity and duration. It was shown that a minimal lifespan reduction by 5% occurs due to a brief exposure to neutrons with the absorbed dose of 5 cGy, whereas same lifespan reduction due to hard X- and γ-radiation occurs after absorption of a minimal dose of 100 cGy. Therefore, according to the estimated minimal ALS reduction in mice, neutron effectiveness is 20-fold higher. Biological effectiveness of protons as regards ALS reduction is virtually equal to that of standard types of radiation. Exposure to X- and γ-radiation with decreasing daily doses, and increasing number of fractions and duration gives rise to an apparent trend toward a less dramatic ALS reduction in mice; on the contrary, exposure to neutrons of varying duration had no effect on threshold doses for the specified ALS reductions. Factors of relative biological effectiveness of neutrons reached 40.}, }
@article {pmid25539896, year = {2015}, author = {Re, RN}, title = {A possible mechanism for the progression of chronic renal disease and congestive heart failure.}, journal = {Journal of the American Society of Hypertension : JASH}, volume = {9}, number = {1}, pages = {54-63}, doi = {10.1016/j.jash.2014.09.016}, pmid = {25539896}, issn = {1878-7436}, mesh = {Angiotensin II/physiology ; Disease Progression ; Heart Failure/epidemiology/*physiopathology ; Humans ; Neurodegenerative Diseases/physiopathology ; Renal Insufficiency, Chronic/epidemiology/*physiopathology ; Renin-Angiotensin System/*physiology ; Up-Regulation/physiology ; }, abstract = {Chronic neurologic diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as various forms of chronic renal disease and systolic congestive heart failure, are among the most common progressive degenerative disorders encountered in medicine. Each disease follows a nearly relentless course, albeit at varying rates, driven by progressive cell dysfunction and drop-out. The neurologic diseases are characterized by the progressive spread of disease-causing proteins (prion-like proteins) from cell to cell. Recent evidence indicates that cell autonomous renin angiotensin systems operate in heart and kidney, and it is known that functional intracrine proteins can also spread between cells. This then suggests that certain progressive degenerative cardiovascular disorders such as forms of chronic renal insufficiency and systolic congestive heart failure result from dysfunctional renin angiotensin system intracrine action spreading in kidney or myocardium.}, }
@article {pmid25538685, year = {2014}, author = {Gong, Z and Tas, E and Muzumdar, R}, title = {Humanin and age-related diseases: a new link?.}, journal = {Frontiers in endocrinology}, volume = {5}, number = {}, pages = {210}, pmid = {25538685}, issn = {1664-2392}, abstract = {Humanin (HN) is 24-amino acid mitochondria-associated peptide. Since its initial discovery over a decade ago, a role for HN has been reported in many biological processes such as apoptosis, cell survival, substrate metabolism, inflammatory response, and response to stressors such as oxidative stress, ischemia, and starvation. HN and its potent analogs have been shown to have beneficial effects in many age-related diseases including Alzheimer's disease, stroke, diabetes, myocardial ischemia and reperfusion, atherosclerosis, amyotrophic lateral sclerosis, and certain types of cancer both in vitro and in vivo. More recently, an association between HN levels, growth hormone/insulin-like growth factor-1 (GH/IGF axis), and life span was demonstrated using various mouse models with mutations in the GH/IGF axis. The goal of this review is to summarize the current understanding of the role of HN in aging and age-related diseases.}, }
@article {pmid25538551, year = {2014}, author = {Al-Mahdawi, S and Virmouni, SA and Pook, MA}, title = {The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {8}, number = {}, pages = {397}, pmid = {25538551}, issn = {1662-4548}, abstract = {DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC) modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC), which is formed by oxidation of 5mC by ten-eleven translocation (TET) enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS). The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA), Huntington's disease (HD), and Parkinson's disease (PD).}, }
@article {pmid25534912, year = {2015}, author = {Chiò, A and Traynor, BJ}, title = {Motor neuron disease in 2014. Biomarkers for ALS--in search of the Promised Land.}, journal = {Nature reviews. Neurology}, volume = {11}, number = {2}, pages = {72-74}, pmid = {25534912}, issn = {1759-4766}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933-02/ImNIH/Intramural NIH HHS/United States ; Z01-AG000949&#x2011;02/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/genetics/*metabolism ; Biomarkers/*metabolism ; Clinical Trials as Topic ; Humans ; Research ; }, abstract = {The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS) research. Two trials were completed, with negative results, but the discovery of novel ALS-associated genes, and body fluid and imaging biomarkers warrants cautious optimism. Here, we provide a snapshot of some of the main findings in 2014.}, }
@article {pmid25531407, year = {2014}, author = {Buchan, JR}, title = {mRNP granules. Assembly, function, and connections with disease.}, journal = {RNA biology}, volume = {11}, number = {8}, pages = {1019-1030}, pmid = {25531407}, issn = {1555-8584}, mesh = {Cytoplasmic Granules/genetics/*metabolism ; Gene Expression Regulation ; Humans ; Neurodegenerative Diseases/*genetics/pathology ; Neuronal Plasticity/genetics ; Neurons/metabolism/pathology ; Protein Biosynthesis/genetics ; RNA Transport/*genetics ; RNA, Messenger/*genetics/metabolism ; Ribonucleoproteins/*genetics/metabolism ; Synapses/genetics/metabolism/pathology ; }, abstract = {Messenger ribonucleoprotein (mRNP) granules are dynamic, self-assembling structures that harbor non-translating mRNAs bound by various proteins that regulate mRNA translation, localization, and turnover. Their importance in gene expression regulation is far reaching, ranging from precise spatial-temporal control of mRNAs that drive developmental programs in oocytes and embryos, to similarly exquisite control of mRNAs in neurons that underpin synaptic plasticity, and thus, memory formation. Analysis of mRNP granules in their various contexts has revealed common themes of assembly, disassembly, and modes of mRNA regulation, yet new studies continue to reveal unexpected and important findings, such as links between aberrant mRNP granule assembly and neurodegenerative disease. Continued study of these enigmatic structures thus promises fascinating new insights into cellular function, and may also suggest novel therapeutic strategies in various disease states.}, }
@article {pmid25520673, year = {2014}, author = {Pettorruso, M and De Risio, L and Di Nicola, M and Martinotti, G and Conte, G and Janiri, L}, title = {Allostasis as a conceptual framework linking bipolar disorder and addiction.}, journal = {Frontiers in psychiatry}, volume = {5}, number = {}, pages = {173}, pmid = {25520673}, issn = {1664-0640}, abstract = {Bipolar disorders (BDs) and addictions constitute reciprocal risk factors and are best considered under a unitary perspective. The concepts of allostasis and allostatic load (AL) may contribute to the understanding of the complex relationships between BD and addictive behaviors. Allostasis entails the safeguarding of reward function stability by recruitment of changes in the reward and stress system neurocircuitry and it may help to elucidate neurobiological underpinnings of vulnerability to addiction in BD patients. Conceptualizing BD as an illness involving the cumulative build-up of allostatic states, we hypothesize a progressive dysregulation of reward circuits clinically expressed as negative affective states (i.e., anhedonia). Such negative affective states may render BD patients more vulnerable to drug addiction, fostering a very rapid transition from occasional drug use to addiction, through mechanisms of negative reinforcement. The resulting addictive behavior-related ALs, in turn, may contribute to illness progression. This framework could have a heuristic value to enhance research on pathophysiology and treatment of BD and addiction comorbidity.}, }
@article {pmid25520620, year = {2014}, author = {Jaronen, M and Goldsteins, G and Koistinaho, J}, title = {ER stress and unfolded protein response in amyotrophic lateral sclerosis-a controversial role of protein disulphide isomerase.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {402}, pmid = {25520620}, issn = {1662-5102}, abstract = {Accumulation of proteins in aberrant conformation occurs in many neurodegenerative diseases. Furthermore, dysfunctions in protein handling in endoplasmic reticulum (ER) and the following ER stress have been implicated in a vast number of diseases, such as amyotrophic lateral sclerosis (ALS). During excessive ER stress unfolded protein response (UPR) is activated to return ER to its normal physiological balance. The exact mechanisms of protein misfolding, accumulation and the following ER stress, which could lead to neurodegeneration, and the question whether UPR is a beneficial compensatory mechanism slowing down the neurodegenerative processes, are of interest. Protein disulphide isomerase (PDI) is a disulphide bond-modulating ER chaperone, which can also facilitate the ER-associated degradation (ERAD) of misfolded proteins. In this review we discuss the recent findings of ER stress, UPR and especially the role of PDI in ALS.}, }
@article {pmid25520025, year = {2014}, author = {Malik, R and Lui, A and Lomen-Hoerth, C}, title = {Amyotrophic lateral sclerosis.}, journal = {Seminars in neurology}, volume = {34}, number = {5}, pages = {534-541}, doi = {10.1055/s-0034-1396007}, pmid = {25520025}, issn = {1098-9021}, mesh = {*Activities of Daily Living ; Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Enteral Nutrition/methods ; Exercise Therapy/methods ; Humans ; Male ; Orthotic Devices/statistics &amp; numerical data ; Respiration, Artificial/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting 20,000 to 30,000 people in the United States. The mainstay of care of patients affected by this disease is supportive and given the multifaceted nature of their needs is provided most efficiently through multidisciplinary clinics that have shown to prolong survival and improve quality of life. The authors discuss in detail evidence-based management of individuals affected by this condition.}, }
@article {pmid25519968, year = {2014}, author = {Ishihara, T and Kakita, A and Takahashi, H and Onodera, O and Nishizawa, M}, title = {[Aberration of the spliceosome in amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {54}, number = {12}, pages = {1155-1157}, doi = {10.5692/clinicalneurol.54.1155}, pmid = {25519968}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; *Chromosome Aberrations ; DNA-Binding Proteins/physiology ; Humans ; RNA/metabolism ; Spinal Muscular Atrophies of Childhood/genetics ; Spliceosomes/*genetics/metabolism ; }, abstract = {TDP-43 is a nuclear protein that plays a role in RNA metabolism, and its dysfunction has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a typical adult-onset motor neuron disease. We investigated RNA metabolism in relation to TDP-43 function in neuronal tissues affected by ALS, and found a decrease in the number of nuclear GEM bodies, as well as reduced expression of minor spliceosomes, which are functional RNA-protein complexes. Similar features have been reported in spinal muscular atrophy (SMA), a motor neuron disease affecting infants. These findings, together with those reported in SMA, strongly suggest that reduction of minor spliceosomes has an important role in the pathomechanism underlying the selective degeneration of motor neurons characteristic of both ALS and SMA.}, }
@article {pmid25519967, year = {2014}, author = {Yamanaka, K}, title = {[Biochemical abnormality of mutant TDP-43 protein].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {54}, number = {12}, pages = {1148-1150}, doi = {10.5692/clinicalneurol.54.1148}, pmid = {25519967}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; DNA-Binding Proteins/*genetics/toxicity ; Humans ; Mice ; *Mutation ; Protein Stability ; Proteostasis Deficiencies/genetics ; RNA, Messenger ; }, abstract = {Dominant mutations in the TDP-43 gene are causative for familial ALS, however, the relationship between mutant protein biochemical phenotypes and disease course and their significance to disease pathomechanism are unclarified. We found that longer half-lives of mutant proteins correlated with accelerated disease onset. Increased stability of TDP-43 protein was also observed in ALS/FTLD linked mutations in RNA recognition motif of TDP-43. Based on our findings, we established a cell model in which chronic stabilization of wild-type TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent sarkosyl, TDP-43 properties that have been observed in the lesions of sporadic ALS. Moreover, these cells expressing stabilized TDP-43 showed proteasomal impairment and dysregulation of their own mRNA levels. These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis.}, }
@article {pmid25515509, year = {2015}, author = {Hroch, L and Aitken, L and Benek, O and Dolezal, M and Kuca, K and Gunn-Moore, F and Musilek, K}, title = {Benzothiazoles - scaffold of interest for CNS targeted drugs.}, journal = {Current medicinal chemistry}, volume = {22}, number = {6}, pages = {730-747}, doi = {10.2174/0929867322666141212120631}, pmid = {25515509}, issn = {1875-533X}, support = {188/ALZS_/Alzheimer's Society/United Kingdom ; }, mesh = {Alzheimer Disease/diagnostic imaging/drug therapy ; Animals ; Anticonvulsants/*chemistry/therapeutic use ; Benzothiazoles/*chemistry/therapeutic use ; Humans ; Neuroprotective Agents/*chemistry/therapeutic use ; Quantitative Structure-Activity Relationship ; Radionuclide Imaging ; }, abstract = {Benzothiazole compounds represent heterocyclic systems comprising a benzene ring fused with a thiazole ring containing nitrogen and sulphur in its structure. Besides the presence of a benzothiazole core in naturally occurring molecules, synthesized compounds containing a benzothiazole moiety in their structure proved to be a significant class of potential therapeutics, as they exhibit biological effects such as antitumor, antibacterial, antitubercular, antiviral, anthelmintic, antidiabetic and many others. Apart from the aforementioned peripheral or microbial active sites, benzothiazole analogues are also biologically active compounds in the central nervous system, where some approved drugs containing a benzothiazole moiety have already been identified and are used in the treatment of various neurological disorders. New benzothiazole molecules are currently under development and are being evaluated for several uses including diagnostics and as therapeutic drug candidates for the treatment of epilepsy and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis amongst others.}, }
@article {pmid25505901, year = {2014}, author = {Cortés-Gutiérrez, EI and López-Fernández, C and Fernández, JL and Dávila-Rodríguez, MI and Johnston, SD and Gosálvez, J}, title = {Interpreting sperm DNA damage in a diverse range of mammalian sperm by means of the two-tailed comet assay.}, journal = {Frontiers in genetics}, volume = {5}, number = {}, pages = {404}, pmid = {25505901}, issn = {1664-8021}, abstract = {Key ConceptsThe two-dimensional Two-Tailed Comet assay (TT-comet) protocol is a valuable technique to differentiate between single-stranded (SSBs) and double-stranded DNA breaks (DSBs) on the same sperm cell.Protein lysis inherent with the TT-comet protocol accounts for differences in sperm protamine composition at a species-specific level to produce reliable visualization of sperm DNA damage.Alkaline treatment may break the sugar-phosphate backbone in abasic sites or at sites with deoxyribose damage, transforming these lesions into DNA breaks that are also converted into ssDNA. These lesions are known as Alkali Labile Sites "ALSs."DBD-FISH permits the in situ visualization of DNA breaks, abasic sites or alkaline-sensitive DNA regions.The alkaline comet single assay reveals that all mammalian species display constitutive ALS related with the requirement of the sperm to undergo transient changes in DNA structure linked with chromatin packing.Sperm DNA damage is associated with fertilization failure, impaired pre-and post- embryo implantation and poor pregnancy outcome.The TT is a valuable tool for identifying SSBs or DSBs in sperm cells with DNA fragmentation and can be therefore used for the purposes of fertility assessment. Sperm DNA damage is associated with fertilization failure, impaired pre-and post- embryo implantation and poor pregnancy outcome. A series of methodologies to assess DNA damage in spermatozoa have been developed but most are unable to differentiate between single-stranded DNA breaks (SSBs) and double-stranded DNA breaks (DSBs) on the same sperm cell. The two-dimensional Two-Tailed Comet assay (TT-comet) protocol highlighted in this review overcomes this limitation and emphasizes the importance in accounting for the difference in sperm protamine composition at a species-specific level for the appropriate preparation of the assay. The TT-comet is a modification of the original comet assay that uses a two dimensional electrophoresis to allow for the simultaneous evaluation of DSBs and SSBs in mammalian spermatozoa. Here we have compiled a retrospective overview of how the TT-comet assay has been used to investigate the structure and function of sperm DNA across a diverse range of mammalian species (eutheria, metatheria, and prototheria). When conducted as part of the TT-comet assay, we illustrate (a) how the alkaline comet single assay has been used to help understand the constitutive and transient changes in DNA structure associated with chromatin packing, (b) the capacity of the TT-comet to differentiate between the presence of SSBs and DSBs (c) and the possible implications of SSBs or DSBs for the assessment of infertility.}, }
@article {pmid25502407, year = {2015}, author = {Simmons, Z}, title = {Patient-Perceived Outcomes and Quality of Life in ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {394-402}, pmid = {25502407}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*therapy ; *Awareness ; Clinical Trials as Topic/*methods ; Humans ; *Outcome Assessment, Health Care ; Quality of Life/*psychology ; }, abstract = {A variety of outcome measures are used in clinical practice and in research to assess patients with amyotrophic lateral sclerosis (ALS). However, there may be discordance between traditional outcome measures such as strength and physical function, and patient-perceived measures of well-being. One such self-perceived measure, reflecting the patient's view, is quality of life (QOL). QOL in patients with severe medical disorder is often underestimated by others. Patients with ALS often have high QOL, and this may persist throughout the disease due to shifting expectations and to reprioritization of factors contributing to QOL. QOL instruments can measure health-related QOL (HRQOL) or global QOL, and can be generic or disease-specific. HRQOL refers primarily to physical and mental health. Global QOL is much broader, and is also determined by non-health-related factors. The choice of a QOL instrument depends on whether the setting is routine patient care or clinical research, whether or not the outcome of a specific intervention is being assessed, and upon the expected efficacy or toxicity of the intervention. Global QOL instruments are best for individual clinical patient care or for comparing groups. HRQOL or a combination of HRQOL and global QOL instruments are most appropriate for assessing specific interventions.}, }
@article {pmid25494299, year = {2015}, author = {Schwartz, JC and Cech, TR and Parker, RR}, title = {Biochemical Properties and Biological Functions of FET Proteins.}, journal = {Annual review of biochemistry}, volume = {84}, number = {}, pages = {355-379}, pmid = {25494299}, issn = {1545-4509}, support = {K99 NS082376/NS/NINDS NIH HHS/United States ; 1K99NS082376-01A1/NS/NINDS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; }, mesh = {Active Transport, Cell Nucleus ; Animals ; DNA Repair ; Humans ; Neoplasms/metabolism ; Neurodegenerative Diseases/metabolism ; RNA Processing, Post-Transcriptional ; RNA-Binding Protein FUS/chemistry/*metabolism ; RNA-Binding Proteins/chemistry/*metabolism ; TATA-Binding Protein Associated Factors/chemistry/*metabolism ; Transcription, Genetic ; }, abstract = {Members of the FET protein family, consisting of FUS, EWSR1, and TAF15, bind to RNA and contribute to the control of transcription, RNA processing, and the cytoplasmic fates of messenger RNAs in metazoa. FET proteins can also bind DNA, which may be important in transcription and DNA damage responses. FET proteins are of medical interest because chromosomal rearrangements of their genes promote various sarcomas and because point mutations in FUS or TAF15 can cause neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. Recent results suggest that both the normal and pathological effects of FET proteins are modulated by low-complexity or prion-like domains, which can form higher-order assemblies with novel interaction properties. Herein, we review FET proteins with an emphasis on how the biochemical properties of FET proteins may relate to their biological functions and to pathogenesis.}, }
@article {pmid25492944, year = {2015}, author = {Bunton-Stasyshyn, RK and Saccon, RA and Fratta, P and Fisher, EM}, title = {SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {21}, number = {5}, pages = {519-529}, doi = {10.1177/1073858414561795}, pmid = {25492944}, issn = {1089-4098}, support = {MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/K018523/1/MRC_/Medical Research Council/United Kingdom ; FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0500288/MRC_/Medical Research Council/United Kingdom ; G1000287/MRC_/Medical Research Council/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Endoplasmic Reticulum/*metabolism ; Humans ; Mutation/physiology ; RNA/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {The canonical role of superoxide dismutase 1 (SOD1) is as an antioxidant enzyme protecting the cell from reactive oxygen species toxicity. SOD1 was also the first gene in which mutations were found to be causative for the neurodegenerative disease amyotrophic lateral sclerosis (ALS), more than 20 years ago. ALS is a relentless and incurable mid-life onset disease, which starts with a progressive paralysis and usually leads to death within 3 to 5 years of diagnosis; in the majority of cases, the intellect appears to remain intact while the motor system degenerates. It rapidly became clear that when mutated SOD1 takes on a toxic gain of function in ALS. However, this novel function remains unknown and many cellular systems have been implicated in disease. Now it seems that SOD1 may play a rather larger role in the cell than originally realized, including as a key modulator of glucose signaling (at least so far in yeast) and in RNA binding. Here, we consider some of the new findings for SOD1 in health and disease, which may shed light on how single amino acid changes at sites throughout this protein can cause devastating neurodegeneration in the mammalian motor system.}, }
@article {pmid25487060, year = {2015}, author = {Smethurst, P and Sidle, KC and Hardy, J}, title = {Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS).}, journal = {Neuropathology and applied neurobiology}, volume = {41}, number = {5}, pages = {578-597}, doi = {10.1111/nan.12206}, pmid = {25487060}, issn = {1365-2990}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Brain/metabolism/pathology ; DNA-Binding Proteins/*metabolism ; Humans ; Inclusion Bodies/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Neuroglia/metabolism/pathology ; Prion Diseases/*metabolism/pathology ; Prions/*metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder which predominantly affects the motor neurons in the brain and spinal cord. The death of the motor neurons in ALS causes subsequent muscle atrophy, paralysis and eventual death. Clinical and biological evidence now demonstrates that ALS has many similarities to prion disease in terms of disease onset, phenotype variability and progressive spread. The pathognomonic ubiquitinated inclusions deposited in the neurons and glial cells in brains and spinal cords of patients with ALS and fronto-temporal lobar degeneration with ubiquitinated inclusions contain aggregated transactive response DNA binding protein of 43 kDa (TDP-43), and evidence now suggests that TDP-43 has cellular prion-like properties. The cellular mechanisms of prion protein misfolding and aggregation are thought to be responsible for the characteristics of prion disease. Therefore, there is a strong mechanistic basis for a prion-like behaviour of the TDP-43 protein being responsible for some characteristics of ALS. In this review, we compare the prion-like mechanisms of TDP-43 to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease.}, }
@article {pmid25484085, year = {2014}, author = {Luo, J}, title = {Autophagy and ethanol neurotoxicity.}, journal = {Autophagy}, volume = {10}, number = {12}, pages = {2099-2108}, pmid = {25484085}, issn = {1554-8635}, support = {I01 BX001721/BX/BLRD VA/United States ; R01 AA015407/AA/NIAAA NIH HHS/United States ; AA019693/AA/NIAAA NIH HHS/United States ; AA015407/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Brain/*drug effects/metabolism ; Ethanol/*adverse effects ; Humans ; Neurons/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Excessive ethanol exposure is detrimental to the brain. The developing brain is particularly vulnerable to ethanol such that prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD). Neuronal loss in the brain is the most devastating consequence and is associated with mental retardation and other behavioral deficits observed in FASD. Since alcohol consumption during pregnancy has not declined, it is imperative to elucidate the underlying mechanisms and develop effective therapeutic strategies. One cellular mechanism that acts as a protective response for the central nervous system (CNS) is autophagy. Autophagy regulates lysosomal turnover of organelles and proteins within cells, and is involved in cell differentiation, survival, metabolism, and immunity. We have recently shown that ethanol activates autophagy in the developing brain. The autophagic preconditioning alleviates ethanol-induced neuron apoptosis, whereas inhibition of autophagy potentiates ethanol-stimulated reactive oxygen species (ROS) and exacerbates ethanol-induced neuroapoptosis. The expression of genes encoding proteins required for autophagy in the CNS is developmentally regulated; their levels are much lower during an ethanol-sensitive period than during an ethanol-resistant period. Ethanol may stimulate autophagy through multiple mechanisms; these include induction of oxidative stress and endoplasmic reticulum stress, modulation of MTOR and AMPK signaling, alterations in BCL2 family proteins, and disruption of intracellular calcium (Ca2+) homeostasis. This review discusses the most recent evidence regarding the involvement of autophagy in ethanol-mediated neurotoxicity as well as the potential therapeutic approach of targeting autophagic pathways.}, }
@article {pmid25479292, year = {2014}, author = {Wang, MD and Gomes, J and Cashman, NR and Little, J and Krewski, D}, title = {A meta-analysis of observational studies of the association between chronic occupational exposure to lead and amyotrophic lateral sclerosis.}, journal = {Journal of occupational and environmental medicine}, volume = {56}, number = {12}, pages = {1235-1242}, pmid = {25479292}, issn = {1536-5948}, mesh = {Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Humans ; Lead/*toxicity ; Observational Studies as Topic ; Occupational Exposure/*adverse effects ; Odds Ratio ; Risk Factors ; }, abstract = {OBJECTIVE: The association between occupational exposure to lead and amyotrophic lateral sclerosis (ALS) was examined through systematic review and meta-analyses of relevant epidemiological studies and reported according to PRISMA guidelines.<br><br>METHODS: Relevant studies were searched in multiple bibliographic databases through September 2013; additional articles were tracked through PubMed until submission. All records were screened in DistillerSR, and the data extracted from included articles were synthesized with meta-analysis.<br><br>RESULTS: The risk of developing ALS among individuals with a history of exposure to lead was almost doubled (odds ratio, 1.81; 95% confidence interval, 1.39 to 2.36) on the basis of nine included case-control studies with specific lead exposure information, with no apparent heterogeneity across included studies (I = 14%). The attributable risk of ALS because of exposure to lead was estimated to be 5%.<br><br>CONCLUSIONS: Previous exposure to lead may be a risk factor for ALS.}, }
@article {pmid25472025, year = {2015}, author = {Yonutas, HM and Pandya, JD and Sullivan, PG}, title = {Changes in mitochondrial bioenergetics in the brain versus spinal cord become more apparent with age.}, journal = {Journal of bioenergetics and biomembranes}, volume = {47}, number = {1-2}, pages = {149-154}, pmid = {25472025}, issn = {1573-6881}, support = {F31 NS086395/NS/NINDS NIH HHS/United States ; P30 NS051220/NS/NINDS NIH HHS/United States ; R01 NS048191/NS/NINDS NIH HHS/United States ; R01 NS069633/NS/NINDS NIH HHS/United States ; }, mesh = {*Aging ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Brain/*metabolism/pathology ; *Energy Metabolism ; Humans ; Mitochondria/*metabolism/pathology ; Organ Specificity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Spinal Cord/*metabolism/pathology ; }, abstract = {The cell is known to be the most basic unit of life. However, this basic unit of life is dependent on the proper function of many intracellular organelles to thrive. One specific organelle that has vast implications on the overall health of the cell and cellular viability is the mitochondrion. These cellular power plants generate the energy currency necessary for cells to maintain homeostasis and function properly. Additionally, when mitochondria become dysfunctional, they can orchestrate the cell to undergo cell-death. Therefore, it is important to understand what insults can lead to mitochondrial dysfunction in order to promote cell health and increase cellular viability. After years of research, is has become increasingly accepted that age has a negative effect on mitochondrial bioenergetics. In support of this, we have found decreased mitochondrial bioenergetics with increased age in Sprague-Dawley rats. Within this same study we found a 200 to 600% increase in ROS production in old rats compared to young rats. Additionally, the extent of mitochondrial dysfunction and ROS production seems to be spatially defined affecting the spinal cord to a greater extent than certain regions of the brain. These tissue specific differences in mitochondrial function may be the reason why certain regions of the Central Nervous System, CNS, are disproportionately affected by aging and may play a pivotal role in specific age-related neurodegenerative diseases like Amyotrophic Lateral Sclerosis, ALS.}, }
@article {pmid25469059, year = {2014}, author = {Kang, H and Cha, ES and Choi, GJ and Lee, WJ}, title = {Amyotrophic lateral sclerosis and agricultural environments: a systematic review.}, journal = {Journal of Korean medical science}, volume = {29}, number = {12}, pages = {1610-1617}, pmid = {25469059}, issn = {1598-6357}, mesh = {Age Distribution ; Agriculture/*statistics &amp; numerical data ; Amyotrophic Lateral Sclerosis/*epidemiology ; Environmental Exposure/*statistics &amp; numerical data ; Female ; Humans ; Incidence ; Male ; Occupational Diseases/*epidemiology ; Pesticides/*analysis ; *Proportional Hazards Models ; Risk Factors ; Sex Distribution ; }, abstract = {The aim of this study was to examine the relationship between the risk of amyotrophic lateral sclerosis (ALS) and exposure to rural environments. Studies were identified through OVID MEDLINE and EMBASE search up to September 2013 using as keywords rural residence, farmers, and pesticide exposure. Twenty-two studies were included for this meta-analysis. Summary odds ratios (ORs) were calculated using random effect model by type of exposure index, and subgroup analyses were conducted according to study design, gender, region, case ascertainment, and exposure assessment. The risk of ALS was significantly increased with pesticide exposure (OR, 1.44; 95% CI, 1.22-1.70) and with farmers (OR, 1.42; 95% CI, 1.17-1.73), but was not significant with rural residence (OR, 1.25; 95% CI, 0.84-1.87). The risk estimates for subgroup analysis between pesticide exposure and ALS indicated a significant positive association with men (OR, 1.96), and in studies using El Escorial criteria for ALS definition (OR, 1.63) and expert judgment for pesticide exposure (OR, 2.04) as well. No significant publication bias was observed. Our findings support the association of pesticide exposure and an increased risk for ALS, stressing that the use of more specific exposure information resulted in more significant associations.}, }
@article {pmid25460198, year = {2015}, author = {Engel, WK}, title = {Diagnostic histochemistry and clinical-pathological testings as molecular pathways to pathogenesis and treatment of the ageing neuromuscular system: a personal view.}, journal = {Biochimica et biophysica acta}, volume = {1852}, number = {4}, pages = {563-584}, doi = {10.1016/j.bbadis.2014.11.015}, pmid = {25460198}, issn = {0006-3002}, mesh = {*Aging/genetics/metabolism/pathology ; Humans ; *Neuromuscular Diseases/diagnosis/genetics/metabolism/pathology/therapy ; }, abstract = {Ageing of the neuromuscular system in elderhood ingravescently contributes to slowness, weakness, falling and death, often accompanied by numbness and pain. This article is to put in perspective examples from a half-century of personal and team neuromuscular histochemical-pathological and clinical-pathological research, including a number of lucky and instructive accomplishments identifying new treatments and new diseases. A major focus currently is on some important, still enigmatic, aspects of the ageing neuromuscular system. It is also includes some of the newest references of others on various closely-related aspects of this ageing system. The article may help guide others in their molecular-based endeavors to identify paths leading to discovering new treatments and new pathogenic aspects. These are certainly needed - our ageing and unsteady constituents are steadily increasing. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.}, }
@article {pmid25457652, year = {2015}, author = {Donadio, V and Liguori, R}, title = {Microneurographic recording from unmyelinated nerve fibers in neurological disorders: an update.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {126}, number = {3}, pages = {437-445}, doi = {10.1016/j.clinph.2014.10.009}, pmid = {25457652}, issn = {1872-8952}, mesh = {Electrodiagnosis/*methods ; Humans ; Nerve Fibers, Unmyelinated/*physiology ; Nervous System Diseases/*diagnosis/physiopathology ; Nociceptors/physiology ; Peripheral Nervous System/*physiopathology ; Sympathetic Nervous System/*physiopathology ; }, abstract = {Microneurography is a unique neurophysiological technique allowing direct recording of unmyelinated postganglionic sympathetic or afferent nociceptive fibers by tungsten needles inserted into a peripheral nerve fascicle. In recent years, microneurography has been used to ascertain autonomic impairments in central neurological disorders such as sleep disorders, Parkinson's disease, amyotrophic lateral sclerosis, or vasovagal syncope. Abnormal resting muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) or the abnormal sympathetic response to arousal have been described in these disorders, thereby clarifying important pathophysiological aspects of the underlying impairment. In addition, microneurography was also recently used to demonstrate absent or decreased sympathetic outflow in diseases affecting the peripheral nervous system such as Ross syndrome, pure autonomic failure, and small-fiber neuropathy. Microneurography has also been used to study nociceptor outflow in pain disorders affecting the peripheral nervous system such as small-fiber neuropathy, diabetic neuropathy, erythromelalgia, complex regional pain syndrome, and fibromyalgia. In these disorders, microneurography mainly documented mechano-insensitive C-nociceptor hyperexcitability that might account for the ongoing pain.}, }
@article {pmid25453462, year = {2014}, author = {Chiò, A and Pagani, M and Agosta, F and Calvo, A and Cistaro, A and Filippi, M}, title = {Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes.}, journal = {The Lancet. Neurology}, volume = {13}, number = {12}, pages = {1228-1240}, doi = {10.1016/S1474-4422(14)70167-X}, pmid = {25453462}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Brain/*pathology/*physiology ; Humans ; Neuroimaging/*methods ; }, abstract = {In the past two decades, structural and functional neuroimaging findings have greatly modified longstanding notions regarding the pathophysiology of amyotrophic lateral sclerosis (ALS). Neuroimaging studies have shown that anatomical and functional lesions spread beyond precentral cortices and corticospinal tracts, to include the corpus callosum; frontal, sensory, and premotor cortices; thalamus; and midbrain. Both MRI and PET studies have shown early and diffuse loss of inhibitory cortical interneurons in the motor cortex (increased levels of functional connectivity and loss of GABAergic neurons, respectively) and diffuse gliosis in white-matter tracts. In ALS endophenotypes, neuroimaging has also shown a diverse spreading of lesions and a dissimilar impairment of functional and structural connections. A possible role of PET in the diagnosis of ALS has recently been proposed. However, most neuroimaging studies have pitfalls, such as a small number and poor clinical characterisation of patients, absence of adequate controls, and scarcity of longitudinal assessments. Studies involving international collaborations, standardised assessments, and large patient cohorts will overcome these shortcomings and provide further insight into the pathogenesis of ALS.}, }
@article {pmid25452025, year = {2015}, author = {Bakkar, N and Boehringer, A and Bowser, R}, title = {Use of biomarkers in ALS drug development and clinical trials.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {94-107}, pmid = {25452025}, issn = {1872-6240}, support = {NS068179/NS/NINDS NIH HHS/United States ; R56 NS061867/NS/NINDS NIH HHS/United States ; R01 NS061867/NS/NINDS NIH HHS/United States ; RC1 NS068179/NS/NINDS NIH HHS/United States ; NS061867/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Biomarkers/metabolism ; *Clinical Trials as Topic ; Drug Discovery/*methods ; Humans ; Prognosis ; }, abstract = {The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25451799, year = {2014}, author = {Galbiati, M and Crippa, V and Rusmini, P and Cristofani, R and Cicardi, ME and Giorgetti, E and Onesto, E and Messi, E and Poletti, A}, title = {ALS-related misfolded protein management in motor neurons and muscle cells.}, journal = {Neurochemistry international}, volume = {79}, number = {}, pages = {70-78}, doi = {10.1016/j.neuint.2014.10.007}, pmid = {25451799}, issn = {1872-9754}, support = {GGP14039/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Autophagy ; Humans ; Motor Neurons/*pathology ; Muscle Cells/*pathology ; Proteostasis Deficiencies/*pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression.}, }
@article {pmid25449570, year = {2015}, author = {Le, NT and Narkiewicz, J and Aulić, S and Salzano, G and Tran, HT and Scaini, D and Moda, F and Giachin, G and Legname, G}, title = {Synthetic prions and other human neurodegenerative proteinopathies.}, journal = {Virus research}, volume = {207}, number = {}, pages = {25-37}, doi = {10.1016/j.virusres.2014.10.020}, pmid = {25449570}, issn = {1872-7492}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/genetics/*metabolism ; Prions/chemical synthesis/chemistry/genetics/*metabolism ; Protein Folding ; Proteins/chemistry/genetics/*metabolism ; }, abstract = {Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau.}, }
@article {pmid25447872, year = {2015}, author = {Fu, L and Sztul, E}, title = {Characterization of intracellular aggresomes by fluorescent microscopy.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1258}, number = {}, pages = {307-317}, doi = {10.1007/978-1-4939-2205-5_17}, pmid = {25447872}, issn = {1940-6029}, support = {P30 DK 072482/DK/NIDDK NIH HHS/United States ; R474-CR11//PHS HHS/United States ; }, mesh = {Cytoplasm/metabolism ; Humans ; Microscopy, Fluorescence/methods ; Microtubule-Organizing Center/metabolism ; Protein Aggregates/*physiology ; Protein Folding ; Proteins/*metabolism ; }, abstract = {Correct folding of newly synthesized proteins is essential to cellular homeostasis and cells have evolved sophisticated means to fold and modify proteins. When misfolding occurs, the misfolded proteins often expose normally buried hydrophobic domains, causing localized aggregation. Individual small aggregates appear to be transported towards the microtubule-organizing center and there coalesce to form larger aggregates called aggresomes. Both cytoplasmic and nuclear proteins can form aggresomes. The study of aggresomes has progressed rapidly because numerous human diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, various myopathies, and prion disease are characterized by the formation of aggresomes. Importantly, aggresomes sequester many cellular proteins and the pathology of aggresomal disease is at least partially caused by the deregulation of cellular components. Thus, it is essential to identify and characterize the composition of aggresomes formed by different proteins. However, most protein aggregates are insoluble even in buffers with high concentration of detergent, which makes them very difficult to analyze by biochemical approaches. An alternative approach that has been used successfully is the in situ characterization of protein components within aggresomes by immunofluorescent microscopy. Here, we provide detailed protocols to study the characteristic features of aggresomes by fluorescent microscopy.}, }
@article {pmid25444447, year = {2015}, author = {Morin, A and Lesourd, A and Cabane, J}, title = {[Lightning strike and lesions outside the brain: Clinical cases and a review of the literature].}, journal = {Revue neurologique}, volume = {171}, number = {1}, pages = {75-80}, doi = {10.1016/j.neurol.2014.08.001}, pmid = {25444447}, issn = {0035-3787}, mesh = {Adult ; Female ; Humans ; Lightning ; Lightning Injuries/*complications/diagnosis ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Paraplegia/diagnosis/*etiology ; Peripheral Nervous System Diseases/diagnosis/*etiology ; Spinal Cord Injuries/diagnosis/*etiology ; Young Adult ; }, abstract = {INTRODUCTION: Every year, 240,000 people are struck by lightning worldwide, causing injuries leading to significant handicaps. Most of the symptoms involve brain lesions; neuromuscular sequelae and myelopathy are less common.<br><br>OBSERVATIONS: We describe five cases of patients struck by lightning with various clinical presentations. The first patient presented painful paresthesias in both upper limbs that disappeared 18 months later; the injury was a plexopathy. The second patient developed proximal weakness in the upper-left limb due to a myopathy. Two patients presented with various motor weaknesses in the lower limbs due to motor neuron disease and myelopathy. The last patient had a transient tetraplegy, which resolved in 5minutes; the diagnosis was keraunoparalysis.<br><br>DISCUSSION: Lightning injuries can have many consequences depending on the different mechanisms involved. The clinical presentation is often due to a very focal lesion without any secondary extension. Motor neuron disease probably results from post-traumatic myelopathy. We discuss the ALS-electrocution association, frequently described in the literature.<br><br>CONCLUSION: Various peripheral nerve and spinal cord lesions can be seen in lightning strike victims involving myelopathy, motor neuron, muscle and plexus. Clinical syndromes are often atypical but outcome is often favorable.}, }
@article {pmid25442938, year = {2014}, author = {Chen-Plotkin, AS}, title = {Unbiased approaches to biomarker discovery in neurodegenerative diseases.}, journal = {Neuron}, volume = {84}, number = {3}, pages = {594-607}, pmid = {25442938}, issn = {1097-4199}, support = {P50 NS053488/NS/NINDS NIH HHS/United States ; U01 NS082134/NS/NINDS NIH HHS/United States ; R01 NS082265/NS/NINDS NIH HHS/United States ; U01NS082134/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biomarkers/*metabolism ; Brain/*metabolism/*pathology ; Humans ; Neurodegenerative Diseases/*diagnosis/*metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia have several important features in common. They are progressive, they affect a relatively inaccessible organ, and we have no disease-modifying therapies for them. For these brain-based diseases, current diagnosis and evaluation of disease severity rely almost entirely on clinical examination, which may be only a rough approximation of disease state. Thus, the development of biomarkers-objective, relatively easily measured, and precise indicators of pathogenic processes-could improve patient care and accelerate therapeutic discovery. Yet existing, rigorously tested neurodegenerative disease biomarkers are few, and even fewer biomarkers have translated into clinical use. To find new biomarkers for these diseases, an unbiased, high-throughput screening approach may be needed. In this review, I will describe the potential utility of such an approach to biomarker discovery, using Parkinson's disease as a case example.}, }
@article {pmid25441979, year = {2014}, author = {González, H and Pacheco, R}, title = {T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases.}, journal = {Journal of neuroinflammation}, volume = {11}, number = {}, pages = {201}, pmid = {25441979}, issn = {1742-2094}, mesh = {Animals ; Humans ; Inflammation/*immunology ; Neurodegenerative Diseases/*immunology ; Neuroimmunomodulation/*immunology ; T-Lymphocytes/*immunology ; }, abstract = {Neuroinflammation is involved in several neurodegenerative disorders and emerging evidence indicates that it constitutes a critical process that is required for the progression of neurodegeneration. Microglial activation constitutes a central event in neuroinflammation. Furthermore, microglia can not only be activated with an inflammatory and neurotoxic phenotype (M1-like phenotype), but they also can acquire a neurosupportive functional phenotype (M2-like phenotype) characterised by the production of anti-inflammatory mediators and neurotrophic factors. Importantly, during the past decade, several studies have shown that CD4(+) T-cells infiltrate the central nervous system (CNS) in many neurodegenerative disorders, in which their participation has a critical influence on the outcome of microglial activation and consequent neurodegeneration. In this review, we focus on the analysis of the interplay of the different sub-populations of CD4(+) T-cells infiltrating the CNS and how they participate in regulating the outcome of neuroinflammation and neurodegeneration in the context of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. In this regard, encephalitogenic inflammatory CD4(+) T-cells, such as Th1, Th17, GM-CSF-producer CD4(+) T-cells and γδT-cells, strongly contribute to chronic neuroinflammation, thus perpetuating neurodegenerative processes. In contrast, encephalitogenic or meningeal Tregs and Th2 cells decrease inflammatory functions in microglial cells and promote a neurosupportive microenvironment. Moreover, whereas some neurodegenerative disorders such as multiple sclerosis, Parkinson's disease and Alzheimer's disease involve the participation of inflammatory CD4(+) T-cells 'naturally', the physiopathology of other neurodegenerative diseases, such as amyotrophic lateral sclerosis, is associated with the participation of anti-inflammatory CD4(+) T-cells that delay the neurodegenerative process. Thus, current evidence supports the hypothesis that the involvement of CD4(+) T-cells against CNS antigens constitutes a key component in regulating the progression of the neurodegenerative process.}, }
@article {pmid25433762, year = {2015}, author = {Cloutier, F and Marrero, A and O'Connell, C and Morin, P}, title = {MicroRNAs as potential circulating biomarkers for amyotrophic lateral sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {56}, number = {1}, pages = {102-112}, pmid = {25433762}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Animals ; Biomarkers/blood ; Humans ; MicroRNAs/*blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a condition primarily characterized by the selective loss of upper and lower motor neurons. Motor neuron loss gives rise to muscle tissue malfunctions, including weakness, spasticity, atrophy, and ultimately paralysis, with death typically due to respiratory failure within 2 to 5 years of symptoms' onset. The mean delay in time from presentation to diagnosis remains at over 1 year. Biomarkers are urgently needed to facilitate ALS diagnosis and prognosis as well as to act as indicators of therapeutic response in clinical trials. MicroRNAs (miRNAs) are small molecules that can influence posttranscriptional gene expression of a variety of transcript targets. Interestingly, miRNAs can be released into the circulation by pathologically affected tissues. This review presents therapeutic and diagnostic challenges associated with ALS, highlights the potential role of miRNAs in ALS, and discusses the diagnostic potential of these molecules in identifying ALS-specific miRNAs or in distinguishing between the various genotypic and phenotypic forms of ALS.}, }
@article {pmid25421001, year = {2015}, author = {Faden, AI and Loane, DJ}, title = {Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {1}, pages = {143-150}, pmid = {25421001}, issn = {1878-7479}, support = {P30 AG028747/AG/NIA NIH HHS/United States ; R01NS082308/NS/NINDS NIH HHS/United States ; R01NS037313/NS/NINDS NIH HHS/United States ; R01 NS037313/NS/NINDS NIH HHS/United States ; R01 NS082308/NS/NINDS NIH HHS/United States ; R01NS052568/NS/NINDS NIH HHS/United States ; R01 NS052568/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*etiology/pathology ; Animals ; Brain Injuries/*complications ; Brain Injury, Chronic/*etiology/pathology ; Encephalitis/*etiology/pathology ; Humans ; Nerve Degeneration/*etiology/pathology ; }, abstract = {It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).}, }
@article {pmid25420446, year = {2015}, author = {Yang, LP and Deeks, ED}, title = {Dextromethorphan/quinidine: a review of its use in adults with pseudobulbar affect.}, journal = {Drugs}, volume = {75}, number = {1}, pages = {83-90}, pmid = {25420446}, issn = {1179-1950}, mesh = {Adult ; Dextromethorphan/*therapeutic use ; Drug Combinations ; Humans ; Mood Disorders/*drug therapy/etiology ; Nervous System Diseases/*complications ; Quinidine/*therapeutic use ; }, abstract = {Fixed-dose dextromethorphan/quinidine capsules (Nuedexta(®)) utilize quinidine to inhibit the metabolism of dextromethorphan, enabling high plasma dextromethorphan concentrations to be reached without using a larger dose of the drug. The drug combination is the first treatment to be approved for pseudobulbar affect (PBA), a condition of contextually inappropriate/exaggerated emotional expression that often occurs in adults with neurological damage conditions, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, traumatic brain injury, Alzheimer's disease or Parkinson's disease. Dextromethorphan/quinidine at the recommended dosages of 20/10 or 30/10 mg twice daily reduced the rate of PBA episodes and improved PBA severity in a 12-week, double-blind, placebo-controlled trial in adults with ALS or MS (STAR), with further improvements in the severity of the condition observed in a 12-week open-label extension phase. Dextromethorphan/quinidine 20/10 mg twice daily also improved PBA secondary to dementia in a cohort of a 12-week noncomparative trial (PRISM II). The drug combination was generally well tolerated in these studies, with no particular safety or tolerability concerns. Although longer-term efficacy and tolerability data for dextromethorphan/quinidine 20/10 or 30/10 mg twice daily would be beneficial, current evidence indicates that it is a useful option in the treatment of adults with PBA.}, }
@article {pmid25409785, year = {2014}, author = {Chang, KA and Lee, JH and Suh, YH}, title = {Therapeutic potential of human adipose-derived stem cells in neurological disorders.}, journal = {Journal of pharmacological sciences}, volume = {126}, number = {4}, pages = {293-301}, doi = {10.1254/jphs.14R10CP}, pmid = {25409785}, issn = {1347-8648}, mesh = {Adipose Tissue/*cytology ; Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell Differentiation ; Cell- and Tissue-Based Therapy/*methods/*trends ; Humans ; Huntington Disease/therapy ; Mice ; Nervous System Diseases/*therapy ; Parkinson Disease/therapy ; Pluripotent Stem Cells/cytology/*transplantation ; Regenerative Medicine/*methods/*trends ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Stem cell therapy has been noted as a novel strategy to various diseases including neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and Huntington's disease that have no effective treatment available to date. The adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency with the ability to differentiate into various types of cells and immuno-modulatory property. These biological features make ASCs a promising source for regenerative cell therapy in neurological disorders. Here we discuss the recent progress of regenerative therapies in various neurological disorders utilizing ASCs.}, }
@article {pmid25408367, year = {2015}, author = {Floris, G and Borghero, G and Cannas, A and Di Stefano, F and Murru, MR and Corongiu, D and Cuccu, S and Tranquilli, S and Cherchi, MV and Serra, A and Loi, G and Marrosu, MG and Chiò, A and Marrosu, F}, title = {Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations.}, journal = {Journal of neurology}, volume = {262}, number = {2}, pages = {375-384}, pmid = {25408367}, issn = {1432-1459}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*genetics/*pathology ; DNA-Binding Proteins/*genetics ; Female ; Frontotemporal Dementia/*genetics/*pathology ; Humans ; Male ; Middle Aged ; *Mutation ; Pedigree ; Phenotype ; }, abstract = {It has been shown that different genes could be associated with distinctive clinical and radiological phenotypes of FTD. TARDBP gene has been described worldwide in few cases of FTD so its phenotype is still unclear. The objective is to study the clinical and radiological characteristics of TARDBP-related FTD. In the present study, we report clinical, neuropsychological and radiological features of five new Sardinian non-related cases of FTD carriers of the p.A382T TARDBP mutation. Furthermore, we reviewed non-related FTD cases with TARDBP mutations previously described in literature. The p.A382T missense mutation of TARDBP was present in the 21.7 % of familial cases of our FTD cohort (5/23) and in no one of the sporadic patients. 3 of 5 patients showed a temporal variant FTD and 4/5 a predominant temporal involvement at MRI. The review of the literature of FTD cases with TARDBP mutations showed that in 5 of 16 cases, the clinical phenotype was consistent with temporal variant of FTD or semantic dementia (31 %) and in 7 of 16 cases neuroimaging showed predominant temporal lobe involvement (43.7 %). Our study further supports the pathogenetic role of TARDBP mutations in pure FTD and in the full spectrum of FTD/ALS. The presence of a predominant temporal lobe involvement in a high percentage of FTD mutated patients with a peculiar clinical pattern could be useful in the differential diagnosis with other forms of dementia/FTD both sporadic and familial.}, }
@article {pmid25398223, year = {2015}, author = {Ientile, R and Currò, M and Caccamo, D}, title = {Transglutaminase 2 and neuroinflammation.}, journal = {Amino acids}, volume = {47}, number = {1}, pages = {19-26}, doi = {10.1007/s00726-014-1864-2}, pmid = {25398223}, issn = {1438-2199}, mesh = {Animals ; Astrocytes/enzymology/immunology ; GTP-Binding Proteins/genetics/*immunology ; Humans ; Microglia/enzymology/immunology ; NF-kappa B/genetics/metabolism ; Nervous System Diseases/*enzymology/genetics/*immunology ; Protein Glutamine gamma Glutamyltransferase 2 ; Transglutaminases/genetics/*immunology ; }, abstract = {Neuroinflammatory processes seem to play a pivotal role in various chronic neurodegenerative diseases, characterized also by the pathogenetic accumulation of specific protein aggregates. Several of these proteins have been shown to be substrates of transglutaminases, calcium-dependent enzymes that catalyze protein crosslinking reactions. However, it has recently been demonstrated that transglutaminase 2 (TG2) may also be involved in molecular mechanisms underlying inflammation. In the central nervous system, astrocytes and microglia are the cell types mainly involved in the inflammatory process. This review is focused on the increases of TG2 protein expression and enzyme activity that occur in astroglial, microglial and monocyte cell models in response to inflammatory stimuli. The transcription factor NF-κB is considered the main regulator of inflammation, being activated by a variety of stimuli including calcium influx, oxidative stress and inflammatory cytokines. Under these conditions, the over-expression of TG2 results in the sustained activation of NF-κB. Several findings emphasize the possible role of the TG2/NF-κB activation pathway in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Although further studies are needed to characterize the TG2/NF-κB cross-talk in monocytes/macrophages/microglia within the central nervous system, some results show that TG2 and NF-κB are co-localized in cell compartments. Together, evidence suggests that TG2 plays a role in neuroinflammation and contributes to the production of compounds that are potentially deleterious to neuronal cells.}, }
@article {pmid25385051, year = {2015}, author = {Creemers, H and Grupstra, H and Nollet, F and van den Berg, LH and Beelen, A}, title = {Prognostic factors for the course of functional status of patients with ALS: a systematic review.}, journal = {Journal of neurology}, volume = {262}, number = {6}, pages = {1407-1423}, pmid = {25385051}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Databases, Factual/statistics &amp; numerical data ; Disability Evaluation ; Humans ; Prognosis ; Severity of Illness Index ; }, abstract = {The progressive course of amyotrophic lateral sclerosis (ALS) results in an ever-changing spectrum of the care needs of patients with ALS. Knowledge of prognostic factors for the functional course of ALS may enhance clinical prediction and improve the timing of appropriate interventions. Our objective was to systematically review the evidence regarding prognostic factors for the rate of functional decline of patients with ALS, assessed with versions of the ALS Functional Rating Scale (ALSFRS). Two reviewers independently assessed the methodological quality of the thirteen included studies using the Quality in Prognosis Studies (QUIPS) tool. The overall quality of evidence for each prognostic factor was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, considering risk of bias, imprecision, inconsistency, indirectness, and publication bias. The quality of evidence for the prognostic value of age at onset, site of onset, time from symptom onset to diagnosis, and ALSFRS-Revised baseline score was low, mainly due to the limited data and inconsistency of results in the small number of studies included. The prognostic value of initial rate of disease progression, age at diagnosis, forced vital capacity, frontotemporal dementia, body mass index, and comorbidity remains unclear. We conclude that the current evidence on prognostic factors for functional decline in ALS is insufficient to allow the development of a prediction tool that can support clinical decisions. Given the limited data, future prognostic studies may need to focus on factors that have a predictive value for a decline in ALSFRS(-R) domain scores, preferably based on internationally collected and shared data.}, }
@article {pmid25378359, year = {2015}, author = {He, J and Mangelsdorf, M and Fan, D and Bartlett, P and Brown, MA}, title = {Amyotrophic Lateral Sclerosis Genetic Studies: From Genome-wide Association Mapping to Genome Sequencing.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {21}, number = {6}, pages = {599-615}, doi = {10.1177/1073858414555404}, pmid = {25378359}, issn = {1089-4098}, mesh = {Amyotrophic Lateral Sclerosis/ethnology/*genetics/metabolism ; Animals ; Genome-Wide Association Study/methods ; Humans ; Research Design ; Sequence Analysis/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of obscure etiology. Multiple genetic studies have been conducted to advance our understanding of the disease, employing a variety of techniques such as linkage mapping in families, to genome-wide association studies and sequencing based approaches such as whole exome sequencing and whole genome sequencing and a few epigenetic analyses. While major progress has been made, the majority of the genetic variation involved in ALS is yet to be undefined. The optimal study designs to investigate ALS depend on the genetic model for the disease, and it is likely that different approaches will be required to map genes involved in familial and sporadic disease. The potential approaches and their strengths and weaknesses are discussed.}, }
@article {pmid25378006, year = {2014}, author = {Lillo, P and Matamala, JM and Valenzuela, D and Verdugo, R and Castillo, JL and Ibáñez, A and Slachevsky, A}, title = {[Overlapping features of frontotemporal dementia and amyotrophic lateral sclerosis].}, journal = {Revista medica de Chile}, volume = {142}, number = {7}, pages = {867-879}, doi = {10.4067/S0034-98872014000700007}, pmid = {25378006}, issn = {0717-6163}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology/psychology ; DNA Repeat Expansion ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/diagnosis/genetics/pathology/psychology ; Genotype ; Humans ; Mutation ; }, abstract = {Recent genetic and neuropathologic advances support the concept that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are overlapping multisystem disorders. While 10-15% of ALS patients fulfil criteria for FTD, features of motor neuron disease appear in approximately 15% of FTD patients, during the evolution of the disease. This overlap has been reinforced by the discovery of Transactive Response DNA Binding Protein 43 kDa (TDP43) inclusions as the main neuropathologic finding in the majority of ALS cases and almost a half of FTD cases. Also, an expansion in the intron of C9ORF72 (chromosome 9p21) has been identified in families affected by ALS, ALS-FTD and FTD. This review provides an update on the recent genetic and neuropathologic findings of ALS and FTD and a characterization of their clinical presentation forms, based on the current diagnostic criteria. Finally it underscores the importance of having a national registry of patients with ALS and FTD, to provide an earlier diagnosis and a multidisciplinary care.}, }
@article {pmid25377282, year = {2015}, author = {Pfeffer, G and Povitz, M and Gibson, GJ and Chinnery, PF}, title = {Diagnosis of muscle diseases presenting with early respiratory failure.}, journal = {Journal of neurology}, volume = {262}, number = {5}, pages = {1101-1114}, pmid = {25377282}, issn = {1432-1459}, support = {101876//Wellcome Trust/United Kingdom ; MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_1501/2/MRC_/Medical Research Council/United Kingdom ; //Department of Health/United Kingdom ; //Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Humans ; Muscular Diseases/*complications/*diagnosis ; Respiratory Insufficiency/*etiology ; }, abstract = {Here we describe a clinical approach and differential diagnosis for chronic muscle diseases which include early respiratory failure as a prominent feature in their presentation (i.e. respiratory failure whilst still ambulant). These patients typically present to neurology or respiratory medicine out-patient clinics and a distinct differential diagnosis of neuromuscular aetiologies should be considered. Amyotrophic lateral sclerosis and myasthenia gravis are the important non-muscle diseases to consider, but once these have been excluded there remains a challenging differential diagnosis of muscle conditions, which will be the focus of this review. The key points in the diagnosis of these disorders are being aware of relevant symptoms, which are initially caused by nocturnal hypoventilation or diaphragmatic weakness; and identifying other features which direct further investigation. Important muscle diseases to identify, because their diagnosis has disease-specific management implications, include adult-onset Pompe disease, inflammatory myopathy, and sporadic adult-onset nemaline myopathy. Cases which are due to metabolic myopathy or muscular dystrophy are important to diagnose because of their implications for genetic counselling. Myopathy from sarcoidosis and colchicine each has a single reported case with this presentation, but should be considered because they are treatable. Disorders which have recently had their genetic aetiologies identified include hereditary myopathy with early respiratory failure (due to TTN mutations), the FHL1-related syndromes, and myofibrillar myopathy due to BAG3 mutation. Recently described syndromes include oculopharyngodistal muscular dystrophy that awaits genetic characterisation.}, }
@article {pmid25375229, year = {2014}, author = {Quartuccio, N and Van Weehaeghe, D and Cistaro, A and Jonsson, C and Van Laere, K and Pagani, M}, title = {Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new?.}, journal = {The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...}, volume = {58}, number = {4}, pages = {344-354}, pmid = {25375229}, issn = {1824-4785}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/*diagnostic imaging ; Artificial Intelligence ; Brain/diagnostic imaging ; Humans ; Inflammation ; Mutation ; Neuroimaging/*methods ; Positron-Emission Tomography/*methods ; Radioisotopes ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving upper and lower motor neurons, extra-motor neurons, microglia and astrocytes. The neurodegenerative process results in progressive muscle paralysis and even in cognitive impairment. Within the complex diagnostic work-up, positron emission tomography (PET) represents a valuable imaging tool in the assessment of patients with ALS. PET, by means of different radiotracers (i.e. 18F-fluorodeoxyglucose, 6-[18F]fluoro-L-dopa, [11C]flumazenil) can assess the status of the wide range of brain regions and neural circuits, which can be affected by ALS. Furthermore, experimental radiocompounds have been developed for the evaluation of white matter, which plays a role in the progression of the disease. Here we present a comprehensive review including in different sections the most relevant PET studies: studies investigating ALS and ALS-mimicking conditions (especially primary lateral sclerosis and other neurodegenerative diseases), articles selecting specific subsets of patients (with bulbar or spinal onset), studies investigating patients with familial type of ALS, studies evaluating the role of the white matter in ALS and papers evaluating the diagnostic sensitivity of PET in ALS patients.}, }
@article {pmid25372080, year = {2014}, author = {Buzhor, E and Leshansky, L and Blumenthal, J and Barash, H and Warshawsky, D and Mazor, Y and Shtrichman, R}, title = {Cell-based therapy approaches: the hope for incurable diseases.}, journal = {Regenerative medicine}, volume = {9}, number = {5}, pages = {649-672}, doi = {10.2217/rme.14.35}, pmid = {25372080}, issn = {1746-076X}, mesh = {Autoimmune Diseases/therapy ; Cell- and Tissue-Based Therapy/*trends ; Humans ; Kidney Diseases/therapy ; Liver Diseases/therapy ; Nervous System Diseases/therapy ; Osteoarthritis/therapy ; Regenerative Medicine/*trends ; Spinal Cord Injuries/therapy ; *Stem Cell Transplantation ; Vascular Diseases/therapy ; }, abstract = {Cell therapies aim to repair the mechanisms underlying disease initiation and progression, achieved through trophic effect or by cell replacement. Multiple cell types can be utilized in such therapies, including stem, progenitor or primary cells. This review covers the current state of cell therapies designed for the prominent disorders, including cardiovascular, neurological (Parkinson's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury), autoimmune (Type 1 diabetes, multiple sclerosis, Crohn's disease), ophthalmologic, renal, liver and skeletal (osteoarthritis) diseases. Various cell therapies have reached advanced clinical trial phases with potential marketing approvals in the near future, many of which are based on mesenchymal stem cells. Advances in pluripotent stem cell research hold great promise for regenerative medicine. The information presented in this review is based on the analysis of the cell therapy collection detailed in LifeMap Discovery(®) (LifeMap Sciences Inc., USA) the database of embryonic development, stem cell research and regenerative medicine.}, }
@article {pmid25372079, year = {2014}, author = {Allers, C and Jones, JA and Lasala, GP and Minguell, JJ}, title = {Mesenchymal stem cell therapy for the treatment of amyotrophic lateral sclerosis: signals for hope?.}, journal = {Regenerative medicine}, volume = {9}, number = {5}, pages = {637-647}, doi = {10.2217/rme.14.30}, pmid = {25372079}, issn = {1746-076X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cell Differentiation ; Cell- and Tissue-Based Therapy/*trends ; Clinical Trials as Topic ; Humans ; Mesenchymal Stem Cell Transplantation/*trends ; Mesenchymal Stem Cells/*cytology ; }, abstract = {Based on the distinctive cellular, molecular and immunomodulatory traits of mesenchymal stem cells (MSC), it has been postulated that these cells may play a critical role in regenerative medicine. In addition to the participation of MSC in the repair of mesodermal-derived tissues (bone, cartilage), robust data have suggested that MSC may also play a reparative role in conditions involving damage of cells of ectodermal origin. The above content has been supported by the capability of MSC to differentiate into neuron-like cells as well as by a competence to generate a 'neuroprotective' environment. In turn, several preclinical studies have put forward the concept that MSC therapy may represent an option for the treatment of several neurological disorders and injuries, including amyotrophic lateral sclerosis. We expect that the above foundations, which have inspired this review, may result in the founding of an effective and/or palliative therapy for amyotrophic lateral sclerosis.}, }
@article {pmid25367385, year = {2015}, author = {Damme, M and Suntio, T and Saftig, P and Eskelinen, EL}, title = {Autophagy in neuronal cells: general principles and physiological and pathological functions.}, journal = {Acta neuropathologica}, volume = {129}, number = {3}, pages = {337-362}, doi = {10.1007/s00401-014-1361-4}, pmid = {25367385}, issn = {1432-0533}, mesh = {Animals ; Autophagy/*physiology ; Humans ; Nervous System Diseases/*physiopathology ; Neurons/*metabolism ; }, abstract = {Autophagy delivers cytoplasmic components and organelles to lysosomes for degradation. This pathway serves to degrade nonfunctional or unnecessary organelles and aggregate-prone and oxidized proteins to produce substrates for energy production and biosynthesis. Macroautophagy delivers large aggregates and whole organelles to lysosomes by first enveloping them into autophagosomes that then fuse with lysosomes. Chaperone-mediated autophagy (CMA) degrades proteins containing the KFERQ-like motif in their amino acid sequence, by transporting them from the cytosol across the lysosomal membrane into the lysosomal lumen. Autophagy is especially important for the survival and homeostasis of postmitotic cells like neurons, because these cells are not able to dilute accumulating detrimental substances and damaged organelles by cell division. Our current knowledge on the autophagic pathways and molecular mechanisms and regulation of autophagy will be summarized in this review. We will describe the physiological functions of macroautophagy and CMA in neuronal cells. Finally, we will summarize the current evidence showing that dysfunction of macroautophagy and/or CMA contributes to neuronal diseases. We will give an overview of our current knowledge on the role of autophagy in aging neurons, and focus on the role of autophagy in four types of neurodegenerative diseases, i.e., amyotrophic lateral sclerosis and frontotemporal dementia, prion diseases, lysosomal storage diseases, and Parkinson's disease.}, }
@article {pmid25365170, year = {2015}, author = {Beard, JD and Kamel, F}, title = {Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival.}, journal = {Epidemiologic reviews}, volume = {37}, number = {1}, pages = {55-70}, pmid = {25365170}, issn = {1478-6729}, support = {T32 ES007018/ES/NIEHS NIH HHS/United States ; Z01 ES049005//Intramural NIH HHS/United States ; T32ES007018/ES/NIEHS NIH HHS/United States ; T42OH00867302/OH/NIOSH CDC HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/*mortality ; Europe/epidemiology ; Humans ; Incidence ; Military Personnel/*statistics &amp; numerical data ; Occupational Exposure/*adverse effects ; Risk Factors ; United States/epidemiology ; }, abstract = {Rates of amyotrophic lateral sclerosis (ALS) have been reported to be higher among US military veterans, who currently number more than 21 million, but the causal factor(s) has not been identified. We conducted a review to examine the weight of evidence for associations between military service, deployments, and exposures and ALS etiology and survival. Thirty articles or abstracts published through 2013 were reviewed. Although the current evidence suggests a positive association with ALS etiology, it is too limited to draw firm conclusions regarding associations between military service and ALS etiology or survival. Some evidence suggests that deployment to the 1990-1991 Persian Gulf War may be associated with ALS etiology, but there is currently no strong evidence that any particular military exposure is associated with ALS etiology. Future studies should address the limitations of previous ones, such as reliance on mortality as a surrogate for incidence, a dearth of survival analyses, lack of clinical data, low statistical power, and limited exposure assessment. The Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis (GENEVA) Study is one such study, but additional research is needed to determine whether military-related factors are associated with ALS and to assess potential prevention strategies.}, }
@article {pmid25364724, year = {2014}, author = {Adami, R and Scesa, G and Bottai, D}, title = {Stem cell transplantation in neurological diseases: improving effectiveness in animal models.}, journal = {Frontiers in cell and developmental biology}, volume = {2}, number = {}, pages = {17}, pmid = {25364724}, issn = {2296-634X}, abstract = {Neurological diseases afflict a growing proportion of the human population. There are two reasons for this: first, the average age of the population (especially in the industrialized world) is increasing, and second, the diagnostic tools to detect these pathologies are now more sophisticated and can be used on a higher percentage of the population. In many cases, neurological disease has a pharmacological treatment which, as in the case of Alzheimer's disease, Parkinson's disease, Epilepsy, and Multiple Sclerosis can reduce the symptoms and slow down the course of the disease but cannot reverse its effects or heal the patient. In the last two decades the transplantation approach, by means of stem cells of different origin, has been suggested for the treatment of neurological diseases. The choice of slightly different animal models and the differences in methods of stem cell preparation make it difficult to compare the results of transplantation experiments. Moreover, the translation of these results into clinical trials with human subjects is difficult and has so far met with little success. This review seeks to discuss the reasons for these difficulties by considering the differences between human and animal cells (including isolation, handling and transplantation) and between the human disease model and the animal disease model.}, }
@article {pmid25353674, year = {2014}, author = {Lindquist, SG and Dunø, M and Svenstrup, K and Nielsen, JE}, title = {[Genetic counselling is relevant in familial as well as sporadic cases of amyotrophic lateral sclerosis].}, journal = {Ugeskrift for laeger}, volume = {176}, number = {43}, pages = {}, pmid = {25353674}, issn = {1603-6824}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*genetics ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; *Genetic Counseling ; Genetic Testing ; Humans ; Mutation ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease of upper and lower motor neurons which often results in death from respiratory failure within 2-4 years. It has been estimated that 5-10% of ALS patients have a family history with ALS. The genetic background of the disorder is heterogeneous, and recently molecular genetic testing has become increasingly relevant, also in the clinical evaluation. As several genes have been identified in which the pathogenic mutations are characterized by reduced age-dependent penetrance, genetic testing can be relevant to consider, also in isolated cases.}, }
@article {pmid25344935, year = {2015}, author = {Malaspina, A and Puentes, F and Amor, S}, title = {Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective.}, journal = {International immunology}, volume = {27}, number = {3}, pages = {117-129}, doi = {10.1093/intimm/dxu099}, pmid = {25344935}, issn = {1460-2377}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/therapy ; Animals ; Astrocytes/*physiology ; Disease Models, Animal ; Disease Progression ; Humans ; Immunity, Innate ; Microglia/*physiology ; Molecular Targeted Therapy ; Motor Neurons/*metabolism/pathology ; Neurogenic Inflammation/*immunology/therapy ; Neuromuscular Junction/immunology ; }, abstract = {The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS, there is a dynamic interplay between the resident innate immune cells, that is, microglia and astrocytes, which may become progressively harmful to motor neurons. Although innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, although auto-antibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the auto-antibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focusing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression.}, }
@article {pmid25339865, year = {2014}, author = {Stankiewicz, TR and Linseman, DA}, title = {Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {314}, pmid = {25339865}, issn = {1662-5102}, abstract = {The Rho family of GTPases belongs to the Ras superfamily of low molecular weight (∼21 kDa) guanine nucleotide binding proteins. The most extensively studied members are RhoA, Rac1, and Cdc42. In the last few decades, studies have demonstrated that Rho family GTPases are important regulatory molecules that link surface receptors to the organization of the actin and microtubule cytoskeletons. Indeed, Rho GTPases mediate many diverse critical cellular processes, such as gene transcription, cell-cell adhesion, and cell cycle progression. However, Rho GTPases also play an essential role in regulating neuronal morphology. In particular, Rho GTPases regulate dendritic arborization, spine morphogenesis, growth cone development, and axon guidance. In addition, more recent efforts have underscored an important function for Rho GTPases in regulating neuronal survival and death. Interestingly, Rho GTPases can exert either a pro-survival or pro-death signal in neurons depending upon both the cell type and neurotoxic insult involved. This review summarizes key findings delineating the involvement of Rho GTPases and their effectors in the regulation of neuronal survival and death. Collectively, these results suggest that dysregulation of Rho family GTPases may potentially underscore the etiology of some forms of neurodegenerative disease such as amyotrophic lateral sclerosis.}, }
@article {pmid25333604, year = {2014}, author = {Sedda, A}, title = {Disorders of emotional processing in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {27}, number = {6}, pages = {659-665}, doi = {10.1097/WCO.0000000000000147}, pmid = {25333604}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*complications/pathology ; Brain/physiopathology ; Humans ; Mood Disorders/*etiology ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a degenerative brain disease characterized by motor, behavioural and cognitive deficits. Only recently, emotional processing disorders have been shown in this disease. The interest in affective processing in ALS is growing given that basic emotion impairments could impact copying strategies and mood.<br><br>RECENT FINDINGS: Studies explore both basic emotion recognition and social cognition. Results are congruent on arousal and valence detection impairments, independently from the stimulus modality (verbal or visual). Further, recognition of facial expressions of anger, sadness and disgust is impaired in ALS, even when cognition is preserved. Clinical features such as type of onset and severity of the disease could be the cause of the heterogeneity in emotional deficits profiles between patients. Finally, a study employing diffusion tensor imaging showed that emotional dysfunctions in ALS are related to right hemispheric connective bundles impairments, involving the inferior longitudinal fasciculus and the inferior frontal occipital fasciculus.<br><br>SUMMARY: Research on emotional processing in ALS is still in its infancy and results are mixed. Future research including more detailed clinical profiles of patients and measures of brain connectivity will provide useful information to understand heterogeneity of results in ALS.}, }
@article {pmid25331742, year = {2014}, author = {Tsai, SY and Pokrass, MJ and Klauer, NR and De Credico, NE and Su, TP}, title = {Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders.}, journal = {Expert opinion on therapeutic targets}, volume = {18}, number = {12}, pages = {1461-1476}, pmid = {25331742}, issn = {1744-7631}, support = {Z01 DA000206-22//Intramural NIH HHS/United States ; Z01 DA000206-23//Intramural NIH HHS/United States ; Z99 DA999999//Intramural NIH HHS/United States ; }, mesh = {Animals ; Drug Delivery Systems/*methods ; Humans ; Mental Disorders/drug therapy/*metabolism ; Molecular Chaperones/antagonists &amp; inhibitors/*biosynthesis ; Narcotic Antagonists/administration &amp; dosage ; Neurodegenerative Diseases/drug therapy/*metabolism ; Receptors, sigma/antagonists &amp; inhibitors/*biosynthesis ; Sigma-1 Receptor ; }, abstract = {INTRODUCTION: Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases.<br><br>AREAS COVERED: This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders.<br><br>EXPERT OPINION: Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders.}, }
@article {pmid25319671, year = {2015}, author = {Walsh, MJ and Cooper-Knock, J and Dodd, JE and Stopford, MJ and Mihaylov, SR and Kirby, J and Shaw, PJ and Hautbergue, GM}, title = {Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art.}, journal = {Neuropathology and applied neurobiology}, volume = {41}, number = {2}, pages = {109-134}, pmid = {25319671}, issn = {1365-2990}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; MR/K003771/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*genetics ; RNA/*genetics ; }, abstract = {Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and noncoding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may coexist within a single neuronal cell, including RNA/protein toxic gain-of-function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins - and how these lead to neurodegeneration - remain unknown. The field of RNA biology research faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterization of pathological mechanisms that trigger disease onset and progression.}, }
@article {pmid25316630, year = {2015}, author = {Marangi, G and Traynor, BJ}, title = {Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {75-93}, pmid = {25316630}, issn = {1872-6240}, support = {ZIA AG000933-03//Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genetic Predisposition to Disease ; Genetic Techniques ; Humans ; Mutation ; }, abstract = {The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25316381, year = {2015}, author = {Hu, Z and Yang, B and Mo, X and Xiao, H}, title = {Mechanism and Regulation of Autophagy and Its Role in Neuronal Diseases.}, journal = {Molecular neurobiology}, volume = {52}, number = {3}, pages = {1190-1209}, pmid = {25316381}, issn = {1559-1182}, mesh = {Animals ; Autophagy/*physiology ; Brain Ischemia/metabolism/pathology/*physiopathology ; Disease Models, Animal ; Humans ; Intracellular Membranes/metabolism ; Lysosomes/physiology ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Mice ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/metabolism/pathology/*physiopathology ; Neurons/metabolism ; Phagosomes/physiology/ultrastructure ; Proteasome Endopeptidase Complex/metabolism ; Protein Processing, Post-Translational ; TOR Serine-Threonine Kinases/metabolism ; Ubiquitination ; ras Proteins/metabolism ; }, abstract = {Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Neuronal survival is highly dependent on autophagy due to its post-mitotic nature, polarized morphology, and active protein trafficking. Autophagic dysfunction has been linked to several neuronal diseases. Our understanding is still incomplete but may highlight up-to-date findings on how autophagy is executed and regulated at the molecular level and its role in neurodegenerative diseases (including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS)), brain ischemia, and myelin diseases, hence providing attractive new avenues for the development of treatment strategies to combat neuronal diseases.}, }
@article {pmid25316019, year = {2014}, author = {Mitsumoto, H and Brooks, BR and Silani, V}, title = {Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?.}, journal = {The Lancet. Neurology}, volume = {13}, number = {11}, pages = {1127-1138}, doi = {10.1016/S1474-4422(14)70129-2}, pmid = {25316019}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic/*standards/trends ; Riluzole/*therapeutic use ; Stem Cell Transplantation/*standards/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most rapidly progressive neurodegenerative diseases of unknown cause. Riluzole is the only drug that slows disease progression. More than 50 randomised controlled trials (RCTs) of proposed disease-modifying drugs have failed to show positive results in the past half-century. In the past decade, at least 18 drugs have been tested in large phase 2 or 3 RCTs, including lithium, which was tested in several RCTs. Potential reasons for the negative results can be classified into three categories: first, issues regarding trial rationale and preclinical study results; second, pharmacological issues; and third, clinical trial design and methodology issues. Clinical trials for stem cell therapy and RCTs targeting pharmacological or non-pharmacological symptomatic treatment in ALS are examples of areas that need novel design strategies. Only through critical analyses of the failed trials can new and important suggestions be identified for the future success of clinical trials in ALS.}, }
@article {pmid25312503, year = {2014}, author = {Soni, N and Reddy, BV and Kumar, P}, title = {GLT-1 transporter: an effective pharmacological target for various neurological disorders.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {127}, number = {}, pages = {70-81}, doi = {10.1016/j.pbb.2014.10.001}, pmid = {25312503}, issn = {1873-5177}, mesh = {Animals ; Drug Delivery Systems/*methods ; Excitatory Amino Acid Agonists/administration &amp; dosage ; Excitatory Amino Acid Antagonists/administration &amp; dosage ; Excitatory Amino Acid Transporter 2 ; Glutamate Plasma Membrane Transport Proteins/agonists/antagonists &amp; inhibitors/*metabolism ; Glutamic Acid/metabolism ; Humans ; Nervous System Diseases/*drug therapy/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {L-Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS) and is directly and indirectly involved in a variety of brain functions. Glutamate is released in the synaptic cleft at a particular concentration that further activates the various glutaminergic receptors. This concentration of glutamate in the synapse is maintained by either glutamine synthetase or excitatory amino acid proteins which reuptake the excessive glutamate from the synapse and named as excitatory amino acid transporters (EAATs). Out of all the subtypes GLT-1 (glutamate transporter 1) is abundantly distributed in the CNS. Down-regulation of GLT-1 is reported in various neurological diseases such as, epilepsy, stroke, Alzheimer's disease and movement disorders. Therefore, positive modulators of GLT-1 which up-regulate the GLT-1 expression can serve as a potential target for the treatment of neurological disorders. GLT-1 translational activators such as ceftriaxone are found to have significant protective effects in ALS and epilepsy animal models, suggesting that this translational activation approach works well in rodents and that these compounds are worth further pursuit for various neurological disorders. This drug is currently in human clinical trials for ALS. In addition, a thorough understanding of the mechanisms underlying translational regulation of GLT-1, such as identifying the molecular targets of the compounds, signaling pathways involved in the regulation, and translational activation processes, is very important for this novel drug-development effort. This review mainly emphasizes the role of glutamate and its transporter, GLT-1 subtype in excitotoxicity. Further, recent reports on GLT-1 transporters for the treatment of various neurological diseases, including a summary of the presumed physiologic mechanisms behind the pharmacology of these disorders are also explained.}, }
@article {pmid25311585, year = {2014}, author = {Swinnen, B and Robberecht, W}, title = {The phenotypic variability of amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {10}, number = {11}, pages = {661-670}, pmid = {25311585}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics/*physiopathology ; Disease Progression ; Frontotemporal Dementia/complications/genetics/*physiopathology ; Frontotemporal Lobar Degeneration/complications/genetics/physiopathology ; Humans ; Phenotype ; }, abstract = {Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset--a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.}, }
@article {pmid25309711, year = {2014}, author = {Leite, MA and Orsini, M and de Freitas, MR and Pereira, JS and Gobbi, FH and Bastos, VH and de Castro Machado, D and Machado, S and Arrias-Carrion, O and de Souza, JA and Oliveira, AB}, title = {Another Perspective on Fasciculations: When is it not Caused by the Classic form of Amyotrophic Lateral Sclerosis or Progressive Spinal Atrophy?.}, journal = {Neurology international}, volume = {6}, number = {3}, pages = {5208}, pmid = {25309711}, issn = {2035-8385}, abstract = {Fasciculations are visible, fine and fast, sometimes vermicular contractions of fine muscle fibers that occur spontaneously and intermittently. The aim of this article is to discuss the main causes for fasciculations and their pathophysiology in different sites of the central/peripheral injury and in particular to disprove that the presence of this finding in the neurological examination is indicative of amyotrophic lateral sclerosis. Undoubtedly, most fasciculations have a distal origin in the motor nerve both in normal subjects and in patients with motor neuron disease. Most of them spread to other dendritic spines often producing an antidromic impulse in the main axon. The clinical and neurophysiological diagnosis must be thorough. It may often take long to record fasciculations with electroneuromyography. In other cases, temporal monitoring is necessary before the diagnosis. The treatment, which may be adequate in some cases, is not always necessary.}, }
@article {pmid25309324, year = {2014}, author = {Droppelmann, CA and Campos-Melo, D and Volkening, K and Strong, MJ}, title = {The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {282}, pmid = {25309324}, issn = {1662-5102}, abstract = {Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl-related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3' untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.}, }
@article {pmid25301687, year = {2015}, author = {Palomo, GM and Manfredi, G}, title = {Exploring new pathways of neurodegeneration in ALS: the role of mitochondria quality control.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {36-46}, pmid = {25301687}, issn = {1872-6240}, support = {R01 NS051419/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; NS051419/NS/NINDS NIH HHS/United States ; NS062055/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Animals ; Humans ; Mitochondria/*metabolism ; Mitophagy/physiology ; Nerve Degeneration/metabolism ; }, abstract = {Neuronal cells are highly dependent on mitochondria, and mitochondrial dysfunction is associated with neurodegenerative diseases. As perturbed mitochondrial function renders neurons extremely sensitive to a wide variety of insults, such as oxidative stress and bioenergetic defects, mitochondrial defects can profoundly affect neuronal fate. Several studies have linked ALS with mitochondrial dysfunction, stemming from observations of mitochondrial abnormalities, both in patients and in cellular and mouse models of familial forms of ALS. Mitochondrial changes have been thoroughly investigated in mutants of superoxide dismutase 1 (SOD1), one of the most common causes of familial ALS, for which excellent cellular and animal models are available, but recently evidence is emerging also in other forms of ALS, both familial and sporadic. Mitochondrial defects in ALS involve many critical physiopathological processes, from defective bioenergetics to abnormal calcium homeostasis, altered morphology and impaired trafficking. In this review, we summarize established evidence of mitochondrial dysfunction in ALS, especially in SOD1 mutant models of familial ALS. The main focus of the review is on defective mitochondrial quality control (MQC) in ALS. MQC operates at multiple levels to clear damaged proteins through proteostasis and to eliminate irreparably damaged organelles through mitophagy. However, since ALS motor neurons progressively accumulate damaged mitochondria, it is plausible that the MQC is ineffective or overwhelmed by excessive workload imposed by the chronic and extensive mitochondrial damage. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25301263, year = {2015}, author = {Lee, YH and Kim, JH and Seo, YH and Choi, SJ and Ji, JD and Song, GG}, title = {Paraoxonase 1 Q192R and L55M polymorphisms and susceptibility to amyotrophic lateral sclerosis: a meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {36}, number = {1}, pages = {11-20}, pmid = {25301263}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Aryldialkylphosphatase/*genetics ; Asian People/genetics ; *Genetic Predisposition to Disease ; Humans ; *Polymorphism, Genetic ; White People/genetics ; }, abstract = {This study aimed to investigate whether paraoxonase 1 (PON1) Q192R and L55M polymorphisms are associated with susceptibility to amyotrophic lateral sclerosis (ALS). We conducted a meta-analysis of the associations between the PON1 Q192R and L55M polymorphisms and ALS. A total of 2,831 patients and 3,123 controls from eight studies of the PON1 Q192R polymorphism and seven studies of the PON1 L55M T polymorphism were considered for this study. Meta-analysis showed no association between ALS and the PON1 192R allele (OR = 1.052, 95 % CI = 0.923-1.207, p = 0.447), and the PON1 55M allele (OR = 1.015, 95 % CI = 0.884-1.164, p = 0.837) in all study subjects. Similarly, no association was found between ALS and the PON1 Q192R and L55M polymorphisms using recessive, dominant or homozygote contrast models. Stratification by ethnicity indicated no association between ALS and the PON1 192R allele (OR = 1.058, 95 % CI = 0.910-1.231, p = 0.464) and the PON1 55M allele (OR = 1.027, 95 % CI = 0.889-1.185, p = 0.721) in the European population. This meta-analysis showed lack of associations between PON1 Q192R and L55M polymorphisms and susceptibility to ALS in the European population.}, }
@article {pmid25299277, year = {2014}, author = {Tiryaki, E and Horak, HA}, title = {ALS and other motor neuron diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {20}, number = {5 Peripheral Nervous System Disorders}, pages = {1185-1207}, doi = {10.1212/01.CON.0000455886.14298.a4}, pmid = {25299277}, issn = {1538-6899}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*physiopathology ; Humans ; Motor Neuron Disease/*diagnosis/genetics/*physiopathology ; }, abstract = {PURPOSE OF REVIEW: This review describes the most common motor neuron disease, ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its pathophysiology, including new genetic underpinnings of the disease. This article also covers other motor neuron diseases, reviews how to distinguish them from ALS, and discusses their pathophysiology.<br><br>RECENT FINDINGS: In this article, the spectrum of cognitive involvement in ALS, new concepts about protein synthesis pathology in the etiology of ALS, and new genetic associations will be covered. This concept has changed over the past 3 to 4 years with the discovery of new genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS.<br><br>SUMMARY: The anterior horn cells control all voluntary movement: motor activity, respiratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron disease, demonstrates the impact of this class of disorders. ALS and other motor neuron diseases can represent diagnostic challenges. Neurologists are often called upon to serve as a "medical home" for these patients: coordinating care, arranging for durable medical equipment, and leading discussions about end-of-life care with patients and caregivers. It is important for neurologists to be able to identify motor neuron diseases and to evaluate and treat patients affected by them.}, }
@article {pmid25295627, year = {2014}, author = {Bucci, C and Alifano, P and Cogli, L}, title = {The role of rab proteins in neuronal cells and in the trafficking of neurotrophin receptors.}, journal = {Membranes}, volume = {4}, number = {4}, pages = {642-677}, pmid = {25295627}, issn = {2077-0375}, abstract = {Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways.}, }
@article {pmid25294995, year = {2014}, author = {de Carvalho, M and Eisen, A and Krieger, C and Swash, M}, title = {Motoneuron firing in amyotrophic lateral sclerosis (ALS).}, journal = {Frontiers in human neuroscience}, volume = {8}, number = {}, pages = {719}, pmid = {25294995}, issn = {1662-5161}, abstract = {Amyotrophic lateral sclerosis is an inexorably progressive neurodegenerative disorder involving the classical motor system and the frontal effector brain, causing muscular weakness and atrophy, with variable upper motor neuron signs and often an associated fronto-temporal dementia. The physiological disturbance consequent on the motor system degeneration is beginning to be well understood. In this review we describe aspects of the motor cortical, neuronal, and lower motor neuron dysfunction. We show how studies of the changes in the pattern of motor unit firing help delineate the underlying pathophysiological disturbance as the disease progresses. Such studies are beginning to illuminate the underlying disordered pathophysiological processes in the disease, and are important in designing new approaches to therapy and especially for clinical trials.}, }
@article {pmid25289647, year = {2014}, author = {Sama, RR and Ward, CL and Bosco, DA}, title = {Functions of FUS/TLS from DNA repair to stress response: implications for ALS.}, journal = {ASN neuro}, volume = {6}, number = {4}, pages = {}, pmid = {25289647}, issn = {1759-0914}, support = {R01 NS078145/NS/NINDS NIH HHS/United States ; R01NS067206/NS/NINDS NIH HHS/United States ; R01NS078145/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; DNA Repair/*physiology ; Humans ; RNA Processing, Post-Transcriptional ; RNA-Binding Protein FUS/*physiology ; Stress, Physiological/*physiology ; }, abstract = {Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional DNA-/RNA-binding protein that is involved in a variety of cellular functions including transcription, protein translation, RNA splicing, and transport. FUS was initially identified as a fusion oncoprotein, and thus, the early literature focused on the role of FUS in cancer. With the recent discoveries revealing the role of FUS in neurodegenerative diseases, namely amyotrophic lateral sclerosis and frontotemporal lobar degeneration, there has been a renewed interest in elucidating the normal functions of FUS. It is not clear which, if any, endogenous functions of FUS are involved in disease pathogenesis. Here, we review what is currently known regarding the normal functions of FUS with an emphasis on DNA damage repair, RNA processing, and cellular stress response. Further, we discuss how ALS-causing mutations can potentially alter the role of FUS in these pathways, thereby contributing to disease pathogenesis.}, }
@article {pmid25289585, year = {2015}, author = {Casci, I and Pandey, UB}, title = {A fruitful endeavor: modeling ALS in the fruit fly.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {47-74}, pmid = {25289585}, issn = {1872-6240}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; R01-NS081303/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Animals, Genetically Modified ; *Disease Models, Animal ; Drosophila melanogaster/genetics/*physiology ; Humans ; }, abstract = {For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25288265, year = {2015}, author = {Turner, MR and Benatar, M}, title = {Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {51}, number = {1}, pages = {14-18}, pmid = {25288265}, issn = {1097-4598}, support = {MR/K000780/1/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Biomarkers/*metabolism ; Humans ; }, abstract = {Multiple candidate biomarkers for amyotrophic lateral sclerosis (ALS) have emerged across a range of platforms. Replication of results, however, has been absent in all but a few cases, and the range of control samples has been limited. If progress toward clinical translation is to continue, the specific biomarker needs of ALS, which differ from those of other neurodegenerative disorders, as well as the challenges inherent to longitudinal ALS biomarker cohorts, must be understood. Appropriate application of multimodal approaches, international collaboration, presymptomatic studies, and biomarker integration into future therapeutic trials are among the essential priorities going forward.}, }
@article {pmid25285651, year = {2015}, author = {Corcia, P and Gordon, PH and Camdessanche, JP}, title = {Is there a paraneoplastic ALS?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {3-4}, pages = {252-257}, doi = {10.3109/21678421.2014.965178}, pmid = {25285651}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*etiology ; Antibodies/metabolism ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/physiopathology ; Nerve Tissue Proteins/immunology/metabolism ; Paraneoplastic Syndromes/*complications/diagnosis ; }, abstract = {Our objective was to examine the strength of evidence in support of the paraneoplastic syndrome (PNS) as one cause of ALS and, if the association appears more likely than chance, determine which features of ALS imply concurrent malignancy. We reviewed the literature on concurrent ALS and neoplasia assessing the strength of evidence for the association. Most accounts of ALS and neoplasm are case reports or small uncontrolled series. In order of strength of evidence, three clinical situations that support a paraneoplastic aetiology for ALS are: 1) laboratory evidence of well-characterized onconeuronal antibodies, most often anti-Hu, anti-Yo or anti-Ri; 2) co-occurrence of ALS and a neoplasm known to cause PNS, usually lymphoma or cancer of the breast; and 3) combined ALS and a neoplasm not classically associated with PNS, without detectable onconeuronal antibodies. Clinical features that warrant evaluation of neoplasm include upper motor neuron disease in elderly females, rapid progression, non-motor signs, and young onset. In conclusion, most examples of ALS and neoplasm do not constitute a classically established PNS. Rare instances of elevated onconeuronal antibody titres or typical neoplasm, implies that, albeit rare, the PNS is one of a multitude of causes of ALS.}, }
@article {pmid25281879, year = {2015}, author = {Lue, LF and Schmitz, C and Walker, DG}, title = {What happens to microglial TREM2 in Alzheimer's disease: Immunoregulatory turned into immunopathogenic?.}, journal = {Neuroscience}, volume = {302}, number = {}, pages = {138-150}, doi = {10.1016/j.neuroscience.2014.09.050}, pmid = {25281879}, issn = {1873-7544}, support = {P30AG19610/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*genetics/*pathology ; Gene Expression Regulation/physiology ; Humans ; Membrane Glycoproteins/*genetics ; Microglia/metabolism/pathology ; Mutation/*genetics ; Receptors, Immunologic/*genetics ; }, abstract = {Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. Under normal conditions, triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the second category. It pairs with the adaptor protein DNAX-activating protein of 12kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation. Although ligands for TREM2 are largely unknown, the mitochondrial heat shock protein 60, expressed on cell surface of apoptotic neurons, is a specific ligand that activates TREM2-mediated phagocytosis by microglia. TREM2 also phagocytoses amyloid beta peptide in cultured cells. Several TREM2 mutations have been identified recently that increase the risk of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Some of these mutations cause impaired proteolysis of full-length TREM2 at the plasma membrane to different degrees. The defects in the intramembrane cleavage result in dysfunction of phagocytosis signaling. The association of TREM2 mutations with neurodegenerative disease also calls for the understanding of the biology and pathological role of non-mutated TREM2 on human brains and microglia. This review provides a summary of current literature in TREM2 and DAP12 from several aspects, and proposes a theory that loss of TREM2 functions might contribute to the immunopathogenic role of microglia in Alzheimer's disease.}, }
@article {pmid25280871, year = {2015}, author = {Yang, Y and Jiang, S and Yan, J and Li, Y and Xin, Z and Lin, Y and Qu, Y}, title = {An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders.}, journal = {Cytokine &amp; growth factor reviews}, volume = {26}, number = {1}, pages = {47-57}, doi = {10.1016/j.cytogfr.2014.09.002}, pmid = {25280871}, issn = {1879-0305}, mesh = {Alzheimer Disease/genetics/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Animals ; Brain/physiology ; Humans ; Huntington Disease/genetics/physiopathology ; Mice ; Multiple Sclerosis/genetics/physiopathology ; NF-E2-Related Factor 2/genetics/*metabolism ; Neurodegenerative Diseases/genetics/*physiopathology ; Parkinson Disease/genetics/physiopathology ; *Signal Transduction ; }, abstract = {Recently, growing evidence has demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of endogenous defense systems that function via the activation of a set of protective genes, and this is particularly clear in the central nervous system (CNS). Therefore, it is highly useful to summarize the current literature on the molecular mechanisms and role of Nrf2 in the CNS. In this review, we first briefly introduce the molecular features of Nrf2. We then discuss the regulation, cerebral actions, upstream modulators and downstream targets of Nrf2 pathway. Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Lastly, we discuss some potential future directions. The information reviewed here may be significant in the design of further experimental research and increase the potential of Nrf2 as a therapeutic target in the future.}, }
@article {pmid25275705, year = {2014}, author = {Kaku, M and Simpson, DM}, title = {HIV neuropathy.}, journal = {Current opinion in HIV and AIDS}, volume = {9}, number = {6}, pages = {521-526}, doi = {10.1097/COH.0000000000000103}, pmid = {25275705}, issn = {1746-6318}, mesh = {Antiretroviral Therapy, Highly Active ; HIV Infections/drug therapy/*pathology ; Humans ; Peripheral Nervous System Diseases/*virology ; }, abstract = {PURPOSE OF REVIEW: To present an overview of HIV-associated distal symmetric polyneuropathy (HIV-DSP) and other HIV-related peripheral neuropathies in the post-highly active retroviral therapy era.<br><br>RECENT FINDINGS: HIV-DSP has become the most common neurologic complication of HIV largely due to the prolonged survival of HIV-positive patients with the advent of highly active retroviral therapy. HIV-DSP can be attributed to the disease itself or to secondary effects of certain HAART agents, and often the two disease entities cannot be distinguished. HIV-DSP can lead to significant morbidity and interfere with daily activities. Diagnosis can be obtained from a detailed history and neurologic exam revealing absent ankle jerks and abnormal, vibratory perception or decreased pinprick or temperature. Supporting studies include nerve conduction studies and skin biopsy. Although there are no United States Food and Drug Administration-approved treatments for HIV-DSP, clinicians often use off-label medications, including antidepressants, anticonvulsants, topical agents and other analgesics.<br><br>SUMMARY: The prevalence of those affected by HIV-DSP will continue to grow with the aging population of HIV-infected individuals. Compared to the diabetic neuropathy drug trials, trials in both symptomatic and disease-modifying agents for HIV-DSP have had little success. Other forms of HIV-related peripheral neuropathies are discussed briefly, and include acute and chronic inflammatory demyelinating polyneuropathy, autonomic neuropathy, polyradiculopathy, mononeuropathies, mononeuritis multiplex, cranial neuropathies, and amyotrophic lateral sclerosis-like motor neuropathy.}, }
@article {pmid25261695, year = {2015}, author = {Mendez, EF and Sattler, R}, title = {Biomarker development for C9orf72 repeat expansion in ALS.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {26-35}, doi = {10.1016/j.brainres.2014.09.041}, pmid = {25261695}, issn = {1872-6240}, support = {R01 NS085207/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Biomarkers/blood/cerebrospinal fluid ; C9orf72 Protein ; *DNA Repeat Expansion ; Epigenesis, Genetic ; Humans ; Proteins/*genetics/*metabolism ; }, abstract = {The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene on chromosome 9p21 has been discovered as the cause of approximately 20-50% of familial and up to 5-20% of sporadic amyotrophic lateral sclerosis (ALS) cases, making this the most common known genetic mutation of ALS to date. At the same time, it represents the most common genetic mutation in frontotemporal dementia (FTD; 10-30%). Because of the high prevalence of mutant C9orf72, pre-clinical efforts in identifying therapeutic targets and developing novel therapeutics for this mutation are highly pursued in the hope of providing a desperately needed disease-modifying treatment for ALS patients, as well as other patient populations affected by the C9orf72 mutation. The current lack of effective treatments for ALS is partially due to the lack of appropriate biomarkers that aide in assessing drug efficacy during clinical trials independent of clinical outcome measures, such as increased survival. In this review we will summarize the opportunities for biomarker development specifically targeted to the newly discovered C9orf72 repeat expansion. While drugs are being developed for this mutation, it will be crucial to provide a reliable biomarker to accompany the clinical development of these novel therapeutic interventions to maximize the chances of a successful clinical trial. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25261035, year = {2014}, author = {Nguyen, L and Kaushal, N and Robson, MJ and Matsumoto, RR}, title = {Sigma receptors as potential therapeutic targets for neuroprotection.}, journal = {European journal of pharmacology}, volume = {743}, number = {}, pages = {42-47}, pmid = {25261035}, issn = {1879-0712}, support = {R01 DA023205/DA/NIDA NIH HHS/United States ; T32 NS007491/NS/NINDS NIH HHS/United States ; R01DA023205/DA/NIDA NIH HHS/United States ; R01DA011979/DA/NIDA NIH HHS/United States ; T32NS007491/NS/NINDS NIH HHS/United States ; R01 DA013978/DA/NIDA NIH HHS/United States ; R01 DA011979/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Ligands ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*pharmacology/*therapeutic use ; Receptors, sigma/*metabolism ; }, abstract = {Sigma receptors comprise a unique family of proteins that have been implicated in the pathophysiology and treatment of many central nervous system disorders, consistent with their high level of expression in the brain and spinal cord. Mounting evidence indicate that targeting sigma receptors may be particularly beneficial in a number of neurodegenerative conditions including Alzheimer׳s disease, Parkinson׳s disease, stroke, methamphetamine neurotoxicity, Huntington׳s disease, amyotrophic lateral sclerosis, and retinal degeneration. In this perspective, a brief overview is given on sigma receptors, followed by a focus on common mechanisms of neurodegeneration that appear amenable to modulation by sigma receptor ligands to convey neuroprotective effects and/or restorative functions. Within each of the major mechanisms discussed herein, the neuroprotective effects of sigma ligands are summarized, and when known, the specific sigma receptor subtype(s) involved are identified. Together, the literature suggests sigma receptors may provide a novel target for combatting neurodegenerative diseases through both neuronal and glial mechanisms.}, }
@article {pmid25258567, year = {2014}, author = {Kim, C and Lee, HC and Sung, JJ}, title = {Amyotrophic lateral sclerosis - cell based therapy and novel therapeutic development.}, journal = {Experimental neurobiology}, volume = {23}, number = {3}, pages = {207-214}, pmid = {25258567}, issn = {1226-2560}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the predominant loss of motor neurons (MNs) in primary motor cortex, the brainstem, and the spinal cord, causing premature death in most cases. Minimal delay of pathological development by available medicine has prompted the search for novel therapeutic treatments to cure ALS. Cell-based therapy has been proposed as an ultimate source for regeneration of MNs. Recent completion of non-autologous fetal spinal stem cell transplant to ALS patients brought renewed hope for further human trials to cure the disease. Autologous somatic stem cell-based human trials are now in track to reveal the outcome of the ongoing trials. Furthermore, induced pluripotent stem cell (iPSC)-based ALS disease drug screen and autologous cell transplant options will broaden therapeutic options. In this review paper, we discuss recent accomplishments in cell transplant treatment for ALS and future options with iPSC technology.}, }
@article {pmid25250042, year = {2014}, author = {Alexander, AG and Marfil, V and Li, C}, title = {Use of Caenorhabditis elegans as a model to study Alzheimer's disease and other neurodegenerative diseases.}, journal = {Frontiers in genetics}, volume = {5}, number = {}, pages = {279}, pmid = {25250042}, issn = {1664-8021}, support = {R01 AG032042/AG/NIA NIH HHS/United States ; R25 GM056833/GM/NIGMS NIH HHS/United States ; }, abstract = {Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer's disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model.}, }
@article {pmid25249940, year = {2014}, author = {D'Ambrosi, N and Rossi, S and Gerbino, V and Cozzolino, M}, title = {Rac1 at the crossroad of actin dynamics and neuroinflammation in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {279}, pmid = {25249940}, issn = {1662-5102}, abstract = {Rac1 is a major player of the Rho family of small GTPases that controls multiple cell signaling pathways, such as the organization of cytoskeleton (including adhesion and motility), cell proliferation, apoptosis and activation of immune cells. In the nervous system, in particular, Rac1 GTPase plays a key regulatory function of both actin and microtubule cytoskeletal dynamics and thus it is central to axonal growth and stability, as well as dendrite and spine structural plasticity. Rac1 is also a crucial regulator of NADPH-dependent membrane oxidase (NOX), a prominent source of reactive oxygen species (ROS), thus having a central role in the inflammatory response and neurotoxicity mediated by microglia cells in the nervous system. As such, alterations in Rac1 activity might well be involved in the processes that give rise to Amyotrophic Lateral Sclerosis (ALS), a complex syndrome where cytoskeletal disturbances in motor neurons and redox alterations in the inflammatory compartment play pivotal and synergic roles in the final disease outcomes. Here we will discuss the genetic and mechanistic evidence indicating the relevance of Rac1 dysregulation in the pathogenesis of ALS.}, }
@article {pmid25248677, year = {2014}, author = {Tanna, T and Sachan, V}, title = {Mesenchymal stem cells: potential in treatment of neurodegenerative diseases.}, journal = {Current stem cell research &amp; therapy}, volume = {9}, number = {6}, pages = {513-521}, doi = {10.2174/1574888x09666140923101110}, pmid = {25248677}, issn = {2212-3946}, mesh = {Animals ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*physiology ; Neurodegenerative Diseases/pathology/*therapy ; Regenerative Medicine ; }, abstract = {Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same.}, }
@article {pmid25245510, year = {2014}, author = {Blasco, H and Mavel, S and Corcia, P and Gordon, PH}, title = {The glutamate hypothesis in ALS: pathophysiology and drug development.}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3551-3575}, doi = {10.2174/0929867321666140916120118}, pmid = {25245510}, issn = {1875-533X}, mesh = {Amino Acid Transport System X-AG/antagonists &amp; inhibitors/genetics/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/*pathology ; Glutamic Acid/*metabolism/toxicity ; Humans ; Motor Neurons/drug effects/metabolism ; Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Receptors, Glutamate/chemistry/genetics/metabolism ; Riluzole/chemistry/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system, comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals. The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and work produce these designer drugs.}, }
@article {pmid25238865, year = {2014}, author = {Eidenberger, M and Nowotny, S}, title = {Inspiratory muscle training in patients with Amyotrophic Lateral Sclerosis: A systematic review.}, journal = {NeuroRehabilitation}, volume = {35}, number = {3}, pages = {349-361}, doi = {10.3233/NRE-141148}, pmid = {25238865}, issn = {1878-6448}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*rehabilitation ; Breathing Exercises/*methods ; Humans ; Quality of Life ; Randomized Controlled Trials as Topic ; Respiratory Muscles/*physiopathology ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis is a neurodegenerative disease with rapid involvement of the inspiratory muscles, leading to respiratory insufficiency. Death often occurs by aspiration and pneumonia. Endurance- and strength therapy within ALS are discussed controversially.<br><br>OBJECTIVE: To review the current literature to assess the efficacy of inspiratory muscle training for ALS.<br><br>METHOD: Systematic review, using databases as PubMed, PEDro, Cochrane and Google Scholar.<br><br>INTERVENTION: Inspiratory muscle training vs. sham training or inspiratory muscle training alone.<br><br>OUTCOME MEASURES: Inspiratory muscle strength, dyspnoea, quality of life and survival time.<br><br>RESULTS: Four studies could be included in this review, two RCT's, one pre-experimental study and one with a historical control group. In total 73 patients underwent inspiratory muscle training.<br><br>CONCLUSION: Studies varied in onset of the training, the training protocol and the outcomes measured. At time, there is limited evidence that inspiratory muscle training leads to strengthening of inspiratory muscles in ALS. Improvements made were minor, in only a few parameters and also in control groups. Survival time was significantly longer in the experimental group in one study. Interesting suppositions (diaphragm training vs. other IM training, improvement of chest wall and lung compliance) need to be examined in robustly designed future trials, defining exact therapeutic windows and interventions.}, }
@article {pmid25238675, year = {2016}, author = {Ishikawa, S and Fuyama, S and Kobayashi, T and Taira, Y and Sugano, A and Iino, M}, title = {Angioleiomyoma of the tongue: a case report and review of the literature.}, journal = {Odontology}, volume = {104}, number = {1}, pages = {119-122}, pmid = {25238675}, issn = {1618-1255}, mesh = {Angiomyoma/*diagnosis/pathology/surgery ; Diagnosis, Differential ; Humans ; Male ; Middle Aged ; Tongue Neoplasms/*diagnosis/pathology/surgery ; }, abstract = {Angioleiomyoma (AL) is a benign tumor derived from smooth muscle. The overwhelming majority of ALs occur in the uterus, gastrointestinal tract, or skin; AL of the oral cavity is infrequent, and AL of the tongue is particularly rare. The present report describes a case of AL of the tongue that resulted in a good outcome. We also review the literature with a special emphasis on the etiology of ALs. It is generally agreed that minor trauma, venous stasis, and hormonal changes are etiological factors for AL. The roles of estrogen and progesterone have been particularly emphasized, and the expression of progesterone receptors (PRs) and estrogen receptors (ERs) has been recently evaluated in some cases of AL. To our knowledge, the presence of PRs and ERs has only been evaluated in seven cases of AL arising in different regions of the body including the oral cavity. This is the first report to demonstrate negative expression of both receptors in an AL of the oral cavity. Further study and additional cases are needed to elucidate the influence of PRs and ERs in AL of the oral cavity.}, }
@article {pmid25237937, year = {2014}, author = {Verma, A}, title = {Tale of two diseases: amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neurology India}, volume = {62}, number = {4}, pages = {347-351}, doi = {10.4103/0028-3886.141174}, pmid = {25237937}, issn = {0028-3886}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; DNA Repeat Expansion ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics ; *Genotype ; Humans ; *Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were independently described in clinical and pathological details more than a century ago. Recent breakthrough discoveries identifying common genes that are causal to either ALS or FTD or an overlapping ALS-FTD syndrome have dramatically transformed our view regarding their pathogenesis. Most recently, a massive hexanucleotide (GGGGCC) repeat expansion mutation in C9orf72 gene has been linked to the majority of familial ALS, FTD and mixed ALS-FTD cases. C9orf72 and other genes causal to ALS and FTD are consistently associated with the formation of cellular RNA inclusions and protein aggregates. This article summarizes the recently reported ALS-FTD-linked genes and the emerging common unifying mechanism in the pathogenesis of ALS-FTD spectrum disorders along with a comment on the potential new therapeutic targets in these hitherto incurable diseases.}, }
@article {pmid25232510, year = {2014}, author = {Rafael, H}, title = {Omental transplantation for neurodegenerative diseases.}, journal = {American journal of neurodegenerative disease}, volume = {3}, number = {2}, pages = {50-63}, pmid = {25232510}, issn = {2165-591X}, abstract = {Up to date, almost all researchers consider that there is still no effective therapy for neurodegenerative diseases (NDDs) and therefore, these diseases are incurable. However, since May 1998, we know that a progressive ischemia in the medial temporal lobes and subcommissural regions can cause Alzheimer's disease; because, in contrast to this, its revascularization by means of omental tissue can cure or improve this disease. Likewise we observed that the aging process, Huntington's disease, Parkinson's disease, and Amyotrophic lateral sclerosis; all of them are of ischemic origin caused by cerebral atherosclerosis, associated with vascular anomalies and/or environmental chemicals. On the contrary, an omental transplantation on the affected zone can stop and improve these diseases. For these reasons, I believe that NDDs, are wrongly classified as neurodegenerative disorders.}, }
@article {pmid25230224, year = {2014}, author = {Hassan, M and Sehgal, SA and Rashid, S}, title = {Regulatory cascade of neuronal loss and glucose metabolism.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {13}, number = {7}, pages = {1232-1245}, doi = {10.2174/1871527313666140917120444}, pmid = {25230224}, issn = {1996-3181}, mesh = {Animals ; Cell Death/genetics/*physiology ; Diabetes Mellitus, Type 2/genetics/physiopathology ; Glucose/*metabolism ; Humans ; Neurodegenerative Diseases/genetics/physiopathology ; Neurons/*physiology ; }, abstract = {During recent years, numerous lines of research including proteomics and molecular biology have highlighted multiple targets and signaling pathways involved in metabolic abnormalities and neurodegeneration. However, correlation studies of individual neurodegenerative disorders (ND) including Alzheimer, Parkinson, Huntington and Amyotrophic lateral sclerosis in association with Diabetes type 2 Mellitus (D2M) are demanding tasks. Here, we report a comprehensive mechanistic overview of major contributors involved in process-based co-regulation of D2M and NDs. D2M is linked with Alzheimer's disease through deregulation of calcium ions thereby leading to metabolic fluctuations of glucose and insulin. Parkinson-associated proteins disturb insulin level through ATP-sensitive potassium ion channels and extracellular signal-regulated kinases to enhance glucose level. Similarly, proteins which perturb carbohydrate metabolism for disturbing glucose homeostasis link Huntington, Amyotrophic lateral sclerosis and D2M. Other misleading processes which interconnect D2M and NDs include oxidative stress, mitochondrial dysfunctions and microRNAs (miRNA29a/b and miRNA-9). Overall, the collective listing of pathway-specific targets would help in establishing novel connections between NDs and D2M to explore better therapeutic interventions.}, }
@article {pmid25230220, year = {2014}, author = {Karim, S and Mirza, Z and Kamal, MA and Abuzenadah, AM and Azhar, EI and Al-Qahtani, MH and Damanhouri, GA and Ahmad, F and Gan, SH and Sohrab, SS}, title = {The role of viruses in neurodegenerative and neurobehavioral diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {13}, number = {7}, pages = {1213-1223}, doi = {10.2174/187152731307141015122638}, pmid = {25230220}, issn = {1996-3181}, mesh = {Animals ; Humans ; Mental Disorders/physiopathology/*virology ; Neurodegenerative Diseases/physiopathology/*virology ; }, abstract = {Neurodegenerative and neurobehavioral diseases may be caused by chronic and neuropathic viral infections and may result in a loss of neurons and axons in the central nervous system that increases with age. To date, there is evidence of systemic viral infections that occur with some neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, and HIV-associated neurocognitive disorders. With increasing lifespan, the incidence of neurodegenerative diseases increases consistently. Neurodegenerative diseases affect approximately 37 million people worldwide and are an important cause of mortality. In addition to established non-viral-induced reasons for neurodegenerative diseases, neuropathic infections and viruses associated with neurodegenerative diseases have been proposed. Neuronal degeneration can be either directly or indirectly affected by viral infection. Viruses that attack the human immune system can also affect the nervous system and interfere with classical pathways of neurodegenerative diseases. Viruses can enter the central nervous system, but the exact mechanism cannot be understood well. Various studies have supported viral- and non-viral-mediated neurodegeneration at the cellular, molecular, genomic and proteomic levels. The main focus of this review is to illustrate the association between viral infections and both neurodegenerative and neurobehavioral diseases, so that the possible mechanism and pathway of neurodegenerative diseases can be better explained. This information will strengthen new concepts and ideas for neurodegenerative and neurobehavioral disease treatment.}, }
@article {pmid25228858, year = {2014}, author = {Takeuchi, H and Suzumura, A}, title = {Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {189}, pmid = {25228858}, issn = {1662-5102}, abstract = {Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g., minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.}, }
@article {pmid25228780, year = {2015}, author = {Banfi, P and Ticozzi, N and Lax, A and Guidugli, GA and Nicolini, A and Silani, V}, title = {A review of options for treating sialorrhea in amyotrophic lateral sclerosis.}, journal = {Respiratory care}, volume = {60}, number = {3}, pages = {446-454}, doi = {10.4187/respcare.02856}, pmid = {25228780}, issn = {1943-3654}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Disease Management ; Humans ; Sialorrhea/etiology/*therapy ; Treatment Outcome ; }, abstract = {Sialorrhea or drooling represents quite a common problem in patients with amyotrophic lateral sclerosis (ALS). In this review, we describe the possible treatments for this issue. Current medical management is not always effective: anticholinergic drugs (atropine, glycopyrrolate, amitriptyline, hyoscyamine, and transdermal scopolamine) are often used, but there is very little evidence of their effectiveness in patients with ALS. More invasive treatments, such as botulinum toxin injections and/or radiation therapy in the salivary glands, can be considered when anticholinergic drugs are not effective. In this review, we also explore the possible surgical options for treatment of sialorrhea. Although no specific studies have been conducted on patients with ALS, surgical therapies might represent a valid option for treatment of sialorrhea since there is no tachyphylaxis or need for repeated therapeutic sessions.}, }
@article {pmid25227723, year = {2014}, author = {Zhou, Z and Zhang, X and Cui, F and Liu, R and Dong, Z and Wang, X and Yu, S}, title = {Subacute motor neuron hyperexcitability with mercury poisoning: a case series and literature review.}, journal = {European neurology}, volume = {72}, number = {3-4}, pages = {218-222}, doi = {10.1159/000363290}, pmid = {25227723}, issn = {1421-9913}, mesh = {Adult ; Creatine Kinase/blood ; Humans ; Male ; Mercury Poisoning/blood/*etiology ; Motor Neuron Disease/*etiology ; }, abstract = {Motor neuron hyperexcitability (MNH) indicates a disorder characterized by an ectopic motor nerve discharge on electromyogram (EMG). Here, we present a series of three cases of subacute MNH with mercury poisoning. The first case showed hyperhidrosis, insomnia, generalied myokymia, cramps, tremor, weight loss, and myokymic and neuromyotonic discharges, followed by encephalopathy with confusion, hallucinations, and memory decrease. The second case was similar to the former but without encephalopathic features. The third case showed widespread fasciculation, fatigue, insomnia, weight loss, and autonomic dysfunction, including constipation, micturition difficulty, and impotence, with multiple fibrillation, unstable fasciculation, widened motor neuron potential, and an incremental response at high-rate stimulation in repetitive nerve stimulation. Based on the symptoms, the three cases were diagnosed as Morvan's syndrome, Isaacs' syndrome, and Lambert-Eaton myasthenic syndrome with ALS-like syndrome, respectively. Mercury poisoning in the three cases was confirmed by analysis of blood and urine samples. All cases recovered several months after chelation therapy and were in good condition at follow-up. Very few cases of MNH linked with mercury exposure have been reported in the literature. The mechanism of mercury-induced MNH may be associated with ion channel dysfunction.}, }
@article {pmid25223906, year = {2015}, author = {Richard, JP and Maragakis, NJ}, title = {Induced pluripotent stem cells from ALS patients for disease modeling.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {15-25}, pmid = {25223906}, issn = {1872-6240}, support = {U01 NS062713/NS/NINDS NIH HHS/United States ; 5U01NS062713/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Drug Evaluation, Preclinical/economics/methods ; Humans ; Induced Pluripotent Stem Cells/*physiology ; }, abstract = {The ability to reprogram adult somatic cells into pluripotent stem cells that can differentiate into all three germ layers of the developing human has fundamentally changed the landscape of biomedical research. For a neurodegenerative disease like Amyotrophic Lateral Sclerosis (ALS), which does not manifest itself until adulthood and is a heterogeneous disease with few animal models, this technology may be particularly important. Induced pluripotent stem cells (iPSC) have been created from patients with several familial forms of ALS as well as some sporadic forms of ALS. These cells have been differentiated into ALS-relevant cell subtypes including motor neurons and astrocytes, among others. ALS-relevant pathologies have also been identified in motor neurons from these cells and may provide a window into understanding disease mechanisms in vitro. Given that this is a relatively new field of research, numerous challenges remain before iPSC methodologies can fulfill their potential as tools for modeling ALS as well as providing a platform for the investigation of ALS therapeutics. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25223628, year = {2014}, author = {Simon, NG and Turner, MR and Vucic, S and Al-Chalabi, A and Shefner, J and Lomen-Hoerth, C and Kiernan, MC}, title = {Quantifying disease progression in amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {76}, number = {5}, pages = {643-657}, pmid = {25223628}, issn = {1531-8249}, support = {MR/K000780/1/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/psychology/therapy ; Brain/pathology ; Disease Progression ; Humans ; Muscle, Skeletal/pathology/physiopathology ; Spinal Cord/pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.}, }
@article {pmid25223574, year = {2014}, author = {Sperlágh, B and Illes, P}, title = {P2X7 receptor: an emerging target in central nervous system diseases.}, journal = {Trends in pharmacological sciences}, volume = {35}, number = {10}, pages = {537-547}, doi = {10.1016/j.tips.2014.08.002}, pmid = {25223574}, issn = {1873-3735}, mesh = {Animals ; Humans ; Mental Disorders/*drug therapy/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; Purinergic P2X Receptor Antagonists/*pharmacology ; Receptors, Purinergic P2X7/*metabolism ; }, abstract = {The ATP-sensitive homomeric P2X7 receptor (P2X7R) has received particular attention as a potential drug target because of its widespread involvement in inflammatory diseases as a key regulatory element of the inflammasome complex. However, it has only recently become evident that P2X7Rs also play a pivotal role in central nervous system (CNS) pathology. There is an explosion of data indicating that genetic deletion and pharmacological blockade of P2X7Rs alter responsiveness in animal models of neurological disorders, such as stroke, neurotrauma, epilepsy, neuropathic pain, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease. Moreover, recent studies suggest that P2X7Rs regulate the pathophysiology of psychiatric disorders, including mood disorders, implicating P2X7Rs as drug targets in a variety of CNS pathology.}, }
@article {pmid25220531, year = {2014}, author = {Roos, PM}, title = {Osteoporosis in neurodegeneration.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {28}, number = {4}, pages = {418-421}, doi = {10.1016/j.jtemb.2014.08.010}, pmid = {25220531}, issn = {1878-3252}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Bone Density/physiology ; Humans ; Neurodegenerative Diseases/metabolism/*pathology ; Osteoporosis/metabolism/*pathology ; }, abstract = {Osteoporosis affects bone microarchitecture and reduces bone mass. There are more than 200 million people with osteoporosis worldwide, and the prevalence is slowly increasing. The highest prevalences are found in Scandinavia and USA, also slowly increasing. A parallel increase in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis has been noted since the middle of this century. Osteoporosis is more common in patients with each of these neurodegenerative conditions than in the general population. Several metals with neurotoxic properties accumulate in bone and can substitute for calcium in hydroxyapatite, the main mineral component of bone. Especially cadmium, but also lead, aluminum and arsenic affect bone mineral density negatively. Metals with neurotoxic properties have also been found in brain and cerebrospinal fluid from patients with Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis, and markers for neurodegeneration such as amyloid beta peptide and amyloid precursor protein have been detected in bone tissue from patients with osteoporosis. A common mechanism contributing to the pathogenesis of both neurodegeneration and osteoporosis can be suspected. The hypothesis that neurodegenerative disorders are associated with osteoporosis is presented and discussed.}, }
@article {pmid25218556, year = {2015}, author = {Doty, KR and Guillot-Sestier, MV and Town, T}, title = {The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?.}, journal = {Brain research}, volume = {1617}, number = {}, pages = {155-173}, pmid = {25218556}, issn = {1872-6240}, support = {1R01NS076794-01/NS/NINDS NIH HHS/United States ; 3R00AG029726-04S1/AG/NIA NIH HHS/United States ; R01 NS076794/NS/NINDS NIH HHS/United States ; R00 AG029726/AG/NIA NIH HHS/United States ; 5R00AG029726-04/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Astrocytes/immunology/metabolism ; Brain/*immunology/metabolism ; Encephalitis/genetics/immunology ; Humans ; Inflammation Mediators/metabolism ; Microglia/*immunology/metabolism ; Neurodegenerative Diseases/genetics/*immunology/metabolism ; Neurons/*immunology/metabolism ; Parkinson Disease/genetics/metabolism ; Risk Factors ; }, abstract = {Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.}, }
@article {pmid25217582, year = {2014}, author = {Wojciechowska, M and Olejniczak, M and Galka-Marciniak, P and Jazurek, M and Krzyzosiak, WJ}, title = {RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders.}, journal = {Nucleic acids research}, volume = {42}, number = {19}, pages = {11849-11864}, pmid = {25217582}, issn = {1362-4962}, mesh = {*DNA Repeat Expansion ; *Frameshifting, Ribosomal ; Heredodegenerative Disorders, Nervous System/*genetics ; Humans ; Huntington Disease/genetics ; Machado-Joseph Disease/genetics ; *Peptide Chain Elongation, Translational ; *Peptide Chain Initiation, Translational ; }, abstract = {Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively. The boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. The contribution of unusual translation products to pathogenesis needs to be better understood. In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions.}, }
@article {pmid25217300, year = {2014}, author = {Hussain, A and Utz, MJ and Tian, W and Liu, X and Ekholm, S}, title = {Imaging and diseases of the ascending and descending pathways.}, journal = {Seminars in ultrasound, CT, and MR}, volume = {35}, number = {5}, pages = {474-486}, doi = {10.1053/j.sult.2014.06.006}, pmid = {25217300}, issn = {1558-5034}, mesh = {Afferent Pathways/*pathology ; Brain Diseases/*pathology ; Connectome/*methods ; Diffusion Tensor Imaging/*methods ; Efferent Pathways/*pathology ; Humans ; Models, Anatomic ; White Matter/*pathology ; }, abstract = {The corticospinal tract and other ascending and descending fibers are important in executing cerebral function. Conventional magnetic resonance and advanced neuroimaging findings of diseases involved in ascending and descending pathways are reviewed, including amyotrophic lateral sclerosis, secondary degeneration diseases, and intracranial tumors.}, }
@article {pmid25216370, year = {2014}, author = {Philips, T and Rothstein, JD and Pouladi, MA}, title = {Preclinical models: needed in translation? A Pro/Con debate.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {29}, number = {11}, pages = {1391-1396}, doi = {10.1002/mds.26010}, pmid = {25216370}, issn = {1531-8257}, mesh = {Animals ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Huntington Disease/genetics/*therapy ; Translational Research, Biomedical/*methods ; }, abstract = {The discovery of the causative mutations and many of the predisposing risk factors for neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Alzheimer's, Parkinson's, and Huntington's disease (HD), has led to the development of a large number of genetic animal models of disease. In the case of HD, for example, over 20 different transgenic rodent models have been generated. These models have been of immense value in providing novel insights into mechanisms of disease, with the promise of accelerating the development of therapies that can delay the onset or slow the progression of the disease. Yet, despite extensive use of such models, no effective treatment for HD has been developed. Here, we discuss the value of animal models, highlighting their strengths and shortcomings in the context of translational research for HD.}, }
@article {pmid25213573, year = {2014}, author = {Finsterer, J and Wahbi, K}, title = {CNS disease triggering Takotsubo stress cardiomyopathy.}, journal = {International journal of cardiology}, volume = {177}, number = {2}, pages = {322-329}, doi = {10.1016/j.ijcard.2014.08.101}, pmid = {25213573}, issn = {1874-1754}, mesh = {Animals ; Central Nervous System Diseases/*complications/*diagnosis/psychology ; Humans ; Precipitating Factors ; Stress, Psychological/complications/diagnosis/psychology ; Takotsubo Cardiomyopathy/*diagnosis/*etiology/psychology ; }, abstract = {There are a number of hereditary and non-hereditary central nervous system (CNS) disorders, which directly or indirectly affect the heart (brain-heart disorders). The most well-known of these CNS disorders are epilepsy, stroke, infectious or immunological encephalitis/meningitis, migraine, and traumatic brain injury. In addition, a number of hereditary and non-hereditary neurodegenerative disorders may impair cardiac functions. Affection of the heart may manifest not only as arrhythmias, myocardial infarction, autonomic impairment, systolic dysfunction/heart failure, arterial hypertension, or pulmonary hypertension, but also as stress cardiomyopathy (Takotsubo syndrome, TTS). CNS disease triggering TTS includes subarachnoid bleeding, epilepsy, ischemic stroke, intracerebral bleeding, migraine, encephalitis, traumatic brain injury, PRES syndrome, or ALS. Usually, TTS is acutely precipitated by stress triggered by various different events. TTS is one of the cardiac abnormalities most frequently induced by CNS disorders. Appropriate management of TTS from CNS disorders is essential to improve the outcome of affected patients.}, }
@article {pmid25206537, year = {2013}, author = {Kesidou, E and Lagoudaki, R and Touloumi, O and Poulatsidou, KN and Simeonidou, C}, title = {Autophagy and neurodegenerative disorders.}, journal = {Neural regeneration research}, volume = {8}, number = {24}, pages = {2275-2283}, pmid = {25206537}, issn = {1673-5374}, abstract = {Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracellular mechanism that removes damaged organelles and misfolded proteins in order to maintain cell homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.}, }
@article {pmid25205348, year = {2015}, author = {Zhu, Y and Fotinos, A and Mao, LL and Atassi, N and Zhou, EW and Ahmad, S and Guan, Y and Berry, JD and Cudkowicz, ME and Wang, X}, title = {Neuroprotective agents target molecular mechanisms of disease in ALS.}, journal = {Drug discovery today}, volume = {20}, number = {1}, pages = {65-75}, doi = {10.1016/j.drudis.2014.08.016}, pmid = {25205348}, issn = {1878-5832}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Muscular Atrophy/*drug therapy ; Neuroprotective Agents/chemistry/pharmacology/*therapeutic use ; Structure-Activity Relationship ; Weight Loss/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weight loss and respiratory failure. Evidence suggests that inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are all responsible for ALS pathogenesis. We review neuroprotective agents with the ability to reduce ALS-related bodyweight loss, summarize the various therapies tested on animal models targeting the proposed molecular mechanisms, compare their effects on bodyweight loss, muscle damage, disease onset, duration and survival, and analyze their structure-activity relationships, with the overall goal of creating a screening strategy for further clinical application.}, }
@article {pmid25202033, year = {2016}, author = {Karam, CY and Paganoni, S and Joyce, N and Carter, GT and Bedlack, R}, title = {Palliative Care Issues in Amyotrophic Lateral Sclerosis: An Evidenced-Based Review.}, journal = {The American journal of hospice &amp; palliative care}, volume = {33}, number = {1}, pages = {84-92}, pmid = {25202033}, issn = {1938-2715}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*nursing ; Caregivers ; Home Care Services, Hospital-Based/*organization &amp; administration ; Humans ; Palliative Care/*standards ; Patient Care Team/*organization &amp; administration ; *Quality of Life ; Terminal Care/*organization &amp; administration ; }, abstract = {As palliative care physicians become increasingly involved in the care of patients with amyotrophic lateral sclerosis (ALS), they will be asked to provide guidance regarding the use of supplements, diet, exercise, and other common preventive medicine interventions. Moreover, palliative care physicians have a crucial role assisting patients with ALS in addressing health care decisions to maximize quality of life and cope with a rapidly disabling disease. It is therefore important for palliative care physicians to be familiar with commonly encountered palliative care issues in ALS. This article provides an evidenced-based review of palliative care options not usually addressed in national and international ALS guidelines.}, }
@article {pmid25199710, year = {2014}, author = {Schwartz, M and Baruch, K}, title = {Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: boosting autoimmunity to fight-off chronic neuroinflammation.}, journal = {Journal of autoimmunity}, volume = {54}, number = {}, pages = {8-14}, doi = {10.1016/j.jaut.2014.08.002}, pmid = {25199710}, issn = {1095-9157}, support = {232835/ERC_/European Research Council/International ; }, mesh = {Acute Disease ; Alzheimer Disease/*immunology/pathology ; Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Autoantigens/*immunology ; Brain/immunology/pathology ; Chronic Disease ; Humans ; *Immune Tolerance ; Multiple Sclerosis/*immunology/pathology ; Spinal Cord/immunology/pathology ; T-Lymphocytes, Regulatory/*immunology/pathology ; }, abstract = {Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS). As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy. Yet, over the last decade, it became clear that autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis. Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis. Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and protective autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging. Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self. Accordingly, we propose that fighting off acute and chronic neurodegenerative conditions requires breaking peripheral immune tolerance to CNS self-antigens, in order to boost protective autoimmunity. Nevertheless, the optimal approach to fine tune such immune response must be individually explored for each condition.}, }
@article {pmid25193343, year = {2014}, author = {Burns, A and Adeli, H and Buford, JA}, title = {Brain-computer interface after nervous system injury.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {20}, number = {6}, pages = {639-651}, doi = {10.1177/1073858414549015}, pmid = {25193343}, issn = {1089-4098}, mesh = {Amyotrophic Lateral Sclerosis/rehabilitation ; Brain/*physiopathology ; *Brain-Computer Interfaces/trends ; Consciousness Disorders/rehabilitation ; Humans ; Parkinson Disease/rehabilitation ; Signal Processing, Computer-Assisted ; Spinal Cord Injuries/rehabilitation ; Stroke Rehabilitation ; Trauma, Nervous System/*rehabilitation ; }, abstract = {Brain-computer interface (BCI) has proven to be a useful tool for providing alternative communication and mobility to patients suffering from nervous system injury. BCI has been and will continue to be implemented into rehabilitation practices for more interactive and speedy neurological recovery. The most exciting BCI technology is evolving to provide therapeutic benefits by inducing cortical reorganization via neuronal plasticity. This article presents a state-of-the-art review of BCI technology used after nervous system injuries, specifically: amyotrophic lateral sclerosis, Parkinson's disease, spinal cord injury, stroke, and disorders of consciousness. Also presented is transcending, innovative research involving new treatment of neurological disorders.}, }
@article {pmid25193032, year = {2015}, author = {Ajroud-Driss, S and Siddique, T}, title = {Sporadic and hereditary amyotrophic lateral sclerosis (ALS).}, journal = {Biochimica et biophysica acta}, volume = {1852}, number = {4}, pages = {679-684}, doi = {10.1016/j.bbadis.2014.08.010}, pmid = {25193032}, issn = {0006-3002}, mesh = {Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/genetics/metabolism ; Cell Survival ; DNA-Binding Proteins/genetics/metabolism ; Epigenesis, Genetic ; *Genetic Diseases, Inborn/genetics/metabolism/pathology ; Humans ; Mice ; *Motor Neurons/metabolism/pathology ; Proteins/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Ubiquitins/genetics/metabolism ; }, abstract = {Genetic discoveries in ALS have a significant impact on deciphering molecular mechanisms of motor neuron degeneration. The identification of SOD1 as the first genetic cause of ALS led to the engineering of the SOD1 mouse, the backbone of ALS research, and set the stage for future genetic breakthroughs. In addition, careful analysis of ALS pathology added valuable pieces to the ALS puzzle. From this joint effort, major pathogenic pathways emerged. Whereas the study of TDP43, FUS and C9ORF72 pointed to the possible involvement of RNA biology in motor neuron survival, recent work on P62 and UBQLN2 refocused research on protein degradation pathways. Despite all these efforts, the etiology of most cases of sporadic ALS remains elusive. Newly acquired genomic tools now allow the identification of genetic and epigenetic factors that can either increase ALS risk or modulate disease phenotype. These developments will certainly allow for better disease modeling to identify novel therapeutic targets for ALS. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.}, }
@article {pmid25191270, year = {2014}, author = {Collingwood, JF and Davidson, MR}, title = {The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light.}, journal = {Frontiers in pharmacology}, volume = {5}, number = {}, pages = {191}, pmid = {25191270}, issn = {1663-9812}, abstract = {There is evidence for iron dysregulation in many forms of disease, including a broad spectrum of neurodegenerative disorders. In order to advance our understanding of the pathophysiological role of iron, it is helpful to be able to determine in detail the distribution of iron as it relates to metabolites, proteins, cells, and tissues, the chemical state and local environment of iron, and its relationship with other metal elements. Synchrotron light sources, providing primarily X-ray beams accompanied by access to longer wavelengths such as infra-red, are an outstanding tool for multi-modal non-destructive analysis of iron in these systems. The micro- and nano-focused X-ray beams that are generated at synchrotron facilities enable measurement of iron and other transition metal elements to be performed with outstanding analytic sensitivity and specificity. Recent developments have increased the scope for methods such as X-ray fluorescence mapping to be used quantitatively rather than semi-quantitatively. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field over the past decade. In this paper we will consider how the field has evolved with regard to the study of iron in proteins, cells, and brain tissue, and identify challenges in sample preparation and analysis. Selected examples will be used to illustrate the contribution, and future potential, of synchrotron X-ray analysis for the characterization of iron in model systems exhibiting iron dysregulation, and for human cases of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis.}, }
@article {pmid25188012, year = {2014}, author = {Mizielinska, S and Isaacs, AM}, title = {C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: gain or loss of function?.}, journal = {Current opinion in neurology}, volume = {27}, number = {5}, pages = {515-523}, pmid = {25188012}, issn = {1473-6551}, support = {ISAACS/APR13/818-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Brain/drug effects/metabolism ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/*genetics/therapy ; Genetic Predisposition to Disease/*genetics ; Humans ; Oligonucleotides, Antisense/therapeutic use ; Proteins/chemistry/*genetics ; RNA, Untranslated/genetics ; }, abstract = {PURPOSE OF REVIEW: The molecular mechanisms that underlie chromosome 9 open reading frame 72 (C9orf72)-associated amyotrophic lateral sclerosis and frontotemporal dementia are rapidly emerging. Two potential disease mechanisms have been postulated - gain or loss of function. We provide an overview of recent advances that support or oppose gain-of-function and loss-of-function mechanisms.<br><br>RECENT FINDINGS: Since the discovery that a noncoding repeat expansion in C9orf72 was responsible for chromosome 9-linked amyotrophic lateral sclerosis and frontotemporal dementia in 2011, a plethora of studies have investigated clinical, pathological and mechanistic aspects of the disease. Loss of function is supported by reduced levels of C9orf72 in patient brain and functional work, revealing a role of the C9orf72 protein in endocytic and autophagic pathways and motor function. Gain of function is supported by the presence in patient brain of both repeat RNA and protein aggregates. Repeat RNA aggregates termed RNA foci, a hallmark of noncoding repeat expansion diseases, have been shown to sequester proteins involved in RNA splicing, editing, nuclear export and nucleolar function. Repeat-associated non-ATG dependent translation gives rise to toxic dipeptide repeat proteins that form inclusions in patient tissue. Antisense oligonucleotides targeting C9orf72 have shown promise for combating gain-of-function toxicity.<br><br>SUMMARY: Rapid progress is being made towards understanding this common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Overall, the weight of data currently sits in favour of gain of function as the most important disease mechanism, which has important implications for the development of effective and targeted therapies.}, }
@article {pmid25186553, year = {2014}, author = {Gooch, CL and Doherty, TJ and Chan, KM and Bromberg, MB and Lewis, RA and Stashuk, DW and Berger, MJ and Andary, MT and Daube, JR}, title = {Motor unit number estimation: a technology and literature review.}, journal = {Muscle &amp; nerve}, volume = {50}, number = {6}, pages = {884-893}, doi = {10.1002/mus.24442}, pmid = {25186553}, issn = {1097-4598}, mesh = {Action Potentials/physiology ; Biomedical Research/*methods ; Cell Count/*methods ; Electric Stimulation ; Electrophysiology/*methods ; Humans ; Motor Neurons/*cytology/physiology ; Neural Conduction/physiology ; Reproducibility of Results ; }, abstract = {INTRODUCTION: Numerous methods for motor unit number estimation (MUNE) have been developed. The objective of this article is to summarize and compare the major methods and the available data regarding their reproducibility, validity, application, refinement, and utility.<br><br>METHODS: Using specified search criteria, a systematic review of the literature was performed. Reproducibility, normative data, application to specific diseases and conditions, technical refinements, and practicality were compiled into a comprehensive database and analyzed.<br><br>RESULTS: The most commonly reported MUNE methods are the incremental, multiple-point stimulation, spike-triggered averaging, and statistical methods. All have established normative data sets and high reproducibility. MUNE provides quantitative assessments of motor neuron loss and has been applied successfully to the study of many clinical conditions, including amyotrophic lateral sclerosis and normal aging.<br><br>CONCLUSIONS: MUNE is an important research technique in human subjects, providing important data regarding motor unit populations and motor unit loss over time.}, }
@article {pmid25177267, year = {2014}, author = {Moloney, EB and de Winter, F and Verhaagen, J}, title = {ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease.}, journal = {Frontiers in neuroscience}, volume = {8}, number = {}, pages = {252}, pmid = {25177267}, issn = {1662-4548}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is being redefined as a distal axonopathy, in that many molecular changes influencing motor neuron degeneration occur at the neuromuscular junction (NMJ) at very early stages of the disease prior to symptom onset. A huge variety of genetic and environmental causes have been associated with ALS, and interestingly, although the cause of the disease can differ, both sporadic and familial forms of ALS show a remarkable similarity in terms of disease progression and clinical manifestation. The NMJ is a highly specialized synapse, allowing for controlled signaling between muscle and nerve necessary for skeletal muscle function. In this review we will evaluate the clinical, animal experimental and cellular/molecular evidence that supports the idea of ALS as a distal axonopathy. We will discuss the early molecular mechanisms that occur at the NMJ, which alter the functional abilities of the NMJ. Specifically, we focus on the role of axon guidance molecules on the stability of the cytoskeleton and how these molecules may directly influence the cells of the NMJ in a way that may initiate or facilitate the dismantling of the neuromuscular synapse in the presymptomatic stages of ALS.}, }
@article {pmid25175835, year = {2015}, author = {Jablonski, M and Miller, DS and Pasinelli, P and Trotti, D}, title = {ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {1-14}, pmid = {25175835}, issn = {1872-6240}, support = {R01 NS051488/NS/NINDS NIH HHS/United States ; F31-NS080539/NS/NINDS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; F31 NS080539/NS/NINDS NIH HHS/United States ; R01 NS074886/NS/NINDS NIH HHS/United States ; R01-NS074886/NS/NINDS NIH HHS/United States ; }, mesh = {ATP-Binding Cassette Transporters/*metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Drug Resistance/*physiology ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a slowly progressing neurodegenerative disease that affects motor neurons of the nervous system. Despite the identification of many potential therapeutics targeting pathogenic mechanisms in in vitro models, there has been limited progress in translating them into a successful pharmacotherapy in the animal model of ALS. Further, efforts to translate any promising results from preclinical trials to effective pharmacotherapies for patients have been unsuccessful, with the exception of riluzole, the only FDA-approved medication, which only modestly extends survival both in the animal model and in patients. Thus, it is essential to reconsider the strategies for developing ALS pharmacotherapies. Growing evidence suggests that problems identifying highly effective ALS treatments may result from an underestimated issue of drug bioavailability and disease-driven pharmacoresistance, mediated by the ATP-binding cassette (ABC) drug efflux transporters. ABC transporters are predominately localized to the lumen of endothelial cells of the blood-brain and blood-spinal cord barriers (BBB, BSCB) where they limit the entry into the central nervous system (CNS) of a wide range of neurotoxicants and xenobiotics, but also therapeutics. In ALS, expression and function of ABC transporters is increased at the BBB/BSCB and their expression has been detected on neurons and glia in the CNS parenchyma, which may further reduce therapeutic action in target cells. Understanding and accounting for the contribution of these transporters to ALS pharmacoresistance could both improve the modest effects of riluzole and set in motion a re-evaluation of previous ALS drug disappointments. In addition, identifying pathogenic mechanisms regulating ABC transporter expression and function in ALS may lead to the development of new therapeutic strategies. It is likely that novel pharmacological approaches require counteracting pharmacoresistance to improve therapeutic efficacy. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25164989, year = {2014}, author = {Aronin, N and DiFiglia, M}, title = {Huntingtin-lowering strategies in Huntington's disease: antisense oligonucleotides, small RNAs, and gene editing.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {29}, number = {11}, pages = {1455-1461}, doi = {10.1002/mds.26020}, pmid = {25164989}, issn = {1531-8257}, mesh = {Animals ; Humans ; Huntingtin Protein ; Huntington Disease/genetics/*therapy ; MicroRNAs/genetics ; Nerve Tissue Proteins/genetics/*metabolism ; Oligodeoxyribonucleotides, Antisense/*therapeutic use ; *RNA Editing ; RNA Interference/*physiology ; }, abstract = {The idea to lower mutant huntingtin is especially appealing in Huntington's disease (HD). It is autosomal dominant, so that expression of the mutant allele causes the disease. Advances in RNA and gene regulation provide foundations for the huntingtin gene (both normal and mutant alleles) and possibly the mutant allele only. There is much preclinical animal work to support the concept of gene and RNA silencing, but, to date, no clinical studies have been attempted in HD. Preventing expression of mutant huntingtin protein is at the cusp for a human trial. Antisense oligonucleotides delivered to patients with amyotrophic lateral sclerosis have been well tolerated; small RNAs administered to rodent and nonhuman primate brain knocked down huntingtin messenger RNA (mRNA); short-hairpin complementary DNA of microRNAs can be expressed in adeno-associated virus to provide long-term silencing of huntingtin mRNA and protein. We expect that these approaches will be ready for clinical studies in the near future, once safety has been validated. Our understanding of gene editing-changing the huntingtin gene itself-is rapidly progressing. Harnessing our knowledge of transcription and translation should push scientific creativity to new and exciting advances that overcome the lethality of the mutant gene in HD.}, }
@article {pmid25157751, year = {2014}, author = {Lewis, CM and Suzuki, M}, title = {Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis.}, journal = {Stem cell research &amp; therapy}, volume = {5}, number = {2}, pages = {32}, pmid = {25157751}, issn = {1757-6512}, support = {R21NS06104/NS/NINDS NIH HHS/United States ; UL1 TR000427/TR/NCATS NIH HHS/United States ; UL1 RR025011/RR/NCRR NIH HHS/United States ; T32 GM008349/GM/NIGMS NIH HHS/United States ; 9U54TR000021/TR/NCATS NIH HHS/United States ; T32GM08349/GM/NIGMS NIH HHS/United States ; R21 NS061049/NS/NINDS NIH HHS/United States ; 1UL1RR025011/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*cytology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS.}, }
@article {pmid25157374, year = {2014}, author = {Calvo, AC and Manzano, R and Mendonça, DM and Muñoz, MJ and Zaragoza, P and Osta, R}, title = {Amyotrophic lateral sclerosis: a focus on disease progression.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {925101}, pmid = {25157374}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*pathology/physiopathology/therapy ; Animals ; Biomarkers/metabolism ; *Disease Progression ; Humans ; Practice Guidelines as Topic ; }, abstract = {Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives.}, }
@article {pmid25156326, year = {2014}, author = {Arbab, M and Baars, S and Geijsen, N}, title = {Modeling motor neuron disease: the matter of time.}, journal = {Trends in neurosciences}, volume = {37}, number = {11}, pages = {642-652}, doi = {10.1016/j.tins.2014.07.008}, pmid = {25156326}, issn = {1878-108X}, mesh = {Animals ; Cell Differentiation/*physiology ; Disease Models, Animal ; Humans ; Motor Neurons/*cytology ; Neurodegenerative Diseases/*therapy ; Stem Cells/*cytology ; Time Factors ; }, abstract = {Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived stem cell models, it is proving more difficult to recapitulate the full phenotypic extent of these disorders. The problem with these stem cell models lies in the disparity between the advanced age of onset of neurodegenerative disorders and the embryonic nature of the in vitro derived cell types. In this review we discuss experimental methods of in vitro aging of neural cell types as a means to elicit late-onset symptoms in induced pluripotent stem cell (iPSC) models of neurodegenerative disease.}, }
@article {pmid25152710, year = {2014}, author = {Jansen, AH and Reits, EA and Hol, EM}, title = {The ubiquitin proteasome system in glia and its role in neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {7}, number = {}, pages = {73}, pmid = {25152710}, issn = {1662-5099}, abstract = {The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.}, }
@article {pmid25148523, year = {2014}, author = {Wang, MD and Gomes, J and Cashman, NR and Little, J and Krewski, D}, title = {Intermediate CAG repeat expansion in the ATXN2 gene is a unique genetic risk factor for ALS--a systematic review and meta-analysis of observational studies.}, journal = {PloS one}, volume = {9}, number = {8}, pages = {e105534}, pmid = {25148523}, issn = {1932-6203}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/epidemiology/*genetics ; Ataxins ; *Genetic Predisposition to Disease ; Humans ; Mortality ; Nerve Tissue Proteins/*genetics ; Odds Ratio ; Prevalence ; Risk Factors ; *Trinucleotide Repeat Expansion ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30-33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91-6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58-8.17) and sporadic ALS cases (OR = 3.16, 1.88-5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.}, }
@article {pmid25147799, year = {2014}, author = {Patterson, AP and Booth, SA and Saba, R}, title = {The emerging use of in vivo optical imaging in the study of neurodegenerative diseases.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {401306}, pmid = {25147799}, issn = {2314-6141}, mesh = {Animals ; Brain/*pathology ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*pathology ; Optical Imaging/*methods ; }, abstract = {The detection and subsequent quantification of photons emitted from living tissues, using highly sensitive charged-couple device (CCD) cameras, have enabled investigators to noninvasively examine the intricate dynamics of molecular reactions in wide assortment of experimental animals under basal and pathophysiological conditions. Nevertheless, extrapolation of this in vivo optical imaging technology to the study of the mammalian brain and related neurodegenerative conditions is still in its infancy. In this review, we introduce the reader to the emerging use of in vivo optical imaging in the study of neurodegenerative diseases. We highlight the current instrumentation that is available and reporter molecules (fluorescent and bioluminescent) that are commonly used. Moreover, we examine how in vivo optical imaging using transgenic reporter mice has provided new insights into Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Prion disease, and neuronal damage arising from excitotoxicity and inflammation. Furthermore, we also touch upon studies that have utilized these technologies for the development of therapeutic strategies for neurodegenerative conditions that afflict humans.}, }
@article {pmid25146848, year = {2015}, author = {Cao, L and Tan, L and Jiang, T and Zhu, XC and Yu, JT}, title = {Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {52}, number = {1}, pages = {244-255}, pmid = {25146848}, issn = {1559-1182}, mesh = {Animals ; Disease Models, Animal ; *Drug Discovery ; Genomics ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*therapy ; }, abstract = {Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.}, }
@article {pmid25146396, year = {2014}, author = {Meyer, H and Weihl, CC}, title = {The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis.}, journal = {Journal of cell science}, volume = {127}, number = {Pt 18}, pages = {3877-3883}, pmid = {25146396}, issn = {1477-9137}, support = {K02 AG042095/AG/NIA NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/genetics/*metabolism ; Animals ; Cell Cycle Proteins/genetics/*metabolism ; Disease/genetics ; Gene Expression Regulation ; Humans ; Pathology ; Stress, Physiological ; Valosin Containing Protein ; }, abstract = {The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system.}, }
@article {pmid25144654, year = {2014}, author = {Jayaraman, S and Sethi, D and Wong, R}, title = {Advanced training in trauma life support for ambulance crews.}, journal = {The Cochrane database of systematic reviews}, volume = {2014}, number = {8}, pages = {CD003109}, pmid = {25144654}, issn = {1469-493X}, support = {001/WHO_/World Health Organization/International ; }, mesh = {*Advanced Trauma Life Support Care ; Ambulances ; Controlled Clinical Trials as Topic ; Emergency Medical Technicians/*education ; Glasgow Coma Scale ; Humans ; *Life Support Care ; Randomized Controlled Trials as Topic ; Traumatology/*education ; Wounds and Injuries/mortality/therapy ; }, abstract = {BACKGROUND: There is an increasing global burden of injury especially in low- and middle-income countries (LMICs). To address this, models of trauma care initially developed in high income countries are being adopted in LMIC settings. In particular, ambulance crews with advanced life support (ALS) training are being promoted in LMICs as a strategy for improving outcomes for victims of trauma. However, there is controversy as to the effectiveness of this health service intervention and the evidence has yet to be rigorously appraised.<br><br>OBJECTIVES: To quantify the impact of ALS-trained ambulance crews versus crews without ALS training on reducing mortality and morbidity in trauma patients.<br><br>SEARCH METHODS: The search for studies was run on the 16th May 2014. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process &amp; Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S &amp; CPSI-SSH), CINAHL Plus (EBSCO), PubMed and screened reference lists.<br><br>SELECTION CRITERIA: Randomised controlled trials, controlled trials and non-randomised studies, including before-and-after studies and interrupted time series studies, comparing the impact of ALS-trained ambulance crews versus crews without ALS training on the reduction of mortality and morbidity in trauma patients.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors assessed study reports against the inclusion criteria, and extracted data.<br><br>MAIN RESULTS: We found one controlled before-and-after trial, one uncontrolled before-and-after study, and one randomised controlled trial that met the inclusion criteria. None demonstrated evidence to support ALS training for pre-hospital personnel. In the uncontrolled before-and-after study, 'a priori' sub-group analysis showed an increase in mortality among patients who had a Glasgow Coma Scale score of less than nine and received care from ALS trained ambulance crews. Additionally, when the pre-hospital trauma score was taken into account in logistic regression analysis, mortality in the patients receiving care from ALS trained crews increased significantly.<br><br>AUTHORS' CONCLUSIONS: At this time, the evidence indicates that there is no benefit of advanced life support training for ambulance crews on patient outcomes.}, }
@article {pmid25143726, year = {2014}, author = {Alvarim, LT and Nucci, LP and Mamani, JB and Marti, LC and Aguiar, MF and Silva, HR and Silva, GS and Nucci-da-Silva, MP and DelBel, EA and Gamarra, LF}, title = {Therapeutics with SPION-labeled stem cells for the main diseases related to brain aging: a systematic review.}, journal = {International journal of nanomedicine}, volume = {9}, number = {}, pages = {3749-3770}, pmid = {25143726}, issn = {1178-2013}, mesh = {Animals ; *Brain/cytology/physiology ; Brain Diseases/*therapy ; Cell Line ; Cellular Senescence/physiology ; Humans ; Magnetite Nanoparticles/*therapeutic use ; Mice ; Rats ; *Stem Cell Transplantation ; }, abstract = {The increase in clinical trials assessing the efficacy of cell therapy for structural and functional regeneration of the nervous system in diseases related to the aging brain is well known. However, the results are inconclusive as to the best cell type to be used or the best methodology for the homing of these stem cells. This systematic review analyzed published data on SPION (superparamagnetic iron oxide nanoparticle)-labeled stem cells as a therapy for brain diseases, such as ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and dementia. This review highlights the therapeutic role of stem cells in reversing the aging process and the pathophysiology of brain aging, as well as emphasizing nanotechnology as an important tool to monitor stem cell migration in affected regions of the brain.}, }
@article {pmid25141979, year = {2014}, author = {Salahuddin, P and Rabbani, G and Khan, RH}, title = {The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach.}, journal = {Cellular &amp; molecular biology letters}, volume = {19}, number = {3}, pages = {407-437}, pmid = {25141979}, issn = {1689-1392}, mesh = {Alzheimer Disease/drug therapy/metabolism ; Animals ; Biological Products/therapeutic use ; Glycation End Products, Advanced/*antagonists &amp; inhibitors/chemistry/*metabolism ; Glycosylation/drug effects ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*therapeutic use ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies have shown that glycation induces the formation of the β-sheet structure in β-amyloid protein, α-synuclein, transthyretin (TTR), copper-zinc superoxide dismutase 1 (Cu, Zn-SOD-1), and prion protein. Aggregation of the β-sheet structure in each case creates fibrillar structures, respectively causing Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and prion disease. It has been suggested that oligomeric species of glycated α-synuclein and prion are more toxic than fibrils. This review focuses on the pathway of AGE formation, the synthesis of different types of AGE, and the molecular mechanisms by which glycation causes various types of neurodegenerative disease. It discusses several new therapeutic approaches that have been applied to treat these devastating disorders, including the use of various synthetic and naturally occurring inhibitors. Modulation of the AGE-RAGE axis is now considered promising in the prevention of neurodegenerative diseases. Additionally, the review covers several defense enzymes and proteins in the human body that are important anti-glycating systems acting to prevent the development of neurodegenerative diseases.}, }
@article {pmid25131449, year = {2014}, author = {Hottman, DA and Chernick, D and Cheng, S and Wang, Z and Li, L}, title = {HDL and cognition in neurodegenerative disorders.}, journal = {Neurobiology of disease}, volume = {72 Pt A}, number = {}, pages = {22-36}, pmid = {25131449}, issn = {1095-953X}, support = {R01 AG031846/AG/NIA NIH HHS/United States ; AG031846/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism/psychology ; Amyotrophic Lateral Sclerosis/metabolism/psychology ; Animals ; Apolipoproteins E/metabolism ; Brain/*metabolism ; Cholesterol, HDL/metabolism ; Cognition/*physiology ; Female ; Humans ; Huntington Disease/metabolism/psychology ; Lipoproteins, HDL/*metabolism ; Liver/metabolism ; Liver X Receptors ; Male ; Neurodegenerative Diseases/*metabolism/psychology ; Orphan Nuclear Receptors/metabolism ; Parkinson Disease/metabolism/psychology ; }, abstract = {High-density lipoproteins (HDLs) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.}, }
@article {pmid25128239, year = {2015}, author = {Karki, P and Smith, K and Johnson, J and Aschner, M and Lee, E}, title = {Role of transcription factor yin yang 1 in manganese-induced reduction of astrocytic glutamate transporters: Putative mechanism for manganese-induced neurotoxicity.}, journal = {Neurochemistry international}, volume = {88}, number = {}, pages = {53-59}, pmid = {25128239}, issn = {1872-9754}, support = {R21 ES025415/ES/NIEHS NIH HHS/United States ; R01ES10563/ES/NIEHS NIH HHS/United States ; G12 MD007586/MD/NIMHD NIH HHS/United States ; SC1 GM089630/GM/NIGMS NIH HHS/United States ; R01ES10563S1/ES/NIEHS NIH HHS/United States ; R25 GM059994/GM/NIGMS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; SC1089630/SC/NCI NIH HHS/United States ; }, mesh = {Amino Acid Transport System X-AG/antagonists &amp; inhibitors/*metabolism ; Animals ; Astrocytes/drug effects/*metabolism ; Humans ; Manganese/*toxicity ; Manganese Poisoning/*metabolism ; Signal Transduction/physiology ; Transcription Factors/physiology ; YY1 Transcription Factor/*physiology ; }, abstract = {Astrocytes are the most abundant non-neuronal glial cells in the brain. Once relegated to a mere supportive role for neurons, contemporary dogmas ascribe multiple active roles for these cells in central nervous system (CNS) function, including maintenance of optimal glutamate levels in synapses. Regulation of glutamate levels in the synaptic cleft is crucial for preventing excitotoxic neuronal injury. Glutamate levels are regulated predominantly by two astrocytic glutamate transporters, glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST). Indeed, the dysregulation of these transporters has been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), as well as manganism, which is caused by overexposure to the trace metal, manganese (Mn). Although Mn is an essential trace element, its excessive accumulation in the brain as a result of chronic occupational or environmental exposures induces a neurological disorder referred to as manganism, which shares common pathological features with Parkinsonism. Mn decreases the expression and function of both GLAST and GLT-1. Astrocytes are commonly targeted by Mn, and thus reduction in astrocytic glutamate transporter function represents a critical mechanism of Mn-induced neurotoxicity. In this review, we will discuss the role of astrocytic glutamate transporters in neurodegenerative diseases and Mn-induced neurotoxicity.}, }
@article {pmid25127851, year = {2014}, author = {Abhinav, K and Yeh, FC and Pathak, S and Suski, V and Lacomis, D and Friedlander, RM and Fernandez-Miranda, JC}, title = {Advanced diffusion MRI fiber tracking in neurosurgical and neurodegenerative disorders and neuroanatomical studies: A review.}, journal = {Biochimica et biophysica acta}, volume = {1842}, number = {11}, pages = {2286-2297}, doi = {10.1016/j.bbadis.2014.08.002}, pmid = {25127851}, issn = {0006-3002}, abstract = {Diffusion MRI enabled in vivo microstructural imaging of the fiber tracts in the brain resulting in its application in a wide range of settings, including in neurological and neurosurgical disorders. Conventional approaches such as diffusion tensor imaging (DTI) have been shown to have limited applications due to the crossing fiber problem and the susceptibility of their quantitative indices to partial volume effects. To overcome these limitations, the recent focus has shifted to the advanced acquisition methods and their related analytical approaches. Advanced white matter imaging techniques provide superior qualitative data in terms of demonstration of multiple crossing fibers in their spatial orientation in a three dimensional manner in the brain. In this review paper, we discuss the advancements in diffusion MRI and introduce their roles. Using examples, we demonstrate the role of advanced diffusion MRI-based fiber tracking in neuroanatomical studies. Results from its preliminary application in the evaluation of intracranial space occupying lesions, including with respect to future directions for prognostication, are also presented. Building upon the previous DTI studies assessing white matter disease in Huntington's disease and Amyotrophic lateral sclerosis; we also discuss approaches which have led to encouraging preliminary results towards developing an imaging biomarker for these conditions.}, }
@article {pmid25110934, year = {2014}, author = {Jenkins, TM and Hollinger, H and McDermott, CJ}, title = {The evidence for symptomatic treatments in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {27}, number = {5}, pages = {524-531}, doi = {10.1097/WCO.0000000000000135}, pmid = {25110934}, issn = {1473-6551}, support = {09/55/33/DH_/Department of Health/United Kingdom ; II-ES-0511-21003/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; *Disease Management ; Humans ; *Quality of Life ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a progressive, incurable and fatal neurodegenerative disease. Few interventions significantly alter the disease course, but many symptomatic treatments exist to improve patients' quality of life. In this review, we describe our approach to symptomatic management of ALS and discuss the underlying evidence base.<br><br>RECENT FINDINGS: Discussion focuses predominantly on recently published articles. We cover management settings, disease-modifying treatment, vitamin D, respiratory management including noninvasive ventilation and diaphragmatic pacing, secretions, nutrition, dysphagia and gastrostomy, communication problems, mobility, spasticity, pain, cognition, depression and emotional lability, fatigue, sleep disturbance, head drop, prevention of deep venous thrombosis and end-of-life issues.<br><br>SUMMARY: Multidisciplinary specialist care appears to improve quality of life and survival. Riluzole remains the only available disease-modifying medication and confers a survival advantage of 2-3 months. Noninvasive ventilation improves quality of life and extends survival by approximately 7 months, at least in patients without severe bulbar problems. Nutrition is an independent prognostic factor; whether gastrostomy improves survival and quality of life remains unclear and further studies are underway. Many other symptomatic treatments appear helpful to individuals in clinic, but further randomized clinical trials are required to provide a more robust evidence base.}, }
@article {pmid25108067, year = {2014}, author = {Ravits, J}, title = {Focality, stochasticity and neuroanatomic propagation in ALS pathogenesis.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {121-126}, pmid = {25108067}, issn = {1090-2430}, support = {R01 EY003878/EY/NEI NIH HHS/United States ; P50 MH077970/MH/NIMH NIH HHS/United States ; R01 EY017210/EY/NEI NIH HHS/United States ; R01NS088578/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*pathology ; Humans ; Motor Neurons/*pathology ; Neural Pathways/*pathology ; *Neuroanatomy ; Phenotype ; Stochastic Processes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) phenotypes such as limb ALS, bulbar ALS, primary lateral sclerosis and primary muscular atrophy are highly heterogeneous and exist on a continuum. These are largely determined by the neuroanatomy of the underlying pathological changes, which can be clinically imputed. Deconstructing these early in disease, before temporal-spatial summation induces complexity, shows that ALS begins focally at a seemingly random location and progresses contiguously. This suggests that focality and anatomic propagation of pathology are significant parts of pathogenesis-disease propagates over space as well as progresses over time. Focality and neuroanatomic propagation can explain how dominant genetic traits manifest with heterogeneous phenotypes, since the anatomic site of outbreak is a prime determinant of phenotype. Focality and neuroanatomic propagation can also explain why frontotemporal dementia (FTD), a neurodegeneration closely related to ALS, has heterogeneous phenotypes, since here too the anatomic site of the outbreak is a prime determinant of phenotype. There are two distinct types of neuroanatomic propagation: contiguous propagation, which occurs side-to-side regionally through the extracellular matrix independent of synaptic connection; and network propagation, which occurs end-to-end dependent on synaptic connections and axonal transmission in connected neuronal networks. The molecular basis of neuroanatomic propagation is unknown, although prion-like misfolding and templating of pathogenic proteins is a compelling unifying hypothesis.}, }
@article {pmid25107477, year = {2014}, author = {Cartier, N and Lewis, CA and Zhang, R and Rossi, FM}, title = {The role of microglia in human disease: therapeutic tool or target?.}, journal = {Acta neuropathologica}, volume = {128}, number = {3}, pages = {363-380}, pmid = {25107477}, issn = {1432-0533}, mesh = {*Central Nervous System Diseases/pathology/physiopathology/therapy ; Humans ; Microglia/*physiology ; }, abstract = {Microglia have long been the focus of much attention due to their strong proliferative response (microgliosis) to essentially any kind of damage to the CNS. More recently, we reached the realization that these cells play specific roles in determining progression and outcomes of essentially all CNS disease. Thus, microglia has ceased to be viewed as an accessory to underlying pathologies and has now taken center stage as a therapeutic target. Here, we review how our understanding of microglia's involvement in promoting or limiting the pathogenesis of diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, multiple sclerosis, X-linked adrenoleukodystrophy (X-ALD) and lysosomal storage diseases (LSD) has changed over time. While strategies to suppress the deleterious and promote the virtuous functions of microglia will undoubtedly be forthcoming, replacement of these cells has already proven its usefulness in a clinical setting. Over the past few years, we have reached the realization that microglia have a developmental origin that is distinct from that of bone marrow-derived myelomonocytic cells. Nevertheless, microglia can be replaced, in specific situations, by the progeny of hematopoietic stem cells (HSCs), pointing to a strategy to engineer the CNS environment through the transplantation of modified HSCs. Thus, microglia replacement has been successfully exploited to deliver therapeutics to the CNS in human diseases such as X-ALD and LSD. With this outlook in mind, we will discuss the evidence existing so far for microglial involvement in the pathogenesis and the therapy of specific CNS disease.}, }
@article {pmid25101284, year = {2014}, author = {Paoli, A and Bianco, A and Damiani, E and Bosco, G}, title = {Ketogenic diet in neuromuscular and neurodegenerative diseases.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {474296}, pmid = {25101284}, issn = {2314-6141}, mesh = {3-Hydroxybutyric Acid/*metabolism ; Alzheimer Disease/diet therapy/metabolism ; Amyotrophic Lateral Sclerosis/diet therapy/metabolism ; Brain/metabolism ; *Diet, Ketogenic ; Glucose/*metabolism ; Glycogen Storage Disease/diet therapy/metabolism ; Humans ; Mitochondrial Diseases/*diet therapy/metabolism ; Parkinson Disease/diet therapy/metabolism ; }, abstract = {An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.}, }
@article {pmid25100994, year = {2014}, author = {Lovejoy, DB and Guillemin, GJ}, title = {The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {6}, number = {}, pages = {173}, pmid = {25100994}, issn = {1663-4365}, abstract = {Modulations of the potentially toxic transition metals iron (Fe) and copper (Cu) are implicated in the neurodegenerative process in a variety of human disease states including amyotrophic lateral sclerosis (ALS). However, the precise role played by these metals is still very much unclear, despite considerable clinical and experimental data suggestive of a role for these elements in the neurodegenerative process. The discovery of mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD-1) in ALS patients established the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper homeostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients, Fe loading can be inferred by studies showing increased expression of serum ferritin, an Fe-storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed to the presence of Fe in the motor cortex. In mutant SOD-1 mouse models, increased Fe is also detected in the spinal cord and treatment with Fe-chelating drugs lowers spinal cord Fe, preserves motor neurons, and extends lifespan. Inflammation may play a key causative role in Fe accumulation, but this is not yet conclusive. Excess transition metals may enhance induction of endoplasmic reticulum (ER) stress, a system that is already under strain in ALS. Taken together, the evidence suggests a role for transition metals in ALS progression and the potential use of metal-chelating drugs as a component of future ALS therapy.}, }
@article {pmid25099276, year = {2014}, author = {Barnham, KJ and Bush, AI}, title = {Biological metals and metal-targeting compounds in major neurodegenerative diseases.}, journal = {Chemical Society reviews}, volume = {43}, number = {19}, pages = {6727-6749}, doi = {10.1039/c4cs00138a}, pmid = {25099276}, issn = {1460-4744}, mesh = {Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Brain/metabolism ; Coordination Complexes/chemistry/therapeutic use ; Humans ; Huntington Disease/drug therapy/metabolism/pathology ; Metals/chemistry/*metabolism ; Neurodegenerative Diseases/drug therapy/metabolism/*pathology ; Parkinson Disease/drug therapy/metabolism/pathology ; }, abstract = {Multiple abnormalities occur in the homeostasis of essential endogenous brain biometals in age-related neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. As a result, metals both accumulate in microscopic proteinopathies, and can be deficient in cells or cellular compartments. Therefore, bulk measurement of metal content in brain tissue samples reveal only the "tip of the iceberg", with most of the important changes occurring on a microscopic and biochemical level. Each of the major proteins implicated in these disorders interacts with biological transition metals. Tau and the amyloid protein precursor have important roles in normal neuronal iron homeostasis. Changes in metal distribution, cellular deficiencies, or sequestration in proteinopathies all present abnormalities that can be corrected in animal models by small molecules. These biochemical targets are more complex than the simple excess of metals that are targeted by chelators. In this review we illustrate some of the richness in the science that has developed in the study of metals in neurodegeneration, and explore its novel pharmacology.}, }
@article {pmid25095817, year = {2014}, author = {Nonneman, A and Robberecht, W and Van Den Bosch, L}, title = {The role of oligodendroglial dysfunction in amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {4}, number = {3}, pages = {223-239}, doi = {10.2217/nmt.14.21}, pmid = {25095817}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Brain/physiology/physiopathology ; Humans ; Motor Neurons/pathology/physiology ; Neural Stem Cells/pathology/physiology ; Oligodendroglia/pathology/*physiology ; Spinal Cord/physiology/physiopathology ; }, abstract = {Healthy oligodendrocytes are crucial for neurons and abnormal functioning of these cells is involved in several neurodegenerative diseases. We will focus on oligodendroglial pathology in amyotrophic lateral sclerosis (ALS), an adult-onset progressive neurodegenerative disease characterized by selective motor neuron loss. Recent discoveries shed new light on the crucial role of oligodendrocytes in this fatal disease. We will first give an overview of the importance of good-functioning oligodendrocytes for neuronal health, in particular for motor neurons. Subsequently, we will discuss the recent data on oligodendroglial abnormalities in ALS. We conclude that oligodendrocytes should be considered as important contributors to motor neuron degeneration. As a consequence, oligodendrocytes are a promising new therapeutic target for ALS and other neurodegenerative diseases.}, }
@article {pmid25091432, year = {2014}, author = {González, H and Elgueta, D and Montoya, A and Pacheco, R}, title = {Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases.}, journal = {Journal of neuroimmunology}, volume = {274}, number = {1-2}, pages = {1-13}, doi = {10.1016/j.jneuroim.2014.07.012}, pmid = {25091432}, issn = {1872-8421}, mesh = {Animals ; Blood-Brain Barrier/immunology ; Humans ; Immune Tolerance/immunology ; Microglia/*immunology ; Neuritis/*immunology ; Neurodegenerative Diseases/*immunology ; Neuroimmunomodulation/*immunology ; }, abstract = {Neuroinflammation constitutes a fundamental process involved in the progression of several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. Microglial cells play a central role in neuroinflammation, promoting neuroprotective or neurotoxic microenvironments, thus controlling neuronal fate. Acquisition of different microglial functions is regulated by intercellular interactions with neurons, astrocytes, the blood-brain barrier, and T-cells infiltrating the central nervous system. In this study, an overview of the regulation of microglial function mediated by different intercellular communications is summarised and discussed. Afterward, we focus in T-cell-mediated regulation of neuroinflammation involved in neurodegenerative disorders.}, }
@article {pmid25090287, year = {2014}, author = {Allcroft, P}, title = {Breathlessness in motor neurone disease: a review of the current strategies and gaps in the evidence.}, journal = {Current opinion in supportive and palliative care}, volume = {8}, number = {3}, pages = {213-217}, doi = {10.1097/SPC.0000000000000077}, pmid = {25090287}, issn = {1751-4266}, mesh = {Analgesics, Opioid/*therapeutic use ; Anxiety/psychology ; Caregivers/psychology ; Dyspnea/psychology/*therapy ; Humans ; Motor Neuron Disease/psychology/*therapy ; Noninvasive Ventilation/*methods/psychology ; Palliative Care/*methods ; Patient Education as Topic ; Quality of Life ; }, abstract = {PURPOSE OF REVIEW: This review on breathlessness and motor neurone disease (MND) is important, as palliative care teams are increasingly becoming involved in the complex care of these patients at an earlier stage in their illness. Subtle cognitive and behavioural changes with MND may make management more challenging. Breathlessness is a distressing symptom, impacting on both patients and carers. Assessment and expectant management of breathlessness improves the quality of life (QoL) and may minimize hospital admission.<br><br>RECENT FINDINGS: Low-dose opioids improve the sensation of breathlessness, with minimal side-effects. It is well established that noninvasive ventilation (NIV) improves survival in patients with MND and also improves health-related QoL of patients with minimal or no bulbar symptoms. Preparation of advance care plans is essential to the provision of care in the final stages of illness in patients with MND and NIV use.<br><br>SUMMARY: Assessment of breathlessness and its successful management improves the QoL of patients with MND. Opioids in titrated doses may play a role in this. NIV improves survival in patients with respiratory failure with minimal or no bulbar symptoms and should be offered when appropriate. Preemptive education improves the uptake and understanding of the role of NIV.}, }
@article {pmid25077344, year = {2014}, author = {Bretón Lesmes, I and Burgos Peláez, R and Cuerda, C and Camblor, M and Velasco, C and Higuera, I and García-Peris, P}, title = {[Nutritional support in chronic neurological diseases].}, journal = {Nutricion hospitalaria}, volume = {29 Suppl 2}, number = {}, pages = {38-46}, pmid = {25077344}, issn = {1699-5198}, mesh = {Chronic Disease ; Humans ; Malnutrition/etiology/therapy ; Nervous System Diseases/complications/metabolism/*therapy ; Neurodegenerative Diseases/therapy ; Nutritional Support/*methods ; }, abstract = {Malnutrition is common in neurodegenerative disorders and is associated with a worse prognosis and an increased risk of complications. Factors leading to malnutrition in these patients are: diseased nutrient intake, due to anorexia, dysphagia and other factors, gastrointestinal symptoms, and energy expenditure alterations. Nutritional evaluation and monitoring is mandatory and should be part of regular clinical evaluation. It will help to identify those patients that need specialized nutritional support. In this paper, relevant aspects regarding nutritional evaluation and support in patients suffering from a neurodegenerative disorder are reviewed, including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and dementia.}, }
@article {pmid25077336, year = {2014}, author = {Planas Vilà, M}, title = {[Nutritional and metabolic aspects of neurological diseases].}, journal = {Nutricion hospitalaria}, volume = {29 Suppl 2}, number = {}, pages = {3-12}, pmid = {25077336}, issn = {1699-5198}, mesh = {Brain Injuries/therapy ; Humans ; Nervous System Diseases/*metabolism/*physiopathology/therapy ; *Nutritional Physiological Phenomena ; Nutritional Support ; }, abstract = {The central nervous system regulates food intake, homoeostasis of glucose and electrolytes, and starts the sensations of hunger and satiety. Different nutritional factors are involved in the pathogenesis of several neurological diseases. Patients with acute neurological diseases (traumatic brain injury, cerebral vascular accident hemorrhagic or ischemic, spinal cord injuries, and cancer) and chronic neurological diseases (Alzheimer's Disease and other dementias, amyotrophic lateral sclerosis, Parkinson's Disease) increase the risk of malnutrition by multiple factors related to nutrient ingestion, abnormalities in the energy expenditure, changes in eating behavior, gastrointestinal changes, and by side effects of drugs administered. Patients with acute neurological diseases have in common the presence of hyper metabolism and hyper catabolism both associated to a period of prolonged fasting mainly for the frequent gastrointestinal complications, many times as a side effect of drugs administered. During the acute phase, spinal cord injuries presented a reduction in the energy expenditure but an increase in the nitrogen elimination. In order to correct the negative nitrogen balance increase intakes is performed with the result of a hyper alimentation that should be avoided due to the complications resulting. In patients with chronic neurological diseases and in the acute phase of cerebrovascular accident, dysphagia could be present which also affects intakes. Several chronic neurological diseases have also dementia, which lead to alterations in the eating behavior. The presence of malnutrition complicates the clinical evolution, increases muscular atrophy with higher incidence of respiratory failure and less capacity to disphagia recuperation, alters the immune response with higher rate of infections, increases the likelihood of fractures and of pressure ulcers, increases the incapacity degree and is an independent factor to increase mortality. The periodic nutritional evaluation due to the evolutionary changes should be part of the treatment. At the same time to know the metabolic and nutritional characteristics is important to be able to prevent and treat early the possible side effects. If nutritional support is indicated, the enteral route is the route of choice although some times, mainly in critical patients, parentral nutrition is necessary to ensure the administration of the required nutrients.}, }
@article {pmid25073774, year = {2015}, author = {Finsterer, J and Aliyev, R}, title = {Fasciculations in human hereditary disease.}, journal = {Acta neurologica Belgica}, volume = {115}, number = {2}, pages = {91-95}, doi = {10.1007/s13760-014-0335-6}, pmid = {25073774}, issn = {2240-2993}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Databases, Bibliographic/statistics &amp; numerical data ; Fasciculation/*etiology/*genetics ; Genetic Diseases, Inborn/complications ; Humans ; Muscular Atrophy, Spinal/complications ; }, abstract = {Fasciculations are a manifestation of peripheral nerve hyperexcitability in addition to myokymia, neuromyotonia, cramps, or tetany. Fasciculations occur in hereditary and non-hereditary diseases. Among the hereditary diseases, fasciculations are most frequently reported in familial amyotrophic lateral sclerosis (FALS), and spinal muscular atrophy (SMA). Among the non-hereditary diseases, fasciculations occur most frequently in peripheral nerve hyperexcitability syndromes (Isaac's syndrome, voltage-gated potassium channelopathy, cramp fasciculation syndrome, Morvan syndrome). If the cause of fasciculations remains unknown, they are called benign. Systematically reviewing the literature about fasciculations in hereditary disease shows that fasciculations can be a phenotypic feature in bulbospinal muscular atrophy (BSMA), GM2-gangliosidosis, triple-A syndrome, or hereditary neuropathy. Additionally, fasciculations have been reported in familial amyloidosis, spinocerebellar ataxias, Huntington's disease, Rett syndrome, central nervous system disease due to L1-cell adhesion molecule (L1CAM) mutations, Fabry's disease, or Gerstmann-Sträussler disease. Rarely, fasciculations may be a phenotypic feature in patients with mitochondrial disorders or other myopathies. Fasciculations are part of the phenotype in much more genetic disorders than commonly assumed. Fasciculations not only occur in motor neuron disease, but also in hereditary neuropathy, spinocerebellar ataxia, GM2-gangliosidosis, Huntington's disease, Rett syndrome, Fabry's disease, Gerstmann-Sträussler disease, mitochondrial disorders, or muscular dystrophies.}, }
@article {pmid25071843, year = {2014}, author = {Coppedè, F}, title = {The potential of epigenetic therapies in neurodegenerative diseases.}, journal = {Frontiers in genetics}, volume = {5}, number = {}, pages = {220}, pmid = {25071843}, issn = {1664-8021}, abstract = {Available treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, do not arrest disease progression but mainly help keeping patients from getting worse for a limited period of time. Increasing evidence suggests that epigenetic mechanisms such as DNA methylation and histone tail modifications are dynamically regulated in neurons and play a fundamental role in learning and memory processes. In addition, both global and gene-specific epigenetic changes and deregulated expression of the writer and eraser proteins of epigenetic marks are believed to contribute to the onset and progression of neurodegeneration. Studies in animal models of neurodegenerative diseases have highlighted the potential role of epigenetic drugs, including inhibitors of histone deacetylases and methyl donor compounds, in ameliorating the cognitive symptoms and preventing or delaying the motor symptoms of the disease, thereby opening the way for a potential application in human pathology.}, }
@article {pmid25071440, year = {2014}, author = {Atkin, G and Paulson, H}, title = {Ubiquitin pathways in neurodegenerative disease.}, journal = {Frontiers in molecular neuroscience}, volume = {7}, number = {}, pages = {63}, pmid = {25071440}, issn = {1662-5099}, abstract = {Control of proper protein synthesis, function, and turnover is essential for the health of all cells. In neurons these demands take on the additional importance of supporting and regulating the highly dynamic connections between neurons that are necessary for cognitive function, learning, and memory. Regulating multiple unique synaptic protein environments within a single neuron while maintaining cell health requires the highly regulated processes of ubiquitination and degradation of ubiquitinated proteins through the proteasome. In this review, we examine the effects of dysregulated ubiquitination and protein clearance on the handling of disease-associated proteins and neuronal health in the most common neurodegenerative diseases.}, }
@article {pmid25064045, year = {2015}, author = {Karki, P and Smith, K and Johnson, J and Aschner, M and Lee, EY}, title = {Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity.}, journal = {Neurochemical research}, volume = {40}, number = {2}, pages = {380-388}, pmid = {25064045}, issn = {1573-6903}, support = {R01ES10563/ES/NIEHS NIH HHS/United States ; SC1 GM089630/GM/NIGMS NIH HHS/United States ; R25 GM059994/GM/NIGMS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; SC1089630/SC/NCI NIH HHS/United States ; G12 RR003032/RR/NCRR NIH HHS/United States ; R01ES10563S1/ES/NIEHS NIH HHS/United States ; }, mesh = {Astrocytes/*metabolism ; Epigenesis, Genetic ; Excitatory Amino Acid Transporter 2/*genetics/metabolism ; Humans ; Manganese/*toxicity ; Nervous System Diseases/chemically induced/*genetics ; Protein Biosynthesis ; Protein Processing, Post-Translational ; Transcription, Genetic ; }, abstract = {Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 (glutamate transporter 1 and glutamate aspartate transporter in rodents, respectively), are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.}, }
@article {pmid25063708, year = {2014}, author = {Heiman, A and Pallottie, A and Heary, RF and Elkabes, S}, title = {Toll-like receptors in central nervous system injury and disease: a focus on the spinal cord.}, journal = {Brain, behavior, and immunity}, volume = {42}, number = {}, pages = {232-245}, doi = {10.1016/j.bbi.2014.06.203}, pmid = {25063708}, issn = {1090-2139}, mesh = {Animals ; Humans ; Spinal Cord/*metabolism/pathology ; Spinal Cord Diseases/*metabolism/pathology ; Spinal Cord Injuries/*metabolism/pathology ; Toll-Like Receptors/*metabolism ; }, abstract = {Toll-like receptors (TLRs) are best known for recognizing pathogens and initiating an innate immune response to protect the host. However, they also detect tissue damage and induce sterile inflammation upon the binding of endogenous ligands released by stressed or injured cells. In addition to immune system-related cells, TLRs have been identified in central nervous system (CNS) neurons and glial subtypes including microglia, astrocytes and oligodendrocytes. Direct and indirect effects of TLR ligands on neurons and glial subtypes have been documented in vitro. Likewise, the effects of TLR ligands have been demonstrated in vivo using animal models of CNS trauma and disease including spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS) and neuropathic pain. The indirect effects are most likely mediated via microglia or immune system cells that infiltrate the diseased or injured CNS. Despite considerable progress over the past decade, the role of TLRs in the physiological and pathological function of the spinal cord remains inadequately defined. Published reports collectively highlight TLRs as promising targets for therapeutic interventions in spinal cord pathology. The findings also underscore the complexity of TLR-mediated mechanisms and the necessity for further research in this field. The goals of the current review are to recapitulate the studies that investigated the role of TLRs in the spinal cord, to discuss potential future research directions, and to examine some of the challenges associated with pre-clinical studies pertinent to TLRs in the injured or diseased spinal cord.}, }
@article {pmid25062761, year = {2014}, author = {Plecash, AR and Leavitt, BR}, title = {Aquatherapy for neurodegenerative disorders.}, journal = {Journal of Huntington's disease}, volume = {3}, number = {1}, pages = {5-11}, doi = {10.3233/JHD-140010}, pmid = {25062761}, issn = {1879-6397}, mesh = {Amyotrophic Lateral Sclerosis/rehabilitation ; Exercise Therapy/*methods ; Humans ; Huntington Disease/rehabilitation ; Hydrotherapy/*methods ; Multiple Sclerosis/rehabilitation ; Neurodegenerative Diseases/*rehabilitation ; Parkinson Disease/rehabilitation ; Resistance Training/methods ; Treatment Outcome ; }, abstract = {Aquatherapy is used for rehabilitation and exercise; water provides a challenging, yet safe exercise environment for many special populations. We have reviewed the use of aquatherapy programs in four neurodegenerative disorders: Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Results support the use of aquatherapy in Parkinson's disease and multiple sclerosis, however further evidence is required to make specific recommendations in all of the aforementioned disorders.}, }
@article {pmid25061302, year = {2014}, author = {Schoedel, KA and Morrow, SA and Sellers, EM}, title = {Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect.}, journal = {Neuropsychiatric disease and treatment}, volume = {10}, number = {}, pages = {1161-1174}, pmid = {25061302}, issn = {1176-6328}, abstract = {Pseudobulbar affect (PBA) is a common manifestation of brain pathology associated with many neurological diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease, and traumatic brain injury. PBA is defined by involuntary and uncontrollable expressed emotion that is exaggerated and inappropriate, and also incongruent with the underlying emotional state. Dextromethorphan/quinidine (DM/Q) is a combination product indicated for the treatment of PBA. The quinidine component of DM/Q inhibits the cytochrome P450 2D6-mediated metabolic conversion of dextromethorphan to its active metabolite dextrorphan, thereby increasing dextromethorphan systemic bioavailability and driving the pharmacology toward that of the parent drug and away from adverse effects of the dextrorphan metabolite. Three published efficacy and safety studies support the use of DM/Q in the treatment of PBA; significant effects were seen on the primary end point, the Center for Neurologic Study-Lability Scale, as well as secondary efficacy end points and quality of life. While concentration-effect relationships appear relatively weak for efficacy parameters, concentrations of DM/Q may have an impact on safety. Some special safety concerns exist with DM/Q, primarily because of the drug interaction and QT prolongation potential of the quinidine component. However, because concentrations of dextrorphan (which is responsible for many of the parent drug's side effects) and quinidine are lower than those observed in clinical practice with these drugs administered alone, some of the perceived safety issues may not be as relevant with this low dose combination product. However, since patients with PBA have a variety of other medical problems and are on numerous other medications, they may not tolerate DM/Q adverse effects, or may be at risk for drug interactions. Some caution is warranted when initiating DM/Q treatment, particularly in patients with underlying risk factors for torsade de pointes and in those receiving medications that may interact with DM/Q.}, }
@article {pmid25056458, year = {2014}, author = {Radi, E and Formichi, P and Battisti, C and Federico, A}, title = {Apoptosis and oxidative stress in neurodegenerative diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {42 Suppl 3}, number = {}, pages = {S125-52}, doi = {10.3233/JAD-132738}, pmid = {25056458}, issn = {1875-8908}, mesh = {Animals ; Apoptosis/*physiology ; Disease Progression ; Humans ; Models, Biological ; Neurodegenerative Diseases/pathology/*physiopathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative disorders affect almost 30 million individuals leading to disability and death. These disorders are characterized by pathological changes in disease-specific areas of the brain and degeneration of distinct neuron subsets. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear similar, suggesting common neurodegenerative pathways. Apoptosis seems to play a key role in the progression of several neurologic disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis as demonstrated by studies on animal models and cell lines. On the other hand, research on human brains reported contradictory results. However, many dying neurons have been detected in brains of patients with neurodegenerative diseases, and these conditions are often associated with significant cell loss accompanied by typical morphological features of apoptosis such as chromatin condensation, DNA fragmentation, and activation of cysteine-proteases, caspases. Cell death and neurodegenerative conditions have been linked to oxidative stress and imbalance between generation of free radicals and antioxidant defenses. Multiple sclerosis, stroke, and neurodegenerative diseases have been associated with reactive oxygen species and nitric oxide. Here we present an overview of the involvement of neuronal apoptosis and oxidative stress in the most important neurodegenerative diseases, mainly focusing the attention on several genetic disorders, discussing the interaction between primary genetic abnormalities and the apoptotic pathways.}, }
@article {pmid25048984, year = {2015}, author = {Zhang, HY and Wang, ZG and Lu, XH and Kong, XX and Wu, FZ and Lin, L and Tan, X and Ye, LB and Xiao, J}, title = {Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases.}, journal = {Molecular neurobiology}, volume = {51}, number = {3}, pages = {1343-1352}, pmid = {25048984}, issn = {1559-1182}, mesh = {Animals ; Central Nervous System Diseases/*metabolism/pathology/*therapy ; Endoplasmic Reticulum/*metabolism/pathology ; Endoplasmic Reticulum Stress/*physiology ; Humans ; Neurons/*metabolism ; Signal Transduction/*physiology ; Unfolded Protein Response/physiology ; }, abstract = {Endoplasmic reticulum (ER) stress plays an important role in a range of neurological disorders, such as neurodegenation diseases, cerebral ischemia, spinal cord injury, sclerosis, and diabetic neuropathy. Protein misfolding and accumulation in the ER lumen initiate unfolded protein response in energy-starved neurons which are relevant to toxic effects. In neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, ER dysfunction is well recognized, but the mechanisms remain unclear. In stroke and ischemia, spinal cord injury, and amyotrophic lateral sclerosis, chronic activation of ER stress is considered as main pathogeny which causes neuronal disorders. By targeting components of these ER signaling responses, to explore clinical treatment strategies or new drugs in CNS neurological diseases might become possible and valuable in the future.}, }
@article {pmid25047909, year = {2014}, author = {Łukaszewicz-Zając, M and Mroczko, B and Słowik, A}, title = {Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in amyotrophic lateral sclerosis (ALS).}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {121}, number = {11}, pages = {1387-1397}, pmid = {25047909}, issn = {1435-1463}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; Matrix Metalloproteinases/*metabolism ; Tissue Inhibitor of Metalloproteinases/*metabolism ; }, abstract = {Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, responsible for the integrity of the basement membrane (BM) via degradation of extracellular matrix and BM components. These enzymes are presented in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, including amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disease, leading to muscle atrophy, paralysis and death within 3-5 years from diagnosis. Currently, there is no treatment that can substantially prolong life of ALS patients. Despite the fact that MMPs are not specific for ALS, there is also strong evidence that these enzymes are involved in the pathology of ALS. MMPs are able to exert direct neurotoxic effects, or may cause cell death by degrading matrix proteins. The objective of this paper is to provide an updated and comprehensive review concerning the role of MMPs and their tissue inhibitors (TIMPs) in the pathology of ALS with an emphasis on the significance of MMP-2 and MMP-9 as well as their tissue inhibitors as potential biomarkers of ALS. Numerous hypotheses have been proposed regarding the role of selected MMPs and TIMPs in ALS pathogenesis. Moreover, selective MMPs' inhibitors might be potential targets for therapeutic strategies for patients with ALS. However, future investigations are necessary before some of those non-specific for ALS enzymes could finally be used as biomarkers of this disease.}, }
@article {pmid25034472, year = {2014}, author = {Lefaucheur, JP and André-Obadia, N and Antal, A and Ayache, SS and Baeken, C and Benninger, DH and Cantello, RM and Cincotta, M and de Carvalho, M and De Ridder, D and Devanne, H and Di Lazzaro, V and Filipović, SR and Hummel, FC and Jääskeläinen, SK and Kimiskidis, VK and Koch, G and Langguth, B and Nyffeler, T and Oliviero, A and Padberg, F and Poulet, E and Rossi, S and Rossini, PM and Rothwell, JC and Schönfeldt-Lecuona, C and Siebner, HR and Slotema, CW and Stagg, CJ and Valls-Sole, J and Ziemann, U and Paulus, W and Garcia-Larrea, L}, title = {Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {125}, number = {11}, pages = {2150-2206}, doi = {10.1016/j.clinph.2014.05.021}, pmid = {25034472}, issn = {1872-8952}, support = {102584//Wellcome Trust/United Kingdom ; }, mesh = {Cerebral Cortex/*physiopathology ; Epilepsy/physiopathology/*therapy ; Evidence-Based Medicine ; Humans ; Mental Disorders/physiopathology/*therapy ; Movement Disorders/physiopathology/*therapy ; Multiple Sclerosis/physiopathology/*therapy ; Stroke/physiopathology/*therapy ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.}, }
@article {pmid25033844, year = {2014}, author = {Srivastava, AK}, title = {Clinical relevance of stem cell therapies in amyotrophic lateral sclerosis.}, journal = {Neurology India}, volume = {62}, number = {3}, pages = {239-248}, doi = {10.4103/0028-3886.136895}, pmid = {25033844}, issn = {0028-3886}, mesh = {Amyotrophic Lateral Sclerosis/surgery/*therapy ; *Clinical Trials as Topic ; Humans ; Stem Cell Transplantation/*methods/standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS), characterized by the progressive loss of both upper and lower motor neurons, is a fatal neurodegenerative disorder. This disease is often accompanied by a tremendous physical and emotional burden not only for the patients, but also for their families and friends as well. There is no clinically relevant treatment available for ALS. To date, only one Food and Drug Administration (FDA)-approved drug, Riluzole, licensed 18 years ago, has been proven to marginally prolong patients' survival without improving the quality of their lives. Because of the lack of an effective drug treatment and the promising outcomes from several preclinical studies, researchers have highlighted this disease as a suitable candidate for stem cell therapy. This review article highlights the finding of key preclinical studies that present a rationale for the use of different types of stem cells for the treatment of ALS, and the most recent updates on the stem cell-based ALS clinical trials around the world.}, }
@article {pmid25033177, year = {2014}, author = {Madabhushi, R and Pan, L and Tsai, LH}, title = {DNA damage and its links to neurodegeneration.}, journal = {Neuron}, volume = {83}, number = {2}, pages = {266-282}, pmid = {25033177}, issn = {1097-4199}, support = {R01 AG046174/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*genetics/pathology ; *DNA Damage ; DNA Repair ; Humans ; Nerve Degeneration/*genetics/pathology ; Neurodegenerative Diseases/*genetics/pathology ; Neurons/*pathology ; }, abstract = {The integrity of our genetic material is under constant attack from numerous endogenous and exogenous agents. The consequences of a defective DNA damage response are well studied in proliferating cells, especially with regards to the development of cancer, yet its precise roles in the nervous system are relatively poorly understood. Here we attempt to provide a comprehensive overview of the consequences of genomic instability in the nervous system. We highlight the neuropathology of congenital syndromes that result from mutations in DNA repair factors and underscore the importance of the DNA damage response in neural development. In addition, we describe the findings of recent studies, which reveal that a robust DNA damage response is also intimately connected to aging and the manifestation of age-related neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid25031631, year = {2014}, author = {Fecto, F and Esengul, YT and Siddique, T}, title = {Protein recycling pathways in neurodegenerative diseases.}, journal = {Alzheimer's research &amp; therapy}, volume = {6}, number = {2}, pages = {13}, pmid = {25031631}, issn = {1758-9193}, support = {R01 NS078504/NS/NINDS NIH HHS/United States ; }, abstract = {Many progressive neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal lobe dementia, are associated with the formation of insoluble intracellular proteinaceous inclusions. It is therefore imperative to understand the factors that regulate normal, as well as abnormal, protein recycling in neurons. Dysfunction of the ubiquitin-proteasome or autophagy pathways might contribute to the pathology of various neurodegenerative diseases. Induction of these pathways may offer a rational therapeutic strategy for a number of these diseases.}, }
@article {pmid25017368, year = {2014}, author = {Poppe, L and Rué, L and Robberecht, W and Van Den Bosch, L}, title = {Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS).}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {138-151}, doi = {10.1016/j.expneurol.2014.07.001}, pmid = {25017368}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Disease Models, Animal ; Humans ; Translational Research, Biomedical/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. It is a neurodegenerative disorder with high genetic and phenotypic variability. In most patients, the cause of the disease is unknown. Until now, no treatment strategy has been discovered with the exception of riluzole which has a moderate effect on the disease process. While developing a new causal therapy targeting a specific disease-causing gene can have a huge effect on the disease process, only a limited number of ALS patients will benefit from such a therapy. Alternatively, pathogenic processes that are common in ALS patients with different etiology can also be targeted. The effect of such a modifying treatment will be smaller, but the target population will be larger as more ALS patients could benefit. In this review, we summarize the evidence for the involvement of different biological processes in the pathogenesis of ALS and will discuss how strategies influencing these processes can be translated into new therapeutic approaches. In order to further improve this translational step, there is an urgent need for a better understanding of the underlying mechanism(s), for new ALS animal models and for rigorous protocols to perform preclinical studies.}, }
@article {pmid25015502, year = {2014}, author = {McKendall, RR}, title = {Neurologic disease due to HTLV-1 infection.}, journal = {Handbook of clinical neurology}, volume = {123}, number = {}, pages = {507-530}, doi = {10.1016/B978-0-444-53488-0.00024-9}, pmid = {25015502}, issn = {0072-9752}, mesh = {Central Nervous System/pathology/virology ; HTLV-I Infections/*complications/epidemiology ; Human T-lymphotropic virus 1/*pathogenicity ; Humans ; Nervous System Diseases/*etiology/*virology ; }, }
@article {pmid25015500, year = {2014}, author = {Douville, RN and Nath, A}, title = {Human endogenous retroviruses and the nervous system.}, journal = {Handbook of clinical neurology}, volume = {123}, number = {}, pages = {465-485}, pmid = {25015500}, issn = {0072-9752}, support = {ZIA NS003130-01//Intramural NIH HHS/United States ; }, mesh = {*Endogenous Retroviruses/genetics/pathogenicity ; Humans ; Nervous System/pathology/*virology ; Nervous System Diseases/*pathology/*virology ; }, }
@article {pmid25007880, year = {2015}, author = {Corona, JC and Duchen, MR}, title = {PPARγ and PGC-1α as therapeutic targets in Parkinson's.}, journal = {Neurochemical research}, volume = {40}, number = {2}, pages = {308-316}, pmid = {25007880}, issn = {1573-6903}, support = {G-1101/PUK_/Parkinson's UK/United Kingdom ; MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; PPAR gamma/*agonists ; Parkinson Disease/*drug therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Transcription Factors/*drug effects ; }, abstract = {The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. PPARγ was initially identified through its role in the regulation of glucose and lipid metabolism and cell differentiation. It also influences the expression or activity of a number of genes in a variety of signalling networks. These include regulation of redox balance, fatty acid oxidation, immune responses and mitochondrial function. Recent studies suggest that the PPARγ agonists may serve as good candidates for the treatment of several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, even though multiple etiological factors contribute to the development of these disorders. Recent reports have also signposted a role for PPARγ coactivator-1α (PGC-1α) in several neurodegenerative disorders including PD. In this review, we explore the current knowledge of mechanisms underlying the beneficial effects of PPARγ agonists and PGC-1α in models of PD.}, }
@article {pmid25005189, year = {2015}, author = {Burnstock, G}, title = {Physiopathological roles of P2X receptors in the central nervous system.}, journal = {Current medicinal chemistry}, volume = {22}, number = {7}, pages = {819-844}, doi = {10.2174/0929867321666140706130415}, pmid = {25005189}, issn = {1875-533X}, mesh = {Animals ; Central Nervous System/*physiopathology ; Central Nervous System Diseases/*physiopathology ; Humans ; Receptors, Purinergic P2X/*physiology ; Signal Transduction ; }, abstract = {Potent actions of ATP in the central nervous system (CNS) were reported in the late 1940's, but cloning and characterisation of receptors for purines and pyrimidines did not take place until the early 1990's, which identified seven P2X ion channel receptor subtypes, three of which form the cation channel as homomultimers or heteromultimers. P2X receptor subtypes are widely expressed in the CNS and their distribution is described in different regions. They function in synaptic cotransmission and neuromodulation, as well as in trophic signalling. ATP released from nerves and astroglial cells are predominantly involved in neuron-glial interactions. Purinergic signalling is involved in normal behaviour, including learning and memory, sleep and arousal, locomotor and feeding activities and cognition. P2X receptors participate in CNS pathophysiology, including injury, inflammation, Alzheimer's and Parkinson's diseases, multiple sclerosis and amyotrophic lateral sclerosis, depression and anxiety. P2X4 and P2X7 receptor antagonists are effective via microglia against neuropathic pain, while P2X3 receptor antagonists also reduce neuropathic pain, but via a different mechanism.}, }
@article {pmid25005187, year = {2014}, author = {Lee, J and Ryu, H and Keum, G and Yoon, YJ and Kowall, NW and Ryu, H}, title = {Therapeutic targeting of epigenetic components in amyotrophic lateral sclerosis (ALS).}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3576-3582}, doi = {10.2174/0929867321666140706131825}, pmid = {25005187}, issn = {1875-533X}, support = {I01 BX000856/BX/BLRD VA/United States ; NS067283/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; Animals ; *Epigenesis, Genetic ; Histone Deacetylase Inhibitors/therapeutic use ; Histone Deacetylases/chemistry/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Valproic Acid/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by degeneration of motor neuron and glial activation followed by the progressive muscle loss and paralysis. Numerous distinct therapeutic interventions have been examined but currently ALS does not have a cure or an efficacious treatment for the disorder. Glutamate- induced excitotoxicity, inflammation, mitochondrial dysfunction, oxidative stress, protein aggregation, transcription deregulation, and epigenetic modifications are associated with the pathogenesis of ALS and known to be therapeutic targets in ALS. In this review, we discuss translational pharmacological studies targeting epigenetic components to ameliorate ALS. Understanding of the epigenetic mechanisms will provide novel insights that will further identify potential biological markers and therapeutic approaches for treating ALS. A combination of treatments that modulate epigenetic components and multiple targets may prove to be the most effective therapy for ALS.}, }
@article {pmid25005000, year = {2014}, author = {Kearse, MG and Todd, PK}, title = {Repeat-associated non-AUG translation and its impact in neurodegenerative disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {11}, number = {4}, pages = {721-731}, pmid = {25005000}, issn = {1878-7479}, support = {K08NS069809/NS/NINDS NIH HHS/United States ; R01 NS086810/NS/NINDS NIH HHS/United States ; F32 NS089124/NS/NINDS NIH HHS/United States ; 30-AG13283/AG/NIA NIH HHS/United States ; R01NS086810/NS/NINDS NIH HHS/United States ; P30 AG013283/AG/NIA NIH HHS/United States ; F32NS089124/NS/NINDS NIH HHS/United States ; K08 NS069809/NS/NINDS NIH HHS/United States ; }, mesh = {DNA Repeat Expansion ; Humans ; Neurodegenerative Diseases/*genetics ; Open Reading Frames ; *Peptide Chain Initiation, Translational ; }, abstract = {Nucleotide repeat expansions underlie numerous human neurological disorders. Repeats can trigger toxicity through multiple pathogenic mechanisms, including RNA gain-of-function, protein gain-of-function, and protein loss-of-function pathways. Traditionally, inference of the underlying pathogenic mechanism derives from the repeat location, with dominantly inherited repeats within transcribed noncoding sequences eliciting toxicity predominantly as RNA via sequestration of specific RNA binding proteins. However, recent findings question this assumption and suggest that repeats outside of annotated open reading frames may also trigger toxicity through a novel form of protein translational initiation known as repeat-associated non-AUG (RAN) translation. To date, RAN translation has been implicated in 4 nucleotide repeat expansion disorders: spinocerebellar ataxia type 8; myotonic dystrophy type 1 with CTG•CAG repeats; C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia with GGGGCC•GGCCCC repeats; and fragile X-associated tremor/ataxia syndrome with CGG repeats. RAN translation contributes to hallmark pathological characteristics in these disorders by producing homopolymeric or dipeptide repeat proteins. Here, we review what is known about RAN translation, with an emphasis on how differences in both repeat sequence and context may confer different requirements for unconventional initiation. We then discuss how this new mechanism of translational initiation might function in normal physiology and lay out a roadmap for addressing the numerous questions that remain.}, }
@article {pmid24991560, year = {2014}, author = {Robelin, L and Gonzalez De Aguilar, JL}, title = {Blood biomarkers for amyotrophic lateral sclerosis: myth or reality?.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {525097}, pmid = {24991560}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/*blood/pathology ; Biomarkers/*blood ; Disease Progression ; Humans ; Motor Neurons/metabolism/pathology ; *Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal condition primarily characterized by the selective loss of upper and lower motor neurons. At present, the diagnosis and monitoring of ALS is based on clinical examination, electrophysiological findings, medical history, and exclusion of confounding disorders. There is therefore an undeniable need for molecular biomarkers that could give reliable information on the onset and progression of ALS in clinical practice and therapeutic trials. From a practical point of view, blood offers a series of advantages, including easy handling and multiple testing at a low cost, that make it an ideal source of biomarkers. In this review, we revisited the findings of many studies that investigated the presence of systemic changes at the molecular and cellular level in patients with ALS. The results of these studies reflect the diversity in the pathological mechanisms contributing to disease (e.g., excitotoxicity, oxidative stress, neuroinflammation, metabolic dysfunction, and neurodegeneration, among others) and provide relatively successful evidence of the usefulness of a wide-ranging panel of molecules as potential biomarkers. More studies, hopefully internationally coordinated, would be needed, however, to translate the application of these biomarkers into benefit for patients.}, }
@article {pmid24987705, year = {2014}, author = {Pronto-Laborinho, AC and Pinto, S and de Carvalho, M}, title = {Roles of vascular endothelial growth factor in amyotrophic lateral sclerosis.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {947513}, pmid = {24987705}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/pathology ; Animals ; Axons/metabolism/pathology ; Brain Stem/metabolism/pathology ; Cell Movement/drug effects ; Disease Models, Animal ; Humans ; Motor Cortex/metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/*metabolism ; Riluzole/therapeutic use ; Spinal Cord/metabolism/pathology ; Vascular Endothelial Growth Factor B ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS.}, }
@article {pmid24986107, year = {2014}, author = {Hamidou, B and Couratier, P and Besançon, C and Nicol, M and Preux, PM and Marin, B}, title = {Epidemiological evidence that physical activity is not a risk factor for ALS.}, journal = {European journal of epidemiology}, volume = {29}, number = {7}, pages = {459-475}, pmid = {24986107}, issn = {1573-7284}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology ; Epidemiologic Studies ; Football ; Humans ; *Motor Activity ; Occupational Exposure/*adverse effects ; Occupations ; Risk Factors ; Soccer ; Sports ; }, abstract = {To elucidate whether physical activity (PA) and sport increase the risk of developing amyotrophic lateral sclerosis (ALS), a literature review of epidemiological studies was conducted according to the Meta-analysis of Observational Studies in Epidemiology guidelines. Six databases (Pubmed, Scopus, ScienceDirect, IngentaConnect, Refdoc and the Cochrane database) were searched to April 2014. Experts were asked to identify studies in press. Studies of interest were examined for their level of evidence and synthetized using Armon's classification for exogenous risk factors for ALS. Of 37 epidemiological works included in the review, two (5.5%) provided class I evidence, and five (13.5%) class II. Others offered evidence of class III (n = 8, 21.6%), IV (n = 16, 43.2%) and V (n = 6, 16.2%). Results were stratified according to type of exposure: (1) PA related to sport and work (n = 14), (2) soccer and American football (n = 9), (3) occupation (n = 12), (4) proxies of PA (n = 2). Among articles which considered "PA related to sport and work", two class I studies and one class II study concluded that PA is not a risk factor for ALS. This evidence establishes (level A) that PA is not a risk factor for ALS. As regards "occupational related activity" a level of evidence of U was obtained (it is unknown whether the professional category "physical worker" is a risk factor for ALS). Football/soccer may be considered as a possible risk factor for ALS (level C) and there is a need for further research taking into account the numerous confounding factors that may arise in this field.}, }
@article {pmid24975171, year = {2015}, author = {Ahuja, A and Dev, K and Tanwar, RS and Selwal, KK and Tyagi, PK}, title = {Copper mediated neurological disorder: visions into amyotrophic lateral sclerosis, Alzheimer and Menkes disease.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {29}, number = {}, pages = {11-23}, doi = {10.1016/j.jtemb.2014.05.003}, pmid = {24975171}, issn = {1878-3252}, mesh = {Alzheimer Disease/*etiology/pathology ; Amyotrophic Lateral Sclerosis/*etiology/pathology ; Brain/metabolism/pathology ; Copper/*adverse effects ; Humans ; Menkes Kinky Hair Syndrome/*etiology/pathology ; Oxidative Stress ; }, abstract = {Copper (Cu) is a vital redox dynamic metal that is possibly poisonous in superfluous. Metals can traditionally or intricately cause propagation in reactive oxygen species (ROS) accretion in cells and this may effect in programmed cell death. Accumulation of Cu causes necrosis that looks to be facilitated by DNA damage, followed by activation of P53. Cu dyshomeostasis has also been concerned in neurodegenerative disorders such as Alzheimer, Amyotrophic lateral sclerosis (ALS) or Menkes disease and is directly related to neurodegenerative syndrome that usually produces senile dementia. These mortal syndromes are closely related with an immense damage of neurons and synaptic failure in the brain. This review focuses on copper mediated neurological disorders with insights into amyotrophic lateral sclerosis, Alzheimer and Menkes disease.}, }
@article {pmid24973986, year = {2015}, author = {Tan, L and Yu, JT and Tan, L}, title = {Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {51}, number = {3}, pages = {1249-1262}, pmid = {24973986}, issn = {1559-1182}, mesh = {Animals ; Biomarkers/*blood ; *Genetic Predisposition to Disease ; *Genetic Therapy ; Humans ; MicroRNAs/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Neurons/*metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), originate from a loss of neurons in the central nervous system (CNS) and are severely debilitating. The incidence of neurodegenerative diseases increases with age, and they are expected to become more common due to extended life expectancy. Because of no clear mechanisms, these diseases have become a major challenge in neurobiology. It is well recognized that these disorders become the culmination of many different genetic and environmental influences. Prior studies have shown that microRNAs (miRNAs) are pathologically altered during the inexorable course of some neurodegenerative diseases, suggesting that miRNAs may be the contributing factor in neurodegeneration. Here, we review what is known about the involvement of miRNAs in the pathogenesis of neurodegenerative diseases. The biogenesis of miRNAs and various functions of miRNAs that act as the chief regulators will be discussed. We focus in particular on dysregulation of miRNAs which leads to several neurodegenerative diseases from three aspects: miRNA-generating disorders, miRNA-targeting genes and epigenetic alterations. Furthermore, recent evidences have shown that circulating miRNA expression levels are changed in patients with neurodegenerative diseases. Circulating miRNA expression levels are reported in patients in order to evaluate their application as biomarkers of these diseases. A discussion is included with a potential diagnostic biomarker and the possible future direction in exploring the nexus between miRNAs and various neurodegenerative diseases.}, }
@article {pmid24973750, year = {2014}, author = {Patten, SA and Armstrong, GA and Lissouba, A and Kabashi, E and Parker, JA and Drapeau, P}, title = {Fishing for causes and cures of motor neuron disorders.}, journal = {Disease models &amp; mechanisms}, volume = {7}, number = {7}, pages = {799-809}, pmid = {24973750}, issn = {1754-8411}, mesh = {Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Motor Neuron Disease/*drug therapy/*etiology/pathology ; Signal Transduction ; Zebrafish/*metabolism ; }, abstract = {Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.}, }
@article {pmid24971285, year = {2013}, author = {Di Iorio, G and Lupi, M and Sarchione, F and Matarazzo, I and Santacroce, R and Petruccelli, F and Martinotti, G and Di Giannantonio, M}, title = {The endocannabinoid system: a putative role in neurodegenerative diseases.}, journal = {International journal of high risk behaviors &amp; addiction}, volume = {2}, number = {3}, pages = {100-106}, pmid = {24971285}, issn = {2251-8711}, abstract = {BACKGROUND: Following the characterization of the chemical structure of D9-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, researchers have moved on with scientific valuable explorations.<br><br>OBJECTIVES: The aim of this review is to highlight the role of endocannabinoid system in neurodegenerative diseases.<br><br>MATERIALS AND METHODS: The article is a critical analysis of the most recent data currently present in scientific literature on the subject; a qualitative synthesis of only the most significant articles has been performed.<br><br>RESULTS: In central nervous system, endocannabinoids show a neuromodulatory function, often of retrograde type. This way, they play an important role in synaptic plasticity and in cognitive, motor, sensory and affective processes. In addition, in some acute or chronic pathologies of central nervous system, such as neurodegenerative and neuroinflammatory diseases, endocannabinoids can perform a pro-homeostatic and neuroprotective function, through the activation of CB1 and CB2 receptors. Scientific evidence shows that an hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's, Parkinson's and Alzheimer's diseases.<br><br>CONCLUSIONS: The important role played by endocannabinoid system promises interesting developments, in particular to evaluate the effectiveness of new drugs in both psychiatry and neurology.}, }
@article {pmid24969686, year = {2014}, author = {Lekoubou, A and Echouffo-Tcheugui, JB and Kengne, AP}, title = {Epidemiology of neurodegenerative diseases in sub-Saharan Africa: a systematic review.}, journal = {BMC public health}, volume = {14}, number = {}, pages = {653}, pmid = {24969686}, issn = {1471-2458}, mesh = {Africa South of the Sahara/epidemiology ; Central Nervous System Diseases/*epidemiology ; Cognition Disorders/*epidemiology/etiology ; Dementia/*epidemiology ; Female ; HIV Infections/complications ; Humans ; Male ; Neurodegenerative Diseases/*epidemiology ; }, abstract = {BACKGROUND: Sub-Saharan African (SSA) countries are experiencing rapid transitions with increased life expectancy. As a result the burden of age-related conditions such as neurodegenerative diseases might be increasing. We conducted a systematic review of published studies on common neurodegenerative diseases, and HIV-related neurocognitive impairment in SSA, in order to identify research gaps and inform prevention and control solutions.<br><br>METHODS: We searched MEDLINE via PubMed, 'Banque de Donn&#xe9;es de Sant&#xe9; Publique' and the database of the 'Institut d'Epidemiologie Neurologique et de Neurologie Tropicale' from inception to February 2013 for published original studies from SSA on neurodegenerative diseases and HIV-related neurocognitive impairment. Screening and data extraction were conducted by two investigators. Bibliographies and citations of eligible studies were investigated.<br><br>RESULTS: In all 144 publications reporting on dementia (n = 49 publications, mainly Alzheimer disease), Parkinsonism (PD, n = 20), HIV-related neurocognitive impairment (n = 47), Huntington disease (HD, n = 19), amyotrophic lateral sclerosis (ALS, n = 15), cerebellar degeneration (n = 4) and Lewy body dementia (n = 1). Of these studies, largely based on prevalent cases from retrospective data on urban populations, half originated from Nigeria and South Africa. The prevalence of dementia (Alzheimer disease) varied between <1% and 10.1% (0.7% and 5.6%) in population-based studies and from <1% to 47.8% in hospital-based studies. Incidence of dementia (Alzheimer disease) ranged from 8.7 to 21.8/1000/year (9.5 to 11.1), and major risk factors were advanced age and female sex. HIV-related neurocognitive impairment's prevalence (all from hospital-based studies) ranged from <1% to 80%. Population-based prevalence of PD and ALS varied from 10 to 235/100,000, and from 5 to 15/100,000 respectively while that for Huntington disease was 3.5/100,000. Equivalent figures for hospital based studies were the following: PD (0.41 to 7.2%), ALS (0.2 to 8.0/1000), and HD (0.2/100,000 to 46.0/100,000).<br><br>CONCLUSIONS: The body of literature on neurodegenerative disorders in SSA is large with regard to dementia and HIV-related neurocognitive disorders but limited for other neurodegenerative disorders. Shortcomings include few population-based studies, heterogeneous diagnostic criteria and uneven representation of countries on the continent. There are important knowledge gaps that need urgent action, in order to prepare the sub-continent for the anticipated local surge in neurodegenerative diseases.}, }
@article {pmid24966471, year = {2014}, author = {Olmos, G and Lladó, J}, title = {Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity.}, journal = {Mediators of inflammation}, volume = {2014}, number = {}, pages = {861231}, pmid = {24966471}, issn = {1466-1861}, mesh = {Analgesics, Opioid/pharmacology ; Animals ; Astrocytes/cytology ; Calcium/metabolism ; Cytokines/metabolism ; Glutamic Acid/metabolism ; Humans ; Inflammation/*pathology ; Neuralgia ; Neuroglia/cytology ; Neuronal Plasticity ; Neurons/*pathology ; Receptors, AMPA/metabolism ; Receptors, GABA-A/metabolism ; Receptors, Glutamate/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Signal Transduction ; Synaptic Transmission ; Tumor Necrosis Factor-alpha/*physiology ; }, abstract = {Tumor necrosis factor alpha (TNF- α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-α; this de novo production of TNF-α is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-α can potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca(+2) permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAA receptors on neurons. Thus, the net effect of TNF-α is to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS). As microglial activation and upregulation of TNF-α expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-α signaling may represent a valuable target for intervention.}, }
@article {pmid24965719, year = {2014}, author = {Goyal, NA and Mozaffar, T}, title = {Experimental trials in amyotrophic lateral sclerosis: a review of recently completed, ongoing and planned trials using existing and novel drugs.}, journal = {Expert opinion on investigational drugs}, volume = {23}, number = {11}, pages = {1541-1551}, doi = {10.1517/13543784.2014.933807}, pmid = {24965719}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/therapy ; Animals ; Biomarkers/metabolism ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Drug Design ; Humans ; Molecular Targeted Therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; Outcome Assessment, Health Care ; Patient Selection ; Riluzole/therapeutic use ; Stem Cell Transplantation/*methods ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects roughly 2 subjects per 100,000 in the United States; however, given the rapid decline and mortality, there are low prevalence rates. Although ALS is considered a single disease, it, in truth, probably represents a series of disorders with different clinical patterns and different pathophysiologic mechanisms that eventually coalesce into a single entity. The challenge has been to target these different pathophysiologic abnormalities, and so far, most drug studies have focused on only one or two different pathways. Over 50 well-designed clinical trials have been conducted in ALS over the last 25 years and with the exception of the Riluzole trial, all have failed.<br><br>AREAS COVERED: In this review, the authors highlight some of the recently concluded, ongoing or planned Phase II and Phase III studies in ALS. Furthermore, they summarize the progress in the recently initiated stem-cell therapy trials in ALS.<br><br>EXPERT OPINION: The challenge remains for developing effective targeted therapeutic interventions for ALS. However, with improved recognition of the complex interplay of several factors that may contribute to ALS pathogenesis, in addition to improved patient selection criteria, outcome measures and biomarkers for drug development, advancements may be made in the future.}, }
@article {pmid24964114, year = {2014}, author = {Batista, CE and Mariano, ED and Marie, SK and Teixeira, MJ and Morgalla, M and Tatagiba, M and Li, J and Lepski, G}, title = {Stem cells in neurology--current perspectives.}, journal = {Arquivos de neuro-psiquiatria}, volume = {72}, number = {6}, pages = {457-465}, doi = {10.1590/0004-282x20140045}, pmid = {24964114}, issn = {1678-4227}, mesh = {Central Nervous System/physiopathology ; Central Nervous System Diseases/*therapy ; Humans ; Nerve Regeneration ; Stem Cell Transplantation/methods/*standards ; Stem Cells/*cytology ; }, abstract = {UNLABELLED: Central nervous system (CNS) restoration is an important clinical challenge and stem cell transplantation has been considered a promising therapeutic option for many neurological diseases.<br><br>OBJECTIVE: The present review aims to briefly describe stem cell biology, as well as to outline the clinical application of stem cells in the treatment of diseases of the CNS.<br><br>METHOD: Literature review of animal and human clinical experimental trials, using the following key words: "stem cell", "neurogenesis", "Parkinson", "Huntington", "amyotrophic lateral sclerosis", "traumatic brain injury", "spinal cord injury", "ischemic stroke", and "demyelinating diseases".<br><br>CONCLUSION: Major recent advances in stem cell research have brought us several steps closer to their effective clinical application, which aims to develop efficient ways of regenerating the damaged CNS.}, }
@article {pmid24964113, year = {2014}, author = {Mariano, ED and Batista, CM and Barbosa, BJ and Marie, SK and Teixeira, MJ and Morgalla, M and Tatagiba, M and Li, J and Lepski, G}, title = {Current perspectives in stem cell therapy for spinal cord repair in humans: a review of work from the past 10 years.}, journal = {Arquivos de neuro-psiquiatria}, volume = {72}, number = {6}, pages = {451-456}, doi = {10.1590/0004-282x20140051}, pmid = {24964113}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Spinal Cord Injuries/*therapy ; *Spinal Cord Regeneration ; Stem Cell Transplantation/*trends ; Stem Cells/cytology ; }, abstract = {UNLABELLED: Spinal cord injury (SCI) and amyotrophic laterals sclerosis (ALS) are devastating neurological conditions that affect individuals worldwide, significantly reducing quality of life, both for patients and their relatives.<br><br>OBJECTIVE: The present review aims to summarize the multiple restorative approaches being developed for spinal cord repair, the use of different stem cell types and the current knowledge regarding stem cell therapy.<br><br>METHOD: Review of the literature from the past 10 years of human studies using stem cell transplantation as the main therapy, with or without adjuvant therapies.<br><br>CONCLUSION: The current review offers an overview of the state of the art regarding spinal cord restoration, and serves as a starting point for future studies.}, }
@article {pmid24962082, year = {2014}, author = {Doxakis, E}, title = {RNA binding proteins: a common denominator of neuronal function and dysfunction.}, journal = {Neuroscience bulletin}, volume = {30}, number = {4}, pages = {610-626}, pmid = {24962082}, issn = {1995-8218}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*genetics ; Neurons/*metabolism ; *RNA Processing, Post-Transcriptional ; RNA, Messenger/*metabolism ; RNA-Binding Proteins/*metabolism ; }, abstract = {In eukaryotic cells, gene activity is not directly reflected by protein levels because mRNA processing, transport, stability, and translation are co- and post-transcriptionally regulated. These processes, collectively known as the ribonome, are tightly controlled and carried out by a plethora of trans-acting RNA-binding proteins (RBPs) that bind to specific cis elements throughout the RNA sequence. Within the nervous system, the role of RBPs in brain function turns out to be essential due to the architectural complexity of neurons exemplified by a relatively small somal size and an extensive network of projections and connections. Thus far, RBPs have been shown to be indispensable for several aspects of neurogenesis, neurite outgrowth, synapse formation, and plasticity. Consequently, perturbation of their function is central in the etiology of an ever-growing spectrum of neurological diseases, including fragile X syndrome and the neurodegenerative disorders frontotemporal lobar degeneration and amyotrophic lateral sclerosis.}, }
@article {pmid24955214, year = {2014}, author = {Papa, L and Manfredi, G and Germain, D}, title = {SOD1, an unexpected novel target for cancer therapy.}, journal = {Genes &amp; cancer}, volume = {5}, number = {1-2}, pages = {15-21}, pmid = {24955214}, issn = {1947-6019}, support = {R01 CA109482/CA/NCI NIH HHS/United States ; R01 NS084486/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; T32 CA078207/CA/NCI NIH HHS/United States ; R01 NS051419/NS/NINDS NIH HHS/United States ; }, abstract = {Cancer cells have elevated levels of reactive oxygen species (ROS), which are generated in majority by the mitochondria. In the mitochondrial matrix, the manganese dismutase SOD2 acts as a major anti-oxidant enzyme. The deacetylase SIRT3 regulates the activity of SOD2. Recently, SIRT3 was reported to be decreased in 87% of breast cancers, resulting therefore in a decrease in the activity of SOD2 and an elevation in ROS. In addition to SIRT3, we recently reported that SOD2 itself is down-regulated in breast cancer cell lines upon activation of oncogenes, such as Ras. Since in absence of SOD2, superoxide levels are elevated and may cause irreversible damage, mechanisms must exist to retain superoxide below a critical threshold and maintain viability of cancer cells. The copper/zinc dismutase SOD1 localizes in the cytoplasm, the inter-membrane space of the mitochondria and the nucleus. Emerging evidences from several groups now indicate that SOD1 is overexpressed in cancers and that the activity of SOD1 may be essential to maintain cellular ROS under this critical threshold. This review summarizes the studies reporting important roles of SOD1 in cancer and addresses the potential cross-talk between the overexpression of SOD1 and the regulation of the mitochondrial unfolded protein response (UPR(mt)). While mutations in SOD1 is the cause of 20% of cases of familial amyotrophic lateral sclerosis (fALS), a devastating neurodegenerative disease, these new studies expand the role of SOD1 to cancer.}, }
@article {pmid24954589, year = {2014}, author = {Stelmashook, EV and Isaev, NK and Genrikhs, EE and Amelkina, GA and Khaspekov, LG and Skrebitsky, VG and Illarioshkin, SN}, title = {Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer's and Parkinson's diseases.}, journal = {Biochemistry. Biokhimiia}, volume = {79}, number = {5}, pages = {391-396}, doi = {10.1134/S0006297914050022}, pmid = {24954589}, issn = {1608-3040}, mesh = {Alzheimer Disease/*metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Copper/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Metallothionein/metabolism ; Oxidative Stress ; Parkinson Disease/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; Zinc/*metabolism ; tau Proteins/metabolism ; }, abstract = {Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.}, }
@article {pmid24949481, year = {2014}, author = {Bataveljic, D and Milosevic, M and Radenovic, L and Andjus, P}, title = {Novel molecular biomarkers at the blood-brain barrier in ALS.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {907545}, pmid = {24949481}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/*blood/pathology ; Animals ; Aquaporin 4/blood ; Astrocytes/metabolism ; Biomarkers/*blood ; Blood-Brain Barrier/*metabolism ; Humans ; *Immunity, Humoral ; Immunoglobulin G/administration &amp; dosage/blood/metabolism ; Inflammation/blood/*metabolism/pathology ; Rats ; }, abstract = {Recently neuroinflammation has gained a particular focus as a key mechanism of ALS. Several studies in vivo as well as in vitro have nominated immunoglobulin G (IgG) isolated from ALS patients as an active contributor to disease onset and progression. We have shown that ALS IgG affects astroglial Ca(2+) excitability and induces downstream activation of phosphatidylinositol 3-kinase. These studies were hampered by a lack of knowledge of the pathway of entry of immune factors in the CNS. Our MRI data revealed the blood-brain barrier BBB leakage and T cell infiltration into brain parenchyma in ALS G93A rats. Since astrocyte ensheathes blood vessel wall contributing to BBB stability and plays an important role in ALS pathogenesis, we have studied astrocytic membrane proteins water channel aquaporin-4 and the inwardly rectifying potassium channel. In this review, we will summarize data related to BBB disruption with particular emphasis on impaired function of astrocytes in ALS. We will discuss implication of membrane proteins expressed on astrocytic endfeet, aquaporin-4, and inwardly rectifying potassium channel in the pathology of ALS. In addition to ALS-specific IgGs, these membrane proteins are proposed as novel biomarkers of the disease.}, }
@article {pmid24949452, year = {2014}, author = {Pradat, PF and El Mendili, MM}, title = {Neuroimaging to investigate multisystem involvement and provide biomarkers in amyotrophic lateral sclerosis.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {467560}, pmid = {24949452}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology ; Biomarkers/chemistry ; Brain/diagnostic imaging ; Diffusion Tensor Imaging/methods ; Humans ; *Magnetic Resonance Imaging ; Motor Neurons/diagnostic imaging ; *Neuroimaging ; Pyramidal Tracts/*diagnostic imaging ; Radiography ; }, abstract = {Neuroimaging allows investigating the extent of neurological systems degeneration in amyotrophic lateral sclerosis (ALS). Advanced MRI methods can detect changes related to the degeneration of upper motor neurons but have also demonstrated the participation of other systems such as the sensory system or basal ganglia, demonstrating in vivo that ALS is a multisystem disorder. Structural and functional imaging also allows studying dysfunction of brain areas associated with cognitive signs. From a biomarker perspective, numerous studies using diffusion tensor imaging showed a decrease of fractional anisotropy in the intracranial portion of the corticospinal tract but its diagnostic value at the individual level remains limited. A multiparametric approach will be required to use MRI in the diagnostic workup of ALS. A promising avenue is the new methodological developments of spinal cord imaging that has the advantage to investigate the two motor system components that are involved in ALS, that is, the lower and upper motor neuron. For all neuroimaging modalities, due to the intrinsic heterogeneity of ALS, larger pooled banks of images with standardized image acquisition and analysis procedures are needed. In this paper, we will review the main findings obtained with MRI, PET, SPECT, and nuclear magnetic resonance spectroscopy in ALS.}, }
@article {pmid24936253, year = {2014}, author = {Auburger, G and Gispert, S and Lahut, S and Omür, O and Damrath, E and Heck, M and Başak, N}, title = {12q24 locus association with type 1 diabetes: SH2B3 or ATXN2?.}, journal = {World journal of diabetes}, volume = {5}, number = {3}, pages = {316-327}, pmid = {24936253}, issn = {1948-9358}, abstract = {Genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the genes SH2B3 and ATXN2 in its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. Hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders (like type 1 diabetes, coeliac disease, juvenile idiopathic arthritis, rheumatoid arthritis, thrombotic antiphospholipid syndrome, lupus erythematosus, multiple sclerosis, hypothyroidism and vitiligo), also vascular pathology (like kidney glomerular filtration rate deficits, serum urate levels, plasma beta-2-microglobulin levels, retinal microcirculation problems, diastolic and systolic blood pressure and hypertension, cardiovascular infarction), furthermore obesity, neurodegenerative conditions (like the polyglutamine-expansion disorder spinocerebellar ataxia type 2, Parkinson's disease, the motor-neuron disease amyotrophic lateral sclerosis, and progressive supranuclear palsy), and finally longevity were reported. Now it is important to clarify, in which ways the loss or gain of function of the locally encoded proteins SH2B3/LNK and ataxin-2, respectively, contribute to these polygenic health problems. SH2B3/LNK is known to repress the JAK2/ABL1 dependent proliferation of white blood cells. Its null mutations in human and mouse are triggers of autoimmune traits and leukemia (acute lymphoblastic leukemia or chronic myeloid leukemia-like), while missense mutations were found in erythrocytosis-1 patients. Ataxin-2 is known to act on RNA-processing and trophic receptor internalization. While its polyglutamine-expansion mediated gain-of-function causes neuronal atrophy in human and mouse, its deletion leads to obesity and insulin resistance in mice. Thus, it is conceivable that the polygenic pathogenesis of type 1 diabetes is enhanced by an SH2B3-dysregulation-mediated predisposition to autoimmune diseases that conspires with an ATXN2-deficiency-mediated predisposition to lipid and glucose metabolism pathology.}, }
@article {pmid24934359, year = {2014}, author = {Menon, P and Kiernan, MC and Vucic, S}, title = {Biomarkers and future targets for development in amyotrophic lateral sclerosis.}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3535-3550}, doi = {10.2174/0929867321666140601161148}, pmid = {24934359}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; Animals ; Biomarkers/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Glutamic Acid/toxicity ; Humans ; Neuroprotective Agents/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Receptors, AMPA/metabolism ; Sodium Channels/chemistry/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Although the pathophysiological mechanisms underlying the development of amyotrophic lateral sclerosis (ALS) remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. Glutamate- mediated excitoxicity is an important pathophysiological pathway in ALS, and was identified as an important therapeutic biomarker leading to development of the only pharmacologically based disease-modifying treatment currently available for ALS. More recently, a putative role of voltage-gated persistent Na(+) channels in ALS pathogenesis has been suggested and underscored by neuroprotective effects of Na(+) channel blocking agents in animal models. In addition, advances in ALS genetics have lead to identification of novel pathophysiological processes that could potentially serve as therapeutic targets in ALS. Genetic therapies, including antisense oligonucleotide approaches have been shown to exert neuroprotective effects in animal models of ALS, and Phase I human trial have been completed demonstrating the feasibility of such a therapeutic approach. The present review summarises the advances in ALS pathogenesis, emphasising the importance of these processes as potential targets for drug development in ALS.}, }
@article {pmid24934358, year = {2014}, author = {Pasquali, L and Lenzi, P and Biagioni, F and Siciliano, G and Fornai, F}, title = {Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease.}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3508-3534}, doi = {10.2174/0929867321666140601161534}, pmid = {24934358}, issn = {1875-533X}, mesh = {Autophagy ; Glycation End Products, Advanced/metabolism ; Humans ; Mitochondria/metabolism ; Motor Neuron Disease/metabolism/*pathology/therapy ; Mutation ; Neurons/metabolism ; *Protein Aggregation, Pathological ; Proteins/genetics/metabolism ; Stem Cell Transplantation ; }, abstract = {Despite a number of genetic mutations and molecular mechanisms are recognized to participate in amyotrophic lateral sclerosis (ALS), such a devastating neurological disorder still lacks a substantial cure. The present manuscript rather than a general overview of potential therapeutic approaches focuses on novel research findings detailing novel molecular mechanisms which appear to be promising for developing future ALS therapeutics. A special emphasis is given to the abnormal autophagy status and to those autophagy substrates which aggregate in the form of misfolded proteins. In fact, as reviewed in the first part of the manuscript, altered autophagy pathway is present in most genetic mutations responsible for familial ALS. These mutations impair clearance of autophagy substrates, which determines accumulation of giant altered mitochondria and misfolded proteins. Therefore, a considerable piece of the review is dedicated to unconventional processing of misfolded proteins leading to unconventional protein secretions which may underlie a prionoid cellto- cell spreading of ALS neuropathology. The intimate mechanisms regulating these steps are analyzed in order to comprehend which potential therapeutic targets might be considered in future studies. At the same time, negative findings concerning recent trials are explained in light of novel disease mechanisms. In the final part of the review the replacement therapy with focal stem cells implantation is discussed in relationship with toxic mechanisms operating in the intercellular space of the spinal cord and motor-related areas.}, }
@article {pmid24927875, year = {2014}, author = {Vucic, S and Rothstein, JD and Kiernan, MC}, title = {Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies.}, journal = {Trends in neurosciences}, volume = {37}, number = {8}, pages = {433-442}, doi = {10.1016/j.tins.2014.05.006}, pmid = {24927875}, issn = {1878-108X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*physiopathology/*therapy ; C9orf72 Protein ; Causality ; DNA-Binding Proteins/genetics ; Humans ; Neuroprotective Agents/therapeutic use ; Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequently occurring of the neuromuscular degenerative disorders, with a median survival time of 3-5 years. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. To date 16 genes and loci have been associated with ALS, with mutations in DNA/RNA-regulating genes including the recently described c9orf72 (chromosome 9 open reading frame 72) gene, suggesting an important role for dysregulation of RNA metabolism in ALS pathogenesis. Further, dysfunction of molecular pathways, including glutamate-mediated excitotoxicity, has been identified in sporadic and familial ALS, indicating the existence of a common pathogenic pathway. These pathophysiological insights have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.}, }
@article {pmid24918689, year = {2014}, author = {Shefner, JM and Mihaila, D}, title = {Assessment of disease progression and functional benefit in neurodegenerative disease: can we tell the difference?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {5-6}, pages = {337-343}, doi = {10.3109/21678421.2014.918150}, pmid = {24918689}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis ; *Clinical Trials as Topic ; Disease Progression ; Humans ; Neurodegenerative Diseases/*diagnosis/*drug therapy ; Parkinson Disease ; *Treatment Outcome ; }, abstract = {Therapeutic strategies for neurodegenerative diseases include modalities intended to modulate disease progression as well as those whose intent is to improve or maintain functional capacity. As the search for pharmacodynamic markers has proved elusive, treatment outcomes most commonly reflect patient function. As a result, even when clinical trials show a beneficial effect, the underlying etiology of that benefit can be difficult to determine. This review summarizes recent trials in ALS and Parkinson's disease, with the goal of increasing understanding of how the choice of outcome measures influences what can be concluded from the results. Although most ALS trials have been negative in recent years, outcomes are reviewed in terms of potential conclusions that could have been drawn. Functional benefit has been established in a number of recent trials; however, the outcomes used have lead to uncertainty as to whether specific agents modify disease or alter function. In the absence of specific markers sensitive to alteration of disease specific pathways, the distinction between agents that alter underlying disease versus those that affect function may depend on underlying hypotheses rather than clinical trial results.}, }
@article {pmid24918636, year = {2014}, author = {Jové, M and Portero-Otín, M and Naudí, A and Ferrer, I and Pamplona, R}, title = {Metabolomics of human brain aging and age-related neurodegenerative diseases.}, journal = {Journal of neuropathology and experimental neurology}, volume = {73}, number = {7}, pages = {640-657}, doi = {10.1097/NEN.0000000000000091}, pmid = {24918636}, issn = {1554-6578}, mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers ; Brain/*growth &amp; development/*metabolism/pathology ; Energy Metabolism/physiology ; Female ; Humans ; Male ; Metabolomics ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurons/pathology ; Parkinson Disease/metabolism/pathology ; Species Specificity ; }, abstract = {Neurons in the mature human central nervous system (CNS) perform a wide range of motor, sensory, regulatory, behavioral, and cognitive functions. Such diverse functional output requires a great diversity of CNS neuronal and non-neuronal populations. Metabolomics encompasses the study of the complete set of metabolites/low-molecular-weight intermediates (metabolome), which are context-dependent and vary according to the physiology, developmental state, or pathologic state of the cell, tissue, organ, or organism. Therefore, the use of metabolomics can help to unravel the diversity-and to disclose the specificity-of metabolic traits and their alterations in the brain and in fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of aging and neurodegenerative diseases. Here, we review the current applications of metabolomics in studies of CNS aging and certain age-related neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Neurometabolomics will increase knowledge of the physiologic and pathologic functions of neural cells and will place the concept of selective neuronal vulnerability in a metabolic context.}, }
@article {pmid24915640, year = {2014}, author = {Bennion Callister, J and Pickering-Brown, SM}, title = {Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {84-90}, pmid = {24915640}, issn = {1090-2430}, support = {089701//Wellcome Trust/United Kingdom ; G0701441/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications/genetics/pathology ; DNA-Binding Proteins/*genetics ; *Frontotemporal Dementia/complications/genetics/pathology ; Humans ; Mutation/*genetics ; }, abstract = {One of the most interesting findings in the field of neurodegeneration in recent years is tfche discovery of a genetic mutation in the C9orf72 gene, the most common mutation found to be causative of sporadic and familial frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and concomitant FTD-ALS (DeJesus-Hernandez et al., 2011b; Renton et al., 2011). While clinical and molecular data, such as the identification of TDP-43 being a common pathological protein (Neumann et al., 2006) have hinted at such a link for years, the identification of what was formally known as "the chromosome 9 FTLD-ALS gene" has provided a foundation for better understanding of the relationship between the two. Indeed, it is now recognized that ALS and FTLD-TDP represent a disease spectrum. In this review, we will discuss the current genetic and pathological features of the FTLD-ALS spectrum.}, }
@article {pmid24910594, year = {2014}, author = {Tadic, V and Prell, T and Lautenschlaeger, J and Grosskreutz, J}, title = {The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {147}, pmid = {24910594}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are essential features of neurodegeneration in this disorder. Here, we review recent research findings on the interaction between endoplasmic reticulum (ER) and mitochondria, and its effect on calcium signaling and oxidative stress. We further provide insights into studies, providing evidence that structures of the ER mitochondria calcium cycle serve as a promising targets for therapeutic approaches for treatment of ALS.}, }
@article {pmid24904276, year = {2014}, author = {Brites, D and Vaz, AR}, title = {Microglia centered pathogenesis in ALS: insights in cell interconnectivity.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {117}, pmid = {24904276}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult motor neuron (MN) degeneration. The cause of the disease is still unknown, but some protein mutations have been linked to the pathological process. Loss of upper and lower MNs results in progressive muscle paralysis and ultimately death due to respiratory failure. Although initially thought to derive from the selective loss of MNs, the pathogenic concept of non-cell-autonomous disease has come to the forefront for the contribution of glial cells in ALS, in particular microglia. Recent studies suggest that microglia may have a protective effect on MN in an early stage. Conversely, activated microglia contribute and enhance MN death by secreting neurotoxic factors, and impaired microglial function at the end-stage may instead accelerate disease progression. However, the nature of microglial-neuronal interactions that lead to MN degeneration remains elusive. We review the contribution of the neurodegenerative network in ALS pathology, with a special focus on each glial cell type from data obtained in the transgenic SOD1G93A rodents, the most widely used model. We further discuss the diverse roles of neuroinflammation and microglia phenotypes in the modulation of ALS pathology. We provide information on the processes associated with dysfunctional cell-cell communication and summarize findings on pathological cross-talk between neurons and astroglia, and neurons and microglia, as well as on the spread of pathogenic factors. We also highlight the relevance of neurovascular disruption and exosome trafficking to ALS pathology. The harmful and beneficial influences of NG2 cells, oligodendrocytes and Schwann cells will be discussed as well. Insights into the complex intercellular perturbations underlying ALS, including target identification, will enhance our efforts to develop effective therapeutic approaches for preventing or reversing symptomatic progression of this devastating disease.}, }
@article {pmid24904255, year = {2014}, author = {Allodi, I and Hedlund, E}, title = {Directed midbrain and spinal cord neurogenesis from pluripotent stem cells to model development and disease in a dish.}, journal = {Frontiers in neuroscience}, volume = {8}, number = {}, pages = {109}, pmid = {24904255}, issn = {1662-4548}, abstract = {Induction of specific neuronal fates is restricted in time and space in the developing CNS through integration of extrinsic morphogen signals and intrinsic determinants. Morphogens impose regional characteristics on neural progenitors and establish distinct progenitor domains. Such domains are defined by unique expression patterns of fate determining transcription factors. These processes of neuronal fate specification can be recapitulated in vitro using pluripotent stem cells. In this review, we focus on the generation of dopamine neurons and motor neurons, which are induced at ventral positions of the neural tube through Sonic hedgehog (Shh) signaling, and defined at anteroposterior positions by fibroblast growth factor (Fgf) 8, Wnt1, and retinoic acid (RA). In vitro utilization of these morphogenic signals typically results in the generation of multiple neuronal cell types, which are defined at the intersection of these signals. If the purpose of in vitro neurogenesis is to generate one cell type only, further lineage restriction can be accomplished by forced expression of specific transcription factors in a permissive environment. Alternatively, cell-sorting strategies allow for selection of neuronal progenitors or mature neurons. However, modeling development, disease and prospective therapies in a dish could benefit from structured heterogeneity, where desired neurons are appropriately synaptically connected and thus better reflect the three-dimensional structure of that region. By modulating the extrinsic environment to direct sequential generation of neural progenitors within a domain, followed by self-organization and synaptic establishment, a reductionist model of that brain region could be created. Here we review recent advances in neuronal fate induction in vitro, with a focus on the interplay between cell intrinsic and extrinsic factors, and discuss the implications for studying development and disease in a dish.}, }
@article {pmid24903509, year = {2014}, author = {Ariga, T}, title = {Pathogenic role of ganglioside metabolism in neurodegenerative diseases.}, journal = {Journal of neuroscience research}, volume = {92}, number = {10}, pages = {1227-1242}, doi = {10.1002/jnr.23411}, pmid = {24903509}, issn = {1097-4547}, mesh = {Animals ; Blood-Brain Barrier ; Central Nervous System/*metabolism ; Gangliosides/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; Protein Folding ; }, abstract = {Ganglioside metabolism is altered in several neurodegenerative diseases, and this may participate in several events related to the pathogenesis of these diseases. Most changes occur in specific areas of the brain and their distinct membrane microdomains or lipid rafts. Antiganglioside antibodies may be involved in dysfunction of the blood-brain barrier and disease progression in these diseases. In lipid rafts, interactions of glycosphingolipids, including ganglioside, with proteins may be responsible for the misfolding events that cause the fibril and/or aggregate processing of disease-specific proteins, such as α-synuclein, in Parkinson's disease, huntingtin protein in Huntington's disease, and copper-zinc superoxide dismutase in amyotrophic lateral sclerosis. Targeting ganglioside metabolism may represent an underexploited opportunity to design novel therapeutic strategies for neurodegeneration in these diseases.}, }
@article {pmid24894177, year = {2014}, author = {Orsucci, D and Rocchi, A and Caldarazzo Ienco, E and Alì, G and LoGerfo, A and Petrozzi, L and Scarpelli, M and Filosto, M and Carlesi, C and Siciliano, G and Bonuccelli, U and Mancuso, M}, title = {Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.}, journal = {Current molecular medicine}, volume = {14}, number = {5}, pages = {598-602}, doi = {10.2174/1566524014666140603100131}, pmid = {24894177}, issn = {1875-5666}, mesh = {Animals ; Bulbo-Spinal Atrophy, X-Linked/genetics/*metabolism/*physiopathology ; DNA, Mitochondrial/genetics ; Humans ; Mitochondria/metabolism/pathology ; Motor Neuron Disease/genetics/*metabolism/*physiopathology ; Receptors, Androgen/genetics ; }, abstract = {Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.}, }
@article {pmid24892269, year = {2014}, author = {Dyson, K and Bray, J and Smith, K and Bernard, S and Finn, J}, title = {A systematic review of the effect of emergency medical service practitioners' experience and exposure to out-of-hospital cardiac arrest on patient survival and procedural performance.}, journal = {Resuscitation}, volume = {85}, number = {9}, pages = {1134-1141}, doi = {10.1016/j.resuscitation.2014.05.020}, pmid = {24892269}, issn = {1873-1570}, mesh = {*Clinical Competence ; Emergency Medical Services/*standards ; Humans ; Intubation, Intratracheal ; Out-of-Hospital Cardiac Arrest/*mortality/*therapy ; Survival Rate ; }, abstract = {BACKGROUND AND OBJECTIVE: Emergency medical service (EMS) practitioners' experience and exposure to out-of-hospital cardiac arrest (OHCA) and advanced life support (ALS) procedures could be an important factor in procedural success and patient survival. We systematically reviewed the literature to examine these associations.<br><br>METHODOLOGY: We searched for publications using MEDLINE, EMBASE, CINAHL, CENTRAL and Web of Science. We included studies examining any type of EMS practitioner (e.g. paramedics, physicians) and OHCA patients of all ages and aetiologies. Two reviewers independently extracted data.<br><br>RESULTS: The search identified 1658 citations, of which 11 observational studies of variable quality were included. The majority of studies did not adjust for important confounding factors and reported across different EMS personnel structures. OHCA survival was not consistently associated with various definitions of career experience in three studies, or with previous OHCA exposure in another study. Endotracheal intubation (ETI) was the only ALS procedure examined. Successful ETI placement was associated with the previous number of ETIs performed in four of five studies, but not career experience in three of four studies. Only one study examined OHCA outcome, and reported an increase in survival to hospital discharge when practitioners had high ETI exposure.<br><br>CONCLUSIONS: There is no clear evidence of an association with EMS practitioner career experience or exposure to OHCA cases and ALS procedures, with the exception of exposure to ETI and successful placement. However, most studies in this field had substantial risk of bias. Therefore, further studies are required before any definitive conclusions can be drawn.}, }
@article {pmid24891994, year = {2014}, author = {Vang, S and Longley, K and Steer, CJ and Low, WC}, title = {The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases.}, journal = {Global advances in health and medicine}, volume = {3}, number = {3}, pages = {58-69}, pmid = {24891994}, issn = {2164-957X}, abstract = {Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases. There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases. Both UDCA and TUDCA are potent inhibitors of apoptosis, in part by interfering with the upstream mitochondrial pathway of cell death, inhibiting oxygen-radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response (UPR). Several studies have demonstrated that TUDCA serves as an anti-apoptotic agent for a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, TUDCA plays an important role in protecting against cell death in certain retinal disorders, such as retinitis pigmentosa. It has been shown to reduce ER stress associated with elevated glucose levels in diabetes by inhibiting caspase activation, up-regulating the UPR, and inhibiting reactive oxygen species. Obesity, stroke, acute myocardial infarction, spinal cord injury, and a long list of acute and chronic non-liver diseases associated with apoptosis are all potential therapeutic targets for T/UDCA. A growing number of pre-clinical and clinical studies underscore the potential benefit of this simple, naturally occurring bile acid, which has been used in Chinese medicine for more than 3000 years.}, }
@article {pmid24889964, year = {2015}, author = {Yeo, WS and Kim, YJ and Kabir, MH and Kang, JW and Ahsan-Ul-Bari, M and Kim, KP}, title = {Mass spectrometric analysis of protein tyrosine nitration in aging and neurodegenerative diseases.}, journal = {Mass spectrometry reviews}, volume = {34}, number = {2}, pages = {166-183}, doi = {10.1002/mas.21429}, pmid = {24889964}, issn = {1098-2787}, mesh = {Aging/*metabolism/pathology ; Amino Acid Sequence ; Chromatography, Affinity ; Humans ; Mass Spectrometry/instrumentation/*methods ; Molecular Sequence Data ; Neurodegenerative Diseases/*metabolism/pathology ; Peptide Fragments/*analysis/chemistry ; Proteins/*analysis/chemistry/metabolism ; Reactive Nitrogen Species/chemistry/metabolism ; Tyrosine/*analogs &amp; derivatives/chemistry/metabolism ; }, abstract = {This review highlights the significance of protein tyrosine nitration (PTN) in signal transduction pathways, the progress achieved in analytical methods, and the implication of nitration in the cellular pathophysiology of aging and age-related neurodegenerative diseases. Although mass spectrometry of nitrated peptides has become a powerful tool for the characterization of nitrated peptides, the low stoichiometry of this modification clearly necessitates the use of affinity chromatography to enrich modified peptides. Analysis of nitropeptides involves identification of endogenous, intact modification as well as chemical conversion of the nitro group to a chemically reactive amine group and further modifications that enable affinity capture and enhance detectability by altering molecular properties. In this review, we focus on the recent progress in chemical derivatization of nitropeptides for enrichment and mass analysis, and for detection and quantification using various analytical tools. PTN participates in physiological processes, such as aging and neurodegenerative diseases. Accumulation of 3-nitrotyrosine has been found to occur during the aging process; this was identified through mass spectrometry. Further, there are several studies implicating the presence of nitrated tyrosine in age-related diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid24874548, year = {2014}, author = {Skerrett, R and Malm, T and Landreth, G}, title = {Nuclear receptors in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {72 Pt A}, number = {}, pages = {104-116}, pmid = {24874548}, issn = {1095-953X}, support = {R01 AG043522/AG/NIA NIH HHS/United States ; R56 NS084856/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism ; Animals ; Disease Models, Animal ; Humans ; Huntington Disease/metabolism ; Liver X Receptors ; Mice ; Microglia/metabolism ; Neurodegenerative Diseases/*metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism ; Orphan Nuclear Receptors/metabolism ; Parkinson Disease/metabolism ; Peroxisome Proliferator-Activated Receptors/metabolism ; Rats ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Retinoid X Receptors/metabolism ; Signal Transduction ; }, abstract = {Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.}, }
@article {pmid24873727, year = {2014}, author = {Heutink, P and Jansen, IE and Lynes, EM}, title = {C9orf72; abnormal RNA expression is the key.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {102-110}, doi = {10.1016/j.expneurol.2014.05.020}, pmid = {24873727}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/complications/*genetics ; C9orf72 Protein ; Frontotemporal Dementia/complications/*genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Mutation/*genetics ; Proteins/*genetics ; RNA/*metabolism ; }, abstract = {An expanded GGGGCC hexanucleotide repeat in the first intron located between the 1st and 2nd non-coding exons of C9orf72 is the most frequent cause of frontotemporal dementia (FTD) and amyothropic lateral sclerosis (ALS). C9orf72 is a protein with largely unknown function and insight into the disease mechanism caused by the repeat expansion is still in an early stage but increases at an amazing pace. Three main hypotheses are currently being considered to explain the disease process including haploinsuffiency due to the loss of expression from the mutated allele, RNA toxicity caused by accumulation of repeat containing transcripts and toxic protein species generated by the abnormal translation of repeat sequences. We review the current status of genetic, population and functional data and discuss the current insights into the biology of C9orf72 and this repeat expansion disease.}, }
@article {pmid24860590, year = {2014}, author = {Therrien, M and Parker, JA}, title = {Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans.}, journal = {Frontiers in genetics}, volume = {5}, number = {}, pages = {85}, pmid = {24860590}, issn = {1664-8021}, abstract = {Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.}, }
@article {pmid24860432, year = {2014}, author = {Pollari, E and Goldsteins, G and Bart, G and Koistinaho, J and Giniatullin, R}, title = {The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {131}, pmid = {24860432}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motoneurons and degradation of the neuromuscular junctions (NMJ). Consistent with the dying-back hypothesis of motoneuron degeneration the decline in synaptic function initiates from the presynaptic terminals in ALS. Oxidative stress is a major contributory factor to ALS pathology and affects the presynaptic transmitter releasing machinery. Indeed, in ALS mouse models nerve terminals are sensitive to reactive oxygen species (ROS) suggesting that oxidative stress, along with compromised mitochondria and increased intracellular Ca(2+) amplifies the presynaptic decline in NMJ. This initial dysfunction is followed by a neurodegeneration induced by inflammatory agents and loss of trophic support. To develop effective therapeutic approaches against ALS, it is important to identify the mechanisms underlying the initial pathological events. Given the role of oxidative stress in ALS, targeted antioxidant treatments could be a promising therapeutic approach. However, the complex nature of ALS and failure of monotherapies suggest that an antioxidant therapy should be accompanied by anti-inflammatory interventions to enhance the restoration of the redox balance.}, }
@article {pmid24859452, year = {2014}, author = {Philips, T and Rothstein, JD}, title = {Glial cells in amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {111-120}, pmid = {24859452}, issn = {1090-2430}, support = {R01 NS033958/NS/NINDS NIH HHS/United States ; R01 NS085207/NS/NINDS NIH HHS/United States ; RC2 NS069395/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Humans ; Neuroglia/*pathology ; }, abstract = {For more than twenty years glial cells have been implicated in the pathogenetic cascades for genetic and sporadic forms of ALS. The biological role of glia, including the principal CNS glia, astroglia and oligodendroglia, as well as the myeloid derived microglia, has uniformly led to converging data sets that implicate these diverse cells in the degeneration of neurons in ALS. Originating as studies in postmortem human brain implicating astroglia, the research progressed to strongly implicate microglia and contributors to CNS injury in all forms of ALS. Most recently and unexpectedly, oligodendroglia have also been shown in animal model systems and human brain to play an early role in the dysfunction and death of ALS neurons. These studies have identified a number of diverse cellular cascades that could be, or have already been, the target of therapeutic interventions. Understanding the temporal and regional role of these cells and the magnitude of their contribution will be important for future interventions. Employing markers of these cell types may also allow for future important patient subgrouping and pharmacodynamic drug development tools.}, }
@article {pmid24852074, year = {2014}, author = {Cleary, JD and Ranum, LP}, title = {Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders.}, journal = {Current opinion in genetics &amp; development}, volume = {26}, number = {}, pages = {6-15}, pmid = {24852074}, issn = {1879-0380}, support = {P01 NS058901/NS/NINDS NIH HHS/United States ; R01 NS040389/NS/NINDS NIH HHS/United States ; P01NS058901/NS/NINDS NIH HHS/United States ; }, mesh = {Base Sequence ; Codon, Initiator/*genetics ; DNA Repeat Expansion/*genetics ; Humans ; Models, Genetic ; Mutant Proteins/genetics ; *Mutation ; Myotonic Dystrophy/genetics ; *Protein Biosynthesis ; Spinocerebellar Degenerations/genetics ; }, abstract = {Microsatellite-expansion diseases are a class of neurological and neuromuscular disorders caused by the expansion of short stretches of repetitive DNA (e.g. GGGGCC, CAG, CTG …) within the human genome. Since their discovery 20 years ago, research into how microsatellites expansions cause disease has been examined using the model that these genes are expressed in one direction and that expansion mutations only encode proteins when located in an ATG-initiated open reading frame. The fact that these mutations are often bidirectionally transcribed combined with the recent discovery of repeat associated non-ATG (RAN) translation provides new perspectives on how these expansion mutations are expressed and impact disease. Two expansion transcripts and a set of unexpected RAN proteins must now be considered for both coding and 'non-coding' expansion disorders. RAN proteins have been reported in a growing number of diseases, including spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), Fragile-X tremor ataxia syndrome (FXTAS), and C9ORF72 amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD).}, }
@article {pmid24848437, year = {2014}, author = {Gentile, I and Coppola, N and Buonomo, AR and Zappulo, E and Borgia, G}, title = {Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus.}, journal = {Expert opinion on investigational drugs}, volume = {23}, number = {9}, pages = {1211-1223}, doi = {10.1517/13543784.2014.921680}, pmid = {24848437}, issn = {1744-7658}, mesh = {Animals ; Antiviral Agents/pharmacology/*therapeutic use ; Disease Progression ; Drug Design ; Drug Therapy, Combination ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Hepacivirus/drug effects/enzymology/genetics ; Hepatitis C, Chronic/*drug therapy/enzymology/virology ; Humans ; Ribavirin/administration &amp; dosage/therapeutic use ; Sofosbuvir ; Uridine Monophosphate/administration &amp; dosage/analogs &amp; derivatives/therapeutic use ; }, abstract = {INTRODUCTION: About 150 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV). Successful antiviral treatment can stop the progression of the disease toward liver cirrhosis, hepatocellular carcinoma and death. IFN has been the drug of choice and the backbone of all combinations in the past two decades. However, an IFN-free combination (sofosbuvir and ribavirin) has been recently approved for genotypes 2 and 3 patients with many other drugs in preclinical and clinical development.<br><br>AREAS COVERED: This review focuses on investigational nucleoside or nucleotide inhibitors of viral polymerase that are potential treatments of HCV. The article reviews drugs that are currently under investigational status.<br><br>EXPERT OPINION: Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time. Other promising molecules are LG-7501, ACH-3422 and EP-NI266, although no clinical studies have been performed thus far, so this must be rectified. Another drug of promise GS-6620 has displayed a high degree of pharmacokinetic and pharmacodynamic variability, which makes further development unlikely.}, }
@article {pmid24847964, year = {2014}, author = {Squires, N and Humberstone, M and Wills, A and Arthur, A}, title = {The use of botulinum toxin injections to manage drooling in amyotrophic lateral sclerosis/motor neurone disease: a systematic review.}, journal = {Dysphagia}, volume = {29}, number = {4}, pages = {500-508}, pmid = {24847964}, issn = {1432-0460}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/*administration &amp; dosage ; Humans ; Injections ; Neurotoxins/administration &amp; dosage ; Sialorrhea/*drug therapy/etiology ; Treatment Outcome ; }, abstract = {Difficulty in managing oral secretions is commonly experienced by patients with amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND) and associated bulbar weakness including dysphagia. There are no definitive evidence-based treatment guidelines to manage the distressing symptom of drooling. We reviewed the evidence for the effectiveness of botulinum toxin injections to reduce saliva in ALS/MND. The search strategy was conducted in four stages: (1) electronic search of relevant databases, (2) hand searches of all international ALS/MND symposium journals, (3) email request to MND care centres in the UK and Ireland, and (4) hand searching of reference lists. All studies were critically appraised and relevant data extracted. Botulinum toxin type A and type B were analysed separately. Due to heterogeneity, it was not possible to calculate a pooled estimate of effect. Twelve studies met the inclusion criteria (9 for type A and 3 for type B). Only two randomised controlled trials were identified. Study sample sizes were small with a mean of 12.5 subjects. The most frequently reported outcomes were weight of cotton rolls and number of tissues used. All studies claimed the intervention tested was effective, but only seven studies (4 for type A and 3 for type B) reported statistically significant differences. Although there is evidence to suggest that botulinum toxin B can reduce drooling, the evidence base is limited by a lack of randomized controlled trials. Evidence to support the use of botulinum toxin A is weaker. Larger trials will help remove the uncertainty practitioners face in treating this disabling symptom.}, }
@article {pmid24847438, year = {2014}, author = {Modgil, S and Lahiri, DK and Sharma, VL and Anand, A}, title = {Role of early life exposure and environment on neurodegeneration: implications on brain disorders.}, journal = {Translational neurodegeneration}, volume = {3}, number = {}, pages = {9}, pmid = {24847438}, issn = {2047-9158}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and retinal degeneration have been studied extensively and varying molecular mechanisms have been proposed for onset of such diseases. Although genetic analysis of these diseases has also been described, yet the mechanisms governing the extent of vulnerability to such diseases remains unresolved. Recent studies have, therefore, focused on the role of environmental exposure in progression of such diseases especially in the context of prenatal and postnatal life, explaining how molecular mechanisms mediate epigenetic changes leading to degenerative diseases. This review summarizes both the animal and human studies describing various environmental stimuli to which an individual or an animal is exposed during in-utero and postnatal period and mechanisms that promote neurodegeneration. The SNPs mediating gene environment interaction are also described. Further, preventive and therapeutic strategies are suggested for effective intervention.}, }
@article {pmid24847211, year = {2014}, author = {Vehviläinen, P and Koistinaho, J and Gundars, G}, title = {Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {126}, pmid = {24847211}, issn = {1662-5102}, abstract = {In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial in vitro and in vivo evidence has accumulated demonstrating that localization of mutSOD1 to the mitochondrial intermembrane space (IMS) inevitably leads to impairment of mitochondrial functions. However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.}, }
@article {pmid24845847, year = {2014}, author = {Mulcahy, PJ and Iremonger, K and Karyka, E and Herranz-Martín, S and Shum, KT and Tam, JK and Azzouz, M}, title = {Gene therapy: a promising approach to treating spinal muscular atrophy.}, journal = {Human gene therapy}, volume = {25}, number = {7}, pages = {575-586}, doi = {10.1089/hum.2013.186}, pmid = {24845847}, issn = {1557-7422}, mesh = {Animals ; Genetic Diseases, Inborn/genetics/pathology/physiopathology/*therapy ; Genetic Therapy/*methods/trends ; Humans ; Muscular Atrophy, Spinal/genetics/pathology/physiopathology/*therapy ; *Mutation ; Survival of Motor Neuron 1 Protein/*genetics ; }, abstract = {Spinal muscular atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of the SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade, and gene delivery to the central nervous system (CNS) by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis being among the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favorable and have been at the fore of this evolution of potential gene therapies, and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialization of the first gene therapies for diseases, such as pancreatitis in the form of Glybera, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors that can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavor to highlight the promising results that may be applicable to various associated diseases and also discuss the potential to overcome present limitations.}, }
@article {pmid24844647, year = {2014}, author = {Kawauchi, T}, title = {Cdk5 regulates multiple cellular events in neural development, function and disease.}, journal = {Development, growth &amp; differentiation}, volume = {56}, number = {5}, pages = {335-348}, doi = {10.1111/dgd.12138}, pmid = {24844647}, issn = {1440-169X}, mesh = {Animals ; Brain/cytology/embryology ; Brain Diseases/metabolism ; Cyclin-Dependent Kinase 5/*metabolism ; Humans ; Mammals/embryology/*metabolism ; Neurons/cytology/*metabolism ; Synapses/metabolism ; }, abstract = {Cyclin-dependent kinases (CDKs) generally regulate cell proliferation in dividing cells, including neural progenitors. In contrast, an unconventional CDK, Cdk5, is predominantly activated in post-mitotic cells, and involved in various cellular events, such as microtubule and actin cytoskeletal organization, cell-cell and cell-extracellular matrix adhesions, and membrane trafficking. Interestingly, recent studies have indicated that Cdk5 is associated with several cell cycle-related proteins, Cyclin-E and p27(kip1) . Taking advantage of multiple functionality, Cdk5 plays important roles in neuronal migration, layer formation, axon elongation and dendrite arborization in many regions of the developing brain, including cerebral cortex and cerebellum. Cdk5 is also required for neurogenesis at least in the cerebral cortex. Furthermore, Cdk5 is reported to control neurotransmitter release at presynaptic sites, endocytosis of the NMDA receptor at postsynaptic sites and dendritic spine remodeling, and thereby regulate synaptic plasticity and memory formation and extinction. In addition to these physiological roles in brain development and function, Cdk5 is associated with many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. In this review, I will introduce the physiological and pathological roles of Cdk5 in mammalian brains from the viewpoint of not only in vivo phenotypes but also its molecular and cellular functions.}, }
@article {pmid24842489, year = {2014}, author = {Roet, KC and Verhaagen, J}, title = {Understanding the neural repair-promoting properties of olfactory ensheathing cells.}, journal = {Experimental neurology}, volume = {261}, number = {}, pages = {594-609}, doi = {10.1016/j.expneurol.2014.05.007}, pmid = {24842489}, issn = {1090-2430}, mesh = {Animals ; Cell Transplantation/*methods ; Humans ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/*surgery ; Neurogenesis/*physiology ; Neuroglia/*physiology ; Olfactory Nerve/*cytology/transplantation ; }, abstract = {Olfactory ensheathing glial cells (OECs) are a specialized type of glia that form a continuously aligned cellular pathway that actively supports unprecedented regeneration of primary olfactory axons from the periphery into the central nervous system. Implantation of OECs stimulates neural repair in experimental models of spinal cord, brain and peripheral nerve injury and delays disease progression in animal models for neurodegenerative diseases like amyotrophic lateral sclerosis. OECs implanted in the injured spinal cord display a plethora of pro-regenerative effects; they promote axonal regeneration, reorganize the glial scar, remyelinate axons, stimulate blood vessel formation, have phagocytic properties and modulate the immune response. Recently genome wide transcriptional profiling and proteomics analysis combined with classical or larger scale "medium-throughput" bioassays have provided novel insights into the molecular mechanism that endow OECs with their pro-regenerative properties. Here we review these studies and show that the gaps that existed in our understanding of the molecular basis of the reparative properties of OECs are narrowing. OECs express functionally connected sets of genes that can be linked to at least 10 distinct processes directly relevant to neural repair. The data indicate that OECs exhibit a range of synergistic cellular activities, including active and passive stimulation of axon regeneration (by secretion of growth factors, axon guidance molecules and basement membrane components) and critical aspects of tissue repair (by structural remodeling and support, modulation of the immune system, enhancement of neurotrophic and antigenic stimuli and by metabolizing toxic macromolecules). Future experimentation will have to further explore the newly acquired knowledge to enhance the therapeutic potential of OECs.}, }
@article {pmid24840975, year = {2014}, author = {Deng, H and Gao, K and Jankovic, J}, title = {The role of FUS gene variants in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {10}, number = {6}, pages = {337-348}, pmid = {24840975}, issn = {1759-4766}, mesh = {Humans ; Neurodegenerative Diseases/*genetics ; RNA-Binding Protein FUS/genetics/*physiology ; }, abstract = {The neurodegenerative diseases are a diverse group of disorders characterized by progressive loss of specific groups of neurons. These diseases affect different populations, and have a variable age of onset, clinical symptoms, and pathological findings. Variants in the FUS gene, which encodes an RNA-binding protein, have been identified as causative or risk factors for amyotrophic lateral sclerosis (ALS), essential tremor and rare forms of frontotemporal lobar degeneration (FTLD). Additionally, abnormal aggregation of FUS protein has been reported in multiple neurodegenerative diseases, including ALS, FTLD and the polyglutamine diseases, suggesting a role for FUS in the pathogenesis of these neurodegenerative diseases. This Review summarizes current understanding of the normal function of FUS, and describes its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases. Comments on the underlying pathogenetic mechanisms of these FUS-related disorders are included. Finally, the clinical implications of recent advances in FUS research are discussed. Further understanding of the role of FUS in neurodegenerative diseases might lead to improvements in the treatment and prevention of these disorders.}, }
@article {pmid24836899, year = {2014}, author = {Vatovec, S and Kovanda, A and Rogelj, B}, title = {Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Neurobiology of aging}, volume = {35}, number = {10}, pages = {2421.e1-2421.e12}, doi = {10.1016/j.neurobiolaging.2014.04.015}, pmid = {24836899}, issn = {1558-1497}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; DNA-Binding Proteins ; Frontotemporal Lobar Degeneration/*genetics ; *Genetic Association Studies ; Humans ; Protein Aggregation, Pathological ; Proteins/*genetics ; RNA/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are devastating neurodegenerative diseases that form two ends of a complex disease spectrum. Aggregation of RNA binding proteins is one of the hallmark pathologic features of ALS and FTDL and suggests perturbance of the RNA metabolism in their etiology. Recent identification of the disease-associated expansions of the intronic hexanucleotide repeat GGGGCC in the C9ORF72 gene further substantiates the case for RNA involvement. The expanded repeat, which has turned out to be the single most common genetic cause of ALS and FTLD, may enable the formation of complex DNA and RNA structures, changes in RNA transcription, and processing and formation of toxic RNA foci, which may sequester and inactivate RNA binding proteins. Additionally, the transcribed expanded repeat can undergo repeat-associated non-ATG-initiated translation resulting in accumulation of a series of dipeptide repeat proteins. Understanding the basis of the proposed mechanisms and shared pathways, as well as interactions with known key proteins such as TAR DNA-binding protein (TDP-43) are needed to clarify the pathology of ALS and/or FTLD, and make possible steps toward therapy development.}, }
@article {pmid24826210, year = {2014}, author = {Pan-Montojo, F and Reichmann, H}, title = {Considerations on the role of environmental toxins in idiopathic Parkinson's disease pathophysiology.}, journal = {Translational neurodegeneration}, volume = {3}, number = {}, pages = {10}, pmid = {24826210}, issn = {2047-9158}, abstract = {Neurodegenerative diseases are characterized by a progressive dysfunction of the nervous system. Often associated with atrophy of the affected central or peripheral nervous structures, they include diseases such as Parkinson's Disease (PD), Alzheimer's Disease and other dementias, Genetic Brain Disorders, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease, Prion Diseases, and others. The prevalence of neurodegenerative diseases has increased over the last years. This has had a major impact both on patients and their families and has exponentially increased the medical bill by hundreds of billions of Euros. Therefore, understanding the role of environmental and genetic factors in the pathogenesis of PD is crucial to develop preventive strategies. While some authors believe that PD is mainly genetic and that the aging of the society is the principal cause for this increase, different studies suggest that PD may be due to an increased exposure to environmental toxins. In this article we review epidemiological, sociological and experimental studies to determine which hypothesis is more plausible. Our conclusion is that, at least in idiopathic PD (iPD), the exposure to toxic environmental substances could play an important role in its aetiology.}, }
@article {pmid24824217, year = {2014}, author = {Ross, CA and Akimov, SS}, title = {Human-induced pluripotent stem cells: potential for neurodegenerative diseases.}, journal = {Human molecular genetics}, volume = {23}, number = {R1}, pages = {R17-26}, pmid = {24824217}, issn = {1460-2083}, support = {R01NS076631/NS/NINDS NIH HHS/United States ; R21NS083365/NS/NINDS NIH HHS/United States ; U24NS078370/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/*therapy ; Animals ; Cell Differentiation ; Disease Models, Animal ; Frontotemporal Dementia/genetics/*therapy ; Humans ; Huntington Disease/genetics/*therapy ; Induced Pluripotent Stem Cells/*transplantation ; Parkinson Disease/genetics/*therapy ; Phenotype ; }, abstract = {The cell biology of human neurodegenerative diseases has been difficult to study till recently. The development of human induced pluripotent stem cell (iPSC) models has greatly enhanced our ability to model disease in human cells. Methods have recently been improved, including increasing reprogramming efficiency, introducing non-viral and non-integrating methods of cell reprogramming, and using novel gene editing techniques for generating genetically corrected lines from patient-derived iPSCs, or for generating mutations in control cell lines. In this review, we highlight accomplishments made using iPSC models to study neurodegenerative disorders such as Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Fronto-Temporal Dementia, Alzheimer's disease, Spinomuscular Atrophy and other polyglutamine diseases. We review disease-related phenotypes shown in patient-derived iPSCs differentiated to relevant neural subtypes, often with stressors or cell "aging", to enhance disease-specific phenotypes. We also discuss prospects for the future of using of iPSC models of neurodegenerative disorders, including screening and testing of therapeutic compounds, and possibly of cell transplantation in regenerative medicine. The new iPSC models have the potential to greatly enhance our understanding of pathogenesis and to facilitate the development of novel therapeutics.}, }
@article {pmid24823743, year = {2014}, author = {Kulshreshtha, D and Singh, AK and Maurya, PK and Thacker, AK}, title = {Familial amyotrophic lateral sclerosis from north India: case report and brief review.}, journal = {Neurology India}, volume = {62}, number = {2}, pages = {210-211}, doi = {10.4103/0028-3886.132421}, pmid = {24823743}, issn = {0028-3886}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Female ; *Genetic Predisposition to Disease ; Genetic Testing/methods ; Humans ; India ; Male ; Middle Aged ; Mutation/*genetics ; Pedigree ; }, }
@article {pmid24821704, year = {2014}, author = {Winner, B and Marchetto, MC and Winkler, J and Gage, FH}, title = {Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease.}, journal = {Human molecular genetics}, volume = {23}, number = {R1}, pages = {R27-34}, doi = {10.1093/hmg/ddu205}, pmid = {24821704}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Humans ; Induced Pluripotent Stem Cells/*cytology/transplantation ; Motor Neuron Disease/*genetics/therapy ; Motor Neurons/cytology ; Muscular Atrophy, Spinal/*genetics/therapy ; Mutation ; Spastic Paraplegia, Hereditary/*genetics/therapy ; }, abstract = {While motor neuron diseases are currently incurable, induced pluripotent stem cell research has uncovered some disease-relevant phenotypes. We will discuss strategies to model different aspects of motor neuron disease and the specific neurons involved in the disease. We will then describe recent progress to investigate common forms of motor neuron disease: amyotrophic lateral sclerosis, hereditary spastic paraplegia and spinal muscular atrophy.}, }
@article {pmid24818133, year = {2014}, author = {Cistaro, A and Cuccurullo, V and Quartuccio, N and Pagani, M and Valentini, MC and Mansi, L}, title = {Role of PET and SPECT in the study of amyotrophic lateral sclerosis.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {237437}, pmid = {24818133}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/metabolism/physiopathology ; Cerebrovascular Circulation ; Glucose/metabolism ; Humans ; Molecular Imaging ; *Positron-Emission Tomography ; *Tomography, Emission-Computed, Single-Photon ; }, abstract = {Amyotrophic lateral sclerosis has been defined as a "heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord." A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals.}, }
@article {pmid24816450, year = {2014}, author = {Chan, TM and Chen, JY and Ho, LI and Lin, HP and Hsueh, KW and Liu, DD and Chen, YH and Hsieh, AC and Tsai, NM and Hueng, DY and Tsai, ST and Chou, PW and Lin, SZ and Harn, HJ}, title = {ADSC therapy in neurodegenerative disorders.}, journal = {Cell transplantation}, volume = {23}, number = {4-5}, pages = {549-557}, doi = {10.3727/096368914X678445}, pmid = {24816450}, issn = {1555-3892}, mesh = {Adipose Tissue/*cytology ; Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell Differentiation ; Cell Lineage ; Humans ; Huntington Disease/therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; *Stem Cell Transplantation ; Stem Cells/*cytology ; }, abstract = {Neurodegenerative disorders, chronic diseases that can severely affect the patient's daily life, include amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. However, these diseases all have the common characteristic that they are due to degenerative irreversibility, and thus no efficient drugs or therapy methods can mitigate symptoms completely. Stem cell therapy, such as adipose tissue-derived stem cells (ADSCs), is a promising treatment for incurable disorders. In this review, we summarized the previous studies using ADSCs to treat neurodegenerative disorders, as well as their therapeutic mechanisms. We also suggested possible expectations for future human clinical trials involving minimized intracerebroventricular combined with intravenous administration, using different cell lineages to finish complementary therapy as well as change the extracellular matrix to create a homing niche. Depending on successful experiments in relevant neurodegenerative disorders models, this could form the theoretical basis for future human clinical trials.}, }
@article {pmid24816247, year = {2014}, author = {Van Damme, P and Robberecht, W}, title = {Developments in treatments for amyotrophic lateral sclerosis via intracerebroventricular or intrathecal delivery.}, journal = {Expert opinion on investigational drugs}, volume = {23}, number = {7}, pages = {955-963}, doi = {10.1517/13543784.2014.912275}, pmid = {24816247}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Humans ; Injections, Intraventricular ; Injections, Spinal ; }, abstract = {INTRODUCTION: Amyotrophic lateral scleroses (ALS) are neurodegenerative disorders primarily affecting the motor system. These incurable disorders are relentlessly progressive and typically limit survival to 2 - 5 years after disease onset. An improved knowledge about disease-causing genes, disease proteins and pathways has revealed considerable heterogeneity in ALS. Novel targeted therapies are being developed, but getting these beyond the BBB remains a challenge.<br><br>AREAS COVERED: The authors review the intracerebroventricular and intrathecal delivery of drugs for the treatment of ALS in preclinical and clinical studies.<br><br>EXPERT OPINION: Lack of BBB permeability should not hold back the development of promising treatments for ALS, as the available evidence suggest that direct intrathecal or intracerebroventricular administration of drug is a feasible delivery route in patients with ALS.}, }
@article {pmid24815224, year = {2015}, author = {Payne, NL and Sylvain, A and O'Brien, C and Herszfeld, D and Sun, G and Bernard, CC}, title = {Application of human induced pluripotent stem cells for modeling and treating neurodegenerative diseases.}, journal = {New biotechnology}, volume = {32}, number = {1}, pages = {212-228}, doi = {10.1016/j.nbt.2014.05.001}, pmid = {24815224}, issn = {1876-4347}, mesh = {Cell Differentiation ; Humans ; Induced Pluripotent Stem Cells/*cytology ; *Models, Biological ; Neurodegenerative Diseases/pathology/*therapy ; *Stem Cell Transplantation ; }, abstract = {The advent of human induced pluripotent stem cells (hiPSCs), reprogrammed in vitro from both healthy and disease-state human somatic cells, has triggered an enormous global research effort to realize personalized regenerative medicine for numerous degenerative conditions. hiPSCs have been generated from cells of many tissue types and can be differentiated in vitro to most somatic lineages, not only for the establishment of disease models that can be utilized as novel drug screening platforms and to study the molecular and cellular processes leading to degeneration, but also for the in vivo cell-based repair or modulation of a patient's disease profile. hiPSCs derived from patients with the neurodegenerative diseases amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and multiple sclerosis have been successfully differentiated in vitro into disease-relevant cell types, including motor neurons, dopaminergic neurons and oligodendrocytes. However, the generation of functional iPSC-derived neural cells that are capable of engraftment in humans and the identification of robust disease phenotypes for modeling neurodegeneration still require several key challenges to be addressed. Here, we discuss these challenges and summarize recent progress toward the application of iPSC technology for these four common neurodegenerative diseases.}, }
@article {pmid24810848, year = {2014}, author = {Harris, DG}, title = {Management of pain in advanced disease.}, journal = {British medical bulletin}, volume = {110}, number = {1}, pages = {117-128}, doi = {10.1093/bmb/ldu010}, pmid = {24810848}, issn = {1471-8391}, mesh = {Analgesics, Opioid/administration &amp; dosage ; Drug Administration Schedule ; Humans ; Kidney/physiopathology ; Liver/physiopathology ; Pain/drug therapy/physiopathology ; Pain Management/*methods/standards ; Practice Guidelines as Topic ; World Health Organization ; }, abstract = {BACKGROUND: Pain is common in advanced malignancy but also prevalent in other non-malignant life-limiting diseases such as advanced heart disease; end stage renal failure and multiple sclerosis. Patients with renal or liver impairment need specific consideration, as most analgesics rely on either or both for their metabolism and excretion.<br><br>SOURCES OF DATA: Recent evidence-based guidelines and the systematic reviews that have informed their recommendations.<br><br>AREAS OF AGREEMENT: The principles of the WHO (World Health Organisation) analgesic ladder are commonly endorsed as a structured approach to the management of pain. For neuropathic pain, the efficacy of different agents is similar and choice of drug more guided by side effects, drug interactions and cost.<br><br>AREAS OF CONTROVERSY: Evidence supporting the WHO analgesic ladder is disputed and alternatives suggested, but no overwhelming evidence for an alternative approach exists to date.<br><br>GROWING POINTS: Alternative approaches to the WHO analgesic ladder, new analgesic agents, e.g. rapid onset oral/intranasal fentanyl.}, }
@article {pmid24809691, year = {2014}, author = {Riboldi, G and Zanetta, C and Ranieri, M and Nizzardo, M and Simone, C and Magri, F and Bresolin, N and Comi, GP and Corti, S}, title = {Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases.}, journal = {Molecular neurobiology}, volume = {50}, number = {3}, pages = {721-732}, pmid = {24809691}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; C9orf72 Protein ; DNA Repeat Expansion ; Frontotemporal Dementia/*drug therapy/genetics ; Humans ; Motor Neurons ; Oligonucleotides, Antisense/*therapeutic use ; Proteins/*genetics ; }, abstract = {Motor neuron disorders, and particularly amyotrophic lateral sclerosis (ALS), are fatal diseases that are due to the loss of motor neurons in the brain and spinal cord, with progressive paralysis and premature death. It has been recently shown that the most frequent genetic cause of ALS, frontotemporal dementia (FTD), and other neurological diseases is the expansion of a hexanucleotide repeat (GGGGCC) in the non-coding region of the C9ORF72 gene. The pathogenic mechanisms that produce cell death in the presence of this expansion are still unclear. One of the most likely hypotheses seems to be the gain-of-function that is achieved through the production of toxic RNA (able to sequester RNA-binding protein) and/or toxic proteins. In recent works, different authors have reported that antisense oligonucleotides complementary to the C9ORF72 RNA transcript sequence were able to significantly reduce RNA foci generated by the expanded RNA, in affected cells. Here, we summarize the recent findings that support the idea that the buildup of "toxic" RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS and also suggest that the use of antisense oligonucleotides targeting this transcript is a promising strategy for treating ALS/frontotemporal lobe dementia (FTLD) patients with the C9ORF72 repeat expansion. These data are particularly important, given the state of the art antisense technology, and they allow researchers to believe that a clinical application of these discoveries will be possible soon.}, }
@article {pmid24807843, year = {2014}, author = {Kamat, PK and Kalani, A and Kyles, P and Tyagi, SC and Tyagi, N}, title = {Autophagy of mitochondria: a promising therapeutic target for neurodegenerative disease.}, journal = {Cell biochemistry and biophysics}, volume = {70}, number = {2}, pages = {707-719}, pmid = {24807843}, issn = {1559-0283}, support = {R01 HL107640/HL/NHLBI NIH HHS/United States ; R01 NS051568/NS/NINDS NIH HHS/United States ; HL107640/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*drug effects ; Humans ; Mitochondria/*drug effects/*pathology ; Molecular Targeted Therapy/*methods ; Neurodegenerative Diseases/*drug therapy/*pathology ; }, abstract = {The autophagic process is the only known mechanism for mitochondrial turnover and it has been speculated that dysfunction of autophagy may result in mitochondrial error and cellular stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is associated with cellular oxidative stress and its impact on neurodegeneration. This impaired autophagic function may be considered as a possible mechanism in the pathogenesis of several neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. It can be suggested that autophagy dysfunction along with oxidative stress is considered main events in neurodegenerative disorders. New therapeutic approaches have now begun to target mitochondria as a potential drug target. This review discusses evidence supporting the notion that oxidative stress and autophagy are intimately associated with neurodegenerative disease pathogenesis. This review also explores new approaches that can prevent mitochondrial dysfunction, improve neurodegenerative etiology, and also offer possible cures to the aforementioned neurodegenerative diseases.}, }
@article {pmid24795623, year = {2014}, author = {Paul, P and de Belleroche, J}, title = {The role of D-serine and glycine as co-agonists of NMDA receptors in motor neuron degeneration and amyotrophic lateral sclerosis (ALS).}, journal = {Frontiers in synaptic neuroscience}, volume = {6}, number = {}, pages = {10}, pmid = {24795623}, issn = {1663-3563}, support = {DEBELLEROCHE/MAR10/6064/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {The fundamental role of D-serine as a co-agonist at the N-methyl-D-aspartate receptor (NMDAR), mediating both physiological actions of glutamate in long term potentiation and nociception and also pathological effects mediated by excitotoxicty, are well-established. More recently, a direct link to a chronic neurodegenerative disease, amyotrophic lateral sclerosis/motor neuron disease (ALS) has been suggested by findings that D-serine levels are elevated in sporadic ALS and the G93A SOD1 model of ALS (Sasabe et al., 2007, 2012) and that a pathogenic mutation (R199W) in the enzyme that degrades D-serine, D-amino acid oxidase (DAO), co-segregates with disease in familial ALS (Mitchell et al., 2010). Moreover, D-serine, its biosynthetic enzyme, serine racemase (SR) and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated aggregates and promotes apoptosis, all of which processes are attenuated by a D-serine/glycine site NMDAR antagonist. These studies provide considerable insight into the crosstalk between neurons and glia and also into potential therapeutic approaches for ALS.}, }
@article {pmid24792485, year = {2014}, author = {Procaccio, V and Bris, C and Chao de la Barca, JM and Oca, F and Chevrollier, A and Amati-Bonneau, P and Bonneau, D and Reynier, P}, title = {Perspectives of drug-based neuroprotection targeting mitochondria.}, journal = {Revue neurologique}, volume = {170}, number = {5}, pages = {390-400}, doi = {10.1016/j.neurol.2014.03.005}, pmid = {24792485}, issn = {0035-3787}, mesh = {Animals ; Cytoprotection/drug effects ; Humans ; Mitochondrial Diseases/*drug therapy ; Molecular Targeted Therapy/*methods ; Neurodegenerative Diseases/*prevention &amp; control ; Neurons/drug effects ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet.}, }
@article {pmid24785140, year = {2014}, author = {Blasco, H and Corcia, P and Pradat, PF}, title = {[What are the applications of biomarkers in ALS today?].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {43}, number = {5}, pages = {569-579}, doi = {10.1016/j.lpm.2013.12.014}, pmid = {24785140}, issn = {2213-0276}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers/analysis ; Humans ; Neuroimaging ; }, abstract = {Numerous biomarkers studies in ALS used targeted and non-targeted approaches, to help for the diagnosis, the prognosis or to identify new pathophysiological ways. The emerging approaches such as "omics" studies are very promising, but the practical and technical limits do not enable their optimization. Even if some biomarkers such as cystatin C or glutamate are highlighted in ALS, to date, no biomarker is currently used in routine practice. Diffusion-based neuroimaging has emerged as a tool to identify the involvement of the central neuron, but a recent meta-analysis shows a poor sensitivity and specificity. Spinal cord imaging has the advantage of simultaneoulsy investigating both the corticospinal tract and the peripheral motor neurons in the anterior horns of the spinal cord. Its interest to provide biomarkers in ALS is illustrated by recent studies that used a multiparametric approach. The limits of biomarkers studies are principally based on small cohorts, involving a control population who does not allow to assess specificity. The discrepancies between the biomarkers identified in the different studies are based on a strong heterogeneity of the disease and a lack of standardization of the research methodology, including the step of the validation of these molecules in independent cohorts. The perspectives in biomarker research in ALS imply the combination of analytical methods, human abilities and harmonization of the strategies.}, }
@article {pmid24780888, year = {2014}, author = {Leblond, CS and Kaneb, HM and Dion, PA and Rouleau, GA}, title = {Dissection of genetic factors associated with amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {91-101}, doi = {10.1016/j.expneurol.2014.04.013}, pmid = {24780888}, issn = {1090-2430}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; DNA-Binding Proteins/genetics ; *Genetic Association Studies ; Genetic Predisposition to Disease/*genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics ; Humans ; Profilins/genetics ; Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal late onset neurological disorder characterized by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. The majority of cases are sporadic (SALS) and only 5-10% have a family history (FALS). FALS cases show a high heritability and this has enabled the identification of several genetic triggers, of which mutations in SOD1, FUS, TARDBP and C9ORF72 are the most frequent. While such advances have contributed to our current understanding of the causes of most cases of FALS and their underlying pathophysiological consequences, they only explain a small fraction of SALS with the etiology of most SALS cases remaining unexplained. Here, we review past and current methods used for the identification of FALS and SALS associated genes and propose a risk-based classification for these. We also discuss how the growing number of whole exome/genome sequencing datasets prepared from SALS cases, and control individuals, may reveal novel insights into the genetic etiology of SALS; for instance through revealing increased mutation burden rates across genes or genomic regions that were not previously associated with ALS or through allowing the examination of a potential "oligogenic" mechanism of the disease. Finally we summarize the three most recently discovered 'high risk' genes in ALS.}, }
@article {pmid24780099, year = {2014}, author = {Twyffels, L and Gueydan, C and Kruys, V}, title = {Transportin-1 and Transportin-2: protein nuclear import and beyond.}, journal = {FEBS letters}, volume = {588}, number = {10}, pages = {1857-1868}, doi = {10.1016/j.febslet.2014.04.023}, pmid = {24780099}, issn = {1873-3468}, mesh = {Active Transport, Cell Nucleus ; Cell Nucleus/*metabolism ; Cilia/physiology ; Gene Expression ; Humans ; Mitosis/physiology ; Models, Biological ; Nuclear Localization Signals/genetics/metabolism/*physiology ; beta Karyopherins/genetics/metabolism/*physiology ; }, abstract = {Nearly 20 years after its identification as a new β-karyopherin mediating the nuclear import of the RNA-binding protein hnRNP A1, Transportin-1 is still commonly overlooked in comparison with its best known cousin, Importin-β. Transportin-1 is nonetheless a considerable player in nucleo-cytoplasmic transport. Over the past few years, significant progress has been made in the characterization of the nuclear localization signals (NLSs) that Transportin-1 recognizes, thereby providing the molecular basis of its diversified repertoire of cargoes. The recent discovery that mutations in the Transportin-dependent NLS of FUS cause mislocalization of this protein and result in amyotrophic lateral sclerosis illustrates the importance of Transportin-dependent import for human health. Besides, new functions of Transportin-1 are emerging in processes other than nuclear import. Here, we summarize what is known about Transportin-1 and the related β-karyopherin Transportin-2.}, }
@article {pmid24766396, year = {2014}, author = {Forlenza, OV and De-Paula, VJ and Diniz, BS}, title = {Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders.}, journal = {ACS chemical neuroscience}, volume = {5}, number = {6}, pages = {443-450}, pmid = {24766396}, issn = {1948-7193}, mesh = {Alzheimer Disease/*drug therapy/physiopathology ; Animals ; Humans ; Lithium Compounds/*pharmacology/therapeutic use ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3β) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases.}, }
@article {pmid24764286, year = {2015}, author = {Pagnini, F and Manzoni, GM and Tagliaferri, A and Gibbons, CJ}, title = {Depression and disease progression in amyotrophic lateral sclerosis: A comprehensive meta-regression analysis.}, journal = {Journal of health psychology}, volume = {20}, number = {8}, pages = {1107-1128}, doi = {10.1177/1359105314530453}, pmid = {24764286}, issn = {1461-7277}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Depression/*diagnosis/etiology ; *Disease Progression ; Humans ; }, abstract = {Depression in people with amyotrophic lateral sclerosis, a fatal and progressive neurodegenerative disorder, is a serious issue with important clinical consequences. However, physical impairment may confound the diagnosis when using generic questionnaires. We conducted a comprehensive review of literature. Mean scores from depression questionnaires were meta-regressed on study-level mean time since onset of symptoms. Data from 103 studies (3190 subjects) indicate that the Beck Depression Inventory and, to a lesser degree, the Hospital Anxiety and Depression Scale are influenced by the time since symptom onset, strongly related to physical impairment. Our results suggest that widely used depression scales overestimate depression due to confounding with physical symptoms.}, }
@article {pmid24762652, year = {2014}, author = {Charng, WL and Yamamoto, S and Bellen, HJ}, title = {Shared mechanisms between Drosophila peripheral nervous system development and human neurodegenerative diseases.}, journal = {Current opinion in neurobiology}, volume = {27}, number = {}, pages = {158-164}, pmid = {24762652}, issn = {1873-6882}, support = {/HHMI_/Howard Hughes Medical Institute/United States ; RC4 GM096355/GM/NIGMS NIH HHS/United States ; 1RC4GM096355-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cytoskeletal Proteins/metabolism ; Disease Models, Animal ; Drosophila ; Humans ; MicroRNAs/physiology ; Muscle Proteins/metabolism ; Neurodegenerative Diseases/genetics/metabolism/pathology/*physiopathology ; Neuromuscular Junction/pathology ; Peripheral Nervous System/embryology/*growth &amp; development ; Signal Transduction/*physiology ; }, abstract = {Signaling pathways and cellular processes that regulate neural development are used post-developmentally for proper function and maintenance of the nervous system. Genes that have been studied in the context of the development of Drosophila peripheral nervous system (PNS) and neuromuscular junction (NMJ) have been identified as players in the pathogenesis of human neurodegenerative diseases, including spinocerebellar ataxia, amyotrophic lateral sclerosis, and spinal muscular atrophy. Hence, by unraveling the molecular mechanisms that underlie proneural induction, cell fate determination, axonal targeting, dendritic branching, and synapse formation in Drosophila, novel features related to these disorders have been revealed. In this review, we summarize and discuss how studies of Drosophila PNS and NMJ development have provided guidance in experimental approaches for these diseases.}, }
@article {pmid24753999, year = {2014}, author = {Yokoyama, JS and Sirkis, DW and Miller, BL}, title = {C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity.}, journal = {American journal of neurodegenerative disease}, volume = {3}, number = {1}, pages = {1-18}, pmid = {24753999}, issn = {2165-591X}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, abstract = {Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia (FTD), a predominantly behavioral disease, and amyotrophic lateral sclerosis (ALS), a disease of motor neurons. The primary objectives of this review are to highlight the clinical heterogeneity associated with C9ORF72 pathogenic expansion and identify potential molecular mechanisms underlying selective vulnerability of distinct neural populations. The proposed mechanisms by which C9ORF72 expansion causes behavioral and motor neuron disease highlight the emerging role of impaired RNA and protein homeostasis in a spectrum of neurodegeneration and strengthen the biological connection between FTD and ALS.}, }
@article {pmid24748119, year = {2014}, author = {Rudrabhatla, P}, title = {Regulation of neuronal cytoskeletal protein phosphorylation in neurodegenerative diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {41}, number = {3}, pages = {671-684}, doi = {10.3233/JAD-130794}, pmid = {24748119}, issn = {1875-8908}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Brain/*pathology ; Cytoskeletal Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/*metabolism ; Phosphorylation ; }, abstract = {Neuronal cytoskeletal proteins such as neurofilaments (NFs) and tau are aberrantly and hyperphosphorylated in neurodegeneration. Under normal physiological conditions, NFs are synthesized in the cell bodies and phosphorylated and transported in the axonal compartment. However, under neurodegenerative disorders such as Alzheimer's disease (AD), spinal cord motor neuron inclusions of amyotrophic lateral sclerosis, Lewy bodies of Parkinson's disease, Pick's disease, Charcot-Marie-Tooth disease, and diabetic neuropathy, NFs are aberrantly and hyperphosphorylated in cell bodies. The proline directed protein kinases, such as cyclin-dependent protein kinase 5, mitogen activated protein kinase, and glycogen synthase kinase 3β, and the non proline-directed kinases, such as casein kinase 1, are deregulated in AD. Moreover, the reversible phosphorylation by protein phosphatase, PP2A, which mainly carries out the dephosphorylation of tau and NFs, is down regulated in AD brain. The aberrant phosphorylation of cytoskeletal proteins such as tau and NFs results in the axonal transport defects in neurodegeneration. The peptidyl-prolyl isomerase Pin1 plays a regulatory role in the post-phosphorylation mechanism of neuronal cytoskeletal proteins in AD brain. Possible therapeutic interventions for neurodegenerative disorders are (1) inhibition of proline-directed kinases, (2) activation of protein phosphatases such as PP2A, and (3) modulation of peptidyl-prolyl isomerases such as Pin1. Here, I discuss the regulation of neuronal cytoskeletal proteins under physiology and pathology.}, }
@article {pmid24739267, year = {2014}, author = {Sunde, K and Olasveengen, TM}, title = {Towards cardiopulmonary resuscitation without vasoactive drugs.}, journal = {Current opinion in critical care}, volume = {20}, number = {3}, pages = {234-241}, doi = {10.1097/MCC.0000000000000082}, pmid = {24739267}, issn = {1531-7072}, mesh = {Anti-Arrhythmia Agents/*administration &amp; dosage ; *Cardiopulmonary Resuscitation/methods/trends ; Electric Countershock/*methods/trends ; *Emergency Medical Services ; Epinephrine/*administration &amp; dosage ; Health Services Research ; Heart Arrest/mortality/*therapy ; Humans ; Life Support Care ; Outcome and Process Assessment, Health Care ; Randomized Controlled Trials as Topic ; Spectrum Analysis ; Survival Rate ; Vasoconstrictor Agents/*administration &amp; dosage ; }, abstract = {PURPOSE OF REVIEW: Whereas there is clear evidence for improved survival with cardiopulmonary resuscitation (CPR) and defibrillation during cardiac arrest management, there is today lacking evidence that any of the recommended and used drugs lead to any long-term benefit for the patients. In this review, we try to discuss our current view on why advanced life support (ALS) today can be performed without the use of drugs, and instead gain all focus on improving the tasks we know improve survival: CPR and defibrillation.<br><br>RECENT FINDINGS: Previous and recent cardiac arrest drug studies have been reviewed. These are mostly consisting of retrospective register data, some experimental data and a few new randomized trials. The alternative drug-free ALS concept is also discussed with relevant studies.<br><br>SUMMARY: There is currently no evidence to support any specific drugs during cardiac arrest. Good-quality CPR, early defibrillation and goal-directed postresuscitation care is more important. Healthcare systems should not prioritize implementation of unproven drugs before good quality of care can be documented. More drug studies are indeed required, and future research needs to incorporate better diagnostic tools to test more specific and tailored therapies that account for underlying causes and individual responsiveness.}, }
@article {pmid24727531, year = {2014}, author = {Magen, I and Hornstein, E}, title = {Oligonucleotide-based therapy for neurodegenerative diseases.}, journal = {Brain research}, volume = {1584}, number = {}, pages = {116-128}, doi = {10.1016/j.brainres.2014.04.005}, pmid = {24727531}, issn = {1872-6240}, mesh = {Animals ; Brain/drug effects ; Humans ; MicroRNAs/drug effects/therapeutic use ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/*drug therapy ; Oligonucleotides, Antisense/administration &amp; dosage/*therapeutic use ; RNA Interference ; RNA-Induced Silencing Complex ; }, abstract = {Molecular genetics insight into the pathogenesis of several neurodegenerative diseases, such as Alzheimer׳s disease, Parkinson׳s disease, Huntington׳s disease and amyotrophic lateral sclerosis, encourages direct interference with the activity of neurotoxic genes or the molecular activation of neuroprotective pathways. Oligonucleotide-based therapies are recently emerging as an efficient strategy for drug development and these can be employed as new treatments of neurodegenerative states. Here we review advances in this field in recent years which suggest an encouraging assessment that oligonucleotide technologies for targeting of RNAs will enable the development of new therapies and will contribute to preservation of brain integrity.}, }
@article {pmid24723858, year = {2014}, author = {Jara, JH and Genç, B and Klessner, JL and Ozdinler, PH}, title = {Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease.}, journal = {Frontiers in neuroanatomy}, volume = {8}, number = {}, pages = {16}, pmid = {24723858}, issn = {1662-5129}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; R01 NS085161/NS/NINDS NIH HHS/United States ; }, abstract = {Corticospinal motor neurons (CSMN) have a unique ability to receive, integrate, translate, and transmit the cerebral cortex's input toward spinal cord targets and therefore act as a "spokesperson" for the initiation and modulation of voluntary movements that require cortical input. CSMN degeneration has an immense impact on motor neuron circuitry and is one of the underlying causes of numerous neurodegenerative diseases, such as primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS). In addition, CSMN death results in long-term paralysis in spinal cord injury patients. Detailed cellular analyses are crucial to gain a better understanding of the pathologies underlying CSMN degeneration. However, visualizing and identifying these vulnerable neuron populations in the complex and heterogeneous environment of the cerebral cortex have proved challenging. Here, we will review recent developments and current applications of novel strategies that reveal the cellular and molecular basis of CSMN health and vulnerability. Such studies hold promise for building long-term effective treatment solutions in the near future.}, }
@article {pmid24705136, year = {2014}, author = {Babin, PJ and Goizet, C and Raldúa, D}, title = {Zebrafish models of human motor neuron diseases: advantages and limitations.}, journal = {Progress in neurobiology}, volume = {118}, number = {}, pages = {36-58}, doi = {10.1016/j.pneurobio.2014.03.001}, pmid = {24705136}, issn = {1873-5118}, mesh = {Animals ; Brain/anatomy &amp; histology/physiopathology ; *Disease Models, Animal ; Humans ; *Motor Neuron Disease/genetics/physiopathology ; Nerve Degeneration/genetics/physiopathology ; Spinal Cord/anatomy &amp; histology/physiopathology ; *Zebrafish/anatomy &amp; histology/genetics/physiology ; }, abstract = {Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.}, }
@article {pmid24704895, year = {2014}, author = {Patatanian, E and Casselman, J}, title = {Dextromethorphan/quinidine for the treatment of pseudobulbar affect.}, journal = {The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists}, volume = {29}, number = {4}, pages = {264-269}, doi = {10.4140/TCP.n.2014.264}, pmid = {24704895}, issn = {2331-0936}, mesh = {Clinical Trials as Topic ; Crying/psychology ; Dextromethorphan/administration &amp; dosage/adverse effects/pharmacology/*therapeutic use ; Drug Combinations ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Laughter/psychology ; Pseudobulbar Palsy/*drug therapy/metabolism/psychology ; Quinidine/administration &amp; dosage/adverse effects/pharmacology/*therapeutic use ; Receptors, sigma/*agonists ; Treatment Outcome ; Sigma-1 Receptor ; }, abstract = {OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA).<br><br>DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine.<br><br>English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations.<br><br>DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration.<br><br>CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.}, }
@article {pmid24699704, year = {2014}, author = {Faravelli, I and Riboldi, G and Nizzardo, M and Simone, C and Zanetta, C and Bresolin, N and Comi, GP and Corti, S}, title = {Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {71}, number = {17}, pages = {3257-3268}, pmid = {24699704}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/genetics/immunology/pathology/*surgery/therapy ; Animals ; Cellular Microenvironment ; Clinical Trials as Topic ; Disease Models, Animal ; Embryonic Stem Cells/transplantation ; Humans ; Induced Pluripotent Stem Cells/transplantation ; Injections, Spinal ; Mesenchymal Stem Cell Transplantation ; Motor Neurons/pathology ; Neural Stem Cells/transplantation ; Neurogenesis ; Neuroglia/physiology ; Spinal Cord/pathology ; *Stem Cell Transplantation ; Therapies, Investigational ; *Translational Research, Biomedical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3-5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.}, }
@article {pmid24698014, year = {2014}, author = {Renner, M and Melki, R}, title = {Protein aggregation and prionopathies.}, journal = {Pathologie-biologie}, volume = {62}, number = {3}, pages = {162-168}, doi = {10.1016/j.patbio.2014.01.003}, pmid = {24698014}, issn = {1768-3114}, mesh = {Aging ; Alzheimer Disease/prevention &amp; control ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Autophagy ; Biopolymers ; Clinical Trials, Phase II as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Endocytosis ; Humans ; Inclusion Bodies/chemistry/pathology ; Mice ; Nerve Tissue Proteins/*chemistry ; Neurodegenerative Diseases/*metabolism/pathology ; Neurofibrillary Tangles/chemistry/pathology ; Plaque, Amyloid/chemistry/pathology ; Polysaccharides/therapeutic use ; Prion Diseases/*metabolism/pathology/veterinary ; Prions/chemistry ; Protein Aggregation, Pathological/*metabolism/pathology ; Protein Conformation ; Solubility ; }, abstract = {Prion protein and prion-like proteins share a number of characteristics. From the molecular point of view, they are constitutive proteins that aggregate following conformational changes into insoluble particles. These particles escape the cellular clearance machinery and amplify by recruiting the soluble for of their constituting proteins. The resulting protein aggregates are responsible for a number of neurodegenerative diseases such as Creutzfeldt-Jacob, Alzheimer, Parkinson and Huntington diseases. In addition, there are increasing evidences supporting the inter-cellular trafficking of these aggregates, meaning that they are "transmissible" between cells. There are also evidences that brain homogenates from individuals developing Alzheimer and Parkinson diseases propagate the disease in recipient model animals in a manner similar to brain extracts of patients developing Creutzfeldt-Jacob's disease. Thus, the propagation of protein aggregates from cell to cell may be a generic phenomenon that contributes to the evolution of neurodegenerative diseases, which has important consequences on human health issues. Moreover, although the distribution of protein aggregates is characteristic for each disease, new evidences indicate the possibility of overlaps and crosstalk between the different disorders. Despite the increasing evidences that support prion or prion-like propagation of protein aggregates, there are many unanswered questions regarding the mechanisms of toxicity and this is a field of intensive research nowadays.}, }
@article {pmid24694032, year = {2014}, author = {Wood, LK and Langford, SJ}, title = {Motor neuron disease: a chemical perspective.}, journal = {Journal of medicinal chemistry}, volume = {57}, number = {15}, pages = {6316-6331}, doi = {10.1021/jm5001584}, pmid = {24694032}, issn = {1520-4804}, mesh = {Amino Acid Transport System X-AG/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use ; Apoptosis ; Disease Models, Animal ; Genetic Therapy ; Glutamic Acid/metabolism ; Humans ; Mice, Transgenic ; Mitochondria/metabolism ; Mutation ; Neuroprotective Agents/*pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Receptors, Glutamate/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {This Perspective provides a background to the pathogenesis of neurodegenerative disease and specifically amyotrophic lateral sclerosis (ALS) and gives an overview of the many pathways, both genetically inheritable and sporadic, that may lead to the premature activation of apoptotic pathways in neurons, as well as current and proposed approaches toward interrupting these pathways.}, }
@article {pmid24692486, year = {2014}, author = {Mandemakers, W}, title = {Purification and culture of corticospinal motor neurons.}, journal = {Cold Spring Harbor protocols}, volume = {2014}, number = {4}, pages = {336-338}, doi = {10.1101/pdb.top070938}, pmid = {24692486}, issn = {1559-6095}, mesh = {Animals ; Cell Culture Techniques ; Cell Separation/*methods ; Motor Neurons/*physiology ; Rodentia ; }, abstract = {Corticospinal motor neurons (CSMNs) residing in cortical layer V of the mammalian brain project their axons to the spinal cord, where they connect with spinal motor neurons (SMNs) located in the ventral horn of the spinal cord. CSMNs and SMNs control voluntary movements, and their importance becomes obvious in situations where this network breaks down (i.e., in amyotrophic lateral sclerosis [ALS] and after spinal cord injury). Here we provide an overview of recent progress in the anatomical, morphological, and genetic characterization of developing CSMNs, as well as their survival requirements. We also describe model systems used to study CSMNs and introduce an immunopanning procedure for the purification and culture of CSMNs. Although these procedures have so far been used to purify only rodent CSMNs, in principle they should work to purify CSMNs from any vertebrate species, as well any type of central nervous system (CNS) or peripheral nervous system (PNS) neuron that can be retrograde labeled.}, }
@article {pmid24683506, year = {2014}, author = {Bavarsad Shahripour, R and Harrigan, MR and Alexandrov, AV}, title = {N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities.}, journal = {Brain and behavior}, volume = {4}, number = {2}, pages = {108-122}, pmid = {24683506}, issn = {2162-3279}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; Humans ; Nervous System Diseases/*drug therapy ; }, abstract = {BACKGROUND: There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.<br><br>AIM AND DISCUSSION: Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht-Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.<br><br>CONCLUSION: Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.}, }
@article {pmid24681158, year = {2014}, author = {Bourassa, MW and Ratan, RR}, title = {The interplay between microRNAs and histone deacetylases in neurological diseases.}, journal = {Neurochemistry international}, volume = {77}, number = {}, pages = {33-39}, pmid = {24681158}, issn = {1872-9754}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; }, mesh = {Histone Deacetylases/*genetics/*metabolism ; Humans ; MicroRNAs/*genetics/*metabolism ; Nervous System Diseases/enzymology/*genetics/*metabolism ; }, abstract = {Neurological conditions, such as Alzheimer's disease and stroke, represent a prevalent group of devastating illnesses with few treatments. Each of these diseases or conditions is in part characterized by the dysregulation of many genes, including those that code for microRNAs (miRNAs) and histone deacetylases (HDACs). Recently, a complex relationship has been uncovered linking miRNAs and HDACs and their ability to regulate one another. This provides a new avenue for potential therapeutics as the ability to reinstate a careful balance between miRNA and HDACs has lead to improved outcomes in a number of in vitro and in vivo models of neurological conditions. In this review, we will discuss recent findings on the interplay between miRNAs and HDACs and its implications for pathogenesis and treatment of neurological conditions, including amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease and stroke.}, }
@article {pmid24678935, year = {2014}, author = {Danborg, PB and Simonsen, AH and Waldemar, G and Heegaard, NH}, title = {The potential of microRNAs as biofluid markers of neurodegenerative diseases--a systematic review.}, journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals}, volume = {19}, number = {4}, pages = {259-268}, doi = {10.3109/1354750X.2014.904001}, pmid = {24678935}, issn = {1366-5804}, mesh = {Biomarkers/*blood ; Cognition Disorders/blood ; Humans ; MicroRNAs/*blood ; Neurodegenerative Diseases/blood/*diagnosis ; }, abstract = {MicroRNAs (miRNA) are biological molecules transcribed from non-protein coding regions of the genome, participating in regulating cellular processes. MiRNAs in biofluids may possess neurodegenerative disease biomarker potential for screening tests, differential diagnosis and disease progression monitoring. This systematic review clarifies biomarker potential of miRNAs detected in biofluids of neurodegenerative disease patients. Thirty-three and ten miRNAs displayed significant expression between patients with multiple sclerosis and Alzheimer's disease, respectively, compared to healthy controls in minimum two studies. Thirty-eight miRNAs showed biomarker potential by distinguishing significantly between minimum two diseases. Summarized data directs future research towards discovering new biomarkers for neurodegenerative diseases.}, }
@article {pmid24678247, year = {2013}, author = {Zeliger, HI}, title = {Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases.}, journal = {Interdisciplinary toxicology}, volume = {6}, number = {3}, pages = {103-110}, pmid = {24678247}, issn = {1337-6853}, abstract = {Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases.}, }
@article {pmid24672430, year = {2014}, author = {Ogawa, M and Furukawa, Y}, title = {A seeded propagation of Cu, Zn-superoxide dismutase aggregates in amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {83}, pmid = {24672430}, issn = {1662-5102}, abstract = {Abnormal accumulation of protein inclusions in motor neurons has been known as a major pathological change in amyotrophic lateral sclerosis (ALS). Increasing numbers of proteins including mutant Cu, Zn-superoxide dismutase (SOD1) have been identified as constituents of pathological inclusions in a form of insoluble fibrillar aggregates. Notably, protein fibrillar aggregates exhibit a self-perpetuating property, which can convert a soluble native protein into insoluble fibrillar aggregates. Such "seeding reaction" of protein fibrils can accelerate the aggregation significantly and would contribute to the spread of inclusion pathologies from an affected cell to its neighboring cells in neurodegenerative diseases. In ALS, a pathological change first occurs at the site of disease onset and then propagates throughout the affected tissues in a time-dependent manner; therefore, it can be assumed that seeded aggregation may be the key factor of disease progression in ALS. In this mini review, we will briefly summarize recent studies on possible roles of a seeded aggregation of SOD1 in pathomechanism of ALS.}, }
@article {pmid24668481, year = {2014}, author = {Sendtner, M}, title = {Motoneuron disease.}, journal = {Handbook of experimental pharmacology}, volume = {220}, number = {}, pages = {411-441}, doi = {10.1007/978-3-642-45106-5_15}, pmid = {24668481}, issn = {0171-2004}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Ciliary Neurotrophic Factor/physiology ; DNA-Binding Proteins/physiology ; Humans ; Motor Neurons/physiology ; Muscular Atrophy, Spinal/genetics/*physiopathology ; Nerve Growth Factors/physiology ; RNA/metabolism ; Signal Transduction/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) represent the two major forms of motoneuron disease. In both forms of disease, spinal and bulbar motoneurons become dysfunctional and degenerate. In ALS, cortical motoneurons are also affected, which contributes to the clinical phenotype. The gene defects for most familial forms of ALS and SMA have been discovered and they point to a broad spectrum of disease mechanisms, including defects in RNA processing, pathological protein aggregation, altered apoptotic signaling, and disturbed energy metabolism. Despite the fact that lack of neurotrophic factors or their corresponding receptors are not found as genetic cause of motoneuron disease, signaling pathways initiated by neurotrophic factors for motoneuron survival, axon growth, presynaptic development, and synaptic function are disturbed in ALS and SMA. Better understanding of how neurotrophic factors and downstream signaling pathways interfere with these disease mechanisms could help to develop new therapies for motoneuron disease and other neurodegenerative disorders.}, }
@article {pmid24664850, year = {2014}, author = {Chen, XJ and Xu, H and Cooper, HM and Liu, Y}, title = {Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases.}, journal = {Science China. Life sciences}, volume = {57}, number = {4}, pages = {372-377}, doi = {10.1007/s11427-014-4639-9}, pmid = {24664850}, issn = {1869-1889}, mesh = {Alzheimer Disease/metabolism ; Animals ; Axonal Transport ; Biological Transport ; Centrosome/ultrastructure ; Charcot-Marie-Tooth Disease/metabolism ; Cytoplasm/*chemistry ; Developmental Disabilities/*metabolism ; Dyneins/*physiology ; Humans ; Huntington Disease/metabolism ; Mice ; Microtubules/chemistry ; Mutation ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; }, abstract = {Cytoplasmic dynein is the most important molecular motor driving the movement of a wide range of cargoes towards the minus ends of microtubules. As a molecular motor protein, dynein performs a variety of basic cellular functions including organelle transport and centrosome assembly. In the nervous system, dynein has been demonstrated to be responsible for axonal retrograde transport. Many studies have revealed direct or indirect evidence of dynein in neurodegenerative diseases such as amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Alzheimer's disease, Parkinson's disease and Huntington's disease. Among them, a number of mutant proteins involved in various neurodegenerative diseases interact with dynein. Axonal transport disruption is presented as a common feature occurring in neurodegenerative diseases. Dynein heavy chain mutant mice also show features of neurodegenerative diseases. Moreover, defects of dynein-dependent processes such as autophagy or clearance of aggregation-prone proteins are found in most of these diseases. Lines of evidence have also shown that dynein is associated with neurodevelopmental diseases. In this review, we focus on dynein involvement in different neurological diseases and discuss potential underlying mechanisms.}, }
@article {pmid24662480, year = {2014}, author = {Faassen, EJ}, title = {Presence of the neurotoxin BMAA in aquatic ecosystems: what do we really know?.}, journal = {Toxins}, volume = {6}, number = {3}, pages = {1109-1138}, pmid = {24662480}, issn = {2072-6651}, mesh = {Amino Acids, Diamino/*analysis ; Cyanobacteria/chemistry ; Cyanobacteria Toxins ; Ecosystem ; Environmental Exposure ; Humans ; Neurotoxins/*analysis ; Water Pollutants, Chemical/*analysis ; }, abstract = {The neurotoxin β-N-methylamino-L-alanine (BMAA) is suspected to play a role in the neurological diseases amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. BMAA production by cyanobacteria has been reported and contact with cyanobacteria infested waters or consumption of aquatic organisms are possible pathways to human exposure. However, there is little consensus regarding whether BMAA is present in cyanobacteria or not, and if so, at what concentrations. The aim of this review is to indicate the current state of knowledge on the presence of BMAA in aquatic ecosystems. Some studies have convincingly shown that BMAA can be present in aquatic samples at the µg/g dry weight level, which is around the detection limit of some equally credible studies in which no BMAA was detected. However, for the majority of the reviewed articles, it was unclear whether BMAA was correctly identified, either because inadequate analytical methods were used, or because poor reporting of analyses made it impossible to verify the results. Poor analysis, reporting and prolific errors have shaken the foundations of BMAA research. First steps towards estimation of human BMAA exposure are to develop and use selective, inter-laboratory validated methods and to correctly report the analytical work.}, }
@article {pmid24661645, year = {2014}, author = {Lekoubou, A and Matsha, TE and Sobngwi, E and Kengne, AP}, title = {Effects of diabetes mellitus on amyotrophic lateral sclerosis: a systematic review.}, journal = {BMC research notes}, volume = {7}, number = {}, pages = {171}, pmid = {24661645}, issn = {1756-0500}, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Diabetes Mellitus/*blood ; Glucose Intolerance/*blood ; Humans ; Risk Assessment ; Risk Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron degenerative disease which onset and course may be affected by concurrent diabetes mellitus (DM). We performed a systematic review to assess the effect of DM/dysglycemic states on ALS.<br><br>METHODS: We searched PubMed MEDLINE, from inception to March 2013 for original articles published in English and in French languages on DM (and related states) and ALS. We made no restriction per study designs.<br><br>RESULTS: Seven studies/1410 citations (5 case-control and 2 cross-sectional) were included in the final selection. The number of participants with ALS ranged from 18 to 2371. The outcome of interest was ALS and DM/dysglycemic states respectively in three and two case control-studies. DM/impaired glucose tolerance status did not affect disease progression, survival, disease severity and disease duration in ALS participants but ALS participants with DM were found to be older in one study. DM/IGT prevalence was similar in both ALS and non ALS participants. This review was limited by the absence of prospective cohort studies and the heterogeneity in ALS and DM diagnosis criteria.<br><br>CONCLUSIONS: This systematic review suggests that evidences for the association of ALS and DM are rather limited and derived from cross-sectional studies. Prospective studies supplemented by ALS registries and animal studies are needed to better understand the relationship between both conditions.}, }
@article {pmid24653700, year = {2014}, author = {Urrutia, PJ and Mena, NP and Núñez, MT}, title = {The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {5}, number = {}, pages = {38}, pmid = {24653700}, issn = {1663-9812}, abstract = {A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich's ataxia and Parkinson's disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson's disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.}, }
@article {pmid24649927, year = {2014}, author = {Budini, M and Baralle, FE and Buratti, E}, title = {Targeting TDP-43 in neurodegenerative diseases.}, journal = {Expert opinion on therapeutic targets}, volume = {18}, number = {6}, pages = {617-632}, doi = {10.1517/14728222.2014.896905}, pmid = {24649927}, issn = {1744-7631}, mesh = {Animals ; DNA-Binding Proteins/*antagonists &amp; inhibitors/chemistry/physiology ; Humans ; Neurodegenerative Diseases/*drug therapy ; Protein Aggregation, Pathological/drug therapy ; RNA/metabolism ; }, abstract = {INTRODUCTION: TAR DNA-binding protein-43 (TDP-43) is a ubiquitously expressed RNA-binding protein belonging to the hnRNP family of nuclear proteins. In human disease, its aberrant aggregation in brains has been shown to play a causative role in several neurodegenerative diseases, especially ALS and FTLD.<br><br>AREAS COVERED: In this work, we have highlighted what could be the most promising avenues that could be exploited in a profitable manner to modulate TDP-43 pathology. These range from its protein-protein interactions, RNA-protein interactions and its aberrant aggregation process. Recently published articles on these subjects have been reviewed in the writing up of this manuscript.<br><br>EXPERT OPINION: Targeting aberrant TDP-43 aggregation in neurodegenerative diseases should be considered both a challenge and an opportunity. The challenge is represented by the central role played by TDP-43 in the general cellular and developmental processes of higher proteins. This characteristic makes it difficult to target this protein in a generalized manner. In addition, and mostly because of this reason, we still lack reliable disease model systems that can reproduce most, if not all, characteristics of the human disease. Nonetheless, recent research is finally starting to provide potential therapeutic targets based on new findings that regard TDP-43 biology and functions.}, }
@article {pmid24648037, year = {2014}, author = {Eisen, A and Kiernan, M and Mitsumoto, H and Swash, M}, title = {Amyotrophic lateral sclerosis: a long preclinical period?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {85}, number = {11}, pages = {1232-1238}, doi = {10.1136/jnnp-2013-307135}, pmid = {24648037}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/etiology/*pathology/physiopathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; *Prodromal Symptoms ; Risk Factors ; Synaptic Transmission/physiology ; Time Factors ; }, abstract = {The onset of amyotrophic lateral sclerosis (ALS) is conventionally considered as commencing with the recognition of clinical symptoms. We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons. We suggest, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.}, }
@article {pmid24645792, year = {2014}, author = {Cauchi, RJ}, title = {Gem depletion: amyotrophic lateral sclerosis and spinal muscular atrophy crossover.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {20}, number = {7}, pages = {574-581}, pmid = {24645792}, issn = {1755-5949}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/metabolism ; Animals ; Humans ; Muscular Atrophy, Spinal/diagnosis/*genetics/metabolism ; Ribonucleoproteins, Small Nuclear/*genetics/metabolism ; SMN Complex Proteins/*genetics/metabolism ; Spliceosomes/genetics/metabolism ; }, abstract = {The determining factor of spinal muscular atrophy (SMA), the most common motor neuron degenerative disease of childhood, is the survival motor neuron (SMN) protein. SMN and its Gemin associates form a complex that is indispensible for the biogenesis of small nuclear ribonucleoproteins (snRNPs), which constitute the building blocks of spliceosomes. It is as yet unclear whether a decreased capacity of SMN in snRNP assembly, and, hence, transcriptome abnormalities, account for the specific neuromuscular phenotype in SMA. Across metazoa, the SMN-Gemins complex concentrates in multiple nuclear gems that frequently neighbour or overlap Cajal bodies. The number of gems has long been known to be a faithful indicator of SMN levels, which are linked to SMA severity. Intriguingly, a flurry of recent studies have revealed that depletion of this nuclear structure is also a signature feature of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease. This review discusses such a surprising crossover in addition to highlighting the most recent work on the intricate world of spliceosome building, which seems to be at the heart of motor neuron physiology and survival.}, }
@article {pmid24640982, year = {2014}, author = {Pinto, S and Carvalho, Md}, title = {Breathing new life into treatment advances for respiratory failure in amyotrophic lateral sclerosis patients.}, journal = {Neurodegenerative disease management}, volume = {4}, number = {1}, pages = {83-102}, doi = {10.2217/nmt.13.74}, pmid = {24640982}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/*complications/epidemiology/physiopathology ; Animals ; Humans ; Respiratory Insufficiency/epidemiology/*etiology/physiopathology/*therapy ; Respiratory Therapy/economics/*methods ; }, abstract = {In the last three decades, improvements in respiratory management are responsible for increasing survival and improving quality of life for amyotrophic lateral sclerosis (ALS) patients. Nowadays, ALS patients with respiratory involvement are offered a support treatment other than the traditional respiratory palliative care. Knowledge about available respiratory support potentialities is essential for appropriate, customized and effective treatment of ALS, which should probably be started sooner than the conventional approach. There is evidence supporting that respiratory support has a larger impact than riluzole on survival. Noninvasive ventilation is essential in the treatment of ALS patients with respiratory involvement. In this article methods to determine respiratory failure in ALS, mechanical invasive and noninvasive ventilation, telemetry, diaphragm pacing, cough aids and respiratory exercise are reviewed, after a brief overlook of respiratory insufficiency in ALS.}, }
@article {pmid24629478, year = {2014}, author = {Ngo, ST and Steyn, FJ and McCombe, PA}, title = {Body mass index and dietary intervention: implications for prognosis of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {340}, number = {1-2}, pages = {5-12}, doi = {10.1016/j.jns.2014.02.035}, pmid = {24629478}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/*drug therapy ; *Body Mass Index ; *Dietary Supplements ; *Energy Intake ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset, neurodegenerative disease that is characterized by the loss of upper (corticospinal) and lower motor neurons. ALS is a multifactorial disease whereby a combination of genetic and environmental factors may contribute to disease pathogenesis. While the majority of studies indicate that the underlying causes for ALS pathology may be due to multiple defects at the cellular level, factors that have recently been identified to be associated with survival could lead to the development of beneficial interventions. In ALS, a higher pre-morbid body mass index (BMI) and the maintenance of BMI and nutritional state is associated with improved outcome. This review will focus on the associations between body composition and adiposity relative to disease duration and risk, and will discuss current evidence that supports the benefits of improving energy balance, and the maintenance of body mass through nutritional intervention in ALS.}, }
@article {pmid24627609, year = {2014}, author = {Yokoyama, S and Sekioka, A and Ueno, K and Higashide, Y and Okishio, Y and Kawaguchi, N and Hagihara, T and Yamada, H and Kamimura, R and Kuwahara, M and Ichimiya, M and Utsunomiya, H and Uyama, S and Kato, H}, title = {Pancreaticoduodenectomy following total gastrectomy: a case report and literature review.}, journal = {World journal of gastroenterology}, volume = {20}, number = {10}, pages = {2721-2724}, pmid = {24627609}, issn = {2219-2840}, mesh = {Adenocarcinoma/pathology/*surgery ; Afferent Loop Syndrome/diagnosis/*etiology/surgery ; Aged ; Anastomosis, Roux-en-Y ; Cholangitis/etiology ; Gastrectomy/*adverse effects ; Humans ; Male ; Pancreatic Neoplasms/pathology/*surgery ; Pancreaticoduodenectomy/*adverse effects ; Plastic Surgery Procedures/*adverse effects ; Reoperation ; Stomach Neoplasms/pathology/*surgery ; Treatment Outcome ; }, abstract = {We present a case of afferent loop syndrome (ALS) occurring after pancreaticoduodenectomy (PD) in a patient who had previously undergone total gastrectomy (TG), and review the English-language literature concerning reconstruction procedures following PD in patients who had undergone TG. The patient was a 69-year-old man who had undergone TG reconstruction by a Roux-en-Y method at age 58 years. The patient underwent PD for pancreas head adenocarcinoma. A jejunal limb previously made at the prior TG was used for pancreaticojejunostomy and hepaticojejunostomy. Despite normal patency of the hepaticojejunostomy, he suffered from repeated postoperative cholangitis which was brought on by ALS due to shortness of the jejunal limb (15 cm in length). We therefore performed receliotomy in which the hepaticojejunostomy was disconnected and reconstructed using a new Y limb 40-cm in length constructed in a double Roux-en-Y fashion. The refractory cholangitis resolved immediately after the receliotomy and did not recur. Review of the literature revealed the lack of any current consensus for a standard procedure for reconstruction following PD in patients who had previously undergone TG. This issue warrants further attention, particularly given the expected future increase in the number of PDs in patients with a history of gastric cancer.}, }
@article {pmid24624329, year = {2014}, author = {Bede, P and Hardiman, O}, title = {Lessons of ALS imaging: Pitfalls and future directions - A critical review.}, journal = {NeuroImage. Clinical}, volume = {4}, number = {}, pages = {436-443}, pmid = {24624329}, issn = {2213-1582}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*pathology ; *Artifacts ; Brain/*diagnostic imaging/*pathology ; Forecasting ; Humans ; Image Enhancement/methods ; Neuroimaging/*methods/trends ; Radionuclide Imaging ; Research Design/trends ; Sample Size ; }, abstract = {BACKGROUND: While neuroimaging in ALS has gained unprecedented momentum in recent years, little progress has been made in the development of viable diagnostic, prognostic and monitoring markers.<br><br>OBJECTIVES: To identify and discuss the common pitfalls in ALS imaging studies and to reflect on optimal study designs based on pioneering studies.<br><br>METHODS: A "PubMed"-based literature&#xa0;search on ALS was performed&#xa0;based on neuroimaging-related keywords. Study limitations were systematically reviewed and classified so that stereotypical trends could be identified.<br><br>RESULTS: Common shortcomings, such&#xa0;as relatively small sample sizes, statistically underpowered study designs, lack of disease controls, poorly&#xa0;characterised patient cohorts and a large number of conflicting studies, remain a significant challenge to the field. Imaging data of ALS continue to be interpreted at a group-level, as opposed to meaningful individual-patient inferences.<br><br>CONCLUSIONS: A systematic, critical review of ALS imaging has identified stereotypical shortcomings, the lessons of which should be considered in the design of future prospective MRI studies. At a time when large multicentre studies are underway a candid discussion of these factors is particularly timely.}, }
@article {pmid24620031, year = {2014}, author = {Redler, RL and Shirvanyants, D and Dagliyan, O and Ding, F and Kim, DN and Kota, P and Proctor, EA and Ramachandran, S and Tandon, A and Dokholyan, NV}, title = {Computational approaches to understanding protein aggregation in neurodegeneration.}, journal = {Journal of molecular cell biology}, volume = {6}, number = {2}, pages = {104-115}, pmid = {24620031}, issn = {1759-4685}, support = {F31AG039266/AG/NIA NIH HHS/United States ; F31NS073435/NS/NINDS NIH HHS/United States ; R01GM080742/GM/NIGMS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Computational Biology/*methods ; Humans ; Molecular Sequence Data ; Nerve Degeneration/*metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; *Protein Aggregates ; Protein Folding ; }, abstract = {The generation of toxic non-native protein conformers has emerged as a unifying thread among disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Atomic-level detail regarding dynamical changes that facilitate protein aggregation, as well as the structural features of large-scale ordered aggregates and soluble non-native oligomers, would contribute significantly to current understanding of these complex phenomena and offer potential strategies for inhibiting formation of cytotoxic species. However, experimental limitations often preclude the acquisition of high-resolution structural and mechanistic information for aggregating systems. Computational methods, particularly those combine both all-atom and coarse-grained simulations to cover a wide range of time and length scales, have thus emerged as crucial tools for investigating protein aggregation. Here we review the current state of computational methodology for the study of protein self-assembly, with a focus on the application of these methods toward understanding of protein aggregates in human neurodegenerative disorders.}, }
@article {pmid24616665, year = {2014}, author = {Tovar-Y-Romo, LB and Ramírez-Jarquín, UN and Lazo-Gómez, R and Tapia, R}, title = {Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {61}, pmid = {24616665}, issn = {1662-5102}, abstract = {Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and insulin-like growth factor 1 (IGF-1). Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this minireview we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.}, }
@article {pmid24613827, year = {2014}, author = {Thomsen, GM and Gowing, G and Svendsen, S and Svendsen, CN}, title = {The past, present and future of stem cell clinical trials for ALS.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {127-137}, doi = {10.1016/j.expneurol.2014.02.021}, pmid = {24613827}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; *Clinical Trials as Topic/history/methods/trends ; History, 20th Century ; History, 21st Century ; Humans ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the cortex, brainstem and spinal cord. This leads to paralysis, respiratory insufficiency and death within an average of 3 to 5 years from disease onset. While the genetics of ALS are becoming more understood in familial cases, the mechanisms underlying disease pathology remain unclear and there are no effective treatment options. Without understanding what causes ALS it is difficult to design treatments. However, in recent years stem cell transplantation has emerged as a potential new therapy for ALS patients. While motor neuron replacement remains a focus of some studies trying to treat ALS with stem cells, there is more rationale for using stem cells as support cells for dying motor neurons as they are already connected to the muscle. This could be through reducing inflammation, releasing growth factors, and other potential less understood mechanisms. Prior to moving into patients, stringent pre-clinical studies are required that have at least some rationale and efficacy in animal models and good safety profiles. However, given our poor understanding of what causes ALS and whether stem cells may ameliorate symptoms, there should be a push to determine cell safety in pre-clinical models and then a quick translation to the clinic where patient trials will show if there is any efficacy. Here, we provide a critical review of current clinical trials using either mesenchymal or neural stem cells to treat ALS patients. Pre-clinical data leading to these trials, as well as those in development are also evaluated in terms of mechanisms of action, validity of conclusions and rationale for advancing stem cell treatment strategies for this devastating disorder.}, }
@article {pmid24610493, year = {2014}, author = {Dolezalova, D and Hruska-Plochan, M and Bjarkam, CR and Sørensen, JC and Cunningham, M and Weingarten, D and Ciacci, JD and Juhas, S and Juhasova, J and Motlik, J and Hefferan, MP and Hazel, T and Johe, K and Carromeu, C and Muotri, A and Bui, J and Strnadel, J and Marsala, M}, title = {Pig models of neurodegenerative disorders: Utilization in cell replacement-based preclinical safety and efficacy studies.}, journal = {The Journal of comparative neurology}, volume = {522}, number = {12}, pages = {2784-2801}, doi = {10.1002/cne.23575}, pmid = {24610493}, issn = {1096-9861}, support = {P30 NS047101/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell- and Tissue-Based Therapy/*methods ; *Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*surgery ; Swine ; }, abstract = {An important component for successful translation of cell replacement-based therapies into clinical practice is the utilization of large animal models to conduct efficacy and/or safety cell dosing studies. Over the past few decades, several large animal models (dog, cat, nonhuman primate) were developed and employed in cell replacement studies; however, none of these models appears to provide a readily available platform to conduct effective and large-scale preclinical studies. In recent years, numerous pig models of neurodegenerative disorders were developed using both a transgenic approach as well as invasive surgical techniques. The pig model (naïve noninjured animals) was recently used successfully to define the safety and optimal dosing of human spinal stem cells after grafting into the central nervous system (CNS) in immunosuppressed animals. The data from these studies were used in the design of a human clinical protocol used in amyotrophic lateral sclerosis (ALS) patients in a Phase I clinical trial. In addition, a highly inbred (complete major histocompatibility complex [MHC] match) strain of miniature pigs is available which permits the design of comparable MHC combinations between the donor cells and the graft recipient as used in human patients. Jointly, these studies show that the pig model can represent an effective large animal model to be used in preclinical cell replacement modeling. This review summarizes the available pig models of neurodegenerative disorders and the use of some of these models in cell replacement studies. The challenges and potential future directions in more effective use of the pig neurodegenerative models are also discussed.}, }
@article {pmid24607947, year = {2014}, author = {Misawa, S}, title = {[Utility of muscle ultrasonography for the diagnosis of amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {66}, number = {3}, pages = {229-236}, pmid = {24607947}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/physiopathology ; Electromyography/methods ; Humans ; Motor Neurons/*diagnostic imaging/physiology ; Muscle, Skeletal/*diagnostic imaging ; Neurologic Examination/methods ; Ultrasonography/*methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is frequently challenging, because motor neuron involvement is usually focal at disease onset and many syndromes mimic ALS. Neurological examination and needle EMG are important in the diagnosis of ALS, and patients with early-stage ALS usually undergo several EMG examinations before the diagnosis is confirmed. Ultrasonography has recently been used for the non-invasive assessment of neuromuscular disorders. This review discusses the recent advances in ultrasonography for ALS diagnosis. Ultrasonography could help detect lower motor neuron involvement by evaluating muscle volume, echo intensity, and fasciculations. Previous reports have documented the diagnostic values of all these parameters. In particular, fasciculations are characteristic features of ALS that can be easily and reliably visualized using ultrasonography. Moreover, the combined use of ultrasonography and EMG to detect fasciculations could substantially increase the diagnostic sensitivity of Awaji criteria for ALS. Attempts to utilize ultrasonography for ALS diagnosis have started only recently, and the technique used is yet to be standardized. However, ultrasonography has a major advantage over EMG in that it is non-invasive. Further studies are needed to understand the use of ultrasound as a novel non-invasive tool for ALS diagnosis.}, }
@article {pmid24604426, year = {2014}, author = {Li, M and Wang, L and Wang, W and Qi, XL and Tang, ZY}, title = {Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {47}, number = {3}, pages = {215-222}, pmid = {24604426}, issn = {1414-431X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genetic Association Studies ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/*genetics ; Humans ; Iron/metabolism ; Membrane Proteins/*genetics ; Mutation/*genetics ; Observational Studies as Topic ; Odds Ratio ; Polymorphism, Genetic/*genetics ; *Protective Factors ; Risk Factors ; White People/genetics ; }, abstract = {Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.}, }
@article {pmid24604371, year = {2014}, author = {Salvioni, CC and Stanich, P and Almeida, CS and Oliveira, AS}, title = {Nutritional care in motor neurone disease/ amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {72}, number = {2}, pages = {157-163}, doi = {10.1590/0004-282X20130185}, pmid = {24604371}, issn = {1678-4227}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*diet therapy ; Female ; Humans ; Nutrition Assessment ; Nutrition Disorders/etiology/*prevention &amp; control ; Nutrition Therapy/*methods ; Nutritional Requirements ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often present changes in nutritional status. Based on weight loss and on difficulty in nutritional management, this study aims to review the different possibilities and to present guidelines concerning nutritional treatment to such patients. Diet characteristics, types of treatment and nutritional therapy indicating administration routes and discussing the details of the disease are described herein. Nutritional therapy has been a substantial therapeutic resource for ALS development.}, }
@article {pmid24600391, year = {2014}, author = {Amadoro, G and Corsetti, V and Florenzano, F and Atlante, A and Bobba, A and Nicolin, V and Nori, SL and Calissano, P}, title = {Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.}, journal = {Frontiers in aging neuroscience}, volume = {6}, number = {}, pages = {18}, pmid = {24600391}, issn = {1663-4365}, abstract = {Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.}, }
@article {pmid24600344, year = {2014}, author = {Schmitt, F and Hussain, G and Dupuis, L and Loeffler, JP and Henriques, A}, title = {A plural role for lipids in motor neuron diseases: energy, signaling and structure.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {25}, pmid = {24600344}, issn = {1662-5102}, abstract = {Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs.}, }
@article {pmid24590317, year = {2014}, author = {Yadav, RS and Tiwari, NK}, title = {Lipid integration in neurodegeneration: an overview of Alzheimer's disease.}, journal = {Molecular neurobiology}, volume = {50}, number = {1}, pages = {168-176}, pmid = {24590317}, issn = {1559-1182}, mesh = {Alzheimer Disease/*metabolism ; Brain/*metabolism ; Homeostasis ; Humans ; Lipid Metabolism/*physiology ; Neurodegenerative Diseases/*metabolism ; Neurons/*metabolism ; Oxidative Stress/physiology ; }, abstract = {Various types of lipids and their metabolic products associated with the biological membrane play a crucial role in signal transduction, modulation, and activation of receptors and as precursors of bioactive lipid mediators. Dysfunction in the lipid homeostasis in the brain could be a risk factor for the many types of neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These neurodegenerative disorders are marked by extensive neuronal apoptosis, gliosis, and alteration in the differentiation, proliferation, and development of neurons. Sphingomyelin, a constituent of plasma membrane, as well as its primary metabolite ceramide acts as a potential lipid second messenger molecule linked with the modulation of various cellular signaling pathways. Excessive production of reactive oxygen species associated with enhanced oxidative stress has been implicated with these molecules and involved in the regulation of a variety of different neurodegenerative and neuroinflammatory disorders. Studies have shown that alterations in the levels of plasma lipid/cholesterol concentration may result to neurodegenerative diseases. Alteration in the levels of inflammatory cytokines and mediators in the brain has also been found to be implicated in the pathophysiology of neurodegenerative diseases. Although several mechanisms involved in neuronal apoptosis have been described, the molecular mechanisms underlying the correlation between lipid metabolism and the neurological deficits are not clearly understood. In the present review, an attempt has been made to provide detailed information about the association of lipids in neurodegeneration especially in Alzheimer's disease.}, }
@article {pmid24589709, year = {2014}, author = {Zhang, KY and Yang, S and Warraich, ST and Blair, IP}, title = {Ubiquilin 2: a component of the ubiquitin-proteasome system with an emerging role in neurodegeneration.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {50}, number = {}, pages = {123-126}, doi = {10.1016/j.biocel.2014.02.018}, pmid = {24589709}, issn = {1878-5875}, mesh = {Adaptor Proteins, Signal Transducing ; Amyotrophic Lateral Sclerosis/enzymology/metabolism ; Animals ; Autophagy-Related Proteins ; Cell Cycle Proteins/metabolism ; Dementia/*etiology ; Humans ; Neurodegenerative Diseases/enzymology/*metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Ubiquitins/*metabolism ; }, abstract = {Ubiquilin 2, which is encoded by the UBQLN2 gene, plays a critical role in protein clearance pathways including the ubiquitin-proteasome system and autophagy. Ubiquilin 2 physically associates with ubiquitin ligases and proteasomes to mediate protein degradation. It also plays a role in the regulation of cell signalling and cell cycle progression, and association with cytoskeletal elements. Recent studies have revealed that ubiquilin 2 also plays a pathogenic role in neurodegenerative disease, including amyotrophic lateral sclerosis (ALS), and ALS-frontotemporal dementia (ALS-FTD). Rare UBQLN2 mutations cause a small subset of ALS and ALS-FTD cases. More widespread is the presence of ubiquilin 2 positive inclusions in the affected neurons of some familial and sporadic ALS and ALS-FTD patients. These discoveries have led to the hypothesis that perturbation in protein clearance, mediated by ubiquilin 2, is an important pathogenic mechanism in neurodegeneration.}, }
@article {pmid24588460, year = {2014}, author = {Berry, JD and Cudkowicz, ME and Shefner, JM}, title = {Predicting success: optimizing phase II ALS trials for the transition to phase III.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {1-2}, pages = {1-8}, doi = {10.3109/21678421.2013.838969}, pmid = {24588460}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials, Phase II as Topic/*methods ; Clinical Trials, Phase III as Topic/*methods ; Humans ; Outcome Assessment, Health Care ; Predictive Value of Tests ; Randomized Controlled Trials as Topic ; *Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) research is advancing quickly, but the transition from phase II to phase III trials remains particularly challenging. In part, this is because of the paradox of phase II ALS trials - they are expected to inform researchers about safety, tolerability, dosage selection, and efficacy using a small number of patients, and relying on essentially the same outcome measures used in phase III trials. We examined pharmacokinetics in the cerebrospinal fluid and pharmacodynamic markers to demonstrate target engagement. In addition, primary outcome measures are often not specified or do not reach pre-specified goals for significance. We conclude that future trials should include pharmacokinetic (preferably in CSF) and pharmacodynamic markers of target engagement when possible. Primary endpoints should be pre-specified. Inclusion criteria should be used to reduce heterogeneity and target a relevant subpopulation of people with ALS when possible. Multiple phase II trials might be required before moving to a large phase III trial.}, }
@article {pmid24577478, year = {2014}, author = {Bolognin, S and Cozzi, B and Zambenedetti, P and Zatta, P}, title = {Metallothioneins and the central nervous system: from a deregulation in neurodegenerative diseases to the development of new therapeutic approaches.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {41}, number = {1}, pages = {29-42}, doi = {10.3233/JAD-130290}, pmid = {24577478}, issn = {1875-8908}, mesh = {Animals ; Brain/drug effects/growth &amp; development/*physiopathology ; Humans ; Metallothionein/*metabolism ; Neurodegenerative Diseases/*drug therapy/*physiopathology ; }, abstract = {Metallothioneins (MT) are a family of proteins actively involved in metal detoxification and storage as well as in prevention of free-radical damage. Changes in the levels of MT have been described in a number of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, prion protein disease, Binswanger type of subcortical vascular dementia, and amyotrophic lateral sclerosis. This suggests that MT functions might be more complex and vast than what was initially thought. In this review, we summarize the current knowledge on the potential involvement of MT in the mentioned neurodegenerative diseases while also discussing the emerging evidence proposing MT modulation as a feasible therapeutic approach. Enhancing repair mechanisms after neurological damage and/or protection against oxidative stress through a proper modulation of this family of protein might indeed represent an important avenue to cope neurodegeneration.}, }
@article {pmid24568860, year = {2014}, author = {Tan, W and Pasinelli, P and Trotti, D}, title = {Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1842}, number = {8}, pages = {1295-1301}, pmid = {24568860}, issn = {0006-3002}, support = {R01-NS051488/NS/NINDS NIH HHS/United States ; R01 NS044292/NS/NINDS NIH HHS/United States ; R01-NS064488/NS/NINDS NIH HHS/United States ; R01 NS051488/NS/NINDS NIH HHS/United States ; R01 NS064488/NS/NINDS NIH HHS/United States ; R01-NS044292/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/etiology/*genetics/pathology ; Animals ; Humans ; Mitochondria/*metabolism ; Models, Biological ; Mutation/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an adult onset characterized by loss of both upper and lower motor neurons. In ~10% of cases, patients developed ALS with an apparent genetic linkage (familial ALS or fALS). Approximately 20% of fALS displays mutations in the SOD1 gene encoding superoxide dismutase 1. There are many proposed cellular and molecular mechanisms among which, mitochondrial dysfunctions occur early, prior to symptoms occurrence. In this review, we modeled the effect of mutant SOD1 protein via the formation of a toxic complex with Bcl2 on mitochondrial bioenergetics. Furthermore, we discuss that the shutdown of ATP permeation through mitochondrial outer membrane could lead to both respiration inhibition and temporary mitochondrial hyperpolarization. Moreover, we reviewed mitochondrial calcium signaling, oxidative stress, fission and fusion, autophagy and apoptosis in mutant SOD1-linked ALS. Functional defects in mitochondria appear early before symptoms are manifested in ALS. Therefore, mitochondrial dysfunction is a promising therapeutic target in ALS.}, }
@article {pmid24566026, year = {2014}, author = {Le Pimpec-Barthes, F and Pricopi, C and Mordant, P and Arame, A and Badia, A and Grand, B and Bagan, P and Hernigou, A and Riquet, M}, title = {[Diaphragmatic palsy and dysfunction: from physiology to surgery].}, journal = {Revue de pneumologie clinique}, volume = {70}, number = {1-2}, pages = {95-107}, doi = {10.1016/j.pneumo.2013.11.002}, pmid = {24566026}, issn = {1776-2561}, mesh = {Diaphragm/anatomy &amp; histology/physiology ; Diaphragmatic Eventration/*physiopathology/*surgery ; Humans ; Respiratory Paralysis/*physiopathology/*surgery ; }, abstract = {The clinical presentations of diaphragm dysfunctions vary according to etiologies and unilateral or bilateral diseases. Elevation of the hemidiaphragm from peripheral origins, the most frequent situation, requires a surgical treatment only in case of major functional impact. Complete morphological and functional analyses of the neuromuscular chain and respiratory tests allow the best selection of patients to be operated. The surgical procedure may be proposed only when the diaphragm dysfunction is permanent and irreversible. Diaphragm plication for eventration through a short lateral thoracotomy, or sometimes by videothoracoscopy, is the only procedure for retensioning the hemidiaphragm. This leads to a decompression of intrathoracic organs and a repositioning of abdominal organs without effect on the hemidiaphragm active contraction. Morbidity and mortality rates after diaphragm plication are very low, more due to the patient's general condition than to surgery itself. Functional improvements after retensioning for most patients with excellent long-term results validate this procedure for symptomatic patients. In case of bilateral diseases, very few bilateral diaphragm plications have been reported. Some patients with diaphragm paralyses from central origins become permanently dependent on mechanical ventilation whereas their lungs, muscles and nerves are intact. In patients selected by rigorous neuromuscular tests, a phrenic pacing may be proposed to wean them from respirator. Two main indications have been validated: high-level tetraplegia above C3 and congenital alveolar hypoventilation from central origin. After progressive reconditioning of the diaphragm muscles following phrenic pacing at thoracic level, more than 90% of patients can be weaned from respirator within a few weeks. This weaning improves the quality of life with more physiological breathing, restored olfaction, better sleep and better speech. The positive impact of diaphragm stimulation has also been evaluated in other degenerative neurological diseases, particularly the amyotrophic lateral sclerosis. For either central or peripheral diaphragm dysfunctions, a successful surgical treatment lies on a strict preoperative selection of patients.}, }
@article {pmid24563850, year = {2014}, author = {Niforou, K and Cheimonidou, C and Trougakos, IP}, title = {Molecular chaperones and proteostasis regulation during redox imbalance.}, journal = {Redox biology}, volume = {2}, number = {}, pages = {323-332}, pmid = {24563850}, issn = {2213-2317}, mesh = {Animals ; Electron Transport ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Free Radicals/metabolism ; Heat-Shock Proteins/physiology ; Homeostasis ; Humans ; Models, Biological ; Molecular Chaperones/*physiology ; Oxidants/metabolism ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Proteasome Endopeptidase Complex/metabolism ; Protein Folding ; Protein Processing, Post-Translational ; Protein Stability ; Proteins/*metabolism ; Proteome ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Free radicals originate from both exogenous environmental sources and as by-products of the respiratory chain and cellular oxygen metabolism. Sustained accumulation of free radicals, beyond a physiological level, induces oxidative stress that is harmful for the cellular homeodynamics as it promotes the oxidative damage and stochastic modification of all cellular biomolecules including proteins. In relation to proteome stability and maintenance, the increased concentration of oxidants disrupts the functionality of cellular protein machines resulting eventually in proteotoxic stress and the deregulation of the proteostasis (homeostasis of the proteome) network (PN). PN curates the proteome in the various cellular compartments and the extracellular milieu by modulating protein synthesis and protein machines assembly, protein recycling and stress responses, as well as refolding or degradation of damaged proteins. Molecular chaperones are key players of the PN since they facilitate folding of nascent polypeptides, as well as holding, folding, and/or degradation of unfolded, misfolded, or non-native proteins. Therefore, the expression and the activity of the molecular chaperones are tightly regulated at both the transcriptional and post-translational level at organismal states of increased oxidative and, consequently, proteotoxic stress, including ageing and various age-related diseases (e.g. degenerative diseases and cancer). In the current review we present a synopsis of the various classes of intra- and extracellular chaperones, the effects of oxidants on cellular homeodynamics and diseases and the redox regulation of chaperones.}, }
@article {pmid24557857, year = {2014}, author = {Petzold, A and Bowser, R and Calabresi, P and Zetterberg, H and Uitdehaag, BM}, title = {Biomarker time out.}, journal = {Multiple sclerosis (Houndmills, Basingstoke, England)}, volume = {20}, number = {12}, pages = {1560-1563}, doi = {10.1177/1352458514524999}, pmid = {24557857}, issn = {1477-0970}, mesh = {Animals ; *Biomarkers ; *Early Diagnosis ; Humans ; Multiple Sclerosis/*diagnosis ; *Prospective Studies ; *Retrospective Studies ; Time Factors ; }, abstract = {The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies. This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept. The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias.}, }
@article {pmid24555412, year = {2014}, author = {Droppelmann, CA and Campos-Melo, D and Ishtiaq, M and Volkening, K and Strong, MJ}, title = {RNA metabolism in ALS: when normal processes become pathological.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {5-6}, pages = {321-336}, doi = {10.3109/21678421.2014.881377}, pmid = {24555412}, issn = {2167-9223}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Humans ; RNA/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of motor neurons. While the exact molecular and cellular basis for motor neuron death is not yet fully understood, the current conceptualization is that multiple aberrant biological processes contribute. Among these, one of the most compelling is based on alterations of RNA metabolism. In this review, we examine how the normal process of cellular response to stress leading to RNA stress granule formation might become pathological, resulting in the formation of stable protein aggregates. We discuss the emerging roles of post-translational modifications of RNA binding proteins in the genesis of these aggregates. We also review the contemporary literature regarding the potential role for more widespread alterations in RNA metabolism in ALS, including alterations in miRNA biogenesis, spliceosome integrity and RNA editing. A hypothesis is presented in which aberrant RNA processing, modulated through pathological stress granule formation as a reflection of either mutations within intrinsically disordered or prion-like domains of critical RNA binding proteins, or the post-translational modification of RNA binding proteins, contributes directly to motor neuron death.}, }
@article {pmid24555050, year = {2013}, author = {Song, J}, title = {Why do proteins aggregate? "Intrinsically insoluble proteins" and "dark mediators" revealed by studies on "insoluble proteins" solubilized in pure water.}, journal = {F1000Research}, volume = {2}, number = {}, pages = {94}, pmid = {24555050}, issn = {2046-1402}, abstract = {In 2008, I reviewed and proposed a model for our discovery in 2005 that unrefoldable and insoluble proteins could in fact be solubilized in unsalted water. Since then, this discovery has offered us and other groups a powerful tool to characterize insoluble proteins, and we have further addressed several fundamental and disease-relevant issues associated with this discovery. Here I review these results, which are conceptualized into several novel scenarios. 1) Unlike 'misfolded proteins', which still retain the capacity to fold into well-defined structures but are misled to 'off-pathway' aggregation, unrefoldable and insoluble proteins completely lack this ability and will unavoidably aggregate in vivo with ~150 mM ions, thus designated as 'intrinsically insoluble proteins (IIPs)' here. IIPs may largely account for the 'wastefully synthesized' DRiPs identified in human cells. 2) The fact that IIPs including membrane proteins are all soluble in unsalted water, but get aggregated upon being exposed to ions, logically suggests that ions existing in the background play a central role in mediating protein aggregation, thus acting as 'dark mediators'. Our study with 14 salts confirms that IIPs lack the capacity to fold into any well-defined structures. We uncover that salts modulate protein dynamics and anions bind proteins with high selectivity and affinity, which is surprisingly masked by pre-existing ions. Accordingly, I modified my previous model. 3) Insoluble proteins interact with lipids to different degrees. Remarkably, an ALS-causing P56S mutation transforms the β-sandwich MSP domain into a helical integral membrane protein. Consequently, the number of membrane-interacting proteins might be much larger than currently recognized. To attack biological membranes may represent a common mechanism by which aggregated proteins initiate human diseases. 4) Our discovery also implies a solution to the 'chicken-and-egg paradox' for the origin of primitive membranes embedded with integral membrane proteins, if proteins originally emerged in unsalted prebiotic media.}, }
@article {pmid24554437, year = {2014}, author = {van der Kant, R and Neefjes, J}, title = {Small regulators, major consequences - Ca[2+] and cholesterol at the endosome-ER interface.}, journal = {Journal of cell science}, volume = {127}, number = {Pt 5}, pages = {929-938}, doi = {10.1242/jcs.137539}, pmid = {24554437}, issn = {1477-9137}, mesh = {Calcium/metabolism ; *Calcium Signaling ; Cholesterol/*metabolism ; Endocytosis ; Endoplasmic Reticulum/*metabolism ; Endosomes/*metabolism ; Humans ; rab GTP-Binding Proteins/metabolism ; }, abstract = {The ER is the largest cellular compartment and a major storage site for lipids and ions. In recent years, much attention has focused on contacts between the ER and other organelles, and one particularly intimate relationship is that between the ER and the endosomal system. ER-endosome contacts intensify when endosomes mature, and the ER participates in endosomal processes, such as the termination of surface receptor signaling, multi-vesicular body formation, and transport and fusion events. Cholesterol and Ca(2+) are transferred between the ER and endosomes, possibly acting as messengers for ER-endosome crosstalk. Here, we summarize different types of ER-endosomal communication and discuss membrane contact sites that might facilitate this crosstalk. We review the protein pairs that interact at the ER-endosome interface and find that many of these have a role in cholesterol exchange. We also summarize Ca(2+) exchange between the ER and endosomes, and hypothesize that ER-endosome contacts integrate several cellular functions to guide endosomal maturation. We post the hypothesis that failure in ER-endosome contacts is an unrecognized but important contributor to diseases, such as Niemann-Pick type C disease, Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid24550780, year = {2014}, author = {Garbuzova-Davis, S and Sanberg, PR}, title = {Blood-CNS Barrier Impairment in ALS patients versus an animal model.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {21}, pmid = {24550780}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Recently, alterations in the blood-Central Nervous System barrier (B-CNS-B) have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been determined in mutant superoxide dismutase (SOD1) rodent models, identifying barrier damage during disease development which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS) has been limited. We recently showed structural and functional impairment in postmortem gray and white matter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degeneration, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages) are indicated in both mutant SOD1 animal models of ALS and SALS patients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnormalities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood-CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies.}, }
@article {pmid24534024, year = {2014}, author = {Turnbull, J}, title = {Why is ALS so Difficult to Treat?.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {41}, number = {2}, pages = {144-155}, doi = {10.1017/s0317167100016516}, pmid = {24534024}, issn = {0317-1671}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Genotype ; Homeostasis ; Humans ; Phenotype ; Proteins/*metabolism ; Proteostasis Deficiencies/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is proving intractable. Difficulties in pre-clinical studies contribute in small measure to this futility, but the chief reason for failure is an inadequate understanding of disease pathogenesis. Many acquired and inherited processes have been advanced as potential causes of ALS but, while they may predispose to disease, it seems increasingly likely that none leads directly to ALS. Rather, two recent overlapping considerations, both involving aberrant protein homeostasis, may provide a better explanation for a common disease phenotype and a common terminal pathogenesis. If so, therapeutic approaches will need to be altered and carefully nuanced, since protein homeostasis is essential and highly conserved. Nonetheless, these considerations provide new optimism in a difficult disease which has hitherto defied treatment.}, }
@article {pmid24533803, year = {2014}, author = {Tiwari, SK and Chaturvedi, RK}, title = {Peptide therapeutics in neurodegenerative disorders.}, journal = {Current medicinal chemistry}, volume = {21}, number = {23}, pages = {2610-2631}, doi = {10.2174/0929867321666140217125857}, pmid = {24533803}, issn = {1875-533X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Mitochondria/drug effects/metabolism ; Neurodegenerative Diseases/*drug therapy ; Peptides/chemistry/pharmacology/*therapeutic use ; Protein Structure, Secondary ; Signal Transduction/drug effects ; }, abstract = {Neurodegenerative diseases are characterized by selective and progressive degeneration of neuronal population in the brain, and associated behavioural, motor, psychiatric and cognitive impairments. Aggregation of pathogenic proteins, mitochondrial dysfunction, oxidative stress, transcriptional dysfunction and apoptosis play an important role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease and Amyotrophic lateral sclerosis. Therefore, novel therapies that target each of these mechanisms may be effective in abating the symptoms and slow down the onset and progression of neurodegenerative disorders. This review offers insights into the tremendous utility and versatility of peptides such as neurotrophins, neurotrophic factors (NGF, BDNF and GDNF), neuropeptides, mitochondrial targeted antioxidants/peptides, MitoQ, neurturin, and β-sheet breaker peptides to address the mechanisms and pathogenesis associated with neurodegenerative disorders.}, }
@article {pmid24529856, year = {2014}, author = {Trotta, T and Porro, C and Calvello, R and Panaro, MA}, title = {Biological role of Toll-like receptor-4 in the brain.}, journal = {Journal of neuroimmunology}, volume = {268}, number = {1-2}, pages = {1-12}, doi = {10.1016/j.jneuroim.2014.01.014}, pmid = {24529856}, issn = {1872-8421}, mesh = {Animals ; Brain/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Toll-Like Receptor 4/*metabolism ; }, abstract = {The Toll-like receptors (TLRs) are a family of microbe-sensing receptors that play a central role in the regulation of the host immune system. TLR4 has been described in the brain and seems to regulate some physiological processes, such as neurogenesis. TLR4 has also been reported to play a role during neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Parkinson's disease. This review is focused on reports concerning recent insights into the role and activation mechanisms of TLR4 in the brain, in pathological and physiological conditions, as well as the therapeutic benefit that could derive from TLR4 modulation.}, }
@article {pmid24518478, year = {2014}, author = {Gjerde, KV and Tysnes, OB}, title = {[Genetic coherence between hereditary amyotrophic lateral sclerosis and frontotemporal dementia].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {134}, number = {3}, pages = {302-306}, doi = {10.4045/tidsskr.13.0049}, pmid = {24518478}, issn = {0807-7096}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/complications/epidemiology/*genetics ; C9orf72 Protein ; Cognition Disorders/etiology ; Frontotemporal Dementia/complications/epidemiology/*genetics ; Genetic Predisposition to Disease ; Humans ; Mutation ; Proteins/*genetics ; Survival Rate ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) has traditionally been considered purely as a motor condition with a progressive loss of upper and lower motor neurons, and without cognitive or behavioural impairment. In 2011 a new genetic mutation that may cause both ALS and frontotemporal dementia (FTD) was detected. In light of this discovery, the article describes genetic and clinical characteristics of ALS and frontotemporal dementia.<br><br>MATERIAL AND METHODS: The article is based on a literature search in PubMed.<br><br>RESULTS: Up to 50% of ALS patients develop some cognitive impairment, while 3-15% develop frontotemporal dementia. The recently discovered C9ORF72 mutation accounts for 20-50% of hereditary ALS and possibly up to 25% of sporadic cases. The mutation is the most common cause of ALS. Patients with C9ORF72 mutation are characterised by earlier disease onset, reduced survival after diagnosis, more frequent cognitive and behavioural dysfunction, and familial disposition for ALS and frontotemporal dementia.<br><br>INTERPRETATION: Cognitive and behavioural changes in amyotrophic lateral sclerosis are common, and can appear along a clinical continuum with development of frontotemporal dementia over time. Detection of the C9ORF72 mutation poses a challenge to our knowledge and management of patients with both hereditary and sporadic ALS.}, }
@article {pmid24515836, year = {2014}, author = {Woollacott, IO and Mead, S}, title = {The C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues.}, journal = {Acta neuropathologica}, volume = {127}, number = {3}, pages = {319-332}, doi = {10.1007/s00401-014-1253-7}, pmid = {24515836}, issn = {1432-0533}, mesh = {Alternative Splicing ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*genetics/pathology ; Brain/pathology ; C9orf72 Protein ; DNA Repeat Expansion ; Frontotemporal Lobar Degeneration/*diagnosis/epidemiology/*genetics/pathology ; Genetic Code ; Genetic Techniques ; Humans ; Nervous System Diseases/diagnosis/genetics/pathology ; Phenotype ; Proteins/*genetics ; }, abstract = {The discovery of the C9ORF72 hexanucleotide repeat expansion in 2011 and the immediate realisation of a remarkably high prevalence in both familial and sporadic frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) triggered an explosion of interest in studies aiming to define the associated clinical and investigation phenotypes and attempts to develop technologies to measure more accurately the size of the repeat region. This article reviews progress in these areas over the subsequent 2 years, focussing on issues directly relevant to the practising physician. First, we summarise findings from studies regarding the global prevalence of the expansion, not only in FTLD and ALS cases, but also in other neurological diseases and its concurrence with other genetic mutations associated with FTLD and ALS. Second, we discuss the variability in normal repeat number in cases and controls and the theories regarding the relevance of intermediate and pathological repeat number for disease risk and clinical phenotype. Third, we discuss the usefulness of various features within the FTLD and ALS clinical phenotype in aiding differentiation between cases with and without the C9ORF72 expansion. Fourth, we review clinical investigations used to identify cases with the expansion, including neuroimaging and cerebrospinal fluid markers, and describe the mechanisms and limitations of the various diagnostic laboratory techniques used to quantify repeat number in cases and controls. Finally, we discuss the issues surrounding accurate clinical and technological diagnosis of patients with FTLD and/or ALS associated with the C9ORF72 expansion, and outline areas for future research that might aid better diagnosis and genetic counselling of patients with seemingly sporadic or familial FTLD or ALS and their relatives.}, }
@article {pmid24515807, year = {2014}, author = {Carocci, A and Rovito, N and Sinicropi, MS and Genchi, G}, title = {Mercury toxicity and neurodegenerative effects.}, journal = {Reviews of environmental contamination and toxicology}, volume = {229}, number = {}, pages = {1-18}, doi = {10.1007/978-3-319-03777-6_1}, pmid = {24515807}, issn = {0179-5953}, mesh = {Animals ; Glutathione/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Mercury/pharmacokinetics/*toxicity ; Mitochondria/drug effects ; Neurodegenerative Diseases/*chemically induced/metabolism ; }, abstract = {Mercury is among the most toxic heavy metals and has no known physiological role in humans. Three forms of mercury exist: elemental, inorganic and organic. Mercury has been used by man since ancient times. Among the earliest were the Chinese and Romans, who employed cinnabar (mercury sulfide) as a red dye in ink (Clarkson et al. 2007). Mercury has also been used to purify gold and silver minerals by forming amalgams. This is a hazardous practice, but is still widespread in Brazil's Amazon basin, in Laos and in Venezuela, where tens of thousands of miners are engaged in local mining activities to find and purify gold or silver. Mercury compounds were long used to treat syphilis and the element is still used as an antiseptic,as a medicinal preservative and as a fungicide. Dental amalgams, which contain about 50% mercury, have been used to repair dental caries in the U.S. since 1856.Mercury still exists in many common household products around the world.Examples are: thermometers, barometers, batteries, and light bulbs (Swain et al.2007). In small amounts, some organo mercury-compounds (e.g., ethylmercury tiosalicylate(thimerosal) and phenylmercury nitrate) are used as preservatives in some medicines and vaccines (Ballet al. 2001).Each mercury form has its own toxicity profile. Exposure to Hg0 vapor and MeHg produce symptoms in CNS, whereas, the kidney is the target organ when exposures to the mono- and di-valent salts of mercury (Hg+ and Hg++, respectively)occur. Chronic exposure to inorganic mercury produces stomatitis, erethism and tremors. Chronic MeHg exposure induced symptoms similar to those observed in ALS, such as the early onset of hind limb weakness (Johnson and Atchison 2009).Among the organic mercury compounds, MeHg is the most biologically available and toxic (Scheuhammer et a!. 2007). MeHg is neurotoxic, reaching high levels of accumulation in the CNS; it can impair physiological function by disrupting endocrine glands (Tan et a!. 2009).The most important mechanism by which mercury causes toxicity appears to bemitochondrial damage via depletion of GSH (Nicole et a!. 1998), coupled with binding to thiol groups (-SH), which generates free radicals. Mercury has a high affinity for thiol groups (-SH) and seleno groups (-SeH) that are present in amino acids as cysteine and N-acetyl cysteine, lipoic acid, proteins, and enzymes. N-acetylcysteine and cysteine are precursors for the biosynthesis of GSH, which is among the most powerful intracellular antioxidants available to protect against oxidative stress and inflammation.Mercury and methylmercury induce mitochondrial dysfunction, which reduces ATP synthesis and increases lipid, protein and DNA peroxidation. The content of metallothioneines, GSH, selenium and fish high in omega-3 fatty acids appear to be strongly related with degree of inorganic and organic mercury toxicity, and with the protective detoxifying mechanisms in humans. In conclusion, depletion of GSH,breakage of mitochondria, increased lipid peroxidation, and oxidation of proteins and DNA in the brain, induced by mercury and his salts, appear to be important factors in conditions such as ALS and AD (Bains and Shaw 1997; Nicole eta!. 1998;Spencer eta!. 1998; Alberti et a!. 1999).}, }
@article {pmid24514864, year = {2014}, author = {Pieper, AA and McKnight, SL and Ready, JM}, title = {P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases.}, journal = {Chemical Society reviews}, volume = {43}, number = {19}, pages = {6716-6726}, pmid = {24514864}, issn = {1460-4744}, support = {I01 BX002444/BX/BLRD VA/United States ; R01 MH087986/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Brain Injuries/drug therapy ; Carbazoles/chemistry/metabolism/*therapeutic use ; Disease Models, Animal ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/metabolism/*therapeutic use ; }, abstract = {A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders.}, }
@article {pmid24510737, year = {2014}, author = {Majmudar, S and Wu, J and Paganoni, S}, title = {Rehabilitation in amyotrophic lateral sclerosis: why it matters.}, journal = {Muscle &amp; nerve}, volume = {50}, number = {1}, pages = {4-13}, pmid = {24510737}, issn = {1097-4598}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; }, mesh = {Accidental Falls ; Activities of Daily Living ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*rehabilitation ; Caregivers ; Disease Progression ; Exercise Therapy ; Female ; Hand ; Humans ; Lower Extremity ; Male ; Middle Aged ; Musculoskeletal Diseases/etiology ; Orthotic Devices ; Patient Care Team ; Self-Help Devices ; Tracheostomy ; Walking ; Wheelchairs ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in a constellation of problematic symptoms and a high patient and caregiver burden. Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. Given the progressive nature of ALS, the clinician must be aware of the expected disease trajectory and apply appropriate interventions at each stage. This review will present rehabilitation strategies that can be utilized to maximize patient independence, function, safety, and quality of life, and to minimize disease-related symptoms. The role of bracing, exercise, assistive devices, and adaptive equipment will be discussed. At each disease stage, an experienced rehabilitation team is well positioned to make a significant impact on the life of ALS patients.}, }
@article {pmid24506814, year = {2014}, author = {Gascon, E and Gao, FB}, title = {The emerging roles of microRNAs in the pathogenesis of frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders.}, journal = {Journal of neurogenetics}, volume = {28}, number = {1-2}, pages = {30-40}, pmid = {24506814}, issn = {1563-5260}, support = {R01 NS057553/NS/NINDS NIH HHS/United States ; R01 NS066586/NS/NINDS NIH HHS/United States ; R01 NS079725/NS/NINDS NIH HHS/United States ; R21 NS077294/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; DNA-Binding Proteins/genetics/metabolism ; Frontotemporal Dementia/*genetics/metabolism/*pathology ; Humans ; MicroRNAs/*genetics/metabolism ; Mutation/genetics ; }, abstract = {Increasing evidence suggests that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share some clinical, pathological, and molecular features as part of a common neurodegenerative spectrum disorder. In recent years, enormous progress has been made in identifying both pathological proteins and genetic mutations associated with FTD-ALS. However, the molecular pathogenic mechanisms of disease onset and progression remain largely unknown. Recent studies have uncovered unexpected links between FTD-ALS and multiple aspects of RNA metabolism, setting the stage for further understanding of the disorder. Here, the authors will focus on microRNAs and review the emerging roles of these small RNAs in several aspects of FTD-ALS pathogenesis.}, }
@article {pmid24503148, year = {2014}, author = {Finsterer, J and Burgunder, JM}, title = {Recent progress in the genetics of motor neuron disease.}, journal = {European journal of medical genetics}, volume = {57}, number = {2-3}, pages = {103-112}, doi = {10.1016/j.ejmg.2014.01.002}, pmid = {24503148}, issn = {1878-0849}, mesh = {Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Motor Neuron Disease/diagnosis/*genetics ; Mutation ; }, abstract = {BACKGROUND: Genetic background and pathogenesis of motor neuron diseases (MNDs) have been increasingly elucidated over recent years.<br><br>AIMS: To give an overview about publications during the last year concerning the genetic background and phenotypic manifestations of MNDs, such as familial or sporadic amyotrophic lateral sclerosis (fALS, sALS), spinal muscular atrophies (SMA), bulbospinal muscular atrophy (BSMA), and unclassified MNDs.<br><br>METHODS: Pubmed search for literature about ALS, SMA, and BSMA for the period 10/2012 to 9/2013.<br><br>RESULTS: An increasing number of mutated genes is recognised in fALS but also sALS patients. Genes mutated in sALS include C9orf72, SOD1, TARDBP, FUS, UBQL2, SQSTM1, DCTN1, and UNC13A. Juvenile (onset <20y) and adult ALS (early onset 20-60y, late onset >60y) are differentiated. Juvenile fALS is most frequently caused by mutations in ALS2, SETX, spatacsin, or Sigmar1 and adult fALS by mutations in C9orf72, SOD1, TARDBP, and FUS. Onset, phenotype, progression, and outcome of ALS are variable between different mutations, different genes, and different countries. Differentiation between sALS and fALS cases becomes artificial.<br><br>CONCLUSIONS: Further progress has been made over the last year in the clarification and understanding of the aetiology and pathogenesis of MNDs. However, further effort is needed to answer the many remaining questions.}, }
@article {pmid24503016, year = {2014}, author = {Baltazar, MT and Dinis-Oliveira, RJ and de Lourdes Bastos, M and Tsatsakis, AM and Duarte, JA and Carvalho, F}, title = {Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases--a mechanistic approach.}, journal = {Toxicology letters}, volume = {230}, number = {2}, pages = {85-103}, doi = {10.1016/j.toxlet.2014.01.039}, pmid = {24503016}, issn = {1879-3169}, mesh = {Animals ; Apoptosis/drug effects ; Dieldrin/toxicity ; Environmental Exposure ; Humans ; Maneb/toxicity ; Neurodegenerative Diseases/*chemically induced ; Organophosphates/toxicity ; Oxidative Stress ; Paraquat/toxicity ; Parkinson Disease, Secondary/*chemically induced ; Pesticides/*toxicity ; Proteasome Inhibitors/toxicity ; Pyrethrins/toxicity ; }, abstract = {The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood. For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss. This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes. For this purpose, the most relevant epidemiological and experimental data is highlighted in order to discuss the molecular mechanisms involved in neurodegeneration.}, }
@article {pmid24494725, year = {2014}, author = {Zhong, C and Luo, Q and Jiang, J}, title = {Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders.}, journal = {The International journal of neuroscience}, volume = {124}, number = {12}, pages = {867-873}, doi = {10.3109/00207454.2014.890935}, pmid = {24494725}, issn = {1563-5279}, mesh = {Animals ; Brain Injuries/drug therapy/*enzymology ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Glutamate Carboxypeptidase II/*antagonists &amp; inhibitors/metabolism ; Humans ; Nervous System Diseases/drug therapy/*enzymology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Receptors, Metabotropic Glutamate/metabolism ; }, abstract = {The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.}, }
@article {pmid24493408, year = {2014}, author = {Cooper-Knock, J and Shaw, PJ and Kirby, J}, title = {The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype.}, journal = {Acta neuropathologica}, volume = {127}, number = {3}, pages = {333-345}, pmid = {24493408}, issn = {1432-0533}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; MR/K003771/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*genetics/pathology ; Animals ; Blotting, Southern ; C9orf72 Protein ; DNA Repeat Expansion ; Frontotemporal Lobar Degeneration/diagnosis/epidemiology/*genetics/pathology ; Humans ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics ; Nervous System Diseases/diagnosis/genetics/pathology ; Phenotype ; Proteins/*genetics ; }, abstract = {The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS-FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer's disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.}, }
@article {pmid24488689, year = {2014}, author = {Su, XW and Broach, JR and Connor, JR and Gerhard, GS and Simmons, Z}, title = {Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research.}, journal = {Muscle &amp; nerve}, volume = {49}, number = {6}, pages = {786-803}, doi = {10.1002/mus.24198}, pmid = {24488689}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/physiopathology ; Biomedical Research/*trends ; Drug Therapy ; Epigenomics ; *Genetic Heterogeneity ; Humans ; Mutation/genetics ; Practice Patterns, Physicians'/*trends ; Prognosis ; }, abstract = {Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786-803, 2014.}, }
@article {pmid24486447, year = {2014}, author = {Rea, SL and Majcher, V and Searle, MS and Layfield, R}, title = {SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD.}, journal = {Experimental cell research}, volume = {325}, number = {1}, pages = {27-37}, doi = {10.1016/j.yexcr.2014.01.020}, pmid = {24486447}, issn = {1090-2422}, mesh = {Adaptor Proteins, Signal Transducing/*genetics/physiology ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Autophagy ; Frontotemporal Lobar Degeneration/*genetics ; Genetic Predisposition to Disease ; Humans ; NF-kappa B/metabolism ; Osteitis Deformans/*genetics ; Sequestosome-1 Protein ; Signal Transduction ; }, abstract = {Paget disease of bone (PDB) is a skeletal disorder common in Western Europe but extremely rare in the Indian subcontinent and Far East. The condition has a strong genetic element with mutations affecting the SQSTM1 gene, encoding the p62 protein, frequently identified. Recently SQSTM1 mutations have also been reported in a small number of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), neurodegenerative disorders in which significant coexistence with PDB has not been previously recognized. Although several SQSTM1 mutations are common to both ALS/FTLD and PDB, many are ALS/FTLD-specific. The p62 protein regulates various cellular processes including NF-κB signaling and autophagy pathways. Here we consider how knowledge of the impact of PDB-associated SQSTM1 mutations (several of which are now known to be relevant for ALS/FTLD) on these pathways, as well as the locations of the mutations within the p62 primary sequence, may provide new insights into ALS/FTLD disease mechanisms.}, }
@article {pmid24485162, year = {2014}, author = {Laffita-Mesa, JM and Bauer, P}, title = {[Epigenetic heredity (deoxyribonucleic acid methylation): Clinical context in neurodegenerative disorders and ATXN2 gene].}, journal = {Medicina clinica}, volume = {143}, number = {8}, pages = {360-365}, doi = {10.1016/j.medcli.2013.11.025}, pmid = {24485162}, issn = {1578-8989}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Ataxins ; *DNA Methylation ; *Epigenesis, Genetic ; Genetic Markers ; Humans ; Nerve Tissue Proteins/*genetics ; Neurodegenerative Diseases/*genetics ; Spinocerebellar Ataxias/genetics ; }, abstract = {Epigenetics is the group of changes in the phenotype which are related with the process independently of the primary DNA sequence. These changes are intimately related with changes in the gene expression level and its profile across the body. These are mediated by histone tail modifications, DNA methylation, micro-RNAs, with chromatin remodeling remaining as the foundation of epigenetic changes. DNA methylation involves the covalent addition of methyl group to cytosine of the DNA, which is mediated by methyltransferases enzymes. DNA methylation regulates gene expression by repressing transcription, while de-methylation activates gene transcription. Several human diseases are related with the epigenetic process: cancer, Alzheimer disease, stroke, Parkinson disease, and diabetes. We present here the basis of epigenetic inheritance and show the pathogenic mechanisms relating epigenetics in human diseases, specifically with regard to neurodegeneration. We discuss current concepts aimed at understanding the contribution of epigenetics to human neurodegenerative diseases. We also discuss recent findings obtained in our and other centers regarding the ATXN2 gene that causes spinocerebellar ataxia 2 and amyotrophic lateral sclerosis. Epigenetics play a pivotal role in the pathogenesis of human diseases and in several neurodegenerative disorders, and this knowledge will illuminate the pathways in the diagnostic and therapeutic field, which ultimately will be translated into the clinic context of neurodegenerative diseases.}, }
@article {pmid24448926, year = {2014}, author = {Lunn, JS and Sakowski, SA and Feldman, EL}, title = {Concise review: Stem cell therapies for amyotrophic lateral sclerosis: recent advances and prospects for the future.}, journal = {Stem cells (Dayton, Ohio)}, volume = {32}, number = {5}, pages = {1099-1109}, pmid = {24448926}, issn = {1549-4918}, support = {R01 NS077982/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Biomedical Research/*methods/trends ; Cell Differentiation ; Forecasting ; Humans ; Models, Neurological ; Motor Neurons/cytology ; Stem Cell Transplantation/*methods/trends ; Stem Cells/*cytology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cell-based therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of long-term safety are required, these studies represent an important first step toward the development of effective cellular therapies for the treatment of ALS.}, }
@article {pmid24433963, year = {2014}, author = {Brunden, KR and Trojanowski, JQ and Smith, AB and Lee, VM and Ballatore, C}, title = {Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {22}, number = {18}, pages = {5040-5049}, pmid = {24433963}, issn = {1464-3391}, support = {R01 AG044332/AG/NIA NIH HHS/United States ; U01 AG029213/AG/NIA NIH HHS/United States ; AG029213/AG/NIA NIH HHS/United States ; AG044332/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Microtubules/*drug effects/metabolism ; Molecular Structure ; Neurodegenerative Diseases/*drug therapy/metabolism ; Structure-Activity Relationship ; Tubulin Modulators/chemistry/*pharmacology/*therapeutic use ; }, abstract = {Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.}, }
@article {pmid24428861, year = {2014}, author = {Gianforcaro, A and Hamadeh, MJ}, title = {Vitamin D as a potential therapy in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {20}, number = {2}, pages = {101-111}, pmid = {24428861}, issn = {1755-5949}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; *Dietary Supplements ; Humans ; Vitamin D/*therapeutic use ; Vitamins/*therapeutic use ; }, abstract = {Vitamin D has been demonstrated to influence multiple aspects of amyotrophic lateral sclerosis (ALS) pathology. Both human and rodent central nervous systems express the vitamin D receptor (VDR) and/or its enzymatic machinery needed to fully activate the hormone. Clinical research suggests that vitamin D treatment can improve compromised human muscular ability and increase muscle size, supported by loss of motor function and muscle mass in animals following VDR knockout, as well as increased muscle protein synthesis and ATP production following vitamin D supplementation. Vitamin D has also been shown to reduce the expression of biomarkers associated with oxidative stress and inflammation in patients with multiple sclerosis, rheumatoid arthritis, congestive heart failure, Parkinson's disease and Alzheimer's disease; diseases that share common pathophysiologies with ALS. Furthermore, vitamin D treatment greatly attenuates hypoxic brain damage in vivo and reduces neuronal lethality of glutamate insult in vitro; a hallmark trait of ALS glutamate excitotoxicity. We have recently shown that high-dose vitamin D3 supplementation improved, whereas vitamin D3 restriction worsened, functional capacity in the G93A mouse model of ALS. In sum, evidence demonstrates that vitamin D, unlike the antiglutamatergic agent Riluzole, affects multiple aspects of ALS pathophysiology and could provide a greater cumulative effect.}, }
@article {pmid24417286, year = {2015}, author = {Perry, DC and Kramer, JH}, title = {Reward processing in neurodegenerative disease.}, journal = {Neurocase}, volume = {21}, number = {1}, pages = {120-133}, pmid = {24417286}, issn = {1465-3656}, support = {R01 AG022983/AG/NIA NIH HHS/United States ; }, mesh = {Brain/*physiopathology ; Decision Making/physiology ; Humans ; Learning/physiology ; Nerve Net/*physiopathology ; Neurodegenerative Diseases/*physiopathology/*psychology ; *Reward ; }, abstract = {Representation of reward value involves a distributed network including cortical and subcortical structures. Because neurodegenerative illnesses target specific anatomic networks that partially overlap with the reward circuit, they would be predicted to have distinct impairments in reward processing. This review presents the existing evidence of reward processing changes in neurodegenerative diseases including mild cognitive impairment (MCI), Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease, as well as in healthy aging. Carefully distinguishing the different aspects of reward processing (primary rewards, secondary rewards, reward-based learning, and reward-based decision-making) and using tasks that differentiate the stages of processing reward will lead to improved understanding of this fundamental process and clarify a contributing cause of behavioral change in these illnesses.}, }
@article {pmid24411700, year = {2014}, author = {Wolozin, B}, title = {Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease.}, journal = {Discovery medicine}, volume = {17}, number = {91}, pages = {47-52}, pmid = {24411700}, issn = {1944-7930}, support = {R01 AG050471/AG/NIA NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cytoplasmic Granules/metabolism/*pathology ; Humans ; Nerve Degeneration/metabolism/pathology ; Neurodegenerative Diseases/*etiology/metabolism/*pathology ; *Protein Structure, Quaternary ; RNA-Binding Proteins/metabolism ; *Stress, Physiological ; }, abstract = {Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.}, }
@article {pmid24402613, year = {2014}, author = {Schmandke, A and Schmandke, A and Schwab, ME}, title = {Nogo-A: Multiple Roles in CNS Development, Maintenance, and Disease.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {20}, number = {4}, pages = {372-386}, doi = {10.1177/1073858413516800}, pmid = {24402613}, issn = {1089-4098}, abstract = {Initially discovered as a potent neurite outgrowth inhibitor in the central nervous system (CNS), Nogo-A has emerged as a multifunctional protein. Involvement of this protein has been demonstrated in numerous developmental processes, ranging from cell migration, axon guidance and fasciculation, dendritic branching and CNS plasticity to oligodendrocyte differentiation and myelination. Although initially necessary and beneficial for shaping and later maintaining CNS structure and functionality, the growth restricting properties of Nogo-A can have negative effects on nervous system injury or disease. Hence, correlating with its various neurobiological roles, Nogo-A was implicated in a range of CNS disturbances, including trauma such as spinal cord injury or stroke, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis or multiple sclerosis, or in schizophrenia. In this review, we summarize the current state of knowledge for Nogo-A's involvement in these nervous system diseases and perturbations and discuss the possible underlying mechanisms. Furthermore, we provide a comprehensive overview on molecular signaling pathways as well as structural properties identified for Nogo-A and point to open questions in the field.}, }
@article {pmid24401672, year = {2014}, author = {Kabir, ME and Safar, JG}, title = {Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.}, journal = {Prion}, volume = {8}, number = {1}, pages = {111-116}, pmid = {24401672}, issn = {1933-690X}, support = {R01 NS074317/NS/NINDS NIH HHS/United States ; UR8/CCU515004//PHS HHS/United States ; NS074317/NS/NINDS NIH HHS/United States ; }, mesh = {*Biological Evolution ; Humans ; Neurodegenerative Diseases/*etiology ; *Prions ; }, abstract = {There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps.}, }
@article {pmid24399773, year = {2014}, author = {Bäumer, D and Talbot, K and Turner, MR}, title = {Advances in motor neurone disease.}, journal = {Journal of the Royal Society of Medicine}, volume = {107}, number = {1}, pages = {14-21}, pmid = {24399773}, issn = {1758-1095}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/etiology/genetics/therapy ; Biomarkers/metabolism ; Humans ; Motor Neuron Disease/diagnosis/epidemiology/etiology/genetics/*therapy ; }, abstract = {Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.}, }
@article {pmid24398724, year = {2014}, author = {Chauhan, NB}, title = {Chronic neurodegenerative consequences of traumatic brain injury.}, journal = {Restorative neurology and neuroscience}, volume = {32}, number = {2}, pages = {337-365}, doi = {10.3233/RNN-130354}, pmid = {24398724}, issn = {1878-3627}, support = {I01 RX000880/RX/RRD VA/United States ; AG039625/AG/NIA NIH HHS/United States ; NS079614/NS/NINDS NIH HHS/United States ; }, mesh = {Amyloid beta-Protein Precursor/*metabolism ; Animals ; Brain Injuries/complications/*metabolism ; Chronic Disease ; Humans ; Neurodegenerative Diseases/complications/*metabolism ; Neurons/cytology/*metabolism ; Risk Factors ; }, abstract = {Traumatic brain injury (TBI) is a serious public health concern and a major cause of death and disability worldwide. Each year, an estimated 1.7 million Americans sustain TBI of which ~52,000 people die, ~275,000 people are hospitalized and 1,365,000 people are treated as emergency outpatients. Currently there are ~5.3 million Americans living with TBI. TBI is more of a disease process than of an event that is associated with immediate and long-term sensomotor, psychological and cognitive impairments. TBI is the best known established epigenetic risk factor for later development of neurodegenerative diseases and dementia. People sustaining TBI are ~4 times more likely to develop dementia at a later stage than people without TBI. Single brain injury is linked to later development of symptoms resembling Alzheimer's disease while repetitive brain injuries are linked to later development of chronic traumatic encephalopathy (CTE) and/or Dementia Pugilistica (DP). Furthermore, genetic background of ß-amyloid precursor protein (APP), Apolipoprotein E (ApoE), presenilin (PS) and neprilysin (NEP) genes is associated with exacerbation of neurodegenerative process after TBI. This review encompasses acute effects and chronic neurodegenerative consequences after TBI.}, }
@article {pmid24394885, year = {2014}, author = {Gendron, TF and Belzil, VV and Zhang, YJ and Petrucelli, L}, title = {Mechanisms of toxicity in C9FTLD/ALS.}, journal = {Acta neuropathologica}, volume = {127}, number = {3}, pages = {359-376}, pmid = {24394885}, issn = {1432-0533}, support = {/CAPMC/CIHR/Canada ; R21 NS074121/NS/NINDS NIH HHS/United States ; R21 NS079807/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; R01 ES20395/ES/NIEHS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Brain/metabolism/pathology ; C9orf72 Protein ; DNA Repeat Expansion ; Frontotemporal Lobar Degeneration/*genetics/*metabolism/pathology ; Humans ; Neurodegenerative Diseases/genetics/metabolism/pathology ; Proteins/*genetics/metabolism ; RNA/metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {A hexanucleotide repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation causative of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Elucidating how this bidirectionally transcribed G4C2·C4G2 expanded repeat causes "C9FTLD/ALS" has since become an important goal of the field. Likely pathogenic mechanisms include toxicity induced by repeat-containing RNAs, and loss of C9orf72 function due to epigenetic changes resulting in decreased C9ORF72 mRNA expression. With regards to the former, sense and antisense transcripts of the expanded repeat aberrantly interact with various RNA-binding proteins and form discrete nuclear structures, termed RNA foci. These foci have the capacity to sequester select RNA-binding proteins, thereby impairing their function. (G4C2)exp and (C4G2)exp transcripts also succumb to an alternative fate: repeat-associated non-ATG (RAN) translation. This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the abnormal production of poly(GA), poly(GP), poly(GR), poly(PR) and poly(PA) peptides, collectively referred to as C9RAN proteins. C9RAN proteins form neuronal inclusions throughout the central nervous system of C9FTLD/ALS patients and may contribute to disease pathogenesis. This review aims to summarize the important findings from studies examining mechanisms of disease in C9FTLD/ALS, and will also highlight some of the many questions in need of further investigation.}, }
@article {pmid24391590, year = {2013}, author = {Boyer, JG and Ferrier, A and Kothary, R}, title = {More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases.}, journal = {Frontiers in physiology}, volume = {4}, number = {}, pages = {356}, pmid = {24391590}, issn = {1664-042X}, abstract = {Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are devastating diseases characterized by the degeneration of motor neurons. Although the molecular causes underlying these diseases differ, recent findings have highlighted the contribution of intrinsic skeletal muscle defects in motor neuron diseases. The use of cell culture and animal models has led to the important finding that muscle defects occur prior to and independently of motor neuron degeneration in motor neuron diseases. In SMA for instance, the muscle specific requirements of the SMA disease-causing gene have been demonstrated by a series of genetic rescue experiments in SMA models. Conditional ALS mouse models expressing a muscle specific mutant SOD1 gene develop atrophy and muscle degeneration in the absence of motor neuron pathology. Treating SBMA mice by over-expressing IGF-1 in a skeletal muscle-specific manner attenuates disease severity and improves motor neuron pathology. In the present review, we provide an in depth description of muscle intrinsic defects, and discuss how they impact muscle function in these diseases. Furthermore, we discuss muscle-specific therapeutic strategies used to treat animal models of SMA, ALS, and SBMA. The study of intrinsic skeletal muscle defects is crucial for the understanding of the pathophysiology of these diseases and will open new therapeutic options for the treatment of motor neuron diseases.}, }
@article {pmid24391543, year = {2013}, author = {Maciotta, S and Meregalli, M and Torrente, Y}, title = {The involvement of microRNAs in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {265}, pmid = {24391543}, issn = {1662-5102}, abstract = {Neurodegenerative diseases (NDDs) originate from a loss of neurons in the central nervous system and are severely debilitating. The incidence of NDDs increases with age, and they are expected to become more common due to extended life expectancy. Because no cure is available, these diseases have become a major challenge in neurobiology. The increasing relevance of microRNAs (miRNAs) in biology has prompted investigation into their possible involvement in neurodegeneration in order to identify new therapeutic targets. The idea of using miRNAs as therapeutic targets is not far from realization, but important issues need to be addressed before moving into the clinics. Here, we review what is known about the involvement of miRNAs in the pathogenesis of NDDs. We also report the miRNA expression levels in peripheral tissues of patients affected by NDDs in order to evaluate their application as biomarkers of disease. Finally, discrepancies, innovations, and the effectiveness of collected data will be elucidated and discussed.}, }
@article {pmid24391540, year = {2013}, author = {Beirowski, B}, title = {Concepts for regulation of axon integrity by enwrapping glia.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {256}, pmid = {24391540}, issn = {1662-5102}, abstract = {Long axons and their enwrapping glia (EG; Schwann cells (SCs) and oligodendrocytes (OLGs)) form a unique compound structure that serves as conduit for transport of electric and chemical information in the nervous system. The peculiar cytoarchitecture over an enormous length as well as its substantial energetic requirements make this conduit particularly susceptible to detrimental alterations. Degeneration of long axons independent of neuronal cell bodies is observed comparatively early in a range of neurodegenerative conditions as a consequence of abnormalities in SCs and OLGs . This leads to the most relevant disease symptoms and highlights the critical role that these glia have for axon integrity, but the underlying mechanisms remain elusive. The quest to understand why and how axons degenerate is now a crucial frontier in disease-oriented research. This challenge is most likely to lead to significant progress if the inextricable link between axons and their flanking glia in pathological situations is recognized. In this review I compile recent advances in our understanding of the molecular programs governing axon degeneration, and mechanisms of EG's non-cell autonomous impact on axon-integrity. A particular focus is placed on emerging evidence suggesting that EG nurture long axons by virtue of their intimate association, release of trophic substances, and neurometabolic coupling. The correction of defects in these functions has the potential to stabilize axons in a variety of neuronal diseases in the peripheral nervous system and central nervous system (PNS and CNS).}, }
@article {pmid24390581, year = {2014}, author = {Cascarina, SM and Ross, ED}, title = {Yeast prions and human prion-like proteins: sequence features and prediction methods.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {71}, number = {11}, pages = {2047-2063}, pmid = {24390581}, issn = {1420-9071}, support = {R01 GM105991/GM/NIGMS NIH HHS/United States ; GM105991/GM/NIGMS NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Gene Expression ; Humans ; Molecular Sequence Data ; Prion Diseases/genetics/metabolism/pathology ; Prions/*chemistry/genetics/metabolism ; Protein Denaturation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/metabolism ; Sequence Homology, Amino Acid ; }, abstract = {Prions are self-propagating infectious protein isoforms. A growing number of prions have been identified in yeast, each resulting from the conversion of soluble proteins into an insoluble amyloid form. These yeast prions have served as a powerful model system for studying the causes and consequences of prion aggregation. Remarkably, a number of human proteins containing prion-like domains, defined as domains with compositional similarity to yeast prion domains, have recently been linked to various human degenerative diseases, including amyotrophic lateral sclerosis. This suggests that the lessons learned from yeast prions may help in understanding these human diseases. In this review, we examine what has been learned about the amino acid sequence basis for prion aggregation in yeast, and how this information has been used to develop methods to predict aggregation propensity. We then discuss how this information is being applied to understand human disease, and the challenges involved in applying yeast prediction methods to higher organisms.}, }
@article {pmid24389194, year = {2014}, author = {Polimeni, G and Esposito, E and Bevelacqua, V and Guarneri, C and Cuzzocrea, S}, title = {Role of melatonin supplementation in neurodegenerative disorders.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {19}, number = {3}, pages = {429-446}, doi = {10.2741/4217}, pmid = {24389194}, issn = {2768-6698}, mesh = {*Dietary Supplements ; Humans ; Melatonin/*administration &amp; dosage/therapeutic use ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory and cognitive systems. Despite their different origin, free radicals accumulation and consequent tissue damage are importantly concerned for the majority of them. In recent years, research on melatonin revealed a potent activity of this hormone against oxidative and nitrosative stress-induced damage within the nervous system. Indeed, melatonin turned out to be more effective than other naturally occurring antioxidants, suggesting its beneficial effects in a number of diseases where oxygen radical-mediated tissue damage is involved. With specific reference to the brain, the considerable amount of evidence accumulated from studies on various neurodegeneration models and recent clinical reports support the use of melatonin for the preventive treatment of major neurodegenerative disorders. This review summarizes the literature on the protective effects of melatonin on Alzheimer disease, Parkinson disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Additional studies are required to test the clinical efficacy of melatonin supplementation in such disorders, and to identify the specific therapeutic concentrations needed.}, }
@article {pmid24381542, year = {2013}, author = {Heath, PR and Kirby, J and Shaw, PJ}, title = {Investigating cell death mechanisms in amyotrophic lateral sclerosis using transcriptomics.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {259}, pmid = {24381542}, issn = {1662-5102}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by degeneration and loss of upper and lower motor neurons from the motor cortex, brainstem and spinal cord although evidence is suggesting that there is further involvement of other cell types in the surrounding tissue. Transcriptomic analysis by gene expression profiling using microarray technology has enabled the determination of patterns of cell death in the degenerating tissues. This work has examined gene expression at the level of the tissue and individual cell types in both sporadic and familial forms of the disease. In addition, further studies have examined the differential vulnerability of neuronal cells in different regions of the central nervous system. Model systems have also provided further information to help unravel the mechanisms that lead to death of the motor neurons in disease and also provided novel insights. In this review we shall describe the methods that have been used in these investigations and describe how they have contributed to our knowledge of the cell death mechanisms in ALS.}, }
@article {pmid26237595, year = {2014}, author = {Faravelli, I and Frattini, E and Ramirez, A and Stuppia, G and Nizzardo, M and Corti, S}, title = {iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development.}, journal = {Journal of clinical medicine}, volume = {3}, number = {4}, pages = {1124-1145}, pmid = {26237595}, issn = {2077-0383}, abstract = {Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS), while the most common infantile MND is represented by spinal muscular atrophy (SMA). No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs) has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders.}, }
@article {pmid26056593, year = {2014}, author = {Jaiswal, MK}, title = {Selective vulnerability of motoneuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motoneurons specific calcium dysregulation.}, journal = {Molecular and cellular therapies}, volume = {2}, number = {}, pages = {26}, pmid = {26056593}, issn = {2052-8426}, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by the selective degeneration of defined subgroups of motoneuron in the brainstem, spinal cord and motor cortex with signature hallmarks of mitochondrial Ca(2+) overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium, and in particular low cytosolic calcium ([Ca(2+)]c) buffering and a strong interaction between metabolic mechanisms and [Ca(2+)]i have been identified predominantly in motoneuron impairment, the causes of these disruptions are unknown. The existing evidence suggests that the mutant superoxide dismutase1 (mtSOD1)-mediated toxicity in ALS acts through mitochondria, and that alteration in cytosolic and mitochondria-ER microdomain calcium accumulation are critical to the neurodegenerative process. Furthermore, chronic excitotoxcity mediated by Ca(2+)-permeable AMPA and NMDA receptors seems to initiate vicious cycle of intracellular calcium dysregulation which leads to toxic Ca(2+) overload and thereby selective neurodegeneration. Recent advancement in the experimental analysis of calcium signals with high spatiotemporal precision has allowed investigations of calcium regulation in-vivo and in-vitro in different cell types, in particular selectively vulnerable/resistant cell types in different animal models of this motoneuron disease. This review provides an overview of latest advances in this field, and focuses on details of what has been learned about disrupted Ca(2+) homeostasis and mitochondrial degeneration. It further emphasizes the critical role of mitochondria in preventing apoptosis by acting as a Ca(2+) buffers, especially in motoneurons, in pathophysiological conditions such as ALS.}, }
@article {pmid24379756, year = {2013}, author = {Rotunno, MS and Bosco, DA}, title = {An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {253}, pmid = {24379756}, issn = {1662-5102}, support = {R01 NS067206/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that targets motor neurons, leading to paralysis and death within a few years of disease onset. While several genes have been linked to the inheritable, or familial, form of ALS, much less is known about the cause(s) of sporadic ALS, which accounts for ~90% of ALS cases. Due to the clinical similarities between familial and sporadic ALS, it is plausible that both forms of the disease converge on a common pathway and, therefore, involve common factors. Recent evidence suggests the Cu,Zn-superoxide dismutase (SOD1) protein to be one such factor that is common to both sporadic and familial ALS. In 1993, mutations were uncovered in SOD1 that represent the first known genetic cause of familial ALS. While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a "toxic conformation" that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS.}, }
@article {pmid24374297, year = {2014}, author = {Rodgers, KJ}, title = {Non-protein amino acids and neurodegeneration: the enemy within.}, journal = {Experimental neurology}, volume = {253}, number = {}, pages = {192-196}, doi = {10.1016/j.expneurol.2013.12.010}, pmid = {24374297}, issn = {1090-2430}, mesh = {Amino Acids/*metabolism/toxicity ; Animals ; Humans ; Neurodegenerative Diseases/*chemically induced/*metabolism ; Proteins/*metabolism ; Proteomics ; }, abstract = {Animals, in common with plants and microorganisms, synthesise proteins from a pool of 20 protein amino acids (plus selenocysteine and pyrolysine) (Hendrickson et al., 2004). This represents a small proportion (~2%) of the total number of amino acids known to exist in nature (Bell, 2003). Many 'non-protein' amino acids are synthesised by plants, and in some cases constitute part of their chemical armoury against pathogens, predators or other species competing for the same resources (Fowden et al., 1967). Microorganisms can also use selectively toxic amino acids to gain advantage over competing organisms (Nunn et al., 2010). Since non-protein amino acids (and imino acids) are present in legumes, fruits, seeds and nuts, they are ubiquitous in the diets of human populations around the world. Toxicity to humans is unlikely to have been the selective force for their evolution, but they have the clear potential to adversely affect human health. In this review we explore the links between exposure to non-protein amino acids and neurodegenerative disorders in humans. Environmental factors play a major role in these complex disorders which are predominantly sporadic (Coppede et al., 2006). The discovery of new genes associated with neurodegenerative diseases, many of which code for aggregation-prone proteins, continues at a spectacular pace but little progress is being made in identifying the environmental factors that impact on these disorders. We make the case that insidious entry of non-protein amino acids into the human food chain and their incorporation into protein might be contributing significantly to neurodegenerative damage.}, }
@article {pmid24369373, year = {2014}, author = {Renton, AE and Chiò, A and Traynor, BJ}, title = {State of play in amyotrophic lateral sclerosis genetics.}, journal = {Nature neuroscience}, volume = {17}, number = {1}, pages = {17-23}, pmid = {24369373}, issn = {1546-1726}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933-02/ImNIH/Intramural NIH HHS/United States ; Z01-AG000949-02/AG/NIA NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing ; Amyotrophic Lateral Sclerosis/*genetics ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Membrane Transport Proteins ; Mutation/genetics ; Profilins/genetics ; Proteins ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transcription Factor TFIIIA/genetics ; Ubiquitins/genetics ; }, abstract = {Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.}, }
@article {pmid24367951, year = {2014}, author = {Arbesman, M and Sheard, K}, title = {Systematic review of the effectiveness of occupational therapy-related interventions for people with amyotrophic lateral sclerosis.}, journal = {The American journal of occupational therapy : official publication of the American Occupational Therapy Association}, volume = {68}, number = {1}, pages = {20-26}, doi = {10.5014/ajot.2014.008649}, pmid = {24367951}, issn = {1943-7676}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Evidence-Based Medicine ; Exercise Therapy ; Humans ; *Occupational Therapy ; Palliative Care ; Patient Care Team ; Self-Help Devices ; Treatment Outcome ; }, abstract = {We describe the results of a systematic review of the literature on occupational therapy-related interventions for people with amyotrophic lateral sclerosis (ALS). The review included 14 studies. We found limited to moderate evidence that people involved in multidisciplinary programs have longer survival than those in general care and limited evidence that those in multidisciplinary programs have a higher percentage of appropriate assistive devices and higher quality of life in social functioning and mental health. Limited evidence indicates that people with ALS are satisfied with the comfort and ease of use of their power wheelchairs (PWCs). In addition, limited evidence is available that PWCs allow people to have increased interaction in the community. Evidence also is limited that some assistive devices are more helpful than others. Moderate evidence indicates that a home exercise program of daily stretching and resistance exercise results in improved function. The implications for practice, education, and research are discussed.}, }
@article {pmid24367722, year = {2013}, author = {Anand, A and Thakur, K and Gupta, PK}, title = {ALS and oxidative stress: the neurovascular scenario.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {635831}, pmid = {24367722}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Blood-Brain Barrier/metabolism/pathology ; Humans ; Motor Neurons/metabolism/pathology ; Nervous System/*blood supply/*pathology ; *Oxidative Stress ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.}, }
@article {pmid24367332, year = {2013}, author = {Lu, H and Liu, X and Deng, Y and Qing, H}, title = {DNA methylation, a hand behind neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {5}, number = {}, pages = {85}, pmid = {24367332}, issn = {1663-4365}, abstract = {Epigenetic alterations represent a sort of functional modifications related to the genome that are not responsible for changes in the nucleotide sequence. DNA methylation is one of such epigenetic modifications that have been studied intensively for the past several decades. The transfer of a methyl group to the 5 position of a cytosine is the key feature of DNA methylation. A simple change as such can be caused by a variety of factors, which can be the cause of many serious diseases including several neurodegenerative diseases. In this review, we have reviewed and summarized recent progress regarding DNA methylation in four major neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The studies of these four major neurodegenerative diseases conclude the strong suggestion of the important role DNA methylation plays in these diseases. However, each of these diseases has not yet been understood completely as details in some areas remain unclear, and will be investigated in future studies. We hope this review can provide new insights into the understanding of neurodegenerative diseases from the epigenetic perspective.}, }
@article {pmid24367290, year = {2013}, author = {Lazo-Gómez, R and Ramírez-Jarquín, UN and Tovar-Y-Romo, LB and Tapia, R}, title = {Histone deacetylases and their role in motor neuron degeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {243}, pmid = {24367290}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases (HATs) and deacetylases, respectively) whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases (HDACs) in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins (SIRT) and their effectors.}, }
@article {pmid24366528, year = {2014}, author = {Stepto, A and Gallo, JM and Shaw, CE and Hirth, F}, title = {Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Acta neuropathologica}, volume = {127}, number = {3}, pages = {377-389}, doi = {10.1007/s00401-013-1235-1}, pmid = {24366528}, issn = {1432-0533}, support = {089701/WT_/Wellcome Trust/United Kingdom ; G0701498/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; HIRTH/OCT13/868-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L010666/1/MRC_/Medical Research Council/United Kingdom ; G-0714/PUK_/Parkinson's UK/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Animals ; Apoptosis/genetics/physiology ; C9orf72 Protein ; Cells, Cultured ; DNA Repeat Expansion ; Disease Models, Animal ; Frontotemporal Dementia/*genetics/*physiopathology ; Humans ; *Open Reading Frames ; Proteins/*genetics/metabolism ; RNA/metabolism ; }, abstract = {GGGGCC (G4C2) hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) has been identified as the most common genetic abnormality in both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To investigate the role of C9ORF72-related G4C2 repeat expansion in ALS and FTLD, several animal and cell culture models have been generated that reveal initial insights into the disease pathogenesis of C9 ALS/FTLD. These models include neurons differentiated from patient-derived pluripotent stem cells as well as genetically engineered cells and organisms that knock down C9ORF72 orthologues or express G4C2 repeats. Targeted reduction or knockdown of C9ORF72 homologues in zebrafish and mice so far produced conflicting results which neither rule out, nor confirm reduced expression of C9ORF72 as a pathogenic mechanism in C9 ALS/FTLD. In contrast, studies using patient-derived cells, as well as Drosophila and zebrafish models overexpressing disease-related hexanucleotide expansions, can cause repeat length-dependent formation of RNA foci, which directly and progressively correlate with cellular toxicity. RNA foci formation is accompanied by sequestration of specific RNA-binding proteins (RBPs), including Pur-alpha, hnRNPH and ADARB2, suggesting that G4C2-mediated sequestration and functional depletion of RBPs are cytotoxic and thus directly contribute to disease. Moreover, these studies provide experimental evidence that repeat-associated non-ATG translation of repeat-containing sense and antisense RNA leads to dipeptide-repeat proteins (DPRs) that can accumulate and aggregate, indicating that accumulation of DPRs may represent another pathogenic pathway underlying C9 ALS/FTLD. These studies in cell and animal models therefore identify RNA toxicity, RBP sequestration and accumulation of DPRs as emerging pathogenic pathways underlying C9 ALS/FTLD.}, }
@article {pmid24360503, year = {2014}, author = {Tan, CC and Yu, JT and Tan, MS and Jiang, T and Zhu, XC and Tan, L}, title = {Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy.}, journal = {Neurobiology of aging}, volume = {35}, number = {5}, pages = {941-957}, doi = {10.1016/j.neurobiolaging.2013.11.019}, pmid = {24360503}, issn = {1558-1497}, mesh = {Aging/*genetics/*pathology ; *Autophagy/genetics/physiology ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*genetics/*pathology/therapy ; Neurons/*pathology/*physiology ; Signal Transduction/genetics/physiology ; TOR Serine-Threonine Kinases/physiology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.}, }
@article {pmid24356984, year = {2014}, author = {Mackenzie, IR and Frick, P and Neumann, M}, title = {The neuropathology associated with repeat expansions in the C9ORF72 gene.}, journal = {Acta neuropathologica}, volume = {127}, number = {3}, pages = {347-357}, doi = {10.1007/s00401-013-1232-4}, pmid = {24356984}, issn = {1432-0533}, support = {74580//Canadian Institutes of Health Research/Canada ; }, mesh = {Brain/metabolism/*pathology ; C9orf72 Protein ; DNA Repeat Expansion ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/diagnosis/genetics/metabolism/pathology ; Humans ; Neurodegenerative Diseases/diagnosis/genetics/metabolism/pathology ; Phenotype ; Proteins/*genetics ; }, abstract = {An abnormal expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) is the most common genetic abnormality in familial and sporadic FTLD and ALS and the cause in most families where both, FTLD and ALS, are inherited. Pathologically, C9ORF72 expansion cases show a combination of FTLD-TDP and classical ALS with abnormal accumulation of TDP-43 into neuronal and oligodendroglial inclusions consistently seen in the frontal and temporal cortex, hippocampus and pyramidal motor system. In addition, a highly specific feature in C9ORF72 expansion cases is the presence of ubiquitin and p62 positive, but TDP-43 negative neuronal cytoplasmic and intranuclear inclusions. These TDP-43 negative inclusions contain dipeptide-repeat (DPR) proteins generated by unconventional repeat-associated translation of C9ORF72 transcripts with the expanded repeats and are most abundant in the cerebellum, hippocampus and all neocortex regions. Another consistent pathological feature associated with the production of C9ORF72 transcripts with expanded repeats is the formation of nuclear RNA foci that are frequently observed in the frontal cortex, hippocampus and cerebellum. Here, we summarize the complexity and heterogeneity of the neuropathology associated with the C9ORF72 expansion. We discuss implications of the data to the current classification of FTLD and critically review current insights from clinico-pathological correlative studies regarding the fundamental questions as to what processes are required and sufficient to trigger neurodegeneration in C9ORF72 disease pathogenesis.}, }
@article {pmid24356272, year = {2013}, author = {Sica, RE}, title = {[Amyotrophic lateral sclerosis: is the astrocyte the cell primarily involved?].}, journal = {Medicina}, volume = {73}, number = {6}, pages = {573-578}, pmid = {24356272}, issn = {0025-7680}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Astrocytes/*pathology/physiology ; Cellular Microenvironment ; Humans ; Models, Biological ; Motor Neurons/pathology/physiology ; }, abstract = {So far, amyotrophic lateral sclerosis (ALS) is thought as due to a primary insult of the motor neurons. None of its pathogenic processes proved to be the cause of the illness, nor can be blamed environmental agents. Motor neurons die by apoptosis, leaving the possibility that their death might be due to an unfriendly environment, unable to sustain their health, rather than being directly targeted themselves. These reasons justify an examination of the astrocytes, because they have the most important role controlling the neurons' environment. It is known that astrocytes are plastic, enslaving their functions to the requirements of the neurons to which they are related. Each population of astrocytes is unique, and if it were affected the consequences would reach the neurons that it normally sustains. In regard to the motor neurons, this situation would lead to a disturbed production and release of astrocytic neurotransmitters and transporters, impairing nutritional and trophic support as well. For explaining the spreading of muscle symptoms in ALS, correlated with the type of spreading observed at the cortical and spinal motor neurons pools, the present hypotheses suggests that the illness-causing process is spreading among astrocytes, through their gap junctions, depriving the motor neurons of their support. Also it is postulated that a normal astrocytic protein becomes misfolded and infectious, inducing the misfolding of its wild type, travelling from one protoplasmatic astrocyte to another and to the fibrous astrocytes encircling the pyramidal pathway which joints the upper and lower motoneurones.}, }
@article {pmid24355598, year = {2014}, author = {Yamashita, T and Kwak, S}, title = {The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients.}, journal = {Brain research}, volume = {1584}, number = {}, pages = {28-38}, doi = {10.1016/j.brainres.2013.12.011}, pmid = {24355598}, issn = {1872-6240}, mesh = {Adenosine Deaminase/genetics ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Calpain/metabolism ; Cell Death/genetics ; DNA-Binding Proteins/*metabolism ; Humans ; Mice ; Motor Neurons/enzymology/*metabolism ; *RNA Editing ; RNA-Binding Proteins/genetics ; Receptors, AMPA/*genetics ; Spinal Cord/pathology ; }, abstract = {TAR DNA-binding protein (TDP-43) pathology and reduced expression of adenosine deaminase acting on RNA 2 (ADAR2), which is the RNA editing enzyme responsible for adenosine-to-inosine conversion at the GluA2 glutamine/arginine (Q/R) site, concomitantly occur in the same motor neurons of amyotrophic lateral sclerosis (ALS) patients; this finding suggests a link between these two ALS-specific molecular abnormalities. AMPA receptors containing Q/R site-unedited GluA2 in their subunit assembly are Ca(2+)-permeable, and motor neurons lacking ADAR2 undergo slow death in conditional ADAR2 knockout (AR2) mice, which is a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons. Moreover, deficient ADAR2 induced mislocalization of TDP-43 similar to TDP-43 pathology seen in the sporadic ALS patients in the motor neurons of AR2 mice. The abnormal mislocalization of TDP-43 specifically resulted from activation of the Ca(2+)-dependent serine protease calpain that specifically cleaved TDP-43 at the C-terminal region, and generated aggregation-prone N-terminal fragments. Notably, the N-terminal fragments of TDP-43 lacking the C-terminus were demonstrated in the brains and spinal cords of ALS patients. Because normalization of either the Ca(2+)-permeability of AMPA receptors or the calpain activity in the motor neurons normalized the subcellular localization of TDP-43 in AR2 mice, it is likely that exaggerated calpain-dependent TDP-43 fragments played a role at least in the initiation of TDP-43 pathology. Elucidation of the molecular cascade of neuronal death induced by ADAR2 downregulation could provide a new specific therapy for sporadic ALS. In this review, we summarized the work from our group on the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discussed possible effects of inefficient ADAR2-mediated RNA editing in general.}, }
@article {pmid24349764, year = {2013}, author = {Fernandes, SA and Douglas, AG and Varela, MA and Wood, MJ and Aoki, Y}, title = {Oligonucleotide-Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion: A Perspective.}, journal = {Journal of nucleic acids}, volume = {2013}, number = {}, pages = {208245}, pmid = {24349764}, issn = {2090-0201}, support = {G0900887/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.}, }
@article {pmid24348042, year = {2013}, author = {Ahmed, A and Simmons, Z}, title = {Pseudobulbar affect: prevalence and management.}, journal = {Therapeutics and clinical risk management}, volume = {9}, number = {}, pages = {483-489}, pmid = {24348042}, issn = {1176-6336}, abstract = {Pseudobulbar affect (PBA) may occur in association with a variety of neurological diseases, and so may be encountered in the setting of amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. The psychological consequences and the impact on social interactions may be substantial. Although it is most commonly misidentified as a mood disorder, particularly depression or a bipolar disorder, there are characteristic features that can be recognized clinically or assessed by validated scales, resulting in accurate identification of PBA, and thus permitting proper management and treatment. Mechanistically, PBA is a disinhibition syndrome in which pathways involving serotonin and glutamate are disrupted. This knowledge has permitted effective treatment for many years with antidepressants, particularly tricyclic antidepressants and selective serotonin reuptake inhibitors. A recent therapeutic breakthrough occurred with the approval by the Food and Drug Administration of a dextromethorphan/quinidine combination as being safe and effective for treatment of PBA. Side effect profiles and contraindications differ for the various treatment options, and the clinician must be familiar with these when choosing the best therapy for an individual, particularly elderly patients and those with multiple comorbidities and concomitant medications.}, }
@article {pmid24339036, year = {2013}, author = {Kisby, GE and Moore, H and Spencer, PS}, title = {Animal models of brain maldevelopment induced by cycad plant genotoxins.}, journal = {Birth defects research. Part C, Embryo today : reviews}, volume = {99}, number = {4}, pages = {247-255}, pmid = {24339036}, issn = {1542-9768}, support = {P42 ES010338/ES/NIEHS NIH HHS/United States ; P50 MH066171/MH/NIMH NIH HHS/United States ; 5P42-ES10338-02/ES/NIEHS NIH HHS/United States ; }, mesh = {Amino Acids, Diamino/toxicity ; Amyotrophic Lateral Sclerosis/chemically induced/pathology ; Animals ; Brain/drug effects/metabolism ; Cyanobacteria Toxins ; Cycas/*chemistry/*toxicity ; DNA Damage/drug effects ; Disease Models, Animal ; Humans ; Mutagens/chemistry/*toxicity ; Neurotoxins/chemistry/toxicity ; }, abstract = {Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably β-N-methylamino-l-alanine l-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction.}, }
@article {pmid24338926, year = {2014}, author = {Yu, Q and Powles, SB}, title = {Resistance to AHAS inhibitor herbicides: current understanding.}, journal = {Pest management science}, volume = {70}, number = {9}, pages = {1340-1350}, doi = {10.1002/ps.3710}, pmid = {24338926}, issn = {1526-4998}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors/metabolism ; Herbicide Resistance/*genetics ; Herbicides/*pharmacology ; Mutation ; Plant Weeds/*drug effects ; }, abstract = {Acetohydroxyacid synthase (AHAS) inhibitor herbicides currently comprise the largest site-of-action group (with 54 active ingredients across five chemical groups) and have been widely used in world agriculture since they were first introduced in 1982. Resistance evolution in weeds to AHAS inhibitors has been rapid and identified in populations of many weed species. Often, evolved resistance is associated with point mutations in the target AHAS gene; however non-target-site enhanced herbicide metabolism occurs as well. Many AHAS gene resistance mutations can occur and be rapidly enriched owing to a high initial resistance gene frequency, simple and dominant genetic inheritance and lack of major fitness cost of the resistance alleles. Major advances in the elucidation of the crystal structure of the AHAS (Arabidopsis thaliana) catalytic subunit in complex with various AHAS inhibitor herbicides have greatly improved current understanding of the detailed molecular interactions between AHAS, cofactors and herbicides. Compared with target-site resistance, non-target-site resistance to AHAS inhibitor herbicides is less studied and hence less understood. In a few well-studied cases, non-target-site resistance is due to enhanced rates of herbicide metabolism (metabolic resistance), mimicking that occurring in tolerant crop species and often involving cytochrome P450 monooxygenases. However, the specific herbicide-metabolising, resistance-endowing genes are yet to be identified in resistant weed species. The current state of mechanistic understanding of AHAS inhibitor herbicide resistance is reviewed, and outstanding research issues are outlined.}, }
@article {pmid24336308, year = {2013}, author = {Ferner, RE and Aronson, JK}, title = {Laughter and MIRTH (Methodical Investigation of Risibility, Therapeutic and Harmful): narrative synthesis.}, journal = {BMJ (Clinical research ed.)}, volume = {347}, number = {}, pages = {f7274}, pmid = {24336308}, issn = {1756-1833}, mesh = {Anger ; Anxiety/prevention &amp; control/psychology ; Cardiovascular Physiological Phenomena ; Central Nervous System/physiology ; Humans ; *Laughter/physiology/psychology ; Respiratory Physiological Phenomena ; }, abstract = {OBJECTIVE: To review the beneficial and harmful effects of laughter.<br><br>DESIGN: Narrative synthesis.<br><br>We searched Medline (1946 to June 2013) and Embase (1974 to June 2013) for reports of benefits or harms from laughter in humans, and counted the number of papers in each category.<br><br>RESULTS: Benefits of laughter include reduced anger, anxiety, depression, and stress; reduced tension (psychological and cardiovascular); increased pain threshold; reduced risk of myocardial infarction (presumably requiring hearty laughter); improved lung function; increased energy expenditure; and reduced blood glucose concentration. However, laughter is no joke-dangers include syncope, cardiac and oesophageal rupture, and protrusion of abdominal hernias (from side splitting laughter or laughing fit to burst), asthma attacks, interlobular emphysema, cataplexy, headaches, jaw dislocation, and stress incontinence (from laughing like a drain). Infectious laughter can disseminate real infection, which is potentially preventable by laughing up your sleeve. As a side effect of our search for side effects, we also list pathological causes of laughter, among them epilepsy (gelastic seizures), cerebral tumours, Angelman's syndrome, strokes, multiple sclerosis, and amyotrophic lateral sclerosis or motor neuron disease.<br><br>CONCLUSIONS: Laughter is not purely beneficial. The harms it can cause are immediate and dose related, the risks being highest for Homeric (uncontrollable) laughter. The benefit-harm balance is probably favourable. It remains to be seen whether sick jokes make you ill or jokes in bad taste cause dysgeusia, and whether our views on comedians stand up to further scrutiny.}, }
@article {pmid24331786, year = {2014}, author = {Kiernan, MC}, title = {ALS and neuromuscular disease: in search of the Holy Grail.}, journal = {The Lancet. Neurology}, volume = {13}, number = {1}, pages = {13-14}, doi = {10.1016/S1474-4422(13)70226-6}, pmid = {24331786}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/*therapy ; C9orf72 Protein ; Humans ; Mutation/*genetics ; Neuromuscular Diseases/diagnosis/genetics/therapy ; Proteins/genetics ; Risk Factors ; }, }
@article {pmid24329535, year = {2014}, author = {Amor, S and Peferoen, LA and Vogel, DY and Breur, M and van der Valk, P and Baker, D and van Noort, JM}, title = {Inflammation in neurodegenerative diseases--an update.}, journal = {Immunology}, volume = {142}, number = {2}, pages = {151-166}, pmid = {24329535}, issn = {1365-2567}, mesh = {Humans ; Inflammation/immunology ; Neurodegenerative Diseases/*immunology/therapy ; }, abstract = {Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases.}, }
@article {pmid24324498, year = {2013}, author = {Matus, S and Valenzuela, V and Medinas, DB and Hetz, C}, title = {ER Dysfunction and Protein Folding Stress in ALS.}, journal = {International journal of cell biology}, volume = {2013}, number = {}, pages = {674751}, pmid = {24324498}, issn = {1687-8876}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent paralytic disease in adults. Most ALS cases are considered sporadic with no clear genetic component. The disruption of protein homeostasis due to chronic stress responses at the endoplasmic reticulum (ER) and the accumulation of abnormal protein inclusions are extensively described in ALS mouse models and patient-derived tissue. Recent studies using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive reaction against ER stress, have demonstrated a complex involvement of the pathway in experimental models of ALS. In addition, quantitative changes in ER stress-responsive chaperones in body fluids have been proposed as possible biomarkers to monitor the disease progression. Here we review most recent advances attributing a causal role of ER stress in ALS.}, }
@article {pmid24323933, year = {2013}, author = {Akiyama, H and Hasegawa, M}, title = {[Neuropathology of TDP-43 proteinopathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {12}, pages = {1477-1489}, pmid = {24323933}, issn = {1881-6096}, mesh = {Animals ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Humans ; Mutation/genetics ; Stress, Physiological ; TDP-43 Proteinopathies/*metabolism/pathology ; Ubiquitin/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a member of the heterogeneous nuclear ribonucleoprotein family, a group of proteins involved in pre-mRNA splicing, RNA stability, transport, and metabolism. TDP-43 was identified as the major component of pathological protein aggregates present in a subset of frontotemporal lobar degeneration (FTLD), which is now referred to as FTLD-TDP. TDP-43 is also deposited in the sporadic form of amyotrophic lateral sclerosis (ALS) as well as in familial ALS with mutations in the gene for TDP-43. Based on histopathology, the accumulation of TDP-43 in the brain cortex is classified into 4 types, type A through D, depending on the forms of TDP-43 accumulation in the cerebral cortex. Type A pathology is frequently observed in frontotemporal dementia and progressive non-fluent aphasia. Type B pathology occurs in FTLD with ALS and ALS with lesions that extend to the cerebral cortex. Type C pathology is associated with semantic dementia. In FTLD and ALS, TDP-43 forms insoluble aggregates and gets phosphorylated, ubiquitinated, and fragmented. The fragment patterns on immunoblot of brain homogenates correspond to each histopathological type, indicating their relevance to the pathogenesis of TDP-43 proteinopathy.}, }
@article {pmid24323921, year = {2014}, author = {McCartney, AJ and Zhang, Y and Weisman, LS}, title = {Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {36}, number = {1}, pages = {52-64}, pmid = {24323921}, issn = {1521-1878}, support = {F31NS074740/NS/NINDS NIH HHS/United States ; R01 NS064015/NS/NINDS NIH HHS/United States ; F31 NS074740/NS/NINDS NIH HHS/United States ; R01 GM050403/GM/NIGMS NIH HHS/United States ; R01-GM50403/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; Phosphatidylinositol Phosphates/*genetics/*metabolism ; Signal Transduction/*genetics ; }, abstract = {Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2 , and mutations that disrupt complex function and/or formation cause profound consequences in cells. Surprisingly, mutations in this pathway are linked with neurological diseases, including Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis. Future studies of PI(3,5)P2 and PI5P are likely to expand the roles of these lipids in regulation of cellular functions, as well as provide new approaches for treatment of some neurological diseases.}, }
@article {pmid24323712, year = {2014}, author = {Wu, LJ}, title = {Microglial voltage-gated proton channel Hv1 in ischemic stroke.}, journal = {Translational stroke research}, volume = {5}, number = {1}, pages = {99-108}, pmid = {24323712}, issn = {1868-601X}, mesh = {Animals ; Brain Ischemia/*metabolism ; Disease Models, Animal ; Humans ; Hydrogen-Ion Concentration ; Ion Channels/*metabolism ; Mice ; Microglia/*metabolism ; Reactive Oxygen Species/metabolism ; Stroke/*metabolism ; }, abstract = {Microglia, resident immune cells in the brain, contribute both to the damage and resolution of ischemic stroke. However, the mechanisms of microglia's detrimental or beneficial role in the disease are poorly understood. The voltage-gated proton channel, Hv1, rapidly removes protons from depolarized cytoplasm, and is highly expressed in the immune system. In the brain, Hv1 is selectively and functionally expressed in microglia but not neurons. Although the physiological function of microglial Hv1 is still not clear, Hv1 is one of major ion channels expressed in resting microglia. Under pathological conditions, microglial Hv1 is required for NADPH oxidase (NOX)-dependent generation of reactive oxygen species (ROS) by providing charge compensation for exported electrons and relieving intracellular acidosis. In a mouse model of cerebral middle artery occlusion, Hv1 knockout mice are protected from ischemic damage, showing reduced NOX-dependent ROS production, microglial activation and neuronal cell death. Therefore, microglial Hv1 aids in NOX-dependent ROS generation, which subsequently induces neuronal cell death and a significant fraction of brain damage after ischemic stroke. These studies illuminate a critical role of microglial Hv1 in ischemic brain injury, providing a rationale for Hv1 as a potential therapeutic target for the treatment of ischemic stroke. The current understanding of Hv1 in ischemic injury through NOX-dependent ROS production may serve as a common model to reveal the deleterious role of microglia in neurological diseases other than ischemic stroke, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, and neuropathic pain.}, }
@article {pmid24323427, year = {2014}, author = {Pal, R and Alves, G and Larsen, JP and Møller, SG}, title = {New insight into neurodegeneration: the role of proteomics.}, journal = {Molecular neurobiology}, volume = {49}, number = {3}, pages = {1181-1199}, pmid = {24323427}, issn = {1559-1182}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*diagnosis/*genetics/metabolism ; Proteomics/methods/*trends ; }, abstract = {Recent advances within the field of proteomics, including both upstream and downstream protocols, have fuelled a transition from simple protein identification to functional analysis. A battery of proteomics approaches is now being employed for the analysis of protein expression levels, the monitoring of cellular activities and for gaining an increased understanding into biochemical pathways. Combined, these approaches are changing the way we study disease by allowing accurate and targeted, large scale protein analysis, which will provide invaluable insight into disease pathogenesis. Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), prion disease, and other diseases that affect the neuromuscular system, are a leading cause of disability in the aging population. There are no effective intervention strategies for these disorders and diagnosis is challenging as it relies primarily on clinical symptomatic features, which often overlap at early stages of disease. There is, therefore, an urgent need to develop reliable biomarkers to improve early and specific diagnosis, to track disease progression, to measure molecular responses towards treatment regimes and ultimately devise new therapeutic strategies. To accomplish this, a better understanding of disease mechanisms is needed. In this review we summarize recent advances in the field of proteomics applicable to neurodegenerative disorders, and how these advances are fueling our understanding, diagnosis, and treatment of these complex disorders.}, }
@article {pmid24315469, year = {2014}, author = {Hannan, LM and Dominelli, GS and Chen, YW and Darlene Reid, W and Road, J}, title = {Systematic review of non-invasive positive pressure ventilation for chronic respiratory failure.}, journal = {Respiratory medicine}, volume = {108}, number = {2}, pages = {229-243}, doi = {10.1016/j.rmed.2013.11.010}, pmid = {24315469}, issn = {1532-3064}, mesh = {Amyotrophic Lateral Sclerosis/complications/therapy ; Chronic Disease ; Humans ; Muscular Dystrophy, Duchenne/complications/therapy ; Obesity Hypoventilation Syndrome/complications/therapy ; Positive-Pressure Respiration/*methods ; Prospective Studies ; Randomized Controlled Trials as Topic ; Respiratory Insufficiency/etiology/*therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: This systematic review examined the effect of non-invasive positive pressure ventilation (NIPPV) on patient reported outcomes (PROs) and survival for individuals with or at risk of chronic respiratory failure (CRF).<br><br>METHODS: Randomised controlled trials (RCTs) and prospective non-randomised studies in those treated with NIPPV for CRF were identified from electronic databases, reference lists and grey literature. Diagnostic groups included in the review were amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), Duchenne muscular dystrophy (DMD), restrictive thoracic disease (RTD) and obesity hypoventilation syndrome (OHS).<br><br>RESULTS: Eighteen studies were included and overall study quality was weak. Those with ALS/MND had improved somnolence and fatigue as well as prolonged survival with NIPPV. For OHS, improvements in somnolence and fatigue, dyspnoea and sleep quality were demonstrated, while for RTD, measures of dyspnoea, sleep quality, physical function and health, mental and emotional health and social function improved. There was insufficient evidence to form conclusions regarding the effect of NIPPV for those with DMD.<br><br>CONCLUSIONS: This review has demonstrated that NIPPV influences PROs differently depending on the underlying cause of CRF. These findings may provide assistance to patients and clinicians to determine the relative costs and benefits of NIPPV therapy and also highlight areas in need of further research.}, }
@article {pmid24312006, year = {2013}, author = {Bowerman, M and Vincent, T and Scamps, F and Perrin, FE and Camu, W and Raoul, C}, title = {Neuroimmunity dynamics and the development of therapeutic strategies for amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {214}, pmid = {24312006}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder characterized by the progressive and selective loss of both upper and lower motoneurons. The neurodegenerative process is accompanied by a sustained inflammation in the brain and spinal cord. The neuron-immune interaction, implicating resident microglia of the central nervous system and blood-derived immune cells, is highly dynamic over the course of the disease. Here, we discuss the timely controlled neuroprotective and neurotoxic cues that are provided by the immune environment of motoneurons and their potential therapeutic applications for ALS.}, }
@article {pmid24306942, year = {2014}, author = {Hargus, G and Ehrlich, M and Hallmann, AL and Kuhlmann, T}, title = {Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development.}, journal = {Acta neuropathologica}, volume = {127}, number = {2}, pages = {151-173}, doi = {10.1007/s00401-013-1222-6}, pmid = {24306942}, issn = {1432-0533}, mesh = {Cells, Cultured ; Disease Progression ; Humans ; In Vitro Techniques ; Induced Pluripotent Stem Cells/*pathology ; *Models, Biological ; Mutation ; Neurodegenerative Diseases/genetics/*pathology ; Neurons/pathology ; }, abstract = {The number of patients with neurodegenerative diseases is increasing significantly worldwide. Thus, intense research is being pursued to uncover mechanisms of disease development in an effort to identify molecular targets for therapeutic intervention. Analysis of postmortem tissue from patients has yielded important histological and biochemical markers of disease progression. However, this approach is inherently limited because it is not possible to study patient neurons prior to degeneration. As such, transgenic and knockout models of neurodegenerative diseases are commonly employed. While these animal models have yielded important insights into some molecular mechanisms of disease development, they do not provide the opportunity to study mechanisms of neurodegeneration in human neurons at risk and thus, it is often difficult or even impossible to replicate human pathogenesis with this approach. The generation of patient-specific induced pluripotent stem (iPS) cells offers a unique opportunity to overcome these obstacles. By expanding and differentiating iPS cells, it is possible to generate large numbers of functional neurons in vitro, which can then be used to study the disease of the donating patient. Here, we provide an overview of human stem cell models of neurodegeneration using iPS cells from patients with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, spinal muscular atrophy and other neurodegenerative diseases. In addition, we describe how further refinements of reprogramming technology resulted in the generation of patient-specific induced neurons, which have also been used to model neurodegenerative changes in vitro.}, }
@article {pmid24305949, year = {2014}, author = {Gallagher, PS and Oeser, ML and Abraham, AC and Kaganovich, D and Gardner, RG}, title = {Cellular maintenance of nuclear protein homeostasis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {71}, number = {10}, pages = {1865-1879}, pmid = {24305949}, issn = {1420-9071}, support = {R01 AG031136/AG/NIA NIH HHS/United States ; R01AG031136/AG/NIA NIH HHS/United States ; }, mesh = {Cell Nucleus/*metabolism ; Homeostasis ; Humans ; Molecular Chaperones/metabolism ; Nuclear Proteins/chemistry/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Signal Transduction ; Sumoylation ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/chemistry/metabolism ; }, abstract = {The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. However, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin-proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.}, }
@article {pmid24302673, year = {2014}, author = {Heap, I}, title = {Global perspective of herbicide-resistant weeds.}, journal = {Pest management science}, volume = {70}, number = {9}, pages = {1306-1315}, doi = {10.1002/ps.3696}, pmid = {24302673}, issn = {1526-4998}, mesh = {Crops, Agricultural ; Glycine/*analogs &amp; derivatives/pharmacology ; Herbicide Resistance/*genetics ; Herbicides/*pharmacology ; Plant Weeds/drug effects/*genetics ; *Weed Control ; Glyphosate ; }, abstract = {Two hundred and twenty weed species have evolved resistance to one or more herbicides, and there are now 404 unique cases (species × site of action) of herbicide-resistant weeds globally. ALS inhibitor-resistant weeds account for about a third of all cases (133/404) and are particularly troublesome in rice and cereals. Although 71 weed species have been identified with triazine resistance, their importance has dwindled with the shift towards Roundup Ready® crops in the USA and the reduction of triazine usage in Europe. Forty-three grasses have evolved resistance to ACCase inhibitors, with the most serious cases being Avena spp., Lolium spp., Phalaris spp., Setaria spp. and Alopecurus myosuroides, infesting more than 25 million hectares of cereal production globally. Of the 24 weed species with glyphosate resistance, 16 have been found in Roundup Ready® cropping systems. Although Conyza canadensis is the most widespread glyphosate-resistant weed, Amaranthus palmeri and Amaranthus tuberculartus are the two most economically important glyphosate-resistant weeds because of the area they infest and the fact that these species have evolved resistance to numerous other herbicide sites of action, leaving growers with few herbicidal options for their control. The agricultural chemical industry has not brought any new herbicides with novel sites of action to market in over 30 years, making growers reliant on using existing herbicides in new ways. In addition, tougher registration and environmental regulations on herbicides have resulted in a loss of some herbicides, particularly in Europe. The lack of novel herbicide chemistries being brought to market combined with the rapid increase in multiple resistance in weeds threatens crop production worldwide.}, }
@article {pmid24301650, year = {2013}, author = {Bharadwaj, PR and Bates, KA and Porter, T and Teimouri, E and Perry, G and Steele, JW and Gandy, S and Groth, D and Martins, RN and Verdile, G}, title = {Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases.}, journal = {Translational psychiatry}, volume = {3}, number = {12}, pages = {e332}, pmid = {24301650}, issn = {2158-3188}, support = {G12 MD007591/MD/NIMHD NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy ; Animals ; Cognition/drug effects ; Humans ; Huntington Disease/*drug therapy ; Indoles/pharmacology/*therapeutic use ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; Nootropic Agents/pharmacology/*therapeutic use ; }, abstract = {Latrepirdine (Dimebon(TM)) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer's disease (AD) and Huntington's disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson's disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.}, }
@article {pmid24297859, year = {2013}, author = {Röösli, M}, title = {[Health effects of electromagnetic fields].}, journal = {Therapeutische Umschau. Revue therapeutique}, volume = {70}, number = {12}, pages = {733-738}, doi = {10.1024/0040-5930/a000472}, pmid = {24297859}, issn = {0040-5930}, mesh = {Brain Neoplasms/epidemiology/etiology ; Causality ; Cell Phone ; Child ; Cross-Sectional Studies ; Double-Blind Method ; Electromagnetic Fields/*adverse effects ; Environmental Exposure/*adverse effects ; Europe ; Humans ; Leukemia/epidemiology/etiology ; Neurodegenerative Diseases/epidemiology/etiology ; Randomized Controlled Trials as Topic ; Risk ; Switzerland ; }, abstract = {Use of electricity causes extremely low frequency magnetic fields (ELF-MF) and wireless communication devices emit radiofrequency electromagnetic fields (RF-EMF). Average ELF-MF exposure is mainly determined by high voltage power lines and transformers at home or at the workplace, whereas RF-EMF exposure is mainly caused by devices operating close to the body (mainly mobile and cordless phones). Health effects of EMF are controversially discussed. The IARC classified ELF-MF and RF-EMF as possible carcinogenic. Most consistent epidemiological evidence was found for an association between ELF-MF and childhood leukaemia. If causal, 1 - 4 percent of all childhood leukaemia cases could be attributed to ELF-MF. Epidemiological research provided some indications for an association between ELF-MF and Alzheimer's diseases as well as amyotrophic lateral sclerosis, although not entirely consistent. Regarding mobile phones and brain tumours, some studies observed an increased risk after heavy or long term use on the one hand. On the other hand, brain tumour incidence was not found to have increased in the last decade in Sweden, England or the US. Acute effects of RF-EMF on non-specific symptoms of ill health seem unlikely according to randomized and double blind provocation studies. However, epidemiological research on long term effects is still limited. Although from the current state of the scientific knowledge a large individual health risk from RF-EMF exposure is unlikely, even a small risk would have substantial public health relevance because of the widespread use of wireless communication technologies.}, }
@article {pmid24292800, year = {2014}, author = {Nuzzo, D and Picone, P and Caruana, L and Vasto, S and Barera, A and Caruso, C and Di Carlo, M}, title = {Inflammatory mediators as biomarkers in brain disorders.}, journal = {Inflammation}, volume = {37}, number = {3}, pages = {639-648}, pmid = {24292800}, issn = {1573-2576}, mesh = {Biomarkers ; Humans ; Inflammation/immunology/pathology ; Inflammation Mediators/*metabolism ; Neurodegenerative Diseases/*diagnosis ; }, abstract = {Neurodegenerative diseases such as Alzheimer, Parkinson, amyotrophic lateral sclerosis, and Huntington are incurable and debilitating conditions that result in progressive death of the neurons. The definite diagnosis of a neurodegenerative disorder is disadvantaged by the difficulty in obtaining biopsies and thereby to validate the clinical diagnosis with pathological results. Biomarkers are valuable indicators for detecting different phases of a disease such as prevention, early onset, treatment, progression, and monitoring the effect of pharmacological responses to a therapeutic intervention. Inflammation occurs in neurodegenerative diseases, and identification and validation of molecules involved in this process could be a strategy for finding new biomarkers. The ideal inflammatory biomarker needs to be easily measurable, must be reproducible, not subject to wide variation in the population, and unaffected by external factors. Our review summarizes the most important inflammation biomarkers currently available, whose specificity could be utilized for identifying and monitoring distinctive phases of different neurodegenerative diseases.}, }
@article {pmid24292005, year = {2013}, author = {Yoshimine, T and Yanagisawa, T and Sawada, J and Hazama, T and Mochizuki, H and Hirata, M}, title = {[Communication with ALS patients: neurosurgical approach].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1405-1407}, doi = {10.5692/clinicalneurol.53.1405}, pmid = {24292005}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*rehabilitation ; *Brain-Computer Interfaces ; *Communication ; *Communication Aids for Disabled ; Electrodes, Implanted ; Electroencephalography ; Equipment Design ; Humans ; Neurosurgery/*instrumentation/*methods ; Thinking/*physiology ; }, abstract = {By progression of the disease, motor neurons degenerate in patients with amyotrophic lateral sclerosis (ALS) eventually lose nearly all voluntary muscles in the body. They are awake and aware but cannot move or communicate (locked-in state). Since the function of the brain is preserved, one possible measure to support their communication is to interpret their motor intention by decoding (deciphering) brain signals and present it with external devices. This technology called "brain-machine interface (BMI)" is now close to clinical use in Japan and USA.In our system, we record electrocorticogram (ECoG) obtained with subudural electrodes during their motor imagery, decode it and determine the movement they intended. So far, one patient of ALS with severe paralysis, implanted with this electrodes, successfully operated the PC communication tool only by thinking.}, }
@article {pmid24292003, year = {2013}, author = {Oyanagi, K and Mochizuki, Y and Nakayama, Y and Hayashi, K and Shimizu, T and Nagao, M and Hashimoto, T and Yamazaki, M and Matsubara, S and Komori, T}, title = {[Amyotrophic lateral sclerosis in totally locked-in state].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1399-1401}, doi = {10.5692/clinicalneurol.53.1399}, pmid = {24292003}, issn = {1882-0654}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*pathology/physiopathology/psychology/*rehabilitation ; Brain/pathology/physiopathology ; *Brain-Computer Interfaces ; *Communication ; *Communication Aids for Disabled ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; }, abstract = {Seven autopsy patients with amyotrophic lateral sclerosis (ALS) in totally locked-in state (TLS) were examined neuropathologically. The patients were composed of 4 males and 3 females, and 3 with familial, 1 sporadic but with mutation in SOD1 gene, and 3 sporadic patients with unremarkable gene mutation. The brains weighed 715, 783, 1,019, 1,050, 1,170, 1,190 or 1,233 g. The tegmentum of the brain stem was markedly degenerated in every patient, and the tracts relating to the somatic sensory and auditory were involved in the lesions.}, }
@article {pmid24292002, year = {2013}, author = {Nakayama, Y and Shimizu, T and Hayashi, K and Mochizuki, Y and Nagao, M and Oyanagi, K}, title = {[Predictors the progression of communication impairment in ALS tracheostomy ventilator users].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1396-1398}, doi = {10.5692/clinicalneurol.53.1396}, pmid = {24292002}, issn = {1882-0654}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*rehabilitation ; Communication Disorders/*etiology ; Disease Progression ; Female ; Forecasting ; Humans ; Male ; Middle Aged ; Oculomotor Nerve Diseases/etiology ; Prognosis ; Severity of Illness Index ; Time Factors ; *Tracheostomy ; Ventilators, Mechanical/*adverse effects ; Young Adult ; }, abstract = {We investigated predictive factors associatied with progression of communication impairment in 76 patients with amyotrophic lateral sclerosis (ALS) using tracheostomy ventilation. We classified the patients into the following three groups: patients capable of communication (stage I), patients with difficulties in communication (stage II to IV), and patients incapable of communication (stage V: so-called totally locked-in state) (Hayashi, et al. Clin Neurol 2013). There were no significant difference of disease duration across stages. Statistically significant differences were noted in the time of ventilator use, the time of tube feeding, and the time of complete quadriplegia among the 3 groups (Kruskal-Wallis). Multivariate analyses showed that the durations from onset to the time of ventilator use and complete quadriplegia had significant effecte on the progression from stage I to II, and that the duration from onset to the development of overt oculomotor limitation had signicant effect on the progression from stage IV to V. Faster progression may predict the extent of communication impairment after ventilator use.Accurate prediction of communication impairment after ventilator use may promote medical and social preparation including early application of the brain-machine interface for future communication problems in ALS patients.}, }
@article {pmid24292001, year = {2013}, author = {Nagao, M}, title = {[Clinical feature of ALS with communication disturbance; the possibility to communicate in TLS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1393-1395}, doi = {10.5692/clinicalneurol.53.1393}, pmid = {24292001}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/complications/diagnosis/*psychology/*rehabilitation ; Brain/pathology ; *Brain-Computer Interfaces/trends ; *Communication ; *Communication Aids for Disabled/trends ; Communication Disorders/*etiology/physiopathology/*rehabilitation ; Electroencephalography ; Humans ; Magnetic Resonance Imaging ; Tomography, Emission-Computed, Single-Photon ; Visual Pathways/*physiology ; }, abstract = {In the subsets of amyotrohic lateral sclerosis (ALS), totally-locked in state (TLS) is shown as the result of marked progression of motor neuron degeneration. In TLS, patients are impossible to move any voluntary muscles. As the result, patients with TLS cannot communicate with any augmentative and alternative communication devices(AACD) at present. To find the AACD that enables for TLS to communicate, we examined the clinical character, brain MRI, SPECT and evoked potentials in TLS. Brain MRI showed marked brain atrophy including the brainstem, but the occipital lobe was spared. SPECT and visual evoked potentials (VEP) showed preserved physiological function of the occipital lobe in TLS. The results suggest that neuronal degeneration in TLS is not restricted to motor system, but that the visual pathways are spared. Patients with TLS may be possible to use AACD that utilize the visual pathway.}, }
@article {pmid24291886, year = {2013}, author = {Katsuno, M and Ikenaka, K and Kawai, K and Sobue, G}, title = {[Dysfunction of dynactin 1 in motor neuron degeneration].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1084-1086}, doi = {10.5692/clinicalneurol.53.1084}, pmid = {24291886}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/metabolism/pathology ; Animals ; Drug Therapy, Combination ; Dynactin Complex ; Humans ; Hydroxamic Acids/therapeutic use ; Microtubule-Associated Proteins/*genetics/*physiology ; Molecular Targeted Therapy ; Motor Neurons/metabolism/pathology ; *Mutation ; Phagosomes/metabolism ; Sirolimus/therapeutic use ; }, abstract = {Dynactin 1 is an axon motor protein regulating retrograde transport of various proteins and vesicles including autophagosome. We previously demonstrated that the expression levels of dynacin 1 are markedly reduced in spinal motor neurons of sporadic ALS patients. We generated a Caenorhabditis elegans model in which the expression of dnc-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed the impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.}, }
@article {pmid24291885, year = {2013}, author = {Aoki, M}, title = {[Amyotrophic lateral sclerosis (ALS) with the mutations in the fused in sarcoma/translocated in liposarcoma gene].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1080-1083}, doi = {10.5692/clinicalneurol.53.1080}, pmid = {24291885}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Brain Stem/pathology ; Humans ; Mutation/*genetics ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been discovered to be associated with familial ALS. In a Japanese family with familial ALS, we found the R521C FUS/TLS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with ALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, and the average age of death was 37.2 years.Neuropathological examination revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We used immunohistochemistry to analyze 3 autopsy cases with the R521C mutation. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions.}, }
@article {pmid24291884, year = {2013}, author = {Onodera, O}, title = {[Molecular pathogenesis of ALS in TDP43 era].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1077-1079}, doi = {10.5692/clinicalneurol.53.1077}, pmid = {24291884}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; DNA-Binding Proteins/chemistry/*genetics/physiology ; Homeostasis/genetics/physiology ; Humans ; Mice ; Molecular Targeted Therapy ; *Mutation ; Prions ; Protein Aggregates/genetics ; Protein Structure, Tertiary ; RNA/metabolism ; Spliceosomes/genetics/metabolism ; }, abstract = {To clarify the molecular pathogenesis of amyotrophic lateral sclerosis (ALS) associated with TAR-DNA binding protein 43 kDd (TDP-43), the quality and quantity of TDP-43 take a crucial role. Regarding to the quality of TDP-43, TDP-43 has been reported as an aggregate-prone protein. Especially the C-terminus of the TDP-43 tends to form aggregate and has prion-like domain. Interestingly the mutations in the genes, which produce proteins with prion-like domain, have been identified in several neurodegenerative disorders. These results suggest the existence of the common property in the causative proteins for neurodegenerative disorders. For the quantity of TDP-43, the adequate amount of TDP-43 is necessary for maintaining cell function and cell survival. The amount of TDP-43 is tightly regulated by TDP-43. However the mechanism for autoregulation has not been fully elucidated. For the function of TDP-43, TDP-43 locates at stress granule, GEM and associates with the large genes and introns. Thus the alteration of TDP-43 may affect the function of stress granule, GEM and RNA metabolism in several genes. Moreover a U12 type spliceosome, which is matured in GEM, is decreased in ALS. The investigation of whether these dysfunctions explain the selective pathology in ALS provides a new therapeutic strategy for ALS.}, }
@article {pmid24291866, year = {2013}, author = {Egawa, N and Inoue, H}, title = {[ALS disease modeling and drug screening using patient-specific iPS cells].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1020-1022}, doi = {10.5692/clinicalneurol.53.1020}, pmid = {24291866}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*pathology ; Anacardic Acids/pharmacology/therapeutic use ; Animals ; Cell Differentiation ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Drug Discovery ; *Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Molecular Targeted Therapy ; *Motor Neurons/cytology/metabolism/pathology ; Mutation ; Neurites/pathology ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron (MN) loss in the spinal cord leads to progressive paralysis and death. Cytosolic aggregations in ALS MNs are composed of Tar DNA-binding protein-43 (TDP-43). Genetic analysis has identified more than twenty mutations of TDP-43 in ALS cases. Although accumulating evidence provides several hypotheses of disease mechanism, it is still needed to discover effective cure for ALS. We aimed to reveal cellular phenotypes in ALS MNs for identifying a drug-screening target for ALS using patient-specific induced pluripotent stem cells (iPSCs). To generate patient-specific iPSCs, dermal fibroblasts were obtained by biopsy from ALS patients carrying mutant TDP-43. The fibroblasts were reprogrammed by retrovirus or episomal vectors. Disease-specific iPSCs were differentiated into MNs expressing HB9 and SMI-32. Despite short culture period, ALS MNs recapitulated several disease phenotypes including detergent-insoluble TDP-43, shortened neurites and cellular vulnerability that observed in patient and animal models. Anacardic acid treatment reverted those phenotypes. Disease-specific iPSCs might provide a first step for drug-screening platform for ALS using patient-specific iPSCs.}, }
@article {pmid24291785, year = {2014}, author = {Tognolini, M and Hassan-Mohamed, I and Giorgio, C and Zanotti, I and Lodola, A}, title = {Therapeutic perspectives of Eph-ephrin system modulation.}, journal = {Drug discovery today}, volume = {19}, number = {5}, pages = {661-669}, doi = {10.1016/j.drudis.2013.11.017}, pmid = {24291785}, issn = {1878-5832}, mesh = {Animals ; Arteriosclerosis/drug therapy/metabolism ; Arthritis/drug therapy/metabolism ; Ephrins/*antagonists &amp; inhibitors/*physiology ; Humans ; Protein Binding/physiology ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Receptors, Eph Family/*antagonists &amp; inhibitors/*physiology ; }, abstract = {Eph receptors are the largest class of kinase receptors and, together with their ligands ephrins, they have a primary role in embryogenesis. Their expression has been found deregulated in several cancer tissues and, in many cases, abnormal levels of these proteins have been correlated to a poor prognosis. Recently, the Eph-ephrin system was found to be deregulated in other pathological processes, involving the nervous and cardiovascular systems. The increasing body of evidence supports the Eph-ephrin system as a target not only for the treatment of solid tumors, but also to face other critical diseases such as amyotrophic lateral sclerosis and diabetes driving current efforts toward the development of pharmacological tools potentially able to treat these pathologies.}, }
@article {pmid24279950, year = {2013}, author = {van Leeuwen, PW and van den Berg, JP and de Goeijen, NJ and Martens, M and Kampelmacher, MJ}, title = {[Terminal care in patients with amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {157}, number = {48}, pages = {A6295}, pmid = {24279950}, issn = {1876-8784}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; Caregivers ; Humans ; Hypercapnia/etiology ; Palliative Care ; Respiration, Artificial/methods ; *Terminal Care ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often fear of dying from suffocation. This fear is also common in relatives and caregivers. Research has, however, shown that ALS patients seldom die from suffocation. More than 90% of all ALS patients die peacefully. Death is mostly preceded by a peracute decrease in consciousness due to hypercapnia caused by alveolar hypoventilation. Mechanical ventilation, especially at night, can reduce the symptoms caused by hypoventilation. However, little by little, the effectiveness of ventilation may decrease to such an extent that it is no longer useful or desirable. Termination of long-standing ventilation requires careful preparation. Intensive guidance of the relevant medical, practical and ethical aspects are necessary. Particularly in the pre-terminal and terminal phases, support given to an ALS patient requires a pro-active attitude on the part of the treating physician. To this end, physicians may seek advice from the Dutch ALS Center, a palliative care consultation team, a hospice physician or a center for home mechanical ventilation.}, }
@article {pmid24279194, year = {2013}, author = {Bali, T and Miller, TM}, title = {Management of amyotrophic lateral sclerosis.}, journal = {Missouri medicine}, volume = {110}, number = {5}, pages = {417-421}, pmid = {24279194}, issn = {0026-6620}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Diagnostic Imaging/*methods ; *Disease Management ; Humans ; }, abstract = {Motor Neuron Diseases (MNDs) are neurological disorders characterized by the selective and progressive degeneration of motor neurons. Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is the most common. ALS causes diffuse muscle weakness and death secondary to respiratory failure. The diagnosis is made clinically, supported by electrodiagnostic testing. Although medications are limited, careful attention to breathing, nutrition, and patient mobility can have a major, positive impact on the course of the disease.}, }
@article {pmid24273101, year = {2014}, author = {Eisen, A and Turner, MR and Lemon, R}, title = {Tools and talk: an evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {49}, number = {4}, pages = {469-477}, doi = {10.1002/mus.24132}, pmid = {24273101}, issn = {1097-4598}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/psychology ; Animals ; *Biological Evolution ; Frontotemporal Dementia/*physiopathology/psychology ; Hand/physiology ; Humans ; Movement/physiology ; Speech/*physiology ; Tool Use Behavior/*physiology ; }, abstract = {We propose that amyotrophic lateral sclerosis (ALS), and frontotemporal dementia may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. We discuss how hand-arm function, locomotion, brainstem function (involving vocalization/speech, swallowing and breathing), and cognitive impairment share complex, interdependent evolutionary adaptations that can be traced back several million years. Fine movements of the hand facilitated tool-making and use enhanced by development of bipedalism. Development of the larynx and integration of respiratory control were central to vocalization, which when combined with gesture are intermediary to human language. These adaptations were accompanied by progressive encephalization, with development of Theory of Mind to facilitate socialization. The varied clinical phenotypes of ALS can thus be understood in the context of inter-related functional complexes that subserve "Tools and Talk"; they have a long evolutionary history and are related to specific developmental neural and gene networks.}, }
@article {pmid24271651, year = {2013}, author = {Miller, RG and Brooks, BR and Swain-Eng, RJ and Basner, RC and Carter, GT and Casey, P and Cohen, AB and Dubinsky, R and Forshew, D and Jackson, CE and Kasarskis, E and Procaccini, NJ and Sanjak, M and Tolin, FP}, title = {Quality improvement in neurology: amyotrophic lateral sclerosis quality measures: report of the quality measurement and reporting subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {81}, number = {24}, pages = {2136-2140}, pmid = {24271651}, issn = {1526-632X}, support = {M01 RR001346/RR/NCRR NIH HHS/United States ; R01HL103676-01A1/HL/NHLBI NIH HHS/United States ; R01HL093081/HL/NHLBI NIH HHS/United States ; }, mesh = {Academies and Institutes/*standards ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*therapy ; Humans ; Neurology/methods/*standards ; Quality Improvement/*standards ; United States/epidemiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disease characterized by loss of motor neurons.(1) Patients with ALS lose function in the limbs, speech, swallowing, and breathing muscles. The cause of the disease is still not known for most patients. Approximately 25,000 people in the United States have ALS, and 5,000 people are diagnosed with ALS annually in the United States.(1) Most patients die from respiratory failure 2 to 5 years after onset of symptoms. Cognitive dysfunction is seen in 20% to 50% of patients.(2) The disease burden for patients and caregivers is enormous. The average cost of care has been estimated at $50,000 per patient per year.(3.)}, }
@article {pmid24269718, year = {2014}, author = {Vinceti, M and Mandrioli, J and Borella, P and Michalke, B and Tsatsakis, A and Finkelstein, Y}, title = {Selenium neurotoxicity in humans: bridging laboratory and epidemiologic studies.}, journal = {Toxicology letters}, volume = {230}, number = {2}, pages = {295-303}, doi = {10.1016/j.toxlet.2013.11.016}, pmid = {24269718}, issn = {1879-3169}, mesh = {Environmental Exposure ; Epidemiologic Studies ; Humans ; Laboratories ; Nervous System/*drug effects ; Risk Assessment ; Selenium/*toxicity ; }, abstract = {Selenium is a metalloid of considerable interest in the human from both a toxicological and a nutritional perspective, with a very narrow safe range of intake. Acute selenium intoxication is followed by adverse effects on the nervous system with special clinical relevance, while the neurotoxicity of long-term overexposure is less characterized and recognized. We aimed to address this issue from a public health perspective, focusing on both laboratory studies and the few epidemiologic human studies available, with emphasis on their methodological strengths and limitations. The frequently overlooked differences in toxicity and biological activity of selenium compounds are also outlined. In addition to lethargy, dizziness, motor weakness and paresthesias, an excess risk of amyotrophic lateral sclerosis is the effect on the nervous system which has been more consistently associated with chronic low-level selenium overexposure, particularly to its inorganic compounds. Additional research efforts are needed to better elucidate the neurotoxic effects exerted by selenium overexposure.}, }
@article {pmid24269091, year = {2014}, author = {Son, M and Elliott, JL}, title = {Mitochondrial defects in transgenic mice expressing Cu,Zn superoxide dismutase mutations: the role of copper chaperone for SOD1.}, journal = {Journal of the neurological sciences}, volume = {336}, number = {1-2}, pages = {1-7}, doi = {10.1016/j.jns.2013.11.004}, pmid = {24269091}, issn = {1878-5883}, support = {R01 NS055315/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Mice, Transgenic ; Mitochondrial Diseases/enzymology/*genetics ; Mitochondrial Proteins/*genetics ; Molecular Chaperones/*genetics/physiology ; Mutation/*genetics ; Protein Folding ; Superoxide Dismutase/*genetics ; }, abstract = {Several hypotheses have been proposed for the mechanisms underlying mutant Cu,Zn Superoxide Dismutase-related Amyotrophic Lateral Sclerosis. These include aggregation pathology, mitochondrial dysfunctions, oxidative stress, and glutamate-mediated excitotoxicity. Mitochondrial disease may be a primary event in neurodegeneration, contributing to oxidative stress and apoptosis, or it may be caused by other cellular processes. Mitochondrial structural abnormalities have been detected in the skeletal muscle, lymphoblast and central nervous system of Amyotrophic Lateral Sclerosis patients. The cause or even the extent of mitochondrial defects in spinal cord and brain of patients with Cu,Zn Superoxide Dismutase mutations is difficult to determine because of rapid mitochondrial deterioration in autopsy samples. The focus of this review is how abnormalities in Cu,Zn Superoxide Dismutase redox states, folding and metallation contribute to mitochondrial deficiencies, investigating the differences in mitochondrial defects observed among transgenic mice expressing various Cu,Zn Superoxide Dismutase mutations.}, }
@article {pmid24262633, year = {2014}, author = {Sandberg, M and Patil, J and D'Angelo, B and Weber, SG and Mallard, C}, title = {NRF2-regulation in brain health and disease: implication of cerebral inflammation.}, journal = {Neuropharmacology}, volume = {79}, number = {}, pages = {298-306}, pmid = {24262633}, issn = {1873-7064}, support = {R01 GM044842/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Brain/immunology/*physiology/*physiopathology ; Humans ; Inflammation/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Signal Transduction/immunology/physiology ; }, abstract = {The nuclear factor erythroid 2 related factor 2 (NRF2) is a key regulator of endogenous inducible defense systems in the body. Under physiological conditions NRF2 is mainly located in the cytoplasm. However, in response to oxidative stress, NRF2 translocates to the nucleus and binds to specific DNA sites termed "anti-oxidant response elements" or "electrophile response elements" to initiate transcription of cytoprotective genes. Acute oxidative stress to the brain, such as stroke and traumatic brain injury is increased in animals that are deficient in NRF2. Insufficient NRF2 activation in humans has been linked to chronic diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. New findings have also linked activation of the NRF2 system to anti-inflammatory effects via interactions with NF-κB. Here we review literature on cellular mechanisms of NRF2 regulation, how to maintain and restore NRF2 function and the relationship between NRF2 regulation and brain damage. We bring forward the hypothesis that inflammation via prolonged activation of key kinases (p38 and GSK-3β) and activation of histone deacetylases gives rise to dysregulation of the NRF2 system in the brain, which contributes to oxidative stress and injury.}, }
@article {pmid24262195, year = {2014}, author = {Liberski, PP}, title = {Prion, prionoids and infectious amyloid.}, journal = {Parkinsonism &amp; related disorders}, volume = {20 Suppl 1}, number = {}, pages = {S80-4}, doi = {10.1016/S1353-8020(13)70021-X}, pmid = {24262195}, issn = {1873-5126}, mesh = {Amyloid/*metabolism ; Brain/*metabolism/pathology ; Humans ; Prion Diseases/metabolism/*pathology ; Prions/chemistry/*metabolism ; Protein Folding ; Proteostasis Deficiencies ; alpha-Synuclein ; }, abstract = {"Amyloid" is a generic term and all amyloids, irrespective of amino acid sequence, are formed in a seeded nucleation mechanism in which a small aggregate (oligomers) of a few amyloid moieties (a seed or a nucleus) seed (nucleate) normal amyloid precursor moieties to change conformation to a β-sheet. All sporadic neurodegenerative disorders are diseases of old age. This epidemiological phenomenon is consistent with a view that spontaneous conformational change from soluble, monomeric precursor protein into an insoluble amyloid aggregate is accomplished via a seeded nucleation process characterized by a long lag phase. Several predictions can be made on the basis of this assumption. First, an increase of the precursor monomer concentration may favor nucleation and, thus, shorten the lag phase. Second, an increase in the number of seeds should lead to amplification of the nucleation reaction. There are several protein misfolding disorders - the most widely known include Alzheimer's disease, Parkinson's disease and other α-synucleinopathies, amyotrophic lateral sclerosis (ALS), frontotemporal dementias in which abnormally phosphorylated MAP-τ protein accumulates and finally, polyglutamine expansion diseases such as Huntington's disease and certain spinocerebellar ataxias. The proteins involved differ in each of these disorders but the molecular mechanism is almost exactly the same, a seeding-nucleation mechanism.}, }
@article {pmid24262168, year = {2014}, author = {Labbé, C and Rayaprolu, S and Soto-Ortolaza, A and Ogaki, K and Uitti, RJ and Wszolek, ZK and Ross, OA}, title = {Investigating FUS variation in Parkinson's disease.}, journal = {Parkinsonism &amp; related disorders}, volume = {20 Suppl 1}, number = {0 1}, pages = {S147-9}, pmid = {24262168}, issn = {1873-5126}, support = {P50 NS072187/NS/NINDS NIH HHS/United States ; R01 NS078086/NS/NINDS NIH HHS/United States ; NINDS R01 #NS078086/NS/NINDS NIH HHS/United States ; NINDS P50 #NS072187/NS/NINDS NIH HHS/United States ; }, mesh = {DNA-Binding Proteins/genetics ; Humans ; Mutation/*genetics ; Parkinson Disease/*genetics ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Mutations of the FUS gene were first reported to cause amyotrophic lateral sclerosis (ALS). Subsequent studies confirmed the role of mutations in ALS and also implicated them in frontotemporal dementia (FTD). Recently, through Next-Generation Exome sequencing approaches a mutation resulting in a substitution (p.Q290X) in the nuclear export domain of the FUS protein was nominated as a cause of autosomal dominant essential tremor (ET) in a large kindred. In addition, recent reports suggest a possible role for TDP-43 mutations in parkinsonism; TDP-43 is another RNA-binding protein implicated in ALS. Given these findings we investigated the role of FUS variants in Parkinson's disease (PD). We sequenced specific regions of the gene encoding three functional domains of the FUS protein in 702 patients with PD. Our sequencing study did not identify any novel non-synonymous variant that would appear to affect the subjects' susceptibility to Parkinson's disease. These findings and previous studies have shown that variants within the FUS gene are not a common cause of PD or ET, in comparison to their role in ALS.}, }
@article {pmid24256261, year = {2013}, author = {Crippa, V and Galbiati, M and Boncoraglio, A and Rusmini, P and Onesto, E and Giorgetti, E and Cristofani, R and Zito, A and Poletti, A}, title = {Motoneuronal and muscle-selective removal of ALS-related misfolded proteins.}, journal = {Biochemical Society transactions}, volume = {41}, number = {6}, pages = {1598-1604}, doi = {10.1042/BST20130118}, pmid = {24256261}, issn = {1470-8752}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Humans ; Motor Neurons/*metabolism/pathology ; Muscles/*metabolism/pathology ; *Protein Folding ; Superoxide Dismutase/chemistry/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {ALS (amyotrophic lateral sclerosis), a fatal motoneuron (motor neuron) disease, occurs in clinically indistinguishable sporadic (sALS) or familial (fALS) forms. Most fALS-related mutant proteins identified so far are prone to misfolding, and must be degraded in order to protect motoneurons from their toxicity. This process, mediated by molecular chaperones, requires proteasome or autophagic systems. Motoneurons are particularly sensitive to misfolded protein toxicity, but other cell types such as the muscle cells could also be affected. Muscle-restricted expression of the fALS protein mutSOD1 (mutant superoxide dismutase 1) induces muscle atrophy and motoneuron death. We found that several genes have an altered expression in muscles of transgenic ALS mice at different stages of disease. MyoD, myogenin, atrogin-1, TGFβ1 (transforming growth factor β1) and components of the cell response to proteotoxicity [HSPB8 (heat shock 22kDa protein 8), Bag3 (Bcl-2-associated athanogene 3) and p62] are all up-regulated by mutSOD1 in skeletal muscle. When we compared the potential mutSOD1 toxicity in motoneuron (NSC34) and muscle (C2C12) cells, we found that muscle ALS models possess much higher chymotryptic proteasome activity and autophagy power than motoneuron ALS models. As a result, mutSOD1 molecular behaviour was found to be very different. MutSOD1 clearance was found to be much higher in muscle than in motoneurons. MutSOD1 aggregated and impaired proteasomes only in motoneurons, which were particularly sensitive to superoxide-induced oxidative stress. Moreover, in muscle cells, mutSOD1 was found to be soluble even after proteasome inhibition. This effect could be associated with a higher mutSOD1 autophagic clearance. Therefore muscle cells seem to manage misfolded mutSOD1 more efficiently than motoneurons, thus mutSOD1 toxicity in muscle may not directly depend on aggregation.}, }
@article {pmid24256260, year = {2013}, author = {Achsel, T and Barabino, S and Cozzolino, M and Carrì, MT}, title = {The intriguing case of motor neuron disease: ALS and SMA come closer.}, journal = {Biochemical Society transactions}, volume = {41}, number = {6}, pages = {1593-1597}, doi = {10.1042/BST20130142}, pmid = {24256260}, issn = {1470-8752}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Humans ; Motor Neurons/metabolism/pathology ; Muscular Atrophy, Spinal/*metabolism/pathology ; RNA, Messenger/metabolism ; }, abstract = {MNDs (motor neuron diseases) form a heterogeneous group of pathologies characterized by the progressive degeneration of motor neurons. More and more genetic factors associated with MND encode proteins that have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a common underlying problem in several, perhaps all, forms of MND. In the present paper we review recent developments showing a functional link between SMN (survival of motor neuron), the causative factor of SMA (spinal muscular atrophy), and FUS (fused in sarcoma), a genetic factor in ALS (amyotrophic lateral sclerosis). SMN is long known to have a crucial role in the biogenesis and localization of the spliceosomal snRNPs (small nuclear ribonucleoproteins), which are essential assembly modules of the splicing machinery. Now we know that FUS interacts with SMN and pathogenic FUS mutations have a significant effect on snRNP localization. Together with other recently published evidence, this finding potentially links ALS pathogenesis to disturbances in the splicing machinery, and implies that pre-mRNA splicing may be the common weak point in MND, although other steps in mRNA metabolism could also play a role. Certainly, further comparison of the RNA metabolism in different MND will greatly help our understanding of the molecular causes of these devastating diseases.}, }
@article {pmid24256250, year = {2013}, author = {Baralle, M and Buratti, E and Baralle, FE}, title = {The role of TDP-43 in the pathogenesis of ALS and FTLD.}, journal = {Biochemical Society transactions}, volume = {41}, number = {6}, pages = {1536-1540}, doi = {10.1042/BST20130186}, pmid = {24256250}, issn = {1470-8752}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/*genetics/metabolism/*pathology ; Humans ; }, abstract = {TDP-43 (TAR DNA-binding protein 43) is an hnRNP (heterogeneous nuclear ribonucleoprotein) protein whose role in cellular processes has come to the forefront of neurodegeneration research after the observation that it is the main component of brain inclusions in ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration) patients. Functionally, this aberrant aggregation and mislocalization implies that, in the affected neurons, transcripts regulated by TDP-43 may be altered. Since then, a considerable amount of data has been gathered on TDP-43 interactions and on the genes that are influenced by its absence or overexpression. At present, however, most of these data come from high-throughput searches, making it problematic to separate the direct effects of TDP-43 from secondary misregulations occurring at different levels of the gene expression process. Furthermore, our knowledge of the biochemistry of TDP-43, its RNA-binding characteristics, its nuclear and cytoplasmic targets, and the details of its interactions with other proteins is still incomplete. The understanding of these features could hold the key for uncovering TDP-43's role in ALS and FTLD pathogenesis. We describe in the present paper our work on TDP-43 RNA binding, self-regulation and aggregation processes, and attempt to relate them to the neurodegenerative pathologies.}, }
@article {pmid24246281, year = {2014}, author = {Hardy, J and Rogaeva, E}, title = {Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {75-83}, doi = {10.1016/j.expneurol.2013.11.006}, pmid = {24246281}, issn = {1090-2430}, mesh = {Animals ; Autophagy/physiology ; DNA/metabolism ; Frontotemporal Dementia/*complications/genetics ; Humans ; Motor Neuron Disease/*complications/genetics ; Mutation/genetics ; Proteins/genetics ; RNA/metabolism ; }, abstract = {Over the last 5 years, several new genes have been described for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While it has long been clear that there are many kindreds in which the two diseases co-occur, there are also many in which the diseases segregate alone. In this brief review, we suggest that keeping the loci which lead to both diseases separate from those which lead to just one gives a clearer conclusion about disease mechanisms than lumping them together. The hypothesis that this separation leads to is that loci which cause both ALS and FTD affect the autophagic machinery leading to damaged protein aggregation and those which lead to just ALS are mainly involved in RNA/DNA metabolism. Two of the genes causing FTD alone (CHMP2B and GRN) are associated with damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology characterized by abnormal tau filaments. We conclude that the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes. This includes the disruption of RNA metabolism in motor neurons and protein clearance, which is common between cortical and motor neurons.}, }
@article {pmid24234359, year = {2013}, author = {Risacher, SL and Saykin, AJ}, title = {Neuroimaging biomarkers of neurodegenerative diseases and dementia.}, journal = {Seminars in neurology}, volume = {33}, number = {4}, pages = {386-416}, pmid = {24234359}, issn = {1098-9021}, support = {R01 AG019771/AG/NIA NIH HHS/United States ; P30 AG10133/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG19771/AG/NIA NIH HHS/United States ; R01 CA101318/CA/NCI NIH HHS/United States ; }, mesh = {AIDS Dementia Complex/*diagnosis ; Alzheimer Disease/*diagnosis ; Amyotrophic Lateral Sclerosis/*diagnosis ; *Biomarkers ; *Brain/metabolism/pathology/physiopathology ; Dementia/*diagnosis ; Dementia, Vascular/*diagnosis ; Frontotemporal Dementia/*diagnosis ; Humans ; Huntington Disease/*diagnosis ; Lewy Body Disease/*diagnosis ; *Magnetic Resonance Imaging ; Multiple Sclerosis/*diagnosis ; *Neuroimaging ; Parkinson Disease/*diagnosis ; *Positron-Emission Tomography ; Prion Diseases/*diagnosis ; *Tomography, Emission-Computed, Single-Photon ; }, abstract = {Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer's disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson's disease with and without dementia, dementia with Lewy bodies, Huntington's disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders.}, }
@article {pmid24228054, year = {2013}, author = {Marciniuk, K and Taschuk, R and Napper, S}, title = {Evidence for prion-like mechanisms in several neurodegenerative diseases: potential implications for immunotherapy.}, journal = {Clinical &amp; developmental immunology}, volume = {2013}, number = {}, pages = {473706}, pmid = {24228054}, issn = {1740-2530}, mesh = {Animals ; Epitopes/immunology ; Humans ; Immunotherapy ; Models, Biological ; Neurodegenerative Diseases/diagnosis/*etiology/*therapy ; PrPC Proteins/immunology/metabolism ; PrPSc Proteins/immunology/metabolism ; Prions/immunology/*pathogenicity ; }, abstract = {Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.}, }
@article {pmid24225313, year = {2014}, author = {Menini, T and Gugliucci, A}, title = {Paraoxonase 1 in neurological disorders.}, journal = {Redox report : communications in free radical research}, volume = {19}, number = {2}, pages = {49-58}, pmid = {24225313}, issn = {1743-2928}, mesh = {Alzheimer Disease/enzymology/genetics ; Animals ; Aryldialkylphosphatase/genetics/*metabolism ; Genotype ; Humans ; Lipoproteins, HDL/metabolism ; Nervous System Diseases/*enzymology/genetics ; Oxidative Stress ; Stroke/enzymology/genetics ; }, abstract = {Paroxonase 1 displays multiple physiological activities that position it as a putative player in the pathogenesis of neurological disorders. Here we reviewed the literature focusing on the role of paraoxonase 1 (PON1) as a factor in the risk of stroke and the major neurodegenerative diseases. PON1 activity is reduced in stroke patients, which significantly correlates inversely with carotid and cerebral atherosclerosis. The presence of the R allele of the Q192R PON1 polymorphism seems to potentiate this risk for stroke. PON1 exerts peroxidase activities that may be important in neurodegenerative disorders associated with oxidative stress. PON1 is also a key detoxifier of organophosphates and organophosphate exposure has been linked to the development of neurological disorders in which acetylcholine plays a significant role. In Parkinson's disease most of the studies suggest no participation of either L55M or the Q192R polymorphisms in its pathogenesis. However, many studies suggest that the MM55 PON1 genotype is associated with a higher risk for Parkinson's disease in individuals exposed to organophosphates. In Alzheimer's disease most studies have failed to find any association between PON1 polymorphisms and the development of the disease. Some studies show that PON1 activity is decreased in patients with Alzheimer's disease or other dementias, suggesting a possible protective role of PON1. No links between PON1 polymorphisms or activity have been found in other neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis. PON1 is a potential player in the pathogenesis of several neurological disorders. More research is warranted to ascertain the precise pathogenic links and the prognostic value of its measurement in neurological patients.}, }
@article {pmid24218324, year = {2014}, author = {Chiurchiù, V and Maccarrone, M and Orlacchio, A}, title = {The role of reticulons in neurodegenerative diseases.}, journal = {Neuromolecular medicine}, volume = {16}, number = {1}, pages = {3-15}, pmid = {24218324}, issn = {1559-1174}, support = {GGP10121/TI_/Telethon/Italy ; }, mesh = {Animals ; Apoptosis/physiology ; Autophagy/physiology ; Carrier Proteins/physiology ; Endoplasmic Reticulum/metabolism/ultrastructure ; Forecasting ; Humans ; Hydrophobic and Hydrophilic Interactions ; Intracellular Membranes/metabolism/ultrastructure ; Membrane Proteins/physiology ; Multigene Family ; Myelin Proteins/physiology ; Nerve Tissue Proteins/chemistry/classification/*physiology ; Neurodegenerative Diseases/*metabolism ; Neurogenesis/physiology ; Nogo Proteins ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Structure-Activity Relationship ; }, abstract = {Reticulons (RTNs) are a group of membrane-associated proteins mainly responsible for shaping the tubular endoplasmic reticulum network, membrane trafficking, inhibition of axonal growth, and apoptosis. These proteins share a common sequence feature, the reticulon homology domain, which consists of paired hydrophobic stretches that are believed to induce membrane curvature by acting as a wedge in bilayer membranes. RTNs are ubiquitously expressed in all tissues, but each RTN member exhibits a unique expression pattern that prefers certain tissues or even cell types. Recently, accumulated evidence has suggested additional and unexpected roles for RTNs, including those on DNA binding, autophagy, and several inflammatory-related functions. These manifold actions of RTNs account for their ever-growing recognition of their involvement in neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as hereditary spastic paraplegia. This review summarizes the latest discoveries on RTNs in human pathophysiology, and the engagement of these in neurodegeneration, along with the implications of these findings for a better understanding of the molecular events triggered by RTNs and their potential exploitation as next-generation therapeutics.}, }
@article {pmid24217521, year = {2013}, author = {Braak, H and Brettschneider, J and Ludolph, AC and Lee, VM and Trojanowski, JQ and Del Tredici, K}, title = {Amyotrophic lateral sclerosis--a model of corticofugal axonal spread.}, journal = {Nature reviews. Neurology}, volume = {9}, number = {12}, pages = {708-714}, pmid = {24217521}, issn = {1759-4766}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; K08 AG039510/AG/NIA NIH HHS/United States ; AG010124/AG/NIA NIH HHS/United States ; K08 AG033101/AG/NIA NIH HHS/United States ; AG039510/AG/NIA NIH HHS/United States ; NS044266/NS/NINDS NIH HHS/United States ; R01 NS044266/NS/NINDS NIH HHS/United States ; P01 AG032953/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; AG017586/AG/NIA NIH HHS/United States ; AG032953/AG/NIA NIH HHS/United States ; AG033101/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Axonal Transport/*physiology ; Axons/physiology ; Cerebral Cortex/*metabolism/pathology ; DNA-Binding Proteins/*metabolism ; Humans ; *Models, Neurological ; Synaptic Transmission/*physiology ; }, abstract = {The pathological process underlying amyotrophic lateral sclerosis (ALS) is associated with the formation of cytoplasmic inclusions consisting mainly of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43), which plays an essential part in the pathogenesis of ALS. Preliminary evidence indicates that neuronal involvement progresses at different rates, but in a similar sequence, in different patients with ALS. This observation supports the emerging concept of prion-like propagation of abnormal proteins in noninfectious neurodegenerative diseases. Although the distance between involved regions is often considerable, the affected neurons are connected by axonal projections, indicating that physical contacts between nerve cells along axons are important for dissemination of ALS pathology. This article posits that the trajectory of the spreading pattern is consistent with the induction and dissemination of pTDP-43 pathology chiefly from cortical neuronal projections, via axonal transport, through synaptic contacts to the spinal cord and other regions of the brain.}, }
@article {pmid24211851, year = {2014}, author = {Ghavami, S and Shojaei, S and Yeganeh, B and Ande, SR and Jangamreddy, JR and Mehrpour, M and Christoffersson, J and Chaabane, W and Moghadam, AR and Kashani, HH and Hashemi, M and Owji, AA and Łos, MJ}, title = {Autophagy and apoptosis dysfunction in neurodegenerative disorders.}, journal = {Progress in neurobiology}, volume = {112}, number = {}, pages = {24-49}, doi = {10.1016/j.pneurobio.2013.10.004}, pmid = {24211851}, issn = {1873-5118}, mesh = {Animals ; *Apoptosis ; *Autophagy ; Brain/pathology/*physiopathology ; Brain Diseases/pathology/*physiopathology ; Humans ; Neurodegenerative Diseases/pathology/*physiopathology ; Neurons/*pathology ; Peripheral Nervous System Diseases/pathology/*physiopathology ; }, abstract = {Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.}, }
@article {pmid24210139, year = {2013}, author = {Magen, I and Gozes, I}, title = {Microtubule-stabilizing peptides and small molecules protecting axonal transport and brain function: focus on davunetide (NAP).}, journal = {Neuropeptides}, volume = {47}, number = {6}, pages = {489-495}, doi = {10.1016/j.npep.2013.10.011}, pmid = {24210139}, issn = {1532-2785}, mesh = {Animals ; Antineoplastic Agents/therapeutic use ; Axonal Transport/*drug effects ; Brain/metabolism ; Clinical Trials as Topic ; Humans ; Mice ; Microtubules/*drug effects ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neuroprotective Agents/*therapeutic use ; Oligopeptides/*therapeutic use ; Rats ; Tauopathies/drug therapy/metabolism ; Tubulin Modulators/*therapeutic use ; tau Proteins/metabolism ; }, abstract = {This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (davunetide) are reviewed paving the path to future developments.}, }
@article {pmid24206195, year = {2014}, author = {Grubman, A and White, AR and Liddell, JR}, title = {Mitochondrial metals as a potential therapeutic target in neurodegeneration.}, journal = {British journal of pharmacology}, volume = {171}, number = {8}, pages = {2159-2173}, pmid = {24206195}, issn = {1476-5381}, mesh = {Cations/therapeutic use ; Chelating Agents/therapeutic use ; Homeostasis ; Humans ; Mitochondria/drug effects/metabolism/*physiology ; Molecular Targeted Therapy/*methods ; Neurodegenerative Diseases/drug therapy/*physiopathology ; Transition Elements/*metabolism ; }, abstract = {Transition metals are critical for enzyme function and protein folding, but in excess can mediate neurotoxic oxidative processes. As mitochondria are particularly vulnerable to oxidative damage due to radicals generated during ATP production, mitochondrial biometal homeostasis must therefore be tightly controlled to safely harness the redox potential of metal enzyme cofactors. Dysregulation of metal functions is evident in numerous neurological disorders including Alzheimer's disease, stroke, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedrich's ataxia. This review describes the mitochondrial metal defects in these disorders and highlights novel metal-based therapeutic approaches that target mitochondrial metal homeostasis in neurological disorders.}, }
@article {pmid24198349, year = {2013}, author = {Schwartz, M and Kipnis, J and Rivest, S and Prat, A}, title = {How do immune cells support and shape the brain in health, disease, and aging?.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {33}, number = {45}, pages = {17587-17596}, pmid = {24198349}, issn = {1529-2401}, support = {R01 NS081026/NS/NINDS NIH HHS/United States ; NS081026/NS/NINDS NIH HHS/United States ; /CAPMC/CIHR/Canada ; }, mesh = {Aging/*immunology/pathology ; Brain/*immunology/pathology ; Central Nervous System Diseases/*immunology/pathology ; Humans ; Macrophages/*immunology/pathology ; Microglia/*immunology/pathology ; Neurodegenerative Diseases/immunology/pathology ; }, abstract = {For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed.}, }
@article {pmid24198230, year = {2014}, author = {Pansarasa, O and Rossi, D and Berardinelli, A and Cereda, C}, title = {Amyotrophic lateral sclerosis and skeletal muscle: an update.}, journal = {Molecular neurobiology}, volume = {49}, number = {2}, pages = {984-990}, pmid = {24198230}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Astrocytes/metabolism/pathology ; Humans ; Mitochondria/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Muscle, Skeletal/*metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons (MNs), generalized weakness and muscle atrophy. The "neurocentric" view of ALS assumes that the disease primarily affects motor neurons, while muscle alterations only represent a consequence, in the periphery, of motor neuron loss. However, this outlook was recently challenged by evidence suggesting that non-neural cells such as microglia, astrocytes, peripheral blood mononuclear cells (PBMCs) and skeletal muscle fibres participate in triggering motor neuron degeneration, and this stressed the concept that alterations in different cell types may act together to exacerbate the disease. In this review, we will summarize the most recent findings on the alterations of skeletal muscle fibres found in ALS, with particular attention to the relationship between mutant SOD1 and skeletal muscle. We will analyze changes in muscle function, in the expression of myogenic regulatory factors, and also mitochondrial dysfunction, SOD1 aggregation and proteasome activity.}, }
@article {pmid24198229, year = {2014}, author = {Veyrat-Durebex, C and Corcia, P and Dangoumau, A and Laumonnier, F and Piver, E and Gordon, PH and Andres, CR and Vourc'h, P and Blasco, H}, title = {Advances in cellular models to explore the pathophysiology of amyotrophic lateral sclerosis.}, journal = {Molecular neurobiology}, volume = {49}, number = {2}, pages = {966-983}, pmid = {24198229}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/*physiopathology ; Animals ; Astrocytes/metabolism/*pathology ; Cell Culture Techniques ; Cell Line ; Coculture Techniques ; Humans ; Neuroglia/metabolism/pathology ; Neurons/metabolism/*pathology ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, is fatal for most patients less than 3 years from when the first symptoms appear. The aetiologies for sporadic and most familial forms of ALS are unknown, but genetic factors are increasingly recognized as causal in a subset of patients. Studies of disease physiology suggest roles for oxidative stress, glutamate-mediated excitotoxicity or protein aggregation; how these pathways interact in the complex pathophysiology of ALS awaits elucidation. Cellular models are being used to examine disease mechanisms. Recent advances include the availability of expanded cell types, from neuronal or glial cell culture to motoneuron-astrocyte co-culture genetically or environmentally modified. Cell culture experiments confirmed the central role of glial cells in ALS. The recent adaptation of induced pluripotent stem cells (iPSC) for ALS modeling could allow a broader perspective and is expected to generate new hypotheses, related particularly to mechanisms underlying genetic factors. Cellular models have provided meaningful advances in the understanding of ALS, but, to date, complete characterization of in vitro models is only partially described. Consensus on methodological approaches, strategies for validation and techniques that allow rapid adaptation to new genetic or environmental influences is needed. In this article, we review the principal cellular models being employed in ALS and highlight their contribution to the understanding of disease mechanisms. We conclude with recommendations on means to enhance the robustness and generalizability of the different concepts for experimental ALS.}, }
@article {pmid24187553, year = {2013}, author = {Fernández-Borges, N and Eraña, H and Elezgarai, SR and Harrathi, C and Gayosso, M and Castilla, J}, title = {Infectivity versus Seeding in Neurodegenerative Diseases Sharing a Prion-Like Mechanism.}, journal = {International journal of cell biology}, volume = {2013}, number = {}, pages = {583498}, pmid = {24187553}, issn = {1687-8876}, abstract = {Prions are considered the best example to prove that the biological information can be transferred protein to protein through a conformational change. The term "prion-like" is used to describe molecular mechanisms that share similarities with the mammalian prion protein self-perpetuating aggregation and spreading characteristics. Since prions are presumably composed only of protein and are infectious, the more similar the mechanisms that occur in the different neurodegenerative diseases, the more these processes will resemble an infection. In vitro and in vivo experiments carried out during the last decade in different neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's diseases (PD), and amyotrophic lateral sclerosis (ALS) have shown a convergence toward a unique mechanism of misfolded protein propagation. In spite of the term "infection" that could be used to explain the mechanism governing the diversity of the pathological processes, other concepts as "seeding" or "de novo induction" are being used to describe the in vivo propagation and transmissibility of misfolded proteins. The current studies are demanding an extended definition of "disease-causing agents" to include those already accepted as well as other misfolded proteins. In this new scenario, "seeding" would be a type of mechanism by which an infectious agent can be transmitted but should not be used to define a whole "infection" process.}, }
@article {pmid24187495, year = {2013}, author = {Wu, M and Kalyanasundaram, A and Zhu, J}, title = {Structural and biomechanical basis of mitochondrial movement in eukaryotic cells.}, journal = {International journal of nanomedicine}, volume = {8}, number = {}, pages = {4033-4042}, pmid = {24187495}, issn = {1178-2013}, mesh = {*Actin Cytoskeleton ; Animals ; Arabidopsis ; *Biomechanical Phenomena ; Drosophila ; *Eukaryotic Cells/cytology/physiology ; *Microtubules ; *Mitochondria ; Movement ; Saccharomycetales ; }, abstract = {Mitochondria serve as energy-producing organelles in eukaryotic cells. In addition to providing the energy supply for cells, the mitochondria are also involved in other processes, such as proliferation, differentiation, information transfer, and apoptosis, and play an important role in regulation of cell growth and the cell cycle. In order to achieve these functions, the mitochondria need to move to the corresponding location. Therefore, mitochondrial movement has a crucial role in normal physiologic activity, and any mitochondrial movement disorder will cause irreparable damage to the organism. For example, recent studies have shown that abnormal movement of the mitochondria is likely to be the reason for Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and schizophrenia. So, in the cell, especially in the particular polarized cell, the appropriate distribution of mitochondria is crucial to the function and survival of the cell. Mitochondrial movement is mainly associated with the cytoskeleton and related proteins. However, those components play different roles according to cell type. In this paper, we summarize the structural basis of mitochondrial movement, including microtubules, actin filaments, motor proteins, and adaptin, and review studies of the biomechanical mechanisms of mitochondrial movement in different types of cells.}, }
@article {pmid24182381, year = {2013}, author = {McCluskey, L}, title = {Ethical issues in states of impaired communication with intact consciousness and language.}, journal = {Handbook of clinical neurology}, volume = {118}, number = {}, pages = {225-231}, doi = {10.1016/B978-0-444-53501-6.00019-6}, pmid = {24182381}, issn = {0072-9752}, mesh = {Adult ; Central Nervous System Diseases/*complications/therapy ; Consciousness ; Humans ; Language ; Neurology/*ethics ; Paralysis ; Withholding Treatment/*ethics ; }, abstract = {Acute and chronic peripheral and/or central disorders of the voluntary motor system can produce profound paresis or paralysis, at times with ophthalmoplegia, while preserving consciousness and language function. Although at times appearing to be unconscious, these patients are awake and alert but unable to communicate, manipulate their environment, or participate in medical decision-making. Clinicians caring for these patients are ethically tasked with recognizing this clinical reality, enacting measures to facilitate communication, and abiding by ethical and legal principles that support autonomous patient-centered decision-making. This chapter reviews the various disorders that may cause this state while using three exemplary disorders - locked-in syndrome, caused by an anterior pontine lesion; high cervical spinal cord lesion; and amyotrophic lateral sclerosis - to discuss the management of these patients.}, }
@article {pmid24182372, year = {2013}, author = {Lorenzl, S and Nübling, G and Perrar, KM and Voltz, R}, title = {Palliative treatment of chronic neurologic disorders.}, journal = {Handbook of clinical neurology}, volume = {118}, number = {}, pages = {133-139}, doi = {10.1016/B978-0-444-53501-6.00010-X}, pmid = {24182372}, issn = {0072-9752}, mesh = {Chronic Disease ; Humans ; Nervous System Diseases/*therapy ; Palliative Care/*methods ; }, abstract = {Patients with chronic neurologic disorders suffer from the burden of disease progression without the hope for a cure. Therefore, symptom management and palliative care approaches should be included from the beginning of the illness. Palliative care aims at improving a patient's quality of life by alleviating suffering due to physical, psychosocial, and spiritual factors. Since no curative and only limited life-prolonging treatment options are available for most chronic neurologic disorders, a palliative care approach can help to create a treatment plan that considers all aspects of the disease. We have provided palliative care approaches for the most common neurodegenerative disorders like dementia, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. A palliative approach to neurologic disorders does not simply mean limiting treatment and focusing on pain. Instead, the whole unit of care, consisting of the patient, relatives, and caregivers, should be perceived with all their needs.}, }
@article {pmid24179604, year = {2013}, author = {Kanno, H}, title = {Regenerative therapy for neuronal diseases with transplantation of somatic stem cells.}, journal = {World journal of stem cells}, volume = {5}, number = {4}, pages = {163-171}, pmid = {24179604}, issn = {1948-0210}, abstract = {Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem (ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease, cerebral infarction and congenital neuronal diseases. Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However, non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors, gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here, the recent progress of regenerative therapies using various somatic stem cells is described.}, }
@article {pmid24177067, year = {2014}, author = {Keifer, OP and O'Connor, DM and Boulis, NM}, title = {Gene and protein therapies utilizing VEGF for ALS.}, journal = {Pharmacology &amp; therapeutics}, volume = {141}, number = {3}, pages = {261-271}, pmid = {24177067}, issn = {1879-016X}, support = {T32 GM008169/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Design ; Gene Expression Regulation ; Genetic Therapy/*methods ; Humans ; Mice ; Proteins/pharmacology/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Vascular Endothelial Growth Factor A/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2-5years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.}, }
@article {pmid24176417, year = {2013}, author = {Harms, MB and Baloh, RH}, title = {Clinical neurogenetics: amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {31}, number = {4}, pages = {929-950}, pmid = {24176417}, issn = {1557-9875}, support = {K08 NS055980/NS/NINDS NIH HHS/United States ; K08 NS075094/NS/NINDS NIH HHS/United States ; NS075094/NS/NINDS NIH HHS/United States ; R01 NS069669/NS/NINDS NIH HHS/United States ; NS069669/NS/NINDS NIH HHS/United States ; NS055980/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Humans ; }, abstract = {Our understanding of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is expanding rapidly as its genetic causes are uncovered. The pace of new gene discovery over the last 5 years has accelerated, providing new insights into the pathogenesis of disease and highlighting biological pathways as targets for therapeutic development. This article reviews our current understanding of the heritability of ALS and provides an overview of each of the major ALS genes, highlighting their phenotypic characteristics and frequencies as a guide for clinicians evaluating patients with ALS.}, }
@article {pmid24171950, year = {2014}, author = {Genç, B and Özdinler, PH}, title = {Moving forward in clinical trials for ALS: motor neurons lead the way please.}, journal = {Drug discovery today}, volume = {19}, number = {4}, pages = {441-449}, pmid = {24171950}, issn = {1878-5832}, support = {R01 AG017139/AG/NIA NIH HHS/United States ; T32 AG020506/AG/NIA NIH HHS/United States ; 5T32AG020506-09/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Animals ; Clinical Trials as Topic ; Glutamic Acid/metabolism ; Humans ; Mitochondria/physiology ; Motor Neurons/*physiology ; Nerve Growth Factors/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most complex motor neuron diseases. Even though scientific discoveries are accelerating with an unprecedented pace, to date more than 30 clinical trials have ended with failure and staggering frustration. There are too many compounds that increase life span in mice, but too little evidence that they will improve human condition. Increasing the chances of success for future clinical trials requires advancement of preclinical tests. Recent developments, which enable the visualization of diseased motor neurons, have the potential to bring novel insight. As we change our focus from mice to motor neurons, it is possible to foster a new vision that translates into effective and long-term treatment strategies in ALS and related motor neuron disorders (MND).}, }
@article {pmid24167857, year = {2013}, author = {Aoki, M}, title = {[New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 10. Amyotrophic lateral sclerosis].}, journal = {Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine}, volume = {102}, number = {8}, pages = {1978-1985}, doi = {10.2169/naika.102.1978}, pmid = {24167857}, issn = {0021-5384}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/genetics/*metabolism ; Animals ; Genetic Predisposition to Disease ; Hepatocyte Growth Factor/therapeutic use ; Humans ; Mutation/genetics ; Pedigree ; Superoxide Dismutase/deficiency/metabolism ; Superoxide Dismutase-1 ; }, }
@article {pmid24167726, year = {2013}, author = {Baek, GH and Cheng, H and Choe, V and Bao, X and Shao, J and Luo, S and Rao, H}, title = {Cdc48: a swiss army knife of cell biology.}, journal = {Journal of amino acids}, volume = {2013}, number = {}, pages = {183421}, pmid = {24167726}, issn = {2090-0104}, support = {P30 CA054174/CA/NCI NIH HHS/United States ; R01 GM078085/GM/NIGMS NIH HHS/United States ; }, abstract = {Cdc48 (also called VCP and p97) is an abundant protein that plays essential regulatory functions in a broad array of cellular processes. Working with various cofactors, Cdc48 utilizes its ATPase activity to promote the assembly and disassembly of protein complexes. Here, we review key biological functions and regulation of Cdc48 in ubiquitin-related events. Given the broad employment of Cdc48 in cell biology and its intimate ties to human diseases (e.g., amyotrophic lateral sclerosis), studies of Cdc48 will bring significant insights into the mechanism and function of ubiquitin in health and diseases.}, }
@article {pmid24164678, year = {2014}, author = {Hadzhieva, M and Kirches, E and Mawrin, C}, title = {Review: iron metabolism and the role of iron in neurodegenerative disorders.}, journal = {Neuropathology and applied neurobiology}, volume = {40}, number = {3}, pages = {240-257}, doi = {10.1111/nan.12096}, pmid = {24164678}, issn = {1365-2990}, mesh = {Animals ; Humans ; Iron/*metabolism ; Metabolic Diseases/metabolism ; Mitochondria/metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Iron plays a role for the biogenesis of two important redox-reactive prosthetic groups of enzymes, iron sulphur clusters (ISC) and heme. A part of these biosynthetic pathways takes plays in the mitochondria. While several important proteins of cellular iron uptake and storage and of mitochondrial iron metabolism are well-characterized, limited knowledge exists regarding the mitochondrial iron importers (mitoferrins). A disturbed distribution of iron, hampered Fe-dependent biosynthetic pathways and eventually oxidative stress resulting from an increased labile iron pool are suggested to play a role in several neurodegenerative diseases. Friedreich's ataxia is associated with mitochondrial iron accumulation and hampered ISC/heme biogenesis due to reduced frataxin expression, thus representing a monogenic mitochondrial disorder, which is clearly elicited solely by a disturbed iron metabolism. Less clear are the controversially discussed impacts of iron dysregulation and iron-dependent oxidative stress in the most common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Amyotrophic lateral sclerosis (ALS) may be viewed as a disease offering a better support for a direct link between iron, oxidative stress and regional neurodegeneration. Altogether, despite significant progress in molecular knowledge, the true impact of iron on the sporadic forms of AD, PD and ALS is still uncertain. Here we summarize the current knowledge of iron metabolism disturbances in neurodegenerative disorders.}, }
@article {pmid24161471, year = {2014}, author = {Rodrigues, MC and Sanberg, PR and Cruz, LE and Garbuzova-Davis, S}, title = {The innate and adaptive immunological aspects in neurodegenerative diseases.}, journal = {Journal of neuroimmunology}, volume = {269}, number = {1-2}, pages = {1-8}, doi = {10.1016/j.jneuroim.2013.09.020}, pmid = {24161471}, issn = {1872-8421}, mesh = {Adaptive Immunity/*physiology ; Animals ; Humans ; Immunity, Innate/*physiology ; Neurodegenerative Diseases/*immunology/metabolism ; }, abstract = {Neurodegenerative diseases affect a considerable percentage of the elderly population. New therapeutic approaches are warranted, aiming to at least delay and possibly reverse disease progression. Strategies to elaborate such approaches require knowledge of specific immune system involvement in disease pathogenesis. In this review, innate and adaptive immunological aspects of neurodegenerative disorders, in particular Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), are discussed. Initiating disease factors, as well as common mechanistic pathways, are detailed and potential immunological therapeutic targets are identified.}, }
@article {pmid24157492, year = {2014}, author = {Ramírez-Jarquín, UN and Lazo-Gómez, R and Tovar-Y-Romo, LB and Tapia, R}, title = {Spinal inhibitory circuits and their role in motor neuron degeneration.}, journal = {Neuropharmacology}, volume = {82}, number = {}, pages = {101-107}, doi = {10.1016/j.neuropharm.2013.10.003}, pmid = {24157492}, issn = {1873-7064}, mesh = {Animals ; Anterior Horn Cells/physiology ; Humans ; Motor Neuron Disease/*physiopathology ; Motor Neurons/*physiology ; Nerve Degeneration/*physiopathology ; Neural Inhibition/*physiology ; Renshaw Cells/physiology ; Spinal Cord/*physiopathology ; }, abstract = {In the spinal cord neuronal activity is controlled by the balance between excitatory and inhibitory neurotransmission, mediated mainly by the neurotransmitters glutamate and GABA/glycine, respectively. Alterations of this equilibrium have been associated with spinal motor neuron hyperexcitability and degeneration, which can be induced by excitotoxicity or by decreasing inhibitory neurotransmission. Here we review the ventral horn neuronal network and the possible involvement of inhibitory circuits in the mechanisms of degeneration of motor neurons characteristic of amyotrophic lateral sclerosis (ALS). Whereas glutamate mediated excitotoxicity seems to be an important factor, recent experimental and histopathological evidence argue in favor of a decreased activity of the inhibitory circuits controlling motor neuron excitability, mainly the recurrent inhibition exerted by Renshaw cells. A decreased Renshaw cell activity may be caused by cell loss or by a reduction of its inhibitory action secondary to a decreased excitation from cholinergic interneurons. Ultimately, inhibitory failure by either mechanism might lead to motor neuron degeneration, and this suggests inhibitory circuits and Renshaw cells as pharmacologic targets for ALS treatment.}, }
@article {pmid24154801, year = {2013}, author = {Finsterer, J and Stöllberger, C}, title = {Unclassified cardiomyopathies in neuromuscular disorders.}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {163}, number = {21-22}, pages = {505-513}, pmid = {24154801}, issn = {1563-258X}, mesh = {Cardiomyopathies/*classification/*diagnosis/therapy ; Heart Ventricles/pathology ; Humans ; Isolated Noncompaction of the Ventricular Myocardium ; Myocardium/pathology ; Neuromuscular Diseases/*classification/*diagnosis/therapy ; Takotsubo Cardiomyopathy/classification/diagnosis/therapy ; Ventricular Dysfunction, Left/classification/diagnosis/therapy ; }, abstract = {OBJECTIVES: Unclassified cardiomyopathies (CMPs) include left ventricular hypertrabeculation or noncompaction (LVHT) and Takotsubo syndrome (TTS). Unclassified CMPs are frequently associated with noncardiac disease, including neuromuscular disorders (NMDs). This review aims at summarizing and discussing recent findings concerning the association of NMDs with unclassified CMPs.<br><br>METHODS: Literature search using the database PubMed from 1966 to June 2013 was performed.<br><br>RESULTS: LVHT has been described in association with dystrophinopathies, myotonic dystrophies, zaspopathies, laminopathies, dystrobrevinopathies, oculopharyngeal muscular dystrophy, tropomyosin-1 mutations, multiminicore disease, Danon disease, mitochondrial disorders, myoadenylate deaminase deficiency, Pompe's disease, glycogen storage disease-IV, fatty acid oxidation disorder, Barth syndrome, ryanodine receptor mutation, inclusion body myopathy, dystrophic epidermolysis bullosa, Charcot-Marie-Tooth neuropathy, hereditary cobolamine deficiency, beta-thalassemia, poliomyelitis, and Friedreich ataxia. Takotsubo syndrome has been described in association with myasthenia gravis, amyotrophic lateral sclerosis, Guillain-Barre syndrome, rhabdomyolysis, mitochondrial disorder, hypokalemia-related myopathy, syndrome malin, hereditary sensorimotor neuropathy, Beals syndrome, polymyalgia rheumatica, and unclassified myopathy. It is important for treating physicians to know about these associations because treatment and outcome of LVHT, including artificial ventilation, are determined by the presence or absence of an NMD. There are also indications that LVHT in NMDs favors the development of TTS.<br><br>CONCLUSIONS: LVHT and TTS may be associated with NMDs. The pathogenetic link between unclassified CMPs and NMDs remains elusive. Outcome of LVHT and treatment of TTS are additionally determined by the presence or absence of an NMD.}, }
@article {pmid24151849, year = {2013}, author = {Höglund, K and Salter, H}, title = {Molecular biomarkers of neurodegeneration.}, journal = {Expert review of molecular diagnostics}, volume = {13}, number = {8}, pages = {845-861}, doi = {10.1586/14737159.2013.850033}, pmid = {24151849}, issn = {1744-8352}, mesh = {Alzheimer Disease/*diagnosis/metabolism/pathology ; Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/pathology ; Biomarkers/metabolism ; Clinical Trials as Topic ; Humans ; Multiple Sclerosis/*diagnosis/metabolism/pathology ; Nerve Tissue Proteins/*metabolism ; Neurons/metabolism/pathology ; Parkinson Disease/*diagnosis/metabolism/pathology ; }, abstract = {Neuronal dysfunction and degeneration are central events of a number of major diseases with significant unmet need. Neuronal dysfunction may not necessarily be the result of cell death, but may also be due to synaptic damage leading to impaired neuronal cell signaling or long-term potentiation. Once degeneration occurs, it is unclear whether axonal or synaptic loss comes first or whether this precedes neuronal cell death. In this review we summarize the pathophysiology of four major neurodegenerative diseases; Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig's disease) For each of these diseases, we describe how biochemical biomarkers are currently understood in relation to the pathophysiology and in terms of neuronal biology, and we discuss the clinical and diagnostic utility of these potential tools, which are at present limited. We discuss how markers may be used to drive drug development and clinical practice.}, }
@article {pmid24148693, year = {2013}, author = {Meamar, R and Nasr-Esfahani, MH and Mousavi, SA and Basiri, K}, title = {Stem cell therapy in amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {20}, number = {12}, pages = {1659-1663}, doi = {10.1016/j.jocn.2013.04.024}, pmid = {24148693}, issn = {1532-2653}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology ; Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons, characterized by progressive muscular atrophy and weakness which culminates in death within 2-5 years. Despite various hypotheses about the responsible mechanisms, the etiology of ALS remains incompletely understood. However, it has been recently postulated that stem cell therapy could potentially target several mechanisms responsible for the etiology of ALS and other nervous system disorders, and could be regarded as one of the most promising therapeutic strategies for ALS treatment. We present a brief review of different methods of stem cell therapy in ALS patients and discuss the results with different cell types and routes of administration.}, }
@article {pmid24148000, year = {2014}, author = {Muyderman, H and Chen, T}, title = {Mitochondrial dysfunction in amyotrophic lateral sclerosis - a valid pharmacological target?.}, journal = {British journal of pharmacology}, volume = {171}, number = {8}, pages = {2191-2205}, pmid = {24148000}, issn = {1476-5381}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/*physiopathology ; Animals ; Calcium/metabolism ; Cell Death/physiology ; Energy Metabolism/physiology ; Glutathione/metabolism ; Homeostasis ; Humans ; Mitochondria/drug effects/metabolism/*physiology ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Molecular Targeted Therapy/*methods ; Mutation ; Oxidative Stress/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics and calcium homeostasis. Converging evidence suggests that impaired mitochondrial function could be pivotal in the rapid neurodegeneration of this condition. In this review, we provide an update of recent advances in understanding mitochondrial biology in the pathogenesis of ALS and highlight the therapeutic value of pharmacologically targeting mitochondrial biology to slow disease progression.}, }
@article {pmid24140266, year = {2014}, author = {van den Heuvel, DM and Harschnitz, O and van den Berg, LH and Pasterkamp, RJ}, title = {Taking a risk: a therapeutic focus on ataxin-2 in amyotrophic lateral sclerosis?.}, journal = {Trends in molecular medicine}, volume = {20}, number = {1}, pages = {25-35}, doi = {10.1016/j.molmed.2013.09.001}, pmid = {24140266}, issn = {1471-499X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/therapy ; Animals ; Ataxins ; DNA-Binding Proteins/genetics/metabolism/toxicity ; Humans ; Motor Neurons/metabolism ; Nerve Tissue Proteins/*genetics/*metabolism ; Peptides ; Protein Binding ; RNA/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Risk Factors ; Trinucleotide Repeat Expansion ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of lower and upper motor neurons leading to progressive muscle weakness and respiratory insufficiency. No treatment is currently available to cure ALS. Recent progress has led to the identification of several novel genetic determinants of this disease, including repeat expansions in the ataxin-2 (ATXN2) gene. Ataxin-2 is mislocalized in ALS patients and represents a relatively common susceptibility gene in ALS, making it a promising therapeutic target. In this review, we summarize genetic and pathological data implicating ataxin-2 in ALS, discuss potential disease mechanisms linked to altered ataxin-2 localization or function, and propose potential strategies for therapeutic intervention in ALS based on ataxin-2.}, }
@article {pmid24133413, year = {2013}, author = {Goodall, EF and Heath, PR and Bandmann, O and Kirby, J and Shaw, PJ}, title = {Neuronal dark matter: the emerging role of microRNAs in neurodegeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {178}, pmid = {24133413}, issn = {1662-5102}, support = {G-1202/PUK_/Parkinson's UK/United Kingdom ; MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {MicroRNAs (miRNAs) are small, abundant RNA molecules that constitute part of the cell's non-coding RNA "dark matter." In recent years, the discovery of miRNAs has revolutionised the traditional view of gene expression and our understanding of miRNA biogenesis and function has expanded. Altered expression of miRNAs is increasingly recognized as a feature of many disease states, including neurodegeneration. Here, we review the emerging role for miRNA dysfunction in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease pathogenesis. We emphasize the complex nature of gene regulatory networks and the need for systematic studies, with larger sample cohorts than have so far been reported, to reveal the most important miRNA regulators in disease. Finally, miRNA diversity and their potential to target multiple pathways, offers novel clinical applications for miRNAs as biomarkers and therapeutic agents in neurodegenerative diseases.}, }
@article {pmid24126629, year = {2013}, author = {Al-Chalabi, A and Hardiman, O}, title = {The epidemiology of ALS: a conspiracy of genes, environment and time.}, journal = {Nature reviews. Neurology}, volume = {9}, number = {11}, pages = {617-628}, pmid = {24126629}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; *Gene-Environment Interaction ; Humans ; Risk Factors ; Time ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death from respiratory failure occurs after about 3 years. Although great advances have been made in our understanding of the genetic causes of ALS, the contribution of environmental factors has been more difficult to assess. Large-scale studies of the clinical patterns of ALS, individual histories preceding the onset of ALS, and the rates of ALS in different populations and groups have led to improved patient care, but have not yet revealed a replicable, definitive environmental risk factor. In this Review, we outline what is currently known of the environmental and genetic epidemiology of ALS, describe the current state of the art with respect to the different types of ALS, and explore whether ALS should be considered a single disease or a syndrome. We examine the relationship between genetic and environmental risk factors, and propose a disease model in which ALS is considered to be the result of environmental risks and time acting on a pre-existing genetic load, followed by an automatic, self-perpetuating decline to death.}, }
@article {pmid24124634, year = {2013}, author = {Gordon, PH}, title = {Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials.}, journal = {Aging and disease}, volume = {4}, number = {5}, pages = {295-310}, pmid = {24124634}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course.}, }
@article {pmid24123880, year = {2014}, author = {Tury, A and Tolentino, K and Zou, Y}, title = {Altered expression of atypical PKC and Ryk in the spinal cord of a mouse model of amyotrophic lateral sclerosis.}, journal = {Developmental neurobiology}, volume = {74}, number = {8}, pages = {839-850}, pmid = {24123880}, issn = {1932-846X}, support = {R01 NS047484/NS/NINDS NIH HHS/United States ; R37 NS047484/NS/NINDS NIH HHS/United States ; R56 NS047484/NS/NINDS NIH HHS/United States ; NS 047484/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Disease Models, Animal ; Humans ; Neurons/*metabolism ; Protein Kinase C/*metabolism ; Receptor Protein-Tyrosine Kinases/*metabolism ; Signal Transduction/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis due to the selective death of motor neurons of unknown causes. Increasing evidence indicates that Wnt signaling is altered in ALS. In this study, we focused on two non-canonical Wnt signaling components, atypical PKC (aPKC) and a Wnt receptor, Ryk, in a mouse model of ALS, SOD1 (G93A). aPKC mediates Wnt signaling to regulate growth cone guidance, axon differentiation and cell survival. Ryk is a Wnt repulsive receptor that regulates axon guidance and inhibits regeneration after spinal cord injury. aPKC expression was increased in motor neurons of the lumbar spinal cord in SOD1 (G93A) mice at both early and late stages. Interestingly, aPKC was co-localized with SOD1 in motor neuron cell bodies and extracellular aggregates, and aPKC-containing extracellular aggregates increased with disease progression. Biochemical fractionation showed that aPKC protein level was increased in the detergent-insoluble protein fraction in SOD1 (G93A) mice at late stage but decreased in the detergent-soluble fraction at symptomatic stage. These results suggest that aPKC may be sequestered in SOD1 aggregates, impairing its ability to protect motor neurons from death. Ryk expression was also increased in the motor neurons and the white matter in the ventral lumbar spinal cord of mutant SOD1 mice with a peak at early stage. These observations indicate that Wnt/aPKC and Wnt/Ryk signaling are altered in SOD1 (G93A) mice, suggesting that changed Wnt signaling may contribute to neurodegeneration in ALS.}, }
@article {pmid24120645, year = {2013}, author = {Filippi, M and van den Heuvel, MP and Fornito, A and He, Y and Hulshoff Pol, HE and Agosta, F and Comi, G and Rocca, MA}, title = {Assessment of system dysfunction in the brain through MRI-based connectomics.}, journal = {The Lancet. Neurology}, volume = {12}, number = {12}, pages = {1189-1199}, doi = {10.1016/S1474-4422(13)70144-3}, pmid = {24120645}, issn = {1474-4465}, mesh = {Adolescent ; Adult ; Aging ; Axonal Transport ; Brain/growth &amp; development ; Child ; Child, Preschool ; Connectome/*methods ; Diffusion Tensor Imaging ; Female ; Humans ; Infant ; Magnetic Resonance Imaging/*methods ; Magnetoencephalography ; Male ; Mental Disorders/*physiopathology ; Models, Neurological ; Nerve Net/*physiopathology ; Nervous System Diseases/*physiopathology ; Neural Pathways/pathology ; Reference Values ; Young Adult ; }, abstract = {Network-based analysis of structural and functional connections has provided a new technique to study the brains of healthy people and patients with neurological and psychiatric disorders. Graph theory provides a powerful method to quantitatively describe the topological organisation of brain connectivity. With such a framework, the brain can be depicted as a set of nodes connected by edges. Distinct modifications of network topological organisation in the brain have been identified during development and normal ageing, whereas disrupted functional and structural connectivities have been associated with several neurological and psychiatric disorders, including dementia, amyotrophic lateral sclerosis, multiple sclerosis, and schizophrenia. These assessments have improved understanding of the clinical manifestations noted in these patients, including disability and cognitive impairment. Future network-based research might enable indentification of different stages of disorders, subtypes for cognitive impairment, and connectivity profiles associated with different clinical outcomes.}, }
@article {pmid24119854, year = {2014}, author = {Gautier, CA and Corti, O and Brice, A}, title = {Mitochondrial dysfunctions in Parkinson's disease.}, journal = {Revue neurologique}, volume = {170}, number = {5}, pages = {339-343}, doi = {10.1016/j.neurol.2013.06.003}, pmid = {24119854}, issn = {0035-3787}, mesh = {Genetic Predisposition to Disease ; Humans ; Mitochondria/*physiology ; Mitochondrial Diseases/*etiology ; Parkinson Disease/*complications/genetics/*physiopathology ; }, abstract = {Neurodegenerative disorders (ND) include a wide spectrum of diseases characterized by progressive neuronal dysfunctions or degeneration. With an estimated cost of 135 billion € in 2010 in the European Union (Olesen et al., 2012), they put an enormous economic as well as social burden on modern societies. Hence, they have been the subject of a huge amount of research for the last fifty years. For many of these diseases, our understanding of their profound causes is incomplete and this hinders the discovery of efficient therapies. ND form a highly heterogeneous group of diseases affecting various neuronal subpopulations reflecting different origins and different pathological mechanisms. However, some common themes in the physiopathology of these disorders are emerging. There is growing evidence that mitochondrial dysfunctions play a pivotal role at some point in the course of neurodegeneration. In some cases (e.g. Alzheimer's disease, amyotrophic lateral sclerosis), impairment of mitochondrial functions probably occurs late in the course of the disease. In a subset of ND, current evidence suggests that mitochondrial dysfunctions play a more seminal role in neuronal demise. Parkinson's disease (PD) presents one of the strongest cases based in part on post-mortem studies that have shown mitochondrial impairment (e.g. reduced complex I activity) and oxidative damage in idiopathic PD brains. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD have been linked to specific environmental insults or to mutations in at least 5 distinct genes (α-synuclein, parkin, DJ-1, PINK1 and LRRK2). It is postulated that the elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial and environmental Parkinsonism should provide important clues to the pathogenic mechanisms responsible for idiopathic PD. Hence, numerous cellular and animal models of the disease have been generated that mimic these environmental or genetic insults. The study of these models has yielded valuable information regarding the pathogenic mechanisms underlying dopaminergic degeneration in PD, many of which point towards an involvement of mitochondrial dysfunction. In this short review we will analyze critically the experimental evidence for the mitochondrial origin of PD and evaluate its relevance for our general understanding of the disease.}, }
@article {pmid24113586, year = {2013}, author = {Liu, YC and Chiang, PM and Tsai, KJ}, title = {Disease animal models of TDP-43 proteinopathy and their pre-clinical applications.}, journal = {International journal of molecular sciences}, volume = {14}, number = {10}, pages = {20079-20111}, pmid = {24113586}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Frontotemporal Lobar Degeneration/metabolism/pathology ; Humans ; TDP-43 Proteinopathies/*metabolism/*pathology ; }, abstract = {Frontotemperal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two common neurodegenerative diseases. TDP-43 is considered to be a major disease protein in FTLD/ALS, but it's exact role in the pathogenesis and the effective treatments remains unknown. To address this question and to determine a potential treatment for FTLD/ALS, the disease animal models of TDP-43 proteinopathy have been established. TDP-43 proteinopathy is the histologic feature of FTLD/ALS and is associated with disease progression. Studies on the disease animal models with TDP-43 proteinopathy and their pre-clinical applications are reviewed and summarized. Through these disease animal models, parts of TDP-43 functions in physiological and pathological conditions will be better understood and possible treatments for FTLD/ALS with TDP-43 proteinopathy may be identified for possible clinical applications in the future.}, }
@article {pmid24112924, year = {2013}, author = {Vucic, S and Kiernan, MC}, title = {Utility of transcranial magnetic stimulation in delineating amyotrophic lateral sclerosis pathophysiology.}, journal = {Handbook of clinical neurology}, volume = {116}, number = {}, pages = {561-575}, doi = {10.1016/B978-0-444-53497-2.00045-0}, pmid = {24112924}, issn = {0072-9752}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Animals ; Evoked Potentials, Motor/physiology ; Humans ; Motor Cortex/physiopathology ; Pyramidal Tracts/physiopathology ; Transcranial Magnetic Stimulation/*methods/*statistics &amp; numerical data ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem, and spinal cord. The clinical phenotype of ALS is underscored by a combination of upper and lower motor neuron dysfunction. Although this phenotype was observed over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables noninvasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established cortical dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde dying-forward mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This chapter reviews the mechanisms underlying the generation of TMS parameters utilized in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology, and the potential diagnostic utility of TMS techniques in ALS.}, }
@article {pmid24112910, year = {2013}, author = {Udupa, K and Chen, R}, title = {Central motor conduction time.}, journal = {Handbook of clinical neurology}, volume = {116}, number = {}, pages = {375-386}, doi = {10.1016/B978-0-444-53497-2.00031-0}, pmid = {24112910}, issn = {0072-9752}, mesh = {Animals ; Evoked Potentials, Motor/physiology ; Humans ; Motor Cortex/*physiology ; Neural Conduction/*physiology ; Reaction Time/*physiology ; *Transcranial Magnetic Stimulation ; }, abstract = {Central motor conduction time (CMCT) is the time taken for neural impulses to travel through the central nervous system on their way to the target muscles. When the motor cortex is stimulated with transcranial magnetic stimulation (TMS), CMCT is calculated by subtracting the peripheral conduction time from the motor evoked potential latency elicited by motor cortical TMS. CMCT in infants and children reaches adult level at about age of 6 years for the lower limbs. The alterations of CMCT in various neurological conditions are reviewed in this chapter. Prolongation of CMCT occurs due to slowing of conduction through rapidly conducting corticospinal fibers, as seen in various disorders such as demyelinating diseases (multiple sclerosis, MS), amyotrophic lateral sclerosis, structural lesions in the corticospinal tract such as stroke and compressive myelopathy, and neurodegenerative disorders including multiple system atrophy and progressive supranuclear palsy. As CMCT is prolonged in certain clinical conditions, it is of diagnostic value in some neurological disorders such as myelopathy, amyotrophic lateral sclerosis, and MS when used together with other clinical and electrophysiological measures. It could also be used as a prognostic marker in some of neurological conditions, such as myelopathy and MS.}, }
@article {pmid24112438, year = {2014}, author = {Onodera, O and Ishihara, T and Shiga, A and Ariizumi, Y and Yokoseki, A and Nishizawa, M}, title = {Minor splicing pathway is not minor any more: implications for the pathogenesis of motor neuron diseases.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {34}, number = {1}, pages = {99-107}, doi = {10.1111/neup.12070}, pmid = {24112438}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/metabolism/pathology ; Cell Nucleus/metabolism/ultrastructure ; DNA-Binding Proteins/*metabolism ; Gemini of Coiled Bodies/*metabolism/ultrastructure ; Humans ; Motor Neuron Disease/*etiology/genetics/metabolism/pathology ; RNA/metabolism ; RNA Splicing ; }, abstract = {To explore the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-DNA binding protein 43 kDa (TDP-43) must be elucidated. TDP-43 is a nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylate-rich (U) snRNAs (small nuclear RNAs) and protein complex, small nuclear ribonuclearprotein (snRNP). Spliceosomes regulate the splicing of pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of pre-mRNA splicing. Although the major class of spliceosomes regulates most pre-mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of pre-mRNA processing. A mouse model of spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs. Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS, the U12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.}, }
@article {pmid24107404, year = {2014}, author = {Jawaid, A and Paganoni, S and Hauser, C and Schulz, PE}, title = {Trials of antidiabetic drugs in amyotrophic lateral sclerosis: proceed with caution?.}, journal = {Neuro-degenerative diseases}, volume = {13}, number = {4}, pages = {205-208}, pmid = {24107404}, issn = {1660-2862}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Humans ; Hypoglycemic Agents/*therapeutic use ; PPAR gamma/agonists ; Pioglitazone ; Thiazolidinediones/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited therapeutic options. Clinical trials of several drugs shown to be effective in the superoxide dismutase (SOD1) model of ALS have shown no or negative effects when tested in humans. Here we discuss the role of pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, which failed to show efficacy in a recently published phase II clinical trial of ALS patients. The antioxidant and anti-inflammatory properties of pioglitazone make it an attractive therapeutic candidate for neurodegenerative disorders. However, its antidiabetic and antidyslipidemic effects might be detrimental, as emerging evidence suggests that some features of the metabolic syndrome may be protective in ALS. A number of clinical studies show that dyslipidemia, high body mass index, and possibly diabetes mellitus type 2 are associated with better clinical outcomes in ALS. This is further corroborated by studies on transgenic animal models and immortalized neuronal cell lines. Finally, the intricate interplay between glucose/lipid metabolism and susceptibility to oxidative damage in neurons warrants a judicious approach in further trials of antidiabetic drugs in ALS.}, }
@article {pmid24100629, year = {2014}, author = {Rizzo, F and Riboldi, G and Salani, S and Nizzardo, M and Simone, C and Corti, S and Hedlund, E}, title = {Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {71}, number = {6}, pages = {999-1015}, pmid = {24100629}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/immunology/pathology/*therapy ; Animals ; Astrocytes/metabolism/*transplantation ; COS Cells ; Cell- and Tissue-Based Therapy/*methods ; Chlorocebus aethiops ; Disease Models, Animal ; Humans ; Inflammation/immunology/therapy ; Macrophages/immunology ; Mice ; Microglia/metabolism/*transplantation ; Motor Neurons/metabolism ; T-Lymphocytes/immunology/*transplantation ; }, abstract = {Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer's disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients.}, }
@article {pmid24095843, year = {2013}, author = {Li, J and Le, W}, title = {Modeling neurodegenerative diseases in Caenorhabditis elegans.}, journal = {Experimental neurology}, volume = {250}, number = {}, pages = {94-103}, doi = {10.1016/j.expneurol.2013.09.024}, pmid = {24095843}, issn = {1090-2430}, mesh = {Animals ; *Caenorhabditis elegans ; *Disease Models, Animal ; Humans ; *Neurodegenerative Diseases ; }, abstract = {Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, an increasing number of research scientists have used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in C. elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in C. elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.}, }
@article {pmid24094633, year = {2013}, author = {Saab, AS and Tzvetanova, ID and Nave, KA}, title = {The role of myelin and oligodendrocytes in axonal energy metabolism.}, journal = {Current opinion in neurobiology}, volume = {23}, number = {6}, pages = {1065-1072}, doi = {10.1016/j.conb.2013.09.008}, pmid = {24094633}, issn = {1873-6882}, mesh = {Animals ; Axons/*metabolism ; Energy Metabolism/*physiology ; Humans ; Myelin Sheath/*metabolism ; Oligodendroglia/*metabolism ; }, abstract = {In vertebrates, the myelination of long axons by oligodendrocytes and Schwann cells enables rapid impulse propagation. However, myelin sheaths are not only passive insulators. Oligodendrocytes are also known to support axonal functions and long-term integrity. Some of the underlying mechanisms have now been identified. It could be shown that oligodendrocytes can survive in vivo by aerobic glycolysis. Myelinating oligodendrocytes release lactate through the monocarboxylate transporter MCT1. Lactate is then utilized by axons for mitochondrial ATP generation. Studying axo-glial signalling and energy metabolism will lead to a better understanding of neurodegenerative diseases, in which axonal energy metabolism fails. These include neurological disorders as diverse as multiple sclerosis, leukodystrophies, and amyotrophic lateral sclerosis.}, }
@article {pmid24093081, year = {2013}, author = {Ramanan, VK and Saykin, AJ}, title = {Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders.}, journal = {American journal of neurodegenerative disease}, volume = {2}, number = {3}, pages = {145-175}, pmid = {24093081}, issn = {2165-591X}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; RC2 AG036535/AG/NIA NIH HHS/United States ; T32 GM077229/GM/NIGMS NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; S10 RR027710/RR/NCRR NIH HHS/United States ; UL1 RR025761/RR/NCRR NIH HHS/United States ; R01 LM011360/LM/NLM NIH HHS/United States ; C06 RR020128/RR/NCRR NIH HHS/United States ; }, abstract = {The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.}, }
@article {pmid24092986, year = {2013}, author = {Jones, SP and Guillemin, GJ and Brew, BJ}, title = {The kynurenine pathway in stem cell biology.}, journal = {International journal of tryptophan research : IJTR}, volume = {6}, number = {}, pages = {57-66}, pmid = {24092986}, issn = {1178-6469}, abstract = {The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.}, }
@article {pmid24085347, year = {2013}, author = {Iguchi, Y and Katsuno, M and Ikenaka, K and Ishigaki, S and Sobue, G}, title = {Amyotrophic lateral sclerosis: an update on recent genetic insights.}, journal = {Journal of neurology}, volume = {260}, number = {11}, pages = {2917-2927}, pmid = {24085347}, issn = {1432-1459}, mesh = {Adaptor Proteins, Signal Transducing ; Adenosine Triphosphatases/genetics ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Ataxins ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/genetics ; D-Amino-Acid Oxidase/genetics ; DNA-Binding Proteins/genetics ; Flavoproteins/genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Membrane Transport Proteins ; Mice ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Phosphoric Monoester Hydrolases ; Profilins/genetics ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Receptors, sigma/genetics ; Transcription Factor TFIIIA/genetics ; Ubiquitins/genetics ; Valosin Containing Protein ; Sigma-1 Receptor ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting both upper and lower motor neurons. The prognosis for ALS is extremely poor, but there is a limited course of treatment with only one approved medication. A most striking recent discovery is that TDP-43 is identified as a key molecule that is associated with both sporadic and familial forms of ALS. TDP-43 is not only a pathological hallmark, but also a genetic cause for ALS. Subsequently, a number of ALS-causative genes have been found. Above all, the RNA-binding protein, such as FUS, TAF15, EWSR1 and hnRNPA1, have structural and functional similarities to TDP-43, and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system. These discoveries provide valuable insight into the pathogenesis of ALS, and open doors for developing an effective disease-modifying therapy.}, }
@article {pmid24081520, year = {2013}, author = {Grehl, T}, title = {[Diagnostics and therapy for amyotrophic lateral sclerosis].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {81}, number = {10}, pages = {592-603; quiz 604}, doi = {10.1055/s-0033-1350151}, pmid = {24081520}, issn = {1439-3522}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/genetics/psychology/*therapy ; Diagnosis, Differential ; Humans ; Laughter/physiology ; Motor Neuron Disease/diagnosis ; Neurologic Examination ; Neuroprotective Agents/therapeutic use ; Palliative Care ; Physical Therapy Modalities ; }, }
@article {pmid24077983, year = {2014}, author = {Douet, V and Chang, L and Cloak, C and Ernst, T}, title = {Genetic influences on brain developmental trajectories on neuroimaging studies: from infancy to young adulthood.}, journal = {Brain imaging and behavior}, volume = {8}, number = {2}, pages = {234-250}, pmid = {24077983}, issn = {1931-7565}, support = {G12 MD007601/MD/NIMHD NIH HHS/United States ; K01 DA021203/DA/NIDA NIH HHS/United States ; K01-DA021203/DA/NIDA NIH HHS/United States ; RC2-DA29475/DA/NIDA NIH HHS/United States ; G12-MD007601/MD/NIMHD NIH HHS/United States ; U54NS56883/NS/NINDS NIH HHS/United States ; L30 DA018596/DA/NIDA NIH HHS/United States ; K24 DA016170/DA/NIDA NIH HHS/United States ; U54 NS056883/NS/NINDS NIH HHS/United States ; 2 K24-DA016170/DA/NIDA NIH HHS/United States ; RC2 DA029475/DA/NIDA NIH HHS/United States ; }, mesh = {Adolescent ; Aging/*genetics ; Animals ; Brain/anatomy &amp; histology/*growth &amp; development/*physiology ; Child ; Child, Preschool ; Female ; *Gene Expression ; *Heredity ; Humans ; Infant ; Male ; *Neuroimaging/methods ; Sex Characteristics ; Young Adult ; }, abstract = {Human brain development has been studied intensively with neuroimaging. However, little is known about how genes influence developmental brain trajectories, even though a significant number of genes (about 10,000, or approximately one-third) in the human genome are expressed primarily in the brain and during brain development. Interestingly, in addition to showing differential expression among tissues, many genes are differentially expressed across the ages (e.g., antagonistic pleiotropy). Age-specific gene expression plays an important role in several critical events in brain development, including neuronal cell migration, synaptogenesis and neurotransmitter receptor specificity, as well as in aging and neurodegenerative disorders (e.g., Alzheimer disease or amyotrophic lateral sclerosis). In addition, the majority of psychiatric and mental disorders are polygenic, and many have onsets during childhood and adolescence. In this review, we summarize the major findings from neuroimaging studies that link genetics with brain development, from infancy to young adulthood. Specifically, we focus on the heritability of brain structures across the ages, age-related genetic influences on brain development and sex-specific developmental trajectories.}, }
@article {pmid24072096, year = {2013}, author = {Hübers, A and Weishaupt, JH and Ludolph, AC}, title = {[Genetics of amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {84}, number = {10}, pages = {1213-1219}, pmid = {24072096}, issn = {1433-0407}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/physiopathology ; C9orf72 Protein ; DNA Mutational Analysis ; Humans ; Introns/genetics ; Motor Neurons/physiology ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; TDP-43 Proteinopathies/diagnosis/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an aggressive rapidly progressing degeneration of both upper and lower motor neurons. Clinically, ALS is characterized by rapidly progressing atrophy and paresis of the muscles of the extremities. The genetics of ALS have become more complex in the last 5 years. The SOD gene is still very important; however, in recent years mutations in the genes for TDP-43 and FUS were discovered and also a most interesting intronic repeat expansion of the hexanucleotide repeat in C9ORF72 has been shown to be the most common in ALS. There are other quantitatively less relevant genes, which, however, are meaningful for pathogenetic aspects. It is also necessary to know that the phenotypes associated with ALS genetics have expanded.}, }
@article {pmid24070095, year = {2013}, author = {Kaushik, DK and Basu, A}, title = {A friend in need may not be a friend indeed: role of microglia in neurodegenerative diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {12}, number = {6}, pages = {726-740}, doi = {10.2174/18715273113126660170}, pmid = {24070095}, issn = {1996-3181}, mesh = {Alzheimer Disease/metabolism/pathology ; Animals ; Brain/metabolism/*pathology ; Humans ; Inflammation Mediators/physiology ; Microglia/metabolism/*pathology/*physiology ; Multiple Sclerosis/metabolism/pathology ; Neurodegenerative Diseases/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; }, abstract = {Inflammation plays a critical role in the progression of neurodegenerative diseases. Microglia are the resident macrophages of the central nervous system (CNS) which actively take part in the neuronal development of CNS and are involved in clearance of pathogens as well as cellular debris from the system upon insult to this organization. Chronic activation of microglia in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) as well as inflammatory conditions of CNS such as multiple sclerosis (MS) results in overall upregulation of pro-inflammatory cytokines and chemokines in the brain parenchyma. This compromises the neuronal health which further activates microglia by releasing death associated molecules such as neuromelanin, Aβ peptides and cellular debris at the lesion site thereby forming a vicious cycle of disease advancement. Targeting microglial activation has proven to be a viable option in the treatment of inflammation related neurodegenerative diseases. This review will discuss the central position of inflammation and therapeutic strategies aiming to alleviate disease progression in some of the important inflammatory conditions of CNS.}, }
@article {pmid24062161, year = {2013}, author = {Foran, E and Rosenblum, L and Bogush, AI and Trotti, D}, title = {Sumoylation of critical proteins in amyotrophic lateral sclerosis: emerging pathways of pathogenesis.}, journal = {Neuromolecular medicine}, volume = {15}, number = {4}, pages = {760-770}, pmid = {24062161}, issn = {1559-1174}, support = {F31 NS073351/NS/NINDS NIH HHS/United States ; R01 NS044292/NS/NINDS NIH HHS/United States ; F31-NS073351/NS/NINDS NIH HHS/United States ; R01-NS44292/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*etiology/metabolism ; Animals ; Astrocytes/metabolism ; Calcium Signaling ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2 ; Glutamate Plasma Membrane Transport Proteins/metabolism ; Glutamic Acid/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Motor Neurons/metabolism ; Muscular Disorders, Atrophic/metabolism ; Nerve Tissue Proteins/*physiology ; Protein Conformation ; RNA-Binding Protein FUS/metabolism ; Small Ubiquitin-Related Modifier Proteins/*physiology ; Sumoylation/*physiology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Emerging lines of evidence suggest a relationship between amyotrophic lateral sclerosis (ALS) and protein sumoylation. Multiple studies have demonstrated that several of the proteins involved in the pathogenesis of ALS, including superoxide dismutase 1, fused in liposarcoma, and TAR DNA-binding protein 43 (TDP-43), are substrates for sumoylation. Additionally, recent studies in cellular and animal models of ALS revealed that sumoylation of these proteins impact their localization, longevity, and how they functionally perform in disease, providing novel areas for mechanistic investigations and therapeutics. In this article, we summarize the current literature examining the impact of sumoylation of critical proteins involved in ALS and discuss the potential impact for the pathogenesis of the disease. In addition, we report and discuss the implications of new evidence demonstrating that sumoylation of a fragment derived from the proteolytic cleavage of the astroglial glutamate transporter, EAAT2, plays a direct role in downregulating the expression levels of full-length EAAT2 by binding to a regulatory region of its promoter.}, }
@article {pmid24055911, year = {2014}, author = {Dhillon, VS and Fenech, M}, title = {Mutations that affect mitochondrial functions and their association with neurodegenerative diseases.}, journal = {Mutation research. Reviews in mutation research}, volume = {759}, number = {}, pages = {1-13}, doi = {10.1016/j.mrrev.2013.09.001}, pmid = {24055911}, issn = {1383-5742}, mesh = {Aging/*genetics ; DNA Repair/genetics ; DNA, Mitochondrial/*genetics ; Humans ; Mitochondria/*genetics/pathology ; Neurodegenerative Diseases/etiology/*genetics/pathology ; Point Mutation ; Sequence Deletion ; }, abstract = {Mitochondria are essential for mammalian and human cell function as they generate ATP via aerobic respiration. The proteins required in the electron transport chain are mainly encoded by the circular mitochondrial genome but other essential mitochondrial proteins such as DNA repair genes, are coded in the nuclear genome and require transport into the mitochondria. In this review we summarize current knowledge on the association of point mutations and deletions in the mitochondrial genome that are detrimental to mitochondrial function and are associated with accelerated ageing and neurological disorders including Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis (ALS). Mutations in the nuclear encoded genes that disrupt mitochondrial functions are also discussed. It is evident that a greater understanding of the causes of mutations that adversely affect mitochondrial metabolism is required to develop preventive measures against accelerated ageing and neurological disorders caused by mitochondrial dysfunction.}, }
@article {pmid24046746, year = {2013}, author = {Kincaid, B and Bossy-Wetzel, E}, title = {Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {5}, number = {}, pages = {48}, pmid = {24046746}, issn = {1663-4365}, support = {R01 EY016164/EY/NEI NIH HHS/United States ; R01 NS055193/NS/NINDS NIH HHS/United States ; }, abstract = {Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets. SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD(+) directly links their activity to the metabolic status of the cell. High NAD(+) levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan. SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases. In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme. The goal of this review is to summarize emerging data supporting a neuroprotective action of SIRT3 against Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid24038380, year = {2013}, author = {Sreedharan, J and Brown, RH}, title = {Amyotrophic lateral sclerosis: Problems and prospects.}, journal = {Annals of neurology}, volume = {74}, number = {3}, pages = {309-316}, doi = {10.1002/ana.24012}, pmid = {24038380}, issn = {1531-8249}, support = {SREEDHARAN/JAN13/943-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; 5RC2NS070342-02/NS/NINDS NIH HHS/United States ; 5R01NS67206-04/NS/NINDS NIH HHS/United States ; 5R01NS079836-02/NS/NINDS NIH HHS/United States ; 1R01FD004127-01/FD/FDA HHS/United States ; MR/K010611/1/MRC_/Medical Research Council/United Kingdom ; 1R01NS073873-03/NS/NINDS NIH HHS/United States ; 5R01NS065847-04/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*therapy ; Genetic Testing ; Genetic Therapy ; Humans ; Motor Neurons/metabolism ; Mutation ; RNA-Binding Protein FUS/*genetics/metabolism ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the ∼10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies.}, }
@article {pmid24036231, year = {2013}, author = {Paulsen, JS and Nance, M and Kim, JI and Carlozzi, NE and Panegyres, PK and Erwin, C and Goh, A and McCusker, E and Williams, JK}, title = {A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {110}, number = {}, pages = {2-28}, pmid = {24036231}, issn = {1873-5118}, support = {NS040068/NS/NINDS NIH HHS/United States ; 5R01HG003330/HG/NHGRI NIH HHS/United States ; R01 NS040068/NS/NINDS NIH HHS/United States ; UL1 TR000442-06/TR/NCATS NIH HHS/United States ; UL1 TR000442/TR/NCATS NIH HHS/United States ; NGHG003330//PHS HHS/United States ; R01 HG003330/HG/NHGRI NIH HHS/United States ; NS077946/NS/NINDS NIH HHS/United States ; R01 NS077946/NS/NINDS NIH HHS/United States ; NS054893/NS/NINDS NIH HHS/United States ; R01 NS054893/NS/NINDS NIH HHS/United States ; }, mesh = {Brain/pathology ; *Early Diagnosis ; Genetic Testing ; Humans ; Neurodegenerative Diseases/*diagnosis/genetics/*psychology ; *Quality of Life ; }, abstract = {The past decade has witnessed an explosion of evidence suggesting that many neurodegenerative diseases can be detected years, if not decades, earlier than previously thought. To date, these scientific advances have not provoked any parallel translational or clinical improvements. There is an urgency to capitalize on this momentum so earlier detection of disease can be more readily translated into improved health-related quality of life for families at risk for, or suffering with, neurodegenerative diseases. In this review, we discuss health-related quality of life (HRQOL) measurement in neurodegenerative diseases and the importance of these "patient reported outcomes" for all clinical research. Next, we address HRQOL following early identification or predictive genetic testing in some neurodegenerative diseases: Huntington disease, Alzheimer's disease, Parkinson's disease, Dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, prion diseases, hereditary ataxias, Dentatorubral-pallidoluysian atrophy and Wilson's disease. After a brief report of available direct-to-consumer genetic tests, we address the juxtaposition of earlier disease identification with assumed reluctance toward predictive genetic testing. Forty-one studies examining health-related outcomes following predictive genetic testing for neurodegenerative disease suggested that (a) extreme or catastrophic outcomes are rare; (b) consequences commonly include transiently increased anxiety and/or depression; (c) most participants report no regret; (d) many persons report extensive benefits to receiving genetic information; and (e) stigmatization and discrimination for genetic diseases are poorly understood and policy and laws are needed. Caution is appropriate for earlier identification of neurodegenerative diseases but findings suggest further progress is safe, feasible and likely to advance clinical care.}, }
@article {pmid24035135, year = {2013}, author = {Schiavo, G and Greensmith, L and Hafezparast, M and Fisher, EM}, title = {Cytoplasmic dynein heavy chain: the servant of many masters.}, journal = {Trends in neurosciences}, volume = {36}, number = {11}, pages = {641-651}, pmid = {24035135}, issn = {1878-108X}, support = {MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; G0500288/MRC_/Medical Research Council/United Kingdom ; G0500865/MRC_/Medical Research Council/United Kingdom ; G0400149/MRC_/Medical Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Animals ; Brain/*metabolism ; Cytoplasmic Dyneins/*genetics/*metabolism ; Genetic Predisposition to Disease/genetics ; Humans ; Mutation/genetics ; Neurons/*metabolism ; Protein Multimerization ; }, abstract = {Cytoplasmic dynein is the main retrograde motor in all eukaryotic cells. This complex comprises different subunits assembled on a cytoplasmic dynein heavy chain 1 (DYNC1H1) dimer. Cytoplasmic dynein is particularly important for neurons because it carries essential signals and organelles from distal sites to the cell body. In the past decade, several mouse models have helped to dissect the numerous functions of DYNC1H1. Additionally, several DYNC1H1 mutations have recently been found in human patients that give rise to a broad spectrum of developmental and midlife-onset disorders. Here, we discuss the effects of mutations of mouse and human DYNC1H1 and how these studies are giving us new insight into the many critical roles DYNC1H1 plays in the nervous system.}, }
@article {pmid24018744, year = {2013}, author = {Tanaka, H}, title = {[Old or new medicine? Vitamin B12 and peripheral nerve neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {9}, pages = {1077-1082}, pmid = {24018744}, issn = {1881-6096}, mesh = {Humans ; Neural Conduction/drug effects ; Neurons/drug effects ; Peripheral Nervous System Diseases/*drug therapy ; Signal Transduction/drug effects ; Vitamin B 12/analogs &amp; derivatives/*pharmacology/therapeutic use ; }, abstract = {Methylcobalamin is a vitamin B12 analog that is necessary for nervous system maintenance. Although methylcobalamin has some positive effects on peripheral nervous system disorders, the mechanism through which it affects neurons are not entirely known. Recent studies have revealed its intracellular signaling pathway and some of its molecular actions on neurons. In this article, I review interactions between methylcobalamin and neurons that have been revealed through in vitro studies, in vivo studies, and clinical use. Methylcobalamin participates in nervous system maintenance through several mechanisms. Methylcobalamin is an active form of vitamin B12, and a coenzyme of methionine synthase, which is required for DNA and protein methylation. In addition, methylcobalamin facilitates neurite outgrowth and inhibits neural apoptosis through the Erk1/2 and Akt signaling pathways. Treatment with high doses of methylcobalamin ameliorates symptoms and negative electrophysiological findings in animal models of peripheral nerve neuropathy and in patients with carpal tunnel syndrome and amyotrophic lateral sclerosis. Thus, high-dose methylcobalamin has great potential for treating nervous system disorders. Further investigations with methylcobalamin may help elucidate its mechanisms of action, which may further enable us to treat many nervous system disorders.}, }
@article {pmid24011980, year = {2013}, author = {Le Ber, I}, title = {Genetics of frontotemporal lobar degeneration: an up-date and diagnosis algorithm.}, journal = {Revue neurologique}, volume = {169}, number = {10}, pages = {811-819}, doi = {10.1016/j.neurol.2013.07.014}, pmid = {24011980}, issn = {0035-3787}, mesh = {Adenosine Triphosphatases/genetics ; *Algorithms ; C9orf72 Protein ; Cell Cycle Proteins/genetics ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; Family ; Frontotemporal Lobar Degeneration/*diagnosis/*genetics ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Molecular Diagnostic Techniques/*methods ; Mutation ; Progranulins ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Valosin Containing Protein ; }, abstract = {The last decade marked a turning point in the knowledge of frontotemporal lobar degenerations (FTLD). Major discoveries were made with the identification of TDP-43 and FUS, two novel key players in FTLD. The growing number of FTLD genes has considerably changed our clinical practice. The high intrafamilial variability of phenotypes underlines the necessity of a careful interview concerning the family history, regarding FTLD diseases, but also other neurodegenerative and extra-neurological disorders. Knowledge of the different genetic forms of FTLD and their associated phenotypes become essential to propose appropriate genetic diagnosis to the patients, and deliver accurate genetic counseling to their families. We propose an algorithm based on four criteria to help to pinpoint the genetic cause of FTLD: Presence of ALS in the patient or family; age at onset of FTLD; progranulin plasma level; and other disorders present in the patient or family. Presence of ALS is strongly indicative of a C9ORF72 expansion; a very early age at onset (<50 years), parkinsonism and oculomotor dysfunction are indicative of MAPT mutations; whereas hallucinations, CBDS and PNFA are indicative of PGRN mutations. A C9ORF72 repeat expansion should be searched for therefore in patients with FTLD-ALS, followed by sequencing of exon 6 of TARDBP gene in negative cases. Since C9ORF72 expansions are as frequent as PGRN mutations in patients with pure FTLD, both should be investigated, except in early familial FTLD (<50) where MAPT mutations should be searched for first. VCP, SQSTM1 and hnRNPA2B1 gene-sequencing could be proposed in patients or families presenting 'multisystem proteinopathy'. The genes currently identified explain 50-60% of familial forms of FTLD. The identification of new FTLD genes involved remains a major challenge to gain further insight into the pathology and even better clarify the classification of FTLD in the future.}, }
@article {pmid24011641, year = {2013}, author = {Neumann, M}, title = {Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: molecular similarities and differences.}, journal = {Revue neurologique}, volume = {169}, number = {10}, pages = {793-798}, doi = {10.1016/j.neurol.2013.07.019}, pmid = {24011641}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; DNA-Binding Proteins/genetics ; Frontotemporal Lobar Degeneration/*genetics ; Humans ; Mutation/physiology ; RNA-Binding Protein EWS/genetics ; RNA-Binding Protein FUS/genetics ; TATA-Binding Protein Associated Factors/genetics ; }, abstract = {In the last years, new disease proteins and genes have been identified in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), leading to a dramatic shift in our understanding of the molecular mechanisms underlying both conditions. The vast majority of FTLD and ALS are characterized by the abnormal accumulation of TDP-43, including genetic forms associated with mutations in the genes C9ORF72, GRN, TARDBP and VCP. The overlap in pathology and of genetic factors, particularly C9ORF72 as common cause of ALS and FTLD, provides molecular evidence that both conditions represent a spectrum of diseases sharing similar pathomechanisms. Accumulation of the protein FUS defines another subset of FTLD and ALS. However, here some striking differences have been identified. All members of the FET family (FUS, EWS, TAF15) are co-accumulating with their nuclear import receptor Transportin in FTLD-FUS which is usually not associated with FUS mutations, whilst ALS-FUS is almost always associated with FUS mutations and reveals only FUS aggregates. Together with recent data demonstrating differences in the arginine methylation status of FUS in FTLD-FUS and ALS-FUS, these findings strongly imply at least partially distinct underlying disease mechanisms in these molecular subtypes of ALS and FTLD.}, }
@article {pmid24010870, year = {2014}, author = {Talbot, K}, title = {Amyotrophic lateral sclerosis: cell vulnerability or system vulnerability?.}, journal = {Journal of anatomy}, volume = {224}, number = {1}, pages = {45-51}, pmid = {24010870}, issn = {1469-7580}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; DNA-Binding Proteins/genetics/physiology ; Frontotemporal Dementia/genetics/pathology ; Humans ; Mutation ; RNA, Messenger/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with clinical, pathological and genetic overlap with frontotemporal dementia (FTD). No longer viewed as one disease with a single unified cause, ALS is now considered to be a clinicopathological syndrome resulting from a complex convergence of genetic susceptibility, age-related loss of cellular homeostasis, and possible environmental influences. The rapid increase in recent years of the number of genes in which mutations have been associated with ALS has led to in vitro and in vivo models that have generated a wealth of data indicating disruption of specific biochemical pathways and sub-cellular compartments. Data implicating pathways including protein misfolding, mRNA splicing, oxidative stress, proteosome and mitochondrial dysfunction in the pathogenesis of ALS reinforce a disease model based on selective age-dependent vulnerability of a specific population of cells. To the clinical neurologist, however, ALS presents as a disease of focal onset and contiguous spread. Characteristic regional patterns of involvement and progression suggest that the disease does not proceed randomly but via a restricted number of anatomical pathways. These clinical observations combined with electrophysiological and brain-imaging studies underpin the concept of ALS at the macroscopic level as a 'system degeneration'. This dichotomy between cellular and systems neurobiology raises the fundamental questions of what initiates the disease process in a specific anatomical site and how the disease is propagated. Is the essence of ALS a cell-to-cell transmission of pathology with, for example, a 'prion-like' mechanism, or does the cellular pathology follow degeneration of specific synaptic networks? Elucidating the interaction between cellular degeneration and system level degeneration will aid modeling of the disease in the earliest phases, improve the development of sensitive markers of disease progression and response to therapy, and expand our understanding of the biological basis of clinical and pathological heterogeneity.}, }
@article {pmid24008580, year = {2013}, author = {Vanderweyde, T and Youmans, K and Liu-Yesucevitz, L and Wolozin, B}, title = {Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review.}, journal = {Gerontology}, volume = {59}, number = {6}, pages = {524-533}, pmid = {24008580}, issn = {1423-0003}, support = {ES020395/ES/NIEHS NIH HHS/United States ; R21 NS066108/NS/NINDS NIH HHS/United States ; R21 NS073679/NS/NINDS NIH HHS/United States ; F31 AG042213/AG/NIA NIH HHS/United States ; NS073679/NS/NINDS NIH HHS/United States ; R01 NS060872/NS/NINDS NIH HHS/United States ; NS066108/NS/NINDS NIH HHS/United States ; NS060872/NS/NINDS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; T32 GM008541/GM/NIGMS NIH HHS/United States ; }, mesh = {Aging/genetics/metabolism ; Animals ; Cytoplasmic Granules/metabolism ; Humans ; Muscular Atrophy, Spinal/etiology/genetics/metabolism ; Mutation ; Nerve Degeneration/etiology/genetics/metabolism ; Neurodegenerative Diseases/*etiology/genetics/*metabolism ; Protein Multimerization ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/genetics/*metabolism ; Ribonucleoproteins/metabolism ; Stress, Physiological ; Tauopathies/etiology/genetics/metabolism ; }, abstract = {The eukaryotic stress response involves translational suppression of non-housekeeping proteins and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA-binding proteins (RBPs) that interact with capped mRNA transcripts through RNA recognition motifs, and exhibit reversible aggregation through hydrophobic polyglycine domains, some of which are homologous to yeast prion proteins. The activity and aggregation of RBPs appears to be important in the context of unfolded protein diseases. The discovery that mutations in these RBPs can cause familial motoneuron diseases and familial dementias indicates the importance of these genes to neuronal degeneration. Some disorders linked to mutations in RBPs include: amyotrophic lateral sclerosis, frontotemporal dementia and spinal muscular atrophy. These RBPs also associate with pathological structures in other neurodegenerative diseases, including Huntington's chorea, Creutzfeldt-Jakob disease, and Alzheimer's disease. Interestingly, protein levels of RBPs change across the aging spectrum and may be linked to other age-related disorders, such as type 2 diabetes. The link between SG pathways and proteins linked to neurodegenerative diseases suggests a potential role for common pathways in both processes, such as those involved in translational control, and highlights potentially novel targets for therapeutic intervention in neurodegenerative diseases.}, }
@article {pmid24005339, year = {2013}, author = {Atassi, N and Yerramilli-Rao, P and Szymonifka, J and Yu, H and Kearney, M and Grasso, D and Deng, J and Levine-Weinberg, M and Shapiro, J and Lee, A and Joseph, L and Macklin, EA and Cudkowicz, ME}, title = {Analysis of start-up, retention, and adherence in ALS clinical trials.}, journal = {Neurology}, volume = {81}, number = {15}, pages = {1350-1355}, pmid = {24005339}, issn = {1526-632X}, support = {U01-NS049640/NS/NINDS NIH HHS/United States ; U01-NS049640-04S1/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*therapy ; *Clinical Trials as Topic ; Humans ; Logistic Models ; Multicenter Studies as Topic ; *Patient Compliance/psychology ; Patient Selection ; Predictive Value of Tests ; PubMed/statistics &amp; numerical data ; Research Design ; Retrospective Studies ; }, abstract = {OBJECTIVE: To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.<br><br>METHODS: Retrospective analysis of start-up times, retention, and protocol adherence was performed on 5 clinical studies conducted by the Northeast ALS Consortium and 50 ALS clinical trials identified by PubMed search. Predictors of start-up times were estimated by accelerated failure time models with random effects. Predictors of retention and protocol deviations were estimated by mixed-model logistic regression.<br><br>RESULTS: Median times for contract execution and institutional review board (IRB) approval were 105 days and 125 days, respectively. Contract execution was faster at sites with more ongoing trials (p = 0.005), and more full-time (p = 0.006) and experienced (p < 0.001) coordinators. IRB approval was faster at sites with more ongoing trials (p = 0.010) and larger ALS clinics (p = 0.038). Site activation after IRB approval was faster at sites with more full-time (p = 0.038) and experienced (p < 0.001) coordinators. Twenty-two percent of surviving participants withdrew before completing the trial. Better participant functional score at baseline was an independent predictor of trial completion (odds ratio 1.29, p = 0.002) and fewer protocol deviations (odds ratio 0.86, p = 0.030).<br><br>CONCLUSION: Delays in IRB review contribute the most to prolonged trial start-up times, and these timelines are faster in sites with more experienced staff. Strategies to improve protocol adherence and participants' retention may include enrolling people at early disease stages.}, }
@article {pmid23999914, year = {2014}, author = {Hölscher, C}, title = {Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases.}, journal = {The Journal of endocrinology}, volume = {221}, number = {1}, pages = {T31-41}, doi = {10.1530/JOE-13-0221}, pmid = {23999914}, issn = {1479-6805}, mesh = {Animals ; Glucagon-Like Peptide 1/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; }, abstract = {The incretin hormone glucagon-like peptide 1 (GLP-1) has many effects in the body. It is best known for the 'incretin effect', facilitating insulin release from the pancreas under hyperglycaemic conditions. Building on this, GLP-1 mimetics have been developed as a treatment for type 2 diabetes. In the course of monitoring of patients, it has become apparent that GLP-1 mimetics have a range of other physiological effects in the body. In preclinical trials, a substantial body of evidence has been built that these mimetics have neuroprotective and anti-inflammatory effects. GLP-1 also has very similar growth-factor-like properties to insulin, which is presumably the underlying basis of the neuroprotective effects. In preclinical studies of Alzheimer's disease (AD), Parkinson's disease (PD), stroke and other neurodegenerative disorders, it has been shown that most GLP-1 mimetics cross the blood-brain barrier and show impressive neuroprotective effects in numerous studies. In animal models of AD, GLP-1 mimetics such as exendin-4, liraglutide and lixisenatide have shown protective effects in the CNS by reducing β-amyloid plaques, preventing loss of synapses and memory impairments, and reducing oxidative stress and the chronic inflammatory response in the brain. In animal models of PD, exendin-4 showed protection of dopaminergic neurons in the substantia nigra and prevention of dopamine loss in the basal ganglia while preserving motor control. These encouraging findings have spawned several clinical trials, some of which have shown encouraging initial results. Therefore, GLP-1 mimetics show great promise as a novel treatment for neurodegenerative conditions.}, }
@article {pmid23994186, year = {2013}, author = {Seo, J and Howell, MD and Singh, NN and Singh, RN}, title = {Spinal muscular atrophy: an update on therapeutic progress.}, journal = {Biochimica et biophysica acta}, volume = {1832}, number = {12}, pages = {2180-2190}, pmid = {23994186}, issn = {0006-3002}, support = {R01 NS055925/NS/NINDS NIH HHS/United States ; R21 NS072259/NS/NINDS NIH HHS/United States ; R21 NS080294/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Muscular Atrophy, Spinal/*therapy ; }, abstract = {Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.}, }
@article {pmid23994163, year = {2013}, author = {Forostyak, S and Jendelova, P and Sykova, E}, title = {The role of mesenchymal stromal cells in spinal cord injury, regenerative medicine and possible clinical applications.}, journal = {Biochimie}, volume = {95}, number = {12}, pages = {2257-2270}, doi = {10.1016/j.biochi.2013.08.004}, pmid = {23994163}, issn = {1638-6183}, mesh = {Animals ; Cell- and Tissue-Based Therapy/methods ; Clinical Trials as Topic ; Humans ; Inflammation/therapy ; Mesenchymal Stem Cells/*physiology ; Nerve Regeneration ; Regenerative Medicine ; Spinal Cord Injuries/*therapy ; }, abstract = {Diseases of the central nervous system still remain among the most challenging pathologies known to mankind, having no or limited therapeutic possibilities and a very pessimistic prognosis. Advances in stem cell biology in the last decade have shown that stem cells might provide an inexhaustible source of neurons and glia as well as exerting a neuroprotective effect on the host tissue, thus opening new horizons for tissue engineering and regenerative medicine. Here, we discuss the progress made in the cell-based therapy of spinal cord injury. An emphasis has been placed on the application of adult mesenchymal stromal cells (MSCs). We then review the latest and most significant results from in vitro and in vivo research focusing on the regenerative/neuroprotective properties of MSCs. We also attempt to correlate the effect of MSCs with the pathological events that are taking place in the nervous tissue after SCI. Finally, we discuss the results from preclinical and clinical trials involving different routes of MSC application into patients with neurological disorders of the spinal cord.}, }
@article {pmid23988427, year = {2013}, author = {Morrison, BM and Lee, Y and Rothstein, JD}, title = {Oligodendroglia: metabolic supporters of axons.}, journal = {Trends in cell biology}, volume = {23}, number = {12}, pages = {644-651}, pmid = {23988427}, issn = {1879-3088}, support = {R01 NS033958/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/metabolism ; Axons/*metabolism ; Biological Transport ; Humans ; Lactic Acid/metabolism ; Monocarboxylic Acid Transporters/metabolism ; Oligodendroglia/*metabolism ; Symporters/metabolism ; }, abstract = {Axons are specialized extensions of neurons that are critical for the organization of the nervous system. To maintain function in axons that often extend some distance from the cell body, specialized mechanisms of energy delivery are likely to be necessary. Over the past decade, greater understanding of human demyelinating diseases and the development of animal models have suggested that oligodendroglia are critical for maintaining the function of axons. In this review, we discuss evidence for the vulnerability of neurons to energy deprivation, the importance of oligodendrocytes for axon function and survival, and recent data suggesting that transfer of energy metabolites from oligodendroglia to axons through monocarboxylate transporter 1 (MCT1) may be critical for the survival of axons. This pathway has important implications both for the basic biology of the nervous system and for human neurological disease. New insights into the role of oligodendroglial biology provide an exciting opportunity for revisions in nervous system biology, understanding myelin-based disorders, and therapeutics development.}, }
@article {pmid23984863, year = {2013}, author = {Stokholm, MG and Bisgård, C and Vilholm, OJ}, title = {Safety and administration of treatment with botulinum neurotoxin for sialorrhoea in ALS patients: review of the literature and a proposal for tailored treatment.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {516-520}, doi = {10.3109/21678421.2013.830312}, pmid = {23984863}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*epidemiology/physiopathology ; Botulinum Toxins/adverse effects/*therapeutic use ; Botulinum Toxins, Type A/adverse effects/*therapeutic use ; Deglutition Disorders/chemically induced ; Humans ; Sialorrhea/*drug therapy/*epidemiology/physiopathology ; Treatment Outcome ; }, abstract = {Botulinum neurotoxin (BoNT) is a second-line treatment of sialorrhoea in ALS (amyotrophic lateral sclerosis) patients. This article is a review of the published literature concerning safety and administration of this treatment to ALS patients. A PubMed search was performed. All original publications on BoNT treatment of sialorrhoea in ALS patients were included in the review. Only a few adverse events were observed concerning treatment with BoNT. The studies performed to date have applied different treatment strategies with different dosages. In conclusion, BoNT treatment for sialorrhoea in ALS patients is safe with few adverse effects. The authors advocate for the implementation of a personalized treatment strategy. Special precautions must be taken when patients do not have the assistance of a ventilator and a feeding tube.}, }
@article {pmid23983902, year = {2013}, author = {Milani, P and Ambrosi, G and Gammoh, O and Blandini, F and Cereda, C}, title = {SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {836760}, pmid = {23983902}, issn = {1942-0994}, mesh = {Animals ; Antioxidants/*therapeutic use ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Oncogene Proteins/*metabolism ; Oxidative Stress/drug effects ; Protein Deglycase DJ-1 ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Neurodegenerative diseases share diverse pathological features and among these oxidative stress (OS) plays a leading role. Impaired activity and reduced expression of antioxidant proteins have been reported as common events in several aging-associated disorders. In this review paper, we first provide an overview of the involvement of reactive oxygen species- (ROS-) induced oxidative damage in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Subsequently, we focus on DJ-1 and SOD1 proteins, which are involved in PD and ALS and also exert a prominent role in the interaction between redox homeostasis and neurodegeneration. Interestingly, recent studies demonstrated that DJ-1 and SOD1 are both tightly connected with Nrf2 protein, a transcriptional factor and master regulator of the expression of many antioxidant/detoxification genes. Nrf2 is emerging as a key neuroprotective protein in neurodegenerative diseases, since it helps neuronal cells to cope with toxic insults and OS. We herein summarize the recent literature providing a detailed picture of the promising therapeutic efficacy of Nrf2 natural and synthetic inducers as disease-modifying molecules for the treatment of neurodegenerative diseases.}, }
@article {pmid23983606, year = {2013}, author = {Willard, SS and Koochekpour, S}, title = {Glutamate signaling in benign and malignant disorders: current status, future perspectives, and therapeutic implications.}, journal = {International journal of biological sciences}, volume = {9}, number = {7}, pages = {728-742}, pmid = {23983606}, issn = {1449-2288}, support = {P30 CA016056/CA/NCI NIH HHS/United States ; }, mesh = {Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Female ; Glutamic Acid/*physiology ; Humans ; Male ; Neoplasms/*physiopathology ; Neurodegenerative Diseases/*physiopathology ; Neurotransmitter Agents ; Receptors, Ionotropic Glutamate/*physiology ; Receptors, Metabotropic Glutamate/*physiology ; Signal Transduction/*physiology ; }, abstract = {Glutamate, a nonessential amino acid, is the major excitatory neurotransmitter in the central nervous system. As such, glutamate has been shown to play a role in not only neural processes, such as learning and memory, but also in bioenergetics, biosynthetic and metabolic oncogenic pathways. Glutamate has been the target of intense investigation for its involvement not only in the pathogenesis of benign neurodegenerative diseases (NDDs) such as Parkinson's disease, Alzheimer's disease, schizophrenia, multiple sclerosis, and amyotropic lateral sclerosis (ALS), but also in carcinogenesis and progression of malignant diseases. In addition to its intracellular activities, glutamate in secreted form is a phylogenetically conserved cell signaling molecule. Glutamate binding activates multiple major receptor families including the metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in various signaling pathways in cancer. Inhibition of extracellular glutamate release or glutamate receptor activation via competitive or non-competitive antagonists decreases growth, migration and invasion and induces apoptosis in breast cancer, melanoma, glioma and prostate cancer cells. In this review, we discuss the current state of glutamate signaling research as it relates to benign and malignant diseases. In addition, we provide a synopsis of clinical trials using glutamate antagonists for the treatment of NDD and malignant diseases. We conclude that in addition to its potential role as a metabolic biomarker, glutamate receptors and glutamate-initiated signaling pathways may provide novel therapeutic opportunities for cancer.}, }
@article {pmid23981712, year = {2013}, author = {Teplow, DB}, title = {On the subject of rigor in the study of amyloid β-protein assembly.}, journal = {Alzheimer's research &amp; therapy}, volume = {5}, number = {4}, pages = {39}, pmid = {23981712}, issn = {1758-9193}, abstract = {According to Thomas Kuhn, the success of 'normal science,' the science we all practice on a daily basis, depends on the adherence to, and practice of, a paradigm accepted by the scientific community. When great scientific upheavals occur, they involve the rejection of the current paradigm in favor of a new paradigm that better integrates the facts available and better predicts the behavior of a particular scientific system. In the field of Alzheimer's disease, a recent example of such a paradigm shift has been the apparent rejection of the 'amyloid cascade hypothesis,' promulgated by Hardy and Higgins in 1992 to explain the etiology of Alzheimer's disease, in favor of what has been referred to as the 'oligomer cascade hypothesis'. This paradigm shift has been breathtaking in its rapidity, its pervasiveness in the Alzheimer's disease field, and its adoption in an increasing number of other fields, including those of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prionoses. However, these facts do not mean, a priori, that the experiments extant, and any re-interpretation of them, should be accepted by rote as support for the new paradigm. In the discussion that follows, I consider the foundational studies leading to the oligomer cascade hypothesis and evaluate the current state of the paradigm. I argue here that, more often than not, insufficient rigor has been applied in studies upon which this new paradigm has been based. Confusion, rather than clarity, has resulted. If the field is to make progress forward using as its paradigmatic basis amyloid β-protein oligomerization, then an epistemological re-evaluation of the amyloid β-protein oligomer system is required.}, }
@article {pmid23978556, year = {2014}, author = {Kalmar, B and Lu, CH and Greensmith, L}, title = {The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol.}, journal = {Pharmacology &amp; therapeutics}, volume = {141}, number = {1}, pages = {40-54}, doi = {10.1016/j.pharmthera.2013.08.003}, pmid = {23978556}, issn = {1879-016X}, support = {MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Endoplasmic Reticulum Chaperone BiP ; Enzyme Induction/drug effects ; Heat-Shock Proteins/biosynthesis/*drug effects/*metabolism ; Heat-Shock Response/drug effects ; Humans ; Hydroxylamines/*pharmacology/*therapeutic use ; Models, Biological ; Molecular Targeted Therapy/methods ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome-ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders.}, }
@article {pmid23974990, year = {2013}, author = {Orozco, D and Edbauer, D}, title = {FUS-mediated alternative splicing in the nervous system: consequences for ALS and FTLD.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {91}, number = {12}, pages = {1343-1354}, pmid = {23974990}, issn = {1432-1440}, mesh = {*Alternative Splicing ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Axons/metabolism/pathology ; Brain/metabolism/pathology ; Frontotemporal Lobar Degeneration/genetics/metabolism ; Gene Expression Regulation ; Humans ; Nervous System/*metabolism/pathology ; RNA-Binding Protein FUS/*metabolism ; }, abstract = {Mutations in fused in sarcoma (FUS) in a subset of patients with amyotrophic lateral sclerosis (ALS) linked this DNA/RNA-binding protein to neurodegeneration. Most of the mutations disrupt the nuclear localization signal which strongly suggests a loss-of-function pathomechanism, supported by cytoplasmic inclusions. FUS-positive neuronal cytoplasmic inclusions are also found in a subset of patients with frontotemporal lobar degeneration (FTLD). Here, we discuss recent data on the role of alternative splicing in FUS-mediated pathology in the central nervous system. Several groups have shown that FUS binds broadly to many transcripts in the brain and have also identified a plethora of putative splice targets; however, only ABLIM1, BRAF, Ewing sarcoma protein R1 (EWSR1), microtubule-associated protein tau (MAPT), NgCAM cell adhesion molecule (NRCAM), and netrin G1 (NTNG1) have been identified in at least three of four studies. Gene ontology analysis of all putative targets unanimously suggests a role in axon growth and cytoskeletal organization, consistent with the altered morphology of dendritic spines and axonal growth cones reported upon loss of FUS. Among the axonal targets, MAPT/tau and NTNG1 have been further validated in biochemical studies. The next challenge will be to confirm changes of FUS-mediated alternative splicing in patients and define their precise role in the pathophysiology of ALS and FTLD.}, }
@article {pmid23965852, year = {2013}, author = {Wakabayashi, K}, title = {[Cellular pathology of neurodegenerative disorders].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {8}, pages = {609-617}, doi = {10.5692/clinicalneurol.53.609}, pmid = {23965852}, issn = {1882-0654}, mesh = {Histocytochemistry ; Humans ; Neurodegenerative Diseases/*pathology ; Peripheral Nervous System/pathology ; Synucleins/analysis ; TDP-43 Proteinopathies/pathology ; Tauopathies/pathology ; }, abstract = {Common cellular and molecular mechanisms including protein aggregation and inclusion body formation are involved in many neurodegenerative diseases. α-Synuclein is a major component of Lewy bodies in Parkinson's disease (PD) as well as in glial cytoplasmic inclusions in multiple system atrophy (MSA). Tau is a principal component of neurofibrillary and glial tangles in tauopathies. Recently, TDP-43 was identified as a component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PD is traditionally considered a movement disorder with hallmark lesions in the brainstem pigmented nuclei. However, pathological changes occur in widespread regions of the central and peripheral nervous systems in this disease. Furthermore, primary glial involvement ("gliodegeneration") can be observed in PD and MSA as well as in tauopathy. The present article reviews abnormal protein accumulation and inclusion body formation inside and outside the central nervous system.}, }
@article {pmid23965408, year = {2013}, author = {Lacomis, D and El-Dokla, A}, title = {What's in the literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {15}, number = {1}, pages = {34-42}, doi = {10.1097/CND.0b013e3182a3b21c}, pmid = {23965408}, issn = {1537-1611}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; Muscular Diseases/drug therapy ; Muscular Dystrophy, Duchenne/drug therapy ; Myasthenia Gravis/therapy ; *Neuromuscular Diseases ; }, abstract = {In amyotrophic lateral sclerosis (ALS), a recent double-blind placebo-controlled trial of acetyl-L-carnitine along with riluzole showed probable benefit in 42 patients compared with 40 patients who received placebo. Using an electrophysiologic measure devised to differentiate ALS from other neuromuscular conditions, a "splint-hand index" was devised and is reviewed. Analysis of skin in ALS may also be of interest, and there was a report of accumulation of fused in sarcoma protein in the epidermis of ALS patients. With regard to myasthenia gravis, there is another report that early treatment of ocular symptoms with corticosteroids may prevent the development of generalized symptoms. A new study of thymus histopathology in muscle-specific tyrosine kinase (MuSK) myasthenia gravis is covered and another article on the use of thymectomy. In Duchenne muscular dystrophy, the best method of administrating corticosteroids is still being debated, and a long-term study of daily versus intermittent prednisolone is reviewed. The study showed less sustained benefit from the intermittent prednisolone but with a better side effect profile. According to 2 recent reports, it seems that titin mutations may be an underrecognized cause of myopathy with early respiratory failure in adults. Keeping with the respiratory failure theme, there was also an interesting article on the long-term benefits and side effects of cyclosporine in patients with interstitial lung disease from antisynthetase syndrome. Finally, the spectrum of small fiber neuropathy may be expanding to include a causative role in some patients with fibromyalgia syndrome and in juveniles with diffuse pain and a possible autoimmune predisposition.}, }
@article {pmid23962997, year = {2013}, author = {Kim, HJ and Tetreault, LA and Massicotte, EM and Arnold, PM and Skelly, AC and Brodt, ED and Riew, KD}, title = {Differential diagnosis for cervical spondylotic myelopathy: literature review.}, journal = {Spine}, volume = {38}, number = {22 Suppl 1}, pages = {S78-88}, doi = {10.1097/BRS.0b013e3182a7eb06}, pmid = {23962997}, issn = {1528-1159}, mesh = {Cervical Vertebrae/*diagnostic imaging ; Diagnosis, Differential ; Humans ; Magnetic Resonance Imaging/*methods ; Radiography ; Sensitivity and Specificity ; Spinal Cord Diseases/*diagnosis ; Spondylosis/*diagnosis ; }, abstract = {STUDY DESIGN: Literature review.<br><br>OBJECTIVE: To identify case series that have been confused with cervical spondylotic myelopathy (CSM) to develop a comprehensive differential diagnosis.<br><br>SUMMARY OF BACKGROUND DATA: Myelopathy can be caused by a number of different etiologies. In those patients with CSM, the presentation is not always clear. Distinct radiographical and clinical characteristics, which are not always obvious, aid in arriving at the correct diagnosis.<br><br>METHODS: A PubMed search was done to identify reports written in English describing conditions that may present in a manner similar to CSM to differentiate them from CSM. Material from review articles and relevant textbooks was also considered. Information regarding the number of patients, the specific diagnosis presenting as myelopathy, the diagnostic findings, and the method(s) for distinguishing CSM from the initial diagnosis was abstracted from included articles. Salient features of the conditions were summarized.<br><br>RESULTS: A total of 35 citations (totaling 474 patients) that reported on diagnoses confused with CSM based on clinical presentation were included. All were case reports or small case series. The differential diagnoses were organized into 7 categories: congenital/anatomic, degenerative, neoplastic, inflammatory/autoimmune, idiopathic, circulatory, and metabolic. The primary conditions in the differential included amyotrophic lateral sclerosis, multiple sclerosis, syringomyelia, and spinal tumors.<br><br>CONCLUSION: In the vast majority of cases, magnetic resonance imaging was an invaluable tool in determining the correct diagnosis. Electrodiagnostic studies, cerebrospinal fluid profile, unique symptomatology, and consideration of patient demographics can also aid in the diagnosis. Bilateral sensory complaints in the hands are suspicious for cervical cord pathology and MR imaging of the same should be done even if the electromyography/nerve conduction studies (NCS) suggest bilateral carpal tunnel syndrome. SUMMARY STATEMENTS: Physical exam findings are not always consistent with severity of disease in CSM; therefore, correlation to plain radiographs, MRI, and patient symptomatology is essential for arriving at the correct diagnosis. In some cases where these studies are still equivocal, use of other studies should be considered including electrodiagnostic studies as well as cerebrospinal fluid examination.}, }
@article {pmid23962993, year = {2013}, author = {Fehlings, MG and Wilson, JR and Karadimas, SK and Arnold, PM and Kopjar, B}, title = {Clinical evaluation of a neuroprotective drug in patients with cervical spondylotic myelopathy undergoing surgical treatment: design and rationale for the CSM-Protect trial.}, journal = {Spine}, volume = {38}, number = {22 Suppl 1}, pages = {S68-75}, doi = {10.1097/BRS.0b013e3182a7e9b0}, pmid = {23962993}, issn = {1528-1159}, mesh = {Cervical Vertebrae/*drug effects/pathology/surgery ; Clinical Trials, Phase III as Topic ; Combined Modality Therapy ; Humans ; Neuroprotective Agents/therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; Spinal Cord Diseases/*drug therapy/surgery ; Spondylosis/*drug therapy/surgery ; Treatment Outcome ; }, abstract = {STUDY DESIGN: Descriptive article and narrative review.<br><br>OBJECTIVE: To explain the rationale and design of the cervical spondylotic myelopathy (CSM)-Protect clinical trial that aims to elucidate the efficacy and safety of riluzole in the context of CSM.<br><br>SUMMARY OF BACKGROUND DATA: CSM is the most common cause of spinal cord-related dysfunction internationally. Although surgery is effective in preventing the progression of impairment, and in some cases improving functional outcomes, many patients continue to exhibit significant disability in the postoperative setting. Evidence from preclinical studies suggests that glutamate-related excitotoxicity may contribute to the pathology of CSM and that administration of the sodium and glutamate-blocking medication riluzole, when combined with spinal cord decompression, may mitigate this effect and improve neurobehavioral outcomes. Although riluzole is FDA approved and has been shown to be safe and effective in the context of amyotrophic lateral sclerosis, its efficacy and safety in the context of CSM remain unknown.<br><br>METHODS: Descriptive article with narrative review of the literature.<br><br>RESULTS: In addition to providing pertinent preclinical background on the topic, this descriptive article and narrative review discusses the design and current status of an ongoing phase III randomized controlled trial evaluating the efficacy and safety of riluzole, combined with surgical decompression, in the treatment of CSM.<br><br>CONCLUSION: On the basis of current projections, we estimate that the interim analysis for this study will take place in the spring of 2014, at which time an adaptive sample size adjustment may take place.}, }
@article {pmid23958438, year = {2014}, author = {Dupuis, L}, title = {Mitochondrial quality control in neurodegenerative diseases.}, journal = {Biochimie}, volume = {100}, number = {}, pages = {177-183}, doi = {10.1016/j.biochi.2013.07.033}, pmid = {23958438}, issn = {1638-6183}, mesh = {Autophagy/genetics ; Dyneins/genetics/metabolism ; GTP Phosphohydrolases/genetics/metabolism ; *Gene Expression Regulation ; Humans ; Mitochondria/*genetics/metabolism/pathology ; Mitochondrial Proteins/genetics/metabolism ; Mutation ; Neurodegenerative Diseases/*genetics/metabolism/pathology ; Neurons/metabolism/pathology ; Protein Kinases/genetics/metabolism ; Signal Transduction ; Ubiquitin-Protein Ligases/genetics/metabolism ; }, abstract = {Mutations causing genetic forms of Parkinson's disease or hereditary neuropathies have been recently shown to affect key molecular players involved in the recycling of defective mitochondria, most notably PARKIN, PINK1, Mitofusin 2 or dynein heavy chain. Interestingly, the same pathways are also indirectly targeted by multiple other mutations involved in familial forms of amyotrophic lateral sclerosis, Huntington's disease or Alzheimer's disease. These recent genetic results strongly reinforce the notion that defective mitochondrial physiology might cause neurodegeneration. Mitochondrial dysfunction has however been observed in virtually every neurodegenerative disease and appears not restricted to the most vulnerable neuronal populations affected by a given disease. Thus, the mechanisms linking defective mitochondrial quality control to death of selective neuronal populations remain to be identified. This review provides an update on the most recent literature on mitochondrial quality control and its impairment during neurodegenerative diseases.}, }
@article {pmid23954928, year = {2013}, author = {Romano, M and Buratti, E}, title = {Targeting RNA binding proteins involved in neurodegeneration.}, journal = {Journal of biomolecular screening}, volume = {18}, number = {9}, pages = {967-983}, doi = {10.1177/1087057113497256}, pmid = {23954928}, issn = {1552-454X}, mesh = {Cell Death/drug effects ; DNA-Binding Proteins/*antagonists &amp; inhibitors/chemistry/metabolism ; Flocculation/drug effects ; Humans ; Ligands ; Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*metabolism/pathology ; Neurons/drug effects/metabolism/pathology ; Protein Binding/drug effects ; Protein Interaction Mapping ; RNA, Messenger/*antagonists &amp; inhibitors/metabolism ; RNA, Untranslated/*antagonists &amp; inhibitors/metabolism ; RNA-Binding Protein FUS/*antagonists &amp; inhibitors/chemistry/metabolism ; Ribonucleoproteins/*antagonists &amp; inhibitors/chemistry/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/chemistry/pharmacology ; }, abstract = {Dysfunctions at the level of RNA processing have recently been shown to play a fundamental role in the pathogenesis of many neurodegenerative diseases. Several proteins responsible for these dysfunctions (TDP-43, FUS/TLS, and hnRNP A/Bs) belong to the nuclear class of heterogeneous ribonucleoproteins (hnRNPs) that predominantly function as general regulators of both coding and noncoding RNA metabolism. The discovery of the importance of these factors in mediating neuronal death has represented a major paradigmatic shift in our understanding of neurodegenerative processes. As a result, these discoveries have also opened the way toward novel biomolecular screening approaches in our search for therapeutic options. One of the major hurdles in this search is represented by the correct identification of the most promising targets to be prioritized. These may include aberrant aggregation processes, protein-protein interactions, RNA-protein interactions, or specific cellular pathways altered by disease. In this review, we discuss these four major options together with their various advantages and drawbacks.}, }
@article {pmid23945281, year = {2013}, author = {Van Damme, P and Robberecht, W}, title = {Clinical implications of recent breakthroughs in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {26}, number = {5}, pages = {466-472}, doi = {10.1097/WCO.0b013e328364c063}, pmid = {23945281}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/therapy ; Animals ; Frontotemporal Lobar Degeneration/diagnosis/genetics/*pathology/therapy ; Genetic Predisposition to Disease/genetics ; Humans ; Motor Neurons/metabolism ; Mutation ; }, abstract = {PURPOSE OF REVIEW: This review examines the clinical implications of recent breakthroughs in amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: ALS has been found to be a highly variable condition at the clinical, genetic and mechanistic level. The study of newly discovered genetic causes for ALS has demonstrated that in addition to the effect of toxic mutant proteins, abnormalities of RNA householding contribute to motor neuron degeneration. Furthermore, the classic distinction between gain of function and loss of function may be an oversimplification of the biological reality. The most important clinical breakthrough was the finding of intronic hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) as a common cause of ALS, frontotemporal lobar degeneration (FTLD) and ALS with concomitant FTLD. This provides unambiguous evidence that ALS and FTLD represent the ends of one spectrum of neurodegenerative diseases. The high prevalence of C9orf72 mutations in patients without family history further blurs the distinction between sporadic and familial forms of ALS and FTLD. It also opens opportunities for stratified clinical trials in ALS and for the development of targeted therapies.<br><br>SUMMARY: ALS is a heterogeneous disorder that overlaps with FTLD. C9orf72 mutations are the most common cause of ALS, and add to the evidence that disturbances in RNA householding contribute to ALS.}, }
@article {pmid23941283, year = {2013}, author = {Chen, S and Sayana, P and Zhang, X and Le, W}, title = {Genetics of amyotrophic lateral sclerosis: an update.}, journal = {Molecular neurodegeneration}, volume = {8}, number = {}, pages = {28}, pmid = {23941283}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.}, }
@article {pmid23939251, year = {2013}, author = {Obayashi, K}, title = {Salivary mental stress proteins.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {425}, number = {}, pages = {196-201}, doi = {10.1016/j.cca.2013.07.028}, pmid = {23939251}, issn = {1873-3492}, mesh = {Biomarkers/metabolism ; Chromogranin A/*metabolism ; Humans ; Hydrocortisone/*metabolism ; Immunoglobulin A/*metabolism ; Protein Stability ; Saliva/chemistry ; Salivary Proteins and Peptides/*metabolism ; Specimen Handling/instrumentation/standards ; Stress, Psychological/diagnosis/*metabolism/physiopathology ; Viscosity ; alpha-Amylases/*metabolism ; }, abstract = {Of the major diagnostic specimen types, saliva is one of the most easily collected. Many studies have focused on the evaluation of salivary proteins secreted by healthy people and patients with various diseases during responses to acute mental stress. In particular, such studies have focused on cortisol, α-amylase, chromogranin A (CgA), and immunoglobulin A (IgA) as salivary stress markers. Each of these salivary stress markers has its own strengths and weaknesses as well as data gaps related to many factors including collection technique. In this review, we summarize the critical knowledge of the positive and negative attributes and data gaps pertaining to each salivary stress marker.}, }
@article {pmid23934648, year = {2014}, author = {Liu, Y and Yu, JT and Zong, Y and Zhou, J and Tan, L}, title = {C9ORF72 mutations in neurodegenerative diseases.}, journal = {Molecular neurobiology}, volume = {49}, number = {1}, pages = {386-398}, pmid = {23934648}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; C9orf72 Protein ; Frontotemporal Dementia/genetics/pathology ; Humans ; Mutation/*genetics ; Neurodegenerative Diseases/*genetics/pathology ; Proteins/*genetics ; }, abstract = {Recent works have demonstrated an expansion of the GGGGCC hexanucleotide repeat in the first intron of chromosome 9 open reading frame 72 (C9ORF72), encoding an unknown C9ORF72 protein, which was responsible for an unprecedented large proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases of European ancestry. C9ORF72 is expressed in most tissues including the brain. Emerging evidence has demonstrated that C9ORF72 mutations could reduce the level of C9ORF72 variant 1, which may influence protein expression and the formation of nuclear RNA foci. The spectrum of mutations is broad and provides new insight into neurological diseases. Clinical manifestations of diseases related with C9ORF72 mutations can vary from FTD, ALS, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Huntington disease-like syndrome (HDL syndrome), to Alzheimer's disease. In this article, we will review the brief characterizations of the C9ORF72 gene, the expansion mutations, the related disorders, and their features, followed by a discussion of the deficiency knowledge of C9ORF72 mutations. Based on the possible pathological mechanisms of C9ORF72 mutations in ALS and FTD, we can find new targets for the treatment of C9ORF72 mutation-related diseases. Future studies into the mechanisms, taking into consideration the discovery of those disorders, will significantly accelerate new discoveries in this field, including targeting identification of new therapy.}, }
@article {pmid23931993, year = {2013}, author = {Ling, SC and Polymenidou, M and Cleveland, DW}, title = {Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.}, journal = {Neuron}, volume = {79}, number = {3}, pages = {416-438}, pmid = {23931993}, issn = {1097-4199}, support = {T32 AG 000216/AG/NIA NIH HHS/United States ; 089701/WT_/Wellcome Trust/United Kingdom ; R01 NS027036/NS/NINDS NIH HHS/United States ; T32 AG000216/AG/NIA NIH HHS/United States ; K99 NS075216/NS/NINDS NIH HHS/United States ; K99-NS075216/NS/NINDS NIH HHS/United States ; R01-NS27036/NS/NINDS NIH HHS/United States ; R01 NS088578/NS/NINDS NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing ; Adenosine Triphosphatases/genetics/metabolism ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Frontotemporal Dementia/*genetics ; Homeostasis/*genetics ; Humans ; Models, Biological ; Mutation/genetics ; Proteins/genetics/*metabolism ; RNA/*metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Ubiquitins/genetics/metabolism ; Valosin Containing Protein ; }, abstract = {Breakthrough discoveries identifying common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have transformed our view of these disorders. They share unexpectedly similar signatures, including dysregulation in common molecular players including TDP-43, FUS/TLS, ubiquilin-2, VCP, and expanded hexanucleotide repeats within the C9ORF72 gene. Dysfunction in RNA processing and protein homeostasis is an emerging theme. We present the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.}, }
@article {pmid23931822, year = {2013}, author = {Hentati, F and Hentati, E and Amouri, R}, title = {Giant axonal neuropathy.}, journal = {Handbook of clinical neurology}, volume = {115}, number = {}, pages = {933-938}, doi = {10.1016/B978-0-444-52902-2.00052-7}, pmid = {23931822}, issn = {0072-9752}, mesh = {Cytoskeletal Proteins/genetics ; Electromyography ; *Giant Axonal Neuropathy/diagnosis/physiopathology/therapy ; Humans ; Mutation/genetics ; Nerve Fibers/pathology/ultrastructure ; }, abstract = {Giant axonal neuropathy (GAN) is a rare hereditary autosomal recessive neurodegenerative disease affecting both the peripheral and the central nervous system. Clinically it is characterized by an age of onset during the first decade, progressive and severe motor sensory neuropathy followed, in some patients, by the occurrence of various central nervous system signs such as cerebellar syndrome, upper motor neuron signs, or epilepsy. Although kinky hairs are reported in the majority of patients, it is not a constant finding. The prognosis is usually severe with death occurring during the second or third decade; nevertheless a less severe course is reported in some patients. The presence of a variable number of giant axons filled with neurofilaments in the nerve biopsy represents the pathological feature of the disease and it is usually associated to a variable degree with axonal loss and demyelization. Giant axons are also found in the central nervous system associated with Rosenthal fibers and a variable degree of involvement of white matter and neuronal loss. The disease is caused by mutation in the GAN gene encoding for gigaxonin, a member of BTB-Kelch. Up to now 37 mutations in the GAN gene have been reported. These mutations are scattered over the 11 exons of the gene without a clear genotype-phenotype correlation. These mutations resulting in gigaxonin deficiency lead to a slow down in ubiquitin-mediated protein degradation and possibly of other unidentified proteins. GAN represents a good model of a neurodegenerative disorder in which there is a primary defect of the ubiquitin proteasome system and its network with neurofilaments. The clarification of molecular mechanisms involved in GAN can help in understanding other frequent neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson disease.}, }
@article {pmid23931813, year = {2013}, author = {Pradat, PF and Delanian, S}, title = {Late radiation injury to peripheral nerves.}, journal = {Handbook of clinical neurology}, volume = {115}, number = {}, pages = {743-758}, doi = {10.1016/B978-0-444-52902-2.00043-6}, pmid = {23931813}, issn = {0072-9752}, mesh = {Humans ; Peripheral Nervous System Diseases/diagnosis/*etiology ; Radiation Injuries/*complications ; }, abstract = {Although the peripheral nerve has often been considered as radioresistant, clinical practice demonstrates the occurrence of radiation-induced peripheral neuropathies. Because these complications appear late, usually several years after the course of radiotherapy, their occurrence is explained by improvement in the prognosis of several cancers. Their physiopathology is not fully understood. Compression by radio-induced fibrosis probably plays a central role but direct injury to nerves and blood vessels is probably also involved. The most frequent and best known form of postradiation neuropathy is brachial plexopathy, which may follow irradiation for breast cancer. Recent reports demonstrate that postradiation neuropathies show a great heterogeneity, particularly in the anatomical sites, but also in the clinical, electrophysiological, and neuroimaging features. The link with radiotherapy may be difficult for the clinician to establish. Patients with radiation-induced lumbosacral radiculoplexopathy may be misdiagnosed with amyotrophic lateral sclerosis as they often present with pure lower motor neuron syndrome, or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased CSF protein content can be observed. From a pathophysiological perspective, radiation-induced neuropathy offers an interesting model for deciphering the mechanisms of peripheral neuropathies due to environmental factors. Recent developments show promising strategies for the prevention and treatment of these complications, which have a considerable impact on a patient's quality of life.}, }
@article {pmid23931786, year = {2013}, author = {Arezzo, JC and Seto, S and Schaumburg, HH}, title = {Sensory-motor assessment in clinical research trials.}, journal = {Handbook of clinical neurology}, volume = {115}, number = {}, pages = {265-278}, doi = {10.1016/B978-0-444-52902-2.00016-3}, pmid = {23931786}, issn = {0072-9752}, mesh = {*Biomedical Research ; Humans ; *Movement ; Outcome Assessment, Health Care ; Peripheral Nervous System Diseases/*diagnosis/physiopathology ; Reproducibility of Results ; *Sensation ; Sensitivity and Specificity ; }, abstract = {The assessment of changes in sensory-motor function in clinical research presents a unique set of difficulties. Clinimetrics is the science of measurement as related to the identification of a clinical disorder, the tracing of the progression of the condition under study, and calculation of its impact. The selection of appropriate measures for clinical studies of sensory-motor function must consider validity, sensitivity, specificity, responsiveness, reliability, and feasibility. Reasonable measures of motor function in clinical research include manual examination of muscle strength, electrophysiology, functional scales, patient-reported outcomes (e.g., quality of life), and for severe conditions such as ALS, survival. The assessment of sensory function includes targeted electrophysiology and QOL, as well as more focused measures such as quantitative sensory testing and the scoring of positive symptoms. Each individual measure and each combination of endpoints has its strengths and limitations.}, }
@article {pmid23931423, year = {2013}, author = {Foerster, BR and Dwamena, BA and Petrou, M and Carlos, RC and Callaghan, BC and Churchill, CL and Mohamed, MA and Bartels, C and Benatar, M and Bonzano, L and Ciccarelli, O and Cosottini, M and Ellis, CM and Ehrenreich, H and Filippini, N and Ito, M and Kalra, S and Melhem, ER and Pyra, T and Roccatagliata, L and Senda, J and Sobue, G and Turner, MR and Feldman, EL and Pomper, MG}, title = {Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: a systematic review and individual patient data meta-analysis.}, journal = {Academic radiology}, volume = {20}, number = {9}, pages = {1099-1106}, pmid = {23931423}, issn = {1878-4046}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/K000780/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; P41 EB015909/EB/NIBIB NIH HHS/United States ; K25 EB003491/EB/NIBIB NIH HHS/United States ; T32 EB006351/EB/NIBIB NIH HHS/United States ; R21 MH082322/MH/NIMH NIH HHS/United States ; P41 RR015241/RR/NCRR NIH HHS/United States ; R21 MH087799/MH/NIMH NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; Diagnostic Errors/*statistics &amp; numerical data ; Diffusion Magnetic Resonance Imaging/*methods/*statistics &amp; numerical data ; Humans ; Prevalence ; Reproducibility of Results ; Risk Assessment ; Sensitivity and Specificity ; }, abstract = {RATIONALE AND OBJECTIVES: There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data.<br><br>MATERIALS AND METHODS: MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.<br><br>RESULTS: Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias.<br><br>CONCLUSION: Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS.}, }
@article {pmid23925784, year = {2013}, author = {Heritier Barras, AC and Adler, D and Iancu Ferfoglia, R and Ricou, B and Gasche, Y and Leuchter, I and Hurst, S and Escher, M and Pollak, P and Janssens, JP and , }, title = {Is tracheostomy still an option in amyotrophic lateral sclerosis? Reflections of a multidisciplinary work group.}, journal = {Swiss medical weekly}, volume = {143}, number = {}, pages = {w13830}, doi = {10.4414/smw.2013.13830}, pmid = {23925784}, issn = {1424-3997}, mesh = {Advance Directives ; Amyotrophic Lateral Sclerosis/complications/*therapy ; France ; Humans ; Noninvasive Ventilation/ethics/methods ; Palliative Care/ethics/methods ; Quality of Life ; Respiration, Artificial/ethics/*methods ; Respiratory Insufficiency/etiology/*therapy ; Switzerland ; Tracheostomy/ethics/methods ; }, abstract = {QUESTION UNDER STUDY: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis. Survival and quality of life of ALS patients have improved through the implementation of multidisciplinary approaches, the use of percutaneous gastrostomy and of noninvasive (NIV) or invasive ventilation. The question of whether or not to propose invasive ventilation (by tracheostomy: TPPV) to ALS patients remains a matter of debate.<br><br>METHODS: The study reviews the medical literature, the practice in three Swiss and two large French ALS expert centres and reports the results of a workgroup on invasive ventilation in ALS.<br><br>RESULTS: Improved management of secretions and use of different interfaces allows NIV to be used 24-hours-a-day for prolonged periods, thus avoiding TPPV in many cases. TPPV is frequently initiated in emergency situations with lack of prior informed consent. TPPV appears associated with a lesser quality of life and a higher risk of institutionalisation than NIV. The high burden placed on caregivers who manage ALS patients is a major problem with a clear impact on their quality of life.<br><br>CONCLUSIONS: Current practice in Switzerland and France tends to discourage the use of TPPV in ALS. Fear of a "locked-in syndrome", the high burden placed on caregivers, and unmasking cognitive disorders occurring in the evolution of ALS are some of the caveats when considering TPPV. Most decisions about TPPV are taken in emergency situations in the absence of advance directives. One exception is that of young motivated patients with predominantly bulbar disease who "fail" NIV.}, }
@article {pmid23909852, year = {2013}, author = {Pitkänen, A and Nehlig, A and Brooks-Kayal, AR and Dudek, FE and Friedman, D and Galanopoulou, AS and Jensen, FE and Kaminski, RM and Kapur, J and Klitgaard, H and Löscher, W and Mody, I and Schmidt, D}, title = {Issues related to development of antiepileptogenic therapies.}, journal = {Epilepsia}, volume = {54 Suppl 4}, number = {0 4}, pages = {35-43}, pmid = {23909852}, issn = {1528-1167}, support = {R01 NS038595/NS/NINDS NIH HHS/United States ; R01 NS044370/NS/NINDS NIH HHS/United States ; DP1 OD003347/OD/NIH HHS/United States ; N01NS42359/NS/NINDS NIH HHS/United States ; R01 NS040337/NS/NINDS NIH HHS/United States ; R01 NS020253/NS/NINDS NIH HHS/United States ; R21 NS079135/NS/NINDS NIH HHS/United States ; R01 NS079274/NS/NINDS NIH HHS/United States ; R25 NS070682/NS/NINDS NIH HHS/United States ; R01 NS045144/NS/NINDS NIH HHS/United States ; RC1 NS068938/NS/NINDS NIH HHS/United States ; R21 NS049525/NS/NINDS NIH HHS/United States ; R01 NS075429/NS/NINDS NIH HHS/United States ; R25 NS065733/NS/NINDS NIH HHS/United States ; R44 NS064661/NS/NINDS NIH HHS/United States ; R21 NS072258/NS/NINDS NIH HHS/United States ; R01 NS030549/NS/NINDS NIH HHS/United States ; R01 NS031718/NS/NINDS NIH HHS/United States ; R56 NS020253/NS/NINDS NIH HHS/United States ; R21 NS078333/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Animals ; Anticonvulsants/adverse effects/*therapeutic use ; Child ; Chronic Disease ; Controlled Clinical Trials as Topic ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Approval ; *Drug Discovery ; *Drug Evaluation, Preclinical ; Drug Resistance ; Drugs, Investigational/adverse effects/*therapeutic use ; Evidence-Based Medicine ; Humans ; National Institute of Neurological Disorders and Stroke (U.S.) ; United States ; }, abstract = {Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.}, }
@article {pmid23921753, year = {2013}, author = {Nixon, RA}, title = {The role of autophagy in neurodegenerative disease.}, journal = {Nature medicine}, volume = {19}, number = {8}, pages = {983-997}, pmid = {23921753}, issn = {1546-170X}, support = {R01 AG005604/AG/NIA NIH HHS/United States ; R01AG005604/AG/NIA NIH HHS/United States ; P01AG017617/AG/NIA NIH HHS/United States ; }, mesh = {*Autophagy ; Humans ; Lysosomes/metabolism ; Models, Biological ; Neurodegenerative Diseases/*pathology/therapy ; Phagosomes/metabolism ; }, abstract = {Autophagy is a lysosomal degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and protein aggregates. These substrates reach lysosomes by several distinct mechanisms, including delivery within endosomes as well as autophagosomes. Completion of digestion involves dynamic interactions among compartments of the autophagic and endocytic pathways. Neurons are particularly vulnerable to disruptions of these interactions, especially as the brain ages. Not surprisingly, mutations of genes regulating autophagy cause neurodegenerative diseases across the age spectrum with exceptional frequency. In late-onset disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and familial Parkinson's disease, defects arise at different stages of the autophagy pathway and have different implications for pathogenesis and therapy. This Review provides an overview of the role of autophagy in neurodegenerative disease, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated.}, }
@article {pmid23920043, year = {2013}, author = {Iacobazzi, V and Castegna, A and Infantino, V and Andria, G}, title = {Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool.}, journal = {Molecular genetics and metabolism}, volume = {110}, number = {1-2}, pages = {25-34}, doi = {10.1016/j.ymgme.2013.07.012}, pmid = {23920043}, issn = {1096-7206}, mesh = {*Biomarkers ; DNA Methylation/*genetics ; DNA, Mitochondrial/*genetics ; *Epigenesis, Genetic ; Humans ; Mitochondria/genetics/metabolism ; S-Adenosylhomocysteine ; }, abstract = {Recent expansion of our knowledge on epigenetic changes strongly suggests that not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) may be subjected to epigenetic modifications related to disease development, environmental exposure, drug treatment and aging. Thus, mtDNA methylation is attracting increasing attention as a potential biomarker for the detection and diagnosis of diseases and the understanding of cellular behavior in particular conditions. In this paper we review the current advances in mtDNA methylation studies with particular attention to the evidences of mtDNA methylation changes in diseases and physiological conditions so far investigated. Technological advances for the analysis of epigenetic variations are promising tools to provide insights into methylation of mtDNA with similar resolution levels as those reached for nDNA. However, many aspects related to mtDNA methylation are still unclear. More studies are needed to understand whether and how changes in mtDNA methylation patterns, global and gene specific, are associated to diseases or risk factors.}, }
@article {pmid23918658, year = {2013}, author = {Cleary, JD and Ranum, LP}, title = {Repeat-associated non-ATG (RAN) translation in neurological disease.}, journal = {Human molecular genetics}, volume = {22}, number = {R1}, pages = {R45-51}, pmid = {23918658}, issn = {1460-2083}, support = {P01 NS058901/NS/NINDS NIH HHS/United States ; R01 NS040389/NS/NINDS NIH HHS/United States ; P01NS058901/NS/NINDS NIH HHS/United States ; R01NS040389/NS/NINDS NIH HHS/United States ; }, mesh = {C9orf72 Protein ; Codon, Initiator ; Fragile X Mental Retardation Protein/genetics/metabolism ; Gene Expression ; Mutant Proteins/genetics/*metabolism ; Mutation ; Myotonin-Protein Kinase ; Nerve Tissue Proteins/genetics/metabolism ; Nervous System Diseases/*genetics/metabolism/pathology ; Open Reading Frames ; *Peptide Chain Initiation, Translational ; *Protein Biosynthesis ; Protein Serine-Threonine Kinases/genetics/metabolism ; Proteins/genetics/metabolism ; RNA Editing ; *Trinucleotide Repeat Expansion ; }, abstract = {Well-established rules of translational initiation have been used as a cornerstone in molecular biology to understand gene expression and to frame fundamental questions on what proteins a cell synthesizes, how proteins work and to predict the consequences of mutations. For a group of neurological diseases caused by the abnormal expansion of short segments of DNA (e.g. CAG•CTG repeats), mutations within or outside of predicted coding and non-coding regions are thought to cause disease by protein gain- or loss-of-function or RNA gain-of-function mechanisms. In contrast to these predictions, the recent discovery of repeat-associated non-ATG (RAN) translation showed expansion mutations can express homopolymeric expansion proteins in all three reading frames without an AUG start codon. This unanticipated, non-canonical type of protein translation is length-and hairpin-dependent, takes place without frameshifting or RNA editing and occurs across a variety of repeat motifs. To date, RAN proteins have been reported in spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), fragile X tremor ataxia syndrome (FXTAS) and C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In this article, we review what is currently known about RAN translation and recent progress toward understanding its contribution to disease.}, }
@article {pmid23917850, year = {2013}, author = {Foerster, BR and Welsh, RC and Feldman, EL}, title = {25 years of neuroimaging in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {9}, number = {9}, pages = {513-524}, pmid = {23917850}, issn = {1759-4766}, support = {R01 NS052514/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology ; Biomarkers ; History, 20th Century ; History, 21st Century ; Humans ; Magnetic Resonance Imaging/history/*methods/trends ; Neuroimaging/history/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which a precise cause has not yet been identified. Standard CT or MRI evaluation does not demonstrate gross structural nervous system changes in ALS, so conventional neuroimaging techniques have provided little insight into the pathophysiology of this disease. Advanced neuroimaging techniques--such as structural MRI, diffusion tensor imaging and proton magnetic resonance spectroscopy--allow evaluation of alterations of the nervous system in ALS. These alterations include focal loss of grey and white matter and reductions in white matter tract integrity, as well as changes in neural networks and in the chemistry, metabolism and receptor distribution in the brain. Given their potential for investigation of both brain structure and function, advanced neuroimaging methods offer important opportunities to improve diagnosis, guide prognosis, and direct future treatment strategies in ALS. In this article, we review the contributions made by various advanced neuroimaging techniques to our understanding of the impact of ALS on different brain regions, and the potential role of such measures in biomarker development.}, }
@article {pmid23912896, year = {2014}, author = {Valori, CF and Brambilla, L and Martorana, F and Rossi, D}, title = {The multifaceted role of glial cells in amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {71}, number = {2}, pages = {287-297}, pmid = {23912896}, issn = {1420-9071}, support = {GGP05244/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology ; Animals ; Astrocytes/cytology/metabolism ; Cell Cycle Proteins ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Humans ; Membrane Transport Proteins ; Microglia/cytology/*metabolism ; Oligodendroglia/cytology/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Transcription Factor TFIIIA/genetics/metabolism ; }, abstract = {Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia-neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.}, }
@article {pmid23900692, year = {2013}, author = {Martin, LJ and Wong, M}, title = {Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {10}, number = {4}, pages = {722-733}, pmid = {23900692}, issn = {1878-7479}, support = {R01 NS079348/NS/NINDS NIH HHS/United States ; R01-NS079348/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; R01-NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Brain/*metabolism/pathology ; *DNA Methylation ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/*genetics/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS pathogenesis that could be relevant to new disease target identification and therapies for ALS.}, }
@article {pmid23900071, year = {2013}, author = {Janssens, J and Van Broeckhoven, C}, title = {Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders.}, journal = {Human molecular genetics}, volume = {22}, number = {R1}, pages = {R77-87}, pmid = {23900071}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Brain/*metabolism/pathology ; C9orf72 Protein ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/*metabolism/pathology ; Genetic Variation ; Humans ; Mutation ; Proteins/genetics/metabolism ; TDP-43 Proteinopathies/genetics/*metabolism/pathology ; }, abstract = {Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions.}, }
@article {pmid23892338, year = {2014}, author = {Finsterer, J and Mahjoub, SZ}, title = {Fatigue in healthy and diseased individuals.}, journal = {The American journal of hospice &amp; palliative care}, volume = {31}, number = {5}, pages = {562-575}, doi = {10.1177/1049909113494748}, pmid = {23892338}, issn = {1938-2715}, mesh = {Acute Disease ; Age Factors ; Biomarkers ; Chronic Disease ; Complementary Therapies ; Diagnostic Techniques and Procedures ; Diet ; Exercise ; Fatigue/*classification/diagnosis/*etiology/therapy ; Female ; Health Status ; Humans ; Male ; Mental Health ; Neuromuscular Diseases/*complications ; Prevalence ; Sex Factors ; }, abstract = {OBJECTIVES: Although fatigue is experienced by everyone, its definition and classification remains under debate.<br><br>METHODS: A review of the previously published data on fatigue.<br><br>RESULTS: Fatigue is influenced by age, gender, physical condition, type of food, latency to last meal, mental status, psychological conditions, personality type, life experience, and the health status of an individual. Fatigue may not only be a symptom but also a measurable and quantifiable dimension, also known as fatigability. Additionally, it may be classified as a condition occurring at rest or under exercise or stress, as physiologic reaction or pathologic condition, as spontaneous phenomenon or triggerable state, as resistant or irresistant to preconditioning, training, or attitude, as prominent or collateral experience, and as accessible or inaccessible to any type of treatment or intervention. Fatigue may be the sole symptom of a disease or one among others. It may be also classified as acute or chronic. Quantification of fatigability is achievable by fatigue scores, force measurement, electromyography, or other means. Fatigue and fatigability need to be delineated from conditions such as sleepiness, apathy, exhaustion, exercise intolerance, lack of vigor, weakness, inertia, or tiredness. Among neurological disorders, the prevalence of fatigue is particularly increased in multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, traumatic brain injury, stroke, and bleeding and also in neuromuscular disorders. Fatigue may be influenced by training, mental preconditioning, or drugs.<br><br>CONCLUSIONS: Fatigue needs to be recognized as an important condition that is not only a symptom but may also be quantified and can be modified by various measures depending on the underlying cause.}, }
@article {pmid23889603, year = {2014}, author = {Toyoshima, Y and Takahashi, H}, title = {TDP-43 pathology in polyglutamine diseases: with reference to amyotrphic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {34}, number = {1}, pages = {77-82}, doi = {10.1111/neup.12053}, pmid = {23889603}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; DNA-Binding Proteins/*analysis ; Humans ; Huntington Disease/pathology ; Inclusion Bodies/pathology ; Machado-Joseph Disease/pathology ; *Peptides ; RNA-Binding Proteins/analysis ; Spinocerebellar Ataxias/pathology ; }, abstract = {A nuclear protein, transactivation response (TAR) DNA binding protein 43 kDa (TDP-43), is the major component of neuronal cytoplasmic inclusions (NCIs) in frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). While initially thought to be relatively specific to FTLD-U and ALS, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In such tauopathies and α-synucleinopathies, occurrence of TDP-43-positive neuronal cytoplasmic inclusions may be associated with other distinct molecular pathologic processes primarily involving their own pathological proteins, tau and α-synuclein, respectively (secondary TDP-43 proteinopathies). On the other hand, in several polyglutamine (polyQ) diseases, TDP-43 appears to play an important pathomechanistic role. Interestingly, intermediate-length polyQ expansions (27-33 Qs) in ataxin 2, the causative gene of spinocerebellar ataxia type 2, have recently been reported to be a genetic risk factor for SALS. Here, with a review of the literature, we discuss the relationship between ALS and polyQ diseases from the viewpoint of TDP-43 neuropathology.}, }
@article {pmid23889583, year = {2013}, author = {Prell, T and Grosskreutz, J}, title = {The involvement of the cerebellum in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {507-515}, doi = {10.3109/21678421.2013.812661}, pmid = {23889583}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Cerebellum/*metabolism/*pathology ; DNA Damage/physiology ; Humans ; Neuroimaging/methods ; }, abstract = {Amyotrophic lateral sclerosis is a multisystemic neurodegenerative disease in which degenerative processes are not exclusively restricted to the upper and lower motor neurons. Herein, imaging and neuropathological evidence for involvement of the cerebellum, which to date is not thought to be involved in ALS, is reviewed. Evidence for involvement of the cerebellum in ALS comes from several neuropathological studies. Especially ubiquitinated forms of TDP-43 and ubiquitinated p62-positive inclusions were frequently observed. The widely used transgenic SOD1-G93A ALS mice model showed prominent cerebellar immunostaining of pERK and alterations of tau expression. Studies using advanced MRI techniques demonstrated that several cerebral areas, including the cerebellum, were recruited in order to compensate for functional motor decline. Functional MRI, voxel based morphometry, and diffusion-tensor imaging showed these cerebellar alterations as being of functional and structural nature.}, }
@article {pmid23887652, year = {2013}, author = {Trojsi, F and Monsurrò, MR and Tedeschi, G}, title = {Exposure to environmental toxicants and pathogenesis of amyotrophic lateral sclerosis: state of the art and research perspectives.}, journal = {International journal of molecular sciences}, volume = {14}, number = {8}, pages = {15286-15311}, pmid = {23887652}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Cyanobacteria/metabolism ; *Environmental Exposure ; Hazardous Substances/*metabolism ; Humans ; Metals, Heavy/metabolism ; Mice ; Pesticides/metabolism ; Protein Folding ; Risk Factors ; }, abstract = {There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene--environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals--including lead and pesticides-agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research.}, }
@article {pmid25206509, year = {2013}, author = {Guo, C and Sun, L and Chen, X and Zhang, D}, title = {Oxidative stress, mitochondrial damage and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {8}, number = {21}, pages = {2003-2014}, pmid = {25206509}, issn = {1673-5374}, abstract = {Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca(2+) homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative eases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.}, }
@article {pmid23881705, year = {2013}, author = {Zhao, W and Beers, DR and Appel, SH}, title = {Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {8}, number = {4}, pages = {888-899}, pmid = {23881705}, issn = {1557-1904}, support = {R21 NS079943/NS/NINDS NIH HHS/United States ; NS079943/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*pathology ; Animals ; Astrocytes/immunology/pathology ; *Disease Progression ; Humans ; Immunity, Innate/*immunology ; Inflammation Mediators/*physiology ; T-Lymphocytes, Regulatory/immunology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with selective loss of upper and lower motor neurons. At sites of motor neuron injury, neuroinflammation is a prominent pathological finding and is characterized by microglial activation, astrogliosis, and infiltration of monocytes and T-cells. Both innate and adaptive immune responses actively influence disease progression in animal models and in ALS patients, and promote neuroprotection or neurotoxicity at different stages of disease. The early immune reaction to signals from injured motor neurons is to rescue and repair damaged tissue. As disease accelerates, a shift occurs from beneficial immune responses (involving M2 microglia and regulatory T-cells) to deleterious immune responses (involving M1 microglia and Th1 cells). In this review, we underscore the importance of immune-mediated mechanisms in the pathogenesis of ALS and discuss the alterations and distinct phenotypes of immune cells at the different stages of disease. The better we understand the dynamic changes that occur within the immune system over the course of disease, the better we will be able to develop effective therapeutic regimens in ALS.}, }
@article {pmid23879681, year = {2013}, author = {Eisen, A and Turner, MR}, title = {Does variation in neurodegenerative disease susceptibility and phenotype reflect cerebral differences at the network level?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {487-493}, doi = {10.3109/21678421.2013.812660}, pmid = {23879681}, issn = {2167-9223}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Animals ; Cerebrum/*metabolism/pathology ; Disease Susceptibility/metabolism ; Humans ; Nerve Net/*metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; *Phenotype ; }, abstract = {Alzheimer's disease (AD) is 10-fold more frequent than Parkinson's disease (PD), which in turn is 10-fold more frequent than amyotrophic lateral sclerosis (ALS). The differences between these neurodegenerative diseases have been ascribed to a selective vulnerability of specific neuronal sub-types that then determine each disorder. However, there are non-neuronal cells that are ubiquitously and possibly primarily involved in all of them, and they share regulatory mechanisms through similar interneurons and, typically inhibitory, neurotransmitters. There is recognized clinical and neuropathological overlap between AD, PD and ALS, the best example being Guamanian Lytico-Bodig, but increasingly recognized in larger populations, e.g. carriers of C9orf72 hexanucleotide expansions. From early embryogenesis to adulthood, genetic and experience-dependent functional neural networks develop primarily in relation to the neocortex. From an evolutionary standpoint, cognition, memory, executive function, linguistics and fine motor function are most prominent in humans. It is concluded that neural networks, rather than specific neuronal sub-types defined regionally or by individual transmitters, underlie the marked differences between neurodegenerative disorders in terms of susceptibility and clinical features. This requires the continued development of strategies to study brain function in health and disease as the 'system', greater than the sum of its parts.}, }
@article {pmid23876150, year = {2013}, author = {Nakagawa, T and Kaneko, S}, title = {SLC1 glutamate transporters and diseases: psychiatric diseases and pathological pain.}, journal = {Current molecular pharmacology}, volume = {6}, number = {2}, pages = {66-73}, doi = {10.2174/18744672113069990033}, pmid = {23876150}, issn = {1874-4702}, mesh = {Amino Acid Transport System ASC/*metabolism ; Animals ; Glutamate Plasma Membrane Transport Proteins/*metabolism ; Glutamic Acid/*metabolism ; Humans ; Minor Histocompatibility Antigens ; Mood Disorders/metabolism ; Pain/metabolism ; Schizophrenia/metabolism ; Substance-Related Disorders/metabolism ; Synaptic Transmission ; }, abstract = {The solute carrier family 1 (SLC1) consists of two neutral amino acid transporters and five high-affinity excitatory amino acid transporters (EAAT1-5). EAATs are expressed in glial cells (EAAT1/GLAST and EAAT2/GLT-1), neurons (EAAT3/EAAC1 and EAAT4), and the retina (EAAT5), where they precisely regulate extracellular glutamate levels at both synaptic and extrasynaptic sites. EAATs play essential roles in the maintenance of normal excitatory synaptic transmission, protection of neurons from the excitotoxic action of excessive glutamate, and regulation of glutamatemediated neuroplasticity. Therefore, dysfunction of EAATs can cause abnormal excitatory synaptic transmission, neuronal excitotoxicity, and the exaggeration of neuroplasticity-based events. EAAT dysfunction has been implicated in a variety of neurodegenerative and neurological diseases, including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, ischemia, and epilepsy. Recent evidence suggests that abnormalities of EAATs contribute to the pathogenesis of psychiatric diseases and pathological pain. The present review will briefly discuss novel findings on the roles of EAATs in the pathogenesis of psychiatric diseases such as schizophrenia, mood disorders, and drug dependence/ addiction, and pathological pain, as well as the potential of EAATs as therapeutic targets.}, }
@article {pmid23870000, year = {2013}, author = {, }, title = {ALS Untangled No. 21: Fecal transplants.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {5-6}, pages = {482-485}, doi = {10.3109/21678421.2013.814981}, pmid = {23870000}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Biological Therapy/methods ; Feces/*microbiology ; Humans ; *Metagenome ; *Transplantation ; }, }
@article {pmid23864030, year = {2013}, author = {Pandya, RS and Zhu, H and Li, W and Bowser, R and Friedlander, RM and Wang, X}, title = {Therapeutic neuroprotective agents for amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {70}, number = {24}, pages = {4729-4745}, pmid = {23864030}, issn = {1420-9071}, support = {K01 NS055072/NS/NINDS NIH HHS/United States ; R01 NS077284/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/genetics ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mitochondria/drug effects ; Motor Neurons/drug effects ; Mutant Proteins/genetics/metabolism ; Neuroprotective Agents/*therapeutic use ; Proteolysis ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient's life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression.}, }
@article {pmid23860588, year = {2013}, author = {Chiò, A and Logroscino, G and Traynor, BJ and Collins, J and Simeone, JC and Goldstein, LA and White, LA}, title = {Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature.}, journal = {Neuroepidemiology}, volume = {41}, number = {2}, pages = {118-130}, pmid = {23860588}, issn = {1423-0208}, support = {ZIA AG000933-06//Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; *Global Health/trends ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of healthcare resources.<br><br>OBJECTIVE: To provide a comprehensive and critical review of the epidemiological literature on ALS.<br><br>METHODS: MEDLINE and EMBASE (1995-2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods and incidence and/or prevalence rates. Medians and interquartile ranges (IQRs) were calculated, and ALS case estimates were derived using 2010 population estimates.<br><br>RESULTS: In all, 37 articles met the inclusion criteria. In Europe, the median incidence rate (/100,000 population) was 2.08 (IQR 1.47-2.43), corresponding to an estimated 15,355 (10,852-17,938) cases. Median prevalence (/100,000 population) was 5.40 (IQR 4.06-7.89), or 39,863 (29,971-58,244) prevalent cases.<br><br>CONCLUSIONS: Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics such as age and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS.}, }
@article {pmid23859483, year = {2013}, author = {Beghi, E}, title = {Are professional soccer players at higher risk for ALS?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {501-506}, doi = {10.3109/21678421.2013.809764}, pmid = {23859483}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*epidemiology/physiopathology ; Animals ; Craniocerebral Trauma/*epidemiology/physiopathology ; Dietary Supplements/*adverse effects ; Environmental Exposure/adverse effects ; Exercise/*physiology ; Humans ; Male ; Pesticides/*adverse effects ; Risk Factors ; Soccer/*physiology ; }, abstract = {Since the observation of several deaths from amyotrophic lateral sclerosis (ALS) among Italian professional soccer players, an association between ALS and soccer has been postulated, supported by high rates of morbidity and mortality risks in large cohorts of professionals. Several factors may explain this. A history of repeated (head) injuries is reported more frequently by ALS patients than by individuals with other clinical conditions. An association between exercise and ALS has also been suggested, but results in animals and humans are conflicting. Some clinical and experimental observations suggest a relation between ALS and use of substances such as non-steroidal anti-inflammatory agents, and dietary supplements including branched-chain amino acids. Although Italian soccer players may be at higher risk of ALS than players in other countries, and higher than expected disease frequency seems soccer-specific, increased attention by the Italian lay press is an explanation that cannot be excluded. However, growing evidence points to the possibility that soccer players with ALS are susceptible individuals who develop the disease in response to combinations of environmental factors. Only cohort and case-control studies carried out with the same design in different European countries can provide a definite answer to this suspected but still unconfirmed association.}, }
@article {pmid23858776, year = {2013}, author = {Xue, H and Fang, X and Wang, W and Gao, G}, title = {[Advances of researches on caspases in neurodegenerative diseases].}, journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}, volume = {30}, number = {2}, pages = {438-442}, pmid = {23858776}, issn = {1001-5515}, mesh = {Animals ; Apoptosis/*physiology ; Caspases/*metabolism ; Cell Death ; Humans ; Neurodegenerative Diseases/enzymology/*pathology ; Neurons/*pathology ; Peptide Hydrolases/metabolism ; }, abstract = {Acute and chronic neurodegenerative diseases are illnesses associated with high morbidity and mortality, and few or no effective options are available for their treatments. Many neurodegenerative diseases are included in them, for example, stroke, brain trauma, spinal cord injury, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, and Parkinson's disease. Given that central nervous system tissue has very limited, if any, regenerative capacity, it is of utmost importance to limit the damage caused by neuronal death. During the past decade, considerable progress has been made in understanding the process of cell death. In this article, we review the causes and mechanisms of neuronal-cell death, especially as it pertains to the caspases family of proteases associated with cell death. The results may be helpful to the experimental research and clinical application of neurodegenerative diseases.}, }
@article {pmid23855817, year = {2013}, author = {Gordon, P and Corcia, P and Meininger, V}, title = {New therapy options for amyotrophic lateral sclerosis.}, journal = {Expert opinion on pharmacotherapy}, volume = {14}, number = {14}, pages = {1907-1917}, doi = {10.1517/14656566.2013.819344}, pmid = {23855817}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology/*therapy ; Animals ; Gene Expression Regulation ; Humans ; Muscles/metabolism/physiopathology ; Nutrition Therapy ; Stem Cell Transplantation ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease leading almost irrevocably to paralysis and death within 5 years after the first symptoms. Since the approval of riluzole, all other therapeutic trials have been negative, including many that followed hopeful preclinical and early clinical data. New approaches are needed to uncover effective treatments for this still-devastating disease.<br><br>AREAS COVERED: The review summarizes the current approaches to clinical drug development in ALS. It focuses on several new trials listed on PubMed Central or the National Institutes of Health online trial registry. New targets for therapeutic intervention in ALS include skeletal muscle, energetic metabolism and cell replacement. Two different approaches are directed at muscle: interventions that influence proteins near the neuromuscular junction such as Nogo-A; in contrast to drugs pointed toward disease physiology, therapies that directly increase strength. Other trials are evaluating nutritional interventions. Current cell therapy strategies utilize various types of stem cells to study disease pathophysiology, support neurons or surrounding cells through gene therapy or release of neurotrophic factors, or directly replace cells. The review includes a section on known genetic influences in ALS and future directions for the field.<br><br>EXPERT OPINION: These new interventions have important implications for the direction of ALS research. Investigators are focusing less on physiological mechanisms inside the neuron, a process that has proved unfruitful for nearly two decades, and more on concepts that have not been examined previously. These studies will surely add to the overall understanding of ALS. Future research will test ways to reduce gene expression in those with known mutations, as well as means to reduce the spread of aggregated protein.}, }
@article {pmid23851159, year = {2013}, author = {Aki, T and Funakoshi, T and Unuma, K and Uemura, K}, title = {Impairment of autophagy: from hereditary disorder to drug intoxication.}, journal = {Toxicology}, volume = {311}, number = {3}, pages = {205-215}, doi = {10.1016/j.tox.2013.07.001}, pmid = {23851159}, issn = {1879-3185}, mesh = {Animals ; Autophagy/drug effects/*physiology ; Drug-Related Side Effects and Adverse Reactions ; Genetic Diseases, Inborn ; Humans ; }, abstract = {At first, the molecular mechanism of autophagy was unveiled in a unicellular organism Saccharomyces cerevisiae (budding yeast), followed by the discovery that the basic mechanism of autophagy is conserved in multicellular organisms including mammals. Although autophagy was considered to be a non-selective bulk protein degradation system to recycle amino acids during periods of nutrient starvation, it is also believed to be an essential mechanism for the selective elimination of proteins/organelles that are damaged under pathological conditions. Research advances made using autophagy-deficient animals have revealed that impairments of autophagy often underlie the pathogenesis of hereditary disorders such as Danon, Parkinson's, Alzheimer's, and Huntington's diseases, and amyotrophic lateral sclerosis. On the other hand, there are many reports that drugs and toxicants, including arsenic, cadmium, paraquat, methamphetamine, and ethanol, induce autophagy during the development of their toxicity on many organs including heart, brain, lung, kidney, and liver. Although the question as to whether autophagic machinery is involved in the execution of cell death or not remains controversial, the current view of the role of autophagy during cell/tissue injury is that it is an important, often essential, cytoprotective reaction; disturbances in cytoprotective autophagy aggravate cell/tissue injuries. The purpose of this review is to provide (1) a gross summarization of autophagy processes, which are becoming more important in the field of toxicology, and (2) examples of important studies reporting the involvement of perturbations in autophagy in cell/tissue injuries caused by acute as well as chronic intoxication.}, }
@article {pmid23850759, year = {2013}, author = {Sano, R and Reed, JC}, title = {ER stress-induced cell death mechanisms.}, journal = {Biochimica et biophysica acta}, volume = {1833}, number = {12}, pages = {3460-3470}, pmid = {23850759}, issn = {0006-3002}, support = {R01 AG015393/AG/NIA NIH HHS/United States ; AG-15393/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cell Death ; Disease ; *Endoplasmic Reticulum Stress ; Humans ; Models, Biological ; Signal Transduction ; Unfolded Protein Response ; }, abstract = {The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways.}, }
@article {pmid23849263, year = {2013}, author = {Sonoda, K and Sasaki, K and Tateishi, T and Yamasaki, R and Hayashi, S and Sakae, N and Ohyagi, Y and Iwaki, T and Kira, J}, title = {TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome: an autopsied case report and a review of the literature.}, journal = {Journal of the neurological sciences}, volume = {332}, number = {1-2}, pages = {148-153}, doi = {10.1016/j.jns.2013.06.027}, pmid = {23849263}, issn = {1878-5883}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Brain Stem/pathology ; DNA-Binding Proteins/*genetics ; Female ; Hereditary Sensory and Motor Neuropathy/drug therapy/*genetics ; Humans ; Middle Aged ; Motor Neurons/metabolism/pathology ; Muscle, Skeletal/pathology ; Mutation/*genetics ; Neural Conduction/drug effects ; }, abstract = {We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.}, }
@article {pmid23834167, year = {2013}, author = {Tsvetkova, D and Obreshkova, D and Zheleva-Dimitrova, D and Saso, L}, title = {Antioxidant activity of galantamine and some of its derivatives.}, journal = {Current medicinal chemistry}, volume = {20}, number = {36}, pages = {4595-4608}, doi = {10.2174/09298673113209990148}, pmid = {23834167}, issn = {1875-533X}, mesh = {Animals ; Antioxidants/*chemistry/*pharmacology ; Galantamine/*analogs &amp; derivatives/*pharmacology ; Humans ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxidative stress is implicated in the pathogenesis of different human diseases: Alzheimer, Parkinson, Huntington, amyotrophic lateral sclerosis (Lou Gehrig's disease), Down's syndrome, atherosclerosis, vascular disease, cancer, diabetes mellitus type 1 and type 2, age - related macular degeneration, psoriatic arthritis. The aim of current study is to summarize the scientific evidences for the antioxidant and neuroprotective activity of Galantamine and some of its derivatives. Galantamine is a scavenger of reactive oxygen species and causes neuroprotective effect by lowering the oxidative neuronal damage, through the following pathways: 1) prevention of the activation of P2X7 receptors; 2) protection of mitochondrial membrane potential; 3) pre - vention of the membrane fluidity disturbances. Another mechanism is the decreasing of the overproduction of reactive oxygen species, a result from the increasing of acetylcholine level due to: 1) acethylcholinesterase inhibition; 2) allosteric potentiation of α7 - subtype of nicotinic acetylcholine receptors. A close relationship between acethylcholinesterase inhibition and reduced oxidative injury is observed. Through allosteric potentiation of the α7 - subtype of nicotinic acetylcholine receptors, the drug leads to induction of phosphorylation of serine - threonine protein kinase, stimulates phosphoinositide 3 - kinase and elevates the expression of protective protein Bcl - 2. By activation of these important neuroprotective cascades, Galantamine exerts neuroprotection against a variety of cytotoxic agents (β- amyloid peptide, glutamate, hydrogen peroxide, oxygen and glucose deprivation). The new trend in therapy of Alzheimer's disease will be the investigation and application of compounds such as Galantamine derivatives, which possess acethylcholinesterase and γ- secretase inhibitory activity and antioxidant properties.}, }
@article {pmid23833266, year = {2014}, author = {Chiò, A and Battistini, S and Calvo, A and Caponnetto, C and Conforti, FL and Corbo, M and Giannini, F and Mandrioli, J and Mora, G and Sabatelli, M and ,  and Ajmone, C and Mastro, E and Pain, D and Mandich, P and Penco, S and Restagno, G and Zollino, M and Surbone, A}, title = {Genetic counselling in ALS: facts, uncertainties and clinical suggestions.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {85}, number = {5}, pages = {478-485}, doi = {10.1136/jnnp-2013-305546}, pmid = {23833266}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/therapy ; Frontotemporal Dementia/diagnosis/genetics/therapy ; *Genetic Counseling ; Genetic Testing ; Genotype ; Humans ; Mutation/genetics ; Phenotype ; }, abstract = {The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.}, }
@article {pmid23829360, year = {2014}, author = {Velayudhan, L and Van Diepen, E and Marudkar, M and Hands, O and Suribhatla, S and Prettyman, R and Murray, J and Baillon, S and Bhattacharyya, S}, title = {Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review.}, journal = {Current pharmaceutical design}, volume = {20}, number = {13}, pages = {2218-2230}, doi = {10.2174/13816128113199990434}, pmid = {23829360}, issn = {1873-4286}, support = {G0501775/MRC_/Medical Research Council/United Kingdom ; NIHR-CS-011-001/DH_/Department of Health/United Kingdom ; MR/J012149/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease/drug therapy/etiology ; Amyotrophic Lateral Sclerosis/drug therapy/etiology ; Animals ; Brain Ischemia/drug therapy/etiology ; Cannabinoids/*therapeutic use ; Endocannabinoids/physiology ; Humans ; Huntington Disease/drug therapy/etiology ; Multiple Sclerosis/drug therapy/etiology ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/drug therapy/etiology ; }, abstract = {The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, Huntington's disease, Tourette's syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson's disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington's disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.}, }
@article {pmid23827971, year = {2013}, author = {Salminen, A and Kaarniranta, K and Kauppinen, A and Ojala, J and Haapasalo, A and Soininen, H and Hiltunen, M}, title = {Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome.}, journal = {Progress in neurobiology}, volume = {106-107}, number = {}, pages = {33-54}, doi = {10.1016/j.pneurobio.2013.06.002}, pmid = {23827971}, issn = {1873-5118}, mesh = {Alzheimer Disease/genetics/*metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/genetics/*metabolism ; Autophagy/genetics/*physiology ; Beclin-1 ; Humans ; Membrane Proteins/genetics/*metabolism ; Proteome/*metabolism ; }, abstract = {The accumulation of amyloid-β-containing neuritic plaques and intracellular tau protein tangles are key histopathological hallmarks of Alzheimer's disease (AD). This type of pathology clearly indicates that the mechanisms of neuronal housekeeping and protein quality control are compromised in AD. There is mounting evidence that the autophagosome-lysosomal degradation is impaired, which could disturb the processing of APP and provoke AD pathology. Beclin 1 is a molecular platform assembling an interactome with stimulating and suppressive components which regulate the initiation of the autophagosome formation. Recent studies have indicated that the expression Beclin 1 is reduced in AD brain. Moreover, the deficiency of Beclin 1 in cultured neurons and transgenic mice provokes the deposition of amyloid-β peptides whereas its overexpression reduces the accumulation of amyloid-β. There are several potential mechanisms, which could inhibit the function of Beclin 1 interactome and thus impair autophagy and promote AD pathology. The mechanisms include (i) reduction of Beclin 1 expression or its increased proteolytic cleavage by caspases, (ii) sequestration of Beclin 1 to non-functional locations, such as tau tangles, (iii) formation of inhibitory complexes between Beclin 1 and antiapoptotic Bcl-2 proteins or inflammasomes, (iv) interaction of Beclin 1 with inhibitory neurovirulent proteins, e.g. herpex simplex ICP34.5, or (v) inhibition of the Beclin 1/Vps34 complex through the activation of CDK1 and CDK5. We will shortly introduce the function of Beclin 1 interactome in autophagy and phagocytosis, review the recent evidence indicating that Beclin 1 regulates autophagy and APP processing in AD, and finally examine the potential mechanisms through which Beclin 1 dysfunction could be involved in the pathogenesis of AD.}, }
@article {pmid23827718, year = {2013}, author = {Langen, RC and Gosker, HR and Remels, AH and Schols, AM}, title = {Triggers and mechanisms of skeletal muscle wasting in chronic obstructive pulmonary disease.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {45}, number = {10}, pages = {2245-2256}, doi = {10.1016/j.biocel.2013.06.015}, pmid = {23827718}, issn = {1878-5875}, mesh = {Animals ; Humans ; Muscle, Skeletal/metabolism/*pathology ; Muscular Atrophy/*etiology/metabolism/pathology ; Protein Biosynthesis ; Pulmonary Disease, Chronic Obstructive/*complications/metabolism/pathology ; Signal Transduction ; }, abstract = {Skeletal muscle wasting contributes to impaired exercise capacity, reduced health-related quality of life and is an independent determinant of mortality in chronic obstructive pulmonary disease. An imbalance between protein synthesis and myogenesis on the one hand, and muscle proteolysis and apoptosis on the other hand, has been proposed to underlie muscle wasting in this disease. In this review, the current understanding of the state and regulation of these processes governing muscle mass in this condition is presented. In addition, a conceptual mode of action of disease-related determinants of muscle wasting including disuse, hypoxemia, malnutrition, inflammation and glucocorticoids is provided by overlaying the available associative clinical data with causal evidence, mostly derived from experimental models. Significant progression has been made in understanding and managing muscle wasting in chronic obstructive pulmonary disease. Further examination of the time course of muscle wasting and specific disease phenotypes, as well as the application of systems biology and omics approaches in future research will allow the development of tailored strategies to prevent or reverse muscle wasting in chronic obstructive pulmonary disease. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.}, }
@article {pmid23797033, year = {2013}, author = {D'Amico, E and Factor-Litvak, P and Santella, RM and Mitsumoto, H}, title = {Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {509-527}, pmid = {23797033}, issn = {1873-4596}, support = {1R01ES016348/ES/NIEHS NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; P30ES009089/ES/NIEHS NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; R03 CA159427/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; R03CA159427/CA/NCI NIH HHS/United States ; R01 ES005116/ES/NIEHS NIH HHS/United States ; R01 ES017024/ES/NIEHS NIH HHS/United States ; 1R01ES017024/ES/NIEHS NIH HHS/United States ; 1R01ES0122315/ES/NIEHS NIH HHS/United States ; R01ES005116/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Humans ; Nerve Degeneration/*physiopathology ; Oxidative Stress/*physiology ; }, abstract = {Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.}, }
@article {pmid23795822, year = {2014}, author = {Hitchler, MJ and Domann, FE}, title = {Regulation of CuZnSOD and its redox signaling potential: implications for amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {20}, number = {10}, pages = {1590-1598}, pmid = {23795822}, issn = {1557-7716}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Humans ; Mutation, Missense ; Oxidation-Reduction ; Oxidative Stress ; Signal Transduction ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Superoxides/metabolism ; }, abstract = {SIGNIFICANCE: Molecular oxygen is a Janus-faced electron acceptor for biological systems, serving as a reductant for respiration, or as the genesis for oxygen-derived free radicals that damage macromolecules. Superoxide is well known to perturb nonheme iron proteins, including Fe/S proteins such as aconitase and succinate dehydrogenase, as well as other enzymes containing labile iron such as the prolyl hydroxylase domain-containing family of enzymes; whereas hydrogen peroxide is more specific for two-electron reactions with thiols on glutathione, glutaredoxin, thioredoxin, and the peroxiredoxins.<br><br>RECENT ADVANCES: Over the past two decades, familial cases of amyotrophic lateral sclerosis (ALS) have been shown to have an association with commonly altered superoxide dismutase 1 (SOD1) activity, expression, and protein structure. This has led to speculation that an altered redox balance may have a role in creating the ALS phenotype.<br><br>CRITICAL ISSUES: While SOD1 alterations in familial ALS are manifold, they generally create perturbations in the flux of electrons. The nexus of SOD1 between one- and two-electron signaling processes places it at a key signaling regulatory checkpoint for governing cellular responses to physiological and environmental cues.<br><br>FUTURE DIRECTIONS: The manner in which ALS-associated mutations adjust SOD1's role in controlling the flow of electrons between one- and two-electron signaling processes remains obscure. Here, we discuss the ways in which SOD1 mutations influence the form and function of copper zinc SOD, the consequences of these alterations on free radical biology, and how these alterations might influence cell signaling during the onset of ALS.}, }
@article {pmid23791192, year = {2013}, author = {Qiang, L and Fujita, R and Abeliovich, A}, title = {Remodeling neurodegeneration: somatic cell reprogramming-based models of adult neurological disorders.}, journal = {Neuron}, volume = {78}, number = {6}, pages = {957-969}, doi = {10.1016/j.neuron.2013.06.002}, pmid = {23791192}, issn = {1097-4199}, mesh = {Adult ; Animals ; Disease Models, Animal ; Fibroblasts/pathology/physiology ; Humans ; Induced Pluripotent Stem Cells/pathology/*physiology ; Neural Stem Cells/pathology/*physiology ; Neurodegenerative Diseases/*pathology ; }, abstract = {Epigenetic reprogramming of adult human somatic cells to alternative fates, such as the conversion of human skin fibroblasts to induced pluripotency stem cells (iPSC), has enabled the generation of novel cellular models of CNS disorders. Cell reprogramming models appear particularly promising in the context of human neurological disorders of aging such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), for which animal models may not recapitulate key aspects of disease pathology. In addition, recent developments in reprogramming technology have allowed for more selective cell fate interconversion events, as from skin fibroblasts directly to diverse induced neuron (iN) subtypes. Challenges to human reprogramming-based cell models of disease are the heterogeneity of the human population and the extended temporal course of these disorders. A major goal is the accurate modeling of common nonfamilial "sporadic" forms of brain disorders.}, }
@article {pmid23790210, year = {2013}, author = {Camero, S and Benítez, MJ and Jiménez, JS}, title = {Anomalous protein-DNA interactions behind neurological disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {91}, number = {}, pages = {37-63}, doi = {10.1016/B978-0-12-411637-5.00002-0}, pmid = {23790210}, issn = {1876-1631}, mesh = {DNA/chemistry/*metabolism ; Humans ; Nervous System Diseases/*metabolism/pathology ; Proteins/chemistry/*metabolism ; }, abstract = {Aggregation, nuclear location, and nucleic acid interaction are common features shared by a number of proteins related to neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, transmissible spongiform encephalopathy, Huntington's disease, spinobulbar muscular atrophy, dentatorubro-pallidoluysian atrophy, and several spinocerebellar ataxias. β-Amyloid peptides, tau protein, α-synuclein, superoxide dismutase1, prion protein, huntingtin, atrophin1, androgen receptor, and several ataxins are proteins prone to becoming aggregated, to translocate inside cell nucleus, and to bind DNA. In this chapter, we review those common features suggesting that neurological diseases too may share a transcriptional disorder, making it an important contribution to the origin of the disease.}, }
@article {pmid23793952, year = {2013}, author = {Binukumar, BK and Shukla, V and Amin, ND and Reddy, P and Skuntz, S and Grant, P and Pant, HC}, title = {Topographic regulation of neuronal intermediate filaments by phosphorylation, role of peptidyl-prolyl isomerase 1: significance in neurodegeneration.}, journal = {Histochemistry and cell biology}, volume = {140}, number = {1}, pages = {23-32}, pmid = {23793952}, issn = {1432-119X}, support = {//Intramural NIH HHS/United States ; }, mesh = {Humans ; Intermediate Filaments/*enzymology/*pathology ; Neurodegenerative Diseases/enzymology/physiopathology ; Neurons/*enzymology/pathology ; Peptidylprolyl Isomerase/*metabolism ; Phosphorylation ; }, abstract = {The neuronal cytoskeleton is tightly regulated by phosphorylation and dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Defects in the relative kinase and phosphatase activities and/or deregulation of compartment-specific phosphorylation result in neurodegenerative disorders. The largest family of cytoskeletal proteins in mammalian cells is the superfamily of intermediate filaments (IFs). The neurofilament (NF) proteins are the major IFs. Aggregated forms of hyperphosphorylated tau and phosphorylated NFs are found in pathological cell body accumulations in the central nervous system of patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The precise mechanisms for this compartment-specific phosphorylation of cytoskeletal proteins are not completely understood. In this review, we focus on the mechanisms of neurofilament phosphorylation in normal physiology and neurodegenerative diseases. We also address the recent breakthroughs in our understanding the role of different kinases and phosphatases involved in regulating the phosphorylation status of the NFs. In addition, special emphasis has been given to describe the role of phosphatases and Pin1 in phosphorylation of NFs.}, }
@article {pmid23791779, year = {2013}, author = {Greek, R and Hansen, LA}, title = {Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse.}, journal = {Progress in biophysics and molecular biology}, volume = {113}, number = {2}, pages = {231-253}, doi = {10.1016/j.pbiomolbio.2013.06.002}, pmid = {23791779}, issn = {1873-1732}, mesh = {Adaptation, Physiological/*genetics ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Brain/*physiopathology ; Computer Simulation ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; *Models, Genetic ; Neuronal Plasticity/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {We surveyed the scientific literature regarding amyotrophic lateral sclerosis, the SOD1 mouse model, complex adaptive systems, evolution, drug development, animal models, and philosophy of science in an attempt to analyze the SOD1 mouse model of amyotrophic lateral sclerosis in the context of evolved complex adaptive systems. Humans and animals are examples of evolved complex adaptive systems. It is difficult to predict the outcome from perturbations to such systems because of the characteristics of complex systems. Modeling even one complex adaptive system in order to predict outcomes from perturbations is difficult. Predicting outcomes to one evolved complex adaptive system based on outcomes from a second, especially when the perturbation occurs at higher levels of organization, is even more problematic. Using animal models to predict human outcomes to perturbations such as disease and drugs should have a very low predictive value. We present empirical evidence confirming this and suggest a theory to explain this phenomenon. We analyze the SOD1 mouse model of amyotrophic lateral sclerosis in order to illustrate this position.}, }
@article {pmid23791710, year = {2013}, author = {Sharma, S and Moon, CS and Khogali, A and Haidous, A and Chabenne, A and Ojo, C and Jelebinkov, M and Kurdi, Y and Ebadi, M}, title = {Biomarkers in Parkinson's disease (recent update).}, journal = {Neurochemistry international}, volume = {63}, number = {3}, pages = {201-229}, doi = {10.1016/j.neuint.2013.06.005}, pmid = {23791710}, issn = {1872-9754}, mesh = {Biomarkers/*metabolism ; Humans ; Parkinson Disease/*metabolism ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of α-Syn, DJ-1, amyloid β and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T2 relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [(18)F]-DOPA for estimating dopaminergic neurotransmission, [(18)F]dG for mitochondrial bioenergetics, [(18)F]BMS for mitochondrial complex-1, [(11)C](R)-PK11195 for microglial activation, SPECT imaging with (123)Iflupane and βCIT for dopamine transporter, and urinary salsolinol and 8-hydroxy, 2-deoxyguanosine for neuronal loss. This brief review describes the merits and limitations of recently discovered biomarkers and proposes coenzyme Q10, mitochondrial ubiquinone-NADH oxidoreductase, melatonin, α-synculein index, Charnoly body, and metallothioneins as novel biomarkers to confirm PD diagnosis for early and effective treatment of PD.}, }
@article {pmid23781715, year = {2013}, author = {Leon-Sarmiento, FE and Granadillo, E and Bayona, EA}, title = {[Present and future of the transcranial magnetic stimulation].}, journal = {Investigacion clinica}, volume = {54}, number = {1}, pages = {74-89}, pmid = {23781715}, issn = {0535-5133}, mesh = {Brain Diseases/diagnosis/metabolism/therapy ; Humans ; Mental Disorders/metabolism/therapy ; Nervous System Diseases/*diagnosis/metabolism/rehabilitation/*therapy ; Neurotransmitter Agents/blood/cerebrospinal fluid ; Patient Safety ; Patient Selection ; Surveys and Questionnaires ; Transcranial Magnetic Stimulation/adverse effects/methods/*trends ; }, abstract = {Magnetic stimulation has called the attention of neuroscientists and the public due to the possibility to stimulate and "control" the nervous system in a non-invasive way. It has helped to make more accurate diagnosis, and apply more effective treatments and rehabilitation protocols in several diseases that affect the nervous system. Likewise, this novel tool has increased our knowledge about complex neural behavior, its connections as well as its plastic modulation. Magnetic stimulation applied in simple or paired-pulse protocols is a useful alternative in the diagnosis of diseases such as multiple sclerosis, Parkinson disease, epilepsy, dystonia, amyotrophic lateral sclerosis, cerebrovascular disease, and sleep disorders. From the therapeutic perspective, magnetic stimulation applied repetitively has been found useful, with different degrees of efficacy, in treating resistant depression, tinnitus, psychogenic dysphonia, Alzheimer disease, autism, Parkinson disease, dystonia, stroke, epilepsy, generalized anxiety as well as post traumatic stress disorder, auditory hallucinations, chronic pain, aphasias, obsessive-compulsive disorders, L-dopa induced dyskynesia, mania and Rasmussen syndrome, among others. The potential of magnetic stimulation in neurorehabilitation is outstanding, with excellent range of safety and, in practical terms, without side effects.}, }
@article {pmid23777095, year = {2013}, author = {Matsui, N and Miyashiro, A and Kaji, R}, title = {[Update of multifocal motor neuropathy].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {71}, number = {5}, pages = {861-864}, pmid = {23777095}, issn = {0047-1852}, mesh = {Age Distribution ; Amyotrophic Lateral Sclerosis/drug therapy/*epidemiology ; Diagnosis, Differential ; Humans ; Immunoglobulins, Intravenous/*therapeutic use ; Japan/epidemiology ; Polyneuropathies/*drug therapy/*epidemiology ; }, abstract = {We surveyed patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. This retrospective study consisted of 47 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.3 cases for MMN and 6.63 cases for ALS per 100,000 persons. Twenty-seven of 47 patients (56.5%) showed conduction block (CB). Of the 45 patients who received intravenous immunoglobulin (MVg), 34(75.6 %) demonstrated clear clinical improvement.}, }
@article {pmid23776162, year = {2013}, author = {Mroczek, S and Dziembowski, A}, title = {U6 RNA biogenesis and disease association.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {4}, number = {5}, pages = {581-592}, doi = {10.1002/wrna.1181}, pmid = {23776162}, issn = {1757-7012}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Genetic Diseases, Inborn/*genetics ; Humans ; Muscular Atrophy, Spinal/genetics ; Neutropenia/genetics ; Phosphoric Diester Hydrolases/deficiency/metabolism ; *RNA Splicing ; RNA, Small Nuclear/*biosynthesis/chemistry ; Retinitis Pigmentosa/genetics ; Skin Abnormalities/genetics ; *Transcription, Genetic ; }, abstract = {U6 snRNA is one of five uridine-rich noncoding RNAs that form the major spliceosome complex. Unlike other U-snRNAs, it reveals many distinctive aspects of biogenesis such as transcription by RNA polymerase III, transcript nuclear retention and particular features of transcript ends: monomethylated 5'-guanosine triphosphate as cap structure and a 2',3'-cyclic phosphate moiety (>P) at the 3' termini. U6-snRNA plays a central role in splicing and thus its transcription, maturation, snRNP formation, and recycling are essential for cellular homeostasis. U6 snRNA enters the splicing cycle as part of the tri-U4/U6.U5snRNP complex, and after significant structural arrangements forms the catalytic site of the spliceosome together with U2 snRNA and Prp8. U6 snRNA also contributes to the splicing reaction by coordinating metal cations required for catalysis. Many human diseases are associated with altered splicing processes. Disruptions of the basal splicing machinery can be lethal or lead to severe diseases such as spinal muscular atrophy, amyotrophic lateral sclerosis, or retinitis pigmentosa. Recent studies have identified a new U6 snRNA biogenesis factor Usb1, the absence of which leads to poikiloderma with neutropenia (PN) (OMIM 604173), an autosomal recessive skin disease. Usb1 is an evolutionarily conserved 3'→5' exoribonuclease that is responsible for removing 3'-terminal uridines from U6 snRNA transcripts, which leads to the formation of a 2',3' cyclic phosphate moiety (>P). This maturation step is fundamental for U6 snRNP assembly and recycling. Usb1 represents the first example of a direct association between a spliceosomal U6 snRNA biogenesis factor and human genetic disease.}, }
@article {pmid23773928, year = {2013}, author = {Lizama-Manibusan, B and McLaughlin, B}, title = {Redox modification of proteins as essential mediators of CNS autophagy and mitophagy.}, journal = {FEBS letters}, volume = {587}, number = {15}, pages = {2291-2298}, pmid = {23773928}, issn = {1873-3468}, support = {R01 ES022936/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; *Autophagy ; Central Nervous System/immunology/*metabolism ; Humans ; *Mitophagy ; Oxidation-Reduction ; Proteins/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Production of cellular reactive oxygen species (ROS) is typically associated with protein and DNA damage, toxicity, and death. However, ROS are also essential regulators of signaling and work in concert with redox-sensitive proteins to regulate cell homeostasis during stress. In this review, we focus on the redox regulation of mitophagy, a process that contributes to energetic tone as well as mitochondrial form and function. Mitophagy has been increasingly implicated in diseases including Parkinson's, Amyotrophic Lateral Sclerosis, and cancer. Although these disease states employ different genetic mutations, they share the common factors of redox dysregulation and autophagic signaling. This review highlights key redox sensitive signaling molecules which can enhance neuronal survival by promoting temporally and spatially controlled autophagic signaling and mitophagy.}, }
@article {pmid23773350, year = {2013}, author = {Ayach, L and Curti, C and Montana, M and Pisano, P and Vanelle, P}, title = {[Amyotrophic lateral sclerosis: update on etiological treatment].}, journal = {Therapie}, volume = {68}, number = {2}, pages = {93-106}, doi = {10.2515/therapie/2013012}, pmid = {23773350}, issn = {0040-5957}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/*therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Longitudinal Studies ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Stem Cell Transplantation ; Survival ; }, abstract = {Amyotrophic lateral sclerosis is a rare neurodegenerative disease. It is characterized by motoneurons progressive degeneration. Associated with a paralysis of the legs, arms and the respiratory muscles, its evolution is lethal. Riluzole is the only drug available with an marketing authorisation (autorisation de mise sur le marché [AMM]) in this indication. In the beginning stages of the disease it demonstrated a modest efficacy by prolonging survival for a few months. Although the physiopathological mechanisms of this disease have not been totally solved, the progression of knowledge in recent years in this area led to the development of a large number of neuroprotective agents which showed effective results in animal models of ALS and which could be good candidates for the treatment of ALS. Several clinical trials have been conducted about antiglutamatergic, antioxidant, antiapoptotic agents and growing cell factors but they failed to demonstrate efficacy on survival or quality of life. Therefore, clinical trials using innovative therapeutics and stem cells are ongoing and offer more distant hope.}, }
@article {pmid23764168, year = {2013}, author = {Prell, T and Lautenschläger, J and Grosskreutz, J}, title = {Calcium-dependent protein folding in amyotrophic lateral sclerosis.}, journal = {Cell calcium}, volume = {54}, number = {2}, pages = {132-143}, doi = {10.1016/j.ceca.2013.05.007}, pmid = {23764168}, issn = {1532-1991}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Calcium/*physiology ; Disease Models, Animal ; Endoplasmic Reticulum/physiology ; Endoplasmic Reticulum Chaperone BiP ; Homeostasis/physiology ; Humans ; Mice ; *Protein Folding ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by a progressive loss of motor neurons. Although the etiology remains unclear, disturbances in Ca2+ homoeostasis and protein folding are essential features of neurodegeneration. The correct folding of proteins is managed by folding proteins, which are regulated by Ca2+ levels. Therefore, Ca(2+)-sensitive folding proteins represent an important link between disturbed Ca2+ handling and protein misfolding in amyotrophic lateral sclerosis. In the first part of this review, we focus on Ca2+ handling in the endoplasmic reticulum and mitochondria in terms of their roles in protein misfolding. In the second part, we draw attention to the main Ca(2+)-sensitive folding proteins that play a role in motor neuron degeneration such as calreticulin and calnexin, which are involved in the folding of glycosylated proteins. In addition, calmodulin and the Ca2+/calmodulin-dependent protein kinase are discussed as one correlation to oxidative stress. The heat shock protein endoplasmin is associated with the anti-apoptotic insulin-like growth factor pathway that is altered in amyotrophic lateral sclerosis. Grp78, which influences Ca2+ homeostasis in the intraluminal endoplasmic reticulum is upregulated in mice models and amyotrophic lateral sclerosis patients and constitutes a core component of the unfolded protein response. Lastly, the protein disulfide isomerase family is responsible for mediating oxidative protein folding in the endoplasmic reticulum.}, }
@article {pmid23759795, year = {2013}, author = {Björkhem, I}, title = {Cerebrotendinous xanthomatosis.}, journal = {Current opinion in lipidology}, volume = {24}, number = {4}, pages = {283-287}, doi = {10.1097/MOL.0b013e328362df13}, pmid = {23759795}, issn = {1473-6535}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Brain/metabolism/pathology ; Cholestanetriol 26-Monooxygenase/genetics ; Cholestanol/metabolism ; Cholesterol/metabolism ; Genetic Predisposition to Disease ; Humans ; Lipid Metabolism ; Tendons/metabolism ; Xanthomatosis, Cerebrotendinous/genetics/*metabolism ; }, abstract = {PURPOSE OF REVIEW: Cerebrotendinous xanthomatosis (CTX) is a rare neurological disease characterized by accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1). The mechanism behind the accumulation of cholestanol in the brain was recently clarified and a role of 27-hydroxycholesterol as a regulator of brain cholesterol homeostasis has been established.<br><br>RECENT FINDINGS: There is a significant flux of the bile acid precursor 7&#x3b1;-hydroxy-4-cholesten-3-one across the blood-brain barrier in cy27-/- mice with its subsequent conversion into cholestanol. CTX patients with white matter lesions and vacuolation are described. CYP27A1 was identified as a candidate gene for sporadic amyotrophic lateral sclerosis (ALS).<br><br>SUMMARY: The mechanism behind accumulation of cholestanol in brain and tendons of patients with CTX has been clarified but it is not known why this accumulation is associated with parallel accumulation of cholesterol and formation of xanthomas. Further studies are needed to understand why some patients with CTX develop white matter lesions in the brain. In view of the fact that CTX can present with upper motor neuronal signs it is interesting that CYP27 has been shown to be a candidate gene for sporadic ALS.}, }
@article {pmid23756188, year = {2013}, author = {Wu, P and Zuo, X and Deng, H and Liu, X and Liu, L and Ji, A}, title = {Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases.}, journal = {Brain research bulletin}, volume = {97}, number = {}, pages = {69-80}, doi = {10.1016/j.brainresbull.2013.06.001}, pmid = {23756188}, issn = {1873-2747}, mesh = {Animals ; Brain/*growth &amp; development/*physiopathology ; Homeobox Protein Nkx-2.2 ; Homeodomain Proteins ; Humans ; Neurodegenerative Diseases/*genetics/physiopathology ; Nuclear Proteins ; RNA, Long Noncoding/*physiology ; Transcription Factors ; }, abstract = {Long noncoding RNAs (lncRNAs) have been attracting immense research interest, while only a handful of lncRNAs have been characterized thoroughly. Their involvement in the fundamental cellular processes including regulate gene expression at epigenetics, transcription, and post-transcription highlighted a central role in cell homeostasis. However, lncRNAs studies are still at a relatively early stage, their definition, conservation, functions, and action mechanisms remain fairly complicated. Here, we give a systematic and comprehensive summary of the existing knowledge of lncRNAs in order to provide a better understanding of this new studying field. lncRNAs play important roles in brain development, neuron function and maintenance, and neurodegenerative diseases are becoming increasingly evident. In this review, we also highlighted recent studies related lncRNAs in central nervous system (CNS) development and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), and elucidated some specific lncRNAs which may be important for understanding the pathophysiology of neurodegenerative diseases, also have the potential as therapeutic targets.}, }
@article {pmid23748053, year = {2013}, author = {Stock, ML and Fiedler, KJ and Acharya, S and Lange, JK and Mlynarczyk, GS and Anderson, SJ and McCormack, GR and Kanuri, SH and Kondru, NC and Brewer, MT and Carlson, SA}, title = {Antibiotics acting as neuroprotectants via mechanisms independent of their anti-infective activities.}, journal = {Neuropharmacology}, volume = {73}, number = {}, pages = {174-182}, doi = {10.1016/j.neuropharm.2013.04.059}, pmid = {23748053}, issn = {1873-7064}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Humans ; Minocycline/pharmacology/therapeutic use ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*pharmacology/therapeutic use ; Sirolimus/pharmacology/therapeutic use ; beta-Lactams/pharmacology/therapeutic use ; }, abstract = {This review considers available evidence that some antibiotics have ancillary neuroprotective effects. Notably, β-lactam antibiotics are believed to increase the expression of glutamate transporter GLT1, potentially relieving the neurological excitotoxicity that characterizes disorders like amyotrophic lateral sclerosis. Minocycline has shown promise in reducing the severity of a number of neurological diseases, including multiple sclerosis, most likely by reducing apoptosis and the expression of inflammatory mediators in the brain. Rapamycin inhibits the activity of a serine/threonine protein kinase that has a role in the pathogenesis of numerous neurologic diseases. Herein we examine the unique neuroprotective aspects of these drugs originally developed as anti-infective agents.}, }
@article {pmid23746459, year = {2013}, author = {Cruts, M and Gijselinck, I and Van Langenhove, T and van der Zee, J and Van Broeckhoven, C}, title = {Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum.}, journal = {Trends in neurosciences}, volume = {36}, number = {8}, pages = {450-459}, doi = {10.1016/j.tins.2013.04.010}, pmid = {23746459}, issn = {1878-108X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/metabolism ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/diagnosis/*genetics/metabolism ; Genetic Predisposition to Disease/*genetics ; Humans ; Inclusion Bodies/metabolism ; Models, Genetic ; Proteins/*genetics ; }, abstract = {An expanded G4C2 hexanucleotide repeat in the proximal regulatory region of C9orf72 is a frequent cause of neurodegenerative diseases in the frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) spectrum. Although primarily characterized by variably abundant pathological inclusions of TDP-43 protein, the lesion load was extended to TDP-43-negative, p62-positive neuronal and glial inclusions in extended regions of the central nervous system (CNS), particularly in cerebellum, where they may be characteristic of a C9orf72 repeat expansion. Disease mechanisms associated with repeat expansion disorders, including haploinsufficiency, RNA toxicity, and abnormal translation of expanded repeat sequences, are beginning to emerge. We review genetic, clinical, and pathological highlights and discuss current insights into the biology of this novel type of repeat expansion disease.}, }
@article {pmid23744169, year = {2013}, author = {Skoczyński, S and Tażbirek, M and Pierzchała, W}, title = {[Non-invasive ventilation in treatment of adults with chronic respiratory failure].}, journal = {Pneumonologia i alergologia polska}, volume = {81}, number = {4}, pages = {380-389}, pmid = {23744169}, issn = {0867-7077}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/epidemiology/therapy ; Causality ; Comorbidity ; Humans ; Noninvasive Ventilation/*methods ; Pulmonary Disease, Chronic Obstructive/epidemiology/therapy ; Respiratory Insufficiency/epidemiology/*therapy ; Sleep Apnea, Central/epidemiology/therapy ; }, abstract = {Non-invasive mechanical ventilation (NIV) is a modern method of chronic respiratory failure (CRF) treatment. With the development of medicine and society known as "western", the number of elderly people, in whom there is overlapping of chronic diseases such as COPD, is growing. In adult population NIV is used in the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. The other main indications include restrictive diseases such as kyphoscoliosis, pulmonary diseases with COPD which is the primary indication, and various forms of central apnea syndrome with epidemiologically essential role of obesity hypoventilation syndrome (OHS). In each of those indications, and in different patients, the mode and ventilation intensity may significantly differ. The aim of this review is to disseminate knowledge on the potential role of NIV in adults with CRF. This paper attempts to analyze the available knowledge concerning NIV in adults with CRF. Special attention is paid to the potential pathomechanisms which should become the subject of future research.}, }
@article {pmid23740607, year = {2013}, author = {Brettschneider, J and Kurent, J and Ludolph, A}, title = {Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2013}, number = {6}, pages = {CD005226}, pmid = {23740607}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications ; Humans ; Motor Neuron Disease/complications ; Pain/*drug therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS. This is an update of a review first published in 2008.<br><br>OBJECTIVES: To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life.<br><br>SEARCH METHODS: On 2 July 2012, we searched the following databases: the Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), CINAHL (January 1982 to June 2012), AMED (January 1985 to June 2012) and LILACS (January 1982 to June 2012). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials.<br><br>SELECTION CRITERIA: We searched for randomised or quasi-randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: We collected data using a specially designed form and analysed them using the Cochrane Review Manager software.<br><br>MAIN RESULTS: We found no randomised or quasi-randomised controlled trials on drug therapy for pain in ALS or MND.<br><br>AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS.}, }
@article {pmid23735671, year = {2013}, author = {Eisen, A and Krieger, C}, title = {Ethical considerations in the management of amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {110}, number = {}, pages = {45-53}, doi = {10.1016/j.pneurobio.2013.05.001}, pmid = {23735671}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/genetics/*therapy ; Clinical Trials as Topic/*ethics/methods ; Cognition Disorders/diagnosis/etiology ; Employment ; Genetic Testing/ethics/methods ; Humans ; Patient Care Management/*ethics ; }, abstract = {This article examines some of the ethical concerns relevant for the management of amyotrophic lateral sclerosis (ALS). We emphasize the importance for providing a competent assessment of the clinical deficit to correctly identify the disease and to avoid incorrect diagnoses. Conveying the diagnosis to the patient and their family requires empathy and it is important to remain supportive and positive, even in the face of this incurable disease. The essence of care in ALS is to permit the patient to have optimal function for their level of ability. This may require the use of gastrostomy and non-invasive or permanent ventilation. Employment of a multi-disciplinary team will permit optimization of patient care to achieve a good quality of life for as long as possible. The patient should also be informed of the risks associated with unproven therapies and the risks and potential benefits of therapeutic trials. The wishes of patients in regard to gastrostomy, long-term ventilation and end-of life decisions must be considered in an unbiased fashion. Recent advances in the genetics of familial ALS (FALS) have demonstrated some overlap between FALS, sporadic ALS and fronto-temporal lobar dementia (FTLD). The interpretation and dissemination of the results of genetic testing although important can induce confusion, considerable anxiety and guilt in patients and their families and proper counseling is imperative.}, }
@article {pmid23728676, year = {2013}, author = {Fang, J and Zhou, M and Yang, M and Zhu, C and He, L}, title = {Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2013}, number = {5}, pages = {CD008554}, pmid = {23728676}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/therapy ; Randomized Controlled Trials as Topic ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain. This is the first update of a review published in 2011.<br><br>OBJECTIVES: To determine the clinical efficacy and safety of rTMS for treating ALS.<br><br>SEARCH METHODS: On 30 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, issue 7 in The Cochrane Library), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012), CINAHL (1937 to July 2012), Science Citation Index Expanded (January 1945 to July 2012), AMED (January 1985 to July 2012). We searched the Chinese Biomedical Database (1979 to August 2012). We also searched for ongoing studies on clinicaltrials.gov (August 2012).<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (&#x2264; 1Hz) rTMS.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information.<br><br>MAIN RESULTS: Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All three trials compared rTMS with sham TMS. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe.<br><br>AUTHORS' CONCLUSIONS: There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS.}, }
@article {pmid23728653, year = {2013}, author = {Dal Bello-Haas, V and Florence, JM}, title = {Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2013}, number = {5}, pages = {CD005229}, pmid = {23728653}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; Exercise Therapy/*methods ; Exercise Tolerance ; Humans ; Motor Neuron Disease/psychology/therapy ; Muscle Weakness/therapy ; Physical Endurance ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. This is an update of a review first published in 2008.<br><br>OBJECTIVES: To systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND.<br><br>SEARCH METHODS: We searched The Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), AMED (January 1985 to June 2012), CINAHL Plus (January 1938 to June 2012), LILACS (January 1982 to June 2012), Ovid HealthSTAR (January 1975 to December 2012). We also searched ProQuest Dissertations &amp; Theses A&amp;I (2007 to 2012), inspected the reference lists of all papers selected for review and contacted authors with expertise in the field.<br><br>SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible ALS, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise, and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. We did not exclude studies on the basis of measurement of outcomes.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. We collected adverse event data from included trials. The review authors contacted the authors of the included studies to obtain information not available in the published articles.<br><br>MAIN RESULTS: We identified two randomised controlled trials that met our inclusion criteria, and we found no new trials when we updated the searches in 2012. The first, a study with overall unclear risk of bias, examined the effects of a twice-daily exercise program of moderate load endurance exercise versus "usual activities" in 25 people with ALS. The second, a study with overall low risk of bias, examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined (43 participants), there was a significant mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in favour of the exercise groups (mean difference 3.21, 95% confidence interval 0.46 to 5.96). No statistically significant differences in quality of life, fatigue or muscle strength were found. In both trials adverse effects, investigators reported no adverse effects such as increased muscle cramping, muscle soreness or fatigue<br><br>AUTHORS' CONCLUSIONS: The included studies were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.}, }
@article {pmid23728364, year = {2013}, author = {Prabhakar, A and Owen, CP and Kaye, AD}, title = {Anesthetic management of the patient with amyotrophic lateral sclerosis.}, journal = {Journal of anesthesia}, volume = {27}, number = {6}, pages = {909-918}, pmid = {23728364}, issn = {1438-8359}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Anesthetics/*administration &amp; dosage ; Humans ; Motor Neurons/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS), with an incidence of 1.5-2.5 for 100 000 per year, is a rare but rapid progression neuromuscular degeneration disorder that poses unique perioperatively challenges to clinical anesthesiologists. The progressive degeneration of motor neurons causes a constellation of symptoms, including muscular weakness, atrophy, fasciculations, spasticity, and hyperreflexia. Therapeutic and experimental treatments, including riluzole, beta lactams, methylcobalamin, dexpramipexole, antiepileptics, antioxidant agents, neutrophin, antiinflammatory agents, and antiapoptosis drugs, are described. Newer therapies, such as neural stem cells and diaphragmatic pacing, are presented. Because of the inherent muscle weakness and associated respiratory insufficiency, certain precautions must be utilized during anesthetic care of ALS patients. In particular, certain neuromuscular agents are contraindicated and anesthetics that leave the body more rapidly present logical and attractive options in this population. A solid understanding of the disease process, therapeutic interventions, and anesthesia considerations are all paramount for the successful management of a patient with ALS in the perioperative setting.}, }
@article {pmid23727226, year = {2013}, author = {Johnson, RA and Mitchell, GS}, title = {Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {189}, number = {2}, pages = {419-428}, pmid = {23727226}, issn = {1878-1519}, support = {R01 HL065383/HL/NHLBI NIH HHS/United States ; R01 HL080209/HL/NHLBI NIH HHS/United States ; R37 HL069064/HL/NHLBI NIH HHS/United States ; UL1 TR000427/TR/NCATS NIH HHS/United States ; }, mesh = {Adaptation, Physiological/*physiology ; Animals ; Humans ; Motor Neurons/physiology ; Nervous System Diseases/diagnosis/*physiopathology ; Neuronal Plasticity/*physiology ; Respiratory Center/physiology ; Respiratory Mechanics/*physiology ; Spinal Cord Injuries/diagnosis/*physiopathology ; }, abstract = {In many neurological disorders that disrupt spinal function and compromise breathing (e.g. ALS, cervical spinal injury, MS), patients often maintain ventilatory capacity well after the onset of severe CNS pathology. In progressive neurodegenerative diseases, patients ultimately reach a point where compensation is no longer possible, leading to catastrophic ventilatory failure. In this brief review, we consider evidence that common mechanisms of compensatory respiratory plasticity preserve breathing capacity in diverse clinical disorders, despite the onset of severe pathology (e.g. respiratory motor neuron denervation and/or death). We propose that a suite of mechanisms, operating at distinct sites in the respiratory control system, underlies compensatory respiratory plasticity, including: (1) increased (descending) central respiratory drive, (2) motor neuron plasticity, (3) plasticity at the neuromuscular junction or spared respiratory motor neurons, and (4) shifts in the balance from more to less severely compromised respiratory muscles. To establish this framework, we contrast three rodent models of neural dysfunction, each posing unique problems for the generation of adequate inspiratory motor output: (1) respiratory motor neuron death, (2) de- or dysmyelination of cervical spinal pathways, and (3) cervical spinal cord injury, a neuropathology with components of demyelination and motor neuron death. Through this contrast, we hope to understand the multilayered strategies used to "fight" for adequate breathing in the face of mounting pathology.}, }
@article {pmid23725821, year = {2014}, author = {Rivadeneyra-Domínguez, E and Rodríguez-Landa, JF}, title = {Cycads and their association with certain neurodegenerative diseases.}, journal = {Neurologia (Barcelona, Spain)}, volume = {29}, number = {9}, pages = {517-522}, doi = {10.1016/j.nrl.2013.03.005}, pmid = {23725821}, issn = {1578-1968}, mesh = {Amino Acids, Diamino/*poisoning/*toxicity ; Animals ; Cyanobacteria Toxins ; Cycas/*poisoning ; Cycasin/*poisoning ; Excitatory Amino Acid Agonists/poisoning ; Guam ; Humans ; Methylazoxymethanol Acetate/*analogs &amp; derivatives/poisoning ; Neurodegenerative Diseases/*chemically induced ; Neurotoxins/*poisoning ; Plant Poisoning ; }, abstract = {INTRODUCTION: Cycads are ornamental plants that in some parts of the world are used as fresh food or raw material for producing flour with a high nutritional value. However, they also contain active compounds, including methylazoxymethanol, β-methylamino-L-alanine, β-alanine-L-oxalylamino and cycasin, which may produce neurotoxic effects. Some studies have associated consuming cycads and their derivatives with neurodegenerative diseases such as amyotrophic lateral sclerosis/Parkinsonism dementia complex, and other diseases characterised by motor impairment. Therefore, we must not forget that any product, no matter how natural, may present health risks or benefits depending on the chemical compounds it contains and the susceptibility of those who consume it.<br><br>DEVELOPMENT: We completed a literature analysis to evaluate the neurotoxic properties of cycads and their association with neurological diseases in order to provide structured scientific information that may contribute to preventing health problems in people who use these plants.<br><br>CONCLUSION: Cycads contain neurotoxic compounds that may contribute to the development of neurological diseases when ingested improperly. We must be mindful of the fact that while some plants have a high nutritional value and may fill the food gap for vulnerable populations, they can also be toxic and have a negative impact on health.}, }
@article {pmid23712361, year = {2013}, author = {Potokar, M and Vardjan, N and Stenovec, M and Gabrijel, M and Trkov, S and Jorgačevski, J and Kreft, M and Zorec, R}, title = {Astrocytic vesicle mobility in health and disease.}, journal = {International journal of molecular sciences}, volume = {14}, number = {6}, pages = {11238-11258}, pmid = {23712361}, issn = {1422-0067}, mesh = {Animals ; Astrocytes/cytology/*metabolism ; *Disease ; Endocytosis ; *Health ; Humans ; Membrane Transport Proteins/metabolism ; Secretory Vesicles/*metabolism ; }, abstract = {Astrocytes are no longer considered subservient to neurons, and are, instead, now understood to play an active role in brain signaling. The intercellular communication of astrocytes with neurons and other non-neuronal cells involves the exchange of molecules by exocytotic and endocytotic processes through the trafficking of intracellular vesicles. Recent studies of single vesicle mobility in astrocytes have prompted new views of how astrocytes contribute to information processing in nervous tissue. Here, we review the trafficking of several types of membrane-bound vesicles that are specifically involved in the processes of (i) intercellular communication by gliotransmitters (glutamate, adenosine 5'-triphosphate, atrial natriuretic peptide), (ii) plasma membrane exchange of transporters and receptors (EAAT2, MHC-II), and (iii) the involvement of vesicle mobility carrying aquaporins (AQP4) in water homeostasis. The properties of vesicle traffic in astrocytes are discussed in respect to networking with neighboring cells in physiologic and pathologic conditions, such as amyotrophic lateral sclerosis, multiple sclerosis, and states in which astrocytes contribute to neuroinflammatory conditions.}, }
@article {pmid23711791, year = {2013}, author = {Harrison, IF and Dexter, DT}, title = {Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?.}, journal = {Pharmacology &amp; therapeutics}, volume = {140}, number = {1}, pages = {34-52}, doi = {10.1016/j.pharmthera.2013.05.010}, pmid = {23711791}, issn = {1879-016X}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Animals ; Epigenesis, Genetic ; Epigenomics ; Gene Expression ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Histone Deacetylases/*metabolism ; Humans ; Parkinson Disease/drug therapy/*genetics/*metabolism ; }, abstract = {Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD?}, }
@article {pmid23711197, year = {2014}, author = {Mori, F and Kakita, A and Takahashi, H and Wakabayashi, K}, title = {Co-localization of Bunina bodies and TDP-43 inclusions in lower motor neurons in amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {34}, number = {1}, pages = {71-76}, doi = {10.1111/neup.12044}, pmid = {23711197}, issn = {1440-1789}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*pathology ; Brain Stem/pathology ; DNA-Binding Proteins/*analysis ; Female ; Humans ; Inclusion Bodies/chemistry/*ultrastructure ; Male ; Medulla Oblongata/pathology ; Middle Aged ; Motor Neurons/chemistry/*ultrastructure ; Spinal Cord/ultrastructure ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron involvement with Bunina bodies (BBs) and transactivation response DNA protein 43 (TDP-43) inclusions. We examined the spinal cord (n = 20), hypoglossal nucleus (n = 6) and facial nucleus (n = 5) from ALS patients to elucidate the relationship between BBs and TDP-43 inclusions. BBs were found in the anterior horn in 16 of 20 cases, in the hypoglossal nucleus in all six cases and in the facial nucleus in four out of five cases. TDP-43 inclusions were found in each region of all the cases. Co-localization of BBs and TDP-43 inclusions was found in 15.2% of total neurons in the anterior horn, 29.2% in the hypoglossal nucleus and 17.3% in the facial nucleus. The frequency of TDP-43 inclusions was significantly higher in neurons with BBs than in those without in each region. Ultrastructurally, TDP-43-positive filamentous structures were intermingled with BBs. These findings suggest that there is a close relationship in the occurrence between BBs and TDP-43 inclusions.}, }
@article {pmid23707220, year = {2013}, author = {Alfahad, T and Nath, A}, title = {Retroviruses and amyotrophic lateral sclerosis.}, journal = {Antiviral research}, volume = {99}, number = {2}, pages = {180-187}, pmid = {23707220}, issn = {1872-9096}, support = {ZIA NS003130-02//Intramural NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*virology ; Central Nervous System/virology ; *Endogenous Retroviruses/genetics/isolation &amp; purification ; Female ; HIV Infections/complications ; HTLV-I Infections/complications ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology/*virology ; Retroviridae Infections/*virology ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, invariably fatal neurologic disorder resulting from upper and lower motor neuron degeneration, which typically develops during the sixth or seventh decade of life, and is diagnosed based on standard clinical criteria. Its underlying cause remains undetermined. The disease may occur with increased frequency within certain families, often in association with specific genomic mutations, while some sporadic cases have been linked to environmental toxins or trauma. Another possibility, first proposed in the 1970s, is that retroviruses play a role in pathogenesis. In this paper, we review the published literature for evidence that ALS is associated either with infection by an exogenous retrovirus or with the expression of human endogenous retroviral (HERV) sequences in cells of the central nervous system. A small percentage of persons infected with the human immunodeficiency virus-1 (HIV-1) or human T cell leukemia virus-1 (HTLV-1) develop ALS-like syndromes. While HTLV-1 associated ALS-like syndrome has several features that may distinguish it from classical ALS, HIV-infected patients may develop neurological manifestations that resemble classical ALS although it occurs at a younger age and they may show a dramatic improvement following the initiation of antiretroviral therapy. However, most patients with probable or definite ALS show no evidence of HIV-1 or HTLV-1 infection. In contrast, recent reports have shown a stronger association with HERV, as analysis of serum samples, and postmortem brain tissue from a number of patients with a classical ALS has revealed significantly increased expression of HERV-K, compared to controls. These findings suggest that endogenous retroviral elements are involved in the pathophysiology of ALS, but there is no evidence that they are the primary cause of the syndrome.}, }
@article {pmid23706004, year = {2014}, author = {Sheng, H and Chaparro, RE and Sasaki, T and Izutsu, M and Pearlstein, RD and Tovmasyan, A and Warner, DS}, title = {Metalloporphyrins as therapeutic catalytic oxidoreductants in central nervous system disorders.}, journal = {Antioxidants &amp; redox signaling}, volume = {20}, number = {15}, pages = {2437-2464}, doi = {10.1089/ars.2013.5413}, pmid = {23706004}, issn = {1557-7716}, mesh = {Animals ; Antioxidants/chemistry/*pharmacology/*therapeutic use ; Central Nervous System Diseases/diagnosis/*drug therapy/metabolism ; Humans ; Metalloporphyrins/chemistry/*pharmacology/*therapeutic use ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {SIGNIFICANCE: Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease.<br><br>RECENT ADVANCES: Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment.<br><br>CRITICAL ISSUES: Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders.<br><br>FUTURE DIRECTIONS: Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.}, }
@article {pmid23678881, year = {2013}, author = {Chad, DA and Bidichandani, S and Bruijn, L and Capra, JD and Dickie, B and Ferguson, J and Figlewicz, D and Forsythe, M and Kaufmann, P and Kirshner, A and Monti, W}, title = {Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14 Suppl 1}, number = {}, pages = {62-66}, doi = {10.3109/21678421.2013.778588}, pmid = {23678881}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/economics/therapy ; Biomedical Research/*economics/organization &amp; administration ; Canada ; Financial Management/*organization &amp; administration ; Health Resources ; Humans ; *Organizations/economics ; United Kingdom ; United States ; United States Government Agencies ; }, abstract = {Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem-cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community.}, }
@article {pmid23678880, year = {2013}, author = {Sherman, AV and Gubitz, AK and Al-Chalabi, A and Bedlack, R and Berry, J and Conwit, R and Harris, BT and Horton, DK and Kaufmann, P and Leitner, ML and Miller, R and Shefner, J and Vonsattel, JP and Mitsumoto, H}, title = {Infrastructure resources for clinical research in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14 Suppl 1}, number = {}, pages = {53-61}, doi = {10.3109/21678421.2013.779058}, pmid = {23678880}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Biomedical Research/*methods ; Databases, Factual/statistics &amp; numerical data ; Europe ; *Health Resources ; Humans ; North America ; }, abstract = {Clinical trial networks, shared clinical databases, and human biospecimen repositories are examples of infrastructure resources aimed at enhancing and expediting clinical and/or patient oriented research to uncover the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS), a rapidly progressive neurodegenerative disease that leads to the paralysis of voluntary muscles. The current status of such infrastructure resources, as well as opportunities and impediments, were discussed at the second Tarrytown ALS meeting held in September 2011. The discussion focused on resources developed and maintained by ALS clinics and centers in North America and Europe, various clinical trial networks, U.S. government federal agencies including the National Institutes of Health (NIH), the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention (CDC), and several voluntary disease organizations that support ALS research activities. Key recommendations included 1) the establishment of shared databases among individual ALS clinics to enhance the coordination of resources and data analyses; 2) the expansion of quality-controlled human biospecimen banks; and 3) the adoption of uniform data standards, such as the recently developed Common Data Elements (CDEs) for ALS clinical research. The value of clinical trial networks such as the Northeast ALS (NEALS) Consortium and the Western ALS (WALS) Consortium was recognized, and strategies to further enhance and complement these networks and their research resources were discussed.}, }
@article {pmid23678879, year = {2013}, author = {Al-Chalabi, A and Kwak, S and Mehler, M and Rouleau, G and Siddique, T and Strong, M and Leigh, PN}, title = {Genetic and epigenetic studies of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14 Suppl 1}, number = {}, pages = {44-52}, doi = {10.3109/21678421.2013.778571}, pmid = {23678879}, issn = {2167-9223}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {*Amyotrophic Lateral Sclerosis/etiology/genetics/physiopathology ; Axonal Transport ; Disease Progression ; *Epigenomics ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Humans ; RNA Processing, Post-Transcriptional/genetics ; }, abstract = {The identification of genetic and epigenetic factors that are associated with an increased risk of developing amyotrophic lateral sclerosis (ALS), or that modify the age of onset or rate of progression, requires a multimodal research strategy, facilitated through international collaboration. The discovery of several ALS genes strongly linked to RNA biology, the proteasome pathway, and axonal transport suggest they have an important role in pathogenesis, but the immense complexity of these processes is also apparent. The increasing rate of genetic discoveries brings the hope of designing more targeted and efficacious therapies.}, }
@article {pmid23678878, year = {2013}, author = {Factor-Litvak, P and Al-Chalabi, A and Ascherio, A and Bradley, W and Chío, A and Garruto, R and Hardiman, O and Kamel, F and Kasarskis, E and McKee, A and Nakano, I and Nelson, LM and Eisen, A}, title = {Current pathways for epidemiological research in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14 Suppl 1}, number = {Suppl 1}, pages = {33-43}, pmid = {23678878}, issn = {2167-9223}, support = {P30 AG013846/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Brain Injury, Chronic ; Case-Control Studies ; Disease Progression ; *Epidemiologic Studies ; Gene-Environment Interaction ; Humans ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. The current status of the epidemiology, challenges to its study, and novel study design options are discussed in this paper. We focus on recent results from large-scale population based prospective studies, case-control studies and population based registries, risk factors, and neuropathologic findings in chronic traumatic encephalomyelopathy. We identify areas of interest for future research, including time-trends in the incidence and prevalence of ALS; the meaning of lifetime risk; the phenotypic description of ALS; the definition of familial versus sporadic ALS, syndromic aspects of ALS; specific risk factors such as military service, life style factors such as smoking, the use of statins, and the presence of β-N-methylamino-L-alanine (BMAA), an excitotoxic amino acid derivative possibly produced by cyanobacteria found in almost every terrestrial and aquatic habitat; the emergence and disappearance of an endemic ALS in areas of the Pacific; and gene-environment interactions in the etiology of ALS. To move the epidemiology forward, we suggest using well-characterized cohorts of newly diagnosed ALS patients to identify risk and prognostic factors; storing biological material for future studies; building on the National ALS Registry as a resource of future studies; working in multidisciplinary consortia; and addressing the possible early life etiology of ALS.}, }
@article {pmid23678877, year = {2013}, author = {Turner, MR and Bowser, R and Bruijn, L and Dupuis, L and Ludolph, A and McGrath, M and Manfredi, G and Maragakis, N and Miller, RG and Pullman, SL and Rutkove, SB and Shaw, PJ and Shefner, J and Fischbeck, KH}, title = {Mechanisms, models and biomarkers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14 Suppl 1}, number = {0 1}, pages = {19-32}, pmid = {23678877}, issn = {2167-9223}, support = {ZIA NS003038-07/ImNIH/Intramural NIH HHS/United States ; G0701923/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS051419/NS/NINDS NIH HHS/United States ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology/*physiopathology ; Animals ; Biomarkers/*metabolism ; *Disease Models, Animal ; Humans ; Mitochondrial Diseases/physiopathology ; Neuroimaging ; Oxidative Stress/physiology ; }, abstract = {The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery.}, }
@article {pmid23700209, year = {2013}, author = {San Sebastian, W and Samaranch, L and Kells, AP and Forsayeth, J and Bankiewicz, KS}, title = {Gene therapy for misfolding protein diseases of the central nervous system.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {10}, number = {3}, pages = {498-510}, pmid = {23700209}, issn = {1878-7479}, support = {R01 NS073940/NS/NINDS NIH HHS/United States ; R01NS073940/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Central Nervous System Diseases/complications/genetics/therapy ; Genetic Therapy/*methods ; Humans ; *Proteostasis Deficiencies/complications/genetics/therapy ; }, abstract = {Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. Accordingly, most recent studies aim to prevent protein misfolding and/or aggregation as a strategy to treat these pathologies. For instance, state-of-the-art approaches, such as silencing protein overexpression by means of RNA interference, are being tested with positive outcomes in preclinical models of animals overexpressing the corresponding protein. Therapies designed to treat central nervous system diseases should provide accurate delivery of the therapeutic agent and long-term or chronic expression by means of a nontoxic delivery vehicle. After several years of technical advances and optimization, gene therapy emerges as a promising approach able to fulfill those requirements. In this review we will summarize the latest improvements achieved in gene therapy for central nervous system diseases associated with protein misfolding (e.g., amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, Huntington's, and prion diseases), as well as the most recent approaches in this field to treat these pathologies.}, }
@article {pmid23694725, year = {2013}, author = {Bousset, L and Melki, R}, title = {[Infectious properties of protein aggregates involved in neurodegenerative diseases].}, journal = {Biologie aujourd'hui}, volume = {207}, number = {1}, pages = {55-59}, doi = {10.1051/jbio/2013004}, pmid = {23694725}, issn = {2105-0686}, mesh = {Cell Communication ; Humans ; Neurodegenerative Diseases/*metabolism ; *Protein Folding ; *Protein Multimerization ; Proteins/*chemistry ; }, abstract = {Several progressive neurodegenerative disorders, e.g. Alzheimer, Parkinson and Huntington diseases, cerebro-spinal ataxia and amyotrophic lateral sclerosis, are the consequence of protein misfolding and aggregation. Recent data indicates that some of these diseases are not cell autonomous as previously thought. We and others have shown that protein assemblies involved in the aforementioned diseases propagate from cell to cell in a manner akin prion high molecular weight assemblies propagation in Creutzfeldt-Jacob disease. The mechanism of propagation and amplification of protein assemblies involved in neurodegenerative diseases and its physiopathological consequences are discussed hereafter.}, }
@article {pmid23692930, year = {2013}, author = {Nichols, NL and Van Dyke, J and Nashold, L and Satriotomo, I and Suzuki, M and Mitchell, GS}, title = {Ventilatory control in ALS.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {189}, number = {2}, pages = {429-437}, pmid = {23692930}, issn = {1878-1519}, support = {R01 HL080209/HL/NHLBI NIH HHS/United States ; NIH NS057778/NS/NINDS NIH HHS/United States ; RR023916/RR/NCRR NIH HHS/United States ; T32 OD010423/OD/NIH HHS/United States ; P01 NS057778/NS/NINDS NIH HHS/United States ; HL007654/HL/NHLBI NIH HHS/United States ; T32 RR023916/RR/NCRR NIH HHS/United States ; HL080209/HL/NHLBI NIH HHS/United States ; T32 HL007654/HL/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology/*therapy ; Animals ; Humans ; Intermittent Positive-Pressure Ventilation/methods ; Nerve Net/physiology ; Noninvasive Ventilation/*methods ; Pulmonary Ventilation/*physiology ; Respiratory Center/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease. ALS selectively causes degeneration in upper and lower (spinal) motor neurons, leading to muscle weakness, paralysis and death by ventilatory failure. Although ventilatory failure is generally the cause of death in ALS, little is known concerning the impact of this disorder on respiratory motor neurons, the consequences of respiratory motor neuron cell death, or the ability of the respiratory control system to "fight back" via mechanisms of compensatory respiratory plasticity. Here we review known effects of ALS on breathing, including possible effects on rhythm generation, respiratory motor neurons, and their target organs: the respiratory muscles. We consider evidence for spontaneous compensatory plasticity, preserving breathing well into disease progression despite dramatic loss of spinal respiratory motor neurons. Finally, we review current and potential therapeutic approaches directed toward preserving the capacity to breathe in ALS patients.}, }
@article {pmid23689277, year = {2013}, author = {Herskovits, AZ and Guarente, L}, title = {Sirtuin deacetylases in neurodegenerative diseases of aging.}, journal = {Cell research}, volume = {23}, number = {6}, pages = {746-758}, pmid = {23689277}, issn = {1748-7838}, support = {R01 AG015339/AG/NIA NIH HHS/United States ; R37 AG011119/AG/NIA NIH HHS/United States ; R56 AG015339/AG/NIA NIH HHS/United States ; }, mesh = {Aging ; Caloric Restriction ; *Energy Metabolism ; Histone Deacetylases ; Humans ; NAD/metabolism ; Neurodegenerative Diseases/*enzymology/*metabolism ; Sirtuins/*metabolism ; }, abstract = {Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.}, }
@article {pmid23687121, year = {2013}, author = {Saccon, RA and Bunton-Stasyshyn, RK and Fisher, EM and Fratta, P}, title = {Is SOD1 loss of function involved in amyotrophic lateral sclerosis?.}, journal = {Brain : a journal of neurology}, volume = {136}, number = {Pt 8}, pages = {2342-2358}, pmid = {23687121}, issn = {1460-2156}, support = {G0500288/MRC_/Medical Research Council/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; G1000287/MRC_/Medical Research Council/United Kingdom ; MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Phenotype ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a--still unknown--toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1-amyotrophic lateral sclerosis. From analysing published data from patients with SOD1-amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1-amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis.}, }
@article {pmid23686823, year = {2013}, author = {DeVos, SL and Miller, TM}, title = {Antisense oligonucleotides: treating neurodegeneration at the level of RNA.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {10}, number = {3}, pages = {486-497}, pmid = {23686823}, issn = {1878-7479}, support = {NIH/NINDS K08NS074194/NS/NINDS NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; K08 NS074194/NS/NINDS NIH HHS/United States ; NIH/NINDS R01NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism/*therapy ; Neuroprotective Agents/*therapeutic use ; Oligodeoxyribonucleotides, Antisense/*therapeutic use ; RNA/*metabolism ; }, abstract = {Adequate therapies are lacking for Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. The ability to use antisense oligonucleotides (ASOs) to target disease-associated genes by means of RNA may offer a potent approach for the treatment of these, and other, neurodegenerative disorders. In modifying the basic backbone chemistry, chemical groups, and target sequence, ASOs can act through numerous mechanisms to decrease or increase total protein levels, preferentially shift splicing patterns, and inhibit microRNAs, all at the level of the RNA molecule. Here, we discuss many of the more commonly used ASO chemistries, as well as the different mechanisms of action that can result from these specific chemical modifications. When applied to multiple neurodegenerative mouse models, ASOs that specifically target the detrimental transgenes have been shown to rescue disease associated phenotypes in vivo. These supporting mouse model data have moved the ASOs from the bench to the clinic, with two neuro-focused human clinical trials now underway and several more being proposed. Although still early in development, translating ASOs into human patients for neurodegeneration appears promising.}, }
@article {pmid23686613, year = {2013}, author = {Hallengren, J and Chen, PC and Wilson, SM}, title = {Neuronal ubiquitin homeostasis.}, journal = {Cell biochemistry and biophysics}, volume = {67}, number = {1}, pages = {67-73}, pmid = {23686613}, issn = {1559-0283}, support = {NS074456/NS/NINDS NIH HHS/United States ; R01 NS047533/NS/NINDS NIH HHS/United States ; NS047533/NS/NINDS NIH HHS/United States ; R21 NS074456/NS/NINDS NIH HHS/United States ; T32 GM008111/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Nervous System Diseases/metabolism/pathology ; Neurons/*metabolism ; Signal Transduction ; Synapses/metabolism ; Ubiquitin/biosynthesis/*metabolism ; Ubiquitin Thiolesterase/metabolism ; Ubiquitination ; }, abstract = {Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson's disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating the synaptic activity.}, }
@article {pmid23673820, year = {2013}, author = {Blokhuis, AM and Groen, EJ and Koppers, M and van den Berg, LH and Pasterkamp, RJ}, title = {Protein aggregation in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {125}, number = {6}, pages = {777-794}, pmid = {23673820}, issn = {1432-0533}, mesh = {Adaptor Proteins, Signal Transducing ; Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology ; Ataxins ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/physiology ; DNA-Binding Proteins/physiology ; Humans ; Inclusion Bodies/*physiology ; Membrane Transport Proteins ; Nerve Tissue Proteins/physiology ; Proteins/physiology ; *Proteolysis ; RNA-Binding Protein FUS/physiology ; Transcription Factor TFIIIA/physiology ; Ubiquitins/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.}, }
@article {pmid23664960, year = {2013}, author = {Fischer-Hayes, LR and Brotherton, T and Glass, JD}, title = {Axonal degeneration in the peripheral nervous system: implications for the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {246}, number = {}, pages = {6-13}, doi = {10.1016/j.expneurol.2013.05.001}, pmid = {23664960}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology ; Animals ; Axons/metabolism/*pathology ; *Disease Models, Animal ; Humans ; Nerve Degeneration/*etiology/metabolism/pathology ; }, abstract = {Axons are the anatomical link between neuronal cell bodies and their target organs, and thus axonal degeneration is the pathological substrate that underlies neurological dysfunction in a large number of neurological conditions. Recent advances in the field of axonal biology demonstrate that axons possess programs for survival and degeneration that are distinct from those of the cell body, indicating that therapeutic strategies must consider protection of both the cell body and the axon. This review discusses axonal degeneration in the peripheral nervous system (PNS) with a focus on amyotrophic lateral sclerosis, examining both the underlying mechanisms, and the cellular and disease models of axonal degeneration that relate to disease pathogenesis.}, }
@article {pmid23649659, year = {2013}, author = {He, YY and Zhang, XY and Yung, WH and Zhu, JN and Wang, JJ}, title = {Role of BDNF in central motor structures and motor diseases.}, journal = {Molecular neurobiology}, volume = {48}, number = {3}, pages = {783-793}, pmid = {23649659}, issn = {1559-1182}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Electrophysiological Phenomena ; Humans ; Motor Neuron Disease/*metabolism/*pathology/physiopathology ; Motor Neurons/*metabolism/*pathology ; Signal Transduction ; }, abstract = {Brain-derived neurotrophic factor (BDNF), belonging to the neurotrophic family of growth factors, has a widespread distribution in the central and peripheral nervous systems. In central motor structures including the motor cortex, cerebellum, basal ganglia, and spinal cord, BDNF exerts both neurotrophic and direct electrophysiological effects via a high-affinity tyrosine receptor kinase B receptor and a common low-affinity p75 neurotrophin receptor. The underlying signaling pathways mainly involve mitogen-activated protein kinase cascades, phosphatidylinositol 3-kinase pathway, and phospholipase C-γ pathway. The loss of BDNF usually leads to neurodegeneration in these motor centers and eventually results in several severe motor diseases, such as amyotrophic lateral sclerosis, spinocerebellar ataxias, Parkinson's disease, Huntington's disease, as well as vestibular syndrome. In this review, we summarize the recent understanding of functions of BDNF in motor structures and suggest that BDNF may be a potent candidate for the treatment of these neurodegenerative motor diseases.}, }
@article {pmid23646984, year = {2013}, author = {Chandler, SF and Senior, M and Nakamura, N and Tsuda, S and Tanaka, Y}, title = {Expression of flavonoid 3',5'-hydroxylase and acetolactate synthase genes in transgenic carnation: assessing the safety of a nonfood plant.}, journal = {Journal of agricultural and food chemistry}, volume = {61}, number = {48}, pages = {11711-11720}, doi = {10.1021/jf4004384}, pmid = {23646984}, issn = {1520-5118}, mesh = {Acetolactate Synthase/*genetics/metabolism ; Animals ; Cytochrome P-450 Enzyme System/*genetics/metabolism ; Dianthus/chemistry/*genetics/metabolism ; Gene Expression Regulation, Plant ; Humans ; Plant Proteins/*genetics/metabolism ; Plants, Genetically Modified/chemistry/*genetics/metabolism ; Risk Assessment ; }, abstract = {For 16 years, genetically modified flowers of carnation (Dianthus caryophyllus) have been sold to the floristry industry. The transgenic carnation carries a herbicide tolerance gene (a mutant gene encoding acetolactate synthase (ALS)) and has been modified to produce delphinidin-based anthocyanins in flowers, which conventionally bred carnation cannot produce. The modified flower color has been achieved by introduction of a gene encoding flavonoid 3',5'-hydroxylase (F3'5'H). Transgenic carnation flowers are produced in South America and are primarily distributed to North America, Europe, and Japan. Although a nonfood crop, the release of the genetically modified carnation varieties required an environmental risk impact assessment and an assessment of the potential for any increased risk of harm to human or animal health compared to conventionally bred carnation. The results of the health safety assessment and the experimental studies that accompanied them are described in this review. The conclusion from the assessments has been that the release of genetically modified carnation varieties which express F3'5'H and ALS genes and which accumulate delphinidin-based anthocyanins do not pose an increased risk of harm to human or animal health.}, }
@article {pmid23644307, year = {2013}, author = {Verma, A}, title = {Protein aggregates and regional disease spread in ALS is reminiscent of prion-like pathogenesis.}, journal = {Neurology India}, volume = {61}, number = {2}, pages = {107-110}, doi = {10.4103/0028-3886.111109}, pmid = {23644307}, issn = {0028-3886}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Brain/metabolism/*pathology ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Prions/genetics/*metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) typically commences in a discrete location in a limb or bulbar territory muscles and then spreads to the adjacent anatomical regions. This pattern is consistent with a contiguous spread of the disease process in motor neuron network resulting in progressive motor weakness. The etiology of ALS onset and the mechanism of the regional ALS spread remain elusive. Over the past 5 years, identification of mutations in two RNA binding proteins, trans active response (TAR) DNA-binding protein (TDP-43) and fused in sarcoma (FUS), in patients with familial ALS has led to a major shift in our understanding of the ALS disease mechanism. In addition to their role in RNA metabolism, TDP-43 and FUS form protein aggregates in the affected neurons. More recent findings demonstrating that both TDP-43 and FUS contain glutamine/asparagine (Q/N) residue-rich prion-like domains have spurred intense research interest. This brief review discusses the prion-related domains in TDP-43 and FUS and their implication in protein aggregate formation and disease spread in ALS.}, }
@article {pmid23642555, year = {2013}, author = {Tanenbaum, LN}, title = {Clinical applications of diffusion imaging in the spine.}, journal = {Magnetic resonance imaging clinics of North America}, volume = {21}, number = {2}, pages = {299-320}, doi = {10.1016/j.mric.2012.12.002}, pmid = {23642555}, issn = {1557-9786}, mesh = {Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Image Enhancement/*methods ; Spinal Cord Diseases/*pathology ; Spinal Diseases/*pathology ; }, abstract = {As in the brain, the sensitivity of diffusion-weighted imaging (DWI) to ischemic damage in the spinal cord may provide early identification of infarction. Diffusion anisotropy may enhance the detection and understanding of damage to the long fiber tracts with clinical implications for diseases such as multiple sclerosis and amyotrophic lateral sclerosis and may also yield insight into damage that occurs with spondylotic and traumatic myelopathy. This article reviews the basis for DWI for the evaluation of the spinal cord, osseous, and soft tissues of the spine and reviews the imaging appearance of a variety of disease states.}, }
@article {pmid23638638, year = {2013}, author = {,  and Fournier, C and Bedlack, B and Hardiman, O and Heiman-Patterson, T and Gutmann, L and Bromberg, M and Ostrow, L and Carter, G and Kabashi, E and Bertorini, T and Mozaffar, T and Andersen, P and Dietz, J and Gamez, J and Dimachkie, M and Wang, Y and Wicks, P and Heywood, J and Novella, S and Rowland, LP and Pioro, E and Kinsley, L and Mitchell, K and Glass, J and Sathornsumetee, S and Kwiecinski, H and Baker, J and Atassi, N and Forshew, D and Ravits, J and Conwit, R and Jackson, C and Sherman, A and Dalton, K and Tindall, K and Gonzalez, G and Robertson, J and Phillips, L and Benatar, M and Sorenson, E and Shoesmith, C and Nash, S and Maragakis, N and Moore, D and Caress, J and Boylan, K and Armon, C and Grosso, M and Gerecke, B and Wymer, J and Oskarsson, B and Bowser, R and Drory, V and Shefner, J and Lechtzin, N and Leitner, M and Miller, R and Mitsumoto, H and Levine, T and Russell, J and Sharma, K and Saperstein, D and McClusky, L and MacGowan, D and Licht, J and Verma, A and Strong, M and Lomen-Hoerth, C and Tandan, R and Rivner, M and Kolb, S and Polak, M and Rudnicki, S and Kittrell, P and Quereshi, M and Sachs, G and Pattee, G and Weiss, M and Kissel, J and Goldstein, J and Rothstein, J and Pastula, D and Gleb, L and Ogino, M and Rosenfeld, J and Carmi, E and Oster, C and Barkhaus, P and Valor, E}, title = {ALS Untangled No. 20: the Deanna protocol.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {4}, pages = {319-323}, doi = {10.3109/21678421.2013.788405}, pmid = {23638638}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*diet therapy/epidemiology ; Animals ; Coconut Oil ; *Dietary Supplements ; Humans ; Nutrition Therapy/methods ; Plant Oils/*administration &amp; dosage ; }, }
@article {pmid23629963, year = {2013}, author = {Li, YR and King, OD and Shorter, J and Gitler, AD}, title = {Stress granules as crucibles of ALS pathogenesis.}, journal = {The Journal of cell biology}, volume = {201}, number = {3}, pages = {361-372}, pmid = {23629963}, issn = {1540-8140}, support = {R01NS073660/NS/NINDS NIH HHS/United States ; DP2 OD004417/OD/NIH HHS/United States ; R21HD074510/HD/NICHD NIH HHS/United States ; R01GM099836/GM/NIGMS NIH HHS/United States ; R21 HD074510/HD/NICHD NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; R21 NS067354/NS/NINDS NIH HHS/United States ; DP2OD004417/OD/NIH HHS/United States ; DP2 OD002177/OD/NIH HHS/United States ; DP2OD002177/OD/NIH HHS/United States ; R01NS065317/NS/NINDS NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; R21NS067354/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Ataxins ; Cytoplasmic Granules/*metabolism ; DNA-Binding Proteins/metabolism ; Environmental Exposure ; Humans ; Nerve Tissue Proteins/metabolism ; Prions/metabolism ; Protein Structure, Tertiary ; RNA-Binding Protein FUS/metabolism ; Stress, Physiological ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.}, }
@article {pmid23628680, year = {2013}, author = {Tamaoka, A}, title = {[Fall risk and fracture. Falls and fractures in patients with neurological disorders].}, journal = {Clinical calcium}, volume = {23}, number = {5}, pages = {679-685}, pmid = {23628680}, issn = {0917-5857}, mesh = {*Accidental Falls/prevention &amp; control ; Fractures, Bone/*etiology/therapy ; Gait Disorders, Neurologic/*complications ; Humans ; Muscle Strength/physiology ; Nervous System Diseases/*complications ; Risk Factors ; }, abstract = {Neurological disorders are frequently associated with risk factors for falls, such as gait and balance disorders, deficits of lower extremity strength, sensation and coordination, in addition to cognitive impairments. Patients with various kinds of neurological disorders, including Parkinson's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, peripheral neuropathy, stroke, etc, easily suffer from falls. To prevent falls among such patients, treatments of the underlying neurological diseases and assessments risk factors for falls are most important to cope effectively with these patients. In general, maintenance of the appropriate environment, consideration of the injury prevention, rehabilitation for increasing muscular strength, etc, are useful for the prevention of falls in patients with neurological disorders.}, }
@article {pmid23623808, year = {2013}, author = {Cordesse, V and Jametal, T and Guy, C and Lefebvre, S and Roussel, M and Ruggeri, J and Schimmel, P and Holstein, J and Meininger, V}, title = {[Analysis of clinical pathway in changing and disabling neurological diseases].}, journal = {Revue neurologique}, volume = {169}, number = {6-7}, pages = {476-484}, doi = {10.1016/j.neurol.2012.12.004}, pmid = {23623808}, issn = {0035-3787}, mesh = {Allied Health Personnel/statistics &amp; numerical data ; Critical Pathways/*organization &amp; administration ; *Disabled Persons ; Disease Progression ; Hospitalization/statistics &amp; numerical data ; Humans ; Neurodegenerative Diseases/epidemiology/psychology/*therapy ; Professional Practice/statistics &amp; numerical data ; Quality of Life ; Social Environment ; }, abstract = {Neurological diseases are characterized by the complexity of care and by a constant and changing disability. More and more frequently, their impact on the clinical pathway remains unknown. Seven postgraduate rehabilitation students (Master coordination du handicap, université Pierre-et-Marie-Curie, Paris) reconstructed the clinical pathway of 123 patients with various neurological diseases: multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis, spinal trauma, Parkinson disease and brain tumors. There was a significant correlation between disease duration and the number of specialists involved in care, the number of prescribed drugs and the number of short-term hospitalizations; there was no correlation with age. This result suggests that with time an increasing number of complications related to the initial neurological disease developed. Hospitalization in rehabilitation units was highly correlated with the degree of disability and also with the help received by the patients during the course of their disease. This result suggests that these hospitalizations were a direct consequence of burn out among relatives. General practitioners (GP) were highly involved only during the initial part of the pathway, and their involvement rapidly declined thereafter, suggesting a probable relation with the specificities and the complexity of care for neurological diseases which induces a progressive transfer of responsibilities from the GP to the hospital. Social care was always incomplete and occurred too late during the course of the disease. The feeling by the patients that their care pathway was chaotic was highly correlated with the quality of the information given to the patient at the time of the announcement of their disease. This study confirms that cares for neurological diseases is highly specific and that expert centers and coordination networks are in a key position to ensure an efficient care pathway.}, }
@article {pmid23616620, year = {2013}, author = {Turner, MR and Talbot, K}, title = {Mimics and chameleons in motor neurone disease.}, journal = {Practical neurology}, volume = {13}, number = {3}, pages = {153-164}, pmid = {23616620}, issn = {1474-7766}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Delayed Diagnosis ; Diagnosis, Differential ; *Disease Progression ; Humans ; Motor Neuron Disease/*diagnosis/*physiopathology ; }, abstract = {The progression of motor neurone disease (MND) is currently irreversible, and the grave implications of diagnosis naturally fuels concern among neurologists over missing a potential mimic disorder. There is no diagnostic test for MND but in reality there are few plausible mimics in routine clinical practice. In the presence of a progressive pure motor disorder, signs such as florid fasciculations, bilateral tongue wasting, the 'split hand', head drop, emotionality, and cognitive or behavioural impairment carry high positive predictive value. MND is clinically heterogeneous, however, with some important chameleon-like presentations and considerable variation in clinical course. Lack of confidence about the scope of such variation, or an approach to diagnosis emphasising investigations over clinical common sense, has the potential to exacerbate diagnostic delay in MND and impede timely planning of the care which is essential to maximising quality of life.}, }
@article {pmid23609067, year = {2013}, author = {Shaw, CA and Tomljenovic, L}, title = {Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity.}, journal = {Immunologic research}, volume = {56}, number = {2-3}, pages = {304-316}, pmid = {23609067}, issn = {1559-0755}, mesh = {Adjuvants, Pharmaceutic/*adverse effects ; Adult ; Aluminum/*adverse effects ; Alzheimer Disease/*chemically induced ; Amyotrophic Lateral Sclerosis/*chemically induced ; Animals ; Autoimmunity/drug effects ; Central Nervous System/*drug effects/immunology ; Child ; Child Development Disorders, Pervasive/*chemically induced ; Disease Models, Animal ; Humans ; Male ; Mice ; Persian Gulf Syndrome/*chemically induced ; Vaccines/*adverse effects ; }, abstract = {We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.}, }
@article {pmid23600759, year = {2013}, author = {Tenreiro, S and Munder, MC and Alberti, S and Outeiro, TF}, title = {Harnessing the power of yeast to unravel the molecular basis of neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {127}, number = {4}, pages = {438-452}, doi = {10.1111/jnc.12271}, pmid = {23600759}, issn = {1471-4159}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Frontotemporal Lobar Degeneration/metabolism/pathology ; Humans ; Huntington Disease/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Parkinson Disease/metabolism/pathology ; Prions/metabolism ; Protein Folding ; Proteostasis Deficiencies/*metabolism/pathology ; Saccharomyces cerevisiae/*metabolism ; }, abstract = {Several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or prion diseases, are known for their intimate association with protein misfolding and aggregation. These disorders are characterized by the loss of specific neuronal populations in the brain and are highly associated with aging, suggesting a decline in proteostasis capacity may contribute to pathogenesis. Nevertheless, the precise molecular mechanisms that lead to the selective demise of neurons remain poorly understood. As a consequence, appropriate therapeutic approaches and effective treatments are largely lacking. The development of cellular and animal models that faithfully reproduce central aspects of neurodegeneration has been crucial for advancing our understanding of these diseases. Approaches involving the sequential use of different model systems, starting with simpler cellular models and ending with validation in more complex animal models, resulted in the discovery of promising therapeutic targets and small molecules with therapeutic potential. Within this framework, the simple and well-characterized eukaryote Saccharomyces cerevisiae, also known as budding yeast, is being increasingly used to study the molecular basis of several neurodegenerative disorders. Yeast provides an unprecedented toolbox for the dissection of complex biological processes and pathways. Here, we summarize how yeast models are adding to our current understanding of several neurodegenerative disorders.}, }
@article {pmid23590262, year = {2013}, author = {Benditt, JO and Boitano, LJ}, title = {Pulmonary issues in patients with chronic neuromuscular disease.}, journal = {American journal of respiratory and critical care medicine}, volume = {187}, number = {10}, pages = {1046-1055}, doi = {10.1164/rccm.201210-1804CI}, pmid = {23590262}, issn = {1535-4970}, mesh = {Chronic Disease ; Humans ; Neuromuscular Diseases/*complications ; Respiration Disorders/*complications/therapy ; Respiration, Artificial/methods ; }, abstract = {Patients with chronic neuromuscular diseases such as spinal cord injury, amyotrophic lateral sclerosis, and muscular dystrophies experience respiratory complications that are cared for by the respiratory practitioner. An organized anatomical approach for evaluation and treatment is helpful to provide appropriate clinical care. Effective noninvasive strategies for management of hypoventilation, sleep-disordered breathing, and cough insufficiency are available for these patients.}, }
@article {pmid23590138, year = {2013}, author = {Hozumi, I}, title = {Roles and therapeutic potential of metallothioneins in neurodegenerative diseases.}, journal = {Current pharmaceutical biotechnology}, volume = {14}, number = {4}, pages = {408-413}, doi = {10.2174/1389201011314040004}, pmid = {23590138}, issn = {1873-4316}, mesh = {Animals ; Antioxidants/pharmacology/therapeutic use ; Brain/drug effects/metabolism ; Humans ; Metallothionein/*pharmacology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {Metallothionein (MT) is a small molecular and multi-functional protein containing four atoms of copper (Cu) and three atoms of zinc (Zn) per molecule. It was isolated from the horse kidney in 1957 and half a century has passed since then. Although MT was found to work as a modulator of Zn and induce anti-oxidant reaction, the precise functions and its functional mechanisms remain to be elucidated. Over the years, a new isoform of MT, MT-III (also called growth inhibitory factor (GIF)), has been found in the brain, which was markedly diminished in the brain of Alzheimer's disease (AD). Many new findings on MT have been discovered in neurodegenerative diseases other than AD such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), prion disease, brain trauma, brain ischemia, and psychiatric diseases. In ALS in particular, MTs were markedly diminished in the spinal cord of patients with ALS. Initially, MT, which easily binds to cadmium (Cd) and copper (Cu), was considered to be toxic to our bodies. Molecular biological technologies enabled the production of recombinant MT saturated with zinc (Zn). MT has a high potential for the treatment of neurodegenerative diseases such as ALS, AD, and PD owing to its various functions including anti-oxidant properties and modulators not only for Zn but for Cu in the extra- and intracellular spaces. On the other hand, there are still various problems on MT to be elucidated in detail, including their binding proteins and functional mechanisms.}, }
@article {pmid23587065, year = {2013}, author = {Bentmann, E and Haass, C and Dormann, D}, title = {Stress granules in neurodegeneration--lessons learnt from TAR DNA binding protein of 43 kDa and fused in sarcoma.}, journal = {The FEBS journal}, volume = {280}, number = {18}, pages = {4348-4370}, doi = {10.1111/febs.12287}, pmid = {23587065}, issn = {1742-4658}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Biomarkers/metabolism ; Cytoplasmic Granules/*genetics/metabolism/pathology ; DNA-Binding Proteins/*genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics/metabolism/pathology ; Gene Expression Regulation ; Heat-Shock Proteins/genetics/metabolism ; Humans ; Protein Folding ; Protein Structure, Tertiary ; RNA, Messenger/genetics/metabolism ; RNA-Binding Protein FUS/*genetics/metabolism ; Signal Transduction ; Stress, Physiological ; }, abstract = {Stress granules (SGs) are cytoplasmic foci that rapidly form when cells are exposed to stress. They transiently store mRNAs encoding house-keeping proteins and allow the selective translation of stress-response proteins (e.g. heat shock proteins). Besides mRNA, SGs contain RNA-binding proteins, such as T cell internal antigen-1 and poly(A)-binding protein 1, which can serve as characteristic SG marker proteins. Recently, some of these SG marker proteins were found to label pathological TAR DNA binding protein of 43 kDa (TDP-43)- or fused in sarcoma (FUS)-positive cytoplasmic inclusions in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In addition, protein aggregates in other neurodegenerative diseases (e.g. tau inclusions in Alzheimer's disease) show a co-localization with T cell internal antigen-1 as well. Moreover, several RNA-binding proteins that are commonly found in SGs have been genetically linked to neurodegeneration. This suggests that SGs might play an important role in the pathogenesis of these proteinopathies, either by acting as a seed for pathological inclusions, by mediating translational repression or by trapping essential RNA-binding proteins, or by a combination of these mechanisms. This minireview gives an overview of the general biology of SGs and highlights the recently identified connection of SGs with TDP-43, FUS and other proteins involved in neurodegenerative diseases. We propose that pathological inclusions containing RNA-binding proteins, such as TDP-43 and FUS, might arise from SGs and discuss how SGs might contribute to neurodegeneration via toxic gain or loss-of-function mechanisms.}, }
@article {pmid23583830, year = {2014}, author = {Franz, A and Ackermann, L and Hoppe, T}, title = {Create and preserve: proteostasis in development and aging is governed by Cdc48/p97/VCP.}, journal = {Biochimica et biophysica acta}, volume = {1843}, number = {1}, pages = {205-215}, doi = {10.1016/j.bbamcr.2013.03.031}, pmid = {23583830}, issn = {0006-3002}, mesh = {Adenosine Triphosphatases/*physiology ; Aging/*genetics ; Animals ; Cell Cycle Proteins/*physiology ; Cell Proliferation ; Growth and Development/*genetics ; Humans ; Protein Stability ; Proteostasis Deficiencies/genetics ; Reproduction/physiology ; Valosin Containing Protein ; }, abstract = {The AAA-ATPase Cdc48 (also called p97 or VCP) acts as a key regulator in proteolytic pathways, coordinating recruitment and targeting of substrate proteins to the 26S proteasome or lysosomal degradation. However, in contrast to the well-known function in ubiquitin-dependent cellular processes, the physiological relevance of Cdc48 in organismic development and maintenance of protein homeostasis is less understood. Therefore, studies on multicellular model organisms help to decipher how Cdc48-dependent proteolysis is regulated in time and space to meet developmental requirements. Given the importance of developmental regulation and tissue maintenance, defects in Cdc48 activity have been linked to several human pathologies including protein aggregation diseases. Thus, addressing the underlying disease mechanisms not only contributes to our understanding on the organism-wide function of Cdc48 but also facilitates the design of specific medical therapies. In this review, we will portray the role of Cdc48 in the context of multicellular organisms, pointing out its importance for developmental processes, tissue surveillance, and disease prevention. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.}, }
@article {pmid23583633, year = {2013}, author = {Modic, M and Ule, J and Sibley, CR}, title = {CLIPing the brain: studies of protein-RNA interactions important for neurodegenerative disorders.}, journal = {Molecular and cellular neurosciences}, volume = {56}, number = {}, pages = {429-435}, pmid = {23583633}, issn = {1095-9327}, support = {089701/WT_/Wellcome Trust/United Kingdom ; 206726/ERC_/European Research Council/International ; MC_U105185858/MRC_/Medical Research Council/United Kingdom ; U105185858/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Binding Sites ; Brain/*metabolism ; Cross-Linking Reagents ; Humans ; Immunoprecipitation/methods ; Neurodegenerative Diseases/genetics/*metabolism ; Protein Binding ; RNA/chemistry/genetics/*metabolism ; RNA-Binding Proteins/genetics/*metabolism ; }, abstract = {The fate of an mRNA is largely determined by its interactions with RNA binding proteins (RBPs). Post-transcriptional processing, RNA stability, localisation and translation are some of the events regulated by the plethora of RBPs present within cells. Mutations in various RBPs cause several diseases of the central nervous system, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and fragile X syndrome. Here we review the studies that integrated UV-induced cross-linked immunoprecipitation (CLIP) with other genome-wide methods to comprehensively characterise the function of diverse RBPs in the brain. We discuss the technical challenges of these studies and review the strategies that can be used to reliably identify the RNAs bound and regulated by an RBP. We conclude by highlighting how CLIP and related techniques have been instrumental in addressing the role of RBPs in neurologic diseases. This article is part of a Special Issue entitled: RNA and splicing regulation in neurodegeneration.}, }
@article {pmid26317018, year = {2013}, author = {Kumar, A and Ghosh, D and Singh, RL}, title = {Amyotrophic Lateral Sclerosis and Metabolomics: Clinical Implication and Therapeutic Approach.}, journal = {Journal of biomarkers}, volume = {2013}, number = {}, pages = {538765}, pmid = {26317018}, issn = {2090-8660}, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common motor neurodegenerative disorders, primarily affecting upper and lower motor neurons in the brain, brainstem, and spinal cord, resulting in paralysis due to muscle weakness and atrophy. The majority of patients die within 3-5 years of symptom onset as a consequence of respiratory failure. Due to relatively fast progression of the disease, early diagnosis is essential. Metabolomics offer a unique opportunity to understand the spatiotemporal metabolic crosstalks through the assessment of body fluids and tissue. So far, one of the most challenging issues related to ALS is to understand the variation of metabolites in body fluids and CNS with the progression of disease. In this paper we will review the changes in metabolic profile in response to disease progression condition and also see the therapeutic implication of various drugs in ALS patients.}, }
@article {pmid26316997, year = {2013}, author = {Aebischer, J and Bernard-Marissal, N and Pettmann, B and Raoul, C}, title = {Death Receptors in the Selective Degeneration of Motoneurons in Amyotrophic Lateral Sclerosis.}, journal = {Journal of neurodegenerative diseases}, volume = {2013}, number = {}, pages = {746845}, pmid = {26316997}, issn = {2090-858X}, abstract = {While studies on death receptors have long been restricted to immune cells, the last decade has provided a strong body of evidence for their implication in neuronal death and hence neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). ALS is a fatal paralytic disorder that primarily affects motoneurons in the brain and spinal cord. A neuroinflammatory process, associated with astrocyte and microglial activation as well as infiltration of immune cells, accompanies motoneuron degeneration and supports the contribution of non-cell-autonomous mechanisms in the disease. Hallmarks of Fas, TNFR, LT-βR, and p75(NTR) signaling have been observed in both animal models and ALS patients. This review summarizes to date knowledge of the role of death receptors in ALS and the link existing between the selective loss of motoneurons and neuroinflammation. It further suggests how this recent evidence could be included in an ultimate multiapproach to treat patients.}, }
@article {pmid26316993, year = {2013}, author = {Sheikh, S and Safia,  and Haque, E and Mir, SS}, title = {Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions.}, journal = {Journal of neurodegenerative diseases}, volume = {2013}, number = {}, pages = {563481}, pmid = {26316993}, issn = {2090-858X}, abstract = {Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.}, }
@article {pmid25562650, year = {2013}, author = {Lee, JJ and Yokota, T}, title = {Antisense therapy in neurology.}, journal = {Journal of personalized medicine}, volume = {3}, number = {3}, pages = {144-176}, pmid = {25562650}, issn = {2075-4426}, abstract = {Antisense therapy is an approach to fighting diseases using short DNA-like molecules called antisense oligonucleotides. Recently, antisense therapy has emerged as an exciting and promising strategy for the treatment of various neurodegenerative and neuromuscular disorders. Previous and ongoing pre-clinical and clinical trials have provided encouraging early results. Spinal muscular atrophy (SMA), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy (including limb-girdle muscular dystrophy 2B; LGMD2B, Miyoshi myopathy; MM, and distal myopathy with anterior tibial onset; DMAT), and myotonic dystrophy (DM) are all reported to be promising targets for antisense therapy. This paper focuses on the current progress of antisense therapies in neurology.}, }
@article {pmid25408873, year = {2013}, author = {Liu, Y and Yang, R and He, Z and Gao, WQ}, title = {Generation of functional organs from stem cells.}, journal = {Cell regeneration (London, England)}, volume = {2}, number = {1}, pages = {1}, pmid = {25408873}, issn = {2045-9769}, abstract = {We are now well entering the exciting era of stem cells. Potential stem cell therapy holds great promise for the treatment of many diseases such as stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral-sclerosis, myocardial infarction, muscular dystrophy, diabetes, and etc. It is generally believed that transplantation of specific stem cells into the injured tissue to replace the lost cells is an effective way to repair the tissue. In fact, organ transplantation has been successfully practiced in clinics for liver or kidney failure. However, the severe shortage of donor organs has been a major obstacle for the expansion of organ transplantation programs. Toward that direction, generation of transplantable organs using stem cells is a desirable approach for organ replacement and would be of great interest for both basic and clinical scientists. Here we review recent progress in the field of organ generation using various methods including single adult tissue stem cells, a blastocyst complementation system, tissue decellularization/recellularization and a combination of stem cells and tissue engineering.}, }
@article {pmid25063512, year = {2013}, author = {Lin, F and Qin, ZH}, title = {Degradation of misfolded proteins by autophagy: is it a strategy for Huntington's disease treatment?.}, journal = {Journal of Huntington's disease}, volume = {2}, number = {2}, pages = {149-157}, doi = {10.3233/JHD-130052}, pmid = {25063512}, issn = {1879-6397}, mesh = {Autophagy/*physiology ; Carbamazepine/therapeutic use ; Humans ; Huntingtin Protein ; Huntington Disease/drug therapy/genetics/*metabolism ; Lithium/therapeutic use ; Mutant Proteins/*metabolism ; Nerve Tissue Proteins/*metabolism ; Oxazoles/therapeutic use ; Peptides/metabolism ; Rilmenidine ; Sirolimus/analogs &amp; derivatives/therapeutic use ; Trehalose/therapeutic use ; Trinucleotide Repeat Expansion/genetics ; Valproic Acid/therapeutic use ; }, abstract = {Autophagy is a degradation pathway for long-lived cytoplasmic proteins, protein complexes, or damaged organelles. The accumulation and aggregation of misfolded proteins are hallmarks of several neurodegenerative diseases. Many researchers have reported that autophagy degrades disease-causing misfolded and aggregated proteins, including mutant huntingtin (Htt) in Huntington's disease, mutant synuclein in familial Parkingson's disease, mutant Cu, Zn-Superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis. In this review, we will bring up new evidence to elucidate the involvement of autophagy in degradation of mutant Htt, discuss the mechanisms regulating the degradation of mutant Htt by autophagy and the therapeutic effects of drugs that enhance autophagy to improve clearance of mutant Htt. We propose that enhancement of autophagy by drugs may be a strategy to treat or retard progression of Huntington's disease.}, }
@article {pmid24940658, year = {2013}, author = {Harris, JP and Tyler, DJ}, title = {Biological, mechanical, and technological considerations affecting the longevity of intracortical electrode recordings.}, journal = {Critical reviews in biomedical engineering}, volume = {41}, number = {6}, pages = {435-456}, pmid = {24940658}, issn = {0278-940X}, mesh = {Animals ; *Biomedical Engineering ; *Brain-Computer Interfaces ; Cerebral Cortex/physiology ; *Electrodes, Implanted ; Electroencephalography/*instrumentation/*methods ; Guinea Pigs ; Haplorhini ; Humans ; Mice ; Rats ; }, abstract = {Intracortical electrodes are important tools, with applications ranging from fundamental laboratory studies to potential solutions to intractable clinical applications. However, the longevity and reliability of the interfaces remain their major limitation to the wider implementation and adoption of this technology, especially in broader translational work. Accordingly, this review summarizes the most significant biological and technical factors influencing the long-term performance of intracortical electrodes. In a laboratory setting, intracortical electrodes have been used to study the normal and abnormal function of the brain. This improved understanding has led to valuable insights regarding many neurological conditions. Likewise, clinical applications of intracortical brain-machine interfaces offer the ability to improve the quality of life of many patients afflicted with high-level paralysis from spinal cord injury, brain stem stroke, amyotrophic lateral sclerosis, or other conditions. It is widely hypothesized that the tissue response to the electrodes, including inflammation, limits their longevity. Many studies have examined and modified the tissue response to intracortical electrodes to improve future intracortical electrode technologies. Overall, the relationship between biological, mechanical, and technological considerations are crucial for the fidelity of chronic electrode recordings and represent a presently active area of investigation in the field of neural engineering.}, }
@article {pmid24592734, year = {2013}, author = {Mavliutov, TA}, title = {[Protective function of sigma-1 receptor in spinal cord motor neurons].}, journal = {Tsitologiia}, volume = {55}, number = {5}, pages = {285-289}, pmid = {24592734}, issn = {0041-3771}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Central Nervous System/metabolism ; Humans ; Motor Neurons/metabolism/pathology ; Mutation ; Receptors, sigma/genetics/*metabolism/physiology ; Signal Transduction ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Sigma-1 Receptor ; }, abstract = {Sigma-1 receptor plays a protective function in various tissues. It was shown recently that a mutation in the sigma-1 receptor results in appearance of Amyotrophic Lateral Sclerosis (ALS). In the central nervous system (CNS) the highest amounts of sigma-1 receptor are found in motoneurons of the spinal cord, where receptor is localized in subsurface cisternae of cholinergic postsynaptic densities. The sigma-1 receptor is thought to regulate the ion channels activity and thus may influence neuron excitability. In this review we consider the possible pathways by which the sigma-1 receptor may reduce the excitability of motoneurons and thereby play a protective function during the progression of ALS.}, }
@article {pmid25624807, year = {2012}, author = {Sakthiswary, R and Raymond, AA}, title = {Stem cell therapy in neurodegenerative diseases: From principles to practice.}, journal = {Neural regeneration research}, volume = {7}, number = {23}, pages = {1822-1831}, pmid = {25624807}, issn = {1673-5374}, abstract = {The lack of curative therapies for neurodegenerative diseases has high economic impact and places huge burden on the society. The contribution of stem cells to cure neurodegenerative diseases has been unraveled and explored extensively over the past few years. Beyond substitution of the lost neurons, stem cells act as immunomodulators and neuroprotectors. A large number of preclinical and a small number of clinical studies have shown beneficial outcomes in this context. In this review, we have summarized the current concepts of stem cell therapy in neurodegenerative diseases and the recent advances in this field, particularly between 2010 and 2012. Further studies should be encouraged to resolve the clinical issues and vague translational findings for maximum optimization of the efficacy of stem cell therapy in neurodegenerative diseases.}, }
@article {pmid25745454, year = {2012}, author = {Wang, H and Wu, M and Zhan, C and Ma, E and Yang, M and Yang, X and Li, Y}, title = {Neurofilament proteins in axonal regeneration and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {7}, number = {8}, pages = {620-626}, pmid = {25745454}, issn = {1673-5374}, abstract = {Neurofilament protein is a component of the mature neuronal cytoskeleton, and it interacts with the zygosome, which is mediated by neurofilament-related proteins. Neurofilament protein regulates enzyme function and the structure of linker proteins. In addition, neurofilament gene expression plays an important role in nervous system development. Previous studies have shown that neurofilament gene transcriptional regulation is crucial for neurofilament protein expression, especially in axonal regeneration and degenerative diseases. Post-transcriptional regulation increased neurofilament protein gene transcription during axonal regeneration, ultimately resulting in a pattern of neurofilament protein expression. An expression imbalance of post-transcriptional regulatory proteins and other disorders could lead to amyotrophic lateral sclerosis or other neurodegenerative diseases. These findings indicated that after transcription, neurofilament protein regulated expression of related proteins and promoted regeneration of damaged axons, suggesting that regulation disorders could lead to neurodegenerative diseases.}, }
@article {pmid25191394, year = {2012}, author = {Bach, JR and Bakshiyev, R and Hon, A}, title = {Noninvasive respiratory management for patients with spinal cord injury and neuromuscular disease.}, journal = {Tanaffos}, volume = {11}, number = {1}, pages = {7-11}, pmid = {25191394}, issn = {1735-0344}, abstract = {The purpose of this article is to describe noninvasive respiratory management for patients with neuromuscular respiratory muscle dysfunction (NMD) and spinal cord injury (SCI) and the role of electrophrenic pacing (EPP) and diaphragm pacing (DP) in this respect. Long term outcomes will be reviewed and the use of noninvasive intermittent positive pressure ventilation (NIV), MAC, and EPP/DP to prevent pneumonia and acute respiratory failure, to facilitate extubation, and to avoid tracheotomy will be evaluated. Although ventilator dependent patients with most NMDs and high level SCI can be indefinitely managed noninvasively, most ALS patients can be managed for a limited time by continuous NIV before tracheostomy is necessary for survival. Glossopharyngeal breathing (GPB) can be learned by patients without any autonomous breathing ability and used by them in the event of ventilator/EPP/DP failure or loss of interface access. EPP/DP can maintain alveolar ventilation for high level SCI patients when they cannot grab a mouth piece to use NIV.}, }
@article {pmid24250855, year = {2012}, author = {Ghasemi, M and Fatehi, F and Asadi, B and Khorvash, F}, title = {Amyotrophic lateral sclerosis with laboratory abnormalities of uncertain significance: A brief review.}, journal = {Iranian journal of neurology}, volume = {11}, number = {1}, pages = {25-27}, pmid = {24250855}, issn = {2008-384X}, abstract = {Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is a progressive and devastating disease involving both lower and upper motor neurons, typically following a relentless progression towards death. Therefore, all efforts must be made by the clinician to exclude alternative and more treatable entities. ALS with laboratory abnormalities of uncertain significance is a subgroup of ALS that occurs in association with laboratory defined abnormalities that are of uncertain significance to the pathogenesis of ALS. The clinical utility of these abnormalities and what they ultimately mean in patients with ALS is discussed here, along with a review of the literature.}, }
@article {pmid24198520, year = {2010}, author = {Cova, L and Silani, V}, title = {Amyotrophic lateral sclerosis: applications of stem cells - an update.}, journal = {Stem cells and cloning : advances and applications}, volume = {3}, number = {}, pages = {145-156}, pmid = {24198520}, issn = {1178-6957}, abstract = {Neurodegenerative diseases are a growing public health challenge, and amyotrophic lateral sclerosis (ALS) remains a fatal incurable disease. The advent of stem cell therapy has opened new horizons for both researchers and ALS patients, desperately looking for a treatment. ALS must be considered a systemic disease affecting many cell phenotypes besides motor neurons, even outside the central nervous system. Cell replacement therapy needs to address the specific neurobiological issues of ALS to safely and efficiently reach clinical settings. Moreover, the enormous potential of induced pluripotent cells directly derived from patients for modeling and understanding the pathological mechanisms, in correlation with the discoveries of new genes and animal models, provides new opportunities that need to be integrated with previously described transplantation strategies. Finally, a careful evaluation of preclinical data in conjunction with wary patient choice in clinical trials needs to be established in order to generate meaningful results.}, }
@article {pmid24855505, year = {2008}, author = {Kim, SU and Lee, HJ and Park, IH and Chu, K and Lee, ST and Kim, M and Roh, JK and Kim, SK and Wang, KC}, title = {Human nerual stem cells for brain repair.}, journal = {International journal of stem cells}, volume = {1}, number = {1}, pages = {27-35}, pmid = {24855505}, issn = {2005-3606}, abstract = {Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases including Parkinson disease, Huntington disease, amyotrophic lateral sclerosis (ALS), Alzheimer disease, multiple sclerosis (MS), stroke, spinal cord injury and brain cancer. In recent years, neurons and glial cells have successfully been generated from neural stem cells, and extensive efforts by investigators to develop neural stem cell-based transplantation therapies have been carried out. We review here notable experimental and pre-clinical studies we have previously conducted involving human neural stem cell-based cell- and gene-therapies for Parkinson disease, Huntington disease, ALS, stroke and brain cancer.}, }
@article {pmid23582371, year = {2016}, author = {Gamez, J and Salvado, M and Martínez de la Ossa, A and Badia, M}, title = {Lithium for treatment of amyotrophic lateral sclerosis: much ado about nothing.}, journal = {Neurologia (Barcelona, Spain)}, volume = {31}, number = {8}, pages = {550-561}, doi = {10.1016/j.nrl.2013.02.001}, pmid = {23582371}, issn = {1578-1968}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Lithium Compounds/*therapeutic use ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: Lithium was proposed in 2008 as an effective candidate in the treatment of ALS after a report claimed that it was able to delay functional deterioration by 40% and that none of the 16 patients treated with a combination of lithium plus riluzole had died during a 15-month follow-up period. The excellent results of this pilot study engendered considerable optimism among patients, their families, patients' associations, and the scientific community. This report sparked numerous phase ii clinical trials. Many patients who were not included in these studies used all resources at their disposal to access the drug as treatment under a compassionate use programme.<br><br>OBJECTIVES: To evaluate the effectiveness of lithium in ALS using a meta-analysis of the information reported in 12 studies which were examined for methodological quality.<br><br>MATERIAL AND METHODS: . Searches were performed using MEDLINE, EMBASE, the Cochrane Neuromuscular Disease Group Trials Register, ClinicalTrials.gov, and EudraCT (January 1996-August 2012).<br><br>RESULTS: To date, we have information on more 1100 patients treated with lithium. Unfortunately, the results do not confirm the positive effect described in the pilot study, which suggests that this drug is not effective at slowing disease progression. Two trials had to be suspended before the scheduled completion date due to the ineffectiveness of the drug as well as numerous adverse effects. A recently published study also ruled out any possible modest effect.<br><br>CONCLUSIONS: There is evidence to suggest that lithium has no short-term benefits in ALS. A comparison of the group of patients treated with lithium+riluzole and the control group treated with riluzole alone showed no statistically significant differences in rates of functional decline, deterioration of respiratory function, or survival time. Furthermore, there was no evidence that it was more effective than the placebo.}, }
@article {pmid23574157, year = {2013}, author = {Salama, M and Yuan, TF and Machado, S and Murillo-Rodríguez, E and Vega, JA and Menéndez-González, M and Nardi, AE and Arias-Carrión, O}, title = {Co-enzyme Q10 to treat neurological disorders: basic mechanisms, clinical outcomes, and future research direction.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {12}, number = {5}, pages = {641-664}, doi = {10.2174/18715273113129990071}, pmid = {23574157}, issn = {1996-3181}, mesh = {Animals ; Biomedical Research/*trends ; Electron Transport Chain Complex Proteins/metabolism ; Humans ; Mitochondria/drug effects ; Nervous System Diseases/*drug therapy/pathology ; Neurons/drug effects/ultrastructure ; Neuroprotective Agents/pharmacology/*therapeutic use ; Ubiquinone/*analogs &amp; derivatives/pharmacology/therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10) is critical for the cell power supply in mitochondria. CoQ10 shuttles electrons from complexes I and II to complex III, and can be anti-oxdiative. Neurons require high energy for synaptic transmission and therefore the mitochondria dysfunction often leads to severe neuronal degeneration, as observed in many neurological disorders. CoQ10 supplementation has been widely used to treat aging, stroke, neuromuscular diseases, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, autosomal recessive cerebellar ataxias, Huntington's disease and amyotrophic lateral sclerosis. Here we discuss a large number of preclinical and clinical trials for CoQ10 to elucidate the mechanisms underlying CoQ10 therapy. The rational applications as a therapeutic agent in neurological disorders are discussed.}, }
@article {pmid23570271, year = {2013}, author = {Long, Kv and Nguyễn, LT}, title = {Roles of vitamin D in amyotrophic lateral sclerosis: possible genetic and cellular signaling mechanisms.}, journal = {Molecular brain}, volume = {6}, number = {}, pages = {16}, pmid = {23570271}, issn = {1756-6606}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Genome/genetics ; Humans ; Oxidative Stress ; Signal Transduction/*genetics ; Vitamin D/*metabolism ; }, abstract = {Evidence suggests that there are aberrations in the vitamin D-endocrine system in subjects with amyotrophic lateral sclerosis (ALS). Here, we review the relationship between vitamin D and ALS. Vitamin D deficiency was reported in patients with ALS. Dietary vitamin D(3) supplementation improves functional capacity in the G93A transgenic mouse model of ALS. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to ALS pathology, including major histocompatibility complex (MHC) class II molecules, toll-like receptors, poly(ADP-ribose) polymerase-1, heme oxygenase-1, and calcium-binding proteins, as well as the reduced form of nicotinamide adenine dinucleotide phosphate. Vitamin D also exerts its effect on ALS through cell-signaling mechanisms, including glutamate, matrix metalloproteinases, mitogen-activated protein kinase pathways, the Wnt/β-catenin signaling pathway, prostaglandins, reactive oxygen species, and nitric oxide synthase. In conclusion, vitamin D may have a role in ALS. Further investigation of vitamin D in ALS patients is needed.}, }
@article {pmid23568995, year = {2013}, author = {Kanemaru, K}, title = {[Immunotherapy targeting misfolded proteins in neurodegenerative disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {4}, pages = {469-474}, pmid = {23568995}, issn = {1881-6096}, mesh = {Amyloid beta-Peptides/immunology ; Animals ; Antibodies/immunology/*therapeutic use ; Humans ; *Immunotherapy/methods ; Neurodegenerative Diseases/diagnosis/immunology/metabolism/*therapy ; *Protein Folding/drug effects ; Proteostasis Deficiencies/diagnosis/immunology/therapy ; }, abstract = {Aberrant protein aggregation is closely linked to the molecular pathogeneses of most neurodegenerative diseases. The major components of pathological aggregates have been characterized in various neurodegenerative diseases; for example, amyloid β-protein and phosphorylated tau in Alzheimer's disease, α-synuclein in Parkinson's disease, SOD1 or TDP-43 in amyotrophic lateral sclerosis, and huntingtin in Huntington's disease. These misfolded protein aggregates play a vital role in disease initiation and progression, and they have recently been shown to have prion-like spreading or seeded aggregation properties. Immunotherapy with specific monoclonal antibodies is a promising approach to clear misfolded protein aggregates and treat various neurodegenerative diseases; it is planned for use in clinical trials in the near future.}, }
@article {pmid23568988, year = {2013}, author = {Watanabe, O}, title = {[VGKC-complex antibodies].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {4}, pages = {401-411}, pmid = {23568988}, issn = {1881-6096}, mesh = {Antibodies/*immunology ; Autoimmune Diseases/diagnosis/immunology ; Humans ; Isaacs Syndrome/diagnosis/immunology ; Limbic Encephalitis/diagnosis/immunology ; Potassium Channels, Voltage-Gated/*immunology ; Syringomyelia/diagnosis/immunology ; }, abstract = {Various antibodies are associated with voltage-gated potassium channels (VGKCs). Representative antibodies to VGKCs were first identified by radioimmunoassays using radioisotope-labeled alpha-dendrotoxin-VGKCs solubilized from rabbit brain. These antibodies were detected only in a proportion of patients with acquired neuromyotonia (Isaacs' syndrome). VGKC antibodies were also detected in patients with Morvan's syndrome and in those with a form of autoimmune limbic encephalitis. Recent studies indicated that the "VGKC" antibodies are mainly directed toward associated proteins (for example LGI-1 and CASPR-2) that complex with the VGKCs themselves. The "VGKC" antibodies are now commonly known as VGKC-complex antibodies. In general, LGI-1 antibodies are most commonly detected in patients with limbic encephalitis with syndrome of inappropriate secretion of antidiuretic hormone. CASPR-2 antibodies are present in the majority of patients with Morvan's syndrome. These patients develop combinations of CNS symptoms, autonomic dysfunction, and peripheral nerve hyperexcitability. Furthermore, VGKC-complex antibodies are tightly associated with chronic idiopathic pain. Hyperexcitability of nociceptive pathways has also been implicated. These antibodies may be detected in sera of some patients with neurodegenerative diseases (for example, amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease).}, }
@article {pmid23567191, year = {2013}, author = {Chaturvedi, RK and Flint Beal, M}, title = {Mitochondrial diseases of the brain.}, journal = {Free radical biology &amp; medicine}, volume = {63}, number = {}, pages = {1-29}, doi = {10.1016/j.freeradbiomed.2013.03.018}, pmid = {23567191}, issn = {1873-4596}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Brain/*metabolism/pathology ; Charcot-Marie-Tooth Disease/metabolism/pathology ; Free Radicals/toxicity ; Friedreich Ataxia/metabolism/pathology ; Humans ; Huntington Disease/metabolism/pathology ; Mitochondria/*metabolism/pathology ; Mitochondrial Diseases/*pathology ; Nerve Degeneration/*metabolism/physiopathology ; Parkinson Disease/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are debilitating diseases of the brain, characterized by behavioral, motor and cognitive impairments. Ample evidence underpins mitochondrial dysfunction as a central causal factor in the pathogenesis of neurodegenerative disorders including Parkinson's disease, Huntington's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia and Charcot-Marie-Tooth disease. In this review, we discuss the role of mitochondrial dysfunction such as bioenergetics defects, mitochondrial DNA mutations, gene mutations, altered mitochondrial dynamics (mitochondrial fusion/fission, morphology, size, transport/trafficking, and movement), impaired transcription and the association of mutated proteins with mitochondria in these diseases. We highlight the therapeutic role of mitochondrial bioenergetic agents in toxin and in cellular and genetic animal models of neurodegenerative disorders. We also discuss clinical trials of bioenergetics agents in neurodegenerative disorders. Lastly, we shed light on PGC-1α, TORC-1, AMP kinase, Nrf2-ARE, and Sirtuins as novel therapeutic targets for neurodegenerative disorders.}, }
@article {pmid23559573, year = {2013}, author = {Lattante, S and Rouleau, GA and Kabashi, E}, title = {TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update.}, journal = {Human mutation}, volume = {34}, number = {6}, pages = {812-826}, doi = {10.1002/humu.22319}, pmid = {23559573}, issn = {1098-1004}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/metabolism ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; Epistasis, Genetic ; Genetic Association Studies ; Humans ; *Mutation ; Polymorphism, Genetic ; RNA-Binding Protein FUS/chemistry/*genetics/metabolism ; }, abstract = {Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.}, }
@article {pmid23558099, year = {2014}, author = {Obrig, H}, title = {NIRS in clinical neurology - a 'promising' tool?.}, journal = {NeuroImage}, volume = {85 Pt 1}, number = {}, pages = {535-546}, doi = {10.1016/j.neuroimage.2013.03.045}, pmid = {23558099}, issn = {1095-9572}, mesh = {Brain Diseases/diagnosis/psychology ; Cerebrovascular Disorders/diagnosis ; Epilepsy/diagnosis ; Functional Neuroimaging/*methods ; Headache Disorders/diagnosis ; Humans ; Nervous System Diseases/*diagnosis ; Neurology/*instrumentation ; Spectroscopy, Near-Infrared/*methods ; Stroke/diagnosis ; }, abstract = {Near-infrared spectroscopy (NIRS) has become a relevant research tool in neuroscience. In special populations such as infants and for special tasks such as walking, NIRS has asserted itself as a low resolution functional imaging technique which profits from its ease of application, portability and the option to co-register other neurophysiological and behavioral data in a 'near natural' environment. For clinical use in neurology this translates into the option to provide a bed-side oximeter for the brain, broadly available at comparatively low costs. However, while some potential for routine brain monitoring during cardiac and vascular surgery and in neonatology has been established, NIRS is largely unknown to clinical neurologists. The article discusses some of the reasons for this lack of use in clinical neurology. Research using NIRS in three major neurologic diseases (cerebrovascular disease, epilepsy and headache) is reviewed. Additionally the potential to exploit the established position of NIRS as a functional imaging tool with regard to clinical questions such as preoperative functional assessment and neurorehabilitation is discussed.}, }
@article {pmid23557964, year = {2013}, author = {Dormann, D and Haass, C}, title = {Fused in sarcoma (FUS): an oncogene goes awry in neurodegeneration.}, journal = {Molecular and cellular neurosciences}, volume = {56}, number = {}, pages = {475-486}, doi = {10.1016/j.mcn.2013.03.006}, pmid = {23557964}, issn = {1095-9327}, support = {321366/ERC_/European Research Council/International ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Frontotemporal Lobar Degeneration/genetics/*metabolism ; Humans ; RNA Splicing ; RNA, Messenger/genetics/metabolism ; RNA-Binding Protein FUS/genetics/*metabolism ; Transcription, Genetic ; }, abstract = {Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients. Moreover, FUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of FUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'.}, }
@article {pmid23557642, year = {2013}, author = {Heberling, MM and Wu, B and Bartsch, S and Janssen, DB}, title = {Priming ammonia lyases and aminomutases for industrial and therapeutic applications.}, journal = {Current opinion in chemical biology}, volume = {17}, number = {2}, pages = {250-260}, doi = {10.1016/j.cbpa.2013.02.013}, pmid = {23557642}, issn = {1879-0402}, mesh = {Ammonia-Lyases/*chemistry ; Bacterial Proteins/chemistry ; Drug Industry/*methods ; Fungal Proteins/chemistry ; Industrial Microbiology/*methods ; Intramolecular Transferases/*chemistry ; Metabolic Networks and Pathways ; Protein Engineering/*methods ; }, abstract = {Ammonia lyases (AL) and aminomutases (AM) are emerging in green synthetic routes to chiral amines and an AL is being explored as an enzyme therapeutic for treating phenylketonuria and cancer. Although the restricted substrate range of the wild-type enzymes limits their widespread application, the non-reliance on external cofactors and direct functionalization of an olefinic bond make ammonia lyases attractive biocatalysts for use in the synthesis of natural and non-natural amino acids, including β-amino acids. The approach of combining structure-guided enzyme engineering with efficient mutant library screening has extended the synthetic scope of these enzymes in recent years and has resolved important mechanistic issues for AMs and ALs, including those containing the MIO (4-methylideneimidazole-5-one) internal cofactor.}, }
@article {pmid23550891, year = {2013}, author = {Hovden, H and Frederiksen, JL and Pedersen, SW}, title = {Immune system alterations in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {128}, number = {5}, pages = {287-296}, doi = {10.1111/ane.12125}, pmid = {23550891}, issn = {1600-0404}, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/*immunology/pathology ; Animals ; Humans ; Immune System/pathology/physiopathology ; Immune System Diseases/*etiology ; }, abstract = {Amyotrophic lateral sclerosis is a disease of which the underlying cause and pathogenesis are unknown. Cumulatative data clearly indicates an active participation by the immune system in the disease. An increasingly recognized theory suggests a non-cell autonomous mechanism, meaning that multiple cells working together are necessary for the pathogenesis of the disease. Observed immune system alterations could indicate an active participation in this mechanism. Damaged motor neurons are able to activate microglia, astrocytes and the complement system, which further can influence each other and contribute to neurodegeneration. Infiltrating peripheral immune cells appears to correlate with disease progression, but their significance and composition is unclear. The deleterious effects of this collaborating system of cells appear to outweigh the protective aspects, and revealing this interplay might give more insight into the disease. Markers from the classical complement pathway are elevated where its initiator C1q appears to derive primarily from motor neurons. Activated microglia and astrocytes are found in close proximity to dying motor neurons. Their activation status and proliferation seemingly increases with disease progression. Infiltrating monocytes, macrophages and T cells are associated with these areas, although with mixed reports regarding T cell composition. This literature review will provide evidence supporting the immune system as an important part of ALS disease mechanism and present a hypothesis to direct the way for further studies.}, }
@article {pmid23549648, year = {2013}, author = {Cohen, BH}, title = {Neuromuscular and systemic presentations in adults: diagnoses beyond MERRF and MELAS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {10}, number = {2}, pages = {227-242}, pmid = {23549648}, issn = {1878-7479}, mesh = {Adult ; Humans ; MELAS Syndrome/*diagnosis/genetics/*physiopathology/therapy ; MERRF Syndrome/*diagnosis/genetics/*physiopathology/therapy ; Mitochondria/genetics/pathology ; Mitochondrial Diseases/*diagnosis/physiopathology ; Nervous System Diseases/*diagnosis/physiopathology ; Precision Medicine ; Terminology as Topic ; }, abstract = {Mitochondrial diseases are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, and exposure to toxins (including some prescription medications). Normal mitochondrial physiology is responsible, in part, for the aging process itself, as free radical production within the mitochondria results in a lifetime burden of oxidative damage to DNA, especially the mitochondrial DNA that, in turn, replicate the mutational burden in future copies of itself, and lipid membranes. Primary mitochondrial diseases are those caused by mutations in genes that encode for mitochondrial structural and enzymatic proteins, and those proteins required for mitochondrial assembly and maintenance. A number of common adult maladies are associated with defective mitochondrial energy production and function, including diabetes, obesity, hyperthyroidism, hypothyroidism, and hyperlipidemia. Mitochondrial dysfunction has been demonstrated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and some cancers. Polymorphisms in mitochondrial DNA have been linked to disease susceptibility, including death from sepsis and survival after head injury. There is considerable overlap in symptoms caused by primary mitochondrial diseases and those illnesses that affect mitochondrial function, but are not caused by primary mutations, as well as disorders that mimic mitochondrial diseases, but are caused by other identified mutations. Evaluation of these disorders is complex, expensive, and not without false-negative and false-positive results that can mislead the physician. Most of the common heritable mitochondrial disorders have been well-described in the literature, but can be overlooked by many clinicians if they are uneducated about these disorders. In general, the evaluation of the classic mitochondrial disorders has become straightforward if the clinician recognized the phenotype and orders appropriate confirmatory testing. However, the majority of patients referred for a mitochondrial evaluation do not have a clear presentation that allows for rapid identification and testing. This article provides introductory comments on mitochondrial structure, physiology, and genetics, but will focus on the presentation and evaluation of adults with mitochondrial symptoms, but who may not have a primary mitochondrial disease.}, }
@article {pmid23549464, year = {2013}, author = {Natale, G and Pompili, E and Biagioni, F and Paparelli, S and Lenzi, P and Fornai, F}, title = {Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases.}, journal = {European journal of histochemistry : EJH}, volume = {57}, number = {1}, pages = {e5}, pmid = {23549464}, issn = {2038-8306}, mesh = {Animals ; *Cell Communication ; Glycation End Products, Advanced/*metabolism ; Humans ; Neurodegenerative Diseases/*mortality/pathology ; Prions/*metabolism/pathogenicity ; *Protein Folding ; Proteostasis Deficiencies/*mortality/pathology ; }, abstract = {Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs); mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs). The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.}, }
@article {pmid23543531, year = {2013}, author = {Radunovic, A and Annane, D and Rafiq, MK and Mustfa, N}, title = {Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD004427}, doi = {10.1002/14651858.CD004427.pub3}, pmid = {23543531}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*mortality ; Disease Progression ; Humans ; Motor Neuron Disease/mortality ; Quality of Life ; Randomized Controlled Trials as Topic ; Respiration, Artificial/*mortality ; Respiratory Insufficiency/etiology/*mortality/therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the commonest cause of death, usually within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the first update of a review first published in 2009.<br><br>OBJECTIVES: The primary objective of the review is to examine the efficacy of mechanical ventilation (tracheostomy and non-invasive ventilation) in improving survival in ALS. The secondary objectives are to examine the effect of mechanical ventilation on functional measures of disease progression and quality of life in people with ALS; and assess adverse events related to the intervention.<br><br>SEARCH METHODS: We searched The Cochrane Neuromuscular Disease Group Specialized Register (1 May 2012), CENTRAL (2012, Issue 4), MEDLINE (January 1966 to April 2012), EMBASE (January 1980 to April 2012), CINAHL Plus (January 1937 to April 2012), and AMED (January 1985 to April 2012). We also searched for ongoing studies on ClinicalTrials.gov.<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving non-invasive or tracheostomy assisted ventilation in participants with a clinical diagnosis of amyotrophic lateral sclerosis, independent of the reported outcomes. We planned to include comparisons with no intervention or the best standard care.<br><br>DATA COLLECTION AND ANALYSIS: For the original review, four authors independently selected studies for assessment and two authors reviewed searches for this update. All authors extracted data independently from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from included studies.<br><br>MAIN RESULTS: For the original Cochrane review, the review authors identified and included two randomised controlled trials involving 54 participants with ALS receiving non-invasive ventilation. There were no new randomised or quasi-randomised controlled trials at this first update.Incomplete data were published for one study and we contacted the trial authors who were not able to provide the missing data. Therefore, the results of the review were based on a single study of 41 participants that compared non-invasive ventilation with standard care. It was a well conducted study with low risk of bias.The study showed that the overall median survival was significantly different between the group treated with non-invasive ventilation and the standard care group. The median survival in the non-invasive ventilation group was 48 days longer (219 days compared to 171 days for the standard care group (estimated 95% CI 12 to 91 days, P = 0.0062)). This survival benefit was accompanied by an enhanced quality of life. On subgroup analysis, the survival and quality of life benefit was much more in the subgroup with normal to moderately impaired bulbar function (20 participants); median survival was 205 days longer (216 days in NIV group versus 11 days in the standard care group, P = 0.0059). Non-invasive ventilation did not prolong survival in participants with poor bulbar function (21 participants), although it showed significant improvement in the mean symptoms domain of the Sleep Apnoea Quality of Life Index but not in the Short Form-36 Health Survey Mental Component Summary score. Neither trial reported clinical data on intervention related adverse effects.<br><br>AUTHORS' CONCLUSIONS: Evidence from a single randomised trial of non-invasive ventilation in 41 participants suggests that it significantly prolongs survival and improves or maintains quality of life in people with ALS. Survival and some measures of quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment. Future studies should examine the health economics of NIV and factors influencing access to NIV. We need to understand the factors, personal and socioeconomic, that determine access to NIV.}, }
@article {pmid23540596, year = {2013}, author = {Güell, MR and Antón, A and Rojas-García, R and Puy, C and Pradas, J and , }, title = {Comprehensive care of amyotrophic lateral sclerosis patients: a care model.}, journal = {Archivos de bronconeumologia}, volume = {49}, number = {12}, pages = {529-533}, doi = {10.1016/j.arbres.2013.01.013}, pmid = {23540596}, issn = {1579-2129}, mesh = {Amyotrophic Lateral Sclerosis/complications/nursing/psychology/*therapy ; Comprehensive Health Care/*organization &amp; administration ; Deglutition Disorders/etiology/therapy ; Dietetics ; Home Care Services ; Hospital Units/organization &amp; administration ; Humans ; Interdisciplinary Communication ; Medicine ; *Models, Theoretical ; Movement Disorders/etiology/therapy ; Outpatient Clinics, Hospital/*organization &amp; administration ; Patient Care Team ; Patient Education as Topic ; Quality of Life ; Respiration Disorders/etiology/therapy ; Social Work ; Spain ; Speech Disorders/etiology/therapy ; Speech Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that presents with muscle weakness, causing progressive difficulty in movement, communication, eating and ultimately, breathing, creating a growing dependence on family members and other carers. The ideal way to address the problems associated with the disease, and the decisions that must be taken, is through multidisciplinary teams. The key objectives of these teams are to optimise medical care, facilitate communication between team members, and thus to improve the quality of care. In our centre, we have extensive experience in the care of patients with ALS through an interdisciplinary team whose aim is to ensure proper patient care from the hospital to the home setting. In this article, we describe the components of the team, their roles and our way of working.}, }
@article {pmid23539154, year = {2013}, author = {Moser, JM and Bigini, P and Schmitt-John, T}, title = {The wobbler mouse, an ALS animal model.}, journal = {Molecular genetics and genomics : MGG}, volume = {288}, number = {5-6}, pages = {207-229}, pmid = {23539154}, issn = {1617-4623}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/drug therapy/*etiology/physiopathology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Disease Models, Animal ; Humans ; Male ; Mice ; Molecular Sequence Data ; Motor Neuron Disease/*etiology ; Mutation ; Spermatogenesis/genetics ; Vesicular Transport Proteins/*genetics ; }, abstract = {This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.}, }
@article {pmid23533690, year = {2013}, author = {Parakh, S and Spencer, DM and Halloran, MA and Soo, KY and Atkin, JD}, title = {Redox regulation in amyotrophic lateral sclerosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {408681}, pmid = {23533690}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Autophagy ; Axonal Transport ; Cholesterol/metabolism ; Endoplasmic Reticulum Stress ; Glutamic Acid/metabolism ; Humans ; Lipid Peroxidation ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Protein Disulfide-Isomerases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.}, }
@article {pmid23530518, year = {2013}, author = {Correia, SC and Carvalho, C and Cardoso, S and Santos, RX and Plácido, AI and Candeias, E and Duarte, AI and Moreira, PI}, title = {Defective HIF signaling pathway and brain response to hypoxia in neurodegenerative diseases: not an "iffy" question!.}, journal = {Current pharmaceutical design}, volume = {19}, number = {38}, pages = {6809-6822}, doi = {10.2174/1381612811319380013}, pmid = {23530518}, issn = {1873-4286}, mesh = {Animals ; Autophagy ; Brain/*physiopathology ; Erythropoiesis ; Humans ; Hypoxia/*physiopathology ; Hypoxia-Inducible Factor 1/*physiology ; Neovascularization, Physiologic ; Neurodegenerative Diseases/*etiology/physiopathology ; Neurogenesis ; Signal Transduction/*physiology ; Vascular Endothelial Growth Factor A/physiology ; }, abstract = {Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the "headquarter" of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus, enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response to hypoxia and its close association with the development of Alzheimer's, and Parkinson's disease and amyotrophic lateral sclerosis. Finally, the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.}, }
@article {pmid23524377, year = {2013}, author = {McGoldrick, P and Joyce, PI and Fisher, EM and Greensmith, L}, title = {Rodent models of amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1832}, number = {9}, pages = {1421-1436}, doi = {10.1016/j.bbadis.2013.03.012}, pmid = {23524377}, issn = {0006-3002}, support = {G0500288/MRC_/Medical Research Council/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology/therapy ; Animals ; Biomarkers/*metabolism ; *Disease Models, Animal ; *Genetic Therapy ; Humans ; Rodentia/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by the degeneration of upper and lower motor neurons. Recent advances in our understanding of some of the genetic causes of ALS, such as mutations in SOD1, TARDBP, FUS and VCP have led to the generation of rodent models of the disease, as a strategy to help our understanding of the pathophysiology of ALS and to assist in the development of therapeutic strategies. This review provides detailed descriptions of TDP-43, FUS and VCP models of ALS, and summarises potential therapeutics which have been recently trialled in rodent models of the disease. This article is part of a Special Issue entitled: Animal Models of Disease.}, }
@article {pmid23523708, year = {2013}, author = {Joyce, NC and Carter, GT}, title = {Electrodiagnosis in persons with amyotrophic lateral sclerosis.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {5}, number = {5 Suppl}, pages = {S89-95}, pmid = {23523708}, issn = {1934-1563}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; 5K12HD001097-15/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Electromyography/*methods ; Humans ; Neural Conduction/physiology ; }, abstract = {Electrophysiology remains an important tool in the evaluation of patients presenting with signs and symptoms of motor neuron disease. The electrodiagnostic study should include peripheral nerve conduction studies and needle electromyography to both exclude treatable disease and gather evidence regarding a diagnosis of amyotrophic lateral sclerosis (ALS). The recent changes in the revised El Escorial criteria, recommended by the Awaji-shima consensus group, have increased the diagnostic significance of fasciculation potentials to equal that of fibrillation and positive sharp-wave potentials in the needle electromyography examination of patients suspected of having ALS. In addition, electrophysiologic evidence is now considered equivalent to clinical signs and symptoms in reaching a diagnostic certainty of ALS. These changes, strategies for the design, and implementation of an effective electrodiagnostic evaluation, in addition to electrophysiologic techniques and their relationship to the evaluation of a patient with ALS, are reviewed and discussed.}, }
@article {pmid23519768, year = {2014}, author = {Zhang, X and Hong, YL and Xu, DS and Feng, Y and Zhao, LJ and Ruan, KF and Yang, XJ}, title = {A review of experimental research on herbal compounds in amyotrophic lateral sclerosis.}, journal = {Phytotherapy research : PTR}, volume = {28}, number = {1}, pages = {9-21}, doi = {10.1002/ptr.4960}, pmid = {23519768}, issn = {1099-1573}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Calcium/metabolism ; Excitatory Amino Acids/antagonists &amp; inhibitors ; Humans ; Inflammation/drug therapy ; Oxidative Stress/*drug effects ; Plant Extracts/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease worldwide, leading to progressive muscle atrophy and paralysis. The limited success of conventional treatment for ALS has prompted investigations into complementary and alternative therapies. Herbal remedies provide good prospects of ALS prevention and treatment, with advantages such as multiple targets, multiple links, and few side effects. Studies in vitro and in vivo have shown that herbs have a great potential for treatment of ALS, with therapeutic effects against oxidative stress, excitatory amino acid toxicity, neuroinflammation, and calcium cytotoxicity. Active monomers or ingredients extracted from herbs are considered promising candidates for ALS. Therefore, we review recent experimental research on monomers and compounds isolated from herbal remedies for preventing and treating ALS.}, }
@article {pmid23518330, year = {2013}, author = {Goldstein, LH and Abrahams, S}, title = {Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment.}, journal = {The Lancet. Neurology}, volume = {12}, number = {4}, pages = {368-380}, doi = {10.1016/S1474-4422(13)70026-7}, pmid = {23518330}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*psychology ; Cognition Disorders/*diagnosis/epidemiology/*psychology ; Humans ; *Neuropsychological Tests ; *Social Behavior ; }, abstract = {Increased awareness of cognitive and behavioural change in amyotrophic lateral sclerosis has been driven by various clinic-based and population-based studies. A frontotemporal syndrome occurs in a substantial proportion of patients, a subgroup of whom present with frontotemporal dementia. Deficits are characterised by executive and working-memory impairments, extending to changes in language and social cognition. Behaviour and social cognition abnormalities are closely similar to those reported in behavioural variant frontotemporal dementia, implying a clinical spectrum linking amyotrophic lateral sclerosis and frontotemporal dementia. Cognitive impairment should be considered in clinical management, but few specialist assessment resources are available, and thus the cognitive status of most patients is unknown. Standard assessment procedures are not appropriate to detect dysfunction due to progressive physical disability; techniques that better measure the problems encountered by this group of patients are needed to further establish disease effects. Screening instruments are needed that are validated specifically for amyotrophic lateral sclerosis, encompass the heterogeneity of impairment, and accommodate physical disability.}, }
@article {pmid23517078, year = {2013}, author = {Waschek, JA}, title = {VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair.}, journal = {British journal of pharmacology}, volume = {169}, number = {3}, pages = {512-523}, pmid = {23517078}, issn = {1476-5381}, support = {MH098506/MH/NIMH NIH HHS/United States ; HD04612/HD/NICHD NIH HHS/United States ; NS070580/NS/NINDS NIH HHS/United States ; P30 HD004612/HD/NICHD NIH HHS/United States ; R03 HD068686/HD/NICHD NIH HHS/United States ; R21 NS070580/NS/NINDS NIH HHS/United States ; HD068686/HD/NICHD NIH HHS/United States ; R21 MH098506/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Brain Diseases/immunology/*metabolism ; Central Nervous System/immunology/*injuries/*metabolism ; Humans ; Ligands ; *Models, Biological ; Pituitary Adenylate Cyclase-Activating Polypeptide/*metabolism ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Receptors, Vasoactive Intestinal Peptide/metabolism ; Signal Transduction ; Spinal Cord Diseases/immunology/*metabolism ; Vasoactive Intestinal Peptide/*metabolism ; }, abstract = {Inflammatory processes play both regenerative and destructive roles in multiple sclerosis, stroke, CNS trauma, amyotrophic lateral sclerosis and aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Endogenous defence mechanisms against these pathologies include those that are directly neuroprotective, and those that modulate the expression of inflammatory mediators in microglia, astrocytes, and invading inflammatory cells. While a number of mechanisms and molecules have been identified that can directly promote neuronal survival, less is known about how the brain protects itself from harmful inflammation, and further, how it co-opts the healing function of the immune system to promote CNS repair. The two closely related neuroprotective peptides, vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP), which are up-regulated in neurons and immune cells after injury and/or inflammation, are known to protect neurons, but also exert powerful in vivo immunomodulatory actions, which are primarily anti-inflammatory. These peptide actions are mediated by high-affinity receptors expressed not only on neurons, but also astrocytes, microglia and peripheral inflammatory cells. Well-established immunomodulatory actions of these peptides are to inhibit macrophage and microglia production and release of inflammatory mediators such as TNF-α and IFN-γ, and polarization of T-cell responses away from Th1 and Th17, and towards a Th2 phenotype. More recent studies have revealed that these peptides can also promote the production of both natural and inducible subsets of regulatory T-cells. The neuroprotective and immunomodulatory actions of VIP and PACAP suggest that receptors for these peptides may be therapeutic targets for neurodegenerative and neuroinflammatory diseases and other forms of CNS injury.}, }
@article {pmid23511908, year = {2013}, author = {Shepherd, GM}, title = {Corticostriatal connectivity and its role in disease.}, journal = {Nature reviews. Neuroscience}, volume = {14}, number = {4}, pages = {278-291}, pmid = {23511908}, issn = {1471-0048}, support = {R01 NS061963/NS/NINDS NIH HHS/United States ; NS061963/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cerebral Cortex/cytology/*physiology ; Corpus Striatum/cytology/*physiology ; Developmental Disabilities/*pathology ; Humans ; Mental Disorders/*pathology ; Movement Disorders/*pathology ; Neural Pathways/*physiology ; Neurons/physiology ; }, abstract = {Corticostriatal projections are essential components of forebrain circuits and are widely involved in motivated behaviour. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) neurons. Convergent evidence points to IT versus PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signalling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an aetiological factor in neurodevelopmental, neuropsychiatric and movement disorders - autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington's and Parkinson's diseases and major depression are highlighted here.}, }
@article {pmid23508986, year = {2013}, author = {Mulligan, VK and Chakrabartty, A}, title = {Protein misfolding in the late-onset neurodegenerative diseases: common themes and the unique case of amyotrophic lateral sclerosis.}, journal = {Proteins}, volume = {81}, number = {8}, pages = {1285-1303}, doi = {10.1002/prot.24285}, pmid = {23508986}, issn = {1097-0134}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Humans ; Models, Molecular ; Mutation ; Neurodegenerative Diseases/genetics/metabolism/*pathology ; *Protein Folding ; Superoxide Dismutase/analysis/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Enormous strides have been made in the last 100 years to extend human life expectancy and to combat the major infectious diseases. Today, the major challenges for medical science are age-related diseases, including cancer, heart disease, lung disease, renal disease, and late-onset neurodegenerative disease. Of these, only the neurodegenerative diseases represent a class of disease so poorly understood that no general strategies for prevention or treatment exist. These diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, the transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis (ALS), are generally fatal and incurable. The first section of this review summarizes the diversity and common features of the late-onset neurodegenerative diseases, with a particular focus on protein misfolding and aggregation-a recurring theme in the molecular pathology. The second section focuses on the particular case of ALS, a late-onset neurodegenerative disease characterized by the death of central nervous system motor neurons, leading to paralysis and patient death. Of the 10% of ALS cases that show familial inheritance (familial ALS), the largest subset is caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). The unusual kinetic stability of SOD1 has provided a unique opportunity for detailed structural characterization of conformational states potentially involved in SOD1-associated ALS. This review discusses past studies exploring the stability, folding, and misfolding behavior of SOD1, as well as the therapeutic possibilities of using detailed knowledge of misfolding pathways to target the molecular mechanisms underlying ALS and other neurodegenerative diseases.}, }
@article {pmid23506891, year = {2013}, author = {Hirabayashi, Y and Nomura, KH and Nomura, K}, title = {The acetyl-CoA transporter family SLC33.}, journal = {Molecular aspects of medicine}, volume = {34}, number = {2-3}, pages = {586-589}, doi = {10.1016/j.mam.2012.05.009}, pmid = {23506891}, issn = {1872-9452}, mesh = {Golgi Apparatus/metabolism ; Humans ; Membrane Transport Proteins/*genetics/metabolism/*physiology ; Models, Biological ; Motor Neurons/metabolism ; Multigene Family/*genetics ; Neurodegenerative Diseases/*genetics ; Phylogeny ; Species Specificity ; }, abstract = {The acetyl-CoA (Ac-CoA) transporter, ACATN is a multiple (11 or 12) transmembrane protein in the endoplasmic reticulum. Ac-CoA is transported into the lumen of the endoplasmic reticulum/Golgi apparatus, where it serves as the substrate of acetyltransferases that modify a variety of molecules including the sialic acid residues of gangliosides and lysine residues of membrane proteins. The ACATN gene, assigned as SLC33A1, was cloned from human melanoma cells and encodes the ACATN/ACATN1 (Acetyl-CoA Transporter 1) protein. Although homologs of this family of proteins have been identified in lower organisms such as Escherichia coli, Drosophila melanogaster and Caenorhabditis elegans, only one member of this SLC33A1 family has been identified. Although acetylated gangliosides are synthesized in the luminal Golgi membrane and show a highly tissue-specific distribution, ACATN1 is enriched in the ER membrane and is ubiquitously expressed. Phylogenetically, the SLC33A1 gene is highly conserved, suggesting that it is particularly significant. In fact, ACATN1 is essential for motor neuron viability. SLC33A1 is associated with neurodegenerative disorders such as sporadic amyotrophic lateral sclerosis (ALS) and Spastic Paraplegia 42, in the Chinese population.}, }
@article {pmid23506861, year = {2013}, author = {Kanai, Y and Clémençon, B and Simonin, A and Leuenberger, M and Lochner, M and Weisstanner, M and Hediger, MA}, title = {The SLC1 high-affinity glutamate and neutral amino acid transporter family.}, journal = {Molecular aspects of medicine}, volume = {34}, number = {2-3}, pages = {108-120}, doi = {10.1016/j.mam.2013.01.001}, pmid = {23506861}, issn = {1872-9452}, mesh = {Amino Acids, Neutral/*metabolism ; Aspartic Acid/analogs &amp; derivatives/pharmacology ; Glutamate Plasma Membrane Transport Proteins/antagonists &amp; inhibitors/*chemistry/metabolism/*physiology ; Humans ; Models, Biological ; *Models, Molecular ; Molecular Structure ; Multigene Family/*genetics ; Phylogeny ; *Protein Conformation ; Synapses/*metabolism ; }, abstract = {Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells throughout the body with glutamate for metabolic purposes. The high-affinity glutamate transporters EAAC1 (SLC1A1), GLT1 (SLC1A2), GLAST (SLC1A3), EAAT4 (SLC1A6), and EAAT5 (SLC1A7) mediate the cellular uptake of glutamate by the co-transport of three sodium ions (Na(+)) and one proton (H(+)), with the counter-transport of one potassium ion (K(+)). Thereby, they protect the CNS from glutamate-induced neurotoxicity. Loss of function of glutamate transporters has been implicated in the pathogenesis of several diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. In addition, glutamate transporters play a role in glutamate excitotoxicity following an ischemic stroke, due to reversed glutamate transport. Besides glutamate transporters, the SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (SLC1A4) and ASCT2 (SLC1A5). Both transporters facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues. Some years ago, a high resolution structure of an archaeal homologue of the SLC1 family was determined, followed by the elucidation of its structure in the presence of the substrate aspartate and the inhibitor d,l-threo-benzyloxy aspartate (d,l-TBOA). Historically, the first few known inhibitors of SLC1 transporters were based on constrained glutamate analogs which were active in the high micromolar range but often also showed off-target activity at glutamate receptors. Further development led to the discovery of l-threo-β-hydroxyaspartate derivatives, some of which effectively inhibited SLC1 transporters at nanomolar concentrations. More recently, small molecule inhibitors have been identified whose structures are not based on amino acids. Activators of SLC1 family members have also been discovered but there are only a few examples known.}, }
@article {pmid23500590, year = {2013}, author = {Buratti, E and Romano, M and Baralle, FE}, title = {TDP-43 high throughput screening analyses in neurodegeneration: advantages and pitfalls.}, journal = {Molecular and cellular neurosciences}, volume = {56}, number = {}, pages = {465-474}, doi = {10.1016/j.mcn.2013.03.001}, pmid = {23500590}, issn = {1095-9327}, mesh = {DNA-Binding Proteins/*metabolism ; Humans ; Oligonucleotide Array Sequence Analysis/*methods ; Protein Binding ; Sensitivity and Specificity ; TDP-43 Proteinopathies/*metabolism ; }, abstract = {Dysfunctions in RNA processing and in particular the aberrant regulation of RNA binding proteins (RBPs) have recently been shown to play a fundamental role in the pathogenesis of neurodegenerative diseases. Understanding the pathogenic mechanisms involved will require the elucidation of the role(s) played by these RBPs in the general cell metabolism and neuronal survival in particular. In the past, the preferred approach has been to determine first of all the functional properties of the factor(s) of interest and then use this knowledge to determine targets in biologically relevant events. More recently, novel experimental approaches such as microarrays, RNA-seq and CLIP-seq have also become very popular to study RBPs. The advantage of these approaches, collectively known as high throughput screening (HTS), is their ability to determine gene expression changes or RNA/protein targets at a global cellular level. In theory, HTS strategies should be ideal for uncovering novel functional roles/targets of any RBP inside the cell. In practice, however, there are still difficulties in getting a coherent picture from all the huge amount of data they generate, frequently not validated experimentally and thus of unknown value. They may even act unfavorably towards a specific increase of knowledge of RBP functions, as the incomplete results are taken as solid data. In this work we will illustrate as an example the use of the HTS methodologies to characterize the interactions of a specific RBP: TDP-43. The multiple functions of this protein in RNA processing and its involvement in the pathogenesis of several forms of amyotrophic lateral sclerosis, frontotemporal lobar degeneration and other neurodegenerative diseases make it an excellent substrate for our analysis of the various advantages and limitations of different HTS experimental approaches.}, }
@article {pmid23452771, year = {2013}, author = {Pouget, J}, title = {[Have ALS centers changed the care and management of amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {169 Suppl 1}, number = {}, pages = {S39-44}, doi = {10.1016/S0035-3787(13)70059-6}, pmid = {23452771}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Delivery of Health Care ; Disease Management ; Enteral Nutrition ; France ; Humans ; *Information Centers ; Palliative Care ; Patient Care Planning ; Prognosis ; }, abstract = {The multidisciplinary care of amyotrophic lateral sclerosis (ALS) patients in clinics with expertise in the disease was created in the 1980s and 1990 s specifically to manage the severe functional impairment caused by the disorder. This specialized care for both diagnosis and management led to the creation of the ALS centers. To facilitate the continuity of care through close liaisons between primary-care physicians and community-based services, a specialized network was also developed. French ALS centers are now 10 years old, and their efficient national coordination has provided an improved and homogeneous care delivery in our country, while their recommendations for care have been published both nationally and internationally. Several studies have indicated positive effects on ALS patients'survival after attending ALS centers and receiving such specialized palliative treatments as assisted ventilation.}, }
@article {pmid23477673, year = {2013}, author = {Calì, T and Ottolini, D and Brini, M}, title = {Calcium and endoplasmic reticulum-mitochondria tethering in neurodegeneration.}, journal = {DNA and cell biology}, volume = {32}, number = {4}, pages = {140-146}, doi = {10.1089/dna.2013.2011}, pmid = {23477673}, issn = {1557-7430}, mesh = {Animals ; Calcium/*metabolism ; Endoplasmic Reticulum/metabolism/*pathology ; Energy Metabolism ; Humans ; Mitochondria/metabolism/*pathology ; Neurodegenerative Diseases/metabolism/*pathology ; Signal Transduction ; }, abstract = {Mitochondria are key players of many physiological processes and deregulation of mitochondrial and/or mitochondria-related activity is unequivocally associated to numerous ageing-linked neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recently, the endoplasmic reticulum (ER) stress condition is emerging as a common feature relevant to the pathogenesis of this type of diseases. Mitochondria and ER are two compartments physically and functionally tightly interconnected and recent evidence revealed that the impairment in their communication might represent a common hit in different neurodegenerative diseases. ER-mitochondria contact sites are crucial for Ca(2+) signaling since, upon the opening of ER Ca(2+) release channels, microdomains of high [Ca(2+)] are generated in their proximity and Ca(2+) can be taken up by the low-affinity mitochondrial uniporter. This transfer is essential in stimulated as well as in resting conditions to sustain cell metabolism and bioenergetics. Alterations in the ER-mitochondria juxtaposition are critical not only because they determine mitochondrial dysfunctions, but also because they compromise lipid metabolism, protein synthesis, and folding, thus demonstrating that the interaction between the two compartments is bi-functional. However, the functional consequences of these alterations on Ca(2+) signaling and the possible involvement in the development of neurodegenerative conditions are currently largely unexplored. Here we will survey the recent literature in the field and discuss recent insights focusing on some cellular models expressing mutant proteins involved in the pathogenesis of familial forms of PD, AD, and ALS.}, }
@article {pmid23475517, year = {2013}, author = {Tanaka, F and Sone, J and Atsuta, N and Nakamura, R and Doi, H and Koyano, S and Sobue, G}, title = {[Personal genome analysis in amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {3}, pages = {257-265}, pmid = {23475517}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Genetic Linkage/*genetics ; *Genetic Privacy ; *Genome, Human ; *Genome-Wide Association Study ; Humans ; Mutation ; }, abstract = {In amyotrophic lateral sclerosis (ALS), 5% of cases are familial, and most of the remaining cases are sporadic. In familial ALS, many causative genes have been identified during the last 20 years of the golden age of genetics. In particular, the recent discovery of a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) has had a large impact on ALS research, as this mutation is the most frequent cause of familial ALS in Europe and the US. However, the relative rarity of this mutation in Japan and Asia suggests the need to identify further other causative genes of familial ALS. In this regard, the advent of next-generation sequencing technology is expected to accelerate the identification of novel genes. In addition, next-generation sequencing will supersede Sanger sequencing in the molecular diagnosis of familial ALS. A number of genome-wide association studies (GWAS) have been conducted to identify the disease-susceptibility genes of sporadic ALS. In 1,305 Japanese ALS samples, the ZNF512B gene was associated with susceptibility to ALS. This gene has been shown to be one of the prognostic factors in sporadic ALS. Although GWAS that are based on the 'common disease-common variants hypothesis' have successfully revealed many disease-susceptibility genes, including ZNF512B, in sporadic ALS, the odds ratios associated with these risk alleles are generally low. The next challenge in ALS research is to use next-generation sequencing techniques to identify disease-relevant alleles with large effect sizes based on the 'common disease-multiple rare variants hypothesis'.}, }
@article {pmid23475514, year = {2013}, author = {Toda, T}, title = {[Personal genome research and neurological diseases: overview].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {3}, pages = {227-234}, pmid = {23475514}, issn = {1881-6096}, mesh = {Genetic Linkage/genetics ; *Genetic Privacy ; Genome, Human ; *Genome-Wide Association Study ; Humans ; Nervous System Diseases/*genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {Neurological diseases include those caused by a single defective gene,e.g., Huntington's disease, other polyglutamine diseases, and muscular dystrophies, and those that are mostly sporadic but rarely show Mendelian inheritance in some families, e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and epilepsy. The latter diseases are considered polygenic disorders. Both sporadic and Mendelian cases of these diseases are believed to share some common pathological mechanisms. Since the detection of causal genes for the Mendelian cases, studies have been initiated on disease pathology. SNPs and rare gene variants play important roles in common neurological diseases. From a technological perspective, next-generation sequencers have become widely available and have contributed to the advancement of research based on individual genome sequences (personal genome). This paper presents an overview, as well as a historical context, of the contribution of personal genome research to neurological disease studies.}, }
@article {pmid23474849, year = {2013}, author = {Thomas, M and Alegre-Abarrategui, J and Wade-Martins, R}, title = {RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum.}, journal = {Brain : a journal of neurology}, volume = {136}, number = {Pt 5}, pages = {1345-1360}, doi = {10.1093/brain/awt030}, pmid = {23474849}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology ; Animals ; Autophagy/*genetics ; Frontotemporal Dementia/*genetics/metabolism/physiopathology ; Humans ; RNA Processing, Post-Transcriptional/*genetics ; Signal Transduction/genetics ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia form two poles of a genetically, pathologically and clinically-related disease continuum. Analysis of the genes and proteins at the heart of this continuum highlights dysfunction of RNA processing and aggrephagy as crucial disease-associated pathways. TAR DNA binding protein and fused in sarcoma (FUS) are both RNA processing proteins whose dysfunction impacts on global cellular RNA regulation. The recent discovery that expression of repeat expansions in the C9orf72 gene may induce RNA foci that could sequester RNA binding proteins such as TAR DNA binding protein and FUS highlights a further possibly important mechanism of RNA dysfunction in disease. Furthermore, sequestration of key RNA binding proteins may also play an important role in sporadic disease due to the association of TAR DNA binding protein and FUS with stress granules. In a further functional convergence, ubiquilin 2, p62, valosin-containing protein and optineurin are all linked to aggrephagy, a cargo-specific subtype of autophagy important for degrading ubiquitinated target proteins through the lysosome. Notably these two key pathways interact; TAR DNA binding protein and FUS bind and regulate key aggrephagy-related genes whereas dysfunction of aggrephagy leads to cytoplasmic relocalization and aggregation of TAR DNA binding protein. The convergence of amyotrophic lateral sclerosis and frontotemporal dementia linked genes into these two pathways highlights RNA dysfunction and aggrephagy as promising areas for drug discovery. In this review we discuss the importance of each of these pathways and suggest mechanisms by which they may cause both sporadic and familial disease.}, }
@article {pmid23472885, year = {2013}, author = {Pedersen, JT and Heegaard, NH}, title = {Analysis of protein aggregation in neurodegenerative disease.}, journal = {Analytical chemistry}, volume = {85}, number = {9}, pages = {4215-4227}, doi = {10.1021/ac400023c}, pmid = {23472885}, issn = {1520-6882}, mesh = {Humans ; Immunoassay ; Mass Spectrometry/methods ; Neurodegenerative Diseases/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Proteins/*analysis/chemistry/*metabolism ; }, abstract = {Pathological protein and peptide aggregation are key events in a number of chronic and devastating neurodegenerative conditions including dementias such as Alzheimer's and Creutzfeldt-Jakob's disease and other central nervous system diseases such as Parkinson's and Huntington's disease and amyotrophic lateral sclerosis. Analytical methods for studying protein aggregation in these diseases are important for mapping pathophysiological events and ultimately for the development of new therapies and better diagnostic tools.}, }
@article {pmid23472505, year = {2013}, author = {Williams, TL}, title = {Motor neurone disease: diagnostic pitfalls.}, journal = {Clinical medicine (London, England)}, volume = {13}, number = {1}, pages = {97-100}, pmid = {23472505}, issn = {1470-2118}, mesh = {Diagnosis, Differential ; Humans ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/physiology ; Neuroimaging/*methods ; }, abstract = {The misdiagnosis of MND (particularly of the ALS phenotype), is uncommon. Atypical presentations, particularly of focal onset and with pure LMN or UMN signs, present a more difficult diagnostic challenge, although perhaps reassuringly, treatable mimics are rare. A working knowledge of potential alternative conditions and MND diagnostic pitfalls should help to reduce the misdiagnosis rate, particularly if the key points are considered.}, }
@article {pmid23466470, year = {2013}, author = {Greenwood, DI}, title = {Nutrition management of amyotrophic lateral sclerosis.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {28}, number = {3}, pages = {392-399}, doi = {10.1177/0884533613476554}, pmid = {23466470}, issn = {1941-2452}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diet therapy ; Body Mass Index ; Enteral Nutrition/methods ; Gastrostomy/methods ; Humans ; Intubation, Gastrointestinal/methods ; Malnutrition/*diagnosis/diet therapy/etiology ; *Nutritional Requirements ; Nutritional Status ; Parenteral Nutrition/methods ; Quality of Life ; Vital Capacity ; Weight Loss ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease with high risk of malnutrition. Symptoms of dysphagia, depression, cognitive impairment, difficulty with self-feeding and meal preparation, hypermetabolism, anxiety, respiratory insufficiency, and fatigue with meals increase the risk of malnutrition. Malnutrition negatively affects prognosis and quality of life, making early and frequent nutrition assessment and intervention essential. Implementation of an adequate calorie diet, dietary texture modification, use of adaptive eating utensils, and placement of a feeding tube aid in preventing malnutrition. When nutrition status is compromised by dysphagia and weight loss (5%-10% of usual body weight) or body mass index <20 kg/m(2) without weight loss and when forced vital capacity is >50%, a percutaneous endoscopic gastrostomy placement is indicated. When forced vital capacity is <50%, a radiologically inserted gastrostomy is the preferred means of enteral placement due to lessened aspiration and respiratory risk. Parenteral nutrition (PN) is indicated only when enteral nutrition (EN) is contraindicated or impossible. This article reviews the background of ALS, nutrition implications and risk of malnutrition, treatment strategies to prevent malnutrition, the role of EN and PN, and feeding tube placement methods according to disease stage.}, }
@article {pmid23463272, year = {2013}, author = {Robberecht, W and Philips, T}, title = {The changing scene of amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neuroscience}, volume = {14}, number = {4}, pages = {248-264}, pmid = {23463272}, issn = {1471-0048}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*etiology/genetics ; Animals ; Frontotemporal Dementia/diagnosis/genetics ; Humans ; Mutation/*genetics ; RNA-Binding Proteins/*genetics ; }, abstract = {Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.}, }
@article {pmid23460617, year = {2013}, author = {Tshala-Katumbay, D and Mumba, N and Okitundu, L and Kazadi, K and Banea, M and Tylleskär, T and Boivin, M and Muyembe-Tamfum, JJ}, title = {Cassava food toxins, konzo disease, and neurodegeneration in sub-Sahara Africans.}, journal = {Neurology}, volume = {80}, number = {10}, pages = {949-951}, pmid = {23460617}, issn = {1526-632X}, support = {R01 ES019841/ES/NIEHS NIH HHS/United States ; R01ES019841/ES/NIEHS NIH HHS/United States ; }, mesh = {Africa South of the Sahara ; Humans ; Manihot/*adverse effects/chemistry ; Motor Neuron Disease/epidemiology/*etiology/physiopathology ; Plant Poisoning/*complications/epidemiology ; Plants, Toxic/*adverse effects ; Toxins, Biological/adverse effects ; }, abstract = {Endemoepidemic neurodegenerative diseases putatively caused by food toxins have been reported around the globe with no clear understanding of their pathogenetic mechanisms. These diseases include the amyotrophic lateral sclerosis/parkinsonism dementia complex among the Guamanians; neurolathyrism among Europeans, Indians, and populations of the Horn of Africa; and tropical ataxic neuropathy or konzo among sub-Sahara Africans.[1,2] We focus on the molecular determinants of susceptibility to konzo, a poorly known self-limited and irreversible upper motor neuron disease (spastic paraparesis) highly prevalent in Congo-Kinshasa, Mozambique, Tanzania, Central African Republic, Angola, and Cameroon. The main clinical picture consists of a symmetrical, permanent, and irreversible spastic paraparesis with no signs of sensory or genitourinary impairments.[2,3] Severely affected individuals may present with a tetraparesis and pseudobulbar signs. The disease konzo was named after a fetish used by the “Yaka” population of Congo-Kinshasa. The World Health Organization has adopted the following epidemiologic criteria for the disease: 1) an abrupt onset (<1 week) of weakness in legs and a nonprogressive course of the disease in a formerly healthy person, 2) a symmetrical spastic abnormality when walking and/or running, and 3) bilaterally exaggerated knee and/or ankle jerks without signs of disease of the spine.}, }
@article {pmid23448465, year = {2013}, author = {Garbes, L and Riessland, M and Wirth, B}, title = {Histone acetylation as a potential therapeutic target in motor neuron degenerative diseases.}, journal = {Current pharmaceutical design}, volume = {19}, number = {28}, pages = {5093-5104}, doi = {10.2174/13816128113199990356}, pmid = {23448465}, issn = {1873-4286}, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy/enzymology/metabolism ; Animals ; Bulbo-Spinal Atrophy, X-Linked/drug therapy/enzymology/metabolism ; Disease Models, Animal ; Histone Deacetylase Inhibitors/therapeutic use ; Histones/*metabolism ; Humans ; Mice ; *Molecular Targeted Therapy ; Motor Neuron Disease/*drug therapy/enzymology/metabolism ; Motor Neurons/*drug effects/enzymology/metabolism ; Muscular Atrophy, Spinal/drug therapy/enzymology/metabolism ; Nerve Tissue Proteins/*antagonists &amp; inhibitors/metabolism ; Neuroprotective Agents/*therapeutic use ; Protein Processing, Post-Translational/*drug effects ; }, abstract = {Among hereditary diseases, the group of motor neuron diseases (MNDs) includes some of the most devastating and rapidly progressive lethal conditions. Although degeneration of motor neurons is common to all of them, the phenotypic spectrum of MNDs is relatively broad and ranges from perinatal conditions like spinal muscular atrophy (SMA) to adult-onset diseases such as amyotrophic lateral sclerosis (ALS). While the understanding of the pathology of the diseases is constantly growing, the development of therapeutic approaches lags behind. In fact, there is no approved therapy for MNDs available at the moment. Recent findings demonstrated the existence of some patterns that are shared by several MNDs such as transcriptional dysregulation. In addition, conditions like SMA or certain types of Charcot-Marie-Tooth disease provide some defined targets which may be amenable to therapeutic approaches. Consequently, counteracting this dysregulation may be a valuable therapeutic option and ameliorate disease progression in MND patients. The feasibility of such an approach has been proven during the past years by the epigenetic treatment of various neoplastic entities with histone deacetylase inhibitors (HDACi). On these grounds, also epigenetic therapy of MNDs has become a promising option. So far, several HDACi have been tested in vitro and in animal models and some proceeded further and were evaluated in clinical trials. This review will summarize the advances of HDACi in MNDs and will give a perspective where the road will lead us.}, }
@article {pmid23441893, year = {2013}, author = {Agnati, LF and Guidolin, D and Woods, AS and Ciruela, F and Carone, C and Vallelunga, A and Escuela, DO and Genedani, S and Fuxe, K}, title = {A new interpretative paradigm for Conformational Protein Diseases.}, journal = {Current protein &amp; peptide science}, volume = {14}, number = {2}, pages = {141-160}, doi = {10.2174/1389203711314020006}, pmid = {23441893}, issn = {1875-5550}, mesh = {Aging/metabolism ; Alzheimer Disease/*metabolism ; Humans ; Parkinson Disease/*metabolism ; Prion Diseases/*metabolism ; Protein Conformation ; Protein Folding ; Proteins/*chemistry/metabolism ; }, abstract = {Conformational Protein Diseases (CPDs) comprise over forty clinically and pathologically diverse disorders in which specific altered proteins accumulate in cells or tissues of the body. The most studied are Alzheimerβ's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, inclusion body myopathy, and the systemic amyloidoses. They are characterised by three dimensional conformational alterations, which are often rich in β- structure. Proteins in this non-native conformation are highly stable, resistant to degradation, and have an enhanced tendency to aggregate with like protein molecules. The misfolded proteins can impart their anomalous properties to soluble, monomeric proteins with the same amino acid sequence by a process that has been likened to seeded crystallization. However, these potentially pathogenic proteins also have important physiological actions, which have not completely characterized. This opens up the question of what process transforms physiological actions into pathological actions and most intriguing, is why potentially dangerous proteins have been maintained during evolution and are present from yeasts to humans. In the present paper, we introduce the concept of mis-exaptation and of mis-tinkering since they may help in clarifying some of the double edged sword aspects of these proteins. Against this background an original interpretative paradigm for CPDs will be given in the frame of the previously proposed Red Queen Theory of Aging.}, }
@article {pmid23441623, year = {2013}, author = {Garrido-Mesa, N and Zarzuelo, A and Gálvez, J}, title = {Minocycline: far beyond an antibiotic.}, journal = {British journal of pharmacology}, volume = {169}, number = {2}, pages = {337-352}, pmid = {23441623}, issn = {1476-5381}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Apoptosis/drug effects ; Disease Models, Animal ; Humans ; Inflammation/drug therapy/pathology ; Minocycline/*pharmacology/therapeutic use ; Neurodegenerative Diseases/drug therapy/physiopathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {Minocycline is a second-generation, semi-synthetic tetracycline that has been in therapeutic use for over 30 years because of its antibiotic properties against both gram-positive and gram-negative bacteria. It is mainly used in the treatment of acne vulgaris and some sexually transmitted diseases. Recently, it has been reported that tetracyclines can exert a variety of biological actions that are independent of their anti-microbial activity, including anti-inflammatory and anti-apoptotic activities, and inhibition of proteolysis, angiogenesis and tumour metastasis. These findings specifically concern to minocycline as it has recently been found to have multiple non-antibiotic biological effects that are beneficial in experimental models of various diseases with an inflammatory basis, including dermatitis, periodontitis, atherosclerosis and autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. Of note, minocycline has also emerged as the most effective tetracycline derivative at providing neuroprotection. This effect has been confirmed in experimental models of ischaemia, traumatic brain injury and neuropathic pain, and of several neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis and spinal cord injury. Moreover, other pre-clinical studies have shown its ability to inhibit malignant cell growth and activation and replication of human immunodeficiency virus, and to prevent bone resorption. Considering the above-mentioned findings, this review will cover the most important topics in the pharmacology of minocycline to date, supporting its evaluation as a new therapeutic approach for many of the diseases described herein.}, }
@article {pmid23436724, year = {2013}, author = {Focant, MC and Hermans, E}, title = {Protein interacting with C kinase and neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {67}, number = {8}, pages = {532-540}, doi = {10.1002/syn.21657}, pmid = {23436724}, issn = {1098-2396}, mesh = {Animals ; Carrier Proteins/chemistry/genetics/*metabolism ; Humans ; Nervous System Diseases/genetics/*metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism ; PDZ Domains ; Receptors, AMPA/metabolism ; Synapses/metabolism ; }, abstract = {Best known for its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and for its influence on excitatory synapse activity, the protein interacting with C kinase, PICK1, is the focus of considerable attention from neurobiologists. Indeed, this PSD-95/DlgA/ZO-1 (PDZ) domain-containing protein has been shown to interact with a wide variety of neurotransmitter receptors, transporters, and enzymes, including glutamate and nicotinic acetylcholine receptors, dopamine and glutamate transporters, and the enzyme serine racemase. Through its lipid binding domain, PICK1 is targeted to the inner surface of the cell membrane where it contributes to anchoring these partners and thereby influences their synaptic localization and function. Under pathological conditions, the regulation of some PICK1-interacting partners is altered, pointing to an involvement of PICK1 in neurological disorders. Also, genetic or pharmacological manipulations of PICK1 expression, localization, or function have been shown to influence several physiological or pathological processes in which putative PICK1 partners are involved. This review will summarize recent experimental observations that highlight the involvement of PICK1 in neurological disorders, including schizophrenia, Parkinson's disease, epilepsy, chronic pain, drug abuse, and amyotrophic lateral sclerosis.}, }
@article {pmid23432063, year = {2013}, author = {Takada, Y and Numata, T and Mori, Y}, title = {Targeting TRPs in neurodegenerative disorders.}, journal = {Current topics in medicinal chemistry}, volume = {13}, number = {3}, pages = {322-334}, doi = {10.2174/1568026611313030009}, pmid = {23432063}, issn = {1873-4294}, mesh = {Animals ; Calcium/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/metabolism ; Signal Transduction/drug effects ; Transient Receptor Potential Channels/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis present a significant medical challenge in the modern world. Recent evidence indicates that perturbation of neuronal Ca2+ homeostasis is involved in the pathogenesis of these neurodegenerative disorders. Transient receptor potential (TRP) channels are non-selective cation channels that are expressed in various cell types and tissues, and play an important role in regulating Ca2+ signaling in both non-neuronal and neuronal cells. TRP channels are related to the onset or progression of several diseases, and defects in the genes encoding TRP channels (so-called "TRP channelopathies") underlie certain neurodegenerative disorders due to their abnormal Ca2+ signaling properties. In this article, we review recent findings regarding the relationship between TRPs and neurodegenerative disorders, and discuss the therapeutic potential of targeting TRP channels pharmacologically.}, }
@article {pmid23421098, year = {2012}, author = {Tkaczyk, M and Florek, E and Piekoszewski, W}, title = {[Marihuana and cannobinoids as medicaments].}, journal = {Przeglad lekarski}, volume = {69}, number = {10}, pages = {1095-1097}, pmid = {23421098}, issn = {0033-2240}, mesh = {Arthritis, Rheumatoid/drug therapy ; Cannabidiol ; Cannabinoids/*therapeutic use ; Cannabis ; Contraindications ; Dronabinol/analogs &amp; derivatives/therapeutic use ; Drug Combinations ; Humans ; Inflammatory Bowel Diseases/drug therapy ; Multiple Sclerosis/drug therapy ; Muscle Spasticity/drug therapy ; Nausea/*drug therapy ; Nervous System Diseases/*drug therapy ; Pain/drug therapy ; Plant Extracts/administration &amp; dosage ; Vomiting/drug therapy ; }, abstract = {Biological activity of cannabinoids is caused by binding to two cannabinoid receptors CB1 and CB2. Psychoactive is not only tetrahydrocannabinol (THC) but also: cannabidiol, cannabigerol or cannabichromen. Formerly, the usefulness of hemp was assessed in the relation to temporary appeasement of the symptoms of some ailments as nausea or vomiting. Present discoveries indicates that cannabis-based drugs has shown ability to alleviate of autoimmunological disorders such as: Multiple sclerosis (MS), Rheumatoid arthritis (RA) or inflammatory bowel disease. Another studies indicates that cannabinoids play role in treatment of neurological disorders like Alzheimer disease or Amyotrophic lateral sclerosis (ALS) or even can reduce spreading of tumor cells. Cannabinoids stand out high safety profile considering acute toxicity, it is low possibility of deadly overdosing and side-effects are comprise in range of tolerated side-effects of other medications. In some countries marinol and nabilone are used as anti vomiting and nausea drug. First cannabis-based drug containg naturally occurring cannabinoids is Sativex. Sativex is delivered in an mucosal spray for patients suffering from spasticity in MS, pain relevant with cancer and neuropathic pain of various origin. Despite the relatively low acute toxicity of cannabinoids they should be avoid in patients with psychotic disorders, pregnant or breastfeeding woman. Cannabinoids prolong a time of reaction and decrease power of concentration that's why driving any vehicles is forbidden. Cannabis side-effects varies and depend from several factors like administrated dose, rout of administration and present state of mind. After sudden break from long-lasting use, withdrawal symptoms can appear, although they entirely disappear after a week or two.}, }
@article {pmid23419876, year = {2013}, author = {Thinnes, FP}, title = {New findings concerning vertebrate porin II--on the relevance of glycine motifs of type-1 VDAC.}, journal = {Molecular genetics and metabolism}, volume = {108}, number = {4}, pages = {212-224}, doi = {10.1016/j.ymgme.2013.01.008}, pmid = {23419876}, issn = {1096-7206}, mesh = {Alzheimer Disease/*metabolism ; Animals ; Apoptosis ; Cell Membrane/metabolism ; Humans ; Membrane Proteins/metabolism ; Mitochondria/*metabolism ; Mitochondrial Membranes/metabolism ; Neoplasms/*metabolism ; Serum Amyloid A Protein/*metabolism ; Voltage-Dependent Anion Channels/*metabolism ; }, abstract = {New findings concerning vertebrate porin part I was published in 1997, then summarizing early data and reflections regarding the molecular structure of vertebrate voltage-dependent anion-selective channels, VDAC/eukaryotic porin, and the extra-mitochondrial expression pattern of human type-1 VDAC. Meanwhile, endeavors of different laboratories confirmed and widened this beginning by encircling the function of the channels. Regarding the function of mitochondrial outer membrane-standing VDACs the channels are established parts of the intrinsic apoptotic pathway and thus therapeutic targets in studies on several diseases: cancer, Alzheimer's disease, Down Syndrome, Parkinson's disease, Amyotrophic Lateral Sclerosis, cystic fibrosis and malaria. Regarding cell membrane-integrated type-1 VDAC it has been documented by different approaches that this porin channel is engaged in cell volume regulation, trans-membrane electron transport and apoptosis. Furthermore, new data insinuate a bridging of extrinsic and intrinsic apoptotic pathways, putatively gaining relevance in Alzheimer research. Mammalian type-1 VDAC, a β-barrel, is basically built up by nineteen β-sheets connected by peptide stretches of varying lengths. The molecule also comprises an N-terminal stretch of some twenty amino acids which, according to biochemical data, traverses the channel lumen towards the cytosolic surface of outer mitochondrial membranes or the plasma lemma, respectively and works as voltage sensor in channel gating. In artificial lipid bilayers VDACs figure as anion or cation-channels, as VDACs are permeable to both cations and anions, with voltage shifts changing the relative permeability. Type-1 VDAC carries several motifs where glycine residues are in critical positions. Motifs of this type, on the on hand, are established nucleotide binding sites. On the other hand, the GxxxG motifs are also discussed as relevant peptide dimerization/aggregation/membrane perturbation motifs. Finally, GxxxG motifs bind cholesterol. Type-1 VDAC shows one such GxxxG motif at the proximal end of its N-terminal voltage sensor while amyloid Aβ peptides include three of them in series. Noteworthy, two additional may be modified versions, GxxxGxG and GxxGxxxG, are found on β-sheet 19 or 9, respectively. Recent data have allowed speculating that amyloid Aβ induces apoptosis via opening type-1 VDAC in cell membranes of hypo-metabolic neurons, a process most likely running over life time--as leaves fall from trees in the tropics--and ending in Alzheimer's disease whenever critical brain regions are affected. The expression of GxxxG motifs on either reactant under consideration is in line with this model of Alzheimer's disease pathogenesis, which clearly differs from the amyloid Aβ cascade theory, and which can, furthermore, be understood as a basic model for apoptosis induction. However, to assume randomly distributed interactions of body wide found amyloid Aβ peptides with the N-terminal voltage sensors of ubiquitously expressed cell membrane-standing human type-1 VDAC opens up a new view on Alzheimer's disease, which might even include a clue on systemic aspects of the disease. While elaborating this concept, my focus was at first only on the GxxxG motif at the proximal end of the N-terminal voltage sensor of type-1 VDAC. Here, I include a corresponding sequence stretch on the channel's β-sheet 19, too.}, }
@article {pmid23415570, year = {2013}, author = {Turner, MR and Hardiman, O and Benatar, M and Brooks, BR and Chio, A and de Carvalho, M and Ince, PG and Lin, C and Miller, RG and Mitsumoto, H and Nicholson, G and Ravits, J and Shaw, PJ and Swash, M and Talbot, K and Traynor, BJ and Van den Berg, LH and Veldink, JH and Vucic, S and Kiernan, MC}, title = {Controversies and priorities in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {12}, number = {3}, pages = {310-322}, pmid = {23415570}, issn = {1474-4465}, support = {ZIA AG000933-02//Intramural NIH HHS/United States ; G0701923/MRC_/Medical Research Council/United Kingdom ; Z01-AG000949-02/AG/NIA NIH HHS/United States ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; Z01 AG000949//Intramural NIH HHS/United States ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/etiology/genetics/physiopathology ; Animals ; Humans ; }, abstract = {Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.}, }
@article {pmid23402800, year = {2013}, author = {Mostafalou, S and Abdollahi, M}, title = {Pesticides and human chronic diseases: evidences, mechanisms, and perspectives.}, journal = {Toxicology and applied pharmacology}, volume = {268}, number = {2}, pages = {157-177}, doi = {10.1016/j.taap.2013.01.025}, pmid = {23402800}, issn = {1096-0333}, mesh = {Abnormalities, Drug-Induced/etiology ; Alzheimer Disease/chemically induced ; Amyotrophic Lateral Sclerosis/chemically induced ; Animals ; Chronic Disease ; Epigenesis, Genetic/drug effects ; Humans ; Mitochondria/drug effects ; Neoplasms/chemically induced ; Oxidative Stress/drug effects ; Parkinson Disease, Secondary/chemically induced ; Pesticides/*toxicity ; Reproduction/drug effects ; Unfolded Protein Response/drug effects ; }, abstract = {Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.}, }
@article {pmid23399675, year = {2013}, author = {Nunomura, A}, title = {[Role of oxidative RNA damage in aging and neurodegenerative disorders].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {2}, pages = {179-194}, pmid = {23399675}, issn = {1881-6096}, mesh = {Aging/*metabolism ; Animals ; Genetic Phenomena ; Humans ; Neurodegenerative Diseases/genetics/*metabolism ; Neurons/metabolism ; Oxidative Stress/*physiology ; RNA/*metabolism ; }, abstract = {It is now clear that RNA species not only encode proteins but also fulfill critical roles in regulating gene expression. Compared to other species, humans probably contain more non-coding RNAs, especially in the brain, where the non-coding RNAs may play a significant role in cognition. In neurons of human and rodent brains, oxidative damage to nucleic acids, predominantly to RNA, increases as a function of age; this may play a crucial role in the development of age-associated neurodegeneration. Indeed, compared to age-matched controls, patients with neurodegenerative disorders, including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis, show higher levels of neuronal RNA oxidation. Furthermore, oxidative damage to RNA has been found in cellular and animal models of neurodegeneration. RNA oxidation has been hypothesized to cause aberrant expression of microRNAs and proteins and subsequently initiate inappropriate cell fate pathways. Interestingly, accumulating evidence obtained from studies on either human samples or experimental models coincidentally suggests that RNA oxidation is a feature of neurons in the aging brain and more prominently observed in vulnerable neurons at an early-stage of age-associated neurodegenerative disorders, indicating that RNA oxidation actively contributes to the prodromal stage, onset, and development of these disorders. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative disorders and pave the way for novel therapeutic strategies.}, }
@article {pmid23392098, year = {2013}, author = {Vottero, A and Guzzetti, C and Loche, S}, title = {New aspects of the physiology of the GH-IGF-1 axis.}, journal = {Endocrine development}, volume = {24}, number = {}, pages = {96-105}, doi = {10.1159/000342573}, pmid = {23392098}, issn = {1662-2979}, mesh = {Animals ; Epigenesis, Genetic/physiology ; *Growth Hormone/genetics/metabolism/physiology ; Humans ; *Insulin-Like Growth Factor I/genetics/metabolism/physiology ; Nutritional Physiological Phenomena/genetics ; Signal Transduction/genetics/*physiology ; }, abstract = {Growth hormone (GH) secretion from the pituitary is regulated by a complex network of CNS and peripheral inputs. Circulating GH binds to its receptor and initiates a cascade of signaling events which involve the JAK2-STAT pathway, the PI3K/Akt pathway and the RAS/MAPK pathway, leading to the transcription of several genes, including insulin-like growth factor 1 (IGF-1), IGFBP3, ALS, and others. Recent findings indicate that nutrition plays an important role in GH secretion and action. Furthermore, data are emerging which suggest that the RAS-MAPK pathway as well as epigenetic regulation of transcription may be important in determining both circulating and locally produced IGF-1.}, }
@article {pmid23384285, year = {2013}, author = {Kim, SU and Lee, HJ and Kim, YB}, title = {Neural stem cell-based treatment for neurodegenerative diseases.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {33}, number = {5}, pages = {491-504}, doi = {10.1111/neup.12020}, pmid = {23384285}, issn = {1440-1789}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell- and Tissue-Based Therapy ; Humans ; Huntington Disease/therapy ; Neural Stem Cells/*transplantation ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; Stem Cell Transplantation ; }, abstract = {Human neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell-based cell therapies for neurodegenerative diseases have been developed. A recent advance in generation of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenerative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell-mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury.}, }
@article {pmid23381726, year = {2013}, author = {Verma, A and Tandan, R}, title = {RNA quality control and protein aggregates in amyotrophic lateral sclerosis: a review.}, journal = {Muscle &amp; nerve}, volume = {47}, number = {3}, pages = {330-338}, doi = {10.1002/mus.23673}, pmid = {23381726}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Cytosol/metabolism ; Disease Progression ; Humans ; MicroRNAs/genetics ; Muscle Proteins/*genetics ; Mutation/genetics/physiology ; Quality Control ; RNA/*genetics/metabolism ; RNA Splicing ; RNA-Binding Protein FUS/genetics ; TDP-43 Proteinopathies/genetics ; Transcription, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. The biologic basis of ALS remains unknown. However, ALS research has taken a dramatic turn over the past 4 years. Ground breaking discoveries of mutations of genes that encode RNA processing proteins, and demonstration that abnormal aggregates of these and other proteins precede motor neuron loss in familial and sporadic ALS, have initiated a paradigm shift in understanding the pathogenic mechanisms of ALS. Curiously, some of these RNA binding proteins have prion-like domains, with a propensity to self-aggregation. The emerging hypothesis that a focal cascade of toxic protein aggregates, and their consequent non-cell-autonomous spread to neighborhood groups of neurons, fits the classical temporo-spatial progression of ALS. This article reviews the current research efforts toward understanding the role of RNA-processing regulation and protein aggregates in ALS.}, }
@article {pmid23379621, year = {2013}, author = {Sabatelli, M and Conte, A and Zollino, M}, title = {Clinical and genetic heterogeneity of amyotrophic lateral sclerosis.}, journal = {Clinical genetics}, volume = {83}, number = {5}, pages = {408-416}, doi = {10.1111/cge.12117}, pmid = {23379621}, issn = {1399-0004}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; *Genetic Heterogeneity ; Genetic Predisposition to Disease ; Humans ; Mutation ; Penetrance ; }, abstract = {Although clinical picture of amyotrophic lateral sclerosis (ALS) is a stereotypical one, resulting from combination of signs secondary to dysfunction of both upper motor neuron (UMN) and lower motor neuron (LMN), clinical heterogeneity is a consistent feature of the disease. Age of onset, relative mix of UMN and LMN signs, duration of the disease and association with other conditions are major factors contributing to variable clinical phenotypes. Genetically, familial forms of ALS are associated with a large number of pleiotropic genes whose mutations impair different biochemical pathways, resulting in overlapping clinical and pathological phenotypes. Over the last few years contribution of large- and low-effect genes to sporadic ALS is increasingly recognized.}, }
@article {pmid23378031, year = {2013}, author = {Chhangani, D and Mishra, A}, title = {Protein quality control system in neurodegeneration: a healing company hard to beat but failure is fatal.}, journal = {Molecular neurobiology}, volume = {48}, number = {1}, pages = {141-156}, pmid = {23378031}, issn = {1559-1182}, mesh = {Animals ; Humans ; Nerve Degeneration/*pathology ; *Nerve Regeneration ; Nerve Tissue Proteins/*metabolism ; Protein Folding ; Proteolysis ; Stress, Physiological ; }, abstract = {A common feature in most neurodegenerative diseases and aging is the progressive accumulation of damaged proteins. Proteins are essential for all crucial biological functions. Under some notorious conditions, proteins loss their three dimensional native conformations and are converted into disordered aggregated structures. Such changes rise into pathological conditions and eventually cause serious protein conformation disorders. Protein aggregation and inclusion bodies formation mediated multifactorial proteotoxic stress has been reported in the progression of Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Prion disease. Ongoing studies have been remarkably informative in providing a systematic outlook for better understanding the concept and fundamentals of protein misfolding and aggregations. However, the precise role of protein quality control system and precursors of this mechanism remains elusive. In this review, we highlight recent insights and discuss emerging cytoprotective strategies of cellular protein quality control system implicated in protein deposition diseases. Our current review provides a clear, understandable framework of protein quality control system that may offer the more suitable therapeutic strategies for protein-associated diseases.}, }
@article {pmid23376471, year = {2013}, author = {Weinreb, O and Mandel, S and Youdim, MBH and Amit, T}, title = {Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators.}, journal = {Free radical biology &amp; medicine}, volume = {62}, number = {}, pages = {52-64}, doi = {10.1016/j.freeradbiomed.2013.01.017}, pmid = {23376471}, issn = {1873-4596}, mesh = {Free Radicals/metabolism ; Homeostasis/drug effects ; Humans ; Iron/*metabolism ; Iron Chelating Agents/*administration &amp; dosage ; Neuroprotective Agents/administration &amp; dosage ; Parkinson Disease/drug therapy/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; Substantia Nigra/drug effects/*metabolism/pathology ; }, abstract = {Brain iron accumulation has been implicated in a host of chronic neurological diseases, including Parkinson's disease (PD). The elevated iron levels observed in the substantia nigra of PD subjects have been suggested to incite the generation of reactive oxygen species and intracellular α-synuclein aggregation, terminating in the oxidative neuronal destruction of this brain area. Thus, elucidation of the molecular mechanisms involved in iron dysregulation and oxidative stress-induced neurodegeneration is a crucial step in deciphering PD pathology and in developing novel iron-complexing compounds aimed at restoring brain iron homeostasis and attenuating neurodegeneration. This review discusses the involvement of dysregulation of brain iron homeostasis in PD pathology, with an emphasis on the potential effectiveness of naturally occurring compounds and novel iron-chelating/antioxidant therapeutic hybrid molecules, exerting a spectrum of neuroprotective interrelated activities: antioxidant/monoamine oxidase inhibition, activation of the hypoxia-inducible factor (HIF)-1 signaling pathway, induction of HIF-1 target iron-regulatory and antioxidative genes, and inhibition of α-synuclein accumulation and aggregation.}, }
@article {pmid23373317, year = {2012}, author = {Aoki, M}, title = {[Restorative therapy in amyotrophic lateral sclerosis].}, journal = {Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology}, volume = {32}, number = {5-6}, pages = {287-292}, pmid = {23373317}, issn = {1340-2544}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Hepatocyte Growth Factor/administration &amp; dosage/therapeutic use ; Humans ; Motor Neurons/cytology/metabolism ; Spinal Cord/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial; approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We developed rats that express a human SOD1 transgene with ALS-associated mutations, developing striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice, will facilitate studies involving manipulations of spinal fluid and the spinal cord. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to the transgenic rats at the onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63%. To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. The intrathecal administration of hrHGF promoted functional recovery. These results prompted further clinical trials in ALS using continuous intrathecal administration of hrHGF.}, }
@article {pmid23368808, year = {2013}, author = {Handel, AE and Disanto, G and Ramagopalan, SV}, title = {Next-generation sequencing in understanding complex neurological disease.}, journal = {Expert review of neurotherapeutics}, volume = {13}, number = {2}, pages = {215-227}, pmid = {23368808}, issn = {1744-8360}, support = {G0801975/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Chromatin Immunoprecipitation ; Databases, Genetic ; Epigenomics ; *Genetic Predisposition to Disease ; Genome, Human/genetics ; Humans ; Nervous System Diseases/*diagnosis/*genetics ; Sequence Analysis, DNA/*methods ; }, abstract = {Next-generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and so on). The authors review current next-generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic etiology of complex neurological diseases with specific focus on multiple sclerosis. The authors highlight particular pitfalls in next-generation sequencing experiments and speculate on both clinical and research applications of these sequencing platforms for complex neurological disorders in the future.}, }
@article {pmid23357359, year = {2013}, author = {Miller, LM and Bourassa, MW and Smith, RJ}, title = {FTIR spectroscopic imaging of protein aggregation in living cells.}, journal = {Biochimica et biophysica acta}, volume = {1828}, number = {10}, pages = {2339-2346}, pmid = {23357359}, issn = {0006-3002}, support = {S10 RR023782/RR/NCRR NIH HHS/United States ; RR23782/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; Neurodegenerative Diseases/metabolism/pathology ; Protein Conformation ; Proteins/*chemistry ; Spectroscopy, Fourier Transform Infrared/*methods ; }, abstract = {Protein misfolding and aggregation are the hallmark of a number of diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prion diseases. In all cases, a naturally-occurring protein misfolds and forms aggregates that are thought to disrupt cell function through a wide range of mechanisms that are yet to be fully unraveled. Fourier transform infrared (FTIR) spectroscopy is a technique that is sensitive to the secondary structure of proteins and has been widely used to investigate the process of misfolding and aggregate formation. This review focuses on how FTIR spectroscopy and spectroscopic microscopy are being used to evaluate the structural changes in disease-related proteins both in vitro and directly within cells and tissues. Finally, ongoing technological advances will be presented that are enabling time-resolved FTIR imaging of protein aggregation directly within living cells, which can provide insight into the structural intermediates, time scale, and mechanisms of cell toxicity associated with aggregate formation. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.}, }
@article {pmid23339308, year = {2012}, author = {Sheng, Y and Chattopadhyay, M and Whitelegge, J and Valentine, JS}, title = {SOD1 aggregation and ALS: role of metallation states and disulfide status.}, journal = {Current topics in medicinal chemistry}, volume = {12}, number = {22}, pages = {2560-2572}, doi = {10.2174/1568026611212220010}, pmid = {23339308}, issn = {1873-4294}, support = {P01 NS049134/NS/NINDS NIH HHS/United States ; P01-NS-49134/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Disulfides/*metabolism ; Humans ; Mutation ; Protein Folding ; Protein Processing, Post-Translational ; Superoxide Dismutase/chemistry/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. About 10% of ALS cases are inherited (familial), and a large subset of them are caused by mutations in the gene encoding the copper-zinc superoxide dismutase (SOD1). The detection of SOD1-positive inclusions in familial ALS patients suggests the role of SOD1 aggregation underlying the pathology of familial ALS. Although SOD1 mutant proteins are different in structure, stability and activity, they all exhibit a higher aggregation propensity than wild-type SOD1. We here review the recent studies on the role of metallation states and disulfide status in the unfolding, misfolding, and aggregation of SOD1. Investigations of the mechanism of SOD1 aggregation enhance our understanding of onset and progression of ALS and have implications for therapeutic approaches for treating ALS.}, }
@article {pmid23339288, year = {2013}, author = {Gentleman, SM}, title = {Review: microglia in protein aggregation disorders: friend or foe?.}, journal = {Neuropathology and applied neurobiology}, volume = {39}, number = {1}, pages = {45-50}, pmid = {23339288}, issn = {1365-2990}, support = {G-0909/PUK_/Parkinson's UK/United Kingdom ; P01 AG012411/AG/NIA NIH HHS/United States ; AG12411/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Microglia/immunology/*pathology ; Neurodegenerative Diseases/immunology/*pathology ; }, abstract = {Microglia cells have been implicated, to some extent, in the pathogenesis of all of the common neurodegenerative disorders involving protein aggregation such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. However, the precise role they play in the development of the pathologies remains unclear and it seems that they contribute to the pathological process in different ways depending on the specific disorder. A better understanding of their varied roles is essential if they are to be the target for novel therapeutic strategies.}, }
@article {pmid23336971, year = {2013}, author = {DeLuca, GC and Kimball, SM and Kolasinski, J and Ramagopalan, SV and Ebers, GC}, title = {Review: the role of vitamin D in nervous system health and disease.}, journal = {Neuropathology and applied neurobiology}, volume = {39}, number = {5}, pages = {458-484}, doi = {10.1111/nan.12020}, pmid = {23336971}, issn = {1365-2990}, mesh = {Humans ; Nervous System/*metabolism/physiopathology ; Nervous System Diseases/*metabolism/physiopathology ; Vitamin D/*metabolism ; Vitamin D Deficiency/metabolism/physiopathology ; }, abstract = {Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.}, }
@article {pmid23336121, year = {2013}, author = {Sakellariou, D and Boniface, G and Brown, P}, title = {Experiences of living with motor neurone disease: a review of qualitative research.}, journal = {Disability and rehabilitation}, volume = {35}, number = {21}, pages = {1765-1773}, doi = {10.3109/09638288.2012.753118}, pmid = {23336121}, issn = {1464-5165}, mesh = {Adaptation, Physiological ; Adaptation, Psychological ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Decision Making ; Disability Evaluation ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/*psychology/*rehabilitation ; *Patient Education as Topic ; Qualitative Research ; *Quality of Life ; Risk Assessment ; Severity of Illness Index ; Sex Factors ; *Sickness Impact Profile ; }, abstract = {PURPOSE: This review sought to answer the question "what is known about people's experiences of living with MND?".<br><br>METHODS: The review followed the guidelines of the Centre of Reviews and Dissemination. Twenty articles met the inclusion criteria and their results were analysed thematically. Data were managed and coded using the software package NVIVO and the analysis was performed in two stages, with the first stage aiming to develop descriptive themes offering an overview of the included data. During the second stage, analytical themes were developed with the explicit aim to answer the review question.<br><br>RESULTS: The themes that emerged point to the following: (a) people with motor neurone disease (MND) develop experiential knowledge that helps them to live with the disease and (b) while people with MND believe they do not have any control over the disease, they try to have control over their lives through active choices, e.g. how and when to use adaptive equipment.<br><br>CONCLUSIONS: This review highlights the decision-making and knowledge generating processes used by people with MND. Further research is required to explore these processes and their implications for the care of people with MND.<br><br>Decision-making process by MND patients regarding their care is complex and takes into account the social elements of the disease as well as the medical. Exploring the practical knowledge that patients develop can offer insights on appropriate care for MND patients.}, }
@article {pmid23333338, year = {2013}, author = {Conrad, M and Schick, J and Angeli, JP}, title = {Glutathione and thioredoxin dependent systems in neurodegenerative disease: what can be learned from reverse genetics in mice.}, journal = {Neurochemistry international}, volume = {62}, number = {5}, pages = {738-749}, doi = {10.1016/j.neuint.2013.01.010}, pmid = {23333338}, issn = {1872-9754}, mesh = {Animals ; Brain/metabolism ; Cell Death ; Glutathione/*metabolism ; Mice ; Neurodegenerative Diseases/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Thioredoxins/*metabolism ; }, abstract = {Oxidative stress is a major common hallmark of many neurodegenerative disease such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. Novel concepts in our understanding of oxidative stress indicate that a perturbed redox circuitry could be strongly linked with the onset of such diseases. In this respect, glutathione and thioredoxin dependent antioxidant enzymes play a central role as key regulators due to the fact that a slight dysfunction of any of these enzymes leads to sustained reactive oxygen species (ROS) production. Apart from their classical role as ROS scavengers, some of these enzymes are also able to control post-translational modifications. Therefore, efficient control of ROS production and reversibility of post-translational modifications are critical as improper control of such events may lead to the activation of pathological redox circuits that eventually culminate in neuronal cell death. To dissect the apparently opposing functions of ROS in cell physiology and pathophysiology, a proper working toolkit is mandatory. In vivo modeling is an absolute requirement due to the complexity of redox signaling systems that often contradict data obtained from in vitro approaches. Hence, inducible/conditional knockout mouse models for key redox enzymes are emerging as powerful tools to perturb redox circuitries in a temporal and spatial manner. In this review we address the basics of ROS generation, chemistry and detoxification as well as examples in where applications of mouse models of important enzymes have been successfully applied in the study of neurodegenerative processes. We also highlight the importance of new models to overcome present technical limitations in order to advance in the study of redox processes in the role of neurodegeneration.}, }
@article {pmid23331517, year = {2013}, author = {Head, MW}, title = {Human prion diseases: molecular, cellular and population biology.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {33}, number = {3}, pages = {221-236}, doi = {10.1111/neup.12016}, pmid = {23331517}, issn = {1440-1789}, support = {CZB/4/588/CSO_/Chief Scientist Office/United Kingdom ; /DH_/Department of Health/United Kingdom ; }, mesh = {Animals ; Cattle ; Creutzfeldt-Jakob Syndrome/genetics/pathology ; Encephalopathy, Bovine Spongiform ; Epigenesis, Genetic ; Humans ; Nervous System Diseases/genetics/pathology ; Peptide Hydrolases/genetics/physiology ; Population ; PrPC Proteins/genetics ; Prion Diseases/genetics/*pathology ; Prions/genetics ; Risk Factors ; Zoonoses ; }, abstract = {The past 20 years have witnessed a dramatic resurgence of interest in a hitherto obscure neurodegenerative disease, Creutzfeldt-Jakob disease (CJD). This was driven partly by the novelty of the prion hypothesis, which sought to provide an explanation for the pathogenesis of transmissible spongiform encephalopathies, involving a unique epigenetic mechanism, and partly by events in the UK, where an outbreak of a new prion disease in cattle (bovine spongiform encephalopathy or BSE) potentially exposed a large section of the UK population to prion infectivity through a dietary route. The numbers of cases of the resultant novel disease variant CJD (vCJD), have so far been limited and peaked in the UK in the year 2000 and have subsequently declined. However, the effects of BSE and vCJD have been far-reaching. The estimated prevalence of vCJD infection in the UK is substantially higher than the numbers of clinical cases would suggest, posing a difficult dilemma for those involved in blood transfusion, tissue transplantation and cellular therapies. The clinico-pathological phenotype of human prion diseases has come under close scrutiny and molecular classification systems have been developed to account for the different diseases and their phenotypic spectra. Moreover, enhanced human and animal surveillance and better diagnostic tools have identified new human and animal prion diseases. Lastly, as the prion hypothesis has gained widespread acceptance, the concepts involved have been applied to other areas, including extra-chromosomal inheritance in fungi, long-term potentiation in memory formation and the spread of molecular pathology in diverse conditions, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Studies at the molecular and cellular level have helped to provide a better understanding of human prion diseases, aided pathological diagnosis and helped inform public health decision-making.}, }
@article {pmid23331301, year = {2013}, author = {Llorens, J}, title = {Toxic neurofilamentous axonopathies -- accumulation of neurofilaments and axonal degeneration.}, journal = {Journal of internal medicine}, volume = {273}, number = {5}, pages = {478-489}, doi = {10.1111/joim.12030}, pmid = {23331301}, issn = {1365-2796}, mesh = {Adhesives/*toxicity ; Amyotrophic Lateral Sclerosis/*chemically induced/metabolism/pathology ; Axons/*drug effects/metabolism/pathology ; Carbon Disulfide/*toxicity ; Hexanes/*toxicity ; Humans ; Neurofilament Proteins/*drug effects/metabolism ; Neurotoxins/toxicity ; Nitriles/*toxicity ; }, abstract = {A number of neurotoxic chemicals induce accumulation of neurofilaments in axonal swellings that appear at varying distances from the cell body. This pathology is associated with axonal degeneration of different degrees. The clinical manifestation is most commonly that of a mixed motor-sensory peripheral axonopathy with a disto-proximal pattern of progression, as in cases of chronic exposure to n-hexane and carbon disulphide. It has been demonstrated that protein adduct formation is a primary molecular mechanism of toxicity in these axonopathies, but how this mechanism leads to neurofilament accumulation and axonal degeneration remains unclear. Furthermore, little is known regarding the mechanisms of neurofilamentous axonopathy caused by 3,3'-iminodipropionitrile, an experimental toxin that induces proximal axon swelling that is strikingly similar to that found in early amyotrophic lateral sclerosis. Here, we review the available data and main hypotheses regarding the toxic axonopathies and compare them with the current knowledge of the biological basis of neurofilament transport. We also review recent studies addressing the question of how these axonopathies may cause axonal degeneration. Understanding the mechanisms underlying the toxic axonopathies may provide insight into the relationship between neurofilament behaviour and axonal degeneration, hopefully enabling the identification of new targets for therapeutic intervention. Because neurofilament abnormalities are a common feature of many neurodegenerative diseases, advances in this area may have a wider impact beyond toxicological significance.}, }
@article {pmid23323713, year = {2013}, author = {Berry, JD and Miller, R and Moore, DH and Cudkowicz, ME and van den Berg, LH and Kerr, DA and Dong, Y and Ingersoll, EW and Archibald, D}, title = {The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {3}, pages = {162-168}, doi = {10.3109/21678421.2012.762930}, pmid = {23323713}, issn = {2167-9223}, mesh = {*Activities of Daily Living/psychology ; Amyotrophic Lateral Sclerosis/mortality/psychology/*therapy ; Clinical Trials as Topic/methods/standards ; Clinical Trials, Phase II as Topic/methods/standards ; Clinical Trials, Phase III as Topic/methods/standards ; Endpoint Determination/methods/*standards ; Humans ; Outcome Assessment, Health Care/methods/*standards ; *Recovery of Function/physiology ; Survival Rate/trends ; }, abstract = {Our objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. Historically, ALS clinical trials have assessed survival and function as independent endpoints. Combined endpoints have been used in other diseases to decrease the confounding effect of mortality on analysis of functional outcomes. We explored the application of a similar approach in ALS, the CAFS endpoint, which was used as a pre-specified secondary analysis in a phase II study of dexpramipexole. Those results and some hypothetical examples based on modeling exercises are presented here. CAFS is the primary endpoint of a dexpramipexole phase III study in ALS. In conclusion, the CAFS is a robust statistical tool for ALS clinical trials and appropriately accounts for and weights mortality in the analysis of function.}, }
@article {pmid23318296, year = {2013}, author = {Rademakers, R and van Blitterswijk, M}, title = {Motor neuron disease in 2012: Novel causal genes and disease modifiers.}, journal = {Nature reviews. Neurology}, volume = {9}, number = {2}, pages = {63-64}, pmid = {23318296}, issn = {1759-4766}, support = {P50 AG016574/AG/NIA NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS065782/NS/NINDS NIH HHS/United States ; R01 NS080882/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Chromosomes, Human, Pair 9/genetics ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Disease Progression ; Frontotemporal Dementia/genetics ; Gene Deletion ; Genome-Wide Association Study ; Humans ; Mice ; Motor Neuron Disease/*drug therapy/*genetics ; Open Reading Frames/genetics ; Rats ; Zebrafish ; }, abstract = {In 2012, researchers published extensively on the genetic and clinicopathological characterization of patients with the newly discovered C9ORF72 repeat expansions, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Novel ALS-linked genes and genetic modifiers were identified through screening in animal models and patients.}, }
@article {pmid23301959, year = {2013}, author = {Behari, M and Shrivastava, M}, title = {Role of platelets in neurodegenerative diseases: a universal pathophysiology.}, journal = {The International journal of neuroscience}, volume = {123}, number = {5}, pages = {287-299}, doi = {10.3109/00207454.2012.751534}, pmid = {23301959}, issn = {1563-5279}, mesh = {Animals ; Biomarkers/blood ; Blood Platelets/*pathology/physiology ; Humans ; Neurodegenerative Diseases/*blood/*pathology/physiopathology ; }, abstract = {Platelets play an important role in a variety of disorders, namely, cardiovascular, psychosomatic, psychiatric, thrombosis, HIV/AIDS in addition to various neurodegenerative diseases (NDDs). Recent evidence indicates that platelet react to diverse stressors, thereby offering an interesting vantage point for understanding their potential role in contemporary medical research. This review addresses the possible role of platelets as a systemic probe in various NDDs, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, etc. The current review based on published literature, describes a probable link between platelets and pathophysiology of various NDDs. It also discusses how platelets epitomize ultrastructural, morphological, biochemical and molecular changes, highlighting their emerging role as systemic tools in different NDDs.}, }
@article {pmid23295632, year = {2014}, author = {Wilson, JR and Fehlings, MG}, title = {Riluzole for acute traumatic spinal cord injury: a promising neuroprotective treatment strategy.}, journal = {World neurosurgery}, volume = {81}, number = {5-6}, pages = {825-829}, doi = {10.1016/j.wneu.2013.01.001}, pmid = {23295632}, issn = {1878-8769}, mesh = {Animals ; Humans ; Neuroprotective Agents/*therapeutic use ; Neurotoxins/metabolism ; Riluzole/*therapeutic use ; Spinal Cord Injuries/*drug therapy/metabolism ; Voltage-Gated Sodium Channels/metabolism ; }, abstract = {BACKGROUND: Over the years, understanding of the specific secondary injury mechanisms that follow traumatic spinal cord injury (SCI) has improved. These pathologic mechanisms collectively serve to increase the extent of neural tissue injury, reducing prospects for neurologic recovery. An enhanced understanding of the pathobiology of SCI has permitted investigation of therapies targeting specific elements of this pathologic cascade. It is now known that the continuous posttraumatic activation of neuronal voltage-gated sodium ion channels leads to increased rates of cell death through the development of cellular swelling, acidosis, and glutaminergic excitotoxicity. The objective herein is to provide an update regarding the current status of the potential neuroprotective drug riluzole in the treatment of traumatic SCI.<br><br>METHODS: Narrative review and summary paper.<br><br>RESULTS: Riluzole is a sodium channel-blocking benzothiazole anticonvulsant drug that is approved by the U.S. Food and Drug Administration for the treatment of amyotrophic lateral sclerosis and has shown efficacy in preclinical models of SCI in reducing the extent of sodium and glutamate mediated secondary injury. This drug is currently under early stages of clinical investigation in SCI and shows promise as an acute neuroprotective therapy in this context.<br><br>CONCLUSION: This article reviews the biologic rationale, existing preclinical evidence, and emerging clinical data for riluzole in the treatment of traumatic SCI.}, }
@article {pmid23289752, year = {2013}, author = {Dangoumau, A and Veyrat-Durebex, C and Blasco, H and Praline, J and Corcia, P and Andres, CR and Vourc'h, P}, title = {Protein SUMOylation, an emerging pathway in amyotrophic lateral sclerosis.}, journal = {The International journal of neuroscience}, volume = {123}, number = {6}, pages = {366-374}, doi = {10.3109/00207454.2012.761984}, pmid = {23289752}, issn = {1563-5279}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Nerve Tissue Proteins/*metabolism ; Oxidative Stress ; *Signal Transduction ; *Sumoylation ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Ubiquitination ; }, abstract = {The covalent attachment of SUMO proteins (small ubiquitin-like modifier) to specific proteins or SUMOylation regulates their functional properties in the nucleus and cytoplasm of neurons. Recent studies reported dysfunction of the SUMO pathway in molecular and cellular abnormalities associated with amyotrophic lateral sclerosis (ALS). Furthermore, several observations support a direct role for SUMOylation in diverse pathogenic mechanisms involved in ALS, such as response to hypoxia, oxidative stress, glutamate excitotoxicity and proteasome impairment. Recent results also suggest that SUMO modifications of superoxide dismutase 1, transactive response DNA-binding protein 43, CTE (COOH terminus of EAAT2) (proteolytic C-terminal fragment of the glutamate transporter excitatory amino acid transporter 2, EAAT2) and proteins regulating the turnover of ALS-related proteins can participate in the pathogenesis of ALS. Moreover, the fused in sarcoma (FUS) gene, mutated in ALS, encodes a protein with a SUMO E3 ligase activity. In this review, we summarize the functioning of the SUMO pathway in normal conditions and in response to stresses, its action on ALS-related proteins and discuss the need for further research on this pathway in ALS.}, }
@article {pmid23286757, year = {2013}, author = {Bradley, WG and Borenstein, AR and Nelson, LM and Codd, GA and Rosen, BH and Stommel, EW and Cox, PA}, title = {Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {5-6}, pages = {325-333}, doi = {10.3109/21678421.2012.750364}, pmid = {23286757}, issn = {2167-9223}, mesh = {*Amino Acids, Diamino ; Amyotrophic Lateral Sclerosis/*epidemiology ; Cyanobacteria/*metabolism ; Cyanobacteria Toxins ; Environmental Exposure/*statistics &amp; numerical data ; Gene-Environment Interaction ; Humans ; Neurodegenerative Diseases/epidemiology ; *Neurotoxins ; Risk Factors ; }, abstract = {There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5-10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals.}, }
@article {pmid23286745, year = {2013}, author = {Vrijsen, B and Testelmans, D and Belge, C and Robberecht, W and Van Damme, P and Buyse, B}, title = {Non-invasive ventilation in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {2}, pages = {85-95}, doi = {10.3109/21678421.2012.745568}, pmid = {23286745}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis/*rehabilitation ; Humans ; Respiration, Artificial/*methods/*trends ; Respiratory Insufficiency/diagnosis/*etiology/*rehabilitation ; Treatment Outcome ; }, abstract = {Abstract Non-invasive ventilation (NIV) is widely used to improve alveolar hypoventilation in amyotrophic lateral sclerosis. Several studies indicate a better survival when NIV is used, certainly in patients with none to moderate bulbar dysfunction. Data on quality of life (QoL) are rather disputable. Overall QoL is shown to be equivalent in patients with or without NIV, although health-related QoL is shown to be increased in patients with none to moderate bulbar dysfunction. NIV improves sleep quality, although patient-ventilator asynchronies are demonstrated. FVC < 50%, seated or supine, has been widely applied as threshold to initiate NIV. Today, measurements of respiratory muscle strength, nocturnal gas exchange and symptomatic complaints are used as indicators to start NIV. Being compliant with NIV therapy increases QoL and survival. Cough augmentation has an important role in appropriate NIV. Patients have today more technical options and patients with benefit from these advances are growing in number. Tracheal ventilation needs to be discussed when NIV seems impossible or becomes insufficient.}, }
@article {pmid23280834, year = {2012}, author = {Holmes, BB and Diamond, MI}, title = {Amyotrophic lateral sclerosis and organ donation: is there risk of disease transmission?.}, journal = {Annals of neurology}, volume = {72}, number = {6}, pages = {832-836}, pmid = {23280834}, issn = {1531-8249}, support = {F31 NS079039/NS/NINDS NIH HHS/United States ; R01 NS071835/NS/NINDS NIH HHS/United States ; 1F31NS079039-01/NS/NINDS NIH HHS/United States ; 1R01NS071835/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Communicable Diseases/*etiology ; Humans ; Longitudinal Studies/*methods ; Risk ; *Tissue and Organ Procurement/methods ; }, abstract = {A new protocol suggests that patients with amyotrophic lateral sclerosis (ALS) are a viable source of tissue for organ transplantation. However, multiple lines of evidence suggest that many neurodegenerative diseases, including ALS, might progress due to transcellular propagation of protein aggregation among neurons. Transmission of the disease state from donor to host thus may be possible under the permissive circumstances of graft transplantation. We argue for careful patient selection and close longitudinal follow-up of recipients when harvesting organs from individuals with neurodegenerative disease, especially dominantly inherited forms.}, }
@article {pmid23279185, year = {2013}, author = {Maruyama, H and Kawakami, H}, title = {Optineurin and amyotrophic lateral sclerosis.}, journal = {Geriatrics &amp; gerontology international}, volume = {13}, number = {3}, pages = {528-532}, doi = {10.1111/ggi.12022}, pmid = {23279185}, issn = {1447-0594}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/genetics/metabolism ; Cell Cycle Proteins ; DNA/*genetics ; Disease Progression ; Genetic Predisposition to Disease ; Global Health ; Humans ; Membrane Transport Proteins ; *Mutation ; Prevalence ; Transcription Factor TFIIIA/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating disease, and thus it is important to identify the causative gene and resolve the mechanism of the disease. We identified optineurin as a causative gene for amyotrophic lateral sclerosis. We found three types of mutations: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Optineurin negatively regulates the tumor necrosis factor-α-induced activation of nuclear factor kappa B. Nonsense and missense mutations abolished this function. Mutations related to amyotrophic lateral sclerosis also negated the inhibition of interferon regulatory factor-3. The missense mutation showed a cyotoplasmic distribution different from that of the wild type. There are no specific clinical symptoms related to optineurin. However, severe brain atrophy was detected in patients with homozygous deletion. Neuropathologically, an E478G patient showed transactive response DNA-binding protein of 43 kDa-positive neuronal intracytoplasmic inclusions in the spinal and medullary motor neurons. Furthermore, Golgi fragmentation was identified in 73% of this patient's anterior horn cells. In addition, optineurin is colocalized with fused in sarcoma in the basophilic inclusions of amyotrophic lateral sclerosis with fused in sarcoma mutations, and in basophilic inclusion body disease. These findings strongly suggest that optineurin is involved in the pathogenesis of amyotrophic lateral sclerosis.}, }
@article {pmid23276136, year = {2013}, author = {Leone, S and Noera, G and Bertolini, A}, title = {Melanocortins as innovative drugs for ischemic diseases and neurodegenerative disorders: established data and perspectives.}, journal = {Current medicinal chemistry}, volume = {20}, number = {6}, pages = {735-750}, pmid = {23276136}, issn = {1875-533X}, mesh = {Amino Acid Sequence ; Animals ; Anti-Inflammatory Agents/chemistry/pharmacology/*therapeutic use ; Central Nervous System Agents/chemistry/pharmacology/*therapeutic use ; Humans ; Inflammation/drug therapy/immunology/physiopathology ; Ischemia/*drug therapy/immunology/physiopathology ; Melanocortins/chemistry/pharmacology/*therapeutic use ; Molecular Sequence Data ; Neurodegenerative Diseases/*drug therapy/immunology/physiopathology ; Receptors, Melanocortin/agonists ; }, abstract = {Ischemic insults and neurodegenerative diseases are by far the leading cause of mortality and disability. Whole-body hypoperfusion, as it occurs in polytraumatic and hemorrhagic shock, is alike an increasingly frequent condition, especially due to traffic accidents, wars and acts of terrorism. It is now clearly established that inflammatory processes play a fundamental role in the pathophysiology of both hypoperfusion/ischemia damage (be it generalized to the whole body, as in the case of shock, or limited to individual organs) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis). On the other hand, concurrent animal and human data show that melanocortin peptides with agonist activity at melanocortin MC3/MC4 receptors are highly effective in different shock conditions as well as in conditions of ischemia/ischemia-reperfusion of individual organs (heart, brain, intestine, kidney, etc.), and accumulating evidence indicates that such effects of melanocortins are mostly due to quite peculiar antiinflammatory mechanisms. Melanocortins have also long been known (i) to exert important neurotrophic effects, not only during fetal development but also in adulthood, in different animal models of brain lesions; (ii) to reduce the morphological correlates of brain aging; (iii) to retard the behavioral deficits that develop during the aging process. Moreover, recent data from different laboratories show that after brain ischemic episodes melanocortins activate the transcription of neurotrophins and their receptors in the cerebral cortex and in the hippocampus, and increase the proliferation of progenitor neuron cells. The above arguments support the view that pharmacokinetically suitable agonists at MC3/MC4 melanocortin receptors may represent a completely innovative class of drugs for an effective treatment of both ischemic and neurodegenerative diseases.}, }
@article {pmid23264687, year = {2013}, author = {Vucic, S and Ziemann, U and Eisen, A and Hallett, M and Kiernan, MC}, title = {Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {84}, number = {10}, pages = {1161-1170}, pmid = {23264687}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Anterior Horn Cells/physiology ; Brain Stem/physiopathology ; Electromyography ; Evoked Potentials, Motor/physiology ; Glutamic Acid/physiology ; Humans ; Interneurons/physiology ; Mitochondria, Muscle/physiology ; Motor Cortex/*physiopathology ; Motor Neurons/physiology ; Muscle, Skeletal/innervation ; Nerve Net/physiopathology ; Neural Inhibition/physiology ; Pyramidal Tracts/*physiopathology ; Recruitment, Neurophysiological/physiology ; Reference Values ; Synaptic Transmission/physiology ; *Transcranial Magnetic Stimulation/instrumentation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS.}, }
@article {pmid23261262, year = {2013}, author = {Guennoc, AM and Camu, W and Corcia, P}, title = {[Awaji criteria: new diagnostic criteria for amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {169}, number = {6-7}, pages = {470-475}, doi = {10.1016/j.neurol.2012.10.007}, pmid = {23261262}, issn = {0035-3787}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*diagnosis ; *Diagnostic Techniques, Neurological ; Electromyography/methods ; Fasciculation/*diagnosis/etiology ; Humans ; Predictive Value of Tests ; }, abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disorder in adults. Although the diagnosis appears obvious in theory, clinical practice shows the contrary as diagnosis is delayed in many patients; the average time between symptom onset and diagnosis can reach 12 months. The delay can be explained by the variability of the clinical presentation and by the absence of diagnostic markers. In order to standardize diagnosis for enrollment in clinical research, diagnostic criteria for ALS were created and revisited during the last 20 years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed, adding two major points to the diagnostic criteria: electromyography is considered equivalent to clinical examination for the identification of LMN signs and fasciculation potentials resume their prominent place in the diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji criteria support improved diagnostic sensitivity without any effect on specificity with the new classification. The only weakness of the new classification involves patients with UMN signs in one region and LMN in two regions; these patients were previously classified as laboratory-supported probable ALS and currently as possible ALS, a lower level of diagnostic certainty. In all other instances the accuracy appears to be improved by the Awaji criteria. Nevertheless, there is a body of evidence suggesting the need for a revision of these new criteria, giving more weight to clinical and complementary findings of UMN involvement. The need to diagnose and treat ALS quickly could be facilitated by the inclusion of complementary investigations that detect UMN signs.}, }
@article {pmid23247072, year = {2013}, author = {Bekenstein, U and Soreq, H}, title = {Heterogeneous nuclear ribonucleoprotein A1 in health and neurodegenerative disease: from structural insights to post-transcriptional regulatory roles.}, journal = {Molecular and cellular neurosciences}, volume = {56}, number = {}, pages = {436-446}, doi = {10.1016/j.mcn.2012.12.002}, pmid = {23247072}, issn = {1095-9327}, mesh = {Amino Acid Sequence ; Animals ; Binding Sites ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/genetics/*metabolism ; Humans ; Molecular Sequence Data ; Neurodegenerative Diseases/genetics/*metabolism ; RNA/metabolism ; *RNA Processing, Post-Transcriptional ; }, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a family of conserved nuclear proteins that associate with nascent RNA polymerase II transcripts to yield hnRNP particles, playing key roles in mRNA metabolism, DNA-related functions and microRNA biogenesis. HnRNPs accompany transcripts from stages of transcriptional regulation through splicing and post-transcriptional regulation, and are believed to affect the majority of expressed genes in mammals. Most hnRNP mRNA transcripts undergo alternative splicing and post-translational modifications, to yield a remarkable diversity of proteins with numerous functional elements that work in concert in their multiple functions. Therefore, mis-regulation of hnRNPs leads to different maladies. Here, we focus on the role of one of the best-known members of this protein family, hnRNP A1 in RNA metabolism, and address recent works that note its multileveled involvement in several neurodegenerative disorders. Initially discovered as a DNA binding protein, hnRNP A1 includes two RNA recognition motifs, and post-translational modifications of these and other regions in this multifunctional protein alter both its nuclear pore shuttling properties and its RNA interactions and affect transcription, mRNA splicing and microRNA biogenesis. HnRNP A1 plays several key roles in neuronal functioning and its depletion, either due to debilitated cholinergic neurotransmission or under autoimmune reactions causes drastic changes in RNA metabolism. Consequently, hnRNP A1 decline contributes to the severity of symptoms in several neurodegenerative diseases, including Alzheimer's disease (AD), spinal muscular atrophy (SMA), fronto-temporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), hereditary spastic paraparesis (HSP) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). At the translational level, these properties of hnRNP A1 led to massive research efforts aimed at developing RNA-targeted therapeutic tools such as splicing-modulating oligonucleotides with promising pharmaceutical potential. HnRNP A1 thus presents an intriguing example for the complexity and importance of heteronuclear ribonucleoproteins in health and disease. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'.}, }
@article {pmid23245644, year = {2012}, author = {Delanian, S and Lefaix, JL and Pradat, PF}, title = {Radiation-induced neuropathy in cancer survivors.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {105}, number = {3}, pages = {273-282}, doi = {10.1016/j.radonc.2012.10.012}, pmid = {23245644}, issn = {1879-0887}, mesh = {Antioxidants/therapeutic use ; Brachial Plexus Neuropathies/etiology ; Breast Neoplasms/radiotherapy ; Disease Progression ; Female ; France/epidemiology ; Hodgkin Disease/radiotherapy ; Humans ; Incidence ; Neoplasms/*radiotherapy ; Peripheral Nervous System Diseases/drug therapy/epidemiology/*etiology ; Quality of Life ; Radiation Injuries/etiology ; Radiotherapy/adverse effects ; *Survivors/statistics &amp; numerical data ; Treatment Outcome ; }, abstract = {Radiation-induced peripheral neuropathy is a chronic handicap, frightening because progressive and usually irreversible, usually appearing several years after radiotherapy. Its occurrence is rare but increasing with improved long-term cancer survival. The pathophysiological mechanisms are not yet fully understood. Nerve compression by indirect extensive radiation-induced fibrosis plays a central role, in addition to direct injury to nerves through axonal damage and demyelination and injury to blood vessels by ischaemia following capillary network failure. There is great clinical heterogeneity in neurological presentation since various anatomic sites are irradiated. The well-known frequent form is radiation-induced brachial plexopathy (RIBP) following breast cancer irradiation, while tumour recurrence is easier to discount today with the help of magnetic resonance imaging and positron emission tomography. RIBP incidence is in accordance with the irradiation technique, and ranges from 66% RIBP with 60Gy in 5Gy fractions in the 1960s to less than 1% with 50Gy in 2Gy fractions today. Whereas a link with previous radiotherapy is forgotten or difficult to establish, this has recently been facilitated by a posteriori conformal radiotherapy with 3D-dosimetric reconstitution: lumbosacral radiculo-plexopathy following testicular seminoma or Hodgkin's disease misdiagnosed as amyotrophic lateral sclerosis. Promising treatments via the antioxidant pathway for radiation-induced fibrosis suggest a way to improve the everyday quality of life of these long-term cancer survivors.}, }
@article {pmid23237905, year = {2013}, author = {Roussel, BD and Kruppa, AJ and Miranda, E and Crowther, DC and Lomas, DA and Marciniak, SJ}, title = {Endoplasmic reticulum dysfunction in neurological disease.}, journal = {The Lancet. Neurology}, volume = {12}, number = {1}, pages = {105-118}, doi = {10.1016/S1474-4422(12)70238-7}, pmid = {23237905}, issn = {1474-4465}, support = {G1002610/WT_/Wellcome Trust/United Kingdom ; G1002610/MRC_/Medical Research Council/United Kingdom ; 089703/WT_/Wellcome Trust/United Kingdom ; GGP11057/TI_/Telethon/Italy ; G0901786/MRC_/Medical Research Council/United Kingdom ; 100140/WT_/Wellcome Trust/United Kingdom ; G0700990/MRC_/Medical Research Council/United Kingdom ; G0601840/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyloid beta-Peptides/genetics ; Animals ; Endoplasmic Reticulum/*pathology/physiology ; Humans ; Nervous System Diseases/genetics/*pathology/*physiopathology ; Protein Folding ; Signal Transduction/physiology ; Unfolded Protein Response/genetics ; }, abstract = {Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurological disorders, including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurological disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognised but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible.}, }
@article {pmid23235621, year = {2012}, author = {Pastula, DM and Moore, DH and Bedlack, RS}, title = {Creatine for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {12}, number = {}, pages = {CD005225}, doi = {10.1002/14651858.CD005225.pub3}, pmid = {23235621}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Creatine/*administration &amp; dosage/adverse effects ; Disease Progression ; Humans ; Motor Neuron Disease/drug therapy/mortality ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Randomized Controlled Trials as Topic ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Results from human trials, however, have been mixed. Given conflicting results regarding the efficacy of creatine, we conducted a systematic review, which was updated in 2012.<br><br>OBJECTIVES: To systematically examine the efficacy of creatine efficacy in prolonging ALS survival and in slowing ALS disease progression.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (16 July 2012), CENTRAL (2012, issue 7 in the Cochrane Library), MEDLINE (January 1966 to July 2012) and EMBASE (January 1980 to July 2012) for any trial involving creatine in the treatment of ALS.&#xa0;We also contacted experts in the field for any additional studies.<br><br>SELECTION CRITERIA: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and per cent predicted forced vital capacity (FVC) over time.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.<br><br>MAIN RESULTS: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo.&#xa0;When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76).&#xa0;In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).<br><br>AUTHORS' CONCLUSIONS: In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.}, }
@article {pmid23229103, year = {2012}, author = {Nass, RD and Meister, IG and Haupt, WF and Fink, GR}, title = {[ALS and frontotemporal dementia - case report and review of the literature].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {80}, number = {12}, pages = {711-719}, doi = {10.1055/s-0032-1325604}, pmid = {23229103}, issn = {1439-3522}, mesh = {Amyotrophic Lateral Sclerosis/*complications/drug therapy/genetics/*psychology ; Behavior ; Cognition Disorders/etiology/psychology ; DNA-Binding Proteins ; Electroencephalography ; Frontotemporal Dementia/*complications/genetics/*psychology/therapy ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Positron-Emission Tomography ; tau Proteins/genetics/metabolism ; }, abstract = {The occurrence of cognitive decline in amyotrophic lateral sclerosis (ALS), especially in the form of frontotemporal dementia (FTD), has been described previously. Recent molecular biology and histopathology data suggest that both ALS and FTD may share common pathological pathways and may present two phenotypes of the same proteinopathy. The underlying pathophysiological mechanism may be defective RNA- and DNA-modulation, mediated by the proteins TDP43 and FUS. These findings are suggestive of a new disease category of TDP43-proteinopathies, which include ALS, FTD and overlap syndromes. While about half of the FTD cases are associated with TDP43-deposits, tau is found in the other half. A significant clinical overlap to other tauopathies exists here as well, for instance with corticobasal degeneration. In this paper, we present a case report and review the clinical spectrum and current pathogenetic concepts of FTD.}, }
@article {pmid23217177, year = {2013}, author = {Musarò, A}, title = {Understanding ALS: new therapeutic approaches.}, journal = {The FEBS journal}, volume = {280}, number = {17}, pages = {4315-4322}, doi = {10.1111/febs.12087}, pmid = {23217177}, issn = {1742-4658}, mesh = {Amyotrophic Lateral Sclerosis/genetics/immunology/*therapy ; Animals ; Antibodies, Monoclonal/*therapeutic use ; *Exercise Therapy ; *Genetic Therapy ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. Although numerous pathological mechanisms have been elucidated, ALS remains an invariably fatal disease in the absence of any effective therapy. The heterogeneity of the disease and the failure to develop satisfactory therapeutic protocols reinforce the view that ALS is a multi-factorial and multi-systemic disease. Thus, a better understanding of the pathogenic mechanisms and study of the potential pathological relationship between the various cellular processes is required to ensure efficacious therapy. The pathogenic mechanisms associated with ALS are reviewed, and the strengths and limitations of some new therapeutic approaches are discussed.}, }
@article {pmid23214132, year = {2012}, author = {Wojda, I}, title = {[MAP kinase pathways--their evolution and role in some neurodegenerative diseases].}, journal = {Postepy biochemii}, volume = {58}, number = {1}, pages = {79-90}, pmid = {23214132}, issn = {0032-5422}, mesh = {Alzheimer Disease/enzymology ; Amyotrophic Lateral Sclerosis/enzymology ; Cell Proliferation ; Humans ; Mitogen-Activated Protein Kinases/*metabolism ; Neoplasms/enzymology ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/enzymology ; Phosphorylation ; Proteins/metabolism ; }, abstract = {The scientific literature is rich in reports concerning the participation of MAP kinases in various aspects of the physiology of different organisms. There are, however few papers devoted to the evolution of these pathways. This paper offers a survey of the scientific literature describing how MAP kinase pathways have evolved. Why is the cascade of protein phosphorylation on serine, threonine and tyrosine residues more advantageous in Eucaryota than the two-component regulatory system, based on the phosphorylation of histidine and aspartic acid, which predominates in bacteria? How were these pathways formed and evolved? Finally, how important role do they play in the physiology of human organism? Disturbances in the proper functioning of the MAP kinase pathways lead to uncontrolled cell proliferation and the emergence of various diseases including cancer. Because the average life span has lenghtened we hear more and more often about neurodegenerative diseases that lead to dementia or paralysis. Disturbances in the proper functioning of the MAP kinase pathways in neurodegenerative diseases have also been reported recently. Therefore, in this paper I present the current state of research on the dysfunction of these pathways in three diseases: Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid23211499, year = {2012}, author = {Fritsch, T and Smyth, KA and Wallendal, MS and Hyde, T and Leo, G and Geldmacher, DS}, title = {Parkinson disease: research update and clinical management.}, journal = {Southern medical journal}, volume = {105}, number = {12}, pages = {650-656}, doi = {10.1097/SMJ.0b013e318273a60d}, pmid = {23211499}, issn = {1541-8243}, mesh = {Disease Progression ; Dopamine Agents/therapeutic use ; Humans ; Parkinson Disease/epidemiology/genetics/physiopathology/*therapy ; Prognosis ; Quality of Life ; Risk Factors ; United States/epidemiology ; }, abstract = {More than 1 million people in the United States have Parkinson disease (PD), more than are diagnosed as having multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, and myasthenia gravis combined. PD affects approximately 1 in 100 Americans older than 60 years. It burdens patients, their care partners, and the overall healthcare system. This article reviews the epidemiology, clinical features, putative environmental risk and protective factors, neuropathological aspects, heterogeneity, medical management, and recent studies regarding genetics and PD. The article suggests that based on new research, the prevalence of PD varies in different regions of the United States. Some progress has been made in identifying the risk and protective factors of PD, and a newly emphasized area of study in PD is genetics. Patient care recommendations, based on American Academy of Neurology practice guidelines, are outlined to show the state of contemporary medical management of PD and related disorders.}, }
@article {pmid23182639, year = {2012}, author = {Abraham, A and Drory, VE}, title = {Fatigue in motor neuron diseases.}, journal = {Neuromuscular disorders : NMD}, volume = {22 Suppl 3}, number = {}, pages = {S198-202}, doi = {10.1016/j.nmd.2012.10.013}, pmid = {23182639}, issn = {1873-2364}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/therapy ; Disease Progression ; Exercise Therapy/methods ; Humans ; Muscle Fatigue/*physiology ; *Neuromuscular Diseases/diagnosis/physiopathology/therapy ; *Postpoliomyelitis Syndrome/diagnosis/physiopathology/therapy ; }, abstract = {Motor neuron diseases as amyotrophic lateral sclerosis and post-polio syndrome are characterized by prominent muscular weakness and severe motor disability. The prevalence of fatigue in motor neuron diseases is remarkably high, and may contribute significantly to patients' disability and a poor quality of life. Despite its high prevalence, fatigue is an understudied clinical problem in motor neuron diseases and is often overlooked. The present review will attempt to explain the pathogenic mechanisms of muscle fatigue in amyotrophic lateral sclerosis and post-polio syndrome, to cover the various methods of quantification of fatigue that measure both subjective and physiological components, and to summarize the evidence regarding therapeutic interventions that can be used in order to minimize this symptom.}, }
@article {pmid23201762, year = {2012}, author = {Johnson, WM and Wilson-Delfosse, AL and Mieyal, JJ}, title = {Dysregulation of glutathione homeostasis in neurodegenerative diseases.}, journal = {Nutrients}, volume = {4}, number = {10}, pages = {1399-1440}, pmid = {23201762}, issn = {2072-6643}, support = {T-32 GM008803/GM/NIGMS NIH HHS/United States ; I01 BX000290/BX/BLRD VA/United States ; T32 GM008803/GM/NIGMS NIH HHS/United States ; R21 NS073170/NS/NINDS NIH HHS/United States ; NIH R21 5R21NS073170-02/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Alzheimer Disease/drug therapy/etiology/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/metabolism ; Brain/cytology/enzymology/*metabolism ; Friedreich Ataxia/drug therapy/etiology/metabolism ; Glutathione/*metabolism/therapeutic use ; *Homeostasis ; Humans ; Huntington Disease/drug therapy/etiology/metabolism ; Neurodegenerative Diseases/drug therapy/etiology/*metabolism ; Parkinson Disease/drug therapy/etiology/metabolism ; }, abstract = {Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, and Friedreich's ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.}, }
@article {pmid23200922, year = {2013}, author = {Spalloni, A and Nutini, M and Longone, P}, title = {Role of the N-methyl-d-aspartate receptors complex in amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1832}, number = {2}, pages = {312-322}, doi = {10.1016/j.bbadis.2012.11.013}, pmid = {23200922}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Cell Death ; Humans ; Motor Neurons/pathology ; Receptors, N-Methyl-D-Aspartate/metabolism/*physiology ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease pathologically characterized by the massive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. There is a consensus in the field that ALS is a multifactorial pathology and a number of possible mechanisms have been suggested. Among the proposed hypothesis, glutamate toxicity has been one of the most investigated. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated cell death and impairment of the glutamate-transport system have been suggested to play a central role in the glutamate-mediated motor neuron degeneration. In this context, the role played by the N-methyl-d-aspartate (NMDA) receptor has received considerable less attention notwithstanding its high Ca(2+) permeability, expression in motor neurons and its importance in excitotoxicity. This review overviews the critical role of NMDA-mediated toxicity in ALS, with a particular emphasis on the endogenous modulators of the NMDAR.}, }
@article {pmid23192390, year = {2013}, author = {Hochgräfe, K and Mandelkow, EM}, title = {Making the brain glow: in vivo bioluminescence imaging to study neurodegeneration.}, journal = {Molecular neurobiology}, volume = {47}, number = {3}, pages = {868-882}, pmid = {23192390}, issn = {1559-1182}, support = {089703//Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Brain/*metabolism/*pathology ; Disease Models, Animal ; Luminescent Measurements/*methods ; Nerve Degeneration/*diagnosis/*pathology ; Neurogenesis ; Transgenes ; }, abstract = {Bioluminescence imaging (BLI) takes advantage of the light-emitting properties of luciferase enzymes, which produce light upon oxidizing a substrate (i.e., D-luciferin) in the presence of molecular oxygen and energy. Photons emitted from living tissues can be detected and quantified by a highly sensitive charge-coupled device camera, enabling the investigator to noninvasively analyze the dynamics of biomolecular reactions in a variety of living model organisms such as transgenic mice. BLI has been used extensively in cancer research, cell transplantation, and for monitoring of infectious diseases, but only recently experimental models have been designed to study processes and pathways in neurological disorders such as Alzheimer disease, Parkinson disease, or amyotrophic lateral sclerosis. In this review, we highlight recent applications of BLI in neuroscience, including transgene expression in the brain, longitudinal studies of neuroinflammatory responses to neurodegeneration and injury, and in vivo imaging studies of neurogenesis and mitochondrial toxicity. Finally, we highlight some new developments of BLI compounds and luciferase substrates with promising potential for in vivo studies of neurological dysfunctions.}, }
@article {pmid23186902, year = {2013}, author = {Rezania, K and Roos, RP}, title = {Spinal cord: motor neuron diseases.}, journal = {Neurologic clinics}, volume = {31}, number = {1}, pages = {219-239}, doi = {10.1016/j.ncl.2012.09.014}, pmid = {23186902}, issn = {1557-9875}, mesh = {Diagnosis, Differential ; Humans ; Motor Neuron Disease/*complications/diagnosis/genetics ; Spinal Cord/*pathology ; Spinal Cord Diseases/*complications/diagnosis/genetics ; }, abstract = {Spinal cord motor neuron diseases affect lower motor neurons in the ventral horn. This article focuses on the most common spinal cord motor neuron disease, amyotrophic lateral sclerosis, which also affects upper motor neurons. Also discussed are other motor neuron diseases that only affect the lower motor neurons. Despite the identification of several genes associated with familial amyotrophic lateral sclerosis, the pathogenesis of this complex disease remains elusive.}, }
@article {pmid23186722, year = {2012}, author = {Mazzini, L and Vercelli, A and Ferrero, I and Boido, M and Cantello, R and Fagioli, F}, title = {Transplantation of mesenchymal stem cells in ALS.}, journal = {Progress in brain research}, volume = {201}, number = {}, pages = {333-359}, doi = {10.1016/B978-0-444-59544-7.00016-0}, pmid = {23186722}, issn = {1875-7855}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating incurable, neurodegenerative disease that targets motor neurons (MNs) in the primary motor cortex, brainstem, and spinal cord, leading to muscle atrophy, paralysis, and death due to respiratory failure within 2-5 years. Currently, there is no cure for ALS. The development of a therapy that can support or restore MN function and attenuate toxicity in the spinal cord provides the most comprehensive approach for treating ALS. Mesenchymal stem cells might be suitable for cell therapy in ALS because of their immunomodulatory and protective properties. In this review, the authors discuss the major challenges to the translation of in vitro and animal studies of MSCs therapy in the clinical setting.}, }
@article {pmid23186721, year = {2012}, author = {Chipman, PH and Toma, JS and Rafuse, VF}, title = {Generation of motor neurons from pluripotent stem cells.}, journal = {Progress in brain research}, volume = {201}, number = {}, pages = {313-331}, doi = {10.1016/B978-0-444-59544-7.00015-9}, pmid = {23186721}, issn = {1875-7855}, mesh = {Animals ; Cell Differentiation/*physiology ; Disease Models, Animal ; Humans ; Motor Neuron Disease/surgery ; Motor Neurons/*physiology ; Pluripotent Stem Cells/*physiology/transplantation ; }, abstract = {Alpha motor neurons (also known as lower or skeletal motor neurons) have been studied extensively for over 100 years. Motor neurons control the contraction of skeletal muscles and thus are the final common pathway in the nervous system responsible for motor behavior. Muscles become paralyzed when their innervating motor neurons die because of injury or disease. Motor neuron diseases (MNDs), such as Amyotrophic Lateral Sclerosis, progressively destroy motor neurons until those inflicted succumb to the illness due to respiratory failure. One strategy being explored to study and treat muscle paralysis due to motor neuron loss involves deriving surrogate motor neurons from pluripotent stem cells. Guided by decades of research on the development of the spinal cord, recent advances in neurobiology have shown that functional motor neurons can be derived from mouse and human embryonic stem (ES) cells. Furthermore, ES cell-derived motor neurons restore motor behavior when transplanted into animal models of motor dysfunction. The recent discovery that mouse and human motor neurons can be derived from induced pluripotent stem (iPS) cells (i.e., somatic cells converted to pluripotency) has set the stage for the development of patient-specific therapies designed to treat movement disorders. Indeed, there is now hope within the scientific community that motor neurons derived from pluripotent stem cells will be used to treat MNDs through cell transplantation and/or to screen molecules that will prevent motor neuron death. In this chapter, we review the journey that led to the generation of motor neurons from ES and iPS cells, how stem cell-derived motor neurons have been used to treat/study motor dysfunction, and where the technology will likely lead to in the future.}, }
@article {pmid23186535, year = {2012}, author = {Sha, SJ and Boxer, A}, title = {Treatment implications of C9ORF72.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {6}, pages = {46}, pmid = {23186535}, issn = {1758-9193}, support = {R01 AG031278/AG/NIA NIH HHS/United States ; R01 AG038791/AG/NIA NIH HHS/United States ; }, abstract = {Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.}, }
@article {pmid23177036, year = {2013}, author = {Duleep, A and Shefner, J}, title = {Electrodiagnosis of motor neuron disease.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {24}, number = {1}, pages = {139-151}, doi = {10.1016/j.pmr.2012.08.022}, pmid = {23177036}, issn = {1558-1381}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Axons/physiology ; *Electrodiagnosis ; Electromyography ; Fasciculation/physiopathology ; Humans ; Neural Conduction ; }, abstract = {Electrodiagnostic testing has proved useful in helping to establish the diagnosis of amyotrophic lateral sclerosis by eliminating possible disease mimics and by demonstrating abnormalities in body areas that are clinically unaffected. Electrodiagnosis begins with an understanding of the clinical features of the disease, because clinical correlation is essential. To improve the sensitivity of the electrophysiologic evaluation, the Awaji criteria have been proposed as a modification to the revised El Escorial criteria. Although techniques to evaluate corticomotor neuron abnormalities and to quantify lower motor neuron loss have been developed, they remain primarily research techniques and have not yet influenced clinical practice.}, }
@article {pmid23172389, year = {2012}, author = {Mehanna, R and Patton, EL and Phan, CL and Harati, Y}, title = {Amyotrophic lateral sclerosis with positive anti-acetylcholine receptor antibodies. Case report and review of the literature.}, journal = {Journal of clinical neuromuscular disease}, volume = {14}, number = {2}, pages = {82-85}, doi = {10.1097/CND.0b013e31824db163}, pmid = {23172389}, issn = {1537-1611}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*immunology/physiopathology ; Autoantibodies/*immunology ; Electromyography ; Female ; Humans ; Muscle, Skeletal/pathology ; Neural Conduction/physiology ; Receptors, Cholinergic/*immunology ; }, abstract = {Myasthenia gravis is a nerve-muscle junction disease, for which the most specific test is an increase in the anti-acetylcholine receptor antibodies (anti-AChR-Abs) titer. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting both upper and lower motor neurons. Positive AChR-Ab in patients with pure ALS are exceedingly rare. We report the case of a patient with confirmed ALS and very high levels of AChR-Ab and review the literature on this topic.}, }
@article {pmid23161174, year = {2012}, author = {Guidolin, D and Agnati, LF and Albertin, G and Tortorella, C and Fuxe, K}, title = {Bioinformatics aggregation predictors in the study of protein conformational diseases of the human nervous system.}, journal = {Electrophoresis}, volume = {33}, number = {24}, pages = {3669-3679}, doi = {10.1002/elps.201200290}, pmid = {23161174}, issn = {1522-2683}, mesh = {Algorithms ; Amyloid/metabolism ; Amyloidosis/*metabolism ; Computational Biology/*methods ; Humans ; Models, Statistical ; Neurodegenerative Diseases/*metabolism ; Software ; }, abstract = {Conformational protein diseases of the human central nervous system represent a subject that has crucial theoretical and medical implications. They include several important neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's and Creutzfeldt-Jacob's diseases, amyotrophic lateral sclerosis, and the tauopathies. They occur when soluble proteins undergo conformational rearrangements becoming capable of aggregate into β-sheets conformations leading to the production of insoluble complexes known as amyloid deposits, that accumulate and lead to neurons and glial cells death. Theoretical and experimental evidence indicates that a key role in the conformational changes leading to amyloid formation is played by short sequence stretches within a given protein. Thus, the identification of protein regions potentially involved in aggregate formation and the characterization of their properties are relevant questions in the study of conformational proteins diseases. To address these questions, bioinformatics methods might provide an important contribution, suggesting possible mechanisms of protein aggregation, and focusing and orienting the experimental work. Thus, in the first part of the present review bioinformatics methods specifically attempting to predict aggregation-prone regions in proteins will be briefly described. Furthermore, the results provided by the combined use of some of them to analyze a set of particularly important proteins involved in human degenerative diseases will be discussed.}, }
@article {pmid23160423, year = {2012}, author = {Gladman, M and Cudkowicz, M and Zinman, L}, title = {Enhancing clinical trials in neurodegenerative disorders: lessons from amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {25}, number = {6}, pages = {735-742}, doi = {10.1097/WCO.0b013e32835a309d}, pmid = {23160423}, issn = {1473-6551}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*methods ; Cooperative Behavior ; Drug Discovery/methods ; Humans ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {PURPOSE OF REVIEW: This review article is focused on strategies that may enhance clinical trial efficiency in neurodegenerative disorders, as demonstrated within the research field of amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: Unravelling ALS pathophysiology will result in an increased number of candidate therapeutics. Recent ALS clinical trials have employed novel study designs that expedite the drug development process and limit sample size, including futility, lead-in, selection, adaptive and sequential designs. The search for sensitive and specific biomarkers in ALS continues to develop, and they are essential in accelerating the drug discovery process. Several candidate cerebrospinal fluid (CSF), neuroimaging and electrophysiological biomarkers have been recently described in ALS, and some have been successfully employed as secondary outcome measures in clinical trials. The advent of web-based technologies has provided a complementary platform to expedite clinical trials, through electronic data capture, teleconferencing and online registries. In addition, the formation of ALS consortia has enhanced collaborative multicentre studies.<br><br>SUMMARY: ALS research studies have employed novel strategies to accelerate the efficiency and pace of drug discovery. The importance of adapting to novel measures that enhance study efficiency is not unique to ALS and can be applied to other neurodegenerative diseases in search of effective treatments.}, }
@article {pmid23160421, year = {2012}, author = {van Blitterswijk, M and DeJesus-Hernandez, M and Rademakers, R}, title = {How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders?.}, journal = {Current opinion in neurology}, volume = {25}, number = {6}, pages = {689-700}, pmid = {23160421}, issn = {1473-6551}, support = {P50 AG016574/AG/NIA NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS065782/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; *DNA Repeat Expansion ; Frontotemporal Dementia/*genetics ; Genotype ; Humans ; Phenotype ; Proteins/*genetics ; }, abstract = {PURPOSE OF REVIEW: The aim of this review is to describe disease mechanisms by which chromosome 9 open reading frame 72 (C9ORF72) repeat expansions could lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and to discuss these diseases in relation to other noncoding repeat expansion disorders.<br><br>RECENT FINDINGS: ALS and FTD are complex neurodegenerative disorders with a considerable clinical and pathological overlap, and this overlap is further substantiated by the recent discovery of C9ORF72 repeat expansions. These repeat expansions are currently the most important genetic cause of familial ALS and FTD, accounting for approximately 34.2 and 25.9% of the cases. Clinical phenotypes associated with these repeat expansions are highly variable, and combinations with mutations in other ALS-associated and/or FTD-associated genes may contribute to this pleiotropy. It is challenging, however, to diagnose patients with C9ORF72 expansions, not only because of large repeat sizes, but also due to somatic heterogeneity. Most other noncoding repeat expansion disorders share an RNA gain-of-function disease mechanism, a mechanism that could underlie the development of ALS and/or FTD as well.<br><br>SUMMARY: The discovery of C9ORF72 repeat expansions provides novel insights into the pathogenesis of ALS and FTD and highlights the importance of noncoding repeat expansions and RNA toxicity in neurodegenerative diseases.}, }
@article {pmid23153366, year = {2012}, author = {Yokoyama, JS and Rosen, HJ}, title = {Neuroimaging features of C9ORF72 expansion.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {6}, pages = {45}, pmid = {23153366}, issn = {1758-9193}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG032306/AG/NIA NIH HHS/United States ; }, abstract = {Hexanucleotide expansion intronic to chromosome 9 open reading frame 72 (C9ORF72) has recently been identified as the most common genetic cause of both familial and sporadic amyotrophic lateral sclerosis and of frontotemporal dementia with or without concomitant motor neuron disease. Given the common frequency of this genetic aberration, clinicians seek to identify neuroimaging hallmarks characteristic of C9ORF72-associated disease, both to provide a better understanding of the underlying degenerative patterns associated with this mutation and to enable better identification of patients for genetic screening and diagnosis. A survey of the literature describing C9ORF72 neuroimaging thus far suggests that patients with this mutation may demonstrate symmetric frontal and temporal lobe, insular, and posterior cortical atrophy, although temporal involvement may be less than that seen in other mutations. Some studies have also suggested cerebellar and thalamic involvement in C9ORF72-associated disease. Diffuse cortical atrophy that includes anterior as well as posterior structures and subcortical involvement thus may represent unique features of C9ORF72.}, }
@article {pmid23152212, year = {2012}, author = {Beauverd, M and Mitchell, JD and Wokke, JH and Borasio, GD}, title = {Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {11}, number = {}, pages = {CD002064}, doi = {10.1002/14651858.CD002064.pub3}, pmid = {23152212}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Randomized Controlled Trials as Topic ; Recombinant Proteins/therapeutic use ; Severity of Illness Index ; }, abstract = {BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)).<br><br>OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I.<br><br>SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials.<br><br>MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias.<br><br>AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.}, }
@article {pmid23137745, year = {2012}, author = {Carter, GT and Joyce, NC and Abresch, AL and Smith, AE and VandeKeift, GK}, title = {Using palliative care in progressive neuromuscular disease to maximize quality of life.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {23}, number = {4}, pages = {903-909}, doi = {10.1016/j.pmr.2012.08.002}, pmid = {23137745}, issn = {1558-1381}, mesh = {Chronic Pain/etiology/therapy ; Humans ; Neuromuscular Diseases/complications/*therapy ; *Palliative Care ; *Quality of Life ; }, abstract = {This article discusses the role of palliative care in the treatment pathway of patients with progressive neuromuscular disease (NDM), including amyotrophic lateral sclerosis and Duchenne muscular dystrophy (DMD). People with severe NMDs like DMD are now living much longer, well in to adulthood. This makes them suitable for the medical model of palliative care. Yet palliative medicine is a new area, especially for "adults" with DMD. Strategies for identifying the most effective modalities to alleviate suffering in patients with an NMD receiving palliative services and creating best practice standards in pain and symptom management for this patient population are discussed.}, }
@article {pmid23137738, year = {2012}, author = {Skalsky, AJ and Oskarsson, B and Han, JJ and Richman, D}, title = {Current pharmacologic management in selected neuromuscular diseases.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {23}, number = {4}, pages = {801-820}, doi = {10.1016/j.pmr.2012.09.003}, pmid = {23137738}, issn = {1558-1381}, mesh = {Amyotrophic Lateral Sclerosis/complications/drug therapy ; Excitatory Amino Acid Antagonists/therapeutic use ; Glycogen Storage Disease Type II/*drug therapy ; Humans ; Muscular Atrophy, Spinal/drug therapy ; Muscular Dystrophy, Duchenne/drug therapy ; Myositis/drug therapy ; Myotonia/drug therapy ; Neuromuscular Diseases/*drug therapy ; Neuromuscular Junction Diseases/drug therapy ; }, abstract = {For generations, the neuromuscular disorder care community has focused on establishing the correct diagnosis and providing supportive care. As the pathophysiology and genetics of these conditions became better understood, novel treatments targeting the disease mechanism were developed. This has led to some significant disease-modifying and supportive treatments for several neuromuscular disorders. The current treatments for amyotrophic lateral sclerosis (ALS), neuromuscular junction disorders, inflammatory myopathies, and myotonia are reviewed. Additionally, investigational treatments for ALS, Duchenne muscular dystrophy, and spinal muscular atrophy are discussed.}, }
@article {pmid23137737, year = {2012}, author = {Joyce, NC and Hache, LP and Clemens, PR}, title = {Bone health and associated metabolic complications in neuromuscular diseases.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {23}, number = {4}, pages = {773-799}, pmid = {23137737}, issn = {1558-1381}, support = {K12 HD001097/HD/NICHD NIH HHS/United States ; }, mesh = {*Bone Density/genetics/physiology ; Bone Development ; Bone and Bones/innervation/metabolism/*physiopathology ; Calcium ; Fractures, Bone/*etiology/prevention &amp; control ; Humans ; Motor Activity ; Neuromuscular Diseases/*complications/*physiopathology ; Risk Assessment ; Scoliosis/etiology ; *Vitamin D/blood/therapeutic use ; }, abstract = {This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed, focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy. Future directions are discussed, including the urgent need for studies both to determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD.}, }
@article {pmid23137736, year = {2012}, author = {Braun, MM and Osecheck, M and Joyce, NC}, title = {Nutrition assessment and management in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {23}, number = {4}, pages = {751-771}, doi = {10.1016/j.pmr.2012.08.006}, pmid = {23137736}, issn = {1558-1381}, mesh = {Amyotrophic Lateral Sclerosis/*complications/metabolism ; Animals ; Deglutition Disorders/etiology ; Dietary Supplements ; Enteral Nutrition ; Gastrostomy ; Humans ; Malnutrition/etiology/*therapy ; Metabolic Diseases/etiology ; *Nutrition Assessment ; Refeeding Syndrome/etiology ; }, abstract = {In recent years nutrition assessment and management in amyotrophic lateral sclerosis (ALS) have drawn increased attention. Frequent evaluation of nutrition status is warranted in ALS, given the common occurrence of dysphagia and hypermetabolism and varying disease progression rates. Nutrition management includes dietary and swallow strategies, possible gastrostomy tube placement, and recommendations for vitamin and mineral supplementation. Strategies to assess and optimize nutrition status and prolong survival in ALS patients are reviewed with recommendations based on current research.}, }
@article {pmid23134508, year = {2013}, author = {Zheng, Z and Sheng, L and Shang, H}, title = {Statins and amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {4}, pages = {241-245}, doi = {10.3109/21678421.2012.732078}, pmid = {23134508}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/epidemiology ; Animals ; Case-Control Studies ; Cohort Studies ; *Disease Progression ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Survival Rate/trends ; }, abstract = {OBJECTIVE: To evaluate the association between statins and the incidence and progression of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Several electronic databases (PubMed, Embase, and EBSCO) and Chinese databases (CBM, Wanfang, and VIP) were searched for original articles on April 1(st), 2012. Case-control and cohort studies that provide information on the association between statins and ALS were considered eligible for inclusion. A systematic review was conducted to evaluate the association of statins and the incidence and progression of ALS.<br><br>RESULTS: Two case-control studies and one cohort study that relate the risk of ALS to statins satisfied the inclusion criteria for the meta-analysis. The pooled rate ratio of statin use was 0.89 [95% CI, 0.55 to 1.42] for ALS patients versus non-ALS patients. Three cohort studies on the association between statins and the progression of ALS were identified; these suggested that no strong evidence for the statin-ALS progression relationship exists. No cohort studies favor the use of statins on ALS patients.<br><br>CONCLUSIONS: No definite association between statin use and ALS incidence and progression has been found. Existing results are currently inconclusive to make scientifically supported conclusions. Further prospective cohort studies are still needed.}, }
@article {pmid23129563, year = {2013}, author = {Krüger, T and Lautenschläger, J and Grosskreutz, J and Rhode, H}, title = {Proteome analysis of body fluids for amyotrophic lateral sclerosis biomarker discovery.}, journal = {Proteomics. Clinical applications}, volume = {7}, number = {1-2}, pages = {123-135}, doi = {10.1002/prca.201200067}, pmid = {23129563}, issn = {1862-8354}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism/therapy ; Biomarkers/analysis/metabolism ; Body Fluids/*metabolism ; Humans ; Proteome/analysis/*metabolism ; *Proteomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons leading to death of the patients, mostly within 2-5 years after disease onset. The pathomechanism of motor neuron degeneration is only partially understood and therapeutic strategies based on mechanistic insights are largely ineffective. The discovery of reliable biomarkers of disease diagnosis and progression is the sine qua non of both the revelation of insights into the ALS pathomechanism and the assessment of treatment efficacies. Proteomic approaches are an important pillar in ALS biomarker discovery. Cerebrospinal fluid is the most promising body fluid for differential proteome analyses, followed by blood (serum, plasma), and even urine and saliva. The present study provides an overview about reported peptide/protein biomarker candidates that showed significantly altered levels in certain body fluids of ALS patients. These findings have to be discussed according to proposed pathomechanisms to identify modifiers of disease progression and to pave the way for the development of potential therapeutic strategies. Furthermore, limitations and advantages of proteomic approaches for ALS biomarker discovery in different body fluids and reliable validation of biomarker candidates have been addressed.}, }
@article {pmid23129362, year = {2012}, author = {Katsouri, L and Blondrath, K and Sastre, M}, title = {Peroxisome proliferator-activated receptor-γ cofactors in neurodegeneration.}, journal = {IUBMB life}, volume = {64}, number = {12}, pages = {958-964}, doi = {10.1002/iub.1097}, pmid = {23129362}, issn = {1521-6551}, mesh = {Adaptor Proteins, Signal Transducing/genetics/*metabolism ; Animals ; Brain/*metabolism/pathology ; Co-Repressor Proteins/genetics/*metabolism ; Heat-Shock Proteins/genetics/*metabolism ; Humans ; Mice ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Nuclear Proteins/genetics/*metabolism ; Nuclear Receptor Interacting Protein 1 ; PPAR gamma/genetics/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Signal Transduction ; Transcription Factors/genetics/*metabolism ; Transcriptional Activation ; }, abstract = {Peroxisome proliferator-activated receptor-γ (PPARγ) was initially involved in the regulation of glucose and lipid metabolism, cell differentiation, as well as in the transcriptional control of a wide range of inflammatory genes. However, during the last decade, there has been evidence of the implication of this nuclear receptor in neurodegeneration. Various studies have shown that the administration of PPARγ ligands leads to a reduced pathology in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, and stroke. PPARγ cofactors have a critical function in regulating the activity of PPARγ. Recent reports have brought to light the role of the PPARγ coactivator-1α (PGC-1α) in several neurodegenerative pathologies. However, very little is know about other PPARγ cofactors in the brain, such as the receptor-interacting protein 140, as well as the nuclear receptor corepressor, which seems to be required for normal neural development at specific embryonic stages. In this review, we aim to analyze the role of the main regulators of PPARγ in the brain and during neurodegeneration.}, }
@article {pmid23127757, year = {2013}, author = {Liu, SP and Fu, RH and Huang, SJ and Huang, YC and Chen, SY and Chang, CH and Liu, CH and Tsai, CH and Shyu, WC and Lin, SZ}, title = {Stem cell applications in regenerative medicine for neurological disorders.}, journal = {Cell transplantation}, volume = {22}, number = {4}, pages = {631-637}, doi = {10.3727/096368912X655145}, pmid = {23127757}, issn = {1555-3892}, mesh = {Animals ; Humans ; Nervous System Diseases/*therapy ; Regenerative Medicine/*methods ; *Stem Cell Transplantation ; Stem Cells/*cytology ; }, abstract = {Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical and therapeutic applications. Stem cells are providing hope for many diseases that currently lack effective therapeutic methods, including stroke, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Embryonic stem (ES) cells were originally targeted for differentiation into functional dopamine neurons for cell therapy. Today, induced pluripotent stem (iPS) cells are being tested for such purposes as generating functional dopamine neurons and treating a rat model of Parkinson's disease. In addition, neural stem cell and mesenchymal stem cells are also being used in neurodegenerative disorder therapies for stroke and Parkinson's disease. Although stem cell therapy is still in its infancy, it will likely become a powerful tool for many diseases that currently do not have effective therapeutic approaches. In this article, we discuss current research on the potential application of neural stem cells, mesenchymal stem cells, ES cells, and iPS cells to neurodegenerative disorders.}, }
@article {pmid23123559, year = {2013}, author = {Brugger, H and Durrer, B and Elsensohn, F and Paal, P and Strapazzon, G and Winterberger, E and Zafren, K and Boyd, J and , }, title = {Resuscitation of avalanche victims: Evidence-based guidelines of the international commission for mountain emergency medicine (ICAR MEDCOM): intended for physicians and other advanced life support personnel.}, journal = {Resuscitation}, volume = {84}, number = {5}, pages = {539-546}, doi = {10.1016/j.resuscitation.2012.10.020}, pmid = {23123559}, issn = {1873-1570}, mesh = {*Avalanches ; Disaster Victims ; Evidence-Based Emergency Medicine/*methods ; Heart Arrest/*therapy ; Humans ; Hypothermia/*therapy ; Life Support Care/*methods ; Resuscitation/*methods ; Transportation of Patients ; }, abstract = {BACKGROUND: In North America and Europe ∼150 persons are killed by avalanches every year.<br><br>METHODS: The International Commission for Mountain Emergency Medicine (ICAR MEDCOM) systematically developed evidence-based guidelines and an algorithm for the management of avalanche victims using a worksheet of 27 Population Intervention Comparator Outcome questions. Classification of recommendations and level of evidence are ranked using the American Heart Association system.<br><br>RESULTS AND CONCLUSIONS: If lethal injuries are excluded and the body is not frozen, the rescue strategy is governed by the duration of snow burial and, if not available, by the victim's core-temperature. If burial time &#x2264;35 min (or core-temperature &#x2265;32 &#xb0;C) rapid extrication and standard ALS is important. If burial time >35 min and core-temperature <32 &#xb0;C, treatment of hypothermia including gentle extrication, full body insulation, ECG and core-temperature monitoring is recommended, and advanced airway management if appropriate. Unresponsive patients presenting with vital signs should be transported to a hospital capable of active external and minimally invasive rewarming such as forced air rewarming. Patients with cardiac instability or in cardiac arrest (with a patent airway) should be transported to a hospital for extracorporeal membrane oxygenation or cardiopulmonary bypass rewarming. Patients in cardiac arrest should receive uninterrupted CPR; with asystole, CPR may be terminated (or withheld) if a patient is lethally injured or completely frozen, the airway is blocked and duration of burial >35 min, serum potassium >12 mmol L(-1), risk to the rescuers is unacceptably high or a valid do-not-resuscitate order exists. Management should include spinal precautions and other trauma care as indicated.}, }
@article {pmid23117941, year = {2012}, author = {Gibson, SB and Bromberg, MB}, title = {Amyotrophic lateral sclerosis: drug therapy from the bench to the bedside.}, journal = {Seminars in neurology}, volume = {32}, number = {3}, pages = {173-178}, doi = {10.1055/s-0032-1329193}, pmid = {23117941}, issn = {1098-9021}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/therapy ; Antioxidants/therapeutic use ; Excitatory Amino Acid Antagonists/therapeutic use ; Genetic Therapy ; Humans ; Imidazoles/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Pyrazines/therapeutic use ; Stem Cell Transplantation ; Superoxide Dismutase/biosynthesis/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.}, }
@article {pmid23116846, year = {2012}, author = {Beuran, M and Paun, S and Gaspar, B and Vartic, N and Hostiuc, S and Chiotoroiu, A and Negoi, I}, title = {Prehospital trauma care: a clinical review.}, journal = {Chirurgia (Bucharest, Romania : 1990)}, volume = {107}, number = {5}, pages = {564-570}, pmid = {23116846}, issn = {1221-9118}, mesh = {Advanced Trauma Life Support Care/*organization &amp; administration ; Ambulances/organization &amp; administration ; *Emergency Medical Services/organization &amp; administration ; Humans ; Injury Severity Score ; Romania ; Time Factors ; Trauma Centers/organization &amp; administration ; Treatment Outcome ; Wounds and Injuries/diagnosis/*therapy ; }, abstract = {INTRODUCTION: There are many controversies related to the trauma patient care during the pre-hospital period nowadays. Due to the heterogeneity of the rescue personnel and variability of protocols used in various countries, the benefit of the prehospital advanced life support on morbidity and mortality has been not established.<br><br>METHOD: Systematic review of the literature using computer search of the Library of Medicine and the National Institutes of Health International PubMed Medline database using Entre interface.We reviewed the literature in what concerns the basic and advanced life support given to the trauma patients during the prehospital period.<br><br>RESULTS: Although the organization of the medical emergency system varies from a country to another, the level of patient'scare can be classified into two main categories: Basic Life Support (BLS) and Advanced Life Support (ALS).There are many studies addressing what to be done at the scene.The prehospital care can be divided into two extremes: stay and play/treat then transfer or scoop and run/load and go.<br><br>CONCLUSIONS: A balance between "scoop and run" and "stay and play" is probably the best approach for trauma patients. The chosen approach should be made according to the mechanism of injury (blunt versus penetrating trauma), distance to the trauma center (urban versus rural) and the available resources.}, }
@article {pmid23110908, year = {2012}, author = {De Martino, C and Caiazzo, P and Albano, M and Pastore, M and Tramutoli, PR and Rocca, R and Botte, M and Sigillito, A}, title = {Acute afferent loop obstruction treated by endoscopic decompression. Case report and review of literature.}, journal = {Annali italiani di chirurgia}, volume = {83}, number = {6}, pages = {555-558}, pmid = {23110908}, issn = {0003-469X}, mesh = {Acute Disease ; Afferent Loop Syndrome/*surgery ; Decompression, Surgical/*methods ; *Endoscopy, Gastrointestinal ; Humans ; Male ; Middle Aged ; }, abstract = {Afferent loop syndrome (ALS) is a rare complication of Billroth-II gastrojejunostomy. Most cases of ALS are caused by obstruction from adhesions, kinking at the anastomosis, internal hernia, stomal stenosis, malignancy, or inflammation surrounding the anastomosis. A 61-years old man, who had undergone gastric resection 30 years before, was admitted at emergency room with severe abdominal pain in acute onset, nausea and vomiting. Ultrasonography and multi-detector computed tomography suggested acute ALS, due probably to adhesions or internal hernia. The patient was conducted to digestive endoscopy unit and successfully treated with endoscopic decompression of dilated afferent loop. Open surgery is actually considered the gold-standard in treatment of ALS. However, some surgeons report a few cases treated by laparoscopic surgery, interventional radiology techniques, endoscopic decompression. Authors suggest endoscopic decompression of acute ALS due to adhesions or internal hernia as the first treatment, especially in high-surgical-risk patients.}, }
@article {pmid23110760, year = {2013}, author = {Evans, MC and Couch, Y and Sibson, N and Turner, MR}, title = {Inflammation and neurovascular changes in amyotrophic lateral sclerosis.}, journal = {Molecular and cellular neurosciences}, volume = {53}, number = {}, pages = {34-41}, doi = {10.1016/j.mcn.2012.10.008}, pmid = {23110760}, issn = {1095-9327}, support = {16945/CRUK_/Cancer Research UK/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Astrocytes/immunology ; Cell Adhesion Molecules/immunology/metabolism ; Cytokines/immunology ; Endothelium, Vascular/*immunology/pathology ; Humans ; Inflammation/*immunology/pathology ; Leukocytes/immunology ; Microglia/immunology ; Motor Neurons/immunology ; T-Lymphocytes/immunology ; Transendothelial and Transepithelial Migration ; }, abstract = {Neuroinflammation in now established as an important factor in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). At various time points, astrocytes and microglia are markedly activated, either producing neuroprotective or pro-inflammatory molecules, which can decrease or increase the rate of primary motor neuron degeneration respectively. Recent research has shown that this neuroinflammatory component is affected by the peripheral immune system; T lymphocytes in particular are able to cross into the brain and spinal cord parenchyma, where they interact with resident microglia, either inducing them to adopt an M1 (cytotoxic) or M2 (protective) phenotype, depending on the stage of disease. Clearly understanding the changes that occur to allow the interaction between peripheral and central immune responses will be essential in any attempt to manipulate the disease process via neuroinflammatory mechanisms. However, our understanding of the endothelial changes, which facilitate the infiltration of peripheral immune cells into the brain and spinal cord, is still in its infancy. There are suggestions, though, of up-regulation of cellular adhesion molecules, which are able to arrest circulating leukocytes and facilitate diapedesis into the brain parenchyma. In addition, tight junction proteins appear to be down-regulated, leading to an increase in vascular permeability, an effect that is amplified by vascular damage late in the disease process. This review summarises our current knowledge regarding neuroinflammation, peripheral immune involvement, and endothelial changes in ALS. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'.}, }
@article {pmid23109841, year = {2012}, author = {Maiese, K and Chong, ZZ and Shang, YC and Wang, S}, title = {Erythropoietin: new directions for the nervous system.}, journal = {International journal of molecular sciences}, volume = {13}, number = {9}, pages = {11102-11129}, pmid = {23109841}, issn = {1422-0067}, mesh = {Apoptosis/physiology ; Disease Progression ; Erythropoietin/*metabolism ; Humans ; Nervous System/metabolism/*pathology ; Neurodegenerative Diseases/*pathology/prevention &amp; control/therapy ; Oxidative Stress/physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Erythropoietin/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Wnt1 Protein/metabolism ; }, abstract = {New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control β-catenin, glycogen synthase kinase-3β, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.}, }
@article {pmid23108552, year = {2012}, author = {Pertwee, RG}, title = {Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {367}, number = {1607}, pages = {3353-3363}, pmid = {23108552}, issn = {1471-2970}, mesh = {Analgesics/administration &amp; dosage/pharmacology/therapeutic use ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; Cannabinoid Receptor Agonists/administration &amp; dosage/*pharmacology/*therapeutic use ; Cardiovascular Diseases/drug therapy/metabolism ; Clinical Trials as Topic ; Dronabinol/pharmacology/therapeutic use ; Drug Discovery ; Endocannabinoids/*metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Pain/drug therapy/metabolism ; Receptor, Cannabinoid, CB1/*agonists/metabolism ; Receptor, Cannabinoid, CB2/agonists/metabolism ; Risk Assessment ; }, abstract = {Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'.}, }
@article {pmid23097262, year = {2013}, author = {Yoo, J and Kim, HS and Hwang, DY}, title = {Stem cells as promising therapeutic options for neurological disorders.}, journal = {Journal of cellular biochemistry}, volume = {114}, number = {4}, pages = {743-753}, doi = {10.1002/jcb.24427}, pmid = {23097262}, issn = {1097-4644}, mesh = {Amyotrophic Lateral Sclerosis/pathology/therapy ; Animals ; Bone Marrow/metabolism ; Brain/metabolism/pathology ; Cell Differentiation ; Clinical Trials as Topic ; Humans ; Huntington Disease/pathology/*therapy ; Neurons/metabolism/pathology ; Parkinson Disease/pathology/*therapy ; Stem Cell Transplantation ; Stem Cells/*metabolism ; Stroke/pathology/therapy ; }, abstract = {Due to the limitations of pharmacological and other current therapeutic strategies, stem cell therapies have emerged as promising options for treating many incurable neurologic diseases. A variety of stem cells including pluripotent stem cells (i.e., embryonic stem cells and induced pluripotent stem cells) and multipotent adult stem cells (i.e., fetal brain tissue, neural stem cells, and mesenchymal stem cells from various sources) have been explored as therapeutic options for treating many neurologic diseases, and it is becoming obvious that each type of stem cell has pros and cons as a source for cell therapy. Wise selection of stem cells with regard to the nature and status of neurologic dysfunctions is required to achieve optimal therapeutic efficacy. To this aim, the stem cell-mediated therapeutic efforts on four major neurological diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke, will be introduced, and current problems and future directions will be discussed.}, }
@article {pmid23093800, year = {2013}, author = {Brambilla, L and Martorana, F and Rossi, D}, title = {Astrocyte signaling and neurodegeneration: new insights into CNS disorders.}, journal = {Prion}, volume = {7}, number = {1}, pages = {28-36}, pmid = {23093800}, issn = {1933-690X}, support = {GGP05244/TI_/Telethon/Italy ; }, mesh = {Alzheimer Disease/metabolism/*pathology ; Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Astrocytes/metabolism/*pathology ; Central Nervous System/metabolism/pathology ; Humans ; Prion Diseases/metabolism/*pathology ; *Signal Transduction ; }, abstract = {Growing evidence indicates that astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal activity and survival, but rather they are involved in a striking number of active functions that are critical to the performance of the central nervous system (CNS). As a consequence, it is becoming more and more evident that the peculiar properties of these cells can actively contribute to the extraordinary functional complexity of the brain and spinal cord. This new perception of the functioning of the CNS opens up a wide range of new possibilities to interpret various physiological and pathological events, and moves the focus beyond the neuronal compartment toward astrocyte-neuron interactions. With this in mind, here we provide a synopsis of the activities astrocytes perform in normal conditions, and we try to discuss what goes wrong with these cells in specific pathological conditions, such as Alzheimer Disease, prion diseases and amyotrophic lateral sclerosis.}, }
@article {pmid23086414, year = {2012}, author = {Wen, PJ and Osborne, SL and Meunier, FA}, title = {Phosphoinositides in neuroexocytosis and neuronal diseases.}, journal = {Current topics in microbiology and immunology}, volume = {362}, number = {}, pages = {87-98}, doi = {10.1007/978-94-007-5025-8_4}, pmid = {23086414}, issn = {0070-217X}, mesh = {Animals ; *Exocytosis ; Humans ; Neurodegenerative Diseases/*etiology ; Neurons/*metabolism ; Phosphatidylinositols/*physiology ; }, abstract = {Phosphoinositides (PIs) are a family of phospholipids derived from phosphatidylinositol (PtdIns), whose location, synthesis, and degradation depend on specific PI kinases and phosphatases. PIs have emerged as fundamental regulators of secretory processes, such as neurotransmitter release, hormone secretion, and histamine release in allergic responses. In neurons and neuroendocrine cells, regulated secretion requires the calcium-dependent fusion of transmitter-containing vesicles with the plasma membrane. The role played by PIs in exocytosis is best exemplified by the Ca[2+]-dependent binding of vesicular Synaptotagmin1 to the plasma membrane PtdIns(4,5)P2, and the recently demonstrated role of PtdIns(4,5)P2 in the mobilization of secretory vesicles to the plasma membrane. New evidence has also recently emerged of an alternative PI pathway that can control exocytosis positively (via PtdIn3P) or negatively (via PtdIns(3,5)P2). However, the positive or negative effectors for these pathways remain to be established. Reducing PtdIns(3,5)P2 potentiates neuroexocytosis but leads to neuronal degeneration and has been linked to certain forms of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. The goal of this review is to describe the role of PIs in neuroexocytosis and explore the current hypotheses linking these effects to human diseases.}, }
@article {pmid23071166, year = {2012}, author = {Benatar, M and Wuu, J}, title = {Presymptomatic studies in ALS: rationale, challenges, and approach.}, journal = {Neurology}, volume = {79}, number = {16}, pages = {1732-1739}, pmid = {23071166}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*pathology/prevention &amp; control/therapy ; Environment ; Humans ; Risk ; }, }
@article {pmid23046254, year = {2013}, author = {Adalbert, R and Coleman, MP}, title = {Review: Axon pathology in age-related neurodegenerative disorders.}, journal = {Neuropathology and applied neurobiology}, volume = {39}, number = {2}, pages = {90-108}, doi = {10.1111/j.1365-2990.2012.01308.x}, pmid = {23046254}, issn = {1365-2990}, support = {BBS/E/B/000C0417/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/L003813/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging/*pathology ; Alzheimer Disease/*pathology ; Amyotrophic Lateral Sclerosis/*pathology ; Axons/*pathology ; Glaucoma/*pathology ; Humans ; Parkinson Disease/*pathology ; }, abstract = {'Dying back' axon degeneration is a prominent feature of many age-related neurodegenerative disorders and is widespread in normal ageing. Although the mechanisms of disease- and age-related losses may differ, both contribute to symptoms. Here, we review recent advances in understanding axon pathology in age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. In particular, we highlight the importance of axonal transport, autophagy, traumatic brain injury and mitochondrial quality control. We then place these disease mechanisms in the context of changes to axons and dendrites that occur during normal ageing. We discuss what makes ageing such an important risk factor for many neurodegenerative disorders and conclude that the processes of normal ageing and disease combine at the molecular, cellular or systems levels in a range of disorders to produce symptoms. Pathology identical to disease also occurs at the cellular level in most elderly individuals. Thus, normal ageing and age-related disease are inextricably linked and the term 'healthy ageing' downplays the important contributions of cellular pathology. For a full understanding of normal ageing or age-related disease we must study both processes.}, }
@article {pmid23041957, year = {2012}, author = {Baloh, RH}, title = {How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other?.}, journal = {Current opinion in neurology}, volume = {25}, number = {6}, pages = {701-707}, doi = {10.1097/WCO.0b013e32835a269b}, pmid = {23041957}, issn = {1473-6551}, support = {R01 NS069669/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/*metabolism ; Humans ; RNA/metabolism ; RNA-Binding Protein FUS/genetics/*metabolism ; }, abstract = {PURPOSE OF REVIEW: This review examines the recent research developments aimed at defining the role of RNA-binding proteins (TDP-43 and FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).<br><br>RECENT FINDINGS: TAR DNA-binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA-binding proteins that form aggregates in ALS and FTLD, and when mutated can drive the pathogenesis of these disorders. However, fundamental questions remain as to the relationship between TDP-43 and FUS aggregation and disease, their normal and pathologic function, and where they converge on the same cellular pathways. Autopsy series point to distinct molecular actions as TDP-43 and FUS neuronal inclusions do not overlap, with FUS inclusions being present in only a small subgroup of patients. By contrast, modeling experiments in lower organisms support a genetic interaction between TDP-43 and FUS, although it is likely indirect. Regardless, the recent finding that additional RNA-binding proteins may also cause ALS, and the observation that TDP-43 aggregation remains a core feature in all of the recently identified genetic forms of ALS (C9ORF72, VCP, UBQLN2, and PFN1), underscores the central role of TDP-43 and RNA metabolism in ALS and FTLD.<br><br>SUMMARY: Recent discoveries point to an unprecedented convergence of molecular pathways in ALS and FTLD involving RNA metabolism. Defining the exact points of convergence will likely be key to advancing therapeutics development in the coming years.}, }
@article {pmid23034079, year = {2012}, author = {Takada, LT and Sha, SJ}, title = {Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {5}, pages = {38}, pmid = {23034079}, issn = {1758-9193}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; }, abstract = {Earlier reports of chromosome 9p-linked frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) kindreds observed psychosis as a prominent feature in some patients. Since the discovery of chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansions as a cause of FTD and ALS, research groups and consortia around the world have reported their respective observations of the clinical features associated with this mutation. We reviewed the recent literature on C9orf72-associated FTD and ALS with focus on the neuropsychiatric features associated with this mutation, as well as the experience at University of California, San Francisco. The results and methodologies varied greatly across studies, making comparison of results challenging. Four reports found that psychotic features (particularly delusions) were frequent among mutation carriers, particularly when present early during the disease course, suggesting that this symptom category may be a marker for the mutation. Disinhibition and apathy were the most commonly reported early behavioral symptoms, but these may not be helpful in distinguishing carriers and noncarriers because of the symptoms' frequency in sporadic behavioral variant FTD. Other neuropsychiatric features were reported in different frequencies across studies, suggesting either a similar behavioral phenotype in carriers and noncarriers or reflecting the heterogeneity in clinical presentation of behavioral variant FTD due to C9orf72 expansions. Further studies with larger cohorts will be necessary to determine the neuropsychiatric presentation associated with this mutation.}, }
@article {pmid23023438, year = {2012}, author = {Kierdaszuk, B and Berdyński, M and Zekanowski, C and Kamińska, A}, title = {[TDP-43 proteinopathies - from frontotemporal lobar degeneration to inclusion body myositis].}, journal = {Neurologia i neurochirurgia polska}, volume = {46}, number = {4}, pages = {384-391}, doi = {10.5114/ninp.2012.30271}, pmid = {23023438}, issn = {0028-3843}, mesh = {DNA-Binding Proteins/*genetics ; Frontotemporal Lobar Degeneration/*genetics/pathology ; Humans ; Mutation ; Myositis, Inclusion Body/*genetics/pathology ; Neurodegenerative Diseases/genetics ; TDP-43 Proteinopathies/*genetics/pathology ; }, abstract = {TDP-43, a newly described neurodegenerative protein, is of great interest to both neurologists and geneticists. At the beginning, its dysfunction was recognized in sporadic amyotrophic lateral sclerosis, frontotemporal lobar degeneration with ubiquitinated inclusions and in mixed forms. However, it was also proved that TDP-43 inclusions are in addition present in many other diseases, for example in inclusion body myositis. Furthermore, many genes and different loci may be involved in pathological TDP-43 accumulation in cells and tissues. Mutations in the TARDPB gene, progranulin gene (PGRNVCP) as well as a gene on chromosome 9p were found. The present paper is a summary on possible involvement of TDP-43 in various neurodegenerative disorders.}, }
@article {pmid23000246, year = {2013}, author = {Dasuri, K and Zhang, L and Keller, JN}, title = {Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis.}, journal = {Free radical biology &amp; medicine}, volume = {62}, number = {}, pages = {170-185}, doi = {10.1016/j.freeradbiomed.2012.09.016}, pmid = {23000246}, issn = {1873-4596}, mesh = {Alzheimer Disease/genetics/metabolism/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Humans ; Nerve Degeneration/genetics/*metabolism/pathology ; Neurons/metabolism/pathology ; *Oxidative Stress ; Parkinson Disease/genetics/metabolism/physiopathology ; Protein Biosynthesis/*genetics ; *Proteolysis ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxidative stress occurs in a variety of disease settings and is strongly linked to the development of neuron death and neuronal dysfunction. Cells are equipped with numerous pathways to prevent the genesis, as well as the consequences, of oxidative stress in the brain. In this review we discuss the various forms and sources of oxidative stress in the brain and briefly discuss some of the complexities in detecting the presence of oxidative stress. We then focus the review on the interplay between the diverse cellular proteolytic pathways and their roles in regulating oxidative stress in the brain. Additionally, we discuss the involvement of protein synthesis in regulating the downstream effects of oxidative stress. Together, these components of the review demonstrate that the removal of damaged proteins by effective proteolysis and the synthesis of new and protective proteins are vital in the preservation of brain homeostasis during periods of increased levels of reactive oxygen species. Last, studies from our laboratory and others have demonstrated that protein synthesis is intricately linked to the rates of protein degradation, with impairment of protein degradation sufficient to decrease the rates of protein synthesis, which has important implications for successfully responding to periods of oxidative stress. Specific neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and stroke, are discussed in this context. Taken together, these findings add to our understanding of how oxidative stress is effectively managed in the healthy brain and help elucidate how impairments in proteolysis and/or protein synthesis contribute to the development of neurodegeneration and neuronal dysfunction in a variety of clinical settings.}, }
@article {pmid22997668, year = {2012}, author = {Sempsrott, J and Schmidt, A and Hawkins, S and Bledsoe, B}, title = {Silent struggle.}, journal = {JEMS : a journal of emergency medical services}, volume = {37}, number = {7}, pages = {60, 62, 64 passim}, pmid = {22997668}, issn = {0197-2510}, mesh = {*Drowning ; Emergency Medical Services/*organization &amp; administration ; Emergency Treatment/*methods ; Humans ; *Near Drowning ; }, abstract = {The past 40-50 years of research and experience have given us improved knowledge of the pathophysiology and treatment of drowning injuries. Still, an all-too-common event, the morbidity and mortality of drowning can be mitigated by prevention, recognition and target treatment. Old terms, such as "near drowning" and "secondary drowning," are confusing and misleading, and use of these terms should be abandoned. Most importantly, EMS personnel should understand that drowning is a hypoxic event resulting from submersion in a liquid. Most BLS and ALS strategies are designed to treat cardiac causes of respiratory and cardiac arrests (with recent change to a CAB algorithm). Drowning, however, is initially a purely hypoxic event and should be treated as such with ventilation and oxygenation (with an ABC algorithm). EMS and the fire service, because of their presence in the community, are uniquely positioned to play a major role in drowning prevention and treatment.}, }
@article {pmid22988859, year = {2012}, author = {Beck, R and Deek, J and Safinya, CR}, title = {Structures and interactions in 'bottlebrush' neurofilaments: the role of charged disordered proteins in forming hydrogel networks.}, journal = {Biochemical Society transactions}, volume = {40}, number = {5}, pages = {1027-1031}, doi = {10.1042/BST20120101}, pmid = {22988859}, issn = {1470-8752}, mesh = {Hydrogel, Polyethylene Glycol Dimethacrylate/*chemistry/metabolism ; Molecular Dynamics Simulation ; Monte Carlo Method ; Neurofilament Proteins/*chemistry/metabolism ; Neurons/chemistry/metabolism ; Protein Conformation ; }, abstract = {NFs (neurofilaments), the major cytoskeletal constituent of myelinated axons in vertebrates, consist of three different molecular-mass subunit proteins, NF-L (low), NF-M (medium) and NF-H (high), assembled to form mature filaments with protruding intrinsically disordered C-terminal side-arms. Liquid crystal gel networks of side-arm-mediated NF assemblies play a key role in the mechanical stability of neuronal processes. Disruptions of the NF network, due to NF overaccumulation or incorrect side-arm interactions, are a hallmark of motor neuron diseases including amyotrophic lateral sclerosis. Using synchrotron small-angle X-ray scattering and various microscopy techniques, we have investigated the role of the peptide charges in the subunit side-arms on the structure and interaction of NFs. Our findings, which delineate the distinct roles of NF-M and NF-H in regulating NF interactions, shed light on possible mechanisms of disruption of optimal mechanical network properties.}, }
@article {pmid22985431, year = {2013}, author = {Stavroulakis, T and Walsh, T and Shaw, PJ and McDermott, CJ and , }, title = {Gastrostomy use in motor neurone disease (MND): a review, meta-analysis and survey of current practice.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {2}, pages = {96-104}, doi = {10.3109/17482968.2012.723722}, pmid = {22985431}, issn = {2167-9223}, mesh = {Causality ; Comorbidity ; Deglutition Disorders/*epidemiology/*surgery ; Enteral Nutrition/*statistics &amp; numerical data ; Gastrostomy/*statistics &amp; numerical data ; Humans ; Motor Neuron Disease/*epidemiology/*surgery ; Practice Patterns, Physicians'/*statistics &amp; numerical data ; Prevalence ; Risk Factors ; Treatment Outcome ; }, abstract = {Abstract Gastrostomy feeding is commonly used to support MND patients with dysphagia. In this paper we review three main methods of gastrostomy insertion (PEG, RIG, PIG); conduct a meta-analysis of mortality data following gastrostomy; and present a survey of current practice. A review of the literature revealed a lack of high quality evidence to indicate the optimal method and timing for gastrostomy insertion in patients with MND. A survey of 20 MND clinics demonstrated a clinic-based variability of gastrostomy practices due to factors such as clinician preference, availability of method, and patient respiratory function. The meta-analysis demonstrated that the estimate of the absolute difference in mortality rates was 2.1% higher for PEG (- 6.3%, + 11.2%), suggesting that RIG and PIG methods may be safer than PEG. These results and observations highlight the need for more research to evaluate and compare the safety of the differerent gastrostomy insertion methods in MND care.}, }
@article {pmid22983160, year = {2012}, author = {Nixon, RA and Yang, DS}, title = {Autophagy and neuronal cell death in neurological disorders.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {4}, number = {10}, pages = {}, pmid = {22983160}, issn = {1943-0264}, mesh = {Apoptosis/physiology ; Autophagy/*physiology ; Humans ; Neurodegenerative Diseases/*pathology ; Neurons/*pathology ; }, abstract = {Autophagy is implicated in the pathogenesis of major neurodegenerative disorders although concepts about how it influences these diseases are still evolving. Once proposed to be mainly an alternative cell death pathway, autophagy is now widely viewed as both a vital homeostatic mechanism in healthy cells and as an important cytoprotective response mobilized in the face of aging- and disease-related metabolic challenges. In Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and other diseases, impairment at different stages of autophagy leads to the buildup of pathogenic proteins and damaged organelles, while defeating autophagy's crucial prosurvival and antiapoptotic effects on neurons. The differences in the location of defects within the autophagy pathway and their molecular basis influence the pattern and pace of neuronal cell death in the various neurological disorders. Future therapeutic strategies for these disorders will be guided in part by understanding the manifold impact of autophagy disruption on neurodegenerative diseases.}, }
@article {pmid22981160, year = {2012}, author = {Blanc-Lapierre, A and Bouvier, G and Garrigou, A and Canal-Raffin, M and Raherison, C and Brochard, P and Baldi, I}, title = {[Chronic central nervous system effects of pesticides: state-of-the-art].}, journal = {Revue d'epidemiologie et de sante publique}, volume = {60}, number = {5}, pages = {389-400}, doi = {10.1016/j.respe.2012.03.006}, pmid = {22981160}, issn = {0398-7620}, mesh = {Chronic Disease ; Humans ; Mental Disorders/chemically induced/epidemiology/etiology ; Nervous System Diseases/*chemically induced/complications/*epidemiology ; Neurodegenerative Diseases/chemically induced/epidemiology/etiology ; Neurotoxicity Syndromes/complications/epidemiology ; Occupational Exposure/statistics &amp; numerical data ; Occupational Medicine/*trends ; Pesticides/*toxicity ; }, abstract = {BACKGROUND: Given the neurotoxic properties of pesticides, suggested by experimental results and clinical observations, many epidemiological studies have investigated neurological effects following acute or chronic exposure to pesticides. This review provides an overview of current knowledge about pesticide effects on the central nervous system: neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), cognitive disorders, and psychiatric disorders (mood disorders, anxiety, depression and suicide).<br><br>RESULTS: Parkinson's disease, the most widely studied in relation with pesticide exposure, particularly with insecticides and herbicides, was observed to be a risk factor of the disease. Evidence is scarce for Alzheimer's disease and amyotrophic lateral sclerosis, but quite consistent. Cognitive and psychiatric disorders were often observed in relation with organophosphate insecticide exposure. Cognitive disorders were found associated with acute and chronic exposures, and psychiatric disorders mostly with poisonings. These epidemiologic studies were limited by a lack of detailed and reliable exposure assessment. The role of genetic susceptibilities has been recently observed, but must be further investigated.}, }
@article {pmid22972143, year = {2012}, author = {Garrison, SR and Allan, GM and Sekhon, RK and Musini, VM and Khan, KM}, title = {Magnesium for skeletal muscle cramps.}, journal = {The Cochrane database of systematic reviews}, volume = {2012}, number = {9}, pages = {CD009402}, pmid = {22972143}, issn = {1469-493X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Age Factors ; Cross-Over Studies ; Female ; Humans ; Magnesium/*therapeutic use ; Male ; Muscle Cramp/*drug therapy/etiology ; *Muscle, Skeletal ; Pregnancy ; Pregnancy Complications/*drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Skeletal muscle cramps are common and often presented to physicians in association with pregnancy, advanced age, exercise or disorders of the motor neuron (such as amyotrophic lateral sclerosis). Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this indication has never been evaluated by systematic review.<br><br>OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps. &#xa0;<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (11 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 3), MEDLINE (January 1966 to September 2011), EMBASE (January 1980 to September 2011), LILACS (January 1982 to September 2011), CINAHL Plus (January 1937 to September 2011), AMED (January 1985 to October 2011) and SPORTDiscus (January 1975 to September 2011).<br><br>SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion and extracted data. Two authors assessed risk of bias. We attempted to contact all study authors and obtained patient level data for three of the included trials, one of which was unpublished. All data on adverse effects were collected from the included RCTs.<br><br>MAIN RESULTS: We identified seven trials (five parallel, two cross-over) enrolling a total of 406 individuals amongst whom 118 cross-over participants additionally served as their own controls. Three trials enrolled women with pregnancy-associated leg cramps (N = 202) and four trials enrolled idiopathic cramp sufferers (N = 322 including cross-over controls). Magnesium was compared to placebo in six trials and to no treatment in one trial.For idiopathic cramps (largely older adults presumed to have nocturnal leg cramps), differences in measures of cramp frequency, magnesium versus placebo, were small, not statistically significant, and without heterogeneity (I(2) = 0%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (-3.93%, 95% confidence interval (CI) -21.12% to 13.26%, moderate quality evidence) and the difference in the number of cramps per week at four weeks (0.01 cramps/week, 95% CI -0.52 to 0.55, moderate quality evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different, being 8% lower in the magnesium group (95% CI -28% to 12%, moderate quality evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity (moderate quality evidence) or cramp duration (low quality evidence).Meta-analysis was not possible for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. The two trials comparing magnesium to placebo differed in that one trial found no benefit on frequency or intensity measures while the other found benefit for both.Withdrawals due to adverse events were not significantly different than placebo. While we could not determine the number of subjects with minor adverse events, studies of oral magnesium generally described potential side effects as similar in frequency to placebo.<br><br>AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this patient population is needed. We found no randomized controlled trials evaluating magnesium for exercise-associated muscle cramps or disease state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease).}, }
@article {pmid22968365, year = {2012}, author = {Benze, G and Alt-Epping, B and Geyer, A and Nauck, F}, title = {[Treatment of nausea and vomiting with prokinetics and neuroleptics in palliative care patients : a review].}, journal = {Schmerz (Berlin, Germany)}, volume = {26}, number = {5}, pages = {500-514}, pmid = {22968365}, issn = {1432-2129}, mesh = {Antiemetics/adverse effects/*therapeutic use ; Antipsychotic Agents/adverse effects/*therapeutic use ; Chronic Disease/drug therapy ; Domperidone/adverse effects/therapeutic use ; Dopamine Antagonists/adverse effects/*therapeutic use ; Drug Therapy, Combination ; Evidence-Based Medicine/methods ; Gastrointestinal Motility/drug effects ; Germany ; Humans ; Metoclopramide/adverse effects/*therapeutic use ; Nausea/*drug therapy ; Palliative Care/*methods ; Randomized Controlled Trials as Topic ; Vomiting/*drug therapy ; }, abstract = {BACKGROUND: Many recommendations concerning the treatment of nausea and vomiting in palliative care patients exist but what is the evidence for this? Most studies dealing with this topic have focused on cancer patients under chemotherapy and/or radiation therapy or on patients with postoperative nausea. Cancer patients without chemotherapy or radiation therapy, patients without postoperative nausea, and patients having other diseases with palliative care aspects, such as acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), progressive heart failure, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) have been underrepresented in studies on nausea and vomiting so far.<br><br>OBJECTIVES: The aim of this review was to determine the level of evidence for the treatment of nausea and vomiting with prokinetics and neuroleptics in palliative care patients suffering from far advanced cancer and no longer being treated with chemotherapy or radiation therapy, AIDS, COPD, progressive heart failure, ALS or MS.<br><br>METHODS: Two different electronic databases (PubMed und Embase) were used to identify studies. Furthermore, a hand search for related articles was performed. No restriction was made concerning study types. Studies with patients undergoing chemotherapy radiation therapy or suffering from postoperative nausea, pediatric studies and studies published neither in English nor in German were excluded.<br><br>RESULTS: A total of 30 studies fulfilling the inclusion criteria were found. All studies focused on cancer patients. Despite intensive research studies in patients with AIDS, COPD, heart failure, ALS or MS were not detected. Metoclopramide is seen as an effective drug in many studies whereas the evidence for it is moderate at best. Within the group of neuroleptics, levosupiride and levomepromazine seem to have good antiemetic potential but the evidence level is low.<br><br>CONCLUSION: In patients with advanced cancer not being treated with chemotherapy or radiation therapy, metoclopramide can be used to reduce nausea and vomiting. Neuroleptics, such as levosulpiride or levomepromazine are alternatives but their adverse effects have to be considered carefully. The evidence level for prokinetics and neuroleptics is moderate to low. Concerning palliative care of patients with diseases other than cancer no studies exist. More well designed studies in palliative care patients are needed in order to facilitate evidence based antiemetic therapy. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").}, }
@article {pmid22961186, year = {2012}, author = {Maas, JW}, title = {Inherited myelopathies.}, journal = {Seminars in neurology}, volume = {32}, number = {2}, pages = {114-122}, doi = {10.1055/s-0032-1322581}, pmid = {22961186}, issn = {1098-9021}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/physiopathology ; Genetic Predisposition to Disease/genetics ; Humans ; Metabolism, Inborn Errors/diagnosis/genetics/physiopathology ; Muscular Atrophy, Spinal/diagnosis/genetics/physiopathology ; Spastic Paraplegia, Hereditary/diagnosis/physiopathology ; Spinal Cord Diseases/*congenital/diagnosis/*physiopathology ; }, abstract = {Inherited myelopathies are a small, but important subset of diseases that cause dysfunction of the spinal cord. Manifestations can include various combinations of signs and symptoms, including disturbance of gait, spasticity, paraplegia, amyotrophy, sensory loss, and urinary sphincter dysfunction. These diseases can be divided into classes that include (1) distal axonopathies-exemplified by hereditary spastic paraplegia, (2) motor neuron diseases including familial amyotrophic lateral sclerosis and spinal muscular atrophy, (3) inborn errors of metabolism such as adrenomyeloneuropathy, and (4) other inherited diseases with myelopathy as part of their spectrum of manifestations. Although the inherited myelopathies are relatively rare diseases, knowledge of them and their manifestations is important for the physician faced with a patient with myelopathy, particularly if there are similarly affected individuals in the patient's family. In addition, understanding the pathophysiologic underpinnings of these diseases provides insight into the molecular biology of the nervous system and provides a gateway toward developing treatments for these diseases.}, }
@article {pmid22956189, year = {2012}, author = {Jouroukhin, Y and Ostritsky, R and Gozes, I}, title = {D-NAP prophylactic treatment in the SOD mutant mouse model of amyotrophic lateral sclerosis: review of discovery and treatment of tauopathy.}, journal = {Journal of molecular neuroscience : MN}, volume = {48}, number = {3}, pages = {597-602}, pmid = {22956189}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*prevention &amp; control ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/therapeutic use ; Oligopeptides/chemistry/pharmacology/*therapeutic use ; Phosphorylation/drug effects ; Point Mutation ; Protein Processing, Post-Translational/drug effects ; Recombinant Fusion Proteins/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tauopathies/classification/*drug therapy/genetics ; tau Proteins/*metabolism/physiology ; }, abstract = {Davunetide (NAP) is a leading drug candidate being tested against tauopathy. Davunetide is an eight-amino-acid peptide fragment derived by structure-activity studies from activity-dependent neuroprotective protein, activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. ADNP haploinsufficiency in mice results in tauopathy and cognitive deficits ameliorated by davunetide treatment. This article summarizes in brief recent reviews about NAP protection against tauopathy including the all D-amino acid analogue-D-NAP (AL-408). D-NAP was discovered to have similar neuroprotective functions to NAP in vitro. Here, D-NAP was tested as prophylactic as well as therapeutic treatment for amytrophic lateral sclerosis (ALS) in the widely used TgN(SOD1-G93A)1Gur transgenic mouse model. Results showed D-NAP-associated prophylactic protection, thus daily treatment starting from day 2 of age resulted in a prolonged life course in the D-NAP-treated mice, which was coupled to a significant decrease in tau hyperphosphorylation. These studies correlate protection against tau hyperphosphorylation and longevity in a severe model of ALS-like motor impairment and early mortality. NAP is a first-in-class drug candidate/investigation compound providing neuroprotection coupled to inhibition of tau pathology. D-NAP (AL-408) is a pipeline product.}, }
@article {pmid22951705, year = {2012}, author = {Intiso, D and Basciani, M}, title = {Botulinum toxin use in neuro-rehabilitation to treat obstetrical plexus palsy and sialorrhea following neurological diseases: a review.}, journal = {NeuroRehabilitation}, volume = {31}, number = {2}, pages = {117-129}, doi = {10.3233/NRE-2012-0781}, pmid = {22951705}, issn = {1878-6448}, mesh = {Anti-Dyskinesia Agents/*therapeutic use ; Botulinum Toxins/*therapeutic use ; *Brachial Plexus Neuropathies/drug therapy/etiology/rehabilitation ; *Cerebral Palsy/drug therapy/etiology/rehabilitation ; Humans ; Nervous System Diseases/*complications ; *Sialorrhea/drug therapy/etiology/rehabilitation ; }, abstract = {In neuro-rehabilitation, botulinum toxin (BTX) as adjunct to other interventions can result in a useful therapeutic tool treating disabled people. Other than spasticity, numerous motor and non motor disorders can complicate clinical course and hamper rehabilitative process of neurological impaired patients. A review of BTX use in treating muscular imbalance of children with obstetrical brachial plexus palsy and in reducing sialorrhea following neurological diseases including amyotrophic lateral sclerosis (ASL), Parkinson disease and cerebral palsy (CP) is provided. Clinicians have to face unique and difficult to treat clinical conditions such as ulcers, sores and abnormal posture and movement disorders due to neurological affections. BTX effectiveness in treating some of these conditions is also provided. Since, neurologically disabled subjects can show complex dysfunction, prior to initiating BTX therapy, specific functional limitations, goals and expected outcomes of treatment should be evaluated and discussed with family and caregivers.}, }
@article {pmid22950490, year = {2012}, author = {Seltman, RE and Matthews, BR}, title = {Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management.}, journal = {CNS drugs}, volume = {26}, number = {10}, pages = {841-870}, pmid = {22950490}, issn = {1179-1934}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; }, mesh = {Frontotemporal Dementia/diagnosis/epidemiology/pathology/therapy ; Frontotemporal Lobar Degeneration/*diagnosis/epidemiology/pathology/*therapy ; Humans ; Neurodegenerative Diseases/diagnosis/epidemiology/pathology/therapy ; }, abstract = {Frontotemporal lobar degeneration (FTLD) describes a spectrum of clinically, pathologically and genetically heterogeneous neurodegenerative disorders of unknown aetiology. FTLD spectrum disorders collectively represent a leading cause of early-onset dementia, with most cases presenting between 45 and 64 years of age. FTLD is characterized by progressive changes in behaviour, executive dysfunction and/or language impairment and can be differentiated clinically into three frontotemporal dementia (FTD) syndromes as follows: (i) behavioural variant (bvFTD); (ii) semantic dementia (SD); and (iii) progressive nonfluent aphasia (PNFA). Additionally, there is a significant clinical, pathological and genetic overlap between FTD and motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). bvFTD is characterized by progressive behavioural impairment and a decline in executive function with frontal lobe-predominant atrophy, SD by a loss of object knowledge with prominent anomia and asymmetrical atrophy of the anterior temporal lobes and PNFA by expressive or motor speech deficits with predominantly left peri-sylvian atrophy. Recent advances in molecular biology and immunohistochemical staining techniques have further classified the FTLD spectrum disorders based upon the predominant neuropathological protein into three main categories: (i) microtubule-associated protein tau (FTLD-TAU); (ii) TAR DNA-binding protein-43 (FTLD-TDP); and (iii) fused in sarcoma protein (FTLD-FUS). Up to 40% of FTD patients report a family history of neurodegenerative illness, and one-third to one-half of familial cases of FTD follow an autosomal dominant inheritance pattern. Mutations in MAPT, PGRN, TARDBP, VCP and CHMP2B have been described, along with a recently identified C9ORF72 hexanucleotide repeat expansion. To date, there are no US FDA-approved treatments or disease-modifying therapies for FTD. Pharmacological strategies have focused on neurotransmitter replacement and modulation for the treatment of behavioural, motor and cognitive symptoms of FTD, and include selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, acetylcholinesterase inhibitors and glutamate NMDA receptor antagonists. At present, adequate management of FTD symptoms involves a combination of pharmacological therapy with behavioural, physical and environmental modification techniques.}, }
@article {pmid22945815, year = {2012}, author = {Schellhaas, S and Breitkreutz, R}, title = {[Basics of emergency ultrasound].}, journal = {Praxis}, volume = {101}, number = {18}, pages = {1153-1160}, doi = {10.1024/1661-8157/a001055}, pmid = {22945815}, issn = {1661-8157}, mesh = {Abdominal Injuries/diagnostic imaging ; Algorithms ; Artifacts ; Cardiopulmonary Resuscitation/methods ; Diagnosis, Differential ; Early Diagnosis ; Echocardiography/methods ; *Emergency Service, Hospital ; Endosonography/methods ; Hemoperitoneum/diagnostic imaging ; Humans ; Image Enhancement/methods ; Image Interpretation, Computer-Assisted/methods ; Life Support Care/methods ; Lung/diagnostic imaging ; Ultrasonography/*methods ; Wounds, Nonpenetrating/diagnostic imaging ; }, abstract = {Focused ultrasound is a key methodology of critical care medicine. By referencing few ultrasound differential diagnosis, it is possible to identifying in real-time the reason of the critical state of a patient. Therefore typical focused ultrasound protocols were developed. The well known Focused Assessment with Sonography for trauma (FAST) was incorporated into the Advanced Trauma Life Support (ATLS) for shock room. Focused echocardiographic evaluation in life support (FEEL) has been designed to be conformed with the universal Advanced Life Support (ALS) algorithm and to identify treatable conditions such as acute right ventricular pressure overload in pulmonary embolism, hypovolemia, or pericardial effusion/tamponade. Using lung ultrasound one can differentiate pulmonary edema, pleural effusion or pneumothorax.}, }
@article {pmid22944662, year = {2012}, author = {Sephton, CF and Cenik, B and Cenik, BK and Herz, J and Yu, G}, title = {TDP-43 in central nervous system development and function: clues to TDP-43-associated neurodegeneration.}, journal = {Biological chemistry}, volume = {393}, number = {7}, pages = {589-594}, pmid = {22944662}, issn = {1437-4315}, support = {P01 HL020948/HL/NHLBI NIH HHS/United States ; RC1 NS068697/NS/NINDS NIH HHS/United States ; R01 HL063762/HL/NHLBI NIH HHS/United States ; R37 HL063762/HL/NHLBI NIH HHS/United States ; R01 AG029547/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/growth &amp; development/metabolism/*physiology/*physiopathology ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/physiopathology ; RNA/metabolism ; Ribonucleoproteins/metabolism ; Spinal Cord/growth &amp; development/metabolism/*physiology/*physiopathology ; }, abstract = {From the earliest stages of embryogenesis and throughout life, transcriptional regulation is carefully orchestrated in order to generate, shape, and reshape the central nervous system (CNS). TAR DNA-binding protein 43 (TDP-43) is identified as a regulator of essential transcriptional events in the CNS. Evidence for its importance comes from the identification of TDP-43 protein aggregates and genetic mutations in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Efforts are being made to learn more about the biological function of TDP-43 and gain a better understanding of its role in neurodegeneration. TDP-43 RNA targets and protein interactions have now been identified, and in vivo evidence shows that TDP-43 is essential in CNS development and function. This review will highlight aspects of these findings.}, }
@article {pmid22939820, year = {2012}, author = {Tan, L and Yu, JT and Tan, L}, title = {The kynurenine pathway in neurodegenerative diseases: mechanistic and therapeutic considerations.}, journal = {Journal of the neurological sciences}, volume = {323}, number = {1-2}, pages = {1-8}, doi = {10.1016/j.jns.2012.08.005}, pmid = {22939820}, issn = {1878-5883}, mesh = {Aging/metabolism ; Alzheimer Disease/drug therapy/metabolism/prevention &amp; control ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Enzyme Inhibitors/pharmacology/therapeutic use ; Humans ; Huntington Disease/drug therapy/metabolism ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Inflammation/metabolism ; Kynurenic Acid/antagonists &amp; inhibitors/metabolism ; Kynurenine/analogs &amp; derivatives/*metabolism/pharmacology/therapeutic use ; Microglia/metabolism ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*metabolism/prevention &amp; control ; Neurons/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Neurotoxins/metabolism ; Parkinson Disease/drug therapy/metabolism/prevention &amp; control ; Quinolinic Acid/antagonists &amp; inhibitors/metabolism ; Receptors, G-Protein-Coupled/drug effects/physiology ; Receptors, N-Methyl-D-Aspartate/drug effects/physiology ; Tryptophan/metabolism ; }, abstract = {The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of many metabolites including kynurenic acid (KYNA), quinolinic acid (QUIN), 3-hydroxykynurenine (3-HK) and picolinic acid (PIC). The former two are neuroactive, while the latter two are molecules with pro-oxidants and antioxidants properties. These agents are considered to be involved in aging and numerous neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Several studies have demonstrated that altered kynurenine metabolism plays an important role in the pathogenesis of this group of diseases. The important metabolites and key enzymes show significant importance in those disorders. Both analogs of the neuroprotective metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. In this review we discuss the mechanistic and therapeutic considerations of KP in aging and the main neurodegenerative diseases and review the updated knowledge in this therapeutic field.}, }
@article {pmid22938097, year = {2012}, author = {Hölscher, C}, title = {Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection.}, journal = {CNS drugs}, volume = {26}, number = {10}, pages = {871-882}, pmid = {22938097}, issn = {1179-1934}, mesh = {Animals ; Clinical Trials, Phase II as Topic ; Glucagon-Like Peptide 1/*metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*pharmacology/*therapeutic use ; Randomized Controlled Trials as Topic ; Risk Factors ; }, abstract = {The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non-diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. Glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor-like properties to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza(®); NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta(®); Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.}, }
@article {pmid22920902, year = {2013}, author = {Crul, T and Toth, N and Piotto, S and Literati-Nagy, P and Tory, K and Haldimann, P and Kalmar, B and Greensmith, L and Torok, Z and Balogh, G and Gombos, I and Campana, F and Concilio, S and Gallyas, F and Nagy, G and Berente, Z and Gungor, B and Peter, M and Glatz, A and Hunya, A and Literati-Nagy, Z and Vigh, L and Hoogstra-Berends, F and Heeres, A and Kuipers, I and Loen, L and Seerden, JP and Zhang, D and Meijering, RA and Henning, RH and Brundel, BJ and Kampinga, HH and Koranyi, L and Szilvassy, Z and Mandl, J and Sumegi, B and Febbraio, MA and Horvath, I and Hooper, PL and Vigh, L}, title = {Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness.}, journal = {Current pharmaceutical design}, volume = {19}, number = {3}, pages = {309-346}, doi = {10.2174/138161213804143716}, pmid = {22920902}, issn = {1873-4286}, support = {MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Genetic Pleiotropy/*physiology ; Heat-Shock Proteins/*biosynthesis/chemistry/genetics ; Heat-Shock Response/*physiology ; Homeostasis/*physiology ; Humans ; Membrane Lipids/chemistry/genetics/metabolism ; Oximes/chemistry/*metabolism ; }, abstract = {According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.}, }
@article {pmid22918487, year = {2012}, author = {Collins, MP}, title = {The vasculitic neuropathies: an update.}, journal = {Current opinion in neurology}, volume = {25}, number = {5}, pages = {573-585}, doi = {10.1097/WCO.0b013e3283580432}, pmid = {22918487}, issn = {1473-6551}, mesh = {Animals ; Diagnosis, Differential ; Humans ; Infections/complications/diagnosis ; Peripheral Nervous System Diseases/classification/epidemiology/*pathology ; Vasa Nervorum/*pathology ; Vasculitis/classification/epidemiology/*pathology ; }, abstract = {PURPOSE OF REVIEW: Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies.<br><br>RECENT FINDINGS: A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV.<br><br>SUMMARY: Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA-associated and cryoglobulinemic vasculitis with neuropathy.}, }
@article {pmid22918486, year = {2012}, author = {Ludolph, AC and Brettschneider, J and Weishaupt, JH}, title = {Amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {25}, number = {5}, pages = {530-535}, doi = {10.1097/WCO.0b013e328356d328}, pmid = {22918486}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; Animals ; Biomarkers ; Frontotemporal Lobar Degeneration/genetics/pathology ; Humans ; Mutation/physiology ; }, abstract = {PURPOSE OF REVIEW: The field of amyotrophic lateral sclerosis (ALS) has seen a number of remarkable advances during recent years that will be summarized in this review.<br><br>RECENT FINDINGS: In particular, the progress in the molecular neuropathology with the discovery of pathogenic mutations in TAR DNA binding protein (TARDBP), fused in sarcoma (FUS), ubiquilin2 (UBQLN2) and most recently C9ORF72 (abbreviation for the open reading frame 72 on chromosome 9) has further substantiated the - clinically temporarily forgotten - relation of classic ALS to frontotemporal degeneration (FTD). Also, major progress has been made by the discovery of genes relevant for the disease, and pathogenetic concepts have been suggested which imply that not one, but multiple genetic and cell biological hits are involved in the causation of the disease. Progress in interventional therapies has remained poor; important recent examples are the failure of the interventional lithium and pioglitazone trials. However, a study of a third interventional compound - dexpramipexol - raises substantial hopes that the class of chemicals originally represented by riluzole - benzothiazoles - may provide additional therapeutic progress for ALS patients.<br><br>SUMMARY: Tremendous progress has been made in the field of ALS based on recent neuropathological and genetic discoveries. Moreover, the role of metabolism and nutrition in the pathogenesis of the disease is debated and may potentially serve as a future therapeutic target. For the facilitation and cost reduction of clinical trials, the development and international standardization of disease-specific 'wet' and 'dry' biomarkers is essential.}, }
@article {pmid22907948, year = {2013}, author = {Aoun, SM and Bentley, B and Funk, L and Toye, C and Grande, G and Stajduhar, KJ}, title = {A 10-year literature review of family caregiving for motor neurone disease: moving from caregiver burden studies to palliative care interventions.}, journal = {Palliative medicine}, volume = {27}, number = {5}, pages = {437-446}, doi = {10.1177/0269216312455729}, pmid = {22907948}, issn = {1477-030X}, mesh = {Caregivers/*psychology ; Cost of Illness ; Family/psychology ; Humans ; Motor Neuron Disease/*nursing/psychology ; Palliative Care/*methods/psychology ; Quality of Life ; Social Support ; *Stress, Psychological ; }, abstract = {BACKGROUND: There is growing awareness that different terminal diseases translate into different family caregiver experiences, and the palliative and supportive care needs of these families are both similar and unique. Family members caring for people with motor neurone disease may experience exceptional strain due to the usually rapid and progressive nature of this terminal illness.<br><br>AIM: The purpose of this review is to synthesize contemporary research and provide a comprehensive summary of findings relevant to motor neurone disease family caregivers, as well as highlight some of the suggested interventions to alleviate burden and improve quality of life for this group.<br><br>DESIGN: We conducted a comprehensive review of empirical research on family caregiving for people with motor neurone disease in peer-reviewed journals published in English, January 2000-April 2011. Fifty-nine studies met the inclusion criteria.<br><br>RESULTS: This comprehensive literature review was consistent with previous research documenting the substantial burden and distress experienced by motor neurone disease family caregivers and revealed important points in the trajectory of care that have the potential for negative effects. The diagnosis experience, assisted ventilation, cognitive changes and end-of-life decision making create challenges within a short time. This review has also implicated the need for improvements in access to palliative care services and highlighted the absence of interventions to improve care.<br><br>CONCLUSIONS: Caregiver burden and quality-of-life studies on motor neurone disease family caregivers have so far dominated the research landscape .The focus needs to be on developing interventions that provide direct practical and psychosocial supports for motor neurone disease family caregivers.}, }
@article {pmid22907221, year = {2012}, author = {Gruis, KL and Lechtzin, N}, title = {Respiratory therapies for amyotrophic lateral sclerosis: a primer.}, journal = {Muscle &amp; nerve}, volume = {46}, number = {3}, pages = {313-331}, doi = {10.1002/mus.23282}, pmid = {22907221}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Evidence-Based Medicine ; Humans ; Respiratory Insufficiency/etiology/*therapy ; Respiratory Therapy/adverse effects/*methods ; }, abstract = {Respiratory complications are a common cause of morbidity and mortality in amyotrophic lateral sclerosis (ALS). Treatment of respiratory insufficiency with noninvasive ventilation (NIV) improves ALS patients' quality of life and survival. Evidence-based practice guidelines for the management of ALS patients recommend treatment of respiratory insufficiency with NIV as well as consideration of insufflation/exsufflation to improve clearance of airway secretions. Despite these recommendations respiratory therapies remain underused. In this review we provide a practical guide for the clinician to prescribe and manage respiratory therapies for the patient with ALS.}, }
@article {pmid22903397, year = {2012}, author = {Al-Chalabi, A and Jones, A and Troakes, C and King, A and Al-Sarraj, S and van den Berg, LH}, title = {The genetics and neuropathology of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {124}, number = {3}, pages = {339-352}, doi = {10.1007/s00401-012-1022-4}, pmid = {22903397}, issn = {1432-0533}, support = {G1100695/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/genetics/pathology ; Genetic Predisposition to Disease ; Humans ; Motor Neurons/*pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.}, }
@article {pmid22899644, year = {2013}, author = {He, F and Balling, R}, title = {The role of regulatory T cells in neurodegenerative diseases.}, journal = {Wiley interdisciplinary reviews. Systems biology and medicine}, volume = {5}, number = {2}, pages = {153-180}, doi = {10.1002/wsbm.1187}, pmid = {22899644}, issn = {1939-005X}, mesh = {Animals ; Biomedical Research ; Cytokines/immunology ; Humans ; Mice ; Neurodegenerative Diseases/*immunology ; Neurotransmitter Agents/immunology ; Systems Biology ; T-Lymphocytes, Regulatory/*immunology ; }, abstract = {A sustained neuroinflammatory response is the hallmark of many neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and HIV-associated neurodegeneration. A specific subset of T cells, currently recognized as FOXP3(+) CD25(+) CD4(+) regulatory T cells (Tregs), are pivotal in suppressing autoimmunity and maintaining immune homeostasis by mediating self-tolerance at the periphery as shown in autoimmune diseases and cancers. A growing body of evidence shows that Tregs are not only important for maintaining immune balance at the periphery but also contribute to self-tolerance and immune privilege in the central nervous system. In this article, we first review the current status of knowledge concerning the development and the suppressive function of Tregs. We then discuss the evidence supporting a dysfunction of Tregs in several neurodegenerative diseases. Interestingly, a dysfunction of Tregs is mainly observed in the early stages of several neurodegenerative diseases, but not in their chronic stages, pointing to a causative role of inflammation in the pathogenesis of neurodegenerative diseases. Furthermore, we provide an overview of a number of molecules, such as hormones, neuropeptides, neurotransmitters, or ion channels, that affect the dysfunction of Tregs in neurodegenerative diseases. We also emphasize the effects of the intestinal microbiome on the induction and function of Tregs and the need to study the crosstalk between the enteric nervous system and Tregs in neurodegenerative diseases. Finally, we point out the need for a systems biology approach in the analysis of the enormous complexity regulating the function of Tregs and their potential role in neurodegenerative diseases.}, }
@article {pmid22899188, year = {2012}, author = {De Chiara, G and Marcocci, ME and Sgarbanti, R and Civitelli, L and Ripoli, C and Piacentini, R and Garaci, E and Grassi, C and Palamara, AT}, title = {Infectious agents and neurodegeneration.}, journal = {Molecular neurobiology}, volume = {46}, number = {3}, pages = {614-638}, pmid = {22899188}, issn = {1559-1182}, mesh = {Animals ; Bacterial Infections/epidemiology ; Central Nervous System/microbiology/pathology/virology ; Humans ; Models, Biological ; Nerve Degeneration/epidemiology/*microbiology/pathology/*virology ; Oxidative Stress ; Virus Diseases/epidemiology ; }, abstract = {A growing body of epidemiologic and experimental data point to chronic bacterial and viral infections as possible risk factors for neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Infections of the central nervous system, especially those characterized by a chronic progressive course, may produce multiple damage in infected and neighbouring cells. The activation of inflammatory processes and host immune responses cause chronic damage resulting in alterations of neuronal function and viability, but different pathogens can also directly trigger neurotoxic pathways. Indeed, viral and microbial agents have been reported to produce molecular hallmarks of neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in synergy with other recognized risk factors, such as aging, concomitant metabolic diseases and the host's specific genetic signature. This review will focus on the contribution given to neurodegeneration by herpes simplex type-1, human immunodeficiency and influenza viruses, and by Chlamydia pneumoniae.}, }
@article {pmid22894036, year = {2012}, author = {Kruger, D}, title = {Amyotrophic lateral sclerosis.}, journal = {JAAPA : official journal of the American Academy of Physician Assistants}, volume = {25}, number = {7}, pages = {53-54}, doi = {10.1097/01720610-201207000-00013}, pmid = {22894036}, issn = {1547-1896}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Humans ; }, }
@article {pmid22892863, year = {2012}, author = {Yamanaka, M and Miyoshi, Y and Ohide, H and Hamase, K and Konno, R}, title = {D-Amino acids in the brain and mutant rodents lacking D-amino-acid oxidase activity.}, journal = {Amino acids}, volume = {43}, number = {5}, pages = {1811-1821}, doi = {10.1007/s00726-012-1384-x}, pmid = {22892863}, issn = {1438-2199}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Animals ; Behavior, Animal/physiology ; Brain/*metabolism/physiopathology ; D-Amino-Acid Oxidase/*deficiency/genetics ; D-Aspartic Acid/*metabolism ; Humans ; Mice ; Mice, Knockout ; Neurotransmitter Agents/*metabolism ; Rats ; Receptors, N-Methyl-D-Aspartate/metabolism ; Schizophrenia/genetics/metabolism/physiopathology ; Serine/*metabolism ; Stereoisomerism ; Synaptic Transmission/physiology ; }, abstract = {D-Amino acids are stereoisomers of L-amino acids. They are often called unnatural amino acids, but several D-amino acids have been found in mammalian brains. Among them, D-serine is abundant in the forebrain and functions as a co-agonist of NMDA receptors to enhance neurotransmission. D-Amino-acid oxidase (DAO), which degrades neutral and basic D-amino acids, is mainly present in the hindbrain. DAO catabolizes D-serine and, therefore, modulates neurotransmission. In the brains of mutant mice and rats lacking DAO activity, the amounts of D-serine and other D-amino acids are markedly increased. Mutant mice manifested behavioral changes characteristic of altered NMDA receptor activity, likely due to increased levels of D-serine. D-Serine and DAO have been demonstrated to play important roles in cerebellar development and synaptic plasticity. They have also implicated in amyotrophic lateral sclerosis and pain response. There have also been several lines of evidence correlating DAO with schizophrenia. Taken together, the experiments indicate that D-amino acids and DAO have pivotal functions in the central nervous system.}, }
@article {pmid22892641, year = {2012}, author = {Costa, J and Swash, M and de Carvalho, M}, title = {Awaji criteria for the diagnosis of amyotrophic lateral sclerosis:a systematic review.}, journal = {Archives of neurology}, volume = {69}, number = {11}, pages = {1410-1416}, doi = {10.1001/archneurol.2012.254}, pmid = {22892641}, issn = {1538-3687}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Databases, Factual/statistics &amp; numerical data ; Electrodiagnosis/*methods/*standards ; Electroencephalography ; Electromyography ; Humans ; Odds Ratio ; Sensitivity and Specificity ; }, abstract = {OBJECTIVE: To estimate the potential diagnostic added value of the Awaji criteria for diagnosis of a myotrophiclateral sclerosis (ALS), which have been compared with the previously accepted gold standard the revised El Escorial criteria in several studies.<br><br>DATA SOURCES: MEDLINE and Web of Science (until October2011).<br><br>STUDY SELECTION: We searched for studies testing the diagnostic accuracy of the Awaji criteria vs the revised El Escorial criteria in patients referred with suspected ALS.<br><br>DATA EXTRACTION: Evaluation and data extraction of identified studies were done independently. The Quality Assessment of Diagnostic Accuracy Studies list was used to assess study quality. We determined the proportion of patients classified as having probable/definite ALS and derived indices of diagnostic performance(sensitivity, specificity, and diagnostic odds ratio). Quantitative data synthesis was accomplished through random-effects meta-analysis, and heterogeneity was assessed with the I2 test.<br><br>DATA SYNTHESIS: Eight studies were included (3 prospective and 5 retrospective) enrolling 1187 patients. Application of Awaji criteria led to a 23% (95% CI, 12% to 33%; I2=84%) increase in the proportion of patients classified as having probable/definite ALS. Diagnostic performance of the Awaji criteria was higher than the revised El Escorial criteria (pooled sensitivity: 81.1% [95%CI, 72.2% to 90.0%; I2=91%] vs 62.2% [95% CI, 49.4%to 75.1%; I2=93%]; pooled diagnostic odds ratio, 35.8[95% CI, 15.2 to 84.7; I2=3%] vs 8.7 [95% CI, 2.2 to 35.6;I2=50%]). Diagnostic accuracy of Awaji criteria was higher in bulbar- than in limb-onset cases.<br><br>CONCLUSION: The Awaji criteria have a significant clinical impact allowing earlier diagnosis and clinical trial entry in ALS.}, }
@article {pmid22890612, year = {2012}, author = {Paul, P and de Belleroche, J}, title = {The role of D-amino acids in amyotrophic lateral sclerosis pathogenesis: a review.}, journal = {Amino acids}, volume = {43}, number = {5}, pages = {1823-1831}, doi = {10.1007/s00726-012-1385-9}, pmid = {22890612}, issn = {1438-2199}, support = {DEBELLEROCHE/MAR10/6064/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Animals ; Brain/*metabolism/physiopathology ; D-Amino-Acid Oxidase/genetics/*metabolism ; Disease Progression ; Gene Expression ; Humans ; Mice ; Neurotransmitter Agents/*metabolism ; Racemases and Epimerases/genetics/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Serine/*metabolism ; Spinal Cord/*metabolism/physiopathology ; Stereoisomerism ; Synaptic Transmission ; }, abstract = {A potential role for D-amino acids in motor neuron disease/amyotrophic lateral sclerosis (ALS) is emerging. D-Serine, which is an activator/co-agonist at the N-methyl-D-aspartate glutamate receptor subtype, is elevated both in spinal cord from sporadic cases of ALS and in an animal model of ALS. Furthermore, we have shown that a mutation in D-amino acid oxidase (DAO), an enzyme strongly localized to spinal cord motor neurons and brain stem motor nuclei, is associated with familial ALS. DAO plays an important role in regulating levels of D-serine, and its function is impaired by the presence of this mutation and this may contribute to the pathogenic process in ALS. In sporadic ALS cases, elevated D-serine may arise from induction of serine racemase, its synthetic enzyme, caused by cell stress and inflammatory processes thought to contribute to disease progression. Both these abnormalities in D-serine metabolism lead to an increase in synaptic D-serine which may contribute to disease pathogenesis.}, }
@article {pmid22890216, year = {2012}, author = {Cooper-Knock, J and Kirby, J and Ferraiuolo, L and Heath, PR and Rattray, M and Shaw, PJ}, title = {Gene expression profiling in human neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {8}, number = {9}, pages = {518-530}, pmid = {22890216}, issn = {1759-4766}, support = {MR/K003771/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Gene Expression Profiling/*methods/trends ; Genetic Predisposition to Disease/*genetics ; Genomics/*methods/trends ; Humans ; Neurodegenerative Diseases/*genetics ; }, abstract = {Transcriptome study in neurodegenerative disease has advanced considerably in the past 5 years. Increasing scientific rigour and improved analytical tools have led to more-reproducible data. Many transcriptome analysis platforms assay the expression of the entire genome, enabling a complete biological context to be captured. Gene expression profiling (GEP) is, therefore, uniquely placed to discover pathways of disease pathogenesis, potential therapeutic targets, and biomarkers. This Review summarizes microarray human GEP studies in the common neurodegenerative diseases amyotrophic lateral sclerosis (ALS), Parkinson disease (PD) and Alzheimer disease (AD). Several interesting reports have compared pathological gene expression in different patient groups, disease stages and anatomical areas. In all three diseases, GEP has revealed dysregulation of genes related to neuroinflammation. In ALS and PD, gene expression related to RNA splicing and protein turnover is disrupted, and several studies in ALS support involvement of the cytoskeleton. GEP studies have implicated the ubiquitin-proteasome system in PD pathogenesis, and have provided evidence of mitochondrial dysfunction in PD and AD. Lastly, in AD, a possible role for dysregulation of intracellular signalling pathways, including calcium signalling, has been highlighted. This Review also provides a discussion of methodological considerations in microarray sample preparation and data analysis.}, }
@article {pmid22886346, year = {2012}, author = {Billard, JM}, title = {D-Amino acids in brain neurotransmission and synaptic plasticity.}, journal = {Amino acids}, volume = {43}, number = {5}, pages = {1851-1860}, doi = {10.1007/s00726-012-1346-3}, pmid = {22886346}, issn = {1438-2199}, mesh = {Animals ; Brain/*metabolism/physiopathology ; D-Amino-Acid Oxidase/metabolism ; D-Aspartic Acid/metabolism ; Humans ; Nervous System Diseases/*metabolism/physiopathology ; Neuronal Plasticity/*physiology ; Neurons/metabolism ; Neurotransmitter Agents/metabolism ; Racemases and Epimerases/metabolism ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Serine/metabolism ; Stereoisomerism ; Synapses/*metabolism ; Synaptic Transmission/*physiology ; }, abstract = {Far from our initial view of D-amino acids as being limited to invertebrates, they are now considered active molecules at synapses of mammalian central and peripheral nervous systems, capable of modulating synaptic communication within neuronal networks. In particular, experimental data accumulated in the last few decades show that through the regulation of glutamatergic neurotransmission, D-serine influences the functional plasticity of cerebral circuitry throughout life. In addition, the modulation of NMDA-R-dependent signalling by D-aspartate has been demonstrated by pharmacological studies and after the targeted deletion of the D-aspartate-degrading enzyme. Considering the major contribution of the glutamatergic system to a wide range of neurological disorders such as schizophrenia, Alzheimer's disease and amyotrophic lateral sclerosis, an improved understanding of the mechanisms of D-amino-acid-dependent neuromodulation will certainly offer new insights for the development of relevant strategies to treat these neurological diseases.}, }
@article {pmid22878865, year = {2012}, author = {Halliday, G and Bigio, EH and Cairns, NJ and Neumann, M and Mackenzie, IR and Mann, DM}, title = {Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects.}, journal = {Acta neuropathologica}, volume = {124}, number = {3}, pages = {373-382}, pmid = {22878865}, issn = {1432-0533}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; P50 AG05681/AG/NIA NIH HHS/United States ; 089701/WT_/Wellcome Trust/United Kingdom ; P30 AG13854/AG/NIA NIH HHS/United States ; 74580/CAPMC/CIHR/Canada ; P01 AG03991/AG/NIA NIH HHS/United States ; 179009/CAPMC/CIHR/Canada ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, mesh = {Brain/metabolism/*pathology ; Frontotemporal Lobar Degeneration/*genetics/metabolism/pathology ; Humans ; Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/*pathology ; tau Proteins/*genetics/metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5-10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.}, }
@article {pmid22873722, year = {2012}, author = {Bhutani, H and Anand, A}, title = {Biomarkers in amyotrophic lateral sclerosis: is there a neurovascular pathway?.}, journal = {Current neurovascular research}, volume = {9}, number = {4}, pages = {302-309}, doi = {10.2174/156720212803530654}, pmid = {22873722}, issn = {1875-5739}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology/physiopathology ; Animals ; Biomarkers/metabolism ; Cell Hypoxia/physiology ; Humans ; Neurons/*pathology ; Oxidative Stress/physiology ; Signal Transduction/*physiology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {The establishment of a link between VEGF, hypoxia and ALS pathogenesis placed angiogenic factors and oxidative stress at the focal point for further studies. Recreation of a phenotype strikingly similar to that of mutant SOD1 mouse and human ALS, like muscle weakness and atrophy owing to lower motor neuron degeneration was observed following the targeted deletion of the hypoxia response element (HRE) from promoter of mouse vascular endothelial growth factor (VEGF). The crucial link between vasculature, angiogenic molecules and motor neuron degeneration has thus been constantly scrutinized. In this review, we have proposed to correlate human, in vitro and cadaveric studies so as to find out whether molecules like VEGF and various others, at the interface of neurovascular network and oxidative stress, have a prognostic, diagnostic and therapeutic potential for treatment of a fatal neurodegenerative disorder namely ALS.}, }
@article {pmid22873563, year = {2012}, author = {Blasco, H and Guennoc, AM and Veyrat-Durebex, C and Gordon, PH and Andres, CR and Camu, W and Corcia, P}, title = {Amyotrophic lateral sclerosis: a hormonal condition?.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {6}, pages = {585-588}, doi = {10.3109/17482968.2012.706303}, pmid = {22873563}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; Endocrine System Diseases/*complications ; Female ; Hormones/*metabolism ; Humans ; Male ; Sex Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disorder in adults. This fatal condition, due to degeneration of upper and lower motor neurons in spinal and bulbar myotomes, leads to death from respiratory failure after median disease duration of 36 months. ALS is sporadic in more than 90% of cases and familial in the remaining cases. Most studies show male predominance with a gender ratio of 3:2, but gender differences are age related. The phenotype of ALS is also different in males and females with a predominance of limb onset in males and bulbar onset in females. While age and site of onset impact survival rate, and are both related to gender, gender by itself has not clearly been shown to have an effect on survival. Given this complex relationship between gender and ALS, we developed a hypothesis about hormone involvement in ALS aetiology by suggesting protective effect of oestrogens and adverse effect of androgens.}, }
@article {pmid22873562, year = {2012}, author = {, }, title = {ALS untangled No. 17: "when ALS is lyme".}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {5}, pages = {487-491}, doi = {10.3109/17482968.2012.717796}, pmid = {22873562}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Cohort Studies ; Diagnosis, Differential ; Humans ; Lyme Disease/*diagnosis/physiopathology ; }, }
@article {pmid22868885, year = {2012}, author = {Abe, K and Ikeda, Y}, title = {[Spinocerebellar ataxia type 36 (nicknamed Asidan)].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {8}, pages = {937-941}, pmid = {22868885}, issn = {1881-6096}, mesh = {Age of Onset ; DNA Mutational Analysis ; Humans ; Introns/*genetics ; Nuclear Proteins/genetics ; Spinocerebellar Ataxias/*genetics/*pathology/physiopathology ; Trinucleotide Repeat Expansion ; }, abstract = {We report the phenotype of spinocerebellar ataxia type 36 (SCA36), which is a novel type of dominant cerebellar ataxia nicknamed as "Asidan," caused by the expansion of a hexanucleotide GGCCTG repeat in intron 1 of the nucleolar protein 56 (NOP56) gene. Age at the onset of ataxia was 53.1 (3.4) years (mean[SD]). Truncal ataxia was the most frequent initial symptom (100%), followed by ataxic dysarthria (100%), limb ataxia (93%), and general hyperreflexia (79%). Tongue fasciculation and subsequent atrophy were observed in 71% of the cases, especially in those of a longer duration. Skeletal muscle fasciculation and atrophy in the limbs and trunk were also observed in 57% of the cases. To our knowledge, we describe for the first time a unique clinical feature of Asidan (SCA36)--relatively pure cerebellar ataxia with progressive motor neuron involvement during the course of disease-that puts SCA36 at the crossroad of SCA and amyotrophic lateral sclerosis.}, }
@article {pmid22849988, year = {2012}, author = {Ando, T}, title = {[Diagnosis and management of cervical spondylosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {52}, number = {7}, pages = {469-479}, doi = {10.5692/clinicalneurol.52.469}, pmid = {22849988}, issn = {1882-0654}, mesh = {Diagnosis, Differential ; Humans ; Radiography ; Spondylosis/*diagnosis/diagnostic imaging/surgery ; }, abstract = {Cervical spondylosis, which can present as radiculopathy and myelopathy, is common in people over the age of 50. Since evidence of radiological spondylotic change is frequently found in many asymptomatic adults, it is necessary to assess whether neurological symptoms result from cervical spondylosis or other neurological disorders. In order to avoid misdiagnosis, it is important to compare the levels of the lesions shown on imaging with the clinical findings. Differential diagnosis between amyotrophic lateral sclerosis and cervical spondylotic myelopathy is an issue of major clinical importance. Though the course of disease development and the ultimate prognosis for patients with cervical spondylosis is highly variable and extremely difficult to predict, many patients experience a relatively benign form of the disease.}, }
@article {pmid22841860, year = {2012}, author = {Walsh, FS and Rutkowski, JL}, title = {Myostatin as a therapeutic target in Amyotrophic lateral sclerosis.}, journal = {Neurochemistry international}, volume = {61}, number = {6}, pages = {931-935}, doi = {10.1016/j.neuint.2012.07.016}, pmid = {22841860}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Antibodies, Monoclonal/*immunology ; Clinical Trials as Topic ; Humans ; Myostatin/*drug effects/immunology ; }, abstract = {Amyotrophic Lateral Sclerosis is a devastating neurological disease that is inevitably fatal after 3-5years duration. Treatment options are minimal and as such new therapeutic modalities are required. In this review, we discuss the role of the myostatin pathway as a modulator of skeletal muscle mass and therapeutic approaches using biological based therapies. Both monoclonal antibodies to myostatin and a soluble receptor decoy to its high affinity receptor have been used in clinical trials of neuromuscular diseases and while there have been efficacy signals with the latter approach there have also been safety issues. Our approach is to target the high affinity receptor-binding site on myostatin and to develop a next generation set of therapeutic reagents built on a novel protein scaffold. This is the natural single domain VNAR found in sharks which is extremely versatile and has the ability to develop products with superior properties compared to existing therapeutics.}, }
@article {pmid22840436, year = {2013}, author = {Allen, JA and Currey, J and Considine, J}, title = {Annual resuscitation competency assessments: a review of the evidence.}, journal = {Australian critical care : official journal of the Confederation of Australian Critical Care Nurses}, volume = {26}, number = {1}, pages = {12-17}, doi = {10.1016/j.aucc.2012.07.001}, pmid = {22840436}, issn = {1036-7314}, mesh = {Advanced Trauma Life Support Care ; Australia ; *Clinical Competence ; Critical Care Nursing/*standards ; Humans ; *Resuscitation/education ; }, abstract = {BACKGROUND: Australian critical care nurses generally undertake assessment of resuscitation competencies on an annual or biannual basis. International resuscitation evidence and guidelines released in 2010 do not support this practice, instead advocating more frequent retraining.<br><br>AIM: To review the evidence for annual assessment of resuscitation knowledge and skills, and for the efficacy of resuscitation training practices.<br><br>METHODS: A search of the Medline and CINAHL databases was conducted using the key search words/terms 'resuscitation' 'advanced life support' 'advanced cardiac life support' 'assessment' 'cardiac arrest', 'in-hospital cardiac arrest', 'competence', 'training', 'ALS', 'ACLS' 'course' and 'competency'. The search was limited to English language publications produced during the last 10 years. The International Liaison Committee On Resuscitation worksheets were reviewed for key references, as were the reference lists of articles from the initial search.<br><br>RESULTS: There is little evidence to support the current practice of annual resuscitation competency assessments. Theoretical knowledge has no correlation with resuscitation performance, and current practical assessment methods are problematic. Both knowledge and skills decline well before the 12-month mark. There is emerging support in the literature for frequent practice sessions using simulation technology.<br><br>CONCLUSION: The current practice of annual assessments is not supported by evidence. Emerging evidence for regular resuscitation practice is not conclusive, but it is likely to produce better outcomes. Changing practice in Australia also represents an opportunity to generate data to inform practice further.}, }
@article {pmid22836461, year = {2012}, author = {Rocha, AJ and Maia Júnior, AC}, title = {Is magnetic resonance imaging a plausible biomarker for upper motor neuron degeneration in amyotrophic lateral sclerosis/primary lateral sclerosis or merely a useful paraclinical tool to exclude mimic syndromes? A critical review of imaging applicability in clinical routine.}, journal = {Arquivos de neuro-psiquiatria}, volume = {70}, number = {7}, pages = {532-539}, doi = {10.1590/s0004-282x2012000700012}, pmid = {22836461}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology ; Biomarkers ; Disease Progression ; Humans ; Magnetic Resonance Imaging/*methods ; Magnetic Resonance Spectroscopy/methods ; Motor Neuron Disease/*diagnosis/pathology ; Motor Neurons/pathology ; Sensitivity and Specificity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the cerebral cortex, brainstem, and spinal cord, brain regions in which conventional magnetic resonance imaging is often uninformative. Although the mean time from symptom onset to diagnosis is estimated to be about one year, the current criteria only prescribe magnetic resonance imaging to exclude "ALS mimic syndromes". Extensive application of non-conventional magnetic resonance imaging (MRI) to the study of ALS has improved our understanding of the in vivo pathological mechanisms involved in the disease. These modern imaging techniques have recently been added to the list of potential ALS biomarkers to aid in both diagnosis and monitoring of disease progression. This article provides a comprehensive review of the clinical applicability of the neuroimaging progress that has been made over the past two decades towards establishing suitable diagnostic tools for upper motor neuron (UMN) degeneration in ALS.}, }
@article {pmid22835154, year = {2012}, author = {Schymick, JC and Traynor, BJ}, title = {Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {4}, pages = {30}, pmid = {22835154}, issn = {1758-9193}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration.}, }
@article {pmid22831893, year = {2012}, author = {Riccio, A and Mattia, D and Simione, L and Olivetti, M and Cincotti, F}, title = {Eye-gaze independent EEG-based brain-computer interfaces for communication.}, journal = {Journal of neural engineering}, volume = {9}, number = {4}, pages = {045001}, doi = {10.1088/1741-2560/9/4/045001}, pmid = {22831893}, issn = {1741-2552}, mesh = {*Auditory Perception/physiology ; *Brain-Computer Interfaces ; *Communication ; Electroencephalography/*methods ; Fixation, Ocular/physiology ; Humans ; *Touch/physiology ; *Visual Perception/physiology ; }, abstract = {The present review systematically examines the literature reporting gaze independent interaction modalities in non-invasive brain-computer interfaces (BCIs) for communication. BCIs measure signals related to specific brain activity and translate them into device control signals. This technology can be used to provide users with severe motor disability (e.g. late stage amyotrophic lateral sclerosis (ALS); acquired brain injury) with an assistive device that does not rely on muscular contraction. Most of the studies on BCIs explored mental tasks and paradigms using visual modality. Considering that in ALS patients the oculomotor control can deteriorate and also other potential users could have impaired visual function, tactile and auditory modalities have been investigated over the past years to seek alternative BCI systems which are independent from vision. In addition, various attentional mechanisms, such as covert attention and feature-directed attention, have been investigated to develop gaze independent visual-based BCI paradigms. Three areas of research were considered in the present review: (i) auditory BCIs, (ii) tactile BCIs and (iii) independent visual BCIs. Out of a total of 130 search results, 34 articles were selected on the basis of pre-defined exclusion criteria. Thirteen articles dealt with independent visual BCIs, 15 reported on auditory BCIs and the last six on tactile BCIs, respectively. From the review of the available literature, it can be concluded that a crucial point is represented by the trade-off between BCI systems/paradigms with high accuracy and speed, but highly demanding in terms of attention and memory load, and systems requiring lower cognitive effort but with a limited amount of communicable information. These issues should be considered as priorities to be explored in future studies to meet users' requirements in a real-life scenario.}, }
@article {pmid22828277, year = {2012}, author = {Andreu, CI and Woehlbier, U and Torres, M and Hetz, C}, title = {Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications.}, journal = {FEBS letters}, volume = {586}, number = {18}, pages = {2826-2834}, doi = {10.1016/j.febslet.2012.07.023}, pmid = {22828277}, issn = {1873-3468}, mesh = {Biocatalysis ; Neurodegenerative Diseases/*enzymology ; Protein Disulfide-Isomerases/*metabolism ; }, abstract = {Protein disulfide isomerases (PDIs) are a family of foldases and chaperones primarily located at the endoplasmic reticulum that catalyze the formation and isomerization of disulfide bonds thereby facilitating protein folding. PDIs also perform important physiological functions in protein quality control, cell death, and cell signaling. Protein misfolding is involved in the etiology of the most common neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, Prion-related disorders, among others. Accumulating evidence indicate altered expression of PDIs as a prominent and common feature of these neurodegenerative conditions. Here we overview most recent advances in our understanding of the possible functional contribution of PDIs to neurodegeneration, depicting a complex and poorly understood scenario. Possible therapeutic benefits of targeting PDIs in a disease context and their use as biomarkers are discussed.}, }
@article {pmid22827270, year = {2012}, author = {Song, CY and Guo, JF and Liu, Y and Tang, BS}, title = {Autophagy and Its Comprehensive Impact on ALS.}, journal = {The International journal of neuroscience}, volume = {122}, number = {12}, pages = {695-703}, doi = {10.3109/00207454.2012.714430}, pmid = {22827270}, issn = {1563-5279}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*physiopathology ; Autophagy/drug effects/*physiology ; Humans ; Immunosuppressive Agents/toxicity ; Microtubule-Associated Proteins/metabolism ; Mutation/genetics ; Sirolimus/toxicity ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Autophagy is a degradative modality that involves intracellular elimination of proteins and organelles by lysosomes. It is a conservative process and plays a crucial role in cell growth and development, and keeping cellular homeostasis especially under stress-induced situations. Recently, increasing evidence suggests that autophagic alternations may contribute to amyotrophic lateral sclerosis (ALS) as one of initial factors. LC3-II and p62 are found increased in spinal cord of both ALS patients and experimental models, indicating overwhelming autophagic level. But the aggregation of ALS-associated proteins, including SOD1 and TDP-43 suggest possible insufficiency of autophagy induction. Besides, augment autophagic level through genetic pathway or rapamycin leads to paradoxical results in different neurodegenerative diseases models. So, it remains controversial about autophagic effects on ALS progress. In this review, we will depict a comprehensive role that autophagy plays in ALS and focus on the influence of impaired autophagic flux and excessive autophagic vacuoles (AVs) that may aggregate ALS development. And we will discuss the potential therapeutic targets through modulating autophagic level to treat this disease.}, }
@article {pmid22819986, year = {2012}, author = {Poletti, M and Enrici, I and Adenzato, M}, title = {Cognitive and affective Theory of Mind in neurodegenerative diseases: neuropsychological, neuroanatomical and neurochemical levels.}, journal = {Neuroscience and biobehavioral reviews}, volume = {36}, number = {9}, pages = {2147-2164}, doi = {10.1016/j.neubiorev.2012.07.004}, pmid = {22819986}, issn = {1873-7528}, mesh = {Affect/*physiology ; Brain/*pathology ; Cognition/*physiology ; Humans ; Neurodegenerative Diseases/pathology/*psychology ; Theory of Mind/*physiology ; }, abstract = {The paper reviews of all of the current evidence on Theory of Mind (ToM) abilities in patients with neurodegenerative diseases. ToM refers to the abilities to attribute mental states to others. Two neural systems are involved in processing other people's beliefs and intentions (cognitive component) and others' emotions and feelings (affective component). We hypothesize that patients with different neurodegenerative diseases may present different patterns of ToM deficits on the basis of how different neuropathological processes affect the neural bases of ToM components during the progression of a disease. The studies we reviewed provided evidence of a deficit of the cognitive ToM component in cortical (Alzheimer's disease and frontotemporal dementia) and frontal-subcortical (amyotrophic lateral sclerosis and basal ganglia disorders) neurodegenerative diseases. As regards the affective ToM component, it resulted markedly impaired in frontotemporal dementia; it also resulted that performances in tasks assessing this process are heterogeneous in Parkinson's disease and amyotrophic lateral sclerosis. The findings presented support the opportunity to introduce validated ToM tasks in the neuropsychological assessment of neurodegenerative diseases.}, }
@article {pmid22819011, year = {2012}, author = {Singh, RK and Cooper, TA}, title = {Pre-mRNA splicing in disease and therapeutics.}, journal = {Trends in molecular medicine}, volume = {18}, number = {8}, pages = {472-482}, pmid = {22819011}, issn = {1471-499X}, support = {R01 AR045653/AR/NIAMS NIH HHS/United States ; R01 AR060733/AR/NIAMS NIH HHS/United States ; R01 HL045565/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Disease/*genetics ; *Genetic Therapy ; Humans ; Mutation ; RNA Precursors/*genetics/metabolism ; *RNA Splicing ; Spliceosomes/genetics/metabolism ; }, abstract = {In metazoans, alternative splicing of genes is essential for regulating gene expression and contributing to functional complexity. Computational predictions, comparative genomics, and transcriptome profiling of normal and diseased tissues indicate that an unexpectedly high fraction of diseases are caused by mutations that alter splicing. Mutations in cis elements cause missplicing of genes that alter gene function and contribute to disease pathology. Mutations of core spliceosomal factors are associated with hematolymphoid neoplasias, retinitis pigmentosa, and microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Mutations in the trans regulatory factors that control alternative splicing are associated with autism spectrum disorder, amyotrophic lateral sclerosis (ALS), and various cancers. In addition to discussing the disorders caused by these mutations, this review summarizes therapeutic approaches that have emerged to correct splicing of individual genes or target the splicing machinery.}, }
@article {pmid22817709, year = {2012}, author = {Wang, Y and Mandelkow, E}, title = {Degradation of tau protein by autophagy and proteasomal pathways.}, journal = {Biochemical Society transactions}, volume = {40}, number = {4}, pages = {644-652}, doi = {10.1042/BST20120071}, pmid = {22817709}, issn = {1470-8752}, support = {MC_G1000734/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Autophagy/*physiology ; Humans ; Proteasome Endopeptidase Complex/*metabolism ; Signal Transduction/physiology ; tau Proteins/*metabolism ; }, abstract = {Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. The impairment of protein-degradation systems might play a role in such processes, as these pathways normally keep tau levels at a low level which may prevent aggregation. Some proteases can process tau and thus contribute to tau aggregation by generating amyloidogenic fragments, but the complete clearance of tau mainly relies on the UPS (ubiquitin-proteasome system) and the ALS (autophagy-lysosome system). In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies.}, }
@article {pmid22817642, year = {2012}, author = {Boeve, BF and Graff-Radford, NR}, title = {Cognitive and behavioral features of c9FTD/ALS.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {4}, pages = {29}, pmid = {22817642}, issn = {1758-9193}, abstract = {Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders.}, }
@article {pmid22811764, year = {2012}, author = {Fujita, K and Yamafuji, M and Nakabeppu, Y and Noda, M}, title = {Therapeutic approach to neurodegenerative diseases by medical gases: focusing on redox signaling and related antioxidant enzymes.}, journal = {Oxidative medicine and cellular longevity}, volume = {2012}, number = {}, pages = {324256}, pmid = {22811764}, issn = {1942-0994}, mesh = {Animals ; Antioxidants/*metabolism ; Gases/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/*enzymology/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {Oxidative stress in the central nervous system is strongly associated with neuronal cell death in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In order to overcome the oxidative damage, there are some protective signaling pathways related to transcriptional upregulation of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD)-1/-2. Their expression is regulated by several transcription factors and/or cofactors like nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). These antioxidant enzymes are associated with, and in some cases, prevent neuronal death in animal models of neurodegenerative diseases. They are activated by endogenous mediators and phytochemicals, and also by several gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and hydrogen (H(2)). These might thereby protect the brain from severe oxidative damage and resultant neurodegenerative diseases. In this paper, we discuss how the expression levels of these antioxidant enzymes are regulated. We also introduce recent advances in the therapeutic uses of medical gases against neurodegenerative diseases.}, }
@article {pmid22808918, year = {2012}, author = {Fong, JC and Karydas, AM and Goldman, JS}, title = {Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {4}, pages = {27}, pmid = {22808918}, issn = {1758-9193}, abstract = {Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) are related but distinct neurodegenerative diseases. The identification of a hexanucleotide repeat expansion in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) gene as a common cause of FTD/ALS, familial FTD, and familial ALS marks the culmination of many years of investigation. This confirms the linkage of disease to chromosome 9 in large, multigenerational families with FTD and ALS, and it promotes deeper understanding of the diseases' shared molecular FTLD-TDP pathology. The discovery of the C9ORF72 repeat expansion has significant implications not only for familial FTD and ALS, but also for sporadic disease. Clinical and pathological correlates of the repeat expansion are being reported but remain to be refined, and a genetic test to detect the expansion has only recently become clinically available. Consequently, individuals and their families who are considering genetic testing for the C9ORF72 expansion should receive genetic counseling to discuss the risks, benefits, and limitations of testing. The following review aims to describe genetic counseling considerations for individuals at risk for a C9ORF72 repeat expansion.}, }
@article {pmid22801549, year = {2012}, author = {Kachaner, D and Génin, P and Laplantine, E and Weil, R}, title = {Toward an integrative view of Optineurin functions.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {11}, number = {15}, pages = {2808-2818}, doi = {10.4161/cc.20946}, pmid = {22801549}, issn = {1551-4005}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Apoptosis ; Biological Transport ; Cell Cycle Proteins ; Cell Division ; Glaucoma/*genetics ; Humans ; Membrane Transport Proteins ; NF-kappa B/metabolism ; Osteitis Deformans/*genetics ; Transcription Factor TFIIIA/genetics/*physiology ; }, abstract = {This review highlights recent advances in our understanding of the mechanisms of Optineurin (Optn) action and its implication in diseases. Optn has emerged as a key player regulating various physiological processes, including membrane trafficking, protein secretion, cell division and host defense against pathogens. Furthermore, there is growing evidence for an association of Optn mutations with human diseases such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget's disease of bone. Optn functions depend on its precise subcellular localization and its interaction with other proteins. Here, we review the mechanisms that allow Optn to ensure a timely and spatially coordinated integration of different physiological processes and discuss how their deregulation may lead to different pathologies.}, }
@article {pmid22797194, year = {2012}, author = {Bourassa, MW and Miller, LM}, title = {Metal imaging in neurodegenerative diseases.}, journal = {Metallomics : integrated biometal science}, volume = {4}, number = {8}, pages = {721-738}, pmid = {22797194}, issn = {1756-591X}, support = {P01 NS049134/NS/NINDS NIH HHS/United States ; R01 GM066873/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Diagnostic Imaging/methods ; Humans ; Mass Spectrometry/methods ; Metals/*analysis/metabolism ; Microscopy, Fluorescence/methods ; Neurodegenerative Diseases/*diagnosis/metabolism ; Spectrometry, X-Ray Emission/methods ; }, abstract = {Metal ions are known to play an important role in many neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases. In these diseases, aberrant metal binding or improper regulation of redox active metal ions can induce oxidative stress by producing cytotoxic reactive oxygen species (ROS). Altered metal homeostasis is also frequently seen in the diseased state. As a result, the imaging of metals in intact biological cells and tissues has been very important for understanding the role of metals in neurodegenerative diseases. A wide range of imaging techniques have been utilized, including X-ray fluorescence microscopy (XFM), particle induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), laser ablation inductively coupled mass spectrometry (LA-ICP-MS), and secondary ion mass spectrometry (SIMS), all of which allow for the imaging of metals in biological specimens with high spatial resolution and detection sensitivity. These techniques represent unique tools for advancing the understanding of the disease mechanisms and for identifying possible targets for developing treatments. In this review, we will highlight the advances in neurodegenerative disease research facilitated by metal imaging techniques.}, }
@article {pmid22776664, year = {2012}, author = {Wang, XN and Cui, LY}, title = {TAR DNA binding protein-43 and fused in sarcoma/translocated in liposarcoma protein in two neurodegenerative diseases.}, journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae}, volume = {34}, number = {3}, pages = {286-292}, doi = {10.3881/j.issn.1000-503X.2012.03.020}, pmid = {22776664}, issn = {1000-503X}, mesh = {*Amyotrophic Lateral Sclerosis ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia ; Humans ; Mutation ; RNA Processing, Post-Transcriptional ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {TAR DNA binding protein-43(TDP-43) and fused in sarcoma/translocated in liposarcoma protein (FUS/TLS) have been found to be associated with two neurodegenerative diseases - amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in TDP-43 and FUS/TLS lead to abnormal protein expressions, which result in altered RNA processing. The pathological changes of TDP-43 and FUS/TLS-associated ALS and FTD are similar. Although the interactions between ALS and FTD remain unknown, it is speculated that TDP-43 and FUS/TLS-associated neurodegenerative diseases may share similar pathogenesis.}, }
@article {pmid22763933, year = {2012}, author = {Jung, HH and Neumann, M and Bloch, KE}, title = {[Amyotrophic lateral sclerosis--diagnosis and treatment].}, journal = {Praxis}, volume = {101}, number = {14}, pages = {907-914}, doi = {10.1024/1661-8157/a000988}, pmid = {22763933}, issn = {1661-8157}, mesh = {Activities of Daily Living/classification ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/genetics/mortality ; Animals ; Cause of Death ; Cross-Sectional Studies ; DNA Mutational Analysis ; Diagnosis, Differential ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; Neurologic Examination ; Palliative Care ; Riluzole/administration &amp; dosage/adverse effects ; Spinal Cord/pathology ; Survival Analysis ; TDP-43 Proteinopathies/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents the most common motoneuron disorder in adulthood. It is characterized by selective degeneration of the motoneurons. About 10% of patients have a genetically determined ALS. Clinically, ALS is characterized by coexistence of signs of the first motoneuron, such as spasticity and hyperreflexia, as well as the second motoneuron, such as muscular atrophy and fasciculations. If such signs are present in at least three regions and if other possible causes have been excluded, a definite diagnosis of ALS can be made based on the revised El-Escorial criteria. Initial manifestations are often focalized and generalization develops during the course. The glutamate antagonist riluzole is worldwide the only approved ALS treatment. However, symptomatic treatments to ameliorate spasticity, drooling, speech and swallowing problems, and assisted ventilation to treat respiratory failure are essential.}, }
@article {pmid22755265, year = {2012}, author = {Vinceti, M and Bottecchi, I and Fan, A and Finkelstein, Y and Mandrioli, J}, title = {Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis?.}, journal = {Reviews on environmental health}, volume = {27}, number = {1}, pages = {19-41}, doi = {10.1515/reveh-2012-0002}, pmid = {22755265}, issn = {0048-7554}, mesh = {Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Cadmium/analysis/toxicity ; Environmental Exposure/*adverse effects/statistics &amp; numerical data ; Environmental Pollutants/*toxicity ; Humans ; Lead Poisoning ; Mercury Poisoning ; Metals, Heavy/analysis/*toxicity ; Occupational Exposure/adverse effects/statistics &amp; numerical data ; Pesticides/analysis/*toxicity ; Risk Factors ; Selenium/analysis/*toxicity ; }, abstract = {The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.}, }
@article {pmid22751173, year = {2013}, author = {Gendron, TF and Rademakers, R and Petrucelli, L}, title = {TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {33 Suppl 1}, number = {Suppl 1}, pages = {S35-45}, pmid = {22751173}, issn = {1875-8908}, support = {R21 NS074121-01/NS/NINDS NIH HHS/United States ; R21 NS074121/NS/NINDS NIH HHS/United States ; R01 NS 063964-01/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; R01AG026251/AG/NIA NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; }, mesh = {Brain/pathology ; DNA Mutational Analysis ; DNA-Binding Proteins/*genetics ; Humans ; Mutation ; TDP-43 Proteinopathies/*genetics/pathology ; }, abstract = {The identification of TAR DNA-binding protein 43 (TDP-43) as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions has defined a new class of neurodegenerative conditions: the TDP-43 proteinopathies. This breakthrough was quickly followed by mutation analysis of TARDBP, the gene encoding TDP-43. Herein, we provide a review of our previously published efforts that led to the identification of 3 TARDBP mutations (p.M337V, p.N345K, and p.I383V) in familial ALS patients, two of which were novel. With over 40 TARDBP mutations now discovered, there exists conclusive evidence that TDP-43 plays a direct role in neurodegeneration. The onus is now on researchers to elucidate the mechanisms by which mutant TDP-43 confers toxicity, and to exploit these findings to gain a better understanding of how TDP-43 contributes to the pathogenesis of disease. Our biochemical analysis of TDP-43 in ALS patient lymphoblastoid cell lines revealed a substantial increase in TDP-43 truncation products, including a ≈ 25 kDa fragment, compared to control lymphoblastoid cell lines. We discuss the putative harmful consequence of abnormal TDP-43 fragmentation, as well as highlight additional mechanisms of toxicity associated with mutant TDP-43.}, }
@article {pmid22748827, year = {2012}, author = {Rodrigues, MC and Hernandez-Ontiveros, DG and Louis, MK and Willing, AE and Borlongan, CV and Sanberg, PR and Voltarelli, JC and Garbuzova-Davis, S}, title = {Neurovascular aspects of amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {102}, number = {}, pages = {91-106}, doi = {10.1016/B978-0-12-386986-9.00004-1}, pmid = {22748827}, issn = {2162-5514}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Biological Transport/physiology ; Blood-Brain Barrier/*physiopathology ; Capillary Permeability/*physiology ; Disease Models, Animal ; Humans ; Models, Neurological ; Spinal Cord/blood supply/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Strong evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models. The present review provides an updated analysis of the microvascular pathology and impaired BBB/BSCB in ALS. Based on experimental and clinical ALS studies, the roles of cellular components, cell interactions, tight junctions, transport systems, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption are discussed. The impact of BBB/BSCB damage in ALS pathogenesis is a novel research topic, and this review will reveal some aspects of microvascular pathology involved in the disease and hopefully engender new therapeutic approaches.}, }
@article {pmid22742890, year = {2012}, author = {Pradat, PF and Maisonobe, T and Psimaras, D and Lenglet, T and Porcher, R and Lefaix, JL and Delanian, S}, title = {[Radiation-induced neuropathies: collateral damage of improved cancer prognosis].}, journal = {Revue neurologique}, volume = {168}, number = {12}, pages = {939-950}, doi = {10.1016/j.neurol.2011.11.013}, pmid = {22742890}, issn = {0035-3787}, mesh = {Humans ; Neoplasms/*radiotherapy ; Neoplasms, Radiation-Induced/epidemiology/therapy ; Nervous System Diseases/diagnosis/*etiology/pathology/physiopathology/therapy ; Prognosis ; Radiation Injuries/diagnosis/*etiology/pathology/physiopathology/therapy ; Radiotherapy/*adverse effects ; Risk Factors ; }, abstract = {INTRODUCTION: Because of the improvement of cancer prognosis, long-term damages of treatments become a medical and public health problem. Among the iatrogenic complications, neurological impairment is crucial to consider since motor disability and pain have a considerable impact on quality of life of long cancer survivors. However, radiation-induced neuropathies have not been the focus of great attention. The objective of this paper is to provide an updated review about the radiation-induced lesions of the peripheral nerve system.<br><br>STATE OF THE ART: Radiation-induced neuropathies are characterized by their heterogeneity in both symptoms and disease course. Signs and symptoms depend on the affected structures of the peripheral nerve system (nerve roots, nerve plexus or nerve trunks). Early-onset complications are often transient and late complications are usually progressive and associated with a poor prognosis. The most frequent and well known is delayed radiation-induced brachial plexopathy, which may follow breast cancer irradiation. Radiation-induced lumbosacral radiculoplexopathy is characterized by pure or predominant lower motor neuron signs. They can be misdiagnosed, confused with amyotrophic lateral sclerosis (ALS) or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased cerebrospinal fluid protein content can be observed. In the absence of specific markers of the link with radiotherapy, the diagnosis of post-radiation neuropathy may be difficult. Recently, a posteriori conformal radiotherapy with 3D dosimetric reconstitution has been developed to link a precise anatomical site to unexpected excess irradiation.<br><br>PERSPECTIVES AND CONCLUSION: The importance of early diagnosis of radiation-induced neuropathies is underscored by the emergence of new disease-modifying treatments. Although the pathophysiology is not fully understood, it is already possible to target radiation-induced fibrosis but also associated factors such as ischemia, oxidative stress and inflammation. A phase III trial evaluating the association of pentoxifylline, tocopherol and clodronate (PENTOCLO, NCT01291433) in radiation-induced neuropathies is now recruiting.}, }
@article {pmid22742420, year = {2012}, author = {Kim, DS and Kim, JY and Han, Y}, title = {Curcuminoids in neurodegenerative diseases.}, journal = {Recent patents on CNS drug discovery}, volume = {7}, number = {3}, pages = {184-204}, doi = {10.2174/157488912803252032}, pmid = {22742420}, issn = {2212-3954}, mesh = {Animals ; Cinnamates/chemistry/pharmacology/therapeutic use ; Curcumin/*analogs &amp; derivatives/chemistry/pharmacology/therapeutic use ; Drugs, Investigational/chemistry/pharmacology/*therapeutic use ; Humans ; *Molecular Targeted Therapy ; Nerve Tissue Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neurons/drug effects/metabolism ; Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Patents as Topic ; }, abstract = {Neurodegeneration is a term used to describe progressive deterioration of structure and/or function of neurons that affects different parts of the central nervous system and leads to eventual death. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Down's syndrome (DS), multiple sclerosis (MS), glaucoma, age-related macular degeneration (AMD), and diabetic encephalopathy (DE). Although the initial events that trigger these disorders may be different from each other, they share similar biochemical reactions that lead to neurodegeneration. Curcuminoids, polyphenol compounds from turmeric (Curcuma longa), possess diverse biological properties that modulate debilitating biochemical processes involved in AD that include attenuation of mitochondrial dysfunction-induced oxidative stress and inflammatory responses to inflammatory cytokines, COX-2, and iNOS. Curcuminoids also bind to β-amyloid (Aβ) plaques to inhibit amyloid accumulation and aggregation in the brain, in addition to inhibiting the toxic Aβ oligomer formation and oligomer-dependent Aβ toxicity. These properties can be further elaborated to DS, glaucoma and AMD. Curcuminoids also prevent α-synuclein aggregation in PD; attenuate ROS-induced COX-2 expression in ALS; ameliorate the symptoms of MS, DE and traumatic brain injury, in addition to neurodamages caused by heavy metal poisoning. These results demonstrate curcuminoids may be potentially effective therapeutic means to treat neurodegenerative diseases. A bulk of patents discloses methods to improve bioavailability of curcuminoids for therapeutic development. This review provides a comprehensive description on the current progress on curcuminoids against neurodegenerative diseases.}, }
@article {pmid22742419, year = {2012}, author = {Joshi, G and Johnson, JA}, title = {The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Recent patents on CNS drug discovery}, volume = {7}, number = {3}, pages = {218-229}, pmid = {22742419}, issn = {2212-3954}, support = {R01 ES008089/ES/NIEHS NIH HHS/United States ; R29 ES008089/ES/NIEHS NIH HHS/United States ; R01 ES010042/ES/NIEHS NIH HHS/United States ; ES08089/ES/NIEHS NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; ES10042/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidant Response Elements/*drug effects ; Brain/drug effects/metabolism ; Drugs, Investigational/chemistry/pharmacology/*therapeutic use ; Humans ; Intracellular Signaling Peptides and Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Kelch-Like ECH-Associated Protein 1 ; *Molecular Targeted Therapy ; NF-E2-Related Factor 2/agonists/antagonists &amp; inhibitors/*metabolism ; Nerve Tissue Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neurons/drug effects/metabolism ; Neuroprotective Agents/chemistry/pharmacology/*therapeutic use ; Oxidative Stress ; Patents as Topic ; Signal Transduction/*drug effects ; }, abstract = {Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.}, }
@article {pmid22741814, year = {2012}, author = {Dunkel, P and Chai, CL and Sperlágh, B and Huleatt, PB and Mátyus, P}, title = {Clinical utility of neuroprotective agents in neurodegenerative diseases: current status of drug development for Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {21}, number = {9}, pages = {1267-1308}, doi = {10.1517/13543784.2012.703178}, pmid = {22741814}, issn = {1744-7658}, mesh = {Alzheimer Disease/drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; *Drug Design ; Humans ; Huntington Disease/drug therapy/physiopathology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Parkinson Disease/drug therapy/physiopathology ; }, abstract = {INTRODUCTION: According to the definition of the Committee to Identify Neuroprotective Agents in Parkinson's Disease (CINAPS), "neuroprotection would be any intervention that favourably influences the disease process or underlying pathogenesis to produce enduring benefits for patients" [Meissner W, et al. Trends Pharmacol Sci 2004;25:249-253]. Preferably, neuroprotective agents should be used before or eventually during the prodromal phase of the diseases that could start decades before the appearance of symptoms. Although several symptomatic drugs are available, a disease-modifying agent is still elusive.<br><br>AREAS COVERED: The aim of the present review is to give an overview of neuroprotective agents being currently investigated for the treatment of AD, PD, HD and ALS in clinical phases.<br><br>EXPERT OPINION: Development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages, both conceptual and methodological. Novel solutions might be offered by evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multi-target approaches and network pharmacology.}, }
@article {pmid22739839, year = {2013}, author = {Pandi-Perumal, SR and BaHammam, AS and Brown, GM and Spence, DW and Bharti, VK and Kaur, C and Hardeland, R and Cardinali, DP}, title = {Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.}, journal = {Neurotoxicity research}, volume = {23}, number = {3}, pages = {267-300}, pmid = {22739839}, issn = {1476-3524}, mesh = {Aging/drug effects/metabolism/*physiology ; Animals ; Antioxidants/*therapeutic use ; Apoptosis/drug effects ; Brain Injuries/drug therapy ; Circadian Rhythm/physiology ; Clinical Trials as Topic ; Double-Blind Method ; Drug Evaluation, Preclinical ; Free Radicals/metabolism ; Homeostasis/physiology ; Humans ; Light ; Melatonin/agonists/pharmacology/*physiology/therapeutic use ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Multicenter Studies as Topic ; Nerve Tissue Proteins/biosynthesis/physiology ; Neurodegenerative Diseases/metabolism/*prevention &amp; control ; Neurons/metabolism/pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Pineal Gland/metabolism/radiation effects ; Sleep Initiation and Maintenance Disorders/drug therapy ; Tryptophan/metabolism ; }, abstract = {The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.}, }
@article {pmid22732773, year = {2012}, author = {Rademakers, R and Neumann, M and Mackenzie, IR}, title = {Advances in understanding the molecular basis of frontotemporal dementia.}, journal = {Nature reviews. Neurology}, volume = {8}, number = {8}, pages = {423-434}, pmid = {22732773}, issn = {1759-4766}, support = {179009/CAPMC/CIHR/Canada ; R01 NS065782/NS/NINDS NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS080882/NS/NINDS NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; 74580/CAPMC/CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein ; DNA-Binding Proteins/*genetics ; Frontotemporal Dementia/*genetics/*metabolism ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation/*genetics ; Proteins/*genetics ; tau Proteins/genetics/metabolism ; }, abstract = {Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Until recently, the underlying cause was known in only a minority of cases that were associated with abnormalities of the tau protein or gene. In 2006, however, mutations in the progranulin gene were discovered as another important cause of familial FTD. That same year, TAR DNA-binding protein 43 (TDP-43) was identified as the pathological protein in the most common subtypes of FTD and amyotrophic lateral sclerosis (ALS). Since then, substantial efforts have been made to understand the functions and regulation of progranulin and TDP-43, as well as their roles in neurodegeneration. More recently, other DNA/RNA binding proteins (FET family proteins) have been identified as the pathological proteins in most of the remaining cases of FTD. In 2011, abnormal expansion of a hexanucleotide repeat in the gene C9orf72 was found to be the most common genetic cause of both FTD and ALS. All common FTD-causing genes have seemingly now been discovered and the main pathological proteins identified. In this Review, we highlight recent advances in understanding the molecular aspects of FTD, which will provide the basis for improved patient care through the development of more-targeted diagnostic tests and therapies.}, }
@article {pmid22731907, year = {2012}, author = {Turner, MR and Agosta, F and Bede, P and Govind, V and Lulé, D and Verstraete, E}, title = {Neuroimaging in amyotrophic lateral sclerosis.}, journal = {Biomarkers in medicine}, volume = {6}, number = {3}, pages = {319-337}, doi = {10.2217/bmm.12.26}, pmid = {22731907}, issn = {1752-0371}, support = {G0701923//Medical Research Council/United Kingdom ; R01 NS060874/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/diagnostic imaging ; Animals ; Brain/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Neuroimaging/*methods ; Radiography ; }, abstract = {The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments.}, }
@article {pmid22731673, year = {2013}, author = {Pagnini, F}, title = {Psychological wellbeing and quality of life in amyotrophic lateral sclerosis: a review.}, journal = {International journal of psychology : Journal international de psychologie}, volume = {48}, number = {3}, pages = {194-205}, doi = {10.1080/00207594.2012.691977}, pmid = {22731673}, issn = {1464-066X}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Anxiety ; Caregivers/psychology ; Depression ; Emotions ; Existentialism ; Humans ; Pain ; *Quality of Life ; Social Support ; Spirituality ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with a progressive and rapid course that, so far, cannot be stopped or reversed. The psychological impact of the disease is huge, on both patients and caregivers. This review summarizes studies that have investigated quality of life, depression, anxiety, pain, spiritual and existential issues, hope, and hopelessness in the ALS field, with attention to both patients and their caregivers. Psychological support and the possible role of psychologists in the ALS field are also discussed.}, }
@article {pmid22727428, year = {2012}, author = {Catalgol, B and Grune, T}, title = {Proteasome and neurodegeneratıve diseases.}, journal = {Progress in molecular biology and translational science}, volume = {109}, number = {}, pages = {397-414}, doi = {10.1016/B978-0-12-397863-9.00011-0}, pmid = {22727428}, issn = {1878-0814}, mesh = {Animals ; Humans ; Models, Biological ; Neurodegenerative Diseases/*enzymology/*pathology ; Proteasome Endopeptidase Complex/*metabolism ; Protein Structure, Quaternary ; }, abstract = {Proteasomal degradation of damaged proteins is involved in the pathogenesis of many neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, stroke, and amyotrophic lateral sclerosis. A malfunction of the proteasomal activity may be the result or the consequence of protein aggregation, which is a key process for most neurodegenerative diseases. Because of the widespread aspects of the proteasomal involvement in the progression of these diseases, many studies are focused on this research.}, }
@article {pmid22720174, year = {2012}, author = {Trojsi, F and Monsurrò, MR and Esposito, F and Tedeschi, G}, title = {Widespread structural and functional connectivity changes in amyotrophic lateral sclerosis: insights from advanced neuroimaging research.}, journal = {Neural plasticity}, volume = {2012}, number = {}, pages = {473538}, pmid = {22720174}, issn = {1687-5443}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Animals ; Brain/*pathology/*physiopathology ; Cognition Disorders/diagnosis/physiopathology ; Humans ; Nerve Net/pathology/physiopathology ; Neuroimaging/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. Besides motor symptoms, a subset of patients develop cognitive disturbances or even frontotemporal dementia (FTD), indicating that ALS may also involve extramotor brain regions. Both neuropathological and neuroimaging findings have provided further insight on the widespread effect of the neurodegeneration on brain connectivity and the underlying neurobiology of motor neurons degeneration. However, associated effects on motor and extramotor brain networks are largely unknown. Particularly, neuropathological findings suggest that ALS not only affects the frontotemporal network but rather is part of a wide clinicopathological spectrum of brain disorders known as TAR-DNA binding protein 43 (TDP-43) proteinopathies. This paper reviews the current state of knowledge concerning the neuropsychological and neuropathological sequelae of TDP-43 proteinopathies, with special focus on the neuroimaging findings associated with cognitive change in ALS.}, }
@article {pmid22708602, year = {2012}, author = {Chang, PK and Verbich, D and McKinney, RA}, title = {AMPA receptors as drug targets in neurological disease--advantages, caveats, and future outlook.}, journal = {The European journal of neuroscience}, volume = {35}, number = {12}, pages = {1908-1916}, doi = {10.1111/j.1460-9568.2012.08165.x}, pmid = {22708602}, issn = {1460-9568}, support = {MOP 86724//Canadian Institutes of Health Research/Canada ; }, mesh = {Alzheimer Disease/drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Epilepsy/drug therapy/physiopathology ; Excitatory Postsynaptic Potentials/drug effects ; Humans ; Mice ; Molecular Targeted Therapy/trends ; Nervous System Diseases/*drug therapy ; Neurotransmitter Agents/pharmacology/therapeutic use ; Rats ; Receptors, AMPA/agonists/*antagonists &amp; inhibitors/physiology ; }, abstract = {Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.}, }
@article {pmid22705710, year = {2013}, author = {Cozzolino, M and Ferri, A and Valle, C and Carrì, MT}, title = {Mitochondria and ALS: implications from novel genes and pathways.}, journal = {Molecular and cellular neurosciences}, volume = {55}, number = {}, pages = {44-49}, doi = {10.1016/j.mcn.2012.06.001}, pmid = {22705710}, issn = {1095-9327}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; DNA-Binding Proteins/genetics/metabolism ; *Genes, Mitochondrial ; Humans ; Mitochondria/genetics/*metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Evidence from patients with sporadic and familiar amyotrophic lateral sclerosis (ALS) and from models based on the overexpression of mutant SOD1 found in a small subset of patients, clearly point to mitochondrial damage as a relevant facet of this neurodegenerative condition. In this mini-review we provide a brief update on the subject in the light of newly discovered genes (such as TDP-43 and FUS/TLS) associated to familial ALS and of a deeper knowledge of the mechanisms of derangement of mitochondria. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.}, }
@article {pmid22700435, year = {2012}, author = {Johri, A and Beal, MF}, title = {Mitochondrial dysfunction in neurodegenerative diseases.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {342}, number = {3}, pages = {619-630}, pmid = {22700435}, issn = {1521-0103}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; P01AG14930/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mitochondria/*pathology ; Mitochondrial Dynamics/physiology ; Neurodegenerative Diseases/*pathology/*physiopathology ; Neurons/*pathology/*physiology ; }, abstract = {Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron.}, }
@article {pmid22697423, year = {2012}, author = {Xu, ZS}, title = {Does a loss of TDP-43 function cause neurodegeneration?.}, journal = {Molecular neurodegeneration}, volume = {7}, number = {}, pages = {27}, pmid = {22697423}, issn = {1750-1326}, support = {R01NS059708/NS/NINDS NIH HHS/United States ; }, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology ; Animals ; DNA-Binding Proteins/*genetics ; Frontotemporal Lobar Degeneration/*genetics/metabolism/physiopathology ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation/*genetics ; }, abstract = {In 2006, TAR-DNA binding protein 43 kDa (TDP-43) was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.}, }
@article {pmid22692995, year = {2012}, author = {Scherer, K and Bedlack, RS}, title = {Diaphragm pacing in amyotrophic lateral sclerosis: a literature review.}, journal = {Muscle &amp; nerve}, volume = {46}, number = {1}, pages = {1-8}, doi = {10.1002/mus.23419}, pmid = {22692995}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Diaphragm/*innervation ; Electric Stimulation Therapy/*instrumentation ; Humans ; *Implantable Neurostimulators ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a rapidly progressive fatal degenerative disease of motor neurons for which there are few interventions to slow disease progression or improve quality of life. A diaphragm pacing system was approved by the U.S. Food and Drug Administration in September 2011 for ALS under a Humanitarian Device Exemption. News of this approval has been met with a combination of excitement and uncertainty by members of the ALS community. We review the currently available data on the diaphragm pacing system and its use in ALS. Diaphragm pacing appears to be reasonably safe in carefully selected patients, but flaws in the reporting on it thus far preclude conclusions regarding efficacy. Further study is needed.}, }
@article {pmid22680643, year = {2012}, author = {Rao, PS and Sari, Y}, title = {Glutamate transporter 1: target for the treatment of alcohol dependence.}, journal = {Current medicinal chemistry}, volume = {19}, number = {30}, pages = {5148-5156}, pmid = {22680643}, issn = {1875-533X}, support = {R01 AA019458/AA/NIAAA NIH HHS/United States ; R01AA019458/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking ; Alcoholism/drug therapy/*metabolism/physiopathology ; Amino Acid Transport System X-AG/*metabolism ; Animals ; Humans ; Illicit Drugs/pharmacology ; }, abstract = {Emerging evidence indicates that many aspects of alcohol and drug dependence involve changes in glutamate transmission. A number of studies have reported that drugs of abuse, including alcohol and cocaine, alter glutamate transport. Extracellular glutamate is regulated by a number of glutamate transporters in various brain regions. Of these transporters, glutamate transporter (GLT1) is a key player in the removal of most of the extracellular glutamate. Similar to neurodegenerative disease models, in which there is dysfunction of the glutamatergic excitatory system, the role of GLT1 has been tested in drug dependence models that show dysfunction of glutamate transmission. We and others have recently found that ceftriaxone, an FDA-approved drug known to elevate GLT1 expression, attenuates cue-induced cocaine relapse. Moreover, we recently found that alcohol-preferring rats treated with ceftriaxone showed a significant dosedependent reduction in alcohol consumption. We also demonstrated that ceftriaxone-induced upregulation of GLT1 expression was associated with increases in glutamate uptake in Huntington's disease mouse model. Importantly, ceftriaxone is currently in clinical trials for the treatment of amyotrophic lateral sclerosis. This review provides information about the potential therapeutic role of GLT1 for the treatment of alcohol abuse and dependence.}, }
@article {pmid22677356, year = {2012}, author = {Muscaritoli, M and Kushta, I and Molfino, A and Inghilleri, M and Sabatelli, M and Rossi Fanelli, F}, title = {Nutritional and metabolic support in patients with amyotrophic lateral sclerosis.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {28}, number = {10}, pages = {959-966}, doi = {10.1016/j.nut.2012.01.011}, pmid = {22677356}, issn = {1873-1244}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Constipation/prevention &amp; control ; Counseling ; Deglutition Disorders/etiology/therapy ; Dietary Fiber ; *Enteral Nutrition ; *Food, Formulated ; Humans ; Metabolic Diseases/etiology/*therapy ; Nutrition Assessment ; Protein-Energy Malnutrition/etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of progressive motor neuron disease and the most devastating neurodegenerative disorder. ALS is characterized by progressive paralysis and respiratory failure leading to death within 3 to 5 years after its onset. Protein-energy malnutrition is a frequent finding in ALS. The pathogenesis of protein-energy malnutrition in ALS is multifactorial. Muscle atrophy, hypophagia, dysphagia, and hypermetabolism play a role in determining the deterioration of nutritional status. A multidisciplinary approach is crucial to set an appropriate plan for metabolic and nutritional support in ALS. Nutritional management incorporates a continuous assessment and implementation of dietary modifications throughout the duration of the disease. The nutritional and metabolic approaches to ALS should start when the diagnosis of ALS is made and should become an integral part of the continuous care to the patient, including nutritional surveillance, dietary counseling, management of dysphagia, and enteral nutrition when needed. Parenteral nutrition is rarely indicated. Standard polymeric enteral formulas are routinely used, usually providing 25 to 30 kcal/kg and protein 0.8 to 1.2 g /kg per day. The use of fiber-enriched formulas may help prevent constipation. However, considering the complex metabolic abnormalities of ALS, standard and/or fiber-enriched formulas might not be sufficient to achieve optimal metabolic and nutritional support. Based on the most recent clinical and experimental evidence, it is tempting to hypothesize that personalized nutritional support including specific nutritional substrates could act on disease progression and improve the quality of life and the response to the few and yet scarcely effective, currently available pharmacologic therapies.}, }
@article {pmid22669748, year = {2012}, author = {Nunomura, A and Moreira, PI and Castellani, RJ and Lee, HG and Zhu, X and Smith, MA and Perry, G}, title = {Oxidative damage to RNA in aging and neurodegenerative disorders.}, journal = {Neurotoxicity research}, volume = {22}, number = {3}, pages = {231-248}, pmid = {22669748}, issn = {1476-3524}, mesh = {*Aging ; Animals ; Humans ; Neurodegenerative Diseases/*metabolism ; *Oxidation-Reduction ; Oxidative Stress/genetics/physiology ; RNA/*metabolism ; }, abstract = {An age-associated increase in oxidative damage to nucleic acids, predominantly to RNA, has been recently demonstrated in neurons of human and rodent brains, which may play a fundamental role in the development of age-associated neurodegeneration. Indeed, more prominent levels of neuronal RNA oxidation compared to normal aging have been described in neurodegenerative disorders including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Moreover, oxidative damage to RNA has been found also in cellular and animal model of neurodegeneration. Oxidative RNA modification can occur not only in protein-coding RNAs but also in non-coding RNAs that are recently revealed to contribute towards the complexity of the mammalian brain. It has been hypothesized that RNA oxidation causes aberrant expression of microRNAs and proteins and subsequently initiates inappropriate cell fate pathways. While less lethal than mutations in the genome and not inheritable, such sublethal damage to cells might be associated with underlying mechanisms of degeneration, especially age-associated neurodegeneration. Of particular interest, the accumulating evidence obtained from studies on either human samples or experimental models coincidentally suggests that RNA oxidation is a feature in neurons of aging brain and more prominently observed in vulnerable neurons at early-stage of age-associated neurodegenerative disorders, indicating that RNA oxidation actively contributes to the background, the onset, and the development of the disorders. Further investigations aimed at understanding of the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative disorders and lead to better therapeutic strategies.}, }
@article {pmid22669122, year = {2012}, author = {Federico, A and Cardaioli, E and Da Pozzo, P and Formichi, P and Gallus, GN and Radi, E}, title = {Mitochondria, oxidative stress and neurodegeneration.}, journal = {Journal of the neurological sciences}, volume = {322}, number = {1-2}, pages = {254-262}, doi = {10.1016/j.jns.2012.05.030}, pmid = {22669122}, issn = {1878-5883}, mesh = {Aging ; Apoptosis ; Brain/pathology ; DNA, Mitochondrial/genetics ; Humans ; Mitochondrial Diseases/*etiology/genetics ; Neurodegenerative Diseases/*complications/genetics ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondria are involved in ATP supply to cells through oxidative phosphorylation (OXPHOS), synthesis of key molecules and response to oxidative stress, as well as in apoptosis. They contain many redox enzymes and naturally occurring inefficiencies of oxidative phosphorylation generate reactive oxygen species (ROS). CNS functions depend heavily on efficient mitochondrial function, since brain tissue has a high energy demand. Mutations in mitochondrial DNA (mtDNA), generation and presence of ROS and environmental factors may contribute to energy failure and lead to neurodegenerative diseases. Many rare metabolic disorders have been associated with mitochondrial dysfunction. More than 300 pathogenic mtDNA mutations involve proteins that regulate OXPHOS and mitochondrial structural integrity, and have also been described in neurodegenerative diseases with autosomal inheritance. Mitochondria may have an important role in ageing-related neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In primary mitochondrial and neurodegenerative disorders, there is strong evidence that mitochondrial dysfunction occurs early and has a primary role in pathogenesis. In the present review, we discuss several mitochondrial diseases as models of neurodegeneration.}, }
@article {pmid22663966, year = {2012}, author = {Hess, DR}, title = {The growing role of noninvasive ventilation in patients requiring prolonged mechanical ventilation.}, journal = {Respiratory care}, volume = {57}, number = {6}, pages = {900-18; discussion 918-20}, doi = {10.4187/respcare.01692}, pmid = {22663966}, issn = {0020-1324}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Cystic Fibrosis/epidemiology/therapy ; Equipment Design ; Humans ; Insurance Coverage ; Medicare/economics ; Muscular Dystrophy, Duchenne/physiopathology/therapy ; Neuromuscular Diseases/physiopathology/*therapy ; Obesity Hypoventilation Syndrome/physiopathology/therapy ; Pulmonary Disease, Chronic Obstructive/epidemiology/physiopathology/*therapy ; Respiration, Artificial/*methods/statistics &amp; numerical data ; Sleep Apnea Syndromes/epidemiology/physiopathology ; Tidal Volume/physiology ; Time Factors ; United States ; Ventilators, Mechanical ; }, abstract = {For many patients with chronic respiratory failure requiring ventilator support, noninvasive ventilation (NIV) is preferable to invasive support by tracheostomy. Currently available evidence does not support the use of nocturnal NIV in unselected patients with stable COPD. Several European studies have reported benefit for high intensity NIV, in which setting of inspiratory pressure and respiratory rate are selected to achieve normocapnia. There have also been studies reporting benefit for the use of NIV as an adjunct to exercise training. NIV may be useful as an adjunct to airway clearance techniques in patients with cystic fibrosis. Accumulating evidence supports the use of NIV in patients with obesity hypoventilation syndrome. There is considerable observational evidence supporting the use of NIV in patients with chronic respiratory failure related to neuromuscular disease, and one randomized controlled trial reported that the use of NIV was life-prolonging in patients with amyotrophic lateral sclerosis. A variety of interfaces can be used to provide NIV in patients with stable chronic respiratory failure. The mouthpiece is an interface that is unique in this patient population, and has been used with success in patients with neuromuscular disease. Bi-level pressure ventilators are commonly used for NIV, although there are now a new generation of intermediate ventilators that are portable, have a long battery life, and can be used for NIV and invasive applications. Pressure support ventilation, pressure controlled ventilation, and volume controlled ventilation have been used successfully for chronic applications of NIV. New modes have recently become available, but their benefits await evidence to support their widespread use. The success of NIV in a given patient population depends on selection of an appropriate patient, selection of an appropriate interface, selection of an appropriate ventilator and ventilator settings, the skills of the clinician, the motivation of the patient, and the support of the family.}, }
@article {pmid22661746, year = {2012}, author = {Turner, MR and Barnwell, J and Al-Chalabi, A and Eisen, A}, title = {Young-onset amyotrophic lateral sclerosis: historical and other observations.}, journal = {Brain : a journal of neurology}, volume = {135}, number = {Pt 9}, pages = {2883-2891}, doi = {10.1093/brain/aws144}, pmid = {22661746}, issn = {1460-2156}, support = {G0701923//Medical Research Council/United Kingdom ; }, mesh = {Age Factors ; Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/genetics/pathology ; Humans ; Phenotype ; }, abstract = {There is a wide range of age at initial symptom onset in amyotrophic lateral sclerosis despite a mean age of 65 years in population-based studies. 'Young-onset' amyotrophic lateral sclerosis typically refers to patients younger than ∼45 years and accounts for about 10% of cases in contemporary series. A review of published cases of amyotrophic lateral sclerosis from 1850 to 1950 revealed a far higher proportion of cases with young onset (>50%), with a steady decline to the contemporary figure. It is possible that this is not solely explained by increases in life expectancy. While there is still a rich variation in phenotypes among cases of young-onset amyotrophic lateral sclerosis, bulbar onset was found to be significantly under-represented in analysis of a large patient database, with implications for age-related vulnerabilities pertaining to focality of symptom onset. The timing of initiating pathological processes in relation to the emergence of symptoms is discussed, including the potential role of very early development and the interaction of epigenetic and environmental factors.}, }
@article {pmid22661348, year = {2012}, author = {Rafiq, MK and Proctor, AR and McDermott, CJ and Shaw, PJ}, title = {Respiratory management of motor neurone disease: a review of current practice and new developments.}, journal = {Practical neurology}, volume = {12}, number = {3}, pages = {166-176}, doi = {10.1136/practneurol-2011-000199}, pmid = {22661348}, issn = {1474-7766}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Disease Management ; Humans ; Motor Neuron Disease/diagnosis/*epidemiology/*therapy ; Palliative Care/methods/trends ; Respiratory Insufficiency/diagnosis/*epidemiology/*therapy ; *Respiratory Mechanics/physiology ; }, abstract = {Motor neurone disease is a neurodegenerative condition with a significant morbidity and shortened life expectancy. Hypoventilatory respiratory failure is the most common cause of death and respiratory function significantly predicts both survival and quality of life in patients with motor neurone disease. Accordingly, supporting and maintaining respiratory function is important in caring for these patients. The most significant advance in motor neurone disease care of recent years has been the domiciliary provision of non-invasive ventilation for treating respiratory failure. Neuromuscular respiratory weakness also leads to ineffective cough and retained airways secretions, predisposing to recurrent chest infections. In this review, we discuss current practice and recent developments in the respiratory management of motor neurone disease, in terms of ventilatory support and cough augmentation.}, }
@article {pmid22652260, year = {2012}, author = {Hantao, LW and Aleme, HG and Pedroso, MP and Sabin, GP and Poppi, RJ and Augusto, F}, title = {Multivariate curve resolution combined with gas chromatography to enhance analytical separation in complex samples: a review.}, journal = {Analytica chimica acta}, volume = {731}, number = {}, pages = {11-23}, doi = {10.1016/j.aca.2012.04.003}, pmid = {22652260}, issn = {1873-4324}, mesh = {Chemical Fractionation/*methods ; Gas Chromatography-Mass Spectrometry/*methods ; Least-Squares Analysis ; Multivariate Analysis ; }, abstract = {This review describes the major advantages and pitfalls of iterative and non-iterative multivariate curve resolution (MCR) methods combined with gas chromatography (GC) data using literature published since 2000 and highlighting the most important combinations of GC coupled to mass spectrometry (GC-MS) and comprehensive two-dimensional gas chromatography with flame ionization detection (GC×GC-FID) and coupled to mass spectrometry (GC×GC-MS). In addition, a brief summary of some pre-processing strategies will be discussed to correct common issues in GC, such as retention time shifts and baseline/background contributions. Additionally, algorithms such as evolving factor analysis (EFA), heuristic evolving latent projection (HELP), subwindow factor analysis (SFA), multivariate curve resolution-alternating least squares (MCR-ALS), positive matrix factorization (PMF), iterative target transformation factor analysis (ITTFA) and orthogonal projection resolution (OPR) will be described in this paper. Even more, examples of applications to food chemistry, lipidomics and medicinal chemistry, as well as in essential oil research, will be shown. Lastly, a brief illustration of the MCR method hierarchy will also be presented.}, }
@article {pmid22647475, year = {2012}, author = {Hasegawa, M}, title = {[Are neurodegenerative diseases "protein cancers"?].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {6}, pages = {675-679}, pmid = {22647475}, issn = {1881-6096}, mesh = {Animals ; Humans ; Neoplasms/etiology/*metabolism/therapy ; Neurodegenerative Diseases/etiology/*metabolism/therapy ; Prions/*metabolism ; Protein Denaturation ; Protein Processing, Post-Translational ; tau Proteins/metabolism ; }, abstract = {In the last 30 years, the elucidation of the molecular pathogenesis of neurodegenerative diseases has undergone remarkable progress, including the discoveries of the causative genes and risk factors of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, the fundamental questions of why different neurons degenerate in different diseases and why these diseases are progressive have received little attention. I have proposed the "protein cancer" hypothesis, which states that abnormal or malignant proteins--such as prion proteins--generated in a cell grow and propagate from cell to cell by converting normal proteins, and this propagation causes disease progression, analogous to the metastasis of cancer cells to multiple different tissues during cancer progression. Intracellular filamentous inclusions composed of amyloid-like proteins, such as tau, α-synuclein, and TDP-43, are common neuropathological features of many neurodegenerative disorders, and the extent of the abnormal protein pathologies is closely related to disease progression. Recent results of experimental model studies as well as biochemical analyses of abnormal proteins in patients have provided support for this hypothesis. Therefore, small molecules or antibodies that can inhibit the intra- and intercellular propagation of abnormal proteins are expected to be promising candidates for clinical therapy.}, }
@article {pmid22647474, year = {2012}, author = {Yoshida, K and Higuchi, K and Ikeda, S}, title = {[Can prion-like propagation occur in neurodegenerative diseases?: in view of transmissible systemic amyloidosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {6}, pages = {665-674}, pmid = {22647474}, issn = {1881-6096}, mesh = {Amyloidosis/*metabolism/therapy ; Animals ; Humans ; Neurodegenerative Diseases/*metabolism/therapy ; Prions/*metabolism ; Protein Folding ; Signal Transduction ; }, abstract = {Common neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are now considered as "protein misfolding diseases," because the misfolding of a small number of proteins is a key event in the pathogenesis and progression of these diseases. Proteins that are prone to misfolding and thereby associated with neurodegenerative diseases include amyloid β (AD), tau (AD and tauopathy), α-synuclein (PD, dementia with Lewy bodies, etc.), polyglutamine proteins (Huntington's disease, spinocerebellar ataxia, etc.), and superoxide dismutase 1 (amyotrophic lateral sclerosis). These proteins share certain essential properties with prions. Similar to abnormal prions, misfolded proteins function as a template to catalyze the misfolding of the native proteins and assemble into insoluble, β-sheet-rich, fibrillar aggregates termed as "amyloids." Furthermore, there is enough evidence supporting the intercellular transfer of misfolded protein aggregates. The transmission of these aggregates from one cell to another may be in accordance with the concept that neuropathological changes propagate along neuronal circuits in neurodegenerative diseases. Prion-like propagation mechanisms have been extensively analyzed in connection with systemic amyloidoses such as amyloid A (AA) amyloidosis and amyloid apolipoprotein AII (AApoAII) amyloidosis. Studies have shown that AA and AApoAII amyloidoses are transmitted from one organism to another through amyloid fibrils. However, studies have not yet proved that protein misfolding diseases, except for prion diseases, are infectious. Given the intercellular transfer of misfolded protein aggregates, we cannot ignore the possibility that disease-specific, misfolded proteins can be transmitted between individuals through surgical procedures or tissue transplantation. Importantly, cell non-autonomous mechanisms underlying the pathogenesis of neurodegenerative diseases may represent a more readily accessible target for novel disease-modifying therapies. In the present review, we discuss some aspects of the prion-like propagation of neurodegenerative diseases, taking into consideration the accumulated evidence supporting the transmissibility of systemic amyloidoses.}, }
@article {pmid22644588, year = {2012}, author = {Burns, TM and Graham, CD and Rose, MR and Simmons, Z}, title = {Quality of life and measures of quality of life in patients with neuromuscular disorders.}, journal = {Muscle &amp; nerve}, volume = {46}, number = {1}, pages = {9-25}, doi = {10.1002/mus.23245}, pmid = {22644588}, issn = {1097-4598}, mesh = {*Activities of Daily Living ; Health Status ; Humans ; Neuromuscular Diseases/*psychology ; Psychometrics ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {In this review we present an overview of quality of life (QOL) and QOL measures in neuromuscular disorders. We discuss the characteristics of QOL measures used in neuromuscular research, highlighting differences between generic versus disease-specific and global versus health-related QOL instruments. The phenomenon of response shift is reviewed. Commonly used QOL instruments are reviewed for amyotrophic lateral sclerosis, muscle diseases, myasthenia gravis, and polyneuropathy. We also review some of what is known about QOL for patients with these neuromuscular disorders.}, }
@article {pmid22643836, year = {2012}, author = {Sorce, S and Krause, KH and Jaquet, V}, title = {Targeting NOX enzymes in the central nervous system: therapeutic opportunities.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {69}, number = {14}, pages = {2387-2407}, pmid = {22643836}, issn = {1420-9071}, mesh = {Central Nervous System Diseases/enzymology/pathology/*therapy ; Enzyme Inhibitors/therapeutic use ; Humans ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Protein Isoforms/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/metabolism ; Small Molecule Libraries/chemical synthesis/chemistry/therapeutic use ; }, abstract = {Among the pathogenic mechanisms underlying central nervous system (CNS) diseases, oxidative stress is almost invariably described. For this reason, numerous attempts have been made to decrease reactive oxygen species (ROS) with the administration of antioxidants as potential therapies for CNS disorders. However, such treatments have always failed in clinical trials. Targeting specific sources of reactive oxygen species in the CNS (e.g. NOX enzymes) represents an alternative promising option. Indeed, NOX enzymes are major generators of ROS, which regulate progression of CNS disorders as diverse as amyotrophic lateral sclerosis, schizophrenia, Alzheimer disease, Parkinson disease, and stroke. On the other hand, in autoimmune demyelinating diseases, ROS generated by NOX enzymes are protective, presumably by dampening the specific immune response. In this review, we discuss the possibility of developing therapeutics targeting NADPH oxidase (NOX) enzymes for the treatment of different CNS pathologies. Specific compounds able to modulate the activation of NOX enzymes, and the consequent production of ROS, could fill the need for disease-modifying drugs for many incurable CNS pathologies.}, }
@article {pmid22632380, year = {2012}, author = {Amirjani, N and Kiernan, MC and McKenzie, DK and Butler, JE and Gandevia, SC}, title = {Is there a case for diaphragm pacing for amyotrophic lateral sclerosis patients?.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {6}, pages = {521-527}, doi = {10.3109/17482968.2012.673169}, pmid = {22632380}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*pathology ; Animals ; Diaphragm/*pathology ; Disease Progression ; Humans ; Muscle Contraction ; Respiratory Insufficiency/etiology/pathology ; }, abstract = {Respiratory pacing has advanced the long-term management of respiratory failure secondary to neurological disorders. It has an established role in curtailing invasive mechanical ventilation after upper motor neuron lesions such as spinal cord injury. There is increasing interest to expand the application of intramuscular diaphragm pacing to amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. Although diaphragm pacing has been offered to ALS patients, evidence-based data to determine its benefits remain lacking. The limited current literature indicates progression of respiratory dysfunction in ALS patients despite diaphragm pacing. The data from clinical trials are inadequate to substantiate its survival and sleep benefits. Its advantages over non-invasive mechanical ventilation have not been directly investigated. Furthermore, there are cautions for ALS patients to consider when opting for diaphragm pacing. Progressive degeneration of the phrenic motor neurons in classic ALS will interrupt the transmission of pacer signals to sustain diaphragm contractions. Pacing protocols that are safe for other neurological conditions may be detrimental for ALS, at least as suggested by transgenic animal models. Issues inherent to the device warrant expert intervention in implanted patients. At present, clinical effectiveness and long-term safety concerns about diaphragm pacing in ALS remain to be addressed.}, }
@article {pmid22608070, year = {2012}, author = {Tsao, W and Jeong, YH and Lin, S and Ling, J and Price, DL and Chiang, PM and Wong, PC}, title = {Rodent models of TDP-43: recent advances.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {26-39}, pmid = {22608070}, issn = {1872-6240}, support = {R01 NS041438/NS/NINDS NIH HHS/United States ; R01 NS41438/NS/NINDS NIH HHS/United States ; }, mesh = {Adiposity/genetics ; Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; DNA/genetics ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mitochondria/metabolism/pathology ; Molecular Sequence Data ; Motor Neurons/metabolism/pathology ; TDP-43 Proteinopathies/*genetics/*pathology ; }, abstract = {Recently, missense mutations in the gene TARDBP encoding TDP-43 have been linked to familial ALS. The discovery of genes encoding these RNA binding proteins, such as TDP-43 and FUS/TLS, raised the notion that altered RNA metabolism is a major factor underlying the pathogenesis of ALS. To begin to unravel how mutations in TDP-43 cause dysfunction and death of motor neurons, investigators have employed both gain- and loss-of-function studies in rodent model systems. Here, we will summarize major findings from the initial sets of TDP-43 transgenic and knockout rodent models, identify their limitations, and point to future directions toward clarification of disease mechanism(s) and testing of therapeutic strategies that ultimately may lead to novel therapy for this devastating disease. This article is part of a Special Issue entitled RNA-Binding Proteins.}, }
@article {pmid22596264, year = {2013}, author = {Cifra, A and Mazzone, GL and Nistri, A}, title = {Riluzole: what it does to spinal and brainstem neurons and how it does it.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {19}, number = {2}, pages = {137-144}, doi = {10.1177/1073858412444932}, pmid = {22596264}, issn = {1089-4098}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Brain Stem/*drug effects/metabolism ; Excitatory Amino Acid Antagonists/*pharmacology/therapeutic use ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Riluzole/*pharmacology/therapeutic use ; Spinal Cord/*drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (Lou Gehrig's disease) is a devastating neurodegenerative disorder for which the only licensed treatment is riluzole. Although riluzole clinical efficacy is rather limited, its use has important implications for identifying those parameters that might improve its clinical benefits (dose, timing, disease stage) and for its off-label administration in other neurodegenerative diseases, such as spinal cord injury. Studies of riluzole also have an intrinsically heuristic value to unveil mechanisms regulating the excitability of brain and spinal neurons because this drug is a pharmacological tool to probe the function of certain ion channels, or to study neurotransmitter release processes, and intracellular neuroprotective pathways. The present review focuses on how riluzole acts on brain and spinal neurons within motor networks, what mechanisms can be deduced from its effects, and what conditions may favor its use to contrast neurodegeneration or to ameliorate late symptoms like spasticity. Taking as an example the experimental neurodegeneration caused by overactivation of glutamatergic synapses (excitotoxicity), it seems likely that protection of motor networks by riluzole involves selected administration timing and dosing to target processes for releasing glutamate from very active synapses or for dampening repetitive firing by hyperfunctional motor cells.}, }
@article {pmid22584188, year = {2012}, author = {Stephen-Haynes, J}, title = {Skin tears: achieving positive clinical and financial outcomes.}, journal = {British journal of community nursing}, volume = {Suppl}, number = {}, pages = {S6, S8, S10 passim}, doi = {10.12968/bjcn.2012.17.sup3.s6}, pmid = {22584188}, issn = {1462-4753}, mesh = {Humans ; Lacerations/*nursing/prevention &amp; control ; Nursing Assessment ; Risk Factors ; Skin/*injuries ; Wound Closure Techniques/*nursing ; Wound Healing/*physiology ; }, abstract = {Skin tears are one of the most common wounds found among frail, older individuals, and are considered to be largely preventable. Skin tears occur frequently in those with fragile skin, in neonates and the elderly; particularly those with comorbidities affecting their balance, e.g. postural hypotension, motor neurone disease, diabetes and cerebral vascular accident (CVA). Those taking oral medications including steroids and anticoagulants are also at risk of developing skin tears. The increase in the population of older people is likely to produce a concurrent rise in the number of skin tears. Health professionals and health care assistants have a significant role to play in skin tear prevention, assessment and management.}, }
@article {pmid22579818, year = {2012}, author = {O'Connor, DM and Boulis, NM}, title = {Cellular and molecular approaches to motor neuron therapy in amyotrophic lateral sclerosis and spinal muscular atrophy.}, journal = {Neuroscience letters}, volume = {527}, number = {2}, pages = {78-84}, doi = {10.1016/j.neulet.2012.04.079}, pmid = {22579818}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Clinical Trials as Topic ; Genetic Therapy/*methods ; Genetic Vectors ; Humans ; Induced Pluripotent Stem Cells/cytology/transplantation ; Mesenchymal Stem Cell Transplantation ; Motor Neurons/*pathology ; Muscular Atrophy, Spinal/genetics/pathology/*therapy ; Neural Stem Cells/cytology/transplantation ; Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive fatal neurodegenerative diseases. They differ in their disease development but have in common a loss of motor neuron as they progress. Research is ongoing to further understand the origin of these diseases but this common thread of motor neuron loss has provided a target for the development of therapies for both ALS and SMA. It is the linked fields of gene and cell therapy that are providing some of the most interesting therapeutic possibilities.}, }
@article {pmid22572535, year = {2012}, author = {Palubinsky, AM and Martin, JA and McLaughlin, B}, title = {The role of central nervous system development in late-onset neurodegenerative disorders.}, journal = {Developmental neuroscience}, volume = {34}, number = {2-3}, pages = {129-139}, pmid = {22572535}, issn = {1421-9859}, support = {P30 HD015052/HD/NICHD NIH HHS/United States ; R01 NS050396/NS/NINDS NIH HHS/United States ; NS050396/NS/NINDS NIH HHS/United States ; P30HD15052/HD/NICHD NIH HHS/United States ; }, mesh = {Brain/*growth &amp; development/metabolism/physiopathology ; Cell Death/physiology ; Humans ; Nerve Degeneration/*metabolism/physiopathology ; Neurodegenerative Diseases/*metabolism/physiopathology ; Neurons/metabolism ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The human brain is dependent upon successfully maintaining ionic, energetic and redox homeostasis within exceptionally narrow margins for proper function. The ability of neurons to adapt to genetic and environmental perturbations and evoke a 'new normal' can be most fully appreciated in the context of neurological disorders in which clinical impairments do not manifest until late in life, although dysfunctional proteins are expressed early in development. We now know that proteins controlling ATP generation, mitochondrial stability, and the redox environment are associated with neurological disorders such as Parkinson's disease and amyotrophic lateral sclerosis. Generally, focus is placed on the role that early or long-term environmental stress has in altering the survival of cells targeted by genetic dysfunctions; however, the central nervous system undergoes several periods of intense stress during normal maturation. One of the most profound periods of stress occurs when 50% of neurons are removed via programmed cell death. Unfortunately, we have virtually no understanding of how these events proceed in individuals who harbor mutations that are lethal later in life. Moreover, there is a profound lack of information on circuit formation, cell fate during development and neurochemical compensation in either humans or the animals used to model neurodegenerative diseases. In this review, we consider the current knowledge of how energetic and oxidative stress signaling differs between neurons in early versus late stages of life, the influence of a new group of proteins that can integrate cell stress signals at the mitochondrial level, and the growing body of evidence that suggests early development should be considered a critical period for the genesis of chronic neurodegenerative diseases.}, }
@article {pmid22570068, year = {2012}, author = {Kwak, S}, title = {[Molecular link between inefficient GluA2 RNA editing and TDP-43 pathology in ALS motor neurons].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {5}, pages = {549-556}, pmid = {22570068}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; DNA-Binding Proteins/*analysis ; Humans ; Mice ; Motor Neurons/*chemistry/*pathology ; *RNA Editing ; }, abstract = {The motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients exhibit several molecular abnormalities, including 2 that are specific to ALS motor neurons: (1) pathological changes related to the mislocalization of the TAR DNA-binding protein (TDP-43), including both the appearance of phosphorylated TDP-43-containing inclusions in the cytoplasm and the loss of TDP-43 from the nucleus; and (2) inefficient RNA editing at the Q/R site of GluA2, a subunit of the AMPA receptor. TDP-43-related pathological features are closely associated with ALS in most ALS patients and with significant behavioral and pathological changes in genetically engineered mice; therefore, abnormal TDP-43 processing is believed to play a role in the pathogenesis of ALS. The extent of GluA2 RNA editing decreases in the motor neurons of sporadic ALS patients in a disease-specific and motor neuron-selective manner. Importantly, this molecular abnormality is a direct cause of death of motor neurons in conditional knockout mice for adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes RNA editing at the GluA2 Q/R site. Notably, these molecular abnormalities, i.e., TDP-43-related pathological features and inefficient GluA2 RNA editing, are found in approximately half of the motor neurons in sporadic ALS patients and both of them always occur in the same motor neurons. Because TDP-43-related pathological features and inefficient GluA2 RNA editing are highly disease specific in ALS motor neurons, investigation into the molecular link between these abnormalities is likely to provide new insights into ALS pathogenesis.}, }
@article {pmid22570065, year = {2012}, author = {Tokuda, T}, title = {[Biomarkers for amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {5}, pages = {515-523}, pmid = {22570065}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers/*cerebrospinal fluid ; DNA-Binding Proteins/*cerebrospinal fluid ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. Modern technology has brought new insights in the underlying pathophysiology of ALS through examination of genomic, proteomic and physiological changes in patients. However, the diagnosis of this disorder is still based on clinical findings, and there is a pronounced delay between the onset of symptoms and diagnosis. Functional rating scales, forced vital capacity, and patient survival have been used as measures of therapeutic response so far. Although effective treatments for ALS are lacking, the discovery of biomarkers for this disease offers clinicians the tools for rapid diagnosis, improved ways to monitor disease progression, and insights into the pathophysiology of sporadic ALS. Potential biomarkers that are useful in the diagnosis of ALS and sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being eagerly investigated through blood and cerebrospinal fluid analyses, as well as physiological and neuroimaging studies. These biomarkers, when used in combination, might be sensitive to early therapeutic effects. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this review article, I have discussed the development of biochemical, physiological and neuroimaging biomarkers for ALS including our recent results on CSF TDP-43 (TAR DNA-binding protein 43 kDa), and have considered the potential future directions for research. We should ultimately aim to broaden the available therapeutic options for patients with this disease.}, }
@article {pmid22566558, year = {2012}, author = {Norris, DP and Grimes, DT}, title = {Mouse models of ciliopathies: the state of the art.}, journal = {Disease models &amp; mechanisms}, volume = {5}, number = {3}, pages = {299-312}, pmid = {22566558}, issn = {1754-8411}, support = {MC_U142670370/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Abnormalities, Multiple/metabolism/*pathology ; Animals ; Cilia/metabolism/*pathology ; *Disease Models, Animal ; Humans ; Mice ; Sense Organs/metabolism/pathology ; Signal Transduction ; Translational Research, Biomedical ; }, abstract = {The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS), Joubert syndrome (JBTS), Bardet-Biedl syndrome (BBS) and Alström syndrome (ALS). Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects.}, }
@article {pmid22555610, year = {2012}, author = {Tarasiuk, J and Kułakowska, A and Drozdowski, W and Kornhuber, J and Lewczuk, P}, title = {CSF markers in amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {119}, number = {7}, pages = {747-757}, pmid = {22555610}, issn = {1435-1463}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/pathology ; Biomarkers/*cerebrospinal fluid ; Blood-Brain Barrier/metabolism/pathology ; Humans ; Motor Neurons/metabolism/pathology ; Neurofilament Proteins/*cerebrospinal fluid ; Oxidative Stress ; tau Proteins/*cerebrospinal fluid ; }, abstract = {Amyotrophic lateral sclerosis (ALS, 'Lou Gehrig disease') is the most common, progressive, neurodegenerative, motor neuron disease, causing damage to upper and lower motor neurons, leading to paralysis and death within 3-5 years. Majority of ALS cases are sporadic ALS (SALS) and only 5-10 % of cases are familial ALS (FALS). Pathogenesis of ALS is complicated and still unclear, including genetic, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurofilament accumulation, impaired trophic support, altered glial function, viral infection, immune imbalance and impairment of the blood-brain, blood-spinal cord and blood-cerebrospinal fluid barriers (BBB/BSCB/BCSFB). The CSF analysis is still one of the basic laboratory tools and might reflect pathophysiological alterations in the course of the disease and could provide an insight into disease pathomechanisms. The most important aim of its analysis is evaluation of blood-CSF barrier, which is altered in 46 % of ALS patients. The CSF biomarkers may give insight into ALS pathophysiology and may be useful for early, presymptomatic diagnosis, therapeutic monitoring and the development of new therapeutic strategies. This review summarizes the general concepts of biomarkers in CSF of ALS patients and their potential usefulness in further research.}, }
@article {pmid22544947, year = {2012}, author = {Kanouchi, T and Ohkubo, T and Yokota, T}, title = {Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {7}, pages = {739-745}, pmid = {22544947}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*pathology ; DNA-Binding Proteins/physiology ; Disease Progression ; Humans ; Motor Neurons/physiology ; Prions/*physiology ; Superoxide Dismutase/physiology ; Superoxide Dismutase-1 ; }, abstract = {Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.}, }
@article {pmid22533462, year = {2012}, author = {Marin, B and Kacem, I and Diagana, M and Boulesteix, M and Gouider, R and Preux, PM and Couratier, P and , }, title = {Juvenile and adult-onset ALS/MND among Africans: incidence, phenotype, survival: a review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {3}, pages = {276-283}, doi = {10.3109/17482968.2011.648644}, pmid = {22533462}, issn = {1471-180X}, mesh = {Africa/epidemiology ; Age of Onset ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology ; Humans ; Incidence ; Motor Neuron Disease/diagnosis/*epidemiology ; Phenotype ; }, abstract = {AIM: We reviewed the epidemiology of ALS among subjects of African origin, considering incidence, phenotype and prognosis.<br><br>METHODS: We searched Medline, Scopus, Science direct, Biblioth&#xe8;que Virtuelle de Neurologie Africaine (BVNA), (http://www-ient.unilim.fr/) and African journal OnLine databases using the following search terms "amyotrophic lateral sclerosis (ALS)", "motor neuron disease (MND)" or "Charcot disease", in combination with "Africa", "ethnic groups", "blacks" or "epidemiology". Of 1264 references examined, 35 were included in this review.<br><br>RESULTS AND DISCUSSION: Among the 35 references, 19 studies were performed in the African continent and dealt with MND/ALS; four other studies focused on ALS-like syndromes; finally, 12 studies were not performed in Africa but focused on either incidence and mortality or survival of ALS in subjects of African origin. Several characteristics of ALS among Africans or subjects of African origin were identified: (i) lower incidence rates among people of African origin living in western countries, (ii) higher incidence of classic ALS among men, (iii) presence of juvenile form, (iv) younger age at onset of classic ALS. We cannot draw firm conclusions about (i) the prognosis in African ALS patients, (ii) prognostic factors, (iii) genetic or behavioral factors affecting incidence or clinical phenotype.<br><br>CONCLUSION: Further multicenter prospective studies with homogeneous methodological approaches need to be performed in Africa to clarify the situation.}, }
@article {pmid22532172, year = {2012}, author = {Cerami, C and Scarpini, E and Cappa, SF and Galimberti, D}, title = {Frontotemporal lobar degeneration: current knowledge and future challenges.}, journal = {Journal of neurology}, volume = {259}, number = {11}, pages = {2278-2286}, pmid = {22532172}, issn = {1432-1459}, mesh = {Animals ; Forecasting ; Frontotemporal Lobar Degeneration/*diagnosis/*genetics/pathology ; Humans ; Microtubules/genetics/pathology ; Mutation/genetics ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is one of the most frequent neurodegenerative disorders with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia. Regarding bvFTD, new criteria include the use of biomarkers. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence of a known causal mutation or at autopsy). Familial aggregation is frequently reported in FTLD, and about 10 % of cases have an autosomal dominant transmission. Microtubule-associated protein tau gene mutations have been the first ones identified, and are generally associated with early onset (40-50 years) and with the bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis. In addition, other genes are linked to rare cases of familiar FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified.}, }
@article {pmid22521219, year = {2012}, author = {Kamel, F and Umbach, DM and Bedlack, RS and Richards, M and Watson, M and Alavanja, MC and Blair, A and Hoppin, JA and Schmidt, S and Sandler, DP}, title = {Pesticide exposure and amyotrophic lateral sclerosis.}, journal = {Neurotoxicology}, volume = {33}, number = {3}, pages = {457-462}, pmid = {22521219}, issn = {1872-9711}, support = {Z01 CP010119/ImNIH/Intramural NIH HHS/United States ; Z01 ES049030/ImNIH/Intramural NIH HHS/United States ; Z01-CP010119/CP/NCI NIH HHS/United States ; Z01-ES049005/ES/NIEHS NIH HHS/United States ; ZIA ES049030-15/ImNIH/Intramural NIH HHS/United States ; ZIA ES049005-20/ImNIH/Intramural NIH HHS/United States ; Z01 ES049005/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Age Factors ; Aged ; Agricultural Workers' Diseases/*chemically induced/mortality ; *Agriculture ; Amyotrophic Lateral Sclerosis/*chemically induced/mortality ; Female ; Humans ; Hydrocarbons, Chlorinated/*adverse effects ; Logistic Models ; Male ; Middle Aged ; *Occupational Exposure ; Odds Ratio ; Pesticides/*adverse effects ; Risk Assessment ; Risk Factors ; Sex Factors ; Spouses ; }, abstract = {Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993-1997. In mortality data collected through February 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta-analysis, ALS was associated with use of pesticides as a group (1.9, 1.1-3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8-3.5), pyrethroids (1.4, 0.6-3.4), herbicides (1.6, 0.7-3.7), and fumigants (1.8, 0.8-3.9). ORs were elevated forever use of the specific OCs aldrin (2.1, 0.8-5.1), dieldrin (2.6, 0.9-7.3), DDT (2.1, 0.9-5.0), and toxaphene (2.0, 0.8-4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations.}, }
@article {pmid22519910, year = {2012}, author = {Dayton, RD and Wang, DB and Klein, RL}, title = {The advent of AAV9 expands applications for brain and spinal cord gene delivery.}, journal = {Expert opinion on biological therapy}, volume = {12}, number = {6}, pages = {757-766}, pmid = {22519910}, issn = {1744-7682}, support = {R01 NS048450/NS/NINDS NIH HHS/United States ; NS048450/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/*metabolism ; Dependovirus/*genetics ; Gene Expression Regulation ; *Gene Transfer Techniques ; Genetic Therapy/*methods ; *Genetic Vectors ; Humans ; Injections, Intravenous ; Injections, Intraventricular ; Injections, Spinal ; Neurons/metabolism ; Spinal Cord/*metabolism ; }, abstract = {INTRODUCTION: Straightforward studies compared adeno-associated virus (AAV) serotypes to determine the most appropriate one for robust expression in the CNS. AAV9 was efficient when directly injected into the brain, but more surprisingly, AAV9 produced global expression in the brain and spinal cord after a peripheral, systemic route of administration to neonatal mice.<br><br>AREAS COVERED: Topics include AAV9 gene delivery from intraparenchymal, intravenous, intrathecal and intrauterine routes of administration, and related preclinical studies and disease models. Systemic AAV9 gene transfer yields remarkably consistent neuronal expression, though only in early development. AAV9 is versatile to study neuropathological proteins: microtubule-associated protein tau and transactive response DNA-binding protein 43 kDa (TDP-43).<br><br>EXPERT OPINION: AAV9 will be more widely used based on current data, although other natural serotypes and recombineered vectors may also support or improve upon wide-scale expression. A peripheral-to-central gene delivery that can affect the entire CNS without having to inject the CNS is promising for basic functional experiments, and potentially for gene therapy. Systemic or intra-cerebrospinal fluid routes of AAV9 administration should be considered for spinal muscular atrophy, lysosomal storage diseases and amyotrophic lateral sclerosis, if more neuronal expression can be achieved in adults, or if glial expression can be exploited.}, }
@article {pmid22513921, year = {2012}, author = {Baldinger, R and Katzberg, HD and Weber, M}, title = {Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD004157}, doi = {10.1002/14651858.CD004157.pub2}, pmid = {22513921}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Muscle Cramp/*drug therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials.<br><br>OBJECTIVES: To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information.<br><br>SELECTION CRITERIA: We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy.<br><br>DATA COLLECTION AND ANALYSIS: All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction.<br><br>MAIN RESULTS: Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small studies showed a statistically nonsignificant result for the amino acid L-threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps.<br><br>AUTHORS' CONCLUSIONS: There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.}, }
@article {pmid22512552, year = {2012}, author = {Camacho, ME and Carrion, MD and Lopez-Cara, LC and Entrena, A and Gallo, MA and Espinosa, A and Escames, G and Acuna-Castroviejo, D}, title = {Melatonin synthetic analogs as nitric oxide synthase inhibitors.}, journal = {Mini reviews in medicinal chemistry}, volume = {12}, number = {7}, pages = {600-617}, doi = {10.2174/138955712800626674}, pmid = {22512552}, issn = {1875-5607}, mesh = {Animals ; Enzyme Inhibitors/chemical synthesis/*chemistry/*pharmacology ; Humans ; Melatonin/*analogs &amp; derivatives/chemical synthesis/chemistry/*pharmacology ; Nitric Oxide Synthase/*antagonists &amp; inhibitors ; }, abstract = {Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer's disease, Huntington's disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson's disease.}, }
@article {pmid22505366, year = {2012}, author = {Wojtera, M and Sobów, T and Kłoszewska, I and Liberski, PP and Brown, DR and Sikorska, B}, title = {Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer's disease: morphometric study and review of the literature.}, journal = {Folia neuropathologica}, volume = {50}, number = {1}, pages = {74-84}, pmid = {22505366}, issn = {1509-572X}, mesh = {Alzheimer Disease/*metabolism/pathology ; Biomarkers/analysis ; Brain/metabolism/pathology ; Creutzfeldt-Jakob Syndrome/*metabolism/pathology ; Humans ; Immunohistochemistry ; Microglia/*metabolism/pathology ; }, abstract = {INTRODUCTION: Microglia are the resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. Activated microglia up-regulate many surface receptors such as the major histocompatibility complex (MHC) or complement receptors and secrete a variety of soluble biologically active factors, which are either neurotrophic (e.g. Glia-Derived Neurotrophic Factor [GDNF]) or proinflammatory and neurotoxic (e.g. tumour necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], nitric oxide [NO], superoxide, eicosanoids, quinolinic acid).<br><br>AIM: The aim of this work was to assess differences in the expression of microglial markers (ferritin, CD68, and HLA-DR) between AD and Creutzfeldt-Jakob disease (CJD) brains.<br><br>MATERIAL AND METHODS: Analyses were performed on 65 slices derived from 26 brains [46 CJD (20 brains), 12 AD (4 brains) and 7 controls (2 brains)]. Slices were labelled immunohistochemically using anti-ferritin, anti-HLA-DR and anti-CD68 antibodies. The nonparametric Mann-Whitney U test was used to assess quantitative differences between groups.<br><br>RESULTS: The expression of microglia markers (HLA-DR and CD68) is more noticeable in CJD than in AD or control brains. There is no difference between AD and controls. The latter statement is only true in the case of using HLA-DR or CD-68 labelling. Furthermore, ferritin is not a recommended marker in this context.<br><br>CONCLUSIONS: CNS inflammation is more prominent in CJD than in AD or controls. The lack of differences between AD and controls may result from a relatively advanced neurodegeneration in AD brains. In late phases of AD, inflammation is no longer present, in contrast to the early stages of the disease.}, }
@article {pmid22496581, year = {2012}, author = {Swash, M}, title = {Why are upper motor neuron signs difficult to elicit in amyotrophic lateral sclerosis?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {6}, pages = {659-662}, doi = {10.1136/jnnp-2012-302315}, pmid = {22496581}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Humans ; Interneurons/physiology ; Motor Neurons, Gamma/*physiology ; Muscle Spasticity/physiopathology ; Nerve Degeneration/physiopathology ; Reflex, Babinski/physiopathology ; Reflex, Stretch/physiology ; Spinal Cord/*physiopathology ; }, abstract = {It is often difficult to identify signs of upper motor neuron lesion in the limbs of patients with amyotrophic lateral sclerosis, in whom there is neurogenic muscle wasting of varying severity. The reasons for this are complex and not related simply to the degree of lower motor neuron muscle wasting but, rather, depend on the pathophysiological abnormalities that develop in response to damage to descending motor pathways and to motor neurons and interneurons in the ventral horns of the spinal cord. The different mechanisms underlying the clinical phenomenology of the functional motor defect in amyotrophic lateral sclerosis, that lead to difficulty in detecting classical upper motor neuron signs, are discussed.}, }
@article {pmid22488161, year = {2012}, author = {Drechsel, DA and Estévez, AG and Barbeito, L and Beckman, JS}, title = {Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS.}, journal = {Neurotoxicity research}, volume = {22}, number = {4}, pages = {251-264}, pmid = {22488161}, issn = {1476-3524}, support = {R01 NS058628/NS/NINDS NIH HHS/United States ; P30ES000210/ES/NIEHS NIH HHS/United States ; P01AT002034/AT/NCCIH NIH HHS/United States ; T32ES07060/ES/NIEHS NIH HHS/United States ; R01NS058628A/NS/NINDS NIH HHS/United States ; P01 AT002034/AT/NCCIH NIH HHS/United States ; T32 ES007060/ES/NIEHS NIH HHS/United States ; P30 ES000210/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Apoptosis/physiology ; Humans ; Models, Biological ; Motor Neurons/*pathology ; Nitric Oxide/*metabolism ; Oxidative Stress/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Oxidative damage is a common and early feature of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. Dr. Mark Smith and his colleagues have built the case for oxidative stress being a primary progenitor rather than a secondary end-stage epiphenomenon of neurodegeneration. They proposed that reactive oxygen species contribute to the "age-related cascade of neurodegeneration," whereby accumulative oxidative damage with age promotes other characteristic pathological changes in afflicted brain regions, including protein aggregation, metabolic deficiencies, and inflammation. Nitric oxide (NO) likely plays a critical role in this age-related cascade. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through stimulating cyclic GMP synthesis. However, the same physiological concentrations of NO, relevant in cellular signaling, may also initiate and amplify oxidative damage by diffusion-limited reactions with superoxide (O(2)(•-)) to produce peroxynitrite (ONOO(-)). This is perhaps best illustrated in ALS where physiological levels of NO promote survival of motor neurons, but the same concentrations can stimulate motor neuron apoptosis and glial cell activation under pathological conditions. While these changes represent a complex mechanism involving multiple cell types in the pathogenesis of ALS, they also reveal general processes underlying neurodegeneration.}, }
@article {pmid22484281, year = {2012}, author = {Benga, I and Benga, O}, title = {Implications of water channel proteins in selected neurological disorders: epilepsies, muscular dystrophies, amyotrophic lateral sclerosis, neuromyelitis optica, Parkinson's disease, and spongiform encephalopathies.}, journal = {Molecular aspects of medicine}, volume = {33}, number = {5-6}, pages = {590-604}, doi = {10.1016/j.mam.2012.03.003}, pmid = {22484281}, issn = {1872-9452}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Aquaporins/antagonists &amp; inhibitors/*metabolism ; Autoantibodies/biosynthesis/immunology ; Biomarkers/metabolism ; Cell Membrane/metabolism ; Cell Membrane Permeability ; Epilepsy/*metabolism/pathology ; Humans ; Immunoglobulin G/biosynthesis/immunology ; Muscular Dystrophy, Duchenne/*metabolism/pathology ; Neuromyelitis Optica/*metabolism/pathology ; Parkinson Disease/*metabolism/pathology ; Prion Diseases/*metabolism/pathology ; Water/*metabolism ; Water-Electrolyte Balance/physiology ; }, abstract = {The aim of this article is to describe the roles of water channel proteins (WCPs) in some neurological diseases in which the implications of these proteins became obvious in the decades after the discovery of WCPs of their presence in the CNS. The diseases which were selected for this review include: epilepsies, muscular dystrophies, amyotrophic lateral sclerosis, neuromyelitis optica, Parkinson's disease, and spongiform encephalopathies. The priorities of Benga group from Cluj-Napoca, Romania, are mentioned, such as the idea of a generalized membrane defect affecting water permeability in epilepsy and in Duchenne muscular dystrophy. Some of these neurological disorders discussed in this article appeared to be water channelopathies. A typical example is neuromyelitis optica (NMO), in which the identification of the specific marker autoantibody against aquaporin 4 in the sera of patients was a milestone in the diagnosis. This has aided understanding of the pathogenesis of NMO and led to better control of its treatment. However, further studies are needed to characterize the function and regulation of WCPs in other neurological diseases, in particular to determine if modulation of WCP function may provide a novel approach to therapy in such diseases.}, }
@article {pmid22482522, year = {2012}, author = {Nevens, F and Laleman, W}, title = {Artificial liver support devices as treatment option for liver failure.}, journal = {Best practice &amp; research. Clinical gastroenterology}, volume = {26}, number = {1}, pages = {17-26}, doi = {10.1016/j.bpg.2012.01.002}, pmid = {22482522}, issn = {1532-1916}, mesh = {Equipment Design ; Hepatic Encephalopathy/therapy ; Humans ; Liver Failure/*therapy ; Liver Failure, Acute/therapy ; Liver Transplantation ; *Liver, Artificial ; Sorption Detoxification/instrumentation ; }, abstract = {Non-biological artificial liver support (ALS) devices aim to remove albumin-bound and water-soluble toxins arising as a result of liver failure. They do not directly improve the liver synthetic capacity. The currently most used devices combine haemodialysis with albumin dialysis (MARS) or plasma separation and filtration (Prometheus). These devices have been used as a treatment for different types of liver failure: acute liver failure, acute-on-chronic liver failure and primary non- or poor-function after liver transplantation. Overall these devices are found to be safe. The following beneficial effects have been documented: improvement of jaundice, amelioration of haemodynamic instability, reduction of portal hypertension, lowering of intracranial pressure and improvement of hepatic encephalopathy. However, recently multicentre controlled trials failed to show a beneficial effect on transplant-free survival. Therefore the use of these devices at present seems only justified as a bridge to liver transplantation.}, }
@article {pmid22482456, year = {2012}, author = {Martin, LJ}, title = {Biology of mitochondria in neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {107}, number = {}, pages = {355-415}, pmid = {22482456}, issn = {1878-0814}, support = {NS034100/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagy ; Calcium Signaling ; Cell Death ; DNA Repair ; DNA, Mitochondrial/genetics/metabolism ; Humans ; Mice ; Mitochondria/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; Translational Research, Biomedical ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal degeneration in these familial diseases, and in the more common idiopathic (sporadic) diseases, are unresolved. Genetic, biochemical, and morphological analyses of human AD, PD, and ALS, as well as their cell and animal models, reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and the overlying genetic variations. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS.}, }
@article {pmid22482452, year = {2012}, author = {Redler, RL and Dokholyan, NV}, title = {The complex molecular biology of amyotrophic lateral sclerosis (ALS).}, journal = {Progress in molecular biology and translational science}, volume = {107}, number = {}, pages = {215-262}, pmid = {22482452}, issn = {1878-0814}, support = {F31 NS073435/NS/NINDS NIH HHS/United States ; R01 GM080742/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/*genetics/*metabolism/pathology ; Animals ; Apoptosis ; Axons/metabolism/pathology ; Humans ; Mice ; Models, Molecular ; Motor Neurons/metabolism/pathology ; Necrosis ; Nerve Growth Factors/metabolism ; Protein Folding ; Protein Multimerization ; RNA Processing, Post-Transcriptional ; Superoxide Dismutase/chemistry/genetics/metabolism ; Superoxide Dismutase-1 ; Translational Research, Biomedical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that causes selective death of motor neurons followed by paralysis and death. A subset of ALS cases is caused by mutations in the gene for Cu, Zn superoxide dismutase (SOD1), which impart a toxic gain of function to this antioxidant enzyme. This neurotoxic property is widely believed to stem from an increased propensity to misfold and aggregate caused by decreased stability of the native homodimer or a tendency to lose stabilizing posttranslational modifications. Study of the molecular mechanisms of SOD1-related ALS has revealed a complex array of interconnected pathological processes, including glutamate excitotoxicity, dysregulation of neurotrophic factors and axon guidance proteins, axonal transport defects, mitochondrial dysfunction, deficient protein quality control, and aberrant RNA processing. Many of these pathologies are directly exacerbated by misfolded and aggregated SOD1 and/or cytosolic calcium overload, suggesting the primacy of these events in disease etiology and their potential as targets for therapeutic intervention.}, }
@article {pmid22477152, year = {2012}, author = {Morris, HR and Waite, AJ and Williams, NM and Neal, JW and Blake, DJ}, title = {Recent advances in the genetics of the ALS-FTLD complex.}, journal = {Current neurology and neuroscience reports}, volume = {12}, number = {3}, pages = {243-250}, pmid = {22477152}, issn = {1534-6293}, support = {G0700943/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adenosine Triphosphatases/genetics ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; C9orf72 Protein ; Cell Cycle Proteins/genetics ; Chromosomes, Human, Pair 9 ; Frontotemporal Lobar Degeneration/*genetics/pathology ; *Genetic Predisposition to Disease ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Mutation/*genetics ; Progranulins ; Proteins/genetics ; RNA-Binding Proteins ; Valosin Containing Protein ; }, abstract = {There is a clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of autosomal-dominant genes have been described that primarily cause ALS or FTLD such as progranulin (GRN), valosin-containing protein (VCP), and TAR DNA-Binding Protein (TARDBP), and for each of these conditions there are a small number of cases with both ALS and FTLD. Two major genes were described in 2011, which cause FTLD and/or ALS within extended kindreds. Ubiquilin2 (UBQLN2) is responsible for X-linked FTLD/ALS. A hexanucleotide repeat expansion in C9ORF72 causes chromosome 9p linked FTLD/ALS and is the most common cause of familial ALS accounting for about 40 % of familial cases. Both UBQLN2 and C9ORF72 mutations lead to TDP-43 positive neuropathology, and C9ORF72-positive cases have p62/ubiquitin-positive pathology, which is not stained by TDP-43 antibodies. Ubiquilin2 is one of a family of proteins thought to be important in targeting abnormal proteins for degradation via lysosomal and proteasomal routes. The pathogenic mechanism of the C9ORF72 expansion is unknown but may involve partial haploinsufficiency of C9ORF72 and/or the formations of toxic RNA inclusions. The identification of mutations in these genes represents an important step forward in our understanding of the clinical, pathological, and genetic spectrum of ALS/FTLD diseases.}, }
@article {pmid22475223, year = {2012}, author = {Bajorath, J}, title = {Modeling of activity landscapes for drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {7}, number = {6}, pages = {463-473}, doi = {10.1517/17460441.2012.679616}, pmid = {22475223}, issn = {1746-045X}, mesh = {Chemistry, Pharmaceutical/*methods ; Computer Simulation ; *Drug Design ; Drug Discovery/*methods ; *Models, Chemical ; Pharmaceutical Preparations/*chemistry ; Software ; Structure-Activity Relationship ; }, abstract = {INTRODUCTION: Activity landscapes (ALs) are graphical representations that integrate compound structure and potency relationships. These computer-generated models enable the interactive large-scale analysis of structure-activity relationships (SARs) and complement traditional approaches to study SARs of individual compound series in a qualitative or quantitative manner. A variety of AL designs have been reported.<br><br>AREAS COVERED: The concept of activity landscapes is introduced and different methodologies to represent 2D or 3D AL representations of large compound data sets are described on the basis of original literature references. Several AL variants and extensions have been generated for special applications in medicinal chemistry. These include, for example, AL views of evolving data sets with constant topology, selectivity landscapes and multi-target ALs, or molecular mechanism and multi-property maps. Furthermore, the applicability domain of the AL concept is discussed including specific requirements for practical utility in medicinal chemistry opportunities for further developments.<br><br>EXPERT OPINION: AL modeling has substantially extended conventional ways to study SARs. The AL concept is inseparable from the notion of activity cliffs that are of high interest in SAR analysis. AL design is an area of active research at the interface between chemoinformatics and medicinal chemistry with potential for further growth. Special emphasis must be put on increasing the usability of AL models for practicing medicinal chemists.}, }
@article {pmid22471903, year = {2012}, author = {Pickles, S and Vande Velde, C}, title = {Misfolded SOD1 and ALS: zeroing in on mitochondria.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {4}, pages = {333-340}, doi = {10.3109/17482968.2012.648645}, pmid = {22471903}, issn = {1471-180X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; *Antibodies ; Humans ; Mitochondria/*metabolism ; Motor Neurons/*metabolism ; Mutation ; *Protein Folding ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mutations in SOD1, causative for a subset of familial ALS cases, are associated with the formation of non-normal SOD1 conformers. Recent studies have defined this pool of SOD1 as misfolded and new antibodies have been developed to selectively detect misfolded SOD1 in vivo and in vitro. We will review these new tools and expand on the evidence demonstrating mitochondria as a common intersecting point for misfolded SOD1.}, }
@article {pmid22450743, year = {2012}, author = {Kill, C and Dersch, W and Wulf, H}, title = {Advanced life support and mechanical ventilation.}, journal = {Current opinion in critical care}, volume = {18}, number = {3}, pages = {251-255}, doi = {10.1097/MCC.0b013e3283523f69}, pmid = {22450743}, issn = {1531-7072}, mesh = {Cardiopulmonary Resuscitation/*methods ; Clinical Trials as Topic ; Heart Arrest/*therapy ; Humans ; Life Support Care/*methods ; Oxygen Inhalation Therapy/*methods ; Positive-Pressure Respiration/methods ; Respiration, Artificial/*methods ; }, abstract = {PURPOSE OF REVIEW: Artificial ventilation is one of the best known resuscitation procedures. It is generally accepted that there must be oxygen delivery to vital organs during cardiac arrest and resuscitation in order to prevent irreversible damage, but there is an increasing number of ventilation concepts for resuscitation. Traditional and alternative methods of ventilation are reviewed.<br><br>RECENT FINDINGS: The need for positive-pressure ventilation during resuscitation as an essential gold standard might be overestimated at least in the first minutes of cardiopulmonary resuscitation (CPR). The co-founders of the concept of cardiocerebral resuscitation could show positive effects of a sole passive oxygenation at the beginning of advanced life support (ALS). Research was published on continuous positive airway pressure (CPAP) ventilation as well as on CPAP plus pressure support ventilation. In addition to positive-pressure ventilation, the use of an impedance threshold device, partly in addition with active compression-decompression CPR, was investigated in both experimental and clinical settings. None of these methods alone could be proven to improve the outcome of cardiac arrest. The role of high oxygen concentration during CPR also remains unclear.<br><br>SUMMARY: Positive-pressure ventilation with pure oxygen remains, in clinical practice, the gold standard in ALS. Further research should focus on the role of passive oxygenation during early ALS. The concentration of oxygen needed during resuscitation has to be defined and alternative ventilation patterns, regarding the impact of CPR, should be investigated.}, }
@article {pmid22445064, year = {2012}, author = {King, OD and Gitler, AD and Shorter, J}, title = {The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {61-80}, pmid = {22445064}, issn = {1872-6240}, support = {R21 NS067354-0110/NS/NINDS NIH HHS/United States ; DP2 OD004417/OD/NIH HHS/United States ; DP2 OD002177-01/OD/NIH HHS/United States ; 1DP2OD002177-01/OD/NIH HHS/United States ; R21 NS067354-02/NS/NINDS NIH HHS/United States ; 1DP2OD004417-01/OD/NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; R21 NS067354/NS/NINDS NIH HHS/United States ; R21 NS067354-01/NS/NINDS NIH HHS/United States ; DP2 OD002177/OD/NIH HHS/United States ; }, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Calmodulin-Binding Proteins/genetics/physiology ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology ; Humans ; Neurodegenerative Diseases/*genetics/metabolism ; Prions/*genetics/metabolism/physiology ; RNA-Binding Protein EWS ; RNA-Binding Protein FUS/genetics/physiology ; RNA-Binding Proteins/*genetics/metabolism/physiology ; TATA-Binding Protein Associated Factors/genetics/physiology ; }, abstract = {Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable 'prion domain' enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease and Huntington's disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system. This article is part of a Special Issue entitled RNA-Binding Proteins.}, }
@article {pmid22444279, year = {2012}, author = {Polymenidou, M and Lagier-Tourenne, C and Hutt, KR and Bennett, CF and Cleveland, DW and Yeo, GW}, title = {Misregulated RNA processing in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {3-15}, pmid = {22444279}, issn = {1872-6240}, support = {RC1 NS069144-02/NS/NINDS NIH HHS/United States ; R01 GM084317/GM/NIGMS NIH HHS/United States ; R37NS27036/NS/NINDS NIH HHS/United States ; GM084317/GM/NIGMS NIH HHS/United States ; RC1 NS069144/NS/NINDS NIH HHS/United States ; K99 NS075216-02/NS/NINDS NIH HHS/United States ; K99 NS075216/NS/NINDS NIH HHS/United States ; R01 NS075449/NS/NINDS NIH HHS/United States ; K99NS075216/NS/NINDS NIH HHS/United States ; 089701/WT_/Wellcome Trust/United Kingdom ; HG004659/HG/NHGRI NIH HHS/United States ; R37 NS027036/NS/NINDS NIH HHS/United States ; R37 NS027036-24/NS/NINDS NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; DNA-Binding Proteins/genetics ; Frontotemporal Lobar Degeneration/genetics ; Homeostasis ; Humans ; RNA/*genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; RNA-Binding Proteins/genetics ; TDP-43 Proteinopathies/genetics/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) research is undergoing an era of unprecedented discoveries with the identification of new genes as major genetic causes of this disease. These discoveries reinforce the genetic, clinical and pathological overlap between ALS and frontotemporal lobar degeneration (FTLD). Common causes of these diseases include mutations in the RNA/DNA-binding proteins, TDP-43 and FUS/TLS and most recently, hexanucleotide expansions in the C9orf72 gene, discoveries that highlight the overlapping pathogenic mechanisms that trigger ALS and FTLD. TDP-43 and FUS/TLS, both of which participate in several steps of RNA processing, are abnormally aggregated and mislocalized in ALS and FTLD, while the expansion in the C9orf72 pre-mRNA strongly suggests sequestration of one or more RNA binding proteins in pathologic RNA foci. Hence, ALS and FTLD converge in pathogenic pathways disrupting the regulation of RNA processing. This article is part of a Special Issue entitled RNA-Binding Proteins.}, }
@article {pmid22438708, year = {2012}, author = {Nicolas-Alonso, LF and Gomez-Gil, J}, title = {Brain computer interfaces, a review.}, journal = {Sensors (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {1211-1279}, pmid = {22438708}, issn = {1424-8220}, mesh = {*Algorithms ; Brain/*physiology ; Electroencephalography/*instrumentation ; Humans ; *Man-Machine Systems ; Pattern Recognition, Automated/*methods ; Signal Processing, Computer-Assisted/instrumentation ; *Transducers ; *User-Computer Interface ; }, abstract = {A brain-computer interface (BCI) is a hardware and software communications system that permits cerebral activity alone to control computers or external devices. The immediate goal of BCI research is to provide communications capabilities to severely disabled people who are totally paralyzed or 'locked in' by neurological neuromuscular disorders, such as amyotrophic lateral sclerosis, brain stem stroke, or spinal cord injury. Here, we review the state-of-the-art of BCIs, looking at the different steps that form a standard BCI: signal acquisition, preprocessing or signal enhancement, feature extraction, classification and the control interface. We discuss their advantages, drawbacks, and latest advances, and we survey the numerous technologies reported in the scientific literature to design each step of a BCI. First, the review examines the neuroimaging modalities used in the signal acquisition step, each of which monitors a different functional brain activity such as electrical, magnetic or metabolic activity. Second, the review discusses different electrophysiological control signals that determine user intentions, which can be detected in brain activity. Third, the review includes some techniques used in the signal enhancement step to deal with the artifacts in the control signals and improve the performance. Fourth, the review studies some mathematic algorithms used in the feature extraction and classification steps which translate the information in the control signals into commands that operate a computer or other device. Finally, the review provides an overview of various BCI applications that control a range of devices.}, }
@article {pmid22428796, year = {2012}, author = {Bosma, R and Stroman, PW}, title = {Diffusion tensor imaging in the human spinal cord: development, limitations, and clinical applications.}, journal = {Critical reviews in biomedical engineering}, volume = {40}, number = {1}, pages = {1-20}, doi = {10.1615/critrevbiomedeng.v40.i1.10}, pmid = {22428796}, issn = {0278-940X}, mesh = {Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Image Enhancement/*methods ; Nerve Fibers, Myelinated/*pathology ; Spinal Cord Diseases/*pathology ; Spinal Cord Injuries/*pathology ; }, abstract = {Diffusion tensor imaging (DTI) is currently the only non-invasive in vivo assessment of white matter tract integrity. Capitalizing on the diffusion properties of water within an axon, DTI enables the visualization of tissue structure at a microscopic scale. Furthermore, measurements of anisotropy and diffusivity enable the detection of subtle details of the effects of injury that cannot be detected using conventional magnetic resonance techniques. Recently, DTI has been applied to the spinal cord, and results have demonstrated it to be a valuable tool for assessing the extent of white matter damage in numerous spinal cord-related conditions including multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, myelitis, and spinal cord tumors. The purpose of this review is to discuss the technical limitations of the imaging method within the spinal cord, review possible solutions, and highlight the current uses and the potential clinical application of this technique.}, }
@article {pmid22424129, year = {2012}, author = {Armon, C and Nelson, LM}, title = {Is head trauma a risk factor for amyotrophic lateral sclerosis? An evidence based review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {4}, pages = {351-356}, doi = {10.3109/17482968.2012.660954}, pmid = {22424129}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; Causality ; Craniocerebral Trauma/complications/*epidemiology ; Humans ; Risk Factors ; }, abstract = {Our objective was to evaluate the epidemiological literature regarding the association between trauma to the head and ALS, in order to determine if trauma to the head is a risk factor for ALS. A Medline literature search was conducted for the period between 1980 and October 2010 using the search terms: ('head trauma' OR 'head injury') AND (ALS OR 'amyotrophic lateral sclerosis' OR MND OR 'motor neuron disease'). The references of primary articles and reviews were checked to assure completeness of the search. Articles with primary data and reference groups were reviewed. The American Academy of Neurology evidence based method for classification of evidence for inferring causality and assigning level of conclusion was used. Twelve of 14 articles published since 1980 met the inclusion criteria. One class II article and three class III articles showed an association between a single instance of head trauma and ALS that did not exceed what might be seen due to chance alone. Eight class IV evidence articles could not inform conclusions. We concluded that evidence based analysis of the epidemiologic literature does not permit concluding that a single instance of head trauma is a risk factor for, or causes, ALS (Level U conclusion).}, }
@article {pmid22420316, year = {2012}, author = {Van Langenhove, T and van der Zee, J and Van Broeckhoven, C}, title = {The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum.}, journal = {Annals of medicine}, volume = {44}, number = {8}, pages = {817-828}, pmid = {22420316}, issn = {1365-2060}, mesh = {Adenosine Triphosphatases/genetics ; Amyotrophic Lateral Sclerosis/complications/*genetics ; C9orf72 Protein ; Cell Cycle Proteins/genetics ; DNA Repeat Expansion ; DNA-Binding Proteins/*genetics ; Frontotemporal Lobar Degeneration/complications/*genetics ; Humans ; Proteins/*genetics ; RNA-Binding Protein FUS/genetics ; Valosin Containing Protein ; }, abstract = {There is increasing evidence that frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) represent a continuum of neurodegenerative diseases. FTLD is complicated by ALS in a significant proportion of patients, and neuropsychological studies have demonstrated frontotemporal dysfunction in up to 50% of ALS patients. More recently, advances in neuropathology and molecular genetics have started to disclose the biological basis for the observed clinical concurrence. TDP-43 and FUS have been discovered as key pathological proteins in both FTLD and ALS. The most recent discovery of a pathological hexanucleotide repeat expansion in the gene C9orf72 as a frequent cause of both FTLD and ALS has eventually confirmed the association of these two at first sight distinct neurodegenerative diseases. Mutations in the TARDBP, FUS, and VCP genes had previously been associated with different phenotypes of the FTLD-ALS spectrum, although in these cases one end of the spectrum predominates. Whilst on the one hand providing evidence for overlap, these discoveries have also highlighted that FTLD and ALS are etiologically diverse. In this review, we review the recent advances that support the existence of an FTLD-ALS spectrum, with particular emphasis on the molecular genetic aspect.}, }
@article {pmid22419278, year = {2012}, author = {Miller, RG and Mitchell, JD and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {2012}, number = {3}, pages = {CD001447}, pmid = {22419278}, issn = {1469-493X}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Humans ; Life Expectancy ; Neuroprotective Agents/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*therapeutic use ; Tracheostomy ; }, abstract = {BACKGROUND: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field.<br><br>SELECTION CRITERIA: Types of studies: randomized controlled trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible.<br><br>MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31).<br><br>AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.}, }
@article {pmid22414400, year = {2012}, author = {Bungener, C}, title = {[Emotions and amyotrophic lateral sclerosis: a psychopathological perspective].}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {10}, number = {1}, pages = {57-64}, doi = {10.1684/pnv.2012.0313}, pmid = {22414400}, issn = {2115-8789}, mesh = {Adaptation, Psychological ; Aged ; Amyotrophic Lateral Sclerosis/epidemiology/*psychology ; Anxiety Disorders/diagnosis/epidemiology/*psychology ; Comorbidity ; Cross-Sectional Studies ; Depressive Disorder/diagnosis/epidemiology/*psychology ; *Emotions ; Humans ; Psychopathology ; Quality of Life/psychology ; Social Support ; }, abstract = {Emotions have not often been studied in amyotrophic lateral sclerosis (ALS). Most existing studies have assessed the psychopathological manifestations involved, essentially depression and less frequently anxiety. The results have shown that major depressive episodes and anxious episodes are not frequent in ALS patients, although moderate depressive or anxious symptoms are often observed, but less frequently than in other diseases like multiple sclerosis or Parkinson's disease. Depressive symptoms are not correlated to the duration or severity of the disease. This has led us to investigate the coping mechanisms involved in ALS. Results of previously published studies have shown that they did not differ from those observed in other somatic diseases, but ALS patients show more frequent concern with spirituality and religious preoccupations. It thus appears necessary to make a more detailed study of how ALS patients cope with the disease and its ominous consequences. Emotional processing difficulties may be a factor underlying quite diverse somatic and psychological disorders. The Baker's model propose five stages in emotional processing: emotional experience, emotional expression, labelling, linkage and awareness. Assessment of the emotional processing used by ALS patients should improve our comprehension of their adaptive functioning. The patients' caregivers play an essential role, and studies have shown that they often suffer themselves from depression and the burdens involved, and that the perceived social support has an impact on the quality of life and on the depression of the patients. Therefore, it seems important to assess the emotional processing not only of patients but also of their caregivers.}, }
@article {pmid22413952, year = {2012}, author = {Cozzolino, M and Pesaresi, MG and Gerbino, V and Grosskreutz, J and Carrì, MT}, title = {Amyotrophic lateral sclerosis: new insights into underlying molecular mechanisms and opportunities for therapeutic intervention.}, journal = {Antioxidants &amp; redox signaling}, volume = {17}, number = {9}, pages = {1277-1330}, doi = {10.1089/ars.2011.4328}, pmid = {22413952}, issn = {1557-7716}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*metabolism ; Animals ; Humans ; Motor Neurons/metabolism/pathology ; }, abstract = {Recent years have witnessed a renewed interest in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a late-onset progressive degeneration of motor neurons. The discovery of new genes associated with the familial form of the disease, along with a deeper insight into pathways already described for this disease, has led scientists to reconsider previous postulates. While protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, and excitotoxicity have not been dismissed, they need to be re-examined as contributors to the onset or progression of ALS in the light of the current knowledge that the mutations of proteins involved in RNA processing, apparently unrelated to the previous "old partners," are causative of the same phenotype. Thus, newly envisaged models and tools may offer unforeseen clues on the etiology of this disease and hopefully provide the key to treatment.}, }
@article {pmid22411250, year = {2012}, author = {Hayashi, M and Miyata, R and Tanuma, N}, title = {Oxidative stress in developmental brain disorders.}, journal = {Advances in experimental medicine and biology}, volume = {724}, number = {}, pages = {278-290}, doi = {10.1007/978-1-4614-0653-2_21}, pmid = {22411250}, issn = {0065-2598}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adolescent ; Adult ; Age Factors ; Aldehydes/metabolism ; Brain/growth &amp; development/metabolism/pathology ; Brain Diseases/genetics/*physiopathology/urine ; Child ; Cockayne Syndrome/metabolism/pathology ; Deoxyguanosine/analogs &amp; derivatives/urine ; Developmental Disabilities/genetics/*physiopathology/urine ; Female ; Humans ; Lipid Peroxidation/genetics ; Male ; Middle Aged ; Oxidative Stress/*physiology ; Xeroderma Pigmentosum/metabolism/pathology ; Young Adult ; }, abstract = {In order to examine the involvement of oxidative stress in developmental brain disorders, we have performed immunohistochemistry in autopsy brains and enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid and urines of patients. Here, we review our data on the hereditary DNA repair disorders, congenital metabolic errors and childhood-onset neurodegenerative disorders. First, in our studies on hereditary DNA repair disorders, increased oxidative DNA damage and lipid peroxidation were carried out in the degeneration of basal ganglia, intracerebral calcification and cerebellar degeneration in patients with xeroderma pigmentosum, Cockayne syndrome and ataxia-telangiectasia-like disorder, respectively. Next, congenital metabolic errors, apoptosis due to lipid peroxidation seemed to cause neuronal damage in neuronal ceroid-lipofuscinosis. Oxidative stress of DNA combined with reduced expression of antioxidant enzymes occurred in the lesion of the cerebral cortex in mucopolysaccharidoses and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. In childhood-onset neurodegenerative disorders, increased oxidative DNA damage and lipid peroxidation may lead to motor neuron death in spinal muscular atrophy like in amyotrophic lateral sclerosis. In patients with dentatorubral-pallidoluysian atrophy, a triplet repeat disease, deposition of oxidative products of nucleosides and reduced expression of antioxidant enzymes were found in the lenticular nucleus. In contrast, the involvement of oxidative stress is not definite in patients with Lafora disease. Rett syndrome patients showed changes of oxidative stress markers and antioxidant power in urines, although the changes may be related to systemic complications.}, }
@article {pmid22410787, year = {2012}, author = {Zhang, W and Duan, S and Li, Y and Xu, X and Qu, J and Zhang, W and Liu, GH}, title = {Converted neural cells: induced to a cure?.}, journal = {Protein &amp; cell}, volume = {3}, number = {2}, pages = {91-97}, pmid = {22410787}, issn = {1674-8018}, support = {R00 CA158055/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell Transdifferentiation ; Cell- and Tissue-Based Therapy ; Induced Pluripotent Stem Cells/cytology ; Neurons/*cytology/transplantation ; Parkinson Disease/therapy ; Stroke/therapy ; }, abstract = {Many neurodegenerative disorders such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and others often occur as a result of progressive loss of structure or function of neurons. Recently, many groups were able to generate neural cells, either differentiated from induced pluripotent stem cells (iPSCs) or converted from somatic cells. Advances in converted neural cells have opened a new era to ease applications for modeling diseases and screening drugs. In addition, the converted neural cells also hold the promise for cell replacement therapy (Kikuchi et al., 2011; Krencik et al., 2011; Kriks et al., 2011; Nori et al., 2011; Rhee et al., 2011; Schwartz et al., 2012). Here we will mainly discuss most recent progress on using converted functional neural cells to treat neurological diseases and highlight potential clinical challenges and future perspectives.}, }
@article {pmid22405725, year = {2012}, author = {Dewey, CM and Cenik, B and Sephton, CF and Johnson, BA and Herz, J and Yu, G}, title = {TDP-43 aggregation in neurodegeneration: are stress granules the key?.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {16-25}, pmid = {22405725}, issn = {1872-6240}, support = {R01 AG029547-04/AG/NIA NIH HHS/United States ; R01 AG029547-01/AG/NIA NIH HHS/United States ; R01 AG029547-02/AG/NIA NIH HHS/United States ; R37 HL063762/HL/NHLBI NIH HHS/United States ; R01 AG029547/AG/NIA NIH HHS/United States ; R01 AG029547-03/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Cytoplasmic Granules/*pathology ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology ; Humans ; Inclusion Bodies/pathology ; Neurodegenerative Diseases/*pathology ; RNA/metabolism ; Signal Transduction/genetics ; TDP-43 Proteinopathies/*pathology ; }, abstract = {The RNA-binding protein TDP-43 is strongly linked to neurodegeneration. Not only are mutations in the gene encoding TDP-43 associated with ALS and FTLD, but this protein is also a major constituent of pathological intracellular inclusions in these diseases. Recent studies have significantly expanded our understanding of TDP-43 physiology. TDP-43 is now known to play important roles in neuronal RNA metabolism. It binds to and regulates the splicing and stability of numerous RNAs encoding proteins involved in neuronal development, synaptic function and neurodegeneration. Thus, a loss of these essential functions is an attractive hypothesis regarding the role of TDP-43 in neurodegeneration. Moreover, TDP-43 is an aggregation-prone protein and, given the role of toxic protein aggregates in neurodegeneration, a toxic gain-of-function mechanism is another rational hypothesis. Importantly, ALS related mutations modulate the propensity of TDP-43 to aggregate in cell culture. Several recent studies have documented that cytoplasmic TDP-43 aggregates co-localize with stress granule markers. Stress granules are cytoplasmic inclusions that repress translation of a subset of RNAs in times of cellular stress, and several proteins implicated in neurodegeneration (i.e. Ataxin-2 and SMN) interact with stress granules. Thus, understanding the interplay between TDP-43 aggregation, stress granules and the effect of ALS-associated TDP-43 mutations may be the key to understanding the role of TDP-43 in neurodegeneration. We propose two models of TDP-43 aggregate formation. The "independent model" stipulates that TDP-43 aggregation is independent of stress granule formation, in contrast to the "precursor model" which presents the idea that stress granule formation contributes to a TDP-43 aggregate "seed" and that chronic stress leads to concentration-dependent TDP-43 aggregation. This article is part of a Special Issue entitled: RNA-Binding Proteins.}, }
@article {pmid22402721, year = {2012}, author = {Fujita, K and Izumi, Y and Kaji, R}, title = {[Inflammatory mechanisms in amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {3}, pages = {273-278}, pmid = {22402721}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Cell Cycle Proteins ; Chemokines/physiology ; Cytokines/physiology ; Humans ; Inflammation/physiopathology ; Membrane Transport Proteins ; NF-kappa B/physiology ; Transcription Factor TFIIIA/genetics ; }, abstract = {Neuroinflammation is a pathological hallmark in human amyotrophic lateral sclerosis (ALS) patients and in the transgenic models of the disease. The importance of glial cell activation and pro-inflammatory cytokines in ALS has been confirmed by numerous studies. For instance, tumor necrosis factor-α (TNF-α), a major pro-inflammatory cytokine, activates microglia and cause neurotoxicity in motor neurons. More recently, the relationship of nuclear factor-κB (NF-κB) and motor neuron degeneration has garnered attention since optineurin (OPTN) mutations were reported in familial ALS. OPTN negatively regulates TNF-α-induced NF-κB activation, but OPTN mutations can lead to dysinhibition of NF-κB-induced neurotoxicity. Notably, OPTN-positive inclusions are observed not only in familial ALS with OPTN mutation but also in sporadic ALS and in familial ALS with SOD1 and fused in sarcoma mutations, suggesting that OPTN- and NF-κB-related pathways are relevant to the general pathomechanisms of ALS. In this review, we discuss inflammatory aspects of ALS comprising the roles of cytokines, glial cells, and T cells.}, }
@article {pmid22399427, year = {2012}, author = {Lezi, E and Swerdlow, RH}, title = {Mitochondria in neurodegeneration.}, journal = {Advances in experimental medicine and biology}, volume = {942}, number = {}, pages = {269-286}, pmid = {22399427}, issn = {0065-2598}, support = {P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/*physiopathology ; }, abstract = {Many neurodegenerative diseases demonstrate abnormal mitochondrial morphology and biochemical dysfunction. Alterations are often systemic rather than brain-limited. Mitochondrial dysfunction may arise as a consequence of abnormal mitochondrial DNA, mutated nuclear proteins that interact directly or indirectly with mitochondria, or through unknown causes. In most cases it is unclear where mitochondria sit in relation to the overall disease cascades that ultimately causes neuronal dysfunction and death, and there is still controversy regarding the question of whether mitochondrial dysfunction is a necessary step in neurodegeneration. In this chapter we highlight and catalogue mitochondrial perturbations in some of the major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We consider data that suggest mitochondria may be critically involved in neurodegenerative disease neurodegeneration cascades.}, }
@article {pmid22391016, year = {2012}, author = {Yang, CW and Yen, ZS and McGowan, JE and Chen, HC and Chiang, WC and Mancini, ME and Soar, J and Lai, MS and Ma, MH}, title = {A systematic review of retention of adult advanced life support knowledge and skills in healthcare providers.}, journal = {Resuscitation}, volume = {83}, number = {9}, pages = {1055-1060}, doi = {10.1016/j.resuscitation.2012.02.027}, pmid = {22391016}, issn = {1873-1570}, mesh = {Advanced Cardiac Life Support/*education ; *Clinical Competence ; Health Personnel/*education ; Humans ; }, abstract = {OBJECTIVE: Advanced life support (ALS) guidelines are widely adopted for healthcare provider training with recommendations for retraining every two years or longer. This systematic review studies the retention of adult ALS knowledge and skills following completion of an ALS course in healthcare providers.<br><br>METHODS: We retrieved original articles using Medline, CINAHL, Cochrane Library, and PubMed, and reviewed reference citations to identify additional studies. We extracted data from included articles using a structured approach and organized outcomes by evaluation method, and knowledge and skills retention.<br><br>RESULTS: Among 336 articles retrieved, 11 papers were included. Most studies used multiple-choice questionnaires to evaluate knowledge retention and cardiac arrest simulation or other skills tests to evaluate skills retention. All studies reported variable rates of knowledge or skills deterioration over time, from 6 weeks to 2 years after training. Two studies noted retention of knowledge at 18 months and up to 2 years, and one reported skills retention at 3 months. Clinical experience, either prior to or after the courses, has a positive impact on retention of knowledge and skills.<br><br>CONCLUSION: There is a lack of large well-designed studies examining the retention of adult ALS knowledge and skills in healthcare providers. The available evidence suggests that ALS knowledge and skills decay by 6 months to 1 year after training and that skills decay faster than knowledge. Additional studies are needed to help provide evidence-based recommendations for assessment of current knowledge and skills and need for refresher training to maximize maintenance of ALS competency.}, }
@article {pmid22381097, year = {2012}, author = {Klein, M}, title = {Postoperative non-steroidal anti-inflammatory drugs and colorectal anastomotic leakage. NSAIDs and anastomotic leakage.}, journal = {Danish medical journal}, volume = {59}, number = {3}, pages = {B4420}, pmid = {22381097}, issn = {2245-1919}, mesh = {*Anastomosis, Surgical ; Anastomotic Leak/*chemically induced ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*adverse effects/therapeutic use ; Collagen/drug effects/metabolism ; Colorectal Surgery ; Confidence Intervals ; Cyclooxygenase 2 Inhibitors/adverse effects/therapeutic use ; Diclofenac/adverse effects/therapeutic use ; Female ; Humans ; Logistic Models ; Male ; Odds Ratio ; Pain, Postoperative/prevention &amp; control ; Postoperative Complications/*chemically induced/etiology/prevention &amp; control ; Rats ; Rats, Wistar ; Risk Factors ; Statistics as Topic ; }, abstract = {Anastomotic leakage (AL) is the most important and one of the most serious complications after colorectal resections with primary anastomosis. Any factors that contribute to increase the risk of AL should be identified and--if possible--eliminated. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for treating pain after surgical procedures, among these also colorectal resections. The objective of this Ph.d. thesis was to investigate whether the use of NSAIDs in the postoperative period increases the risk of AL, and investigate the effect on pathophysiological mechanisms. In order to achieve this, the following studies were performed. Study I was a retrospective, case-control study in 75 patients undergoing laparoscopic colorectal resection for colorectal cancer. 33 of these patients received the NSAID diclofenac in the postoperative period; the remaining 42 did not receive any NSAID. There were significantly more ALs among the patients receiving diclofenac (7/33 vs. 1/42, p=0.018). In uni- and multivariate logistic regression analyses, diclofenac was the only factor associated with increased AL rate. This study functioned as a hypothesis generating study and laid the ground for the subsequent studies. Study II was an experimental, randomized, case-control study in 32 Wistar rats. The rats had a colonic anastomosis performed and were randomized to diclofenac or placebo treatment. After three days, the rats were sacrificed and the anastomoses were harvested. First, the anastomotic strengths were tested by longitudinal; subsequently, the levels of the enzyme cyclooxygenase-2 (COX-2) in the anastomotic tissues were measured. There was no difference among the groups with regard to anastomotic strength, but the animals treated with diclofenac had significantly lower COX-2 levels (median (range) 1.30 (0.42-3.31) ng/mg vs. 2.44 (0.88 - 18.94) ng/mg, p<0.001). This study showed that the used dose of diclofenac was sufficient and relevant, but did not show a direct damaging effect on the anastomoses due to NSAID treatment. Study III was also an experimental, randomized, case-control study. This time round, 60 Wistar rats were included. Again, colonic anastomoses were performed and the rats were randomized to diclofenac or placebo. Also, expanded polytetrafluoruethylene (ePTFE) tubes were placed under the skin of the rats. In this material, substituents of connective tissue accumulate and the amount of accumulation can be measured. After 7 days, the rats were sacrificed and, again, anastomotic strengths were measured along with collagen content in the ePTFE tubes. Anastomotic strength was similar in the two groups while collagen accumulation was significantly decreased among the rats treated with diclofenac (median (i.q.r.) 0.29 (0.13-0.47) vs. 0.47 (0.28-0.62) mcg/mg, p = 0.03). This study for the first time showed that NSAID inhibit subcutaneous collagen formation and that this formation is reversely correlated to anastomotic strength. This information can be used in further studies in this subject. Study IV was the final experimental case-control study in 40 Wistar rats. This time, in order to more easily extrapolate experimental results to daily clinical life, the colonic anastomoses were sutured with the same type of suture material as used in the clinical setting. Thus, half the anastomoses was performed with resorbable suture; the other half with non-resorbable suture. None of the rats received NSAID. The breaking strength was compared and found similar in the two groups. This study showed that experimental studies can be optimized in order to make comparisons and extrapolations to the clinical setting easier. Study V was a database study based on data from the Danish Colorectal Cancer Group's (DCCG) prospective database and electronically registered medical records. From the database information on demographic, surgical and postoperative variables (including AL) were provided. Information on NSAID consumption was retrieved by individual searches in the patients' medical records. Based on these data, uni- and multivariate logistic regression analyses were performed. These analyses identified NSAID treatment in the postoperative period as an individual risk factor for AL. Other risk factors identified were consistent with the available literature. The detrimental effect of the NSAIDs are possibly due to an effect on collagen metabolism leading to weakened tissue around the anastomosis and/or on the risk of thrombosis formation leading to more thromboses in the vessels supplying the anastomosis, thereby limiting anastomotic blood flow. In conclusion, the studies included in this thesis have elucidated some of the physiological and pathophysiological mechanisms involved in anastomotic healing and leakage, and furthermore have shown that the use of NSAIDs in the postoperative period increase the risk of AL in patients undergoing colorectal surgery with primary anastomosis. Based on the findings in these studies, and based on existing knowledge, it is recommended that NSAIDs be abandoned after colorectal resection with primary anastomosis. It should be investigated whether the NSAIDs are also harmful to other types of anastomoses and after other surgical procedures where early tissue healing is crucial.}, }
@article {pmid22364875, year = {2012}, author = {Ying, H and Yue, BY}, title = {Cellular and molecular biology of optineurin.}, journal = {International review of cell and molecular biology}, volume = {294}, number = {}, pages = {223-258}, pmid = {22364875}, issn = {1937-6448}, support = {P30 EY001792/EY/NEI NIH HHS/United States ; EY001792/EY/NEI NIH HHS/United States ; R01 EY005628/EY/NEI NIH HHS/United States ; R01 EY018828/EY/NEI NIH HHS/United States ; EY018828/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Anti-Bacterial Agents/chemistry/metabolism ; Antiviral Agents/chemistry/metabolism ; Cell Cycle Proteins ; Golgi Apparatus/chemistry/metabolism ; Humans ; Membrane Transport Proteins ; Protein Transport/physiology ; Signal Transduction/genetics/physiology ; Transcription Factor TFIIIA/*chemistry/genetics/*physiology ; }, abstract = {Optineurin is a gene linked to glaucoma, amyotrophic lateral sclerosis, other neurodegenerative diseases, and Paget's disease of bone. This review describes the characteristics of optineurin and summarizes the cellular and molecular biology investigations conducted so far on optineurin. Data from a number of laboratories indicate that optineurin is a cytosolic protein containing 577 amino acid residues. Interacting with proteins such as myosin VI, Rab8, huntingtin, transferrin receptor, and TANK-binding kinase 1, optineurin is involved in basic cellular functions including protein trafficking, maintenance of the Golgi apparatus, as well as NF-κB pathway, antiviral, and antibacteria signaling. Mutation or alteration of homeostasis of optineurin (such as overexpression or knockdown) results in adverse consequences in the cells, leading to the development of neurodegenerative diseases including glaucoma.}, }
@article {pmid22361843, year = {2012}, author = {Khansari, PS and Sperlagh, B}, title = {Inflammation in neurological and psychiatric diseases.}, journal = {Inflammopharmacology}, volume = {20}, number = {3}, pages = {103-107}, pmid = {22361843}, issn = {1568-5608}, mesh = {Animals ; Humans ; Immunotherapy/adverse effects/methods/trends ; Inflammation/pathology/psychology/therapy ; Mental Disorders/*pathology/*psychology/therapy ; Nervous System Diseases/*pathology/*psychology/therapy ; }, abstract = {In recent years, compelling evidence suggests that inflammation plays a critical role in the pathology of a vast number of neurological diseases such as stroke, Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis as well as neuropsychiatric diseases such as major depression and schizophrenia. Despite emerging evidence in human and animal models alike, modulating inflammatory responses have yet to be proven as an effective treatment to prevent or delay the progression of these diseases. The primary focus of this special edition is to highlight some of our current findings on the complexities of targeting neuroinflammation as a novel therapy, and its role in neurological and psychiatric disorders.}, }
@article {pmid22361376, year = {2012}, author = {Sorenson, EJ}, title = {The electrophysiology of the motor neuron diseases.}, journal = {Neurologic clinics}, volume = {30}, number = {2}, pages = {605-620}, doi = {10.1016/j.ncl.2011.12.006}, pmid = {22361376}, issn = {1557-9875}, mesh = {Electrophysiological Phenomena/*physiology ; Humans ; Motor Neuron Disease/*physiopathology ; }, abstract = {The motor neuron diseases are a set of disorders associated with the selective degeneration of motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common and confers the gravest prognosis. Although ALS occurs with known genetic causes in a small minority, other motor neuron disorders have well-defined genetic mutations. Electrodiagnostic testing is important to distinguish these various disorders. Electrodiagnostic testing is also crucial for distinguishing potential mimic syndromes, such as multifocal motor neuropathy and inclusion body myositis. Newer neurophysiology techniques have been developed in the past several years. What role these techniques will play in clinical practice is currently unknown.}, }
@article {pmid22359076, year = {2012}, author = {Larijani, B and Esfahani, EN and Amini, P and Nikbin, B and Alimoghaddam, K and Amiri, S and Malekzadeh, R and Yazdi, NM and Ghodsi, M and Dowlati, Y and Sahraian, MA and Ghavamzadeh, A}, title = {Stem cell therapy in treatment of different diseases.}, journal = {Acta medica Iranica}, volume = {50}, number = {2}, pages = {79-96}, pmid = {22359076}, issn = {1735-9694}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Humans ; Inflammatory Bowel Diseases/therapy ; Multiple Sclerosis/therapy ; Muscular Dystrophy, Duchenne/therapy ; Parkinson Disease/therapy ; Spinal Cord Injuries/therapy ; *Stem Cell Transplantation ; }, abstract = {Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells.So far usage of stem cells in treatment of various blood diseases has been studied (such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia). In this paper the goal is evaluation of cell therapy in treatment of Parkinson's disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article.}, }
@article {pmid22357218, year = {2012}, author = {Jung, YW and Hysolli, E and Kim, KY and Tanaka, Y and Park, IH}, title = {Human induced pluripotent stem cells and neurodegenerative disease: prospects for novel therapies.}, journal = {Current opinion in neurology}, volume = {25}, number = {2}, pages = {125-130}, pmid = {22357218}, issn = {1473-6551}, support = {P01 GM099130/GM/NIGMS NIH HHS/United States ; GM099130-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Cell Differentiation ; Cell Proliferation ; Humans ; Kruppel-Like Factor 4 ; Neurodegenerative Diseases/*surgery ; Pluripotent Stem Cells/*physiology ; Stem Cell Transplantation/*methods ; }, abstract = {PURPOSE OF REVIEW: The lack of effective treatments for various neurodegenerative disorders has placed huge burdens on society. We review the current status in applying induced pluripotent stem cell (iPSC) technology for the cellular therapy, drug screening, and in-vitro modeling of neurodegenerative diseases.<br><br>RECENT FINDINGS: iPSCs are generated from somatic cells by overexpressing four reprogramming factors (Oct4, Sox2, Klf4, and Myc). Like human embryonic stem cells, iPSCs have features of self-renewal and pluripotency, and allow in-vitro disease modeling, drug screening, and cell replacement therapy. Disease-specific iPSCs were derived from patients of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Neurons differentiated from these iPSCs recapitulated the in-vivo phenotypes, providing platforms for drug screening. In the case of Parkinson's disease, iPSC-derived dopaminergic neurons gave positive therapeutic effect on a rodent Parkinson's disease model as a proof of principle in using iPSCs as sources of cell replacement therapy. Beyond iPSC technology, much effort is being made to generate neurons directly from dermal fibroblasts with neuron-specific transcription factors, which does not require making iPSCs as an intermediate cell type.<br><br>SUMMARY: We summarize recent progress in using iPSCs for modeling the progress and treatment of neurodegenerative diseases and provide evidence for future perspectives in this field.}, }
@article {pmid22351797, year = {2012}, author = {Seeber, AA and Hijdra, A and Vermeulen, M and Willems, DL}, title = {Discussions about treatment restrictions in chronic neurologic diseases: a structured review.}, journal = {Neurology}, volume = {78}, number = {8}, pages = {590-597}, doi = {10.1212/WNL.0b013e318247cc56}, pmid = {22351797}, issn = {1526-632X}, mesh = {Chronic Disease ; *Decision Making ; Humans ; Nervous System Diseases/*therapy ; Professional-Family Relations ; *Terminal Care ; }, abstract = {OBJECTIVE: Many incurable neurologic diseases have predictable complications during their course or at their end stage. Timely discussions of potential treatment restrictions may improve the quality of treatment decisions toward the end of life. What is known about the actual practice of these discussions?<br><br>METHODS: We performed a literature search in MEDLINE, EMBASE, and CINAHL for empirical studies about discussions and decisions to restrict treatment in the course of 6 conditions: motor neuron disease (amyotrophic lateral sclerosis [ALS]), primary malignant brain tumors, multiple sclerosis, stroke, Parkinson disease, and dementia (Alzheimer disease).<br><br>RESULTS: In 10 of 43 studies, the actual practice of decision-making was studied; in the remaining 33, caregivers were interviewed about this practice. Three scenarios were described: 1) acute devastating disease (severe stroke); 2) stable severe neurologic deficit with complications (poststroke brain damage); and 3) chronic progressive disease with complications (dementia and ALS). We found no studies concerning the other conditions. In all 3 scenarios, discussions and decisions seemed to be mostly triggered by the occurrence of life-threatening situations, either caused by the disease itself (1), or complications (2 and 3, including many patients with ALS). Some ALS studies showed that timely discussion of treatment options improved end-of-life decision-making.<br><br>CONCLUSIONS: The actual practice of discussions about treatment restrictions in chronic neurologic disease has hardly been studied. The currently available empirical data suggest that discussions are mainly triggered by life-threatening situations, whereas anticipation of such situations may be beneficial for patients and their families.}, }
@article {pmid22349304, year = {2012}, author = {Groppa, S and Oliviero, A and Eisen, A and Quartarone, A and Cohen, LG and Mall, V and Kaelin-Lang, A and Mima, T and Rossi, S and Thickbroom, GW and Rossini, PM and Ziemann, U and Valls-Solé, J and Siebner, HR}, title = {A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {123}, number = {5}, pages = {858-882}, pmid = {22349304}, issn = {1872-8952}, support = {ZIA NS002978-12//Intramural NIH HHS/United States ; }, mesh = {Biophysics ; Cortical Spreading Depression ; Electric Stimulation/*methods ; Electromyography ; Evoked Potentials, Motor ; Functional Laterality ; Guidelines as Topic/*standards ; Humans ; Muscle, Skeletal/innervation/physiopathology ; Nervous System Diseases/*diagnosis ; Neural Conduction ; Transcranial Magnetic Stimulation/*methods/*standards ; }, abstract = {Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.}, }
@article {pmid22342159, year = {2012}, author = {Lanson, NA and Pandey, UB}, title = {FUS-related proteinopathies: lessons from animal models.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {44-60}, doi = {10.1016/j.brainres.2012.01.039}, pmid = {22342159}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Caenorhabditis elegans ; Disease Models, Animal ; Drosophila ; Frontotemporal Lobar Degeneration/genetics/pathology ; Humans ; Mice ; Nervous System Diseases/*genetics/physiopathology ; Protein Processing, Post-Translational/genetics ; RNA-Binding Protein FUS/*genetics/physiology ; Rats ; TDP-43 Proteinopathies/genetics/physiopathology ; Yeasts ; Zebrafish ; }, abstract = {The recent identification of ALS-linked mutations in FUS and TDP-43 has led to a major shift in our thinking in regard to the potential molecular mechanisms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RNA-mediated proteinopathy is increasingly being recognized as a potential cause of neurodegenerative disorders. FUS and TDP-43 are structurally and functionally similar proteins. FUS is a DNA/RNA binding protein that may regulate aspects of RNA metabolism, including splicing, mRNA processing, and micro RNA biogenesis. It is unclear how ALS-linked mutations perturb the functions of FUS. This review highlights recent advances in understanding the functions of FUS and discusses findings from FUS animal models that provide several key insights into understanding the molecular mechanisms that might contribute to ALS pathogenesis.}, }
@article {pmid22336799, year = {2012}, author = {Ashworth, NL and Satkunam, LE and Deforge, D}, title = {Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD004156}, doi = {10.1002/14651858.CD004156.pub4}, pmid = {22336799}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Exercise Therapy/*methods ; Humans ; Muscle Spasticity/etiology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Spasticity commonly affects patients with motor neuron disease. It is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life. This is an update of a review first published in 2003 and previously updated in 2005 and 2008.<br><br>OBJECTIVES: The objective of this review is to systematically review treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011), CINAHL Plus (January 1937 to July 2011), AMED (January 1985 to July 2011) and LILACS (January 1982 to July 2011). We reviewed the bibliographies of the randomized controlled trials identified, and contacted authors and experts in the field.<br><br>SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, and alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by the Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, all adverse events, and measures of cost.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently screened the abstracts of potential trials retrieved from the searches. Two authors extracted the data. We also contacted the author of the paper and obtained information not available in the published article. All three authors assessed the methodological quality of all included trials independently.<br><br>MAIN RESULTS: We identified only one randomized controlled trial that met our inclusion criteria and no further trials were identified in subsequent updates. The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. The risk of bias was high and no adverse events were reported. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity overall (mean reduction of -0.43, 95% confidence interval (CI) -1.03 to +0.17 in the treatment group versus an increase of +0.25, 95% CI -0.46 to +0.96 in control) but the mean change between groups was not significant (-0.68, 95% CI -1.62 to +0.26), as measured by the Ashworth scale (possible scores 0 to 5, where higher is worse).<br><br>AUTHORS' CONCLUSIONS: The single trial performed was too small to determine whether individualized moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population. More research is needed.}, }
@article {pmid22334165, year = {2012}, author = {Blackhall, LJ}, title = {Amyotrophic lateral sclerosis and palliative care: where we are, and the road ahead.}, journal = {Muscle &amp; nerve}, volume = {45}, number = {3}, pages = {311-318}, doi = {10.1002/mus.22305}, pmid = {22334165}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/psychology/therapy ; Decision Making ; Dyspnea/etiology/therapy ; Humans ; Mood Disorders/etiology/therapy ; *Pain Management ; *Palliative Care/methods/trends ; Respiratory Insufficiency/etiology/therapy ; Sialorrhea/etiology/therapy ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) have high symptom burdens, including pain, fatigue, dyspnea, and sialorrhea, and they must make difficult decisions about the use of life-prolonging therapies, such as long-term mechanical ventilation. The impact of ALS is also felt by family caregivers who often struggle to meet the heavy physical, financial, and emotional demands associated with the illness. Expert multidisciplinary care may improve both quality and length of life of patients with ALS. However, although advances have been made in the treatment of some symptoms, others, including pain management, remain poorly studied. Involvement of palliative care specialists as part of the ALS multidisciplinary team is recommended, as we continue to work toward improving the quality of life for patients and their families.}, }
@article {pmid22333068, year = {2012}, author = {Bednar, MM and Perry, A}, title = {Neurorestoration therapeutics for neurodegenerative and psychiatric disease.}, journal = {Neurological research}, volume = {34}, number = {2}, pages = {129-142}, doi = {10.1179/1743132811Y.0000000069}, pmid = {22333068}, issn = {1743-1328}, mesh = {Clinical Trials as Topic ; Humans ; Mental Disorders/*therapy ; *Nerve Regeneration ; Neurodegenerative Diseases/*therapy ; Neurogenesis ; *Stem Cell Research ; Stem Cell Transplantation/*trends ; }, abstract = {OBJECTIVE: Neurorestoration within the human central nervous system (CNS) is a concept that is barely a decade old. Despite this, there is significant clinical activity in this area, although there has not been any attempt to systematically identify these trials and organize them by disease area and phase of development. The objective of this investigation is to broadly review the current state of neurorestorative clinical trial activity ongoing worldwide.<br><br>METHODS: Iterative searches of the databases clinicaltrials.gov, EU Clinical Trials Register and ADIS Insight were used to locate clinical trials identified as involving neurorecovery/restoration strategies or stem cells for central nervous system diseases.<br><br>RESULTS: A wide range of neurorestorative clinical trials (N = 106) are ongoing or planned. Nearly three-fourths of all clinical trials (75/106) are targeting one of four disease areas: multiple sclerosis, stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Nearly two-thirds (63%) of 106 ongoing and planned clinical trials focus on cell-based therapy, although these are almost exclusively in phase 1 or 2 of development.<br><br>DISCUSSION: Neurorecovery is an emerging field that is currently focused on earlier stages of clinical development, primarily in four disease areas. As the field matures, it is expected that there will be a greater balance of studies across a wider spectrum of CNS diseases as well as in late-stage development.}, }
@article {pmid22329869, year = {2012}, author = {Bede, P and Bokde, AL and Byrne, S and Elamin, M and Fagan, AJ and Hardiman, O}, title = {Spinal cord markers in ALS: diagnostic and biomarker considerations.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {5}, pages = {407-415}, doi = {10.3109/17482968.2011.649760}, pmid = {22329869}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/physiopathology ; Animals ; Biomarkers/*metabolism ; Diagnostic Imaging/*methods ; *Disease Models, Animal ; Humans ; Spinal Cord/metabolism/physiopathology ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Despite considerable involvement of the spinal cord in amyotrophic lateral sclerosis (ALS), current biomarker research is primarily centred on brain imaging and CSF proteomics. In clinical practice, spinal cord imaging in ALS is performed primarily to rule out alternative conditions in the diagnostic phase of the disease. Quantitative spinal cord imaging has traditionally been regarded as challenging, as it requires high spatial resolution while minimizing partial volume effects, physiological motion and susceptibility distortions. In recent years however, as acquisition and post-processing methods have been perfected, a number of exciting and promising quantitative spinal imaging and electrophysiology techniques have been developed. We performed a systematic review of the trends, methodologies, limitations and conclusions of recent spinal cord studies in ALS to explore the diagnostic and prognostic potential of spinal markers. Novel corrective techniques for quantitative spinal cord imaging are systematically reviewed. Recent findings demonstrate that imaging techniques previously used in brain imaging, such as diffusion tensor, functional and metabolic imaging can now be successfully applied to the human spinal cord. Optimized electrophysiological approaches make the non-invasive assessment of corticospinal pathways possible, and multimodal spinal techniques are likely to increase the specificity and sensitivity of proposed spinal markers. In conclusion, spinal cord imaging is an emerging area of ALS biomarker research. Novel quantitative spinal modalities have already been successfully used in ALS animal models and have the potential for development into sensitive ALS biomarkers in humans.}, }
@article {pmid22325364, year = {2012}, author = {Shih, JJ and Krusienski, DJ and Wolpaw, JR}, title = {Brain-computer interfaces in medicine.}, journal = {Mayo Clinic proceedings}, volume = {87}, number = {3}, pages = {268-279}, pmid = {22325364}, issn = {1942-5546}, mesh = {*Brain/physiology ; Electrodes, Implanted ; Electroencephalography ; Humans ; *Man-Machine Systems ; Signal Processing, Computer-Assisted ; *User-Computer Interface ; }, abstract = {Brain-computer interfaces (BCIs) acquire brain signals, analyze them, and translate them into commands that are relayed to output devices that carry out desired actions. BCIs do not use normal neuromuscular output pathways. The main goal of BCI is to replace or restore useful function to people disabled by neuromuscular disorders such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. From initial demonstrations of electroencephalography-based spelling and single-neuron-based device control, researchers have gone on to use electroencephalographic, intracortical, electrocorticographic, and other brain signals for increasingly complex control of cursors, robotic arms, prostheses, wheelchairs, and other devices. Brain-computer interfaces may also prove useful for rehabilitation after stroke and for other disorders. In the future, they might augment the performance of surgeons or other medical professionals. Brain-computer interface technology is the focus of a rapidly growing research and development enterprise that is greatly exciting scientists, engineers, clinicians, and the public in general. Its future achievements will depend on advances in 3 crucial areas. Brain-computer interfaces need signal-acquisition hardware that is convenient, portable, safe, and able to function in all environments. Brain-computer interface systems need to be validated in long-term studies of real-world use by people with severe disabilities, and effective and viable models for their widespread dissemination must be implemented. Finally, the day-to-day and moment-to-moment reliability of BCI performance must be improved so that it approaches the reliability of natural muscle-based function.}, }
@article {pmid22312314, year = {2012}, author = {Ikenaka, K and Katsuno, M and Kawai, K and Ishigaki, S and Tanaka, F and Sobue, G}, title = {Disruption of axonal transport in motor neuron diseases.}, journal = {International journal of molecular sciences}, volume = {13}, number = {1}, pages = {1225-1238}, pmid = {22312314}, issn = {1422-0067}, mesh = {Animals ; Axonal Transport/*physiology ; Axons/metabolism ; Dynactin Complex ; Dyneins/chemistry/metabolism ; Humans ; Intermediate Filaments/metabolism ; Kinesins/chemistry/metabolism ; Microtubule-Associated Proteins/chemistry/metabolism ; Mitochondria/metabolism ; Motor Neuron Disease/*metabolism/pathology ; }, abstract = {Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.}, }
@article {pmid22306345, year = {2012}, author = {Caraci, F and Battaglia, G and Sortino, MA and Spampinato, S and Molinaro, G and Copani, A and Nicoletti, F and Bruno, V}, title = {Metabotropic glutamate receptors in neurodegeneration/neuroprotection: still a hot topic?.}, journal = {Neurochemistry international}, volume = {61}, number = {4}, pages = {559-565}, doi = {10.1016/j.neuint.2012.01.017}, pmid = {22306345}, issn = {1872-9754}, mesh = {Allosteric Regulation ; Animals ; Haplorhini ; Mice ; Neuroprotective Agents/pharmacology ; Receptors, Metabotropic Glutamate/*metabolism ; }, abstract = {Moving from early studies, we here review the most recent evidence linking metabotropic glutamate (mGlu) receptors to processes of neurodegeneration/neuroprotection. The use of knockout mice and subtype-selective drugs has increased our knowledge of the precise role played by individual mGlu receptor subtypes in these processes. Activation of mGlu1 and mGlu5 receptors may either amplify or reduce neuronal damage depending on the context and the nature of the toxic insults. In contrast, mGlu1 and mGlu5 receptors antagonists are consistently protective in in vitro and in vivo models of neuronal death. A series of studies suggest that mGlu1 receptor antagonists or negative allosteric modulators (NAMs) are promising candidates for the treatment of ischemic brain damage, whereas mGlu5 receptor NAMs, which have been clinically developed for the treatment of Parkinson's disease (PD) and l-DOPA-induced dyskinesias, protect nigro-striatal dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice and monkeys. Activation of glial mGlu3 receptors promotes the formation of various neurotrophic factors, such as transforming growth factor-β (TGF-β), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). Hence, selective mGlu3 receptor agonists or positive allosteric modulators (PAMs) (not yet available) are potentially helpful in the treatment of chronic neurodegenerative disorders such as PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis. Selective mGlu2 receptor PAMs should be used with caution in AD patients because these drugs are shown to amplify β-amyloid neurotoxicity. Finally, mGlu4 receptor agonists/PAMs share with mGlu5 receptor NAMs the ability to improve motor symptoms associated with PD and attenuate nigro-striatal degeneration at the same time. No data are yet available on the role of mGlu7 and mGlu8 receptors in neurodegeneration/neuroprotection.}, }
@article {pmid22305647, year = {2012}, author = {Albarracin, SL and Stab, B and Casas, Z and Sutachan, JJ and Samudio, I and Gonzalez, J and Gonzalo, L and Capani, F and Morales, L and Barreto, GE}, title = {Effects of natural antioxidants in neurodegenerative disease.}, journal = {Nutritional neuroscience}, volume = {15}, number = {1}, pages = {1-9}, doi = {10.1179/1476830511Y.0000000028}, pmid = {22305647}, issn = {1476-8305}, mesh = {Alzheimer Disease/*metabolism/prevention &amp; control ; Amyotrophic Lateral Sclerosis/*metabolism/prevention &amp; control ; Antioxidants/*metabolism ; Brain/drug effects/metabolism ; *Diet ; Humans ; Neuroprotective Agents/*metabolism ; Oxidative Stress/drug effects ; Parkinson Disease/*metabolism/prevention &amp; control ; Polyphenols/metabolism ; }, abstract = {Polyphenols are secondary metabolites with antioxidant properties and are abundant in the diet. Fruits, vegetables, herbs, and various drinks (tea, wine, and juices) are all sources of these molecules. Despite their abundance, investigations into the benefits of polyphenols in human health have only recently begun. Phenolic compounds have received increasing interest because of numerous epidemiological studies. These studies have suggested associations between the consumption of polyphenol-rich aliments and the prevention of chronic diseases, such as cancer, cardiovascular diseases, and neurodegenerative diseases. More specifically, in the last 10 years literature on the neuroprotective effects of a polyphenol-rich diet has grown considerably. It has been demonstrated, in various cell culture and animal models, that these metabolites are able to protect neuronal cells by attenuating oxidative stress and damage. However, it remains unclear as to how these compounds reach the brain, what concentrations are necessary, and what biologically active forms are needed to exert beneficial effects. Therefore, further research is needed to identify the molecular pathways and intracellular targets responsible for polyphenol's neuroprotective effects. The aim of this paper is to present various well-known dietary polyphenols and their mechanisms of neuroprotection with an emphasis on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid22304712, year = {2012}, author = {Rahn, KA and Slusher, BS and Kaplin, AI}, title = {Glutamate in CNS neurodegeneration and cognition and its regulation by GCPII inhibition.}, journal = {Current medicinal chemistry}, volume = {19}, number = {9}, pages = {1335-1345}, doi = {10.2174/092986712799462649}, pmid = {22304712}, issn = {1875-533X}, mesh = {Animals ; Central Nervous System/drug effects/metabolism/pathology ; Central Nervous System Diseases/*drug therapy/metabolism/pathology ; Cognition/*drug effects ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Glutamate Carboxypeptidase II/*antagonists &amp; inhibitors/metabolism ; Glutamic Acid/*metabolism ; Humans ; Neuroprotective Agents/pharmacology/therapeutic use ; Synaptic Transmission/drug effects ; }, abstract = {Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.}, }
@article {pmid22303913, year = {2012}, author = {Morren, JA and Galvez-Jimenez, N}, title = {Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {21}, number = {3}, pages = {297-320}, doi = {10.1517/13543784.2012.657303}, pmid = {22303913}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/physiopathology ; Animals ; Clinical Trials as Topic ; *Drug Delivery Systems ; *Drug Design ; Drugs, Investigational/adverse effects/pharmacology/therapeutic use ; Genetic Testing/methods ; Humans ; Neuroprotective Agents/adverse effects/pharmacology/therapeutic use ; Riluzole/adverse effects/pharmacology/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating illness of unclear etiology affecting motor neurons. It causes unremitting muscle paralysis, atrophy and death usually within 3 - 5 years from diagnosis. The human and economic costs for those affected are sobering. To date, tremendous efforts have failed to find a cure.<br><br>AREAS COVERED: An extensive literature search was undertaken using Medline and the Cochrane Systematic Review and Clinical Trial databases. Riluzole and investigational ALS drugs are discussed. Riluzole is the only approved disease-modifying therapy despite its modest effect on survival. Recent research has produced promising agents aimed at better disease control if not a cure. This review discusses agents targeting neuronal glutamate excitotoxicity, protein misfolding and accumulation, autophagy, apoptosis, mitochondrial dysfunction, free radical oxidative injury, immunomodulation, mutant mRNA counteraction, muscle physiology, neurotrophic factors and stem cell applications. The challenges in ALS drug development are highlighted.<br><br>EXPERT OPINION: Riluzole should be used for patients with definite, probable, suspected or possible ALS by World Federation of Neurology diagnostic criteria. Systematic monitoring for hepatic dysfunction, neutropenia and other serious adverse effects should be done routinely as outlined. All ALS patients should consider genetic screening and enrollment in ALS trials guided by the data reviewed.}, }
@article {pmid22292840, year = {2012}, author = {Lautenschlaeger, J and Prell, T and Grosskreutz, J}, title = {Endoplasmic reticulum stress and the ER mitochondrial calcium cycle in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {2}, pages = {166-177}, doi = {10.3109/17482968.2011.641569}, pmid = {22292840}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Calcium/*metabolism ; DNA-Binding Proteins/metabolism ; Endoplasmic Reticulum/*physiology/ultrastructure ; Endoplasmic Reticulum Stress/*physiology ; Golgi Apparatus/physiology/ultrastructure ; Humans ; Mitochondria/*metabolism ; Unfolded Protein Response/*physiology ; }, abstract = {The endoplasmic reticulum (ER) is a multifunctional organelle involved in protein synthesis, processing and folding, in intracellular transport and calcium signalling. ER stress can be triggered by depletion of ER calcium content and the accumulation of un- and mis-folded proteins, and relays stress signals to the ER mitochondria calcium cycle (ERMCC) and to the nucleus and protein translation machinery. The ensuing unfolded protein response (UPR) helps to cope with ER stress. Total protein synthesis is inhibited to keep protein load low, while the synthesis of ER chaperones, which assist protein folding, is induced. If cell integrity cannot be restored, signal cascades mediating cell death are activated. This review focuses on the role of ER stress and the UPR in the pathology of amyotrophic lateral sclerosis (ALS). The triggers for ER stress are as yet unclear, but induction of UPR sensor proteins, up-regulation of chaperones and induction of cell death proteins have been described in human post mortem ALS tissue and in mutant superoxide dismutase-1 (SOD1) expressing models of ALS. TDP-43 and VAPB seem to be involved in UPR signalling as well. Recent reports raise hope that UPR sensor proteins become effective therapeutic targets in the treatment of ALS.}, }
@article {pmid22285437, year = {2012}, author = {Patani, R and Sibley, CR and Chandran, S and Ule, J}, title = {Using human pluripotent stem cells to study post-transcriptional mechanisms of neurodegenerative diseases.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {129-138}, doi = {10.1016/j.brainres.2011.12.057}, pmid = {22285437}, issn = {1872-6240}, support = {089701/WT_/Wellcome Trust/United Kingdom ; MC_U105185858/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Disease Models, Animal ; Humans ; Models, Biological ; Neurodegenerative Diseases/*genetics ; Pluripotent Stem Cells/*physiology ; Protein Processing, Post-Translational/*genetics ; RNA/biosynthesis/genetics ; RNA-Binding Proteins/metabolism ; Species Specificity ; Stem Cells/classification/physiology ; }, abstract = {Post-transcriptional regulation plays a major role in the generation of cell type diversity. In particular, alternative splicing increases diversification of transcriptome between tissues, in different cell types within a tissue, and even in different compartments of the same cell. The complexity of alternative splicing has increased during evolution. With increasing sophistication, however, comes greater potential for malfunction of these intricate processes. Indeed, recent years have uncovered a wealth of disease-causing mutations affecting RNA-binding proteins and non-coding regions on RNAs, highlighting the importance of studying disease mechanisms that act at the level of RNA processing. For instance, mutations in TARDBP and FUS, or a repeat expansion in the intronic region of the C9ORF72 gene, can all cause amyotrophic lateral sclerosis. We discuss how interspecies differences highlight the necessity for human model systems to complement existing non-human approaches to study neurodegenerative disorders. We conclude by discussing the improvements that could further increase the promise of human pluripotent stem for cell-based disease modeling. This article is part of a Special Issue entitled "RNA-Binding Proteins".}, }
@article {pmid22283698, year = {2012}, author = {Pandya, RS and Mao, LL and Zhou, EW and Bowser, R and Zhu, Z and Zhu, Y and Wang, X}, title = {Neuroprotection for amyotrophic lateral sclerosis: role of stem cells, growth factors, and gene therapy.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {12}, number = {1}, pages = {15-27}, pmid = {22283698}, issn = {1875-6166}, support = {K01 NS055072/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Genetic Therapy/*methods/trends ; Humans ; Intercellular Signaling Peptides and Proteins/*physiology ; Neuroprotective Agents/*administration &amp; dosage/chemistry ; Stem Cell Transplantation/*methods/trends ; Stem Cells/*physiology ; }, abstract = {Various molecular mechanisms including apoptosis, inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, growth factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS.}, }
@article {pmid22277530, year = {2011}, author = {Tanaka, F and Ikenaka, K and Sobue, G}, title = {[Role of axonal transport in ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {51}, number = {11}, pages = {1189-1191}, doi = {10.5692/clinicalneurol.51.1189}, pmid = {22277530}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Axonal Transport/*physiology ; Disease Models, Animal ; Dynactin Complex ; Mice ; Microtubule-Associated Proteins/analysis ; }, abstract = {Proposed hypothesis for pathomechanisms of sporadic ALS include oxidative stress, glutamate toxicity, axonal transport defects, mitochondrial impairment and so on. Although these mechanisms may be interrelated mutually, the whole picture has not been clarified. As for axonal transport defect, it is also prominently involved in the pathogenesis of many major human neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, suggesting a crucial role of axonal transport in maintaining the normal neuronal function. In mutant SOD1 transgenic mice, the most popular disease model of familial ALS, the mutant SOD1 selectively associates with and damages mitochondria, leading to defect of axonal transport because of diminished ATP fuel supply for the molecular motors such as kinesin family or dynein/dynactin complex. Furthermore, the finding that mutations in the dynactin subunit p150Glued cause familial ALS demonstrates a direct role of molecular motor dysfunction and axonal transport defects in ALS. On the other hand, the mechanism of axonal transport impairment in sporadic ALS has been elusive. We have previously demonstrated that gene expression of dynactin subunit p150Glued (dynactin-1) is down-regulated in motor neurons of sporadic ALS patient from the early stage of neurodegeneration. In this article we review the role of axonal transport in the pathogenesis of ALS.}, }
@article {pmid22277388, year = {2011}, author = {Nakano, I}, title = {[Frontotemporal lobar degeneration (FTLD) concept and classification update].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {51}, number = {11}, pages = {844-847}, doi = {10.5692/clinicalneurol.51.844}, pmid = {22277388}, issn = {1882-0654}, mesh = {*Frontotemporal Lobar Degeneration/classification ; Humans ; }, abstract = {FTLD is a neuroanatomical disease concept defined only by the presence of degeneration of the frontal and temporal lobes regardless of the underlying histopathological features, and therefore inevitably includes heterogeneous diseases that affect those cerebral regions. The ambiguous idea of Pick disease, the prototype of FTLD, constantly caused great nosological confusion as to FTLD. Progress in molecular neuropathology aimed at clarification of the protein constituents of the inclusion bodies seen in conditions causing FTLD, however, has resolved this problem by providing FTLD with a new concise nomenclature and classification based on the inclusion body proteins. The substances in inclusions in FTLD with ubiquitin-only inclusions (FTLD-U) have been discovered one after another; TDP-43 was the first, being found in inclusions in ALS and ALS with dementia (ALSD) too, and soon FUS/TLS was identified in some TDP-43-negative FTLD-U groups. Thus, FTLD has been divided into three main subgroups; 1) FTLD-tau, which includes Pick disease, PSP, CBD, etc., 2) FTLD-TDP, which is further divided to types A-D, ALSD belonging to type B, and 3) FTLD-FUS, which includes aFTLD-U, NIFID, and BIBD. Further deciphering of yet-unidentified proteins of some FTLD-U subsets will add more subclasses.}, }
@article {pmid22272119, year = {2011}, author = {Soo, KY and Farg, M and Atkin, JD}, title = {Molecular motor proteins and amyotrophic lateral sclerosis.}, journal = {International journal of molecular sciences}, volume = {12}, number = {12}, pages = {9057-9082}, pmid = {22272119}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Axonal Transport ; Humans ; Molecular Motor Proteins/chemistry/genetics/*metabolism ; Protein Folding ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons in the brain, brainstem and spinal cord, which is characterized by motor dysfunction, muscle dystrophy and progressive paralysis. Both inherited and sporadic forms of ALS share common pathological features, however, the initial trigger of neurodegeneration remains unknown. Motor neurons are uniquely targeted by ubiquitously expressed proteins in ALS but the reason for this selectively vulnerability is unclear. However motor neurons have unique characteristics such as very long axons, large cell bodies and high energetic metabolism, therefore placing high demands on cellular transport processes. Defects in cellular trafficking are now widely reported in ALS, including dysfunction to the molecular motors dynein and kinesin. Abnormalities to dynein in particular are linked to ALS, and defects in dynein-mediated axonal transport processes have been reported as one of the earliest pathologies in transgenic SOD1 mice. Furthermore, dynein is very highly expressed in neurons and neurons are particularly sensitive to dynein dysfunction. Hence, unravelling cellular transport processes mediated by molecular motor proteins may help shed light on motor neuron loss in ALS.}, }
@article {pmid22266890, year = {2011}, author = {Lill, CM and Bertram, L}, title = {Towards unveiling the genetics of neurodegenerative diseases.}, journal = {Seminars in neurology}, volume = {31}, number = {5}, pages = {531-541}, doi = {10.1055/s-0031-1299791}, pmid = {22266890}, issn = {1098-9021}, mesh = {Alzheimer Disease/*genetics ; Amyotrophic Lateral Sclerosis/*genetics ; Frontotemporal Dementia/*genetics ; Genome-Wide Association Study ; Humans ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/*genetics ; }, abstract = {In addition to sharing several clinical, pathologic, and molecular characteristics, many neurodegenerative disorders show extensive familial histories suggesting a substantial contribution of genetic factors to disease causation and progression. In this review, the authors provide overviews of the status of current genetics research in Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Across these four disorders alone, nearly 60 different loci can now be considered as established to be involved in pathogenesis for both Mendelian and non-Mendelian disease forms. In addition to reviewing the most compelling of these loci based on current data from genome-wide association studies and next-generation sequencing projects, genes that have been linked to more than one disease entity are emphasized. Such overlapping findings could point to one or several common genetic and mechanistic denominators for neuronal death in neurodegeneration. Unveiling the identity of these and other genetic factors will not only improve our understanding of the underlying pathophysiology, but may also lead to new avenues for preventing and treating these devastating diseases.}, }
@article {pmid22265380, year = {2012}, author = {Jones, U and Enright, S and Busse, M}, title = {Management of respiratory problems in people with neurodegenerative conditions: a narrative review.}, journal = {Physiotherapy}, volume = {98}, number = {1}, pages = {1-12}, doi = {10.1016/j.physio.2011.03.002}, pmid = {22265380}, issn = {1873-1465}, mesh = {Cough/physiopathology ; Dyspnea/etiology/rehabilitation ; Humans ; Neurodegenerative Diseases/*complications/epidemiology ; Physical Therapy Modalities ; Positive-Pressure Respiration/methods ; Respiration Disorders/epidemiology/*etiology/*rehabilitation/therapy ; Respiratory Function Tests ; Respiratory Muscles ; }, abstract = {BACKGROUND: Respiratory failure and dysfunction are common problems in many neurodegenerative conditions. Although physiotherapists manage these problems, it is not known which treatments have been studied and their efficacy.<br><br>OBJECTIVE: To review evidence on the management of respiratory problems in people with neurodegenerative conditions using the PRISMA approach.<br><br>DATA SOURCES: Comprehensive searches were conducted using the following electronic databases from inception to May 2010: HUGEnet, SIGLE, British Library Direct, CINAHL, Medline, AMED and Web of Knowledge. Bibliographies of all studies and systematic reviews were searched by hand.<br><br>STUDY SELECTION: Studies were selected based on: self-ventilating participants with neurodegenerative conditions; interventions aimed at improving respiratory function; and any valid and reliable measures of respiratory function as outcomes.<br><br>STUDY APPRAISAL: Studies were appraised by one reviewer using the Critical Appraisal Skills Programme. Data were synthesised using a narrative approach.<br><br>RESULTS: Thirty-five studies were included in the review. The strongest evidence was for the use of non-invasive ventilation for people with amyotrophic lateral sclerosis, although this was weak. The evidence for the use of respiratory muscle training and methods to increase peak cough flow showed a positive effect, but was also weak.<br><br>CONCLUSION: There is weak evidence for the positive effects of physiotherapeutic interventions for respiratory problems in people with neurodegenerative conditions. Further work is necessary in specific neurodegenerative conditions to identify why respiratory problems occur, and larger scale studies should be undertaken to investigate management of these problems.}, }
@article {pmid22262194, year = {2012}, author = {Romi, F and Helgeland, G and Gilhus, NE}, title = {Serum levels of matrix metalloproteinases: implications in clinical neurology.}, journal = {European neurology}, volume = {67}, number = {2}, pages = {121-128}, doi = {10.1159/000334862}, pmid = {22262194}, issn = {1421-9913}, mesh = {Humans ; Matrix Metalloproteinases/*blood ; Nervous System Diseases/*blood/*enzymology ; }, abstract = {Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in remodeling extracellular matrix and cell-matrix interactions. A pathogenic role of MMPs in neurological disorders is likely. This paper focuses on serological clinical aspects only. In multiple sclerosis, higher serum MMP-3 is seen during relapses. Lower serum MMP-8 and -9 levels correlate with fewer contrast-enhanced T(2)-weighted MRI lesions, and serum MMP-9 can be used in monitoring treatment. In myasthenia gravis, serum MMP-2, -3, and -9 levels are elevated in both generalized and ocular diseases. A proportion of the patients have markedly increased serum MMP-3. In acute stroke, higher serum MMP-9 correlates with larger infarct volume, stroke severity, and worse functional outcome, and serum MMP-3 is significantly lower than in several other neurological disorders and healthy controls. In amyotrophic lateral sclerosis, serum MMP-2 correlates with disease progression, and both serum MMP-1 and -2 are elevated. In Alzheimer's disease, serum MMP-3, -9, and -10 are elevated. In migraine, serum MMP-2 is elevated, and also MMP-9 in those patients with migraine without aura. MMP-9 is implicated in the pathogenesis of experimental epilepsy. A pathogenic role of MMPs in these conditions could be related to their ability to degrade extracellular matrix. MMPs may also facilitate autoimmunity.}, }
@article {pmid22261247, year = {2012}, author = {Mackenzie, IR and Neumann, M}, title = {FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1462}, number = {}, pages = {40-43}, doi = {10.1016/j.brainres.2011.12.010}, pmid = {22261247}, issn = {1872-6240}, support = {74580//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Frontotemporal Lobar Degeneration/*genetics ; Humans ; Inclusion Bodies/genetics/metabolism ; RNA-Binding Protein EWS/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; RNA-Binding Proteins/*metabolism ; TATA-Binding Protein Associated Factors/genetics/metabolism ; TDP-43 Proteinopathies/genetics ; tau Proteins/genetics ; }, abstract = {Mutations in the fused in sarcoma gene (FUS) cause amyotrophic lateral sclerosis (ALS) with TDP-43-negative, FUS-positive pathology. FUS is also the pathological protein in most tau/TDP-43-negative subtypes of frontotemporal lobar degeneration (FTLD-FUS). FUS, together with Ewing's sarcoma protein (EWS) and TATA-binding protein associated factor 15 (TAF15), make up the FET family of DNA/RNA binding proteins that share functional homology and have the potential to interact. We recently investigated the role of the other FET proteins in the clinicopathological spectrum of FUS-opathies. In all FTLD-FUS subtypes, FUS-positive pathology was also labeled for TAF15 and EWS and cells with inclusions showed a reduction in the normal nuclear staining of all FET proteins. In contrast, in cases of ALS-FUS, TAF15 and EWS remained localized to the nucleus and did not label FUS-positive inclusions. Cell culture models replicated the human diseases. These findings indicate that ALS-FUS and FTLD-FUS have different pathomechanisms and add TAF15 and EWS to the growing list of RNA-binding proteins involved in neurodegeneration. This article is part of a Special Issue entitled: RNA-Binding Proteins.}, }
@article {pmid22260971, year = {2012}, author = {Maruyama, H}, title = {[Identification of a new causative gene of amyotrophic lateral sclerosis; optineurin].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {52}, number = {1}, pages = {1-5}, doi = {10.5692/clinicalneurol.52.1}, pmid = {22260971}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Autoantibodies/metabolism ; Cell Cycle Proteins ; Codon, Nonsense ; Consanguinity ; Exons/genetics ; Humans ; Membrane Transport Proteins ; Mutation, Missense ; NF-kappa B ; Spinal Cord/cytology/metabolism/pathology ; Transcription Factor TFIIIA/*genetics/immunology/metabolism/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. ALS patients die within 3 to 5 years without respiratory support. Detecting the causing gene is necessary to elucidate ALS. We identified mutations of optineurin (OPTN) in ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Cell transfection experiments showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B. The missense mutation revealed a cytoplasmic distribution different from that of the wild type. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic retention, and Golgi fragmentation was identified in 70% of the anterior horn cells. TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also immunolabelled with anti-OPTN antibodies. Furthermore, optineurin is co-localized with fused in sarcoma (FUS) in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Our findings suggest that OPTN is involved in the great part of pathogenesis of ALS.}, }
@article {pmid22258985, year = {2012}, author = {Payne, C and Wiffen, PJ and Martin, S}, title = {Interventions for fatigue and weight loss in adults with advanced progressive illness.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {}, pages = {CD008427}, doi = {10.1002/14651858.CD008427.pub2}, pmid = {22258985}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications ; Cystic Fibrosis/complications ; Disease Progression ; Emaciation/etiology/*therapy ; Fatigue/etiology/*therapy ; HIV Infections/complications ; Humans ; Multiple Sclerosis/complications ; Neoplasms/complications ; Pulmonary Disease, Chronic Obstructive/complications ; Review Literature as Topic ; *Weight Loss ; }, abstract = {BACKGROUND: Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress.<br><br>OBJECTIVES: To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews.<br><br>METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review.<br><br>MAIN RESULTS: We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies.Management of fatigue Amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration.Management of weight loss ALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness - we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition.<br><br>AUTHORS' CONCLUSIONS: There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures.}, }
@article {pmid22258797, year = {2012}, author = {Füvesi, J and Rajda, C and Bencsik, K and Toldi, J and Vécsei, L}, title = {The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {119}, number = {2}, pages = {225-234}, pmid = {22258797}, issn = {1435-1463}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology/physiopathology ; Animals ; Humans ; Kynurenine/administration &amp; dosage/*physiology ; Multiple Sclerosis/*drug therapy/*pathology/physiopathology ; Neural Pathways/drug effects/physiology/physiopathology ; Prodrugs/administration &amp; dosage/*therapeutic use ; }, abstract = {Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood-brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.}, }
@article {pmid22257884, year = {2012}, author = {Son, JH and Shim, JH and Kim, KH and Ha, JY and Han, JY}, title = {Neuronal autophagy and neurodegenerative diseases.}, journal = {Experimental &amp; molecular medicine}, volume = {44}, number = {2}, pages = {89-98}, pmid = {22257884}, issn = {2092-6413}, mesh = {Alzheimer Disease/metabolism/pathology/physiopathology ; Animals ; Autophagy/*physiology ; Humans ; Huntington Disease/metabolism/pathology/physiopathology ; Models, Biological ; Neurodegenerative Diseases/metabolism/*pathology/physiopathology ; Neurons/*cytology ; Parkinson Disease/metabolism/pathology/physiopathology ; }, abstract = {Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non-neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma. Defects in autophagy affect the intercellular communication and subsequently, contributing to neurodegeneration. The presence of abnormal autophagic activity is frequently observed in selective neuronal populations afflicted in common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These observations have provoked controversy regarding whether the increase in autophagosomes observed in the degenerating neurons play a protective role or instead contribute to pathogenic neuronal cell death. It is still unknown what factors may determine whether active autophagy is beneficial or pathogenic during neurodegeneration. In this review, we consider both the normal and pathophysiological roles of neuronal autophagy and its potential therapeutic implications for common neurodegenerative diseases.}, }
@article {pmid22252304, year = {2012}, author = {Birbaumer, N and Piccione, F and Silvoni, S and Wildgruber, M}, title = {Ideomotor silence: the case of complete paralysis and brain-computer interfaces (BCI).}, journal = {Psychological research}, volume = {76}, number = {2}, pages = {183-191}, pmid = {22252304}, issn = {1430-2772}, mesh = {Amyotrophic Lateral Sclerosis/psychology ; Animals ; Brain/*physiology ; *Communication Aids for Disabled ; Conditioning, Classical/physiology ; Humans ; Paralysis/*psychology ; Rats ; Thinking ; *User-Computer Interface ; }, abstract = {The paper presents some speculations on the loss of voluntary responses and operant learning in long-term paralysis in human patients and curarized rats. Based on a reformulation of the ideomotor thinking hypothesis already described in the 19th century, we present evidence that instrumentally learned responses and intentional cognitive processes extinguish as a consequence of long-term complete paralysis in patients with amyotrophic lateral sclerosis (ALS). Preliminary data collected with ALS patients during extended and complete paralysis suggest semantic classical conditioning of brain activity as the only remaining communication possibility in those states.}, }
@article {pmid22252239, year = {2012}, author = {Abe, K and Yamashita, T and Takizawa, S and Kuroda, S and Kinouchi, H and Kawahara, N}, title = {Stem cell therapy for cerebral ischemia: from basic science to clinical applications.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {32}, number = {7}, pages = {1317-1331}, pmid = {22252239}, issn = {1559-7016}, mesh = {Animals ; Brain Ischemia/*surgery ; Humans ; Nerve Regeneration/physiology ; Stem Cell Transplantation/*methods ; Translational Research, Biomedical ; }, abstract = {Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future.}, }
@article {pmid22249490, year = {2012}, author = {Gaig, C and Iranzo, A}, title = {Sleep-disordered breathing in neurodegenerative diseases.}, journal = {Current neurology and neuroscience reports}, volume = {12}, number = {2}, pages = {205-217}, pmid = {22249490}, issn = {1534-6293}, mesh = {Humans ; Neurodegenerative Diseases/classification/*complications ; Sleep Apnea Syndromes/diagnosis/*etiology/therapy ; }, abstract = {Sleep disorders are common in neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), hereditary ataxias, and Alzheimer's disease (AD). Type, frequency, and severity of sleep disturbances vary depending on each of these diseases. Cell loss of the brainstem nuclei that modulates respiration, and dysfunction of bulbar and diaphragmatic muscles increase the risk for sleep-disordered breathing (SDB) in MSA and ALS. The most relevant SDB in MSA is stridor, whereas in ALS nocturnal hypoventilation due to diaphragmatic weakness is the most common sleep breathing abnormality. Stridor and nocturnal hypoventilation are associated with reduced survival in MSA and ALS. In contrast, sleep apnea seems not to be more prevalent in PD than in the general population. In some PD patients, however, coincidental obstructive sleep apnea (OSA) can be the cause of excessive daytime sleepiness (EDS). SDB can also occur in some hereditary ataxias, such as stridor in spinocerebellar ataxia type 3 (Machado-Joseph disease). The presence of concomitant OSA in patients with AD can have deleterious effects on nocturnal sleep, may result in EDS, and might aggravate the cognitive deficits inherent to the disease. However, whether OSA is more frequent in patients with AD than in the general population is uncertain. Recognition of SDB in neurodegenerative disease is important because they are associated with significant morbidity and potential effective treatments are available.}, }
@article {pmid22245492, year = {2012}, author = {Münch, C and Bertolotti, A}, title = {Propagation of the prion phenomenon: beyond the seeding principle.}, journal = {Journal of molecular biology}, volume = {421}, number = {4-5}, pages = {491-498}, doi = {10.1016/j.jmb.2011.12.061}, pmid = {22245492}, issn = {1089-8638}, support = {MC_U105185860/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Models, Biological ; Prion Diseases/pathology/physiopathology ; Prions/*chemistry/*metabolism ; Protein Denaturation ; Protein Folding ; Protein Multimerization ; }, abstract = {The deposition of misfolded proteins is the hallmark of the late-onset, rapidly progressive and devastating neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These diseases are caused by a gain of toxic properties associated with the propensity of otherwise soluble proteins to misfold. What governs the deposition of the disease-causing proteins in aged neurons is unclear, but recent evidence suggests that once misfolded, the diverse proteins associated with the neurodegenerative diseases can induce aggregation of their soluble counterpart, thereby sharing one of the defining properties of prions. In addition to the seeded polymerization, prions have the ability to replicate their aberrant conformation indefinitely and are transmissible. Are these properties also shared by diverse misfolded proteins?}, }
@article {pmid22228269, year = {2012}, author = {de Almeida, JP and Silvestre, R and Pinto, AC and de Carvalho, M}, title = {Exercise and amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {33}, number = {1}, pages = {9-15}, pmid = {22228269}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/psychology/*rehabilitation ; Exercise/*physiology/psychology ; Exercise Therapy/*psychology ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease in which much burden is geared towards end-of-life care. Particularly in the earlier stages of ALS, many people have found both physiological and psychological boosts from various types of physical exercise for disused muscles. Proper exercise is important for preventing atrophy of muscles from disuse-a key for remaining mobile for as long as possible-and as long as it is possible to exercise comfortably and safely, for preserving cardiovascular fitness. However, the typical neuromuscular patient features a great physical inactivity and disuse weakness, and for that reason many controversial authors have contested exercise in these patients during years, especially in ALS which is rapidly progressive. There is an urgent need for dissecting in detail the real risks or benefits of exercise in controlled clinical trials to demystify this ancient paradigm. Yet, recent research studies document significant benefits in terms of survival and quality of life in ALS, poor cooperation, small sample size, uncontrolled and short-duration trials, remain the main handicaps. Sedentary barriers such as early fatigue and inherent muscle misuse should be overcome, for instance with body-weight supporting systems or non-invasive ventilation, and exercise should be faced as a potential non-monotonous way for contributing to better health-related quality of life.}, }
@article {pmid22214450, year = {2012}, author = {Bařinka, C and Rojas, C and Slusher, B and Pomper, M}, title = {Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer.}, journal = {Current medicinal chemistry}, volume = {19}, number = {6}, pages = {856-870}, pmid = {22214450}, issn = {1875-533X}, support = {R01 CA134675/CA/NCI NIH HHS/United States ; CA 134675/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Glutamate Carboxypeptidase II/antagonists &amp; inhibitors/*metabolism ; Humans ; Male ; Nervous System Diseases/diagnosis/drug therapy/*metabolism ; Prostatic Neoplasms/diagnosis/drug therapy/*metabolism ; }, abstract = {Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N-acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.}, }
@article {pmid22214351, year = {2012}, author = {Caller, TA and Field, NC and Chipman, JW and Shi, X and Harris, BT and Stommel, EW}, title = {Spatial clustering of amyotrophic lateral sclerosis and the potential role of BMAA.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {1}, pages = {25-32}, doi = {10.3109/17482968.2011.621436}, pmid = {22214351}, issn = {1471-180X}, mesh = {Amino Acids, Diamino/*pharmacology ; Amyotrophic Lateral Sclerosis/*chemically induced/*epidemiology ; Animals ; *Cluster Analysis ; Cyanobacteria/chemistry ; Cyanobacteria Toxins ; Environment ; Epidemiologic Studies ; Excitatory Amino Acid Agonists/pharmacology ; Humans ; Neurotoxins/*pharmacology ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome which has no known cause, except for a small proportion of cases which are genetically inherited. The development of ALS likely involves both genetic and environmental risk factors. Environmental risk factors implicated in ALS have included heavy metals, trauma, pesticides, electrical injuries, electromagnetic radiation and the cyanobacterial-derived neurotoxin beta-N-methylamino-L-alanine (BMAA). To investigate possible environmental risks, a number of epidemiological studies of ALS have been conducted. Some of these studies employ spatial analysis techniques that examine for spatial clusters of ALS and can help guide further research into identifying environmental exposures. Despite identifying geographical disparities in the distribution of ALS cases, these studies have not provided any clear associations with environmental factors. We review the literature on important studies of spatial clustering of ALS and explore the hypothesized link between the neurotoxin BMAA and ALS.}, }
@article {pmid22214350, year = {2012}, author = {Otto, M and Bowser, R and Turner, M and Berry, J and Brettschneider, J and Connor, J and Costa, J and Cudkowicz, M and Glass, J and Jahn, O and Lehnert, S and Malaspina, A and Parnetti, L and Petzold, A and Shaw, P and Sherman, A and Steinacker, P and Süssmuth, S and Teunissen, C and Tumani, H and Wuolikainen, A and Ludolph, A and , }, title = {Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {1}, pages = {1-10}, doi = {10.3109/17482968.2011.627589}, pmid = {22214350}, issn = {1471-180X}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology/*physiopathology ; Biomarkers/*metabolism ; *Brain Chemistry ; Humans ; Proteomics/methods ; }, abstract = {Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.}, }
@article {pmid22201586, year = {2012}, author = {Konofagou, EE and Tung, YS and Choi, J and Deffieux, T and Baseri, B and Vlachos, F}, title = {Ultrasound-induced blood-brain barrier opening.}, journal = {Current pharmaceutical biotechnology}, volume = {13}, number = {7}, pages = {1332-1345}, pmid = {22201586}, issn = {1873-4316}, support = {R01 EB009041/EB/NIBIB NIH HHS/United States ; R21 EY018505/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/*diagnostic imaging/drug effects/*metabolism ; Brain/*drug effects ; Drug Delivery Systems/*methods ; Humans ; Microbubbles/*therapeutic use ; Ultrasonics/*methods ; Ultrasonography ; }, abstract = {Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&amp;E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.}, }
@article {pmid22190368, year = {2011}, author = {van Es, MA and Schelhaas, HJ and van Vught, PW and Ticozzi, N and Andersen, PM and Groen, EJ and Schulte, C and Blauw, HM and Koppers, M and Diekstra, FP and Fumoto, K and LeClerc, AL and Keagle, P and Bloem, BR and Scheffer, H and van Nuenen, BF and van Blitterswijk, M and van Rheenen, W and Wills, AM and Lowe, PP and Hu, GF and Yu, W and Kishikawa, H and Wu, D and Folkerth, RD and Mariani, C and Goldwurm, S and Pezzoli, G and Van Damme, P and Lemmens, R and Dahlberg, C and Birve, A and Fernández-Santiago, R and Waibel, S and Klein, C and Weber, M and van der Kooi, AJ and de Visser, M and Verbaan, D and van Hilten, JJ and Heutink, P and Hennekam, EA and Cuppen, E and Berg, D and Brown, RH and Silani, V and Gasser, T and Ludolph, AC and Robberecht, W and Ophoff, RA and Veldink, JH and Pasterkamp, RJ and de Bakker, PI and Landers, JE and van de Warrenburg, BP and van den Berg, LH}, title = {Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {70}, number = {6}, pages = {964-973}, pmid = {22190368}, issn = {1531-8249}, support = {5U10NS053369-05/NS/NINDS NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; R01 NS065847/NS/NINDS NIH HHS/United States ; 5P50AG005134-27/AG/NIA NIH HHS/United States ; R01 MH084676/MH/NIMH NIH HHS/United States ; R01 NS050557/NS/NINDS NIH HHS/United States ; U10 NS053369/NS/NINDS NIH HHS/United States ; R01MH084676/MH/NIMH NIH HHS/United States ; 1R01NS065847/NS/NINDS NIH HHS/United States ; GTB07001/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Databases, Factual/statistics &amp; numerical data ; Europe ; Female ; *Genetic Predisposition to Disease ; Genetic Variation/*genetics ; Humans ; Male ; Multicenter Studies as Topic ; Parkinson Disease/*genetics ; Ribonuclease, Pancreatic/*genetics ; United States ; }, abstract = {OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.<br><br>METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.<br><br>RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 &#xd7; 10(-6) for ALS and p = 4.3 &#xd7; 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.<br><br>INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.}, }
@article {pmid22187969, year = {2012}, author = {Tanaka, F and Ikenaka, K and Yamamoto, M and Sobue, G}, title = {Neuropathology and omics in motor neuron diseases.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {32}, number = {4}, pages = {458-462}, doi = {10.1111/j.1440-1789.2011.01281.x}, pmid = {22187969}, issn = {1440-1789}, mesh = {Animals ; Gene Expression Profiling/*methods ; Genomics/*methods ; Humans ; Motor Neuron Disease/*genetics/metabolism/*pathology ; Proteomics/*methods ; }, abstract = {Motor neuron diseases, including amyotrophic lateral sclerosis (ALS), are devastating disorders and effective therapies have not yet been established. One of the reasons for this lack of therapeutics, especially in sporadic ALS (SALS), is attributed to the absence of excellent disease models reflecting its pathology. For this purpose, identifying important key molecules for ALS pathomechanisms and developing disease models is crucial, and omics approaches, including genomics, transcriptomics and proteomics, have been employed. In particular, transcriptome analysis using cDNA microarray is the most popular omics approach and we have previously identified dynactin-1 as an important molecule downregulated in the motor neurons of SALS patients from the early stage of the disease. Dynactin-1 is also known as a causative gene in familial ALS (FALS). Dynactin-1 is a major component of the dynein/dynactin motor protein complex functioning in retrograde axonal transport. In motor neuron diseases as well as other neurodegenerative diseases, the role of axonal transport dysfunction in their pathogenesis always draws attention, but its precise mechanisms remain to be fully elucidated. In this article, we review our previous omics approach to SALS and the role of dynactin-1 in the pathogenesis of ALS. Finally, we emphasize the need for creating novel SALS disease models based on the results of omics analysis, especially based on the observation that dynactin-1 gene expression was downregulated in SALS motor neurons.}, }
@article {pmid22166431, year = {2012}, author = {Kaji, R and Izumi, Y and Adachi, Y and Kuzuhara, S}, title = {ALS-parkinsonism-dementia complex of Kii and other related diseases in Japan.}, journal = {Parkinsonism &amp; related disorders}, volume = {18 Suppl 1}, number = {}, pages = {S190-1}, doi = {10.1016/S1353-8020(11)70059-1}, pmid = {22166431}, issn = {1873-5126}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology/genetics ; Animals ; Dementia/*diagnosis/*epidemiology/genetics ; Humans ; Japan/epidemiology ; Male ; Mutation/genetics ; Neurofibrillary Tangles/genetics/pathology ; Parkinsonian Disorders/*diagnosis/*epidemiology/genetics ; }, abstract = {The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990 s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990 s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC. We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors.}, }
@article {pmid22166418, year = {2012}, author = {Youdim, MB}, title = {M30, a brain permeable multitarget neurorestorative drug in post nigrostriatal dopamine neuron lesion of parkinsonism animal models.}, journal = {Parkinsonism &amp; related disorders}, volume = {18 Suppl 1}, number = {}, pages = {S151-4}, doi = {10.1016/S1353-8020(11)70047-5}, pmid = {22166418}, issn = {1873-5126}, mesh = {Animals ; Corpus Striatum/drug effects/*metabolism ; *Disease Models, Animal ; Dopaminergic Neurons/*drug effects/*metabolism/pathology ; Drug Delivery Systems/methods ; Humans ; Hydroxyquinolines/administration &amp; dosage/*metabolism ; Mice ; Parkinsonian Disorders/*drug therapy/*metabolism/pathology ; Permeability/drug effects ; Substantia Nigra/drug effects/*metabolism/pathology ; }, abstract = {The anti-Parkinson iron chelator brain selective monoamine oxidase (MAO) AB inhibitor M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD) and ALS. We examined the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue/neurorestorative paradigm, M30 was orally administered to mice for 14 days (2.5-5 mg/kg/day) following post MPTP or lactacystin lesion and was shown to significantly elevate striatal dopamine, serotonin and noradrenaline levels, reduce their metabolism, and elevate tyrosine-hydroxylase protein levels. Importantly, M30 elevated MPTP-reduced dopaminergic and transferrin receptor cell count in the substantia nigra pars compacta (SNpc). Finally, M30 was shown to decrease mitosis and elevate HIF (hypoxia induced factor) which regulates the neurotrophins BDNF, GDNF, VEGF and erythropoietin by elevating their brain levels, thus providing additional protection. These findings indicates that brain-permeable M30 has neurorestorative activity, which may clearly be of clinical importance for the treatment of PD.}, }
@article {pmid22172070, year = {2011}, author = {Contestabile, A}, title = {Amyotrophic lateral sclerosis: from research to therapeutic attempts and therapeutic perspectives.}, journal = {Current medicinal chemistry}, volume = {18}, number = {36}, pages = {5655-5665}, doi = {10.2174/092986711798347289}, pmid = {22172070}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons which brings to muscular atrophy, paralysis and death in 3-5 years from starting symptoms. In about 10% of cases ALS is familiar and in a relevant percent of these cases, mutations of the enzyme copper-zinc superoxide dismutase 1 (SOD1) are found. Transgenic mice expressing mutated forms of SOD1 replicate with fidelity the onset and progression of the disease and have been largely used to test therapies to be translated to patients in clinical trials. Over years, many therapeutic approaches have been attempted in mice model often with significant, albeit limited, benefits on disease onset, progression and lifespan. Unfortunately almost all the clinical trials based on these preclinical results, have been unsuccessful. In the present review, both results of preclinical and clinical studies are summarized, focusing on the main mechanisms that are believed to contribute to this complex disease: oxidative stress, excitotoxicity, neuroinflammation, mitochondrial dysfunction, errors in protein folding and disposal, lack of trophic factors. Future perspectives related to genetic and stem cell approaches are briefly considered.}, }
@article {pmid22167414, year = {2012}, author = {Gama Sosa, MA and De Gasperi, R and Elder, GA}, title = {Modeling human neurodegenerative diseases in transgenic systems.}, journal = {Human genetics}, volume = {131}, number = {4}, pages = {535-563}, pmid = {22167414}, issn = {1432-1203}, mesh = {Alzheimer Disease/genetics/therapy ; Amyloid beta-Protein Precursor/genetics ; Animals ; Animals, Genetically Modified ; *Disease Models, Animal ; Humans ; Huntingtin Protein ; Huntington Disease/genetics/therapy ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*genetics/therapy ; Nuclear Proteins/genetics ; Transgenes/*genetics ; }, abstract = {Transgenic systems are widely used to study the cellular and molecular basis of human neurodegenerative diseases. A wide variety of model organisms have been utilized, including bacteria (Escherichia coli), plants (Arabidopsis thaliana), nematodes (Caenorhabditis elegans), arthropods (Drosophila melanogaster), fish (zebrafish, Danio rerio), rodents (mouse, Mus musculus and rat, Rattus norvegicus) as well as non-human primates (rhesus monkey, Macaca mulatta). These transgenic systems have enormous value for understanding the pathophysiological basis of these disorders and have, in some cases, been instrumental in the development of therapeutic approaches to treat these conditions. In this review, we discuss the most commonly used model organisms and the methodologies available for the preparation of transgenic organisms. Moreover, we provide selected examples of the use of these technologies for the preparation of transgenic animal models of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) and discuss the application of these technologies to AD as an example of how transgenic modeling has affected the study of human neurodegenerative diseases.}, }
@article {pmid22161544, year = {2012}, author = {Olson, SD and Pollock, K and Kambal, A and Cary, W and Mitchell, GM and Tempkin, J and Stewart, H and McGee, J and Bauer, G and Kim, HS and Tempkin, T and Wheelock, V and Annett, G and Dunbar, G and Nolta, JA}, title = {Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease.}, journal = {Molecular neurobiology}, volume = {45}, number = {1}, pages = {87-98}, pmid = {22161544}, issn = {1559-1182}, support = {1R01GM099688/GM/NIGMS NIH HHS/United States ; 2P51RR000169-49/RR/NCRR NIH HHS/United States ; R01 GM099688/GM/NIGMS NIH HHS/United States ; 1R01 HL073256-01/HL/NHLBI NIH HHS/United States ; 5P30AG010129-19/AG/NIA NIH HHS/United States ; P51 RR000169/RR/NCRR NIH HHS/United States ; R01 HL073256/HL/NHLBI NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Disease Models, Animal ; Genetic Engineering/*methods/trends ; Humans ; Huntington Disease/pathology/physiopathology/*therapy ; Mesenchymal Stem Cell Transplantation/*methods/trends ; Mesenchymal Stem Cells/*metabolism ; Nerve Growth Factors/biosynthesis/genetics/*metabolism ; }, abstract = {There is much interest in the use of mesenchymal stem cells/marrow stromal cells (MSC) to treat neurodegenerative disorders, in particular those that are fatal and difficult to treat, such as Huntington's disease. MSC present a promising tool for cell therapy and are currently being tested in FDA-approved phase I-III clinical trials for many disorders. In preclinical studies of neurodegenerative disorders, MSC have demonstrated efficacy, when used as delivery vehicles for neural growth factors. A number of investigators have examined the potential benefits of innate MSC-secreted trophic support and augmented growth factors to support injured neurons. These include overexpression of brain-derived neurotrophic factor and glial-derived neurotrophic factor, using genetically engineered MSC as a vehicle to deliver the cytokines directly into the microenvironment. Proposed regenerative approaches to neurological diseases using MSC include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation, MSC in the brain promote endogenous neuronal growth, encourage synaptic connection from damaged neurons, decrease apoptosis, reduce levels of free radicals, and regulate inflammation. These abilities are primarily modulated through paracrine actions. Clinical trials for MSC injection into the central nervous system to treat amyotrophic lateral sclerosis, traumatic brain injury, and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of Huntington's disease is discussed.}, }
@article {pmid22160849, year = {2011}, author = {Sack, GH}, title = {Introduction to the minireviews series on mitochondrial matters in amyotrophic lateral sclerosis, Lou Gehrig’s disease.}, journal = {Journal of bioenergetics and biomembranes}, volume = {43}, number = {6}, pages = {565-567}, pmid = {22160849}, issn = {1573-6881}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Genetic Diseases, Inborn/*enzymology ; Humans ; Mitochondria/*enzymology ; *Protein Folding ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, }
@article {pmid22158518, year = {2011}, author = {Boulis, NM and Federici, T and Glass, JD and Lunn, JS and Sakowski, SA and Feldman, EL}, title = {Translational stem cell therapy for amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {8}, number = {3}, pages = {172-176}, pmid = {22158518}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials, Phase I as Topic ; Disease Models, Animal ; Humans ; Magnetic Resonance Imaging ; Nerve Growth Factors/pharmacology/therapeutic use ; Stem Cell Transplantation/*methods/trends ; }, abstract = {Effective treatments are urgently needed for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of motor neurons. In 2009, the FDA approved the first phase I safety trial of direct intraspinal transplantation of neural stem cells into patients with ALS, which is currently in progress. Stem cell technologies represent a promising approach for treating ALS, but several issues must be addressed when translating promising experimental ALS therapies to patients. This article highlights the key research that supports the use of stem cells as a therapy for ALS, and discusses the rationale behind and approach to the phase I trial. Completion of the trial could pave the way for continued advances in stem cell therapy for ALS and other neurodegenerative diseases.}, }
@article {pmid22156453, year = {2012}, author = {Weinreb, O and Amit, T and Mandel, S and Youdim, MB}, title = {Novel therapeutic approach for neurodegenerative pathologies: multitarget iron-chelating drugs regulating hypoxia-inducible factor 1 signal transduction pathway.}, journal = {Neuro-degenerative diseases}, volume = {10}, number = {1-4}, pages = {112-115}, doi = {10.1159/000332597}, pmid = {22156453}, issn = {1660-2862}, mesh = {Animals ; Humans ; Hypoxia-Inducible Factor 1/*metabolism ; Iron Chelating Agents/pharmacology/*therapeutic use ; Models, Biological ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Signal Transduction/*drug effects ; }, abstract = {Our novel multimodal brain-permeable iron-chelating compounds M30 and HLA20 were demonstrated to possess neuroprotective/neurorescue activities in vitro and in vivo against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent reactive oxygen species generation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron-chelating compounds is associated with their ability to regulate the transcriptional activator hypoxia-inducible factor 1 (HIF-1). HIF-1 is a 'master switch' being an important physiological response mechanism, likely enhancing neuroprotective compensatory pathways involved in many physiological processes within the brain. This mini-review will discuss the multifunctional mechanisms of action of the drugs, M30 and HLA20 in preclinical models of neurodegeneration with a specific emphasis on their ability to activate the HIF-1 signal transduction pathway.}, }
@article {pmid22150926, year = {2012}, author = {Chen, S and Zhang, X and Song, L and Le, W}, title = {Autophagy dysregulation in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {22}, number = {1}, pages = {110-116}, pmid = {22150926}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Animals ; *Autophagy/genetics ; Humans ; Lysosomes/metabolism ; }, abstract = {Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.}, }
@article {pmid22143516, year = {2012}, author = {Karbowski, M and Neutzner, A}, title = {Neurodegeneration as a consequence of failed mitochondrial maintenance.}, journal = {Acta neuropathologica}, volume = {123}, number = {2}, pages = {157-171}, doi = {10.1007/s00401-011-0921-0}, pmid = {22143516}, issn = {1432-0533}, support = {R01 GM083131/GM/NIGMS NIH HHS/United States ; R01 GM102177/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; DNA, Mitochondrial/physiology ; Energy Metabolism/genetics ; Humans ; Mitochondria/genetics/*metabolism/*pathology ; Mitochondrial Diseases/genetics/*metabolism/*pathology ; Mitochondrial Proteins/genetics/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism/*pathology ; }, abstract = {Maintaining the functional integrity of mitochondria is pivotal for cellular survival. It appears that neuronal homeostasis depends on high-fidelity mitochondria, in particular. Consequently, mitochondrial dysfunction is a fundamental problem associated with a significant number of neurological diseases, including Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and various peripheral neuropathies, as well as the normal aging process. To ensure optimal mitochondrial function, diverse, evolutionarily conserved mitochondrial quality control mechanisms are in place, including the scavenging of toxic reactive oxygen species (ROS) and degradation of damaged mitochondrial proteins, but also turnover of whole organelles. In this review we will discuss various mitochondria-associated conditions, focusing on the role of protein turnover in mitochondrial maintenance with special emphasis on neurodegenerative disorders.}, }
@article {pmid22137288, year = {2012}, author = {Lehéricey, G and Le Forestier, N and Dupuis, L and Gonzalez-Bermejo, J and Meininger, V and Pradat, PF}, title = {[Nutritional management in amyotrophic lateral sclerosis: A medical and ethical stake].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {41}, number = {6 Pt 1}, pages = {560-574}, doi = {10.1016/j.lpm.2011.09.024}, pmid = {22137288}, issn = {2213-0276}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diet therapy/metabolism ; Deglutition Disorders/complications/*diet therapy ; Humans ; Malnutrition/complications/*diet therapy ; Nutrition Assessment ; Nutritional Status ; }, abstract = {Malnutrition and dehydration are common and result from swallowing disorders secondary to degeneration of brainstem motor neurons. Recent knowledge argues in favor of the associated primary metabolism abnormalities. Though muscle atrophy, a paradoxical hypermetabolism at rest has often been observed. Hyperlipidemia and glucose intolerance are more frequent than in general population. The heterogeneity of the nutritional assessment of patients in published series is due, partially at least, to the use of disparate criteria and evaluating procedures. Weight lost is an independent negative survival prognostic factor. Overweight may be beneficial for the survival of ALS patients. A specific nutritional management for ALS is an essential point in the multidisciplinary support. The criteria leading to artificial nutrition indication are medical, mainly based on percentage of weight loss, but also psychological and ethical.}, }
@article {pmid22133357, year = {2012}, author = {Thomson, SR and Wishart, TM and Patani, R and Chandran, S and Gillingwater, TH}, title = {Using induced pluripotent stem cells (iPSC) to model human neuromuscular connectivity: promise or reality?.}, journal = {Journal of anatomy}, volume = {220}, number = {2}, pages = {122-130}, pmid = {22133357}, issn = {1469-7580}, support = {BBS/E/D/20251969/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Disease Models, Animal ; Humans ; *Induced Pluripotent Stem Cells ; *Models, Biological ; Motor Neuron Disease/*physiopathology ; Neuromuscular Junction/*physiology ; Synapses/physiology ; }, abstract = {Motor neuron diseases (MND) such as amyotrophic lateral sclerosis and spinal muscular atrophy are devastating, progressive and ultimately fatal diseases for which there are no effective treatments. Recent evidence from systematic studies of animal models and human patients suggests that the neuromuscular junction (NMJ) is an important early target in MND, demonstrating functional and structural abnormalities in advance of pathological changes occurring in the motor neuron cell body. The ability to study pathological changes occurring at the NMJ in humans is therefore likely to be important for furthering our understanding of disease pathogenesis, and also for designing and testing new therapeutics. However, there are many practical and technical reasons why it is not possible to visualise or record from NMJs in pre- and early-symptomatic MND patients in vivo. Other approaches are therefore required. The development of stem cell technologies has opened up the possibility of creating human NMJs in vitro, using pluripotent cells generated from healthy individuals and patients with MND. This review covers historical attempts to develop mature and functional NMJs in vitro, using co-cultures of muscle and nerve from animals, and discusses how recent developments in the generation and specification of human induced pluripotent stem cells provides an opportunity to build on these previous successes to recapitulate human neuromuscular connectivity in vitro.}, }
@article {pmid22129991, year = {2011}, author = {Neef, DW and Jaeger, AM and Thiele, DJ}, title = {Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases.}, journal = {Nature reviews. Drug discovery}, volume = {10}, number = {12}, pages = {930-944}, pmid = {22129991}, issn = {1474-1784}, support = {R01-GM059911/GM/NIGMS NIH HHS/United States ; GM076954/GM/NIGMS NIH HHS/United States ; F32 GM076954/GM/NIGMS NIH HHS/United States ; R01 NS065890/NS/NINDS NIH HHS/United States ; R01 GM059911/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; *Drug Delivery Systems/methods ; Heat Shock Transcription Factors ; Heat-Shock Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism/pathology ; Transcription Factors/antagonists &amp; inhibitors/genetics/*metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-based neurodegeneration are associated with the accumulation of misfolded proteins, resulting in neuronal dysfunction and cell death. However, current treatments for these diseases predominantly address disease symptoms, rather than the underlying protein misfolding and cell death, and are not able to halt or reverse the degenerative process. Studies in cell culture, fruitfly, worm and mouse models of protein misfolding-based neurodegenerative diseases indicate that enhancing the protein-folding capacity of cells, via elevated expression of chaperone proteins, has therapeutic potential. Here, we review advances in strategies to harness the power of the natural cellular protein-folding machinery through pharmacological activation of heat shock transcription factor 1--the master activator of chaperone protein gene expression--to treat neurodegenerative diseases.}, }
@article {pmid22125427, year = {2011}, author = {Coppedè, F}, title = {An overview of DNA repair in amyotrophic lateral sclerosis.}, journal = {TheScientificWorldJournal}, volume = {11}, number = {}, pages = {1679-1691}, pmid = {22125427}, issn = {1537-744X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; DNA Damage ; *DNA Repair ; Humans ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is an adult onset neurodegenerative disorder characterised by the degeneration of cortical and spinal cord motor neurons, resulting in progressive muscular weakness and death. Increasing evidence supports mitochondrial dysfunction and oxidative DNA damage in ALS motor neurons. Several DNA repair enzymes are activated following DNA damage to restore genome integrity, and impairments in DNA repair capabilities could contribute to motor neuron degeneration. After a brief description of the evidence of DNA damage in ALS, this paper focuses on the available data on DNA repair activity in ALS neuronal tissue and disease animal models. Moreover, biochemical and genetic data on DNA repair in ALS are discussed in light of similar findings in other neurodegenerative diseases.}, }
@article {pmid22117132, year = {2012}, author = {Evans, MC and Modo, M and Talbot, K and Sibson, N and Turner, MR}, title = {Magnetic resonance imaging of pathological processes in rodent models of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {3}, pages = {288-301}, doi = {10.3109/17482968.2011.623300}, pmid = {22117132}, issn = {1471-180X}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Animals ; Contrast Media ; Disease Models, Animal ; Humans ; Magnetic Resonance Imaging ; Neuroimaging ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Non-human models of neurodegenerative diseases have potential for the identification of key pathways in pathogenesis and for the more rapid assessment of therapeutic candidates. While there are legitimate concerns about the physiological differences between the rodent and human motor systems, mice expressing the 'G93A' superoxide dismutase-1 gene mutation are a predictable and robustly-characterized model for amyotrophic lateral sclerosis (ALS). This model has provided evidence for an important role of inflammatory processes during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. While magnetic resonance imaging is now an established and leading modality for the identification of ALS biomarkers in humans, it can also be increasingly applied to rodent models to probe structural, functional and biochemical changes throughout the course of the disease, with additional potential to generate surrogate markers for the efficacy of therapeutic interventions. Targeted MRI contrast agents, through tagging of various cell types and even individual molecules, will deliver an era of in vivo molecular neuroimaging, with greater specificity for the most relevant pathological processes. These are potentially important steps towards the ultimate goal of human therapeutic translation.}, }
@article {pmid22106714, year = {2011}, author = {Siddique, T and Ajroud-Driss, S}, title = {Familial amyotrophic lateral sclerosis, a historical perspective.}, journal = {Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology}, volume = {30}, number = {2}, pages = {117-120}, pmid = {22106714}, issn = {1128-2460}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology ; Family Health ; Gene-Environment Interaction ; Genome-Wide Association Study ; Humans ; Motor Neurons/*metabolism/pathology ; Neural Pathways/*metabolism/pathology ; Pedigree ; *Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Therapies, Investigational ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease of the upper and lower motor neuron of unknown etiology. Although a familial cause for this disease has been suspected early one, it is only in the past two decades that advances in modern genetics led to the identification of more than 10 genes linked to familial ALS and helped us understand some of the complex genetic and environmental interactions that may contribute to sporadic ALS. In this article, we chronologically summarize the genetic breakthroughs in familial and sporadic ALS and depict how it shaped our understanding of disease pathogenesis and our quest for rational therapies.}, }
@article {pmid22105541, year = {2011}, author = {Ince, PG and Highley, JR and Kirby, J and Wharton, SB and Takahashi, H and Strong, MJ and Shaw, PJ}, title = {Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology.}, journal = {Acta neuropathologica}, volume = {122}, number = {6}, pages = {657-671}, doi = {10.1007/s00401-011-0913-0}, pmid = {22105541}, issn = {1432-0533}, support = {G0800380/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Mutation/genetics ; Neuroglia/*pathology ; Pathology, Molecular/*trends ; RNA-Binding Protein FUS/genetics/metabolism ; Signal Transduction/*genetics ; }, abstract = {Research into amyotrophic lateral sclerosis (ALS) has been stimulated by a series of genetic and molecular pathology discoveries. The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS. The link between RNA processing and ALS was further strengthened by the discovery that another genetic locus linking familial ALS (fALS) and FTD was due to mutation of the fused in sarcoma (FUS) gene. Of potentially even greater importance it emerges that TDP-43 accumulation and inclusion formation characterises not only most sALS cases but also those that arise from mutations in several genes including TARDBP (predominantly ALS cases) itself, C9ORF72 (ALS and FTD cases), progranulin (predominantly FTD phenotypes), VAPB (predominantly ALS cases) and in some ALS cases with rare genetic variants of uncertain pathogenicity (CHMP2B). "TDP-proteinopathy" therefore now represents a final common pathology associated with changes in multiple genes and opens the possibility of research by triangulation towards key common upstream molecular events. It also delivers final proof of the hypothesis that ALS and most FTD cases are disorders within a common pathology expressed as a clinico-anatomical spectrum. The emergence of TDP-proteinopathy also confirms the view that glial pathology is a crucial facet in this class of neurodegeneration, adding to the established view of non-nerve cell autonomous degeneration of the motor system from previous research on SOD1 fALS. Future research into the mechanisms of TDP-43 and FUS-related neurodegeneration, taking into account the major component of glial pathology now revealed in those disorders will significantly accelerate new discoveries in this field, including target identification for new therapy.}, }
@article {pmid22105211, year = {2011}, author = {Vlam, L and van der Pol, WL and Cats, EA and Straver, DC and Piepers, S and Franssen, H and van den Berg, LH}, title = {Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies.}, journal = {Nature reviews. Neurology}, volume = {8}, number = {1}, pages = {48-58}, pmid = {22105211}, issn = {1759-4766}, mesh = {Humans ; Motor Neuron Disease/*diagnosis/*physiopathology/therapy ; Polyneuropathies/*diagnosis/*physiopathology/therapy ; }, abstract = {Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.}, }
@article {pmid22101998, year = {2011}, author = {Jóźwiak, S and Kossoff, EH and Kotulska-Jóźwiak, K}, title = {Dietary treatment of epilepsy: rebirth of an ancient treatment.}, journal = {Neurologia i neurochirurgia polska}, volume = {45}, number = {4}, pages = {370-378}, doi = {10.1016/s0028-3843(14)60108-0}, pmid = {22101998}, issn = {0028-3843}, mesh = {Child ; Child Welfare ; Diet, Carbohydrate-Restricted/*methods ; Diet, Ketogenic/*methods ; Dietary Fats/*administration &amp; dosage ; Epilepsy/*diet therapy/metabolism ; Humans ; Ketones/metabolism ; }, abstract = {Since its introduction in 1921, the ketogenic diet has been in continuous use for children with difficult-to-control epilepsy. After decades of relative disuse, it is now both extremely popular and well studied, with approximately two-thirds of children demonstrating significant seizure reduction after 6 months. It is being used for less intractable seizures in children as well as recently adults. Modifications that help improve tolerability include the medium chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. Major side effects include acidosis, increased cholesterol, kidney stones, gastroesophageal reflux, and growth disturbance. However, these side effects are usually treatable and nowadays often even preventable. Future non-epilepsy indications such as Alzheimer disease, amyotrophic lateral sclerosis, autism, and brain tumors are under active investigation. This dietary treatment for epilepsy has undergone a rebirth. Its widespread use in Poland and Europe is a welcome additional treatment for those with drug-resistant epilepsy.}, }
@article {pmid22100761, year = {2012}, author = {Eisen, A and Kuwabara, S}, title = {The split hand syndrome in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {4}, pages = {399-403}, doi = {10.1136/jnnp-2011-301456}, pmid = {22100761}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*physiopathology ; Anterior Horn Cells/metabolism/pathology ; Axons/metabolism ; Comorbidity ; Evoked Potentials, Motor ; Genetic Diseases, X-Linked/diagnosis/*epidemiology/*physiopathology ; Humans ; Limb Deformities, Congenital/diagnosis/*epidemiology/*physiopathology ; Sensitivity and Specificity ; Ulnar Nerve/physiopathology ; }, abstract = {In amyotrophic lateral sclerosis (ALS), hand muscle wasting preferentially affects the 'thenar (lateral) hand', including the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles, with relative sparing of the hypothenar muscles (the abductor digiti minimi (ADM)). This peculiar pattern of dissociated atrophy of the intrinsic hand muscles is termed the 'split hand' and is rarely seen in diseases other than ALS. The muscles involved in the split hand are innervated through the same spinal segments (C8 and T1), and FDI and ADM, which are differentially affected, are both ulnar nerve innervated. The physiological mechanisms underlying the split hand in ALS are incompletely understood but both cortical and spinal/peripheral mechanisms are probably involved. Motor potentials evoked by magnetic stimulation are significantly smaller when recorded from the thenar complex, compared with the hypothenar muscles, supporting a cortical mechanism. But peripheral axonal excitability studies have suggested that APB/FDI motor axons have more prominent persistent sodium currents than ADM axons, leading to higher axonal excitability and thereby more ready degeneration. Pincer or precision grip is vital to human hand function, and frequent use of thenar complex muscles may lead to greater oxidative stress and metabolic demands at both upper and lower motoneurons innervating the APB and FDI. The split hand is a useful diagnostic sign in early ALS, and recent objective studies indicate that the sign has a high degree of specificity.}, }
@article {pmid22094924, year = {2012}, author = {Nizzardo, M and Simone, C and Falcone, M and Riboldi, G and Rizzo, F and Magri, F and Bresolin, N and Comi, GP and Corti, S}, title = {Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {69}, number = {10}, pages = {1641-1650}, pmid = {22094924}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Dependovirus ; Disease Models, Animal ; Genetic Therapy/*trends ; Genetic Vectors/therapeutic use ; Mice ; Neuroprotective Agents/therapeutic use ; RNA Interference ; Rats ; Superoxide Dismutase/antagonists &amp; inhibitors/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle weakness, paralysis, and premature death. No effective therapy is available. Research in the motor neuron field continues to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal muscular atrophy, a genetic motor neuron disease. With adeno-associated virus (AAV) vectors, gene transfer can be achieved with systemic non-invasive injection and minimal toxicity. In the context of this success, we review gene therapy approaches for ALS, considering what has been done and the possible future directions for effective application of the latest generation of vectors for clinical translation. We focus on recent developments in the areas of RNA/antisense-mediated silencing of specific ALS causative genes like superoxide dismutase-1 and other molecular pathogenetic targets, as well as the administration of neuroprotective factors with viral vectors. We argue that gene therapy offers new opportunities to open the path for clinical progress in treating ALS.}, }
@article {pmid22089637, year = {2011}, author = {Barrett, EF and Barrett, JN and David, G}, title = {Mitochondria in motor nerve terminals: function in health and in mutant superoxide dismutase 1 mouse models of familial ALS.}, journal = {Journal of bioenergetics and biomembranes}, volume = {43}, number = {6}, pages = {581-586}, pmid = {22089637}, issn = {1573-6881}, support = {R01 NS058888/NS/NINDS NIH HHS/United States ; R01 NS058888-04/NS/NINDS NIH HHS/United States ; R01 58888//PHS HHS/United States ; R01 12404//PHS HHS/United States ; }, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; Calcium/metabolism ; Disease Models, Animal ; Genetic Diseases, Inborn/*enzymology/genetics/pathology ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/*enzymology/genetics/pathology ; Motor Endplate/*enzymology/genetics/pathology ; Motor Neurons/*enzymology/pathology ; Mutation ; Mutation, Missense ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mitochondria contribute to neuronal function not only via their ability to generate ATP, but also via their ability to buffer large Ca(2+) loads. This review summarizes evidence that mitochondrial Ca(2+) sequestration is especially important for sustaining the function of vertebrate motor nerve terminals during repetitive stimulation. Motor terminal mitochondria can sequester large amounts of Ca(2+) because they have mechanisms for limiting both the mitochondrial depolarization and the increase in matrix free [Ca(2+)] associated with Ca(2+) influx. In mice expressing mutations of human superoxide dismutase -1 (SOD1) that cause some cases of familial amyotrophic lateral sclerosis (fALS), motor terminals degenerate well before the death of motor neuron cell bodies. This review presents evidence for early and progressive mitochondrial dysfunction in motor terminals of mutant SOD1 mice (G93A, G85R). This dysfunction would impair mitochondrial ability to sequester stimulation-associated Ca(2+) loads, and thus likely contributes to the early degeneration of motor terminals.}, }
@article {pmid22087831, year = {2011}, author = {Chattopadhaya, S and Harikishore, A and Yoon, HS}, title = {Role of FK506 binding proteins in neurodegenerative disorders.}, journal = {Current medicinal chemistry}, volume = {18}, number = {35}, pages = {5380-5397}, doi = {10.2174/092986711798194441}, pmid = {22087831}, issn = {1875-533X}, mesh = {Amyloidosis/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Frontotemporal Dementia/metabolism/pathology ; Humans ; Neurodegenerative Diseases/classification/*metabolism/pathology ; Protein Folding ; Tacrolimus Binding Proteins/chemistry/*metabolism ; }, abstract = {Protein misfolding has been implicated in the pathophysiology of several neurodegenerative 'amyloidoses' that includes Alzheimer's, Parkinson's, Huntington's disease, frontotemporal dementia and amyotrophic lateral sclerosis. Accumulation of misfolded proteins into ordered fibrillar intra- or extracellular amyloids results in brain lesions that in turn lead to injury and neuronal loss. The appearance of protein aggregates in the diseased brain hints at an inability of cellular chaperones to properly assist folding of client proteins. Not surprisingly, studies involving cell-based and animal models of the neurodegenerative diseases have shown that overexpression of molecular chaperones can provide neuroprotection. Together with identification of new targets for symptomatic relief of motor and non-motor defects in neurodegenerative disorders, there is a critical unmet clinical need for the development of novel neuroprotective molecules. One such promising class of compounds are neuroimmunophilin ligands (NILs). Derived from FK506 (tacrolimus), NILs have been shown to be efficacious in a number of neurodegenerative disorders. The ability of these nonimmunosuppressive NILs to protect neurons is modulated, in part, by a large family of co-chaperone proteins called the FK506 binding proteins (FKBPs). This review focuses on the roles of FKBPs in neurodegenerative disorders with an emphasis on the cellular mechanisms responsible for their neuroprotective and neurotrophic activities. We discuss the structural features of FKBPs and the mode of action of NILs. For brevity, we limit our discussion to those FKBPs that are particularly enriched in the nervous system. We hope that such information will aid in the rational design of new and improved NILs for ameliorating neurodegenerative disorders.}, }
@article {pmid22083126, year = {2011}, author = {Martin, LJ}, title = {Mitochondrial pathobiology in ALS.}, journal = {Journal of bioenergetics and biomembranes}, volume = {43}, number = {6}, pages = {569-579}, pmid = {22083126}, issn = {1573-6881}, support = {R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; *Apoptosis ; Disease Models, Animal ; Electron Transport/genetics ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/genetics/*metabolism/pathology ; Neurons/*metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most common human adult-onset neurodegenerative disease. Some forms of ALS are inherited, and disease-causing genes have been identified. Nevertheless, the mechanisms of neurodegeneration in ALS are unresolved. Genetic, biochemical, and morphological analyses of human ALS as well as cell and animal models of ALS reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations. Changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins in ALS. Transgenic mouse models of ALS reveal possible principles governing the biology of neurodegeneration that implicate mitochondria and the mitochondrial permeability transition pore. This paper reviews how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in ALS.}, }
@article {pmid22081209, year = {2011}, author = {Carrì, MT and Cozzolino, M}, title = {SOD1 and mitochondria in ALS: a dangerous liaison.}, journal = {Journal of bioenergetics and biomembranes}, volume = {43}, number = {6}, pages = {593-599}, pmid = {22081209}, issn = {1573-6881}, support = {GGP07018/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Calcium/metabolism ; Energy Metabolism/genetics ; Humans ; Mitochondria/*enzymology/genetics ; *Protein Folding ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mutant Cu,Zn superoxide dismutase (mutSOD1) is found in a subset of patients with familial amyotrophic lateral sclerosis (ALS), a fatal progressive paralysis due to loss of motor neurons. In the present article, we review existing evidence linking the expression of mutSOD1 to the many facets of mitochondrial dysfunction in ALS, with a focus on recent studies suggesting that the association and misfolding of the mutant protein (and possibly of the wild type protein as well) within these organelles is causally linked to their functional and structural alterations. Energy deficit, calcium mishandling and oxidative stress are paralleled by alteration in mitochondrial motility, dynamics and turnover and most probably lead to mitochondria-dependent cell death. Thus, the development of new, selective mitochondria-targeted therapies may constitute a promising approach in the treatment of SOD1-linked ALS.}, }
@article {pmid22073019, year = {2011}, author = {Kisby, GE and Spencer, PS}, title = {Is neurodegenerative disease a long-latency response to early-life genotoxin exposure?.}, journal = {International journal of environmental research and public health}, volume = {8}, number = {10}, pages = {3889-3921}, pmid = {22073019}, issn = {1660-4601}, support = {U19 ES011384/ES/NIEHS NIH HHS/United States ; ES11384/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Brain/drug effects/growth &amp; development/*metabolism ; Cycas/*chemistry ; Cycasin/pharmacology/toxicity ; DNA Damage ; Glycosides/pharmacology/toxicity ; Guam/epidemiology ; Humans ; Methylazoxymethanol Acetate/*analogs &amp; derivatives/pharmacology/toxicity ; Mutagens/pharmacology/*toxicity ; Neurotoxins/pharmacology/*toxicity ; Pacific Islands/epidemiology ; Tauopathies/epidemiology/etiology ; }, abstract = {Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, a disappearing neurodegenerative disease linked to use of the neurotoxic cycad plant for food and/or medicine, is intensively studied because the neuropathology (tauopathy) is similar to that of Alzheimer's disease. Cycads contain neurotoxic and genotoxic principles, notably cycasin and methylazoxymethanol, the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.}, }
@article {pmid22072931, year = {2011}, author = {Ido, A and Fukuyama, H and Urushitani, M}, title = {Protein misdirection inside and outside motor neurons in Amyotrophic Lateral Sclerosis (ALS): a possible clue for therapeutic strategies.}, journal = {International journal of molecular sciences}, volume = {12}, number = {10}, pages = {6980-7003}, pmid = {22072931}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; Animals ; Antibodies/immunology/therapeutic use ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Motor Neurons/*metabolism ; Mutation ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.}, }
@article {pmid22072660, year = {2011}, author = {Liu-Yesucevitz, L and Bassell, GJ and Gitler, AD and Hart, AC and Klann, E and Richter, JD and Warren, ST and Wolozin, B}, title = {Local RNA translation at the synapse and in disease.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {31}, number = {45}, pages = {16086-16093}, pmid = {22072660}, issn = {1529-2401}, support = {ES15567/ES/NIEHS NIH HHS/United States ; R01 NS060872-02/NS/NINDS NIH HHS/United States ; R21 NS066108/NS/NINDS NIH HHS/United States ; R21 NS073679/NS/NINDS NIH HHS/United States ; R01 NS060872-03/NS/NINDS NIH HHS/United States ; R21 NS073679-01A1/NS/NINDS NIH HHS/United States ; R21 NS073679-02/NS/NINDS NIH HHS/United States ; R01 NS060872-02S1/NS/NINDS NIH HHS/United States ; R01 NS060872/NS/NINDS NIH HHS/United States ; R01 NS060872-04/NS/NINDS NIH HHS/United States ; NS066108/NS/NINDS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R21 NS066108-01A1/NS/NINDS NIH HHS/United States ; R21 NS066108-02/NS/NINDS NIH HHS/United States ; R01 ES015567/ES/NIEHS NIH HHS/United States ; NS060872/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Nerve Tissue Proteins/genetics/metabolism ; *Nervous System Diseases/genetics/metabolism/pathology ; Neurons/*metabolism ; Protein Biosynthesis/*physiology ; RNA/genetics/*metabolism ; RNA-Binding Proteins/genetics/metabolism ; Signal Transduction/genetics ; Synapses/genetics/metabolism ; }, abstract = {Local regulation of protein synthesis in neurons has emerged as a leading research focus because of its importance in synaptic plasticity and neurological diseases. The complexity of neuronal subcellular domains and their distance from the soma demand local spatial and temporal control of protein synthesis. Synthesis of many synaptic proteins, such as GluR and PSD-95, is under local control. mRNA binding proteins (RBPs), such as FMRP, function as key regulators of local RNA translation, and the mTORC1 pathway acts as a primary signaling cascade for regulation of these proteins. Much of the regulation occurs through structures termed RNA granules, which are based on reversible aggregation of the RBPs, some of which have aggregation prone domains with sequence features similar to yeast prion proteins. Mutations in many of these RBPs are associated with neurological diseases, including FMRP in fragile X syndrome; TDP-43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of motor neuron protein) in spinal muscular atrophy.}, }
@article {pmid22072396, year = {2012}, author = {Martin, LJ and Chang, Q}, title = {Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis.}, journal = {Molecular neurobiology}, volume = {45}, number = {1}, pages = {30-42}, pmid = {22072396}, issn = {1559-1182}, support = {R01-AG016282/AG/NIA NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; R01 AG016282-01A1/AG/NIA NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; R01-NS034100/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01-NS052098/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; R01-NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*physiopathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Models, Neurological ; Motor Neurons/*physiology ; Neural Inhibition/*genetics/physiology ; Receptors, GABA/physiology ; Receptors, Glycine/deficiency/genetics ; Superoxide Dismutase/deficiency/genetics ; Superoxide Dismutase-1 ; Synaptic Transmission/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. It causes the degeneration of motoneurons and is fatal due to paralysis, particularly of respiratory muscles. ALS can be inherited, and specific disease-causing genes have been identified, but the mechanisms causing motoneuron death in ALS are not understood. No effective treatments exist for ALS. One well-studied theory of ALS pathogenesis involves faulty RNA editing and abnormal activation of specific glutamate receptors as well as failure of glutamate transport resulting in glutamate excitotoxicity; however, the excitotoxicity theory is challenged by the inability of anti-glutamate drugs to have major disease-modifying effects clinically. Nevertheless, hyperexcitability of upper and lower motoneurons is a feature of human ALS and transgenic (tg) mouse models of ALS. Motoneuron excitability is strongly modulated by synaptic inhibition mediated by presynaptic glycinergic and GABAergic innervations and postsynaptic glycine receptors (GlyR) and GABA(A) receptors; yet, the integrity of inhibitory systems regulating motoneurons has been understudied in experimental models, despite findings in human ALS suggesting that they may be affected. We have found in tg mice expressing a mutant form of human superoxide dismutase-1 (hSOD1) with a Gly93 → Ala substitution (G93A-hSOD1), causing familial ALS, that subsets of spinal interneurons degenerate. Inhibitory glycinergic innervation of spinal motoneurons becomes deficient before motoneuron degeneration is evident in G93A-hSOD1 mice. Motoneurons in these ALS mice also have insufficient synaptic inhibition as reflected by smaller GlyR currents, smaller GlyR clusters on their plasma membrane, and lower expression of GlyR1α mRNA compared to wild-type motoneurons. In contrast, GABAergic innervation of ALS mouse motoneurons and GABA(A) receptor function appear normal. Abnormal synaptic inhibition resulting from dysfunction of interneurons and motoneuron GlyRs is a new direction for unveiling mechanisms of ALS pathogenesis that could be relevant to new therapies for ALS.}, }
@article {pmid22072073, year = {2011}, author = {Faes, L and Callewaert, G}, title = {Mitochondrial dysfunction in familial amyotrophic lateral sclerosis.}, journal = {Journal of bioenergetics and biomembranes}, volume = {43}, number = {6}, pages = {587-592}, pmid = {22072073}, issn = {1573-6881}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; Genetic Diseases, Inborn/*enzymology/genetics/pathology ; Humans ; Mitochondria/*enzymology/genetics/pathology ; Mutation ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.}, }
@article {pmid22070610, year = {2012}, author = {Feng, Z and Gao, F}, title = {Stem cell challenges in the treatment of neurodegenerative disease.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {18}, number = {2}, pages = {142-148}, pmid = {22070610}, issn = {1755-5949}, mesh = {Alzheimer Disease/pathology/surgery ; Amyotrophic Lateral Sclerosis/pathology/surgery ; Animals ; Clinical Trials as Topic ; Humans ; Neurodegenerative Diseases/pathology/*surgery ; Parkinson Disease/pathology/surgery ; Stem Cell Transplantation/*methods/*trends ; Stem Cells/physiology ; Treatment Outcome ; }, abstract = {Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases.}, }
@article {pmid22069578, year = {2010}, author = {Banack, SA and Caller, TA and Stommel, EW}, title = {The cyanobacteria derived toxin Beta-N-methylamino-L-alanine and amyotrophic lateral sclerosis.}, journal = {Toxins}, volume = {2}, number = {12}, pages = {2837-2850}, pmid = {22069578}, issn = {2072-6651}, mesh = {Amino Acids, Diamino/*toxicity ; Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Bacterial Toxins/*toxicity ; Brain/metabolism ; *Cyanobacteria ; Cyanobacteria Toxins ; Environmental Exposure ; Guam ; Humans ; }, abstract = {There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis). The non-protein amino acid beta-N-methylamino-L-alanine (BMAA) was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer's disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin.}, }
@article {pmid22035690, year = {2011}, author = {Stern, RA and Riley, DO and Daneshvar, DH and Nowinski, CJ and Cantu, RC and McKee, AC}, title = {Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {3}, number = {10 Suppl 2}, pages = {S460-7}, doi = {10.1016/j.pmrj.2011.08.008}, pmid = {22035690}, issn = {1934-1563}, mesh = {Age Factors ; Athletic Injuries/complications ; Brain/*pathology ; Brain Concussion/*complications ; Brain Injury, Chronic/diagnosis/*etiology ; Humans ; Microscopy ; Risk Factors ; Sex Factors ; }, abstract = {Chronic traumatic encephalopathy (CTE) has been linked to participation in contact sports such as boxing and American football. CTE results in a progressive decline of memory and cognition, as well as depression, suicidal behavior, poor impulse control, aggressiveness, parkinsonism, and, eventually, dementia. In some individuals, it is associated with motor neuron disease, referred to as chronic traumatic encephalomyelopathy, which appears clinically similar to amyotrophic lateral sclerosis. Results of neuropathologic research has shown that CTE may be more common in former contact sports athletes than previously believed. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, is responsible for neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and TDP-43 proteins. Given the millions of youth, high school, collegiate, and professional athletes participating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from blast and other injuries in the military, CTE represents an important public health issue. Focused and intensive study of the risk factors and in vivo diagnosis of CTE will potentially allow for methods to prevent and treat these diseases. Research also will provide policy makers with the scientific knowledge to make appropriate guidelines regarding the prevention and treatment of brain trauma in all levels of athletic involvement as well as the military theater.}, }
@article {pmid22052354, year = {2011}, author = {Kryndushkin, D and Shewmaker, F}, title = {Modeling ALS and FTLD proteinopathies in yeast: an efficient approach for studying protein aggregation and toxicity.}, journal = {Prion}, volume = {5}, number = {4}, pages = {250-257}, pmid = {22052354}, issn = {1933-690X}, mesh = {Amyloid/chemistry/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; DNA-Binding Proteins ; Frontotemporal Lobar Degeneration/*metabolism/pathology ; Humans ; Models, Molecular ; Prions/chemistry/*metabolism ; RNA-Binding Protein FUS/chemistry/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Superoxide Dismutase/chemistry/metabolism ; Superoxide Dismutase-1 ; }, abstract = {In recent years there have been several reports of human neurodegenerative diseases that involve protein misfolding being modeled in the yeast Saccharomyces cerevisiae. This review summarizes recent advances in understanding the specific mechanisms underlying intracellular neuronal pathology during Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), including SOD1, TDP-43 and FUS protein inclusions and the potential of these proteins to be involved in pathogenic prion-like mechanisms. More specifically, we focus on findings from yeast systems that offer tremendous possibilities for screening for genetic and chemical modifiers of disease-related proteotoxicity.}, }
@article {pmid22051914, year = {2011}, author = {Ferraiuolo, L and Kirby, J and Grierson, AJ and Sendtner, M and Shaw, PJ}, title = {Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {616-630}, pmid = {22051914}, issn = {1759-4766}, support = {//Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Humans ; Motor Neurons/*pathology ; Nerve Degeneration/genetics/*metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology. New insights have also indicated the importance of dysregulated glial cell-motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.}, }
@article {pmid22043906, year = {2011}, author = {Guest, WC and Silverman, JM and Pokrishevsky, E and O'Neill, MA and Grad, LI and Cashman, NR}, title = {Generalization of the prion hypothesis to other neurodegenerative diseases: an imperfect fit.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {74}, number = {22-24}, pages = {1433-1459}, doi = {10.1080/15287394.2011.618967}, pmid = {22043906}, issn = {1528-7394}, mesh = {Animals ; Humans ; Nerve Degeneration/metabolism/pathology ; Neurodegenerative Diseases/classification/*metabolism/pathology ; Prion Diseases/*metabolism/pathology ; Prions/chemistry/*metabolism ; Protein Conformation ; Protein Folding ; }, abstract = {Protein misfolding diseases have been classically understood as diffuse errors in protein folding, with misfolded protein arising autonomously throughout a tissue due to a pathologic stressor. The field of prion science has provided an alternative mechanism whereby a seed of pathologically misfolded protein, arising exogenously or through a rare endogenous structural fluctuation, yields a template to catalyze misfolding of the native protein. The misfolded protein may then spread intercellularly to communicate the misfold to adjacent areas and ultimately infect a whole tissue. Mounting evidence implicates a prion-like process in the propagation of several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and the tauopathies. However, the parallels between the events observed in these conditions and those in prion disease are often incomplete. The aim of this review was to examine the current state of knowledge concerning the mechanisms of protein misfolding and aggregation for neurodegeneration-associated proteins. In addition, possible methods of intercellular spread are described that focus on the hypothesis that released microvesicles function as misfolded protein delivery vehicles, and the therapeutic options enabled by viewing these diseases from the prion perspective.}, }
@article {pmid22041967, year = {2012}, author = {Raghavan, A and Shah, ZA}, title = {Sirtuins in neurodegenerative diseases: a biological-chemical perspective.}, journal = {Neuro-degenerative diseases}, volume = {9}, number = {1}, pages = {1-10}, pmid = {22041967}, issn = {1660-2862}, support = {R00 AT004197/AT/NCCIH NIH HHS/United States ; R00AT004197/AT/NCCIH NIH HHS/United States ; }, mesh = {Aging ; Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Brain Ischemia/drug therapy ; Group III Histone Deacetylases/chemistry/metabolism/therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/drug therapy ; Protein Structure, Tertiary ; *Sirtuins/chemistry/metabolism/therapeutic use ; Substrate Specificity ; }, abstract = {Sirtuins, commonly known as NAD(+)-dependent class III histone deacetylase enzymes, have been extensively studied to evaluate their potential role in different disease states. Based on the published literature, sirtuins have been implicated in providing a myriad of intrinsic and extrinsic biological effects, which in turn may play an important role in the treatment of various disorders such as type II diabetes, obesity, cancer, aging and different neurodegenerative diseases. In particular, a number of studies have unequivocally supported the idea of sirtuins having therapeutic potential in neurodegenerative diseases such as stroke, ischemic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. To exploit the therapeutic potential of sirtuins, their manipulation in terms of development of small-molecule modulators, inhibitors and analogs has increased dramatically since their inception, in both scientific and industrial worlds. Studies on the structure and catalytic core of sirtuins along with chemical mechanisms and substrate specificity have provided important input into the design and synthesis of sirtuin modulators. To study the role of sirtuins in the biological system, it has become extremely important to understand the molecular and chemical structure of sirtuins. In this review, we have discussed the biological role of sirtuins in various neurodegenerative diseases, and also provided an insight into their chemical structure.}, }
@article {pmid22041805, year = {2011}, author = {Cellura, E}, title = {[Extramotor disorders in amyotrophic lateral sclerosis: multisystem disease?].}, journal = {La Clinica terapeutica}, volume = {162}, number = {5}, pages = {457-459}, pmid = {22041805}, issn = {1972-6007}, mesh = {Amyotrophic Lateral Sclerosis/*complications/metabolism/pathology/psychology ; Arrhythmias, Cardiac/etiology/physiopathology ; Autonomic Nervous System Diseases/etiology ; Brain/pathology ; Cognition Disorders/etiology ; DNA-Binding Proteins/analysis ; Frontotemporal Dementia/classification ; Humans ; Neuroimaging ; Sensation Disorders/etiology ; TDP-43 Proteinopathies/classification ; }, abstract = {The purpose of this article is to review several studies on extramotor feature in Amyotrophic Lateral Sclerosis (ALS), its association with cognitive impairment, dementia, sensory and autonomic abnormalities suggesting that ALS is a multisystem disorder rather than a pure motor neuron disease. Evidence from neuroimaging, neuropsychological and histologic studies suggests that other brain regions can be involved in the pathologic process. However, the extent of the extramotor involvement remains unclear. A recent finding on the deposition of pathological TDP-43 (43 kDA transactivating responsive sequence DNA binding protein) in the Central Nervous System of Amyotrophic Lateral Sclerosis patients implies that ALS may be situated of clinicopathological spectrum of multisystem degeneration including Fronto-Temporal Lobar degeneration, that is related to the same protein.}, }
@article {pmid22040776, year = {2012}, author = {McLennan, S}, title = {CPR policies and the patient's best interests.}, journal = {Resuscitation}, volume = {83}, number = {2}, pages = {168-170}, doi = {10.1016/j.resuscitation.2011.10.007}, pmid = {22040776}, issn = {1873-1570}, mesh = {Cardiopulmonary Resuscitation/*standards ; Humans ; *Policy ; *Quality Improvement ; }, abstract = {Standard hospital CPR policies in many countries require CPR to be attempted on all patients having a cardiac arrest unless a Not-for-CPR order is in place. It has recently been shown that this approach is legally inappropriate in New Zealand. It appears that this argument may also potentially apply in other common law countries given the role that 'best interests' has in these jurisdictions in providing treatment to patients lacking decision-making capacity. Not-for-CPR orders provide an important and transparent mechanism for making advanced decisions regarding resuscitation. However, advanced planning is not always possible and it is legally inappropriate to require CPR to be performed when it is not in the patient's best interests. Notwithstanding the difficult practical balance that exists at the time of arrest between initiating CPR without delay or interruption for it to be effective for those whom CPR is in their best interests, and recognising as quickly as possible those patients for who CPR is not appropriate, it is argued that policies should be modified to allow clinicians to consider whether CPR is appropriate at time of arrest. Such a change may require ALS training to include a stronger emphasis on early recognition of patients for whom CPR is not in their best interests.}, }
@article {pmid22035195, year = {2012}, author = {Ibrahim, F and Nakaya, T and Mourelatos, Z}, title = {RNA dysregulation in diseases of motor neurons.}, journal = {Annual review of pathology}, volume = {7}, number = {}, pages = {323-352}, doi = {10.1146/annurev-pathol-011110-130307}, pmid = {22035195}, issn = {1553-4014}, support = {R01-NS056070/NS/NINDS NIH HHS/United States ; R21-072561//PHS HHS/United States ; T32-AG00255/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Humans ; Motor Neuron Disease/*genetics/pathology/physiopathology ; Motor Neurons/metabolism/pathology ; Muscular Atrophy, Spinal/genetics/metabolism/pathology ; Nerve Degeneration/genetics/metabolism/pathology ; RNA/*metabolism ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {Motor neuron diseases (MNDs) are neurodegenerative disorders that lead to paralysis and typically carry a dismal prognosis. In children, inherited spinal muscular atrophies are the predominant diseases that affect motor neurons, whereas in adults, amyotrophic lateral sclerosis, which is inherited but mostly sporadic, is the most common MND. In recent years, we have witnessed a revolution in this field, sparked by the discovery of the genes that cause MNDs. Remarkably, at least 10 genes, whose products are either RNA-binding proteins or proteins that function in RNA processing and regulation, cause MNDs and place the dysregulation of RNA pathways at the center of motor neuron degeneration pathogenesis.}, }
@article {pmid22033150, year = {2012}, author = {Bendotti, C and Marino, M and Cheroni, C and Fontana, E and Crippa, V and Poletti, A and De Biasi, S}, title = {Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response.}, journal = {Progress in neurobiology}, volume = {97}, number = {2}, pages = {101-126}, doi = {10.1016/j.pneurobio.2011.10.001}, pmid = {22033150}, issn = {1873-5118}, support = {GGP06063/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/*metabolism ; Animals ; Humans ; Immunity/*physiology ; Inflammation ; Mice ; Proteasome Endopeptidase Complex/genetics/*metabolism ; Protein Folding ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Ubiquitin/genetics/*metabolism ; }, abstract = {The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive. Although proteolysis is a complex mechanism requiring the participation of different pathways, the abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to these neuropathological features. The use of cellular and animal models of ALS, particularly those expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These subunits form the immunoproteasome and generate peptides for the major histocompatibility complex class I molecules, suggesting a role of this system in the immune responses associated with the pathological features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the disease process, in this review we will also provide evidence of a possible connection between immune-inflammatory reactions and UPS function, in the attempt to better understand the etiopathology of ALS and to identify appropriate targets for novel treatment strategies of this devastating disease.}, }
@article {pmid22028385, year = {2012}, author = {Rossor, AM and Kalmar, B and Greensmith, L and Reilly, MM}, title = {The distal hereditary motor neuropathies.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {1}, pages = {6-14}, doi = {10.1136/jnnp-2011-300952}, pmid = {22028385}, issn = {1468-330X}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; U54NS065712/NS/NINDS NIH HHS/United States ; /DH_/Department of Health/United Kingdom ; }, mesh = {Adenosine Triphosphatases/genetics ; Cation Transport Proteins/genetics ; Copper-Transporting ATPases ; DNA Helicases ; DNA-Binding Proteins/genetics ; Dynactin Complex ; GTP-Binding Protein gamma Subunits/genetics ; Glycine-tRNA Ligase/genetics ; HSP27 Heat-Shock Proteins/genetics ; Heat-Shock Proteins/genetics ; Hereditary Sensory and Motor Neuropathy/diagnosis/*genetics ; Humans ; Microtubule-Associated Proteins/genetics ; Molecular Chaperones ; Multifunctional Enzymes ; Protein Serine-Threonine Kinases/genetics ; RNA Helicases/genetics ; TRPV Cation Channels/genetics ; Transcription Factors/genetics ; }, abstract = {The distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot-Marie-Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.}, }
@article {pmid22028219, year = {2011}, author = {Jucker, M and Walker, LC}, title = {Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.}, journal = {Annals of neurology}, volume = {70}, number = {4}, pages = {532-540}, pmid = {22028219}, issn = {1531-8249}, support = {P01AG026423/AG/NIA NIH HHS/United States ; P01 AG026423-01A2/AG/NIA NIH HHS/United States ; P01 AG026423/AG/NIA NIH HHS/United States ; NCRR RR-00165//PHS HHS/United States ; P51 RR000165/RR/NCRR NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P51 RR000165-39/RR/NCRR NIH HHS/United States ; P50AG025688/AG/NIA NIH HHS/United States ; P50 AG025688-01S1/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*metabolism/*pathology ; Amyloid beta-Peptides/metabolism ; Animals ; DNA-Binding Proteins/metabolism ; Humans ; Neurodegenerative Diseases/metabolism/pathology ; Prions/metabolism ; Proteins/chemistry/*metabolism ; tau Proteins/metabolism ; }, abstract = {The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.}, }
@article {pmid22028183, year = {2012}, author = {Hanson, KA and Kim, SH and Tibbetts, RS}, title = {RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {3}, number = {2}, pages = {265-285}, pmid = {22028183}, issn = {1757-7012}, support = {R21 NS067572/NS/NINDS NIH HHS/United States ; T32 GM008692/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Mutant Proteins/genetics/metabolism ; Neurodegenerative Diseases/congenital/*physiopathology ; RNA Processing, Post-Transcriptional ; RNA-Binding Proteins/genetics/*metabolism ; }, abstract = {Neurodegenerative diseases are a diverse group of disorders that affect different neuron populations, differ in onset and severity, and can be either inherited or sporadic. One common pathological feature of most of these diseases is the presence of insoluble inclusions in and around neurons, which largely consist of misfolded and aggregated protein. For this reason, neurodegenerative diseases are typically thought to be disorders of aberrant protein processing, in which the cumulative effects of misfolded protein aggregates overwhelm the neuron's proteostatic capacity. However, a growing body of evidence suggests a role for abnormal RNA processing in neurodegenerative disease. The importance of RNA metabolism in disease was highlighted by the discovery of TDP-43 (TAR DNA-binding protein of 43 kDa), an RNA-binding protein (RBP), as a primary component of insoluble aggregates in patients with sporadic amyotrophic lateral sclerosis (ALS). Subsequently, inherited mutations in TDP-43 and the structurally related RBP, FUS/TLS (fused in sarcoma/translated in liposarcoma), were found to cause ALS. These exciting findings have ushered in a new era of ALS research in which the deregulation of RNA metabolism is viewed as a central cause of motor neuron deterioration. In addition, the fact that neuropathologically and anatomically distinct neurodegenerative diseases display altered RNA metabolism suggests that common pathologic mechanisms may underlie many of these disorders.}, }
@article {pmid22017410, year = {2011}, author = {Khomane, KS and Meena, CL and Jain, R and Bansal, AK}, title = {Novel thyrotropin-releasing hormone analogs: a patent review.}, journal = {Expert opinion on therapeutic patents}, volume = {21}, number = {11}, pages = {1673-1691}, doi = {10.1517/13543776.2011.623127}, pmid = {22017410}, issn = {1744-7674}, mesh = {Animals ; Central Nervous System Diseases/*drug therapy/physiopathology ; *Drug Design ; Half-Life ; Humans ; Patents as Topic ; Receptors, Thyrotropin-Releasing Hormone/drug effects/metabolism ; Thyrotropin-Releasing Hormone/analogs &amp; derivatives/pharmacokinetics/*pharmacology ; Tissue Distribution ; }, abstract = {INTRODUCTION: The potential therapeutic applications of thyrotropin-releasing hormone (TRH) have attracted attention, based on its broad-spectrum neuropharmacological action rather than its endocrine properties. These central nervous system (CNS)-mediated effects provide the rationale for use of TRH and its analogs in the treatment of brain and spinal injury, and CNS disorders like schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, depression, shock and ischemia.<br><br>AREAS COVERED: This review summarizes the patent literature and advances in the discovery and development of novel TRH analogs over the past 20 years. It provides a comprehensive overview of the development of new TRH analogs, giving emphasis to their pharmaceutical profile.<br><br>EXPERT OPINION: The use of TRH in the treatment of various CNS disorders has been proven clinically. However, TRH itself is a poor drug candidate due to its short plasma half-life (5 min), poor biopharmaceutical properties (low intestinal and CNS permeability) and endocrine side effect. Nevertheless, researchers have come up with metabolically stable, more potent and selective TRH analogs and prodrugs. Taltirelin, one of the TRH analogs, has been approved under the trade name of Ceredist(&#xae;) in Japan for the treatment of spinocerebellar degeneration. Several other TRH analogs are in various stages of preclinical or clinical development.}, }
@article {pmid22016712, year = {2011}, author = {Chiu, AS and Gehringer, MM and Welch, JH and Neilan, BA}, title = {Does α-amino-β-methylaminopropionic acid (BMAA) play a role in neurodegeneration?.}, journal = {International journal of environmental research and public health}, volume = {8}, number = {9}, pages = {3728-3746}, pmid = {22016712}, issn = {1660-4601}, mesh = {Amino Acids, Diamino/*toxicity ; Animals ; Cyanobacteria Toxins ; Cycas ; Flour/adverse effects ; Humans ; Neurodegenerative Diseases/*chemically induced/metabolism ; Neurotoxins/*toxicity ; Receptors, Glutamate/metabolism ; }, abstract = {The association of α-amino-β-methylaminopropionic acid (BMAA) with elevated incidence of amyotrophic lateral sclerosis/Parkinson's disease complex (ALS/PDC) was first identified on the island of Guam. BMAA has been shown to be produced across the cyanobacterial order and its detection has been reported in a variety of aquatic and terrestrial environments worldwide, suggesting that it is ubiquitous. Various in vivo studies on rats, mice, chicks and monkeys have shown that it can cause neurodegenerative symptoms such as ataxia and convulsions. Zebrafish research has also shown disruption to neural development after BMAA exposure. In vitro studies on mice, rats and leeches have shown that BMAA acts predominantly on motor neurons. Observed increases in the generation of reactive oxygen species (ROS) and Ca(2+) influx, coupled with disruption to mitochondrial activity and general neuronal death, indicate that the main mode of activity is via excitotoxic mechanisms. The current review pertaining to the neurotoxicity of BMAA clearly demonstrates its ability to adversely affect neural tissues, and implicates it as a potentially significant compound in the aetiology of neurodegenerative disease. When considering the potential adverse health effects upon exposure to this compound, further research to better understand the modes of toxicity of BMAA and the environmental exposure limits is essential.}, }
@article {pmid22009125, year = {2011}, author = {Chen, KH and Chiu, MJ and Cheng, TW and Su, JJ}, title = {Frontotemporal dementia and motor neuron disease: report of 3 cases in Taiwan and literature review.}, journal = {Acta neurologica Taiwanica}, volume = {20}, number = {3}, pages = {202-208}, pmid = {22009125}, issn = {1028-768X}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Frontotemporal Dementia/*complications ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*complications ; }, abstract = {PURPOSE: Case reports and a review of literature of the coexistence of motor neuron disease (MND) and frontotemporal dementia (FTD).<br><br>CASE REPORT: All three patients demonstrated generalized lower motor neuron signs and very few upper motor neuron signs. In the level of patterns of cognitive impairments, neuropsychological studies do not distinguish between patients with onset of weakness from bulbar palsy and patients with onset of weakness from limbs. All patients of FTD had their onset of MND or amyotrophic lateral sclerosis symptoms within a two-year interval which is similar to previous reports. FTD combined with MND may shorten the survival to less than three years shorter than cases with FTD only. Respiratory failure occurred one to two years after onset of the behavioral symptoms in all patients.<br><br>CONCLUSION: We reported three patients of FTD with MND to remind clinicians that these two disorders may occur together on the same patient and that these two disorders may belong to one broad spectrum neurodegenerative disease.<br><br>KEYWORDS: motor neuron disease, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobar degeneration.}, }
@article {pmid22003929, year = {2011}, author = {Park, SB and Lin, CS and Burke, D and Kiernan, MC}, title = {Activity-dependent conduction failure: molecular insights.}, journal = {Journal of the peripheral nervous system : JPNS}, volume = {16}, number = {3}, pages = {159-168}, doi = {10.1111/j.1529-8027.2011.00358.x}, pmid = {22003929}, issn = {1529-8027}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Axons/*physiology ; Membrane Potentials/*physiology ; Neural Conduction/*physiology ; Peripheral Nervous System Diseases/*physiopathology ; }, abstract = {Weakness and fatigue are commonly encountered symptoms in neurological disorders and significantly impair quality of life. In the case of motor axons, conduction block contributes to weakness and fatigue and may be associated with aberrant nerve activity including fasciculations and cramp. These symptoms result from dysfunction of the constituent channels and pumps of the axonal membrane. In critically conducting axons, impulse conduction can be impaired by the effects of activity or by other mechanisms that produce a significant shift in membrane potential. Conduction failure may be accentuated or relieved by maneuvers that manipulate the time course of the driving current, including the administration of agents that interfere with Na(+) channel function. In patients with inflammatory neuropathies, normal activity may be sufficient to precipitate conduction failure at sites of impaired function in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). From a clinical perspective, these features are not assessed adequately by conventional neurophysiological techniques. As weakness and fatigue may only develop following activity or exertion, it is useful to assess the effects of impulse trains to determine the extent of conduction failure and the resulting symptoms in neurological patients. These techniques and the physiological mechanisms underlying the development of activity-dependent hyperpolarization will be critically appraised in this review, with a focus on demyelinating neuropathies, MMN and the neurodegenerative disease, and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid22001604, year = {2012}, author = {Lentz, TB and Gray, SJ and Samulski, RJ}, title = {Viral vectors for gene delivery to the central nervous system.}, journal = {Neurobiology of disease}, volume = {48}, number = {2}, pages = {179-188}, pmid = {22001604}, issn = {1095-953X}, support = {U54-AR056953/AR/NIAMS NIH HHS/United States ; U54 AR056953-02S1/AR/NIAMS NIH HHS/United States ; U54 AR056953-01/AR/NIAMS NIH HHS/United States ; U54 AR056953/AR/NIAMS NIH HHS/United States ; U54 AR056953-02/AR/NIAMS NIH HHS/United States ; U54 AR056953-03/AR/NIAMS NIH HHS/United States ; U54 AR056953-04/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/*physiology ; Central Nervous System Diseases/*therapy ; Dependovirus/genetics ; Gene Transfer Techniques ; Genetic Therapy/*methods ; *Genetic Vectors ; Herpesviridae/genetics ; Humans ; RNA, Viral/genetics ; Retroviridae/genetics ; Viruses/*genetics ; }, abstract = {The potential benefits of gene therapy for neurological diseases such as Parkinson's, Amyotrophic Lateral Sclerosis (ALS), Epilepsy, and Alzheimer's are enormous. Even a delay in the onset of severe symptoms would be invaluable to patients suffering from these and other diseases. Significant effort has been placed in developing vectors capable of delivering therapeutic genes to the CNS in order to treat neurological disorders. At the forefront of potential vectors, viral systems have evolved to efficiently deliver their genetic material to a cell. The biology of different viruses offers unique solutions to the challenges of gene therapy, such as cell targeting, transgene expression and vector production. It is important to consider the natural biology of a vector when deciding whether it will be the most effective for a specific therapeutic function. In this review, we outline desired features of the ideal vector for gene delivery to the CNS and discuss how well available viral vectors compare to this model. Adeno-associated virus, retrovirus, adenovirus and herpesvirus vectors are covered. Focus is placed on features of the natural biology that have made these viruses effective tools for gene delivery with emphasis on their application in the CNS. Our goal is to provide insight into features of the optimal vector and which viral vectors can provide these features.}, }
@article {pmid21989247, year = {2011}, author = {Hardiman, O and van den Berg, LH and Kiernan, MC}, title = {Clinical diagnosis and management of amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {639-649}, pmid = {21989247}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Humans ; Neuroprotective Agents/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.}, }
@article {pmid21989245, year = {2011}, author = {Andersen, PM and Al-Chalabi, A}, title = {Clinical genetics of amyotrophic lateral sclerosis: what do we really know?.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {603-615}, pmid = {21989245}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Genetic Predisposition to Disease/*genetics ; Humans ; }, abstract = {Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most common being SOD1, FUS and TARDBP-mutations in the other genes are rare. The identified genes explain 25-35% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can be inherited in an autosomal dominant, autosomal recessive or X-linked manner, and families with low disease penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing the specific gene defect and the disease penetrance in the particular family.}, }
@article {pmid21989244, year = {2011}, author = {Bowser, R and Turner, MR and Shefner, J}, title = {Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {631-638}, pmid = {21989244}, issn = {1759-4766}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism ; Biomarkers/*analysis ; Humans ; }, abstract = {Insights into the mechanisms of amyotrophic lateral sclerosis (ALS) have relied predominantly on the study of postmortem tissue. Modern technology has improved the ability of scientists to probe effectively the underlying biology of ALS by examination of genomic, proteomic and physiological changes in patients, as well as to monitor functional and structural changes in patients over the course of disease. While effective treatments for ALS are lacking, the discovery of biomarkers for this disease offers clinicians tools for rapid diagnosis, improved ways to monitor disease progression, and insights into the pathophysiology of sporadic ALS. The ultimate aim is to broaden the therapeutic options for patients with this disease.}, }
@article {pmid21989221, year = {2011}, author = {Quinlan, KA}, title = {Links between electrophysiological and molecular pathology of amyotrophic lateral sclerosis.}, journal = {Integrative and comparative biology}, volume = {51}, number = {6}, pages = {913-925}, pmid = {21989221}, issn = {1557-7023}, support = {F32 NS063535/NS/NINDS NIH HHS/United States ; NS034382/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*physiopathology ; Animals ; Astrocytes/metabolism/physiology ; Calcium/metabolism ; Calcium-Binding Proteins/metabolism ; Disease Models, Animal ; *Electrophysiological Phenomena ; Endoplasmic Reticulum/physiology ; Glutamic Acid/metabolism ; Membrane Potential, Mitochondrial ; Mice ; Motor Neurons/physiology ; Neural Conduction ; Proteolysis ; Stress, Physiological ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Multiple deficits have been described in amyotrophic lateral sclerosis (ALS), from the first changes in normal functioning of the motoneurons and glia to the eventual loss of spinal and cortical motoneurons. In this review, current results, including changes in size, and electrical properties of motoneurons, glutamate excitotoxicity, calcium buffering, deficits in mitochondrial and cellular transport, impediments to proteostasis which lead to stress of the endoplasmic reticulum (ER), and glial contributions to motoneuronal vulnerability are recapitulated. Results are mainly drawn from the mutant SOD1 mouse model of ALS, and emphasis is placed on early changes that precede the onset of symptoms and the interplay between molecular and electrical processes.}, }
@article {pmid21987561, year = {2011}, author = {Murayama, S and Saito, Y}, title = {[Progressive nonfluent aphasia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {63}, number = {10}, pages = {1037-1046}, pmid = {21987561}, issn = {1881-6096}, mesh = {Aged ; Biomarkers/analysis ; DNA-Binding Proteins/analysis ; Female ; Frontotemporal Dementia/pathology ; Frontotemporal Lobar Degeneration/pathology ; Humans ; Primary Progressive Nonfluent Aphasia/*pathology ; tau Proteins/analysis ; }, abstract = {Progressive nonfluent aphasia (PNFA) is one of the three clinically defined phenotypes of pathologically determined frontotemporal lobar degeneration (FTLD); the other 2 phenotypes are semantic dementia (SD) and behavioral variant of frontotemporal dementia (bvFTD). FTLD is classified on the basis of the accumulated proteins-tau, TDP-43, and FUS. FTLD-TDP-43 is further subclassified into 4 types, including cases with progranulin mutation in type 3, on the basis of immunocytochemical and immunochemical properties. FTLD-tau is classified into the following 4 types: Pick's disease (accumulation of three-repeat tau); corticobasal degeneration (CBD, accumulation of CBD-type four-repeat tau); progressive supranuclear palsy (PSP, accumulation of PSP-type four-repeat tau); and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17, mutation of the tau gene). Because the Cambridge group included CBD, PSP, and FTDP-17 in FTLD-tau and the Manchester group excluded these 3 disorders from FTLD-tau, different descriptions of the PNFA background pathology are present in the literature. Clinical and pathological correlations have been well established between SD and FTLD-TDP-43 type 3, similar to those observed between Yuasa-Mitsuyama-type amyotrophic lateral sclerosis with dementia (ALSD) and TDP-43 proteinopathy type 2. However, no such correlation has been established between PNFA and bvFTD; the pathological background of PNFA includes PSP, CBD, Pick's disease, FTDP-17, FTLD-TDP-43 type 3, and even Alzheimer disease (AD). Surrogate biomarkers including CSF tau, phosphorylated tau, and Aβ as well as carbon-11-labeled Pittsburgh compound-B ((11)C-PIB) positron emission tomography (PET) scans can be used to differentiate between AD and FTLD. Further clinical, radiological, and pathological studies (dynamic neuropathology) are necessary for elucidating PNFA and bvFTD, which will help in establishing clinical and pathological correlations between these conditions.}, }
@article {pmid21986681, year = {2011}, author = {Lee, SE}, title = {Guam dementia syndrome revisited in 2011.}, journal = {Current opinion in neurology}, volume = {24}, number = {6}, pages = {517-524}, doi = {10.1097/WCO.0b013e32834cd50a}, pmid = {21986681}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/history/*pathology/*physiopathology ; Emigrants and Immigrants ; Ethnicity ; Guam/epidemiology ; History, 16th Century ; History, 18th Century ; History, 20th Century ; History, 21st Century ; Humans ; Syndrome ; }, abstract = {PURPOSE OF REVIEW: This review covers the amyotrophic lateral sclerosis (ALS)/parkinsonism dementia complex (PDC) of Guam. Clinical and epidemiological characteristics, genetic possible and environmental causes, and neuropathological features of the disease are discussed.<br><br>RECENT FINDINGS: Recent studies of clinical syndromes and neuropathological studies are compared with previous descriptions of the disease. The latest genetic and environmental studies are also reviewed.<br><br>SUMMARY: In recent years, understanding of the molecular pathogenesis of neurodegenerative diseases has evolved. ALS/PDC shares neuropathological features found in many neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, and frontotemporal lobar degeneration. Thus, examining ALS/PDC may provide further explanations on how various proteins seen in neurodegenerative disorders may be interrelated.}, }
@article {pmid21971978, year = {2011}, author = {Lomen-Hoerth, C}, title = {Clinical phenomenology and neuroimaging correlates in ALS-FTD.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {656-662}, pmid = {21971978}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/genetics/*pathology/*physiopathology ; Comorbidity ; Diagnosis, Differential ; Frontotemporal Dementia/epidemiology/genetics/*pathology/*physiopathology ; Humans ; Neuropsychological Tests ; }, abstract = {The overlap of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) has been well documented in FTD patients with co-morbid motor neuron degeneration and in ALS patients with frontotemporal dysfunction. Up to 15% of FTD patients and 30% of ALS patients experience the overlap syndrome. The syndrome may be difficult to identify since patients often present either to a neuromuscular clinic or a memory disorder's center, each which may have limited expertise in the other specialty. Survival is greatly impacted for both disorders in the co-morbid condition, making identification of this syndrome critical. The clinical characteristics of the overlap syndrome with new diagnostic criteria will be discussed along with screening strategies, including the UCSF Screening battery and clinical neurophysiology techniques. Treatable mimics of this disorder will also be described and management techniques. Neuroimaging findings will be summarized, which show that the frontotemporal impairment in ALS patients lies on a continuum. Identification of the overlap syndrome also provides a unique opportunity to study very early signs of FTD and conversely, very early signs of ALS, to gain greater insight into both disorders.}, }
@article {pmid21964848, year = {2011}, author = {Halperin, JJ}, title = {Nervous system lyme disease: is there a controversy?.}, journal = {Seminars in neurology}, volume = {31}, number = {3}, pages = {317-324}, doi = {10.1055/s-0031-1287652}, pmid = {21964848}, issn = {1098-9021}, mesh = {Animals ; Borrelia/*pathogenicity ; Humans ; Lyme Neuroborreliosis/complications/*diagnosis/*therapy ; Nervous System Diseases/etiology/*microbiology ; }, abstract = {Infection with the tick-borne spirochete, BORRELIA BURGDORFERI, affects the nervous system in well-defined ways. Accurate diagnostic tools and effective therapeutic regimens are now well established. Persistent misconceptions about (1) the role and interpretation of laboratory tests, (2) what is and is not evidence of nervous system infection, and (3) what constitutes an expected response to treatment have fostered widespread perceptions that this disease is highly controversial. Infection causes the classically described triad of meningitis, radiculoneuritis, and cranial neuritis; however, virtually every known neurologic disorder has been blamed on this infection. For most (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease), evidence is scant, nonexistent, or coincidental. For some (cerebral vasculitis with stroke, optic neuritis) a few case reports suggest a rare possible causal link.}, }
@article {pmid21964637, year = {2011}, author = {Sipp, D}, title = {The unregulated commercialization of stem cell treatments: a global perspective.}, journal = {Frontiers of medicine}, volume = {5}, number = {4}, pages = {348-355}, pmid = {21964637}, issn = {2095-0225}, mesh = {Amyotrophic Lateral Sclerosis/*economics/therapy ; Complementary Therapies/economics/ethics/legislation &amp; jurisprudence ; Evidence-Based Medicine/economics/legislation &amp; jurisprudence/standards ; Fraud/economics/prevention &amp; control ; Global Health ; Government Regulation ; Health Policy ; Humans ; Internationality ; Marketing of Health Services/*economics/ethics/legislation &amp; jurisprudence ; Stem Cell Transplantation/*economics/ethics/legislation &amp; jurisprudence ; Stem Cells/*cytology ; }, abstract = {Research into the biological properties and clinical potential of stem cells has spurred strong public investment, industry development, media coverage, and patient interest in recent years. To date, however, few clinical applications of demonstrated safety and efficacy have been developed with the exception of uses of hematopoietic stem cells in the treatment of diseases of the blood and immune systems. This lack of an evidence basis notwithstanding, hundreds of companies and private clinics around the world now sell putative stem cell treatments for an enormously broad range of medical and quality-of-life conditions. This represents a major challenge for legitimate scientists working in the field, for authorities seeking to protect their constituencies, and for patients and consumers targeted by such companies' marketing strategies. In this review, I provide an overview of the global industry in pseudomedical stem cell treatments, with an investigation of claims in a single disease area (amyotrophic lateral sclerosis), and make recommendations for the introduction and enforcement of appropriate regulatory responses to this problem.}, }
@article {pmid21963226, year = {2011}, author = {Bowman, AB and Kwakye, GF and Herrero Hernández, E and Aschner, M}, title = {Role of manganese in neurodegenerative diseases.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {25}, number = {4}, pages = {191-203}, pmid = {21963226}, issn = {1878-3252}, support = {R01ES10563/ES/NIEHS NIH HHS/United States ; R01 ES016931/ES/NIEHS NIH HHS/United States ; R01 ES010563-11/ES/NIEHS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; R01ES016931/ES/NIEHS NIH HHS/United States ; }, mesh = {Brain/drug effects/metabolism/pathology ; Cation Transport Proteins/metabolism ; Homeostasis/drug effects ; Humans ; Manganese/*metabolism/toxicity ; Mitochondria/drug effects/metabolism/pathology ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Manganese (Mn) is an essential ubiquitous trace element that is required for normal growth, development and cellular homeostasis. Exposure to high Mn levels causes a clinical disease characterized by extrapyramidal symptom resembling idiopathic Parkinson's disease (IPD). The present review focuses on the role of various transporters in maintaining brain Mn homeostasis along with recent methodological advances in real-time measurements of intracellular Mn levels. We also provide an overview on the role for Mn in IPD, discussing the similarities (and differences) between manganism and IPD, and the relationship between α-synuclein and Mn-related protein aggregation, as well as mitochondrial dysfunction, Mn and PD. Additional sections of the review discuss the link between Mn and Huntington's disease (HD), with emphasis on huntingtin function and the potential role for altered Mn homeostasis and toxicity in HD. We conclude with a brief survey on the potential role of Mn in the etiologies of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and prion disease. Where possible, we discuss the mechanistic commonalities inherent to Mn-induced neurotoxicity and neurodegenerative disorders.}, }
@article {pmid21956718, year = {2011}, author = {Ito, D and Suzuki, N}, title = {Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS.}, journal = {Neurology}, volume = {77}, number = {17}, pages = {1636-1643}, pmid = {21956718}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Ataxins ; DNA-Binding Proteins/*genetics/metabolism ; Genetic Predisposition to Disease/genetics ; Humans ; *Mutation/genetics ; Nerve Tissue Proteins/genetics ; Peptides/genetics ; Protein Transport/genetics ; RNA-Binding Protein FUS/*genetics/metabolism ; }, abstract = {The RNA-binding proteins TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) play central roles in neurodegeneration associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Normally localized in the nucleus, in sites affected by ALS and FTLD-U they are mislocalized to the cytoplasm and form cytoplasmic inclusions. TDP-43 and FUS are transported to the nucleus in a Ran-GTPase-dependent manner via nuclear import receptors, but they also contribute to the formation of stress granules (SGs), which are intracytoplasmic structures incorporating RNA. C-terminal truncations of TDP-43 eliminate the nuclear transport signal and cause mislocalization of the protein to the cytoplasm, where it accumulates and forms SGs. ALS-associated FUS mutations impair nuclear transport and cause mislocalization of FUS to the cytoplasm, where it also contributes to assembly of SGs. Furthermore, the ALS susceptibility factor ataxin-2, recently identified as a potent modifier of TDP-43 toxicity, is also a predicted cytoplasmic RNA-binding protein and a constituent protein of SGs, suggesting that it is a part of the common pathologic cascade formed by TDP-43 and FUS. Thus, we propose that excessive mislocalization of the RNA-binding proteins TDP-43, FUS, and ataxin-2 into the cytoplasm leads to impairment of the RNA quality control system, forming the core of the ALS/FTLD-U degenerative cascade. In this review, we discuss the molecular basis of the novel disease spectrum of ALS/FTLD-U, including the neurodegenerative mechanism of the cytoplasmic RNA-binding proteins TDP-43 and FUS and the possibility of a novel therapeutic strategy.}, }
@article {pmid21951862, year = {2011}, author = {Natale, G and Pasquali, L and Paparelli, A and Fornai, F}, title = {Parallel manifestations of neuropathologies in the enteric and central nervous systems.}, journal = {Neurogastroenterology and motility}, volume = {23}, number = {12}, pages = {1056-1065}, doi = {10.1111/j.1365-2982.2011.01794.x}, pmid = {21951862}, issn = {1365-2982}, mesh = {Amyloid beta-Peptides/metabolism ; Animals ; Biomarkers/metabolism ; Central Nervous System/*pathology/physiopathology ; Enteric Nervous System/*pathology/physiopathology ; Gastrointestinal Tract/innervation/pathology/physiopathology ; Humans ; Neurodegenerative Diseases/*pathology/physiopathology ; Prion Diseases/pathology/physiopathology ; Prions/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {BACKGROUND: Neurodegenerative diseases may extend outside the central nervous system (CNS) and involve the gastrointestinal (GI) tract. The gut would appear to be a pathological marker for neurodegeneration, as well as a site for studying the pathophysiology of neurodegeneration. In fact, both in the ENS and CNS, misfolded proteins are likely to initiate a process of neurodegeneration. For example, the very same protein aggregates can be detected both in the ENS and CNS. In both systems, misfolded proteins are likely to share common cell-to-cell diffusion mechanisms, which may occur through a parallel prion-like diffusion process. Independently from the enteric or central origin, misfolded proteins may proceed along the following steps, they: (i) form aggregates; (ii) are expressed on plasma membrane; (iii) are secreted extracellularly; (iv) are glycated to form advanced glycation end-products (AGEs); (v) are internalized through specific receptors placed on neighboring cells (RAGEs); (vi) are cleared by autophagy; and (vii) are neurotoxic. These features are common for a-synuclein (in Parkinson's disease and other synucleinopathies), β-amyloid and tau (in degenerative dementia), SOD-1 and TDP43 (in amyotrophic lateral sclerosis), and PrPsc (in prion diseases). While in some diseases these features are common to both ENS and CNS, in others this remains a working hypothesis.<br><br>PURPOSE: This review analyzes GI alterations from a pathological perspective to assess whether the enteric nervous system (ENS) mirrors the neuropathology described in the CNS. We discuss the potential mechanisms that lead to the onset and spread of neurodegeneration within the gut, from the gut to the brain, and vice versa.}, }
@article {pmid21948886, year = {2011}, author = {Lauterbach, EC and Mendez, MF}, title = {Psychopharmacological neuroprotection in neurodegenerative diseases, part III: criteria-based assessment: a report of the ANPA committee on research.}, journal = {The Journal of neuropsychiatry and clinical neurosciences}, volume = {23}, number = {3}, pages = {242-260}, doi = {10.1176/jnp.23.3.jnp242}, pmid = {21948886}, issn = {1545-7222}, mesh = {Animals ; Biomedical Research/methods/*standards ; Brain/drug effects/metabolism ; Databases, Factual/statistics &amp; numerical data ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods/standards ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neurologic Examination/*methods/*standards ; Neuroprotective Agents/pharmacology/*therapeutic use ; Psychopharmacology/*methods ; }, abstract = {Neuroprotective therapies for neurodegenerative diseases (NDDs) have proven elusive. The established psychotropic agents commonly used to treat the neuropsychiatric manifestations of NDDs are potential neuroprotective therapies, and neuropsychiatrists and others may benefit from a knowledge of the neuroprotective properties of these medications. This report identifies FDA-approved, first-line psychotropic drugs affecting intracellular mechanisms and meriting disease-modifying clinical trials in NDDs. The authors evaluated evidence for neuroprotection according to 1) preclinical; and 2) clinical criteria. Despite low-to-moderate preclinical evidence scores and scant clinical evidence, the most promising investigative priorities are 1) lithium and paroxetine in Alzheimer's disease (AD); 2) lithium in tauopathies (frontotemporal lobar degeneration [FTLD], FTDP-17); 3) lithium-plus-valproate in AD and amyotrophic lateral sclerosis; 4) pramipexole and valproate in Parkinson's disease; 5) amantadine and buspirone in multiple system atrophy; and 6) antidepressants in Huntington's disease. Preliminary clinical results signal caution regarding olanzapine use in AD and poor tolerability of lithium in progressive supranuclear palsy and corticobasal degeneration. These preliminary findings can lead to further clinical drug trials on the use of these well-known medications, not only for their psychotropic effects, but also for neuroprotection in NDDs.}, }
@article {pmid21948012, year = {2011}, author = {Arias, M}, title = {[Neurology of laughter and humour: pathological laughing and crying].}, journal = {Revista de neurologia}, volume = {53}, number = {7}, pages = {415-421}, pmid = {21948012}, issn = {1576-6578}, mesh = {*Brain/anatomy &amp; histology/physiology/physiopathology ; Crying/*physiology ; Humans ; Laughter/*physiology ; Magnetic Resonance Imaging ; Syndrome ; }, abstract = {INTRODUCTION: Laughter, which is usually a healthy biological phenomenon, may be also a symptom of several severe brain pathologies.<br><br>AIM: To review the neurobiological bases of laughter and humour, as well as those of pathological laughing and crying syndrome.<br><br>DEVELOPMENT: At the mesencephalic-pontine junction there is a central coordinator of the nuclei that innervate the muscles involved in laughter (facial expression, respiratory and phonatory). This centre receives connections from three systems: inhibitory (pre-motor and motor cortex), excitatory (temporal cortex, amygdala, hypothalamus) and modulator (cerebellum). Humour is a complex phenomenon with a range of components: the perception of the unexpected incongruence (occipitotemporal area, prefrontal cortex), emotional (reward circuit) and volitional (temporal and frontal cortex). Functional magnetic resonance imaging studies do not reveal a markedly prominent role of the right frontal lobe in processing humour, as had been suggested in the classical studies. The causes of pathological laughing and crying syndrome can be classified in two groups: altered behaviour with unmotivated happiness (Angelman syndrome, schizophrenia, manias, dementia) and interference with the inhibitory/excitatory mechanisms (gelastic epilepsy, fou rire prodromique in strokes, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Parkinson-plus, traumatic injuries, tumours). Serotonin and noradrenalin reuptake inhibitors, levodopa, lamotrigine and the association of dextromethorphan/quinidine can be effective in certain cases of pathological laughing and crying.<br><br>CONCLUSIONS: As human neurobiological phenomena, laughter and humour also belong to the field of clinical neurology; their processing is affected in a number of different diseases and, in certain cases, effective treatment can be established.}, }
@article {pmid21947135, year = {2011}, author = {Gordon, PH and Meininger, V}, title = {How can we improve clinical trials in amyotrophic lateral sclerosis?.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {650-654}, pmid = {21947135}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Neuroprotective Agents/*therapeutic use ; Translational Research, Biomedical/methods ; }, abstract = {Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.}, }
@article {pmid21936838, year = {2011}, author = {Bastow, EL and Gourlay, CW and Tuite, MF}, title = {Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis.}, journal = {Biochemical Society transactions}, volume = {39}, number = {5}, pages = {1482-1487}, doi = {10.1042/BST0391482}, pmid = {21936838}, issn = {1470-8752}, support = {G0600085/MRC_/Medical Research Council/United Kingdom ; 78573/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*physiopathology/therapy ; DNA-Binding Proteins/genetics/metabolism ; Heat-Shock Response/physiology ; Humans ; Mutation ; Protein Folding ; RNA-Binding Protein FUS/genetics/metabolism ; Saccharomyces cerevisiae/*physiology ; Superoxide Dismutase/chemistry/*genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease attributable to the death of motor neurons. Associated with ALS are mutations in the genes encoding SOD1 (superoxide dismutase 1), FUS (fused in Sarcoma) protein and TDP-43 (TAR DNA-binding protein-43) each of which leads to aggregation of the respective protein. For example, the ALS-associated mutations in the hSOD1 (human SOD1) gene typically destabilize the native SOD homodimer, leading to misfolding, aggregation and degradation of SOD1. The ALS-associated pathology is not a consequence of the functional inactivation of SOD1 itself, but is rather due to a toxic gain-of-function triggered by mutant SOD1. Recently, the molecular basis of a number of human neurodegenerative diseases resulting from protein misfolding and aggregation, including fALS (familial ALS), was probed by using the baker's yeast, Saccharomyces cerevisiae, as a highly tractable model. Such studies have, for example, identified novel mutant SOD1-specific interactions and demonstrated that mutant SOD1 disrupts mitochondrial homoeostasis. Features of ALS associated with TDP-43 aggregation have also been recapitulated in S. cerevisiae including the identification of modulators of the toxicity of TDP-43. In this paper, we review recent studies of ALS pathogenesis using S. cerevisiae as a model organism and summarize the potential mechanisms involved in ALS progression.}, }
@article {pmid21930182, year = {2011}, author = {Zhang, F and Wang, S and Gan, L and Vosler, PS and Gao, Y and Zigmond, MJ and Chen, J}, title = {Protective effects and mechanisms of sirtuins in the nervous system.}, journal = {Progress in neurobiology}, volume = {95}, number = {3}, pages = {373-395}, pmid = {21930182}, issn = {1873-5118}, support = {R01 NS036736-14/NS/NINDS NIH HHS/United States ; NS43802/NS/NINDS NIH HHS/United States ; R01 NS062157/NS/NINDS NIH HHS/United States ; R01 NS056118/NS/NINDS NIH HHS/United States ; R01 NS043802/NS/NINDS NIH HHS/United States ; R01 NS070825/NS/NINDS NIH HHS/United States ; R01 NS056118-05/NS/NINDS NIH HHS/United States ; R01 NS062157-03/NS/NINDS NIH HHS/United States ; NS36736/NS/NINDS NIH HHS/United States ; NS45048/NS/NINDS NIH HHS/United States ; R01 NS045048-06/NS/NINDS NIH HHS/United States ; NS62157/NS/NINDS NIH HHS/United States ; R01 NS036736/NS/NINDS NIH HHS/United States ; R01 NS045048/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain Chemistry/genetics ; Caloric Restriction ; Cell Nucleus/drug effects ; Cytosol/drug effects ; Gene Expression Regulation/drug effects/physiology ; Histone Deacetylases/physiology ; Humans ; Longevity/physiology ; Mitochondria/drug effects ; *Nervous System Physiological Phenomena/drug effects ; Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents ; Sirtuin 1/metabolism/physiology ; Sirtuins/genetics/metabolism/pharmacology/*physiology/therapeutic use ; }, abstract = {Silent information regulator two proteins (sirtuins or SIRTs) are a group of histone deacetylases whose activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD(+)). They suppress genome-wide transcription, yet upregulate a select set of proteins related to energy metabolism and pro-survival mechanisms, and therefore play a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of sirtuins has been reported for both acute and chronic neurological diseases. The focus of this review is to summarize the latest progress regarding the protective effects of sirtuins, with a focus on SIRT1. We first introduce the distribution of sirtuins in the brain and how their expression and activity are regulated. We then highlight their protective effects against common neurological disorders, such as cerebral ischemia, axonal injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Finally, we analyze the mechanisms underlying sirtuin-mediated neuroprotection, centering on their non-histone substrates such as DNA repair enzymes, protein kinases, transcription factors, and coactivators. Collectively, the information compiled here will serve as a comprehensive reference for the actions of sirtuins in the nervous system to date, and will hopefully help to design further experimental research and expand sirtuins as therapeutic targets in the future.}, }
@article {pmid21921554, year = {2010}, author = {Shimizu, T}, title = {[Withdrawal of life-support from ALS patients in so called totally locked in state: from the viewpoint of clinical ethics].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {11}, pages = {1029-1030}, doi = {10.5692/clinicalneurol.50.1029}, pmid = {21921554}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Culture ; Decision Making/ethics ; *Ethics, Clinical ; Humans ; Japan ; Life Support Systems/*ethics ; Ventilators, Mechanical/*ethics ; Withholding Treatment/*ethics ; }, abstract = {In Japanese context, there has been a controversy concerning the withdrawal of life-support, i.e. respiratory system, from ALS patients when, along of the progress of the disease, they have become not able to express themselves at all to people around them, i.e. when they are in so called 'totally locked in state (TLS)'. Basing himself on the system of clinical ethics he has been developing in accord with Japanese culture, the author (1) reconstitutes the logic of justifying the withdrawal in dispute, (2) examines objections against officially recognizing such withdrawal, and (3) proposes an appropriate process of decision making which he hopes to be acceptable to both sides in the controversy.}, }
@article {pmid21921552, year = {2010}, author = {Ishihara, T and Ariizumi, Y and Shiga, A and Yokoseki, A and Sato, T and Toyoshima, Y and Kakita, A and Takahashi, H and Nishizawa, M and Onodera, O}, title = {[FTLD/ALS as TDP-43 proteinopathies].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {11}, pages = {1022-1024}, doi = {10.5692/clinicalneurol.50.1022}, pmid = {21921552}, issn = {1882-0654}, mesh = {*Amyotrophic Lateral Sclerosis/classification/pathology/physiopathology ; DNA-Binding Proteins/genetics/physiology ; *Frontotemporal Lobar Degeneration/pathology/physiopathology ; Humans ; Inclusion Bodies/metabolism ; Mutation ; *TDP-43 Proteinopathies/pathology/physiopathology ; }, abstract = {Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) often coexist in the same patients: FTLD/MND. However, it is unclear whether FTLD/MND can be distinguished from ALS or FTLD. TAR DNA binding protein 43 KDa (TDP-43) has been identified as the major component of the ubiquitin-positive inclusion bodies in ALS, FTLD, and FTLD/MND. On the basis of this finding, a new concept of neurodegenerative disorders, namely TDP-43 proteinopathy, has been proposed for these disorders. In ALS, more than 30 mutations of the TDP-43 gene have been identified. The clinical features and neuropathological findings of ALS with TDP-43 mutation are identical to those of sporadic ALS. Therefore, TDP-43 plays a primary role in the pathogenesis of ALS. In contrast, only few patients with FTLD phenotype have TDP-43 mutations. Therefore, we have speculated that TDP-43 does not play a primary role in the pathogenesis of FTLD. The analysis of distribution of TDP-43 inclusion bodies in ALS patients revealed that ALS has two subtypes: (1) limited in the motor neuron system and (2) extended into the frontotemporal lobe. Additionally, causative genes of familial FTLD/MND have not been mapped to TDP-43. These results suggest that FTLD/MND is a disease distinct from FTLD and ALS.}, }
@article {pmid21921549, year = {2010}, author = {Ichikawa, H}, title = {[Language disorders in ALS/FTLD].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {11}, pages = {1014-1016}, doi = {10.5692/clinicalneurol.50.1014}, pmid = {21921549}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Frontotemporal Lobar Degeneration/*complications ; Humans ; Language Disorders/*etiology/physiopathology/psychology ; }, abstract = {In the 1990s, the concept of frontotemporal lobar degeneration (FTLD) was proposed as a clinicopathological entity preferentially involving the frontotemporal lobes, and recent pathological findings have suggested a linkage of FTLD with ALS. FTLD includes frontotemporal dementia (FTD), reflecting behavioral changes, and progressive non-fluent aphasia (PNFA) and semantic dementia (SD) as language disorders. Although language problems appear to have become of interest relatively recently, an historical Japanese account (1893) written by Watanabe described aphasia in bulbar-onset ALS. This report is entitled "A patient who manifested cortical motor aphasia concurrently with bulbar palsy and progressive muscular atrophy", and is the first case report of aphasia published in Japan. Thus, language problems in ALS may have been overlooked for many years. We have reported that ALS patients frequently show omission and paragraphia of kana letters, and syntactic errors in writing, and that these observations differ across patients. We also showed double dissociation between errors in kana and kanji characters in some patients, with preferential involvement of the frontotemporal lobes and frontal- and temporal-lobe predominance for kana and kanji, respectively. We also showed that the writing errors can appear as agraphia without aphasia.}, }
@article {pmid21921534, year = {2010}, author = {Kawahara, Y}, title = {[Implications of microRNA dysfunction in the pathogenesis of ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {11}, pages = {979-981}, doi = {10.5692/clinicalneurol.50.979}, pmid = {21921534}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/therapy ; DNA-Binding Proteins/*physiology ; Humans ; MicroRNAs/*metabolism ; Molecular Targeted Therapy ; Motor Neurons/pathology ; }, abstract = {Recent studies have identified mutations in the genes encoding TDP-43 and FUS/TLS in patients with amyotrophic lateral sclerosis (ALS). Both TDP-43 and FUS/TLS display all the characteristics of a heterogeneous nuclear ribonucleoprotein, which regulates various aspects of RNA processing. In addition, TDP-43 is partly cleared from the nuclei of neurons containing cytoplasmic aggregates, suggesting loss of normal TDP-43 function in the nucleus, leading to defects or alterations in RNA metabolism, plays, at least in part, a causative role in the pathogenesis of ALS. TDP-43 has been reported to be involved in the Drosha complex required for the biogenesis of microRNAs. The high expression level of microRNAs and the exclusive expression of certain microRNAs in the central nervous system highlights their biological importance at all stages of neural development as well as in differentiated neurons. In addition, the altered expression of certain microRNAs has been implicated in the pathogenesis of neurodegenerative diseases. Therefore, elucidation of the role of TDP-43 in microRNA biogenesis as a component of the Drosha complex is indispensable to understanding pathophysiology of ALS. In addition, the identification of TDP-43-regulated microRNAs associated with motor neuron death is expected to further contribute to the development of novel therapeutic strategies for ALS treatment.}, }
@article {pmid21921519, year = {2010}, author = {Onodera, O and Yokoseki, A and Tan, CF and Ishihara, T and Nishiira, Y and Toyoshima, Y and Kakita, A and Nishizawa, M and Takahashi, H}, title = {[Clinical and pathological spectrum of TDP-43 associated ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {11}, pages = {940-942}, doi = {10.5692/clinicalneurol.50.940}, pmid = {21921519}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; DNA-Binding Proteins/*genetics/metabolism ; Exons/genetics ; Frontotemporal Lobar Degeneration ; Humans ; Inclusion Bodies/metabolism/pathology ; *Mutation, Missense ; Neuroglia/pathology ; Neurons/pathology ; TDP-43 Proteinopathies ; }, abstract = {The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 KDa (TDP-43) immunopositive cytoplasmic inclusions have been found in glia and neurons of ALS patients. The discovery of TDP-43 mutations in ALS patients indicates a direct role of TDP-43 in ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP-43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 immunopositive inclusions and Bunina bodies, are identical to those in sporadic ALS. Most of the mutations are located in the C-terminus of TDP-43, which may function as a binding domain of heterogeneous nuclear ribonucleoprotein. Frontotemporal lobar degeneration: FTLD and FTLD/MND (motor neuron disease) also have TDP-43 immunopositive inclusions. These disorders have been named as TDP-43 proteinopathy. However, patients with TDP-43 mutations rarely develop FTLD. Causative genes for familial FTLD and FTLD/MND are not linked to the TDP-43 gene. Thus, other factors may contribute to the TDP-43 pathology in these diseases. Further analysis is required to elucidate the molecular mechanism of ALS-10 and TDP-43 proteinopathy.}, }
@article {pmid21920445, year = {2011}, author = {Steinacker, P and Aitken, A and Otto, M}, title = {14-3-3 proteins in neurodegeneration.}, journal = {Seminars in cell &amp; developmental biology}, volume = {22}, number = {7}, pages = {696-704}, doi = {10.1016/j.semcdb.2011.08.005}, pmid = {21920445}, issn = {1096-3634}, mesh = {14-3-3 Proteins/*metabolism ; Animals ; Apoptosis/physiology ; DNA-Binding Proteins/metabolism ; Endoplasmic Reticulum Stress ; Humans ; Nervous System/metabolism/*pathology ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; Oxidative Stress ; Protein Stability ; RNA-Binding Proteins/metabolism ; Signal Transduction ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Among the first reported functions of 14-3-3 proteins was the regulation of tyrosine hydroxylase (TH) activity suggesting a possible involvement of 14-3-3 proteins in Parkinson's disease. Since then the relevance of 14-3-3 proteins in the pathogenesis of chronic as well as acute neurodegenerative diseases, including Alzheimer's disease, polyglutamine diseases, amyotrophic lateral sclerosis and stroke has been recognized. The reported function of 14-3-3 proteins in this context are as diverse as the mechanism involved in neurodegeneration, reaching from basal cellular processes like apoptosis, over involvement in features common to many neurodegenerative diseases, like protein stabilization and aggregation, to very specific processes responsible for the selective vulnerability of cellular populations in single neurodegenerative diseases. Here, we review what is currently known of the function of 14-3-3 proteins in nervous tissue focussing on the properties of 14-3-3 proteins important in neurodegenerative disease pathogenesis.}, }
@article {pmid21914720, year = {2011}, author = {Cannon, JR and Greenamyre, JT}, title = {The role of environmental exposures in neurodegeneration and neurodegenerative diseases.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {124}, number = {2}, pages = {225-250}, pmid = {21914720}, issn = {1096-0929}, support = {1K99ES019879-01/ES/NIEHS NIH HHS/United States ; 1P01NS059806-01A2/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/drug effects/metabolism/pathology ; *Environmental Exposure/adverse effects/analysis ; Environmental Pollutants/chemistry/*toxicity ; Humans ; Neurodegenerative Diseases/*chemically induced/metabolism/pathology ; Risk Factors ; }, abstract = {Neurodegeneration describes the loss of neuronal structure and function. Numerous neurodegenerative diseases are associated with neurodegeneration. Many are rare and stem from purely genetic causes. However, the prevalence of major neurodegenerative diseases is increasing with improvements in treating major diseases such as cancers and cardiovascular diseases, resulting in an aging population. The neurological consequences of neurodegeneration in patients can have devastating effects on mental and physical functioning. The causes of most cases of prevalent neurodegenerative diseases are unknown. The role of neurotoxicant exposures in neurodegenerative disease has long been suspected, with much effort devoted to identifying causative agents. However, causative factors for a significant number of cases have yet to be identified. In this review, the role of environmental neurotoxicant exposures on neurodegeneration in selected major neurodegenerative diseases is discussed. Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis were chosen because of available data on environmental influences. The special sensitivity the nervous system exhibits to toxicant exposure and unifying mechanisms of neurodegeneration are explored.}, }
@article {pmid21911035, year = {2011}, author = {Geser, F and Prvulovic, D and O'Dwyer, L and Hardiman, O and Bede, P and Bokde, AL and Trojanowski, JQ and Hampel, H}, title = {On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.}, journal = {Progress in neurobiology}, volume = {95}, number = {4}, pages = {649-662}, pmid = {21911035}, issn = {1873-5118}, support = {P30 AG010124-21/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; AG10124-21-25/AG/NIA NIH HHS/United States ; AG032953-1-5/AG/NIA NIH HHS/United States ; P01 AG017586-01/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; AG017586/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications/metabolism/pathology ; DNA-Binding Proteins/*metabolism ; Dementia/*complications ; Humans ; Models, Biological ; Muscle, Skeletal/metabolism ; }, abstract = {Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated.}, }
@article {pmid21907261, year = {2011}, author = {Burnstock, G and Krügel, U and Abbracchio, MP and Illes, P}, title = {Purinergic signalling: from normal behaviour to pathological brain function.}, journal = {Progress in neurobiology}, volume = {95}, number = {2}, pages = {229-274}, doi = {10.1016/j.pneurobio.2011.08.006}, pmid = {21907261}, issn = {1873-5118}, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Brain/*metabolism ; Brain Diseases/*metabolism ; Brain Injuries/metabolism ; Humans ; Mental Disorders/metabolism ; Nerve Tissue Proteins/*metabolism ; Nervous System Diseases/metabolism ; Neurons/*metabolism ; Receptors, Purinergic/*metabolism ; *Synaptic Transmission ; }, abstract = {Purinergic neurotransmission, involving release of ATP as an efferent neurotransmitter was first proposed in 1972. Later, ATP was recognised as a cotransmitter in peripheral nerves and more recently as a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the CNS. Both ATP, together with some of its enzymatic breakdown products (ADP and adenosine) and uracil nucleotides are now recognised to act via P2X ion channels and P1 and P2Y G protein-coupled receptors, which are widely expressed in the brain. They mediate both fast signalling in neurotransmission and neuromodulation and long-term (trophic) signalling in cell proliferation, differentiation and death. Purinergic signalling is prominent in neurone-glial cell interactions. In this review we discuss first the evidence implicating purinergic signalling in normal behaviour, including learning and memory, sleep and arousal, locomotor activity and exploration, feeding behaviour and mood and motivation. Then we turn to the involvement of P1 and P2 receptors in pathological brain function; firstly in trauma, ischemia and stroke, then in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's, as well as multiple sclerosis and amyotrophic lateral sclerosis. Finally, the role of purinergic signalling in neuropsychiatric diseases (including schizophrenia), epilepsy, migraine, cognitive impairment and neuropathic pain will be considered.}, }
@article {pmid21905078, year = {2011}, author = {Lunn, JS and Sakowski, SA and Hur, J and Feldman, EL}, title = {Stem cell technology for neurodegenerative diseases.}, journal = {Annals of neurology}, volume = {70}, number = {3}, pages = {353-361}, pmid = {21905078}, issn = {1531-8249}, support = {T32 NS007222/NS/NINDS NIH HHS/United States ; T32 NS007222-28/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Humans ; Huntington Disease/therapy ; Muscular Atrophy, Spinal/therapy ; Neurodegenerative Diseases/pathology/*therapy ; Parkinson Disease/therapy ; *Stem Cell Research ; Stem Cell Transplantation/methods ; Stem Cells/classification/*physiology ; Technology ; }, abstract = {Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases.}, }
@article {pmid21904789, year = {2011}, author = {Gowing, G and Svendsen, CN}, title = {Stem cell transplantation for motor neuron disease: current approaches and future perspectives.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {4}, pages = {591-606}, pmid = {21904789}, issn = {1878-7479}, mesh = {Animals ; Humans ; Mice ; Motor Neuron Disease/*surgery ; Neurons/*physiology ; Stem Cell Transplantation/*methods/trends ; }, abstract = {Motor neuron degeneration leading to muscle atrophy and death is a pathological hallmark of disorders, such as amyotrophic lateral sclerosis or spinal muscular atrophy. No effective treatment is available for these devastating diseases. At present, cell-based therapies targeting motor neuron replacement, support, or as a vehicle for the delivery of neuroprotective molecules are being investigated. Although many challenges and questions remain, the beneficial effects observed following transplantation therapy in animal models of motor neuron disease has sparked hope and a number of clinical trials. Here, we provide a comprehensive review of cell-based therapeutics for motor neuron disorders, with a particular emphasis on amyotrophic lateral sclerosis.}, }
@article {pmid21901724, year = {2011}, author = {Guo, J and Zhou, M and Yang, M and Zhu, C and He, L}, title = {Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {9}, pages = {CD008554}, doi = {10.1002/14651858.CD008554.pub2}, pmid = {21901724}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Motor Neuron Disease/therapy ; Randomized Controlled Trials as Topic ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain.<br><br>OBJECTIVES: We aimed to determine the clinical efficacy and safety of rTMS for treating ALS.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL (1937 to July 2010), Science Citation Index Expanded (January 1945 to June 2010), AMED (January 1985 to July 2010) and the Chinese Biomedical Database (1979 to September 2010). We also searched for ongoing studies on clinicaltrials.gov (September 2010).<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (&#x2264; 1Hz) rTMS.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information.<br><br>MAIN RESULTS: Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe.<br><br>AUTHORS' CONCLUSIONS: There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS.}, }
@article {pmid21901585, year = {2011}, author = {Chiu, AY and Rao, MS}, title = {Cell-based therapy for neural disorders--anticipating challenges.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {4}, pages = {744-752}, pmid = {21901585}, issn = {1878-7479}, mesh = {Animals ; Cell Differentiation ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Nervous System Diseases/*surgery ; Stem Cells/*physiology ; }, abstract = {Neurological syndromes, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, and lysosomal storage disorders, such as Battens disease, are devastating because they result in increasing loss of cognitive and physical function. Sadly, no drugs are currently available to halt their progression. The relative paucity of curative approaches for these and other conditions of the nervous system have led to a widespread evaluation of alternative treatment modalities including cell-based interventions. Several cell types have been tested successfully in animal models where safety and efficacy have been demonstrated. Early clinical trials have also been initiated in humans, and some have shown a degree of success albeit on a more limited scale than in animal experiments. Recent demonstrations that pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, can differentiate into a variety of specific neural phenotypes has stimulated worldwide enthusiasm for developing cell-based intervention of neurological disease. Indeed, several groups are preparing investigational new drug applications to treat disorders as diverse as macular degeneration, lysosomal storage diseases, and Parkinson's disease. It is noteworthy that cell replacement therapies for neurological conditions face key challenges, some of which are unique, because of the development and organization of the nervous system, its metabolism, and connectivity. Choice of the cell (or cells), the process of manufacturing them, defining the delivery pathway, developing and testing in an appropriate preclinical model, selecting a patient population, and visualizing and following or monitoring patients all pose specific issues as related to the central and peripheral nervous systems. In this review, we address a myriad of challenges that are solvable, but require careful planning and attention to the special demands of the human nervous system.}, }
@article {pmid21901496, year = {2011}, author = {Fecto, F and Siddique, T}, title = {Making connections: pathology and genetics link amyotrophic lateral sclerosis with frontotemporal lobe dementia.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {663-675}, pmid = {21901496}, issn = {1559-1166}, mesh = {Adaptor Proteins, Signal Transducing ; Age of Onset ; Amyotrophic Lateral Sclerosis/*genetics/*pathology/physiopathology ; Autophagy-Related Proteins ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia/*genetics/*pathology/physiopathology ; Genetic Predisposition to Disease ; Humans ; Membrane Transport Proteins ; Motor Neurons/pathology ; Pedigree ; Phenotype ; RNA-Binding Protein FUS/genetics ; Transcription Factor TFIIIA/genetics ; Ubiquitins/genetics ; }, abstract = {Over the last couple of decades, there has been a growing body of clinical, genetic, and histopathological evidence that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal lobe dementia (FTD). Even though there is great diversity in the genetic causes of these disorders, there is a high degree of overlap in their histopathology. Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Additionally, there are major loci for ALS-FTD on chromosomes 9p and 15q. Identification of causative genetic alterations at those loci will be an important step in understanding the pathogenesis of juvenile- and adult-onset ALS and ALS-FTD. Interactions between TDP-43, FUS, optineurin, and ubiquilin 2 need to be studied to understand their common molecular pathways. Future efforts should also be directed towards generation and characterization of in vivo models to dissect the pathogenic mechanisms of these diseases. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences.}, }
@article {pmid21899641, year = {2011}, author = {Davis, M and Lou, JS}, title = {Management of amyotrophic lateral sclerosis (ALS) by the family nurse practitioner: a timeline for anticipated referrals.}, journal = {Journal of the American Academy of Nurse Practitioners}, volume = {23}, number = {9}, pages = {464-472}, doi = {10.1111/j.1745-7599.2011.00628.x}, pmid = {21899641}, issn = {1745-7599}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/*nursing ; Disease Progression ; Family Practice/*methods ; Humans ; *Nurse Practitioners ; Palliative Care/methods ; Prognosis ; *Referral and Consultation ; Time Factors ; }, abstract = {PURPOSE: This article reviews characteristics of amyotrophic lateral sclerosis (ALS) and appropriate timing of referrals by the nurse practitioner (NP).<br><br>DATA SOURCES: Selected research and clinical articles.<br><br>CONCLUSION: Management of patients with ALS by the NP requires anticipation of needed referrals based on symptom assessment and knowledge of the common timeline of ALS progression. Close collaboration with specialists such as neurologists, pulmonologists, and a palliative care team provides patients and families with much needed support and improves outcomes.<br><br>IMPLICATIONS FOR PRACTICE: Anticipating and initiating appropriate and timely referrals for patients with ALS may improve quality of life for patients with this devastating condition.}, }
@article {pmid21893121, year = {2012}, author = {Rogers, ML and Rush, RA}, title = {Non-viral gene therapy for neurological diseases, with an emphasis on targeted gene delivery.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {157}, number = {2}, pages = {183-189}, doi = {10.1016/j.jconrel.2011.08.026}, pmid = {21893121}, issn = {1873-4995}, mesh = {Animals ; Antibodies, Monoclonal/therapeutic use ; Central Nervous System Diseases/*therapy ; *Gene Transfer Techniques ; Genetic Therapy/*methods ; Humans ; }, abstract = {Non-viral gene therapy systems are considered safer than viral delivery. This article reviews recent research describing novel, non-viral gene delivery to the central nervous system, with a special emphasis on receptor mediated gene delivery using antibodies (termed immunogenes) to specific receptors. By using targeting agents such as antibodies that can be retrogradely transported within neurons, non-viral gene therapies can deliver genes to specific neurons protected by the blood brain barrier. Components of effective non-viral gene therapy are described including DNA/RNA carriers, receptor-mediated endocytosis, endosomal escape and nuclear entry. In addition, stealth agents such as polyethylene glycol that can be used to improve in-vivo delivery are discussed. The value of immunogenes as therapeutic agents for fatal diseases such as Amyotrophic Lateral Sclerosis is significant but further in-vivo work to confirm efficacy is required before truly effective therapies can be achieved.}, }
@article {pmid21892620, year = {2011}, author = {Nalbandian, A and Donkervoort, S and Dec, E and Badadani, M and Katheria, V and Rana, P and Nguyen, C and Mukherjee, J and Caiozzo, V and Martin, B and Watts, GD and Vesa, J and Smith, C and Kimonis, VE}, title = {The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {522-531}, pmid = {21892620}, issn = {1559-1166}, support = {S10 RR024546/RR/NCRR NIH HHS/United States ; AG025159/AG/NIA NIH HHS/United States ; AR050236/AR/NIAMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/*genetics ; Amyotrophic Lateral Sclerosis/*genetics/*pathology/physiopathology ; Animals ; Autophagy ; Cell Cycle Proteins/*genetics ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Frontotemporal Dementia/*genetics/*pathology/physiopathology ; Genetic Association Studies ; Humans ; Mutation ; *Myositis, Inclusion Body/genetics/pathology/physiopathology ; *Osteitis Deformans/genetics/pathology/physiopathology ; Valosin Containing Protein ; }, abstract = {Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype-phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.}, }
@article {pmid21889591, year = {2012}, author = {Federici, T and Boulis, NM}, title = {Gene therapy for amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {48}, number = {2}, pages = {236-242}, doi = {10.1016/j.nbd.2011.08.018}, pmid = {21889591}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/pathology/*therapy ; Animals ; Animals, Genetically Modified ; Astrocytes/physiology ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; Gene Silencing ; Genetic Therapy/*methods ; Humans ; Motor Neurons/physiology ; Muscular Atrophy, Spinal/therapy ; Neuromuscular Junction/physiology ; }, abstract = {Gene therapy continues to be a potential option for amyotrophic lateral sclerosis (ALS). This chapter will inform the reader about promising therapeutic transgenes and proof-of-principle studies in transgenic rodent models of ALS. Challenges regarding the disease targets and time for therapeutic intervention will be also discussed. Finally, restorative therapy for ALS, as well as gene therapy for other motor neuron diseases will be briefly reviewed.}, }
@article {pmid21879834, year = {2012}, author = {Foley, G and Timonen, V and Hardiman, O}, title = {Patients' perceptions of services and preferences for care in amyotrophic lateral sclerosis: a review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {1}, pages = {11-24}, doi = {10.3109/17482968.2011.607500}, pmid = {21879834}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*therapy ; Databases, Factual ; Decision Making ; *Delivery of Health Care ; Humans ; *Patient Satisfaction ; *Quality of Health Care ; *Social Work ; }, abstract = {Service providers and service users often have different perspectives on health and social care services. We have undertaken a systematic review of empirical data between 1988 and March 2011 relating to ALS service users' perspectives on health and social care services. Forty-seven texts were extracted and a narrative synthesis conducted. Few studies have explored ALS patients' experiences in relation to their satisfaction with services. Our review showed that ALS patients expect dignified care but they are often dissatisfied with health care services and have unmet expectations of their care. Most studies of decision-making and preferences for care have focused on end-of-life intervention. Various factors influence preferences for care from the service user perspective and people with ALS may adjust their use of services as they negotiate change. In conclusion, further research on the timeliness of services to meet changing needs of service users is required. The service user experience of allied health care services prior to end-of-life care also warrants investigation. Service providers need to support people with ALS as they negotiate feelings of acceptance and independence. Research to identify the key parameters of the ALS patient experience of services is required.}, }
@article {pmid21877044, year = {2011}, author = {Sica, RE and Nicola, AF and González Deniselle, MC and Rodriguez, G and Monachelli, GM and Peralta, LM and Bettini, M}, title = {Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent.}, journal = {Arquivos de neuro-psiquiatria}, volume = {69}, number = {4}, pages = {699-706}, doi = {10.1590/s0004-282x2011000500023}, pmid = {21877044}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology/physiopathology ; Astrocytes/*pathology ; Cell Death/physiology ; Glutamic Acid/metabolism ; Humans ; Neurons/physiology ; Neurotoxins/metabolism ; Nuclear Proteins/metabolism ; Oxidative Stress/*physiology ; }, abstract = {This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task.}, }
@article {pmid21872441, year = {2012}, author = {Hartman, AL}, title = {Neuroprotection in metabolism-based therapy.}, journal = {Epilepsy research}, volume = {100}, number = {3}, pages = {286-294}, pmid = {21872441}, issn = {1872-6844}, support = {K12 NS001696/NS/NINDS NIH HHS/United States ; K12 NS001696-05/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*diet therapy ; Animals ; *Caloric Restriction ; *Diet, Ketogenic ; Humans ; Neurodegenerative Diseases/*diet therapy ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/*diet therapy ; }, abstract = {Metabolism-based therapy has been used successfully in the treatment of seizures but study of its use in other neurodegenerative disorders is growing. Data demonstrating the use of different forms of metabolism-based therapy in human trials of Alzheimer disease and Parkinson disease are discussed. Animal and in vitro studies have shed light on metabolism-based therapy's mechanisms in these diseases, as well as ALS, aging, ischemia, trauma and mitochondrial cytopathies. Additional insights may be obtained by considering the role of metabolism-based therapy in cell disability and death (specifically apoptosis, excitotoxicity, and autophagy).}, }
@article {pmid21870889, year = {2011}, author = {Bar-Or, A and Rieckmann, P and Traboulsee, A and Yong, VW}, title = {Targeting progressive neuroaxonal injury: lessons from multiple sclerosis.}, journal = {CNS drugs}, volume = {25}, number = {9}, pages = {783-799}, pmid = {21870889}, issn = {1179-1934}, mesh = {Animals ; Clinical Trials, Phase II as Topic ; Disease Progression ; Humans ; Multiple Sclerosis/diagnosis/*pathology/*therapy ; Neurodegenerative Diseases/*diagnosis/pathology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuroaxonal injury, suggesting a common pathophysiological pathway. Identification and development of neuroprotective therapies for such diseases has proven a major challenge, particularly because of an already substantial neuroaxonal compromise at the time of initial onset of clinical symptoms. Methods for early identification of neurodegeneration are therefore vital to ensure that neuroprotective therapies are applied as early as possible. Recent investigations have enhanced our understanding of the role of neuroaxonal injury in multiple sclerosis (MS). As MS generally manifests earlier in life and can be diagnosed much earlier in the course of the disease than the above-mentioned 'classic' neurodegenerative diseases, it is possible that MS could be used as a model disease to study degeneration and regeneration of the CNS. The mechanism of neuroaxonal injury in MS is believed to be inflammation-led neurodegeneration; however, the reverse may also be true (i.e. neuroaxonal degeneration may precede inflammation). Animal models of PD, AD and ALS have shown that it is likely that most cases of disease are due to initial inflammation, followed by a degenerative process, providing a parallel between MS and the classic neurodegenerative diseases. Other common factors between MS and the neurodegenerative diseases include iron and mitochondrial dysregulation, abnormalities in α-synuclein and tau protein, and a number of immune mediators. Conventional MRI techniques, using markers such as T2-weighted lesions, gadolinium-enhancing lesions and T1-weighted hypointensities, are readily available and routinely used in clinical practice; however, the utility of these MRI measures to predict disease progression in MS is limited. More recently, MRI techniques that provide more pathology-specific data have been applied in MS studies, including magnetic resonance spectroscopy, magnetization transfer ratio and myelin water imaging. Optical coherence tomography (OCT) is a non-MRI technique that quantifies optic nerve integrity and retinal ganglion cell loss as markers of neuroaxonal injury; more research is needed to evaluate whether information obtained from OCT is a reliable marker of axonal injury and long-term disability in MS. Using these advanced techniques, it may become possible to follow degeneration and regeneration longitudinally in patients with MS and to better differentiate the effects of drugs under investigation. Currently available immune-directed therapies that are approved by the US FDA for the first-line treatment of MS (interferon-β and glatiramer acetate) have been shown to decelerate the inflammatory process in MS; however, such therapy is less effective in preventing the progression of the disease and neuroaxonal injury. The use of MS as a clinical model to study modulation of neuroaxonal injury in the brain could have direct implications for the development of treatment strategies in neurodegenerative diseases such as AD, PD and ALS.}, }
@article {pmid21864557, year = {2011}, author = {Androutsopoulos, VP and Kanavouras, K and Tsatsakis, AM}, title = {Role of paraoxonase 1 (PON1) in organophosphate metabolism: implications in neurodegenerative diseases.}, journal = {Toxicology and applied pharmacology}, volume = {256}, number = {3}, pages = {418-424}, doi = {10.1016/j.taap.2011.08.009}, pmid = {21864557}, issn = {1096-0333}, mesh = {Alzheimer Disease/chemically induced/enzymology/genetics ; Amyotrophic Lateral Sclerosis/chemically induced/enzymology/genetics ; Animals ; Aryldialkylphosphatase/genetics/*physiology ; Genetic Predisposition to Disease/genetics ; Humans ; Neurodegenerative Diseases/chemically induced/*enzymology ; Organophosphorus Compounds/*toxicity ; Parkinson Disease, Secondary/chemically induced/enzymology/genetics ; }, abstract = {Organophosphate pesticides are a class of compounds that are widely used in agricultural and rural areas. Paraoxonase 1 (PON1) is a phase-I enzyme that is involved in the hydrolysis of organophosphate esters. Environmental poisoning by organophosphate compounds has been the main driving force of previous research on PON1 enzymes. Recent discoveries in animal models have revealed the important role of the enzyme in lipid metabolism. However although PON1 function is well established in experimental models, the contribution of PON1 in neurodegenerative diseases remains unclear. In this minireview we summarize the involvement of PON1 genotypes in the occurrence of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. A brief overview of latest epidemiological studies, regarding the two most important PON1 coding region polymorphisms PON1-L55M and PON1-Q192R is presented. Positive and negative associations of PON1 with disease occurrence are reported. Notably the MM and RR alleles contribute a risk enhancing effect for the development of some neurodegenerative diseases, which may be explained by the reduced lipoprotein free radical scavenging activity that may give rise to neuronal damage, through distinct mechanism. Conflicting findings that fail to support this postulate may represent the human population ethnic heterogeneity, different sample size and environmental parameters affecting PON1 status. We conclude that further epidemiological studies are required in order to address the exact contribution of PON1 genome in combination with organophosphate exposure in populations with neurodegenerative diseases.}, }
@article {pmid21864284, year = {2011}, author = {Sanmartin, C and Plano, D and Font, M and Palop, JA}, title = {Selenium and clinical trials: new therapeutic evidence for multiple diseases.}, journal = {Current medicinal chemistry}, volume = {18}, number = {30}, pages = {4635-4650}, doi = {10.2174/092986711797379249}, pmid = {21864284}, issn = {1875-533X}, mesh = {Animals ; Antioxidants/therapeutic use ; Arthritis, Rheumatoid/drug therapy/physiopathology ; Cardiovascular Diseases/drug therapy ; Clinical Trials as Topic ; Depression/drug therapy ; Diabetes Mellitus/drug therapy ; HIV Infections/prevention &amp; control ; HIV-1/drug effects ; Humans ; Leishmaniasis/drug therapy ; Micronutrients/physiology ; Neoplasms/drug therapy/prevention &amp; control ; Neurodegenerative Diseases/drug therapy ; Pancreatitis/physiopathology ; Selenium/adverse effects/metabolism/physiology/*therapeutic use ; Selenoproteins/physiology ; Thyroid Diseases/drug therapy/physiopathology ; }, abstract = {The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases.}, }
@article {pmid21863317, year = {2011}, author = {Kumar-Singh, S}, title = {Progranulin and TDP-43: mechanistic links and future directions.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {561-573}, pmid = {21863317}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; Caspases/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/*genetics/pathology/physiopathology ; Humans ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism ; Microglia/metabolism/pathology ; Mutation ; Neurons/metabolism/pathology ; Progranulins ; Signal Transduction/genetics ; Stress, Physiological ; TDP-43 Proteinopathies/genetics/pathology/physiopathology ; }, abstract = {Loss-of-function mutations in the multifunctional growth factor progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) with TDP-43 protein accumulation. Nuclear TDP-43 protein with key roles in RNA metabolism is also aggregated in amyotrophic lateral sclerosis (ALS), suggesting that ALS and FTLD constitute a broad disease continuum. However, the fact that mutations in GRN are associated with FTLD, while mutations in TDP-43 cause a preferential loss of motor neurons resulting in ALS-end of the disease spectrum, suggests involvement of both cell-autonomous and non-autonomous mechanisms. Studies on animal models and in vitro studies have been instrumental in understanding the link between GRN and TDP-43 and also their role in neurodegeneration. For instance, in mouse models, allelic deficiencies of Grn do not recapitulate human pathology of TDP-43 brain accumulations, but embryonic neurons derived from these mice do show abnormal TDP-43 accumulation after additional cellular challenges, suggesting that TDP-43 changes observed in GRN mutation carriers might also relate to stress. Recent results have shown that the dual action of GRN in growth modulation and inflammation could be due to its negative regulation of TNF-α signaling. In addition, GRN also interacts with sortilin and is endocytosed, thereby regulating its own levels and possibly also modulating the turnover of other proteins including that of TDP-43. Accumulating evidence suggests that TDP-43 abnormal cellular aggregation causes a possible gain of function, also suggested by recently constructed mouse models of TDP-43 proteinopathy; however, it would be inconvincible that sequestration of physiological TDP-43 within cellular aggregates observed in patients would be innocuous for disease pathogenesis. This review discusses some of these data on the possible link between GRN and TDP-43 as well as mechanisms involved in TDP-43-led neurodegeneration. Continued multitiered efforts on genetic, cell biological, and animal modeling approaches would prove crucial in finding a cure for GRN-related diseases.}, }
@article {pmid21861938, year = {2011}, author = {Peng, J and Zeng, X}, title = {The role of induced pluripotent stem cells in regenerative medicine: neurodegenerative diseases.}, journal = {Stem cell research &amp; therapy}, volume = {2}, number = {4}, pages = {32}, pmid = {21861938}, issn = {1757-6512}, mesh = {Adult ; Cell Culture Techniques ; *Cell Differentiation ; Humans ; Induced Pluripotent Stem Cells/*cytology/transplantation ; Neurodegenerative Diseases/pathology/*therapy ; Neurons/pathology/physiology ; Regenerative Medicine ; Research Design ; }, abstract = {Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia are the most common human neurodegenerative diseases pathologically characterized by a progressive and specific loss of certain neuronal populations. The exact mechanisms of neuronal cell death in these diseases are unclear, although some forms of the diseases are inherited and genes causing these diseases have been identified. Currently there are no effective clinical therapies for many of these diseases. The recently acquired ability to reprogram human adult somatic cells to induced pluripotent stem cells (iPSCs) in culture may provide a powerful tool for in vitro neurodegenerative disease modeling and an unlimited source for cell replacement therapy. In the present review, we summarize recent progress on iPSC generation and differentiation into neuronal cell types and discuss the potential application for in vitro disease mechanism study and in vivo cell replacement therapy.}, }
@article {pmid21861815, year = {2011}, author = {Zhang, Z and Yan, J and Chang, Y and ShiDu Yan, S and Shi, H}, title = {Hypoxia inducible factor-1 as a target for neurodegenerative diseases.}, journal = {Current medicinal chemistry}, volume = {18}, number = {28}, pages = {4335-4343}, pmid = {21861815}, issn = {1875-533X}, support = {R37 AG037319/AG/NIA NIH HHS/United States ; P01 AG017490/AG/NIA NIH HHS/United States ; AG037319/AG/NIA NIH HHS/United States ; P01AG17490/AG/NIA NIH HHS/United States ; R01NS058807/NS/NINDS NIH HHS/United States ; R01 NS058807-01A1/NS/NINDS NIH HHS/United States ; R01 NS058807/NS/NINDS NIH HHS/United States ; }, mesh = {Gluconates/therapeutic use ; Humans ; Hypoxia-Inducible Factor 1/antagonists &amp; inhibitors/*metabolism ; Iron Chelating Agents/therapeutic use ; Neurodegenerative Diseases/drug therapy/*metabolism/pathology ; Protein Processing, Post-Translational ; }, abstract = {Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. HIF-1, a heterodimer consisting of a constitutively expressed β subunit and an oxygen-regulated α subunit, regulates a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The activity of HIF-1 is controlled by post-translational modifications on different amino acid residues of its subunits, mainly the alpha subunit. Besides in ischemic stroke (see review [1]), emerging evidence has revealed that HIF-1 activity and expression of its down-stream genes, such as vascular endothelial growth factor and erythropoietin, are altered in a range of neurodegenerative diseases. At the same time, experimental and clinical evidence has demonstrated that regulating HIF-1 might ameliorate the cellular and tissue damage in the neurodegenerative diseases. These new findings suggest HIF-1 as a potential medicinal target for the neurodegenerative diseases. This review focuses on HIF-1α protein modifications and HIF-1's potential neuroprotective roles in Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid21847013, year = {2011}, author = {Gitler, AD and Shorter, J}, title = {RNA-binding proteins with prion-like domains in ALS and FTLD-U.}, journal = {Prion}, volume = {5}, number = {3}, pages = {179-187}, pmid = {21847013}, issn = {1933-690X}, support = {R21 NS067354-0110/NS/NINDS NIH HHS/United States ; DP2 OD004417/OD/NIH HHS/United States ; 1DP2OD002177-01/OD/NIH HHS/United States ; 1DP2OD004417-01/OD/NIH HHS/United States ; DP2 OD002177/OD/NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; DNA-Binding Proteins/genetics/metabolism ; Frontotemporal Lobar Degeneration/genetics/*metabolism/pathology ; Humans ; Prions/*chemistry/genetics/metabolism ; RNA-Binding Proteins/*chemistry/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) is a debilitating, and universally fatal, neurodegenerative disease that devastates upper and lower motor neurons. The causes of ALS are poorly understood. A central role for RNA-binding proteins and RNA metabolism in ALS has recently emerged. The RNA-binding proteins, TDP-43 and FUS, are principal components of cytoplasmic inclusions found in motor neurons of ALS patients and mutations in TDP-43 and FUS are linked to familial and sporadic ALS. Pathology and genetics also connect TDP-43 and FUS with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). It was unknown whether mechanisms of FUS aggregation and toxicity were similar or different to those of TDP-43. To address this issue, we have employed yeast models and pure protein biochemistry to define mechanisms underlying TDP-43 and FUS aggregation and toxicity, and to identify genetic modifiers relevant for human disease. We have identified prion-like domains in FUS and TDP-43 and provide evidence that these domains are required for aggregation. Our studies have defined key similarities as well as important differences between the two proteins. Collectively, however, our findings lead us to suggest that FUS and TDP-43, though similar RNA-binding proteins, likely aggregate and confer disease phenotypes via distinct mechanisms.}, }
@article {pmid21844169, year = {2011}, author = {Bosco, DA and LaVoie, MJ and Petsko, GA and Ringe, D}, title = {Proteostasis and movement disorders: Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {3}, number = {10}, pages = {a007500}, pmid = {21844169}, issn = {1943-0264}, mesh = {Amyotrophic Lateral Sclerosis/complications/*metabolism ; Animals ; DNA-Binding Proteins/genetics/metabolism ; HEK293 Cells ; Humans ; Inclusion Bodies ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Mice ; Parkinson Disease/complications/genetics/*metabolism ; Protein Folding ; Protein Serine-Threonine Kinases/genetics/metabolism ; Protein Stability ; Protein Transport ; Proteostasis Deficiencies/*metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Ubiquitin-Protein Ligases/genetics/metabolism ; alpha-Synuclein/genetics/metabolism ; }, abstract = {Parkinson's disease (PD) is a movement disorder that afflicts over one million in the U.S.; amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is less prevalent but also has a high incidence. The two disorders sometimes present together, making a comparative study of interest. Both ALS and PD are neurodegenerative diseases, and are characterized by the presence of intraneuronal inclusions; however, different classes of neurons are affected and the primary protein in the inclusions differs between the diseases, and in some cases is different in distinct forms of the same disease. These observations might suggest that the more general approach of proteostasis pathway alteration would be a powerful one in treating these disorders. Examining results from human genetics and studies in model organisms, as well as from biochemical and biophysical characterization of the proteins involved in both diseases, we find that most instances of PD can be considered as arising from the misfolding, and self-association to a toxic species, of the small neuronal protein α-synuclein, and that proteostasis strategies are likely to be of value for this disorder. For ALS, the situation is much more complex and less clear-cut; the available data are most consistent with a view that ALS may actually be a family of disorders, presenting similarly but arising from distinct and nonoverlapping causes, including mislocalization of some properly folded proteins and derangement of RNA quality control pathways. Applying proteostasis approaches to this disease may require rethinking or broadening the concept of what proteostasis means.}, }
@article {pmid21842590, year = {2011}, author = {Rowland, LP}, title = {HIV-related neuromuscular diseases: nemaline myopathy, amyotrophic lateral sclerosis and bibrachial amyotrophic diplegia.}, journal = {Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology}, volume = {30}, number = {1}, pages = {29-31}, pmid = {21842590}, issn = {1128-2460}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis ; HIV Infections/*complications/drug therapy ; Humans ; Motor Neuron Disease/*complications/diagnosis ; Myopathies, Nemaline/*complications ; }, abstract = {The human immunodeficiency virus (HIV) causes diverse disorders of the brain, spinal cord and peripheral nerves. Rarely, polymyositis and myoglobinuria are seen. Two other neuromuscular syndromes in people with HIV antibodies are nemaline myopathy and bibrachial amyotrophic diplegia, a form of motor neuron disease. The associations between these diseases and the possibility that HIV infection could be a risk factor for either amyotrophic lateral sclerosis (ALS) itself or other motor neuron diseases are investigated.}, }
@article {pmid21842586, year = {2011}, author = {Appel, SH and Zhao, W and Beers, DR and Henkel, JS}, title = {The microglial-motoneuron dialogue in ALS.}, journal = {Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology}, volume = {30}, number = {1}, pages = {4-8}, pmid = {21842586}, issn = {1128-2460}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Cell Communication ; Cell Death ; Endoplasmic Reticulum/physiology ; Humans ; Inflammation Mediators/metabolism ; Microglia/*physiology ; Mitochondria, Muscle/physiology ; Motor Neurons/*physiology ; Protein Folding ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxide Dismutase/physiology ; Superoxide Dismutase-1 ; }, abstract = {Neuroinflammation is a pathological hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia at sites of neuronal injury. In ALS, neurons do not die alone; neuronal injury is noncell-autonomous and depends upon a well-orchestrated dialogue between motor neurons and microglia. Evidence from transgenic models expressing mutant superoxide dismutase 1 (SOD) suggests that the dialogue between motor neurons and microglia initially protects motor neurons. However, with increasing stress and injury within motor neurons, induced by the presence of misfolded proteins such as mSOD1, mitochondrial function and axoplasmic flow are impaired and endoplasmic reticulum stress is induced; misfolded proteins themselves or alternate signals are released from motor neurons and activate microglia. Activated microglia, in turn, switch from anti-inflammatory and neuroprotective to proinflammatory and neurotoxic. Neurotoxic signaling from motor neurons promotes microglial release of reactive oxygen species and pro-inflammatory cytokines further enhancing motor neuron stress and cell injury and initiating a self-propagating cycle of motor neuron injury and cell death. A greater understanding of how to restore the imbalance between neuroprotection and cytotoxicity will depend upon a greater understanding of the motor neuron-microglial dialogue.}, }
@article {pmid21839829, year = {2012}, author = {Rohrer, JD}, title = {Structural brain imaging in frontotemporal dementia.}, journal = {Biochimica et biophysica acta}, volume = {1822}, number = {3}, pages = {325-332}, doi = {10.1016/j.bbadis.2011.07.014}, pmid = {21839829}, issn = {0006-3002}, support = {//Department of Health/United Kingdom ; }, mesh = {Brain/*pathology ; Disease Progression ; Frontotemporal Dementia/*diagnosis/pathology ; Humans ; Neuroimaging/*methods ; }, abstract = {Frontotemporal dementia (FTD) is the second commonest young-onset neurodegenerative dementia. The canonical clinical syndromes are a behavioural variant (bvFTD) and two language variants (progressive nonfluent aphasia, PNFA, and semantic dementia, SD) although there is overlap with motor neurone disease and the atypical parkinsonian disorders corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Characteristic patterns of atrophy or hypometabolism are described in each of the variants but in reality imaging studies are rather heterogeneous. This review attempts to address four key questions in the neuroimaging of FTD: 1) what are the early imaging features of the different FTD syndromes (and how do these change as the disease progresses); 2) what do studies of presymptomatic genetic cases of FTD tell us about the very early stages of the disease; 3) can neuroimaging help to differentiate the different FTD syndromes; and 4) can neuroimaging help to differentiate FTD from other neurodegenerative diseases? This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.}, }
@article {pmid21834058, year = {2011}, author = {Walker, AK and Atkin, JD}, title = {Stress signaling from the endoplasmic reticulum: A central player in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {IUBMB life}, volume = {63}, number = {9}, pages = {754-763}, doi = {10.1002/iub.520}, pmid = {21834058}, issn = {1521-6551}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; DNA-Binding Proteins/metabolism ; Endoplasmic Reticulum/metabolism/*physiology ; Gene Expression Regulation/*physiology ; Humans ; Mice ; *Models, Biological ; Signal Transduction/*physiology ; Stress, Physiological/*physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Unfolded Protein Response/physiology ; Vesicular Transport Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the misfolding and aggregation of distinct proteins in affected tissues, however, the pathogenic cause of disease remains unknown. Recent evidence indicates that endoplasmic reticulum (ER) stress plays a central role in ALS pathogenesis. ER stress activates the unfolded protein response (UPR), a homeostatic response to misfolded proteins. The UPR is initially protective by up-regulation of specific ER stress-regulated genes and inhibition of general protein translation. However, long-term ER stress leads to cell death via apoptotic signaling, thus providing a link to neurodegeneration. Activation of the UPR is one of the earliest events in affected motor neurons of transgenic rodent models expressing ALS-linked mutant superoxide dismutase 1 (SOD1). Recently, genetic manipulation of ER stress in several different SOD1 mouse models was shown to alter disease onset and progression, implicating an active role for the UPR in disease mechanisms. Furthermore, mutations to vesicle-associated membrane protein-associated protein B (VAPB), an ER transmembrane protein involved in ER stress regulation, also cause some cases of familial ALS. ER stress also occurs in spinal cord tissues of human sporadic ALS patients, and recent evidence suggests that perturbation of the ER could occur in ALS cases associated with TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS) and valosin containing protein (VCP). Together these findings implicate ER stress as a potential upstream mechanism involved in both familial and sporadic forms of ALS.}, }
@article {pmid21830350, year = {2011}, author = {Omura, Y and O'Young, B and Jones, M and Pallos, A and Duvvi, H and Shimotsuura, Y}, title = {Caprylic acid in the effective treatment of intractable medical problems of frequent urination, incontinence, chronic upper respiratory infection, root canalled tooth infection, ALS, etc., caused by asbestos &amp; mixed infections of Candida albicans, Helicobacter pylori &amp; cytomegalovirus with or without other microorganisms &amp; mercury.}, journal = {Acupuncture &amp; electro-therapeutics research}, volume = {36}, number = {1-2}, pages = {19-64}, doi = {10.3727/036012911803860886}, pmid = {21830350}, issn = {0360-1293}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Asbestos/*adverse effects ; Candidiasis/*complications ; Caprylates/*therapeutic use ; Chronic Disease ; Cytomegalovirus Infections/*complications ; Helicobacter Infections/*complications ; *Helicobacter pylori ; Humans ; Respiratory Tract Infections/*drug therapy ; Root Canal Therapy/adverse effects ; Urinary Incontinence/*drug therapy ; Urination Disorders/*drug therapy ; }, abstract = {There are many causes of frequent urination. Whenever water or fluids are consumed, the patient has to urinate within 10 or 20 min. Often urinary bladder examinations &amp; blood tests show no significant abnormalities, &amp; treatment by anti-bacterial or anti-viral agents does not improve the symptoms significantly. In intractable frequent urination with difficulty holding urine, as well as other intractable medical problems such as frequent coughing, white pus in gingiva, infection of the apex of a root canalled tooth, slow-healing wounds, &amp; ALS, the authors often found coexisting mixed infections of Candida albicans (C.A.), Helicobacter pylori (H.P.), &amp; Cytomegalovirus (CMV) with or without additional bacterial (Chlamydia trachomatis, etc.) or viral infections &amp; increased Asbestos, with or without Hg deposits. We often found various degrees of mixed infections with C.A., H.P., &amp; CMV in the external sphincters of the urethra &amp; in the Trigone of the urinary bladder which consists of (1) a horizontal, band-like area between the 2 ureter openings &amp; (2) the funnel shaped part of the Trigone at the lower half of the urinary bladder. In the coexistence of significant amounts of C.A., H.P. &amp; CMV, the infection cannot be reduced by otherwise effective medicines for H.P. &amp; CMV. However, one optimal dose of Diflucan, or Caprylic acid taken orally or externally applied, rapidly reduced the symptoms significantly. We found the best treatment is to give a combination of an optimal dose of Caprylic acid orally in the form of "CaprilyCare" or "Caprylic Acid," with a capsule of Omega-3 Fish Oil as an anti-viral agent, Amoxicillin, Substance Z &amp; a Cilantro tablet. We found that an optimal dose of Caprylic acid increases normal cell telomere (NCT) to a desirable 750 ng BDORT units while Diflucan increases NCT by only 25 ng BDORT units, &amp; with Omega-3 fish oil, leads to a mutual cancellation of both drugs. Thus, Caprylic acid is superior to &amp; less expensive than Diflucan, &amp; has potential application for anti-cancer, anti-aging, anti-Alzheimer's disease, anti-Autism, anti-infection, &amp; general circulatory improvement.}, }
@article {pmid21827820, year = {2012}, author = {Cozzolino, M and Carrì, MT}, title = {Mitochondrial dysfunction in ALS.}, journal = {Progress in neurobiology}, volume = {97}, number = {2}, pages = {54-66}, doi = {10.1016/j.pneurobio.2011.06.003}, pmid = {21827820}, issn = {1873-5118}, support = {GGP07018/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications/*pathology ; Animals ; Calcium/metabolism ; Humans ; Mitochondria/metabolism/*pathology ; Mitochondrial Diseases/*etiology/pathology ; Motor Neurons/pathology/*ultrastructure ; Oxidative Stress ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {In the present article, we review the many facets of mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease due to loss of upper motor neurons in cerebral cortex and lower motor neurons in brainstem and spinal cord. Accumulating evidence from recent studies suggests that the many, interconnected facets of mitochondrial dysfunction may play a more significant role in the etiopathogenesis of this disorder than previously thought. This notion stems from our expanding knowledge of the complex physiology of mitochondria and of alteration of their properties that might confer an intrinsic susceptibility to long-lived, post-mitotic motor neurons to energy deficit, calcium mishandling and oxidative stress. The wealth of evidence implicating mitochondrial dysfunction as a major event in the pathology of ALS has prompted new studies aimed to the development of new mitochondria-targeted therapies. However, it is now clear that drugs targeting more than one aspect of mitochondrial dysfunction are needed to fight this devastating disease.}, }
@article {pmid21825986, year = {2011}, author = {Finsterer, J and Papić, L and Auer-Grumbach, M}, title = {Motor neuron, nerve, and neuromuscular junction disease.}, journal = {Current opinion in neurology}, volume = {24}, number = {5}, pages = {469-474}, doi = {10.1097/WCO.0b013e32834a9448}, pmid = {21825986}, issn = {1473-6551}, mesh = {Animals ; Disease Models, Animal ; Humans ; *Motor Neuron Disease/classification/genetics/pathology/therapy ; *Neuromuscular Junction Diseases/classification/genetics/pathology/therapy ; *Peripheral Nervous System Diseases/classification/genetics/pathology/therapy ; }, abstract = {PURPOSE OF REVIEW: The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders.<br><br>RECENT FINDINGS: Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis.<br><br>SUMMARY: Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies.}, }
@article {pmid21824087, year = {2011}, author = {Orsucci, D and Mancuso, M and Ienco, EC and LoGerfo, A and Siciliano, G}, title = {Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues.}, journal = {Current medicinal chemistry}, volume = {18}, number = {26}, pages = {4053-4064}, doi = {10.2174/092986711796957257}, pmid = {21824087}, issn = {1875-533X}, support = {GUP09004/TI_/Telethon/Italy ; }, mesh = {Animals ; Humans ; Micronutrients/metabolism/pharmacology/*therapeutic use ; Mitochondria/*metabolism ; Mitochondrial Diseases/*drug therapy/metabolism/physiopathology ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Ubiquinone/*analogs &amp; derivatives/metabolism/pharmacology/physiology/*therapeutic use ; }, abstract = {Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology.}, }
@article {pmid21820744, year = {2011}, author = {Khandelwal, PJ and Herman, AM and Moussa, CE}, title = {Inflammation in the early stages of neurodegenerative pathology.}, journal = {Journal of neuroimmunology}, volume = {238}, number = {1-2}, pages = {1-11}, pmid = {21820744}, issn = {1872-8421}, support = {K01 AG030378/AG/NIA NIH HHS/United States ; K01 AG030378-04/AG/NIA NIH HHS/United States ; AG 30378/AG/NIA NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides/metabolism ; Animals ; Central Nervous System/*metabolism ; Humans ; Inflammation/*etiology/metabolism ; Neurodegenerative Diseases/classification/*complications/*pathology ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Inflammation is secondary to protein accumulation in neurodegenerative diseases, including Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis. Emerging evidence indicate sustained inflammatory responses, involving microglia and astrocytes in animal models of neurodegeneration. It is unknown whether inflammation is beneficial or detrimental to disease progression and how inflammatory responses are induced within the CNS. Persistence of an inflammatory stimulus or failure to resolve sustained inflammation can result in pathology, thus, mechanisms that counteract inflammation are indispensable. Here we review studies on inflammation mediated by innate and adaptive immunity in the early stages of neurodegeneration and highlight important areas for future investigation.}, }
@article {pmid21816207, year = {2011}, author = {Riboldi, G and Nizzardo, M and Simone, C and Falcone, M and Bresolin, N and Comi, GP and Corti, S}, title = {ALS genetic modifiers that increase survival of SOD1 mice and are suitable for therapeutic development.}, journal = {Progress in neurobiology}, volume = {95}, number = {2}, pages = {133-148}, doi = {10.1016/j.pneurobio.2011.07.009}, pmid = {21816207}, issn = {1873-5118}, support = {GGP09107/TI_/Telethon/Italy ; GGP10062/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology/therapy ; Animals ; Crosses, Genetic ; Disease Models, Animal ; Female ; *Genetic Therapy ; Humans ; Male ; Mice ; Mice, Transgenic ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a frequently fatal motor neuron disease without any cure. To find molecular therapeutic targets, several studies crossed transgenic ALS murine models with animals transgenic for some ALS target genes. We aimed to revise the new discoveries and new works in this field. We selected the 10 most promising genes, according to their capability when down-regulated or up-regulated in ALS animal models, for increasing life span and mitigating disease progression: XBP-1, NogoA and NogoB, dynein, heavy and medium neurofilament, NOX1 and NOX2, MLC-mIGF-1, NSE-VEGF, and MMP-9. Interestingly, some crucial modifier genes have been described as being involved in common pathways, the most significant of which are inflammation and cytoskeletal activities. The endoplasmic reticulum also seems to play an important role in ALS pathogenesis, as it is involved in different selected gene pathways. In addition, these genes have evident links to each other, introducing the hypothesis of a single unknown, common pathway involving all of these identified genes and others to be discovered.}, }
@article {pmid21815469, year = {2011}, author = {Arai, T and Hosokawa, M and Hasegawa, M and Akiyama, H and Asada, T}, title = {[A new dementia group caused by TDP-43 abnormality].}, journal = {Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica}, volume = {113}, number = {6}, pages = {574-583}, pmid = {21815469}, issn = {0033-2658}, mesh = {DNA-Binding Proteins/metabolism ; Humans ; TDP-43 Proteinopathies/genetics/*metabolism ; }, abstract = {The TAR DNA-binding protein Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathies. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role in the pathological process. Understanding the mechanism of phosphorylation and truncation of TDP-43, and aggregate formation, may be crucial to clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapies.}, }
@article {pmid21813273, year = {2011}, author = {Da Cruz, S and Cleveland, DW}, title = {Understanding the role of TDP-43 and FUS/TLS in ALS and beyond.}, journal = {Current opinion in neurobiology}, volume = {21}, number = {6}, pages = {904-919}, pmid = {21813273}, issn = {1873-6882}, support = {RC1 NS069144-02/NS/NINDS NIH HHS/United States ; NS27036/NS/NINDS NIH HHS/United States ; R01 NS027036/NS/NINDS NIH HHS/United States ; R37 NS027036-24/NS/NINDS NIH HHS/United States ; RC1 NS069144/NS/NINDS NIH HHS/United States ; 089701/WT_/Wellcome Trust/United Kingdom ; R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; DNA-Binding Proteins/*genetics/*metabolism ; Humans ; Mutation ; RNA-Binding Protein FUS/*genetics/*metabolism ; }, abstract = {Dominant mutations in two DNA/RNA binding proteins, TDP-43 and FUS/TLS, are causes of inherited Amyotrophic Lateral Sclerosis (ALS). TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as central in ALS. TDP-43 has binding sites within a third of all mouse and human mRNAs in brain and this binding influences the levels and splicing patterns of at least 20% of those mRNAs. Disease modeling in rodents of the first known cause of inherited ALS-mutation in the ubiquitously expressed superoxide dismutase (SOD1)-has yielded non-cell autonomous fatal motor neuron disease caused by one or more toxic properties acquired by the mutant proteins. In contrast, initial disease modeling for TDP-43 and FUS/TLS has produced highly varied phenotypes. It remains unsettled whether TDP-43 and FUS/TLS mutants provoke disease from a loss of function or gain of toxicity or both. TDP-43 or FUS/TLS misaccumulation seems central not just to ALS (where it is found in almost all instances of disease), but more broadly in neurodegenerative disease, including frontal temporal lobular dementia (FTLD-U) and many examples of Alzheimer's or Huntington's disease.}, }
@article {pmid21811811, year = {2011}, author = {Gendron, TF and Petrucelli, L}, title = {Rodent models of TDP-43 proteinopathy: investigating the mechanisms of TDP-43-mediated neurodegeneration.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {486-499}, pmid = {21811811}, issn = {1559-1166}, support = {R21 NS074121-01/NS/NINDS NIH HHS/United States ; R21 NS074121/NS/NINDS NIH HHS/United States ; R01 NS 063964-01/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; R01AG026251/AG/NIA NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Animals, Genetically Modified ; Behavior, Animal/physiology ; DNA-Binding Proteins/genetics/*metabolism ; Disease Models, Animal ; Frontotemporal Dementia/pathology/physiopathology ; Humans ; Inclusion Bodies/metabolism/pathology ; Mitochondria/metabolism/ultrastructure ; Nerve Degeneration/*pathology/physiopathology ; *Rodentia ; TDP-43 Proteinopathies/*pathology/physiopathology ; }, abstract = {Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions, much effort has been directed towards ascertaining how TDP-43 contributes to the pathogenesis of disease. As with other protein misfolding disorders, TDP-43-mediated neuronal death is likely caused by both a toxic gain and loss of TDP-43 function. Indeed, the presence of cytoplasmic TDP-43 inclusions is associated with loss of nuclear TDP-43. Moreover, post-translational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage into C-terminal fragments, may bestow toxic properties upon TDP-43 and cause TDP-43 dysfunction. However, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neurotoxicity. Additionally, given our incomplete understanding of the roles of TDP-43, both in the nucleus and the cytoplasm, it is difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. The development of TDP-43 transgenic animal models is expected to narrow these gaps in our knowledge. The aim of this review is to highlight the key findings emerging from TDP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration.}, }
@article {pmid21810174, year = {2011}, author = {Strong, MJ and Volkening, K}, title = {TDP-43 and FUS/TLS: sending a complex message about messenger RNA in amyotrophic lateral sclerosis?.}, journal = {The FEBS journal}, volume = {278}, number = {19}, pages = {3569-3577}, doi = {10.1111/j.1742-4658.2011.08277.x}, pmid = {21810174}, issn = {1742-4658}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology/physiopathology ; Animals ; DNA/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Protein Structure, Tertiary ; RNA, Messenger/*metabolism ; RNA-Binding Protein FUS/chemistry/genetics/*metabolism ; }, abstract = {TAR DNA binding protein of 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) have recently been linked to the pathology of amyotrophic lateral sclerosis (ALS). These proteins share many common features that include interaction with either DNA or RNA, participation in the formation of RNP complexes, the formation of pathological aggregates in degenerating motor neurons in ALS, and the ability to impact the RNA metabolism pathway at multiple levels from transcription to translation. Coupled with the observation that mutations in either TDP-43 or FUS/TLS are associated with ALS, this provides further support for the integral role of altered RNA metabolism in ALS.}, }
@article {pmid21809041, year = {2011}, author = {Strong, MJ and Yang, W}, title = {The frontotemporal syndromes of ALS. Clinicopathological correlates.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {648-655}, pmid = {21809041}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/*physiopathology ; DNA-Binding Proteins/genetics/metabolism ; Frontotemporal Lobar Degeneration/genetics/*pathology/*physiopathology ; Humans ; Syndrome ; tau Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a syndromic disorder in which the degeneration of motor neurons is frequently accompanied by a range of syndromes reflective of frontotemporal dysfunction, including a behavioural or cognitive syndrome, a dysexecutive syndrome or a frontotemporal dementia. Both sporadic and familial variants of ALS can be affected. The anatomic substrate of each is a frontotemporal lobar degeneration (FTLD) characterized by superficial linear spongiosus, atrophy and neuronal loss, and both astrocytic and neuronal deposition of TDP-43 as pathological inclusions. Largely unrecognized however is the extent of alterations in tau protein metabolism, particularly in cognitively impaired patients (ALSci). This includes hyper-phosphorylation (pThr(175)) and tau phosphatase resistance, increased fibril formation ex vivo of tau isolated from ALSci and tau immunoreactive aggregates in neurons, dystrophic neurites and astrocytes. In this article, we will review the contemporary clinical, genetic and neuropathological characteristics of the frontotemporal syndromes of ALS and propose that as opposed to being a FTLD in which TDP-43 is the primary disease protein (FTLD-TDP) and that the frontotemporal syndromes of ALS represent a hybrid of both TDP-43 and tau pathology.}, }
@article {pmid21806316, year = {2011}, author = {Habib, AA and Mitsumoto, H}, title = {Emerging drugs for amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {16}, number = {3}, pages = {537-558}, doi = {10.1517/14728214.2011.604312}, pmid = {21806316}, issn = {1744-7623}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Drug Evaluation, Preclinical/methods ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that results in increasing disability and that is uniformly fatal. Since its approval in the 1990s, riluzole remains the sole treatment for ALS offering modest survival benefit. While significant advances have been made in the symptomatic management of the disease, more effective drug therapy targeting disease progression is sorely needed.<br><br>AREAS COVERED: Advances in the understanding of pathogenic mechanisms involved in disease development and progression have provided multiple avenues for developing effective treatment strategies. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of drug therapy. Previous human clinical trials that have targeted these pathways are mentioned and ongoing drug trials are discussed.<br><br>EXPERT OPINION: The search for effective drug therapy faces important challenges in the areas of basic science and animal research, translation of these results into human clinical trials, inherent bias in human studies and issues related to delays in clinical diagnosis. How these issues may be addressed and why ALS research constitutes fertile grounds for drug development not only for this devastating disease, but also for other more prevalent neurodegenerative diseases, is discussed in this review.}, }
@article {pmid21805118, year = {2011}, author = {Otto, M and Ludolph, AC and Landwehrmeyer, B and Förstl, H and Diehl-Schmid, J and Neumann, M and Kretzschmar, HA and Schroeter, M and Kornhuber, J and Danek, A and , }, title = {[German consortium for frontotemporal lobar degeneration].}, journal = {Der Nervenarzt}, volume = {82}, number = {8}, pages = {1002-1005}, pmid = {21805118}, issn = {1433-0407}, mesh = {Atrophy ; Cross-Sectional Studies ; DNA-Binding Proteins/genetics ; Disease Progression ; Early Diagnosis ; Frontal Lobe/pathology ; Frontotemporal Lobar Degeneration/classification/*diagnosis/epidemiology/genetics ; Genetic Markers/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Testing ; Humans ; Prognosis ; Risk Factors ; TDP-43 Proteinopathies/classification/diagnosis/epidemiology/genetics ; Temporal Lobe/pathology ; tau Proteins/genetics ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is an umbrella term for an aetiologically diverse group of neurodegenerative disorders with prominent lobar cortical atrophy. First this disease group was restricted to Pick's disease or Pick's complex. Several updates of the clinical classification systems were performed and discussed. Currently we summarize the following diseases under the FTLD spectrum: frontotemporal dementia (FTD) as a behavioural variant, primary non-fluent aphasia (PNFA) and semantic dementia as language variants, amyotrophic lateral sclerosis with FTD (ALS-FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).From the pathophysiological aspect major progress was made. Neuropathologically FTLDs are now defined based on the molecular composition of these protein accumulations. A major distinction of tau-associated (FTLD-tau) and TDP43-associated (FTLD-TDP43) and to a lesser extend FUS-associated (FTLD-FUS) has been made. Additional risk genes were described. However from the therapeutic perspective even symptomatic therapy is under discussion. A major aim of our consortium is to develop parameters allowing an early diagnosis and follow-up, thus providing effective and objective parameters for therapeutic strategies.}, }
@article {pmid21803219, year = {2011}, author = {Ahmed, A and Wicklund, MP}, title = {Amyotrophic lateral sclerosis: what role does environment play?.}, journal = {Neurologic clinics}, volume = {29}, number = {3}, pages = {689-711}, doi = {10.1016/j.ncl.2011.06.001}, pmid = {21803219}, issn = {1557-9875}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Environment ; Environmental Exposure/*adverse effects ; Humans ; }, abstract = {The cause of sporadic amyotrophic lateral sclerosis (ALS) is not known. Studies associate toxic, dietary, infectious, neoplastic, and physical factors as underlying, predisposing, or pathogenic influences. Historical, conventional, and novel disease mechanisms, acting solely or in concert, convert previously healthy individuals into terminally ill patients. Despite intensive investigations in the previous decades, the underlying cause and effective treatments elude researchers. Discovering causative mechanisms in sporadic ALS will facilitate effective treatments and cures for this disorder. After a brief review of the disease process itself, this article discusses potential environmental influences on the development of ALS.}, }
@article {pmid21798636, year = {2011}, author = {Genton, L and Viatte, V and Janssens, JP and Héritier, AC and Pichard, C}, title = {Nutritional state, energy intakes and energy expenditure of amyotrophic lateral sclerosis (ALS) patients.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {30}, number = {5}, pages = {553-559}, doi = {10.1016/j.clnu.2011.06.004}, pmid = {21798636}, issn = {1532-1983}, mesh = {Amyotrophic Lateral Sclerosis/diet therapy/*metabolism/*physiopathology/therapy ; Basal Metabolism ; Body Composition ; Decision Trees ; *Energy Intake ; *Energy Metabolism ; Female ; Humans ; Male ; Malnutrition/etiology/prevention &amp; control ; Motor Activity ; Nutrition Assessment ; *Nutritional Status ; Respiration, Artificial ; Respiratory System/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) alters nutritional state, energy intake and energy expenditure. This article aims at reviewing present knowledge on these topics in order to determine energy requirements for maintaining a neutral energy balance in ALS patients. Maintaining a neutral energy balance prevents malnutrition and its complications and may improve physical functioning, quality of life and survival. Prevalence of malnutrition varies between 16 and 55% in ALS patients. Energy intakes are below recommended dietary allowances in 70% of ALS patients at least. These elements suggest a chronic negative energy balance with an imbalance between requirements and intakes. While insufficient intakes can be compensated with nutritional support, the energy requirements are unclear. Studies generally report hypermetabolism in ALS patients. Estimation of total energy expenditure and as a corollary energy needs, necessitates taking into account this hypermetabolism, physical activity and possibly mechanical ventilation. The review suggests a flow chart for optimal nutritional follow-up in clinics. Further studies are required to assess whether optimal nutritional follow-up improves outcome.}, }
@article {pmid21796043, year = {2011}, author = {Clarke, K and Levine, T}, title = {Clinical recognition and management of amyotrophic lateral sclerosis: the nurse's role.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {43}, number = {4}, pages = {205-214}, doi = {10.1097/JNN.0b013e3182212a6c}, pmid = {21796043}, issn = {1945-2810}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*nursing/therapy ; Combined Modality Therapy ; Delayed Diagnosis ; Diagnosis, Differential ; Disease Progression ; Humans ; *Nurse's Role ; Nursing Assessment ; *Nursing Diagnosis ; Palliative Care/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes a progressive wasting and loss of the upper and lower motor neurons that facilitate the movement of body parts. At onset, ALS patients may show symptoms such as muscle weakness, atrophy, hyperreflexia, or bulbar symptoms such as dysphagia or dysarthria. Deterioration progresses rapidly, and the later stages of ALS are characterized by severely limited mobility and respiratory failure, which is the primary cause of death. There is no specific diagnostic test for ALS, and there are a number of other conditions that may resemble ALS, making a diagnosis difficult. The variability of the initial presentation combined with the broad differential diagnosis may result in significant delays in diagnosis or, in some cases, misdiagnosis, which in turn have a negative impact on patient outcomes. There is no cure for ALS; however, many of the symptoms are treatable, and the physical and psychological symptoms are best managed through the efforts of a coordinated, multidisciplinary team. Nurses play a critical role in the clinical management of ALS and may be involved in coordinating the activities of the team, facilitating treatment, and helping patients and caregivers in making informed treatment and end-of-life decisions. Drug therapy for ALS is currently limited to riluzole; however, patients may be treated with a number of nonpharmacologic methods on the basis of their symptoms. A number of other treatment modalities, such as stem-cell-based therapy or gene therapy, and an array of neuroprotective clinical trials are currently under development for the treatment of ALS. Nurses may also have a key role in these various ALS studies.}, }
@article {pmid21792905, year = {2011}, author = {Kim, K and Lee, SG and Kegelman, TP and Su, ZZ and Das, SK and Dash, R and Dasgupta, S and Barral, PM and Hedvat, M and Diaz, P and Reed, JC and Stebbins, JL and Pellecchia, M and Sarkar, D and Fisher, PB}, title = {Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics.}, journal = {Journal of cellular physiology}, volume = {226}, number = {10}, pages = {2484-2493}, pmid = {21792905}, issn = {1097-4652}, support = {R01 CA134721-02/CA/NCI NIH HHS/United States ; P01 NS031492/NS/NINDS NIH HHS/United States ; P01 NS31492/NS/NINDS NIH HHS/United States ; R01 CA134721/CA/NCI NIH HHS/United States ; R03 MH093195/MH/NIMH NIH HHS/United States ; P01 NS031492-15/NS/NINDS NIH HHS/United States ; R01 CA134721-01A1/CA/NCI NIH HHS/United States ; R03 MH093195-01/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Excitatory Amino Acid Transporter 2/genetics/metabolism/*physiology ; Glutamic Acid/metabolism/*physiology ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*pharmacology/*therapeutic use ; }, abstract = {Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Analysis of the 2.5 kb human EAAT2 promoter showed that NF-κB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a β-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes through the NF-κB signaling pathway. The NF-κB binding site at -272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.}, }
@article {pmid21787329, year = {2011}, author = {Janssens, J and Kleinberger, G and Wils, H and Van Broeckhoven, C}, title = {The role of mutant TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Biochemical Society transactions}, volume = {39}, number = {4}, pages = {954-959}, doi = {10.1042/BST0390954}, pmid = {21787329}, issn = {1470-8752}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; DNA-Binding Proteins/*genetics/metabolism ; *Disease Models, Animal ; Frontotemporal Lobar Degeneration/*genetics/metabolism ; Humans ; Mutant Proteins/*genetics/metabolism ; }, abstract = {TDP-43 (TAR DNA-binding protein 43) has been identified as a key protein of ubiquitinated inclusions in brains of patients with ALS (amyotrophic lateral sclerosis) or FTLD (frontotemporal lobar degeneration), defining a new pathological disease spectrum. Recently, coding mutations have been identified in the TDP-43 gene (TARDBP), which further confirmed the pathogenic nature of the protein. Today, several animal models have been generated to gain more insight into the disease-causing pathways of the FTLD/ALS spectrum. This mini-review summarizes the current status of TDP-43 models, with a focus on mutant TDP-43.}, }
@article {pmid21783422, year = {2011}, author = {Cohen, TJ and Lee, VM and Trojanowski, JQ}, title = {TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies.}, journal = {Trends in molecular medicine}, volume = {17}, number = {11}, pages = {659-667}, pmid = {21783422}, issn = {1471-499X}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; P30 AG010124-20/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/chemistry/*genetics/metabolism ; Gene Expression Regulation ; Humans ; Inclusion Bodies/metabolism ; Mutation, Missense ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; RNA, Messenger/metabolism ; Stress, Physiological ; TDP-43 Proteinopathies/*genetics/metabolism/physiopathology ; }, abstract = {Given the critical role for TDP-43 in diverse neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), there has been a recent surge in efforts to understand the normal functions of TDP-43 and the molecular basis of dysregulation that occurs in TDP-43 proteinopathies. Here, we highlight recent findings examining TDP-43 molecular functions with particular emphasis on stress-mediated regulation of TDP-43 localization, putative downstream TDP-43 target genes and RNAs, as well as TDP-43 interacting proteins, all of which represent viable points of therapeutic intervention for ALS, FTLD-TDP and related proteinopathies. Finally, we review current mouse models of TDP-43 and discuss their similarities and potential relevance to human TDP-43 proteinopathies including ALS and FTLD-TDP.}, }
@article {pmid21781992, year = {2012}, author = {Yamanaka, K and Sasagawa, Y and Ogura, T}, title = {Recent advances in p97/VCP/Cdc48 cellular functions.}, journal = {Biochimica et biophysica acta}, volume = {1823}, number = {1}, pages = {130-137}, doi = {10.1016/j.bbamcr.2011.07.001}, pmid = {21781992}, issn = {0006-3002}, mesh = {Adenosine Triphosphatases/antagonists &amp; inhibitors/genetics/*metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Cell Cycle ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Endoplasmic Reticulum-Associated Degradation ; Humans ; Mitochondria/enzymology/metabolism ; Mutation ; Myositis, Inclusion Body/genetics ; Neoplasms/drug therapy/enzymology ; Proteolysis ; Ubiquitinated Proteins/metabolism ; Valosin Containing Protein ; }, abstract = {p97/VCP/Cdc48 is one of the best-characterized type II AAA (ATPases associated with diverse cellular activities) ATPases. p97 is suggested to be a ubiquitin-selective chaperone and its key function is to disassemble protein complexes. p97 is involved in a wide variety of cellular activities. Recently, novel functions, namely autophagy and mitochondrial quality control, for p97 have been uncovered. p97 was identified as a causative factor for inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) and more recently as a causative factor for amyotrophic lateral sclerosis (ALS). In this review, we will summarize and discuss recent progress and topics in p97 functions and the relationship to its associated diseases.}, }
@article {pmid21777407, year = {2011}, author = {Wang, DB and Gitcho, MA and Kraemer, BC and Klein, RL}, title = {Genetic strategies to study TDP-43 in rodents and to develop preclinical therapeutics for amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {34}, number = {8}, pages = {1179-1188}, pmid = {21777407}, issn = {1460-9568}, support = {R01 NS048450/NS/NINDS NIH HHS/United States ; R01 NS048450-04/NS/NINDS NIH HHS/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/physiopathology/*therapy ; Animals ; Animals, Genetically Modified ; DNA-Binding Proteins/*genetics ; *Disease Models, Animal ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Genetic Vectors/genetics/therapeutic use ; Germ Cells/physiology ; Humans ; *Rodentia ; Spinal Cord/pathology/physiology/physiopathology ; }, abstract = {The neuropathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) and a class of frontotemporal lobar degeneration is ubiquitinated cytoplasmic aggregates composed of transactive response DNA binding protein 43 kDa (TDP-43). Genetic manipulation of TDP-43 in animal models has been used to study the protein's role in pathogenesis. Transgenic rodents for TDP-43 have recapitulated key aspects of ALS such as paralysis, loss of spinal motor neurons and muscle atrophy. Viral vectors are an alternate approach to express pathological proteins in animals. Use of the recombinant adeno-associated virus vector serotype 9 has permitted widespread transgene expression throughout the central nervous system after intravenous administration. Expressing TDP-43 in rats with this method produced a phenotype that was consistent with and similar to TDP-43 transgenic lines. Increased levels of TDP-43 in the nucleus are toxic to neurons and sufficient to produce ALS-like symptoms. Animal models based on TDP-43 will address the relationships between TDP-43 expression levels, pathology, neuronal loss, muscle atrophy, motor function and causative mechanisms of disease. New targets that modify TDP-43 function, or targets from previous ALS models and other models of spinal cord diseases, could be tested for efficacy in the recent rodent models of ALS based on TDP-43. The vector approach could be an important therapeutic channel because the entire spinal cord can be affected from a one-time peripheral administration.}, }
@article {pmid21777389, year = {2011}, author = {Fiesel, FC and Kahle, PJ}, title = {TDP-43 and FUS/TLS: cellular functions and implications for neurodegeneration.}, journal = {The FEBS journal}, volume = {278}, number = {19}, pages = {3550-3568}, doi = {10.1111/j.1742-4658.2011.08258.x}, pmid = {21777389}, issn = {1742-4658}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Autophagy/physiology ; Cytoplasmic Granules/chemistry/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/pathology/physiopathology ; Gene Expression Regulation ; Humans ; Nerve Degeneration/*pathology/physiopathology ; RNA/metabolism ; RNA Stability ; RNA-Binding Protein FUS/genetics/*metabolism ; }, abstract = {TDP-43 (transactive response binding protein of 43 kDa) and FUS (fused in sarcoma) comprise the neuropathological protein aggregates of distinct subtypes of the neurodegenerative diseases frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Moreover, the genes encoding TDP-43 and FUS are linked to these diseases. Both TDP-43 and FUS contain RNA binding motifs, and specific targets are being identified. Potential actions of TDP-43 and FUS include transcriptional regulation, mRNA processing and micro RNA biogenesis. These activities are probably modulated by interacting proteins in cell type specific manners as well as distinctly within the nucleus and cytosol, as both proteins shuttle between these compartments. In this minireview the specific functions of TDP-43 and FUS are described and discussed in the context of how TDP-43 and FUS may contribute to the pathogenesis of frontotemporal lobar degeneration and amyotrophic lateral sclerosis.}, }
@article {pmid21777387, year = {2011}, author = {Baloh, RH}, title = {TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {The FEBS journal}, volume = {278}, number = {19}, pages = {3539-3549}, pmid = {21777387}, issn = {1742-4658}, support = {K08 NS055980/NS/NINDS NIH HHS/United States ; K08 NS055980-05/NS/NINDS NIH HHS/United States ; R01 NS069669/NS/NINDS NIH HHS/United States ; R01 NS069669-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Brain/pathology/physiopathology ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/*pathology/physiopathology ; Humans ; Inclusion Bodies/metabolism/pathology ; Nerve Degeneration/*pathology ; RNA/metabolism ; Ubiquitin/metabolism ; }, abstract = {Accumulations of aggregated proteins are a key feature of the pathology of all of the major neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) was brought into this fold quite recently with the discovery of TDP-43 (TAR DNA binding protein, 43 kDa) inclusions in nearly all ALS cases. In part this discovery was fueled by the recognition of the clinical overlap between ALS and frontotemporal lobar degeneration, where ubiquitinated TDP-43 inclusions were first identified. Later the identification of TDP-43 mutations in rare familial forms of ALS confirmed that altered TDP-43 function can be a primary cause of the disease. However, the simple concept that TDP-43 is an aggregation-prone protein that forms toxic inclusions capable of promoting neurodegeneration has not been upheld by initial investigations. This review discusses observations from human pathology, cell culture and animal model systems, to highlight our somewhat murky understanding of the relationship between TDP-43 aggregation and neurodegeneration.}, }
@article {pmid21774784, year = {2011}, author = {Majima, HJ and Indo, HP and Suenaga, S and Matsui, H and Yen, HC and Ozawa, T}, title = {Mitochondria as possible pharmaceutical targets for the effects of vitamin E and its homologues in oxidative stress-related diseases.}, journal = {Current pharmaceutical design}, volume = {17}, number = {21}, pages = {2190-2195}, doi = {10.2174/138161211796957490}, pmid = {21774784}, issn = {1873-4286}, mesh = {Aging/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/*prevention &amp; control ; Animals ; Humans ; Mitochondria/*drug effects/metabolism ; Neoplasms/metabolism/*prevention &amp; control ; Oxidative Stress/*drug effects ; Superoxide Dismutase/genetics/metabolism ; Vitamin E/administration &amp; dosage/*analogs &amp; derivatives/*therapeutic use ; }, abstract = {It is well known that vitamin E functions as an antioxidant, and it is expected to exert an antioxidant effect when taken as a supplement. However, a number of cohort studies have shown that vitamin E does not alleviate oxidative stress and could even worsen it. Recently, Wang et al. investigated whether vitamin E intake was associated with amyotrophic lateral sclerosis (ALS) based on data from 5 cohort studies with 1,055,546 participants, of which 805 of them had developed ALS. They concluded in this large pooled prospective study, in which long-term vitamin E supplementation was associated with lower ALS rates, and therefore, a possible protective effect of vitamin E deserves further consideration. Performing further large cohort studies may reveal similar findings for other oxidative stress-related diseases. It is still controversial if antioxidants such as vitamin E provide a clinical therapeutic effect against oxidative stress-related diseases. If effective, the dose at which they should be administered and the duration of supplement exposure should be of interest. Vitamin E reduces production of reactive oxygen species by mitochondria and elicits further reactions in cells. It should be noted that mitochondria are important targets for vitamin E and its homologues. Therefore, a proper usage of vitamin E in subjects under high oxidative stress, due to its individually targeting property, will arise its importance in healthy life.}, }
@article {pmid21761185, year = {2011}, author = {Zipp, F and Gold, R}, title = {[Neuroprotection in the treatment of multiple sclerosis].}, journal = {Der Nervenarzt}, volume = {82}, number = {8}, pages = {973-977}, pmid = {21761185}, issn = {1433-0407}, mesh = {Alemtuzumab ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antibodies, Neoplasm/therapeutic use ; Axons/drug effects/immunology/pathology ; Brain/drug effects/immunology/pathology ; Cell Death/drug effects/physiology ; Disease Progression ; Humans ; Immunologic Factors/therapeutic use ; Multiple Sclerosis/*drug therapy/immunology/pathology ; Nerve Regeneration/drug effects ; Neurodegenerative Diseases/*drug therapy/immunology/pathology ; Neurons/drug effects/immunology/pathology ; Neuroprotective Agents/*therapeutic use ; Prognosis ; Retrograde Degeneration/drug therapy/immunology/pathology ; Spinal Cord/drug effects/immunology/pathology ; }, abstract = {Atrophy, the wasting or shrinkage of tissue, of the nervous system is the main feature of neurodegeneration, i.e. the umbrella term for the progressive loss of structure or function of neurons. Loss of neurons due to cell death and axonal degeneration characterize neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis. In these illnesses, it still has to be elucidated to which extent inflammation is part of the pathology. Conversely, in chronic inflammation of the central nervous system (CNS), atrophy has previously also been described and neurodegeneration is discussed as a pathologic feature. The most frequent chronic inflammatory disease of the CNS is multiple sclerosis (MS), which leads to devastating relapsing-remitting symptoms and disability during the relapses, increasingly during the course of disease in patients. Meanwhile it became clear that axons already reveal pathology early in the disease and neurons are affected in the cortex and the spinal cord, albeit to a different extent. The broadening of understanding neurodegenerative aspects of MS pathology demands and creates new therapeutic strategies. Current medication used in MS treatment as well as medications about to be approved are primarily anti-inflammatory therapies. By modulating the immune system and thereby blocking key steps of the pathology, the immunomodulation therapies in MS have a slight impact on disability progression. There is, however, clinical and experimental data concerning the potential neuroprotective properties of novel therapies. Combining anti-inflammatory and direct neuroprotective or even neuroregenerative therapy strategies would be a step forward in the treatment of multiple sclerosis.}, }
@article {pmid21757921, year = {2011}, author = {Romi, F and Helgeland, G and Gilhus, NE}, title = {Heat-shock proteins in clinical neurology.}, journal = {European neurology}, volume = {66}, number = {2}, pages = {65-69}, doi = {10.1159/000329373}, pmid = {21757921}, issn = {1421-9913}, mesh = {Heat-Shock Proteins/*metabolism ; Humans ; Nervous System Diseases/classification/*metabolism/pathology ; *Neurology ; }, abstract = {Heat-shock proteins (HSPs) are antigen-presenting protein-aggregation-preventing chaperones, induced by cellular stress in eukaryotic cells. In this review, we focus on recent HSP advances in neurological disorders. In myasthenia gravis, patients responding to immunosuppressive therapy have reduced serum HSP-71 antibodies. Generalized and ocular myasthenia gravis patients have elevated serum HSP-70 antibodies, indicating common pathogenic mechanisms. In Guillain-Barré syndrome, HSP-70 antibodies are elevated in serum and cerebrospinal fluid, and serum levels are higher than in myasthenia gravis and multiple sclerosis. In multiple sclerosis, serum HSP-27 antibodies are elevated during relapses providing disease activation marker, while α,β-crystallin expression in brain lesions indicates remission phase initiation. In acute stroke, serum HSP-27 antibodies are elevated irrespective of stroke type and duration. In epilepsy, HSP-27 is induced in patients' astrocytes and cerebral blood vessel walls, and α,β-crystallin is expressed in epileptic foci. In neurodegenerative disorders such as Alzheimer dementia and Parkinson's disease, HSPs are upregulated in brain tissue, and α,β-crystallin modulates superoxide dismutase-1 (SOD-1) tissue accumulation in familial amyotrophic lateral sclerosis. HSPs play an important role in antigen-presentation and tolerance development. Antibody-mediated interference with their function alters immune responses causing neuropathology. The role of HSPs in clinical neurology should be the subject of future investigation.}, }
@article {pmid21747027, year = {2011}, author = {Sharma, R and Hicks, S and Berna, CM and Kennard, C and Talbot, K and Turner, MR}, title = {Oculomotor dysfunction in amyotrophic lateral sclerosis: a comprehensive review.}, journal = {Archives of neurology}, volume = {68}, number = {7}, pages = {857-861}, doi = {10.1001/archneurol.2011.130}, pmid = {21747027}, issn = {1538-3687}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications/pathology ; Animals ; Humans ; Neural Pathways/pathology ; Ocular Motility Disorders/*etiology/pathology ; }, abstract = {Although traditionally regarded as spared, a range of oculomotor dysfunction has been recorded in patients with amyotrophic lateral sclerosis (ALS). Most frequent is ophthalmoparesis, particularly in patients with prolonged survival; however, pursuit, nystagmus, and saccadic impairments have also been reported. The apparent resistance to pathologic involvement of oculomotor (and sphincter) control pathways in most patients with ALS has prompted comparative study to establish the key pathways that underlie motor neuronal vulnerability, with the hope of generating novel therapeutic strategies. Developments in the assessment of oculomotor function, including portable eye-tracking devices, have revealed more subtle impairments in ALS in relation to phenotype, which can now be better understood through parallel elucidation of the normal cerebral oculomotor control network. Given the clinicopathologic overlap between ALS and some types of frontotemporal dementia, the study of oculomotor function has particular value in probing the variable but consistent cognitive impairment seen in ALS and that reflects frontotemporal extramotor cerebral abnormalities. By transcending the requirement to write or speak, loss of which precludes standard neuropsychological testing in some patients with advanced ALS, cognitive tests performed using only oculomotor functions offer additional potential, allowing the study of patients much later in their disease course. The study of oculomotor dysfunction holds significant promise as an additional source of much needed prognostic, monitoring, and mechanistic biomarkers for ALS.}, }
@article {pmid21745636, year = {2011}, author = {Saxena, S and Caroni, P}, title = {Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration.}, journal = {Neuron}, volume = {71}, number = {1}, pages = {35-48}, doi = {10.1016/j.neuron.2011.06.031}, pmid = {21745636}, issn = {1097-4199}, mesh = {Animals ; Humans ; Models, Biological ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/*metabolism/*pathology/physiopathology ; Proteostasis Deficiencies/*metabolism/*pathology/physiopathology ; Signal Transduction/physiology ; Stress, Physiological/*physiology ; }, abstract = {Neurodegenerative diseases selectively target subpopulations of neurons, leading to the progressive failure of defined brain systems, but the basis of such selective neuronal vulnerability has remained elusive. Here, we discuss how a stressor-threshold model of how particular neurons and circuits are selectively vulnerable to disease may underly the etiology of familial and sporadic forms of diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS. According to this model, the intrinsic vulnerabilities of neuronal subpopulations to stressors and specific disease-related misfolding proteins determine neuronal morbidity. Neurodegenerative diseases then involve specific combinations of genetic predispositions and environmental stressors, triggering increasing age-related stress and proteostasis dysfunction in affected vulnerable neurons. Damage to vasculature, immune system, and local glial cells mediates environmental stress, which could drive disease at all stages.}, }
@article {pmid21743136, year = {2011}, author = {Chiu, CT and Chuang, DM}, title = {Neuroprotective action of lithium in disorders of the central nervous system.}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {36}, number = {6}, pages = {461-476}, pmid = {21743136}, issn = {1672-7347}, support = {ZIA MH002468-23//Intramural NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Diseases/*drug therapy ; Humans ; Lithium/*pharmacology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Nootropic Agents/pharmacology/therapeutic use ; }, abstract = {Substantial in vitro and in vivo evidence of neurotrophic and neuroprotective effects of lithium suggests that it may also have considerable potential for the treatment of neurodegenerative conditions. Lithium's main mechanisms of action appear to stem from its ability to inhibit glycogen synthase kinase-3 activity and also to induce signaling mediated by brain-derived neurotrophic factor. This in turn alters a wide variety of downstream effectors, with the ultimate effect of enhancing pathways to cell survival. In addition, lithium contributes to calcium homeostasis. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, for instance, it suppresses the calcium-dependent activation of pro-apoptotic signaling pathways. By inhibiting the activity of phosphoinositol phosphatases, it decreases levels of inositol 1,4,5-trisphosphate, a process recently identified as a novel mechanism for inducing autophagy. These mechanisms allow therapeutic doses of lithium to protect neuronal cells from diverse insults that would otherwise lead to massive cell death. Lithium, moreover, has been shown to improve behavioral and cognitive deficits in animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, and Huntington's, Alzheimer's, and Parkinson's diseases. Since lithium is already FDA-approved for the treatment of bipolar disorder, our conclusions support the notion that its clinical relevance can be expanded to include the treatment of several neurological and neurodegenerative-related diseases.}, }
@article {pmid21740381, year = {2011}, author = {Rizvanov, AA and Gulluoglu, S and Yalvaç, ME and Palotás, A and Islamov, RR}, title = {RNA interference and amyotrophic lateral sclerosis.}, journal = {Current drug metabolism}, volume = {12}, number = {7}, pages = {679-683}, doi = {10.2174/138920011796504464}, pmid = {21740381}, issn = {1875-5453}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/*therapy ; Animals ; Cell Death/physiology ; Genetic Therapy/*trends ; Humans ; Mutation/genetics ; RNA Interference/*physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neuro-degenerative disorder characterized by progressive loss of motor neurons. The etiology and molecular pathogenesis of cell death in most sub-types of the disease are largely unknown. The best documented cause of moto-neuron degeneration is the mutation in the superoxide dismutase-1 (SOD1) gene, which occurs in 10% of the familial forms of ALS. Discovery of RNA interference (RNAi), which plays an important role in the regulation of gene expression, has proven to be a powerful tool to study the pathogenesis and to develop innovative treatment options for hereditary diseases, including familial variants of ALS. This review summarizes current research advances in RNAi in relation to ALS.}, }
@article {pmid21740229, year = {2011}, author = {Su, SC and Tsai, LH}, title = {Cyclin-dependent kinases in brain development and disease.}, journal = {Annual review of cell and developmental biology}, volume = {27}, number = {}, pages = {465-491}, doi = {10.1146/annurev-cellbio-092910-154023}, pmid = {21740229}, issn = {1530-8995}, support = {R01 NS051874/NS/NINDS NIH HHS/United States ; T32 MH074249/MH/NIMH NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 NS 051874/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/anatomy &amp; histology/*enzymology/*growth &amp; development/*physiopathology ; Cell Movement/physiology ; Cyclin-Dependent Kinase 5/genetics/*metabolism ; Epigenesis, Genetic ; Homeostasis ; Humans ; Learning/physiology ; Memory/physiology ; Nerve Tissue Proteins/genetics/metabolism ; Neurites/metabolism ; Neurodegenerative Diseases/*enzymology/*pathology/*physiopathology ; Neuronal Plasticity/physiology ; Synaptic Transmission/physiology ; Synaptic Vesicles/metabolism ; }, abstract = {Cyclin-dependent kinase 5 (Cdk5) is a multifaceted serine/threonine kinase protein with important roles in the nervous system. Two related proteins, p35 and p39, activate Cdk5 upon direct binding. Over the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development, including neuronal migration as well as axon and dendrite development. Recent evidence also suggests a pivotal role for Cdk5 in synaptic plasticity, behavior, and cognition. Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia. Hyperactivation of Cdk5 due to the conversion of p35 to p25 by the calcium-dependent protease calpain during neurotoxicity also contributes to the pathological state. This review surveys recent literature surrounding Cdk5 in synaptic plasticity and homeostasis, with particular emphasis on Cdk5 kinase activity under neurodegenerative conditions.}, }
@article {pmid21736686, year = {2012}, author = {Ho, CY and Alghamdi, TA and Botelho, RJ}, title = {Phosphatidylinositol-3,5-bisphosphate: no longer the poor PIP2.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {13}, number = {1}, pages = {1-8}, doi = {10.1111/j.1600-0854.2011.01246.x}, pmid = {21736686}, issn = {1600-0854}, mesh = {Animals ; Cell Membrane/metabolism ; Gene Expression Regulation ; Humans ; Lysosomes/metabolism ; Models, Biological ; Neurodegenerative Diseases/genetics/metabolism ; *Phosphatidylinositol Phosphates/genetics/metabolism/physiology ; Protein Transport ; Signal Transduction ; Vacuoles/metabolism ; }, abstract = {Phosphoinositides play an important role in organelle identity by recruiting effector proteins to the host membrane organelle, thus decorating that organelle with molecular identity. Phosphatidylinositol-3,5-bisphos- phate [PtdIns(3,5)P(2) ] is a low-abundance phosphoinositide that predominates in endolysosomes in higher eukaryotes and in the yeast vacuole. Compared to other phosphoinositides such as PtdIns(4,5)P(2) , our understanding of the regulation and function of PtdIns(3,5)P(2) remained rudimentary until more recently. Here, we review many of the recent developments in PtdIns(3,5)P(2) function and regulation. PtdIns(3,5)P(2) is now known to espouse functions, not only in the regulation of endolysosome morphology, trafficking and acidification, but also in autophagy, signaling mediation in response to stresses and hormonal cues and control of membrane and ion transport. In fact, PtdIns(3,5)P(2) misregulation is now linked with several human neuropathologies including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Given the functional versatility of PtdIns(3,5)P(2) , it is not surprising that regulation of PtdIns(3,5)P(2) metabolism is proving rather elaborate. PtdIns(3,5)P(2) synthesis and turnover are tightly coupled via a protein complex that includes the Fab1/PIKfyve lipid kinase and its antagonistic Fig4/Sac3 lipid phosphatase. Most interestingly, many PtdIns(3,5)P(2) regulators play simultaneous roles in its synthesis and turnover.}, }
@article {pmid21729715, year = {2011}, author = {Yang, JL and Sykora, P and Wilson, DM and Mattson, MP and Bohr, VA}, title = {The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency.}, journal = {Mechanisms of ageing and development}, volume = {132}, number = {8-9}, pages = {405-411}, pmid = {21729715}, issn = {1872-6216}, support = {Z01 AG000735-12/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Calcium/*metabolism ; *Calcium Signaling ; Cyclic AMP Response Element-Binding Protein/metabolism ; *DNA Repair ; Glutamic Acid/*metabolism ; Humans ; Mitochondria/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Neurons/*metabolism/pathology ; Neurotransmitter Agents/*metabolism ; Oxidation-Reduction ; Protein Kinase C/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system and plays an important role in synaptic plasticity required for learning and memory. Activation of glutamate ionotropic receptors promptly triggers membrane depolarization and Ca(2+) influx, resulting in the activation of several different protein kinases and transcription factors. For example, glutamate-mediated Ca(2+) influx activates Ca(2+)/calmodulin-dependent kinase, protein kinase C, and mitogen activated protein kinases resulting in activation of transcription factors such as cyclic AMP response element binding protein (CREB). Abnormally prolonged exposure to glutamate causes neuronal injury, and such "excitotoxicity" has been implicated in many acute and chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's, Huntington's and Parkinson's diseases. Interestingly, although glutamate-induced Ca(2+) influx can cause DNA damage by a mitochondrial reactive oxygen species-mediated mechanism, the Ca(2+) simultaneously activates CREB, resulting in up-regulation of the DNA repair and redox protein apurinic/apyrimidinic endonuclease 1. Here, we review connections between physiological or aberrant glutamate receptor activation, Ca(2+)-mediated signaling, oxidative DNA damage and repair efficiency, and neuronal vulnerability. We conclude that glutamate signaling involves an adaptive cellular stress response pathway that enhances DNA repair capability, thereby protecting neurons against injury and disease.}, }
@article {pmid21725240, year = {2011}, author = {de Carvalho, M and Swash, M}, title = {Amyotrophic lateral sclerosis: an update.}, journal = {Current opinion in neurology}, volume = {24}, number = {5}, pages = {497-503}, doi = {10.1097/WCO.0b013e32834916a9}, pmid = {21725240}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers/analysis ; Early Diagnosis ; Electrodiagnosis ; Frontotemporal Lobar Degeneration/diagnosis/*genetics/pathology/therapy ; Humans ; }, abstract = {PURPOSE OF REVIEW: The aim is to review recent publications on amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: The Awaji recommendations for electrophysiological diagnosis will permit earlier clinical trials entry. The use of ultrasound to visualize fasciculations, even in deep muscles, will contribute to earlier diagnosis, as well. Unfortunately, recent clinical trials in ALS have been disappointing, as illustrated by the negative lithium trials. New, less expensive, trial designs and the inclusion of patients early in the course of ALS are positive approaches for future trials. The search for ALS biomarkers continues and a number of encouraging reports have been published, but no features unique to ALS have yet transformed this field. The most exciting advances in ALS arise from protein studies and genetics. Recognition that the ubiquitinated cytosolic inclusions in sporadic ALS, as well as in some patients with frontotemporal dementia (FTD), contain TDP-43, and that some familial cases (and a few sporadic cases) have mutations of the TDP-43 gene has transformed previous concepts on ALS pathogenesis. Other newly recognized mutations linked to ALS, such as fused-in-sarcoma (FUS) and valosin-containing protein (VCP), have not only widened the spectrum of genes involved in ALS but also consolidated the close relation between ALS and FTD.<br><br>SUMMARY: ALS research is entering a new phase that should generate new proposals regarding putative therapies, or strategies for disease treatment. A continuing difficulty, however, is early clinical diagnosis and, especially, the need for identification of a unique biomarker, sensitive to clinical change in the course of the disease.}, }
@article {pmid21708901, year = {2011}, author = {Sleigh, JN and Gillingwater, TH and Talbot, K}, title = {The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy.}, journal = {Disease models &amp; mechanisms}, volume = {4}, number = {4}, pages = {457-467}, pmid = {21708901}, issn = {1754-8411}, support = {//Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Disease Models, Animal ; Humans ; Mice ; Motor Neurons/pathology ; Muscular Atrophy, Spinal/*etiology/genetics/*pathology ; Nerve Degeneration/complications/pathology ; RNA Splicing/genetics ; SMN Complex Proteins/metabolism ; }, abstract = {Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration.}, }
@article {pmid21706386, year = {2011}, author = {Joyce, PI and Fratta, P and Fisher, EM and Acevedo-Arozena, A}, title = {SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {22}, number = {7-8}, pages = {420-448}, pmid = {21706386}, issn = {1432-1777}, support = {MC_U142684175/MRC_/Medical Research Council/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; MC_U142684172/MRC_/Medical Research Council/United Kingdom ; G0500288/MRC_/Medical Research Council/United Kingdom ; G1000287/MRC_/Medical Research Council/United Kingdom ; MR/K018523/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*therapy ; Animals ; Caenorhabditis elegans ; DNA-Binding Proteins/*genetics/metabolism ; *Disease Models, Animal ; Dogs ; Drosophila ; Humans ; Mice ; Rats ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Zebrafish ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure. Breakthroughs in understanding ALS pathogenesis came with the discovery of dominant mutations in the superoxide dismutase 1 gene (SOD1) and other genes, including the gene encoding transactivating response element DNA binding protein-43 (TDP-43). This has led to the creation of animal models to further our understanding of the disease and identify a number of ALS-causing mechanisms, including mitochondrial dysfunction, protein misfolding and aggregation, oxidative damage, neuronal excitotoxicity, non-cell autonomous effects and neuroinflammation, axonal transport defects, neurotrophin depletion, effects from extracellular mutant SOD1, and aberrant RNA processing. Here we summarise the SOD1 and TDP-43 animal models created to date, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic.}, }
@article {pmid21702733, year = {2011}, author = {Lill, CM and Abel, O and Bertram, L and Al-Chalabi, A}, title = {Keeping up with genetic discoveries in amyotrophic lateral sclerosis: the ALSoD and ALSGene databases.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {4}, pages = {238-249}, doi = {10.3109/17482968.2011.584629}, pmid = {21702733}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; *Databases, Factual ; Genetic Predisposition to Disease ; Genotype ; Humans ; Mutation ; Phenotype ; Software ; User-Computer Interface ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous disorder that shows a characteristic dichotomy of familial forms typically displaying Mendelian inheritance patterns, and sporadic ALS showing no or less obvious familial aggregation. While the former is caused by rare, highly penetrant, and pathogenic mutations, risk for sporadic ALS is probably the result of the combined effects of common polymorphisms with minor to moderate effect sizes. Owing to recent advances in high-throughput genotyping and sequencing technologies, genetic research in both fields is evolving at a rapidly increasing pace making it more and more difficult to follow and evaluate the most significant progress in the field. To alleviate this problem, our groups have created dedicated and freely available online databases, ALSoD (http://alsod.iop.kcl.ac.uk/) and ALSGene (http://www.alsgene.org), which provide systematic and in-depth qualitative and quantitative overviews of genetic research in both familial and sporadic ALS. This review briefly introduces the background and main features of both databases and provides an overview of the currently most compelling genetic findings in ALS derived from analyses using these resources.}, }
@article {pmid21699269, year = {2011}, author = {Xu, X and Warrington, AE and Bieber, AJ and Rodriguez, M}, title = {Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.}, journal = {CNS drugs}, volume = {25}, number = {7}, pages = {555-573}, pmid = {21699269}, issn = {1179-1934}, support = {R01NS032129/NS/NINDS NIH HHS/United States ; R01 NS032129/NS/NINDS NIH HHS/United States ; R01 NS032129-14/NS/NINDS NIH HHS/United States ; R01 CA096859-02/CA/NCI NIH HHS/United States ; R01 CA104996/CA/NCI NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R01 CA104996-07/CA/NCI NIH HHS/United States ; R01 NS024180/NS/NINDS NIH HHS/United States ; R01 NS024180-21/NS/NINDS NIH HHS/United States ; R01 CA096859/CA/NCI NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; R01 GM092993/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System Diseases/physiopathology/*therapy ; Humans ; Nerve Net/metabolism ; *Nerve Regeneration ; Neurodegenerative Diseases/physiopathology/*therapy ; Stem Cell Transplantation/methods ; }, abstract = {Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes not only encompass the lesions/pathogens but may also form glial scars to impede regenerating axons from traversing the lesions. In addition, myelin debris can prevent axon growth. Myelination enables saltatory transduction of electrical impulses along axonal calibers and actually provides trophic support to stabilize the axons. Therefore, repair strategies should be designed to promote axonal growth, myelination and modulate astrocytic responses. Finally, we discuss recent progress in developing human monoclonal IgMs that regulate CNS homeostasis and promote neural regeneration.}, }
@article {pmid21696410, year = {2011}, author = {Costanza, A and Weber, K and Gandy, S and Bouras, C and Hof, PR and Giannakopoulos, P and Canuto, A}, title = {Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates.}, journal = {Neuropathology and applied neurobiology}, volume = {37}, number = {6}, pages = {570-584}, pmid = {21696410}, issn = {1365-2990}, support = {AG05138/AG/NIA NIH HHS/United States ; AG02219/AG/NIA NIH HHS/United States ; P01 AG002219/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R01 AG035071-01A1/AG/NIA NIH HHS/United States ; R01 AG035071/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Alzheimer Disease/etiology/*pathology ; Athletic Injuries/complications/*pathology ; Brain/*pathology ; Brain Injuries/etiology/*pathology ; Frontotemporal Dementia/etiology/*pathology ; Humans ; }, abstract = {Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer's disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia.}, }
@article {pmid21692041, year = {2011}, author = {de Filippis, L}, title = {Neural stem cell-mediated therapy for rare brain diseases: perspectives in the near future for LSDs and MNDs.}, journal = {Histology and histopathology}, volume = {26}, number = {8}, pages = {1093-1109}, doi = {10.14670/HH-26.1093}, pmid = {21692041}, issn = {1699-5848}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Humans ; Lysosomal Storage Diseases/pathology/*surgery ; Neural Stem Cells/pathology/*transplantation ; *Stem Cell Transplantation ; }, abstract = {Lysosomal storage diseases (LSDs) are genetically inherited disorders affecting most patients in pediatric age and progressively lead to severe, even lethal, multiorgan dysfunction and brain neurodegeneration. Motor neuron diseases (MNDs) or Amyotrophic Lateral Sclerosis (ALS)-related syndromes are neurodegenerative disorders occurring in the majority of cases sporadically and affect adult middle-aged patients. Despite being divergent in most pathological and physiological hallmarks, both MNDs and LSDs are characterized by tremendous clinical heterogeneity due to poor prognosis and variable onset of the symptoms. Moreover, both LSDs and MNDs are characterized by the concurrence of multiple pathogenetic processes, such as the development of inflammatory and excitotoxic environments. Furthermore, pharmacological, enzyme or genetic therapies have proven to be ineffective and no cure is currently available for the neurodegeneration in either LSD or ALS affected patients. Recent studies have identified non-neuronal cell types, such as astrocytes and microglia, as being involved in non cell-autonomous effects on MND or LSD progression. These findings have prompted the use of neural stem cells for the replacement of non-neuronal cells rather than neuronal cells, which may result in neuroprotection and immunomodulation. The choice of an appropriate tissue source and the establishment of standardized paradigms to culture human neural stem cells (hNSC) will allow their use for future clinical trials on both ALS and LSD affected patients and parallel drug screening studies with novel breakthroughs in the knowledge of neurodegenerative diseases.}, }
@article {pmid21681666, year = {2011}, author = {Budini, M and Buratti, E}, title = {TDP-43 autoregulation: implications for disease.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {473-479}, pmid = {21681666}, issn = {1559-1166}, mesh = {3' Untranslated Regions ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology/*physiopathology ; *Gene Expression Regulation ; Humans ; Inclusion Bodies/metabolism/pathology ; Neurodegenerative Diseases/genetics/pathology/*physiopathology ; RNA, Messenger/genetics/metabolism ; }, abstract = {TDP-43 is a nuclear protein that has been shown to play a central role in RNA metabolism. In recent years, this protein has become very important in the study of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration (FTLD). These diseases share, as common feature, the presence of abnormally aggregated, posttranslationally modified, and mislocalized TDP-43 in the cell cytoplasm of both neurons and glial cells. A major question in TDP-43 research is represented by the investigation of the mechanism(s) that trigger this process and its potential consequences. Regarding the first issue, it is likely that relative protein expression levels might play an important role as has been demonstrated for many protein aggregation processes. In fact, the eventual misregulation of TDP-43 expression leading to enhanced protein production might well correlate with enhanced aggregation, and thus results in increasingly harmful gain- or loss-of-function effects on cellular metabolism. For this reason, it is important to determine the mechanisms that act to regulate TDP-43 levels within the cell. In normal conditions, it is now clear that TDP-43 can modulate its own protein levels through a negative feedback loop triggered by binding to its own RNA in the 3'UTR region leading to mRNA degradation. This work discusses how an eventual disruption of this mechanism might affect TDP-43 pathology, focusing in particular on its association with stress granules and intrinsic aggregation properties.}, }
@article {pmid21679120, year = {2011}, author = {D'Alessandro, A and Zolla, L}, title = {The SODyssey: superoxide dismutases from biochemistry, through proteomics, to oxidative stress, aging and nutraceuticals.}, journal = {Expert review of proteomics}, volume = {8}, number = {3}, pages = {405-421}, doi = {10.1586/epr.11.13}, pmid = {21679120}, issn = {1744-8387}, mesh = {Aging/genetics/physiology ; Animals ; Biochemistry/*methods ; Humans ; Oxidative Stress/genetics/physiology ; Proteomics/*methods ; Superoxide Dismutase/*metabolism ; }, abstract = {A total of 40 years have already passed since the pioneering work of McCord and Fridovich on erythrocuprein superoxide dismutase (SOD) activity. This modern scientific 'Odyssey' has been accompanied by a series of successes in the fields of biochemistry, biomedicine and proteomics. In this article, we resume the main strides in these fields, mainly aiming at delivering an exhaustive portrait of SOD's involvement in several oxidative stress-triggered threats to human health, including neurodegenerative disorders (amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and Huntington's diseases), cardiovascular diseases, cancer and aging. In parallel, food-derived chemical compounds appear to be intertwined with cellular redox poise modulation, as this increasingly emerges from clinical biochemical and proteomic investigations. Thus, we will also consider the involvement of these nutraceuticals in oxidative stress-triggered diseases and SOD activity modulation. Like a modern Ulysses, researchers know that the journey is not yet over. Nevertheless, much information has been gathered over the last four decades.}, }
@article {pmid21676380, year = {2011}, author = {Fuchs, SA and Berger, R and de Koning, TJ}, title = {D-serine: the right or wrong isoform?.}, journal = {Brain research}, volume = {1401}, number = {}, pages = {104-117}, doi = {10.1016/j.brainres.2011.05.039}, pmid = {21676380}, issn = {1872-6240}, mesh = {Animals ; Central Nervous System/*metabolism ; Humans ; Nervous System Diseases/*metabolism ; Protein Binding/physiology ; Protein Isoforms/chemistry/metabolism ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Serine/*chemistry/*metabolism ; }, abstract = {Only recently, d-amino acids have been identified in mammals. Of these, d-serine has been most extensively studied. d-Serine was found to play an important role as a neurotransmitter in the human central nervous system (CNS) by binding to the N-methyl-d-aspartate receptor (NMDAr), similar to glycine. Therefore, d-serine may well play a role in all physiological and pathological processes in which NMDArs have been implied. In this review, we discuss the findings implying an important role for d-serine in human physiology (CNS development and memory and learning) and pathology (excitotoxicity, perinatal asphyxia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, epilepsy, schizophrenia and bipolar disorder). We will debate on the relative contribution of d-serine versus glycine and conclude with clinical applications derived from these results and future directions to progress in this field. In general, adequate concentrations of d-serine are required for normal CNS development and function, while both decreased and increased concentrations can lead to CNS pathology. Therefore, d-serine appears to be the right isoform when present in the right concentrations.}, }
@article {pmid21676288, year = {2011}, author = {Grammas, P and Martinez, J and Miller, B}, title = {Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases.}, journal = {Expert reviews in molecular medicine}, volume = {13}, number = {}, pages = {e19}, doi = {10.1017/S1462399411001918}, pmid = {21676288}, issn = {1462-3994}, support = {AG020569/AG/NIA NIH HHS/United States ; AG028367/AG/NIA NIH HHS/United States ; AG15964/AG/NIA NIH HHS/United States ; }, mesh = {*Blood-Brain Barrier ; Brain/*blood supply ; Endothelial Cells/pathology/physiology ; Endothelium, Vascular/pathology/physiology ; Humans ; Microvessels/*pathology ; Neurodegenerative Diseases/*pathology/*physiopathology/therapy ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Tight Junctions/ultrastructure ; }, abstract = {Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood-brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells.}, }
@article {pmid21674586, year = {2011}, author = {Bartanusz, V and Jezova, D and Alajajian, B and Digicaylioglu, M}, title = {The blood-spinal cord barrier: morphology and clinical implications.}, journal = {Annals of neurology}, volume = {70}, number = {2}, pages = {194-206}, doi = {10.1002/ana.22421}, pmid = {21674586}, issn = {1531-8249}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Blood-Brain Barrier/*anatomy &amp; histology/pathology/*physiology/physiopathology ; Disease Models, Animal ; Drug Delivery Systems ; Endothelial Cells/cytology/physiology ; Humans ; Spinal Cord/*anatomy &amp; histology/pathology/*physiology/physiopathology ; Spinal Cord Diseases/etiology/pathology/physiopathology ; Spinal Cord Injuries/complications/pathology/physiopathology/therapy ; }, abstract = {The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood-brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. Even if intuitively the BSCB could be considered as the morphological extension of the BBB into the spinal cord, evidence suggests that this is not so. The BSCB shares the same principal building blocks with the BBB; nevertheless, it seems that morphological and functional differences may exist between them. Dysfunction of the BSCB plays a fundamental role in the etiology or progression of several pathological conditions of the spinal cord, such as spinal cord injury, amyotrophic lateral sclerosis, and radiation-induced myelopathy. This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the BSCB, and the potential role of BSCB dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BSCB.}, }
@article {pmid21665413, year = {2012}, author = {Boyd, T and Brady, W}, title = {The "Code Drugs in Cardiac Arrest"--the use of cardioactive medications in cardiac arrest resuscitation.}, journal = {The American journal of emergency medicine}, volume = {30}, number = {5}, pages = {811-818}, doi = {10.1016/j.ajem.2011.04.009}, pmid = {21665413}, issn = {1532-8171}, mesh = {Advanced Cardiac Life Support/methods ; Amiodarone/*therapeutic use ; Atropine/*therapeutic use ; Cardiotonic Agents/*therapeutic use ; Epinephrine/*therapeutic use ; Heart Arrest/*drug therapy ; Humans ; Lidocaine/*therapeutic use ; Practice Guidelines as Topic ; Resuscitation/methods ; Vasopressins/*therapeutic use ; }, abstract = {In October of 2010, the American Heart Association (AHA) published the 2010 Guidelines on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. These guidelines place significant emphasis on 5 major areas of therapy in patient with cardiac arrest, including immediate recognition and activation of the emergency response team, effective chest compressions, rapid defibrillation, effective advanced life support (ALS), and integrated postresuscitation care. "Effective ALS" includes the placement of an advanced airway, establishment of parenteral access, and the administration of cardioactive medications. Advanced life support encompasses only 1 of these 5 major areas of cardiac arrest intervention-in sharp contrast to past renditions of the AHA guidelines in which ALS was significantly emphasized. In fact, recent research and the AHA guidelines note that ALS therapy is less important than previously thought. This article will briefly review the evidence regarding the use of the 5 principal medications--epinephrine, vasopressin, atropine, lidocaine, and amiodarone--used in Advanced Cardiac Life Support cardiac arrest algorithm.}, }
@article {pmid21660502, year = {2011}, author = {Bonini, NM and Gitler, AD}, title = {Model organisms reveal insight into human neurodegenerative disease: ataxin-2 intermediate-length polyglutamine expansions are a risk factor for ALS.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {676-683}, pmid = {21660502}, issn = {1559-1166}, support = {DP2 OD004417/OD/NIH HHS/United States ; 1R01NS065317-01/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01-NS043578/NS/NINDS NIH HHS/United States ; 1DP2OD004417-01/OD/NIH HHS/United States ; R01 NS043578/NS/NINDS NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/physiopathology ; Animals ; Ataxins ; DNA-Binding Proteins/genetics/*toxicity ; Disease Models, Animal ; Humans ; Nerve Tissue Proteins/*genetics/metabolism ; Neurodegenerative Diseases/*genetics/pathology/physiopathology ; Peptides/*genetics ; Risk Factors ; Trinucleotide Repeat Expansion/*genetics ; Yeasts/genetics/metabolism ; }, abstract = {Model organisms include yeast Saccromyces cerevisae and fly Drosophila melanogaster. These systems have powerful genetic approaches, as well as highly conserved pathways, both for normal function and disease. Here, we review and highlight how we applied these systems to provide mechanistic insight into the toxicity of TDP-43. TDP-43 accumulates in pathological aggregates in ALS and about half of FTD. Yeast and fly studies revealed an interaction with the counterparts of human Ataxin-2, a gene whose polyglutamine repeat expansion is associated with spinocerebellar ataxia type 2. This finding raised the hypothesis that repeat expansions in ataxin-2 may associate with diseases characterized by TDP-43 pathology such as ALS. DNA analysis of patients revealed that intermediate-length polyglutamine expansions in ataxin-2 are a risk factor for ALS, such that repeat lengths are greater than normal, but lower than that associated with spinocerebellar ataxia type 2 (SCA2), and are more frequent in ALS patients than in matched controls. Moreover, repeat expansions associated with ALS are interrupted CAA-CAG sequences as opposed to the pure CAG repeat expansions typically associated with SCA2. These studies provide an example of how model systems, when extended to human cells and human patient tissue, can reveal new mechanistic insight into disease.}, }
@article {pmid21651477, year = {2011}, author = {Palomo, V and Perez, DI and Gil, C and Martinez, A}, title = {The potential role of glycogen synthase kinase 3 inhibitors as amyotrophic lateral sclerosis pharmacological therapy.}, journal = {Current medicinal chemistry}, volume = {18}, number = {20}, pages = {3028-3034}, doi = {10.2174/092986711796391697}, pmid = {21651477}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/metabolism ; Humans ; Protein Kinase Inhibitors/*chemistry/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Lately, this disease has often been related to the protein kinase called glycogen synthase kinase 3 (GSK-3), through the experimental evidence of alterations of this enzyme on ALS patients. Therefore, there have been several experimental studies using GSK-3 inhibitors, in cellular and animal models and also in clinical studies that showed the potential of the therapeutic role of these molecules. GSK-3 inhibitors might play a pivotal role in the pharmacology of ALS disease with no curative treatment nowadays. In this review we give an overview of the current research in the area, showing all the evidences of the implication of dysfunctional GSK-3 in this disease on one hand, and on the other presenting the potential role of the GSK-3 inhibitors as a future pharmacological ALS therapy.}, }
@article {pmid21646048, year = {2011}, author = {Pignataro, G and Capone, D and Polichetti, G and Vinciguerra, A and Gentile, A and Di Renzo, G and Annunziato, L}, title = {Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: current and emerging therapeutic options.}, journal = {Current opinion in pharmacology}, volume = {11}, number = {4}, pages = {378-394}, doi = {10.1016/j.coph.2011.05.003}, pmid = {21646048}, issn = {1471-4973}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Excitatory Amino Acid Transporter 2/metabolism ; Humans ; Immunosuppressive Agents/*pharmacology ; Neuroprotective Agents/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; TOR Serine-Threonine Kinases/*antagonists &amp; inhibitors/metabolism ; Up-Regulation ; }, abstract = {The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), involved in the control of a wide variety of cellular processes. It has been recently reported that compounds acting modulating mTOR activity, beside mediating the well recognized processes exploited in the anticancer and immunosuppressant effects, are provided with neuroprotective properties. In fact, mTOR is involved in the mechanism of PI3K/Akt-induced upregulation of glutamate transporter 1, GLT1, that is linked to several neuronal disorders such as stroke, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, in adult brain mTOR is crucial for numerous physiological processes such as synaptic plasticity, learning, memory, and brain control of food uptake. Moreover, the activation of mTOR pathway is involved in neuronal development, dendrite development and spine morphogenesis.}, }
@article {pmid21632035, year = {2011}, author = {Garbuzova-Davis, S and Rodrigues, MC and Hernandez-Ontiveros, DG and Louis, MK and Willing, AE and Borlongan, CV and Sanberg, PR}, title = {Amyotrophic lateral sclerosis: a neurovascular disease.}, journal = {Brain research}, volume = {1398}, number = {}, pages = {113-125}, doi = {10.1016/j.brainres.2011.04.049}, pmid = {21632035}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Animals ; Blood-Brain Barrier/metabolism/pathology/physiopathology ; Central Nervous System/*blood supply/metabolism/*physiopathology ; Cerebral Arteries/metabolism/physiopathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated pathogenesis. Compelling evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models, leading to classification of ALS as a neurovascular disease. The present review provides an updated analysis of the normal and impaired BBB/BSCB, focusing on the ALS-altered barrier. Here we describe the roles of cellular components, tight junctions, transport systems, cell interactions, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption, along with recent evidence from experimental and clinical ALS studies. The BBB/BSCB is a promising research area in ALS and this review will reveal some aspects of microvascular pathology in ALS and hopefully provide ideas for the development of new therapeutic strategies.}, }
@article {pmid21631404, year = {2011}, author = {Pizza, V and Agresta, A and D'Acunto, CW and Festa, M and Capasso, A}, title = {Neuroinflamm-aging and neurodegenerative diseases: an overview.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {10}, number = {5}, pages = {621-634}, doi = {10.2174/187152711796235014}, pmid = {21631404}, issn = {1996-3181}, mesh = {Aging/immunology/*physiology ; Brain/immunology/*pathology/physiopathology ; Central Nervous System/immunology/pathology/physiopathology ; Cytokines/*physiology ; Humans ; Neurodegenerative Diseases/*drug therapy/*pathology/physiopathology/psychology ; Neuroimmunomodulation/drug effects/immunology/*physiology ; }, abstract = {Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.}, }
@article {pmid21621298, year = {2012}, author = {Li, J and Pan, P and Song, W and Huang, R and Chen, K and Shang, H}, title = {A meta-analysis of diffusion tensor imaging studies in amyotrophic lateral sclerosis.}, journal = {Neurobiology of aging}, volume = {33}, number = {8}, pages = {1833-1838}, doi = {10.1016/j.neurobiolaging.2011.04.007}, pmid = {21621298}, issn = {1558-1497}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*pathology ; Brain/*pathology ; Diffusion Magnetic Resonance Imaging/*statistics &amp; numerical data ; *Evidence-Based Medicine ; Humans ; Nerve Fibers, Myelinated/*pathology ; Prevalence ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {Studies involving diffusion tensor imaging (DTI) of amyotrophic lateral sclerosis (ALS) with whole-brain voxel-based analysis yielded variable findings. A systematic review was conducted on whole-brain voxel-based diffusion tensor imaging fractional anisotropy (FA) studies of ALS patients and healthy controls (HC) in PubMed, ISI Web of Science, Embase, and MEDLINE databases from 1990 to December 25, 2010. Coordinates were extracted from clusters with significant difference in FA between ALS patients and HC. Meta-analysis was performed using signed differential mapping. Eight studies were enrolled, comprising 143 ALS patients and 145 HC. The included studies reported FA reduction at 67 coordinates in ALS and no FA increased. Significant reductions were present in the bilateral frontal white matter/cingulate gyrus and the posterior limb of bilateral internal capsule. The findings remain largely unchanged in quartile and jackknife sensitivity analyses. Our finding suggests that ALS is a multisystem disease beyond motor dysfunction and provides evidence that FA reduction in the frontal white matter and cingulate gyrus may be a special biomarker of ALS.}, }
@article {pmid21616142, year = {2011}, author = {Batinic-Haberle, I and Rajic, Z and Tovmasyan, A and Reboucas, JS and Ye, X and Leong, KW and Dewhirst, MW and Vujaskovic, Z and Benov, L and Spasojevic, I}, title = {Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics.}, journal = {Free radical biology &amp; medicine}, volume = {51}, number = {5}, pages = {1035-1053}, pmid = {21616142}, issn = {1873-4596}, support = {UL1 RR024128-01/RR/NCRR NIH HHS/United States ; U19 AI067798-05/AI/NIAID NIH HHS/United States ; UL1 RR024128/RR/NCRR NIH HHS/United States ; 1UL 1RR024128-01/RR/NCRR NIH HHS/United States ; P30 CA014236-35/CA/NCI NIH HHS/United States ; P30 CA014236/CA/NCI NIH HHS/United States ; 5-P30-CA14236-35/CA/NCI NIH HHS/United States ; R01 CA040355-28/CA/NCI NIH HHS/United States ; R01 CA040355/CA/NCI NIH HHS/United States ; R01 CA40355/CA/NCI NIH HHS/United States ; U19 AI067798/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/chemistry/pharmacology/*therapeutic use ; Biomimetics/trends ; Brain Injuries/*drug therapy ; Clinical Trials as Topic ; Hematoporphyrins/chemistry/pharmacology/*therapeutic use ; Humans ; Metalloporphyrins/chemistry/pharmacology/*therapeutic use ; Neoplasms/*drug therapy ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Superoxide Dismutase/*chemistry ; }, abstract = {Oxidative stress, a redox imbalance between the endogenous reactive species and antioxidant systems, is common to numerous pathological conditions such as cancer, central nervous system injuries, radiation injury, diabetes etc. Therefore, compounds able to reduce oxidative stress have been actively sought for over 3 decades. Superoxide is the major species involved in oxidative stress either in its own right or through its progeny, such as ONOO[-], H2O2, •OH, CO3•[-], and •NO2. Hence, the very first compounds developed in the late 1970-ies were the superoxide dismutase (SOD) mimics. Thus far the most potent mimics have been the cationic meso Mn(III) N-substituted pyridylporphyrins and N,N'-disubstituted imidazolylporphyrins (MnPs), some of them with k(cat)(O2·[-]) similar to the k(cat) of SOD enzymes. Most frequently studied are ortho isomers MnTE-2-PyP[5+], MnTnHex-2-PyP[5+], and MnTDE-2-ImP[5+]. The ability to disproportionate O2·[-] parallels their ability to remove the other major oxidizing species, peroxynitrite, ONOO[-]. The same structural feature that gives rise to the high k(cat)(O2·[-]) and k(red)(ONOO[-]), allows MnPs to strongly impact the activation of the redox-sensitive transcription factors, HIF-1α, NF-κB, AP-1, and SP-1, and therefore modify the excessive inflammatory and immune responses. Coupling with cellular reductants and other redox-active endogenous proteins seems to be involved in the actions of Mn porphyrins. While hydrophilic analogues, such as MnTE-2-PyP[5+] and MnTDE-2-ImP[5+] are potent in numerous animal models of diseases, the lipophilic analogues, such as MnTnHex-2-PyP[5+], were developed to cross blood brain barrier and target central nervous system and critical cellular compartments, mitochondria. The modification of its structure, aimed to preserve the SOD-like potency and lipophilicity, and diminish the toxicity, has presently been pursued. The pulmonary radioprotection by MnTnHex-2-PyP[5+] was the first efficacy study performed successfully with non-human primates. The Phase I toxicity clinical trials were done on amyotrophic lateral sclerosis patients with N,N'-diethylimidazolium analogue, MnTDE-2-ImP[5+] (AEOL10150). Its aggressive development as a wide spectrum radioprotector by Aeolus Pharmaceuticals has been supported by USA Federal government. The latest generation of compounds, bearing oxygens in pyridyl substituents is presently under aggressive development for cancer and CNS injuries at Duke University and is supported by Duke Translational Research Institute, The Wallace H. Coulter Translational Partners Grant Program, Preston Robert Tisch Brain Tumor Center at Duke, and National Institute of Allergy and Infectious Diseases. Metal center of cationic MnPs easily accepts and donates electrons as exemplified in the catalysis of O2·[-] dismutation. Thus such compounds may be equally good anti- and pro-oxidants; in either case the beneficial therapeutic effects may be observed. Moreover, while the in vivo effects may appear antioxidative, the mechanism of action of MnPs that produced such effects may be pro-oxidative; the most obvious example being the inhibition of NF-κB. The experimental data therefore teach us that we need to distinguish between the mechanism/s of action/s of MnPs and the effects we observe. A number of factors impact the type of action of MnPs leading to favorable therapeutic effects: levels of reactive species and oxygen, levels of endogenous antioxidants (enzymes and low-molecular compounds), levels of MnPs, their site of accumulation, and the mutual encounters of all of those species. The complexity of in vivo redox systems and the complex redox chemistry of MnPs challenge and motivate us to further our understanding of the physiology of the normal and diseased cell with ultimate goal to successfully treat human diseases.}, }
@article {pmid21613656, year = {2011}, author = {Shimatani, Y and Nodera, H and Kaji, R}, title = {[Threshold tracking for beginners].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {63}, number = {6}, pages = {531-538}, pmid = {21613656}, issn = {1881-6096}, mesh = {*Action Potentials ; Amyotrophic Lateral Sclerosis/physiopathology ; Electric Stimulation ; Humans ; Ion Channels/physiology ; Peripheral Nerves/*physiology ; Sensory Thresholds ; }, abstract = {Nerve excitability has been studied for a longer time than has nerve conduction. Prof. Joseph Bergmans pioneered the use of threshold current measurement for studying axonal excitability. However nerve excitability testing has not been used because of technical difficulties. Prof. Hugh Bostock developed a semiautomatic program called QTRAC. This program enables the examiner to perform various nerve excitability tests within 15 min. Nerve excitability testing can provide information regarding physiological conditions, ion channels and the functions of energy-dependent pumps in normal controls and in individuals with diseases such as amyotrophic lateral sclerosis (ALS) and multifocal motor neuropathy (MMN). For understanding threshold tracking, information regarding basic physiological principles including the function of ion channels is required. This review provides important insights on the function of axonal ion channels and investigational methods.}, }
@article {pmid21604203, year = {2011}, author = {Filosto, M and Scarpelli, M and Cotelli, MS and Vielmi, V and Todeschini, A and Gregorelli, V and Tonin, P and Tomelleri, G and Padovani, A}, title = {The role of mitochondria in neurodegenerative diseases.}, journal = {Journal of neurology}, volume = {258}, number = {10}, pages = {1763-1774}, pmid = {21604203}, issn = {1432-1459}, mesh = {Animals ; Humans ; Mitochondria/metabolism/*pathology ; Neurodegenerative Diseases/metabolism/*physiopathology ; }, abstract = {Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field.}, }
@article {pmid21586410, year = {2011}, author = {Magnuson, B and Peppard, A and Auer Flomenhoft, D}, title = {Hypocaloric considerations in patients with potentially hypometabolic disease States.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {26}, number = {3}, pages = {253-260}, doi = {10.1177/0884533611405673}, pmid = {21586410}, issn = {1941-2452}, mesh = {Aging ; Amyotrophic Lateral Sclerosis/diet therapy ; Basal Metabolism ; *Caloric Restriction ; Cerebral Palsy/diet therapy ; Critical Illness ; *Energy Intake ; Energy Metabolism ; Humans ; Long-Term Care ; Nutrition Assessment ; Nutritional Requirements ; *Nutritional Support ; Obesity/diet therapy ; Respiration, Artificial/methods ; Spinal Cord Injuries/diet therapy ; Stroke/diet therapy ; }, abstract = {The provision of nutrition has traditionally been driven by the desire to provide adequate calories. However, over the past decade it has become evident that provision of excess calories can be detrimental to patients' outcomes in both critical care and long-term care settings. This review examines patient populations for whom hypocaloric nutrition can be both appropriate and beneficial. In specific situations, critically ill patients, such as those with obesity, stroke, and spinal cord injury, may have decreased energy requirements. In patients with spinal cord injury, the level of injury significantly correlates with the extent of reduced caloric energy expenditure. Ventilator-dependent patients with amyotrophic lateral sclerosis (ALS) have decreased energy needs; energy expenditure for ALS patients is lower than the predictive equation value. Aging patients will have decreased energy needs relative to a reduction in lean body mass. Patients with cerebral palsy (CP) have significantly lower caloric requirements than anticipated using predictive equations. Patients with CP pose a particular challenge in nutrition assessment. Several studies demonstrate that patients with CP have significantly lower caloric requirements than anticipated using predictive equations; thus, patients with CP benefit from indirect calorimetry. Provision of nutrition for obese patients is briefly addressed, as this is an increasingly important consideration for nutrition support in both the critical care and long-term care settings. When indirect calorimetry is not available, clinicians should remember that most patients will have low resting energy expenditure regardless of functional status and require frequent evaluation during institution of nutrition recommendations to guard against overfeeding and obesity.}, }
@article {pmid21573992, year = {2011}, author = {Naeem, A and Fazili, NA}, title = {Defective protein folding and aggregation as the basis of neurodegenerative diseases: the darker aspect of proteins.}, journal = {Cell biochemistry and biophysics}, volume = {61}, number = {2}, pages = {237-250}, doi = {10.1007/s12013-011-9200-x}, pmid = {21573992}, issn = {1559-0283}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/genetics/*metabolism ; Protein Conformation ; *Protein Folding ; *Protein Multimerization ; Proteins/*chemistry/genetics/metabolism ; *Proteostasis Deficiencies ; }, abstract = {The ability of a polypeptide to fold into a unique, functional, and three-dimensional structure depends on the intrinsic properties of the amino acid sequence, function of the molecular chaperones, proteins, and enzymes. Every polypeptide has a finite tendency to misfold and this forms the darker side of the protein world. Partially folded and misfolded proteins that escape the cellular quality control mechanism have the high tendency to form inter-molecular hydrogen bonding between the same protein molecules resulting in aggregation. This review summarizes the underlying and universal mechanism of protein folding. It also deals with the factors responsible for protein misfolding and aggregation. This article describes some of the consequences of such behavior particularly in the context of neurodegenerative conformational diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and other non-neurodegenerative conformational diseases such as cancer and cystic fibrosis etc. This will encourage a more proactive approach to the early diagnosis of conformational diseases and nutritional counseling for patients.}, }
@article {pmid21563158, year = {2011}, author = {Young, CA and Ellis, C and Johnson, J and Sathasivam, S and Pih, N}, title = {Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {5}, pages = {CD006981}, doi = {10.1002/14651858.CD006981.pub2}, pmid = {21563158}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins/*administration &amp; dosage ; Botulinum Toxins, Type A ; Humans ; Motor Neuron Disease/complications ; Neuromuscular Agents/*administration &amp; dosage ; Parotid Gland ; Randomized Controlled Trials as Topic ; Salivation/drug effects ; Sialorrhea/*drug therapy/etiology ; Submandibular Gland ; }, abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a progressive, neurodegenerative condition which may cause dysphagia, as well as limb weakness, dysarthria, emotional lability and respiratory failure. Since normal salivary production is 0.5 to 1.5 litres daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to patients.<br><br>OBJECTIVES: To systematically review evidence on treatment of sialorrhea in MND, including medications, radiotherapy and surgery.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (1 October 2010), the Cochrane Central Register of Controlled Trials)(CENTRAL) (The Cochrane Library issue 3, 2010), MEDLINE (January 1966 to September 2010), EMBASE (January 1980 to September 2010), AMED (1985 to September 2010) and CINAHL Plus (January 1937 September 2010). All bibliographies of the identified randomized trials were reviewed and authors contacted as needed. Known experts in the field were contacted to identify further published and unpublished papers.<br><br>SELECTION CRITERIA: We included randomized and quasi-randomised controlled studies on any intervention for sialorrhea and related symptoms, in people with MND.<br><br>DATA COLLECTION AND ANALYSIS: Review authors summarised data independently in a customised data collection form and confirmed data presented in Cochrane Review Manager software.<br><br>MAIN RESULTS: Only one randomized controlled trial was identified. This was a well designed study of botulinum toxin B injected into parotid and submandibular glands of 20 patients, which showed positive results for four weeks (Jackson 2009). There was low risk of bias in the study and no significant adverse events reported.<br><br>AUTHORS' CONCLUSIONS: There is some evidence for use of botulinum toxin injections to salivary glands for the treatment of sialorrhea in MND. Further research is required on this important symptom. Data are needed on the problem of sialorrhea in MND and its measurement, both by patient self report measures and objective tests. These will allow the development of better randomized controlled trials.}, }
@article {pmid21555244, year = {2011}, author = {Martin, R and Wächtler, B and Schaller, M and Wilson, D and Hube, B}, title = {Host-pathogen interactions and virulence-associated genes during Candida albicans oral infections.}, journal = {International journal of medical microbiology : IJMM}, volume = {301}, number = {5}, pages = {417-422}, doi = {10.1016/j.ijmm.2011.04.009}, pmid = {21555244}, issn = {1618-0607}, mesh = {Candida albicans/cytology/genetics/metabolism/*pathogenicity ; Candidiasis, Oral/*microbiology ; Epithelial Cells/microbiology ; Gene Expression Profiling ; Gene Expression Regulation, Fungal ; *Host-Pathogen Interactions ; Humans ; Reverse Transcriptase Polymerase Chain Reaction ; Virulence ; Virulence Factors/*biosynthesis ; }, abstract = {Oral infections with Candida albicans are very common diseases in even only mildly immunocompromised patients. By using genome-wide microarrays, in vitro infection models and samples from patients with pseudomembranous candidiasis, several genes have been identified which encode known and unknown fungal factors associated with oral infection. The expression of selected genes has been investigated via qRT-PCR in both in vitro models and in vivo samples from patients. Several lines of evidence suggest that fungal morphology plays a key role in adhesion to and invasion into oral epithelial cells and mutants lacking regulators of hyphal formation are attenuated in their ability to invade and damage epithelial cells. Adhesion is mediated by hyphal-associated factors such as Hwp1 and the Als adhesin family. Hyphal formation facilitates epithelial invasion via two routes: active penetration and induced endocytosis. While induced endocytosis is predominantly mediated by the adhesin and invasin Als3, active penetration seems to be supported by hydrolase activity and mechanical pressure. Expression profiles reflect the morphological switch and an adaptive response to neutral pH, non-glucose carbon sources, and nitrosative stress.}, }
@article {pmid21555177, year = {2011}, author = {Bakalos, G and Mamali, M and Komninos, C and Koukou, E and Tsantilas, A and Tzima, S and Rosenberg, T}, title = {Advanced life support versus basic life support in the pre-hospital setting: a meta-analysis.}, journal = {Resuscitation}, volume = {82}, number = {9}, pages = {1130-1137}, doi = {10.1016/j.resuscitation.2011.04.006}, pmid = {21555177}, issn = {1873-1570}, mesh = {*Advanced Cardiac Life Support ; Cardiopulmonary Resuscitation/methods ; Emergency Medical Services/*methods ; Female ; Greece ; Heart Arrest/*mortality/*therapy ; Humans ; Male ; Risk Assessment ; Survival Analysis ; }, abstract = {BACKGROUND: The scientific evidence of a beneficial effect of ALS in pre-hospital treatment in trauma patients or patients with any acute illness is scarce. The objective of this systematic review of controlled studies was to examine whether ALS, as opposed to BLS, increases patient survival in pre-hospital treatment and if so, to identify the patient groups that gain benefit.<br><br>METHODS: A systematic review of studies published in the databases Medline (PubMed), EMBASE, Cochrane Library and Scopus up to July 31st, 2010. Controlled studies comparing survival after the pre-hospital ALS treatment versus BLS treatment in trauma patients or patients with cardiac arrest were included.<br><br>RESULTS: We identified 1081 studies of which 18 met our inclusion criteria. In nine of 18 studies including 16,857 trauma patients in the intervention group, ALS care did not increase survival compared to BLS treatment (pooled OR 0.892, 95% CI, 0.775-1.026). In nine of 18 studies including 7659 patients with cardiac arrest in the intervention group, ALS care increased survival compared to BLS treatment (OR 1.468, 95% CI, 1.257-1.715). Most subgroup analyses revealed no significant interactions, but data from six trials, where ALS was provided by physicians, increases the probability of survival at hospital discharge even more (OR 2.047, 95% CI 1.593-2.631).<br><br>CONCLUSION: Implementation of ALS care to non-traumatic cardiac arrest patients can increase survival and further research is unlikely to change our confidence in the estimate of the effect. On the contrary, in trauma patients our meta-analysis revealed that ALS care is not associated with increased survival. However, only few controlled studies of sufficient quality and strength examining survival with pre-hospital ALS treatment exist.}, }
@article {pmid21554923, year = {2011}, author = {Hu, WT and Trojanowski, JQ and Shaw, LM}, title = {Biomarkers in frontotemporal lobar degenerations--progress and challenges.}, journal = {Progress in neurobiology}, volume = {95}, number = {4}, pages = {636-648}, pmid = {21554923}, issn = {1873-5118}, support = {P30 AG010124-20/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; AG10124/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; P01 AG017586-12/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/complications ; Biomarkers/*metabolism ; DNA-Binding Proteins/genetics ; *Disease Progression ; *Frontotemporal Lobar Degeneration/diagnosis/genetics/metabolism ; Humans ; Mutation ; Neuroimaging ; RNA-Binding Protein FUS/genetics ; Supranuclear Palsy, Progressive/complications ; tau Proteins/genetics ; }, abstract = {Neuronal and glial changes associated with tau, TAR DNA binding protein of ∼43 kDa (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice.}, }
@article {pmid21550379, year = {2011}, author = {Jeppesen, DK and Bohr, VA and Stevnsner, T}, title = {DNA repair deficiency in neurodegeneration.}, journal = {Progress in neurobiology}, volume = {94}, number = {2}, pages = {166-200}, pmid = {21550379}, issn = {1873-5118}, support = {ZIA AG000723-03/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Aging/metabolism ; Animals ; Brain/metabolism ; DNA Repair ; DNA Repair-Deficiency Disorders/genetics/metabolism/*physiopathology ; Genomic Instability ; Humans ; Neurodegenerative Diseases/etiology/*genetics/metabolism ; Neurons/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.}, }
@article {pmid21537948, year = {2011}, author = {Seyhan, AA}, title = {RNAi: a potential new class of therapeutic for human genetic disease.}, journal = {Human genetics}, volume = {130}, number = {5}, pages = {583-605}, pmid = {21537948}, issn = {1432-1203}, mesh = {Alzheimer Disease/drug therapy/genetics/therapy ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Anemia, Sickle Cell/drug therapy/genetics/therapy ; Animals ; Clinical Trials as Topic ; Genes, Dominant ; Genetic Diseases, Inborn/drug therapy/*therapy ; Genetic Therapy/*methods ; Humans ; Huntington Disease/drug therapy/genetics/therapy ; Mice ; *Molecular Targeted Therapy ; Muscular Dystrophies/drug therapy/genetics/therapy ; Neoplasms/drug therapy/genetics/therapy ; Parkinson Disease/drug therapy/genetics/therapy ; Point Mutation ; *RNA Interference ; Rats ; Spinocerebellar Ataxias/drug therapy/genetics/therapy ; }, abstract = {Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed.}, }
@article {pmid21533607, year = {2011}, author = {Willis, M and Leitner, I and Jellinger, KA and Marksteiner, J}, title = {Chromogranin peptides in brain diseases.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {118}, number = {5}, pages = {727-735}, pmid = {21533607}, issn = {1435-1463}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Brain Diseases/classification/*metabolism ; Chromogranins/*metabolism ; Humans ; Nerve Degeneration/metabolism ; }, abstract = {Synaptic disturbances may play a key role in the pathophysiology of neuropsychiatric diseases. In this article, we review immunohistological findings of chromogranin peptides in neurodegenerative and neurodevelopmental disorders, with particular emphasis on Alzheimer's disease, the disorder chromogranins have been studied most extensively. Data was collected from existing and new experimental data and medline research. This review focuses on synaptic changes elicited by chromogranin peptides immunoreactivity in Alzheimer's disease, as well in schizophrenia and amyotrophic lateral sclerosis (ALS). An imbalanced availability of chromogranin peptides may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Since chromogranin A was postulated as a potent proinflammatory agent, we focused on chromogranin A in neuroinflammation in Alzheimer's disease and ALS. Further understanding of role and function of chromogranin peptides in neuropathological conditions is still required.}, }
@article {pmid21527311, year = {2011}, author = {McGeer, PL and Steele, JC}, title = {The ALS/PDC syndrome of Guam: potential biomarkers for an enigmatic disorder.}, journal = {Progress in neurobiology}, volume = {95}, number = {4}, pages = {663-669}, doi = {10.1016/j.pneurobio.2011.04.001}, pmid = {21527311}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/genetics/*metabolism/pathology ; Biomarkers/*blood/*cerebrospinal fluid ; Environment ; Female ; Guam/epidemiology ; Humans ; Male ; Retinal Detachment/epidemiology/etiology/pathology ; }, abstract = {The ALS/parkinsonism-dementia complex of Guam is a long latency disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. It is remarkably similar to a syndrome localized to the Kii Peninsula of Japan. There are as yet no identified pathological features that will clearly distinguish the Guam or Kii ALS/PDC syndrome from other degenerative neurological disorders. At present, ALS/PDC of Guam and the Kii Peninsula can be confirmed only by postmortem examination. The most prominent pathological hallmark is the widespread occurrence of neurofibrillary tangles which express the same balance of 3R and 4R tau that is found in Alzheimer disease. They both show an increased prevalence of a peculiar retinal disorder termed linear retinal pigmentary epitheliopathy. The disorders are both highly familial. Several environmental factors have been proposed but no supportive evidence for an environmental or dietary factor has been found. Genome searches have so far failed to identify causative genes although two single nuclear polymorphisms related to MAPT that increase the risk of the Guam syndrome have been located. The two syndromes are clearly unique, and clues as to their causation could be beneficial in understanding the etiology of similar, but much more prevalent disorders in North America, Europe and Asia. Identification of biomarkers for premortem diagnosis would be helpful in management as well as in revealing the true etiology.}, }
@article {pmid21511200, year = {2011}, author = {Zinman, L and Cudkowicz, M}, title = {Emerging targets and treatments in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {10}, number = {5}, pages = {481-490}, doi = {10.1016/S1474-4422(11)70024-2}, pmid = {21511200}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/physiopathology ; Animals ; Drug Delivery Systems/*methods/*trends ; Genetic Therapy/*methods/*trends ; Humans ; Riluzole/administration &amp; dosage ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that is currently untreatable. Many compounds have been tested in laboratory-based models and in patients with ALS, but so far only one drug, riluzole, has shown efficacy, yet it only slightly slows disease progression. Several new insights into the causes of motor neuron death have led to the identification of some important novel targets for intervention. At no time have studies involved such a wide range of innovations and such advanced technologies. Many promising studies are underway to test potential targets that will hopefully translate into meaningful therapeutics for patients with ALS.}, }
@article {pmid21495794, year = {2011}, author = {Board, PG}, title = {The omega-class glutathione transferases: structure, function, and genetics.}, journal = {Drug metabolism reviews}, volume = {43}, number = {2}, pages = {226-235}, doi = {10.3109/03602532.2011.561353}, pmid = {21495794}, issn = {1097-9883}, mesh = {Animals ; Arsenicals/metabolism ; Biotransformation ; Catalysis ; *Glutathione Transferase/antagonists &amp; inhibitors/chemistry/genetics/physiology ; Humans ; Ketones/metabolism ; Models, Molecular ; Organ Specificity ; Protein Conformation ; }, abstract = {The omega class of glutathione transferases (GSTs) is a relatively ancient member of the cytosolic GST superfamily, and the omega-class GSTs are found in plants, animals, and some microbial species. The omega-class GSTs exhibit the canonical GST fold, but, unlike other GSTs, the omega-class GSTs have a cysteine residue in their active site. Consequently, the omega-class GSTs catalyze a range of thiol transferase and reduction reactions that are not catalyzed by members of the other classes. Human GSTO1-1 can catalyze the reduction of monomethylarsonic acid (V), but this does not appear to be physiologically important in cases of high environmental arsenic exposure. GSTO1-1 also plays an important role in the biotransformation of reactive α-haloketones to nontoxic acetophenones. Genetic variation is common in the omega-class GST genes, and variants that result in deficiency of GSTO1-1 have been characterized. Genetic linkage studies have discovered associations between GSTO genes and the age at onset of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The mechanism underlying this association with neurological disease may derive from the capacity of omega-class GSTs to mitigate oxidative stress or their role in activating the proinflammatory cytokine, interleukin-1β.}, }
@article {pmid21488479, year = {2011}, author = {Galante, E and Gazzi, L and Caffarra, S}, title = {Psychological activities in neurorehabilitation: from research to clinical practice.}, journal = {Giornale italiano di medicina del lavoro ed ergonomia}, volume = {33}, number = {1 Suppl A}, pages = {A19-28}, pmid = {21488479}, issn = {1592-7830}, mesh = {Biomedical Research ; Humans ; Nervous System Diseases/*psychology/*rehabilitation ; *Psychotherapy ; }, abstract = {The goal of the present review was to present a critical description of psychological research and practice in neurorehabilitation with regard to the efficacy of treatments proposed in the clinical and neuropsychological field. PubMed, Web of Science and Cochrane databases were searched by using the keywords "psychological intervention" and one of the following neurological diseases: "stroke", "TBI", "Parkinson", "ALS", "multiple sclerosis", "dementia". Randomized and pseudo-randomized trials, reviews and single case studies were included. We identified 134 papers: 54 concerning dementia, 24 stroke, 20 multiple sclerosis, 16 Parkinson, 13 TBI and 7 ALS. Most of these papers concern the evaluation of the effectiveness of psychological treatments in chronic or progressive neurological diseases. However, they are often characterized by methodological limitations, such as a small sample size, absence of a follow-up study or a control group. Further, high quality studies could help better understand treatment effects. There was some evidence for effectiveness of cognitive-behavioural and cognitive therapies, often applied both in clinical and neuropsychological interventions. Evidence coming from individualized treatment and single case studies are also described. In line with the data collected, we summarize some evidence available for psychological testing and treatment and argue that a multidisciplinary approach and a multidimensional evaluation should be adopted. According to this position, both randomized trials and single-case studies could be taken into account. Finally, it is proposed that in order to establish the efficacy of a given treatment, both standardized and individualized measures are to be used.}, }
@article {pmid21487518, year = {2011}, author = {Patel, VP and Chu, CT}, title = {Nuclear transport, oxidative stress, and neurodegeneration.}, journal = {International journal of clinical and experimental pathology}, volume = {4}, number = {3}, pages = {215-229}, pmid = {21487518}, issn = {1936-2625}, support = {T32 NS007433/NS/NINDS NIH HHS/United States ; T32GM008208/GM/NIGMS NIH HHS/United States ; T32NS007433/NS/NINDS NIH HHS/United States ; T32 GM008208/GM/NIGMS NIH HHS/United States ; R01 AG026389/AG/NIA NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/physiology ; Cell Nucleus/*metabolism ; Humans ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/*metabolism ; Oxidative Stress/*physiology ; }, abstract = {Trafficking of transcription factors between the cytoplasm and the nucleus is an essential aspect of signal transduction, which is particularly challenging in neurons due to their highly polarized structure. Disruption in the subcellular localization of many proteins, including transcription factors, is observed in affected neurons of human neurodegenerative diseases. In these diseases, there is also growing evidence supporting alterations in nuclear transport as potential mechanisms underlying the observed mislocalization of proteins. Oxidative stress, which plays a key pathogenic role in these diseases, has also been associated with significant alterations in nuclear transport. After providing an overview of the major nuclear import and export pathways and discussing the impact of oxidative injury on nuclear trafficking of proteins, this review synthesizes emerging evidence for altered nuclear transport as a possible mechanism in the pathogenesis of neurodegenerative diseases. Potential strategies to overcome such deficits are also discussed.}, }
@article {pmid21482412, year = {2011}, author = {Sarge, KD and Park-Sarge, OK}, title = {SUMO and its role in human diseases.}, journal = {International review of cell and molecular biology}, volume = {288}, number = {}, pages = {167-183}, doi = {10.1016/B978-0-12-386041-5.00004-2}, pmid = {21482412}, issn = {1937-6448}, support = {GM61053/GM/NIGMS NIH HHS/United States ; GM64606/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; Ataxin-1 ; Ataxins ; *Disease ; Humans ; Huntingtin Protein ; Intracellular Signaling Peptides and Proteins/metabolism ; Neoplasms/metabolism/*physiopathology ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/metabolism/*physiopathology ; Nuclear Proteins/metabolism ; Oncogene Proteins/metabolism ; Protein Deglycase DJ-1 ; Small Ubiquitin-Related Modifier Proteins/genetics/*metabolism ; Sumoylation ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {The covalent attachment of small ubiquition-like modifier (SUMO) polypeptides, or sumoylation, is an important regulator of the functional properties of many proteins. Among these are many proteins implicated in human diseases including cancer and Huntington's, Alzheimer's, and Parkinson's diseases, as well as spinocerebellar ataxia 1 and amyotrophic lateral sclerosis. The results of two more recent studies identify two additional human disease-associated proteins that are sumoylated, amyloid precursor protein (APP), and lamin A. APP sumoylation modulates Aβ peptide levels, suggesting a potential role in Alzheimer's disease, and decreased lamin A sumoylation due to mutations near its SUMO site has been implicated in causing some forms of familial dilated cardiomyopathy.}, }
@article {pmid21476614, year = {2011}, author = {Garnock-Jones, KP}, title = {Dextromethorphan/quinidine: in pseudobulbar affect.}, journal = {CNS drugs}, volume = {25}, number = {5}, pages = {435-445}, pmid = {21476614}, issn = {1179-1934}, mesh = {Amyotrophic Lateral Sclerosis/*complications/psychology ; Crying ; Dextromethorphan/adverse effects/pharmacokinetics/*therapeutic use ; Drug Combinations ; Emotions ; Female ; Humans ; Laughter ; Male ; Mood Disorders/*complications/*drug therapy ; Multiple Sclerosis/*complications/psychology ; Quinidine/adverse effects/pharmacokinetics/*therapeutic use ; }, abstract = {Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the patient and occurs in patients with neurological disorders, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis or traumatic brain injury. Dextromethorphan/quinidine is indicated in the US for the treatment of pseudobulbar affect. Dextromethorphan, when its metabolism is inhibited by the coadministration of quinidine, has been shown to have a positive effect on the symptoms of pseudobulbar affect. Dextromethorphan/quinidine 20 mg/10 mg twice daily was associated with a significantly greater decrease in the rate of pseudobulbar affect episodes per day (primary endpoint) than placebo in the 12-week, randomized, double-blind, placebo-controlled, multicentre STAR trial (Safety, Tolerability, And efficacy Results trial of AVP-923 in PBA [pseudobulbar affect]) involving patients with pseudobulbar affect and ALS or multiple sclerosis. Moreover, the mean change from baseline in Center for Neurologic Study-Lability Scale score at 12 weeks was significantly greater among recipients of dextromethorphan/quinidine 20 mg/10 mg twice daily than those receiving placebo. Dextromethorphan/quinidine 20 mg/10 mg twice daily was generally well tolerated. The drug has been shown to cause dosage-dependent corrected QT interval (QTc) prolongation; however, in the STAR trial, dextromethorphan/quinidine 20 mg/10 mg twice daily appeared to be well tolerated with regard to QTc prolongation.}, }
@article {pmid21473943, year = {2011}, author = {Krishnamurthy, PK and Sigurdsson, EM}, title = {Therapeutic applications of antibodies in non-infectious neurodegenerative diseases.}, journal = {New biotechnology}, volume = {28}, number = {5}, pages = {511-517}, pmid = {21473943}, issn = {1876-4347}, support = {R01 AG032611/AG/NIA NIH HHS/United States ; R01 AG020197/AG/NIA NIH HHS/United States ; R01 NS077239/NS/NINDS NIH HHS/United States ; R01 AG020197-06A2/AG/NIA NIH HHS/United States ; AG032611/AG/NIA NIH HHS/United States ; R01 AG020197-01/AG/NIA NIH HHS/United States ; R01 AG032611-01/AG/NIA NIH HHS/United States ; AG020197/AG/NIA NIH HHS/United States ; DK075494/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antibodies/immunology/*therapeutic use ; Disease Progression ; Humans ; Immunologic Techniques ; Immunotherapy ; Neurodegenerative Diseases/*drug therapy/immunology/pathology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS) are all characterised histologically by the presence of deposits of misfolded proteins, tau and amyloid-β, α-synuclein, huntingtin or superoxide dismutase, respectively. Currently, these illnesses do not have any disease modifying treatment options. A novel therapeutic strategy that is being pursued is immunomodulation, which is using the body's immune system to target the self-proteins that are deposited. Most of these promising approaches are still in preclinical development while some have progressed to Phase III clinical trials. As new insights are gained, it is hoped that these immunotherapies will be effective tools at slowing the progression of these debilitating diseases.}, }
@article {pmid21473899, year = {2011}, author = {Lopes, JP and Agostinho, P}, title = {Cdk5: multitasking between physiological and pathological conditions.}, journal = {Progress in neurobiology}, volume = {94}, number = {1}, pages = {49-63}, doi = {10.1016/j.pneurobio.2011.03.006}, pmid = {21473899}, issn = {1873-5118}, mesh = {Animals ; *Brain Diseases/enzymology/pathology/physiopathology ; Cell Cycle/physiology ; *Central Nervous System/enzymology/pathology/physiopathology ; Cyclin-Dependent Kinase 5/*metabolism ; Humans ; Models, Biological ; Synapses/metabolism/pathology/physiology ; }, abstract = {Cyclin-dependent kinase 5 (Cdk5) is a peculiar proline-directed serine/threonine kinase. Unlike the other members of the Cdk family, Cdk5 is not directly involved in cell cycle regulation, being normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity. This kinase is present mainly in post-mitotic neurons and its activity is tightly regulated by the interaction with the specific activators, p35 and p39. Despite its pivotal role in CNS development, Cdk5 dysregulation has been implicated in different pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and, most recently, prion-related encephalopathies (PRE). In these neurodegenerative conditions, Cdk5 overactivation and relocalization occurs upon association with p25, a truncated form of the normal activator p35. This activator switching will cause a shift in the phosphorylative pattern of Cdk5, with an alteration both in targets and activity, ultimately leading to neuronal demise. In AD and PRE, two disorders that share clinical and neuropathological features, Cdk5 dysregulation is a linking event between the major neuropathological markers: amyloid plaques, tau hyperphosphorylation and synaptic and neuronal loss. Moreover, this kinase was shown to be involved in abortive cell cycle re-entry, a feature recently proposed as a possible step in the neuronal apoptosis mechanism of several neurological diseases. This review focuses on the role of Cdk5 in neurons, namely in the regulation of cytoskeletal dynamics, synaptic function and cell survival, both in physiological and in pathological conditions, highlighting the relevance of Cdk5 in the main mechanisms of neurodegeneration in Alzheimer's disease and other brain pathologies.}, }
@article {pmid21470101, year = {2011}, author = {Reddy, PH and Reddy, TP}, title = {Mitochondria as a therapeutic target for aging and neurodegenerative diseases.}, journal = {Current Alzheimer research}, volume = {8}, number = {4}, pages = {393-409}, pmid = {21470101}, issn = {1875-5828}, support = {RR00163/RR/NCRR NIH HHS/United States ; R03 AG026051/AG/NIA NIH HHS/United States ; P51 RR000163-51/RR/NCRR NIH HHS/United States ; AG020872/AG/NIA NIH HHS/United States ; AG025061/AG/NIA NIH HHS/United States ; P51 RR000163/RR/NCRR NIH HHS/United States ; R03 AG026051-02/AG/NIA NIH HHS/United States ; R01 AG028072-04/AG/NIA NIH HHS/United States ; R01 AG028072/AG/NIA NIH HHS/United States ; K01 RR000163/RR/NCRR NIH HHS/United States ; }, mesh = {Aging/pathology/physiology ; Animals ; Brain/*ultrastructure ; DNA, Mitochondrial/*physiology ; Humans ; Mitochondria/*pathology ; Mitochondrial Diseases/*etiology ; Models, Biological ; Neurodegenerative Diseases/*complications/pathology ; }, abstract = {Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases.}, }
@article {pmid21460436, year = {2011}, author = {Gadad, BS and Britton, GB and Rao, KS}, title = {Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {24 Suppl 2}, number = {}, pages = {223-232}, doi = {10.3233/JAD-2011-110182}, pmid = {21460436}, issn = {1875-8908}, mesh = {Amyloid beta-Peptides/*metabolism ; Animals ; Humans ; Models, Biological ; Neurodegenerative Diseases/*metabolism/*therapy ; alpha-Synuclein/*metabolism ; tau Proteins/*metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and amyotrophic lateral sclerosis are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as 'soluble oligomers' in the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics.}, }
@article {pmid21458831, year = {2011}, author = {Alvarez-Uría Tejero, MJ and Sáiz Ayala, A and Fernández Rey, C and Santamarta Liébana, ME and Costilla García, S}, title = {[Diagnosis of amyotrophic lateral sclerosis: advances in magnetic resonance imaging].}, journal = {Radiologia}, volume = {53}, number = {2}, pages = {146-155}, doi = {10.1016/j.rx.2010.10.004}, pmid = {21458831}, issn = {1578-178X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; *Magnetic Resonance Imaging ; }, abstract = {Amyotrophic lateral sclerosis is a chronic progressive neurodegenerative disease of unknown etiology. It selectively affects both upper and lower motor neurons. Nowadays, amyotrophic lateral sclerosis is diagnosed on the basis of clinical and electromyographic findings and by ruling out other diseases with similar symptoms. To date, there are no specific tests or biologic markers to confirm the diagnosis. This article discusses new MRI techniques like magnetization transfer imaging, MR spectroscopy, functional MRI, diffusion tensor imaging, and volumetric techniques that can contribute to early confirmation of the diagnosis and to the follow-up of this disease. We review the usefulness of each of these techniques and discuss their possible applications in clinical practice.}, }
@article {pmid21455838, year = {2011}, author = {Naganska, E and Matyja, E}, title = {Amyotrophic lateral sclerosis - looking for pathogenesis and effective therapy.}, journal = {Folia neuropathologica}, volume = {49}, number = {1}, pages = {1-13}, pmid = {21455838}, issn = {1509-572X}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/pathology/therapy ; Humans ; Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons in the spinal cord, brain stem and motor cortex which dramatically reduces life expectancy. ALS occurs either in familial or, more frequently, in sporadic forms. It finally results in death due to respiratory failure that occurs typically 2-5 years after the disease onset. Although the aetiology of ALS remains largely unclear, its heterogeneity suggests that a combination of various factors, including endogenous and/or environmental ones, may be implicated in progressive motor neuron stress that results in the activation of different cell death pathways. Interactions between genetic, environmental, and age-dependent risk factors have been hypothesized to trigger disease onset. Despite extensive neurobiological, molecular and genetic research, at the beginning of the 21st century ALS still remains one of the most devastating neurodegenerative diseases because of the lack of effective therapeutic strategies. It is a challenge for the clinical and scientific community. Better understanding of the aetiology of amyotrophic lateral sclerosis is necessary to develop effective treatment of this progressive neurodegenerative disease. This review presents the current state of knowledge in ALS research.}, }
@article {pmid21453285, year = {2011}, author = {McCown, TJ}, title = {Adeno-Associated Virus (AAV) Vectors in the CNS.}, journal = {Current gene therapy}, volume = {11}, number = {3}, pages = {181-188}, doi = {10.2174/156652311795684759}, pmid = {21453285}, issn = {1875-5631}, support = {NS 35633/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/*virology ; Central Nervous System Diseases/*therapy ; Dependovirus/*genetics ; Genetic Therapy/*methods ; *Genetic Vectors ; Humans ; }, abstract = {Adeno-associated virus (AAV) vectors exhibit a number of properties that have made this vector system an excellent choice for both CNS gene therapy and basic neurobiological investigations. In vivo, the preponderance of AAV vector transduction occurs in neurons where it is possible to obtain long-term, stable gene expression with very little accompanying toxicity. Promoter selection, however, significantly influences the pattern and longevity of neuronal transduction distinct from the tropism inherent to AAV vectors. AAV vectors have successfully manipulated CNS function using a wide variety of approaches including expression of foreign genes, expression of endogenous genes, expression of antisense RNA and expression of RNAi. With the discovery and characterization of different AAV serotypes, as well as the creation of novel chimeric serotypes, the potential patterns of in vivo vector transduction have been expanded substantially, offering alternatives to the more studied AAV 2 serotype. Furthermore, the development of specific AAV chimeras offers the potential to further refine targeting strategies. These different AAV serotypes also provide a solution to the immune silencing that proves to be a realistic likelihood given broad exposure of the human population to the AAV 2 serotype. These advantageous CNS properties of AAV vectors have fostered a wide range of clinically relevant applications including Parkinson's disease, lysosomal storage diseases, Canavan's disease, epilepsy, Huntington's disease and ALS. In many cases the proposed therapies have progressed to phase I/II clinical trials. Each individual application, however, presents a unique set of challenges that must be solved in order to attain clinically effective gene therapies.}, }
@article {pmid21448659, year = {2011}, author = {Beal, MF}, title = {Neuroprotective effects of creatine.}, journal = {Amino acids}, volume = {40}, number = {5}, pages = {1305-1313}, doi = {10.1007/s00726-011-0851-0}, pmid = {21448659}, issn = {1438-2199}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/antagonists &amp; inhibitors ; Animals ; Creatine/administration &amp; dosage/*pharmacology ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Nitro Compounds/antagonists &amp; inhibitors ; Propionates/antagonists &amp; inhibitors ; }, abstract = {There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic lesions produced by N-methyl-D: -aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the R6/2 and the N-171-82Q transgenic mouse models of Huntington's disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine, however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical trials for the treatment of Parkinson's disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson's Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases.}, }
@article {pmid21446901, year = {2011}, author = {Starakis, I and Panos, G and Koutras, A and Mazokopakis, EE}, title = {Pathogens and chronic or long-term neurologic disorders.}, journal = {Cardiovascular &amp; hematological disorders drug targets}, volume = {11}, number = {1}, pages = {40-52}, doi = {10.2174/187152911795945123}, pmid = {21446901}, issn = {2212-4063}, mesh = {Chronic Disease ; Humans ; Infections/*complications ; Mental Disorders/*microbiology ; Neurodegenerative Diseases/*microbiology ; }, abstract = {Infections of the central nervous system may provoke glial and autoimmune responses but a definitive linkage between these infections and the pathogenesis of chronic neurologic disorders is still elusive. There are controversial reports implicating infectious agents in the pathogenetic mechanisms of chronic or long-term neurologic disorders, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and autistic spectrum disorders, but the specific role of bacterial or viral infections in the pathogenesis of these medical entities has not been fully elucidated. Up till now, the evidence is distant from definite, but certain cases may be attributed to infections in the millieu of multiple toxic events such as trauma, nutritional deficits, immune dysregulation and excitotoxicity in genetically vulnerable indiniduals. There is an ongoing debate concering the direct involvement of various infectious agents in the neurodegenerative and neurobehavioral diseases pathogenesis and/or their contribution to the deterioration of the disease or co-morbidity in these patients. These patients are exceptionally difficult to be treated by using single therapeutic modalities, because their disese is multifocal and treatment is aimed to control signs and symptoms rather than the true causes of the disease and its progressive course. Furthermore, even if these causative links were indetifiable, our therapeutic interventions would come too late due to the irreversible damages at the time of the initiation of treatment. Our aim is to comprehensively review all available data suggesting that infections could be common antecedent events of progressive neurologic degenerative or behavioural diseases.}, }
@article {pmid21443969, year = {2011}, author = {Cifra, A and Nani, F and Nistri, A}, title = {Respiratory motoneurons and pathological conditions: lessons from hypoglossal motoneurons challenged by excitotoxic or oxidative stress.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {179}, number = {1}, pages = {89-96}, doi = {10.1016/j.resp.2011.03.017}, pmid = {21443969}, issn = {1878-1519}, mesh = {Animals ; Excitatory Amino Acid Agents/*toxicity ; Humans ; Hypoglossal Nerve/drug effects/*pathology/physiology ; Motor Neurons/drug effects/*pathology/physiology ; Neurodegenerative Diseases/chemically induced/*pathology/physiopathology ; Oxidative Stress/drug effects/*physiology ; Respiratory Mechanics/drug effects/*physiology ; }, abstract = {Hypoglossal motoneurons (HMs) are respiration-related brainstem neurons that command rhythmic contraction of the tongue muscles in concert with the respiratory drive. In experimental conditions, HMs can exhibit a range of rhythmic patterns that may subserve different motor outputs and functions. Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS; Lou-Gehrig disease) often damage HMs with distressing symptoms like dysarthria, dysphagia and breathing difficulty related to degeneration of respiratory motoneurons. While the cause of ALS remains unclear, early diagnosis remains an important goal for potential treatment because fully blown clinical symptoms appear with degeneration of about 30% motoneurons. Using a simple in vitro model of the rat brainstem to study the consequences of excitotoxicity or oxidative stress (believed to occur during the onset of ALS) on HMs, it is possible to observe distinct electrophysiological effects associated with HM experimental pathology. In fact, excitotoxicity caused by glutamate uptake block triggers sustained bursting and enhanced synaptic transmission, whereas oxidative stress generates slow depolarization, augmented repeated firing, and decreased synaptic transmission. In either case, only a subpopulation of HMs shows abnormal functional changes. Although these two insults induce separate functional signatures, the consequences on HMs after a few hours are similar and are preceded by activation of the stress transcription factor ATF-3. The deleterious action of excitotoxicity is inhibited by early administration of riluzole, a drug currently employed for the symptomatic treatment of ALS, demonstrating that this in vitro model can be useful for testing potential neuroprotective agents.}, }
@article {pmid21441972, year = {2011}, author = {Chen, C and Xiao, SF}, title = {Induced pluripotent stem cells and neurodegenerative diseases.}, journal = {Neuroscience bulletin}, volume = {27}, number = {2}, pages = {107-114}, pmid = {21441972}, issn = {1995-8218}, mesh = {Animals ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/*physiology/*transplantation ; Neurodegenerative Diseases/*surgery ; }, abstract = {Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis, are characterized by idiopathic neuron loss in different regions of the central nervous system, which contributes to the relevant dysfunctions in the patients. The application of cell replacement therapy using human embryonic stem (hES) cells, though having attracted much attention, has been hampered by the intrinsic ethical problems. It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state, called induced pluripotent stem (iPS) cells. It is soon realized that iPS cells may be an alternative source for cell replacement therapy, because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection. What's more, certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes. Thus, patient-specific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient, and to study the vulnerability of neural cells to pathogenic factors in vitro, which may help reveal the pathogenesis of many neurodegenerative diseases. In this review, the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized, and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.}, }
@article {pmid21441485, year = {2011}, author = {Martin, JN}, title = {Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and Kaposi sarcoma.}, journal = {Advances in dental research}, volume = {23}, number = {1}, pages = {76-78}, doi = {10.1177/0022034511399913}, pmid = {21441485}, issn = {1544-0737}, mesh = {Africa ; Castleman Disease/virology ; Herpesvirus 8, Human/*pathogenicity ; *Homosexuality, Male ; Humans ; Immunocompromised Host ; Male ; Middle East ; Saliva/*virology ; Sarcoma, Kaposi/*virology ; Sexual Behavior ; }, abstract = {Kaposi sarcoma-associated herpesvirus (KSHV) was discovered in 1994 and is now known to be a necessary but not sufficient causative agent of Kaposi sarcoma. While KSHV is likely also the causative agent of primary effusion lymphoma and multicentric Castleman's disease, its causal role has been refuted in the case of multiple myeloma, sarcoidosis, prostate cancer, and amyotrophic lateral sclerosis. The epidemiology of KSHV is both intriguing and challenging. Two epidemiologic findings are clear, but their explanation is unknown. The first is that KSHV is distributed disparately throughout the world, with the virus being common in the general population throughout Africa and the Middle East, but uncommon virtually everywhere else. The second is that even though the virus is uncommon in the general population in industrialized settings, it is disproportionately concentrated among homosexual men in these areas. KSHV has special importance to the dental profession because saliva is the body fluid that harbors it most commonly, although exactly in which ways saliva spreads the virus are not known.}, }
@article {pmid21429918, year = {2011}, author = {Bowers, WJ and Breakefield, XO and Sena-Esteves, M}, title = {Genetic therapy for the nervous system.}, journal = {Human molecular genetics}, volume = {20}, number = {R1}, pages = {R28-41}, pmid = {21429918}, issn = {1460-2083}, support = {R01-AG026328/AG/NIA NIH HHS/United States ; NS242791/NS/NINDS NIH HHS/United States ; U01NS064096/NS/NINDS NIH HHS/United States ; R01NS066310/NS/NINDS NIH HHS/United States ; CA069246/CA/NCI NIH HHS/United States ; R01HD060576/HD/NICHD NIH HHS/United States ; }, mesh = {Alzheimer Disease/therapy ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Lysosomal Storage Diseases/therapy ; Nervous System Diseases/*therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; RNA Splicing ; }, abstract = {Genetic therapy is undergoing a renaissance with expansion of viral and synthetic vectors, use of oligonucleotides (RNA and DNA) and sequence-targeted regulatory molecules, as well as genetically modified cells, including induced pluripotent stem cells from the patients themselves. Several clinical trials for neurologic syndromes appear quite promising. This review covers genetic strategies to ameliorate neurologic syndromes of different etiologies, including lysosomal storage diseases, Alzheimer's disease and other amyloidopathies, Parkinson's disease, spinal muscular atrophy, amyotrophic lateral sclerosis and brain tumors. This field has been propelled by genetic technologies, including identifying disease genes and disruptive mutations, design of genomic interacting elements to regulate transcription and splicing of specific precursor mRNAs and use of novel non-coding regulatory RNAs. These versatile new tools for manipulation of genetic elements provide the ability to tailor the mode of genetic intervention to specific aspects of a disease state.}, }
@article {pmid21425112, year = {2011}, author = {Soler, B and Fadic, R and von Bernhardi, R}, title = {[Stem cells therapy in amyotrophic lateral sclerosis treatment. A critical view].}, journal = {Revista de neurologia}, volume = {52}, number = {7}, pages = {426-434}, pmid = {21425112}, issn = {1576-6578}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*surgery ; Animals ; Cell- and Tissue-Based Therapy/*methods ; Clinical Trials as Topic ; Disease Progression ; Humans ; Mesenchymal Stem Cells/cytology/*physiology ; *Stem Cell Transplantation ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. At present, there are not curative therapies for ALS. Pathogenic and progression mechanisms suggest the existence of oxidative stress, abnormal intracellular protein aggregation, mitochondrial dysfunction, axonal transport impairment, impairment of trophic support, altered glial cell function, and glutamate excitoxicity.<br><br>AIM: To evaluate therapeutic results with adult stem cell for ALS treatment.<br><br>DEVELOPMENT: Stem cells represent a potential therapeutic strategy, because their biological mechanisms could act on several of the pathogenic mechanisms proposed for ALS. Bone marrow mesenchymal stem cells are especially interesting among adult stem cells. Mesenchymal stem cells can differentiate in all central nervous system cells and potentially replace them. Furthermore, they have immunomodulatory effects, secreting, especially in neuroinflammatory environments, neurotrophic and antiinflammatory factors. Studies in murine models of ALS show decrease of inflammation and disease progression, and increase on animal highly heterogeneous, suggest that mesenchymal stem cells transplant in ALS appears to be safe. However, they fail showing clinical improvement of patients.<br><br>CONCLUSION: Additional preclinical studies are necessary to refine this therapeutic approach, to assess long term survival and differentiation of mesenchymal stem cells, dosing, biological activity and safety should be conducted before any planning further human testing occurs.}, }
@article {pmid21412722, year = {2011}, author = {Carlesi, C and Pasquali, L and Piazza, S and Lo Gerfo, A and Caldarazzo Ienco, E and Alessi, R and Fornai, F and Siciliano, G}, title = {Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {151-167}, doi = {10.4449/aib.v149i1.1267}, pmid = {21412722}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; Humans ; *Nerve Degeneration/diagnosis/etiology/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration.}, }
@article {pmid21412720, year = {2011}, author = {Pizzuti, A and Petrucci, S}, title = {Mitochondrial disfunction as a cause of ALS.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {113-119}, doi = {10.4449/aib.v149i1.1266}, pmid = {21412720}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology ; Animals ; Axonal Transport/physiology ; Calcium/metabolism ; Energy Metabolism/physiology ; Humans ; Mitochondria/*pathology/physiology/ultrastructure ; Mitochondrial Diseases/*complications ; Organelle Biogenesis ; }, abstract = {Recent studies on patient with sporadic ALS and on in vitro and in vivo models of mendelian diseases have been addressed toward the unravelling of the mitochondrial behaviour in ALS, whether as a primarily pathogenic factor, or as a fundamental contributor to the cell death. Morphological evidence suggests mitochondria pathology in ALS and many physiological mechanisms involving these organelles appear deranged in ALS, such as energy production, apoptotic triggering, calcium homeostasis and axonal transport of mitochondria. The article briefly addresses recent advances on this field.}, }
@article {pmid21412718, year = {2011}, author = {Colombrita, C and Onesto, E and Tiloca, C and Ticozzi, N and Silani, V and Ratti, A}, title = {RNA-binding proteins and RNA metabolism: a new scenario in the pathogenesis of Amyotrophic lateral sclerosis.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {83-99}, doi = {10.4449/aib.v149i1.1261}, pmid = {21412718}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; DNA-Binding Proteins/genetics ; Humans ; Models, Biological ; RNA/*metabolism ; RNA-Binding Protein FUS/genetics ; RNA-Binding Proteins/*genetics/*metabolism ; }, abstract = {Several RNA-processing genes have been implicated in the pathogenesis of Amyotrophic lateral sclerosis (ALS). In particular, causative mutations in the genes encoding for two DNA/RNA binding proteins, TAR DNA binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), were recently identified in ALS patients. These genetic findings and the presence of abnormal aggregates of these two RNA-binding proteins in ALS affected tissues suggest that molecular mechanisms regulating RNA metabolism are implicated in ALS pathogenesis through common pathways. In this review similarities and differences between TDP-43 and FUS/TLS proteins and their activities in physiological and pathological conditions will be discussed.}, }
@article {pmid21412717, year = {2011}, author = {Ticozzi, N and Tiloca, C and Morelli, C and Colombrita, C and Poletti, B and Doretti, A and Maderna, L and Messina, S and Ratti, A and Silani, V}, title = {Genetics of familial Amyotrophic lateral sclerosis.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {65-82}, doi = {10.4449/aib.v149i1.1262}, pmid = {21412717}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Brain/pathology ; DNA-Binding Proteins/genetics ; *Family Health ; Genetic Predisposition to Disease/*genetics ; Humans ; Motor Neurons/pathology ; Mutation/*genetics ; RNA-Binding Protein FUS/genetics ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurodegenerative disease, caused by the loss of motor neurons in the brain and spinal cord. About 10% of all ALS cases are familial (FALS), and constitute a clinically and genetically heterogeneous entity. To date, FALS has been linked to mutations in 10 different genes and to four additional chromosomal loci. Research on FALS genetics, and in particular the discoveries of mutations in the SOD1, TARDBP, and FUS genes, has provided essential information toward the understanding of the pathogenesis of ALS in general. This review presents a tentative classification of all FALS-associated genes identified so far.}, }
@article {pmid21412716, year = {2011}, author = {Inghilleri, M and Iacovelli, E}, title = {Clinical neurophysiology in ALS.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {57-63}, doi = {10.4449/aib.v149i1.1264}, pmid = {21412716}, issn = {0003-9829}, mesh = {Action Potentials/physiology ; Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Electrophysiological Phenomena/*physiology ; Humans ; Neural Conduction/physiology ; Neurophysiology/*methods ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) belongs to a group of disorders known as motor neuron diseases. Despite being one of the most devastating diseases known, there is little evidence for diagnosing and managing patients with ALS. Clinical neurophysiologic tests are essential, when no biological marker exists to aid early diagnosis, not only in relation to diagnosis, but also in the development of disease progression, and perhaps, in the future, in measuring patients' response to therapy. The electrophysiological features used in the diagnosis of ALS are based on Awaji-shima consensus recommendations for the application of electrophysiological tests, as applied to the revised El Escorial Criteria. Measurements of axonal excitability through nerve conduction study (ENG) is useful to evaluate axonal degeneration. Electromyography (EMG) recordings with needle examination are essential for confirming lower motor neuron involvement in the initial diagnosis of ALS. EMG abnormalities are frequent and these include fibrillation potentials or positive sharp wave potentials, or both, with fasciculation potentials in resting muscle, and an incomplete interference pattern, with abnormal motor unit potentials. Collateral or terminal nerve sprouting is common in ALS and is frequent large macro-motor unit potentials (MUPs). Motor unit number estimation (MUNE) may be useful in measuring loss of functioning motor units and is an attractive endpoint measure in clinical drug trials in ALS because it directly assesses loss of lower motor neurons and is sensitive to disease progression. Transcortical magnetic stimulation protocols, and cortical excitability may be useful to assess the involvement of upper motor neuron system. In this chapter the advantages, limitations and promise of these various methods are discussed, in order to indicate the direction for further neurophysiological studies in this disorder.}, }
@article {pmid21412714, year = {2011}, author = {Meininger, V}, title = {ALS, what new 144 years after Charcot?.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {29-37}, doi = {10.4449/aib.v149i1.1265}, pmid = {21412714}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*history/metabolism ; Biomarkers ; Diagnostic Imaging ; History, 19th Century ; History, 20th Century ; History, 21st Century ; Humans ; Neurophysiology ; }, abstract = {The most important challenge of ALS remains finding biomarkers. Clinical features remain of key importance in the diagnosis and for follow up. Neurophysiology remains difficult to use in clinical trials. Neuroimaging have some utility for upper motor neuron integrity and function. Among proteins and chemical markers, one of the most promising marker is the level of Nogo in muscle biopsy. In CSF, many candidate proteins have been suggested but their sensitivity and specificity remains disappointing. Recently, -omics technologies have been applied to try to discover biomarkers in ALS, including genomic, proteomic and metabolomic methodologies.}, }
@article {pmid21412713, year = {2011}, author = {Silani, V and Messina, S and Poletti, B and Morelli, C and Doretti, A and Ticozzi, N and Maderna, L}, title = {The diagnosis of Amyotrophic lateral sclerosis in 2010.}, journal = {Archives italiennes de biologie}, volume = {149}, number = {1}, pages = {5-27}, doi = {10.4449/aib.v149i1.1260}, pmid = {21412713}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/classification/complications/*diagnosis/genetics ; Biomarkers ; Cognition Disorders/diagnosis/etiology/genetics ; DNA-Binding Proteins/metabolism ; Early Diagnosis ; Humans ; Motor Neuron Disease ; Ubiquitin/metabolism ; }, abstract = {The diagnosis of Amyotrophic lateral sclerosis (ALS) remains in 2010 clinical with neurophysiological support in absence of specific biomarker(s). The disease is diverse in its presentation, cause, and progression. Treatable mimic syndromes must be excluded before the diagnosis is ascribed: ALS and its variants are recognized by neurologists, but 10% of patients are misdiagnosed. Delays in diagnosis are common. Less than 10% of cases are familial and associated with several interactive genes. The onset of ALS predates development of the clinical symptoms by an unknown interval which may extend several years. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and family, a positive care plan are pre-requisites for the good clinical management of ALS patients.}, }
@article {pmid21396632, year = {2012}, author = {Tsermentseli, S and Leigh, PN and Goldstein, LH}, title = {The anatomy of cognitive impairment in amyotrophic lateral sclerosis: more than frontal lobe dysfunction.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {48}, number = {2}, pages = {166-182}, doi = {10.1016/j.cortex.2011.02.004}, pmid = {21396632}, issn = {1973-8102}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*pathology/*psychology ; Behavior ; Cognition Disorders/etiology/*pathology/*psychology ; Diffusion Tensor Imaging ; Frontal Lobe/*pathology ; Humans ; Magnetic Resonance Imaging ; Neural Pathways/pathology ; Neuropsychological Tests ; Temporal Lobe/pathology ; }, abstract = {Cognitive and behavioural impairments accompanying amyotrophic lateral sclerosis (ALS) have been reported since the early 20th century. Typically, these changes can be associated with a dysexecutive syndrome or manifest as a frontotemporal dementia (FTD). Although the nature of specific frontotemporal dysfunction in ALS remains to be refined, as with the clinical presentation, there is likely to be significant heterogeneity. This article will review the current state of knowledge regarding the neuropathological and neuroanatomical basis for cognitive dysfunction in ALS. Neuropathological findings suggest that ALS does not selectively affect the frontotemporal network but rather is part of a broad clinico-pathological spectrum now known as TAR-DNA binding protein (TDP)-43 proteinopathies. Functional neuroimaging has supported neuropsychological findings of frontotemporal dysfunction but has also implied the involvement of somatosensory areas. Structural neuroimaging has not been able to establish a specific hypothesis of extra-motor cortical atrophy beyond the combination of various frontal, temporal and limbic areas. The finding of reduction in the integrity of white matter in the frontal, temporal and parietal lobes including long association fibers suggests that subcortical involvement may underlie both cognitive and functional changes in ALS. Future perspectives for further investigations are highlighted.}, }
@article {pmid21396577, year = {2011}, author = {Domené, HM and Hwa, V and Jasper, HG and Rosenfeld, RG}, title = {Acid-labile subunit (ALS) deficiency.}, journal = {Best practice &amp; research. Clinical endocrinology &amp; metabolism}, volume = {25}, number = {1}, pages = {101-113}, doi = {10.1016/j.beem.2010.08.010}, pmid = {21396577}, issn = {1878-1594}, mesh = {Adolescent ; Animals ; Carrier Proteins/genetics ; Child ; Female ; Glycoproteins/*deficiency/genetics ; Growth Disorders/physiopathology ; Humans ; Insulin Resistance/physiology ; Insulin-Like Growth Factor Binding Protein 3/blood/deficiency ; Insulin-Like Growth Factor I/metabolism ; Male ; Mice ; }, abstract = {The acid-labile subunit (ALS) protein is crucial for maintaining the integrity of the circulating IGF/IGFBP system. In humans, complete ALS deficiency is characterized by severely reduced serum IGF-I and IGFBP-3 concentrations that is incongruent with the associated mild growth retardation (height SDS -2 to -3 SDS before and during puberty). Twenty-one patients have been described with ALS deficiency, representing 16 unique homozygous or compound heterozygous inactivating mutations of the IGFALS gene. Pubertal delay in boys and insulin insensitivity are common findings. In the assessment of a child with short stature ALS deficiency should be consider in those patients presenting: 1) a normal response to GH stimulation test, 2) low IGF-I levels associated with more profoundly reduced IGFBP-3 levels, 3) a mild growth retardation, apparently out of proportion to the degree of IGF-I and IGFBP-3 deficits, 4) lack of response to an IGF generation test and 5) insulin insensitivity.}, }
@article {pmid21391902, year = {2011}, author = {Chiurchiù, V and Maccarrone, M}, title = {Chronic inflammatory disorders and their redox control: from molecular mechanisms to therapeutic opportunities.}, journal = {Antioxidants &amp; redox signaling}, volume = {15}, number = {9}, pages = {2605-2641}, doi = {10.1089/ars.2010.3547}, pmid = {21391902}, issn = {1557-7716}, mesh = {Arthritis, Rheumatoid/metabolism/physiopathology ; Autoimmune Diseases/metabolism/physiopathology ; Cardiovascular Diseases/metabolism/physiopathology ; Diabetes Mellitus/metabolism/physiopathology ; Humans ; Inflammatory Bowel Diseases ; Neoplasms/metabolism/physiopathology ; Neurodegenerative Diseases/metabolism/physiopathology ; Oxidative Stress/*physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {A chronic inflammatory disease is a condition characterized by persistent inflammation. A number of human pathologies fall into this category, and a great deal of research has been conducted to learn more about their characteristics and underlying mechanisms. In many cases, a genetic component has been identified, but also external factors like food, smoke, or environmental pollutants can significantly contribute to worsen their symptoms. Accumulated evidence clearly shows that chronic inflammatory diseases are subjected to a redox control. Here, we shall review the identity, source, regulation, and biological activity of redox molecules, to put in a better perspective their key-role in cancer, diabetes, cardiovascular diseases, atherosclerosis, chronic obstructive pulmonary diseases, and inflammatory bowel diseases. In addition, the impact of redox species on autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and celiac disease) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) will be discussed, along with their potential therapeutic implications as novel drugs to combat chronic inflammatory disorders.}, }
@article {pmid21391854, year = {2011}, author = {Lunn, JS and Sakowski, SA and Federici, T and Glass, JD and Boulis, NM and Feldman, EL}, title = {Stem cell technology for the study and treatment of motor neuron diseases.}, journal = {Regenerative medicine}, volume = {6}, number = {2}, pages = {201-213}, pmid = {21391854}, issn = {1746-076X}, support = {T32 NS007222/NS/NINDS NIH HHS/United States ; T32 NS007222-28/NS/NINDS NIH HHS/United States ; T32 NS007222&#x2011;28/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Animals ; Biomedical Research/*methods ; Clinical Trials, Phase I as Topic ; Humans ; Models, Biological ; Motor Neuron Disease/*etiology/*therapy ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; Translational Research, Biomedical/methods ; }, abstract = {Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurological diseases.}, }
@article {pmid21390530, year = {2011}, author = {Klopstock, T and Elstner, M and Bender, A}, title = {Creatine in mouse models of neurodegeneration and aging.}, journal = {Amino acids}, volume = {40}, number = {5}, pages = {1297-1303}, doi = {10.1007/s00726-011-0850-1}, pmid = {21390530}, issn = {1438-2199}, mesh = {Aging/*drug effects ; Animals ; Creatine/administration &amp; dosage/*pharmacology/*therapeutic use ; *Disease Models, Animal ; Humans ; Mice ; Neurodegenerative Diseases/*drug therapy/metabolism ; Rejuvenation/physiology ; }, abstract = {The supplementation of creatine has shown a marked neuroprotective effect in mouse models of neurodegenerative diseases (Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis). This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic and anti-oxidant properties of creatine. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral creatine supplementation on aging in 162 aged wild-type C57Bl/6J mice. The median healthy life span of creatine-fed mice was 9% higher than in their control littermates, and they performed significantly better in neurobehavioral tests. In brains of creatine-treated mice, there was a trend toward a reduction of reactive oxygen species and significantly lower accumulation of the "aging pigment" lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data showed that creatine improves health and longevity in mice. Creatine may, therefore, be a promising food supplement to promote healthy human aging. However, the strong neuroprotective effects in animal studies of creatine have not been reproduced in human clinical trials (that have been conducted in Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis). The reasons for this translational gap are discussed. One obvious cause seems to be that all previous human studies may have been underpowered. Large phase III trials over long time periods are currently being conducted for Parkinson's disease and Huntington's disease, and will possibly solve this issue.}, }
@article {pmid21377633, year = {2011}, author = {Trancikova, A and Ramonet, D and Moore, DJ}, title = {Genetic mouse models of neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {100}, number = {}, pages = {419-482}, doi = {10.1016/B978-0-12-384878-9.00012-1}, pmid = {21377633}, issn = {1878-0814}, mesh = {Animals ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; *Models, Genetic ; Neurodegenerative Diseases/*genetics/*pathology ; }, abstract = {Neurodegenerative diseases are generally characterized by the selective degeneration of particular neuronal populations and the accumulation of abnormal or aggregated proteins within, but occasionally external to, neurons in affected brain regions. These diseases can be broadly classified as disorders of cognition and memory or movement, and both features can often coexist in a single disease. In recent years, the identification of genetic mutations that cause rare monogenic familial disease has revolutionized our understanding of the molecular basis of neurodegenerative disease and has provided new targets for the development of disease-modifying therapies. An essential part of this process has been the development of genetic animal models that accurately recapitulate the essential features of each disease, with particular emphasis on the use of mouse models. Such mouse models have provided unique insight into the molecular mechanism(s) through which genetic mutations precipitate neurodegeneration and produce associated clinical and pathological phenotypes. In this review, we provide an overview of the current status, uses and limitations of genetic mouse models for understanding major neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid21376667, year = {2011}, author = {Masters, SL and O'Neill, LA}, title = {Disease-associated amyloid and misfolded protein aggregates activate the inflammasome.}, journal = {Trends in molecular medicine}, volume = {17}, number = {5}, pages = {276-282}, doi = {10.1016/j.molmed.2011.01.005}, pmid = {21376667}, issn = {1471-499X}, mesh = {Alzheimer Disease/metabolism ; Amyloid/*metabolism ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Autophagy/physiology ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Inflammasomes/*metabolism ; Inflammation/metabolism ; Islet Amyloid Polypeptide/metabolism ; *Protein Folding ; Proteostasis Deficiencies/metabolism/*physiopathology ; }, abstract = {The pathogenesis of type 2 diabetes, Alzheimer's disease and amyotrophic lateral sclerosis continues to be debated. Recently, the inflammasome protein complex has been shown to be a key regulator of IL-1β, a cytokine implicated in each of these diseases. In all three cases, it is now apparent that unique protein aggregates caused by inappropriate oligomerization or misfolding are sensed by the inflammasome, providing a unifying mechanism for this IL-1β production. What evolved as an innate defense against infection-related particles, therefore, now seems to be a driving force for inflammation in these diseases. This review discusses the basic research behind these findings and the potential for new therapeutic interventions this affords.}, }
@article {pmid21375489, year = {2011}, author = {McCombe, PA and Henderson, RD}, title = {The Role of immune and inflammatory mechanisms in ALS.}, journal = {Current molecular medicine}, volume = {11}, number = {3}, pages = {246-254}, pmid = {21375489}, issn = {1875-5666}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/immunology/pathology ; CD4-Positive T-Lymphocytes ; Central Nervous System/immunology/injuries/pathology ; Humans ; Inflammation/*immunology ; Mutation ; Occupational Exposure/adverse effects ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.}, }
@article {pmid21375141, year = {2010}, author = {Somma, F and Castagnola, R and Bollino, D and Marigo, L}, title = {Oral inflammatory process and general health. Part 1: The focal infection and the oral inflammatory lesion.}, journal = {European review for medical and pharmacological sciences}, volume = {14}, number = {12}, pages = {1085-1095}, pmid = {21375141}, issn = {1128-3602}, mesh = {Antibodies, Bacterial/blood ; Autoantibodies/blood ; *Autoimmune Diseases/immunology/microbiology ; *Bacterial Infections/immunology/microbiology ; *Endocarditis, Bacterial/immunology/microbiology ; Humans ; Inflammation Mediators/*metabolism ; *Mouth Diseases/immunology/microbiology ; Risk Assessment ; Risk Factors ; }, abstract = {A focal infection is a localized or generalized infection caused by the dissemination of microorganisms or toxic products from a focus of infection in various organic districts, including the oral district. In the Part 1 of this two-part review article, after historical signs, the Authors describe the current pathogenic concepts like the "immuno-allergic theory" and the formation of auto-antibodies in human body, contributing to the genesis of autoimmune illnesses sustained by individual reactivity linked to eredo-constitutionality. Some theories suppose a focal origin even for general pathology such as cancer, sarcoidosis, multiple sclerosis, amyotrophic lateral sclerosis, autism, Guillain-Barré syndrome, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS), Tourette's syndrome, myasthenia gravis, polycystic kidney disease, obesity, Alzheimer's disease and diabetes mellitus. Laboratory analyses (leucocytic formula, protein electrophoresis, C-reactive protein, REUMA test VES, TAS, etc.) are suggestive of the presence of an inflammatory process or of the presence of an aspecific answer to an inflammatory situation. The DNA-Polymerase Chain Reaction method (PCR) is fundamental for the diagnosis of bacterial and viral infections, particularly for those that have non-culturable microorganisms or in cases where are present but in extremely small number in the sample to be analyzed. A positive result confirms the diagnosis, but negative result is not indicator of the absence of illness. Even for oral inflammatory lesions, different basic mechanisms concerning the possible association with systemic diseases exist. They concern local spread, metastatic spread or immunologic cross-reactivity. In this case we assume that most of the ailments come from dental or periodontal foci, as in the bacterial endocarditis, but instead of considering them as possible pathogenetic mechanism of an immune nature, we consider them as originated by the body's response to the presence of bacterial antigens through the formation of specific antibodies. Much researche, sometimes contrasting, has evaluated periodontal pathogens in atheromatous plaques isolated from patients with chronic periodontitis. Oral inflammatory lesions have been shown unequivocally to contribute to elevated systemic inflammatory responses. In some researches intensive periodontal therapy showed a significant reduction of lymphocyte formula, of CRP levels, of interleukin-6 (IL-6) and of LDL cholesterol after two months.}, }
@article {pmid21361856, year = {2011}, author = {Rybakowski, JK}, title = {Lithium in neuropsychiatry: a 2010 update.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {12}, number = {5}, pages = {340-348}, doi = {10.3109/15622975.2011.559274}, pmid = {21361856}, issn = {1814-1412}, mesh = {Antidepressive Agents/*therapeutic use ; Antimanic Agents/*therapeutic use ; Brain/drug effects ; Dementia/drug therapy ; Humans ; Lithium Compounds/*therapeutic use ; Mood Disorders/*drug therapy ; Neuroimaging ; }, abstract = {OBJECTIVES. More than 60 years have passed since the introduction of lithium into modern psychiatry and special issues of Bipolar Disorders in 2009 and Neuropsychobiology in 2010 were devoted to this anniversary. Notwithstanding such a long tradition, a number of key articles on the neuropsychiatric aspects of lithium have appeared in recent years. METHODS. This update was based on the most important original papers and reviews on lithium published in recent years. The main topics were the efficacy of lithium in mood disorders, with a special focus on cognitive functions, the neuroprotective effects of this ion and the potential of using lithium in neurology. RESULTS. Clinical studies and reviews point to lithium being still a cornerstone for the prophylaxis of mood disorders, especially bipolar. The pro-cognitive and antisuicidal properties of lithium have been confirmed as an augmentation of antidepressants in treatment-resistant depression. The neuroprotective effects of lithium have been evidenced in both experimental research and in clinical studies using brain imaging. The possible use of lithium in the prophylaxis of dementia and in neurodegenerative disorders, such as Huntington's disease and amyotrophic lateral sclerosis is discussed. CONCLUSIONS. Although not promoted by pharmaceutical companies, lithium remains a highly important drug in neuropsychiatry.}, }
@article {pmid21360301, year = {2011}, author = {Weinreb, O and Mandel, S and Bar-Am, O and Amit, T}, title = {Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic agents for Alzheimer's disease: a tribute to Moussa Youdim.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {118}, number = {3}, pages = {479-492}, pmid = {21360301}, issn = {1435-1463}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; History, 20th Century ; Humans ; Iron/*metabolism ; Iron Chelating Agents/*therapeutic use ; Monoamine Oxidase Inhibitors/*therapeutic use ; }, abstract = {It is for these authors a great privilege to dedicate this review article to Moussa Youdim, who is one of the most imperative pharmacologists and pioneer investigators in the search and development of novel therapeutics for neurodegenerative diseases. 40 years ago, Moussa Youdim has started studying brain iron, catecholamine receptor and monoamine oxidase (MAO)-A and -B functions. Although Moussa Youdim succeeded in exploring the novel anti-Parkinsonian, selective MAO-B inhibitor drug, rasagiline (Azilect, Teva Pharmaceutical Co.), he did not stop searching for superior therapeutic approaches for neurodegenerative disorders. To date, Moussa Youdim and his research group are designing and synthesizing pluripotential drug candidates possessing diverse pharmacological properties that can act on multiple targets and pathological features ascribed to Parkinson's disease, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. One such example is the multimodal non-toxic, brain-permeable iron-chelating compound, M30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), which amalgamates the propargyl moiety of rasagiline with the backbone of the potent iron chelator, VK28. This review discusses the multiple effects of several leading compounds of this series, concerning their neuroprotective/neurorestorative molecular mechanisms in vivo and in vitro, with a special focus on the pathological features ascribed to AD, including antioxidant and iron chelating activities, regulation of amyloid precursor protein and amyloid β peptide expression processing, activation of pro-survival signaling pathways and regulation of cell cycle and neurite outgrowth.}, }
@article {pmid21349470, year = {2012}, author = {Núñez-Batalla, F and Díaz-Molina, JP and Costales-Marcos, M and Moreno Galindo, C and Suárez-Nieto, C}, title = {[Neurolaryngology].}, journal = {Acta otorrinolaringologica espanola}, volume = {63}, number = {2}, pages = {132-140}, doi = {10.1016/j.otorri.2010.12.003}, pmid = {21349470}, issn = {1988-3013}, mesh = {Algorithms ; Botulinum Toxins, Type A/therapeutic use ; Diagnostic Techniques, Neurological ; Electric Stimulation Therapy ; Electromyography ; Genetic Therapy ; Humans ; Laryngeal Diseases/diagnosis/*etiology/therapy ; Laryngeal Muscles/innervation/physiopathology ; Laryngeal Nerves/physiopathology ; Laryngoscopy ; Motor Neurons/physiology ; Nerve Net/physiology ; Nerve Transfer ; Nervous System Diseases/*complications/diagnosis/physiopathology/therapy ; Neurologic Examination ; Neurophysiology ; Physical Examination ; Sound Spectrography ; Voice Disorders/diagnosis/etiology/therapy ; }, abstract = {The neuroanatomy of voice and speech is complex. An intricate neural network is responsible for ensuring the main functions of the larynx: airway protection, cough and Valsalva production, and providing voice. Coordination of these roles is very susceptible to disruption by neurological disorders. Neurological disorders that affect laryngeal function include Parkinson's disease, stroke, amyotrophic lateral sclerosis, multiple sclerosis, dystonia and essential tremor. A thorough neurological evaluation should be routine for any patient presenting with voice complaints suggestive of neurogenic cause. Endoscopic visualisation of the larynx using a dynamic voice assessment with a flexible laryngoscope is a crucial part of the evaluation and ancillary tests are sometimes performed. Otolaryngologic evaluation is important in the diagnosis and treatment of neurological disorders that affect laryngeal function.}, }
@article {pmid21349440, year = {2011}, author = {Philips, T and Robberecht, W}, title = {Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease.}, journal = {The Lancet. Neurology}, volume = {10}, number = {3}, pages = {253-263}, doi = {10.1016/S1474-4422(11)70015-1}, pmid = {21349440}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*metabolism ; Animals ; Humans ; Inflammation/immunology/metabolism ; Motor Neuron Disease/immunology/metabolism ; Neuroglia/*immunology/*metabolism ; Signal Transduction/physiology ; T-Lymphocytes/physiology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are characterised by the appearance of reactive microglial and astroglial cells, a process referred to as neuroinflammation. In transgenic mouse models of mutant SOD1-associated familial ALS, reactive microglial cells and astrocytes actively contribute to the death of motor neurons. The biological processes that drive this glial reaction are complex and have both beneficial and deleterious effects on motor neurons. Therapeutic interventions targeting these cells are being explored. An improved understanding of the biological processes that cause neuroinflammation will help to define its medical importance and to identify the therapeutic potential of interfering with this reaction.}, }
@article {pmid21348825, year = {2011}, author = {Cavallucci, V and D'Amelio, M}, title = {Matter of life and death: the pharmacological approaches targeting apoptosis in brain diseases.}, journal = {Current pharmaceutical design}, volume = {17}, number = {3}, pages = {215-229}, doi = {10.2174/138161211795049705}, pmid = {21348825}, issn = {1873-4286}, mesh = {Animals ; Apoptosis/*drug effects ; Brain Diseases/*drug therapy/physiopathology ; Brain Injuries/drug therapy/physiopathology ; Humans ; Mice ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neurons/cytology/*physiology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Rats ; }, abstract = {Neurodegenerative diseases that include amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, stroke, brain trauma and spinal cord injury, are associated with the inappropriate activation of a neuronal cell-suicide program called apoptosis. Given that central nervous system tissue has very limited regenerative capacity it is of extreme importance to limit the damage caused by neuronal death. During the past decade, considerable progress has been made in understanding the process of apoptosis and, significantly, a number of studies have shown that a variety of small molecules can activate or inhibit cell death by acting on crucial checkpoints of apoptosis. Here, we review evidence linking apoptosis to brain diseases and discuss how knowledge of the mechanisms of cell death has led to novel therapeutic strategies.}, }
@article {pmid21346098, year = {2011}, author = {Nandar, W and Connor, JR}, title = {HFE gene variants affect iron in the brain.}, journal = {The Journal of nutrition}, volume = {141}, number = {4}, pages = {729S-739S}, doi = {10.3945/jn.110.130351}, pmid = {21346098}, issn = {1541-6100}, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Blood-Brain Barrier ; Brain/*metabolism ; Hemochromatosis/genetics ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/chemistry/*genetics/physiology ; Humans ; Iron/*metabolism ; Membrane Proteins/chemistry/*genetics/physiology ; Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics ; Polymorphism, Genetic ; }, abstract = {Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.}, }
@article {pmid21326809, year = {2011}, author = {Wilson, AC and Dugger, BN and Dickson, DW and Wang, DS}, title = {TDP-43 in aging and Alzheimer's disease - a review.}, journal = {International journal of clinical and experimental pathology}, volume = {4}, number = {2}, pages = {147-155}, pmid = {21326809}, issn = {1936-2625}, support = {R21 AG029972/AG/NIA NIH HHS/United States ; P50NS072187/NS/NINDS NIH HHS/United States ; P01AG017216/AG/NIA NIH HHS/United States ; AG029972/AG/NIA NIH HHS/United States ; P50 NS072187/NS/NINDS NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Aging/genetics/*metabolism ; Alzheimer Disease/genetics/*metabolism/pathology ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Motor Neurons/*metabolism/pathology ; TDP-43 Proteinopathies/genetics/*metabolism/pathology ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43), an RNA and DNA binding protein involved in transcriptional repression, RNA splicing and RNA metabolism during the stress response, is the major component of neuronal inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions, now referred to as FTLD-TDP. While initially thought to be relatively specific to ALS and FTLD-TDP, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, many associated with tau pathology, including Guam Parkinson dementia complex and Alzheimer's disease (AD). TDP-43 pathology is detected in 25% to 50% of AD cases, especially those with more severe clinical phenotype and greater Alzheimer type pathology, as well as AD cases with hippocampal sclerosis (HS). HS is characterized by selective neuronal loss affecting CA1 sector of the hippocampus, and most cases of HS, with or without AD, have TDP-43 pathology. Whether TDP-43 pathology is merely an incidental finding in AD or actually contributing to the more severe clinical phenotype remains unresolved. Presence of TDP-43 in normal elderly, who are at increased risk for AD, would strengthen the argument that it is not merely a secondary or incidental finding in end stage AD. Limited studies suggest that TDP-43 pathology is infrequent in neurologically normal elderly (3% or less). We provide an overview of what is known about TDP-43 in AD, normal aging and in other disorders and suggest that TDP-43 proteinopathies be considered in two classes - primary and secondary.}, }
@article {pmid21323908, year = {2011}, author = {Maccarrone, M and Bernardi, G and Agrò, AF and Centonze, D}, title = {Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance.}, journal = {British journal of pharmacology}, volume = {163}, number = {7}, pages = {1379-1390}, pmid = {21323908}, issn = {1476-5381}, mesh = {Animals ; Brain/metabolism ; Cannabinoid Receptor Modulators/*metabolism ; Humans ; Membrane Fluidity/*physiology ; Neurodegenerative Diseases/*metabolism ; Receptor, Cannabinoid, CB1/*agonists/*metabolism ; Signal Transduction ; }, abstract = {Type-1 cannabinoid receptor (CB(1)) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB(1) and its endogenous agonists, the so-called 'endocannabinoids (eCBs)', belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB(1) signalling in vitro and on CB(1) -dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB(1) , and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB(1).}, }
@article {pmid21310297, year = {2011}, author = {Coleman, M}, title = {Molecular signaling how do axons die?.}, journal = {Advances in genetics}, volume = {73}, number = {}, pages = {185-217}, doi = {10.1016/B978-0-12-380860-8.00005-7}, pmid = {21310297}, issn = {0065-2660}, support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Aging/genetics/metabolism ; Animals ; Axonal Transport/*physiology ; Axons/*physiology ; Cell Adhesion Molecules, Neuronal/metabolism ; Cell Death ; Cell Survival ; Gangliosides/metabolism ; Gene Expression ; Humans ; MAP Kinase Kinase 4/metabolism ; MAP Kinase Kinase Kinases/metabolism ; Mice ; Mice, Transgenic ; Nerve Growth Factors/metabolism ; Neurodegenerative Diseases/genetics/metabolism/physiopathology ; Neuroglia/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Transport/physiology ; *Signal Transduction ; }, abstract = {Axons depend critically on axonal transport both for supplying materials and for communicating with cell bodies. This chapter looks at each activity, asking what aspects are essential for axon survival. Axonal transport declines in neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and in normal ageing, but whether all cargoes are equally affected and what limits axon survival remains unclear. Cargoes can be differentially blocked in some disorders, either individually or in groups. Each missing protein cargo results in localized loss-of-function that can be partially modeled by disrupting the corresponding gene, sometimes with surprising results. The axonal response to losing specific proteins also depends on the rates of protein turnover and on whether the protein can be locally synthesized. Among cargoes with important axonal roles are components of the PI3 kinase, Mek/Erk, and Jnk signaling pathways, which help to communicate with cell bodies and to regulate axonal transport itself. Bidirectional trafficking of Bdnf, NT-3, and other neurotrophic factors contribute to intra- and intercellular signaling, affecting the axon's cellular environment and survival. Finally, several adhesion molecules and gangliosides are key determinants of axon survival, probably by mediating axon-glia interactions. Thus, failure of long-distance intracellular transport can deprive axons of one, few, or many cargoes. This can lead to axon degeneration either directly, through the absence of essential axonal proteins, or indirectly, through failures in communication with cell bodies and nonneuronal cells.}, }
@article {pmid21310295, year = {2011}, author = {Hogg, M and Paro, S and Keegan, LP and O'Connell, MA}, title = {RNA editing by mammalian ADARs.}, journal = {Advances in genetics}, volume = {73}, number = {}, pages = {87-120}, doi = {10.1016/B978-0-12-380860-8.00003-3}, pmid = {21310295}, issn = {0065-2660}, support = {U.1275.01.005.00001.01//Medical Research Council/United Kingdom ; }, mesh = {Adenosine/genetics/metabolism ; Adenosine Deaminase/*genetics/*metabolism ; *Alu Elements ; Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Animals ; Central Nervous System/metabolism ; Genetic Association Studies ; Humans ; Inosine/genetics/metabolism ; Male ; Mammals/genetics/metabolism ; Mice ; Mice, Transgenic ; Neurons/metabolism ; Protein Binding/genetics ; *RNA Editing ; RNA Interference ; RNA, Double-Stranded/*metabolism ; RNA-Binding Proteins ; Rats ; }, abstract = {The main type of RNA editing in mammals is the conversion of adenosine to inosine which is translated as if it were guanosine. The enzymes that catalyze this reaction are ADARs (adenosine deaminases that act on RNA), of which there are four in mammals, two of which are catalytically inactive. ADARs edit transcripts that encode proteins expressed mainly in the CNS and editing is crucial to maintain a correctly functioning nervous system. However, the majority of editing has been found in transcripts encoding Alu repeat elements and the biological role of this editing remains a mystery. This chapter describes in detail the different ADAR enzymes and the phenotype of animals that are deficient in their activity. Besides being enzymes, ADARs are also double-stranded RNA-binding proteins, so by binding alone they can interfere with other processes such as RNA interference. Lack of editing by ADARs has been implicated in disorders such as forebrain ischemia and Amyotrophic Lateral Sclerosis (ALS) and this will also be discussed.}, }
@article {pmid21310146, year = {2011}, author = {Liu, M and Duggan, J and Salt, TE and Cordeiro, MF}, title = {Dendritic changes in visual pathways in glaucoma and other neurodegenerative conditions.}, journal = {Experimental eye research}, volume = {92}, number = {4}, pages = {244-250}, doi = {10.1016/j.exer.2011.01.014}, pmid = {21310146}, issn = {1096-0007}, mesh = {Animals ; Dendrites/*pathology ; Geniculate Bodies/pathology ; Glaucoma/*diagnosis ; Humans ; Neurodegenerative Diseases/*diagnosis ; Retinal Ganglion Cells/pathology ; Superior Colliculi/pathology ; Visual Pathways/*pathology ; }, abstract = {Visual information is sent from the retina to central visual targets through the optic nerve formed of retinal ganglion cells' (RGCs) axons. In rodents, the superior colliculus (SC) is the major site of termination of retinal axons, whilst in primates and felines, it is the lateral geniculate nucleus (LGN). Glaucoma is a progressive optic neuropathy characterized by RGC death. There is increasing evidence that neuronal changes occur both in retina and central visual targets in glaucoma and other neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Dendrites are fine neuronal processes which support postsynaptic contact elements and are responsible for receiving synaptic signals. The morphology of dendrites has a profound impact on integrating neuronal input to the central nervous system from peripheral targets. This review summarizes different dendritic changes that have been recorded in neurodegenerative processes including those occurring in development, ageing and diseases. The findings suggest dendritic pathology is an early sign in disease and underline the importance of synapto-dendritic structure, providing new insights into therapeutic strategies.}, }
@article {pmid21303299, year = {2011}, author = {Steiner, J and Bogerts, B and Schroeter, ML and Bernstein, HG}, title = {S100B protein in neurodegenerative disorders.}, journal = {Clinical chemistry and laboratory medicine}, volume = {49}, number = {3}, pages = {409-424}, doi = {10.1515/CCLM.2011.083}, pmid = {21303299}, issn = {1437-4331}, mesh = {Biomarkers/analysis/blood/cerebrospinal fluid ; Cerebrospinal Fluid/chemistry ; Humans ; *Nerve Growth Factors/blood/cerebrospinal fluid ; Neurodegenerative Diseases/*diagnosis ; S100 Calcium Binding Protein beta Subunit ; *S100 Proteins/blood/cerebrospinal fluid ; }, abstract = {"Classic" neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis share common pathophysiological features and involve progressive loss of specific neuronal populations, axonal or synaptic loss and dysfunction, reactive astrogliosis, and reduction in myelin. Furthermore, despite the absence of astrogliosis, impaired expression of astrocyte- and oligodendrocyte-related genes has been observed in patients with major psychiatric disorders, including schizophrenia and mood disorders. Because S100B is expressed in astrocytes and oligodendrocytes, its concentration in cerebrospinal fluid (CSF) or serum has been considered a suitable surrogate marker for the diagnostic or prognostic assessment of neurodegeneration. This review summarizes previous postmortem, CSF and serum studies regarding the role of S100B in this context. A general drawback is that only small single-center studies have been performed. Many potential confounding factors exist because of the wide extra-astrocytic and extracerebral expression of S100B. Due to lack of disease specificity, reliance on S100B concentrations for differential diagnostic purposes in cases of suspected neurodegenerative disorders is not recommended. Moreover, there is no consistent evidence for a correlation between disease severity and concentrations of S100B in CSF or serum. Therefore, S100B has limited usefulness for monitoring disease progression.}, }
@article {pmid21301041, year = {2011}, author = {Oda, M and Izumi, Y and Kaji, R}, title = {[Gene mutations in familial amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {63}, number = {2}, pages = {165-170}, pmid = {21301041}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Cell Cycle Proteins ; D-Amino-Acid Oxidase/genetics ; DNA Helicases ; DNA-Binding Proteins/genetics ; Flavoproteins/genetics ; Guanine Nucleotide Exchange Factors/*genetics ; Humans ; Membrane Transport Proteins ; Multifunctional Enzymes ; *Mutation ; Phosphoric Monoester Hydrolases ; R-SNARE Proteins/genetics ; RNA Helicases/*genetics ; Ribonuclease, Pancreatic/genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Transcription Factor TFIIIA/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness that reflects degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem, and spinal cord. Most ALS cases are sporadic, but about 5%-10% are familial. The majority of familial ALS (FALS) cases follow an autosomal dominant inheritance pattern, and include the following mutations: ALS1, Cu/Zn superoxide dismutase (SOD1); ALS3; ALS4, senataxin; ALS6, fused in sarcoma (FUS); ALS7; ALS8, vesicle-associated membrane protein; ALS9, angiogenin; ALS10, TAR DNA-binding protein (TARDBP); and ALS11/FIG4. Some of these gene mutations are rarely seen in sporadic ALS cases. ALS2/alsin and ALS5 show an autosomal recessive inheritance pattern. Recently, mutations in the gene encoding optineurin, earlier reported to be a causative gene for primary open-angle glaucoma, have also been found in patients with ALS. It has also been demonstrated that a mutation in the D-amino acid oxidase gene is associated with classic adult-onset FALS. However, these genetic defects occur in only about 20%-30% FLAS cases, while most genes causing FALS remain unknown.}, }
@article {pmid21301036, year = {2011}, author = {Kuzuhara, S}, title = {[Muro disease: amyotrophic lateral sclerosis/parkinsonism-dementia complex in Kii peninsula of Japan].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {63}, number = {2}, pages = {119-129}, pmid = {21301036}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology/pathology ; Brain/metabolism/pathology ; DNA-Binding Proteins/metabolism ; *Dementia/epidemiology/etiology/pathology ; Humans ; Japan/epidemiology ; Neurofibrillary Tangles/metabolism/pathology ; *Parkinsonian Disorders/epidemiology/etiology/pathology ; Syndrome ; }, abstract = {Muro disease refers to the endemic amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in the high incidence ALS focus in the Muro district of the Kii peninsula. Kii paralysis was first described in the 1680s in a folk literature, and as ALS in the medical literature by Kin-no-suke Miura in 1911. Two high-incidence ALS foci were discovered in 1960s by Kimura and Yase, and retro- and anterospective epidemiological surveys were started. Kii ALS was neuropathologically characterized by classical ALS pathology together with many neurofibrillary tangles (NFTs) in the brain, similar to Guamanian ALS. The incidence rates of ALS dramatically declined during the 1950s and 1980s, resulting in the disappearance of the high-incidence foci. In the early 1990s, however, Kuzuhara found existence of high-incidence of ALS in the region, and, in addition, of a high-incidence of PDC with abundant NFTs, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced ALS. Unsuccessful attempts were made to identify cause and pathogenesis of the disease in minerals and environmental factors. More than 70% of patients in the endemic region had a family history of ALS or PDC; therefore, genetic factors were suspected as the cause. The authors analyzed the causative and risk candidate genes in the affected and unaffected family members, but failed to find genes related to ALS/PDC. The changing pattern of Muro disease from ALS with a younger onset and rapid progression to PDC with a later onset and longer survival suggests that some unknown environmental factor(s) might modulate the disease process, which basically might be programmed in the gene(s).}, }
@article {pmid21301035, year = {2011}, author = {Mitsuyama, Y}, title = {[Yuasa-Mitsuyama disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {63}, number = {2}, pages = {109-118}, pmid = {21301035}, issn = {1881-6096}, mesh = {Central Nervous System/pathology ; DNA-Binding Proteins/genetics ; Diagnostic Imaging ; *Frontotemporal Dementia/diagnosis/genetics/pathology/physiopathology ; Humans ; *Motor Neuron Disease/diagnosis/genetics/pathology/physiopathology ; Syndrome ; }, abstract = {Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with tau-negative and ubiquitin-positive inclusions (FTLD-U). FTLD-U is now usually referred to as FTLD-TAR DNA binding protein 43 (TDP-43). FTLD-TDP-43, but not Pick's disease with tau-positive Pick bodies, is often associated with motor neuron disease (MND). More than 200 cases of this combined form, i.e., FTD-MND, have been reported in Japan. The neuropathological characteristics of MND in patients with FTD are essentially similar to the MND in patients without dementia. However the other characteristics of the combination of FTD and MND are such that the author has considered this disease a unique clinicopathological entity. These characteristics are as follows: (1) frontotemporal lobe-type dementia with insidious onset, usually in the presenile period; (2) neurogenic muscular wasting during the course of the illness [amyotrophic lateral sclerosis (ALS)]-- or [spinal progressive muscular atrophy (SPMA)]-like symptoms); (3) duration from the onset of illness to death is 2-5 years (average duration, 30.6 months); (4) both extrapyramidal symptoms and definite sensory deficiency are less commonly observed; (5) no characteristic abnormalities in the cerebrospinal fluid (CSF) or on the electroencephalogram (EEG) in screening tests; (6) no known parental consanguinity or familial occurrence; and (7) nonspecific mild-to-slight degenerative changes in the frontotemporal cortex, hypoglossal nuclei, spinal cord, and frequently in the substantia nigra. FTD-MND is characterized by ubiquitin-immunoreactive intraneuronal inclusions in cortical layers II and III and the hippocampal dentate granule cells. The occurrence of ubiquitin-positive, tau-negative and ubiquitinated TDP-43 positive inclusions could be the key to determining the pathological background of this disease. Further studies are required clinicopathological differentiation between FTD-MND and ALS-dementia (ALS-D).}, }
@article {pmid21299590, year = {2011}, author = {Duffy, LM and Chapman, AL and Shaw, PJ and Grierson, AJ}, title = {Review: The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {37}, number = {4}, pages = {336-352}, doi = {10.1111/j.1365-2990.2011.01166.x}, pmid = {21299590}, issn = {1365-2990}, support = {G0700628/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Animals ; Humans ; Mitochondria/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurones leading to muscle weakness and paralysis. Despite recent advances in the genetics of ALS, the mechanisms underlying motor neurone degeneration are not fully understood. Mitochondria are known to be involved in the pathogenesis of ALS, principally through mitochondrial dysfunction, the generation of free radicals, and impaired calcium handling in ALS patients and models of disease. However, recent studies have highlighted the potential importance of altered mitochondrial morphology and defective axonal transport of mitochondria in ALS. Here, we review the evidence for mitochondrial involvement in ALS and discuss potential therapeutic strategies targeting mitochondria.}, }
@article {pmid21297150, year = {2011}, author = {Bede, P and Oliver, D and Stodart, J and van den Berg, L and Simmons, Z and O Brannagáin, D and Borasio, GD and Hardiman, O}, title = {Palliative care in amyotrophic lateral sclerosis: a review of current international guidelines and initiatives.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {82}, number = {4}, pages = {413-418}, doi = {10.1136/jnnp.2010.232637}, pmid = {21297150}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*nursing ; Caregivers/psychology ; Cognition Disorders/complications/psychology ; Consensus Development Conferences as Topic ; Humans ; Palliative Care/*standards ; *Practice Guidelines as Topic ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. Optimal management requires a palliative approach from diagnosis with emphasis on patient autonomy, dignity and quality of life.<br><br>OBJECTIVE: To conduct a systematic analysis of the type, level and timing of specialist palliative care intervention in ALS.<br><br>RESULTS: Despite an international consensus that ALS management should adopt a multidisciplinary approach, integration of palliative care into ALS management varies considerably across health care systems. Late referral to palliative services in ALS is not uncommon and may impact negatively on the quality of life of ALS patients and their caregivers. However, common themes and principles of engagement can be identified across different jurisdictions, and measurement systems have been established that can assess the impact of palliative care intervention.<br><br>CONCLUSIONS: There is considerable evidence that palliative care intervention improves quality of life in patients and carers. International consensus guidelines would assist in the development of a framework for active palliative care engagement in ALS and other neurodegenerative diseases.}, }
@article {pmid21296405, year = {2011}, author = {Kiernan, MC and Vucic, S and Cheah, BC and Turner, MR and Eisen, A and Hardiman, O and Burrell, JR and Zoing, MC}, title = {Amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {377}, number = {9769}, pages = {942-955}, doi = {10.1016/S0140-6736(10)61156-7}, pmid = {21296405}, issn = {1474-547X}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/physiopathology/therapy ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.}, }
@article {pmid21291385, year = {2011}, author = {Jirásková-Vaníčková, J and Ettrich, R and Vorlová, B and Hoffman, HE and Lepšík, M and Jansa, P and Konvalinka, J}, title = {Inhibition of human serine racemase, an emerging target for medicinal chemistry.}, journal = {Current drug targets}, volume = {12}, number = {7}, pages = {1037-1055}, doi = {10.2174/138945011795677755}, pmid = {21291385}, issn = {1873-5592}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; *Drug Delivery Systems ; Drug Design ; Enzyme Inhibitors/*pharmacology ; Humans ; Nervous System Diseases/drug therapy/physiopathology ; Racemases and Epimerases/*antagonists &amp; inhibitors/metabolism ; Receptors, N-Methyl-D-Aspartate/drug effects/metabolism ; Serine/metabolism ; }, abstract = {Proteins of glutamatergic NMDA receptor signaling pathways have been studied as targets for intervention in a variety of neuropathological conditions, including neurodegenerations, epilepsy, neuropathic pain, drug addiction, and schizophrenia. High activity NMDA-blocking agents have been designed to treat some of these disorders; however, their effect is often compromised by undesirable side effects. Therefore, alternative ways of modulating NMDA receptor function need to be sought after. The opening of the NMDA receptor ion channel requires occupation of two distinct binding sites, the glutamate site and the glycine site. It has been shown that D-serine, rather than glycine, can trigger the physiological NMDA receptor function. D-serine is a product of the activity of a specific enzyme, serine racemase (SR), which was identified a decade ago. SR has therefore emerged as a new potential target for the NMDA-receptor-based diseases. There is evidence linking increased levels of D-Ser to amyotrophic lateral sclerosis and Alzheimer's disease and decreased concentrations of D-serine to schizophrenia. SR is a pyridoxal-5'-phosphate dependent enzyme found in the cytosol of glial and neuronal cells. It is activated by ATP, divalent cations like Mg(2+) or Ca(2+), and reducing agents. This paper reviews the present literature on the activity and inhibition of mammalian SRs. It summarizes approaches that have been applied to design SR inhibitors and lists the known active compounds. Based on biochemical and docking analyses, i) we delineate for the first time the ATP binding site of human SR, and ii) we suggest possible mechanisms of action for the active compounds. In the end, we discuss the SR features that make the discovery of its inhibitors a challenging, yet very important, task of medicinal chemistry.}, }
@article {pmid21290295, year = {2011}, author = {Bates-Withers, C and Sah, R and Clapham, DE}, title = {TRPM7, the Mg(2+) inhibited channel and kinase.}, journal = {Advances in experimental medicine and biology}, volume = {704}, number = {}, pages = {173-183}, doi = {10.1007/978-94-007-0265-3_9}, pmid = {21290295}, issn = {0065-2598}, mesh = {Amino Acid Sequence ; Animals ; Gene Expression Regulation ; Humans ; Magnesium/*pharmacology ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Protein Serine-Threonine Kinases ; TRPM Cation Channels/antagonists &amp; inhibitors/chemistry/genetics/*physiology ; }, abstract = {TRPM7 is a ubiquitously expressed nonselective cation channel fused to a C-terminal alpha kinase. TRPM7 current is typically small at physiological magnesium concentrations, but large outwardly rectifying currents develop in low-magnesium extracellular solution when cells are dialyzed with magnesium free solutions during whole-cell patch clamp recordings. In addition to regulation by magnesium, TRPM7 current is potentiated by low extracellular pH and inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)) during phospholipase C mediated signaling events. A diverse body of literature has implicated TRPM7 in fundamental cellular processes including death, survival, proliferation, cell cycle progression, magnesium homeostasis and responses to shear stress and oxidative stress. Global deletion of TRPM7 in mouse results in embryonic lethality and a thymocyte-restricted conditional knockout exhibits defective thymopoeisis, suggesting a role for TRPM7 in development and organogenesis. In disease states, TRPM7 has been linked to Guamanian amyotrophic lateral sclerosis and parkinsonian dementia (ALS/PD), various forms of neoplasia, hypertension and delayed neuronal death following cerebral ischemia.}, }
@article {pmid21288189, year = {2011}, author = {Frankola, KA and Greig, NH and Luo, W and Tweedie, D}, title = {Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {10}, number = {3}, pages = {391-403}, pmid = {21288189}, issn = {1996-3181}, support = {Z01 AG000311-08/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/physiopathology ; Cell Survival ; Humans ; *Molecular Targeted Therapy ; Neuritis/*drug therapy/metabolism/pathology ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Parkinson Disease/drug therapy/physiopathology ; Signal Transduction/physiology ; Tumor Necrosis Factor-alpha/*physiology ; Up-Regulation ; }, abstract = {Inflammatory signals generated within the brain and peripheral nervous system direct diverse biological processes. Key amongst the inflammatory molecules is tumor necrosis factor-α (TNF-α), a potent pro-inflammatory cytokine that, via binding to its associated receptors, is considered to be a master regulator of cellular cascades that control a number of diverse processes coupled to cell viability, gene expression, synaptic integrity and ion homeostasis. Whereas a self-limiting neuroinflammatory response generally results in the resolution of an intrinsically or extrinsically triggered insult by the elimination of toxic material or injured tissue to restore brain homeostasis and function, in the event of an unregulated reaction, where the immune response persists, inappropriate chronic neuroinflammation can ensue. Uncontrolled neuroinflammatory activity can induce cellular dysfunction and demise, and lead to a self-propagating cascade of harmful pathogenic events. Such chronic neuroinflammation is a typical feature across a range of debilitating common neurodegenerative diseases, epitomized by Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, in which TNF-α expression appears to be upregulated and may represent a valuable target for intervention. Elaboration of the protective homeostasis signaling cascades from the harmful pathogenic ones that likely drive disease onset and progression could aid in the clinical translation of approaches to lower brain and peripheral nervous system TNF-α levels, and amelioration of inappropriate neuroinflammation.}, }
@article {pmid21170888, year = {2010}, author = {Trepiccione, F and Christensen, BM}, title = {Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings.}, journal = {Journal of nephrology}, volume = {23 Suppl 16}, number = {}, pages = {S43-8}, pmid = {21170888}, issn = {1121-8428}, mesh = {Animals ; Diabetes Insipidus, Nephrogenic/*chemically induced ; Glycogen Synthase Kinase 3/physiology ; Glycogen Synthase Kinase 3 beta ; Humans ; Kidney/metabolism ; Kidney Tubules, Collecting/metabolism ; Lithium/metabolism/*toxicity ; }, abstract = {Lithium (Li+) salts are widely used to treat bipolar mood disorders. Recent trials suggest a potential efficacy also in the treatment of amyotrophic lateral sclerosis and Alzheimer's disease. Li+ is freely filtered by the glomerulus and mainly reabsorbed in the proximal convoluted tubule. Reabsorption in the distal nephron becomes significant under sodium-restricted conditions. Nevertheless, the distal nephron is greatly affected by Li+ even under normal sodium intake. Polyuria, renal tubular acidosis and finally chronic renal failure are the most frequent adverse effects. The occurrence of an overt nephrogenic diabetes insipidus (NDI) limits Li+ usage and imposes suspension. The molecular mechanisms of Li+-related urinary concentration defect involve a dysregulation of the aquaporin system in principal cells of the collecting duct. ENaC is crucial as the entry route for intracellular Li+ accumulation. The basolateral exit route is not clearly identified, but some evidence suggests Na+/H+ exchanger 1 (NHE1) as a potential candidate. Li+ promotes polyuria mainly counteracting the intracellular vasopressin signaling. An additional role of the inner medullary interstitial cells and PGE-2 pathway has to be considered. The GSK3ß cascade is also regulated by Li+. GSK3ß inhibition could lead not only to the polyuria, but also to the Li+-dependent proliferative effect on principal cells. Cellular reorganization of the collecting duct and microcysts are the main pathological findings during Li+ treatment. Their relationship with the urinary concentration defect and an eventual Li+-induced ciliopathy has to been investigated. Li+-induced NDI has been a matter of investigation since the early 1970s. This manuscript reports the latest clinical and experimental findings in combination with the older fundamental results.}, }
@article {pmid21274688, year = {2011}, author = {Tartaglia, MC and Rosen, HJ and Miller, BL}, title = {Neuroimaging in dementia.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {1}, pages = {82-92}, pmid = {21274688}, issn = {1878-7479}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/complications/diagnosis ; Dementia/*diagnosis/etiology ; Frontotemporal Dementia/complications/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; *Positron-Emission Tomography/methods ; }, abstract = {Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, progressive supranuclear palsy, multiple system atrophy, Parkinson's disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.}, }
@article {pmid21274686, year = {2011}, author = {Wang, S and Melhem, ER and Poptani, H and Woo, JH}, title = {Neuroimaging in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {1}, pages = {63-71}, pmid = {21274686}, issn = {1878-7479}, support = {R21 NS063111/NS/NINDS NIH HHS/United States ; 1R21NS063111/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; Magnetic Resonance Imaging/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive degeneration of upper motor neurons (UMN) and lower motor neurons (LMN). While LMN dysfunction can be confirmed by electromyography (EMG) and muscle biopsy, UMN involvement is more difficult to detect, particularly in the early phase. Objective and sensitive measures of UMN dysfunction are needed for early diagnosis and monitoring of disease progression and therapeutic efficacy. Advanced magnetic resonance imaging (MRI) techniques, such as diffusion, perfusion, magnetization transfer imaging, functional MRI, and MR spectroscopy, provide insight into the pathophysiological processes of ALS and may have a role in the identification and monitoring of UMN pathology. This article provides an overview of these neuroimaging techniques and their potential roles in ALS.}, }
@article {pmid21274268, year = {2011}, author = {Van Den Bosch, L}, title = {Genetic rodent models of amyotrophic lateral sclerosis.}, journal = {Journal of biomedicine &amp; biotechnology}, volume = {2011}, number = {}, pages = {348765}, pmid = {21274268}, issn = {1110-7251}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Animals, Genetically Modified ; *Disease Models, Animal ; Mice ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. A large number of rodent models are available that show motor neuron death and a progressive motor phenotype that is more or less reminiscent of what occurs in patients. These rodent models contain genes with spontaneous or induced mutations or (over) express different (mutant) genes. Some of these models have been of great value to delineate potential pathogenic mechanisms that cause and/or modulate selective motor neuron degeneration. In addition, these genetic rodent models play a crucial role in testing and selecting potential therapeutics that can be used to treat ALS and/or other motor neuron disorders. In this paper, we give a systematic overview of the most important genetic rodent models that show motor neuron degeneration and/or develop a motor phenotype. In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS.}, }
@article {pmid21258799, year = {2011}, author = {Padovan, M and Caniatti, LM and Trotta, F and Govoni, M}, title = {Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis: report of two new cases and review of literature.}, journal = {Rheumatology international}, volume = {31}, number = {6}, pages = {715-719}, pmid = {21258799}, issn = {1437-160X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*pathology ; Antibodies, Monoclonal/therapeutic use ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/complications/drug therapy/*pathology ; Bulbar Palsy, Progressive/etiology/pathology ; Female ; Humans ; Infliximab ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; }, abstract = {To describe a rare association between rheumatoid arthritis (RA) and amyotrophic lateral sclerosis (ALS). Two new cases of patients with RA who developed amyotrophic lateral sclerosis (ALS), one receiving anti-TNFα agents, were reported. Only other five cases of this rare association have been previously described in literature. The simultaneous presence of the two diseases represents a difficult diagnostic challenge because RA may mimic some musculoskeletal symptoms of ALS. There is no evidence in favor of a common pathophysiologic mechanism, and thus the possibility of a fortuitous association must be raised. A neurotoxic side effect of various drugs for RA treatment could be considered. Casual or causal association remains a difficult choice. The possibility of a coincidental association must be raised but neurologic side effects of TNFα blockers lead to discussion.}, }
@article {pmid21249659, year = {2011}, author = {Katzberg, HD and Benatar, M}, title = {Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2011}, number = {1}, pages = {CD004030}, pmid = {21249659}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Deglutition Disorders/complications ; *Enteral Nutrition ; Gastrostomy ; Humans ; Motor Neuron Disease/*therapy ; Prospective Studies ; Retrospective Studies ; }, abstract = {BACKGROUND: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss.<br><br>OBJECTIVES: To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on:&#xa0;(1) survival;(2) nutritional status;&#xa0;(3) quality of life;(4) minor and major complications of percutaneous endoscopic gastrostomy.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references.&#xa0;<br><br>SELECTION CRITERIA: A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review.<br><br>DATA COLLECTION AND ANALYSIS: We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion.&#xa0;<br><br>MAIN RESULTS: We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section.<br><br>AUTHORS' CONCLUSIONS: There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable.&#xa0; Quality of life has been addressed in studies and needs more attention. Based on a number of recent non-randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent.}, }
@article {pmid21241159, year = {2011}, author = {Heiman-Patterson, TD and Sher, RB and Blankenhorn, EA and Alexander, G and Deitch, JS and Kunst, CB and Maragakis, N and Cox, G}, title = {Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {2}, pages = {79-86}, doi = {10.3109/17482968.2010.550626}, pmid = {21241159}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/physiopathology ; Animals ; Disease Models, Animal ; Drug Design ; Female ; *Genotype ; Humans ; Male ; Mice ; *Mice, Transgenic ; Nerve Degeneration/genetics/pathology ; *Phenotype ; Protein Isoforms/genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.}, }
@article {pmid21236501, year = {2011}, author = {Allaman, I and Bélanger, M and Magistretti, PJ}, title = {Astrocyte-neuron metabolic relationships: for better and for worse.}, journal = {Trends in neurosciences}, volume = {34}, number = {2}, pages = {76-87}, doi = {10.1016/j.tins.2010.12.001}, pmid = {21236501}, issn = {1878-108X}, mesh = {Animals ; Astrocytes/*metabolism ; Encephalitis/pathology/physiopathology ; Energy Metabolism/physiology ; Homeostasis/physiology ; Humans ; Nerve Degeneration/metabolism/pathology ; Neurodegenerative Diseases/pathology/physiopathology ; Neurons/*metabolism ; }, abstract = {In recent years, previously unsuspected roles of astrocytes have been revealed, largely owing to the development of new tools enabling their selective study in situ. These exciting findings add to the large body of evidence demonstrating that astrocytes play a central role in brain homeostasis, in particular via the numerous cooperative metabolic processes they establish with neurons, such as the supply of energy metabolites and neurotransmitter recycling functions. Furthermore, impairments in astrocytic function are increasingly being recognized as an important contributor to neuronal dysfunction and, in particular, neurodegenerative processes. In this review, we discuss recent evidence supporting important roles for astrocytes in neuropathological conditions such as neuroinflammation, amyotrophic lateral sclerosis and Alzheimer's disease. We also explore the potential for neuroprotective therapeutics based on the modulation of astrocytic functions.}, }
@article {pmid21224790, year = {2010}, author = {Ishikawa, Y and Bach, JR}, title = {Physical medicine respiratory muscle aids to avert respiratory complications of pediatric chest wall and vertebral deformity and muscle dysfunction.}, journal = {European journal of physical and rehabilitation medicine}, volume = {46}, number = {4}, pages = {581-597}, pmid = {21224790}, issn = {1973-9095}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*rehabilitation ; Cough ; Humans ; Muscular Dystrophy, Duchenne/*physiopathology/*rehabilitation ; Respiration, Artificial/*methods ; Respiratory Muscles/*physiopathology ; Respiratory Therapy/*methods ; Spinal Muscular Atrophies of Childhood/*physiopathology/*rehabilitation ; Thoracic Wall/*abnormalities ; Tracheostomy ; Vital Capacity ; }, abstract = {The purpose of this article was to describe the use of noninvasive inspiratory and expiratory muscle aids to prevent chest wall deformities including pectus excavatum, to prevent respiratory complications of vertebral surgery, to prevent acute and long-term ventilatory insufficiency and failure in children with paralytic disorders who develop these deformities, and to permit the extubation and tracheostomy tube decanulation of "unweanable" patients. Noninvasive airway pressure aids can provide up to continuous ventilator support for patients with little or no vital capacity and can provide for effective cough flows for patients with severely dysfunctional expiratory muscles. An April 2010 consensus of clinicians from 20 centers in 14 countries reported over 1500 spinal muscular atrophy type 1 (SMA1), Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS) patients who survived using continuous ventilatory support without tracheostomy tubes. Four of the centers routinely extubated unweanable DMD patients so that none of their over 250 such patients has undergone tracheotomy.}, }
@article {pmid21222602, year = {2011}, author = {Budini, M and Baralle, FE and Buratti, E}, title = {Regulation of gene expression by TDP-43 and FUS/TLS in frontotemporal lobar degeneration.}, journal = {Current Alzheimer research}, volume = {8}, number = {3}, pages = {237-245}, doi = {10.2174/156720511795563719}, pmid = {21222602}, issn = {1875-5828}, support = {GGP06147/TI_/Telethon/Italy ; }, mesh = {Animals ; DNA-Binding Proteins/*genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics/metabolism ; Gene Expression Regulation/*genetics ; Humans ; RNA-Binding Protein FUS/*genetics/*physiology ; }, abstract = {Two proteins have recently received considerable attention in the neurodegenerative research field: TDP-43 and FUS/TLS. The reason is that both proteins have been found to represent major protein components of the intracellular inclusions occurring in the neuronal tissues of patients affected by Fronto Temporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. One of the most interesting features of this discovery is that both proteins have in common several structural properties. In particular, they are multifunctional RNA-binding proteins (RBPs) already known to play a role in several cellular processes such as transcription, pre-mRNA splicing, and mRNA stability. The potential consequences of changes in their intracellular localization and protein modification status (phosphorylation, ubiquitination, and cleavage) on neuronal metabolism represent one of the major research challenges faced today by researchers. There is hope that a detailed knowledge of the gain- or loss-of-function mechanisms mediated by alterations in these proteins in the neuronal environment may provide novel therapeutic strategies for the treatment of these diseases. Here, we aim to provide an updated review of ways by which TDP-43 and FUS/TLS influence gene expression. In particular, we will focus on the characterized properties of both proteins that involve gene transcription and also RNA splicing, transport and stability processes.}, }
@article {pmid21222600, year = {2011}, author = {Ferrari, R and Kapogiannis, D and Huey, ED and Momeni, P}, title = {FTD and ALS: a tale of two diseases.}, journal = {Current Alzheimer research}, volume = {8}, number = {3}, pages = {273-294}, pmid = {21222600}, issn = {1875-5828}, support = {R99 AG999999/AG/NIA NIH HHS/United States ; Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; ZIA AG000975/ImNIH/Intramural NIH HHS/United States ; ZIA AG000975-02/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/*pathology ; Comorbidity ; Frontotemporal Dementia/epidemiology/*genetics/*pathology ; Humans ; }, abstract = {The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders.FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.}, }
@article {pmid21214557, year = {2011}, author = {Amadio, S and Apolloni, S and D'Ambrosi, N and Volonté, C}, title = {Purinergic signalling at the plasma membrane: a multipurpose and multidirectional mode to deal with amyotrophic lateral sclerosis and multiple sclerosis.}, journal = {Journal of neurochemistry}, volume = {116}, number = {5}, pages = {796-805}, doi = {10.1111/j.1471-4159.2010.07025.x}, pmid = {21214557}, issn = {1471-4159}, mesh = {Adenosine Triphosphate/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Cell Membrane/*metabolism ; Disease Models, Animal ; Humans ; Multiple Sclerosis/genetics/*metabolism/pathology ; Purines/*metabolism ; Receptors, Purinergic/metabolism ; Signal Transduction/*physiology ; }, abstract = {ATP is a widespread and multipurpose signalling molecule copiously released in the extracellular environment of the whole nervous system upon cell activation, stress, or damage. Extracellular ATP is also a multidirectional information molecule, given the concurrent presence at the plasma membrane of various targets for ATP. These include ectonucleotidases (metabolizing ATP down to adenosine), ATP/adenosine transporters, P2 receptors for purine/pyrimidine nucleotides (ligand-gated ion channels P2X receptors and G-protein-coupled P2Y receptors), in addition to metabotropic P1 receptors for nucleosides. All these targets rarely operate as single units, rather they associate with each other at the plasma membrane as multi-protein complexes. Altogether, they control the duration, magnitude and/or direction of the signals triggered and propagated by purine/pyrimidine ligands, and the impact that each single ligand has on a variety of short- and long-term functions. A strict control system allows assorted, even divergent, biological outcomes. Among these, we enumerate cell-to-cell communication, tropic, trophic, but also noxious actions causing the insurgence/progression of pathological conditions. Here, we show that purinergic signalling in the nervous system can be instrumental for instance to neurodegenerative and neuroinflammatory diseases such as amyotrophic lateral sclerosis and multiple sclerosis.}, }
@article {pmid21196395, year = {2011}, author = {Gauthier, S and Kaur, G and Mi, W and Tizon, B and Levy, E}, title = {Protective mechanisms by cystatin C in neurodegenerative diseases.}, journal = {Frontiers in bioscience (Scholar edition)}, volume = {3}, number = {2}, pages = {541-554}, pmid = {21196395}, issn = {1945-0524}, support = {R01 NS042029/NS/NINDS NIH HHS/United States ; P01 AG017617-09/AG/NIA NIH HHS/United States ; R01 NS042029-06/NS/NINDS NIH HHS/United States ; P01 AG017617/AG/NIA NIH HHS/United States ; NS42029/NS/NINDS NIH HHS/United States ; AG017617/AG/NIA NIH HHS/United States ; }, mesh = {Amyloid/antagonists &amp; inhibitors ; Animals ; Autophagy/drug effects/physiology ; Brain/*drug effects/metabolism/pathology ; Cystatin C/metabolism/*therapeutic use ; Cysteine Proteinase Inhibitors/metabolism/*therapeutic use ; *Cytoprotection ; Gene Expression Regulation/physiology ; Humans ; Mice ; Neurodegenerative Diseases/metabolism/pathology/*prevention &amp; control ; Neurogenesis/*drug effects ; Neuroprotective Agents/metabolism/*therapeutic use ; }, abstract = {Neurodegeneration occurs in acute pathological conditions such as stroke, ischemia, and head trauma and in chronic disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. While the cause of neuronal death is different and not always known in these varied conditions, hindrance of cell death would be beneficial in the prevention of, slowing of, or halting disease progression. Enhanced cystatin C (CysC) expression in these conditions caused a debate as to whether CysC up-regulation facilitates neurodegeneration or it is an endogenous neuroprotective attempt to prevent the progression of the pathology. However, recent in vitro and in vivo data have demonstrated that CysC plays protective roles via pathways that are dependent on inhibition of cysteine proteases, such as cathepsin B, or by induction of autophagy, induction of proliferation, and inhibition of amyloid-beta aggregation. Here we review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced under various conditions. These data suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.}, }
@article {pmid21195356, year = {2010}, author = {McCombe, PA and Henderson, RD}, title = {Effects of gender in amyotrophic lateral sclerosis.}, journal = {Gender medicine}, volume = {7}, number = {6}, pages = {557-570}, doi = {10.1016/j.genm.2010.11.010}, pmid = {21195356}, issn = {1878-7398}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*epidemiology/*genetics/physiopathology ; Animals ; Environmental Exposure ; Female ; Humans ; Incidence ; Male ; Mice ; Models, Animal ; Nervous System Physiological Phenomena ; Prevalence ; Sex Factors ; }, abstract = {BACKGROUND: There is evidence that amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is more common in men than in women and that gender influences the clinical features of the disease. The causes of this are unknown.<br><br>OBJECTIVE: This review examines the gender differences that are found in ALS and postulates reasons for these differences.<br><br>METHODS: A literature review of PubMed (with no date limits) was performed to find information about gender differences in the incidence, prevalence, and clinical features of ALS, using the search terms ALS or MND and gender or sex, ALS prevalence, and SOD1 mice and gender. Articles were reviewed for information about gender differences, together with other articles that were already known to the authors.<br><br>RESULTS: The incidence and prevalence of ALS are greater in men than in women. This gender difference is seen in large studies that included all ALS patients (sporadic and familial), but is not seen when familial ALS is studied independently. Men predominate in the younger age groups of patients with ALS. Sporadic ALS has different clinical features in men and women, with men having a greater likelihood of onset in the spinal regions, and women tending to have onset in the bulbar region. Gender appears to have no clear effect on survival. In animals with superoxide dismutase 1 (sod1) mutations, sex does affect the clinical course of disease, with earlier onset in males. Possible reasons for the differences in ALS between men and women include different exposures to environmental toxins, different biological responses to exogenous toxins, and possibly underlying differences between the male and female nervous systems and different abilities to repair damage.<br><br>CONCLUSIONS: There is a complex interaction between gender and clinical phenotypes in ALS. Understanding the causes of the gender differences could give clues to processes that modify the disease.}, }
@article {pmid22997874, year = {2011}, author = {Checkoway, H and Lundin, JI and Kelada, SN}, title = {Neurodegenerative diseases.}, journal = {IARC scientific publications}, volume = {}, number = {163}, pages = {407-419}, pmid = {22997874}, issn = {0300-5038}, support = {P42ES04696/ES/NIEHS NIH HHS/United States ; }, mesh = {Biomarkers/*analysis ; Disease Susceptibility ; Humans ; *Molecular Epidemiology ; Neurodegenerative Diseases/*diagnosis/epidemiology/*etiology ; Risk Factors ; }, abstract = {Degenerative diseases of the nervous system impose substantial medical and public health burdens on populations throughout the world. Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are three of the major neurodegenerative diseases. The prevalence and incidence of these diseases rise dramatically with age; thus the number of cases is expected to increase for the foreseeable future as life spans in many countries continue to increase. Causal contributions from genetic and environmental factors are, with some exceptions, poorly understood. Nonetheless, molecular epidemiology approaches have proven valuable for improving disease diagnoses, characterizing disease prognostic factors, identifying high-risk genes for familial neurodegenerative diseases, investigating common genetic variants that may predict susceptibility for the non-familial forms of these diseases, and for quantifying environmental exposures. Incorporation of molecular techniques, including genomics, proteomics, and measurements of environmental toxicant body burdens into epidemiologic research, offer considerable promise for enhancing progress on characterizing pathogenesis mechanisms and identifying specific risk factors, especially for the non-familial forms of these diseases. In this chapter, brief overviews are provided of the epidemiologic features of PD, AD, and ALS, as well as illustrative examples in which molecular epidemiologic approaches have advanced knowledge on underlying disease mechanisms and risk factors that might lead to improved medical management and ultimately disease prevention. The chapter concludes with some recommendations for future molecular epidemiology research.}, }
@article {pmid21190141, year = {2011}, author = {Moreno-López, B and Sunico, CR and González-Forero, D}, title = {NO orchestrates the loss of synaptic boutons from adult "sick" motoneurons: modeling a molecular mechanism.}, journal = {Molecular neurobiology}, volume = {43}, number = {1}, pages = {41-66}, pmid = {21190141}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Cell Communication ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/*pathology/*ultrastructure ; Neurodegenerative Diseases/*pathology/*physiopathology ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type I/metabolism ; Peripheral Nervous System Diseases/pathology/physiopathology ; Presynaptic Terminals/*metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Synapse elimination is the main factor responsible for the cognitive decline accompanying many of the neuropathological conditions affecting humans. Synaptic stripping of motoneurons is also a common hallmark of several motor pathologies. Therefore, knowledge of the molecular basis underlying this plastic process is of central interest for the development of new therapeutic tools. Recent advances from our group highlight the role of nitric oxide (NO) as a key molecule triggering synapse loss in two models of motor pathologies. De novo expression of the neuronal isoform of NO synthase (nNOS) in motoneurons commonly occurs in response to the physical injury of a motor nerve and in the course of amyotrophic lateral sclerosis. In both conditions, this event precedes synaptic withdrawal from motoneurons. Strikingly, nNOS-synthesized NO is "necessary" and "sufficient" to induce synaptic detachment from motoneurons. The mechanism involves a paracrine/retrograde action of NO on pre-synaptic structures, initiating a downstream signaling cascade that includes sequential activation of (1) soluble guanylyl cyclase, (2) cyclic guanosine monophosphate-dependent protein kinase, and (3) RhoA/Rho kinase (ROCK) signaling. Finally, ROCK activation promotes phosphorylation of regulatory myosin light chain, which leads to myosin activation and actomyosin contraction. This latter event presumably contributes to the contractile force to produce ending axon retraction. Several findings support that this mechanism may operate in the most prevalent neurodegenerative diseases.}, }
@article {pmid21189118, year = {2011}, author = {Katsuno, M and Adachi, H and Banno, H and Suzuki, K and Tanaka, F and Sobue, G}, title = {Transforming growth factor-β signaling in motor neuron diseases.}, journal = {Current molecular medicine}, volume = {11}, number = {1}, pages = {48-56}, doi = {10.2174/156652411794474356}, pmid = {21189118}, issn = {1875-5666}, mesh = {Animals ; Humans ; Motor Neuron Disease/*metabolism/pathology/physiopathology ; Motor Neurons/physiology ; Muscle, Skeletal/metabolism ; Neuromuscular Junction/physiology ; Receptors, Transforming Growth Factor beta/metabolism ; Signal Transduction ; Spastic Paraplegia, Hereditary/*metabolism/physiopathology ; Transforming Growth Factor beta/*physiology ; }, abstract = {Transforming growth factor β (TGF-β), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. The TGF-β1, -β2, and -β3 isoforms are expressed by neurons and glial cells, and their receptors are expressed throughout the central nervous system. Several lines of evidence demonstrate that TGF-β signaling protects neurons from glutamate-mediated excitotoxicity, a putative mechanism underlying the pathogenesis of various neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Recent studies indicate that the TGF-β-Smad2/3 pathway restores motor function in a mouse model of ALS, and that disruption of TGF-β signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, the TGF-β-Smad2/3 pathway regulates the function of glial cells, although the implication of this regulation in neurodegeneration remains elusive. Conversely, myostatin, a member of the TGF-β superfamily, has gained attention as a potential therapeutic target for neuromuscular disorders because genetic deletion of this factor results in increased muscle volume. Signal transduction by BMP, a member of the TGF-β super family, regulates the function and growth of the neuromuscular junction, while the disruption of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-β signaling is an important molecular event in the pathogenesis of motor neuron diseases, and that the modification of this signaling pathway represents a new therapeutic strategy against these devastating disorders.}, }
@article {pmid21167830, year = {2011}, author = {Manuel, M and Heckman, CJ}, title = {Stronger is not always better: could a bodybuilding dietary supplement lead to ALS?.}, journal = {Experimental neurology}, volume = {228}, number = {1}, pages = {5-8}, pmid = {21167830}, issn = {1090-2430}, support = {R01 NS051462/NS/NINDS NIH HHS/United States ; R01 NS071951/NS/NINDS NIH HHS/United States ; R01 NS051462-05/NS/NINDS NIH HHS/United States ; R01 NS034382-15/NS/NINDS NIH HHS/United States ; R01 NS034382/NS/NINDS NIH HHS/United States ; R01 NS071951-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acids, Branched-Chain/adverse effects/chemistry ; Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Animals ; Dietary Supplements/*adverse effects ; Humans ; Muscle Strength/*drug effects/physiology ; *Resistance Training/methods ; }, }
@article {pmid21161612, year = {2011}, author = {Rodríguez, JJ and Verkhratsky, A}, title = {Neuroglial roots of neurodegenerative diseases?.}, journal = {Molecular neurobiology}, volume = {43}, number = {2}, pages = {87-96}, pmid = {21161612}, issn = {1559-1182}, mesh = {Animals ; Brain/pathology ; Humans ; Nerve Degeneration/complications/pathology ; Nerve Net/pathology ; Neurodegenerative Diseases/*pathology ; Neuroglia/*pathology ; Neurons/pathology ; }, abstract = {Neuroglia is critically important for controlling the brain homeostasis and for mounting the brain defence against pathological insults. Here, we overview recent data about the role of neuroglia in various types of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, Wernicke encephalopathy, amyotrophic lateral sclerosis and immunodeficiency virus-1-associated dementia). In all these forms of neurodegeneration, astroglia undergoes complex morphological and functional changes. The early and mid-term stages of neurodegenerative processes, and specifically of Alzheimer's disease, are associated with generalised atrophy of astroglia, whereas the later stages are characterised with an astrogliosis and microglial activation linked to neuropathological lesions such as senile plaques. Atrophic changes in astroglia may contribute to the initial cognitive deficits due to reduced glial synaptic coverage and decreased neuroprotection.}, }
@article {pmid21161300, year = {2011}, author = {Li, X and Jankovic, J and Le, W}, title = {Iron chelation and neuroprotection in neurodegenerative diseases.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {118}, number = {3}, pages = {473-477}, pmid = {21161300}, issn = {1435-1463}, mesh = {Humans ; Iron/*metabolism ; Iron Chelating Agents/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neurons/metabolism/pathology ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Iron is an essential element for multiple functions of the brain. Maintenance of iron homeostasis involves regulation of iron influx, iron efflux and iron storage. Mismanagement of brain iron has been implicated in neuronal injury and death in several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (PD) and Amyotrophic lateral sclerosis (ALS). Multiple iron chelators have been shown neuroprotective and neurorestorative in these diseases, suggesting that iron chelation might be a promising therapeutics. In this paper, we briefly review the new findings of biological function of several molecules that regulate iron homeostasis in the brain, the possible role of iron mismanagement in the pathogenesis of PD, AD and ALS, and then discuss the putative mechanisms for current available iron chelators as potential therapeutics for neurodegenerative diseases.}, }
@article {pmid21158735, year = {2011}, author = {Bodera, P}, title = {Immunostimulatory oligonucleotides.}, journal = {Recent patents on inflammation &amp; allergy drug discovery}, volume = {5}, number = {1}, pages = {87-93}, doi = {10.2174/187221311794474856}, pmid = {21158735}, issn = {1872-213X}, mesh = {Adjuvants, Immunologic/*pharmacology ; Animals ; Humans ; Oligodeoxyribonucleotides/pharmacology/therapeutic use ; Oligonucleotides/chemistry/*pharmacology ; Patents as Topic ; }, abstract = {RNA-protein interactions have been characterized often. Above all, the proteins which are associated with the studied RNA should be precisely identified. The pharmaceutical compositions containing nucleic acids and/or other compounds can be administered by any suitable route for administering medications. The immunostimulatory oligonucleotides play the role of antisense drugs which are being researched to treat cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, Amyotrophic lateral sclerosis (ALS), and diseases such as asthma and arthritis with an inflammatory component. The immunostimulatory oligonucleotides may contain one or more natural or unnatural amino acid residues which are connected to the polymer by peptide (amide) linkages. The vaccine against cancer which has been produced during this work can be prophylactic or therapeutic. Since most studies so far have been performed with first-generation antisense oligonucleotides (ODNs), it is interesting to observe how second-generation immune stimulatory drug candidates with enhanced potency and efficacy can further improve the utility of this class of therapeutic agents. The aim of this article is to review most significant patents on immunostimulatory oligonucleotides.}, }
@article {pmid21154313, year = {2010}, author = {Szymański, P and Markowicz, M and Janik, A and Ciesielski, M and Mikiciuk-Olasik, E}, title = {Neuroimaging diagnosis in neurodegenerative diseases.}, journal = {Nuclear medicine review. Central &amp; Eastern Europe}, volume = {13}, number = {1}, pages = {23-31}, pmid = {21154313}, issn = {1506-9680}, mesh = {Brain/blood supply/diagnostic imaging/metabolism/pathology ; Diagnostic Imaging/*methods ; Humans ; Neurodegenerative Diseases/*diagnosis/metabolism/pathology/physiopathology ; Radionuclide Imaging ; }, abstract = {Dementia affects about 8% of people age 65 years and older. Identification of dementia is particularly difficult in its early phases when family members and physicians often incorrectly attribute the patient's symptoms to normal aging. The most frequently occurring ailments that are connected with neurodegeneration are: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. A variety of powerful techniques that have allowed visualization of organ structure and function with exact detail have been introduced in the last twenty-five years. One such neuroimaging technique is positron emission tomography (PET), which measures in detail the functioning of distinct areas of the human brain and as a result plays a critical role in clinical and research applications. Radiotracer-based functional imaging provides a sensitive means of recognizing and characterizing the regional changes in brain metabolism and receptor binding associated with cognitive disorders. The next functional imaging technique widely used in the diagnosis of cognitive disorders is single photon emission computed tomography (SPECT). New radiotracers are being developed and promise to expand further the list of indications for PET. Prospects for developing new tracers for imaging other organ diseases also appear to be very promising. In this review, we present current opportunities of neuroimaging techniques in the diagnosis and differentiation of neurodegenerative disorders.}, }
@article {pmid21154151, year = {2010}, author = {Cheah, BC and Kiernan, MC}, title = {Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {12}, pages = {911-920}, pmid = {21154151}, issn = {2040-3410}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Benzothiazoles/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Dopamine Agonists/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Drugs, Investigational/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Humans ; Isomerism ; Pramipexole ; }, abstract = {Dexpramipexole (KNS-760704), the R(+) enantiomer of pramipexole, is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. Pramipexole, exclusively the S(-) enantiomer, is a non-ergot dopaminergic autoreceptor agonist that is currently marketed for use in the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity. More recent work has suggested that pramipexole possesses anti-excitotoxic properties, raising the possibility of beneficial effects in patients with ALS. However, pramipexole has high intrinsic dopaminergic receptor activity and, consequently, dose-limiting side effects, including orthostatic hypotension and hallucination, are frequent. Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects. In clinical trials to date, dexpramipexole has been safe and well tolerated at doses up to 67-fold higher than the maximum recommended daily dose of pramipexole in patients with Parkinson's disease, and has demonstrated signs of neuroprotective benefit. This report summarizes the chemical and pharmacological properties of dexpramipexole and describes the potential utility of the drug in the pharmaceutical development pipeline.}, }
@article {pmid21145355, year = {2011}, author = {Reddy, PH and Reddy, TP and Manczak, M and Calkins, MJ and Shirendeb, U and Mao, P}, title = {Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases.}, journal = {Brain research reviews}, volume = {67}, number = {1-2}, pages = {103-118}, pmid = {21145355}, issn = {1872-6321}, support = {P51 RR000163/RR/NCRR NIH HHS/United States ; R01 AG028072-04/AG/NIA NIH HHS/United States ; RR00163/RR/NCRR NIH HHS/United States ; AG026051/AG/NIA NIH HHS/United States ; R03 AG026051/AG/NIA NIH HHS/United States ; AG028072/AG/NIA NIH HHS/United States ; R01 AG028072/AG/NIA NIH HHS/United States ; K01 RR000163/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Cell Respiration/genetics/physiology ; Dynamins ; GTP Phosphohydrolases/genetics/*physiology ; Humans ; Microtubule-Associated Proteins/genetics/*physiology ; Mitochondria/genetics/*metabolism/pathology ; Mitochondrial Diseases/genetics/*metabolism/*pathology ; Mitochondrial Proteins/genetics/*physiology ; Models, Animal ; Mutation ; Neurodegenerative Diseases/genetics/*metabolism/*pathology ; }, abstract = {The purpose of this article is to review the recent developments of abnormal mitochondrial dynamics, mitochondrial fragmentation, and neuronal damage in neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The GTPase family of proteins, including fission proteins, dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1), and fusion proteins (Mfn1, Mfn2 and Opa1) are essential to maintain mitochondrial fission and fusion balance, and to provide necessary adenosine triphosphate to neurons. Among these, Drp1 is involved in several important aspects of mitochondria, including shape, size, distribution, remodeling, and maintenance of mitochondria in mammalian cells. In addition, recent advancements in molecular, cellular, electron microscopy, and confocal imaging studies revealed that Drp1 is associated with several cellular functions, including mitochondrial and peroxisomal fragmentation, phosphorylation, SUMOylation, ubiquitination, and cell death. In the last two decades, tremendous progress has been made in researching mitochondrial dynamics, in yeast, worms, and mammalian cells; and this research has provided evidence linking Drp1 to neurodegenerative diseases. Researchers in the neurodegenerative disease field are beginning to recognize the possible involvement of Drp1 in causing mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases. This article summarizes research findings relating Drp1 to mitochondrial fission and fusion, in yeast, worms, and mammals. Based on findings from the Reddy laboratory and others', we propose that mutant proteins of neurodegenerative diseases, including AD, PD, HD, and ALS, interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics, ultimately causing mitochondrial dysfunction and neuronal damage.}, }
@article {pmid21144012, year = {2010}, author = {Dantuma, E and Merchant, S and Sugaya, K}, title = {Stem cells for the treatment of neurodegenerative diseases.}, journal = {Stem cell research &amp; therapy}, volume = {1}, number = {5}, pages = {37}, pmid = {21144012}, issn = {1757-6512}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Multiple Sclerosis/therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; *Stem Cell Transplantation ; Stem Cells/metabolism ; }, abstract = {Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising.}, }
@article {pmid21143139, year = {2011}, author = {Skaper, SD}, title = {Ion channels on microglia: therapeutic targets for neuroprotection.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {10}, number = {1}, pages = {44-56}, doi = {10.2174/187152711794488638}, pmid = {21143139}, issn = {1996-3181}, mesh = {Animals ; Chloride Channels/metabolism ; Ion Channels/*metabolism ; Mice ; Microglia/metabolism/*physiology ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neurons/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Potassium Channels, Calcium-Activated/metabolism ; Rats ; Receptors, Purinergic P2X7/metabolism ; }, abstract = {Under pathological conditions microglia (resident CNS immune cells) become activated, and produce reactive oxygen and nitrogen species and pro-inflammatory cytokines: molecules that can contribute to axon demyelination and neuron death. Because some microglia functions can exacerbate CNS disorders, including stroke, traumatic brain injury, progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and several retinal diseases, controlling their activation might ameliorate immune-mediated CNS disorders. A growing body of evidence now points to ion channels on microglia as contributing to the above neuropathologies. For example, the ATP-gated P2X7 purinergic receptor cation channel is up-regulated around amyloid β-peptide plaques in transgenic mouse models of Alzheimer's disease and co-localizes to microglia and astrocytes. Upregulation of the P2X7 receptor subtype on microglia occurs also following spinal cord injury and after ischemia in the cerebral cortex of rats, while P2X7 receptor-like immunoreactivity is increased in activated microglial cells of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. Utilizing neuron/microglia co-cultures as an in vitro model for neuroinflammation, P2X7 receptor activation on microglia appears necessary for microglial cell-mediated injury of neurons. A second example can be found in the chloride intracellular channel 1 (CLIC1), whose expression is related to macrophage activation, undergoes translocation from the cytosol to the plasma membrane (activation) of microglia exposed to amyloid β-peptide, and participates in amyloid β-peptide-induced neurotoxicity through the generation of reactive oxygen species. A final example is the small-conductance Ca2+/calmodulin-activated K+ channel KCNN4/KCa3.1/SK4/IK1, which is highly expressed in rat microglia. Lipopolysaccharide-activated microglia are capable of killing adjacent neurons in co-culture, and show markedly reduced toxicity when treated with an inhibitor of KCa3.1 channels. Moreover, blocking KCa3.1 channels mitigated the neurotoxicity of amyloid β-peptide-stimulated microglia. Excessive microglial cell activation and production of potentially neurotoxic molecules, mediated by ion channels, may thus constitute viable targets for the discovery and development of neurodegenerative disease therapeutics. This chapter will review recent data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, with a focus on microglial ion channels and their neuroprotective potential.}, }
@article {pmid21135790, year = {2010}, author = {Dand, P and Sakel, M}, title = {The management of drooling in motor neurone disease.}, journal = {International journal of palliative nursing}, volume = {16}, number = {11}, pages = {560-564}, doi = {10.12968/ijpn.2010.16.11.80024}, pmid = {21135790}, issn = {1357-6321}, mesh = {Amyotrophic Lateral Sclerosis/*complications/nursing ; Botulinum Toxins/adverse effects/therapeutic use ; Humans ; Muscarinic Antagonists/adverse effects/therapeutic use ; Nursing Assessment ; Sialorrhea/etiology/*prevention &amp; control ; }, abstract = {Drooling is a common and potentially distressing symptom in those with motor neurone disease. A coordinated multidisciplinary approach is required to optimally manage this symptom. Both pharmacological and non-pharmacological strategies are required, and when drugs are used, off-label prescribing in terms of indication or route of administration is common. Further research needs to explore ways of enhancing swallowing ability as well as ways of optimizing drug therapies.}, }
@article {pmid21135580, year = {2011}, author = {Udan, M and Baloh, RH}, title = {Implications of the prion-related Q/N domains in TDP-43 and FUS.}, journal = {Prion}, volume = {5}, number = {1}, pages = {1-5}, pmid = {21135580}, issn = {1933-690X}, support = {K08 NS055980/NS/NINDS NIH HHS/United States ; R01 NS069669/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Asparagine/genetics ; DNA-Binding Proteins/*chemistry/*genetics/metabolism ; Frontotemporal Lobar Degeneration/genetics/metabolism ; Glutamine/genetics ; Humans ; Models, Genetic ; Mutation ; Neurons/metabolism ; Prions/*chemistry/metabolism ; Protein Structure, Tertiary ; RNA-Binding Protein FUS/*chemistry/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are clinically overlapping neurodegenerative disorders whose pathophysiology remains incompletely understood. ALS initiates in a discrete location, and typically progresses in a pattern consistent with spread of the degenerative process to involve neighboring regions of the motor system, although the basis of the apparent "spread" remains elusive. Recently mutations in two RNA binding proteins, TDP-43 and FUS, were identified in patients with familial ALS. In addition to being involved in numerous events related to RNA metabolism, each forms aggregates in neurons in ALS and FTLD. Recent evidence also indicates that both TDP-43 and FUS contain prion-related domains rich in glutamine (Q) and asparagine (N) residues, and in the case of TDP-43 this is the location of most disease causing mutations. This review discusses the potential relevance of the prion-related domains in TDP-43 and FUS in normal physiology, pathologic aggregation, and disease progression in ALS and FTLD.}, }
@article {pmid21133819, year = {2011}, author = {Kuzma-Kozakiewicz, M and Kwiecinski, H}, title = {New therapeutic targets for amyotrophic lateral sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {15}, number = {2}, pages = {127-143}, doi = {10.1517/14728222.2011.542152}, pmid = {21133819}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology/*therapy ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; *Molecular Targeted Therapy ; Motor Neurons/pathology ; Nerve Degeneration/genetics/pathology ; Oligonucleotides, Antisense/genetics/*pharmacology ; *RNA Interference ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; *Stem Cell Transplantation ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological disorders, affecting approximately half a million people worldwide. Currently there is no cure or prevention for ALS. Although ALS is a rare condition, it places a tremendous socioeconomic burden on patients, family members, caregivers and health systems.<br><br>AREAS COVERED: The review examines the mechanisms that may contribute to motor neuron degeneration in ALS, among which oxidative damage, glutatamate excitoxicity, mitochondrial dysfunction, impaired axonal transport, apoptotic cell death, growth factor deficiency, glial cell pathology and abnormal RNA metabolism are potential targets for ALS treatment. The article provides an overview of clinical trials performed to date in attempts to treat ALS with regard to molecular mechanisms and pathways they act on. It also discusses new trials based on recently developed molecular biology techniques.<br><br>EXPERT OPINION: Despite significant effectiveness of several potential therapeutics observed in preclinical trials, the results were not translatable to patients with ALS. The development of effective treatments of ALS strictly depends on understanding the primary cause of the disease. This goal will only be achieved when we identify the trigger point for motor neuron death in ALS.}, }
@article {pmid21130821, year = {2011}, author = {Jhala, SS and Hazell, AS}, title = {Modeling neurodegenerative disease pathophysiology in thiamine deficiency: consequences of impaired oxidative metabolism.}, journal = {Neurochemistry international}, volume = {58}, number = {3}, pages = {248-260}, doi = {10.1016/j.neuint.2010.11.019}, pmid = {21130821}, issn = {1872-9754}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Energy Metabolism/*physiology ; Humans ; Neurodegenerative Diseases/etiology/*metabolism/physiopathology ; Oxidation-Reduction ; Oxidative Phosphorylation/drug effects ; Thiamine/*metabolism ; Thiamine Deficiency/complications/*metabolism/physiopathology ; }, abstract = {Emerging evidence suggests that thiamine deficiency (TD), the cause of Wernicke's encephalopathy, produces alterations in brain function and structural damage that closely model a number of maladies in which neurodegeneration is a characteristic feature, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, along with alcoholic brain disease, stroke, and traumatic brain injury. Impaired oxidative metabolism in TD due to decreased activity of thiamine-dependent enzymes leads to a multifactorial cascade of events in the brain that include focal decreases in energy status, oxidative stress, lactic acidosis, blood-brain barrier disruption, astrocyte dysfunction, glutamate-mediated excitotoxicity, amyloid deposition, decreased glucose utilization, immediate-early gene induction, and inflammation. This review describes our current understanding of the basis of these abnormal processes in TD, their interrelationships, and why this disorder can be useful for our understanding of how decreased cerebral energy metabolism can give rise to cell death in different neurodegenerative disease states.}, }
@article {pmid21129596, year = {2010}, author = {Muñoz Blanco, JL}, title = {[Catastrophic neuromuscular diseases].}, journal = {Neurologia (Barcelona, Spain)}, volume = {25 Suppl 1}, number = {}, pages = {37-45}, doi = {10.1016/S0213-4853(10)70049-9}, pmid = {21129596}, issn = {1578-1968}, mesh = {*Acute Disease ; Guillain-Barre Syndrome/complications/diagnosis/physiopathology/therapy ; Humans ; Muscular Diseases/complications/diagnosis/physiopathology/therapy ; Myasthenia Gravis/complications/diagnosis/physiopathology/therapy ; Neuromuscular Diseases/*complications/diagnosis/*physiopathology/therapy ; Polyneuropathies/complications/diagnosis/physiopathology/therapy ; Prognosis ; Respiratory Insufficiency/*etiology/physiopathology/therapy ; Spirometry/instrumentation/methods ; }, abstract = {Neurologists should anticipate and recognize the onset of respiratory failure in patients with neuromuscular diseases. Symptoms vary according to the speed of onset of respiratory muscle weakness. Catastrophic situations usually occur in three clinical scenarios: 1) incorrect management of acute respiratory failure of neuromuscular origin, autonomic dysfunction or during general anaesthesia of patients with neuromuscular diseases ; 2) incorrect prognosis and treatment due to the lack of a correct diagnosis. This situation is more common in ventilated patients with associated muscular weakness, acute neuropathies or motor neuron disease, and 3) inappropriate medical intervention in patients with neuromuscular disease with a definitive diagnosis but longstanding disease (amyotrophic lateral sclerosis, spinal muscular atrophy, myotonic dystrophy and other muscular dystrophies).}, }
@article {pmid21128691, year = {2011}, author = {Gordon, PH}, title = {Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management.}, journal = {CNS drugs}, volume = {25}, number = {1}, pages = {1-15}, pmid = {21128691}, issn = {1179-1934}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/physiopathology ; Animals ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with a life expectancy of approximately 3 years after symptom onset, but the range of survival extends from a few months for some to decades for approximately 5% of patients. There is no clear cause in the majority of cases and just one medication, riluzole, has been shown to modestly prolong survival. Research has identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, generation of free radicals, excitotoxicity, inflammation and apoptosis, but for most patients the underlying cause is unknown. While ALS is considered to be a complex genetic disorder in which multiple genes in combination with environmental exposures combine to render a person susceptible, few genetic or environmental risks have been discovered to date. The diagnosis is based on the history and examination showing progressive upper and lower motor neuron findings. The electromyogram can help confirm the diagnosis, and additional tests are used to exclude other conditions. Published practice parameters guide the care of patients with ALS. Until the elucidation of aetiologies leads to the development of more robust neuroprotective agents, both pharmacological and nonpharmacological treatments are directed at maintaining quality of life and prolonging life to the greatest extent possible. Riluzole, ventilatory support for those with respiratory insufficiency, gastrostomy for those with dysphagia and multidisciplinary care may help extend life. The off-label use of many symptomatic agents can have a meaningful impact for those with the illness. Palliative care ensures dignity toward the end stages of the disease. Clinical trials currently aim to slow disease progression by testing drugs that impact one or more of the processes that are initiated after disease onset. Novel therapies currently in trials include potential neuroprotective agents with differing mechanisms of action, vaccine therapies, stem cell injections and diaphragmatic pacing.}, }
@article {pmid21124004, year = {2011}, author = {Wegorzewska, I and Baloh, RH}, title = {TDP-43-based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology.}, journal = {Neuro-degenerative diseases}, volume = {8}, number = {4}, pages = {262-274}, pmid = {21124004}, issn = {1660-2862}, support = {K08 NS055980/NS/NINDS NIH HHS/United States ; R01 NS069669/NS/NINDS NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Animals ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; Frontotemporal Lobar Degeneration/genetics/physiopathology ; Humans ; Nerve Degeneration/genetics/physiopathology ; }, abstract = {The clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) suggests these diseases share common underlying mechanisms, a suggestion underscored by the discovery that TDP-43 inclusions are a key pathologic feature in both ALS and FTLD. This finding, combined with the identification of TDP-43 mutations in ALS, directly implicates this DNA/RNA binding protein in disease pathogenesis in ALS and FTLD. However, many key questions remain, including what is the normal function of TDP-43, and whether disease-associated mutations produce toxicity in the nucleus, cytoplasm or both. Furthermore, although pathologic TDP-43 inclusions are clearly associated with many forms of neurodegeneration, whether TDP-43 aggregation is a key step in the pathogenesis in ALS, FTLD and other disorders remains to be proven. This review will compare the features of numerous recently developed animal models of TDP-43-related neurodegeneration, and discuss how they contribute to our understanding of the pathogenesis of human ALS and FTLD.}, }
@article {pmid21123936, year = {2010}, author = {Ishizaki, F and Koyama, T and Sunayashiki, T and Murata, Y and Iida, T and Harada, T}, title = {[Control of bone remodeling by nervous system. Bone metabolic changes in neurological diseases].}, journal = {Clinical calcium}, volume = {20}, number = {12}, pages = {1841-1849}, pmid = {21123936}, issn = {0917-5857}, mesh = {Bone Diseases, Metabolic/*etiology/*metabolism ; *Bone Remodeling ; Bone Resorption/etiology/metabolism ; Bone and Bones/*metabolism ; Cardiovascular Diseases/complications/metabolism ; Fractures, Spontaneous/etiology/prevention &amp; control ; Humans ; Neurodegenerative Diseases/*complications/*metabolism ; }, abstract = {We introduced the relationship between bone change and neurological disturbance in the patients with cerebrovascular disease (CVD) , Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) . High incidence of osteoporosis and right/left difference in osteopenia are found in the diseases. CVD and PD patients with asymmetrical osteopenia show an association between clinical symptoms, peripheral circulatory symptoms, and predominant osteopenia. Although the muscle strength of PD patients was normal, the more severely affected side for PD symptoms and autonomic symptoms coincided with predominant osteopenia in the body. Increased bone resorption was detected in ALS patients. We speculated that neurological disturbances affect the remodeling of local sites of the bone. We have to start treatment from an early stage of the neurological disease to prevent a fracture.}, }
@article {pmid21122469, year = {2010}, author = {Maas, S}, title = {Gene regulation through RNA editing.}, journal = {Discovery medicine}, volume = {10}, number = {54}, pages = {379-386}, pmid = {21122469}, issn = {1944-7930}, mesh = {Gene Expression Regulation/*genetics ; Genetic Therapy ; Humans ; *RNA Editing ; }, abstract = {RNA editing by adenosine deamination is a posttranscriptional mechanism for the regulation of gene expression and is particularly widespread in mammals. A-to-I RNA editing generates transcriptome and proteome diversity allowing organisms to produce many more gene products and functions than predicted based on the number of genes within their genome. Also, it regulates important functional properties of neurotransmitter receptor genes in the central nervous system by changing single codons in pre-mRNA. The deficiency or misregulation of editing has been implicated in the etiology of neurological diseases, such as epilepsy, amyotrophic lateral sclerosis (ALS), depression and tumor progression. Widespread A-to-I modification of repeat sequences in the human transcriptome suggests additional roles for RNA editing and links it to other processes of gene regulation, such as RNA splicing as well as siRNA mediated gene silencing and miRNA function. Here, I am reviewing main features of this epigenetic phenomenon, its relevance for health and disease, as well as potential prospects for using RNA editing as a therapeutic tool.}, }
@article {pmid21117312, year = {2010}, author = {Jodko, K and Litwinienko, G}, title = {[Oxidative stress in the neurodegenerative diseases--potential antioxidant activity of catecholamines].}, journal = {Postepy biochemii}, volume = {56}, number = {3}, pages = {248-259}, pmid = {21117312}, issn = {0032-5422}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Antioxidants/metabolism ; Dopamine/*metabolism ; Epinephrine/*metabolism ; Free Radical Scavengers/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Norepinephrine/*metabolism ; *Oxidative Stress ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis), are characterized by the deposition of misfolded proteins (alpha beta-peptide, alpha-synucleine and Cu, Zn superoxide dismutase, respectively). Oxidative stress is accompanied by the diminished level of catecholamines in neuronal tissue. Beside their role in transduction of nervous stimuli, catecholamines might act as antioxidants. Herein, we focused on the antioxidant activity of catecholamine neurotransmitters--dopamine (and its precursor L-DOPA), adrenaline and noradrenaline. There is an increasing evidence that catecholamines might act as scavengers of free radicals and experimental data indicate the antioxidant potency of catecholamines. However, the exact mechanism of this action is not defined.}, }
@article {pmid21115738, year = {2011}, author = {Liu, Y and Filler, SG}, title = {Candida albicans Als3, a multifunctional adhesin and invasin.}, journal = {Eukaryotic cell}, volume = {10}, number = {2}, pages = {168-173}, pmid = {21115738}, issn = {1535-9786}, support = {R01 AI054928/AI/NIAID NIH HHS/United States ; R01 DE017088/DE/NIDCR NIH HHS/United States ; R01AI054928/AI/NIAID NIH HHS/United States ; R01DE017088/DE/NIDCR NIH HHS/United States ; }, mesh = {Biofilms/*growth &amp; development ; Candida albicans/immunology/pathogenicity/*physiology ; Candidiasis/immunology/prevention &amp; control ; Cell Adhesion ; Fungal Proteins/*metabolism ; Fungal Vaccines ; Humans ; Iron/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Sequence Homology ; Streptococcus gordonii/growth &amp; development ; }, abstract = {Candida albicans is part of the normal human flora, and it grows on mucosal surfaces in healthy individuals. In susceptible hosts, this organism can cause both mucosal and hematogenously disseminated disease. For C. albicans to persist in the host and induce disease, it must be able to adhere to biotic and abiotic surfaces, invade host cells, and obtain iron. The C. albicans hypha-specific surface protein Als3 is a member of the agglutinin-like sequence (Als) family of proteins and is important in all of these processes. Functioning as an adhesin, Als3 mediates attachment to epithelial cells, endothelial cells, and extracellular matrix proteins. It also plays an important role in biofilm formation on prosthetic surfaces, both alone and in mixed infection with Streptococcus gordonii. Als3 is one of two known C. albicans invasins. It binds to host cell receptors such as E-cadherin and N-cadherin and thereby induces host cells to endocytose the organism. Als3 also binds to host cell ferritin and enables C. albicans to utilize this protein as a source of iron. Because of its multiple functions and its high expression level in vivo, Als3 is a promising target for vaccines that induce protective cell-mediated and antibody responses. This review will summarize the multiple functions of this interesting and multifunctional protein.}, }
@article {pmid21115123, year = {2011}, author = {Armakola, M and Hart, MP and Gitler, AD}, title = {TDP-43 toxicity in yeast.}, journal = {Methods (San Diego, Calif.)}, volume = {53}, number = {3}, pages = {238-245}, pmid = {21115123}, issn = {1095-9130}, support = {DP2 OD004417-01/OD/NIH HHS/United States ; DP2 OD004417/OD/NIH HHS/United States ; 1R01NS065317-01/NS/NINDS NIH HHS/United States ; R01 NS065317-01/NS/NINDS NIH HHS/United States ; 1DP2OD004417-01/OD/NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/pathology ; Gene Deletion ; Genetic Testing ; Humans ; Inclusion Bodies/metabolism ; Mutation, Missense ; Organisms, Genetically Modified ; Parkinson Disease/pathology ; Prion Diseases/pathology ; Protein Folding ; Saccharomyces cerevisiae/*genetics ; }, abstract = {The budding yeast Saccharomyces cerevisiae is an emerging tool for investigating the molecular pathways that underpin several human neurodegenerative disorders associated with protein misfolding. Amyotrophic lateral sclerosis (ALS) is a devastating adult onset neurodegenerative disease primarily affecting motor neurons. The protein TDP-43 has recently been demonstrated to play an important role in the disease, however, the mechanisms by which TDP-43 contributes to pathogenesis are unclear. To explore the mechanistic details that result in aberrant accumulation of TDP-43 and to discover potential strategies for therapeutic intervention, we employed a yeast TDP-43 proteinopathy model system. These studies allowed us to determine the regions of TDP-43 required for aggregation and toxicity and to define the effects of ALS-linked mutant forms of TDP-43. We have also been able to harness the power of yeast genetics to identify potent modifiers of TDP-43 toxicity using high-throughput yeast genetic screens. Here, we describe the methods and approaches that we have used in order to gain insight into TDP-43 biology and its role in disease. These approaches are readily adaptable to other neurodegenerative disease proteins.}, }
@article {pmid21097546, year = {2011}, author = {Donaghy, C and Thurtell, MJ and Pioro, EP and Gibson, JM and Leigh, RJ}, title = {Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {82}, number = {1}, pages = {110-116}, doi = {10.1136/jnnp.2010.212407}, pmid = {21097546}, issn = {1468-330X}, support = {EY06717/EY/NEI NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*physiopathology ; Disease Progression ; Eye Movements/*physiology ; Fixation, Ocular/physiology ; Humans ; Male ; Nystagmus, Pathologic/etiology ; Ocular Motility Disorders/diagnosis/*etiology/physiopathology ; Ophthalmoplegia/etiology ; Saccades ; Supranuclear Palsy, Progressive/physiopathology ; }, abstract = {Abnormal eye movements are increasingly recognised in patients with amyotrophic lateral sclerosis (ALS) and, when they occur, may provide insights into the pattern and pathogenesis of the disease process. In patients with disorders that mimic ALS, abnormal eye movements may point to the correct diagnosis. In both of these circumstances, systematic examination of eye movements and interpretation of the findings with reference to modern concepts of their neural substrate will aid diagnosis and suggest pathogenesis. Here, key points with illustrative case histories and eye movement records are highlighted.}, }
@article {pmid21092256, year = {2010}, author = {Ryynänen, OP and Iirola, T and Reitala, J and Pälve, H and Malmivaara, A}, title = {Is advanced life support better than basic life support in prehospital care? A systematic review.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {18}, number = {}, pages = {62}, pmid = {21092256}, issn = {1757-7241}, mesh = {*Advanced Cardiac Life Support ; Emergency Medical Services/*methods/standards ; Humans ; *Life Support Care ; Outcome Assessment, Health Care ; Quality-Adjusted Life Years ; Survival Analysis ; }, abstract = {BACKGROUND: Prehospital care is classified into ALS- (advanced life support) and BLS- (basic life support) levels according to the methods used. ALS-level prehospital care uses invasive methods, such as intravenous fluids, medications and intubation. However, the effectiveness of ALS care compared to BLS has been questionable.<br><br>AIM: The aim of this systematic review is to compare the effectiveness of ALS- and BLS-level prehospital care.<br><br>MATERIAL AND METHODS: In a systematic review, articles where ALS-level prehospital care was compared to BLS-level or any other treatment were included. The outcome variables were mortality or patient's health-related quality of life or patient's capacity to perform daily activities.<br><br>RESULTS: We identified 46 articles, mostly retrospective observational studies. The results on the effectiveness of ALS in unselected patient cohorts are contradictory. In cardiac arrest, early cardiopulmonary resuscitation and defibrillation are essential for survival, but prehospital ALS interventions have not improved survival. Prehospital thrombolytic treatment reduces mortality in patients having a myocardial infarction. The majority of research into trauma favours BLS in the case of penetrating trauma and also in cases of short distance to a hospital. In patients with severe head injuries, ALS provided by paramedics and intubation without anaesthesia can even be harmful. If the prehospital care is provided by an experienced physician and by a HEMS organisation (Helicopter Emergency Medical Service), ALS interventions may be beneficial for patients with multiple injuries and severe brain injuries. However, the results are contradictory.<br><br>CONCLUSIONS: ALS seems to improve survival in patients with myocardial infarction and BLS seems to be the proper level of care for patients with penetrating injuries. Some studies indicate a beneficial effect of ALS among patients with blunt head injuries or multiple injuries. There is also some evidence in favour of ALS among patients with epileptic seizures as well as those with a respiratory distress.}, }
@article {pmid21088432, year = {2011}, author = {Marin, B and Couratier, P and Preux, PM and Logroscino, G}, title = {Can mortality data be used to estimate amyotrophic lateral sclerosis incidence?.}, journal = {Neuroepidemiology}, volume = {36}, number = {1}, pages = {29-38}, doi = {10.1159/000321930}, pmid = {21088432}, issn = {1423-0208}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/mortality ; *Death Certificates ; Humans ; Incidence ; United States/epidemiology ; }, abstract = {BACKGROUND: Because studies of the incidence of amyotrophic lateral sclerosis (ALS) have uncertain feasibility and high costs, mortality rates are often used to provide an estimate. We performed a systematic review of the literature concerning mortality related to ALS. We aimed to use well-known criteria of good epidemiological practice to assess the methodological quality of the studies.<br><br>METHODS: A Medline and ScienceDirect literature search was performed to identify studies on ALS mortality published from 1971 to 2009. The literature was examined following 6 criteria.<br><br>RESULTS: Of the 29 studies examined, almost all presented a clear definition of the population at risk, but 55% of the papers did not report on the accuracy of death certificates, and the use of both 'underlying' and 'contributory' causes of death was identified in only 41% of cases. When comparing ALS mortality data between calendar dates, the codes from the International Classification of Diseases were consistent overall, except in 3 studies. A majority of articles that compared mortality patterns between geographical regions or ethnic groups discussed the key issues of comparability of health care and equality of access. Overall, among the 29 ALS mortality studies, only 3 complied with all the criteria. In 2 of them, the mortality rates were highly consistent with available incidence data.<br><br>CONCLUSION: Only few studies on mortality data followed a high-quality methodology. When studies complied with the criteria, they showed good accuracy with regard to incidence rates. The criteria used in this study could also be used to guide future studies based on mortality data.}, }
@article {pmid21088431, year = {2011}, author = {Hoppitt, T and Pall, H and Calvert, M and Gill, P and Yao, G and Ramsay, J and James, G and Conduit, J and Sackley, C}, title = {A systematic review of the incidence and prevalence of long-term neurological conditions in the UK.}, journal = {Neuroepidemiology}, volume = {36}, number = {1}, pages = {19-28}, pmid = {21088431}, issn = {1423-0208}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Ataxia/*epidemiology ; Charcot-Marie-Tooth Disease/*epidemiology ; Humans ; Huntington Disease/*epidemiology ; Incidence ; Multiple System Atrophy/*epidemiology ; Postpoliomyelitis Syndrome/*epidemiology ; Prevalence ; Supranuclear Palsy, Progressive/*epidemiology ; United Kingdom/epidemiology ; }, abstract = {BACKGROUND: Updated, robust estimates of the incidence and prevalence of rare long-term neurological conditions in the UK are not available. Global estimates may be misrepresentative as disease aetiology may vary by location.<br><br>OBJECTIVES: To systematically review the incidence and prevalence of long-term neurological conditions in the UK since 1988.<br><br>SEARCH STRATEGY: Medline (January 1988 to January 2009), Embase (January 1988 to January 2009), CINAHL (January 1988 to January 2009) and Cochrane CENTRAL databases.<br><br>SELECTION CRITERIA: UK population-based incidence/prevalence studies of long-term neurological conditions since 1988. Exclusion criteria included inappropriate diagnoses and incomprehensive case ascertainment.<br><br>DATA COLLECTION AND ANALYSIS: Articles were included based on the selection criteria. Data were extracted from articles with ranges of incidence and prevalence reported.<br><br>MAIN RESULTS: Eight studies met the criteria (3 on motor neurone disease; 4 on Huntington's disease; 1 on progressive supranuclear palsy). The incidence of motor neurone disease ranged from 1.06 to 2.4/100,000 person-years. The prevalence ranged from 4.02 to 4.91/100,000. The prevalence of Huntington's disease ranged from 4.0 to 9.94/100,000. The prevalence of progressive supranuclear palsy ranged from 3.1 to 6.5/100,000.<br><br>CONCLUSIONS: The review updates the incidence/prevalence of long-term neurological conditions. Future epidemiological studies must incorporate comprehensive case ascertainment methods and strict diagnostic criteria.}, }
@article {pmid21086759, year = {2010}, author = {Barmada, SJ and Finkbeiner, S}, title = {Pathogenic TARDBP mutations in amyotrophic lateral sclerosis and frontotemporal dementia: disease-associated pathways.}, journal = {Reviews in the neurosciences}, volume = {21}, number = {4}, pages = {251-272}, doi = {10.1515/revneuro.2010.21.4.251}, pmid = {21086759}, issn = {0334-1763}, support = {2R01 NS039074/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; DNA-Binding Proteins/*genetics/metabolism ; Frontotemporal Dementia/*genetics/pathology ; Humans ; Models, Biological ; Mutation/*genetics ; RNA, Messenger/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are late-onset neurodegenerative disorders that are associated with mutations in the TARDBP gene. The product of this gene, TDP-43, has also been identified as the main component of the intracellular inclusions typical of most cases of ALS and FTD. Recent evidence suggests that TDP-43 is essential for proper development and involved in several fundamental cellular processes, including gene transcription, RNA processing, and the spatial regulation of mRNA translation. Pathogenic TARDBP mutations that impair TDP-43 function could therefore be related to neuronal degeneration in ALS and FTD. Conversely, cellular and animal studies have shown that pathogenic TARDBP mutations induce neuronal toxicity through mislocalization or elevated concentrations of TDP-43, consistent with a gain-of-function mechanism. In this review, we focus on the physiologic functions of TDP-43 within the central nervous system and discuss how these functions may be perturbed or pathologically altered by disease-associated mutations.}, }
@article {pmid21082892, year = {2010}, author = {Joyce, N and Annett, G and Wirthlin, L and Olson, S and Bauer, G and Nolta, JA}, title = {Mesenchymal stem cells for the treatment of neurodegenerative disease.}, journal = {Regenerative medicine}, volume = {5}, number = {6}, pages = {933-946}, pmid = {21082892}, issn = {1746-076X}, support = {R01 DK061848/DK/NIDDK NIH HHS/United States ; R01 GM099688/GM/NIGMS NIH HHS/United States ; 1R01 HL073256-01/HL/NHLBI NIH HHS/United States ; S10 RR026825/RR/NCRR NIH HHS/United States ; R01 HL073256-06/HL/NHLBI NIH HHS/United States ; 5P30AG010129-19/AG/NIA NIH HHS/United States ; S10 RR026825-01/RR/NCRR NIH HHS/United States ; R01 HL073256/HL/NHLBI NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Clinical Trials as Topic ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; Neurodegenerative Diseases/pathology/*therapy ; Neurotransmitter Agents/metabolism ; Wound Healing ; }, abstract = {Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.}, }
@article {pmid21082322, year = {2011}, author = {Hardiman, O}, title = {Management of respiratory symptoms in ALS.}, journal = {Journal of neurology}, volume = {258}, number = {3}, pages = {359-365}, pmid = {21082322}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology/*therapy ; Animals ; Disease Management ; Humans ; Palliative Care/methods ; Respiration, Artificial/methods ; Respiratory Insufficiency/etiology/*physiopathology/*therapy ; Respiratory Mechanics/physiology ; Respiratory Muscles/physiopathology ; }, abstract = {Respiratory insufficiency is a frequent feature of ALS and is present in almost all cases at some stage of the illness. It is the commonest cause of death in ALS. FVC is used as important endpoint in many clinical trials, and in decision-making events for patients with ALS, although there are limitations to its predictive utility. There are multiple causes of respiratory muscle failure, all of which act to produce a progressive decline in pulmonary function. Diaphragmatic fatigue and weakness, coupled with respiratory muscle weakness, lead to reduced lung compliance and atelectasis. Increased secretions increase the risk of aspiration pneumonia, which further compromises respiratory function. Bulbar dysfunction can lead to nutritional deficiency, which in turn increases the fatigue of respiratory muscles. Early recognition of respiratory decline and symptomatic intervention, including non-invasive ventilation can significantly enhance both quality of life and life expectancy in ALS. Patients with respiratory failure should be advised to consider an advance directive to avoid emergency mechanical ventilation.}, }
@article {pmid21080240, year = {2011}, author = {Traub, R and Mitsumoto, H and Rowland, LP}, title = {Research advances in amyotrophic lateral sclerosis, 2009 to 2010.}, journal = {Current neurology and neuroscience reports}, volume = {11}, number = {1}, pages = {67-77}, pmid = {21080240}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology/*physiopathology/therapy ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Genetic Therapy ; Humans ; Mitochondria/metabolism/pathology ; Mutation ; RNA-Binding Protein FUS/genetics ; Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons that causes progressive weakness and death. The breadth of research in ALS continues to grow with exciting new discoveries in disease pathogenesis and potential future therapeutics. There is a growing list of identified mutations in familial ALS, including those in genes encoding TDP-43 and FUS/TLS, which are expanding our understanding of the role of RNA modulation in ALS pathogenesis. There is a greater appreciation for the role of glial cells in motor neuron disease. Mitochondrial dysfunction is also being shown to be critical for motor neuron degeneration. In addition to pharmacotherapy, there are promising early developments with therapeutic implications in the areas of RNA interference, stem cell therapies, viral vector-mediated gene therapy, and immunotherapy. With greater understanding of ALS pathogenesis and exciting new therapeutic technologies, there is hope for future progress in treating this disease.}, }
@article {pmid21059520, year = {2010}, author = {Schellenberg, KL and Johnston, WS and Kalra, S and Resch, L and Johnson, ES}, title = {Inclusion body myositis masquerading as amyotrophic lateral sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {37}, number = {5}, pages = {687-691}, doi = {10.1017/s031716710001091x}, pmid = {21059520}, issn = {0317-1671}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; CD8 Antigens/metabolism ; Humans ; Inclusion Bodies/pathology/ultrastructure ; Male ; Myositis, Inclusion Body/*diagnosis/metabolism/pathology ; }, }
@article {pmid21057983, year = {2011}, author = {Dadon-Nachum, M and Melamed, E and Offen, D}, title = {The "dying-back" phenomenon of motor neurons in ALS.}, journal = {Journal of molecular neuroscience : MN}, volume = {43}, number = {3}, pages = {470-477}, pmid = {21057983}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Cell Death/*physiology ; Humans ; Mice ; Motor Neurons/cytology/*pathology/physiology ; Muscle, Skeletal/pathology/physiopathology ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal disease, characterized by progressive death of motor neurons with unknown etiology. Evidence from animal models indicates that neuronal dysfunction precedes the clinical phase of the disease. However, in parallel extensive nerve sprouting and synaptic remodeling as part of a compensatory reinnervation processes and possibly also of motor neurons pathology was demonstrated. Therefore, the weakness in muscle groups will not be clinically apparent until a large proportion of motor units are lost. This motor unit loss and associated muscle function which precedes the death of motor neurons may resemble the "die-back" phenomena. Studies indicated that in the early stages the nerve terminals and motor neuron junctions are partially degraded while the cell bodies in the spinal cord are mostly intact. Treatments to rescue motor neurons according to "dying-forward" model of motor neuron pathology in ALS have shown only limited success in SOD1(G93A) transgenic mice as well as in humans. If cell body degeneration is late compared with axonal degeneration, early intervention could potentially prevent loss of motor neurons. Therefore, it should be considered, according to the dying back hypothesis, to focus on motor neurons terminals in order to delay or prevent the progressive degradation.}, }
@article {pmid21047878, year = {2011}, author = {Byrne, S and Walsh, C and Lynch, C and Bede, P and Elamin, M and Kenna, K and McLaughlin, R and Hardiman, O}, title = {Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {82}, number = {6}, pages = {623-627}, doi = {10.1136/jnnp.2010.224501}, pmid = {21047878}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/genetics ; Humans ; Mutation ; Superoxide Dismutase/genetics ; }, abstract = {BACKGROUND: The population rate of familial amyotrophic lateral sclerosis (FALS) is frequently reported as 10%. However, a systematic review and meta-analysis of the true population based frequency of FALS has never been performed.<br><br>METHOD: A Medline literature review identified all original articles reporting a rate of FALS. Studies were grouped according to the type of data presented and examined for sources of case ascertainment. A systematic review and meta-analysis of reported rates of FALS was then conducted to facilitate comparison between studies and calculate a pooled rate of FALS.<br><br>RESULTS: 38 papers reported a rate of FALS. Thirty-three papers were included in analysis and the rate of FALS for all studies was 4.6% (95% CI 3.9% to 5.5%). Restricting the analysis to prospective population based registry data revealed a rate of 5.1% (95% CI 4.1% to 6.1%). The incidence of FALS was lower in southern Europe. There was no correlation between rate of FALS and reported SOD1 mutation rates.<br><br>CONCLUSION: The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.}, }
@article {pmid21046450, year = {2010}, author = {Elias, S and Delestre, C and Courel, M and Anouar, Y and Montero-Hadjadje, M}, title = {Chromogranin A as a crucial factor in the sorting of peptide hormones to secretory granules.}, journal = {Cellular and molecular neurobiology}, volume = {30}, number = {8}, pages = {1189-1195}, pmid = {21046450}, issn = {1573-6830}, mesh = {Animals ; Chromogranin A/*metabolism ; Humans ; Models, Biological ; Peptide Hormones/chemistry/*metabolism ; Protein Structure, Quaternary ; Protein Transport ; Secretory Vesicles/*metabolism ; }, abstract = {Chromogranin A (CgA) is a soluble glycoprotein stored along with hormones and neuropeptides in secretory granules of endocrine cells. In the last four decades, intense efforts have been concentrated to characterize the structure and the biological function of CgA. Besides, CgA has been widely used as a diagnostic marker for tumors of endocrine origin, essential hypertension, various inflammatory diseases, and neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. CgA displays peculiar structural features, including numerous multibasic cleavage sites for prohormone convertases as well as a high proportion of acidic residues. Thus, it has been proposed that CgA represents a precursor of biologically active peptides, and a "granulogenic protein" that plays an important role as a chaperone for catecholamine storage in adrenal chromaffin cells. The widespread distribution of CgA throughout the neuroendocrine system prompted several groups to investigate the role of CgA in peptide hormone sorting to the regulated secretory pathway. This review summarizes the findings and theoretical concepts around the molecular machinery used by CgA to exert this putative intracellular function. Since CgA terminal regions exhibited strong sequence conservation through evolution, our work focused on the implication of these domains as potential functional determinants of CgA. Characterization of the molecular signals implicating CgA in the intracellular traffic of hormones represents a major biological issue that may contribute to unraveling the mechanisms defining the secretory competence of neuroendocrine cells.}, }
@article {pmid21043995, year = {2011}, author = {Eccles, FJ and Simpson, J}, title = {A review of the demographic, clinical and psychosocial correlates of perceived control in three chronic motor illnesses.}, journal = {Disability and rehabilitation}, volume = {33}, number = {13-14}, pages = {1065-1088}, doi = {10.3109/09638288.2010.525287}, pmid = {21043995}, issn = {1464-5165}, mesh = {Adaptation, Psychological ; Helplessness, Learned ; Humans ; *Internal-External Control ; Motor Neuron Disease/*psychology/rehabilitation ; Multiple Sclerosis/*psychology/rehabilitation ; Parkinson Disease/*psychology/rehabilitation ; Self Efficacy ; }, abstract = {PURPOSE: To review the correlates of measures of control in people with multiple sclerosis (MS), Parkinson's disease (PD) and motor neurone disease (MND).<br><br>METHOD: Studies on the relationship between aspects of control and demographic, clinical and psychological factors were collated and reviewed using a narrative synthesis.<br><br>RESULTS: Forty-four papers were found which examined different types of both disease and life control. PD studies had not examined self-efficacy or helplessness and only locus of control was used in MND studies. Age, gender and disease duration were not consistently related to control, but greater participant-rated physical impairment was associated with lower perception of some control concepts. The association between symptom control and psychological wellbeing was weak and may be disease dependent. Stronger positive relationships were found between psychosocial wellbeing and both global life control and self-efficacy for disease management and adjustment.<br><br>CONCLUSIONS: Further research, particularly longitudinal, is needed. Perceptions of control were not completely determined by disease stage/disability. Increased perception of certain types of control was associated with wellbeing and thus interventions should be developed to promote increased control. Although results were dominated by MS, they appear largely applicable to people with PD but more caution is needed for MND.}, }
@article {pmid21035400, year = {2011}, author = {Dupuis, L and Pradat, PF and Ludolph, AC and Loeffler, JP}, title = {Energy metabolism in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {10}, number = {1}, pages = {75-82}, doi = {10.1016/S1474-4422(10)70224-6}, pmid = {21035400}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism/physiopathology/therapy ; *Energy Metabolism/drug effects ; Exercise/physiology ; Foodborne Diseases/etiology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Nutritional Physiological Phenomena ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised by the progressive degeneration of upper and lower motor neurons. Besides motor neuron degeneration, ALS is associated with several defects in energy metabolism, including weight loss, hypermetabolism, and hyperlipidaemia. Most of these abnormalities correlate with duration of survival, and available clinical evidence supports a negative contribution of defective energy metabolism to the overall pathogenic process. Findings from animal models of ALS support this view and provide insights into the underlying mechanisms. Altogether, these results have clinical consequences for the management of defective energy metabolism in patients with ALS and pave the way for future therapeutic interventions.}, }
@article {pmid20971753, year = {2011}, author = {Seelaar, H and Rohrer, JD and Pijnenburg, YA and Fox, NC and van Swieten, JC}, title = {Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {82}, number = {5}, pages = {476-486}, doi = {10.1136/jnnp.2010.212225}, pmid = {20971753}, issn = {1468-330X}, support = {G0401247/MRC_/Medical Research Council/United Kingdom ; G0601846/MRC_/Medical Research Council/United Kingdom ; G0801306/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Biomarkers/blood/cerebrospinal fluid ; Brain/pathology ; Cognition ; Executive Function ; Frontotemporal Dementia/diagnosis/genetics/*pathology/psychology ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Magnetic Resonance Imaging ; Progranulins ; Risk Factors ; Social Perception ; tau Proteins/genetics ; }, abstract = {Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43&amp;emsp14;kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.}, }
@article {pmid20971133, year = {2011}, author = {Gould, TW and Oppenheim, RW}, title = {Motor neuron trophic factors: therapeutic use in ALS?.}, journal = {Brain research reviews}, volume = {67}, number = {1-2}, pages = {1-39}, pmid = {20971133}, issn = {1872-6321}, support = {R01 NS048982/NS/NINDS NIH HHS/United States ; R01 NS048982-04/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*pathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Motor Neurons/*drug effects/metabolism/pathology ; Nerve Degeneration/*drug therapy/metabolism/*pathology ; Nerve Growth Factors/*pharmacology/physiology/therapeutic use ; }, abstract = {The modest effects of neurotrophic factor (NTF) treatment on lifespan in both animal models and clinical studies of Amyotropic Lateral Sclerosis (ALS) may result from any one or combination of the four following explanations: 1.) NTFs block cell death in some physiological contexts but not in ALS; 2.) NTFs do not rescue motoneurons (MNs) from death in any physiological context; 3.) NTFs block cell death in ALS but to no avail; and 4.) NTFs are physiologically effective but limited by pharmacokinetic constraints. The object of this review is to critically evaluate the role of both NTFs and the intracellular cell death pathway itself in regulating the survival of spinal and cranial (lower) MNs during development, after injury and in response to disease. Because the role of molecules mediating MN survival has been most clearly resolved by the in vivo analysis of genetically engineered mice, this review will focus on studies of such mice expressing reporter, null or other mutant alleles of NTFs, NTF receptors, cell death or ALS-associated genes.}, }
@article {pmid20967131, year = {2010}, author = {Perry, VH and O'Connor, V}, title = {The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective.}, journal = {ASN neuro}, volume = {2}, number = {5}, pages = {e00047}, pmid = {20967131}, issn = {1759-0914}, support = {G0501636/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Microglia/*pathology/physiology ; Nerve Degeneration/pathology/physiopathology ; Presynaptic Terminals/*pathology/physiology ; Synapses/*pathology/physiology ; Synaptic Transmission/physiology ; }, abstract = {Chronic neurodegenerative diseases of the CNS (central nervous system) are characterized by the loss of neurons. There is, however, growing evidence to show that an early stage of this process involves degeneration of presynaptic terminals prior to the loss of the cell body. Synaptic plasticity in CNS pathology has been associated with microglia and the phenomenon of synaptic stripping. We review here the evidence for the involvement of microglia in synaptic stripping and synapse degeneration and we conclude that this is a case of guilt by association. In disease models of chronic neurodegeneration, there is no evidence that microglia play an active role in either synaptic stripping or synapse degeneration, but the degeneration of the synapse and the envelopment of a degenerating terminal appears to be a neuron autonomous event. We highlight here some of the gaps in our understanding of synapse degeneration in chronic neurodegenerative disease.}, }
@article {pmid20962641, year = {2010}, author = {Lillo, P and Hodges, JR}, title = {Cognition and behaviour in motor neurone disease.}, journal = {Current opinion in neurology}, volume = {23}, number = {6}, pages = {638-642}, doi = {10.1097/WCO.0b013e3283400b41}, pmid = {20962641}, issn = {1473-6551}, mesh = {Cognition Disorders/complications/*pathology/psychology ; Disability Evaluation ; Frontotemporal Dementia/etiology/pathology/psychology ; Humans ; Mental Disorders/complications/*pathology/psychology ; Motor Neuron Disease/complications/*pathology/*psychology ; Neurons/metabolism/*pathology ; }, abstract = {PURPOSE OF REVIEW: Motor neurone disease has traditionally been considered a pure motor syndrome which spares aspects of cognition and behaviour, although in recent years it has been suggested that up to 50% of patients with motor neurone disease may develop frontal dysfunction which, in some cases, is severe enough to reach criteria for frontotemporal dementia. We review the cognitive and behavioural changes in motor neurone disease emphasizing the recent advances.<br><br>RECENT FINDINGS: A major advance in pathology has been the recent discovery of TDP-43 and FUS inclusions as the key components in cases of motor neurone disease, frontotemporal dementia-motor neurone disease and some cases with pure frontotemporal dementia. In addition, mutations in TARDBP and FUS genes have been reported in recent years. Longitudinal studies showed that progression of cognitive impairment over the course of motor neurone disease appears to be mild and occurs only in a proportion of motor neurone disease patients. The presence of cognitive impairment seems to be related to a faster disease and a shorter survival.<br><br>SUMMARY: Motor neurone disease is a multi-system disorder which overlaps with frontotemporal dementia. Behavioural and cognitive changes appear to occur in a subset of patients with motor neurone disease, but the cause of this variability remains unclear.}, }
@article {pmid20953810, year = {2011}, author = {Giordana, MT and Ferrero, P and Grifoni, S and Pellerino, A and Naldi, A and Montuschi, A}, title = {Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {32}, number = {1}, pages = {9-16}, pmid = {20953810}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics ; Behavioral Symptoms/diagnosis/etiology ; Cognition Disorders/*diagnosis/*etiology ; Dementia/*diagnosis/*etiology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is generally considered to be a paradigm of pure motor neuron disorder; nevertheless, the possible occurrence of cognitive impairment up to a frank dementia in patients affected by ALS is recognized. The appraisal of the cognitive impairment in ALS patients is crucial not only to the therapeutic trials of this incurable disease, but also to the planning of care, compliance to interventions, the end-of-life decisions. The cognitive/behavioral changes of ALS patients are consistent with frontotemporal dysfunctions; the overlap of neuropathological features of ALS and frontotemporal lobe degeneration (FTLD) supports, in addition, the putative spectrum of ALS and FTD. In the present review, the pertinent clinical, genetic, neuropathological, neuropsychological and neuroimaging data of the literature are comprehensively and critically discussed. The distinct and overlapping features of ALS and FTD are pointed out, as well as the undisclosed questions deserving additional studies.}, }
@article {pmid20947179, year = {2010}, author = {Banerjee, R and Beal, MF and Thomas, B}, title = {Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications.}, journal = {Trends in neurosciences}, volume = {33}, number = {12}, pages = {541-549}, pmid = {20947179}, issn = {1878-108X}, support = {ES017295/ES/NIEHS NIH HHS/United States ; R21 NS062165-01A2/NS/NINDS NIH HHS/United States ; R01 ES017295-02/ES/NIEHS NIH HHS/United States ; R01 ES017295/ES/NIEHS NIH HHS/United States ; R01 NS060885-03/NS/NINDS NIH HHS/United States ; R21 NS062165/NS/NINDS NIH HHS/United States ; NS062165/NS/NINDS NIH HHS/United States ; R01 NS060885/NS/NINDS NIH HHS/United States ; NS060885/NS/NINDS NIH HHS/United States ; }, mesh = {Autophagy/*physiology ; Humans ; *Neurodegenerative Diseases/pathology/physiopathology/therapy ; Stress, Physiological ; }, abstract = {Autophagy is a highly conserved intracellular pathway involved in the elimination of proteins and organelles by lysosomes. Known originally as an adaptive response to nutrient deprivation in mitotic cells, autophagy is now recognized as an arbiter of neuronal survival and death decisions in neurodegenerative diseases. Studies using postmortem human tissue, genetic and toxin-induced animal and cellular models indicate that many of the etiological factors associated with neurodegenerative disorders can perturb the autophagy process. Emerging data support the view that dysregulation of autophagy might play a critical role in the pathogenesis of neurodegenerative disorders. In this review, we highlight the pathophysiological roles of autophagy and its potential therapeutic implications in debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer's, Parkinson's and Huntington's diseases.}, }
@article {pmid20942787, year = {2010}, author = {Diógenes, MJ and Outeiro, TF}, title = {Neurotrophic factors as a protective strategy in Parkinson's disease.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {6}, pages = {754-763}, doi = {10.2174/187152710793237449}, pmid = {20942787}, issn = {1996-3181}, mesh = {Animals ; Drug Synergism ; Humans ; Models, Biological ; Models, Neurological ; Nerve Growth Factors/*therapeutic use ; Parkinson Disease/*drug therapy ; }, abstract = {Neurodegenerative disorders are devastating human diseases that include Parkinson's, Huntington's, Alzheimer's, amyotrophic lateral sclerosis, and the frontal temporal dementias. Although the clinical manifestations of these disorders have been known for quite some time, our understanding of the molecular underpinnings is only starting to emerge. Protein misfolding and aggregation is a common hallmark among these diseases, and produce a number of cellular and functional alterations. The loss of dopaminergic neurons in the substantia nigra justified the use of dopaminergic therapies in patients. However, these strategies do not appear to confer disease-modifying effects, and do not prevent progression. The idea that neurotrophic factors might promote cell survival is an attractive one. Existing evidence from clinical trials is currently inconclusive, but some patients display clear clinical benefits. Thus, the current challenge is to develop novel strategies that make the use of neurotrophic factors more consistent.}, }
@article {pmid20942786, year = {2010}, author = {Costa, J and Gomes, C and de Carvalho, M}, title = {Diagnosis, pathogenesis and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {6}, pages = {764-778}, doi = {10.2174/187152710793237502}, pmid = {20942786}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/genetics ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Delivery Systems/*methods ; Genetic Predisposition to Disease ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. The diagnosis is clinical, but additional investigations such as electromyography, transcranial magnetic stimulation and neuroimaging have demonstrated their usefulness in supporting diagnosis. Exhaustive research for the identification of molecular markers in the cerebrospinal fluid and plasma of ALS patients have been made; however, at present, there are no validated biomarkers for the disease. Between 5 to 10% of the ALS cases have a positive familial history, up to now eleven genes have been identified as associated with the disease. The most studied gene encodes for copper, zinc superoxide dismutase enzyme. The identified abnormal genes potentially allow the generation of experimental cell and animal models to study the mechanisms of the disease and to test potential therapeutic compounds. The pathological characteristics of ALS include protein aggregation, proteasome inhibition, impaired axonal transport, mitochondria damage and apoptosis, oxidative stress, glutamate induced excitotoxicity, neuroinflammation and transcriptional dysfunction. Many compounds targeted to one or more of these mechanisms have been tested in multiple clinical trials. Nonetheless, nowadays only one drug, riluzole, has demonstrated a positive effect in the disease progression, but a number of recent compounds are promising in ALS therapy.}, }
@article {pmid20942785, year = {2010}, author = {Bosco, DA and Landers, JE}, title = {Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {6}, pages = {779-790}, doi = {10.2174/187152710793237494}, pmid = {20942785}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Drug Delivery Systems/*methods ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Models, Biological ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable disease resulting from the deterioration of motor neurons. The onset of disease typically occurs in the fifth decade of life and progresses rapidly; death occurs for 75% of patients within 5 years. The only drug that is available to treat ALS is riluzole, which extends survival by just 2-3 months. Thus, new therapeutic directions are being sought to prolong the lifespan of ALS patients. Since the discovery of SOD1 as a genetic determinant of ALS in 1993, SOD1-models of ALS have been extensively employed for the development of ALS therapeutics. Novel genetic targets are now under investigation following the recent discoveries linking TDP-43, FUS/TLS, angiogenin, KIFAP3 and UNC13A to ALS. In this review, we present several of the genetic contributors to both sporadic and familial forms of ALS and discuss their potential as therapeutic targets for this devastating disease.}, }
@article {pmid20931247, year = {2011}, author = {Harvey, BK and Richie, CT and Hoffer, BJ and Airavaara, M}, title = {Transgenic animal models of neurodegeneration based on human genetic studies.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {118}, number = {1}, pages = {27-45}, pmid = {20931247}, issn = {1435-1463}, support = {R01 NS070825/NS/NINDS NIH HHS/United States ; ZIA DA000443-09/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Humans ; Huntington Disease/genetics/pathology ; Nerve Degeneration/*genetics/*pathology ; Parkinson Disease/genetics/pathology ; }, abstract = {The identification of genes linked to neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) has led to the development of animal models for studying mechanism and evaluating potential therapies. None of the transgenic models developed based on disease-associated genes have been able to fully recapitulate the behavioral and pathological features of the corresponding disease. However, there has been enormous progress made in identifying potential therapeutic targets and understanding some of the common mechanisms of neurodegeneration. In this review, we will discuss transgenic animal models for AD, ALS, HD and PD that are based on human genetic studies. All of the diseases discussed have active or complete clinical trials for experimental treatments that benefited from transgenic models of the disease.}, }
@article {pmid20920073, year = {2010}, author = {Green, AJ and De-Vries, K}, title = {Cannabis use in palliative care - an examination of the evidence and the implications for nurses.}, journal = {Journal of clinical nursing}, volume = {19}, number = {17-18}, pages = {2454-2462}, doi = {10.1111/j.1365-2702.2010.03274.x}, pmid = {20920073}, issn = {1365-2702}, mesh = {Amyotrophic Lateral Sclerosis ; *Evidence-Based Medicine ; Humans ; *Marijuana Smoking ; Multiple Sclerosis ; *Nursing Care ; Palliative Care/*methods ; Quality of Life ; United Kingdom ; }, abstract = {AIM AND OBJECTIVE: Examine the pharmaceutical qualities of cannabis including a historical overview of cannabis use. Discuss the use of cannabis as a clinical intervention for people experiencing palliative care, including those with life-threatening chronic illness such as multiple sclerosis and motor neurone disease [amyotrophic lateral sclerosis] in the UK.<br><br>BACKGROUND: The non-medicinal use of cannabis has been well documented in the media. There is a growing scientific literature on the benefits of cannabis in symptom management in cancer care. Service users, nurses and carers need to be aware of the implications for care and treatment if cannabis is being used medicinally.<br><br>DESIGN: A comprehensive literature review.<br><br>METHOD: Literature searches were made of databases from 1996 using the term cannabis and the combination terms of cannabis and palliative care; symptom management; cancer; oncology; chronic illness; motor neurone disease/amyotrophic lateral sclerosis; and multiple sclerosis. Internet material provided for service users searching for information about the medicinal use of cannabis was also examined.<br><br>RESULTS: The literature on the use of cannabis in health care repeatedly refers to changes for users that may be equated with improvement in quality of life as an outcome of its use. This has led to increased use of cannabis by these service users. However, the cannabis used is usually obtained illegally and can have consequences for those who choose to use it for its therapeutic value and for nurses who are providing care.<br><br>Questions and dilemmas are raised concerning the role of the nurse when caring and supporting a person making therapeutic use of cannabis.}, }
@article {pmid20887784, year = {2011}, author = {Kabashi, E and Brustein, E and Champagne, N and Drapeau, P}, title = {Zebrafish models for the functional genomics of neurogenetic disorders.}, journal = {Biochimica et biophysica acta}, volume = {1812}, number = {3}, pages = {335-345}, doi = {10.1016/j.bbadis.2010.09.011}, pmid = {20887784}, issn = {0006-3002}, mesh = {Animals ; *Disease Models, Animal ; *Genomics ; Humans ; Neurodegenerative Diseases/*genetics/pathology ; Zebrafish/*genetics ; }, abstract = {In this review, we consider recent work using zebrafish to validate and study the functional consequences of mutations of human genes implicated in a broad range of degenerative and developmental disorders of the brain and spinal cord. Also we present technical considerations for those wishing to study their own genes of interest by taking advantage of this easily manipulated and clinically relevant model organism. Zebrafish permit mutational analyses of genetic function (gain or loss of function) and the rapid validation of human variants as pathological mutations. In particular, neural degeneration can be characterized at genetic, cellular, functional, and behavioral levels. Zebrafish have been used to knock down or express mutations in zebrafish homologs of human genes and to directly express human genes bearing mutations related to neurodegenerative disorders such as spinal muscular atrophy, ataxia, hereditary spastic paraplegia, amyotrophic lateral sclerosis (ALS), epilepsy, Huntington's disease, Parkinson's disease, fronto-temporal dementia, and Alzheimer's disease. More recently, we have been using zebrafish to validate mutations of synaptic genes discovered by large-scale genomic approaches in developmental disorders such as autism, schizophrenia, and non-syndromic mental retardation. Advances in zebrafish genetics such as multigenic analyses and chemical genetics now offer a unique potential for disease research. Thus, zebrafish hold much promise for advancing the functional genomics of human diseases, the understanding of the genetics and cell biology of degenerative and developmental disorders, and the discovery of therapeutics. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.}, }
@article {pmid20887684, year = {2011}, author = {Sanberg, PR and Eve, DJ and Willing, AE and Garbuzova-Davis, S and Tan, J and Sanberg, CD and Allickson, JG and Cruz, LE and Borlongan, CV}, title = {The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells.}, journal = {Cell transplantation}, volume = {20}, number = {1}, pages = {85-94}, doi = {10.3727/096368910X532855}, pmid = {20887684}, issn = {1555-3892}, mesh = {Adult Stem Cells/*cytology/transplantation ; Blood Cells/*cytology ; Fetal Blood/*cytology ; Humans ; Neurodegenerative Diseases/*therapy ; *Stem Cell Transplantation ; }, abstract = {Stem cell transplantation is a potentially important means of treatment for a number of disorders. Two different stem cell populations of interest are mononuclear umbilical cord blood cells and menstrual blood-derived stem cells. These cells are relatively easy to obtain, appear to be pluripotent, and are immunologically immature. These cells, particularly umbilical cord blood cells, have been studied as either single or multiple injections in a number of animal models of neurodegenerative disorders with some degree of success, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Sanfilippo syndrome type B. Evidence of anti-inflammatory effects and secretion of specific cytokines and growth factors that promote cell survival, rather than cell replacement, have been detected in both transplanted cells.}, }
@article {pmid20886766, year = {2010}, author = {Vinciguerra, M and Musaro, A and Rosenthal, N}, title = {Regulation of muscle atrophy in aging and disease.}, journal = {Advances in experimental medicine and biology}, volume = {694}, number = {}, pages = {211-233}, doi = {10.1007/978-1-4419-7002-2_15}, pmid = {20886766}, issn = {0065-2598}, mesh = {Aging/*physiology ; Animals ; Humans ; Muscular Atrophy/*metabolism ; Muscular Disorders, Atrophic/*physiopathology/therapy ; *Signal Transduction ; }, abstract = {Muscle aging is characterized by a decline in functional performance and restriction of adaptability, due to progressive loss of muscle tissue coupled with a decrease in strength and force output. Together with selective activation ofapoptotic pathways, a hallmark of age-related muscle loss or sarcopenia is the progressive incapacity of regeneration machinery to replace damaged muscle. These characteristics are shared by pathologies involving muscle wasting, such as muscular dystrophies or amyotrophic lateral sclerosis, cancer and AIDS, all characterized by alterations in metabolic and physiological parameters, progressive weakness in specific muscle groups. Modulation ofextracellular agonists, receptors, protein kinases, intermediate molecules, transcription factors and tissue-specific gene expression collectively compromise the functionality of skeletal muscle tissue, leading to muscle degeneration and persistent protein degradation through activation ofproteolytic systems, such as calpain, ubiquitin-proteasome and caspase. Additional decrements in muscle growth factors compromise skeletal muscle growth, differentiation, survival and regeneration. A better understanding of the mechanisms underlying the pathogenesis of muscle atrophy and wasting associated with different diseases has been the objective of numerous studies and represents an important first step for the development of therapeutic approaches. Among these, insulin-like growth factor-1 (IGF-1) has emerged as a growth factor with a remarkably wide range of actions and a tremendous potential as a therapeutic in attenuating the atrophy and frailty associated with muscle aging and diseases. In this chapter we provide an overview of current concepts in muscle atrophy, focusing specifically on the molecular basis of IGF-1 action and survey current gene and cell therapeutic approaches to rescue muscle atrophy in aging and disease.}, }
@article {pmid20880509, year = {2010}, author = {Vargas, MR and Johnson, JA}, title = {Astrogliosis in amyotrophic lateral sclerosis: role and therapeutic potential of astrocytes.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {7}, number = {4}, pages = {471-481}, pmid = {20880509}, issn = {1878-7479}, support = {R01 ES008089/ES/NIEHS NIH HHS/United States ; ES08089/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/therapy ; Animals ; Astrocytes/pathology/*physiology ; Cell Communication/physiology ; Humans ; Motor Neurons/pathology/physiology ; Nitric Oxide/metabolism ; Receptors, Death Domain/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of motor neurons. Although the molecular mechanism underlying motor neuron degeneration remains unknown; non-neuronal cells (including astrocytes) shape motor neuron survival in ALS. Astrocytes closely interact with neurons to provide an optimized environment for neuronal function and respond to all forms of injury in a typical manner known as reactive astrogliosis. A strong reactive astrogliosis surrounds degenerating motor neurons in ALS patients and ALS-animal models. Although reactive astrogliosis in ALS is probably both primary and secondary to motor neuron degeneration; astrocytes are not passive observers and they can influence motor neuron fate. Due to the important functions that astrocytes perform in the central nervous system; it is of key importance to understand how these functions are altered when astrocytes become reactive in ALS. Here; we review the current evidences supporting a potential toxic role of astrocytes and their viability as therapeutic targets to alter motor neuron degeneration in ALS.}, }
@article {pmid20880505, year = {2010}, author = {Rappold, PM and Tieu, K}, title = {Astrocytes and therapeutics for Parkinson's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {7}, number = {4}, pages = {413-423}, pmid = {20880505}, issn = {1878-7479}, support = {T32 GM07356/GM/NIGMS NIH HHS/United States ; R21 ES017470/ES/NIEHS NIH HHS/United States ; ES014899/ES/NIEHS NIH HHS/United States ; ES17470/ES/NIEHS NIH HHS/United States ; R01 ES014899/ES/NIEHS NIH HHS/United States ; TL1RR024135/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/drug effects/pathology/*physiology ; Glutathione/metabolism ; Humans ; Models, Biological ; Nerve Degeneration/etiology/therapy ; Nerve Tissue Proteins/metabolism ; Neuroprotective Agents/pharmacology/*therapeutic use ; Parkinson Disease/complications/*drug therapy/*pathology ; }, abstract = {Astrocytes play direct, active, and critical roles in mediating neuronal survival and function in various neurodegenerative disorders. This role of astrocytes is well illustrated in amyotrophic lateral sclerosis (ALS), in which the removal of glutamate from the extracellular space by astrocytes confers neuroprotection, whereas astrocytic release of soluble toxic molecules promotes neurodegeneration. In recent years, this context-dependent dual role of astrocytes has also been documented in experimental models of Parkinson's disease. The present review addresses these studies and some potential mechanisms by which astrocytes may influence the neurodegenerative processes in Parkinson's disease, and in particular examines how astrocytes confer neuroprotection either through the removal of toxic molecules from the extracellular space or through the release of trophic factors and antioxidant molecules. In contrast, under pathological conditions, astrocytes release proinflammatory cytokines and other toxic molecules that are detrimental to dopaminergic neurons. These emerging roles of astrocytes in the pathogenesis of Parkinson's disease constitute an exciting development with promising novel therapeutic targets.}, }
@article {pmid20880504, year = {2010}, author = {Verkhratsky, A and Olabarria, M and Noristani, HN and Yeh, CY and Rodriguez, JJ}, title = {Astrocytes in Alzheimer's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {7}, number = {4}, pages = {399-412}, pmid = {20880504}, issn = {1878-7479}, mesh = {Alzheimer Disease/complications/*pathology ; Animals ; Astrocytes/*pathology/*physiology ; Brain/*pathology ; Cell Communication ; Homeostasis/physiology ; Humans ; Neurodegenerative Diseases/pathology ; Neurons/pathology/physiology ; Signal Transduction ; }, abstract = {The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs. Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.}, }
@article {pmid20874702, year = {2011}, author = {Campos, HC and da Rocha, MD and Viegas, FP and Nicastro, PC and Fossaluzza, PC and Fraga, CA and Barreiro, EJ and Viegas, C}, title = {The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders I: Parkinson's disease.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {10}, number = {2}, pages = {239-250}, doi = {10.2174/187152711794480483}, pmid = {20874702}, issn = {1996-3181}, mesh = {Biological Products/chemistry/metabolism/*therapeutic use ; Central Nervous System/physiopathology ; *Drug Discovery ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/pathology/physiopathology ; Neuroprotective Agents/*therapeutic use ; Parkinson Disease/*drug therapy/metabolism/physiopathology ; }, abstract = {Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are currently incurable pathologies with huge social and economic impacts closely related to the increasing of life expectancy in modern times. Although the clinical and neuropathological aspects of these debilitating disorders are distinct, they share a pattern of neurodegeneration in anatomically or functionally related regions. For each disease, presently available treatments only address symptoms and do not alter the course or progression of the underlying diseases. In this context, the search for new effective chemical entities, capable of acting on diverse biochemical targets, with new mechanisms of action and low toxicity are genuine challenges to research groups and the pharmaceutical industry. This medical need has led to the reemerging of modern natural products chemistry that has yielded sophisticated and complex new lead molecules for drug discovery and development. In this review we discuss some of the main contributions of the natural products chemistry that covers multiple and varied plant species. Advances in the discovery of active constituents of plants, herbs, and extracts prescribed by traditional medicine practices for the treatment of senile neurodegenerative disorders, especially for PD, in the period after the 2000s is reviewed. The most important contributions from the 1990s are also discussed. The review also focuses on the pharmacological mechanisms of action that might underlie the purported beneficial improvements in memory and cognition, neurovascular function, and in neuroprotection. It is concluded that natural product chemistry brings tremendous diversity and historical precedent to a huge area of unmet medical need.}, }
@article {pmid20868358, year = {2010}, author = {Limón-Pacheco, JH and Gonsebatt, ME}, title = {The glutathione system and its regulation by neurohormone melatonin in the central nervous system.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {10}, number = {4}, pages = {287-297}, doi = {10.2174/187152410793429683}, pmid = {20868358}, issn = {1875-6166}, mesh = {Animals ; Antioxidants/pharmacology ; Astrocytes/physiology ; Central Nervous System/*physiology ; Glutathione/*physiology ; Glutathione Peroxidase/metabolism ; Humans ; Melatonin/pharmacology/*physiology ; Neurons/physiology ; }, abstract = {The glutathione system includes reduced (GSH) and oxidized (GSSG) forms of glutathione; the enzymes required for its synthesis and recycling, such as gamma-glutamate cysteine ligase (γ-GCL), glutathione synthetase (GS), glutathione reductase (GSR) and gamma glutamyl transpeptidase (γ-GGT); and the enzymes required for its use in metabolism and in mechanisms of defense against free radical-induced oxidative damage, such as glutathione s-transferases (GSTs) and glutathione peroxidases (GPxs). Glutathione functions in the central nervous system (CNS) include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. A common pathological hallmark in various neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's and Parkinson's diseases is the increase in oxidative stress and the failure of antioxidant systems, such as the decrease in the GSH content. The administration of exogenous neurohormone melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of GSH and the expression and activities of the GSH-related enzymes including γ-GCL, GPxs, and GSR. The exact mechanisms by which melatonin regulates the glutathione system are not fully understood. The main purpose of this short review is to discuss evidence relating to the potential common modulation signals between the glutathione system and melatonin in the CNS. The potential regulatory mechanisms and interactions between neurons and non-neuronal cells are also discussed.}, }
@article {pmid20864052, year = {2010}, author = {Mackenzie, IR and Rademakers, R and Neumann, M}, title = {TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {The Lancet. Neurology}, volume = {9}, number = {10}, pages = {995-1007}, doi = {10.1016/S1474-4422(10)70195-2}, pmid = {20864052}, issn = {1474-4465}, support = {74580//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics/metabolism ; Animals ; DNA-Binding Proteins/chemistry/*genetics/physiology ; Frontotemporal Dementia/*diagnosis/*genetics/metabolism ; Genetic Markers/genetics/physiology ; Humans ; Mutation/genetics ; RNA-Binding Protein FUS/chemistry/*genetics/physiology ; }, abstract = {Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.}, }
@article {pmid20859849, year = {2011}, author = {Rockenbauch, K and Schildmann, J}, title = {[Shared decision making (SDM): a systematic survey of terminology use and concepts].}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {73}, number = {7}, pages = {399-408}, doi = {10.1055/s-0030-1262870}, pmid = {20859849}, issn = {1439-4421}, mesh = {Chronic Disease/*therapy ; *Decision Making/ethics ; Ethics, Medical ; Germany ; Health Services Research/ethics ; Humans ; *National Health Programs/ethics ; Physician-Patient Relations/ethics ; Surveys and Questionnaires ; Terminology as Topic ; }, abstract = {Shared decision making (SDM) has been investigated in numerous research projects. In 2001 the German Ministry of Health initiated a research program on patients as partners in medical decision making ("Der Patient als Partner im medizinischen Entscheidungsprozess"). In this context a large number of studies has been conducted on SDM. In this review the concept of SDM and the use of this term in scientific publications of German study groups is explored. A systematic literature review generated 147 publications on SDM by German researchers, which had been published between 2000 and 2009. The majority of publications identified in this study refer to clinical studies on patients with chronic diseases. Content analysis of the retrieved publications indicates that SDM as a term is used heterogeneously. There is only little research on the theoretical foundations and ethical implications of SDM. In addition to existent Anglo-Saxon definitions of SDM, new concepts of SDM such as involvement of relatives in the process of decision making were identified as part of this review of the German literature. There is only a limited number of empirical studies with a consistent approach towards a definition of SDM and the respective measurements. Against this background, the "SDM questionnaire", which had been developed as part of the German Ministry of Health's research programme, is an important contribution with respect to operationalising SDM and testing possible effects of SDM in clinical practice.}, }
@article {pmid20857664, year = {2010}, author = {Kimura, M and Saito, S}, title = {[Anesthesia for patients with neurological diseases].}, journal = {Masui. The Japanese journal of anesthesiology}, volume = {59}, number = {9}, pages = {1100-1104}, pmid = {20857664}, issn = {0021-4892}, mesh = {Anesthesia/*methods ; Demyelinating Diseases/*complications ; Humans ; Neurodegenerative Diseases/*complications ; Perioperative Care/methods ; Spinal Cord Injuries/complications ; }, abstract = {Several surgical treatments can be employed for the patients with neurological disorders, such as multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer disease and spinal cord injury. It is possible that anesthesia related complications are induced in these neurologically complicated patients in the perioperative period. Respiratory dysfunction and autonomic nervous system dysfunction are most common in this population. Respiratory muscle weakness and bulbar palsy may cause aspiration pneumonia. Sometimes, postoperative ventilatory support is mandatory in these patients. Autonomic nervous system dysfunction may cause hypotension secondary to postural changes, blood loss, or positive airway pressure. Some therapeutic agents prescribed for neurological symptoms have drug interaction with anesthetic agents. Patients with motor neuron disease should be considered to be vulnerable to hyperkalemia in response to a depolarizing muscle relaxant. Although perioperative treatment guideline for most neurologic disorders has not been reported to lessen perioperative morbidity, knowledge of the clinical features and the interaction of common anesthetics with the drug therapy is important in planning intraoperative and postoperative management.}, }
@article {pmid20847461, year = {2010}, author = {Vinceti, M and Bonvicini, F and Bergomi, M and Malagoli, C}, title = {Possible involvement of overexposure to environmental selenium in the etiology of amyotrophic lateral sclerosis: a short review.}, journal = {Annali dell'Istituto superiore di sanita}, volume = {46}, number = {3}, pages = {279-283}, doi = {10.4415/ANN_10_03_09}, pmid = {20847461}, issn = {2384-8553}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology ; Environmental Exposure/*adverse effects ; Humans ; Italy/epidemiology ; Selenium/*adverse effects/toxicity ; }, abstract = {Excess exposure to the metalloid selenium (Se), a trace element with both toxicological and nutritional properties, has been implicated in the etiology of a human motor neuron disease of unknown origin and extremely severe prognosis, sporadic amyotrophic lateral sclerosis (ALS). This relation has been suggested on the basis of two epidemiologic investigations which found an increased risk of ALS associated with residence in a seleniferous area or with consumption of drinking water with unusually high levels of inorganic hexavalent Se, in South Dakota and in northern Italy respectively. Biological plausibility to a Se-ALS relation is provided by veterinary medicine observations and toxicological studies, showing that Se, particularly the inorganic forms, has a selective toxicity to motor neurons in swine and in cattle. Neurotoxic effects of Se species have also been demonstrated in laboratory studies and, for the inorganic forms, even at very low concentrations. Selenium has also been shown to affect muscle function in experimental animal models. Overall, these findings from the epidemiologic and the toxicological literature indicate that environmental Se, particularly in its inorganic forms and at unexpectedly low levels of exposure, might be a risk factor for ALS, suggesting the opportunity to further investigate this issue.}, }
@article {pmid20847445, year = {2010}, author = {Jiménez, JS}, title = {Protein-DNA interaction at the origin of neurological diseases: a hypothesis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {22}, number = {2}, pages = {375-391}, doi = {10.3233/JAD-2010-100189}, pmid = {20847445}, issn = {1875-8908}, mesh = {Animals ; DNA/*metabolism ; Humans ; *Nervous System Diseases/etiology/genetics/metabolism ; Proteins/*metabolism ; }, abstract = {A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-β, tau protein, α-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, α 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation.}, }
@article {pmid20840068, year = {2010}, author = {Róna-Vörös, K and Weydt, P}, title = {The role of PGC-1α in the pathogenesis of neurodegenerative disorders.}, journal = {Current drug targets}, volume = {11}, number = {10}, pages = {1262-1269}, doi = {10.2174/1389450111007011262}, pmid = {20840068}, issn = {1873-5592}, mesh = {Aging ; Animals ; Disease Models, Animal ; *Drug Delivery Systems ; Gene Expression Profiling ; Heat-Shock Proteins/genetics/*metabolism ; Humans ; Mice ; Mice, Knockout ; Neurodegenerative Diseases/drug therapy/genetics/*physiopathology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Trans-Activators/genetics/metabolism ; Transcription Factors/genetics/*metabolism ; }, abstract = {Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntington's disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1α, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC-1α knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1α regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD - previously thought to be unrelated mechanisms of neurodegeneration - appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1α in HD is further highlighted by the finding that common genetic variations in the PGC-1α gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1α system in HD pathogenesis and explores the implications for ALS, AD and PD.}, }
@article {pmid20840067, year = {2010}, author = {Dupuis, L and Echaniz-Laguna, A}, title = {Skeletal muscle in motor neuron diseases: therapeutic target and delivery route for potential treatments.}, journal = {Current drug targets}, volume = {11}, number = {10}, pages = {1250-1261}, pmid = {20840067}, issn = {1873-5592}, mesh = {Animals ; *Drug Delivery Systems ; Humans ; Motor Neuron Disease/drug therapy/genetics/*physiopathology ; Motor Neurons/drug effects/pathology ; Muscle Fibers, Skeletal/pathology ; Muscle, Skeletal/drug effects/*physiopathology ; Muscular Atrophy/pathology ; }, abstract = {Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy's disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurrence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons.}, }
@article {pmid20833281, year = {2010}, author = {Selvi, BR and Cassel, JC and Kundu, TK and Boutillier, AL}, title = {Tuning acetylation levels with HAT activators: therapeutic strategy in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta}, volume = {1799}, number = {10-12}, pages = {840-853}, doi = {10.1016/j.bbagrm.2010.08.012}, pmid = {20833281}, issn = {0006-3002}, mesh = {Animals ; Cell Death/drug effects ; Cell Survival/drug effects ; Chromatin/*metabolism ; Enzyme Activators/chemistry/*therapeutic use ; Histone Acetyltransferases/chemistry/*metabolism ; Histone Deacetylase Inhibitors/chemistry/therapeutic use ; Humans ; Memory/*drug effects ; Neurodegenerative Diseases/*drug therapy/enzymology/pathology ; Neuronal Plasticity/*drug effects ; Neurons/enzymology/pathology ; }, abstract = {Neurodegenerative diseases, such as polyglutamine-related diseases, amyotrophic lateral sclerosis, and Alzheimer's disease are accompanied by transcriptional dysfunctions, leading to neuronal death. It is becoming more evident that the chromatin acetylation status is impaired during the lifetime of neurons, by a common mechanism related to the loss of function of histone acetyltransferase (HAT) activity. Notably, the HAT termed cAMP response element binding protein (CREB)-binding protein (CBP) was shown to display neuroprotective functions. Several other HATs have now been shown to participate in basic but vital neuronal functions. In addition, there is increasing evidence of several HATs (including CBP), as essential regulators of neuronal plasticity and memory formation processes. In order to counteract neuronal loss and/or memory deficits in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules antagonizing histone deacetylase (HDAC) activity (i.e. HDAC inhibitors). Although this strategy lacks specificity, some of these molecules display promising therapeutic properties. With the rapidly evolving literature on HATs and their respective functions in neuronal survival and memory formation, it seems essential to envisage direct stimulation of the acetyltransferase function as a new therapeutic tool in neurodegenerative diseases. In this review, we will highlight the present understanding and the future prospects of such therapeutic approach.}, }
@article {pmid20832291, year = {2011}, author = {Bayat, V and Jaiswal, M and Bellen, HJ}, title = {The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases.}, journal = {Current opinion in neurobiology}, volume = {21}, number = {1}, pages = {182-188}, pmid = {20832291}, issn = {1873-6882}, support = {/HHMI/Howard Hughes Medical Institute/United States ; T32 HD055200/HD/NICHD NIH HHS/United States ; T32 HD055200-05/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Bone Morphogenetic Proteins/*metabolism ; Drosophila/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Neuromuscular Junction/*metabolism ; Signal Transduction/*physiology ; Transforming Growth Factor beta/*metabolism ; }, abstract = {The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington's Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-β signaling in ALS, SMA and HD and increased signaling in HSP and MS.}, }
@article {pmid20816718, year = {2011}, author = {Nunn, PB and Lyddiard, JR and Christopher Perera, KP}, title = {Brain glutathione as a target for aetiological factors in neurolathyrism and konzo.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {49}, number = {3}, pages = {662-667}, doi = {10.1016/j.fct.2010.08.037}, pmid = {20816718}, issn = {1873-6351}, mesh = {Amino Acids, Diamino/poisoning ; Amino Acids, Sulfur/deficiency ; Brain/*metabolism ; Cyanides/poisoning ; Cystine/blood ; Diet ; Foodborne Diseases/epidemiology ; Glutathione/*biosynthesis ; Humans ; Lathyrism/*chemically induced ; Lathyrus/*chemistry/poisoning ; Manihot/*chemistry/poisoning ; Methionine/blood ; Motor Neuron Disease/*chemically induced ; }, abstract = {Both neurolathyrism and konzo are associated with the nutritional dependence of human populations on a single plant food. These diseases express themselves as chronic disorders of upper motor neurones, leading to signs and symptoms that characterise amyotrophic lateral sclerosis (motor neurone disease). The plant food associated with neurolathyrism is grass pea, which contains the neurotoxic β-N-oxalyl-α,β-diaminopropionic acid (β-ODAP). The plant food associated with konzo is cassava, which may contain significant concentrations of cyanogenic glycosides and their degradation products. A monotonous diet of grass pea is likely to generate nutritional deficiencies; it is proposed that one of these, plasma methionine deficiency, may predispose neurones to the neurotoxic effects of β-ODAP. Subjects suffering from konzo also have low concentrations of plasma methionine as a result of a dietary deficiency of this amino acid. However, the plasma cystine concentration is also compromised because cyanide released from cyanogenic glycosides in cassava probably reacts with plasma cystine non-enzymatically. The product of this reaction is 2-imino-4-thiazolidine carboxylic acid. Since both plasma methionine and cystine are used for glutathione synthesis it seems likely that one common feature that leads to motor neurone death in neurolathyrism and konzo is the depletion of glutathione in the central nervous system.}, }
@article {pmid20812868, year = {2011}, author = {Nakamura, T and Lipton, SA}, title = {S-nitrosylation of critical protein thiols mediates protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.}, journal = {Antioxidants &amp; redox signaling}, volume = {14}, number = {8}, pages = {1479-1492}, pmid = {20812868}, issn = {1557-7716}, mesh = {Animals ; Humans ; Mitochondria/*metabolism/pathology ; Neurodegenerative Diseases/enzymology/*metabolism/pathology ; Nitric Oxide/*metabolism ; Protein Disulfide-Isomerases/*metabolism ; Protein Folding ; Proteostasis Deficiencies/enzymology/*metabolism/pathology ; Sulfhydryl Compounds/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {Excessive nitrosative and oxidative stress is thought to trigger cellular signaling pathways leading to neurodegenerative conditions. Such redox dysregulation can result from many cellular events, including hyperactivation of the N-methyl-D-aspartate-type glutamate receptor, mitochondrial dysfunction, and cellular aging. Recently, we and our colleagues have shown that excessive generation of free radicals and related molecules, in particular nitric oxide species (NO), can trigger pathological production of misfolded proteins, abnormal mitochondrial dynamics (comprised of mitochondrial fission and fusion events), and apoptotic pathways in neuronal cells. Emerging evidence suggests that excessive NO production can contribute to these pathological processes, specifically by S-nitrosylation of specific target proteins. Here, we highlight examples of S-nitrosylated proteins that regulate misfolded protein accumulation and mitochondrial dynamics. For instance, in models of Parkinson's disease, these S-nitrosylation targets include parkin, a ubiquitin E3 ligase and neuroprotective molecule, and protein-disulfide isomerase, a chaperone enzyme for nascent protein folding. S-Nitrosylation of protein-disulfide isomerase may also be associated with mutant Cu/Zn superoxide dismutase toxicity in amyotrophic lateral sclerosis. Additionally, in models of Alzheimer's disease, excessive NO generation leads to the formation of S-nitrosylated dynamin-related protein 1 (forming SNO-Drp1), which contributes to abnormal mitochondrial fragmentation and resultant synaptic damage.}, }
@article {pmid20732599, year = {2010}, author = {Coates, JR and Wininger, FA}, title = {Canine degenerative myelopathy.}, journal = {The Veterinary clinics of North America. Small animal practice}, volume = {40}, number = {5}, pages = {929-950}, doi = {10.1016/j.cvsm.2010.05.001}, pmid = {20732599}, issn = {1878-1306}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/*veterinary ; Animals ; Dog Diseases/diagnosis/*genetics/therapy ; Dogs ; Female ; Genetic Predisposition to Disease ; Male ; Muscular Diseases/diagnosis/genetics/therapy/*veterinary ; Mutation, Missense ; Species Specificity ; Superoxide Dismutase/*genetics ; }, abstract = {Canine degenerative myelopathy (DM) is an adult-onset fatal neurodegenerative disease that occurs in many breeds. The initial upper motor neuron spastic paraparesis and general proprioceptive ataxia in the pelvic limbs progress to a flaccid lower motor neuron tetraparesis. Recently, a missense mutation in the superoxide dismutase 1 (SOD1) gene was found to be a risk factor for DM, suggesting that DM is similar to some forms of human amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). This article reviews the current knowledge of canine DM with regard to its signalment, clinical spectrum, diagnostic approach, and treatment. The implications of the SOD1 mutation on both diseases are discussed, comparing pathogenic mechanisms while conveying perspectives to translational medicine.}, }
@article {pmid20726497, year = {2010}, author = {Veldink, JH and Weikamp, J and Schelhaas, HJ and van den Berg, LH}, title = {[Amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {117}, number = {7-8}, pages = {380-382}, doi = {10.5177/ntvt.2010.08.10122}, pmid = {20726497}, issn = {0028-2200}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/mortality/*therapy ; Humans ; Muscles/*physiopathology ; Neuroprotective Agents/*therapeutic use ; Quality of Life ; Riluzole/*therapeutic use ; Survival Analysis ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis is one of the most severe and disabling diseases of the nervous system. Amyotrophic lateral sclerosis leads to the progressive weakening of the muscles in the arms, legs, face, mouth and trunk. The onset of the disease is insidious, starting with weakness in the hands or feet or with slurred speech. The weakness worsens and patients pass away as a result of weakness of the respiratory muscles on average within 3 years of the onset of the disease. In the Netherlands, approximately 400 patients are diagnosed with amyotrophic lateral sclerosis every year. There is no diagnostic test for this neuro-muscular disease; the diagnosis is established by excluding other disorders that resemble amyotrophic lateral sclerosis. Only one drug is able to inhibit the progression of the disease to any extent: riluzole. Treatment, therefore, is mainly focused on supportive measures and those which enhance the quality of life optimally.}, }
@article {pmid20721828, year = {2010}, author = {Martin, LJ}, title = {Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {8}, pages = {568-580}, pmid = {20721828}, issn = {2040-3410}, support = {R01 NS065895-01/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282-01A1/AG/NIA NIH HHS/United States ; R01 NS052098-02/NS/NINDS NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Cholestenones/adverse effects/pharmacology/*therapeutic use ; Humans ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Neuroprotective Agents/adverse effects/pharmacology/*therapeutic use ; }, abstract = {Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are beginning to reveal possible principles governing the biology of motor neuron-selective vulnerability that implicate mitochondria and the mitochondrial permeability pore (mPTP). Proteins associated with the mPTP are known to be enriched in motor neurons and the genetic deletion of a major regulator of the mPTP has robust effects in ALS transgenic mice, delaying disease onset and extending survival. Thus, the mPTP is a rational, mechanism-based target for the development of drugs designed to treat ALS. Trophos SA has discovered olesoxime (TRO-19622), a small-molecule with a cholesterol-like structure, which has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. Olesoxime appears to act on mitochondria, possibly at the mPTP. Phase I clinical trials of olesoxime have been completed successfully. Olesoxime is well tolerated and achieves levels predicted to be clinically effective when administered orally. It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe.}, }
@article {pmid20717630, year = {2010}, author = {Chen, J and Wang, ZF}, title = {[Roles of cyclin-dependent kinase 5 in central nervous system development and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {62}, number = {4}, pages = {295-308}, pmid = {20717630}, issn = {0371-0874}, mesh = {Alzheimer Disease/physiopathology ; Animals ; Central Nervous System/*growth &amp; development ; Cyclin-Dependent Kinase 5/*physiology ; Humans ; Huntington Disease/physiopathology ; Neurodegenerative Diseases/enzymology/*physiopathology ; Neuronal Plasticity/*physiology ; Neurons/cytology ; Parkinson Disease/physiopathology ; Synaptic Transmission/physiology ; }, abstract = {Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, and plays multiple roles in neuron development and synaptic plasticity. The active form of Cdk5 is found primarily in the central nervous system (CNS) due to its activator proteins p35 or p39 ubiquitously expressed in neuronal cells. Normally, the transcription and activity of Cdk5 are strictly regulated by several ways. In the physiological condition, Cdk5 plays a key role in the CNS development by phosphorylating the specific serine or threonine site of numerous substrate proteins that are closely associated with the neuronal migration, synaptogenesis, synaptic transmission as well as synaptic plasticity. Under pathological conditions, p35 can be truncated into p25, which can strongly and consistently activate Cdk5, change the cellular localization of Cdk5 and lead to neuronal death ultimately. The increasing evidence has showed that Cdk5 is involved in the pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis etc., indicating that Cdk5 may be a potential target in the treatment of the neurodegenerative diseases. In this article, we reviewed the recent progress regarding the roles of Cdk5 in CNS development and neurodegenerative diseases.}, }
@article {pmid20715576, year = {2010}, author = {Sasabe, J and Aiso, S}, title = {[D-serine in the pathogenesis of amyotrophic lateral sclerosis].}, journal = {Seikagaku. The Journal of Japanese Biochemical Society}, volume = {82}, number = {7}, pages = {628-632}, pmid = {20715576}, issn = {0037-1017}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology ; Animals ; Cell Death ; Humans ; Mice ; Neurons/pathology ; Receptors, N-Methyl-D-Aspartate/metabolism/physiology ; Serine/metabolism/*physiology ; Spinal Cord/metabolism ; }, }
@article {pmid20714037, year = {2010}, author = {Kuwabara, S}, title = {[Amyotrophic lateral sclerosis--electrophysiologic aspects of its pathophysiology and new therapeutic options].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {62}, number = {8}, pages = {885-891}, pmid = {20714037}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology/physiopathology/*therapy ; Axons/physiology ; Cell Death ; *Electrophysiological Phenomena ; Humans ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Potassium Channels/physiology ; Sodium Channels/physiology ; }, abstract = {It is essential to perform electromyography and nerve-conduction studies for diagnosis amyotrophic lateral sclerosis (ALS), but these conventional electrophysiologic methods cannot be used for studies on the mechanism underlying ALS. The recently developed nerve-excitability test can provide new insights into the pathophysiology of this disease. Fasciculation is one of the characteristic features of ALS. Ectopic firing of motor units originates usually from the motor nerve terminals and occasionally from the motor neurons, indicating a widespread abnormality in axonal excitability. ALS is a multifactorial disease in which some genetic abnormalities and environmental factors lead to cell death through a complex cascade, which includes oxidative stress, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. It is important to elucidate the pathophysiology of axonal excitability in ALS because increased axonal excitability enhances oxidative stress and excitotoxicity, ultimately contributing to motor neuron death. To date, 2 axonal ion channel abnormalities have been identified: (1) increased persistent sodium currents and (2) reduced potassium currents; both abnormalities cause an increase in axonal excitability and are responsible for fasciculations. The results for excitability testing in such patients are characterized by the following features: (1) a prolonged strength-duration time constant, which suggests increased persistent sodium currents; (2) greater threshold changes in depolarizing threshold electrotonus; and (3) greater supernormality, which suggests impaired potassium channels. The altered axonal properties in patients with ALS may provide new insights into the pathophysiology of ALS and have implications for the development of ion channel modulators as therapeutic options for patients with ALS.}, }
@article {pmid20706642, year = {2010}, author = {Trudler, D and Farfara, D and Frenkel, D}, title = {Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application.}, journal = {Mediators of inflammation}, volume = {2010}, number = {}, pages = {}, pmid = {20706642}, issn = {1466-1861}, mesh = {*Amyloidosis/metabolism/pathology/therapy ; Animals ; Humans ; Immunity, Innate/immunology ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Neurogenesis/physiology ; Neuroglia/*metabolism ; Neurons/metabolism ; Signal Transduction/*physiology ; Toll-Like Receptors/*metabolism ; }, abstract = {Toll-like receptors (TLRs) are known to be expressed by innate immune response cells and to play a critical role in their activation against foreign pathogens. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system (CNS). TLR signaling was reported to be associated with a yin-yang effect in the CNS. While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases. This paper will focus on TLR signaling in glial cells in neurodegenerative diseases such as Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis, and Parkinson's disease. Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application.}, }
@article {pmid20705090, year = {2010}, author = {Chiu, CT and Chuang, DM}, title = {Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {128}, number = {2}, pages = {281-304}, pmid = {20705090}, issn = {1879-016X}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects/physiology ; Bipolar Disorder/diagnosis/*drug therapy/metabolism ; Central Nervous System Diseases/diagnosis/*drug therapy/metabolism ; Clinical Trials as Topic/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Lithium/*pharmacology/*therapeutic use ; Neurodegenerative Diseases/diagnosis/*drug therapy/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.}, }
@article {pmid20698807, year = {2011}, author = {Beghi, E and Chiò, A and Couratier, P and Esteban, J and Hardiman, O and Logroscino, G and Millul, A and Mitchell, D and Preux, PM and Pupillo, E and Stevic, Z and Swingler, R and Traynor, BJ and Van den Berg, LH and Veldink, JH and Zoccolella, S and , }, title = {The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {1}, pages = {1-10}, pmid = {20698807}, issn = {1471-180X}, support = {Z01 AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933-05/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*epidemiology/metabolism/*therapy ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Enteral Nutrition ; Europe/epidemiology ; Glutamic Acid/metabolism ; Humans ; Incidence ; Intercellular Signaling Peptides and Proteins/therapeutic use ; Middle Aged ; Prognosis ; Randomized Controlled Trials as Topic ; Registries ; Research Design ; Respiration, Artificial ; Riluzole/therapeutic use ; Treatment Outcome ; United States/epidemiology ; White People/statistics &amp; numerical data ; }, abstract = {Abstract Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.}, }
@article {pmid20696237, year = {2010}, author = {Matés, JM and Segura, JA and Alonso, FJ and Márquez, J}, title = {Roles of dioxins and heavy metals in cancer and neurological diseases using ROS-mediated mechanisms.}, journal = {Free radical biology &amp; medicine}, volume = {49}, number = {9}, pages = {1328-1341}, doi = {10.1016/j.freeradbiomed.2010.07.028}, pmid = {20696237}, issn = {1873-4596}, mesh = {Animals ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic ; Dioxins/*adverse effects ; Environmental Pollutants/*adverse effects ; Humans ; Metals, Heavy/*adverse effects ; Neoplasms/*chemically induced/pathology ; Nervous System Diseases/*chemically induced/genetics/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxidants have critical functions inside healthy and unhealthy cells. Deregulated cell cycle and apoptosis, both regulated by oxidative stress, have been described as hallmarks of mitotic (cancer) and postmitotic (neuronal) cells. This review provides an updated revision of the oxidant effects of some environmental contaminants such as dioxins and the heavy metals cadmium, cobalt, and copper. Dioxins exert their toxic actions by acting on phase I and phase II enzymes, such as cytochromes P450, superoxide dismutase, and glutathione peroxidase, promoting cell proliferation, growth arrest, and apoptosis, affecting cancer homeostasis and neuronal function. Heavy metals manifest cytotoxic effects in various cells and tissues, and tight regulation of metals is essential to the health of organisms. Cadmium modulates gene expression and signal transduction and reduces activities of proteins involved in antioxidant defense, interfering with DNA repair and modifying cancer development and brain function. Cobalt provokes generation of reactive oxygen species and DNA damage in cancer cells and brain tissues, altering proliferation and differentiation and causing apoptosis. Copper is a key metal in cell division processes in both normal and tumor cells. Copper also has been shown to have an important role in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis.}, }
@article {pmid20689252, year = {2011}, author = {Callaghan, B and Feldman, D and Gruis, K and Feldman, E}, title = {The association of exposure to lead, mercury, and selenium and the development of amyotrophic lateral sclerosis and the epigenetic implications.}, journal = {Neuro-degenerative diseases}, volume = {8}, number = {1-2}, pages = {1-8}, doi = {10.1159/000315405}, pmid = {20689252}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; Environmental Exposure ; *Epigenomics ; Humans ; Lead/pharmacokinetics/*toxicity ; Mercury/pharmacokinetics/*toxicity ; Selenium/pharmacokinetics/*toxicity ; Trace Elements/toxicity ; }, abstract = {Metal exposures are an intriguing potential culprit in the cause of sporadic amyotrophic lateral sclerosis (ALS). For one, there are numerous case reports linking different metals to an ALS phenotype. Furthermore, some investigators have demonstrated higher levels of certain metals in the blood, bone, cerebrospinal fluid, urine, or spinal cords of patients with ALS compared to controls. There are also many case-control studies looking at the possible association of certain metals with the development of ALS. We have reviewed the relevant literature regarding metal exposures and the risk of developing ALS. We found that many different metals have been implicated as having a role in ALS, but there is more literature investigating the role of lead than any other metal. Despite many studies, the role, if any, of this metal in the pathogenesis of ALS remains unclear. Similarly, other metals either have inconclusive, conflicting, or insufficient results in order to make a definitive conclusion. One explanation for these findings is that metal exposures alone are insufficient for the development of ALS. Perhaps an interaction between the metal exposure and an individual's genetic makeup is required to produce epigenetic changes that ultimately lead to ALS.}, }
@article {pmid20687491, year = {2010}, author = {Perry, JJ and Shin, DS and Tainer, JA}, title = {Amyotrophic lateral sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {685}, number = {}, pages = {9-20}, doi = {10.1007/978-1-4419-6448-9_2}, pmid = {20687491}, issn = {0065-2598}, support = {P01 CA092584/CA/NCI NIH HHS/United States ; R01 GM039345/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; DNA/biosynthesis/genetics ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Mutation ; RNA/biosynthesis/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; *Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurological disorder that results in loss of motor neurons, leading to a rapidly progressive form of muscle paralysis that is fatal. There is no available cure and current therapies only provide minimal benefit at best. The disease is predominantly sporadic and until very recently only the Cu,Zn superoxide dismutase (Cu,ZnSOD), which is involved in a small number of sporadic cases and a larger component of familial ones, have been analyzed in any detail. Here we describe the clinical aspects of ALS and highlight the genetics and molecular mechanisms behind the disease. We discuss the current understanding and controversies of how mutations in Cu,ZnSOD may cause the disease. We also focus on the recent discovery that mutations in either TDP-43 or FUS/TLS, which are both involved in DNA/RNA synthesis, are likely the cause behind many cases of ALS that are not linked to Cu,ZnSOD.}, }
@article {pmid20673740, year = {2011}, author = {Fuglsang-Frederiksen, A and Pugdahl, K}, title = {Current status on electrodiagnostic standards and guidelines in neuromuscular disorders.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {122}, number = {3}, pages = {440-455}, doi = {10.1016/j.clinph.2010.06.025}, pmid = {20673740}, issn = {1872-8952}, mesh = {Electrodiagnosis/instrumentation/*standards ; Evidence-Based Medicine ; Guidelines as Topic/*standards ; Humans ; Medical Laboratory Science ; Neuromuscular Diseases/*diagnosis ; Quality Control ; Quality Improvement ; Technology Assessment, Biomedical ; Treatment Outcome ; }, abstract = {The aim of this review is to present the status of electrodiagnostic standards and guidelines in neuromuscular disorders. Electrodiagnostic guidelines are developed on the background of medical technology assessment, wherefore a short presentation of medical technology assessment is given covering: (1) Evidence-based medicine, i.e. "to do the right thing", describing practice parameters and the STARD initiative which introduces evidence-based medicine in electrodiagnostic medicine, (2) Continuous quality improvement, i.e. "to do the thing right", describing variation among laboratories in methods and interpretation of tests, and the need for medical audit and implementation of electrodiagnostic guidelines, (3) Outcome studies, i.e. "is it worthwhile to do the right thing right?". In electrodiagnostic medicine there are very few outcome studies. Standards and guidelines described in the literature for different neuromuscular disorders are presented, often as figures or tables. These cover guidelines developed in detail for CIDP by expert consensus multicentre groups by AAN, INCAT, EFNS/PNS and for other inflammatory demyelinating neuropathies are described, as well as guidelines differentiating between demyelinating pathophysiology and axonal loss by motor and sensory nerve conduction studies. Furthermore, electrodiagnostic guidelines for ALS as detailed in the El Escorial, the modified El Escorial and the recent supplementary Awaji criteria are described and presented in a comprehensive table. Only few electrodiagnostic guidelines are published for nerve entrapment, cervical radiculopathy and neuromuscular transmission failure whereas none are known for myopathy. If no electrodiagnostic criteria for a given disorder exist, criteria for the electrodiagnostic examination are described if present. It is concluded that future research is needed in order to develop more electrodiagnostic guidelines in neuromuscular disorders by international expert consensus groups. Such research should use an evidence-based medicine approach and medical technology assessment and include continuous quality development and outcome studies.}, }
@article {pmid20655970, year = {2011}, author = {Liscic, RM and Breljak, D}, title = {Molecular basis of amyotrophic lateral sclerosis.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {35}, number = {2}, pages = {370-372}, doi = {10.1016/j.pnpbp.2010.07.017}, pmid = {20655970}, issn = {1878-4216}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Cognition Disorders/genetics/*metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics/*metabolism ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration with unclear etiology and no effective treatment to date. ALS is, however, increasingly recognized as a multisystem disorder associated with impaired cognition. The overlap between ALS and dementia at clinical, genetic and neuropathologic levels indicates a spectrum of clinical phenotypes that may include features of frontotemporal lobar degeneration (FTLD). Most cases of ALS are sporadic (SALS), but approximately 10% of all ALS cases are familial ALS (FALS). Mutations in the Cu/Zn superoxide dismutase-1 gene (SOD-1) occur in about 20% of FALS cases. Mutations in the TAR DNA-binding protein 43 gene (TARDBP or TDP-43) may occur in 3-4% of FALS cases, and less frequently, in FTLD. Recently, mutations in the fused in sarcoma/translation in liposarcoma gene (FUS/TLS) were identified as causing about 4-5% of FALS, SALS, and FTLD cases, but not SOD-1 ALS cases, indicating a pathogenic role of FUS, together with TDP-43, in possibly all types of ALS, except for SOD-1 linked ALS. TDP-43 and FUS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. Thus, TARDBP and FUS/TLS mutations define a novel class of neurodegenerative diseases called TDP-43- and FUS-proteinopathies, in which both misfolded proteins are novel targets for the development of therapeutics in this spectrum of diseases. However, SOD-1 linked ALS may have a pathogenic pathway distinct from other types of ALS.}, }
@article {pmid20653508, year = {2010}, author = {Rodolfo, C and Ciccosanti, F and Giacomo, GD and Piacentini, M and Fimia, GM}, title = {Proteomic analysis of mitochondrial dysfunction in neurodegenerative diseases.}, journal = {Expert review of proteomics}, volume = {7}, number = {4}, pages = {519-542}, doi = {10.1586/epr.10.43}, pmid = {20653508}, issn = {1744-8387}, support = {GGP06254/TI_/Telethon/Italy ; }, mesh = {Humans ; Mitochondria/*pathology ; Neurodegenerative Diseases/*etiology/pathology ; Oxidative Stress ; Proteins/analysis/metabolism ; Proteomics/*methods ; }, abstract = {Alzheimer's, Parkinson's and Huntington's disease, and amyotrophic lateral sclerosis are the most relevant neurodegenerative syndromes worldwide. The identification of the etiology and additional factors contributing to the onset and progression of these diseases is of great importance in order to develop both preventive and therapeutic intervention. A common feature of these pathologies is the formation of aggregates, containing mutated and/or misfolded proteins, in specific subsets of neurons, which progressively undergo functional impairment and die. The relationship between protein aggregation and the molecular events leading to neurodegeneration has not yet been clarified. In the last decade, several lines of evidence pointed to a major role for mitochondrial dysfunction in the onset of these pathologies. Here, we review how proteomics has been applied to neurodegenerative diseases in order to characterize the relationship existing between protein aggregation and mitochondrial alterations. Moreover, we highlight recent advances in the use of proteomics to identify protein modifications caused by oxidative stress. Future developments in this field are expected to significantly contribute to the full comprehension of the molecular mechanisms at the heart of neurodegeneration.}, }
@article {pmid20642879, year = {2010}, author = {Bäumer, D and Ansorge, O and Almeida, M and Talbot, K}, title = {The role of RNA processing in the pathogenesis of motor neuron degeneration.}, journal = {Expert reviews in molecular medicine}, volume = {12}, number = {}, pages = {e21}, doi = {10.1017/S1462399410001523}, pmid = {20642879}, issn = {1462-3994}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Humans ; Models, Biological ; Motor Neurons/*metabolism/*pathology ; Muscular Atrophy, Spinal/genetics/pathology ; Nerve Degeneration/*genetics/pathology ; RNA Processing, Post-Transcriptional/genetics/physiology ; }, abstract = {Motor neurons are large, highly polarised cells with very long axons and a requirement for precise spatial and temporal gene expression. Neurodegenerative disorders characterised by selective motor neuron vulnerability include various forms of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A rapid expansion in knowledge on the pathophysiology of motor neuron degeneration has occurred in recent years, largely through the identification of genes leading to familial forms of ALS and SMA. The major emerging theme is that motor neuron degeneration can result from mutation in genes that encode factors important for ribonucleoprotein biogenesis and RNA processing, including splicing regulation, transcript stabilisation, translational repression and localisation of mRNA. Complete understanding of how these pathways interact and elucidation of specialised mechanisms for mRNA targeting and processing in motor neurons are likely to produce new targets for therapy in ALS and related disorders.}, }
@article {pmid20639382, year = {2010}, author = {Alonso, A and Logroscino, G and Hernán, MA}, title = {Smoking and the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {81}, number = {11}, pages = {1249-1252}, doi = {10.1136/jnnp.2009.180232}, pmid = {20639382}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Female ; Humans ; Incidence ; Male ; Risk Factors ; Sex Distribution ; Smoking/*epidemiology ; }, abstract = {BACKGROUND: Epidemiologic studies have provided inconsistent results on the association of cigarette smoking with the incidence of amyotrophic lateral sclerosis (ALS). To summarise published evidence and explore sources of heterogeneity, we conducted a systematic review and meta-analysis of studies that evaluated this association.<br><br>METHODS: Published studies evaluating the association of smoking with incidence of ALS were searched in bibliographic databases, with relevant information collected from each article. A random effects approach was used to pool the relative rate (RR) estimates from different studies. Between study heterogeneity was explored with a meta-regression approach.<br><br>RESULTS: 18 publications reported associations between smoking and ALS risk in 15 case control studies and five cohort studies. The pooled RR (95% CI) of ALS was 1.28 (0.97 to 1.68) for current versus never smokers and 1.12 (0.98 to 1.27) for ever versus never smokers. The study specifics RRs were heterogeneous (p<0.01). The proportion of women in the study population explained 46% of between study variability. The estimated RR (95% CI) of ALS for ever versus never smokers was 0.86 (0.71 to 1.03) in men and 1.66 (1.31 to 2.10) in women.<br><br>INTERPRETATION: This meta-analysis does not support an overall strong association of smoking with ALS risk but suggests that smoking might be associated with a higher risk of ALS in women.}, }
@article {pmid20632965, year = {2010}, author = {Pantaleo, N and Chadwick, W and Park, SS and Wang, L and Zhou, Y and Martin, B and Maudsley, S}, title = {The mammalian tachykinin ligand-receptor system: an emerging target for central neurological disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {5}, pages = {627-635}, pmid = {20632965}, issn = {1996-3181}, support = {Z01 AG000318-01/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/drug effects/metabolism/*physiopathology ; Central Nervous System Diseases/*physiopathology ; Drug Delivery Systems/*methods ; Humans ; Mammals ; Receptors, Tachykinin/*drug effects/metabolism/*physiology ; Tachykinins/metabolism/pharmacology/*physiology ; }, abstract = {Our understanding of the complex signaling neurophysiology of the central nervous system has facilitated the exploration of potential novel receptor-ligand system targets for disorders of this most complex organ. In recent years, many relatively neglected receptor-ligand systems have been re-evaluated with respect to their ability to potently modulate discrete tracts in the central nervous system. One such system is the tachykinin (previously neurokinin) system. The multiple heptahelical G protein-coupled receptors and neuropeptide ligands that comprise this system may be significantly involved in more central nervous systems actions than previously thought, including sleep disorders, amyotrophic lateral sclerosis, Alzheimer's disease and Machado-Joseph disease. The development of our understanding of the role of the tachykinin receptor-ligand system in higher order central functions is likely to allow the creation of more specific and selective tachykinin-related neurotherapeutics.}, }
@article {pmid20621283, year = {2010}, author = {Shaw, BF and Moustakas, DT and Whitelegge, JP and Faull, KF}, title = {Taking charge of proteins from neurodegeneration to industrial biotechnology.}, journal = {Advances in protein chemistry and structural biology}, volume = {79}, number = {}, pages = {127-164}, doi = {10.1016/S1876-1623(10)79004-0}, pmid = {20621283}, issn = {1876-1631}, support = {P01 NS049134/NS/NINDS NIH HHS/United States ; }, mesh = {*Biotechnology ; Neurodegenerative Diseases/*metabolism ; Protein Folding ; Proteins/*chemistry/*metabolism ; Static Electricity ; }, abstract = {The aggregation and precipitation of a soluble protein-within a motor neuron, or a pharmaceutical vial, or even inside a industrial-scale hydrolysis chamber-is a problem in human health and in biotechnology. A growing body of research is suggesting that the magnitude of the net charge of a protein is a determinant of the rate at which proteins self-assemble in solution into aggregates with amorphous or fibrillar (or uncharacterized) morphologies. This chapter discusses how this apparently simple electrostatic effect might explain-in part or entirely-the pathogenicity of some mutations that cause familial protein aggregation diseases-especially the familial forms of amyotrophic lateral sclerosis that are caused by mutations in the gene encoding superoxide dismutase-1 (SOD1). In parallel, this chapter also discusses how understanding these electrostatic effects can guide the engineering of industrial enzymes (such as alpha-amylase from Bacillus licheniformis) into forms that are more resistant to aggregation and thermal precipitation than the enzymes that are currently used, for example, in the production of ethanol from starch or cellulose.}, }
@article {pmid20613515, year = {2010}, author = {Bedlack, RS}, title = {Amyotrophic lateral sclerosis: current practice and future treatments.}, journal = {Current opinion in neurology}, volume = {23}, number = {5}, pages = {524-529}, doi = {10.1097/WCO.0b013e32833c7ac2}, pmid = {20613515}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Biomarkers ; Cognition Disorders/diagnosis ; Evidence-Based Medicine ; Forecasting ; Humans ; Neuroprotective Agents/therapeutic use ; Palliative Care ; Riluzole/therapeutic use ; Survival Rate ; }, abstract = {PURPOSE OF REVIEW: Knowledge of amyotrophic lateral sclerosis, and in particular the care of patients with it, is evolving exponentially. More than 1700 articles with the phrase 'amyotrophic lateral sclerosis' have been published in the past 2 years; these form the basis for this timely review.<br><br>RECENT FINDINGS: In part 1, I give an update on the care of patients with amyotrophic lateral sclerosis, including ways to speed diagnosis, optimal use of riluzole, multidisciplinary teams, mechanical ventilation, gastrostomy tubes, lipid-lowering agents and symptom management. Although care has become more evidence-based, there remain a number of quandaries; for these, I will provide suggestions based upon my own experience. In part 2, I identify some exciting new treatment options that are under study. These include agents designed for novel targets within motor neurons and nonneuronal cells, agents designed for specific amyotrophic lateral sclerosis subtypes and interesting new technologies. Finally, in part 3, I define current barriers to developing even better therapeutics and offer ways around them.<br><br>SUMMARY: The care of patients with amyotrophic lateral sclerosis has evolved and is now more evidence-based than ever before. Exciting new therapies are currently being tested, which may revolutionize care even further. Barriers exist, but they are surmountable.}, }
@article {pmid20602248, year = {2010}, author = {Galat, A and Bua, J}, title = {Molecular aspects of cyclophilins mediating therapeutic actions of their ligands.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {67}, number = {20}, pages = {3467-3488}, pmid = {20602248}, issn = {1420-9071}, support = {D43TW007888/TW/FIC NIH HHS/United States ; }, mesh = {Animals ; Conserved Sequence/genetics ; Cyclophilins/chemistry/*metabolism ; Cyclosporine/chemistry/*metabolism/*therapeutic use ; Disease ; Humans ; Ligands ; }, abstract = {Cyclosporine A (CsA) is an immunosuppressive cyclic peptide that binds with a high affinity to 18 kDa human cyclophilin-A (hCyPA). CsA and its several natural derivatives have some pharmacological potential in treatment of diverse immune disorders. More than 20 paralogues of CyPA are expressed in the human body while expression levels and functions of numerous ORFs encoding cyclophilin-like sequences remain unknown. Certain derivatives of CsA devoid of immunosuppressive activity may have some potential in treatments of Alzheimer diseases, Hepatitis C and HIV infections, amyotrophic lateral sclerosis, congenital muscular dystrophy, asthma and various parasitic infections. Here, we discuss structural and functional aspects of the human cyclophilins and their interaction with various intra-cellular targets that can be under the control of CsA or its complexes with diverse cyclophilins that are selectively expressed in different cellular compartments. Some molecular aspects of the cyclophilins expressed in parasites invading humans and causing diseases were also analyzed.}, }
@article {pmid20601083, year = {2010}, author = {Warraich, ST and Yang, S and Nicholson, GA and Blair, IP}, title = {TDP-43: a DNA and RNA binding protein with roles in neurodegenerative diseases.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {42}, number = {10}, pages = {1606-1609}, doi = {10.1016/j.biocel.2010.06.016}, pmid = {20601083}, issn = {1878-5875}, mesh = {Animals ; DNA-Binding Proteins/genetics/*metabolism ; Disease Progression ; Embryonic Development ; Humans ; Inclusion Bodies/*metabolism/pathology ; Mutation/genetics ; RNA Processing, Post-Transcriptional ; RNA Splicing ; RNA-Binding Proteins/genetics/*metabolism ; TDP-43 Proteinopathies/genetics/*metabolism/pathology/physiopathology ; Transcriptional Activation ; }, abstract = {Transactive response DNA binding protein 43 kDa (TDP-43) is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs). TDP-43 serves multiple functions with roles in transcriptional regulation, pre-mRNA splicing and translational regulation. TDP-43 is also crucial for embryonic development with increasing evidence indirectly implicating its involvement in other cellular processes including microRNA biogenesis, apoptosis and cell division. The role of TDP-43 in neurodegeneration has been actively studied since identification as a major component of the ubiquitinated inclusions seen in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 pathology has also been identified in several other neurodegenerative diseases. These disorders are collectively referred to as TDP-43 proteinopathies. The identification of rare TDP-43 mutations in sporadic and familial forms of ALS and FTLD suggests TDP-43 plays an important pathogenic role, rather than merely being a marker of the disease.}, }
@article {pmid20600637, year = {2010}, author = {Bartolomucci, A and Pasinetti, GM and Salton, SR}, title = {Granins as disease-biomarkers: translational potential for psychiatric and neurological disorders.}, journal = {Neuroscience}, volume = {170}, number = {1}, pages = {289-297}, doi = {10.1016/j.neuroscience.2010.06.057}, pmid = {20600637}, issn = {1873-7544}, mesh = {Amino Acid Sequence ; Animals ; Biomarkers/metabolism ; Chromogranins/cerebrospinal fluid/*genetics/metabolism ; Genetic Markers/genetics ; Humans ; Mental Disorders/diagnosis/*genetics ; Molecular Sequence Data ; Nervous System Diseases/diagnosis/*genetics ; Protein Biosynthesis/*genetics ; }, abstract = {The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery.}, }
@article {pmid20593140, year = {2010}, author = {Sathasivam, S}, title = {Motor neurone disease: clinical features, diagnosis, diagnostic pitfalls and prognostic markers.}, journal = {Singapore medical journal}, volume = {51}, number = {5}, pages = {367-72; quiz 373}, pmid = {20593140}, issn = {2737-5935}, mesh = {Biomarkers ; Diagnosis, Differential ; Diagnostic Errors ; Electromyography ; Health Status Indicators ; Humans ; Magnetic Resonance Imaging ; Motor Neuron Disease/*diagnosis/epidemiology/physiopathology ; Neural Conduction ; Prognosis ; Risk Factors ; }, abstract = {Motor neurone disease (MND) is a rapidly progressive adult-onset neurodegenerative disorder. In recent years, there has been an increased understanding regarding the epidemiology and clinical features of the different variants of MND. In addition, new diagnostic criteria have been proposed to increase the sensitivity of the diagnosis. This review highlights these new concepts and discusses the differential diagnoses of MND, highlighting the common pitfalls and misdiagnoses. It also discusses the prognostic markers for MND and a possible change in the natural history of the disease course.}, }
@article {pmid20582873, year = {2010}, author = {Phukan, J}, title = {Arimoclomol, a coinducer of heat shock proteins for the potential treatment of amyotrophic lateral sclerosis.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {7}, pages = {482-496}, pmid = {20582873}, issn = {2040-3410}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Chaperonins/agonists ; Drugs, Investigational/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Heat-Shock Proteins/*metabolism ; Heat-Shock Response/drug effects ; Humans ; Hydroxylamines/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Nerve Degeneration/drug therapy/prevention &amp; control ; Neurons/drug effects ; Neuroprotective Agents/adverse effects/pharmacokinetics/pharmacology/therapeutic use ; Stress, Physiological ; Up-Regulation/*drug effects ; }, abstract = {Recent years have seen an explosion of research into increasingly prevalent neurodegenerative diseases. Arimoclomol (BRX-220), being developed by CytRx Corp, is an oral therapeutic candidate for the treatment of amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. ALS is a fatal, incurable disorder, which can present as sporadic (90 to 95% of cases) or familial (5 to 10% of cases) forms. The etiology of sporadic ALS remains unknown and much of the understanding of ALS pathogenesis has been derived through study of its familial forms; in particular, through study of autosomal dominant mutations in the SOD1 (copper/zinc superoxide dismutase) gene, which cause approximately 20% of familial ALS cases. Under conditions of excessive stress, arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death. Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival, even after symptom onset. Clinical trials have reported good tolerability and safety. This paper discusses the rationale for arimoclomol use in ALS, the preclinical and clinical evidence collected to date, the likelihood of its promising preclinical results translating to humans, and the relevance of this research for neurodegeneration as a whole.}, }
@article {pmid20577972, year = {2011}, author = {Perez, DI and Gil, C and Martinez, A}, title = {Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases.}, journal = {Medicinal research reviews}, volume = {31}, number = {6}, pages = {924-954}, doi = {10.1002/med.20207}, pmid = {20577972}, issn = {1098-1128}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Binding, Competitive ; Casein Kinase I/*metabolism ; Casein Kinase II/*metabolism ; Drug Design ; Enzyme Inhibitors/pharmacology ; Humans ; Inhibitory Concentration 50 ; Mice ; Neurodegenerative Diseases/*drug therapy/enzymology ; Parkinson Disease/drug therapy ; Phosphorylation ; Rats ; }, abstract = {Following the discovery of the human kinome, protein kinases have become the second most important group of drug targets as they can be modulated by small ligand molecules. Moreover, orally active protein kinase inhibitors have recently reached the market and there are many more in clinical trials. The lack of treatments for neurodegenerative diseases has increased human and financial efforts in the search for new therapeutic targets that could provide new effective drug candidates. The importance of kinases in the molecular pathway of neuronal survival is under study, but different key pathways have been described. New roles for the old casein kinases 1 and 2, currently known as protein kinases CK1 and CK2, have recently been discovered in the molecular pathology of different neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. The search for specific inhibitors of these enzymes has become an important challenge for the treatment of these devastating diseases. The role of these two kinases in the molecular pathology of different neurodegenerative diseases together with different chemical families that are able to more or less specifically inhibit CK1 and CK2 are discussed in this review.}, }
@article {pmid20565332, year = {2010}, author = {Mitchell, JD and Callagher, P and Gardham, J and Mitchell, C and Dixon, M and Addison-Jones, R and Bennett, W and O'Brien, MR}, title = {Timelines in the diagnostic evaluation of people with suspected amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)--a 20-year review: can we do better?.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {6}, pages = {537-541}, doi = {10.3109/17482968.2010.495158}, pmid = {20565332}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Clinical Trials as Topic ; Humans ; Motor Neuron Disease/*diagnosis ; Time Factors ; United Kingdom ; }, abstract = {This paper examines diagnostic timelines for people suspected of having ALS/MND over a 20-year period, evaluates the impact of a 'fast track' diagnostic process and discusses typical causes of diagnostic delay. Key diagnostic timelines (dates of first symptom, diagnosis and death) were reviewed for people diagnosed between 1989 and 2008. Patients evaluated through a fast-track diagnostic process and those investigated through traditional neurology clinics were compared. Typical causes of diagnostic delay were investigated. Results showed that diagnostic timelines have been surprisingly consistent over this 20-year period. Time from first symptom to diagnosis hovered around 12 months, with the diagnosis typically being made around the midpoint (50% of total disease duration elapsed) of the disease pathway. The introduction of a fast-track process has not to date affected overall performance but has shortened times from referral to diagnosis. Diagnostic delays appear to be associated with clinical complexity and delays in referral, both within primary and secondary care services. In conclusion, more widespread implementation of fast-track processes could potentially reduce diagnostic delays. Educational interventions among health care professionals both in primary and secondary care may also help shorten diagnostic pathways.}, }
@article {pmid20564566, year = {2010}, author = {Sasabe, J and Aiso, S}, title = {Aberrant control of motoneuronal excitability in amyotrophic lateral sclerosis: excitatory glutamate/D-serine vs. inhibitory glycine/gamma-aminobutanoic acid (GABA).}, journal = {Chemistry &amp; biodiversity}, volume = {7}, number = {6}, pages = {1479-1490}, doi = {10.1002/cbdv.200900306}, pmid = {20564566}, issn = {1612-1880}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Excitatory Amino Acids/metabolism ; Glutamic Acid/*metabolism ; Glycine/*metabolism ; Motor Neurons/metabolism ; Neurotransmitter Agents/metabolism ; Receptors, Glutamate/metabolism ; Serine/*metabolism ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {The mechanism underlying selective motoneuronal loss in amyotrophic lateral sclerosis (ALS) remains uncertain. The pathogenesis appears to be a complex and multifactorial process. Glutamate excitotoxicity to motoneuron is one of the most intensely investigated targets for the treatment of ALS, and excessive motoneuronal excitation by glutamate through ionotropic glutamate receptors has been mainly demonstrated. However, development of clinically effective drug targeting glutamate is sometimes difficult, because some aspects of glutamergic signals also could be beneficial, as the injured neurons attempt to recruit endogenous recovery. This review is focused on identifying other mechanisms of imbalanced excitation in ALS motoneurons including excitation-modulating D-serine and inhibitory glycine/GABA. Further, validation of these mechanisms might ultimately lead us to new therapeutic targets for ALS.}, }
@article {pmid20561920, year = {2010}, author = {Ambegaokar, SS and Roy, B and Jackson, GR}, title = {Neurodegenerative models in Drosophila: polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {40}, number = {1}, pages = {29-39}, pmid = {20561920}, issn = {1095-953X}, support = {P50 AG016570/AG/NIA NIH HHS/United States ; R01 NS046489/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; *Disease Models, Animal ; Drosophila melanogaster/genetics/*metabolism ; Humans ; Huntington Disease/genetics/*metabolism ; *Models, Genetic ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Parkinson Disease/genetics/*metabolism/pathology ; Peptides/genetics/*metabolism ; }, abstract = {Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue.}, }
@article {pmid20560784, year = {2010}, author = {Nassif, M and Matus, S and Castillo, K and Hetz, C}, title = {Amyotrophic lateral sclerosis pathogenesis: a journey through the secretory pathway.}, journal = {Antioxidants &amp; redox signaling}, volume = {13}, number = {12}, pages = {1955-1989}, doi = {10.1089/ars.2009.2991}, pmid = {20560784}, issn = {1557-7716}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*physiopathology ; Animals ; Endocytosis/physiology ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus/metabolism ; Humans ; *Secretory Pathway/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motoneuron degenerative disease characterized by the selective loss of motoneurons in the spinal ventral horn, most brainstem nuclei, and the cerebral cortex. Although approximately 90% of ALS cases are sporadic (sALS), analyses of familial ALS (fALS)-causative genes have generated relevant insight into molecular events involved in the pathology. Here we overview an emerging concept indicating the occurrence of secretory pathway stress in the disease process. These alterations include a failure in the protein folding machinery at the endoplasmic reticulum (ER), engagement of the unfolded protein response (UPR), modifications of the Golgi apparatus network, impaired vesicular trafficking, inhibition of protein quality control mechanisms, oxidative damage to ER proteins, and sustained activation of degradative pathways such as autophagy. A common feature predicted for most of these alterations is abnormal protein homeostasis associated with the accumulation of misfolded proteins at the ER, possibly leading to chronic ER stress and neuronal dysfunction. Signs of ER stress are observed even during presymptomatic stages in fALS mouse models, and pharmacological strategies to alleviate protein misfolding slow disease progression. Because the secretory pathway stress occurs in both sALS and several forms of fALS, it may offer a unique common target for possible therapeutic strategies to treat this devastating disease.}, }
@article {pmid20556761, year = {2010}, author = {Pastula, DM and Moore, DH and Bedlack, RS}, title = {Creatine for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {6}, pages = {CD005225}, doi = {10.1002/14651858.CD005225.pub2}, pmid = {20556761}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Creatine/*administration &amp; dosage/adverse effects ; Disease Progression ; Humans ; Motor Neuron Disease/drug therapy/mortality ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Randomized Controlled Trials as Topic ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS). Results from human trials, however, have been mixed. Given conflicting results regarding creatine's efficacy, we conducted a systematic review.<br><br>OBJECTIVES: To systematically examine creatine's efficacy in prolonging ALS survival and in slowing ALS disease progression.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2009), MEDLINE and EMBASE in October 2009 for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies.<br><br>SELECTION CRITERIA: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and percent predicted forced vital capacity (FVC) over time.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.<br><br>MAIN RESULTS: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).<br><br>AUTHORS' CONCLUSIONS: In patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALS functional rating revised scores (ALSFRS-R) progression or percent predicted forced vital capacity (FVC) progression.}, }
@article {pmid20552235, year = {2010}, author = {Barbeito, AG and Mesci, P and Boillée, S}, title = {Motor neuron-immune interactions: the vicious circle of ALS.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {117}, number = {8}, pages = {981-1000}, pmid = {20552235}, issn = {1435-1463}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/metabolism/pathology ; Animals ; Humans ; Immune System/*immunology/*pathology ; Macrophages/physiology ; Motor Neurons/*immunology ; T-Lymphocytes/physiology ; }, abstract = {Because microglial cells, the resident macrophages of the CNS, react to any lesion of the nervous system, they have for long been regarded as potential players in the pathogenesis of several neurodegenerative disorders including amyotrophic lateral sclerosis, the most common motor neuron disease in the adult. In recent years, this microglial reaction to motor neuron injury, in particular, and the innate immune response, in general, has been implicated in the progression of the disease, in mouse models of ALS. The mechanisms by which microglial cells influence motor neuron death in ALS are still largely unknown. Microglial activation increases over the course of the disease and is associated with an alteration in the production of toxic factors and also neurotrophic factors. Adding to the microglial/macrophage response to motor neuron degeneration, the adaptive immune system can likewise influence the disease process. Exploring these motor neuron-immune interactions could lead to a better understanding in the physiopathology of ALS to find new pathways to slow down motor neuron degeneration.}, }
@article {pmid20550485, year = {2010}, author = {Oliver, DJ and Turner, MR}, title = {Some difficult decisions in ALS/MND.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {4}, pages = {339-343}, pmid = {20550485}, issn = {1471-180X}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; TURNER/NOV07/6501/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/mortality/psychology/therapy ; *Decision Making ; Gastrostomy ; Humans ; Pulmonary Ventilation ; Suicide, Assisted/psychology ; }, }
@article {pmid20541840, year = {2012}, author = {Vadakkadath Meethal, S and Atwood, CS}, title = {Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis.}, journal = {Neurobiology of aging}, volume = {33}, number = {3}, pages = {569-581}, doi = {10.1016/j.neurobiolaging.2010.04.012}, pmid = {20541840}, issn = {1558-1497}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism/physiopathology ; Animals ; Humans ; Lactic Acid/*metabolism ; Mitochondrial Diseases/etiology/metabolism/physiopathology ; Nerve Degeneration/etiology/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS.}, }
@article {pmid20532896, year = {2010}, author = {Wakabayashi, K and Mori, F and Tanji, K and Orimo, S and Takahashi, H}, title = {Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain.}, journal = {Acta neuropathologica}, volume = {120}, number = {1}, pages = {1-12}, doi = {10.1007/s00401-010-0706-x}, pmid = {20532896}, issn = {1432-0533}, mesh = {Animals ; Brain Diseases/*physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Peripheral Nervous System/*physiopathology ; Synucleins/metabolism ; Tauopathies/*physiopathology ; }, abstract = {Involvement of the peripheral nervous system (PNS) is relatively common in some neurodegenerative proteinopathies of the brain and may be pathogenetically and diagnostically important. In Parkinson's disease, neuronal alpha-synuclein aggregates are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. The pathological process may target the PNS and CNS at the same time. In multiple system atrophy, numerous glial cytoplasmic inclusions composed of filamentous alpha-synuclein are widely distributed in the CNS, while alpha-synuclein accumulation is minimal in the sympathetic ganglia and is restricted to neurons. Neurofibrillary tangles can occur in the sympathetic and spinal ganglia in tauopathy, although they appear to develop independently of cerebral Alzheimer's disease pathology. In amyotrophic lateral sclerosis, neuronal loss with TDP-43-positive neuronal cytoplasmic inclusions in the spinal ganglia is more frequent than previously thought. Peripheral ganglia and visceral organs are also involved in polyglutamine diseases. Further elucidation and characterization of PNS lesions will have implications for intravital biopsy diagnosis in neurodegenerative proteinopathy, particularly in Parkinson's disease.}, }
@article {pmid20531383, year = {2010}, author = {Schwartz, M and Shechter, R}, title = {Systemic inflammatory cells fight off neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {6}, number = {7}, pages = {405-410}, pmid = {20531383}, issn = {1759-4766}, mesh = {Adaptive Immunity/physiology ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Humans ; Immune System Diseases/pathology ; Inflammation/immunology/*pathology ; Leukocytes/*physiology ; Macrophages/physiology ; Microglia/physiology ; Neurodegenerative Diseases/drug therapy/immunology/*pathology ; }, abstract = {Treatment of Alzheimer disease or amyotrophic lateral sclerosis with anti-inflammatory drugs (to prevent disease or slow its progression) has yielded mixed results, despite evidence indicating that local cytotoxic inflammation occurs in these conditions. Here, through consideration of the importance of immune cell origin (resident versus blood-derived immune cells) and activity (pro-inflammatory versus anti-inflammatory activity) under neurodegenerative conditions, we propose a model that reconciles these seemingly inconsistent data. We suggest that systemic immune cells (CD4(+) T cells and peripheral blood-derived monocytes) must be recruited to the CNS to modify potentially destructive local inflammation, and that the failure of systemic anti-inflammatory drug therapies to arrest neurodegenerative disease progression might result from drug-induced suppression of such recruitment. Thus, we propose that an appreciation of the distinctive temporal and spatial contributions of resident and systemic leukocytes to disease progression is essential for the development of effective therapeutic regimens.}, }
@article {pmid20529130, year = {2010}, author = {Bento-Abreu, A and Van Damme, P and Van Den Bosch, L and Robberecht, W}, title = {The neurobiology of amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {31}, number = {12}, pages = {2247-2265}, doi = {10.1111/j.1460-9568.2010.07260.x}, pmid = {20529130}, issn = {1460-9568}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Genome-Wide Association Study ; Humans ; Mutation ; *Neurobiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis is a degenerative disease affecting the motor neurons. In spite of our growing insights into its biology, it remains a lethal condition. The identification of the cause of several of the familial forms of ALS allowed generation of models to study this disease both in vitro and in vivo. Here, we summarize what is known about the pathogenic mechanisms of ALS induced by hereditary mutations, and attempt to identify the relevance of these findings for understanding the pathogenic mechanisms of the sporadic form of this disease.}, }
@article {pmid20522008, year = {2010}, author = {Peviani, M and Caron, I and Pizzasegola, C and Gensano, F and Tortarolo, M and Bendotti, C}, title = {Unraveling the complexity of amyotrophic lateral sclerosis: recent advances from the transgenic mutant SOD1 mice.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {4}, pages = {491-503}, doi = {10.2174/187152710791556096}, pmid = {20522008}, issn = {1996-3181}, support = {GGP06063/TI_/Telethon/Italy ; }, mesh = {Amino Acid Transport System X-AG/genetics/physiology ; Amyotrophic Lateral Sclerosis/*enzymology/etiology/genetics ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, Neurologic Mutants/genetics/physiology ; Mice, Transgenic/*genetics ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism/physiopathology ; Oxidative Stress/genetics/physiology ; Superoxide Dismutase/*genetics/physiology ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), which accounts for the majority of motor neuron disorders, is a progressive and fatal neurodegenerative disease leading to complete paralysis of skeletal muscles and premature death usually from respiratory failure. About 10% of all ALS cases are inherited, with the responsible gene having been identified in approximately 25% of these individuals. Mutations in the copper-zinc superoxide dismutase (SOD1) gene were the first to be recognized nearly twenty years ago, and since then different animal models, in particular transgenic rodents, have been developed. They replicate many of the clinical, neuropathological and molecular features of ALS patients and have contributed significantly to our understanding of the pathogenic mechanisms of this disease. Although results obtained so far with mutant SOD1 mice have not translated into effective therapies in ALS patients, these models still represent the only experimentally accessible system to study multiple aspects of disease pathogenesis and to provide proof-of-principle for the development of new therapeutic strategies. This review will examine the most recent discoveries obtained from these animal models in an attempt to elucidate the complex mechanisms of the disease. In particular it will focus on the contribution of multiple cell types in governing the disease development and progression.}, }
@article {pmid20520853, year = {2010}, author = {Kaundal, RK and Sharma, SS}, title = {Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents.}, journal = {Drug news &amp; perspectives}, volume = {23}, number = {4}, pages = {241-256}, doi = {10.1358/dnp.2010.23.4.1437710}, pmid = {20520853}, issn = {0214-0934}, mesh = {Alzheimer Disease/drug therapy ; Amyloid Precursor Protein Secretases/genetics ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Aspartic Acid Endopeptidases/genetics ; Brain Ischemia/drug therapy ; Humans ; Matrix Metalloproteinase Inhibitors ; Multiple Sclerosis/drug therapy ; Neuroprotective Agents/*pharmacology/therapeutic use ; PPAR gamma/*agonists/physiology ; Parkinson Disease/drug therapy ; }, abstract = {Peroxisome proliferator-activated receptor gamma (PPARgamma) has already been considered as an attractive therapeutic target for the treatment of metabolic disorders. Recently, PPARgamma agonists were shown to effectively attenuate oxidative stress, inflammation and apoptosis in the central nervous system. There are several preclinical and clinical studies indicating neuroprotective potential of PPARgamma agonists in the treatment of cerebral ischemia, Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. In these disorders, apart from inhibiting oxidative stress, inflammation and apoptosis, PPARgamma agonists have the potential to modulate various signaling molecules/pathways, including matrix metalloproteinase-9, mitogen-activated protein kinases, signal transducer and activator of transcription, mitochondrial uncoupling protein 2, mitoNEET expression, amyloid precursor protein degradation, beta-site amyloid precursor protein cleaving enzyme 1 and Wnt signaling. This article discusses evidence and mechanisms supporting the neuroprotective effects of PPARgamma agonists in central nervous system disorders.}, }
@article {pmid20510327, year = {2011}, author = {Van Moorhem, M and Lambein, F and Leybaert, L}, title = {Unraveling the mechanism of β-N-oxalyl-α,β-diaminopropionic acid (β-ODAP) induced excitotoxicity and oxidative stress, relevance for neurolathyrism prevention.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {49}, number = {3}, pages = {550-555}, doi = {10.1016/j.fct.2010.03.054}, pmid = {20510327}, issn = {1873-6351}, mesh = {Amino Acids, Diamino/*chemistry/*poisoning ; Calcium/metabolism ; Cell Death ; Cystine/metabolism ; Endoplasmic Reticulum/metabolism ; Excitatory Amino Acids/metabolism ; Lathyrism/*chemically induced/*prevention &amp; control ; Lathyrus/chemistry ; Mitochondria/metabolism ; *Oxidative Stress ; }, abstract = {β-N-Oxalyl-α,β-diaminopropionic acid (β-ODAP) is a plant metabolite present in Lathyrus sativus (L. Sativus) seeds that is proposed to be responsible for the neurodegenerative disease neurolathyrism. This excitatory amino acid binds to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and several lines of evidence indicate that β-ODAP triggers motor neuron degeneration by inducing excitotoxic cell death and increasing oxidative stress. In addition, this toxin is known to disturb the mitochondrial respiration chain and recent data indicate that β-ODAP may inhibit the uptake of cystine thereby compromising the cells' abilities to cope with oxidative stress. Recent work from our group furthermore suggests that β-ODAP disturbs the cellular Ca(2+) homeostasis machinery with increased Ca(2+) loading in the endoplasmic reticulum (ER)-mitochondrial axis. In this review, we aim to integrate the various mechanistic levels of β-ODAP toxicity into a consistent pathophysiological picture. Interestingly, the proposed cascade contains several aspects that are common with other neurodegenerative diseases, for example amyotrophic lateral sclerosis (ALS). Based on these mechanistic insights, we conclude that dietary supplementation with methionine (Met) and cysteine (Cys) may significantly lower the risk for neurolathyrism and can thus be considered, in line with epidemiological data, as a preventive measure for neurolathyrism.}, }
@article {pmid20509745, year = {2010}, author = {Maragakis, NJ}, title = {Stem cells and the ALS neurologist.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {5}, pages = {417-423}, doi = {10.3109/17482968.2010.489116}, pmid = {20509745}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Animals ; Humans ; Nerve Regeneration/physiology ; *Neurology ; Stem Cell Transplantation ; Stem Cells/*physiology ; Workforce ; }, abstract = {Stem cells have captured the imagination of people with ALS. The potential promise of neuronal replacement and regeneration, as well as replacement and regeneration of other neural tissues, through stem cell therapies, has become a source of great hope and expectation. While just more than a decade has passed since the discovery of human stem cells, the field has made substantial advances in the use of stem cells as tools for understanding the process of motor neuron degeneration. Although the therapeutic role of stems cells in ALS and other neurodegenerations remains to be established, recent experimental data provide grounds for considered optimism.}, }
@article {pmid20496755, year = {2010}, author = {Fujishiro, H and Hasegawa, M and Arai, T}, title = {[The molecular pathology of frontotemporal lobar degeneration].}, journal = {Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica}, volume = {112}, number = {4}, pages = {313-324}, pmid = {20496755}, issn = {0033-2658}, mesh = {DNA-Binding Proteins/analysis ; Frontotemporal Lobar Degeneration/*metabolism/pathology ; Histocytochemistry ; Humans ; RNA-Binding Protein FUS/analysis ; tau Proteins/analysis ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is a clinical syndrome characterized by behavioral and language difficulties, which refers to a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative disorders. Familial FTLD has been linked to mutations in several genes: the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B), and genetic locus on chromosome 9p linked to familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The associated neuropathology is characterized by selective degeneration of the frontal and temporal lobes with the neuronal and/or glial inclusions. The current classification of FTLD neuropathology is based on the major constituent protein of them: tau, TAR DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma (FUS). Abnormal phosphorylation, ubiquitination, and proteolytic cleavage are the common pathologic signature of tau and TDP-43 accumulated in diseased brains. Recent findings of TDP-43 and FUS reveal that FTLD and ALS share a common mechanism of pathogenesis. This review focuses on the current understanding of the molecular neuropathology of FTLD, and their relevance to the development of the therapeutics.}, }
@article {pmid20493207, year = {2010}, author = {Kawamata, H and Manfredi, G}, title = {Mitochondrial dysfunction and intracellular calcium dysregulation in ALS.}, journal = {Mechanisms of ageing and development}, volume = {131}, number = {7-8}, pages = {517-526}, pmid = {20493207}, issn = {1872-6216}, support = {R01 NS051419-01A1/NS/NINDS NIH HHS/United States ; R01 NS051419-05/NS/NINDS NIH HHS/United States ; R01 NS051419-02/NS/NINDS NIH HHS/United States ; R01 NS051419/NS/NINDS NIH HHS/United States ; R01 NS062055-03/NS/NINDS NIH HHS/United States ; R01 NS051419-03/NS/NINDS NIH HHS/United States ; R01 NS051419-04/NS/NINDS NIH HHS/United States ; R01-NS051419/NS/NINDS NIH HHS/United States ; R01-NS062055/NS/NINDS NIH HHS/United States ; R01 NS062055-01A1/NS/NINDS NIH HHS/United States ; R01 NS062055-02/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; }, mesh = {Age Factors ; Aging/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism/pathology/physiopathology ; Animals ; Astrocytes/metabolism ; Calcium/*metabolism ; Cell Death ; Homeostasis ; Humans ; Mitochondria/*metabolism/pathology ; Motor Neurons/*metabolism/pathology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that affects the aging population. A progressive loss of motor neurons in the spinal cord and brain leads to muscle paralysis and death. As in other common neurodegenerative diseases, aging-related mitochondrial dysfunction is increasingly being considered among the pathogenic factors. Mitochondria are critical for cell survival: they provide energy to the cell, buffer intracellular calcium, and regulate apoptotic cell death. Whether mitochondrial abnormalities are a trigger or a consequence of the neurodegenerative process and the mechanisms whereby mitochondrial dysfunction contributes to disease are not clear yet. Calcium homeostasis is a major function of mitochondria in neurons, and there is ample evidence that intracellular calcium is dysregulated in ALS. The impact of mitochondrial dysfunction on intracellular calcium homeostasis and its role in motor neuron demise are intriguing issues that warrants in depth discussion. Clearly, unraveling the causal relationship between mitochondrial dysfunction, calcium dysregulation, and neuronal death is critical for the understanding of ALS pathogenesis. In this review, we will outline the current knowledge of various aspects of mitochondrial dysfunction in ALS, with a special emphasis on the role of these abnormalities on intracellular calcium handling.}, }
@article {pmid20472062, year = {2010}, author = {Voisine, C and Pedersen, JS and Morimoto, RI}, title = {Chaperone networks: tipping the balance in protein folding diseases.}, journal = {Neurobiology of disease}, volume = {40}, number = {1}, pages = {12-20}, pmid = {20472062}, issn = {1095-953X}, support = {R01 AG026647/AG/NIA NIH HHS/United States ; R01 GM038109/GM/NIGMS NIH HHS/United States ; R37 GM038109/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/chemistry/genetics ; Gene Regulatory Networks/*physiology ; Humans ; Molecular Chaperones/*chemistry/*genetics ; Protein Conformation ; *Protein Folding ; Proteostasis Deficiencies/*genetics/*metabolism ; }, abstract = {Adult-onset neurodegeneration and other protein conformational diseases are associated with the appearance, persistence, and accumulation of misfolded and aggregation-prone proteins. To protect the proteome from long-term damage, the cell expresses a highly integrated protein homeostasis (proteostasis) machinery to ensure that proteins are properly expressed, folded, and cleared, and to recognize damaged proteins. Molecular chaperones have a central role in proteostasis as they have been shown to be essential to prevent the accumulation of alternate folded proteotoxic states as occurs in protein conformation diseases exemplified by neurodegeneration. Studies using invertebrate models expressing proteins associated with Huntington's disease, Alzheimer's disease, ALS, and Parkinson's disease have provided insights into the genetic networks and stress signaling pathways that regulate the proteostasis machinery to prevent cellular dysfunction, tissue pathology, and organismal failure. These events appear to be further amplified by aging and provide evidence that age-related failures in proteostasis may be a common element in many diseases.}, }
@article {pmid20463464, year = {2010}, author = {Price, S and Uddin, S and Quinn, T}, title = {Echocardiography in cardiac arrest.}, journal = {Current opinion in critical care}, volume = {16}, number = {3}, pages = {211-215}, doi = {10.1097/MCC.0b013e3283399d4c}, pmid = {20463464}, issn = {1531-7072}, mesh = {Algorithms ; Cardiopulmonary Resuscitation/*methods ; *Critical Illness ; Echocardiography ; Embolism/diagnosis/diagnostic imaging ; Emergency Service, Hospital/organization &amp; administration ; Heart Arrest/*diagnostic imaging/prevention &amp; control/therapy ; Heart Diseases/diagnosis/diagnostic imaging ; Hemodynamics ; Humans ; Intensive Care Units/*organization &amp; administration ; Thrombosis/diagnosis/diagnostic imaging ; }, abstract = {PURPOSE OF REVIEW: Successful resuscitation requires potentially reversible causes to be diagnosed and reversed, and many of these can readily be diagnosed using echocardiography. Although members of the resuscitation team routinely use adjuncts to their clinical examination in order to differentiate these causes, the use of echocardiography is not yet considered standard. The purpose of this review is to discuss the potential for echocardiography to aid diagnosis and treatment during resuscitation, together with some of the perceived challenges that currently limit its widespread use.<br><br>RECENT FINDINGS: Many studies have demonstrated the value of echocardiography in the assessment of critically ill patients in the intensive care unit and emergency room settings, including more recently the use of focused echocardiography. This can be performed within the time frame allowed during the pulse check of the advanced life support (ALS) algorithm. ALS-compliant focused echocardiography can be taught to nonexpert practitioners such that high-quality cardiopulmonary resuscitation is not compromised while diagnosing/excluding some of the potential causes of cardiac arrest.<br><br>SUMMARY: Persistent and worsening haemodynamic instability are regarded as clear indications for echocardiography. The focused application of this well established technique within the ALS algorithm provides the resuscitation team with a potentially powerful diagnostic tool that can be used to diagnose/exclude some of the potentially treatable causes of cardiac arrest as well as to guide therapeutic interventions. The impact of routine periresuscitation echocardiography on patient outcomes both for in-hospital and prehospital care remains an exciting avenue for future research.}, }
@article {pmid20463400, year = {2010}, author = {Shi, P and Wei, Y and Zhang, J and Gal, J and Zhu, H}, title = {Mitochondrial dysfunction is a converging point of multiple pathological pathways in amyotrophic lateral sclerosis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {20 Suppl 2}, number = {}, pages = {S311-24}, doi = {10.3233/JAD-2010-100366}, pmid = {20463400}, issn = {1875-8908}, support = {P20RR020171/RR/NCRR NIH HHS/United States ; R01NS049126/NS/NINDS NIH HHS/United States ; R11AG032567/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*pathology ; Animals ; Axonal Transport/physiology ; Homeostasis/physiology ; Humans ; Mitochondrial Diseases/*complications/genetics/*pathology ; Models, Biological ; Mutation/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {A better understanding of the etiology of amyotrophic lateral sclerosis (ALS) is needed to develop effective therapies for the treatment of this fatal neurodegenerative disease. Extensive studies have produced a general agreement that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology, and aberrant RNA metabolism. Mitochondria have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules is disrupted in ALS. Furthermore, new evidence suggests that mitochondrial fission and fusion as well as mitophagy clearance may also be affected by mutant SOD1. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging "dying-back" axonopathy model of ALS. In this review, we will discuss findings supporting that mitochondrial dysfunction is likely to be a converging point of multiple pathways underlying the ALS pathogenesis and progression.}, }
@article {pmid20462789, year = {2010}, author = {ElBasiouny, SM and Schuster, JE and Heckman, CJ}, title = {Persistent inward currents in spinal motoneurons: important for normal function but potentially harmful after spinal cord injury and in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {121}, number = {10}, pages = {1669-1679}, pmid = {20462789}, issn = {1872-8952}, support = {F31 NS060532/NS/NINDS NIH HHS/United States ; R01 NS034382/NS/NINDS NIH HHS/United States ; R01 NS051462/NS/NINDS NIH HHS/United States ; /CAPMC/CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Humans ; Membrane Potentials/*physiology ; Motor Neurons/*physiology ; Neuronal Plasticity/physiology ; Spinal Cord/*pathology ; Spinal Cord Injuries/*pathology ; }, abstract = {Meaningful body movements depend on the interplay between synaptic inputs to motoneurons and their intrinsic properties. Injury and disease often alter either or both of these factors and cause motoneuron and movement dysfunction. The ability of the motoneuronal membrane to generate persistent inward currents (PICs) is especially potent in setting the intrinsic excitability of motoneurons and can drastically change the motoneuron output to a given input. In this article, we review the role of PICs in modulating the excitability of spinal motoneurons during health, and their contribution to motoneuron excitability after spinal cord injury (SCI) and in amyotrophic lateral sclerosis (ALS) leading to exaggerated long-lasting reflexes and muscle spasms, and contributing to neuronal degeneration, respectively.}, }
@article {pmid20443977, year = {2010}, author = {Raggi, A and Ferri, R}, title = {Sleep disorders in neurodegenerative diseases.}, journal = {European journal of neurology}, volume = {17}, number = {11}, pages = {1326-1338}, doi = {10.1111/j.1468-1331.2010.03034.x}, pmid = {20443977}, issn = {1468-1331}, mesh = {Humans ; Magnetic Resonance Imaging ; Neurodegenerative Diseases/classification/*complications ; Polysomnography/methods ; Sleep Wake Disorders/diagnosis/*etiology ; }, abstract = {The aim of this review is to provide data on sleep disturbances in three categories of neurodegenerative disorders: synucleinopathies, tauopathies, and other diseases (this heterogeneous group includes also spinocerebellar degeneration and amyotrophic lateral sclerosis). Analysing and knowing sleep disorders in neurodegenerative diseases may offer important insights into the pathomechanism of some of these diseases and calls attention to the still insufficiently known 'sleep neurology'. The identification of sleep disorders in some neurodegenerative conditions may make their diagnosis easier and earlier; for example, rapid eye movements sleep behaviour disorder may precede any other clinical manifestation of synucleinopathies by more than 10 years.}, }
@article {pmid20434225, year = {2010}, author = {Perlson, E and Maday, S and Fu, MM and Moughamian, AJ and Holzbaur, EL}, title = {Retrograde axonal transport: pathways to cell death?.}, journal = {Trends in neurosciences}, volume = {33}, number = {7}, pages = {335-344}, pmid = {20434225}, issn = {1878-108X}, support = {R01 NS060698/NS/NINDS NIH HHS/United States ; R01 NS060698-02/NS/NINDS NIH HHS/United States ; T32 GM007517/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport/*physiology ; Cell Death/*physiology ; Humans ; Microtubules/metabolism ; Molecular Motor Proteins/*metabolism ; *Nerve Degeneration/metabolism/pathology/physiopathology ; *Neurodegenerative Diseases/pathology/physiopathology ; Neurons/cytology/physiology ; Signal Transduction/*physiology ; }, abstract = {Active transport along the axon is crucial to the neuron. Motor-driven transport supplies the distal synapse with newly synthesized proteins and lipids, and clears damaged or misfolded proteins. Microtubule motors also drive long-distance signaling along the axon via signaling endosomes. Although positive signaling initiated by neurotrophic factors has been well-studied, recent research has focused on stress-signaling along the axon. Here, the connections between axonal transport alterations and neurodegeneration are discussed, including evidence for defective transport of vesicles, mitochondria, degradative organelles, and signaling endosomes in models of amyotrophic lateral sclerosis, Huntington's, Parkinson's and Alzheimer's disease. Defects in transport are sufficient to induce neurodegeneration, but recent progress suggests that changes in retrograde signaling pathways correlate with rapidly progressive neuronal cell death.}, }
@article {pmid20424386, year = {2010}, author = {Hideyama, T and Yamashita, T and Nishimoto, Y and Suzuki, T and Kwak, S}, title = {Novel etiological and therapeutic strategies for neurodiseases: RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of pharmacological sciences}, volume = {113}, number = {1}, pages = {9-13}, doi = {10.1254/jphs.09r21fm}, pmid = {20424386}, issn = {1347-8648}, mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adenosine Deaminase/*genetics/metabolism ; Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Animals ; Cell Death/genetics ; Humans ; Mice ; Mice, Knockout ; Models, Biological ; Motor Neurons/*metabolism ; *RNA Editing ; RNA-Binding Proteins ; Receptors, AMPA/genetics ; }, abstract = {The motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS) express abundant Q/R site-unedited GluR2 mRNA, whereas those of patients with other motor neuron diseases including familial ALS associated with mutated SOD1 (ALS1) and those of normal subjects express only Q/R site-edited GluR2 mRNA. Because adenosine deaminase acting on RNA type 2 (ADAR2) specifically catalyzes GluR2 Q/R site-editing, it is likely that ADAR2 activity is not sufficient to edit this site completely in motor neurons of patients with sporadic ALS. Because these molecular abnormalities occur in disease- and motor neuron-specific fashion and induce fatal epilepsy in mice, we have hypothesized that GluR2 Q/R site-underediting due to ADAR2 underactivity is a cause of neuronal death in sporadic ALS. We found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position using RNA interference knockdown. Our review will include a discussion of new ADAR2 substrates that may be useful for research on sporadic ALS.}, }
@article {pmid20421690, year = {2010}, author = {Patten, DA and Germain, M and Kelly, MA and Slack, RS}, title = {Reactive oxygen species: stuck in the middle of neurodegeneration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {20 Suppl 2}, number = {}, pages = {S357-67}, doi = {10.3233/JAD-2010-100498}, pmid = {20421690}, issn = {1875-8908}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Apoptosis/physiology ; Humans ; Mitochondria/metabolism/pathology ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/*metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Neuronal cell loss associated with neurodegeneration has recently been linked to mitochondrial dysfunction. Electron transport chain defects and reactive oxygen species (ROS) production are emerging as important players in the etiology of neurodegenerative diseases. Proper management of ROS and disposal of damaged cellular components are vital to the survival and function of neurons. Proteins involved in these pathways are often mutated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In this review, we will discuss the roles of ROS in normal physiology, how changes in ROS production affect neuronal survival in neurodegenerative diseases, and the recent advances in mitochondrial antioxidants as potential therapeutics.}, }
@article {pmid20420829, year = {2010}, author = {Inoue, H}, title = {Neurodegenerative disease-specific induced pluripotent stem cell research.}, journal = {Experimental cell research}, volume = {316}, number = {16}, pages = {2560-2564}, doi = {10.1016/j.yexcr.2010.04.022}, pmid = {20420829}, issn = {1090-2422}, mesh = {*Biomedical Research ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Neurodegenerative Diseases/*physiopathology/therapy ; }, abstract = {Neurodegenerative disease-specific induced pluripotent stem cell (iPSC) research contributes to the following 3 areas; "Disease modeling", "Disease material" and "Disease therapy". "Disease modeling", by recapitulating the disease phenotype in vitro, will reveal the pathomechanisms. Neurodegenerative disease-specific iPSC-derived non-neuronal cells harboring disease-causative protein(s), which play critical roles in neurodegeneration including motor neuron degeneration in amyotrophic lateral sclerosis, could be "Disease material", the target cell(s) for drug screening. These differentiated cells also could be used for "Disease therapy", an autologous cellular replacement/neuroprotection strategy, for patients with neurodegenerative disease. Further progress in these areas of research can be made for currently incurable neurodegenerative diseases.}, }
@article {pmid20420185, year = {2010}, author = {Ichikawa, H and Kawamura, M}, title = {[Language impairment in amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {62}, number = {4}, pages = {435-440}, pmid = {20420185}, issn = {1881-6096}, mesh = {Agraphia/etiology ; Amyotrophic Lateral Sclerosis/*complications ; Aphasia, Broca/etiology ; Frontotemporal Lobar Degeneration/etiology ; Humans ; Language Disorders/*etiology ; Writing ; }, abstract = {For a long time, amyotrophic lateral sclerosis (ALS) was thought to be a neuro-degenerative disease with selective involvement of the motor neuron system. However, it has recently been established that ALS is a multisystem disorder that not only involve the motor system but also affects cognition. A typical cognitive impairment in ALS is frontotemporal dementia: a clinical subtype of frontotemporal lobar degeneration (FTLD). Furthermore, language impairment, including progressive non-fluent aphasia (PA) and semantic dementia (SD), which are also FTLD subtypes, have been linked to bulbar-onset ALS. Beside recent studies a Japanese paper published in 1893 gives an account of aphasia in bulbar-onset ALS. Interestingly, this was the first account of aphasia in Japan. Thus, language-related problems in ALS may have been overlooked, because evaluation of aphasic problems in ALS patients is difficult, mainly because of progressive bulbar or pseudo-bulbar palsy that results in and dysarthria. From a clinical point of view, progressing bulbar symptoms and medical interventions, such artificial ventilation make it difficult to evaluate language functions in ALS. However, we do observe frequent omission and paragraphia of kana letters, and syntactic errors in writing. Interestingly, some patients make exhibit errors exclusively in the case of kanji characters. Thus, evaluation of writing samples is important if order to identify language problems in ALS patients. The findings may also provide additional information such as dissociation between errors made in kana and kanji characters. The characteristic features of writing errors are thought to reflect the nature of aphasia including PA and SD, that are easily masked by dysarthria. In addition, writing errors can appear as "isolated agraphia" without aphasia and dementia. Pathologically, writing errors should indicate the brain regions involved by ALS, e.g., hemispheric dominance and frontal or temporal lobe involvement. In addition, selective involvement of Exner's writing center in the frontal lobe may be responsible for "isolated agraphia". Hence, further studies are required to determine the clinical significance of writing errors in ALS patients and their pathological correlation.}, }
@article {pmid20420119, year = {2010}, author = {Kertesz, A}, title = {Frontotemporal dementia, Pick's disease.}, journal = {Ideggyogyaszati szemle}, volume = {63}, number = {1-2}, pages = {4-12}, pmid = {20420119}, issn = {0019-1442}, mesh = {Aphasia/etiology ; *Frontotemporal Dementia/complications/diagnosis/epidemiology/genetics/therapy ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Motor Neuron Disease/complications ; Mutation ; *Pick Disease of the Brain/complications/diagnosis/epidemiology/genetics/therapy ; Prognosis ; Progranulins ; Semantics ; tau Proteins/genetics ; }, abstract = {A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP also belong. These seemingly different presentations converge, as one or other areas in the brain are affected. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.}, }
@article {pmid20418487, year = {2010}, author = {Marchetto, MC and Winner, B and Gage, FH}, title = {Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases.}, journal = {Human molecular genetics}, volume = {19}, number = {R1}, pages = {R71-6}, pmid = {20418487}, issn = {1460-2083}, mesh = {Drug Evaluation, Preclinical ; Humans ; Neurodegenerative Diseases/*pathology ; Pluripotent Stem Cells/*cytology ; }, abstract = {Most of our current knowledge about cellular phenotypes in neurodevelopmental and neurodegenerative diseases in humans was gathered from studies in postmortem brain tissues. These samples often represent the end-stage of the disease and therefore are not always a fair representation of how the disease developed. Moreover, under these circumstances, the pathology observed could be a secondary effect rather than the authentic disease cellular phenotype. Likewise, the rodent models available do not always recapitulate the pathology from human diseases. In this review, we will examine recent literature on the use of induced pluripotent stem cells to model neurodegenerative and neurodevelopmental diseases. We highlight the characteristics of diseases like spinal muscular atrophy and familial dysautonomia that allowed partial modeling of the disease phenotype. We review human stem cell literature on common neurodegenerative late-onset diseases such as Parkinson's disease and amyotrophic lateral sclerosis where patients' cells have been successfully reprogrammed but a disease phenotype has not yet been described. So far, the technique is of great interest for early onset monogenetic neurodevelopmental diseases. We speculate about potential further experimental requirements and settings for reprogrammed neurons for in vitro disease modeling and drug discovery.}, }
@article {pmid20415586, year = {2010}, author = {Sleegers, K and Cruts, M and Van Broeckhoven, C}, title = {Molecular pathways of frontotemporal lobar degeneration.}, journal = {Annual review of neuroscience}, volume = {33}, number = {}, pages = {71-88}, doi = {10.1146/annurev-neuro-060909-153144}, pmid = {20415586}, issn = {1545-4126}, mesh = {Frontotemporal Lobar Degeneration/etiology/*genetics/*metabolism ; Genetic Predisposition to Disease/genetics ; Humans ; Nerve Degeneration/etiology/*genetics/*metabolism ; Phosphorylation/genetics ; Signal Transduction/*genetics ; tau Proteins/genetics/metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition that predominantly affects behavior, social awareness, and language. It is characterized by extensive heterogeneity at the clinical, pathological, and genetic levels. Recognition of these levels of heterogeneity is important for proper disease management. The identification of progranulin and TDP-43 as key proteins in a significant proportion of FTLD patients has provided the impetus for a wealth of studies probing their role in neurodegeneration. This review highlights the most recent developments and future directions in this field and puts them in perspective of the novel insights into the neurodegenerative process, which have been gained from related disorders, e.g., the role of FUS in amyotrophic lateral sclerosis.}, }
@article {pmid20413882, year = {2010}, author = {Burrell, JR and Hodges, JR}, title = {From FUS to Fibs: what's new in frontotemporal dementia?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {21}, number = {2}, pages = {349-360}, doi = {10.3233/JAD-2010-091513}, pmid = {20413882}, issn = {1875-8908}, mesh = {*Frontotemporal Dementia/genetics/pathology/physiopathology ; Humans ; *Primary Progressive Nonfluent Aphasia/genetics/pathology/physiopathology ; *TDP-43 Proteinopathies/genetics/pathology/physiopathology ; }, abstract = {Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries.}, }
@article {pmid20413846, year = {2010}, author = {Martin, LJ}, title = {Mitochondrial pathobiology in Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {20 Suppl 2}, number = {}, pages = {S335-56}, doi = {10.3233/JAD-2010-100348}, pmid = {20413846}, issn = {1875-8908}, support = {AG016282/AG/NIA NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/*pathology ; Animals ; DNA, Mitochondrial/genetics ; Disease Models, Animal ; Humans ; Mitochondria/genetics/metabolism/*pathology/ultrastructure ; Mitochondrial Diseases/complications/genetics/pathology ; Models, Biological ; Mutation/genetics ; Parkinson Disease/etiology/genetics/*pathology ; Protein Kinases/genetics ; Ubiquitin Thiolesterase/genetics ; alpha-Synuclein/genetics ; }, abstract = {Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are the second and third most common human adult-onset neurodegenerative diseases, respectively, after Alzheimer's disease. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of PD and ALS are inherited, and genes causing these diseases have been identified. Morphological, biochemical, and genetic, as well as cell and animal model, studies reveal that mitochondria could have a role in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review will present how mitochondrial pathobiology might contribute to neurodegeneration in PD and ALS and could serve as a target for drug therapy.}, }
@article {pmid20406185, year = {2010}, author = {Sreedharan, J}, title = {Neuronal death in amyotrophic lateral sclerosis (ALS): what can we learn from genetics?.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {259-267}, doi = {10.2174/187152710791292558}, pmid = {20406185}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; Animals ; Cell Death/genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Nerve Degeneration/*genetics/metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a difficult disease to study as it is mostly sporadic and rapidly progressive. Identification of genes causing familial ALS (FALS) has been instrumental in advancing our understanding of ALS pathogenesis, most notably with the use of mutant superoxide dismutase 1 (SOD1) models of disease. For 15 years SOD1 models have been the backbone of ALS research, but no effective reatments have been developed. However, recent advances have been made in the genetics of ALS with the identification of mutations in TAR DNA binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), both of which have roles in RNA-processing and gene expression. Molecular links between ALS and frontotemporal dementia (FTD) are also suggested by linkage of ALS-FTD to chromosome 9. The study of the genetics of sporadic ALS (SALS) has been less fruitful, although this may change as we enter the era of resequencing. Further important clues as to the causes of ALS will come from the identification of other gene mutations that cause FALS, variants that increase susceptibility to SALS, and genetic factors that modify the ALS phenotype.}, }
@article {pmid20406184, year = {2010}, author = {Pasquali, L and Ruffoli, R and Fulceri, F and Pietracupa, S and Siciliano, G and Paparelli, A and Fornai, F}, title = {The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {268-278}, doi = {10.2174/187152710791292594}, pmid = {20406184}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; Animals ; Autophagy/*genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Motor Neurons/metabolism/pathology ; Nerve Degeneration/*genetics/metabolism/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by loss of motor neurons both in the brain and spinal cord, which dramatically reduces life expectancy. ALS occurs either in familial ALS or, more frequently, in sporadic ALS forms. Several mechanisms have been postulated to underlie motor neuron death. In the present paper, starting from some of the genes related to familial ALS, we overview and discuss their potential role in modifying of the physiological clearance of altered proteins and organelles in motor neurons. Special emphasis is placed on the role of autophagy, which seems to prevail as a protein clearing system over other multienzymatic pathways such as the proteasome within motor neurons. The evidence which links an altered autophagy to the onset of motor neuron death proposes that this biochemical pathway might represent a final common mechanism underlying both inherited and sporadic forms of ALS. In light of these findings we also analyze the potential significance of a novel association between ALS, altered autophagy, and mutations of nuclear proteins such as TAR-DNA-Binding Protein 43 and fused in sarcoma/translated in liposarcoma. Such an association appears to be critical since it is now well demonstrated that all sporadic and most familiar forms of ALS are characterized by altered deposition and mislocalization of TAR-DNA-Binding Protein 43. These novel insights into the pathogenesis of ALS may lead to the identification of novel strategies to promote motor neuron survival.}, }
@article {pmid20406183, year = {2010}, author = {Schmalbach, S and Petri, S}, title = {Histone deacetylation and motor neuron degeneration.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {279-284}, doi = {10.2174/187152710791292684}, pmid = {20406183}, issn = {1996-3181}, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy/enzymology/genetics/*pathology ; Animals ; Histone Deacetylases/*metabolism ; Humans ; Motor Neurons/drug effects/*enzymology/*pathology ; Nerve Degeneration/drug therapy/*enzymology/genetics/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with progressive muscular wasting and paralysis due to loss of motor neurons in the primary motor cortex, brainstem and spinal cord. Alterations of transcriptional activity due to an unbalance of the activity of histone acetyl transferases (HAT) and histone deacetylases (HDACs) have been described in a variety of neurodegenerative conditions in vitro and in vivo. HDACs can be grouped into four different classes with distinct cellular localization and functions. HDAC inhibitors have recently been discovered as potential neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors causing a variety of toxic side effects.}, }
@article {pmid20406182, year = {2010}, author = {Ticozzi, N and Ratti, A and Silani, V}, title = {Protein aggregation and defective RNA metabolism as mechanisms for motor neuron damage.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {285-296}, doi = {10.2174/187152710791292585}, pmid = {20406182}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Humans ; Motor Neurons/*metabolism/*pathology ; Nerve Degeneration/genetics/*metabolism/pathology ; Nerve Tissue Proteins/genetics/*metabolism ; RNA/genetics/*metabolism ; }, abstract = {The presence of protein inclusions within the central nervous system is a characteristic of most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Aggregates may induce cell death trough several mechanisms, such as sequestration of essential cellular components, clogging of the proteasome system, and/or disruption of axonal transport. The neuropathological signature of ALS is represented by the presence of ubiquitinated inclusions immunoreactive for the protein TDP-43 in the cytoplasm of motor neurons. Recent studies demonstrated that a significant percentage of familial ALS cases are caused by pathogenic mutations in the TAR DNA binding protein and fused in sarcoma/translocated in liposarcoma genes encoding, respectively, for TDP-43 and FUS proteins. Both TDP-43 and FUS are DNA/RNA-binding proteins involved in transcriptional regulation and splicing, shuttling, maturation and transport of mRNA molecules. Mutations in the two genes seem to induce a nucleo-cytoplasmic redistribution of FUS and TDP-43, possibly promoting aggregate formation and/or disrupting their physiological nuclear functions or their interactions with specific RNA targets. Those findings collectively suggest that alterations in cellular RNA metabolism may trigger motor neuron degeneration.}, }
@article {pmid20406181, year = {2010}, author = {Bogaert, E and d'Ydewalle, C and Van Den Bosch, L}, title = {Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {297-304}, doi = {10.2174/187152710791292576}, pmid = {20406181}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/*pathology ; Animals ; Humans ; Motor Neurons/*metabolism/*pathology ; Neurotoxins/*metabolism/toxicity ; }, abstract = {Glutamate-induced excitotoxicity is responsible for neuronal death in acute neurological conditions as well as in chronic neurodegeneration. In this review, we give an overview of the contribution of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS). The selective motor neuron death that is the hallmark of this neurodegenerative disease seems to be related to a number of intrinsic characteristics of these neurons. Most of these characteristics relate to calcium entry and calcium handling in the motor neurons as intracellular free calcium concentrations increase quickly due to a high glutamate-induced calcium influx in combination with a low calcium buffering capacity. The high calcium influx is because of the presence of GluR2 lacking, calcium-permeable AMPA receptors while a low expression of calcium binding proteins explains the low calcium buffering capacity. In the absence of these proteins, mitochondria play an important role to remove calcium from the cytoplasm. While all of these characteristics make at least a subpopulation of motor neurons intrinsically very prone to AMPA receptor mediated excitotoxicity, this vulnerability is further increased by the disease process. Mutated genes as well as unknown factors do not only influence the intrinsic characteristics of the motor neurons, but also the properties of the surrounding astrocytes. In conclusion, excitotoxicity remains an intriguing pathological pathway that could not only explain the selectivity of the motor neuron death but also the role of surrounding non-neuronal cells in ALS. In addition, excitotoxicity is also an interesting drug-able target as indicated by the only FDA-approved drug, riluzole, as well as by a number of ongoing clinical trials.}, }
@article {pmid20406180, year = {2010}, author = {Siciliano, G and Carlesi, C and Pasquali, L and Piazza, S and Pietracupa, S and Fornai, F and Ruggieri, S and Murri, L}, title = {Clinical trials for neuroprotection in ALS.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {305-313}, doi = {10.2174/187152710791292648}, pmid = {20406180}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/*pathology ; Animals ; Clinical Trials as Topic/*trends ; Humans ; Neuropharmacology/methods/*trends ; Neuroprotective Agents/*pharmacology/therapeutic use ; Neurotoxins/antagonists &amp; inhibitors ; }, abstract = {Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.}, }
@article {pmid20406179, year = {2010}, author = {Silani, V and Calzarossa, C and Cova, L and Ticozzi, N}, title = {Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement?.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {314-324}, doi = {10.2174/187152710791292666}, pmid = {20406179}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology/physiology ; Nerve Degeneration/etiology/pathology/therapy ; Stem Cell Transplantation/*methods/*trends ; Stem Cells/*pathology/physiology ; }, abstract = {Given the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), compelling preclinical data on stem cell research has targeted this disease as a candidate for stem cell treatment. Stem cell transplantation has been effective in several animal models, but the underlying biological pathways of restorative processes are still unresolved. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results in preclinical animal models, in addition to replacement of lost motor neurons. The clinical target in ALS has shifted from being neuroncentered to focus on the interaction between motor neurons and non-neuronal cells (mainly astroglial or microglial). In fact, one of the fundamental unanswered questions in ALS is whether and how much motor neuron death depends on neighboring cells, and how wildtype non-neuronal cells may protect motor neurons expressing an ALS-causing mutation. Lately, motor neuron replacement has been successfully achieved in animal models with reinnervation of the muscle target. Even if many biological issues need to be solved in preclinical models, preliminary stem cell transplantation trials have been performed in ALS patients with conflicting results. The review discusses relevant topics regarding the application of stem cell research to ALS focusing on their therapeutic relevance and mechanisms of action.}, }
@article {pmid20406178, year = {2010}, author = {Calvo, A and Moglia, C and Balma, M and Chiò, A}, title = {Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity?.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {325-330}, doi = {10.2174/187152710791292657}, pmid = {20406178}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*immunology/therapy ; Animals ; Disease Models, Animal ; Humans ; Immunity, Innate/drug effects/*immunology ; Immunoglobulins, Intravenous/administration &amp; dosage/therapeutic use ; Immunosuppressive Agents/*administration &amp; dosage/therapeutic use ; }, abstract = {The immune system has been found to be involved with positive and negative effects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. In general, T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage. Several mechanisms of action, such as production of neurotrophic growth factors and interaction with neurons and glial cells, have been shown to preserve these latter from injury and stimulate growth and repair. The immune system also participates in proliferation of neural progenitor stem cells and their migration to sites of injury and this activity has been documented in various neurologic disorders including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and ALS). Many therapies have been shown to stimulate the protective and regenerative aspects of the immune system in humans, such as intravenous immunoglobulins, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of ALS. Consequently, several immunosuppressive and immunomodulatory therapies have been tried in ALS, generally with no success, in particular intravenous immunoglobulins. The multiple aspects of the immune response in ALS are beginning to be appreciated, and their potential as pharmacologic targets in neurologic disease is being explored.}, }
@article {pmid20406177, year = {2010}, author = {Dileone, M and Profice, P and Pilato, F and Ranieri, F and Capone, F and Musumeci, G and Florio, L and Di Iorio, R and Di Lazzaro, V}, title = {Repetitive transcranial magnetic stimulation for ALS.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {331-334}, doi = {10.2174/187152710791292620}, pmid = {20406177}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/*therapy ; Animals ; Humans ; Nerve Degeneration/metabolism/*pathology/*therapy ; Transcranial Magnetic Stimulation/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons characterized by progressive weakness, respiratory failure and death within 3-5 years. It has been proposed that glutamate-related excitotoxicity may promote motor neuron death in ALS. Glutamatergic circuits of the human motor cortex can be activated noninvasively using transcranial magnetic stimulation (TMS) of the brain, and repetitive TMS (rTMS) can produce changes in neurotransmission that outlast the period of stimulation. In recent years a remarkable number of papers about the potential effects of rTMS in several neurological disorders including ALS has been published. Preliminary studies have shown that rTMS of the motor cortex, at frequencies that decrease cortical excitability, causes a slight slowing in the progression rate of ALS, suggesting that these effects might be related to a diminution of glutamate-driven excitotoxicity. RTMS could also interfere with motor neuron death through different mechanisms: rTMS could modulate the production of brain-derived neurotrophic factor (BDNF), a potent survival factor for neurons, that in turn might represent a promoter of motor neuron sparing in ALS. Despite some promising preliminary data, recent studies have demonstrated a lack of significant long-term beneficial effects of rTMS on neurological deterioration in ALS. However, further studies are warranted to evaluate the potential efficacy of different protocols of motor cortex stimulation (in terms of technique, duration and frequency of stimulation), particularly during the early stages of the disease when the progression rate is more pronounced.}, }
@article {pmid20400460, year = {2010}, author = {Lagier-Tourenne, C and Polymenidou, M and Cleveland, DW}, title = {TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration.}, journal = {Human molecular genetics}, volume = {19}, number = {R1}, pages = {R46-64}, pmid = {20400460}, issn = {1460-2083}, support = {089701/WT_/Wellcome Trust/United Kingdom ; R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Biological Transport ; DNA-Binding Proteins/metabolism/*physiology ; Frontotemporal Lobar Degeneration/genetics/*pathology ; Humans ; RNA Processing, Post-Transcriptional/*physiology ; RNA-Binding Protein FUS/metabolism/*physiology ; Subcellular Fractions/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases with clinical and pathological overlap. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and FTLD, combined with the abnormal aggregation of these proteins, have initiated a shifting paradigm for the underlying pathogenesis of multiple neurodegenerative diseases. TDP-43 and FUS/TLS are both RNA/DNA-binding proteins with striking structural and functional similarities. Their association with ALS and other neurodegenerative diseases is redirecting research efforts toward understanding the role of RNA processing regulation in neurodegeneration.}, }
@article {pmid20399900, year = {2010}, author = {Vallières, M and du Souich, P}, title = {Modulation of inflammation by chondroitin sulfate.}, journal = {Osteoarthritis and cartilage}, volume = {18 Suppl 1}, number = {}, pages = {S1-6}, doi = {10.1016/j.joca.2010.02.017}, pmid = {20399900}, issn = {1522-9653}, mesh = {Anti-Inflammatory Agents/*therapeutic use ; Atherosclerosis/drug therapy ; Chondroitin Sulfates/*therapeutic use ; Humans ; Inflammation/*drug therapy ; Inflammatory Bowel Diseases/drug therapy ; Osteoarthritis/drug therapy ; Psoriasis/drug therapy ; }, abstract = {OBJECTIVE AND METHODS: To evaluate the immune-modulator effect of chondroitin sulfate (CS) by means of the review of the literature.<br><br>RESULTS: Inflammatory reactions are primarily originated by infectious agents, immune reactions and by sterile tissue lesions that activate membrane receptors by means of pathogen-associated molecular patterns, tissue breakdown products and cytokines. The activation of membrane receptors triggers the phosphorylation of mitogen activated protein kinases and of the nuclear factor kappaB (NF-kappaB). The binding of NF-kappaB to the promoter of target genes enhances the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase 2, phospholipase A2, and matrix metalloproteases, proteins that contribute to tissue damage and to the inflammatory reaction. The activation of NF-kappaB has a key role in the immune homeostasis and the inflammatory response and therefore, in the pathogenesis of numerous diseases. Chondroitin sulfate (CS) is able to diminish NF-kappaB activation and nuclear translocation in chondrocytes and synovial membrane, effects that may explain the benefits of CS in osteoarthritis. In addition, systemic CS reduces NF-kappaB nuclear translocation in macrophages and hepatocytes, raising the hypothesis that CS might be of benefit to treat other diseases with a strong inflammatory component. There is preliminary evidence in humans that CS improves moderate to severe psoriasis. Moreover, experimental and clinical data suggest that CS might be a useful therapeutic agent in diseases such as inflammatory bowel diseases, atherosclerosis, Parkinson's and Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis and systemic lupus erythematosus.<br><br>DISCUSSION: These results urge for double blinded placebo-controlled trials to confirm the utility of CS in diseases with immune and inflammatory components.}, }
@article {pmid20399203, year = {2010}, author = {Rivera-Mancía, S and Pérez-Neri, I and Ríos, C and Tristán-López, L and Rivera-Espinosa, L and Montes, S}, title = {The transition metals copper and iron in neurodegenerative diseases.}, journal = {Chemico-biological interactions}, volume = {186}, number = {2}, pages = {184-199}, doi = {10.1016/j.cbi.2010.04.010}, pmid = {20399203}, issn = {1872-7786}, mesh = {Alzheimer Disease/drug therapy/etiology/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/metabolism ; Carrier Proteins/metabolism ; Chelating Agents/therapeutic use ; Copper/*metabolism ; Homeostasis ; Humans ; Huntington Disease/drug therapy/etiology/metabolism ; Iron/*metabolism ; Models, Biological ; Neurodegenerative Diseases/etiology/*metabolism ; Parkinson Disease/drug therapy/etiology/metabolism ; }, abstract = {Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenic mechanisms and possible therapeutic relevance are discussed regarding four of the most common neurodegenerative diseases, Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those disorders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. The interaction between metals and proteins in the nervous system seems to be a crucial factor for the development or absence of neurodegeneration. The present review also deals with the therapeutic strategies tested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed in those diseases could be the result of compensatory mechanisms to improve metal availability for physiological processes.}, }
@article {pmid20377511, year = {2010}, author = {Cheah, BC and Vucic, S and Krishnan, AV and Kiernan, MC}, title = {Riluzole, neuroprotection and amyotrophic lateral sclerosis.}, journal = {Current medicinal chemistry}, volume = {17}, number = {18}, pages = {1942-1199}, doi = {10.2174/092986710791163939}, pmid = {20377511}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/*therapeutic use ; Riluzole/chemistry/pharmacokinetics/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This 'excitotoxicity' theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na+ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990 s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na+ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.}, }
@article {pmid20373255, year = {2010}, author = {Olney, N and Rosen, H}, title = {AVP-923, a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect and neuropathic pain.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {4}, pages = {254-265}, pmid = {20373255}, issn = {2040-3410}, support = {T32 AG023481/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Clinical Trials as Topic ; Dextromethorphan/adverse effects/chemistry/pharmacokinetics/*therapeutic use ; Diabetic Neuropathies/*drug therapy ; Drug Combinations ; Humans ; Mood Disorders/*drug therapy ; Quinidine/adverse effects/chemistry/pharmacokinetics/*therapeutic use ; }, abstract = {AVANIR Pharmaceuticals Inc, under license from Irisys Research &amp; Development, is developing AVP-923 (Zenvia, Neurodex) for the treatment of pseudobulbar affect (PBA; in collaboration with Medison Pharma Ltd) and neuropathic pain associated with diabetic peripheral neuropathy. PBA, the main indication of AVP-923, is a neurological disorder characterized by uncontrollable and unpredictable episodes of laughing and/or crying. AVP-923 consists of a combination of the NMDA antagonist/sigma1 receptor agonist dextromethorphan hydrobromide (DM) and the cytochrome P450 2D6 (CYP2D6) enzyme inhibitor quinidine sulfate (Q). DM has been under investigation for several years as a neuroprotective agent in stroke, neurosurgery and amyotrophic lateral sclerosis (ALS); however, it is rapidly metabolized by CYP2D6, reducing the drug's bioavailability at neuronal targets. The inclusion of Q inhibits the rapid first-pass metabolism of DM to increase systemic concentrations of the drug in the plasma and, in theory, increase the potential efficacy. The initial clinical data for AVP-923 in the treatment of PBA demonstrated the combination was effective, but exhibited significant side effects. Of particular concern to the FDA were increased QTc intervals reported in patients dosed with a 30-/30-mg dose of DM/Q. A subsequent phase III clinical trial assessing a lower dose of AVP-923 (20 or 30 mg DM/10 mg Q) for the treatment of PBA in patients with ALS or multiple sclerosis was implemented by AVANIR and demonstrated a favorable safety profile of AVP-923 while maintaining efficacy. Pending approval of the data from the FDA, AVP-923 would be the first FDA-approved treatment for PBA.}, }
@article {pmid20370663, year = {2010}, author = {Pawlyk, AC and Cassel, JA and Reitz, AB}, title = {Current nervous system related drug targets for the treatment of amyotrophic lateral sclerosis.}, journal = {Current pharmaceutical design}, volume = {16}, number = {18}, pages = {2053-2073}, doi = {10.2174/138161210791293024}, pmid = {20370663}, issn = {1873-4286}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Animals ; DNA-Binding Proteins/metabolism ; *Drug Delivery Systems ; *Drug Discovery ; Humans ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and ultimately fatal indication that is the most prevalent adult-onset motoneuron disorder. ALS imparts tremendous suffering upon patients and caregivers alike. Exciting new insight has been obtained as to the etiology and initiation of the disease during the past decade, particularly affecting the larger, sporadic patient population. An important new discovery is the involvement of the TAR DNA binding protein (TDP-43) based upon genetic evidence and the presence of the cytosolic ubiquitylated TDP-43 aggregates found during post-mortem analysis of damaged motoneurons in the spinal cord of ALS patients. Superoxide dismutase SOD1 continues to be of interest for the approximately 20% of the familial ALS patients who have the inherited form of the disease (approximately 15% of the total), but SOD1 does not appear to be as relevant as was once imagined for the sporadic patent population. We can now target specific biochemical pathways and deficits via traditional drug discovery efforts and may thus be able to achieve more effective therapeutic relief for patients who suffer from this disease. In this review we present a comprehensive discussion of current molecular targets and pathways that are of interest to small molecule drug discovery efforts for the treatment of ALS.}, }
@article {pmid20369906, year = {2010}, author = {Rabinovici, GD and Miller, BL}, title = {Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management.}, journal = {CNS drugs}, volume = {24}, number = {5}, pages = {375-398}, pmid = {20369906}, issn = {1179-1934}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; K23 AG031861-02/AG/NIA NIH HHS/United States ; P01 AG019724-01A1/AG/NIA NIH HHS/United States ; P50-AG023501/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501-01/AG/NIA NIH HHS/United States ; K23-AG031861/AG/NIA NIH HHS/United States ; P01-AG1972403/AG/NIA NIH HHS/United States ; K23 AG031861/AG/NIA NIH HHS/United States ; }, mesh = {Biomarkers/analysis ; Brain/metabolism/pathology ; DNA-Binding Proteins/genetics ; *Frontotemporal Lobar Degeneration/diagnosis/epidemiology/etiology/therapy ; Genetic Markers/genetics ; Humans ; Mutation ; tau Proteins/genetics ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathological heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.}, }
@article {pmid20367447, year = {2010}, author = {Kanning, KC and Kaplan, A and Henderson, CE}, title = {Motor neuron diversity in development and disease.}, journal = {Annual review of neuroscience}, volume = {33}, number = {}, pages = {409-440}, doi = {10.1146/annurev.neuro.051508.135722}, pmid = {20367447}, issn = {1545-4126}, mesh = {Animals ; Cell Differentiation/*physiology ; Humans ; Motor Neuron Disease/*metabolism/*pathology/physiopathology ; Motor Neurons/classification/*cytology/pathology/*physiology ; }, abstract = {Although often considered as a group, spinal motor neurons are highly diverse in terms of their morphology, connectivity, and functional properties and differ significantly in their response to disease. Recent studies of motor neuron diversity have clarified developmental mechanisms and provided novel insights into neurodegeneration in amyotrophic lateral sclerosis (ALS). Motor neurons of different classes and subtypes--fast/slow, alpha/gamma--are grouped together into motor pools, each of which innervates a single skeletal muscle. Distinct mechanisms regulate their development. For example, glial cell line-derived neurotrophic factor (GDNF) has effects that are pool-specific on motor neuron connectivity, column-specific on axonal growth, and subtype-specific on survival. In multiple degenerative contexts including ALS, spinal muscular atrophy (SMA), and aging, fast-fatigable (FF) motor units degenerate early, whereas motor neurons innervating slow muscles and those involved in eye movement and pelvic sphincter control are strikingly preserved. Extrinsic and intrinsic mechanisms that confer resistance represent promising therapeutic targets in these currently incurable diseases.}, }
@article {pmid20367259, year = {2010}, author = {Kawamata, H and Manfredi, G}, title = {Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space.}, journal = {Antioxidants &amp; redox signaling}, volume = {13}, number = {9}, pages = {1375-1384}, pmid = {20367259}, issn = {1557-7716}, support = {R01-NS051419/NS/NINDS NIH HHS/United States ; R01-NS062055/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/metabolism ; Animals ; Humans ; Intracellular Membranes/metabolism ; Mice ; Mitochondria/enzymology/genetics/*metabolism ; Mitochondrial Membrane Transport Proteins/genetics/*metabolism ; Mitochondrial Membranes/enzymology/metabolism ; Molecular Chaperones/genetics/metabolism ; Mutation ; Superoxide Dismutase/chemistry/genetics/*metabolism ; }, abstract = {Cu, Zn, superoxide dismutase (SOD1) is a ubiquitous enzyme localized in multiple cellular compartments, including mitochondria, where it concentrates in the intermembrane space (IMS). Similar to other small IMS proteins, the import and retention of SOD1 in the IMS is linked to its folding and maturation, involving the formation of critical intra- and intermolecular disulfide bonds. Therefore, the cysteine residues of SOD1 play a fundamental role in its IMS localization. IMS import of SOD1 involves its copper chaperone, CCS, whose mitochondrial distribution is regulated by the Mia40/Erv1 disulfide relay system in a redox-dependent manner: CCS promotes SOD1 maturation and retention in the IMS. The function of SOD1 in the IMS is still unknown, but it is plausible that it serves to remove superoxide released from the mitochondrial respiratory chain. Mutations in SOD1 cause familial amyotrophic lateral sclerosis (ALS), whose pathologic features include mitochondrial bioenergetic dysfunction. Mutant SOD1 localization in the IMS is not dictated by oxygen concentration and the Mia40/Erv1 system, but is primarily dependent on aberrant protein folding and aggregation. Mutant SOD1 localization and aggregation in the IMS might cause the mitochondrial abnormalities observed in familial ALS and could play a significant role in disease pathogenesis.}, }
@article {pmid20360339, year = {2010}, author = {Agosta, F and Chiò, A and Cosottini, M and De Stefano, N and Falini, A and Mascalchi, M and Rocca, MA and Silani, V and Tedeschi, G and Filippi, M}, title = {The present and the future of neuroimaging in amyotrophic lateral sclerosis.}, journal = {AJNR. American journal of neuroradiology}, volume = {31}, number = {10}, pages = {1769-1777}, pmid = {20360339}, issn = {1936-959X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/physiopathology ; Diagnostic Techniques, Neurological/*trends ; Disease Progression ; Humans ; Magnetic Resonance Imaging/*trends ; *Magnetic Resonance Spectroscopy ; }, abstract = {In patients with ALS, conventional MR imaging is frequently noninformative, and its use has been restricted to excluding other conditions that can mimic ALS. Conversely, the extensive application of modern MR imaging-based techniques to the study of ALS has undoubtedly improved our understanding of disease pathophysiology and is likely to have a role in the identification of potential biomarkers of disease progression. This review summarizes how new MR imaging technology is changing dramatically our understanding of the factors associated with ALS evolution and highlights the reasons why it should be used more extensively in studies of disease progression, including clinical trials.}, }
@article {pmid20353779, year = {2010}, author = {Bari, M and Rapino, C and Mozetic, P and Maccarrone, M}, title = {The endocannabinoid system in gp120-mediated insults and HIV-associated dementia.}, journal = {Experimental neurology}, volume = {224}, number = {1}, pages = {74-84}, doi = {10.1016/j.expneurol.2010.03.025}, pmid = {20353779}, issn = {1090-2430}, mesh = {AIDS Dementia Complex/*metabolism ; Animals ; Brain/*metabolism ; Cannabinoid Receptor Modulators/*metabolism ; Cytoprotection/physiology ; *Endocannabinoids ; HIV Envelope Protein gp120/*metabolism ; Humans ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Receptors, Cannabinoid/metabolism ; Signal Transduction/physiology ; }, abstract = {Endocannabinoids (eCBs) include a group of lipid mediators that act as endogenous agonists at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors. In the last two decades a number of eCBs-metabolizing enzymes have been discovered that, together with eCBs and congeners, target receptors and proteins responsible for their transport and intracellular trafficking form the so-called "endocannabinoid system" (ECS). Within the central nervous system ECS elements participate in neuroprotection against neuroinflammatory/neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. More recently, a role for eCBs has been documented also in human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120-mediated insults, and in HIV-associated dementia (HAD). The modulation of ECS in the latter disease conditions is the subject of this review, that will also address the molecular mechanisms underlying the neuroprotective effects of eCBs. In particular, the interactions between neurons and glia during neuroinflammation, and the alterations of ECS in these cells upon gp120 insults and HAD will be discussed, along with the potential therapeutic exploitation of ECS-oriented drugs for the treatment of HAD and related disorders.}, }
@article {pmid20353778, year = {2010}, author = {Rossi, S and Bernardi, G and Centonze, D}, title = {The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {224}, number = {1}, pages = {92-102}, doi = {10.1016/j.expneurol.2010.03.030}, pmid = {20353778}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Cannabinoid Receptor Modulators/*metabolism ; *Endocannabinoids ; Humans ; Inflammation/metabolism/pathology ; Multiple Sclerosis/*metabolism/pathology ; Nerve Degeneration/*metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are chronic diseases of the central nervous system (CNS), featured by a complex interplay between inflammation and neurodegeneration. Increasing evidence supports the involvement of the endocannabinoid system (ECS) in both inflammatory and neurodegenerative processes typical of these pathological conditions. Exogenous or endogenous cannabinoids regulate the function of immune system by limiting immune response. On the other hand, by preventing excitotoxic damage, cannabinoids protect neuronal integrity and function. Of note, the ECS not only plays a role as modulator of disease processes, but it can also be disrupted by the same diseases. Agents modulating cannabinoid receptors or endocannabinoid tone provide promising therapeutic opportunities in the treatment of inflammatory neurodegenerative disorders of the CNS.}, }
@article {pmid20349096, year = {2010}, author = {van Blitterswijk, M and Landers, JE}, title = {RNA processing pathways in amyotrophic lateral sclerosis.}, journal = {Neurogenetics}, volume = {11}, number = {3}, pages = {275-290}, pmid = {20349096}, issn = {1364-6753}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; DNA Helicases ; DNA-Binding Proteins/genetics ; *Genetic Predisposition to Disease ; Histone Acetyltransferases/genetics ; Humans ; Mice ; Multifunctional Enzymes ; Nerve Tissue Proteins/genetics ; RNA Helicases/genetics ; *RNA Processing, Post-Transcriptional ; RNA Splicing ; RNA-Binding Protein FUS/genetics ; Ribonuclease, Pancreatic/genetics ; SMN Complex Proteins/genetics ; Transcription, Genetic ; }, abstract = {RNA processing is a tightly regulated, highly complex pathway which includes RNA transcription, pre-mRNA splicing, editing, transportation, translation, and degradation of RNA. Over the past few years, several RNA processing genes have been shown to be mutated or genetically associated with amyotrophic lateral sclerosis (ALS), including the RNA-binding proteins TDP-43 and FUS/TLS. These findings suggest that RNA processing may represent a common pathogenic mechanism involved in development of ALS. In this review, we will discuss six ALS-related, RNA processing genes including their discovery, function, and commonalities.}, }
@article {pmid20345752, year = {2010}, author = {Johnstone, D and Milward, EA}, title = {Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease.}, journal = {Journal of neurochemistry}, volume = {113}, number = {6}, pages = {1387-1402}, doi = {10.1111/j.1471-4159.2010.06697.x}, pmid = {20345752}, issn = {1471-4159}, mesh = {Animals ; Brain/*metabolism ; *Brain Diseases/genetics/metabolism/pathology ; Gene Expression Regulation/*genetics ; Genetic Predisposition to Disease/genetics ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/genetics ; Humans ; Iron/*metabolism/toxicity ; Membrane Proteins/genetics ; Molecular Biology ; Polymorphism, Genetic/genetics ; }, abstract = {Iron is essential in the brain, yet too much iron can be toxic. Tight regulation of iron in the brain may involve intrinsic mechanisms that control internal homeostasis independent of systemic iron status. Iron abnormalities occur in various neurological disorders, usually with symptoms or neuropathology associated with movement impairment or behavioral disturbances rather than cognitive impairment or dementia. Consistent with this, polymorphisms in the HFE gene, associated with the iron overload disorder hemochromatosis, show stronger associations with the movement disorder amyotrophic lateral sclerosis (motor neuron disease) than with cognitive impairment. Such associations may arise because certain brain regions involved in movement or executive control are particularly iron-rich, notably the basal ganglia, and may be highly reliant on iron. Various mechanisms, including iron redistribution causing functional iron deficiency, lysosomal and mitochondrial abnormalities or oxidative damage, could underlie iron-related neuropathogenesis. Clarifying how iron contributes causatively to neurodegeneration may improve treatment options in a range of neurodegenerative disorders. This review considers how modern molecular genetic approaches can be applied to resolve the complex molecular systems and pathways by which brain iron homeostasis is regulated and the molecular changes that occur with iron dyshomeostasis and neuropathogenesis.}, }
@article {pmid20329565, year = {2010}, author = {Testa, A and Cibinel, GA and Portale, G and Forte, P and Giannuzzi, R and Pignataro, G and Silveri, NG}, title = {The proposal of an integrated ultrasonographic approach into the ALS algorithm for cardiac arrest: the PEA protocol.}, journal = {European review for medical and pharmacological sciences}, volume = {14}, number = {2}, pages = {77-88}, pmid = {20329565}, issn = {1128-3602}, mesh = {Algorithms ; Cardiopulmonary Resuscitation ; Emergency Medical Services ; Heart Arrest/*diagnostic imaging/etiology/physiopathology ; Humans ; Hypovolemia/diagnostic imaging ; Pneumothorax/diagnostic imaging ; Pulmonary Embolism/diagnostic imaging ; Ultrasonography ; }, abstract = {BACKGROUND AND OBJECTIVE: Guidelines on cardiac arrest (CA) recommend the prompt beginning of cardio-pulmonary resuscitation (CPR) and the identification and correction of reversible causes. This article deals with the application of clinical ultrasonography (US) in resuscitation, presenting a simple codified US protocol usable during CPR to recognize reversible causes of CA. EVIDENCE ON US IN CA AND STATE OF THE ART: Emergency US is a bedside, point-of-care, focused diagnostic procedure with aim to complete the physical examination. It is performed by emergency physician everywhere to answer briefly important clinical questions. Several trials recently experimented US employment during advanced life support, demonstrating its feasibility without delaying CPR.<br><br>PERSPECTIVES: The PEA Protocol: We propose a simplified US protocol for non-shockable rhythms, called "PEA protocol" to remember the applications of the study (CA in Pulseless Electrical Activity, PEA) and the US scan sequence: Pulmonary scans to depict pneumothorax and pleural effusion and to differentiate wet or dry lung; Epigastric for pericardial effusion, left and right ventricular sides and motion, IVC filling; Abdominal and other scans for aortic aneurism and dissection, peritoneal effusion, bowel occlusion or perforation, deep venous thrombosis. The PEA protocol could be performed both during CA in PEA and during periarrest conditions.<br><br>CONCLUSIONS: Clinical US, using a well codified protocol, could effectively help to identify reversible causes in CA, even improving patients outcome.}, }
@article {pmid20303880, year = {2010}, author = {Glass, CK and Saijo, K and Winner, B and Marchetto, MC and Gage, FH}, title = {Mechanisms underlying inflammation in neurodegeneration.}, journal = {Cell}, volume = {140}, number = {6}, pages = {918-934}, pmid = {20303880}, issn = {1097-4172}, support = {R01 MH088485/MH/NIMH NIH HHS/United States ; R01 MH088485-01/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Brain/pathology ; Humans ; Inflammation/drug therapy/*immunology/pathology/physiopathology ; Neurodegenerative Diseases/drug therapy/*immunology/pathology/physiopathology ; }, abstract = {Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfunction and death. Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease.}, }
@article {pmid20298165, year = {2010}, author = {Coppedè, F and Migliore, L}, title = {DNA repair in premature aging disorders and neurodegeneration.}, journal = {Current aging science}, volume = {3}, number = {1}, pages = {3-19}, doi = {10.2174/1874609811003010003}, pmid = {20298165}, issn = {1874-6128}, mesh = {Aging, Premature/genetics/*physiopathology ; Animals ; DNA Damage/physiology ; DNA Repair/*physiology ; Disease Models, Animal ; Humans ; Mice ; Neurodegenerative Diseases/genetics/*physiopathology ; }, abstract = {The accumulation of DNA damage has been widely implicated in premature aging and neurodegeneration. Progeroid syndromes with defects in the cellular response to DNA damage suggest that progressive genome instability represents an important aspect of the aging process. Moreover, most of the major neurodegenerative diseases are characterized by the accumulation of neuronal DNA damage, suggesting that impaired DNA repair mechanisms might be relevant to both premature aging and neurodegeneration. Two progeroid syndromes, Hutchinson-Gilford progeria syndrome and Werner's syndrome, are characterized by clinical features mimicking physiological aging at an early age and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases. Defects in nucleotide excision repair cause three distinct human diseases: xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy; each of them is characterized by premature onset of pathologies that overlap with those associated with old age in humans. Increasing evidence also suggests that an impaired DNA repair, particularly the base excision repair pathway, might play a fundamental role in the development of age-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington' s disease. Here, we review the current knowledge on the role of DNA repair in premature aging and neurodegenerative diseases.}, }
@article {pmid20237255, year = {2010}, author = {Walker, AK}, title = {Protein disulfide isomerase and the endoplasmic reticulum in amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {30}, number = {11}, pages = {3865-3867}, pmid = {20237255}, issn = {1529-2401}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*enzymology ; Animals ; Endoplasmic Reticulum/*enzymology ; Humans ; Protein Disulfide-Isomerases/*metabolism ; Protein Folding ; }, }
@article {pmid20236142, year = {2011}, author = {Bellingham, MC}, title = {A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade?.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {17}, number = {1}, pages = {4-31}, pmid = {20236142}, issn = {1755-5949}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain/*drug effects/physiopathology ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/pharmacology/*therapeutic use ; Humans ; Middle Aged ; Motor Neurons/*drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of adults which preferentially attacks the neuromotor system. Riluzole has been used as the only approved treatment for amyotrophic lateral sclerosis since 1995, but its mechanism(s) of action in slowing the progression of this disease remain obscure. Searching PubMed for "riluzole" found 705 articles published between January 1996 and June 2009. A systematic review of this literature found that riluzole had a wide range of effects on factors influencing neural activity in general, and the neuromotor system in particular. These effects occurred over a large dose range (<1 μM to >1 mM). Reported neural effects of riluzole included (in approximate ascending order of dose range): inhibition of persistent Na(+) current = inhibition of repetitive firing < potentiation of calcium-dependent K(+) current < inhibition of neurotransmitter release < inhibition of fast Na(+) current < inhibition of voltage-gated Ca(2+) current = promotion of neuronal survival or growth factors < inhibition of voltage-gated K(+) current = modulation of two-pore K(+) current = modulation of ligand-gated neurotransmitter receptors = potentiation of glutamate transporters. Only the first four of these effects commonly occurred at clinically relevant concentrations of riluzole (plasma levels of 1-2 μM with three- to four-fold higher concentrations in brain tissue). Treatment of human ALS patients or transgenic rodent models of ALS with riluzole most commonly produced a modest but significant extension of lifespan. Riluzole treatment was well tolerated in humans and animals. In animals, despite in vitro evidence that riluzole may inhibit rhythmic motor behaviors, in vivo administration of riluzole produced relatively minor effects on normal respiration parameters, but inhibited hypoxia-induced gasping. This effect may have implications for the management of hypoventilation and sleep-disordered breathing during end-stage ALS in humans.}, }
@article {pmid20236058, year = {2010}, author = {Yabe, T and Sanagi, T and Yamada, H}, title = {The neuroprotective role of PEDF: implication for the therapy of neurological disorders.}, journal = {Current molecular medicine}, volume = {10}, number = {3}, pages = {259-266}, doi = {10.2174/156652410791065354}, pmid = {20236058}, issn = {1875-5666}, mesh = {Animals ; Brain Injuries/prevention &amp; control ; Cells, Cultured ; *Eye Proteins/genetics/pharmacology/therapeutic use ; Humans ; *Nerve Growth Factors/genetics/pharmacology/therapeutic use ; Nervous System/anatomy &amp; histology/drug effects ; Nervous System Diseases/pathology/physiopathology/*therapy ; Neuroglia/drug effects ; Neurons/cytology/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; *Protease Inhibitors/pharmacology/therapeutic use ; *Serpins/genetics/pharmacology/therapeutic use ; Stem Cells/drug effects ; Tissue Distribution ; }, abstract = {Neuronal degeneration is closely associated with cognitive, motor and visual dysfunctions. Neuroprotective strategies have been investigated with the view to being employed as potential therapy for patients with these disabilities. Pigment epithelium-derived factor (PEDF) is a 50-kDa secreted glycoprotein and a non-inhibitory member of the serine protease inhibitor (SERPIN) gene family. PEDF is detected in a broad range of human tissues, including almost all brain areas, and has been shown to have strong neuroprotective properties for various types of neurons including cerebellar granule neurons, hippocampal neurons, striatal neurons, retinal neurons and spinal cord motor neurons. These observations raise the possibility that application of PEDF may be helpful in designing new therapeutic strategies for neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease and brain ischemia.}, }
@article {pmid20235485, year = {2010}, author = {Iwashima, T and Tateishi, T and Yamasaki, R and Motomura, K and Ohyagi, Y and Kira, J}, title = {[Two cases of familial amyotrophic lateral sclerosis with a SOD1L126S mutation showing high age at onset and slow progression].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {3}, pages = {163-167}, doi = {10.5692/clinicalneurol.50.163}, pmid = {20235485}, issn = {0009-918X}, mesh = {Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics ; Disease Progression ; Humans ; Male ; Point Mutation/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {An 80-year-old man (patient 1) was admitted to our hospital with numbness of the right leg and weakness of the lower extremities, predominantly in the right leg, for 1 year previously. Neurological examination revealed moderate weakness without atrophy, and fasciculation in the bilateral lower extremities. No hyperreflexia was noted, and the plantar response was flexor. Neither bulbar palsy nor sensory disturbance was observed. Electromyography (EMG) showed a chronic neurogenic pattern, including giant motor unit potentials and reduced interference in all four limb muscles. MRI images of the cervical and lumbar spines showed severe age-related spondylosis. The clinical and laboratory findings led to a diagnosis of spinal progressive muscular atrophy. Motor paralysis progressed slowly for the following four years, culminating in respiratory failure. A 79-year-man, the younger brother of patient 1 (patient 2), suffered from gait disturbance for 3 years before the admission to our hospital. During the following 3 years, bilateral leg weakness developed, causing difficulty walking. Neurological examination revealed a diffuse mild weakness with atrophy and fasciculation in the bilateral lower extremities; the right deltoid muscle was also mildly weak. Mild hyperreflexia was also noted on the left side, and the plantar response was extensor on the left. EMG showed acute and chronic neurogenic patterns in the four limb muscles. Because the missense mutation c.377 T > C; p.L126S was found on exon 5 of the superoxide dismutase (SOD) 1 gene in this patient, a diagnosis of familial ALS was made. Eight patients reported as familial ALS with the SOD1L126S mutation, including the present cases, all developed an onset of weakness in the lower extremities, but showed few upper motor neuron signs. It is important to consider the possibility of this type of familial ALS in a case of spinal progressive muscular atrophy with late-onset and mild progression, if family history is positive.}, }
@article {pmid20234357, year = {2010}, author = {Chen-Plotkin, AS and Lee, VM and Trojanowski, JQ}, title = {TAR DNA-binding protein 43 in neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {6}, number = {4}, pages = {211-220}, pmid = {20234357}, issn = {1759-4766}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; P30 AG010124-20/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/*pathology ; }, abstract = {In 2006, TAR DNA-binding protein 43 (TDP-43), a highly conserved nuclear protein, was identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD), FTLD-U, which is characterized by cytoplasmic inclusions that stain positive for ubiquitin but negative for tau and alpha-synuclein. Since then, rapid advances have been made in our understanding of the physiological function of TDP-43 and the role of this protein in neurodegeneration. These advances link ALS and FTLD-U (now designated FTLD-TDP) to a shared mechanism of disease. In this Review, we summarize the current evidence regarding the normal function of TDP-43 and the TDP-43 pathology observed in FTLD-TDP, ALS, and other neurodegenerative diseases wherein TDP-43 pathology co-occurs with other disease-specific lesions (for example, with amyloid plaques and neurofibrillary tangles in Alzheimer disease). Moreover, we discuss the accumulating data that support our view that FTLD-TDP and ALS represent two ends of a spectrum of primary TDP-43 proteinopathies. Finally, we comment on the importance of recent advances in TDP-43-related research to neurological practice, including the new opportunities to develop better diagnostics and disease-modifying therapies for ALS, FTLD-TDP, and related disorders exhibiting TDP-43 pathology.}, }
@article {pmid20229265, year = {2010}, author = {Lau, A and Tymianski, M}, title = {Glutamate receptors, neurotoxicity and neurodegeneration.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {460}, number = {2}, pages = {525-542}, pmid = {20229265}, issn = {1432-2013}, mesh = {Animals ; Antioxidants/therapeutic use ; Calcium/metabolism ; Calpain/physiology ; Caspases/physiology ; Cell Death/physiology ; Free Radical Scavengers/therapeutic use ; Free Radicals/metabolism ; Glutamic Acid/*adverse effects/physiology ; Humans ; Hypothalamus/drug effects ; Nerve Degeneration/*physiopathology ; Neurodegenerative Diseases/*physiopathology ; Neurotoxicity Syndromes/*physiopathology ; Nitric Oxide/physiology ; Receptors, AMPA/antagonists &amp; inhibitors/physiology ; Receptors, Glutamate/*physiology ; Receptors, Kainic Acid ; Receptors, Metabotropic Glutamate/physiology ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/physiology ; Sodium-Calcium Exchanger/therapeutic use ; Zinc/physiology ; }, abstract = {Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration. As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching. Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research. However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and others. Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury. This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.}, }
@article {pmid20226177, year = {2010}, author = {Anthony, K and Gallo, JM}, title = {Aberrant RNA processing events in neurological disorders.}, journal = {Brain research}, volume = {1338}, number = {}, pages = {67-77}, doi = {10.1016/j.brainres.2010.03.008}, pmid = {20226177}, issn = {1872-6240}, mesh = {Animals ; Humans ; Nervous System Diseases/*genetics/metabolism ; RNA/metabolism ; *RNA Processing, Post-Transcriptional ; }, abstract = {The importance of aberrant RNA processing in neurodegeneration is becoming increasingly clear; a recent example being the identification of the splicing factor TDP-43 as the major component of inclusions characteristic of a number of neurodegenerative conditions including amyotrophic lateral sclerosis (ALS). Due to the enormous diversity generated by alternative splicing and its importance in the nervous system, it is no surprise that defective alternative splicing in disease has been particularly well documented. However, in addition to splicing, other RNA processing events such as RNA editing, polyadenylation and mRNA stability are also disrupted in some neurological disorders. For instance: the editing efficiency of specific ionotropic receptors is reduced in ALS affecting ion permeability and the function of RNA-processing proteins is affected by their sequestration to trinucleotide repeat expanded mRNAs in several disorders. Due to the extensive coupling between RNA processing events and the multifunctionality of the RNA processing factors that regulate them, it is important to consider RNA processing as a whole. Here we review RNA processing events and their extensive coupling to one another and detail the associations of RNA processing including, but not exclusively, alternative splicing with neurodegeneration.}, }
@article {pmid20206240, year = {2010}, author = {Schengrund, CL}, title = {Lipid rafts: keys to neurodegeneration.}, journal = {Brain research bulletin}, volume = {82}, number = {1-2}, pages = {7-17}, doi = {10.1016/j.brainresbull.2010.02.013}, pmid = {20206240}, issn = {1873-2747}, mesh = {Cholesterol/metabolism ; Clinical Trials as Topic ; Gangliosides/chemistry/metabolism ; Humans ; Membrane Microdomains/*chemistry/metabolism ; Models, Molecular ; *Nerve Degeneration/metabolism/pathology ; Neuroblastoma/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; }, abstract = {The increase in life expectancy seen in many countries has been accompanied by an increase in the number of people living with dementia and a growing need for health care. The large number of affected individuals emphasizes the need to identify causes for the phenotypes associated with diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, Huntington's, and those caused by prions. This review addresses the hypothesis that changes in lipid rafts induced by alterations in their ganglioside and/or cholesterol content or the interaction of mutant proteins with them provide the keys to understanding the onset of neurodegeneration that can lead to dementia. The biological function(s) of raft-associated gangliosides and cholesterol are discussed prior to reviewing what is known about their roles in lipid rafts in the aforementioned diseases. It concludes with some questions that need to be addressed in order to provide investigators with the basis for identifying small molecule agonists or antagonists to test as potential therapeutics.}, }
@article {pmid20202122, year = {2010}, author = {Gendron, TF and Josephs, KA and Petrucelli, L}, title = {Review: transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration.}, journal = {Neuropathology and applied neurobiology}, volume = {36}, number = {2}, pages = {97-112}, pmid = {20202122}, issn = {1365-2990}, support = {R01 AG026251-03A2/AG/NIA NIH HHS/United States ; R56 AG026251-03A1/AG/NIA NIH HHS/United States ; 2R56AG026251-03A1/AG/NIA NIH HHS/United States ; P01-AG17216-08/AG/NIA NIH HHS/United States ; R01 NS 063964-01/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; R01AG026251/AG/NIA NIH HHS/United States ; K12 HD049078/HD/NICHD NIH HHS/United States ; K12/NICHD-HD49078//PHS HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R56 AG026251/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Nerve Degeneration/genetics/metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; TDP-43 Proteinopathies/genetics/metabolism/pathology ; }, abstract = {Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions, and the discovery that mutations in the TDP-43 gene cause ALS, much effort has been directed towards establishing how TDP-43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP-43 in promoting TDP-43 aggregation and cellular mislocalization. Therefore, TDP-43-mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP-43 inclusions as well as from the loss of normal TDP-43 function. Nonetheless, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP-43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. This review will summarize what is currently understood regarding normal TDP-43 function and the involvement of TDP-43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation.}, }
@article {pmid20202121, year = {2010}, author = {Murray, LM and Talbot, K and Gillingwater, TH}, title = {Review: neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy.}, journal = {Neuropathology and applied neurobiology}, volume = {36}, number = {2}, pages = {133-156}, doi = {10.1111/j.1365-2990.2010.01061.x}, pmid = {20202121}, issn = {1365-2990}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Humans ; Motor Neuron Disease/*physiopathology ; Muscular Atrophy, Spinal/physiopathology ; Neuromuscular Junction/*physiopathology ; Synapses/physiology ; }, abstract = {Amid the great diversity of neurodegenerative conditions, there is a growing body of evidence that non-somatic (that is, synaptic and distal axonal) compartments of neurones are early and important subcellular sites of pathological change. In this review we discuss experimental data from human patients, animal models and in vitro systems showing that neuromuscular synapses are targeted in different forms of motor neurone disease (MND), including amyotrophic lateral sclerosis and spinal muscular atrophy. We highlight important developments revealing the heterogeneous nature of vulnerability in populations of lower motor units in MND and examine how progress in our understanding of the molecular pathways underlying MND may provide insights into the regulation of synaptic vulnerability and pathology. We conclude that future experiments developing therapeutic approaches specifically targeting neuromuscular synaptic vulnerability are likely to be required to prevent or delay disease onset and progression in human MND patients.}, }
@article {pmid20184514, year = {2010}, author = {Ludolph, AC and Bendotti, C and Blaugrund, E and Chio, A and Greensmith, L and Loeffler, JP and Mead, R and Niessen, HG and Petri, S and Pradat, PF and Robberecht, W and Ruegg, M and Schwalenstöcker, B and Stiller, D and van den Berg, L and Vieira, F and von Horsten, S}, title = {Guidelines for preclinical animal research in ALS/MND: A consensus meeting.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {38-45}, doi = {10.3109/17482960903545334}, pmid = {20184514}, issn = {1471-180X}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Consensus ; *Disease Models, Animal ; Drug Evaluation, Preclinical/*methods/*standards ; *Guidelines as Topic ; }, abstract = {The development of therapeutics for ALS/MND is largely based on work in experimental animals carrying human SOD mutations. However, translation of apparent therapeutic successes from in vivo to the human disease has proven difficult and a considerable amount of financial resources has been apparently wasted. Standard operating procedures (SOPs) for preclinical animal research in ALS/MND are urgently required. Such SOPs will help to establish SOPs for translational research for other neurological diseases within the next few years. To identify the challenges and to improve the research methodology, the European ALS/MND group held a meeting in 2006 and published guidelines in 2007 (1). A second international conference to improve the guidelines was held in 2009. These second and improved guidelines are dedicated to the memory of Sean F. Scott.}, }
@article {pmid20184513, year = {2010}, author = {Tomik, B and Guiloff, RJ}, title = {Dysarthria in amyotrophic lateral sclerosis: A review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {4-15}, doi = {10.3109/17482960802379004}, pmid = {20184513}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*physiopathology ; *Dysarthria/etiology/physiopathology/therapy ; Humans ; *Speech Therapy ; }, abstract = {Dysarthria is a motor disorder of speech characterized by abnormalities of the articulation and intelligibility of speech. Phonation and the rate of facial movements may also be affected. Understanding the nature and course of dysarthria in amyotrophic lateral sclerosis (ALS) is important because loss of communication prevents patients from participating in many activities, may lead to social isolation, and reduces the quality of life. The goal of management of dysarthria in ALS patients is to optimize communication effectiveness for as long as possible. The information about dysarthria in ALS is dispersed in physiological, pathological, speech therapy, otorhinolaringological and neurological publications. This review summarizes the current state of knowledge on the clinical features, differential diagnosis, pathophysiology, investigations and management of dysarthria in ALS patients. There is a need to compare the different methods used to assess dysarthria and for controlled clinical trials to assess therapeutic strategies.}, }
@article {pmid20178658, year = {2010}, author = {Raaphorst, J and Grupstra, HF and Linssen, WH and van Swieten, JC and Schmand, B and de Visser, M}, title = {[Amyotrophic lateral sclerosis and frontotemporal dementia: overlapping characteristics].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {154}, number = {}, pages = {A631}, pmid = {20178658}, issn = {1876-8784}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/pathology ; Diagnosis, Differential ; Frontotemporal Dementia/*diagnosis/genetics/pathology ; Humans ; Inclusion Bodies/metabolism/pathology ; Intercellular Signaling Peptides and Proteins/*genetics ; *Mutation/genetics ; Progranulins ; }, abstract = {There is an overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Some 5-10% of ALS patients show changes in their behaviour and personality that are characteristic of FTD and about 10% of FTD patients develop ALS. Mild cognitive impairment occurs in 30% of ALS patients. The progressive decline of muscle strength in ALS patients and social skills in FTD patients places severe demands on the patient and his or her contacts. In some ALS and FTD patients, ubiquitin-positive inclusions have been found in the hippocampus and anterior horn cells. In patients with familial FTD who have ubiquitin-positive inclusions, mutations have been found in the progranulin (PGRN) gene. TAR-DNA-binding protein-43, encoded by the TARDBP gene, has recently been identified as a constituent of the ubiquitin inclusions. TARDBP and PGRN mutations are found in patients with ALS. The overlapping characteristics provide clues for further research into the pathogenesis of ALS and FTD.}, }
@article {pmid20170473, year = {2010}, author = {Arawaka, S and Machiya, Y and Kato, T}, title = {Heat shock proteins as suppressors of accumulation of toxic prefibrillar intermediates and misfolded proteins in neurodegenerative diseases.}, journal = {Current pharmaceutical biotechnology}, volume = {11}, number = {2}, pages = {158-166}, doi = {10.2174/138920110790909713}, pmid = {20170473}, issn = {1873-4316}, mesh = {Amyloid/*antagonists &amp; inhibitors/metabolism ; Animals ; Heat-Shock Proteins/genetics/metabolism/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Protein Folding ; Protein Structure, Secondary ; Solubility ; }, abstract = {The most characteristic feature of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, is the occurrence of extra- or intracellular fibrillar aggregates containing misfolded proteins with beta-sheet conformation. These aggregates are composed of distinct proteins in each neurodegenerative disease. However, mutations in genes encoding major constituents of aggregates, such as Abeta, tau, alpha-synuclein, SOD1 and huntingtin, have been identified to causally associate with familial forms of the diseases. Biochemical studies demonstrate that these mutant and some wild-type proteins tend to be misfolded or form aggregates. It has been proposed that these diseases are caused by a common mechanism involving misfolded proteins that trigger a toxic cascade leading to neuronal degeneration. This hypothesis is the basis of the therapeutic potential of heat shock proteins (HSPs), which prevent protein misfolding and aggregation. Transgenic animal models of the diseases have demonstrated that induction or overexpression of HSPs can suppress neuronal dysfunction and degeneration. Do the results promise clinical success for HSP-based therapy in neurodegenerative diseases? Recent findings regarding the pathogenic species generated during fibril formation have highlighted some of the beneficial and problematic aspects of HSP-based therapy. In this review, we focus on the pathogenic role of prefibrillar intermediates, including soluble oligomers and protofibrils, on neurodegeneration, and the relationship between prefibrillar intermediates and the proteins targeted by HSPs. We discuss in vitro and in vivo experimental data showing that HSPs counteract disease progression by acting as suppressors of toxic prefibrillar intermediates and toxic misfolded proteins in neurodegenerative diseases.}, }
@article {pmid20166962, year = {2010}, author = {Nagai, Y and Fujikake, N and Popiel, HA and Wada, K}, title = {Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases.}, journal = {Current pharmaceutical biotechnology}, volume = {11}, number = {2}, pages = {188-197}, doi = {10.2174/138920110790909650}, pmid = {20166962}, issn = {1873-4316}, mesh = {Amyloid/genetics/metabolism ; Animals ; Brain/metabolism ; Heredodegenerative Disorders, Nervous System/genetics/metabolism/*therapy ; Humans ; Molecular Chaperones/*biosynthesis/genetics/physiology ; Peptides/genetics/*metabolism ; Protein Folding ; }, abstract = {Protein misfolding and aggregation in the brain have been implicated as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) diseases. The polyQ diseases are a group of nine hereditary neurodegenerative diseases, including Huntington's disease (HD) and various types of spinocerebellar ataxia (SCA), which are caused by abnormal expansions of the polyQ stretch (> 35-40 repeats) in unrelated disease-causative proteins. The expanded polyQ stretch is thought to trigger misfolding of these proteins, leading to their aggregation and accumulation as inclusion bodies in affected neurons, eventually resulting in neurodegeneration. Misfolding and aggregation of the polyQ protein are the most ideal therapeutic targets since they are the most upstream events in the pathogenic cascade, and therefore, therapeutic approaches using molecular chaperones, which prevent protein misfolding and assist the refolding of misfolded proteins, are being extensively investigated. Indeed, a variety of molecular chaperones such as Hsp70 and Hsp40 have been demonstrated to exert therapeutic effects against various experimental models of the polyQ diseases. Furthermore, toward developing pharmacological therapies, small chemical activators of heat shock transcription factor 1 (HSF1) such as geldanamycin and its derivative 17-AAG, which induce multiple endogenous molecular chaperones, have been proven to be effective not only in polyQ disease models, but also in other neurodegenerative disease models. We hope that brain-permeable molecular chaperone inducers will be developed as drugs against a wide range of neurodegenerative diseases in the near future.}, }
@article {pmid20166961, year = {2010}, author = {Sajjad, MU and Samson, B and Wyttenbach, A}, title = {Heat shock proteins: therapeutic drug targets for chronic neurodegeneration?.}, journal = {Current pharmaceutical biotechnology}, volume = {11}, number = {2}, pages = {198-215}, doi = {10.2174/138920110790909641}, pmid = {20166961}, issn = {1873-4316}, support = {G120/881/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Brain/drug effects/metabolism ; Chronic Disease ; Heat-Shock Proteins/*biosynthesis/genetics/physiology ; Humans ; Molecular Structure ; Neurodegenerative Diseases/*drug therapy/genetics/metabolism ; Neuroprotective Agents/adverse effects/chemistry/*pharmacology/therapeutic use ; Prions/metabolism ; Protein Folding ; }, abstract = {Intra- and extracellular protein misfolding and aggregation is likely to contribute to a number of age-related central nervous system diseases ("proteinopathies"). Therefore, molecular chaperones, such as heat shock proteins (HSPs), that regulate protein folding, misfolding and adaption to cellular stress are emerging as therapeutic targets. Here we review the current knowledge of HSP-modulating drugs and discuss the opportunities and difficulties of their therapeutic use to treat proteinopathies such as Alzheimer's- and Parkinson's disease, the polyglutamine- and prion disorders and Amyotrophic Lateral Sclerosis.}, }
@article {pmid20148962, year = {2010}, author = {Kitamura, A and Kubota, H}, title = {Amyloid oligomers: dynamics and toxicity in the cytosol and nucleus.}, journal = {The FEBS journal}, volume = {277}, number = {6}, pages = {1369-1379}, doi = {10.1111/j.1742-4658.2010.07570.x}, pmid = {20148962}, issn = {1742-4658}, mesh = {Amyloid/*toxicity ; Amyotrophic Lateral Sclerosis/physiopathology ; Cell Nucleus/*drug effects ; Cytosol/*drug effects ; Humans ; Macromolecular Substances/*toxicity ; Neurodegenerative Diseases/physiopathology ; Peptides/toxicity ; Protein Folding ; Solubility ; }, abstract = {The accumulation of misfolded proteins in the cytosol and nucleus of neuronal cells leads to neurodegenerative disorders. Polyglutamine diseases are caused by polyglutamine-expanded proteins, whereas mutations in superoxide dismutase 1 lead to amyotrophic lateral sclerosis. These structurally unstable mutant species perturb essential interactions between normal proteins and tend to aggregate because of the presence of exposed hydrophobic surfaces. Accumulating evidence suggests that soluble species, including misfolded monomers and oligomers, are more toxic than large insoluble aggregates or inclusions. Spectroscopic analysis, including fluorescence recovery after photobleaching and fluorescence loss in photobleaching, in living cells revealed that protein aggregates of misfolded proteins are dynamic structures that interact with other proteins, such as molecular chaperones. Fluorescence correlation spectroscopy analysis detected soluble oligomers/aggregates of misfolded proteins in cell extracts. Fluorescence resonance energy transfer analysis supported the notion that soluble oligomers/aggregates are formed before the formation of inclusions in vivo. Here, we reviewed the characteristics of oligomers and aggregates of misfolded proteins, with a particular focus on those revealed by spectroscopic analysis, and discussed how these oligomers may be toxic to cells.}, }
@article {pmid20146928, year = {2010}, author = {Naegele, JR and Maisano, X and Yang, J and Royston, S and Ribeiro, E}, title = {Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy.}, journal = {Neuropharmacology}, volume = {58}, number = {6}, pages = {855-864}, pmid = {20146928}, issn = {1873-7064}, support = {R01 NS042826/NS/NINDS NIH HHS/United States ; R01 NS042826-05/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Epilepsy/physiopathology/surgery/*therapy ; Genetic Therapy/*methods ; Humans ; Nervous System Diseases/physiopathology/surgery/*therapy ; Stem Cell Transplantation/*methods ; }, abstract = {The potential applications of stem cell therapies for treating neurological disorders are enormous. Many laboratories are focusing on stem cell treatments for CNS diseases, including spinal cord injury, Amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, stroke, traumatic brain injury, and epilepsy. Among the many stem cell types under testing for neurological treatments, the most common are fetal and adult brain stem cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells. An expanding toolbox of molecular probes is now available to allow analyses of neural stem cell fates prior to and after transplantation. Concomitantly, protocols are being developed to direct the fates of stem cell-derived neural progenitors, and also to screen stem cells for tumorigenicity and aneuploidy. The rapid progress in the field suggests that novel stem cell and gene therapies for neurological disorders are in the pipeline.}, }
@article {pmid20131003, year = {2010}, author = {Huang, Q and Figueiredo-Pereira, ME}, title = {Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {15}, number = {11}, pages = {1292-1311}, pmid = {20131003}, issn = {1573-675X}, support = {U54 NS041073-06A10001/NS/NINDS NIH HHS/United States ; R01 AG028847/AG/NIA NIH HHS/United States ; AG028847/AG/NIA NIH HHS/United States ; U54 NS041073-080001/NS/NINDS NIH HHS/United States ; RR03037/RR/NCRR NIH HHS/United States ; NS41073/NS/NINDS NIH HHS/United States ; U54 NS041073-100001/NS/NINDS NIH HHS/United States ; R01 AG028847-02/AG/NIA NIH HHS/United States ; U54 NS041073-070001/NS/NINDS NIH HHS/United States ; G12 RR003037/RR/NCRR NIH HHS/United States ; U54 NS041073/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/drug therapy/genetics/*metabolism ; Proteasome Endopeptidase Complex/genetics/*metabolism ; Proteasome Inhibitors ; Proteins/genetics/metabolism ; Signal Transduction ; Ubiquitin/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The ubiquitin/proteasome pathway is the major proteolytic quality control system in cells. In this review we discuss the impact of a deregulation of this pathway on neuronal function and its causal relationship to the intracellular deposition of ubiquitin protein conjugates in pathological inclusion bodies in all the major chronic neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. We describe the intricate nature of the ubiquitin/proteasome pathway and discuss the paradox of protein aggregation, i.e. its potential toxic/protective effect in neurodegeneration. The relations between some of the dysfunctional components of the pathway and neurodegeneration are presented. We highlight possible ubiquitin/proteasome pathway-targeting therapeutic approaches, such as activating the proteasome, enhancing ubiquitination and promoting SUMOylation that might be important to slow/treat the progression of neurodegeneration. Finally, a model time line is presented for neurodegeneration starting at the initial injurious events up to protein aggregation and cell death, with potential time points for therapeutic intervention.}, }
@article {pmid20121474, year = {2010}, author = {Tumani, H and Lehmensiek, V and Lehnert, S and Otto, M and Brettschneider, J}, title = {2D DIGE of the cerebrospinal fluid proteome in neurological diseases.}, journal = {Expert review of proteomics}, volume = {7}, number = {1}, pages = {29-38}, doi = {10.1586/epr.09.99}, pmid = {20121474}, issn = {1744-8387}, mesh = {Cerebrospinal Fluid Proteins/*analysis ; Electrophoresis, Gel, Two-Dimensional/*methods ; Humans ; Nervous System Diseases/*cerebrospinal fluid ; Proteome/*analysis ; Proteomics/methods ; }, abstract = {2D DIGE is a promising approach to comparative proteome analysis known for a high sensitivity and high reproducibility compared with classical 2DE techniques. It offers new possibilities for the detection of cerebrospinal fluid (CSF) biomarkers in neurological diseases, such as dementia, amyotrophic lateral sclerosis or multiple sclerosis. We review the first studies using 2D DIGE for analysis of the CSF proteome in neurological diseases and discuss advantages, as well as drawbacks, of the methodological approach with special emphasis on CSF-related aspects.}, }
@article {pmid20116097, year = {2010}, author = {Grosskreutz, J and Van Den Bosch, L and Keller, BU}, title = {Calcium dysregulation in amyotrophic lateral sclerosis.}, journal = {Cell calcium}, volume = {47}, number = {2}, pages = {165-174}, doi = {10.1016/j.ceca.2009.12.002}, pmid = {20116097}, issn = {1532-1991}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/pathology/physiopathology ; Animals ; Brain Stem/pathology ; Calcium/*metabolism ; *Calcium Signaling ; Cell Death ; Humans ; Motor Neurons/*metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Receptors, AMPA/metabolism ; Riluzole/therapeutic use ; Spinal Cord/pathology ; }, abstract = {In the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), motor neurons degenerate with signs of organelle fragmentation, free radical damage, mitochondrial Ca2+ overload, impaired axonal transport and accumulation of proteins in intracellular inclusion bodies. Subgroups of motor neurons of the brainstem and the spinal cord expressing low amounts of Ca2+ buffering proteins are particularly vulnerable. In ALS, chronic excitotoxicity mediated by Ca2+-permeable AMPA type glutamate receptors seems to initiate a self-perpetuating process of intracellular Ca2+ dysregulation with consecutive endoplasmic reticulum Ca2+ depletion and mitochondrial Ca2+ overload. The only known effective treatment, riluzole, seems to reduce glutamatergic input. This review introduces the hypothesis of a "toxic shift of Ca2+" within the endoplasmic reticulum-mitochondria Ca2+ cycle (ERMCC) as a key mechanism in motor neuron degeneration, and discusses molecular targets which may be of interest for future ERMCC modulating neuroprotective therapies.}, }
@article {pmid20110589, year = {2010}, author = {Rudrabhatla, P and Pant, HC}, title = {Phosphorylation-specific peptidyl-prolyl isomerization of neuronal cytoskeletal proteins by Pin1: implications for therapeutics in neurodegeneration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {19}, number = {2}, pages = {389-403}, doi = {10.3233/JAD-2010-1243}, pmid = {20110589}, issn = {1875-8908}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Cytoskeletal Proteins/*metabolism ; Humans ; Models, Biological ; Models, Molecular ; NIMA-Interacting Peptidylprolyl Isomerase ; Nerve Degeneration/*enzymology/genetics/therapy ; Parkinson Disease/metabolism ; Peptidylprolyl Isomerase/*physiology ; Phosphorylation/drug effects/physiology ; Protein Binding/physiology ; tau Proteins/metabolism ; }, abstract = {Pin1 [Protein Interacting with NIMA (never in mitosis A)] is a peptidyl prolyl cis-trans isomerase that isomerizes phospho-Serine/Threonine-Proline [p(S/T)-P] motifs of its target proteins. Pin1 functions in concert with proline directed kinases such as cyclin-dependent protein kinases, extracellular signal-regulated kinases, and c-Jun N- terminal kinase, and protein phosphatases such as protein phosphatase 2A (PP2A) and PP2B, in the regulation of a wide range of cellular processes including cell division, DNA damage response, and gene transcription, and in susceptibility to cancer and neurodegenerative diseases. This review focuses on the roles of Pin1 in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Frontotemporal dementia associated with parkinsonism linked to chromosome 17. Pin1 interacts with neuronal cytoskeletal proteins such as tau, amyloid-beta protein precursor, alpha-synuclein, and neurofilaments, often in association with phosphorylation events that influence their functions in the neuronal cytoskeleton. Overexpression of Pin1 reduces WT tau stability but increases P301L mutant tau stability. Pin1 associates with neurofilament H (NF-H) and modulates excitotoxic and oxidative stress induced perikaryal phosphorylation of NF-H. Pin1 mediates the neural specific apoptosis machinery. The specific inhibitors of Pin1 may have potential therapeutic implications in neurodegeneration.}, }
@article {pmid20102523, year = {2010}, author = {Okamoto, K and Fujita, Y and Mizuno, Y}, title = {Pathology of protein synthesis and degradation systems in ALS.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {30}, number = {2}, pages = {189-193}, doi = {10.1111/j.1440-1789.2009.01088.x}, pmid = {20102523}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Autophagy ; Golgi Apparatus/metabolism/pathology ; Humans ; Neurons/metabolism/*pathology ; Oxidative Stress ; Proteasome Endopeptidase Complex/metabolism ; Protein Biosynthesis ; Ubiquitination ; }, abstract = {Protein synthesis and degradation systems in neurons are among the major subjects of study in neurobiology. These systems are believed to be the main pathways involved in ALS; however, the essential pathomechanisms that underlie this disease remain obscure. In addition to the ubiquitin-proteasomal and autophagic systems, several cytoplasmic organelles are also involved in ALS. Here, we present our data and discuss the main morphological abnormalities detected in the anterior horn cells of ALS patients.}, }
@article {pmid20102522, year = {2010}, author = {Arai, T and Hasegawa, M and Nonoka, T and Kametani, F and Yamashita, M and Hosokawa, M and Niizato, K and Tsuchiya, K and Kobayashi, Z and Ikeda, K and Yoshida, M and Onaya, M and Fujishiro, H and Akiyama, H}, title = {Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {30}, number = {2}, pages = {170-181}, doi = {10.1111/j.1440-1789.2009.01089.x}, pmid = {20102522}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Brain/*metabolism/pathology ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/*metabolism/pathology ; Humans ; Inclusion Bodies/metabolism/pathology ; Phosphorylation ; alpha-Synuclein/metabolism ; }, abstract = {Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics.}, }
@article {pmid20102521, year = {2010}, author = {Kwak, S and Hideyama, T and Yamashita, T and Aizawa, H}, title = {AMPA receptor-mediated neuronal death in sporadic ALS.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {30}, number = {2}, pages = {182-188}, doi = {10.1111/j.1440-1789.2009.01090.x}, pmid = {20102521}, issn = {1440-1789}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Cell Death ; Humans ; Motor Neurons/metabolism/*pathology ; Nerve Degeneration/metabolism/*pathology ; Receptors, AMPA/*metabolism ; }, abstract = {alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated excitotoxicity has been proposed to play a role in death of motor neurons in amyotrophic lateral sclerosis (ALS). We demonstrated that RNA editing of GluR2 mRNA at the glutamine/arginine (Q/R) site was decreased in autopsy-obtained spinal motor neurons, but not in cerebellar Purkinje cells, of patients with sporadic ALS. This molecular change occurs in motor neurons of sporadic ALS cases with various phenotypes, but not in degenerating neurons of patients with other neurodegenerative diseases, including SOD1-associated familial ALS. Because GluR2 Q/R site-editing is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), it is likely that regulatory mechanism of ADAR2 activity does not work well in the motor neurons of sporadic ALS. Indeed, ADAR2 expression level was significantly decreased in the spinal ventral gray matter of sporadic ALS as compared to normal control subjects. It is likely that ADAR2 underactivity selective in motor neurons induced deficient GluR2 Q/R site-editing, which results in the neuronal death of sporadic ALS. Thus, among multiple different molecular mechanisms underlying death of motor neurons, it is likely that an increase of the proportion of Q/R site-unedited GluR2-containing Ca(2+)-permeable AMPA receptors initiates the death of motor neurons in sporadic ALS. To this end, normalization of ADAR2 activity in motor neurons may become a therapeutic strategy for sporadic ALS.}, }
@article {pmid20102519, year = {2010}, author = {Geser, F and Lee, VM and Trojanowski, JQ}, title = {Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {30}, number = {2}, pages = {103-112}, pmid = {20102519}, issn = {1440-1789}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; P30 AG010124-20/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Brain/metabolism/*pathology ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/metabolism/*pathology ; Humans ; Neurons/metabolism/pathology ; }, abstract = {It is now established that pathological transactive response DNA-binding protein with a Mr of 43 kD (TDP-43) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (now known as FTLD-TDP). In fact, the discovery of pathological TDP-43 solidified the idea that these disorders are multi-system diseases and this led to the concept of a TDP-43 proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD-TDP without or with motor neuron disease (FTLD-MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP-43. We here review salient findings in the development of a concept of TDP-43 proteinopathy as a novel group of neurodegenerative diseases similar in concept to alpha-synucleinopathies and tauopathies.}, }
@article {pmid20091630, year = {2010}, author = {Simon, ST and Higginson, IJ and Booth, S and Harding, R and Bausewein, C}, title = {Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD007354}, doi = {10.1002/14651858.CD007354.pub2}, pmid = {20091630}, issn = {1469-493X}, support = {PB-PG-0808-17311/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Benzodiazepines/*therapeutic use ; Dyspnea/*drug therapy/etiology ; Humans ; Lung Neoplasms/*complications ; Pulmonary Disease, Chronic Obstructive/*complications ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. However, the evidence for their use for this symptom is unclear.<br><br>OBJECTIVES: To determine the efficacy of benzodiazepines for the relief of breathlessness in patients with advanced disease.<br><br>SEARCH STRATEGY: We searched 14 electronic databases up to September 2009. We checked the reference lists of all relevant studies, key textbooks, reviews, and websites. We contacted investigators and specialists in palliative care for unpublished data.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines in relieving breathlessness in patients with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary fibrosis (IPF).<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies (full text), data extraction, and assessment of methodological quality. We carried out meta-analysis where appropriate.<br><br>MAIN RESULTS: Seven studies were identified, including 200 analysed participants with advanced cancer and COPD. Analysis of all seven studies (including a meta-analysis of six out of seven studies) did not show a beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer and COPD. Furthermore, no significant effect could be observed in the prevention of breakthrough dyspnoea in cancer patients. Sensitivity analysis demonstrated no significant differences regarding type of benzodiazepine, dose, route and frequency of delivery, duration of treatment, or type of control.<br><br>AUTHORS' CONCLUSIONS: There is no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer and COPD. There is a slight but non-significant trend towards a beneficial effect but the overall effect size is small. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. These results justify considering benzodiazepines as a second or third-line treatment within an individual therapeutic trial, when opioids and non-pharmacological measures have failed to control breathlessness. Although a few good quality studies were included in this review, there is still a further need for well-conducted and adequately powered studies.}, }
@article {pmid20091538, year = {2010}, author = {Jayaraman, S and Sethi, D}, title = {Advanced trauma life support training for ambulance crews.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD003109}, doi = {10.1002/14651858.CD003109.pub2}, pmid = {20091538}, issn = {1469-493X}, mesh = {Ambulances ; Controlled Clinical Trials as Topic ; Emergency Medical Technicians/*education ; Humans ; *Life Support Care ; Randomized Controlled Trials as Topic ; Traumatology/*education ; }, abstract = {BACKGROUND: There is an increasing global burden of injury especially in low- and middle-income countries (LMICs). To address this, models of trauma care initially developed in high income countries are being adopted in LMIC settings. In particular, ambulance crews with advanced life support (ALS) training are being promoted in LMICs as a strategy for improving outcomes for victims of trauma. However, there is controversy as to the effectiveness of this health service intervention and the evidence has yet to be rigorously appraised.<br><br>OBJECTIVES: To quantify the impact of ALS-trained ambulance crews versus crews without ALS training on reducing mortality and morbidity in trauma patients.<br><br>SEARCH STRATEGY: Searches were not restricted by date, language or publication status. We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2009, Issue 3), MEDLINE (Ovid SP), EMBASE (Ovid SP), CINAHL (EBSCO) and PubMed in all years up to July 2009. We also searched the reference lists of relevant studies and reviews in order to identify unpublished material.<br><br>SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials and non-randomised studies, including before-and-after studies and interrupted time series studies, comparing the impact of ALS-trained ambulance crews versus crews without ALS training on the reduction of mortality and morbidity in trauma patients.<br><br>DATA COLLECTION AND ANALYSIS: One review author applied eligibility criteria to trial reports for inclusion and extracted data.<br><br>MAIN RESULTS: We found one controlled before-and-after trial, one uncontrolled before-and-after study, and one randomised controlled trial that met the inclusion criteria. None demonstrated evidence to support ALS training for pre-hospital personnel. In the uncontrolled before-and-after study, 'a priori' sub-group analysis showed an increase in mortality among patients who had a Glasgow Coma Scale score of less than nine and received care from ALS trained ambulance crews. Additionally, when the pre-hospital trauma score was taken into account in logistic regression analysis, mortality in the patients receiving care from ALS trained crews increased significantly.<br><br>AUTHORS' CONCLUSIONS: At this time, the evidence indicates that there is no benefit of advanced life support training for ambulance crews.}, }
@article {pmid20088765, year = {2010}, author = {Orlacchio, A and Bernardi, G and Orlacchio, A and Martino, S}, title = {Stem cells: an overview of the current status of therapies for central and peripheral nervous system diseases.}, journal = {Current medicinal chemistry}, volume = {17}, number = {7}, pages = {595-608}, doi = {10.2174/092986710790416272}, pmid = {20088765}, issn = {1875-533X}, support = {GGP06209/TI_/Telethon/Italy ; }, mesh = {Adult Stem Cells/cytology/metabolism ; Embryonic Stem Cells/cytology/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Neurodegenerative Diseases/*therapy ; Peripheral Nervous System Diseases/*therapy ; *Stem Cell Transplantation ; Stem Cells/*cytology/metabolism ; }, abstract = {In regenerative medicine, stem cells are currently considered ideal candidates for the treatment of diseases and injuries of the nervous system, for which, at present, there are no effective treatments. Promising results have been shown by clinical trials for neurodegenerative diseases such as Parkinson's diseases, but also for demyelinising disorders and traumatic lesions of the brain and spinal cord. The proof-of-principle is that the replacement of damaged cells and the restoration of function can be accomplished by the transplantation of embryonic or adult stem cells. Advancements in stem cell biology were recently propelled by the ability to generate induced pluripotent stem (iPS) cells from fibroblasts of several neurodegenerative diseases (e.g. Parkinson's and Huntington's diseases, Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy). In this review, we discuss the molecular basis of stem cell therapy and the advancement of research on regenerative medicine for diseases and injuries of the nervous system.}, }
@article {pmid20082418, year = {2010}, author = {Mazzocchio, R and Rossi, A}, title = {Role of Renshaw cells in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {41}, number = {4}, pages = {441-443}, doi = {10.1002/mus.21602}, pmid = {20082418}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology/therapy ; Animals ; Humans ; Motor Neurons/*pathology/physiology ; Neural Inhibition/physiology ; Spinal Cord/pathology/physiology ; }, abstract = {In this article the role of Renshaw cell involvement in experimental amyotrophic lateral sclerosis (ALS) is discussed, with an emphasis on the anatomy, physiology, and possible role in motor control of Renshaw cells. These cells are located in lamina VII of the spinal cord, are excited by motor axon collaterals, and inhibit homonymous and synergistic motoneurons in a negative-feedback fashion (recurrent inhibition). Early dysfunction and/or loss of Renshaw cells has been suggested to occur in experimental ALS, and the hypothesis has been put forward that this may be the event that makes motoneurons more susceptible to glutamatergic toxicity in ALS. However, Renshaw cell properties and connectivity-in particular, the lack of recurrent inhibition in the more distal muscles of the limbs where, on the contrary, initial wasting is prominent in human ALS-make it unlikely that impairment of Renshaw cells is a general feature of the human form of the disease.}, }
@article {pmid20079433, year = {2010}, author = {Kim, EK and Choi, EJ}, title = {Pathological roles of MAPK signaling pathways in human diseases.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {4}, pages = {396-405}, doi = {10.1016/j.bbadis.2009.12.009}, pmid = {20079433}, issn = {0006-3002}, mesh = {Cytokines/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; *MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/*metabolism ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; *Oxidative Stress ; *Unfolded Protein Response ; }, abstract = {The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS.}, }
@article {pmid20054757, year = {2009}, author = {Kuźma-Kozakiewicz, M and Kwieciński, H}, title = {The genetics of amyotrophic lateral sclerosis.}, journal = {Neurologia i neurochirurgia polska}, volume = {43}, number = {6}, pages = {538-549}, pmid = {20054757}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Inheritance Patterns/genetics ; RNA-Binding Protein FUS/genetics ; Risk Factors ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vesicular Transport Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disorder of still unknown aetiology and pathogenesis. It is characterized by a progressive and selective loss of motor neurons in the brain and spinal cord. The majority of ALS cases (90%) are sporadic and in approximately 10% the disorder is familial. In the light of recent studies, the familial forms might however be more frequent. The article describes mutations of genes linked to both sporadic and familial ALS and the role of the proteins they encode.}, }
@article {pmid20052865, year = {2009}, author = {Adler, D and Contal, O and Janssens, JP}, title = {[A lung specialist in ALS care: towards less pessimism].}, journal = {Revue medicale suisse}, volume = {5}, number = {226}, pages = {2329-32, 2334-5}, pmid = {20052865}, issn = {1660-9379}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Blood Gas Analysis ; Congresses as Topic ; Cough/etiology ; Evidence-Based Medicine ; Humans ; Oximetry ; Positive-Pressure Respiration/instrumentation/*methods ; Prognosis ; Pulmonary Ventilation ; Respiratory Insufficiency/diagnosis/therapy ; Respiratory Therapy/methods ; Respiratory Tract Diseases/*diagnosis/etiology/*therapy ; Spirometry ; Treatment Outcome ; Weight Loss ; }, abstract = {Specialized and multidisciplinary care is needed for patients with amyotrophic lateral sclerosis (ALS). Respiratory failure secondary to respiratory muscle dysfunction, ineffective cough, weight loss and progressive loss of autonomy should always be sought and explored. Very few tests are needed to assess a patient with ALS: spirometry, blood gases, nocturnal oximetry, cough peak-flow, and follow-up of body weight. Patients should be informed clearly as to the nature and evolution of ALS, and as to the potential benefits and disadvantages associated with each treatment modality in order to be involved in therapeutic decisions. This evidence-based review focuses on respiratory care of patients with ALS.}, }
@article {pmid21438193, year = {2010}, author = {Machado, S and Araújo, F and Paes, F and Velasques, B and Cunha, M and Budde, H and Basile, LF and Anghinah, R and Arias-Carrión, O and Cagy, M and Piedade, R and de Graaf, TA and Sack, AT and Ribeiro, P}, title = {EEG-based brain-computer interfaces: an overview of basic concepts and clinical applications in neurorehabilitation.}, journal = {Reviews in the neurosciences}, volume = {21}, number = {6}, pages = {451-468}, doi = {10.1515/revneuro.2010.21.6.451}, pmid = {21438193}, issn = {0334-1763}, mesh = {Brain/*physiology ; Central Nervous System Diseases/*pathology/*rehabilitation ; *Communication Aids for Disabled ; Electroencephalography/*methods ; Humans ; *User-Computer Interface ; }, abstract = {Some patients are no longer able to communicate effectively or even interact with the outside world in ways that most of us take for granted. In the most severe cases, tetraplegic or post-stroke patients are literally 'locked in' their bodies, unable to exert any motor control after, for example, a spinal cord injury or a brainstem stroke, requiring alternative methods of communication and control. But we suggest that, in the near future, their brains may offer them a way out. Non-invasive electroencephalogram (EEG)-based brain-computer interfaces (BCI) can be characterized by the technique used to measure brain activity and by the way that different brain signals are translated into commands that control an effector (e.g., controlling a computer cursor for word processing and accessing the internet). This review focuses on the basic concepts of EEG-based BCI, the main advances in communication, motor control restoration and the downregulation of cortical activity, and the mirror neuron system (MNS) in the context of BCI. The latter appears to be relevant for clinical applications in the coming years, particularly for severely limited patients. Hypothetically, MNS could provide a robust way to map neural activity to behavior, representing the high-level information about goals and intentions of these patients. Non-invasive EEG-based BCIs allow brain-derived communication in patients with amyotrophic lateral sclerosis and motor control restoration in patients after spinal cord injury and stroke. Epilepsy and attention deficit and hyperactive disorder patients were able to downregulate their cortical activity. Given the rapid progression of EEG-based BCI research over the last few years and the swift ascent of computer processing speeds and signal analysis techniques, we suggest that emerging ideas (e.g., MNS in the context of BCI) related to clinical neurorehabilitation of severely limited patients will generate viable clinical applications in the near future.}, }
@article {pmid21395520, year = {2010}, author = {Mankikar, SD}, title = {Stem cells: a new paradigm in medical therapeutics.}, journal = {Journal of long-term effects of medical implants}, volume = {20}, number = {3}, pages = {219-250}, doi = {10.1615/jlongtermeffmedimplants.v20.i3.50}, pmid = {21395520}, issn = {1050-6934}, mesh = {Bioreactors ; Cell Culture Techniques ; Humans ; *Stem Cell Transplantation/trends ; *Stem Cells ; *Tissue Engineering ; }, abstract = {Even though the stem cells have been studied for decades, only during the past few years has there been an overwhelming proliferation of publications covering isolation, cultivation and utilization of the body's master cells. This paper attempts to summarize the recent studies in the field of stem cells. A number of studies have reported the existence of multipotent stem cells in the cord, cord blood, placenta, bone marrow, brain, heart, teeth, skin, liver, hair follicles and many other tissues and organs, giving rise to cell types other than their tissue of origin. Increased therapeutic use of stem cells has resulted in scientific methods of collection, testing, processing and storage of these cells, with minimal cell damage and differentiation. Cell expansion, bioreactors and tissue engineering are employed extensively to improve the cell dose and outcome. Stem cell infusion, transplantation and implantation are accepted curative therapies for many malignant and non-malignant conditions. Stem cell therapies also provide alternative solutions for the repair and regeneration of various tissues and organs. There has been a dramatic improvement in the understanding of immunosuppressive properties of stem cells on various immune cell types. Stem cells are found to secrete angiogenic cytokines that increase neovascularization. They bring the promise of curing a disease state as these cells normally regenerate tissues in a healthy organism. Stem cell transplantation, in isolation or in combination with other procedures, has been found to be effective. Stem cell therapy is also seen as a possible alternative for the treatment of different diseases such as juvenile diabetes, amyotrophic lateral sclerosis, cerebral palsy, stroke, spinal cord injury and Parkinson's disease. Regenerative medicine using human stem cells is one of the new and promising fields for treating various intractable diseases and damaged organs.}, }
@article {pmid21387816, year = {2010}, author = {Banach, M and Rakowicz, M}, title = {[Electrophysiological diagnosis of arnyotrophic lateral sclerosis].}, journal = {Przeglad lekarski}, volume = {67}, number = {9}, pages = {736-740}, pmid = {21387816}, issn = {0033-2240}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Electromyography ; Humans ; Transcranial Magnetic Stimulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of unclear etiology. Diagnostic challenges often appear already at the early stage of the disease. Detecting developed neuropathies on time, including multifocal motor neuropathy with a conduction block, allows administering a treatment, which can prove to be successful quickly. Electrophysiological studies assess the lesion of the peripheral and central motor neuron and serve as markers supporting the diagnosis of ALS. Electromyographic and neurographic studies make it possible to take an objective look at the involvement of the peripheral nervous system and constitute, apart form the clinical assessment, an important element of the ALS diagnosis. Transcranial magnetic stimulation, augmented with a new method of triple stimulation technique (TST) helps in the diagnosis of lesions in the cortico-bulbar and cortico-spinal tract in patients with no clinical symptoms of the upper motor neuron involvement. Additionally, this technique allows making the diagnosis of the conduction block localized in the proximal nerve segments, especially when the results of neurographic studies are not unequivocal. In experimental studies assessing responses to treatment attempts and monitoring the development of the disease there has been used the MUNE method (motor unit number estimation), which informs of the number of active motor neurons. In this review there have been described the up-to-date electrophysiological methods, facilitating the diagnosis and monitoring of the progressive lesion of the lower and upper motor neuron in patients with amyotrophic lateral sclerosis. Besides, there have been presented other clinical syndromes, which must be distinguished from amyotrophic lateral sclerosis.}, }
@article {pmid20036953, year = {2010}, author = {Ientile, R and Curro', M and Ferlazzo, N and Condello, S and Caccamo, D and Pisani, F}, title = {Homocysteine, vitamin determinants and neurological diseases.}, journal = {Frontiers in bioscience (Scholar edition)}, volume = {2}, number = {1}, pages = {359-372}, doi = {10.2741/s70}, pmid = {20036953}, issn = {1945-0524}, mesh = {Avitaminosis/*metabolism ; Homocysteine/blood/*metabolism ; Humans ; Hyperhomocysteinemia/*complications ; Nervous System Diseases/blood/*etiology/*genetics ; *Polymorphism, Genetic ; Vascular Diseases/blood/*etiology ; Vitamin B Complex/metabolism ; }, abstract = {This review focuses on the putative role of hyper-homocysteinemia in the pathogenesis of different diseases affecting the nervous system, including stroke, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis and amyotrophic lateral sclerosis. However, a firm pathogenic role of homocysteine in these diseases has never been established. Lowering plasma homocysteine levels trough vitamin therapy failed to prevent vascular diseases. Conversely, normalization of hyper-homocysteinemia caused improvement in patients with cognitive impairment. B vitamin deficiency is the main determinant of homocysteine levels. However, it has been hypothesized that homocysteine might be a mere marker of vitamin deficiency or an indicator of disease rather than a risk factor. A more consistent use of thresholds to define deficiency is needed to recommend routine screening, monitoring and supplementation of B vitamins to ameliorate the prognosis of the above mentioned disorders. To date, data are insufficient to firmly establish which one of the hypotheses made is correct and the question concerning the real meaning of hyper-homocysteinemia in the pathology of the nervous system still remains an intriguing medical dilemma.}, }
@article {pmid20034089, year = {2010}, author = {Han, SM and Cottee, PA and Miller, MA}, title = {Sperm and oocyte communication mechanisms controlling C. elegans fertility.}, journal = {Developmental dynamics : an official publication of the American Association of Anatomists}, volume = {239}, number = {5}, pages = {1265-1281}, pmid = {20034089}, issn = {1097-0177}, support = {R01 GM085105/GM/NIGMS NIH HHS/United States ; R01 GM085105-04/GM/NIGMS NIH HHS/United States ; GM085105/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/physiology ; Female ; Fertility ; Humans ; Male ; Oocytes/*physiology ; Signal Transduction/*physiology ; Spermatozoa/*physiology ; }, abstract = {During sexual reproduction in many species, sperm and oocyte secrete diffusible signaling molecules to help orchestrate the biological symphony of fertilization. In the Caenorhabditis elegans gonad, bidirectional signaling between sperm and oocyte is important for guiding sperm to the fertilization site and inducing oocyte maturation. The molecular mechanisms that regulate sperm guidance and oocyte maturation are being delineated. Unexpectedly, these mechanisms are providing insight into human diseases, such as amyotrophic lateral sclerosis, spinal muscular atrophy, and cancer. Here we review sperm and oocyte communication in C. elegans and discuss relationships to human disorders.}, }
@article {pmid20030257, year = {2009}, author = {Nakagawa, M}, title = {[Wide spectrum of hereditary motor sensory neuropathy (HMSN)].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {950-952}, doi = {10.5692/clinicalneurol.49.950}, pmid = {20030257}, issn = {0009-918X}, mesh = {Chromosomes, Human, Pair 3/genetics ; Exons/genetics ; Gene Deletion ; Gene Duplication ; Genetic Linkage/genetics ; *Hereditary Sensory and Motor Neuropathy/diagnosis/genetics/pathology/therapy ; Humans ; Informed Consent ; Myelin Proteins ; Oligonucleotide Array Sequence Analysis ; Survival of Motor Neuron 1 Protein ; }, abstract = {Hereditary neuropathies are classified into HMSN/Charcot-Marie-Tooth disease (CMT), familial amyloid polyneuropathy (FAP), hereditary motor neuropathies (HMN) and hereditary sensory (and autonomic) neuropathies (HSAN). The clinical features of HMSN are generally characterized as distal dominant motor and sensory involvements. However, we have reported a novel HMSN with proximal dominancy (HMSN-P) originated in Okinawa and Shiga prefectures, Japan. The gene locus is located in the centromere region of chromosome 3. In 2008, a new family with the HMSN-P was reported from Brazilians of Japanese ancestry. This Brazilian family was initially diagnosed as having "a familial ALS". The HMSN-P linked to ch.3 is not limited in Japan, but may be present in the worldwide. The overseas scientific research for the elucidation of the mechanism of HMSN-P supported by JSPS KAKENHI (21406026) is planning. Recently several other types of HMSN-P have been reported; HMSN-P with urinary disturbance and paroxysmal dry cough, a patient with both CMT 1A and mild spinal muscular atrophy and CMT1A with severe paresis of the proximal lower limb muscles. Therefore the clinical concept of HMSN is not limited as the disease with distal dominant motor sensory involvement. HMSN has the wider spectrum from distal to proximal and motor/sensory to autonomic neuropathies.}, }
@article {pmid20030220, year = {2009}, author = {Yokota, T}, title = {[Gene therapy of ALS with RNA interference].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {821-823}, doi = {10.5692/clinicalneurol.49.821}, pmid = {20030220}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Dependovirus ; Disease Models, Animal ; Gene Transfer Techniques ; *Genetic Therapy ; Genetic Vectors ; Humans ; Mice ; Mice, Transgenic ; Mutation ; *RNA Interference ; RNA, Small Interfering/therapeutic use ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {RNA interference (RNAi) is the process of sequence-specific, post-tanscriptional gene silencing, initiated by double-stranded RNA (dsRNA). The gene therapy for familial ALS with siRNA had been started and showed promising results in the model mouse. There is a recent progress in the delivery of siRNA to the central nervous system. There are still important problems for application of gene therapy including off-target effect and gene delivery of siRNA, but a rapid progress can be expected because of the extremely high efficiency of siRNA.}, }
@article {pmid20030219, year = {2009}, author = {Urushitani, M}, title = {[Future perspectives of immunotherapy against ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {818-820}, doi = {10.5692/clinicalneurol.49.818}, pmid = {20030219}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Cell Death ; DNA-Binding Proteins ; Disease Models, Animal ; Humans ; Immunization, Passive ; Immunotherapy/*trends ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Superoxide Dismutase/genetics/*immunology/metabolism ; Superoxide Dismutase-1 ; Vaccines/*therapeutic use ; }, abstract = {Emerging evidence suggests that misfolded proteins in the various neurodegenerative diseases can be targets for immunotherapy including vaccination antibody therapy. To date, vaccination strategies have been shown to be effective in Alzheimer's disease, Parkinson's disease, Huntington's disease and Prion disease. Interestingly, the subcellular localization of the target proteins varies, including cytosol, synaptosomes and extracellular spaces. We have documented that mutant SOD1 is secreted together with a neurosecretory protein chromogranin, and that vaccination against the SOD1 mutant is beneficial in delaying the onset and prolonging the lifespan. However, the mechanism of vaccination on the mutant SOD1 mice remains unclear. Moreover, vaccination induces diverse inflammatory reactions, which are reported to modify both the onset and the progression of ALS. Therefore, it is important to clarify the role of innate or acquired immunity in the pathogenesis of ALS to avoid the adverse reactions of the vaccination, and rather to apply it for amelioration. Passive immunization is also promising since only aberrant proteins can be targeted using a specific monoclonal antibody. The development of the current immunization techniques is very important for the future application, since key molecules for the sporadic ALS have emerged and are intensively investigated such as TDP-43.}, }
@article {pmid20030218, year = {2009}, author = {Aoki, M and Warita, H and Suzuki, N and Itoyama, Y}, title = {[Development of motor neuron restorative therapy in amyotrophic lateral sclerosis using hepatocyte growth factor].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {814-817}, doi = {10.5692/clinicalneurol.49.814}, pmid = {20030218}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Disease Models, Animal ; Hepatocyte Growth Factor/*administration &amp; dosage ; Humans ; Injections, Spinal ; Mice ; *Motor Neurons ; Mutation ; RNA-Binding Protein FUS/genetics ; Rats ; Rats, Transgenic ; Recombinant Proteins/administration &amp; dosage ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been recently discovered to be associated with familial ALS. We found FUS/TLS mutations in familial ALS cases in Japan. Even in Asian races, ALS with FUS/TLS mutations may have common characteristics of early onset, rapid progress, high penerence trait. We developed rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. In addition, HGF is capable of reducing astrocytosis and microglial accumulation, and thus supports the attention of a glial-dependent mechanism of ALS progression. These results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.}, }
@article {pmid20030217, year = {2009}, author = {Tanaka, F and Waza, M and Yamamoto, M and Sobue, G}, title = {[Exploration of pathogenesis and therapy development for ALS employing sporadic disease model].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {811-813}, doi = {10.5692/clinicalneurol.49.811}, pmid = {20030217}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; Cell Cycle/genetics ; Cyclin C ; Disease Models, Animal ; Dynactin Complex ; Humans ; Microtubule-Associated Proteins/genetics/metabolism ; Mutation ; Oligonucleotide Array Sequence Analysis ; }, abstract = {The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain poorly understood even now 140 years after the first description of the disease in 1869 by Jean-Martin Charcot. Exploration of pathogenesis of ALS has long been dependent on transgenic animal models with mutations in the copper/ zinc superoxide dismutase 1 (SOD1) gene. However, the lack of therapeutic concordance between these animal models and human sporadic ALS patients is troubling. The reasons include that there might exist the differences of pathogenesis between sporadic and familial ALS and/or the disease models for sporadic ALS have not been established. We have been working on screening motor neuron-specific genes critical for pathogenesis of sporadic ALS using cDNA microarray and laser capture microdissection techniques. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of sporadic ALS. In particular, dynactin-1, a major component of dynein/dynactin complex and several cell cycle-related genes are the targets of our research. Development and analysis of new disease models for sporadic ALS based on these genes will open an avenue for novel therapeutics.}, }
@article {pmid20030209, year = {2009}, author = {Hasegawa, M and Nonaka, T and Yamashita, M and Kametani, F and Arai, T and Yoshida, M and Hashizume, Y and Tsuchiya, K and Akiyama, H}, title = {[TDP-43 proteinopathies, toward understanding of the molecular pathogenesis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {783-785}, doi = {10.5692/clinicalneurol.49.783}, pmid = {20030209}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/etiology/genetics ; Brain/*metabolism ; Clinical Trials, Phase II as Topic ; DNA-Binding Proteins/genetics/*metabolism ; Drug Design ; Humans ; Mutation ; Nuclear Localization Signals ; Phosphorylation ; TDP-43 Proteinopathies/drug therapy/*etiology/genetics ; Ubiquitin ; }, abstract = {The TDP-43 proteinopathies: Toward understanding of the molecular pathogenesis. TAR DNA binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein was identified as a major component of ubiquitin-positive inclusions in FTLD and ALS, and the concept of TDP-43 proteinopathies was proposed. Immunoblot and immunohistochemical analyses using multiple anti-phosphorylated TDP-43 antibodies revealed that hyperphosphorylated 18-26 kDa C-terminal fragments in addition to the full-length TDP-43 are major constituents of inclusions in FTLD-U and ALS. Recent discovery of mutations in the TDP-43 gene in familial and sporadic ALS, indicating that abnormality of TDP-43 protein cause neurodegeneration. It also strongly suggests that aggregation of TDP-43 or the process is responsible for neurodegeneration in FTLD-U and ALS. To investigate the molecular mechanisms of aggregation of TDP-43, we have established two cellular models for intracellular aggregates of TDP-43 similar to those in brains of TDP-43 proteinopathies patients. The first consists of SH-SY5Y cells expressing mutant TDP-43 that lacks both the nuclear localization signal (NLS) and residues 187-192 (deltaNLS &amp; 187-192). The second model consists of SH-SY5Y cells expressing an aggregation-prone TDP-43 C-terminal fragment as a green fluorescent protein (GFP)-fusion. In these cells, round structures positive for both anti-pS409/410 and anti-Ub are observed. These results suggest that intracellular localization of TDP-43, truncation of TDP-43 and proteasomal dysfunction of cells may be involved in the pathological process of TDP-43 proteinopathies. We also found that two small compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease, inhibited the formation of TDP-43 aggregates in these two cellular models, suggesting that these compounds may be effective for the treatment of ALS and FTLD-U.}, }
@article {pmid20017723, year = {2010}, author = {Mancuso, M and Orsucci, D and Volpi, L and Calsolaro, V and Siciliano, G}, title = {Coenzyme Q10 in neuromuscular and neurodegenerative disorders.}, journal = {Current drug targets}, volume = {11}, number = {1}, pages = {111-121}, doi = {10.2174/138945010790031018}, pmid = {20017723}, issn = {1873-5592}, mesh = {Animals ; Humans ; Mitochondrial Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuromuscular Diseases/*drug therapy/*metabolism ; Ubiquinone/*analogs &amp; derivatives/deficiency/physiology/therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.}, }
@article {pmid20015852, year = {2010}, author = {Orrell, RW}, title = {Motor neuron disease: systematic reviews of treatment for ALS and SMA.}, journal = {British medical bulletin}, volume = {93}, number = {}, pages = {145-159}, doi = {10.1093/bmb/ldp049}, pmid = {20015852}, issn = {1471-8391}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Databases as Topic ; Humans ; Motor Neuron Disease/therapy ; Muscular Atrophy, Spinal/*therapy ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; }, abstract = {INTRODUCTION: There is no curative treatment for the common motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Nevertheless, there is an increasing volume of published studies. This review assesses the current evidence for treatment of these conditions.<br><br>SOURCES OF DATA: Primarily, the systematic reviews of the Cochrane Collaboration, with additional reference to other systematic reviews and online sites.<br><br>AREAS OF AGREEMENT: Riluzole remains the only medication with demonstrated efficacy and regulatory approval for the treatment of ALS. AREAS OF CONTROVERSY, GROWING POINTS, AND AREAS TIMELY FOR DEVELOPING RESEARCH: The design of clinical trials and the publication of unsatisfactory studies, in both human and animal models, continue to cause confusion in advising on patient management. Improvements in trial design, critical assessment of studies for publication and avoidance of bias towards publication of positive results are needed. A better understanding of pathogenesis should lead to more potent interventions.}, }
@article {pmid20008649, year = {2009}, author = {Wright, BR and Warrington, AE and Edberg, DD and Rodriguez, M}, title = {Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies.}, journal = {Archives of neurology}, volume = {66}, number = {12}, pages = {1456-1459}, pmid = {20008649}, issn = {1538-3687}, support = {P01 NS038468-05/NS/NINDS NIH HHS/United States ; R01 NS032129/NS/NINDS NIH HHS/United States ; P01 NS038468/NS/NINDS NIH HHS/United States ; R01 NS 24180/NS/NINDS NIH HHS/United States ; R01 NS032129-14/NS/NINDS NIH HHS/United States ; R56 CA104996/CA/NCI NIH HHS/United States ; P01 NS038468-03/NS/NINDS NIH HHS/United States ; R56 CA104996-05/CA/NCI NIH HHS/United States ; R01 CA104996/CA/NCI NIH HHS/United States ; R01 CA 104996/CA/NCI NIH HHS/United States ; R01 NS024180-22/NS/NINDS NIH HHS/United States ; R01 NS 32129/NS/NINDS NIH HHS/United States ; R01 CA096859/CA/NCI NIH HHS/United States ; R01 CA096859-03/CA/NCI NIH HHS/United States ; P01 NS 38468/NS/NINDS NIH HHS/United States ; R01 NS024180/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Monoclonal/metabolism/*physiology/*therapeutic use ; Autoantibodies/metabolism/*physiology/*therapeutic use ; Autoantigens/immunology/metabolism ; Central Nervous System/immunology/metabolism/pathology ; Humans ; Multiple Sclerosis/immunology/metabolism/*pathology/therapy ; }, abstract = {Natural autoreactive monoclonal IgM antibodies have demonstrated potential as therapeutic agents for central nervous system (CNS) disease. These antibodies bind surface antigens on specific CNS cells, activating intracellular repair-promoting signals. IgM antibodies that bind to surface antigens on oligodendrocytes enhanced remyelination in animal models of multiple sclerosis. IgM antibodies that bind to neurons stimulate neurite outgrowth and prevent neuron apoptosis. The neuron-binding IgM antibodies may have utility in CNS axon- or neuron-damaging diseases, such as amyotrophic lateral sclerosis, stroke, spinal cord injury, or secondary progressive multiple sclerosis. Recombinant remyelination-promoting IgM antibodies have been generated for formal toxicology studies and, after Food and Drug Administration approval, a phase 1 clinical trial. Natural autoreactive monoclonal antibodies directed against CNS cells represent novel therapeutic molecules to induce repair of the nervous system.}, }
@article {pmid20007187, year = {2010}, author = {Pellis, T and Kohl, P}, title = {Extracorporeal cardiac mechanical stimulation: precordial thump and precordial percussion.}, journal = {British medical bulletin}, volume = {93}, number = {}, pages = {161-177}, doi = {10.1093/bmb/ldp045}, pmid = {20007187}, issn = {1471-8391}, support = {G0400145/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Cardiopulmonary Resuscitation/*methods/standards ; Electrophysiologic Techniques, Cardiac ; Heart Arrest/*therapy ; Heart Massage/*methods/standards ; Humans ; Physical Stimulation/methods ; }, abstract = {INTRODUCTION: External cardiac mechanical stimulation is one of the fastest resuscitative manoeuvres possible in the emergency setting. Precordial thump (PT), initially reported for treatment of atrio-ventricular block, has been subsequently described to cardiovert also ventricular tachycardia (VT) and fibrillation (VF). PT efficacy, mechanics and mechanisms remain poorly characterized.<br><br>SOURCES OF DATA: Appropriate MESH and free terms were searched on PubMed, Embase and the Cochrane Library. Cross-referencing from articles and reviews, and forward search using SCOPUS and Google scholar have also been performed. Pre-set inclusion and exclusion criteria were applied to retrieved references on PT, which were then reviewed, summarized and interpreted.<br><br>AREAS OF AGREEMENT: PT is not effective in treating VF, and of limited use for VT, although it has a very good safety profile (97% no changed/improved rhythm). If delivered, PT should be applied as early as possible after cardiac arrest, and cardio-pulmonary resuscitation (CPR) should begin with no delay if not effective.<br><br>AREAS OF CONTROVERSY: A relatively large fraction of reported positive outcomes (both for PT and the less forceful but serially applied precordial percussion) in witnessed asystole should be considered when critically reviewing present CPR recommendations. In addition, mechanisms, energy requirements and timing are analysed and discussed.<br><br>The 2005 ALS guidelines recommend PT delivery only by healthcare professionals trained in the technique. The use of training aids should therefore be explored, regardless of whether they are based on stand-alone devices or integrated within resuscitation mannequins.}, }
@article {pmid19929743, year = {2009}, author = {Bradley, WG}, title = {Possible therapy for ALS based on the cyanobacteria/BMAA hypothesis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10 Suppl 2}, number = {}, pages = {118-123}, doi = {10.3109/17482960903285951}, pmid = {19929743}, issn = {1471-180X}, mesh = {Amino Acids/therapeutic use ; Amino Acids, Diamino/analysis/metabolism/*toxicity ; Amino Acids, Dicarboxylic/analysis/metabolism/*toxicity ; Amino Acyl-tRNA Synthetases/antagonists &amp; inhibitors/drug effects ; Amyotrophic Lateral Sclerosis/*chemically induced/diagnosis/*therapy ; Cyanobacteria/chemistry/*physiology ; Enzyme Inhibitors/therapeutic use ; Hair/chemistry ; Humans ; Neurotoxins/analysis/metabolism/*toxicity ; Protein Transport/drug effects ; }, abstract = {Although the cyanobacteria/BMAA hypothesis of the cause of ALS and other age-related neurodegenerative diseases remains to be proven, it is not too early to ask whether treatment would be possible if the hypothesis were correct. This paper reviews the possible ways that chronic BMAA neurotoxicity could be prevented or treated.}, }
@article {pmid19927084, year = {2009}, author = {Federici, T and Boulis, NM}, title = {Invited review: festschrift edition of neurosurgery peripheral nervous system as a conduit for delivering therapies for diabetic neuropathy, amyotrophic lateral sclerosis, and nerve regeneration.}, journal = {Neurosurgery}, volume = {65}, number = {4 Suppl}, pages = {A87-92}, doi = {10.1227/01.NEU.0000335653.52938.F2}, pmid = {19927084}, issn = {1524-4040}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*surgery ; Animals ; Axonal Transport/genetics ; Diabetic Neuropathies/physiopathology/*surgery ; Ganglia, Spinal/drug effects/metabolism/surgery ; Gene Transfer Techniques/*trends ; Humans ; Nerve Regeneration/genetics ; Nerve Tissue Proteins/genetics/therapeutic use ; Peripheral Nerves/metabolism/physiopathology/*surgery ; Peripheral Nervous System Diseases/metabolism/physiopathology/*surgery ; Recovery of Function/genetics ; }, abstract = {In this review, we describe how therapies that promote axonal regeneration and neuronal protection can complement surgery for a successful functional restoration in peripheral nerve disorders. We discuss the advantages of peripheral drug delivery and the role of the neurosurgeon in the precise delivery of molecular therapies to surgically inaccessible structures. Strategies for enhancing uptake and retrograde transport of therapeutics, including gene therapy, are emphasized as conduits for delivery of therapeutics. Finally, candidate therapeutic proteins and genes are discussed in the context of application to degenerative disorders of the nervous system, including nerve injury, peripheral neuropathy, and amyotrophic lateral sclerosis.}, }
@article {pmid19969067, year = {2010}, author = {Barber, SC and Shaw, PJ}, title = {Oxidative stress in ALS: key role in motor neuron injury and therapeutic target.}, journal = {Free radical biology &amp; medicine}, volume = {48}, number = {5}, pages = {629-641}, doi = {10.1016/j.freeradbiomed.2009.11.018}, pmid = {19969067}, issn = {1873-4596}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/physiopathology ; Animals ; Antioxidants/*therapeutic use ; Apoptosis ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Motor Neurons/pathology/*physiology ; Mutation/genetics ; *Oxidative Stress ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2-3 years of symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.}, }
@article {pmid19961263, year = {2010}, author = {Cudkowicz, ME and Katz, J and Moore, DH and O'Neill, G and Glass, JD and Mitsumoto, H and Appel, S and Ravina, B and Kieburtz, K and Shoulson, I and Kaufmann, P and Khan, J and Simpson, E and Shefner, J and Levin, B and Cwik, V and Schoenfeld, D and Aggarwal, S and McDermott, MP and Miller, RG}, title = {Toward more efficient clinical trials for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {3}, pages = {259-265}, doi = {10.3109/17482960903358865}, pmid = {19961263}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Biomarkers ; Clinical Trials, Phase II as Topic/*methods ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Research Design ; Riluzole/pharmacology/*therapeutic use ; Treatment Outcome ; }, abstract = {More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.}, }
@article {pmid19955991, year = {2009}, author = {Harati, Y}, title = {What's in the Literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {11}, number = {2}, pages = {88-95}, doi = {10.1097/CND.0b013e3181c75e35}, pmid = {19955991}, issn = {1537-1611}, mesh = {*Amyotrophic Lateral Sclerosis ; *Guillain-Barre Syndrome ; *Hereditary Sensory and Autonomic Neuropathies ; Humans ; *Muscular Diseases ; *Myasthenia Gravis ; }, abstract = {For this issue of Journal, a few recent publications that discuss disorders of motor unit (motor neuron, nerve, neuromuscular junction, and muscle) are selected. Articles about amyotrophic lateral sclerosis, Guillain-Barré syndrome, hereditary neuropathies, myasthenia gravis, and myopathies that convey a salient clinical lesson are discussed. There have been many other excellent publications in the past few months, but the space constrains do not allow to include them all.}, }
@article {pmid19890241, year = {2009}, author = {Reddy, PH}, title = {Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer's disease.}, journal = {CNS spectrums}, volume = {14}, number = {8 Suppl 7}, pages = {8-13; discussion 16-8}, pmid = {19890241}, issn = {1092-8529}, support = {R01 AG028072/AG/NIA NIH HHS/United States ; R01 AG028072-03/AG/NIA NIH HHS/United States ; AG020872/AG/NIA NIH HHS/United States ; AG025061/AG/NIA NIH HHS/United States ; }, mesh = {*Aging ; Alzheimer Disease/drug therapy/*metabolism/*pathology ; Animals ; Antioxidants/therapeutic use ; Epigenesis, Genetic ; Humans ; Mitochondria/drug effects/genetics/*metabolism/*pathology ; Neurodegenerative Diseases/genetics/physiopathology ; }, abstract = {A growing body of evidence suggests that mitochondrial abnormalities are involved in aging and in age-related neurodegenerative diseases as well as cancer, diabetes, and several other diseases known to be affected by mitochondria. Causal factors for most age-related neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA)-are largely unknown. Genetic defects are reported to cause a small number of neurodegenerative diseases, but cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. However, based on several cellular, molecular, and animal model studies of Alzheimer's disease, Parkinson's disease, ALS, FRDA, cancer, and diabetes, aging may play a large role in cell death in these diseases. Age-dependent, mitochondrially-generated reactive oxygen species (ROS) have been identified as important factors responsible for disease progression and cell death, particularly in late-onset diseases, in which genetic mutations are not causal factors.}, }
@article {pmid19951898, year = {2009}, author = {Ilieva, H and Polymenidou, M and Cleveland, DW}, title = {Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond.}, journal = {The Journal of cell biology}, volume = {187}, number = {6}, pages = {761-772}, pmid = {19951898}, issn = {1540-8140}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*pathology ; Animals ; Astrocytes/enzymology/pathology ; Axonal Transport ; Capillaries/enzymology/pathology ; Cell Death ; Endoplasmic Reticulum/enzymology/pathology ; Glutamic Acid/metabolism ; Humans ; Microglia/enzymology/pathology ; Mutation ; Nerve Degeneration/enzymology/genetics/*pathology ; Neurons/enzymology/*pathology ; Stress, Physiological ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Superoxides/metabolism ; T-Lymphocytes/enzymology/pathology ; }, abstract = {Selective degeneration and death of one or more classes of neurons is the defining feature of human neurodegenerative disease. Although traditionally viewed as diseases mainly affecting the most vulnerable neurons, in most instances of inherited disease the causative genes are widely-usually ubiquitously-expressed. Focusing on amyotrophic lateral sclerosis (ALS), especially disease caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1), we review here the evidence that it is the convergence of damage developed within multiple cell types, including within neighboring nonneuronal supporting cells, which is crucial to neuronal dysfunction. Damage to a specific set of key partner cells as well as to vulnerable neurons may account for the selective susceptibility of neuronal subtypes in many human neurodegenerative diseases, including Huntington's disease (HD), Parkinson's disease (PD), prion disease, the spinal cerebellar ataxias (SCAs), and Alzheimer's disease (AD).}, }
@article {pmid19951254, year = {2010}, author = {Taha, MF}, title = {Cell based-gene delivery approaches for the treatment of spinal cord injury and neurodegenerative disorders.}, journal = {Current stem cell research &amp; therapy}, volume = {5}, number = {1}, pages = {23-36}, doi = {10.2174/157488810790442778}, pmid = {19951254}, issn = {2212-3946}, mesh = {Animals ; *Cell Transplantation ; Cytoprotection ; Disease Models, Animal ; *Genetic Therapy ; Genetic Vectors/genetics ; Humans ; Nerve Growth Factors/genetics/metabolism ; Neurodegenerative Diseases/pathology/physiopathology/*therapy ; Neurons/pathology ; Recovery of Function ; Retroviridae/genetics ; Spinal Cord Injuries/pathology/physiopathology/*therapy ; Stem Cells/*metabolism/pathology ; Transgenes/genetics ; }, abstract = {Cell based-gene delivery has provided an important therapeutic strategy for different disorders in the recent years. This strategy is based on the transplantation of genetically modified cells to express specific genes and to target the delivery of therapeutic factors, especially for the treatment of cancers and neurological, immunological, cardiovascular and heamatopoietic disorders. Although, preliminary reports are encouraging, and experimental studies indicate functionally and structurally improvements in the animal models of different disorders, universal application of this strategy for human diseases requires more evidence. There are a number of parameters that need to be evaluated, including the optimal cell source, the most effective gene/genes to be delivered, the optimal vector and method of gene delivery into the cells and the most efficient route for the delivery of genetically modified cells into the patient. Also, some obstacles have to be overcome, including the safety and usefulness of the approaches and the stability of the improvements. Here, recent studies concerning with the cell-based gene delivery for spinal cord injury and some neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease are briefly reviewed, and their exciting consequences are discussed.}, }
@article {pmid19946766, year = {2009}, author = {Bolognin, S and Messori, L and Zatta, P}, title = {Metal ion physiopathology in neurodegenerative disorders.}, journal = {Neuromolecular medicine}, volume = {11}, number = {4}, pages = {223-238}, pmid = {19946766}, issn = {1559-1174}, mesh = {Aged ; Aging/*metabolism ; Animals ; Chelating Agents/therapeutic use ; Chelation Therapy ; Homeostasis ; Humans ; Metalloproteins/metabolism ; Metals/*metabolism/*toxicity ; Mice ; Neurodegenerative Diseases/*chemically induced/drug therapy/*metabolism ; Oxidative Stress ; Rats ; }, abstract = {Metal dyshomeostasis in the brain (BMD) has often been proposed as a possible cause for several neurodegenerative disorders (NDs). Nevertheless, the precise nature of the biochemical mechanisms of metal involvement in NDs is still largely unknown. Mounting evidence suggests that normal aging itself is characterized by, among other features, a significant degree of metal ion dysmetabolism in the brain. This is probably the result of a progressive deterioration of the metal regulatory systems and, at least in some cases, of life-long metal exposure and brain accumulation. Although alterations of metal metabolism do occur to some extent in normal aging, they appear to be highly enhanced under various neuropathological conditions, causing increased oxidative stress and favoring abnormal metal-protein interactions. Intriguingly, despite the fact that most common NDs have a distinct etiological basis, they share striking similarities as they are all characterized by a documented brain metal impairment. This review will primarily focus on the alterations of metal homeostasis that are observed in normal aging and in Alzheimer's disease. We also present a brief survey on BMD in other NDs (Amyotrophic Lateral Sclerosis, Parkinson's, and Prion Protein disease) in order to highlight what represents the most reliable evidence supporting a crucial involvement of metals in neurodegeneration. The opportunities for metal-targeted pharmacological strategies in the major NDs are briefly outlined as well.}, }
@article {pmid19943351, year = {2009}, author = {Mitrecić, D and Gajović, S and Pochet, R}, title = {Toward the treatments with neural stem cells: experiences from amyotrophic lateral sclerosis.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {292}, number = {12}, pages = {1962-1967}, doi = {10.1002/ar.20971}, pmid = {19943351}, issn = {1932-8494}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Cell Culture Techniques ; Cell Differentiation/physiology ; Cell Separation/methods ; Graft Survival/immunology ; Humans ; Mesoderm/cytology/physiology/transplantation ; Neurogenesis/physiology ; Rats ; Stem Cell Transplantation/*methods/trends ; Stem Cells/cytology/*physiology ; Transplantation, Autologous/methods ; }, abstract = {Common pathological features of neurodegenerative diseases are progressive dysfunction and neuronal death. In amyotrophic lateral sclerosis (ALS), motor neurons are selectively affected, leading to death because of paralysis. The main therapeutic goal in neurodegenerative diseases is to diminish neural dysfunction and to replace non-functional cells with the new ones. "Cell-oriented" treatment strategies include isolation of neural stem cells (NSC), their controlled differentiation, and cellular injections targeting the affected region. Beneficial effects of injected cells result from the combination of cell replacement and secretion of the growth factors. Here, we summarize the current state of isolation and differentiation of NSC, and emphasize the embryo tail bud as a particular region where neuroepithelium differentiates from undifferentiated mesenchymal cells over the course of normal development. The possibility to obtain cells from autologous mesenchyme capable of integrating into affected regions represents a major challenge whose achievement should circumvent the pitfall of the immune reaction against transplanted cells. We also present our own results: when intravenously injected in symptomatic ALS rats, NSC migrated to the motor cortex and continued to differentiate. Thus, we illustrate that the use of NSC in rodent models of ALS may represent a paradigm for other neurodegenerative diseases.}, }
@article {pmid19943341, year = {2009}, author = {Andjus, PR and Bataveljić, D and Vanhoutte, G and Mitrecic, D and Pizzolante, F and Djogo, N and Nicaise, C and Gankam Kengne, F and Gangitano, C and Michetti, F and van der Linden, A and Pochet, R and Bacić, G}, title = {In vivo morphological changes in animal models of amyotrophic lateral sclerosis and Alzheimer's-like disease: MRI approach.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {292}, number = {12}, pages = {1882-1892}, doi = {10.1002/ar.20995}, pmid = {19943341}, issn = {1932-8494}, mesh = {Alzheimer Disease/metabolism/*pathology/physiopathology ; Amyotrophic Lateral Sclerosis/metabolism/*pathology/physiopathology ; Animals ; Blood-Brain Barrier/metabolism/pathology/physiopathology ; Brain/metabolism/*pathology/physiopathology ; Chemotaxis, Leukocyte/immunology ; Disease Models, Animal ; Encephalitis/metabolism/pathology/physiopathology ; Gliosis/metabolism/pathology/physiopathology ; Humans ; Magnetic Resonance Imaging/*methods ; Nerve Degeneration/metabolism/pathology/physiopathology ; Rats ; }, abstract = {Magnetic resonance imaging (MRI) is the only noninvasive technique that provides structural information on both cell loss and metabolic changes. After reviewing all the results obtained in clinical studies, reliable biomarkers in neurological diseases are still lacking. Diffusional MRI, MR spectroscopy, and the assessment of regional atrophy are promising approaches, but they cannot be simultaneously used on a single patient. Thus, for further research progress, reliable animal models are needed. To this aim, we have used the clinical MRI to assess neurodegenerative processes in the hSOD-1(G93A) ALS rat model and in the trimethyltin (TMT)-treated model of Alzheimer's-like disease. T2-weighted (T2W) hyperintensive neurodegenerative foci were found in the brainstem of the ALS rat with apparent lateral ventricle dilation (T1W-hypointensity vs. T2W-hyperintensity). Degenerative processes in these areas were also confirmed by confocal images of GFAP-positive astrogliosis. MRI after i.v.i. of magnetic anti-CD4 antibodies indicated an accumulation of inflammatory cells near dilated ventricles. TMT-treated rats also revealed the dilation of lateral ventricles. Expected deterioration in the hippocampus was not observed by clinical MRI, but immunocytochemistry could reveal significant redistribution of macro- and microglia in this structure. In both models, Gd-DTPA contrast revealed a compromised blood brain barrier that may serve as the passage for inflammatory immune cells in the vicinity of dilated lateral ventricles. Moreover, in both models the midbrain region of the dorsal hippocampus was the target of BBB compromise, thus revealing a potentially vulnerable point that can be the primary target of neurodegeneration in the central nervous system.}, }
@article {pmid19938902, year = {2009}, author = {Lanka, V and Wieland, S and Barber, J and Cudkowicz, M}, title = {Arimoclomol: a potential therapy under development for ALS.}, journal = {Expert opinion on investigational drugs}, volume = {18}, number = {12}, pages = {1907-1918}, doi = {10.1517/13543780903357486}, pmid = {19938902}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Cytoprotection/drug effects ; Drug Approval ; Drug Evaluation, Preclinical ; Heat-Shock Proteins/biosynthesis/drug effects ; Humans ; Hydroxylamines/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; }, abstract = {Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.}, }
@article {pmid19938690, year = {2009}, author = {Ikeda, K}, title = {[FTLD-U and Pick disease without Pick bodies--a clinical and pathological review].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1328-1336}, pmid = {19938690}, issn = {1881-6096}, mesh = {Brain/pathology ; Frontotemporal Dementia/*pathology ; Humans ; Pick Disease of the Brain/*pathology ; }, abstract = {Circumscribed cerebral lobar atrophy is observed in Pick disease with or without Pick bodies (conventional Pick disease) show circumscribed cerebral lobar atrophy. Pick disease with Pick bodies was initially termed as 3-repeat tauopathy to distinguish this disease from the conventional Pick disease. Case of Pick disease without Pick bodies formed a heterogeneous group. In all cases of Pick disease without Pick bodies, except for rare cases without any type of inclusions [dementia lacking distinctive histology (DLDH)] the presence of ubiquitinated inclusions was confirmed, which were broadly termed as frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). In Japan, the number of cases of Pick disease with Pick bodies and those with FTLD-U appears to be almost the same. The patterns of cerebral and subcortical nuclear degeneration are quite simillar in cases of Pick disease with Pick bodies and in cases of Pick disease with FLTD-U. Investigation of the motor neuron system in FTLD-U cases revealed that approximately two-third patients had mild to severe degeneration in the upper motor neural system (pyramidal tract). These cases of FTLD-U with motor neuron involvement formed an important group, namely, FTLD with motor neuron disease (FTLD-MND). Amyotrophic lateral sclerosis with dementia (ALS-D) in which degeneration of the lower motor neurons was generally prominent in comparison to the mild pyramidal tract degeneration in the case of FTLD-MND, is also a type of FTLD-MND. Thus, conventional Pick disease was further classified into Pick disease, FTLD-MND, FTLD-U (in a narrow sense), and DLDH.}, }
@article {pmid19938688, year = {2009}, author = {Yoshida, M}, title = {[Neuropathology of frontotemporal lobar degeneration with ubiquitinated inclusions].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1308-1318}, pmid = {19938688}, issn = {1881-6096}, mesh = {Aged ; DNA-Binding Proteins/*analysis ; Female ; Frontotemporal Lobar Degeneration/*pathology ; Humans ; Inclusion Bodies/*chemistry ; Male ; Middle Aged ; Ubiquitin/*analysis ; }, abstract = {Frontotemporal lobar degeneration (FTLD) has two pathological types: tau-positive and tau-negative. The most common tau-negative type is FTLD with ubiquitinated inclusions, which are composed of TAR DNA-binding protein-43 (TDP-43) (FTLD-TDP). FTLD-TDP can be subdivided into at least three main types based on the histological patterns of TDP-43-positive neuronal cytoplasmic inclusions (NCI), dystrophic neurites (DN), and neuronal intranuclear inclusions (NII). Type 1 is characterized by the predominance of long, thick DN in the cortices with numerous NCI in the hippocampus, amygdala, and basal ganglia, accompanied by the degeneration of the pyramidal tract in the spinal cord. Type 2 is characterized by numerous NCI in the cortices, associated with the involvement of lower motor neurons. TDP-43-positive skein-like inclusions and round inclusions identical to those observed in amyotrophic lateral sclerosis (ALS) patients are also seen in the lower motor neurons in type 2. Type 3 is characterized by both NCI and DN with variable NII. Lower motor neuron involvement is usually less prominent in types 1 and 3 than in type 2. These findings suggest that FTLD-TDP and ALS are at two ends of the same disease spectrum, i. e., TDP-43 proteinopathy.}, }
@article {pmid19938687, year = {2009}, author = {Ishihara, T and Yokoseki, A and Nishizawa, M and Takahashi, H and Onodera, O}, title = {[The implications of TDP-43 mutations in pathogenesis of amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1301-1307}, pmid = {19938687}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; DNA-Binding Proteins/*genetics ; Humans ; Mutation ; }, abstract = {The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 kDa (TDP-43) -positive-cytoplasmic inclusions have been found in the glia and neurons of ALS patients. TDP-43 -positive inclusions have been reported in several neurodegenerative disorders other than ALS. Therefore it is not clear whether TDP-43 plays a primary role in the pathogenesis of ALS. The discovery of TDP-43 mutations in ALS patients indicates that TDP-43 plays a pivotal role in the pathogenesis of ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP-43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 -positive inclusions and Bunina bodies, are identical to those in sporadic ALS; these findings indicate that the study of ALS-10 may lead to a better understanding of sporadic ALS. Most of the mutations are located in the C-terminus of TDP-43, which may function as a binding domain for heterogeneous nuclear ribonucleoprotein. Biochemical analyses of TDP-43 in sporadic ALS patients indicate that the TDP-43 is truncated, and the C-terminus is phosphorylated forming insoluble inclusions in the neurons and glia. In certain ALS-10 cases, missense mutated TDP-43s tend to be truncated and form inclusions. The cytotoxicity of these mutated TDP-43s has also been reported; however, these results are still controversial. Therefore, further analysis is required to elucidate the molecular mechanism underlying the development of ALS-10.}, }
@article {pmid19938686, year = {2009}, author = {Nonaka, T and Arai, T and Hasegawa, M}, title = {[The molecular mechanisms of intracellular TDP-43 aggregates].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1292-1300}, pmid = {19938686}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Brain/*metabolism ; Cell Death ; Cells, Cultured ; DNA-Binding Proteins/*metabolism ; Frontotemporal Lobar Degeneration/*metabolism ; Humans ; TDP-43 Proteinopathies/metabolism ; }, abstract = {TAR DNA binding protein of 43 kDa (TDP-43) was identified as a major component of the ubiquitin-positive inclusions found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To investigate the molecular mechanisms underlying the formation of intracellular aggregates of TDP-43, we have established cellular models of intracellular TDP-43 aggregates similar to the pathological inclusions found in the brain FTLD and ALS patients. Deletion of the sequences near the nuclear localization signal resulted in cytoplasmic localization of TDP-43, whereas deletion mutants that lack the region around the RNA recognition motif localized in the nuclei, forming unique dot-like structures. Proteasome inhibition caused these structures to assemble into round aggregates that are reactive with anti-phosphorylated TDP-43 and anti-ubiquitin antibodies. Green fluorescent protein (GFP)-tagged N-terminal or C-terminal fragments of TDP-43 also promoted the formation of the abnormal intracellular inclusions. Co-expression of DsRed-tagged full-length TDP-43 with GFP-tagged C-terminal fragments of TDP-43 causes the formation of cytoplasmic inclusions that are positive for both GFP and DsRed. Cells with GFP and DsRed positive inclusions were nagative for normal nuclear staining for endogenous TDP-43. These results suggest that GFP-tagged C-terminal fragments of TDP-43 are bound not only to transfected DsRed-full-length TDP-43 but also to endogenous TDP-43. Endogenous TDP-43 may also be included in the cytoplasmic aggregates of TDP-43 C-terminal fragments, which results in the failure of its nuclear localization and therefore inhibits its function. We propose that the generation and aggregation of phosphorylated C-terminal fragments of TDP-43 play a primary role in the formation of inclusions, and the resultant loss of normal TDP-43 localization leads to neuronal degeneration in TDP-43 proteinopathy.}, }
@article {pmid19938683, year = {2009}, author = {Oba, H and Tokumaru, A}, title = {[Magnetic resonance imaging for frontotemporal lobar degeneration].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1269-1273}, pmid = {19938683}, issn = {1881-6096}, mesh = {Frontotemporal Lobar Degeneration/*diagnosis ; Humans ; *Magnetic Resonance Imaging ; Pick Disease of the Brain/diagnosis ; Primary Progressive Nonfluent Aphasia/diagnosis ; Tauopathies/diagnosis ; }, abstract = {Frontotemporal lobar degeneration (FTLD) has been clinically categorized into 3 subtypes: frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia. The histological subtypes of FTLD are Pick disease, corticobasal degeneration, dementia with grain, dementia with ubiquitin-positive tau-negative inclusions, and amyotrophic lateral sclerosis with dementia. In this paper, I briefly describe the magnetic resonance imaging (MRI) findings in Pick disease, progressive nonfluent aphasia, semantic dementia, and dementia with grain. In Pick disease, so-called knife-blade atrophy is seen in the frontal and temporal lobes at a relatively early stage of the disease. In progressive nonfluent aphasia atrophy is seen in the upper part of the left frontal lobe. Marked atrophy in the left temporal pole is observed in patients with semantic dementia, and asymmetrical atrophy around the ambient gyri is detected in patients who have dementia with grains. Although such focal atrophy can be observed on routine MRI, it is more easily detected on voxel-based morphometry and voxel-based specific regional analysis system for Alzheimer disease (VSRAD).}, }
@article {pmid19938682, year = {2009}, author = {Sato, K and Aoki, S and Iwata, NK and Abe, O and Mori, H and Ohtomo, K}, title = {[Magnetic resonance imaging in patients of amyotrophic lateral sclerosis with and without dementia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1259-1268}, pmid = {19938682}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Brain/pathology ; Diffusion Tensor Imaging ; Humans ; *Magnetic Resonance Imaging/methods ; }, abstract = {Classic magnetic resonance imaging (MRI) findings in patients with amyotrophic lateral sclerosis (ALS) are subtle, but some findings have been reported such as signal changes in the primary motor cortex and the corticospinal tract (CST). Only a few reports have discussed MRI findings of ALS with dementia (ALS-D), in which frontotemporal atrophy and hyperintensity in subcortical white matter of bilateral temporal tips have been reported. Recent development of diffusion tensor imaging (DTI) techniques allows us to extract specific white matter tracts and to analyze them quantitatively, i.e. we can visualize the CST and can also measure its integrity using DTI parameters such as fractional anisotropy (FA) or apparent diffusion coefficient (ADC). In patients with ALS, general decrease in FA and increase in ADC in the CST have been reported. In patients with ALS-D, several authors detected decrease in fractional anisotropy in the corpus callosum, the thalamus, frontal/parietal/temporal, the cingulate gyrus, and the uncinate fasciculus in addition to the CST. Voxel based morphometry or statistical analysis of imaging are the newly developed methods which enable to make objective and reliable imaging analysis based on automated procedure using standardized database. We also presented several researches using these techniques. In this article, we reviewed classic imaging findings and recent development of MRI including DTI and statistical imaging analysis in patients with ALS/ALS-D.}, }
@article {pmid19938679, year = {2009}, author = {Ichikawa, H and Kawamura, M}, title = {[Symptoms of frontotemporal dementia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {11}, pages = {1227-1235}, pmid = {19938679}, issn = {1881-6096}, mesh = {Frontotemporal Dementia/*psychology ; Humans ; Male ; Middle Aged ; }, abstract = {Frontotemporal dementia (FTD)-a common clinical manifestation of frontotemporal lobar degeneration (FTLD)--is characterized by alterations in personality and social conduct. Its symptoms include inertia, loss of volition, social disinhibition, and distractibility, with relative preservation of memory and visuospatial function. We present the typical case of patient with typical clinical symptoms including "going my way" behavior, inactivity, lack of awareness of illness, stereotypic behavior, perseveration, and environmental dependency syndrome. These clinical symptoms can be interpreted on the basis of extent of damage to the frontal lobes and the interaction between the frontal lobes and other neural systems such as the posterior association cortices, basal ganglia or limbic systems. We also address several complex clinical issues, including the relationship between clinical manifestations and pathological findings, underestimation of FTD in patients with amyotrophic lateral sclerosis (ALS) and/or motor neuron disease (MND), and impairment in a single cognitive domain such as isolated agraphia in ALS/MND and FTD. To address these problems, it is essential to observe the clinical symptoms in patients with FTD and ALS/MND in detail and to compare clinical characteristics with pathological findings. It is also critical to develop clinical tests that minimize the impact of speech and motor dysfunction on performance, particularly on the basis of a longitudinal analysis.}, }
@article {pmid19930099, year = {2009}, author = {Sørensen, HT and Lash, TL}, title = {Statins and amyotrophic lateral sclerosis--the level of evidence for an association.}, journal = {Journal of internal medicine}, volume = {266}, number = {6}, pages = {520-526}, doi = {10.1111/j.1365-2796.2009.02173.x}, pmid = {19930099}, issn = {1365-2796}, mesh = {Adverse Drug Reaction Reporting Systems ; Aged ; Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Anticholesteremic Agents/*adverse effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects ; Male ; Randomized Controlled Trials as Topic ; Risk Factors ; }, abstract = {Myopathy is a known side effect of statins, but neurotoxicity is not. Two studies reported that statins and amyotrophic lateral sclerosis (ALS) appear together more than expected amongst adverse events in overlapping surveillance databases. A pooled analysis of clinical trials, many with short follow-up, showed no higher rate of ALS in the statins arms. In older age groups, statin use increased from approximately 5% in 1991 to approximately 40% in 1998 and then remained constant. There was no similar increase in ALS incidence. The initial signals of a strong association from drug surveillance systems should now be discounted, but not disregarded.}, }
@article {pmid19922118, year = {2009}, author = {Chiò, A and Logroscino, G and Hardiman, O and Swingler, R and Mitchell, D and Beghi, E and Traynor, BG and , }, title = {Prognostic factors in ALS: A critical review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {310-323}, pmid = {19922118}, issn = {1471-180X}, support = {ZIA AG000933-05/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology/psychology ; Biomarkers/metabolism ; *Clinical Trials as Topic/classification ; Disease Progression ; Humans ; Nutritional Status ; Prognosis ; Prospective Studies ; Respiration ; Retrospective Studies ; Severity of Illness Index ; Survival Rate ; }, abstract = {We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10-20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.}, }
@article {pmid19922117, year = {2009}, author = {Sutedja, NA and Veldink, JH and Fischer, K and Kromhout, H and Heederik, D and Huisman, MH and Wokke, JH and van den Berg, LH}, title = {Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {302-309}, doi = {10.3109/17482960802455416}, pmid = {19922117}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Databases, Factual ; Humans ; Metals/*adverse effects ; Occupational Exposure/*adverse effects ; Pesticides/*adverse effects ; Reproducibility of Results ; Review Literature as Topic ; Risk Assessment ; Risk Factors ; Solvents/*adverse effects ; }, abstract = {Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort studies investigating the associations between sporadic ALS and exposure to chemical agents or metals. Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38 studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled the validity criteria. In two independent studies meeting the validity criteria, a significant association with increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies are needed to provide a definitive answer about exogenous factors of ALS.}, }
@article {pmid19922116, year = {2009}, author = {Sutedja, NA and Fischer, K and Veldink, JH and van der Heijden, GJ and Kromhout, H and Heederik, D and Huisman, MH and Wokke, JJ and van den Berg, LH}, title = {What we truly know about occupation as a risk factor for ALS: a critical and systematic review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {295-301}, doi = {10.3109/17482960802430799}, pmid = {19922116}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Databases, Factual ; Humans ; Occupational Exposure/*adverse effects ; *Occupations ; Review Literature as Topic ; *Risk Assessment ; Risk Factors ; United States ; }, abstract = {Occupational and environmental exposures may contribute to the risk of developing sporadic amyotrophic lateral sclerosis (ALS). To summarize the available evidence, a systematic review of the literature on occupation as a potential determinant of ALS was performed according to the MOOSE guidelines. From MEDLINE, EMBASE, CINAHL, and Cochrane databases, selected studies were methodologically appraised according to Armon's classification system for ALS risk factor studies. Each occupation studied was reclassified according to the International Standard Classification of Occupations (ISCO-88). The vote-counting method was applied to summarize the data. Of 3773 potentially relevant studies, 51 were initially included. Of these, 12 studies provided risk estimates for individual occupations--one case-control, two register-based case-control, and nine register-based cohort studies. All studies fell into Armon's level of evidence class IV, indicating methodological limitations. Due to the heterogeneity of study methodology, data could not be pooled. The vote-counting method revealed several candidate occupations: veterinarians and other health workers, athletes, hairdressers, power-production plant, electrical and military workers. However, well designed studies with standardized assessment of occupation are needed to provide a more definitive answer about exogenous risk factors of ALS.}, }
@article {pmid19922112, year = {2009}, author = {Lulé, D and Ludolph, AC and Kassubek, J}, title = {MRI-based functional neuroimaging in ALS: an update.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {258-268}, doi = {10.3109/17482960802353504}, pmid = {19922112}, issn = {1471-180X}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Brain/anatomy &amp; histology/*pathology/physiology/*physiopathology ; Diagnostic Imaging ; Humans ; Image Processing, Computer-Assisted/*methods ; Magnetic Resonance Imaging/*methods ; Neurons/metabolism ; Neurosciences ; Oxygen/blood ; }, abstract = {With non-invasive functional imaging techniques, neuroscience has reached a new era of connecting anatomy and function. Although other techniques bear the advantage of either higher temporal or spatial resolution, functional magnetic resonance imaging (fMRI) is the most widely used non-invasive brain imaging technique. fMRI provides an acceptable balance between low patient load and high information capacity with good spatial resolution, making it ideal for clinical research in patients with physical restrictions like those with ALS. Most fMRI studies have provided evidence of a spatial shift of function in motor and extramotor areas in ALS patients. Furthermore, MRI-based functional imaging has supported the clinical findings of frontal cortical involvement not only in patients with ALS/dementia complex but also in patients with ALS and sub-clinical cognitive impairment. Functional MRI will identify the preserved but non-executable functions in ALS patients in the end stage and will set the direction for a new way of thinking on the functional capacities of these patients which will have a major impact on our way of thinking about end-of-life decisions.}, }
@article {pmid19917993, year = {2009}, author = {Armon, C}, title = {Smoking may be considered an established risk factor for sporadic ALS.}, journal = {Neurology}, volume = {73}, number = {20}, pages = {1693-1698}, pmid = {19917993}, issn = {1526-632X}, support = {N01-NS-2-2349/NS/NINDS NIH HHS/United States ; R01 NS 048125/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Evidence-Based Medicine ; Humans ; Risk Factors ; Smoking/*adverse effects ; Time Factors ; }, abstract = {OBJECTIVES: A 2003 evidence-based review of exogenous risk factors for sporadic amyotrophic lateral sclerosis (ALS) identified smoking as the only risk factor that attained "probable" (more likely than not) status, based on 2 class II studies. The purpose of the current, evidence-based, update was to see if the conclusion of the previous review needed to be modified, based on studies published since.<br><br>METHODS: A Medline literature search was conducted for the period between 2003 and April 2009 using the search terms smoking and (ALS or "amyotrophic lateral sclerosis" or MND or "motor neuron disease"). The references of primary articles and reviews were checked to assure completeness of the search. Primary articles published since the previous review were classified as before.<br><br>RESULTS: Twenty-eight titles were identified, but only 7 articles met inclusion criteria. Of these, 1 provided class II evidence, and 1 class III evidence: both showed increased risk of ALS with smoking. The class II study showed a dose-response effect, and risk decreasing with number of years since quitting smoking. Five articles provided class IV or V evidence, which may not be relied upon to draw conclusions.<br><br>CONCLUSIONS: Smoking may be considered an established risk factor for sporadic amyotrophic lateral sclerosis (ALS) (level A rating; 3 class II studies, 1 class III study). Evidence-based analysis of epidemiologic data shows concordance among results of better-designed studies linking smoking to ALS, and lets those results drive the conclusions.}, }
@article {pmid19914407, year = {2010}, author = {Perry, JJ and Shin, DS and Getzoff, ED and Tainer, JA}, title = {The structural biochemistry of the superoxide dismutases.}, journal = {Biochimica et biophysica acta}, volume = {1804}, number = {2}, pages = {245-262}, pmid = {19914407}, issn = {0006-3002}, support = {GM39345/GM/NIGMS NIH HHS/United States ; R01 GM039345/GM/NIGMS NIH HHS/United States ; R01 GM037684/GM/NIGMS NIH HHS/United States ; R01 GM039345-15/GM/NIGMS NIH HHS/United States ; R01 GM037684-21/GM/NIGMS NIH HHS/United States ; GM37684/GM/NIGMS NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Humans ; Molecular Sequence Data ; Sequence Homology, Amino Acid ; Superoxide Dismutase/*chemistry/metabolism ; }, abstract = {The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate. SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu,ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu,ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.}, }
@article {pmid19906448, year = {2010}, author = {Szaro, BG and Strong, MJ}, title = {Post-transcriptional control of neurofilaments: New roles in development, regeneration and neurodegenerative disease.}, journal = {Trends in neurosciences}, volume = {33}, number = {1}, pages = {27-37}, doi = {10.1016/j.tins.2009.10.002}, pmid = {19906448}, issn = {1878-108X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Gene Expression ; Gene Expression Regulation ; Humans ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/genetics/*metabolism/*physiopathology ; Neurofilament Proteins/*physiology ; RNA Processing, Post-Transcriptional/*physiology ; RNA, Messenger/genetics ; }, abstract = {Neurofilament (NF) protein expression is coupled to axon development and the maintenance of neuronal homeostasis. Here, we present evidence that this tight regulation depends critically on post-transcriptionally regulated changes in NF mRNA transport, translation and stability. Recent studies have shown that post-transcriptional mechanisms modulate increases in NF gene transcription during axon regeneration to yield the final pattern of NF protein expression. Other recent work has found that post-transcriptional control of NFs shares elements with that of other axonal proteins and that its dysregulation contributes to amyotrophic lateral sclerosis. Such studies herald a novel approach to understanding how neurons coordinate the expressions of functionally related proteins and provide new insights into how the dysregulation of this control can lead to disease.}, }
@article {pmid19896414, year = {2009}, author = {Dresselhaus, T and Márton, ML}, title = {Micropylar pollen tube guidance and burst: adapted from defense mechanisms?.}, journal = {Current opinion in plant biology}, volume = {12}, number = {6}, pages = {773-780}, doi = {10.1016/j.pbi.2009.09.015}, pmid = {19896414}, issn = {1879-0356}, mesh = {Biological Evolution ; Defensins/metabolism ; *Fertilization ; Genes, Plant ; *Plant Development ; Plants/genetics ; Pollen Tube/*growth &amp; development ; *Signal Transduction ; }, abstract = {After the first description of fertilization in flowering plants some 125 years ago (Strasburger E: Neue-Untersuchungen über den Befruchtungsvorgang bei den Phanerogamen als Grundlage für eine Theorie der Zeugung. Gustav Fischer; 1884), we are finally beginning to understand the various molecular mechanisms leading to sperm delivery and discharge inside the hidden micropylar region of the female gametophyte (embryo sac). The last phase of pollen tube guidance culminating in tube burst and explosive release of tube contents requires extensive crosstalk between both male and female gametophytes. The first molecules identified that play key roles in these processes represent highly polymorphic proteins, similar to major components of the plant innate immune system. Here we summarize recent advances and briefly discuss the underlying molecular mechanisms also in respect to prezygotic barriers of reproductive isolation.}, }
@article {pmid19891121, year = {2009}, author = {Vinceti, M and Maraldi, T and Bergomi, M and Malagoli, C}, title = {Risk of chronic low-dose selenium overexposure in humans: insights from epidemiology and biochemistry.}, journal = {Reviews on environmental health}, volume = {24}, number = {3}, pages = {231-248}, doi = {10.1515/reveh.2009.24.3.231}, pmid = {19891121}, issn = {0048-7554}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; Diabetes Mellitus/chemically induced/epidemiology ; Dose-Response Relationship, Drug ; *Environmental Exposure ; Humans ; Neoplasms/chemically induced/epidemiology ; Selenium/*toxicity ; }, abstract = {The latest developments of epidemiologic and biochemical research suggest that current upper limits of intake for dietary selenium and for overall selenium exposure may be inadequate to protect human health. In particular, recent experimental and observational prospective studies indicate a diabetogenic effect of selenium at unexpectedly low levels of intake. Experimental evidence from laboratory studies and veterinary medicine appears to confirm previous epidemiologic observations that selenium overexposure is associated with an increased risk of amyotrophic lateral sclerosis, and a recent large trial indicated no beneficial effect in preventing prostate cancer. Moreover, the pro-oxidant properties of selenium species and the observation that the selenium-containing enzymes glutathione peroxidases are induced by oxidative stress imply that the increase in enzymatic activity induced by this metalloid may represent at least in part a compensatory response. Taken together, the data indicate that the upper safe limit of organic and inorganic selenium intake in humans may be lower than has been thought and that low-dose chronic overexposure to selenium may be considerably more widespread than supposed.}, }
@article {pmid19882358, year = {2009}, author = {Chadi, G and Maximino, JR and de Oliveira, GP}, title = {The importance of molecular histology to study glial influence on neurodegenerative disorders. Focus on recent developed single cell laser microdissection.}, journal = {Journal of molecular histology}, volume = {40}, number = {4}, pages = {241-250}, pmid = {19882358}, issn = {1567-2387}, mesh = {Alzheimer Disease/*metabolism/pathology ; Animals ; Brain Ischemia/*metabolism/pathology ; Humans ; Immunohistochemistry/methods ; In Situ Hybridization/methods ; Lasers ; Microdissection/*methods ; Neuroglia/*metabolism/pathology ; Neurons/metabolism/pathology ; Parkinson Disease/*metabolism/pathology ; Rats ; }, abstract = {Neuron-glia interaction is involved in physiological function of neurons, however recent evidences have suggested glial cells as participants in neurotoxic and neurotrophic mechanisms of neurodegenerative/neuroregenerative processes. Histological techniques employing immunolabeling, historadiography and in situ hybridization have been useful to localize at cell levels molecules in normal and pathological situations. The intercellular accomplishment leading to neuronal injury in central nervous system disorders implies the performance of quantitative assays to better interpret the role of related molecules or signal pathways, however one limitation employing the whole tissue is the loss of cellular resolution. The laser capture microdissection was developed recently and allows the selection of specific cell types from their original environment after freezing and sectioning the tissue sampling, leading to the quantification of gene expression in individual cells, thus providing a unique opportunity to get new informations on cell signaling related to neurodegeneration. Here we reviewed the role of glial cell signaling on neurodegenerative disorders like ischemia, Parkinson and Alzheimer diseases, and also amyotrophic lateral sclerosis and what has been published with regards to single cell laser capture microdissection technique in the molecular biology investigation on these issues.}, }
@article {pmid19879804, year = {2010}, author = {Appel, SH and Beers, DR and Henkel, JS}, title = {T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening?.}, journal = {Trends in immunology}, volume = {31}, number = {1}, pages = {7-17}, pmid = {19879804}, issn = {1471-4981}, support = {R01 NS048950/NS/NINDS NIH HHS/United States ; NS048950/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Cell Communication ; Mice ; Microglia/cytology/immunology/pathology ; Parkinson Disease/*immunology/pathology ; T-Lymphocytes/*immunology/pathology ; }, abstract = {Neuroinflammation is a pathological hallmark in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia and infiltrating T cells at sites of neuronal injury. In PD and ALS, neurons do not die alone; neuronal injury is non-cell-autonomous and depends on a well-orchestrated dialogue in which neuronally secreted misfolded proteins activate microglia and initiate a self-propagating cycle of neurotoxicity. Diverse populations and phenotypes of CD4(+) T cells crosstalk with microglia, and depending on their activation status, influence this dialogue and promote neuroprotection or neurotoxicity. A greater understanding of the T cell population that mediates these effects, as well as the molecular signals involved should provide targets for neuroprotective immunomodulation to treat these devastating neurodegenerative diseases.}, }
@article {pmid19860665, year = {2009}, author = {Stetler, RA and Gao, Y and Signore, AP and Cao, G and Chen, J}, title = {HSP27: mechanisms of cellular protection against neuronal injury.}, journal = {Current molecular medicine}, volume = {9}, number = {7}, pages = {863-872}, pmid = {19860665}, issn = {1875-5666}, support = {R01 NS036736-11/NS/NINDS NIH HHS/United States ; R01 NS056118/NS/NINDS NIH HHS/United States ; R01 NS045048-05/NS/NINDS NIH HHS/United States ; R01 NS043802/NS/NINDS NIH HHS/United States ; R01 NS043802-05/NS/NINDS NIH HHS/United States ; NS36736/NS/NINDS NIH HHS/United States ; NS43802/NS/NINDS NIH HHS/United States ; R01 NS044178-05/NS/NINDS NIH HHS/United States ; R01 NS056118-03/NS/NINDS NIH HHS/United States ; NS45048/NS/NINDS NIH HHS/United States ; NS44178/NS/NINDS NIH HHS/United States ; R01 NS036736/NS/NINDS NIH HHS/United States ; R01 NS045048/NS/NINDS NIH HHS/United States ; NS56118/NS/NINDS NIH HHS/United States ; R01 NS044178/NS/NINDS NIH HHS/United States ; }, mesh = {Cell Death/physiology ; Gene Expression Regulation ; HSP27 Heat-Shock Proteins/genetics/*metabolism ; Heat-Shock Response/physiology ; Humans ; Nervous System Diseases/metabolism/pathology/physiopathology ; Neurons/metabolism/*pathology ; Neuroprotective Agents/*metabolism ; Protein Folding ; Protein Processing, Post-Translational ; Signal Transduction/physiology ; }, abstract = {The heat shock protein (HSP) family has long been associated with a generalized cellular stress response, particularly in terms of recognizing and chaperoning misfolded proteins. While HSPs in general appear to be protective, HSP27 has recently emerged as a particularly potent neuroprotectant in a number of diverse neurological disorders, ranging from ALS to stroke. Although its robust protective effect on a number of insults has been recognized, the mechanisms and regulation of HSP27's protective actions are still undergoing intense investigation. On the basis of recent studies, HSP27 appears to have a dynamic and diverse range of function in cellular survival. This review provides a forum to compare and contrast recent literature exploring the protective mechanism and regulation of HSP27, focusing on neurological disorders in particular, as they represent a range from protein aggregate-associated diseases to acute stress.}, }
@article {pmid19860657, year = {2009}, author = {Hester, ME and Foust, KD and Kaspar, RW and Kaspar, BK}, title = {AAV as a gene transfer vector for the treatment of neurological disorders: novel treatment thoughts for ALS.}, journal = {Current gene therapy}, volume = {9}, number = {5}, pages = {428-433}, doi = {10.2174/156652309789753383}, pmid = {19860657}, issn = {1875-5631}, support = {P20 RR015576/RR/NCRR NIH HHS/United States ; R01 NS064492/NS/NINDS NIH HHS/United States ; UL1 RR025755/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Blood-Brain Barrier ; Dependovirus/*genetics ; Gene Transfer Techniques ; *Genetic Therapy ; *Genetic Vectors ; Humans ; }, abstract = {Therapeutic delivery to the central nervous system has challenged scientists and clinicians due to the difficulty in delivering molecules and genes in an efficient manner across the blood brain barrier (BBB). This has particularly hampered efforts to deliver therapeutics to widely dispersed neurons that perish in diseases such as Amyotrophic Lateral Sclerosis (ALS), a disease affecting motor neurons throughout the brainstem and the entire spinal cord. Gene therapy has offered several potential routes to overcome the difficulties in delivering therapeutics to the brain and spinal cord. Adeno-associated viral vectors (AAV) have taken center stage for gene delivery to the central nervous system, given their ability to express genes in post mitotic cells for long periods with minimal to no toxicity. This review will focus on recent approaches to treat motor neuron disease, in particular ALS using AAV vectors.}, }
@article {pmid19858353, year = {2009}, author = {Aboussouan, LS}, title = {Mechanisms of exercise limitation and pulmonary rehabilitation for patients with neuromuscular disease.}, journal = {Chronic respiratory disease}, volume = {6}, number = {4}, pages = {231-249}, doi = {10.1177/1479972309345927}, pmid = {19858353}, issn = {1479-9731}, mesh = {Exercise Therapy/*methods ; Exercise Tolerance/*physiology ; Humans ; Lung Diseases/etiology/physiopathology/*rehabilitation ; Neuromuscular Diseases/complications/physiopathology/*rehabilitation ; Quality of Life ; Treatment Outcome ; }, abstract = {Indications for exercise and pulmonary rehabilitation extend to neuromuscular diseases tough these conditions pose particular challenges given the associated skeletal muscle impairment and respiratory muscle dysfunction. These challenges are compounded by the variety of exercise prescriptions (aerobic, muscle strengthening, and respiratory muscle training) and the variety of neuromuscular disorders (muscular, motor neuron, motor nerve root, and neuromuscular transmission disorders). Studies support a level II evidence of effectiveness (i.e., likely to be effective) for a combination of aerobic exercise and strengthening exercises in muscular disorders, and for strengthening exercises in amyotrophic lateral sclerosis. The potential deleterious effects of work overload in the dystrophinopathies have not been confirmed in Becker muscular dystrophy. Adjunctive pharmacologic interventions (e.g., theophylline, steroids, PDE5 inhibitors, creatine), training recommendations (e.g., interval or lower intensity training) and supportive techniques (e.g., noninvasive ventilation, neuromuscular electrical stimulation, and diaphragm pacing) may result in more effective training but require more study before formal recommendations can be made. The exercise prescription should include avoidance of inspiratory muscle training in hypercapnia or low vital capacity, and should match the desired outcome (e.g., extremity training for task-specific performance, exercise training to enhance exercise performance, respiratory muscle training where respiratory muscle involvement contributes to the impairment).}, }
@article {pmid19858352, year = {2009}, author = {Frost, J and Massagli, M}, title = {PatientsLikeMe the case for a data-centered patient community and how ALS patients use the community to inform treatment decisions and manage pulmonary health.}, journal = {Chronic respiratory disease}, volume = {6}, number = {4}, pages = {225-229}, doi = {10.1177/1479972309348655}, pmid = {19858352}, issn = {1479-9731}, mesh = {*Activities of Daily Living ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Community Networks/*statistics &amp; numerical data ; *Decision Making, Organizational ; Humans ; Lung Diseases/etiology/*prevention &amp; control ; Outcome Assessment, Health Care/*methods ; Patient-Centered Care/*organization &amp; administration ; Quality of Life ; }, abstract = {What happens when patients go online to not only discuss health and daily living but to share detailed health data? PatientsLikeMe is an online platform where patients with life-altering conditions share structured information about symptoms, treatments, and outcomes, view individual and aggregated reports of these data, and discuss health and garner support on forums and through private messages. In this case study, we describe the components of this platform and how people with Amyotrophic lateral sclerosis have used the site to manage and improve pulmonary health. A qualitative analysis of forum content containing preset terms reveals patterns in use. As in other online communities, members of PatientsLikeMe offer one another support based on their own personal experience and advise each other on both medical issues and how to improve day-to-day life. Unique to this patient platform, members tailor questions and consults by referencing concrete data displayed for each patient member. PatientsLikeMe adds data into patient investigations on how to improve daily life and long term health outcomes.}, }
@article {pmid19853657, year = {2010}, author = {Moreira, PI and Zhu, X and Wang, X and Lee, HG and Nunomura, A and Petersen, RB and Perry, G and Smith, MA}, title = {Mitochondria: a therapeutic target in neurodegeneration.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {1}, pages = {212-220}, pmid = {19853657}, issn = {0006-3002}, support = {R01 AG026151/AG/NIA NIH HHS/United States ; R01 AG031852-02/AG/NIA NIH HHS/United States ; R01 AG031852/AG/NIA NIH HHS/United States ; AG031852/AG/NIA NIH HHS/United States ; AG026151/AG/NIA NIH HHS/United States ; R01 AG026151-03/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/metabolism ; Animals ; Antioxidants/metabolism/therapeutic use ; Humans ; Mitochondria/*drug effects/*metabolism ; Mitochondrial Proteins/metabolism ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/metabolism ; Oxidative Stress ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria.}, }
@article {pmid19840884, year = {2010}, author = {Strong, MJ}, title = {The evidence for altered RNA metabolism in amyotrophic lateral sclerosis (ALS).}, journal = {Journal of the neurological sciences}, volume = {288}, number = {1-2}, pages = {1-12}, doi = {10.1016/j.jns.2009.09.029}, pmid = {19840884}, issn = {1878-5883}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Biological Transport, Active ; Humans ; Protein Biosynthesis ; RNA/*genetics/*metabolism ; RNA, Messenger/biosynthesis/genetics ; Transcription, Genetic ; }, abstract = {In this review, the role of aberrant RNA metabolism in ALS is examined, including the evidence that a majority of the genetic mutations observed in familial ALS (including mutations in TDP-43, FUS/TLS, SOD1, angiogenin (ANG) and senataxin (SETX)) can impact directly on either gene transcription, pre-mRNA splicing, ribonucleoprotein complex formation, transport, RNA translation or degradation. The evidence that perturbed expression or function of RNA binding proteins is causally related to the selective suppression of the low molecular weight subunit protein (NFL) steady state mRNA levels in degenerating motor neurons in ALS is examined. The discovery that mtSOD1, TDP-43 and 14-3-3 proteins, all of which form cytosolic aggregates in ALS, can each modulate the stability of NFL mRNA, suggests that a fundamental alteration in the interaction of mRNA species with key trans-acting binding factors has occurred in ALS. These observations lead directly to the hypothesis that ALS can be viewed as a disorder of RNA metabolism, thus providing a novel pathway for the development of molecular pharmacotherapies.}, }
@article {pmid19840549, year = {2009}, author = {Yong, VW and Rivest, S}, title = {Taking advantage of the systemic immune system to cure brain diseases.}, journal = {Neuron}, volume = {64}, number = {1}, pages = {55-60}, doi = {10.1016/j.neuron.2009.09.035}, pmid = {19840549}, issn = {1097-4199}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Alzheimer Disease/immunology/physiopathology/therapy ; Animals ; Brain Diseases/*immunology/physiopathology/*therapy ; Humans ; Immunologic Factors/therapeutic use ; Inflammation/physiopathology ; Macrophages/physiology ; Models, Neurological ; Monocytes/physiology ; Neuroimmunomodulation/*physiology ; }, abstract = {The systemic immune system has the ability to modulate multiple brain functions, including autonomic responses, glial reactivity following neural injuries, and neuronal excitability. Immune stimuli also influence microglia subpopulations originating from blood progenitors, and neuroprotective and reparative capacities of blood-derived microglia were recently described in mouse models of spinal cord injury and brain disorders. Furthermore, reparative roles for various immune subsets have been recognized, such as in inducing myelin repair. Nonetheless, uncontrolled and excessive activation of immune responses can be detrimental. The development of strategies to stimulate the systemic immune system safely to protect or repair brain disorders remains a major challenge ahead, but important inroads have been made. We discuss here some of the mechanisms underlying the neuroprotective and reparative effects of the systemic immune system and the most promising immunotherapies tested in mouse models of injuries and diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis.}, }
@article {pmid19839933, year = {2009}, author = {Romero, J and Orgado, JM}, title = {Cannabinoids and neurodegenerative diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {8}, number = {6}, pages = {440-450}, doi = {10.2174/187152709789824589}, pmid = {19839933}, issn = {1996-3181}, mesh = {Animals ; Cannabinoids/metabolism/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/metabolism/*therapeutic use ; }, abstract = {Although significant advances have taken place in recent years on our understanding of the molecular mechanisms of different neurodegenerative diseases, its translation into effective therapeutic treatments has not been as successful as could be expected. There is still a dramatic lack of curative treatments for the most frequent disorders and only symptomatic relief for many others. Under this perspective, the search for novel therapeutic approaches is demanding and significant attention and efforts have been directed to studying additional neurotransmission systems including the endocannabinoid system (ECS). The neuroprotective properties of exogenous as well as endogenous cannabinoids have been known for years and the underlying molecular mechanisms have been recently unveiled. As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now recognized as derived from cannabinoid action and are known to be of common interest for many neurodegenerative processes. Thus, these characteristics make cannabinoids attractive candidates for the development of novel therapeutic strategies [1]. The present review will focus on the existing data regarding the possible usefulness of cannabinoid agents for the treatment of relevant neurological pathologies for our society such as Alzheimer's disease, multiple sclerosis, Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid19833297, year = {2009}, author = {Urdinguio, RG and Sanchez-Mut, JV and Esteller, M}, title = {Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies.}, journal = {The Lancet. Neurology}, volume = {8}, number = {11}, pages = {1056-1072}, doi = {10.1016/S1474-4422(09)70262-5}, pmid = {19833297}, issn = {1474-4465}, mesh = {Animals ; DNA/*genetics ; DNA Methylation/drug effects ; *Genetics, Medical ; Histones/genetics/metabolism ; Humans ; Nervous System Diseases/*genetics ; Nervous System Neoplasms/genetics ; Neurodegenerative Diseases/genetics ; }, abstract = {Epigenetic mechanisms such as DNA methylation and modifications to histone proteins regulate high-order DNA structure and gene expression. Aberrant epigenetic mechanisms are involved in the development of many diseases, including cancer. The neurological disorder most intensely studied with regard to epigenetic changes is Rett syndrome; patients with Rett syndrome have neurodevelopmental defects associated with mutations in MeCP2, which encodes the methyl CpG binding protein 2, that binds to methylated DNA. Other mental retardation disorders are also linked to the disruption of genes involved in epigenetic mechanisms; such disorders include alpha thalassaemia/mental retardation X-linked syndrome, Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome. Moreover, aberrant DNA methylation and histone modification profiles of discrete DNA sequences, and those at a genome-wide level, have just begun to be described for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and in other neurological disorders such as multiple sclerosis, epilepsy, and amyotrophic lateral sclerosis. In this Review, we describe epigenetic changes present in neurological diseases and discuss the therapeutic potential of epigenetic drugs, such as histone deacetylase inhibitors.}, }
@article {pmid19833209, year = {2010}, author = {Papadimitriou, D and Le Verche, V and Jacquier, A and Ikiz, B and Przedborski, S and Re, DB}, title = {Inflammation in ALS and SMA: sorting out the good from the evil.}, journal = {Neurobiology of disease}, volume = {37}, number = {3}, pages = {493-502}, pmid = {19833209}, issn = {1095-953X}, support = {NS11766/NS/NINDS NIH HHS/United States ; P50 NS038370/NS/NINDS NIH HHS/United States ; R21 NS062180-01/NS/NINDS NIH HHS/United States ; NS042269/NS/NINDS NIH HHS/United States ; R01 AG021617-05/AG/NIA NIH HHS/United States ; R01 NS051419/NS/NINDS NIH HHS/United States ; R21 NS064191/NS/NINDS NIH HHS/United States ; P01 NS011766/NS/NINDS NIH HHS/United States ; NS062180/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; R21 NS062180-02/NS/NINDS NIH HHS/United States ; NS062055/NS/NINDS NIH HHS/United States ; R01 AG021617/AG/NIA NIH HHS/United States ; P01 NS011766-310040/NS/NINDS NIH HHS/United States ; NS38370/NS/NINDS NIH HHS/United States ; P50 NS038370-115286/NS/NINDS NIH HHS/United States ; R01 NS042269-04/NS/NINDS NIH HHS/United States ; R21 NS064191-01A1/NS/NINDS NIH HHS/United States ; R21 NS062180/NS/NINDS NIH HHS/United States ; AG 21617/AG/NIA NIH HHS/United States ; R01 NS042269-05A2/NS/NINDS NIH HHS/United States ; R21 NS072182/NS/NINDS NIH HHS/United States ; NS064191/NS/NINDS NIH HHS/United States ; R01 NS062055-01A1/NS/NINDS NIH HHS/United States ; R01 NS042269/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/physiopathology ; Astrocytes/immunology ; Cytoprotection/physiology ; Gliosis/genetics/*immunology/physiopathology ; Humans ; Microglia/immunology ; Muscular Atrophy, Spinal/genetics/*immunology/physiopathology ; Myelitis/genetics/*immunology/physiopathology ; Nerve Degeneration/immunology/physiopathology ; Neuroglia/*immunology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Indices of neuroinflammation are found in a variety of diseases of the CNS including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Over the years, neuroinflammation, in degenerative disorders of the CNS, has evolved from being regarded as an innocent bystander accomplishing its housekeeping function secondary to neurodegeneration to being considered as a bona fide contributor to the disease process and, in some situations, as a putative initiator of the disease. Herein, we will review neuroinflammation in both ALS and SMA not only from the angle of neuropathology but also from the angle of its potential role in the pathogenesis and treatment of these two dreadful paralytic disorders.}, }
@article {pmid19823194, year = {2009}, author = {Dion, PA and Daoud, H and Rouleau, GA}, title = {Genetics of motor neuron disorders: new insights into pathogenic mechanisms.}, journal = {Nature reviews. Genetics}, volume = {10}, number = {11}, pages = {769-782}, pmid = {19823194}, issn = {1471-0064}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Humans ; Motor Neuron Disease/*genetics/*pathology ; }, abstract = {The past few years have seen the identification of dozens of genes with causal roles in motor neuron diseases (MNDs), particularly for amyotrophic lateral sclerosis and hereditary spastic paraplegia. Although many additional MND genes remain to be identified, the accumulated genetic evidence has already provided new insights into MND pathogenesis, which adds to the well-established involvement of superoxide dismutase 1 (SOD1) mutations. The pathways that have been recently implicated include those that affect RNA processing, axonal transport and mitochondrial function. The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases.}, }
@article {pmid19822873, year = {2009}, author = {Miller, RG and Jackson, CE and Kasarskis, EJ and England, JD and Forshew, D and Johnston, W and Kalra, S and Katz, JS and Mitsumoto, H and Rosenfeld, J and Shoesmith, C and Strong, MJ and Woolley, SC and , }, title = {Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {73}, number = {15}, pages = {1227-1233}, pmid = {19822873}, issn = {1526-632X}, support = {R01NS045087-01A2/NS/NINDS NIH HHS/United States ; R01 NS 44887/NS/NINDS NIH HHS/United States ; N01-AR-2250/AR/NIAMS NIH HHS/United States ; R01-NS045087/NS/NINDS NIH HHS/United States ; 1U01 NS049640/NS/NINDS NIH HHS/United States ; U01NS042685-0/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Cognition Disorders/*diagnosis ; Dementia/diagnosis ; Evidence-Based Medicine ; Fatigue/drug therapy ; Humans ; Muscle Cramp/drug therapy ; Palliative Care/methods ; *Patient Care Team ; Pseudobulbar Palsy/drug therapy ; Sialorrhea/drug therapy/radiotherapy ; Terminal Care/methods ; Truth Disclosure ; }, abstract = {OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS.<br><br>RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS.<br><br>RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.}, }
@article {pmid19822872, year = {2009}, author = {Miller, RG and Jackson, CE and Kasarskis, EJ and England, JD and Forshew, D and Johnston, W and Kalra, S and Katz, JS and Mitsumoto, H and Rosenfeld, J and Shoesmith, C and Strong, MJ and Woolley, SC and , }, title = {Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {73}, number = {15}, pages = {1218-1226}, pmid = {19822872}, issn = {1526-632X}, support = {R01NS045087-01A2/NS/NINDS NIH HHS/United States ; U01 NS042685-0/NS/NINDS NIH HHS/United States ; R01 NS 44887/NS/NINDS NIH HHS/United States ; N01-AR-2250/AR/NIAMS NIH HHS/United States ; R01-NS045087/NS/NINDS NIH HHS/United States ; 1U01 NS049640/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diet therapy/drug therapy/*therapy ; Enteral Nutrition/methods ; Evidence-Based Medicine ; Humans ; Lithium Carbonate/therapeutic use ; Quality of Life ; Respiratory Therapy/*methods ; Riluzole/therapeutic use ; }, abstract = {OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS.<br><br>RESULTS: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS.<br><br>RECOMMENDATIONS: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).}, }
@article {pmid19821796, year = {2009}, author = {Sadan, O and Melamed, E and Offen, D}, title = {Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases.}, journal = {Expert opinion on biological therapy}, volume = {9}, number = {12}, pages = {1487-1497}, doi = {10.1517/14712590903321439}, pmid = {19821796}, issn = {1744-7682}, mesh = {Animals ; *Bone Marrow Transplantation/adverse effects ; Cell Movement ; Combined Modality Therapy ; Cytokines/immunology ; Genetic Therapy ; Humans ; *Mesenchymal Stem Cell Transplantation/adverse effects ; Neurodegenerative Diseases/genetics/immunology/*surgery ; Neurogenesis ; Neurons/immunology/*transplantation ; Paracrine Communication ; Transplantation, Autologous ; Treatment Outcome ; }, abstract = {BACKGROUND: Stem-cell-based therapy is a promising new approach to handling neurodegenerative diseases. One of the most promising cellular sources is bone-marrow-derived mesenchymal stem cells (MSCs) also termed multipotent stromal cells. MSCs represent an autologous source and are abundant and non-tumorigenic. Additionally, MSCs possess the useful characteristics of homing and chemokine secretion.<br><br>OBJECTIVE/METHODS: Since neurodegenerative diseases have many pathological processes in common, a specific therapeutic agent could potentially ameliorate the symptoms of several distinct neurodegenerative diseases. In this review we demonstrate the wide variety of mechanisms by which MSCs can influence neurodegenerative processes.<br><br>RESULTS/CONCLUSIONS: The mechanisms by which transplanted MSCs influence neurodegenerative diseases can be broadly classified as cellular replacement or paracrine secretion, with the latter subdivided into trophic factor secretion or immunomodulation by cytokines. Emerging research suggests that genetic manipulations before transplantation could enhance the therapeutic potential of MSCs. Such manipulation could turn the cells into a 'Trojan horse', to deliver specific proteins, or promote reprogramming of the MSCs into the neural lineage. Clinical trials testing MSC-based therapies for familial amyotrophic lateral sclerosis and multiple sclerosis are in progress.}, }
@article {pmid19821416, year = {2009}, author = {Ng, L and Khan, F and Mathers, S}, title = {Multidisciplinary care for adults with amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD007425}, doi = {10.1002/14651858.CD007425.pub2}, pmid = {19821416}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*rehabilitation ; Cross-Sectional Studies ; Humans ; Prospective Studies ; }, abstract = {BACKGROUND: Multidisciplinary care (MDC) is increasingly thought to be an important means of symptomatic and supportive management for motor neuron disease (MND) but the evidence base for its effectiveness is unclear.<br><br>OBJECTIVES: To assess the effectiveness of MDC in adults with MND, especially the types of approaches that are effective (settings, intensity) and the outcomes that are affected.<br><br>SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Specialized Register (11 May 2009), and The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2009), MEDLINE (1966 to April 2009), EMBASE (1980 to April 2009), CINAHLPlus (1937 to April 2009), AMED (1985 to April 2009) and LILACS (1982 to April 2009).<br><br>SELECTION CRITERIA: Randomised and controlled clinical trials that compared MDC in MND with either routinely available local services or lower levels of intervention; or studies that compared MDC in different settings or at different levels of intensity.Studies of 'other designs' (such as observational studies) were included only in the Discussion since such studies could only be of limited contribution to the best evidence synthesis.<br><br>DATA COLLECTION AND ANALYSIS: We performed a 'best evidence' synthesis based on methodological quality. We grouped studies in terms of setting and intensity (high or low) of therapy.<br><br>MAIN RESULTS: No randomised controlled trials or controlled clinical trials were identified. We summarised the results of five observational studies (including one with two reports) in the Discussion section of this review.<br><br>AUTHORS' CONCLUSIONS: In the absence of randomised controlled trials or controlled clinical trials, the 'best' evidence to date is based on three 'low' and two 'very low quality' observational studies. These suggest 'very low quality evidence' for an advantage for mental health domains (only) of quality of life without increasing healthcare costs, and 'low level quality' evidence for reduced hospitalisation for MDC in low-intensity outpatient settings; and 'very low quality' evidence for improved disability in high-intensity settings. The evidence for survival is conflicting. These conclusions are tentative and the gap in current research should not be interpreted as proof that MDC is ineffective. Further research is needed into appropriate study designs; outcome measurement; caregiver needs; and the evaluation of optimal settings, type, intensity or frequency and cost-effectiveness of MDC in the MND population. Future research should focus on observational designs to assess care and outcomes in 'real-life' settings. The interface between neurology, rehabilitation and palliative care should be explored to provide long-term support for MND.}, }
@article {pmid19821325, year = {2009}, author = {Radunovic, A and Annane, D and Jewitt, K and Mustfa, N}, title = {Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD004427}, doi = {10.1002/14651858.CD004427.pub2}, pmid = {19821325}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*mortality ; Disease Progression ; Humans ; Motor Neuron Disease/mortality ; Quality of Life ; Randomized Controlled Trials as Topic ; Respiration, Artificial/*mortality ; Respiratory Insufficiency/etiology/*mortality/therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a fatal neurodegenerative disease. Without mechanical ventilation, death from respiratory failure usually follows within two to five years of the onset of symptoms.<br><br>OBJECTIVES: To examine the efficacy of mechanical ventilation (tracheostomy and non-invasive ventilation) in improving survival, on disease progression and quality of life in amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Trials Specialized Register (December 8 2008), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2008), MEDLINE (January 1966 to December 2008), EMBASE (January 1947 to December 2008), CINAHL Plus (January 1937 to December 2008), and AMED (January 1985 to December 2008). We also searched for ongoing studies on clinicaltrials.gov.<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving non-invasive or tracheostomy assisted ventilation in participants with a clinical diagnosis of amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: Four authors independently selected studies for assessment. All authors extracted data independently from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible.<br><br>MAIN RESULTS: Two randomised controlled trials involving 54 participants receiving non-invasive ventilation were identified and included. Incomplete data were published for one study and we contacted the trial authors who were not able to provide the missing data. Therefore the results of the review were based on a single study of 41 participants. The study showed that the overall median survival in the whole cohort after initiation of assisted ventilation was significantly different between the non-invasive ventilation and standard care groups (P = 0.0062) with a median survival for the non-invasive ventilation group patients of 48 days longer than the standard care group participants. Non-invasive ventilation significantly improved survival and quality of life in the subgroup with normal to moderately impaired bulbar function. Non-invasive ventilation did not prolong survival in patients with poor bulbar function although it showed significant improvement in the mean symptoms domain of the sleep apnoea quality-of-life index but not in the Short Form-36 quality of life mental component summary score .<br><br>AUTHORS' CONCLUSIONS: Evidence from a single randomised trial of non-invasive ventilation in 41 participants suggests that it significantly prolongs survival and improves or maintains quality of life in people with ALS. Survival and some measures of quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment.}, }
@article {pmid19819686, year = {2009}, author = {Papadeas, ST and Maragakis, NJ}, title = {Advances in stem cell research for Amyotrophic Lateral Sclerosis.}, journal = {Current opinion in biotechnology}, volume = {20}, number = {5}, pages = {545-551}, doi = {10.1016/j.copbio.2009.09.003}, pmid = {19819686}, issn = {1879-0429}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*surgery ; Animals ; Cell Separation ; Drug Discovery ; Humans ; Pluripotent Stem Cells/metabolism/pathology/*transplantation ; Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized primarily by motor neuron loss in the motor cortex and spinal cord leading to progressive disability and death. Despite the relative selectivity of motor neuron loss, recent studies have implicated other cell types including astrocytes and microglia as contributors to this cell death. This understanding has resulted in stem-cell-replacement strategies of these cell types, which may result in neuroprotection. In addition to cell-replacement strategies, the development of induced pluripotent stem cell (iPSC) technologies has resulted in the establishment of motor neuron cell lines from patients with ALS. The use of iPSCs from ALS patients will allow for potential autologous cell transplantation, drug discovery, and an increased understanding of ALS pathobiology.}, }
@article {pmid19818912, year = {2009}, author = {Lulé, D and Zickler, C and Häcker, S and Bruno, MA and Demertzi, A and Pellas, F and Laureys, S and Kübler, A}, title = {Life can be worth living in locked-in syndrome.}, journal = {Progress in brain research}, volume = {177}, number = {}, pages = {339-351}, doi = {10.1016/S0079-6123(09)17723-3}, pmid = {19818912}, issn = {1875-7855}, mesh = {Adaptation, Psychological/*physiology ; Consciousness Disorders/complications/*psychology ; Depression/etiology/psychology ; Disabled Persons/psychology ; Humans ; Quadriplegia/complications/*psychology ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {The locked-in syndrome (LIS) describes patients who are awake and conscious but severely deefferented leaving the patient in a state of almost complete immobility and loss of verbal communication. The etiology ranges from acute (e.g., brainstem stroke, which is the most frequent cause of LIS) to chronic causes (e.g., amyotrophic lateral sclerosis; ALS). In this article we review and present new data on the psychosocial adjustment to LIS. We refer to quality of life (QoL) and the degree of depressive symptoms as a measure of psychosocial adjustment. Various studies suggest that despite their extreme motor impairment, a significant number of LIS patients maintain a good QoL that seems unrelated to their state of physical functioning. Likewise, depression is not predicted by the physical state of the patients. A successful psychological adjustment to the disease was shown to be related to problem-oriented coping strategies, like seeking for information, and emotional coping strategies like denial--the latter may, nevertheless, vary with disease stage. Perceived social support seems to be the strongest predictor of psychosocial adjustment. QoL in LIS patients is often in the same range as in age-matched healthy individuals. Interestingly, there is evidence that significant others, like primary caregivers or spouses, rate LIS patients' QoL significantly lower than the patients themselves. With regard to depressed mood, ALS patients without symptoms focus significantly more often on internal factors that can be retained in the course of the disease contrary to patients with depressive symptoms who preferably name external factors as very important, such as health, which will degrade in the course of the disease. Typically, ALS patients with a higher degree of depressive symptoms experience significantly less "very pleasant" situations. The herein presented data strongly question the assumption among doctors, health-care workers, lay persons, and politicians that severe motor disability necessarily is intolerable and leads to end-of-life decisions or euthanasia. Existing evidence supports that biased clinicians provide less-aggressive medical treatment in LIS patients. Thus, psychological treatment for depression, effective strategies for coping with the disease, and support concerning the maintenance of the social network are needed to cope with the disease. Novel communication devices and assistive technology now offers an increasing number of LIS patients to resume a meaningful life and an active role in society.}, }
@article {pmid19818070, year = {2009}, author = {Wang, X}, title = {The antiapoptotic activity of melatonin in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {15}, number = {4}, pages = {345-357}, pmid = {19818070}, issn = {1755-5949}, support = {K01 NS055072/NS/NINDS NIH HHS/United States ; K01 NS055072-03/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Humans ; Melatonin/*pharmacology/*therapeutic use ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*pharmacology/*therapeutic use ; }, abstract = {Melatonin plays a neuroprotective role in models of neurodegenerative diseases. However, the molecular mechanisms underlying neuroprotection by melatonin are not well understood. Apoptotic cell death in the central nervous system is a feature of neurodegenerative diseases. The intrinsic and extrinsic apoptotic pathways and the antiapoptotic survival signal pathways play critical roles in neurodegeneration. This review summarizes the reports to date showing inhibition by melatonin of the intrinsic apoptotic pathways in neurodegenerative diseases including stroke, Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Furthermore, the activation of survival signal pathways by melatonin in neurodegenerative diseases is discussed.}, }
@article {pmid19817707, year = {2009}, author = {Laukens, D and Waeytens, A and De Bleser, P and Cuvelier, C and De Vos, M}, title = {Human metallothionein expression under normal and pathological conditions: mechanisms of gene regulation based on in silico promoter analysis.}, journal = {Critical reviews in eukaryotic gene expression}, volume = {19}, number = {4}, pages = {301-317}, doi = {10.1615/critreveukargeneexpr.v19.i4.40}, pmid = {19817707}, issn = {1045-4403}, mesh = {Alzheimer Disease/genetics ; Animals ; Crohn Disease/genetics ; *Gene Expression Regulation ; Hepatolenticular Degeneration/genetics ; Humans ; Menkes Kinky Hair Syndrome/genetics ; Metallothionein/chemistry/*genetics ; Mice ; Neoplasms/genetics ; Phylogeny ; *Promoter Regions, Genetic ; }, abstract = {Metallothioneins (MTs) are ubiquitous metal-binding proteins that have been highly conserved throughout evolution. Although their physiological function is not completely understood, they are involved in diverse processes including metal homeostasis and detoxification, the oxidative stress response, inflammation, and cell proliferation. Te human MT gene family consists of at least 18 isoforms, containing pseudogenes as well as genes encoding functional proteins. Most of the MT isoforms can be induced by a wide variety of substances, such as metals, cytokines, and hormones. Different cell types express discrete MT isoforms, which reflects the specifically adapted functions of MTs and a divergence in their regulation. Te aberrant expression of MTs has been described in a number of diseases, including Crohn's disease, cancer, Alzheimer's disease, amyotrophic lateral sclerosis, Menkes disease, and Wilson's disease. Therefore, a thorough understanding of MT gene regulation is imperative. To date, the transcriptional regulation of MTs has primarily been studied in mice. While only four murine MT isoforms exist, the homology between murine and human MTs allows for the evaluation of the regulatory regions in their respective promoters. Here, we review the aberrant expression of MTs in human diseases and the mechanisms that regulate MT1 expression based on an in silico evaluation of transcription factor binding sites.}, }
@article {pmid19814656, year = {2009}, author = {Porzner, M and Müller, T and Seufferlein, T}, title = {SR 57746A/xaliproden, a non-peptide neurotrophic compound: prospects and constraints for the treatment of nervous system diseases.}, journal = {Expert opinion on investigational drugs}, volume = {18}, number = {11}, pages = {1765-1772}, doi = {10.1517/13543780903329089}, pmid = {19814656}, issn = {1744-7658}, mesh = {Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Naphthalenes/adverse effects/pharmacology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/adverse effects/pharmacology/*therapeutic use ; Pyridines/adverse effects/pharmacology/*therapeutic use ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease or amyotrophic lateral sclerosis as well as peripheral neuropathies are difficult to treat due to a limited range of effective drugs. Neurotrophic growth factors promote neuronal survival and differentiation and could hence be interesting tools to treat these diseases. Their therapeutic use is limited due their short half-life, their inability to cross the BBB and potential side effects including tumor promotion. SR 57746A is a non-peptide, orally active compound that exhibits neuroprotective effects in various model systems in vitro and in vivo. SR 57746A shows--amongst other activities--agonistic activity on 5-HT(1A) receptors. Several clinical trials examined SR 57746A in patients with Alzheimer's disease, amyotrophic lateral sclerosis or chemotherapy-induced peripheral sensory neuropathy. This article reviews the preclinical and clinical data on SR 57746A and points out potential future applications of this compound. However, due to disapointing results in phase III trials, Sanofi-Aventis recently decided to discontinue the development of this drug.}, }
@article {pmid19808791, year = {2009}, author = {Pesiridis, GS and Lee, VM and Trojanowski, JQ}, title = {Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {18}, number = {R2}, pages = {R156-62}, pmid = {19808791}, issn = {1460-2083}, support = {AG10124/AG/NIA NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; T32 AG00255/AG/NIA NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; DNA-Binding Proteins/*chemistry/*genetics ; Glycine/*metabolism ; Humans ; Immunohistochemistry ; Molecular Sequence Data ; Mutation/*genetics ; Protein Structure, Tertiary ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease that affects approximately 2/100,000 individuals each year worldwide. Patients with ALS suffer from rapidly progressive degeneration of motor neurons ultimately leading to death. The major pathological features observed in post-mortem tissue from patients with ALS are motor neuron loss, cortical spinal tract degeneration, gliosis and cytoplasmic neuronal inclusions formed by TDP-43 or TAR DNA binding Protein with a molecular mass of 43 kDa, which are now recognized as the signature lesions of sporadic ALS. TDP-43 possesses two RNA binding domains (RBD) and a glycine-rich C terminus classifying it with other heterogeneous nuclear ribonucleoproteins known as 2XRBD-Gly proteins. A number of reports showed that a subset of patients with ALS possess mutations in the TDP-43 (TARDBP) gene. This further strengthens the hypotheses that gain of toxic function or loss of function in TDP-43 causes ALS. Currently, 29 different TARDBP missense mutations have been reported in 51 unrelated sporadic or familial ALS cases and two cases of ALS plus concomitant frontotemporal lobar degeneration with a remarkable concentration of mutations in the C-terminal glycine-rich domain of TDP-43. As these mutations will most certainly be an invaluable tool for the design and implementation of ALS animal and cell models, as well as serve as a platform for exploring the pathobiology of TDP-43, here we summarize the identified pathogenic TARDBP mutations and their potential impact on our understanding of the role of TDP-43 in disease.}, }
@article {pmid19805033, year = {2010}, author = {Frank, SA}, title = {Evolution in health and medicine Sackler colloquium: Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107 Suppl 1}, number = {Suppl 1}, pages = {1725-1730}, pmid = {19805033}, issn = {1091-6490}, support = {U01 GM076499/GM/NIGMS NIH HHS/United States ; U01-GM-76499/GM/NIGMS NIH HHS/United States ; }, mesh = {Biological Evolution ; Cell Lineage ; Humans ; *Mosaicism ; *Mutation ; Neoplasms/*etiology/genetics ; Neurodegenerative Diseases/*etiology/genetics ; Risk Factors ; }, abstract = {Somatic mutations must happen often during development because of the large number of cell divisions to expand from a single-cell zygote to a full organism. A mutation in development carries forward to all descendant cells, causing genetic mosaicism. Widespread genetic mosaicism may influence diseases that derive from a few genetically altered cells, such as cancer. I show how to predict the expected amount of mosaicism and the variation in mosaicism between individuals. I then calculate the predicted risk of cancer derived from developmental mutations. The calculations show that a significant fraction of cancer in later life likely arises from developmental mutations in early life. In addition, much of the variation in the risk of cancer between individuals may arise from variation in the degree of genetic mosaicism set in early life. I also suggest that certain types of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), may derive from a small focus of genetically altered cells. If so, then the risk of ALS would be influenced by developmental mutations and the consequent variation in genetic mosaicism. New technologies promise the ability to measure genetic mosaicism by sampling a large number of cellular genomes within an individual. The sampling of many genomes within an individual will eventually allow one to reconstruct the cell lineage history of genetic change in a single body. Somatic evolutionary genomics will follow from this technology, providing new insight into the origin and progression of disease with increasing age.}, }
@article {pmid19801203, year = {2009}, author = {Segura, I and De Smet, F and Hohensinner, PJ and Ruiz de Almodovar, C and Carmeliet, P}, title = {The neurovascular link in health and disease: an update.}, journal = {Trends in molecular medicine}, volume = {15}, number = {10}, pages = {439-451}, doi = {10.1016/j.molmed.2009.08.005}, pmid = {19801203}, issn = {1471-499X}, mesh = {Animals ; *Health ; Humans ; Nervous System/*blood supply/metabolism/pathology ; Neurodegenerative Diseases/*pathology/therapy ; }, abstract = {Although the nervous and vascular systems are functionally different, they show a high degree of anatomic parallelism and cross-talk. They also share similar mechanisms and molecular cues that regulate their development and maintenance. Malfunctioning of this cross-talk can cause or influence several vascular and neuronal disorders. In this review, we first provide a brief overview of the molecular and cellular mechanisms that govern the neurovascular link. Second, we focus on two neurodegenerative diseases, Alzheimer's disease and amyotrophic lateral sclerosis, to illustrate how a defective neurovascular link might contribute to their pathogenesis. Finally, we briefly discuss some therapeutic implications of the neurovascular link for designing strategies to treat these diseases.}, }
@article {pmid19799998, year = {2010}, author = {Su, B and Wang, X and Zheng, L and Perry, G and Smith, MA and Zhu, X}, title = {Abnormal mitochondrial dynamics and neurodegenerative diseases.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {1}, pages = {135-142}, pmid = {19799998}, issn = {0006-3002}, support = {R01 AG031852/AG/NIA NIH HHS/United States ; R01 AG031852-02/AG/NIA NIH HHS/United States ; AG031852/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism ; Animals ; Humans ; Mitochondria/*metabolism ; Neurodegenerative Diseases/*metabolism/physiopathology ; Parkinson Disease/metabolism ; }, abstract = {Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases. A deeper understanding of the remarkably dynamic nature of mitochondria, characterized by a delicate balance of fission and fusion, has helped to fertilize a recent wave of new studies demonstrating abnormal mitochondrial dynamics in neurodegenerative diseases. This review highlights mitochondrial dysfunction and abnormal mitochondrial dynamics in Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease and discusses how these abnormal mitochondrial dynamics may contribute to mitochondrial and neuronal dysfunction. We propose that abnormal mitochondrial dynamics represents a key common pathway that mediates or amplifies mitochondrial dysfunction and neuronal dysfunction during the course of neurodegeneration.}, }
@article {pmid19795356, year = {2009}, author = {Angka, HE and Kablar, B}, title = {Role of skeletal muscle in the epigenetic shaping of motor neuron fate choices.}, journal = {Histology and histopathology}, volume = {24}, number = {12}, pages = {1579-1592}, doi = {10.14670/HH-24.1579}, pmid = {19795356}, issn = {1699-5848}, mesh = {Animals ; Embryo, Mammalian ; Mice ; Motor Neurons/*metabolism/physiology ; Muscle, Skeletal/embryology/*metabolism ; Myogenic Regulatory Factors/genetics/metabolism ; }, abstract = {We study the role of muscle in the epigenetic (N.B., we use this term with the broader and more integrative meaning) shaping of developing motor neuron fate choices employing an approach based on mouse mutagenesis and pathology. The developmental role of skeletal muscle is studied in the whole mouse embryo by knocking out myogenic regulatory factors Myf5 and MyoD, to obtain an embryo without any skeletal musculature (Rudnicki et al., 1993). Our goal is to find muscle-provided trigger(s) of motor neuron death relevant to motor neuron diseases such as amyotrophic lateral sclerosis. The reason for this kind of thinking is the fact that a complete absence of lower and upper motor neurons, which is the pathological definition of amyotrophic lateral sclerosis, is only achieved in the complete absence of the muscle (Kablar and Rudnicki, 1999). Mutual embryonic inductive interactions between different tissue types and organs, between individual cell types belonging to the same or different lineages, and between various kinds of molecular players, are only some examples of the complex machinery that operates to connect genotype and phenotype. So far, our studies indicate that some aspects of this interplay can indeed be studied as proposed in this review article, suggesting the role of skeletal muscle in the epigenetic shaping of motor neuron fate choices. We will therefore continue this investigation as outlined to gain more insight into the nature of the epigenetic events that lead to the emergent properties of a phenotype.}, }
@article {pmid19782443, year = {2009}, author = {Patel, BP and Hamadeh, MJ}, title = {Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {28}, number = {6}, pages = {604-617}, doi = {10.1016/j.clnu.2009.06.002}, pmid = {19782443}, issn = {1532-1983}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/*therapy ; Animals ; Clinical Trials as Topic ; *Exercise ; Humans ; *Nutritional Status ; Treatment Outcome ; }, abstract = {BACKGROUND &amp; AIMS: Disease pathogenesis in amyotrophic lateral sclerosis (ALS) involves a number of interconnected mechanisms all resulting in the rapid deterioration of motor neurons. The main mechanisms include enhanced free radical production, protein misfolding, aberrant protein aggregation, excitotoxicity, mitochondrial dysfunction, neuroinflammation and apoptosis. The aim of this review is to assess the efficacy of using nutrition- and exercise-related interventions to improve disease outcomes in ALS.<br><br>METHODS: Studies involving nutrition or exercise in human and animal models of ALS were reviewed.<br><br>RESULTS: Treatments conducted in animal models of ALS have not consistently translated into beneficial results in clinical trials due to poor design, lack of power and short study duration, as well as differences in the genetic backgrounds, treatment dosages and disease pathology between animals and humans. However, vitamin E, folic acid, alpha lipoic acid, lyophilized red wine, coenzyme Q10, epigallocatechin gallate, Ginkgo biloba, melatonin, Cu chelators, and regular low and moderate intensity exercise, as well as treatments with catalase and l-carnitine, hold promise to mitigating the effects of ALS, whereas caloric restriction, malnutrition and high-intensity exercise are contraindicated in this disease model.<br><br>CONCLUSIONS: Improved nutritional status is of utmost importance in mitigating the detrimental effects of ALS.}, }
@article {pmid19768775, year = {2010}, author = {Witt, SN}, title = {Hsp70 molecular chaperones and Parkinson's disease.}, journal = {Biopolymers}, volume = {93}, number = {3}, pages = {218-228}, doi = {10.1002/bip.21302}, pmid = {19768775}, issn = {0006-3525}, mesh = {Amyloid/metabolism ; Animals ; Autophagy/physiology ; Biomarkers/metabolism ; HSP70 Heat-Shock Proteins/chemistry/*metabolism ; Humans ; Models, Molecular ; Molecular Chaperones/chemistry/*metabolism ; Nerve Degeneration/chemically induced/metabolism/pathology ; Parkinson Disease/drug therapy/*metabolism/pathology ; Prokaryotic Cells/metabolism ; Protein Conformation ; alpha-Synuclein/metabolism/toxicity ; }, abstract = {Because over expression of Hsp70 molecular chaperones suppresses the toxicity of aberrantly folded proteins that occur in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, and various polyQ-diseases (Huntington's disease and ataxias), Hsp70 is garnering attention as a possible therapeutic agent for these various diseases. Here, I review progress in this fascinating field of molecular chaperones and neurodegeneration and describe our current understanding of the mechanisms by which Hsp70 protects cells from the PD-related protein called alpha-synuclein (alpha-syn).}, }
@article {pmid19761955, year = {2009}, author = {Blatzheim, K}, title = {Interdisciplinary palliative care, including massage, in treatment of amyotrophic lateral sclerosis.}, journal = {Journal of bodywork and movement therapies}, volume = {13}, number = {4}, pages = {328-335}, doi = {10.1016/j.jbmt.2008.04.040}, pmid = {19761955}, issn = {1532-9283}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; *Massage ; *Palliative Care ; *Patient Care Team ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurological disease that affects approximately 20,000 Americans. Symptoms include muscle weakness, fatigue, twitching, atrophy, spasticity, pain, oropharyngeal dysfunction, pseudobulbar affect, weight loss, and respiratory impairment. Death occurs within 3-5 yr after onset of symptoms, with diagnosis taking from 11 to 17.5 months. The only FDA-approved drug for ALS is Riluzole, which only increases the life expectancy by a few months. All other treatments for ALS provide symptom management to improve the patient's quality of life. An interdisciplinary palliative care team for the ALS patient helps to reduce the stress that the illness places on families. Massage can be a useful adjunctive treatment for spasticity and pain when medication side effects are unwanted. A holistic interdisciplinary palliative care team supports both the patient and the family improving their quality of life.}, }
@article {pmid19751830, year = {2010}, author = {Nagley, P and Higgins, GC and Atkin, JD and Beart, PM}, title = {Multifaceted deaths orchestrated by mitochondria in neurones.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {1}, pages = {167-185}, doi = {10.1016/j.bbadis.2009.09.004}, pmid = {19751830}, issn = {0006-3002}, mesh = {Animals ; Apoptosis ; Cell Death ; Humans ; Huntington Disease/metabolism ; Mitochondria/*metabolism ; Neurons/*metabolism ; Parkinson Disease/metabolism ; }, abstract = {Neurones undergo diverse forms of cell death depending on the nature and severity of the stress. These death outcomes are now classified into various types of programmed cell death, including apoptosis, autophagy and necrosis. Each of these pathways can run in parallel and all have mitochondria as a central feature. Recruitment of mitochondria into cell death signalling involves either (or both) induction of specific death responses through release of apoptogenic proteins into the cytosol, or perturbation in function leading to loss of mitochondrial energization and ATP synthesis. Cross-talk between these signalling pathways, particularly downstream of mitochondria, determines the resultant pattern of cell death. The differential recruitment of specific death pathways depends on the timing of engagement of mitochondrial signalling. Other influences on programmed cell death pathways occur through stress of the endoplasmic reticulum and the associated ubiquitin-proteasome system normally handling potentially neurotoxic protein aggregates. Based upon contemporary evidence apoptosis is a relatively rare in the mature brain whereas the contribution of programmed necrosis to various neuropathologies has been underestimated. The death outcomes that neurones exhibit during acute or chronic injury or pathological conditions considered here (oxidative stress, hypoxic-ischaemic injury, amyotrophic lateral sclerosis, Parkinson's and Huntington's diseases) fall within a spectrum of the diverse death types across the apoptosis-necrosis continuum. Indeed, dying or dead neurones may simultaneously manifest characteristics of more than one type of death pathway. Understanding neuronal death pathways and their cross-talk not only informs the detailed pathobiology but also suggests novel therapeutic strategies.}, }
@article {pmid19751205, year = {2009}, author = {Maxwell, MM}, title = {RNAi applications in therapy development for neurodegenerative disease.}, journal = {Current pharmaceutical design}, volume = {15}, number = {34}, pages = {3977-3991}, doi = {10.2174/138161209789649295}, pmid = {19751205}, issn = {1873-4286}, mesh = {Animals ; Genetic Therapy ; Humans ; Neurodegenerative Diseases/*therapy ; RNA/pharmacology/therapeutic use ; *RNA Interference ; }, abstract = {RNA-mediated interference (RNAi) is a powerful tool for experimental manipulation of gene expression and is widely used to investigate gene function both in vitro and in vivo. RNAi refers to an evolutionarily conserved cellular mechanism for sequence-specific post-transcriptional gene silencing, in which double-stranded RNAs promote selective degradation of homologous cellular mRNAs. Because RNAi-based techniques can be employed to reduce expression of specific genes, this approach holds great promise as a therapy for diverse diseases, including devastating neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis (ALS). Importantly, in recent years RNAi has also emerged as a key tool in target identification and validation studies designed to complement traditional (i.e., small molecule-based) drug development strategies. These studies harness the power of RNAi-mediated reverse genetics to probe disease-associated pathways in both cell-based and animal models, and thus may provide critical data needed to focus drug development efforts around disease-relevant targets. This review highlights recent progress in the preclinical development of RNAi-based therapeutics for neurodegenerative disease and discusses the particular challenges that disorders of the central nervous system (CNS) pose for this approach. It further describes current applications of RNAi techniques for target identification and validation studies and underscores the importance of this methodology to developing treatments for neurological diseases.}, }
@article {pmid19751204, year = {2009}, author = {Cuny, GD}, title = {Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions.}, journal = {Current pharmaceutical design}, volume = {15}, number = {34}, pages = {3919-3939}, doi = {10.2174/138161209789649330}, pmid = {19751204}, issn = {1873-4286}, mesh = {Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/*therapeutic use ; Phosphotransferases/*antagonists &amp; inhibitors ; }, abstract = {Kinases, which number > 500 in humans, are a class of enzymes that participate in an array of important functions within normal cellular physiology and during various pathological conditions. Due to the key role of kinases in the regulation of all aspects of cellular signaling and the well established contribution of kinase dysregulation to the etiology of many human pathologies, the development of kinase inhibitors has emerged as a therapeutic strategy for the treatment of human disease, including most notably oncology. Difficulties generating selective inhibitors have hampered their use in other therapeutic areas with less tolerance for off-target effects. However, with an increasing understanding of kinase structures and with the advent of newer inhibitor design strategies more highly selective inhibitors are beginning to emerge. This has prompted interest in utilizing kinase inhibitors in therapeutic areas beyond oncology, including acute and chronic neurodegenerative conditions for which disease modify therapies are lacking. This review provides a background in acute (i.e. brain ischemia and traumatic brain injury) and chronic (i.e. Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis) neurodegenerative conditions. Then, the role of several kinase (i.e. JNK3, p38 MAPK, ERK, PKC, ROCKII, GSK3, Cdk5, MLK, EphB3 kinase, RIP1 kinase, LRRK2, TTBK1, ASK1, CK, DAPK, and PKN1) that could serve as potential therapeutic targets for these maladies are reviewed.}, }
@article {pmid19738176, year = {2009}, author = {Ravits, JM and La Spada, AR}, title = {ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration.}, journal = {Neurology}, volume = {73}, number = {10}, pages = {805-811}, pmid = {19738176}, issn = {1526-632X}, support = {R21 NS051738/NS/NINDS NIH HHS/United States ; NS051738/NS/NINDS NIH HHS/United States ; NS041648/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*physiopathology ; Animals ; Humans ; Motor Neurons/*physiology ; Nerve Degeneration/*diagnosis/genetics/*physiopathology ; Neural Conduction/physiology ; Phenotype ; }, abstract = {Heterogeneity of motor phenotypes is a clinically well-recognized fundamental aspect of amyotrophic lateral sclerosis (ALS) and is determined by variability of 3 independent primary attributes: body region of onset; relative mix of upper motor neuron (UMN) and lower motor neuron (LMN) deficits; and rate of progression. Motor phenotypes are determined by the anatomy of the underlying neuropathology and the common defining elements underlying their heterogeneity are that motor neuron degeneration is fundamentally a focal process and that it spreads contiguously through the 3-dimensional anatomy of the UMN and LMN levels, thus causing seemingly complex and varied clinical manifestations. This suggests motor neuron degeneration in ALS is in actuality a very orderly and actively propagating process and that fundamental molecular mechanisms may be uniform and their chief properties deduced. This also suggests opportunities for translational research to seek pathobiology directly in the less affected regions of the nervous system.}, }
@article {pmid19737636, year = {2009}, author = {Buratti, E and Baralle, FE}, title = {The molecular links between TDP-43 dysfunction and neurodegeneration.}, journal = {Advances in genetics}, volume = {66}, number = {}, pages = {1-34}, doi = {10.1016/S0065-2660(09)66001-6}, pmid = {19737636}, issn = {0065-2660}, support = {GGP06147/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; DNA-Binding Proteins/*genetics/*metabolism ; Humans ; Nerve Degeneration/*metabolism/pathology ; }, abstract = {TDP-43 nuclear protein is involved in several major neurodegenerative diseases that include frontotemporal lobar degeneration with ubiquitin (FTLD-U) bodies and amyotrophic lateral sclerosis (ALS). As a consequence, the role played by this protein in both normal and diseased cellular metabolism has come under very close scrutiny. In the neuronal tissues of affected individuals TDP-43 undergoes aberrant localization to the cytoplasm to form insoluble aggregates. Furthermore, it is subject to degradation, ubiquitination, and phosphorylation. Understanding the pathways that lead to these changes will be crucial to define the functional role played by this protein in disease. Several recent biochemical and molecular studies have provided new information regarding the potential physiological consequences of these modifications. Moreover, the discovery of TDP-43 mutations associated with disease in a limited number of cases and the data from existing animal models have strengthened the proposed links between this protein and disease. In this review we will discuss the available data regarding the biochemical and functional changes that transform the wild-type endogenous TDP-43 in its pathological form. Furthermore, we will concentrate on examining the potential pathological mechanisms mediated by TDP-43 in different gain- versus loss-of-function scenarios. In the near future, this knowledge will hopefully increase our knowledge on disease progression and development. Moreover, it will allow the design of innovative therapeutic strategies for these pathologies based on the specific molecular defects causing the disease.}, }
@article {pmid19733171, year = {2009}, author = {Dupuis, L}, title = {Oxidative stress sensitivity in ALS muscle cells.}, journal = {Experimental neurology}, volume = {220}, number = {2}, pages = {219-223}, doi = {10.1016/j.expneurol.2009.08.023}, pmid = {19733171}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Mitochondria, Muscle/pathology ; Mitochondrial Myopathies/pathology ; Muscle Fibers, Skeletal/metabolism/*pathology ; Muscle, Skeletal/metabolism/*pathology ; Myoblasts/pathology ; Oxidative Stress/*physiology ; }, }
@article {pmid19731042, year = {2009}, author = {Henkel, JS and Beers, DR and Zhao, W and Appel, SH}, title = {Microglia in ALS: the good, the bad, and the resting.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {4}, number = {4}, pages = {389-398}, pmid = {19731042}, issn = {1557-1904}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; *Disease Progression ; Humans ; Microglia/*immunology/pathology ; Motor Neurons/immunology/pathology ; Resting Phase, Cell Cycle/*physiology ; Signal Transduction/immunology ; }, abstract = {Inflammation, including microglial activation and T cell infiltration, is a neuropathological hallmark of amyotrophic lateral sclerosis (ALS), a rapidly progressing neurodegenerative disease. The identification of mutations in the gene for Cu2+/Zn2+ superoxide dismutase (SOD1) from patients with an inherited form of ALS enabled the creation of transgenic mice overexpressing mutant forms of SOD1 (mSOD1) which develop a motoneuron disease that resembles the disease seen in ALS patients. These transgenic mice display similar inflammatory reactions at sites of motoneuron injury as detected in ALS patients, enabling the observation that this inflammation is not simply a late consequence of motoneuron degeneration, but actively contributes to the balance between neuroprotection and neurotoxicity. The microglial and T cell activation states influence the rate of disease progression. Initially, microglia and T cells can slow disease progression, while they may later contribute to the acceleration of disease. Accumulation of intracellular and extracellular misfolded mSOD1 may be key events regulating the transformation from neuroprotective alternatively activated M2 microglia to cytotoxic classically activated M1 microglia. Intracellular and extracellular mSOD1 utilizing different pathways may enhance the production and release of reactive oxygen species (ROS) and augment the inflammatory cytokine cascade from microglia. These ROS and cytokines may increase the susceptibility of motoneurons to glutamate toxicity and inhibit the function and expression of astrocytic glutamate transporters resulting in further neurotoxicity. Thus, the cumulative evidence suggests that inflammation plays a central role in ALS and manipulating these microglial effector functions may potentially modify the outcome of this devastating disease.}, }
@article {pmid19729943, year = {2009}, author = {Domené, HM and Hwa, V and Argente, J and Wit, JM and Camacho-Hübner, C and Jasper, HG and Pozo, J and van Duyvenvoorde, HA and Yakar, S and Fofanova-Gambetti, OV and Rosenfeld, RG and , }, title = {Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences.}, journal = {Hormone research}, volume = {72}, number = {3}, pages = {129-141}, doi = {10.1159/000232486}, pmid = {19729943}, issn = {1423-0046}, mesh = {Adolescent ; Adult ; Animals ; Birth Weight ; Body Height/genetics ; Bone and Bones/metabolism ; Calcification, Physiologic ; Carbohydrate Metabolism ; Carrier Proteins/genetics ; Child ; Child, Preschool ; Female ; Frameshift Mutation ; Glycoproteins/*deficiency/genetics ; Humans ; Infant, Newborn ; Insulin-Like Growth Factor Binding Protein 1/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor II/metabolism ; Male ; Mice ; Mice, Knockout ; Mutation, Missense ; }, abstract = {The majority of insulin-like growth factor (IGF)-I and IGF-II circulate in the serum as a complex with the insulin-like growth factor binding protein (IGFBP)-3 or IGFBP-5, and an acid-labile subunit (ALS). The function of ALS is to prolong the half-life of the IGF-I-IGFBP-3/IGFBP-5 binary complexes. Fourteen different mutations of the human IGFALS gene have been identified in 17 patients, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon growth hormone stimulation. Postnatal growth was clearly affected. Commonly, the height standard deviation score before puberty was between -2 and -3, and approximately 1.4 SD shorter than the midparental height SDS. Pubertal delay was found in 50% of the patients. Circulating IGF-II, IGFBP-1, -2 and -3 levels were reduced, with the greatest reduction observed for IGFBP-3. Insulin insensitivity was a common finding, and some patients presented low bone mineral density. Human ALS deficiency represents a unique condition in which the lack of ALS proteins results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. The preserved expression of locally produced IGF-I might be responsible for the preservation of linear growth near normal limits.}, }
@article {pmid19725834, year = {2010}, author = {Martínez, A and Portero-Otin, M and Pamplona, R and Ferrer, I}, title = {Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {20}, number = {2}, pages = {281-297}, pmid = {19725834}, issn = {1750-3639}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress/*physiology ; Proteins/*metabolism ; }, abstract = {Human neurodegenerative diseases with abnormal protein aggregates are associated with aberrant post-translational modifications, solubility, aggregation and fibril formation of selected proteins which cannot be degraded by cytosolic proteases, ubiquitin-protesome system and autophagy, and, therefore, accumulate in cells and extracellular compartments as residual debris. In addition to the accumulation of "primary" proteins, several other mechanisms are involved in the degenerative process and probably may explain crucial aspects such as the timing, selective cellular vulnerability and progression of the disease in particular individuals. One of these mechanisms is oxidative stress, which occurs in the vast majority of, if not all, degenerative diseases of the nervous system. The present review covers most of the protein targets that have been recognized as modified proteins mainly using bidimensional gel electrophoresis, Western blotting with oxidative and nitrosative markers, and identified by mass spectrometry in Alzheimer disease; certain tauopathies such as progressive supranuclear palsy, Pick disease, argyrophilic grain disease and frontotemporal lobar degeneration linked to mutations in tau protein, for example, FTLD-tau, Parkinson disease and related alpha-synucleinopathies; Huntington disease; and amyotrophic lateral sclerosis, together with related animal and cellular models. Vulnerable proteins can be mostly grouped in defined metabolic pathways covering glycolysis and energy metabolism, cytoskeletal, chaperoning, cellular stress responses, and members of the ubiquitin-proteasome system. Available information points to the fact that vital metabolic pathways are hampered by protein oxidative damage in several human degenerative diseases and that oxidative damage occurs at very early stages of the disease. Yet parallel functional studies are limited and further work is needed to document whether protein oxidation results in loss of activity and impaired performance. A better understanding of proteins susceptible to oxidation and nitration may serve to define damaged metabolic networks at early stages of disease and to advance therapeutic interventions to attenuate disease progression.}, }
@article {pmid19724286, year = {2009}, author = {Singh, AV and Zamboni, P}, title = {Anomalous venous blood flow and iron deposition in multiple sclerosis.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {29}, number = {12}, pages = {1867-1878}, doi = {10.1038/jcbfm.2009.180}, pmid = {19724286}, issn = {1559-7016}, mesh = {Animals ; Brain/blood supply/pathology/physiopathology ; Cerebral Veins/pathology/*physiopathology ; Cerebrovascular Disorders/pathology/physiopathology ; Hemodynamics ; Humans ; Immunomodulation ; Iron Overload/*complications ; Magnetic Resonance Imaging ; Multiple Sclerosis/*immunology/pathology/*physiopathology ; *Oxidative Stress ; }, abstract = {Multiple sclerosis (MS) is primarily an autoimmune disorder of unknown origin. This review focuses iron overload and oxidative stress as surrounding cause that leads to immunomodulation in chronic MS. Iron overload has been demonstrated in MS lesions, as a feature common with other neurodegenerative disorders. However, the recent description of chronic cerebrospinal venous insufficiency (CCSVI) associated to MS, with significant anomalies in cerebral venous outflow hemodynamics, permit to propose a parallel with chronic venous disorders (CVDs) in the mechanism of iron deposition. Abnormal cerebral venous reflux is peculiar to MS, and was not found in a miscellaneous of patients affected by other neurodegenerative disorders characterized by iron stores, such as Parkinson's, Alzheimer's, amyotrophic lateral sclerosis. Several recently published studies support the hypothesis that MS progresses along the venous vasculature. The peculiarity of CCSVI-related cerebral venous blood flow disturbances, together with the histology of the perivenous spaces and recent findings from advanced magnetic resonance imaging techniques, support the hypothesis that iron deposits in MS are a consequence of altered cerebral venous return and chronic insufficient venous drainage.}, }
@article {pmid19722069, year = {2009}, author = {Oliveira, AS and Pereira, RD}, title = {Amyotrophic lateral sclerosis (ALS): three letters that change the people's life. For ever.}, journal = {Arquivos de neuro-psiquiatria}, volume = {67}, number = {3A}, pages = {750-782}, doi = {10.1590/s0004-282x2009000400040}, pmid = {19722069}, issn = {1678-4227}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/psychology/therapy ; Animals ; Clinical Trials as Topic ; Humans ; *Life Change Events ; Prognosis ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. Although amyotrophic lateral sclerosis and its variants are readily recognized by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with Riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. Multiple problems require a multidisciplinary approach including aggressive symptomatic management, rehabilitation to maintain motor function, nutritional support (enteric feeding, gastrostomy), respiratory support (non invasive home ventilation, invasive ventilation, tracheotomy), augmentative communication devices, palliative care, psychological support for both patients and families (because family members so often play a central role in management and care), communication between the care team, the patient and his or her family, and recognition of the clinical and social effects of cognitive impairment. Social, bioethical, and financial issues as well as advance directives should be addressed. A plethora of evidence-based guidelines should be compiled into an internationally agreed guideline of best practice. The multidisciplinary team has changed the history of disease, with still no curative therapy available.}, }
@article {pmid19716395, year = {2009}, author = {Lee, J and Boo, JH and Ryu, H}, title = {The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start?.}, journal = {Advanced drug delivery reviews}, volume = {61}, number = {14}, pages = {1316-1323}, pmid = {19716395}, issn = {1872-8294}, support = {P30 AG013846/AG/NIA NIH HHS/United States ; NS52724/NS/NINDS NIH HHS/United States ; R01 NS052724/NS/NINDS NIH HHS/United States ; R01 NS052724-05/NS/NINDS NIH HHS/United States ; P30 AG13846/AG/NIA NIH HHS/United States ; }, mesh = {Drug Delivery Systems/*methods ; Humans ; Mitochondria/drug effects/*metabolism ; Mitochondrial Diseases/*metabolism ; Neurodegenerative Diseases/etiology/*metabolism ; }, abstract = {Mitochondria are the power engine generating biochemical energy in the cell. Mitochondrial dysfunction and bioenergy deficiency is closely linked to the pathogenesis of neurodegenerative disorders. Mitochondria play a variety of roles by integrating extracellular signals and executing important intracellular events in neuronal survival and death. In this context, the regulation of mitochondrial function via therapeutic approaches may exert some salutary and neuroprotective mechanisms. Understanding the relationship of mitochondria-dependent pathogenesis may provide important pharmacological utility in the treatment of neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease. Indeed, the modulation of mitochondrial pathways is rapidly emerging as a novel therapeutic target. This review focuses on how mitochondria are involved in neurodegeneration and what therapeutics are available to target mitochondrial pathways.}, }
@article {pmid19715760, year = {2010}, author = {Shi, P and Gal, J and Kwinter, DM and Liu, X and Zhu, H}, title = {Mitochondrial dysfunction in amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {1}, pages = {45-51}, pmid = {19715760}, issn = {0006-3002}, support = {P20RR020171/RR/NCRR NIH HHS/United States ; P20 RR020171/RR/NCRR NIH HHS/United States ; R21 AG032567-01/AG/NIA NIH HHS/United States ; R01 NS049126-05/NS/NINDS NIH HHS/United States ; P20 RR020171-057026/RR/NCRR NIH HHS/United States ; R21 AG032567/AG/NIA NIH HHS/United States ; R01NS049126/NS/NINDS NIH HHS/United States ; R01 NS049126/NS/NINDS NIH HHS/United States ; R21AG032567/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Axonal Transport ; Axons/metabolism ; Humans ; Mice ; Mitochondria/*metabolism/ultrastructure ; Models, Biological ; Mutation ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {The etiology of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains to be better understood. Based on the studies from ALS patients and transgenic animal models, it is believed that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology and aberrant RNA metabolism. Mitochondria, which play crucial roles in excitotoxicity, apoptosis and cell survival, have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules and mitochondrial dynamics may also be disrupted in ALS. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging "dying-back" axonopathy model of ALS. In this review, we will discuss how mitochondrial dysfunction has been linked to the ALS variants of SOD1 and the mechanisms by which mitochondrial damage contributes to the disease etiology.}, }
@article {pmid19699774, year = {2009}, author = {Krishnan, AV and Lin, CS and Park, SB and Kiernan, MC}, title = {Axonal ion channels from bench to bedside: a translational neuroscience perspective.}, journal = {Progress in neurobiology}, volume = {89}, number = {3}, pages = {288-313}, doi = {10.1016/j.pneurobio.2009.08.002}, pmid = {19699774}, issn = {1873-5118}, mesh = {Animals ; Axons/*physiology ; Humans ; Ion Channel Gating/drug effects/*physiology ; Ion Channels/drug effects/*physiology ; Membrane Potentials/drug effects/physiology ; Nervous System Diseases/pathology/physiopathology ; Neural Conduction/drug effects/physiology ; Neurons/classification/cytology/*physiology ; }, abstract = {Over recent decades, the development of specialised techniques such as patch clamping and site-directed mutagenesis have established the contribution of neuronal ion channel dysfunction to the pathophysiology of common neurological conditions including epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, episodic ataxia, amyotrophic lateral sclerosis and neuropathic pain. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, novel clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during impulse conduction in peripheral axons. These non-invasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and disease. This review will provide a translational perspective, focusing on an overview of the investigational method, the clinical utility in assessing the biophysical basis of ectopic symptom generation in peripheral nerve disease and a review of the major findings of excitability studies in acquired and inherited neurological disease states.}, }
@article {pmid19697878, year = {2009}, author = {Banno, H and Katsuno, M and Suzuki, K and Iguchi, Y and Adachi, H and Tanaka, F and Sobue, G}, title = {[Molecular-targeted therapy for motor neuron disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {8}, pages = {891-900}, pmid = {19697878}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Butyrates/administration &amp; dosage ; DNA-Binding Proteins/genetics ; Dyslipidemias ; Free Radical Scavengers/therapeutic use ; Heat-Shock Proteins/antagonists &amp; inhibitors ; Histone Deacetylase Inhibitors ; Humans ; Leuprolide/therapeutic use ; Male ; Mice ; Muscular Disorders, Atrophic/*genetics/*therapy ; Mutation ; Nerve Growth Factors/therapeutic use ; Receptors, Androgen/physiology ; Superoxide Dismutase/genetics/physiology ; Superoxide Dismutase-1 ; }, abstract = {The mechanisms underlying selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain unknown. There have been several important clinical trials on the treatment of ALS and treatment efficacy studies using mouse (SOD1) models of ALS. The latter revealed that diminished mutant SOD1 expression in the astrocytes delayed microglial activation and slowed disease progression. Dyslipidemia has been reported to have a protective effect in ALS patients. Current evidence has implicated a 43-kDa TAR DNA-binding protein (TDP-43) in the pathologenesis of ALS. Several mutations in TDP-43 were discovered in families with inherited motor neuron disease. Although phase III trials revealed that creatine monohydrate and IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with lithium, NADPH oxidase inhibitor, free-radical scavenger, and ammonium tetrathiomolybdate. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease affecting only males. Animal studies have revealed that the pathogenesis of SBMA depends on the serum testosterone level and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic androgen receptor (AR). Our studies have also identified several candidates for the treatment of SBMA. Selective inhibition of heat shock protein (HSP) facilitates the proteasomal degradation of pathogenic AR, leading to improvements in the signs and symptoms of SBMA mice. Oral administration of sodium butyrate--a histone deacetylase inhibitor--resulted in the improvement of neurological dysfunction in the SBMA mouse model, although its therapeutic dose range is narrow.}, }
@article {pmid19697368, year = {2010}, author = {Kolb, SJ and Sutton, S and Schoenberg, DR}, title = {RNA processing defects associated with diseases of the motor neuron.}, journal = {Muscle &amp; nerve}, volume = {41}, number = {1}, pages = {5-17}, pmid = {19697368}, issn = {1097-4598}, support = {R01 GM038277/GM/NIGMS NIH HHS/United States ; R01 GM079707/GM/NIGMS NIH HHS/United States ; R01 GM084177/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Motor Neuron Disease/*genetics/metabolism/physiopathology ; Motor Neurons/*physiology ; *Mutation ; RNA/genetics/*metabolism ; RNA Processing, Post-Transcriptional/*genetics ; Ribonucleoproteins/genetics/metabolism ; }, abstract = {Rapid progress in the discovery of motor neuron disease genes in amyotrophic lateral sclerosis, the spinal muscular atrophies, hereditary motor neuropathies, and lethal congenital contracture syndromes is providing new perspectives and insights into the molecular pathogenesis of the motor neuron. Motor neuron disease genes are often expressed throughout the body with essential functions in all cells. A survey of these functions indicates that motor neurons are uniquely sensitive to perturbations in RNA processing pathways dependent on the interaction of specific RNAs with specific RNA-binding proteins, which presumably result in aberrant formation and function of ribonucleoprotein complexes. This review provides a summary of currently recognized RNA processing defects linked to human motor neuron diseases.}, }
@article {pmid19686775, year = {2010}, author = {Chapter, MC and White, CM and DeRidder, A and Chadwick, W and Martin, B and Maudsley, S}, title = {Chemical modification of class II G protein-coupled receptor ligands: frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies.}, journal = {Pharmacology &amp; therapeutics}, volume = {125}, number = {1}, pages = {39-54}, pmid = {19686775}, issn = {1879-016X}, support = {Z01 AG000318-01/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; *Drug Design ; Humans ; Ligands ; Molecular Sequence Data ; Molecular Structure ; Neurosecretory Systems/*drug effects/metabolism ; Neurotransmitter Agents/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Peptide Hormones/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Receptors, G-Protein-Coupled/*drug effects/metabolism ; Receptors, Gastrointestinal Hormone/drug effects/metabolism ; Structure-Activity Relationship ; }, abstract = {Recent research and clinical data have begun to demonstrate the huge potential therapeutic importance of ligands that modulate the activity of the secretin-like, Class II, G protein-coupled receptors (GPCRs). Ligands that can modulate the activity of these Class II GPCRs may have important clinical roles in the treatment of a wide variety of conditions such as osteoporosis, diabetes, amyotrophic lateral sclerosis and autism spectrum disorders. While these receptors present important new therapeutic targets, the large glycoprotein nature of their cognate ligands poses many problems with respect to therapeutic peptidergic drug design. These native peptides often exhibit poor bioavailability, metabolic instability, poor receptor selectivity and resultant low potencies in vivo. Recently, increased attention has been paid to the structural modification of these peptides to enhance their therapeutic efficacy. Successful modification strategies have included d-amino acid substitutions, selective truncation, and fatty acid acylation of the peptide. Through these and other processes, these novel peptide ligand analogs can demonstrate enhanced receptor subtype selectivity, directed signal transduction pathway activation, resistance to proteolytic degradation, and improved systemic bioavailability. In the future, it is likely, through additional modification strategies such as addition of circulation-stabilizing transferrin moieties, that the therapeutic pharmacopeia of drugs targeted towards Class II secretin-like receptors may rival that of the Class I rhodopsin-like receptors that currently provide the majority of clinically used GPCR-based therapeutics. Currently, Class II-based drugs include synthesized analogs of vasoactive intestinal peptide for type 2 diabetes or parathyroid hormone for osteoporosis.}, }
@article {pmid19685392, year = {2009}, author = {Wittstock, M}, title = {[Neurophysiological analysis of interhemispheric motor tracts in neurodegenerative diseases].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {77 Suppl 1}, number = {}, pages = {S42-4}, doi = {10.1055/s-0028-1109607}, pmid = {19685392}, issn = {1439-3522}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Cerebrovascular Disorders/pathology/physiopathology ; Corpus Callosum/*pathology/physiopathology ; Efferent Pathways/*pathology/physiopathology ; Electroencephalography ; Electrophysiology ; Humans ; Magnetic Resonance Imaging ; Neurodegenerative Diseases/*pathology/physiopathology ; Parkinsonian Disorders/pathology/physiopathology ; Transcranial Magnetic Stimulation ; }, abstract = {The corpus callosum (CC) is the morphological correlate of inter-hemispheric connectivity. Its integrity is of great importance for motor function and inter-hemispheric coordination of bimanual movements. Callosal fibre tracts show a high vulnerability as they are involved in number of neurodegenerative disease like parkinsonian syndromes and amyotrophic lateral sclerosis, even at early stages of the diseases. The integrity of callosal fibre bundles may be investigated by magnetic resonance imaging techniques and electrophysiologically by transcranial magnetic stimulation (TMS) investigating the transcallosal inhibition (TI). TMS investigation of the TI may be performed by measurement of the ipsilateral silent period (iSP). Most common findings are a loss or a prolongation of the iSP latency. Alternatively, a double pulse paradigm may be used to demonstrate altered TI. Furthermore, the transcallosal conduction time may be lengthened. TMS investigation of TI may a helpful diagnostic tool and may give new insights into the pathophysiology.}, }
@article {pmid19683034, year = {2009}, author = {Vickers, JC and King, AE and Woodhouse, A and Kirkcaldie, MT and Staal, JA and McCormack, GH and Blizzard, CA and Musgrove, RE and Mitew, S and Liu, Y and Chuckowree, JA and Bibari, O and Dickson, TC}, title = {Axonopathy and cytoskeletal disruption in degenerative diseases of the central nervous system.}, journal = {Brain research bulletin}, volume = {80}, number = {4-5}, pages = {217-223}, doi = {10.1016/j.brainresbull.2009.08.004}, pmid = {19683034}, issn = {1873-2747}, mesh = {Alzheimer Disease/*pathology ; Amyotrophic Lateral Sclerosis/*pathology ; Axons/*pathology ; Cytoskeleton/*pathology ; Humans ; Multiple Sclerosis/*pathology ; }, abstract = {There has been growing interest in the axon as the initial focus of pathological change in a number of neurodegenerative diseases of the central nervous system. This review concentrates on three major neurodegenerative conditions--amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer's disease--with emphasis on key cellular changes that may underlie early axonal dysfunction and pathology and, potentially, the degeneration of neurons. In particular, this review will address recent data that indicate that the main pathological stimuli for these conditions, though often not definitively determined, result in an initial perturbation of the axon and its cytoskeleton, which then results in slow neuronal degeneration and loss of connectivity. The identification of a degenerative process initiated in the axon may provide new therapeutic targets for early intervention to inhibit the grim outcomes related to the progression of these diseases.}, }
@article {pmid19670321, year = {2009}, author = {Bowser, R and Lacomis, D}, title = {Applying proteomics to the diagnosis and treatment of ALS and related diseases.}, journal = {Muscle &amp; nerve}, volume = {40}, number = {5}, pages = {753-762}, pmid = {19670321}, issn = {1097-4598}, support = {R01 NS042724/NS/NINDS NIH HHS/United States ; R21 ES013469/ES/NIEHS NIH HHS/United States ; R01 NS042724-04/NS/NINDS NIH HHS/United States ; R21 ES013469-02/ES/NIEHS NIH HHS/United States ; NS042724/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/*therapy ; Animals ; Biomarkers/metabolism ; Humans ; Nervous System Diseases/diagnosis/metabolism/therapy ; Proteomics/*methods/trends ; }, abstract = {Protein-based biomarkers for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MNDs) have many potential clinical utilities, including diagnostic, prognostic, and drug development indications. During the past decade a number of potential protein biomarkers have been proposed for MNDs. Further verification studies, followed by large validation and qualification studies, are required to advance these initial discoveries toward clinical use. Study of additional patient populations, including disease mimics, is required during the validation phase of biomarker development. Important regulatory issues are discussed that will affect the timing and strategy for biomarker assay development in ALS and other MNDs. The continued development of protein biomarkers for MNDs requires extensive collaboration between academic clinicians and scientists in conjunction with the biotechnology and pharmaceutical industries.}, }
@article {pmid19669892, year = {2009}, author = {Rezai-Zadeh, K and Gate, D and Town, T}, title = {CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {4}, number = {4}, pages = {462-475}, pmid = {19669892}, issn = {1557-1904}, support = {R00 AG029726/AG/NIA NIH HHS/United States ; 4R00AG029726-02/AG/NIA NIH HHS/United States ; 5R00AG029726-03/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/immunology/pathology ; Cell Movement/*immunology ; Central Nervous System/*immunology/pathology ; Humans ; Leukocytes/*immunology/pathology ; Neurodegenerative Diseases/*immunology/pathology ; }, abstract = {While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.}, }
@article {pmid19664364, year = {2009}, author = {Hu, WT and Grossman, M}, title = {TDP-43 and frontotemporal dementia.}, journal = {Current neurology and neuroscience reports}, volume = {9}, number = {5}, pages = {353-358}, pmid = {19664364}, issn = {1534-6293}, mesh = {Biomarkers ; Brain/metabolism/*pathology ; DNA-Binding Proteins/genetics/*metabolism ; Dementia/genetics/metabolism/*pathology ; Humans ; Inclusion Bodies/metabolism ; Mutation ; Neurons/metabolism ; }, abstract = {TAR DNA-binding protein of about 43 kDa (TDP-43) is the main ubiquitinated peptide in tau-negative frontotemporal lobar degeneration (FTLD). TDP-43 is typically a nuclear protein, and its aggregation and cytoplasmic translocation are thought to represent major steps in the pathogenesis of FTLD due to TDP-43 proteinopathy (FTLD-TDP). Certain clinical syndromes of frontotemporal dementia are preferentially associated with pathologic findings of FTLD-TDP, and TDP-43 pathology represents the connection between FTLD-TDP and amyotrophic lateral sclerosis. Recent advances in clinical, genetic, and pathologic studies of FTLD-TDP and amyotrophic lateral sclerosis have shed light on the potentially pathogenic role of TDP-43 and identified TDP-43 itself as a candidate biomarker for antemortem diagnosis of FTLD-TDP.}, }
@article {pmid19663719, year = {2009}, author = {Mazzini, L and Vercelli, A and Ferrero, I and Mareschi, K and Boido, M and Servo, S and Oggioni, GD and Testa, L and Monaco, F and Fagioli, F}, title = {Stem cells in amyotrophic lateral sclerosis: state of the art.}, journal = {Expert opinion on biological therapy}, volume = {9}, number = {10}, pages = {1245-1258}, doi = {10.1517/14712590903186956}, pmid = {19663719}, issn = {1744-7682}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/cytology ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurodegenerative disease that targets motor neurons, manifesting as a linear decline in muscular function and leading to death within 2 - 5 years of diagnosis. The vast majority of ALS cases are sporadic, the aetiopathology of which is incompletely understood. Recent data have implicated the microenvironment of the motor neuron as a primary target of the pathophysiology. Any experimental therapeutic approach to ALS is very difficult because of some peculiarities of the disease, such as the unknown origin, the spatial diffusion of motor neuron loss and the paucity of animal models. Despite such daunting challenges, in experimental models a number of potential benefits of stem cells in ALS therapy have been demonstrated: by providing non-compromised supporting cells such as astrocytes, microglia or growth factor-excreting cells, onset can be delayed and survival increased. Moreover, in animal models of acute or chronic motor neuron injury, neural stem cells implanted into the spinal cord have been shown to differentiate into motor neurons, with some evidence of axonal sprouting and formation of nerumuscular junctions with host muscle. Here we summarise and discuss current preclinical and clinical evidence regarding stem cells application in ALS, particularly focusing on methodological issues.}, }
@article {pmid19660777, year = {2010}, author = {Moreau, C and Devos, D and Gosset, P and Brunaud-Danel, V and Tonnel, AB and Lassalle, P and Defebvre, L and Destée, A}, title = {[Mechanisms of deregulated response to hypoxia in sporadic amyotrophic lateral sclerosis: a clinical study].}, journal = {Revue neurologique}, volume = {166}, number = {3}, pages = {279-283}, doi = {10.1016/j.neurol.2009.05.018}, pmid = {19660777}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/epidemiology/*physiopathology ; Biomarkers ; Cell Hypoxia/physiology ; Humans ; Hypoxia/epidemiology/*physiopathology ; Inflammation/metabolism ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motorneurons, leading to death in 3 to 5 years. Respiratory insufficiency and hypoxemia are closely linked during the clinical course of ALS. Chronic respiratory insufficiency and hypoxemia generally occur late in the disease course but rapid episodes of intermittent hypoxemia followed by reoxygenation can occur early and insidiously. Two pathways are involved in the response to hypoxemia: (i) hypoxia inducible factor-1 (HIF-1) and VEGF/HIF-2 and an erythropoietin (EPO) mediated pathway, in response to prolonged hypoxemia; and (ii) nuclear factor kappa-B (NFkappa-B) during acute hypoxemia followed by reoxygenation episodes, inducing inflammatory mediators: interleukin-6 (IL-6), TNF-alpha, cyclo oxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2). Our aim was to specify the role of the different functional pathways of response to hypoxemia in sporadic ALS patients, compared with neurological controls and according to the level of hypoxemia. We report the results of several studies of hypoxemic and/or inflammatory mediators in the cerebrospinal fluid (CSF) from ALS patients, according to their respiratory status, showing a selective defect of HIF-1 mediated angiogenic factors (VEGF and angiogenin [ANG]) during chronic hypoxia in sporadic ALS patients, compared to hypoxemic neurological controls; contrasting with an early activation of the NFkappa-B pathway since the isolated desaturation stage (IL-6, TNF-alpha, PGE-2, angiopoietin-2) in the same cohort of sporadic ALS patients. All these results are consistent with a selective impairment of the HIF-1 pathway during chronic hypoxemia in ALS patients. Inflammatory mediators were strongly elevated, since the early stage of the disease until chronic hypoxemia, suggesting a compensatory mechanism.}, }
@article {pmid19660657, year = {2009}, author = {Nanou, A and Azzouz, M}, title = {Gene therapy for neurodegenerative diseases based on lentiviral vectors.}, journal = {Progress in brain research}, volume = {175}, number = {}, pages = {187-200}, doi = {10.1016/S0079-6123(09)17513-1}, pmid = {19660657}, issn = {1875-7855}, mesh = {Animals ; Genetic Therapy/*methods ; *Genetic Vectors ; Humans ; Lentivirus/*genetics ; Neurodegenerative Diseases/*therapy ; }, abstract = {Gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches. For neurodegenerative diseases, gene therapy is particularly attractive due to the restricted bioavailability of conventional therapeutic substances to the affected structures of the brain and progressive nature of these diseases. With the development of lentiviral vector systems, many issues have been addressed and new delivery routes to the nervous system have been identified. Lentiviral vectors can efficiently deliver genes to postmitotic neuronal cell types offering long-term expression, can be generated in high titers, and do not give immunological complications. Various animal studies have demonstrated the effectiveness of these vectors to deliver therapeutic genes into the nervous system, as well as to model human diseases. This chapter will describe the basic features of lentiviral vectors, the progress, and their applications as a therapeutic strategy to treat diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson's disease, and Huntington's disease.}, }
@article {pmid19660486, year = {2010}, author = {Aráoz, R and Molgó, J and Tandeau de Marsac, N}, title = {Neurotoxic cyanobacterial toxins.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {56}, number = {5}, pages = {813-828}, doi = {10.1016/j.toxicon.2009.07.036}, pmid = {19660486}, issn = {1879-3150}, mesh = {Bacterial Toxins/*toxicity ; Cyanobacteria/*chemistry ; Fresh Water/chemistry ; Neurotoxins/*toxicity ; Spectrometry, Mass, Electrospray Ionization ; Spectrophotometry, Ultraviolet ; Water Microbiology ; }, abstract = {Worldwide development of cyanobacterial blooms has significantly increased in marine and continental waters in the last century due to water eutrophication. This phenomenon is favoured by the ability of planktonic cyanobacteria to synthesize gas vesicles that allow them to float in the water column. Besides, benthic cyanobacteria that proliferate at the bottom of lakes, rivers and costal waters form dense mats near the shore. Cyanobacterial massive proliferation is of public concern regarding the capacity of certain cyanobacterial strains to produce hepatotoxic and neurotoxic compounds that can affect public health, human activities and wild and stock animals. The cholinergic synapses and voltage-gated sodium channels constitute the targets of choice of cyanobacterial neurotoxins. Anatoxin-a and homoanatoxin-a are agonists of nicotinic acetylcholine receptors. Anatoxin-a(s) is an irreversible inhibitor of acetylcholinesterase. Saxitoxin, kalkitoxin and jamaicamide are blockers of voltage-gated sodium channels, whereas antillatoxin is an activator of such channels. Moreover the neurotoxic amino acid l-beta-N-methylamino-l-alanine was shown to be produced by diverse cyanobacterial taxa. Although controversial, increasing in vivo and in vitro evidence suggest a link between the ingestion of l-beta-N-methylamino-l-alanine and the development of amyotrophic lateral sclerosis/Parkinsonism-dementia complex, a neurodegenerative disease. This paper reviews the occurrence of cyanobacterial neurotoxins, their chemical properties, mode of action and biosynthetic pathways.}, }
@article {pmid19657198, year = {2009}, author = {Linde, K}, title = {St. John's wort - an overview.}, journal = {Forschende Komplementarmedizin (2006)}, volume = {16}, number = {3}, pages = {146-155}, doi = {10.1159/000209290}, pmid = {19657198}, issn = {1661-4127}, mesh = {Antidepressive Agents/adverse effects/*therapeutic use ; Depressive Disorder/*drug therapy ; Depressive Disorder, Major/*drug therapy ; Herb-Drug Interactions ; Humans ; *Hypericum ; *Phytotherapy ; Plant Extracts/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Risk Factors ; Somatoform Disorders/drug therapy ; }, abstract = {This article aims to summarize the current state of knowledge on St. John's wort (Hypericum perforatum L.) which is one of the oldest and best investigated medicinal herbs. Dried alcoholic extracts are the most important preparations on the market although a variety of other preparations are available. Depressive disorders according to modern diagnostic standards are the best known and most widely investigated indication although the more traditional, broader indication of 'psycho-vegetative disorders, depressive disorders, anxiety and/or nervous agitation', including diagnoses such as somatoform disorders, might more adequately describe what Hypericum extracts are actually used for by many practitioners. The exact mechanisms of action are still unclear, but the available research clearly shows that various bioactive constituents contribute to the clinical effects reported, often in a synergistic manner. Hypericum extracts have consistently shown activity in pharmacological models related to antidepressant effects. Randomized clinical trials show that Hypericum extracts are more effective than placebo and similarly effective as standard antidepressants while having better tolerability in the acute treatment of major depressive episodes. The most important risk associated with Hypericum extracts are interactions with other drugs. Therefore, physicians need to be informed whether their patients take St. John's wort products. If the risk of interactions is adequately taken into account, high quality Hypericum extracts are an effective and safe tool in the hand of qualified health profession-als in primary care.}, }
@article {pmid19651206, year = {2010}, author = {Martin, LJ}, title = {The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis therapy.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {1}, pages = {186-197}, pmid = {19651206}, issn = {0006-3002}, support = {R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282-09/AG/NIA NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Cell Death ; Humans ; Mice ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Permeability Transition Pore ; Models, Biological ; }, abstract = {Effective therapies are needed for the treatment of amyotrophic lateral sclerosis (ALS), a fatal type of motor neuron disease. Morphological, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria have potentially diverse roles in neurodegenerative disease mechanisms and neuronal cell death. In human ALS, abnormalities have been found in mitochondrial structure, mitochondrial respiratory chain enzymes, and mitochondrial cell death proteins indicative of some non-classical form of programmed cell death. Mouse models of ALS are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria. This minireview summarizes work on the how malfunctioning mitochondria might contribute to neuronal death in ALS through the biophysical entity called the mitochondrial permeability pore (mPTP). The major protein components of the mPTP are enriched in mouse motor neurons. Early in the course of disease in ALS mice expressing human mutant superoxide dismutase-1, mitochondria in motor neurons undergo trafficking abnormalities and dramatic remodeling resulting in the formation of mega-mitochondria and coinciding with increased protein carbonyl formation and nitration of mPTP components. The genetic deletion of a major mPTP component, cyclophilin D, has robust effects in ALS mice by delaying disease onset and extending survival. Thus, attention should be directed to the mPTP as a rational target for the development of drugs designed to treat ALS.}, }
@article {pmid19648521, year = {2009}, author = {Ambrosino, N and Carpenè, N and Gherardi, M}, title = {Chronic respiratory care for neuromuscular diseases in adults.}, journal = {The European respiratory journal}, volume = {34}, number = {2}, pages = {444-451}, doi = {10.1183/09031936.00182208}, pmid = {19648521}, issn = {1399-3003}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Cough ; Humans ; Insufflation ; Muscular Dystrophies/physiopathology/therapy ; Neuromuscular Diseases/physiopathology/*therapy ; Pulmonary Medicine/*methods/trends ; Quality of Life ; Respiration, Artificial ; Respiratory Insufficiency/physiopathology/therapy ; Respiratory System ; Respiratory Therapy/methods ; Tracheostomy/methods ; }, abstract = {Neuromuscular diseases (NMD) may affect respiratory muscles, leading to respiratory failure. Studies show that long-term noninvasive mechanical ventilation (NIV) improves symptoms, gas exchange, quality of life and survival. NIV improved these parameters in muscular dystrophies and also in patients with amyotrophic lateral sclerosis without severe bulbar dysfunction. NIV should be started at the onset of nocturnal hypoventilation. In selected cases, NIV may be simpler, better accepted by patients and cheaper than invasive mechanical ventilation, but it cannot be used as an alternative. Tracheostomy may be preferred by patients unable to protect their airways and wishing to survive as long as possible, or by ventilator-dependent patients. Glossopharyngeal breathing consists of taking air and propelling it into the lungs. Chest percussions and vibrations can help to mobilise airway secretions but they cannot substitute coughing. Manually assisted coughing requires substantial lung inflation through air stacking or deep lung insufflation, followed by an abdominal thrust with open glottis. The combination of mechanical in-exsufflation with an abdominal thrust is a mechanically assisted cough. In conclusion, recent advances in respiratory care of NMD have improved prognosis and many caregivers have changed from a traditional noninterventional to a more aggressive, supportive approach.}, }
@article {pmid19639292, year = {2009}, author = {Sebastião, AM and Ribeiro, JA}, title = {Adenosine receptors and the central nervous system.}, journal = {Handbook of experimental pharmacology}, volume = {}, number = {193}, pages = {471-534}, doi = {10.1007/978-3-540-89615-9_16}, pmid = {19639292}, issn = {0171-2004}, mesh = {Adenosine/physiology ; Aging/physiology ; Animals ; Brain/*physiology ; Brain-Derived Neurotrophic Factor/physiology ; Humans ; Neurotransmitter Agents/physiology ; Pain/etiology ; Receptors, Cannabinoid/physiology ; Receptors, Metabotropic Glutamate/physiology ; Receptors, Purinergic P1/analysis/*physiology ; Sleep/physiology ; Synaptic Transmission ; }, abstract = {The adenosine receptors (ARs) in the nervous system act as a kind of "go-between" to regulate the release of neurotransmitters (this includes all known neurotransmitters) and the action of neuromodulators (e.g., neuropeptides, neurotrophic factors). Receptor-receptor interactions and AR-transporter interplay occur as part of the adenosine's attempt to control synaptic transmission. A(2A)ARs are more abundant in the striatum and A(1)ARs in the hippocampus, but both receptors interfere with the efficiency and plasticity-regulated synaptic transmission in most brain areas. The omnipresence of adenosine and A(2A) and A(1) ARs in all nervous system cells (neurons and glia), together with the intensive release of adenosine following insults, makes adenosine a kind of "maestro" of the tripartite synapse in the homeostatic coordination of the brain function. Under physiological conditions, both A(2A) and A(1) ARs play an important role in sleep and arousal, cognition, memory and learning, whereas under pathological conditions (e.g., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, epilepsy, drug addiction, pain, schizophrenia, depression), ARs operate a time/circumstance window where in some circumstances A(1)AR agonists may predominate as early neuroprotectors, and in other circumstances A(2A)AR antagonists may alter the outcomes of some of the pathological deficiencies. In some circumstances, and depending on the therapeutic window, the use of A(2A)AR agonists may be initially beneficial; however, at later time points, the use of A(2A)AR antagonists proved beneficial in several pathologies. Since selective ligands for A(1) and A(2A) ARs are now entering clinical trials, the time has come to determine the role of these receptors in neurological and psychiatric diseases and identify therapies that will alter the outcomes of these diseases, therefore providing a hopeful future for the patients who suffer from these diseases.}, }
@article {pmid19631259, year = {2009}, author = {Rossi, D and Volterra, A}, title = {Astrocytic dysfunction: insights on the role in neurodegeneration.}, journal = {Brain research bulletin}, volume = {80}, number = {4-5}, pages = {224-232}, doi = {10.1016/j.brainresbull.2009.07.012}, pmid = {19631259}, issn = {1873-2747}, mesh = {Animals ; Astrocytes/metabolism/*pathology ; Calcium/metabolism ; Glutamic Acid/metabolism ; Humans ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/metabolism/pathology ; }, abstract = {For decades, astrocytes have been regarded as passive partners of neurons in central nervous system (CNS) function. Studies of the last 20 years, however, challenged this view by demonstrating that astrocytes possess functional receptors for neurotransmitters and respond to their stimulation via release of gliotransmitters, including glutamate. Notably, astrocytes react to synaptically released neurotransmitters with intracellular calcium ([Ca(2+)]) elevations, which result in the release of glutamate via regulated exocytosis and, possibly, other mechanisms. These findings have led to a new concept of neuron-glia intercommunication where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity. The additional observation that glutamate release from astrocytes is controlled by molecules linked to inflammatory reactions, such as the cytokine tumor necrosis factor alpha (TNFalpha) and prostaglandins (PGs), suggests that glia-to-neuron signalling may be sensitive to changes in the production of these mediators occurring in pathological conditions. Indeed, a local, parenchymal brain inflammatory reaction (neuroinflammation) characterized by astrocytic and microglial activation has been reported in several neurodegenerative disorders, including AIDS dementia complex, Alzheimer's disease and amyotrophic lateral sclerosis. This transition may be accompanied by functional de-regulation and even degeneration of the astrocytes with the consequent disruption of the cross-talk normally occurring between these cells and neurons. Incorrect neuron-astrocyte interactions may be involved in neuronal derangement and contribute to disease development. The findings reported in this review suggest that a better comprehension of the glutamatergic interplay between neurons and astrocytes may provide information about normal brain function and also highlight potential molecular targets for therapeutic interventions in pathology.}, }
@article {pmid19624272, year = {2010}, author = {Adibhatla, RM and Hatcher, JF}, title = {Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities.}, journal = {Antioxidants &amp; redox signaling}, volume = {12}, number = {1}, pages = {125-169}, doi = {10.1089/ars.2009.2668}, pmid = {19624272}, issn = {1557-7716}, mesh = {Cell Membrane/metabolism ; Central Nervous System/*physiology ; Central Nervous System Diseases/*physiopathology/therapy ; Humans ; *Lipid Metabolism ; *Lipid Peroxidation ; }, abstract = {Reactive oxygen species (ROS) are produced at low levels in mammalian cells by various metabolic processes, such as oxidative phosphorylation by the mitochondrial respiratory chain, NAD(P)H oxidases, and arachidonic acid oxidative metabolism. To maintain physiological redox balance, cells have endogenous antioxidant defenses regulated at the transcriptional level by Nrf2/ARE. Oxidative stress results when ROS production exceeds the cell's ability to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Reaction of ROS with lipids produces oxidized phospholipids, which give rise to 4-hydroxynonenal, 4-oxo-2-nonenal, and acrolein. The brain is susceptible to oxidative damage due to its high lipid content and oxygen consumption. Neurodegenerative diseases (AD, ALS, bipolar disorder, epilepsy, Friedreich's ataxia, HD, MS, NBIA, NPC, PD, peroxisomal disorders, schizophrenia, Wallerian degeneration, Zellweger syndrome) and CNS traumas (stroke, TBI, SCI) are problems of vast clinical importance. Free iron can react with H(2)O(2) via the Fenton reaction, a primary cause of lipid peroxidation, and may be of particular importance for these CNS injuries and disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Atherosclerosis, the major risk factor for ischemic stroke, involves accumulation of oxidized LDL in the arteries, leading to foam cell formation and plaque development. This review will discuss the role of lipid oxidation/peroxidation in various CNS injuries/disorders.}, }
@article {pmid19623531, year = {2009}, author = {Bitanihirwe, BK and Cunningham, MG}, title = {Zinc: the brain's dark horse.}, journal = {Synapse (New York, N.Y.)}, volume = {63}, number = {11}, pages = {1029-1049}, doi = {10.1002/syn.20683}, pmid = {19623531}, issn = {1098-2396}, mesh = {Animals ; Brain/*metabolism/physiopathology ; Brain Diseases/metabolism/physiopathology ; Humans ; Trace Elements/metabolism ; Zinc/*metabolism ; }, abstract = {Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.}, }
@article {pmid19619927, year = {2009}, author = {Wang, W and Bu, B and Xie, M and Zhang, M and Yu, Z and Tao, D}, title = {Neural cell cycle dysregulation and central nervous system diseases.}, journal = {Progress in neurobiology}, volume = {89}, number = {1}, pages = {1-17}, doi = {10.1016/j.pneurobio.2009.01.007}, pmid = {19619927}, issn = {1873-5118}, mesh = {Animals ; Cell Cycle/*physiology ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Central Nervous System Diseases/*pathology/*physiopathology ; Humans ; Neurons/*pathology/physiology ; Signal Transduction ; }, abstract = {The cell cycle is a delicately manipulated process essential for the development, differentiation, proliferation and death of cells. Inappropriate activation of cell cycle regulators is implicated in the pathophysiology of a wide range of central nervous system (CNS) diseases, including both acute damage and chronic neurodegenerative disorders. Cell cycle activation induces the dividing astrocytes and microglia to activate and proliferate in association with glial scar formation and inflammatory factor production, which play crucial roles in the development of pathology in CNS diseases. On the other hand, in terminally differentiated neurons, aberrant re-entry into the cell cycle triggers neuronal death instead of proliferation, which may be a common pathway shared by some acquired and neurodegenerative disorders, even though multiple pathways of the cell cycle machinery are involved in distinct neuronal demise in specific pathological circumstances. In this paper, we first provide a concise description of the roles of cell cycle in neural development. We then focus on how neural cell cycle dysregulation is related to CNS diseases. Neuronal apoptosis is often detected in acute injury to the CNS such as stroke and trauma, which are usually related to the blockade of the cell cycle at the G1-S phase. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Niemann-Pick disease type C, however, some populations of neurons complete DNA synthesis but the cell cycle is arrested at the G2/M transition. This review summarizes advances in findings implicating cell cycle machinery in neuronal death in CNS diseases.}, }
@article {pmid19618338, year = {2009}, author = {Garruto, RM and Yanagihara, R}, title = {Contributions of isolated Pacific populations to understanding neurodegenerative diseases.}, journal = {Folia neuropathologica}, volume = {47}, number = {2}, pages = {149-170}, pmid = {19618338}, issn = {1641-4640}, mesh = {Environmental Exposure/*adverse effects ; Genetic Predisposition to Disease ; History, 20th Century ; Humans ; Neurodegenerative Diseases/*epidemiology/*etiology/*history ; Pacific Islands/epidemiology/ethnology ; }, abstract = {Isolated human populations have provided a natural experimental laboratory for the ongoing study of human disease. In the mid-20th century a number of high-incidence foci of neurodegenerative diseases were brought to medical attention including kuru, amyotrophic lateral sclerosis, and parkinsonism-dementia. These foci were discovered in Papua New Guinea, West New Guinea, the Kii Peninsula of Japan, and in the Mariana Islands. The study of these diseases in isolated human groups has significantly contributed to our understanding of the cause and mechanisms of pathogenesis of these and related neurodegenerative disorders globally. This paper is dedicated to D. Carleton Gajdusek, a pioneer in the study of neurodegenerative diseases, whose decades of fieldwork and laboratory studies have led to numerous scientific discoveries that have reshaped our thinking and understanding about neurodegeneration.}, }
@article {pmid19618103, year = {2009}, author = {Prieto, R and Pascual, JM and Gutiérrez, R and Santos, E}, title = {Recovery from paraplegia after the treatment of spinal dural arteriovenous fistula: case report and review of the literature.}, journal = {Acta neurochirurgica}, volume = {151}, number = {11}, pages = {1385-1397}, doi = {10.1007/s00701-009-0439-6}, pmid = {19618103}, issn = {0942-0940}, mesh = {Aged ; Central Nervous System Vascular Malformations/pathology/*physiopathology/surgery ; Disease Progression ; Female ; Gait Disorders, Neurologic/etiology/*physiopathology/surgery ; Humans ; Male ; Middle Aged ; Paraplegia/etiology/*physiopathology/surgery ; Prognosis ; Recovery of Function/physiology ; Spinal Cord/pathology/*physiopathology ; Spinal Cord Diseases/pathology/*physiopathology/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) is a rare and enigmatic disease. Functional outcome is particularly uncertain for the small group of patients that are unable to stand at the time of diagnosis (grade 5 gait disturbance on the Aminoff-Logue scale, ALS). The objective of this study is to examine the final functional outcome of patients with SDAVF in grade 5 gait ALS before treatment.<br><br>METHODS: We conducted a PubMed search using the keyword "spinal dural arteriovenous fistula." A review of the clinical series and single well-detailed case reports of SDAVF gathered 106 patients with grade 5 gait ALS on the initial examination. Additionally, we report the case of a 56-year-old man presenting acute paraplegia and urinary retention on admission who had complained of sporadic motor and sphincter disturbances for 1 year. Spine T2-weighted MR imaging showed a central hyperintensity within the spinal cord, and the angiography demonstrated a T-11 SDAVF. Interruption of the fistula was performed through an urgent one-level laminectomy.<br><br>RESULTS: Grade 5 gait ALS was present in 25% of the patients with SDAVF included in the clinical series. Latest follow-up showed that gait disturbance improved in 73% of patients after treatment, although less than 6% became grade 1 gait ALS. Micturition disturbances improved in 39%. Exploration of our patient showed improvement to grade 1 gait ALS 1 year after the surgical treatment.<br><br>CONCLUSION: Interruption of SDAVF in paraplegic patients may improve the final functional gait outcome in some cases. No complete recovery (grade 0 gait ALS) was achieved after treatment. Micturition disturbances had a worse prognosis than motor deficits.}, }
@article {pmid19609902, year = {2009}, author = {Pasquali, L and Longone, P and Isidoro, C and Ruggieri, S and Paparelli, A and Fornai, F}, title = {Autophagy, lithium, and amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {40}, number = {2}, pages = {173-194}, doi = {10.1002/mus.21423}, pmid = {19609902}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Autophagy/*drug effects/physiology ; Humans ; Lithium Compounds/pharmacology/*therapeutic use ; Mitochondria/drug effects/metabolism ; Models, Biological ; Neurons/drug effects/ultrastructure ; Neuroprotective Agents/pharmacology/*therapeutic use ; Signal Transduction/drug effects ; }, abstract = {In this article we provide an overview of the intersection between amyotrophic lateral sclerosis (ALS) and the autophagy pathway and discuss the potential protective effects of lithium through mechanisms that recruit autophagy and other effects. The autophagy pathway is recruited during motor neuron (MN) death both in vitro and in vivo. Despite a few controversial issues concerning the significance (detrimental/protective) of autophagy in ALS, recent findings indicate a protective role. Lithium in low doses is a well-known autophagy inducer that clears misfolded proteins and altered mitochondria from MNs. Moreover, lithium preserves mitochondria and sustains their genesis. This effect is replicated by rapamycin, which is an autophagy inducer but with a different mechanism from lithium. Lithium also increases the number of Renshaw cells that are affected early during the progression of experimental ALS. Again, lithium has been reported to decrease glial proliferation in the ALS spinal cord and induces sprouting in corticospinal fibers. Muscle Nerve 40: 173-194, 2009.}, }
@article {pmid19607994, year = {2009}, author = {Birbaumer, N and Ramos Murguialday, A and Weber, C and Montoya, P}, title = {Neurofeedback and brain-computer interface clinical applications.}, journal = {International review of neurobiology}, volume = {86}, number = {}, pages = {107-117}, doi = {10.1016/S0074-7742(09)86008-X}, pmid = {19607994}, issn = {0074-7742}, mesh = {*Biofeedback, Psychology ; Brain/blood supply/*physiology ; *Communication Aids for Disabled ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; *Man-Machine Systems ; Oxygen/blood ; *User-Computer Interface ; }, abstract = {Most of the research devoted to BMI development consists of methodological studies comparing different online mathematical algorithms, ranging from simple linear discriminant analysis (LDA) (Dornhege et al., 2007) to nonlinear artificial neural networks (ANNs) or support vector machine (SVM) classification. Single cell spiking for the reconstruction of hand movements requires different statistical solutions than electroencephalography (EEG)-rhythm classification for communication. In general, the algorithm for BMI applications is computationally simple and differences in classification accuracy between algorithms used for a particular purpose are small. Only a very limited number of clinical studies with neurological patients are available, most of them single case studies. The clinical target populations for BMI-treatment consist primarily of patients with amyotrophic lateral sclerosis (ALS) and severe CNS damage including spinal cord injuries and stroke resulting in substantial deficits in communication and motor function. However, an extensive body of literature started in the 1970s using neurofeedback training. Such training implemented to control various EEG-measures provided solid evidence of positive effects in patients with otherwise pharmacologically intractable epilepsy, attention deficit disorder, and hyperactivity ADHD. More recently, the successful introduction and testing of real-time fMRI and a NIRS-BMI opened an exciting field of interest in patients with psychopathological conditions.}, }
@article {pmid19607977, year = {2009}, author = {Milanese, M and Bonifacino, T and Zappettini, S and Usai, C and Tacchetti, C and Nobile, M and Bonanno, G}, title = {Glutamate release from astrocytic gliosomes under physiological and pathological conditions.}, journal = {International review of neurobiology}, volume = {85}, number = {}, pages = {295-318}, doi = {10.1016/S0074-7742(09)85021-6}, pmid = {19607977}, issn = {0074-7742}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Astrocytes/metabolism/*physiology/*ultrastructure ; Brain/metabolism/physiology/physiopathology ; Exocytosis/physiology ; Glutamic Acid/*metabolism ; Spinal Cord/metabolism/physiology/physiopathology ; Subcellular Fractions/*metabolism/*physiology ; Symporters/physiology ; }, abstract = {Glial subcellular particles (gliosomes) have been purified from rat cerebral cortex or mouse spinal cord and investigated for their ability to release glutamate. Confocal microscopy showed that gliosomes are enriched with glia-specific proteins, such as GFAP and S-100 but not neuronal proteins, such as PSD-95, MAP-2, and beta-tubulin III. Furthermore, gliosomes exhibit labeling neither for integrin-alphaM nor for myelin basic protein, specific for microglia and oligodendrocytes, respectively. The gliosomal fraction contains proteins of the exocytotic machinery coexisting with GFAP. Consistent with ultrastructural analysis, several nonclustered vesicles are present in the gliosome cytoplasm. Finally, gliosomes represent functional organelles that actively export glutamate when subjected to releasing stimuli, such as ionomycin, high KCl, veratrine, 4-aminopyridine, AMPA, or ATP by mechanisms involving extracellular Ca2+, Ca2+ release from intracellular stores as well as reversal of glutamate transporters. In addition, gliosomes can release glutamate also by a mechanism involving heterologous transporter activation (heterotransporters) located on glutamate-releasing and glutamate transporter-expressing (homotransporters) gliosomes. This glutamate release involves reversal of glutamate transporters and anion channel opening, but not exocytosis. Both the exocytotic and the heterotransporter-mediated glutamate release were more abundant in gliosomes prepared from the spinal cord of transgenic mice, model of amyotrophic lateral sclerosis, than in controls; suggesting the involvement of astrocytic glutamate release in the excitotoxicity proposed as a cause of motor neuron degeneration. The results support the view that gliosomes may represent a viable preparation that allows to study mechanisms of astrocytic transmitter release and its regulation in healthy animals and in animal models of brain diseases.}, }
@article {pmid19596823, year = {2009}, author = {Seetharaman, SV and Prudencio, M and Karch, C and Holloway, SP and Borchelt, DR and Hart, PJ}, title = {Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {234}, number = {10}, pages = {1140-1154}, pmid = {19596823}, issn = {1535-3699}, support = {P01 NS049134/NS/NINDS NIH HHS/United States ; R01 NS039112/NS/NINDS NIH HHS/United States ; R01 NS039112-08/NS/NINDS NIH HHS/United States ; }, mesh = {Amyloid/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Dimerization ; Disease Models, Animal ; Disulfides/metabolism ; Humans ; Mice ; Mice, Transgenic ; Models, Biological ; Models, Molecular ; Molecular Chaperones/genetics/metabolism ; Motor Neurons/metabolism ; Mutation ; Protein Folding ; Protein Structure, Secondary ; Static Electricity ; Superoxide Dismutase/chemistry/genetics/*metabolism ; }, abstract = {Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease, motor neuron disease). Insoluble forms of mutant SOD1 accumulate in neural tissues of human ALS patients and in spinal cords of transgenic mice expressing these polypeptides, suggesting that SOD1-linked ALS is a protein misfolding disorder. Understanding the molecular basis for how the pathogenic mutations give rise to SOD1 folding intermediates, which may themselves be toxic, is therefore of keen interest. A critical step on the SOD1 folding pathway occurs when the copper chaperone for SOD1 (CCS) modifies the nascent SOD1 polypeptide by inserting the catalytic copper cofactor and oxidizing its intrasubunit disulfide bond. Recent studies reveal that pathogenic SOD1 proteins coming from cultured cells and from the spinal cords of transgenic mice tend to be metal-deficient and/or lacking the disulfide bond, raising the possibility that the disease-causing mutations may enhance levels of SOD1-folding intermediates by preventing or hindering CCS-mediated SOD1 maturation. This mini-review explores this hypothesis by highlighting the structural and biophysical properties of the pathogenic SOD1 mutants in the context of what is currently known about CCS structure and action. Other hypotheses as to the nature of toxicity inherent in pathogenic SOD1 proteins are not covered.}, }
@article {pmid19593125, year = {2009}, author = {Van Damme, P and Robberecht, W}, title = {Recent advances in motor neuron disease.}, journal = {Current opinion in neurology}, volume = {22}, number = {5}, pages = {486-492}, doi = {10.1097/WCO.0b013e32832ffbe3}, pmid = {19593125}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; Genotype ; Humans ; Mutation ; Patient Care Team ; Positive-Pressure Respiration ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult onset motor neuron degeneration. Despite intensive research, riluzole remains the only drug with proven efficacy. The cause and pathogenesis of the motor neuron degeneration in ALS appears to be a complex and multifactorial process. In this study, we review recent advances in our understanding of the molecular basis of sporadic and familial forms of ALS and improvements in the treatment of ALS patients.<br><br>RECENT FINDINGS: The discovery of mutations in the DNA/RNA-binding proteins transactive response DNA-binding protein 43 (TDP-43) and fused in sarcoma in familial ALS and the cytosolic sequestration of TDP-43 occurring in sporadic ALS opens new avenues in ALS research and suggests that altered RNA processing may be involved in the disease pathogenesis. The survival of ALS patients continues to increase most likely due to noninvasive respiratory ventilation, early percutaneous endoscopic gastrostomy and multidisciplinary care in ALS clinics.<br><br>SUMMARY: Recent insights in the pathology and genetics of ALS have improved our understanding of motor neuron degeneration and will hopefully lead to novel treatment strategies in ALS. Awaiting these, the beneficial effect of multidisciplinary care of ALS patients on survival and quality of life has become clear.}, }
@article {pmid19586921, year = {2009}, author = {Leitch, JM and Yick, PJ and Culotta, VC}, title = {The right to choose: multiple pathways for activating copper,zinc superoxide dismutase.}, journal = {The Journal of biological chemistry}, volume = {284}, number = {37}, pages = {24679-24683}, pmid = {19586921}, issn = {1083-351X}, support = {GM 50016/GM/NIGMS NIH HHS/United States ; F32 GM 087904/GM/NIGMS NIH HHS/United States ; R01 GM050016/GM/NIGMS NIH HHS/United States ; R37 GM050016/GM/NIGMS NIH HHS/United States ; ES 007308/ES/NIEHS NIH HHS/United States ; P30 ES003819/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Disulfides/chemistry ; Evolution, Molecular ; Humans ; Mitochondria/enzymology ; Models, Biological ; Models, Molecular ; *Mutation ; Oxygen/chemistry ; Plants/genetics ; Saccharomyces cerevisiae/genetics ; Signal Transduction ; Superoxide Dismutase/chemistry/genetics/*metabolism ; }, abstract = {Since the discovery of SOD1 in 1969, there have been numerous achievements made in our understanding of the enzyme's biochemical reactivity and its role in oxidative stress protection and as a genetic determinant in amyotrophic lateral sclerosis. Many recent advances have also been made in understanding the "activation" of SOD1, i.e. the process by which an inert polypeptide is converted to a mature active enzyme through post-translational modifications. To date, two such activation pathways have been identified: one requiring the CCS copper chaperone and one that works independently of CCS to insert copper and activate SOD1 through oxidation of an intramolecular disulfide. Depending on an organism's lifestyle and complexity, different eukaryotes have evolved to favor one pathway over the other. Some organisms rely solely on CCS for activating SOD1, and others can only activate SOD1 independently of CCS, whereas the majority of eukaryotes appear to have evolved to use both pathways. In this minireview, we shall highlight recent advances made in understanding the mechanisms by which the CCS-dependent and CCS-independent pathways control the activity, structure, and intracellular localization of copper,zinc superoxide dismutase, with relevance to amyotrophic lateral sclerosis and an emphasis on evolutionary biology.}, }
@article {pmid19584011, year = {2009}, author = {Bakota, L and Brandt, R}, title = {Live-cell imaging in the study of neurodegeneration.}, journal = {International review of cell and molecular biology}, volume = {276}, number = {}, pages = {49-103}, doi = {10.1016/S1937-6448(09)76002-2}, pmid = {19584011}, issn = {1937-6448}, mesh = {Animals ; Animals, Genetically Modified ; Cell Line ; Gene Transfer Techniques ; Humans ; *Microscopy, Fluorescence/methods ; Mitochondria/metabolism ; *Nerve Degeneration/metabolism/pathology ; Nerve Tissue Proteins/genetics/metabolism ; *Neurodegenerative Diseases/pathology/physiopathology ; *Neurons/cytology/metabolism/pathology ; Spectrometry, Fluorescence/methods ; Staining and Labeling/methods ; }, abstract = {The development of vital fluorescent synthetic dyes and the generation of a myriad of genetically encoded fluorescent proteins permit sensitive visualization of a broad range of dynamic features in living cells with fluorescence microscopy. Many neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Creutzfeld-Jacob disease (CJD), Huntington's disease (HD), multiple sclerosis (MS), and Parkinson's disease (PD) share common aspects on a cellular level that are associated with a change in the dynamic behavior of the whole cell, cell compartments, or single proteins. These include disturbances of transport mechanisms or protein turnover, missorting and aggregation of proteins, and changes in the structural plasticity of neurons. In this chapter, we describe different live-cell-imaging techniques, present representative examples, and discuss the current and potentially future use of live-cell-imaging approaches to answer key questions regarding the mechanisms or potential treatments of neurodegenerative diseases.}, }
@article {pmid19582217, year = {2009}, author = {Choonara, YE and Pillay, V and Du Toit, LC and Modi, G and Naidoo, D and Ndesendo, VMK and Sibambo, SR}, title = {Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders.}, journal = {International journal of molecular sciences}, volume = {10}, number = {6}, pages = {2510-2557}, pmid = {19582217}, issn = {1422-0067}, mesh = {Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Anticonvulsants/therapeutic use ; Antipsychotic Agents/therapeutic use ; Cholinergic Antagonists/therapeutic use ; Dopamine Agents/therapeutic use ; Humans ; Huntingtin Protein ; Huntington Disease/drug therapy/metabolism/pathology ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism/*pathology ; Neurons/metabolism ; Parkinson Disease/drug therapy/metabolism/pathology ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Huntington's disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders' in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.}, }
@article {pmid19573504, year = {2009}, author = {Jellinger, KA}, title = {[Functional pathophysiology of consciousness].}, journal = {Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater}, volume = {23}, number = {2}, pages = {115-133}, pmid = {19573504}, issn = {0948-6259}, mesh = {Arousal/physiology ; Awareness/*physiology ; Brain/*physiopathology ; Brain Damage, Chronic/physiopathology/psychology ; Brain Ischemia/physiopathology/psychology ; Brain Mapping ; Cognition/physiology ; Coma/physiopathology/psychology ; Consciousness Disorders/*physiopathology/psychology ; Electroencephalography ; Humans ; Neural Pathways/physiology ; Neurotransmitter Agents/physiology ; Oxygen Consumption/physiology ; Psychotic Disorders/physiopathology/psychology ; Quantum Theory ; Self Concept ; Sleep Stages/physiology ; }, abstract = {Consciousness (Latin conscientia "moral conscience"), according to the English philosopher John Locke (1632-1704) [103], is the awareness of all that occurs in the mind of a person, whereas the American philosopher John Searle (2000) defined it as "inner qualitative, subjective states and processes of awareness". In modern science it is defined as a continuous state of full awareness of the Self and one's relationship to the external and internal environment, describing the degree of wakefulness in which an organism recognizes stimuli. This widely discussed biological term for complex neuronal processes that allow an individuum to recognize itself and its environment and to act accordingly, has been and still is the subject of much research in philosophy and natural/neuroscience. Its definition is often used for awareness and recognition, too. While the Egyptians in the papyrus Edwin Smith already recognized the brain as the seat of consciousness, René Descartes (1644 [36]) believed its special structure should be "a small gland in the middle", but the anatomical structures and physiological processes involved in consciousness were elucidated only in the middle of the 20th century. Neuronal substrates include several functional networks that are hierarchically organized and cooperate functionally. The lowest level is the mesencephalic formatio reticularis and its projections to the thalamus that were identified als ascending reticular system (ARAS) by the classical experiments of Moruzzi and Magoun, whereas later analyses of patients with impaired consciousness provided further insights. The mesencephalic ARAS as motor of the function of higher structures projects 1. via the reticular thalamus diffusely to the cortex, 2. via hypothalamus to the basal forebrain and limbic system, and 3. to the medial raphe of the brainstem and locus coeruleus and their diffuse cortical projections. The reticular system is stimulated directly and indirectly via numerous collaterals from important somatic and sensory pathways and acts as a control system of neuronal activities of the cerebral cortex. The principal function of the ARAS is to focus our alertness on specific stimuli or internal processes, which run via complex neuronal cell groups and numerous neurotransmitters that influence various aspects of consciousness and wakefulness. Stimulation of the ARAS produces an arousal reaction as the electric correlate of consciousness; its destruction causes coma and related states. The highest level are cortical (prefrontal and association) networks for recognition, motor activity, longterm memory and attention, the left hemisphere being considered as the dominant one. Different levels of consciousness are distinguished: 1. hyperalertness, 2. alertness (normal state of wakefulness), 3. somnolence or lethargy, 4. obtundation with tendency to fall asleep, 5. stupor, 6. coma and its subtypes, like akinetic mutism, apallic syndrome or persistent vegative state, locked-in syndrome, delirium, and catatonia. They are caused by damages in various functional levels of the brain, by psychogenic factors or experimentally, and are accompanied by characteristic neurological and psychiatric disorders. The relevant morphological lesions can be detected by electrophysiological and imaging studies. The bases of functional anatomy and pathophysiology of consciousness, its cognitive aspects and its major disorders, their causes and functional substrates with reference to sleep and both spontaneous and iatrogenic disorders of consciousness are critically summarized.}, }
@article {pmid19572820, year = {2009}, author = {Nowacek, A and Kosloski, LM and Gendelman, HE}, title = {Neurodegenerative disorders and nanoformulated drug development.}, journal = {Nanomedicine (London, England)}, volume = {4}, number = {5}, pages = {541-555}, pmid = {19572820}, issn = {1748-6963}, support = {P01 NS043985-01A1/NS/NINDS NIH HHS/United States ; P01 MH057556-010003/MH/NIMH NIH HHS/United States ; R01 NS034239-09/NS/NINDS NIH HHS/United States ; U54 NS043011/NS/NINDS NIH HHS/United States ; P01 DA026146/DA/NIDA NIH HHS/United States ; P01 NS043985-07/NS/NINDS NIH HHS/United States ; R01 NS036126-12A1/NS/NINDS NIH HHS/United States ; P01 MH064570/MH/NIMH NIH HHS/United States ; P01 DA026146-010001/DA/NIDA NIH HHS/United States ; R01 NS034239-15/NS/NINDS NIH HHS/United States ; P01 NS031492-110008/NS/NINDS NIH HHS/United States ; R01 NS036126/NS/NINDS NIH HHS/United States ; U54 NS043011-08/NS/NINDS NIH HHS/United States ; R37 NS036126-05A1/NS/NINDS NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; P20 RR015635-10/RR/NCRR NIH HHS/United States ; P01 NS043985-06A10006/NS/NINDS NIH HHS/United States ; P01 NS043985-02/NS/NINDS NIH HHS/United States ; P01 NS031492/NS/NINDS NIH HHS/United States ; R01 NS036127-03/NS/NINDS NIH HHS/United States ; P01 MH064570-049001/MH/NIMH NIH HHS/United States ; P01 MH064570-019001/MH/NIMH NIH HHS/United States ; P01 NS043985-03/NS/NINDS NIH HHS/United States ; R01 NS034239-05/NS/NINDS NIH HHS/United States ; R37 NS036126/NS/NINDS NIH HHS/United States ; R37 NS036126-11/NS/NINDS NIH HHS/United States ; P20 RR015635/RR/NCRR NIH HHS/United States ; P01 NS043985-030004/NS/NINDS NIH HHS/United States ; P01 NS031492-150008/NS/NINDS NIH HHS/United States ; P01 NS043985-06A19006/NS/NINDS NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Drug Design ; Humans ; *Nanoparticles ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders.}, }
@article {pmid19558211, year = {2009}, author = {Calabrese, V and Cornelius, C and Rizzarelli, E and Owen, JB and Dinkova-Kostova, AT and Butterfield, DA}, title = {Nitric oxide in cell survival: a janus molecule.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {11}, pages = {2717-2739}, doi = {10.1089/ars.2009.2721}, pmid = {19558211}, issn = {1557-7716}, mesh = {Animals ; Cell Survival/physiology ; Central Nervous System/metabolism ; Humans ; Models, Biological ; Nitric Oxide/*metabolism ; Reactive Nitrogen Species/metabolism ; Signal Transduction/physiology ; }, abstract = {Nitric oxide (NO), plays multiple roles in the nervous system. In addition to regulating proliferation, survival and differentiation of neurons, NO is involved in synaptic activity, neural plasticity, and memory function. Nitric oxide promotes survival and differentiation of neural cells and exerts long-lasting effects through regulation of transcription factors and modulation of gene expression. Signaling by reactive nitrogen species is carried out mainly by targeted modifications of critical cysteine residues in proteins, including S-nitrosylation and S-oxidation, as well as by lipid nitration. NO and other reactive nitrogen species are also involved in neuroinflammation and neurodegeneration, such as in Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, Friedreich ataxia, and Huntington disease. Susceptibility to NO and peroxynitrite exposure may depend on factors such as the intracellular reduced glutathione and cellular stress resistance signaling pathways. Thus, neurons, in contrast to astrocytes, appear particularly vulnerable to the effects of nitrosative stress. This article reviews the current understanding of the cytotoxic versus cytoprotective effects of NO in the central nervous system, highlighting the Janus-faced properties of this small molecule. The significance of NO in redox signaling and modulation of the adaptive cellular stress responses and its exciting future perspectives also are discussed.}, }
@article {pmid19556916, year = {2009}, author = {Lui, AJ and Byl, NN}, title = {A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurologic physical therapy : JNPT}, volume = {33}, number = {2}, pages = {68-87}, doi = {10.1097/NPT.0b013e31819912d0}, pmid = {19556916}, issn = {1557-0576}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Animals ; Disease Progression ; Exercise Therapy/*methods ; Humans ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is an idiopathic disease of adults affecting upper and lower motor neurons. In one to four years, progressive weakness, spasticity, and respiratory insufficiency compromise independence and survival. Current medical treatment is limited to medication and supportive care. The benefit and harm of moderate physical exercise are controversial. This review examined current research related to moderate exercise for maintaining independence without accelerating disease progression in persons with ALS.<br><br>METHODS: An evidence-based search was conducted using keywords alone and in combination (ALS, exercise, Lou Gehrig's disease, physical therapy) to search PubMed, PEDro, Hooked on Evidence, Ovid, and Cochrane databases. Human and animal models were included and graded on level of evidence and strength of recommendations for developing guidelines to practice. A secondary reviewer evaluated all selected studies, and statistics were calculated.<br><br>RESULTS: The search yielded the following nine studies: four small clinical studies, one clinical systematic review, and four randomized, controlled trials based on animal models. In human studies, there were small to moderate effect sizes supporting the benefit of moderate exercise in persons with early-stage ALS, with no adverse affects on disease progression or survival time. In transgenic mice with superoxide dismutase-1 ALS, moderate exercise most often had a moderate effect size for increasing life span.<br><br>DISCUSSION AND CONCLUSION: Large randomized clinical trials are needed to develop specific exercise guidelines. However, evidence suggests that moderate exercise is not associated with adverse outcomes in persons with early-stage ALS. Moderate exercise programs can be safely adapted to abilities, interests, specific response to exercise, accessibility, and family support.}, }
@article {pmid19556136, year = {2009}, author = {Lillo, P and Hodges, JR}, title = {Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {16}, number = {9}, pages = {1131-1135}, doi = {10.1016/j.jocn.2009.03.005}, pmid = {19556136}, issn = {0967-5868}, support = {G9724461/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; DNA-Binding Proteins/genetics/physiology ; Dementia/genetics/*pathology/psychology ; Humans ; Motor Neuron Disease/genetics/*pathology/psychology ; }, abstract = {Advances in genetics and pathology have supported the idea of a continuum between frontotemporal dementia (FTD) and motor neurone disease (MND), which is strengthened by the discovery of the trans-activating responsive (Tar) sequence DNA binding protein (TDP-43) as a key component in the underlying pathology of FTD, FTD-MND and sporadic and familial MND patients. MND is a multisystem disorder associated with cognitive and behavioural changes which in some instances reaches the criteria for FTD, while a proportion of patients with FTD develop frank MND. We review the overlap between FTD and MND, emphasizing areas of controversy and uncertainty.}, }
@article {pmid19554515, year = {2009}, author = {Rohn, TT}, title = {Cytoplasmic inclusions of TDP-43 in neurodegenerative diseases: a potential role for caspases.}, journal = {Histology and histopathology}, volume = {24}, number = {8}, pages = {1081-1086}, pmid = {19554515}, issn = {1699-5848}, support = {P20 RR016454/RR/NCRR NIH HHS/United States ; P20 RR016454-066710/RR/NCRR NIH HHS/United States ; P20RR016454/RR/NCRR NIH HHS/United States ; }, mesh = {Caspases/*metabolism ; Cytoskeleton/metabolism ; DNA-Binding Proteins/*metabolism ; Humans ; Inclusion Bodies/*metabolism ; Models, Biological ; Neurodegenerative Diseases/*metabolism ; }, abstract = {TAR DNA-binding protein-43 (TDP-43) proteinopathies are classified based upon the extent of modified TDP-43 inclusions and include a growing number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin immunoreactive, tau negative inclusions (FTLD-U) and FTLD with motor neuron disease (FTLD-MND). In addition, TDP-43 inclusions have also been identified in a number of other neurodegenerative disorders including Alzheimer's disease, corticobasal degeneration, Lewy body related diseases and Pick's disease. Current understanding suggests that in these diseases, TDP-43 is relocated from the nucleus to the cytoplasm and sequestered into inclusions that contain modified TDP-43. Major modifications of TDP-43 have been identified as being hyperphosphorylation and proteolytic cleavage by caspases. In this review a summary of the major findings regarding the proteolytic modification of TDP-43 will be discussed as well as potential toxic-gain mechanisms these fragments may cause including cytoskeletal disruptions.}, }
@article {pmid19551535, year = {2010}, author = {Zoccolella, S and Bendotti, C and Beghi, E and Logroscino, G}, title = {Homocysteine levels and amyotrophic lateral sclerosis: A possible link.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {140-147}, doi = {10.3109/17482960902919360}, pmid = {19551535}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*blood/*epidemiology ; Animals ; Homocysteine/*blood ; Humans ; Hyperhomocysteinemia/*blood/*epidemiology ; Oxidative Stress ; Risk Factors ; }, abstract = {Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset.}, }
@article {pmid19537846, year = {2009}, author = {Pradat, PF and Dib, M}, title = {Biomarkers in amyotrophic lateral sclerosis: facts and future horizons.}, journal = {Molecular diagnosis &amp; therapy}, volume = {13}, number = {2}, pages = {115-125}, pmid = {19537846}, issn = {1177-1062}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/pathology ; Biomarkers/blood/cerebrospinal fluid/metabolism ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Muscle, Skeletal/metabolism ; Positron-Emission Tomography ; }, abstract = {The only specific marker of sporadic amyotrophic lateral sclerosis (ALS) is neuropathologic, namely the presence of inclusions staining positively for ubiquitin and TAR DNA-binding protein (TARDBP, also known as TDP-43) in degenerating motor neurons. Abnormalities in various physiopathologic pathways associated with ALS, such as oxidative stress, inflammation, and excitotoxicity, have been reported in blood, cerebrospinal fluid, and muscle biopsies. A number of studies in ALS patients have indicated that nuclear magnetic resonance (NMR) spectroscopy and diffusion tensor magnetic resonance imaging (MRI) can detect corticospinal lesions. However, because of their relative lack of sensitivity and specificity, these techniques are currently inadequate for use as diagnostic tools in individual patients. Recently, there has been much interest in the use of high-throughput techniques such as transcriptomics, proteomics, and metabolomics for the detection of biomarkers. In the future, a combination of biologic, radiologic, and electrophysiologic markers, rather than a single marker, may prove a useful tool for the diagnosis and follow-up of ALS patients. This article provides an overview of recently described biologic and radiologic markers of the disease.}, }
@article {pmid19524991, year = {2009}, author = {Soriani, MH and Desnuelle, C}, title = {[Epidemiology of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {165}, number = {8-9}, pages = {627-640}, doi = {10.1016/j.neurol.2009.04.004}, pmid = {19524991}, issn = {0035-3787}, mesh = {Adult ; Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology ; Cohort Studies ; Environment ; Environmental Exposure ; Feeding Behavior ; Female ; France/epidemiology ; Geography ; Humans ; Male ; Middle Aged ; Motor Activity ; Occupational Exposure ; Prognosis ; Registries ; Risk Factors ; Sex Factors ; Sports ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Loss of pyramidal and anterior horn motor neurons leads to progressive limb weakness, disability, dysarthria, dysphagia and respiratory insufficiency with a progressive fatal course. The incidence of ALS ranges between 1.5 to 2.5 for 100,000 per year. Although there are familial cases of ALS, about 90% are sporadic and of unknown etiology. Several exogenous risk factors have been documented. However, no convincing evidence has demonstrated in a reproducible manner an association between an environmental or lifestyle risk factor and ALS. Disease duration varies considerably, ranging from a few months to 10-15 years with a mean survival of about 36 months. Prognostic factors such as age, site of disease onset, nutritional, functional and respiratory status at the diagnosis or delay between beginning of the disease and diagnosis have been reported but they appear to be insufficient to explain prognostic variability. These last 15 years, development of supportive care for ALS patients and management in ALS centers may have contributed to improve survival. Finally, ALS centres, and particularly French ALS centres, have developed databases to improve our knowledge of ALS, phenotypic characterization, more accurate phenotype-genotype correlations and thus contribute to new therapeutics developments.}, }
@article {pmid19524172, year = {2009}, author = {Sathasivam, S}, title = {Managing patients with amyotrophic lateral sclerosis.}, journal = {European journal of internal medicine}, volume = {20}, number = {4}, pages = {355-358}, doi = {10.1016/j.ejim.2008.09.002}, pmid = {19524172}, issn = {1879-0828}, mesh = {Amyotrophic Lateral Sclerosis/*mortality/*therapy ; Humans ; *Patient Care Team ; *Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common rapidly progressive adult-onset neurodegenerative disorder. There have been great advances in the management of patients with ALS over the past decade. It starts with the giving of the diagnosis and continues to the terminal phase of the disease. This review will examine the impact of medical and non-medical interventions on improving survival and quality of life in these patients, emphasizing the importance of a multidisciplinary approach.}, }
@article {pmid19523502, year = {2009}, author = {Schmidt, ER and Pasterkamp, RJ and van den Berg, LH}, title = {Axon guidance proteins: novel therapeutic targets for ALS?.}, journal = {Progress in neurobiology}, volume = {88}, number = {4}, pages = {286-301}, doi = {10.1016/j.pneurobio.2009.05.004}, pmid = {19523502}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/physiopathology ; Animals ; Cell Differentiation/drug effects/physiology ; Cell Survival/drug effects/physiology ; Efferent Pathways/drug effects/*metabolism/physiopathology ; Growth Cones/*metabolism/pathology ; Humans ; Motor Neurons/drug effects/*metabolism/pathology ; Nerve Growth Factors/*metabolism ; Signal Transduction/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord. Death due to respiratory failure occurs typically 2-5 years after disease onset. The pathogenic mechanism that underlies ALS remains largely unknown, but is known to include both genetic and environmental factors. At the cellular level, pathological changes in motor neuron connections and loss of neuromuscular contacts precede motor neuron degeneration and clinical symptoms. Several lines of recent evidence support the challenging hypothesis that aberrant expression or function of axon guidance proteins such as Semaphorins, Ephrins, Netrins and Slits, normally involved in sculpting and maintaining motor neuron circuits, may induce such pathological changes in motor neuron circuitry and contribute to the pathogenic mechanism involved in ALS. In the present review, we discuss the emerging roles of axon guidance proteins in the pathogenesis of ALS. First, we summarize our current understanding of the role of axon guidance proteins during the formation of motor neuron circuits. Subsequently, we present several lines of evidence showing an association between aberrant axon guidance protein function or expression and ALS. Finally, we discuss the therapeutic potential of axon guidance proteins in understanding and treating the changes in motor neuron connectivity that underlie this debilitating disease.}, }
@article {pmid19523343, year = {2009}, author = {Young, W}, title = {Review of lithium effects on brain and blood.}, journal = {Cell transplantation}, volume = {18}, number = {9}, pages = {951-975}, doi = {10.3727/096368909X471251}, pmid = {19523343}, issn = {1555-3892}, mesh = {Animals ; Antipsychotic Agents/blood/*pharmacology/therapeutic use ; Bipolar Disorder/drug therapy ; Brain/*drug effects/pathology ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Lithium/blood/*pharmacology/therapeutic use ; }, abstract = {Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.}, }
@article {pmid19499146, year = {2009}, author = {Zhang, L and Sheng, R and Qin, Z}, title = {The lysosome and neurodegenerative diseases.}, journal = {Acta biochimica et biophysica Sinica}, volume = {41}, number = {6}, pages = {437-445}, doi = {10.1093/abbs/gmp031}, pmid = {19499146}, issn = {1745-7270}, mesh = {Humans ; Lysosomes/*physiology ; Neurodegenerative Diseases/*physiopathology ; }, abstract = {It has long been believed that the lysosome is an important digestive organelle. There is increasing evidence that the lysosome is also involved in pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition induced by lysosomal dysfunction may be the primary contributor to age-related neurodegeneration. In this review, the possible relationship between lysosome and various neurodegenerative diseases is described.}, }
@article {pmid19497409, year = {2009}, author = {Chang, PA and Wu, YJ}, title = {Motor neuron diseases and neurotoxic substances: a possible link?.}, journal = {Chemico-biological interactions}, volume = {180}, number = {2}, pages = {127-130}, doi = {10.1016/j.cbi.2009.03.008}, pmid = {19497409}, issn = {1872-7786}, mesh = {Humans ; Motor Neuron Disease/*chemically induced ; Neurotoxins/*toxicity ; Organophosphates/chemistry/toxicity ; }, abstract = {The motor neuron diseases (MNDs) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. Exploring the molecular mechanisms underlying MND phenotypes has been hampered by their multifactorial nature and high incidence of sporadic cases, although genetic factors are considered to play a considerable role at present. However, environmental factors, especial exposure to neurotoxic substances, could induce neurotoxicity with the same phenotypes of specific MNDs. Organophosphate-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by ataxia and progression to paralysis, with a concomitant distal axonal degeneration and secondary demyelination of central and peripheral axons. The inhibition and subsequent aging of neuropathy target esterase (NTE) by organophosphate has been proposed to be the initiating event in OPIDN. NTE is characterized to be a lysophospholipase/phospholipase B mostly in the nervous system to regulate phospholipid homeostasis. Brain-specific deletion of mouse NTE contributes to the behavioral defects characterized by neuronal loss. Recently, mutations in human NTE have also been shown to cause a hereditary spastic paraplegia called NTE-related motor neuron disorder with the same characteristics of OPIDN, which supported the role of NTE abnormalities in OPIDN, and raised the possibility that NTE pathway disturbances contribute to other MNDs. Together with the identified association of paraoxonase polymorphisms with amyotrophic lateral sclerosis, there is a possibility that neurotoxic substances contribute to MND in genetically vulnerable people by gene-environment interactions.}, }
@article {pmid19494548, year = {2009}, author = {Wolfson, C and Kilborn, S and Oskoui, M and Genge, A}, title = {Incidence and prevalence of amyotrophic lateral sclerosis in Canada: a systematic review of the literature.}, journal = {Neuroepidemiology}, volume = {33}, number = {2}, pages = {79-88}, doi = {10.1159/000222089}, pmid = {19494548}, issn = {1423-0208}, mesh = {Age Factors ; Alberta/epidemiology ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology ; Canada/epidemiology ; Data Collection ; Humans ; Newfoundland and Labrador/epidemiology ; Nova Scotia/epidemiology ; Ontario/epidemiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease of unknown etiology. Although known to be rare, precise information on the frequency of ALS is essential to anticipate future demands on health resources and as baseline information for epidemiological studies. As part of a new ALS epidemiological initiative in Canada, we conducted a systematic review of published incidence and prevalence research in Canada.<br><br>METHODS: Electronic searches and bibliographic reviews of pertinent publications were conducted.<br><br>RESULTS: We identified 6 published studies from 4 Canadian provinces conducted between 1974 and 2004; 2 were available only as abstracts. Reported annual incidence rates were similar and study quality was generally good, but there was insufficient detail to adequately assess the methodological quality of 3 of the studies. The most recent studies reported an annual ALS age-adjusted incidence of 2.13 per 100,000 in Nova Scotia (2003-2004) and a crude mean annual incidence of 2.4 per 100,000 in Newfoundland and Labrador (2000-2004).<br><br>CONCLUSIONS: There are limited data on the frequency of ALS in Canada. We found no studies from 6 of the Canadian provinces or from the territories. Future research is needed to estimate the frequency of occurrence of ALS in Canada.}, }
@article {pmid19492980, year = {2009}, author = {Thonhoff, JR and Ojeda, L and Wu, P}, title = {Stem cell-derived motor neurons: applications and challenges in amyotrophic lateral sclerosis.}, journal = {Current stem cell research &amp; therapy}, volume = {4}, number = {3}, pages = {178-199}, pmid = {19492980}, issn = {2212-3946}, support = {F30NS060387/NS/NINDS NIH HHS/United States ; R01 NS046025/NS/NINDS NIH HHS/United States ; NS046025/NS/NINDS NIH HHS/United States ; F30 NS060387-04/NS/NINDS NIH HHS/United States ; F30 NS060387/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Animals ; Astrocytes/metabolism ; Cell Differentiation/*physiology ; Cell- and Tissue-Based Therapy/*methods ; Cells, Cultured ; Coculture Techniques ; Disease Models, Animal ; Humans ; Microglia/metabolism ; Motor Neurons/cytology/*physiology ; Oxidative Stress ; Spinal Cord/cytology ; *Stem Cell Transplantation ; Stem Cells/cytology/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the selective loss of both spinal and upper motor neurons. One strategy in treating ALS is to use stem cells to replace lost spinal motor neurons. However, transplanted stem cell-derived motor neurons may not survive when exposed to the harsh microenvironment in the spinal cord of ALS. In particular, dysfunctional astrocytes and overactivated microglia in ALS may limit the survival of motor neurons generated from cell replacement therapy. On the other hand, stem cells may provide large quantities of motor neurons that can be used for studying glia-mediated toxic mechanisms and potential therapies in ALS. Here we will review methods and molecular factors for directed differentiation of stem cells into spinal motor neurons, the potential uses of these models for dissecting the mechanisms underlying glia-induced motor neuron degeneration and screening for new therapeutics aimed at protecting motor neurons in ALS, as well as discuss challenges facing the development of motor neuron replacement-based cell therapies for recovery in ALS.}, }
@article {pmid19477268, year = {2009}, author = {Miao, L and St Clair, DK}, title = {Regulation of superoxide dismutase genes: implications in disease.}, journal = {Free radical biology &amp; medicine}, volume = {47}, number = {4}, pages = {344-356}, pmid = {19477268}, issn = {1873-4596}, support = {R01 CA049797-18/CA/NCI NIH HHS/United States ; CA 73599/CA/NCI NIH HHS/United States ; R01 CA073599/CA/NCI NIH HHS/United States ; R01 CA139843/CA/NCI NIH HHS/United States ; CA 49797/CA/NCI NIH HHS/United States ; R01 CA139843-01/CA/NCI NIH HHS/United States ; R01 CA049797/CA/NCI NIH HHS/United States ; R01 CA073599-09A1/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; *Gene Expression Regulation, Enzymologic ; Genetic Predisposition to Disease ; Humans ; Oxidative Stress ; Polymorphism, Genetic ; Reactive Oxygen Species/metabolism ; Regulatory Sequences, Nucleic Acid ; Structure-Activity Relationship ; Superoxide Dismutase/chemistry/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Numerous short-lived and highly reactive oxygen species (ROS) such as superoxide (O2(.-)), hydroxyl radical, and hydrogen peroxide are continuously generated in vivo. Depending upon concentration, location, and intracellular conditions, ROS can cause toxicity or act as signaling molecules. The cellular levels of ROS are controlled by antioxidant enzymes and small-molecule antioxidants. As major antioxidant enzymes, superoxide dismutases (SODs), including copper-zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase, and extracellular superoxide dismutase, play a crucial role in scavenging O2(.-). This review focuses on the regulation of the sod genes coding for these enzymes, with an emphasis on the human genes. Current knowledge about sod structure and regulation is summarized and depicted as diagrams. Studies to date on genes coding for Cu/ZnSOD (sod1) are mostly focused on alterations in the coding region and their associations with amyotrophic lateral sclerosis. Evaluation of nucleotide sequences reveals that regulatory elements of the sod2 gene reside in both the noncoding and the coding region. Changes associated with sod2 lead to alterations in expression levels as well as protein function. We also discuss the structural basis for the changes in SOD expression associated with pathological conditions and where more work is needed to establish the relationship between SODs and diseases.}, }
@article {pmid19419744, year = {2009}, author = {Pradat, PF and Camdessanché, JP and Carluer, L and Cintas, P and Corcia, P and Danel-Brunaud, V and Echaniz-Laguna, A and Gonzalez, J and Nicolas, G and Vandenberghe, N and Verschueren, A and , }, title = {[Update on fundamental and clinical research in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {165}, number = {6-7}, pages = {532-541}, doi = {10.1016/j.neurol.2009.01.038}, pmid = {19419744}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/genetics/physiopathology/*therapy ; Electrophysiology ; Humans ; Neuroprotective Agents/therapeutic use ; Nutritional Support ; Respiratory Mechanics/physiology ; }, abstract = {This paper from a group of French experts in amyotrophic lateral sclerosis (ALS) presents an update of recent advances in fundamental, epidemiological and clinical research in ALS. Recent development in the pathogenesis of ALS suggests that motor neuron degeneration is a multifactorial and noncell autonomous process. Research has been advanced through the identification of the TAR-DNA-binding protein (TDP-43) as a common neuropathological marker of ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Recently, mutations in the TDP-43 gene have been described in individuals with familial and sporadic ALS. Fundamental research in ALS is expected to lead to the disclosure of new diagnostic markers and therapeutic targets. A small trial has suggested that lithium carbonate may slow ALS progression but larger trials will be needed to confirm these results.}, }
@article {pmid19407495, year = {2009}, author = {Rosenfeld, RG and Hwa, V}, title = {The growth hormone cascade and its role in mammalian growth.}, journal = {Hormone research}, volume = {71 Suppl 2}, number = {}, pages = {36-40}, doi = {10.1159/000192434}, pmid = {19407495}, issn = {1423-0046}, mesh = {Animals ; Body Size/*physiology ; Human Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor II/metabolism ; Janus Kinase 2/metabolism ; STAT5 Transcription Factor ; Signal Transduction/*physiology ; }, abstract = {The myriad actions of growth hormone (GH) are still incompletely understood, despite decades of research. Although it is a major regulator of post-natal growth in mammals, much of its effects on skeletal growth are recognized to be mediated indirectly, through the stimulation of production of insulin-like growth factor (IGF)-I, as well as some of the major serum carrier proteins for IGF-I and -II, such as IGF-binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). The regulation of IGF-I production by GH appears to be mediated entirely by signalling through the Janus kinase (JAK) 2 pathway, via the phosphorylation of the transcription factor, signal transducer and activator of transcription (STAT) 5b. GH also signals, however, through additional pathways that are likely to be critical to the metabolic actions of GH.}, }
@article {pmid19413484, year = {2009}, author = {Foran, E and Trotti, D}, title = {Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {7}, pages = {1587-1602}, pmid = {19413484}, issn = {1557-7716}, support = {NS044993/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Transport System X-AG/*physiology ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Humans ; Mice ; *Motor Neurons ; }, abstract = {Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na(+)-dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system.}, }
@article {pmid19412819, year = {2010}, author = {Raggi, A and Iannaccone, S and Cappa, SF}, title = {Event-related brain potentials in amyotrophic lateral sclerosis: A review of the international literature.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {16-26}, doi = {10.3109/17482960902912399}, pmid = {19412819}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Brain/*physiopathology ; Cognition Disorders/etiology/*physiopathology ; *Evoked Potentials ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS), traditionally considered as a disorder limited to the motor system, is increasingly recognized to be a multisystem disease, involving associative areas in addition to the motor cortex and therefore affecting cognition. ALS patients may present with subtle behavioural and executive dysfunctions or, less frequently, with a manifest frontotemporal dementia. Event-related potentials (ERPs) are a high-temporal resolution technique, which can be used to explore the presence of cognitive dysfunction. All the primary studies reviewed here have shown ERP abnormalities in groups of non-demented patients affected by sporadic ALS compared to healthy controls. The ERP results support findings of neuropsychological and imaging studies. Prospective studies combining simultaneous neuropsychological and imaging investigations are needed to assess the possible role of ERPs in the early detection and follow-up of cognitive dysfunction in ALS patients.}, }
@article {pmid19412148, year = {2009}, author = {Roppolo, LP and Wigginton, JG and Pepe, PE}, title = {Revolving back to the basics in cardiopulmonary resuscitation.}, journal = {Minerva anestesiologica}, volume = {75}, number = {5}, pages = {301-305}, pmid = {19412148}, issn = {1827-1596}, mesh = {Adult ; Cardiopulmonary Resuscitation/education/*methods/standards ; Child ; Death, Sudden, Cardiac/prevention &amp; control ; Defibrillators ; First Aid ; Heart Arrest/therapy ; Humans ; Practice Guidelines as Topic ; Time Factors ; }, abstract = {Since the 1970s, most of the research and debate regarding interventions for cardiopulmonary arrest have focused on advanced life support (ALS) therapies and early defibrillation strategies. During the past decade, however, international guidelines for cardiopulmonary resuscitation (CPR) have not only emphasized the concept of uninterrupted chest compressions, but also improvements in the timing, rate and quality of those compressions. In essence, it has been a ''revolution'' in resuscitation medicine in terms of ''coming full circle'' to the 1960s when basic CPR was first developed. Recent data have indicated the need for minimally-interrupted chest compressions with an accompanying emphasis toward removing rescue ventilation altogether in sudden cardiac arrest, at least in the few minutes after a sudden unheralded collapse. In other studies, transient delays in defibrillation attempts and ALS interventions are even recommended so that basic CPR can be prioritized to first restore and maintain better coronary artery perfusion. New devices have now been developed to modify, in real-time, the performance of basic CPR, during both training and an actual resuscitative effort. Several new adjuncts have been created to augment chest compressions or enhance venous return and evolving technology may now be able to identify ventricular fibrillation (VF) without interrupting chest compressions. A renewed focus on widespread CPR training for the average person has also returned to center stage with ground-breaking training initiatives including validated video-based adult learning courses that can reliably teach and enable long term retention of basic CPR skills and automated external defibrillator (AED) use.}, }
@article {pmid19399611, year = {2009}, author = {Muyderman, H and Hutson, PG and Matusica, D and Rogers, ML and Rush, RA}, title = {The human G93A-superoxide dismutase-1 mutation, mitochondrial glutathione and apoptotic cell death.}, journal = {Neurochemical research}, volume = {34}, number = {10}, pages = {1847-1856}, pmid = {19399611}, issn = {1573-6903}, mesh = {Alanine/genetics ; Amino Acid Substitution/*genetics ; Amyotrophic Lateral Sclerosis/enzymology/*genetics/*pathology ; Animals ; Apoptosis/*genetics ; Cell Death/genetics ; Glutathione/*genetics/metabolism ; Glycine/genetics ; Humans ; Mitochondria/*genetics/metabolism/pathology ; Motor Neurons/enzymology/*pathology ; Oxidative Stress/genetics ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Mutations in Cu/Zn superoxide dismutase are a cause of motor neuron death in about 20% of cases of familial amyotrophic lateral sclerosis (ALS). Although the molecular mechanism of which these mutations induce motor neuron cell death is to a large extent unknown, there is significant evidence that effects on mitochondrial function and development of oxidative stress make a major contribution to the selective death of motor neurons in this disease. In this overview article we review the current understanding of mutant SOD1-mediated motor neuron degeneration in ALS with focus on oxidative damage and mitochondrial dysfunction. We also present novel information on the role of mitochondrial glutathione for the survival of NSC-34 cells stably transfected with the human SOD1(G93A) mutation, putting forward the hypothesis that this antioxidant pool provides a potentially useful target for therapeutic intervention.}, }
@article {pmid19386549, year = {2009}, author = {Dupuis, L and Loeffler, JP}, title = {Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models.}, journal = {Current opinion in pharmacology}, volume = {9}, number = {3}, pages = {341-346}, doi = {10.1016/j.coph.2009.03.007}, pmid = {19386549}, issn = {1471-4892}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Axons/pathology ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*pathology ; Muscle, Skeletal/pathology ; Neuroglia/pathology ; Neuromuscular Junction/*physiopathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents the major adult-onset motor neuron disease. Analyses of ALS animal models have shown that motor neuron death starts with neuromuscular junction (NMJ) destruction and distal axonal degeneration. Most importantly, motor neuron death results from pathological events occurring outside the motor neuron, especially in glial cells and skeletal muscle and, surprisingly, is associated with pathological defects outside the motor system. In particular, ALS pathogenesis includes systemic defects such as muscle hypermetabolism, energy deficit, and widespread alterations of lipid metabolism that were shown to participate in motor neuron degeneration. Current research should now focus on understanding the relationships between these pathological hallmarks and how such global defects lead to the ALS-linked selective loss of motor neurons.}, }
@article {pmid19378813, year = {2009}, author = {Wakabayashi, K and Tanji, K and Mori, F}, title = {[Pathology of basal ganglia in neurodegenerative diseases].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {4}, pages = {429-439}, pmid = {19378813}, issn = {1881-6096}, mesh = {Amyloid beta-Peptides/metabolism ; Basal Ganglia/anatomy &amp; histology/cytology/metabolism/*pathology ; DNA-Binding Proteins/metabolism ; Humans ; Neurodegenerative Diseases/metabolism/*pathology ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Intra- and/or extracellular proteinaceous inclusions in the brain tissue are characteristic pathological markers of many neurodegenerative diseases. Tau protein in neurofibrillary tangles and beta-amyloid in senile plaques are associated with Alzheimer's disease. Tau is associated with various neurological conditions, which are collectively referred to as tauopathies. Alpha-synucleinopathy is a term that collectively refers to a set of diseases in which neurodegeneration is accompanied by intracellular accumulation of alpha-synuclein in neurons or glial cells. Recently, TDP-43 has been identified as a major disease protein in the ubiquitinated inclusions in deseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration with tau-negative, ubiquitin-positive inclusions. Thus, these neurodegenerative disorders comprise a new disease class, namely, TDP-43 proteinopathy. In this article, we review the present understanding of histopathological features of basal ganglia lesions in protein conformation disorders, including tauopathy, alpha-synucleinopathy, and TDP-43 proteinopathy.}, }
@article {pmid19364361, year = {2009}, author = {Ludolph, AC and Kassubek, J and Landwehrmeyer, BG and Mandelkow, E and Mandelkow, EM and Burn, DJ and Caparros-Lefebvre, D and Frey, KA and de Yebenes, JG and Gasser, T and Heutink, P and Höglinger, G and Jamrozik, Z and Jellinger, KA and Kazantsev, A and Kretzschmar, H and Lang, AE and Litvan, I and Lucas, JJ and McGeer, PL and Melquist, S and Oertel, W and Otto, M and Paviour, D and Reum, T and Saint-Raymond, A and Steele, JC and Tolnay, M and Tumani, H and van Swieten, JC and Vanier, MT and Vonsattel, JP and Wagner, S and Wszolek, ZK and , }, title = {Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.}, journal = {European journal of neurology}, volume = {16}, number = {3}, pages = {297-309}, pmid = {19364361}, issn = {1468-1331}, support = {P50 AG008702/AG/NIA NIH HHS/United States ; P50 AG008702-11A19002/AG/NIA NIH HHS/United States ; P50 NS040256/NS/NINDS NIH HHS/United States ; P50-NS40256/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biomarkers ; Dementia/complications/genetics/physiopathology ; Drug Design ; Geography ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Models, Biological ; Mutation ; Niemann-Pick Disease, Type C/complications/diagnosis/physiopathology ; Parkinson Disease, Postencephalitic/complications/physiopathology ; Parkinsonian Disorders/*complications/pathology/physiopathology/therapy ; Pick Disease of the Brain/complications/pathology ; Protein Serine-Threonine Kinases/genetics ; Supranuclear Palsy, Progressive/complications/diagnosis/physiopathology ; Tauopathies/*complications/pathology/physiopathology/therapy ; tau Proteins/genetics ; }, abstract = {Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.}, }
@article {pmid19355908, year = {2009}, author = {Vucic, S and Kiernan, MC}, title = {Pathophysiology of neurodegeneration in familial amyotrophic lateral sclerosis.}, journal = {Current molecular medicine}, volume = {9}, number = {3}, pages = {255-272}, doi = {10.2174/156652409787847173}, pmid = {19355908}, issn = {1566-5240}, mesh = {Amyotrophic Lateral Sclerosis/classification/genetics/*pathology/*physiopathology ; Animals ; Ciliary Neurotrophic Factor/metabolism ; Glutamic Acid/toxicity ; Humans ; Intermediate Filament Proteins/genetics/metabolism ; Membrane Glycoproteins/genetics/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism/*pathology ; Mutation ; *Nerve Degeneration/pathology/physiopathology ; Nerve Tissue Proteins/genetics/metabolism ; Neurofilament Proteins/genetics/metabolism ; Peripherins ; Ribonuclease, Pancreatic/genetics/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival of Motor Neuron 1 Protein/genetics ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor neurons in the spinal cord, brainstem, and motor cortex. Ten percent of ALS cases are familial, with both autosomal dominant and recessive modes of inheritance reported. Mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the first gene linked with ALS, result in the classical ALS phenotype. To date, 135 mutations have been identified in the SOD-1 gene, accounting for approximately 20% of familial ALS cases. Mutations are widely distributed throughout the gene with preponderance for exon 4 and 5. Although mutations result in a toxic gain of function of the SOD-1 enzyme, which normally functions as a free radical scavenger, the mechanisms underlying motor neuron degeneration have not been clearly elucidated. Evidence is emerging of a complex interaction between genetic and molecular factors, with resultant damage of critical target proteins and organelles within the motor neuron. The clinical effectiveness afforded by anti-glutamatergic agents such as riluzole, suggests that glutamate excitotoxicity contributes to neurodegeneration in ALS, with glutamate excitotoxicity mediated via corticomotoneurons that provide a direct link between the motor cortex and the spinal motor neuron. This review provides an overview of the genetics of ALS, and describes recent advances in the understanding of the pathophysiological mechanisms underlying neurodegeneration.}, }
@article {pmid19348708, year = {2009}, author = {Valdmanis, PN and Daoud, H and Dion, PA and Rouleau, GA}, title = {Recent advances in the genetics of amyotrophic lateral sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {9}, number = {3}, pages = {198-205}, pmid = {19348708}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Chromosome Mapping ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; *Genetic Predisposition to Disease ; *Genetics ; Genome-Wide Association Study ; Humans ; Microsatellite Repeats/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with a low survival rate beyond 5 years from symptom onset. Although the genes that cause most cases of ALS are still unknown, several important genetic discoveries have been made recently that will bring substantial insight into some of the mechanisms involved in ALS. Mutations in two genes with related functions were recently reported in patients with familial ALS: the FUS/TLS gene at the ALS6 locus on chromosome 16 and the TARDBP gene at the ALS10 locus on chromosome 1. In addition, the first wave of genomewide association studies in ALS has been published. While these studies clearly show that there is no definitive and common highly penetrant allele that causes ALS, some interesting candidate genes emerged from these studies. The findings help to better delineate the types of genes and genetic variants that are involved in ALS and provide substantial material for future research.}, }
@article {pmid19348236, year = {2009}, author = {Mogi, M and Horiuchi, M}, title = {[New insights of ARB in central nervous system].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {67}, number = {4}, pages = {735-741}, pmid = {19348236}, issn = {0047-1852}, mesh = {Alzheimer Disease/drug therapy ; *Angiotensin Receptor Antagonists ; Animals ; Brain Diseases/*drug therapy ; Central Nervous System/*physiology ; Humans ; Stroke/drug therapy ; }, abstract = {Renin angiotensin aldosterone system (RAAS) in the central nervous system (CNS) and therapeutical effects of angiotensin II receptor blockers (ARBs) have been highlighted. In stroke, clinical trials exhibit to prevent primary onset or recurrence of stroke beyond anti-hypertensive effect, inhibition of atrial fibrillation and diabetes mellitus. ARB could be also expected to prevent cognitive impairment induced by such as Alzheimer disease, stroke and metabolic syndrome; however, clinical evidence has not been revealed to date. Angiotensin II levels in cerebrospinal fluid in patients with neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis is reduced, suggesting the role of RAAS in neural intractable diseases. These findings will provide us new therapeutic approaches of ARB in CNS disorder in t hefuture.}, }
@article {pmid19344253, year = {2009}, author = {Magrané, J and Manfredi, G}, title = {Mitochondrial function, morphology, and axonal transport in amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {7}, pages = {1615-1626}, pmid = {19344253}, issn = {1557-7716}, support = {R01 NS051419/NS/NINDS NIH HHS/United States ; R01 NS062055-01A1/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; R01 NS051419-04/NS/NINDS NIH HHS/United States ; R01-NS051419/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; *Axons ; Humans ; Mitochondria/*physiology ; Neurons/physiology ; }, abstract = {Perturbation of organellar axonal transport is increasingly recognized as an important contributor in a number of neurodegenerative diseases. Although the specificity of this impairment remains to be elucidated, growing evidence suggests that in certain disease conditions, mitochondria are affected primarily by transport defects. Many hypotheses have been formulated to explain the pathogenic mechanisms involved in amyotrophic lateral sclerosis (ALS). The mutations described so far in genetic forms of ALS (familial ALS, fALS) affect proteins involved in a wide variety of cellular mechanisms, including free radical scavenging, energy metabolism, axonal transport, RNA processing, DNA repair, vesicular transport, and angiogenesis. Here we review the current knowledge on mitochondrial transport and its role in ALS.}, }
@article {pmid19333444, year = {2009}, author = {Neumann, M}, title = {Molecular neuropathology of TDP-43 proteinopathies.}, journal = {International journal of molecular sciences}, volume = {10}, number = {1}, pages = {232-246}, pmid = {19333444}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Dementia/*genetics/metabolism/pathology ; Humans ; }, abstract = {The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.}, }
@article {pmid19309264, year = {2009}, author = {Trumbull, KA and Beckman, JS}, title = {A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {7}, pages = {1627-1639}, pmid = {19309264}, issn = {1557-7716}, support = {AT002034/AT/NCCIH NIH HHS/United States ; ES00240/ES/NIEHS NIH HHS/United States ; NS058628/NS/NINDS NIH HHS/United States ; T32 AT002688/AT/NCCIH NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Copper/*physiology ; Mice ; Mice, Transgenic ; Models, Molecular ; Motor Neurons/*physiology ; Protein Conformation ; Superoxide Dismutase/chemistry/*metabolism ; }, abstract = {In the 16 years since mutations to copper, zinc superoxide dismutase (SOD1) were first linked to familial amyotrophic lateral sclerosis (ALS), a multitude of apparently contradictory results have prevented any general consensus to emerge about the mechanism of toxicity. A decade ago, we showed that the loss of zinc from SOD1 results in the remaining copper in SOD1 to become extremely toxic to motor neurons in culture by a mechanism requiring nitric oxide. The loss of zinc causes SOD1 to become more accessible, more redox reactive, and a better catalyst of tyrosine nitration. Although SOD1 mutant proteins have a modestly reduced affinity for zinc, wild-type SOD1 can be induced to lose zinc by dialysis at slightly acidic pH. Our zinc-deficient hypothesis offers a compelling explanation for how mutant SOD1s have an increased propensity to become selectively toxic to motor neurons and also explains how wild-type SOD1 can be toxic in nonfamilial ALS patients. One critical prediction is that a therapeutic agent directed at zinc-deficient mutant SOD1 could be even more effective in treating sporadic ALS patients. Although transgenic mice experiments have yielded contradictory evidence to the zinc-deficient hypothesis, we will review more recent studies that support a role for copper in ALS. A more careful examination of the role of copper and zinc binding to SOD1 may help counter the growing disillusion in the ALS field about understanding the pathological role of SOD1.}, }
@article {pmid19303844, year = {2009}, author = {Lagier-Tourenne, C and Cleveland, DW}, title = {Rethinking ALS: the FUS about TDP-43.}, journal = {Cell}, volume = {136}, number = {6}, pages = {1001-1004}, pmid = {19303844}, issn = {1097-4172}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; R37 NS027036-23/NS/NINDS NIH HHS/United States ; RC1 NS069144/NS/NINDS NIH HHS/United States ; RC1 NS069144-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation ; Humans ; Mutation ; RNA-Binding Protein FUS/*metabolism ; }, abstract = {Mutations in TDP-43, a DNA/RNA-binding protein, cause an inherited form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Two recent studies (Kwiatkowski et al., 2009; Vance et al., 2009) now report that mutations in FUS/TLS, another DNA/RNA-binding protein, also trigger premature degeneration of motor neurons. TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as a key event in ALS pathogenesis.}, }
@article {pmid19303440, year = {2009}, author = {Quinones, MP and Kaddurah-Daouk, R}, title = {Metabolomics tools for identifying biomarkers for neuropsychiatric diseases.}, journal = {Neurobiology of disease}, volume = {35}, number = {2}, pages = {165-176}, doi = {10.1016/j.nbd.2009.02.019}, pmid = {19303440}, issn = {1095-953X}, support = {R01 NS054008/NS/NINDS NIH HHS/United States ; R24 GM078233/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Biomarkers/*metabolism ; Bipolar Disorder/genetics/metabolism/therapy ; Depressive Disorder/genetics/metabolism/therapy ; Depressive Disorder, Major/genetics/metabolism/therapy ; Environment ; Humans ; Huntington Disease/genetics/metabolism/therapy ; Mental Disorders/genetics/*metabolism/therapy ; Metabolomics/*methods ; Motor Neuron Disease/genetics/metabolism/therapy ; Parkinson Disease/genetics/metabolism/therapy ; Schizophrenia/genetics/metabolism/therapy ; }, abstract = {The repertoire of biochemicals (or small molecules) present in cells, tissue, and body fluids is known as the metabolome. Today, clinicians utilize only a very small part of the information contained in the metabolome, as revealed by the quantification of a limited set of analytes to gain information on human health. Examples include measuring glucose or cholesterol to monitor diabetes and cardiovascular health, respectively. With a focus on comprehensively studying the metabolome, the rapidly growing field of metabolomics captures the metabolic state of organisms at the global or "-omics" level. Given that the overall health status of an individual is captured by his or her metabolic state, which is a reflection of what has been encoded by the genome and modified by environmental factors, metabolomics has the potential to have a great impact upon medical practice by providing a wealth of relevant biochemical data. Metabolomics promises to improve current, single metabolites-based clinical assessments by identifying metabolic signatures (biomarkers) that embody global biochemical changes in disease, predict responses to treatment or medication side effects (pharmachometabolomics). State of the art metabolomic analytical platforms and informatics tools are being used to map potential biomarkers for a multitude of disorders including those of the central nervous system (CNS). Indeed, CNS disorders are linked to disturbances in metabolic pathways related to neurotransmitter systems (dopamine, serotonin, GABA and glutamate); fatty acids such as arachidonic acid-cascade; oxidative stress and mitochondrial function. Metabolomics tools are enabling us to map in greater detail perturbations in many biochemical pathways and links among these pathways this information is key for development of biomarkers that are disease-specific. In this review, we elaborate on some of the concepts and technologies used in metabolomics and its promise for biomarker discovery. We also highlight early findings from metabolomic studies in CNS disorders such as schizophrenia, Major Depressive Disorder (MDD), Bipolar Disorder (BD), Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD).}, }
@article {pmid19301596, year = {2009}, author = {Shindo, K}, title = {[Sympathetic neurograms in patients with neurodegenerative disorders--an overview].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {3}, pages = {263-269}, pmid = {19301596}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Electrophysiology/*methods ; Humans ; Microelectrodes ; Muscle, Skeletal/innervation ; Neurodegenerative Diseases/*diagnosis/physiopathology ; Parkinson Disease/diagnosis/physiopathology ; Skin/innervation ; Spinocerebellar Degenerations/diagnosis/physiopathology ; Sympathetic Nervous System/*physiopathology ; }, abstract = {Sympathetic nerve functions in patients with amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), and Parkinson disease (PD) were evaluated using microneurography. In patients with ALS, the muscle sympathetic nerve activity (MSNA) at rest was greater than that in healthy subjects and patients with other neuromuscular disorders. This finding is not observed in the advanced stages of ALS. The resting frequency of skin sympathetic nerve activity (SSNA) significantly greater in ALS patients than in healthy controls. In patients with SCD, the MSNA was slightly reduced, although these patients did not experience orthostatic dizziness or syncope, or significant fall in blood pressure during the head-up tilt test. The reflex latency of SSNA induced by electric stimulation was slightly but significantly prolonged in patients with cortical cerebellar atrophy and markedly prolonged in patients with multiple system atrophy-C (MSA-C). In patients with PD, a significantly negative correlation was observed between MSNA and age, and between MSNA and disease duration. In these patients, the resting frequency of SSNA was significantly lower than in healthy controls, while SSNA reflex latencies were similar to those in the controls. Further investigations to determine whether the autonomic nervous system was impaired are imperative for elucidating the pathogenesis of neurodegenerative disorders.}, }
@article {pmid19301431, year = {2009}, author = {Kim, SU and de Vellis, J}, title = {Stem cell-based cell therapy in neurological diseases: a review.}, journal = {Journal of neuroscience research}, volume = {87}, number = {10}, pages = {2183-2200}, doi = {10.1002/jnr.22054}, pmid = {19301431}, issn = {1097-4547}, support = {HD-006576/HD/NICHD NIH HHS/United States ; HD004612/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Nervous System Diseases/classification/*therapy ; *Stem Cell Transplantation ; Stem Cells/*physiology ; }, abstract = {Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.}, }
@article {pmid19294549, year = {2009}, author = {Lunn, JS and Hefferan, MP and Marsala, M and Feldman, EL}, title = {Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery.}, journal = {Growth factors (Chur, Switzerland)}, volume = {27}, number = {3}, pages = {133-140}, doi = {10.1080/08977190902814855}, pmid = {19294549}, issn = {1029-2292}, support = {NS051644-01A2/NS/NINDS NIH HHS/United States ; NS40386/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/therapy ; Axons/physiology ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacology/*therapeutic use ; Motor Neurons/*cytology/physiology ; Oxidative Stress ; Stem Cell Transplantation ; Stem Cells/*cytology/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by loss of both upper and lower motor neurons. ALS progression is complex and likely due to cellular dysfunction at multiple levels, including mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, axonal dysfunction, reactive astrocytosis, and mutant superoxide dismutase expression, therefore, treatment must provide neuronal protection from multiple insults. A significant amount of ALS research focuses on growth factor-based therapies. Growth factors including insulin-like growth factor-I, vascular endothelial growth factor, brain-derived neurotrophic factor, and glial-derived neurotrophic factor exhibit robust neuroprotective effects on motor neurons in ALS models. Issues concerning growth factor delivery, stability and unwanted side effects slow the transfer of these treatments to human ALS patients. Stem cells represent a new therapeutic approach offering both cellular replacement and trophic support for the existing population. Combination therapy consisting of stem cells expressing beneficial growth factors may provide a comprehensive treatment for ALS.}, }
@article {pmid19288861, year = {2009}, author = {Nishitoh, H and Ichijo, H}, title = {[Molecular mechanisms of ALS-linked mutant SOD1-induced motor neuron death].}, journal = {Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme}, volume = {54}, number = {3}, pages = {237-244}, pmid = {19288861}, issn = {0039-9450}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Animals ; Apoptosis/*genetics ; Endoplasmic Reticulum/physiology ; Humans ; MAP Kinase Kinase Kinase 5/physiology ; Membrane Proteins/metabolism ; Motor Neurons/*pathology ; Mutation ; Protein Binding ; Superoxide Dismutase/genetics/metabolism/*physiology ; Superoxide Dismutase-1 ; }, }
@article {pmid19282183, year = {2009}, author = {Sarge, KD and Park-Sarge, OK}, title = {Sumoylation and human disease pathogenesis.}, journal = {Trends in biochemical sciences}, volume = {34}, number = {4}, pages = {200-205}, pmid = {19282183}, issn = {0968-0004}, support = {R01 GM064606/GM/NIGMS NIH HHS/United States ; R01 GM061053/GM/NIGMS NIH HHS/United States ; R01 GM064606-04/GM/NIGMS NIH HHS/United States ; GM64606/GM/NIGMS NIH HHS/United States ; R01 GM064606-02/GM/NIGMS NIH HHS/United States ; R01 GM064606-03/GM/NIGMS NIH HHS/United States ; GM61053/GM/NIGMS NIH HHS/United States ; R01 GM061053-04/GM/NIGMS NIH HHS/United States ; R01 GM061053-03/GM/NIGMS NIH HHS/United States ; R01 GM064606-01A2/GM/NIGMS NIH HHS/United States ; }, mesh = {*Disease ; Humans ; Protein Binding ; SUMO-1 Protein/genetics/*metabolism ; }, abstract = {Covalent modification by SUMO polypeptides, or sumoylation, is an important regulator of the functional properties of many proteins. Among these are several proteins implicated in human diseases including cancer, Huntington's, Alzheimer's, and Parkinson's diseases, as well as spinocerebellar ataxia 1 and amyotrophic lateral sclerosis. Recent reports reveal two new examples of human disease-associated proteins that are SUMO modified: amyloid precursor protein and lamin A. These findings point to a function for sumoylation in modulating amyloid-beta peptide levels, indicating a potential role in Alzheimer's disease, and for decreased lamin A sumoylation as a causative factor in familial dilated cardiomyopathy.}, }
@article {pmid19280593, year = {2009}, author = {Gressel, J}, title = {Crops with target-site herbicide resistance for Orobanche and Striga control.}, journal = {Pest management science}, volume = {65}, number = {5}, pages = {560-565}, doi = {10.1002/ps.1738}, pmid = {19280593}, issn = {1526-4998}, mesh = {Crops, Agricultural/*drug effects/enzymology/genetics/parasitology ; *Herbicide Resistance ; Herbicides/*pharmacology ; Orobanche/*physiology ; Plant Diseases/*parasitology ; Plant Proteins/genetics/metabolism ; Striga/*physiology ; }, abstract = {It is necessary to control root parasitic weeds before or as they attach to the crop. This can only be easily achieved chemically with herbicides that are systemic, or with herbicides that are active in soil. Long-term control can only be attained if the crops do not metabolise the herbicide, i.e. have target-site resistance. Such target-site resistances have allowed foliar applications of herbicides inhibiting enol-pyruvylshikimate phosphate synthase (EPSPS) (glyphosate), acetolactate synthase (ALS) (e.g. chlorsulfuron, imazapyr) and dihydropteroate synthase (asulam) for Orobanche control in experimental conditions with various crops. Large-scale use of imazapyr as a seed dressing of imidazolinone-resistant maize has been commercialised for Striga control. Crops with two target-site resistances will be more resilient to the evolution of resistance in the parasite, if well managed.}, }
@article {pmid19271992, year = {2009}, author = {Chattopadhyay, M and Valentine, JS}, title = {Aggregation of copper-zinc superoxide dismutase in familial and sporadic ALS.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {7}, pages = {1603-1614}, pmid = {19271992}, issn = {1557-7716}, support = {P01 NS049134/NS/NINDS NIH HHS/United States ; P01 NS049134-04/NS/NINDS NIH HHS/United States ; P01-NS-49134/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Protein Folding ; Protein Structure, Secondary ; Superoxide Dismutase/chemistry/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by the selective death of motor neurons. While the most common form of ALS is sporadic and has no known cause, a small subset of cases is familial because of underlying genetic mutations. The best-studies example of familial ALS is that caused by mutations in the protein copper-zinc superoxide dismutase. The formation of SOD1-rich inclusions in the spinal cord is an early and prominent feature of SOD1-linked familial ALS in human patients and animal models of this disease. These inclusions have been shown to consist of SOD1-rich fibrils, suggesting that the conversion of soluble SOD1 into amyloid fibrils may play an important role in the etiology of familial ALS. SOD1 is also present in inclusions found in spinal cords of sporadic ALS patients, allowing speculations to arise regarding a possible involvement of SOD1 in the sporadic form of this disease. We here review the recent research on the significance, causes, and mechanisms of SOD1 fibril formation from a biophysical perspective.}, }
@article {pmid19271225, year = {2009}, author = {Nunomura, A and Hofer, T and Moreira, PI and Castellani, RJ and Smith, MA and Perry, G}, title = {RNA oxidation in Alzheimer disease and related neurodegenerative disorders.}, journal = {Acta neuropathologica}, volume = {118}, number = {1}, pages = {151-166}, doi = {10.1007/s00401-009-0508-1}, pmid = {19271225}, issn = {1432-0533}, mesh = {Aging ; Alzheimer Disease/*metabolism ; Animals ; Brain/*metabolism ; DNA/metabolism ; Disease Models, Animal ; Guanosine/analogs &amp; derivatives/metabolism ; Humans ; Hypoxia, Brain/physiopathology ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; RNA/*metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {RNA oxidation and its biological effects are less well studied compared to DNA oxidation. However, RNA may be more susceptible to oxidative insults than DNA, for RNA is largely single-stranded and its bases are not protected by hydrogen bonding and less protected by specific proteins. Also, cellular RNA locates in the vicinity of mitochondria, the primary source of reactive oxygen species. Oxidative modification can occur not only in protein-coding RNAs, but also in non-coding RNAs that have been recently revealed to contribute towards the complexity of the mammalian brain. Damage to coding and non-coding RNAs will cause errors in proteins and disturbances in the regulation of gene expression. While less lethal than mutations in the genome and not inheritable, such sublethal damage to cells might be associated with underlying mechanisms of degeneration, especially age-associated neurodegeneration that is commonly found in the elderly population. Indeed, oxidative RNA damage has been described recently in most of the common neurodegenerative disorders including Alzheimer disease, Parkinson disease, dementia with Lewy bodies and amyotrophic lateral sclerosis. Of particular interest, the accumulating evidence obtained from studies on either human samples or experimental models coincidentally suggests that oxidative RNA damage is a feature in vulnerable neurons at early-stage of these neurodegenerative disorders, indicating that RNA oxidation actively contributes to the onset or the development of the disorders. Further investigations aimed at understanding of the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative disorders and lead to better therapeutic strategies.}, }
@article {pmid19271105, year = {2009}, author = {Geser, F and Martinez-Lage, M and Kwong, LK and Lee, VM and Trojanowski, JQ}, title = {Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases.}, journal = {Journal of neurology}, volume = {256}, number = {8}, pages = {1205-1214}, pmid = {19271105}, issn = {1432-1459}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; AG10124/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; P01 AG017586-109002/AG/NIA NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; P30 AG010124-19S1/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Central Nervous System/*metabolism/pathology/physiopathology ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dementia/genetics/*metabolism/physiopathology ; Disease Progression ; Evolution, Molecular ; Genetic Predisposition to Disease/genetics ; Humans ; Nerve Degeneration/genetics/metabolism/physiopathology ; Neural Pathways/metabolism/pathology/physiopathology ; }, abstract = {Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to alpha-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.}, }
@article {pmid19263215, year = {2009}, author = {Bugos, O and Bhide, M and Zilka, N}, title = {Beyond the rat models of human neurodegenerative disorders.}, journal = {Cellular and molecular neurobiology}, volume = {29}, number = {6-7}, pages = {859-869}, pmid = {19263215}, issn = {1573-6830}, mesh = {Animals ; *Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*pathology ; Rats ; Rats, Transgenic ; }, abstract = {The rat is a model of choice in biomedical research for over a century. Currently, the rat presents the best "functionally" characterized mammalian model system. Despite this fact, the transgenic rats have lagged behind the transgenic mice as an experimental model of human neurodegenerative disorders. The number of transgenic rat models recapitulating key pathological hallmarks of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or human tauopathies is still limited. The reason is that the transgenic rats remain more difficult to produce than transgenic mice. The gene targeting technology is not yet established in rats due to the lack of truly totipotent embryonic stem cells and cloning technology. This extremely powerful technique has given the mouse a clear advantage over the rat in generation of new transgenic models. Despite these limitations, transgenic rats have greatly expanded the range of potential experimental approaches. The large size of rats permits intrathecal administration of drugs, stem cell transplantation, serial sampling of the cerebrospinal fluid, microsurgical techniques, in vivo nerve recordings, and neuroimaging procedures. Moreover, the rat is routinely employed to demonstrate therapeutic efficacy and to assess toxicity of novel therapeutic compounds in drug development. Here we suggest that the rat constitutes a slightly underestimated but perspective animal model well-suited for understanding the mechanisms and pathways underlying the human neurodegenerative disorders.}, }
@article {pmid19241985, year = {2009}, author = {Samphao, S and Eremin, JM and El-Sheemy, M and Eremin, O}, title = {Treatment of established breast cancer in post-menopausal women: role of aromatase inhibitors.}, journal = {The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland}, volume = {7}, number = {1}, pages = {42-55}, doi = {10.1016/s1479-666x(09)80066-8}, pmid = {19241985}, issn = {1479-666X}, mesh = {Aged ; Aromatase Inhibitors/*therapeutic use ; Breast Neoplasms/*drug therapy/pathology ; Female ; Humans ; Middle Aged ; *Postmenopause ; }, abstract = {Endocrine therapy plays a crucial and historically important role in the treatment ofwomen with hormone-responsive breast cancer. Tamoxifen has been the standard endocrine treatment for advanced and early-stage breast cancer for almost three decades. However, patients receiving tamoxifen may either fail to respond or develop disease recurrence following completion of therapy. The aromatase inhibitors (Als) have become the new and alternative modalities of endocrine treatment for post-menopausal women with oestrogen receptor-positive breast cancer, as a result of promising data from randomised trials in metastatic and locally advanced breast cancers. Recently, the results from several large, randomised, controlled adjuvant trials have provided further evidence that the use of Als, either as initial treatment or sequentially after tamoxifen, improves disease-free survival and, in certain patients, overall survival. With relatively short-term follow-up, the use of Als has been shown to be safe and welltolerated. Nevertheless, some detrimental adverse effects, particularly skeletal-related events or cardiovascular disease, remain important issues of concern and warrant continued monitoring and follow-up. The optimal use of Als, the appropriate timing of treatment, and the superiority of individual agents are under investigation. Use of Als in women with chemotherapy-induced amenorrhoea should be cautious due to the possibility of return of ovarian function. Cost-effectiveness and quality of life remain issues of interest since the high and ever increasing incidence of breast cancer has contributed to significant healthcare costs and patients with breast cancer following appropriate treatment are living longer but not necessarily being cured of their diseases.}, }
@article {pmid19241975, year = {2008}, author = {Zhang, YG and Tao, LY}, title = {[Recent advances of NF-kappaB in nervous system injury].}, journal = {Fa yi xue za zhi}, volume = {24}, number = {6}, pages = {453-456}, pmid = {19241975}, issn = {1004-5619}, mesh = {Alzheimer Disease/metabolism ; Brain Injuries/*metabolism ; Brain Ischemia/*metabolism ; *Forensic Medicine ; Humans ; NF-kappa B/*metabolism ; Reperfusion Injury/metabolism ; Time Factors ; }, abstract = {Diagnosis of nervous system injury is one of the most difficult issues in medical-legal practice. Nowadays, the activation of NF-kappaB has been studied by many researchers in order to find objective evidence and indicators to calculate the injury time and to diagnose the severity of brain injury for forensic practice. It was reviewed that the advances and problems of NF-kappaB and its correlation with nervous system injury and diseases, such as cerebral ischemia, traumatic brain injury, Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid19235466, year = {2009}, author = {Nonaka, T and Inukai, Y and Arai, T and Hasegawa, M}, title = {[Neurodegenerative disorders and TDP-43].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {2}, pages = {161-166}, pmid = {19235466}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Brain/*metabolism ; Casein Kinase I/physiology ; DNA-Binding Proteins/genetics/*metabolism ; Dementia/genetics ; Humans ; Mutation, Missense ; Neurodegenerative Diseases/*genetics ; Phosphorylation ; Protein Processing, Post-Translational ; Ubiquitination ; }, abstract = {In most neurodegenerative disorders, distinctive intracellular inclusion bodies are found in degenerative neurons, which are known to be neuropathological hallmarks of diseases. Recently, TAR DNA-binding protein of 43 KDa (TDP-43) has been identified as a major constituent protein of ubiquitin-positive inclusions in brains with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). These disorders are now referred to as TDP-43 proteinopathy. TDP-43 deposited in brains with FTLD and ALS was found to be phosphorylated and ubiquitinated. To study the role of these posttranslational modifications in the formation of TDP-43 aggregates, we have produced polyclonal and monoclonal antibodies specific for TDP-43 phosphorylated at Ser409 and Ser 410. These antibodies specifically recognized abnormally phosphorylated TDP-43, but not normal TDP-43 in immunohistochemical analyses of brains of FTLD and ALS patients. Immunoblot analyses using these antibodies showed that phosphorylated and fragmented TDP-43 was deposited in diseased brains. Furthermore, we identified casein kinase 1 as a candidate protein kinase, which was responsible for abnormal phosphorylation of TDP-43. Phosphorylated recombinant TDP-43 proteins were demonstrated to be easier to fibrillate than wild-type TDP-43 in vitro. Recent discoveries of the missense mutations in the TDP-43 gene in familial or sporadic ALS cases prove a direct link between altered TDP-43 function and neurodegeneration. Elucidating the biochemical processes responsible for phosphorylation, fragmentation, and intracellular aggregation of TDP-43 may provide important insights into the pathogenesis of TDP-43 proteinopathy.}, }
@article {pmid19231200, year = {2009}, author = {Eisen, A}, title = {Amyotrophic lateral sclerosis: A 40-year personal perspective.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {16}, number = {4}, pages = {505-512}, doi = {10.1016/j.jocn.2008.07.072}, pmid = {19231200}, issn = {0967-5868}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics/pathology/*therapy ; Animals ; Enteral Nutrition/methods ; Gastrostomy/methods ; Genetic Therapy/methods ; Humans ; Palliative Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) shares with other neurodegenetrative disorders of the aging nervous system a polygenic, multifactorial aetiology. Less than 10% are familial and these too probably are associated with several interactive genes. The onset of ALS predates development of clinical symptoms by an unknown interval which may extend several years. The cause of neurodegeneration remains unknown but a common end-point is protein misfolding which in turn causes cell function failure. The complex nature of ALS has hindered therapeutic advances. In recent years longer survival is attributable largely to institution of non-invasive ventilation with BiPAP and timely implementation of percutaneous endoscopic gastrostomy (PEG) feeding. Symptomatic treatment has advanced improving quality of life. Several encouraging avenues of therapy for ALS are beginning to be emerge raising hope for real benefit. They include protective autoimmunity, vaccines against misfolded protein epitopes and other deleterious species, new drug delivery systems employing nanotechnology and the potential of stem cell therapy.}, }
@article {pmid19229345, year = {2008}, author = {Staines, DR and Brenu, EW and Marshall-Gradisnik, S}, title = {Postulated role of vasoactive neuropeptide-related immunopathology of the blood brain barrier and Virchow-Robin spaces in the aetiology of neurological-related conditions.}, journal = {Mediators of inflammation}, volume = {2008}, number = {}, pages = {792428}, pmid = {19229345}, issn = {1466-1861}, mesh = {Animals ; Aquaporin 4/physiology ; Blood-Brain Barrier/*immunology/*pathology ; Brain/*immunology/*pathology ; Brain Diseases/etiology/*immunology/*pathology ; Humans ; Pituitary Adenylate Cyclase-Activating Polypeptide/*physiology ; Vasoactive Intestinal Peptide/*physiology ; }, abstract = {Vasoactive neuropeptides (VNs) such as pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, as well as immune and nociception modulators. They have key roles in blood vessels in the central nervous system (CNS) including maintaining functional integrity of the blood brain barrier (BBB) and blood spinal barrier (BSB). VNs are potent activators of adenylate cyclase and thus also have a key role in cyclic AMP production affecting regulatory T cell and other immune functions. Virchow-Robin spaces (VRSs) are perivascular compartments surrounding small vessels within the CNS and contain VNs. Autoimmunity of VNs or VN receptors may affect BBB and VRS function and, therefore, may contribute to the aetiology of neurological-related conditions including multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. VN autoimmunity will likely affect CNS and immunological homeostasis. Various pharmacological and immunological treatments including phosphodiesterase inhibitors and plasmapheresis may be indicated.}, }
@article {pmid19225343, year = {2009}, author = {Kong, GY and Van Bergen, NJ and Trounce, IA and Crowston, JG}, title = {Mitochondrial dysfunction and glaucoma.}, journal = {Journal of glaucoma}, volume = {18}, number = {2}, pages = {93-100}, doi = {10.1097/IJG.0b013e318181284f}, pmid = {19225343}, issn = {1536-481X}, mesh = {Age Factors ; Aging/physiology ; Animals ; Apoptosis ; Axons/metabolism/ultrastructure ; DNA, Mitochondrial/analysis/genetics ; Glaucoma, Open-Angle/genetics/*metabolism/pathology ; Humans ; Microscopy, Electron, Transmission ; Mitochondrial Diseases/genetics/*metabolism/pathology ; Optic Nerve Diseases/*metabolism/pathology ; Oxidative Stress ; Retinal Ganglion Cells/*metabolism/ultrastructure ; Risk Factors ; }, abstract = {Glaucoma is increasingly recognized as a neurodegenerative disorder, characterized by the accelerated loss of retinal ganglion cells (RGCs) and their axons. Open angle glaucoma prevalence and incidence increase exponentially with increasing age, yet the pathophysiology underlying increasing age as a risk factor for glaucoma is not well understood. Accumulating evidence points to age-related mitochondrial dysfunction playing a key role in the etiology of other neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer and Parkinson disease. The 2 major functions of mitochondria are the generation of ATP through oxidative phosphorylation and the regulation of cell death by apoptosis. This review details evidence to support our hypothesis that age-associated mitochondrial dysfunction renders RGCs susceptible to glaucomatous injury by reducing the energy available for repair processes and predisposing RGCs to apoptosis. Eliciting the role of mitochondria in glaucoma pathogenesis may uncover novel therapeutic targets for protecting the optic nerve and preventing vision loss in glaucoma.}, }
@article {pmid19224316, year = {2009}, author = {Phukan, J and Hardiman, O}, title = {The management of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {256}, number = {2}, pages = {176-186}, pmid = {19224316}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Caregivers/ethics/psychology/statistics &amp; numerical data ; Cognition Disorders/etiology/psychology/*therapy ; Genetic Predisposition to Disease/genetics ; Long-Term Care/ethics/methods/psychology ; Palliative Care/methods/standards ; Physician-Patient Relations/ethics ; Respiration, Artificial/standards ; Respiratory Insufficiency/etiology/physiopathology/therapy ; Withholding Treatment/ethics/standards ; }, abstract = {The terms amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) refer to a condition characterized by motor system degeneration with relative preservation of other pathways. Although there have been advances in symptomatic treatment, ALS remains an incurable condition. Advances in ALS management prolong survival but simultaneously raise challenging ethical dilemmas for physicians, patients and their families. Here, we review current practice in the management of ALS including pharmacological treatment, nutritional management, respiratory care, and evolving strategies in the management of cognitive impairment.}, }
@article {pmid19205885, year = {2009}, author = {Gogvadze, V and Orrenius, S and Zhivotovsky, B}, title = {Mitochondria as targets for chemotherapy.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {14}, number = {4}, pages = {624-640}, doi = {10.1007/s10495-009-0323-0}, pmid = {19205885}, issn = {1573-675X}, mesh = {Cell Death ; Humans ; Mitochondria/*physiology ; Models, Biological ; Neoplasms/*drug therapy ; Neurodegenerative Diseases/*physiopathology ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial malfunctioning is implicated in the pathogenesis of a variety of disorders, including cancer and multiple neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. Disturbance of mitochondrial vital functions, e.g., production of ATP, calcium buffering capacity, and generation of reactive oxygen species, can be potentially involved in disease pathogenesis. Neurological disorders caused by mitochondrial deterioration are often associated with cell loss within specific brain regions. In contrast, mitochondrial alterations in tumor cells and the "Warburg effect" might lead to cell survival and resistance of tumor cells to chemotherapy. This review is devoted to the role of mitochondria in neurodegeneration and tumor formation, and describes how targeting of mitochondria can be beneficial in the therapy of these diseases, which affect a large human population.}, }
@article {pmid19200006, year = {2009}, author = {Rapposelli, S and Digiacomo, M and Balsamo, A}, title = {P-gp transporter and its role in neurodegenerative diseases.}, journal = {Current topics in medicinal chemistry}, volume = {9}, number = {2}, pages = {209-217}, doi = {10.2174/156802609787521544}, pmid = {19200006}, issn = {1873-4294}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism ; Alzheimer Disease/metabolism ; Animals ; Brain/pathology ; Creutzfeldt-Jakob Syndrome/metabolism ; Humans ; Huntington Disease/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Parkinson Disease/metabolism ; }, abstract = {This paper describes an overview of recent insights concerning some socially relevant neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and Creutzfeldt-Jakob's (CJD) diseases, amyotrophic lateral sclerosis (ALS) and epilepsy. For each pathological state, the direct and/or indirect involvement of P-glycoprotein (P-gp) efflux transport is underlined. On this basis, P-gp still represents an innovative target which can offer new tools for the development of more effective and preventive therapeutic strategies for neurodegenerative disorders. For each of them, therefore, a possible use of drugs affecting P-gp transport activity has been suggested.}, }
@article {pmid19199926, year = {2009}, author = {Scheper, W and Hoozemans, JJ}, title = {Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy.}, journal = {Current medicinal chemistry}, volume = {16}, number = {5}, pages = {615-626}, doi = {10.2174/092986709787458506}, pmid = {19199926}, issn = {0929-8673}, mesh = {Animals ; Endoplasmic Reticulum/*metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress ; Proteins/*metabolism ; }, abstract = {Neurodegenerative disorders are often characterized by the aggregation and accumulation of misfolded proteins (e.g. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis). Aggregated proteins are very toxic to cells in culture and both in vitro and in vivo there is overwhelming evidence that these aberrant proteins are key players in neurodegeneration. Protein quality control is a cellular defense mechanism against misfolded proteins that prevents aggregate formation under physiological conditions. The presence of accumulated aggregates of misfolded proteins in many neurodegenerative disorders, suggests that protein quality control failed to restore homeostasis in these pathological conditions. In fact, evidence from observations in cellular disease models, mouse models, as well as from post mortem patient material indicates activation of the quality control machinery in response to the pathological process. In addition, interference with protein quality control by genetic or chemical manipulation often results in aggregate formation and neurodegeneration. This stresses the importance of proper quality control in neurodegenerative disorders and indicates that it may provide a target for therapeutic intervention. In this review we will focus on the protein quality control systems in the endoplasmic reticulum (ER) and address the involvement of ER quality control in neurodegenerative disease as well as its potential as therapeutic target.}, }
@article {pmid19198769, year = {2009}, author = {Rosenbloom, AL}, title = {Mecasermin (recombinant human insulin-like growth factor I).}, journal = {Advances in therapy}, volume = {26}, number = {1}, pages = {40-54}, doi = {10.1007/s12325-008-0136-5}, pmid = {19198769}, issn = {1865-8652}, mesh = {Cardiovascular Diseases/drug therapy ; Central Nervous System Diseases/drug therapy ; Clinical Trials as Topic ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; Dose-Response Relationship, Drug ; Growth Disorders/*drug therapy/physiopathology ; Growth Hormone/metabolism ; Human Growth Hormone/therapeutic use ; Humans ; Insulin Resistance ; Insulin-Like Growth Factor Binding Protein 3/therapeutic use ; Insulin-Like Growth Factor I/administration &amp; dosage/adverse effects/*therapeutic use ; Janus Kinase 2/metabolism ; Osteoporosis, Postmenopausal/drug therapy ; Receptor, IGF Type 1/metabolism ; Recombinant Proteins/administration &amp; dosage/adverse effects/*therapeutic use ; Time Factors ; }, abstract = {Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. Although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis-a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.}, }
@article {pmid19198144, year = {2008}, author = {Okamoto, K}, title = {[Early symptoms of frontotemporal lobar degeneration].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {999-1001}, doi = {10.5692/clinicalneurol.48.999}, pmid = {19198144}, issn = {0009-918X}, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*psychology ; Dementia/complications/diagnosis/*psychology ; Diagnosis, Differential ; Humans ; Reference Standards ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is the third most common cause of cortical dementia, following Alzheimer disease and dementia with Lewy body. Clinical criteria of FTLD were reviewed, and the initial symptoms, early neuropsychological and behavioral characteristics were also reviewed. In our own 205 ALS patients, 20 patients were dementia with ALS. In those cases, early and progressive loss of social awareness and insight and paragraphia were frequently observed. In ALS patients, especially patients with bulbar symptoms, we must carefully examine the mental functions and study the brains with MRI and SPECT/PET for detection of frontotemporal dysfunction.}, }
@article {pmid19198142, year = {2008}, author = {Hasegawa, M and Arai, T and Nonaka, T and Kametani, F and Yoshida, M and Hashizume, Y and Beach, TG and Morita, M and Nakano, I and Oda, T and Tsuchiya, K and Akiyama, H}, title = {[Significance of the TDP-43 deposition in FTLD-U and ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {994-997}, doi = {10.5692/clinicalneurol.48.994}, pmid = {19198142}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Antibodies ; DNA-Binding Proteins/*genetics/immunology ; Dementia/*genetics ; Humans ; Intranuclear Inclusion Bodies ; *Mutation ; Oligopeptides ; Ubiquitin ; }, abstract = {Tau-negative and ubiquitin-positive inclusions (UPI) are the pathological hallmarks of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, TDP-43, a heterogeneous nuclear ribonucleoprotein was identified as a component of these UPI. However, it remains to be determined whether TDP-43 is the major component of UPI, because only antibodies recognizing both normal and abnormal TDP-43 have been available. We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43. Of the generated antibodies, pS379, pS403/404, pS409, pS410 and pS409/410 clearly labeled UPI and glial cytoplasmic inclusions but not the nuclei. Immunoblot analyses of sarkosyl insoluble fractions demonstrated that the phosphorylation-specific antibodies recognized TDP-43 at -45 kDa, smearing substances and the -25 kDa fragment, all of which were present in the brains of FTLD-U and ALS but not controls. These antibodies did not recognize normal TDP-43 at 43 kDa. These results clearly indicate that abnormally phosphorylated full-length TDP-43 and the C-terminal fragments are the major component of UPI in FTLD-U and ALS. These findings together with recent discovery of mutations in the TDP-43 gene in ALS strongly suggest that TDP-43 is the}, }
@article {pmid19198141, year = {2008}, author = {Arai, T and Hasegawa, M and Nishihara, M and Nonaka, T and Kametani, F and Yoshida, M and Hashizume, Y and Beach, TG and Morita, M and Nakano, I and Oda, T and Tsuchiya, K and Akiyama, H}, title = {[Frontotemporal dementia (FTD) and genetic mutations including progranulin gene].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {990-993}, doi = {10.5692/clinicalneurol.48.990}, pmid = {19198141}, issn = {0009-918X}, mesh = {Adenosine Triphosphatases/*genetics ; Amyotrophic Lateral Sclerosis/genetics ; Cell Cycle Proteins/*genetics ; DNA-Binding Proteins/*genetics ; Dementia/classification/*genetics ; Humans ; Intercellular Signaling Peptides and Proteins/*genetics ; Intranuclear Inclusion Bodies/metabolism ; *Mutation ; Phosphorylation ; Progranulins ; Valosin Containing Protein ; tau Proteins/*genetics ; }, abstract = {Research on familial frontotemporal lobar degeneration (FTLD) has led to the discovery of disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN) and valosin-containing protein (VCP). TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a major component of tau-negative ubiquitin-positive inclusions in familial and sporadic FTLD and amyotrophic lateral sclerosis (ALS), which are now referred to as TDP-43 proteinopathy. Recent findings of mutations in TDP-43 gene in familial and sporadic ALS cases confirm the pathogenetic role for TDP-43 in neurodegeneration. TDP-43 proteinopathies have been classified into 4 pathological subtypes. Type 1 is characterized by numerous dystrophic neurites (DNs), Type 2 has numerous neuronal cytoplasmic inclusions (NCIs), Type 3 has NCIs and DNs and Type 4 has neuronal intranuclear inclusions (NIIs) and DNs. There is a close relationship between such pathological subtypes of TDP-43 proteinopathy and the immunoblot pattern of C-terminal fragments of accumulated TDP-43. These results parallel our earlier findings of differing C-terminal tau fragments in progressive supranuclear palsy and corticobasal degeneration, despite identical composition of tau isoforms. Taken together, these results suggest that elucidating the mechanism of C-terminal fragment origination may shed light on the pathogenesis of several neurodegenerative disorders involving TDP-43 proteinopathy and tauopathy.}, }
@article {pmid19198134, year = {2008}, author = {Tanaka, F and Waza, M and Niwa, J and Yamamoto, M and Sobue, G}, title = {[Exploration of pathogenesis-associated molecules and development of disease models for sporadic ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {970-972}, doi = {10.5692/clinicalneurol.48.970}, pmid = {19198134}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; *Disease Models, Animal ; Dynactin Complex ; Humans ; Mice ; Microtubule-Associated Proteins/genetics ; Mutation ; Superoxide Dismutase ; Superoxide Dismutase-1 ; Ubiquitin-Protein Ligases ; }, abstract = {The mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS and by the development and analysis of mutant SOD1 transgenic animal models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of SALS. Of these, in this paper, we will focus on Dorfin, a RING finger-type E3 ubiquitin ligase and dynactin1, a major component of dynein/dynactin complex that is important for retrograde axonal transport. We are now challenging creation of the disease models by simulating the gene expression changes specifically observed in SALS patients.}, }
@article {pmid19198133, year = {2008}, author = {Aoki, M and Warita, H and Itoyama, Y}, title = {[Amyotrophic lateral sclerosis with the SOD1 mutations].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {966-969}, doi = {10.5692/clinicalneurol.48.966}, pmid = {19198133}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Disease Models, Animal ; Hepatocyte Growth Factor/administration &amp; dosage ; Humans ; Injections, Spinal ; Mice ; *Mutation ; Rats ; Rats, Transgenic ; Recombinant Proteins/administration &amp; dosage ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Mutations in Cu/Zn superoxide dismutase (SOD1) have been linked to some familial cases of amyotrophic lateral sclerosis (ALS). In familial ALS kinders with mutations in the SOD1 gene, the age of onset of weakness varies greatly but the duration of illness appears to be characteristic to each mutation. For example, in patients with the L84V mutation, the average life expectancy is less than 1.5 year after the onset of symptoms, whereas patients harboring the H46R mutation have an average life expectancy of 18 years after the disease onset. In view of the evidence supporting the idea that familial ALS variants of SOD1 enzymes acquire toxic properties, the variations in the duration of illness in the different kinders might arise because each mutation imparts different degrees of toxicity to the mutant protein. We developed rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic (Tg) rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in Tg rats. The results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.}, }
@article {pmid19198130, year = {2008}, author = {Nakajima, T}, title = {[Ethics does not solve issues of ALS care, but palliative care does].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {958-960}, doi = {10.5692/clinicalneurol.48.958}, pmid = {19198130}, issn = {0009-918X}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Palliative Care/*ethics ; Patient Care/*ethics ; Quality of Health Care ; Quality of Life ; }, }
@article {pmid19198126, year = {2008}, author = {Mori, H}, title = {[Diffusion tensor imaging].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {945-946}, doi = {10.5692/clinicalneurol.48.945}, pmid = {19198126}, issn = {0009-918X}, mesh = {Alzheimer Disease/diagnosis ; Amyotrophic Lateral Sclerosis/diagnosis ; Brain/*pathology ; Diagnosis, Differential ; Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Radiosurgery ; Schizophrenia/diagnosis ; }, abstract = {Diffusion tensor imaging of magnetic resonance imaging, including diffusion tensor tractography, is a unique tool to visualize and segment the white matter pathways in vivo and one can evaluate the segmented trace quantitatively. Three dimensional visualization of the white matter fibers, such as corticospinal (pyramidal) tracts, with relationship to brain lesions (infarcts, vascular malformations and brain tumors) is extremely helpful for stereotactic radiosurgery, preoperative evaluation and intraoperative navigation. Quantitative measurement of the tract is a very sensitive method to detect differences in the tract in neurodegenerative/neurocognitive/psychiatric patients such as amyotrophic lateral sclerosis, schizophrenia and Alzheimer diseases. Importance of this tool will become more significant in clinical and neuroscience fields in the future.}, }
@article {pmid19198093, year = {2008}, author = {Horikawa, Y}, title = {[Construction of regional system in support of homecare--what's required for clinical neurologist from patients].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {11}, pages = {826-830}, doi = {10.5692/clinicalneurol.48.826}, pmid = {19198093}, issn = {0009-918X}, mesh = {Aged ; Caregivers ; Community Health Services/organization &amp; administration ; Female ; Home Care Services/*organization &amp; administration ; *House Calls ; Humans ; Insurance, Long-Term Care ; Japan ; Male ; Nervous System Diseases/*nursing ; *Neurology ; Patient Discharge ; *Physician's Role ; Respiration, Artificial ; }, abstract = {In 1965 I became a member of the newly-established department of neurology in Brain Research Institute of Niigata University. One of the most important theme for clinical neurologist was to offer medical care after discharge from hospital for serious or intractable neurological disease patients who would soon become unable to come to outpatient clinic. In 1978 Shinrakuen hospital in Niigata City launched the Continuing Medical Care Section providing home visit by doctors and periodical home nursing for medically dependent homecare patients. The stuff of that section started home care program for TPPV patient suffering from ALS from 1987. In 1990, they promoted with the members of Japan ALS Association the establishment the public rental system of Niigata prefecture of ventilator and the accessory medical instruments. They also collaborated with the stuff of the city office to establish the liaison conference for care of the intractable disease patients in Niigata City, which resulted in improvement of education and produced many useful system. The author opened in 1997 an organized clinic of internal and neurological medicine and on the basis of long term care insurance program in 2000 put into practice the home care system of cooperation between municipal administration, medicine and nursing.}, }
@article {pmid19192301, year = {2009}, author = {Wijesekera, LC and Leigh, PN}, title = {Amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {4}, number = {}, pages = {3}, pmid = {19192301}, issn = {1750-1172}, support = {/WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics/pathology ; DNA-Binding Proteins/genetics ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; Mutation ; Prognosis ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per 100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio approximately 1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases. Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2-5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.}, }
@article {pmid19191306, year = {2009}, author = {Brooks, BR}, title = {Managing amyotrophic lateral sclerosis: slowing disease progression and improving patient quality of life.}, journal = {Annals of neurology}, volume = {65 Suppl 1}, number = {}, pages = {S17-23}, doi = {10.1002/ana.21544}, pmid = {19191306}, issn = {1531-8249}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/psychology/*therapy ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Apoptosis/drug effects ; Disease Models, Animal ; Disease Progression ; Genetic Therapy ; Humans ; Immunization/methods ; Motor Neurons/pathology ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; *Quality of Life ; RNA, Small Interfering/genetics ; Stem Cell Transplantation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {It is now possible to slow the disease progression of amyotrophic lateral sclerosis (ALS), but documented improvement in the quality of life of ALS patients has been difficult to quantitate. Putative mechanisms involved in motor neuron degeneration in ALS include oxidative damage, mitochondrial dysfunction, neuroinflammation, growth factor deficiency, and glutamate excitotoxicity. Several pharmacological agents that target these potential targets have demonstrated therapeutic potential in animal models with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Many treatments that have been moderately effective in this animal model have not been successfully translated into effective treatments for humans with ALS. Only the glutamate modulator riluzole has demonstrated efficacy in clinical trials and is approved for treating ALS. Combination treatments may represent a potential therapeutic strategy to more robustly prolong life and preserve function, but only vitamin E with riluzole has been formally studied in clinical trials, and to date, no combination treatments have been found to be more effective than currently available single agents.}, }
@article {pmid19191304, year = {2009}, author = {Rothstein, JD}, title = {Current hypotheses for the underlying biology of amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {65 Suppl 1}, number = {}, pages = {S3-9}, doi = {10.1002/ana.21543}, pmid = {19191304}, issn = {1531-8249}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/pathology/*physiopathology ; Animals ; Axonal Transport ; Axons/pathology ; Caspases/metabolism ; Cell Death ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Humans ; Mitochondria/pathology ; Motor Neurons/pathology ; *Mutation ; Neuroglia/pathology ; Oxidative Stress ; Polymorphism, Single Nucleotide ; RNA/genetics/metabolism ; Superoxide Dismutase/deficiency/*genetics ; Superoxide Dismutase-1 ; }, abstract = {The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression.}, }
@article {pmid19187001, year = {2009}, author = {Carter, BJ and Anklesaria, P and Choi, S and Engelhardt, JF}, title = {Redox modifier genes and pathways in amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {7}, pages = {1569-1586}, pmid = {19187001}, issn = {1557-7716}, support = {P30 DK054759/DK/NIDDK NIH HHS/United States ; R01 DK051315/DK/NIDDK NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, Transgenic ; NADPH Oxidases/metabolism ; Oxidation-Reduction ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism/catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches.}, }
@article {pmid19184563, year = {2009}, author = {Kanekura, K and Suzuki, H and Aiso, S and Matsuoka, M}, title = {ER stress and unfolded protein response in amyotrophic lateral sclerosis.}, journal = {Molecular neurobiology}, volume = {39}, number = {2}, pages = {81-89}, pmid = {19184563}, issn = {0893-7648}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Endoplasmic Reticulum/*metabolism ; Humans ; Oxidative Stress ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Vesicular Transport Proteins/genetics/metabolism ; }, abstract = {Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.}, }
@article {pmid19182472, year = {2009}, author = {Kertesz, A}, title = {Clinical features and diagnosis of frontotemporal dementia.}, journal = {Frontiers of neurology and neuroscience}, volume = {24}, number = {}, pages = {140-148}, doi = {10.1159/000197893}, pmid = {19182472}, issn = {1660-4431}, mesh = {Dementia/classification/*diagnosis/*physiopathology ; Humans ; }, abstract = {Frontotemporal degeneration (FTD), formerly known as Pick's disease has become recognized as a distinct and relatively common entity encompassing behavioural (bvFTD language (PPA) and extrapyramidal (CBD/PSP) presentations. Further clinical subdivisions such as semantic dementia(SD), and pathological subtypes such as mesial temporal sclerosis increase the complexity of diagnosis.The relatively younger age of onset, the typical presentations of syndromes and focal asymmetrical frontotemporal atrophy on imaging allows experienced clinicians to make the diagnosis confidently as long as the overlap between the syndromes is recognized. There is also an overlap with ALS pathologically and clinically. The underlying histology in FTD/Pick complex is ubiquitin positive tau and synuclein negative neuronal inclusions (FTLD-U) in more than half of autopsies and tau positive CBD/PSP/ Pick bodies (FTLD-T) in the rest. The clinical syndromes of bvFTD and SD are likely associated with FTLD-U and PPA/CBDS/PSP with FTLD-T, but there is too much overlap to predict the pathology from the clinical syndromes reliably. The ubiquitin-tau pathological dichotomy is best considered under the Pick complex umbrella to allow for the significant overlap. So far trazodone in behavior and galantamine in aphasia had symptomatic benefit in small trials and SSRI-sand antipsychotics in uncontrolled reports were used as symptomatic therapies. Recent discoveries of tau and progranulin (in the ubiquitin-positive cases) mutations on chromosome 17 and other mutations on chromosome 3 and 9 in the high incidence of autosomal dominant families and a common protein abnormality, the TDP-43 in FTLD-U and ALS are likely to be important in finding therapeutic targets.}, }
@article {pmid19180349, year = {2010}, author = {Raaphorst, J and de Visser, M and Linssen, WH and de Haan, RJ and Schmand, B}, title = {The cognitive profile of amyotrophic lateral sclerosis: A meta-analysis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {27-37}, doi = {10.3109/17482960802645008}, pmid = {19180349}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Cognition Disorders/etiology/*physiopathology ; Humans ; Memory Disorders/etiology/*physiopathology ; }, abstract = {We aimed to clarify the profile of cognitive impairment in ALS, by meta-analysis of published studies. Criteria for inclusion were: ALS diagnosed according to El Escorial criteria; control group matched for age and education; correction for bias due to motor impairment or dysarthria; no dementia in patients and controls. Effect sizes reflecting a difference in neuropsychological performance between ALS patients and controls were calculated for 12 cognitive domains. The effect of demographic and clinical variables (age, disease duration, site of onset) on cognition was assessed in a moderator analysis. Of 48 eligible articles, 16 studies encompassing 554 ALS patients were included. Significant effect sizes were found for the Mini Mental State Examination (d=0.8), immediate verbal memory (d=0.5), visual memory (d=0.4), fluency (d=0.5), psychomotor speed (d=0.7), language (d=0.5) and executive functioning (d=0.3). The results of the latter three domains are less reliable due to the possibility of publication bias. Psychomotor speed, and to a lesser extent fluency, may have been influenced by motor impairment, despite attempts to correct for motor slowness. In conclusion, the diversity of cognitive problems in ALS seems greater than was previously thought. ALS patients may suffer from cognitive impairment in multiple domains, including memory dysfunction.}, }
@article {pmid19160266, year = {2009}, author = {Benatar, M and Kurent, J and Moore, DH}, title = {Treatment for familial amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2009}, number = {1}, pages = {CD006153}, pmid = {19160266}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Celecoxib ; Creatine/therapeutic use ; Fructose/analogs &amp; derivatives/therapeutic use ; Humans ; Motor Neuron Disease/drug therapy ; Neuroprotective Agents/therapeutic use ; Pyrazoles/therapeutic use ; Randomized Controlled Trials as Topic ; Sulfonamides/therapeutic use ; Topiramate ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a rare neurodegenerative disease. Approximately 5% to 7% of ALS/MND patients report a family history of a similarly affected relative. Superoxide dismutase-1 gene mutations are the cause in about 20% of familial cases. In those with non-familial (sporadic) ALS/MND the cause is unknown. Also unknown is whether patients with familial and sporadic ALS/MND respond differently to treatment.<br><br>OBJECTIVES: To systematically review the literature and to answer the specific question: 'Is there a difference in the response to treatment between patients with sporadic and familial forms of ALS?'<br><br>SEARCH STRATEGY: In May 2006 we searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966 to May 2006) and EMBASE (January 1980 to May 2006) for randomized controlled trials (RCTs). Two review authors read the titles and abstracts of all articles and reviewed the full text of all possibly relevant articles. We scanned references of all included trials to identify additional relevant articles. For all trials eligible for inclusion we contacted the authors to request the necessary raw data.<br><br>SELECTION CRITERIA: Studies had to meet two criteria: (a) randomized controlled study design, and (b) inclusion of patients with both familial and sporadic ALS/MND.<br><br>DATA COLLECTION AND ANALYSIS: We attempted to contact authors of all trials that met inclusion criteria. We obtained data regarding ALS/MND type (sporadic versus familial), treatment assignment (active versus placebo), survival and ALS Functional Rating Scale scores for four large RCTs that included 822 sporadic and 41 familial ALS patients. We could not obtain data from 25 potentially eligible studies (17 trial authors could not be contacted and eight were unwilling to provide data).<br><br>MAIN RESULTS: There was no statistical evidence for a different response to treatment in patients with familial ALS/MND compared to those with sporadic ALS/MND. The pooled estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among patients with familial ALS/MND, but the result was not statistically significant. Estimates of the rate of decline on the ALS Functional Rating Scale also suggested a slightly better response to treatment among those with familial ALS/MND, but the result was not statistically significant.<br><br>AUTHORS' CONCLUSIONS: Future RCTs should document whether patients with familial ALS/MND are included and the presence or absence of a mutation in the superoxide dismutase-1 gene amongst those with familial ALS/MND.}, }
@article {pmid19137121, year = {2008}, author = {Rosen, H}, title = {Dextromethorphan/quinidine sulfate for pseudobulbar affect.}, journal = {Drugs of today (Barcelona, Spain : 1998)}, volume = {44}, number = {9}, pages = {661-668}, pmid = {19137121}, issn = {1699-3993}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; P01 AG019724-080005/AG/NIA NIH HHS/United States ; 1 P50 AG-03-006-01/AG/NIA NIH HHS/United States ; P50 AG023501-066166/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; 2 P01 AG019724-06/AG/NIA NIH HHS/United States ; }, mesh = {Antidepressive Agents, Tricyclic/therapeutic use ; Clinical Trials as Topic ; Dextromethorphan/adverse effects/pharmacology/*therapeutic use ; Drug Combinations ; Humans ; Pseudobulbar Palsy/diagnosis/*drug therapy/physiopathology ; Quinidine/adverse effects/pharmacology/*therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; }, abstract = {A new agent containing a combination of dextromethorphan (DM) and quinidine (Q) is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a disorder of emotional regulation, characterized by uncontrollable outbursts of laughing and/or crying that are disproportionate to the emotions being experienced. The pathophysiology of PBA is currently unknown, although the disorder is thought to occur exclusively in the setting of neurological disease. The most influential theory on PBA posits that emotional outbursts are being generated autonomously in the brain stem due to loss of regulatory control by the frontal lobe. Although rarely life-threatening, PBA can have significant impact on patient quality of life, and thus merits treatment. There are currently no approved treatments for PBA. Several agents have been found to be effective in small placebo-controlled trials and case series, with the most commonly used agents being tricyclic antidepressants and selective serotonin reuptake inhibitors. Both these treatments are inexpensive and relatively low-risk, although the quality and quantity of data available on their efficacy are not optimal. DM has several pharmacological mechanisms of action relevant to the brain. It is an N-methyl-D-aspartate (NMDA) receptor antagonist, which prompted investigators to study its potential for slowing progression in amyotrophic lateral sclerosis (ALS), where glutamate toxicity is thought to be a factor. The combination agent DM/Q was developed to slow the metabolism of DM by P450 2D6 enzymes in the liver. DM/Q was not effective in slowing ALS progression, but patients noted that it helped to control their emotional outbursts, suggesting it might be useful as a treatment for PBA. DM is also a sigma-1 receptor agonist. These receptors are widely distributed in the brain, but probably most heavily in the limbic system, suggesting that DM may exert its emotion-controlling effects via these receptors. The endogenous ligands for sigma-1 receptors are not altogether known, although they appear to include gonadal steroids. DM/Q was recently shown to be effective in reducing the severity of PBA in two large studies of ALS and multiple sclerosis, which are probably the most common neurological settings. These are the largest treatment studies of PBA ever done. The agent was safe and relatively well tolerated. Further studies are being conducted to see if efficacy can be maintained with lower doses of quinidine. If DM/Q is approved by the U.S. Food and Drug Administration for treatment of PBA, it would be the first agent approved for this purpose. Currently, the antidepressants are probably the most attractive pharmacologic options for treatment of PBA. The choice of whether to use DM/Q in this setting will likely depend on individual patient factors as well as cost.}, }
@article {pmid19134494, year = {2009}, author = {Cohen, SM and Elackattu, A and Noordzij, JP and Walsh, MJ and Langmore, SE}, title = {Palliative treatment of dysphonia and dysarthria.}, journal = {Otolaryngologic clinics of North America}, volume = {42}, number = {1}, pages = {107-21, x}, doi = {10.1016/j.otc.2008.09.010}, pmid = {19134494}, issn = {0030-6665}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Communication Aids for Disabled ; Disease Progression ; Dysarthria/etiology/*therapy ; Dysphonia/etiology/*therapy ; Humans ; Laryngectomy ; Multiple Sclerosis/complications ; *Palliative Care ; Parkinson Disease/therapy ; Prognosis ; Quality of Life ; Stroke/complications/therapy ; Vocal Cord Paralysis/therapy ; }, abstract = {The focus of this article is the palliative treatment of a variety of dysphonic conditions. Symptomatic relief of hoarseness can be achieved by voice therapy, augmentative alternative communication modalities, and surgery. The causes of dysphonia addressed herein include amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, stroke, head and neck cancers requiring glossectomy or laryngectomy, unilateral vocal fold paralysis, and presbyphonia. Palliative treatment of dysphonia and voice disorders provides symptomatic relief but not a cure of the underlying disease state. For these patients there are a number of palliative interventions that can greatly improve their quality of life.}, }
@article {pmid19128238, year = {2008}, author = {Srivastava, AS and Malhotra, R and Sharp, J and Berggren, T}, title = {Potentials of ES cell therapy in neurodegenerative diseases.}, journal = {Current pharmaceutical design}, volume = {14}, number = {36}, pages = {3873-3879}, doi = {10.2174/138161208786898617}, pmid = {19128238}, issn = {1873-4286}, mesh = {Animals ; Cell Transplantation ; *Embryonic Stem Cells ; Humans ; Mice ; Nerve Growth Factors/administration &amp; dosage/therapeutic use ; Neurodegenerative Diseases/drug therapy/*therapy ; }, abstract = {Neurodegenerative diseases comprise a heterogeneous spectrum of neural disorders that cause severe and progressive cognitive and motor deficits. A histological hallmark of these disorders is the occurrence of disease-specific cell death in specific regional subpopulations of neurons, such as the loss of dopaminergic neurons in the substantia nigra in Parkinson's disease. Neurodegenerative disease can also possibly occur from the loss or dysfunction of selected glial cell subsets, such as the dysfunction of supportive glial cells around somatic motor neurons in amyotrophic lateral sclerosis. The central nervous system (CNS), unlike many other tissues, has a very limited capacity for self-repair. Mature nerve cells lack the ability to regenerate, although endogenous neural stem cells exist in the adult brain that do have very limited ability to generate new functional neurons in response to injury. Rapid advances in stem cell biology have opened an alternative, fascinating perspective of neurogenesis by activation of endogenous neural stem cells and/or transplantation of in vitro-expanded stem cells and/or their neuronal- or glial-differentiated progeny. Embryonic stem (ES) cells, because of their ability to provide seemingly unlimited supply of specific cell types, their amenability to genetic engineering manipulations, and their broad developmental potential, are expected to become a cell source and biological delivery system for use in a variety of neurodegenerative diseases, and are likely to play a role in the development of novel cell-based therapies for these indications. However, before the full potential of ES cells can be realized for regenerative medicine, we need to understand mechanisms regulating their proliferation, differentiation into therapeutically relevant cells, and most importantly in the case of neuronal and glial lineages, to characterize their functional properties. In the present review we will be focusing on the factors and methodologies responsible for differentiation of ES cell into different neural precursors and neural cell lineages with particular emphasis on the potential research and clinical applications of ES cells in the field of neurodegenerative disease.}, }
@article {pmid19128208, year = {2008}, author = {Chen, LW and Yung, KK and Chan, YS and Shum, DK and Bolam, JP}, title = {The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson's disease.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {6}, pages = {512-523}, doi = {10.2174/187152708787122923}, pmid = {19128208}, issn = {1996-3181}, mesh = {Adaptor Proteins, Vesicular Transport/*metabolism/physiology ; Animals ; Antiparkinson Agents/metabolism/pharmacology/*therapeutic use ; Drug Delivery Systems/*methods/trends ; Humans ; Nerve Growth Factor/*metabolism ; Parkinson Disease/drug therapy/*metabolism ; Protein Precursors/*metabolism ; Receptor, Nerve Growth Factor/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Growing evidence has shown that the p75 neurotrophin receptor (p75NTR) may play important roles in controlling neuronal survival or cell apoptosis within the central nervous system in development, and in pathological or neural injury. Recent studies have further revealed that p75NTR acts as a "molecular signal switch" that determines cell death or survival by three processes. First, pro-nerve growth factor (proNGF) triggers cell apoptosis by its high affinity binding to p75NTR, while NGF induces neuronal survival with low-affinity binding. Second, p75NTR mediates cell death by combining with co-receptor sortilin, whereas it promotes neuronal survival through combination with proNGF. Third, release of the intracellular domain chopper or cleavaged "short p75NTR" can independently initiate neuronal apoptosis. We have identified the cell self-destructive proNGF-p75NTR-sortilin signalling apparatus assembled in ventral tier dopamine neurons of the substantia nigra pars compacta, suggesting that p75NTR signalling might be involved in selective cell death mechanisms of substantia nigra neurons or disease progression of Parkinson's disease (PD). In addition, experimental manipulation of p75NTR benefited cell survival of cholinergic or motor neurons and improved disease progression of the neurodegenerative diseases Alzheimer's disease and Amyotrophic lateral sclerosis. The proNGF-p75NTR-sortilin signalling complex may thus provide new target for neuroprotection of substantia nigra neurons and the therapeutic treatment of PD.}, }
@article {pmid20225023, year = {2009}, author = {Palau, F and Estela, A and Pla-Martín, D and Sánchez-Piris, M}, title = {The role of mitochondrial network dynamics in the pathogenesis of Charcot-Marie-Tooth disease.}, journal = {Advances in experimental medicine and biology}, volume = {652}, number = {}, pages = {129-137}, doi = {10.1007/978-90-481-2813-6_9}, pmid = {20225023}, issn = {0065-2598}, mesh = {Charcot-Marie-Tooth Disease/*etiology/*metabolism/pathology ; Humans ; Mitochondria/*metabolism ; Nerve Degeneration/metabolism/pathology ; }, abstract = {Mitochondrial dysfunction plays a relevant role in the pathogenesis of neurological and neuromuscular diseases. Mitochondria may be involved as a primary defect of either the mtDNA or nuclear genome encoded subunits of the respiratory chain. These organelles have also been directly involved in the pathogenesis of Mendelian neurodegenerative disorders caused by mutations in nuclear-encoded proteins targeted to mitochondria, such as Friedreich ataxia, hereditary spastic paraplegia, or some monogenic forms of Parkinson disease. In addition, mitochondria also participate in the pathogenic mechanisms affecting neurodegenerative disorders such Huntington disease or amyotrophic lateral sclerosis. Cell death in neurodegeneration associated with neurological diseases usually occurs by apoptosis being the most common route the intrinsic mitochondria pathway. Along with regulation of apoptosis, mitochondria also modulate cell pathogenesis by means of energy production, reactive oxygen species (ROS) generation, and calcium buffering. Mitochondria form dynamic tubular networks that continually change their shape and move throughout the cell. Here we review the critical role of mitochondria in monogenic neuromuscular disorders, especially inherited peripheral neuropathies caused by abnormal mitochondrial network dynamics. In yeast, at least three proteins are required for mitochondrial fusion, Fzo1, Ugo1 and Mgm1. The human counterparts of Fzo1p and Mgm1p, MFN1/MFN2 and OPA1 respectively, are related to human disease. Mutations in the MFN2 gene cause the most frequent form of autosomal dominant axonal Charcot-Marie-Tooth disease, CMT2A. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA). For the opposite process of mitochondrial fission, four proteins are at least involved in yeast. Very recently a mutation in the DRP1 gene (the human homologue of yeast Dnm1) has been reported in an infant with a syndrome with encephalopathy, optic atrophy and lactic acidosis. GDAP1 has been recently related to the mitochondrial fission in mammalian cells and, interestingly, mutations in the GDAP1 gene are the cause of the most common form of autosomal recessive CMT, either axonal or demyelinating. These and other disorders are the most recent instances of disease related with mitochondrial abnormal motility, fusion and fission. We propose that the pathomechanisms underlying these disorders also include a complex relationship between mitochondrial dynamics and transport across the axon.}, }
@article {pmid19116946, year = {2010}, author = {Maurer, MH}, title = {Proteomics of brain extracellular fluid (ECF) and cerebrospinal fluid (CSF).}, journal = {Mass spectrometry reviews}, volume = {29}, number = {1}, pages = {17-28}, doi = {10.1002/mas.20213}, pmid = {19116946}, issn = {1098-2787}, mesh = {*Brain Chemistry ; Brain Injuries/cerebrospinal fluid/diagnosis ; Cerebrospinal Fluid/*chemistry ; Cerebrospinal Fluid Proteins/analysis ; Equipment Design ; Extracellular Fluid/*chemistry ; Humans ; Microdialysis/instrumentation/*methods ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Proteins/*analysis ; Proteomics/*methods ; }, abstract = {Mass spectrometry has become the gold standard for the identification of proteins in proteomics. In this review, I will discuss the available literature on proteomic experiments that analyze human cerebrospinal fluid (CSF) and brain extracellular fluid (ECF), mostly obtained by cerebral microdialysis. Both materials are of high diagnostic value in clinical neurology, for example, in cerebrovascular disorders like stroke, neurodegenerative diseases like Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury and cerebral infectious and inflammatory disease, such as multiple sclerosis. Moreover, there are standard procedures for sampling. In a number of studies in recent years, biomarkers have been proposed in CSF and ECF for improved diagnosis or to control therapy, based on proteomics and mass spectrometry. I will also discuss the needs for a transition of research-based experimental screening with mass spectrometry to fast and reliable diagnostic instrumentation for clinical use.}, }
@article {pmid19116118, year = {2008}, author = {Dupuis, L and Loeffler, JP}, title = {[Amyotrophic lateral sclerosis: role of energy deficiency in neuromuscular junction dismantlement].}, journal = {Medecine sciences : M/S}, volume = {24}, number = {12}, pages = {1077-1082}, doi = {10.1051/medsci/200824121077}, pmid = {19116118}, issn = {0767-0974}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/genetics/*metabolism ; Animals ; Astrocytes/enzymology ; Disease Models, Animal ; *Energy Metabolism ; Humans ; Macrophages/enzymology ; Mice ; Mice, Transgenic ; Models, Neurological ; Motor Neurons/enzymology ; Muscle Cells/enzymology ; Muscle Proteins/metabolism ; Myelin Proteins/deficiency/physiology ; Nerve Tissue Proteins/metabolism ; Neuromuscular Junction/*metabolism ; Nogo Proteins ; Phenotype ; Species Specificity ; Superoxide Dismutase/deficiency/genetics/physiology ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent adult onset motor neuron disorder. A subset of ALS cases is linked to mutations in the copper/zinc superoxide dismutase (sod1) gene and detailed phenotypic analysis of transgenic mice overexpressing mutant forms of SOD1 (mSOD1) allowed a better understanding of the pathophysiological mechanisms leading to motor neuron death. The promising results obtained in these animal models however poorly translated into conclusive clinical trials. In this review, we summarize the main pathological mechanisms at work in mSOD1 mice. In particular, recent results showed that the key pathological event was the destruction of the neuromuscular junction rather than motor neuron death. Neuromuscular junction dismantlement is likely the result of a chronic energy deficiency at the level of the whole organism. These results, along with a comparative analysis between the phenotype of mSOD1 mice and ALS patients, suggest new therapeutic strategies and show the interests but also the limits of the animal models.}, }
@article {pmid19081518, year = {2009}, author = {Turner, MR and Kiernan, MC and Leigh, PN and Talbot, K}, title = {Biomarkers in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {8}, number = {1}, pages = {94-109}, doi = {10.1016/S1474-4422(08)70293-X}, pmid = {19081518}, issn = {1474-4422}, support = {E-2-6501/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; TURNER/NOV07/6501/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*diagnosis/physiopathology/therapy ; Biomarkers ; Brain Chemistry ; Disease Progression ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS; motor neuron disease) is a relentlessly progressive disorder. After half a century of trials, only one drug with modest disease-modifying potency--riluzole--has been developed. The diagnosis of this disorder is still clinical and there is a pronounced delay between the onset of symptoms and diagnosis, possibly beyond the therapeutic window. Bedside quantification of the involvement of the corticospinal tract and extramotor areas is inadequate and functional rating scales, forced vital capacity, and patient survival have been the measures of therapeutic response so far. Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies. In combination, these biomarkers might be sensitive to early therapeutic effects and would reduce our reliance on animal models, which have uncertain relevance to sporadic ALS in human beings. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this Review, we discuss the development of biomarkers in ALS and consider potential future directions for research.}, }
@article {pmid19081372, year = {2008}, author = {Mattson, MP and Gleichmann, M and Cheng, A}, title = {Mitochondria in neuroplasticity and neurological disorders.}, journal = {Neuron}, volume = {60}, number = {5}, pages = {748-766}, pmid = {19081372}, issn = {1097-4199}, support = {Z01 AG000317-07/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Electron Transport Complex I/metabolism ; Humans ; Mitochondria/*physiology ; Mitochondrial Proteins/metabolism ; Models, Biological ; Nervous System Diseases/*pathology/*physiopathology ; Neuronal Plasticity/*physiology ; }, abstract = {Mitochondrial electron transport generates the ATP that is essential for the excitability and survival of neurons, and the protein phosphorylation reactions that mediate synaptic signaling and related long-term changes in neuronal structure and function. Mitochondria are highly dynamic organelles that divide, fuse, and move purposefully within axons and dendrites. Major functions of mitochondria in neurons include the regulation of Ca(2+) and redox signaling, developmental and synaptic plasticity, and the arbitration of cell survival and death. The importance of mitochondria in neurons is evident in the neurological phenotypes in rare diseases caused by mutations in mitochondrial genes. Mitochondria-mediated oxidative stress, perturbed Ca(2+) homeostasis, and apoptosis may also contribute to the pathogenesis of prominent neurological diseases including Alzheimer's, Parkinson's, and Huntington's diseases; stroke; amyotrophic lateral sclerosis; and psychiatric disorders. Advances in understanding the molecular and cell biology of mitochondria are leading to novel approaches for the prevention and treatment of neurological disorders.}, }
@article {pmid19076459, year = {2008}, author = {Chaturvedi, RK and Beal, MF}, title = {Mitochondrial approaches for neuroprotection.}, journal = {Annals of the New York Academy of Sciences}, volume = {1147}, number = {}, pages = {395-412}, pmid = {19076459}, issn = {1749-6632}, support = {R01 NS039258/NS/NINDS NIH HHS/United States ; R01 NS039258-06/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/*physiopathology/prevention &amp; control ; Neuroprotective Agents/*pharmacology ; }, abstract = {A large body of evidence from postmortem brain tissue and genetic analysis in humans and biochemical and pathological studies in animal models (transgenic and toxin) of neurodegeneration suggest that mitochondrial dysfunction is a common pathological mechanism. Mitochondrial dysfunction from oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology, and interaction of pathogenic proteins with mitochondria leads to neuronal demise. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. This review discusses the potential therapeutic efficacy of creatine, coenzyme Q10, idebenone, synthetic triterpenoids, and mitochondrial targeted antioxidants (MitoQ) and peptides (SS-31) in in vitro studies and in animal models of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We have also reviewed the current status of clinical trials of creatine, coenzyme Q10, idebenone, and MitoQ in neurodegenerative disorders. Further, we discuss newly identified therapeutic targets, including peroxisome proliferator-activated receptor-gamma-coactivator and sirtuins, which provide promise for future therapeutic developments in neurodegenerative disorders.}, }
@article {pmid19076436, year = {2008}, author = {Szeto, HH}, title = {Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases.}, journal = {Annals of the New York Academy of Sciences}, volume = {1147}, number = {}, pages = {112-121}, doi = {10.1196/annals.1427.013}, pmid = {19076436}, issn = {1749-6632}, support = {P01 DA08924/DA/NIDA NIH HHS/United States ; R21 NS48295/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; Cations ; Humans ; Mitochondria/metabolism/*physiology ; Models, Animal ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress ; Peptides/*administration &amp; dosage/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial impairment and oxidative damage are intimately involved in the pathogenesis of neurodegenerative diseases. Which is the initiating event is probably irrelevant because each can set into motion a self-sustaining and amplifying feed-forward cycle between reactive oxygen species (ROS) generation and mitochondrial impairment. Recent approaches to the development of neuroprotective agents have therefore targeted mitochondria protection and/or reduction of oxidative stress. There are several hurdles in the quest for neuroprotective drugs. The difficulties include penetration of the blood-brain barrier and delivery of drugs to mitochondria. Here we describe a novel class of mitochondria-targeted peptides that can promote mitochondrial function, reduce mitochondrial ROS generation, inhibit mitochondrial permeability transition, and prevent apoptosis and necrosis. These peptides can readily penetrate the blood-brain barrier and have demonstrated efficacy in animal models of Parkinson's disease and amyotrophic lateral sclerosis.}, }
@article {pmid19076431, year = {2008}, author = {Johnson, JA and Johnson, DA and Kraft, AD and Calkins, MJ and Jakel, RJ and Vargas, MR and Chen, PC}, title = {The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.}, journal = {Annals of the New York Academy of Sciences}, volume = {1147}, number = {}, pages = {61-69}, pmid = {19076431}, issn = {1749-6632}, support = {R01 ES10042/ES/NIEHS NIH HHS/United States ; R01 ES008089/ES/NIEHS NIH HHS/United States ; T32 GM008692/GM/NIGMS NIH HHS/United States ; R29 ES008089/ES/NIEHS NIH HHS/United States ; R01 ES010042-08/ES/NIEHS NIH HHS/United States ; ES08089/ES/NIEHS NIH HHS/United States ; R01 ES010042/ES/NIEHS NIH HHS/United States ; R01 ES008089-08/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Astrocytes/metabolism ; Cells, Cultured ; Humans ; Models, Animal ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; Neurons/metabolism ; *Oxidative Stress ; }, abstract = {Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.}, }
@article {pmid19076216, year = {2009}, author = {Apolloni, S and Montilli, C and Finocchi, P and Amadio, S}, title = {Membrane compartments and purinergic signalling: P2X receptors in neurodegenerative and neuroinflammatory events.}, journal = {The FEBS journal}, volume = {276}, number = {2}, pages = {354-364}, doi = {10.1111/j.1742-4658.2008.06796.x}, pmid = {19076216}, issn = {1742-4658}, mesh = {Animals ; Humans ; Inflammation/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Purines/*metabolism ; Receptors, Purinergic P2/*metabolism ; Receptors, Purinergic P2X ; *Signal Transduction ; }, abstract = {ATP is a potent signalling molecule abundantly present in the nervous system, where it exerts physiological actions ranging from short-term responses such as neurotransmission, neuromodulation and glial communication, to long-term effects such as trophic actions. The fast signalling targets of extracellular ATP are represented by the ionotropic P2X receptors, which are broadly and abundantly expressed in neurons and glia in the whole central and peripheral nervous systems. Because massive extracellular release of ATP often occurs by lytic and non-lytic mechanisms, especially after stressful events and pathological conditions, purinergic signalling is correlated to and involved in the aetiopathology and/or progression of many neurodegenerative diseases. In this minireview, we highlight the contribution of the subclass of ionotropic P2X receptors to several diseases of the human nervous system, such as neurodegenerative disorders and immune-mediated neuroinflammatory dysfunctions including ischaemia, Parkinson's, Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis and multiple sclerosis. The role of P2X receptors as novel and effective targets for the genetic/pharmacological manipulation of purinergic mechanisms in several neuropathological conditions is now well established. Nevertheless, any successful therapeutic intervention against these diseases cannot be restricted to P2X receptors, but should take into consideration the whole and multipart ATP signalling machinery.}, }
@article {pmid19075944, year = {2008}, author = {Grinberg, D}, title = {Recent patents relating to siRNAs and therapeutic strategies for genetic diseases.}, journal = {Recent patents on DNA &amp; gene sequences}, volume = {2}, number = {1}, pages = {40-43}, doi = {10.2174/187221508783406530}, pmid = {19075944}, issn = {2212-3431}, mesh = {Genetic Diseases, Inborn/*drug therapy/genetics ; Humans ; *Patents as Topic ; RNA Interference ; RNA, Small Interfering/genetics/*physiology ; }, abstract = {RNA interference has been implicated in diverse biological process. It is a powerful method for specific gene silencing which may also lead to promising novel therapeutic strategies. The success of early studies of therapeutic RNAi in rodent models has generated considerable interest on the development of RNAi as a potential therapy. A number of recent patents have been published that deal with the use of siRNA as therapeutic tools for human diseases. In this review, I will comment on some of the patents issued on siRNA-based strategies for cancer, ocular diseases, cardiovascular disease, Alzheimer's disease, Parkinson's disease, bone healing, and monogenic diseases such as amyotrophic lateral sclerosis, Marfan syndrome or Huntingon's disease. Progress in developing RNAi-based drugs and potential obstacles will also be discussed.}, }
@article {pmid19075654, year = {2008}, author = {Kaur, C and Ling, EA}, title = {Antioxidants and neuroprotection in the adult and developing central nervous system.}, journal = {Current medicinal chemistry}, volume = {15}, number = {29}, pages = {3068-3080}, doi = {10.2174/092986708786848640}, pmid = {19075654}, issn = {0929-8673}, mesh = {Animals ; Antioxidants/*pharmacology ; Antipyrine/analogs &amp; derivatives/pharmacology ; Apoptosis/physiology ; Central Nervous System/*growth &amp; development/*physiology ; Edaravone ; Free Radical Scavengers/pharmacology ; Humans ; Melatonin/pharmacology/physiology ; Neurodegenerative Diseases/pathology/physiopathology ; Neurons/pathology/physiology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/physiology ; }, abstract = {Oxidative stress is implicated in the pathogenesis of a number of neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis and stroke in the adult as well as in conditions such as periventricular white matter damage in the neonatal brain. It has also been linked to the disruption of blood brain barrier (BBB) in hypoxic-ischemic injury. Both experimental and clinical results have shown that antioxidants such as melatonin, a neurohormone synthesized and secreted by the pineal gland and edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly developed drug, are effective in reducing oxidative stress and are promising neuroprotectants in reducing brain damage. Indeed, the neuroprotective effects of melatonin in many central nervous system (CNS) disease conditions such as amyotrophic lateral sclerosis, PD, AD, ischemic injury, neuropsychiatric disorders and head injury are well documented. Melatonin affords protection to the BBB in hypoxic conditions by suppressing the production of vascular endothelial growth factor and nitric oxide which are known to increase vascular permeability. The protective effects of melatonin against hypoxic damage have also been demonstrated in newborn animals whereby it attenuated damage in different areas of the brain. Furthermore, exogenous administration of melatonin in newborn animals effectively enhanced the surface receptors and antigens on the macrophages/microglia in the CNS indicating its immunoregulatory actions. Edaravone has been shown to reduce oxidative stress, edema, infarct volume, inflammation and apoptosis following ischemic injury of the brain in the adult as well as decrease free radical production in the neonatal brain following hypoxic-ischemic insult. It can counteract toxicity from activated microglia. This review summarizes the clinical and experimental data highlighting the therapeutic potential of melatonin and edaravone in neuroprotection in various disorders of the CNS.}, }
@article {pmid19075629, year = {2008}, author = {Lundberg, C and Björklund, T and Carlsson, T and Jakobsson, J and Hantraye, P and Déglon, N and Kirik, D}, title = {Applications of lentiviral vectors for biology and gene therapy of neurological disorders.}, journal = {Current gene therapy}, volume = {8}, number = {6}, pages = {461-473}, doi = {10.2174/156652308786847996}, pmid = {19075629}, issn = {1566-5232}, mesh = {Animals ; Ciliary Neurotrophic Factor/metabolism ; Clinical Trials as Topic ; Gene Expression Regulation ; Genetic Engineering/methods ; Genetic Therapy/*methods ; Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Humans ; Huntington Disease/genetics/therapy ; Lentivirus/*genetics ; Nerve Growth Factors/metabolism ; Nervous System Diseases/*genetics/*therapy ; Parkinson Disease/genetics/therapy ; RNA Interference ; }, abstract = {Recombinant lentiviral vectors (rLV) are powerful tools for gene transfer to the central nervous system (CNS) and hold great potential as a therapeutic gene therapy strategy for neurological disorders. Recent data indicate that rLVs are suitable for functional studies in the CNS by over expression or knock down of specific proteins. Based on a variety of lentiviruses species, different vector systems have been developed. However, the most commonly used rLV vector is based on the human immunodeficiency virus 1 (HIV-1). Here we describe the use of such vectors to achieve cell-specific transgene expression in the brain. In this setting, rLVs are versatile tools both due to their relatively large cloning capacity and their ability to transduce non-dividing cells. Furthermore, we discuss the preclinical development of gene therapy based on enzyme replacement and/or delivery of neurotrophic factors for neurodegenerative diseases and CNS manifestations of lysosomal storage diseases. Neuroprotective strategies that aim to deliver glial cell line-derived neurotrophic factor and ciliary neurotrophic factor for Parkinson's and Huntington's diseases in particular have been documented with success in appropriate animal models. More recently, rLVs were shown to be suitable to express small interfering RNA for treatment in models of Alzheimer's disease and amyotrophic lateral sclerosis. Finally, we present a review of the use of rLVs to model neurodegenerative diseases. rLVs have proven to be a very versatile tool to create genetic models of both Parkinson's and Huntington's diseases and thus provide possibilities to study complex genetic interactions in otherwise wild-type animals evading the necessity to create transgenic mice. Moreover, the potential of these vectors in the development of gene therapy to treat neurological disorders is considerable, which is supported by the fact that clinical trials using rLVs are underway.}, }
@article {pmid19074550, year = {2009}, author = {Gabbi, C and Warner, M and Gustafsson, JA}, title = {Minireview: liver X receptor beta: emerging roles in physiology and diseases.}, journal = {Molecular endocrinology (Baltimore, Md.)}, volume = {23}, number = {2}, pages = {129-136}, pmid = {19074550}, issn = {0888-8809}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Diet ; *Disease ; Humans ; Liver X Receptors ; Mice ; Mice, Knockout ; Orphan Nuclear Receptors ; Phenotype ; Protein Isoforms/genetics/*metabolism ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism ; Tissue Distribution ; }, abstract = {Liver X receptors, LXRalpha and LXRbeta, are nuclear receptors belonging to the large family of transcription factors. After activation by oxysterols, LXRs play a central role in the control of lipid and carbohydrate metabolism as well as inflammation. The role of LXRalpha has been extensively studied, particularly in the liver and macrophages. In the liver it prevents cholesterol accumulation by increasing bile acid synthesis and secretion into the bile through ATP-binding cassette G5/G8 transporters, whereas in macrophages it increases cholesterol reverse transport. The function of LXRbeta is still under investigation with most of the current knowledge coming from the study of phenotypes of LXRbeta-/- mice. With these mice new emerging roles for LXRbeta have been demonstrated in the pathogenesis of diseases such as amyotrophic lateral sclerosis and chronic pancreatitis. The present review will focus on the abnormalities described so far in LXRbeta-/- mice and the insight gained into the possible roles of LXRbeta in human diseases.}, }
@article {pmid19070491, year = {2009}, author = {van der Graaff, MM and de Jong, JM and Baas, F and de Visser, M}, title = {Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review.}, journal = {Neuromuscular disorders : NMD}, volume = {19}, number = {1}, pages = {53-58}, doi = {10.1016/j.nmd.2008.10.002}, pmid = {19070491}, issn = {0960-8966}, mesh = {Amyotrophic Lateral Sclerosis/complications/pathology/*physiopathology ; Autonomic Nervous System Diseases/etiology/pathology/physiopathology ; Brain/diagnostic imaging/pathology/*physiopathology ; DNA-Binding Proteins/genetics/metabolism ; Dementia/etiology/pathology/physiopathology ; Diagnostic Imaging ; Humans ; Motor Neuron Disease/complications/pathology/*physiopathology ; Radionuclide Imaging ; Spinal Cord/diagnostic imaging/pathology/*physiopathology ; }, abstract = {There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary targets and disease progression in ALS and variants of ALS, (2) brain imaging markers for upper motor neuron lesion, and (3) evidence for ALS being a multisystem disorder. Clinically, upper motor and lower motor neuron symptoms can occur in any order over time. Brain imaging markers show upper motor neuron involvement in early disease. Overlap syndromes of ALS and dementia, and involvement of autonomic and sensory nerves occur frequently. PET/SPECT scans, functional MRI and voxel based morphometry studies clearly show abnormalities in extra-motor areas of the brain. Pathologically, the 43 kDa TAR DNA-binding protein (TDP-43) provides a clue to these overlapping disorders. In conclusion, evidence accumulates that ALS is a multisystem disorder rather than a pure lower and/or upper motor neuron disorder.}, }
@article {pmid19048944, year = {2008}, author = {Kuzuhara, S}, title = {[Recent progress in ALS research: ALS and TDP-43].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {9}, pages = {625-633}, doi = {10.5692/clinicalneurol.48.625}, pmid = {19048944}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; *DNA-Binding Proteins/genetics ; Frontal Lobe/pathology ; Humans ; Intranuclear Inclusion Bodies/metabolism ; Motor Neurons/pathology ; Mutation ; Nerve Degeneration/genetics ; Protein Binding ; Temporal Lobe/pathology ; Ubiquitin/metabolism ; }, abstract = {Selective involvements of upper and lower motor neurons have been regarded as one of the most characteristic features of amyotrophic lateral sclerosis (ALS). However, evidences of more extensive involvements affecting the systems other than the pure motor systems have been accumulated since the discovery of ubiquitin-positive inclusions (UbIs) in ALS, ALS-dementia (ALS-D), and frontotemporal lobar degeneration (FTLD) with UbIs (FTLD-U). A breakthrough occurred in ALS research in October 2006, when TAR DNA-binding protein43 (TDP-43) was identified as the core protein that is ubiquitinated in the cytoplasm, neurites and nucleus as UbIs. Antibody to phosphorylated TDP-43 selectively reacts to the inclusions and Western blotting demonstrates abnormal bands of phosphorylated TDP-43 in the brains of patients with ALS/FTLD-U. Similar findings were observed in ALS/parkinsonism-dementia complex (PDC) of Guam and Kii peninsula. These diseases are lumped in the "TDP-43 proteinopathy". In early 2008, several mutations of the TDP-43 gene were identified as the causative gene of autosomal-dominant familial ALS without SOD1 gene mutations. These findings suggest that abnormalities of TDP-43 directly or indirectly produce severe motor neuron degeneration. TDP-43 is thus one of the key proteins causing TDP-43 proteinopathies such as ALS, ALS-D, FTLD-U, and ALS/PDC of Guam and Kii. New revolutionary developments on ALS research for molecular mechanism and therapy are expected.}, }
@article {pmid19041769, year = {2008}, author = {Hedlund, E and Isacson, O}, title = {ALS model glia can mediate toxicity to motor neurons derived from human embryonic stem cells.}, journal = {Cell stem cell}, volume = {3}, number = {6}, pages = {575-576}, doi = {10.1016/j.stem.2008.11.004}, pmid = {19041769}, issn = {1875-9777}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Astrocytes/*metabolism ; Cell Communication/physiology ; Embryonic Stem Cells/*physiology ; Humans ; Models, Biological ; Motor Neurons/metabolism/*pathology ; Mutation/genetics ; Nerve Degeneration/metabolism/*physiopathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {In this issue of Cell Stem Cell, Di Giorgio et al. (2008) and Marchetto et al. (2008) culture motor neurons derived from human embryonic stem cells with astrocytes expressing mutant SOD1. In these human ALS models, motor neurons are selectively destroyed by mutant astrocyte-secreted factors, and potential neuroprotective pathways are revealed.}, }
@article {pmid19026668, year = {2009}, author = {Migliore, L and Coppedè, F}, title = {Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases.}, journal = {Mutation research}, volume = {667}, number = {1-2}, pages = {82-97}, doi = {10.1016/j.mrfmmm.2008.10.011}, pmid = {19026668}, issn = {0027-5107}, mesh = {DNA, Mitochondrial ; Diet ; *Environment ; Environmental Pollutants/toxicity ; *Epigenesis, Genetic ; Humans ; Neurodegenerative Diseases/*etiology/*genetics ; Oxidative Stress ; }, abstract = {In the present review we summarize recent advances in the understanding of the interaction between genetics and environmental factors involved in complex multi-factorial neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The discovery of several genes responsible for the familial forms has led to a better comprehension of the molecular pathways involved in the selective neuronal degeneration which is specific for each of these disorders. However, the vast majority of the cases occurs as sporadic forms, likely resulting from complex gene-gene and gene-environment interplay. Several environmental factors, including, pesticides, metals, head injuries, lifestyles and dietary habits have been associated with increased disease risk or even with protection. Hundreds of genetic variants have been investigated as possible risk factors for the sporadic forms, but results are often conflicting, not repeated or inconclusive. New approaches to environmental health research are revealing us that at the basis there could be chemically induced changes in gene regulation and emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.}, }
@article {pmid19025120, year = {2008}, author = {Woodruff, TM and Costantini, KJ and Taylor, SM and Noakes, PG}, title = {Role of complement in motor neuron disease: animal models and therapeutic potential of complement inhibitors.}, journal = {Advances in experimental medicine and biology}, volume = {632}, number = {}, pages = {143-158}, pmid = {19025120}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Complement Activation ; *Complement C5a/antagonists &amp; inhibitors/immunology/therapeutic use ; *Disease Models, Animal ; Motor Neuron Disease/genetics/*metabolism/pathology ; Motor Neurons/metabolism/pathology ; RNA, Messenger/metabolism ; Rats ; Rats, Transgenic ; Receptor, Anaphylatoxin C5a/*antagonists &amp; inhibitors ; Spinal Cord/enzymology/metabolism/pathology ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the major forms of motor neuron disease (MND), a group of degenerative disorders causing progressive motor neuron death leading to eventual paralysis and death. The pathogenesis of MND is poorly understood and may include genetic and/or environmental factors, with a common end-stage outcome. The majority of cases are sporadic, with a small percentage of familial cases identified. Mutations in the copper/zinc superoxide dismutase (SOD1) enzyme are frequent in familial ALS, and have allowed for the development of transgenic SOD1 rodent models of ALS. There has been evidence for immune system involvement in the disease, and activated components of the classical complement pathway have been observed in the serum, cerebrospinal fluid and neuronal tissue of diseased individuals. Furthermore, motor neurons and spinal cord tissue from SOD1 transgenic mice show an upregulation in C1q mRNA transcript and protein, in some cases prior to disease onset. Our laboratory has preliminary data indicating a specific pathogenic role for the activation fragment of complement C5 (C5a) in this disease. Using selective C5a receptor antagonists, we dosed SOD1 transgenic rats and observed an extension in survival and reduced motor symptoms compared to untreated rats. Collectively, these clinical and experimental findings suggest that targeting complement using specific inhibitors may represent a novel therapeutic approach to treating MND. Further experimental and clinical studies are required to validate this hypothesis. This review will summarize the clinical and experimental evidence to date implicating complement in the pathogenesis of MND.}, }
@article {pmid19021549, year = {2008}, author = {Vonk, WI and Klomp, LW}, title = {Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Biochemical Society transactions}, volume = {36}, number = {Pt 6}, pages = {1322-1328}, doi = {10.1042/BST0361322}, pmid = {19021549}, issn = {1470-8752}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*pathology ; Animals ; Axons/metabolism ; Humans ; Neurotoxins/metabolism ; Oxidative Stress ; Superoxide Dismutase/chemistry/metabolism ; Transition Elements/*metabolism ; }, abstract = {ALS (amyotrophic lateral sclerosis) is a devastating progressive neurodegenerative disorder resulting in selective degeneration of motor neurons in brain and spinal cord and muscle atrophy. In approx. 2% of all cases, the disease is caused by a mutation in the Cu,Zn-superoxide dismutase (SOD1) gene. The transition metals zinc and copper regulate SOD1 protein stability and activity, and disbalance of the homoeostasis of these metals has therefore been implicated in the pathogenesis of ALS. Recent data strengthen the hypothesis that these transition metals are excellent potential targets to develop an effective therapy for ALS.}, }
@article {pmid19019302, year = {2008}, author = {Aggarwal, S and Cudkowicz, M}, title = {ALS drug development: reflections from the past and a way forward.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {5}, number = {4}, pages = {516-527}, pmid = {19019302}, issn = {1933-7213}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/pathology/*therapy ; Animals ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/therapeutic use ; Research Design ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {Tremendous advances in our understanding of pathogenesis of amyotrophic lateral sclerosis (ALS) have provided a rich pipeline of drugs for clinical trialists. At least 32 unique compounds have been tested. Nevertheless, riluzole is currently the only treatment that prolongs survival. We present a critical overview of past clinical trials, how therapies are selected for testing in people, challenges with ALS clinical trial design and conduct, and ways to best move forward.}, }
@article {pmid19015387, year = {2008}, author = {Beaulieu, JM and Caron, MG}, title = {Looking at lithium: molecular moods and complex behaviour.}, journal = {Molecular interventions}, volume = {8}, number = {5}, pages = {230-241}, doi = {10.1124/mi.8.5.8}, pmid = {19015387}, issn = {1534-0384}, support = {DA-13511/DA/NIDA NIH HHS/United States ; MH-40159/MH/NIMH NIH HHS/United States ; MH-73853/MH/NIMH NIH HHS/United States ; NS-19576/NS/NINDS NIH HHS/United States ; }, mesh = {Affect/*drug effects ; Animals ; Antipsychotic Agents/*pharmacology/therapeutic use ; Arrestins/metabolism ; Behavior/*drug effects ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/metabolism ; Humans ; Inositol/metabolism ; Lithium Compounds/*pharmacology/therapeutic use ; Protein Phosphatase 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Second Messenger Systems/physiology ; beta-Arrestin 2 ; beta-Arrestins ; }, abstract = {Lithium and other mood-stabilizing drugs are used for the management of bipolar mood disorders and, to a lesser extent, for augmentation of other psychoactive drugs. Lithium also has neuroprotective properties that may be useful for treatment of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Over the years, lithium has been shown to inhibit inositol monophosphatases and glycogen synthase kinase 3, but the relevance of such enzyme inhibition to the therapeutic effects of lithium has remained difficult to assess. Here, we provide an overview of recent advances in the identification of molecular mechanisms involved in the regulation of behavior by lithium. We also highlight recent findings suggesting that lithium could exert some of its behavioral effects by acting on a dopamine receptor regulated signaling complex composed of Akt, protein phosphatase 2A, and the multifunctional protein scaffold beta-arrestin 2.}, }
@article {pmid19005780, year = {2008}, author = {Adhihetty, PJ and Beal, MF}, title = {Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases.}, journal = {Neuromolecular medicine}, volume = {10}, number = {4}, pages = {275-290}, pmid = {19005780}, issn = {1559-1174}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; P01 AG014930-09/AG/NIA NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Creatine/metabolism/*pharmacology/therapeutic use ; Dietary Supplements ; Energy Metabolism/*drug effects/physiology ; Humans ; Mitochondria/*drug effects/metabolism ; Mitochondrial Diseases/*drug therapy/*metabolism/physiopathology ; Neurodegenerative Diseases/*drug therapy/*metabolism/physiopathology ; Phosphocreatine/metabolism ; }, abstract = {Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be less effective for ALS and Alzheimer's disease.}, }
@article {pmid19000712, year = {2009}, author = {Graber, JJ and Dhib-Jalbut, S}, title = {Protective autoimmunity in the nervous system.}, journal = {Pharmacology &amp; therapeutics}, volume = {121}, number = {2}, pages = {147-159}, doi = {10.1016/j.pharmthera.2008.10.001}, pmid = {19000712}, issn = {0163-7258}, mesh = {Animals ; *Autoimmunity ; Central Nervous System/immunology/injuries ; Central Nervous System Diseases/drug therapy/*immunology ; Disease Models, Animal ; Drug Delivery Systems ; Humans ; Peripheral Nervous System/immunology/injuries ; Peripheral Nervous System Diseases/drug therapy/*immunology ; }, abstract = {The immune system can play both detrimental and beneficial roles in the nervous system. Multiple arms of the immune system, including T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage to the nervous system during toxic, ischemic, hemorrhagic, infective, degenerative, metabolic and immune-mediated insults and also assist in the process of repair after injury has occurred. Immune cells have been shown to produce neurotrophic growth factors and interact with neurons and glial cells to preserve them from injury and stimulate growth and repair. The immune system also appears to participate in proliferation of neural progenitor stem cells and their migration to sites of injury. Neural stem cells can also modify the immune response in the central and peripheral nervous system to enhance neuroprotective effects. Evidence for protective and reparative functions of the immune system has been found in diverse neurologic diseases including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis). Existing therapies including glatiramer acetate, interferon-beta and immunoglobulin have been shown to augment the protective and regenerative aspects of the immune system in humans, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of disease. The beneficent aspects of the immune response in the nervous system are beginning to be appreciated and their potential as pharmacologic targets in neurologic disease is being explored.}, }
@article {pmid18997301, year = {2008}, author = {Kamat, CD and Gadal, S and Mhatre, M and Williamson, KS and Pye, QN and Hensley, K}, title = {Antioxidants in central nervous system diseases: preclinical promise and translational challenges.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {15}, number = {3}, pages = {473-493}, pmid = {18997301}, issn = {1387-2877}, support = {R01 NS044154/NS/NINDS NIH HHS/United States ; R01 NS044154-03/NS/NINDS NIH HHS/United States ; NS044154/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Antioxidants/*metabolism/*therapeutic use ; Central Nervous System Diseases/*drug therapy/*metabolism ; Humans ; Huntington Disease/drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Parkinson Disease/drug therapy/metabolism/pathology ; Stroke/drug therapy/metabolism/pathology ; }, abstract = {Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (alpha-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson's disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate's mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials.}, }
@article {pmid18991666, year = {2008}, author = {Miyaoka, T}, title = {Clinical potential of minocycline for schizophrenia.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {4}, pages = {376-381}, doi = {10.2174/187152708786441858}, pmid = {18991666}, issn = {1996-3181}, mesh = {Animals ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Antipsychotic Agents/pharmacology/*therapeutic use ; Apoptosis/drug effects/physiology ; Humans ; Microglia/drug effects ; Minocycline/pharmacology/*therapeutic use ; Nerve Degeneration/drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/pharmacology/therapeutic use ; Schizophrenia/*drug therapy ; Treatment Outcome ; }, abstract = {Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to various clinical trials. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline as an open-label adjunct to antipsychotic medication to patients with schizophrenia. The results of this trial suggested that minocycline might be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia. The present review summarizes the available data supporting the clinical testing of minocycline for patients with schizophrenia. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.}, }
@article {pmid18989115, year = {2008}, author = {Mackenzie, IR and Rademakers, R}, title = {The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Current opinion in neurology}, volume = {21}, number = {6}, pages = {693-700}, pmid = {18989115}, issn = {1350-7540}, support = {P50 AG016574/AG/NIA NIH HHS/United States ; P50 AG016574-116180/AG/NIA NIH HHS/United States ; P50 AG16574/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dementia/genetics/*metabolism/pathology ; Humans ; }, abstract = {PURPOSE OF REVIEW: We examine current evidence that the transactive response DNA-binding protein (TDP-43) plays a pathogenic role in both amyotrophic lateral sclerosis and frontotemporal dementia.<br><br>RECENT FINDINGS: TDP-43 was recently identified as the major pathological protein in sporadic amyotrophic lateral sclerosis and in the most common pathological subtype of frontotemporal dementia, frontotemporal lobar degeneration with ubiquitinated inclusions. In these conditions, abnormal C-terminal fragments of TDP-43 are ubiquitinated, hyperphosphorylated and accumulate as cellular inclusions in neurons and glia. Cells with inclusions show absence of the normal nuclear TDP-43 localization. Recently, missense mutations in the gene encoding TDP-43 have been identified in patients with sporadic and familial amyotrophic lateral sclerosis.<br><br>SUMMARY: The recent discovery of pathological TDP-43 in both amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions confirms that these are closely related conditions within a new biochemical class of neurodegenerative disease, the TDP-43 proteinopathies.}, }
@article {pmid18989104, year = {2008}, author = {Birbaumer, N and Murguialday, AR and Cohen, L}, title = {Brain-computer interface in paralysis.}, journal = {Current opinion in neurology}, volume = {21}, number = {6}, pages = {634-638}, doi = {10.1097/WCO.0b013e328315ee2d}, pmid = {18989104}, issn = {1350-7540}, mesh = {Brain/*physiology ; *Communication Aids for Disabled ; Humans ; Paralysis/psychology/*rehabilitation ; *User-Computer Interface ; }, abstract = {PURPOSE OF REVIEW: Communication with patients suffering from locked-in syndrome and other forms of paralysis is an unsolved challenge. Movement restoration for patients with chronic stroke or other brain damage also remains a therapeutic problem and available treatments do not offer significant improvements. This review considers recent research in brain-computer interfaces (BCIs) as promising solutions to these challenges.<br><br>RECENT FINDINGS: Experimentation with nonhuman primates suggests that intentional goal directed movements of the upper limbs can be reconstructed and transmitted to external manipulandum or robotic devices controlled from a relatively small number of microelectrodes implanted into movement-relevant brain areas after some training, opening the door for the development of BCI or brain-machine interfaces in humans. Although noninvasive BCIs using electroencephalographic recordings or event-related-brain-potentials in healthy individuals and patients with amyotrophic lateral sclerosis or stroke can transmit up to 80 bits/min of information, the use of BCIs - invasive or noninvasive - in severely or totally paralyzed patients has met some unforeseen difficulties.<br><br>SUMMARY: Invasive and noninvasive BCIs using recordings from nerve cells, large neuronal pools such as electrocorticogram and electroencephalography, or blood flow based measures such as functional magnetic resonance imaging and near-infrared spectroscopy show potential for communication in locked-in syndrome and movement restoration in chronic stroke, but controlled phase III clinical trials with larger populations of severely disturbed patients are urgently needed.}, }
@article {pmid18977395, year = {2009}, author = {Kim, HS and Suh, YH}, title = {Minocycline and neurodegenerative diseases.}, journal = {Behavioural brain research}, volume = {196}, number = {2}, pages = {168-179}, doi = {10.1016/j.bbr.2008.09.040}, pmid = {18977395}, issn = {1872-7549}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; *Anti-Inflammatory Agents, Non-Steroidal ; Apoptosis/drug effects ; Humans ; Minocycline/*pharmacology/therapeutic use ; Neurodegenerative Diseases/*drug therapy/pathology ; *Neuroprotective Agents ; Signal Transduction/drug effects ; }, abstract = {Minocycline is a semi-synthetic, second-generation tetracycline analog which is effectively crossing the blood-brain barrier, effective against gram-positive and -negative infections. In addition to its own antimicrobacterial properties, minocycline has been reported to exert neuroprotective effects over various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, kainic acid treatment, Huntington' disease and multiple sclerosis. Minocycline has been focused as a neuroprotective agent over neurodegenerative disease since it has been first reported that minocycline has neuroprotective effects in animal models of ischemic injury [Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koisinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769-74; Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999;96:13496-500]. Recently, the effect of minocycline on Alzheimer's disease has been also reported. Although its precise primary target is not clear, the action mechanisms of minocycline for neuroprotection reported so far are; via; the inhibition of mitochondrial permeability-transition mediated cytochrome c release from mitochondria, the inhibition of caspase-1 and -3 expressions, and the suppression of microglial activation, involvement in some signaling pathways, metalloprotease activity inhibition. Because of the high tolerance and the excellent penetration into the brain, minocycline has been clinically tried for some neurodegenerative diseases such as stroke, multiple sclerosis, spinal cord injury, amyotropic lateral sclerosis, Hungtington's disease and Parkinson's disease. This review will briefly summarize the effects and action mechanisms of minocycline on neurodegenerative diseases.}, }
@article {pmid18952194, year = {2009}, author = {Migliore, L and Coppedè, F}, title = {Environmental-induced oxidative stress in neurodegenerative disorders and aging.}, journal = {Mutation research}, volume = {674}, number = {1-2}, pages = {73-84}, doi = {10.1016/j.mrgentox.2008.09.013}, pmid = {18952194}, issn = {0027-5107}, mesh = {Aging/genetics/*physiology ; Environment ; Environmental Pollution/*adverse effects ; Epigenesis, Genetic/physiology ; Free Radicals/metabolism/pharmacology ; Humans ; Models, Biological ; Neurodegenerative Diseases/*etiology/genetics ; Oxidative Stress/genetics/*physiology ; }, abstract = {The aetiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. Free radicals derived primarily from molecular oxygen have been implicated and considered as associated risk factors for a variety of human disorders including neurodegenerative diseases and aging. Damage to tissue biomolecules, including lipids, proteins and DNA, by free radicals is postulated to contribute importantly to the pathophysiology of oxidative stress. The potential of environmental exposure to metals, air pollution and pesticides as well as diet as risk factors via the induction of oxidative stress for neurodegenerative diseases and aging is discussed. The role of genetic background is discussed on the light of the oxidative stress implication, focusing on both complex neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and monogenic neurological disorders (Huntington's disease, Ataxia telangiectasia, Friedreich Ataxia and others). Emphasis is given to role of the repair mechanisms of oxidative DNA damage in delaying aging and protecting against neurodegeneration. The emerging interplay between environmental-induced oxidative stress and epigenetic modifications of critical genes for neurodegeneration is also discussed.}, }
@article {pmid18937367, year = {2008}, author = {Buckingham, SD and Kwak, S and Jones, AK and Blackshaw, SE and Sattelle, DB}, title = {Edited GluR2, a gatekeeper for motor neurone survival?.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {30}, number = {11-12}, pages = {1185-1192}, doi = {10.1002/bies.20836}, pmid = {18937367}, issn = {1521-1878}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Calcium/metabolism ; Humans ; Ions ; Models, Biological ; Motor Neurons/*physiology ; Neurons/metabolism ; Permeability ; Protein Biosynthesis ; RNA Editing ; Receptors, AMPA/*metabolism ; Transcription, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of motor neurones. Although the genetic basis of familial forms of ALS has been well explored, the molecular basis of sporadic ALS is less well understood. Recent evidence has linked sporadic ALS with the failure to edit key residues in ionotropic glutamate receptors, resulting in excessive influx of calcium ions into motor neurones which in turn triggers cell death. Here we suggest that edited AMPA glutamate (GluR2) receptor subunits serve as gatekeepers for motor neurone survival.}, }
@article {pmid18929119, year = {2008}, author = {Whitcup, SM}, title = {Clinical trials in neuroprotection.}, journal = {Progress in brain research}, volume = {173}, number = {}, pages = {323-335}, doi = {10.1016/S0079-6123(08)01123-0}, pmid = {18929119}, issn = {1875-7855}, mesh = {Disease Progression ; Endpoint Determination ; Glaucoma/pathology/therapy ; Humans ; Kaplan-Meier Estimate ; Neurodegenerative Diseases/pathology/*therapy ; Neuroprotective Agents/*therapeutic use ; Optic Nerve Diseases/pathology/therapy ; Randomized Controlled Trials as Topic/*methods ; Visual Fields/physiology ; }, abstract = {Neuroprotection is a therapeutic approach that aims to prevent neuronal degeneration and loss of function. Research has focused on developing neuroprotective agents for the therapy of various degenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and glaucoma. Clinical trials for the evaluation of neuroprotective agents pose unique challenges in terms of experimental design and data interpretation. In order to generate meaningful results, clinical trials on neuroprotective agents should ideally be designed to minimize the potential for bias and optimize the ability to detect the neuroprotective effect of a therapeutic intervention in as short a time as possible. Key issues for the design of clinical trials of neuroprotective therapies include identifying appropriate endpoints and determining the ideal timing of the intervention. Neuroprotection trials in glaucoma must be designed to distinguish between the neuroprotective effects of the therapy and the protective effect of intraocular pressure lowering. The choice of suitable functional endpoints in glaucoma trials is also a critical consideration. For example, visual field loss can be used as a functional endpoint; however, it occurs slowly and may require many years before meaningful changes occur. New methods for assessing visual function may be useful for assessing neuroprotective effects of therapeutic interventions. Although there have been a plethora of medications studied for neuroprotective effects in clinical trials, few have been approved by regulatory agencies for use in patients. Despite these challenges, properly designed clinical trials with validated endpoints will yield the most useful information on the neuroprotective effects of therapy, and may provide new treatment options to prevent the loss of neurologic function, including vision.}, }
@article {pmid18925972, year = {2008}, author = {McCoy, MK and Tansey, MG}, title = {TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease.}, journal = {Journal of neuroinflammation}, volume = {5}, number = {}, pages = {45}, pmid = {18925972}, issn = {1742-2094}, support = {R01 NS049433/NS/NINDS NIH HHS/United States ; R01 NS049433-03/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/*immunology/physiopathology ; Encephalitis/*immunology/physiopathology ; Humans ; Immunologic Factors/pharmacology ; Neurodegenerative Diseases/*immunology/physiopathology ; Neurogenesis/immunology ; Neuroimmunomodulation/drug effects/*immunology ; Receptors, Tumor Necrosis Factor/drug effects/immunology ; Signal Transduction/drug effects/*immunology ; Tumor Necrosis Factor-alpha/*immunology ; }, abstract = {The role of tumor necrosis factor (TNF) as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1) is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF) or transmembrane TNF (tmTNF), with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.}, }
@article {pmid18855638, year = {2008}, author = {Conti, E and Musumeci, MB and Assenza, GE and Quarta, G and Autore, C and Volpe, M}, title = {Recombinant human insulin-like growth factor-1: a new cardiovascular disease treatment option?.}, journal = {Cardiovascular &amp; hematological agents in medicinal chemistry}, volume = {6}, number = {4}, pages = {258-271}, doi = {10.2174/187152508785909456}, pmid = {18855638}, issn = {1871-5257}, mesh = {Animals ; Cardiovascular Diseases/*drug therapy/etiology ; Endocrine System Diseases/drug therapy ; Heart Failure/drug therapy ; Humans ; Insulin-Like Growth Factor I/physiology/*therapeutic use ; Myocardial Ischemia/drug therapy ; Recombinant Proteins/therapeutic use ; }, abstract = {The Insulin-like growth factor-1 (IGF-1) system is dynamic and complex, involving many binding proteins, binding-protein-related proteases, and receptors. It has emerged in time as a powerful defence to life processes of many cytotypes, tissues and systems. Mainly in body metabolism, diabetes and cardiovascular system, but also in brain and kidney, IGF-1 plays a key role in maintaining homeostasis, increasing progenitor cell potential, and improving physiologic performance both in rest and stress conditions. Its vasculoprotective and insulin sensitizing ability exerts a protective role on flow-metabolism coupling and organs function. Therapeutical human use of recombinant human IGF-1 (rhIGF-1) has been widely applied only in Laron syndrome, while being verified in many randomized controlled trials to improve glycemic control in type 1 and type 2 diabetes, and proposed in neurological disease such as amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer disease. Sparse evidence exists moreover about rhIGF-1 use in insulin resistance, burns, catabolic and post-surgery states, acute and chronic renal failure, amyotrophic lateral and multiple sclerosis, brain injury, and immunoincompetence. Along with these data, results are available on cardiovascular benefit of administration of other growth factors, such as erythropoietin and vascular endothelial growth factor, or on cardiovascular side effects of growth factor antagonists such as trastuzumab in cancer therapy. We intended therefore to summarize in this review available human and animals evidence about rhIGF-1 effects on different systems with insights on rhIGF-1 cardiovascular effects. In view of its ability to improve flow-metabolism coupling, IGF-1 could indeed represent a new cardiovascular disease treatment option for many cardiac disorders such as ischemic heart disease and heart failure.}, }
@article {pmid18843710, year = {2008}, author = {Good, P and Cavenagh, J and Mather, M and Ravenscroft, P}, title = {Medically assisted nutrition for palliative care in adult patients.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD006274}, doi = {10.1002/14651858.CD006274.pub2}, pmid = {18843710}, issn = {1469-493X}, mesh = {Adult ; *Enteral Nutrition/adverse effects/methods ; Humans ; Longevity ; Palliative Care/*methods ; *Parenteral Nutrition/adverse effects/methods ; Quality of Life ; }, abstract = {BACKGROUND: Many palliative care patients have a reduced oral intake during their illness. The management of this can include the provision of medically assisted nutrition with the aim of prolonging the length of life of a patient, improving their quality of life, or both.<br><br>OBJECTIVES: To determine the effect of medically assisted nutrition on the quality and length of life of palliative care patients.<br><br>SEARCH STRATEGY: Studies were identified from searching The Cochrane Library, MEDLINE (1966 to 2008), EMBASE (1980 to 2008), CINAHL, CANCERLIT, Caresearch, Dissertation abstracts, SCIENCE CITATION INDEX and the reference lists of all eligible trials, key textbooks, and previous systematic reviews. The date of the latest search was July 2008.<br><br>SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) or prospective controlled trials (if no RCTs were found).<br><br>DATA COLLECTION AND ANALYSIS: There were no RCTs or prospectively controlled trials found that met the inclusion criteria.<br><br>MAIN RESULTS: There were four prospective non-controlled trials (including one qualitative study) that studied medically assisted nutrition in palliative care participants, and one Cochrane systematic review (on Motor Neurone disease), but no RCTs or prospective controlled studies.<br><br>AUTHORS' CONCLUSIONS: There are insufficient good quality trials to make any recommendations for practice with regards to the use of medically assisted nutrition in palliative care patients.}, }
@article {pmid18842276, year = {2009}, author = {Le Forestier, N and Meininger, V}, title = {[Primary lateral sclerosis: the era of international diagnosis criteria].}, journal = {Revue neurologique}, volume = {165}, number = {5}, pages = {415-429}, doi = {10.1016/j.neurol.2008.07.022}, pmid = {18842276}, issn = {0035-3787}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/genetics/history/pathology ; Child ; Diagnosis, Differential ; History, 19th Century ; History, 20th Century ; Humans ; Motor Neuron Disease/*diagnosis/genetics/history ; Spastic Paraplegia, Hereditary/diagnosis ; }, abstract = {Since Charcot's first description, primary lateral sclerosis (PLS) remains a rare clinical syndrome, a neuropathological phenotype of motor system degeneration. In turn, PLS has been described as belonging to the large spectrum of motoneuron diseases or to the diverse degenerative diseases of the nervous system. Clinically, it is characterized by progressive pyramidal involvement in patients who present insidiously progressive gait disorders and, on examination, have relatively symmetrical lower limb weakness, increased muscle tone, pathologic hyper-reflexia, and exaggerated extensor plantar responses. Pinprick, light touch, and temperature sensations are preserved. Viewed in another way, PLS mimicks progressive hereditary spastic paraparesis (HSP) and the "central" phenotype of amyotrophic lateral sclerosis (ALS). PLS is considered "idiopathic" and, depending on the presence or absence of similarly affected family members, the syndrome of idiopathic HSP and ALS are labeled "hereditary" or "apparently sporadic". The juvenile form of PLS and early age at onset in cases of HSP complicate our understanding of the relationship between these two disorders. Guidelines for diagnosis and genetic counseling have been published for HSP and ALS. Recently, since the first international workshop, guidelines for diagnosis of PLS propose a classification system, e.g. for heterogeneous HSP into "pure PLS", complicated or "plus PLS", symptomatic PLS and upper motor neuron-dominant ALS. However, when reviewing known cases of PLS drawn from the literature, rigorous retrospective application of these new PLS criteria raises an unanswered question: does pure PLS exist?}, }
@article {pmid18835541, year = {2008}, author = {Daly, JJ and Wolpaw, JR}, title = {Brain-computer interfaces in neurological rehabilitation.}, journal = {The Lancet. Neurology}, volume = {7}, number = {11}, pages = {1032-1043}, doi = {10.1016/S1474-4422(08)70223-0}, pmid = {18835541}, issn = {1474-4422}, support = {EB00856/EB/NIBIB NIH HHS/United States ; HD30146/HD/NICHD NIH HHS/United States ; R01NS063275/NS/NINDS NIH HHS/United States ; }, mesh = {Algorithms ; Communication Aids for Disabled/trends ; Computers/*trends ; Electroencephalography/instrumentation/methods/*trends ; Humans ; *Man-Machine Systems ; Movement Disorders/physiopathology/*rehabilitation ; Paralysis/physiopathology/*rehabilitation ; Signal Processing, Computer-Assisted/instrumentation ; Teaching/methods/trends ; *User-Computer Interface ; }, abstract = {Recent advances in analysis of brain signals, training patients to control these signals, and improved computing capabilities have enabled people with severe motor disabilities to use their brain signals for communication and control of objects in their environment, thereby bypassing their impaired neuromuscular system. Non-invasive, electroencephalogram (EEG)-based brain-computer interface (BCI) technologies can be used to control a computer cursor or a limb orthosis, for word processing and accessing the internet, and for other functions such as environmental control or entertainment. By re-establishing some independence, BCI technologies can substantially improve the lives of people with devastating neurological disorders such as advanced amyotrophic lateral sclerosis. BCI technology might also restore more effective motor control to people after stroke or other traumatic brain disorders by helping to guide activity-dependent brain plasticity by use of EEG brain signals to indicate to the patient the current state of brain activity and to enable the user to subsequently lower abnormal activity. Alternatively, by use of brain signals to supplement impaired muscle control, BCIs might increase the efficacy of a rehabilitation protocol and thus improve muscle control for the patient.}, }
@article {pmid18830913, year = {2008}, author = {Beukelman, DR and Ball, LJ and Fager, S}, title = {An AAC personnel framework: adults with acquired complex communication needs.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {24}, number = {3}, pages = {255-267}, doi = {10.1080/07434610802388477}, pmid = {18830913}, issn = {1477-3848}, mesh = {Adult ; Brain Diseases/rehabilitation/therapy ; *Communication ; *Communication Aids for Disabled ; Communication Disorders/rehabilitation/*therapy ; Humans ; }, abstract = {A personnel framework designed to support people who rely on augmentative and alternative communication (AAC) because of acquired medical conditions and those who assist them is described. The roles of AAC finders, general practice clinicians, AAC intervention specialists, AAC facilitators, and AAC experts are summarized. These roles are described in detail for people with amyotrophic lateral sclerosis, brainstem impairment, and severe chronic aphasia. The personnel preparation needs for each of these support personnel groups are identified.}, }
@article {pmid18819027, year = {2008}, author = {Badayan, I and Cudkowicz, ME}, title = {Is it too soon for mesenchymal stem cell trials in people with ALS?.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {6}, pages = {321-322}, doi = {10.1080/17482960802425559}, pmid = {18819027}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Animals ; Clinical Trials as Topic/*trends ; Humans ; Mesenchymal Stem Cell Transplantation/*methods/trends ; Pilot Projects ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting primarily the motor neurons. Stem cell therapy is under development as a possible treatment approach. A pilot study of intraspinal injections of mesenchymal stem cells (MSC) was conducted in 9 participants. We review this paper, the rationale, preclinical data and study design.}, }
@article {pmid18808763, year = {2009}, author = {Le Forestier, N and Lacomblez, L and Meininger, V}, title = {[Parkinson disease and amyotrophic lateral sclerosis. Tauopathies, TDP-43 and SOD mutations].}, journal = {Revue neurologique}, volume = {165}, number = {1}, pages = {15-30}, doi = {10.1016/j.neurol.2008.02.043}, pmid = {18808763}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Basal Ganglia Diseases/genetics/metabolism ; DNA-Binding Proteins/*genetics/*metabolism ; Humans ; Mutation/genetics/physiology ; Parkinson Disease/*genetics/metabolism ; Superoxide Dismutase/*genetics/*metabolism ; tau Proteins/*genetics/*metabolism ; }, abstract = {In addition to a large number of clinical descriptions of atypical cases, recent pathological, biochemical and genetic studies challenge the view that amyotrophic lateral sclerosis (ALS) is a disorder restricted to the pyramidal motor system. Relations between ALS, Parkinson disease, fronto-temporal dementia, progressive supranuclear paralysis, and cortico-basal degeneration have now been identified. We propose a review of the topic and discuss the contribution of various clinical and pathological features leading to consider motoneuron diseases as neurodegenerative processes included in a broad spectrum of tauopathies.}, }
@article {pmid18805878, year = {2009}, author = {Kheifets, L and Bowman, JD and Checkoway, H and Feychting, M and Harrington, JM and Kavet, R and Marsh, G and Mezei, G and Renew, DC and van Wijngaarden, E}, title = {Future needs of occupational epidemiology of extremely low frequency electric and magnetic fields: review and recommendations.}, journal = {Occupational and environmental medicine}, volume = {66}, number = {2}, pages = {72-80}, doi = {10.1136/oem.2007.037994}, pmid = {18805878}, issn = {1470-7926}, mesh = {Cardiovascular Diseases/epidemiology/etiology ; Electromagnetic Fields/*adverse effects ; Environmental Monitoring/methods ; Epidemiological Monitoring ; Forecasting ; Humans ; Neoplasms, Radiation-Induced/epidemiology/etiology ; Neurodegenerative Diseases/epidemiology/etiology ; Occupational Diseases/*epidemiology/etiology ; Occupational Exposure/*adverse effects/analysis ; Risk Assessment/methods ; }, abstract = {The occupational epidemiological literature on extremely low frequency electric and magnetic fields (EMF) and health encompasses a large number of studies of varying design and quality that have addressed many health outcomes, including various cancers, cardiovascular disease, depression and suicide, and neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis (ALS). At a 2006 workshop we reviewed studies of occupational EMF exposure with an emphasis on methodological weaknesses, and proposed analytical ways to address some of these. We also developed research priorities that we hope will address remaining uncertainties. Broadly speaking, extensive epidemiological research conducted during the past 20 years on occupational EMF exposure does not indicate strong or consistent associations with cancer or any other health outcomes. Inconsistent results for many of the outcomes may be attributable to numerous shortcomings in the studies, most notably in exposure assessment. There is, however, no obvious correlation between exposure assessment quality and observed associations. Nevertheless, for future research, the highest priorities emerge in both the areas of exposure assessment and investigation of ALS. To better assess exposure, we call for the development of a more complete job-exposure matrix that combines job title, work environment and task, and an index of exposure to electric fields, magnetic fields, spark discharge, contact current, and other chemical and physical agents. For ALS, we propose an international collaborative study capable of illuminating a reported association with electrical occupations by disentangling the potential roles of electric shocks, magnetic fields and bias. Such a study will potentially lead to evidence-based measures to protect public health.}, }
@article {pmid18801114, year = {2008}, author = {Gribkoff, VK and Bozik, ME}, title = {KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {14}, number = {3}, pages = {215-226}, pmid = {18801114}, issn = {1755-5930}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Benzothiazoles/chemistry/*pharmacology/therapeutic use ; Dopamine Agonists/chemistry/*therapeutic use ; Humans ; Mitochondria/drug effects/metabolism ; Neuroprotective Agents/chemistry/*therapeutic use ; Pramipexole ; Stereoisomerism ; }, abstract = {Developing effective treatments for chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) has proven extremely difficult. ALS is universally fatal, characterized by progressive weakness due to the degeneration of upper and lower motor neurons, and leads eventually to respiratory failure which is the usual cause of death. Only a single treatment has been approved, the modestly effective nonspecific neuroprotectant Rilutek (riluzole; 2-amino-6-(trifluoromethoxy)benzothiazole). KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, RPPX], a synthetic amino-benzothiazole with demonstrated activity in maintaining mitochondrial function, is being developed as a treatment for ALS. It has proven to be effective in multiple in vitro and in vivo assays of neuroprotection, including the G93A-SOD1 mutant mouse model; however, its specific mechanism of action remains unknown. The potential of KNS-760604 as a treatment for ALS was first suggested by studies showing that its optical enantiomer, Mirapex[(6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine; pramipexole dihydrochloride; PPX], a high-affinity agonist at dopamine D2, D3, and D4 receptors, exhibits important neuroprotective properties independent of its dopamine receptor agonism. In cell-based assays, both RPPX and PPX reduce the production of reactive oxygen species (ROS), attenuate the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins. However, PPX has limited utility as a clinical neuroprotective agent because the drug concentrations required for neuroprotection would likely produce unacceptable dopaminergic side effects. RPPX, on the other hand, while possessing the same neuroprotective potential as PPX, is a much lower-affinity dopamine receptor agonist and may therefore be more useful in the treatment of ALS. This review will examine the data supporting the hypothesis that the RPPX may have therapeutic potential for the treatment of neurodegenerative disorders including ALS. In addition, we will briefly review recent preclinical data in support of RPPX, and discuss the current status of its clinical development.}, }
@article {pmid18790819, year = {2009}, author = {Ito, D and Suzuki, N}, title = {Seipinopathy: a novel endoplasmic reticulum stress-associated disease.}, journal = {Brain : a journal of neurology}, volume = {132}, number = {Pt 1}, pages = {8-15}, doi = {10.1093/brain/awn216}, pmid = {18790819}, issn = {1460-2156}, mesh = {Endoplasmic Reticulum/*physiology ; GTP-Binding Protein gamma Subunits/*genetics/physiology ; Humans ; Lipodystrophy, Congenital Generalized/*genetics/physiopathology ; Motor Neuron Disease/*genetics/physiopathology ; Mutation ; Oxidative Stress ; Syndrome ; Terminology as Topic ; }, abstract = {The Seipin/BSCL2 gene was originally identified as a loss-of-function gene for congenital generalized lipodystrophy type 2 (CGL2), a condition characterized by severe lipoatrophy, insulin resistance, hypertriglyceridaemia and mental retardation. Recently, gain-of-toxic-function mutations (namely, mutations N88S and S90L) in the seipin gene have been identified in autosomal dominant motor neuron diseases such as Silver syndrome/spastic paraplegia 17 (SPG17) (OMIM #270685) and distal hereditary motor neuropathy type V (dHMN-V) (OMIM #182960). Detailed phenotypic analyses have revealed that upper motor neurons, lower motor neurons and peripheral motor axons are variously affected in patients with these mutations. The clinical spectrum for these mutations is broad, encompassing Silver syndrome, some variants of Charcot-Marie-Tooth disease type 2, dHMNV and spastic paraplegia, even within a common pedigree. Therefore, we propose that seipin-related motor neuron diseases can be collectively referred to as 'seipinopathies'. Expression of the seipin protein can be detected in motor neurons in the spinal cord and white matter in the frontal lobe. This is consistent with the distribution of seipinopathies in the upper and lower motor neurons. Recent studies have shown that seipin, an endoplasmic reticulum (ER)-resident membrane protein, is an N-glycosylated protein that is proteolytically cleaved into N- and C-terminal fragments and is polyubiquitinated. Interestingly, the N88S and S90L mutations are in the N-glycosylation motif, and these mutations enhance ubiquitination and degradation of seipin by the ubiquitin-proteasome system (UPS). Furthermore, both mutations appear to result in proteins that are improperly folded, which leads to accumulation of the mutant protein in the ER. We have shown that expression of mutant forms of seipin in cultured cells activates the unfolded protein response (UPR) pathway and induces ER stress-mediated cell death. These findings suggest that seipinopathies are novel conformational diseases and that neurodegeneration in these diseases is tightly associated with ER stress, which has recently been reported to be associated with other neurodegenerative diseases. Further study of the pathological mechanisms of the mutant forms of seipin may lead to important new insights into motor neuron diseases, including other spastic paraplegia diseases and amyotrophic lateral sclerosis.}, }
@article {pmid18790114, year = {2008}, author = {Ni, Y and Kokot, S}, title = {Does chemometrics enhance the performance of electroanalysis?.}, journal = {Analytica chimica acta}, volume = {626}, number = {2}, pages = {130-146}, doi = {10.1016/j.aca.2008.08.009}, pmid = {18790114}, issn = {1873-4324}, mesh = {Algorithms ; Conductometry ; Drug Residues/*analysis ; Electrochemistry ; Environmental Pollutants/*analysis ; Food Analysis ; Pesticide Residues/*analysis ; Polarography ; Potentiometry ; }, abstract = {This review explores the question whether chemometrics methods enhance the performance of electroanalytical methods. Electroanalysis has long benefited from the well-established techniques such as potentiometric titrations, polarography and voltammetry, and the more novel ones such as electronic tongues and noses, which have enlarged the scope of applications. The electroanalytical methods have been improved with the application of chemometrics for simultaneous quantitative prediction of analytes or qualitative resolution of complex overlapping responses. Typical methods include partial least squares (PLS), artificial neural networks (ANNs), and multiple curve resolution methods (MCR-ALS, N-PLS and PARAFAC). This review aims to provide the practising analyst with a broad guide to electroanalytical applications supported by chemometrics. In this context, after a general consideration of the use of a number of electroanalytical techniques with the aid of chemometrics methods, several overviews follow with each one focusing on an important field of application such as food, pharmaceuticals, pesticides and the environment. The growth of chemometrics in conjunction with electronic tongue and nose sensors is highlighted, and this is followed by an overview of the use of chemometrics for the resolution of complicated profiles for qualitative identification of analytes, especially with the use of the MCR-ALS methodology. Finally, the performance of electroanalytical methods is compared with that of some spectrophotometric procedures on the basis of figures-of-merit. This showed that electroanalytical methods can perform as well as the spectrophotometric ones. PLS-1 appears to be the method of practical choice if the %relative prediction error of approximately +/-10% is acceptable.}, }
@article {pmid18782012, year = {2008}, author = {Cabral, GA and Griffin-Thomas, L}, title = {Cannabinoids as therapeutic agents for ablating neuroinflammatory disease.}, journal = {Endocrine, metabolic &amp; immune disorders drug targets}, volume = {8}, number = {3}, pages = {159-172}, pmid = {18782012}, issn = {1871-5303}, support = {R01 DA005832/DA/NIDA NIH HHS/United States ; R01 DA005832-14/DA/NIDA NIH HHS/United States ; R01 DA029532/DA/NIDA NIH HHS/United States ; R01 DA05832/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Cannabinoid Receptor Modulators/metabolism/physiology ; Cannabinoids/metabolism/*therapeutic use ; Humans ; Immunity/drug effects ; Inflammation/*drug therapy ; Nervous System Diseases/*drug therapy ; Receptors, Cannabinoid/drug effects ; Signal Transduction/drug effects ; }, abstract = {Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB(1) and CB(2). CB(1) appears to be constitutively expressed within the CNS while CB(2) apparently is induced during inflammation. The inducible nature of expression of CB(2) extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, HIV encephalitis, closed head injury, and granulomatous amebic encephalitis.}, }
@article {pmid18781981, year = {2008}, author = {Bilsland, LG and Greensmith, L}, title = {The endocannabinoid system in amyotrophic lateral sclerosis.}, journal = {Current pharmaceutical design}, volume = {14}, number = {23}, pages = {2306-2316}, doi = {10.2174/138161208785740081}, pmid = {18781981}, issn = {1873-4286}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Cannabinoid Receptor Modulators/*metabolism ; Cannabinoids/*pharmacology ; Drug Delivery Systems ; *Endocannabinoids ; Humans ; Motor Neurons/pathology ; Neuroprotective Agents/pharmacology ; Receptor, Cannabinoid, CB1/drug effects/metabolism ; Receptor, Cannabinoid, CB2/drug effects/metabolism ; Riluzole/pharmacology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition characterised by the selective loss of motor neurons from the spinal cord, brainstem and motor cortex. Although the pathogenic mechanisms that underlie ALS are not yet fully understood, there is significant evidence that several neurotoxic mechanisms including excitotoxicity, inflammation and oxidative stress, all contribute to disease pathogenesis. Furthermore, recent results have established that although primarily a motor neuron specific disorder, ALS is not cell-autonomous and non-neuronal cells including astroglia and microglia play a critical role in mechanism of disease. Currently the only licensed therapy available for the treatment of ALS is the anti-glutamatergic agent Riluzole, which has limited therapeutic effects. However, there is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors, respectively. Activation of CB(1) receptors may therefore inhibit glutamate release from presynaptic nerve terminals and reduce the postsynaptic calcium influx in response to glutamate receptor stimulation. Meanwhile, CB(2) receptors may influence inflammation, whereby receptor activation reduces microglial activation, resulting in a decrease in microglial secretion of neurotoxic mediators. Finally, cannabinoid agents may also exert anti-oxidant actions by a receptor-independent mechanism. Therefore the ability of cannabinoids to target multiple neurotoxic pathways in different cell populations may increase their therapeutic potential in the treatment of ALS. Recent studies investigating this potential in models of ALS, in particular those that focus on strategies that activate CB(2) receptors, are discussed in this review.}, }
@article {pmid18781822, year = {2008}, author = {Kishikawa, H and Wu, D and Hu, GF}, title = {Targeting angiogenin in therapy of amyotropic lateral sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {12}, number = {10}, pages = {1229-1242}, pmid = {18781822}, issn = {1744-7631}, support = {R01 CA105241/CA/NCI NIH HHS/United States ; R01 CA105241-04/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Clinical Trials as Topic ; Humans ; RNA, Ribosomal/genetics ; Ribonuclease, Pancreatic/*genetics/physiology ; Transcription, Genetic/physiology ; }, abstract = {BACKGROUND: Missense heterozygous mutations in the coding region of angiogenin (ANG) gene, encoding a 14 kDa angiogenic RNase, were recently found in patients of amyotropic lateral sclerosis (ALS). Functional analyses have shown that these are loss-of-function mutations, implying that angiogenin deficiency is associated with ALS pathogenesis and that increasing ANG expression or angiogenin activity could be a novel approach for ALS therapy.<br><br>OBJECTIVE: Review the evidence showing the involvement of angiogenin in motor neuron physiology and function, and provide a rationale for targeting angiogenin in ALS therapy.<br><br>METHODS: Review the current understanding of the mechanism of angiogenin action in connection with ALS genetics, pathogenesis and therapy.<br><br>CONCLUSION: ANG is the first gene whose loss-of-function mutations are associated with ALS pathogenesis. Therapeutic modulation of angiogenin level and activity in the spinal cord, either by systemic delivery of angiogenin protein or through retrograde transport of ANG-encoding viral particles, may be beneficial for ALS patients.}, }
@article {pmid18778111, year = {2008}, author = {Schwartz, M and Bukshpan, S and Kunis, G}, title = {Application of glatiramer acetate to neurodegenerative diseases beyond multiple sclerosis: the need for disease-specific approaches.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {22}, number = {5}, pages = {293-299}, doi = {10.2165/00063030-200822050-00002}, pmid = {18778111}, issn = {1173-8804}, mesh = {Animals ; Autoimmunity ; Brain/immunology ; Glatiramer Acetate ; Humans ; Multiple Sclerosis/*therapy ; Neurodegenerative Diseases/*therapy ; Peptides/adverse effects/*immunology ; T-Lymphocytes/immunology ; *Vaccination ; }, abstract = {Adaptive and innate immunity, if well controlled, contribute to the maintenance of the CNS, as well as to downregulation of adverse acute and chronic neurological conditions. T cells that recognize CNS antigens are needed to activate resident immune cells and to recruit blood-borne monocytes, which act to restore homeostasis and facilitate repair. However, boosting such a T-cell response in a risk-free way requires a careful choice of the antigen, carrier, and regimen. A single vaccination with CNS-derived peptides or their weak agonists reduces neuronal loss in animal models of acute neurodegeneration. Repeated injections are needed to maintain a long-lasting effect in chronic neurodegenerative conditions, yet the frequency of the injections seems to have a critical effect on the outcome. An example is glatiramer acetate, a compound that is administered in a daily regimen to patients with multiple sclerosis. A single injection of glatiramer acetate, with or without an adjuvant, is neuroprotective in some animal models of acute CNS injuries. However, in an animal model of amyotrophic lateral sclerosis, a single injection of adjuvant-free glatiramer acetate is insufficient, while daily injections are not only ineffective but can carry an increased risk of mortality in female mice.Thus, considering immune-based therapies as a single therapy, rather than as a family of therapies that are regimen dependent, may be misleading. Moreover, the vaccination regimen and administration of a compound, even one shown to be safe in humans for the treatment of a particular neurodegenerative disease, must be studied in preclinical experiments before it is tested in a clinical trial for a novel indication; otherwise, an effective drug in a certain regimen for one disease may be ineffective or even carry risks when used for another disorder.}, }
@article {pmid18775634, year = {2008}, author = {Viel, E and Pellas, F and Ripart, J and Pélissier, J and Eledjam, JJ}, title = {[Peripheral nerve blocks and spasticity. Why and how should we use regional blocks?].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {37}, number = {12}, pages = {1793-1801}, doi = {10.1016/j.lpm.2008.07.007}, pmid = {18775634}, issn = {2213-0276}, mesh = {Humans ; Muscle Spasticity/complications/diagnosis/*therapy ; *Nerve Block/methods ; Pain/etiology ; Pain Management ; }, abstract = {Muscle spasticity causes pain, disability, and difficulties in the rehabilitation of patients with cerebrovascular lesions, head, brain or spine trauma, coma, or neurologic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, or cerebral palsy. Regional blocks have a threefold use in patients with painful spasticity: diagnostic, prognostic, and therapeutic. Blocks are feasible on an outpatient or day-hospital basis. Blocks are applied most often to 4 peripheral sites: the pectoral nerve loop, median, obturator, and tibial nerves. The main indication is debilitating or painful spasticity. Peripheral blocks with local anesthetics are used as tests, to mimic the effects of motor blocks and determine their potential adverse effects, transiently and reversibly. Peripheral neurolytic blocks are easy to perform, effective, and inexpensive.}, }
@article {pmid18771956, year = {2008}, author = {van Swieten, JC and Heutink, P}, title = {Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia.}, journal = {The Lancet. Neurology}, volume = {7}, number = {10}, pages = {965-974}, doi = {10.1016/S1474-4422(08)70194-7}, pmid = {18771956}, issn = {1474-4422}, mesh = {Age of Onset ; Chromosomes, Human, Pair 17 ; *Dementia/genetics/pathology/physiopathology ; Humans ; Intercellular Signaling Peptides and Proteins/*genetics ; Magnetic Resonance Imaging ; Mutation/*genetics ; Neurons/metabolism ; *Phenotype ; Progranulins ; Ribosomal Proteins/metabolism ; }, abstract = {BACKGROUND: Frontotemporal dementia (FTD) is predominantly a presenile disorder that is characterised by behavioural changes and cognitive impairment, particularly in language and executive functions, and is associated with neurodegeneration in the frontal or temporal cortices, or both. Research into FTD has made many advances over the past 20 years that have important implications for clinical practice. Different clinical variants (ie, behavioural, aphasic, and motor neuron disease variants) are now recognised as part of the clinical spectrum of FTD. Neuropathologically, the disease can be divided into two main pathological subtypes: frontotemporal lobar degeneration (FTLD) with neuronal and glial tau inclusions (FTLD-tau); and FTLD with neuronal inclusions that are positive for ubiquitin (FTLD-U). 20-30% of cases of FTD follow an autosomal dominant pattern of inheritance, and half of which are caused by defects in MAPT, CHMP2B, and VCP.<br><br>RECENT DEVELOPMENTS: Mutations in the gene that encodes progranulin (GRN) on chromosome 17q21-22 have been identified in patients with hereditary FTD who have tau-negative, ubiquitin-positive inclusions. The recognition of the clinical phenotype associated with more than 50 different mutations in GRN has expanded the clinical knowledge of FTD to include presentations that resemble Alzheimer's disease, Lewy body disease, and corticobasal syndrome, with a variable age at onset (35-89 years) within families. Another recent breakthrough is the identification of the TAR DNA-binding protein (TARDBP; also known as TDP-43) as the main constituent of FTLD-U with mutations in GRN and with mutations in VCP, as well as in FTLD with amyotrophic lateral sclerosis. WHERE NEXT?: To develop therapeutic strategies to prevent FTD or delay its progression we must understand whether the loss of progranulin leads to the accumulation of TARDBP. In this Rapid Review, we focus on the clinical and pathological phenotypes associated with mutations in GRN, and distinguish those from other forms of hereditary FTD. In addition, we discuss the potential association of mutations in GRN on the pathophysiology of FTD with the accumulation of TARDBP.}, }
@article {pmid18770054, year = {2008}, author = {Matias-Guiu, J and García-Ramos, R and Galán, L and Barcia, J}, title = {[Neuronal death in amyotrofic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {23}, number = {8}, pages = {518-529}, pmid = {18770054}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/*pathology ; Animals ; Anti-Bacterial Agents/therapeutic use ; Cell Death/*physiology ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Minocycline/therapeutic use ; Neurons/cytology/*physiology ; Oxidative Stress ; }, abstract = {INTRODUCTION: The recent failure of the clinical trial of ninocycline outlines if the mechanism of development of the death neuronal in the sporadic amyotrophic lateral sclerosis (SALS) is different to that happens in models of transgenic mice with human mutations related with SOD (TgALS).<br><br>METHOD: Differences on profile and intensity exist among the oxidative stress mechanisms between TgALS and SALS. Whereas the origin of apoptosis pathway in TgALS comes from the mithocondria and drives to caspase 9 with previous Bid and citocrome C discharge, in SALS, if apoptosis exists, that could proceed through activation of FAS pathway by means of cathepsin B, or alpha-TNF, for microgl&#xed;a activation or from cell cytosol. In FAS pathway, TNF-alpha acts receptor ligands what drives to caspase 8 activation, although cathepsine B could act directly. Considering that the minocyicline decreases Citocrome discharge, reducing executors caspases expression proceeding from intrinsic pathway, is justified its effectiveness in TgALS, but could not be explained if apoptosis in SALS was developed primarily on FAS pathway.<br><br>CONCLUSIONS: Better knowledge of how cellular death occurs in SALS, could allow to suggest therapeutic options, and could permit to discriminate drugs that, showing effectiveness in TgALS, could not be beneficials in SALS.}, }
@article {pmid18754709, year = {2009}, author = {Golden, TR and Patel, M}, title = {Catalytic antioxidants and neurodegeneration.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {3}, pages = {555-570}, pmid = {18754709}, issn = {1557-7716}, support = {R01NS39587/NS/NINDS NIH HHS/United States ; R0NS45748/NS/NINDS NIH HHS/United States ; R21NS53548/NS/NINDS NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; Catalysis ; Humans ; Neurodegenerative Diseases/chemically induced/*prevention &amp; control ; }, abstract = {Oxidative stress, resulting from mitochondrial dysfunction, excitotoxicity, or neuroinflammation, is implicated in numerous neurodegenerative conditions. Damage due to superoxide, hydroxyl radical, and peroxynitrite has been observed in diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as in acute conditions that lead to neuronal death, such as stroke and epilepsy. Antioxidant therapies to remove these toxic compounds have been of great interest in treating these disorders. Catalytic antioxidants mimic the activities of superoxide dismutase or catalase or both, detoxifying superoxide and hydrogen peroxide, and in some cases, peroxynitrite and other toxic species as well. Several compounds have demonstrated efficacy in in vitro and in animal models of neurodegeneration, leading to optimism that catalytic antioxidants may prove to be useful therapies in human disease.}, }
@article {pmid18752088, year = {2008}, author = {Strong, MJ}, title = {The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {6}, pages = {323-338}, doi = {10.1080/17482960802372371}, pmid = {18752088}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*pathology/psychology ; Animals ; Dementia/*complications/*pathology/psychology ; Humans ; Syndrome ; tau Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is increasingly recognized to be a complex multisystems disorder both at the level of its pathobiology and in the breadth of non-motor manifestations that can accompany it. Paramount among these are disorders of frontotemporal function which can be associated with syndromes of behavioural, cognitive or executive dysfunction or manifest as a frontotemporal dementia (FTD). While these may occur in isolation and precede the development of motor deficits, more commonly they insidiously onset following the initial neuromuscular dysfunction. The earliest clinical manifestation is a loss of verbal fluency, disproportionate to impairments in oromotor control. There is good correlation between the presence of a syndrome of frontotemporal dysfunction and alterations in brain structure or function as identified with a wide variety of neuroimaging techniques and which reflect a frontotemporal lobar degeneration (FTLD). Although the cause(s) of this process remain to be defined, as with the clinical heterogeneity, there is likely to be significant biochemical heterogeneity. This includes alterations in tau protein metabolism which are present in a proportion of familial and sporadic ALS cases, as well as the western Pacific variant, and recently described alterations in the metabolism of the TAR DNA binding protein 43 (TDP-43).}, }
@article {pmid18752087, year = {2009}, author = {Epton, J and Harris, R and Jenkinson, C}, title = {Quality of life in amyotrophic lateral sclerosis/motor neuron disease: a structured review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {1}, pages = {15-26}, doi = {10.1080/17482960802163721}, pmid = {18752087}, issn = {1471-180X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Health Status ; Health Surveys ; Humans ; *Motor Neuron Disease/physiopathology/psychology ; *Quality of Life ; Random Allocation ; Reproducibility of Results ; Review Literature as Topic ; Sickness Impact Profile ; Surveys and Questionnaires ; }, abstract = {Amyotrophic lateral sclerosis/motor neuron disease and other related disorders are fatal progressive neurodegenerative conditions that have a substantial impact on quality of life (QoL). This systematic review examines the different methods and instruments used to assess QoL in this condition from which recommendations are made of those that evidence suggests are the most appropriate. Databases were used to survey the available literature to cover as many different approaches and papers as possible. Due to the wide variety of approaches to the measurement of QoL data across the papers, no meta-analysis was possible. The available evidence suggests that at the present time the most appropriate measures are the SF-36, a generic widely used QoL measure, and the disease specific ALSAQ-40. However, as many of the validation studies on the ALSAQ-40 were undertaken by the developers of this instrument, further independent research is desirable to confirm these conclusions.}, }
@article {pmid18751914, year = {2008}, author = {Adibhatla, RM and Hatcher, JF}, title = {Altered lipid metabolism in brain injury and disorders.}, journal = {Sub-cellular biochemistry}, volume = {49}, number = {}, pages = {241-268}, pmid = {18751914}, issn = {0306-0225}, support = {NS42008/NS/NINDS NIH HHS/United States ; R01 NS042008-04/NS/NINDS NIH HHS/United States ; R01 NS042008-03/NS/NINDS NIH HHS/United States ; R01 NS042008-01A2/NS/NINDS NIH HHS/United States ; R01 NS042008/NS/NINDS NIH HHS/United States ; R01 NS042008-02/NS/NINDS NIH HHS/United States ; }, mesh = {1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Apolipoproteins E/metabolism ; Atherosclerosis/complications/metabolism ; Bipolar Disorder/metabolism ; Brain Diseases/*metabolism ; Brain Injuries/*metabolism ; Central Nervous System Diseases/*metabolism ; Cholesterol/metabolism ; Cytokines/metabolism ; Group II Phospholipases A2/metabolism ; Humans ; Inflammation/physiopathology ; *Lipid Metabolism ; Lipid Peroxidation ; Membrane Lipids/metabolism ; Niemann-Pick Diseases/metabolism ; Oxidative Stress ; Parkinson Disease/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Risk Factors ; Schizophrenia/metabolism ; Sphingomyelin Phosphodiesterase/metabolism ; Spinal Cord Injuries/metabolism ; Stroke/etiology/metabolism ; }, abstract = {Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.}, }
@article {pmid18725296, year = {2008}, author = {Haase, G and Pettmann, B and Raoul, C and Henderson, CE}, title = {Signaling by death receptors in the nervous system.}, journal = {Current opinion in neurobiology}, volume = {18}, number = {3}, pages = {284-291}, pmid = {18725296}, issn = {0959-4388}, support = {R01 NS056422/NS/NINDS NIH HHS/United States ; R01 NS056422-01A1/NS/NINDS NIH HHS/United States ; R01 NS056422-02/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Nervous System Physiological Phenomena ; Receptors, Death Domain/*metabolism ; Signal Transduction/*physiology ; }, abstract = {Cell death plays an important role both in shaping the developing nervous system and in neurological disease and traumatic injury. In spite of their name, death receptors can trigger either cell death or survival and growth. Recent studies implicate five death receptors--Fas/CD95, TNFR1 (tumor necrosis factor receptor-1), p75NTR (p75 neurotrophin receptor), DR4, and DR5 (death receptors-4 and -5)--in different aspects of neural development or degeneration. Their roles may be neuroprotective in models of Parkinson's disease, or pro-apoptotic in ALS and stroke. Such different outcomes probably reflect the diversity of transcriptional and posttranslational signaling pathways downstream of death receptors in neurons and glia.}, }
@article {pmid18721116, year = {2008}, author = {Zarate, CA and Manji, HK}, title = {Riluzole in psychiatry: a systematic review of the literature.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {4}, number = {9}, pages = {1223-1234}, pmid = {18721116}, issn = {1742-5255}, support = {Z01 MH002828-05/ImNIH/Intramural NIH HHS/United States ; Z01 MH002857-03/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Clinical Trials as Topic ; Dose-Response Relationship, Drug ; Drug Interactions ; Female ; Humans ; Male ; Mental Disorders/*drug therapy ; Neuroprotective Agents/*administration &amp; dosage/adverse effects/pharmacokinetics ; Riluzole/*administration &amp; dosage/adverse effects/pharmacokinetics ; }, abstract = {BACKGROUND: The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent.<br><br>OBJECTIVE: To assess the potential risks and benefits of riluzole treatment in psychiatric patients.<br><br>METHODS: A PubMed search was performed using the keywords 'riluzole', 'inhibitor of glutamate release' and 'glutamatergic modulator' to identify all clinical studies and case reports involving riluzole in psychiatric patients.<br><br>RESULTS/CONCLUSION: Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging.}, }
@article {pmid18719018, year = {2008}, author = {Sullivan, KA and Kim, B and Feldman, EL}, title = {Insulin-like growth factors in the peripheral nervous system.}, journal = {Endocrinology}, volume = {149}, number = {12}, pages = {5963-5971}, pmid = {18719018}, issn = {0013-7227}, support = {U01 DK076160/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Gene Expression ; Humans ; Insulin-Like Growth Factor Binding Proteins/genetics/metabolism/physiology ; Models, Biological ; Peripheral Nervous System/*metabolism/physiology ; Receptors, Somatomedin/genetics/metabolism/physiology ; Signal Transduction/genetics/physiology ; Somatomedins/genetics/*metabolism/physiology ; }, abstract = {IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins regulate the bioavailability of the IGFs. Cell viability correlates with IGF-IR expression and intact IGF-I/IGF-IR signaling pathways, including activation of MAPK/phosphatidylinositol-3 kinase. The expression of IGF-I and -II, IGF-IR, and IGF binding proteins are developmentally regulated in the central and peripheral nervous system. IGF-I therapy demonstrates mixed therapeutic results in the treatment of peripheral nerve injury, neuropathy, and motor neuron diseases such as amyotrophic lateral sclerosis. In this review we discuss the role of IGFs during peripheral nervous system development and the IGF signaling system as the potential therapeutic target for the treatment of nerve injury and motor neuron diseases.}, }
@article {pmid18714162, year = {2008}, author = {Cai, H and Shim, H and Lai, C and Xie, C and Lin, X and Yang, WJ and Chandran, J}, title = {ALS2/alsin knockout mice and motor neuron diseases.}, journal = {Neuro-degenerative diseases}, volume = {5}, number = {6}, pages = {359-366}, pmid = {18714162}, issn = {1660-2862}, support = {Z01 AG000959-04/ImNIH/Intramural NIH HHS/United States ; Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; DNA Mutational Analysis ; *Disease Models, Animal ; Endocytosis/physiology ; Guanine Nucleotide Exchange Factors/*genetics/metabolism ; Humans ; Mice ; Mice, Knockout ; Motor Activity ; *Motor Neuron Disease/genetics/metabolism/pathology/physiopathology ; Motor Neurons/*physiology ; Spastic Paraplegia, Hereditary/genetics/metabolism/pathology/physiopathology ; rab5 GTP-Binding Proteins/metabolism ; }, abstract = {Autosomal recessive mutations in the ALS2 gene have been linked to juvenile-onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis and juvenile-onset ascending hereditary spastic paraplegia. Except for two recently identified missense mutations, all other mutations in the ALS2 gene lead to a premature stop codon and likely abrogate all the potential functions of alsin, the protein encoded by the ALS2 gene. To study the pathologic mechanisms of ALS2 deficiency, four different lines of ALS2 knockout (ALS2(-/-)) mice have been generated by independent groups. The loss of ALS2/alsin does not have a drastic effect on the survival or function of motor neurons in mice. However, subtle deficits observed in the behavior and pathology of these mice have aided in our understanding of the relationship between alsin and motor neuron dysfunction. In this review, we summarize and reconcile major findings of ALS2(-/-) mice and attempt to place these results within the larger context of modeling recessive movement disorders in mice.}, }
@article {pmid18713569, year = {2008}, author = {Appel, SH and Beers, DR and Henkel, JS and Zhao, W}, title = {Novel therapeutic targets in neurodegenerative diseases: lessons from amyotrophic lateral sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {8}, number = {5}, pages = {353-355}, pmid = {18713569}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Disease Models, Animal ; *Drug Delivery Systems ; Drug Evaluation, Preclinical ; Humans ; Mice ; Mice, Transgenic ; Microglia/physiology ; Motor Neurons/pathology ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/*drug therapy/pathology ; Oligonucleotides, Antisense/therapeutic use ; Oxidation-Reduction ; Protein Folding ; Superoxide Dismutase/genetics/physiology ; Superoxide Dismutase-1 ; }, }
@article {pmid18704227, year = {2008}, author = {Sarkar, S and Rubinsztein, DC}, title = {Small molecule enhancers of autophagy for neurodegenerative diseases.}, journal = {Molecular bioSystems}, volume = {4}, number = {9}, pages = {895-901}, doi = {10.1039/b804606a}, pmid = {18704227}, issn = {1742-2051}, support = {064354/WT_/Wellcome Trust/United Kingdom ; G0600194/MRC_/Medical Research Council/United Kingdom ; G0600194(77639)/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Autophagy/*physiology ; Inositol/metabolism ; Models, Biological ; Neurodegenerative Diseases/*metabolism/therapy ; Protein Folding ; Protein Kinases/metabolism ; Proteins/chemistry/metabolism ; Signal Transduction ; Sirolimus/metabolism ; TOR Serine-Threonine Kinases ; Trehalose/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, prion diseases and polyglutamine disorders, including Huntington's disease and various spinocerebellar ataxias, are associated with the formation of protein aggregates. These aggregates and/or their precursors are thought to be toxic disease-causing species. Autophagy is a major degradation pathway for intracytosolic aggregate-prone proteins, including those associated with neurodegeneration. It is a constitutive self-degradative process involved both in the basal turnover of cellular components and in response to nutrient starvation in eukaryotes. Enhancing autophagy may be a possible therapeutic strategy for neurodegenerative disorders where the mutant proteins are autophagy substrates. In cell and animal models, chemical induction of autophagy protects against the toxic insults of these mutant aggregate-prone proteins by enhancing their clearance. We will discuss various autophagy-inducing small molecules that have emerged in the past few years that may be leads towards the treatment of such devastating diseases.}, }
@article {pmid18700928, year = {2008}, author = {Schober, MS and Chidlow, G and Wood, JP and Casson, RJ}, title = {Bioenergetic-based neuroprotection and glaucoma.}, journal = {Clinical &amp; experimental ophthalmology}, volume = {36}, number = {4}, pages = {377-385}, doi = {10.1111/j.1442-9071.2008.01740.x}, pmid = {18700928}, issn = {1442-9071}, mesh = {Animals ; Calcium/metabolism ; Cell Death ; Energy Metabolism/*drug effects ; Free Radical Scavengers/therapeutic use ; Glaucoma/*etiology/physiopathology/*prevention &amp; control ; Glucose/metabolism ; Humans ; Lactic Acid/metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; Retina/*metabolism ; Retinal Ganglion Cells ; }, abstract = {Primary open-angle glaucoma (POAG) is a pressure-sensitive optic neuropathy which results in the death of retinal ganglion cells and causes associated loss of vision. Presently, the only accepted treatment strategy is to lower the intraocular pressure; however, for some patients this is insufficient to prevent progressive disease. Although the pathogenesis of POAG remains unclear, there is considerable evidence that energy failure at the optic nerve head may be involved. Neuroprotection, a strategy which directly enhances the survival of neurons, is desirable, but remains clinically elusive. One particular form of neuroprotection involves the notion of enhancing the energy supply of neurons. These 'bioenergetic' methods of neuroprotection have proven successful in animal models of other neurodegenerative diseases and conditions, including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury, but have been relatively unexplored in glaucoma models. This review focuses on some of the potential approaches for bioenergetic neuroprotection in the retina, including increasing the energy buffering capacity of damaged cells, decreasing the permeability of the mitochondrial membrane pore and free radical scavenging.}, }
@article {pmid18698875, year = {2008}, author = {Pittenger, C and Coric, V and Banasr, M and Bloch, M and Krystal, JH and Sanacora, G}, title = {Riluzole in the treatment of mood and anxiety disorders.}, journal = {CNS drugs}, volume = {22}, number = {9}, pages = {761-786}, pmid = {18698875}, issn = {1172-7047}, support = {T32 MH019961/MH/NIMH NIH HHS/United States ; T32-MH19961/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Anxiety Disorders/*drug therapy ; Excitatory Amino Acid Antagonists/pharmacology/*therapeutic use ; Humans ; Models, Biological ; Mood Disorders/*drug therapy ; Nervous System Diseases/drug therapy ; Receptors, Glutamate/physiology ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {Recent advances implicate amino acid neurotransmission in the pathophysiology and treatment of mood and anxiety disorders. Riluzole, which is approved and marketed for the treatment of amyotrophic lateral sclerosis, is thought to be neuroprotective through its modulation of glutamatergic neurotransmission. Riluzole has multiple molecular actions in vitro; the two that have been documented to occur at physiologically realistic drug concentrations and are therefore most likely to be clinically relevant are inhibition of certain voltage-gated sodium channels, which can lead to reduced neurotransmitter release, and enhanced astrocytic uptake of extracellular glutamate.Although double-blind, placebo-controlled trials are lacking, several open-label trials have suggested that riluzole, either as monotherapy or as augmentation of standard therapy, reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression, and generalized anxiety disorder. In studies of psychiatrically ill patients conducted to date, the drug has been quite well tolerated; common adverse effects include nausea and sedation. Elevation of liver function tests is common and necessitates periodic monitoring, but has been without clinical consequence in studies conducted to date in psychiatric populations. Case reports suggest utility in other conditions, including trichotillomania and self-injurious behaviour associated with borderline personality disorder. Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation.}, }
@article {pmid18691387, year = {2008}, author = {Olsen, ML and Sontheimer, H}, title = {Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation.}, journal = {Journal of neurochemistry}, volume = {107}, number = {3}, pages = {589-601}, pmid = {18691387}, issn = {1471-4159}, support = {R01 NS031234/NS/NINDS NIH HHS/United States ; R01 NS052634-03/NS/NINDS NIH HHS/United States ; R01 NS031234-13/NS/NINDS NIH HHS/United States ; R01 NS052634-02/NS/NINDS NIH HHS/United States ; R01 NS052634-04/NS/NINDS NIH HHS/United States ; R01 NS-31234/NS/NINDS NIH HHS/United States ; R01 NS052634/NS/NINDS NIH HHS/United States ; R01 NS036692/NS/NINDS NIH HHS/United States ; R01 NS031234-14A1/NS/NINDS NIH HHS/United States ; R01 NS-36692/NS/NINDS NIH HHS/United States ; R01 NS036692-08/NS/NINDS NIH HHS/United States ; R01 NS-52634/NS/NINDS NIH HHS/United States ; R01 NS036692-07/NS/NINDS NIH HHS/United States ; R01 NS031234-15/NS/NINDS NIH HHS/United States ; R01 NS036692-09A2/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Buffers ; Cell Differentiation ; Humans ; Membrane Potentials/*physiology ; Neuroglia/*cytology/*metabolism ; Potassium/*metabolism ; Potassium Channels, Inwardly Rectifying/*physiology ; }, abstract = {Astrocytes and oligodendrocytes are characterized by a very negative resting potential and a high resting permeability for K(+) ions. Early pharmacological and biophysical studies suggested that the resting potential is established by the activity of inwardly rectifying, Ba(2+) sensitive, weakly rectifying Kir channels. Molecular cloning has identified 16 Kir channels genes of which several mRNA transcripts and protein products have been identified in glial cells. However, genetic deletion and siRNA knock-down studies suggest that the resting conductance of astrocytes and oligodendrocytes is largely due to Kir4.1. Loss of Kir4.1 causes membrane depolarization, and a break-down of K(+) and glutamate homeostasis which results in seizures and wide-spread white matter pathology. Kir channels have also been shown to act as critical regulators of cell division whereby Kir function is correlated with an exit from the cell cycle. Conversely, loss of functional Kir channels is associated with re-entry of cells into the cell cycle and gliosis. A loss of functional Kir channels has been shown in a number of neurological diseases including temporal lobe epilepsy, amyotrophic lateral sclerosis, retinal degeneration and malignant gliomas. In the latter, expression of Kir4.1 is sufficient to arrest the aberrant growth of these glial derived tumor cells. Kir4.1 therefore represents a potential therapeutic target in a wide variety of neurological conditions.}, }
@article {pmid18691044, year = {2008}, author = {Cimino, PJ and Keene, CD and Breyer, RM and Montine, KS and Montine, TJ}, title = {Therapeutic targets in prostaglandin E2 signaling for neurologic disease.}, journal = {Current medicinal chemistry}, volume = {15}, number = {19}, pages = {1863-1869}, pmid = {18691044}, issn = {0929-8673}, support = {P50 AG005136/AG/NIA NIH HHS/United States ; P01 GM015431/GM/NIGMS NIH HHS/United States ; P50 GM015431/GM/NIGMS NIH HHS/United States ; P50 AG005136-239003/AG/NIA NIH HHS/United States ; P50 GM015431-390002/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Binding Sites ; Cyclooxygenase Inhibitors/chemistry/pharmacology ; Dinoprostone/*metabolism ; Humans ; Ligands ; Nervous System Diseases/drug therapy/*metabolism ; Receptors, Prostaglandin E/drug effects/genetics/metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship ; }, abstract = {Prostaglandins (PGs) are potent autocrine and paracrine oxygenated lipid molecules that contribute appreciably to physiologic and pathophysiologic responses in almost all organs, including brain. Emerging data indicate that the PGs, and more specifically PGE2, play a central role in brain diseases including ischemic injury and several neurodegenerative diseases. Given concerns over the potential toxicity from protracted use of cyclooxygenase inhibitors in the elderly, attention is now focused on blocking PGE2 signaling that is mediated by interactions with four distinct G protein-coupled receptors, EP1-4, which are differentially expressed on neuronal and glial cells throughout the central nervous system. EP1 activation has been shown to mediate Ca2+-dependent neurotoxicity in ischemic injury. EP2 activation has been shown to mediate microglial-induced paracrine neurotoxicity as well as suppress microglia internalization of aggregated neurotoxic peptides. Animal models support the potential efficacy of targeting specific EP receptor subtypes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke. However promising these preclinical studies are, they have yet to be followed by clinical trials targeting any EP receptor in neurologic diseases.}, }
@article {pmid18691039, year = {2008}, author = {Süssmuth, SD and Brettschneider, J and Ludolph, AC and Tumani, H}, title = {Biochemical markers in CSF of ALS patients.}, journal = {Current medicinal chemistry}, volume = {15}, number = {18}, pages = {1788-1801}, doi = {10.2174/092986708785133031}, pmid = {18691039}, issn = {0929-8673}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Antioxidants/metabolism ; Biomarkers/*cerebrospinal fluid ; Cerebrospinal Fluid Proteins/analysis ; DNA/chemistry ; Humans ; Inflammation ; Lipid Peroxidation ; Models, Biological ; Models, Chemical ; Motor Neurons/pathology ; Neurons/metabolism/pathology ; Oxidative Stress ; Proteomics/methods ; tau Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases (MND) characterized by progressive selective degeneration of motor neurons. Although several mutations underlying rare cases of familial ALS were identified during the last decade, the pathogenesis of ALS remains poorly understood. Various mechanisms have been suggested to contribute to disease pathology such as excitotoxicity, oxidative stress, protein aggregation, and inflammation. Accordingly, several candidate biochemical markers related to these pathomechanisms were investigated in cerebrospinal fluid (CSF). Although none of these markers gained clinical importance so far, CSF might reflect pathophysiological alterations in the course of the disease and could therefore provide an insight into pathomechanisms in vivo. It is suggested that cellular and proteinchemical processes are better reflected in the CSF than in other body fluids such as blood or urine due to the proximity of the affected motor neurons to the CSF compartment. Accordingly, alterations in protein expression, post-translational modification or turnover within the tissue of the central nervous system may be mirrored in corresponding changes in CSF protein content. Research on biomarkers in CSF using novel discovery technologies such as proteomics allows to search for a set of proteins that reflect different disease specific molecular pathways and might therefore be of relevance for the establishment of biomarkers for therapeutic monitoring and the development of novel therapies. In this review, an updated overview is given on CSF biomarkers related to the pathomechanisms supposed to be participating in the complex disease process of ALS.}, }
@article {pmid18685417, year = {2008}, author = {Tripodoro, VA and De Vito, EL}, title = {Management of dyspnea in advanced motor neuron diseases.}, journal = {Current opinion in supportive and palliative care}, volume = {2}, number = {3}, pages = {173-179}, doi = {10.1097/SPC.0b013e32830c9049}, pmid = {18685417}, issn = {1751-4266}, mesh = {Advance Directives ; Dyspnea/etiology/*therapy ; Humans ; Motor Neuron Disease/*complications ; Positive-Pressure Respiration/*methods ; Terminal Care/organization &amp; administration ; }, abstract = {PURPOSE OF REVIEW: Patients with amyotrophic lateral sclerosis or motor neuron disease (ALS/MND) invariably develop respiratory muscle weakness and most die from pulmonary complications. Little evidence is available that identifies optimal management approaches for caring for the dying patient. This review discusses the state of the art on dyspnea in advanced ALS/MND and its treatment.<br><br>RECENT FINDINGS: Multiple observational studies have demonstrated that noninvasive positive pressure ventilation is beneficial in ALS/MND. It is a relatively safe intervention in the late stages of disease with additional survival benefits when it is started relatively early and it can improve survival. Despite guidelines related to pulmonary function testing about the use of noninvasive positive pressure ventilation, the factors, which are most closely associated with noninvasive positive pressure ventilation utilization, are dyspnea and orthopnea.<br><br>SUMMARY: In ALS/MND, loss of function relentlessly progresses, and subsequent death occurs mostly in a predictable manner. Therefore, the end of life care is heavily influenced by the type and quality of care provided from the earliest stages. Most patients with ALS/MND develop dyspnea, agitation, anxiety and air hunger in the final phase. Noninvasive positive pressure ventilation has become the standard of care for patients with ALS/MND and advanced respiratory insufficiency. A multidisciplinary approach is strongly recommended.}, }
@article {pmid18684309, year = {2008}, author = {Liscic, RM and Grinberg, LT and Zidar, J and Gitcho, MA and Cairns, NJ}, title = {ALS and FTLD: two faces of TDP-43 proteinopathy.}, journal = {European journal of neurology}, volume = {15}, number = {8}, pages = {772-780}, pmid = {18684309}, issn = {1468-1331}, support = {P01-AG03991/AG/NIA NIH HHS/United States ; U01-AG16976/AG/NIA NIH HHS/United States ; P50-AG05681/AG/NIA NIH HHS/United States ; P50 AG005681-25/AG/NIA NIH HHS/United States ; P01 AG003991-268681/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; DNA-Binding Proteins/genetics/*metabolism ; Dementia/genetics/metabolism/*pathology ; Humans ; }, abstract = {Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.}, }
@article {pmid18684235, year = {2008}, author = {Rocha-González, HI and Ambriz-Tututi, M and Granados-Soto, V}, title = {Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {14}, number = {3}, pages = {234-247}, pmid = {18684235}, issn = {1755-5930}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/pharmacokinetics/*pharmacology ; Pain/drug therapy ; Resveratrol ; Sesquiterpenes ; Stilbenes/chemistry/pharmacokinetics/*pharmacology ; Terpenes/*pharmacology ; Phytoalexins ; }, abstract = {Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.}, }
@article {pmid18676117, year = {2009}, author = {Stone, CA and O'Leary, N}, title = {Systematic review of the effectiveness of botulinum toxin or radiotherapy for sialorrhea in patients with amyotrophic lateral sclerosis.}, journal = {Journal of pain and symptom management}, volume = {37}, number = {2}, pages = {246-258}, doi = {10.1016/j.jpainsymman.2008.02.006}, pmid = {18676117}, issn = {1873-6513}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*therapy ; Botulinum Toxins/*therapeutic use ; *Clinical Trials as Topic ; Comorbidity ; Humans ; Radiotherapy, Conformal/*statistics &amp; numerical data ; Sialorrhea/*epidemiology/*therapy ; Treatment Outcome ; }, abstract = {Fifty percent of patients with amyotrophic lateral sclerosis (ALS) experience problems handling serous saliva and 20% fail to achieve adequate control of sialorrhea with anticholinergic medications, or experience intolerable adverse effects from these drugs. Both botulinum and radiotherapy have been suggested in the literature as treatments for intractable sialorrhea. In this review, we assess the evidence for the effectiveness and toxicity of botulinum toxin and radiotherapy for sialorrhea in patients with ALS. Relevant studies were retrieved from Medline, Embase and Cochrane Databases. Handsearching of Neurology, Journal of Pain and Symptom Management, and Palliative Medicine and of reference lists, was carried out. Five studies (28 patients) were included in the analysis of botulinum. Of the four studies using an intraglandular method of injection, no adverse effects occurred. Two of these had positive findings of the effect of botulinum in salivary secretion rate and quality of life. In contrast, significant adverse effects were experienced by two patients in a study of retrograde injections into the salivary ducts. Two studies were included in the analysis of radiotherapy (27 patients). Both demonstrated a positive effect of radiotherapy on salivary secretion rate. Some patients experienced mild acute side effects. Because of the small numbers of studies, small sample sizes, and poor quality of reporting, it is not possible to draw firm conclusions. There is some evidence indicating that both botulinum and radiotherapy are well tolerated, effective treatments for persistent sialorrhea in patients with ALS and that the duration of action is up to three months with botulinum and six months with radiotherapy.}, }
@article {pmid18661427, year = {2008}, author = {Kong, Q and Shan, X and Chang, Y and Tashiro, H and Lin, CL}, title = {RNA oxidation: a contributing factor or an epiphenomenon in the process of neurodegeneration.}, journal = {Free radical research}, volume = {42}, number = {9}, pages = {773-777}, doi = {10.1080/10715760802311187}, pmid = {18661427}, issn = {1029-2470}, support = {AG17317/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Mice ; Neurodegenerative Diseases/*metabolism ; Oxidants/metabolism ; Oxidative Stress ; Oxygen/*metabolism ; RNA/*metabolism ; RNA, Messenger/metabolism ; RNA, Ribosomal/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {In the past decade, RNA oxidation has caught the attention of many researchers, working to uncover its role in the pathogenesis of neurodegenerative diseases. It has been well documented that RNA oxidation is involved in a wide variety of neurological diseases and is an early event in the process of neurodegeneration. The analysis of oxidized RNA species revealed that at least messenger RNA (mRNA) and ribosomal RNA (rRNA) are damaged in several neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS). The magnitude of the RNA oxidation, at least in mRNA, is significantly high at the early stage of the disease. Oxidative damage to mRNA is not random but selective and many oxidized mRNAs are related to the pathogenesis of the disease. Several studies have suggested that oxidative modification of RNA affects the translational process and consequently produces less protein and/or defective protein. Furthermore, several proteins have been identified to be involved in handling of damaged RNA. Although a growing body of studies suggests that oxidative damage to RNA may be associated with neuron deterioration, further investigation and solid evidence are needed. In addition, further uncovering of the consequences and cellular handling of the oxidatively damaged RNA should be important focuses in this area and may provide significant insights into the pathogenesis of neurodegenerative diseases.}, }
@article {pmid18656504, year = {2008}, author = {Sathasivam, S}, title = {VEGF and ALS.}, journal = {Neuroscience research}, volume = {62}, number = {2}, pages = {71-77}, doi = {10.1016/j.neures.2008.06.008}, pmid = {18656504}, issn = {0168-0102}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {In amyotrophic lateral sclerosis (ALS), an adult-onset progressive degeneration of motor neurons occurring as sporadic and familial disease, there is emerging evidence for and against the role of vascular endothelial growth factor (VEGF), an endothelial cell mitogen crucial for angiogenesis, in its etiopathogenesis. Our understanding of the role of VEGF in ALS has come from studies of both experimental models and human cases. In this article, I have examined in detail the in vitro and in vivo evidence for and against VEGF in ALS, concluding that more compelling evidence is required before we can conclusively link VEGF to ALS in humans.}, }
@article {pmid18652079, year = {2007}, author = {Klein, AM and Ferrante, RJ}, title = {The neuroprotective role of creatine.}, journal = {Sub-cellular biochemistry}, volume = {46}, number = {}, pages = {205-243}, doi = {10.1007/978-1-4020-6486-9_11}, pmid = {18652079}, issn = {0306-0225}, support = {AT00613/AT/NCCIH NIH HHS/United States ; NS045242/NS/NINDS NIH HHS/United States ; NS045806/NS/NINDS NIH HHS/United States ; }, mesh = {Acute Disease ; Adenosine Triphosphate/metabolism ; Animals ; Cell Death/drug effects ; Chronic Disease ; Creatine/metabolism/*therapeutic use ; Disease Models, Animal ; Energy Metabolism/*drug effects ; Homeostasis/*drug effects ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neurons/metabolism ; Neuroprotective Agents/metabolism/*therapeutic use ; }, abstract = {Significant progress has been made in identifying neuroprotective agents and their translation to patients with neurological disorders. While the direct causative pathways of neurodegeneration remain unclear, they are under great clinical and experimental investigation. There are a number of interrelated pathogenic mechanisms triggering molecular events that lead to neuronal death. One putative mechanism reported to play a prominent role in the pathogenesis of neurological diseases is impaired energy metabolism. If reduced energy stores play a role in neuronal loss, then therapeutic strategies that buffer intracellular energy levels may prevent or impede the neurodegenerative process. Recent studies suggest that impaired energy production promotes neurological disease onset and progression. Sustained ATP levels are critical to cellular homeostasis and may have both direct and indirect influence on pathogenic mechanisms associated with neurological disorders. Creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease. In the context of this chapter, we will review the experimental evidence for creatine supplementation as a neurotherapeutic strategy in patients with neurological disorders, including Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, as well as in ischemic stroke, brain and spinal cord trauma, and epilepsy.}, }
@article {pmid18646122, year = {2008}, author = {Brettschneider, J and Kurent, J and Ludolph, A and Mitchell, JD}, title = {Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD005226}, doi = {10.1002/14651858.CD005226.pub2}, pmid = {18646122}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Motor Neuron Disease/complications ; Pain/*drug therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS.<br><br>OBJECTIVES: To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life.<br><br>SEARCH STRATEGY: The authors searched the following databases: the Cochrane Neuromuscular Disease Group Trials Register (October 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to October 2007), EMBASE (January 1980 to October 2007), CINAHL (January 1982 to October 2007), AMED (January 1985 to October 2007) and LILACS (January 1982 to October 2007). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials.<br><br>SELECTION CRITERIA: We searched for randomised or quasi-randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: Data were collected using a specially designed form and analysed using the Cochrane Review Manager software.<br><br>MAIN RESULTS: No randomised or quasi-randomised controlled trials on drug therapy for pain in ALS or MND were found.<br><br>AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS.}, }
@article {pmid18635022, year = {2008}, author = {Kalia, LV and Kalia, SK and Salter, MW}, title = {NMDA receptors in clinical neurology: excitatory times ahead.}, journal = {The Lancet. Neurology}, volume = {7}, number = {8}, pages = {742-755}, pmid = {18635022}, issn = {1474-4422}, mesh = {Animals ; Humans ; Models, Neurological ; Nervous System Diseases/drug therapy/*metabolism/pathology ; *Neurology ; Receptors, N-Methyl-D-Aspartate/chemistry/*physiology ; }, abstract = {Since the N-methyl-D-aspartate receptor (NMDAR) subunits were cloned less than two decades ago, a substantial amount of research has been invested into understanding their physiological function in the healthy CNS. Research has also been directed at their pathological roles in various neurological diseases, including disorders resulting from acute excitotoxic insults (eg, ischaemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (eg, Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis), disorders arising from sensitisation of neurons (eg, epilepsy, neuropathic pain), and neurodevelopmental disorders associated with NMDAR hypofunction (eg, schizophrenia). Selective NMDAR antagonists have not produced positive results in clinical trials. However, there are other NMDAR-targeted therapies used in current practice that are effective for treating some neurological disorders. In this Review, we describe the evidence for the use of these therapies and provide an overview of drugs being investigated in clinical trials. We also discuss new NMDAR-targeted strategies in clinical neurology.}, }
@article {pmid18625421, year = {2008}, author = {Distad, BJ and Meekins, GD and Liou, LL and Weiss, MD and Carter, GT and Miller, RG}, title = {Drug therapy in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {633-51, xi-xii}, doi = {10.1016/j.pmr.2008.04.005}, pmid = {18625421}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Humans ; Immunologic Factors/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of approximately 5 to 7 cases/100,000 population. Epidemiologic studies have identified some potential risk factors for developing ALS, including a high-fat, low-fiber diet; cigarette smoking; slimness and athleticism; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified. Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.}, }
@article {pmid18625420, year = {2008}, author = {Mayadev, AS and Weiss, MD and Distad, BJ and Krivickas, LS and Carter, GT}, title = {The amyotrophic lateral sclerosis center: a model of multidisciplinary management.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {619-31, xi}, doi = {10.1016/j.pmr.2008.04.004}, pmid = {18625420}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Comprehensive Health Care/*organization &amp; administration ; Disease Progression ; Humans ; Patient Care Planning/*organization &amp; administration ; Patient Care Team/*organization &amp; administration ; Terminal Care/organization &amp; administration ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, progressive motor neuron disorder that poses a myriad of clinical problems. Patients who have ALS are best cared for in a multidisciplinary fashion, with involvement of clinicians from various specialties, including neurology, physical medicine and rehabilitation, pulmonary medicine, clinical nurse specialists or nurse practitioners, physical and occupational therapists, speech language pathologists, dietitians, psychologists, social workers, and case managers. This article provides a summary of the current research into the rehabilitation of ALS, including the role of exercise, spasticity management, mood disorders, pain, and palliative care.}, }
@article {pmid18625419, year = {2008}, author = {Woolley, SC and Jonathan S Katz, }, title = {Cognitive and behavioral impairment in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {607-17, xi}, doi = {10.1016/j.pmr.2008.04.002}, pmid = {18625419}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*complications/psychology ; Cognition/physiology ; Cognition Disorders/*etiology ; Humans ; Mental Disorders/*etiology ; }, abstract = {Cognitive impairment in amyotrophic lateral sclerosis (ALS) is correlated with pathologic and radiographic changes in cerebral cortex beyond the motor regions. Clinically, evidence of impairment can be detected in up to 50 percent of patients through direct neuropsychological testing, although frank frontotemporal dementia (FTD) occurs in a limited percentage. Behavioral changes are also common and can be characterized primarily by the presence of increased apathy. Determining the underlying causes of cognitive or behavioral change may be confounded by several disease-related factors, including fatigue, respiratory compromise, depression, and treatment with medications such as riluzole. Studies assessing the evolution and relative risk for cognitive and behavioral impairment in ALS suggest at least two types of patients: those who have clear FTD in whom cognitive decline develops gradually and those who have mild cognitive or behavioral impairments in whom progression either does not occur or is difficult to detect. Limited data suggest that cognition and behavior influence compliance, management, and survival, although this requires further assessment.}, }
@article {pmid18625418, year = {2008}, author = {Bromberg, MB}, title = {Quality of life in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {591-605, x-xi}, doi = {10.1016/j.pmr.2008.02.005}, pmid = {18625418}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; *Health Status Indicators ; Humans ; *Quality of Life ; }, abstract = {Although quality of life is difficult to define clearly, a number of instruments and questionnaires have been developed and applied to patients who have amyotrophic lateral sclerosis (ALS). This article reviews the spectrum of quality-of-life questionnaires and instruments used for ALS and the data generated from them. It discusses positive and negative factors that can affect quality of life for the patient and caregiver and concludes with suggestions for ongoing management to enhance quality of life.}, }
@article {pmid18625417, year = {2008}, author = {Rosenfeld, J and Ellis, A}, title = {Nutrition and dietary supplements in motor neuron disease.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {573-89, x}, pmid = {18625417}, issn = {1047-9651}, support = {R01 AT000967-03/AT/NCCIH NIH HHS/United States ; }, mesh = {*Dietary Supplements ; Humans ; Motor Neuron Disease/*diet therapy ; Nutrition Therapy/*methods ; Nutritional Support/*methods ; }, abstract = {Compromised nutrition leading to weight loss is a common and significant problem in the amyotrophic lateral sclerosis (ALS) patient population. The benefit of aggressive and early nutritional therapy can profoundly influence the disease course, quality of life, and survival. This article reviews the role of nutrition, both as sustenance and treatment for patients who have ALS. Self-medication with dietary supplements has become increasingly popular within this patient population. Despite their popularity, the efficacy of these compounds has been largely unsupported by formal clinical trials. Available data will be highlighted to provide a basis upon which to advise patients requesting guidance.}, }
@article {pmid18625416, year = {2008}, author = {Benditt, JO and Boitano, L}, title = {Respiratory treatment of amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {559-72, x}, doi = {10.1016/j.pmr.2008.02.007}, pmid = {18625416}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; Respiratory Therapy/*methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease with no known cure. The major cause of mortality and major morbidities is related to the effects of the disease on the muscles of the respiratory system (ie, the inspiratory, expiratory, and upper airway muscles). Dyspnea, swallowing difficulties, sialorrhea, and impaired cough are all symptoms that can be palliated through pharmacologic and nonpharmacologic means. Noninvasive positive pressure ventilation, in particular, is a technique that not only relieves dyspnea but may also extend the lives of patients who have this disease. It should be offered to all patients who have amyotrophic lateral sclerosis with a forced vital capacity of less than 50 percent.}, }
@article {pmid18625415, year = {2008}, author = {Chen, A and Montes, J and Mitsumoto, H}, title = {The role of exercise in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {545-57, ix-x}, doi = {10.1016/j.pmr.2008.02.003}, pmid = {18625415}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*rehabilitation ; Energy Metabolism/physiology ; Exercise/*physiology ; Exercise Therapy/*methods ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. In this article, the authors review the literature on the role of exercise in patients who have ALS, and briefly compare what is known about exercise in other neuromuscular diseases.}, }
@article {pmid18625414, year = {2008}, author = {Lou, JS}, title = {Fatigue in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {533-43, ix}, doi = {10.1016/j.pmr.2008.02.001}, pmid = {18625414}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Disease Progression ; Humans ; Muscle Fatigue/*physiology ; Prognosis ; Quality of Life ; Severity of Illness Index ; }, abstract = {Fatigue is a common and potentially debilitating symptom of amyotrophic lateral sclerosis (ALS). Questionnaire studies show that ALS subjects have increased subjective fatigue. Physiologic studies demonstrate that ALS subjects have increased physical fatigue, both central and peripheral in origin. No treatment has been proved effective through evidence-based medicine; however, modafinil (Provigil) may be a helpful pharmacologic treatment. Palliative care measures, such as noninvasive ventilation and high-frequency chest wall oscillation, may also reduce fatigue.}, }
@article {pmid18625413, year = {2008}, author = {Bromberg, MB and Brownell, AA}, title = {Motor unit number estimation in the assessment of performance and function in motor neuron disease.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {509-32, ix}, doi = {10.1016/j.pmr.2008.02.006}, pmid = {18625413}, issn = {1047-9651}, mesh = {Animals ; Electromyography ; Evoked Potentials, Motor ; Humans ; Motor Neuron Disease/*pathology/*physiopathology ; Motor Neurons/*pathology ; Recruitment, Neurophysiological/*physiology ; }, abstract = {Motor unit number estimation (MUNE) is a unique electrophysiologic test used to estimate the number of surviving motor units in a muscle or group of muscles. It is used most frequently to monitor lower motor neuron loss in amyotrophic lateral sclerosis and spinal muscle atrophy. Of particular interest is its use as an endpoint measure in clinical trials for these diseases. This article describes the principles of MUNE and the factors that need to be considered, and reviews several techniques that have been used in clinical trials and in monitoring progression. It then reviews experience with MUNE in clinical trials for amyotrophic lateral sclerosis and spinal muscle atrophy and discusses how MUNE correlates with measures of function.}, }
@article {pmid18625412, year = {2008}, author = {Shefner, JM}, title = {Designing clinical trials in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {495-508, ix}, doi = {10.1016/j.pmr.2008.02.002}, pmid = {18625412}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*methods ; Humans ; Neuroprotective Agents/*therapeutic use ; *Research Design ; Treatment Outcome ; }, abstract = {Clinical trials in amyotrophic lateral sclerosis have significantly evolved over the last decade. New outcome measures have been developed that have reduced the sample size requirement as compared with survival studies. There has been increasing recognition that dose-ranging studies are crucial to full evaluation of experimental agents. While the requirements of late stage trials have not changed, many new designs have been suggested for earlier phase development. While no design achieves the perfect balance of sensitivity and efficiency, clinical trialists continue to work toward the goals of smaller and shorter trials so that more compounds can be studied concurrently.}, }
@article {pmid18625410, year = {2008}, author = {Ravits, J and Traynor, BJ}, title = {Current and future directions in genomics of amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {461-77, viii}, pmid = {18625410}, issn = {1047-9651}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933-05/ImNIH/Intramural NIH HHS/United States ; R21 NS051738-01A1/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; *Gene Expression ; Genetic Markers/*genetics ; Genetic Predisposition to Disease ; Genomics/*methods ; Humans ; RNA/*genetics ; }, abstract = {New knowledge of the structure and function of the human genome and novel genomic technologies are being applied to the study of sporadic amyotrophic lateral sclerosis (ALS). These studies can examine tens to hundreds of thousands of items at once, and depend on sophisticated computer processing. Current studies are focused on genetic susceptibility and gene expression and future studies will likely focus on structural variation, gene regulation and non-protein coding regions. The hope is that they will lead to deeper understanding of molecular aspects of the disease and to rational therapeutic targets.}, }
@article {pmid18625409, year = {2008}, author = {Raibon, E and Todd, LM and Möller, T}, title = {Glial cells in ALS: the missing link?.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {441-59, vii-viii}, doi = {10.1016/j.pmr.2008.04.003}, pmid = {18625409}, issn = {1047-9651}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology/physiopathology ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Disease Progression ; Humans ; Inflammation/metabolism/pathology ; Neuroglia/metabolism/*pathology ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) was initially known as Charcot's sclerosis, named after the French neurobiologist and physician Jean-Martin Charcot who first described this type of muscular atrophy in the early nineteenth century. In the United States, ALS became widely known as Lou Gehrig's disease after the famous baseball player who succumbed to the disease in the late 1930s. Currently, ALS is the most common motor neuron disease, with a worldwide incidence of 8 cases per 100,000 population per year. Familial forms constitute approximately 5% to 10% of all cases. Onset increases with age, with a peak in the seventh decade and a slight preponderance (relative risk, 1.3-1.5) among men compared with women. Rapid progression of motor neuron loss leads to death an average of 3 to 5 years after symptom onset. The cause of ALS remains unknown and there is still no curative therapy.}, }
@article {pmid18625408, year = {2008}, author = {Siddique, N and Siddique, T}, title = {Genetics of amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {429-39, vii}, pmid = {18625408}, issn = {1047-9651}, support = {R01 NS046535/NS/NINDS NIH HHS/United States ; NS40308/NS/NINDS NIH HHS/United States ; R01 NS050641-04/NS/NINDS NIH HHS/United States ; ES014469/ES/NIEHS NIH HHS/United States ; NS046535/NS/NINDS NIH HHS/United States ; R01 NS040308/NS/NINDS NIH HHS/United States ; R01 ES014469/ES/NIEHS NIH HHS/United States ; R01 NS046535-05/NS/NINDS NIH HHS/United States ; NS050641/NS/NINDS NIH HHS/United States ; R01 NS046535-04/NS/NINDS NIH HHS/United States ; R01 NS050641/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Genetic Markers/*genetics ; *Genetic Predisposition to Disease ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) was first described by Charcot in 1869 as what we would now call a sporadic disease-a disease believed to occur without a strong genetic influence. Only within the past 10 years has it been possible to fully explore genetic influence on disorders that seem to occur sporadically but likely result from the convergence of multiple genetic and environmental factors. This article reviews the genetics of familial ALS and summarizes current investigations of genetic influence in sporadic ALS. Genetic study clearly offers the potential for identification of molecular targets that would allow development of rational therapies for various forms of ALS, but much work remains.}, }
@article {pmid18608100, year = {2009}, author = {Sakowski, SA and Schuyler, AD and Feldman, EL}, title = {Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {2}, pages = {63-73}, pmid = {18608100}, issn = {1471-180X}, support = {T32 NS007222/NS/NINDS NIH HHS/United States ; T32 NS007222-26/NS/NINDS NIH HHS/United States ; T32 NS 007222-26/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motorneurons (MN) resulting in weakness, paralysis and subsequent death. Insulin-like growth factor-I (IGF-I) is a potent neurotrophic factor that has neuroprotective properties in the central and peripheral nervous systems. Due to the efficacy of IGF-I in the treatment of other diseases and its ability to promote neuronal survival, IGF-I is being extensively studied in ALS therapeutic trials. This review covers in vitro and in vivo studies examining the efficacy of IGF-I in ALS model systems and also addresses the mechanisms by which IGF-I asserts its effects in these models, the status of the IGF-I system in ALS patients, results of clinical trials, and the need for the development of better delivery mechanisms to maximize IGF-I efficacy. The knowledge obtained from these studies suggests that IGF-I has the potential to be a safe and efficacious therapy for ALS.}, }
@article {pmid19750024, year = {2008}, author = {Maiese, K and Chong, ZZ and Shang, YC and Hou, J}, title = {Therapeutic promise and principles: metabotropic glutamate receptors.}, journal = {Oxidative medicine and cellular longevity}, volume = {1}, number = {1}, pages = {1-14}, pmid = {19750024}, issn = {1942-0994}, support = {P30 ES06639/ES/NIEHS NIH HHS/United States ; R01 NS053946-01A2/NS/NINDS NIH HHS/United States ; R01 NS053946-03/NS/NINDS NIH HHS/United States ; P30 ES006639/ES/NIEHS NIH HHS/United States ; R01 NS053946-02/NS/NINDS NIH HHS/United States ; R01 NS053946/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Glutamic Acid/metabolism ; Humans ; Molecular Targeted Therapy/*methods ; Oxidative Stress/physiology ; Receptors, Metabotropic Glutamate/*metabolism ; Signal Transduction ; }, abstract = {For a number of disease entities, oxidative stress becomes a significant factor in the etiology and progression of cell dysfunction and injury. Therapeutic strategies that can identify novel signal transduction pathways to ameliorate the toxic effects of oxidative stress may lead to new avenues of treatment for a spectrum of disorders that include diabetes, Alzheimer's disease, Parkinson's disease and immune system dysfunction. In this respect, metabotropic glutamate receptors (mGluRs) may offer exciting prospects for several disorders since these receptors can limit or prevent apoptotic cell injury as well as impact upon cellular development and function. Yet the role of mGluRs is complex in nature and may require specific mGluR modulation for a particular disease entity to maximize clinical efficacy and limit potential disability. Here we discuss the potential clinical translation of mGluRs and highlight the role of novel signal transduction pathways in the metabotropic glutamate system that may be vital for the clinical utility of mGluRs.}, }
@article {pmid20021425, year = {2008}, author = {Tauber, SC and Nau, R}, title = {Immunomodulatory properties of antibiotics.}, journal = {Current molecular pharmacology}, volume = {1}, number = {1}, pages = {68-79}, pmid = {20021425}, issn = {1874-4702}, mesh = {Anti-Bacterial Agents/*pharmacology ; Fluoroquinolones/pharmacology ; Humans ; Immunologic Factors/*pharmacology ; Lung Diseases/drug therapy/immunology ; Macrolides/pharmacology ; Neurodegenerative Diseases/drug therapy/immunology ; Protein Synthesis Inhibitors/pharmacology ; Rifampin/pharmacology ; Tetracyclines/pharmacology ; }, abstract = {There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunological and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammtory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in experimental bacterial sepsis, plague and meningitis. Clinically, macrolides have been well established as an adjunctive treatment to beta-lactam antibiotics in pulmonary diseases. For other indications, appropriate clinical trials are necessary before using the immunomodulatory properties of antibiotics in clinical practice.}, }
@article {pmid19714406, year = {2000}, author = {Mitchell, JD}, title = {Guidelines in motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) - from diagnosis to patient care.}, journal = {Journal of neurology}, volume = {247 Suppl 6}, number = {}, pages = {VI/7-12}, doi = {10.1007/PL00007786}, pmid = {19714406}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Clinical Trials as Topic/standards ; Guidelines as Topic ; Humans ; Motor Neuron Disease/diagnosis/*therapy ; Patient Care ; Treatment Outcome ; }, abstract = {This paper reviews the scope of current guidelines in motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) and examines issues which have arisen in the preparation of these documents. The review concludes with an evaluation of the impact of the guidelines which have been produced to date and looks towards potential future developments in this area.}, }
@article {pmid19714405, year = {2000}, author = {Robberecht, W}, title = {Genetics of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {247 Suppl 6}, number = {}, pages = {VI/2-6}, doi = {10.1007/PL00007785}, pmid = {19714405}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/epidemiology/*genetics ; Gene Frequency ; Humans ; Mutation/physiology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {The genetic cause of amyotrophic lateral sclerosis (ALS) is known in a minority of cases. Mutations in SOD1, the gene encoding a superoxide dismutase on chromosome 21, are indeed found in 20% of familial ALS patients, who constitute only 5 or 10% of all ALS patients. In rare cases, a mutation in NFH, the gene encoding the heavy subunit of neurofilament, is present. Familial ALS has been linked to other loci but the genes involved remain to be identified. A genetic component is also thought to at least contribute to the pathogenesis of sporadic ALS. Their identification is now possible thanks to progress in molecular genetics.}, }
@article {pmid19714404, year = {2000}, author = {Meininger, V and Lacomblez, L and Salachas, F}, title = {What has changed with riluzole?.}, journal = {Journal of neurology}, volume = {247 Suppl 6}, number = {}, pages = {VI/19-22}, doi = {10.1007/PL00007784}, pmid = {19714404}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Glutamic Acid/physiology ; Humans ; Neuroprotective Agents/*therapeutic use ; Research/trends ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {Riluzole, after two significant trials, was introduced as the first standard treatment of amyotrophic lateral sclerosis (ALS) in the early 95'. After 5 years what has changed in the field of ALS? In the field of basic science, riluzole as an active drug has largely contributed to stimulate the research of the possible role of glutamate in the genesis of ALS. However, the apparent simplicity of the relation between the drug and its mechanisms has to modulated in the light of the negativity of other trials (gabapentin) and the display of other mechanisms of the disease and of the compound. Possible relation with other putative mechanisms of ALS, as oxydative stress or growth factors, could be (and probably are) also involved. In the field of its activity, riluzole has an impact on the survival rate which has been largely debated. Comparison with historical databases are supporting the results of the two initial trials. Other information have been published supporting the probable activity of the drug on the muscle strength decline, a controversial matter. They strengthen the initial data and give additional reasons to use riluzole as a standard treatment of patients. In the field of the daily care, riluzole provided a real and unique hope for ALS sufferers. Even if its activity is not as complete as patients would have expected, it provides a hope for slowing down the rate of evolution and abolishes the myth of "no hope, no cure" which was the leitmotiv of patients care until recently. We have to better define the mode of administration with regard to the clinical status of the patients (respiratory disorders, fatigue, stiffness). In the field of care givers, riluzole was one major factor which provided the basis for national and international collaborations either for therapeutic trials or for standard of care. It made possible large collaborative programs in and among many countries. We do hope that this impulse will continue and be stimulated by additional results both in the field of basic science and clinical research.}, }
@article {pmid19714403, year = {2000}, author = {Ludolph, AC}, title = {Treatment of amyotrophic lateral sclerosis - what is the next step?.}, journal = {Journal of neurology}, volume = {247 Suppl 6}, number = {}, pages = {VI/13-8}, doi = {10.1007/PL00007783}, pmid = {19714403}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology/genetics/prevention &amp; control ; Animals ; Biomarkers ; Disease Models, Animal ; Humans ; Indonesia/epidemiology ; Mice ; Micronesia/epidemiology ; Neuroprotective Agents/therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable. However, recent evidence in both experimental animals and men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of drugs is still small, this process cannot only be seen as a success of the present but must also be acknowledged as a basis for future developments. How will future studies be designed? They will have to take into account that the disease presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have been shown to be effective in transgenic animal models. This also implies that we are likely to use a combination of therapies and we will try to treat patients early. The latter will be associated with the demand for a novel clinical attitude toward the diagnosis of the disease and the development of novel markers for both the preclinical period and the longitudinal course of the disease.}, }
@article {pmid18608098, year = {2008}, author = {Qureshi, M and Shui, A and Dibernardo, AB and Brown, RH and Schoenfeld, DA and Cudkowicz, ME}, title = {Medications and laboratory parameters as prognostic factors in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {6}, pages = {369-374}, doi = {10.1080/17482960802163614}, pmid = {18608098}, issn = {1471-180X}, support = {5R01 NS05050641-04/NS/NINDS NIH HHS/United States ; 5R01 NS050557-02/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/mortality ; Aspirin/therapeutic use ; Clinical Laboratory Techniques ; Female ; Fructose/analogs &amp; derivatives/therapeutic use ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic/methods ; Prognosis ; Prospective Studies ; Randomized Controlled Trials as Topic/methods ; Survival Rate ; Topiramate ; }, abstract = {We sought to examine the influence of medication usage and laboratory measurements on disease progression in amyotrophic lateral sclerosis (ALS). A database of 596 volunteers with ALS was generated from three clinical trials and one observational study. Disease course was measured by survival and three functional measures: the ALS Functional Rating Scale (ALSFRS), Vital Capacity (VC) and Maximum Voluntary Isometric Contraction (MVIC). Survival modeling was performed using Cox proportional hazards regression. The association of medication or laboratory measurements with disease progression was determined using a random effects model. In the multivariate analysis, survival was shorter in participants who took aspirin (HR =1.93, p =0.046); NSAIDs (HR =1.51, p =0.054); had low blood chloride (HR =0.76, p =0.020) or high bicarbonate levels (HR =1.37, p =0.006). Individuals who took calcium had better survival (HR =0.37, p =0.008) and a slower rate of decline of MVIC arm megascore (p =0.033). Vital capacity declined faster in individuals with lower serum chloride (p<0.0001), or higher bicarbonate (p =0.002) levels and those taking paracetamol (acetaminophen) (p =0.035). We conclude that aspirin or NSAID use may shorten survival in ALS, while calcium use may prolong survival. Our results support a need to further explore the role of neuroinflammation in the pathogenesis of ALS.}, }
@article {pmid18608090, year = {2008}, author = {Orrell, RW and Lane, RJ and Ross, M}, title = {A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {4}, pages = {195-211}, doi = {10.1080/17482960801900032}, pmid = {18608090}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid18604453, year = {2008}, author = {Gao, X and Xu, Z}, title = {Mechanisms of action of angiogenin.}, journal = {Acta biochimica et biophysica Sinica}, volume = {40}, number = {7}, pages = {619-624}, doi = {10.1111/j.1745-7270.2008.00442.x}, pmid = {18604453}, issn = {1745-7270}, mesh = {Active Transport, Cell Nucleus/*physiology ; Animals ; Cell Membrane/*metabolism ; Humans ; *Models, Biological ; Neovascularization, Pathologic/*metabolism ; Ribonuclease, Pancreatic/*metabolism ; }, abstract = {Angiogenin induces angiogenesis by activating vessel endothelial and smooth muscle cells and triggering a number of biological processes, including cell migration, invasion, proliferation, and formation of tubular structures. It has been reported that angiogenin plays its functions mainly through four pathways: (1) exerting its ribonucleolytic activity; (2) binding to membrane actin and then inducing basement membrane degradation; (3) binding to a putative 170-kDa protein and subsequently transducing signal into cytoplasm; and (4) translocating into the nucleus of target cells directly and then enhancing ribosomal RNA transcription. Angiogenin can also translocate into the nucleus of cancer cells and induces the corresponding cell proliferation. Furthermore, angiogenin has neuroprotective activities in the central nervous system and the loss of its function may be related to amyotrophic lateral sclerosis. This review intends to conclude the mechanisms underlying these actions of angiogenin and give a perspective on future research.}, }
@article {pmid18598229, year = {2008}, author = {Tumani, H and Teunissen, C and Süssmuth, S and Otto, M and Ludolph, AC and Brettschneider, J}, title = {Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases.}, journal = {Expert review of molecular diagnostics}, volume = {8}, number = {4}, pages = {479-494}, doi = {10.1586/14737159.8.4.479}, pmid = {18598229}, issn = {1744-8352}, mesh = {*Apoptosis ; Axons/*metabolism/pathology ; Biomarkers/*cerebrospinal fluid ; Gliosis/*cerebrospinal fluid/diagnosis/pathology ; Humans ; Neurodegenerative Diseases/*cerebrospinal fluid/diagnosis/pathology ; }, abstract = {Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.}, }
@article {pmid18592728, year = {2008}, author = {Grujic, J and Coutaz, M and Morisod, J}, title = {[Amyotrophic lateral sclerosis also threatens the octogenarian].}, journal = {Revue medicale suisse}, volume = {4}, number = {159}, pages = {1353-1357}, pmid = {18592728}, issn = {1660-9379}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Diagnosis, Differential ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, incurable, mostly declared near the age of sixty-seventy, but more rarely for the older individuals. Because presenting symptoms are non specific (muscle weakness, functional decline, loss of ambulation, dyspnea, dysphagia), diagnosis in early stages may be difficult and delayed, particularly on polymorbid older patients. Symptomatic management is the mainstay of treatment for ALS; care in multidisciplinary team, with maximal psychologic support, is associated with enhanced quality of life. In this article we remind markings aspects of ALS of the older subject, in the light of the follow-up of five patients in our geriatric service.}, }
@article {pmid18592312, year = {2008}, author = {Banks, GT and Kuta, A and Isaacs, AM and Fisher, EM}, title = {TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {19}, number = {5}, pages = {299-305}, pmid = {18592312}, issn = {0938-8990}, support = {/WT_/Wellcome Trust/United Kingdom ; G0500288/MRC_/Medical Research Council/United Kingdom ; MC_U123182015/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; DNA-Binding Proteins/chemistry/*genetics/physiology ; Genetic Diseases, Inborn/genetics ; Humans ; Models, Biological ; Mutation/physiology ; Neurodegenerative Diseases/*genetics ; Plaque, Amyloid/genetics ; }, abstract = {In 2006 the protein TDP-43 was identified as the major ubiquitinated component deposited in the inclusion bodies found in two human neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The pathogenesis of both disorders is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. Now, in 2008, several papers have been published in quick succession describing mutations in the TDP-43 gene, showing they can be a primary cause of amyotrophic lateral sclerosis. There are many precedents in neurodegenerative disease in which rare single-gene mutations have given great insight into understanding disease processes, which is why the TDP-43 mutations are potentially very important.}, }
@article {pmid18588875, year = {2009}, author = {Brennan, LA and Kantorow, M}, title = {Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations.}, journal = {Experimental eye research}, volume = {88}, number = {2}, pages = {195-203}, pmid = {18588875}, issn = {1096-0007}, support = {R01 EY013022/EY/NEI NIH HHS/United States ; R01 EY013022-10/EY/NEI NIH HHS/United States ; }, mesh = {Aging/*physiology ; Antioxidants/*metabolism ; Cataract/metabolism ; Eye/*metabolism ; Humans ; Macular Degeneration/metabolism ; Methionine Sulfoxide Reductases ; Mitochondria/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Oxidoreductases/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age-related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself. In the anterior segment of the eye, oxidative stress has been linked to lens cataract and glaucoma while in the posterior segment of the eye oxidative stress has been associated with macular degeneration. Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O(2)(-)) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (OH), hydrogen peroxide (H(2)O(2)) and peroxynitrite (OONO(-)). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria. Generation of superoxide at complexes I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane. While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Fig. 1). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr) protein repair system and other redox systems play key roles in the function and maintenance of the aging eye.}, }
@article {pmid18582500, year = {2008}, author = {Lopachin, RM and Gavin, T and Barber, DS}, title = {Type-2 alkenes mediate synaptotoxicity in neurodegenerative diseases.}, journal = {Neurotoxicology}, volume = {29}, number = {5}, pages = {871-882}, doi = {10.1016/j.neuro.2008.04.016}, pmid = {18582500}, issn = {0161-813X}, support = {R01 ES003830/ES/NIEHS NIH HHS/United States ; R01 ES03830-21/ES/NIEHS NIH HHS/United States ; ES07912-10/ES/NIEHS NIH HHS/United States ; }, mesh = {Alkenes/chemistry/classification/*toxicity ; Animals ; Humans ; Models, Biological ; Neurodegenerative Diseases/*pathology ; Synapses/*drug effects/*pathology ; }, abstract = {Synaptic dysfunction appears to be an early pathogenic event in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. Although the molecular mechanism of this synaptotoxicity is not known, evidence suggests that these diseases are characterized by a common pathophysiological cascade involving oxidative stress, lipid peroxidation and the subsequent liberation of alpha,beta-unsaturated carbonyl derivatives such as acrolein and 4-hydroxy-2-nonenal (HNE). A diverse body of in vivo and in vitro data have shown that these soft electrophilic chemicals can cause nerve terminal damage by forming Michael-type adducts with nucleophilic sulfhydryl groups on presynaptic proteins. Therefore, the endogenous generation of acrolein and HNE in oxidatively stressed neurons of certain brain regions might be mechanistically related to the synaptotoxicity associated with neurodegenerative conditions. In addition, acrolein and HNE are members of a large class of structurally related chemicals known as the type-2 alkenes. Chemicals in this class (e.g., acrylamide, methylvinyl ketone, and methyl acrylate) are pervasive pollutants in human environments and new research has shown that these alpha,beta-unsaturated carbonyl derivatives are also toxic to nerve terminals. In this review, we provide evidence that the regional synaptotoxicity, which develops during the early stages of many neurodegenerative diseases, is mediated by endogenous generation of acrolein and HNE. Based on a presumed common nerve terminal site of action, we propose that the onset and progression of this neuropathogenic process is accelerated by environmental exposure to other type-2 alkenes.}, }
@article {pmid18574927, year = {2008}, author = {Rashidipour, O and Chan, KM}, title = {Motor unit number estimation in neuromuscular disease.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {35}, number = {2}, pages = {153-159}, doi = {10.1017/s0317167100008568}, pmid = {18574927}, issn = {0317-1671}, mesh = {Electric Stimulation/methods ; Electromyography/methods ; Evoked Potentials, Motor/physiology ; Humans ; Motor Neurons/*pathology ; Muscle, Skeletal/physiopathology ; Neuromuscular Diseases/*pathology ; }, abstract = {Motor unit number estimation (MUNE) is an electrophysiological method designed to quantify motor unit loss in target muscles of interest. Most of the techniques are noninvasive and are therefore well suited for longitudinal monitoring. In this brief review, we describe the more commonly used techniques and their applications in amyotrophic lateral sclerosis, poliomyelitis, spinal muscular atrophy and hereditary sensorimotor neuropathies. Findings in some of these studies offer important pathophysiological insights. Since conventional electrophysiologic methods are not sensible measures of motor neuronal loss, MUNE could play a potentially important role in the diagnosis, monitoring of disease progression and response to treatment in neuromuscular diseases in which motor unit loss is a major feature.}, }
@article {pmid18574756, year = {2008}, author = {Lanka, V and Cudkowicz, M}, title = {Therapy development for ALS: lessons learned and path forward.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {3}, pages = {131-140}, doi = {10.1080/17482960802112819}, pmid = {18574756}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Biomarkers/metabolism ; Disease Models, Animal ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Several therapies have shown promise in preclinical models of motor neuron disease. Several of these treatment approaches, however, failed in human studies. In moving forward with new promising therapies, it is important to first identify whether the past trials were unsuccessful due to wrong therapy and biological target or because of flaws in trial design and conduct. We review treatment development in ALS and discuss the strengths and limitations of past clinical trials. Better biomarkers of disease and markers of biological activity of the therapies under development are urgently needed. Obtaining information regarding dosage, pharmacokinetics, short-term safety and biological activity in well designed phase I and II studies is critical to the design of phase III trials that will yield meaningful results.}, }
@article {pmid18567360, year = {2008}, author = {Urushitani, M}, title = {[Implications of successful immunotherapy in ALS model mice].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {60}, number = {6}, pages = {643-651}, pmid = {18567360}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Antibodies/administration &amp; dosage ; Chromogranins ; *Disease Models, Animal ; Forecasting ; Humans ; *Immunotherapy/trends ; Immunotherapy, Active ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Protein Folding ; Superoxide Dismutase/*genetics/*immunology/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Recent progress in clinical genetics has explored various mutations or associated genes in both familial and sporadic amyotrophic lateral sclerosis (ALS). Mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS, and mutant SOD1 transgenic mice are still regarded as the best ALS model animals for the first step of therapeutic estimation. Emerging evidence indicates that SOD1 is secreted in spite of lacking translocation signal. We previously found chromogranins interact with ALS-linked SOD1 mutants, but not with wild-type, and promote the secretion SOD1 mutants. Moreover, extracellular SOD1 mutant activates microglia and kills motor neuron. This scenario may well explain non-cell-autonomous fashion of mutant SOD1-induced pathology in ALS. Accordingly, vaccination targeting extracellular SOD1 mutants significantly delays disease onset and prolongs lifespan of mutant SOD1 transgenic mice. Moreover, intraventricular application of ant-mutant SOD1 antibody also showed beneficial effect. In this review, the rationale between protein misfolding of mutant SOD1 and effect of immunization is delineated and further perspective of this non-invasive treatment not only for mutant SOD1 but also for sporadic ALS is discussed.}, }
@article {pmid18566926, year = {2008}, author = {Simpson, RC and LoPresti, EF and Cooper, RA}, title = {How many people would benefit from a smart wheelchair?.}, journal = {Journal of rehabilitation research and development}, volume = {45}, number = {1}, pages = {53-71}, doi = {10.1682/jrrd.2007.01.0015}, pmid = {18566926}, issn = {1938-1352}, mesh = {*Disabled Persons ; Electric Power Supplies ; Equipment Design ; Equipment Safety ; *Ergonomics ; Expert Systems ; Humans ; Man-Machine Systems ; Robotics ; User-Computer Interface ; *Wheelchairs ; }, abstract = {Independent mobility is important, but some wheelchair users find operating existing manual or powered wheelchairs difficult or impossible. Challenges to safe, independent wheelchair use can result from various overlapping physical, perceptual, or cognitive symptoms of diagnoses such as spinal cord injury, cerebrovascular accident, multiple sclerosis, amyotrophic lateral sclerosis, and cerebral palsy. Persons with different symptom combinations can benefit from different types of assistance from a smart wheelchair and different wheelchair form factors. The sizes of these user populations have been estimated based on published estimates of the number of individuals with each of several diseases who (1) also need a wheeled mobility device and (2) have specific symptoms that could interfere with mobility device use.}, }
@article {pmid18566920, year = {2008}, author = {Reddy, PH}, title = {Mitochondrial medicine for aging and neurodegenerative diseases.}, journal = {Neuromolecular medicine}, volume = {10}, number = {4}, pages = {291-315}, pmid = {18566920}, issn = {1559-1174}, support = {R01 AG028072-01A2/AG/NIA NIH HHS/United States ; AG026051/AG/NIA NIH HHS/United States ; R03 AG026051-01A2/AG/NIA NIH HHS/United States ; R01 AG028072/AG/NIA NIH HHS/United States ; R03 AG026051/AG/NIA NIH HHS/United States ; AG028072/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*drug effects/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use ; Energy Metabolism/physiology ; Humans ; Mitochondria/genetics/*metabolism/pathology ; Mitochondrial Diseases/*drug therapy/metabolism/physiopathology ; Mitochondrial Proteins/metabolism ; Nerve Tissue Proteins/metabolism/toxicity ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/physiology ; }, abstract = {Mitochondria are key cytoplasmic organelles, responsible for generating cellular energy, regulating intracellular calcium levels, altering the reduction-oxidation potential of cells, and regulating cell death. Increasing evidence suggests that mitochondria play a central role in aging and in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Freidriech ataxia. Further, several lines of evidence suggest that mitochondrial dysfunction is an early event in most late-onset neurodegenerative diseases. Biochemical and animal model studies of inherited neurodegenerative diseases have revealed that mutant proteins of these diseases are associated with mitochondria. Mutant proteins are reported to block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins and disrupt the electron transport chain, induce free radicals, cause mitochondrial dysfunction, and, ultimately, damage neurons. This article discusses critical issues of mitochondria causing dysfunction in aging and neurodegenerative diseases, and discusses the potential of developing mitochondrial medicine, particularly mitochondrially targeted antioxidants, to treat aging and neurodegenerative diseases.}, }
@article {pmid18564527, year = {2008}, author = {Woodson, G}, title = {Management of neurologic disorders of the larynx.}, journal = {The Annals of otology, rhinology, and laryngology}, volume = {117}, number = {5}, pages = {317-326}, doi = {10.1177/000348940811700501}, pmid = {18564527}, issn = {0003-4894}, mesh = {Electromyography/methods ; Humans ; *Laryngeal Diseases/diagnosis/etiology/therapy ; Laryngoscopy/methods ; Larynx/*physiopathology ; *Nervous System Diseases/complications/diagnosis/therapy ; Otolaryngology/methods ; Physical Examination/methods ; }, abstract = {OBJECTIVES: I review the literature on management of neurologic disorders of the larynx.<br><br>METHODS: I reviewed the literature on laryngeal physiology, clinical evaluation of laryngeal function, and the clinical presentation and treatment of neurologic disorders that frequently affect the larynx.<br><br>RESULTS: Laryngeal function is complex, as this organ is important in breathing, speech, and swallowing. Coordination of these roles is very susceptible to disruption by neurologic disorders. Diagnosis of neurologic disease is primarily based on history and physical examination; however, the diagnosis of laryngeal dysfunction is frequently overlooked, because the larynx is not easily accessible to examination by non-otolaryngologists. Evaluation of laryngeal function includes listening to the voice, systematic observation of the larynx during speech and nonspeech tasks, and, sometimes, ancillary tests. Neurologic disorders that affect laryngeal function include Parkinson's disease, essential tremor, stroke, amyotrophic lateral sclerosis, multiple sclerosis, and dystonia. The otolaryngologist can sometimes provide treatment to specifically improve symptoms of laryngeal involvement.<br><br>CONCLUSIONS: Otolaryngology consultation is important in the diagnosis and treatment of neurologic disorders that affect laryngeal function. The otolaryngologist should be able to perform a systematic evaluation of laryngeal and pharyngeal function, and should be aware of the clinical presentation of neurologic disorders that affect the larynx.}, }
@article {pmid18564179, year = {2008}, author = {Yoshimura, T and Goto, M}, title = {D-amino acids in the brain: structure and function of pyridoxal phosphate-dependent amino acid racemases.}, journal = {The FEBS journal}, volume = {275}, number = {14}, pages = {3527-3537}, doi = {10.1111/j.1742-4658.2008.06516.x}, pmid = {18564179}, issn = {1742-464X}, mesh = {Alanine Racemase/*chemistry ; Amino Acid Isomerases/chemistry ; Animals ; Bacteria/enzymology ; Brain/enzymology ; Isomerism ; Pyridoxal Phosphate/*chemistry ; Racemases and Epimerases/*chemistry ; Serine/*biosynthesis/chemistry ; }, abstract = {D-serine serves as a co-agonist of the N-methyl D-aspartate receptor in mammalian brains, and its behavior is probably related to neurological disorders such as schizophrenia, Alzheimer's disease and amyotrophic lateral sclerosis. D-Serine is synthesized by a pyridoxal 5'-phosphate (PLP)-dependent serine racemase. In this minireview, we provide a detailed discussion on the reaction mechanism of the PLP-dependent amino acid racemase on the basis of its 3D structure. We compared the eukaryotic serine racemase with bacterial alanine racemase, the best-studied enzyme among the PLP-dependent amino acid racemases, and thus suggested a putative reaction mechanism for mammalian D-serine synthesis.}, }
@article {pmid18562817, year = {2008}, author = {Hoffman, JJ}, title = {Toward a better understanding of amyotrophic lateral sclerosis.}, journal = {Home healthcare nurse}, volume = {26}, number = {6}, pages = {337-42; quiz 343-4}, doi = {10.1097/01.NHH.0000324305.71459.81}, pmid = {18562817}, issn = {1539-0713}, mesh = {Adult ; Advance Care Planning ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/psychology/therapy ; Community Health Nursing ; Disease Progression ; Excitatory Amino Acid Antagonists/therapeutic use ; Fatal Outcome ; Home Care Services ; Humans ; Incidence ; Male ; Morale ; *Nurse's Role ; Palliative Care ; Patient Care Planning ; Patient Care Team/organization &amp; administration ; Patient Participation ; Respiratory Insufficiency/etiology ; Riluzole/therapeutic use ; United States/epidemiology ; }, }
@article {pmid18560390, year = {2008}, author = {Kühnlein, P and Gdynia, HJ and Sperfeld, AD and Lindner-Pfleghar, B and Ludolph, AC and Prosiegel, M and Riecker, A}, title = {Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis.}, journal = {Nature clinical practice. Neurology}, volume = {4}, number = {7}, pages = {366-374}, doi = {10.1038/ncpneuro0853}, pmid = {18560390}, issn = {1745-8358}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Bulbar Palsy, Progressive/complications/diagnosis/therapy ; Deglutition Disorders/complications/diagnosis/therapy ; Dysarthria/complications/diagnosis/therapy ; Humans ; Speech Disorders/complications/diagnosis/therapy ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. Bulbar symptoms such as dysphagia and dysarthria are frequent features of ALS and can result in reductions in life expectancy and quality of life. These dysfunctions are assessed by clinical examination and by use of instrumented methods such as fiberendoscopic evaluation of swallowing and videofluoroscopy. Laryngospasm, another well-known complication of ALS, commonly comes to light during intubation and extubation procedures in patients undergoing surgery. Laryngeal and pharyngeal complications are treated by use of an array of measures, including body positioning, compensatory techniques, voice and breathing exercises, communication devices, dietary modifications, various safety strategies, and neuropsychological assistance. Meticulous monitoring of clinical symptoms and close cooperation within a multidisciplinary team (physicians, speech and language therapists, occupational therapists, dietitians, caregivers, the patients and their relatives) are vital.}, }
@article {pmid18558852, year = {2008}, author = {De Vos, KJ and Grierson, AJ and Ackerley, S and Miller, CC}, title = {Role of axonal transport in neurodegenerative diseases.}, journal = {Annual review of neuroscience}, volume = {31}, number = {}, pages = {151-173}, doi = {10.1146/annurev.neuro.31.061307.090711}, pmid = {18558852}, issn = {0147-006X}, support = {/WT_/Wellcome Trust/United Kingdom ; G0000749/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; G0401352/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease/genetics/metabolism/physiopathology ; Animals ; Axonal Transport/*genetics ; Axons/*metabolism/pathology ; Central Nervous System/*metabolism/pathology/physiopathology ; Charcot-Marie-Tooth Disease/genetics/metabolism/physiopathology ; Humans ; Huntington Disease/genetics/metabolism/physiopathology ; Motor Neuron Disease/genetics/metabolism/physiopathology ; Neurodegenerative Diseases/*genetics/*metabolism/physiopathology ; Parkinson Disease/genetics/metabolism/physiopathology ; }, abstract = {Many major human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), display axonal pathologies including abnormal accumulations of proteins and organelles. Such pathologies highlight damage to the axon as part of the pathogenic process and, in particular, damage to transport of cargoes through axons. Indeed, we now know that disruption of axonal transport is an early and perhaps causative event in many of these diseases. Here, we review the role of axonal transport in neurodegenerative disease.}, }
@article {pmid18439227, year = {2008}, author = {Tysnes, OB}, title = {Treatment of sialorrhea in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica. Supplementum}, volume = {188}, number = {}, pages = {77-81}, doi = {10.1111/j.1600-0404.2008.01037.x}, pmid = {18439227}, issn = {0065-1427}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Sialorrhea/*etiology/*therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating progressive disease of all voluntary muscles. Bulbar symptoms with reduced ability to swallow occur frequently and may also be an early symptom. For some patients drooling may represent a severe social problem.<br><br>AIM: To review the literature on treatment of sialorrhea in ALS and describe possible treatments.<br><br>METHOD: PubMed was searched combining the words amyotrophic or ALS with sialorrhea or drooling. Publications more recent than 2000 were selected.<br><br>RESULTS: A total of 31 publications were found. Of these, 22 are from 2000 or later. Thirteen of the 22 most recent publications are original papers whereas 9 are review articles. Of the original articles, four describe treatment of sialorrhea with radiotherapy, five describe effects of botolinum toxin injections into the salivary grands and two describe serious side-effects of botolinum toxin injections for sialorrhea in ALS. The remaining original articles are case descriptions or practice surveys.<br><br>DISCUSSION: The treatment of sialorrhea in ALS is discussed in the view of current knowledge.}, }
@article {pmid18555873, year = {2008}, author = {Serratrice, G}, title = {[Primary muscle cramps].}, journal = {Revue neurologique}, volume = {164}, number = {5}, pages = {416-425}, doi = {10.1016/j.neurol.2008.02.042}, pmid = {18555873}, issn = {0035-3787}, mesh = {Animals ; Diagnosis, Differential ; Humans ; Muscle Cramp/classification/drug therapy/*physiopathology/*therapy ; Muscle Relaxants, Central/therapeutic use ; Quinine/therapeutic use ; }, abstract = {Primary muscle cramps, without known cause, are very frequent especially in the elderly and during the night. They are different from secondary cramps. Likewise they are to be separated from several syndromes erroneously quoted as cramps. The pathophysiological mechanism seems due to result from an initial dysfunction in the distal part of the motoneuron. When the cramps are severe, differential diagnosis with amyotrophic lateral sclerosis may be difficult. Quinine is the best empiric treatment largely used in spite of moderate side effects.}, }
@article {pmid18541989, year = {2008}, author = {Nieuwenhuis-Mark, RE and van Hoek, A and Vingerhoets, A}, title = {Understanding excessive crying in neurologic disorders: nature, pathophysiology, assessment, consequences, and treatment.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {21}, number = {2}, pages = {111-123}, doi = {10.1097/WNN.0b013e31816be8f8}, pmid = {18541989}, issn = {1543-3641}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Antidepressive Agents/therapeutic use ; Brain/drug effects/physiopathology ; Central Nervous System Diseases/diagnosis/*physiopathology ; Crying/*physiology ; Emotions/physiology ; Humans ; Multiple Sclerosis/diagnosis/physiopathology ; Stroke/diagnosis/physiopathology ; }, abstract = {OBJECTIVE: The goal of this review is to provide an overview of the literature on excessive crying (EC) in neurologic disorders.<br><br>BACKGROUND: EC implies that a person has difficulty keeping his emotional behavior under control and it occurs in a number of neurologic disorders.<br><br>METHOD: Intensive literature searches were carried out to address the following 4 questions: (1) What is EC and what effects does it have? (2) In which disorders is EC common? (3) How can EC be diagnosed? and finally, (4) Can EC be treated?<br><br>RESULTS: EC is common in a variety of neurologic disorders including amyotrophic lateral sclerosis, stroke, and multiple sclerosis whereas brain regions implicated may be both focal and/or diffuse. Both in a qualitative and quantitative way, EC does not clearly differ from crying in normal adults. There is a remarkable similarity between the precipitating factors in normal crying and EC. Three questionnaires for the diagnosis of EC have been developed. Treatment with low doses of antidepressants yields promising results.<br><br>CONCLUSIONS: We recommend choosing one term for the phenomenon of EC that does justice to the fact that the threshold for such crying is exceptionally low. This may reduce confusion in the literature and among health professionals. The neurologic origin of EC has yet to be fully mapped out. Antidepressants are the treatment of choice for EC whereas early treatment should be the goal for both patients and their carers.}, }
@article {pmid18537646, year = {2008}, author = {Abdipranoto, A and Wu, S and Stayte, S and Vissel, B}, title = {The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {2}, pages = {187-210}, doi = {10.2174/187152708784083858}, pmid = {18537646}, issn = {1871-5273}, mesh = {Animals ; Antidepressive Agents/pharmacology ; Cell Proliferation ; Encephalitis/drug therapy/pathology ; Humans ; Nervous System/drug effects/*growth &amp; development ; Neurodegenerative Diseases/*drug therapy/*pathology ; Neurons/*physiology ; }, abstract = {Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.}, }
@article {pmid18537618, year = {2008}, author = {Maurer, MH and Schäbitz, WR and Schneider, A}, title = {Old friends in new constellations--the hematopoetic growth factors G-CSF, GM-CSF, and EPO for the treatment of neurological diseases.}, journal = {Current medicinal chemistry}, volume = {15}, number = {14}, pages = {1407-1411}, doi = {10.2174/092986708784567671}, pmid = {18537618}, issn = {0929-8673}, mesh = {Animals ; Erythropoietin/chemistry/metabolism/*therapeutic use ; Granulocyte Colony-Stimulating Factor/chemistry/metabolism/*therapeutic use ; Granulocyte-Macrophage Colony-Stimulating Factor/chemistry/metabolism/*therapeutic use ; Humans ; Nervous System Diseases/*drug therapy ; }, abstract = {Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.}, }
@article {pmid18537606, year = {2008}, author = {Echaniz-Laguna, A and Bousiges, O and Loeffler, JP and Boutillier, AL}, title = {Histone deacetylase inhibitors: therapeutic agents and research tools for deciphering motor neuron diseases.}, journal = {Current medicinal chemistry}, volume = {15}, number = {13}, pages = {1263-1273}, doi = {10.2174/092986708784534974}, pmid = {18537606}, issn = {0929-8673}, mesh = {Animals ; Cell Death/drug effects ; Drug Tolerance ; Enzyme Inhibitors/chemistry/metabolism/*pharmacology/*therapeutic use ; *Histone Deacetylase Inhibitors ; Histone Deacetylases/*metabolism ; Humans ; Motor Neuron Disease/*drug therapy/metabolism/*pathology ; Neurons/drug effects/pathology ; }, abstract = {Histone deacetylase (HDAC) inhibition as a therapeutic regimen in motor neuron diseases (MND) is generating intense interest in both the scientific and medical areas, with a number of potent compounds having demonstrated good safety profiles and hints of clinical activity on animal models. In this review, we discuss recent developments in dissecting the mechanism of action of HDAC inhibitors (HDACi) as a new group of mechanism-based drugs for motor neuron diseases, together with current progress in understanding their clinical application. We also discuss how the use of HDACi on animal models with motor neuron defects has allowed critical advances in the understanding of the pathophysiology of motor neuron diseases. The use of HDACi and possible mechanisms of action will be reviewed in three MND, i.e. amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA), diseases among which clinical trials with HDACi are currently perfomed (ALS, SMA).}, }
@article {pmid18497106, year = {2008}, author = {Spedding, M and Gressens, P}, title = {Neurotrophins and cytokines in neuronal plasticity.}, journal = {Novartis Foundation symposium}, volume = {289}, number = {}, pages = {222-33; discussion 233-40}, doi = {10.1002/9780470751251.ch18}, pmid = {18497106}, issn = {1528-2511}, mesh = {Animals ; Brain/*physiology/physiopathology ; Brain-Derived Neurotrophic Factor/physiology ; Cytokines/*physiology ; Energy Metabolism ; Humans ; Models, Biological ; Nerve Growth Factors/*physiology ; Neuronal Plasticity/*physiology ; Pain/physiopathology ; Synapses/physiology ; }, abstract = {Nerve growth factor (NGF) binds to TrkA receptors (neurotrophic) and P75(NTR) (apoptosis or other pathways depending on the coupled adaptor proteins). Brain derived growth factor (BDNF) can bind to TrkB (neurotrophic) and P75(NTR) receptors. BDNF is the main, activity-dependent, neurotrophin and sculpts neuronal organisation dependent on activity, thereby coupling and balancing effects on excitatory (glutamate) and inhibitory (GABA) transmission--in a synapse-specific manner. Some drugs can interact in a specific way. Positive modulators of AMPA receptors induce BDNF and favour long term potentiation (LTP) and memory processes. Some antidepressants such as tianeptine reverse stress-induced inhibition of LTP and restore neuronal plasticity in brain areas at risk. Inflammatory cytokines are produced in sickness behaviour mimicking depression. Interleukin (IL)1beta can exacerbate the immediate effects of stressors, and enhance and prolong the overall effects, which may be protective in preventing overuse or by increasing conservation-withdrawal: in some synapses IL1beta induces long term depression (LTD) or blocks LTP. The interactions with neurotrophins are complex and frequently reciprocal. However, NGF also contributes to inflammatory situations and mediates pain responses. This interplay is poorly understood but may be critical in cerebral palsy, neurodegenerative disorders such as amyotrophic lateral sclerosis and multiple sclerosis, and even Alzheimer's disease.}, }
@article {pmid18490618, year = {2008}, author = {Steele, JC and McGeer, PL}, title = {The ALS/PDC syndrome of Guam and the cycad hypothesis.}, journal = {Neurology}, volume = {70}, number = {21}, pages = {1984-1990}, doi = {10.1212/01.wnl.0000312571.81091.26}, pmid = {18490618}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Cycas/*toxicity ; Dementia/epidemiology/etiology ; Guam/epidemiology ; Humans ; Incidence ; Parkinsonian Disorders/epidemiology/etiology ; Tauopathies/epidemiology/etiology ; }, abstract = {There is a high incidence on Guam of a severe tauopathy known as the Parkinson- dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.}, }
@article {pmid18484797, year = {2008}, author = {Corcia, P and Meininger, V}, title = {Management of amyotrophic lateral sclerosis.}, journal = {Drugs}, volume = {68}, number = {8}, pages = {1037-1048}, pmid = {18484797}, issn = {0012-6667}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/*therapy ; Genetic Counseling ; Humans ; Mutation ; Nutritional Support ; Physical Therapy Modalities ; Speech Therapy ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons, in both the spinal cord and medulla (lower motor neurons) and cerebral cortex (upper motor neurons). Even though ALS remains fatal, several advances have been made during the last decade in improving the consequences of motor dysfunction, quality of life and survival time of patients. Treatment of ALS cannot be restricted to riluzole, the only molecule that has been proved to modify the evolution of the disease. Symptomatic treatments have an important role in controlling the major consequences of the disease, such as pain, sleep disorders, spasticity, hypersialhorroea, emotional lability, depression and digestive disorders (constipation and reflux). All these symptoms need to be recognized and their possible causes identified in order to provide the most appropriate management of patients with ALS. However, an advance in the daily care of patients is the identification of two important phenomena that occur during the evolution of the disease: swallowing difficulties and the occurrence of diaphragmatic dysfunction. For both, specific medical interventions have been developed to allow correction of the consequences (i.e. weight loss and respiratory insufficiency). Although no controlled trials have been performed, observational studies suggest that gastrostomy and non-invasive ventilation may improve at least quality of life and survival. All of these various approaches, pharmaceutical and non-pharmaceutical therapies, are prescribed according to individual symptoms and require the involvement of a large range of health professionals. This multidisciplinary approach in ALS clinics is considered to be one of the more important factors impacting on survival rate and appears to be the gold standard of medical care of ALS patients. Important findings have been made in understanding the nature of the degenerative process that affects the motor neurons. All these data have allowed new therapeutic molecules to be tested alone or in combination with riluzole. Despite the negative results obtained until now, we hope to demonstrate very soon a greater improvement in therapy.}, }
@article {pmid18483718, year = {2008}, author = {Schmezer, P and Plass, C}, title = {[Epigenetic aspects in carcinomas of the head and neck].}, journal = {HNO}, volume = {56}, number = {6}, pages = {594-602}, pmid = {18483718}, issn = {1433-0458}, support = {R01 DE013123/DE/NIDCR NIH HHS/United States ; R01 DE013123-07/DE/NIDCR NIH HHS/United States ; }, mesh = {Biomarkers, Tumor/*genetics ; Carcinoma, Squamous Cell/*genetics ; *DNA Methylation ; Epigenesis, Genetic/*genetics ; Genetic Markers/*genetics ; Genetic Predisposition to Disease/*genetics ; Head and Neck Neoplasms/*genetics ; Humans ; Models, Genetic ; }, abstract = {Plattenepithelkarzinome der Kopf-Hals-Region (HNSCC) zählen seit Jahren zu den weltweit häufigsten Krebsarten. Trotz vieler Bemühungen hat sich das 5-Jahres-Überleben bei Patienten mit HNSCC kaum verbessert. Um einen Fortschritt zu erzielen, ist es notwendig, die der Erkrankung zugrunde liegenden biologischen Prozesse besser zu verstehen. Neben den bekannten genetischen Veränderungen haben molekular-zytogenetische Untersuchungen bei HNSCC gezeigt, dass es weitere Veränderungen gibt, die mit Vermehrung und Verlust chromosomaler Bereiche einhergehen, für die jedoch die krankheitsverursachenden Gene bisher nicht identifiziert wurden. Darüberhinaus haben jüngste Forschungsergebnisse verdeutlicht, dass epigenetische Modifikationen wie die DNA Methylierung eine wichtige Rolle spielen. So konnte gezeigt werden, dass bei HNSCC eine Reihe von Genen (z.B. das Tumorsuppressorgen CDKN2A sowie DAPK1, MGMT, TIMP3, TCF21, und C/EBPα) hypermethylierte Bereiche in regulatorischen DNA Sequenzen aufweisen, wodurch ihre Expression verringert oder unterbunden wird. Die Hypermethylierung solcher Gene könnte als Biomarker zur Früherkennung von HNSCC genutzt werden und nicht zuletzt dadurch zur Verbesserung von Prävention und Therapieerfolg beitragen.}, }
@article {pmid18478527, year = {2008}, author = {Wojda, U and Salinska, E and Kuznicki, J}, title = {Calcium ions in neuronal degeneration.}, journal = {IUBMB life}, volume = {60}, number = {9}, pages = {575-590}, doi = {10.1002/iub.91}, pmid = {18478527}, issn = {1521-6551}, mesh = {Aging/physiology ; Animals ; Calcium/*metabolism ; Calcium Channels/metabolism ; Calcium Signaling/*physiology ; *Homeostasis ; Humans ; Nerve Degeneration/metabolism ; Neurodegenerative Diseases/pathology/physiopathology ; *Neurons/metabolism/pathology ; Receptors, Glutamate/metabolism ; }, abstract = {Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.}, }
@article {pmid18473817, year = {2008}, author = {Matus, S and Lisbona, F and Torres, M and León, C and Thielen, P and Hetz, C}, title = {The stress rheostat: an interplay between the unfolded protein response (UPR) and autophagy in neurodegeneration.}, journal = {Current molecular medicine}, volume = {8}, number = {3}, pages = {157-172}, doi = {10.2174/156652408784221324}, pmid = {18473817}, issn = {1566-5240}, mesh = {Alzheimer Disease/metabolism ; Animals ; *Autophagy ; Endoplasmic Reticulum/metabolism ; Humans ; Membrane Proteins/chemistry/metabolism ; Models, Biological ; Nerve Degeneration/metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; *Protein Folding ; Stress, Physiological/metabolism ; }, abstract = {The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under conditions of endoplasmic reticulum (ER) stress. The UPR controls diverse processes such as protein folding, secretion, ER biogenesis, protein quality control and macroautophagy. Occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation, including Amyotrophic lateral sclerosis, Prion-related disorders, and conditions such as Parkinson's, Huntington's, and Alzheimer's disease. Strong correlations are observed between disease progression, accumulation of protein aggregates, and induction of the UPR in animal and in vitro models of neurodegeneration. In addition, the first reports are available describing the engagement of ER stress responses in brain post-mortem samples from human patients. Despite such findings, the role of the UPR in the central nervous system has not been addressed directly and its contribution to neurodegeneration remains speculative. Recently, however, pharmacological manipulation of ER stress and autophagy - a stress pathway modulated by the UPR - using chemical chaperones and autophagy activators has shown therapeutic benefits by attenuating protein misfolding in models of neurodegenerative disease. The most recent evidence addressing the role of the UPR and ER stress in neurodegenerative disorders is reviewed here, along with therapeutic strategies to alleviate ER stress in a disease context.}, }
@article {pmid18466063, year = {2008}, author = {Schubert, W and Bode, M and Hillert, R and Krusche, A and Friedenberger, M}, title = {Toponomics and neurotoponomics: a new way to medical systems biology.}, journal = {Expert review of proteomics}, volume = {5}, number = {2}, pages = {361-369}, doi = {10.1586/14789450.5.2.361}, pmid = {18466063}, issn = {1744-8387}, mesh = {Animals ; Humans ; Nerve Tissue Proteins/*analysis ; Organelles/*chemistry ; Proteomics/*methods ; *Systems Biology ; }, abstract = {The fluorescence robot imaging technology multi-epitope-ligand-cartography/toponome imaging system has revolutionized the field of proteomics/functional genomics, because it enables the investigator to locate and decipher functional protein networks, the toponome, consisting of hundreds of different proteins in a single cell or tissue section. The technology has been proven to solve key problems in biology and therapy research. It has uncovered a new cellular transdifferentiation mechanism of vascular cells giving rise to myogenic cells in situ and in vivo; a finding that has led to efficient cell therapy models of muscle disorders, and discovered a new target protein in sporadic amyotrophic lateral sclerosis by hierarchical protein network analysis, a finding that has been confirmed by a mouse knockout model. A lead target protein in tumor cells that controls cell polarization as a mechanism that is fundamental for migration and metastasis formation has also been uncovered, and new functional territories in the CNS defined by high-dimensional synaptic protein clusters have been unveiled. The technology can be effectively interlocked with genomics and proteomics to optimize time-to-market and the overall attrition rate of new drugs. This review outlines major proofs of principle with an emphasis on neurotoponomics.}, }
@article {pmid18466055, year = {2008}, author = {Ryberg, H and Bowser, R}, title = {Protein biomarkers for amyotrophic lateral sclerosis.}, journal = {Expert review of proteomics}, volume = {5}, number = {2}, pages = {249-262}, doi = {10.1586/14789450.5.2.249}, pmid = {18466055}, issn = {1744-8387}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers ; Humans ; Proteins/*analysis ; Proteomics/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with largely unknown pathogenesis that typically results in death within a few years from diagnosis. There are currently no effective therapies for ALS. Clinical diagnosis usually takes several months to complete and the long delay between symptom onset and diagnosis limits the possibilities for effective intervention and clinical trials. The establishment of protein biomarkers for ALS may aid an earlier diagnosis, facilitating the search for effective therapeutic interventions and monitoring drug efficacy during clinical trials. Biomarkers could also be used to discriminate between subtypes of ALS, to measure disease progression and to detect susceptibility for developing ALS or monitor adverse effects of drug treatment. The present review will discuss the opportunities and proteomic platforms used for biomarker discovery efforts in ALS, summarizing putative ALS protein biomarkers identified in different biofluids.}, }
@article {pmid18466051, year = {2008}, author = {Zabel, C and Andreew, A and Mao, L and Hartl, D}, title = {Protein expression overlap: more important than which proteins change in expression?.}, journal = {Expert review of proteomics}, volume = {5}, number = {2}, pages = {187-205}, doi = {10.1586/14789450.5.2.187}, pmid = {18466051}, issn = {1744-8387}, mesh = {Animals ; Disease Susceptibility ; *Gene Expression ; Humans ; Metabolism ; Neurodegenerative Diseases/*metabolism ; Proteins/*analysis/genetics ; Proteomics/*methods ; }, abstract = {In recent years, a large number of proteomics studies for various diseases were conducted, such as for cancer, cardiovascular and neurodegenerative disorders (NDs). The availability of huge data sets with a large number of differentially expressed proteins showed for the first time that not all protein changes between a diseased and a control state were specific. This review focuses on this protein expression overlap, specifically between NDs, and tries to investigate the possible reasons for this overlap by investigating 14 ND proteomics studies of Alzheimer's (six studies), Parkinson's (four studies) and Huntington's disease (three studies), as well as amyotrophic lateral sclerosis (one study). Studies were selected according to the availability of quantitative changes, number of (biological) repeats and numbers of proteins changed. The studies include investigations of human tissue and mouse, as well as cell culture, models. A change in metabolism-related proteins was found to be common among all disorders. These changes can be explained by alterations in key regulatory proteins, such as those involved in transcription. Since most NDs affect, at least initially, very specific areas of the brain, the location of the changes may be more important than the kind of protein alterations that occur, since they are very similar among NDs.}, }
@article {pmid18463003, year = {2008}, author = {Yang, JL and Weissman, L and Bohr, VA and Mattson, MP}, title = {Mitochondrial DNA damage and repair in neurodegenerative disorders.}, journal = {DNA repair}, volume = {7}, number = {7}, pages = {1110-1120}, pmid = {18463003}, issn = {1568-7864}, support = {Z01 AG000313-07/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; *DNA Damage ; DNA Repair ; DNA, Mitochondrial/*metabolism ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism ; Oxidative Stress ; Parkinson Disease/genetics/metabolism ; }, abstract = {By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders-Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.}, }
@article {pmid18453002, year = {2008}, author = {Schwartz, M and Ziv, Y}, title = {Immunity to self and self-maintenance: what can tumor immunology teach us about ALS and Alzheimer's disease?.}, journal = {Trends in pharmacological sciences}, volume = {29}, number = {6}, pages = {287-293}, doi = {10.1016/j.tips.2008.03.006}, pmid = {18453002}, issn = {0165-6147}, mesh = {Alzheimer Disease/drug therapy/*immunology/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy/*immunology/physiopathology ; Animals ; Humans ; Immune System/drug effects/physiopathology ; Immunologic Surveillance/physiology ; Neoplasms/*immunology/physiopathology ; Neuroprotective Agents/immunology/pharmacology ; }, abstract = {Mounting evidence from the last decade has shown that the immune system not only fights pathogens but also protects the body against cancer. More recently, immune surveillance has been shown to be important for maintaining the functional integrity of the central nervous system. The immune system, however, does not always prevail; tumors do grow and eventually kill their host, and devastating neurodegenerative conditions do develop. Neurodegenerative diseases, like tumors, lie dormant long before clinical symptoms appear. We propose that at this dormant stage, an ongoing competition between the local disease-causing factors and the immune system's attempts to contain them takes place. Onset of clinical symptoms occurs after disease-causing factors escape immune surveillance. Identifying the immune escape mechanisms and circumventing them soon after the emergence of clinical symptoms could lead to the development of novel therapeutic intervention for some of the most devastating neurodegenerative disorders.}, }
@article {pmid18431258, year = {2008}, author = {Martin, LJ}, title = {DNA damage and repair: relevance to mechanisms of neurodegeneration.}, journal = {Journal of neuropathology and experimental neurology}, volume = {67}, number = {5}, pages = {377-387}, pmid = {18431258}, issn = {0022-3069}, support = {NS034100/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 NS034100-10/NS/NINDS NIH HHS/United States ; R01 NS052098-04/NS/NINDS NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; R01 AG016282-08/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cell Death/genetics ; DNA Damage/*genetics ; DNA Repair/*genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Nerve Degeneration/*genetics/metabolism/physiopathology ; Nerve Tissue Proteins/genetics ; Neurons/*metabolism/pathology ; Oxidative Stress/genetics ; Signal Transduction/genetics ; }, abstract = {DNA damage is a form of cell stress and injury that has been implicated in the pathogenesis of many neurologic disorders, including amyotrophic lateral sclerosis, Alzheimer disease, Down syndrome, Parkinson disease, cerebral ischemia, and head trauma. However, most data reveal only associations, and the role for DNA damage in direct mechanisms of neurodegeneration is vague with respect to being a definitive upstream cause of neuron cell death, rather than a consequence of the degeneration. Although neurons seem inclined to develop DNA damage during oxidative stress, most of the existing work on DNA damage and repair mechanisms has been done in the context of cancer biology using cycling nonneuronal cells but not nondividing (i.e. postmitotic) neurons. Nevertheless, the identification of mutations in genes that encode proteins that function in DNA repair and DNA damage response in human hereditary DNA repair deficiency syndromes and ataxic disorders is establishing a mechanistic precedent that clearly links DNA damage and DNA repair abnormalities with progressive neurodegeneration. This review summarizes DNA damage and repair mechanisms and their potential relevance to the evolution of degeneration in postmitotic neurons.}, }
@article {pmid18428572, year = {2002}, author = {Jackson, M and Ganel, R and Rothstein, JD}, title = {Models of amyotrophic lateral sclerosis.}, journal = {Current protocols in neuroscience}, volume = {Chapter 9}, number = {}, pages = {Unit 9.13}, doi = {10.1002/0471142301.ns0913s20}, pmid = {18428572}, issn = {1934-8576}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/physiopathology ; Animals ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Organ Culture Techniques/methods ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder caused by degeneration of the motor neurons in cortex, brainstem and spinal cord. Two experimental models of ALS are described in this unit: organotypic cultures of spinal cord, and transgenic mice expressing a human mutant superoxide dismutase 1 (SOD1) gene. Appropriate animal and cell culture models of ALS can be used to help unravel the sequence of events in motor neuronal degeneration and test potential therapies.}, }
@article {pmid18425927, year = {2008}, author = {Bausewein, C and Booth, S and Gysels, M and Higginson, I}, title = {Non-pharmacological interventions for breathlessness in advanced stages of malignant and non-malignant diseases.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD005623}, doi = {10.1002/14651858.CD005623.pub2}, pmid = {18425927}, issn = {1469-493X}, mesh = {Acupuncture Therapy ; Breathing Exercises ; Case Management ; Dyspnea/etiology/*therapy ; Electric Stimulation Therapy/methods ; Humans ; Music Therapy ; Psychotherapy ; Randomized Controlled Trials as Topic ; Relaxation Therapy ; Vibration/therapeutic use ; Walking ; }, abstract = {BACKGROUND: Breathlessness is a common and distressing symptom in the advanced stages of malignant and non-malignant diseases. Appropriate management requires both pharmacological and non-pharmacological interventions.<br><br>OBJECTIVES: The primary objective was to determine the effectiveness of non-pharmacological and non-invasive interventions to relieve breathlessness in participants suffering from the five most common conditions causing breathlessness in advanced disease.<br><br>SEARCH STRATEGY: We searched the following databases: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, British Nursing Index, PsycINFO, Science Citation Index Expanded, AMED, The Cochrane Pain, Palliative and Supportive Care Trials Register, The Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effectiveness in June 2007. We also searched various websites and reference lists of relevant articles and textbooks.<br><br>SELECTION CRITERIA: We included randomised controlled and controlled clinical trials assessing the effects of non-pharmacological and non-invasive interventions to relieve breathlessness in participants described as suffering from breathlessness due to advanced stages of cancer, chronic obstructive pulmonary disease (COPD), interstitial lung disease, chronic heart failure or motor neurone disease.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed relevant studies for inclusion. Data extraction and quality assessment was performed by three review authors and checked by two other review authors. Meta-analysis was not attempted due to heterogeneity of studies.<br><br>MAIN RESULTS: Forty-seven studies were included (2532 participants) and categorised as follows: single component interventions with subcategories of walking aids (n = 7), distractive auditory stimuli (music) (n = 6), chest wall vibration (CWV, n = 5), acupuncture/acupressure (n = 5), relaxation (n = 4), neuro-electrical muscle stimulation (NMES, n = 3) and fan (n = 2). Multi-component interventions were categorised in to counselling and support (n = 5), breathing training (n = 3), counselling and support with breathing-relaxation training (n = 2), case management (n = 2) and psychotherapy (n = 2). There was a high strength of evidence that NMES and CWV could relieve breathlessness and moderate strength for the use of walking aids and breathing training. There is a low strength of evidence that acupuncture/acupressure is helpful. There is not enough data to judge the evidence for distractive auditory stimuli (music), relaxation, fan, counselling and support, counselling and support with breathing-relaxation training, case management and psychotherapy. Most studies have been conducted in COPD patients, only a few studies included participants with other conditions.<br><br>AUTHORS' CONCLUSIONS: Breathing training, walking aids, NMES and CWV appear to be effective non-pharmacological interventions for relieving breathlessness in advanced stages of disease.}, }
@article {pmid18425913, year = {2008}, author = {Dalbello-Haas, V and Florence, JM and Krivickas, LS}, title = {Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD005229}, doi = {10.1002/14651858.CD005229.pub2}, pmid = {18425913}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; Exercise Therapy/*methods ; Exercise Tolerance ; Humans ; Motor Neuron Disease/psychology/therapy ; Physical Endurance ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood.<br><br>OBJECTIVES: The objective was to systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, EMBASE (January 1980 to August 2007), LILACS (January 1982 to August 2007), MEDLINE (January 1966 to August 2007), Cochrane Central Register of Controlled Trials (CENTRAL), PEDro (January 1980 to August 2007), AMED (January 1985 to August 2007), HealthSTAR (January 1975 to August 2007), CINAHL (January 1982 to August 2007). We also searched Dissertation Abstracts, inspected the reference lists of all papers selected for review and contacted the authors with expertise in the field.<br><br>SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible amyotrophic lateral sclerosis, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. The authors of the papers were contacted to obtain information not available in the published articles.<br><br>MAIN RESULTS: We identified two randomised controlled trials that met our inclusion criteria. The first examined the effects of a twice-daily exercise program of moderate load, endurance exercise versus "usual activities" in 25 people with ALS. The second examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined, there was a significant weighted mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in the exercise compared with the control groups (3.21, 95% confidence interval 0.46 to 5.96) in favour of the exercise group. No statistically significant differences in quality of life, fatigue or muscle strength were found.<br><br>AUTHORS' CONCLUSIONS: The only studies detected were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.}, }
@article {pmid18425887, year = {2008}, author = {Parton, M and Mitsumoto, H and Leigh, PN}, title = {WITHDRAWN: Amino acids for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD003457}, doi = {10.1002/14651858.CD003457.pub2}, pmid = {18425887}, issn = {1469-493X}, mesh = {Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; Threonine/*therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a progressive neuromuscular disease that causes disability and eventual death. Various amino acid preparations, the three branched-chain amino acids (L-leucine, L-valine and L-isoleucine) or, alternatively, L-threonine have been used as experimental therapy.<br><br>OBJECTIVES: To examine the efficacy of amino acid therapies in prolonging survival and/or slowing the progression of amyotrophic lateral sclerosis/motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2003), MEDLINE (from January 1966 to December 2002) and EMBASE (from January 1980 to December 2002) databases and reports of specialist conferences. Authors of known studies were contacted.<br><br>SELECTION CRITERIA: We included randomised or quasi-randomised trials of participants with a clinical diagnosis of amyotrophic lateral sclerosis/motor neuron disease treated with all combinations of amino acids. Our primary outcome measure was survival determined by a pooled hazard ratio of all studies. Our secondary outcome measures were (in order of priority): survival at six and 12 months, muscle strength, any validated rating scale of physical function, quality of life, proportion of patients completing therapy and proportion of patients reporting adverse events attributable to treatment.<br><br>DATA COLLECTION AND ANALYSIS: We identified six eligible trials and rejected a further seven because of incomplete data or inadequate duration. Eligible studies were rated for methodological quality and missing data sought from the authors. After this examination two studies were excluded from analysis. Our pooled survival analysis was performed by the Parmar method, other statistical calculations were done using the Review Manager 4.2 software package.<br><br>MAIN RESULTS: No benefit could be demonstrated for either branched-chain amino acids or L-threonine in improving survival in amyotrophic lateral sclerosis/motor neuron disease. Neither could we find evidence of an effect of either treatment on muscle strength or disability as measured by functional rating scales. No study assessed quality of life. Both branched-chain amino acids and L-threonine appeared well tolerated and caused a degree of adverse events comparable to that of the control medication.<br><br>AUTHORS' CONCLUSIONS: There is no evidence to support a beneficial effect of either branched-chain amino acids or L-threonine in amyotrophic lateral sclerosis/motor neuron disease.}, }
@article {pmid18423450, year = {2008}, author = {Beal, MF}, title = {The urokinase system of plasminogen activator plays a role in amyotrophic lateral sclerosis (ALS) pathogenesis.}, journal = {Experimental neurology}, volume = {211}, number = {2}, pages = {332-333}, doi = {10.1016/j.expneurol.2008.02.029}, pmid = {18423450}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*etiology/pathology ; Animals ; Disease Models, Animal ; Humans ; Plasminogen Activators/metabolism/*physiology ; Receptors, Cell Surface/biosynthesis/genetics/physiology ; Receptors, Urokinase Plasminogen Activator ; Urokinase-Type Plasminogen Activator/biosynthesis/genetics/*physiology ; }, }
@article {pmid18423227, year = {2008}, author = {Sultana, R and Butterfield, DA}, title = {Slot-blot analysis of 3-nitrotyrosine-modified brain proteins.}, journal = {Methods in enzymology}, volume = {440}, number = {}, pages = {309-316}, doi = {10.1016/S0076-6879(07)00820-8}, pmid = {18423227}, issn = {0076-6879}, support = {P50 AG005144/AG/NIA NIH HHS/United States ; P50 AG005144-21/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; AG-05119/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/*metabolism ; Humans ; Immunoblotting/*methods ; Nerve Tissue Proteins/*analysis/chemistry/*metabolism ; Tyrosine/*analogs &amp; derivatives/analysis/chemistry/metabolism ; }, abstract = {3-Nitrotyrosine (3-NT) is used as a biomarker of nitrosative stress. The formation of 3-NT has been reported in a number of diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cancer. The nitration of proteins is a reversible process, but it can induce a conformational change and thereby functional alterations of the affected protein. 3-NT measurements in biological samples are usually carried out by methodologies such as immunohistochemistry, high-performance liquid chromatography, gas chromatography, and immunochemical detection. This chapter describes the immunochemical method for the determination of protein-bound 3-NT using slot-blot analysis.}, }
@article {pmid18419791, year = {2008}, author = {Teng, FY and Tang, BL}, title = {Nogo-A and Nogo-66 receptor in amyotrophic lateral sclerosis.}, journal = {Journal of cellular and molecular medicine}, volume = {12}, number = {4}, pages = {1199-1204}, pmid = {18419791}, issn = {1582-1838}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/therapy ; Animals ; Cell Death ; Humans ; Motor Neurons/cytology/metabolism ; Myelin Proteins/*metabolism ; Nogo Proteins ; Protein Isoforms/metabolism ; Receptor, Nerve Growth Factor/metabolism ; }, abstract = {Nogo/reticulon (RTN)-4 has been strongly implicated as a disease marker for the motor neuron disease amyotrophic lateral sclerosis (ALS). Nogo isoforms, including Nogo-A, are ectopically expressed in the skeletal muscle of ALS mouse models and patients and their levels correlate with the disease severity. The notion of a direct involvement of Nogo-A in ALS aetiology is supported by the findings that Nogo-A deletion in mice reduces muscle denervation and prolongs survival, whereas overexpression of Nogo-A destabilizes motor nerve terminals and promotes denervation. Another intriguing, and somewhat paradoxical, recent finding revealed that binding of the Nogo-66 receptor (NgR) by either agonistic or antagonistic Nogo-66-derived peptides protects against p75 neurotrophin receptor (p75(NTR))-dependent motor neuron death. Ligand binding by NgR could result in subsequent engagement of p75(NTR), and this association could preclude pro-apoptotic signalling by the latter. Understanding the intricate interplay among Nogo isoforms, NgR and p75(NTR) in ALS disease progression may provide important, therapeutically exploitable information.}, }
@article {pmid18418046, year = {2008}, author = {Rusten, TE and Simonsen, A}, title = {ESCRT functions in autophagy and associated disease.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {7}, number = {9}, pages = {1166-1172}, doi = {10.4161/cc.7.9.5784}, pmid = {18418046}, issn = {1551-4005}, mesh = {Animals ; Autophagy/*genetics ; Central Nervous System/metabolism/physiopathology ; Endocytosis/*genetics ; Endosomal Sorting Complexes Required for Transport ; Endosomes/genetics/*metabolism ; Humans ; Nerve Tissue Proteins/*genetics ; Neurodegenerative Diseases/genetics/*metabolism/physiopathology ; Protein Transport/genetics ; Proteins/metabolism ; Transport Vesicles/genetics/*metabolism ; }, abstract = {Mutations in the endosomal sorting complexes required for transport (ESCRT)-III subunit CHMP2B are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both human neurodegenerative diseases characterized by accumulation of ubiquitinated proteins aggregates in affected neurons. The ESCRT proteins are known to be involved in diverse cellular processes such as mRNA transport, cytokinesis, transcriptional regulation and sorting of transmembrane proteins into the inner vesicles of the multivesicular body (MVB) during endocytosis. It was until recently not clear how ESCRT function may be involved in neurodegeneration. New findings in mammalian cells and in Drosophila melanogaster show that functional ESCRTs are required for efficient fusion of autophagic vesicles with the endocytic pathway and for degradation of autophagic cargo. Moreover, defective ESCRT function led to the accumulation of cytoplasmic protein aggregates containing ubiquitin, p62/Sequestosome-1 and TAR DNA binding protein 43 (TDP-43). Using cellular and Drosophila models for Huntington's disease it was also shown that reduced ESCRT levels inhibit clearance of expanded polyglutamine aggregates and aggravate their neurotoxic effect. These data indicate that efficient autophagic degradation requires functional MVBs and provides a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.}, }
@article {pmid18416855, year = {2008}, author = {Sathasivam, S}, title = {Brown-Vialetto-Van Laere syndrome.}, journal = {Orphanet journal of rare diseases}, volume = {3}, number = {}, pages = {9}, pmid = {18416855}, issn = {1750-1172}, mesh = {Adolescent ; Adult ; *Bulbar Palsy, Progressive/diagnosis/epidemiology/physiopathology/therapy ; Child ; Child, Preschool ; Diagnosis, Differential ; Female ; *Hearing Loss, Sensorineural/diagnosis/epidemiology/physiopathology/therapy ; Humans ; Infant ; Infant, Newborn ; Male ; Syndrome ; }, abstract = {The Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurological disorder characterized by progressive pontobulbar palsy associated with sensorineural deafness. Fifty-eight cases have been reported in just over 100 years. The female to male ratio is approximately 3:1. The age of onset of the initial symptom varies from infancy to the third decade. The syndrome most frequently presents with sensorineural deafness, which is usually progressive and severe. Lower cranial nerve involvement and lower and upper motor neuron limb signs are common neurological features. Other features include respiratory compromise (the most frequent non-neurological finding), limb weakness, slurring of speech, facial weakness, and neck and shoulder weakness. Optic atrophy, retinitis pigmentosa, macular hyperpigmentation, autonomic dysfunction, epilepsy may occur. The etiopathogenesis of the condition remains elusive. Approximately 50% of cases are familial, of which autosomal recessive is suggested. The remaining cases are sporadic. The diagnosis is usually based on the clinical presentation. Investigations (neurophysiological studies, magnetic resonance imaging of the brain, muscle biopsy, cerebrospinal fluid examination) are done to exclude other causes or to confirm the clinical findings. The differential diagnoses include the Fazio-Londe syndrome, amyotrophic lateral sclerosis, Nathalie syndrome, Boltshauser syndrome and Madras motor neuron disease. Treatment with steroids or intravenous immunoglobulin may result in temporary stabilization of the syndrome. However, the mainstays of management are supportive and symptomatic treatment, in particular assisted ventilation and maintenance of nutrition via gastrostomy. The clinical course of BVVL is variable and includes gradual deterioration (almost half of cases), gradual deterioration with stable periods in between (a third of cases) and deterioration with abrupt periods of worsening (just under a fifth of cases). After the initial presentation, one third of patients survive for ten years or longer.}, }
@article {pmid18416436, year = {2008}, author = {Ekegren, T and Hanrieder, J and Bergquist, J}, title = {Clinical perspectives of high-resolution mass spectrometry-based proteomics in neuroscience: exemplified in amyotrophic lateral sclerosis biomarker discovery research.}, journal = {Journal of mass spectrometry : JMS}, volume = {43}, number = {5}, pages = {559-571}, doi = {10.1002/jms.1409}, pmid = {18416436}, issn = {1076-5174}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Biomarkers/*analysis ; Brain/*metabolism ; Humans ; Mass Spectrometry/*trends ; Nerve Tissue Proteins/*analysis ; Neurosciences/trends ; Proteome/*analysis ; Proteomics/*trends ; }, abstract = {Biomarker discovery is a central application in today's proteomic research. There is an urgent need for valid biomarkers to improve diagnostic tools and treatment in many disorders, such as the rapidly progressing neurodegenerative disorder amyotrophic lateral sclerosis (ALS) that has a fatal outcome in about 3 years and yet no curative treatment. Screening for clinically relevant biomarkers puts high demands on high-throughput, rapid and precise proteomic techniques. There is a large variety in the methods of choice involving mainly gel-based approaches as well as chromatographic techniques for multi-dimensional protein and peptide separations followed by mass spectrometry (MS) analysis. This special feature article will discuss some important aspects of MS-based clinical proteomics and biomarker discovery in the field of neurodegenerative diseases and ALS research respectively, with the aim to provide a prospective view on current and future research aspects in the field. Furthermore, examples for application of high-resolution MS-based proteomic strategies for ALS biomarker discovery will be demonstrated with two studies previously reported by our group. These studies include among others, utilization of capillary liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS) for advanced protein pattern classification in cerebrospinal fluid (CSF) samples of ALS patients as well as highly sensitive protein identification in minimal amounts of postmortem spinal cord tissue and laser micro-dissected motor neurons using FT-ICR-MS in conjunction with nanoflow LC coupled to matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (LC-MALDI-TOF-TOF-MS).}, }
@article {pmid18401228, year = {2008}, author = {Bian, K and Doursout, MF and Murad, F}, title = {Vascular system: role of nitric oxide in cardiovascular diseases.}, journal = {Journal of clinical hypertension (Greenwich, Conn.)}, volume = {10}, number = {4}, pages = {304-310}, pmid = {18401228}, issn = {1524-6175}, support = {GM 061731/GM/NIGMS NIH HHS/United States ; }, mesh = {Atherosclerosis/metabolism ; Cardiovascular Agents/therapeutic use ; Cardiovascular Diseases/*metabolism/physiopathology ; Cardiovascular System/drug effects/*metabolism/physiopathology ; Endothelium/metabolism/physiopathology ; Humans ; Hypertension/metabolism ; Nitric Oxide/*metabolism ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {In contrast with the short research history of the enzymatic synthesis of nitric oxide (NO), the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin) is the first compound of this category. On October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning NO as a signaling molecule in the cardiovascular system. NO-mediated signaling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defense), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, and nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signaling. Other processes are associated with direct interaction of NO or reactive nitrogen species derived from it with target proteins and requires a more sustained production of NO at higher concentrations but do not involve the cGMP pathway.}, }
@article {pmid18384649, year = {2008}, author = {Chaturvedi, RK and Beal, MF}, title = {PPAR: a therapeutic target in Parkinson's disease.}, journal = {Journal of neurochemistry}, volume = {106}, number = {2}, pages = {506-518}, doi = {10.1111/j.1471-4159.2008.05388.x}, pmid = {18384649}, issn = {1471-4159}, mesh = {Animals ; Antiparkinson Agents/*therapeutic use ; Humans ; Parkinson Disease/*metabolism/*therapy ; Peroxisome Proliferator-Activated Receptors/agonists/*metabolism ; }, abstract = {Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons in substantia nigra. The etiology and pathogenesis of PD is still elusive, however, a large body of evidence suggests a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction in the pathogenesis of PD. Due to multifactorial nature of the disease, currently available drug therapy cannot halt / slow down the disease progression, and only provides symptomatic relief. Peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Recently, several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation and apoptosis in several neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and multiple sclerosis. Similarly, regular intake of PPAR activating non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen was associated with reduced incidence and progression of neurodegenerative disorders in several epidemiological studies. In this article, we review studies relating to the neuroprotective effect of PPAR agonists in in vitro and in vivo models of PD. Similarly, the pharmacological mechanism in neuroprotective actions of PPAR agonists is also reviewed. In conclusion, PPAR agonists exert neuroprotective actions by regulating the expression of a set of genes involved in cell survival processes, and could be a therapeutic target in debilitating neurodegenerative illnesses such as PD.}, }
@article {pmid18384644, year = {2008}, author = {Ström, AL and Gal, J and Shi, P and Kasarskis, EJ and Hayward, LJ and Zhu, H}, title = {Retrograde axonal transport and motor neuron disease.}, journal = {Journal of neurochemistry}, volume = {106}, number = {2}, pages = {495-505}, pmid = {18384644}, issn = {1471-4159}, support = {R01-NS44170/NS/NINDS NIH HHS/United States ; R01 NS049126/NS/NINDS NIH HHS/United States ; R01-NS49126/NS/NINDS NIH HHS/United States ; R01 NS044170/NS/NINDS NIH HHS/United States ; R01-NS045087/NS/NINDS NIH HHS/United States ; R01 NS045087/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport/*physiology ; Dyneins/metabolism ; Humans ; Motor Neuron Disease/genetics/*pathology/*physiopathology ; Motor Neurons/*physiology ; Mutation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Transport of material between extensive neuronal processes and the cell body is crucial for neuronal function and survival. Growing evidence shows that deficits in axonal transport contribute to the pathogenesis of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we review recent data indicating that defects in dynein-mediated retrograde axonal transport are involved in ALS etiology. We discuss how mutant copper-zinc superoxide dismutase (SOD1) and an aberrant interaction between mutant SOD1 and dynein could perturb retrograde transport of neurotrophic factors and mitochondria. A possible contribution of axonal transport to the aggregation and degradation processes of mutant SOD1 is also reviewed. We further consider how the interference with axonal transport and protein turnover by mutant SOD1 could influence the function and viability of motor neurons in ALS.}, }
@article {pmid18370853, year = {2008}, author = {Cozzolino, M and Ferri, A and Carrì, MT}, title = {Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications.}, journal = {Antioxidants &amp; redox signaling}, volume = {10}, number = {3}, pages = {405-443}, doi = {10.1089/ars.2007.1760}, pmid = {18370853}, issn = {1523-0864}, support = {GGP07018/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/metabolism/pathology/*physiopathology ; Animals ; Cell Death ; Humans ; Mitochondria/physiology ; Motor Neurons/pathology ; Mutation ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset progressive degeneration of motor neurons occurring both as a sporadic and a familial disease. The etiology of ALS remains unknown, but one fifth of instances are due to specific gene defects, the best characterized of which is point mutations in the gene coding for Cu/Zn superoxide dismutase (SOD1). Because sporadic and familial ALS affect the same neurons with similar pathology, it is hoped that understanding these gene defects will help in devising therapies effective in both forms. A wealth of evidence has been collected in rodents made transgenic for mutant SOD1, which represent the best available models for familial ALS. Mutant SOD1 likely induces selective vulnerability of motor neurons through a combination of several mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities and defective axonal transport, excitotoxicity, inadequate growth factor signaling, and inflammation. Damage within motor neurons is enhanced by noxious signals originating from nonneuronal neighboring cells, where mutant SOD1 induces an inflammatory response that accelerates disease progression. The clinical implication of these findings is that promising therapeutic approaches can be derived from multidrug treatments aimed at the simultaneous interception of damage in both motor neurons and nonmotor neuronal cells.}, }
@article {pmid18370336, year = {2008}, author = {Matías-Guiu, J and García-Ramos, G and Galán, L and Vela, A and Guerrero, A}, title = {[Analytic epidemiological information of amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {23}, number = {3}, pages = {168-178}, pmid = {18370336}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/etiology/genetics ; *Epidemiologic Methods ; Humans ; Metals, Heavy/toxicity ; Risk Factors ; }, abstract = {INTRODUCTION: The analytical epidemiological information on amyotrophic lateral sclerosis (ALS) is extensive and is based on case-control studies, selective patient series and few cohort studies that analyze the risk factors for the disease.<br><br>REVIEW: The studies found in the literature on analytical epidemiology have been reviewed in an attempt to analyze the methodology, compare their results and comment on the possible biases and confounding factors such as the different roles of the risk factors.<br><br>CONCLUSION: In spite of the extensive information available, the analytical epidemiology of ALS has still not clarified the etiological factors of the disease. This may be due to the influence of the genetic factors, but also to the variability of the methodological designs. However, the analytical factor that has the greatest consistency is that of exhibition to heavy metals. Greater physical activity or increased frequency in special situations such as is the cases from the first Gulf War could be suggested as a more than casual precipitating factor.}, }
@article {pmid18368375, year = {2007}, author = {Kinoshita, J and Clark, T}, title = {Alzforum.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {401}, number = {}, pages = {365-381}, doi = {10.1007/978-1-59745-520-6_19}, pmid = {18368375}, issn = {1064-3745}, mesh = {*Alzheimer Disease ; History, 20th Century ; History, 21st Century ; Humans ; *Information Dissemination ; *Internet/history/trends ; *Knowledge Bases ; }, abstract = {The Alzheimer Research Forum Web site (http://www.alzforum.org) is an independent research project to develop an online community resource to manage scientific knowledge, information, and data about Alzheimer disease (AD). Its goals are to promote rapid communication, research efficiency, and collaborative, multidisciplinary interactions. Introducing new knowledge management approaches to AD research has a potentially large societal value. AD is among the leading causes of disability and death in older people. According to the Alzheimer's Association, four million Americans currently suffer from AD. That number is expected to escalate to over 10 million in coming decades. Patients progress from memory loss to a bedridden state over many years and require near-constant care. In addition to imposing a heavy burden on family caregivers and society at large, AD and related neurodegenerative disorders are among the most complex and challenging in biomedicine. Researchers have produced an abundance of data implicating diverse biological mechanisms. Important factors include genes, environmental risks, changes in cell functions, DNA damage, accumulation of misfolded proteins, cell death, immune responses, changes related to aging, and reduced regenerative capacity. Yet there is no agreement on the fundamental causes of AD. The situations regarding Parkinson, Huntington, and amyotrophic lateral sclerosis (ALS) are similar. The challenge of integrating so much data into testable hypotheses and unified concepts is formidable. What is more, basic understanding of these diseases needs to intersect with an equally complex universe of pharmacology, medicinal chemistry, animal studies, and clinical trials. In this chapter, we will describe the approaches developed by Alzforum to achieve knowledge integration through information technology and virtual community-building. We will also propose some future directions in the application of Web-based knowledge management systems in neuromedicine.}, }
@article {pmid18368305, year = {2008}, author = {Hou, L and Hong, T}, title = {Stem cells and neurodegenerative diseases.}, journal = {Science in China. Series C, Life sciences}, volume = {51}, number = {4}, pages = {287-294}, doi = {10.1007/s11427-008-0049-1}, pmid = {18368305}, issn = {1006-9305}, mesh = {Alzheimer Disease/pathology/physiopathology/therapy ; Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Animals ; Humans ; *Neurodegenerative Diseases/pathology/physiopathology/therapy ; Parkinson Disease/pathology/physiopathology/therapy ; Stem Cell Transplantation ; *Stem Cells/physiology ; }, abstract = {Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the development of old-aging society, the incidence of neurodegenerative diseases is on the increase. However, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegenerative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington' disease and Amyotrophic lateral sclerosis/Lou Gehrig's disease.}, }
@article {pmid18212398, year = {2007}, author = {Reiter, RJ and Tan, DX and Manchester, LC and Tamura, H}, title = {Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {58 Suppl 6}, number = {}, pages = {5-22}, pmid = {18212398}, issn = {0867-5910}, mesh = {Animals ; Antioxidants/*metabolism/physiology/therapeutic use ; Free Radical Scavengers/*metabolism/therapeutic use ; Free Radicals/metabolism ; Head Injuries, Closed/metabolism/prevention &amp; control ; Humans ; Melatonin/*physiology/therapeutic use ; Multiple Sclerosis/metabolism/prevention &amp; control ; Neuroprotective Agents/therapeutic use ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/metabolism/prevention &amp; control ; Spinal Injuries/metabolism/prevention &amp; control ; Stroke/metabolism ; }, abstract = {Melatonin and its metabolites are potent antioxidants by virtue of their ability to scavenge both oxygen-based and nitrogen-based radicals and intermediates but also as a consequence of their ability to stimulate the activity of antioxidative enzymes. Melatonin also prevents electron leakage from the mitochondrial electron transport chain thereby diminishing free radical generation; this process is referred to as radical avoidance. The fact that melatonin and its metabolites are all efficient radical scavengers indicates that melatonin is a precursor molecule for a variety of intracellular reducing agents. In specific reference to the brain, melatonin also has an advantage over some other antioxidants given that it readily passes through the blood-brain-barrier. This, coupled with the fact that it and its by-products are particularly efficient detoxifiers of reactive species, make these molecules of major importance in protecting the brain from oxidative/nitrosative abuse. This review summarizes the literature on two brain-related situations, i.e., traumatic brain and spinal cord injury and ischemia/reperfusion, and the neurodegenerative disease, amyotrophic lateral sclerosis, where melatonin has been shown to have efficacy in abating neural damage. These, however, are not the only age-associated neurodegenerative states where melatonin has been found to be protective.}, }
@article {pmid18356234, year = {2008}, author = {McDermott, CJ and Shaw, PJ}, title = {Diagnosis and management of motor neurone disease.}, journal = {BMJ (Clinical research ed.)}, volume = {336}, number = {7645}, pages = {658-662}, pmid = {18356234}, issn = {1756-1833}, mesh = {Antioxidants/therapeutic use ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/*diagnosis/*therapy ; Neuroprotective Agents/therapeutic use ; Physician-Patient Relations ; Respiratory Therapy ; Riluzole/therapeutic use ; }, }
@article {pmid18351522, year = {2008}, author = {Lomen-Hoerth, C}, title = {Amyotrophic lateral sclerosis from bench to bedside.}, journal = {Seminars in neurology}, volume = {28}, number = {2}, pages = {205-211}, doi = {10.1055/s-2008-1062265}, pmid = {18351522}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*etiology/therapy ; Animals ; Biomarkers/analysis/metabolism ; Central Nervous System/*metabolism/pathology/*physiopathology ; Diagnosis, Differential ; Disease Models, Animal ; Disease Progression ; Humans ; Long-Term Care/methods/standards ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/metabolism/pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease for which there are currently no significant treatments to alter the fatal outcome. The cause of the disease is still elusive, except in familial cases where significant advances have been made in identifying new genetic causes. ALS is a relatively rare disease affecting approximately 1 in 100,000 people equally across geographic and ethnic distributions. It is a difficult disease to diagnose, and there are many mimics of ALS. Overlap with dementia may provide new clues to the etiology and treatment. There have been many advances in symptomatic treatments and improvements in the quality of life for ALS patients due to technological advancements.}, }
@article {pmid18341386, year = {2008}, author = {Riley, J and Sweeney, W and Boulis, N}, title = {Shifting the balance: cell-based therapeutics as modifiers of the amyotrophic lateral sclerosis-specific neuronal microenvironment.}, journal = {Neurosurgical focus}, volume = {24}, number = {3-4}, pages = {E10}, doi = {10.3171/FOC/2008/24/3-4/E9}, pmid = {18341386}, issn = {1092-0684}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*pathology/*therapy ; Animals ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Nerve Net/pathology/*physiopathology ; Neurons/*physiology ; }, abstract = {Recent advances in the laboratory have improved the current understanding of neurobiological mechanisms underlying the initiating events and pathological progression observed in amyotrophic lateral sclerosis (ALS). Whereas initial studies have revealed the late-stage intracellular cascades contributing to neuronal dysfunction and cell death, more recently collected data have begun to elucidate the presence and importance of a "non-cell autonomous" component indicating that affected glial cell subtypes may serve distinct and required roles. Pharmacological interventions for ALS have largely been disappointing likely in part because they have failed to address either the proximate events contributing to neuronal dysfunction and death or the deleterious contributions of non-neuronal cells within the local microenvironment. Alternatively, cell-based therapeutics offer the potential of a multifaceted approach oriented toward the dual ends of protecting remaining viable neurons and attempting to restore neuronal function lost as a manifestation of disease progression. The authors review the evolving knowledge of disease initiation and progression, with specific emphasis on the role of affected glia as crucial contributors to the observed ALS phenotype. This basis is used to underscore the potential roles of cell-based therapeutics as modifiers of the ALS-specific microenvironment.}, }
@article {pmid18332255, year = {2008}, author = {Hirano, M and Angelini, C and Montagna, P and Hays, AP and Tanji, K and Mitsumoto, H and Gordon, PH and Naini, AB and DiMauro, S and Rowland, LP}, title = {Amyotrophic lateral sclerosis with ragged-red fibers.}, journal = {Archives of neurology}, volume = {65}, number = {3}, pages = {403-406}, doi = {10.1001/archneurol.2007.65}, pmid = {18332255}, issn = {0003-9942}, support = {GTF05003/TI_/Telethon/Italy ; HD32062/HD/NICHD NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Biopsy/methods ; Carrier Proteins ; Cyclic AMP Response Element-Binding Protein/genetics ; Cytochrome-c Oxidase Deficiency/complications ; DNA Mutational Analysis/methods ; DNA, Mitochondrial ; Electron Transport Complex IV/metabolism ; Gene Deletion ; Humans ; Male ; Mitochondrial Proteins ; Molecular Chaperones ; Muscle Fibers, Fast-Twitch/*pathology ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; RNA-Binding Proteins/genetics ; SMN Complex Proteins ; }, abstract = {BACKGROUND: Motor neuron diseases (amyotrophic lateral sclerosis [ALS] and spinal muscular atrophy [SMA]) have been rarely associated with mitochondrial respiratory chain defects.<br><br>OBJECTIVES: To describe a patient with typical ALS and the finding of ragged-red fibers in muscle biopsy specimens and to review the literature on respiratory chain defects in ALS and SMA.<br><br>DESIGN: Case report and review of the literature.<br><br>SETTING: Collaboration between tertiary care academic hospitals.<br><br>PATIENT: A 65-year-old man with typical ALS.<br><br>MAIN OUTCOME MEASURES: The patient had 10% ragged-red fibers and 3% cytochrome-c oxidase-negative fibers in muscle biopsy specimens but no biochemical defects of respiratory chain enzymes or alterations of mitochondrial DNA (mtDNA).<br><br>RESULTS: Amyotrophic lateral sclerosis with ragged-red fibers has been reported in 5 families and is associated with mtDNA mutations in some subjects. Spinal muscular atrophy without mutations in the survival motor neuron gene (SMN; OMIM 600354) has been associated with mtDNA depletion or with mutations in the cytochrome-c oxidase assembly gene (SCO2; OMIM 604377).<br><br>CONCLUSION: Respiratory chain defects can mimic ALS or SMA and should be considered in the differential diagnosis.}, }
@article {pmid18329734, year = {2008}, author = {Suzuki, M and Svendsen, CN}, title = {Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis.}, journal = {Trends in neurosciences}, volume = {31}, number = {4}, pages = {192-198}, doi = {10.1016/j.tins.2008.01.006}, pmid = {18329734}, issn = {0166-2236}, support = {1P01NS057778/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Genetic Therapy ; Humans ; Intercellular Signaling Peptides and Proteins/*therapeutic use ; Neurons/*transplantation ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons within the brain and spinal cord are lost, leading to paralysis and death. Certain growth factors should, in principle, be able to protect dying motor neurons. However, targeted delivery to the spinal cord or brain has been a constant problem. There is also accumulating evidence that glial cells might play a crucial role in maintaining motor neuron function and survival in ALS. Stem cells isolated and expanded in culture can be modified to release growth factors and generate glial cells following transplantation into the spinal cord or brain. As such, they might be able to both detoxify the local environment around dying motor neurons and deliver trophic factors. Here we examine the feasibility of translating these findings into new treatments for ALS patients.}, }
@article {pmid18320174, year = {2008}, author = {Garrido, M and Rius, FX and Larrechi, MS}, title = {Multivariate curve resolution-alternating least squares (MCR-ALS) applied to spectroscopic data from monitoring chemical reactions processes.}, journal = {Analytical and bioanalytical chemistry}, volume = {390}, number = {8}, pages = {2059-2066}, doi = {10.1007/s00216-008-1955-6}, pmid = {18320174}, issn = {1618-2650}, mesh = {Chromium/chemistry ; Coloring Agents/chemistry ; Electronic Data Processing/methods ; Enzymes/chemistry ; Least-Squares Analysis ; Lipids/chemistry ; Multivariate Analysis ; Nucleic Acids/chemistry ; Organic Chemicals/chemistry ; Proteins/chemistry ; Spectrum Analysis/*methods ; }, abstract = {This paper overviews the application of multivariate curve resolution (optimized by alternating least squares) to spectroscopic data acquired by monitoring chemical reactions and other processes. The goals of the resolution methods and the principles for understanding their applications are described. Some of the problems arising from these evolving systems and the limitations of the multivariate curve resolution methods are also discussed. This article reviews most of the applications of multivariate curve resolution applied to reacting systems published between January 2000 and June 2007. Some basic papers dated before 2000 have also been included.}, }
@article {pmid18317986, year = {2008}, author = {Kalbitz, F}, title = {[NIV--modes and prognosis].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {62 Suppl 1}, number = {}, pages = {S7-S10}, doi = {10.1055/s-2007-1016428}, pmid = {18317986}, issn = {1438-8790}, mesh = {Cough/etiology/*prevention &amp; control/*rehabilitation ; Germany ; Humans ; Neuromuscular Diseases/complications/*rehabilitation ; Prognosis ; Respiration, Artificial/instrumentation/*methods/*trends ; }, abstract = {Non-invasive (NIV) as well as invasive mechanical ventilation are established for the treatment of ventilatory failure in neuromuscular diseases. The EUROVENT study provides data about mechanical ventilation at home. In this survey there is a trend towards pressure-derived ventilation in these patient groups. Volume-cycled ventilators had been used in 41% patients with neuromuscular diseases. During the past decade a remarkable change towards pressure-cycled ventilation has occurred. Two recently published, randomised cross-over studies demonstrated equal efficacy of volume-cycled ventilation compared to pressure-cycled ventilation in terms of gas exchange and sleep efficacy in chronic ventilatory failure. In both groups the median survival times were equal. In respiratory muscle failure, assisted ventilation, assist/controlled ventilation as well as controlled ventilation are applied. Between 1977 and 2001, long-term survival improved in patients with Duchenne muscular dystrophy (DMD) in Denmark based on a strict organisation of care, home ventilation as standard treatment and the establishment of centres for home ventilation. The proportion of ventilated patients rose from 0.9% to 43.4% of all DMD patients. The median survival of an untreated DMD patient is 9.7 months. Simonds demonstrated a 5-year survival rate of 73% in these groups of patients under home mechanical ventilation. In patients with the more rapidly deteriorating amyotrophic lateral sclerosis, the efficacy of home ventilation is less impressive and bulbar involvement serves as an independent negative predictor.}, }
@article {pmid18317978, year = {2008}, author = {Wiebel, M}, title = {[Non-invasive ventilation: possibilities and limitations in patients with reduced ability to cough].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {62 Suppl 1}, number = {}, pages = {S2-6}, doi = {10.1055/s-2007-1016429}, pmid = {18317978}, issn = {1438-8790}, mesh = {Cough/etiology/*prevention &amp; control/*rehabilitation ; Germany ; Humans ; Neuromuscular Diseases/complications/*rehabilitation ; Respiration, Artificial/*instrumentation/*methods/trends ; }, abstract = {BACKGROUND: Neuromuscular diseases cover a wide range of pathologies, which are slowly or rapidly progressive. Besides the reduced capacity of the inspiratory muscles there is a limitation of expiration which compromises coughing. Ventilatory respiratory insufficiency (VRI) develops in stages, beginning during sleep with hypercapnia manifesting later on. Several retrospective studies have shown an improved alveolar ventilation, survival and quality of life for most NMD, even in non-bulbar ALS. The initiation of NIV is seen as apropriate when VRI in sleep develops. But patient acceptance to use NIV for more than 4 hours must be taken into account. NIV is limited by the interface which may cause skin abrasions or leakage due to pressure. NIV may be used day and night in stable conditions and with assistance experienced in mechanically-assisted coughing (MAC). The discussion of whether to perform tracheostomy remains a preeminent topic especially in ALS.<br><br>CONCLUSION: NIV is effective in NMD and improves and prolongs life in slowly progressive NMD. Mask problems, leakage and bulbar dysfunction can limit the effectiveness. MAC is a tool that is very useful for elimination of bronchial secretions.}, }
@article {pmid18307053, year = {2008}, author = {Matías-Guiu, J and Barcia, JA and García-Verdugo, JM and Galán, L and Vela, A and García-Ramos, R}, title = {[Cellular therapy in amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {23}, number = {4}, pages = {226-237}, pmid = {18307053}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Humans ; *Stem Cell Transplantation ; }, abstract = {INTRODUCTION: The possible role of stem cells transplantation in therapy for traumatic lesions or for diseases has been outlined in recent years. Amyotrophic lateral sclerosis (ALS) is one of the diseases where cellular therapy may be useful.<br><br>DEVELOPMENT: The authors make an analytic review of the studies carried out in humans with ALS and in G93A transgenic rodent model of ALS to evaluate the effect of stem cell transplantation. They also review cellular responses from NSC-EZ cells in the spinal cord.<br><br>CONCLUSIONS: Research on the potential uses of cellular therapy for ALS is on-going, however, the different studies are not homogeneous. Thus, many questions need to be answered, such as which is the most appropriate type of cells or which should be the volume of cells to implant, which is the best method for the transplantation and in the case of spinal cord implant which is the best target for the implant, or if it is necessary to administer concomitant substances, such as immunosuppressant drugs.}, }
@article {pmid18306664, year = {2008}, author = {Shibata, N and Kobayashi, M}, title = {[The role for oxidative stress in neurodegenerative diseases].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {60}, number = {2}, pages = {157-170}, pmid = {18306664}, issn = {1881-6096}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; *Oxidative Stress ; Parkinson Disease/metabolism ; }, abstract = {A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.}, }
@article {pmid18303472, year = {2008}, author = {Meijer, JW and van Kuijk, AA and Geurts, AC and Schelhaas, HJ and Zwarts, MJ}, title = {Acute deterioration of bulbar function after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {87}, number = {4}, pages = {321-324}, doi = {10.1097/PHM.0b013e318164a931}, pmid = {18303472}, issn = {0894-9115}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Apnea/*chemically induced ; Botulinum Toxins, Type A/administration &amp; dosage/*adverse effects ; Deglutition Disorders/chemically induced/drug therapy ; Fatal Outcome ; Female ; Humans ; Injections ; Middle Aged ; Neuromuscular Agents/administration &amp; dosage/*adverse effects ; Parotid Gland/drug effects ; Sialorrhea/*drug therapy/etiology ; Submandibular Gland/drug effects ; }, abstract = {Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant literature. A 64-yr-old woman with bulbar ALS for 6 mos was treated for disabling sialorrhoea. She had moderate dysphagia, but she was able to swallow. The submandibular and parotid glands were injected transcutaneously, under ultrasound guidance, with botulinum toxin (Dysport), 80 U on each side. Four days later, her bulbar function rapidly deteriorated, resulting in complete aphagia and anarthria on the fifth day. A PEG catheter was placed. Although according to the literature this treatment can be made safer by cautiously increasing the dosage and injecting the parotid glands first, BTX should not be the first-line treatment of sialorrhoea in ALS; comparative studies of BTX, amitryptiline, scopolamine, and radiation should be performed first.}, }
@article {pmid18297142, year = {2007}, author = {Khurdayan, VK}, title = {Stem cells: therapeutic present and future.}, journal = {Timely topics in medicine. Cardiovascular diseases}, volume = {11}, number = {}, pages = {E14}, pmid = {18297142}, issn = {1579-0789}, mesh = {Cardiovascular Diseases/*therapy ; Drug Evaluation, Preclinical ; Hematologic Diseases/*therapy ; Humans ; Neoplasms/*therapy ; Nervous System Diseases/*therapy ; *Stem Cell Transplantation ; Stem Cells/cytology ; }, abstract = {Ever since the first embryonic stem cells were isolated in the 1990s scientists and clinicians as well as the general public have followed the development of the field with great attention. As unspecialized cells capable of dividing, renewing and differentiating into specialized cells, stem cells hold great promise as a therapeutic strategy for many diseases, especially those of degenerative nature. In 2006, stem cells were actively investigated in preclinical and clinical settings to manage heart failure, amyotrophic lateral sclerosis, spinal cord injury, stroke, hematologic disorders, renal cell carcinoma, solid tumor cancer, Crohn's disease and cirrhosis, among other disorders. Likewise, biotech and pharmaceutical industry highlighted stem cells and associated products and technologies as useful tools for drug discovery that provide relevant clinical models and ensure efficacious transition of investigational compounds into preclinical testing.}, }
@article {pmid18291574, year = {2008}, author = {Fernández-Ruiz, J and Pazos, MR and García-Arencibia, M and Sagredo, O and Ramos, JA}, title = {Role of CB2 receptors in neuroprotective effects of cannabinoids.}, journal = {Molecular and cellular endocrinology}, volume = {286}, number = {1-2 Suppl 1}, pages = {S91-6}, doi = {10.1016/j.mce.2008.01.001}, pmid = {18291574}, issn = {0303-7207}, mesh = {Animals ; Cannabinoids/*pharmacology ; Humans ; Neuroprotective Agents/*pharmacology ; Receptor, Cannabinoid, CB2/*metabolism ; Signal Transduction/drug effects ; }, abstract = {CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system, but they have been recently identified in the brain in healthy conditions and, in particular, after several types of cytotoxic stimuli. Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons. Given the lack of psychoactivity demonstrated by selective CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases, in particular, the case of certain neurodegenerative disorders in which induction/up-regulation of CB2 receptors has been already demonstrated. These disorders include Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and others. Interestingly, in experimental models of these disorders, the activation of CB2 receptors has been related to a delayed progression of neurodegenerative events, in particular, those related to the toxic influence of microglial cells on neuronal homeostasis. The present article will review the evidence supporting that CB2 receptors might represent a key element in the endogenous response against different types of cytotoxic events, and that this receptor type may be a clinically promising target for the control of brain damage in neurodegenerative disorders.}, }
@article {pmid18291372, year = {2008}, author = {Van Den Bosch, L and Robberecht, W}, title = {Crosstalk between astrocytes and motor neurons: what is the message?.}, journal = {Experimental neurology}, volume = {211}, number = {1}, pages = {1-6}, doi = {10.1016/j.expneurol.2008.01.008}, pmid = {18291372}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Astrocytes/*physiology ; Cell Communication/*physiology ; Motor Neurons/*physiology ; }, abstract = {Motor neuron death as seen in amyotrophic lateral sclerosis (ALS) is likely to be a non-cell autonomous process. One cell type that may be involved in the pathogenesis of the disease is the astrocyte. Under normal conditions, astrocytes affect survival of motor neurons by releasing growth factors and removing glutamate from the synaptic cleft. In addition, they determine some of the functional characteristics of motor neurons. In turn, motor neurons affect the functional characteristics of astrocytes. Recent evidence suggests that activation of astrocytes in a degenerative disease like ALS leads to a disturbance of this crosstalk between astrocytes and motor neurons, and that this may contribute to the death of motor neurons. As a consequence, understanding the interactions between motor neurons and astrocytes in health and disease may have important therapeutic implications.}, }
@article {pmid18289037, year = {2008}, author = {Molina-Holgado, F and Doherty, P and Williams, G}, title = {Tandem repeat peptide strategy for the design of neurotrophic factor mimetics.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {1}, pages = {110-119}, doi = {10.2174/187152708783885200}, pmid = {18289037}, issn = {1871-5273}, mesh = {Animals ; *Biomimetics ; Humans ; Intercellular Signaling Peptides and Proteins/chemistry ; Models, Molecular ; Nerve Growth Factors/*drug effects/*physiology ; Signal Transduction/drug effects/physiology ; Tandem Repeat Sequences/*physiology ; }, abstract = {Neurotrophic factors comprise a broad family of secreted proteins that have growth promoting, survival promoting and differentiation inducing activities. Disruption of neurotrophic factor signalling is a characteristic of many central and peripheral nervous system disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and peripheral neuropathy and pain. It follows that treating patients with neurotrophic factors might be beneficial in a range of neurological diseases. However, the promising results seen in animal models of disease have not translated well into clinical trials due to the poor pharmacokinetics associated with the intact proteins, in particular, their short in vivo half-life, low blood brain barrier permeability, limited diffusion, and undesirable effects through multiple receptor interactions. This has been the main motivation for the design of small molecule modulators of the neurotrophic factor pathways. The review gives a brief survey of the various strategies to design mimetics that have been reported in the literature with special emphasis on the tandem repeat peptide agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.}, }
@article {pmid18289027, year = {2008}, author = {Tripathi, VB and Al-Chalabi, A}, title = {Molecular insights and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {1}, pages = {11-19}, doi = {10.2174/187152708783885110}, pmid = {18289027}, issn = {1871-5273}, support = {G0600974/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/*metabolism/*therapy ; Animals ; Cell Death/physiology ; Humans ; Models, Biological ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis and respiratory failure. About 1 in every 400 people dies of ALS, usually within 3 to 5 years of symptom onset. The lack of effective therapy means that although the incidence is comparable to that of multiple sclerosis, the prevalence is low. The causes of ALS are largely unknown, but the only disease-modifying therapy, riluzole, was designed based on one hypothesis of disease causation, the excitotoxic hypothesis. In this paper we will review current ideas about the causes of ALS and the therapeutic opportunities they suggest.}, }
@article {pmid18286388, year = {2008}, author = {McCrate, ME and Kaspar, BK}, title = {Physical activity and neuroprotection in amyotrophic lateral sclerosis.}, journal = {Neuromolecular medicine}, volume = {10}, number = {2}, pages = {108-117}, pmid = {18286388}, issn = {1535-1084}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Cell Survival/physiology ; Central Nervous System/*metabolism/physiopathology ; Cytoprotection/*physiology ; Disease Models, Animal ; *Exercise Therapy ; Humans ; Motor Neurons/metabolism ; Nerve Degeneration/physiopathology/prevention &amp; control/therapy ; Physical Fitness/*physiology ; }, abstract = {Physical exercise exerts a wide range of benefits on an organism's overall health and well-being. Exercise contributes positively toward an individual's healthy weight, muscle strength, immune system, and cardiovascular health. Indeed, exercise has been demonstrated to reduce life-threatening conditions such as high blood pressure, heart disease, obesity, and diabetes. Of particular interest to this review, exercise has also been shown to be neuroprotective in both the central and peripheral nervous systems. Naturally, such findings apply broadly to the study of neurodegenerative disease with numerous reports demonstrating that exercise has beneficial effects on disease progression. One of the most devastating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease in the United States, or motor neuron disease in the United Kingdom, resulting from the progressive loss of brain and spinal cord motor neurons. Several human studies show that moderate exercise regimens improve ALS patients' scoring on functionality tests and ameliorate disease symptoms. Other promising recent works using transgenic mouse models of familial ALS have shown markedly slowed disease progression, improved function, and extension of survival in moderately exercised animals. Possible explanations for these findings include the exercise-induced changes in motor neuron morphology, muscle-nerve interaction, glial activation, and altering levels of gene expression of anti-apoptotic proteins and neurotrophic factors in the active tissue. Here we review the current literature on exercise and motor neuron disease, focusing on rodent and human studies to define the proper type, intensity, and duration of exercise necessary to enhance neuron survival as well discuss current mechanistic studies to further define the exercise-mediated pathways of neuroprotection.}, }
@article {pmid18282652, year = {2008}, author = {Turner, BJ and Talbot, K}, title = {Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.}, journal = {Progress in neurobiology}, volume = {85}, number = {1}, pages = {94-134}, doi = {10.1016/j.pneurobio.2008.01.001}, pmid = {18282652}, issn = {0301-0082}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/therapy ; Animals ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Biological ; Motor Neurons/enzymology/metabolism/pathology ; *Mutation ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Gain-of-function mutations in the Cu,Zn-superoxide dismutase (SOD1) gene are implicated in progressive motor neuron death and paralysis in one form of inherited amyotrophic lateral sclerosis (ALS). At present, transgenic expression of 12 human SOD1 mutations driven by the endogenous promoter is disease-causative and uniformly lethal in mice and rats, despite tremendous biochemical and biophysical variation between the mutants tested. This contrasts with the subclinical motor neuron disease phenotypes of wild-type SOD1 transgenic and knockout mice. Molecular mechanisms such as glutamate-induced excitotoxicity, axonal transport blockade, mitochondrial dysfunction, neuroinflammation and apoptosis triggered by mutant SOD1 catalysed oxidative reactions and/or protein misfolding are proposed to drive ALS pathogenesis. Around 100 genetic cross-breeding experiments with transgenic mutant SOD1 mice have been performed to verify these mechanisms in vivo. Furthermore, mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS. Transgenic mutant SOD1 rodents have also provided the benchmark preclinical tool for evaluation of over 150 potential therapeutic anti-oxidant, anti-aggregation, anti-glutamatergic, anti-inflammatory, anti-apoptotic and neurotrophic pharmacological agents. Recent promising findings from gene and antisense therapies, cell replacement and combinatorial drug approaches in transgenic mutant SOD1 rodents are also emerging, but await successful translation in patients. This review summarises the wealth of known genetic and therapeutic modifiers in rodent models with SOD1 mutations and discusses these in the wider context of ALS pathoetiology and treatment.}, }
@article {pmid18279484, year = {2008}, author = {Zetterberg, H and Rüetschi, U and Portelius, E and Brinkmalm, G and Andreasson, U and Blennow, K and Brinkmalm, A}, title = {Clinical proteomics in neurodegenerative disorders.}, journal = {Acta neurologica Scandinavica}, volume = {118}, number = {1}, pages = {1-11}, doi = {10.1111/j.1600-0404.2007.00985.x}, pmid = {18279484}, issn = {1600-0404}, mesh = {Biomarkers/metabolism ; Humans ; Mass Spectrometry ; Neurodegenerative Diseases/diagnosis/genetics/*metabolism ; *Proteomics ; }, abstract = {Neurodegenerative disorders are characterized by neuronal impairment that eventually leads to neuronal death. In spite of the brain's known capacity for regeneration, lost neurons are difficult to replace. Therefore, drugs aimed at inhibiting neurodegenerative processes are likely to be most effective if the treatment is initiated as early as possible. However, clinical manifestations in early disease stages are often numerous, subtle and difficult to diagnose. This is where biomarkers that specifically reflect onset of pathology, directly or indirectly, may have a profound impact on diagnosis making in the future. A triplet of biomarkers for Alzheimer's disease (AD), total and hyperphosphorylated tau and the 42 amino acid isoform of beta-amyloid, has already been established for early detection of AD before the onset of dementia. However, more biomarkers are needed both for AD and for other neurodegenerative disorders, such as Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis. This review provides an update on recent advances in clinical neuroproteomics, a biomarker discovery field that has expanded immensely during the last decade, and gives an overview of the most commonly used techniques and the major clinically relevant findings these techniques have lead to.}, }
@article {pmid18266871, year = {2008}, author = {Holmøy, T}, title = {T cells in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {15}, number = {4}, pages = {360-366}, doi = {10.1111/j.1468-1331.2008.02065.x}, pmid = {18266871}, issn = {1468-1331}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*pathology ; Animals ; Cytokines/metabolism ; Disease Models, Animal ; Glatiramer Acetate ; Humans ; Immunosuppressive Agents/pharmacology/therapeutic use ; Motor Neurons/drug effects/pathology ; Peptides/pharmacology/therapeutic use ; T-Lymphocytes/drug effects/*physiology ; }, abstract = {The inflammatory process in ALS involves infiltration of T cells and activation of antigen presenting cells co-localizing with motor neuron damage in the brain and spinal cord. The role of T cells in the pathogenic process is not settled. T cells may damage motor neurons by cell-cell contact or cytokine secretion, or contribute indirectly to motor neuron damage through activation of microglia and macrophages. Alternatively, T cell infiltration may be an epiphenomenon related to clearance of dead motor neurons. Lessons from animal models of neuroinflammation and neurodegeneration have shown that T cell responses can be neuroprotective or even enhance neurogenesis. Therefore, it is possible that T cells can be induced to slow motor neuron destruction and facilitate repair in ALS. The T cell modulating drug glatiramer acetate has shown promising results in animal models, and is being currently investigated in a phase II trial in ALS. This paper reviews the evidence for T cells as pathogenic players and therapeutic targets in ALS.}, }
@article {pmid18256992, year = {2008}, author = {Greenberg, BM and Calabresi, PA}, title = {Future research directions in multiple sclerosis therapies.}, journal = {Seminars in neurology}, volume = {28}, number = {1}, pages = {121-127}, doi = {10.1055/s-2007-1019133}, pmid = {18256992}, issn = {0271-8235}, support = {NS041435/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Immunologic Factors/therapeutic use ; Immunotherapy ; Multiple Sclerosis/*therapy ; Neuroprotective Agents/therapeutic use ; }, abstract = {The success of presently available injectable immunomodulatory therapies in treating multiple sclerosis has led to heightened interest in finding even more efficacious and better tolerated therapies. Several oral agents have shown efficacy in phase-II clinical trials and are now entering phase-III pivotal trials. In addition, monoclonal antibodies targeting surface receptors on various cells of the peripheral immune system have also shown efficacy in early studies and will soon be entering phase III. All of these approaches target immune molecules that are not specific for multiple sclerosis (MS) and carry inherent risk of infection and systemic side effects. Novel immunotherapies in preclinical or phases I to IIa testing are attempting to more selectively target pathogenic effector cells and thereby block abnormal immune cell activation without compromising normal healthy immune responses. The induction of tolerance to self-proteins continues to be a goal of MS immunotherapy, but as yet has not been accomplished outside of the laboratory. There is increasing awareness of the need to understand and modulate nonclassical immune targets as well as central nervous system degenerative processes. The roles of vitamins, antimicrobials, and hormones continue to be studied. The mechanisms of neurodegeneration in MS are likely multifactorial and include direct damage by T cells and humoral immunity as well as oxidative stress, glutamate-mediated excitotoxicity, and neuronal and oligodendrocyte apoptosis. Neuroprotective drugs that were once only considered for classical degenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease, are now being considered in MS.}, }
@article {pmid18184368, year = {2008}, author = {Thompson, A and Boekhoorn, K and Van Dam, AM and Lucassen, PJ}, title = {Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?.}, journal = {Genes, brain, and behavior}, volume = {7 Suppl 1}, number = {}, pages = {28-42}, doi = {10.1111/j.1601-183X.2007.00379.x}, pmid = {18184368}, issn = {1601-183X}, mesh = {Adult ; Animals ; Brain/pathology ; Cell Division ; Disease Models, Animal ; Hippocampus/*pathology ; Humans ; Mice ; Neurodegenerative Diseases/*pathology ; Neurons/*pathology ; }, abstract = {This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.}, }
@article {pmid18221222, year = {2007}, author = {Lecanu, L and Papadopoulos, V}, title = {Cutting-edge patents in Alzheimer's disease drug discovery: anticipation of potential future treatments.}, journal = {Recent patents on CNS drug discovery}, volume = {2}, number = {2}, pages = {113-123}, doi = {10.2174/157488907780832715}, pmid = {18221222}, issn = {1574-8898}, mesh = {Alzheimer Disease/*drug therapy ; Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors ; Amyloid beta-Peptides/immunology ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Calmodulin-Binding Proteins/antagonists &amp; inhibitors ; Chelating Agents/therapeutic use ; Cholinesterase Inhibitors/therapeutic use ; *Drug Design ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors ; Humans ; Immunization ; Patents as Topic ; }, abstract = {Neurodegenerative disease broadly includes many different diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's, dementias with Lewy bodies, post-traumatic brain injury, and stroke. Although few common physiopathological changes have been discovered among these conditions, the semiology (if known), the triggered molecular pathways that lead to the observed pathologies, and the symptomatology are essentially different. These differences entail that the treatments, both current and future, have disease-specific indications. This idea led us to believe than it would be quite impossible to comprehensively review the progress made in drug discovery for all the neurodegenerative diseases and, therefore, we focused our attention in this review on the cutting-edge patents that pertain to the treatment of Alzheimer's disease (AD). Basic science discoveries have identified new targets/leads that have led the scientific community to develop new research initiatives in order to develop novel therapeutics entities and approaches. The purpose of this review is to discuss, through cutting-edge patents, the emergence of potential future treatments of AD. We hope to provide the reader with a broader and better understanding of what could be new therapies for AD during the next decade.}, }
@article {pmid18220777, year = {2007}, author = {de Lago, E and Fernández-Ruiz, J}, title = {Cannabinoids and neuroprotection in motor-related disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {6}, number = {6}, pages = {377-387}, doi = {10.2174/187152707783399210}, pmid = {18220777}, issn = {1871-5273}, mesh = {Animals ; Cannabinoids/pharmacology/*therapeutic use ; Humans ; Models, Biological ; Movement Disorders/classification/*drug therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; }, abstract = {Neuroprotective properties of cannabinoids have been extensively studied in the last years in different neurodegenerative pathologies. This potential is based on the antioxidant, anti-inflammatory and anti-excitotoxic properties exhibited by these compounds that allow them to afford neuroprotection in different neurodegenerative disorders like Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and others. PD and HD are chronic pathologies that are caused by the degeneration of specific structures within the basal ganglia. In both disorders, the key mechanisms involved in the neuroprotection provided by cannabinoids include cannabinoid receptor-independent effects aimed at reducing the oxidative injury, and also cannabinoid 2 receptors (CB2)-mediated effects exerted by regulating the influence of reactive microglia on neuronal homeostasis. MS is an inflammatory demyelinating disorder primarily affecting spinal neurons and secondarily producing a malfunctioning and/or degeneration of other neuronal subpopulations located in supraspinal brain structures. There is evidence that both cannabinoid 1 receptors (CB1) and CB2 may afford a protective effect in this disease due to their immunomodulatory, anti-inflammatory and anti-excitotoxic properties. Lastly, neuroprotective effects of cannabinoids exerted by the activation of CB1 but also CB2 receptors have been also identified in amyotrophic lateral sclerosis (ALS), another degenerative disease characterized by the selective death of spinal motoneurons. In the present review, we will collect the latest advances in the knowledge of the cellular and molecular mechanisms through which cannabinoids might arrest/delay the degeneration of specific neuronal subpopulations in these motor-related disorders. This should serve to encourage that the present promising evidence obtained mainly at the preclinical level might progress to a real exploitation of neuroprotective benefits of potential cannabinoid-based medicines.}, }
@article {pmid18220762, year = {2008}, author = {Olzmann, JA and Li, L and Chin, LS}, title = {Aggresome formation and neurodegenerative diseases: therapeutic implications.}, journal = {Current medicinal chemistry}, volume = {15}, number = {1}, pages = {47-60}, pmid = {18220762}, issn = {0929-8673}, support = {F31 NS054597-02/NS/NINDS NIH HHS/United States ; R01 NS050650/NS/NINDS NIH HHS/United States ; AG021489/AG/NIA NIH HHS/United States ; NS050650/NS/NINDS NIH HHS/United States ; F31 NS054597-01/NS/NINDS NIH HHS/United States ; R01 AG021489/AG/NIA NIH HHS/United States ; NS047199/NS/NINDS NIH HHS/United States ; F31 NS054597/NS/NINDS NIH HHS/United States ; NS054597/NS/NINDS NIH HHS/United States ; R01 NS047199/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Inclusion Bodies/drug effects/*metabolism ; Models, Biological ; Molecular Chaperones/chemistry/metabolism ; Molecular Structure ; Neurodegenerative Diseases/drug therapy/*metabolism ; Proteasome Endopeptidase Complex/chemistry/metabolism ; *Protein Folding ; }, abstract = {Accumulation of misfolded proteins in proteinaceous inclusions is a prominent pathological feature common to many age-related neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In cultured cells, when the production of misfolded proteins exceeds the capacity of the chaperone refolding system and the ubiquitin-proteasome degradation pathway, misfolded proteins are actively transported to a cytoplasmic juxtanuclear structure called an aggresome. Aggresome formation is recognized as a cytoprotective response serving to sequester potentially toxic misfolded proteins and facilitate their clearance by autophagy. Recent evidence indicates that aggresome formation is mediated by dynein/dynactin-mediated microtubule-based transport of misfolded proteins to the centrosome and involves several regulators, including histone deacetylase 6, E3 ubiquitin-protein ligase parkin, deubiquitinating enzyme ataxin-3, and ubiquilin-1. Characterization of the molecular mechanisms underlying aggresome formation and its regulation has begun to provide promising therapeutic targets that may be relevant to neurodegenerative diseases. In this review, we provide an overview of the molecular machinery controlling aggresome formation and discuss potential useful compounds and intervention strategies for preventing or reducing the cytotoxicity of misfolded and aggregated proteins.}, }
@article {pmid18220753, year = {2007}, author = {Beghi, E and Mennini, T and Bendotti, C and Bigini, P and Logroscino, G and Chiò, A and Hardiman, O and Mitchell, D and Swingler, R and Traynor, BJ and Al-Chalabi, A}, title = {The heterogeneity of amyotrophic lateral sclerosis: a possible explanation of treatment failure.}, journal = {Current medicinal chemistry}, volume = {14}, number = {30}, pages = {3185-3200}, doi = {10.2174/092986707782793862}, pmid = {18220753}, issn = {0929-8673}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology ; Animals ; Biomarkers ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe clinical condition characterized by upper and lower motor neuron degeneration for which there is no truly effective treatment. The absence of an effective treatment can be explained in part by the complex and heterogeneous genetic, biochemical, and clinical features of ALS. While ALS accounts for the majority of the motor neuron diseases, the recognition of disease variants and mimic syndromes may lead to further insights into possible causes for the generality of ALS. From a biochemical perspective, the process of motor neuron degeneration is complex and the multifactorial influences and potential biomarkers of ALS have never been assessed in the light of the clinical heterogeneity of ALS. Several genes and environmental influences have been suggested as possible risk factors of ALS. A better understanding of interactions between these risk factors, potential biomarkers and heterogeneous clinical features may lead to more clearly defined pathological profiles among individuals or groups of ALS patients and in turn lead to more focused therapeutic trials.}, }
@article {pmid18215617, year = {2008}, author = {Zlokovic, BV}, title = {The blood-brain barrier in health and chronic neurodegenerative disorders.}, journal = {Neuron}, volume = {57}, number = {2}, pages = {178-201}, doi = {10.1016/j.neuron.2008.01.003}, pmid = {18215617}, issn = {0896-6273}, support = {HL081528/HL/NHLBI NIH HHS/United States ; HL63290/HL/NHLBI NIH HHS/United States ; R37 AG023084/AG/NIA NIH HHS/United States ; R37 NS34467/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/*physiopathology ; Humans ; Membrane Proteins/*physiology ; Models, Biological ; Neurodegenerative Diseases/*etiology/pathology ; Receptors, Immunologic/*physiology ; }, abstract = {The blood-brain barrier (BBB) is a highly specialized brain endothelial structure of the fully differentiated neurovascular system. In concert with pericytes, astrocytes, and microglia, the BBB separates components of the circulating blood from neurons. Moreover, the BBB maintains the chemical composition of the neuronal "milieu," which is required for proper functioning of neuronal circuits, synaptic transmission, synaptic remodeling, angiogenesis, and neurogenesis in the adult brain. BBB breakdown, due to disruption of the tight junctions, altered transport of molecules between blood and brain and brain and blood, aberrant angiogenesis, vessel regression, brain hypoperfusion, and inflammatory responses, may initiate and/or contribute to a "vicious circle" of the disease process, resulting in progressive synaptic and neuronal dysfunction and loss in disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others. These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the BBB and other nonneuronal cells of the neurovascular unit.}, }
@article {pmid18214824, year = {2008}, author = {San-juan, OD and Castro-Macías, JI and Cárdenas-Hernández, G}, title = {[Brachial diplegia as a variant of amyotrophic lateral sclerosis (Vulpian-Bernhart syndrome): the first case reported in Mexico and a review of the literature].}, journal = {Revista de neurologia}, volume = {46}, number = {1}, pages = {30-31}, pmid = {18214824}, issn = {1576-6578}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*classification/*diagnosis ; Brachial Plexus Neuropathies/*diagnosis ; Female ; Humans ; Mexico ; }, abstract = {INTRODUCTION: Brachial diplegia refers to an atypical clinical variant of amyotrophic lateral sclerosis (ALS), which is defined as a lower motor neuron disease in the upper limbs, with no significant functional complications in other regions.<br><br>CASE REPORT: A 65-year-old female who presented a clinical picture of brachial diplegia that slowly progressed over a period of 72 months. Neurophysiology studies revealed a chronic denervation process. Throughout a follow-up lasting one year the clinical course remained stable.<br><br>CONCLUSIONS: Brachial diplegia in females is a rare form of presentation of ALS and they probably have a higher survival rate than males.}, }
@article {pmid18210840, year = {2007}, author = {Yamanaka, K}, title = {[Animal models of amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {47}, number = {11}, pages = {934-937}, pmid = {18210840}, issn = {0009-918X}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; }, abstract = {Dominant mutation in the gene of superoxide dismutase 1 (SOD1) leads amyotrophic lateral sclerosis (ALS), an adult-onset progressive fatal motor neuron disease. Recent research progress in ALS has been made by the use of transgenic mouse model of familial ALS, which expresses mutant form of SOD1 and recapitulates the phenotype and pathology of motor neuron disease. There is accumulating evidence indicating non-cell-autonomous motor neuron death in ALS mouse model. In this symposium, I review the recent advance of ALS research focusing on the development of animal models, the role of glial cells in ALS, and therapeutic intervention of rodent models and discuss their prospect.}, }
@article {pmid18210200, year = {2008}, author = {Gilmore, JL and Yi, X and Quan, L and Kabanov, AV}, title = {Novel nanomaterials for clinical neuroscience.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {3}, number = {2}, pages = {83-94}, pmid = {18210200}, issn = {1557-1904}, support = {R01 NS051334-01A1/NS/NINDS NIH HHS/United States ; R01 CA89225/CA/NCI NIH HHS/United States ; R01 NS051334-03/NS/NINDS NIH HHS/United States ; R01 CA089225-06/CA/NCI NIH HHS/United States ; R01 CA116591/CA/NCI NIH HHS/United States ; R01 CA116591-02/CA/NCI NIH HHS/United States ; R01 NS051334-02/NS/NINDS NIH HHS/United States ; R01 NS036229-09/NS/NINDS NIH HHS/United States ; R01 CA089225-05/CA/NCI NIH HHS/United States ; R01 CA116591-01A1/CA/NCI NIH HHS/United States ; R01 CA089225/CA/NCI NIH HHS/United States ; R01 NS051334/NS/NINDS NIH HHS/United States ; R01 NS051335/NS/NINDS NIH HHS/United States ; R01 NS036229/NS/NINDS NIH HHS/United States ; R01 CA116591-03/CA/NCI NIH HHS/United States ; R01 NS36229/NS/NINDS NIH HHS/United States ; R01 NS036229-08/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biopolymers/chemistry ; Blood-Brain Barrier ; Central Nervous System Diseases/diagnosis/drug therapy ; Coated Materials, Biocompatible ; Drug Delivery Systems ; Drug Evaluation, Preclinical ; Fullerenes/chemistry/therapeutic use/toxicity ; Humans ; Hydrophobic and Hydrophilic Interactions ; Materials Testing ; Nanogels ; *Nanostructures/administration &amp; dosage/chemistry/therapeutic use ; Nanotubes, Carbon/chemistry/toxicity ; Nerve Regeneration/drug effects ; Neurodegenerative Diseases/diagnosis/drug therapy ; Neuroprotective Agents/chemistry/therapeutic use ; Oxidative Stress ; Pharmaceutical Vehicles ; Polyethylene Glycols/administration &amp; dosage ; Polyethyleneimine/administration &amp; dosage ; Tissue Scaffolds ; }, abstract = {Neurodegenerative disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population ages. The field of nanomedicine is rapidly expanding and promises revolutionary advances to the diagnosis and treatment of devastating human diseases. This paper provides an overview of novel nanomaterials that have potential to improve diagnosis and therapy of neurodegenerative disorders. Examples include liposomes, nanoparticles, polymeric micelles, block ionomer complexes, nanogels, and dendrimers that have been tested clinically or in experimental models for delivery of drugs, genes, and imaging agents. More recently discovered nanotubes and nanofibers are evaluated as promising scaffolds for neuroregeneration. Novel experimental neuroprotective strategies also include nanomaterials, such as fullerenes, which have antioxidant properties to eliminate reactive oxygen species in the brain to mitigate oxidative stress. Novel technologies to enable these materials to cross the blood brain barrier will allow efficient systemic delivery of therapeutic and diagnostic agents to the brain. Furthermore, by combining such nanomaterials with cell-based delivery strategies, the outcomes of neurodegenerative disorders can be greatly improved.}, }
@article {pmid18210046, year = {2008}, author = {Kollewe, K and Dengler, R and Petri, S}, title = {[Amyotrophic lateral sclerosis. Current clinical trials and underlying pathomechanisms].}, journal = {Der Nervenarzt}, volume = {79}, number = {6}, pages = {653-661}, pmid = {18210046}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Animals ; Clinical Trials as Topic/*trends ; *Disease Models, Animal ; Drug Evaluation, Preclinical/*trends ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to death after 3 to 5 years. The glutamate antagonist Riluzole currently is the only drug with marginal therapeutic benefit, but its effect on survival is modest, with an average increase of only 3-4 months. Therefore symptomatic treatment still is the most important. Further neuroprotective agents are currently under investigation, both in transgenic animal models of ALS and clinical trials in ALS patients. This review summarizes the current state of clinical studies in ALS patients in the context of underlying therapeutic mechanisms.}, }
@article {pmid18198432, year = {2007}, author = {McCluskey, L}, title = {Amyotrophic Lateral Sclerosis: ethical issues from diagnosis to end of life.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {463-472}, pmid = {18198432}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Humans ; Terminal Care/*ethics/legislation &amp; jurisprudence ; }, abstract = {The variable clinical course of Amyotrophic Lateral Sclerosis (ALS) confronts the clinician, the patient and caregivers with many ethical challenges from the moment of breaking the news of the diagnosis and throughout the relentlessly progressive trajectory of the disease. Each patient faces the prospect of life-threatening bulbar and respiratory muscle dysfunction that may ensue soon after disease onset or after months or years of progressive weakness. This reality eventually forces the patient to choose life extension via gastrostomy tube insertion, mechanical ventilation or both or to forego these treatments in favor of terminal palliative care. Faced with these prospects some patients contemplate voluntary cessation of food and water, physician assisted suicide or euthanasia. Depending upon the presence and severity of frontotemporal dementia (FTD) related to frontotemporal lobar degeneration (FTLD) the capacity to make these forced choices may be compromised. Clinicians caring for ALS patients should appreciate and communicate the significance of life threatening symptoms, monitor capacity for decision making, anticipate and manage multiple possible end of life scenarios, and aggressively manage symptoms.}, }
@article {pmid18198431, year = {2007}, author = {Lewis, M and Rushanan, S}, title = {The role of physical therapy and occupational therapy in the treatment of amyotrophic lateral sclerosis.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {451-461}, pmid = {18198431}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/complications/psychology/*rehabilitation ; Humans ; *Occupational Therapy ; Patient Education as Topic ; *Physical Therapy Modalities ; Range of Motion, Articular ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. There is a general misunderstanding among healthcare professionals of the proper use and potential benefits of physical and occupational therapy to treat the symptoms and resulting loss of independence. These services can help maximize mobility and comfort through equipment prescription, activity adaptation, patient and family education, and the use of appropriate exercise and range of motion techniques. The literature is controversial on the prescription of exercise in this population. Individual muscle strength, fatigue and spasticity must all be taken into account when discussing exercise with persons with ALS. It can be concluded that physical and occupational therapy intervention is beneficial to persons with ALS. However, more research is needed to decisively determine the effects of exercise on the person with ALS.}, }
@article {pmid18198430, year = {2007}, author = {Brownlee, A and Palovcak, M}, title = {The role of augmentative communication devices in the medical management of ALS.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {445-450}, pmid = {18198430}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Communication Aids for Disabled ; Humans ; Patient Acceptance of Health Care ; Speech Disorders/diagnosis/etiology/*rehabilitation ; }, abstract = {When an individual has a severe verbal communication impairment, Augmentative and Alternative Communication (AAC) can meet the overall goals of palliative care. AAC can improve quality of life by optimizing function, assisting with decision making, and providing opportunities for personal growth. This article will define AAC and its importance in the medical management of a person with ALS. The process of obtaining an electronic AAC device, issues affecting use, and communication challenges and obstacles unique to ALS will be described including dysarthria and the diagnostic testing for speech and rationale for AAC. Communication solutions, which may include no-technology, low-technology and high-technology options will be discussed, as well as the importance of psychosocial issues and the factors that may influence the use of these systems.}, }
@article {pmid18198429, year = {2007}, author = {Gregory, SA}, title = {Evaluation and management of respiratory muscle dysfunction in ALS.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {435-443}, pmid = {18198429}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Humans ; Muscle Strength ; Respiration, Artificial ; Respiratory Muscles/*physiopathology ; Respiratory Paralysis/*diagnosis/etiology/*therapy ; Tracheotomy ; }, abstract = {Neuromuscular respiratory failure is the cause of death in the majority of patients with ALS. Respiratory muscle dysfunction impacts on quality of life and survival. Attentive management of respiratory muscle weakness is an important aspect of the management of the ALS patient. The respiratory muscles may be thought of as four functional groups: the inspiratory muscles, the expiratory muscles, the accessory muscles of respiration, and the upper airway muscles. This paper will review the structure and function of the neuromuscular respiratory system, and the evaluation and management of respiratory muscle dysfunction in ALS patients.}, }
@article {pmid18198428, year = {2007}, author = {Golaszewski, A}, title = {Nutrition throughout the course of ALS.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {431-434}, pmid = {18198428}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology/therapy ; Enteral Nutrition ; Humans ; Nutrition Disorders/*etiology ; *Nutritional Requirements ; }, }
@article {pmid18198427, year = {2007}, author = {Elman, LB and Grossman, M}, title = {Neuropsychiatric features of amyotrophic lateral sclerosis.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {425-429}, pmid = {18198427}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Cognition Disorders/*etiology ; Humans ; Language Disorders/*etiology ; Mental Disorders/*etiology ; }, }
@article {pmid18198426, year = {2007}, author = {Palovcak, M and Mancinelli, JM and Elman, LB and McCluskey, L}, title = {Diagnostic and therapeutic methods in the management of dysphagia in the ALS population: issues in efficacy for the out-patient setting.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {417-423}, pmid = {18198426}, issn = {1053-8135}, mesh = {*Ambulatory Care ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Deglutition Disorders/*diagnosis/etiology/*therapy ; Humans ; Treatment Outcome ; }, abstract = {ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord that control voluntary skeletal muscle. The muscle weakness that results from ALS is relentlessly progressive and rehabilitative attempts to strengthen affected muscles usually fail. When managing swallowing and communication disorders in individuals with ALS, the goals are to maximize function and safety through the use of compensatory strategies, energy conservation, and patient and caregiver education and counseling. This paper will review the current methods of assessment and treatment used with this population in the outpatient setting.}, }
@article {pmid18198425, year = {2007}, author = {Ferguson, TA and Elman, LB}, title = {Clinical presentation and diagnosis of amyotrophic lateral sclerosis.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {409-416}, pmid = {18198425}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/etiology/physiopathology ; Diagnosis, Differential ; Humans ; Neural Conduction/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Progressive loss of motor neurons causes Amyotrophic Lateral Sclerosis. Patients complain, most often, of progressive weakness in the distal limbs. However, weakness may manifest in any body segment (bulbar, cervical, thoracic, or lumbosacral). The diagnosis of ALS is suggested by clinical examination that reveals both upper and lower motor neuron failure. Formal diagnostic criteria have been developed and validated. Nerve conduction and electromyography studies improve diagnostic sensitivity and exclude some alternate, treatable diagnoses. Likewise, conventional imaging studies and laboratory evaluation refute other diseases that may masquerade as ALS. Experimental imaging and laboratory evaluations may improve ALS diagnosis in the future. The cause of motor neuron death is not known but inherited forms of motor neuron disease may suggest mechanisms. The goal of ALS treatment is control of the symptoms of progressive weakness, especially respiratory insufficiency and dysphagia and is best managed in an integrated clinic.}, }
@article {pmid18191417, year = {2008}, author = {Karamyan, VT and Speth, RC}, title = {Animal models of BMAA neurotoxicity: a critical review.}, journal = {Life sciences}, volume = {82}, number = {5-6}, pages = {233-246}, doi = {10.1016/j.lfs.2007.11.020}, pmid = {18191417}, issn = {0024-3205}, support = {RR-0212929/RR/NCRR NIH HHS/United States ; }, mesh = {Amino Acids, Diamino/metabolism/*toxicity ; Amyotrophic Lateral Sclerosis/*chemically induced/metabolism/pathology ; Animals ; Brain/*drug effects ; Cyanobacteria Toxins ; *Disease Models, Animal ; Environmental Exposure ; Excitatory Amino Acid Antagonists/metabolism/*toxicity ; Food Chain ; Food Contamination ; Guam ; Meat/analysis ; Neurotoxins/metabolism/*toxicity ; Parkinson Disease, Secondary/*chemically induced/metabolism/pathology ; Plants, Edible/chemistry/metabolism ; }, abstract = {Of all the molecules reported to have toxicological effects, BMAA (beta-methylamino alanine) stands out as having the most checkered past. In the late 1960's it was reported to be a toxic component of the cycad flour consumed by Chamorros on Guam which caused the high incidence of amyotrophic lateral sclerosis (ALS) in Guam, that was associated with a Parkinson's disease-like dementia complex (ALS-PDC). However, because ALS-PDC is a slow onset disease, manifesting itself as long as 30 years following exposure to the putative neurotoxin, and only acute toxic effects of BMAA were observed in animal studies, interest in BMAA waned. A seminal study by Spencer et al., in 1987 showing neurological impairments with long-term BMAA-fed monkeys revived the hypothesis that BMAA could cause ALS-PDC. However, the amounts of BMAA used in that study were viewed as being the equivalent of a person consuming their body weight of cycad flour every day. Again, the BMAA hypothesis was discarded. Recently a third iteration of the BMAA hypothesis has been proposed. It is based on the discovery of a novel dietary source of BMAA via biomagnification of BMAA in flying foxes, once consumed in great amounts by Chamorros. Also, reports that BMAA can be incorporated into plant and animal proteins, a heretofore unrecognized dietary source of BMAA, further solidified this new hypothesis. However, once again this hypothesis has its detractors and it remains controversial. This manuscript critically evaluates in vivo studies directed at establishing an animal model of BMAA-induced ALS-PDC and their implications for this hypothesis.}, }
@article {pmid18190866, year = {2008}, author = {Vincent, AM and Sakowski, SA and Schuyler, A and Feldman, EL}, title = {Strategic approaches to developing drug treatments for ALS.}, journal = {Drug discovery today}, volume = {13}, number = {1-2}, pages = {67-72}, pmid = {18190866}, issn = {1359-6446}, support = {R01 NS036778/NS/NINDS NIH HHS/United States ; R01 NS036778-05/NS/NINDS NIH HHS/United States ; R01 NS038849/NS/NINDS NIH HHS/United States ; R01 NS038849-05/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Computer Simulation ; Disease Models, Animal ; *Drug Design ; Drug Evaluation, Preclinical ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Significant progress in understanding the cellular mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has not been matched with the development of therapeutic strategies to prevent disease progression. The multiple potential causes and relative rarity of the disease are two significant factors that make drug development and assessment in clinical trials extremely difficult. We review recent progress in promoting therapeutics into clinical trials and highlight the value of moderate throughput screening for the acceleration and improvement of drug design.}, }
@article {pmid18183483, year = {2008}, author = {Dhariwala, FA and Rajadhyaksha, MS}, title = {An unusual member of the Cdk family: Cdk5.}, journal = {Cellular and molecular neurobiology}, volume = {28}, number = {3}, pages = {351-369}, pmid = {18183483}, issn = {0272-4340}, mesh = {Animals ; Coenzymes/physiology ; Cyclin-Dependent Kinase 5/genetics/metabolism/*physiology ; Enzyme Activators/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Models, Biological ; Nervous System/embryology/growth &amp; development ; Neurodegenerative Diseases/enzymology/etiology ; Substrate Specificity ; }, abstract = {The proline-directed serine threonine kinase, Cdk5, is an unusual molecule that belongs to the well-known large family of proteins, cyclin-dependent kinases (Cdks). While it has significant homology with the mammalian Cdk2 and yeast cdc2, unlike the other Cdks, it has little role to play in cell cycle regulation and is activated by non-cyclin proteins, p35 and p39. It phosphorylates a spectrum of proteins, most of them associated with cell morphology and motility. A majority of known substrates of Cdk5 are cytoskeletal elements, signalling molecules or regulatory proteins. It also appears to be an important player in cell-cell communication. Highly conserved, Cdk5 is most abundant in the nervous system and is of special interest to neuroscientists as it appears to be indispensable for normal neural development and function. In normal cells, transcription and activity of Cdk5 is tightly regulated. Present essentially in post-mitotic neurons, its normal activity is obligatory for migration and differentiation of neurons in developing brain. Deregulation of Cdk5 has been implicated in Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease and acute neuronal injury. Regulators of Cdk5 activity are considered as potential therapeutic molecules for degenerative diseases. This review focuses on the role of Cdk5 in neural cells as regulator of cytoskeletal elements, axonal guidance, membrane transport, synaptogenesis and cell survival in normal and pathological conditions.}, }
@article {pmid18180444, year = {2008}, author = {Valdmanis, PN and Rouleau, GA}, title = {Genetics of familial amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {70}, number = {2}, pages = {144-152}, doi = {10.1212/01.wnl.0000296811.19811.db}, pmid = {18180444}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; *Family Health ; *Genetics ; Humans ; }, abstract = {The completion of the Human Genome Project, together with a better understanding of some of the emerging genetic patterns of human disease, has enabled a thorough examination of the most appropriate genetic models for amyotrophic lateral sclerosis (ALS). The pathology and epidemiology of ALS have been intensively studied since Adar, Charcot, and Duchenne first described the disease in the 1860 s. Results of genetic studies that have emerged over the past two decades have led to the identification of SOD1 as a well-established causative gene for ALS. However, the identification of SOD1 has not been followed up by the identification of other genes responsible for classic ALS. This leads to the speculation that more complex genetic mechanisms are involved than initially assumed. While mutations in single genes are still likely to constitute a small proportion of ALS cases, the genes responsible for ALS in families with clusters of two or three affected individuals, and more particularly in sporadic cases, are far from being determined. Multigenic, somatic mutation, and gene-environment models may all contribute to the genetic etiology of ALS. The challenge now lies in determining which models are the most appropriate to dissect out the genetic components involved. This research will ultimately aid in identifying the cumulative risk of developing ALS.}, }
@article {pmid18177508, year = {2007}, author = {Yang, YS and Strittmatter, SM}, title = {The reticulons: a family of proteins with diverse functions.}, journal = {Genome biology}, volume = {8}, number = {12}, pages = {234}, pmid = {18177508}, issn = {1474-760X}, support = {R37 NS033020-16/NS/NINDS NIH HHS/United States ; R37 NS033020/NS/NINDS NIH HHS/United States ; R01 NS056485/NS/NINDS NIH HHS/United States ; R01 NS039962-10/NS/NINDS NIH HHS/United States ; R01 NS042304/NS/NINDS NIH HHS/United States ; R01 NS056485-04/NS/NINDS NIH HHS/United States ; R01 NS039962/NS/NINDS NIH HHS/United States ; R01 NS042304-08/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Membrane Proteins/*chemistry/genetics/metabolism ; Nerve Tissue Proteins/*chemistry/genetics/metabolism ; }, abstract = {The reticulon family is a large and diverse group of membrane-associated proteins found throughout the eukaryotic kingdom. All of its members contain a carboxy-terminal reticulon homology domain that consists of two hydrophobic regions flanking a hydrophilic loop of 60-70 amino acids, but reticulon amino-terminal domains display little or no similarity to each other. Reticulons principally localize to the endoplasmic reticulum, and there is evidence that they influence endoplasmic reticulum-Golgi trafficking, vesicle formation and membrane morphogenesis. However, mammalian reticulons have also been found on the cell surface and mammalian reticulon 4 expressed on the surface of oligodendrocytes is an inhibitor of axon growth both in culture and in vivo. There is also growing evidence that reticulons may be important in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. The diversity of structure, topology, localization and expression patterns of reticulons is reflected in their multiple, diverse functions in the cell.}, }
@article {pmid18164242, year = {2008}, author = {de Carvalho, M and Dengler, R and Eisen, A and England, JD and Kaji, R and Kimura, J and Mills, K and Mitsumoto, H and Nodera, H and Shefner, J and Swash, M}, title = {Electrodiagnostic criteria for diagnosis of ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {119}, number = {3}, pages = {497-503}, doi = {10.1016/j.clinph.2007.09.143}, pmid = {18164242}, issn = {1388-2457}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Electrodiagnosis/*methods/*standards ; }, abstract = {A consensus meeting was held to determine the best use and interpretation of electrophysiological data in the diagnosis of ALS. The utility of needle EMG and nerve conduction studies was affirmed. It is recommended that electrophysiological evidence for chronic neurogenic change should be taken as equivalent to clinical information in the recognition of involvement of individual muscles in a limb. In addition, in the context of a suspected clinical diagnosis of ALS, fasciculation potentials should be taken as equivalent to fibrillation potentials and positive sharp waves in recognising denervation. The importance of searching for instability in fasciculation potentials and in motor unit potentials in ALS is stressed. These changes in the interpretation of electrophysiological data render obsolete the category Probable Laboratory-Supported ALS in the modified El Escorial diagnostic criteria for ALS. Methods for detection of upper motor neuron abnormality appear sensitive but require further study, particularly regarding their value when clinical signs of upper motor neuron lesion are uncertain.}, }
@article {pmid18097214, year = {2007}, author = {Thomas, JA}, title = {Guidelines for bottle feeding your premature baby.}, journal = {Advances in neonatal care : official journal of the National Association of Neonatal Nurses}, volume = {7}, number = {6}, pages = {311-318}, doi = {10.1097/01.ANC.0000304971.69578.f7}, pmid = {18097214}, issn = {1536-0903}, mesh = {Bottle Feeding/*methods ; Child Development ; Humans ; Infant, Newborn ; *Infant, Premature/physiology ; Neonatal Nursing ; Practice Guidelines as Topic ; Sucking Behavior/physiology ; }, abstract = {Prolonged use of gavage feedings is common in premature infants who have not yet acquired suck, swallow, and breathing coordination. Preterm infants must be developmentally mature to orally feed successfully. Als' Synactive Theory of Development offers a conceptual framework to facilitate understanding of how premature infants dynamically differentiate to attain developmental milestones such as oral feeding. Key clinical implications for neonatal nurses are contingent upon incorporating evidence-based research into practice and providing consistent quality care to improve feeding outcomes.}, }
@article {pmid18097160, year = {2008}, author = {Gitler, AD}, title = {Beer and bread to brains and beyond: can yeast cells teach us about neurodegenerative disease?.}, journal = {Neuro-Signals}, volume = {16}, number = {1}, pages = {52-62}, doi = {10.1159/000109759}, pmid = {18097160}, issn = {1424-862X}, mesh = {Animals ; Beer ; Brain/*metabolism ; Bread ; Gene Expression Regulation ; Humans ; *Neurodegenerative Diseases/genetics/pathology/physiopathology ; Protein Folding ; Saccharomyces cerevisiae/*metabolism ; alpha-Synuclein/genetics/metabolism ; }, abstract = {For millennia, humans have harnessed the astonishing power of yeast, producing such culinary masterpieces as bread, beer and wine. Therefore, in this new millennium, is it very farfetched to ask if we can also use yeast to unlock some of the modern day mysteries of human disease? Remarkably, these seemingly simple cells possess most of the same basic cellular machinery as the neurons in the brain. We and others have been using the baker's yeast, Saccharomyces cerevisiae, as a model system to study the mechanisms of devastating neurodegenerative diseases such as Parkinson's, Huntington's, Alzheimer's and amyotrophic lateral sclerosis. While very different in their pathophysiology, they are collectively referred to as protein-misfolding disorders because of the presence of misfolded and aggregated forms of various proteins in the brains of affected individuals. Using yeast genetics and the latest high-throughput screening technologies, we have identified some of the potential causes underpinning these disorders and discovered conserved genes that have proven effective in preventing neuron loss in animal models. Thus, these genes represent new potential drug targets. In this review, I highlight recent work investigating mechanisms of cellular toxicity in a yeast Parkinson's disease model and discuss how similar approaches are being applied to additional neurodegenerative diseases.}, }
@article {pmid18097159, year = {2008}, author = {Kwong, LK and Uryu, K and Trojanowski, JQ and Lee, VM}, title = {TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis.}, journal = {Neuro-Signals}, volume = {16}, number = {1}, pages = {41-51}, doi = {10.1159/000109758}, pmid = {18097159}, issn = {1424-862X}, support = {AG10124/AG/NIA NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; }, mesh = {Amyloidosis ; DNA-Binding Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Phosphorylation ; *Protein Folding ; Ubiquitin ; }, abstract = {In this review, we summarize recent advances in understanding frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders that are collectively known as TDP-43 proteinopathies, since transactive response DNA-binding protein 43 (TDP-43) was recently shown to be the major component of the ubiquitinated inclusions that are their pathological hallmarks. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders because TDP-43 inclusions are not amyloid deposits. Besides TDP-43-positive inclusions, both sporadic and familial forms of FTLD and ALS have the pathologic TDP-43 signature of abnormal hyperphosphorylation, ubiquitination and C-terminal fragments in affected brain and spinal cord, suggesting that they share a common mechanism of pathogenesis. Thus, these findings support the concept that FTLD and ALS represent a clinicopathologic spectrum of one disease, that is, TDP-43 proteinopathy.}, }
@article {pmid18090686, year = {2007}, author = {Bromberg, MB}, title = {Assessing quality of life in ALS.}, journal = {Journal of clinical neuromuscular disease}, volume = {9}, number = {2}, pages = {318-325}, doi = {10.1097/CND.0b013e31815af9b7}, pmid = {18090686}, issn = {1537-1611}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Humans ; Quality of Life/*psychology ; Research Design ; Surveys and Questionnaires ; }, abstract = {The issue of quality of life is important for the patient with amyotrophic lateral sclerosis (ALS) and his or her family. Although initial thoughts frequently are that quality of life will be poor, there are strong data to support a relatively good quality of life despite the inexorable decline in strength and loss of function with disease progression. This article discusses how quality of life can be measured in ALS patients and caregivers, the results of studies, and factors affecting quality. It ends with 10 suggestions for clinicians who care for ALS patients and their caregivers.}, }
@article {pmid18090423, year = {2007}, author = {Mackenzie, IR}, title = {The neuropathology of FTD associated With ALS.}, journal = {Alzheimer disease and associated disorders}, volume = {21}, number = {4}, pages = {S44-9}, doi = {10.1097/WAD.0b013e31815c3486}, pmid = {18090423}, issn = {0893-0341}, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/*pathology ; Brain/*pathology ; DNA-Binding Proteins/metabolism ; Dementia/*complications/genetics/*pathology ; Humans ; Inclusion Bodies/metabolism ; Ubiquitination ; }, abstract = {There is increasing recognition of a clinical overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent advances in our understanding of the neuropathologic, biochemical, and genetic basis of these conditions provides evidence for a common underlying pathogenesis. The neuropathology in most cases of FTD with ALS is a subtype of frontotemporal lobar degeneration, characterized by neuronal inclusions that are immunoreactive for ubiquitin but not tau (frontotemporal lobar degeneration with ubiquitinated inclusions). These cases show significant pathologic overlap with clinically pure FTD and those with classic ALS. Moreover, the ubiquitinated pathologic protein in all these conditions has recently been identified as TDP-43. A number of families have been reported with autosomal dominant FTD-ALS linked to chromosome 9p and these also have TDP-43-positive frontotemporal lobar degeneration with ubiquitinated inclusions pathology. Together, these findings suggest that FTD-ALS is part of a clinicopathologic spectrum of disease, now identified as TDP-43 proteinopathies.}, }
@article {pmid18090421, year = {2007}, author = {Boeve, BF}, title = {Links between frontotemporal lobar degeneration, corticobasal degeneration, progressive supranuclear palsy, and amyotrophic lateral sclerosis.}, journal = {Alzheimer disease and associated disorders}, volume = {21}, number = {4}, pages = {S31-8}, doi = {10.1097/WAD.0b013e31815bf454}, pmid = {18090421}, issn = {0893-0341}, mesh = {Amyotrophic Lateral Sclerosis/*classification/genetics/pathology ; Dementia/*classification/genetics/pathology ; Humans ; Neurodegenerative Diseases/classification/pathology ; Supranuclear Palsy, Progressive/*classification/genetics/pathology ; }, abstract = {Frontotemporal lobar degeneration, corticobasal degeneration (CBD), progressive supranuclear palsy, and amyotrophic lateral sclerosis have been considered distinct clinicopathologic entities with few issues in common other than neurodegeneration being central to all. The aim of this paper is to highlight the clinical, topographic, pathologic, proteomic, and genetic similarities among these disorders and the syndromes through which each disorder is exhibited. The critical roles of tau and TAR DNA-binding protein 43 (TDP-43) dysfunction in the disorders and syndromes are emphasized. Although confusion certainly remains, and the ability to predict the underlying proteinopathy in the various neurodegenerative syndromes is far from perfect, there is optimism that insights gained over the next few years will enhance our ability to accurately identify the amyloidopathies, tauopathies, and TDP-43opathies early in the disease course, potentially improving the ability to impact these diseases once targeted therapies have been developed.}, }
@article {pmid18084903, year = {2007}, author = {Hattori, F and Oikawa, S}, title = {Peroxiredoxins in the central nervous system.}, journal = {Sub-cellular biochemistry}, volume = {44}, number = {}, pages = {357-374}, doi = {10.1007/978-1-4020-6051-9_17}, pmid = {18084903}, issn = {0306-0225}, mesh = {Adenoviridae ; Animals ; Central Nervous System Diseases/chemically induced/*enzymology/genetics/therapy ; Disease Models, Animal ; Excitatory Amino Acid Agonists/toxicity ; *Gene Expression Regulation, Enzymologic/drug effects/genetics ; Humans ; Ibotenic Acid/toxicity ; Isoenzymes/genetics/metabolism/pharmacology ; Neurodegenerative Diseases/chemically induced/*enzymology/genetics/therapy ; Neuroprotective Agents/*metabolism/pharmacology ; *Oxidative Stress/drug effects/genetics ; Peroxiredoxins/genetics/*metabolism/pharmacology ; Rats ; Transduction, Genetic ; }, abstract = {Oxidative stress is considered one of the causative pathomechanisms of nervous system diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke and excitotoxicity. The basal expression of six different peroxiredoxin (Prx) isozymes show distinct distribution profiles in different brain regions and different cell types. PrxI and VI are expressed in glial cells but not in neurons; while PrxII, III, IV and V are expressed in neurons. Various diseases or models show altered expression levels of these isozymes, such as by upregulation of PrxI, II and VI and downregulation of PrxIII. Thioredoxin (Trx)I mRNA is distributed widely in the rat brain. This distribution pattern may reflect the specific functions of these isozymes. Recently, the neuroprotective roles of Prx III and V against ibotenate-induced-excitotoxicity were reported by two independent groups. Adenovirus transduction of PrxIII eliminated protein nitration and prevented gliosis caused by direct infusion of ibotenate. Systemic administration of recombinant PrxV diminished brain lesions in animals treated with ibotenate. In this chapter, we review the causative mechanisms of oxidative stress in neurodegenerative diseases, as well as describe the basal and disease-induced changes in Prxs/Trxs/Trx reductases expression levels and neuroprotective roles of Trxs and Prxs as demonstrated in overexpression models.}, }
@article {pmid18080037, year = {2007}, author = {Kazantsev, AG}, title = {Cellular pathways leading to neuronal dysfunction and degeneration.}, journal = {Drug news &amp; perspectives}, volume = {20}, number = {8}, pages = {501-509}, doi = {10.1358/dnp.2007.20.8.1157616}, pmid = {18080037}, issn = {0214-0934}, mesh = {Animals ; Calcium/metabolism ; Caspases/metabolism ; Humans ; Models, Neurological ; Nerve Degeneration/drug therapy/metabolism/*physiopathology ; Neural Pathways/drug effects/metabolism/*physiology ; Neurodegenerative Diseases/drug therapy/metabolism/*physiopathology ; Neurons/drug effects/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {There is no cure for devastating neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's diseases or amyotrophic lateral sclerosis, which cause longterm suffering and ultimately death. Slowly progressing neurodegenerative diseases affect the lives of many thousands of patients and their families. These disorders are characterized by pathological changes in disease-specific areas of the brain. In each disease, these pathological processes lead to dysfunction and degeneration in distinct subsets of neurons. Research on neurodegenerative disorders has revealed a complex picture of cellular pathology involving abnormalities in biochemical processes, gene regulation, responses to external stimuli, etc. However, despite the differences in the clinical manifestations and selective neuronal vulnerability, on cellular and molecular levels the underlying pathological processes appear similar across different diseases, suggesting common pathways of neurodegeneration. Elucidation of the precise neurodegenerative mechanism(s) is essential for development of effective and safe therapy for these lethal human disorders.}, }
@article {pmid18079297, year = {2008}, author = {Logroscino, G and Traynor, BJ and Hardiman, O and Chio', A and Couratier, P and Mitchell, JD and Swingler, RJ and Beghi, E and , }, title = {Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {79}, number = {1}, pages = {6-11}, doi = {10.1136/jnnp.2006.104828}, pmid = {18079297}, issn = {1468-330X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/mortality/therapy ; Dementia/epidemiology ; Female ; Humans ; Incidence ; Interdisciplinary Communication ; Male ; Middle Aged ; Palliative Care ; Parkinson Disease ; Prevalence ; Registries ; Risk Factors ; Sex Distribution ; Survival Rate ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.}, }
@article {pmid18077562, year = {2007}, author = {Skaper, SD}, title = {The brain as a target for inflammatory processes and neuroprotective strategies.}, journal = {Annals of the New York Academy of Sciences}, volume = {1122}, number = {}, pages = {23-34}, doi = {10.1196/annals.1403.002}, pmid = {18077562}, issn = {0077-8923}, mesh = {Animals ; Brain/*drug effects/pathology/physiopathology ; Disease Models, Animal ; Encephalitis/genetics/*pathology/*prevention &amp; control ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Microglia/drug effects/physiology ; Models, Biological ; Neuroprotective Agents/*therapeutic use ; Peroxisomal Targeting Signal 2 Receptor ; Protein Serine-Threonine Kinases/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics/metabolism ; }, abstract = {The importance of glial cell-propagated inflammation (i.e., neuroinflammation) disorders such as Alzheimer's disease (AD) was viewed previously as a bystander effect, or epiphenomenon, with inflammation occurring when damaged neurons elicit an activation response by glia. However, an accumulating body of evidence has challenged this earlier perspective and indicates a more active role of neuroinflammation in the pathophysiology of progressive neurodegenerative disorders such as AD, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This insight into pathophysiology evolved in concert with the appreciation that the brain is not as immunologically privileged as once thought. The central nervous system (CNS) has its own resident immune system, in which glial cells (microglia, astrocytes, and oligodendrocytes) not only serve supportive and nutritive roles for neurons but also engage from time to time in several "inflammatory" processes that defend the CNS from pathogens and help it to recover from stress and injury. These otherwise "normal" glial functions can sometimes result in a more severe and chronic neuroinflammatory cycle that actually promotes or propagates neurodegenerative disease. Excessive glial cell activation may thus constitute a viable target for the discovery of and development of neurodegenerative disease therapeutics. Suggestive clinical evidence in support of neuroinflammation as a drug discovery target for chronic neurodegenerative diseases, such as AD, comes from epidemiological and genetic linkage data. For example, long-term use of nonsteroidal anti-inflammatory drugs is correlated with a protective effect against AD, and certain polymorphisms in the genes for interleukin 1 and other proinflammatory mediator genes are associated with increased risk. In AD and Parkinson's disease, activated microglia and complement proteins have been identified in the brain regions most affected in these disorders. This report will briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, as well as their neuroprotective potential.}, }
@article {pmid18074639, year = {2007}, author = {Beal, MF}, title = {Mitochondria and neurodegeneration.}, journal = {Novartis Foundation symposium}, volume = {287}, number = {}, pages = {183-92; discussion 192-6}, doi = {10.1002/9780470725207.ch13}, pmid = {18074639}, issn = {1528-2511}, mesh = {Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/*physiopathology ; Nitric Oxide/*physiology ; }, abstract = {There is increasing evidence linking mitochondrial dysfunction to neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. This is the case in Alzheimer's disease, in which there is evidence that both beta-amyloid and the amyloid precursor protein may directly interact with mitochondria, leading to increased free radical production. In the case of Huntington's disease (HD), recent evidence suggests that the coactivator PGC1alpha, a key regulator of mitochondrial biogenesis in respiration, is down-regulated in patients with HD and in several animal models of this neurodegenerative disorder. In Parkinson's disease, the autosomal recessive genes parkin, DJ1 and PINK1 are all linked to either oxidative stress or mitochondrial dysfunction. In amyotrophic lateral sclerosis, there is strong evidence that mutant superoxide dismutase directly interacts with the outer mitochondrial membrane as well as the intermembrane space and matrix. Therefore, an impressive number of disease specific proteins interact with mitochondria. Therapies that target basic mitochondrial processes such as energy metabolism in free radical generation, or specific interactions of disease-related protein with mitochondria, hold great promise.}, }
@article {pmid18074357, year = {2007}, author = {Kabashi, E and Valdmanis, PN and Dion, P and Rouleau, GA}, title = {Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?.}, journal = {Annals of neurology}, volume = {62}, number = {6}, pages = {553-559}, doi = {10.1002/ana.21319}, pmid = {18074357}, issn = {1531-8249}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Animals ; Humans ; Mutation ; Oxidation-Reduction ; Protein Folding ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments.}, }
@article {pmid18072333, year = {2007}, author = {Dewil, M and Van Den Bosch, L and Robberecht, W}, title = {Microglia in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Belgica}, volume = {107}, number = {3}, pages = {63-70}, pmid = {18072333}, issn = {0300-9009}, mesh = {Amyotrophic Lateral Sclerosis/etiology/pathology/*physiopathology ; Astrocytes/pathology ; Cell Proliferation ; Central Nervous System/pathology/*physiopathology ; Encephalitis/pathology/*physiopathology ; Humans ; Microglia/immunology/*pathology ; Motor Neurons/immunology/metabolism/pathology ; Nerve Degeneration/pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder that results in the selective death of motor neurons in the central nervous system. This progressive motor neuron degeneration leads to death of the patient on average three to five years after onset of the disease. To date, no therapy is available. Many hypotheses have been formulated to explain the selective degeneration of motor neurons. One of the most studied hypotheses is the putative role of the inflammatory response that accompanies motor neuron death. The proliferation of microglia and astrocytes has been considered to be a secondary phenomenon, but recently, evidence is accumulating in favour of a contributory role of the non-neuronal cell populations to the pathogenesis of the disease. In this review, we will introduce the characteristics of microglial cells in the central nervous system. We will summarize the evidence of the expansion and the activation of the microglial cell population that accompanies motor neuron degeneration. Finally, an overview will be given of the different therapeutic strategies that targeted the inflammatory process in amyotrophic lateral sclerosis.}, }
@article {pmid18069968, year = {2008}, author = {Okamoto, K and Mizuno, Y and Fujita, Y}, title = {Bunina bodies in amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {28}, number = {2}, pages = {109-115}, doi = {10.1111/j.1440-1789.2007.00873.x}, pmid = {18069968}, issn = {0919-6544}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Inclusion Bodies/*ultrastructure ; Motor Neurons/*ultrastructure ; }, abstract = {Bunina bodies, which are small eosinophilic intraneuronal inclusions in the remaining lower motor neurons, are generally considered to be a specific pathologic hallmark of amyotrophic lateral sclerosis (ALS). One year before a publication by Bunina, van Reeth et al. described similar intracytoplasmic inclusions in the anterior horn cells in a patient with Pick's dementia with atypical ALS. At present, only two proteins have been shown to be present in Bunina bodies, one is cystatin C and the other is transferrin. Bunina bodies consist of amorphous electron-dense material surrounded by tubular and vesicular structures on electron microscopy. Although the nature and significance of Bunina bodies in ALS are not yet clear, the bodies may be abnormal accumulations of unknown proteinous materials.}, }
@article {pmid18069651, year = {2008}, author = {Green, JM and Hazel, CB and Forney, DR and Pugh, LM}, title = {New multiple-herbicide crop resistance and formulation technology to augment the utility of glyphosate.}, journal = {Pest management science}, volume = {64}, number = {4}, pages = {332-339}, doi = {10.1002/ps.1486}, pmid = {18069651}, issn = {1526-498X}, mesh = {Acetolactate Synthase/antagonists &amp; inhibitors ; Agriculture/*trends ; Crops, Agricultural/*genetics ; Glycine/analogs &amp; derivatives ; Herbicide Resistance/*genetics ; *Herbicides/pharmacology ; *Plants, Genetically Modified ; Glyphosate ; }, abstract = {Glyphosate has performed long and well, but now some weed communities are shifting to populations that survive glyphosate, and growers need new weed management technologies to augment glyphosate performance in glyphosate-resistant crops. Unfortunately, most companies are not developing any new selective herbicides with new modes of action to fill this need. Fortunately, companies are developing new herbicide-resistant crop technologies to combine with glyphosate resistance and expand the utility of existing herbicides. One of the first multiple-herbicide-resistant crops will have a molecular stack of a new metabolically based glyphosate resistance mechanism with an active-site-based resistance to a broad spectrum of ALS-inhibiting herbicides. Additionally, new formulation technology called homogeneous blends will be used in conjunction with glyphosate and ALS-resistant crops. This formulation technology satisfies governmental regulations, so that new herbicide mixture offerings with diverse modes of action can be commercialized more rapidly and less expensively. Together, homogeneous blends and multiple-herbicide-resistant crops can offer growers a wider choice of herbicide mixtures at rates and ratios to augment glyphosate and satisfy changing weed management needs.}, }
@article {pmid18063409, year = {2008}, author = {Chen, R and Cros, D and Curra, A and Di Lazzaro, V and Lefaucheur, JP and Magistris, MR and Mills, K and Rösler, KM and Triggs, WJ and Ugawa, Y and Ziemann, U}, title = {The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {119}, number = {3}, pages = {504-532}, doi = {10.1016/j.clinph.2007.10.014}, pmid = {18063409}, issn = {1388-2457}, mesh = {Electric Stimulation/*methods ; Electromyography/methods/statistics &amp; numerical data ; Evoked Potentials, Motor/physiology ; Humans ; Nervous System Diseases/*diagnosis/physiopathology ; Neural Conduction/physiology ; Transcranial Magnetic Stimulation/*methods/*statistics &amp; numerical data ; }, abstract = {The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.}, }
@article {pmid18053617, year = {2009}, author = {Everse, J and Coates, PW}, title = {Neurodegeneration and peroxidases.}, journal = {Neurobiology of aging}, volume = {30}, number = {7}, pages = {1011-1025}, doi = {10.1016/j.neurobiolaging.2007.10.007}, pmid = {18053617}, issn = {1558-1497}, mesh = {Apoptosis/*physiology ; Central Nervous System/*enzymology/physiopathology ; Lipid Peroxidation/physiology ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/*enzymology/physiopathology ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Peroxidases/*metabolism ; Signal Transduction/physiology ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that affect different parts of the central nervous system. However, a review of the literature indicates that certain biochemical reactions involved in neurodegeneration in these three diseases are quite similar and could be partly identical. This article critically examines the similarities and, based on data from our own and other laboratories, proposes a novel explanation for neurodegeneration in these three diseases. We identified about 20 commonalities that exist in the neurodegenerative process of each disease. We hypothesize that there are two enzyme-catalyzed pathways that operate in affected neurons: an oxidative pathway leading to destruction of various neuronal proteins and lipids, and an apoptotic pathway which the body normally uses to remove unwanted and dysfunctional cells. Data from many laboratories indicate that oxidative reactions are primarily responsible for neurodegeneration, whereas apoptosis may well be a secondary response to the presence of neurons that have already been severely damaged by oxidative reactions. Attempts to inhibit apoptosis for the purpose of attenuating progression of these diseases may therefore be only of marginal benefit. Specific oxidative reactions within affected neurons led us to propose that one or more heme peroxidases may be the catalyst(s) involved in oxidation of proteins and lipids. Support for this proposal is provided by the recent finding that amyloi-beta peptide may act as a peroxidase in AD. Possible participation of the peroxidase activity of cytochrome c, herein designated as cytochrome c(px) to distinguish it from yeast cytochrome c peroxidase, is discussed. Of special interest is our recent finding that many compounds that cause attenuation of neurodegeneration are inhibitors of the peroxidase activity of cytochrome c. Several inhibitors were subsequently identified as suicide substrates. Such inhibitors could be ideally suited for targeted clinical approaches aimed at arresting progression of neurodegeneration. Finally, it is possible that immobilized yet still active peroxidase(s) may be present in protein aggregates in AD, PD, and ALS. This activity could be the catalyst for the slow, self-perpetuating and irreversible degeneration of affected neurons that occurs over long periods of time in these neurodegenerative diseases.}, }
@article {pmid18052107, year = {2008}, author = {Sayre, LM and Perry, G and Smith, MA}, title = {Oxidative stress and neurotoxicity.}, journal = {Chemical research in toxicology}, volume = {21}, number = {1}, pages = {172-188}, doi = {10.1021/tx700210j}, pmid = {18052107}, issn = {0893-228X}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Cell Death/physiology ; Humans ; Huntington Disease/metabolism/pathology ; Multiple Sclerosis/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/pathology ; Neurotoxicity Syndromes/*metabolism/pathology ; Oxidative Stress/*physiology ; Parkinson Disease/metabolism/pathology ; }, abstract = {There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.}, }
@article {pmid18043408, year = {2007}, author = {Valente, SM and Karp, JR}, title = {Life with Lou Gehrig's disease: managing ALS symptoms.}, journal = {The Nurse practitioner}, volume = {32}, number = {12}, pages = {26-33; quiz 33-4}, doi = {10.1097/01.NPR.0000300824.66840.5d}, pmid = {18043408}, issn = {0361-1817}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; Male ; Middle Aged ; }, }
@article {pmid18040778, year = {2006}, author = {Rock, RB and Peterson, PK}, title = {Microglia as a pharmacological target in infectious and inflammatory diseases of the brain.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {1}, number = {2}, pages = {117-126}, pmid = {18040778}, issn = {1557-1904}, support = {DA020398/DA/NIDA NIH HHS/United States ; DA04381/DA/NIDA NIH HHS/United States ; DA09783/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Blood-Brain Barrier/drug effects/physiology ; Brain/cytology/*immunology/pathology ; Brain Diseases/drug therapy/*immunology/physiopathology ; Communicable Diseases/drug therapy/*immunology/physiopathology ; Humans ; Inflammation/drug therapy/immunology/*physiopathology ; Microglia/cytology/drug effects/*physiology ; }, abstract = {Following an eclipse of scientific inquiry regarding the biology of microglia that lasted 50 years, recognition toward the end of the 20th century of their neuropathogenic role in HIV-associated dementia and in neuroinflammatory/neurodegenerative diseases fueled a renaissance of interest in these resident macrophages of the brain parenchyma. Results of a large number of in vitro studies, using isolated microglial cells or glial/neuronal cell cultures, and parallel findings emerging from animal models and clinical studies have demonstrated that activated microglia produce a myriad of inflammatory mediators that both serve important defense functions against invading neurotropic pathogens and have been implicated in brain damage in infectious as well as neuroinflammatory/neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review provides a brief background regarding the physiological and pathophysiological roles of microglia and highlights current pharmacological approaches that target activated microglia with the goal of ameliorating infectious and neuroinflammatory/neurodegenerative diseases of the brain. Although this aspect of the field of neuroimmunopharmacology is in its infancy, it holds great promise for developing new treatments and prevention of diseases that are, in many cases, epidemic throughout the world.}, }
@article {pmid18038122, year = {2007}, author = {Gastl, R and Ludolph, AC}, title = {[Amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {78}, number = {12}, pages = {1449-57; quiz 1458-9}, pmid = {18038122}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Humans ; *Practice Guidelines as Topic ; *Practice Patterns, Physicians' ; Respiratory Insufficiency/complications/*diagnosis/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system characterized by signs and symptoms of upper and lower motor dysfunction. This results in the presence of focal amyotrophies and pareses affecting voluntary muscles. Patients die after a few years, in most cases by respiratory failure. ALS is the most frequent motor neuron disease; however, its etiology and pathogenesis are only known in fragments. Its genetic basis is only partially understood and major gaps remain in the understanding of its pathogenesis with the basic principle of selective vulnerability and potentially resulting therapeutic consequences.}, }
@article {pmid18035718, year = {2007}, author = {Dubinina, EE and Pustygina, AV}, title = {[Free radical processes in aging, neurodegenerative diseases and other pathological states].}, journal = {Biomeditsinskaia khimiia}, volume = {53}, number = {4}, pages = {351-372}, pmid = {18035718}, issn = {2310-6972}, mesh = {Aging/*metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; DNA, Mitochondrial/metabolism ; Free Radicals/metabolism ; Humans ; Mitochondria/metabolism ; Neurodegenerative Diseases/*metabolism/*pathology ; Oxidative Stress ; Parkinson Disease/metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Literature data on the role of oxidative stress in the aging of an organism have been summarized. The connection of some parameters of free radical processes (intensity of generation of reactive oxygen species in mitochondria, oxidative modification to the mitochondrial DNA, the activity of desaturases participating in biosynthesis of polyunsaturated C20 and C22 fatty acids) with life expectancy has been demonstrated. Oxidative stress is one of pathogenetical events in many diseases, including various neurodegenerative disorders. The special attention is paid to oxidatively modified proteins as one of early and reliable indicators of tissue injury in freeradical pathology. Oxidative protein destruction plays an important role in etiology of such neurodegenerative diseases, as Alzheimer's and Parkinson's diseases. Oxidative stress and the aggregation of proteins connected with it are considered to be a pathogenetical part in the development of familial amyotrophic lateral sclerosis. Oxidatively modified proteins are also associated with the development of cataract. The increase of the oxidatized protein ratio with the age and in various pathologies is assessed as an early and specific parameter of oxidative stress.}, }
@article {pmid18033645, year = {2007}, author = {Tomik, B}, title = {[Diagnosis and treatment of amyotrophic lateral sclerosis according to EFNS recommendations (2005)].}, journal = {Neurologia i neurochirurgia polska}, volume = {41}, number = {5}, pages = {445-456}, pmid = {18033645}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Humans ; *Palliative Care ; *Patient Care Team ; *Quality of Life ; }, abstract = {The article is focused on recent EFNS recommendations for the diagnosis and management of amyotrophic lateral sclerosis (ALS). In the commentary, the need for use of EFNS recommendations for ALS in clinical practice in Poland is emphasized. The importance of 1) complex respiratory and nutritional care, 2) symptomatic treatment, 3) multidisciplinary teamwork and palliative care, as well as 4) an individual rehabilitation programme and 5) communication status improvement, is stressed as a necessary step for improving the quality of life of Polish ALS patients.}, }
@article {pmid18033040, year = {2007}, author = {Gil, J and Funalot, B and Torny, F and Lacoste, M and Couratier, P}, title = {[Exogenous risk factors in sporadic ALS: a review of the literature].}, journal = {Revue neurologique}, volume = {163}, number = {11}, pages = {1021-1030}, doi = {10.1016/s0035-3787(07)74174-7}, pmid = {18033040}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Electric Injuries/complications ; Environment ; Humans ; Metals, Heavy/adverse effects ; Pesticides/adverse effects ; Risk Factors ; Solvents/adverse effects ; Wounds and Injuries/complications ; }, abstract = {The latest reviews of the literature devoted to the epidemiology of ALS all agree that exogenic risk factors play a role in sporadic ALS. Nevertheless, there is no convincing evidence demonstrating in a reproducible manner an association between an environmental risk factor and ALS. This discordance is mainly explained by methodological skews. Over the last ten years, exogenic factors have been analyzed within the framework of specific lifestyle factors such as place of residence, smoking or not, or certain eating practices. The most recent work suggests that interactions between genetic and environmental factors depend on the age at exposure and the duration of exposure. The objectives of this general review is: to analyze the principal case-control studies, historical cohort studies or mortality studies which looked at the associations between an environmental factor and ALS, to present main results of studies having analyzed lifestyles in relation to one or more exogenic factors, and to discuss the limitations of epidemiologic studies on ALS.}, }
@article {pmid18030461, year = {2008}, author = {Aisenbrey, C and Borowik, T and Byström, R and Bokvist, M and Lindström, F and Misiak, H and Sani, MA and Gröbner, G}, title = {How is protein aggregation in amyloidogenic diseases modulated by biological membranes?.}, journal = {European biophysics journal : EBJ}, volume = {37}, number = {3}, pages = {247-255}, pmid = {18030461}, issn = {0175-7571}, mesh = {Amyloid beta-Peptides/chemistry/metabolism ; Animals ; Cell Membrane/*chemistry/*pathology ; Dimerization ; Humans ; Multiprotein Complexes/chemistry/*metabolism ; Neurodegenerative Diseases/*etiology/*physiopathology ; Protein Binding ; Protein Conformation ; Protein Folding ; Solubility ; Superoxide Dismutase/chemistry/metabolism ; Superoxide Dismutase-1 ; Surface Properties ; alpha-Synuclein/chemistry/metabolism ; }, abstract = {The fate of proteins with amyloidogenic properties depends critically on their immediate biochemical environment. However, the role of biological interfaces such as membrane surfaces, as promoters of pathological aggregation of amyloidogenic proteins, is rarely studied and only established for the amyloid-beta protein (A beta) involved in Alzheimer's disease, and alpha-synuclein in Parkinsonism. The occurrence of binding and misfolding of these proteins on membrane surfaces, is poorly understood, not at least due to the two-dimensional character of this event. Clearly, the nature of the folding pathway for A beta protein adsorbed upon two-dimensional aggregation templates, must be fundamentally different from the three-dimensional situation in solution. Here, we summarize the current research and focus on the function of membrane interfaces as aggregation templates for amyloidogenic proteins (and even prionic ones). One major aspect will be the relationship between membrane properties and protein association and the consequences for amyloidogenic products. The other focus will be on a general understanding of protein folding pathways on two-dimensional templates on a molecular level. Finally, we will demonstrate the potential importance of membrane-mediated aggregation for non-amphiphatic soluble amyloidogenic proteins, by using the SOD1 protein involved in the amyotrophic lateral sclerosis syndrome.}, }
@article {pmid18028007, year = {2007}, author = {Corona, JC and Tovar-y-Romo, LB and Tapia, R}, title = {Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {11}, number = {11}, pages = {1415-1428}, doi = {10.1517/14728222.11.11.1415}, pmid = {18028007}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Calcium/metabolism ; Cell Death ; Cytoplasm/metabolism ; Disease Models, Animal ; *Drug Delivery Systems ; Excitatory Amino Acid Antagonists/administration &amp; dosage ; Glutamic Acid/*physiology ; Humans ; Neurons ; Receptors, AMPA/*metabolism ; }, abstract = {Two forms of amyotrophic lateral sclerosis (ALS) are known, the familial (FALS), due in part to mutations in superoxide dismutase 1 (SOD1), and the sporadic (SALS), which accounts for > 90% of all cases. The cause of SALS is not known, but excitotoxicity due to overactivation of glutamate receptors may mediate the motor neuron degeneration in the spinal cord, which is the hallmark of this disease. Overactivation of calcium-permeable alpha-amino-3-hydroxy-5-isoxazole propionate receptors lacking the subunit glutamate receptor 2, leading to an increase in calcium cytoplasmic concentration, seems to play an important role in the mechanism of neuronal death. The knowledge of this mechanism, in addition to other factors, provides several possible targets for therapeutic strategies that are reviewed in this article. Some of these strategies have proven to be partially effective in both human mutant superoxide dismutase 1 transgenic rodents (FALS model) and the few existing in vivo models of spinal motor neurodegeneration induced by excitotoxicity (SALS models), although observable benefits are still to be shown in clinical trials.}, }
@article {pmid18026741, year = {2008}, author = {Kato, S}, title = {Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences.}, journal = {Acta neuropathologica}, volume = {115}, number = {1}, pages = {97-114}, doi = {10.1007/s00401-007-0308-4}, pmid = {18026741}, issn = {0001-6322}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Animals, Genetically Modified ; Brain/pathology ; *Disease Models, Animal ; Humans ; Mice ; Motor Neurons/*pathology ; Mutation ; Rats ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. The author initially summarizes the principal features of human ALS neuropathology, and subsequently describes in detail ALS animal models mainly from the viewpoint of pathological similarities and differences. ALS animal models in this review include strains of rodents that are transgenic for superoxide dismutase 1 (SOD1), ALS2 knockout mice, and mice that are transgenic for cytoskeletal abnormalities. Although the neuropathological results obtained from human ALS autopsy cases are valuable and important, almost all of such cases represent only the terminal stage. This makes it difficult to clarify how and why ALS motor neurons are impaired at each clinical stage from disease onset to death, and as a consequence, human autopsy cases alone yield little insight into potential therapies for ALS. Although ALS animal models cannot replicate human ALS, in order to compensate for the shortcomings of studies using human ALS autopsy samples, researchers must inevitably rely on ALS animal models that can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy. Of course, human ALS and all ALS animal models share one most important similarity in that both exhibit motor neuron degeneration/death. This important point of similarity has shed much light on the pathomechanisms of the motor neuron degeneration/death at the cellular and molecular levels that would not have been appreciated if only human ALS autopsy samples had been available. On the basis of the aspects covered in this review, it can be concluded that ALS animal models can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy only in combination with detailed neuropathological data obtained from human ALS autopsy cases.}, }
@article {pmid18004590, year = {2008}, author = {Nadif Kasri, N and Van Aelst, L}, title = {Rho-linked genes and neurological disorders.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {455}, number = {5}, pages = {787-797}, pmid = {18004590}, issn = {0031-6768}, support = {R01 MH082808/MH/NIMH NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*physiopathology ; Animals ; Humans ; Mental Retardation, X-Linked/genetics/*metabolism/*physiopathology ; Signal Transduction/physiology ; rho GTP-Binding Proteins/genetics/*metabolism ; }, abstract = {Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3% of children and young adults. Many forms of MR are associated with abnormalities in dendritic structure and/or dendritic spine morphology. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to underlie or contribute to the cognitive disabilities associated with MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. Significantly, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotrophic lateral sclerosis (ALS). Here, we will discuss Rho GTPase-related genes and their signaling pathways involved in MR and ALS.}, }
@article {pmid17986822, year = {2007}, author = {Woods, K}, title = {Genetic defects of the growth-hormone-IGF axis associated with growth hormone insensitivity.}, journal = {Endocrine development}, volume = {11}, number = {}, pages = {6-15}, doi = {10.1159/000111053}, pmid = {17986822}, issn = {1421-7082}, mesh = {Carrier Proteins/genetics ; Glycoproteins/genetics ; Growth Hormone/*genetics/physiology ; Humans ; Insulin-Like Growth Factor I/genetics ; Laron Syndrome/*genetics ; Models, Biological ; Mutation ; STAT5 Transcription Factor/genetics ; Signal Transduction/genetics ; Somatomedins/*genetics ; }, abstract = {The central feature of growth hormone (GH) insensitivity is deficiency of insulin-like growth factor-1 (IGF-1) in association with elevated GH secretion. This condition is also known as primary IGF deficiency. There are currently four known genetic causes of GH insensitivity/primary IGF deficiency: GH receptor deficiency (also known as Laron syndrome or GH insensitivity syndrome), IGF-1 deficiency, signal transducer and activator of transcription 5b (STAT5b) deficiency and acid labile subunit (ALS) deficiency. Despite sharing the classical biochemical features of GH insensitivity, the phenotype in each of these conditions is quite distinct. This review will discuss each of these causes in turn, highlighting the insights these rare causes of growth failure afford into the functioning of the human GH-IGF-1 axis.}, }
@article {pmid17985252, year = {2008}, author = {Shaw, CA and Höglinger, GU}, title = {Neurodegenerative diseases: neurotoxins as sufficient etiologic agents?.}, journal = {Neuromolecular medicine}, volume = {10}, number = {1}, pages = {1-9}, pmid = {17985252}, issn = {1559-1174}, support = {R01 NS051723/NS/NINDS NIH HHS/United States ; R01 NS051723-03/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; Animals ; Dementia/chemically induced/epidemiology ; Guadeloupe/epidemiology ; Guam/epidemiology ; Humans ; MPTP Poisoning/epidemiology/etiology ; Neurodegenerative Diseases/*chemically induced/epidemiology/*genetics ; Neurotoxins/*toxicity ; Parkinson Disease, Secondary/chemically induced/epidemiology ; Parkinsonian Disorders/chemically induced/epidemiology ; Toxins, Biological/*toxicity ; }, abstract = {A dominant paradigm in neurological disease research is that the primary etiological factors for diseases such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS) are genetic. Opposed to this perspective are the clear observations from epidemiology that purely genetic casual factors account for a relatively small fraction of all cases. Many who support a genetic etiology for neurological disease take the view that while the percentages may be relatively small, these numbers will rise in the future with the inevitable discoveries of additional genetic mutations. The follow up argument is that even if the last is not true, the events triggered by the aberrant genes identified so far will be shown to impact the same neuronal cell death pathways as those activated by environmental factors that trigger most sporadic disease cases. In this article we present a countervailing view that environmental neurotoxins may be the sole sufficient factor in at least three neurological disease clusters. For each, neurotoxins have been isolated and characterized that, at least in animal models, faithfully reproduce each disorder without the need for genetic co-factors. Based on these data, we will propose a set of principles that would enable any potential toxin to be evaluated as an etiological factor in a given neurodegenerative disease. Finally, we will attempt to put environmental toxins into the context of possible genetically-determined susceptibility.}, }
@article {pmid17982877, year = {2007}, author = {Koutsilieri, E and Rethwilm, A and Scheller, C}, title = {The therapeutic potential of siRNA in gene therapy of neurodegenerative disorders.}, journal = {Journal of neural transmission. Supplementum}, volume = {}, number = {72}, pages = {43-49}, doi = {10.1007/978-3-211-73574-9_7}, pmid = {17982877}, issn = {0303-6995}, mesh = {Alleles ; Alzheimer Disease/genetics/therapy ; Amyloid beta-Protein Precursor/genetics ; Animals ; Disease Models, Animal ; Down-Regulation/genetics ; Gene Expression/physiology ; *Gene Silencing ; *Gene Transfer Techniques ; Genetic Therapy/*methods ; Humans ; Huntington Disease/genetics/therapy ; Motor Neuron Disease/genetics/therapy ; Neurodegenerative Diseases/*genetics/therapy ; Point Mutation ; Protease Nexins ; RNA, Messenger/*genetics ; *RNA, Small Interfering ; Receptors, Cell Surface/genetics ; Sequence Analysis, DNA ; Spinocerebellar Ataxias/genetics/therapy ; }, abstract = {RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxia (SCA1).}, }
@article {pmid17981578, year = {2008}, author = {Linseman, DA and Loucks, FA}, title = {Diverse roles of Rho family GTPases in neuronal development, survival, and death.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {13}, number = {}, pages = {657-676}, doi = {10.2741/2710}, pmid = {17981578}, issn = {1093-9946}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Cell Survival ; Dendritic Spines/metabolism ; Fragile X Syndrome/metabolism ; *Gene Expression Regulation ; Humans ; Mental Retardation, X-Linked/metabolism ; Models, Biological ; Motor Neurons/*metabolism ; Neurons/*metabolism/pathology ; Tuberous Sclerosis/metabolism ; cdc42 GTP-Binding Protein/metabolism ; p21-Activated Kinases/metabolism ; rho GTP-Binding Proteins/*metabolism ; }, abstract = {Rho family GTPases (eg., RhoA, Rac1 and Cdc42) are monomeric G-proteins that act as key transducers of extracellular signals to the actin cytoskeleton. In the nervous system, Rho family GTPases are essential regulators of neuronal growth cone motility, axonal migration, and dendritic spine morphogenesis. Given these vital functions, it is perhaps not surprising that mutations in several proteins involved in Rho GTPase signaling are causative in some forms of mental retardation. In addition, numerous recent studies have identified Rho family GTPases as central players in the molecular pathways that determine neuronal survival and death. Interestingly, individual Rho family members have been shown to play either a pro-death or pro-survival role in the nervous system depending on both the type of neuron and the particular neurodegenerative insult involved. This review summarizes current work demonstrating a critical role for Rho family GTPases and their effectors in the regulation of neuronal development, survival, and death. These findings may be particularly relevant in the context of specific neurodegenerative disorders in which Rho family GTPase function is altered, such as loss-of-function of the Rac1 guanine nucleotide exchange factor, alsin, in juvenile-onset amyotrophic lateral sclerosis.}, }
@article {pmid17978775, year = {2007}, author = {Fuster Torres, MA and Berini Aytés, L and Gay Escoda, C}, title = {Salivary gland application of botulinum toxin for the treatment of sialorrhea.}, journal = {Medicina oral, patologia oral y cirugia bucal}, volume = {12}, number = {7}, pages = {E511-7}, pmid = {17978775}, issn = {1698-6946}, mesh = {Botulinum Toxins, Type A/*administration &amp; dosage ; Humans ; Injections, Intralesional ; Neurotoxins/*administration &amp; dosage ; Salivary Glands ; Sialorrhea/*drug therapy/etiology ; }, abstract = {Sialorrhea or excessive salivation, and drooling, are common and disabling manifestations in different neurological disorders. A review is made of the literature, based on a PubMed search, selecting those articles describing clinical trials involving the injection of botulinum toxin A in the salivary glands of patients with different diseases characterized by sialorrhea. The most frequently treated diseases were infant cerebral palsy (30%), Parkinson's disease (20%) and amyotrophic lateral sclerosis (15%). Over half of the authors injected the product into the parotid glands, 9.5% into the submaxillary glands, and 38% into both. The total doses of toxin injected varied from 10-100 units of Botox or 30-450 units of Dysport according to the different authors. A reduction was observed in the production of saliva following these injections, and the duration of the therapeutic effect was 1.5-6 months. Six articles (30%) described the presence of adverse effects such as dysphagia, xerostomia and chewing difficulties. Most of the clinical studies involved small patient samples, with no blinding or randomization, and no control group. Moreover, no data are available on the efficacy and adverse effects of treatment in the context of long-term prospective studies. The effective therapeutic dose and ideal form of application remain to be established, and require the conduction of further controlled clinical trials involving large sample sizes.}, }
@article {pmid17975550, year = {2008}, author = {Zuchner, T and Brundin, P}, title = {Mutant huntingtin can paradoxically protect neurons from death.}, journal = {Cell death and differentiation}, volume = {15}, number = {3}, pages = {435-442}, doi = {10.1038/sj.cdd.4402261}, pmid = {17975550}, issn = {1350-9047}, mesh = {Animals ; Brain/pathology ; Cell Death ; Disease Models, Animal ; Humans ; Huntingtin Protein ; Huntington Disease/*genetics/pathology ; Mice ; Mice, Transgenic ; Mutation ; Nerve Tissue Proteins/chemistry/*genetics/metabolism ; Neurons/pathology ; Nuclear Proteins/chemistry/*genetics/metabolism ; Protein Structure, Tertiary ; Receptors, Glutamate/metabolism ; }, abstract = {Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.}, }
@article {pmid17969557, year = {2007}, author = {Federici, T and Boulis, N}, title = {Gene therapy for peripheral nervous system diseases.}, journal = {Current gene therapy}, volume = {7}, number = {4}, pages = {239-248}, doi = {10.2174/156652307781369083}, pmid = {17969557}, issn = {1566-5232}, support = {K08 NS43305/NS/NINDS NIH HHS/United States ; }, mesh = {Charcot-Marie-Tooth Disease/therapy ; Diabetic Neuropathies/therapy ; Genetic Therapy/*methods ; Genetic Vectors ; Humans ; Models, Neurological ; Motor Neuron Disease/therapy ; Nerve Degeneration/therapy ; Nerve Regeneration ; Pain Management ; Peripheral Nerve Injuries ; Peripheral Nervous System Diseases/*therapy ; Viruses/genetics ; }, abstract = {Peripheral nerve diseases, also known as peripheral neuropathies, affect 15-20 million of Americans and diabetic neuropathy is the most common condition. Currently, the treatment of peripheral neuropathies is more focused on managing pain rather than providing permissive conditions for regeneration. Despite advances in microsurgical techniques, including nerve grafting and reanastomosis, axonal regeneration after peripheral nerve injury remains suboptimal. Also, no satisfactory treatments are available at this time for peripheral neurodegeneration occurring in motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Peripheral nerves have the inherent capacity of regeneration. Gene therapy strategies focused on neuroprotection may help optimizing axonal regrowth. A better understanding of the cellular and molecular events involved in axonal degeneration and regeneration have helped researchers to identify targets for intervention. This review summarizes the current state on the clinical experience as well as gene therapy strategies for peripheral neuropathies, including MND, peripheral nerve injury, neuropathic pain, and diabetic neuropathy.}, }
@article {pmid17969361, year = {2007}, author = {Funakoshi, H and Ohya, W and Kadoyama, K and Nakamura, T}, title = {[ALS and neurotrophic factors--HGF as a novel neurotrophic and neuroregenerative factor].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1195-1202}, pmid = {17969361}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*etiology ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor/physiology/therapeutic use ; Hepatocyte Growth Factor/genetics/*physiology/therapeutic use ; Humans ; Mice ; Nerve Growth Factors/physiology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons and their axons. Although a variety of responsive mutations in superoxide dismutase-1 (SOD1) have been identified in familial cases, more than 90% of ALS cases are sporadic. Therefore, the most beneficial approach to treatment would be to find the common pathological pathway that functions in both familial and sporadic cases during disease onset and progression. Neurotrophic factors may function to prevent the neuronal death and axonal degeneration in ALS that is thought to be the result of aberrant apoptotic cell death. Here we summarize the potential role of classical neurotrophic factors in ALS. We also describe the potential role of hepatocyte growth factor (HGF), a novel neurotrophic factor, in retarding the progression of the disease in a transgenic mouse model expressing SOD1G93A (G93A). In addition to direct neurotrophic activities, HGF functions on the astrocytes of G93A mice to maintain levels of EAAT2, a glial-specific glutamate transporter that might be responsible for the reduction of glutamatergic neurotoxicity of motoneurons. Furthermore, HGF is capable of reducing astrocytosis and microglial accumulation, and thus supports the attention of a glial-dependent mechanism of ALS progression. Although it is a challenging issue, recent advancements in the elucidation of the role of neurotrophic factors in ALS raise the possibility of their use in the treatment of ALS and related disorders.}, }
@article {pmid17969360, year = {2007}, author = {Yokota, T}, title = {[Gene therapy of ALS with short interfering RNA].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1187-1194}, pmid = {17969360}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Central Nervous System ; Disease Models, Animal ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; Humans ; *RNA Interference ; RNA, Double-Stranded ; RNA, Small Interfering/*administration &amp; dosage ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Viruses/genetics ; }, abstract = {RNA interference (RNAi) is the process of sequence-specific, post-tanscriptional gene silencing, initiated by double-stranded RNA (dsRNA). The gene therapy for familial ALS with siRNA had been started and showed promising results in the model mouse. There is a recent progress in the delivery of siRNA to the central nervous syste. There are still important problems for application of gene therapy including off-target effect and gene delivery of siRNA, but a rapid progress can be expected because of the extremely high efficiency of siRNA.}, }
@article {pmid17969359, year = {2007}, author = {Watabe, K}, title = {[Proximal axonal injuries as experimental models for adult motoneuron degeneration].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1179-1186}, pmid = {17969359}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/pathology/therapy ; Animals ; *Axotomy ; Cell Death ; *Disease Models, Animal ; Facial Nerve ; Humans ; Mice ; Motor Neurons/pathology ; Mutation ; Rats ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by selective loss of motoneurons leading to progressive paralysis and death by respiratory failure. Since the discovery of the mutation of Cu/Zn superoxide dismutase (SOD1) gene in patients with familial ALS, transgenic mice and rats expressing human mutant SOD1 have been the most widely used experimental models to elucidate the pathomechanism of and the therapeutic approach against familial ALS as well as sporadic ALS. Most cases of ALS, however, are considered to be sporadic and of unknown etiology. In another animal model of adult motoneuron degeneration, proximal axonal injury (avulsion) of peripheral nerves exhibits extensive loss of motoneurons in adult rats. The mechanism of motoneuron degeneration after avulsion also remains unclear, but peroxinitrite-mediated oxidative damage and perikaryal accumulation of phosphorylated neurofilaments have been demonstrated in injured motoneurons after avulsion. Both of these pathological features have also been shown in spinal motoneurons in mutant SOD1-tg animals as well as in patients with familial and sporadic ALS. In this review, we presented experimental studies on peripheral nerve avulsion models in adult rats to investigate pathomechanisms of motoneuron degeneration and to explore therapeutic strategies against motoneuron injury and motoneuron diseases such as ALS.}, }
@article {pmid17969358, year = {2007}, author = {Hasegawa, M and Arai, T}, title = {[Component of ubiquitin-positive inclusions in ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1171-1177}, pmid = {17969358}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology/therapy ; Animals ; DNA-Binding Proteins/*metabolism ; Frontal Lobe/cytology/pathology ; Humans ; Inclusion Bodies/*metabolism ; Motor Neurons/cytology/pathology ; Nerve Degeneration ; Phosphorylation ; Temporal Lobe/cytology/pathology ; Ubiquitin/*metabolism ; }, abstract = {TAR DNA-binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein that functions in regulating transcription and alternative splicing, was identified as a component of ubiquitin-positive tau-negative cytoplasimic inclusions in frontotemporal lobar degeneration (FTLD-U), and subsequently of ubiquitin-positive skein-like inclusions in amyotrophic lateral sclerosis (ALS). Dephosphorylation treatment of sarkosyl-insoluble fractions have suggested that abnormal phosphorylation takes place in the deposited TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43. This article reviews the ubiquitin-positive inclusions in ALS and the recent discovery of TDP-43 in tau-negative inclusions in FTLD-U and ALS. We also discuss the biological implications of these findings for the pathogenesis of ALS.}, }
@article {pmid17969357, year = {2007}, author = {Yamanaka, K and Yamashita, H}, title = {[ALS and microglia--a player for non-cell-autonomous neuron death].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1163-1170}, pmid = {17969357}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology/therapy ; Animals ; Cell Death ; Cytokines/metabolism ; Humans ; Integrases ; Mice ; Microglia/enzymology/*physiology ; Motor Neurons ; Mutation ; Superoxide Dismutase/genetics/toxicity ; Superoxide Dismutase-1 ; }, abstract = {Dominant mutation in the gene of superoxide dismutase 1 (SOD1) leads to amyotrophic lateral sclerosis (ALS), an adult-onset progressive fatal motor neuron disease. Recent progress in research on ALS has been made by the use of transgenic mouse model of familial ALS, which expresses mutant form of SOD1 and recapitulates the phenotype and pathology of motor neuron disease. There is accumulating evidence indicating non-cell-autonomous motor neuron death in ALS mouse model. Using the mice carrying deletable mutant SOD1 transgene by the action of Cre recombinase, we have demonstrated that diminishing mutant SOD1 toxicity within microglia significantly slowed disease progression of ALS, indicating the active role of microglia in disease progression of ALS. In this paper, we review the recent advance of ALS research focusing on the role of glial cells in ALS and discuss its prospect.}, }
@article {pmid17969356, year = {2007}, author = {Mori, H}, title = {[ALS and communication aid--a linguistic approach to scanning input].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1155-1162}, pmid = {17969356}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; *Communication Aids for Disabled ; Humans ; *Language ; Microcomputers ; Models, Statistical ; *Nonverbal Communication ; }, abstract = {Supporting communication disorders is one of the most important tasks that Information Technology is imposed. In this commentary, recent progress in improving efficiency of the scanning communicator, on which considerable number of amyotrophic lateral sclerosis (ALS) patients are relying, is presented. Scanning is a human interface for selecting items such as commands or characters. Scanning communication aids are widely used by a number of physically-challenged people. However, it has a serious disadvantage of its time-consuming input operation. The author's group has developed a novel scanning input method, which is called pairwise scanning. It adopts multiple cursors for accelerating character selection. A sequence optimization algorithm with a statistical language model finds the most likely combination of characters that the user is expected to input. Assuming 95% precision in the estimation, proposed method can accelerate the communication throughput up to 30%. The author's another approach is the automatic error correction in scanning input based on statistical language model. The key idea is to model the individual user's motor characteristics by examining her/his switch timing distribution, which yields another statistical model called switch timing model. A dramatic improvement to the accuracy is obtained by introducing the model. As a result, proposed method improved the character correct rate from 77.7% to 97.7% for an ALS patient.}, }
@article {pmid17969355, year = {2007}, author = {Mita, S}, title = {[Laryngotracheal separation and tracheoesophageal diversion for intractable aspiration in ALS--usefulness and indication].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1149-1154}, pmid = {17969355}, issn = {1881-6096}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology/*surgery ; Esophagus/surgery ; Humans ; Larynx/surgery ; Male ; Otorhinolaryngologic Surgical Procedures/methods ; Pneumonia, Aspiration/etiology/prevention &amp; control ; Quality of Life ; Respiratory Aspiration/*etiology/*prevention &amp; control ; Trachea/surgery ; Treatment Outcome ; }, abstract = {To evaluate the usefulness of laryngotracheal separation or tracheoesophageal diversion (LTS/TED), we investigated changes in medical management after LTS/TED. We performed LTS/TED for intractable aspiration in patients with amyotrophic lateral sclerosis (ALS) and patients with other neurological diseases. Most of the subjects had already received a tracheostomy, and all the patients with ALS had tracheostomy positive pressure ventilation. However, they remained at risk of intractable aspiration, had experienced frequent suctioning of aspiration material, and could not eat. In all cases, LTS/TED was performed safely within 3 hours and without any complications. After LTS/TED, there was no aspiration of saliva in any of the patients. In most subjects, the frequency of suctioning by medical staff and caregivers was much reduced. The frequency of aspiration pneumonia was also extremely lowered. Follow-up study demonstrated that complete control over aspiration was achieved in all of the patients. Some of them were completely self-sufficient in their ability to eat. Some of the other patients were at least able to enjoy taste. Nutritional status was significantly improved. All the patients, family caregivers, and medical staff involved in this study were satisfied with the outcome. These results indicate that LTS/TED is a very useful procedure in several aspects: it benefits patients who have a fear of aspiration; it reduces the burden on patients and family caregivers; it promotes their quality of life; and it limits the aspiration-associated demands on medical staff. Based on the results, we have proposed an indication of LTS/TED for dysphasia in ALS.}, }
@article {pmid17969354, year = {2007}, author = {Izumi, Y and Kaji, R}, title = {[Clinical trials of ultra-high-dose methylcobalamin in ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1141-1147}, pmid = {17969354}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/physiopathology ; Animals ; Disease Progression ; Double-Blind Method ; Glutamic Acid/toxicity ; Humans ; Pulse Therapy, Drug ; Randomized Controlled Trials as Topic ; Rats ; Time Factors ; Vitamin B 12/administration &amp; dosage/*analogs &amp; derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motor neurons. Weakness may begin in the legs, hands, proximal arms, or pharynx. The course is relentless and progressive without remissions, relapses, or even stable plateaus. There is no effective drug therapy for ALS, although riluzole has been shown to prolong life in sufferers, without tracheostomy. A vitamin B12 analog, methylcobalamin, has a protective effect on cultured cortical neurons against glutamate-induced cytotoxicity. We have shown the ultra-high-dose methylcobalamin (25 mg/day i.m.) slows down the progressive reduction of the CMAP (compound muscle action potential) amplitudes in ALS in the short term (4 weeks). The latencies of SSR (sympathetic skin response) were shorter after treatment (50 mg/day i.v., 2 weeks). In the long-term effect of methylcobalamin (50 mg/day i.m., twice a week), the survival time (or the period to become respirator-bound) was significantly longer in the treated group than in the untreated. Larger-scale randomized double blind trial was started in Japan in order to evaluate the long-term efficacy and the safety of ultra-high-dose methylcobalamin for sporadic or familial cases of ALS.}, }
@article {pmid17969353, year = {2007}, author = {Yamamoto, M and Tanaka, F and Sobue, G}, title = {[Gene expression profile of spinal ventral horn in ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1129-1139}, pmid = {17969353}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Anterior Horn Cells/*metabolism ; Dynactin Complex ; *Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Microdissection ; Microtubule-Associated Proteins/genetics/metabolism ; Protein Array Analysis ; Proteins/*genetics/*metabolism ; }, abstract = {The causative pathomechanism of sporadic amyotrophic lateral sclerosis (ALS) is not clearly understood. Using microarray technology combined with laser-captured microdissection, gene expression profiles of degenerating spinal motor neurons as well as spinal ventral horn from autopsied patients with sporadic ALS were examined. Spinal motor neurons showed a distinct gene expression profile from the whole spinal ventral horn. Three percent of genes examined were significantly downregulated, and 1% were upregulated in motor neurons. In contrast with motor neurons, the total spinal ventral horn homogenates demonstrated 0.7% and 0.2% significant upregulation and downregulation of gene expression, respectively. Downregulated genes in motor neurons included those associated with cytoskeleton/axonal transport, transcription and cell surface antigens/receptors, such as dynactin 1 (DCTN1) and early growth response 3 (EGR3). In particular, DCTN1 was markedly downregulated in most residual motor neurons prior to the accumulation of pNF-H and ubiquitylated protein. Promoters for cell death pathway, death receptor 5 (DR5), cyclins C (CCNC) and A1 (CCNA), and caspases were upregulated, whereas cell death inhibitors, acetyl-CoA transporter (ACATN) and NF-kappaB (NFKB) were also upregulated. In terms of spinal ventral horn, the expression of genes related to cell surface antigens/receptors, transcription and cell adhesion/ECM were increased. The gene expression resulting in neurodegenerative and neuroprotective changes were both present in spinal motor neurons and ventral horn. Moreover, Inflammation-related genes, such as belonging to the cytokine family were not, however, significantly upregulated in either motor neurons or ventral horn. The sequence of motor neuron-specific gene expression changes from early DCTN1 downregulation to late CCNC upregulation in sporadic ALS can provide direct information on the genes leading to neurodegeneration and neuronal death, and are helpful for developing new therapeutic strategies.}, }
@article {pmid17969352, year = {2007}, author = {Aizawa, H and Kwak, S}, title = {[ALS and excitatory amino acid].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1117-1127}, pmid = {17969352}, issn = {1881-6096}, mesh = {Adenosine Deaminase ; Amyotrophic Lateral Sclerosis/*etiology/*therapy ; Animals ; Calcium/metabolism ; Cell Death ; Humans ; Motor Neurons ; Mutation ; *RNA Editing ; RNA-Binding Proteins ; Receptors, AMPA/*genetics/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {AMPA receptor, one of ionotropic glutamate receptors, has been proposed to play a critical role to initiate the neuronal death cascade in motor neuron disease by an increase of Ca2+ influx. There are at least two mechanisms to increase Ca2+ influx through Ca2+-permiable AMPA receptor: a decrease of RNA editing efficacy at the GluR2 Q/R site and a decrease of GluR2 level relative to AMPA receptor subunits. Deficient RNA editing of the AMPA receptor subunit GluR2 at the Q/R site is a primary cause of neuronal death and recently has been reported to be a tightly linked etiological cause of motor neuron death in sporadic amyotrophic lateral sclerosis (ALS). On the other hand, relative low GluR2 level among AMPA receptor subunits seems to increase Ca2+ permeability of motor neurons in familial ALS (ALS1) linked to mutated cupper-zinc superoxide dismutase gene (SOD1). AMPA receptor-mediated mechanism does not seem to play any role in death of motor neurons in X-linked spinal and bulbar muscular atrophy (SBMA). From the molecular pathomechanism of sporadic ALS and ALS1, drugs which increase RNA editing efficacy at the GluR2 Q/R site could be a potent therapy for sporadic ALS, while AMPA receptor antagonists could prevent deterioration from ALS1.}, }
@article {pmid17969351, year = {2007}, author = {Kuwabara, S and Kanai, K}, title = {[Altered axonal ion channel function in amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1109-1115}, pmid = {17969351}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*physiopathology ; Axonal Transport ; Axons/*physiology ; Cell Death ; Fasciculation ; Humans ; Membrane Potentials ; Mitochondria/physiology ; Motor Neurons/physiology ; Oxidative Stress ; Potassium Channels/*physiology ; Sodium Channels/*physiology ; }, abstract = {Fasciculation is a characteristic feature of amyotrophic lateral sclerosis (ALS). The ectopic firing of motor units usually arises from the motor nerve terminals, and occasionally from the motor neurons, indicating a wide-spread abnormality in axonal excitability properties. ALS is a multi-factorial disease; some gene abnormalities and environmental factors lead to a cell death through a complex cascade, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. It is important to elucidate the pathophysiology of axonal excitability in ALS, because increased axonal excitability would enhance oxidative stress and excitotoxicity, and therefore contribute to motor neuronal death. So far, two kinds of axonal ion channel abnormalities have been found; (1) increased persistent sodium currents, and (2) reduced potassium currents, both increasing axonal excitability and responsible for generation of fasciculations. In excitability testing, findings in ALS are characterized prolonged strength-duration time constant, suggesting increased persistent sodium currents, and greater threshold changes in depolarizing threshold electrotonus and greater supernormality, suggestive of impaired potassium channels. In relation to disease stage, persistent sodium currents increase in the early phase of the disease, possibly associated with collateral sprouting, and then, potassium currents decline. These serial changes in axonal properties could provide new insights into the pathophysiology of ALS, and implications for future therapeutic options.}, }
@article {pmid17969350, year = {2007}, author = {Ono, S}, title = {[Skin changes in amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1099-1107}, pmid = {17969350}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/physiopathology ; Ciliary Neurotrophic Factor/metabolism/physiology ; Fibrillar Collagens/metabolism/physiology ; Glycosaminoglycans/metabolism/physiology ; Humans ; Immunohistochemistry ; Insulin-Like Growth Factor I/metabolism/physiology ; Neurotrophin 3/metabolism/physiology ; Skin/metabolism/*pathology/physiopathology ; Vascular Endothelial Growth Factor A/metabolism/physiology ; }, abstract = {It has been repeatedly noted, but never as yet fully explained, that patients with amyotrophic lateral sclerosis (ALS) do not develop bedsores even at the terminal stage. Furthermore, the skin of ALS patients feels supple, like tanned leather, and loses elasticity. When the skin is stretched, it returns only sluggishly to its original position. We termed this property of skin "delayed return phenomenon (DRP)"; it is usually seen more than 2.5 years after the onset of symptoms. Although it is thought that a phenomena such as DRP and the absence of bedsores are characteristic of this disease, little attention has been paid to these unique features in ALS patients. In this review we summarize recent developments in research on skin from ALS patients. From our own works cited in this review it is clear that not only the motor neuron but also the skin is affected in ALS, and that abnormalities of collagen, glycosaminoglycans, vascular endotherial growth factor (VEGF) and neurotrophic factors like ciliary neurotrophic factor (CNTF), neurotrophin-3 (NT-3) and insulin-like growth factor-1 (IGF-1) do occur in the skin of ALS. Examination of the skin in patients with ALS would be easy to carry out as an additional examination. Further analysis of the complex skin abnormalities will be useful in elucidating the basic pathological mechanism of ALS.}, }
@article {pmid17969349, year = {2007}, author = {Ishikawa, T and Morita, M and Nakano, I}, title = {[Brain perfusion imaging in amyotrophic lateral sclerosis with dementia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1093-1098}, pmid = {17969349}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/physiopathology ; *Cerebrovascular Circulation ; Humans ; Imaging, Three-Dimensional ; Regional Blood Flow ; Tomography, Emission-Computed, Single-Photon/*methods ; }, abstract = {Single photon emission computed tomography (SPECT) studies have been applied for evaluation of regional cerebral blood flow (rCBF) in various neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALS-D). Brain perfusion SPECT using statistical image analysis is useful for accurate and objective diagnosis to evaluate slight decreases in rCBF, even in cases difficult to assess by visual inspection. We have used statistical parametric mapping (SPM), three-dimensional stereotactic surface projection (3D-SSP), easy Z-score imaging system (eZIS) as statistical image analyses. ALS-D cases, even if a case manifests minimal mentality change, showed obvious rCBF reduction in the bilateral prefrontal area with some irregularity and laterality of its decrease. This abnormality was clear in ALS-D compared with classic ALS. Our study has demonstrated that brain perfusion SPECT imaging using statistical image analyses is quite useful as an adjunct to presume the existence of dementia in ALS, even if ALS patients have trouble in verbal or manual communication of the language because of progressive bulbar symptoms and muscle weakness. Thus, for ALS patients with any subtle signs and symptoms suggesting dementia, we recommend a SPECT study with use of statistical image analyses.}, }
@article {pmid17969348, year = {2007}, author = {Kawamura, M and Ichikawa, H and Koyama, S and Ishihara, K}, title = {[Amyotrophic lateral sclerosis with dementia-neuropsychological aspect].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1083-1091}, pmid = {17969348}, issn = {1881-6096}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/*psychology ; Atrophy ; Cognition ; Female ; Frontal Lobe/pathology ; Handwriting ; Humans ; Male ; Middle Aged ; *Neuropsychological Tests ; Speech ; Temporal Lobe/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) with dementia (ALS-D) is characterized clinically by frontal and neurological signs and symptoms, and pathologically by localized atrophy of front-temporal lobes and neuronal ubiquitin-positive inclusion. In this paper, we reviewed the neuropsychological findings of ALS-D. ALS-D is known to exhibit characteristics of fronto-temporal dementia. However, in clinical situations, it is often difficult to evaluate their cognitive functions due to impaired voluntary speech and physical disabilities. In order to identify characteristic and diagnostic cognitive symptoms of relatively advanced ALS-D patients, we reviewed the clinical features of recent studies of clinically definitive ALS Patients who had dementia, impaired voluntary speech, and physical disability. Their medical records showed that the patients made writing errors, and some of the patients demonstrated anosognosia. The writing errors of these cases consisted of paragraphia such as substitution, omission, or syntactic errors and individual differences in error types. We emphasize that aphasic writing errors have been underestimated, particularly in ALS-D patients with impaired voluntary speech. We also emphasize that anosognosia is one of the important symptoms in ALS-D. The relationship between writing errors and anosognosia should be investigated further.}, }
@article {pmid17969346, year = {2007}, author = {Kuzuhara, S}, title = {[Revisit to Kii ALS--the innovated concept of ALS-Parkinsonism-dementia complex, clinicopathological features, epidemiology and etiology].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1065-1074}, pmid = {17969346}, issn = {1881-6096}, mesh = {Amino Acids, Diamino/adverse effects ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/pathology/physiopathology ; Brain/pathology ; Cyanobacteria Toxins ; DNA-Binding Proteins ; *Dementia/epidemiology/etiology/pathology/physiopathology ; Humans ; Japan/epidemiology ; Minerals/metabolism ; Morbidity ; Mutation ; *Parkinsonian Disorders/epidemiology/etiology/pathology/physiopathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; tau Proteins ; }, abstract = {The high incidence of amyotrophic lateral sclerosis (ALS) in the residents of Hohara and Kozagawa in the Kii peninsula was reported to have disappeared by early 1980 with its etiology unsolved. However, we found continuous high incidence in Hohara that was neuropathologically characterized by ALS pathology associated with many neurofibrillar tangles (NFTs) similar to Guam ALS. We confirmed existence of neuropathologically-verified parkinsonism-dementia complex (PDC) identical to Guamanian PDC clinically and neuropathologically. The core clinical features consisted of motor neuron signs, parkinsonism and dementia, and patients presented with clinical manifestations of ALS, PDC or PDC followed by ALS. PDC predominated over ALS in incidence. Approximately 70% of patients had family history of ALS/PDC. Neuropathological findings of 12 cases revealed that they were very similar to each others, consisting of many NFTs, no or scanty amyloid plaques, and ALS pathology affecting the upper and lower motor neurons. These findings suggest that ALS and PDC may be different clinical manifestations of a single entity "ALS-parkinsonism-dementia complex". TDP-43 positive inclusions were seen in the neurons of the dentate gyrus and spinal cord in all 6 cases examined. A comparison of age-adjusted prevalence rates in 1967 and 1998 revealed moderate decline of ALS and marked increase of PDC in the latter. The age-adjusted 5-year average incidence rates during 1950 and 2000 showed gradual decline of ALS for 50 years and dramatic increase of PDC after 1990. These findings suggest that the clinical manifestations may have changed in Kii ALS/PDC as in ALS/PDC on Guam, partly because of rapid aging of the population. Gene analyses have so far failed to demonstrate mutations of SOD1, parkin, alpha-synuclein, tau, progranulin, TDP-43 and other genes related to dementia, parkinsonism and motor neuron disease. There have been no differences in drinking water and food between the residents in the high incidence area and those in the neighboring low incidence areas, and none of the patients had habits of eating the cycad, flying fox or any other odd materials. These findings suggest that genetic factors may be etiologically primary and environmental factors may modify the clinical phenotypes.}, }
@article {pmid17969345, year = {2007}, author = {Iwata, NK}, title = {[Objective markers for upper motor neuron involvement in amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1053-1064}, pmid = {17969345}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology ; Biomarkers ; Diffusion Magnetic Resonance Imaging ; Early Diagnosis ; Humans ; Magnetic Resonance Spectroscopy ; Motor Neurons/*pathology/physiology ; Neural Conduction ; Pyramidal Tracts/pathology/*physiopathology ; Transcranial Magnetic Stimulation ; }, abstract = {A reliable objective marker of upper motor neuron (UMN) involvement is critical for early diagnosis and monitoring disease course in patients with amyotrophic lateral sclerosis (ALS). Lower motor neuron (LMN) involvement can be identified by electromyography, whereas UMN dysfunction has been currently distinguished solely by neurological examination. In the search for diagnostic tests to evaluate UMN involvement in ALS, numerous reports on new markers using neurophysiological and imaging techniques are accumulating. Transcranial magnetic stimulation evaluates the neurophysiological integrity of UMN. Although the diagnostic reliability and sensitivity of various parameters of central motor conduction measurement differ, central motor conduction time measurement using brainstem stimulation is potentially useful for determining UMN dysfunction by distinguishing lesions above the pyramidal decussation. MR-based techniques also have the potential to be used as diagnostic markers and are continuously improving as a modality to pursue early diagnosis and monitoring of the disease progression. Conventional MRI reveals hyperintensity along the corticospinal tract, hypointensity in the motor cortex, and atrophy of the precentral gyrus. There is a lack of agreement regarding sensitivity and specificity in detecting UMN abnormalities. Recent advances in magnetizing transfer imaging (MTI) provide more sensitive and accurate detection of corticospinal tract abnormality than conventional MRI. Reduction in N-acetyl-aspartate by proton magnetic spectroscopy in the motor cortex or the brainstem of the patients with ALS is reported with different techniques. Its diagnostic value in clinical assessment is uncertain and remains to be established. Diffusion tensor imaging (DTI) reveals the structural integrity of neuronal fibers, and has great diagnostic promise for ALS. It shows reduced diffusion anisotropy in the corticospinal tract with good correlation with physiological index, reflecting UMN pathology. Diffusion tensor tractography allows for visualization and evaluation of corticospinal and corticobulbar tract dysfunction individually in patients with ALS. Although many of these new approaches do not yet reach clinical significance, they have been extensively explored in objective evaluation of upper motor function in patients with ALS. Further investigation is needed to determine and to compare the utility of various neurophysiological and neuroimaging markers.}, }
@article {pmid17969344, year = {2007}, author = {Naito, Y}, title = {[Motor unit number estimation in motor neuron disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1043-1052}, pmid = {17969344}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Axons/*pathology/physiology ; Biomarkers ; Electrophysiology/*methods ; Humans ; Muscle, Skeletal/innervation ; }, abstract = {Motor unit number estimation (MUNE) is a special electrophysiologic technique that can provide a numeric estimate of the number of axons innervating a muscle or group of muscles. Since 1971, many investigators have suggested methods for making such a measurement; the lack of general acceptance of a single method points to both theoretical and practical problems inherent in all techniques so far proposed. MUNE consists of a number of different methods, with each having specific advantages and limitations. This review will briefly describe the available MUNE methods, the incremental, multiple point stimulation, spike-triggered averaging, F-wave, and statistical methods, including models of muscles that allow evaluation of MUNE techniques and comparisons between techniques. In addition, MUNE data relating to motor neuron disease especially ALS will be discussed. Despite the lack of a perfect single method for performing MUNE, it has great clinical value in the assessment of progressive motor axon loss in ALS. Further refinements in the method will likely increase its utility in the future. Modifications to MUNE techniques have been offered that permit more rapid acquisition of data. There is now more experience with MUNE as endpoint measures in clinical trials.}, }
@article {pmid17969343, year = {2007}, author = {Higashihara, M and Sonoo, M}, title = {[Electrodiagnosis of ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1031-1041}, pmid = {17969343}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Diagnosis, Differential ; Disease Progression ; Early Diagnosis ; *Electrodiagnosis/methods ; Electromyography/methods ; Humans ; Membrane Potentials ; Neural Conduction ; Reference Standards ; }, abstract = {Electrodiagnostic methods play important roles for the diagnosis and evaluation of ALS. They are useful for 1) the early establishment of the diagnosis, 2) the differential diagnosis, and 3) the quantitative evaluation of the progression. Needle electromyography reveals active neurogenic changes over the wide territories of the body. Fibrillation potentials and positive sharp waves indicate presence of denervated fibers. However, they are not specific for ALS or even neurogenic process, and widespread occurrence of fibrillations are also characteristic for myositis and inclusion body myositis (IBM). Fasciculation potentials are spontaneous firing of the lower motor neuron and most of them are supposed to arise from the nerve endings. Fasciculation potentials are seen solely in neurogenic process and sufficiently specific for ALS. Its diagnostic role, especially in the early diagnosis, has been stressed by several researchers, including the present authors (Sonoo 1996), and fasciculation potentials will be given the same significance as fibrillation potentials in the coming Awaji criteria for the diagnosis of ALS. Motor unit potentials (MUPs) in ALS often show polyphasia and instability reflecting the presence of immature sprouts. Unstable MUPs (increased jiggle) are counterparts of instability in SFEMG. Giant MUPs are frequent, but low amplitude MUPs may be also observed in rapidly progressing cases. Observation of the recruitment pattern is crucial for the differential diagnosis from myopathies. Nerve conduction studies are important for the exclusion of other diagnoses, especially multifocal motor neuropathy (MMN). Some degree of slowing and disappearance of F-waves can occur simply due to loss of motor units. The utility of Neurophsiological Index remains to be confirmed. Repetitive nerve stimulation often reveals decremental responses, whose presence supports the diagnosis of ALS. Decremental responses in ALS usually occur in wasted muscles with low CMAP amplitude, and may predict the speed of further deterioration of the CMAP.}, }
@article {pmid17969342, year = {2007}, author = {Nodera, H and Izumi, Y and Kaji, R}, title = {[New diagnostic criteria of ALS (Awaji criteria)].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1023-1029}, pmid = {17969342}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Early Diagnosis ; Electrodiagnosis/standards ; Humans ; Reference Standards ; }, abstract = {Several diagnostic criteria for amyotrophic lateral sclerosis (ALS) exist, namely, Lambert criteria and revised E1 Escorial criteria, however, these criteria may not be useful in diagnosing early ALS. It may be possible that clinical trials in humans for ALS have been mostly unsuccessful because of inclusion of only advanced patients meeting such "tight" criteria. In December 2006, researchers around the globe met in Awaji Island, Japan to discuss about proposing the new ALS criteria (Awaji criteria) to facilitate detection of ALS in an early stage.}, }
@article {pmid17969341, year = {2007}, author = {Sasaki, S}, title = {[Phenotypes in ALS--clinical features and pathology].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1013-1021}, pmid = {17969341}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/classification/diagnosis/etiology/pathology ; Diagnosis, Differential ; Humans ; *Phenotype ; }, abstract = {Typical amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) is not hard to diagnose, but when it comes to atypical forms of MND which account for about 20% in clinical setting, we may face some difficulties in differentiating clearly between atypical forms of ALS/MND and other non-ALS diseases, such as multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy and cervical spondylosis. There is striking phenotypic variation in sporadic ALS/MND, i.e. flail arm syndrome (brachial amyotrophic diplegia), pseudopolyneuritic form, hemiplegic type, ALS/MND with markedly extended involvement beyond the motor system, MND with basophilic inclusion bodies, spinal progressive muscular atrophy, primary lateral sclerosis, progressive bulbar palsy and motor neuron disease with dementia. These variations must be recognized when physicians are to tailor advice on disease progression, prognosis, drug therapy, and care to the needs of the individual. Clinical trials of new therapeutic agents have been performed, on the assumption that patients with ALS/MND have the same underlying etiology, addressing the heterogeneous population of the patients under a single diagnostic category. This can be detrimental to the well-being of the individual, because clinical heterogeneity may mask drug effects in clinical trials. The attempt to categorize subgroups based on the clinical and pathological background within the spectrum of ALS/MND may be a critical step in facilitating clinical research in ALS/MND. Definition of clinicopathologic syndromes in patients with ALS/MND is an important challenging task. It will be necessary to accumulate motor neuron disease cases with phenotypic variation and analyze them clinically and pathologically to elucidate whether various kinds of subgroups of motor neuron diseases lie on the same spectrum of ALS.}, }
@article {pmid17965655, year = {2007}, author = {Lobsiger, CS and Cleveland, DW}, title = {Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease.}, journal = {Nature neuroscience}, volume = {10}, number = {11}, pages = {1355-1360}, pmid = {17965655}, issn = {1097-6256}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; R37 NS027036-22/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Humans ; Models, Biological ; Neurodegenerative Diseases/genetics/*pathology/physiopathology ; Neuroglia/cytology/*physiology ; }, abstract = {A lesson from dominantly inherited forms of diverse neurodegenerative diseases, including amyotrophic lateral sclerosis, spinocerebellar ataxia and Huntington's disease, is that the selective dysfunction or death of the neuronal population most at risk in each disease is not mediated solely by damage from the mutant protein within the target neurons. The disease-causing toxic process, which in each case is caused by mutation in a gene that is widely or ubiquitously expressed, involves damage done by mutant proteins within the non-neuronal glial cells of the central nervous system, especially astrocytes and microglia. The disease mechanism is non-cell-autonomous, with toxicity derived from glia as a prominent contributor driving disease progression and in some instances even disease initiation.}, }
@article {pmid17957689, year = {2007}, author = {Holzgrabe, U}, title = {[An old drug as a carcinostatic. The new career of thalidomide].}, journal = {Pharmazie in unserer Zeit}, volume = {36}, number = {6}, pages = {446-449}, doi = {10.1002/pauz.200700241}, pmid = {17957689}, issn = {0048-3664}, mesh = {Angiogenesis Inhibitors/pharmacology/therapeutic use ; Antineoplastic Agents/pharmacology/*therapeutic use ; Erythema Nodosum/drug therapy ; Humans ; Immunologic Factors/pharmacology/therapeutic use ; Multiple Myeloma/drug therapy ; Myelodysplastic Syndromes/drug therapy ; Thalidomide/pharmacology/*therapeutic use ; }, abstract = {Thalidomid hat eine wechselhafte Geschichte; anfangs als Schlafmittel wegen seiner teratogenen Wirksamkeit verpönt, hat es in der Behandlung des Erythema nodosum leprosum schon seit fast zehn Jahren seinen festen Platz. In den beiden letzten Jahren konnte in Klinischen Studien seine Bedeutung in der Therapie des Multiplen Myeloms und des Myelodysplastischen Syndroms nachgewiesen werden. Eines ist geblieben: Auf Grund der Teratogenität ist eine Schwangerschaft eine absolute Kontraindikation.}, }
@article {pmid17956327, year = {2007}, author = {Wilkerson, JE and Macfarlane, PM and Hoffman, MS and Mitchell, GS}, title = {Respiratory plasticity following intermittent hypoxia: roles of protein phosphatases and reactive oxygen species.}, journal = {Biochemical Society transactions}, volume = {35}, number = {Pt 5}, pages = {1269-1272}, doi = {10.1042/BST0351269}, pmid = {17956327}, issn = {0300-5127}, support = {HL 80209/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Hypoxia/*physiopathology ; *Neuronal Plasticity ; Phosphoprotein Phosphatases/*metabolism ; Reactive Oxygen Species/*metabolism ; *Respiration ; }, abstract = {Plasticity is an important property of the respiratory control system. One of the best-studied models of respiratory plasticity is pLTF (phrenic long-term facilitation). pLTF is a progressive increase in phrenic motor output lasting several hours following acute exposure to intermittent hypoxia. Similar to many other forms of neuroplasticity, pLTF is pattern-sensitive; it is induced by intermittent, but not sustained hypoxia of similar cumulative duration. Our understanding of the cellular/synaptic mechanisms underlying pLTF has increased considerably in recent years. Here, we review accumulating evidence suggesting that the pattern-sensitivity of pLTF arises substantially from differential reactive oxygen species formation and subsequent protein phosphatase inhibition during intermittent compared with sustained hypoxia in or near phrenic motor neurons. A detailed understanding of the cellular/synaptic mechanisms of pLTF may provide the rationale for new pharmacological approaches in the treatment of severe ventilatory control disorders, such as obstructive sleep apnoea and respiratory insufficiency either following spinal cord injury or during neurodegenerative diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid17956319, year = {2007}, author = {Baron, M and Kudin, AP and Kunz, WS}, title = {Mitochondrial dysfunction in neurodegenerative disorders.}, journal = {Biochemical Society transactions}, volume = {35}, number = {Pt 5}, pages = {1228-1231}, doi = {10.1042/BST0351228}, pmid = {17956319}, issn = {0300-5127}, mesh = {Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/*physiopathology ; }, abstract = {There is compelling evidence for the direct involvement of mitochondria in certain neurodegenerative disorders, such as Morbus Parkinson, FRDA (Friedreich's ataxia), ALS (amyotrophic lateral sclerosis), and temporal lobe epilepsy with Ammon's horn sclerosis. This evidence includes the direct genetic evidence of pathogenic mutations in mitochondrial proteins in inherited Parkinsonism {such as PARK6, with mutations in the mitochondrial PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1]} and in FRDA (with mutations in the mitochondrial protein frataxin). Moreover, there is functional evidence of impairment of the respiratory chain in sporadic forms of Parkinsonism, ALS, and temporal lobe epilepsy with Ammon's horn sclerosis. In the sporadic forms of the above-mentioned neurodegenerative disorders, increased oxidative stress appears to be the crucial initiating event that affects respiratory chain function and starts a vicious cycle finally leading to neuronal cell death. We suggest that the critical factor that determines the survival of neurons in neurodegenerative disorders is the degree of mitochondrial DNA damage and the maintenance of an appropriate mitochondrial DNA copy number. Evidence for a depletion of intact copies of the mitochondrial genome has been provided in all above-mentioned neurodegenerative disorders including ALS and temporal lobe epilepsy with Ammon's horn sclerosis. In the present study, we critically review the available data.}, }
@article {pmid17955197, year = {2007}, author = {Chandran, J and Ding, J and Cai, H}, title = {Alsin and the molecular pathways of amyotrophic lateral sclerosis.}, journal = {Molecular neurobiology}, volume = {36}, number = {3}, pages = {224-231}, pmid = {17955197}, issn = {0893-7648}, support = {Z01 AG000959-04/ImNIH/Intramural NIH HHS/United States ; Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Guanine Nucleotide Exchange Factors/chemistry/*genetics ; Humans ; Mice ; Mice, Knockout ; Models, Molecular ; Motor Neuron Disease/*genetics ; Motor Neurons/*physiology ; Mutation ; Polymorphism, Single Nucleotide ; Protein Conformation ; Sequence Deletion ; Spastic Paraplegia, Hereditary/*genetics ; }, abstract = {Autosomal recessive mutations in the ALS2 gene lead to a clinical spectrum of motor dysfunction including juvenile onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis, and hereditary spastic paraplegia. The 184-kDa alsin protein, encoded by the full-length ALS2 gene, contains three different guanine-nucleotide-exchange factor-like domains, which may play a role in the etiology of the disease. Multiple in vitro biochemical and cell biology assays suggest that alsin dysfunction affects endosome trafficking through a Rab5 small GTPase family-mediated mechanism. Four ALS2-deficient mouse models have been generated by different groups and used to study the behavioral and pathological impact of alsin deficiency. These mouse models largely fail to recapitulate hallmarks of motor neuron disease, but the subtle deficits that are observed in behavior and pathology have aided in our understanding of the relationship between alsin and motor dysfunction. In this review, we summarize recent clinical and molecular reports regarding alsin and attempt to place these results within the larger context of motor neuron disease.}, }
@article {pmid17945153, year = {2007}, author = {Phukan, J and Pender, NP and Hardiman, O}, title = {Cognitive impairment in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {6}, number = {11}, pages = {994-1003}, doi = {10.1016/S1474-4422(07)70265-X}, pmid = {17945153}, issn = {1474-4422}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Cognition Disorders/diagnosis/epidemiology/*etiology/psychology ; Dementia/etiology ; Humans ; Incidence ; Neuropsychological Tests ; Prevalence ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that has sporadic and inherited forms. ALS is the most common neurodegenerative disorder of young and middle-aged adults, and few treatments are available. Although the degeneration predominantly affects the motor system, cognitive and behavioural symptoms have been described for over a century, and there is evidence that ALS and frontotemporal dementia overlap clinically, radiologically, pathologically, and genetically. Cognitive decline in ALS is characterised by personality change, irritability, obsessions, poor insight, and pervasive deficits in frontal executive tests. This presentation is consistent with the changes to character, social conduct, and executive function in frontotemporal dementia. We highlight genetic, imaging, and neuropathological evidence that non-motor systems are affected in ALS and explain the importance of recent discoveries. We review studies of cognitive impairment in ALS and common neuropsychological test results. We also provide advice about clinical assessment of frontotemporal dysfunction in patients with ALS, and suggest future research. Understanding of cognitive impairment in ALS will improve care for patients and their families and provide valuable insights into the pathogenesis of neurodegeneration.}, }
@article {pmid17943766, year = {2007}, author = {Mitchell, JD and Wokke, JH and Borasio, GD}, title = {Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD002064}, doi = {10.1002/14651858.CD002064.pub2}, pmid = {17943766}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Randomized Controlled Trials as Topic ; Recombinant Proteins/therapeutic use ; }, abstract = {BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I (rhIGF-I) are possible disease modifying therapies for amyotrophic lateral sclerosis.<br><br>OBJECTIVES: To examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (March 2006), MEDLINE (January 1966 to March 2006) and EMBASE (January 1980 to March 2006) and asked the authors of randomised clinical trials and manufacturers of recombinant human insulin-like growth factor I.<br><br>SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of amyotrophic lateral sclerosis in adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified three randomised clinical trials. Only two were included in the analysis. Each author graded the studies for methodological quality. Data were extracted and entered by the lead author and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs.<br><br>MAIN RESULTS: In a European trial with 59 participants on placebo and 124 on rhIGF-I, 0.1 mg/kg/day the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08), non-significantly less in the treated than the placebo group. In a North American trial, in which 90 participants on placebo were compared with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day, and 87 participants on 0.1 mg/kg/day, the MD after nine months was -6.00 (95%CI -10.99 to -1.01), significantly less on treatment. The combined analysis from both randomised clinical trials showed a weighted mean difference after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. Similarly the data with the 0.05 mg/kg/day dose showed trends favouring rhIGF-I at all time points but did not reach significance at the five per cent level at any point. There was an increased risk of injection site reactions with rhIGF-I (relative risk 2.53, 95% CI 1.40 to 4.59).<br><br>AUTHORS' CONCLUSIONS: The available randomised placebo controlled trials do not permit a definitive assessment of the clinical efficacy of rhIGF-I on ALS. More research is needed and one trial is in progress. Future trials should include survival as an outcome measure.}, }
@article {pmid17937892, year = {2007}, author = {Rasouri, S and Lagouge, M and Auwerx, J}, title = {[SIRT1/PGC-1: a neuroprotective axis?].}, journal = {Medecine sciences : M/S}, volume = {23}, number = {10}, pages = {840-844}, doi = {10.1051/medsci/20072310840}, pmid = {17937892}, issn = {0767-0974}, mesh = {Acetylation ; Amyloid beta-Peptides/metabolism ; Animals ; Cells, Cultured/drug effects ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mitochondria/*physiology ; Neurodegenerative Diseases/metabolism/*physiopathology/prevention &amp; control ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Protein Processing, Post-Translational/drug effects ; Reactive Oxygen Species ; Resveratrol ; Sirtuin 1 ; Sirtuins/genetics/*physiology ; Stilbenes/pharmacology/therapeutic use ; Transcription Factors/deficiency/genetics/*physiology ; Transcriptional Activation ; }, abstract = {Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.}, }
@article {pmid17934327, year = {2007}, author = {Fischer, LR and Glass, JD}, title = {Axonal degeneration in motor neuron disease.}, journal = {Neuro-degenerative diseases}, volume = {4}, number = {6}, pages = {431-442}, doi = {10.1159/000107704}, pmid = {17934327}, issn = {1660-2854}, mesh = {Animals ; Axons/*pathology ; Disease Models, Animal ; Humans ; Mice ; Mice, Knockout ; Motor Neuron Disease/*pathology/*physiopathology ; Nerve Degeneration/*etiology/*pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Growing evidence from animal models and patients with amyotrophic lateral sclerosis (ALS) suggests that distal axonal degeneration begins very early in this disease, long before symptom onset and motor neuron death. The cause of axonal degeneration is unknown, and may involve local axonal damage, withdrawal of trophic support from a diseased cell body, or both. It is increasingly clear that axons are not passive extensions of their parent cell bodies, and may die by mechanisms independent of cell death. This is supported by studies in which protection of motor neurons in models of ALS did not significantly improve symptoms or prolong lifespan, likely due to a failure to protect axons. Here, we will review the evidence for early axonal degeneration in ALS, and discuss possible mechanisms by which it might occur, with a focus on oxidative stress. We contend that axonal degeneration may be a primary feature in the pathogenesis of motor neuron disease, and that preventing axonal degeneration represents an important therapeutic target that deserves increased attention.}, }
@article {pmid17785693, year = {2007}, author = {Rosenfeld, RG}, title = {Pharmacogenomics and pharmacoproteomics in the evaluation and management of short stature.}, journal = {European journal of endocrinology}, volume = {157 Suppl 1}, number = {}, pages = {S27-31}, doi = {10.1530/EJE-07-0186}, pmid = {17785693}, issn = {0804-4643}, mesh = {*Body Height ; *Genomics ; Growth Disorders/*diagnosis/*drug therapy ; Humans ; *Pharmacogenetics ; *Proteomics ; }, abstract = {It has long been recognized that growth failure encompasses a diverse spectrum of underlying pathophysiological processes, a characteristic that has significantly impacted both the diagnosis and management of growth disorders. This problem is exacerbated by inherent difficulty in distinguishing the borders between the 'normal range' for stature and defined abnormal growth. Evaluation of GH secretion has proven problematic, both diagnostically and prognostically, except in cases of unequivocal GH deficiency. Measurement of serum concentrations of IGF-I, IGFBP-3, and ALS have proven useful in the assessment of GH responsiveness and have contributed to the concept of primary and secondary 'IGF deficiency'. Nevertheless, there is great need for biochemical and/or molecular biomarkers that could: i) predict short- and long-term responsiveness to various therapeutic modalities, such as GH and IGF-I, and ii) predict potential risk for adverse effects of therapy. Candidate proteins and genes identified to date, and worthy of further evaluation, include IGF-I, IGF-I receptor, GH receptor and its variants (such as exon 3-deleted GHR), STAT5b and short stature homeobox. Proteomic analysis of serum samples pre- and post-treatment and correlation with clinical responsiveness should provide additional candidate biomarkers. Molecular studies to consider include: i) sequencing and mutation analysis of known genetic components of the GH-IGF axis; ii) evaluation of single nucleotide polymorphisms of candidate genes; and iii) identification of new candidate genes. It is proposed that the major target population to study is that of children currently labeled as idiopathic short stature (ISS). These children can be divided into those with: i) primary IGFD, where the focus should be on genes related to GHR, GHR signaling, and IGF-I gene expression, or ii) no IGFD (i.e. 'true ISS'), where the focus should be on genes related to IGFR, IGF signaling and epiphyseal growth.}, }
@article {pmid17923623, year = {2007}, author = {Neumann, M and Kwong, LK and Sampathu, DM and Trojanowski, JQ and Lee, VM}, title = {TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis.}, journal = {Archives of neurology}, volume = {64}, number = {10}, pages = {1388-1394}, doi = {10.1001/archneur.64.10.1388}, pmid = {17923623}, issn = {0003-9942}, support = {AG10124/AG/NIA NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; T32 AG00255/AG/NIA NIH HHS/United States ; }, mesh = {Amyloidosis/*pathology ; Amyotrophic Lateral Sclerosis/classification/diagnosis/*pathology ; DNA-Binding Proteins/*physiology ; Dementia/classification/diagnosis/*pathology ; Humans ; Phosphorylation ; Protein Folding ; Ubiquitin/metabolism ; }, }
@article {pmid17917848, year = {2007}, author = {Ionov, ID}, title = {Survey of ALS-associated factors potentially promoting Ca2+ overload of motor neurons.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {5}, pages = {260-265}, doi = {10.1080/17482960701523124}, pmid = {17917848}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*pathology/*physiopathology ; Brain Chemistry/physiology ; Calcium/*metabolism ; Cell Death ; Cerebral Cortex/physiopathology ; Humans ; Motor Neurons/*metabolism ; Neurotransmitter Agents/cerebrospinal fluid ; Receptors, Glutamate/physiology ; }, abstract = {The deleterious consequences of Ca(2+) overload are thought to be a probable cause of motoneuronal death in ALS, although the overloading mechanism is currently unclear. In this paper some ALS-linked factors are analysed with regard to their influence on Ca(2+)influx into neurons. Intensive cortex activity can render motor neurons susceptible to stimulation of calcium-permeable glutamate NMDA-receptors; increase in CSF concentrations of glutamate, glycine, and norepinephrine supposedly can intensify these receptors' activity. Elevated CSF levels of GABA and reduced levels of serotonin can promote Ca(2+)influx through glutamate AMPA-receptors and voltage-gated channels of L-, N-, and P-type. Additionally, brain ischaemia can contribute to Ca(2+)overload of motor neurons. Thus, ALS is characterized by the unique combination of factors potentially able to promote the overload of motor neurons with calcium.}, }
@article {pmid17917581, year = {2007}, author = {Chu, CT and Plowey, ED and Wang, Y and Patel, V and Jordan-Sciutto, KL}, title = {Location, location, location: altered transcription factor trafficking in neurodegeneration.}, journal = {Journal of neuropathology and experimental neurology}, volume = {66}, number = {10}, pages = {873-883}, pmid = {17917581}, issn = {0022-3069}, support = {R01 NS041202/NS/NINDS NIH HHS/United States ; NS053777/NS/NINDS NIH HHS/United States ; R21 NS053777-02/NS/NINDS NIH HHS/United States ; NS41202/NS/NINDS NIH HHS/United States ; R01 NS040817/NS/NINDS NIH HHS/United States ; R01 NS041202-07/NS/NINDS NIH HHS/United States ; R21 NS053777/NS/NINDS NIH HHS/United States ; NS040817/NS/NINDS NIH HHS/United States ; AG026389/AG/NIA NIH HHS/United States ; R01 AG026389-01A2/AG/NIA NIH HHS/United States ; R01 NS040817-04/NS/NINDS NIH HHS/United States ; R01 AG026389/AG/NIA NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/genetics/physiology ; Animals ; Cytoplasm/metabolism/physiology ; Humans ; Nerve Degeneration/drug therapy/*physiopathology ; Neurons/metabolism/physiology ; Oxidative Stress/physiology ; Transcription Factors/*physiology ; }, abstract = {Neurons may be particularly sensitive to disruptions in transcription factor trafficking. Survival and injury signals must traverse dendrites or axons, in addition to soma, to affect nuclear transcriptional responses. Transcription factors exhibit continued nucleocytoplasmic shuttling; the predominant localization is regulated by binding to anchoring proteins that mask nuclear localization/export signals and/or target the factor for degradation. Two functional groups of karyopherins, importins and exportins, mediate RanGTPase-dependent transport through the nuclear pore. A growing number of recent studies, in Alzheimer, Parkinson, and Lewy body diseases, amyotrophic lateral sclerosis, and human immunodeficiency virus encephalitis, implicate aberrant cytoplasmic localization of transcription factors and their regulatory kinases in degenerating neurons. Potential mechanisms include impaired nuclear import, enhanced export, suppression of degradation, and sequestration in protein aggregates or organelles and may reflect unmasking of alternative cytoplasmic functions, both physiologic and pathologic. Some "nuclear" factors also function in mitochondria, and importins are also involved in axonal protein trafficking. Detrimental consequences of a decreased nuclear to cytoplasmic balance include suppression of neuroprotective transcription mediated by cAMP- and electrophile/antioxidant-response elements and gain of toxic cytoplasmic effects. Studying the pathophysiologic mechanisms regulating transcription factor localization should facilitate strategies to bypass deficits and restore adaptive neuroprotective transcriptional responses.}, }
@article {pmid17917110, year = {2007}, author = {Charbonnier, F}, title = {Exercise-induced neuroprotection in SMA model mice: a means for determining new therapeutic strategies.}, journal = {Molecular neurobiology}, volume = {35}, number = {3}, pages = {217-223}, pmid = {17917110}, issn = {0893-7648}, mesh = {Animals ; *Exercise ; Humans ; Mice ; Mice, Inbred Strains ; Motor Neurons/physiology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuromuscular Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*therapeutic use ; Signal Transduction/physiology ; }, abstract = {Due to the prevalence of neuromuscular disorders such as amyotrophic lateral sclerosis and spinal muscular atrophy in modern societies, defining new and efficient strategies for the treatment of these two neurodegenerative diseases has become a vital and still unfulfilled urge. Several lines of experimental evidence have emphasized the benefits of regular exercise training in mouse models for these affections in terms of life span increase and improvement of both motor capacities and motoneuron survival. Identifying molecules that could mimic the neuroprotective effects of exercise represents a promising way to find novel therapies. Some of the effects of exercise are caused by the overproduction of circulating neurotrophic factors, such as IGF-I, whereas others may be due to modifications of the intrinsic properties of the motoneurons within the spinal cord. The causal relationship that links these potential effects of exercise training and the improvement of motor capacity and life span expectancy is consequently discussed.}, }
@article {pmid17911221, year = {2007}, author = {Villmann, C and Becker, CM}, title = {On the hypes and falls in neuroprotection: targeting the NMDA receptor.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {13}, number = {6}, pages = {594-615}, doi = {10.1177/1073858406296259}, pmid = {17911221}, issn = {1073-8584}, mesh = {Animals ; Humans ; Models, Neurological ; Neurodegenerative Diseases/*drug therapy/pathology ; Neuronal Plasticity/*drug effects/physiology ; Neurons/drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; Receptors, N-Methyl-D-Aspartate/*physiology ; }, abstract = {Activation of the NMDA (N-methyl-D-aspartate) responsive subclass of glutamate receptors is an important mechanism of excitatory synaptic transmission. Moreover, NMDA receptors are widely involved in many forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to underlie complex tasks, including learning and memory. Dysfunction of these ligand-gated cation channels has been identified as an underlying molecular mechanism in neurological disorders ranging from acute stroke to chronic neurodegeneration in amyotrophic lateral sclerosis. Excessive glutamate levels have been detected following brain trauma and cerebral ischemia, resulting in an unregulated stimulation of NMDA receptors. These conditions are thought to elicit a cascade of excitation-mediated neuronal damage where massive increases in intracellular calcium concentrations finally trigger neuronal damage and apoptosis. Consistent with the hypothesis of NMDA receptors as essential mediators of excitotoxicity, the different functional domains of these ion channels have been identified as potential targets for neuroprotective agents. Following an initial hype on potential NMDA receptor therapeutics, the authors currently see a period of skepticism that, in reverse, appears to neglect the therapeutic potential of this receptor class. This review attempts a reappraisal of this important class of neurotransmitter receptors, with a focus on NMDA receptor heterogeneity, ligand binding domains, and candidate diseases for a potential neuroprotective therapy.}, }
@article {pmid17911166, year = {2007}, author = {Schymick, JC and Talbot, K and Traynor, BJ}, title = {Genetics of sporadic amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {16 Spec No. 2}, number = {}, pages = {R233-42}, doi = {10.1093/hmg/ddm215}, pmid = {17911166}, issn = {0964-6906}, support = {//Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Aryldialkylphosphatase/genetics ; Cyclic AMP Response Element-Binding Protein/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Dynactin Complex ; Endosomal Sorting Complexes Required for Transport ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/genetics ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intermediate Filament Proteins/genetics ; Membrane Glycoproteins/genetics ; Membrane Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Nerve Degeneration/genetics ; Nerve Tissue Proteins/genetics ; Neurofilament Proteins/genetics ; Peripherins ; Progranulins ; RNA-Binding Proteins/genetics ; Ribonuclease, Pancreatic/genetics ; SMN Complex Proteins ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration.}, }
@article {pmid17908040, year = {2007}, author = {Tweedie, D and Sambamurti, K and Greig, NH}, title = {TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets.}, journal = {Current Alzheimer research}, volume = {4}, number = {4}, pages = {378-385}, doi = {10.2174/156720507781788873}, pmid = {17908040}, issn = {1567-2050}, support = {R01 AG023055-04/AG/NIA NIH HHS/United States ; R01 AG023055/AG/NIA NIH HHS/United States ; R01 AG023055-05/AG/NIA NIH HHS/United States ; R01 AG023055-03/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; R01 AG023055-01A1/AG/NIA NIH HHS/United States ; R01 AG023055-02/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Enzyme Inhibitors/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Tumor Necrosis Factor-alpha/physiology/*therapeutic use ; }, abstract = {As the average ages of North Americans and Europeans continue to rise; similarly the incidence of "old age" associated illnesses likewise increases. Most notably among these ailments are conditions linked to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. While in the early stages, these conditions are associated with cellular dysfunction in distinctly different brain regions, thus affecting different neuronal cell types; it is most likely that the final stages share similar cellular and molecular processes leading to neuronal death and ultimately overt clinical symptoms. In this regard, different environmental and genetic triggers ranging from head trauma to protein mutations and toxicological exposure may instigate a cascade of intracellular events that ultimately lead to neuronal death. One strong candidate trigger protein, and thus a potential target for therapeutic manipulation is the potent pro-inflammatory / pro-apoptotic cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is secreted by the brain resident marcophage (the microglial cell) in response to various stimuli. It has been demonstrated to play a major role in central nervous system (CNS) neuroinflammation-mediated cell death in AD, PD and amyotrophic lateral sclerosis (ALS) as well as several other CNS complications. Recently, agents that modulate the levels of circulating peripheral TNF-alpha protein have been shown to be worthwhile therapeutic agents with the use of Enbrel (Etanercept) and Remicade (Infliximab), both of which display beneficial properties against rheumatoid arthritis and other peripheral inflammatory diseases. Unfortunately, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in the setting of neuroinflammation in the CNS. However, thalidomide, a small molecule drug, can inhibit TNF-alpha protein synthesis and, unlike larger molecules, is readily capable of crossing the blood-brain barrier. Thus thalidomide and its analogs are excellent candidate agents for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases underpinned by inflammation within the nervous system. Consequently, we have chosen to discuss the relevance of unregulated TNF-alpha expression in illnesses of the CNS and, to an extent, the peripheral nervous system. Additionally, we consider the utilization of thalidomide-derived agents as anti-TNF-alpha therapeutics in the setting of neuroinflammation.}, }
@article {pmid17901552, year = {2007}, author = {Liang, X and Wu, L and Wang, Q and Hand, T and Bilak, M and McCullough, L and Andreasson, K}, title = {Function of COX-2 and prostaglandins in neurological disease.}, journal = {Journal of molecular neuroscience : MN}, volume = {33}, number = {1}, pages = {94-99}, pmid = {17901552}, issn = {0895-8696}, support = {AG15799/AG/NIA NIH HHS/United States ; NS045727/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cyclooxygenase 2/*metabolism ; Humans ; Nervous System Diseases/*metabolism ; Prostaglandins/*metabolism ; Receptors, Prostaglandin E/metabolism ; Receptors, Prostaglandin E, EP2 Subtype ; }, abstract = {Induction of COX-2 expression and enzymatic activity promotes neuronal injury in a number of models of neurological disease. Inhibition of COX-2 activity, either genetically or pharmacologically, has been shown to be neuroprotective in rodent models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Inhibition of COX activity with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces inflammation and amyloid accumulation in murine transgenic models of Familial Alzheimer's disease, and the use of NSAIDs decreases the risk of developing Alzheimer's disease in healthy aging populations. COX-mediated neuronal injury is presumed be due to downstream effects of one or more prostaglandin products including PGE2, PGD2, PGF2alpha, PGI2 (prostacylin) and TXA2 (thromboxane) that effect cellular changes through activation of specific prostaglandin receptor subtypes and second messenger systems. In this proceeding, we review recent data demonstrating effects of prostaglandin signaling on neuronal viability that are paradoxically protective, when taken in the context that COX-2 induces neuronal injury in the setting of excitotoxicity. Conversely, in the context of an inflammatory stimulus, the EP2 receptor enhances neuronal injury. These findings argue for an additional level of complexity in the prostaglandin response in neurological disease.}, }
@article {pmid17897390, year = {2007}, author = {Hedlund, E and Hefferan, MP and Marsala, M and Isacson, O}, title = {Cell therapy and stem cells in animal models of motor neuron disorders.}, journal = {The European journal of neuroscience}, volume = {26}, number = {7}, pages = {1721-1737}, doi = {10.1111/j.1460-9568.2007.05780.x}, pmid = {17897390}, issn = {0953-816X}, support = {NS 40386/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell- and Tissue-Based Therapy/*methods ; Disease Models, Animal ; Humans ; Motor Neuron Disease/*therapy ; Stem Cells/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (or Kennedy's disease), spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 are neurodegenerative disorders mainly affecting motor neurons and which currently lack effective therapies. Recent studies in animal models as well as primary and embryonic stem cell models of ALS, utilizing over-expression of mutated forms of Cu/Zn superoxide dismutase 1, have shown that motor neuron degeneration in these models is in part a non cell-autonomous event and that by providing genetically non-compromised supporting cells such as microglia or growth factor-excreting cells, onset can be delayed and survival increased. Using models of acute motor neuron injury it has been shown that embryonic stem cell-derived motor neurons implanted into the spinal cord can innervate muscle targets and improve functional recovery. Thus, a rationale exists for the development of cell therapies in motor neuron diseases aimed at either protecting and/or replacing lost motor neurons, interneurons as well as non-neuronal cells. This review evaluates approaches used in animal models of motor neuron disorders and their therapeutic relevance.}, }
@article {pmid17896980, year = {2007}, author = {Schulte-Herbrüggen, O and Braun, A and Rochlitzer, S and Jockers-Scherübl, MC and Hellweg, R}, title = {Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases?.}, journal = {Current medicinal chemistry}, volume = {14}, number = {22}, pages = {2318-2329}, doi = {10.2174/092986707781745578}, pmid = {17896980}, issn = {0929-8673}, mesh = {Alzheimer Disease/drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Asthma/*drug therapy/physiopathology ; Brain-Derived Neurotrophic Factor/*metabolism/*therapeutic use ; Diabetic Neuropathies/drug therapy/physiopathology ; Humans ; Inflammation/drug therapy/physiopathology ; Keratitis/drug therapy/physiopathology ; Nerve Growth Factor/*metabolism/*therapeutic use ; Nervous System Diseases/*drug therapy/physiopathology ; Pain/*drug therapy ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.}, }
@article {pmid17894648, year = {2007}, author = {Chabrier, PE and Auguet, M}, title = {Pharmacological properties of BN82451: a novel multitargeting neuroprotective agent.}, journal = {CNS drug reviews}, volume = {13}, number = {3}, pages = {317-332}, pmid = {17894648}, issn = {1080-563X}, mesh = {Animals ; Disease Models, Animal ; Nervous System Diseases/*prevention &amp; control ; Neuroprotective Agents/*pharmacology/*therapeutic use ; Phenols/chemistry/*pharmacology/therapeutic use ; Thiazoles/pharmacology/therapeutic use ; }, abstract = {BN82451 belongs to a new family of small molecules designated as multitargeting or hybrid molecules. BN82451 is orally active, has good central nervous system penetration, and elicits potent neuronal protection and antiinflammatory properties. Neuronal protection is due to Na+ channel blockade, antioxidant properties, and mitochondria-protecting activity, whereas inhibition of cyclooxygenases is mostly responsible for its antiinflammatory activity. BN82451 has been shown to exert a potent neuroprotective effect in various in vitro and in vivo animal models. BN82451 was found to exert a significant protection in experimental animal models mimicking aspects of cerebral ischemia, Parkinson disease, Huntington disease, and more particularly amyotrophic lateral sclerosis. Collectively, its pharmacological properties designate BN82451 as a promising neuroprotective agent.}, }
@article {pmid17884681, year = {2007}, author = {Radunović, A and Mitsumoto, H and Leigh, PN}, title = {Clinical care of patients with amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {6}, number = {10}, pages = {913-925}, doi = {10.1016/S1474-4422(07)70244-2}, pmid = {17884681}, issn = {1474-4422}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/physiopathology/*therapy ; Deglutition Disorders/etiology/therapy ; Disease Progression ; Humans ; Neuroprotective Agents/therapeutic use ; Palliative Care ; Patient Care Team ; Respiration Disorders/etiology/therapy ; Riluzole/therapeutic use ; }, abstract = {Although amyotrophic lateral sclerosis and its variants are readily recognised by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this Review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. We highlight the need for research on the effectiveness of gastrostomy, access to non-invasive ventilation and palliative care, communication between the care team, the patient and his or her family, and recognition of the clinical and social effects of cognitive impairment. We recommend that the plethora of evidence-based guidelines should be compiled into an internationally agreed guideline of best practice.}, }
@article {pmid17869376, year = {2007}, author = {Rockenstein, E and Crews, L and Masliah, E}, title = {Transgenic animal models of neurodegenerative diseases and their application to treatment development.}, journal = {Advanced drug delivery reviews}, volume = {59}, number = {11}, pages = {1093-1102}, doi = {10.1016/j.addr.2007.08.013}, pmid = {17869376}, issn = {0169-409X}, support = {AG10435/AG/NIA NIH HHS/United States ; AG11385/AG/NIA NIH HHS/United States ; AG18440/AG/NIA NIH HHS/United States ; AG5131/AG/NIA NIH HHS/United States ; NS44233/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/etiology ; Amyloid beta-Protein Precursor/genetics ; Animals ; *Animals, Genetically Modified ; *Disease Models, Animal ; Humans ; Lewy Body Disease/drug therapy/etiology ; Multiple System Atrophy/drug therapy/etiology ; Neurodegenerative Diseases/*drug therapy/etiology ; Parkinson Disease/drug therapy/etiology ; alpha-Synuclein/genetics ; tau Proteins/analysis ; }, abstract = {Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.}, }
@article {pmid17868522, year = {2007}, author = {Rocha, JA and Miranda, MJ}, title = {[Ventilatory dysfunction in motor neuron disease: when and how to act?].}, journal = {Acta medica portuguesa}, volume = {20}, number = {2}, pages = {157-165}, pmid = {17868522}, issn = {1646-0758}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*physiopathology ; Clinical Protocols ; Humans ; *Respiration ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis is a devastating progressive neurodegenerative disorder, involving motor neurons in the cerebral cortex, brainstem and spinal cord. Mean duration of survival from the time of diagnosis is around 15 months, being pulmonary complications and respiratory failure responsible for more than 85% of deaths. Albeit the inevitability of respiratory failure and short-term death, standardized intervention protocols have been shown to significantly delay the need for invasive ventilatory support, thus prolonging survival and enhancing quality of life. The authors present an intervention protocol based on clinical progression and respiratory parameters. Decisions regarding initiation of non-invasive positive pressure ventilation (NIPPV) and mechanically assisted coughing, depend on development of symptoms of hypoventilation and on objective deterioration of respiratory parameters especially in what concerns bulbar muscle function. These include maximum inspiratory capacity (MIC), difference between MIC and vital capacity (MIC-VC), and assisted peak cough flow (PCF). These standardized protocols along with patient and caregivers education, allow for improved quality of life, prolonged survival and delay or eventually prevent the need for tracheotomy and invasive ventilatory support. Supplemental oxygen should be avoided in these patients, since it precludes use of oxymetry as feedback for titrating NIPPV and MAC, and is associated with decreased ventilatory drive and aggravated hypercapnia.}, }
@article {pmid17854436, year = {2007}, author = {Christou, YA and Moore, HD and Shaw, PJ and Monk, PN}, title = {Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease.}, journal = {Neuropathology and applied neurobiology}, volume = {33}, number = {5}, pages = {485-498}, doi = {10.1111/j.1365-2990.2007.00883.x}, pmid = {17854436}, issn = {0305-1846}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Cell Differentiation ; Embryonic Stem Cells/*physiology ; Humans ; Motor Neuron Disease/*therapy ; Motor Neurons/*cytology ; Nerve Regeneration ; Regenerative Medicine/*methods/trends ; *Stem Cell Transplantation ; }, abstract = {Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease.}, }
@article {pmid17852717, year = {2008}, author = {Hoyer, LL and Green, CB and Oh, SH and Zhao, X}, title = {Discovering the secrets of the Candida albicans agglutinin-like sequence (ALS) gene family--a sticky pursuit.}, journal = {Medical mycology}, volume = {46}, number = {1}, pages = {1-15}, pmid = {17852717}, issn = {1369-3786}, support = {C06 RR16515-01/RR/NCRR NIH HHS/United States ; R01 DE014158-13/DE/NIDCR NIH HHS/United States ; R01 DE014158/DE/NIDCR NIH HHS/United States ; DE14158/DE/NIDCR NIH HHS/United States ; C06 RR016515/RR/NCRR NIH HHS/United States ; }, mesh = {Adhesins, Bacterial/chemistry/*genetics/metabolism ; Agglutinins/genetics/metabolism ; Alleles ; Bacterial Adhesion ; Candida/genetics/metabolism ; Candida albicans/*genetics/metabolism/*pathogenicity ; Candidiasis/microbiology ; Fungal Proteins/chemistry/*genetics/metabolism ; Gene Expression Regulation, Fungal ; Genome, Fungal ; Humans ; *Multigene Family ; }, abstract = {The agglutinin-like sequence (ALS) family of Candida albicans includes eight genes that encode large cell-surface glycoproteins. The high degree of sequence relatedness between the ALS genes and the tremendous allelic variability often present in the same C. albicans strain complicated definition and characterization of the gene family. The main hypothesis driving ALS family research is that the genes encode adhesins, primarily involved in host-pathogen interactions. Although adhesive function has been demonstrated for several Als proteins, the challenge of studying putative adhesins in a highly adhesive organism like C. albicans has led to varying ideas about how best to pursue such investigations, and results that are sometimes contradictory. Recent analysis of alsdelta/alsdelta strains suggested roles for Als proteins outside of adhesion to host surfaces, and a broader scope of Als protein function than commonly believed. The availability and use of experimental methodologies to study C. albicans at the genomic level, and the ALS family en masse, have advanced knowledge of these genes and emphasized their importance in C. albicans biology and pathogenesis.}, }
@article {pmid17852021, year = {2007}, author = {Gouveia, LO and de Carvalho, M}, title = {Young-onset sporadic amyotrophic lateral sclerosis: a distinct nosological entity?.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {6}, pages = {323-327}, doi = {10.1080/17482960701553956}, pmid = {17852021}, issn = {1471-180X}, mesh = {Adolescent ; Adult ; Age Factors ; Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology/physiopathology ; Child ; Child, Preschool ; Female ; Humans ; Male ; }, abstract = {There are few reports describing young-onset amyotrophic lateral sclerosis (ALS). Age at onset is a prognostic factor in ALS, and thus it is relevant to investigate the clinical features of very young ALS patients. We describe three young-onset ALS cases and review the literature. SOD1 mutations were not identified. Our cases and 24 others from the literature indicate that young-onset ALS is characterized by slowly progressive symmetrical weakness; nevertheless, progression is variable. Young-onset ALS seems to be a distinct clinical syndrome but its aetiological background is largely unknown.}, }
@article {pmid17848867, year = {2007}, author = {Werling, LL and Lauterbach, EC and Calef, U}, title = {Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action.}, journal = {The neurologist}, volume = {13}, number = {5}, pages = {272-293}, doi = {10.1097/NRL.0b013e3180f60bd8}, pmid = {17848867}, issn = {1074-7931}, mesh = {Animals ; Clinical Trials as Topic ; Dextromethorphan/pharmacokinetics/*pharmacology/therapeutic use ; Humans ; Nervous System Diseases/drug therapy ; *Neuroprotective Agents ; Receptors, N-Methyl-D-Aspartate/drug effects ; Trauma, Nervous System/drug therapy ; }, abstract = {BACKGROUND: Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism.<br><br>REVIEW SUMMARY: Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed.<br><br>CONCLUSIONS: Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.}, }
@article {pmid17846922, year = {2007}, author = {Harrison, RS and Sharpe, PC and Singh, Y and Fairlie, DP}, title = {Amyloid peptides and proteins in review.}, journal = {Reviews of physiology, biochemistry and pharmacology}, volume = {159}, number = {}, pages = {1-77}, doi = {10.1007/112_2007_0701}, pmid = {17846922}, issn = {0303-4240}, mesh = {Amyloid/*chemistry ; Animals ; Cysteine/chemistry ; Humans ; Hydrogen-Ion Concentration ; Macromolecular Substances ; Models, Molecular ; Molecular Conformation ; Neurodegenerative Diseases/metabolism ; Peptides/*chemistry ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Proteins/*chemistry ; Static Electricity ; }, abstract = {Amyloids are filamentous protein deposits ranging in size from nanometres to microns and composed of aggregated peptide beta-sheets formed from parallel or anti-parallel alignments of peptide beta-strands. Amyloid-forming proteins have attracted a great deal of recent attention because of their association with over 30 diseases, notably neurodegenerative conditions like Alzheimer's, Huntington's, Parkinson's, Creutzfeldt-Jacob and prion disorders, but also systemic diseases such as amyotrophic lateral sclerosis (Lou Gehrig's disease) and type II diabetes. These diseases are all thought to involve important conformational changes in proteins, sometimes termed misfolding, that usually produce beta-sheet structures with a strong tendency to aggregate into water-insoluble fibrous polymers. Reasons for such conformational changes in vivo are still unclear. Intermediate aggregated state(s), rather than precipitated insoluble polymeric aggregates, have recently been implicated in cellular toxicity and may be the source of aberrant pathology in amyloid diseases. Numerous in vitro studies of short and medium length peptides that form amyloids have provided some clues to amyloid formation, with an alpha-helix to beta-sheet folding transition sometimes implicated as an intermediary step leading to amyloid formation. More recently, quite a few non-pathological amyloidogenic proteins have also been identified and physiological properties have been ascribed, challenging previous implications that amyloids were always disease causing. This article summarises a great deal of current knowledge on the occurrence, structure, folding pathways, chemistry and biology associated with amyloidogenic peptides and proteins and highlights some key factors that have been found to influence amyloidogenesis.}, }
@article {pmid17805965, year = {2008}, author = {Dikshit, P and Jana, NR}, title = {Role of ubiquitin protein ligases in the pathogenesis of polyglutamine diseases.}, journal = {Neurochemical research}, volume = {33}, number = {5}, pages = {945-951}, pmid = {17805965}, issn = {0364-3190}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*enzymology ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age related neurodegenerative disorders including polyglutamine diseases. Appearances of aggregates of the misfolded mutant disease proteins suggest that the cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. The quality control ubiquitin ligases are now increasingly implicated in the biology of polyglutamine diseases, Parkinson's diseases, Amyotrophic lateral sclerosis and Alzheimer's disease. Here we review the recent studies that have revealed a critical role of E3 ubiquitin ligases in understanding the pathogenesis of polyglutamine diseases.}, }
@article {pmid17805244, year = {2007}, author = {Heneka, MT and Landreth, GE and Hüll, M}, title = {Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders.}, journal = {Nature clinical practice. Neurology}, volume = {3}, number = {9}, pages = {496-504}, doi = {10.1038/ncpneuro0586}, pmid = {17805244}, issn = {1745-8358}, support = {AG16740/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Diseases/*drug therapy/*metabolism ; Humans ; PPAR gamma/agonists/*physiology ; Pharmaceutical Preparations/*administration &amp; dosage/metabolism ; }, abstract = {The finding that activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) suppresses inflammation in peripheral macrophages and in models of human autoimmune disease instigated the evaluation of this salutary action for the treatment of CNS disorders with an inflammatory component. The fact that NSAIDs delay the onset of and reduce the risk of developing Alzheimer's disease (AD), while also binding to and activating PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD is mediated by PPARgamma. Several lines of evidence from experiments using AD-related transgenic cellular and animal models have supported this hypothesis. The capacity of PPARgamma agonists to elicit anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects might account for their observed protective effects. Several clinical trials employing PPARgamma agonists have yielded promising results, and further trials are in preparation. Positive outcomes following PPARgamma administration have been obtained in animal models of other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, both of which are associated with a considerable degree of neuroinflammation. Finally, activation of PPARgamma has been found to be protective in several models of multiple sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in patients with multiple sclerosis.}, }
@article {pmid17764635, year = {2007}, author = {Rademakers, R and Hutton, M}, title = {The genetics of frontotemporal lobar degeneration.}, journal = {Current neurology and neuroscience reports}, volume = {7}, number = {5}, pages = {434-442}, pmid = {17764635}, issn = {1528-4042}, support = {P01 AG017216/AG/NIA NIH HHS/United States ; P50 AG16574/AG/NIA NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/genetics ; Brain/*metabolism/physiopathology ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics ; Dementia/*genetics/*metabolism/physiopathology ; Endosomal Sorting Complexes Required for Transport ; Genetic Predisposition to Disease/*genetics ; Humans ; Inclusion Bodies/genetics/metabolism ; Intercellular Signaling Peptides and Proteins/genetics ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Progranulins ; Valosin Containing Protein ; }, abstract = {The clinical disorders associated with frontotemporal lobar degeneration (FTLD) are increasingly recognized as an important cause of early-onset dementia. Patients usually present with progressive changes in personality, behavior, or language, progressing to general cognitive impairment and ultimately death. In the past decade, improved clinical and histopathologic characterization uncovered extensive heterogeneity, and multiple clinical and pathologic FTLD subtypes were defined. Simultaneously, the discovery of four causal FTLD genes emphasized the genetic complexity associated with FTLD. More recently, the field of FTLD has gained increased attention as a result of two major findings. First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLD-U), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS). In this report, we outline the progress made in the study of the genetic etiologies and neuropathologic substrates in FTLD.}, }
@article {pmid17763684, year = {2007}, author = {Oka, K}, title = {[Psychopathology on "as if" experience and statement].}, journal = {Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica}, volume = {109}, number = {6}, pages = {516-533}, pmid = {17763684}, issn = {0033-2658}, mesh = {Delusions/*psychology ; Female ; Humans ; Obsessive-Compulsive Disorder/*psychology ; *Psychopathology ; }, abstract = {After an overview of the psychiatric literature on the psychopathology of "as if" or that is to say "Als ob Erlebnis", we made a study of one obsessive-compulsive patient from the view point of "as if". Through this approach, we identified a specific experience-field, namely the appearance, what seems to a person such and such. The psychopathology of "as if" could be linked closely to the appearance. Without the possibility of error, one cannot recognize the reality of being in the world and being accessible to anybody. In contrast to this, one escapes any errors with regard to the appearance because the appearance relates to nobody but the person to whom it appears. So, concerning the appearance that seems to a person such and such, he/she is subjectively certain and not to be corrected by others, just like a delusional patient. In daily life, we are often unaware that there are confusions between reality and appearance. The obsessive patient cannot permit themselves such customary confusions. The delusional patient cannot realize irrelevant confusions of reality and appearance in spite of encounters with other persons. To elucidate the delusion, we used a similar analytical way to that introduced by Spitzer. In spite of this, we arrived at a different consequence. We discussed such a discrepancy emerging and mentioned some problems associated with the delusion by investigating the uniqueness of the appearance.}, }
@article {pmid17724975, year = {2007}, author = {Bufler, J}, title = {[Diagnosis and treatment of amyotrophic lateral sclerosis].}, journal = {MMW Fortschritte der Medizin}, volume = {149 Suppl 2}, number = {}, pages = {84-87}, pmid = {17724975}, issn = {1438-3276}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/mortality/physiopathology/therapy ; Diagnosis, Differential ; Disease Progression ; Electromyography ; Humans ; Incidence ; Middle Aged ; Neurologic Examination ; Prevalence ; Time Factors ; }, abstract = {Like Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which a very defined population of neurons selectively degenerates. Muscular atrophy and central paresis develop in ALS patients relatively quickly--usually within months to a few years. Bulbar symptoms such as swallowing disorders and dysarthria are frequently observed in the beginning. The disease progresses steadily and without remission. The average length of survival after diagnosis is two to three years. The diagnosis is made on the basis of a characteristic group of symptoms and confirmed or substantiated through additional clinical neurological tests. Currently, the cause of the disease cannot be treated. Treatment concentrates primarily on symptomatic measures and providing supportive devices.}, }
@article {pmid17713120, year = {2007}, author = {Tomiyama, H and Hatano, T and Hattori, N}, title = {[Clinical molecular genetics for PARK8 (LRRK2)].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {8}, pages = {839-850}, pmid = {17713120}, issn = {1881-6096}, mesh = {Animals ; Diagnostic Imaging ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Mutation ; Parkinson Disease/diagnosis/*genetics/pathology/physiopathology ; Polymorphism, Genetic ; Protein Serine-Threonine Kinases/*genetics/physiology ; Racial Groups ; }, abstract = {Parkinson's disease (PD) is an etiologically heterogeneous disorder characterized by parkinsonism (bradykinesia, resting tremor, rigidity, and postural instability) with good response to L-dopa. PD is the second most prevalent neurodegenerative disorder after Alzheimer disease. Although the majority of PD cases are sporadic, 5-10% of PD is monogenic form of PD as familial PD (FPD). Multifactorial genetic-environmental interaction has been thought in PD pathogenesis, although these interactions are still poorly understood. In 2004, LRRK2 was identified as the causative gene for PARK8 originally mapped in the large Japanese Sagamihara family with late-onset autosomal dominant PD (ADPD). Patients with LRRK2 mutations account for approximately 2-13% of ADPD and 0.5-3% of sporadic PD. Genetically, LRRK2 mutations have been distributed worldwide with some ethnic differences by single founder effect such as G2019S, R1441G, and G2385R variants. LRRK2 G2385R was reported to be a risk factor for sporadic PD in Asia. Clinically, most patients with LRRK2 mutations develop typical idiopathic PD, however, variable clinical features and pathologies such as diffuse Lewy body disease, multiple system atrophy, progressive supranuclear palsy, and amyotrophic lateral sclerosis have been reported. Although Lewy bodies have been considered as a pathological hallmark for sporadic PD classically, some FPD and sporadic PD patients with heterozygous LRRK2 mutations or homozygous parkin mutations have no Lewy bodies. On the other hand, LRRK2 was reported as a component of Lewy bodies. Based on the variability, multifunction of LRRK2 such as phosphorylation of other proteins, especially, alpha-synuclein and tau, have been suggested. As interaction of Parkin and LRRK2 was reported, interaction and intersection among the autosomal-recessive or autosomal-dominant PD proteins could be involved in some common pathways, and LRRK2 may play an important role as a key FPD gene product. Identification of PARK8 and LRRK2 has given meaningful insights in not only PD but also numerous neurodegenerative disorders such as synucleinopathies and tauopathies with or without Lewy bodies.}, }
@article {pmid17712161, year = {2007}, author = {Irwin, D and Lippa, CF and Swearer, JM}, title = {Cognition and amyotrophic lateral sclerosis (ALS).}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {22}, number = {4}, pages = {300-312}, pmid = {17712161}, issn = {1533-3175}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/pathology/therapy ; Cognition Disorders/diagnosis/*epidemiology/therapy ; Cognitive Behavioral Therapy ; Combined Modality Therapy ; Frontal Lobe/pathology ; Humans ; Neuropsychological Tests ; Severity of Illness Index ; Temporal Lobe/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is classically described as a pure motor disease; however, there is growing evidence of a range of cognitive impairment. Cognitive abnormalities include deficiencies in frontal executive skills, varying from mild deficits to meeting criteria for diagnosis of frontotemporal dementia (FTD). Cognitive impairment occurs in sporadic and familial forms of ALS. Patients may present with cognitive deficits before, after, or at the onset of motor neuron disease. Structural and functional imaging studies have shown extramotor cortical degeneration corresponding to levels of frontal executive impairment on neuropsychologic testing. In addition, ALS and a subset of FTD patients display common pathological findings on immunohistochemistry staining. It is believed that these disorders represent a continuum between motor and nonmotor cortical degeneration. The purpose of this article is to review the literature on cognitive deficits in ALS. Identifying changes in cognition is critical for physicians and caregivers of ALS patients, as cognitive decline may interfere with patient compliance. Diagnosis and treatment of cognitive symptoms in ALS patients may improve quality of life.}, }
@article {pmid17701742, year = {2007}, author = {Beukelman, DR and Fager, S and Ball, L and Dietz, A}, title = {AAC for adults with acquired neurological conditions: a review.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {23}, number = {3}, pages = {230-242}, doi = {10.1080/07434610701553668}, pmid = {17701742}, issn = {1477-3848}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*rehabilitation ; Aphasia/rehabilitation ; Brain Injuries/*rehabilitation ; Communication Aids for Disabled/*trends ; Dementia/rehabilitation ; Humans ; }, abstract = {The purpose of this review is to describe the state of the science of augmentative and alternative communication (AAC) for adults with acquired neurogenic communication disorders. Recent advances in AAC for six groups of people with degenerative and chronic acquired neurological conditions are detailed. Specifically, the topics of recent AAC technological advances, acceptance, use, limitations, and future needs of individuals with amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), brainstem impairment, severe, chronic aphasia and apraxia of speech, primary progressive aphasia (PPA), and dementia are discussed.}, }
@article {pmid17702495, year = {2007}, author = {Tolnay, M and Frank, S}, title = {Pathology and genetics of frontotemporal lobar degeneration: an update.}, journal = {Clinical neuropathology}, volume = {26}, number = {4}, pages = {143-156}, doi = {10.5414/npp26143}, pmid = {17702495}, issn = {0722-5091}, mesh = {Adenosine Triphosphatases/genetics/metabolism ; Brain/pathology ; Cell Cycle Proteins/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Dementia/classification/*genetics/*metabolism/pathology ; Endosomal Sorting Complexes Required for Transport ; Humans ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; Mutation/genetics ; Nerve Tissue Proteins/genetics/metabolism ; Progranulins ; Tauopathies/classification/*metabolism/pathology ; Valosin Containing Protein ; tau Proteins/genetics/*metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) is a common form of dementia that usually afflicts patients in their mid-life. Clinically, patients with FTLD present with changes in behavior and/or language dysfunction. According to their underlying neuropathological substrate, these neurodegenerative conditions can now be classified into two main groups: those with tau pathology (tauopathies), and those without tau pathology. In the majority of nontauopathy disorders the recently identified TAR DNA-binding protein-43 (TDP-43) is found as the major inclusion protein (TDP-43 proteinopathies), and TDP-43 is also present in motor neuron inclusions of amyotrophic lateral sclerosis. Presently, mutations in 4 genes (MAPT, PGRN, VCP, CHMP2B) are known to cause diverse types of FTLD pathology. Here, we summarize the recent neuropathological and genetic advances in FTLD research.}, }
@article {pmid17691370, year = {2007}, author = {Panourias, IG and Themistocleous, M and Sakas, DE}, title = {Intrathecal baclofen in current neuromodulatory practice: established indications and emerging applications.}, journal = {Acta neurochirurgica. Supplement}, volume = {97}, number = {Pt 1}, pages = {145-154}, doi = {10.1007/978-3-211-33079-1_20}, pmid = {17691370}, issn = {0065-1419}, mesh = {Baclofen/*therapeutic use ; Electric Stimulation Therapy ; Electrodes, Implanted ; Humans ; Muscle Relaxants, Central/*therapeutic use ; Muscle Spasticity/*drug therapy/etiology/surgery ; Nervous System Diseases/complications ; Spinal Cord/drug effects/*physiology/radiation effects ; }, abstract = {Intrathecal baclofen (ITB) has evolved into a standard treatment for severe spasticity of both spinal and cerebral origin. The accumulated promising data from reported series of patients receiving ITB therapy together with the fact that spastic hypertonia commonly coexists with other neurological disorders have constituted a solid basis for offering this kind of treatment to patients suffering from other movement disorders. These include motor disorders such as dystonia, amyotrophic lateral sclerosis, status dystonicus, Hallervorden-Spatz disease, Freidreich's ataxia, "stiff-man" syndrome, but also vegetative states after revere brain trauma, anoxic encephalopathy or other pathology and more recently, various chronic pain syndromes. In this article, on the basis of the established applications of ITB therapy, we review the important emerging indications of this rewarding neuromodulation method and attempt to identify its future potential beneficial role in other chronic and otherwise refractory neurological disorders.}, }
@article {pmid17689905, year = {2007}, author = {Makrantonaki, E and Zouboulis, CC and , }, title = {The skin as a mirror of the aging process in the human organism--state of the art and results of the aging research in the German National Genome Research Network 2 (NGFN-2).}, journal = {Experimental gerontology}, volume = {42}, number = {9}, pages = {879-886}, doi = {10.1016/j.exger.2007.07.002}, pmid = {17689905}, issn = {0531-5565}, mesh = {Aging/genetics/*physiology ; Gene Expression Profiling ; Genome, Human ; Hormones/*metabolism ; Humans ; Models, Biological ; Sebaceous Glands/*metabolism ; Skin Aging/genetics/physiology ; }, abstract = {As our society is growing older, the consequences of aging have begun to gain particular attention. Improvement of quality of life at old age and prevention of age-associated diseases have become the main focus of the aging research. The process of aging in humans is complex and underlies multiple influences, with the probable involvement of heritable and various environmental factors. In particular, hormones are decisively involved in the generation of aging. Over time, important circulating hormones decline due to a reduced secretion of the pituitary, the adrenal glands and the gonads or due to an intercurrent disease. Among them, serum levels of growth factors and sexual steroids show significant aging-associated changes. Within the scope of the Explorative Project 'Genetic aetiology of human longevity' supported by the German National Genome Research Network 2 (NGFN-2) an in vitro model of human hormonal aging has been developed. Human SZ95 sebocytes were maintained under a hormone-substituted environment consisting of growth factors and sexual steroids in concentrations corresponding to those circulating in 20- and in 60-year-old women. Eight hundred and ninety-nine genes showed a differential expression in SZ95 sebocytes maintained under the 20- and 60-year-old hormone mixture, respectively. Among them genes were regulated which are involved in biological processes which are all hallmarks of aging. The most significantly altered signaling pathway identified was that of the transforming growth factor-beta (TGF-beta). A disturbed function of this cascade has been associated with tumorigenesis, i.e. in pancreatic, prostate, intestine, breast, and uterine cancer. Interestingly, genes expressed in signaling pathways operative in age-associated diseases such as Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and amyotrophic lateral sclerosis (ALS) were also identified. These data demonstrate that skin and its appendages may represent an adequate model for aging research. Hormones interact in a complex fashion, and aging may be partly attributed to the changes in their circulating blood levels. Furthermore, a disturbed hormone status may partially act towards the manifestation of neurodegenerative diseases. Thus, these results could be a basis for an integrated and interdisciplinary approach to the analysis of the aging process.}, }
@article {pmid17685869, year = {2007}, author = {Bhatt, JM and Gordon, PH}, title = {Current clinical trials in amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {16}, number = {8}, pages = {1197-1207}, doi = {10.1517/13543784.16.8.1197}, pmid = {17685869}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology ; Animals ; Humans ; Randomized Controlled Trials as Topic/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis is caused by selective degeneration of motor neurons in the brain and spinal cord. There are still no other effective therapies 10 years after the approval of riluzole for the treatment of amyotrophic lateral sclerosis, but advances in drug development and screening are substantially increasing the number of potential therapeutic agents. This review provides an overview of clinical trial methodology in amyotrophic lateral sclerosis followed by a systematic evaluation of drugs that are presently in Phase I, II and III clinical trials. There is an emphasis on the scientific evidence supporting the selection of each drug being tested, as well as on trial design.}, }
@article {pmid17681549, year = {2007}, author = {Armon, C}, title = {Sports and trauma in amyotrophic lateral sclerosis revisited.}, journal = {Journal of the neurological sciences}, volume = {262}, number = {1-2}, pages = {45-53}, doi = {10.1016/j.jns.2007.06.021}, pmid = {17681549}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Athletic Injuries/*epidemiology ; Comorbidity ; Data Interpretation, Statistical ; Evidence-Based Medicine ; Humans ; Incidence ; Mortality ; Reproducibility of Results ; Risk Factors ; Wounds and Injuries/*epidemiology ; }, abstract = {An evidence-based review was undertaken of the literature published between 2002 and 2006 about sports, trauma and ALS in order to see if there were new data to modify the conclusions of a previous review (2003). The new data support the previous conclusions that physical activity and trauma are probably ("more likely than not") not risk factors for ALS (Level II conclusions). This review concludes also that the reports of an apparent excess of ALS in Italian soccer players likely reflect incorrect analysis of the data. The appearance of excess relies on accepting as valid estimation methods resulting in improbably low numbers of expected cases. A different method is proposed: it generates more plausible numbers of expected cases, compared to which there is no excess of total cases (Level C conclusion). A theoretical framework is developed to analyze the possible influence of a "healthy worker effect" on incidence of neurodegenerative diseases in cohorts of employed or formerly employed individuals. In lieu of theoretical speculations, data are needed to measure this effect, while controlling for known lifestyle factors and accounting for the effect of loss of competing causes of mortality.}, }
@article {pmid17678968, year = {2007}, author = {Reynolds, A and Laurie, C and Mosley, RL and Gendelman, HE}, title = {Oxidative stress and the pathogenesis of neurodegenerative disorders.}, journal = {International review of neurobiology}, volume = {82}, number = {}, pages = {297-325}, doi = {10.1016/S0074-7742(07)82016-2}, pmid = {17678968}, issn = {0074-7742}, support = {P01 MH64570-03/MH/NIMH NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; P01 NS31492/NS/NINDS NIH HHS/United States ; R01 NS34239/NS/NINDS NIH HHS/United States ; R21 NS049264/NS/NINDS NIH HHS/United States ; R37 NS36136/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Free Radicals ; Glutamic Acid/physiology ; Glutamine/physiology ; Glutathione/physiology ; Humans ; Immunologic Factors/therapeutic use ; Intercellular Signaling Peptides and Proteins/physiology ; Macrophage Activation/physiology ; Microglia/physiology ; Neurodegenerative Diseases/drug therapy/immunology/*pathology ; Oxidative Stress/drug effects/*physiology ; }, abstract = {Microglia-derived inflammatory neurotoxins play a principal role in the pathogenesis of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and HIV-associated dementia; chief among these is reactive oxygen species. The detrimental effects of oxidative stress in the brain and nervous system are primarily a result of the diminished capacity of the central nervous system to prevent ongoing oxidative damage. A spectrum of environmental cues, mitochondrial dysfunction, accumulation of aberrant misfolded proteins, inflammation, and defects in protein clearance are known to evolve and form as a result of disease progression. These factors likely affect glial function serving to accelerate the tempo of disease. Understanding the relationships between disease progression, free radical formation, neuroinflammation, and neurotoxicity is critical to elucidating disease mechanisms and the development of therapeutic modalities to combat disease processes. In an era where populations continue to age, the prevalence and incidence of age-related neurodegenerative diseases are on the rise; therefore, the need for novel therapeutic strategies that attenuate neuroinflammation and protect neurons against oxidative stress is ever more immediate.}, }
@article {pmid17678961, year = {2007}, author = {Centonze, D and Rossi, S and Finazzi-Agrò, A and Bernardi, G and Maccarrone, M}, title = {The (endo)cannabinoid system in multiple sclerosis and amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {82}, number = {}, pages = {171-186}, doi = {10.1016/S0074-7742(07)82009-5}, pmid = {17678961}, issn = {0074-7742}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Cannabinoid Receptor Modulators/*physiology ; Glutamic Acid/physiology ; Humans ; Microglia/physiology ; Multiple Sclerosis/*pathology ; Neurodegenerative Diseases/pathology ; Oxidative Stress/physiology ; Synaptic Transmission/physiology ; }, abstract = {Alterations of the endocannabinoid system (ECS) have been recently implicated in a number of neuroinflammatory and neurodegenerative conditions so that the pharmacological modulation of cannabinoid (CB) receptors and/or of the enzymes controlling synthesis, transport, and degradation of these substances has emerged as a valuable option to treat neurological diseases. Here, we describe the current knowledge concerning the rearrangement of ECS in a primarily inflammatory disorder of the central nervous system such as multiple sclerosis (MS), and in a primarily degenerative condition such as amyotrophic lateral sclerosis (ALS). Furthermore, the data supporting a therapeutic role of agents modulating CB receptors or endocannabinoid tone in these disorders will also be reviewed. Complex changes of ECS take place in both diseases, influencing crucial aspects of their pathophysiology and clinical manifestations. Neuroinflammation, microglial activation, oxidative stress, and excitotoxicity are variably combined in MS and in ALS and can be modulated by endocannabinoids or by drugs targeting the ECS.}, }
@article {pmid17678953, year = {2007}, author = {Lipton, SA and Gu, Z and Nakamura, T}, title = {Inflammatory mediators leading to protein misfolding and uncompetitive/fast off-rate drug therapy for neurodegenerative disorders.}, journal = {International review of neurobiology}, volume = {82}, number = {}, pages = {1-27}, doi = {10.1016/S0074-7742(07)82001-0}, pmid = {17678953}, issn = {0074-7742}, support = {P01 HD29587/HD/NICHD NIH HHS/United States ; R01 EY05477/EY/NEI NIH HHS/United States ; R01 EY09024/EY/NEI NIH HHS/United States ; R01 NS046994/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/pathology ; Animals ; Cell Death ; Free Radicals/metabolism ; Humans ; Inflammation Mediators/*physiology ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neurons/physiology ; Parkinson Disease/pathology ; *Protein Folding ; Ubiquitin-Protein Ligases/physiology ; }, abstract = {Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which contributes to the pathogenesis of PD. One way to ameliorate excessive NO production and hence abnormal S-nitrosylations would be to inhibit NMDA receptors. In fact, blockade of excessive NMDA receptor activity can in large measure protect neurons from this type of injury and death. However, inhibition of the NMDA receptor by high-affinity antagonists also blocks the receptor's normal function in synaptic transmission and leads to unacceptable side effects. For this reason, many NMDA receptor antagonists have disappointingly failed in advanced clinical trials. Our group was the first to demonstrate that gentle blockade of NMDA receptors by memantine, via a mechanism of uncompetitive open-channel block with a rapid "off-rate," can prevent this type of damage in a clinically efficacious manner without substantial side effects. For these Uncompetitive/Fast Off-rate therapeutics, we use the term "UFO drugs" because like Unidentified Flying Objects, they leave very quickly as soon as their job is finished. As a result, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this by preferentially entering the receptor-associated ion channel when it is excessively open, and, most importantly, when its off-rate from the channel is relatively fast so that it does not accumulate to interfere with normal synaptic transmission. Hence, memantine is clinically well tolerated, has been used in Europe for PD for many years, and recently passed multiple phase III trials for dementia, leading to its approval by the FDA and European Union for moderate-to-severe AD. Clinical studies of memantine for additional neurological disorders, including other dementias, neuropathic pain, and glaucoma, are underway. We have also developed a series of second-generation drugs that display greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, including critical thiol groups that are S-nitrosylated. In this case, in contrast to PDI or parkin, S-nitrosylation proves to be neuroprotective by decreasing excessive NMDA receptor activity. Targeted S-nitrosylation of the NMDA receptor can be achieved by coupling NO to memantine, yielding second-generation "UFO drugs" known as NitroMemantines.}, }
@article {pmid17672180, year = {2007}, author = {Buysschaert, I and Carmeliet, P and Dewerchin, M}, title = {Clinical and fundamental aspects of angiogenesis and anti-angiogenesis.}, journal = {Acta clinica Belgica}, volume = {62}, number = {3}, pages = {162-169}, doi = {10.1179/acb.2007.027}, pmid = {17672180}, issn = {1784-3286}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Angiogenesis Inducing Agents/therapeutic use ; Angiogenesis Inhibitors/therapeutic use ; Angiopoietins/physiology ; Animals ; Cardiovascular Diseases/physiopathology ; Fibroblast Growth Factors/physiology ; Humans ; Myocardial Ischemia/drug therapy ; *Neovascularization, Pathologic/physiopathology ; *Neovascularization, Physiologic/physiology ; Peripheral Vascular Diseases/physiopathology ; Vascular Endothelial Growth Factor A/physiology ; }, abstract = {Insight into the fundamental physiological mechanisms of blood vessel development and neoformation has led to the discovery of multiple angiogenic growth factors and inhibitors. To date, at least 5 angiogenesis inhibitors are readily available for clinical use, mainly in the treatment of cancers and age-related macular degeneration. More inhibitors are yet to come and the indications for their clinical use are expected to broaden. Conversely, the use of angiogenic stimulators, although initially promising in animal models and in small uncontrolled pilot studies in patients with ischaemic heart disease or peripheral arterial occlusive disease, could thus far not show any convincing therapeutic improvement. Challenges still remain as to which angiogenic factor or combination of factors should be administered and in which form (protein versus gene), and what route and duration of administration should be used. Further clinical perspective might come from the recent identification of vascular endothelial growth factor (VEGF) as a modifier of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), and as a promising therapy in the treatment of ALS in preclinical animal models. This review discusses the different clinical trials of angiogenic inhibitors and stimulators, preceded by some fundamental aspects of angiogenesis, giving the clinician a brief overview of the most relevant angiogenic topics.}, }
@article {pmid17668854, year = {2008}, author = {Weissmann, C and Brandt, R}, title = {Mechanisms of neurodegenerative diseases: insights from live cell imaging.}, journal = {Journal of neuroscience research}, volume = {86}, number = {3}, pages = {504-511}, doi = {10.1002/jnr.21448}, pmid = {17668854}, issn = {1097-4547}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Microscopy, Fluorescence ; Nerve Tissue Proteins/chemistry/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Peptides ; Protein Folding ; Staining and Labeling ; Tauopathies/metabolism ; Trinucleotide Repeats ; }, abstract = {Pathologic alterations in protein dynamics such as changes in protein degradation, accumulation of misfolded proteins, and deficits in cellular transport mechanisms are a common feature of most if not all neurodegenerative diseases. Live cell imaging studies promise to contribute to a better understanding of the molecular mechanisms underlying these diseases by visualizing the turnover, accumulation, and transport of proteins in a living cellular context in real time. In this review, we discuss recent work in which different live cell imaging approaches are applied in cellular models of amyotrophic lateral sclerosis, polyQ diseases, and tauopathies as paradigmatic examples of diseases with different types of alterations in protein dynamics. It becomes evident that live cell imaging studies provide new insights into different aspects of protein dynamics, such as the understanding that aggregates are not as static as concluded from previous studies but exhibit a remarkable molecular exchange and that the dynamicity state of the neuronal cytoskeleton might have a critical role in neuronal degeneration. It can be anticipated that live cell imaging studies will lead to a more dynamic view of protein turnover and aggregation, which may aid in identifying drugs that specifically interfere with disease-related changes.}, }
@article {pmid17656567, year = {2007}, author = {Brown, IR}, title = {Heat shock proteins and protection of the nervous system.}, journal = {Annals of the New York Academy of Sciences}, volume = {1113}, number = {}, pages = {147-158}, doi = {10.1196/annals.1391.032}, pmid = {17656567}, issn = {0077-8923}, mesh = {Animals ; Heat-Shock Proteins/*physiology ; Humans ; Nervous System Diseases/metabolism/pathology/prevention &amp; control ; *Nervous System Physiological Phenomena ; }, abstract = {Manipulation of the cellular stress response offers strategies to protect brain cells from damage induced by ischemia and neurodegenerative diseases. Overexpression of Hsp70 reduced ischemic injury in the mammalian brain. Investigation of the domains within Hsp70 that confers ischemic neuroprotection revealed the importance of the carboxyl-terminal domain. Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate. Celastrol, a promising candidate as an agent to counter neurodegenerative diseases, induced expression of a set of Hsps in differentiated neurons grown in tissue culture. Heat shock "preconditioning" protected the nervous system at the functional level of the synapse and selective overexpression of Hsp70 enhanced the level of synaptic protection. Following hyperthermia, constitutively expressed Hsc70 increased in synapse-rich areas of the brain where it associates with Hsp40 to form a complex that can refold denatured proteins. Stress tolerance in neurons is not solely dependent on their own Hsps but can be supplemented by Hsps from adjacent glial cells. Hence, application of exogenous Hsps at neural injury sites is an effective strategy to maintain neuronal viability.}, }
@article {pmid17653923, year = {2007}, author = {Averill, AJ and Kasarskis, EJ and Segerstrom, SC}, title = {Psychological health in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {4}, pages = {243-254}, doi = {10.1080/17482960701374643}, pmid = {17653923}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/complications/epidemiology/*psychology ; Depression/epidemiology/etiology/*psychology ; Humans ; Mental Health/*statistics &amp; numerical data ; Prevalence ; Review Literature as Topic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with no known effective treatment or cure. Clinicians often expect that ALS patients will experience depression following the diagnosis because ALS is a terminal disease. The objective of the current study was to examine the evidence from the literature on psychological health in ALS patients in order to determine the prevalence and severity of depression in this population. Twenty-eight studies of ALS patients, conducted over the past 20 years, were reviewed and evaluated. The cumulative evidence suggests that clinically significant depression is neither as prevalent nor as severe as might be expected. Methodological limitations that are inherent to the measurement of depression in ALS, including the lack of appropriate instruments, small sample sizes, and reliance on cross-sectional data, have contributed to the wide range of reported results. We conclude that ALS patients are more likely to present with hopelessness and end-of-life concerns than clinically significant depression. It is important to assess a broad range of potential psychological distress early in the course of ALS, rather than focus specifically on depression, because the manner in which patients cope with their disease can affect their longevity.}, }
@article {pmid17653917, year = {2007}, author = {Andersen, PM and Borasio, GD and Dengler, R and Hardiman, O and Kollewe, K and Leigh, PN and Pradat, PF and Silani, V and Tomik, B and , }, title = {Good practice in the management of amyotrophic lateral sclerosis: clinical guidelines. An evidence-based review with good practice points. EALSC Working Group.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {4}, pages = {195-213}, doi = {10.1080/17482960701262376}, pmid = {17653917}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; *Evidence-Based Medicine ; Humans ; }, abstract = {The evidence base for diagnosis and management of ALS is still weak, and curative therapy is lacking. Nonetheless, early diagnosis and symptomatic therapy can profoundly influence care and quality of life of the patient and relatives, and may increase survival time. This review addresses the current optimal clinical approach to ALS. The literature search is complete to December 2006. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. We conclude that a diagnosis of ALS can be achieved by early examination by an experienced neurologist. The patient should be informed of the diagnosis by the consultant. Following diagnosis, a multi-diciplinary care team should support the patient and relatives. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with VC <50%: RIG may be a better alternative. Non-invasive positive pressure ventilation improves survival and quality of life but is underused in Europe. Maintaining the patient's ability to communicate is essential. During the course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be discussed early with the patient and relatives if they so wish.}, }
@article {pmid17620231, year = {2007}, author = {Schucher, B and Magnussen, H}, title = {[Mechanical ventilation in chronic ventilatory insufficiency].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {61}, number = {10}, pages = {644-652}, doi = {10.1055/s-2007-980063}, pmid = {17620231}, issn = {1438-8790}, mesh = {Germany ; Humans ; Lung Diseases/*rehabilitation ; Practice Patterns, Physicians'/trends ; Respiration, Artificial/*methods/*trends ; Respiratory Insufficiency/*nursing/prevention &amp; control/*rehabilitation ; Self Care/*methods/*trends ; }, abstract = {Mechanical ventilation has become an important treatment option in chronic ventilatory failure. There are different diseases which lead to ventilatory failure and to home mechanical ventilation (HMV). A primary loss of in- and expiratory muscle strength is the reason for respiratory deterioration in neuromuscular disease. In most of these diseases ventilatory failure develops because of the progressive character of muscular damage. Initially, ventilatory failure can be found during night-time. In the case of hypercapnia at daytime, life expectancy is strongly reduced, especially in amyotrophic lateral sclerosis and Duchenne muscular dystrophy. HMV leads to a prolongation of life and to an increase in quality of life, if bulbar involvement is not severe. Impressive clinical improvements under HMV have been found in restrictive disorders of the rib cage like kyphoscoliosis or posttuberculosis sequelae, with an increase of quality of life, walking distance and a decrease in pulmonary hypertension. Only few data are published about long-term results of HMV in Obesity Hypoventilation. In terms of retrospective analyses of clinical data HMV seems to improve survival in this population. Some patients only need CPAP treatment, but most patients have to be treated with ventilatory support. The application of HMV in patients with chronic ventilatory failure due to chronic obstructive pulmonary disease (COPD) is growing, but there are controversial results in randomised clinical trials. Analysis of these data suggest better results of HMV in patients with severe hypercapnia, with the application of higher effective ventilatory pressure and a ventilator mode with a significant reduction in the work of breathing. Under such conditions HMV leads to a reduction of hypercapnia, an improvement in sleep quality, walking distance and quality of life, but until now there is no evidence in reduction of mortality in COPD.}, }
@article {pmid17610166, year = {2007}, author = {Galán, L and Vela, A and Guerrero, A and Barcia, JA and García-Verdugo, JM and Matias-Guiu, J}, title = {[Experimental models of amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {22}, number = {6}, pages = {381-388}, pmid = {17610166}, issn = {0213-4853}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; *Disease Models, Animal ; Mice ; Rats ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that affects almost selectively motor neurons. Its ethiopathogeny is not fully understood, although there are several mechanisms that could play a role. It has no curative treatment and just a drug (riluzole) and mechanical ventilation has demonstrated to improve survival of these patients. In the last decades experimental models have been developed which have led us to better understand this disease and to design possible therapeutic strategies.<br><br>METHOD: We reviewed published articles concerning experimental models for ALS and neurodegeneratives diseases using the PubMed database.<br><br>RESULTS: Several experimental models for ALS have been described, from animal models (mainly transgenic animals for human mutations in superoxidedismutase [SOD1]) to cellular models, each of them with advantages and objections.<br><br>CONCLUSIONS: ALS experimental models have implied a great advance in the knowledge of this disease and the design of new therapeutic strategies.}, }
@article {pmid17610165, year = {2007}, author = {Matias-Guiu, J and Galán, L and Garcia-Ramos, R and Vela, A and Guerrero, A}, title = {[Descriptive epidemiology of amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {22}, number = {6}, pages = {368-380}, pmid = {17610165}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Humans ; }, abstract = {INTRODUCTION: ALS descriptive epidemiological information is wide, and is based on hospital registries, selective patients series and community studies of incidence, prevalence and mortality rates.<br><br>REVIEW: It has been revised studies found in the literature trying to analyse the methodology looking for approaches for a systematic review on the ALS descriptive epidemiology. The analysed works include on incidence, prevalence and mortality rates studies and we discuss possible biases and confounding factors.<br><br>CONCLUSIONS: Systematic review of ALS descriptive epidemiology should be based on the following criteria: community studies in non-selective geographic areas excluding aggregated cases zones, determination of crude prevalence rate and sex-age specific and standard population adjusted prevalence rates, presented with confidence intervals, selection of the cases should fulfil El Escorial criteria, sample size of source population greater than one hundred thousands in habitants, study period greater than five years and the dates should be accessible through Medline or other bibliographic sources.}, }
@article {pmid17610160, year = {2007}, author = {Martínez-Vila, E and Matias-Guiu, J}, title = {[Clinical pathways for non-acute neurological diseases as amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {22}, number = {6}, pages = {337-341}, pmid = {17610160}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Chronic Disease ; *Critical Pathways ; Humans ; Nervous System Diseases/therapy ; }, abstract = {Clinical pathways are integrated plans of tasks dedicated to obtain the major benefit for the patients, considering all aspects of the management, as the role of physicians and nurses and standardizing the procedures in forms and time. Their interest has grown since the developing of clinical management models. In neurological diseases their use has been restricted to acute phases, and in the case of chronic neurological diseases for specific techniques. The authors analyze the interest of the design and use of clinical pathways for chronic neurological diseases starting from the paper from Rodriguez de la Rivera et al. on a clinical pathway for amyotrophic lateral sclerosis. For the authors, the specific differences between clinical pathways for acute neurological diseases and chronic diseases are changes in the design of temporal matrix using stages, multispeciality teams, the standardised access to social benefits and the role of case-manager, as professional who maintain a direct relation with patients. The authors also approach the setting difficulties in the development of clinical pathways that should be greater in the chronic neurological disease and suggest the role of scientific societies in their promotion.}, }
@article {pmid17604499, year = {2007}, author = {Bedlack, RS and Traynor, BJ and Cudkowicz, ME}, title = {Emerging disease-modifying therapies for the treatment of motor neuron disease/amyotropic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {12}, number = {2}, pages = {229-252}, doi = {10.1517/14728214.12.2.229}, pmid = {17604499}, issn = {1744-7623}, support = {//Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology ; Animals ; Humans ; Motor Neuron Disease/*drug therapy/genetics/*pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects/physiology ; }, abstract = {It has been > 130 years since the first description of the upper and lower motor neuron disease called amyotropic lateral sclerosis (ALS). Sadly, there has been little change in the long interval over which this disease is diagnosed, or in its poor prognosis. Significant gains have been made, however, in understanding its pathophysiology and in symptomatic care. Disease-causing mutations have been identified and used to create animal models. Other identified mutations may increase susceptibility and cause disease only in a particular environment and at a particular age. A number of 'downstream' molecular pathways have been implicated, including transcriptional disturbances, protein aggregation, excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation, cytoskeletal and axonal transport derangements, growth factor dysregulation and apoptosis. This knowledge has led to an impressive pipeline of candidate therapies that offer hope for finally being able to alter ALS disease progression. These are described and prioritized herein, and suggestions are offered for efficiently sifting through them.}, }
@article {pmid17597554, year = {2007}, author = {Rochet, JC}, title = {Novel therapeutic strategies for the treatment of protein-misfolding diseases.}, journal = {Expert reviews in molecular medicine}, volume = {9}, number = {17}, pages = {1-34}, doi = {10.1017/S1462399407000385}, pmid = {17597554}, issn = {1462-3994}, mesh = {Amyloid/adverse effects ; Dimerization ; Drug Design ; Humans ; Neurodegenerative Diseases/*drug therapy/*etiology ; *Protein Denaturation ; Protein Folding ; }, abstract = {Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.}, }
@article {pmid17593875, year = {2007}, author = {Martin, LJ}, title = {Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration.}, journal = {Reviews in the neurosciences}, volume = {18}, number = {2}, pages = {115-136}, doi = {10.1515/revneuro.2007.18.2.115}, pmid = {17593875}, issn = {0334-1763}, support = {AG16282/AG/NIA NIH HHS/United States ; NS34100/NS/NINDS NIH HHS/United States ; NS52098/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Cell Death ; Humans ; Mice ; Mice, Transgenic/*genetics/*physiology ; Mitochondria/pathology ; Motor Neurons/*pathology ; Mutation/*physiology ; Nerve Degeneration/*pathology ; Parkinson Disease/*genetics/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; alpha-Synuclein/genetics ; }, abstract = {A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.}, }
@article {pmid17585605, year = {2007}, author = {Fukushima, T and Hasegawa, A and Matsubara, N and Koike, R}, title = {[An apraxia of eyelid closure in association with frontal lobe atrophy in a patient with amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {47}, number = {5}, pages = {226-230}, pmid = {17585605}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*pathology ; Apraxia, Ideomotor/*etiology ; Atrophy ; *Eyelids ; Female ; Frontal Lobe/*pathology ; Humans ; Middle Aged ; Motor Neuron Disease/etiology ; }, abstract = {A 57 year-old woman with amyotrophic lateral sclerosis (ALS) and an apraxia of eyelid closure was reported. Her first symptom was muscle weakness in the right arm. Since neurological examination showed mainly upper motor neuron sign with neurogenic pattern in the needle electromyograms of the tongue and limb muscles, she was diagnosed as ALS. Two years and 6 months later from onset, she showed an inability to close her eyelids voluntarily or on command with normal reflex closure. MRI of the brain showed atrophy in the frontal lobe and anterior of the temporal lobe, where 123 I-IMP SPECT revealed hypoperfusion. Considering previous reports, there might be an ALS subset who showed atrophy of frontal lobe together with apraxia of eyelid closure.}, }
@article {pmid17574095, year = {2007}, author = {Mitchell, JD and Borasio, GD}, title = {Amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {369}, number = {9578}, pages = {2031-2041}, doi = {10.1016/S0140-6736(07)60944-1}, pmid = {17574095}, issn = {1474-547X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/therapy ; Female ; Humans ; Male ; Nerve Growth Factors/*therapeutic use ; *Palliative Care ; Randomized Controlled Trials as Topic ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (known in the UK as motor neuron disease) is a devastating illness with uncertain pathogenesis. In this Seminar, we review its natural history, clinical features, diagnostic criteria, variant and mimic syndromes, genetic forms, and epidemiology. Several hypotheses about causes of the disorder are discussed, such as excitotoxicity and oxidant stress, and we review past and present putative disease-modifying treatments. Disease-management strategies, from telling the patient about their illness to end-of-life decisions and palliative care, are presented. We review options for control of the main symptoms of amyotrophic lateral sclerosis--including dysphagia, dysarthria, respiratory distress, pain, and psychological disorders--and care in the terminal phase. The need for good psychosocial and spiritual care of patients and families is emphasised. We conclude with an overview of some current major issues and future prospects, ranging from the search for disease markers to challenging developments such as stem-cell and gene therapy.}, }
@article {pmid17573112, year = {2007}, author = {Gould, TW and Oppenheim, RW}, title = {Synaptic dysfunction in disease and following injury in the developing and adult nervous system: caveats in the choice of therapeutic intervention.}, journal = {Neuroscience and biobehavioral reviews}, volume = {31}, number = {8}, pages = {1073-1087}, doi = {10.1016/j.neubiorev.2007.04.015}, pmid = {17573112}, issn = {0149-7634}, support = {NS 048982/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Cell Death ; Disease Models, Animal ; Humans ; Mice ; Nervous System/*pathology ; Neuromuscular Junction/*pathology ; Presynaptic Terminals/*physiology/ultrastructure ; }, abstract = {A cardinal feature of most developmental and adult onset neurodegenerative diseases is the death of specific populations of neurons. Largely as a result of the progress made in elucidating the cellular and molecular mechanisms underlying the neuronal death that occurs during development, approaches ameliorating them often focus on the manipulation of neuronal death pathways. Recent evidence derived from the study of animal models of various neuropathological conditions, however, has revealed that damage to axons and synapses long precedes the activation of death pathways. We recently extended these findings to the most commonly studied animal model of familial amyotrophic lateral sclerosis (fALS). Inhibiting the cell death pathway by deletion of the pro-apoptotic gene Bax completely rescued spinal MNs yet failed to prevent disease in fALS transgenic mice. However, we observed distinct abnormalities within presynaptic terminals of spinal MNs at the neuromuscular junction (NMJ), as well as profound denervation. These results suggest that therapies aimed at preserving the synapse rather than the soma may be more effective at treating these neuropathologies.}, }
@article {pmid17571960, year = {2007}, author = {Okouchi, M and Ekshyyan, O and Maracine, M and Aw, TY}, title = {Neuronal apoptosis in neurodegeneration.}, journal = {Antioxidants &amp; redox signaling}, volume = {9}, number = {8}, pages = {1059-1096}, doi = {10.1089/ars.2007.1511}, pmid = {17571960}, issn = {1523-0864}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-12S1/DK/NIDDK NIH HHS/United States ; DK43785/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; DNA Damage ; Disease Progression ; Humans ; Models, Biological ; Mutation ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/*metabolism/*pathology ; Oxidation-Reduction ; Reactive Oxygen Species ; Signal Transduction ; }, abstract = {Apoptosis mediates the precise and programmed natural death of neurons and is a physiologically important process in neurogenesis during maturation of the central nervous system. However, premature apoptosis and/or an aberration in apoptosis regulation is implicated in the pathogenesis of neurodegeneration, a multifaceted process that leads to various chronic disease states, such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and diabetic encephalopathy. The current review focuses on two major areas (a) the fundamentals of apoptosis, which includes elements of the apoptotic machinery, apoptosis inducers, and emerging concepts in apoptosis research, and (b) apoptotic involvement in neurodegenerative disorders, neuroprotective treatment strategies/modalities, and the mechanisms of, and signaling in, neuronal apoptosis. Current and new experimental models for apoptosis research in neurodegenerative diseases are also discussed.}, }
@article {pmid17569578, year = {2007}, author = {Heneka, MT and Landreth, GE}, title = {PPARs in the brain.}, journal = {Biochimica et biophysica acta}, volume = {1771}, number = {8}, pages = {1031-1045}, doi = {10.1016/j.bbalip.2007.04.016}, pmid = {17569578}, issn = {0006-3002}, mesh = {Animals ; Brain/*physiology/physiopathology ; Brain Ischemia/physiopathology ; Brain Neoplasms/physiopathology ; Central Nervous System Diseases/*physiopathology ; Encephalomyelitis, Autoimmune, Experimental/physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Peroxisome Proliferator-Activated Receptors/*physiology ; }, abstract = {The biology of peroxisome proliferator activated receptors (PPARs) in physiological and pathophysiological processes has been primarily studied in peripherial organs and tissues. Recently it became clear that PPARs play an important role for the pathogenesis of various disorders of the CNS. The finding that activation of PPARs, and in particular, the PPARgamma isoform, suppresses inflammation in peripherial macrophages and in models of human autoimmune disease, instigated the experimental evaluation of these salutary actions for several CNS disorders that have an inflammatory component. Activation of all PPAR isoforms, but especially of PPARgamma, has been found to be protective in murine in vitro and in vivo models of Multiple Sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in Multiple Sclerosis patients. Likewise, Alzheimer's disease has a prominent inflammatory component that arises in response to neurodegeneration and to extracellular deposition of beta-amyloid peptides. The fact that non steroidal anti-inflammatory drugs (NSAIDs) delay the onset and reduce the risk to develop Alzheimer's disease, while they also bind to and activate PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD may be mediated by PPARgamma. Several lines of evidence from in vitro and in vivo studies have supported this hypothesis, using Alzheimer disease related transgenic cellular and animal models. The ability of PPAR agonists to elicit anti-amyloidogenic, anti-inflammatory and insulin sensitizing effects may account for the observed effects. A number of clinical trials employing PPAR agonists have yielded promising results and further trials are in preparation, which aim to delineate the exact mechanism of interaction. Animal models of other neurodegenerative diseases such as Parkinson's and Amyotrophic lateral sclerosis, both associated with a considerable degree of CNS inflammation, have been studied with a positive outcome. Yet it is not clear whether reduction of inflammation or additional mechanisms account for the observed neuroprotection. Less is known about the physiological role of PPARs for brain development, maintenance and function. Lesions from transgenic mouse models, however, provide evidence that PPARs may play pivotal roles for CNS development and function.}, }
@article {pmid17569065, year = {2007}, author = {Snowden, J and Neary, D and Mann, D}, title = {Frontotemporal lobar degeneration: clinical and pathological relationships.}, journal = {Acta neuropathologica}, volume = {114}, number = {1}, pages = {31-38}, doi = {10.1007/s00401-007-0236-3}, pmid = {17569065}, issn = {0001-6322}, mesh = {Aphasia/pathology ; Aphasia, Primary Progressive/pathology ; Dementia/*pathology ; Humans ; Motor Neuron Disease/pathology ; *Phenotype ; }, abstract = {Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.}, }
@article {pmid17568873, year = {2007}, author = {Paschoal, IA and Villalba, Wde O and Pereira, MC}, title = {Chronic respiratory failure in patients with neuromuscular diseases: diagnosis and treatment.}, journal = {Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia}, volume = {33}, number = {1}, pages = {81-92}, doi = {10.1590/s1806-37132007000100016}, pmid = {17568873}, issn = {1806-3756}, mesh = {Algorithms ; Chronic Disease ; Humans ; Hypoventilation/diagnosis/therapy ; Neuromuscular Diseases/*complications ; Respiration, Artificial ; Respiratory Insufficiency/diagnosis/*etiology/therapy ; Respiratory Muscles/physiopathology ; Respiratory System/physiopathology ; }, abstract = {Neuromuscular diseases affect alveolar air exchange and therefore cause chronic respiratory failure. The onset of respiratory failure can be acute, as in traumas, or progressive (slow or rapid), as in amyotrophic lateral sclerosis, muscular dystrophies, diseases of the myoneural junction, etc. Respiratory muscle impairment also affects cough efficiency and, according to the current knowledge regarding the type of treatment available in Brazil to these patients, it can be said that the high rates of morbidity and mortality in these individuals are more often related to the fact that they cough inefficiently rather than to the fact that they ventilate poorly. In this review, with the objective of presenting the options of devices available to support and substitute for natural ventilation in patients with neuromuscular diseases, we have compiled a brief history of the evolution of orthopedic braces and prostheses used to aid respiration since the end of the 19th century. In addition, we highlight the elements that are fundamental to the diagnosis of alveolar hypoventilation and of failure of the protective cough mechanism: taking of a clinical history; determination of peak cough flow; measurement of maximal inspiratory and expiratory pressures; spirometry in two positions (sitting and supine); pulse oximetry; capnography; and polysomnography. Furthermore, the threshold values available in the literature for the use of nocturnal ventilatory support and for the extension of this support through the daytime period are presented. Moreover, the maneuvers used to increase cough efficiency, as well as the proper timing of their introduction, are discussed.}, }
@article {pmid17566607, year = {2007}, author = {Hadano, S and Kunita, R and Otomo, A and Suzuki-Utsunomiya, K and Ikeda, JE}, title = {Molecular and cellular function of ALS2/alsin: implication of membrane dynamics in neuronal development and degeneration.}, journal = {Neurochemistry international}, volume = {51}, number = {2-4}, pages = {74-84}, doi = {10.1016/j.neuint.2007.04.010}, pmid = {17566607}, issn = {0197-0186}, mesh = {Animals ; Central Nervous System/growth &amp; development/*metabolism/physiopathology ; Cytoprotection/physiology ; Genetic Predisposition to Disease/genetics ; Guanine Nucleotide Exchange Factors/chemistry/genetics/*physiology ; Humans ; Motor Neuron Disease/genetics/*metabolism/physiopathology ; Motor Neurons/*metabolism/pathology ; Mutation/genetics ; Protein Structure, Tertiary/physiology ; Transport Vesicles/genetics/*metabolism ; }, abstract = {ALS2 is a causative gene for a juvenile autosomal recessive form of motor neuron diseases (MNDs), including amyotrophic lateral sclerosis 2 (ALS2), juvenile primary lateral sclerosis, and infantile-onset ascending hereditary spastic paralysis. These disorders are characterized by ascending degeneration of the upper motor neurons with or without lower motor neuron involvement. Thus far, a total of 12 independent ALS2 mutations, which include a small deletion, non-sense mutation, or missense mutation spreading widely across the entire coding sequence, are reported. They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid. Thus, a loss of functions in the ALS2-coded protein accounts for motor dysfunction and/or degeneration in the ALS2-linked MNDs. The ALS2 gene encodes a novel 184kDa protein of 1657 amino acids, ALS2 or alsin, comprising three predicted guanine nucleotide exchange factor (GEF) domains: the N-terminal RCC1-like domain, the central Dbl homology and pleckstrin homology (DH/PH) domains, and the C-terminal vacuolar protein sorting 9 (VPS9) domain. In addition, eight consecutive membrane occupation and recognition nexus (MORN) motifs are noted in the region between DH/PH and VPS9 domains. ALS2 activates Rab5 small GTPase and involves in endosome/membrane trafficking and fusions in the cells, and also promotes neurite outgrowth in neuronal cultures. Further, a neuroprotective role for ALS2 against cytotoxicity; i.e., the mutant Cu/Zn-superoxide dismutase 1 (SOD1)-mediated toxicity, oxidative stress, and excitotoxicity, has recently been implied. This review outlines current understandings of the molecular and cellular functions of ALS2 and its related proteins on safeguarding the integrity of motor neurons, and sheds light on the molecular pathogenesis of MNDs as well as other conditions of neurodegenerative diseases.}, }
@article {pmid17564284, year = {2007}, author = {Chetta, A and Aiello, M and Tzani, P and Olivieri, D}, title = {Assessment and monitoring of ventilatory function and cough efficacy in patients with amyotrophic lateral sclerosis.}, journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace}, volume = {67}, number = {1}, pages = {43-52}, doi = {10.4081/monaldi.2007.509}, pmid = {17564284}, issn = {1122-0643}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology/therapy ; Cough/*physiopathology ; Drainage, Postural ; Humans ; *Muscle Strength ; Respiration ; Respiration, Artificial ; Respiratory Function Tests/methods ; Respiratory Insufficiency/etiology/physiopathology/therapy ; Respiratory Muscles/*physiopathology ; }, abstract = {Assessing and monitoring respiratory muscle function is crucial in patients with Amyotrophic Lateral Sclerosis, since impaired function can lead to either ventilatory failure or respiratory tract infection. Spirometry, diffusing capacity of the lung, breathing pattern, sleep study, blood gas analysis and respiratory muscle strength tests, as well as cough peak flow and cough expiratory volume measurements can provide relevant information on ventilatory function and cough efficacy. With regard to respiratory muscle strength testing, the rational approach consists in starting with volitional and non-invasive tests and later using invasive and non-volitional tests. This review focuses on both ventilatory and respiratory muscle strength testing, in order to undertake a timely treatment of respiratory failure and/or impaired cough efficacy. So far, the current literature has not highlighted any gold standard which stipulates when to commence ventilation and cough support in patients with Amyotrophic Lateral Sclerosis. A composite set of clinical and functional parameters is required for treatment scheduling to monitor lung involvement and follow-up in these patients.}, }
@article {pmid17556854, year = {2007}, author = {Yorkston, KM}, title = {The degenerative dysarthrias: a window into critical clinical and research issues.}, journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)}, volume = {59}, number = {3}, pages = {107-117}, doi = {10.1159/000101769}, pmid = {17556854}, issn = {1421-9972}, mesh = {Dysarthria/*physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Research/trends ; }, abstract = {Although diversity of symptoms and urgency of needs pose many challenges, management of the degenerative dysarthrias is a crucial aspect of clinical practice. The purpose of this article is to review current research literature on selected degenerative dysarthrias including those associated with Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. These dysarthrias are prevalent yet represent distinct patterns of underlying neuropathology, symptoms, age of onset, and rate of progression. Literature searches including the period 1997-2006 yielded 148 different studies reporting data on communication issues related to dysarthria. By far the largest category of studies was that which provided a basic description of speech production including the neurophysiologic, acoustic, or perceptual properties of dysarthria. Other categories included management (assessment and treatment) and the psychosocial consequences of dysarthria. While the topic of management of degenerative dysarthria is a focused one, it provides a window into many issues critical to the field of communication disorders including fundamental properties of speech production, development of evidence-based treatment techniques, the staging of these techniques into an effective management sequence, and the psychosocial consequences of communication disorders along with techniques to maintain communicative participation in the face of degenerative conditions.}, }
@article {pmid17554046, year = {2007}, author = {Dranginis, AM and Rauceo, JM and Coronado, JE and Lipke, PN}, title = {A biochemical guide to yeast adhesins: glycoproteins for social and antisocial occasions.}, journal = {Microbiology and molecular biology reviews : MMBR}, volume = {71}, number = {2}, pages = {282-294}, pmid = {17554046}, issn = {1092-2172}, support = {S06 GM060654/GM/NIGMS NIH HHS/United States ; F31 GM 070122/GM/NIGMS NIH HHS/United States ; F31 GM070122/GM/NIGMS NIH HHS/United States ; S06 GM076168/GM/NIGMS NIH HHS/United States ; RR03037/RR/NCRR NIH HHS/United States ; R15 AI 43927/AI/NIAID NIH HHS/United States ; G12 RR003037/RR/NCRR NIH HHS/United States ; S06 GM60654/GM/NIGMS NIH HHS/United States ; }, mesh = {Cell Adhesion/physiology ; Cell Adhesion Molecules/physiology ; Glycoproteins/*physiology ; Mating Factor ; Peptides/physiology ; Pheromones/physiology ; Saccharomyces cerevisiae/genetics/*physiology ; }, abstract = {Fungi are nonmotile eukaryotes that rely on their adhesins for selective interaction with the environment and with other fungal cells. Glycosylphosphatidylinositol (GPI)-cross-linked adhesins have essential roles in mating, colony morphology, host-pathogen interactions, and biofilm formation. We review the structure and binding properties of cell wall-bound adhesins of ascomycetous yeasts and relate them to their effects on cellular interactions, with particular emphasis on the agglutinins and flocculins of Saccharomyces and the Als proteins of Candida. These glycoproteins share common structural motifs tailored to surface activity and biological function. After being secreted to the outer face of the plasma membrane, they are covalently anchored in the wall through modified GPI anchors, with their binding domains elevated beyond the wall surface on highly glycosylated extended stalks. N-terminal globular domains bind peptide or sugar ligands, with between millimolar and nanomolar affinities. These affinities and the high density of adhesins and ligands at the cell surface determine microscopic and macroscopic characteristics of cell-cell associations. Central domains often include Thr-rich tandemly repeated sequences that are highly glycosylated. These domains potentiate cell-to-cell binding, but the molecular mechanism of such an association is not yet clear. These repeats also mediate recombination between repeats and between genes. The high levels of recombination and epigenetic regulation are sources of variation which enable the population to continually exploit new niches and resources.}, }
@article {pmid17542619, year = {2007}, author = {Reynolds, MR and Berry, RW and Binder, LI}, title = {Nitration in neurodegeneration: deciphering the "Hows" "nYs".}, journal = {Biochemistry}, volume = {46}, number = {25}, pages = {7325-7336}, doi = {10.1021/bi700430y}, pmid = {17542619}, issn = {0006-2960}, support = {AG14453/AG/NIA NIH HHS/United States ; AG21184/AG/NIA NIH HHS/United States ; F30 NS051043/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*metabolism/pathology ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Humans ; Nitrates/*metabolism ; Parkinson Disease/*metabolism/pathology ; Protein Processing, Post-Translational ; Superoxide Dismutase/chemistry/genetics/*metabolism ; Tyrosine 3-Monooxygenase/chemistry/genetics/*metabolism ; alpha-Synuclein/chemistry/genetics/*metabolism ; tau Proteins/chemistry/genetics/*metabolism ; }, abstract = {Recent literature has ushered in a new awareness of the diverse post-translational events that can influence protein folding and function. Among these modifications, protein nitration is thought to play a critical role in the onset and progression of several neurodegenerative diseases. While previously considered a late-stage epiphenomenon, nitration of protein tyrosine residues appears to be an early event in the lesions of amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The advent of highly specific biochemical and immunological detection methods reveals that nitration occurs in vivo with biological selectively and site specificity. In fact, nitration of only a single Tyr residue is often sufficient to induce profound changes in the activity of catalytic proteins and the three-dimensional conformation of structural proteins. Presumably, nitration modifies protein function by altering the hydrophobicity, hydrogen bonding, and electrostatic properties within the targeted protein. Most importantly, however, nitrative injury may represent a unifying mechanism that explains how genetic and environmental causes of neurological disease manifest a singular phenotype. In this review and synthesis, we first examine the pathways of protein nitration in biological systems and the factors that influence site-directed nitration. Subsequently, we turn our attention to the structural implications of site-specific nitration and how it affects the function of several neurodegeneration-related proteins. These proteins include Mn superoxide dismutase and neurofilament light subunit in amyotrophic lateral sclerosis, alpha-synuclein and tyrosine hydroxylase in Parkinson's disease, and tau in Alzheimer's disease.}, }
@article {pmid17538774, year = {2007}, author = {Smith, AP and Lee, NM}, title = {Role of zinc in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {3}, pages = {131-143}, doi = {10.1080/17482960701249241}, pmid = {17538774}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*physiopathology ; Animals ; Glutamic Acid/physiology ; Humans ; Mitochondria/pathology ; Oxidative Stress/physiology ; Zinc/*physiology ; }, abstract = {The causes of amyotrophic lateral sclerosis (ALS) are poorly understood. A small proportion, about 2%, is associated with a mutation in the superoxide dismutase (SOD1) gene, and mice expressing this mutant gene exhibit a progressive, ALS-like neurodegenerative disease. Studies of these animals, as well as of human post mortem tissue, reveal the presence of multiple pathological processes, including oxidative stress, glutamate excitotoxicity, neuroinflammation, mitochondrial degeneration, alterations in neurofilaments and neurotubules, mitochondrial damage, aggregation of proteins, abnormalities in growth factors, and apoptosis. We propose that alterations in the disposition of zinc ions may be important in the initiation and development of ALS. SOD1 binds zinc, and many of the mutant forms of this enzyme associated with ALS show altered zinc binding. Alterations in the expression of metallothioneins (MTs), which regulate cellular levels of zinc, have been reported in mutant SOD1 mice, and deletion of MTs in these animals accelerates disease progression. Zinc plays a key role in all the pathological processes associated with ALS. Our zinc hypothesis also may help explain evidence for environmental factors in some cases of ALS, such as in the Chamorro tribe in Guam and in the Gulf War.}, }
@article {pmid17533972, year = {2007}, author = {Aoki, S and Masutani, Y and Abe, O}, title = {[Magnetic resonance diffusion tractography in the brain--its application and limitation].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {5}, pages = {467-476}, pmid = {17533972}, issn = {1881-6096}, mesh = {Brain/*anatomy &amp; histology ; Diffusion Magnetic Resonance Imaging/*methods ; Humans ; }, abstract = {Diffusion tractography of magnetic resonance imaging (MRI), such as diffusion tensor tractography, allows us to visualize white matter tracts in vivo and to study white matter integrity quantitatively. Virtual dissection of the living human brain can be performed in the first time. We developed tracking software, dTV and VOLUME-ONE, in 2001, as a freeware (http://www.ut-radiology.umin.jp/people/masutani/dTV. htm), and we used it to visualize eloquent white matter bundles with relationship to brain tumors, cerebral infarctions and other lesions. We also used it for quantitative measurement of the specific tracts segmented by diffusion tensor tractography (tract-specific analysis) to reveal abnormalities in so-called normal appearing white matter. Three dimensional visualization of the white matter fibers such as corticospinal (pyramidal) tract, optic radiation and arcuate fasciculus with relationship to brain tumors such as gliomas was extremely helpful for preoperative evaluation and intraoperative navigation. We correlated tracking with intraoperative electric fiber stimulation to validate fiber tracking. In patients with small lacunar infarctions near the corticospinal tracts, relationship between the tract and fresh infarction correlated well with final (2 weeks-later) motor function. Quantitative measurement of the tract is a very sensitive tool. We analyzed the corticospinal and corticobulbar tracts in patients with amyotrophic lateral sclerosis (ALS). Changes of the diffusion parameters (fractional anisotropy and ADC) of the tracts were observed not only between normal controls but also between subtypes of ALS (limb- and bulbar-onset). Tract- specific analysis can also apply for the limbic-related tracts such as fornix, cingulum, uncinate fasciculus and etc. We observed differences in some of the fibers in neurocognitive/psychiatric patients such as schizophrenia and Alzheimer disease. Using fiber tracking, we can now develop white matter mapping. We visualized components of the pyramidal tract (fibers from foot, hand, face motor areas separately) and made a probabilistic map. Diffusion tractography is a unique tool to visualize and segment the white matter pathways and one can evaluate the segmented tract quantitatively. Importance of this tool will become more significant in clinical and neuroscience fields in the future.}, }
@article {pmid17526058, year = {2007}, author = {Kesavapany, S and Zheng, YL and Amin, N and Pant, HC}, title = {Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5.}, journal = {Biotechnology journal}, volume = {2}, number = {8}, pages = {978-987}, doi = {10.1002/biot.200700057}, pmid = {17526058}, issn = {1860-7314}, mesh = {Animals ; Brain/*enzymology ; Cyclin-Dependent Kinase 5/*metabolism ; Enzyme Activation ; Humans ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*enzymology ; Peptides/*metabolism ; }, abstract = {Normal Cdk5 activity, conferred mainly by association with its primary activator p35, is critical for normal function of the cell and must be tightly regulated. During neurotoxicity, p35 is cleaved to form p25, which becomes a potent and mislocalized hyperactivator of Cdk5, resulting in a deregulation of Cdk5 activity. p25 levels have been found to be elevated in Alzheimer's disease (AD) brain and overexpression of p25 in a transgenic mouse results in the formation of phosphorylated tau, neurofibrillary tangles and cognitive deficits that are pathological hallmarks of AD. p25/Cdk5 also hyperphosphorylates neurofilament proteins that constitute pathological hallmarks found in Parkinson's disease and amyotrophic lateral sclerosis. The selective targeting of p25/Cdk5 activity without affecting p35/Cdk5 activity has been unsuccessful. In this review we detail our recent studies of selective p25/Cdk5 inhibition without affecting p35/Cdk5 or mitotic Cdk activities. We found that a further truncation of p25 to yield a Cdk5 inhibitory peptide (CIP) can specifically inhibit p25/Cdk5 activity in transfected HEK cells and primary cortical neurons. CIP was able to reduce tau hyperphosphorylation and neuronal death induced caused by p25/Cdk5 and further studies with CIP may develop a specific Cdk5 inhibition strategy in the treatment of neurodegeneration.}, }
@article {pmid17516042, year = {2007}, author = {Meyer, T and Münch, C and van Landeghem, FK and Borisow, N and Dullinger, J and Linke, P}, title = {[Progressive muscle atrophy. A rarely diagnosed variant of amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {78}, number = {12}, pages = {1383-1388}, pmid = {17516042}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/*therapy ; Diagnosis, Differential ; Diagnostic Errors/*prevention &amp; control ; Humans ; Muscular Atrophy, Spinal/classification/*diagnosis/*therapy ; Practice Patterns, Physicians'/trends ; }, abstract = {Progressive muscle atrophy (PMA) is a degenerative disease of the lower motor neuron. The course of the illness and the fatal prognosis correspond to those of amyotrophic lateral sclerosis (ALS). Neuropathologic and genetic findings support categorizing PMA within the spectrum of ALS, even though no clinical sign of a disorder of the upper motor neuron is demonstrable. The diagnosis of PMA is based on advanced extremity pareses and atrophies with a high progression rate. Respiratory insufficiency is determinative of the prognosis. Absent or late affection of bulbar functions is characteristic of the disease. Intraneuronal bunina bodies and ubiquitine-positive inclusions, which are established morphologic characteristics of ALS, are found post mortem. The treatment options of riluzol medication, respiratory therapy, and nutrition are analogous to those for typical ALS.}, }
@article {pmid17505405, year = {2007}, author = {Travers, E and Jones, K and Nichol, J}, title = {Palliative care provision in Huntington's disease.}, journal = {International journal of palliative nursing}, volume = {13}, number = {3}, pages = {125-130}, doi = {10.12968/ijpn.2007.13.3.23274}, pmid = {17505405}, issn = {1357-6321}, mesh = {Aftercare/organization &amp; administration ; Evidence-Based Medicine ; Family/psychology ; Health Services Accessibility/organization &amp; administration ; Health Services Needs and Demand/*organization &amp; administration ; Humans ; Huntington Disease/epidemiology/psychology/*therapy ; Long-Term Care ; Palliative Care/*organization &amp; administration ; Patient Care Planning/organization &amp; administration ; Prognosis ; Quality of Life ; Scotland/epidemiology ; Social Support ; State Medicine/organization &amp; administration ; }, abstract = {There is currently much interest regarding the needs of people affected by non-malignant disease and whether or not these are being met by palliative care services. The evidence available appears to support the conclusion that while there is a general inequality of access, some individuals with non-malignant conditions such as cardiac disease and motor neurone disease are able to access palliative care services more readily than others. Huntington's disease (HD) is a devastating neurological condition of long duration and as such may have a lengthy palliative phase. Consequently, a diagnosis of HD will have a major impact on the quality of life of the affected individual and their family. For carers, an understanding of this challenging disease and its prognosis is essential for the provision of appropriate and effective care. This article reviews the links between HD and palliative care and discusses some of the challenges facing patients, families and health care professionals in adopting a palliative approach in the management of the disease.}, }
@article {pmid17504097, year = {2007}, author = {Kastenholz, B}, title = {New hope for the diagnosis and therapy of Alzheimer's disease.}, journal = {Protein and peptide letters}, volume = {14}, number = {4}, pages = {389-393}, doi = {10.2174/092986607780363970}, pmid = {17504097}, issn = {0929-8665}, mesh = {*Alzheimer Disease/diagnosis/therapy ; Electrophoresis, Polyacrylamide Gel ; Humans ; Metalloproteins/chemistry ; Molecular Chaperones/chemistry/*isolation &amp; purification ; Protein Conformation ; Protein Denaturation ; Protein Folding ; }, abstract = {Improperly folded metal cofactor-containing proteins (e.g., copper chaperone for superoxide dismutase, CCS) are believed to play a key role in several protein-misfolding diseases (e.g., Alzheimer's disease or Amyotrophic Lateral Sclerosis) because under regular physiological conditions, metallochaperones activate or stabilize the native conformation of important metalloproteins (e.g., superoxide dismutase) in certain cellular processes. For an improved diagnosis and therapy of neurodegenerative diseases, new methodologies have to be developed that enable a well-defined differentiation between properly folded and inactive metalloproteins in clinical samples. In the literature it is reported that different high molecular mass metal-containing proteins were isolated in brain samples from Alzheimer's patients and in vegetables by using a 2-dimensional polyacrylamide gel electrophoresis (2-DE) procedure. In the present article, selected results of these studies are scrutinized and compared with some results obtained by a standardized method termed 'quantitative preparative native continuous polyacrylamide gel electrophoresis (QPNC-PAGE)'. Conclusively, QPNC-PAGE is a highly efficient approach used by biochemists to resolve native and denatured metalloproteins (MW 6 - > or = 200 kDa) in complex protein mixtures.}, }
@article {pmid17498699, year = {2007}, author = {Butsch, PO and Cudkowicz, ME}, title = {Is erythropoietin a potential therapy for amyotrophic lateral sclerosis?.}, journal = {Experimental neurology}, volume = {206}, number = {1}, pages = {11-15}, doi = {10.1016/j.expneurol.2007.04.001}, pmid = {17498699}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/physiopathology ; Animals ; Cell Death/drug effects/physiology ; Clinical Trials as Topic/standards ; Disease Models, Animal ; Erythropoietin/metabolism/*pharmacology/therapeutic use ; Humans ; Mice ; Motor Neurons/drug effects/metabolism ; Neuroprotective Agents/metabolism/*pharmacology/therapeutic use ; Rats ; Receptors, Cell Surface/drug effects/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, }
@article {pmid17497670, year = {2007}, author = {Tilleux, S and Hermans, E}, title = {Neuroinflammation and regulation of glial glutamate uptake in neurological disorders.}, journal = {Journal of neuroscience research}, volume = {85}, number = {10}, pages = {2059-2070}, doi = {10.1002/jnr.21325}, pmid = {17497670}, issn = {0360-4012}, mesh = {Animals ; Free Radicals/metabolism ; Glucose Transport Proteins, Facilitative/metabolism ; Glutamic Acid/*metabolism ; Humans ; Inflammation Mediators/metabolism ; Nervous System Diseases/*complications/*metabolism ; Neuritis/*etiology ; Neuroglia/*metabolism ; }, abstract = {Oxidative stress, neuroinflammation, and excitotoxicity are frequently considered distinct but common hallmarks of several neurological disorders, including Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease. Although neuron degeneration and death are the ultimate consequences of these pathological processes, it is now widely accepted that alterations in the function of surrounding glial cells are key features in the progression of these diseases. In response to alteration in their local environment, microglia, commonly considered the resident immune cells of the nervous parenchyma, become activated and release a variety of soluble factors. Among these, proinflammatory cytokines and free radicals actively participate in the degenerative insults. In addition, excitotoxic neuronal damage resulting from excessive glutamate is frequently associated with impaired handling of extracellular glutamate by gliotic astrocytes. Although several research projects have focused on the biochemical mechanisms of the regulation of glial glutamate transporters, a relationship between activation of microglia and modulation of astrocytic glutamate uptake is now suggested. The aim of this review is to summarize and discuss the data showing an influence of inflammatory mediators and related free radicals on the expression and activity of glial glutamate transporters.}, }
@article {pmid17496232, year = {2007}, author = {Carreras, MC and Poderoso, JJ}, title = {Mitochondrial nitric oxide in the signaling of cell integrated responses.}, journal = {American journal of physiology. Cell physiology}, volume = {292}, number = {5}, pages = {C1569-80}, doi = {10.1152/ajpcell.00248.2006}, pmid = {17496232}, issn = {0363-6143}, mesh = {Animals ; Apoptosis ; Brain/growth &amp; development/metabolism ; Cell Cycle/physiology ; Cell Proliferation ; Humans ; Hydrogen Peroxide/metabolism ; Hypothyroidism/metabolism/physiopathology ; Liver/growth &amp; development/metabolism ; Mitochondria/*metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Peroxynitrous Acid/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {Mitochondria are the specialized organelles for energy metabolism, but, as a typical example of system biology, they also activate a multiplicity of pathways that modulate cell proliferation and mitochondrial biogenesis or oppositely promote cell arrest and programmed cell death by a limited number of oxidative or nitrosative reactions. These reactions are influenced by matrix nitric oxide (NO) steady-state concentration, either from local production or by gas diffusion to mitochondria from the canonical sources. Likewise, in a range of approximately 30-200 nM, NO turns mitochondrial O(2) utilization down by binding to cytochrome oxidase and elicits a burst of superoxide anion and hydrogen peroxide that diffuses outside mitochondria. Depending on NO levels and antioxidant defenses, more or less H(2)O(2) accumulates in cytosol and nucleus, and the resulting redox grading contributes to dual activation of proliferating and proapoptotic cascades, like ERK1/2 or p38 MAPK. Moreover, these sequential activating pathways participate in rat liver and brain development and in thyroid modulation of mitochondrial metabolism and contribute to hypothyroid phenotype through complex I nitration. On the contrary, lack of NO disrupts pathways like S-nitrosylation or H(2)O(2) production and likewise is a gateway to disease in amyotrophic lateral sclerosis with superoxide dismutase 1 mutations or to cancer proliferation.}, }
@article {pmid17493044, year = {2007}, author = {Kumar-Singh, S and Van Broeckhoven, C}, title = {Frontotemporal lobar degeneration: current concepts in the light of recent advances.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {17}, number = {1}, pages = {104-114}, pmid = {17493044}, issn = {1015-6305}, mesh = {Brain/metabolism/*pathology/physiopathology ; Dementia/classification/metabolism/pathology/*physiopathology ; Humans ; tau Proteins/*metabolism ; }, abstract = {Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS). Mutations in MAPT were found to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a familial disorder with filamentous tau inclusions in nerve cells and glial cells. FTDP-17 can result in clinical syndromes that closely resemble progressive supranuclear palsy, corticobasal degeneration and Pick's disease. More recently, mutations in three genes (VCP, CHMP2B and PGRN) have been found to cause FTLD with ubiquitin-positive, tau-negative neuronal inclusions (FTLD-U). They explain a large proportion of inherited FTLD-U. It remains to be seen whether dementia lacking distinctive histopathology (DLDH) constitutes a third disease category, as many of these cases are now being reclassified as FTLD-U. Recently, TAR DNA-binding protein-43 (TDP-43) has been identified as a key protein of the ubiquitin inclusions of FTLD-U and ALS. Thus, for familial forms of FTLD and related disorders, we now know the primary etiologies and accumulating proteins. These findings are pivotal for dissecting the pathways by which different etiologies lead to the varied clinicopathological presentations of FTLD.}, }
@article {pmid17492294, year = {2007}, author = {Kwong, LK and Neumann, M and Sampathu, DM and Lee, VM and Trojanowski, JQ}, title = {TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease.}, journal = {Acta neuropathologica}, volume = {114}, number = {1}, pages = {63-70}, doi = {10.1007/s00401-007-0226-5}, pmid = {17492294}, issn = {0001-6322}, support = {AG10124/AG/NIA NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; T32 AG00255/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers/metabolism ; DNA-Binding Proteins/*metabolism ; Dementia/diagnosis/*metabolism ; Humans ; Motor Neuron Disease/diagnosis/*metabolism ; }, abstract = {The rapid confirmation of the initial report by Neumann et al. (Science 314:130-133, 2006) that transactive response (TAR)-DNA-binding protein 43 (TDP-43) is the major disease protein linking frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease (MND) as well as amyotrophic lateral sclerosis (ALS) implies that TDP-43 proteinopathy underlies major forms of sporadic as well as familial FTLD and ALS. Not only was the identity of the ubiquitinated proteins that accumulate in neurons and glia of these disorders finally resolved, but it also was shown that pathologic TDP-43 was hyperphosphorylated, ubiquitinated and cleaved to generate C-terminal fragments in affected brain and spinal cord of FTLD-U and ALS. This review summarizes the growing evidence that TDP-43 proteinopathy is the common pathologic substrate linking FTLD and ALS, and it considers the implications of these findings for developing better strategies to diagnose and treat these neurodegenerative disorders.}, }
@article {pmid17492293, year = {2007}, author = {Raab, S and Plate, KH}, title = {Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system.}, journal = {Acta neuropathologica}, volume = {113}, number = {6}, pages = {607-626}, doi = {10.1007/s00401-007-0228-3}, pmid = {17492293}, issn = {0001-6322}, mesh = {Animals ; Blood Vessels/*physiology ; Ephrins/physiology ; Humans ; Intercellular Signaling Peptides and Proteins/*physiology ; Nerve Growth Factors/physiology ; Nervous System/growth &amp; development ; *Nervous System Physiological Phenomena ; Neuroprotective Agents/pharmacology ; Receptors, Nerve Growth Factor/physiology ; Receptors, Vascular Endothelial Growth Factor/physiology ; Signal Transduction/*physiology ; Vascular Endothelial Growth Factors/physiology ; }, abstract = {Growth factors and their respective receptors are key regulators during development and for homeostasis of the nervous system. In addition, changes in growth factor function, availability or downstream signaling is involved in many neuropathological disorders like Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke and brain tumours. Research of the recent years revealed that some growth factors, initially discovered as neural growth factors are also affecting blood vessels [e.g. nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF)]. Likewise, vascular growth factors, such as vascular endothelial growth factor (VEGF), which was previously described as an endothelial cell specific mitogen, also affect neural cells. The discovery of shared growth factors affecting the vascular and the nervous system is of relevance for potential therapies of vascular and neurological diseases. This review aims to give an overview about the growing field of common growth factors and receptors within the two different networks.}, }
@article {pmid17488226, year = {2007}, author = {Yun, AJ and Lee, PY and Doux, JD}, title = {Negative pressure ventilation via diaphragmatic pacing: a potential gateway for treating systemic dysfunctions.}, journal = {Expert review of medical devices}, volume = {4}, number = {3}, pages = {315-319}, doi = {10.1586/17434440.4.3.315}, pmid = {17488226}, issn = {1743-4440}, mesh = {Diaphragm/*physiology ; Humans ; Hypoventilation/*therapy ; Respiration, Artificial/*instrumentation ; Sleep Apnea, Central/*therapy ; *Ventilators, Negative-Pressure ; }, abstract = {Programmed diaphragmatic pacing using implanted neuromodulators represents an emerging method for providing pulmonary support using negative pressure ventilation. The implantable, rechargeable, programmable and miniaturized nature of diaphragmatic pacers may obviate many of the management issues associated with noninvasive positive pressure ventilation devices. Closed loop systems may facilitate the implementation of diaphragmatic pacing for the treatment of many indications. They may allow for wider adoption of ventilatory support in central sleep apnea and improve quality of life in diseases of chronic hypoventilation, such as amyotrophic lateral sclerosis. In addition, it might alleviate subclinical hypoventilation--a condition that may affect a significant proportion of the aging population. Diaphragmatic pacing could also reduce sympathetic bias, which may contribute to a wide range of diseases associated with autonomic dysfunction.}, }
@article {pmid17486441, year = {2007}, author = {Petrozzi, L and Ricci, G and Giglioli, NJ and Siciliano, G and Mancuso, M}, title = {Mitochondria and neurodegeneration.}, journal = {Bioscience reports}, volume = {27}, number = {1-3}, pages = {87-104}, doi = {10.1007/s10540-007-9038-z}, pmid = {17486441}, issn = {0144-8463}, mesh = {Alzheimer Disease/genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA, Mitochondrial/*genetics ; Humans ; Huntington Disease/genetics/metabolism/pathology ; Mitochondria/*metabolism ; *Mutation ; Neurodegenerative Diseases/genetics/metabolism/*pathology ; Parkinson Disease/genetics/metabolism/pathology ; }, abstract = {Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question "is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration.}, }
@article {pmid17485247, year = {2007}, author = {Galpern, WR and Cudkowicz, ME}, title = {Coenzyme Q treatment of neurodegenerative diseases of aging.}, journal = {Mitochondrion}, volume = {7 Suppl}, number = {}, pages = {S146-53}, doi = {10.1016/j.mito.2007.01.004}, pmid = {17485247}, issn = {1567-7249}, mesh = {*Aging ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Clinical Trials as Topic ; Humans ; Huntington Disease/drug therapy ; Models, Biological ; Mutation ; Neurodegenerative Diseases/*drug therapy/*pathology ; Parkinson Disease/drug therapy/metabolism ; Time Factors ; Treatment Outcome ; Ubiquinone/*therapeutic use ; }, abstract = {The etiology of several neurodegenerative disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q-10 (CoQ10) acts both as an antioxidant and as an electron acceptor at the level of the mitochondria. In several animal models of neurodegenerative diseases including amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease, CoQ10 has shown beneficial effects. Based on its biochemical properties and the effects in animal models, several clinical trials evaluating CoQ10 have been undertaken in many neurodegenerative diseases. CoQ10 appears to be safe and well tolerated, and several efficacy trials are planned.}, }
@article {pmid17484132, year = {2007}, author = {Anne-Laurence, B and Caroline, R and Irina, P and Jean-Philippe, L}, title = {Chromatin acetylation status in the manifestation of neurodegenerative diseases: HDAC inhibitors as therapeutic tools.}, journal = {Sub-cellular biochemistry}, volume = {41}, number = {}, pages = {263-293}, pmid = {17484132}, issn = {0306-0225}, mesh = {Acetylation/drug effects ; Animals ; Apoptosis/drug effects ; CREB-Binding Protein/metabolism ; Chromatin/*metabolism ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Histone Acetyltransferases/metabolism ; *Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Histones/*metabolism ; Humans ; Isoenzymes/antagonists &amp; inhibitors/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism/physiopathology ; Neurons/drug effects/metabolism ; Protein Processing, Post-Translational/*drug effects ; }, abstract = {During the development and maintenance of the central nervous system, neurons receive specific instructions to differentiate, survive or die, the correct choice being crucial for the maturation of a functional brain and to face pathological conditions. At the transcriptional level, chromatin remodeling enzymes participates in such processes. In this paper, we will see that disruption of the Histone acetyl transferase (HAT)/Deacetylase (HDAC) balance is often observed in different contexts of neurological disorders and more particularly during neuronal apoptosis. During the last 5 years, it has been evidenced that the chromatin acetylation status was greatly impaired in different neurodegenerative diseases, a common mechanism being the loss of function of a specific HAT: the CREB-binding protein (CBP). We will review the last attempts of the use of small molecules antagonizing HDAC activity (HDAC inhibitors) to restore proper levels of acetylation and enhance neuronal survival, both in in vitro and in vivo models of neurodegenerative diseases such as polyglutamine-related diseases and amyotrophic lateral sclerosis. Although this strategy lacks specificity towards CBP, certain of these molecules display promising therapeutic properties}, }
@article {pmid17472516, year = {2007}, author = {Elman, LB and Houghton, DJ and Wu, GF and Hurtig, HI and Markowitz, CE and McCluskey, L}, title = {Palliative care in amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis.}, journal = {Journal of palliative medicine}, volume = {10}, number = {2}, pages = {433-457}, doi = {10.1089/jpm.2006.9978}, pmid = {17472516}, issn = {1096-6218}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Multiple Sclerosis/*physiopathology ; Palliative Care/*methods ; Parkinson Disease/*physiopathology ; Quality of Life ; Terminal Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, Parkinson's disease, atypical parkinsonian syndromes, and multiple sclerosis are progressive neurologic disorders that cumulatively afflict a large number of people. Effective end-of-life palliative care depends upon an understanding of the clinical aspects of each of these disorders.<br><br>OBJECTIVES: The authors review the unique and overlapping aspects of each of these disorders with an emphasis upon the clinical management of symptoms.<br><br>DESIGN: The authors review current management and the supporting literature.<br><br>CONCLUSIONS: Clinicians have many effective therapeutic options to choose from when managing the symptoms produced by these disorders.}, }
@article {pmid17456035, year = {2007}, author = {Farah, MH}, title = {RNAi silencing in mouse models of neurodegenerative diseases.}, journal = {Current drug delivery}, volume = {4}, number = {2}, pages = {161-167}, doi = {10.2174/156720107780362276}, pmid = {17456035}, issn = {1567-2018}, support = {AG005146/AG/NIA NIH HHS/United States ; AG025658/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism/therapy ; Amyloid Precursor Protein Secretases/genetics/metabolism ; Amyloidosis/genetics/metabolism/therapy ; Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Aspartic Acid Endopeptidases/genetics/metabolism ; Ataxin-1 ; Ataxins ; Blood-Brain Barrier ; Disease Models, Animal ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Genetic Vectors ; Huntingtin Protein ; Huntington Disease/genetics/metabolism/therapy ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/genetics/*metabolism/therapy ; Nuclear Proteins/genetics/metabolism ; *RNA Interference ; RNA, Double-Stranded/genetics/metabolism ; RNA, Small Interfering/*biosynthesis/genetics ; Spinocerebellar Ataxias/genetics/metabolism/therapy ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {RNA interference (RNAi) has emerged as a potential therapeutic approach for neurodegenerative diseases, particularly those associated with autosomal dominant patterns of inheritance. In proof of concept experiments, several groups have demonstrated efficacy of using viral vectors expressing short hairpin RNA (shRNA) directed against therapeutically relevant genes in mouse models of neurodegenerative diseases, including spinocerebellar ataxia, Amyotrophic Lateral Sclerosis, Huntington's Disease and amyloidosis (a pathological aspect of Alzheimer's Disease). Although viral-based RNAi has limitations that most likely will preclude its usage in humans, a few recent developments underscore the potential of non-viral-based delivery of relevant RNAi as therapeutics for neurodegenerative diseases. Here, I will review the recent literature on effectiveness of RNAi as a therapeutic strategy in mouse models of neurodegenerative diseases.}, }
@article {pmid17447525, year = {2007}, author = {Mitsumoto, H}, title = {[A strategy to develop effective ALS therapy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {4}, pages = {383-391}, pmid = {17447525}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mice ; Practice Guidelines as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {In the early 1990s, a number of major events took place in the history of the treatment and science of ALS. A cause of familial ALS, the mutation of superoxide dismutase 1, was discovered and very shortly after, an animal model expressing the human SOD1 mutation for familial ALS was generated. Around the same time, the first medication for the treatment of ALS, riluzole, was approved. Clinical neurologists started to focus more attention on quality of life and standardizing care for patients with ALS, including devising approaches for presenting and discussing the diagnosis, using aggressive symptomatic treatments, and developing a multidisciplinary care system. Since then, nutritional and respiratory care has markedly improved. Respiratory care for those with terminal ALS in Japan has been distinct and perhaps more effective compared to the rest of the world, and this unique experience must be broadly published and shared with others. In 1999, the ALS Treatment Guidelines were published by the American Academy of Neurology and are now under revision. A monitoring system to determine the impact the Guidelines had on actual patient care has taught us that caregivers have only slowly accepted the recommendation to improve quality of care. The team approach, using a multidisciplinary care system from diagnosis to the end of life, is essential to improve care for both the patient and family. Coinciding with the progress in ALS treatment, basic science and translational research also produced dramatic progress in ALS drug discovery. Over the past 15 years, more than 25 potential drugs have been tested in randomized controlled trials. Despite this progress, we have no medications other than riluzole. Although it may be true that ALS research is in its early stages compared to research in other diseases with no cure--it is probably behind cancer research by at least 20 or 30 years--we need to drastically change our approach to drug development. At a national level, we need to create a strong, cohesive team with support from a number of funding agencies, oversight from a regulatory agency, and investigators who all think "outside the box." In addition, we should obtain ideas and suggestions from accomplished experts outside of the field of ALS and put competition aside as we work together to develop strategic plans for the ALS drug development that is essential to beat this devastating disease.}, }
@article {pmid17447008, year = {2007}, author = {Lleo, A and Galea, E and Sastre, M}, title = {Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {64}, number = {11}, pages = {1403-1418}, doi = {10.1007/s00018-007-6516-1}, pmid = {17447008}, issn = {1420-682X}, mesh = {Amyloid Precursor Protein Secretases/metabolism ; *Anti-Inflammatory Agents, Non-Steroidal/metabolism/therapeutic use ; Endothelial Cells/metabolism ; Humans ; NF-kappa B/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism/prevention &amp; control ; Neuroglia/metabolism ; Neurons/metabolism ; PPAR gamma/metabolism ; Prostaglandin-Endoperoxide Synthases/metabolism ; rho GTP-Binding Proteins/metabolism ; }, abstract = {During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in neurodegeneration, particularly in pathologies such as Alzheimer's (AD) and Parkinson's (PD) disease. Evidence from epidemiological studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze the molecular (cyclooxygenases, secretases, NF-kappaB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration.}, }
@article {pmid17445834, year = {2007}, author = {McLeod, JE and Clarke, DM}, title = {A review of psychosocial aspects of motor neurone disease.}, journal = {Journal of the neurological sciences}, volume = {258}, number = {1-2}, pages = {4-10}, doi = {10.1016/j.jns.2007.03.001}, pmid = {17445834}, issn = {0022-510X}, mesh = {Activities of Daily Living ; Databases, Factual/statistics &amp; numerical data ; Humans ; Interpersonal Relations ; Motor Neuron Disease/*psychology ; Personal Satisfaction ; Quality of Life ; Retrospective Studies ; *Social Support ; Spirituality ; Surveys and Questionnaires ; }, abstract = {Motor neurone disease (MND) is an illness involving the progressive degeneration of upper and lower motor neurones. There is no known cause or cure. The physical aspects of MND frequently receive the majority of attention, with psychosocial aspects accorded secondary importance. We undertook a comprehensive search of the available literature published between 1966 and 2006 on the psychosocial aspects of MND, including quality of life (QoL), depression, social support, life sustaining treatment (LST), coping, spirituality and current practice. The literature identified that QoL correlated more strongly with measures of suffering, social support and hopelessness than with the physical state of the patient. Depression is relatively common (prevalence rates up to 50%), as are other forms of psychological distress in the MND population, and is not associated with illness severity and functional status. Depression strongly correlates with QoL. Social support is often limited for MND patients and this also influences QoL. Hope and hopelessness are important issues for MND patients with hopelessness contributing significantly to suffering and, for some, a desire for hastened death. Choices and decisions about life sustaining treatments pose a burden for patients and carers. Despite the physical and emotional suffering associated with MND, a significant number cope well and find positive meaning in life. Many patients opting for life sustaining treatment report a satisfactory QoL. In conclusion, psychosocial aspects of life are important for patients with MND. Depression and other expressions of distress require recognition and treatment. Issues of hope, spirituality and life and death also require attention in clinical practice. Although guidelines exist to direct physicians to attend to the physical care, there is a distinct lack of guidance to attend to the psychological state of the MND patient.}, }
@article {pmid17440635, year = {2007}, author = {Khurdayan, VK}, title = {Stem cells: therapeutic present and future.}, journal = {Drug news &amp; perspectives}, volume = {20}, number = {2}, pages = {119-128}, doi = {10.1358/dnp.2007.20.2.1083433}, pmid = {17440635}, issn = {0214-0934}, mesh = {Animals ; Diffusion of Innovation ; History, 20th Century ; History, 21st Century ; Humans ; Phenotype ; Regeneration ; Regenerative Medicine/history/*trends ; *Stem Cell Research/history ; Stem Cell Transplantation/history/*trends ; Stem Cells/*physiology ; }, abstract = {Ever since the first embryonic stem cells were isolated in the 1990s scientists and clinicians as well as the general public have followed the development of the field with great attention. As unspecialized cells capable of dividing, renewing and differentiating into specialized cells, stem cells hold great promise as a therapeutic strategy for many diseases, especially those of degenerative nature. In 2006, stem cells were actively investigated in preclinical and clinical settings to manage heart failure, amyotrophic lateral sclerosis, spinal cord injury, stroke, hematologic disorders, renal cell carcinoma, solid tumor cancer, Crohn's disease and cirrhosis, among other disorders. Likewise, biotech and pharmaceutical industry highlighted stem cells and associated products and technologies as useful tools for drug discovery that provide relevant clinical models and ensure efficacious transition of investigational compounds into preclinical testing.}, }
@article {pmid17433820, year = {2007}, author = {Miller, A and Panitch, H}, title = {Therapeutic use of dextromethorphan: key learnings from treatment of pseudobulbar affect.}, journal = {Journal of the neurological sciences}, volume = {259}, number = {1-2}, pages = {67-73}, doi = {10.1016/j.jns.2006.06.030}, pmid = {17433820}, issn = {0022-510X}, mesh = {Animals ; Brain/drug effects ; Dextromethorphan/*therapeutic use ; Enzyme Inhibitors/therapeutic use ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Multiple Sclerosis/drug therapy ; Pseudobulbar Palsy/*drug therapy/etiology/pathology ; Quinidine/therapeutic use ; }, abstract = {A variety of neurological conditions and disease states are accompanied by pseudobulbar affect (PBA), an emotional disorder characterized by uncontrollable outbursts of laughing and crying. The causes of PBA are unclear but may involve lesions in neural circuits regulating the motor output of emotional expression. Several agents used in treating other psychiatric disorders have been applied in the treatment of PBA with some success but data are limited and these agents are associated with unpleasant side effects due to nonspecific activity in diffuse neural networks. Dextromethorphan (DM), a widely used cough suppressant, acts at receptors in the brainstem and cerebellum, brain regions implicated in the regulation of emotional output. The combination of DM and quinidine (Q), an enzyme inhibitor that blocks DM metabolism, has recently been tested in phase III clinical trials in patients with multiple sclerosis and amyotrophic lateral sclerosis and was both safe and effective in palliating PBA symptoms. In addition, clinical studies pertaining to the safety and efficacy of DM/Q in a variety of neurological disease states are ongoing.}, }
@article {pmid17432192, year = {2006}, author = {Mitsumoto, H and Howe, WJ}, title = {[Management and care for patients with ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {46}, number = {11}, pages = {828-831}, pmid = {17432192}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Informed Consent ; }, abstract = {For the past decade or so, the research in ALS has dramatically changed, coinciding with the discovery of SOD1 mutations, the generation of SOD1 transgenic rodents, and the introduction of riluzole. The ALS practice guidelines have been published in a number of countries, whereas the National Database has shown the actual reality of patient practice in ALS. Multidisciplinary ALS Clinics, consisting of a team of health care professionals, provide highly specialized quality care for patients and families, and have become the standard of care in many countries. A number of mostly retrospective studies report that non-invasive positive pressure ventilation prolongs survival and improves the quality of life and other functions. Enteral feeding certainly improves quality of life, but it is still uncertain if it prolongs survival. Although end of life issues in ALS care have been difficult more and more ALS clinicians are paying serious attention to it. Clinical trials are imperative to find effective medications for ALS, and many different pharmacological agents, based on a number of different hypotheses in ALS, are being actively tested or are about to be tested in the near future. Undoubtedly, we are in the midst of incredible progress in ALS.}, }
@article {pmid17430871, year = {2007}, author = {Baek, WS and Desai, NP}, title = {ALS: pitfalls in the diagnosis.}, journal = {Practical neurology}, volume = {7}, number = {2}, pages = {74-81}, pmid = {17430871}, issn = {1474-7766}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/diagnosis/physiopathology ; Muscular Atrophy, Spinal/diagnosis/physiopathology ; Neurologic Examination/methods ; }, }
@article {pmid17428473, year = {2007}, author = {Thyagarajan, A and Strong, MJ and Szaro, BG}, title = {Post-transcriptional control of neurofilaments in development and disease.}, journal = {Experimental cell research}, volume = {313}, number = {10}, pages = {2088-2097}, doi = {10.1016/j.yexcr.2007.02.014}, pmid = {17428473}, issn = {0014-4827}, mesh = {3' Untranslated Regions/genetics ; Animals ; Central Nervous System/*metabolism/pathology/physiopathology ; Humans ; Inclusion Bodies/genetics/metabolism/pathology ; Motor Neuron Disease/genetics/metabolism/physiopathology ; Neurodegenerative Diseases/genetics/*metabolism/physiopathology ; Neurofilament Proteins/*biosynthesis/*genetics ; Neurons/*metabolism/pathology ; RNA Processing, Post-Transcriptional/*genetics ; RNA, Messenger/*genetics/metabolism ; }, abstract = {Tight coordination of the expression of neurofilament subunits is integral to the normal development and function of the nervous system. Imbalances in their expression are increasingly implicated in the induction of neurodegeneration in which formation of neurofilamentous aggregates is central to the pathology. Neurofilament expression can be controlled not only at the transcriptional level but also through post-transcriptional regulation of mRNA localization, stability, and translational efficiency. The critical role that post-transcriptional mechanisms play in maintaining neurofilament homeostasis is highlighted, for example, by the human disease amyotrophic lateral sclerosis, in which selective destabilization of NF-L mRNA (or failure to stabilize it) is associated with the formation of neurofilamentous aggregates - a hallmark of the disease process. This review discusses the post-transcriptional regulatory mechanisms and associated ribonucleoproteins that have been implicated to date in controlling neurofilament expression during normal development and in disrupting neurofilament homeostasis during neurodegenerative disease.}, }
@article {pmid17426672, year = {2007}, author = {Brooks, BR}, title = {Involuntary emotional expression disorder: treating the untreated.}, journal = {CNS spectrums}, volume = {12}, number = {4 Suppl 5}, pages = {23-27}, doi = {10.1017/s1092852900025980}, pmid = {17426672}, issn = {1092-8529}, mesh = {Affective Symptoms/diagnosis/*drug therapy/psychology ; Antidepressive Agents/adverse effects/therapeutic use ; Clinical Trials as Topic ; Dextromethorphan/adverse effects/therapeutic use ; Dopamine Agents/therapeutic use ; Drug Therapy, Combination ; Humans ; Psychotropic Drugs/adverse effects/*therapeutic use ; Quinidine/adverse effects/therapeutic use ; Treatment Outcome ; }, abstract = {Patients with involuntary emotional expression disorder (IEED) have impaired social and occupational functioning and there is currently no Food an Drug Administration-approved treatment. Treatment options include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), dopaminergic agents, and a combination of dextromethorphan and quinidine. Studies of monaminergic agents have typically been small and executed in single-center settings. Assessment measures generally show significant symptomatic improvements, including a reduction in the number of laughing or crying episodes and improvements in patients' clinical condition. The tolerability profiles of these agents are well defined, and include dizziness, tachycardia and QTc prolongation (TCAs), and sleep and sexual disturbances (SSRIs). The combination of dextromethorphan and quinidine has also been assessed in two large multicenter studies in patients with amyotrophic lateral sclerosis and multiple sclerosis. Compared with placebo and either agent alone, there were significant improvements in symptoms, quality of life, and relationships. The most common side effects were dizziness and nausea, and potential drug interactions with quinidine should also be considered. Choice of treatment should be evidence-based, taking into account both efficacy and tolerability.}, }
@article {pmid17426669, year = {2007}, author = {Duda, JE}, title = {History and prevalence of involuntary emotional expression disorder.}, journal = {CNS spectrums}, volume = {12}, number = {4 Suppl 5}, pages = {6-10}, doi = {10.1017/s1092852900025955}, pmid = {17426669}, issn = {1092-8529}, mesh = {Affective Symptoms/*diagnosis/etiology/psychology ; Brain Diseases/diagnosis/psychology ; Crying ; Diagnosis, Differential ; Humans ; Inhibition, Psychological ; Internal-External Control ; Laughter ; Nervous System Diseases/diagnosis/psychology ; Social Environment ; Terminology as Topic ; }, abstract = {The syndrome now known as involuntary emotional expression disorder (IEED) is a condition characterized by uncontrollable episodes of laughing and/or crying. It has been known for more than a century, but confusing and conflicting terminology may have hampered the progress of physicians in recognizing this condition. IEED is associated with various neurological disorders and neurodegenerative diseases, including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and neurological injuries such as stroke and traumatic brain injury. It is hoped that better defined terminology for IEED may help in the future diagnosis of this debilitating condition, the establishment of accurate prevalence rates for IEED in the varying underlying conditions, and also in removing blame and stigma from sufferers by providing reassurance about the nature of their condition.}, }
@article {pmid17410592, year = {2007}, author = {Renaud, S and Leppert, D}, title = {Matrix metalloproteinases in neuromuscular disease.}, journal = {Muscle &amp; nerve}, volume = {36}, number = {1}, pages = {1-13}, doi = {10.1002/mus.20772}, pmid = {17410592}, issn = {0148-639X}, mesh = {Animals ; Disease Models, Animal ; Humans ; Matrix Metalloproteinases/*metabolism ; Neuromuscular Diseases/*enzymology/pathology/physiopathology ; }, abstract = {Matrix metalloproteinases (MMPs), a family of zinc-dependent endoproteinases, are effector molecules in the breakdown of the blood-brain and blood-nerve barrier, and promote neural tissue invasion by leukocytes in inflammatory diseases of the central and peripheral nervous systems. Moreover, MMPs play an important role in synaptic remodeling, neuronal regeneration, and remyelination. Recent work concerning MMPs in patients with neuropathy, myopathy, spinal cord injury, and amyotrophic lateral sclerosis (ALS), and in corresponding animal models, is discussed in this review.}, }
@article {pmid17397969, year = {2007}, author = {Norenberg, MD and Rao, KV}, title = {The mitochondrial permeability transition in neurologic disease.}, journal = {Neurochemistry international}, volume = {50}, number = {7-8}, pages = {983-997}, pmid = {17397969}, issn = {0197-0186}, support = {R01 DK063311-01A1/DK/NIDDK NIH HHS/United States ; R01 DK063311-04/DK/NIDDK NIH HHS/United States ; R01 DK063311-02/DK/NIDDK NIH HHS/United States ; R01 DK063311-03/DK/NIDDK NIH HHS/United States ; R01 DK063311/DK/NIDDK NIH HHS/United States ; DK063311/DK/NIDDK NIH HHS/United States ; }, mesh = {Alzheimer Disease/etiology/physiopathology ; Calcium/physiology ; Energy Metabolism ; Humans ; Huntington Disease/physiopathology ; Hyperglycemia/physiopathology ; Manganese/toxicity ; Mitochondrial Membranes/*physiology ; Mitochondrial Swelling/physiology ; Motor Neuron Disease/physiopathology ; Nervous System Diseases/etiology/*physiopathology ; Neurodegenerative Diseases/etiology/physiopathology ; Neurotoxins/toxicity ; Parkinsonian Disorders/etiology/physiopathology ; Permeability ; }, abstract = {Mitochondria, being the principal source of cellular energy, are vital for cell life. Yet, ironically, they are also major mediators of cell death, either by necrosis or apoptosis. One means by which these adverse effects occur is through the mitochondrial permeability transition (mPT) whereby the inner mitochondrial membrane suddenly becomes excessively permeable to ions and other solutes, resulting in a collapse of the inner membrane potential, ultimately leading to energy failure and cell necrosis. The mPT may also bring about the release of various factors known to cause apoptotic cell death. The principal factors leading to the mPT are elevated levels of intracellular Ca2+ and oxidative stress. Characteristically, the mPT is inhibited by cyclosporin A. This article will briefly discuss the concept of the mPT, its molecular composition, its inducers and regulators, agents that influence its activity and describe the consequences of its induction. Lastly, we will review its potential contribution to acute neurological disorders, including ischemia, trauma, and toxic-metabolic conditions, as well as its role in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid17395433, year = {2007}, author = {Hermosura, MC and Garruto, RM}, title = {TRPM7 and TRPM2-Candidate susceptibility genes for Western Pacific ALS and PD?.}, journal = {Biochimica et biophysica acta}, volume = {1772}, number = {8}, pages = {822-835}, pmid = {17395433}, issn = {0006-3002}, support = {S11 NS043462/NS/NINDS NIH HHS/United States ; S11 NS043462-05/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Cell Death ; Dementia/*genetics ; Environment ; *Genetic Predisposition to Disease ; Humans ; Microglia/metabolism ; Mitochondria/pathology ; Neurons/physiology ; Oxidative Stress/physiology ; Parkinsonian Disorders/*genetics ; Protein Serine-Threonine Kinases ; Reactive Nitrogen Species/pharmacology ; TRPM Cation Channels/genetics/metabolism/*physiology ; }, abstract = {Recent findings implicating TRPM7 and TRPM2 in oxidative stress-induced neuronal death thrust these channels into the spotlight as possible therapeutic targets for neurodegenerative diseases. In this review, we describe how the functional properties of TRPM7 and TRPM2 are interconnected with calcium (Ca(2+)) and magnesium (Mg(2+)) homeostasis, oxidative stress, mitochondrial dysfunction, and immune mechanisms, all principal suspects in neurodegeneration. We focus our discussion on Western Pacific Amyotrophic Lateral Sclerosis (ALS) and Parkinsonism Dementia (PD) because extensive studies conducted over the years strongly suggest that these diseases are ideal candidates for a gene-environment model of etiology. The unique mineral environment identified in connection with Western Pacific ALS and PD, low Mg(2+) and Ca(2+), yet high in transition metals, creates a condition that could affect the proper function of these two channels.}, }
@article {pmid17389304, year = {2007}, author = {Cronin, S and Hardiman, O and Traynor, BJ}, title = {Ethnic variation in the incidence of ALS: a systematic review.}, journal = {Neurology}, volume = {68}, number = {13}, pages = {1002-1007}, doi = {10.1212/01.wnl.0000258551.96893.6f}, pmid = {17389304}, issn = {1526-632X}, support = {//Intramural NIH HHS/United States ; }, mesh = {Black or African American/statistics &amp; numerical data ; Aged ; Amyotrophic Lateral Sclerosis/*ethnology/mortality ; Ethnicity/*statistics &amp; numerical data ; Hispanic or Latino/statistics &amp; numerical data ; Humans ; Incidence ; Middle Aged ; Prevalence ; United States/epidemiology ; White People/statistics &amp; numerical data ; }, abstract = {BACKGROUND: The findings of recent genetic polymorphism studies in ALS suggest that the influence of genetic risk factors for the disease may vary by ethnicity. It is now widely accepted that the incidence of ALS is uniform across Caucasian populations, but whether racial variation across other ethnicities exists remains unknown.<br><br>METHOD: Systematic review of the known literature on the incidence, prevalence, and mortality of ALS across all ethnicities. To facilitate comparison, studies were grouped according to the type of data presented and examined for sources of case ascertainment and inclusion criteria.<br><br>RESULTS: The literature search identified 61 publications. Lower standardized incidence rates were observed in Asian than Caucasian populations. Within the United States, several incidence and mortality studies have identified lower ALS frequency among African American and Hispanic populations than among non-Hispanic Caucasians. These observations are supported by the other data sources.<br><br>CONCLUSIONS: The incidence of ALS may be lower among African, Asian, and Hispanic ethnicities than among whites. We conclude with proposals for a prospective epidemiologic study concentrating on non-Caucasian populations.}, }
@article {pmid17381183, year = {2007}, author = {Kurt, A and Nijboer, F and Matuz, T and Kübler, A}, title = {Depression and anxiety in individuals with amyotrophic lateral sclerosis: epidemiology and management.}, journal = {CNS drugs}, volume = {21}, number = {4}, pages = {279-291}, pmid = {17381183}, issn = {1172-7047}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Anxiety/*epidemiology/etiology/*therapy ; Depression/*epidemiology/etiology/*therapy ; Humans ; Male ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no curative treatment. Considering the devastating nature of the disease, a high prevalence of depression and anxiety in affected patients would be expected. A review of the literature shows prevalence rates for depression in ALS patients ranging from 0% to 44%, but studies using the structured interview according to DSM-IV criteria find highly consistent rates of 9-11%. Prevalence rates for anxiety in ALS range from 0% to 30%. Depression and anxiety appear to be not always properly addressed aspects of ALS, as there are only a few references in the literature about psychological and pharmacological interventions. Additionally, pharmacological antidepressant therapy is often not continuously monitored and its effectiveness remains unevaluated. A review of the literature and our own experiences show that there is a lack of psychological care and, to our knowledge, there is no specific psychological intervention method for ALS patients. Concerning pharmacological treatment of depression in patients with ALS, there is broad consensus among clinical experts that SSRIs and TCAs are helpful, but there have been no controlled clinical studies of these medications in ALS patients. TCAs can be prescribed if anticholinergic effects are desired simultaneously for treating pseudohypersalivation or insomnia. Anxiety is usually treated with anxiolytics, but again there have been no systematic studies of these drugs in patients with ALS. For psychological intervention we suggest a cognitive behavioural approach, which has to be integrated into an intervention programme that includes teaching of appropriate coping strategies and reappraisal skills and encourages engagement in activities that are still practicable and pleasant. We propose that the treatment of depression and anxiety should involve both cognitive behavioural therapy and pharmacological intervention. Pharmacological treatment should be strictly monitored for effectiveness. To date, no clinical trials are available that would allow us to recommend pharmacotherapy over psychotherapy or vice versa; however, evidence from other patient groups, such as elderly patients diagnosed with major depressive disorder, suggests that a combination of both therapies has the potential to also improve depression and anxiety in patients with ALS.}, }
@article {pmid17373702, year = {2007}, author = {Neusch, C and Bähr, M and Schneider-Gold, C}, title = {Glia cells in amyotrophic lateral sclerosis: new clues to understanding an old disease?.}, journal = {Muscle &amp; nerve}, volume = {35}, number = {6}, pages = {712-724}, doi = {10.1002/mus.20768}, pmid = {17373702}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/immunology/*physiopathology ; Animals ; Cell Communication/genetics/immunology ; Central Nervous System/immunology/*physiopathology ; Gliosis/genetics/immunology/physiopathology ; Humans ; Membrane Proteins/genetics/immunology/metabolism ; Motor Neurons/immunology/*metabolism ; Nerve Degeneration/genetics/immunology/physiopathology ; Neuroglia/immunology/*metabolism ; Signal Transduction/genetics/immunology ; }, abstract = {In classic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the pathogenic concept of a cell-autonomous disease of motor neurons has been challenged increasingly in recent years. Macro- and microglial cells have come to the forefront for their role in multistep degenerative processes in ALS and respective disease models. The activation of astroglial and microglial cells occurs early in the pathogenesis of the disease and seems to greatly influence disease onset and promotion. The role of oligodendrocytes and Schwann cells remains elusive. In this review we highlight the impact of nonneuronal cells in ALS pathology. We discuss diverse glial membrane proteins that are necessary to control neuronal activity and neuronal cell survival, and summarize the contribution of these proteins to motor neuron death in ALS. We also describe recently discovered glial mechanisms that promote motor neuron degeneration using state-of-the-art genetic mouse technology. Finally, we provide an outlook on the extent to which these new pathomechanistic insights may offer novel therapeutic approaches.}, }
@article {pmid17364255, year = {2007}, author = {Brea, D and Cristobo, I and Sobrino, T and Rodríguez-González, R and Mosquera, E and Moldes, O and Castillo, J}, title = {[Application of proteomics to neurological diseases].}, journal = {Neurologia (Barcelona, Spain)}, volume = {22}, number = {3}, pages = {170-179}, pmid = {17364255}, issn = {0213-4853}, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cells, Cultured/metabolism ; Chromatography, Liquid/methods ; Electrophoresis, Gel, Two-Dimensional ; Epilepsy/genetics/metabolism ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Humans ; Huntington Disease/genetics/metabolism ; Mass Spectrometry/methods ; Nerve Tissue Proteins/analysis/biosynthesis/genetics ; Nervous System Diseases/diagnosis/genetics/*metabolism ; Proteins/*analysis/genetics ; Proteomics/*methods ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Stroke/genetics/metabolism ; Subtraction Technique ; }, abstract = {Proteomic is a set of tools that allows the separation and identification of proteins expressed by a cell, tissue or organism. Two-dimensional electrophoresis is the central tool that allows qualitative and quantitative comparisons of protein patterns between samples. Differential analysis of protein expression patterns in different neurological diseases (stroke, Alzheimer, Parkinson, amyotrophic lateral sclerosis, Hungtington, epilepsy) allows the identification of diagnostic and/or prognostic biomarkers. Subsequently, validation of these markers may help to identify new diagnostic and therapeutic targets.}, }
@article {pmid17359641, year = {2007}, author = {Lee, H and Park, HJ and Park, J and Kim, MJ and Hong, M and Yang, J and Choi, S and Lee, H}, title = {Acupuncture application for neurological disorders.}, journal = {Neurological research}, volume = {29 Suppl 1}, number = {}, pages = {S49-54}, doi = {10.1179/016164107X172211}, pmid = {17359641}, issn = {0161-6412}, mesh = {Acupuncture/*methods ; Humans ; Nervous System Diseases/*therapy ; }, abstract = {BACKGROUND: Acupuncture has been widely used for a range of neurological disorders. Despite its popularity, the evidence to support the use of acupuncture is contradictory.<br><br>METHODS: This review was designed to summarize and to evaluate the available evidence of acupuncture for neurological disorders.<br><br>RESULTS: Most of the reviewed studies suffer from lack of methodological rigor. Owing to paucity and poor quality of the primary studies, no firm conclusion could be drawn on the use of acupuncture for epilepsy, Alzheimer's disease, Parkinson's disease, ataxic disorders, multiple sclerosis, amyotrophic lateral sclerosis and spinal cord injury. For stroke rehabilitation, the evidence from recent high-quality trials and previous systematic reviews is not convincing.<br><br>CONCLUSION: More rigorous trials are warranted to establish acupuncture's role in neurological disorders.}, }
@article {pmid17359355, year = {2007}, author = {Adachi, H and Waza, M and Katsuno, M and Tanaka, F and Doyu, M and Sobue, G}, title = {Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy.}, journal = {Neuropathology and applied neurobiology}, volume = {33}, number = {2}, pages = {135-151}, doi = {10.1111/j.1365-2990.2007.00830.x}, pmid = {17359355}, issn = {0305-1846}, mesh = {*Androgen Receptor Antagonists ; Animals ; Benzoquinones/*therapeutic use ; Gonadotropin-Releasing Hormone/analogs &amp; derivatives ; HSP90 Heat-Shock Proteins/*antagonists &amp; inhibitors/genetics ; Humans ; Lactams, Macrocyclic/*therapeutic use ; Muscular Atrophy, Spinal/*drug therapy/*genetics/pathology ; Receptors, Androgen/genetics ; }, abstract = {Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a motor neurone disease characterized by muscle atrophy, weakness, contraction fasciculations and bulbar involvement. SBMA mainly affects males, while females are usually asymptomatic. SBMA is caused by expansion of a polyglutamine (polyQ)-encoding CAG trinucleotide repeat in the androgen receptor (AR) gene. AR belongs to the heat shock protein 90 (Hsp90) client protein family. The histopathologic hallmarks of SBMA are diffuse nuclear accumulation and nuclear inclusions of the mutant AR with expanded polyQ in residual motor neurones in the brainstem and spinal cord as well as in some other visceral organs. There is increasing evidence that the ligand of AR and molecular chaperones play a crucial role in the pathogenesis of SBMA. The success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, that is, Hsp90 inhibitor and Hsp inducer, which inhibit the pathogenic process of neuronal degeneration. SBMA is a slowly progressive disease by nature. The degree of nuclear accumulation of mutant AR in scrotal skin epithelial cells was correlated with that in spinal motor neurones in autopsy specimens; therefore, the results of scrotal skin biopsy may be used to assess the efficacy of therapeutic trials. Clinical and pathological parameters that reflect the pathogenic process of SBMA should be extensively investigated.}, }
@article {pmid17353375, year = {2007}, author = {Murphy, J and Henry, R and Lomen-Hoerth, C}, title = {Establishing subtypes of the continuum of frontal lobe impairment in amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {64}, number = {3}, pages = {330-334}, doi = {10.1001/archneur.64.3.330}, pmid = {17353375}, issn = {0003-9942}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*pathology ; Brain Mapping ; *Cognition Disorders/classification/etiology/pathology ; Frontal Lobe/pathology/physiopathology ; Humans ; Magnetic Resonance Imaging ; }, abstract = {This review summarizes recent advances in our understanding of the cognitive changes seen in patients with amyotrophic lateral sclerosis (ALS). Emphasis is placed on identifying and diagnosing subtypes of ALS patients with a continuum of frontotemporal impairment. The reviewed literature focuses on progress made in the past 20 years, with an emphasis on studies measuring abnormalities in ALS patients without dementia. We describe peer-reviewed journal articles using neuropsychological batteries and imaging techniques. We also discuss debates raised in recent meetings. In the past 2 decades, the field of ALS has been transformed in terms of its understanding of extramotor cerebral changes. Particularly in the past 10 years, investigators have invalidated the theory that cognitive abnormality in ALS patients is simply a rarely occurring, frank frontotemporal lobar degeneration syndrome. Instead, a growing body of evidence suggests that ALS patients with comorbid frontotemporal lobar degeneration lie on a spectrum of frontotemporal abnormality, with a large proportion of ALS patients possessing a range of behavioral and cognitive changes. As more investigations use standardized tools measuring behavior and cognition, distinct subtypes may be diagnosed.}, }
@article {pmid17350694, year = {2007}, author = {Centonze, D and Finazzi-Agrò, A and Bernardi, G and Maccarrone, M}, title = {The endocannabinoid system in targeting inflammatory neurodegenerative diseases.}, journal = {Trends in pharmacological sciences}, volume = {28}, number = {4}, pages = {180-187}, doi = {10.1016/j.tips.2007.02.004}, pmid = {17350694}, issn = {0165-6147}, mesh = {Animals ; Cannabinoid Receptor Modulators/antagonists &amp; inhibitors/*metabolism ; Central Nervous System Diseases/drug therapy/*metabolism/pathology ; *Endocannabinoids ; Humans ; Inflammation/metabolism ; Nerve Degeneration ; Receptors, Cannabinoid/metabolism ; }, abstract = {The classical divide between degenerative and inflammatory disorders of the CNS is vanishing as accumulating evidence shows that inflammatory processes are important in the pathophysiology of primarily degenerative disorders, and neurodegeneration complicates primarily inflammatory diseases of the brain and spinal cord. Here, we review the contribution of degenerative and inflammatory processes to CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and HIV-associated dementia. An early combination of neuroprotective and anti-inflammatory approaches to these disorders seems particularly desirable because isolated treatment of one pathological process might worsen another. We also discuss the apparently unique opportunity to modify neurodegeneration and neuroinflammation simultaneously by pharmacological manipulation of the endocannabinoid system in the CNS and in peripheral immune cells. Current knowledge of this system and its involvement in the above CNS disorders are also reviewed.}, }
@article {pmid17345579, year = {2007}, author = {Lederer, CW and Santama, N}, title = {Amyotrophic lateral sclerosis--the tools of the trait.}, journal = {Biotechnology journal}, volume = {2}, number = {5}, pages = {608-621}, doi = {10.1002/biot.200600247}, pmid = {17345579}, issn = {1860-7314}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism/*therapy ; Animals ; Biomarkers/*metabolism ; Biotechnology/*methods ; Drug Delivery Systems/*methods ; Humans ; Nerve Tissue Proteins/*metabolism ; }, abstract = {The aim of this review is to analyze how our knowledge on the etiology, pathology, and treatment of amyotrophic lateral sclerosis (ALS) has profited from the application of biotechnology tools for the identification of disease markers, the development of animal disease models, and the design of innovative therapeutics. In humans, ALS-specific clinical, genetic or protein biomarkers, or panels of biomarkers stemming from genomics and proteomics analyses can be critical for early diagnosis, monitoring of disease progression, drug validation in clinical trials, and identification of therapeutic targets for subsequent drug development. At the same time, animal models representing a number of human superoxide dismutase 1 mutations, intermediate-filament disorganization or axonal-transport defects have been invaluable in unraveling aspects of the pathophysiology of the disease; in each case, these only represent a small proportion of all ALS patients. Preclinical and clinical trials, although at present heavily concentrating on pharmacological approaches, are embracing the emerging alternative strategies of stem-cell and gene therapy. In combination with a further subcategorization of patients and the development of corresponding model systems for functional analyses, they will significantly influence the already changing face of ALS therapy.}, }
@article {pmid17342681, year = {2007}, author = {Alves, C and Veiga, S and Souza, T and Toralles, MB and da Silva-Bacellar, AL}, title = {[The role of the human histocompatibility antigens in the pathogenesis of neurological disorders].}, journal = {Revista de neurologia}, volume = {44}, number = {5}, pages = {298-302}, pmid = {17342681}, issn = {0210-0010}, mesh = {Alleles ; Genetic Markers ; Genetic Predisposition to Disease ; Haplotypes ; Histocompatibility Antigens/*immunology ; Humans ; *Nervous System Diseases/immunology/physiopathology ; Polymorphism, Genetic ; Retrospective Studies ; }, abstract = {INTRODUCTION: Several studies have been trying to define genetic markers of neurological disorders. Among them, antigens and alleles of the HLA (human leukocyte antigens) system are distinguished. The HLA exerts genetic influence on the susceptibility, clinical aspects and severity of many diseases. The discovery of new molecular methods to typify HLA alleles and the recent nomenclature updates have been contributing to a better understanding of this system. Unfortunately, this information has not been adequately published in the clinical literature.<br><br>AIM: To review the structure, function, nomenclature and methods of detection of the HLA polymorphism and its associations with common neurological disorders.<br><br>DEVELOPMENT: Articles that were published between 1990 and 2004 were searched in the MEDLINE and LILACS databases. This review demonstrated that although the HLA association is well established for some neurological disorders (e.g., HLA-DQB1*0602 with multiple sclerosis and narcolepsy; HLA-B7 e HLA-A2 with Alzheimer's disease; HLA-DR3-DR8 with Lamber-Eaton syndrome; and HLA class II Parkinson's disease and amyotrophic lateral sclerosis), these associations are not consistent and vary in different ethnic groups.<br><br>CONCLUSIONS: It is necessary to study populations from different ethnic backgrounds to identify new associations or to strength the ones already identified. This knowledge will contribute in the evaluation of the risk that a person carrying a particular allele or haplotype has to develop a neurological disease and therefore contribute towards a better understanding of its pathogenesis.}, }
@article {pmid17342192, year = {2007}, author = {Subba Rao, K}, title = {Mechanisms of disease: DNA repair defects and neurological disease.}, journal = {Nature clinical practice. Neurology}, volume = {3}, number = {3}, pages = {162-172}, doi = {10.1038/ncpneuro0448}, pmid = {17342192}, issn = {1745-8358}, mesh = {Animals ; DNA Damage ; DNA Repair ; DNA Repair-Deficiency Disorders/*genetics/*physiopathology ; Humans ; Nervous System Diseases/*genetics/*physiopathology ; }, abstract = {In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six--spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis--seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.}, }
@article {pmid17339056, year = {2007}, author = {Conforti, L and Adalbert, R and Coleman, MP}, title = {Neuronal death: where does the end begin?.}, journal = {Trends in neurosciences}, volume = {30}, number = {4}, pages = {159-166}, doi = {10.1016/j.tins.2007.02.004}, pmid = {17339056}, issn = {0166-2236}, mesh = {Animals ; Apoptosis/*physiology ; Disease Progression ; Humans ; Neurodegenerative Diseases/*pathology/*physiopathology ; Neurons/*physiology ; }, abstract = {Neurodegenerative disorders involve death of cell bodies, axons, dendrites and synapses, but it is surprisingly difficult to determine the spatiotemporal sequence of events and the causal relationships among these events. Neuronal compartments often crucially depend upon one another for survival, and molecular defects in one compartment can trigger cellular degeneration in distant parts of the neuron. Here, we consider the novel approaches used to understand these biologically complex and technically challenging questions in amyotrophic lateral sclerosis, spinal muscular atrophy, glaucoma, Alzheimer's disease, Parkinson's disease and polyglutamine disorders. We conclude that there is partial understanding of what degenerates first and why, but that controversy remains the rule not the exception. Finally, we highlight strategies for resolving these fundamental issues.}, }
@article {pmid17338130, year = {2006}, author = {Kumor, K and Pierzchała, K}, title = {[The problem of fatigue in neurological disorders].}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {59}, number = {9-10}, pages = {685-691}, pmid = {17338130}, issn = {0043-5147}, mesh = {Chronic Disease ; Depression/etiology/physiopathology ; Disability Evaluation ; Fatigue/diagnosis/*etiology/therapy ; Humans ; Mental Fatigue/etiology/physiopathology ; Multiple Sclerosis/complications/physiopathology ; Nervous System Diseases/*complications/diagnosis ; Parkinson Disease/complications/physiopathology ; Postpoliomyelitis Syndrome/complications/physiopathology ; Severity of Illness Index ; Stroke/complications/physiopathology ; }, abstract = {Fatigue or piercing feeling of weakness, lack of strength and energy or total exhaustion is a common complaint of patients with neurological disorders. From 40 to over 90 per cent of individuals with multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, neuroboreliosis, post polio syndrome or stroke confirm its experience. It is not infrequently numbered among most disabling complaints. A separate entity, with fatigue as a cardinal sign, is a chronic fatigue syndrome, a disorder, though controversial, more and more frequently diagnosed. Fatigue ought to be discriminated from fatigability, paresis, somnolence and, first of all depression which commonly coexists in chronic disorders. The assessment is almost entirely based on self-estimate scales filled in by a patient. Attainable results of neuroimaging, electrophysiological, polisomnographic, vegetative, psychological and biochemical surveys have not allowed yet to define the pathogenesis of fatigue. The treatment basis consists of behavioral therapy, psychotherapy and a proper treatment of the basic disease.}, }
@article {pmid17322959, year = {2006}, author = {Pozza, AM and Delamura, MK and Ramirez, C and Valério, NI and Marino, LH and Lamari, NM}, title = {Physiotherapeutic conduct in amyotrophic lateral sclerosis.}, journal = {Sao Paulo medical journal = Revista paulista de medicina}, volume = {124}, number = {6}, pages = {350-354}, doi = {10.1590/s1516-31802006000600011}, pmid = {17322959}, issn = {1516-3180}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Breathing Exercises ; Fatigue/therapy ; Humans ; *Physical Therapy Modalities ; Quality of Life ; Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disease with multifactorial etiology for which, so far, there is no effective medicinal treatment. However, by means of kinesiotherapy intervention and patient guidance and care, physiotherapy can delay physical functional losses, muscle fatigue and immobility of the joint-muscle system, thereby improving the quality of life. This survey had the aim of reviewing the physiotherapeutic conduct currently used in ALS cases. Monthly monitoring is recommended, with changes in goals and conduct at each stage of the disease, activities to be pursued around the home, and emphasis on stretching, muscle strengthening, posture adequacy and respiratory kinesiotherapy.}, }
@article {pmid17319446, year = {2006}, author = {Prommer, E}, title = {Modafinil: is it ready for prime time?.}, journal = {Journal of opioid management}, volume = {2}, number = {3}, pages = {130-136}, doi = {10.5055/jom.2006.0022}, pmid = {17319446}, issn = {1551-7489}, mesh = {Attention Deficit Disorder with Hyperactivity/drug therapy ; Benzhydryl Compounds/chemistry/pharmacokinetics/*therapeutic use ; Central Nervous System Stimulants/chemistry/pharmacokinetics/*therapeutic use ; Depression/*drug therapy/etiology ; Fatigue/*drug therapy/etiology ; Humans ; Modafinil ; *Neoplasms/complications ; Pain/*drug therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {Psychostimulants have been used to treat many symptoms associated with advanced cancer. The primary role of psychostimulants in such cases is the treatment of symptoms such as cancer-related fatigue, opioid-induced sedation, depression, and cognitive dysfunction associated with malignancies. These uses for psychostimulants came after approval for treatment of disorders such as attention deficit disorder. Modafinil, a new psychostimulant, is following a similar path after its approval for use in attention deficit disorder in 1998. Modafinil has been used to treat fatigue associated with neurodegenerative disorders such as multiple sclerosis and amyotrophic lateral sclerosis. It is now being increasingly used for cancer-related symptoms targeted by psychostimulants. Preliminary evidence from literature review suggests that modafinil is efficacious in improving opioid-induced sedation, cancer-related fatigue, and depression. There is no evidence to support its use in the treatment of cognitive dysfunction related to cancer or to support its having analgesic properties. Well-designed, randomized, controlled clinical trials are still needed to further elucidate the precise role of this drug in the care of patients with cancer. Specifically, large placebo-controlled trials with modafinil must be conducted in patients with cancer, with specific attention paid to pain control, depression, cognitive function, and adverse effects.}, }
@article {pmid17317654, year = {2006}, author = {Al-Omar, MA}, title = {The X-linked adrenoleukodystrophy (X-ALD) and oxidative stress.}, journal = {Journal of herbal pharmacotherapy}, volume = {6}, number = {3-4}, pages = {125-134}, doi = {10.1080/j157v06n03_07}, pmid = {17317654}, issn = {1522-8940}, mesh = {Adrenoleukodystrophy/metabolism/*therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Antioxidants/*therapeutic use ; Drug Combinations ; Erucic Acids/*therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; *Oxidative Stress ; *Reactive Oxygen Species ; Triolein/*therapeutic use ; }, abstract = {Most of the studies indicate that there is as yet no complete cure for X-ALD. However, methods of the treatment seem to slow rather than treat the disease. One method is the use of Lorenzo's oil in conjunction with a low fat diet, which may help in cerebral X-ALD. X-ALD is in very close resemblance to another neurodegenerative disease, amyotrophic lateral sclerosis (ALS). One of the believed pathomechanisms of ALS is oxidative stress; therefore, this article's emphasis on the role of reactive oxygen species in X-ALD. The aim of the present study was to review the literature concerning the advances in the treatment of X-adrenoleukodystrophy (X-ALD, OMIM # 300100) in the last two decades and to shed more light on the link between oxidative stress and X-ALD. This review article may point to a deficit in reactive oxygen species (ROS) scavenging and/or ROS overproduction being involved in the aetiopathology of these neurodegenerative diseases. Consequently, one of the useful neuronal rescue strategies could be the treatment with antioxidant agents.}, }
@article {pmid17316166, year = {2007}, author = {Harguindey, S and Reshkin, SJ and Orive, G and Arranz, JL and Anitua, E}, title = {Growth and trophic factors, pH and the Na+/H+ exchanger in Alzheimer's disease, other neurodegenerative diseases and cancer: new therapeutic possibilities and potential dangers.}, journal = {Current Alzheimer research}, volume = {4}, number = {1}, pages = {53-65}, doi = {10.2174/156720507779939841}, pmid = {17316166}, issn = {1567-2050}, mesh = {Animals ; Apoptosis/drug effects ; Humans ; *Hydrogen-Ion Concentration ; Intercellular Signaling Peptides and Proteins/*metabolism/therapeutic use ; Models, Biological ; Neoplasms/*metabolism/physiopathology ; Neurodegenerative Diseases/drug therapy/*metabolism/physiopathology ; Sodium-Hydrogen Exchangers/*metabolism ; }, abstract = {Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntington's disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pH(i))-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.}, }
@article {pmid17311555, year = {2007}, author = {Cornelis, S and Kersse, K and Festjens, N and Lamkanfi, M and Vandenabeele, P}, title = {Inflammatory caspases: targets for novel therapies.}, journal = {Current pharmaceutical design}, volume = {13}, number = {4}, pages = {367-385}, doi = {10.2174/138161207780163006}, pmid = {17311555}, issn = {1873-4286}, mesh = {Animals ; Anti-Inflammatory Agents/chemistry/*pharmacology/therapeutic use ; Autoimmune Diseases/drug therapy/enzymology ; Azepines/pharmacology ; Brain Diseases/drug therapy/enzymology ; *Caspase Inhibitors ; Caspases/chemistry/metabolism ; Disease Models, Animal ; *Drug Design ; Enzyme Activation ; Humans ; Inflammation/*drug therapy/enzymology ; Isoquinolines/pharmacology ; Models, Molecular ; Molecular Structure ; Neurodegenerative Diseases/drug therapy/enzymology ; Protease Inhibitors/chemistry/*pharmacology/therapeutic use ; Protein Conformation ; Pyridazines/pharmacology ; Structure-Activity Relationship ; Treatment Outcome ; }, abstract = {This review provides an overview of the biochemistry and activation of inflammatory caspases, and focuses on their therapeutic potential as disease targets in pathologies such as sepsis, Crohn's disease, rheumatoid arthritis, traumatic brain injury and amyotrophic lateral sclerosis (ALS). We summarize the proof-of-principal evidence obtained by studies in several corresponding experimental disease models confirming the validity of strategies targeting inflammatory caspases. We discuss the use of inflammatory caspase inhibitors, such as VX-740 (Pralnacasan) and VX-765, in clinical studies for rheumatoid arthritis and osteoarthritis. Finally, we point out recent approaches identifying novel peptidomimetic or non-peptide caspase inhibitors with suitable clinical profiles.}, }
@article {pmid17306357, year = {2007}, author = {Ricciarelli, R and Argellati, F and Pronzato, MA and Domenicotti, C}, title = {Vitamin E and neurodegenerative diseases.}, journal = {Molecular aspects of medicine}, volume = {28}, number = {5-6}, pages = {591-606}, doi = {10.1016/j.mam.2007.01.004}, pmid = {17306357}, issn = {0098-2997}, mesh = {Alzheimer Disease/metabolism/prevention &amp; control ; Amyotrophic Lateral Sclerosis/metabolism/prevention &amp; control ; Animals ; Humans ; Neurodegenerative Diseases/*metabolism/*prevention &amp; control ; Parkinson Disease/metabolism/prevention &amp; control ; Vitamin E/*metabolism/*pharmacology ; Vitamin E Deficiency/metabolism/prevention &amp; control ; }, abstract = {Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E. In this review, some aspects related to the role of vitamin E against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.}, }
@article {pmid17305588, year = {2007}, author = {Ryu, H and Ferrante, RJ}, title = {Translational therapeutic strategies in amyotrophic lateral sclerosis.}, journal = {Mini reviews in medicinal chemistry}, volume = {7}, number = {2}, pages = {141-150}, doi = {10.2174/138955707779802570}, pmid = {17305588}, issn = {1389-5575}, support = {NS 045242/NS/NINDS NIH HHS/United States ; NS 045806/NS/NINDS NIH HHS/United States ; NS 52724-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Humans ; Mitochondrial Diseases/drug therapy/metabolism ; Oxidative Stress ; Signal Transduction ; Transcription, Genetic/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically severe and fatal neurodegenerative disease characterized by a loss of both upper and lower motor neurons, resulting in progressive muscle loss and paralysis. While the exact cause of neuronal death in ALS remains unknown, it is proposed that multiple molecular defects trigger motor neuron cell death. These pathophysiological mechanisms include oxidative stress, mitochondrial impairment, protein aggregation, glutamate cytotoxicity, transcription dysfunction, inflammation, and apoptotic cell death. An understanding of how these potential therapeutic targets interrelate will provide direction both in the development of a pharmacotherapy and in the design of clinical trials in ALS. Important issues related to therapeutic development are the principals that should be followed in designing and conducting experiments using genetic animal models and what body of evidence is desirable to fully inform clinical decision making. In the context of ALS, we review some of the salient issues related to the use of genetic models in providing a guide to assessing studies in translating therapeutic strategies to patients with ALS and discuss therapeutic targets and pharmacological approaches to slowing disease progression. As in other neurodegenerative diseases, the most effective neuroprotection may result from combined treatment strategies.}, }
@article {pmid17303360, year = {2007}, author = {Kim, SU}, title = {Genetically engineered human neural stem cells for brain repair in neurological diseases.}, journal = {Brain &amp; development}, volume = {29}, number = {4}, pages = {193-201}, doi = {10.1016/j.braindev.2006.07.012}, pmid = {17303360}, issn = {0387-7604}, mesh = {Animals ; Brain Injuries/etiology/*therapy ; Genetic Engineering/*methods ; Humans ; Nervous System Diseases/complications/therapy ; Neurons/*physiology ; Stem Cell Transplantation/methods ; Stem Cells/*physiology ; }, abstract = {Neural stem cells (NSCs)of the central nervous system (CNS) have recently received a great deal of attention and interest for their therapeutic potential for neurological disorders. NSCs are defined as CNS progenitor cells that have the capacity for self-renewal and multipotent potential to become neurons or glial cells. Recent studies have shown that NSCs isolated from mammalian CNS including human can be propagated in vitro and then implanted into the brain of animal models of human neurological disorders. Recently, we have generated clonally derived immortalized human NSC cell lines via a retroviral vector encoded with v-myc oncogene. One of the human NSC lines, HB1.F3, was utilized in stem-cell based therapy in animal models of human neurological disorders. When F3 human NSCs were implanted into the brain of murine models of lysosomal storage diseases, stroke, Parkinson disease, Huntington disease or stroke, implanted F3 NSCs were found to migrate to the lesion sites, differentiate into neurons and glial cells, and restore functional deficits found in these neurological disorders. In animal models of brain tumors, F3 NSCs could deliver a bioactive therapeutically relevant molecules to effect a significant anti-tumor response intracranial tumor mass. Since these genetically engineered human NSCs are immortalized and continuously multiplying, there would be limitless supply of human neurons for treatment for patients suffering from neurological disorders including stroke, Parkinson disease, Huntington disease, ALS, multiple sclerosis and spinal cord injury. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research.}, }
@article {pmid17300945, year = {2007}, author = {Benatar, M}, title = {Lost in translation: treatment trials in the SOD1 mouse and in human ALS.}, journal = {Neurobiology of disease}, volume = {26}, number = {1}, pages = {1-13}, doi = {10.1016/j.nbd.2006.12.015}, pmid = {17300945}, issn = {0969-9961}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Animals ; Disease Models, Animal ; Humans ; Mice ; Publication Bias ; Research Design ; Sex Characteristics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Therapeutic success in the superoxide dismutase (SOD1) mouse model of amyotrophic lateral sclerosis (ALS) has not translated into effective therapy for human ALS, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans. This random effects meta-analysis of treatment trials in the superoxide dismutase (SOD1) mouse was undertaken in order to explore possible reasons for this failure of translational research and to identify potential pharmacological interventions that might be used in either a preventative or therapeutic trial in familial ALS. Among studies in which treatment was initiated presymptomatically, the weighted mean differences (WMDs) comparing the active treatment to control treated animals were 12 days (onset), 13 days (survival) and 5 days (survival interval). Among studies in which treatment was initiated at the time of symptom onset, the WMDs were 15 days (survival) and 8 days (survival interval). Subgroup analysis suggests that drugs such as minocycline and Cox-2 inhibitors with an anti-inflammatory mechanism of action, and anti-oxidative agents such as creatine or the manganese porphyrin AEOL-10150, appear to be the most promising for preventative and therapeutic trials respectively in patients with familial ALS. These conclusions should be tempered by the methodological limitations of the relevant literature.}, }
@article {pmid17296249, year = {2007}, author = {Papapetropoulos, S}, title = {Is there a role for naturally occurring cyanobacterial toxins in neurodegeneration? The beta-N-methylamino-L-alanine (BMAA) paradigm.}, journal = {Neurochemistry international}, volume = {50}, number = {7-8}, pages = {998-1003}, doi = {10.1016/j.neuint.2006.12.011}, pmid = {17296249}, issn = {0197-0186}, mesh = {Amino Acids, Diamino/*toxicity ; Cyanobacteria Toxins ; Diet ; Guam/epidemiology ; Humans ; Motor Neuron Disease/epidemiology ; Nerve Degeneration/chemically induced ; Neurodegenerative Diseases/*chemically induced ; Neurotoxins/toxicity ; Parkinsonian Disorders/epidemiology ; }, abstract = {The naturally occurring, non-essential amino acid beta-N-methylamino-L-alanine (BMAA) has been recently found in high concentrations in brain tissues of patients with tauopathies such as the Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS/PDC) in the South Pacific island of Guam and in a small number of Caucasian, North American patients with sporadic Alzheimer's disease. BMAA is produced by cyanobacteria that are present in all conceivable aquatic and/or terrestrial ecosystems and may be accumulated in living tissues in free and protein-bound forms through the process of biomagnification. Although its role in human degenerative disease is highly debated, there is mounting evidence in support of the neurotoxic properties of BMAA that may be mediated via mechanisms involving among others the regulation of glutamate. Glutamate-related excitotoxicity is among the most prominent factors in the etiopathogenesis of human neurodegenerative diseases. Due to the wide geographical distribution of cyanobacteria and the possible implications of BMAA neurotoxic properties in public health more research towards this direction is warranted.}, }
@article {pmid17279431, year = {2007}, author = {Martin, WR}, title = {MR spectroscopy in neurodegenerative disease.}, journal = {Molecular imaging and biology}, volume = {9}, number = {4}, pages = {196-203}, pmid = {17279431}, issn = {1536-1632}, mesh = {Brain/metabolism ; Brain Chemistry ; Humans ; Isotopes ; Neurodegenerative Diseases/diagnosis/*metabolism ; Nuclear Magnetic Resonance, Biomolecular/*methods ; }, abstract = {Unlike traditional, tracer-based methods of molecular imaging, magnetic resonance spectroscopy (MRS) is based on the behavior of specific nuclei within a magnetic field and the general principle that the resonant frequency depends on the nucleus' immediate chemical environment. Most clinical MRS research has concentrated on the metabolites visible with proton spectroscopy and measured in specified tissue volumes in the brain. This methodology has been applied in various neurodegenerative disorders, most frequently utilizing measures of N-acetylaspartate as a neuronal marker. At short echo times, additional compounds can be quantified, including myo-inositol, a putative marker for neuroglia, the excitatory neurotransmitter glutamate and its metabolic counterpart glutamine, and the inhibitory neurotransmitter gamma-aminobutyric acid. 31P-MRS can be used to study high-energy phosphate metabolites, providing an in vivo assessment of tissue bioenergetic status. This review discusses the application of these techniques to patients with neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid17279237, year = {2006}, author = {Shoesmith, CL and Strong, MJ}, title = {Amyotrophic lateral sclerosis: update for family physicians.}, journal = {Canadian family physician Medecin de famille canadien}, volume = {52}, number = {12}, pages = {1563-1569}, pmid = {17279237}, issn = {1715-5258}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Contraindications ; Diagnosis, Differential ; Disease Progression ; Enteral Nutrition ; Family Practice ; Humans ; Nutrition Assessment ; Prognosis ; }, abstract = {OBJECTIVE: To discuss the epidemiology, pathogenesis, diagnosis, expected course, prognosis, and treatment of amyotrophic lateral sclerosis (ALS), a degenerative disorder of the nervous system associated with progressive weakness.<br><br>QUALITY OF EVIDENCE: PubMed and the Cochrane Database of Systematic Reviews were searched using the MeSH headings "amyotrophic lateral sclerosis," "therapy," "epidemiology," and "etiology." Articles containing the best available evidence were reviewed. Most provided level II and III evidence. There were some level I drug trials.<br><br>MAIN MESSAGE: Amyotrophic lateral sclerosis is associated with progressive dysarthria, dysphagia, and weakness in the extremities. Diagnosis is based on physical examination, electrophysiology, and excluding other confounding conditions. There is no cure for this devastating disorder. Certain treatments, however, can improve survival and quality of life.<br><br>CONCLUSION: Because ALS is a complex disease, care of ALS patients is best provided at multidisciplinary clinics that specialize in managing patients with this disorder.}, }
@article {pmid17274531, year = {2006}, author = {Calabrese, V and Guagliano, E and Sapienza, M and Mancuso, C and Butterfield, DA and Stella, AM}, title = {Redox regulation of cellular stress response in neurodegenerative disorders.}, journal = {The Italian journal of biochemistry}, volume = {55}, number = {3-4}, pages = {263-282}, pmid = {17274531}, issn = {0021-2938}, mesh = {Animals ; Antioxidants/physiology ; Female ; Free Radicals/metabolism ; Heme Oxygenase (Decyclizing)/physiology ; Humans ; Longevity/physiology ; Male ; Neurodegenerative Diseases/*physiopathology ; Nitric Oxide/physiology ; Nitric Oxide Synthase Type II/metabolism ; Oxidation-Reduction ; Oxidoreductases Acting on CH-CH Group Donors/physiology ; Reactive Nitrogen Species/physiology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Stress, Physiological/*physiopathology ; Thioredoxin-Disulfide Reductase/physiology ; Thioredoxins/metabolism ; }, abstract = {There is increasing evidence that reactive oxygen species (ROS) are not only toxic but play an important role in cellular signaling and in the regulation of gene expression. A number of biochemical and physiologic stimuli, such as perturbation in redox status, expression of misfolded proteins, altered glyc(osyl)ation and glucose deprivation, overloading of products of polyunsaturated fatty acid peroxidation (Hydroxynonenals, HNE) or cholesterol oxidation and decomposition, can disrupt redox homeostasis, impose stress and subsequently lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), Amyothrophic lateral sclerosis (ALS) and Friedreich ataxia (FRDA) are major neurological disorders associated with production of abnormal proteins and, as such, belong to the so called "protein conformational diseases". The Central Nervous System has evolved highly specific signaling pathways called the unfolded protein response to cope with the accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to major new insights into the diverse processes that are regulated by cellular stress response. Thus, the pathogenic dysfunctional aggregation of proteins in non-native conformations is associated with metabolic derangements and excessive production of ROS. The brain response to detect and control metabolic or oxidative stress is accomplished by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat shock proteins are a highly conserved system responsible for the preservation and repair of correct protein conformation. Heme oxygenase-1, a inducible and redox-regulated enzyme, is currently considered as having an important role in cellular antioxidant defense. A neuroprotective effect, due to its heme degrading activity, and tissue-specific antioxidant effects due to its products CO and biliverdin, this latter being further reduced by biliverdin reductase in bilirubin is an emerging concept. There is a current interest in dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiology of Alzheimer disease, with a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, two powerful antioxidants, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, have emerged as strong inducers of the heat shock response. Food supplementation with curcumin and ferulic acid is considered a nutritional approach to reduce oxidative damage and amyloid pathology in Alzheimer disease. This review summarizes the complex regulation of cellular stress signaling and its relevance to human physiology and disease.}, }
@article {pmid17259011, year = {2007}, author = {Malaspina, A and Turkheimer, F}, title = {A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord.}, journal = {Brain research bulletin}, volume = {71}, number = {5}, pages = {437-446}, doi = {10.1016/j.brainresbull.2006.10.032}, pmid = {17259011}, issn = {0361-9230}, support = {MC_U120085814/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Animals ; Gene Expression/*physiology ; Humans ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Retinoids/*physiology ; Signal Transduction/*physiology ; *Spinal Cord/embryology/growth &amp; development/metabolism ; }, abstract = {Spinal cord degenerative pathologies in humans cause extensive disability and require a broad range of specialist and palliative medical interventions. In amyotrophic lateral sclerosis (ALS), motor cell loss leads to extensive paralysis and to death from respiratory failure in 3-5 years form disease onset. A wide range of molecular changes forms the basis of spinal cord involvement in ALS, including the reactivation of molecular pathways with potentially neurorestorative properties. Central to this tissue repair mechanism is the differential regulation of components of the retinoid signaling (ReS), a molecular pathway encompassing a variety of proteins functioning as transporters, signaling factors and metabolizing enzymes for retinoic acid. In this paper, we review the strong body of experimental evidence supporting retinoid signaling's primary role in spinal cord embryonic differentiation and its likely survival-promoting function in ALS. We discuss the potential involvement in ALS pathogenesis of a subgroup of nuclear receptors (NRs) that act as functional partners of retinoid receptors in human spinal cord. We also provide a review of the expression profile of 25 ReS and NRs genes in human adult spinal cord and in motor neurons of healthy and ALS individuals, using data retrieved from independent datasets obtained through serial analysis of gene expression and array investigations. Based on published expression data, we outline a tentative expression profile of ReS and functionally synergic NR genes in human spinal cord that could guide further experiments to clarify the role of these molecules in mature nervous tissue and suggest potential treatment strategies that could have therapeutic potentials in ALS.}, }
@article {pmid17253482, year = {2007}, author = {Orrell, RW and Lane, RJ and Ross, M}, title = {Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2007}, number = {1}, pages = {CD002829}, pmid = {17253482}, issn = {1469-493X}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.<br><br>OBJECTIVES: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (from January 1966 to August 2005), EMBASE (from January 1980 to August 2005) and other sources.<br><br>SELECTION CRITERIA: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction.<br><br>MAIN RESULTS: The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure, (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures.<br><br>AUTHORS' CONCLUSIONS: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid17253460, year = {2007}, author = {Miller, RG and Mitchell, JD and Lyon, M and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD001447}, doi = {10.1002/14651858.CD001447.pub2}, pmid = {17253460}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Humans ; Life Expectancy ; Neuroprotective Agents/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register for randomized trials in December 2004 and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. We searched MEDLINE (January 1966 to August 25 2006) and EMBASE (January 1980 to September 30th 2006).<br><br>SELECTION CRITERIA: Types of studies: randomized trials.<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis. Types of interventions: treatment with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50, 100 and 200 mg; neurologic function, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials.<br><br>MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole treated patients and 503 placebo treated patients. The methodological quality was acceptable and three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis and one had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (P value = 0.042, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (P value = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P value < 0.0001) and the random effects model, which takes this into account, resulted in the overall treatment effect estimate falling just short of significance (P value = 0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represented a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.62, 95% confidence interval 1.59 to 4.31).<br><br>AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.}, }
@article {pmid17250677, year = {2007}, author = {Gonzalez de Aguilar, JL and Echaniz-Laguna, A and Fergani, A and René, F and Meininger, V and Loeffler, JP and Dupuis, L}, title = {Amyotrophic lateral sclerosis: all roads lead to Rome.}, journal = {Journal of neurochemistry}, volume = {101}, number = {5}, pages = {1153-1160}, doi = {10.1111/j.1471-4159.2006.04408.x}, pmid = {17250677}, issn = {0022-3042}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/genetics/pathology ; Animals ; Disease Models, Animal ; Dynactin Complex ; Humans ; Microtubule-Associated Proteins/genetics ; Models, Biological ; Motor Neurons/*pathology ; *Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons, generalized weakness and muscle atrophy. Most cases of ALS appear sporadically but some forms of the disease result from mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1). Several other mutated genes have also been found to predispose to ALS including, among others, one that encodes the regulator of axonal retrograde transport dynactin. As all roads lead to the proverbial Rome, we discuss here how distinct molecular pathways may converge to the same final result that is motor neuron death. We critically review the basic research on SOD1-linked ALS to propose a pioneering model of a 'systemic' form of the disease, causally involving multiple cell types, either neuronal or non-neuronal. Contrasting this, we also postulate that other neuron-specific defects, as those triggered by dynactin dysfunction, may account for a primary motor neuron disease that would represent 'pure' neuronal forms of ALS. Identifying different disease subtypes is an unavoidable step toward the understanding of the physiopathology of ALS and will hopefully help to design specific treatments for each subset of patients.}, }
@article {pmid17240849, year = {2006}, author = {Tsuchida, K}, title = {[Development of therapies against neuromuscular diseases causing muscle atrophy].}, journal = {Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology}, volume = {26}, number = {5-6}, pages = {229-233}, pmid = {17240849}, issn = {1340-2544}, mesh = {Amyotrophic Lateral Sclerosis/genetics/therapy ; Animals ; Cell Differentiation/genetics/physiology ; Cell Division/genetics/physiology ; Drug Design ; *Genetic Therapy ; Guanine Nucleotide Exchange Factors/genetics ; Humans ; Muscle, Skeletal/cytology/embryology ; Muscular Atrophy/genetics/therapy ; Mutation ; Myostatin ; Neuromuscular Diseases/genetics/*therapy ; Signal Transduction/genetics/physiology ; *Stem Cell Transplantation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transforming Growth Factor beta/*antagonists &amp; inhibitors/immunology/physiology ; }, abstract = {Skeletal muscles become atrophied by muscular disorders such as muscular dystrophy, wasting and even aging. In addition to muscle atrophy, progressive muscle damage, inflammation and replacement of muscle fibers with fibrous and fatty tissues are observed in muscular dystrophy. Neuronal innervation is required for skeletal muscle, and muscles become atrophic when motor neurons are affected by neurodegenerative disorders such as amyotrophic lateral sclerosis. Restoring muscle mass and function lost by diseases such as muscular dystrophy and neurodegenerative disorders is important. There are three rational therapies for muscular dystrophy and related diseases: gene therapy, cell therapy and drug therapy. Gene therapies to replace the defective genes have been tried with various degrees of effectiveness. Multiple myogenic stem cells including satellite cells, bone marrow cells, muscle side population cells, muscle-derived stem cells and mesoangioblast have been characterized. Cell therapies using these stem cells are one of the promising therapies for neuromuscular diseases causing muscle atrophy. As pharmacological drug therapies, increasing skeletal muscle mass by myostatin inhibition is quite promising and will be applied clinically in the near future.}, }
@article {pmid17234696, year = {2007}, author = {Birbaumer, N and Cohen, LG}, title = {Brain-computer interfaces: communication and restoration of movement in paralysis.}, journal = {The Journal of physiology}, volume = {579}, number = {Pt 3}, pages = {621-636}, pmid = {17234696}, issn = {0022-3751}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Brain/*physiology ; *Communication Aids for Disabled ; Humans ; Movement/*physiology ; Paralysis/*rehabilitation ; *User-Computer Interface ; }, abstract = {The review describes the status of brain-computer or brain-machine interface research. We focus on non-invasive brain-computer interfaces (BCIs) and their clinical utility for direct brain communication in paralysis and motor restoration in stroke. A large gap between the promises of invasive animal and human BCI preparations and the clinical reality characterizes the literature: while intact monkeys learn to execute more or less complex upper limb movements with spike patterns from motor brain regions alone without concomitant peripheral motor activity usually after extensive training, clinical applications in human diseases such as amyotrophic lateral sclerosis and paralysis from stroke or spinal cord lesions show only limited success, with the exception of verbal communication in paralysed and locked-in patients. BCIs based on electroencephalographic potentials or oscillations are ready to undergo large clinical studies and commercial production as an adjunct or a major assisted communication device for paralysed and locked-in patients. However, attempts to train completely locked-in patients with BCI communication after entering the complete locked-in state with no remaining eye movement failed. We propose that a lack of contingencies between goal directed thoughts and intentions may be at the heart of this problem. Experiments with chronically curarized rats support our hypothesis; operant conditioning and voluntary control of autonomic physiological functions turned out to be impossible in this preparation. In addition to assisted communication, BCIs consisting of operant learning of EEG slow cortical potentials and sensorimotor rhythm were demonstrated to be successful in drug resistant focal epilepsy and attention deficit disorder. First studies of non-invasive BCIs using sensorimotor rhythm of the EEG and MEG in restoration of paralysed hand movements in chronic stroke and single cases of high spinal cord lesions show some promise, but need extensive evaluation in well-controlled experiments. Invasive BMIs based on neuronal spike patterns, local field potentials or electrocorticogram may constitute the strategy of choice in severe cases of stroke and spinal cord paralysis. Future directions of BCI research should include the regulation of brain metabolism and blood flow and electrical and magnetic stimulation of the human brain (invasive and non-invasive). A series of studies using BOLD response regulation with functional magnetic resonance imaging (fMRI) and near infrared spectroscopy demonstrated a tight correlation between voluntary changes in brain metabolism and behaviour.}, }
@article {pmid17226788, year = {2007}, author = {Giordano, A and Galderisi, U and Marino, IR}, title = {From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells.}, journal = {Journal of cellular physiology}, volume = {211}, number = {1}, pages = {27-35}, doi = {10.1002/jcp.20959}, pmid = {17226788}, issn = {0021-9541}, mesh = {Bone Marrow Cells/cytology ; *Cell- and Tissue-Based Therapy/trends ; *Clinical Trials as Topic ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; }, abstract = {Mesenchymal Stem Cells (MSCs) are non-hematopoietic multi-potent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo. MSCs are of interest because they are isolated from a small aspirate of bone marrow and can be easily expanded in vitro. As such, these cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality, and anatomical localization of MSCs. In this review, we discuss clinical trials based on the use of MSCs in cardiovascular diseases, such as treatment of acute myocardial infarction, endstage ischemic heart disease, or prevention of vascular restenosis through stem cell-mediated injury repair. We analyze data from clinical trials for treatment of osteogenesis imperfecta (OI), which is a genetic disease characterized by production of defective type I collagen. We describe progress for neurological disease treatment with MSC transplants. We discuss data on amyotrophic lateral sclerosis (ALS) and on lysosomal storage diseases (Hurler syndrome and metachromatic leukodystrophy). A section of review is dedicated to ongoing clinical trials, involving MSCs in treatment of steroid refractory Graft Versus Host Disease (GVHD); periodontitis, which is a chronic disease affecting periodontium and causing destruction of attachment apparatus, heart failure, and bone fractures. Finally, we will provide information about biotech companies developing MSC therapy.}, }
@article {pmid17218019, year = {2007}, author = {Bespalov, MM and Saarma, M}, title = {GDNF family receptor complexes are emerging drug targets.}, journal = {Trends in pharmacological sciences}, volume = {28}, number = {2}, pages = {68-74}, doi = {10.1016/j.tips.2006.12.005}, pmid = {17218019}, issn = {0165-6147}, mesh = {Animals ; Chronic Disease ; Glial Cell Line-Derived Neurotrophic Factor/*physiology ; Glial Cell Line-Derived Neurotrophic Factor Receptors/*drug effects/*physiology ; Humans ; Molecular Mimicry ; Nerve Growth Factors/pharmacology ; Nervous System Diseases/*drug therapy/*physiopathology ; }, abstract = {Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), which consist of GDNF, neurturin, artemin and persephin, regulate the development and maintenance of the nervous system. GDNF protects and repairs dopamine-containing neurons, which degenerate in Parkinson's disease, and motoneurons, which die in amyotrophic lateral sclerosis. GDNF and neurturin have shown promise in clinical trials of Parkinson's disease, and artemin is currently undergoing clinical trials for chronic pain treatment. However, the delivery of GFLs into the brain through invasive approaches such as neurosurgery, viral vectors or by the use of encapsulated cells is associated with multiple obstacles. The development of small molecules that specifically activate GFL receptors and that can be applied systemically would overcome most of these problems. The unique nature of the GFL receptors, recent progress in elucidation of the 3D structures of GFLs and GFL-receptor complexes and the use of high-throughput screening have resulted in the development of the first small molecules that mimic the effects of the different GFLs.}, }
@article {pmid17214440, year = {2006}, author = {Van den Bosch, L}, title = {[The causes and mechanism of selective motor neuron death in amyotrophic lateral sclerosis].}, journal = {Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie}, volume = {68}, number = {4}, pages = {249-269}, pmid = {17214440}, issn = {0302-6469}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*pathology/*physiopathology ; Animals ; Calcium Signaling ; Cell Death ; Humans ; Motor Neuron Disease/pathology ; Motor Neurons/*pathology ; Nerve Degeneration ; Receptors, Neurotransmitter/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. In most cases, the cause of ALS is unknown although in a number of familial ALS cases mutations in the superoxide dismutase 1 (SOD1) gene were discovered. The mechanism underlying the selective motor neuron death is not yet clarified. However, it is clear that excitotoxicity could play a role in the selectivity of the motor neuron death. Excitotoxicity is the phenomenon in which the normal glutamate-mediated communication between neurons is disturbed and ultimately leads to neuronal death. In the first part of this study, we have investigated the intrinsic characteristics of motor neurons that could be responsible for the fact that these cells are extremely sensitive to excitotoxicity. Despite the fact that only the motor neurons die during ALS, it is clear that also other cell types play an important role during this process. In the second part of this study, we have concentrated on the potential role of the microglia. These cells are the macrophages of the brain and they become activated during inflammation. Using minocycline, we have inhibited the activation of the microglia and we have investigated its effect on the start of the disease and on the survival of a mouse model for ALS. Furthermore, we have investigated the cellular mechanism underlying the effect of minocycline. The goal of this research is to get insight into the mechanisms responsible for the selective motor neuron death during ALS and we hope that this information can help in the development of a therapy for this dramatic and incurable disease.}, }
@article {pmid17212349, year = {2007}, author = {Singer, MA and Statland, JM and Wolfe, GI and Barohn, RJ}, title = {Primary lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {35}, number = {3}, pages = {291-302}, doi = {10.1002/mus.20728}, pmid = {17212349}, issn = {0148-639X}, mesh = {Age of Onset ; Brain/pathology/*physiopathology ; Diagnosis, Differential ; Disease Progression ; Efferent Pathways/pathology/*physiopathology ; Genetic Predisposition to Disease/genetics ; Humans ; Motor Neuron Disease/*diagnosis/*physiopathology ; Motor Neurons/*pathology ; Pyramidal Tracts/pathology/physiopathology ; }, abstract = {The spectrum of motor neuron diseases ranges from disorders that clinically are limited to lower motor neurons to those that exclusively affect upper motor neurons. Primary lateral sclerosis (PLS) is the designation for the syndrome of progressive upper motor neuron dysfunction when no other etiology is identified. Distinction between PLS and the more common amyotrophic lateral sclerosis (ALS) relies primarily on recognition of their symptoms and signs, as well as on ancillary, although non-specific, laboratory data. In this review, we survey the history of PLS from the initial descriptions to the present. We discuss the role of laboratory, electrodiagnostic, and imaging studies in excluding other diagnoses; the findings from major case series of PLS patients; and proposed diagnostic criteria. Consistent differences are evident in patients classified as PLS compared to those with ALS, indicating that, despite its limitations, this clinical designation retains important utility.}, }
@article {pmid17208444, year = {2007}, author = {Shaw, BF and Valentine, JS}, title = {How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein?.}, journal = {Trends in biochemical sciences}, volume = {32}, number = {2}, pages = {78-85}, doi = {10.1016/j.tibs.2006.12.005}, pmid = {17208444}, issn = {0968-0004}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Enzyme Stability ; Humans ; *Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {More than 100 different mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS)--a fatal neurodegenerative disease in which aggregation of the SOD1 protein is considered to be the primary mode of pathogenesis. Recent results show that these mutations have remarkably diverse and unexpected effects on the structure, activity and native state stability of SOD1. Intriguingly, many mutations seem to have no measurable effect on the biophysical and biochemical properties of SOD1, except for decreasing the net charge of the protein. Thus, it seems likely that different ALS-associated mutations promote SOD1 aggregation by fundamentally distinct mechanisms. Understanding this complexity has implications for drug development and treatment of the disease.}, }
@article {pmid17193783, year = {2006}, author = {Hug, K and Röösli, M and Rapp, R}, title = {Magnetic field exposure and neurodegenerative diseases--recent epidemiological studies.}, journal = {Sozial- und Praventivmedizin}, volume = {51}, number = {4}, pages = {210-220}, doi = {10.1007/s00038-006-5096-4}, pmid = {17193783}, issn = {0303-8408}, mesh = {Alzheimer Disease/epidemiology/etiology ; Cross-Sectional Studies ; Electromagnetic Fields/*adverse effects ; Environmental Exposure/*adverse effects ; Health Status Indicators ; Humans ; Motor Neuron Disease/epidemiology/etiology ; Neurodegenerative Diseases/*epidemiology/etiology ; Occupational Exposure/adverse effects ; Parkinson Disease/epidemiology/etiology ; Risk ; Risk Factors ; }, abstract = {OBJECTIVES: To analyse the results of recent studies not yet included in a 2003 report of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) on occupational exposure to low-frequency electromagnetic fields as potential risk factor for neurodegenerative diseases.<br><br>METHODS: A literature search was conducted in the online databases of PubMed, ISI Web of Knowledge, DIMDI and COCHRANE, as well as in specialised databases and journals. Eight studies published between January 2000 and July 2005 were included in the review.<br><br>RESULTS: The findings of these studies contribute to the evidence of an association between occupational magnetic field exposure and the risk of dementia. Regarding amyotrophic lateral sclerosis, the recent results confirm earlier observations of an association with electric and electronic work and welding. Its relationship with magnetic field exposure remains unsolved. There are only few findings pointing towards an association between magnetic field exposure and Parkinson's disease.<br><br>CONCLUSIONS: The epidemiological evidence for an association between occupational exposure to low-frequency electromagnetic fields and the risk of dementia has increased during the last five years. The impact of potential confounders should be evaluated in further studies.}, }
@article {pmid17192723, year = {2006}, author = {Cauchi, RJ and van den Heuvel, M}, title = {The fly as a model for neurodegenerative diseases: is it worth the jump?.}, journal = {Neuro-degenerative diseases}, volume = {3}, number = {6}, pages = {338-356}, doi = {10.1159/000097303}, pmid = {17192723}, issn = {1660-2854}, support = {MC_U137761451/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Disease Models, Animal ; *Drosophila melanogaster/genetics/physiology ; Humans ; Neurodegenerative Diseases/drug therapy/*genetics/metabolism/*physiopathology ; Neuropharmacology/trends ; RNA/metabolism ; }, abstract = {Neurodegenerative diseases are responsible for agonizing symptoms that take their toll on the fragile human life. Aberrant protein processing and accumulation are considered to be the culprits of many classical neurodegenerative diseases such as Alzheimer's disease, tauopathies, Parkinson's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia and various polyglutamine diseases. However, recently it has been shown that toxic RNA species or disruption of RNA processing and metabolism may be partly to blame as clearly illustrated in spinal muscular atrophy, spinocerebellar ataxia 8 and fragile X-associated tremor/ataxia syndrome. At the dawn of the twenty-first century, the fruit fly or Drosophila melanogaster has taken its place at the forefront of an uphill struggle to unveil the molecular and cellular pathophysiology of both protein- and RNA-induced neurodegeneration, as well as discovery of novel drug targets. We review here the various fly models of neurodegenerative conditions, and summarise the novel insights that the fly has contributed to the field of neuroprotection and neurodegeneration.}, }
@article {pmid17191135, year = {2007}, author = {Calabrese, V and Guagliano, E and Sapienza, M and Panebianco, M and Calafato, S and Puleo, E and Pennisi, G and Mancuso, C and Butterfield, DA and Stella, AG}, title = {Redox regulation of cellular stress response in aging and neurodegenerative disorders: role of vitagenes.}, journal = {Neurochemical research}, volume = {32}, number = {4-5}, pages = {757-773}, pmid = {17191135}, issn = {0364-3190}, support = {AG 05119/AG/NIA NIH HHS/United States ; AG 10836/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Alzheimer Disease/genetics/metabolism ; Animals ; Gene Expression ; Heme Oxygenase (Decyclizing)/metabolism ; Humans ; Longevity/*genetics ; Neurodegenerative Diseases/genetics/*physiopathology ; Oxidation-Reduction ; Oxidative Stress/*genetics/*physiology ; Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism ; }, abstract = {Reduced expression and/or activity of antioxidant proteins lead to oxidative stress, accelerated aging and neurodegeneration. However, while excess reactive oxygen species (ROS) are toxic, regulated ROS play an important role in cell signaling. Perturbation of redox status, mutations favoring protein misfolding, altered glyc(osyl)ation, overloading of the product of polyunsaturated fatty acid peroxidation (hydroxynonenals, HNE) or cholesterol oxidation, can disrupt redox homeostasis. Collectively or individually these effects may impose stress and lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's and Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia are major neurological disorders associated with production of abnormally aggregated proteins and, as such, belong to the so-called "protein conformational diseases". The pathogenic aggregation of proteins in non-native conformation is generally associated with metabolic derangements and excessive production of ROS. The "unfolded protein response" has evolved to prevent accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to new insights into the diverse processes that are regulated by cellular stress responses. The brain detects and overcomes oxidative stress by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat-shock proteins are highly conserved and facilitate correct protein folding. Heme oxygenase-1, an inducible and redox-regulated enzyme, has having an important role in cellular antioxidant defense. An emerging concept is neuroprotection afforded by heme oxygenase by its heme degrading activity and tissue-specific antioxidant effects, due to its products carbon monoxide and biliverdin, which is then reduced by biliverdin reductase in bilirubin. There is increasing interest in dietary compounds that can inhibit, retard or reverse the steps leading to neurodegeneration in AD. Specifically any dietary components that inhibit inappropriate inflammation, AbetaP oligomerization and consequent increased apoptosis are of particular interest, with respect to a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, are candidates in this regard. Not only do these compounds serve as antioxidants but, in addition, they are strong inducers of the heat-shock response. Food supplementation with curcumin and ferulic acid are therefore being considered as a novel nutritional approach to reduce oxidative damage and amyloid pathology in AD. We review here some of the emerging concepts of pathways to neurodegeneration and how these may be overcome by a nutritional approach.}, }
@article {pmid17187916, year = {2007}, author = {Alfonzo, AV and Simpson, K and Deighan, C and Campbell, S and Fox, J}, title = {Modifications to advanced life support in renal failure.}, journal = {Resuscitation}, volume = {73}, number = {1}, pages = {12-28}, doi = {10.1016/j.resuscitation.2006.07.019}, pmid = {17187916}, issn = {0300-9572}, mesh = {Advance Directives ; Arrhythmias, Cardiac/complications/therapy ; Attitude to Health ; *Cardiopulmonary Resuscitation ; Electric Countershock ; Heart Arrest/*complications/therapy ; Humans ; Renal Dialysis ; Renal Insufficiency/*complications/therapy ; Resuscitation Orders ; Risk Factors ; }, abstract = {The outcome of cardiopulmonary resuscitation (CPR) has been reported to be worse in patients with renal failure compared with those with normal renal function. It is likely that this increased mortality may be at least partly attributable to sub-optimal and highly variable treatment strategies used in cardiac arrest in patients with renal failure, but this issue has not previously been explored. Such patients undoubtedly pose a challenge to advanced life support (ALS) providers, and renal unit staff are not trained to provide specialist advice after a patient has sustained a cardiac arrest. There are few studies investigating the epidemiology, safety or outcome of cardiac arrest in patients with renal failure and there are no generally accepted resuscitation guidelines for this special circumstance. In this article we discuss the unique problems of resuscitating patients with renal failure and propose a suitable management strategy.}, }
@article {pmid17185501, year = {2006}, author = {Tanaka, F and Niwa, J and Ishigaki, S and Katsuno, M and Waza, M and Yamamoto, M and Doyu, M and Sobue, G}, title = {Gene expression profiling toward understanding of ALS pathogenesis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1086}, number = {}, pages = {1-10}, doi = {10.1196/annals.1377.011}, pmid = {17185501}, issn = {0077-8923}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; *Gene Expression Profiling ; Humans ; Mice ; Mice, Mutant Strains ; Motor Neurons/metabolism/pathology ; Neoplasms/genetics ; Nerve Degeneration/genetics/metabolism/pathology ; Oligonucleotide Array Sequence Analysis ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Although more than 130 years have gone by since the first description in 1869 by Jean-Martin Charcot, the mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS (FALS) and by the development and analysis of mutant SOD1 transgenic mouse models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. To approach genes causative or critical for ALS, gene expression profiling in tissues primarily affected by the disease has represented an attractive research strategy. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of ALS. However, we have barely arrived at the starting point and are confronting an enormous number of genes whose roles remain undetermined. Challenging tasks lie ahead of us such as identifying which genes are really causative for ALS and developing a disease model of SALS with due consideration for the expression changes in those genes.}, }
@article {pmid17176609, year = {2006}, author = {Nandoe Tewarie, RD and Hurtado, A and Levi, AD and Grotenhuis, JA and Oudega, M}, title = {Bone marrow stromal cells for repair of the spinal cord: towards clinical application.}, journal = {Cell transplantation}, volume = {15}, number = {7}, pages = {563-577}, doi = {10.3727/000000006783981602}, pmid = {17176609}, issn = {0963-6897}, mesh = {Bone Marrow Transplantation/*methods ; Cell Culture Techniques ; Cell Differentiation ; Cell Lineage ; Humans ; Nerve Regeneration ; Neurons/cytology ; Spinal Cord Diseases/pathology/*surgery ; Spinal Cord Injuries/pathology/*surgery ; Stromal Cells/cytology/*transplantation ; }, abstract = {Stem cells have been recognized and intensively studied for their potential use in restorative approaches for degenerative diseases and traumatic injuries. In the central nervous system (CNS), stem cell-based strategies have been proposed to replace lost neurons in degenerative diseases such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease), or to replace lost oligodendrocytes in demyelinating diseases such as multiple sclerosis. Stem cells have also been implicated in repair of the adult spinal cord. An impact to the spinal cord results in immediate damage to tissue including blood vessels, causing loss of neurons, astrocytes, and oligodendrocytes. In time, more tissue nearby or away from the injury site is lost due to secondary injury. In case of relatively minor damage to the cord some return of function can be observed, but in most cases the neurological loss is permanent. This review will focus on in vitro and in vivo studies on the use of bone marrow stromal cells (BMSCs), a heterogeneous cell population that includes mesenchymal stem cells, for repair of the spinal cord in experimental injury models and their potential for human application. To optimally benefit from BMSCs for repair of the spinal cord it is imperative to develop in vitro techniques that will generate the desired cell type and/or a large enough number for in vivo transplantation approaches. We will also assess the potential and possible pitfalls for use of BMSCs in humans and ongoing clinical trials.}, }
@article {pmid17174478, year = {2007}, author = {Perry, JJ and Fan, L and Tainer, JA}, title = {Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair.}, journal = {Neuroscience}, volume = {145}, number = {4}, pages = {1280-1299}, pmid = {17174478}, issn = {0306-4522}, support = {AI022160/AI/NIAID NIH HHS/United States ; CA92584/CA/NCI NIH HHS/United States ; R01 CA112093/CA/NCI NIH HHS/United States ; CA112093/CA/NCI NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 AI022160/AI/NIAID NIH HHS/United States ; CA104660/CA/NCI NIH HHS/United States ; R01 CA117638/CA/NCI NIH HHS/United States ; R01 CA104660/CA/NCI NIH HHS/United States ; }, mesh = {Aging/genetics/metabolism ; Animals ; Binding Sites/genetics ; Brain Diseases/*enzymology/genetics/physiopathology ; Brain Neoplasms/enzymology/genetics/physiopathology ; DNA Damage/*genetics ; DNA Repair/*genetics ; Enzymes/*chemistry/genetics/metabolism ; Humans ; Molecular Structure ; Reactive Oxygen Species/*metabolism ; }, abstract = {This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to various extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression.}, }
@article {pmid17171827, year = {2006}, author = {Steele, AD and Yi, CH}, title = {Neuromuscular denervation: Bax up against the wall in amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {26}, number = {50}, pages = {12849-12851}, pmid = {17171827}, issn = {1529-2401}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Humans ; Muscle Denervation/methods ; Muscle, Skeletal/*innervation/*metabolism/pathology ; Neuromuscular Junction/metabolism/pathology ; bcl-2-Associated X Protein/*physiology ; }, }
@article {pmid17167012, year = {2006}, author = {Simonds, AK}, title = {Recent advances in respiratory care for neuromuscular disease.}, journal = {Chest}, volume = {130}, number = {6}, pages = {1879-1886}, doi = {10.1378/chest.130.6.1879}, pmid = {17167012}, issn = {0012-3692}, mesh = {Adult ; Child ; *Continuous Positive Airway Pressure ; Home Care Services, Hospital-Based ; Humans ; Motor Neuron Disease/mortality/therapy ; Muscular Dystrophy, Duchenne/mortality/therapy ; Neuromuscular Diseases/mortality/*therapy ; Palliative Care ; Respiratory Insufficiency/mortality/*therapy ; Survival Analysis ; Treatment Outcome ; }, abstract = {The impact of ventilatory support on the natural history of neuromuscular disease (NMD) has become clearer over the last 2 decades as techniques have been more widely applied. Noninvasive ventilation (NIV) allows some patients with nonprogressive pathology to live to nearly normal life expectancy, extends survival by many years in patients with other conditions (eg, Duchenne muscular dystrophy), and in those patients with rapidly deteriorating disease (eg, amyotrophic lateral sclerosis) survival may be increased, but symptoms can be palliated even if mortality is not reduced. A growing number of children with NMD are surviving to adulthood with the aid of ventilatory support. The combination of NIV with cough-assist techniques decreases pulmonary morbidity and hospital admissions. Trials have confirmed that NIV works in part by enhancing chemosensitivity, and in patients with many different neuromuscular conditions the most effective time to introduce NIV is when symptomatic sleep-disordered breathing develops.}, }
@article {pmid17153762, year = {2006}, author = {Castellanos Ortega, A and Rey Galán, C and Alvarez Carrillo, A and López-Herce Cid, J and Delgado Domínguez, MA}, title = {[Pediatric advanced life support].}, journal = {Anales de pediatria (Barcelona, Spain : 2003)}, volume = {65}, number = {4}, pages = {342-363}, doi = {10.1016/s1695-4033(06)70207-7}, pmid = {17153762}, issn = {1695-4033}, mesh = {Advanced Cardiac Life Support/methods/*standards ; Child ; Child, Preschool ; Critical Pathways ; Heart Arrest/*therapy ; Humans ; Infant ; Infant, Newborn ; Intubation, Intratracheal/methods/standards ; Pediatrics ; }, abstract = {Advanced life support (ALS) includes all the procedures and maneuvers used to restore spontaneous circulation and breathing, thus minimizing brain injury. The fundamental steps of ALS are airway control with adjuncts, ventilation with 100% oxygen, vascular access and fluid and drug administration, and monitoring to diagnose and treat arrhythmias. Airway control can be achieved by means of oropharyngeal airway, endotracheal intubation, and alternative methods (laryngeal mask and cricothyroidotomy). Vascular access can be achieved by the peripheral venous, intraosseous, central venous, and tracheal routes. The most frequent rhythms found in children with cardiorespiratory arrest are nonshockable (asystole, severe bradycardia, pulseless electrical activity, and complete atrioventricular block). In these cases, adrenaline continues to be the essential drug. Currently, low adrenaline doses (0.01 mg/kg IV and 0.1 mg/kg intratracheal administration) are recommended throughout the resuscitation period. Amiodarone (5 mg/kg) is the drug of choice in cases of ventricular fibrillation refractory to electric shock. The treatment sequence for shockable rhythms (ventricular fibrillation and pulseless ventricular tachycardia) is one 4 J/kg electric shock, followed by cardiopulmonary resuscitation (chest compressions and ventilation) for 2 minutes with subsequent reassessment of the electrocardiographic rhythm. Adrenaline must be administered immediately before the third electric shock and subsequently every 3-5 minutes. Amiodarone must be administered immediately before the fourth shock.}, }
@article {pmid17152798, year = {2006}, author = {Olszewski, J}, title = {[Causes, diagnosis and treatment of neurogenic dysphagia as an interdisciplinary clinical problem].}, journal = {Otolaryngologia polska = The Polish otolaryngology}, volume = {60}, number = {4}, pages = {491-500}, pmid = {17152798}, issn = {0030-6657}, mesh = {Brain Injuries/complications ; Central Nervous System Diseases/*complications ; Deglutition/physiology ; Deglutition Disorders/diagnosis/*etiology/*therapy ; Esophageal Motility Disorders/etiology ; Esophagus/*physiopathology ; Humans ; Neuromuscular Diseases/*complications/physiopathology ; Parkinson Disease/complications ; Pneumonia, Aspiration/etiology ; }, abstract = {The intricate mechanism of swallowing can be divided into three phases: oral, pharyngeal, and esophageal. Dysphagia is a disruption in the swallowing process, which include difficulty in transporting (or a lack of transporting) a food or liquid bolus from the mouth through the pharynx and esophagus into the stomach. Causes of disruptions in the swallowing process can be divided into superior (oropharyngeal) and inferior (esophageal) according to Paradowski et al. Neurlologic dysphagia may be caused by a disruption in different parts of the central nervous system (supranuclear level, level of motor and sensory nuclei taking part in swallowing process, peripherial nerves level and a pathology of muscle cells and spindles) or neuromuscular and muscular disorders. Neuromuscular disorders causes according to Waśko-Czopnik et al. are: stroke, brain tumors, brain injury, bulbar and pseudobulbar paralysis, neurodegenerative diseases (amyotrophic lateral sclerosis, multiple sclerosis), tabes dorsalis, multisystem degenerations, Parkinson's disease, delayed dyskineses, Huntington's disease, myasthenia and myasthenic syndromes, myopathies and peripherial neuropathies. The correct diagnosis evaluation include history taking, physical examination with palpation and consultations (laryngological, gastrological and neurological). According to Halama radiological esophagogram, videofluoroscopy, flexible endoscopic examination, ultrasound examination, manometry, electromyography, scintigraphy and 24 hour pH monitoring are main diagnostic procedures of dysphagia. Some of the reasons for the neurologic dysphagia may be treated by surgical and pharmacological methods. Neurologic dysphagia rehabilitation is difficult, long-lasting and often falling far short of expected results. Primary it should include neurologic cause treatment if it is possible. According to WHO International Classification of Functioning and Health in 2001 non-invasive methods of dysphagia treatment may be divided into reconstitution, compensatory and adaptive techniques. The most popular reconstitution methods are thermal stimulation (Lazzar's) or tactilethermal application (Rosenbeck's) techniques which may be applied for abnormal duration of stage transition (DST). Abnormal duration of stage transition considerably increase probability of aspiration. Dysphagia treatment by compensatory methods consist in various techniques of swallowing and posture changes application. Adaptive techniques include dietary changes--avoiding of sustenances strengthening dysphagia and adequate dietary intake. The basic principle of dysphagia rehabilitation is that the most effective way to regain efficiency is the regeneration on remains of lost function. Carrying out imperfect swallowing acts is probably the best way of increasing effectiveness and efficiency of swallowing. On the other hand imperfect swallowing acts may be hazardous because of the danger of aspiration and inhalation pneumonia.}, }
@article {pmid17149752, year = {2007}, author = {Ly, PT and Singh, S and Shaw, CA}, title = {Novel environmental toxins: steryl glycosides as a potential etiological factor for age-related neurodegenerative diseases.}, journal = {Journal of neuroscience research}, volume = {85}, number = {2}, pages = {231-237}, doi = {10.1002/jnr.21147}, pmid = {17149752}, issn = {0360-4012}, mesh = {*Aging ; Animals ; Bacteria/*chemistry ; Bacterial Infections/complications ; Cycas/*chemistry ; Glycosides/chemistry/isolation &amp; purification/*toxicity ; Humans ; Neurodegenerative Diseases/*etiology ; *Neurotoxins ; }, abstract = {Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) is a unique neurodegenerative disease found on the island of Guam. This disease presents as a spectrum of neurological disorders characterized by features of ALS, parkinsonism, dementia, or a combination. The strongest epidemiological link has been to the consumption of the seeds from the cycad plant that purportedly contained a neurotoxin. Mice fed washed cycad flour show signs that mimic ALS-PDC, which include progressive deficits in motor, cognitive, and olfactory functions associated with neuron loss in the spinal cord, nigrostriatal system, cortex, hippocampus, and olfactory bulb. Through a series of chemical extractions of washed cycad flour, we identified steryl glycoside molecules as bioactive molecules that are neurotoxic in culture and in mice. A detailed review of this class of molecule revealed that the molecules are abundant in the environment, particularly in plants and bacteria. Lipid analysis showed that some bacteria that are associated with some forms of neurodegenerative disorders have the capacity to synthesize steryl glycosides. Furthermore, certain steryl glycosides have been found to be a cell stress mediator and may have some immunomodulary effects. We hypothesize that steryl glycosides are putative neurotoxins involved in the etiopathogenesis of several age-related neurodegenerative disorders.}, }
@article {pmid17146283, year = {2006}, author = {Martin, LJ}, title = {Mitochondriopathy in Parkinson disease and amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {65}, number = {12}, pages = {1103-1110}, doi = {10.1097/01.jnen.0000248541.05552.c4}, pmid = {17146283}, issn = {0022-3069}, support = {AG 16282/AG/NIA NIH HHS/United States ; NS 34100/NS/NINDS NIH HHS/United States ; NS 52098/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*physiopathology ; Animals ; *Apoptosis ; Apoptosis Regulatory Proteins/genetics/metabolism ; Disease Models, Animal ; Electron Transport/genetics ; Humans ; Mitochondrial Diseases/genetics/metabolism/*physiopathology ; Mitochondrial Proteins/genetics/metabolism ; Nerve Degeneration/genetics/metabolism/*physiopathology ; Parkinson Disease/genetics/metabolism/*physiopathology ; }, abstract = {The causes of the selective neurodegeneration in Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS) are unknown and commonalities among these and other age-related neurodegenerative diseases continue to be sought. Morphologic, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria might be a convergence point for neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress. In PD, mutations in putative mitochondrial proteins have been identified recently and mitochondrial DNA mutations have been found in nigral neurons. In ALS, changes occur in mitochondrial respiratory chain enzymes and in mitochondrial cell death proteins, indicative of an activation of programmed cell death pathways. Mouse models are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria in neuronal death processes ranging from apoptosis to necrosis. This review presents how malfunctioning mitochondria might contribute to neuronal death in PD and ALS.}, }
@article {pmid17136919, year = {2005}, author = {Heffernan, C and Jenkinson, C}, title = {Measuring outcomes for neurological disorders: a review of disease-specific health status instruments for three degenerative neurological conditions.}, journal = {Chronic illness}, volume = {1}, number = {2}, pages = {131-142}, doi = {10.1177/17423953050010021001}, pmid = {17136919}, issn = {1742-3953}, mesh = {Health Status ; Humans ; Motor Neuron Disease/*therapy ; Multiple Sclerosis/*therapy ; *Outcome Assessment, Health Care ; Parkinson Disease/*therapy ; Quality of Life ; }, abstract = {Health-related quality-of-life measures have been increasingly used in research into neurological disorders in recent years. The aim of this paper is to provide an objective appraisal of the evidence in regard to disease-specific quality-of-life measures used in research on health interventions for three degenerative neurological disorders: multiple sclerosis, motor neurone disease/amyotrophic lateral sclerosis and Parkinson's disease. A comprehensive search strategy was developed to include nine relevant electronic databases. Only studies pertaining to patient-based outcome measurements in multiple sclerosis, motor neurone disease and Parkinson's disease were included. We identified 76 eligible studies. As studies consisted of descriptive and cross-sectional survey study designs, results were reported qualitatively rather than in the form of a meta-analysis. Four disease-specific measures were found for Parkinson's disease, 11 for multiple sclerosis and one for motor neurone disease. We conclude that health-related quality-of-life measures are useful in assessing the impact of treatments and interventions for neurological disorders. However, further research is needed on the development of instruments using psychometric methods and on the validation, utilization and responsiveness of instruments to change.}, }
@article {pmid17136506, year = {2007}, author = {Golubnitschaja, O}, title = {Cell cycle checkpoints: the role and evaluation for early diagnosis of senescence, cardiovascular, cancer, and neurodegenerative diseases.}, journal = {Amino acids}, volume = {32}, number = {3}, pages = {359-371}, doi = {10.1007/s00726-006-0473-0}, pmid = {17136506}, issn = {0939-4451}, mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; Biomarkers, Tumor/*metabolism ; Calcinosis/diagnosis/metabolism ; Cardiovascular Diseases/*diagnosis/*metabolism/therapy ; *Cell Cycle ; Cell Cycle Proteins/metabolism ; Cell Transformation, Neoplastic/metabolism ; *Cellular Senescence ; DNA Damage ; DNA Methylation ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/metabolism ; Diagnosis, Differential ; Epigenesis, Genetic ; Genome, Human ; Humans ; Neoplasms/*diagnosis/*metabolism/therapy ; Neurodegenerative Diseases/*diagnosis/*metabolism/therapy ; Protein Serine-Threonine Kinases/metabolism ; Proteome/metabolism ; Tumor Suppressor Proteins/metabolism ; }, abstract = {Maintenance of genomic integrity is critical for prevention of a wide variety of adverse cellular effects including apoptosis, cellular senescence, and malignant cell transformation. Under stress conditions and even during an unperturbed cell cycle, checkpoint proteins play the key role in genome maintenance by and mediating cellular response to DNA damage, and represent an essential part of the "cellular stress response proteome". Intact checkpoint signal transduction cascades check the presence of genome damage, trigger cell cycle arrest, and forward the information to the protein core of cell cycle machinery, replication apparatus, repair, and/or apoptotic protein cores. Genetic checkpoint defects lead to syndromes that demonstrate chromosomal instability, increased sensitivity to genotoxic stress, tissue degeneration, developmental retardation, premature aging, and cancer predisposition that is most extensively studied for the ATM-checkpoint mutated in Ataxia telangiectasia. Tissue specific epigenetic control over the function of cell cycle checkpoints can be, further, misregulated by aberrant DNA methylation status. The consequent checkpoint dysregulation may result in tissue specific degenerative processes such as degeneration and calcification of heart aortic valves, diabetic cardiomyopathy, hyperhomocysteinemic cerebrovascular, peripheral vascular and coronary heart diseases, neurodegenerative disorders (Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, glaucoma), and accelerated aging frequently accompanied with cancer. This review focuses on the checkpoints shown to be crucial for unperturbed cell cycle regulation, dysregulation of which might be considered as a potential molecular marker for early diagnosis of and therapy efficiency in neurodegenerative, cardiovascular and cancer diseases. An application of the most potent detection technologies such as "Disease Proteomics and Transcriptomics" also considered here, allows a most specific selection of diagnostic markers.}, }
@article {pmid17133899, year = {2006}, author = {Williams, AL}, title = {Perspectives on spirituality at the end of life: a meta-summary.}, journal = {Palliative &amp; supportive care}, volume = {4}, number = {4}, pages = {407-417}, doi = {10.1017/s1478951506060500}, pmid = {17133899}, issn = {1478-9515}, mesh = {Acquired Immunodeficiency Syndrome/psychology ; Adult ; Aged ; Aged, 80 and over ; *Attitude to Death ; Cardiovascular Diseases/psychology ; HIV Infections/psychology ; Hospices ; Humans ; Interviews as Topic ; Middle Aged ; Neoplasms/psychology ; *Quality of Life ; *Religion and Medicine ; Research ; Research Design ; *Spirituality ; Terminally Ill/*psychology ; }, abstract = {OBJECTIVE: A meta-summary of the qualitative literature on spiritual perspectives of adults who are at the end of life was undertaken to summarily analyze the research to date and identify areas for future research on the relationship of spirituality with physical, functional, and psychosocial outcomes in the health care setting.<br><br>METHODS: Included were all English language reports from 1966 to the present catalogued in PubMed, Medline, PsycInfo, and CINAHL, identifiable as qualitative investigations of the spiritual perspectives of adults at the end of life. The final sample includes 11 articles, collectively representing data from 217 adults.<br><br>RESULTS: The preponderance of participants had a diagnosis of cancer; those with HIV/AIDS, cardiovascular disease, and ALS were also represented. Approximately half the studies were conducted in the United States; others were performed in Australia, Finland, Scotland, and Taiwan. Following a process of theme extraction and abstraction, thematic patterns emerged and effect sizes were calculated. A spectrum of spirituality at the end of life encompassing spiritual despair (alienation, loss of self, dissonance), spiritual work (forgiveness, self-exploration, search for balance), and spiritual well-being (connection, self-actualization, consonance) emerged.<br><br>SIGNIFICANCE: The findings from this meta-summary confirm the fundamental importance of spirituality at the end of life and highlight the shifts in spiritual health that are possible when a terminally ill person is able to do the necessary spiritual work. Existing end-of-life frameworks neglect spiritual work and consequently may be deficient in guiding research. The area of spiritual work is fertile ground for further investigation, especially interventions aimed at improving spiritual health and general quality of life among the dying.}, }
@article {pmid17131224, year = {2006}, author = {Fujimoto, K}, title = {Dropped head in Parkinson's disease.}, journal = {Journal of neurology}, volume = {253 Suppl 7}, number = {}, pages = {VII21-26}, pmid = {17131224}, issn = {0340-5354}, mesh = {Female ; Head Movements/*physiology ; History, 19th Century ; History, 20th Century ; Humans ; Male ; Movement Disorders/*etiology/history/pathology ; Neck Muscles/physiopathology ; Parkinson Disease/*complications ; }, abstract = {"A propensity to bend the trunk forward" and "the chin is now almost immovably bent down upon the sternum" were described by James Parkinson in patients with Parkinson's disease (PD). The term "dropped head" was first reported in "Gerlier disease" in Switzerland and 'kubisagari' in Japan and since then also reported in myositis, myopathy, myasthenia gravis, amyotrophic lateral sclerosis, neuropathy, and hypothyroidism. Disproportionate antecollis occurs in about half cases of multiple system atrophy (MSA) and is considered dystonic in nature. Dropped head is considered rare in PD, both in advanced and early stages of PD. However, it is known to progress subacutely over a period of several days. In my experience, dropped head is relatively common in PD. The mechanism of dropped head in PD is either dystonia of flexor neck muscles or weakness of extensor neck muscles. The response of dropped head to various anti-parkinsonian medications is rather inconsistent. Levodopa is reported to induce amelioration in some patients while dopamine agonists can cause deterioration. Muscle afferent block with lidocaine and ethanol is reported to be effective, while the effect of botulinum toxin injection into the affected muscles is limited. The effect of stereotaxic neurosurgery on dropped head is controversial. Early diagnosis and prompt treatment is necessary to prevent muscle damage associated with longterm overstretch of extensor neck muscles.}, }
@article {pmid17130405, year = {2006}, author = {Cheung, YK and Gordon, PH and Levin, B}, title = {Selecting promising ALS therapies in clinical trials.}, journal = {Neurology}, volume = {67}, number = {10}, pages = {1748-1751}, doi = {10.1212/01.wnl.0000244464.73221.13}, pmid = {17130405}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic/*standards/statistics &amp; numerical data/trends ; Clinical Trials, Phase II as Topic/standards/statistics &amp; numerical data/trends ; Data Interpretation, Statistical ; Dose-Response Relationship, Drug ; *Drug Design ; Humans ; Nerve Degeneration/*drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/*administration &amp; dosage/adverse effects/isolation &amp; purification ; Sample Size ; }, abstract = {Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.}, }
@article {pmid17128137, year = {2006}, author = {, }, title = {[HAS recommendations on amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S363-4S393}, pmid = {17128137}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Humans ; }, }
@article {pmid17128136, year = {2006}, author = {, }, title = {[HAS recommendations on amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S360-4S362}, pmid = {17128136}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Humans ; }, }
@article {pmid17128135, year = {2006}, author = {Guerrier, M}, title = {[Ethical issues and supportive tools and their reversibility in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S334-4S359}, pmid = {17128135}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Practice Guidelines as Topic ; Respiration, Artificial/ethics ; Terminal Care/*ethics/legislation &amp; jurisprudence ; Withholding Treatment/ethics ; }, }
@article {pmid17128134, year = {2006}, author = {Meininger, V and Hirsch, E}, title = {[Ethical aspects for substitute decisions and their reversion in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S329-4S333}, pmid = {17128134}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Terminal Care/*ethics ; }, abstract = {Related to its clinical characteristics, amyotrophic lateral sclerosis (ALS) is a paradigm of the ethical difficulties due to a chronic and relentless fatal disease. Its fatal evolution in relation with a respiratory failure, but mainly the choices imposed by the respiratory insufficiency at the end of live, makes that the medical team faces very difficult situations. These situation can be solved only case per case, with repeated discussion with the patients and its relatives. The appeal to the shared dossier becomes essential in this approach. It makes easier the communication, and the appropriation and sharing of information and knowledge that are necessary to anticipate the end of life decisions. ALS sparks off constantly renewed dilemmas.}, }
@article {pmid17128133, year = {2006}, author = {Ciais, JF}, title = {[Questions concerning an endotracheal intubation or a tracheotomy in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S323-4S328}, pmid = {17128133}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Emergency Treatment ; Humans ; *Intubation, Intratracheal ; *Tracheotomy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an illness in which respiratory complications often determine the terminal prognosis. Emergency situations lead one to pose questions concerning an endotracheal intubation or a tracheotomy. A tracheotomy should not be performed during an emergency situation. A tracheotomy necessitates a stable condition and prior reflection. Orotrachael intubation is the method of choice during emergency situations requiring invasive ventilation or airway protection. Intubation during an emergency situation presents specific problems: the lack of knowledge concerning the person and their pre-established desires, the impossibility of evaluating the potential reversibility of an acute pathology, the risk of not being able to wean the patient off the ventilator and the lack of time to gather all the elements necessary for a well-thought out decision. It may be appropriate for emergency personnel to introduce mechanical ventilation and leave the reflection for a later moment, but this approach is not suitable for people in end of life situations in which the person and the family wish to avoid all unreasonable therapeutics. One solution may be to develop among emergency care teams the practice of using non-invasive ventilation and airway clearance techniques as well as developing palliative care knowledge. Orotracheal intubation in an emergency situation presents certain practical difficulties, notably regarding the choice of anesthetics. Preventings situations where emergency intubation may be necessary is probably best obtained by anticipating acute problems, by preparing the ill person, the family and the care givers, by coordinating the potential care providers and by educating emergency personnel in palliative care.}, }
@article {pmid17128132, year = {2006}, author = {Gonzalez-Bermejo, J}, title = {[Indications and equipment needs for ventilatory support in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S320-4S322}, pmid = {17128132}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Respiration, Artificial/*instrumentation ; }, abstract = {Long term mechanical ventilation improves survival and quality of life in patients with Amyotrophic Lateral Sclerosis (ALS). There is an enormous range of equipment available but there is little evidence pointing to the superiority of one device over another. Another problem is the lack of adaptation of equipment for use by handicapped patients. Indication on mechanical ventilation in ALS is discuss in this article: Symptoms associated with an objective criteria of hypoventilation are often used. In the monitoring of this mechanical ventilation new tools are needed, initiating nocturnal ventilation with systematic respiratory polygraphic studies seems to be justified.}, }
@article {pmid17128131, year = {2006}, author = {Bouteloup, C}, title = {[What are the means of alimentary function supply and their indications in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S309-4S319}, pmid = {17128131}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Enteral Nutrition ; Gastrostomy ; Humans ; *Nutritional Support ; }, abstract = {Artificial nutrition is necessary when oral feeding becomes insufficient to cover protein and energetic needs and becomes dangerous (risk of malnutrition, dehydration and aspiration). In ALS patients, enteral nutrition is the method of choice and gastrostomy is preferable to nasogastric tube which must be limited for a short term enteral nutrition or if gastrostomy is at risk (because of pulmonary function) or refused by the patient. The percutaneous gastrostomy can be placed endoscopically (PEG) or radiologically (RIG), surgical gastrostomy has to be avoided because of general anaesthesia. Advantages of RIG are a success rate of about 100 percent and a placement feasible without sedation but its superiority on PEG in ALS patients especially if pulmonary functions are altered is not demonstrated. No objective criterion permits to define the exact moment of enteral nutrition. However, enteral nutrition is recommended when dysphagia becomes symptomatic (insufficient caloric intake with weight loss, dehydration, frequent choking and aspiration). Swallowing disorders must be detected early to give to patients and their family information about enteral nutrition and gastrostomy as soon as possible and to help them to decide. It is desirable to propose gastrostomy when forced vital capacity is yet above 50 percent and nutritional state not altered (body mass index>18kg/m2 and/or weight loss<10 percent). Enteral nutrition is not desirable in ALS patients with dementia or in the preterminal phase. Suitable enteral nutrition with regular nutritional evaluation can improve nutritional status. Currently, improvement of quality of life and survival due to enteral nutrition has not been proved in ALS patients.}, }
@article {pmid17128130, year = {2006}, author = {Havet, V}, title = {[Psychological management of patient with amyotrophic lateral sclerosis and their caregivers].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S301-4S307}, pmid = {17128130}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Caregivers ; Family Health ; Humans ; *Psychotherapy ; }, abstract = {Psychological management of patients with amyotrophic lateral sclerosis (ALS) and their caregivers is a relatively recent concern, probably because there was previously a tendency to consider only physical functioning. Recent work have focused more on psychological well-being concerning patient and their close relative and have highlighted the great need for considering psychological reactions after such a diagnosis. The needs and goals of the patients cannot be limited to functional factors and should be considered in their psychological, social and familial settings. Currently, we consider that close relatives should benefit from psychological support just like patients with ALS. This review suggests different ways to improve management of patients with ALS, while considering personal for strategies coping with the disease, the familial and social context, and individual factors that could improve quality of life (QOL). Studies have demonstrated the significant role of psychological, existential and support factors in determining QOL in these patients.}, }
@article {pmid17128129, year = {2006}, author = {Roy-Bellina, S and Camu, W}, title = {[Psychological treatment for the patient and caregivers during the course of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S295-4S300}, pmid = {17128129}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Caregivers ; Family Health ; Humans ; *Psychotherapy ; }, abstract = {Amyotrophic lateral sclerosis is a devastating disorder for which the psychological consequences of both the diagnosis announcement and the evolution of paralysis not only concern the patient but also his family. The role of the psychologist is to develop an individualized follow up considering the patient in his globality. The first consultation is, ideally, initiated after a medical consultation explaining the importance of the psychological area in ALS patient care. The psychological follow up will consist in an empathic listening of history and problems. Information will also be given to the patient by the psychologist who's role should not be only passive. When talking about "globality" of the psychological intervention for a given patient, his family takes a determinant place. The psychologist should be able to establish a contact with the family members concerned by the daily support to the patient. The psychological processes through which a patient will evolve should be explained to the family. Depression frequently affects family members, and a specific follow up in those cases has to be undertaken as soon as possible. Such a depressive reaction may also take place after death and a psychological follow up do not end after the death of a patient. The role of a psychologist in ALS care ideally takes places in the context of a multidisciplinary team such as a motoneuron clinic now largely available in our country. The burden of care is frequently heavy both for the family and the team of professional carers into and outside the hospital. The psychologist has a role of mediation between those persons, facilitating verbal exchanges, paying attention to specific difficulties and maintaining a fruitful exchange between the carers, the patient and his family. More prospectively, the psychologist also has a pedagogic role for the carers explaining psychological processes and giving clues for a constructive relationship between the patient and his family and also between this patient and his carers.}, }
@article {pmid17128128, year = {2006}, author = {Guerrier, M}, title = {[What is the role of health volunteers in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S291-4S294}, pmid = {17128128}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Hospital Volunteers ; Humans ; }, abstract = {OBJECTIVE: Analysis of the literature about functions of health volunteers in ALS.<br><br>METHOD: Article selection in MEDLINE, CINHAL and EMBASE.<br><br>RESULTS: The notion of health volunteer has several meanings, and relates to different models varying between substitution and supply. The role of volunteers in a French and two Canadian NPO are described.<br><br>CONCLUSIONS: The function of the volunteer integrates potentially interpersonal aid relationships, social mediation, and active functional help components.}, }
@article {pmid17128127, year = {2006}, author = {Bardet, L}, title = {[Role of health volunteers for patients with amyotrophic lateral sclerosis and their family].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S284-4S290}, pmid = {17128127}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Follow-Up Studies ; *Hospital Volunteers ; Humans ; }, abstract = {In ALS Centers, the patient receives coordinated care from Health Volunteers and the medical team including specialized physicians, therapists and social workers. There are two types of volunteers: those who assist the patient in hospital, the Medical Volunteers (MV), and those who make home visits, the Home Volunteers (HV). Both are recruited and trained by the ARS and have a single motivation: help the patient's; they are emotionally and morally fully qualified to accomplish their task in accordance with the rules that have been set by the Association. The ALS patient is seen for the first time by the Medical Volunteer at the ALS Center, immediately after his or her disease has been diagnosed by the clinic's director. The MV takes the initiative for the dialogue, which he/she leads gently and tactfully. The discussion is aimed at gathering useful information to be put in the document: "Connaissance du malade" (knowledge of the patient), working out the patient's primary concerns and assessing the carer's commitment, in a friendly atmosphere. Finally the volunteer gives the guidebook, "Livret d'accueil" to the patient. After the conversation, the MV decides which confidential pieces of information are to be passed on to the medical staff with a view to sorting out problems; information is then set the HV who will provide follow up care for this patient. Long-term care management of ALS patients is achieved through three regular monthly appointments at the ALS Center. With the help of the document "Connaissance du malade" the MV keeps better in touch with the patient using the feedback from the HV about what has been going on in the interval between the two visits to the ALS Center. This collaboration enables appropriate follow up care for the patients with clearly-defined objectives: dealing with the patient's anxiety, understanding his/her position at the present time, his/her daily routine and needs, comforting, checking compliance with treatment, counselling and supporting the family, answering delicate questions. Thus, the Health Volunteer's mission contributes meaningfully to medical treatment. This approach likely helps the person affected by ALS to regain the initially deteriorated sense of belonging to the social body.}, }
@article {pmid17128126, year = {2006}, author = {Vandenberghe, N}, title = {[The coverage of the social consequences of the disease and the loss of autonomy in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S278-4S283}, pmid = {17128126}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; France ; Home Care Services ; Humans ; *Social Adjustment ; *Social Security ; }, abstract = {There is no specific social answer to amyotrophic lateral sclerosis, which alters quickly autonomy of the patients. Different financial and human assistances can be set up to compensate the loss of autonomy. To date, to obtain this assistance, delays are often long; and there is no individual evaluation of the situation at home. The creation of reference centres should allow a better coverage focused on an individualized answer with a management of systems based on the nearness.}, }
@article {pmid17128125, year = {2006}, author = {Moutet, F}, title = {[Management of lost independence and its social consequences in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S275-4S277}, pmid = {17128125}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; *Quality of Life ; *Social Adjustment ; }, abstract = {Amyotrophic lateral sclerosis is characterized by progressive unavoidable loss of independence but with preserved intellectual capacity. Care requires human and technical compensation taking into account the desires of the patient and his/her family. Care should be taken to avoid isolating from the social environment by implementing coherent material and human organizations aimed at maintaining patient comfort and acceptable quality of life "to the end" while respecting the rights and will of the care recipient.}, }
@article {pmid17128124, year = {2006}, author = {Sancho, PO and Boisson, D}, title = {[What are management practices for speech therapy in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S273-4S274}, pmid = {17128124}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Speech Disorders/*etiology/*therapy ; *Speech Therapy ; }, abstract = {Amyotrophic lateral sclerosis involves deterioration of speech and swallowing. The objectives of rehabilitation are to maintain a comprehensible speech, using exercises on airflow-phonic coordination and breath, lingual and labial movements. Rehabilitation exercises also focus on the different times of swallowing to improve management of the food bolus in the mouth, to learn facilitating techniques and to adopt postures favoring passage of the food bolus. No studies have addressed the question of the effectiveness of rehabilitation in amyotrophic lateral sclerosis, in term of quality of life, maintenance of comprehensible speech or reduction of respiratory risks. Rehabilitation programs are established on an individual basis according to the clinical presentation and course.}, }
@article {pmid17128123, year = {2006}, author = {Lévêque, N}, title = {[Speech therapy guidelines in patients with amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S269-4S272}, pmid = {17128123}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Disease Progression ; Humans ; Speech Disorders/*etiology/*therapy ; *Speech Therapy ; }, abstract = {Bulbar involvement is usual in patients with amyotrophic lateral sclerosis (ALS), leading to a progressive loss of speech, phonation and swallowing abilities. The goal of the speech therapy is to maintain, as long as possible, those abilities and to devise alternative communication strategies when oral communication is ineffective. This paper presents guidelines for speech therapy during disease progression.}, }
@article {pmid17128122, year = {2006}, author = {Pinet, C}, title = {[What is the role of life support systems in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S266-4S268}, pmid = {17128122}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Intubation, Intratracheal ; *Life Support Care ; Tracheotomy ; }, abstract = {There is very little information in the medical literature concerning the problems of tracheotomy and emergency intubation in amyotrophic lateral sclerosis. Nevertheless, we can assumed that: explicative information for the patient is important, emergency ventilation is not very frequent, emergency ventilation was not systematic, prognosis of emergency ventilation is very poor.}, }
@article {pmid17128121, year = {2006}, author = {Perrin, C}, title = {[Types of ventilatory support and their indications in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S261-4S265}, pmid = {17128121}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; *Respiration, Artificial ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {Respiratory muscle weakness represents the major cause of mortality in patients with amyotrophic lateral sclerosis (ALS). As a result, ventilatory assistance is an important part of disease management. Nowadays, noninvasive ventilation (NIV) has become the first choice modality for most patients and represents an alternative to tracheostomy intermittent positive-pressure ventilation. Although, some consensus guidelines have been proposed to initiate NIV in patients with restrictive chronic respiratory failure, these criteria are discussed regarding ALS. While the current consensus recommends that NIV may be used in symptomatic patients with hypercapnia or forced vital capacity<50p.cent of predicted value, early use of NIV is proposed in the literature and reported in this paper.}, }
@article {pmid17128120, year = {2006}, author = {Perrin, C}, title = {[Techniques favoring airway clearance in patients with amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S256-4S260}, pmid = {17128120}, issn = {0035-3787}, mesh = {Airway Obstruction/*etiology/*prevention &amp; control ; Amyotrophic Lateral Sclerosis/*complications ; Bronchial Diseases/*etiology/*prevention &amp; control ; Cough ; Humans ; }, abstract = {Although noninvasive ventilation may improve survival in patients with amyotrophic lateral sclerosis (ALS), ineffective airway clearance is an important cause of therapeutic failure. We report in this paper the main studies which have assessed assisted cough techniques in patients with ALS. Manually assisted cough (in particular with previous air stacking) and mechanical insufflation/exsufflation may significantly increase cough peak flow. Characteristics, limitations and long-term benefits of these techniques are also discussed.}, }
@article {pmid17128119, year = {2006}, author = {Sancho, PO and Boisson, D}, title = {[Physical therapy in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S253-4S255}, pmid = {17128119}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; *Physical Therapy Modalities ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease, without any curative treatment. Clinical expression is variable and related to loss of motor neurons in the cortex, brain stem and spinal cord. There is little scientific evidence demonstrating the usefulness of physical therapy in this disease. Only stretching exercises, proprioceptive neuromuscular facilitation techniques and functional mobility training seem to have a real benefit in terms of spasticity, quality-of-life and pain. The main objective of physical therapy appears to be the preservation of optimal quality-of-life throughout the course of this incurable degenerative disease.}, }
@article {pmid17128118, year = {2006}, author = {Desnuelle, C and Bruno, M and Soriani, MH and Perrin, C}, title = {[What physical therapy techniques can be used to improve airway freedom in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S244-4S252}, pmid = {17128118}, issn = {0035-3787}, mesh = {Airway Obstruction/prevention &amp; control ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*rehabilitation ; Humans ; *Physical Therapy Modalities ; }, abstract = {In individuals with ALS rehabilitation is mainly designed to prevent fatigue and contracture, to improve independence and activities for as long as possible, to optimize ability to live with the handicap, and finally to maximize quality of life. The functional impairment must be defined and physical therapy techniques have to be adapted to each patient and reevaluated frequently during the course of the disease. Various types of massage and exercise, monitored by a physical therapist are effective. Strengthening or endurance exercises are controversial as exercise may injure muscle fibres and motor neurons. Isometric exercise, short of fatigue, of unaffected muscles is recommended. Range of motion exercise is critically important for preventing contraction. Assistive and adaptative equipments are essential for maintaining the patient's activities of daily living and home equipment preserves independence. Several orthoses for hand, arm, foot or cervical weakness are available. A wheelchair is an important adaptative device when walking becomes too fatiguing or impossible. Choice for special options and features may require attention. Pulmonary complications are prevented with adapted techniques for bronchic obstruction. Based on the degree of weakness of limb and axial muscles six stages of functional impairment can be defined ranging from fully ambulatory in stage I to bedridden and totally dependent in stage VI. This staging provides a framework for physical therapy evaluation and guidance for appropriate rehabilitation in ALS patients.}, }
@article {pmid17128117, year = {2006}, author = {Cintas, P}, title = {[Drug therapy for symptomatic relief in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S235-4S243}, pmid = {17128117}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*drug therapy ; Humans ; Muscle Spasticity/drug therapy/etiology ; Pain/drug therapy/etiology ; Sialorrhea/drug therapy/etiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that has no curative treatment. However, some symptoms of the disease can respond to specific treatments. The aim of these treatments is to enhance the patient's quality of life and in some instances survival. Besides physical therapy, and nutritional and respiratory supportive systems, several specific medications can be useful. However, despite the frequency of these symptoms, few studies have evaluated the benefit of these medications in ALS. Their use is most often based on clinical experience or on studies conducted in other neurological diseases. So, for most of these medications, available evidence does not permit a precise evaluation if their impact on quality of life and survival.}, }
@article {pmid17128116, year = {2006}, author = {Clavelou, P and Guy, N}, title = {[Symptomatic treatments in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S228-4S234}, pmid = {17128116}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*therapy ; Humans ; Muscle Spasticity/drug therapy/etiology ; Sialorrhea/etiology/therapy ; }, abstract = {ALS is a progressive, fatal, degenerative motor neuron disease of unknown cause. Although advances in understanding pathophysiology of ALS have stimulated the development of new therapies, most of them remain few efficient or ineffective and the main management of ALS patient, to improve quality of life by alleviating symptoms, is symptomatic treatment. This article discusses the approaches now in use to manage some of the most common symptoms of ALS including the following: spasticity, cramps, pain, laryngospasm, pseudobulbar syndrome, salivation and drooling, sleep disorders and fatigue, constipation and trophic troubles.}, }
@article {pmid17128115, year = {2006}, author = {Cintas, P}, title = {[Etiological drug therapy for amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S220-4S227}, pmid = {17128115}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/metabolism ; Glutamic Acid/metabolism ; Humans ; Neuroprotective Agents/therapeutic use ; Oxidative Stress/drug effects ; Riluzole/therapeutic use ; }, abstract = {Progress in the last decades has greatly strengthened our understanding of the etiopathogenic mechanisms of amyotrophic lateral sclerosis. Such progress has lead to an evaluation of several compounds affecting excitotoxicity, oxidative stress, apoptosis, growth factors and inflammation. Riluzole has clearly proven efficiency on mortality with a 35 p.cent reduction of death or tracheotomy at 18 months. While the mechanism of action of this compound remains to be fully elucidated, there is evidence in favor of a neuroprotective effect. Other compounds have been tried in ALS. To date, results have been disappointing with worsening even being noted in some cases. These negative studies offer some insight into the pathophysiological mechanism regulating the disease, raising pertinent questions concerning the transposition of animals models to humans and about interractions between these different compounds and riluzole.}, }
@article {pmid17128114, year = {2006}, author = {Dib, M}, title = {[What are the etiological medical therapies in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S215-4S219}, pmid = {17128114}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {The increasing knowledge about Amyotrophic Lateral sclerosis (ALS) led to the development of the first and only available treatment: riluzole. The efficacy of this drug has been demonstrated in two controlled clinical trials. The data showed that riluzole increases the rates of survival in patients suffering from ALS. This increase was about 25 percent over a period of 12 months of treatment. Since its marketing, the clinical efficacy of riluzole was confirmed in several epidemiological studies. Tested initially because of its anti-glutamates qualities, the exact mechanisms of action responsible for the efficacy of Riluzole in ALS remains unknown. Furthermore, despite a strong rational based on important literature, several other anti-glutamates drugs failed to demonstrate efficacy in ALS, nor did numerous anti-oxydant, neurotrophics, immunomodulators, and favoring mitochondrial metabolism drugs. Despite the low rate of patients showing an increase of liver enzymes, a strict control of liver functions is necessary with a treatment by riluzole. its dose should be increased gradually in case of important fatigue, a change of the general state, or respiratory incapacity. Because of the neuroprotectrives qualities of riluzole, early neuronal death in ALS, the difficulty to confirm early the diagnosis, and the evident interest to treat in the first stage, the treatment of the suspected forms of the disease becomes justifiable. The perspectives of treatment of ALS will depend on our capacity to understand better the physiopathology, the reasons of failures in the past, and to develop new biomarkers. They will depend also on our capacity to include in clinical trials and to follow up over a long time, an important number of patients. Different new methods, as the cellular therapy are in development, and represent a real hope for the future.}, }
@article {pmid17128113, year = {2006}, author = {Fussellier, M}, title = {[Caring for a patient with amyotrophic lateral sclerosis: the patient's and the caregiver's experience].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S209-4S214}, pmid = {17128113}, issn = {0035-3787}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/*therapy ; Caregivers/*psychology ; Family Health ; Humans ; }, abstract = {ALS usually affects highly active, working, sportive individuals. The disease has a devastating impact on the patient's personal life and family ties. Indeed, the disease requires constant attention from the carer for its rapidly progressive nature leads the patient to a complete state of isolation without affecting his/her intellect. For the patient days, are numbered, for the carer, time is limited. The carer must cope with a number of medical, administrative and financial difficulties. These include belated diagnosis with its disastrous consequences on medication, lack of response from the decision-making services, home-improvements or car-fitting. All this requires amazing tenacity from the carer. All the more so as the progress of handicap is relentless and the patient is bound to use different forms of support, walking-stick, zimmer, wheel-chair, hoist, speech synthesis, gastrostomy, tracheotomy or palliative care, which turn out to be more or less effective. But mechanical devices are not enough. Assistance by a nurse, a physiotherapist, a speech therapist and/or a nursing auxiliary is necessary. There are not enough of these assistants and the result cannot be guaranteed, but their role is essential in home care. The carer's investment can be terribly consuming. The burden of 24h care wears out the carer whose days and nights are being regulated by the disease. Not to mention lonely patients with no means of support who find themselves confronted with inevitable daunting problems Institutions providing either temporary or permanent care for ALS patients are scarce. As the condition worsens steadily, the patient suffers sheer desperation and guilt feelings and resents being a burden for family yet would rather stay with them. ARS volunteers who collaborate with medical teams can provide much help. The carer's burden should be greatly lightened too by the newly-installed tutorial system: patients' files will be followed up by one single person after the center's social worker has drawn them up. Medical and home volunteers cooperate to give the patient the feeling that far from being abandoned or ostracized by society, he/she is constantly being given care.}, }
@article {pmid17128112, year = {2006}, author = {Sancho, PO and Boisson, D}, title = {[Handicap and quality of life evaluation in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S205-4S207}, pmid = {17128112}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; *Disability Evaluation ; Humans ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {The impact of amyotrophic lateral sclerosis and consequent disability on everyday life can be assessed with generic or specific and/or functional quality of life scales. Generic scales SF36, SIP (Sickness Impact Profiles) and SIP/ALS 19, SEIQoL have been validated for the assessment of quality of life in SLA. A specific scale has also been worked out and validated in this disease, the ALSAQ-40 scale. The ALSFRS (ALS Functional Rating Scale) is a tool validated to evaluate the patient's functional capacities. However, the patient's quality of life felt does not depend only on the disease course but also the patient's previous psychological profile, the environmental, social conditions and spiritual aspirations. The absence of a cognitive deficit makes the patient particularly lucid about the progressive degradation of health status. Evaluation must be carried out with individually for each patient, taking into account the social and familial environments, to appreciate real living conditions, and the impact of this degenerative disease.}, }
@article {pmid17128111, year = {2006}, author = {Danel-Brunaud, V}, title = {[Handicap and quality of life assessment in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S200-4S204}, pmid = {17128111}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; *Disability Evaluation ; Humans ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {Measures of handicap progression alone are insufficient for assessing what a patient experiences. Handicap results from the interaction between a person's disabilities and the social, familial and environmental factors which determine his or her living conditions. Other factors condition quality of life: of these, psychological and existential factors and an individual's ability to adapt play a fundamental role. Measuring handicap and quality of life must provide medical care providers with comprehensive knowledge of the way in which an individual experiences the disease, his or her handicap and the side effects and constraints of treatments within his or her own life context.}, }
@article {pmid17128110, year = {2006}, author = {Pinet, C}, title = {[Evaluation of ventilatory functions in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S195-4S199}, pmid = {17128110}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; *Pulmonary Ventilation ; *Respiration ; Spirometry ; }, abstract = {As the clinical signs of amyotrophic of lateral sclerosis (ALS) are late and not specific, spirometric measurements, study of respiratory strength muscles and analysis of night respiratory parameters are used to evaluate ventilatory functions. The prognostic value of vital capacity is well established, but with a poor sensitivity to detect the initial form of ALS. Gazometric parameters remain normal for a long time. Hypercapnia is late and due to a major reduction in the force of the inspiratory muscles. Level of diurnal venous bicarbonate could detect nighttime hypoventilation. Noninvasive techniques (Pimax, Pemax, snifftest) are available to explore the strength of respiratory muscles. Sleep is characterized by a long period of hypoventilation, essentially during REM-sleep. There are no guidelines concerning the appropriate mode, type and rhythm of explorations of diurnal and nocturnal respiratory functions.}, }
@article {pmid17128109, year = {2006}, author = {Perez, T}, title = {[Amyotrophic lateral sclerosis (ALS): evaluation of respiratory function].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S188-4S194}, pmid = {17128109}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; *Respiration ; Respiratory Function Tests ; }, abstract = {Respiratory involvement is an almost constant feature of als, with a usually rapid progression leading to respiratory failure. These characteristics justify a close follow up, usually at three-month intervals. A systematic, careful clinical evaluation is essential to detect the subtle respiratory symptoms and signs related to respiratory muscle failure. Dyspnea and orthopnea are often late findings in patients with a usually severe functional impairment due to peripheral muscle weakness. Nocturnal respiratory events (obstructive sleep apnea syndrome and hypoventilation) are strongly suggested by daytime hypersomnolence and frequent morning headaches. Physical evaluation is essential to detect accessory muscle recruitment, supine abdominal paradox, and encumbrance of upper or lower airways. Vital capacity (VC) is the most classical lung function test. The major limitation of spirometry is its poor sensitivity to detect a moderate inspiratory muscle weakness. Supine VC may improve the detection of diaphragmatic involvement. Peak expiratory flow during cough (cough PEF) gives an overall evaluation of cough efficiency, values below 160 to 270 L/min suggesting poor airway clearance. Arterial blood gases are performed at first evaluation and subsequently in case of clinical signs, significant deterioration of lung function tests, or sleep desaturations. Hypercapnia is weakly related to lung function results in bulbar patients. A specific evaluation of respiratory muscle strength is mandatory, as these tests are both sensitive and highly prognostic. Possible discrepancies (particularly in bulbar patients) between Maximal inspiratory pressure (PImax) and sniff nasal inspiratory pressure (SNIP) justify to perform both measurements and to select the highest pressure. A maximal expiratory pressure (PEmax) below 45 cm H2O may indicate a compromised cough efficiency but the correlation with cough PEF may be poor. Screening nocturnal oxymetry is useful to detect sleep apneas and hypoventilation. Criteria defining significant desaturations remain however controversial. Suspicion of obstructive sleep apnea syndrome on clinical grounds or oxymetry findings should be confirmed by a conventional polysomnography.}, }
@article {pmid17128108, year = {2006}, author = {Piquet, MA}, title = {[Nutritional approach for patients with amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S177-4S187}, pmid = {17128108}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy ; Dietary Supplements ; Gastrostomy ; Humans ; *Nutrition Assessment ; Nutritional Requirements ; }, abstract = {Prevalence of malnutrition in ALS ranges between 16 and 53 p. 100. The percentage of loss of weight greater than 10 p. 100 or, in a more inconstant way, body mass index lower than 18.5, are relevant criteria of malnutrition because predictive of survival. Arm muscle circumference and bioelectrical impedance analysis can assess body composition, but their impact on disease progression has not been evaluated. Measurement of serum albumin levels is of no interest. NUTRITIONAL REQUIREMENTS: Considering that energy expenditure is increased 10 to 20 p. cent in the majority of patients, energy needs can be estimated to be approximately 35 kcal/kg/d. In order to limit the accumulation of fat mass in the sub-group of patients with decreased energy expenditure, monitoring of triceps skin fold or impedance could be proposed, but their interest remains to be evaluated. In the absence of available data on protein requirements in ALS, an intake ranging between 1 and 1,5 g/kg/d seems reasonable, knowing that there is a risk of deficiency when intake is less than 1 g/kg/d and that an increase to 1,5 g/kg/d, considered as harmless, could be useful in the event of hypercatabolism. Supplementation with creatine, antioxidants or amino acids has not proven to be effective. These nutrients being provided by a balanced diet, specific supplementations have no proven utility provided that the patient receives sufficient proteins and energy. Systematic supplementation with vitamin D is however warranted to prevent osteoporosis due to the known risk related to a common state of deficiency. RELEVANCE OF GASTROSTOMY: Studies with good methodological quality evaluating percutaneous endoscopic gastrostomy (PEG) in ALS are not available. Because of the impact of malnutrition on survival, PEG must be considered when oral intake becomes insufficient. Retrospective studies suggest that the PEG tube is usually inserted too late during the disease course, minimizing expected benefits. Criteria useful for making the decision to installation a PEG tube should be the subject of randomized controlled studies. Mortality in the month which follows PEG, approximately 10 p. cent, is primarily due to respiratory failure. It occurs more frequently among patients having a forced vital capacity<50 p. cent. To avoid a degradation of pulmonary function in this sub-group of patients, several approaches are suggested in the literature: earlier PEG, peri-operative noninvasive ventilation, and radiological gastrostomy which does not require a general anesthesia. Whatever the technique used for gastrostomy, it should be carried out in an expert centre, because patients with ALS are more exposed to complications than others.}, }
@article {pmid17128107, year = {2006}, author = {Desport, JC and Couratier, P}, title = {[Nutritional assessment in amyotrophic lateral sclerosis patients].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S173-4S176}, pmid = {17128107}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Humans ; Malnutrition/diagnosis/etiology ; *Nutrition Assessment ; }, abstract = {During ALS, malnutrition may occur. The causes are multiple. A reduction in caloric and protein intakes, due to swallowing disorders, play a major role. Moreover, (2/3) of patients develop an hypermetabolism of unknown cause, leading to an increase in resting energy expenditure. Malnutrition, whose prevalence is 10-55 percent, is an independant significant prognostic factor for survival. Nutritional assessment is recommanded every 3-6 months at least, and more often if needed. After a simple clinical examination, nutritional assessment includes the measurement of weight (W) and height (H), in order to calculate the Body Mass Index (BMI=W/H(2)). BMI<18.5 (age: 18-65ys) or<20kg/m2 (age>65ys) indicates malnutrition. A weight loss more than 5 to 10 percent of usual weight in the last six months is another malnutrition criterion. The measurement of skinfolds and the calculation of mid arm muscle circumference give informations on respectively fat mass and fat-free mass, but their interest is mainly during the follow-up, or for triceps skinfold when included in a validated bioimpedance formula. Bioimpedance analysis (BIA) is a simple bedside technique, recently validated for measurement of fat-free mass in ALS patients. The BIA phase angle could be an easy obtained parameter of severity. Dietary interview is important when patients still use oral route, but is difficult if they have elocution or writing problems. Indirect calorimetry and dual X-ray absorptiometry give reliable informations on respectively energy expenditure and body compartments, but remain scarcely used. Additional methods, like swallowing tests, psychological, digestive or respiratory assessments are often useful for optimal nutritional prescriptions. We recommand as minimal nutritional assessment a systematic clinical examination, anthropometric measurements and bioimpedance evaluation.}, }
@article {pmid17128106, year = {2006}, author = {Havet, V}, title = {[Psychological and psychopathological assessment of the patient with amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S164-4S172}, pmid = {17128106}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Humans ; Psychological Tests ; Quality of Life ; }, abstract = {Management of patients with amyotrophic lateral sclerosis (ALS) implies the participation of many health care professionals. The needs and goals of the patients cannot be limited to functional factors and should be considered in their full psychological, social and familial settings. Thus, much of the care for patients with ALS must focus on symptom relief, comfort and psychological support in order to improve their quality of life (QOL). Studies have demonstrated the significant role of psychological, existential and supportive factors in determining QOL in these patients. This work deals with psychological assessment in patients with ALS and reported studies within this population. Psychological assessment may vary and its methodology depends on the goals. Most frequently, psychological assessment implies depression and anxiety, coping strategies or quality of life.}, }
@article {pmid17128105, year = {2006}, author = {Bungener, C}, title = {[Psychological and psychopathological evaluation in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S158-4S163}, pmid = {17128105}, issn = {0035-3787}, mesh = {Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/*psychology ; Humans ; Psychological Tests ; }, abstract = {In the literature, few studies refer specifically to the psychological and psychopathological aspects of the ALS. However most of these studies mention the psychological specificities observed in ALS patients. In fact, they are not depressed, nor anxious, and they seem to accept surprisingly well the threathening diagnosis. Some authors have mentionned the presence of denial as an adaptive mechanism. It remains very difficult to compare the various studies. First, the stage of the evolution of the disease and the physical abilities of the patients differ greatly; in fact it has been demonstrated that at each stages the patient present specific psychological concerns. Second, the psychological concepts refer to different level of understanding. Some authors study depression or anxiety, others focus on the global psychological status and others focus on a psychological mechanism, such as denial for example. Third, the scales used to assess these psychological or psychopathological aspects are, on one hand, never specific to ALS and, on the other hand, are sometimes filled by the clinicien or sometimes self reports filled by the patient, his caregiver or even by the medical staff. Thus, many studies have created their own scales or interview, which are not validated. So, it appears necessary, in order to be able to compare the different results, to use validated scales which are recognized by the scientific community, while waiting for specific tools created and validated in populations of ALS patients.}, }
@article {pmid17128104, year = {2006}, author = {Havet, V}, title = {[Neuropsychological assessment in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S151-4S157}, pmid = {17128104}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*psychology ; Depression/etiology ; Humans ; Neuropsychological Tests ; }, abstract = {Neuropsychological assessment in the ALS population is relatively recent probably because this disease was traditionally considered to spare cognitive abilities. However, evidence is emerging from neuropsychological testing that some patients with classical ALS, who are thought not to be demented, develop cognitive deficits and particularly frontal executive disturbances. Neuroimaging gives support to frontal lobe involvement in ALS. Nevertheless, cognitive impairment does not concern all ALS patients and appears to be mild when it is described compared with rather severe frontotemporal dementia observed in association with ALS. Most of the references in this work question the cognitive perspective in the ALS population but few of them can provide a real useful tool for cognitive investigation in this disease.}, }
@article {pmid17128103, year = {2006}, author = {Lacomblez, L and Piquard, A and Vercelletto, M}, title = {[Amyotrophic lateral sclerosis: cognitive and behavioral evaluation].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S145-4S150}, pmid = {17128103}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; *Behavior ; *Cognition ; Humans ; }, abstract = {Cognitive impairment in nondemented ALS patients has been demonstrated, although its incidence remains to be determined. FTD is the most frequently form of dementia in ALS. The clinical profile of patients with dementia or mild cognitive deficit evokes neuropsychological deficits and behavioural changes resulting from executive dysfunction. The psychometric evaluation, centred on executive disturbances, goes with behavioural scales in order to accurately appreciate the repercussion of cognitive and behavioural changes on daily life.}, }
@article {pmid17128102, year = {2006}, author = {Campana-Salort, E}, title = {[Evaluation of strength in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S138-4S144}, pmid = {17128102}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Muscle Contraction ; *Muscle Strength ; Muscle Strength Dynamometer ; }, abstract = {The hallmark of progression in patients with amyotrophic lateral sclerosis (ALS) is the development of progressive weakness and muscular wasting. Strength testing has been used to monitor the course of the disease and to test the efficacy of new drugs. This paper review the methods used to quantify the weakness and compare their accuracy and reproducibility.}, }
@article {pmid17128101, year = {2006}, author = {Benaïm, C and Desnuelle, C and Fournier-Méhouas, M}, title = {[Functional scales and motor assessment in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S131-4S137}, pmid = {17128101}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; *Health Status ; Humans ; *Muscle Strength ; *Severity of Illness Index ; }, abstract = {There is a need of standardized and quantitative clinical assessments of ALS patients receiving new treatments. Some clinical scales, that are based on patients interviews and/or on physical examination, allow to quantify the patient functional status over time. The ALSFRS has been validated for that purpose and is one the most commonly used scales in clinical trials. Its revised version (the ALSFRS-R) has recently shown excellent metric properties. Functional scales are part of the clinical evaluation of ALS patients, and complete the quantitative assessment of muscle strength, that includes the Manual Muscular Testing (MMT) and the Maximal Voluntary Isometric Contraction (MVIC). Readers will find in this article a (non-exhaustive) listing of functional and motor scales that can be useful both in clinical trials of experimental agents and in daily practice.}, }
@article {pmid17128100, year = {2006}, author = {Salachas, F}, title = {[Breaking bad news during the course of amyotrophic lateral sclerosis: how and when].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S127-4S129}, pmid = {17128100}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Disease Progression ; Humans ; *Truth Disclosure/ethics ; }, abstract = {Operatory procedures can help to break bad news in ALS but the main goal of this unpleasant task stands in the quality of the relationship between the physician and his patient which must be preserved throughout the course of the disease. Plasticity is obviously the best way to characterize the appropriate kind of care in such a variable disease. The caregivers and the psychological factors must also be taken into account. As it is the case for therapeutic research, breaking bad news in ALS requieres a specific know-how which should be ideally performed by specialized teams within the framework of dedicated ALS centers.}, }
@article {pmid17128099, year = {2006}, author = {Corcia, P}, title = {[Methods of the announcement of amyotrophic lateral sclerosis diagnosis in familial forms].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S122-4S126}, pmid = {17128099}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; *Family Health ; Humans ; *Truth Disclosure/ethics ; }, abstract = {Between 10 percent and 20 percent of amyotrophic lateral sclerosis cases are familial (FALS). The announcement of a diagnosis of ALS to a patient having relatives already affected with this disease must take into account the familial history and should focus on the improvement in management of ALS patients. Diagnosis of FALS implicitly raises the notion of genetic factors and the possibility for an heritability of the disease (risk of ALS for relatives). Although it is possible to search for mutations in SOD1 gene in ALS patients and asymptomatic relatives, the incomplete penetrance of the disease, the low percentage (10 to 20 percent) of FALS linked to SOD1 mutation and the existence of non causal SOD1 mutations complicate the conclusions of genetic investigations concerning the real risk for a relative with a SOD1 mutation to develop ALS.}, }
@article {pmid17128098, year = {2006}, author = {Campana-Salort, E}, title = {[How should the diagnosis of amyotrophic lateral sclerosis be announced?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S113-4S121}, pmid = {17128098}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Disease Progression ; Humans ; Palliative Care ; Respiration, Artificial ; *Truth Disclosure/ethics ; }, abstract = {In amyotrophic lateral sclerosis (ALS) announcement of the diagnosis is an important step in the process of comprehensive care. The patterns of psychological reactions following bad news must be considered with precaution. The neurologist must take into consideration the specific aspects of announcing familial ALS. This paper reviews the modalities of announcement of the diagnosis and course in ALS patients.}, }
@article {pmid17128097, year = {2006}, author = {Couratier, P and Desport, JC and Torny, F and Lacoste, M}, title = {[Announcement of amyotrophic lateral sclerosis diagnosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S108-4S112}, pmid = {17128097}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Truth Disclosure/ethics ; }, abstract = {Breaking the news of amyotrophic lateral sclerosis (ALS) is considered as a daunting task in most cases and is not a standardizable procedure. However, proven techniques exist to reduce the trauma to the patient. Announcing ALS falls upen the neurologist who must respect the ethical principle of the patient's independence. After the diagnosis is firmly established, the patient should be informed that he or she has a progressive disease of the motor nerves, for which no curative therapy is available. The name of the disease must be stated and explained. If the family history is negative, it is reassuring for the patient and family to know that their children are unlikely to be at risk. Positive aspects (no pain, no disturbances in sensation, cognition, memory and continence) should be stressed as well as the availability of efficient palliative measures for practically all symptoms. Current research efforts, and when available, the possibility of taking part in clinical studies of new drugs should be pointed out as a means of hope. The answer to the question of prognosis should include the information that there are no sudden worsenings to be expected, that the course of ALS may vary between months and decades, that making a firm statement on prognosis all but impossible for any single patient and that respiratory function may worsen during the disease course. It is therefore mandatory to inform patients and families about the existence of ALS patients'associations. The way the patient is told the diagnosis is of great importance and is considered as a multiple-step procedure. Discussion should take place in a private and quiet room and respect some fundamental objectives such as finding out what the patient already knows or suspects and how much more the patient wants to know, observing and responding to the patient's reactions, reinforcing the information and planning the future. It is proven that communicating the diagnosis of ALS in an empathetic fashion is an important and sensitive step to disease management.}, }
@article {pmid17128096, year = {2006}, author = {Brocq, H and Soriani, MH and Desnuelle, C}, title = {[Psychological reactions to the announcement of a severe disease diagnosis: the amyotrophic lateral sclerosis example].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S104-4S107}, pmid = {17128096}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Humans ; *Truth Disclosure ; }, abstract = {To face the traumatic shock after the announcement of a severe and fatal disease, patients build psychological defences that physician must identify and respect as long as they don't endanger the patient's psychological fate and his medical care. ALS patient's do not have any curative perspective thus they will try "to escape" using different strategies the traumatic reality, that they cannot integrate and control. The physician has to prove his understanding and empathy facing these psychological reactions that could become of pathological appearance. The physician has to progressively bring the patient to consult the clinical psychologist; however he has not to forget that he is equally responsible about the way the patient go though his disease.}, }
@article {pmid17128095, year = {2006}, author = {Vandenberghe, N}, title = {[Where is the role of the genetic investigations in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S96-4S101}, pmid = {17128095}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genetic Testing ; Genotype ; Humans ; Mutation ; Phenotype ; }, abstract = {About 10 p. cent of amyotrophic lateral sclerosis (ALS) cases are familial. Most of the familial ALS (FALS) cases are clinically homogeneous. Among these families, autosomal dominant, X-linked or autosomal recessive transmission can be observed. Most of the causal mutations have been observed in the SOD1 gene. To date, more than one hundred different mutations have been described, but it remains unclear whether the mutation is always responsible for the phenotype. Penetrance of the mutation depends on age, with almost 90 p. 100 of penetrance at age 70 years. There is no anticipation. Worldwide, the most frequent mutation is A4V with dominant transmission, responsible for a severe, rapid form of the disease. The second most frequent mutation is D90A which is generally transmitted recessively, predominantly in the Scandinavian countries. The phenotype is characterized by a long lasting course (mean: 11 years). Other causal mutations have been described in the Alsine, Apex, NF-H and NAIP genes. Other genes can be considered as risk factors, like SMN2, APO E4, APEX, Dynactine, P-450 D6. Presymptomatic testing for FALS seems difficult because little information can be given to the patient regarding the responsibility of the mutation in the disease, age of onset, and disease trends. The same precautions as for Huntington's disease are needed. Genetic investigations can contribute to better understanding of the pathophysiology of ALS. Other causal genes in the 90 p. 100 of FALS without SOD1 mutation and eventually in the sporadic ALS cases may be disclosed. Genetic investigations also determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode and the non-exceptional absence of proven causality for ALS.}, }
@article {pmid17128094, year = {2006}, author = {Camu, W}, title = {[What is the role of the genetic survey in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S91-4S95}, pmid = {17128094}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; Diagnosis, Differential ; Genetic Testing ; Humans ; }, abstract = {The genetic inquiry in the diagnostic process of amyotrophic lateral sclerosis (ALS) need to be precise and systematic. Several hereditary neurologic disorders may initially mimic ALS, such as dominant spino-cerebellar ataxia or spastic paraplegia. Other hereditary motor neuron disorders are clinically more difficult to distinct from ALS such as Kennedy's disease, adult-onset spinal muscular atrophies or juvenile ALS. When a final diagnostic of ALS is established, the genetic inquiry aims at identifying a familial ALS (FALS) case. Almost 10 to 20 percent of ALS cases are familial. It is now admitted that 10 to 20 percent of those cases are due to SOD1 gene mutations. Such mutations may have a dominant or recessive inheritance. They are mainly found in multigenerational families. In 80 percent of the FALS cases, only two ALS cases are found in the pedigree. One cannot know whether this represent dominant cases with low penetrance, recessive inheritance or a multigenic, hereditary complex, disorder. More other, not all the SOD1 mutations have been demonstrated as causal. These elements are strong enough to suggest to precisely study, in the presence of a given SOD1 mutation, both the clinical phenotype, the data from the literature and, as often as possible, the segregation of the mutation into the family, before ascertaining that the mutation is responsible for a hereditary case of ALS. In every case, the genetic inquiry together with its conclusions should be done with caution, taking into account both the patient's need of a clear information and his anxiety regarding his descent.}, }
@article {pmid17128093, year = {2006}, author = {Pradat, PF and Bruneteau, G}, title = {[Differential diagnosis and atypical subsets of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S81-4S90}, pmid = {17128093}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/diagnosis ; Peripheral Nervous System Diseases/diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and lower motor neurons. In the absence of any validated biological marker, the diagnosis of ALS depends upon recognition of characteristic symptoms and signs together with supportive electrophysiological findings. The diagnosis of ALS is easy to recognize in its fully developed form but during the early stages both false positive and false negative diagnoses are common. In clinical practice, diagnostic difficulties mostly arise with patients who present either with only upper motor neuron, or with only lower motor neuron signs. It may be difficult to distinguish ALS with clinically predominant lower motor neuron involvement from alternative diagnoses including spinal atrophies of adult onset, Kennedy's disease, inclusion body myositis and motor neuropathies with conduction blocks. The diagnosis of ALS related syndromes (progressive muscular atrophy, primary lateral sclerosis and progressive bulbar palsy) requires the elimination of alternate diagnoses. This paper reviews the main characteristics of diseases mimicking ALS and the atypical subsets of ALS.}, }
@article {pmid17128092, year = {2006}, author = {Magistris, MR}, title = {[Amyotrophic lateral sclerosis: differential diagnosis and frontier forms].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S67-4S80}, pmid = {17128092}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) may be mimicked by disorders affecting the different levels of the motor system from cortex to muscle. Clinical heterogeneity is a feature of both ALS and related syndromes allowing for a large differential diagnosis. During the initial stage of a motor disorder false positive and false negative diagnoses of ALS are possible. Examples of disorders that should not be misdiagnosed as ALS, because their prognosis and treatment differ, are multifocal motor neuropathy, Kennedy's bulbospinal atrophy, cervical myelopathy, hyperthyroidism and hyperparathyroidism. Syndromes remote from polio and radiation treatments should be recognised. Eventually, frontier forms of ALS with signs restricted to either the upper or lower motor neurons deserve particular attention. Electrodiagnosis is pivotal to disclose signs and extension of the peripheral motor neuron, to detect and quantify cortico-spinal involvement, to search for specific signs of conditions that mimic ALS. Until specific markers become available, clinical evaluation supported by electrodiagnosis and other ancillary tests are crucial to provide with the correct diagnosis, prognosis and treatment.}, }
@article {pmid17128091, year = {2006}, author = {Vandenberghe, N}, title = {[Ancillary exams in the diagnosis of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S57-4S66}, pmid = {17128091}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; Transcranial Magnetic Stimulation/methods ; }, abstract = {The diagnosis of ALS is established on the basis of the revised El Escorial criteria revealing involvement of the upper and lower motor neuron. The presence of upper motor neuron signs is recognized by physical examination, but is not always easy to demonstrate. For the patient, early diagnosis reduces the uncertainty and the long waiting period before exclusion test can be performed. Early referral to ALS specialty clinics will have a beneficial effect on the patient's quality of life. Early diagnosis of ALS allows early use of drugs, slowing the rate of disease progression. MR proton spectroscopy and diffusion tensor imaging are potentially useful diagnosis tools but require further analysis of reproducibility in studies with more carefully matched patients and standardized techniques. There is no biochemical marker found in serum or cerebrospinal fluid to establish the definite diagnosis of ALS. Detection of Nogo-A in muscle offers an easy tool for detecting the presence of ALS but further studies are needed to determine the specificity, sensitivity and predictive value of such modifications. When applying standard transcranial magnetic stimulation, examination of several territories improves sensitivity and the probability of detection of infraclinical upper motor neuron dysfunction. The cortical silent period seems most sensitive. The triple stimulation technique (TST) is a very sensitive method but needs to be confirmed by other teams. Some teams have stated that the technique is painful and time consuming for the patient. To date, the corticobulbar tract cannot be studied with TST and we have little experience for the lower limb in very few ALS patients.}, }
@article {pmid17128090, year = {2006}, author = {Tranchant, C}, title = {[What is the role of other complementary examination in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S50-4S56}, pmid = {17128090}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Humans ; Magnetic Resonance Imaging ; }, abstract = {Amotrophic lateral sclerosis diagnosis is based on clinical and electrophysiological findings. Transcranial magnetic stimulation and MRI can show abnormalities which are not specific, but which can confirm upper motor neuron involvement. The other tests are performed to exclude differential diagnosis. Tests which should be performed in every cases are: medullar MRI, blood counts, erythrocyte sedimentation, serum protein electrophoresis, calcium, phosphore, serological tests for HIV, siphylis, Lyme disease. Other tests are made in some clinical circonstances to exclude genetical disease or metabolic disorders (SMN gene, Kennedy gene, Hexosaminidase A, very long chaine fatty acids), haematological or paraneoplasic disorders (anti-neurons antibodies, PSA, CT of chest and abdomen, mammography, bone marrow biopsy) or inclusion myositis (muscle biopsy).}, }
@article {pmid17128089, year = {2006}, author = {Cintas, P}, title = {[What electroneuromyographic criteria are required for the diagnosis of amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S43-4S49}, pmid = {17128089}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electromyography ; Humans ; }, abstract = {Electroneuromyography is essential for the diagnostic of amyotrophic lateral sclerosis. The aim of conventional needle examen is to detect peripheral motoneuron involvement by the identification of active and chronic diffuse neurogenic activities. This brings up the problem of the selection of the muscle to test to enhance the sensitivity of the exam. Recent techniques permit to study the reorganization of the motor units more precisely. Motoneuron loss is appraised by several methods for macro-EMG estimates of the number of motor units. The collateral reinnervation can be evaluated by single fibre EMG. The other main objective is to detect conduction abnormalities. These lead to differential diagnoses of pure motor neuropathy with conduction blocks. The different prognostic value of these different conditions required defining both sensitive and specific electrophysiological diagnostic criteria.}, }
@article {pmid17128088, year = {2006}, author = {Pouget, J}, title = {[Electroneuromyographic criteria of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S34-4S42}, pmid = {17128088}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Electromyography ; Humans ; Neural Conduction ; Peripheral Nervous System/physiopathology ; }, abstract = {Electrophysiological study plays a key role in the diagnosis of amyotrophic lateral sclerosis (ALS). ENMG demonstrates lower motor neuron involvement in muscles clinically involved but also in non clinically involved territories. Conventional EMG shows mixed signs of active denervation, partial chronic denervation and fasciculation, in a variable pattern from one muscle to another. The choice of the muscles to be recorded will privilege muscles innervated by motor neurons from bulbar region, cervical, thoracic and lumbar medulla in order to define the extension of the pathological process. Special ENMG techniques (single fiber EMG, macro-EMG, motor unit firing study, motor unit number estimate) have been proposed for the evaluation and better understanding of pathophysiology. They are not used in routine. Motor conduction study demonstrates motor axons loss and excludes nerve conduction abnormalities of a demyelinating motor neuropathy. Sensory conduction and sensory nerve action potential amplitude are normal in ALS, even in severely motor involved territory. Electrophysiological study can show upper motor neuron involvement when studying motor evoked potentials using transcranial magnetic stimulation of motor cortex. Several parameters have been studied. They are diversely affected and so their diagnostic sensitivity also varies.}, }
@article {pmid17128087, year = {2006}, author = {Pradat, PF and Bruneteau, G}, title = {[Clinical characteristics of amyotrophic lateral sclerosis subsets].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S29-4S33}, pmid = {17128087}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by significant clinical variability. Different subsets are classically individualized: bulbar onset and limb onset ALS, sporadic and familial ALS, ALS-plus syndromes (characterized by the presence of atypical clinical features, e.g. extrapyramidal signs or dementia, in association with the classical phenotype of ALS) and Western Pacific ALS. In addition, ALS-related syndromes include progressive muscular atrophy, primary lateral sclerosis and progressive bulbar palsy. The recognition of ALS subsets and ALS-related syndromes is important in clinical practice since the prognosis may vary depending on the clinical presentation. The prognosis of bulbar-onset ALS is poor compared with the spinal-onset type. Primary lateral sclerosis, defined by pure upper motor neuron findings, has a more benign course than classical ALS. It has also important implications for therapeutic trials to ensure the homogeneity of clinical material since inclusion of atypical forms with different prognoses can skew the outcome analysis. This paper reviews the clinical characteristics of the ALS subsets and ALS-related syndromes.}, }
@article {pmid17128086, year = {2006}, author = {Vial, C}, title = {[What are the clinical criteria of amyotrophic lateral sclerosis by clinical form?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S25-4S28}, pmid = {17128086}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis ; Humans ; }, abstract = {The diagnosis of ALS requires the presence of lower and upper motor neuron degeneration and a progressive spread of symptoms and signs. Due to the lack of any biological diagnostic marker, the World Federation of Neurology established clinical and paraclinical criteria (El Escorial 1991; Airlie House 1998). These criteria allow to establish a diagnosis with various levels of certainty. In practice they have a low sensitivity, especially at the beginning of the disease, and may delay the diagnosis. They exclude also some clinical forms and are not helpful in the differential diagnosis.}, }
@article {pmid17128085, year = {2006}, author = {Pradat, PF and Bruneteau, G}, title = {[Classical and atypical clinical features in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S17-4S24}, pmid = {17128085}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving primarily motor neurons in the cerebral cortex, brainstem and spinal cord. In the absence of any biological marker, the diagnosis of ALS is based on clinical analysis, combined with the results of electromyography. Consensus diagnosis criteria (El Escorial criteria) have been developed to define workable and internationally acceptable guidelines for the diagnosis of ALS. A combination of lower and upper motor neuron signs with evidence of spread within a region or to other regions is required. The diagnosis of ALS has been categorized into various levels of certainty depending on the presence of upper motor neuron and lower motor neuron signs together in the same topographical anatomic region (brainstem and cervical, thoracic or lumbosacral spinal cord). Clinical types and patterns of ALS have been defined. The emerging concept of "ALS plus" is characterized by the presence of atypical clinical features, e.g. extrapyramidal signs or dementia, in association with the classical phenotype of ALS. This paper reviews the classical and atypical clinical features of ALS.}, }
@article {pmid17128084, year = {2006}, author = {Maugin, D}, title = {[What usual and unusual clinical signs suggest amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S14-4S16}, pmid = {17128084}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; }, abstract = {Diagnosis of amyotrophic lateral sclerosis (ALS) is typically restricted to clinical and electromyographical upper motoneuron (UMN) and lower motoneuron (LMN) features. However, the initial presentation is sometimes misleading. These unusual presentations are discussed. They can delay the diagnosis of ALS.}, }
@article {pmid17127557, year = {2006}, author = {Piepers, S and van den Berg, JP and Kalmijn, S and van der Pol, WL and Wokke, JH and Lindeman, E and van den Berg, LH}, title = {Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {4}, pages = {195-200}, doi = {10.1080/14660820500514974}, pmid = {17127557}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*mortality/*rehabilitation ; Clinical Trials as Topic/statistics &amp; numerical data ; Cognition Disorders/*mortality/prevention &amp; control ; Comorbidity ; Humans ; Hypoventilation/*mortality/*rehabilitation ; Incidence ; Outcome Assessment, Health Care ; Prognosis ; *Quality of Life ; Respiration, Artificial/*statistics &amp; numerical data ; Respiratory Function Tests/statistics &amp; numerical data ; Survival Analysis ; Survival Rate ; Treatment Outcome ; }, abstract = {Symptoms of nocturnal hypoventilation may negatively influence the quality of life (QoL) of ALS patients long before respiratory failure ensues. Non-invasive mechanical ventilation (NIV) is considered a treatment option for nocturnal hypoventilation. The primary objective of NIV is improving quality of life (QoL). It may also prolong life by several months. A systematic review of the literature was performed to analyse what is known of the effect of NIV on survival, QoL and other outcome measures. A computerized literature search was performed to identify controlled clinical trials and observational studies of treatment of ALS-associated nocturnal hypoventilation from 1985 until May 2005. Twelve studies fulfilled the inclusion criteria. Four studies were retrospective, seven prospective and in one study randomization was used. All studies reported beneficial effects of NIV on all outcome measures. In seven studies NIV was associated with prolonged survival in patients tolerant for NIV, and five studies reported an improved QoL. In conclusion, studies on the use of NIV in ALS differ in study design and endpoint definitions. All studies suggest a beneficial effect on QoL and other outcome measures (Evidence level Class II-III). Well-designed randomized controlled trials comparing the effect on QoL and survival have not been performed.}, }
@article {pmid17127346, year = {2007}, author = {Ruan, Q and Johnson, GV}, title = {Transglutaminase 2 in neurodegenerative disorders.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {12}, number = {}, pages = {891-904}, doi = {10.2741/2111}, pmid = {17127346}, issn = {1093-9946}, support = {AG012396/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; GTP-Binding Proteins ; Humans ; Mice ; Nervous System/embryology/enzymology/growth &amp; development ; Neurodegenerative Diseases/*enzymology/etiology ; Neurons/cytology/enzymology ; Protein Glutamine gamma Glutamyltransferase 2 ; Transglutaminases/*physiology ; Trauma, Nervous System/enzymology ; }, abstract = {Type 2 transglutaminase (TG2) is a calcium-dependent acyltransferase which also undergoes a GTP-binding/GTPase cycle even though it lacks any obvious sequence similarity with canonical GTP-binding (G) proteins. As an enzyme which is responsible for the majority of transglutaminase (TG) activity in the brain, TG2 is likely to play a modulatory role in nervous system development and has regulatory effect on neuronal cell death as well. Most importantly, numerous studies have presented data demonstrating that dysregulation of TG2 may contribute to the pathogenesis of many neurodegenerative disorders, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis as well as nervous system injuries. Although TG2's involvement in these disease conditions is strongly suggested by various findings, such as the increase of TG2 mRNA expression, protein level and TG activity in the pathological process of these neurodegenerative disorders, as well as the therapeutic effect of TG2 genetic deletion in animal models of Huntington's disease, the precise mechanism underlying TG2's role remain unclear. TG2 was originally proposed to contribute to the pathogenesis of these diseases by facilitating the formation of insoluble protein aggregates, however recent findings clearly indicate that this is likely not the case. Nonetheless, there is data to suggest that TG2 may play a role in neurodegenerative processes by stabilizing toxic oligomers of the disease-relevant proteins, although further studies are needed to validate these initial in vitro findings.}, }
@article {pmid17119468, year = {2006}, author = {Favier, A}, title = {[Oxidative stress in human diseases].}, journal = {Annales pharmaceutiques francaises}, volume = {64}, number = {6}, pages = {390-396}, doi = {10.1016/s0003-4509(06)75334-2}, pmid = {17119468}, issn = {0003-4509}, mesh = {*Disease ; Humans ; Oxidants/metabolism ; Oxidative Stress/*physiology ; }, abstract = {Oxidative stress is an abnormal phenomenon occurring inside our cells or tissues when production of oxygen radicals exceeds their antioxidant capacity. Excess of free radicals damage essential macromolecules of the cell, leading to abnormal gene expression, disturbance in receptor activity, proliferation or cell dye, immunity perturbation, mutagenesis, protein or lipofushin deposition. Numerous human diseases involve during the pathological process such a stress, localized or general (in the same way as inflammation). In many serious diseases such as cancer, ocular degeneration (age related macular degeneration or cataract), neurodegenerative diseases (ataxia, amyotrophic lateral sclerosis, Alzheimer's disease) stress is the factor original. In familial amyotrophic lateral sclerosis the genetic abnormality occurred an abnormal coding for an antioxidant enzyme, copper-zinc super oxide dismutase. In various other diseases oxidative stress occur secondary to the initial disease but plays an important in role immune or vascular complications. This is the case in infectious disease such as AIDS or septic shock, Parkinson's disease or renal failure. So antioxidant treatment seems logical to be tested in these pathologies. But they have to be applied early in the process, before irreversible mechanisms. They need also to be prescribed at low doses as baseline free radical production have to be preserved to maintain useful activity that cannot be suppressed.}, }
@article {pmid17117171, year = {2006}, author = {Maragakis, NJ and Rothstein, JD}, title = {Mechanisms of Disease: astrocytes in neurodegenerative disease.}, journal = {Nature clinical practice. Neurology}, volume = {2}, number = {12}, pages = {679-689}, doi = {10.1038/ncpneuro0355}, pmid = {17117171}, issn = {1745-834X}, mesh = {Animals ; Astrocytes/*pathology/*physiology ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/classification/genetics/*pathology ; }, abstract = {The term neurodegenerative disease refers to the principal pathology associated with disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease and Parkinson's disease, and it is presumed that neurodegeneration results in the clinical findings seen in patients with these diseases. Decades of pathological and physiological studies have focused on neuronal abnormalities in these disorders, but it is becoming increasingly evident that astrocytes are also important players in these and other neurological disorders. Our understanding of the normative biology of astrocytes has been aided by the development of animal models in which astrocyte-specific proteins and pathways have been manipulated, and mouse models of neurodegenerative diseases have also revealed astrocyte-specific pathologies that contribute to neurodegeneration. These models have led to the development of targeted therapies for pathways in which astrocytes participate, and this research should ultimately influence the clinical treatment of neurodegenerative disorders.}, }
@article {pmid17098839, year = {2007}, author = {Abhinav, K and Al-Chalabi, A and Hortobagyi, T and Leigh, PN}, title = {Electrical injury and amyotrophic lateral sclerosis: a systematic review of the literature.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {78}, number = {5}, pages = {450-453}, pmid = {17098839}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology ; Electric Injuries/*complications ; Humans ; Motor Skills Disorders/epidemiology/*etiology ; Risk Factors ; Syndrome ; Time Factors ; }, abstract = {Electrical injury may act as a potential precipitating or risk factor for amyotrophic lateral sclerosis (ALS). A systematic review of the literature was undertaken to assess the relationship between electrical injury and the development of ALS. Information for the review was obtained using five medical databases, and from manual searching of individual papers. Patients presenting with a neurological syndrome after electrical injury, including lightning, were included and classified into four categories: ALS; progressive upper motor neurone (UMN) syndrome; progressive lower motor neurone (LMN) syndrome; and non-progressive syndrome. Linear regression and chi2 testing were used for analysis of the data. 96 individuals, comprising 44 with ALS, 1 with a progressive UMN syndrome, 7 with a progressive LMN syndrome and 44 with a non-progressive syndrome, were identified from 31 papers with publication dates between 1906 and 2002. The median interval between electrical injury and disease onset was 2.25 years for all progressive syndromes and just over 1 week for the non-progressive syndrome. The more severe the shock (excluding lightning), the more likely individuals were to have a non-progressive motor syndrome. A non-progressive spinal cord syndrome is associated with more severe electrical injury. Overall, the evidence reviewed does not support a causal relationship between ALS and electric shock.}, }
@article {pmid17095557, year = {2007}, author = {Dobkin, BH}, title = {Brain-computer interface technology as a tool to augment plasticity and outcomes for neurological rehabilitation.}, journal = {The Journal of physiology}, volume = {579}, number = {Pt 3}, pages = {637-642}, pmid = {17095557}, issn = {0022-3751}, mesh = {Brain/physiology ; *Communication Aids for Disabled ; Humans ; Movement/*physiology ; Neuronal Plasticity/*physiology ; Quadriplegia/*rehabilitation ; *User-Computer Interface ; }, abstract = {Brain-computer interfaces (BCIs) are a rehabilitation tool for tetraplegic patients that aim to improve quality of life by augmenting communication, control of the environment, and self-care. The neurobiology of both rehabilitation and BCI control depends upon learning to modify the efficacy of spared neural ensembles that represent movement, sensation and cognition through progressive practice with feedback and reward. To serve patients, BCI systems must become safe, reliable, cosmetically acceptable, quickly mastered with minimal ongoing technical support, and highly accurate even in the face of mental distractions and the uncontrolled environment beyond a laboratory. BCI technologies may raise ethical concerns if their availability affects the decisions of patients who become locked-in with brain stem stroke or amyotrophic lateral sclerosis to be sustained with ventilator support. If BCI technology becomes flexible and affordable, volitional control of cortical signals could be employed for the rehabilitation of motor and cognitive impairments in hemiplegic or paraplegic patients by offering on-line feedback about cortical activity associated with mental practice, motor intention, and other neural recruitment strategies during progressive task-oriented practice. Clinical trials with measures of quality of life will be necessary to demonstrate the value of near-term and future BCI applications.}, }
@article {pmid17095122, year = {2007}, author = {Wilson, JM and Shaw, CA}, title = {Late appearance of glutamate transporter defects in a murine model of ALS-parkinsonism dementia complex.}, journal = {Neurochemistry international}, volume = {50}, number = {7-8}, pages = {1067-1077}, doi = {10.1016/j.neuint.2006.09.017}, pmid = {17095122}, issn = {0197-0186}, mesh = {Amino Acid Transport System X-AG/*deficiency/physiology ; Animals ; Apolipoproteins E/genetics ; Brain/pathology ; Dementia/genetics/*physiopathology ; Disease Models, Animal ; Genetic Predisposition to Disease ; Mice ; Motor Neuron Disease/genetics/*physiopathology ; Nerve Degeneration/physiopathology ; Parkinsonian Disorders/genetics/*physiopathology ; }, abstract = {Excitotoxicity has been widely hypothesized to play a major role in various neurodegenerative diseases. We have used a mouse model of ALS-parkinsonism dementia complex (ALS-PDC) of the Western Pacific to explore this hypothesis. Mice fed washed cycad flour, the major epidemiological link to ALS-PDC, showed significant and progressive motor, cognitive, and sensory behavioural deficits [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221]. In addition, glutamate transporter (GLT-1/EAAT2) levels measured by immunohistochemistry with antibodies specific for two glial glutamate transporter splice variants (GLT-1alpha and GLT-1B) were significantly down-regulated showing a 'patchy' loss of antibody label centered on blood vessels [Wilson, J.M., Khabazian, I., Pow, D.V., Craig, U.K., Shaw, C.A., 2003. Decrease in glial glutamate transporter variants and excitatory amino acid receptor down-regulation in a murine model of ALS-PDC. Neuromol. Med. 3 (2), 105-118]. Receptor binding assays showed decreased NMDA and AMPA receptor levels combined with increased GABA(A) receptor levels in various CNS regions. The alterations in GLT-1 variants and the ionotropic receptors are consistent with an increased level of extracellular glutamate. The interaction between environmental toxicity and genetic susceptibility was also tested using mice expressing various Apolipoprotein E (ApoE) genotypes. Mice lacking the ApoE gene showed relative resistance to cycad-induced toxicity as measured by GLT-1B labeling, but all mice expressing the human ApoE isoforms showed a similar loss of GLT-1B. We have further shown that an isolated cycad toxin (beta-sitosterol-beta-d-glucoside, BSSG), previously shown to release glutamate in vitro [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221], can be directly toxic to motor neurons in vivo [Wilson, J.M., Petrik, M.S., Moghadasian, M.H., Shaw, C.A., 2005. Examining the interaction of apo E and neurotoxicity on a murine model of ALS-PDC. Can. J. Physiol. Pharmacol. 83 (2), 131-141]. However, BSSG-fed mice did not show altered GLT-1B labeling in the spinal cord suggesting that an initial excitotoxic mechanism may not be responsible for the final neuronal loss observed. While glutamate-mediated excitotoxicity is likely involved in the outcomes following cycad/BSSG exposure, the precise location in the cascade of events ultimately leading to neuronal death remains to be determined.}, }
@article {pmid17088867, year = {2007}, author = {Beart, PM and O'Shea, RD}, title = {Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement.}, journal = {British journal of pharmacology}, volume = {150}, number = {1}, pages = {5-17}, pmid = {17088867}, issn = {0007-1188}, mesh = {Amino Acid Transport System X-AG/classification/drug effects/*physiology ; Animals ; Biological Transport ; Humans ; }, abstract = {L-Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian CNS and five types of high-affinity Glu transporters (EAAT1-5) have been identified. The transporters EAAT1 and EAAT2 in glial cells are responsible for the majority of Glu uptake while neuronal EAATs appear to have specialized roles at particular types of synapses. Dysfunction of EAATs is specifically implicated in the pathology of neurodegenerative conditions such as amyotrophic lateral sclerosis, epilepsy, Huntington's disease, Alzheimer's disease and ischemic stroke injury, and thus treatments that can modulate EAAT function may prove beneficial in these conditions. Recent advances have been made in our understanding of the regulation of EAATs, including their trafficking, splicing and post-translational modification. This article summarises some recent developments that improve our understanding of the roles and regulation of EAATs.}, }
@article {pmid17082170, year = {2006}, author = {Robinson, EM and Phipps, M and Purtilo, RB and Tsoumas, A and Hamel-Nardozzi, M}, title = {Complexities in decision making for persons with disabilities nearing end of life.}, journal = {Topics in stroke rehabilitation}, volume = {13}, number = {4}, pages = {54-67}, doi = {10.1310/tsr1304-54}, pmid = {17082170}, issn = {1074-9357}, mesh = {Aged ; *Decision Making ; Disabled Persons/*psychology ; Female ; Humans ; Male ; Middle Aged ; Personal Autonomy ; Personality ; Terminal Care/*ethics ; }, abstract = {Good end-of-life care requires that clinicians, families, and ethicists be aware of biases that influence patient cases, particularly in the acute care setting where the aim is primarily cure and return to optimal functional level. Persons with disabilities may pose unique challenges; their potential for quality of life is viewed through the lens of highly functional clinicians who might have a biased view of the disabled person's quality of life. The authors aim to present three categories of disability that do not claim to be absolute but rather offer clinicians and ethicists a lens through which to reflect on bias that unconsciously may influence their approach to the patient who is seriously ill and may be nearing the end of life. The categories include (a) a person who has lived with a disability from birth or early life, due to trauma or disease, and is now faced with a serious illness that requires that life-sustaining treatment; (b) the otherwise healthy person who acquires a disability through an acute event of disease or trauma and whose condition requires that life-sustaining treatment decisions be made; and (c) the person who has lived with a progressive chronic illness, such as lung or heart disease or amyotrophic lateral sclerosis, and may have gradually adjusted to disabilities imposed by the condition and now is faced with life-sustaining treatment decisions. The concept of inherent dignity (Pellegrino 2005) is suggested as a filtering lens in case consideration.}, }
@article {pmid17072811, year = {2006}, author = {Orient-López, F and Terré-Boliart, R and Guevara-Espinosa, D and Bernabeu-Guitart, M}, title = {[Neurorehabilitation treatment of amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {43}, number = {9}, pages = {549-555}, pmid = {17072811}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*rehabilitation/therapy ; Humans ; }, abstract = {AIM: To carry out a review of the literature with the aim of defining, evaluating, establishing and making more widely known the value of neurorehabilitation therapy in the different phases of the course of amyotrophic lateral sclerosis (ALS). Special emphasis will be given to the role this type of treatment plays in improving both survival rates and these patients' functional independence and quality of life.<br><br>DEVELOPMENT: Although ALS is a disease that follows an unrelenting course, patients' quality of life, and even their survival time, can be changed dramatically with suitable medical management. Neurorehabilitation therapy consists of an integral process carried out by an interdisciplinary team that includes the basic pharmacological treatment, symptomatic treatment of the associated problems and rehabilitation therapy, the aim being to prolong the functional capacity of these patients and to promote their independence. Its ultimate goal is to ensure the highest possible quality of life throughout the whole health care process.<br><br>CONCLUSIONS: Until a cure is found for ALS, neurorehabilitation therapy is clearly today's most promising therapeutic option as far as improving these patients' quality of life, health and survival rates is concerned. This treatment should not only involve the medical care of the patient, but also provide the appropriate technical aids and home help, together with training and preparation of both the main caregiver and the patient's family. This instruction should cover the whole period from the moment the disease is diagnosed to its terminal phase.}, }
@article {pmid17071060, year = {2006}, author = {Beghi, E and Logroscino, G and Chiò, A and Hardiman, O and Mitchell, D and Swingler, R and Traynor, BJ and , }, title = {The epidemiology of ALS and the role of population-based registries.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1150-1157}, doi = {10.1016/j.bbadis.2006.09.008}, pmid = {17071060}, issn = {0006-3002}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*epidemiology/mortality ; Cohort Studies ; Environmental Exposure ; Female ; Humans ; Incidence ; Male ; Middle Aged ; *Registries ; Risk Factors ; Survival Analysis ; }, }
@article {pmid17060310, year = {2006}, author = {Carter, GT and Han, JJ and Mayadev, A and Weiss, MD}, title = {Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series.}, journal = {The American journal of hospice &amp; palliative care}, volume = {23}, number = {5}, pages = {412-416}, doi = {10.1177/1049909106292169}, pmid = {17060310}, issn = {1049-9091}, mesh = {Adult ; Aged ; Anxiety/chemically induced ; Benzhydryl Compounds/adverse effects/*therapeutic use ; Central Nervous System Stimulants/adverse effects/*therapeutic use ; Charcot-Marie-Tooth Disease/*complications/diagnosis/genetics ; Diarrhea/chemically induced ; Fatigue/*drug therapy/etiology ; Female ; Headache/chemically induced ; Humans ; Male ; Middle Aged ; Modafinil ; Research Design ; Sleep Initiation and Maintenance Disorders/chemically induced ; Treatment Outcome ; }, abstract = {Charcot-Marie-Tooth disease, the most common hereditary motor and sensory neuropathy, is a slowly progressive disorder characterized by diffuse muscle weakness and prominent distal atrophy that predominantly involves the intrinsic muscles of the feet and the peroneal muscles. It results in marked reduction in functional aerobic capacity during exercise and fatigue is commonly reported. To date, no pharmacologic treatment has been shown to be effective for treating fatigue in Charcot-Marie-Tooth. Modafinil is used to treat the symptoms of fatigue and excessive daytime sleepiness in narcolepsy. However, fatigue and subsequent excessive daytime sleepiness secondary to fatigue are common symptoms in many neurologic disorders. Prior reports on patients with myotonic muscular dystrophy, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, have shown beneficial effects of modafinil in treating fatigue. We report 4 patients with genetically confirmed Charcot-Marie-Tooth disease who had significant fatigue that was almost completely relieved by modafinil.}, }
@article {pmid17055612, year = {2007}, author = {Lepore, AC and Maragakis, NJ}, title = {Targeted stem cell transplantation strategies in ALS.}, journal = {Neurochemistry international}, volume = {50}, number = {7-8}, pages = {966-975}, doi = {10.1016/j.neuint.2006.09.005}, pmid = {17055612}, issn = {0197-0186}, mesh = {Cell Division ; Hematopoietic Stem Cell Mobilization ; Humans ; Motor Neuron Disease/*therapy ; Neuroglia/transplantation ; Neurons/cytology/transplantation ; Spinal Cord/cytology/pathology ; *Stem Cell Transplantation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of neural precursor cells (NPCs) derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS. ALS is a particularly challenging disease for designing relevant therapies, and presently no effective treatment exists. Despite such daunting challenges, a number of the potential benefits of NPC transplantation coincide with the neuropathological obstacles associated with ALS, including neuronal and glial replacement and non-replacement functions such as delivery of trophic support. Knowledge of the underlying disease-specific pathways involved in neurodegeneration and the contributions of different cellular subtypes to the disease go hand-in-hand with advances in NPC transplantation biology, and will aid in targeting cell-specific therapies to neurodegenerative disorders such as ALS. It is with these multiple cell targets that NPC transplantation may lend itself well to understanding and possibly slowing disease processes. A number of studies have already demonstrated the potential benefits of cell transplantation in ALS models. Lastly, practical issues such as timing and method of cell delivery, immune suppression, and the need for combinatorial approaches with non-cell based strategies must all be considered for eventual translation to the clinic.}, }
@article {pmid17054441, year = {2006}, author = {Van der Schyf, CJ and Geldenhuys, WJ and Youdim, MB}, title = {Multifunctional drugs with different CNS targets for neuropsychiatric disorders.}, journal = {Journal of neurochemistry}, volume = {99}, number = {4}, pages = {1033-1048}, doi = {10.1111/j.1471-4159.2006.04141.x}, pmid = {17054441}, issn = {0022-3042}, mesh = {Animals ; Brain/drug effects/metabolism/physiopathology ; Brain Chemistry/*drug effects/genetics ; Brain Diseases/*drug therapy/*genetics/physiopathology ; Drug Design ; Humans ; Molecular Structure ; Neurocognitive Disorders/*drug therapy/*genetics/physiopathology ; Neurotransmitter Agents/agonists/biosynthesis/genetics ; Nootropic Agents/chemistry/isolation &amp; purification/pharmacology ; Psychotropic Drugs/chemistry/isolation &amp; purification/*pharmacology ; }, abstract = {The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders.}, }
@article {pmid17054194, year = {2006}, author = {Langmore, SE and Kasarskis, EJ and Manca, ML and Olney, RK}, title = {Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD004030}, doi = {10.1002/14651858.CD004030.pub2}, pmid = {17054194}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; *Enteral Nutrition ; Humans ; Motor Neuron Disease/*therapy ; }, abstract = {BACKGROUND: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss.<br><br>OBJECTIVES: The aim of this review is to examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival; (2) nutritional status; (3) quality of life. Another aim is to examine the minor and major complications of percutaneous endoscopic gastrostomy.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (June 2005), MEDLINE (from January 1966 to June 2005), and EMBASE (from January 1980 to June 2005) for randomized controlled trials. In addition we searched MEDLINE (January 1966 to June 2005) and EMBASE (January 1980 to June 2005) to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles, proceedings of scientific meetings, and enlisted personal communications to identify any additional references.<br><br>SELECTION CRITERIA: All randomized and quasi-randomized controlled trials were to have been selected. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review.<br><br>DATA COLLECTION AND ANALYSIS: We independently assessed study methodological design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, and (3) self-perceived quality of life We were also interested in reports of safety of the procedure as indicated by (4) minor and major complications of percutaneous endoscopic gastrostomy or other feeding tube placement.<br><br>MAIN RESULTS: We found no randomized controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective case controlled studies in the 'Discussion' section of this review.<br><br>AUTHORS' CONCLUSIONS: There are no randomized controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for survival. The 'best' evidence to date, based on controlled prospective cohort studies, suggests an advantage for survival in all people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has only been addressed by a few researchers and needs more serious attention.}, }
@article {pmid17045786, year = {2006}, author = {Xiao, S and McLean, J and Robertson, J}, title = {Neuronal intermediate filaments and ALS: a new look at an old question.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1001-1012}, doi = {10.1016/j.bbadis.2006.09.003}, pmid = {17045786}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Humans ; Inclusion Bodies/ultrastructure ; Intermediate Filament Proteins/*genetics/metabolism ; Intermediate Filaments/*genetics/metabolism ; Membrane Glycoproteins/*genetics/metabolism ; Mice ; Mice, Transgenic ; Motor Neuron Disease/metabolism/pathology ; Motor Neurons/metabolism/*pathology ; Nerve Tissue Proteins/*genetics/metabolism ; Neurofilament Proteins/*genetics ; Peripherins ; Phosphorylation ; }, abstract = {One of the pathological hallmarks of ALS is the presence of axonal spheroids and perikaryal accumulations/aggregations comprised of the neuronal intermediate filament proteins, neurofilaments and peripherin. These abnormalities represent a point of convergence of both familial and sporadic forms of the disease and understanding their formation may reveal shared pathways in what is otherwise considered a highly heterogeneous disorder. Here we provide a review of the basic biology of neurofilaments and peripherin and the evidence linking them with ALS disease pathogenesis.}, }
@article {pmid17043768, year = {2007}, author = {Madhusoodanan, KS and Murad, F}, title = {NO-cGMP signaling and regenerative medicine involving stem cells.}, journal = {Neurochemical research}, volume = {32}, number = {4-5}, pages = {681-694}, pmid = {17043768}, issn = {0364-3190}, mesh = {2',3'-Cyclic-Nucleotide Phosphodiesterases/physiology ; Animals ; Cyclic GMP/*physiology ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Ion Channel Gating/physiology ; Neurodegenerative Diseases/metabolism/therapy ; Nitric Oxide/*physiology ; Nitric Oxide Synthase Type I/physiology ; *Regenerative Medicine ; Signal Transduction/*physiology ; *Stem Cell Transplantation ; }, abstract = {Nitric oxide (NO) is a short lived diatomic free radical species synthesized by nitric oxide synthases (NOS). The physiological roles of NO depend on its local concentrations as well as availability and the nature of downstream target molecules. At low nanomolar concentrations, activation of soluble guanylyl cyclase (sGC) is the major event initiated by NO. The resulting elevation in the intracellular cyclic GMP (cGMP) levels serves as signals for regulating diverse cellular and physiological processes. The participation of NO and cGMP in diverse physiological processes is made possible through cell type specific spatio-temporal regulation of NO and cGMP synthesis and signal diversity downstream of cGMP achieved through specific target selection. Thus cyclic GMP directly regulates the activities of its downstream effectors such as Protein Kinase G (PKG), Cyclic Nucleotide Gated channels (CNG) and Cyclic nucleotide phosphodiesterases, which in turn regulate the activities of a number of proteins that are involved in regulating diverse cellular and physiological processes. Localization and activity of the NO-cGMP signaling pathway components are regulated by G-protein coupled receptors, receptor and non receptor tyrosine kinases, phosphatases and other signaling molecules. NO also serves as a powerful paracrine factor. At micromolar concentrations, NO reacts with superoxide anion to form reactive peroxinitrite, thereby leading to the oxidation of important cellular proteins. Extensive research efforts over the past two decades have shown that NO is an important modulator of axon outgrowth and guidance, synaptic plasticity, neural precursor proliferation as well as neuronal survival. Excessive NO production as that evoked by inflammatory signals has been identified as one of the major causative reasons for the pathogenesis of a number of neurodegenerative diseases such as ALS, Alzheimers and Parkinson diseases. Regenerative therapies involving transplantation of embryonic stem cells (ES cells) and ES cell derived lineage committed neural precursor cells have recently shown promising results in animal models of Parkinson disease (PD). Recent studies from our laboratory have shown that a functional NO-cGMP signaling system is operative early during the differentiation of embryonic stem cells. The cell type specific, spatio-temporally regulated NO-cGMP signaling pathways are well suited for inductive signals to use them for important cell fate decision making and lineage commitment processes. We believe that manipulating the NO-cGMP signaling system will be an important tool for large scale generation of lineage committed precursor cells to be used for regenerative therapies.}, }
@article {pmid17034351, year = {2006}, author = {Hensley, K and Mhatre, M and Mou, S and Pye, QN and Stewart, C and West, M and Williamson, KS}, title = {On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {8}, number = {11-12}, pages = {2075-2087}, doi = {10.1089/ars.2006.8.2075}, pmid = {17034351}, issn = {1523-0864}, support = {AG20783/AG/NIA NIH HHS/United States ; NS044154/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; *Disease Models, Animal ; Humans ; Inflammation ; Mice ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; *Oxidative Stress ; Superoxide Dismutase/genetics ; }, abstract = {The central nervous system (CNS) presents both challenges and opportunities to researchers of redox biochemistry. The CNS is sensitive to oxidative damage during aging or disease; excellent transgenic models of specific neurodegenerative diseases have been created that reproduce oxidative stress components of the corresponding human disorder. Mouse models of familial amyotrophic lateral sclerosis (ALS) based on overexpressed mutant human Cu, Zn-superoxide dismutase (SOD1) are cases in point. These animals experience predictably staged, age-dependent motor neuron degeneration with profound cellular and biochemical damage to nerve fibers and spinal cord tissue. Severe protein and lipid oxidation occurs in these animals, apparently as an indirect consequence of protein aggregation or cytopathic protein-protein interactions, as opposed to aberrant redox catalysis by the mutant enzyme. Recent studies of G93A-SOD1 mice and rats suggest that oxidative damage is part of an unmitigated neuroinflammatory reaction, possibly arising in combination from mitochondrial dysfunction plus pathophysiologic activation of both astrocytes and microglia. Lesions to redox signal-transduction pathways in mutant SOD1+ glial cells may stimulate broad-spectrum upregulation of proinflammatory genes, including arachidonic acid-metabolizing enzymes [e.g., cyclooxygenase-II (COX-II) and 5-lipoxygenase (5LOX)]; nitric oxide synthase (NOS) isoforms; cytokines (particularly tumor necrosis factor alpha, TNF-alpha); chemokines; and immunoglobulin Fc receptors (FcgammaRs). The integration of these processes creates a paracrine milieu inconsistent with healthy neural function. This review summarizes what has been learned to date from studies of mutant SOD1 transgenic animals and demonstrates that the G93A-SOD1 mouse in particular is a robust laboratory for the study of neuroinflammation and redox biochemistry.}, }
@article {pmid17034349, year = {2006}, author = {Barron, AM and Fuller, SJ and Verdile, G and Martins, RN}, title = {Reproductive hormones modulate oxidative stress in Alzheimer's disease.}, journal = {Antioxidants &amp; redox signaling}, volume = {8}, number = {11-12}, pages = {2047-2059}, doi = {10.1089/ars.2006.8.2047}, pmid = {17034349}, issn = {1523-0864}, mesh = {Alzheimer Disease/drug therapy/*metabolism ; Amyloid beta-Peptides/*metabolism ; Animals ; Gonadal Steroid Hormones/*metabolism/pharmacology/therapeutic use ; Humans ; *Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by gradual cognitive decline, impairments in speech and language, and dysfunction in the sensorimotor systems, culminating in complete reliance on nursing care. Oxidative stress, caused by an imbalance in the pro-oxidant/antioxidant mechanisms in the body, has been implicated in AD pathogenesis, as in many other age-associated diseases such as atherosclerosis, Parkinson disease, and amyotrophic lateral sclerosis. Although the hormones estrogen, progesterone, testosterone, and luteinizing hormone are best known for their roles in reproduction, many studies show these hormones have other roles, including neuroprotection. Changes in the levels of these hormones that occur in reproductive senescence are hypothesized to increase risk of AD, as a result of reduced protection against oxidative insults. The Abeta peptide, overproduction of which is thought to be a key pathogenic event in the development of AD, is neurotoxic, most likely due to its ability to promote oxidative stress. The reproductive hormones are known to influence Abeta metabolism, and this review discusses the beneficial and detrimental effects these hormones have on Abeta production and oxidative stress, and their relevance in potential AD therapies.}, }
@article {pmid17029001, year = {2006}, author = {Coppedè, F and Mancuso, M and Siciliano, G and Migliore, L and Murri, L}, title = {Genes and the environment in neurodegeneration.}, journal = {Bioscience reports}, volume = {26}, number = {5}, pages = {341-367}, doi = {10.1007/s10540-006-9028-6}, pmid = {17029001}, issn = {0144-8463}, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Environment ; Genetic Predisposition to Disease ; Humans ; Huntington Disease/genetics/pathology ; Mitochondria ; Models, Genetic ; *Mutation ; Neurodegenerative Diseases/*genetics/*pathology ; Parkinson Disease/genetics/pathology ; Prion Diseases/genetics/pathology ; }, abstract = {Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and prion diseases.) and discuss possible links of gene-environment interplay including, where implicated, mitochondrial genes.}, }
@article {pmid17028559, year = {2006}, author = {Duyckaerts, C}, title = {[Nosology of dementias: the neuropathologist's point of view].}, journal = {Revue neurologique}, volume = {162}, number = {10}, pages = {921-928}, doi = {10.1016/s0035-3787(06)75101-3}, pmid = {17028559}, issn = {0035-3787}, mesh = {Aged ; Alzheimer Disease/*pathology ; Brain/pathology ; Dementia/*pathology ; Humans ; Neurodegenerative Diseases/*pathology ; Oligodendroglia/pathology ; Pick Disease of the Brain/pathology ; Tauopathies/pathology ; Ubiquitin/physiology ; alpha-Synuclein/physiology ; }, abstract = {The diagnosis of degenerative dementias heavily relies on the identification of neuronal or glial inclusions. Tauopathy is probably the largest group including Alzheimer and Pick disease, mutation of the tau gene, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Lewy bodies, when numerous in the cerebral cortex, are usually associated with the cognitive deficit of Parkinson disease dementia or of dementia with Lewy bodies--both conditions being distinguished by clinical information. The inclusions of the dentate gyrus, only labeled by anti-ubiquitin antibodies, isolate a subgroup of fronto-temporal dementia (FTDu), sometimes familial and sometimes associated with amyotrophic lateral sclerosis. Mutations of the progranulin gene have been recently discovered among a significant proportion of these patients. Neuronal Intermediate Filament Inclusion Disease (NIFID) is a rare, apparently sporadic dementia, characterized by the presence of large inclusions in the cell body of many neurons. These inclusions react with antibodies directed against neurofilaments or against other intermediate filaments (such as alpha-internexin). The diagnostic value of some of these inclusions allowing the classification of the degenerative dementias has been discussed. The link between the inclusions and the pathogenetic mechanism is indeed probably variable. It should however be stressed that whenever their composition has been elucidated, the inclusions have given important clues to the pathogenesis of the disease in which they had been found.}, }
@article {pmid17025271, year = {2006}, author = {Szeto, HH}, title = {Mitochondria-targeted peptide antioxidants: novel neuroprotective agents.}, journal = {The AAPS journal}, volume = {8}, number = {3}, pages = {E521-31}, pmid = {17025271}, issn = {1550-7416}, support = {P01 DA08924/DA/NIDA NIH HHS/United States ; R21 NS48295/NS/NINDS NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology/therapeutic use ; Apoptosis/drug effects ; Humans ; Mitochondria/*drug effects/metabolism/pathology ; Neurodegenerative Diseases/prevention &amp; control ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/*drug effects ; Parkinson Disease/prevention &amp; control ; Reactive Oxygen Species/*metabolism ; }, abstract = {Increasing evidence suggests that mitochondrial dysfunction and oxidative stress play a crucial role in the majority of neurodegenerative diseases. Mitochondria are a major source of intracellular reactive oxygen species (ROS) and are particularly vulnerable to oxidative stress. Oxidative damage to mitochondria has been shown to impair mitochondrial function and lead to cell death via apoptosis and necrosis. Because dysfunctional mitochondria will produce more ROS, a feed-forward loop is set up whereby ROS-mediated oxidative damage to mitochondria favors more ROS generation, resulting in a vicious cycle. It is now appreciated that reduction of mitochondrial oxidative stress may prevent or slow down the progression of these neurodegenerative disorders. However, if mitochondria are the major source of intracellular ROS and mitochondria are most vulnerable to oxidative damage, then it would be ideal to deliver the antioxidant therapy to mitochondria. This review will summarize the development of a novel class of mitochondria-targeted antioxidants that can protect mitochondria against oxidative stress and prevent neuronal cell death in animal models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid17022691, year = {2006}, author = {Kolarcik, C and Bowser, R}, title = {Plasma and cerebrospinal fluid-based protein biomarkers for motor neuron disease.}, journal = {Molecular diagnosis &amp; therapy}, volume = {10}, number = {5}, pages = {281-292}, pmid = {17022691}, issn = {1177-1062}, support = {ES013469/ES/NIEHS NIH HHS/United States ; T32 EB001026/EB/NIBIB NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers/blood/cerebrospinal fluid ; Blood Proteins/*analysis ; Cerebrospinal Fluid Proteins/*analysis ; Humans ; Molecular Diagnostic Techniques ; Motor Neuron Disease/*diagnosis/metabolism ; Proteomics ; }, abstract = {Motor neuron diseases (MNDs) and, in particular, amyotrophic lateral sclerosis (ALS), are a heterogeneous group of neurologic disorders characterized by the progressive loss of motor function. In ALS, a selective and relentless degeneration of both upper and lower motor neurons occurs, culminating in mortality typically within 5 years of symptom onset. However, survival rates vary among individual patients and can be from a few months to >10 years from diagnosis. Inadequacies in disease detection and treatment, along with a lack of diagnostic and prognostic tools, have prompted many to turn to proteomics-based biomarker discovery efforts. Proteomics refers to the study of the proteins expressed by a genome at a particular time, and the proteome can respond to and reflect the status of an organism, including health and disease states. Although an emerging field, proteomic applications promise to uncover biomarkers critical for differentiating patients with ALS and other MNDs from healthy individuals and from patients affected by other diseases. Ideally, these studies will also provide mechanistic information to facilitate identification of new drug targets for subsequent therapeutic development. In addition to proper experimental design, standard operating procedures for sample acquisition, preprocessing, and storage must be developed. Biological samples typically analyzed in proteomic studies of neurologic diseases include both plasma and cerebrospinal fluid (CSF). Recent studies have identified individual proteins and/or protein panels from blood plasma and CSF that represent putative biomarkers for ALS, although many of these proteins are not unique to this disease. Continued investigations are required to validate these initial findings and to further pursue the role of these proteins as diagnostic biomarkers or surrogate markers of disease progression. Protein biomarkers specific to ALS will additionally function to evaluate drug efficacy in clinical trials and to identify novel targets for drug design. It is hoped that proteomic technologies will soon integrate the basic biology of ALS with mechanistic disease information to achieve success in the clinical setting.}, }
@article {pmid17017870, year = {2006}, author = {Garruto, RM}, title = {A commentary on neuronal degeneration and cell death in Guam ALS and PD: an evolutionary process of understanding.}, journal = {Current Alzheimer research}, volume = {3}, number = {4}, pages = {397-401}, doi = {10.2174/156720506778249425}, pmid = {17017870}, issn = {1567-2050}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*physiopathology ; Animals ; Cell Death/drug effects/genetics ; Environmental Exposure/adverse effects ; Genetic Predisposition to Disease/*genetics ; Guam/epidemiology ; Humans ; Mitochondrial Diseases/genetics/metabolism/physiopathology ; Nerve Degeneration/genetics/metabolism/*physiopathology ; Neurotoxins/metabolism/toxicity ; Parkinson Disease/genetics/metabolism/*physiopathology ; }, abstract = {The Twentieth Century witnessed tremendous advances in our understanding of neurodegenerative diseases. Not least among them were the contributions from hyperendemic foci of neurodegenerative disorders in isolated human groups worldwide, with the knowledge gained applicable to our understanding of related neurodegenerative diseases globally.}, }
@article {pmid17017544, year = {2006}, author = {Németh, H and Toldi, J and Vécsei, L}, title = {Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies.}, journal = {Journal of neural transmission. Supplementum}, volume = {}, number = {70}, pages = {285-304}, doi = {10.1007/978-3-211-45295-0_45}, pmid = {17017544}, issn = {0303-6995}, mesh = {Animals ; Humans ; Kynurenine/*physiology ; Neurodegenerative Diseases/*genetics/metabolism ; Parkinson Disease/*genetics/metabolism ; Quinolinic Acid/metabolism ; Receptors, N-Methyl-D-Aspartate/physiology ; Signal Transduction/physiology ; }, abstract = {The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson's disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.}, }
@article {pmid17015226, year = {2006}, author = {Boillée, S and Vande Velde, C and Cleveland, DW}, title = {ALS: a disease of motor neurons and their nonneuronal neighbors.}, journal = {Neuron}, volume = {52}, number = {1}, pages = {39-59}, doi = {10.1016/j.neuron.2006.09.018}, pmid = {17015226}, issn = {0896-6273}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Animals ; Axonal Transport/physiology ; Cell Death ; Humans ; Inflammation/etiology/genetics/pathology ; Mitochondria/pathology/physiology ; Models, Biological ; Motor Neurons/*pathology/*physiology ; Mutation ; Neuroglia/*pathology/*physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis is a late-onset progressive neurodegenerative disease affecting motor neurons. The etiology of most ALS cases remains unknown, but 2% of instances are due to mutations in Cu/Zn superoxide dismutase (SOD1). Since sporadic and familial ALS affects the same neurons with similar pathology, it is hoped that therapies effective in mutant SOD1 models will translate to sporadic ALS. Mutant SOD1 induces non-cell-autonomous motor neuron killing by an unknown gain of toxicity. Selective vulnerability of motor neurons likely arises from a combination of several mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, excitotoxicity, insufficient growth factor signaling, and inflammation. Damage within motor neurons is enhanced by damage incurred by nonneuronal neighboring cells, via an inflammatory response that accelerates disease progression. These findings validate therapeutic approaches aimed at nonneuronal cells.}, }
@article {pmid17006927, year = {2006}, author = {Lin, H and Schlaepfer, WW}, title = {Role of neurofilament aggregation in motor neuron disease.}, journal = {Annals of neurology}, volume = {60}, number = {4}, pages = {399-406}, doi = {10.1002/ana.20965}, pmid = {17006927}, issn = {0364-5134}, mesh = {Animals ; Cell Aggregation ; Guanine Nucleotide Exchange Factors/genetics ; Humans ; Motor Neuron Disease/genetics/*pathology ; Nerve Fibers/*pathology ; RNA/biosynthesis/genetics ; RNA-Binding Proteins/genetics ; Repressor Proteins/genetics ; }, abstract = {A major question in the pathogenesis of motor neuron disease is why motor neurons are selectively susceptible to mutations in widely expressed gene products. Reexamination of motor neuron degeneration due to alterations of neurofilament (NF) expression suggests that disruption of assembly with aggregation of the light neurofilament (NFL) protein may be an upstream event and contributing factor leading to the preferential degeneration of motor neurons. The implications of these findings are that aggregation of NFL is not only a triggering mechanism to account for the hallmark aggregates of NF protein in sporadic and familial forms of amyotrophic lateral sclerosis, but that aggregates of NFL may also promote aggregation of wildly expressed proteins that are destabilized by missense mutations, such as by mutations in superoxide dismutase-1 protein. This review examines the potential role of NFs in determining and promoting the preferential degeneration of motor neurons in motor neuron disease. The underlying premise is that motor neurons are selectively susceptible to alterations in NF expression, that alterations in NF expression lead to NF aggregates in motor neurons, and that elevated levels of NF aggregates provide a favorable microenvironment for the formation of neurotoxic aggregation and degeneration of motor neurons.}, }
@article {pmid17004365, year = {2006}, author = {Perl, DP and Moalem, S}, title = {Aluminum and Alzheimer's disease, a personal perspective after 25 years.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {9}, number = {3 Suppl}, pages = {291-300}, doi = {10.3233/jad-2006-9s332}, pmid = {17004365}, issn = {1387-2877}, support = {AD-08812/AD/ADAMHA HHS/United States ; AD-14382/AD/ADAMHA HHS/United States ; }, mesh = {Aluminum/*adverse effects ; Alzheimer Disease/*chemically induced/pathology ; Humans ; Neurofibrillary Tangles/drug effects/pathology ; Phosphorylation ; }, abstract = {It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesion in Alzheimer's disease and other related disorders.}, }
@article {pmid16987882, year = {2006}, author = {Talbot, K and Ansorge, O}, title = {Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease.}, journal = {Human molecular genetics}, volume = {15 Spec No 2}, number = {}, pages = {R182-7}, doi = {10.1093/hmg/ddl202}, pmid = {16987882}, issn = {0964-6906}, mesh = {Adenosine Triphosphatases ; Amyotrophic Lateral Sclerosis/etiology/*genetics/metabolism/pathology ; Cell Cycle Proteins/genetics ; Dementia/etiology/*genetics/metabolism/pathology ; Dynactin Complex ; Endosomal Sorting Complexes Required for Transport ; Genetic Linkage ; Humans ; Inclusion Bodies/metabolism/pathology ; Intercellular Signaling Peptides and Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Nerve Degeneration/genetics ; Nerve Tissue Proteins/genetics ; Progranulins ; Ubiquitin/metabolism ; Valosin Containing Protein ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically defined by the impairment of the voluntary motor system and ubiquitin-positive intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD) is a common form of neurodegenerative dementia and presents with personality change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD. The identification of two further genetic causes of FTD-U with (rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for exploring the pathways associated with ubiquitin-mediated protein mishandling in FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS-FTD to pure FTD-U, may represent a continuous spectrum of ubiquitin-associated neurodegenerative disease.}, }
@article {pmid16973338, year = {2006}, author = {Simpson, CL and Al-Chalabi, A}, title = {Amyotrophic lateral sclerosis as a complex genetic disease.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {973-985}, doi = {10.1016/j.bbadis.2006.08.001}, pmid = {16973338}, issn = {0006-3002}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/epidemiology/*genetics ; Animals ; Gene Dosage ; *Genetic Predisposition to Disease ; Humans ; Intermediate Filaments/genetics/metabolism ; Mice ; Mice, Transgenic ; *Mutation ; Neurons/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {In complex diseases like ALS, there are multiple genetic and environmental factors all contributing to disease liability. The genetic factors causing susceptibility to developing ALS can be considered a spectrum from single genes with large effect sizes causing classical Mendelian ALS, to genes of smaller effect, producing apparently sporadic disease. We examine the statistical genetic principles that underpin this model and review what is known about ALS as a disease with complex genetics.}, }
@article {pmid16958985, year = {2006}, author = {Matsuoka, M and Hashimoto, Y and Aiso, S and Nishimoto, I}, title = {Humanin and colivelin: neuronal-death-suppressing peptides for Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {CNS drug reviews}, volume = {12}, number = {2}, pages = {113-122}, pmid = {16958985}, issn = {1080-563X}, mesh = {Alzheimer Disease/*drug therapy ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Cell Death/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/pharmacology/*therapeutic use ; Models, Biological ; }, abstract = {Humanin (HN), a 24-amino-acid neuroprotective peptide, was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient. HN inhibits neuronal death by binding to its specific receptor on the cell membrane and triggering a Jak2/STAT3 prosurvival pathway. The activation of this pathway may represent a therapeutic approach to AD. HN also exhibits neuroprotective activity against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant superoxide dismutase (SOD1). Recent investigations established that AGA-(C8R)-HNG17, a 17-amno-acid derivative of HN, is 10(5) times more potent as a neuroprotective than HN; at 10-picomolar and higher concentrations in vitro it completely suppresses neuronal death. Moreover, a 26-amino-acid peptide colivelin (CL), composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)-HNG17, provides complete neuroprotection at 100-femtomolar or higher concentrations in vitro. A series of experiments using mouse AD and ALS models further established the efficacy of HN derivatives, including CL, against these diseases in vivo. HN and CL can be viewed as drug candidates for neuronal death suppression therapy in AD or ALS.}, }
@article {pmid16934166, year = {2006}, author = {Dhand, UK}, title = {Clinical approach to the weak patient in the intensive care unit.}, journal = {Respiratory care}, volume = {51}, number = {9}, pages = {1024-40; discussion 1040-1}, pmid = {16934166}, issn = {0020-1324}, mesh = {Biopsy ; Clinical Chemistry Tests ; Critical Care/*methods ; Electrophysiology/methods ; Humans ; Muscle Weakness/diagnosis/*etiology/pathology ; Muscles/pathology ; Nerve Tissue/pathology ; Neurologic Examination ; Neuromuscular Diseases/*diagnosis/pathology ; }, abstract = {Motor weakness in a patient in the intensive care unit (ICU) may be related to (1) pre-existing neuromuscular disorder that leads to ICU admission, (2) new-onset or previously undiagnosed neurological disorder, or (3) complications of non-neuromuscular critical illness. Neuromuscular syndromes related to ICU treatment consist of critical illness polyneuropathy, critical illness myopathy, and prolonged neuromuscular blockade, and are now recognized as a frequent cause of newly acquired weakness in ICU patients. Clinical features include quadriparesis, muscle wasting, and difficulty weaning from the ventilator. Evaluation of these patients is based on knowledge of clinical setting and predisposing factors, focused neurological examination, detailed electrophysiological investigation, serum creatine kinase level, other laboratory studies as needed, and histological examination of muscle biopsy. If a central nervous system (brain or spinal cord) lesion is suspected, neuroimaging studies are required. In addition to conventional nerve conduction and needle electromyography, phrenic nerve conduction, diaphragm electromyography, blink reflex, and (recently) the technique of direct muscle stimulation have been employed. Critical illness polyneuropathy is an axonal motor and sensory neuropathy that often follows sepsis and multiorgan failure. Risk factors for critical illness myopathy are corticosteroids and neuromuscular blocking drugs, acute respiratory illness, and organ transplant. Three subtypes (acute necrotizing myopathy, thick myosin filament loss myopathy, and type II fiber atrophy) are recognized. Major differential diagnoses of critical illness related paralysis are incidental Guillain-Barré syndrome and unmasked myasthenia gravis. Rarely, atypical presentation of amyotrophic lateral sclerosis, polymyositis or other myopathies, and precipitation of porphyria or rhabdomyolysis due to drugs used in the ICU have been described. Recently a poliomyelitis-like flaccid paralysis due to West Nile virus infection was reported. A subgroup of patients with myasthenia gravis with muscle-specific tyrosine kinase antibody is noted to present as respiratory crisis. Muscle biopsy in ICU paralysis syndromes may be helpful in arriving at a specific diagnosis or to classify the type of critical illness myopathy. Nerve biopsy is only rarely indicated.}, }
@article {pmid16932606, year = {2006}, author = {Miller, TM and Smith, RA and Cleveland, DW}, title = {Amyotrophic lateral sclerosis and gene therapy.}, journal = {Nature clinical practice. Neurology}, volume = {2}, number = {9}, pages = {462-463}, doi = {10.1038/ncpneuro0270}, pmid = {16932606}, issn = {1745-834X}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; Dependovirus ; *Genetic Therapy ; Genetic Vectors ; Humans ; Lentivirus ; Mice ; RNA, Small Interfering ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid16928353, year = {2006}, author = {Van Den Bosch, L and Timmerman, V}, title = {Genetics of motor neuron disease.}, journal = {Current neurology and neuroscience reports}, volume = {6}, number = {5}, pages = {423-431}, pmid = {16928353}, issn = {1528-4042}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Hereditary Sensory and Motor Neuropathy/genetics ; Humans ; Motor Neuron Disease/classification/*genetics ; Muscular Atrophy, Spinal/genetics ; Mutation/*genetics ; }, abstract = {The number of genes associated with motor neuron degeneration has increased considerably over the past few years. As more gene mutations are identified, the hope arises that certain common themes and/or pathways become clear. In this overview, we focus on recent discoveries related to amyotrophic lateral sclerosis (ALS), spinal muscular atrophies (SMA), and distal hereditary motor neuropathies (dHMN). It is striking that many of the mutated genes that were linked to these diseases encode proteins that are either directly or indirectly involved in axonal transport or play a role in RNA metabolism. We hypothesize that both phenomena are not only crucial for the normal functioning of motor neurons, but that they could also be interconnected. In analogy with the situation after acute stress, axonal mRNA translation followed by retrograde transport of the signal back to the nucleus could play an important role in chronic motor neuron diseases. We hope that information on the genetic causes of these diseases and the insight into the pathologic processes involved could ultimately lead to therapeutic strategies that prevent or at least slow this degenerative process.}, }
@article {pmid16928348, year = {2006}, author = {Ringholz, GM and Greene, SR}, title = {The relationship between amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Current neurology and neuroscience reports}, volume = {6}, number = {5}, pages = {387-392}, pmid = {16928348}, issn = {1528-4042}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics/pathology/*physiopathology ; Dementia/complications/genetics/pathology/*physiopathology ; Diagnostic Imaging ; Humans ; }, abstract = {Despite the traditional view of amyotrophic lateral sclerosis (ALS) as an isolated motor neuron disorder, recent evidence suggests that ALS is, in fact, a multisystem disorder with a varying presentation and with widespread extramotor neuropathologic involvement. Support for a concept of ALS as a multisystem disorder has some basis in historical clinical reports that have highlighted the existence of a frank dementia in at least a small percentage of ALS patients. More recent evidence of extramotor involvement in ALS, derived from neurocognitive, neuropathologic, genetic, proteomic, and neuroradiologic perspectives, provides further support for these early observations and has drawn considerable attention to a possible association between ALS and frontotemporal dementia (FTD). Literature from these diverse clinical and basic scientific disciplines, when integrated, demonstrates commonalities between ALS and FTD and suggests that these disorders not only affect the same general neuroanatomic substrate, but also may represent two points on the same neuropathologic continuum. This review discusses this putative association between ALS and FTD and provides possible directions for future research in this area.}, }
@article {pmid16924260, year = {2006}, author = {Pasinelli, P and Brown, RH}, title = {Molecular biology of amyotrophic lateral sclerosis: insights from genetics.}, journal = {Nature reviews. Neuroscience}, volume = {7}, number = {9}, pages = {710-723}, doi = {10.1038/nrn1971}, pmid = {16924260}, issn = {1471-003X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*physiopathology ; Animals ; Apoptosis/genetics ; Central Nervous System/metabolism/pathology/*physiopathology ; Genetic Predisposition to Disease/*genetics ; Humans ; Mitochondria/genetics/metabolism ; Mutation/*genetics ; Nerve Tissue Proteins/genetics/metabolism ; Signal Transduction/genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.}, }
@article {pmid16909028, year = {2005}, author = {Ludolph, AC and Sperfeld, AD}, title = {Preclinical trials--an update on translational research in ALS.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {215-219}, doi = {10.1159/000089628}, pmid = {16909028}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Animals, Genetically Modified ; *Disease Models, Animal ; Humans ; Mice ; *Research Design ; }, abstract = {Translational research has become a strategy which describes the steps from in vitro experimental therapy, its translation into experimental animals and finally to humans. However, this translation of hypotheses from one of these levels to another faces a number of difficulties which are currently of major interest for the development of therapeutics. In particular, in the previously untreatable motor neuron diseases, the steps from genes to transgenic animals and finally to the patient have proven difficult. High expectations have not met with the transfer of numerous therapies from experimental animals to men; there are many in- and outside the field which already question the value of animal models. It is the opinion of the authors that we should not dismiss the models before we have not defined generally accepted standards of protocols for therapeutic studies in experimental animals. Only if a generally agreed standardized and validated methodology in mice cannot predict the human response to therapeutics, an animal model should be abandoned. In contrast, the value of translating genetic findings to experimental animals and men is currently shown for motor proteins; in particular the functional impact of dynactin and dynein for the integrity of motor neurons of rodents and men are in the center of interest.}, }
@article {pmid16909027, year = {2005}, author = {Meininger, V}, title = {Clinical trials in ALS: what did we learn from recent trials in humans?.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {208-214}, doi = {10.1159/000089627}, pmid = {16909027}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Female ; Humans ; Male ; Mice ; Middle Aged ; Prognosis ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. No treatment is currently able to stop the disease process. In the absence of new active compounds there is an urgent need to develop new strategies based on the neuroprotective activity of available drugs. ALS is a heterogeneous disease. To build up these therapeutic trials, we need to have a better understanding of the prognostic factors in this disease. During the Phase IV Rilutek Trial in France, we developed in a large population of patients a prognostic score based on clinical parameters available at the bedside. The most significant variables are vital capacity, spasticity, fasciculations, swallowing, cough and creatininemia. This score proved to be very useful in daily use in the clinic and for planning disease management in ALS as in the design of therapeutic trials. In ALS clinical trials, efficacy can be evaluated using survival or functional parameters. In phase II trials, function remains the most commonly used. In phase III trials, the gold standard endpoint remains the survival rate at month 18. We analyzed the most recent ALS trials published in the literature. This review suggests that in these trials there is a discrepancy between drug effects on survival versus function. These results suggest that a reappraisal of strategies to identify therapeutic targets for ALS is required.}, }
@article {pmid16909024, year = {2005}, author = {Fergani, A and Dupuis, L and Jokic, N and Larmet, Y and de Tapia, M and Rene, F and Loeffler, JP and Gonzalez de Aguilar, JL}, title = {Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {185-194}, doi = {10.1159/000089624}, pmid = {16909024}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Biomarkers/*metabolism ; Carrier Proteins/chemistry/genetics/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/chemistry/genetics/*metabolism ; Membrane Proteins/chemistry/genetics/*metabolism ; Nerve Tissue Proteins/chemistry/genetics/*metabolism ; }, abstract = {Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150-200 amino-acid residues. The N-terminal regions of RTNs are highly variable, and result from alternative splicing or differential promoter usage. Although widely distributed, the functions of RTNs are still poorly understood. Much interest has been focused on rtn4/nogo because of its activity as a potent inhibitor of axonal growth and repair. In the present study, we update recent knowledge on mammalian RTNs paying special attention to the involvement of these proteins as markers of neurological diseases. We also present recent data concerning RTN expression in amyotrophic lateral sclerosis, a fatal degenerative disorder characterized by loss of upper and lower motor neurons, and muscle atrophy. The rearrangement of RTN expression is regulated not only in suffering skeletal muscle but also preceding the onset of symptoms, and may relate to the disease process.}, }
@article {pmid16909023, year = {2005}, author = {Dengler, R and von Neuhoff, N and Bufler, J and Krampfl, K and Peschel, T and Grosskreutz, J}, title = {Amyotrophic lateral sclerosis: new developments in diagnostic markers.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {177-184}, doi = {10.1159/000089623}, pmid = {16909023}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Animals ; *Biomarkers ; Brain/pathology ; *Diffusion Magnetic Resonance Imaging ; Humans ; Motor Neurons/pathology ; *Proteomics ; *Transcranial Magnetic Stimulation ; }, abstract = {There is an intensive search for diagnostic markers in amyotrophic lateral sclerosis (ALS). Protein analysis (proteomics) of the cerebrospinal fluid (CSF) appears particularly promising using mass spectrometry and 2-D gel electrophoresis to detect low and high molecular weight proteins, respectively. It is open whether protein changes specific for ALS will be found. This also holds true for inflammatory proteins such as the cytokine monocyte chemoattractant protein-1 which has been detected in CSF in ALS and for other cytokines such as interleukin-1beta. Increases of the protein Nogo A and B in muscle tissue and decreases of the growth factor vascular endothelial growth factor in blood may also be useful for monitoring the course of ALS. Clinical neurophysiology provides markers for upper and lower motor neuron damage. A very sensitive method to detect early upper motor neuron involvement is the transcranial magnetic stimulation modification 'triple stimulation technique' which can show significant changes in patients without clinical upper motor neuron signs. The loss of lower motor neurons can be closely monitored by MUNE techniques (motor unit number estimate). In modern imaging, the MRI technique DTI (diffusion tensor imaging) has the greatest diagnostic potential for ALS. It can separate between normal and ALS in group comparisons and may be improved to be diagnostic in individual patients. Voxel-based morphometry can reliably demonstrate regional cortical atrophy in motor areas and beyond although it is not appropriate for use in individual patients.}, }
@article {pmid16909022, year = {2005}, author = {Guillemin, GJ and Meininger, V and Brew, BJ}, title = {Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {166-176}, doi = {10.1159/000089622}, pmid = {16909022}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Humans ; Inflammation/pathology ; Kynurenine/*metabolism ; *Models, Neurological ; Motor Neurons/metabolism/pathology ; Quinolinic Acid/*metabolism ; Signal Transduction/*physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.}, }
@article {pmid16909020, year = {2005}, author = {Van Damme, P and Dewil, M and Robberecht, W and Van Den Bosch, L}, title = {Excitotoxicity and amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {147-159}, doi = {10.1159/000089620}, pmid = {16909020}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Calcium/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/*metabolism ; Humans ; Motor Neurons/drug effects/metabolism/pathology ; Nerve Degeneration/*etiology ; Receptors, Glutamate/*metabolism ; }, abstract = {Since its description by Charcot more than 130 years ago, the pathogenesis of selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains unsolved. Over the years, many pathogenic mechanisms have been proposed. Amongst others these include: oxidative stress, excitotoxicity, aggregate formation, inflammation, growth factor deficiency and neurofilament disorganization. This multitude of contributing factors indicates that ALS is a complex disease and also suggests that ALS is a multifactorial disorder. Excitotoxicity is not the newest and most spectacular hypothesis in the ALS field, but it is undoubtedly one of the most robust pathogenic mechanisms supported by an impressive amount of evidence. Moreover, the therapeutic efficacy of riluzole, the only drug proven to slow disease progression in ALS, is most likely related to its anti-excitotoxic properties. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS and of the possible mechanisms leading to motor neuron death. We will also summarize the intrinsic properties of motor neurons that render these cells particularly vulnerable to excitotoxicity and could explain the selective vulnerability of motor neurons in ALS. All this information could help to develop new and better therapeutic strategies that could protect motor neurons from excitotoxicity.}, }
@article {pmid16909019, year = {2005}, author = {Pehar, M and Vargas, MR and Cassina, P and Barbeito, AG and Beckman, JS and Barbeito, L}, title = {Complexity of astrocyte-motor neuron interactions in amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {139-146}, doi = {10.1159/000089619}, pmid = {16909019}, issn = {1660-2854}, support = {ES00210/ES/NIEHS NIH HHS/United States ; R03 TW006482/TW/FIC NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Astrocytes/*metabolism/pathology ; Cell Communication/*physiology ; Cell Death/physiology ; Fibroblast Growth Factor 1/metabolism ; Gliosis/metabolism ; Humans ; Mice ; Motor Neurons/*metabolism/pathology ; Nerve Growth Factor/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclerosis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experiments using chimeric mice expressing ALS-linked mutations to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuronal cell types on disease phenotype. When perturbed by primary neuronal damage, e.g. expression of SOD-1 mutations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the receptor FGFR1. FGF-1 stimulates nerve growth factor (NGF) expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Nrf2 leads to the expression of antioxidant and cytoprotective enzymes such as heme oxygenase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neurotrophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astrocytes may be a mechanism to eliminate critically damaged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role.}, }
@article {pmid16909018, year = {2005}, author = {Matsuoka, M and Nishimoto, I}, title = {Anti-ALS activity of alsin, the product of the ALS2 gene, and activity-dependent neurotrophic factor.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {135-138}, doi = {10.1159/000089618}, pmid = {16909018}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Death/physiology ; Guanine Nucleotide Exchange Factors/*metabolism ; Humans ; Motor Neurons/metabolism/pathology ; Mutation ; Nerve Tissue Proteins/*metabolism ; Neuroprotective Agents/*metabolism ; Signal Transduction/*physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable degenerative motoneuronal disease. The complete suppression of motoneuronal death is the ultimate goal of ALS therapy. Two new prosurvival pathways have been recently demonstrated to antagonize neurotoxicity by familial ALS-linked mutant Cu/Zn-superoxide dismutase (FSOD1). Alsin, the product of the recently cloned ALS-causative gene, the ALS2 gene, is linked to a Rac1/phosphatidylinositol-3 kinase/Akt3 pathway that specifically suppresses motoneuronal death induced by FSOD1. Activity-dependent neurotrophic factor, originally identified as an anti-Alzheimer neurotrophic factor, has been shown to suppress motoneuronal death by FSOD1 through a prosurvival pathway mediated by Ca(2+)/calmodulin-dependent protein kinase IV. Activation of these novel anti-ALS pathways may serve as a promising way to suppress ALS-related motoneuronal cell death.}, }
@article {pmid16909017, year = {2005}, author = {Bendotti, C and Bao Cutrona, M and Cheroni, C and Grignaschi, G and Lo Coco, D and Peviani, M and Tortarolo, M and Veglianese, P and Zennaro, E}, title = {Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {128-134}, doi = {10.1159/000089617}, pmid = {16909017}, issn = {1660-2854}, support = {GP0222Y01/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Communication/*physiology ; Humans ; Motor Neurons/*metabolism/pathology ; Neuroglia/*metabolism/pathology ; Receptor Cross-Talk/physiology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The pathogenetic processes underlying the selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are complex and still not completely understood even in the cases of inherited disease caused by mutations in the Cu/Zn superoxide dismutase-dependent (SOD1) gene. Recent evidence supports the view that ALS is not a cell-autonomous disease and that glial-neuron cross-talk, throughout cytokines and other toxic factors like the nitric oxide and superoxide, is a crucial determinant for the induction of motor neuron death. This cell-cell interaction may determine the progression of the disease through processes that are likely independent of the initial trigger and that may converge on the activation of intracellular death pathways in the motor neurons. In this review we provide support to the hypothesis that aberrant expression and activity of p38 mitogen protein-activated kinases cascade (p38MAPK) in motor neurons and glial cells may play a role in the development and progression of ALS. Increased activation of p38MAPK may phosphorylate neuron-specific substrates altering their physiological properties and it may turn on responsive genes leading to neurotoxicity.}, }
@article {pmid16909016, year = {2005}, author = {Tiwari, A and Hayward, LJ}, title = {Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {115-127}, doi = {10.1159/000089616}, pmid = {16909016}, issn = {1660-2854}, support = {R01 NS044170/NS/NINDS NIH HHS/United States ; R01-NS44170/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Humans ; Mutation ; Protein Structure, Quaternary ; Superoxide Dismutase/*chemistry/*metabolism/*toxicity ; Superoxide Dismutase-1 ; }, abstract = {The biological basis of preferential motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains incompletely understood, and effective therapies to prevent the lethal consequences of this disorder are not yet available. Since 1993, more than 100 mutant variants of the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) have been identified in familial ALS. Many studies have sought to distinguish abnormal properties shared by these proteins that may contribute to their toxic effects and cause age-dependent motor neuron loss. Complex networks of cellular interactions and changes associated with aging may link mutant SOD1s and other stresses to motor neuron death in ALS. Our laboratory and collaborators have compared physicochemical properties of biologically metallated wild-type and mutant SOD1 proteins to discern specific vulnerabilities that may be relevant to the mutant toxicity in vivo. X-ray crystal structures obtained from metallated 'wild-type-like' (WTL) SOD1 mutants, which retain the ability to bind copper and zinc and exhibit normal specific activity, indicate a native-like structure with only subtle changes to the backbone fold. In contrast, a group of 'metal-binding region' (MBR) SOD1 mutants that are deficient in copper and zinc exhibit severe thermal destabilization and structural disorder of conserved loops near the metal-binding sites. A growing body of evidence highlights specific stresses in vivo that may perturb well-folded, metallated SOD1 variants and thereby favor an increased burden of partially unfolded, metal-deficient species. For example, WTL SOD1 mutants are more susceptible than wild-type SOD1 to reduction of the intrasubunit disulfide bond between Cys-57 and Cys-146 at physiological pH and temperature. This bond anchors the disulfide loop to the SOD1 beta-barrel and helps to maintain the dimeric configuration of the protein. Cleavage of the disulfide linkage renders the well-folded WTL mutants vulnerable to metal loss and monomerization such that they may resemble the destabilized and locally misfolded MBR mutant species. SOD1 proteins with disordered loops or monomeric structure are expected to be more susceptible to aberrant self-association or detrimental interactions with other cellular constituents. The challenge for future investigations is to relate these abnormal properties of partially unfolded SOD1 to specific mechanisms of toxicity in motor neurons, supporting cells, or target tissues.}, }
@article {pmid16908980, year = {2004}, author = {Ekestern, E}, title = {Neurotrophic factors and amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {1}, number = {2-3}, pages = {88-100}, doi = {10.1159/000080049}, pmid = {16908980}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/pathology ; Nerve Growth Factors/biosynthesis/metabolism/*physiology ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {The cause of motor neuron death in amyotrophic lateral sclerosis (ALS) remains a mystery. Initial implications of neurotrophic factor impairment involved in disease progression causing selective motor neuron death were brought forward in the late 1980s. These implications were based on several in vitro studies of motor neuron cultures in which a near to complete rescue of axotomized neonatal motor neurons in the presence of supplementary neurotrophic factors were revealed. These findings pawed the way for extensive investigations in experimental animal models of ALS. Neurotrophic factor administration in rodent ALS models demonstrated a remarkable effect on survival of degenerating motor neurons and rescue of axotomized motor neurons, both in vivo and in vitro. In the absence of efficient therapy for ALS, some of these promising neurotrophic factors have been administered to groups of ALS patients, as they appeared available for clinical trials. Up to date, none of tested factors has lived up to expectations, altering the outcome of the disease. This review summarizes current findings on neurotrophic factor expression in ALS tissue and these factors' potential/debatable clinical relevance to ALS and the treatment of ALS. It also discusses possible interventions improving clinical trial design to obtain efficacy of neurotrophic factor treatment in patients suffering from ALS.}, }
@article {pmid16908975, year = {2004}, author = {Dupuis, L and Gonzalez de Aguilar, JL and Oudart, H and de Tapia, M and Barbeito, L and Loeffler, JP}, title = {Mitochondria in amyotrophic lateral sclerosis: a trigger and a target.}, journal = {Neuro-degenerative diseases}, volume = {1}, number = {6}, pages = {245-254}, doi = {10.1159/000085063}, pmid = {16908975}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism/physiopathology ; Animals ; Cell Death/genetics ; Cell Respiration/genetics ; Humans ; Mitochondria/*enzymology/pathology ; Mitochondrial Diseases/*complications/*metabolism/physiopathology ; Motor Neurons/*enzymology/pathology ; Muscle, Skeletal/enzymology/physiopathology ; Oxidative Stress/genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Strong evidence shows that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. Morphological and functional abnormalities occur in mitochondria in ALS patients and related animal models, although their exact nature and extent are controversial. Recent studies postulate that the mislocalization in mitochondria of mutant forms of copper-zinc superoxide dismutase (SOD1), the only well-documented cause of familial ALS, may account for the toxic gain of function of the enzyme, and hence induce motor neuron death. On the other hand, mitochondrial dysfunction in ALS does not seem to be restricted only to motor neurons as it is also present in other tissues, particularly the skeletal muscle. The presence of this 'systemic' defect in energy metabolism associated with the disease is supported in skeletal muscle tissue by impaired mitochondrial respiration and overexpression of uncoupling protein 3. In addition, the lifespan of transgenic mutant SOD1 mice is increased by a highly energetic diet compensating both the metabolic defect and the motorneuronal function. In this review, we will focus on the mitochondrial dysfunction linked to ALS and the cause-and-effect relationships between mitochondria and the pathological mechanisms thought to be involved in the disease.}, }
@article {pmid16908969, year = {2004}, author = {Kermer, P and Liman, J and Weishaupt, JH and Bähr, M}, title = {Neuronal apoptosis in neurodegenerative diseases: from basic research to clinical application.}, journal = {Neuro-degenerative diseases}, volume = {1}, number = {1}, pages = {9-19}, doi = {10.1159/000076665}, pmid = {16908969}, issn = {1660-2854}, mesh = {Animals ; Apoptosis/*physiology ; *Biomedical Research ; Humans ; Neurodegenerative Diseases/*pathology ; Neurons/*pathology ; Signal Transduction/*physiology ; }, abstract = {In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's and Lou-Gehrig's disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.}, }
@article {pmid16903584, year = {2006}, author = {Ganzini, L}, title = {Artificial nutrition and hydration at the end of life: ethics and evidence.}, journal = {Palliative &amp; supportive care}, volume = {4}, number = {2}, pages = {135-143}, doi = {10.1017/s1478951506060196}, pmid = {16903584}, issn = {1478-9515}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Gastrostomy/*ethics ; Humans ; Neoplasms/therapy ; Nutritional Support/*ethics ; Palliative Care/*ethics ; Withholding Treatment/*ethics ; }, abstract = {The case of Terri Schiavo resulted in substantial media attention about the use of artificial nutrition and hydration (ANH) especially by percutaneous endoscopic gastrostomy (PEG). In this article, I review ethical and legal principles governing decisions to choose or forgo ANH at the end of life, including issues of autonomy and decision-making capacity, similarities and differences between ANH and other medical treatments, the role of proxies when patients lack decision-making capacity, and the equivalence of withholding and withdrawing treatment. Evidence for palliative or life-sustaining benefits for ANH are reviewed in three disease processes: amyotrophic lateral sclerosis (ALS), cancer, and dementias, including Alzheimer's disease. Although more recent studies suggest a possible palliative role for ANH in ALS and terminal cancer, feeding tubes do not appear to prolong survival or increase comfort in advanced dementia of the Alzheimer's type.}, }
@article {pmid16898257, year = {2006}, author = {Franssen, H and van den Bergh, PY}, title = {Nerve conduction studies in polyneuropathy: practical physiology and patterns of abnormality.}, journal = {Acta neurologica Belgica}, volume = {106}, number = {2}, pages = {73-81}, pmid = {16898257}, issn = {0300-9009}, mesh = {Adult ; Animals ; Demyelinating Diseases/diagnosis/physiopathology ; Electrodiagnosis/*methods ; Female ; Humans ; Neural Conduction/*physiology ; Polyneuropathies/*diagnosis/*physiopathology ; }, abstract = {Nerve conduction studies are an essential part of the work-up of peripheral neuropathies. Many neuropathic syndromes can be suspected on clinical grounds, but optimal use of nerve conduction study techniques (in combination with needle electromyography) allows diagnostic classification and is therefore crucial to understanding and separation of neuropathies. Multifocal motor neuropathy, for example, may clinically present as ALS. Detection of evidence of demyelination (conduction blocks) leads to the correct diagnosis and to proper treatment. Nerve conduction studies provide essential information on (1) the spatial pattern of neuropathy, (2) the pattern of abnormalities distinguishing between primarily axonal and demyelinating pathology, and (3) the severity of neuropathic damage. This information is very comprehensive since many nerves and long segments of individual nerves can be sampled. Moreover the information is extremely detailed to the extent that the cellular pathology of a patient's neuropathy is usually defined best by physiological testing rather than by biopsy. Neuropathies can be generalized, focal, or multifocal; they can be symmetric or asymmetric; they can be distally predominant or proximal and distal. Primarily axonal neuropathies mainly affect sensory nerve and compound muscle action potential amplitudes, whereas demyelinating neuropathies lead to slowing of nerve conductions, and to increased temporal dispersion or conduction block. Usually, the pattern of demyelination allows to distinguish hereditary (uniform demyelination) from acquired (segmental demyelination) neuropathies. Electrodiagnostic criteria for primary demyelination are helpful to identify acquired demyelinating neuropathies.}, }
@article {pmid16893129, year = {2006}, author = {Mitsumoto, H and Floyd, A and Tang, MX and Kaufmann, P and Battista, V and Hristova, A and Pullman, SL}, title = {Transcranial magnetic stimulation for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS).}, journal = {Supplements to Clinical neurophysiology}, volume = {59}, number = {}, pages = {327-332}, doi = {10.1016/s1567-424x(09)70048-0}, pmid = {16893129}, issn = {1567-424X}, support = {NS41672-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Humans ; Motor Neurons/*physiology ; *Transcranial Magnetic Stimulation ; }, }
@article {pmid16883679, year = {2006}, author = {Menendez, A and Kuffler, D}, title = {Are there causal relationships between the development of the inflammatory diseases amyotrophic lateral sclerosis and asthma?.}, journal = {Puerto Rico health sciences journal}, volume = {25}, number = {1}, pages = {51-66}, pmid = {16883679}, issn = {0738-0658}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/immunology ; Asthma/*etiology/immunology ; Humans ; Inflammation/complications ; Nerve Growth Factors/physiology ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and asthma are inflammatory diseases. ALS is a fatal progressive, neurodegenerative disease with inflammation around the upper and lower motor neurons leading to their degeneration, muscle atrophy, paralysis, and death. Asthma is a chronic inflammatory disease with reversible airway obstruction and nonspecific airway hyper-reactivity. The local release of sensory neuropeptides from capsaicin-sensitive primary afferents causes motor neuron pathophysiology and airway inflammation and hyper-reactivity. While there is no cure for ALS, asthma is managed according to its symptoms and severity, to decrease the symptoms, improve pulmonary function, and reduce morbidity. To determine whether understanding asthma may provide insights into how to clinically deal with ALS, the authors examined the etiologies of ALS and asthma, and the factors that exacerbate the symptoms. Although no direct correlations were found, the similar multifactorial triggers, and the critical roles of neuronal inflammation, suggest that one or more exists.}, }
@article {pmid16879837, year = {2007}, author = {Fishel, ML and Vasko, MR and Kelley, MR}, title = {DNA repair in neurons: so if they don't divide what's to repair?.}, journal = {Mutation research}, volume = {614}, number = {1-2}, pages = {24-36}, doi = {10.1016/j.mrfmmm.2006.06.007}, pmid = {16879837}, issn = {0027-5107}, support = {CA094025/CA/NCI NIH HHS/United States ; CA106298/CA/NCI NIH HHS/United States ; ES03456/ES/NIEHS NIH HHS/United States ; NS048565/NS/NINDS NIH HHS/United States ; P30 CA82709/CA/NCI NIH HHS/United States ; }, mesh = {Aging/metabolism/pathology ; Animals ; Antineoplastic Agents/adverse effects ; Brain/metabolism/pathology ; Cell Nucleus/metabolism ; Cell Proliferation ; DNA Damage ; *DNA Repair ; Humans ; Mitochondria/metabolism ; Models, Neurological ; Neurons/cytology/drug effects/*metabolism/radiation effects ; Oxidative Stress ; }, abstract = {Neuronal DNA repair remains one of the most exciting areas for investigation, particularly as a means to compare the DNA repair response in mitotic (cancer) vs. post-mitotic (neuronal) cells. In addition, the role of DNA repair in neuronal cell survival and response to aging and environmental insults is of particular interest. DNA damage caused by reactive oxygen species (ROS) such as generated by mitochondrial respiration includes altered bases, abasic sites, and single- and double-strand breaks which can be prevented by the DNA base excision repair (BER) pathway. Oxidative stress accumulates in the DNA of the human brain over time especially in the mitochondrial DNA (mtDNA) and is proposed to play a critical role in aging and in the pathogenesis of several neurological disorders including Parkinson's disease, ALS, and Alzheimer's diseases. Because DNA damage accumulates in the mtDNA more than nuclear DNA, there is increased interest in DNA repair pathways and the consequence of DNA damage in the mitochondria of neurons. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the BER pathway. Following the notion that the bulk of neuronal DNA damage is acquired by oxidative DNA damage and ROS, the BER pathway is a likely area of focus for neuronal studies of DNA repair. BER variations in brain aging and pathology in various brain regions and tissues are presented. Therefore, the BER pathway is discussed in greater detail in this review than other repair pathways. Other repair pathways including direct reversal, nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination and non-homologous end joining are also discussed. Finally, there is a growing interest in the role that DNA repair pathways play in the clinical arena as they relate to the neurotoxicity and neuropathy associated with cancer treatments. Among the numerous side effects of cancer treatments, major clinical effects include neurocognitive dysfunction and peripheral neuropathy. These symptoms occur frequently and have not been effectively studied at the cellular or molecular level. Studies of DNA repair may help our understanding of how those cells that are not dividing could succumb to neurotoxicity with the clinical manifestations discussed in the following article.}, }
@article {pmid16878402, year = {2006}, author = {Moreno-López, B and González-Forero, D}, title = {Nitric oxide and synaptic dynamics in the adult brain: physiopathological aspects.}, journal = {Reviews in the neurosciences}, volume = {17}, number = {3}, pages = {309-357}, doi = {10.1515/revneuro.2006.17.3.309}, pmid = {16878402}, issn = {0334-1763}, mesh = {Animals ; Brain/*enzymology/*physiopathology ; Humans ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/enzymology/physiopathology ; Nitric Oxide/*metabolism ; *Nonlinear Dynamics ; Synapses/*physiology ; }, abstract = {The adult brain retains the capacity to rewire mature neural circuits in response to environmental changes, brain damage or sensory and motor experiences. Two plastic processes, synaptic remodeling and neurogenesis, have been the subject of numerous studies due to their involvement in the maturation of the nervous system, their prevalence and re-activation in adulthood, and therapeutic relevance. However, most of the research looking for the mechanistic and molecular events underlying synaptogenic phenomena has been focused on the extensive synaptic reorganization occurring in the developing brain. In this stage, a vast number of synapses are initially established, which subsequently undergo a process of activity-dependent refinement guided by target-derived signals that act as synaptotoxins or synaptotrophins, promoting either loss or consolidation of pre-existing synaptic contacts, respectively. Nitric oxide (NO), an autocrine and/or paracrine-acting gaseous molecule synthesized in an activity-dependent manner, has ambivalent actions. It can act by mediating synapse formation, segregation of afferent inputs, or growth cone collapse and retraction in immature neural systems. Nevertheless, little information exists about the role of this ambiguous molecule in synaptic plasticity processes occurring in the adult brain. Suitable conditions for elucidating the role of NO in adult synaptic rearrangement include physiopathological conditions, such as peripheral nerve injury. We have recently developed a crush lesion model of the XIIth nerve that induces a pronounced stripping of excitatory synaptic boutons from the cell bodies of hypoglossal motoneurons. The decline in synaptic coverage was concomitant with de novo expression of the neuronal isoform of NO synthase in motoneurons. We have demonstrated a synaptotoxic action of NO mediating synaptic withdrawal and preventing synapse formation by cyclic GMP (cGMP)-dependent and, probably, S-nitrosylation-mediated mechanisms, respectively. This action possibly involves the participation of other signaling molecules working together with NO. Brain-derived neurotrophic factor (BDNF), a target-derived synaptotrophin synthesized and released postsynaptically in an activity-dependent form, is a potential candidate for effecting such a concerted action. Several items of evidence support an interrelationship between NO and BDNF in the regulation of synaptic remodeling processes in adulthood: i) BDNF and its receptor TrkB are expressed by motoneurons and upregulated by axonal injury; ii) they promote axon arborization and synaptic formation, and modulate the structural dynamics of excitatory synapses; iii) NO and BDNF each control the production and activity of the other at the level of individual synapses; iv) the NO/cGMP pathway inhibits BDNF secretion; and finally, v) BDNF protects F-actin from depolymerization by NO, thus preventing the collapsing and retracting effects of NO on growth cones. Therefore, we propose a mechanism of action in which the NO/BDNF ratio regulates synapse dynamics after peripheral nerve lesion. This hypothesis also raises the possibility that variations in this NO/BDNF balance constitute a common hallmark leading to synapse loss in the progression of diverse neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases.}, }
@article {pmid16876390, year = {2006}, author = {Kabashi, E and Durham, HD}, title = {Failure of protein quality control in amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1038-1050}, doi = {10.1016/j.bbadis.2006.06.006}, pmid = {16876390}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Humans ; Lumbar Vertebrae/metabolism ; Mice ; Mice, Transgenic ; Models, Biological ; Molecular Chaperones/physiology ; Neurons/*pathology ; Oxidative Stress ; Proteasome Endopeptidase Complex/chemistry/*physiology ; Protein Folding ; Signal Transduction ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Ubiquitin/chemistry/*physiology ; }, abstract = {The protein chaperoning and ubiquitin-proteasome systems perform many homeostatic functions within cells involving protein folding, transport and degradation. Of paramount importance is ridding cells of mutant or post-translationally modified proteins that otherwise tend to aggregate into insoluble complexes and form inclusions. Such inclusions are characteristic of many neurodegenerative diseases and implicate protein misfolding and aggregation as common aspects of pathogenesis. In the most common familial form of ALS, mutations in SOD1 promote misfolding of the protein and target it for degradation by proteasomes. Although proteasomes can degrade the mutant proteins efficiently, altered solubility and aggregation of mutant SOD1 are features of the disease and occur most prominently in the most vulnerable cells and tissues. Indeed, lumbar spinal cord of mutant SOD1 transgenic mice show early reduction in their capacity for protein chaperoning and proteasome-mediated hydrolysis of substrates, and motor neurons are particularly vulnerable to aggregation of mutant SOD1. A high threshold for upregulating key pathways in response to the stress of added substrate load may contribute to this vulnerability. The broad spectrum neuroprotective capability and efficacy of some chaperone-based therapies in preclinical models makes these pathways attractive as targets for therapy in ALS, as well as other neurodegenerative diseases. A better understanding of the mechanisms governing the regulation of protein chaperones and UPS components would facilitate development of treatments that upregulate these pathways in a coordinated manner in neural tissue without long term toxicity.}, }
@article {pmid16874665, year = {2006}, author = {Pérez-Navarro, E and Canals, JM and Ginés, S and Alberch, J}, title = {Cellular and molecular mechanisms involved in the selective vulnerability of striatal projection neurons in Huntington's disease.}, journal = {Histology and histopathology}, volume = {21}, number = {11}, pages = {1217-1232}, doi = {10.14670/HH-21.1217}, pmid = {16874665}, issn = {1699-5848}, mesh = {Animals ; Brain/metabolism/pathology ; Corpus Striatum/pathology ; Cytoplasm/metabolism ; Humans ; Huntingtin Protein ; Huntington Disease/*pathology ; Interneurons/*pathology ; Mitochondria/metabolism/pathology ; Models, Biological ; Mutation ; Nerve Degeneration/pathology ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/pathology ; Neurons/metabolism ; Nuclear Proteins/genetics ; }, abstract = {Neurodegenerative disorders affecting the central nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea (HD) and amyotrophic lateral sclerosis are characterized by the loss of selected neuronal populations. Another striking feature shared by these diseases is the deposition of proteinaceous inclusion bodies in the brain, which may be intracytoplasmatic or intranuclear, or even extracellular. However, the density and prevalence of aggregates are not always directly related to neurodegeneration. Although some of these diseases are the result of mutations in known proteins, with HD a clear example, the expression and location of the affected protein do not explain the selective neurodegeneration. Therefore, other intrinsic mechanisms, characteristic of each neuronal population, might be involved in the neurodegenerative process. In this review we focus on several proposed mechanisms such as excitotoxicity, mitochondrial dysfunction and altered expression of trophic factors, which could account for the pathogenesis of HD.}, }
@article {pmid16872810, year = {2006}, author = {Nayak, MS and Kim, YS and Goldman, M and Keirstead, HS and Kerr, DA}, title = {Cellular therapies in motor neuron diseases.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1128-1138}, doi = {10.1016/j.bbadis.2006.06.004}, pmid = {16872810}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Animals, Genetically Modified ; Cell Differentiation ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacokinetics ; Mice ; Models, Neurological ; Motor Neuron Disease/*therapy ; Motor Neurons/*physiology ; Rats ; Stem Cell Transplantation/legislation &amp; jurisprudence/*standards ; Stem Cells/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are prototypical motor neuron diseases that result in progressive weakness as a result of motor neuron dysfunction and death. Though much work has been done in both diseases to identify the cellular mechanisms of motor neuron dysfunction, once motor neurons have died, one of potential therapies to restore function would be through the use of cellular transplantation. In this review, we discuss potential strategies whereby cellular therapies, including the use of stem cells, neural progenitors and cells engineered to secrete trophic factors, may be used in motor neuron diseases. We review pre-clinical data in rodents with each of these approaches and discuss advances and regulatory issues regarding the use of cellular therapies in human motor neuron diseases.}, }
@article {pmid16869150, year = {2006}, author = {Cristini, J}, title = {Misdiagnosis and missed diagnoses in patients with ALS.}, journal = {JAAPA : official journal of the American Academy of Physician Assistants}, volume = {19}, number = {7}, pages = {29-35}, pmid = {16869150}, issn = {1547-1896}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy ; Baclofen/therapeutic use ; *Diagnostic Errors ; Early Diagnosis ; Education, Medical, Continuing ; Humans ; Lorazepam/therapeutic use ; Riluzole/therapeutic use ; }, }
@article {pmid16867200, year = {2006}, author = {Hess, DR}, title = {Noninvasive ventilation in neuromuscular disease: equipment and application.}, journal = {Respiratory care}, volume = {51}, number = {8}, pages = {896-911; discussion 911-2}, pmid = {16867200}, issn = {0020-1324}, mesh = {Equipment Design ; Humans ; Masks ; Neuromuscular Diseases/*therapy ; Physical Therapy Modalities ; Positive-Pressure Respiration ; Respiration, Artificial/instrumentation ; Respiratory Insufficiency ; Respiratory Therapy ; Ventilators, Mechanical/classification/*standards ; }, abstract = {Noninvasive support of ventilation is commonly needed in patients with neuromuscular disease. Body ventilators, which are used rarely, function by applying intermittent negative pressure to the thorax or abdomen. More commonly, noninvasive positive-pressure ventilation (NPPV) is used. This therapy can be applied with a variety of interfaces, ventilators, and ventilator settings. The patient interface has a major impact on comfort during NPPV. The most commonly used interfaces are nasal masks and oronasal masks. Other interfaces include nasal pillows, total face masks, helmets, and mouthpieces. Theoretically, any ventilator can be attached to a mask rather than an artificial airway. Portable pressure ventilators (bi-level positive airway pressure) are available specifically to provide NPPV and are commonly used to provide this therapy. Selection of NPPV settings in patients with neuromuscular disease is often done empirically and is symptom-based. Selection of settings can also be based on the results of physiologic studies or sleep studies. The use of NPPV in this patient population is likely to expand, particularly with increasing evidence that it is life-prolonging in patients with diseases such as amyotrophic lateral sclerosis. Appropriate selection of equipment and settings for NPPV is paramount to the success of this therapy.}, }
@article {pmid16861147, year = {2006}, author = {Sandyk, R}, title = {Serotonergic mechanisms in amyotrophic lateral sclerosis.}, journal = {The International journal of neuroscience}, volume = {116}, number = {7}, pages = {775-826}, doi = {10.1080/00207450600754087}, pmid = {16861147}, issn = {0020-7454}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/pathology ; Animals ; Glutamic Acid/metabolism ; Humans ; Motor Activity/drug effects/physiology ; Neurons/metabolism ; Serotonin/*metabolism/*therapeutic use ; Sleep, REM/drug effects/physiology ; }, abstract = {Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.}, }
@article {pmid16856151, year = {2006}, author = {Bogaert, E and Van Damme, P and Van Den Bosch, L and Robberecht, W}, title = {Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases.}, journal = {Muscle &amp; nerve}, volume = {34}, number = {4}, pages = {391-405}, doi = {10.1002/mus.20609}, pmid = {16856151}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*physiopathology ; Animals ; Central Nervous System Diseases/etiology/physiopathology ; Gene Expression Regulation ; Humans ; Motor Neurons/metabolism/pathology ; Neurodegenerative Diseases/etiology/*physiopathology ; Peripheral Nervous System Diseases/etiology/physiopathology ; Receptors, Vascular Endothelial Growth Factor/genetics/physiology ; Vascular Endothelial Growth Factor A/genetics/*physiology/therapeutic use ; }, abstract = {The angiogenic activity of vascular endothelial growth factor (VEGF) is well known. Recently, it has become evident that VEGF is involved in central nervous system physiology and may play a role in the pathogenesis of neurological diseases. In particular, it may be involved in the mechanism of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), and has been hypothesized to be implicated in the pathogenesis of peripheral neuropathies such as occur in the so-called POEMS syndrome and diabetes. VEGF is also being studied as a possible treatment option in some of these disorders. In this review we critically analyze the data supporting the notion that VEGF is a factor involved in motor neuron degeneration and review the studies linking VEGF to other diseases of the peripheral and central nervous systems.}, }
@article {pmid16840705, year = {2006}, author = {Ly, CV and Verstreken, P}, title = {Mitochondria at the synapse.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {12}, number = {4}, pages = {291-299}, doi = {10.1177/1073858406287661}, pmid = {16840705}, issn = {1073-8584}, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; Calcium/metabolism ; Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/physiopathology ; Neurons/metabolism ; Neurotransmitter Agents/metabolism ; Synapses/*physiology ; Synaptic Transmission/physiology ; }, abstract = {Synapses are packed with mitochondria, complex organelles with roles in energy metabolism, cell signaling, and calcium homeostasis. However, the precise mechanisms by which mitochondria influence neurotrans mission remain undefined. In this review, the authors discuss pharmacological and genetic analyses of synaptic mitochondrial function, focusing on their role in Ca2+ buffering and ATP production. Additionally, they will summarize recent data that implicate synaptic mitochondria in the regulation of neurotransmitter release during intense neuronal activity and link these findings to the pathogenesis of neurodegenerative diseases that feature disrupted synaptic mitochondria, including amyotrophic lateral sclerosis and hereditary spastic paraplegia.}, }
@article {pmid16837237, year = {2006}, author = {Filler, SG}, title = {Candida-host cell receptor-ligand interactions.}, journal = {Current opinion in microbiology}, volume = {9}, number = {4}, pages = {333-339}, doi = {10.1016/j.mib.2006.06.005}, pmid = {16837237}, issn = {1369-5274}, support = {DE017088/DE/NIDCR NIH HHS/United States ; R01AI054928/AI/NIAID NIH HHS/United States ; R01DE013974/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; Candida/*pathogenicity ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/physiology ; Ligands ; Macrophages/physiology ; Receptors, Cell Surface/*physiology ; Signal Transduction ; Toll-Like Receptor 2/physiology ; Toll-Like Receptor 4/physiology ; Virulence ; }, abstract = {The interaction of Candida species with their cognate host receptors is a key factor in the pathogenesis of different types of candidiasis. The recognition of different forms of Candida albicans by Toll-like receptors 2 and 4 on mononuclear leukocytes has recently been discovered to determine the function and activity of regulatory T-cells, determine the balance of Type 1 and Type 2 cytokines and, thereby, influence the antifungal activity of both the innate and adaptive immune response. Different forms of C. albicans are also recognized by different lectins that are expressed on the surface macrophages. C. albicans and Candida glabrata express the ALS (agglutinin-like sequence) and EPA (epithelial adhesin) families of adhesins, respectively. A key difference between C. glabrata and C. albicans is that EPA expression in C. glabrata is governed by sub-telomeric silencing, whereas ALS expression in C. albicans is regulated by other mechanisms.}, }
@article {pmid16832072, year = {2006}, author = {Traynor, BJ and Bruijn, L and Conwit, R and Beal, F and O'Neill, G and Fagan, SC and Cudkowicz, ME}, title = {Neuroprotective agents for clinical trials in ALS: a systematic assessment.}, journal = {Neurology}, volume = {67}, number = {1}, pages = {20-27}, doi = {10.1212/01.wnl.0000223353.34006.54}, pmid = {16832072}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*methods ; Evaluation Studies as Topic ; Humans ; Neuroprotective Agents/*therapeutic use ; *Outcome Assessment, Health Care ; }, abstract = {BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest.<br><br>OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug.<br><br>METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation.<br><br>RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered.<br><br>CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.}, }
@article {pmid16828895, year = {2006}, author = {Culotta, VC and Yang, M and O'Halloran, TV}, title = {Activation of superoxide dismutases: putting the metal to the pedal.}, journal = {Biochimica et biophysica acta}, volume = {1763}, number = {7}, pages = {747-758}, pmid = {16828895}, issn = {0006-3002}, support = {R01 GM054111/GM/NIGMS NIH HHS/United States ; }, mesh = {Enzyme Activation ; Iron/metabolism ; Oxidation-Reduction ; Protein Binding ; Protein Conformation ; Subcellular Fractions/enzymology ; Superoxide Dismutase/chemistry/*metabolism ; }, abstract = {Superoxide dismutases (SOD) are important anti-oxidant enzymes that guard against superoxide toxicity. Various SOD enzymes have been characterized that employ either a copper, manganese, iron or nickel co-factor to carry out the disproportionation of superoxide. This review focuses on the copper and manganese forms, with particular emphasis on how the metal is inserted in vivo into the active site of SOD. Copper and manganese SODs diverge greatly in sequence and also in the metal insertion process. The intracellular copper SODs of eukaryotes (SOD1) can obtain copper post-translationally, by way of interactions with the CCS copper chaperone. CCS also oxidizes an intrasubunit disulfide in SOD1. Adventitious oxidation of the disulfide can lead to gross misfolding of immature forms of SOD1, particularly with SOD1 mutants linked to amyotrophic lateral sclerosis. In the case of mitochondrial MnSOD of eukaryotes (SOD2), metal insertion cannot occur post-translationally, but requires new synthesis and mitochondrial import of the SOD2 polypeptide. SOD2 can also bind iron in vivo, but is inactive with iron. Such metal ion mis-incorporation with SOD2 can become prevalent upon disruption of mitochondrial metal homeostasis. Accurate and regulated metallation of copper and manganese SOD molecules is vital to cell survival in an oxygenated environment.}, }
@article {pmid16815477, year = {2006}, author = {Sah, DW}, title = {Therapeutic potential of RNA interference for neurological disorders.}, journal = {Life sciences}, volume = {79}, number = {19}, pages = {1773-1780}, doi = {10.1016/j.lfs.2006.06.011}, pmid = {16815477}, issn = {0024-3205}, mesh = {Animals ; *Genetic Therapy ; Humans ; Nervous System Diseases/genetics/*therapy ; *RNA Interference ; RNA, Small Interfering/administration &amp; dosage/genetics/therapeutic use ; }, abstract = {During the past decade, numerous molecular mediators of neurodegenerative diseases and neurological disorders have been identified and validated, yet few novel therapies have emerged and the unmet medical needs remain high. These molecular mediators belong to target classes such as ion channels, neurotransmitters and neurotransmitter receptors, cytokines, growth factors, enzymes and other proteins. In some cases, substantial pre-clinical validation exists, but the molecular target has not been readily druggable with small molecules, proteins or antibodies. RNA interference represents a therapeutic approach applicable to such non-druggable targets. Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma. These proof-of-concept data in animal models, together with the commencement of clinical trials using RNA interference for macular degeneration and respiratory syncytial virus infection, point to the potential of direct RNA interference for neurological disorders and neurodegenerative diseases.}, }
@article {pmid16814528, year = {2006}, author = {Rakhit, R and Chakrabartty, A}, title = {Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1025-1037}, doi = {10.1016/j.bbadis.2006.05.004}, pmid = {16814528}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Binding Sites ; Drug Delivery Systems ; Humans ; Mice ; Mice, Transgenic ; Models, Molecular ; Mutation ; Oxidation-Reduction ; Protein Folding ; Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Superoxide Dismutase/*chemistry/genetics/metabolism/physiology ; Superoxide Dismutase-1 ; }, abstract = {Fourteen years after the discovery that mutations in Cu, Zn superoxide dismutase (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS), the mechanism by which mutant SOD1 exerts toxicity remains unknown. The two principle hypotheses are (a) oxidative damage stemming from aberrant SOD1 redox chemistry, and (b) misfolding of the mutant protein. Here we review the structure and function of wild-type SOD1, as well as the changes to the structure and function in mutant SOD1. The relative merits of the two hypotheses are compared and a common unifying principle is outlined. Lastly, the potential for therapies targeting SOD1 misfolding is discussed.}, }
@article {pmid16806844, year = {2006}, author = {Van Den Bosch, L and Van Damme, P and Bogaert, E and Robberecht, W}, title = {The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1068-1082}, doi = {10.1016/j.bbadis.2006.05.002}, pmid = {16806844}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism ; Animals ; *Calcium Signaling ; Humans ; Mice ; Mice, Transgenic ; *Models, Neurological ; Motor Neurons/*drug effects ; Nerve Degeneration ; Receptors, Neurotransmitter/metabolism ; }, abstract = {Unfortunately and despite all efforts, amyotrophic lateral sclerosis (ALS) remains an incurable neurodegenerative disorder characterized by the progressive and selective death of motor neurons. The cause of this process is mostly unknown, but evidence is available that excitotoxicity plays an important role. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS. The most important one is that the only drug proven to slow the disease process in humans, riluzole, has anti-excitotoxic properties. Moreover, consumption of excitotoxins can give rise to selective motor neuron death, indicating that motor neurons are extremely sensitive to excessive stimulation of glutamate receptors. We will summarize the intrinsic properties of motor neurons that could render these cells particularly sensitive to excitotoxicity. Most of these characteristics relate to the way motor neurons handle Ca(2+), as they combine two exceptional characteristics: a low Ca(2+)-buffering capacity and a high number of Ca(2+)-permeable AMPA receptors. These properties most likely are essential to perform their normal function, but under pathological conditions they could become responsible for the selective death of motor neurons. In order to achieve this worst-case scenario, additional factors/mechanisms could be required. In 1 to 2% of the ALS patients, mutations in the SOD1 gene could shift the balance from normal motor neuron excitation to excitotoxicity by decreasing glutamate uptake in the surrounding astrocytes and/or by interfering with mitochondrial function. We will discuss point by point these different pathogenic mechanisms that could give rise to classical and/or slow excitotoxicity leading to selective motor neuron death.}, }
@article {pmid16806843, year = {2006}, author = {Azzouz, M}, title = {Gene Therapy for ALS: progress and prospects.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1122-1127}, doi = {10.1016/j.bbadis.2006.05.003}, pmid = {16806843}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Disease Models, Animal ; Gene Transfer Techniques ; *Genetic Therapy ; *Genetic Vectors ; Humans ; Lentivirus/*genetics ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; RNA Interference ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease for which there are no effective drug treatments to date. Recent advances in Gene Therapy open up the possibility of developing an effective treatment aiming at halting or delaying the degeneration of motor neurons. Viral vectors such as lentiviral vectors and adeno-associated virus can transfer genes into many different types of primary neurons from a broad range of species including man and the resulting gene expression is long-term. Numerous animal studies have now been undertaken with these vectors and correction of disease models has been obtained. These vectors have been refined to a very high level and can be produced safely for the clinic. However, we believe that there are some major issues that need to be addressed in order to see a Gene Therapy approach with viral vectors proceed to the clinic for ALS patients. This review will describe the general features of lentiviral vectors. It will then describe some key examples of gene transfer and genetic correction in animal models of motor neuron disease. The prospects for the clinical evaluation of lentiviral vectors for the treatment of human motor neuron disease will be outlined.}, }
@article {pmid16805775, year = {2006}, author = {Kwong, JQ and Beal, MF and Manfredi, G}, title = {The role of mitochondria in inherited neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {97}, number = {6}, pages = {1659-1675}, doi = {10.1111/j.1471-4159.2006.03990.x}, pmid = {16805775}, issn = {0022-3042}, support = {P01 NS011766-27/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Heredodegenerative Disorders, Nervous System/*pathology/*physiopathology ; Humans ; Mitochondria/*physiology ; }, abstract = {In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential 'lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be 'secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases.}, }
@article {pmid16805772, year = {2006}, author = {Chen, HS and Lipton, SA}, title = {The chemical biology of clinically tolerated NMDA receptor antagonists.}, journal = {Journal of neurochemistry}, volume = {97}, number = {6}, pages = {1611-1626}, doi = {10.1111/j.1471-4159.2006.03991.x}, pmid = {16805772}, issn = {0022-3042}, support = {P01 HD29587/HD/NICHD NIH HHS/United States ; R01 EY09024/EY/NEI NIH HHS/United States ; R01 EY50477/EY/NEI NIH HHS/United States ; }, mesh = {Apoptosis/drug effects ; Excitatory Amino Acid Antagonists/*therapeutic use ; Ion Channel Gating/drug effects ; Models, Biological ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Neurotoxins/toxicity ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/*physiology ; }, abstract = {Most neuroprotective drugs have failed in clinical trials because of side-effects, causing normal brain function to become compromised. A case in point concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids, such as glutamate itself, is thought to contribute to neuronal damage in many neurological disorders ranging from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurological diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist (NMDA) or co-agonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side-effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, even although effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block with the property of uncompetitive antagonism is the most appealing strategy for therapeutic intervention during excessive NMDAR activation as this action of blockade requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiological neurotransmission. Utilizing this molecular strategy of action, we review here the logical process that we applied over the past decade to help develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderate-to-severe Alzheimer's disease while being well tolerated. Memantine is also currently in trials for additional neurological disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. Additionally, taking advantage of memantine's preferential binding to open channels and the fact that excessive NMDAR activity can be down-regulated by S-nitrosylation, we have recently developed combinatorial drugs called NitroMemantines. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs in order to avoid systemic side-effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies appear to have even greater neuroprotective properties than memantine.}, }
@article {pmid16805430, year = {2006}, author = {Jeanneteau, F and Chao, MV}, title = {Promoting neurotrophic effects by GPCR ligands.}, journal = {Novartis Foundation symposium}, volume = {276}, number = {}, pages = {181-9; discussion 189-92, 233-7, 275-81}, pmid = {16805430}, issn = {1528-2511}, mesh = {Adenosine/metabolism ; Enzyme Activation ; ErbB Receptors/metabolism ; Humans ; *Ligands ; Nerve Growth Factors/*metabolism/therapeutic use ; Neurons/metabolism ; Receptor, trkA/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Signal Transduction/physiology ; Transcriptional Activation ; }, abstract = {The neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3 and NT-4-represent a family of proteins essential for neuronal survival and plasticity. Each neurotrophin can signal through two different transmembrane receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, the first member of the TNF receptor superfamily. Neurotrophic factors play an important role in neurodegenerative diseases, as well as neuropsychiatric disorders such as depression, bipolar disease and eating disorders. Indeed, a number of approaches have been taken to use neurotrophins to treat Alzheimer's dementia, amyotrophic lateral sclerosis and peripheral sensory neuropathy. However, many of these clinical trails have failed, due to problems in delivery and unforeseen side effects of neurotrophic factors. An alternative approach is to use ligands in the G protein-coupled receptor (GPCR) family to transactivate trophic activities. We have discovered that treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors, is capable of activating Trk tyrosine kinase receptors. Transactivation of neurotrophic receptors by GPCR ligands raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases. This approach would allow for selective targeting of neurons that express specific G protein-coupled receptors and trophic factor receptors. GPCRs transduce information provided by extracellular signals to modulate synaptic activity and neurotransmission. In addition to the classical G protein signalling, GPCR ligands also activate receptor tyrosine kinases (RTK), including neurotrophin receptors. Activation of Trk neurotrophin receptors can occur by GPCR ligands in the absence of neurotrophins. Adenosine and PACAP (pituitary adenylate cyclase activating polypeptide) induce Trk activation specifically through their respective GPCRs to promote cell survival. Transactivation of Trks by GPCRs has emerged as a new theme in the biology of neurotrophin function. Although the precise role of transactivation is unknown, one possibility is that it adds a safety factor that might protect neurons from death in the absence of neurotrophins. Abnormal activity of the neurotrophin system has been implicated in several psychiatric and neurobiological illnesses. However, the lack of knowledge about the precise site of neurotrophin dysfunction has compromised the ability to improve the efficacy and the safety of drugs used in treatment modalities. If small-molecule GPCR ligands can ameliorate neuronal cell loss through Trk, transactivation may offer a new strategy for promoting trophic effects during neurodegeneration.}, }
@article {pmid16802724, year = {2006}, author = {Thomas, AG and Wozniak, KM and Tsukamoto, T and Calvin, D and Wu, Y and Rojas, C and Vornov, J and Slusher, BS}, title = {Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy.}, journal = {Advances in experimental medicine and biology}, volume = {576}, number = {}, pages = {327-37; discussion 361-3}, doi = {10.1007/0-387-30172-0_24}, pmid = {16802724}, issn = {0065-2598}, mesh = {Analgesics/chemistry/metabolism ; Animals ; Aspartic Acid/analogs &amp; derivatives/chemistry/metabolism ; Dipeptides/chemistry/metabolism ; Glutamate Carboxypeptidase II/*antagonists &amp; inhibitors/genetics/*metabolism ; Glutamic Acid/chemistry/metabolism ; Humans ; Molecular Structure ; Neurons/metabolism/pathology ; Neuroprotective Agents/chemistry/metabolism ; Organophosphorus Compounds/chemistry/metabolism ; }, abstract = {GCP II inhibition decreases extracellular excitotoxic glutamate and increases extracellular NAAG, both of which provide neuroprotection. We have demonstrated with our potent and selective GCP II inhibitors efficacy in models of stroke, ALS and neuropathic pain. GCP II inhibition may have significant potential benefits over existing glutamate-based neuroprotection strategies. The upstream mechanism seems selective for excitotoxic induced glutamate release, as GCP II inhibitors in normal animals induced no change in basal glutamate. This suggestion has recently been corroborated by Lieberman and coworkers24 who found that both NAAG release and increase in GCP II activity appear to be induced by electrical stimulation in crayfish nerve fibers and that subsequent NAAG hydrolysis to glutamate contributes, at least in part, to subsequent NMDA receptor activation. Interestingly, even at relatively high doses of compounds, GCP II inhibition did not appear to be associated with learning/memory deficits in animals. Additionally, quantitative neurophysiological testing data and visual analog scales for 'psychedelic effects' in Phase I single dose and repeat dose studies showed GCP II inhibition to be safe and well tolerated by both healthy volunteers and diabetic patients. GCP II inhibition may represent a novel glutamate regulating strategy devoid of the side effects that have hampered the development of postsynaptic glutamate receptor antagonists.}, }
@article {pmid16802719, year = {2006}, author = {Kalra, S and Arnold, DL}, title = {Magnetic resonance spectroscopy for monitoring neuronal integrity in amyotrophic lateral sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {576}, number = {}, pages = {275-82; discussion 361-3}, doi = {10.1007/0-387-30172-0_19}, pmid = {16802719}, issn = {0065-2598}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Animals ; Humans ; Magnetic Resonance Spectroscopy ; Neurons/cytology/*metabolism ; }, }
@article {pmid16787273, year = {2006}, author = {Bonanno, G and Raiteri, L and Paluzzi, S and Zappettini, S and Usai, C and Raiteri, M}, title = {Co-existence of GABA and Glu transporters in the central nervous system.}, journal = {Current topics in medicinal chemistry}, volume = {6}, number = {10}, pages = {979-988}, doi = {10.2174/156802606777323746}, pmid = {16787273}, issn = {1568-0266}, mesh = {Amino Acid Transport System X-AG/*metabolism ; Animals ; Central Nervous System/*metabolism ; GABA Plasma Membrane Transport Proteins/*metabolism ; Humans ; Neurotransmitter Agents/metabolism ; Synaptosomes/metabolism ; }, abstract = {Co-localization of transporters able to recapture the released or endogenously synthesized transmitter (homotransporters) and of transporters that can selectively take up transmitters/modulators originating from neighbouring structures (heterotransporters) has been demonstrated to occur within the same axon terminal of several neuronal phenotypes. Activation of terminal heterotransporters invariably leads to the release of the transmitter specific to the terminal. Heterotransporters are also increasingly reported to exist on neuronal soma/dendrites and nerve terminals, on the basis of morphological experiments. The functions of somatodendritic heterotransporters has been investigated only in a very limited number of cases. Release-regulating GABA heterotransporters of the GAT-1 type exist on Glu nerve terminals in different rodent brain regions including spinal cord. Activation of GABA heterotransporters provokes release of Glu, which takes place by reversal of the Glu homotransporter and by anion channel opening. Interestingly, the release of Glu induced by GABA in spinal cord is dramatically enhanced in a transgenic mouse model of amyotrophic lateral sclerosis and this effect seems to represent the most precocious mechanism that increases extracellular Glu concentration, reported to occur in the pathomechanism.}, }
@article {pmid16786226, year = {2006}, author = {Hallam, TM and Bourtchouladze, R}, title = {Rubinstein-Taybi syndrome: molecular findings and therapeutic approaches to improve cognitive dysfunction.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {63}, number = {15}, pages = {1725-1735}, doi = {10.1007/s00018-005-5555-8}, pmid = {16786226}, issn = {1420-682X}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; CREB-Binding Protein/genetics/*metabolism ; Chromosomes, Human, Pair 16 ; Cognition Disorders/drug therapy/*genetics/metabolism ; Cyclic AMP Response Element-Binding Protein/genetics/*metabolism ; Humans ; Huntington Disease/metabolism ; Mutation ; Phosphorylation ; Rubinstein-Taybi Syndrome/drug therapy/*genetics/metabolism ; }, abstract = {Rubinstein-Taybi syndrome (RTS) is a rare human genetic disorder characterized by mental retardation and physical abnormalities. Many RTS patients have a genetic mutation which has been mapped to chromosome 16p13.3, a genomic region encoding cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP). CBP is a transcriptional co-activator that binds to CREB when the latter is phosphorylated and promotes gene transcription. CREB-dependent gene transcription has been shown to underlie long-term memory formation. In this review we will focus on recent findings regarding the biology of CBP and its role in memory formation and cognitive dysfunction in RTS. We will also review the role of CBP in other neurological disorders, including Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Finally, we will discuss novel therapeutic approaches targeted to CBP/CREB function for treating the cognitive dysfunction of RTS and other neurological disorders.}, }
@article {pmid16785600, year = {2006}, author = {Członkowska, A and Ciesielska, A and Gromadzka, G and Kurkowska-Jastrzebska, I}, title = {Gender differences in neurological disease: role of estrogens and cytokines.}, journal = {Endocrine}, volume = {29}, number = {2}, pages = {243-256}, pmid = {16785600}, issn = {1355-008X}, mesh = {Animals ; Atherosclerosis/drug therapy ; Cytokines/metabolism/pharmacology ; Estrogens/metabolism/pharmacology ; Humans ; Nervous System Diseases/*physiopathology ; Prognosis ; *Sex Characteristics ; Stroke/mortality/pathology ; }, abstract = {Increasing evidence suggests that inflammatory response may be a critical component of different brain pathologies. However, the role played by this reaction is not fully understood. The present findings suggest that neuroinflammtory mediators such as cytokines may be involved in a number of key steps in the pathological cascade of events leading to neuronal injury. This hypothesis is strongly supported by experimental and clinical observations indicating that inhibition of the inflammatory reaction correlates with less neuronal damage. Estrogens are thought to play a role in the sex difference observed in many neurological diseases with inflammatory components including stroke, Alzheimer's and Parkinson's diseases, multiple sclerosis, or amyotrophic lateral sclerosis. Clinical and experimental studies have established estrogen as a neuroprotective hormone in these diseases. However, the exact mechanisms involved in the neuroprotective effects of estrogens are still unclear. It is possible that the beneficial effects of these hormones may be dependent on their inhibitory activity on the inflammatory reaction associated with the above-mentioned brain pathologies. Here, we review the current clinical and experimental evidence with respect to the inflammation-modulating effects of estrogens as one potential explanatory factor for sexual dimorzphism in the prevalence of numerous neurological diseases.}, }
@article {pmid16784838, year = {2006}, author = {Lambrechts, D and Carmeliet, P}, title = {VEGF at the neurovascular interface: therapeutic implications for motor neuron disease.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1109-1121}, doi = {10.1016/j.bbadis.2006.04.005}, pmid = {16784838}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Angiogenesis Inducing Agents/pharmacology ; Animals ; Central Nervous System/*blood supply ; Chromosomes, Human, X ; *Genetic Therapy ; Humans ; Immunophilins/genetics/physiology ; Lentivirus/genetics ; Mice ; Mice, Transgenic ; Models, Biological ; Motor Neuron Disease/genetics/metabolism/*therapy ; Motor Neurons/drug effects/physiology ; Muscular Atrophy, Spinal/therapy ; Ribonuclease, Pancreatic/genetics ; Vascular Endothelial Growth Factor A/genetics/*metabolism/therapeutic use ; }, abstract = {VEGF was discovered almost 25 years ago, and its angiogenic activity has been extensively studied ever since. Accumulating evidence indicates, however, that VEGF also has direct effects on neuronal cells. VEGF exerts neuroprotective effects on various cultured neurons of the central nervous system. In vivo, VEGF controls the correct migration of facial branchiomotor neurons in the developing hindbrain and stimulates the proliferation of neural stem cells in enriched environments and after cerebral ischemia. Transgenic mice expressing reduced levels of VEGF develop late-onset motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis (ALS), whereas reduced levels of VEGF have been implicated in a polyglutamine-induced model of motor neuron degeneration. Recent data further reveal that intracerebroventricular delivery of recombinant VEGF protein delays disease onset and prolongs survival of ALS rats, whereas intramuscular administration of a VEGF-expressing lentiviral vector increases the life expectancy of ALS mice by as much as 30%. Deciphering the precise role of VEGF at the neurovascular interface promises to uncover new insights into the development and pathology of the nervous system, helpful to design novel strategies to treat (motor) neurodegenerative disorders.}, }
@article {pmid16780988, year = {2006}, author = {Féasson, L and Camdessanché, JP and El Mandhi, L and Calmels, P and Millet, GY}, title = {Fatigue and neuromuscular diseases.}, journal = {Annales de readaptation et de medecine physique : revue scientifique de la Societe francaise de reeducation fonctionnelle de readaptation et de medecine physique}, volume = {49}, number = {6}, pages = {289-300, 375-84}, doi = {10.1016/j.annrmp.2006.04.015}, pmid = {16780988}, issn = {0168-6054}, mesh = {Fatigue/diagnosis/*etiology ; Humans ; Neuromuscular Diseases/*complications ; Surveys and Questionnaires ; }, abstract = {PURPOSE: To identify the role of fatigue, its evaluation and its causes in the pathophysiology context of acquired or hereditary neuromuscular diseases of the spinal anterior horn cell, peripheral nerve, neuromuscular junction and muscle.<br><br>MATERIAL AND METHODS: A literature review has been done on Medline with the following keywords: neuromuscular disease, peripheral neuropathy, myopathy, fatigue assessment, exercise intolerance, force assessment, fatigue scale and questionnaire, then with the terms: Fatigue Severity Scale, Chalder Fatigue Scale, Fatigue Questionnaire, Piper Fatigue Scale, electromyography and the combination of the word Fatigue with the following terms: Amyotrophic Lateral Sclerosis (ALS), Post-Polio Syndrome (PPS), Guillain-Barre Syndrome, Immune Neuropathy, Charcot-Marie-Tooth Disease, Myasthenia Gravis (MG), Metabolic Myopathy, Mitochondrial Myopathy, Muscular Dystrophy, Facioscapulohumeral Dystrophy, Myotonic Dystrophy.<br><br>RESULTS: Fatigue is a symptom very frequently reported by patients. Fatigue is mainly evaluated by strength loss after an exercise, by change in electromyographic activity during a given exercise and by questionnaires that takes into account the subjective (psychological) part of fatigue. Due to the large diversity of motor disorders, there are multiple clinical expressions of fatigue that differ in their presentation, consequences and therapeutic approach.<br><br>CONCLUSION: This review shows that fatigue has to be taken into account in patients with neuromuscular diseases. In this context, pathophysiology of fatigue often implies the motor component but the disease evolution and the physical obligates of daily life also induce an important psychological component.}, }
@article {pmid16771675, year = {2006}, author = {Furukawa, Y and O'Halloran, TV}, title = {Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyotrophic lateral sclerosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {8}, number = {5-6}, pages = {847-867}, pmid = {16771675}, issn = {1523-0864}, support = {R01 GM054111/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Dimerization ; Disulfides/metabolism ; Enzyme Activation ; Humans ; Molecular Chaperones/metabolism ; Molecular Sequence Data ; *Mutation ; Oxidation-Reduction ; Protein Conformation ; *Protein Processing, Post-Translational ; *Superoxide Dismutase/chemistry/genetics/metabolism ; Zinc/metabolism ; }, abstract = {Activation of the enzyme Cu,Zn-superoxide dismutase (SOD1) involves several posttranslational modifications including copper and zinc binding, as well as formation of the intramolecular disulfide bond. The copper chaperone for SOD1, CCS, is responsible for intracellular copper loading in SOD1 under most physiological conditions. Recent in vitro and in vivo assays reveal that CCS not only delivers copper to SOD1 under stringent copper limitation, but it also facilitates the stepwise conversion of the disulfide-reduced immature SOD1 to the active disulfide-containing enzyme. The two new functions attributed to CCS, (i.e., O(2)-dependent sulfhydryl oxidase- and disulfide isomerase-like activities) indicate that this protein has attributes of the larger class of molecular chaperones. The CCS-dependent activation of SOD1 is dependent upon oxygen availability, suggesting that the cell only loads copper and activates this enzyme when O(2)-based oxidative stress is present. Thiol/disulfide status as well as metallation state of SOD1 significantly affects its structure and protein aggregation, which are relevant in pathologies of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The authors review here a mechanism for posttranslational activation of SOD1 and discuss models for ALS in which the most immature forms of the SOD1 polypeptide exhibits propensity to form toxic aggregates.}, }
@article {pmid16771441, year = {2006}, author = {Gaggelli, E and Kozlowski, H and Valensin, D and Valensin, G}, title = {Copper homeostasis and neurodegenerative disorders (Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis).}, journal = {Chemical reviews}, volume = {106}, number = {6}, pages = {1995-2044}, doi = {10.1021/cr040410w}, pmid = {16771441}, issn = {0009-2665}, mesh = {Adenosine Triphosphatases/chemistry/metabolism ; Alzheimer Disease/*metabolism/pathology ; Amyloid beta-Peptides/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; *Copper/chemistry/metabolism ; Histidine/chemistry/metabolism ; Homeostasis ; Humans ; Mice ; Models, Chemical ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Neurodegenerative Diseases/metabolism/pathology ; Oxidative Stress ; Parkinson Disease/*metabolism/pathology ; Prion Diseases/*metabolism/pathology ; Protein Binding ; }, }
@article {pmid16766086, year = {2006}, author = {Sundararajan, S and Jiang, Q and Heneka, M and Landreth, G}, title = {PPARgamma as a therapeutic target in central nervous system diseases.}, journal = {Neurochemistry international}, volume = {49}, number = {2}, pages = {136-144}, doi = {10.1016/j.neuint.2006.03.020}, pmid = {16766086}, issn = {0197-0186}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Brain/*drug effects/immunology/physiopathology ; Brain Diseases/*drug therapy/immunology/physiopathology ; Disease Models, Animal ; Encephalitis/*drug therapy/genetics/immunology ; Gene Expression Regulation/drug effects/genetics/immunology ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/immunology/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; PPAR gamma/*agonists/immunology/metabolism ; Transcriptional Activation/drug effects/genetics/immunology ; }, abstract = {Diseases of the central nervous system present a challenge for the development of new therapeutic agents. Nuclear receptors are ligand-activated transcription factors that have proven to be valuable targets for development of new drugs owing to their ability to directly regulate gene expression. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), has been investigated for its action in ameliorating the development and progression of a number of CNS diseases. PPARgamma agonists exhibit potent anti-inflammatory effects and appear to have direct neuroprotective actions. PPARgamma agonists have been shown to be efficacious in animal models of Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis. The availability of FDA-approved agonists of this receptor will facilitate the rapid translation of these findings into clinical trials for a number of CNS diseases.}, }
@article {pmid16765570, year = {2006}, author = {James, PA and Talbot, K}, title = {The molecular genetics of non-ALS motor neuron diseases.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {986-1000}, doi = {10.1016/j.bbadis.2006.04.003}, pmid = {16765570}, issn = {0006-3002}, mesh = {Adolescent ; Adult ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Axonal Transport ; GTP-Binding Protein gamma Subunits/genetics ; Heat-Shock Proteins/genetics/metabolism ; Humans ; Mice ; Mice, Transgenic ; *Models, Neurological ; Molecular Chaperones ; Motor Neuron Disease/diagnosis/*genetics/metabolism ; Muscles/pathology ; *Mutation ; Neoplasm Proteins/genetics/metabolism ; Phenotype ; Signal Transduction ; Syndrome ; }, abstract = {Hereditary disorders of voluntary motor neurons are individually relatively uncommon, but have the potential to provide significant insights into motor neuron function in general and into the mechanisms underlying the more common form of sporadic Amyotrophic Lateral Sclerosis. Recently, mutations in a number of novel genes have been associated with Lower Motor Neuron (HSPB1, HSPB8, GARS, Dynactin), Upper Motor Neuron (Spastin, Atlastin, Paraplegin, HSP60, KIF5A, NIPA1) or mixed ALS-like phenotypes (Alsin, Senataxin, VAPB, BSCL2). In comparison to sporadic ALS these conditions are usually associated with slow progression, but as experience increases, a wide variation in clinical phenotype has become apparent. At the molecular level common themes are emerging that point to areas of specific vulnerability for motor neurons such as axonal transport, endosomal trafficking and RNA processing. We review the clinical and molecular features of this diverse group of genetically determined conditions and consider the implications for the broad group of motor neuron diseases in general.}, }
@article {pmid16759580, year = {2006}, author = {Alonso-Navarro, H and Jiménez-Jiménez, FJ and García-Agúndez, JA}, title = {[The role of CYP2C19 polymorphism in the development of adverse effects to drugs and the risk for diseases].}, journal = {Medicina clinica}, volume = {126}, number = {18}, pages = {697-706}, doi = {10.1157/13088772}, pmid = {16759580}, issn = {0025-7753}, mesh = {Aryl Hydrocarbon Hydroxylases/*genetics ; Cytochrome P-450 CYP2C19 ; *Drug-Related Side Effects and Adverse Reactions ; *Genetic Predisposition to Disease ; Humans ; Mixed Function Oxygenases/*genetics ; Pharmacogenetics ; *Polymorphism, Genetic ; }, abstract = {There are a great number of polymorphic genes in the human genome. Many of them codify enzymes that metabolizes drugs and xenobiotic agents, including carcinogens. Among the better known of them, there are a number of isozymes of the microsomal oxidative system (CYP3A4, CYP2C9, CYP2C19 y CYP2D6). This article reviews the following issues: a) frequency of presentation of the "poor metabolizer" genotype and/or phenotype for substrates of CYP2C19; b) role of CYP2C19 polymorphism on the metabolism of some drugs (mephenytoine and other antiepileptic drugs, proton pump inhibitors, several antidepressants and anxyolitics, the antimalaria aggent proguanyl, and propranolol, among others, use this metabolic pathway), and c) possible role of CYP2C19 polymorphism in the risk for development of neoplasia and other diseases (systemic lupus erythematosus, psoriasis, hip osteonecrosis, Alzheimer's disease, amyotrophic lateral sclerosis, essential tremor).}, }
@article {pmid16753239, year = {2006}, author = {Drew, PD and Xu, J and Storer, PD and Chavis, JA and Racke, MK}, title = {Peroxisome proliferator-activated receptor agonist regulation of glial activation: relevance to CNS inflammatory disorders.}, journal = {Neurochemistry international}, volume = {49}, number = {2}, pages = {183-189}, doi = {10.1016/j.neuint.2006.04.003}, pmid = {16753239}, issn = {0197-0186}, support = {NS047546/NS/NINDS NIH HHS/United States ; NS042860/NS/NINDS NIH HHS/United States ; R01 NS042860/NS/NINDS NIH HHS/United States ; P30 NS047546/NS/NINDS NIH HHS/United States ; R01 NS042860-04/NS/NINDS NIH HHS/United States ; P30 NS047546-02/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Central Nervous System/drug effects/*metabolism/physiopathology ; Encephalitis/drug therapy/*metabolism/physiopathology ; Gliosis/drug therapy/*metabolism/physiopathology ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Neuroglia/drug effects/*metabolism ; Peroxisome Proliferator-Activated Receptors/agonists/*metabolism ; }, abstract = {Peroxisome proliferator-activated receptors (PPARs) play key roles in lipid metabolism and inflammation. Recent studies indicated that PPARs are also capable of modulating immune responses. Microglia and astrocytes are cells resident to the central nervous system (CNS) that function to protect against environmental insults including pathogens. However, following CNS inflammation, reactive gliosis occurs which is characterized by astrocyte hypertrophy and increased glial proliferation. Under such conditions, glia can become chronically activated and may contribute to the neuropathology associated with a variety of neuroinflammatory disorders including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. A review of the role of PPAR agonists in modulating glial cell activation is presented. Included is a discussion of the molecular mechanisms of action of these PPAR agonists and the potential utility of these agents for the treatment of neuroinflammatory disorders.}, }
@article {pmid16736722, year = {2006}, author = {Kertesz, A}, title = {Progress in clinical neurosciences: Frontotemporal dementia-pick's disease.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {33}, number = {2}, pages = {141-148}, doi = {10.1017/s0317167100004893}, pmid = {16736722}, issn = {0317-1671}, mesh = {Brain/*pathology/*physiopathology ; Dementia/*diagnosis/genetics/*physiopathology ; Diagnosis, Differential ; Genetic Predisposition to Disease/genetics ; Humans ; Inclusion Bodies/metabolism/pathology ; Mutation/genetics ; Neurons/metabolism/pathology ; Pick Disease of the Brain/*diagnosis/genetics/*physiopathology ; tau Proteins/genetics/metabolism ; }, abstract = {Frontotemporal dementia (clinical Pick's disease) is a relatively common, but underdiagnosed degenerative disease in the presenium. Estimated prevalence ranges from 6-12% of dementias. The behavioural, aphasic and extrapyramidal presentations are labeled FTD-behavioural variant, Primary Progressive Aphasia (PPA) and Corticobasal Degeneration/Progressive Supranuclear Palsy (CBD/PSP). The diagnostic features and course of each are described and their overlap in the evolution of the illness is emphasized. The neuropathology ranges from the most common tau negative ubiquitin positive amyotrophic lateral sclerosis (ALS) type inclusions to the tau positive classical Pick bodies and more or less distinct changes of PSP and CBD. The genetics of the relatively frequent tau mutations and the yet unsolved problem of tau negative families are discussed. The tau negative cases tend to be associated with the behavioural presentation and semantic dementia and the tau positive ones with PPA and the CBD/PSP syndrome. However the overlap is too great to split the disease. A glossary to navigate the proliferating terminology is included.}, }
@article {pmid16734186, year = {2006}, author = {Kato, AC and Vingerhoets, FJ and Magistris, MR and Kuntzer, T and Burkhard, PR}, title = {[Pathogenic mechanisms of neurodegenerative diseases: amyotrophic lateral sclerosis].}, journal = {Revue medicale suisse}, volume = {2}, number = {64}, pages = {1152-4, 1156-7}, pmid = {16734186}, issn = {1660-9379}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Humans ; }, abstract = {Since its description by Charcot in 1869, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis (ALS) has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics have now identified two genes, SODI and ALS2 as primary causes of the disease and has implicated others as potential contributors. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response that it provokes, these model systems underscore the involvement of non-neuronal cells in disease progression and provide new therapeutic strategies.}, }
@article {pmid16730956, year = {2006}, author = {Chevalier-Larsen, E and Holzbaur, EL}, title = {Axonal transport and neurodegenerative disease.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1094-1108}, doi = {10.1016/j.bbadis.2006.04.002}, pmid = {16730956}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Axonal Transport/*genetics ; Cytoskeleton/genetics/metabolism ; Dynactin Complex ; Dyneins/metabolism ; Humans ; Intermediate Filaments/metabolism ; Kinesins/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Models, Immunological ; Motor Neurons/*metabolism ; Nerve Degeneration/*genetics ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; }, abstract = {Neurons have extensive processes and communication between those processes and the cell body is crucial to neuronal function and survival. Thus, neurons are uniquely dependent on microtubule based transport. Growing evidence supports the idea that deficits in axonal transport contribute to pathogenesis in multiple neurodegenerative diseases. We describe the motor, cytoskeletal, and adaptor proteins involved in axonal transport and their interactions. Data linking disruption of axonal transport to diseases such as ALS are discussed. Finally, we explore the pathways that may cause neuronal dysfunction and death.}, }
@article {pmid16723044, year = {2006}, author = {Goodall, EF and Morrison, KE}, title = {Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment.}, journal = {Expert reviews in molecular medicine}, volume = {8}, number = {11}, pages = {1-22}, doi = {10.1017/S1462399406010854}, pmid = {16723044}, issn = {1462-3994}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/pathology/*therapy ; Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Clinical Trials as Topic ; Cytoskeleton/metabolism ; Genetic Predisposition to Disease ; Humans ; Mice ; Models, Biological ; Motor Neurons/*pathology ; Oxidative Stress ; Protein Binding ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation - based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.}, }
@article {pmid16719819, year = {2006}, author = {Catarzi, D and Colotta, V and Varano, F}, title = {Competitive Gly/NMDA receptor antagonists.}, journal = {Current topics in medicinal chemistry}, volume = {6}, number = {8}, pages = {809-821}, doi = {10.2174/156802606777057544}, pmid = {16719819}, issn = {1568-0266}, mesh = {Animals ; Epilepsy/drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Pain/drug therapy ; Receptors, Glycine/*antagonists &amp; inhibitors ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors ; Stroke/drug therapy ; Substance-Related Disorders/drug therapy ; }, abstract = {Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischemia, epilepsy, amiotrophic lateral sclerosis (ALS), Parkinson's and Alzheimer's diseases. In addition to the classical competitive glutamate receptor (GluR) antagonists, much effort has been directed toward the development of many different non-competitive antagonists of these receptors and, among them, compounds blocking the glycine site on the NMDA receptor complex (Gly/NMDA) have been widely investigated. Many Gly/NMDA receptor antagonists showed to be potential therapeutic agents in many neurological diseases such as stroke, epilepsy and neuropathic pain. Some of them, endowed also with favourable physicochemical properties and low secondary undesiderable effects, reached clinical trials.}, }
@article {pmid16719808, year = {2006}, author = {Schrattenholz, A and Soskic, V}, title = {NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.}, journal = {Current topics in medicinal chemistry}, volume = {6}, number = {7}, pages = {663-686}, doi = {10.2174/156802606776894519}, pmid = {16719808}, issn = {1568-0266}, mesh = {Alternative Splicing ; Cell Membrane/metabolism ; Cholesterol/*metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamates/metabolism ; Humans ; Ligands ; Phosphorylation ; RNA Editing ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/*chemistry/*physiology ; Signal Transduction ; Structure-Activity Relationship ; Tyrosine/metabolism ; }, abstract = {Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.}, }
@article {pmid16718739, year = {2006}, author = {Corbett, CA and Tardif, FJ}, title = {Detection of resistance to acetolactate synthase inhibitors in weeds with emphasis on DNA-based techniques: a review.}, journal = {Pest management science}, volume = {62}, number = {7}, pages = {584-597}, doi = {10.1002/ps.1219}, pmid = {16718739}, issn = {1526-498X}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors/genetics ; Alleles ; Chromatography, High Pressure Liquid/methods ; DNA Mutational Analysis/*methods ; Drug Resistance/genetics ; Herbicides/chemistry/*pharmacology ; Mutation ; Plants/*drug effects/enzymology/genetics ; Polymerase Chain Reaction/methods ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Seedlings/drug effects/enzymology/genetics ; }, abstract = {Resistance to herbicides inhibiting acetolactate synthase (ALS) has been increasing at a faster rate than in any other herbicide group. The great majority of these cases are due to various single-nucleotide polymorphisms in the ALS gene endowing target site resistance. Many diagnostic techniques have been devised in order to confirm resistance and help producers to adopt the best management strategies. Recent advances in DNA technologies coupled with the knowledge of sequence information have allowed the development of accurate and rapid diagnostic tests. While whole plant-based diagnostic techniques such as seedling bioassays or enzyme-based in vitro bioassays provide accurate results, they tend to be labour- and/or space-intensive and will only respond to the particular herbicides tested, making resolution of cross-resistance patterns more difficult. Successful DNA-based diagnosis of ALS inhibitor resistance has been achieved with three main techniques, (1) restriction fragment length polymorphism, (2) polymerase chain reaction amplification of specific alleles and (3) denaturing high-performance liquid chromatography. All DNA-based techniques are relatively rapid and provide clear identification of the mutations causing resistance. Resistance based on non-target mechanisms is not identified by these DNA-based methods; however, given the prevalence of target site-based ALS inhibitor resistance, this is a minor inconvenience.}, }
@article {pmid16713196, year = {2006}, author = {DiBernardo, AB and Cudkowicz, ME}, title = {Translating preclinical insights into effective human trials in ALS.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1139-1149}, doi = {10.1016/j.bbadis.2006.03.007}, pmid = {16713196}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic/*methods/standards ; *Disease Models, Animal ; Drug Design ; Humans ; Mice ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset neurodegenerative disease characterized by selective dysfunction and death of motor neurons in the brain and spinal cord. The disease is typically fatal within 3-5 years of symptom onset. There is no known cure and only riluzole, which was approved by the FDA in 1996 for treatment of ALS, has shown some efficacy in humans. Preclinical insights from model systems continue to furnish ample therapeutic targets, however, translation into effective therapies for humans remains challenging. We present an overview of clinical trial methodology for ALS, including a summary rationale for target selection and challenges to ALS clinical research.}, }
@article {pmid16713195, year = {2006}, author = {Barber, SC and Mead, RJ and Shaw, PJ}, title = {Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1051-1067}, doi = {10.1016/j.bbadis.2006.03.008}, pmid = {16713195}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology/therapy ; Animals ; Antioxidants/therapeutic use ; DNA Damage ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Models, Neurological ; Molecular Structure ; Motor Neurons/metabolism ; Nerve Degeneration/*etiology ; *Oxidative Stress ; Superoxide Dismutase/*chemistry/genetics ; Superoxide Dismutase-1 ; }, abstract = {The cause(s) of amyotrophic lateral sclerosis (ALS) is not fully understood in the vast majority of cases and the mechanisms involved in motor neuron degeneration are multi-factorial and complex. There is substantial evidence to support the hypothesis that oxidative stress is one mechanism by which motor neuron death occurs. This theory becomes more persuasive with the discovery that mutation of the anti-oxidant enzyme, superoxide dismutase 1 (SOD1), causes disease in a significant minority of cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration have not been defined with certainty, and trials of anti-oxidant therapies have been disappointing. Here, we review the evidence implicating oxidative stress in ALS pathogenesis, discuss how oxidative stress may affect and be affected by other proposed mechanisms of neurodegeneration, and review the trials of various anti-oxidants as potential therapies for ALS.}, }
@article {pmid16706741, year = {2006}, author = {Bowser, R and Cudkowicz, M and Kaddurah-Daouk, R}, title = {Biomarkers for amyotrophic lateral sclerosis.}, journal = {Expert review of molecular diagnostics}, volume = {6}, number = {3}, pages = {387-398}, doi = {10.1586/14737159.6.3.387}, pmid = {16706741}, issn = {1744-8352}, support = {R21 ES013470/ES/NIEHS NIH HHS/United States ; }, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; *Biomarkers ; Gene Expression Profiling ; Genomics/methods ; Humans ; *Molecular Diagnostic Techniques ; Motor Neurons/metabolism ; Muscles/pathology ; Mutation ; Proteomics/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. ALS is a fatal neurodegenerative disease and clinical diagnosis typically takes many months to complete. Early disease diagnosis through the use of biomarkers may aid in correct clinical management of patients and possibly delay time to ventilator and morbidity. This review explores the progress of biomarker discovery efforts for ALS and the many challenges that remain. Included are different technologies utilized in biomarker discovery efforts (proteomic, genomic and metabolomic) and putative biomarkers uncovered using these techniques. These studies have discovered genetic mutations leading to familial forms of ALS, and specific protein alterations that occur in biological fluids (cerebrospinal fluid and blood) and/or tissues of ALS subjects. More recent high-throughput technologies have revealed panels of proteomic or metabolic biomarkers that can discriminate between ALS and control groups. The identification of disease-specific biomarkers will provide opportunities to develop early diagnostic measures as well as surrogate markers to monitor disease progression and test drug efficacy in clinical trials.}, }
@article {pmid16701996, year = {2006}, author = {Ludolph, AC}, title = {135th ENMC International Workshop: nutrition in amyotrophic lateral sclerosis 18-20 of March 2005, Naarden, The Netherlands.}, journal = {Neuromuscular disorders : NMD}, volume = {16}, number = {8}, pages = {530-538}, doi = {10.1016/j.nmd.2006.04.005}, pmid = {16701996}, issn = {0960-8966}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Clinical Protocols ; Deglutition Disorders/etiology/physiopathology ; Eating/*physiology ; Energy Metabolism/physiology ; Gastrostomy/methods/standards/trends ; Humans ; Life Expectancy/trends ; Malnutrition/etiology/*prevention &amp; control/*therapy ; Netherlands ; Nutritional Requirements ; Nutritional Status/physiology ; Nutritional Support/*methods/*standards/trends ; }, }
@article {pmid16698262, year = {2006}, author = {Kwak, S and Weiss, JH}, title = {Calcium-permeable AMPA channels in neurodegenerative disease and ischemia.}, journal = {Current opinion in neurobiology}, volume = {16}, number = {3}, pages = {281-287}, doi = {10.1016/j.conb.2006.05.004}, pmid = {16698262}, issn = {0959-4388}, support = {NS36548/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Animals ; Brain Ischemia/genetics/*metabolism/physiopathology ; Calcium/*metabolism ; Calcium Signaling/*physiology ; Cell Death/drug effects/physiology ; Cell Membrane Permeability/physiology ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/physiopathology ; Protein Subunits/genetics/metabolism ; Receptors, AMPA/drug effects/genetics/*metabolism ; Zinc/metabolism/toxicity ; }, abstract = {Compelling evidence supports contributions of glutamate receptor overactivation ('excitotoxicity') to neurodegeneration in both acute conditions, such as stroke, and chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis. However, anti-excitotoxic therapeutic trials, which have generally targeted highly Ca2+ permeable NMDA-type glutamate channels, have to date failed to demonstrate impressive efficacy. Whereas most AMPA type glutamate channels are Ca2+ impermeable, an evolving body of evidence supports the contention that relatively unusual Ca2+ permeable AMPA channels might be crucial contributors to injury in these conditions. These channels are preferentially expressed in discrete neuronal subpopulations, and their numbers appear to be upregulated in amyotrophic lateral sclerosis and stroke. In addition, unlike NMDA channels, Ca2+ permeable AMPA channels are not blocked by Mg2+, but are highly permeable to another potentially harmful endogenous cation, Zn2+. The targeting of these channels might provide efficacious new avenues in the therapy of certain neurological diseases.}, }
@article {pmid16690390, year = {2006}, author = {Carrì, MT and Grignaschi, G and Bendotti, C}, title = {Targets in ALS: designing multidrug therapies.}, journal = {Trends in pharmacological sciences}, volume = {27}, number = {5}, pages = {267-273}, doi = {10.1016/j.tips.2006.03.009}, pmid = {16690390}, issn = {0165-6147}, support = {GGP030066/TI_/Telethon/Italy ; GP0024Y01/TI_/Telethon/Italy ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/etiology/physiopathology ; Animals ; Disease Models, Animal ; Drug Delivery Systems ; Drug Therapy, Combination ; Humans ; Mice ; Stem Cell Transplantation ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable disease that arises from the progressive loss of motoneurons. Even when caused by a single gene defect, as in the case of mutations in the enzyme Cu-Zn superoxide dismutase (SOD1), ALS is the result of a complex cascade that involves crosstalk among motoneurons, glia and muscles, and evolves through the action of converging toxic mechanisms. Transgenic rodents that express human mutant SOD1 and develop a progressive paralytic disease are widely used to screen potential therapeutics. Treatments that interfere with a specific event in the neurotoxic cascade have been reported to produce a modest increase in rodent lifespan. Multi-intervention approaches, including novel methods to intercept the damage and to deliver molecules to vulnerable cells, have recently been shown to be more effective. Thus, new avenues for promising therapeutic approaches can be derived from multidrug treatments and/or the delivery of growth factors by viral vectors, in combination with exercise and/or diet regimens.}, }
@article {pmid16687265, year = {2006}, author = {Rose, MR and Brix, KA}, title = {Neurological disorders in Gulf War veterans.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {361}, number = {1468}, pages = {605-618}, pmid = {16687265}, issn = {0962-8436}, mesh = {*Gulf War ; Humans ; Incidence ; Nervous System Diseases/*diagnosis/*epidemiology ; Prevalence ; Veterans/*psychology/*statistics &amp; numerical data ; }, abstract = {We present a review of neurological function in Gulf War veterans (GWV). Twenty-two studies were reviewed, including large hospitalization and registry studies, large population-based epidemiological studies, investigations of a single military unit, small uncontrolled studies of ill veterans and small controlled studies of veterans. In nearly all studies, neurological function was normal in most GWVs, except for a small proportion who were diagnosed with compression neuropathies (carpal tunnel syndrome or ulnar neuropathy). In the great majority of controlled studies, there were no differences in the rates of neurological abnormalities in GWVs and controls. In a national US study, the incidence of amyotrophic lateral sclerosis (ALS) seems to be significantly increased in GWVs, compared to the rate in controls. However, it is possible that military service, in general, might be associated with an increased risk of ALS, rather than Gulf War service in particular. Taken together, the conclusion is that if a neurological examination in a GWV is within normal limits, then extensive neurological testing is unlikely to diagnose occult neurological disorders.}, }
@article {pmid16687261, year = {2006}, author = {Gray, GC and Kang, HK}, title = {Healthcare utilization and mortality among veterans of the Gulf War.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {361}, number = {1468}, pages = {553-569}, pmid = {16687261}, issn = {0962-8436}, mesh = {*Gulf War ; Health Care Surveys ; Humans ; Military Personnel/psychology/*statistics &amp; numerical data ; Persian Gulf Syndrome/*mortality/*therapy ; Veterans/psychology/*statistics &amp; numerical data ; }, abstract = {The authors conducted an extensive search for published works concerning healthcare utilization and mortality among Gulf War veterans of the Coalition forces who served during the 1990-1991 Gulf War. Reports concerning the health experience of US, UK, Canadian, Saudi and Australian veterans were reviewed. This report summarizes 15 years of observations and research in four categories: Gulf War veteran healthcare registry studies, hospitalization studies, outpatient studies and mortality studies. A total of 149728 (19.8%) of 756373 US, UK, Canadian and Australian Gulf War veterans received health registry evaluations revealing a vast number of symptoms and clinical conditions but no suggestion that a new unique illness was associated with service during the Gulf War. Additionally, no Gulf War exposure was uniquely implicated as a cause for post-war morbidity. Numerous large, controlled studies of US Gulf War veterans' hospitalizations, often involving more than a million veterans, have been conducted. They revealed an increased post-war risk for mental health diagnoses, multi-symptom conditions and musculoskeletal disorders. Again, these data failed to demonstrate that Gulf War veterans suffered from a unique Gulf War-related illness. The sparsely available ambulatory care reports documented that respiratory and gastrointestinal complaints were quite common during deployment. Using perhaps the most reliable data, controlled mortality studies have revealed that Gulf War veterans were at increased risk of injuries, especially those due to vehicular accidents. In general, healthcare utilization data are now exhausted. These findings have now been incorporated into preventive measures in support of current military forces. With a few diagnostic exceptions such as amyotrophic lateral sclerosis, mental disorders and cancer, it now seems time to cease examining Gulf War veteran morbidity and to direct future research efforts to preventing illness among current and future military personnel.}, }
@article {pmid16675207, year = {2006}, author = {Julien, JP and Kriz, J}, title = {Transgenic mouse models of amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1013-1024}, doi = {10.1016/j.bbadis.2006.03.006}, pmid = {16675207}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; Guanine Nucleotide Exchange Factors/genetics ; Humans ; Intermediate Filaments/genetics/metabolism/pathology ; Mice ; Mice, Transgenic ; Microtubules/physiology ; *Models, Neurological ; Motor Neurons/metabolism/*pathology ; Mutation ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {The discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial cases was rapidly followed by the generation of transgenic mice expressing various forms of SOD1 mutants. The mice overexpressing high levels of mutant SOD1 mRNAs do develop motor neuron disease but unraveling the mechanisms of pathogenesis has been very challenging. Studies with mouse lines suggest that the toxicity of mutant SOD1 is unrelated to copper-mediated catalysis but rather to propensity of a subfraction of mutant SOD1 proteins to form misfolded protein species and aggregates. However, the mechanism of toxicity of SOD1 mutants remains to be elucidated. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Here, we describe how transgenic mouse models have been used for understanding pathogenic pathways of motor neuron disease and for pre-clinical drug testing.}, }
@article {pmid16674978, year = {2006}, author = {Miller, A}, title = {Pseudobulbar affect in multiple sclerosis: toward the development of innovative therapeutic strategies.}, journal = {Journal of the neurological sciences}, volume = {245}, number = {1-2}, pages = {153-159}, doi = {10.1016/j.jns.2005.09.018}, pmid = {16674978}, issn = {0022-510X}, mesh = {Adrenergic alpha-Antagonists/therapeutic use ; Dextromethorphan/therapeutic use ; *Emotions/drug effects ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mood Disorders/drug therapy/etiology/*psychology ; Multiple Sclerosis/*physiopathology/*psychology ; Quinidine/therapeutic use ; }, abstract = {Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia including Alzheimer's disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated. Agents used to treat psychiatric disorders--particularly tricyclic antidepressants and selective serotonin reuptake inhibitors--are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma(1) receptors concentrated in the brainstem and cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.}, }
@article {pmid16650805, year = {2006}, author = {Miller, JB and Girgenrath, M}, title = {The role of apoptosis in neuromuscular diseases and prospects for anti-apoptosis therapy.}, journal = {Trends in molecular medicine}, volume = {12}, number = {6}, pages = {279-286}, doi = {10.1016/j.molmed.2006.04.003}, pmid = {16650805}, issn = {1471-4914}, support = {AR49496/AR/NIAMS NIH HHS/United States ; ES11384/ES/NIEHS NIH HHS/United States ; HL64641/HL/NHLBI NIH HHS/United States ; }, mesh = {Agrin/genetics/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics ; Animals ; Anti-Bacterial Agents/pharmacology/*therapeutic use ; Apoptosis/*genetics ; Apoptosis Regulatory Proteins/genetics/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Doxycycline/pharmacology/*therapeutic use ; Gene Expression Regulation/drug effects ; *Genetic Therapy/methods ; Humans ; Laminin/genetics/metabolism ; Mice ; Minocycline/pharmacology/*therapeutic use ; Muscular Dystrophies/genetics/metabolism/*therapy ; Muscular Dystrophy, Oculopharyngeal/drug therapy/genetics/metabolism ; Mutation ; Poly(A)-Binding Protein II/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Although genetic mutations that are responsible for most of the inherited neuromuscular diseases have been identified, the molecular and cellular mechanisms that cause muscle and nerve depletion are not well understood and therapies are lacking. Histological studies of many neuromuscular diseases indicated that loss of motor-nerve and/or skeletal-muscle function might be due to excessive cell death by apoptosis. Recent studies have confirmed this possibility by showing that pathology in mouse models of amyotrophic lateral sclerosis, congenital muscular dystrophy, oculopharyngeal muscular dystrophy and collagen-VI deficiency, but not Duchenne muscular dystrophy, is significantly ameliorated by genetic or pharmacological interventions that have been designed to inhibit apoptosis. Thus, apoptosis greatly contributes to pathology in mouse models of several neuromuscular diseases, and appropriate anti-apoptosis therapy might therefore be beneficial for the corresponding human diseases.}, }
@article {pmid16649207, year = {2006}, author = {Weiller, C and May, A and Sach, M and Buhmann, C and Rijntjes, M}, title = {Role of functional imaging in neurological disorders.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {23}, number = {6}, pages = {840-850}, doi = {10.1002/jmri.20591}, pmid = {16649207}, issn = {1053-1807}, mesh = {Animals ; Brain/pathology/*physiopathology ; Brain Mapping/*methods ; Clinical Medicine/*methods ; Evoked Potentials ; Humans ; Image Interpretation, Computer-Assisted/*methods ; Magnetic Resonance Imaging/*methods ; Nervous System Diseases/*diagnosis/pathology/*physiopathology/psychology ; }, abstract = {Neuroimaging in recent years has greatly contributed to our understanding of a wide range of aspects related to central neurological diseases. These include the classification and localization of disease, such as in headache; the understanding of pathology, such as in Parkinson's disease (PD); the mechanisms of reorganization, such as in stroke and multiple sclerosis (MS); and the subclinical progress of disease, such as in amyotrophic lateral sclerosis (ALS). Apart from presurgical mapping, however, the clinical applications so far are limited. Nevertheless, functional imaging does enable the formulation of neurobiological hypotheses that can be tested clinically, and thus is well suited for testing classic clinical hypotheses about how the brain works. Understanding the mechanisms and sites of pathology, such as has been achieved in cluster headaches, facilitates the development of new therapeutic strategies.}, }
@article {pmid16647138, year = {2006}, author = {Phillis, JW and Horrocks, LA and Farooqui, AA}, title = {Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders.}, journal = {Brain research reviews}, volume = {52}, number = {2}, pages = {201-243}, doi = {10.1016/j.brainresrev.2006.02.002}, pmid = {16647138}, issn = {0165-0173}, mesh = {Animals ; Arachidonic Acid/*metabolism ; Brain Diseases/*enzymology/physiopathology ; Central Nervous System/*enzymology/physiopathology ; Encephalitis/enzymology/physiopathology ; Humans ; Inflammation Mediators/metabolism ; Lipoxygenase/genetics/*metabolism ; Membrane Lipids/metabolism ; Oxidoreductases/genetics/*metabolism ; Prostaglandin-Endoperoxide Synthases/genetics/*metabolism ; }, abstract = {Three enzyme systems, cyclooxygenases that generate prostaglandins, lipoxygenases that form hydroxy derivatives and leukotrienes, and epoxygenases that give rise to epoxyeicosatrienoic products, metabolize arachidonic acid after its release from neural membrane phospholipids by the action of phospholipase A(2). Lysophospholipids, the other products of phospholipase A(2) reactions, are either reacylated or metabolized to platelet-activating factor. Under normal conditions, these metabolites play important roles in synaptic function, cerebral blood flow regulation, apoptosis, angiogenesis, and gene expression. Increased activities of cyclooxygenases, lipoxygenases, and epoxygenases under pathological situations such as ischemia, epilepsy, Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease produce neuroinflammation involving vasodilation and vasoconstriction, platelet aggregation, leukocyte chemotaxis and release of cytokines, and oxidative stress. These are closely associated with the neural cell injury which occurs in these neurological conditions. The metabolic products of docosahexaenoic acid, through these enzymes, generate a new class of lipid mediators, namely docosatrienes and resolvins. These metabolites antagonize the effect of metabolites derived from arachidonic acid. Recent studies provide insight into how these arachidonic acid metabolites interact with each other and other bioactive mediators such as platelet-activating factor, endocannabinoids, and docosatrienes under normal and pathological conditions. Here, we review present knowledge of the functions of cyclooxygenases, lipoxygenases, and epoxygenases in brain and their association with neurodegenerative diseases.}, }
@article {pmid16637591, year = {2006}, author = {Tateishi, N and Shimoda, T and Yada, N and Shinagawa, R and Kagamiishi, Y}, title = {[S100B: astrocyte specific protein].}, journal = {Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology}, volume = {26}, number = {1}, pages = {11-16}, pmid = {16637591}, issn = {1340-2544}, mesh = {Animals ; Astrocytes/chemistry ; Cerebral Infarction/blood ; Humans ; Nerve Growth Factors/blood/*physiology ; Nervous System Diseases/metabolism ; Rats ; S100 Calcium Binding Protein beta Subunit ; S100 Proteins/blood/*physiology ; }, abstract = {The S100B is a Ca2+ binding proteins of EF-hand type and is produced primarily by astrocytes in the central nervous system. This protein has been implicated in the Ca2+-dependent regulation of a variety of intracellular functions such as protein phosphorylation, enzyme activities, cell proliferation and differentiation, dynamics of cytoskeleton constituents, structural organization of membranes, intracellular Ca2+ homeostasis, inflammation, and protection from oxidative cell damage. Recent studies suggest that released S100B exerts paracrine and autocrine effects on neurons and glia. On the other hand, elevations of S100B levels in blood or cerebrospinal fluid have been observed in patients with Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, depression, cerebral stroke and traumatic brain injury, and the levels have reached micromol/L-order at focal regions. It has been documented that the excessive S100B promotes the expression of inducible nitric oxide synthase or pro-inflammatory cytokines and exhibits detrimental effects on neurons. On studies using some animal models of the cerebral stroke or Alzheimer's disease, it is suggested that the excessive S100B produced by activated astrocytes precedes neurodegenerations. Authors discussed the relationship between neurological disorders and the S100B.}, }
@article {pmid16625548, year = {2006}, author = {Symington, A and Pinelli, J}, title = {Developmental care for promoting development and preventing morbidity in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {2006}, number = {2}, pages = {CD001814}, pmid = {16625548}, issn = {1469-493X}, mesh = {Developmental Disabilities/*prevention &amp; control ; Environment, Controlled ; Humans ; Infant, Newborn ; *Infant, Premature ; Intensive Care, Neonatal/*methods/standards ; Length of Stay ; Randomized Controlled Trials as Topic ; Respiration, Artificial ; Stress, Physiological/prevention &amp; control ; Treatment Outcome ; Weight Gain ; }, abstract = {BACKGROUND: Preterm infants experience a range of morbidity related to the immaturity of their organ systems and to concurrent disease states. There is concern that an unfavourable environment in the neonatal intensive care unit (NICU) may compound this morbidity. Modification of the environment could minimize the iatrogenic effects. Developmental care is a broad category of interventions designed to minimize the stress of the NICU environment. These interventions may include elements such as control of external stimuli (vestibular, auditory, visual, tactile), clustering of nursery care activities, and positioning or swaddling of the preterm infant. Individual strategies have also been combined to form programs, such as the 'Newborn Individualized Developmental Care and Assessment Program' (NIDCAP) (Als 1986).<br><br>OBJECTIVES: In preterm infants, do developmental care interventions reduce neurodevelopmental delay, poor weight gain, length of hospital stay, length of mechanical ventilation, physiological stress and other clinically relevant adverse outcomes?<br><br>SEARCH STRATEGY: The Neonatal Review Group search strategy was utilized. Searches were made of MEDLINE from 1966 to June, 2005 and of CINAHL, The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), and conference and symposia proceedings in the English language from 1990 to June, 2005. A search of EMBASE was also made from 2003 to June 2005. A list of all relevant articles was sent to two experts in the field to identify any omissions or additional unpublished studies.<br><br>SELECTION CRITERIA: Randomized trials in which elements of developmental care are compared to routine nursery care for infants < 37 weeks gestation and that measured clinically relevant outcomes. Reports were in English or a language for which a translator was available. Computerized searches were conducted and all potentially relevant titles and abstracts were extracted. Retrieved articles were assessed for relevance independently by two reviewers, based on predetermined criteria. Articles that met all criteria for relevance were assessed for methodological quality based on predetermined criteria. Articles judged to have the appropriate quality by both reviewers were included in the analysis.<br><br>DATA COLLECTION AND ANALYSIS: Data were extracted independently by the two authors. Meta-analyses were conducted for each intervention where the same outcome measures and/or instruments were used within comparable time points.<br><br>MAIN RESULTS: This review detected 36 eligible randomized controlled trials involving four major groups of developmental care interventions, 19 sub-groups and multiple clinical outcomes. In addition, the long-term outcomes of a previously included trial were added to the review. The results of the review indicate that developmental care interventions demonstrate limited benefit to preterm infants with respect to: decreased moderate-severe chronic lung disease, decreased incidence of necrotizing enterocolitis and improved family outcome. Conversely, an increase in mild lung disease and an increase in the length of stay were demonstrated in infants receiving developmental care compared to controls. There is also very limited evidence of the long-term positive effect of NIDCAP on behavior and movement at 5 years corrected age but no effect on cognition. Other individualized developmental care interventions have also demonstrated some effect in enhancing neurodevelopmental outcome. Although a limited number of other benefits were demonstrated, those results were from single studies with small sample sizes. The lack of blinding of the assessors was a significant methodological flaw in half of the studies. The cost of the interventions and personnel was not considered in any of the studies.<br><br>AUTHORS' CONCLUSIONS: Because of the inclusion of multiple interventions in most studies, the determination of the effect of any single intervention is difficult. Although there is evidence of limited benefit of developmental care interventions overall, and no major harmful effects reported, there were a large number of outcomes for which no or conflicting effects were demonstrated. The single trials that did show a significant effect of an intervention on a major clinical outcome were based on small sample sizes, and the findings were often not supported in other small trials. Before a clear direction for practice can be supported, evidence demonstrating more consistent effects of developmental care interventions on important short- and long-term clinical outcomes is needed. The economic impact of the implementation and maintenance of developmental care practices should be considered by individual institutions.}, }
@article {pmid16624536, year = {2006}, author = {Moisse, K and Strong, MJ}, title = {Innate immunity in amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1083-1093}, doi = {10.1016/j.bbadis.2006.03.001}, pmid = {16624536}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Astrocytes/immunology/pathology ; Disease Models, Animal ; Humans ; *Immunity, Innate ; Inflammation ; Mice ; Mice, Transgenic ; Microglia/pathology ; Models, Immunological ; Models, Neurological ; Motor Neurons/*immunology/pathology ; Nerve Degeneration/*immunology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients. Efforts aimed at attenuating the inflammatory response in ALS animal models have delayed symptom onset and extended survival. Seemingly conversely, attempts to sensitize cells of the innate immune system and modulate their phenotype have also shown efficacy. Effectors of innate immunity in the CNS appear to have ambivalent potential to promote either repair or injury. Because ALS is a syndromic disease in which glutamate excitotoxicity, altered cytoskeletal protein metabolism, oxidative injury, mitochondrial dysfunction and neuroinflammation all contribute to motor neuron degeneration, targeting inflammation via modulation of microglial function therefore holds significant potential as one aspect of therapeutic intervention and could provide insight into the exclusive vulnerability of motor neurons.}, }
@article {pmid16613402, year = {2006}, author = {Eng, D}, title = {Management guidelines for motor neurone disease patients on non-invasive ventilation at home.}, journal = {Palliative medicine}, volume = {20}, number = {2}, pages = {69-79}, doi = {10.1191/0269216306pm1113oa}, pmid = {16613402}, issn = {0269-2163}, mesh = {Caregivers/psychology ; Cost of Illness ; Ethics, Medical ; Home Care Services/ethics ; Humans ; Motor Neuron Disease/*therapy ; Palliative Care/ethics/methods ; Patient Acceptance of Health Care ; Patient Care Team ; Positive-Pressure Respiration/ethics/*methods ; Practice Guidelines as Topic/*standards ; Respiratory Insufficiency/prevention &amp; control ; Stress, Psychological/etiology ; Withholding Treatment ; }, abstract = {Most motor neurone disease (MND) patients die of respiratory system complications. When patients have advanced disease with symptoms of respiratory failure, management issues can become complicated by the introduction of assisted ventilatory devices. Therefore, care provision by a multidisciplinary team must be structured and co-ordinated in order to ensure that patients and their carers receive the optimal level of care. The objective of this article is to review the literature and explore the complex issues surrounding the use of non-invasive positive pressure ventilation (NIPPV) in home care MND patients as a justification for the development of a management guideline for medical practitioners. A guideline for multidisciplinary care of home ventilated MND patients will be proposed.}, }
@article {pmid16603792, year = {2006}, author = {Bacman, SR and Bradley, WG and Moraes, CT}, title = {Mitochondrial involvement in amyotrophic lateral sclerosis: trigger or target?.}, journal = {Molecular neurobiology}, volume = {33}, number = {2}, pages = {113-131}, pmid = {16603792}, issn = {0893-7648}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/physiopathology ; Animals ; Apoptosis/genetics ; Central Nervous System/*metabolism/pathology/physiopathology ; Cytochromes c/metabolism ; Humans ; Mice ; Mitochondria/*metabolism/pathology ; Motor Neurons/*metabolism/pathology ; Mutation/genetics ; Oxidative Stress/genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Despite numerous reports demonstrating mitochondrial abnormalities associated with amyotrophic lateral sclerosis (ALS), the role of mitochondrial dysfunction in the disease onset and progression remains unknown. The intrinsic mitochondrial apoptotic program is activated in the central nervous system of mouse models of ALS harboring mutant superoxide dismutase 1 protein. This is associated with the release of cytochrome-c from the mitochondrial intermembrane space and mitochondrial swelling. However, it is unclear if the observed mitochondrial changes are caused by the decreasing cellular viability or if these changes precede and actually trigger apoptosis. This article discusses the current evidence for mitochondrial involvement in familial and sporadic ALS and concludes that mitochondria is likely to be both a trigger and a target in ALS and that their demise is a critical step in the motor neuron death.}, }
@article {pmid16585919, year = {2006}, author = {,  and ,  and , }, title = {[Case management of amyotrophic lateral sclerosis patients. Consensus development conference, Nice, France, 23-24 November 2005. French Neurology Society. Association of Independent French-speaking Neurologists].}, journal = {Revue neurologique}, volume = {162}, number = {4}, pages = {544-548}, doi = {10.1016/s0035-3787(06)75049-4}, pmid = {16585919}, issn = {0035-3787}, mesh = {Acute Disease ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*therapy ; Case Management ; Humans ; Life Support Care ; Palliative Care ; Patient Care Team ; Respiration, Artificial ; Respiratory Insufficiency/etiology/therapy ; }, }
@article {pmid16585911, year = {2006}, author = {Couratier, P and Torny, F and Lacoste, M}, title = {[Functional rating scales for amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162}, number = {4}, pages = {502-507}, doi = {10.1016/s0035-3787(06)75041-x}, pmid = {16585911}, issn = {0035-3787}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/*classification/physiopathology ; Disability Evaluation ; Humans ; Predictive Value of Tests ; Reproducibility of Results ; *Severity of Illness Index ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of the peripheral and central motor neurons. The principal consequence is a loss of motor functions. Evaluation of motor deficit implies an assessment of the resulting deficiency or incapacity and final disability. Many evaluation are proposed for patient follow-up in order to analyze the state of motor function and their consequences on activities of everyday life. Few recommendations can be formulated. Scales must be validated and relatively simple to use and generate ordinate results allowing statistical analysis. The choice of which scale to use depends on the clinical objective. Global scales (ALS Functional rating Scale, ALS Severity Scale, Appel scale, Norris scale and Honda scale) can be used to evaluate progression of the disability. Some of these scales are strongly correlated with patient survival. Other scales (ALS Health State Scale, global clinical impression) are used to classify patients by homogeneous stage of gravity. Still other scales, such as the Sadoul and Borg scales and the Epworth score are designed for more specific evaluation of a given function. The clinician should be aware of these different scales and their relative utility. Knowledge of these scales, their validity, their sensitivity to modification, and their specificity and interpretation pitfalls is a prerequisite to good evaluation in daily practice and clinical research.}, }
@article {pmid16585905, year = {2006}, author = {Robert, D and Bianco-Blache, A and Spezza, C and Verschueren, A and Pouget, J and Giovanni, A}, title = {[Assessment of dysarthria and dysphagia in ALS patients].}, journal = {Revue neurologique}, volume = {162}, number = {4}, pages = {445-453}, doi = {10.1016/s0035-3787(06)75035-4}, pmid = {16585905}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/diagnosis/*etiology/physiopathology ; *Diagnostic Techniques, Neurological ; Dysarthria/diagnosis/*etiology/physiopathology ; Electromyography ; Humans ; Manometry ; Physical Examination ; Severity of Illness Index ; Speech Acoustics ; Speech Articulation Tests ; }, abstract = {Swallowing and speech disorders are the dramatic consequences of bulbar and pseudo-bulbar syndrome in ALS. Evaluation is necessary to guide speech therapy and to measure the effects of treatment. This article revues the different examinations used to assess bulbar and pseudobulbar involvement in an ALS patient: oromotor assessment, evaluation of the functions with self assessment, perceptive and objective evaluation of speech disorders, fiberoptic endoscopic evaluation of dysphagia (FEES) and videofluoroscopy.}, }
@article {pmid16546753, year = {2006}, author = {Heffernan, C and Jenkinson, C and Holmes, T and Macleod, H and Kinnear, W and Oliver, D and Leigh, N and Ampong, MA}, title = {Management of respiration in MND/ALS patients: an evidence based review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {1}, pages = {5-15}, doi = {10.1080/14660820510043235}, pmid = {16546753}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/complications/therapy ; *Clinical Trials as Topic ; Databases, Factual ; Evidence-Based Medicine ; Humans ; Motor Neuron Disease/*complications/*therapy ; *Practice Guidelines as Topic ; Practice Patterns, Physicians'/trends ; Respiration, Artificial/adverse effects/*methods ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {This systematic review comprises an objective appraisal of the evidence in regard to the management of respiration in patients with motor neuron disease (MND/ALS). Studies were identified through computerised searches of 32 databases. Internet searches of websites of drug companies and MND/ALS research web sites, 'snow balling' and hand searches were also employed to locate any unpublished study or other 'grey literature' on respiration and MND/ALS. Since management of MND/ALS involves a number of health professionals and care workers, searches were made across multiple disciplines. No time frame was imposed on the search in order to increase the probability of identifying all relevant studies, although there was a final limit of March 2005. Recommendations for patient and carer-based guidelines for the clinical management of respiration for MND/ALS patients are suggested on the basis of qualitative analyses of the available evidence. However, these recommendations are based on current evidence of best practice, which largely comprises observational research and clinical opinion. There is a clear need for further evidence, in particular randomised and non-randomised controlled trials on the effects of non-invasive ventilation and additional larger scale cohort studies on the issues of initial assessment of respiratory symptoms, and management and timing of interventions.}, }
@article {pmid16545397, year = {2006}, author = {Gonatas, NK and Stieber, A and Gonatas, JO}, title = {Fragmentation of the Golgi apparatus in neurodegenerative diseases and cell death.}, journal = {Journal of the neurological sciences}, volume = {246}, number = {1-2}, pages = {21-30}, doi = {10.1016/j.jns.2006.01.019}, pmid = {16545397}, issn = {0022-510X}, support = {NS 34732/NS/NINDS NIH HHS/United States ; }, mesh = {Cell Death ; Golgi Apparatus/*pathology ; Humans ; Mutation/genetics/physiology ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*pathology ; Organelles/pathology ; }, abstract = {Fragmentation of the neuronal Golgi apparatus (GA) was reported in amyotrophic lateral sclerosis (ALS), corticobasal degeneration, Alzheimer's and Creutzfeldt-Jacob disease, and in spinocerebelar ataxia type 2 (SCA2). In transgenic mice expressing the G93A mutant of Cu/Zn superoxide dismutase (SOD1) of familial ALS (fALS), fragmentation of the GA of spinal cord motor neurons and aggregation of mutant protein were detected months before the onset of paralysis. Moreover, cells that expressed the G93A and G85R mutants of SOD1 showed fragmentation of the GA and decreased viability without apoptosis. We summarize here mechanisms involved in Golgi fragmentation implicating: (a) the dysregulation by mutant SOD1of the microtubule-destabilizing protein Stathmin, (b) the disruption by mutant SOD1of the neuronal cytoplasmic dynein, (c) the coprecipitation of mutant SOD1 with Hsp25 and Hsp27, (d) the reduction of detyrosinated microtubules by aggregated tau which resulted in non-apoptotic cell death and (e) the disruption by mutant growth hormone of the trafficking from the rough endoplasmic reticulum to the GA. The data indicate that neuronal Golgi fragmentation is an early and probably irreversible lesion in neurodegeneration, caused by a variety of mechanisms. Golgi fragmentation is not secondary to apoptosis but it may "trigger" apoptosis.}, }
@article {pmid16544320, year = {2006}, author = {D'Angelo, MG and Bresolin, N}, title = {Cognitive impairment in neuromuscular disorders.}, journal = {Muscle &amp; nerve}, volume = {34}, number = {1}, pages = {16-33}, doi = {10.1002/mus.20535}, pmid = {16544320}, issn = {0148-639X}, mesh = {Animals ; Cognition Disorders/*etiology/genetics ; Humans ; Muscular Diseases/classification/complications/genetics/physiopathology ; Neuromuscular Diseases/classification/*complications/genetics/*physiopathology ; }, abstract = {Several studies have suggested the presence of central nervous system involvement manifesting as cognitive impairment in diseases traditionally confined to the peripheral nervous system. The aim of this review is to highlight the character of clinical, genetic, neurofunctional, cognitive, and psychiatric deficits in neuromuscular disorders. A high correlation between cognitive features and cerebral protein expression or function is evident in Duchenne muscular dystrophy, myotonic dystrophy (Steinert disease), and mitochondrial encephalomyopathies; direct correlation between tissue-specific protein expression and cognitive deficits is still elusive in certain neuromuscular disorders presenting with or without a cerebral abnormality, such as congenital muscular dystrophies, congenital myopathies, amyotrophic lateral sclerosis, adult polyglucosan body disease, and limb-girdle muscular dystrophies. No clear cognitive deficits have been found in spinal muscular atrophy and facioscapulohumeral dystrophy.}, }
@article {pmid16533145, year = {2006}, author = {Bruijn, LI and Cudkowicz, M}, title = {Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies.}, journal = {Expert review of neurotherapeutics}, volume = {6}, number = {3}, pages = {417-428}, doi = {10.1586/14737175.6.3.417}, pmid = {16533145}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Drug Delivery Systems/*methods/trends ; Gene Targeting/*methods/trends ; Humans ; }, abstract = {Although amyotrophic lateral sclerosis (ALS) was described more than 130 years ago, the cause(s) of most cases of this adult motor neuron disease remains a mystery. With the discovery of mutations in one gene (Cu/Zn superoxide dismutase) as a primary cause of some forms of ALS, model systems have been developed that have helped us begin to understand mechanisms involved in motor neuron death and enabled testing of potential new therapies. Several other genes have been implicated as risk factors in motor neuron diseases, including neurofilaments, cytoplasmic dynein and dynactin, vascular endothelial growth factor, and angiogenin. With advances in the basic research of the disease, many hypotheses accounting for motor neuron death are being explored, including loss of trophic support, protein mishandling, mitochondrial dysfunction, excitotoxicity, axonal abnormalities and inflammation. Many of these mechanisms are the focus of research in other neurodegenerative disorders, such as Parkinson's, Alzheimer's and Huntington's disease.}, }
@article {pmid16523990, year = {2006}, author = {Czaplinski, A and Schweikert, K and Strobel, W and Steck, AJ and Weber, M}, title = {[Symptomatic management in amyotrophic lateral sclerosis (ALS)].}, journal = {Praxis}, volume = {95}, number = {8}, pages = {263-8, 269-71}, doi = {10.1024/0369-8394.95.8.263}, pmid = {16523990}, issn = {1661-8157}, mesh = {Disease Progression ; Humans ; Motor Neuron Disease/diagnosis/psychology/*therapy ; *Palliative Care/psychology ; Patient Care Team ; Quality of Life/psychology ; Terminal Care/psychology ; }, abstract = {Although disease-specific treatment of amyotrophic lateral sclerosis is still unsatisfactory, a number of advances have been made in the symptomatic therapy of ALS patients within the last decade. Current data suggest that active and aggressive multidisciplinary management of ALS patients improve their quality of life and prolong their survival. Patient and caregiver communications and decisions are increasingly recognized to be a relevant part of this management. A wide range of supportive and palliative measures, in particular the widely use of symptomatic drugs for pseudobulbar affect, sialorrhea, and sleep disorders is available to relieve patients symptomatology. In addition, patients quality of life has been profoundly improved by the introduction of enteral nutrition and non-invasive ventilation.}, }
@article {pmid16516535, year = {2006}, author = {Hart, PJ}, title = {Pathogenic superoxide dismutase structure, folding, aggregation and turnover.}, journal = {Current opinion in chemical biology}, volume = {10}, number = {2}, pages = {131-138}, doi = {10.1016/j.cbpa.2006.02.034}, pmid = {16516535}, issn = {1367-5931}, support = {R01 NS039112/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Mutation ; Proteasome Endopeptidase Complex/metabolism ; *Protein Folding ; Protein Structure, Quaternary ; Superoxide Dismutase/chemistry/genetics/*metabolism ; }, abstract = {Significant advances have been made during the past two years toward an understanding of the molecular basis for how mutations in human cytosolic copper-zinc superoxide dismutase (SOD1) cause the inherited form of amyotrophic lateral sclerosis (ALS). Biophysical studies suggest that the pathogenic mutations destabilize loop or beta-barrel structural elements of the protein. With few exceptions, the loss of metal ions and reduction of the intrasubunit disulfide bond enhance this destabilization. In mouse models of the disease, the formation of visible aggregates containing mutant SOD1 occurs relatively late in the lifespan, hinting that the quality control and protein turnover systems of motor neurons eventually become overwhelmed or compromised. Studies probing SOD1 turnover have suggested the possibility that proteolytic breakdown products may play a role in pathogenesis.}, }
@article {pmid16503123, year = {2006}, author = {Gros-Louis, F and Gaspar, C and Rouleau, GA}, title = {Genetics of familial and sporadic amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {956-972}, doi = {10.1016/j.bbadis.2006.01.004}, pmid = {16503123}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Dementia/genetics ; Disease Models, Animal ; Environment ; *Genetic Predisposition to Disease ; Guanine Nucleotide Exchange Factors/genetics ; Humans ; Mice ; Mice, Transgenic ; *Mutation ; Parkinson Disease/genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) are a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade, identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of total cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. This review provides an overview of the genetics of both familial and sporadic forms of ALS.}, }
@article {pmid16490414, year = {2006}, author = {Pittenger, C and Krystal, JH and Coric, V}, title = {Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder.}, journal = {NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {3}, number = {1}, pages = {69-81}, pmid = {16490414}, issn = {1545-5343}, support = {K05 AA 14906-01/AA/NIAAA NIH HHS/United States ; }, mesh = {Antidepressive Agents, Tricyclic/therapeutic use ; Brain/anatomy &amp; histology/pathology ; Excitatory Amino Acid Antagonists/*therapeutic use ; Glutamic Acid/cerebrospinal fluid/*physiology ; Humans ; Magnetic Resonance Imaging ; Obsessive-Compulsive Disorder/classification/*drug therapy/*physiopathology ; }, abstract = {Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD. These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.}, }
@article {pmid16488481, year = {2006}, author = {Bloom, FE and Morrison, JH and Young, WG}, title = {Neuroinformatics: a new tool for studying the brain.}, journal = {Journal of affective disorders}, volume = {92}, number = {1}, pages = {133-138}, doi = {10.1016/j.jad.2005.12.043}, pmid = {16488481}, issn = {0165-0327}, mesh = {Alzheimer Disease/genetics/*pathology/*physiopathology ; Amyloid beta-Protein Precursor/genetics ; Brain/*pathology/*physiopathology ; *Databases as Topic ; Humans ; }, abstract = {BACKGROUND: Central nervous system diseases constitute a major target for drug development. Genes expressed by the nervous system may represent half or more of the mammalian genome, with literally tens of thousands of gene products.<br><br>METHODS: Better methods are therefore required to accelerate the pace of mapping gene expression patterns in the mouse brain and to evaluate the progressive phenotypic changes in genetic models of human brain diseases.<br><br>CONCLUSIONS: Recent studies of mouse models of Amyotrophic Lateral Sclerosis and Alzheimer's disease illustrate how such data could be used for drug development. Since these two diseases-- especially Alzheimer's Disease-- entail disordered behavior, cognition and emotions, the framework and the methodology described in this article might in the future find applications in research on affective disorders.}, }
@article {pmid16472116, year = {2006}, author = {Sekine, Y and Takeda, K and Ichijo, H}, title = {The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases.}, journal = {Current molecular medicine}, volume = {6}, number = {1}, pages = {87-97}, doi = {10.2174/156652406775574541}, pmid = {16472116}, issn = {1566-5240}, mesh = {Animals ; Apoptosis ; Endoplasmic Reticulum/metabolism/*pathology ; Humans ; MAP Kinase Kinase Kinase 5/chemistry/*metabolism ; Neurodegenerative Diseases/*enzymology/*metabolism/pathology ; *Signal Transduction ; }, abstract = {Accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) lumen induces ER stress. ER stress triggers the unfolded protein response (UPR), which includes the attenuation of general protein synthesis and the transcriptional activation of the genes encoding ER-resident chaperones and molecules involved in the ER-associated degradation (ERAD). The UPR coordinately reduces ER stress by restoration of the protein-folding capacity of the ER. However, severe and/or prolonged ER stress eventually leads cells to apoptosis. Several lines of evidence suggest that ER stress-induced apoptosis plays critical roles in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPKKK family that constitutes the JNK and p38 MAP kinase (MAPK) cascades, is activated by physiological and cytotoxic stresses and induces various stress responses including apoptosis. Recent studies have shown that the ASK1-MAPK cascades are involved in ER stress-induced apoptosis and in the neuronal cell death in some model systems of neurodegenerative diseases. This review highlights the current understanding of regulatory mechanisms of ASK1 with a special focus on the ER stress-dependent and -independent neuronal cell death in the context of neurodegenerative diseases.}, }
@article {pmid16469270, year = {2006}, author = {Andersen, PM}, title = {Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.}, journal = {Current neurology and neuroscience reports}, volume = {6}, number = {1}, pages = {37-46}, pmid = {16469270}, issn = {1528-4042}, mesh = {*Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; DNA Mutational Analysis ; Disease Models, Animal ; Genetic Heterogeneity ; Humans ; Isoenzymes/genetics/metabolism ; *Mutation ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {This review highlights recent epidemiologic, clinical-genetic, and neurochemical advances in our understanding of sporadic amyotrophic lateral sclerosis (ALS) and their relationships to familial ALS caused by superoxide dismutase (SOD1) gene mutations. It is of fundamental importance to recognize that ALS is a biologically heterogeneous syndrome in which genetics, environment, and aging are inter-related. The discovery of mutations in the SOD1 gene is the greatest breakthrough in ALS research since Charcot's description of the disorder, but the putative toxic gain of function of mutant SOD1 remains elusive despite intense research. Currently, two dominant theories for the pathogenesis of SOD1 mutations exist: specific protein cytotoxicity and protein aggregation. Mutant SOD1 interacts specifically with neurofilament-light chain mRNA and the dynein/dynactin complex, suggesting that cytoskeletal defects and axonal transport are key players. In addition, mutant SOD1 protein has increased propensity to form aggregate-prone monomers, and the degree of instability correlates inversely with length of survival; therefore, increased propensity to aggregate may be the unifying common denominator for the 119 diverse SOD1 mutations.}, }
@article {pmid16450149, year = {2006}, author = {Müller, W and Fiebich, BL and Stratz, T}, title = {[5-HT3 receptor antagonist als analgetics in rheumatic diseases].}, journal = {Zeitschrift fur Rheumatologie}, volume = {65}, number = {6}, pages = {546, 548-52}, pmid = {16450149}, issn = {0340-1855}, mesh = {Analgesics/*therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Dose-Response Relationship, Drug ; Humans ; Indoles/*therapeutic use ; Pain Measurement ; Pain Threshold/drug effects ; Rheumatic Diseases/*drug therapy ; *Serotonin 5-HT3 Receptor Antagonists ; Serotonin Antagonists/*therapeutic use ; Tropisetron ; }, abstract = {Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.}, }
@article {pmid16448809, year = {2006}, author = {Durand, J and Amendola, J and Bories, C and Lamotte d'Incamps, B}, title = {Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis.}, journal = {Journal of physiology, Paris}, volume = {99}, number = {2-3}, pages = {211-220}, doi = {10.1016/j.jphysparis.2005.12.014}, pmid = {16448809}, issn = {0928-4257}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/pathology/physiology ; Nerve Net/pathology/physiopathology ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Synapses/pathology/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative and fatal human disorder characterized by progressive loss of motor neurons. Transgenic mouse models of ALS are very useful to study the initial mechanisms underlying this neurodegenerative disease. We will focus here on the earlier abnormalities observed in superoxide dismutase 1 (SOD1) mutant mice. Several hypotheses have been advanced to explain the selective loss of motor neurons such as apoptosis, neurofilament disorganisation, oxidative stress, mitochondrial dysfunction, astrogliosis and excitotoxicity. Although disease onset appears at adulthood, recent studies have detected abnormalities during embryonic and postnatal maturation in animal models of ALS. We reported that SOD1(G85R) mutant mice exhibit specific delays in acquiring sensory-motor skills during the first week after birth. In addition, physiological measurements on in vitro spinal cord preparations reveal defects in evoking rhythmic activity with N-methyl-DL-aspartate and serotonin at lumbar, but not sacral roots. This is potentially significant, as functions involving sacral roots are spared at late stages of the disease. Moreover, electrical properties of SOD1 lumbar motoneurons are altered as early as the second postnatal week when mice begin to walk. Alterations concern the input resistance and the gain of SOD1 motoneurons which are lower than in control motoneurons. Whether or not the early changes in discharge firing are responsible for the uncoupling between motor axon terminals and muscles is still an open question. A link between these early electrical abnormalities and the late degeneration of motoneurons is proposed in this short review. Our data suggest that ALS, as other neurodegenerative diseases, could be a consequence of an abnormal development of neurons and network properties. We hypothesize that the SOD1 mutation could induce early changes during the period of maturation of motor systems and that compensatory mechanisms-linked to developmental spinal plasticity-might explain the late onset of the disease.}, }
@article {pmid16445350, year = {2006}, author = {Sheta, EA and Appel, SH and Goldknopf, IL}, title = {2D gel blood serum biomarkers reveal differential clinical proteomics of the neurodegenerative diseases.}, journal = {Expert review of proteomics}, volume = {3}, number = {1}, pages = {45-62}, doi = {10.1586/14789450.3.1.45}, pmid = {16445350}, issn = {1744-8387}, mesh = {Biomarkers/blood/chemistry ; Biometry ; Electrophoresis, Gel, Two-Dimensional ; Humans ; Neurodegenerative Diseases/*blood/immunology/*metabolism ; *Proteomics ; }, abstract = {This review addresses the challenges of neuroproteomics and recent progress in biomarkers and tests for neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The review will discuss how the application of quantitative 2D gel electrophoresis, combined with appropriate single-variable and multivariate biostatistics, allows for selection of disease-specific serum biomarkers. It will also address how the use of large cohorts of specifically targeted patient blood serum samples and complimentary age-matched controls, in parallel with the use of selected panels of these biomarkers, are being applied to the development of blood tests to specifically address unmet pressing needs in the differential diagnosis of these diseases, and to provide potential avenues for mechanism-based drug targeting and treatment monitoring. While exploring recent findings in this area, the review discusses differences in critical pathways of immune/inflammation and amyloid formation between Parkinson's disease and amyotrophic lateral sclerosis, as well as discernable synergistic relationships between these pathways that are revealed by this approach. The potential for pathway measurement in blood tests for differential diagnosis, disease burden and therapeutic monitoring is also outlined.}, }
@article {pmid16437474, year = {2006}, author = {Ashworth, NL and Satkunam, LE and Deforge, D}, title = {Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD004156}, doi = {10.1002/14651858.CD004156.pub3}, pmid = {16437474}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Exercise Therapy ; Humans ; Muscle Spasticity/etiology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Spasticity commonly affects patients with motor neuron disease. It is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life.<br><br>OBJECTIVES: The objective of this review is to systematically review treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (January 2003 and January 2005), MEDLINE (January 1966 to February 2005), EMBASE (January 1980 to February 2005), CINAHL (January 1982 to February 2005), AMED (January 1985 to February 2005) and LILACS (January 1982 to January 2003). We reviewed the bibliographies of the randomized controlled trials identified, and contacted authors and experts in the field.<br><br>SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, and alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by the Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, serious adverse events, and measures of cost.<br><br>DATA COLLECTION AND ANALYSIS: We identified only one randomized controlled trial that met our inclusion criteria. Two authors extracted the data. We also contacted the author of the paper and obtained information not available in the published article.<br><br>MAIN RESULTS: The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity overall (mean reduction of -0.43, 95% CI -1.03 to +0.17 in the treatment group versus an increase of +0.25, 95% CI -0.46 to +0.96 in control) but the mean change between groups was not significant (-0.68, 95% CI -1.62 to +0.26), as measured by the Ashworth scale.<br><br>AUTHORS' CONCLUSIONS: The single trial performed was too small to determine whether individualised moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population. More research is needed.}, }
@article {pmid16425674, year = {2006}, author = {Orrell, RW}, title = {AEOL-10150 (Aeolus).}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {7}, number = {1}, pages = {70-80}, pmid = {16425674}, issn = {1472-4472}, mesh = {Animals ; Antioxidants/adverse effects/chemistry/pharmacokinetics/*therapeutic use ; Clinical Trials as Topic ; Humans ; Lung Diseases/drug therapy ; Metalloporphyrins/adverse effects/chemistry/pharmacology/*therapeutic use ; Molecular Structure ; Neoplasms/drug therapy ; Nervous System Diseases/drug therapy ; Neuroprotective Agents/adverse effects/chemistry/pharmacology/*therapeutic use ; Structure-Activity Relationship ; Treatment Outcome ; }, abstract = {AEOL-10150, a small-molecule antioxidant analogous to the catalytic site of superoxide dismutase, is under development by Aeolus (formerly Incara) as a potential subcutaneous treatment for amyotrophic lateral sclerosis (ALS), stroke, spinal cord injury, lung inflammation and mucositis. The compound is currently undergoing a phase I clinical trial for ALS. In October 2005, the company had applied for Fast Track status, and planned to submit a special protocol assessment for a pivotal phase II/III trial.}, }
@article {pmid16425672, year = {2006}, author = {Iłzecka, J}, title = {Does VEGF represent a potential treatment for amyotrophic lateral sclerosis?.}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {7}, number = {1}, pages = {54-59}, pmid = {16425672}, issn = {1472-4472}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; *Genetic Therapy ; Humans ; Motor Neurons/metabolism ; *Stem Cell Transplantation ; *Vascular Endothelial Growth Factor A/biosynthesis/genetics/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. The pathogenesis of ALS is unclear and there is no effective treatment. Vascular endothelial growth factor (VEGF) is a cytokine that has a protective function via angiogenic, neurotrophic, gliotrophic and anti-apoptotic activity. Data indicate that VEGF can inhibit neurodegeneration in ALS and may have therapeutic potential in this disease. The use of gene therapy to deliver VEGF into the central nervous system is being evaluated.}, }
@article {pmid16425251, year = {2005}, author = {Banks, GB and Chamberlain, JS}, title = {Relevance of motoneuron specification and programmed cell death in embryos to therapy of ALS.}, journal = {Birth defects research. Part C, Embryo today : reviews}, volume = {75}, number = {4}, pages = {294-304}, doi = {10.1002/bdrc.20051}, pmid = {16425251}, issn = {1542-975X}, support = {AG015434/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Animals, Genetically Modified ; *Apoptosis ; Cell Differentiation ; Embryo, Mammalian/*cytology/embryology ; Embryonic Development ; Genetic Therapy ; Humans ; Motor Neurons/*cytology/physiology ; }, abstract = {The molecular cues that generate spinal motoneurons in early embryonic development are well defined. Motoneurons are generated in excess and consequently undergo a natural period of programmed cell death. Although it is not known exactly how motoneurons compete for survival in embryonic development, it is hypothesized that they rely on the ability to access limited amounts of trophic factors from peripheral tissues, a process that is tightly regulated by skeletal muscle activity. Attempts to elucidate the molecular mechanisms that underlie motoneuron generation and programmed cell death in embryos have led to various effective strategies for treating injury and disease in animal models. Such studies provide great hope for the amelioration of human amyotrophic lateral sclerosis (ALS), a devastating progressive motoneuron degenerative disease. Here we review the clinical relevance of studying motoneuron specification and death during embryonic development.}, }
@article {pmid16416395, year = {2005}, author = {Wojtera, M and Sikorska, B and Sobow, T and Liberski, PP}, title = {Microglial cells in neurodegenerative disorders.}, journal = {Folia neuropathologica}, volume = {43}, number = {4}, pages = {311-321}, pmid = {16416395}, issn = {1641-4640}, mesh = {Alzheimer Disease/metabolism/pathology ; Animals ; Brain/*metabolism/pathology ; Disease Models, Animal ; Humans ; Microglia/*metabolism ; Nerve Degeneration/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Parkinson Disease/metabolism/pathology ; Prion Diseases/metabolism/pathology ; }, abstract = {Microglia are resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. It is widely accepted that microglia contribute to the neurodegeneration through a release of a variety of proinflammatory substances. In fact, they are not the only cells which contribute to immunological processes inside the nervous system. The CNS is composed of different cell populations that answer to pathological factors and influence each other and modulate their reactions. These complex interactions are responsible for the development of brain pathology. This paper reviews the available information on microglial cells contribution to AD, PD and prion diseases development.}, }
@article {pmid16416394, year = {2005}, author = {Bursch, W and Ellinger, A}, title = {Autophagy--a basic mechanism and a potential role for neurodegeneration.}, journal = {Folia neuropathologica}, volume = {43}, number = {4}, pages = {297-310}, pmid = {16416394}, issn = {1641-4640}, mesh = {Animals ; Autophagy/*physiology ; Cell Death/*physiology ; Humans ; Nerve Degeneration/*metabolism ; Neurons/*pathology ; }, abstract = {Autophagy constitutes a fundamental survival strategy of cells; its disturbance contributes to the pathogenesis of cancer, liver and immune disease, pathogen infection, myopathies as well as neurodegenerative disorders such as Amyotrophic lateral sclerosis, Parkinson;s, Huntington;s and Alzheimer;s disease. The pathogenesis of neurodegenerative diseases also involves a gradual and progressive loss of neuronal cells. Cells may use different pathways for active self-destruction as reflected by different morphology: while in apoptosis (or "type I") nuclear fragmentation associated with cytoplasmic condensation but preservation of organelles is predominant, autophagic degradation of the cytoplasmic structures preceding nuclear collapse is a characteristic of a second type of programmed cell death (PCD). Linking autophagy to programmed cell death initiated a controversial discussion on how a suggested role of autophagy in cell suicide might meet with its established survival function. To some extent, the diverse morphologies can be associated with distinct biochemical and molecular events [caspase-dependent and -independent death programs, DAP-kinase activity, Ras-expression, induction of autophagy genes, fate of cytoskeleton, among others]. However, there is a broad overlap between cell death pathways. Conceivably, diverse PCD programs emerged during evolution, the conservation of which allows eukaryotic cells a flexible response to physiological or pathological demands.}, }
@article {pmid16408392, year = {2005}, author = {Ingelsson, M and Nilsson, L and Basun, H and Aquilonius, SM and Lannfelt, L}, title = {[Conformationally altered proteins cause neurodegenerative diseases].}, journal = {Lakartidningen}, volume = {102}, number = {47}, pages = {3542-3, 3545-6, 3549 passim}, pmid = {16408392}, issn = {0023-7205}, mesh = {Alzheimer Disease/genetics ; Amyloid beta-Peptides/chemistry/genetics/metabolism ; Amyloid beta-Protein Precursor/chemistry/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; Brain/metabolism ; Creutzfeldt-Jakob Syndrome/genetics ; Dementia/genetics ; Humans ; Huntington Disease/genetics ; Lewy Body Disease/genetics ; Mutation ; Nerve Tissue Proteins/*genetics ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/genetics ; Prions/chemistry/genetics/metabolism ; Superoxide Dismutase/chemistry/genetics/metabolism ; alpha-Synuclein/chemistry/genetics/metabolism ; tau Proteins/chemistry/genetics/metabolism ; }, abstract = {Brain aggregates of conformationally altered proteins are key features of neurodegeneration and are believed to directly cause or contribute to disease development. Mechanisms underlying the dysregulation of proteins in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerative disorders are now being characterized, due to the discovery of genes causing rare disease forms. As of today, only symptomatic pharmacotherapies are available, but new insights into the underlying molecular mechanisms are providing strategies to prevent or even cure these devastating disorders.}, }
@article {pmid16406002, year = {2006}, author = {Maser, E}, title = {Neuroprotective role for carbonyl reductase?.}, journal = {Biochemical and biophysical research communications}, volume = {340}, number = {4}, pages = {1019-1022}, doi = {10.1016/j.bbrc.2005.12.113}, pmid = {16406002}, issn = {0006-291X}, mesh = {Alcohol Oxidoreductases/*metabolism ; Animals ; Apoptosis ; Brain/*metabolism ; Humans ; *Lipid Peroxidation ; Neurodegenerative Diseases/*metabolism ; Neurons/*metabolism ; Neuroprotective Agents/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Oxidative stress is increasingly implicated in neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, and Creutzfeld-Jakob diseases or amyotrophic lateral sclerosis. Reactive oxygen species seem to play a significant role in neuronal cell death in that they generate reactive aldehydes from membrane lipid peroxidation. Several neuronal diseases are associated with increased accumulation of abnormal protein adducts of reactive aldehydes, which mediate oxidative stress-linked pathological events, including cellular growth inhibition and apoptosis induction. Combining findings on neurodegeneration and oxidative stress in Drosophila with studies on the metabolic characteristics of the human enzyme carbonyl reductase (CR), it is clear now that CR has a potential physiological role for neuroprotection in humans. Several lines of evidence suggest that CR represents a significant pathway for the detoxification of reactive aldehydes derived from lipid peroxidation and that CR in humans is essential for neuronal cell survival and to confer protection against oxidative stress-induced brain degeneration.}, }
@article {pmid16394148, year = {2005}, author = {Wang, S and Melhem, ER}, title = {Amyotrophic lateral sclerosis and primary lateral sclerosis: The role of diffusion tensor imaging and other advanced MR-based techniques as objective upper motor neuron markers.}, journal = {Annals of the New York Academy of Sciences}, volume = {1064}, number = {}, pages = {61-77}, doi = {10.1196/annals.1340.013}, pmid = {16394148}, issn = {0077-8923}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Biomarkers ; Brain/*pathology/physiopathology ; Diagnosis, Differential ; Diffusion Magnetic Resonance Imaging/*methods/trends ; Efferent Pathways/*pathology/physiopathology ; Humans ; Magnetic Resonance Imaging/methods/trends ; Magnetic Resonance Spectroscopy/methods ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/*pathology ; Predictive Value of Tests ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a motor neuron disease characterized by progressive degeneration of upper motor neuron (UMN) and lower motor neuron (LMN), while primary lateral sclerosis (PLS) is defined by pure UMN involvement. A reliable objective marker of UMN involvement is critical for the early diagnosis and monitoring of disease progression in patients with ALS and PLS. Diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and magnetic resonance spectroscopy (MRS), which provide insight into the pathophysiological process of ALS and PLS, show great promise in this regard. Further investigation is needed to determine and to compare the utility of various neuroimaging markers.}, }
@article {pmid16389307, year = {2005}, author = {Sang, TK and Jackson, GR}, title = {Drosophila models of neurodegenerative disease.}, journal = {NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {2}, number = {3}, pages = {438-446}, pmid = {16389307}, issn = {1545-5343}, support = {U54 ES012078/ES/NIEHS NIH HHS/United States ; AG016570/AG/NIA NIH HHS/United States ; NS002116/NS/NINDS NIH HHS/United States ; P50 AG016570/AG/NIA NIH HHS/United States ; R01 NS046489/NS/NINDS NIH HHS/United States ; ES12078/ES/NIEHS NIH HHS/United States ; NS046489/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/pathology ; Animals ; Disease Models, Animal ; Drosophila/*genetics/*physiology ; Eye/pathology ; Humans ; Neurodegenerative Diseases/*genetics/*pathology ; Parkinson Disease/genetics/pathology ; Trinucleotide Repeats ; }, abstract = {Over the last two decades, a number of mutations have been identified that give rise to neurodegenerative disorders, including familial forms of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although in most cases sporadic cases vastly outnumber familial forms of such diseases, study of such inherited forms has the potential to provide powerful clues regarding the pathophysiological basis of neurodegeneration. One powerful approach to analyzing disease mechanisms is the development of transgenic animal models, most notably in the mouse. However, development and analysis of such models can be costly and time consuming. Development of improved transgenic technologies have contributed to the development of Drosophila models of a number of neurodegenerative disorders that have shown striking similarities to the human diseases. Moreover, genetic screens using such models have begun to unravel aspects of the pathophysiological basis of neurodegenerative disorders. Here, we provide a general overview of fly models pertinent to trinucleotide repeat expansion disorders, Alzheimer's, and Parkinson's diseases, and highlight key genetic modifiers that have been identified to date using such models.}, }
@article {pmid16382340, year = {2005}, author = {Kitzberger, R and Madl, C and Ferenci, P}, title = {Wilson disease.}, journal = {Metabolic brain disease}, volume = {20}, number = {4}, pages = {295-302}, pmid = {16382340}, issn = {0885-7490}, mesh = {Animals ; Brain/pathology ; Copper/metabolism ; Hepatolenticular Degeneration/diagnosis/*metabolism/pathology/psychology ; Humans ; Liver/metabolism ; }, abstract = {Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism, resulting in pathological accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings. The leading neurologic symptoms in WD are dysathria, dyspraxia, ataxia, and Parkinsonian-like extrapyramidal signs. Changes in the basal ganglia in brain magnetic resonance imaging (MRI) are characteristic features of the disease. In presence of liver cirrhosis, some features may resemble hepatic encephalopathy. Symptoms and MRI abnormalities may be fully reversible on treatment with zinc or copper chelators. Improvement can be monitored by serial recording of brain-stem-evoked responses. The basic defect is an impaired trafficking of copper in hepatocytes. ATP7B is the gene product of the WD gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. While about 40% of patients preset with neurologic symptoms, little is known about the role of copper and ATP7B in the central nervous system. In some brain areas, like in the pineal gland, ATP7B is expressed and functionally active. Increasing evidence supports an important role for metals in neurobiology. Two proteins related to neurodegeneration are copper-binding proteins (1) the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and (2) the Prion protein, related to Creutzfeldt-Jakob disease. A major source of free-radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. APP is a major regulator of neuronal copper homeostasis and has a copper-binding domain (CuBD). The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter. There are several copper-containing enzymes in the brain, like dopamine beta hydroxylase or Cu/Zn superoxide dismutase (SOD1). Their function may be altered because of copper overload. WD appears to be associated with a dopaminergic deficit. Mutations in the SOD1gene cause familial amyotrophic lateral sclerosis. Survival of transgenic mice with a mutant SOD1 which fails to incorporate Cu((2+)) in its active site was improved by copper depletion. Wilson disease (WD) is an autosomal recessive inherited disorder in which copper pathologically accumulates primarily within the liver and subsequently in the neurologic system and many other organs and tissues. Presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings are the hallmarks of the disease.}, }
@article {pmid16375723, year = {2005}, author = {Maiese, K and Chong, ZZ and Li, F}, title = {Driving cellular plasticity and survival through the signal transduction pathways of metabotropic glutamate receptors.}, journal = {Current neurovascular research}, volume = {2}, number = {5}, pages = {425-446}, pmid = {16375723}, issn = {1567-2026}, support = {P30 ES006639/ES/NIEHS NIH HHS/United States ; R01 NS053946/NS/NINDS NIH HHS/United States ; R01 NS053946-01A2/NS/NINDS NIH HHS/United States ; P30 ES06639/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cell Survival/physiology ; Central Nervous System/*metabolism ; Cytoprotection/physiology ; Glutamic Acid/*metabolism ; Humans ; Neurodegenerative Diseases/metabolism/physiopathology ; Neuronal Plasticity/*physiology ; Neurons/*metabolism ; Receptors, Metabotropic Glutamate/*metabolism ; Signal Transduction/*physiology ; }, abstract = {Metabotropic glutamate receptors (mGluRs) share a common molecular morphology with other G protein-linked receptors, but there expression throughout the mammalian nervous system places these receptors as essential mediators not only for the initial development of an organism, but also for the vital determination of a cell's fate during many disorders in the nervous system that include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, Multiple Sclerosis, epilepsy, trauma, and stroke. Given the ubiquitous distribution of these receptors, the mGluR system impacts upon neuronal, vascular, and glial cell function and is activated by a wide variety of stimuli that includes neurotransmitters, peptides, hormones, growth factors, ions, lipids, and light. Employing signal transduction pathways that can modulate both excitatory and inhibitory responses, the mGluR system drives a spectrum of cellular pathways that involve protein kinases, endonucleases, cellular acidity, energy metabolism, mitochondrial membrane potential, caspases, and specific mitogen-activated protein kinases. Ultimately these pathways can converge to regulate genomic DNA degradation, membrane phosphatidylserine (PS) residue exposure, and inflammatory microglial activation. As we continue to push the envelope for our understanding of this complex and critical family of metabotropic receptors, we should be able to reap enormous benefits for both clinical disease as well as our understanding of basic biology in the nervous system.}, }
@article {pmid16372325, year = {2006}, author = {Hervias, I and Beal, MF and Manfredi, G}, title = {Mitochondrial dysfunction and amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {33}, number = {5}, pages = {598-608}, doi = {10.1002/mus.20489}, pmid = {16372325}, issn = {0148-639X}, support = {P01 NS011766-27/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*pathology ; Animals ; Apoptosis/physiology ; Calcium/metabolism ; Humans ; Mitochondrial Diseases/*complications/genetics ; Models, Biological ; Mutation ; Neurons/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are still unknown. Several lines of evidence suggest that mitochondrial dysfunction may be involved in the pathogenesis of ALS. Biochemical and morphological mitochondrial abnormalities have been demonstrated in postmortem spinal cords of ALS patients. Furthermore, in transgenic mice expressing mutant Cu,Zn-superoxide dismutase (SOD1), the antioxidant enzyme associated with familial ALS (FALS), mitochondrial abnormalities precede the disease onset, suggesting that mitochondrial dysfunction is causally involved in the pathogenesis of SOD1-FALS. Despite this evidence, it is not yet fully understood how mutant SOD1 damages mitochondria. Recent work has demonstrated that a portion of mutant SOD1 is localized in mitochondria, both in transgenic mice and in FALS patients, where it forms proteinaceous aggregates. These findings have opened new avenues of investigation addressing the hypothesis that mutant SOD1 may directly damage mitochondria. Major future challenges will be to better understand the mechanisms and the consequences of mitochondrial dysfunction in ALS. If mitochondrial dysfunction is convincingly involved in ALS pathogenesis, either as a primary cause or as contributing factor, it is likely to become a novel target for therapeutic intervention.}, }
@article {pmid16370379, year = {2005}, author = {Kawaja, MD}, title = {A proteomic approach to assess intraneuronal inclusions associated with neurodegenerative disorders.}, journal = {Current opinion in molecular therapeutics}, volume = {7}, number = {6}, pages = {565-568}, pmid = {16370379}, issn = {1464-8431}, mesh = {Animals ; Humans ; Inclusion Bodies/*metabolism ; Lewy Bodies/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurofibrillary Tangles/metabolism ; Proteomics/*methods ; }, abstract = {In neuroscience, proteomic technology is being used to discover the chemical features of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Pathologically, one hallmark feature common to these diseases is the presence of proteinaceous inclusions within affected neurons. Proteomic assessment of diseased tissues and animal models reveals that the occurrence of these protein-rich aggregations may be due to perturbed functioning of a neuron-specific ubiquitin-recycling enzyme.}, }
@article {pmid16370136, year = {2005}, author = {Silha, JV and Murphy, LJ}, title = {Insulin-like growth factor binding proteins in development.}, journal = {Advances in experimental medicine and biology}, volume = {567}, number = {}, pages = {55-89}, doi = {10.1007/0-387-26274-1_3}, pmid = {16370136}, issn = {0065-2598}, mesh = {Animals ; Embryo, Mammalian/*physiology ; Humans ; Insulin-Like Growth Factor Binding Proteins/*physiology ; }, abstract = {IGFBPs regulate growth and development by regulating IGF transport to tissues and IGF bioavailability to IGF receptors at cell membrane level. IGFBP excess leads predominantly to inhibition of IGF action and growth retardation with impaired organogenesis. Absence of human and also mouse ALS leads to decreased IGF-I levels in circulation and causes mild growth retardation. Although IGFBP KO mice demonstrate relatively minor phenotypes, the possibility of compensatory mechanisms that mask the phenotypic manifestation of lack of individual binding proteins needs to be further investigated. Recent studies of hepatic regeneration in IGFBP-1 KO mice and also with mutant IGFBP-3 Tg mice provide some limited support for the existence of IGF-independent mechanism of action in vivo.}, }
@article {pmid16369209, year = {2005}, author = {Yakar, S and Sun, H and Zhao, H and Pennisi, P and Toyoshima, Y and Setser, J and Stannard, B and Scavo, L and Leroith, D}, title = {Metabolic effects of IGF-I deficiency: lessons from mouse models.}, journal = {Pediatric endocrinology reviews : PER}, volume = {3}, number = {1}, pages = {11-19}, pmid = {16369209}, issn = {1565-4753}, mesh = {Animals ; *Disease Models, Animal ; Drug Interactions ; Human Growth Hormone/pharmacology/physiology ; Insulin/pharmacology ; Insulin-Like Growth Factor I/*deficiency/genetics/physiology ; Liver/metabolism ; Metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; }, abstract = {Insulin and insulin-like growth factors (IGFs) belong to the most biologically characterized family of peptides involved in metabolism, growth and development. The cellular responses to the IGFs are mediated primarily by the IGF-I receptor. The IGF-I receptor is a member of the family of tyrosine kinase growth factor receptors, and is highly homologous (70%) to the insulin receptor, especially in the tyrosine kinase domain (84%) ADDIN. Upon ligand binding to the extracellular region, the intrinsic tyrosine kinase domain of the receptor is activated. In the past it was believed that insulin activates primarily metabolic processes while IGFs promote cell growth and differentiation. However, in the last two decades many animal models of IGFI deficiency and excess revealed the importance of IGF-I in carbohydrate and lipid metabolism and now it is clear that these peptide hormones together with growth hormone (GH) work in a coordinate and interdependent manner. In the circulation, IGFs are bound in a binary complex with a family of high affinity IGF-binding proteins (IGFBPs) ADDIN. However, most of the circulating IGF-I associates with a high molecular weight complex approximately 150 KDa consisting of IGFBP-3 and the acid labile subunit (ALS) ADDIN. Once the ternary complex dissociates, the binary complexes of IGFBP-IGFs are removed from the circulation and by crossing the endothelium to reach the target tissues and to interact with cell surface receptors. In the present review we will summarize the role of GH and IGF in somatic growth and focus on the metabolic effects of IGF-I deficiency as assessed in various mouse models.}, }
@article {pmid16366737, year = {2005}, author = {Kidd, PM}, title = {Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management.}, journal = {Alternative medicine review : a journal of clinical therapeutic}, volume = {10}, number = {4}, pages = {268-293}, pmid = {16366737}, issn = {1089-5159}, mesh = {Aging/physiology ; *Dietary Supplements ; Humans ; Mitochondria/physiology ; Mitochondrial Diseases/complications/*therapy ; Nerve Growth Factor/*therapeutic use ; Neurodegenerative Diseases/etiology/*therapy ; Oxidative Stress ; *Stem Cell Transplantation ; }, abstract = {Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.}, }
@article {pmid16362828, year = {2005}, author = {Rocha, JA and Reis, C and Simões, F and Fonseca, J and Mendes Ribeiro, J}, title = {Diagnostic investigation and multidisciplinary management in motor neuron disease.}, journal = {Journal of neurology}, volume = {252}, number = {12}, pages = {1435-1447}, pmid = {16362828}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/physiopathology/therapy ; Bulbar Palsy, Progressive ; Diagnosis, Differential ; Diagnostic Imaging/methods ; Electrophysiology/methods ; Humans ; Motor Neuron Disease/classification/*diagnosis/*therapy ; Muscle Weakness/etiology ; Neurologic Examination ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Spinocerebellar Degenerations ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. ALS is a progressive neurodegenerative disorder, involving motor neurons in the cerebral cortex, brainstem and spinal cord, presenting with a combination of upper and lower motor neuron signs. Etiology remains undetermined, although a multifactorial origin is widely accepted including genetic factors, auto-immunity, oxidative stress, glutamate excitotoxicity and abnormal neurofilament aggregation. The absence of specific diagnostic testing, and variable clinical presentations make the diagnosis of ALS challenging, relying upon correlation of clinical, electrophysiological and neuroimaging data. The disease is relentlessly progressive, with dysarthria, dysphagia, tetraparesis, and respiratory insufficiency due to ongoing respiratory muscle paresis. There is no specific treatment for ALS. Riluzole, a glutamate antagonist, is the only FDA approved drug for ALS, but has only a modest effect on survival. The multiplicity and progressiveness of the disabilities in ALS, highlights the need for a coordinated multidisciplinary rehabilitation program managing symptoms, respiratory care, dysphagia and nutrition, dysarthria and communication, physical and occupational therapy. The main goals are to prolong independence, prevent complications and improve quality of life.}, }
@article {pmid16341066, year = {2005}, author = {Zhou, J and Neale, JH and Pomper, MG and Kozikowski, AP}, title = {NAAG peptidase inhibitors and their potential for diagnosis and therapy.}, journal = {Nature reviews. Drug discovery}, volume = {4}, number = {12}, pages = {1015-1026}, doi = {10.1038/nrd1903}, pmid = {16341066}, issn = {1474-1776}, mesh = {Animals ; Glutamate Carboxypeptidase II/*antagonists &amp; inhibitors ; Humans ; Male ; Nervous System Diseases/diagnosis/drug therapy ; Prostatic Neoplasms/diagnosis/drug therapy ; Protease Inhibitors/chemistry/*therapeutic use ; }, abstract = {Modulation of N-acetyl-L-aspartyl-L-glutamate peptidase activity with small-molecule inhibitors holds promise for a wide variety of diseases that involve glutamatergic transmission, and has implications for the diagnosis and therapy of cancer. This new class of compounds, of which at least one has entered clinical trials and proven to be well tolerated, has demonstrated efficacy in experimental models of pain, schizophrenia, amyotrophic lateral sclerosis, traumatic brain injury and, when appropriately functionalized, can image prostate cancer. Further investigation of these promising drug candidates will be needed to bring them to the marketplace. The recent publication of the X-ray crystal structure for the enzymatic target of these compounds should facilitate the development of other new agents with enhanced activity that could improve both the diagnosis and treatment of neurological disorders.}, }
@article {pmid16341065, year = {2005}, author = {O'Connor, KA and Roth, BL}, title = {Finding new tricks for old drugs: an efficient route for public-sector drug discovery.}, journal = {Nature reviews. Drug discovery}, volume = {4}, number = {12}, pages = {1005-1014}, doi = {10.1038/nrd1900}, pmid = {16341065}, issn = {1474-1776}, mesh = {Anti-Bacterial Agents/pharmacology ; Antipsychotic Agents/pharmacology ; *Drug Design ; Drug Evaluation, Preclinical/methods ; Drug Therapy/economics/methods/*trends ; Efficiency ; *Efficiency, Organizational/economics/trends ; Fenfluramine/adverse effects ; Humans ; Neuroprotective Agents/pharmacology ; Phentermine/adverse effects ; Public Sector/*economics/trends ; Technology, Pharmaceutical/economics/methods/trends ; }, abstract = {With the annotation of the human genome approaching completion, public-sector researchers - spurred in part by various National Institutes of Health Roadmap Initiatives - have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of 'drug-like' compounds can be readily screened to yield chemically novel scaffolds, transforming these 'chemical probes' into drugs is a daunting endeavour. A more efficient approach involves screening libraries of approved and off-patent medications; both phenotypic- and molecular target-based screening of 'old drugs' can readily yield compounds that could be immediately used in clinical trials. Using case studies, we describe how this approach has rapidly identified candidate medications suitable for clinical trials in disorders such as progressive multifocal leukoencephalopathy and amyotrophic lateral sclerosis. This approach has also led to the discovery of the molecular targets responsible for serious drug side effects, thereby allowing efficient 'counter-screening' to avoid these side effects.}, }
@article {pmid16326257, year = {2006}, author = {Vesely, MR and Kelemen, MD}, title = {Cardiac risk assessment: matching intensity of therapy to risk.}, journal = {Cardiology clinics}, volume = {24}, number = {1}, pages = {67-78}, doi = {10.1016/j.ccl.2005.09.010}, pmid = {16326257}, issn = {0733-8651}, mesh = {Age Distribution ; Aged ; Aged, 80 and over ; Critical Care/organization &amp; administration/standards ; *Electrocardiography ; Emergency Service, Hospital/*organization &amp; administration ; Female ; Guidelines as Topic/standards ; Humans ; Incidence ; Male ; Middle Aged ; Myocardial Infarction/diagnosis/epidemiology/*therapy ; Prognosis ; Risk Assessment/*methods ; Sensitivity and Specificity ; Severity of Illness Index ; Sex Distribution ; Survival Rate ; Thrombolytic Therapy/methods ; }, abstract = {Simple RSS allow for rapid decision making in the emergency department. The data presented in this article suggest that for patients at the highest risk and the lowest risk for complications of NSTEACS, the scoring systems work well and allow effective triage and treatment. For patients at intermediate risk (30%-40% of all patients who have ACS), however, it is not clear whether early aggressive treatment with cardiac catheterization or routine conservative management should be the standard of care. The consensus guidelines are vague, and the scoring systems discriminate less well for these patients. The authors think that patients at intermediate risk are best served by initial screening with an RSS like the TRS (with risk scores of 3-4), followed by a multimarker strategy to define risk better. They also think that the next step is to design clinical trials to test strategies of care defined prospectively by risk. This step would, in the authors' opinion, begin the next round of the cycle of clinical therapeutics [31]. The treatment of patients who have NSTE ACS has been characterized in the past 2 decades by care based on evidence from many excellent clinical tri-als. The consensus panels have convened and guide patient management. Quality-improvement initiatives such as CRUSADE and GRACE give feedback to improve compliance with guidelines. The understanding of risk is developing with the help of these scoring systems. Discovery is ongoing. The next decade of acute cardiac care will focus on early identification of patients at high risk and on matching the most intensive treatments to the patients most in need. Excessive testing and care promotes cost inefficiency and, perhaps, increased hazard for some patients. New trials are needed to move these new hypotheses back into practice.}, }
@article {pmid16325011, year = {2005}, author = {Pekarik, V}, title = {Design of shRNAs for RNAi-A lesson from pre-miRNA processing: possible clinical applications.}, journal = {Brain research bulletin}, volume = {68}, number = {1-2}, pages = {115-120}, doi = {10.1016/j.brainresbull.2005.08.007}, pmid = {16325011}, issn = {0361-9230}, mesh = {Animals ; Humans ; Huntington Disease/*genetics ; MicroRNAs/*genetics ; *RNA Interference ; RNA Processing, Post-Transcriptional ; Spinocerebellar Ataxias/*genetics ; }, abstract = {RNA interference has become the tool of choice to analyse the loss-of-function of individual genes and has been exploited to identify complex regulatory pathways following genomic screening. RNAi has both admirers and detractors, but is undeniably a technique with great potential, which has come a long way in the short time since its discovery. RNAi utilises cellular machinery associated with the processing of naturally occurring micro RNA (miRNAs). Effective use of RNAi requires detailed knowledge of the individual steps and the proteins involved, as well as the similarities and distinctions between miRNA and siRNA pathways. RNAi was originally induced by the introduction of long double stranded RNAs (dsRNAs) into cells in which the RNA was cleaved into short RNAs which effectively interfered with a transcription of cognate mRNA. More recently an introduction of short approximately 22 nucleotide RNA duplexes has become the standard in short-term experiments, but is insufficient for long-term knock-down assays. Long-term expression of siRNAs has been achieved by in vivo transcription from plasmids coding for short hairpin RNAs (shRNAs). The cellular processing of shRNAs shares common features with the biogenesis of naturally occurring miRNA such as cleavage by nuclear RNase Drosha, export from the nucleus, processing by a cytoplasmic RNase Dicer, and incorporation into the RNA-induced silencing complex (RISC). Each step has a crucial influence on the efficiency of RNAi and their consideration should be a part of a standard experimental design. RNAi has moved from a purely experimental technique to the stage of potential clinical applications. The possible use of RNAi in the treatment of spinocerebellar ataxia or amyotrophic lateral sclerosis, with its advantages and pitfalls and possible extensions to other diseases are discussed.}, }
@article {pmid16324529, year = {2005}, author = {Valdés Chavarri, M and Pascual Figal, D and Prósper Cardoso, F and Moreno Montañés, J and García Olmos, D and Barcia Albacar, JA}, title = {[Regenerative medicine with adult stem cells].}, journal = {Revista clinica espanola}, volume = {205}, number = {11}, pages = {556-564}, doi = {10.1016/s0014-2565(05)72638-2}, pmid = {16324529}, issn = {0014-2565}, mesh = {Brain Diseases/surgery ; Heart Diseases/surgery ; Humans ; Nerve Regeneration ; Regenerative Medicine/methods ; *Stem Cell Transplantation ; }, abstract = {The present state of clinical regenerative medicine with adult stem cells in the cardiology, digestive, corneal and neurological fields are reviewed. From the cardiology point of view, there is clinical experience with bone marrow stem cells and peripheral blood cells and with skeletal myoblasts. At present, the adult stem cells (bone marrow hematopoietic or mesenchymal) constitute the best option for the regeneration of heart tissue, the clinical studies showing favorable results without ethical or safety problems. Most of the studies with skeletal myoblasts have also been demonstrated to significantly contribute to improve heart function, above all, the systolic one. However they have the disadvantage that has not been totally clarified that they induce malignant ventricular arrhythmias. In either case, the clinical studies are in the initial phase and new studies, above all randomized, are necessary. In the digestive field, there is the pioneer experience of the Hospital La Paz on the use of stem cells from abdominal fat in the treatment of fistulous condition of patients with Crohn's disease. In ophthalmology, the limbal corneal transplant is a recognized practice, using cells from the contralateral eye when the damage is in a single eye and cells from a donor when the damage is bilateral. Finally, in the neurological field, different zones of the adult mammal brain where there are stem cells have been identified: the hippocampus, subventricular zone, olfactory bulb and periependymal zone of the spinal cord. On the other hand, neurons may be obtained from adult stem cells from other tissues, such as the bone marrow or adipose tissue, which means a practically unendable source of neural precursors, either by direct implant after their selection or after their in vitro culture. However, most of the experimentation is animal up to now, clinical trails on safety in amyotrophic lateral sclerosis are now being initiated.}, }
@article {pmid16319945, year = {2006}, author = {Raoul, C and Barker, SD and Aebischer, P}, title = {Viral-based modelling and correction of neurodegenerative diseases by RNA interference.}, journal = {Gene therapy}, volume = {13}, number = {6}, pages = {487-495}, doi = {10.1038/sj.gt.3302690}, pmid = {16319945}, issn = {0969-7128}, mesh = {Animals ; Genetic Engineering ; Genetic Therapy/*methods ; Genetic Vectors/administration &amp; dosage/genetics ; Humans ; Models, Animal ; Neurodegenerative Diseases/*therapy ; *RNA Interference ; Virus Diseases/genetics ; Viruses/genetics ; }, abstract = {Experimental recapitulation of recessive human genetic neurodegenerative disease in rodents can be classically addressed through genetic disruption of the related gene. Although very informative, this specific gene targeting is restricted to mice and precludes a species scale-up towards non-human primates. Concomitantly, this requirement to silence a specific gene in a broad range of animal models is important in the design of therapeutic approaches to dominantly inherited neurodegenerative diseases. The emergence of RNA interference (RNAi), a highly specific mechanism of post-translational gene silencing, has opened a plethora of biological application ranging from reverse genetic analysis to therapeutic schemes. Recombinant viral vectors, by promoting a long-lasting delivery of genetic instructions in a broad range of cellular types of different species origins, represent potential platforms mandating silencing of specific gene products through RNAi. This review aims at providing an overview of the different viral systems engineered so far for efficient in vitro and in vivo delivery of RNAi instructions. Additionally, the potential of RNAi for functional analysis and therapy for polyglutamine disorders or amyotrophic lateral sclerosis is discussed.}, }
@article {pmid16319023, year = {2005}, author = {de Carvalho, M and Costa, J and Swash, M}, title = {Clinical trials in ALS: a review of the role of clinical and neurophysiological measurements.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {4}, pages = {202-212}, doi = {10.1080/14660820510011997}, pmid = {16319023}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Clinical Trials as Topic ; Data Interpretation, Statistical ; Disease Progression ; Humans ; Neurophysiology ; Quality Control ; *Randomized Controlled Trials as Topic ; Reproducibility of Results ; Survival Rate ; Treatment Outcome ; }, abstract = {We have reviewed all the published clinical trials of ALS and, from those considered sufficiently large, and containing a control group, we have evaluated their methodology with regard to statistical power. This implies a critical analysis of the endpoint measurements. We have concluded that clinical endpoints used in clinical trials of ALS have frequently been insufficiently sensitive, non-linear, or even not intuitively highly relevant to the disease. We suggest that the ALS-FRS, perhaps also MUNE and the Neurophysiological Index, may be the best measures currently available. These techniques have complementary characteristics that allow them to be used to address different aspects of the disease and its treatment in various trials designs. In the past some trials may have failed to demonstrate a treatment effect because the chosen endpoint measures and the trial design were inappropriate.}, }
@article {pmid16317253, year = {2005}, author = {Kertesz, A}, title = {Frontotemporal dementia: one disease, or many?: probably one, possibly two.}, journal = {Alzheimer disease and associated disorders}, volume = {19 Suppl 1}, number = {}, pages = {S19-24}, doi = {10.1097/01.wad.0000183080.69196.64}, pmid = {16317253}, issn = {0893-0341}, mesh = {Aphasia/etiology ; Female ; Humans ; Male ; Middle Aged ; Nerve Tissue Proteins/genetics ; Pick Disease of the Brain/genetics/*pathology/*psychology ; Social Behavior Disorders/etiology ; tau Proteins ; }, abstract = {Accumulating evidence suggest that frontotemporal dementia is best viewed as a clinical syndrome even though there are distinct presentations of the behavioral variety, progressive aphasia, semantic dementia, corticobasal degeneration and progressive supranuclear palsy. Similarly the pathology should be regarded as a spectrum even though histological varieties are distinguished. More than half of FTD pathology is associated with ubiquitin positive and tau negative inclusions that are common in ALS. However the majority of FTD cases do not have ALS clinically and relatively few ALS cases develop FTD. The pathological and biochemical varieties can be dichotomized as tau positive and tau negative pathology and biochemistry. The genetics of the tau positive variety is associated with tau mutations and so far the tau negative variety is not, although some are linked to chromosome-17 also. There is a corresponding clinical dichotomy combining the behavioral variety of FTD presentation with semantic dementia and usually ubiquitin positive tau negative pathology on one hand and the association of primary progressive aphasia and cortical basal degeneration/PSP syndrome with tau positive pathology on the other. The overlap between them is too great to establish two separate diseases.}, }
@article {pmid16314222, year = {2005}, author = {Ritch, R}, title = {Complementary therapy for the treatment of glaucoma: a perspective.}, journal = {Ophthalmology clinics of North America}, volume = {18}, number = {4}, pages = {597-609}, doi = {10.1016/j.ohc.2005.07.004}, pmid = {16314222}, issn = {0896-1549}, mesh = {Complementary Therapies/*methods ; Glaucoma/*drug therapy ; Humans ; *Phytotherapy ; Plant Preparations/*therapeutic use ; Treatment Outcome ; }, abstract = {Although neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems, including trauma, epilepsy, stroke, Huntington disease, amyotrophic lateral sclerosis,and AIDS dementia, none have yet been applied to the treatment of glaucoma. A prospective, placebo-controlled, multi-institutional trial of memantine is underway. One would not expect the treatment modalities that form the bases of nonpharmaceutical, traditional medical systems to be used to lower IOP. Glaucoma was unknown when these medicinal treatments were developed over the centuries. Their primary use is in improving the cardiovascular and immune systems and in what is now called neuro-protection. Rather than single compounds that target a specific receptor and have demarcated side effects in other systems, plant products are a blend of many compounds and, according to those most versed in them, they achieve a balanced therapy, helping in specific symptomatic complexes while reducing side effects through ameliorating effects in other areas. It is not insignificant that, now that the rain forests are rapidly dwindling, together with their inhabitants and the knowledge of medicinal plants (especially in South America), the pharmaceutical companies are spending large amounts of money in a sudden, almost frantic attempt to gather the knowledge about rainforest plants before all has been completely lost. Proof of effects clinically in a chronic disease such as glaucoma remains largely lacking, and controlled trials are unlikely to be initiated, except perhaps through the National Institutes of Health, because these compounds have been in the public domain for many years. Perhaps those as yet unknown or un-recorded are patentable and perhaps these include drugs known only to small surviving communities of hunter-gatherers, which explains the pharmaceutical interest in these areas. When more accurate and rapid means of assessment of progression of glaucomatous damage than perimetry and optic nerve head photography are eventually developed and trials can be reduced in time, number of subjects, or even the use of nonhuman subjects for the bulk of studies, studies could be done for verification of effect of various compounds and also comparative studies. At the present time, GBE is the best documented of all the complementary medicinal agents and seems to have the greatest potential value. Ginkgo biloba extract has numerous properties that theoretically should be beneficial in treating non-IOP-dependent mechanisms in glaucoma. Its multi-ple beneficial actions, including increased ocular blood flow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity, combine to suggest that GBE could prove to be of major therapeutic value in the treatment of glaucoma.}, }
@article {pmid16308486, year = {2005}, author = {Kawahara, M}, title = {Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {8}, number = {2}, pages = {171-82; discussion 209-15}, doi = {10.3233/jad-2005-8210}, pmid = {16308486}, issn = {1387-2877}, mesh = {Aluminum/metabolism/*toxicity ; Alzheimer Disease/*physiopathology ; Amyloid beta-Peptides/metabolism ; Apoptosis/drug effects ; Brain/drug effects/physiopathology ; Homeostasis/drug effects ; Humans ; Metals/metabolism/toxicity ; Neurodegenerative Diseases/*physiopathology ; Neurons/drug effects ; Protein Conformation/drug effects ; }, abstract = {Aluminum is environmentally abundant, but not an essential element. Aluminum has been associated with several neurodegenerative diseases, such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this association remains controversial, there is increasing evidence which suggests the implication of metal homeostasis in the pathogenesis of Alzheimer's disease. Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's amyloid-beta protein. Al causes the accumulation of tau protein and amyloid-beta protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as well as in vitro. Furthermore, a relationship between aluminum and the iron-homeostasis or calcium-homeostasis has been suggested. Based on these findings, the characteristics of aluminum neurotoxicity are reviewed, and the potential link between aluminum and neurodegenerative diseases is reconsidered.}, }
@article {pmid16301836, year = {2005}, author = {Zachary, I}, title = {Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential.}, journal = {Neuro-Signals}, volume = {14}, number = {5}, pages = {207-221}, doi = {10.1159/000088637}, pmid = {16301836}, issn = {1424-862X}, mesh = {Animals ; Humans ; Nervous System Diseases/drug therapy ; Neurons/physiology ; *Neuroprotective Agents ; Receptors, Vascular Endothelial Growth Factor/biosynthesis/genetics ; Signal Transduction/*drug effects ; Vascular Endothelial Growth Factor A/genetics/*pharmacology/*physiology/therapeutic use ; }, abstract = {Vascular endothelial growth factor (VEGF or VEGF-A) and its receptors play essential roles in the formation of blood vessels during embryogenesis and in disease. Most biological effects of VEGF are mediated via two receptor tyrosine kinases, VEGFR1 and VEGFR2, but specific VEGF isoforms also bind neuropilins (NP) 1 and 2, non-tyrosine kinase receptors originally identified as receptors for semaphorins, polypeptides with essential roles in neuronal patterning. There is abundant evidence that VEGF-A has neurotrophic and neuroprotective effects on neuronal and glial cells in culture and in vivo, and can stimulate the proliferation and survival of neural stem cells. VEGFR2 and NP1 are the major VEGF receptors expressed on neuronal cells and, while the mechanisms mediating neuroprotective effects of VEGF are not fully understood, VEGF stimulates several signalling events in neuronal cell types, including activation of phospholipase C-gamma, Akt and ERK. Findings in diverse models of nerve damage and disease suggest that VEGF has therapeutic potential as a neuroprotective factor. VEGF is a key mediator of the angiogenic response to cerebral and peripheral ischaemia, and promotes nerve repair following traumatic spinal injury. Recent work has revealed a role for reduced VEGF expression in the pathogenesis of amyotrophic lateral sclerosis, a rare neurodegenerative disease caused by selective loss of motor neurons. In many instances, the neuroprotective effects of VEGF appear to result from a combination of the indirect consequences of increased angiogenesis, and the direct stimulation of neuronal function. However, more work is required to determine the specific functional role of direct neuronal effects of VEGF.}, }
@article {pmid16296872, year = {2005}, author = {Dib, M}, title = {Issues for clinical drug development in neurodegenerative diseases.}, journal = {Drugs}, volume = {65}, number = {17}, pages = {2463-2479}, pmid = {16296872}, issn = {0012-6667}, mesh = {Animals ; Biomarkers ; Clinical Trials as Topic ; Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*drug therapy/genetics/physiopathology ; Neuroprotective Agents ; Survival Analysis ; Treatment Outcome ; }, abstract = {Neurodegenerative diseases pose specific challenges for drug development. These diseases typically have a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost. It is important to identify vulnerability factors and other determinants of clinical course in order to be able in the future to select patient populations for clinical trials with a predictable prognosis. The neurodegenerative process itself is not amenable to direct observation and, thus, cannot be monitored in clinical trials. For this reason, surrogate biomarkers are required for use as outcome parameters. In this respect, magnetic resonance imaging has proved valuable for assessing disease activity and progression in multiple sclerosis. Rating scales are of use as outcome measures but, as these generally measure symptom severity, they are most appropriate for use in assessing symptomatic treatments. Survival has been used with success as an outcome measure in trials in amyotrophic lateral sclerosis, where disease progression is rapid. The optimal outcome measure, the sample size required and the treatment duration need to be chosen in relation to the phase of the disease. Potential new treatments can be chosen based upon new knowledge of the genetics and physiopathology of neurodegenerative diseases and, in some cases, screened in transgenic mouse models, although it should be recognised that the validity of these models in terms of treatment response has yet to be established empirically.}, }
@article {pmid16291708, year = {2005}, author = {Choudry, RB and Cudkowicz, ME}, title = {Clinical trials in amyotrophic lateral sclerosis: the tenuous past and the promising future.}, journal = {Journal of clinical pharmacology}, volume = {45}, number = {12}, pages = {1334-1344}, doi = {10.1177/0091270005282631}, pmid = {16291708}, issn = {0091-2700}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Animals ; Antioxidants/therapeutic use ; Apoptosis ; Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Forecasting ; Humans ; Nerve Growth Factors/therapeutic use ; }, abstract = {The past decade of research in amyotrophic lateral sclerosis has contributed to a greater understanding of the disease process, the development of relevant animal models, and the identification of several therapeutic approaches that may delay disease progression. Completed and ongoing clinical trials and the process of selecting drugs for clinical trials are presented.}, }
@article {pmid16281669, year = {2004}, author = {Simonds, AK}, title = {Living and dying with respiratory failure: facilitating decision making.}, journal = {Chronic respiratory disease}, volume = {1}, number = {1}, pages = {56-59}, doi = {10.1191/1479972304cd014rs}, pmid = {16281669}, issn = {1479-9723}, mesh = {*Decision Making ; Humans ; Palliative Care/*standards ; Quality of Health Care ; Quality of Life ; Respiratory Insufficiency/psychology/*therapy ; }, abstract = {Respiratory failure is a predictable cause of death in end stage lung disease including COPD and neuromuscular disorders, and the symptom burden for these individuals in the last six months of life is significant. Palliative care services are less well-developed for patients with chronic disorders compared to those with malignant disease; and communication problems can be compounded by a mismatch in expectations between patients and health care providers on prognosis and other issues. Most patients want more information about their illness to facilitate participation in decision making. Noninvasive ventilation may extend life and palliate symptoms in neuromuscular disorders such as Duchenne muscular dystrophy and motor neurone disease/ALS.}, }
@article {pmid16280684, year = {2005}, author = {Nirmalananthan, N and Greensmith, L}, title = {Amyotrophic lateral sclerosis: recent advances and future therapies.}, journal = {Current opinion in neurology}, volume = {18}, number = {6}, pages = {712-719}, doi = {10.1097/01.wco.0000187248.21103.c5}, pmid = {16280684}, issn = {1350-7540}, support = {G84/6699/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Biomedical Research ; Docosahexaenoic Acids/classification/*therapeutic use ; Drug Evaluation, Preclinical ; Forecasting ; Humans ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis is a rare but fatal motoneuron disorder. Despite intensive research riluzole remains the only available therapy, with only marginal effects on survival. Here we review some of the recent advances in the search for a disease-modifying therapy for amyotrophic lateral sclerosis.<br><br>RECENT FINDINGS: A number of established agents have recently been re-investigated for their potential as neuroprotective agents, including beta-lactam antibiotics and minocycline. Progress has also been made in exploiting growth factors for the treatment of amyotrophic lateral sclerosis, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, heat-shock protein co-inducers, which upregulate cell stress responses thereby mediating neuroprotection. Non-drug-based therapies are also under development, with progress in gene-silencing and stem cell therapies.<br><br>SUMMARY: In the past few years, significant advances have been made in both our understanding of amyotrophic lateral sclerosis pathogenesis and the development of new therapeutic approaches. However, caution must be exercised in view of the long-standing failure to successfully transfer therapeutic compounds to the clinic. A deeper awareness in the research community of the need for clinically relevant preclinical studies, coupled with a better understanding of the issues surrounding clinical trial design for amyotrophic lateral sclerosis, offers hope that the growing list of validated preclinical therapeutics can finally yield an effective disease-modifying treatment.}, }
@article {pmid16240489, year = {2005}, author = {Novakovic, KE and Villemagne, VL and Rowe, CC and Masters, CL}, title = {Rare genetically defined causes of dementia.}, journal = {International psychogeriatrics}, volume = {17 Suppl 1}, number = {}, pages = {S149-94}, doi = {10.1017/s1041610205002012}, pmid = {16240489}, issn = {1041-6102}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Dementia/complications/diagnosis/*genetics ; Diagnosis, Differential ; Energy Metabolism/physiology ; Gerstmann-Straussler-Scheinker Disease/genetics ; Humans ; Huntington Disease/complications ; Insomnia, Fatal Familial/complications/genetics ; Lipoproteins/metabolism ; Nerve Degeneration/complications ; Proteins/metabolism ; Spinocerebellar Ataxias/complications ; Supranuclear Palsy, Progressive/complications ; }, abstract = {Several genetic disorders, though rare, are associated or present with dementia. Developments in the field of genetics are contributing to clarify and expand our knowledge of the complex physiopathological mechanisms leading to neurodegeneration and cognitive decline. Disorders associated with misfolded and aggregated proteins and lipid, metal or energy metabolism are examples of the multifarious disease processes converging in the clinical features of dementia, either as its predominant feature, as in cases of Alzheimer's disease (AD) or frontotemporal dementia (FTD), or as part of a cohort of accompanying or late-developing symptoms, as in Parkinson's disease (PD) or amyotrophic lateral sclerosis with dementia (ALS-D). Awareness of these disorders, allied with recent advances in genetic, biochemical and neuroimaging techniques, may lead to early diagnosis, successful treatment and better prognosis.}, }
@article {pmid16240482, year = {2005}, author = {Kurz, AF}, title = {Uncommon neurodegenerative causes of dementia.}, journal = {International psychogeriatrics}, volume = {17 Suppl 1}, number = {}, pages = {S35-49}, doi = {10.1017/s1041610205001936}, pmid = {16240482}, issn = {1041-6102}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Atrophy/pathology/physiopathology ; Basal Ganglia Diseases/pathology/physiopathology ; Cerebral Cortex/pathology/physiopathology ; Dementia/*etiology/*pathology/physiopathology ; Diagnosis, Differential ; Frontal Lobe/pathology/physiopathology ; Humans ; Huntington Disease/pathology/physiopathology ; Nerve Degeneration/*pathology/physiopathology ; Perceptual Disorders/epidemiology ; Personality Disorders/diagnosis/epidemiology ; Space Perception/physiology ; Supranuclear Palsy, Progressive/pathology/physiopathology ; Temporal Lobe/pathology/physiopathology ; Visual Perception/physiology ; }, abstract = {A group of neurodegenerative diseases is outlined that affect cortical and subcortical areas of the brain. These diseases give rise to atypical forms of dementia and, unlike Alzheimer's disease (AD), are often associated with neurological symptoms. Clinical symptoms reflect the localization of the degenerative process rather than the nature of the underlying histopathology. Degeneration of the frontal and anterior temporal lobe presents initially with behavioral alterations, but later in the course, impairment of cognition and activities of daily living develops. Posterior cortical atrophy affects the parietal and occipital association cortices and causes complex visual disturbances. In corticobasal degeneration (CBD) the focus of pathology includes the frontoparietal cortex and several subcortical nuclei, causing symmetrical rigidity, bradykinesia, myoclonus and dystonia. Progressive supranuclear palsy (PSP) involves the frontal, temporal and parietal cortex as well as parts of the brain stem. Clinical features include a hypokinetic rigid syndrome with nuchal dystonia and vertical gaze palsy. Huntington's disease is a prototypical autosomal dominant disorder that affects the extrapyramidal system and causes choreatic movements in combination with personality changes and cognitive deterioration. Amyotrophic lateral sclerosis (ALS) with dementia is a neurodegeneration of the frontotemporal cortex and of the anterior horn of the spinal cord. Behavioral change similar to frontotemporal dementia (FTD) is paralleled or followed by the classic features of motor neuron disease.}, }
@article {pmid16236322, year = {2006}, author = {Verma, A and Berger, JR}, title = {ALS syndrome in patients with HIV-1 infection.}, journal = {Journal of the neurological sciences}, volume = {240}, number = {1-2}, pages = {59-64}, doi = {10.1016/j.jns.2005.09.005}, pmid = {16236322}, issn = {0022-510X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications/drug therapy/*virology ; Anti-HIV Agents/therapeutic use ; Disease Progression ; Drug Therapy, Combination ; Female ; HIV Infections/*complications/drug therapy ; HIV-1/*isolation &amp; purification ; Humans ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {BACKGROUND: A viral etiology of amyotrophic lateral sclerosis (ALS) has been proposed because of the selective vulnerability of motor neurons to certain viruses. During the last 20 years, at least 19 cases of ALS or ALS-like disease have been reported in HIV-1 (HIV) seropositive individuals.<br><br>OBJECTIVE: To describe two cases of clinically definite ALS in patients with HIV infection and to review the previously reported cases of HIV-associated ALS syndrome.<br><br>SETTING: A multidisciplinary ALS center and Neuro-AIDS clinic at a tertiary care university hospital.<br><br>PATIENTS/DESIGN: We investigated and prospectively monitored two patients who had developed clinically definite ALS by El Escorial criteria several years after acquiring the HIV infection. The previously reported cases of ALS or ALS-like disease in patients with HIV infection were reviewed for comparison and contrast with the characteristics of sporadic ALS.<br><br>RESULTS: The clinical course of ALS in our two HIV seropositive individuals mirrored that of classical sporadic ALS. A review of previously described 19 patients with ALS syndrome revealed clinically definite ALS in 4 cases and clinically probable or possible ALS in 15. ALS commenced at different stages of the HIV disease; in 7 patients, HIV infection was discovered contemporaneously with diagnosis of ALS. CD4+ T cell count ranged from 2 to 560 cells/mm3. Three (1 definite ALS) of the fatal cases were studied at autopsy and all exhibited pathology outside the motor neuron pool. Unlike our patients, 7 of 8 patients with HIV-associated ALS syndrome receiving HAART demonstrated at least partial recovery of their motor deficit.<br><br>CONCLUSIONS: ALS-like syndrome can occur in association with HIV infection; however, the causal relationship remains uncertain. Patients with ALS syndrome related to HIV infection are generally younger in age and often demonstrate pathology outside the motor neuron system. Patients with HIV-associated ALS syndrome may improve following antiretroviral therapy. An aggressive HAART regimen to reduce viral load should be pursued in all such cases.}, }
@article {pmid16228969, year = {2006}, author = {Federici, T and Boulis, NM}, title = {Gene-based treatment of motor neuron diseases.}, journal = {Muscle &amp; nerve}, volume = {33}, number = {3}, pages = {302-323}, doi = {10.1002/mus.20439}, pmid = {16228969}, issn = {0148-639X}, support = {K08 NS43305/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Apoptosis/physiology ; Gene Silencing ; *Genetic Therapy ; Genetic Vectors ; Humans ; Motor Neuron Disease/*therapy ; Muscular Atrophy, Spinal/therapy ; }, abstract = {Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation.}, }
@article {pmid16214062, year = {2005}, author = {Abmayr, S and Weydt, P}, title = {Skeletal muscle in amyotrophic lateral sclerosis: emerging concepts and therapeutic implications.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {16}, number = {4}, pages = {1091-7, xi-xii}, doi = {10.1016/j.pmr.2005.08.013}, pmid = {16214062}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Animals ; Disease Models, Animal ; Genetic Therapy ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons ; Muscle, Skeletal/*physiopathology ; Superoxide Dismutase/metabolism ; }, }
@article {pmid16214061, year = {2005}, author = {Weydt, P and Möller, T}, title = {The role of microglial cells in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {16}, number = {4}, pages = {1081-90, xi}, doi = {10.1016/j.pmr.2005.08.021}, pmid = {16214061}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Disease Models, Animal ; Humans ; Microglia/*immunology ; Motor Neurons/*immunology ; }, }
@article {pmid16214051, year = {2005}, author = {Ravits, J and Laurie, P and Stone, B}, title = {Amyotrophic lateral sclerosis microgenomics.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {16}, number = {4}, pages = {909-24, viii}, doi = {10.1016/j.pmr.2005.08.007}, pmid = {16214051}, issn = {1047-9651}, support = {R21 NS051738/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology/therapy ; Apoptosis/genetics/physiology ; Genetic Therapy/methods ; Genomics/*methods ; Humans ; Microdissection ; Motor Neurons/*pathology ; Nucleic Acid Amplification Techniques/methods ; Oligonucleotide Array Sequence Analysis/methods ; RNA, Messenger/metabolism ; }, }
@article {pmid16197805, year = {2005}, author = {Streit, WJ and Conde, JR and Fendrick, SE and Flanary, BE and Mariani, CL}, title = {Role of microglia in the central nervous system's immune response.}, journal = {Neurological research}, volume = {27}, number = {7}, pages = {685-691}, doi = {10.1179/016164105X49463a}, pmid = {16197805}, issn = {0161-6412}, support = {AG023665/AG/NIA NIH HHS/United States ; NS049185/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/immunology ; Animals ; Brain/*immunology ; Brain Neoplasms/immunology ; Humans ; Inflammation ; Microglia/*immunology ; Motor Neuron Disease/immunology ; Spinal Cord/*immunology ; }, abstract = {Microglial cells comprise a network of endogenous immunocompetent cells that pervade the brain and spinal cord. The primary function of this system is to provide continuous surveillance of the parenchyma and protect the central nervous system (CNS) during injury and disease. Here we discuss the involvement of microglia during brain aging and aging-related neurodegenerative disease, i.e. Alzheimer's disease, and briefly summarize their possible roles in amyotrophic lateral sclerosis (ALS). In addition, we provide an overview of the neuroinflammation associated with primary brain tumors and how microglial tumor cytotoxicity could be targeted for immunotherapeutic approaches designed to treat these lesions.}, }
@article {pmid16194581, year = {2005}, author = {Lau, FC and Shukitt-Hale, B and Joseph, JA}, title = {The beneficial effects of fruit polyphenols on brain aging.}, journal = {Neurobiology of aging}, volume = {26 Suppl 1}, number = {}, pages = {128-132}, doi = {10.1016/j.neurobiolaging.2005.08.007}, pmid = {16194581}, issn = {0197-4580}, mesh = {Aging/*drug effects/physiology ; Animals ; Brain/cytology/*drug effects ; Flavonoids/*pharmacology/therapeutic use ; Fruit/*chemistry ; Humans ; Motor Activity/drug effects ; Neurons/drug effects/physiology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Phenols/*pharmacology/therapeutic use ; Polyphenols ; Signal Transduction/drug effects ; }, abstract = {Brain aging is characterized by the continual concession to battle against insults accumulated over the years. One of the major insults is oxidative stress, which is the inability to balance and to defend against the cellular generation of reactive oxygen species (ROS). These ROS cause oxidative damage to nucleic acid, carbohydrate, protein, and lipids. Oxidative damage is particularly detrimental to the brain, where the neuronal cells are largely post-mitotic. Therefore, damaged neurons cannot be replaced readily via mitosis. During normal aging, the brain undergoes morphological and functional modifications resulting in the observed behavioral declines such as decrements in motor and cognitive performance. These declines are augmented by neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). Research from our laboratory has shown that nutritional antioxidants, such as the polyphenols found in blueberries, can reverse age-related declines in neuronal signal transduction as well as cognitive and motor deficits. Furthermore, we have shown that short-term blueberry (BB) supplementation increases hippocampal plasticity. These findings are briefly reviewed in this paper.}, }
@article {pmid16183556, year = {2005}, author = {Mitsumoto, H and Bromberg, M and Johnston, W and Tandan, R and Byock, I and Lyon, M and Miller, RG and Appel, SH and Benditt, J and Bernat, JL and Borasio, GD and Carver, AC and Clawson, L and Del Bene, ML and Kasarskis, EJ and LeGrand, SB and Mandler, R and McCarthy, J and Munsat, T and Newman, D and Sufit, RL and Versenyi, A}, title = {Promoting excellence in end-of-life care in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {3}, pages = {145-154}, doi = {10.1080/14660820510028647}, pmid = {16183556}, issn = {1466-0822}, mesh = {*Advance Care Planning ; Amyotrophic Lateral Sclerosis/*psychology ; Attitude to Death ; Health Services Research ; Humans ; Quality of Health Care ; Quality of Life ; Spirituality ; Terminal Care/*psychology ; }, abstract = {The type and quality of end-of-life care varies greatly in ALS; the time to initiate end-of-life care is not defined, and decision making is hampered by logistical and financial barriers. There has been no systematic review of these issues in ALS. The goals of this initiative are to: 1) improve end-of-life care for patients with ALS and families based on what limited evidence is available; 2) increase awareness, interest, and debate on the end-of-life care in ALS; and 3) identify areas needed for new prospective clinical research. The ALS Peer Workgroup reviewed the literature and 1) identified the current state of knowledge, 2) analysed the gaps in care, and 3) provided recommendations for standard of care and future research. It was shown that areas of investigation are needed on the incorporation of an interdisciplinary approach to care in ALS that includes: psychosocial evaluation and spiritual care; the use of validated instruments to assess patient and caregiver quality of life; and the establishment of proactive caregiver programs. Several public policy changes that will improve coverage for medical care, hospice, and caregiver costs are also reviewed. More clinical evidence is needed on how to provide optimal end-of-life care specifically in ALS.}, }
@article {pmid16183555, year = {2005}, author = {Kawahara, Y and Kwak, S}, title = {Excitotoxicity and ALS: what is unique about the AMPA receptors expressed on spinal motor neurons?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {3}, pages = {131-144}, doi = {10.1080/14660820510037872}, pmid = {16183555}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; Cell Death ; Humans ; Models, Molecular ; Motor Neurons/*metabolism ; Neurotoxins/*adverse effects ; RNA Editing ; Receptors, AMPA/chemistry/classification/*metabolism ; Spinal Cord/*pathology ; }, abstract = {It has been repeatedly reported that spinal motor neurons are selectively vulnerable to AMPA receptor-mediated excitotoxicity. Therefore, identifying the uniqueness of AMPA receptors that are expressed on motor neurons, especially in individuals affected with sporadic amyotrophic lateral sclerosis (ALS) is essential for elucidating the etiology of this disorder. The mechanism that initiates motor neuronal death appears to be an exaggerated influx of Ca(2+) through AMPA receptors. The determinants that affect this Ca(2+) influx are Ca(2+) permeability, which is regulated by the presence of the GluR2 subunit and by RNA editing at the Q/R site of GluR2; channel desensitization, which is regulated by alternative splicing at the flip/flop site and by RNA editing at the R/G site of GluR subunits; and receptor density on the cell surface, which is controlled by many factors including regulatory proteins, direct phosphorylation and RNA editing at the Q/R site. This review focuses on recent progress on the molecular dynamics of AMPA receptors and discusses the pathophysiology of selective motor neuron death mediated by AMPA receptors in individuals affected with sporadic ALS.}, }
@article {pmid16183338, year = {2005}, author = {Mariani, E and Polidori, MC and Cherubini, A and Mecocci, P}, title = {Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {827}, number = {1}, pages = {65-75}, doi = {10.1016/j.jchromb.2005.04.023}, pmid = {16183338}, issn = {1570-0232}, mesh = {Aging/*physiology ; Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Biomarkers/analysis ; Brain/*physiopathology ; Heart Failure/*physiopathology ; Humans ; Huntington Disease/physiopathology ; Neurodegenerative Diseases/*physiopathology ; Oxidative Stress/*physiology ; Parkinson Disease/physiopathology ; Stroke/*physiopathology ; }, abstract = {According to the free radical theory, aging can be considered as a progressive, inevitable process partially related to the accumulation of oxidative damage into biomolecules -- nucleic acids, lipids, proteins or carbohydrates -- due to an imbalance between prooxidants and antioxidants in favor of the former. More recently also the pathogenesis of several diseases has been linked to a condition of oxidative stress. In this review we focus our attention on the evidence of oxidative stress in aging brain, some of the most important neurodegenerative diseases -- Alzheimer's disease (AD), mild cognitive impairment (MCI), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) -- and in two common and highly disabling vascular pathologies--stroke and cardiac failure. Particular attention will be given to the current knowledge about the biomarkers of oxidative stress that can be possibly used to monitor their severity and outcome.}, }
@article {pmid16181085, year = {2004}, author = {Kuwabara, S and Misawa, S}, title = {Axonal ionic pathophysiology in human peripheral neuropathy and motor neuron disease.}, journal = {Current neurovascular research}, volume = {1}, number = {4}, pages = {373-379}, doi = {10.2174/1567202043362162}, pmid = {16181085}, issn = {1567-2026}, mesh = {Animals ; Axons/pathology/*physiology ; Humans ; Ion Channels/*physiology ; Membrane Potentials/physiology ; Motor Neuron Disease/pathology/*physiopathology ; Muscle Contraction/physiology ; Muscle, Skeletal/physiopathology ; Neural Conduction/physiology ; Peripheral Nervous System Diseases/pathology/*physiopathology ; }, abstract = {Testing the excitability of axons can provide insights into the ionic mechanisms underlying the pathophysiology of axonal dysfunction in human neuropathies and motor neuron diseases. Threshold tracking, which was developed in the 1990's, non-invasively measures a number of axonal excitability indices, which depend on membrane potential and on the Na+ and K+ conductances. This paper reviews recent advances in ionic-pathophysiological studies in human subjects in vivo. Membrane potential of human axons can be estimated, because most of the ion channels expressed on the axolemma are voltage-dependent, and patterns of changes in multiple excitability indices can suggest whether axons are depolarized or hyperpolarized. This has been clearly demonstrated in a single patient with acute hypokalemia (hyperpolarization) and patients with chronic renal failure (depolarization due to hyperkalemia). Muscle cramps/fasciculations arise from hyperexcitability of the motor axons. The enhanced excitability can result from altered ion channel function; an increase in persistent Na+ conductance, a decrease in accommodative K+ conductance, and focal membrane depolarization, all of which increase excitability, have been demonstrated in amyotrophic lateral sclerosis or other disorders affecting lower motor neurons. Patients with demyelinating neuropathy often complain of muscle fatigue. During voluntary contraction, the activation of the electrogenic Na+-K+ pump and resulting membrane hyperpolarization can cause activity-dependent conduction block when the safety factor for impulse transmission is critically reduced. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms is of clinical relevance, because once a specific ionic conductance is identified, blocking or activating it may provide a new therapeutic option for a variety of neuromuscular diseases.}, }
@article {pmid16181084, year = {2004}, author = {Ekshyyan, O and Aw, TY}, title = {Apoptosis: a key in neurodegenerative disorders.}, journal = {Current neurovascular research}, volume = {1}, number = {4}, pages = {355-371}, doi = {10.2174/1567202043362018}, pmid = {16181084}, issn = {1567-2026}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-11/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; DK 43785/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Humans ; Models, Biological ; Neurodegenerative Diseases/classification/*pathology ; }, abstract = {Apoptosis is an important process in the development of the nervous system. Typically, approximately 50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and/or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.}, }
@article {pmid16181078, year = {2004}, author = {Silani, V and Corbo, M}, title = {Cell-replacement therapy with stem cells in neurodegenerative diseases.}, journal = {Current neurovascular research}, volume = {1}, number = {3}, pages = {283-289}, doi = {10.2174/1567202043362243}, pmid = {16181078}, issn = {1567-2026}, mesh = {Amyotrophic Lateral Sclerosis/surgery ; Humans ; Neurodegenerative Diseases/*surgery ; *Stem Cell Transplantation/adverse effects ; }, abstract = {In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate.}, }
@article {pmid16178023, year = {2005}, author = {Beal, MF}, title = {Mitochondria take center stage in aging and neurodegeneration.}, journal = {Annals of neurology}, volume = {58}, number = {4}, pages = {495-505}, doi = {10.1002/ana.20624}, pmid = {16178023}, issn = {0364-5134}, support = {AG14930/AG/NIA NIH HHS/United States ; AG20729/AG/NIA NIH HHS/United States ; NS049077/NS/NINDS NIH HHS/United States ; NS39258/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/*physiology ; Animals ; DNA, Mitochondrial/genetics ; Humans ; Mitochondria/*physiology ; Mitochondrial Myopathies/genetics/*physiopathology ; Models, Biological ; Mutation ; Neurodegenerative Diseases/*physiopathology ; Oxidative Stress/physiology ; }, abstract = {A critical role of mitochondrial dysfunction and oxidative damage has been hypothesized in both aging and neurodegenerative diseases. Much of the evidence has been correlative, but recent evidence has shown that the accumulation of mitochondrial DNA mutations accelerates normal aging, leads to oxidative damage to nuclear DNA, and impairs gene transcription. Furthermore, overexpression of the antioxidant enzyme catalase in mitochondria increases murine life span. There is strong evidence from genetics and transgenic mouse models that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia, and cerebellar degenerations. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage in these diseases therefore have great promise.}, }
@article {pmid16173291, year = {2005}, author = {Ghosh, B and Mishra, A and Sengupta, P}, title = {Is Parkinson's disease a homogeneous disorder--what is the burden of Parkinson's disease in India.}, journal = {Journal of the Indian Medical Association}, volume = {103}, number = {3}, pages = {146, 148, 150 passim}, pmid = {16173291}, issn = {0019-5847}, mesh = {Aged ; Basal Ganglia Diseases/*diagnosis/*epidemiology/prevention &amp; control ; Diagnosis, Differential ; Essential Tremor/diagnosis ; Female ; Humans ; Incidence ; India/epidemiology ; Male ; Middle Aged ; Parkinson Disease/*diagnosis/*epidemiology/prevention &amp; control ; Prevalence ; Risk Factors ; Syndrome ; }, abstract = {Movement disorders are common neurological illnesses among the elderly. These include essential tremor, Perkinsonian disorders and chorea of different aetiologies. Parkinsonian disorders can be divided into two major groups of disorders--classical idiopathic Parkinson's disease and Parkinson plus syndrome. The most common and important cause of Parkinsonism is idiopathic Parkinson's disease. Idiopathic Parkinson's disease is most confidently clinically diagnosed if we follow the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria for Parkinson's disease. The most common degnerative diseases, which minic idiopathic Parkinson's disease are collectively called Parkinson plus syndrome. The most important diseases comprising Parkinson plus syndrome are: progressive supranuclear palsy, multiple system atrophy, cortical-basal ganglionic degneration, diffuse Lewy body disease and Parkinson-dementia-ALS complex. In India the prevalence of Parkinson's disease varied markedly from one study to another. The prevalence rate is high among the urban Parsi community of Mumbai. Incidence and prevalence of Parkinson's disease increase with increasing age. Some risk factors for Parkinson's disease have been narrated briefly. As the number of cases of Parkinsonism is likely to increase along with increasing population, the general practitioners or consultant physicans should have to play a greater role referring the cases to attend neurologists or movement disorder clinic early.}, }
@article {pmid16169146, year = {2005}, author = {Hoerndli, F and David, DC and Götz, J}, title = {Functional Genomics meets neurodegenerative disorders. Part II: application and data integration.}, journal = {Progress in neurobiology}, volume = {76}, number = {3}, pages = {169-188}, doi = {10.1016/j.pneurobio.2005.07.002}, pmid = {16169146}, issn = {0301-0082}, mesh = {Animals ; Brain/metabolism/pathology/physiopathology ; Brain Chemistry/genetics ; Disease Models, Animal ; Gene Expression Profiling/*methods/trends ; Genomics/*methods/trends ; Humans ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*genetics/metabolism/physiopathology ; Proteomics/*methods/trends ; }, abstract = {The transcriptomic and proteomic techniques presented in part I (Functional Genomics meets neurodegenerative disorders. Part I: transcriptomic and proteomic technology) of this back-to-back review have been applied to a range of neurodegenerative disorders, including Huntington's disease (HD), Prion diseases (PrD), Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). Samples have been derived either from human brain and cerebrospinal fluid, tissue culture cells or brains and spinal cord of experimental animal models. With the availability of huge data sets it will firstly be a major challenge to extract meaningful information and secondly, not to obtain contradicting results when data are collected in parallel from the same source of biological specimen using different techniques. Reliability of the data highly depends on proper normalization and validation both of which are discussed together with an outlook on developments that can be anticipated in the future and are expected to fuel the field. The new insight undoubtedly will lead to a redefinition and subdivision of disease entities based on biochemical criteria rather than the clinical presentation. This will have important implications for treatment strategies.}, }
@article {pmid16163970, year = {2005}, author = {Morrison, KE}, title = {Managing motor neurone disease.}, journal = {The Practitioner}, volume = {249}, number = {1674}, pages = {612, 614, 617 passim}, pmid = {16163970}, issn = {0032-6518}, mesh = {Advance Directives ; Early Diagnosis ; Humans ; Middle Aged ; Motor Neuron Disease/diagnosis/*therapy ; Palliative Care/methods ; Patient Care Team ; Prognosis ; Treatment Outcome ; }, }
@article {pmid16155429, year = {2005}, author = {Baltadzhieva, R and Gurevich, T and Korczyn, AD}, title = {Autonomic impairment in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {18}, number = {5}, pages = {487-493}, doi = {10.1097/01.wco.0000183114.76056.0e}, pmid = {16155429}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; Autonomic Nervous System Diseases/*etiology ; Cognition Disorders/etiology ; Digestive System Physiological Phenomena ; Humans ; Pupil/physiology ; Sweat/physiology ; Urination/physiology ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurones, but it is increasingly recognized to be a more disseminated disease. The autonomic nervous system may also be involved. Here we review the literature with specific emphasis on autonomic functions in ALS.<br><br>RECENT STUDIES: Ample evidence exists for subclinical dysfunction of cardiovascular, sudomotor, gastrointestinal, salivary and lacrimal regulation, even in early ALS cases. Autonomic disturbances may lead to circulatory collapse or sudden death in respirator dependent patients. Several studies suggest the existence of sympathetic hyperactivity in ALS. We discuss some possible pathophysiological mechanisms of the subtle abnormalities and some clinical and treatment implications.<br><br>SUMMARY: The wide range of autonomic involvement, together with results suggesting cognitive and extrapyramidal dysfunction, supports the view that ALS is a multisystem degenerative disease.}, }
@article {pmid16148733, year = {2005}, author = {Simmons, Z}, title = {Management strategies for patients with amyotrophic lateral sclerosis from diagnosis through death.}, journal = {The neurologist}, volume = {11}, number = {5}, pages = {257-270}, doi = {10.1097/01.nrl.0000178758.30374.34}, pmid = {16148733}, issn = {1074-7931}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/psychology/*therapy ; Hospices ; Humans ; Neuroprotective Agents/therapeutic use ; Nutritional Physiological Phenomena ; Pain/etiology ; Quality of Life ; Riluzole/therapeutic use ; Spirituality ; Suicide ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is inevitably fatal. There are no effective treatments to stop or reverse the natural course of the disease. The role of the physician is to provide comfort and optimize quality of life.<br><br>REVIEW SUMMARY: Management of patients with ALS is a process extending over months to years. It begins with breaking the news of the diagnosis and extends through the terminal phase. Medication may extend lifespan by a small amount. However, most efforts are centered around symptom management. Areas of importance include respiration, nutrition, secretions, communication, pseudobulbar affect, therapy and exercise, spasticity and cramps, pain, depression and suicide, spirituality and religion, cognitive changes, the development of advance directives, and care at the end of life. Multidisciplinary ALS clinics provide much-needed support for patients with ALS and their caregivers.<br><br>CONCLUSION: Although physicians cannot cure ALS or even halt progression, there is much that can be done to manage the physical and emotional symptoms, thereby maintaining or enhancing quality of life.}, }
@article {pmid16140637, year = {2005}, author = {Brown, RC and Lockwood, AH and Sonawane, BR}, title = {Neurodegenerative diseases: an overview of environmental risk factors.}, journal = {Environmental health perspectives}, volume = {113}, number = {9}, pages = {1250-1256}, pmid = {16140637}, issn = {0091-6765}, mesh = {Age Factors ; Bias ; Case-Control Studies ; Confounding Factors, Epidemiologic ; Environmental Exposure ; Environmental Pollutants/*toxicity ; Humans ; Neurodegenerative Diseases/epidemiology/*etiology ; Risk Factors ; Sample Size ; Xenobiotics/*toxicity ; }, abstract = {The population of the United States is aging, and an ever-increasing number of Americans are afflicted with neurodegenerative diseases. Because the pathogenesis of many of these diseases remains unknown, we must consider that environmental factors may play a causal role. This review provides an overview of the epidemiologic evidence for environmental etiologies for neurodegenerative diseases such as Alzheimer disease, Parkinson disease, parkinsonian syndromes (multiple system atrophy and progressive supranuclear palsy), and amyotrophic lateral sclerosis. Epidemiologic evidence for an association between environmental agents' exposure and neurodegenerative diseases is not conclusive. However, there are indications that there may be causal links, and the need for more research is obvious.}, }
@article {pmid16133422, year = {2005}, author = {Züchner, S and Vance, JM}, title = {Emerging pathways for hereditary axonopathies.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {83}, number = {12}, pages = {935-943}, pmid = {16133422}, issn = {0946-2716}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Charcot-Marie-Tooth Disease/*genetics ; Hereditary Sensory and Autonomic Neuropathies/*genetics ; Humans ; Motor Neurons/*pathology ; Muscular Atrophy, Spinal/*genetics ; Penetrance ; }, abstract = {Motor neurons are affected in a number of neurological diseases. Their unifying pathological signature is degeneration of extended projecting axons and loss of motor neurons in the prefrontal cortex and/or the spinal cord. Based on clinical criteria, hereditary forms have been traditionally divided into distinct entities, such as familial amyotrophic lateral sclerosis, hereditary motor neuropathy, spinal muscular atrophy, familial spinal paraplegia, and Charcot-Marie-Tooth disease type 2, also known as hereditary motor and sensory neuropathy II. Genetic research of the last decade has revealed remarkable heterogeneity within these disorders. Most of the identified genes to date cause disease in a classic Mendelian inheritance pattern with a high phenotypic penetrance. This rich source of molecular genetic data has already provided insight into the underlying major pathways of these diseases and should continue to do so in the future. This review attempts to cross the traditional clinical classifications in order to draw an emerging picture of common pathways between causative genes, providing a different perspective of this rapidly growing scientific field.}, }
@article {pmid16128477, year = {2005}, author = {Isenberg, DL and Bissell, R}, title = {Does advanced life support provide benefits to patients?: A literature review.}, journal = {Prehospital and disaster medicine}, volume = {20}, number = {4}, pages = {265-270}, doi = {10.1017/s1049023x0000265x}, pmid = {16128477}, issn = {1049-023X}, mesh = {*Advanced Cardiac Life Support ; Cardiopulmonary Resuscitation ; *Emergency Medical Services ; Humans ; *Risk Assessment ; United States ; }, abstract = {INTRODUCTION: Emergency medical services have invested substantial resources to establish advanced life support (ALS) programs. However, it is unclear whether ALS care provides better outcomes to patients compared to basic life support (BLS) care.<br><br>OBJECTIVE: To evaluate the current evidence regarding the benefits of ALS.<br><br>METHODS: Electronic medical databases were searched to identify articles that directly compared ALS versus BLS care. A total of 455 articles were found. Articles were excluded for the following reasons: (1) the article was not written in English; (2) BLS response was not compared to an ALS response; (3) a physician or nurse was included as part of the ALS response; (4) it was an aeromedical response; or (5) defibrillation was included in the ALS, but not the BLS, scope of care. Twenty-one articles met the inclusion criteria for this literature review.<br><br>RESULTS: Results were divided into four categories: (1) trauma; (2) cardiac arrest; (3) myocardial infarction; and (4) altered mental status. Trauma: The majority of articles showed that ALS provided no benefits over BLS in urban trauma patients. In fact, most studies showed higher mortality rates for trauma patients receiving ALS care. Further research is needed to evaluate the benefits of ALS for rural trauma patients, and whether ALS care improves outcomes in subgroups of urban trauma patents. Cardiac Arrest: Cardiac arrest studies show that early CPR plus early defibrillation provide the greatest improvement in survival. However, most cardiac arrest research includes defibrillation as an ALS skill which has now moved into the BLS scope of care. The 2004 multi-center OPALS study provided good evidence that ALS does not improve cardiac arrest survival over early defibrillation. Further research is needed to address whether any ALS interventions improve cardiac arrest outcome. Myocardial Infarction: Only one study directly compared the outcome of BLS and ALS care on myocardial infarction. The study found no difference in outcomes between BLS and ALS care in an urban setting. Advanced Life Support: Only one study directly compared the outcome of BLS and ALS care on patients with altered mental status. The study found that the same number of patients had improved to "alert" on arrival at the emergency department, but there was a decreased length of emergency department stay for patients treated by ALS for hypoglycemia.<br><br>LIMITATIONS: This review article does not take into account the benefits of 2005 ALS interventions, such as thrombolytics, dextrose, or nitroglycerin, since no studies directly compared these interventions to BLS care. Furthermore, only one study in this literature review was a large, multi-center trial.<br><br>CONCLUSIONS: ALS shows little, if any, benefits for urban trauma patients. Cardiac arrest studies show that ALS does not provide additional benefits over BLS-defibrillation care, but more research is needed in this area. In two small studies, ALS care did not provide benefits over BLS care for patients with myocardial infarctions or altered mental status. Larger-scale studies are needed to evaluate which specific ALS interventions improve patient outcomes.}, }
@article {pmid16125208, year = {2005}, author = {Levenson, CW}, title = {Trace metal regulation of neuronal apoptosis: from genes to behavior.}, journal = {Physiology &amp; behavior}, volume = {86}, number = {3}, pages = {399-406}, doi = {10.1016/j.physbeh.2005.08.010}, pmid = {16125208}, issn = {0031-9384}, mesh = {Animals ; Apoptosis/*physiology ; Behavior/*physiology ; Humans ; Metals/*metabolism ; Models, Neurological ; Neurons/cytology/*metabolism ; }, abstract = {The genetically programmed form of neuronal death known as apoptosis plays a role in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease. Apoptosis is also responsible for neuronal death after traumatic brain and spinal cord injury, stroke, and seizures. The cognitive and behavioral consequences of all of these disorders can be devastating. Unfortunately the mechanisms that regulate neuronal apoptosis are complex. However, it is this very complexity that provides us with a wide array of potential targets for the development of anti-apoptotic strategies. Thus, our lab is currently exploring the molecular and cellular mechanisms responsible for neuronal apoptosis, with a particular focus on the role of the metals copper, zinc, and iron. Each of these metals is essential for normal central nervous system (CNS) development and function. However, imbalances, either excess or deficiency, can result in neuronal apoptosis. In this review, we show the relationship between these metals in neurodegenerative disorders and CNS injury, and the mechanisms that govern neuronal survival and apoptosis.}, }
@article {pmid16121086, year = {2005}, author = {Carrick, C and Collins, KA and Lee, CJ and Prahlow, JA and Barnard, JJ}, title = {Sudden death due to asphyxia by esophageal polyp: two case reports and review of asphyxial deaths.}, journal = {The American journal of forensic medicine and pathology}, volume = {26}, number = {3}, pages = {275-281}, doi = {10.1097/01.paf.0000178098.33597.de}, pmid = {16121086}, issn = {0195-7910}, mesh = {Adult ; Airway Obstruction/etiology/mortality ; Asphyxia/*etiology/mortality ; Death, Sudden/*etiology ; Esophageal Diseases/*complications/pathology ; Female ; Forensic Pathology ; Humans ; Male ; Middle Aged ; Polyps/*complications/pathology ; Pregnancy ; }, abstract = {Asphyxia, not an uncommon cause of sudden death, may result from numerous etiologies. Foreign-body aspiration and strangulation are 2 extrinsic causes. Airway obstruction may also be caused by laryngeal edema, asthma, infection, or anaphylaxis. Chronic causes of asphyxia include musculoskeletal diseases (eg, muscular dystrophy, amyotrophic lateral sclerosis), neurologic disorders (eg, myasthenia gravis, multiple sclerosis), respiratory disease (eg, emphysema, chronic bronchitis), or tumors. The manner of death in cases of asphyxiation may be natural, accidental, homicide, or suicide. For the death investigator, determining the cause and manner of death can often be quite challenging. We report here 2 cases of an esophageal fibrovascular polyp causing sudden asphyxial death, review of the literature, and discussion of other differential diagnoses in the case of asphyxial death.}, }
@article {pmid16114275, year = {2005}, author = {Domené, HM and Bengolea, SV and Jasper, HG and Boisclair, YR}, title = {Acid-labile subunit deficiency: phenotypic similarities and differences between human and mouse.}, journal = {Journal of endocrinological investigation}, volume = {28}, number = {5 Suppl}, pages = {43-46}, pmid = {16114275}, issn = {0391-4097}, mesh = {Animals ; Carrier Proteins/*genetics ; Glycoproteins/*genetics ; Growth Disorders/*genetics/*physiopathology ; Humans ; Insulin-Like Growth Factor I/*genetics ; Mice ; Mice, Knockout ; Phenotype ; }, abstract = {IGF-I and IGF-II (IGFs) form higher molecular weight complexes with specific binding proteins (IGFBP-1 to -6). These complexes are referred to as binary complexes consisting of IGF-I or IGF-II and one IGFBP, or as ternary complexes each consisting of either of IGF-I or IGF-II, IGFBP-3 or -5, and an acid-labile subunit known as ALS. Ternary complex formation restricts the IGFs to the circulation and prolongs their half-life. Recently, the development of an animal model for ALS deficiency (the ALS-KO mouse) and the identification of a patient with an inactivating mutation in the IGFALS gene have provided the opportunity to assess the physiological role of this protein in the circulating IGF system. ALS deficiency has no effect on fetal growth in both the ALS-KO mice and the ALS-deficient patients. A modest reduction in post-natal growth in the null ALS mice and in the ALS-deficient patients was observed. The plasma concentrations of IGF-I and IGFBP-3 were markedly reduced both in ALS-KO mice and in the ALS-deficient patients. Basal GH levels remained normal in the ALS-KO mice and moderately increased in the ALS-deficient patients. Insulin-resistance was present in the ALS-deficient patients but not in the ALS-KO mice. Reduced bone mineral density (BMD) was present in mice and human ALS deficiency. Phenotypic features of complete ALS deficiency, that are very similar in mouse and human, include: a) the inability to form ternary complex, b) the small growth impairment in spite of the marked reduction in circulating IGF-I, and c) the reduction in BMD. On the other hand, insulin resistance and pubertal delay were observed only in human ALS deficiency. These findings underlie the important physiological role of ALS in the maintenance of the circulating IGF-I reservoir. Both models will be useful in identifying the respective roles of plasma and locally derived IGF-I in regulating metabolism and growth of specific tissues.}, }
@article {pmid16106621, year = {2004}, author = {Andersen, PM}, title = {The genetics of amyotrophic lateral sclerosis (ALS).}, journal = {Supplements to Clinical neurophysiology}, volume = {57}, number = {}, pages = {211-227}, doi = {10.1016/s1567-424x(09)70359-9}, pmid = {16106621}, issn = {1567-424X}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/therapy ; Animals ; Humans ; }, }
@article {pmid16106618, year = {2004}, author = {Eisen, A}, title = {Recent considerations in the etiopathogenesis of ALS.}, journal = {Supplements to Clinical neurophysiology}, volume = {57}, number = {}, pages = {187-190}, doi = {10.1016/s1567-424x(09)70356-3}, pmid = {16106618}, issn = {1567-424X}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*etiology/genetics/*pathology ; Humans ; Models, Molecular ; Superoxide Dismutase/chemistry/metabolism ; }, }
@article {pmid16106213, year = {2005}, author = {Strong, MJ and Kesavapany, S and Pant, HC}, title = {The pathobiology of amyotrophic lateral sclerosis: a proteinopathy?.}, journal = {Journal of neuropathology and experimental neurology}, volume = {64}, number = {8}, pages = {649-664}, doi = {10.1097/01.jnen.0000173889.71434.ea}, pmid = {16106213}, issn = {0022-3069}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology/physiopathology ; Animals ; Brain Chemistry/physiology ; Cell Death/physiology ; Cytoskeletal Proteins/*metabolism ; Frontal Lobe/pathology ; Humans ; Models, Biological ; Motor Neurons/metabolism/pathology ; Neuroglia/pathology ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinases/metabolism ; Signal Transduction/physiology ; Spinal Cord/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is increasingly considered to be a disorder of multiple etiologies that have in common progressive degeneration of both upper and lower motor neurons, ultimately giving rise to a relentless loss of muscle function. This progressive degeneration is associated with heightened levels of oxidative injury, excitotoxicity, and mitochondrial dysfunction--all occurring concurrently. In this article, we review the evidence that suggests, in common with other age-dependent neurodegenerative disorders, that ALS can be considered a disorder of protein aggregation. Morphologically, this is evident as Bunina bodies, ubiquitin-immunoreactive fibrils or aggregates, neurofilamentous aggregates, mutant copper/zinc superoxide dismutase (SOD1) aggregates in familial ALS variants harboring mutations in SOD1, peripherin-immunoreactive aggregates within spinal motor neurons and as neuroaxonal spheroids, and in an increasingly greater population of patients with ALS with cognitive impairment, both intra- and extraneuronal tau aggregates. We review the evidence that somatotopically specific patterns of altered kinase and phosphatase activity are associated with alterations in the phosphorylation state of these proteins, altering either solubility or assembly characteristics. The role of nonneuronal cells in mediating motor neuronal injury is discussed in the context of alterations in tyrosine kinase activity and enhanced protein phosphorylation.}, }
@article {pmid16104843, year = {2005}, author = {Takahashi, H and Shibuya, M}, title = {The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions.}, journal = {Clinical science (London, England : 1979)}, volume = {109}, number = {3}, pages = {227-241}, doi = {10.1042/CS20040370}, pmid = {16104843}, issn = {0143-5221}, mesh = {Animals ; Capillary Permeability/physiology ; Humans ; Inflammation/metabolism ; Mice ; Neoplasms/blood supply/metabolism ; Neovascularization, Pathologic/physiopathology ; Neovascularization, Physiologic/physiology ; Receptors, Vascular Endothelial Growth Factor/*physiology ; Signal Transduction/physiology ; Vascular Endothelial Growth Factor A/*physiology ; }, abstract = {The VEGF (vascular endothelial growth factor) family and its receptors are essential regulators of angiogenesis and vascular permeability. Currently, the VEGF family consists of VEGF-A, PlGF (placenta growth factor), VEGF-B, VEGF-C, VEGF-D, VEGF-E and snake venom VEGF. VEGF-A has at least nine subtypes due to the alternative splicing of a single gene. Although the VEGF165 isoform plays a central role in vascular development, recent studies have demonstrated that each VEGF isoform plays distinct roles in vascular patterning and arterial development. VEGF-A binds to and activates two tyrosine kinase receptors, VEGFR (VEGF receptor)-1 and VEGFR-2. VEGFR-2 mediates most of the endothelial growth and survival signals, but VEGFR-1-mediated signalling plays important roles in pathological conditions such as cancer, ischaemia and inflammation. In solid tumours, VEGF-A and its receptor are involved in carcinogenesis, invasion and distant metastasis as well as tumour angiogenesis. VEGF-A also has a neuroprotective effect on hypoxic motor neurons, and is a modifier of ALS (amyotrophic lateral sclerosis). Recent progress in the molecular and biological understanding of the VEGF/VEGFR system provides us with novel and promising therapeutic strategies and target proteins for overcoming a variety of diseases.}, }
@article {pmid16101543, year = {2005}, author = {Tzeng, SF and Hsiao, HY and Mak, OT}, title = {Prostaglandins and cyclooxygenases in glial cells during brain inflammation.}, journal = {Current drug targets. Inflammation and allergy}, volume = {4}, number = {3}, pages = {335-340}, doi = {10.2174/1568010054022051}, pmid = {16101543}, issn = {1568-010X}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Astrocytes/physiology ; Cyclooxygenase Inhibitors/pharmacology ; Encephalitis/enzymology/immunology/metabolism/*pathology ; Humans ; Inflammation Mediators/physiology ; Macrophage Activation/physiology ; Microglia/physiology ; Neuroglia/enzymology/metabolism/*physiology ; Prostaglandin-Endoperoxide Synthases/*physiology ; Prostaglandins/*physiology ; }, abstract = {Many brain disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington, stroke, head trauma, and infection, are associated with inflammation that is involved in neuropathologenesis and hyperalgesis. Microglia and astrocytes act as immune cells in the inflamed brain. Both cell types, but especially microglia, are thought to contribute to the onset of inflammation in many brain diseases by producing deleterious proinflammatory mediators. Prostaglandins (PGs), which are critical mediators of physiologic processes and inflammation, are largely produced by activated microglia and reactive astrocytes during brain inflammation. These compounds are converted from arachnoidic acid (AA) by two isoforms of the cyclooxygenase (COX) enzyme, namely COX-1 and COX-2. In particular, the action of COX-2 and PGs in CNS inflammation has gained much attention recently. PGs have been found to act neuroprotectively by elevating intracellular cAMP levels in neurons. These molecules also function as anti-inflammatory molecules to reduce the production of nitric oxide and proinflammatory cytokines, and to increase the expression of anti-inflammatory cytokines. However, accumulating evidence also shows that COX inhibitors alleviate various types of brain damage via suppressing inflammatory reactions. Accordingly, the roles of two COX enzymes in mediating inflammation and anti-inflammation have recently been debated. We provide here a review of recent findings indicating that the reciprocal interaction of glial cell activation, COX enzymes and PGs mediates neurodegeneration and neuroprotection during brain inflammation. In addition, the mechanism by which PGs mediate signaling is discussed.}, }
@article {pmid16099509, year = {2006}, author = {Fleischer, A and Ghadiri, A and Dessauge, F and Duhamel, M and Rebollo, MP and Alvarez-Franco, F and Rebollo, A}, title = {Modulating apoptosis as a target for effective therapy.}, journal = {Molecular immunology}, volume = {43}, number = {8}, pages = {1065-1079}, doi = {10.1016/j.molimm.2005.07.013}, pmid = {16099509}, issn = {0161-5890}, mesh = {Apoptosis/*drug effects ; Autoimmunity ; *Drug Evaluation, Preclinical ; Humans ; Neoplasms/drug therapy/pathology ; Neurodegenerative Diseases/drug therapy/pathology ; }, abstract = {Alterations in cell proliferation and cell death are essential determinants in the pathogenesis and progression of several diseases such as cancer, neurodegenerative disorders or autoimmune diseases among others. Complex networks of regulatory factors determine whether cells proliferate or die. Recent progress in understanding the molecular changes offer the possibility of specifically targeting molecules and pathways to achieve more effective and rational therapies. Drugs that target molecules involved in apoptosis are used as treatment against several diseases. Candidates such as TNF death receptor family, caspase inhibitors, antagonists of the p53-MDM2 interaction, NF-kappaB and PI3K pathways and Bcl-2 family members have been targeted as cancer cell killing agents. Moreover, apoptosis of tumor cells can also be achieved by targeting the inhibitor of apoptosis proteins, IAPs, in addition to the classical antiproliferative approach. Disruption of STAT activation and interferon beta therapy have been used as a treatment to prevent the progression of some autoimmune diseases. In models of Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, blocking of Par-4 expression or function, as well as caspase activation, prevents neuronal cell death. Finally, it has been shown that gene therapy may be an encouraging approach for treatment of neurodegenerative disorders.}, }
@article {pmid16098325, year = {2005}, author = {Søreide, E and Deakin, CD}, title = {Pre-hospital fluid therapy in the critically injured patient--a clinical update.}, journal = {Injury}, volume = {36}, number = {9}, pages = {1001-1010}, doi = {10.1016/j.injury.2005.01.002}, pmid = {16098325}, issn = {0020-1383}, mesh = {Blood Pressure/physiology ; Blood Substitutes/therapeutic use ; Brain Injuries/therapy ; Colloids/therapeutic use ; Critical Illness ; Crystalloid Solutions ; Emergency Medical Services/*methods ; Fluid Therapy/*methods ; Humans ; Hypotension/therapy ; Isotonic Solutions/therapeutic use ; Life Support Care/*methods ; Rehydration Solutions/therapeutic use ; Resuscitation/methods ; Saline Solution, Hypertonic/therapeutic use ; Wounds and Injuries/*therapy ; Wounds, Nonpenetrating/therapy ; Wounds, Penetrating/therapy ; }, abstract = {Venous access and fluid therapy should still be considered to be essential elements of pre-hospital advanced life support (ALS) in the critically injured patient. Initiation of fluid therapy should be based on a clinical assessment, most importantly the presence, or otherwise, of a radial pulse. The goal in penetrating injury is to avoid hypovolaemic cardiac arrest during transport, but at the same time not to delay transport, or increase systolic blood pressure. The goal in blunt injury is to secure safe perfusion of the injured brain through an adequate cerebral perfusion pressure, which generally requires a systolic blood pressure well above 100 mmHg. Patients without severe brain injury tolerate lower blood pressures (hypotensive resuscitation). Importantly, using systolic blood pressure targets to titrate therapy is not as easy as it seems. Automated (oscillometric) blood pressure measurement devices frequently give erroneously high values. The concept of hypotensive resuscitation has not been validated in the few studies done in humans. Hence, the suggested targeted systolic blood pressures should only provide a mental framework for the decision-making. The ideal pre-hospital fluid regimen may be a combination of an initial hypertonic solution given as a 10-20 minutes infusion, followed by crystalloids and, in some cases, artificial colloids. This review is intended to help the clinician to balance the pros and cons of fluid therapy in the individual patient.}, }
@article {pmid16097403, year = {2005}, author = {Schmidt, AJ and Krieg, JC and Vedder, H}, title = {Antioxidative and steroid systems in neurological and psychiatric disorders.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {6}, number = {1}, pages = {26-35}, doi = {10.1080/15622970510029759}, pmid = {16097403}, issn = {1562-2975}, mesh = {Animals ; Antioxidants/*physiology/therapeutic use ; Brain/drug effects/physiopathology ; Brain Diseases/drug therapy/*physiopathology ; Brain Mapping ; Catalase/physiology ; Glutathione Peroxidase/physiology ; Humans ; Mental Disorders/drug therapy/*physiopathology ; Steroids/*physiology/therapeutic use ; Superoxide Dismutase/physiology ; }, abstract = {A large number of neurological and psychiatric diseases like Morbus Parkinson, amyotrophic lateral sclerosis, dementia, schizophrenia and probably also affective disorders show an enhanced production of reactive oxygen species. Moreover, alterations of antioxidative systems and beneficial effects of antioxidative substances including steroid compounds such as estrogens have been described in several of these diseases. This review focuses on alterations of antioxidative systems in the course of neurological diseases and psychiatric disorders and on the differential effects of steroids on these systems in the central nervous system. Moreover, a possible clinical relevance of alterations of circulating steroids and of steroid treatment under these conditions is discussed.}, }
@article {pmid16095220, year = {2005}, author = {Hideyama, T and Kawahara, Y and Kwak, S}, title = {[AMPA receptor-mediated neuronal death and amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {57}, number = {7}, pages = {585-598}, pmid = {16095220}, issn = {0006-8969}, mesh = {Adenosine Deaminase/metabolism ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; Animals ; Calcium-Binding Proteins/genetics ; Cell Death/physiology ; Humans ; Kv Channel-Interacting Proteins ; Mice ; Motor Neurons/*pathology ; Mutation ; RNA Editing/physiology ; RNA-Binding Proteins ; Receptors, AMPA/chemistry/genetics/*physiology ; Receptors, N-Methyl-D-Aspartate/genetics/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid16087231, year = {2005}, author = {Paschen, W and Mengesdorf, T}, title = {Endoplasmic reticulum stress response and neurodegeneration.}, journal = {Cell calcium}, volume = {38}, number = {3-4}, pages = {409-415}, doi = {10.1016/j.ceca.2005.06.019}, pmid = {16087231}, issn = {0143-4160}, mesh = {Animals ; Brain/metabolism/pathology ; Endoplasmic Reticulum/pathology/*physiology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Oxidative Stress/*physiology ; }, abstract = {The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in calcium storage and signaling. Disturbances of ER calcium homeostasis constitute a severe form of stress interfering with central functions of this structure including the folding and processing of newly synthesized membrane and secretory proteins. Blocking the folding and processing reactions results in the accumulation of unfolded proteins forming potentially toxic aggregates. To restore ER functioning, specific stress responses are activated one of which is the unfolded protein response (UPR). UPR is characterized by a shutdown of global protein synthesis and activation of expression of genes coding for ER-resident proteins that are involved in the folding and processing reactions. ER calcium homeostasis is therefore inevitably associated with major cellular functions, including gene transcription and translation. ER calcium homeostasis und ER functions are believed to be impaired in various degenerative diseases of the brain including Alzheimer's, Parkinson's and Huntington's disease, and amyotrophic lateral sclerosis. ER functioning has also been shown to be disturbed in acute pathological states of the brain such as ischemia and trauma, which have been identified as risk factors for the development of degenerative diseases. This implies that there are common underlying pathomechanisms. This review will summarize new observations suggesting that impairment of ER functioning may be a common denominator of pathological processes resulting in neuronal cell injury in acute disorders and degenerative diseases of the brain.}, }
@article {pmid16055199, year = {2005}, author = {Neale, JH and Olszewski, RT and Gehl, LM and Wroblewska, B and Bzdega, T}, title = {The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia.}, journal = {Trends in pharmacological sciences}, volume = {26}, number = {9}, pages = {477-484}, doi = {10.1016/j.tips.2005.07.004}, pmid = {16055199}, issn = {0165-6147}, support = {NS 38080/NS/NINDS NIH HHS/United States ; NS 42672/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain Ischemia/*drug therapy ; Diabetic Neuropathies/*drug therapy ; Dipeptides/*metabolism ; Glutamate Carboxypeptidase II/*antagonists &amp; inhibitors ; Humans ; Pain/*drug therapy ; Protease Inhibitors/*therapeutic use ; Schizophrenia/*drug therapy ; }, abstract = {N-Acetylaspartylglutamate (NAAG) is the most abundant and widely distributed peptide transmitter in the mammalian nervous system. NAAG activates the metabotropic glutamate mGlu(3) receptor at presynaptic sites, inhibiting the release of neurotransmitters, including glutamate, and activates mGlu(3) receptors on glial cells, stimulating the release of neuroprotective growth factors from these cells. Elevated levels of glutamate released from neurons are associated with the pathology of stroke, traumatic nervous system injury, amyotrophic lateral sclerosis, inflammatory and neuropathic pain, diabetic neuropathy and the schizophrenia-like symptoms elicited by phencyclidine. NAAG is inactivated by specific peptidases following its synaptic release. Novel compounds that inhibit these enzymes prolong the activity of synaptically released NAAG and have significant therapeutic efficacy in animal models of these diverse clinical conditions. In this review, we summarize recent studies in these animal models and discuss the mechanisms by which NAAG peptidase inhibitors achieve these effects.}, }
@article {pmid16050975, year = {2005}, author = {Manfredi, G and Xu, Z}, title = {Mitochondrial dysfunction and its role in motor neuron degeneration in ALS.}, journal = {Mitochondrion}, volume = {5}, number = {2}, pages = {77-87}, doi = {10.1016/j.mito.2005.01.002}, pmid = {16050975}, issn = {1567-7249}, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/pathology/*physiopathology ; Animals ; Apoptosis ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Mitochondria/*physiology ; Models, Neurological ; Motor Neurons/pathology/*physiology ; Mutation ; Nerve Degeneration/pathology/*physiopathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Mitochondria play a pivotal role in many metabolic and apoptotic pathways that regulate the life and death of cells. Accumulating evidence suggests that mitochondrial dysfunction is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mitochondrial dysfunction may cause motor neuron death by predisposing them to calcium-mediated excitotoxicity, by increasing generation of reactive oxygen species, and by initiating the intrinsic apoptotic pathway. Morphological and biochemical mitochondrial abnormalities have been described in sporadic human ALS cases, but the implications of these findings in terminally ill individuals or in post-mortem tissues are difficult to decipher. However, remarkable mitochondrial abnormalities have also been identified in transgenic mouse models of familial ALS expressing mutant Cu, Zn superoxide dismutase (SOD1). Detailed studies in these mouse models indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting that mitochondrial dysfunction may be causally involved in the pathogenesis of ALS. Although the mechanisms whereby mutant SOD1 damages mitochondria remain to be fully understood, the finding that a portion of mutant SOD1 is localized in mitochondria, where it forms aberrant aggregates and protein interactions, has opened a number of avenues of investigation. The future challenges are to devise models to better understand the effects of mutant SOD1 in mitochondria and the relative contribution of mitochondrial dysfunction to the pathogenesis of ALS, as well as to identify therapeutic approaches that target mitochondrial dysfunction and its consequences.}, }
@article {pmid16048838, year = {2005}, author = {Meriin, AB and Sherman, MY}, title = {Role of molecular chaperones in neurodegenerative disorders.}, journal = {International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group}, volume = {21}, number = {5}, pages = {403-419}, doi = {10.1080/02656730500041871}, pmid = {16048838}, issn = {0265-6736}, mesh = {Apoptosis/physiology ; Cellular Senescence/physiology ; Heat-Shock Proteins/physiology ; Humans ; Inclusion Bodies/metabolism ; Models, Biological ; Molecular Chaperones/chemistry/metabolism/*physiology ; Neurodegenerative Diseases/metabolism/*physiopathology/therapy ; Protein Conformation ; Protein Folding ; Ubiquitin-Protein Ligases/physiology ; }, abstract = {Many major neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington Disease and other polyglutamine expansion disorders, are associated with degeneration and death of specific neuronal populations due to accumulation of certain abnormal polypeptides. These misfolded species aggregate and form inclusion bodies and their neurotoxicity is associated with the aggregation. To handle a build-up of abnormal proteins cells employ a complicated machinery of molecular chaperones and various proteolytic systems. Chaperones facilitate refolding or degradation of misfolded polypeptides, prevent protein aggregation and play a role in formation of aggresome, a centrosome-associated body to which small cytoplasmic aggregates are transported. The ubiquitin-proteasome proteolytic system is critical for reducing the levels of soluble abnormal proteins, while autophagy plays the major role in clearing of cells from protein aggregates. Accumulation of the aggregation prone proteins activates signal transduction pathways that control cell death, including JNK pathway that controls viability of a cell in various models of Parkinson's and Huntington's diseases. The major chaperone Hsp72 can interfere with this signalling pathway, thus promoting survival. A very important consequence of a build-up and aggregation of misfolded proteins is impairment of the ubiquitin-proteasome degradation system and suppression of the heat shock response. Such an inhibition of the major cell defense systems may play a critical role in neurodegeneration. Here, it is suggested that these changes may reflect a senescence-like programme initiated by the aggregated abnormal polypeptides. Pathways that control the fate of misfolded proteins, for example molecular chaperones or proteolytic systems, may become interesting novel targets for therapy of neurodegenerative disorders.}, }
@article {pmid16037768, year = {2005}, author = {Richardson, DT and Dodson, TB}, title = {Risk of periodontal defects after third molar surgery: An exercise in evidence-based clinical decision-making.}, journal = {Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics}, volume = {100}, number = {2}, pages = {133-137}, doi = {10.1016/j.tripleo.2005.02.063}, pmid = {16037768}, issn = {1528-395X}, support = {K24 DE00048/DE/NIDCR NIH HHS/United States ; }, mesh = {Alveolar Bone Loss/*etiology ; Decision Making ; Evidence-Based Medicine ; Humans ; Molar, Third/*surgery ; Periodontal Attachment Loss/*etiology ; Risk Factors ; Tooth Extraction/*adverse effects ; Tooth, Impacted/surgery ; }, abstract = {OBJECTIVE: The object of this study was to apply evidence-based principles to answer the question, What is the risk of having periodontal defects on the distal aspect of the mandibular second molar (M2) following third molar (M3) removal?<br><br>STUDY DESIGN: To identify relevant articles for review, we completed a computerized literature search of Medline. The inclusion criteria for articles included prospective cohort studies or randomized clinical trials with follow-up periods of 6 months or more, and preoperative and postoperative measurements of periodontal probing depths (PDs) or attachment levels (ALs).<br><br>RESULTS: Eight articles met the inclusion criteria. Overall, the reported mean changes in ALs or PDs on the distal of M2 6 months after M3 removal were clinically insignificant, ie, less than 2 mm. Six months after M3 removal, 52% to 100% of subjects had no change or improvement in ALs or PDs. Given periodontal disease present preoperatively, the number needed to treat (NNT) ranged from 3 to 10. Given healthy periodontal status preoperatively, 48% had worsening of their periodontal measures after M3 removal and the number needed to harm (NNH) was 2.<br><br>CONCLUSION: Commonly, the second molar periodontal probing depth or attachment levels either remain unchanged or improve after third molar removal. For subjects with healthy second molar periodontium preoperatively, the indication for third molar removal needs to be evaluated carefully as these subjects have an increased risk for worsening of probing depths or attachment levels after third molar removal.}, }
@article {pmid16036430, year = {2005}, author = {Ravits, J}, title = {Sporadic amyotrophic lateral sclerosis: a hypothesis of persistent (non-lytic) enteroviral infection.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {2}, pages = {77-87}, doi = {10.1080/14660820510027026}, pmid = {16036430}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*virology ; Animals ; Apoptosis/physiology ; Capsid Proteins/genetics/metabolism ; Enterovirus/*isolation &amp; purification ; Enterovirus Infections/*physiopathology ; Humans ; Poliovirus/isolation &amp; purification ; Reverse Transcriptase Polymerase Chain Reaction/methods ; }, abstract = {Because of recently reported reverse transcriptase polymerase chain reaction evidence of enterovirus in sporadic amyotrophic lateral sclerosis (SALS) and because of newly available anti-enteroviral drugs binding enteroviral capsids, it is reasonable to re-formulate an enteroviral hypothesis of SALS using recent advances in molecular virology. Viral persistence is non-lytic and non-cytopathic infection that evades host's immune surveillance. Enteroviruses are known to cause persistent as well as lytic infection both in vitro and in vivo. Both virion as well as host factors modulate between persistent and lytic infection. Apoptosis, or programmed cell death, is a process of active non-necrotic cell death. It has complex interplay with viruses and may be either promoted or opposed by them. Apoptosis is a major factor in motor neuron death in SALS. Viral tropism is the process by which viruses select and propagate to target cells. It is controlled by capsid conformation and surface receptors on host cells. Enteroviruses have a region on their capsids known as the canyon which docks on such receptors. Docking induces conformational changes of the capsid and genome release. Poliovirus, tropic for motor neurons, docks on the poliovirus receptor, about which much is known. The virus penetrates the motor system focally after crossing either the blood-muscle or the blood-brain barriers. It propagates bidirectionally along axons and synapses to contiguous motor neurons, upper as well as lower, which sequester infection and create avenues for spread over long distances. If chronic and persistent rather than acute and lytic, such viruses trafficking in a finite system of non-dividing cells and inducing apoptosis would cause cell death that summates linearly rather than exponentially. Taken together, these explain signature clinical features of SALS - focal onset weakness, contiguous or regional spread of weakness, confinement to upper and lower motor neurons, and linear rates of progression. The hypothesis predicts the following testable investigations: 1) viral detection may be possible by applying amplification technology to optimally acquired nervous tissue processed by laser microdissection; 2) genetic susceptibility factors such as cell surface receptor polymorphisms may combine with sporadic exposure and chance penetration of the motor system in SALS; 3) a transgenic animal model might be created by inserting such genetic factors into an animal host and inoculating intramuscularly rather than intracerebrally biochemical fractions of SALS motor neurons at vulnerable periods in the developmental life cycle of the transgenic host; and 4) continual long-term administration of anti-enteroviral agents called capsid-binding compounds which stabilize capsids and prevent genome release might be efficacious.}, }
@article {pmid16036422, year = {2005}, author = {de Carvalho, M and Chio, A and Dengler, R and Hecht, M and Weber, M and Swash, M}, title = {Neurophysiological measures in amyotrophic lateral sclerosis: markers of progression in clinical trials.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {1}, pages = {17-28}, doi = {10.1080/14660820410020600}, pmid = {16036422}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Animals ; Biomarkers/analysis ; Clinical Trials as Topic/*methods ; Disease Progression ; Electric Stimulation/methods ; Electromyography/methods ; Electrophysiology/methods ; Evoked Potentials, Motor/physiology/radiation effects ; Humans ; Magnetics ; Motor Neurons/physiology ; Neurophysiology/*methods ; }, abstract = {In this review we evaluate clinical neurophysiological methods, originally described for use in diagnosis that can be applied to measurement of change during the progress of amyotrophic lateral sclerosis (ALS). Such measurements are potentially important in clinical trials, and also in clinical practice. We have assessed methods for lower and upper motor neuron function, including conventional EMG, nerve conduction and F-wave studies, the derived Neurophysiological Index, motor unit counting methods (MUNE), and transcranial magnetic motor cortex stimulation. We have also addressed the validity of measurements of electromechanical coupling. Methods for measuring muscle strength are beyond the scope of this review. We conclude that MUNE, M-wave amplitude and the Neurophysiological Index are sufficiently reliable, sensitive, and relevant to the clinical problem of ALS, to be used in clinical trials in the disease. Transcranial magnetic stimulation is of limited value, but a combination of the measurements made as part of this technique may also be useful. We conclude that clinical neurophysiological techniques should now be used in measuring change in clinical trials in ALS.}, }
@article {pmid16036421, year = {2005}, author = {Strong, MJ and Gordon, PH}, title = {Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {1}, pages = {8-16}, doi = {10.1080/14660820410021267}, pmid = {16036421}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/classification/complications/*diagnosis ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/classification/complications/*diagnosis ; Motor Neurons/physiology ; Spastic Paraplegia, Hereditary/classification/complications/*diagnosis ; }, abstract = {Among the motor neuron diseases, three share the clinical features of prominent upper motor neuron signs--amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic testing can assist in the identification of several variants of the latter, in the remaining cases, including those in which spasticity may be associated with amyotrophy, clinical differentiation of the three disorders may prove difficult. In this paper we review the evidence that these are distinct disorders and conclude that, for ALS and PLS particularly, there may be justification in considering them as single points along a continuum of multisystem disorders with conspicuous motor neuron involvement. Only through the development and application of exacting clinical diagnostic criteria to epidemiological studies, along with greater numbers of post-mortem examinations, however, will these questions be answered fully.}, }
@article {pmid16033692, year = {2005}, author = {Sathasivam, S and Shaw, PJ}, title = {Apoptosis in amyotrophic lateral sclerosis--what is the evidence?.}, journal = {The Lancet. Neurology}, volume = {4}, number = {8}, pages = {500-509}, doi = {10.1016/S1474-4422(05)70142-3}, pmid = {16033692}, issn = {1474-4422}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Apoptosis/*physiology ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, Tumor Necrosis Factor/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {There is increasing evidence that a programmed mechanism of cell death resembling apoptosis is responsible for motor-neuron degeneration in amyotrophic lateral sclerosis. Our understanding of the cell-death pathway has come from studies of both experimental models and human tissue. Here we examine in detail the in vitro and in vivo evidence for and against apoptosis in amyotrophic lateral sclerosis, looking at morphological changes, caspase activation, alterations in Bcl-2 oncoproteins, involvement of death receptors, expression of apoptosis-related molecules, and the role of the p53 pathway. Finally, we present evidence of potential therapeutic agents that could modulate the apoptotic pathway in amyotrophic lateral sclerosis and slow disease progression.}, }
@article {pmid16033687, year = {2005}, author = {Chiò, A}, title = {Mortality trends in ALS: an increasingly intricate puzzle.}, journal = {The Lancet. Neurology}, volume = {4}, number = {8}, pages = {453-454}, doi = {10.1016/S1474-4422(05)70125-3}, pmid = {16033687}, issn = {1474-4422}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*mortality ; Death Certificates ; Female ; Humans ; Incidence ; Male ; }, }
@article {pmid16026864, year = {2005}, author = {von Lewinski, F and Keller, BU}, title = {Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.}, journal = {Trends in neurosciences}, volume = {28}, number = {9}, pages = {494-500}, doi = {10.1016/j.tins.2005.07.001}, pmid = {16026864}, issn = {0166-2236}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Brain/metabolism/*pathology ; Calcium/*metabolism ; Humans ; Mitochondria/metabolism/*pathology ; *Models, Neurological ; Motor Neurons/metabolism/*pathology ; Reactive Oxygen Species ; Spinal Cord/metabolism/pathology ; }, abstract = {Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca(2+)-dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca(2+)-buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca(2+) buffers are valuable because they facilitate rapid relaxation times of Ca(2+) transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca(2+) buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca(2+) disregulation and excitotoxic cell damage.}, }
@article {pmid16026259, year = {2005}, author = {Kato, T and Ren, CH and Wada, M and Kawanami, T}, title = {Galectin-1 as a potential therapeutic agent for amyotrophic lateral sclerosis.}, journal = {Current drug targets}, volume = {6}, number = {4}, pages = {407-418}, doi = {10.2174/1389450054021846}, pmid = {16026259}, issn = {1389-4501}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Galectin 1/analysis/pharmacology/*therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects almost selectively motor neurons in the central nervous system. Most ALS patients die within five years of onset. One of the neuropathological features of ALS is an "axonal spheroid," a large swelling of a motor axon within the anterior horn of the spinal cord; this abnormal structure seems to be related to the pathogenesis of motor neuron degeneration in ALS. In 2001, using biochemical and immunohistochemical methods, we found an accumulation of galectin-1 in ALS spheroids. By immuno-electron microscopy, the galectin-1 accumulated in the spheroids was observed to be closely associated with neurofilaments. Furthermore, we observed a marked depletion of galectin-1 in the skin of ALS patients; another abnormality frequently observed in ALS. These findings, therefore, suggest that galectin-1 may be involved in the pathogenesis of ALS. It is known that an oxidized form of galectin-1 promotes axonal regeneration; however, it is not known whether oxidized galectin-1 has a beneficial or an adverse effect on the pathophysiology of ALS. To examine this issue, we administered oxidized galectin-1 to transgenic mice with H46R mutant SOD1, an ALS model mouse. The results showed that the administration of oxidized galectin-1 improved the motor activity, delayed the onset of symptoms, and prolonged the survival of the galectin-1-treated mice. Furthermore, the number of remaining motor neurons in the spinal cord was more preserved in the galectin-1-treated mice than in the non-treated mice. We conclude that galectin-1 could be a candidate agent for the treatment of ALS.}, }
@article {pmid16025525, year = {2006}, author = {Thomas, CK and Zijdewind, I}, title = {Fatigue of muscles weakened by death of motoneurons.}, journal = {Muscle &amp; nerve}, volume = {33}, number = {1}, pages = {21-41}, doi = {10.1002/mus.20400}, pmid = {16025525}, issn = {0148-639X}, support = {NS-30226/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Cell Death ; Humans ; Motor Neurons/*pathology ; *Muscle Fatigue ; Muscles/innervation/physiopathology ; Postpoliomyelitis Syndrome/*physiopathology ; Spinal Cord Injuries/*physiopathology ; }, abstract = {Weakness is a characteristic of muscles influenced by the postpolio syndrome (PPS), amyotrophic lateral sclerosis (ALS), and spinal cord injury (SCI). The strength deficits relate to changes in muscle use and to the chronic denervation that can follow the spinal motoneuron death common to these disorders. PPS, ALS, and SCI also involve variable amounts of supraspinal neuron death, the effects of which on muscle weakness remains unclear. Nevertheless, weakness of muscle itself defines the functional consequences of these disorders. A weaker muscle requires an individual to work that muscle at higher than usual intensities relative to its maximal capacity, inducing progressive fatigue and an increased sense of effort. Little evidence is available to suggest that the fatigue commonly experienced by individuals with these disorders relates to an increase in the intrinsic fatigability of the muscle fibers. The only exception is when SCI induces chronic muscle paralysis. To reduce long-term functional deficits in these disorders, studies must identify the signaling pathways that influence neuron survival and determine the factors that encourage and limit sprouting of motor axons. This may ensure that a greater proportion of the fibers in each muscle remain innervated and available for use.}, }
@article {pmid16024877, year = {2005}, author = {Shaw, PJ}, title = {Molecular and cellular pathways of neurodegeneration in motor neurone disease.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {76}, number = {8}, pages = {1046-1057}, pmid = {16024877}, issn = {0022-3050}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/genetics/pathology ; Axonal Transport/genetics ; Biological Transport ; Calcium-Binding Proteins/genetics ; Cell Aggregation ; Cell Death/physiology ; Chromosomes, Human, Pair 9/genetics ; DNA Helicases ; Dynactin Complex ; Environment ; Exons/genetics ; Humans ; Kv Channel-Interacting Proteins ; Microtubule-Associated Proteins/genetics ; Mitochondrial Myopathies/epidemiology/pathology/physiopathology ; Motor Neuron Disease/epidemiology/*genetics/*pathology ; Multifunctional Enzymes ; Nerve Degeneration/epidemiology/*pathology ; Neural Pathways/*pathology ; Oxidative Stress/physiology ; Point Mutation/genetics ; RNA Helicases/genetics ; Risk Factors ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The process of neuronal degeneration in motor neurone disease is complex. Several genetic alterations may be involved in motor neurone injury in familial amyotrophic lateral sclerosis, less is known about the genetic and environmental factors involved in the commoner sporadic form of the disease. Most is known about the mechanisms of motor neurone degeneration in the subtype of disease caused by SOD1 mutations, but even here there appears to be a complex interplay between multiple pathogenic processes including oxidative stress, protein aggregation, mitochondrial dysfunction excitotoxicity, and impaired axonal transport. There is new evidence that non-neuronal cells in the vicinity of motor neurones may contribute to neuronal injury. The final demise of motor neurones is likely to involve a programmed cell death pathway resembling apoptosis.}, }
@article {pmid16024755, year = {2005}, author = {Dykens, JA and Moos, WH and Howell, N}, title = {Development of 17alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study.}, journal = {Annals of the New York Academy of Sciences}, volume = {1052}, number = {}, pages = {116-135}, doi = {10.1196/annals.1347.008}, pmid = {16024755}, issn = {0077-8923}, mesh = {Aged ; Alzheimer Disease/prevention &amp; control ; Animals ; Apoptosis/drug effects ; Clinical Trials, Phase I as Topic ; Estradiol/blood/chemistry/*therapeutic use ; Female ; Humans ; Lipid Peroxidation/drug effects ; Middle Aged ; Mitochondria/drug effects ; Neurodegenerative Diseases/prevention &amp; control ; Neurons/drug effects ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; Parkinson Disease/prevention &amp; control ; Receptors, Estrogen/physiology ; Stereoisomerism ; Stroke/prevention &amp; control ; }, abstract = {17alpha-estradiol (17alpha-E2) differs from its isomer, the potent feminizing hormone 17beta-estradiol (17beta-E2), only in the stereochemistry at one carbon, but this is sufficient to render it at least 200-fold less active as a transactivating hormone. Despite its meager hormonal activity, 17alpha-E2 is as potent as 17beta-E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others. Moreover, both estradiol isomers have shown efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). Data from many labs have yielded a mechanistic model in which 17alpha-E2 intercalates into cell membranes, where it terminates lipid peroxidation chain reactions, thereby preserving membrane integrity, and where it in turn is redox cycled by glutathione or by NADPH through enzymatic coupling. Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues. Positive safety and pharmacokinetic data from a successful phase I clinical study with oral 17alpha-E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.}, }
@article {pmid16008818, year = {2005}, author = {Ince, PG and Codd, GA}, title = {Return of the cycad hypothesis - does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?.}, journal = {Neuropathology and applied neurobiology}, volume = {31}, number = {4}, pages = {345-353}, doi = {10.1111/j.1365-2990.2005.00686.x}, pmid = {16008818}, issn = {0305-1846}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology ; Bacterial Toxins/*toxicity ; Brain/*pathology ; Cyanobacteria/physiology ; Cyanobacteria Toxins ; Cycas/*microbiology ; Guam ; Humans ; Marine Toxins/*toxicity ; Microcystins ; Neurofibrillary Tangles/pathology ; Parkinsonian Disorders/*etiology/pathology ; Plant Roots/microbiology ; Plants, Edible/microbiology ; }, abstract = {Recently published work provides evidence in support of the cycad hypothesis for Lytico--Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of beta-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a 'tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of 'AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for 'ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for alpha-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of 'incidental'alpha-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico-Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies.}, }
@article {pmid15975084, year = {2004}, author = {Takeuchi, M and Kikuchi, S and Sasaki, N and Suzuki, T and Watai, T and Iwaki, M and Bucala, R and Yamagishi, S}, title = {Involvement of advanced glycation end-products (AGEs) in Alzheimer's disease.}, journal = {Current Alzheimer research}, volume = {1}, number = {1}, pages = {39-46}, doi = {10.2174/1567205043480582}, pmid = {15975084}, issn = {1567-2050}, mesh = {Alzheimer Disease/*metabolism ; Brain/metabolism ; Glycation End Products, Advanced/*metabolism ; Humans ; }, abstract = {The advanced stage of the glycation process (one of the post-translational modifications of proteins) leads to the formation of advanced glycation end-products (AGEs) and plays an important role in the pathogenesis of angiopathy in diabetic patients. It has recently become clear that AGEs also influence physiological aging and neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Recently we have provided direct immunochemical evidence for the existence of six distinct AGE structures within the AGE-modified proteins and peptides that circulate in the serum of diabetic patients on hemodialysis (DM-HD). We showed a direct toxic effect of the synthetic AGE-2 (glyceraldehyde-derived AGEs) on cortical neuronal cells and provided evidence for a toxic effect of AGE-2 present in DM-HD serum. These results indicate that of the various types of AGE structures that can form in vivo, the AGE-2 structure is likely to play an important role in the pathophysiological processes associated with AGE formation. In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. Protein cross-linking by AGE structures results in the formation of protease-resistant aggregates. Such protein aggregates may interfere with both axonal transport and intracellular protein traffic in neuron. In this review, we provide an outline of AGEs formation in vivo and propose that the novel structural epitope AGE-2 is an important toxic moiety for neuronal cells in AD.}, }
@article {pmid15975029, year = {2005}, author = {van Muiswinkel, FL and Kuiperij, HB}, title = {The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {4}, number = {3}, pages = {267-281}, doi = {10.2174/1568007054038238}, pmid = {15975029}, issn = {1568-007X}, mesh = {Alzheimer Disease/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Antioxidants/*metabolism ; Central Nervous System/metabolism ; DNA-Binding Proteins/*metabolism ; Drug Design ; Gene Expression Regulation/drug effects/physiology ; Humans ; NF-E2-Related Factor 2 ; Neurodegenerative Diseases/drug therapy/*metabolism ; Oxidative Stress/*physiology ; Parkinson Disease/drug therapy/metabolism ; Response Elements/drug effects/*physiology ; Signal Transduction/physiology ; Trans-Activators/*metabolism ; Transcription, Genetic/drug effects ; }, abstract = {A large body of evidence indicates that oxidative stress is a salient pathological feature in many neurodegenerative diseases, including Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In addition to signs of systemic oxidative stress, at the biochemical and neuropathological level, neuronal degeneration in these disorders has been shown to coincide with several markers of oxidative damage to lipids, nucleic acids, and proteins in affected brain regions. Neuroinflammatory processes, often associated with the induction of free radical generating enzymes and the accumulation of reactive astrocytes and microglial cells, are considered as a major source of oxidative stress. Given the pathogenic impact of oxidative stress and neuroinflammation, therapeutic strategies aimed to blunt these processes are considered an effective way to confer neuroprotection. Recently, the nuclear transcription factor Nrf2, that binds to the antioxidant response element (ARE) in gene promoters, has been reported to constitute a key regulatory factor in the co-ordinate induction of a battery of endogenous cytoprotective genes, including those encoding for both antioxidant- and anti-inflammatory proteins. In the present review, besides discussing recent evidence underscoring the thesis that the Nrf2-ARE signalling pathway is an attractive therapeutic target for neurodegenerative diseases, we advocate the view that chemopreventive agents might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.}, }
@article {pmid15975010, year = {2005}, author = {McCown, TJ}, title = {Adeno-associated virus (AAV) vectors in the CNS.}, journal = {Current gene therapy}, volume = {5}, number = {3}, pages = {333-338}, doi = {10.2174/1566523054064995}, pmid = {15975010}, issn = {1566-5232}, mesh = {Animals ; Central Nervous System/*virology ; Central Nervous System Diseases/enzymology/*therapy ; Dependovirus/*genetics ; Enzymes/genetics ; *Genetic Therapy ; *Genetic Vectors ; Humans ; }, abstract = {Adeno-associated virus (AAV) vectors exhibit a number of properties that have made this vector system an excellent choice for both CNS gene therapy and basic neurobiological investigations. In vivo, the preponderance of AAV vector transduction occurs in neurons where it is possible to obtain long-term, stable gene expression with very little accompanying toxicity. Promoter selection, however, significantly influences the pattern and longevity of neuronal transduction distinct from the tropism inherent to AAV vectors. AAV vectors have successfully manipulated CNS function using a wide variety of approaches including expression of foreign genes, expression of endogenous genes, expression of antisense RNA and expression of RNAi. With the discovery and characterization of different AAV serotypes, the potential patterns of in vivo vector transduction have been expanded substantially, offering alternatives to the more studied AAV 2 serotype. Furthermore, the development of specific AAV chimeras offers the potential to further refine targeting strategies. These different AAV serotypes also provide a solution to the immune silencing that proves to be a realistic likelihood given broad exposure of the human population to the AAV 2 serotype. These advantageous CNS properties of AAV vectors have fostered a wide range of clinically relevant applications including Parkinson's disease, lysosomal storage diseases, Canavan's disease, epilepsy, Huntington's disease and ALS. Each individual application, however, presents a unique set of challenges that must be solved in order to attain clinically effective gene therapies.}, }
@article {pmid15974901, year = {2005}, author = {Klegeris, A and McGeer, PL}, title = {Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease.}, journal = {Current Alzheimer research}, volume = {2}, number = {3}, pages = {355-365}, doi = {10.2174/1567205054367883}, pmid = {15974901}, issn = {1567-2050}, mesh = {Alzheimer Disease/drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Humans ; Inflammation/etiology ; Microglia/drug effects ; Neurodegenerative Diseases/complications/*drug therapy/physiopathology ; Prostaglandin-Endoperoxide Synthases/metabolism ; }, abstract = {Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.}, }
@article {pmid15956815, year = {2005}, author = {Doré, S}, title = {Unique properties of polyphenol stilbenes in the brain: more than direct antioxidant actions; gene/protein regulatory activity.}, journal = {Neuro-Signals}, volume = {14}, number = {1-2}, pages = {61-70}, doi = {10.1159/000085386}, pmid = {15956815}, issn = {1424-862X}, support = {AA014911/AA/NIAAA NIH HHS/United States ; AT002113/AT/NCCIH NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/chemistry/*pharmacology/therapeutic use ; Cerebrovascular Disorders/*drug therapy/metabolism/physiopathology ; Encephalitis/drug therapy/physiopathology/prevention &amp; control ; Flavonoids/*pharmacology ; Gene Expression Regulation, Enzymologic/drug effects/physiology ; Heme Oxygenase (Decyclizing)/drug effects/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Oxidative Stress/drug effects/physiology ; Phenols/*pharmacology ; Polyphenols ; Resveratrol ; Stilbenes/chemistry/*pharmacology/therapeutic use ; }, abstract = {The 'French Paradox' has been typically associated with moderate consumption of wine, especially red wine. A polyphenol 3,4',5-trihydroxy-trans-stilbene (a member of the non-flavonoids family), better known as resveratrol, has been purported to have many health benefits. A number of these valuable properties have been attributed to its intrinsic antioxidant capabilities, although the potential level of resveratrol in the circulation is likely not enough to neutralize free radical scavenging. The brain and the heart are uniquely vulnerable to hypoxic conditions and oxidative stress injuries. Recently, evidence suggests that resveratrol could act as a signaling molecule within tissues and cells to modulate the expression of genes and proteins. Stimulation of such proteins and enzymes could explain some the intracellular antioxidative properties. The modulation of genes could suffice as an explanation of some of resveratrol's cytoprotective actions, as well as its influence on blood flow, cell death, and inflammatory cascades. Resveratrol stimulation of the expression of heme oxygenase is one example. Increased heme oxygenase activity has led to significant protection against models of in vitro and in vivo oxidative stress injury. Resveratrol could provide cellular resistance against insults; although more work is necessary before it is prescribed as a potential prophylactic in models of either acute or chronic conditions, such as stroke, amyotrophic lateral sclerosis, Parkinson, Alzheimer, and a variety of age-related vascular disorders.}, }
@article {pmid15952898, year = {2005}, author = {Valentine, JS and Doucette, PA and Zittin Potter, S}, title = {Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.}, journal = {Annual review of biochemistry}, volume = {74}, number = {}, pages = {563-593}, doi = {10.1146/annurev.biochem.72.121801.161647}, pmid = {15952898}, issn = {0066-4154}, support = {DK46828/DK/NIDDK NIH HHS/United States ; GM28222/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics ; Animals ; Disease Models, Animal ; Enzyme Stability ; Humans ; Mice ; Models, Molecular ; Mutation ; Rats ; Superoxide Dismutase/*chemistry/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Copper-zinc superoxide dismutase (CuZnSOD, SOD1 protein) is an abundant copper- and zinc-containing protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial intermembrane space of human cells. Its primary function is to act as an antioxidant enzyme, lowering the steady-state concentration of superoxide, but when mutated, it can also cause disease. Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS). These mutations result in a highly diverse group of mutant proteins, some of them very similar to and others enormously different from wild-type SOD1. Despite their differences in properties, each member of this diverse set of mutant proteins causes the same clinical disease, presenting a challenge in formulating hypotheses as to what causes SOD1-associated fALS. In this review, we draw together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of SOD1-associated fALS.}, }
@article {pmid15948205, year = {2005}, author = {Armon, C}, title = {Acquired nucleic acid changes may trigger sporadic amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {32}, number = {3}, pages = {373-377}, doi = {10.1002/mus.20372}, pmid = {15948205}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/genetics ; Causality ; DNA Damage/genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation/*genetics ; Neurotoxins/adverse effects ; Nucleic Acids/*genetics ; Risk Factors ; Smoking/*adverse effects ; }, abstract = {This article brings together evidence to support the hypothesis that acquired nucleic acid changes are the proximate causes, "triggers," or "initiators" of sporadic amyotrophic lateral sclerosis (ALS). Clinical features that support this hypothesis include focal onset and spread, and the individualized rate of progression. Clues from the epidemiology of sporadic ALS include the increase in its incidence with age, suggesting accrual of time-dependent changes, and the emergence of smoking, a known carcinogen, as its first "more likely than not" exogenous risk factor. The identification of any exogenous risk factor suggests that a large proportion of sporadic cases have a triggering mechanism susceptible to that factor. Ingestion of the products of cycad circinalis has been hypothesized to be implicated in causing Western Pacific ALS. Cycad contains both neurotoxic factors and carcinogens. The dissimilarity of Western Pacific ALS from neurotoxic diseases suggests a greater likelihood that the effects of DNA alkylation are its proximate cause.}, }
@article {pmid15937610, year = {2005}, author = {Leveck, DE and Davies, GA}, title = {Rapid progression of amyotrophic lateral sclerosis presenting during pregnancy: a case report.}, journal = {Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC}, volume = {27}, number = {4}, pages = {360-362}, doi = {10.1016/s1701-2163(16)30463-7}, pmid = {15937610}, issn = {1701-2163}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications ; Fatal Outcome ; Female ; Gestational Age ; Humans ; Pregnancy ; *Pregnancy Complications ; Pregnancy Outcome ; Respiratory Insufficiency/etiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurologic disease that is rare within the obstetric population. Only 5 reports of ALS in pregnancy have appeared in the medical literature since 1977.<br><br>CASE: A previously healthy 25-year-old pregnant woman with 2 previous births presented with generalized weakness at 22 weeks' gestation. Initial laboratory values were all normal. She was admitted to hospital at 29 weeks' gestation and intubated because of respiratory compromise. Daily biophysical profiles and amniotic fluid indices were normal. Labour was induced at 34.5 weeks' gestation, and delivery was uncomplicated. She died at 9 months postpartum.<br><br>CONCLUSION: Pregnancy complicated by the onset of ALS is a rare event. Complications of this disease mainly affect the respiratory system. Death in this case occurred more rapidly than in other previously reported cases.}, }
@article {pmid15931380, year = {2005}, author = {Bertram, L and Tanzi, RE}, title = {The genetic epidemiology of neurodegenerative disease.}, journal = {The Journal of clinical investigation}, volume = {115}, number = {6}, pages = {1449-1457}, pmid = {15931380}, issn = {0021-9738}, mesh = {Chromosome Mapping ; Genetic Predisposition to Disease/*genetics ; *Molecular Epidemiology ; Nerve Degeneration/epidemiology/*genetics/pathology ; Neurodegenerative Diseases/*epidemiology/*genetics/pathology ; *Physical Chromosome Mapping ; }, abstract = {Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.}, }
@article {pmid15928806, year = {2005}, author = {Gee, CE and Mansuy, IM}, title = {Protein phosphatases and their potential implications in neuroprotective processes.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {62}, number = {10}, pages = {1120-1130}, doi = {10.1007/s00018-005-5008-4}, pmid = {15928806}, issn = {1420-682X}, mesh = {Animals ; Cell Death/physiology ; Cell Survival/physiology ; Humans ; Models, Biological ; Nervous System/*enzymology ; Phosphoprotein Phosphatases/*metabolism ; Protein Tyrosine Phosphatases/metabolism ; Signal Transduction/physiology ; }, abstract = {Several neurological disorders such as stroke, amyotrophic lateral sclerosis and epilepsy result from excitotoxic events and are accompanied by neuronal cell death. These processes engage multiple signalling pathways and recruit numerous molecular components, in particular several families of protein kinases and protein phosphatases. While many investigations have examined the importance of protein kinases in excitotoxicity, protein phosphatases have not been well studied in this context. However, recent advances in understanding the functions of protein phosphatases have suggested that they may play a neuroprotective role. In this review, we summarize some of the recent findings that illustrate the pleiotropic and complex functions of tyrosine and serine/threonine protein phosphatases in the cascade of events leading to neuronal cell death, and highlight their potential intervention in limiting the extent of neuronal death.}, }
@article {pmid15924088, year = {2005}, author = {Danel-Brunaud, V and Perez, T and Just, N and Destée, A}, title = {[Management and treatment of respiratory failure associated with amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {161}, number = {4}, pages = {480-485}, doi = {10.1016/s0035-3787(05)85082-9}, pmid = {15924088}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS), respiratory muscle involvement is highly predictive of survival and quality of life (QOL). There is compelling evidence that non invasive ventilation (NIV) prolongs survival by several months and improves QOL more than any other currently available treatment. Frequent testing of pulmonary function and regular evaluations are recommended since 1999 by the American Academy of Neurology in order to take appropriate treatment decisions.<br><br>STATE OF ART: There are numerous tests available to evaluate respiratory status in ALS and it is important to know their sensitivity and specificity to recognize clinical risk situations. Some recent data suggest that sniff nasal pressure and maximal inspiratory pressure (MIP) can be performed reliably by most ALS patients and are more sensitive to decrements in inspiratory muscle strength than spirometry or arterial blood gasometry.<br><br>PERSPECTIVES: Airway obstruction caused by ineffective coughing is the principal cause of intolerance to NIV. Several factors other than respiratory muscle strength may affect pulmonary function: postural changes, nutritional status, infectious disease, drugs.<br><br>CONCLUSION: The neurologist has to coordinate multidisciplinary care, with attention to individual patient preferences, and with a frank and compassionate discussion between the patient, the family, the physicians and the caregivers.}, }
@article {pmid15899498, year = {2005}, author = {Coleman, MP and Adalbert, R and Beirowski, B}, title = {Neuroprotective strategies in MS: lessons from C57BL/Wld(S) mice.}, journal = {Journal of the neurological sciences}, volume = {233}, number = {1-2}, pages = {133-138}, doi = {10.1016/j.jns.2005.03.028}, pmid = {15899498}, issn = {0022-510X}, mesh = {Animals ; Axons/pathology ; Disease Models, Animal ; Humans ; Mice ; *Mice, Inbred C57BL ; Mice, Neurologic Mutants/*physiology ; Multiple Sclerosis/*therapy ; Recombinant Fusion Proteins/metabolism ; Ubiquitin-Protein Ligases/chemistry/metabolism ; Wallerian Degeneration/etiology/genetics/*prevention &amp; control ; }, abstract = {Valuable clues about how axons degenerate in MS can be gained from axon pathology in other disorders and experimental models. We discuss the similarities in mechanism and morphology of axon pathology in diverse circumstances revealed using mutant mice. The slow Wallerian degeneration mutation, Wld(S), delays three types of axon degeneration previously considered distinct: Wallerian degeneration of injured axons, 'dying-back' of axons in peripheral nervous system disease, and axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Therefore, axon degeneration mechanisms are more uniform than previously thought and, in gad at least, axonal swelling is either related to or a consequence of Wallerian degeneration. Both axonal swelling and the accumulation of amyloid precursor protein through impaired axonal transport are common to MS, gad, and many other CNS disorders, indicating a degree of shared mechanism. YFP-H transgenic mice express YFP in a representative subset of neurons enabling unprecedented imaging of axon morphology and pathology over considerable longitudinal distances. Using this method, we have observed unbroken axons with multiple constrictions and dilatations in VEGF(delta/delta) mice, a model of amyotrophic lateral sclerosis (ALS). Similar morphologies have been described in MS, stroke, and other disorders, again suggesting a uniformity of axon degeneration mechanisms.}, }
@article {pmid15896810, year = {2005}, author = {Calabrese, V and Lodi, R and Tonon, C and D'Agata, V and Sapienza, M and Scapagnini, G and Mangiameli, A and Pennisi, G and Stella, AM and Butterfield, DA}, title = {Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia.}, journal = {Journal of the neurological sciences}, volume = {233}, number = {1-2}, pages = {145-162}, doi = {10.1016/j.jns.2005.03.012}, pmid = {15896810}, issn = {0022-510X}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Aging/physiology ; Animals ; Antioxidants/therapeutic use ; DNA, Mitochondrial/genetics/metabolism ; Energy Metabolism/physiology ; Friedreich Ataxia/genetics/metabolism/*physiopathology ; Heat-Shock Proteins/metabolism ; Humans ; Mitochondrial Diseases/genetics/metabolism/*physiopathology ; Neurodegenerative Diseases/drug therapy/genetics/metabolism/*physiopathology ; Oxidative Stress/*physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.}, }
@article {pmid15885623, year = {2005}, author = {Oyanagi, K}, title = {The nature of the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam and magnesium deficiency.}, journal = {Parkinsonism &amp; related disorders}, volume = {11 Suppl 1}, number = {}, pages = {S17-23}, doi = {10.1016/j.parkreldis.2005.02.010}, pmid = {15885623}, issn = {1353-8020}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Dementia/metabolism/pathology ; Guam ; Humans ; Magnesium Deficiency/*pathology ; Parkinson Disease/*metabolism/*pathology ; }, abstract = {The parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) were the fatal neurological diseases, showing very high incidence during 1950-1970 and dramatic decrease after 1970 on Guam. Through the research, the present author insisted that; (1) NFTs in Guam ALS patients are merely a background feature widely dispersed in the population, (2) Guam ALS and PDC are basically different diseases, and (3) Guam ALS occurs initially as classic ALS. As pathogeneses of the diseases, intake of low calcium (Ca) and magnesium (Mg) and high aluminum water and of some plant excitatory neurotoxin has been speculated. To elucidate the pathogenesis, the author performed an experiment exposing rats to low Ca and/or Mg intake for two generations, so as to follow the actual way of human living on the island, since several generations live continuously in the same environment. The study indicates that continuous low Mg intake for two generations induces exclusive loss of dopaminergic neurons in in rats, and may support the Mg hypothesis in the pathogenesis of PDC of Guam.}, }
@article {pmid15883271, year = {2005}, author = {Berger, JR and Espinosa, PS and Kissel, J}, title = {Brachial amyotrophic diplegia in a patient with human immunodeficiency virus infection: widening the spectrum of motor neuron diseases occurring with the human immunodeficiency virus.}, journal = {Archives of neurology}, volume = {62}, number = {5}, pages = {817-823}, doi = {10.1001/archneur.62.5.817}, pmid = {15883271}, issn = {0003-9942}, mesh = {Acquired Immunodeficiency Syndrome/*complications ; Adult ; Brachial Plexus Neuropathies/*etiology/virology ; Cerebral Palsy/*complications/virology ; Female ; HIV ; Humans ; Male ; Motor Neuron Disease/*etiology ; Muscle Weakness/etiology ; }, abstract = {Although amyotrophic lateral sclerosis and progressive spinal muscular atrophy have been recognized to occur in association with human immunodeficiency virus infection, to our knowledge, brachial amyotrophic diplegia, a form of segmental motor neuron disease, has not been previously reported. Brachial amyotrophic diplegia results in severe lower motor neuron weakness and atrophy of the upper extremities in the absence of bulbar or lower extremity involvement, pyramidal features, bowel and bladder incontinence, and sensory loss. We describe a human immunodeficiency virus-seropositive man without severe immunosuppression or prior AIDS-defining illnesses who had brachial amyotrophic diplegia. This disorder may represent one end of a spectrum of motor neuron diseases occurring with this retrovirus infection.}, }
@article {pmid15879696, year = {2005}, author = {Wilczak, N and Keyser, J}, title = {Insulin-like growth factor system in amyotrophic lateral sclerosis.}, journal = {Endocrine development}, volume = {9}, number = {}, pages = {160-169}, doi = {10.1159/000085764}, pmid = {15879696}, issn = {1421-7082}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Nerve Regeneration/*drug effects ; }, abstract = {Insulin-like growth factor-I (IGF-I) is a neurotrophic factor with insulin-like metabolic activities, and possesses potential clinical applications, particularly in neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a chronic progressive devastating disorder of the central nervous system, characterized by the death of upper and lower motor neurons. Both in vivo and in vitro studies have shown that IGF-I promotes motor neuron survival and strongly enhances motor nerve regeneration. Evidence that IGF-I rescues motor neurons has led to clinical trials of human recombinant IGF-I in ALS patients. However, systemic delivery of human recombinant IGF-I in these trials did not lead to beneficial clinical effects in ALS patients and may be due through inactivation of IGF-I by binding to IGF binding proteins (IGFBPs), and or limited delivery of IGF-I to motor neurons. Recently it was shown that both IGF-I receptors and IGFBPs were increased on motor neurons of ALS patients and free levels of IGF-I were decreased by 50%. In this study it was suggested that IGFBPs inactivate IGF-I by forming inactive complexes. The uses of IGF analogues with low affinity for IGFBPs and analogues that are able to displace IGF-I from IGFBPs are better candidates in new clinical trials. Another possibility is to find a way of IGF-I transport without hindrance of circulating and tissue-specific IGFBPs, such as IGF-I delivery based on gene therapy.}, }
@article {pmid15879692, year = {2005}, author = {Savage, MO and Blair, JC and Jorge, AJ and Street, ME and Ranke, MB and Camacho-Hübner, C}, title = {IGFs and IGFBPs in GH insensitivity.}, journal = {Endocrine development}, volume = {9}, number = {}, pages = {100-106}, doi = {10.1159/000085760}, pmid = {15879692}, issn = {1421-7082}, mesh = {Biomarkers ; Humans ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor I/*metabolism ; Laron Syndrome/*blood/*diagnosis ; *Severity of Illness Index ; }, abstract = {IGF-I, IGFBP-3 and ALS are GH-dependent peptides and their production is disturbed in states of GH insensitivity. This chapter explores the relative degrees of IGF-I, IGFBP-3 and ALS deficiency across the spectrum of GH insensitivity. In classical GH insensitivity syndrome (GHIS), known as Laron syndrome, due to GH receptor (GHR) deficiency, serum IGF-I, IGFBP-3 and ALS are severely reduced with inability to produce these peptides during an IGF-I generation test. Across the spectrum of severity of GHR defects, some patients have short stature and normal facial appearance, so-called partial or non-classical GH insensitivity. In these cases the IGF-I, IGFBP-3 deficiency is less severe. A positive relationship exists between height SDS and IGFBP-3 SDS (r2 = 0.45, p < 0.001) in patients from the European series with GHIS. In a new series of GHIS cases (n = 36) there was a significant difference in IGFBP-3 and ALS (p < 0.05) between classical (n = 25) and non-classical cases (n = 11). IGF-I, IGFBP-3 and ALS were significantly higher (p < 0.05) in pubertal compared with pre-pubertal subjects in the same series. In idiopathic short stature (ISS), heterozygous mutations of the GHR may have a dominant negative effect. ISS patients have lower IGF-I levels than the normal population. In 21 cases, mean IGF-I SDS was -1.39 (-2.4 to -1.16) and IGFBP-3; -0.45 (-1.13 to 0.38). However, IGF-I and IGFBP-3 responses in the IGF-I generation test were generally normal. In acquired GHI due to chronic illness such as Crohn's disease, juvenile arthritis and cystic fibrosis, IGF-I deficiency is present, although IGFBP-3 is usually normal. In summary, assessment of IGF-I, IGFBP-3 and ALS contributes to diagnosis in GH insensitivity states. In our experience, IGF-I is more sensitive to disturbance of GH action that IGFBP-3, however in severe GHIS cases, IGF-I is usually undetectable and measurement of IGFBP-3 is valuable as a guide to the severity of the biological defect.}, }
@article {pmid15847835, year = {2005}, author = {Simpson, EP}, title = {Antioxidant treatment for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {4}, number = {5}, pages = {266}, doi = {10.1016/S1474-4422(05)70052-1}, pmid = {15847835}, issn = {1474-4422}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*physiopathology ; Antioxidants/*administration &amp; dosage ; Biomarkers/analysis ; Central Nervous System/metabolism/*physiopathology ; Clinical Trials as Topic/trends ; Humans ; Oxidative Stress/*drug effects/physiology ; Treatment Outcome ; }, }
@article {pmid15846792, year = {2005}, author = {Sargsyan, SA and Monk, PN and Shaw, PJ}, title = {Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis.}, journal = {Glia}, volume = {51}, number = {4}, pages = {241-253}, doi = {10.1002/glia.20210}, pmid = {15846792}, issn = {0894-1491}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Disease Progression ; Gliosis/pathology/*physiopathology ; Humans ; Inflammation/pathology/physiopathology ; Inflammation Mediators/metabolism ; Mice ; Microglia/immunology/*metabolism/*pathology ; Models, Animal ; Motor Neurons/*pathology ; Nerve Degeneration/pathology/*physiopathology ; Signal Transduction/immunology ; }, abstract = {The central nervous system (CNS) is equipped with a variety of cell types, all of which are assigned particular roles during the development, maintenance, function and repair of neural tissue. One glial cell type, microglia, deserves particular attention, as its role in the healthy or injured CNS is incompletely understood. Evidence exists for both regenerative and degenerative functions of these glial cells during neuronal injury. This review integrates the current knowledge of the role of microglia in an adult-onset neurodegenerative disease, amyotrophic lateral sclerosis (ALS), and pays particular attention to the possible mechanisms of initiation and propagation of neuronal damage during disease onset and progression. Microglial cell properties, behavior and detected inflammatory reactions during the course of the disease are described. The neuroinflammatory changes that occur in a mouse model of ALS are summarized. The understanding of microglial function in the healthy and injured CNS could offer better diagnostic as well as therapeutic approaches for prevention, retardation, or repair of neural tissue degeneration.}, }
@article {pmid15834017, year = {2005}, author = {Wright, AF}, title = {Neurogenetics II: complex disorders.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {76}, number = {5}, pages = {623-631}, pmid = {15834017}, issn = {0022-3050}, mesh = {Alleles ; Alzheimer Disease/*genetics/*physiopathology ; Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Apolipoproteins E/genetics ; Brain/*physiopathology ; Carrier Proteins/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Genetic Linkage ; Genetic Predisposition to Disease ; Humans ; Immunoglobulin E/genetics ; Insulysin/genetics ; Membrane Proteins/genetics ; Neurofibrillary Tangles/genetics ; Parkinson Disease/*genetics/*physiopathology ; Presenilin-1 ; Presenilin-2 ; Stroke/*genetics/*physiopathology ; Ubiquitin-Protein Ligases ; tau Proteins/genetics ; }, abstract = {The genetic analysis of common neurological disorders will be a difficult and protracted endeavour. Genetics is only one of many disciplines that will be required but it has already thrown considerable light on the aetiology of several major neurological disorders through the analysis of rare inherited subgroups. The identification of individual susceptibility genes with variants of smaller effect will be more difficult but there is no sharp demarcation between large and small genetic effects, so that many new and important insights will emerge using existing and new technologies. The availability of improved neuroimaging, better animal models of disease and new genetic tools, such as high-throughput gene chips, expression microarrays and proteomics, are extending the range of traditional genetic mapping tools. Finally, an understanding of the genetic and epigenetic mechanisms that restrain the differentiation and integration of human neural stem cells into mature neuronal networks could have a major impact on clinical practice. These approaches will be illustrated in the context of Alzheimer disease, Parkinson disease and synucleinopathies, tauopathies, amyotrophic lateral sclerosis and stroke.}, }
@article {pmid15832858, year = {2004}, author = {Solomon, NP}, title = {Assessment of tongue weakness and fatigue.}, journal = {The International journal of orofacial myology : official publication of the International Association of Orofacial Myology}, volume = {30}, number = {}, pages = {8-19}, pmid = {15832858}, issn = {0735-0120}, support = {R03 DC006096/DC/NIDCD NIH HHS/United States ; P60 DC00976/DC/NIDCD NIH HHS/United States ; R03-DC06096/DC/NIDCD NIH HHS/United States ; }, mesh = {Dysarthria/physiopathology ; Humans ; Muscle Fatigue/*physiology ; Muscle Weakness/*diagnosis ; Parkinson Disease/physiopathology ; Physical Endurance ; Physical Exertion ; Tongue/*physiopathology ; Tongue Diseases/*diagnosis ; }, abstract = {Assessment of nonspeech tongue function is common in speech-language pathology. This paper reviews techniques used to determine tongue strength and endurance, and describes a constant-effort task. These techniques are intended to reveal and quantify the presence of weakness or fatigue of the tongue. The consequences of performing these tasks with and without a bite block, used to fix jaw position, are considered. Whether nonspeech tongue impairment is associated with speech dysfunction in Parkinson's disease is another topic of interest. Past studies indicated reduced tongue strength and endurance in Parkinson's disease, but these measures did not correlate with speech measures. It was hypothesized that weakness and fatigue need to be impaired to a "critical" level before speech is perceptibly affected. To examine whether experimentally induced tongue fatigue affects speech, normal speakers performed prolonged strenuous tongue exercise. Speech deteriorated following these exercises. A new investigation examines whether 1 hour of speech-like tongue exercise (rapid syllable repetitions) affects dysarthric speech. Preliminary data from 6 participants with Parkinson's disease, 1 person with bulbar ALS, and 6 neurologically normal control subjects indicate that sentences sound more precise but less natural after the exercises. Surprisingly, results did not differ significantly between the groups. Continued collection of data and refinement of tasks will contribute to our understanding of the potential relationships between weakness, fatigue, and speech.}, }
@article {pmid15815202, year = {2005}, author = {Achem, SR and Devault, KR}, title = {Dysphagia in aging.}, journal = {Journal of clinical gastroenterology}, volume = {39}, number = {5}, pages = {357-371}, doi = {10.1097/01.mcg.0000159272.88974.54}, pmid = {15815202}, issn = {0192-0790}, mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; *Deglutition Disorders/epidemiology/etiology/physiopathology ; Esophagus/physiology ; Humans ; Netherlands/epidemiology ; Peristalsis ; Prevalence ; }, abstract = {Dysphagia is a common problem in older patients and is becoming a larger health care problem as the populations of the United States and other developed countries rapidly age. Changes in physiology with aging are seen in the upper esophageal sphincter and pharyngeal region in both symptomatic and asymptomatic older individuals. Age related changes in the esophageal body and lower esophageal sphincter are more difficult to identify, while esophageal sensation certainly is blunted with age. Stroke, Parkinson's disease, amyotrophic lateral sclerosis, Zenker's diverticula, and several other motility and structural disorders may cause oropharyngeal dysphagia in an older patient. Esophageal dysphagia can also be caused by both disorders of motility (achalasia, diffuse esophageal spasm, scleroderma and others) and structure (malignancy, strictures, rings, external compression, and others). Many of these disorders have an increased prevalence in older patients and should be sought with an appropriate diagnostic evaluation in older patients. The treatment of dysphagia in older patients is similar to that in younger patients, but more invasive therapies such as surgery may not be possible in some older patients making less aggressive medical and endoscopic therapy more attractive.}, }
@article {pmid15812300, year = {2005}, author = {Weydt, P and Möller, T}, title = {Neuroinflammation in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Neuroreport}, volume = {16}, number = {6}, pages = {527-531}, doi = {10.1097/00001756-200504250-00001}, pmid = {15812300}, issn = {0959-4965}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*immunology ; Encephalitis/*immunology ; Humans ; Microglia/*immunology ; Motor Neurons/*immunology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating motor neuron disorder. Traditionally regarded as a 'neuron only' disease, recent evidence suggested that other cells contribute critically to the pathogenesis. This review provides a short synopsis of the role neuroinflammation and microglial cells play in the disease and its animal models. A better understanding of neuroinflammation in motor neuron degeneration and amyotrophic lateral sclerosis disease progression promises to improve the rational design of greatly needed therapies.}, }
@article {pmid15807629, year = {2005}, author = {Levy, YS and Gilgun-Sherki, Y and Melamed, E and Offen, D}, title = {Therapeutic potential of neurotrophic factors in neurodegenerative diseases.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {19}, number = {2}, pages = {97-127}, doi = {10.2165/00063030-200519020-00003}, pmid = {15807629}, issn = {1173-8804}, mesh = {Animals ; Humans ; Meta-Analysis as Topic ; Nerve Growth Factors/classification/physiology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/genetics/physiopathology ; }, abstract = {There is a vast amount of evidence indicating that neurotrophic factors play a major role in the development, maintenance, and survival of neurons and neuron-supporting cells such as glia and oligodendrocytes. In addition, it is well known that alterations in levels of neurotrophic factors or their receptors can lead to neuronal death and contribute to the pathogenesis of neurodegenerative diseases such as Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and also aging. Although various treatments alleviate the symptoms of neurodegenerative diseases, none of them prevent or halt the neurodegenerative process. The high potency of neurotrophic factors, as shown by many experimental studies, makes them a rational candidate co-therapeutic agent in neurodegenerative disease. However, in practice, their clinical use is limited because of difficulties in protein delivery and pharmacokinetics in the central nervous system. To overcome these disadvantages and to facilitate the development of drugs with improved pharmacotherapeutic profiles, research is underway on neurotrophic factors and their receptors, and the molecular mechanisms by which they work, together with the development of new technologies for their delivery into the brain.}, }
@article {pmid15804752, year = {2005}, author = {Fernie, KJ and Reynolds, SJ}, title = {The effects of electromagnetic fields from power lines on avian reproductive biology and physiology: a review.}, journal = {Journal of toxicology and environmental health. Part B, Critical reviews}, volume = {8}, number = {2}, pages = {127-140}, doi = {10.1080/10937400590909022}, pmid = {15804752}, issn = {1093-7404}, mesh = {Animals ; Behavior, Animal/radiation effects ; Birds/*physiology ; *Electricity ; *Electromagnetic Fields ; Endocrine Glands/radiation effects ; Growth/radiation effects ; Immunity/radiation effects ; Oxidative Stress ; Reproduction/*radiation effects ; }, abstract = {Electrical power lines are ubiquitous in the developed world and in urban areas of the developing world. All electrical currents, including those running through power lines, generate electric and magnetic fields (EMFs). Electrical power lines, towers,and distribution poles are used by birds for perching, hunting, and nesting. Therefore, many bird species, like humans, are exposed to EMFs throughout their lives. EMFs have been implicated in adversely affecting multiple facets of human health,including increasing the risks of life-threatening illnesses such as leukemia, brain cancer, amyotrophic lateral sclerosis, clinical depression, suicide, and Alzheimer's disease. A great deal of research and controversy exists as to whether or not exposure to EMFs affects the cellular, endocrine, immune, and reproductive systems of vertebrates. Laboratory work has used mice, rats, and chickens as models for this EMF research in an effort to understand better the possible implications of EMF exposure for humans. However, EMF exposure of wild birds may also provide insight into the impacts of EMFs on human health. This review focuses on research examining the effects of EMFs on birds; most studies indicate that EMF exposure of birds generally changes, but not always consistently in effect or in direction, their behavior, reproductive success, growth and development, physiology and endocrinology, and oxidative stress under EMF conditions. Some of this work has involved birds under aviary conditions, while other research has focused on free-ranging birds exposed to EMFs. Finally, a number of future research directions are discussed that may help to provide a better understanding of EMF effects on vertebrate health and conservation.}, }
@article {pmid15799552, year = {2004}, author = {Hardiman, O and Hickey, A and O'Donerty, LJ}, title = {Physical decline and quality of life in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {230-234}, doi = {10.1080/226-14660820410021294}, pmid = {15799552}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/therapy ; Disease Progression ; Humans ; Quality of Life/*psychology ; }, }
@article {pmid15799546, year = {2004}, author = {Chiò, A and Borasio, GD}, title = {Breaking the news in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {195-201}, doi = {10.1080/14660820310017326}, pmid = {15799546}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Humans ; *Physician-Patient Relations/ethics ; *Truth Disclosure/ethics ; }, abstract = {Diagnosis communication is a mainstay of the patient-physician relationship and in ALS represents the beginning of the treatment. In Europe, the diagnosis is now communicated to most patients, but with some differences from north to south. Communication is the basis of the patient's autonomy. When adequately informed, patients are able to consider their preferences about life-extending interventions. However, this discussion is sometimes entertained too late. Both the style and the context of this discussion have profound impact on patient satisfaction. The content of the communication should include all relevant information about the disease and should be performed honestly while preserving hope. Collusion with relatives can create difficulties in the relationship with a patient and isolate them from their family. Diagnostic communication is an ongoing process and should form part of every follow-up visit. Communication with the dying patient is often reinforced by non-verbal messages, acknowledgements of patients' emotions, and by listening. Written material may increase satisfaction of patients and their relatives, but should never substitute for face-to-face discussion.}, }
@article {pmid15777251, year = {2005}, author = {Czlonkowska, A and Ciesielska, A and Gromadzka, G and Kurkowska-Jastrzebska, I}, title = {Estrogen and cytokines production - the possible cause of gender differences in neurological diseases.}, journal = {Current pharmaceutical design}, volume = {11}, number = {8}, pages = {1017-1030}, doi = {10.2174/1381612053381693}, pmid = {15777251}, issn = {1381-6128}, mesh = {Animals ; Cytokines/*biosynthesis/physiology ; Estrogens/*physiology ; Female ; Humans ; Male ; Nervous System Diseases/metabolism/*physiopathology ; Sex Characteristics ; }, abstract = {Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogen's wide range of effects within the mammalian central nervous system (CNS), with it's neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of it's anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.}, }
@article {pmid15773754, year = {2005}, author = {Julien, JP and Millecamps, S and Kriz, J}, title = {Cytoskeletal defects in amyotrophic lateral sclerosis (motor neuron disease).}, journal = {Novartis Foundation symposium}, volume = {264}, number = {}, pages = {183-92; discussion 192-6, 227-30}, pmid = {15773754}, issn = {1528-2511}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cytoskeleton/*metabolism ; Disease Models, Animal ; Gene Deletion ; Intermediate Filament Proteins/*physiology ; Membrane Glycoproteins/*physiology ; Mice ; Mice, Knockout ; Motor Neurons/*metabolism ; Nerve Tissue Proteins/*physiology ; Peripherins ; }, abstract = {There is growing evidence for the involvement of cytoskeletal defects in the pathogenesis of motor neuron disease and especially in components of the microtubule-based transport system. Here we will review our recent work aiming to elucidate the role of peripherin in amyotrophic lateral sclerosis (ALS) and to address the mechanism of disease caused by deletions in the ALS2 gene that cause recessive forms of juvenile ALS and primary lateral sclerosis (PLS). Peripherin is an intermediate filament protein detected in spheroids, a hallmark of ALS, and increased levels of peripherin mRNA have been found in some ALS cases. Our transgenic mouse and cell culture studies support the view of a peripherin involvement in ALS. However, a gene knockout approach demonstrated that peripherin is not a key contributor of motor neuron disease caused by mutant superoxide dismutase linked to familial ALS. A recent breakthrough in the field of ALS came with the discovery of frameshift deletions in the ALS2 gene coding for Alsin. Our transfection experiments in cultured cells suggest that Alsin is a cytoskeletal protein with dual endosomal and centrosomal localizations. We have generated a mouse knockout for Alsin that develops progressive motor dysfunction during ageing. Thus, it is anticipated that this mouse model will be useful to investigate the pathogenic pathways linked to Alsin gene mutations.}, }
@article {pmid15757794, year = {2005}, author = {Caban-Holt, A and Mattingly, M and Cooper, G and Schmitt, FA}, title = {Neurodegenerative memory disorders: a potential role of environmental toxins.}, journal = {Neurologic clinics}, volume = {23}, number = {2}, pages = {485-521}, doi = {10.1016/j.ncl.2004.12.005}, pmid = {15757794}, issn = {0733-8619}, support = {1R01AG19241/AG/NIA NIH HHS/United States ; 5P50AG005144/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System/pathology ; Environmental Exposure/adverse effects ; Hazardous Substances/*adverse effects ; Humans ; Memory Disorders/*etiology ; Neurodegenerative Diseases/*etiology ; Neurotoxins/adverse effects ; }, abstract = {The hypothesis that neurotoxins may play a role in neurodegenerative disorders remains an elusive one, given that epidemiologic studies often provide conflicting results. Although these conflicting results may result from methodological differences within and between studies, the complexity of chemical disruption of the central nervous system cannot be ignored in attempts to evaluate this hypothesis in different neurodegenerative disorders. Spencer provides a detailed review of the complex processes involved in defining the neurotoxic potential of naturally occurring and synthetic agents. Even concepts such as exposure and dose, as often reported in studies attempting to evaluate the risk imparted by a potential compound, can be deceptive. For example, although dose reflects "that amount of chemical transferred to the exposed subject", factors such as time and concentration in the organism, the ability to access the central nervous system, and how a compound reaches the central nervous system (routes of administration) or secondarily affects other organ systems leading to central nervous system disruption are clearly important to the concept of neurotoxic risk in neurodegenerative disorders. These factors would appear to explain the observed disagreements between studies using animal or neuronal models of neurotoxicity and population-based studies in humans. The importance of these factors and how a potential neurotoxin is investigated are clearly seen in the data on AD and aluminum. In contrast, the impact of MTPT on the central nervous system is more direct and compelling. Added complexity in the study of neurotoxins in human neurodegeneration is derived from data showing that agents may have additive, potentiating, synergistic, or antagonistic effects. Therefore, data from studies evaluating EMF risks could be readily confounded by the presence or absence of heavy metals (eg, arc welding). Other factors that may conceal neurotoxic causes for a given disorder focus on additional features such as genetic predispositions, physiologic changes that occur in aging, and even nutritional status that can support or hinder the affect of a given agent on the central nervous system. Finally, many studies that investigate exposure risk do not readily incorporate the five criteria proposed by Schaumburg for establishing causation. For example, if we apply Schaumburg's first criterion, epidemiologic studies often determines the presence of an agent through history, yet they cannot readily confirm exposure based on environmental or clinical chemical analyses to fulfill this criterion for causation. Additional limitations in research design along with the populations and methods that are sued to study neurotoxins in human neurodegenerative disorders often fail to meet other criteria such as linking the severity and onset with duration and exposure level. Therefore, although studies of agents such as MTPT provide compelling models of neurotoxins and neurodegeneration in humans, disorders such as ALS, PD, and particularly AD will require additional effort if research is to determine the contribution (presence or absence) of neurotoxins to these neurologic disorders.}, }
@article {pmid15757793, year = {2005}, author = {Wicklund, MP}, title = {Amyotrophic lateral sclerosis: possible role of environmental influences.}, journal = {Neurologic clinics}, volume = {23}, number = {2}, pages = {461-484}, doi = {10.1016/j.ncl.2004.12.016}, pmid = {15757793}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Environmental Exposure/*adverse effects ; Humans ; }, abstract = {This treatise briefly discusses the genetic features of ALS and reviews environmental exposures in sporadic ALS. At least 10 genetic foci are responsible for cases of familial motor neuron disease and more are yet to be discovered. Research into sporadic ALS suggests that abundant factors apparently participate in the disease process. A singular cause and unifying disease and nerve dysfunction in polyneuropathies, a multitude of genetic, toxic, autoimmune, infectious, and systematic processes seem to be at play. The ALS syndrome likely will not be dissimilar.}, }
@article {pmid15757788, year = {2005}, author = {Rusyniak, DE and Furbee, RB and Pascuzzi, R}, title = {Historical neurotoxins: what we have learned from toxins of the past about diseases of the present.}, journal = {Neurologic clinics}, volume = {23}, number = {2}, pages = {337-352}, doi = {10.1016/j.ncl.2004.12.012}, pmid = {15757788}, issn = {0733-8619}, mesh = {Animals ; History, 20th Century ; Humans ; Neurotoxicity Syndromes/*etiology/*history ; Neurotoxins/*adverse effects/*history ; }, abstract = {Throughout history, humans have fallen victim to a variety of neurotoxins, with exposures coming in the form of tainted products, industrial pollution, drugs of abuse, and even the bread and water that sustain them. Despite this long and tumultuous history, neurotoxic outbreaks still occur with regular frequency. Although many difficulties currently exist in linking many of today's unexplained neurologic disorders to toxins, the past suggests a prominent role for neurotoxins in diseases (such as amyotrophic lateral sclerosis and PD), unexplained peripheral neuropathies, neurodevelopmental disorders, and many psychiatric disturbances.}, }
@article {pmid15750484, year = {2005}, author = {Skelton, J}, title = {Nursing role in the multidisciplinary management of motor neurone disease.}, journal = {British journal of nursing (Mark Allen Publishing)}, volume = {14}, number = {1}, pages = {20-24}, doi = {10.12968/bjon.2005.14.1.17367}, pmid = {15750484}, issn = {0966-0461}, mesh = {Bulbar Palsy, Progressive/nursing ; Clinical Competence ; Humans ; Motor Neuron Disease/complications/diagnosis/*nursing ; *Nurse's Role ; Nurse-Patient Relations ; Nutrition Therapy/methods/nursing ; Patient Care Team/*organization &amp; administration ; Respiratory Tract Diseases/etiology/nursing ; Terminal Care/methods ; }, abstract = {Motor neurone disease (MND) is a debilitating and progressive neurological disorder in which degeneration of the motor neurones results in muscle weakness and wasting. Recent high-profile media coverage about assisted suicide and euthanasia has increased awareness of MND and yet still relatively little is known or understood about it, even among the healthcare profession. This article looks at the key areas in management of patients with MND, including the role of the nurse and the importance of a well-coordinated multidisciplinary team. Ways to deal with communication problems, respiratory dysfunction, feeding and nutrition, and legal and ethical issues are examined. Good management of patients with MND involves a hospital and community-based multidisciplinary team. The essence of care is good symptomatic management of respiratory failure and nutritional problems that result from difficulties in swallowing and increasing dependency. Palliative care should be introduced before the terminal stages after careful discussion with the patient and carers. Most patients with MND die from pulmonary infections or respiratory failure, but contrary to popular belief, death by choking attacks is rare and the final stages of MND are usually peaceful and dignified.}, }
@article {pmid15745367, year = {2005}, author = {Laaksovirta, H}, title = {[Palliative care tailored according to the symptoms of the ALS patient is an art form].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {121}, number = {2}, pages = {220-224}, pmid = {15745367}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Combined Modality Therapy ; Female ; Finland ; Humans ; Male ; Palliative Care/*methods ; Prognosis ; Risk Assessment ; Severity of Illness Index ; Survival Rate ; }, }
@article {pmid15735983, year = {2005}, author = {Rowland, LP}, title = {Research advances in amyotrophic lateral sclerosis (ALS): a personal view.}, journal = {Neurologia i neurochirurgia polska}, volume = {39}, number = {1}, pages = {3-10}, pmid = {15735983}, issn = {0028-3843}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Animals ; Diagnosis, Differential ; Humans ; Motor Neurons/pathology ; Research Design ; }, }
@article {pmid15723612, year = {2005}, author = {Langley, B and Gensert, JM and Beal, MF and Ratan, RR}, title = {Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {4}, number = {1}, pages = {41-50}, doi = {10.2174/1568007053005091}, pmid = {15723612}, issn = {1568-007X}, mesh = {Acetylation/drug effects ; Acetyltransferases/antagonists &amp; inhibitors/metabolism ; Animals ; Cell Division/drug effects ; Central Nervous System/drug effects/*enzymology ; Chromatin/*metabolism ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Gene Expression Regulation/drug effects ; Histone Acetyltransferases ; *Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Neoplasms/drug therapy ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*pharmacology/therapeutic use ; Protein Processing, Post-Translational ; Stress, Physiological/drug therapy/enzymology ; }, abstract = {Acetylation and deacetylation of histone protein plays a critical role in regulating gene expression in a host of biological processes including cellular proliferation, development, and differentiation. Accordingly, aberrant acetylation and deacetylation resulting from the misregulation of histone acetyltransferases (HATs) and/or histone deacetylases (HDACs) has been linked to clinical disorders such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, and various cancers. Of significant import has been the development of small molecule HDAC inhibitors that permit pharmacological manipulation of histone acetylation levels and treatment of some of these diseases including cancer. In this Review we discuss evidence that aberrant HAT and HDAC activity may also be a common underlying mechanism contributing to neurodegeneration during acute and chronic neurological diseases, including stroke, Huntington's disease Amyotrophic Lateral Sclerosis and Alzheimer's disease. With this in mind, a number of studies examining the use of HDAC inhibitors as therapy for restoring histone acetylation and transcriptional activation in in vitro and in vivo neurodegenerative models are discussed. These studies demonstrate that pharmacological HDAC inhibition is a promising therapeutic approach for the treatment of a range of central nervous system disorders.}, }
@article {pmid15723611, year = {2005}, author = {Shacka, JJ and Roth, KA}, title = {Regulation of neuronal cell death and neurodegeneration by members of the Bcl-2 family: therapeutic implications.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {4}, number = {1}, pages = {25-39}, doi = {10.2174/1568007053005127}, pmid = {15723611}, issn = {1568-007X}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Drug Design ; Humans ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neurons/*metabolism ; Neuroprotective Agents/pharmacology ; Protein Structure, Tertiary/physiology ; Proto-Oncogene Proteins c-bcl-2/classification/drug effects/*metabolism ; }, abstract = {The Bcl-2 family of proteins contains both anti and pro-apoptotic members that have been shown to regulate neuronal cell death during development and in many models of acute and chronic neurodegeneration. This family of proteins can be divided into three distinct classes based on structure and function: the anti-apoptotic sub-group; the pro-apoptotic, multi-domain sub-group; and the pro-apoptotic, BH3 domain-only sub-group. Alterations in the expression of Bcl-2 family members occur in several animal and human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's diseases and Amyotrophic Lateral Sclerosis. Similar changes are seen in in vivo and in vitro models of acute neurodegeneration, including stroke and traumatic brain injury. Methods to increase the overall expression and/or function of anti-apoptotic Bcl-2 family members, and thus promote neuron survival, have been studied extensively in these models. Most treatment efforts focus on either the targeted delivery via viral vectors of anti-apoptotic members of Bcl-2 family members into the affected brain regions of interest, the generation of direct interactions of small molecule inhibitors with Bcl-2 family members, or the induced expression of Bcl-2 family members secondary to pharmacological manipulation. Although many challenges exist in the design of safe and efficacious Bcl-2 family mimetics for the treatment of neurodegeneration, such strategies offer great promise for preserving neuron viability, and hopefully function, in a variety of human neurological diseases.}, }
@article {pmid15717028, year = {2004}, author = {Cudkowicz, M and Qureshi, M and Shefner, J}, title = {Measures and markers in amyotrophic lateral sclerosis.}, journal = {NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {1}, number = {2}, pages = {273-283}, pmid = {15717028}, issn = {1545-5343}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers ; Electrodiagnosis ; Humans ; *Magnetic Resonance Spectroscopy ; *Magnetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by loss of spinal and cortical motor neurons, leading to progressive weakness and ultimately, death. Clinically, there appears to be an anatomic focus at disease onset, from which the disease then spreads. Because the focus of initial symptoms and the subsequent direction of spread can vary from patient to patient, disease monitoring is difficult, especially in a clinical trial, in which outcome measures must be identical and able to capture progression of all types. Thus, the search for markers of disease progression is especially important in ALS. Many approaches have been taken, from voluntary strength assessment and functional rating scales to physiological and pathological sampling of affected portions of nervous system. No proposed marker has been demonstrated to meet the desired criteria of biological meaning, sensitivity to disease progression, clear relationship to overall prognosis and survival, and ease of measurement. However, progress is being made in all of these regards.}, }
@article {pmid15713848, year = {2005}, author = {Al-Chalabi, A and Leigh, PN}, title = {Trouble on the pitch: are professional football players at increased risk of developing amyotrophic lateral sclerosis?.}, journal = {Brain : a journal of neurology}, volume = {128}, number = {Pt 3}, pages = {451-453}, doi = {10.1093/brain/awh426}, pmid = {15713848}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Humans ; Occupational Diseases/*etiology ; Risk Factors ; *Soccer ; }, }
@article {pmid15707828, year = {2005}, author = {Lewin, MR and Hori, S and Aikawa, N}, title = {Emergency medical services in Japan: an opportunity for the rational development of pre-hospital care and research.}, journal = {The Journal of emergency medicine}, volume = {28}, number = {2}, pages = {237-241}, doi = {10.1016/j.jemermed.2004.09.009}, pmid = {15707828}, issn = {0736-4679}, mesh = {Ambulances/organization &amp; administration ; Clinical Protocols ; Cross-Cultural Comparison ; Emergency Medical Services/*organization &amp; administration ; Emergency Medical Technicians/organization &amp; administration ; Humans ; Japan ; Program Development/*methods ; United States ; }, abstract = {Japan is at a crossroads in the development of its Emergency Medical Services (EMS). At present, Japan has an essentially pure scoop-and-run, defibrillation system. However, there is a strong movement toward expanding the scope of paramedic practice to include more complex, Advanced Life Support (ALS) and trauma protocols to its nationally standardized pre-hospital protocols. The implications of introducing complex pre-hospital protocols guided by the use of existing scientific evidence to support such action is discussed in the context of Japan's unique opportunity to test many fundamental questions in pre-hospital medical care and the public's understanding and acceptance of these practices. Japan, a technologically advanced country that is not encumbered by entrenched "standards of care," has the opportunity to develop an efficient and rational EMS system.}, }
@article {pmid15704143, year = {2005}, author = {Greenberg, SA and Walsh, RJ}, title = {Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease.}, journal = {Muscle &amp; nerve}, volume = {31}, number = {4}, pages = {431-451}, doi = {10.1002/mus.20279}, pmid = {15704143}, issn = {0148-639X}, mesh = {Humans ; Molecular Diagnostic Techniques/*methods ; Neuromuscular Diseases/*diagnosis/*genetics ; }, abstract = {Molecular genetic advances have led to refinements in the classification of inherited neuromuscular disease, and to methods of molecular testing useful for diagnosis and management of selected patients. Testing should be performed as targeted studies, sometimes sequentially, but not as wasteful panels of multiple genetic tests performed simultaneously. Accurate diagnosis through molecular testing is available for the vast majority of patients with inherited neuropathies, resulting from mutations in three genes (PMP22, MPZ, and GJB1); the most common types of muscular dystrophies (Duchenne and Becker, facioscapulohumeral, and myotonic dystrophies); the inherited motor neuron disorders (spinal muscular atrophy, Kennedy's disease, and SOD1 related amyotrophic lateral sclerosis); and many other neuromuscular disorders. The role of potential multiple genetic influences on the development of acquired neuromuscular diseases is an increasingly active area of research.}, }
@article {pmid15691215, year = {2005}, author = {McGeer, EG and McGeer, PL}, title = {Pharmacologic approaches to the treatment of amyotrophic lateral sclerosis.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {19}, number = {1}, pages = {31-37}, doi = {10.2165/00063030-200519010-00004}, pmid = {15691215}, issn = {1173-8804}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; *Excitatory Amino Acid Antagonists ; Humans ; Mice ; Mice, Transgenic ; Oxidative Stress/*drug effects ; Superoxide Dismutase/*genetics ; Treatment Failure ; Vascular Endothelial Growth Factor A/drug effects/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which no cure or effective treatment presently exists. Many different types of drugs have been tested; most are based on various hypotheses of mechanisms for neuronal death, including oxidative damage, loss of trophic factor support, glutamate-mediated excitotoxicity, and chronic inflammation. The discovery that a small percentage of ALS cases are familial and involve mutation in a superoxide dismutase gene (SOD1) led to the development of transgenic mouse models presently widely used for testing possible drugs. Mutations in the vascular endothelial growth factor gene (VEGF) also appear to be involved. Riluzole, an inhibitor of glutamate release and the only agent presently approved for clinical use, only extends survival by a few months. A number of trophic factors, anti-inflammatory agents, and inhibitors of oxidative stress have been reported to prolong survival in mouse models and some are now in clinical trials. Gene transfer of VEGF or glial cell-line derived neurotrophic factor, anti-inflammatory COX-2 inhibitors, and minocycline have had particularly promising results in mice. No breakthrough has yet occurred and present thinking is that combinations of drugs may be required to slow the multifactorial neurodegeneration process effectively.}, }
@article {pmid15684843, year = {2004}, author = {Mast, KR and Salama, M and Silverman, GK and Arnold, RM}, title = {End-of-life content in treatment guidelines for life-limiting diseases.}, journal = {Journal of palliative medicine}, volume = {7}, number = {6}, pages = {754-773}, doi = {10.1089/jpm.2004.7.754}, pmid = {15684843}, issn = {1096-6218}, mesh = {Chronic Disease/*therapy ; *Disease Management ; Hospice Care/*standards ; Humans ; Palliative Care/*standards ; Practice Guidelines as Topic/*standards ; Terminal Care/*standards ; United States ; }, abstract = {BACKGROUND: Clinical guidelines are systematically developed statements that influence medical practice, education, and funding. Guidelines represent the consensus of leaders, often based on systematic reviews of the literature, regarding the "state of the art."<br><br>OBJECTIVE: To assess the degree to which end-of-life care is integrated into nationally developed guidelines for chronic, noncurable, life-limiting diseases.<br><br>DESIGN: Four compendia were reviewed: The Healthcare Standards Directory ECRI, 2001; the Clinical Practice Guidelines Directory, 2000 edition; the National Guidelines Clearinghouse, (guideline.gov); and the National Library of Medicine's MEDLINE database on the OVID platform for guidelines on nine chronic diseases (chronic obstructive pulmonary disease, end-stage liver disease, amyotrophic lateral sclerosis, congestive heart failure, dementia, cerebrovascular accident, end-stage renal disease, cancer [breast, colon, prostate, lung], and human immunodeficiency virus). They were assessed by two reviewers for end-of-life content in 15 domains (e.g., epidemiology of death, symptom management, spiritual, family roles, and settings of care), the presence of eight specific terms dealing with palliative care, integration of palliative care information into the guideline, and descriptive variables.<br><br>SETTING/SUBJECTS: Not available.<br><br>MEASUREMENTS: Each guideline was examined and rated on a 0-2 scale (0, absent content; 1, minimal content; 2, helpful content) using 15 end-of-life content domains. Scores from domains were summed and classified into 3 categories: 4 or less, minimal; 5-12, moderate; and more than 12, significant content.<br><br>RESULTS: Ten percent of guidelines had significant palliative care content, 64% had minimal content, and 26% had moderate content. The least addressed domains dealt with spirituality, ethics, advocacy and family roles. When guidelines that dealt solely with prevention, acute exacerbations or complications of an illness, or specific treatment modalities were excluded 28% and 16% of these general guidelines (n = 58) had moderate and significant palliative care content, respectively, compared to 24% and 0% of all nongeneral guidelines. Similar results were found when analyzing the data by disease course or treatment focus. Only 14% of guidelines advised physicians to consider palliative care at a specific point in the disease course. Ninety-one percent of the guidelines mentioned death, dying, end of life, mortality, or terminal illness but only 36% mentioned palliation or hospice.<br><br>CONCLUSION: Current national guidelines on nine chronic, life-limiting illnesses offer little guidance in end-of-life care issues despite a recent increase in attention to this aspect of medical care.}, }
@article {pmid15681814, year = {2004}, author = {Greig, NH and Mattson, MP and Perry, T and Chan, SL and Giordano, T and Sambamurti, K and Rogers, JT and Ovadia, H and Lahiri, DK}, title = {New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists.}, journal = {Annals of the New York Academy of Sciences}, volume = {1035}, number = {}, pages = {290-315}, doi = {10.1196/annals.1332.018}, pmid = {15681814}, issn = {0077-8923}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Dose-Response Relationship, Drug ; Glucagon-Like Peptide-1 Receptor ; Humans ; Inflammation/drug therapy/etiology ; Models, Neurological ; Neoplasm Proteins/pharmacology/*therapeutic use ; Neurodegenerative Diseases/complications/*drug therapy ; Receptors, Glucagon/*agonists/chemistry ; Receptors, Tumor Necrosis Factor, Type II/*therapeutic use ; Signal Transduction/drug effects/physiology ; Tumor Necrosis Factor Decoy Receptors ; Tumor Suppressor Protein p53/pharmacology/*therapeutic use ; }, abstract = {Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-alpha, p53, and GLP-1 receptor. The cytokine TNF-alpha is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Abeta, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.}, }
@article {pmid15681803, year = {2004}, author = {McGeer, PL and McGeer, EG}, title = {Inflammation and the degenerative diseases of aging.}, journal = {Annals of the New York Academy of Sciences}, volume = {1035}, number = {}, pages = {104-116}, doi = {10.1196/annals.1332.007}, pmid = {15681803}, issn = {0077-8923}, mesh = {Aging/*physiology ; Animals ; C-Reactive Protein ; Complement System Proteins/metabolism ; Cytokines/metabolism ; Humans ; Inflammation/metabolism/*physiopathology ; Neurodegenerative Diseases/metabolism/*physiopathology ; }, abstract = {Chronic inflammation is associated with a broad spectrum of neurodegenerative diseases of aging. Included are such disorders as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, the Parkinson-dementia complex of Guam, all of the tauopathies, and age-related macular degeneration. Also included are such peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial infarction. Inflammation is a two-edged sword. In acute situations, or at low levels, it deals with the abnormality and promotes healing. When chronically sustained at high levels, it can seriously damage viable host tissue. We describe this latter phenomenon as autotoxicity to distinguish it from autoimmunity. The latter involves a lymphocyte-directed attack against self proteins. Autotoxicity, on the other hand, is determined by the concentration and degree of activation of tissue-based monocytic phagocytes. Microglial cells are the brain representatives of the monocyte phagocytic system. Biochemically, the intensity of their activation is related to a spectrum of inflammatory mediators generated by a variety of local cells. The known spectrum includes, but is not limited to, prostaglandins, pentraxins, complement components, anaphylotoxins, cytokines, chemokines, proteases, protease inhibitors, adhesion molecules, and free radicals. This spectrum offers a huge variety of targets for new anti-inflammatory agents. It has been suggested, largely on the basis of transgenic mouse models, that stimulating inflammation rather than inhibiting it can be beneficial in such diseases as AD. If this were the case, administration of NSAIDs, or other anti-inflammatory drugs, would be expected to exacerbate conditions such as AD, PD, and atherosclerosis. However, epidemiological evidence overwhelmingly demonstrates that the reverse is true. This indicates that, at least in these diseases, the inflammation is harmful. So far, advantage has not been taken of opportunities indicated by these epidemiological studies to treat AD and PD with appropriate anti-inflammatory agents. Based on this evidence, classical NSAIDs are the most logical choice. Dosage, though, must be sufficient to combat the inflammation. Analysis of mRNA levels of inflammatory mediators indicates that the intensity of inflammation is considerably higher in AD hippocampus and in PD substantia nigra than in osteoarthritic joints. Thus, full therapeutic doses of NSAIDs, or combinations of anti-inflammatory agents, are needed to achieve the suggested neurological benefits.}, }
@article {pmid15679043, year = {2004}, author = {Grieb, P}, title = {Transgenic models of amyotrophic lateral sclerosis.}, journal = {Folia neuropathologica}, volume = {42}, number = {4}, pages = {239-248}, pmid = {15679043}, issn = {1641-4640}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; Animals ; *Animals, Genetically Modified ; Disease Models, Animal ; Humans ; Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most frequent paralytic disease of adults, is untreatable and invariably fatal. Up to 20% of ALS cases are inherited (familial, fALS) and associated with mutations, usually of the superoxide dismutase type 1 (SOD-1) gene. This paper shortly reviews the background for and the use of rodent transgenic models of ALS. Silencing the SOD-1 gene does not produce paralytic phenotype, but transgenic rodents expressing human mutated (hm) SOD-1 atop their own enzyme develop relatively selective and fatal degeneration of motoneurons. Many essential neuropathological and biochemical features of the paralytic disease in hmSOD-1 transgenic mice and rats are similar to human fALS, and these animals are currently considered a model of the human disease. Two types of hypotheses put forward to explain pathomechanism of motoneuron degeneration in hmSOD-1 transgenics (hence also in human ALS) are the "gain of function" hypotheses which assume that the mutated enzyme displays new toxic catalytic properties, and the "gain of interaction" hypotheses which assume that the mutated protein molecules are toxic because they became misfolded and undergo oligomerization. Transgenic animal models of ALS are used for preclinical assessments of new therapeutic approaches ranging from mono- and polipharmacotherapy to gene therapy and stem cell therapy.}, }
@article {pmid15676108, year = {2005}, author = {Gordon, PH}, title = {Advances in clinical trials for amyotrophic lateral sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {5}, number = {1}, pages = {48-54}, pmid = {15676108}, issn = {1528-4042}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Humans ; Randomized Controlled Trials as Topic/*methods/*trends ; Riluzole/therapeutic use ; }, abstract = {Because treatments are not yet powerful enough to reverse the symptoms of amyotrophic lateral sclerosis (ALS), randomized placebo-controlled trials remain the gold standard for testing new therapies. To date, only one drug, riluzole, has been shown to slow the course of ALS, albeit in a very modest way. Since the approval of riluzole almost 10 years ago, there have been a number of negative trials, and we still await the discovery of a medication with a truly meaningful effect. With each study, our sophistication in trial design grows, but hurdles remain, including how to use transgenic animal models optimally, which outcome measures most accurately reflect changes in the disease, and how to reduce the often high dropout rates in trials of ALS. This article is devoted to the recent evolution of clinical trials in ALS and discusses specific trials conducted during the past 5 years.}, }
@article {pmid15674899, year = {2005}, author = {Orrell, RW and Lane, RJ and Ross, M}, title = {Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD002829}, doi = {10.1002/14651858.CD002829.pub3}, pmid = {15674899}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.<br><br>OBJECTIVES: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (July 2003), MEDLINE (from January 1966 to July 2003), EMBASE (from January 1980 to July 2003) and other sources.<br><br>SELECTION CRITERIA: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: The reviewers independently applied the selection criteria, assessed study quality and two reviewers performed independent data extraction.<br><br>MAIN RESULTS: The search identified 21 studies for consideration but only eight studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure, (survival at 12 months treatment). Sufficient data were available from three studies to allow analysis of the primary outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed of vitamin E 500 mg twice daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of antioxidants in general when combining the results. No significant differences were demonstrated in secondary outcome measures.<br><br>AUTHORS' CONCLUSIONS: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and patients. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid15668420, year = {2005}, author = {Veldink, JH and Kalmijn, S and Groeneveld, GJ and Titulaer, MJ and Wokke, JH and van den Berg, LH}, title = {Physical activity and the association with sporadic ALS.}, journal = {Neurology}, volume = {64}, number = {2}, pages = {241-245}, doi = {10.1212/01.WNL.0000149513.82332.5C}, pmid = {15668420}, issn = {1526-632X}, mesh = {Adult ; Age of Onset ; Aged ; Alcohol Drinking/epidemiology ; Amyotrophic Lateral Sclerosis/*epidemiology ; Body Mass Index ; Case-Control Studies ; Female ; Humans ; Leisure Activities ; Life Tables ; Male ; Middle Aged ; *Motor Activity ; Netherlands/epidemiology ; Occupations ; Odds Ratio ; Risk Factors ; Smoking/epidemiology ; Sports ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: To assess whether lifetime physical activity during work and leisure time is associated with an increased risk of developing ALS and to determine the association between physical activity and duration or age at onset of disease.<br><br>METHODS: Patients referred to our clinic during the 1-year period 2001 to 2002 who had definite, probable, or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in the study. A case-control study was performed taking into account all occupational and leisure time activities of patients (n = 219) and controls (n = 254). Multivariate analysis included confounding factors (sex, age, level of education, body mass index, alcohol use, and smoking). Three quantitative measures of cumulative physical activity were calculated: until 1 year before the onset of disease (total physical activity), the last 10 years before the onset of disease (late physical activity), and until the age of 25 (early physical activity). In addition, a systematic review of all published data is presented.<br><br>RESULTS: Smoking and alcohol use were independently associated with ALS (current smoking increased risk, OR = 1.8, 95% CI = 1.0 to 3.0, p = 0.03, ever/current alcohol use decreased risk, OR = 0.6, 95% CI = 0.3 to 0.9, p = 0.04). No significant association with occupational or leisure time physical activity was found (all ORs < or = 1.7), which was in agreement with most studies with the highest level of evidence in the systematic review. Higher leisure time activities were associated with an earlier age at onset: activity levels before age of 25 (p < 0.001, 7 years earlier), and activity during the last 10 years (p < 0.001, 3 years earlier).<br><br>CONCLUSIONS: There is no association between physical activity and the risk of developing ALS.}, }
@article {pmid15651293, year = {2004}, author = {Ikeda, JE}, title = {[Recessive motor neuron diseases: mutations in the ALS2 gene and molecular pathogenesis for the upper motor neurodegeneration].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {44}, number = {11}, pages = {792-794}, pmid = {15651293}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Genes, Recessive ; Guanine Nucleotide Exchange Factors/*genetics ; Humans ; Mice ; Mutation ; }, abstract = {We have initially identified a mutation in ALS2 as a causative for a juvenile autosomal recessive form of amyotrophic lateral sclerosis (ALS), termed ALS2 (OMIM 205100). ALS2 mutations also are causative for an autosomal recessive juvenile primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis. To date, nine homozygous ALS2 mutaions from nine independent families have been identified. All of these mutations result in predicted premature translation termination caused by the recessive frameshift or nonsense mutation. ALS2 is a 184-kD protein comprising several putative guanine nucleotide exchange factor (GEF) domains [RLD; RCC1 like domain, DH. PH domain, VPS9; Vacuolar protein sorting 9 domain]. In vitro, ALS2 specifically binds to the small GTPase Rab5 and functions as a GEF for Rab5. Ectopic expression of full-length ALS2 has further implied an association with endosomal membranes mediated by the VPS9 domain, consistent with ALS2 involvement in endosomal trafficking and fusion in conjunction with the activation of Rab5. These results combined with our findings suggest that an obstruction of endosomal dynamics might underlie neuronal dysfunction and degeneration in ALS2, PLSJ, and HSP, as well as in a number of other motor neuron diseases.}, }
@article {pmid15651292, year = {2004}, author = {Aoki, M}, title = {[Amyotrophic lateral sclerosis: recent insights from transgenic animal models with SOD1 mutations].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {44}, number = {11}, pages = {788-791}, pmid = {15651292}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Disease Models, Animal ; Mice ; Mice, Mutant Strains ; Mutation ; Rats ; Superoxide Dismutase/*genetics ; }, abstract = {Mutations in Cu/Zn superoxide dismutase (SOD1) have been linked to some familial cases of amyotrophic lateral sclerosis (ALS). In order to reproduce the different degree of toxicity to the mutant protein by mutations, we generated new transgenic mice with two mutations from which the progression of the disease in human family is rapid (L84V) or extremely slow (H46R). By comparing the two transgenic mice with different SOD1 mutations, we demonstrate that the time course and the first symptoms in these mice were likely to human SOD1-mediated familial ALS. In addition, we report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Using this rat model we showed that intrathecal administration of the hepatocyte growth factor attenuates motoneuron death and prolongs the duration of the disease of transgenic rats.}, }
@article {pmid15645308, year = {2005}, author = {Yakar, S and Kim, H and Zhao, H and Toyoshima, Y and Pennisi, P and Gavrilova, O and Leroith, D}, title = {The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {20}, number = {3}, pages = {251-254}, pmid = {15645308}, issn = {0931-041X}, mesh = {Animals ; *Gene Targeting ; Growth Hormone/biosynthesis/*genetics ; Insulin-Like Growth Factor Binding Protein 1/biosynthesis/*genetics ; Liver/metabolism ; Mice ; Mice, Transgenic ; Receptor, IGF Type 1/biosynthesis/*genetics ; }, abstract = {We have created a liver-specific igf1 gene-deletion mouse model (LID) with markedly reduced circulating IGF-I levels. They demonstrate that while they have normal growth and development they develop insulin resistance secondary to the elevation of circulating growth hormone. When mated with an acid-labile subunit (ALS) gene-deleted mouse they also show osteopenia suggesting that circulating IGF-I levels play a significant role in bone formation. In a separate transgenic mouse we created a model of severe insulin resistance and type 2 diabetes by the overexpression of a dominant-negative IGF-I receptor in skeletal muscle. In this model we show that lipotoxicity plays a major role in the progression of the disease and is affected by treatment with a fibrate, which reverses the insulin resistance and diabetic state. These models are therefore very useful in studying human physiology and disease states.}, }
@article {pmid15642894, year = {2005}, author = {Beghi, E and Morrison, KE}, title = {ALS and military service.}, journal = {Neurology}, volume = {64}, number = {1}, pages = {6-7}, doi = {10.1212/01.WNL.0000150535.90358.2D}, pmid = {15642894}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Humans ; *Military Medicine ; }, }
@article {pmid15633943, year = {2004}, author = {Zhu, X and Smith, MA and Perry, G and Aliev, G}, title = {Mitochondrial failures in Alzheimer's disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {19}, number = {6}, pages = {345-352}, pmid = {15633943}, issn = {1533-3175}, mesh = {Aged ; Alzheimer Disease/*metabolism/*pathology/*physiopathology ; Amyloid beta-Peptides/metabolism ; Brain/blood supply/metabolism/pathology ; Cerebrovascular Circulation/physiology ; DNA, Mitochondrial/genetics/*metabolism ; Energy Metabolism ; Free Radicals/metabolism ; Humans ; Lipid Peroxidation ; Mitochondrial Diseases/genetics/*metabolism/*physiopathology ; Nerve Degeneration/pathology ; Point Mutation/genetics ; }, abstract = {Mitochondrial dysfunction and free radical-induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Alzheimer's disease (AD). The defective adenosine triphosphate (ATP) production and increased oxygen radicals may induce mitochondria-dependent cell death because damaged mitochondria are unable to maintain the energy demands of the cell. The role of vascular hypoperfusion-induced mitochondria failure in the pathogenesis of AD now has been widely accepted. However, the exact cellular mechanisms behind vascular lesions and their relation to oxidative stress markers identified by RNA oxidation, lipid peroxidation, or mitochondrial DNA (mtDNA) deletion remain unknown. Future studies comparing the spectrum of mitochondrial damage and the relationship to oxidative stress-induced damage during the aging process or, more importantly, during the maturation of AD pathology are warranted.}, }
@article {pmid15627242, year = {2005}, author = {Tan, S and Evans, RR and Dahmer, ML and Singh, BK and Shaner, DL}, title = {Imidazolinone-tolerant crops: history, current status and future.}, journal = {Pest management science}, volume = {61}, number = {3}, pages = {246-257}, doi = {10.1002/ps.993}, pmid = {15627242}, issn = {1526-498X}, mesh = {Acetolactate Synthase/antagonists &amp; inhibitors/*genetics ; Amino Acid Sequence ; Crops, Agricultural/*drug effects/enzymology/*genetics ; Drug Resistance/physiology ; Herbicides/chemistry/*pharmacology ; Imidazoles/chemistry/*pharmacology ; Molecular Sequence Data ; Molecular Structure ; Plants, Genetically Modified/drug effects/*enzymology ; }, abstract = {Imidazolinone herbicides, which include imazapyr, imazapic, imazethapyr, imazamox, imazamethabenz and imazaquin, control weeds by inhibiting the enzyme acetohydroxyacid synthase (AHAS), also called acetolactate synthase (ALS). AHAS is a critical enzyme for the biosynthesis of branched-chain amino acids in plants. Several variant AHAS genes conferring imidazolinone tolerance were discovered in plants through mutagenesis and selection, and were used to create imidazolinone-tolerant maize (Zea mays L), wheat (Triticum aestivum L), rice (Oryza sativa L), oilseed rape (Brassica napus L) and sunflower (Helianthus annuus L). These crops were developed using conventional breeding methods and commercialized as Clearfield* crops from 1992 to the present. Imidazolinone herbicides control a broad spectrum of grass and broadleaf weeds in imidazolinone-tolerant crops, including weeds that are closely related to the crop itself and some key parasitic weeds. Imidazolinone-tolerant crops may also prevent rotational crop injury and injury caused by interaction between AHAS-inhibiting herbicides and insecticides. A single target-site mutation in the AHAS gene may confer tolerance to AHAS-inhibiting herbicides, so that it is technically possible to develop the imidazolinone-tolerance trait in many crops. Activities are currently directed toward the continued improvement of imidazolinone tolerance and development of new Clearfield* crops. Management of herbicide-resistant weeds and gene flow from crops to weeds are issues that must be considered with the development of any herbicide-resistant crop. Thus extensive stewardship programs have been developed to address these issues for Clearfield* crops.}, }
@article {pmid15624111, year = {2005}, author = {Kwak, S and Kawahara, Y}, title = {Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {83}, number = {2}, pages = {110-120}, pmid = {15624111}, issn = {0946-2716}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; *Cell Death ; Humans ; Motor Neurons/*pathology ; *RNA Editing ; Receptors, AMPA/*genetics/metabolism ; }, abstract = {One plausible hypothesis for selective neuronal death in sporadic amyotropic lateral sclerosis (ALS) is excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, which are a subtype of ionotropic glutamate receptors. The Ca2+ conductance of AMPA receptors differs markedly depending on whether the GluR2 (or GluR-B) subunit is a component of the receptor. The properties of GluR2 are generated posttranscriptionally by RNA editing at the Q/R site in the putative second membrane domain (M2), during which the glutamine (Q) codon is substituted by an arginine (R) codon. AMPA receptors containing the unedited form of GluR2Q have high Ca2+ permeability in contrast to the low Ca2+ conductance of those containing the edited form of GluR2R. The role of Ca(2+)-permeable AMPA receptors, particularly GluR2 Q/R site RNA editing status, in neuronal death has been clearly demonstrated both in mice deficient in editing at the GluR2 Q/R site and in mice transgenic for an artificial Ca(2+)-permeable GluR2 subunit. We analyzed the expression level of mRNA of each AMPA receptor subunit in individual motor neurons, as well as the editing efficiency of GluR2 mRNA at the Q/R site in the single neuron level in control subjects and ALS cases. There was no significant difference as to the expression profile of AMPA receptor subunits or the proportion of GluR2 mRNA to total GluRs mRNA between normal subjects and ALS cases. By contrast, the editing efficiency varied greatly, from 0% to 100%, among the motor neurons of each individual with ALS, and was not complete in 44 of them (56%), whereas it remained 100% in normal controls. In addition, GluR2 editing efficiency was more than 99% in the cerebellar Purkinje cells of ALS, spinocerebellar degeneration and normal control groups. Thus, GluR2 underediting occurs in a disease specific and region selective manner. GluR2 modification by RNA editing is a biologically crucial event for neuronal survival, and its deficiency is a direct cause of neuronal death. Therefore, marked reduction of RNA editing in ALS motor neurons may be a direct cause of the selective motor neuron death seen in ALS. It is likely that the molecular mechanism underlying the deficiency in RNA editing is a reduction in the activity of ADAR2, a double- strand RNA specific deaminase. The restoration of this enzyme activity in ALS motor neurons may open the novel strategy for specific ALS therapy.}, }
@article {pmid15622408, year = {2005}, author = {Vande Velde, C and Cleveland, DW}, title = {VEGF: multitasking in ALS.}, journal = {Nature neuroscience}, volume = {8}, number = {1}, pages = {5-7}, doi = {10.1038/nn0105-5}, pmid = {15622408}, issn = {1097-6256}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Cell Survival/drug effects ; Humans ; Injections, Intraventricular ; Motor Neurons/*drug effects ; Vascular Endothelial Growth Factor A/administration &amp; dosage/*pharmacology ; }, }
@article {pmid15621213, year = {2005}, author = {Youdim, MB and Fridkin, M and Zheng, H}, title = {Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {126}, number = {2}, pages = {317-326}, doi = {10.1016/j.mad.2004.08.023}, pmid = {15621213}, issn = {0047-6374}, mesh = {Alzheimer Disease/*drug therapy/pathology ; Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism ; Chelating Agents/*pharmacology ; Cholinesterase Inhibitors/pharmacology ; Cholinesterases/metabolism ; Culture Media, Serum-Free/pharmacology ; Dementia/*drug therapy/pathology ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Humans ; Indans/chemistry/*pharmacology ; Iron/chemistry/*metabolism ; Lewy Bodies/drug effects/metabolism ; MAP Kinase Signaling System ; Models, Chemical ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/*pharmacology ; Neurodegenerative Diseases/pathology ; Neurons/metabolism ; Piperazines/chemistry/*pharmacology ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Quinolines/chemistry/*pharmacology ; }, abstract = {Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.}, }
@article {pmid15619232, year = {2005}, author = {Teng, FY and Tang, BL}, title = {Nogo signaling and non-physical injury-induced nervous system pathology.}, journal = {Journal of neuroscience research}, volume = {79}, number = {3}, pages = {273-278}, doi = {10.1002/jnr.20361}, pmid = {15619232}, issn = {0360-4012}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Central Nervous System Diseases/*metabolism/physiopathology ; Encephalomyelitis, Autoimmune, Experimental/metabolism/physiopathology ; Epilepsy/metabolism/physiopathology ; GPI-Linked Proteins ; Humans ; Myelin Proteins/genetics/*metabolism ; Nerve Degeneration/*metabolism/physiopathology ; Nogo Proteins ; Nogo Receptor 1 ; Receptors, Cell Surface/genetics/metabolism ; Signal Transduction/physiology ; }, abstract = {The Nogo gene products were described first as myelin-associated inhibitors that prevent neuronal regeneration upon injury. Recent findings have also implicated Nogo in several neuronal pathologies that are not induced by physical injury. Nogo-A may be an important determinant of autoimmune demyelinating diseases, as active immunization with Nogo-A fragments attenuates the symptoms of experimental autoimmune encephalomyelitis (EAE). Nogo-A levels are elevated markedly in hippocampal neurons of patients with temporal lobe epilepsy (TLE), in brain and muscle of patients with amyotrophic lateral sclerosis (ALS), and in schizophrenic patients. Concrete evidence for a direct role of Nogo-A in the latter neuropathies is not yet available, but such a role is logically in line with new findings associated with localization of Nogo-A and Nogo-Nogo-66 receptor (NgR)-mediated signaling. We speculate on possible linkages between the effect of aberrant elevation of Nogo levels and the signaling consequences that could lead to nervous system pathology.}, }
@article {pmid15611723, year = {2005}, author = {Muchowski, PJ and Wacker, JL}, title = {Modulation of neurodegeneration by molecular chaperones.}, journal = {Nature reviews. Neuroscience}, volume = {6}, number = {1}, pages = {11-22}, doi = {10.1038/nrn1587}, pmid = {15611723}, issn = {1471-003X}, mesh = {Animals ; Drug Delivery Systems/methods ; Humans ; Molecular Chaperones/genetics/metabolism/*physiology ; Neurodegenerative Diseases/genetics/*metabolism/prevention &amp; control ; Neuroprotective Agents/metabolism ; }, abstract = {Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.}, }
@article {pmid15584767, year = {2004}, author = {Ellis, AC and Rosenfeld, J}, title = {The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders.}, journal = {CNS drugs}, volume = {18}, number = {14}, pages = {967-980}, pmid = {15584767}, issn = {1172-7047}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Animals ; Creatine/metabolism/*therapeutic use ; *Dietary Supplements ; Disease Models, Animal ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {Creatine is consumed in the diet and endogenously synthesised in the body. Over the past decade, the ergogenic benefits of synthetic creatine monohydrate have made it a popular dietary supplement, particularly among athletes. The anabolic properties of creatine also offer hope for the treatment of diseases characterised by weakness and muscle atrophy. Moreover, because of its cellular mechanisms of action, creatine offers potential benefits for diseases involving mitochondrial dysfunction. Recent data also support the hypothesis that creatine may have a neuroprotective effect. Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in weakening and atrophy of skeletal muscles. In patients with this condition, creatine offers potential benefits in terms of facilitating residual muscle contractility as well as improving neuronal function. It may also help stabilise mitochondrial dysfunction, which plays a key role in the pathogenesis of ALS. Indeed, the likely multifactorial aetiology of ALS means the combined pharmacodynamic properties of creatine offer promise for the treatment of this condition. Evidence from available animal models of ALS supports the utility of treatment with creatine in this setting. Limited data available in other neuromuscular and neurodegenerative diseases further support the potential benefit of creatine monohydrate in ALS. However, few randomised, controlled trials have been conducted. To date, two clinical trials of creatine monohydrate in ALS have been completed without demonstration of significant improvements in overall survival or a composite measure of muscle strength. These trials have also posed unanswered questions about the optimal dosage of creatine and its beneficial effects on muscle fatigue, a measure distinct from muscle strength. A large, multicentre, clinical trial is currently underway to further investigate the efficacy of creatine monohydrate in ALS and address these unresolved issues. Evidence to date shows that creatine supplementation has a good safety profile and is well tolerated by ALS patients. The purpose of this article is to provide a short, balanced review of the literature concerning creatine monohydrate in the treatment of ALS and related neurodegenerative diseases. The pharmacokinetics and rationale for the use of creatine are described along with available evidence from animal models and clinical trials for ALS and related neurodegenerative or neuromuscular diseases.}, }
@article {pmid15583867, year = {2004}, author = {Liu, Q and Xie, F and Siedlak, SL and Nunomura, A and Honda, K and Moreira, PI and Zhua, X and Smith, MA and Perry, G}, title = {Neurofilament proteins in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {61}, number = {24}, pages = {3057-3075}, doi = {10.1007/s00018-004-4268-8}, pmid = {15583867}, issn = {1420-682X}, mesh = {Animals ; Biological Transport ; Disease Models, Animal ; Gene Expression Regulation ; Humans ; Neurodegenerative Diseases/*metabolism ; Neurofilament Proteins/genetics/*metabolism ; Protein Processing, Post-Translational ; }, abstract = {The function of neurofilaments, the major component in large myelinated neurons, is not well understood even though they were discovered as structures over 100 years ago. Recent studies have suggested that neuro-filaments are closely related to many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson disease Alzheimer disease, and diabetes. Using in vitro assays, cultures and transgenic mice, these studies provided new insights into neurofilament function. The function of each subunit, the relationship of neurofilaments with other cytoskeletal elements and their clinical significance are topics of increasing attention.}, }
@article {pmid15581409, year = {2004}, author = {Tremolizzo, L and Beretta, S and Ferrarese, C}, title = {Peripheral markers of glutamatergic dysfunction in neurological diseases: focus on ex vivo tools.}, journal = {Critical reviews in neurobiology}, volume = {16}, number = {1-2}, pages = {141-146}, doi = {10.1615/critrevneurobiol.v16.i12.150}, pmid = {15581409}, issn = {0892-0915}, mesh = {Biomarkers ; Blood Platelets/metabolism ; Fibroblasts/metabolism ; Glutamates/cerebrospinal fluid/metabolism/*physiology ; Humans ; Nervous System Diseases/*physiopathology ; }, abstract = {Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suffering and death, excitotoxicity and glutamate uptake deficits have been repeatedly confirmed to play a key role in the pathogenesis of different neurological diseases. Therefore, it is conceivable that assessing the glutamatergic system function directly in patients could be extremely useful for early diagnosis, prognostic evaluation, and optimization of the therapy. A possibility is offered by assessing glutamate levels in biological fluid, such as plasma and CSF, where increased levels of this amino acid have been reported in patients affected by stroke, amyotrophic lateral sclerosis (ALS), and AIDS dementia complex. However, the metabolic role of this amino acid acts as a confounding factor, and the possibility of directly assessing glutamatergic functional parameters, such as amino acid reuptake, would probably mirror closely the actual excitotoxic damage operative in each patient. Here we will describe our findings obtained in peripheral ex vivo cells, such as platelets and fibroblasts, both displaying a functional glutamate reuptake system. Consistent with a systemic-impairment assumption, glutamate uptake was shown to be reduced in peripheral cells of Alzheimer's disease, Down syndrome, Parkinson's disease, ALS, and stroke patients. Different systemic factors might be responsible for this phenomenon, including genetic predisposition, oxidative stress, and inflammatory response, raising new, exciting questions about the relevance of their possible interactions for the pathogenesis of neurological disorders.}, }
@article {pmid15580100, year = {2004}, author = {Griffith, R}, title = {Living wills, duty of care and the right to treatment.}, journal = {British journal of community nursing}, volume = {9}, number = {11}, pages = {488-491}, doi = {10.12968/bjcn.2004.9.11.16875}, pmid = {15580100}, issn = {1462-4753}, mesh = {Community Health Nursing/*legislation &amp; jurisprudence ; Humans ; Living Wills/*legislation &amp; jurisprudence ; Mental Competency/legislation &amp; jurisprudence ; Parenteral Nutrition/*nursing ; Patient Rights/*legislation &amp; jurisprudence ; Personal Autonomy ; Refusal to Treat/legislation &amp; jurisprudence ; United Kingdom ; }, abstract = {Agnes Simon, a district nurse with 20 years' experience, has been caring for a man with motor neurone disease for the last 5 years. During this time the patient has shown remarkable tenacity but the disease has now progressed to the stage where artificial nutrition and hydration (ANH) is required. A percutaneous endoscopic gastrostomy tube has been inserted through which the patient receives food, water and medication. On her most recent visit the patient gave Agnes a signed and witnessed living will. Unusually, the living will did not indicate the patient's wishes regarding the limitation of treatment. Instead it made clear that the patient wished to continue to receive ANH up to the time of his death. He did not want the care team to withdraw this treatment without his permission, as he feared he would suffer from the indignity of slowly dying from thirst and starvation. Agnes has never seen a living will where a patient demands a right to treatment and wonders whether such a document is lawful and binding on her.}, }
@article {pmid15572176, year = {2004}, author = {Barbeito, LH and Pehar, M and Cassina, P and Vargas, MR and Peluffo, H and Viera, L and Estévez, AG and Beckman, JS}, title = {A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis.}, journal = {Brain research. Brain research reviews}, volume = {47}, number = {1-3}, pages = {263-274}, doi = {10.1016/j.brainresrev.2004.05.003}, pmid = {15572176}, support = {P01AT002034/AT/NCCIH NIH HHS/United States ; R01 NS033291/NS/NINDS NIH HHS/United States ; R06-TW0006482/TW/FIC NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/physiopathology ; Animals ; Apoptosis/*physiology ; Astrocytes/immunology/*metabolism ; Cell Communication/physiology ; Gliosis/metabolism/pathology/physiopathology ; Glutamic Acid/metabolism ; Humans ; Inflammation Mediators/metabolism ; Motor Neurons/*metabolism/pathology ; }, abstract = {A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease.}, }
@article {pmid15571972, year = {2004}, author = {Blum, D and Chtarto, A and Tenenbaum, L and Brotchi, J and Levivier, M}, title = {Clinical potential of minocycline for neurodegenerative disorders.}, journal = {Neurobiology of disease}, volume = {17}, number = {3}, pages = {359-366}, doi = {10.1016/j.nbd.2004.07.012}, pmid = {15571972}, issn = {0969-9961}, mesh = {Animals ; Apoptosis ; Humans ; Huntington Disease/drug therapy ; Inflammation ; Minocycline/*therapeutic use ; Motor Neuron Disease/drug therapy ; Neurodegenerative Diseases/*drug therapy/pathology/physiopathology ; Neuroprotective Agents/*therapeutic use ; Parkinson Disease/drug therapy ; }, abstract = {Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to the launching of various clinical trials. The present review summarizes the available data supporting the clinical testing of minocycline for these neurodegenerative disorders. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.}, }
@article {pmid15566317, year = {2004}, author = {Strong, MJ}, title = {Amyotrophic lateral sclerosis: contemporary concepts in etiopathogenesis and pharmacotherapy.}, journal = {Expert opinion on investigational drugs}, volume = {13}, number = {12}, pages = {1593-1614}, doi = {10.1517/13543784.13.12.1593}, pmid = {15566317}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/*physiopathology ; Drug Therapy/*trends ; Humans ; Mitochondria/metabolism ; Motor Neurons/*pathology ; Nerve Degeneration/pathology ; Superoxide Dismutase/metabolism ; }, abstract = {Among the neurodegenerative diseases associated with ageing, amyotrophic lateral sclerosis (ALS) remains the most devastating. The disease inexorably progresses, the vast majority of pharmacotherapies have failed to modify the disease course, death ensues on average within 5 years of symptom onset and increasing numbers of individuals are afflicted with the disease. However, significant advances in our understanding of the natural history of ALS and of the fundamental nature of the biological defect underlying motor neuron degeneration have been gained, providing hope for the development of novel pharmacotherapies for ALS. Among these is the recognition that ALS is a biologically heterogeneous disorder in which genetics, environment and ageing all interrelate. The observation of clinical heterogeneity, with initial clinical manifestations serving as predictors of survivorship, is of considerable importance in designing therapeutic trials. The presence of frontotemporal dysfunction in a subset of patients has led to increased interest in the relationship between ALS and the degenerative tauopathies. Ultimately, the degenerating motor neurons do not die alone. The contribution of both microglia and astrocytes to the degenerative process are increasingly recognised. Understanding how these processes interrelate has become critical to understanding the pharmacotherapy of ALS and in the design of clinical trials. This review will highlight recent epidemiological and neurochemical advances in our understanding of ALS, and place them into the context of understanding the development of novel treatment avenues for this devastating disease.}, }
@article {pmid15565532, year = {2004}, author = {Tomik, J and Tomik, B}, title = {[The importance of laryngological and phoniatric evaluation at the early stage of amyotrophic lateral sclerosis].}, journal = {Neurologia i neurochirurgia polska}, volume = {38}, number = {5}, pages = {423-426}, pmid = {15565532}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Humans ; Laryngeal Muscles/*physiopathology ; Severity of Illness Index ; Time Factors ; Voice Disorders/*diagnosis/etiology/*physiopathology ; }, abstract = {The bulbar symptoms of amyotrophic lateral sclerosis (ALS) include difficulty with the management of swallowing, saliva production, aspiration of secretion to the air ways and problems with spoken communication. These symptoms originate from the malfunction of the face muscles and pharynx sphincters. Patients with early symptoms of bulbar ALS are often referred to the otolaryngologist for the evaluation and management of dysphagia and dysarthria. The bulbar onset of ALS with hypernasality, articulation defects and voice harshness make the otolaryngologists the primary diagnostician for these signs. Careful examination of the speech quality and morphology as well as the function of vocal cords should be undertaken. Once the diagnosis of ALS is made, the otolaryngologist's involvement in medical treatment is necessary at different stages of the disease.}, }
@article {pmid15564998, year = {2004}, author = {Dimond, B}, title = {The refusal of treatment: living wills and the current law in the UK.}, journal = {British journal of nursing (Mark Allen Publishing)}, volume = {13}, number = {18}, pages = {1104-1106}, doi = {10.12968/bjon.2004.13.18.16146}, pmid = {15564998}, issn = {0966-0461}, mesh = {Accidents, Traffic ; Family/psychology ; Humans ; Living Wills/*legislation &amp; jurisprudence ; Mental Competency/legislation &amp; jurisprudence ; Motor Neuron Disease/therapy ; Treatment Refusal/*legislation &amp; jurisprudence ; Unconsciousness/therapy ; United Kingdom ; }, abstract = {David Browne was suffering from motor neurone disease and was anxious to ensure that as his disease progressed and he ceased to be mentally capacitated he would not be given artificial feeding and ventilation. He therefore arranged to draw up a living will in which he gave an advanced refusal of such treatments. The document was duly signed and witnessed. Only 3 months after signing the living will he was severely injured in a road accident and brought into hospital unconscious. He was carrying his living will in his pocket. The doctors were concerned that if they operated and he required ventilation in intensive care, would the living will prevent their providing such treatment and care? What is the law?}, }
@article {pmid15556807, year = {2004}, author = {Yong, VW and Wells, J and Giuliani, F and Casha, S and Power, C and Metz, LM}, title = {The promise of minocycline in neurology.}, journal = {The Lancet. Neurology}, volume = {3}, number = {12}, pages = {744-751}, doi = {10.1016/S1474-4422(04)00937-8}, pmid = {15556807}, issn = {1474-4422}, mesh = {Animals ; Humans ; Minocycline/*therapeutic use ; Nervous System Diseases/*drug therapy/pathology ; }, abstract = {The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.}, }
@article {pmid15553356, year = {2004}, author = {van Vught, PW and Veldink, JH and Baas, F and van Muiswinkel, FL and van den Berg, LH}, title = {[From gene to disease: amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {148}, number = {43}, pages = {2125-2127}, pmid = {15553356}, issn = {0028-2162}, mesh = {Amyotrophic Lateral Sclerosis/complications/*genetics ; Genetic Predisposition to Disease ; Humans ; Mutation ; Oxidative Stress ; Respiratory Insufficiency/etiology/mortality ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurological disorder. It is characterised by selective motor-neuron degeneration in the cortex, brainstem, and spinal cord. Consequently, patients suffer from muscle weakness and usually die within 3-5 years after diagnosis from respiratory insufficiency. About 5-10% of the patients have a family history of ALS, the remaining are classified as sporadic ALS. There is only limited information about genetic susceptibility factors in sporadic ALS. Some patients with familial ALS have mutations in the gene encoding for copper/zinc superoxide dismutase, a protein involved in scavenging superoxide radicals. This results in a toxic gain of function. Mutations in the gene coding for alsin, ALS2, have been shown to be responsible for an autosomal recessive form of juvenile ALS.}, }
@article {pmid15538967, year = {2004}, author = {Rachakonda, V and Pan, TH and LE, WD}, title = {Biomarkers of neurodegenerative disorders: how good are they?.}, journal = {Cell research}, volume = {14}, number = {5}, pages = {347-358}, doi = {10.1038/sj.cr.7290235}, pmid = {15538967}, issn = {1001-0602}, mesh = {Alzheimer Disease/diagnosis/genetics/pathology ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; Animals ; Biomarkers/*analysis ; Humans ; Huntington Disease/diagnosis/genetics/pathology ; Models, Biological ; Neurodegenerative Diseases/*diagnosis/genetics/pathology ; Parkinson Disease/diagnosis/genetics/pathology ; }, abstract = {Biomarkers are very important indicators of normal and abnormal biological processes. Specific changes in pathologies, biochemistries and genetics can give us comprehensive information regarding the nature of any particular disease. A good biomarker should be precise and reliable, distinguishable between normal and interested disease, and differential between different diseases. It is believed that biomarkers have great potential in predicting chances for diseases, aiding in early diagnosis, and setting standards for the development of new remedies to treat diseases. New technologies have enabled scientists to identify biomarkers of several different neurodegenerative diseases. The followings, for instance, are only a few of the many new biomarkers that have been recently identified: the phosphorylated tau protein and aggregated Beta-amyloid peptide for Alzheimer's disease (AD), Alpha-synuclein contained Lewy bodies and altered dopamine transporter (DAT) imaging for Parkinson's disease (PD), SOD mutations for familial amyotrophic lateral sclerosis (ALS), and CAG repeats resulted from Huntington's gene mutations in Huntington's disease (HD). This article will focus on the most-recent findings of biomarkers belonging to the four mentioned neurodegenerative diseases.}, }
@article {pmid15537049, year = {2004}, author = {Mandel, RJ and Burger, C}, title = {Clinical trials in neurological disorders using AAV vectors: promises and challenges.}, journal = {Current opinion in molecular therapeutics}, volume = {6}, number = {5}, pages = {482-490}, pmid = {15537049}, issn = {1464-8431}, mesh = {*Clinical Trials as Topic ; Dependovirus/*genetics ; Genetic Therapy/*instrumentation/*trends ; Genetic Vectors/*genetics ; Humans ; Nervous System Diseases/*genetics/pathology/physiopathology/*therapy ; }, abstract = {Currently, there are five phase I clinical trials of recombinant adeno-associated viral vectors for the treatment of neurological disorders that are approved or likely to be approved shortly. Two trials are testing different strategies to treat Parkinson's disease (PD), the third trial is aimed at treating Canavan's disease, a pediatric leukodystrophy, the fourth trial targets Alzheimer's disease (AD), and the fifth will attempt to target the lysosomal storage disorder, Batten's disease. All four clinical trials rely on the de novo expression of an enzyme or a trophic factor to correct neuropathology. Ironically, the theories used to choose enzymes for the two PD trials were widely divergent, whereas the enzymatic strategy used for one of the PD trials and the Canavan's trial have remarkable similarities. Other gene therapy treatment strategies for PD and other disorders, such as amyotrophic lateral sclerosis, are also on the horizon.}, }
@article {pmid15530868, year = {2004}, author = {Bohn, MC}, title = {Motoneurons crave glial cell line-derived neurotrophic factor.}, journal = {Experimental neurology}, volume = {190}, number = {2}, pages = {263-275}, doi = {10.1016/j.expneurol.2004.08.012}, pmid = {15530868}, issn = {0014-4886}, mesh = {Animals ; Astrocytes/metabolism ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism ; Nerve Growth Factors/*metabolism ; }, abstract = {This is a commentary on the developmental and therapeutic relevance of recent studies in the glial fibrillary acid protein (GFAP)-glial cell line-derived neurotrophic factor (GDNF) transgenic mouse reported by Zhao et al. (2004). This interesting study demonstrated that increased expression of GDNF in astrocytes increases the number of neighboring motoneurons of certain motoneuron subpopulations by diminishing programmed cell death during development. In addition, astrocyte-derived GDNF was shown to protect facial motoneurons from injury-induced cell death. Since this is the first direct demonstration that secretion of GDNF from astrocytes in the CNS can affect motoneuron development in utero and motoneuron survival after axotomy, novel approaches for motor neuron disease are suggested. The known target neurons that respond to GDNF are reviewed, as are studies using GDNF gene delivery in animal models of amyotrophic lateral sclerosis (ALS). It is postulated that GDNF is a factor to which many motoneurons respond along their whole extent from soma to axon to terminal.}, }
@article {pmid15519530, year = {2005}, author = {Sonkusare, SK and Kaul, CL and Ramarao, P}, title = {Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope.}, journal = {Pharmacological research}, volume = {51}, number = {1}, pages = {1-17}, doi = {10.1016/j.phrs.2004.05.005}, pmid = {15519530}, issn = {1043-6618}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Animals ; Clinical Trials as Topic/statistics &amp; numerical data ; Humans ; Memantine/chemistry/pharmacokinetics/*therapeutic use ; Neurodegenerative Diseases/drug therapy/metabolism ; Neuroprotective Agents/chemistry/pharmacokinetics/therapeutic use ; }, abstract = {Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.}, }
@article {pmid15512890, year = {2004}, author = {Rosenfeld, J}, title = {ALS combination treatment. Drug cocktails.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {115-117}, doi = {10.1080/17434470410020067}, pmid = {15512890}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology/physiopathology ; Cell Death/drug effects ; Clinical Trials as Topic/methods ; Disease Progression ; *Drug Therapy, Combination ; Humans ; Motor Neurons/drug effects ; Research Design ; }, }
@article {pmid15512889, year = {2004}, author = {Kalra, S and Arnold, DL}, title = {ALS surrogate markers. MRS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {111-114}, doi = {10.1080/17434470410019861}, pmid = {15512889}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Aspartic Acid/*analogs &amp; derivatives/*metabolism ; Biomarkers/*metabolism ; Creatine/*metabolism ; Humans ; Longitudinal Studies ; Magnetic Resonance Spectroscopy/*methods ; Motor Cortex/pathology ; }, abstract = {Magnetic resonance spectroscopy (MRS) allows the quantitative assessment of neuronal integrity in vivo based on the resonance intensity of N-acetylaspartate (NAA). A simple approach to quantitation that is commonly used is to quantify the resonance intensity of NAA with respect to creatine (Cr). In patients with ALS, NAA/Cr density is decreased in areas of the brain that contribute significantly to the corticospinal tract. Since MRS is non-invasive, it can be easily used to monitor the evolution of regional changes in NAA/Cr over time. The changes in NAA/Cr over a period of months are small, however, and challenge the precision of the method.}, }
@article {pmid15512888, year = {2004}, author = {Swash, M and de Carvalho, M}, title = {The Neurophysiological Index in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {108-110}, doi = {10.1080/17434470410020067}, pmid = {15512888}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Evoked Potentials, Motor/physiology ; Humans ; Isometric Contraction/physiology ; Motor Neurons/physiology ; Muscle, Skeletal/physiopathology ; Neural Conduction/physiology ; Neurophysiology/*methods ; Reaction Time ; }, abstract = {The Neurophysiological Index (NI) consists of a mathematical derivation of three standardised neurophysiological measurements. Since these measurements are part of routine practice in any clinical neurophysiology laboratory, calculation of the NI is within the capability of any laboratory. The NI is derived from the CMAP, the DML and the F-wave frequency (CMAP amplitude/DML) x F frequency %), representing aspects of the effects of denervation and reinnervation, of degeneration of the terminal part of the motor axons, and of the excitability of anterior horn cells. We have shown that this simple index is reproducible in consecutive studies of normal subjects and of patients with ALS (intra-rater reliability), and is sensitive to change. In ALS, the NI differentiates rapidly and slowly progressive disease at least as sensitively as other measures in common use, including the ALS-FRS. We propose that the NI could be used as a sensitive measure of change during the course of ALS and its treatment. In combination with relevant measures of clinical benefit, such as ALS-FRS and a QoL measure, this could simplify trial design and allow more rapid determination of the efficacy of putative new therapies in clinical trials.}, }
@article {pmid15512887, year = {2004}, author = {Gooch, CL and Shefner, JM}, title = {ALS surrogate markers. MUNE.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {104-107}, doi = {10.1080/17434470410019889}, pmid = {15512887}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Biomarkers/analysis ; Electric Stimulation/methods ; Evoked Potentials, Motor/*physiology ; Humans ; Muscle, Skeletal/physiopathology ; Predictive Value of Tests ; Reproducibility of Results ; Retrospective Studies ; Time Factors ; }, abstract = {Over the last decade, motor unit number estimation (MUNE) methods have been applied with increasing frequency to the study of amyotrophic lateral sclerosis. MUNE is the ideal tool for the assessment of diseases in which the primary defect is motor unit loss, as it enables quantitation and tracking of motor unit numbers while simultaneously gauging countervailing collateral reinervation. These properties make it particularly useful for assessing the effects of both neuroprotective therapies and therapies designed to enhance collateral reinervation, not only in animal models but also in the living patient. Previous studies have supplied important natural history information, confirming an average 50% loss of motor units for every six months of disease progression, and newer pathophysiological investigations are providing unique insight into motor unit behavior in the face of progressive anterior horn cell death. More recent efforts have incorporated MUNE into ongoing, multi-center clinical trials as a putative early biomarker, with encouraging results. As MUNE methods continue to be refined and disseminated, they are proving to be useful and unique tools for the study of motor neuron disease.}, }
@article {pmid15512883, year = {2004}, author = {Gordon, PH and Miller, RG and Moore, DH}, title = {ALSFRS-R.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {90-93}, doi = {10.1080/17434470410019906}, pmid = {15512883}, issn = {1466-0822}, mesh = {*Activities of Daily Living ; Amyotrophic Lateral Sclerosis/drug therapy/*psychology ; Clinical Trials as Topic ; Humans ; Outcome Assessment, Health Care/*methods ; Reproducibility of Results ; Severity of Illness Index ; *Sickness Impact Profile ; }, abstract = {The ALSFRS-R is an attractive primary outcome measure in clinical trials of ALS because it is validated, easy to administer, minimizes dropout, reduces cost, and correlates with survival. Unlike the other standard outcome measures currently employed, the ALSFRS-R is also a measure of global function.}, }
@article {pmid15512872, year = {2004}, author = {Thompson, JL and Levy, G}, title = {ALS issues in clinical trials. Missing data.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {48-51}, doi = {10.1080/17434470410019753}, pmid = {15512872}, issn = {1466-0822}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; *Data Interpretation, Statistical ; Humans ; Randomized Controlled Trials as Topic/methods/*statistics &amp; numerical data ; Research Design/*statistics &amp; numerical data ; }, }
@article {pmid15512868, year = {2004}, author = {Bryan, WW}, title = {Regulatory issues in ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {36-41}, doi = {10.1080/17434470410015964}, pmid = {15512868}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*legislation &amp; jurisprudence ; Drug Approval ; Drug Therapy, Combination ; Humans ; *Legislation, Medical ; }, }
@article {pmid15512867, year = {2004}, author = {Schold, SC}, title = {ALS lessons learned from other neurological diseases. Neuro-oncology.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {34-35}, doi = {10.1080/17434470410019771}, pmid = {15512867}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Brain Neoplasms/physiopathology/*therapy ; Controlled Clinical Trials as Topic/methods ; Humans ; Medical Oncology/*methods ; Research Design ; Time Factors ; }, }
@article {pmid15512866, year = {2004}, author = {Mohr, JP}, title = {ALS lessons learned from other neurological diseases. Stroke.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {31-33}, doi = {10.1080/17434470410019870}, pmid = {15512866}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Anticoagulants/*therapeutic use ; Aspirin/therapeutic use ; Humans ; Intracranial Arteriovenous Malformations/drug therapy ; *Meta-Analysis as Topic ; Randomized Controlled Trials as Topic/methods ; Stroke/*drug therapy/physiopathology ; Warfarin/*therapeutic use ; }, }
@article {pmid15512865, year = {2004}, author = {Fahn, S}, title = {ALS lessons learned from other neurological diseases. Parkinson's disease.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {26-30}, doi = {10.1080/17434470410019852}, pmid = {15512865}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Antiparkinson Agents/therapeutic use ; Behavioral Symptoms/drug therapy/etiology ; Coenzymes ; Controlled Clinical Trials as Topic/methods ; Disease Progression ; Humans ; Levodopa/therapeutic use ; Neuroprotective Agents/*therapeutic use ; Parkinson Disease/diagnosis/*drug therapy/physiopathology ; Ubiquinone/*analogs &amp; derivatives/therapeutic use ; }, }
@article {pmid15512862, year = {2004}, author = {Przedborski, S}, title = {Molecular targets for neuroprotection.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {14-18}, doi = {10.1080/1734470410019780}, pmid = {15512862}, issn = {1466-0822}, support = {P01 NS11766-27A1/NS/NINDS NIH HHS/United States ; P50 NS38370/NS/NINDS NIH HHS/United States ; R01 NS38586/NS/NINDS NIH HHS/United States ; R01 NS42269/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Animals ; Apoptosis/genetics ; Caspases/metabolism ; Disease Models, Animal ; Humans ; Inflammation ; Neuroprotective Agents/*therapeutic use ; Peptide Hydrolases/physiology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal paralytic neurodegenerative disorder. Experimental models of ALS such as the transgenic rodents expressing mutant superoxide dimutase-1 are playing a pivotal role in our understanding of ALS pathogenesis, and in our testing of new therapeutic interventions aimed at protecting against neurodegeneration. Apoptosis has emerged as a significant pathogenic factor in several neurodegenerative diseases, including ALS. Constructed of multiple interacting molecules, the apoptosis machinery offers a host of attractive targets for pharmacological and genetic interventions to be tested in experimental models of ALS. Information generated by these pre-clinical studies holds the promise to provide sound scientific basis for the development of effective neuroprotective therapies for ALS.}, }
@article {pmid15512861, year = {2004}, author = {Mitsumoto, H and Gordon, P and Kaufmann, P and Gooch, CL and Przedborski, S and Rowland, LP}, title = {Randomized control trials in ALS: lessons learned.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {8-13}, doi = {10.1080/17434470410019942}, pmid = {15512861}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Randomized Controlled Trials as Topic/*methods/standards ; *Research Design ; Treatment Outcome ; }, }
@article {pmid15507874, year = {2004}, author = {Kim, SY}, title = {New target against inflammatory diseases: transglutaminase 2.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {52}, number = {5}, pages = {332-337}, pmid = {15507874}, issn = {0004-069X}, mesh = {Autoimmune Diseases/drug therapy ; Celiac Disease/drug therapy ; Enzyme Inhibitors/*therapeutic use ; GTP-Binding Proteins/*antagonists &amp; inhibitors ; Humans ; Inflammation/*drug therapy ; Liver Cirrhosis/drug therapy ; Myositis/drug therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; Transglutaminases/*antagonists &amp; inhibitors ; }, abstract = {Transglutaminase (TGase)2 is an enzyme that is widely used in many biological systems for generic tissue stabilization or immediate defense for wounds. Many reports showed that TGase 2 is aberrantly activated in tissues and cells and contributes to a variety of diseases, including neurodegenerative diseases and autoimmune diseases. In most cases, TGase 2 appears to be a factor in the formation of inappropriate proteinaceous aggregates that may be cytotoxic. However, in other cases, such as celiac disease, arthritis, lupus, and amyotrophic lateral sclerosis, TGase 2 is involved in the generation of autoantibodies. This suggests the possibility that inappropriate expression and/or presentation of TGase 2 to T cells might contribute to these diseases in genetically predisposed individuals. We and others have found that TGase 2 expression is also increased in the inflammation process. Furthermore, we also demonstrated a reversal of inflammation by Tgase inhibition. This review will examine a possibility of TGase inhibitors as therapeutic agents in a variety of inflammatory diseases.}, }
@article {pmid15500412, year = {2004}, author = {Bensimon, G and Doble, A}, title = {The tolerability of riluzole in the treatment of patients with amyotrophic lateral sclerosis.}, journal = {Expert opinion on drug safety}, volume = {3}, number = {6}, pages = {525-534}, doi = {10.1517/14740338.3.6.525}, pmid = {15500412}, issn = {1744-764X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Asthenia/chemically induced ; Biotransformation ; Chemical and Drug Induced Liver Injury/etiology ; Clinical Trials, Phase IV as Topic ; Contraindications ; Disease Progression ; Drug Interactions ; Humans ; Liver Function Tests ; Middle Aged ; Multicenter Studies as Topic ; Nausea/chemically induced ; Neutropenia/chemically induced ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/pharmacokinetics/*therapeutic use ; Risk ; }, abstract = {Riluzole is the only disease-modifying drug approved for the treatment of amyotrophic lateral sclerosis (ALS), in which it has been demonstrated to extend survival. The overall tolerability of riluzole is good and the drug can be used in all patients with ALS except those with elevated transaminase levels or active liver disease. The most frequently encountered adverse events (AEs) that appear to be attributed to riluzole are asthenia and nausea, observed in 18 and 15% of patients taking riluzole in the randomised clinical trial programme, respectively. These same AEs, albeit at a lower frequency, are also reported in Phase IV observational studies and in pharmacovigilance surveys. No unexpected AE clearly related to riluzole has emerged in the seven years that riluzole has been in extensive use in ALS patients. The most important potential safety issue with riluzole is hepatic impact with elevations of transaminases. Serum alanine aminotransferase levels more than three times the upper limit of normal are observed in 10 - 15% of patients. For this reason, strict monitoring of liver enzymes is recommended in patients with ALS taking riluzole, and treatment is contraindicated in subjects with elevated transaminases before the start of treatment. There is a suspicion that riluzole may, in rare cases, cause neutropenia, and physicians should be vigilant towards this risk.}, }
@article {pmid15495240, year = {2004}, author = {Cairns, NJ and Lee, VM and Trojanowski, JQ}, title = {The cytoskeleton in neurodegenerative diseases.}, journal = {The Journal of pathology}, volume = {204}, number = {4}, pages = {438-449}, pmid = {15495240}, issn = {0022-3417}, support = {P01 AG017586-069002/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P01 AG009215/AG/NIA NIH HHS/United States ; P01 AG009215-159002/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; AG-09215/AG/NIA NIH HHS/United States ; P30 AG010124-09S19002/AG/NIA NIH HHS/United States ; AG-10124/AG/NIA NIH HHS/United States ; AG-17556/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cytoskeletal Proteins/*metabolism ; Cytoskeleton/pathology/physiology ; Disease Models, Animal ; Humans ; Intermediate Filaments/pathology/physiology ; Mutation ; Neurodegenerative Diseases/genetics/metabolism/*physiopathology ; Neurons/pathology/physiology ; Peripheral Nervous System Diseases/genetics/metabolism/physiopathology ; tau Proteins/chemistry/genetics/physiology ; }, abstract = {Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS)--in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases. In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.}, }
@article {pmid15495036, year = {2004}, author = {Orrell, RW and Lane, JM and Ross, MA}, title = {Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD002829}, doi = {10.1002/14651858.CD002829.pub2}, pmid = {15495036}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.<br><br>OBJECTIVES: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (July 2003), MEDLINE (from January 1966 to July 2003), EMBASE (from January 1980 to July 2003) and other sources.<br><br>SELECTION CRITERIA: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: The reviewers independently applied the selection criteria, assessed study quality and two reviewers performed independent data extraction.<br><br>MAIN RESULTS: The search identified 21 studies for consideration but only eight studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure, (survival at 12 months treatment). Sufficient data were available from three studies to allow analysis of the primary outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed of vitamin E 500 mg twice daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of antioxidants in general when combining the results. No significant differences were demonstrated in secondary outcome measures.<br><br>REVIEWERS' CONCLUSIONS: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and patients. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid15488020, year = {2004}, author = {Brockington, A and Lewis, C and Wharton, S and Shaw, PJ}, title = {Vascular endothelial growth factor and the nervous system.}, journal = {Neuropathology and applied neurobiology}, volume = {30}, number = {5}, pages = {427-446}, doi = {10.1111/j.1365-2990.2004.00600.x}, pmid = {15488020}, issn = {0305-1846}, mesh = {Animals ; Brain/*blood supply/*physiology ; Humans ; Spinal Cord/*blood supply/*physiology ; *Vascular Endothelial Growth Factor A ; }, abstract = {Vascular endothelial growth factor (VEGF) is an angiogenic factor essential for the formation of new blood vessels during embryogenesis and in many pathological conditions. A new role for VEGF as a neurotrophic factor has recently emerged. In the developing nervous system, VEGF plays a pivotal role not only in vascularization, but also in neuronal proliferation, and the growth of coordinated vascular and neuronal networks. After injury to the nervous system, activation of VEGF and its receptors may restore blood supply and promote neuronal survival and repair. There is a growing body of evidence that VEGF is essential for motor neurone survival, and that aberrant regulation of VEGF may play a role in the degeneration of neurones in diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid15484701, year = {2004}, author = {Tsuchiya, K and Sano, M and Shiotsu, H and Akiyama, H and Watabiki, S and Taki, K and Kondo, H and Nakano, I and Ikeda, K}, title = {Sporadic amyotrophic lateral sclerosis of long duration mimicking spinal progressive muscular atrophy exists: additional autopsy case with a clinical course of 19 years.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {24}, number = {3}, pages = {228-235}, doi = {10.1111/j.1440-1789.2004.00546.x}, pmid = {15484701}, issn = {0919-6544}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/pathology ; Diagnosis, Differential ; Female ; Humans ; Muscular Atrophy, Spinal/*diagnosis/pathology ; Time Factors ; }, abstract = {This report concerns an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) clinically diagnosed as having spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness in the distal part of the right upper extremity at age 52, followed by muscle weakness in the left upper extremity and lower extremities at age 54 and 64, respectively. At age 66 she could not walk, even with assistance. Fasciculation and atrophy of the tongue appeared at age 68, followed by dysphagia and dysarthria at age 70. She died of respiratory disturbance at age 71. During the clinical course, neurological examination revealed neither Babinski sign nor hyperreflexia. No respirator administration was performed throughout the clinical course. Neuropathological examination disclosed not only neuronal loss with gliosis in the hypoglossal nucleus and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tract. Based on these clinicopathological findings and a literature review of sporadic autopsy cases of ALS with long clinical course (10 years or more), including four cases without pyramidal signs, we believe that sporadic ALS of long clinical course mimicking SPMA exists.}, }
@article {pmid15484521, year = {2003}, author = {Morgan, A}, title = {Understanding motor neurone disease.}, journal = {Nursing New Zealand (Wellington, N.Z. : 1995)}, volume = {9}, number = {5}, pages = {22-23}, pmid = {15484521}, issn = {1173-2032}, mesh = {Analgesia/methods ; Deglutition Disorders/etiology/therapy ; Dyspnea/etiology/therapy ; Humans ; Motor Neuron Disease/complications/*therapy ; Palliative Care/*methods ; Patient Care Team ; Terminal Care/methods ; }, }
@article {pmid15478096, year = {2004}, author = {Kunst, CB}, title = {Complex genetics of amyotrophic lateral sclerosis.}, journal = {American journal of human genetics}, volume = {75}, number = {6}, pages = {933-947}, pmid = {15478096}, issn = {0002-9297}, support = {R01 NS041646/NS/NINDS NIH HHS/United States ; NS041646/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Transport System X-AG/metabolism ; Amyotrophic Lateral Sclerosis/classification/drug therapy/*genetics/physiopathology ; Animals ; Apolipoproteins E/metabolism ; Ciliary Neurotrophic Factor/metabolism ; *Disease Models, Animal ; *Gene Expression Regulation ; Humans ; Mice ; Neurofilament Proteins/genetics ; Receptors, Glutamate/metabolism ; Riluzole/therapeutic use ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, }
@article {pmid15455310, year = {2004}, author = {Bernarducci, MP}, title = {Radiolabeled peptides: overcoming the challenges of post-surgical patient management of venous thromboembolism.}, journal = {Surgical technology international}, volume = {12}, number = {}, pages = {50-67}, pmid = {15455310}, issn = {1090-3941}, mesh = {Humans ; Oligopeptides ; *Organotechnetium Compounds ; *Peptides, Cyclic ; Platelet Glycoprotein GPIIb-IIIa Complex/antagonists &amp; inhibitors ; Postoperative Complications ; Radionuclide Imaging ; Risk Factors ; Sensitivity and Specificity ; Thrombolytic Therapy ; Thrombophlebitis/diagnostic imaging ; Ultrasonography, Doppler, Duplex ; Venous Thrombosis/diagnosis/*diagnostic imaging/physiopathology/surgery ; }, abstract = {The serious clinical and economic impact of venous thromboembolic (VTE) disease is undisputed. What concerns practitioners and researchers alike is the seeming inability to truly mitigate the ramification of VTE, especially in the post-surgical or postoperative subpopulation, in whom the risk of VTE is disproportionately high and often asymptomatic. Ironically, current approaches to the diagnostic evaluation of suspected VTE patients tend to favor the application of anatomic modalities, either invasive or technically challenging (eg, venography) or the performance of which is clinically inadequate (eg, ultrasonography) for post-surgical/postoperative patients. These modalities' primary principle of detection rely on the effects or results of an intricate pathophysiologic process, seemingly ignoring the critical role and potentially better prognostic value of endogenous hemostatic mechanisms. In other words, are we using the correct tools to seek the appropriate types of information in patients with suspected VTE? Research in nuclear medicine techniques for detecting VTE began approximately 25 years ago. Recently, the emergence of radiolabeled peptides as a clinically applicable technology platform has encouraged a different approach to evaluating VTE. Many radiolabeled peptide candidates are undergoing preclinical and clinical research. Currently,only one, 99'Tc-apcitide (AcuTect), has been approved (since 1998) for clinical use in the United States. The growing numbers of physicians with experience using 9mTc-apcitide (including those who remember using "'In-fibrinogen) has fueled ongoing clinical research to further elucidate the benefits of this unique peptide technology. Consequently, significant insight has been gained from large prospective clinical tri-als, of which one was conducted to support the approval of 99mTc-apcitide in Europe. Furthermore, this insight has kindled increasing interest in 99'Tc-apcitide and potential new entrants into this special " diagnostic class" (ie, radiolabeled peptides). Unlike the more popular anatomic modalities, radiolabeled pep-tides circumvent many of the clinical and anatomic challenges to objectively and accurately diagnose VTE. The importance of an objective and accurate diagnosis is understood, because it is paramount to a cost-effective treatment strategy. In addition to describing the current activities concerning the development and use of radiolabeled peptides for clinical practice, this manuscript is intended to promulgate a thought-provoking argument for changing our current approach to the diagnostic evaluation of VTE,which also may transcend the post-surgical/postoperative subpopulation.}, }
@article {pmid15453089, year = {2004}, author = {Minghetti, L}, title = {Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases.}, journal = {Journal of neuropathology and experimental neurology}, volume = {63}, number = {9}, pages = {901-910}, doi = {10.1093/jnen/63.9.901}, pmid = {15453089}, issn = {0022-3069}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Central Nervous System/cytology/*enzymology ; Cyclooxygenase 2 ; Eicosanoids/metabolism ; Encephalitis/*enzymology/physiopathology ; Humans ; Inflammation Mediators/metabolism ; Isoenzymes/*metabolism ; Membrane Proteins ; Microglia/metabolism ; Neurodegenerative Diseases/*enzymology/physiopathology ; Prostaglandin-Endoperoxide Synthases/*metabolism ; }, abstract = {Cyclooxygenase (COX) catalyses the first committed step in the synthesis of prostanoids, a large family of arachidonic acid metabolites comprising prostaglandins, prostacyclin, and thromboxanes, and is a major target of non-steroidal anti-inflammatory drugs (NSAIDs). COX exists as constitutive and inducible isoforms. COX-2 is the inducible isoform, rapidly expressed in several cell types in response to growth factors, cytokines, and pro-inflammatory molecules. Since its discovery in the early 1990s, COX-2 has emerged as a major player in inflammatory reactions in peripheral tissues. By extension, COX-2 expression in brain has been associated with pro-inflammatory activities, thought to be instrumental in neurodegenerative processes of several acute and chronic diseases. However, 2 major aspects should be borne in mind. First, in the central nervous system, COX-2 is expressed under normal conditions and contributes to fundamental brain functions, such as synaptic activity, memory consolidation, and functional hyperemia. Second, "neuroinflammation" is a much more controlled reaction than inflammation in peripheral tissues, and in many cases is triggered and sustained by activation of resident cells, particularly microglia. In spite of the intense research of the last decade, the evidence of a direct role of COX-2 in neurodegenerative events is still controversial. This article will review new data in this area, focusing on some major human neurological diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, Creutzfeldt-Jakob disease, and Alzheimer disease. Furthermore, the emerging role of COX-2 in behavioral and cognitive functions will be discussed.}, }
@article {pmid15452840, year = {2004}, author = {Rosenfeld, J}, title = {Multi-drug therapy in amyotrophic lateral sclerosis: the case for a multi-drug approach.}, journal = {Muscle &amp; nerve}, volume = {30}, number = {5}, pages = {673-675}, doi = {10.1002/mus.20186}, pmid = {15452840}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic/methods/trends ; *Drug Therapy, Combination ; Humans ; }, }
@article {pmid15452839, year = {2004}, author = {Shefner, JM}, title = {Multi-drug therapy in amyotrophic lateral sclerosis: combinations of multiple, untested drugs should not be used at this time.}, journal = {Muscle &amp; nerve}, volume = {30}, number = {5}, pages = {676-678}, doi = {10.1002/mus.20187}, pmid = {15452839}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Clinical Trials as Topic/trends ; *Drug Therapy, Combination ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; Pharmaceutical Preparations/administration &amp; dosage ; }, }
@article {pmid15448912, year = {2005}, author = {Hagenah, J and Kahl, KG and Steinlechner, S and Lencer, R and Klein, C}, title = {[Treatment of sialorrhea with botulinum toxin: an overview].}, journal = {Der Nervenarzt}, volume = {76}, number = {4}, pages = {418-425}, pmid = {15448912}, issn = {1433-0407}, mesh = {Botulinum Toxins/*therapeutic use ; Humans ; *Randomized Controlled Trials as Topic ; Sialorrhea/*drug therapy ; Treatment Outcome ; }, abstract = {Hypersalivation (sialorrhea) is a common complaint of patients with neurodegenerative disorders such as Parkinson's disease or amyotrophic lateral sclerosis and a frequently disabling side effect of atypical antipsychotic drugs. Conventional treatment including oral anticholinergic or antihistamine medication is often limited by adverse effects and lack of efficacy. Over the past few years, several studies reported decreased drooling after injections of botulinum toxin into the salivary glands. This review describes the current state of treatment of sialorrhea with botulinum toxin.}, }
@article {pmid15384941, year = {2004}, author = {Azzouz, M and Mazarakis, N}, title = {Non-primate EIAV-based lentiviral vectors as gene delivery system for motor neuron diseases.}, journal = {Current gene therapy}, volume = {4}, number = {3}, pages = {277-286}, doi = {10.2174/1566523043346291}, pmid = {15384941}, issn = {1566-5232}, mesh = {Genetic Therapy/*methods ; *Genetic Vectors ; Humans ; Infectious Anemia Virus, Equine/*genetics ; Motor Neuron Disease/genetics/*therapy ; *Motor Neurons ; }, abstract = {Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neurodegenerative diseases, which cause progressive paralysis and premature death in affected adults and children. The treatment rational for these diseases is to halt or delay the degeneration of motor neurons but to date there are no effective drugs. This may however change with recent advances in gene therapy using lentiviral vectors. These vectors can transfer genes to motor neurons with high efficiency and give long term expression. One of these vector systems, based on the equine infectious anaemia virus (EIAV), can insert genes into the cells of the central nervous system after remote delivery including delivery into the muscle by exploiting retrograde transport pathways. This opens up the exciting possibility of rescuing the denervation of key muscle groups in patients by simple injections of these neurotropic lentiviral vectors into the muscle. This review will describe the general features of lentiviral vectors derived from the EIAV. It will then describe some key examples of gene transfer and genetic correction in animal models of motor neuron disease. The prospects for the clinical evaluation of lentiviral vectors for the treatment of human motor neuron disease will be outlined.}, }
@article {pmid15377878, year = {2004}, author = {Xu, Z and Jung, C and Higgins, C and Levine, J and Kong, J}, title = {Mitochondrial degeneration in amyotrophic lateral sclerosis.}, journal = {Journal of bioenergetics and biomembranes}, volume = {36}, number = {4}, pages = {395-399}, pmid = {15377878}, issn = {0145-479X}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics/*pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; Mitochondria/*pathology ; Mitochondrial Diseases/etiology/genetics/*pathology ; Nerve Degeneration/*pathology ; Neurons/*pathology ; Peroxisomes/*pathology ; Vacuoles/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that causes motor neuron degeneration, progressive skeletal muscle atrophy, paralysis, and death. To understand the mechanism of motor neuron degeneration, we have analyzed the clinical disease progression and the pathological changes in a transgenic mouse model for ALS. We found massive mitochondrial vacuolation at the onset of disease. By detailed morphological observations, we have determined that this mitochondrial vacuolation is developed from expansion of mitochondrial intermembrane space and extension of the outer membrane and involves peroxisomes. Lysosomes do not actively participate at all stages of this vacuolation. We conclude that this mitochondrial vacuolation is neither classical mitochondrial permeability transition nor autophagic vacuolation. Thus, this appears to be a new form of mitochondrial vacuolation and we term this as mitochondrial vacuolation by intermembrane space expansion or MVISE.}, }
@article {pmid15351965, year = {2004}, author = {Storkebaum, E and Lambrechts, D and Carmeliet, P}, title = {VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {26}, number = {9}, pages = {943-954}, doi = {10.1002/bies.20092}, pmid = {15351965}, issn = {0265-9247}, mesh = {Angiogenesis Inducing Agents/*pharmacology ; Animals ; Brain Ischemia ; Gene Expression Regulation ; Humans ; Hypoxia ; Ischemia/pathology ; Mice ; Models, Biological ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism/pathology ; Neuroprotective Agents ; Oxygen/metabolism ; Regeneration ; Spinal Cord/pathology ; Vascular Endothelial Growth Factor A/*physiology ; }, abstract = {Both blood vessels and nerves are guided to their target. Vascular endothelial growth factor (VEGF)A is a key signal in the induction of vessel growth (a process termed angiogenesis). Though initial studies, now a decade ago, indicated that VEGF is an endothelial cell-specific factor, more recent findings revealed that VEGF also has direct effects on neural cells. Genetic studies showed that mice with reduced VEGF levels develop adult-onset motor neuron degeneration, reminiscent of the human neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Additional genetic studies confirmed that VEGF is a modifier of motor neuron degeneration in humans and in SOD1(G93A) mice--a model of ALS. Reduced VEGF levels may promote motor neuron degeneration by limiting neural tissue perfusion and VEGF-dependent neuroprotection. VEGF also affects neuron death after acute spinal cord or cerebral ischemia, and has also been implicated in other neurological disorders such as diabetic and ischemic neuropathy, nerve regeneration, Parkinson's disease, Alzheimer's disease and multiple sclerosis. These findings have raised growing interest in assessing the therapeutic potential of VEGF for neurodegenerative disorders.}, }
@article {pmid15341181, year = {2004}, author = {Calabrese, V and Boyd-Kimball, D and Scapagnini, G and Butterfield, DA}, title = {Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes.}, journal = {In vivo (Athens, Greece)}, volume = {18}, number = {3}, pages = {245-267}, pmid = {15341181}, issn = {0258-851X}, mesh = {Aging/*physiology ; Animals ; Brain/*growth &amp; development ; Cell Death ; Cell Survival ; Humans ; Neurodegenerative Diseases/genetics/*physiopathology ; Nitric Oxide/*physiology ; Oxidative Stress/*physiology ; }, abstract = {Nitric oxide and other reactive nitrogen species appear to play crucial roles in the brain such as neuromodulation, neurotransmission and synaptic plasticity, but are also involved in pathological processes such as neurodegeneration and neuroinflammation. Acute and chronic inflammation result in increased nitrogen monoxide formation and nitrosative stress. It is now well documented that NO and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading to cellular energy deficiency and, eventually, to cell death. Within the brain, the susceptibility of different brain cell types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced glutathione and cellular stress resistance signal pathways. Thus neurons, in contrast to astrocytes, appear particularly vulnerable to the effect of nitrosative stress. Evidence is now available to support this scenario for neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis and Huntington's disease, but also in the brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. To survive different types of injuries, brain cells have evolved integrated responses, the so-called longevity assurance processes, composed of several genes termed vitagenes and including, among others, members of the HSP system, such as HSP70 and HSP32, to detect and control diverse forms of stress. In particular, HSP32, also known as heme oxygenase-1 (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Increasing evidence suggests that the HO-1 gene is redox-regulated and its expression appears closely related to conditions of oxidative and nitrosative stress. An amount of experimental evidence indicates that increased rate of free radical generation and decreased efficiency of the reparative/degradative mechanisms, such as proteolysis, are factors that primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing such a response. These findings have led to new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel, cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes may possibly delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.}, }
@article {pmid15338308, year = {2004}, author = {Allen, NJ and Káradóttir, R and Attwell, D}, title = {Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {449}, number = {2}, pages = {132-142}, pmid = {15338308}, issn = {0031-6768}, mesh = {Acute Disease ; Animals ; Central Nervous System Diseases/*metabolism/*pathology/therapy ; Chronic Disease ; Glutamic Acid/*metabolism ; Humans ; Synaptic Transmission/*physiology ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {A dysfunction of amino acid neurotransmitter transporters occurs in a number of central nervous system disorders, including stroke, epilepsy, cerebral palsy and amyotrophic lateral sclerosis. This dysfunction can comprise a reversal of transport direction, leading to the release of neurotransmitter into the extracellular space, or an alteration in transporter expression level. This review analyses the role of glutamate and GABA transporters in the pathogenesis and therapy of a number of acute and chronic neurological disorders.}, }
@article {pmid15336685, year = {2004}, author = {Crawford, TO}, title = {Concerns about the design of clinical trials for spinal muscular atrophy.}, journal = {Neuromuscular disorders : NMD}, volume = {14}, number = {8-9}, pages = {456-460}, doi = {10.1016/j.nmd.2004.04.004}, pmid = {15336685}, issn = {0960-8966}, mesh = {Animals ; Clinical Trials as Topic/*methods ; Humans ; Muscular Atrophy, Spinal/*therapy ; Research Design/*standards ; }, abstract = {The distinctive clinical course of SMA, characterized by slowing of the rate of degeneration with the passage of time, presents a special challenge to therapeutic clinical trial planning. Much of the actual functional decline may represent either an inevitable consequence of growth or the result of various secondary complications of weakness, making the study of agents intended to improve the course by increasing the level of SMN protein that much more difficult. Studies intended to demonstrate a slowing of the rate of degeneration, modeled upon clinical trials for ALS, are problematic. In contrast, short-term trials designed to demonstrate improved strength have substantial design advantages, but depend upon the demonstration of salutary effects of increased SMN that are plausible but at present only theoretical. This form of study thus has some potential for type II error, falsely rejecting a useful drug. Despite this limitation, logistic and statistical concerns suggest that the best strategy for evaluating any promising new therapy will be to use first a short-term study.}, }
@article {pmid15326266, year = {2004}, author = {Haggiag, S and Steiner-Birmanns, B and Wirguin, I and Sicsic, C and Brenner, T and Steiner, I}, title = {Seroconversion of anti-GM1 antibodies in patients with amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {63}, number = {4}, pages = {755-756}, doi = {10.1212/01.wnl.0000134709.82830.12}, pmid = {15326266}, issn = {1526-632X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/genetics/*immunology ; Antibody Specificity ; Autoantibodies/biosynthesis/*blood/immunology ; Disease Progression ; Female ; G(M1) Ganglioside/*immunology ; Humans ; Immunoglobulin M/blood/immunology ; Male ; Middle Aged ; Retrospective Studies ; }, }
@article {pmid15319099, year = {2004}, author = {Volpi, A}, title = {Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system.}, journal = {Herpes : the journal of the IHMF}, volume = {11 Suppl 2}, number = {}, pages = {120A-127A}, pmid = {15319099}, issn = {0969-7667}, mesh = {Antiviral Agents/therapeutic use ; Central Nervous System Viral Diseases/cerebrospinal fluid/*diagnosis/drug therapy/pathology ; Epstein-Barr Virus Infections/cerebrospinal fluid/*diagnosis/drug therapy/pathology ; Herpesviridae Infections/cerebrospinal fluid/*diagnosis/drug therapy/pathology ; Herpesvirus 4, Human/*isolation &amp; purification ; Herpesvirus 8, Human/*isolation &amp; purification ; Humans ; Practice Guidelines as Topic ; }, abstract = {In developing guidelines for the improved management of herpesvirus infections of the central nervous system (CNS), the International Herpes Management Forum (IHMF) has studied Epstein-Barr virus (EBV) and human herpesvirus type 8 (HHV-8)- related diseases. EBV has been associated with numerous CNS diseases including meningitis, encephalitis and post transplant lymphoproliferative disorder (PTLD). The pathogenesis of EBV-associated CNS disorders is not completely understood but may be due to direct virus invasion of the CNS. Alternatively, damage may be immunologically mediated by infiltration of cytotoxic CD8+ lymphocytes into neural tissue or deposition of antibody-antigen complexes. The IHMF recommends that diagnosis of EBV infections of the CNS may involve polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) for EBV DNA but the sensitivity and specificity of the technique remains to be determined. Furthermore, the value of PCR in this context may be limited as EBV DNA is often detected in patients without neurological symptoms. Antiviral therapy has not demonstrated clinical efficacy in the treatment of EBV-related CNS disorders. CNS complications of HHV-8 infection are rare, but the virus has been associated with AIDS-dementia complex, amyotrophic lateral sclerosis (ALS) and primary CNS lymphoma; however these links remain to be proven.}, }
@article {pmid15313413, year = {2004}, author = {Rouaux, C and Loeffler, JP and Boutillier, AL}, title = {Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders.}, journal = {Biochemical pharmacology}, volume = {68}, number = {6}, pages = {1157-1164}, doi = {10.1016/j.bcp.2004.05.035}, pmid = {15313413}, issn = {0006-2952}, mesh = {Animals ; Apoptosis ; CREB-Binding Protein ; Drug Delivery Systems ; Enzyme Inhibitors/pharmacology/*therapeutic use ; *Histone Deacetylase Inhibitors ; Histones/metabolism ; Humans ; Hydroxamic Acids/pharmacology/therapeutic use ; Nervous System Diseases/*drug therapy ; Neurodegenerative Diseases/drug therapy ; Nuclear Proteins/*antagonists &amp; inhibitors/physiology ; Trans-Activators/*antagonists &amp; inhibitors/physiology ; Transcription, Genetic ; Vorinostat ; }, abstract = {Histone acetylation/deacetylation is a master regulation of gene expression. Among the enzymes involved in this process, the CREB-binding protein (CBP) displays important functions during central nervous system development. Increasing evidence shows that CBP function is altered during neurodegenerative processes. CBP loss of function has now been reported in several diseases characterized by neurological disorders such as the Rubinstein-Taybi syndrome or polyglutamine-related pathologies (Huntington's disease). Our recent work suggests that CBP loss of function could also be involved in Alzheimer's disease and amyotrophic lateral sclerosis. In a simplified apoptotic model of primary neurons, we described CBP as a substrate of apoptotic caspases, an alternative to its classical proteasomal degradation. In these neuronal death contexts, histone acetylation levels were decreased as well. Altogether, these data point to a central role of CBP loss of function during neurodegeneration. In order to restore proper acetylation levels, a proposed therapeutic strategy relies on HDAC inhibition. Nevertheless, this approach lacks of specificity. Therefore new drugs targeted at counteracting CBP loss of function could stand as a valid therapeutic approach in neurodegenerative disorders. The challenge will be to respect the fine-tuning between cellular HAT/HDAC activities.}, }
@article {pmid15310460, year = {2004}, author = {Bendotti, C and Carrì, MT}, title = {Lessons from models of SOD1-linked familial ALS.}, journal = {Trends in molecular medicine}, volume = {10}, number = {8}, pages = {393-400}, doi = {10.1016/j.molmed.2004.06.009}, pmid = {15310460}, issn = {1471-4914}, support = {GP0222Y01/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics/pathology ; Animals ; Genetic Linkage ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/enzymology/*pathology ; Mutation/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Ten years ago, the linkage between mutations in the gene coding for the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) and the neurodegenerative disease known as familial amyotrophic lateral sclerosis (FALS) was established. This finding has prompted a myriad of new studies in experimental models aimed at investigating the toxic function of the mutant enzymes. The cellular functions that are impaired in motoneurons as a consequence of molecular alterations induced by the expression of FALS SOD1 converge on pathways that might be activated in sporadic ALS by other toxic factors. Recent data demonstrate that, although motoneurons are lost in patients, other cell types are also affected and actively contribute to the pathogenesis of the disease.}, }
@article {pmid15287506, year = {2004}, author = {Hattori, N}, title = {[Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {44}, number = {4-5}, pages = {241-262}, pmid = {15287506}, issn = {0009-918X}, mesh = {Chromosomes, Human, Pair 6 ; Electron Transport Complex I/genetics ; Family ; Female ; Humans ; Male ; Mitochondrial Diseases/genetics ; Mutation ; Parkinson Disease/*genetics ; Superoxide Dismutase/genetics ; Ubiquitin-Protein Ligases/genetics ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. It is urgently needed to elucidate the cause of the disease and to establish neuroprotective treatment. We have been working on the etiology and pathogenesis of PD for many years and we found selective loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the nigral neurons of patients with PD. Our observation firmly established mitochondrial defects in PD. Mitochondrial respiratory failure induces oxidative damage in neurons, and we found increase in hydroxynonenal and 8-oxo-deoxyguanine, indices of oxidative damage, in the nigral neurons of PD. These abnormalities can trigger apoptotic cell death. The primary events which induce mitochondrial failure and oxidative damage are not known, however, it has been postulated that the interaction of genetic risk factors and environmental factors would initiate the degenerative process. Based on this assumption, we conducted genetic association studies by the candidate gene methods. We found that polymorphic mutations of superoxide dismutase-2 and 24-kDa subunit of mitochondrial complex I were associated increased risk of developing Parkinson's disease. While we were doing this genetic association study, we found a family, in which parkinsonian phenotype completely segregated with a polymorphic mutation of the superoxide dismutase-2 gene. In this family, 4 out of 6 siblings were affected with early onset parkinsonism and the parents were apparently normal. Thus the mode of inheritance appeared to be autosomal recessive and this type is now called as AR-JP or Park2. We confirmed the linkage of this type of familial Parkinson's disease to the superoxide dismutase loci that is located in the telomeric region of chromosome 6 by the linkage analysis using microsatellite markers in this region. Then we found another family, in which an affected patient showed lack of one of the microsatellite markers (D6S315), which we were using in the linkage analysis. This observation prompted us to initiate the molecular cloning of the disease gene utilizing D6S315 as the initial probe. The molecular cloning was done with the collaboration with Professor Nobuyoshi Shimizu of Keio University. We identified a novel gene and confirmed that mutations of this novel gene were found only in the patients with autosomal recessive Parkinson's disease. The novel gene was named parkin. We conducted mutational analysis on more than 700 families with Parkinson's disease. We also established a method to detect compound heterozygotes of parkin mutations. Mutinous of the parkin gene were found in approximately 50% of autosomal recessive families. Many kinds of exonic deletions and point mutations were found. This type of familial Parkinson's disease had been considered to be unique among Japanese, but since we started mutational analysis of the parkin gene, we confirmed the world wide distribution of parkin gene mutations. Then we analyzed functions of parkin protein with the collaboration with Dr. Keiji Tanaka of Tokyo Metropolitan Institute of Medical Sciences. We found that parkin protein was a ubiquitin-protein ligase of the ubiquitin system. Now we are working on the candidate substrates of parkin protein as a ubiquitin ligase. We found that CDCrel-1, a synaptic vesicle protein, was a candidate substrate of parkin protein. In addition, we found two additional candidate proteins, i.e., alpha-synuclein 22 and PAEL receptor, with the collaboration of Professor Denis Selkoe of Harvard Medical School and Dr. Ryosuke Takahashi of RIKEN, respectively. Accumulation of PAEL receptor in the endoplasmic reticulum causes endoplasmic reticulum stress and apoptotic cell death. We found evidence to indicate accumulation of PAEL receptor and the presence of endoplasmic reticulum stress in a patient with AR-JP (Park2). Thus our studies firmly established that a genetic defect of an enzyme in the ubiquitin-proteasome system induces selective nigral neuronal death. We indicated the important role of the ubiquitin-proteasome system in neurodegeneration in general. In many other neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, and ALS, ubiquitinated proteins are accumulated in neurons. Thus protein handling in the ubiquitin-proteasome system appears to be affected in these neurodegenerative disorders despite the difference in the primary defects. Our studies also suggest many potential approaches for the discovery of neuroprotective treatment for not only Parkinson's disease but also other neurodegenerative disorders.}, }
@article {pmid15284966, year = {2004}, author = {Gómez-Lázaro, M and Fernández-Gómez, FJ and Jordán, J}, title = {[The role of protein p53 in neurodegenerative processes throughout the 25 years of its history].}, journal = {Revista de neurologia}, volume = {39}, number = {3}, pages = {243-250}, pmid = {15284966}, issn = {0210-0010}, mesh = {Humans ; Neurodegenerative Diseases/*etiology ; Transcription Factors/physiology ; Tumor Suppressor Protein p53/*physiology ; }, abstract = {INTRODUCTION: In this review we will study the role of protein p53 in neurodegenerative processes and conduct a detailed analysis of the mechanisms responsible for regulating its levels and biological activity. We analyse the neuropathologies in which this protein is involved, such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis, and we will also examine its regulation by second messengers such as the reactive species of oxygen and calcium, showing the signalling paths involved in the apoptotic processes.<br><br>DEVELOPMENT: The year 2004 sees the 25th anniversary of the discovery of protein p53. At first p53 was wrongly attributed with an oncogenic function due to its capacity to bind to the T antigen of the virus SV40 in transformed cells. Nevertheless, it was not until 1989 that it was attributed with its true physiological function as a tumour-suppressing protein. This milestone constitutes a turning point in the short life of this protein. Protein p53 plays a fundamental role in the mechanisms the cell uses to respond to damage or mutation in the genome. There is, therefore, a correlation between deletions or mutations in the p53 gene and the development of some kinds of cancer; additionally, increases in the protein levels of its native form have been reported in pathologies where apoptotic processes are high.<br><br>CONCLUSIONS: Protein p53 plays an essential role in the mechanisms by which the cell responds to damage or mutation in the genome. It can activate two signalling mechanisms that lead either to stopping the cell cycle or to the death of the cell due to apoptosis if the cell cannot repair the damage to the genome. There is a correlation between its deletions and mutations and the development of cancer, and increases in its native form have been described in pathologies where apoptotic processes are high, as is the case of some neurodegenerative diseases.}, }
@article {pmid15272267, year = {2004}, author = {Ross, CA and Poirier, MA}, title = {Protein aggregation and neurodegenerative disease.}, journal = {Nature medicine}, volume = {10 Suppl}, number = {}, pages = {S10-7}, doi = {10.1038/nm1066}, pmid = {15272267}, issn = {1078-8956}, support = {AG05146/AG/NIA NIH HHS/United States ; NS16375/NS/NINDS NIH HHS/United States ; NS34172/NS/NINDS NIH HHS/United States ; NS38144/NS/NINDS NIH HHS/United States ; NS38377/NS/NINDS NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides/chemistry/metabolism ; Animals ; Humans ; Huntingtin Protein ; Inclusion Bodies/*metabolism/pathology ; Mice ; Models, Biological ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/etiology/*metabolism/pathology/physiopathology ; Nuclear Proteins/metabolism ; Peptides/metabolism ; Protein Folding ; Protein Structure, Secondary ; Ubiquitin/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.}, }
@article {pmid15266948, year = {2003}, author = {Gupta, YK and Gupta, M and Kohli, K}, title = {Neuroprotective role of melatonin in oxidative stress vulnerable brain.}, journal = {Indian journal of physiology and pharmacology}, volume = {47}, number = {4}, pages = {373-386}, pmid = {15266948}, issn = {0019-5499}, mesh = {Animals ; Antioxidants/*physiology/therapeutic use ; Brain/metabolism/*physiology ; Humans ; Melatonin/*physiology/therapeutic use ; Nervous System Diseases/drug therapy/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/*physiology ; }, abstract = {The brain is deficient in oxidative defense mechanisms and hence is at greater risk of damage mediated by reactive oxygen species (ROS) resulting in molecular and cellular dysfunction. Emerging evidence suggesting the activation of glutamate gated cation channels, may be another source of oxidative stress, leading to neuronal degeneration. Oxidative stress has been implicated in the development of neurodegenerative diseases like Parkinsonism, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epileptic seizures, and stroke. Melatonin, the pineal hormone, acts as a direct free radical scavenger and indirect antioxidant. It is suggested that the increase in neurodegenerative diseases is attributable to a decrease in the levels of melatonin with age. Melatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. Additionally, it neutralizes hydoxyl radical, superoxide radical, peroxyl radical, peroxynitrite anion, singlet oxygen, hydrogen peroxide, nitric oxide, and hypochlorous acid. Unlike other antioxidants, melatonin can easily cross all morphophysiological barriers, e.g., the blood brain barrier, and enters cells and subcellular compartments. Though evidence are accumulating to suggest the potential of melatonin in neurodegenerative conditions, much information needs to be generated before the drug can find place in neurology clinics.}, }
@article {pmid15266526, year = {2004}, author = {Bongioanni, P and Reali, C and Sogos, V}, title = {Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2004}, number = {3}, pages = {CD004302}, pmid = {15266526}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Ciliary Neurotrophic Factor/*therapeutic use ; Disease Progression ; Humans ; Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a fatal neuromuscular disease characterized by progressive muscle weakness resulting in paralysis, which might be treated with ciliary neurotrophic factor.<br><br>OBJECTIVES: The objective of this review was to examine the efficacy of ciliary neutrophic factor in amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched June 2003) for randomized trials, MEDLINE (from January 1966 to October 2003) and EMBASE (from January 1980 to October 2003), checked the reference lists of papers identified and contacted the authors of studies identified to get additional unpublished results.<br><br>SELECTION CRITERIA: We considered the following selection criteria: Types of studies: randomized controlled clinical trials;<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of either probable or definite amyotrophic lateral sclerosis according to the El Escorial criteria; Types of interventions: treatment with ciliary neurotrophic factor for at least six months, in a placebo-controlled randomized format; Types of outcome measures Primary: survival; Secondary: muscle strength, respiratory function, changes in bulbar functions, changes in quality of life, proportion of patients with adverse side effects (such as cough, asthenia, nausea, anorexia, weight loss and increased salivation).<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomized trials. The data were extracted and examined independently by the reviewers. Some missing data were obtained from investigators.<br><br>MAIN RESULTS: Two trials, with a total population of 1,300 amyotrophic lateral sclerosis patients treated with subcutaneous injections of recombinant human ciliary neurotrophic factor, were examined in this review. The methodological quality of these trials was considered adequate. No significant difference was observed between ciliary neurotrophic factor and placebo groups for survival, the primary outcome measure. The relative risk was 1.07 (95% CI 0.81 to 1.41). No significant differences between the groups were observed for most of the secondary outcomes. However, a significant increase of the incidence of several adverse events was noted in groups treated with higher doses of CNTF.<br><br>REVIEWERS' CONCLUSIONS: Ciliary neurotrophic factor treatment has no effect on amyotrophic lateral sclerosis progression. At high concentration, several side effects were observed. A combination of ciliary neurotrophic factor with other neurotrophic factors (as suggested by results on animal models), and more efficient delivery methods should be tested.}, }
@article {pmid15255560, year = {2004}, author = {Johansen, C}, title = {Electromagnetic fields and health effects--epidemiologic studies of cancer, diseases of the central nervous system and arrhythmia-related heart disease.}, journal = {Scandinavian journal of work, environment &amp; health}, volume = {30 Suppl 1}, number = {}, pages = {1-30}, pmid = {15255560}, issn = {0355-3140}, mesh = {Adolescent ; Adult ; Arrhythmias, Cardiac/*epidemiology/etiology ; Central Nervous System Diseases/*epidemiology/etiology ; Child ; Cohort Studies ; Electromagnetic Fields/*adverse effects ; Environmental Exposure/*adverse effects ; Female ; Humans ; Male ; Middle Aged ; Neoplasms, Radiation-Induced/*epidemiology ; Risk Assessment ; Scandinavian and Nordic Countries/epidemiology ; }, abstract = {This epidemiologic investigation comprised separate studies of the risk of cancer, cause-specific mortality rates, risks for neurodegenerative diseases, and the risk of arrhythmia-related heart disease among employees exposed to extremely low-frequency (50-Hz) electromagnetic fields (EMF) in the Danish utility industry. All the employees in this industry were followed-up in several registers. The risk of disease was analyzed in relation to occupational exposure to EMF, latency, and duration of employment. A specific job-exposure matrix was developed and validated by comparison with direct measurements of EMF during a workday. Linkage with the Danish Cancer Register did not identify increased risks for the cancers suggested a priori to be associated with exposure to EMF, including leukemia, brain tumors, and breast cancer. Significantly increased risks for lung cancer and mesothelioma were identified for workers highly exposed to asbestos. Linkage with the National Mortality Register revealed a significantly increased overall mortality rate from amyotrophic lateral sclerosis (ALS), with an increasing trend with duration of employment and EMF exposure. In addition, a significantly increased mortality rate from electric accidents was observed. It was hypothesized that the observation of increased mortality from ALS was associated with exposure to EMF or electric shocks. No increased mortality rate from cardiovascular or cerebrovascular disease was observed. Linkage with the National Hospital Register also revealed an increased risk of ALS and, thereby confirmed the finding of an increased mortality rate for this disease in the previous study. Linkage of the cohort with the Multiple Sclerosis Register revealed an increased risk of multiple sclerosis, which was not, however, significant. Linkage with the Pacemaker Register showed no increased risk of severe arrhythmia-related heart disease. The second part of the study included the establishment of a large, nationwide cohort of mobile phone subscribers comprising some 420 000 persons. No increased risk was observed for the cancers considered a priori to be possibly associated with the radiofrequency fields emitted by mobile phones, which were brain tumors, including acoustic neuroma, salivary gland tumors, and leukemia. The data were analyzed by duration of phone use, latency, system used (NMT, GSM or both) and age at first subscription. A study of the incidence of ocular malignant melanoma in comparison with the annual increase among the mobile phone subscribers showed a highly stable incidence rate for this rare cancer in Denmark over close to 50 years of registration. On the basis of these studies and the scientific literature, it is concluded that occupational exposure to 50-Hz EMF is not associated with an increased risk of cancer, but that these fields, electric shocks, or some other unknown factor related to alternating current electricity may be associated with the risk of ALS. There is no clear evidence that 50-Hz EMF is associated with other neurodegenerative or cardiovascular diseases. At present, there is little, if any, evidence that the use of mobile phones is associated with cancer in adults, including brain tumors, acoustic neuroma, cancer of the salivary glands, leukemia, or malignant melanoma of the eye.}, }
@article {pmid15247881, year = {2004}, author = {Kreuter, M and Langer, C and Kerkhoff, C and Reddanna, P and Kania, AL and Maddika, S and Chlichlia, K and Bui, TN and Los, M}, title = {Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {52}, number = {3}, pages = {141-155}, pmid = {15247881}, issn = {0004-069X}, mesh = {Animals ; Apoptosis/*physiology ; Caspases/*metabolism ; Cell Cycle/physiology ; Clinical Trials as Topic ; Cytokines/immunology ; *Drug Design ; Drug Industry ; Enzyme Activation ; Humans ; *Inflammation/drug therapy/metabolism/physiopathology ; *Myocardial Infarction/drug therapy/metabolism ; *Stroke/drug therapy/metabolism ; }, abstract = {Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.}, }
@article {pmid15246734, year = {2004}, author = {Silani, V and Cova, L and Corbo, M and Ciammola, A and Polli, E}, title = {Stem-cell therapy for amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {364}, number = {9429}, pages = {200-202}, doi = {10.1016/S0140-6736(04)16634-8}, pmid = {15246734}, issn = {1474-547X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Embryo, Mammalian/cytology ; Fetal Blood/cytology ; Hematopoietic Stem Cell Transplantation ; Humans ; Neurons/cytology ; Spinal Cord ; *Stem Cell Transplantation ; }, abstract = {CONTEXT: With the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), and compelling preclinical data, stem-cell research has highlighted this disease as a candidate for stem-cell treatment. Stem-cell transplantation is an attractive strategy for neurological diseases and early successes in animal models of neurodegnerative disease generated optimism about restoring function or delaying degeneration in human beings. The restricted potential of adult stem cells has been challenged over the past 5 years by reports on their ability to acquire new unexpected fates beyond their embryonic lineage (transdifferentiation). Therefore, autologous or allogeneic stem cells, undifferentiated or transdifferentiated and manipulated epigenetically or genetically, could be a candidate source for local or systemic cell-therapies in ALS.<br><br>STARTING POINT: Albert Clement and colleagues (Science 2003; 302: 113-17) showed that in SOD1G93A chimeric mice, motorneuron degeneration requires damage from mutant SOD1 acting in non-neuronal cells. Wild-type non-neuronal (glial) cells could delay degeneration and extend survival of mutant-expressing motorneurons. Letizia Mazzini and colleagues (Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 158-61) injected autologous bone-marrow-derived stem cells into the spinal cord of seven ALS patients. These investigators reported that the procedure had a reasonable margin of clinical safety. WHERE NEXT? The success of cell-replacement therapy in ALS will depend a lot on preclinical evidence, because of the complexity and precision of the pattern of connectivity that needs to be restored in degenerating motoneurons. Stem-cell therapy will need to be used with other drugs or treatments, such as antioxidants and/or infusion of trophic molecules.}, }
@article {pmid15244158, year = {2004}, author = {Wang, FC and Gérard, P and Bouquiaux, O}, title = {[Advantages and limitations of the motor unit number estimation techniques].}, journal = {Revue medicale de Liege}, volume = {59 Suppl 1}, number = {}, pages = {38-48}, pmid = {15244158}, issn = {0370-629X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Cell Count/methods ; Electrophysiology ; Humans ; Motor Neurons/*pathology ; }, abstract = {It is now 30 years since the first motor unit number estimation (MUNE) technique was introduced by Allan McComas as a way of providing an objective, sensitive and reproducible means of measuring the number of motor axons in living human muscle or muscle group. MUNE techniques have substantially evolved over the past decade and have been applied, with increasing frequency, to the study of age effects on motoneurone population and muscle denervating disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, poliomyelitis and different types of inherited and acquired peripheral neuropathies. In the future, one of the most important topics involving MUNE, will probably be its use in monitoring the progress of ALS patients undergoing experimental drug trials. However, among incremental, multiple point stimulation, spike-triggered averaging, F-wave analysis and statistical methods, there is no consensus about the best MUNE method. There is only a general feeling that some techniques are more valid than others. For this reason, in the present review, brief descriptions of the distinct MUNE methods are presented. In the second part of the paper, advantages and limitations (alternation, sampling errors, temporal registration etc...) of the most commonly employed procedures are considered.}, }
@article {pmid15244157, year = {2004}, author = {Pouget, J}, title = {[Clinical neurophysiology for estimation of progression and prognosis in ALS].}, journal = {Revue medicale de Liege}, volume = {59 Suppl 1}, number = {}, pages = {32-37}, pmid = {15244157}, issn = {0370-629X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Diagnostic Techniques, Neurological ; Disease Progression ; Electrophysiology ; Humans ; Prognosis ; }, abstract = {The role of clinical neurophysiology in the evaluation of disease progression in ALS has to be precised. To be included in the methodology of therapeutic trials, neurophysiological methods have to be quantitative, sensitive and reproducible. Their goal is to assess peripheral and central motor neuron loss but also compensatory processes such as reinnervation. The peripheral motor neuron loss can be evaluated by compound muscle action potential amplitude and mainly by motor unit number estimate (MUNE). Peripheral reinnervation can be evaluated by fiber density and macro-MUP amplitude. Functional aspects of reinnervation can be assessed by jitter measurement or the occurrence of decrement when using repetitive stimulation. Central motor neuron loss can be evaluated by transcranial magnetic stimulation and the triple collision technique (TST). Among the various electrophysiological approaches, MUNE and TST seem to be the most appropriate to evaluate peripheral and central motor neuron loss over time in ALS.}, }
@article {pmid15244156, year = {2004}, author = {Le Forestier, N}, title = {[The differential diagnosis of amyotrophic lateral sclerosis].}, journal = {Revue medicale de Liege}, volume = {59 Suppl 1}, number = {}, pages = {25-31}, pmid = {15244156}, issn = {0370-629X}, mesh = {Adult ; Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Diagnosis, Differential ; Electrophysiology ; Follow-Up Studies ; Humans ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is mainly a clinical one. Nonetheless, electrophysiological studies must be performed early in order to confirm the diagnosis. The El Escorial criteria for the diagnosis of ALS, recently revisited in order to increase their sensitivity, have been widely accepted and help neurologists to categorize patients into various levels of certainty from clinical assessment. However, the variability in clinical findings early in the course of the disease and the lack of any biological diagnostic marker make absolute diagnosis difficult. In this review, I propose a strategy for establishing differential diagnoses when faced to a pure motor deficit at the first evaluation, or at the electrophysiological study or during follow up.}, }
@article {pmid15224658, year = {2004}, author = {Petrucelli, L and Dawson, TM}, title = {Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system.}, journal = {Annals of medicine}, volume = {36}, number = {4}, pages = {315-320}, doi = {10.1080/07853890410031948}, pmid = {15224658}, issn = {0785-3890}, support = {NS38377/NS/NINDS NIH HHS/United States ; NS41486/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Brain/physiopathology ; Cysteine Endopeptidases/*metabolism ; Endopeptidases/chemistry/*physiology ; Humans ; Huntington Disease/physiopathology ; Multienzyme Complexes/*metabolism ; Neurodegenerative Diseases/*physiopathology ; Parkinson Disease/physiopathology ; Proteasome Endopeptidase Complex ; Signal Transduction/physiology ; Ubiquitin/*metabolism ; Ubiquitin-Specific Proteases ; }, abstract = {Many neurodegenerative disorders such as Alzheimer's disease (AD) Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are characterized by neuronal damage that may be caused by toxic, abnormal, aggregation-prone proteins. The purpose of this review is threefold: 1) to provide the reader with an overview of the genes involved in the abnormal processing and accumulation of misfolded proteins in neurodegenerative diseases using PD as a model disease; 2) to understand the cellular mechanisms for disposal of abnormal proteins, and the effects of toxic protein accumulation on ubiquitin proteasome system (UPS) and neuronal survival and 3) to discuss the development and challenges of cell culture and animal models for a rational and effective treatment for these disorders.}, }
@article {pmid15218778, year = {2004}, author = {Reniewska, B and Mulak, M and Misiuk-Hojło, M and Kostuś, E}, title = {[Coexistence of Alzheimer's disease with pseudoexfoliation syndrome PEX].}, journal = {Klinika oczna}, volume = {106}, number = {1-2}, pages = {107-109}, pmid = {15218778}, issn = {0023-2157}, mesh = {Alzheimer Disease/*complications/diagnosis ; Exfoliation Syndrome/*complications/diagnosis ; Humans ; }, abstract = {Alzheimer disease is a type of cerebral amyloidosis, which is most frequently recognized after the age of 80. In pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and age-related cataract changes in protein aggregation play important role, for that reason they form common group of diseases, called conformational diseases. Patients with Alzheimer disease have more common pseudoexfoliation syndrome (PEX), characterized by the accumulation of an abnormal pathognomonic material in the anterior segment of the eye. Regarding common feature of the structure of fibrillar pseudoexfoliation and amyloid material, it is considered that eye examination could be useful in the early diagnosis of Alzheimer disease.}, }
@article {pmid15217349, year = {2004}, author = {Bruijn, LI and Miller, TM and Cleveland, DW}, title = {Unraveling the mechanisms involved in motor neuron degeneration in ALS.}, journal = {Annual review of neuroscience}, volume = {27}, number = {}, pages = {723-749}, doi = {10.1146/annurev.neuro.27.070203.144244}, pmid = {15217349}, issn = {0147-006X}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/metabolism ; Animals ; Dyneins/metabolism ; Glutamic Acid/metabolism/toxicity ; Humans ; Models, Neurological ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/*etiology/genetics/metabolism ; Neurofilament Proteins/metabolism ; Superoxide Dismutase/deficiency/genetics ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, these model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.}, }
@article {pmid15210307, year = {2004}, author = {Shigeri, Y and Seal, RP and Shimamoto, K}, title = {Molecular pharmacology of glutamate transporters, EAATs and VGLUTs.}, journal = {Brain research. Brain research reviews}, volume = {45}, number = {3}, pages = {250-265}, doi = {10.1016/j.brainresrev.2004.04.004}, pmid = {15210307}, support = {06808501//PHS HHS/United States ; }, mesh = {Amino Acid Transport Systems, Neutral/agonists/antagonists &amp; inhibitors/*metabolism ; Animals ; Carrier Proteins/agonists/antagonists &amp; inhibitors/*metabolism ; Excitatory Amino Acid Transporter 1/agonists/antagonists &amp; inhibitors/*metabolism ; Glutamic Acid/analogs &amp; derivatives/metabolism/pharmacology ; Humans ; Ligands ; *Membrane Transport Proteins ; Models, Neurological ; Molecular Conformation ; Molecular Structure ; Neuroglia/drug effects/metabolism ; Neurons/drug effects/metabolism ; Structure-Activity Relationship ; Vesicular Glutamate Transport Protein 1 ; *Vesicular Transport Proteins ; }, abstract = {L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.}, }
@article {pmid15210305, year = {2004}, author = {Malaspina, A and de Belleroche, J}, title = {Spinal cord molecular profiling provides a better understanding of amyotrophic lateral sclerosis pathogenesis.}, journal = {Brain research. Brain research reviews}, volume = {45}, number = {3}, pages = {213-229}, doi = {10.1016/j.brainresrev.2004.04.002}, pmid = {15210305}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Antioxidants/therapeutic use ; Cell Differentiation/physiology ; Cell Survival/physiology ; Cytoskeleton/physiology ; Disease Models, Animal ; Gene Expression/physiology ; *Gene Expression Profiling ; Humans ; Inflammation/genetics/physiopathology ; Motor Neurons/metabolism/pathology ; Neurodegenerative Diseases/genetics ; Postmortem Changes ; RNA, Messenger/metabolism ; Spinal Cord/*metabolism/pathology ; }, abstract = {Research efforts in amyotrophic lateral sclerosis (ALS) have not yet provided a comprehensive explanation of the disease pathogenesis, which is emerging as a complex interaction between multiple factors. Gene expression studies traditionally based on single mRNA specie analysis have recently progressed to allow entire transcriptional profiles of affected tissues to be obtained through array-based methods. This experimental approach has significantly improved our understanding of the molecular changes occurring in ALS, although its limitations in the detection of low-abundance transcripts in tissues with a high level of complexity are becoming increasingly recognized. In this paper, experimental findings based on an expression study in post-mortem spinal cord from sporadic ALS individuals will be discussed in light of recently published data using array analysis in an animal model of the disease. Previous expression data obtained using conventional techniques are also compared. Through the analysis of the information arising from ALS post-mortem and animal model tissues studies, we have identified a pattern of molecular events in which factors implicated in the immune response, cytoprotection and growth-differentiation are differentially regulated in a time-dependent way from early to advanced stages of disease progression.}, }
@article {pmid15204010, year = {2004}, author = {Leigh, PN and Swash, M and Iwasaki, Y and Ludolph, A and Meininger, V and Miller, RG and Mitsumoto, H and Shaw, P and Tashiro, K and Van Den Berg, L}, title = {Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {2}, pages = {84-98}, doi = {10.1080/14660820410020187}, pmid = {15204010}, issn = {1466-0822}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology/therapy ; Animals ; Clinical Trials as Topic/*methods/statistics &amp; numerical data ; *Consensus Development Conferences as Topic ; Humans ; Oxepins/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {In November 2002, an advisory board meeting was convened by Novartis Pharma to provide recommendations and rationale for clinical trials designed to evaluate new treatments, such as TCH346, for amyotrophic lateral sclerosis (ALS). In terms of selecting appropriate outcome measures, the panel recommended the use of the ALS Functional Rating Scale (ALSFRS-R) to measure primary endpoints. A review of other key issues in this area including regional variations in the epidemiology, diagnosis and management of ALS, defining patient populations and doses of trial medication, and accommodating the likelihood of co-medication with pre-existing treatment in trial design, are discussed.}, }
@article {pmid15204009, year = {2004}, author = {Heffernan, C and Jenkinson, C and Holmes, T and Feder, G and Kupfer, R and Leigh, PN and McGowan, S and Rio, A and Sidhu, P}, title = {Nutritional management in MND/ALS patients: an evidence based review.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {2}, pages = {72-83}, doi = {10.1080/14660820410020349}, pmid = {15204009}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/diet therapy/*therapy ; Animals ; Deglutition Disorders/diet therapy/therapy ; Enteral Nutrition/methods/standards ; Evidence-Based Medicine/*methods/standards ; Humans ; Practice Guidelines as Topic/standards ; }, }
@article {pmid15204008, year = {2004}, author = {Bourke, SC and Gibson, GJ}, title = {Non-invasive ventilation in ALS: current practice and future role.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {2}, pages = {67-71}, doi = {10.1080/14660820410020330}, pmid = {15204008}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/mortality/physiopathology/*therapy ; Forecasting ; Humans ; Respiration, Artificial/ethics/*methods ; }, }
@article {pmid15197603, year = {2004}, author = {Beghi, E and Mennini, T and , }, title = {Basic and clinical research on amyotrophic lateral sclerosis and other motor neuron disorders in Italy: recent findings and achievements from a network of laboratories.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {25 Suppl 2}, number = {}, pages = {S41-60}, doi = {10.1007/s10072-004-0228-1}, pmid = {15197603}, issn = {1590-1874}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/epidemiology/*genetics ; Animals ; Central Nervous System/*enzymology/pathology/physiopathology ; Disease Models, Animal ; Humans ; Incidence ; Italy ; Motor Neurons/*enzymology/pathology ; Neurology/trends ; Neurosciences/trends ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {An Italian collaborative group on motor neuron disorders, including amyotrophic lateral sclerosis (ALS) and its variants, has been recently created, combining various academic groups and laboratories involved in basic and clinical research. The aim is to exploit all the specific expertise and combine efforts at a national level to better understand and fight these fatal diseases. This review summarizes the achievements of the different groups and outlines prospects for future research. Basic research deals with the etiopathogenesis of motor neuron diseases. In vitro and in vivo models of superoxide dismutase 1 (SOD1) mutations are used to investigate the mechanisms of motor neuron death associated with this gene defect. The role of excitotoxicity, immune response, intracellular aggregates and mitochondrial alterations is studied with an integrated approach, at the molecular and cellular levels. Transgenic mice carrying the human mutated SOD1, and the wobbler mouse, a spontaneous model for motor neuron degeneration, offer unique opportunities for testing new therapies in vivo related or not to SOD1 mutations. Clinical research has focused mostly on the incidence and determinants of ALS in several areas of Italy. The incidence of the disease is now among the highest according to the results of population-based regional registries. Compared to earlier studies, more recent Italian investigations show an increase in the incidence and mortality related to ALS. Findings on the role of environmental risk factors are inconsistent. Methodological issues have also been raised by Italian groups regarding the diagnosis and treatment. The validity of the El Escorial diagnostic classification has been questioned where investigators and carers have not received formal training. Pitfalls and methodological drawbacks of randomized clinical trials have been highlighted based on the results of collaborative trials by Italian investigators. Information is now available on non-pharmacological treatments and palliative care, and the economic aspects and quality of life of ALS patients are being investigated.}, }
@article {pmid15177192, year = {2004}, author = {Lambrechts, D and Storkebaum, E and Carmeliet, P}, title = {VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS?.}, journal = {Trends in molecular medicine}, volume = {10}, number = {6}, pages = {275-282}, doi = {10.1016/j.molmed.2004.04.004}, pmid = {15177192}, issn = {1471-4914}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Genetic Predisposition to Disease ; Humans ; Mice ; Mice, Knockout ; Motor Neurons/metabolism/*pathology ; Neuroprotective Agents/metabolism ; Risk Factors ; Vascular Endothelial Growth Factor A/*deficiency/genetics ; }, abstract = {Since Charcot recognized the devastating disorder amyotrophic lateral sclerosis (ALS) in 1874, many theories have been proposed to explain its pathogenesis, but it remains as deadly and incurable as ever. Three years ago it was reported that reduced levels of vascular endothelial growth factor (VEGF) caused ALS-like motoneuron degeneration in mice. Recent evidence indicates that insufficient VEGF is also a risk factor for ALS in humans. Although VEGF was once considered to be only a specific angiogenic factor, emerging evidence indicates that it also displays important neuroprotective activity. These insights have primed widespread interest in developing VEGF-based therapies for (moto)neuron degenerative disorders, raising new hope for the treatment of ALS and other neurodegenerative diseases.}, }
@article {pmid15163105, year = {2004}, author = {Mattson, MP}, title = {Infectious agents and age-related neurodegenerative disorders.}, journal = {Ageing research reviews}, volume = {3}, number = {1}, pages = {105-120}, pmid = {15163105}, issn = {1568-1637}, mesh = {*Aging/genetics/immunology/metabolism ; Central Nervous System Infections/genetics/immunology/*virology ; Humans ; Neurodegenerative Diseases/genetics/immunology/*virology ; }, abstract = {chlamdAs with other organ systems, the vulnerability of the nervous system to infectious agents increases with aging. Several different infectious agents can cause neurodegenerative conditions, with prominent examples being human immunodeficiency virus (HIV-1) dementia and prion disorders. Such infections of the central nervous system (CNS) typically have a relatively long incubation period and a chronic progressive course, and are therefore increasing in frequency as more people live longer. Infectious agents may enter the central nervous system in infected migratory macrophages, by transcytosis across blood-brain barrier cells or by intraneuronal transfer from peripheral nerves. Synapses and lipid rafts are important sites at which infectious agents may enter neurons and/or exert their cytotoxic effects. Recent findings suggest the possibility that infectious agents may increase the risk of common age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and stroke. While scenarios can be envisioned whereby viruses such as Chlamydia pneumoniae, herpes simplex and influenza promote damage to neurons during aging, there is no conclusive evidence for a major role of these pathogens in neurodegenerative disorders. In the case of stroke, blood vessels may be adversely affected by bacteria or viruses resulting in atherosclerosis.}, }
@article {pmid15152464, year = {2003}, author = {Fukunaga, H}, title = {[Intractable neurological diseases and neurology].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {43}, number = {11}, pages = {785-787}, pmid = {15152464}, issn = {0009-918X}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/therapy ; Chronic Disease ; *Home Care Services/economics/statistics &amp; numerical data ; Home Health Aides ; Humans ; Insurance, Long-Term Care ; Japan/epidemiology ; *Long-Term Care/economics/statistics &amp; numerical data ; Neurodegenerative Diseases/economics/*rehabilitation/therapy ; Quality of Life ; Suction ; }, abstract = {In intractable neurological diseases, there are often no appropriate treatment methods even after admission and the course is frequently chronic. Therefore treatment at home is a major choice. In particular, in Parkinson's disease and amyotrophic lateral sclerosis, care at home while symptoms are stable is appropriate in terms of extension of ADL and the QOL of the patient and family. We have performed continuous treatment at home according to our plan for the previous 9 years. This treatment was favorably accepted by the patient and family without major problems. It is important to organize network to support patient with intractable neurological diseases. By virtue of the care insurance system established in 2000, services of medical care, health and welfare are being collectively provided at present. But, there still remain many issues awaiting solution on the support to advanced intractable neurological diseases. A pending problem about suction of sputa for the ALS patients serving at home are being allowed to non-medical profession like home helper.}, }
@article {pmid15152463, year = {2003}, author = {Nagoshi, K}, title = {[Neurological disease in measures against intractable diseases in Japan].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {43}, number = {11}, pages = {783-784}, pmid = {15152463}, issn = {0009-918X}, mesh = {Delivery of Health Care ; *Health Care Reform/organization &amp; administration ; Insurance, Long-Term Care ; Japan ; Neurodegenerative Diseases/economics/*rehabilitation/therapy ; Quality of Life ; }, abstract = {Japan has been taking measures to cope with intractable diseases centering on five principles: "promoting investigation and research", "providing medical care facilities", "reducing co-payment for medical costs", "improving and coordinating community-based health care", "medical care and welfare services", and "promoting welfare measures aimed at improving the quality of life (QOL)". As the object of measures, 118 diseases including serious neurological diseases (e.g. ALS, CJD, PD etc.) have been specified. Thirty years have passed since the specific diseases treatment research program was launched, during which the environment surrounding intractable diseases has changed significantly. In light of this, "Committee on Measures Against Intractable Diseases" was organized in Sept 2001 under the Health Science Council. Based on the interim report of the committee, the government is going to take new measures against the intractable diseases.}, }
@article {pmid15152452, year = {2003}, author = {Hirano, A}, title = {[Changes in neurological diseases during the last half century. Neuropathological view point].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {43}, number = {11}, pages = {732-737}, pmid = {15152452}, issn = {0009-918X}, mesh = {Acquired Immunodeficiency Syndrome/history/*pathology ; Amyotrophic Lateral Sclerosis/epidemiology/history/*pathology ; Central Nervous System/*pathology ; Dementia/epidemiology/history/*pathology ; Female ; Guam/epidemiology ; History, 20th Century ; Humans ; Male ; Parkinson Disease/epidemiology/history/*pathology ; }, abstract = {Environmental changes are intensifying at an increasing tempo along with the advance of civilization. The appearance change and disappearance of certain diseases are remarkable. The author has been studying the neuropathology of fatal neurodegenerative diseases endemic to the native Chamorro population on Guam during the last half century. During this time, significant advances in scientific technology, such as electron microscopy, immunohistochemistry and molecular biology has contributed to an impressive development of neuropathology. Many new findings have been discovered allowing delineation of additional disease entities. In addition, many new neurological disorders have appeared. This communication reviews clinicopathology of amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam as well as improvement of the nervous system as a complication of AIDS studied at Montefiore Medical Center in New York.}, }
@article {pmid15147078, year = {2004}, author = {Siniscalchi, A}, title = {[Tolerability of riluzole: a review of the literature].}, journal = {La Clinica terapeutica}, volume = {155}, number = {1}, pages = {25-28}, pmid = {15147078}, issn = {0009-9074}, mesh = {Excitatory Amino Acid Antagonists/*adverse effects/pharmacokinetics ; Humans ; Riluzole/*adverse effects/pharmacokinetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with the fatal evolution. Recent studies in knowledge of the pathogenic mechanisms underlying ALS showed that the excitotoxicity has an important role in the neurodegeneration. The riluzole, an antagonist of glutamate, is the first drug approved by FDA for the treatment of patients with ALS. The efficacy of riluzole (dose recommended 50 mg twice a day) in prolonging the survival of patients with ALS has been demostrated in two principal controlled clinical trials. The most frequent adverse events related to riluzole treatment were: nausea, vomiting, anorexia, diarrhea, asthenia, somnolence, vertigo, circumoral paresthesia, abdominal pain and dizziness. Some events tend to be related to the dose: vertigo, diarrhea, nausea, circumoral paresthesia and anorexia appear more frequently with 200 mg/die that with lower dose. Generally with tree months from the beginning of the treatment with riluzole, an increase serum transaminase levels has been noted; mostly transient and regressing after two-sex months of treatment. A monitoring of serum transaminase levels is suggested during the first year of treatment with riluzole The clinical studies shows that the adverse events produced by riluzole are mostly reversible and dose-dependent, this demostrates a satifying profile of tolerability of the drug. Anyway, a deeper knowledge of its tolerability may lead us to a better use of riluzole, avoiding in this way the interruption of treatment.}, }
@article {pmid15139588, year = {2004}, author = {Ikeda, K and Tsuchiya, K}, title = {Motor neuron disease group accompanied by inclusions of unidentified protein signaled by ubiquitin.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {24}, number = {2}, pages = {117-124}, doi = {10.1111/j.1440-1789.2003.00537.x}, pmid = {15139588}, issn = {0919-6544}, mesh = {Brain/metabolism/*pathology ; Humans ; Inclusion Bodies/*metabolism ; Motor Neuron Disease/metabolism/*pathology ; Ubiquitin/*metabolism ; }, abstract = {Peculiar tau-negative, ubiquitin-positive inclusions appear in dementia with ALS (ALS-D), the majority of lobar atrophy (Pick's disease) without Pick body and a small portion of ALS. Another common neuropathological lesion in these diseases is the motor neuron involvement with the degenerative processes. The lower motor neuron is predominantly involved in ALS and ALS-D the upper motor neuron is predominantly involved, but in varying degrees in a considerable number of patients with lobar atrophy that lack Pick bodies. There are, however, some points that have yet to be elucidated. The boundary between these diseases is not always clear and a significant number of cases are considered to be the transitional form. Lobar atrophy without Pick body seems to be a heterogeneous disease group. The nature of ubiquitin inclusions also needs to be clarified. Nevertheless, we postulate that these diseases are grouped with the concept of motor neuron disease-inclusion dementia.}, }
@article {pmid15135890, year = {2004}, author = {Cheung, ZH and Ip, NY}, title = {Cdk5: mediator of neuronal death and survival.}, journal = {Neuroscience letters}, volume = {361}, number = {1-3}, pages = {47-51}, doi = {10.1016/j.neulet.2003.12.117}, pmid = {15135890}, issn = {0304-3940}, mesh = {Animals ; Cell Death/genetics ; Cell Survival/genetics ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/genetics/*metabolism ; Humans ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/*enzymology/genetics/physiopathology ; Neurons/enzymology/*metabolism ; Oncogene Proteins v-erbB/genetics/metabolism ; Proto-Oncogene Proteins c-jun/genetics/metabolism ; Signal Transduction/genetics ; }, abstract = {Cdk5 (cyclin-dependent kinase 5) is a serine/threonine kinase implicated to play pivotal roles in neuronal development. Recently, its potential involvement as a regulator of neuronal death and survival has attracted considerable interests. Importantly, increasing evidence has linked Cdk5 to the etiopathology of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we summarize the recent findings on Cdk5 not only as an important participant in neuronal death, but also a key player in neuronal survival. Elucidating the mechanisms of regulation of Cdk5 and its downstream signaling might prove to be crucial in the therapeutic treatment of neurodegenerative diseases.}, }
@article {pmid15135171, year = {2004}, author = {Zhang, H and Andrekopoulos, C and Joseph, J and Crow, J and Kalyanaraman, B}, title = {The carbonate radical anion-induced covalent aggregation of human copper, zinc superoxide dismutase, and alpha-synuclein: intermediacy of tryptophan- and tyrosine-derived oxidation products.}, journal = {Free radical biology &amp; medicine}, volume = {36}, number = {11}, pages = {1355-1365}, doi = {10.1016/j.freeradbiomed.2004.02.038}, pmid = {15135171}, issn = {0891-5849}, support = {NS40494/NS/NINDS NIH HHS/United States ; }, mesh = {Carbonates/*chemistry ; *Free Radicals ; Humans ; Monophenol Monooxygenase/*chemistry ; Nerve Tissue Proteins/*chemistry ; Oxidation-Reduction ; Superoxide Dismutase/*chemistry ; Synucleins ; Tryptophan/*chemistry ; alpha-Synuclein ; }, abstract = {In this review, we describe the free radical mechanism of covalent aggregation of human copper, zinc superoxide dismutase (hSOD1). Bicarbonate anion (HCO3-) enhances the covalent aggregation of hSOD1 mediated by the SOD1 peroxidase-dependent formation of carbonate radical anion (CO3*-), a potent and selective oxidant. This species presumably diffuses out the active site of hSOD1 and reacts with tryptophan residue located on the surface of hSOD1. The oxidative degradation of tryptophan to kynurenine and N-formyl kynurenine results in the covalent crosslinking and aggregation of hSOD1. Implications of oxidant-mediated aggregation of hSOD1 in the increased cytotoxicity of motor neurons in amyotrophic lateral sclerosis are discussed.}, }
@article {pmid15134689, year = {2004}, author = {Ziemann, U and Eisen, A}, title = {TMS for ALS: why and why not.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {115}, number = {6}, pages = {1237-1238}, doi = {10.1016/j.clinph.2004.02.008}, pmid = {15134689}, issn = {1388-2457}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Brain/*physiology ; *Electric Stimulation Therapy ; Humans ; *Magnetics ; }, }
@article {pmid15119987, year = {2004}, author = {Piazza, O and Sirén, AL and Ehrenreich, H}, title = {Soccer, neurotrauma and amyotrophic lateral sclerosis: is there a connection?.}, journal = {Current medical research and opinion}, volume = {20}, number = {4}, pages = {505-508}, doi = {10.1185/030079904125003296}, pmid = {15119987}, issn = {0300-7995}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Animals ; Brain Injuries/*complications ; Humans ; Mutation ; Risk Factors ; Soccer/*injuries ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Trauma has long been hypothesized but never proven to be a risk factor for amyotrophic lateral sclerosis (ALS). This hypothesis may now have a renaissance due to recent reports in the lay press on 'the Italian motoneuron mystery', i.e. the disclosure of 33 diagnosed ALS cases in a subpopulation of 24000 soccer players of the top three Italian divisions from the 1960s to 1996. Could the repetitive brain trauma that soccer players experience for controlling and advancing the ball with their heads represent an environmental risk factor for developing ALS in genetically predisposed individuals? By critically reviewing the scarce literature and 'surrounding evidence' (Medline, CDC, lay press, Italian health officials), we have looked for a potential relationship between (1) soccer and head trauma and (2) head trauma and subsequent development of amyotrophic lateral sclerosis. Whereas the brain traumatizing effect of soccer seems to be out of the question, the findings of the few retrospective studies on ALS and neurotrauma are conflicting. Taken together, however, the literature would still support the concept of soccer, head trauma, and ALS being interrelated, with high levels of athleticism/physical activity perhaps playing an additive part. To further clarify this issue, extensive prospective epidemiological investigations on ALS following neurotrauma as well as carefully designed animal studies will have to be conducted.}, }
@article {pmid15111001, year = {2004}, author = {Boillée, S and Cleveland, DW}, title = {Gene therapy for ALS delivers.}, journal = {Trends in neurosciences}, volume = {27}, number = {5}, pages = {235-238}, doi = {10.1016/j.tins.2004.03.002}, pmid = {15111001}, issn = {0166-2236}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic ; Dependovirus ; Disease Models, Animal ; Genetic Therapy/*methods ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Somatomedins/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that kills motor neurons. Despite a long disappointing history of human trials with neurotrophins, including insulin-like growth factor 1 (IGF-1), Kaspar and colleagues have successfully slowed disease in transgenic ALS mice by forcing motor neurons to produce IGF-1 following retrograde delivery of recombinant adeno-associated virus (AAV) injected into muscle. With the clinical safety of both IGF-1 and AAV already established, this provides real hope for an effective treatment of ALS.}, }
@article {pmid15105254, year = {2004}, author = {Mattson, MP}, title = {Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders.}, journal = {Annals of the New York Academy of Sciences}, volume = {1012}, number = {}, pages = {37-50}, doi = {10.1196/annals.1306.004}, pmid = {15105254}, issn = {0077-8923}, mesh = {Alzheimer Disease/metabolism/physiopathology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Copper/metabolism ; Humans ; Huntington Disease/metabolism/physiopathology ; Iron, Dietary/metabolism ; Lipid Peroxidation/*physiology ; Membrane Proteins/*metabolism ; Metals/*metabolism ; Neurodegenerative Diseases/*metabolism/physiopathology ; Neurons/physiology ; Oxidative Stress/physiology ; Parkinson Disease/metabolism/physiopathology ; Signal Transduction/*physiology ; Stroke/metabolism/physiopathology ; }, abstract = {Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.}, }
@article {pmid15102560, year = {2004}, author = {Weiss, MD and Weydt, P and Carter, GT}, title = {Current pharmacological management of amyotrophic [corrected] lateral sclerosis and a role for rational polypharmacy.}, journal = {Expert opinion on pharmacotherapy}, volume = {5}, number = {4}, pages = {735-746}, doi = {10.1517/14656566.5.4.735}, pmid = {15102560}, issn = {1465-6566}, support = {HB133B98008/HB/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/therapeutic use ; Antioxidants/administration &amp; dosage/therapeutic use ; Apoptosis/drug effects ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Delivery Systems ; Excitatory Amino Acid Antagonists/administration &amp; dosage/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Nerve Growth Factors/administration &amp; dosage/therapeutic use ; *Polypharmacy ; }, abstract = {Amyotrophic [corrected] lateral sclerosis (ALS) is a progressive degenerative condition of motor neurons that is ultimately fatal. Even though scientific discovery over the past few decades has led to a greater understanding of the pathogenic mechanisms of ALS, effective pharmacotherapy intended to slow, arrest or reverse the disease progression remains difficult to obtain. Riluzole, a drug that has only modest benefit in extending survival, is still the only medication approved by the FDA for the treatment of ALS. However, a number of pharmacological agents are currently being investigated as potential therapy for ALS. This paper will review the pathophysiology of ALS and current pharmacological management of the disease and recent directions in research and clinical trials. Based on the available data, it is our opinion that combination drug therapies should be considered for future clinical trials.}, }
@article {pmid15096702, year = {2004}, author = {Facheris, M and Beretta, S and Ferrarese, C}, title = {Peripheral markers of oxidative stress and excitotoxicity in neurodegenerative disorders: tools for diagnosis and therapy?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {6}, number = {2}, pages = {177-184}, doi = {10.3233/jad-2004-6210}, pmid = {15096702}, issn = {1387-2877}, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Lipid Peroxidation/physiology ; *Neurodegenerative Diseases/diagnosis/physiopathology/therapy ; Oxidative Stress/*physiology ; Parkinson Disease/physiopathology ; Reactive Oxygen Species ; }, abstract = {Oxidative stress has been implicated as a common pathogenetic mechanism in neurodegenerative disorders. Central nervous system is particularly exposed to free radical injury, given its high metal content, which can catalyze the formation of oxygen free radicals, and the relatively low content of antioxidant defenses. Indeed, several studies show markers of oxidative damage - lipid peroxidation, protein oxidation, DNA oxidation and glycoxidation markers - in brain areas affected by neurodegenerative disorders. Oxidative stress damage is intimately linked to glutamate neurotoxicity - known as "excitotoxicity". An excessive concentration of extracellular glutamate over-activates ionotropic glutamate receptors, resulting in intracellular calcium overload and a cascade of events leading to neural cell death. In this study we reviewed pathogenetic mechanisms that link oxidative stress and excitotoxicity in three neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) and described peripheral markers of these mechanisms, that may be analyzed in patients as possible diagnostic and therapeutic tools.}, }
@article {pmid15096698, year = {2004}, author = {Mhatre, M and Floyd, RA and Hensley, K}, title = {Oxidative stress and neuroinflammation in Alzheimer's disease and amyotrophic lateral sclerosis: common links and potential therapeutic targets.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {6}, number = {2}, pages = {147-157}, doi = {10.3233/jad-2004-6206}, pmid = {15096698}, issn = {1387-2877}, support = {R03 AG20783-01/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism/*pathology/*prevention &amp; control ; Amyotrophic Lateral Sclerosis/metabolism/*pathology/*therapy ; Arachidonic Acid/metabolism ; Cyclooxygenase 2 ; Humans ; Isoenzymes/*antagonists &amp; inhibitors ; Lipoxygenase/metabolism ; Membrane Proteins ; Microglia/metabolism/pathology ; Nerve Degeneration/metabolism/pathology ; Neurons/*pathology ; Oxidative Stress/*physiology ; Prostaglandin-Endoperoxide Synthases ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Many neurological diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), are now recognized to share atypical inflammatory reactions as a major pathological feature. Neuroinflammation can both be a cause, and a consequence, of chronic oxidative stress. Cytokine-stimulated microglia generate copious amounts of reactive oxygen and reactive nitrogen species, creating a stress upon ambient neurons. Conversely, oxidants can stimulate pro-inflammatory gene transcription in glia, leading to various inflammatory reactions. This review compares literature regarding neuroinflammation in AD and ALS, with special emphasis on roles played by tumor necrosis factor alpha (TNFalpha) and aberrant arachidonic acid metabolism in the genesis of chronic oxidative conditions. Based on our observations made in the G93A-SOD1 mouse model of ALS, and a body of Alzheimer's disease findings, we hypothesize a prominent pathological role for the TNFalpha-signaling axis and neuroinflammation in the pathogenesis of both diseases. A discussion is made regarding the relevance of neuroinflammation to potential therapeutic implications for both ALS and AD.}, }
@article {pmid15083302, year = {2004}, author = {Veldink, JH and Van den Berg, LH and Wokke, JH}, title = {The future of motor neuron disease: the challenge is in the genes.}, journal = {Journal of neurology}, volume = {251}, number = {4}, pages = {491-500}, doi = {10.1007/s00415-004-0322-6}, pmid = {15083302}, issn = {0340-5354}, mesh = {Forecasting ; Genomics/*methods/*trends ; Humans ; Motor Neuron Disease/classification/diagnosis/*genetics/*therapy ; }, abstract = {Adult-onset motor neuron disease (MND) includes sporadic and familial forms of amyotrophic lateral sclerosis (ALS), lower motor neuron disease including progressive and segmental spinal muscular atrophy (LMND) and primary lateral sclerosis (PLS). ALS/MND can be considered to be a spectrum of neurodegenerative diseases characterised by a preferential degeneration of upper and/or lower motor neurons. ALS and LMND have a complex multifactorial aetiology and a large clinical variability. This combination warrants an increasing genomics approach in future research. Genomics is the structural and functional study of genomes--i. e. the complete set of chromosomes and the genes they contain. Several methods may help to understand gene functions, and every method has led to its own "omics". The study of the complex relationship between on the one hand genomics data, transcriptomics data, proteomics data, and interactomics data and on the other hand the phenotype, is called "phenomics". In phenomics, the extensive and detailed phenotyping by the clinician is a prerequisite for meaningful associations. As a consequence, in ALS/MND clinicians have the task to agree about different clinical subtypes in order to make these associations and hence to gain further insight into the complex pathogenesis and identification of diagnostic markers in ALS/MND. Also, several new approaches in the treatment of ALS/MND are here discussed, including the viral delivery of protective compounds, RNA-interference, and stem cell therapy. Further, we argue that a future challenge is to allow for patients to have early access to multidisciplinary centres with specialist knowledge of ALS/MND. These centres can apply specific models of care for people with ALS/MND, but must be designed in a patient-centred format. Ultimately, these models should be assessed according to their outcomes.}, }
@article {pmid15081582, year = {2004}, author = {Consilvio, C and Vincent, AM and Feldman, EL}, title = {Neuroinflammation, COX-2, and ALS--a dual role?.}, journal = {Experimental neurology}, volume = {187}, number = {1}, pages = {1-10}, doi = {10.1016/j.expneurol.2003.12.009}, pmid = {15081582}, issn = {0014-4886}, support = {NS36778/NS/NINDS NIH HHS/United States ; NS38849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/immunology/*metabolism ; Animals ; Apoptosis/physiology ; Cyclooxygenase 2 ; Humans ; Isoenzymes/*metabolism ; Membrane Proteins ; Neuritis/immunology/*metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Prostaglandins/metabolism ; }, abstract = {Although the root cause of many neurodegenerative diseases is unknown, neuroinflammation may play a key role in these types of disease, including amyotrophic lateral sclerosis (ALS). In the context of neurodegeneration, it is unclear if the disease is propagated through inflammation, or whether in contrast, evidence of inflammation reflects an attempt to protect against further cellular injury. Inflammatory pathways involving the cyclooxygenase (COX) enzymes and subsequent generation of prostaglandins are potential target sites for treatments to halt the progression of ALS. In the CNS, COX enzymes are localized to neurons, astrocytes, and microglia and can be induced under various conditions. In addition, there appears to be a dual role for the prostaglandin products of COX enzymes in the nervous system. Some prostaglandins promote the survival of neurons, while others promote apoptosis. In this review, the pathways of COX activity and prostaglandin production form the center of the debate regarding the dual nature of neuroinflammation. We will also discuss how this duality may affect future treatments for neurodegenerative diseases such as ALS.}, }
@article {pmid15072637, year = {2004}, author = {Gordon, T and Hegedus, J and Tam, SL}, title = {Adaptive and maladaptive motor axonal sprouting in aging and motoneuron disease.}, journal = {Neurological research}, volume = {26}, number = {2}, pages = {174-185}, doi = {10.1179/016164104225013806}, pmid = {15072637}, issn = {0161-6412}, mesh = {Adaptation, Physiological/*physiology ; Aging/*physiology ; Animals ; Axons/*physiology ; Humans ; Motor Neuron Disease/*physiopathology/therapy ; Oxidative Stress/physiology ; }, abstract = {Motor unit (MU) enlargement by sprouting is an important compensatory mechanism for loss of functional MUs during normal aging and neuromuscular disease. Perisynaptic Schwann cells at neuromuscular junctions extend processes that bridge between denervated and reinnervated endplates, and guide axonal sprouts to reinnervate the denervated endplates. In a rat model of partial denervation, high levels of daily neuromuscular activity have been shown to inhibit the outgrowth of sprouts by preventing Schwann cell bridging. In this review, we consider (1) the relative roles of increasing levels of oxidative stress and neuromuscular activity to the destabilization of neuromuscular junctions with age and disease, and (2) how a progressive increase in the neuromuscular activity of declining numbers of functional MUs contributes to the progressive failure of adaptive sprouting and, in turn, to the progressive muscle weakness in the motoneuron diseases of post-polio syndrome and amyotrophic lateral sclerosis. We conclude that there is a time-related progression of MU loss, adaptive sprouting followed by maladaptive sprouting, and continuing recession of terminals during normal aging. The progression is accelerated in motoneuron disease, progressing more rapidly in the post-polio syndrome after prolonged denervation and extremely rapidly in ALS.}, }
@article {pmid15068700, year = {2004}, author = {Cova, L and Ratti, A and Volta, M and Fogh, I and Cardin, V and Corbo, M and Silani, V}, title = {Stem cell therapy for neurodegenerative diseases: the issue of transdifferentiation.}, journal = {Stem cells and development}, volume = {13}, number = {1}, pages = {121-131}, doi = {10.1089/154732804773099326}, pmid = {15068700}, issn = {1547-3287}, mesh = {Animals ; *Cell Differentiation ; Cell Division ; Cell Fusion ; Humans ; Nerve Growth Factors/metabolism ; Neurodegenerative Diseases/*therapy ; Stem Cell Transplantation/*methods ; Stem Cells/*cytology ; }, abstract = {In the past few years research on stem cells has exploded as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several events such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation (adult cell acquisition of new unexpected identities) may explain therapeutic success, in addition to replacement of lost cells. This issue needs to be clarified further to maximize the potential for effective therapies. Preliminary stem transplantation trials have already been performed for some neurodegenerative diseases. There is no effective pharmacological treatment for amyotrophic lateral sclerosis, but recent preliminary data both in experimental and clinical settings have targeted it as an ideal candidate disease for the development of stem cell therapy in humans. This review summarizes recent advances gained in stem cell research applied to neurodegenerative diseases with a special emphasis to the criticisms put forward.}, }
@article {pmid15062777, year = {2004}, author = {Miller, AF}, title = {Superoxide dismutases: active sites that save, but a protein that kills.}, journal = {Current opinion in chemical biology}, volume = {8}, number = {2}, pages = {162-168}, doi = {10.1016/j.cbpa.2004.02.011}, pmid = {15062777}, issn = {1367-5931}, mesh = {Binding Sites ; Oxidative Stress ; Structural Homology, Protein ; Superoxide Dismutase/*chemistry/*metabolism ; }, abstract = {Protection from oxidative damage is sufficiently important that biology has evolved three independent enzymes for hastening superoxide dismutation: the Cu- and Zn-containing superoxide dismutases (Cu,Zn-SODs), the SODs that are specific for Fe or Mn or function with either of the two (Fe-SODs, Mn-SODs or Fe/Mn-SODs), and the SODs that use Ni (Ni-SODs). Despite the overwhelming similarities between the active sites of Fe-SOD and Mn-SOD, the mechanisms and redox tuning of these two sites appear to incorporate crucial differences consistent with the differences between Fe3+/2+ and Mn3+/2+. Ni-SOD is revealed by spectroscopy to employ completely different ligation to that of the other SODs while nonetheless incorporating a device also found in Cu,Zn-SOD. Finally, the protein of human Cu,Zn-SOD appears to be an important contributor to the development of amyotrophic lateral sclerosis, possibly because of its propensity for extended beta-sheet formation.}, }
@article {pmid15055923, year = {2004}, author = {Falcão, JP and Sharp, F and Sperandio, V}, title = {Cell-to-cell signaling in intestinal pathogens.}, journal = {Current issues in intestinal microbiology}, volume = {5}, number = {1}, pages = {9-17}, pmid = {15055923}, issn = {1466-531X}, mesh = {Bacterial Proteins/physiology ; Gene Expression Regulation, Bacterial ; Gram-Negative Bacteria/genetics/*growth &amp; development ; Gram-Positive Bacteria/genetics/*growth &amp; development ; Intestines/*microbiology ; *Signal Transduction/*physiology ; }, abstract = {In the conventional view of prokaryotic life, bacteria live a unicellular existence, with responses to external stimuli limited to the detection of chemical and physical signals of environmental origin. This view of bacteriology is now recognized as overly simplistic, because bacteria communicate with each other through small "hormone-like" organic compounds referred to as autoinducers (Als). These bacterial cell-to-cell signaling systems were initially described as mechanisms through which bacteria regulate gene expression via cell density, and, therefore, they have been named quorum sensing. When the Als reach a threshold concentration, they interact with regulatory proteins, thereby driving bacterial gene expression. Bacterial intercellular communication provides a mechanism for the regulation of gene expression resulting in coordinated population behavior. The functions controlled by quorum sensing are varied and reflect the needs of a particular species of bacteria inhabiting a given niche. Quorum sensing-controlled processes include bioluminescence, virulence factor expression, biofilm development, and conjugation among others. Enteric pathogens use quorum sensing to regulate genes involved in virulence, such as motility, and type III secretion. Quorum sensing is utilized to sense the presence of the normal intestinal flora and to warrant successful colonization of the host.}, }
@article {pmid15054949, year = {2004}, author = {van den Berg, LH and van den Berg, JP and Mathus-Vliegen, EM and Kampelmacher, MJ and van Kesteren, RG and Jennekens, FG}, title = {[The symptomatic treatment of amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {148}, number = {11}, pages = {513-518}, pmid = {15054949}, issn = {0028-2162}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*therapy ; Deglutition Disorders/etiology/prevention &amp; control ; Dysarthria/etiology/prevention &amp; control ; Dyspnea/etiology/prevention &amp; control ; Humans ; Muscle Weakness/etiology/prevention &amp; control ; Pain/etiology/prevention &amp; control ; *Palliative Care ; Sialorrhea/etiology/prevention &amp; control ; Weight Loss ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) have symptoms of progressive muscle weakness, of disturbed speech and swallowing, and in the terminal phase those of respiratory weakness. Treatment options, in particular those for excessive weight loss and respiratory weakness, should be introduced to the patients and their families when the patient is emotionally capable and before dysarthria severely hampers communication. Special equipment for keeping the patient as mobile as possible should be made available much earlier than in the case of other diseases of the muscles as in ALS progression is much faster. Cramps, pathological crying or laughter, spasms, and spasticity can all be treated by medication. When speech can no longer be understood, adaptive strategies such as sign language, mime, posture and communication apparatus varying from a note pad to advanced computer systems can be used. Sialorrhoea, caused by difficulty swallowing with its accompanying danger of aspiration can be halted by the use of medication, by radiotherapy and by the injection into the salivary glands of botulin A toxin. Weight loss, also a result of dysphagia, can be avoided by eating frequent small meals or if necessary performing a percutaneous endoscopic or radiological gastroscopy. Excess mucus in the respiratory tract can be treated with anticholinergics. Difficulty in coughing up thick and sticky mucus cannot always be adequately helped. Respiratory weakness is treatable by external respiratory supportive therapy using a nasal mask, as well as invasive respiratory support via a trachcostoma and by treating the symptoms of respiratory weakness. The latter form of treatment is palliative and forms part of terminal care. During the terminal phase restlessness, anxiety, pain, and dyspnoea require the most attention. Treatment requires careful multidisciplinary cooperation.}, }
@article {pmid15038597, year = {2004}, author = {Rossi, L and Lombardo, MF and Ciriolo, MR and Rotilio, G}, title = {Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance.}, journal = {Neurochemical research}, volume = {29}, number = {3}, pages = {493-504}, pmid = {15038597}, issn = {0364-3190}, mesh = {Animals ; Apoptosis ; Copper/deficiency/*metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Myopathies/*metabolism ; Nerve Degeneration/metabolism/pathology ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {Copper is an essential transition metal ion for the function of key metabolic enzymes, but its uncontrolled redox reactivity is source of reactive oxygen species. Therefore a network of transporters strictly controls the trafficking of copper in living systems. Deficit, excess, or aberrant coordination of copper are conditions that may be detrimental, especially for neuronal cells, which are particularly sensitive to oxidative stress. Indeed, the genetic disturbances of copper homeostasis, Menkes' and Wilson's diseases, are associated with neurodegeneration. Furthermore, copper interacts with the proteins that are the hallmarks of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion diseases, and familial amyotrophic lateral sclerosis. In all cases, copper-mediated oxidative stress is linked to mitochondrial dysfunction, which is a common feature of neurodegeneration. In particular we recently demonstrated that in copper deficiency, mitochondrial function is impaired due to decreased activity of cytochrome c oxidase, leading to production of reactive oxygen species, which in turn triggers mitochondria-mediated apoptotic neurodegeneration.}, }
@article {pmid15034853, year = {2004}, author = {Bryant, PR and Geis, CC and Moroz, A and O'neill, BJ and Bogey, RA}, title = {Stroke and neurodegenerative disorders. 4. Neurodegenerative disorders.}, journal = {Archives of physical medicine and rehabilitation}, volume = {85}, number = {3 Suppl 1}, pages = {S21-33}, doi = {10.1053/j.apmr.2003.12.007}, pmid = {15034853}, issn = {0003-9993}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Diagnosis, Differential ; Humans ; Multiple Sclerosis/complications/*diagnosis/*therapy ; Parkinson Disease/complications/*diagnosis/*therapy ; }, abstract = {UNLABELLED: This self-directed learning module highlights diagnosis, treatment, and rehabilitation issues in patients with neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease, and amyotrophic lateral sclerosis (ALS). It is part of the study guide on stroke and neurodegenerative disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the differential diagnosis, diagnostic evaluation, medical management, and rehabilitation issues in MS. Similarly, the differential diagnosis treatment and rehabilitation in Parkinson's disease is discussed. Electrodiagnosis, pharmacologic treatment, and rehabilitation options for ALS are also discussed.<br><br>OVERALL ARTICLE OBJECTIVES: To review the differential diagnosis, evaluation, medical treatment, and rehabilitation management of patients with MS, Parkinson's disease, and ALS.}, }
@article {pmid15034484, year = {2004}, author = {Couratier, P and Desport, JC and Antonini, MT and Mabrouk, T and Perna, A and Vincent, F and Melloni, B}, title = {[Review of nutritional and respiratory support in ALS].}, journal = {Revue neurologique}, volume = {160}, number = {2}, pages = {243-250}, doi = {10.1016/s0035-3787(04)70898-x}, pmid = {15034484}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Gastrostomy ; Humans ; Malnutrition/etiology/prevention &amp; control ; *Nutritional Support ; Patient Acceptance of Health Care ; Respiration Disorders/diagnosis/etiology/prevention &amp; control/therapy ; Respiration, Artificial ; *Respiratory Therapy ; Sleep Wake Disorders/etiology/physiopathology ; }, abstract = {During the evolution of amyotrophic lateral sclerosis (ALS), quality of life and survival of patients are related to respiratory and nutritional status. After diagnosis, a multidisciplinary care has to be promptly organized and coordinated by the referring neurologist. The nutritional and respiratory support imply that neurologists know their specific means of evaluation with their sensitivity and sensibility and be able to recognize clinical risk situations. The informations of patients on assisted-ventilation and nutritional support by using gastrostomy may be done early, precisely and trustfully. Well informed patient's choices must be respected. Nutritional and respiratory supports may be based on recommendations established by the American Academy of Neurology. This review will present and discuss their main aspects in patients with ALS.}, }
@article {pmid15034483, year = {2004}, author = {Bruneteau, G and Demeret, S and Meininger, V}, title = {[Physiopathology of ALS: therapeutic approach].}, journal = {Revue neurologique}, volume = {160}, number = {2}, pages = {235-241}, doi = {10.1016/s0035-3787(04)70897-8}, pmid = {15034483}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*physiopathology/therapy ; Animals ; Apoptosis ; Axons/pathology ; Calcium/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Glutamic Acid/metabolism ; Growth Substances/physiology/therapeutic use ; Humans ; Intermediate Filaments/pathology ; Mitochondria, Muscle/physiology ; Motor Neurons/pathology ; Oxidative Stress ; Superoxide Dismutase/genetics ; }, abstract = {The finding in 1993 of a mutation of the copper zinc super oxyde dismutase (SOD1) provides a major breakthrough in the understanding of the etiopathogenic mechanism of amyotrophic lateral sclerosis. Various mechanisms are commonly implied in the motor neurons degeneration. Excitotoxicity and calcium metabolism abnormalities are one of the most frequently confirmed hypotheses. It allowed proposing riluzole which remains the only one drug proved to be active in the disease. The role of growth factors remains controversial and all therapeutic trials performed with these molecules remained negative. Oxidative stress abnormalities are demonstrated by number of studies but their direct therapeutic application remains to be demonstrated. Apoptosis and the role of mitochondria has been definitely confirmed and open a new therapeutic avenue for the next few years.}, }
@article {pmid15034481, year = {2004}, author = {Camu, W}, title = {[Spinal muscular atrophies in the adult].}, journal = {Revue neurologique}, volume = {160}, number = {2}, pages = {225-228}, doi = {10.1016/s0035-3787(04)70895-4}, pmid = {15034481}, issn = {0035-3787}, mesh = {Adult ; Case Management ; Diagnosis, Differential ; Humans ; *Muscular Atrophy, Spinal/classification/diagnosis/genetics ; Prognosis ; Syndrome ; }, abstract = {Spinal muscular atrophies are heterogeneous group. The diagnostic process should be careful to uncover the main differential diagnoses and to identify familial cases. Clinical phenotype is highly variable. In familial ALS cases with SOD1 mutation, the clinical scene may mimic spinal muscular atrophy. A careful questionning and a complete electroneuromyographic exam are warranted to allow the neurologist to choose among more invasive investigations for differential and positive diagnosis such as MRI, nerve or muscle biopsy, genetic analysis.}, }
@article {pmid15031734, year = {2004}, author = {Barnham, KJ and Masters, CL and Bush, AI}, title = {Neurodegenerative diseases and oxidative stress.}, journal = {Nature reviews. Drug discovery}, volume = {3}, number = {3}, pages = {205-214}, doi = {10.1038/nrd1330}, pmid = {15031734}, issn = {1474-1776}, mesh = {Animals ; Antioxidants/therapeutic use ; Clioquinol/therapeutic use ; Homeostasis ; Humans ; Metals/metabolism ; Neurodegenerative Diseases/*etiology/metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism/toxicity ; }, abstract = {Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.}, }
@article {pmid15027066, year = {2004}, author = {Naumann, M and Jost, W}, title = {Botulinum toxin treatment of secretory disorders.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {19 Suppl 8}, number = {}, pages = {S137-41}, doi = {10.1002/mds.20067}, pmid = {15027066}, issn = {0885-3185}, mesh = {Anti-Dyskinesia Agents/*therapeutic use ; Axilla/innervation ; Botulinum Toxins/*therapeutic use ; Hand/innervation ; Humans ; Hyperhidrosis/drug therapy ; Parkinson Disease/drug therapy ; Salivary Gland Diseases/*drug therapy ; Sialorrhea/drug therapy ; }, abstract = {Botulinum neurotoxin serotype A (BoNT/A) has revolutionised the treatment of a variety of autonomic hypersecretory disorders. Several open and controlled studies indicate that BoNT/A is a safe and effective treatment for focal hyperhidrosis of the axillae and palms, for gustatory sweating, and for some other rare conditions associated with focal hyperhidrosis. There is class I evidence for the efficacy of botulinum toxin in axillary hyperhidrosis and class II evidence for palmar hyperhidrosis and gustatory sweating. BoNT/A has the potential to replace current invasive and surgical techniques and should at least be considered as a viable alternative. The results of pilot studies to treat sialorrhea are encouraging. However, the optimal dose, best mode of application, side effects, and duration of BoNT/A action in this condition remain uncertain. We need further formal clinical trials to evaluate risks and benefits of BoNT/A for palliative treatment in of sialorrhea in Parkinson's disease and in bulbar amyotrophic lateral sclerosis. Based on the few reports published, BoNT/A injections into the lacrimal gland for hyperlacrimation may be an elegant method to treat this sometimes disabling condition. Again, larger studies are needed to evaluate the risks and long-term benefits of this treatment option.}, }
@article {pmid15011337, year = {2004}, author = {Kuzuhara, S}, title = {[Amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula of Japan].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {62 Suppl}, number = {}, pages = {141-146}, pmid = {15011337}, issn = {0047-1852}, mesh = {Age of Onset ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology/psychology ; Central Nervous System/pathology ; *Dementia/diagnosis/epidemiology/physiopathology/psychology ; Diagnosis, Differential ; Female ; Humans ; Japan/epidemiology ; Male ; Middle Aged ; *Parkinsonian Disorders/diagnosis/epidemiology/physiopathology/psychology ; Prevalence ; Syndrome ; Tomography, Emission-Computed, Single-Photon ; Tomography, X-Ray Computed ; }, }
@article {pmid15011336, year = {2004}, author = {Okumura, H and Tashiro, K}, title = {[Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {62 Suppl}, number = {}, pages = {136-140}, pmid = {15011336}, issn = {0047-1852}, mesh = {Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/etiology/pathology ; Dementia/*epidemiology/etiology/pathology ; Female ; Guam/epidemiology ; Humans ; Incidence ; Male ; Middle Aged ; Neurofibrillary Tangles/pathology ; Parkinsonian Disorders/*epidemiology/etiology/pathology ; Sex Factors ; Substantia Nigra/pathology ; Syndrome ; Time Factors ; }, }
@article {pmid15009657, year = {2004}, author = {Mandel, S and Weinreb, O and Amit, T and Youdim, MB}, title = {Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {88}, number = {6}, pages = {1555-1569}, doi = {10.1046/j.1471-4159.2003.02291.x}, pmid = {15009657}, issn = {0022-3042}, mesh = {Animals ; Catechin/*analogs &amp; derivatives/*pharmacology ; Flavonoids/*pharmacology ; Humans ; Neurodegenerative Diseases/etiology/metabolism/*prevention &amp; control ; Neuroprotective Agents/*pharmacology ; Phenols/*pharmacology ; Polyphenols ; Signal Transduction/*drug effects/physiology ; *Tea ; }, abstract = {Accumulating evidence supports the hypothesis that brain iron misregulation and oxidative stress (OS), resulting in reactive oxygen species (ROS) generation from H2O2 and inflammatory processes, trigger a cascade of events leading to apoptotic/necrotic cell death in neurodegenerative disorders, such as Parkinson's (PD), Alzheimer's (AD) and Huntington's diseases, and amyotrophic lateral sclerosis (ALS). Thus, novel therapeutic approaches aimed at neutralization of OS-induced neurotoxicity, support the application of ROS scavengers, transition metals (e.g. iron and copper) chelators and non-vitamin natural antioxidant polyphenols, in monotherapy, or as part of antioxidant cocktail formulation for these diseases. Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols, particularly from green tea and blueberries, improve age-related cognitive decline and are neuroprotective in models of PD, AD and cerebral ischemia/reperfusion injuries. However, recent studies indicate that the radical scavenger property of green tea polyphenols is unlikely to be the sole explanation for their neuroprotective capacity and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this article, the currently established mechanisms involved in the beneficial health action and emerging studies concerning the putative novel molecular neuroprotective activity of green tea and its major polyphenol (-)-epigallocatechin-3-gallate (EGCG), will be reviewed and discussed.}, }
@article {pmid14997748, year = {2004}, author = {Kawakami, M and Saji, S and Toi, M}, title = {[Controversies in endocrine therapy for breast cancer].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {31}, number = {2}, pages = {181-187}, pmid = {14997748}, issn = {0385-0684}, mesh = {Anastrozole ; Androstadienes/therapeutic use ; Antineoplastic Agents, Hormonal/*therapeutic use ; *Aromatase Inhibitors ; Breast Neoplasms/*drug therapy/surgery ; Chemotherapy, Adjuvant ; Enzyme Inhibitors/*therapeutic use ; Estrogen Replacement Therapy ; Female ; Humans ; Letrozole ; Mastectomy, Segmental ; Neoplasms, Hormone-Dependent ; Nitriles/therapeutic use ; Postmenopause ; Randomized Controlled Trials as Topic ; Receptors, Estrogen/analysis ; Receptors, Progesterone/analysis ; Risk Factors ; Tamoxifen/therapeutic use ; Triazoles/therapeutic use ; }, abstract = {Major advances have been made in the treatment of postmenopausal women with hormone-sensitive breast cancer. Although tamoxifen has been the standard endocrine therapy for the past twenty years, the development of a third generation of aromatase inhibitors (Als), which effectively inhibit estrogen synthesis in extragonadal sites, gives us a wider range of choices in endocrine therapy. However, many questions remain with respect to the optimal use of Als. Differences between Als and tamoxifen as well as non-steroidal and steroidal Als in their long-term adverse effects on bone demineralization and lipid metabolism are only starting to emerge. The preferable orders for use of non-steroidal and steroidal Als, Als and pure anti-estrogen in patients with metastatic disease are emerging subjects to be examined, following several studies that showed non-cross reactivity between these types of drug. Neo-adjuvant endocrine therapy is now attempting to apply breast conserving surgery in larger numbers of elderly patients who are not suitable for neo-adjuvant chemotherapy. Moreover, many investigators are currently searching for surrogate markers in neo-adjuvant endocrine treatment that can predict the responsiveness and prognosis with adjuvant endocrine therapy. Further research concomitant with clinical trials may lead to a more reliable endocrine therapy modality in the treatment of breast cancer.}, }
@article {pmid14989595, year = {2004}, author = {Peel, AL}, title = {PKR activation in neurodegenerative disease.}, journal = {Journal of neuropathology and experimental neurology}, volume = {63}, number = {2}, pages = {97-105}, doi = {10.1093/jnen/63.2.97}, pmid = {14989595}, issn = {0022-3069}, mesh = {Aging ; Animals ; Apoptosis ; Humans ; NF-kappa B/metabolism ; Neurodegenerative Diseases/*enzymology ; Protein Biosynthesis ; RNA, Double-Stranded/metabolism ; Stress, Physiological/metabolism ; eIF-2 Kinase/genetics/*metabolism ; }, abstract = {Interferon-inducible, double-stranded RNA-dependent protein kinase PKR is well known as an early cellular responder to viral infection. Activation of PKR has been associated with a number of downstream cell stress and cell death events, including a generalized shutdown of protein translation, activation of caspase-8, participation in JNK and p38 MAPK pathways, activation of NF-kappaB, etc. Recently, the activation of PKR has also been described in several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis. Although the relationship between PKR and these diseases is still unclear, the overlap between known functions of PKR and biochemical events that occur in these neuropathologies are discussed here.}, }
@article {pmid14978764, year = {2004}, author = {Tenenbaum, L and Chtarto, A and Lehtonen, E and Velu, T and Brotchi, J and Levivier, M}, title = {Recombinant AAV-mediated gene delivery to the central nervous system.}, journal = {The journal of gene medicine}, volume = {6 Suppl 1}, number = {}, pages = {S212-22}, doi = {10.1002/jgm.506}, pmid = {14978764}, issn = {1099-498X}, mesh = {Animals ; Brain/*metabolism ; *Dependovirus ; Enzymes/genetics/metabolism ; Genetic Engineering ; *Genetic Vectors ; Nervous System Diseases/drug therapy ; *Transduction, Genetic ; Transgenes ; }, abstract = {Various regions of the brain have been successfully transduced by recombinant adeno-associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. In contrast, the use of cellular promoters such as the neuron-specific enolase promoter or hybrid promoters such as the chicken beta-actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV-mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4-mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells. No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection. Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease. Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors.}, }
@article {pmid14978757, year = {2004}, author = {Kremer, EJ}, title = {CAR chasing: canine adenovirus vectors-all bite and no bark?.}, journal = {The journal of gene medicine}, volume = {6 Suppl 1}, number = {}, pages = {S139-51}, doi = {10.1002/jgm.497}, pmid = {14978757}, issn = {1099-498X}, mesh = {Adenovirus Vaccines ; *Adenoviruses, Canine/immunology ; Animals ; Dogs ; Genes, Reporter ; *Genetic Therapy ; *Genetic Vectors/immunology ; Humans ; Mice ; Neurodegenerative Diseases/genetics ; Viral Hepatitis Vaccines/genetics/immunology ; }, abstract = {This review deals primarily with canine adenovirus serotype 2 (CAV-2) vectors and gives a simplified overview of how the various domains of virology, cellular and molecular biology, as well as immunology, come into play when trying to understand and ameliorate adenovirus (Ad)-mediated gene transfer. The generation of early region 1 (E1)-deleted (DeltaE1) CAV-2 vectors, the lack of pre-existing humoral immunity, trafficking, the use of the coxsackie B adenovirus receptor (CAR), the surprising neuronal tropism, and the ability to migrate via axons to afferent regions of the central and peripheral nervous system, are described. Due to these intrinsic properties, CAV-2 vectors may be powerful tools for the study of the pathophysiology and potential treatment of neurodegenerative diseases like lysosomal storage disorders, Parkinson's, Alzheimer's, Huntington's, amyotrophic lateral sclerosis, and others. Other potential uses include anti-tumoral and anti-viral vaccines, tracer of synaptic junctions, pain therapy, cancer therapy (e.g. K9 CRAds), and gene transfer to other somatic tissues.}, }
@article {pmid14978393, year = {2004}, author = {Jafari-Schluep, HF and Khoris, J and Mayeux-Portas, V and Hand, C and Rouleau, G and Camu, W and , }, title = {[Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature].}, journal = {Revue neurologique}, volume = {160}, number = {1}, pages = {44-50}, doi = {10.1016/s0035-3787(04)70846-2}, pmid = {14978393}, issn = {0035-3787}, mesh = {Family ; Genotype ; Humans ; Motor Neuron Disease/enzymology/*genetics ; Phenotype ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {About 20 p. cent of cases of amyotrophic lateral sclerosis are familial (FALS). Fifteen percent of FALS cases are associated with an abnormality in the superoxide dismutase 1 (SOD1) gene. To date, more than 100 different genetic abnormalities have been reported, all except two are autosomal dominant. The clinical characteristics of patients presenting with FALS associated with an SOD1 abnormality is homogeneous when there is no doubt about the hereditary aspect of the genetic abnormality: mean age at onset 42 years, limb onset, slow evolution. Except when present in the setting of a clearly inherited disease (FALS) (several patients through several generations), the causality of a given SOD1 mutation often remains an open question. Consequently, search for SOD1 mutation is not warranted when atypical features such as young age at onset or slow progression are present. Conversely, a complete family study is justified to determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode, and the non-exceptional absence of proven causality for ALS. Specific cases where a frequent SOD1 mutation with a recognized causal effect is recognized (no more than 15 out of more than 90 mutations) would be an exception.}, }
@article {pmid14978392, year = {2004}, author = {Dupuis, L and Muller, A and Meininger, V and Loeffler, JP}, title = {[Molecular mechanisms of amyotrophic lateral sclerosis: recent contributions from studies in animal models].}, journal = {Revue neurologique}, volume = {160}, number = {1}, pages = {35-43}, doi = {10.1016/s0035-3787(04)70845-0}, pmid = {14978392}, issn = {0035-3787}, mesh = {Animals ; Disease Models, Animal ; Humans ; Isoenzymes/genetics ; Mice ; Mice, Transgenic ; Motor Neuron Disease/enzymology/*genetics/pathology ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic Lateral Sclerosis is a neurodegenerative condition defined by loss of both upper and lower motor neurons. The molecular mechanisms underlying this pathology are currently elucidated using transgenic mice lines expressing mutated alleles of the copper-zinc superoxide dismutase, an enzyme mutated in about 2 p. cent of ALS cases. These transgenic mice also provide a valuable animal model to set up new therapeutic tools.}, }
@article {pmid14977568, year = {2004}, author = {Ekshyyan, O and Aw, TY}, title = {Apoptosis in acute and chronic neurological disorders.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {9}, number = {}, pages = {1567-1576}, doi = {10.2741/1357}, pmid = {14977568}, issn = {1093-9946}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-11/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; DK 43785/DK/NIDDK NIH HHS/United States ; }, mesh = {Acute Disease ; Animals ; *Apoptosis ; Brain Ischemia/pathology ; Caspases/metabolism ; Chronic Disease ; Humans ; Mice ; Nervous System Diseases/metabolism/*pathology ; Neurodegenerative Diseases/pathology ; Signal Transduction ; Stroke/pathology ; }, abstract = {Programmed cell death or apoptosis is a physiologically important process in neurogenesis wherein approximately 50% of the neurons apoptose during maturation of the nervous system. However, premature apoptosis and/or aberrations in apoptosis control contribute to the pathogenesis of a variety of neurological disorders including acute brain injury such as trauma, spinal cord injury, ischemic stroke and ischemia/reperfusion as well as chronic disease states such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, spinal muscular atrophy, and diabetic neuropathy. The current review will focus on two major topics, namely, the general concepts of our current understanding of the apoptosis death machinery, its mediators and regulation, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. This knowledge of apoptosis mechanisms will underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.}, }
@article {pmid14974059, year = {2004}, author = {Ashworth, NL and Satkunam, LE and Deforge, D}, title = {Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD004156}, doi = {10.1002/14651858.CD004156.pub2}, pmid = {14974059}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Exercise Therapy ; Humans ; Muscle Spasticity/etiology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Spasticity commonly affects patients with motor neuron disease and it is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life.<br><br>OBJECTIVES: The objective of this review is to systematically review all types of treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (searched January 2003), MEDLINE (January 1966 to January 2003), EMBASE (January 1980 to January 2003), CINAHL (January 1982 to January 2003), AMED (January 1985 to January 2003) and LILACS (January 1982 to January 2003) for randomized controlled trials. We reviewed the bibliographies of the randomized trials identified, and contacted trial authors and known experts in the field.<br><br>SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, serious adverse events, and measures of cost.<br><br>DATA COLLECTION AND ANALYSIS: We identified only one randomized controlled trial that met the inclusion criteria for this review. Two authors extracted the data. We also contacted the author of the paper and obtained further information not available in the published article.<br><br>MAIN RESULTS: The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity (mean reduction of 0.43 Ashworth grades versus an increase of 0.25 in controls), as measured by the Ashworth scale.<br><br>REVIEWER'S CONCLUSIONS: Individualized, moderate intensity, endurance type exercises for the trunk and limbs may help to reduce spasticity in motor neuron disease. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population.}, }
@article {pmid14964446, year = {2003}, author = {Minuto, F and Barreca, A and Melioli, G}, title = {Indirect evidence of hormone abuse. Proof of doping?.}, journal = {Journal of endocrinological investigation}, volume = {26}, number = {9}, pages = {919-923}, pmid = {14964446}, issn = {0391-4097}, mesh = {Antibodies/analysis ; Biomarkers/*analysis ; *Doping in Sports ; Erythropoietin/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Gonadotropins/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Half-Life ; Hematocrit ; Human Growth Hormone/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Humans ; Substance Abuse Detection/*methods ; Time Factors ; }, abstract = {Besides anabolic steroids, the most common performance-enhancing hormones are erythropoietin (EPO), insulin, GH, and gonadotropins, mostly indistinguishable from endogenous hormones and with very short half-life. This makes virtually impossible to demonstrate their use by measuring their concentration in the blood or urine. A possible approach to the problem may lie in in-direct demonstration through detection of the biological effects of these substances. The finding of an increased hematocrit level is suspicious but not clearly demonstrative of EPO abuse. Very high levels of circulating EPO could be associated with a strong suspicion of doping, when associated to other abnormal parameters, such as Ht, sTFRr, EPO, RDW. The presence of antibodies against the polysaccharide fraction of lateral chains of EPO has been observed only in patients treated with rhEPO. Owing to the pulsatile pattern of GH, particularly during physical exercise, pathologically high values may be found in normal subjects. Therefore, as in the case of EPO, evidence of GH abuse can be gathered only indirectly by detecting the biological effects of its administration. In training subjects GH treatment increased GH, IGF-I, IGFBP-3 and ALS, and decreased IGBP-2. After cessation of treatment IGF-I, IGFBP-3 and ALS approached basal values between 49 and 96 h. Also the bone parameters PICP ICIP, PIUP and osteocalcin increased significantly. Four days after cessation of treatment, levels of PIIIP and ICTP were still abnormally elevated. In conclusion, increases in IGF-I, IGFBP-3, ALS, PIIIP and ICTP are all indicative of recent GH abuse or of acromegaly.}, }
@article {pmid14963853, year = {2004}, author = {Bevilacqua, JA and Dellarossa, D and Sinning, M}, title = {[Chiari type I malformation in a patient with bulbar onset amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {38}, number = {3}, pages = {247-249}, pmid = {14963853}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Arnold-Chiari Malformation/*complications/diagnosis ; Bulbar Palsy, Progressive/*complications/diagnosis ; Diagnosis, Differential ; Female ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Spinal Cord Compression/etiology ; }, abstract = {INTRODUCTION: Diagnosis of amyotrophic lateral sclerosis (ALS) requires of the exclusion of several pathologies of the cranio cervical junction that mimic ALS. The importance of such exclusion is in fact sustained by the prognostic implications that ALS has.<br><br>CASE REPORT: We report the case of a 58-year-old woman with bulbar onset sporadic ALS associated with Chiari type I malformation on the MRI of the craniocervical junction. At the time of consultation, ALS was clinically defined but some of the symptoms were contributed by cerebellar amygdala compression of the medulla.<br><br>CONCLUSION: To our knowledge this is the first time were both diseases are reported symptomatic on the same patient, and despite its rarity, it is important to be aware of this possible association for the diagnostic, therapeutic and prognostic implications it has.}, }
@article {pmid14872166, year = {2003}, author = {Bammer, R and Fazekas, F}, title = {Diffusion imaging of the human spinal cord and the vertebral column.}, journal = {Topics in magnetic resonance imaging : TMRI}, volume = {14}, number = {6}, pages = {461-476}, doi = {10.1097/00002142-200312000-00004}, pmid = {14872166}, issn = {0899-3459}, support = {1R01EB002771/EB/NIBIB NIH HHS/United States ; 1R01NS35959/NS/NINDS NIH HHS/United States ; RR-09784/RR/NCRR NIH HHS/United States ; }, mesh = {Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Spinal Cord/*pathology ; Spinal Diseases/*diagnosis ; }, abstract = {During the last decade, diffusion-weighted imaging (DWI) has matured from an experimental tool to a clinically useful modality that has not only significantly impacted the diagnosis of (acute) cerebral stroke but has also shown utility in other abnormalities of the brain. Although DWI should be equally sensitive to changes in the spine, it has been used far less frequently in this region of the body. This is mainly because of the inhomogeneous magnetic environment, the small size of the spinal cord, and increased motion in and around the spine. However, once these limitations are overcome, a whole range of applications can be envisioned. Already now, DWI promises to be able to differentiate between benign and malignant vertebral compression fractures. As in the brain, the immediate reduction of diffusivity following ischemic damage in the spinal cord may provide an early identification of patients with infarction. The study of diffusion anisotropy may open new avenues for the detection and better understanding of damage to the long fiber tracts with important clinical implications for disorders like multiple sclerosis and amyotrophic lateral sclerosis. It may also be possible to address, in a more refined manner, mechanisms of damage such as occur with spondylotic myelopathy. To lay the basis for future research in these areas, we will discuss the most appropriate DWI methods for the spine. Following an overview of the basic principles of DWI and associated pitfalls, the most commonly used imaging methods are addressed. Finally, experimental and clinical applications in the spinal cord and the vertebral column and their clinical relevance thus far are reviewed.}, }
@article {pmid14766406, year = {2004}, author = {Boje, KM}, title = {Nitric oxide neurotoxicity in neurodegenerative diseases.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {9}, number = {}, pages = {763-776}, doi = {10.2741/1268}, pmid = {14766406}, issn = {1093-9946}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism ; Neuroprotective Agents/toxicity ; Neurotoxicity Syndromes ; Nitric Oxide/metabolism/*toxicity ; Reactive Nitrogen Species/*metabolism ; }, abstract = {Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"}, }
@article {pmid14758071, year = {2002}, author = {Horie, H and Kadoya, T}, title = {Galectin-1 plays essential roles in adult mammalian nervous tissues. Roles of oxidized galectin-1.}, journal = {Glycoconjugate journal}, volume = {19}, number = {7-9}, pages = {479-489}, pmid = {14758071}, issn = {0282-0080}, mesh = {Animals ; Galectin 1/chemistry/genetics/*metabolism ; Humans ; Nerve Regeneration ; Nervous System/cytology/*metabolism/pathology ; Nervous System Diseases/metabolism/pathology ; Oxidation-Reduction ; }, abstract = {Previous data have suggested that galectin-1 is expressed widely in nervous tissues at embryonic stages but becomes restricted mainly to peripheral nervous tissues with maturation. Though the expression is intense in adult mammalian peripheral neurons, there had been no report about functions of galectin-1 there. Recently we discovered a factor that enhanced peripheral axonal regeneration. The factor was identified as oxidized galectin-1 with three intramolecular disulfide bonds and showed no lectin activity. Oxidized recombinant human galectin-1 (rhGAL-1/Ox) showed the same nerve growth promoting activity at very low concentrations (pg/ml). rhGAL-1/Ox at similarly low concentration was also effective in in vivo experiments of axonal regeneration. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited the axonal regeneration in vivo as well as in vitro. Since galectin-1 is expressed in the regenerating sciatic nerves as well as in both sensory neurons and motor neurons, these results suggest that galectin-1 is secreted into the extracellular space to be oxidized, and then, in its oxidized form, to regulate initial repair after axotomy. The administration of oxidized galectin-1 effectively promoted functional recovery after sciatic nerve injury in vivo. Oxidized galectin-1, hence, appears to play an important role in promoting axonal regeneration, working as a kind of cytokine, not as a lectin. Recent reports indicated additional roles of cytosolic galectin-1 in neural diseases, such as ALS. Furthermore galectin-1 has been proved to be a downstream target of DeltaFosB. In hippocampus of rat brain, expression of DeltaFosB is induced immediately after ischemia-reperfusion, suggesting that galectin-1 may also play important roles in central nervous system after injury.}, }
@article {pmid14753658, year = {2003}, author = {Kalra, S and Arnold, D}, title = {Neuroimaging in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {4}, pages = {243-248}, doi = {10.1080/14660820310011269}, pmid = {14753658}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Animals ; Brain Mapping ; Diagnosis, Differential ; *Diagnostic Imaging ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Tomography, Emission-Computed ; }, abstract = {Several neuroimaging modalities have been used with varying success to aid the clinical process of establishing the diagnosis of amyotrophic lateral sclerosis (ALS). By demonstrating evidence of occult upper motor neuron degeneration in vivo, a speedier and more definitive diagnosis in suspected cases could lead to earlier treatment and earlier enrollment in clinical trials. Findings compatible with ALS on routine MRI are not consistently found and are non-specific. Thus, routine anatomic imaging is useful in ruling out diseases that mimic ALS, but not in classification of new cases. Functional imaging techniques, such as PET and fMRI, have provided fascinating insights into the cortical functional reorganization that accompanies muscular weakness. PET and SPECT have revealed involvement of regions of the brain beyond the motor cortex, something not well appreciated by pathological examination. Of great need is a surrogate marker of therapeutic efficacy to make drug evaluation more efficient; neuroimaging, and magnetic resonance spectroscopy in particular, holds great promise in this regard in addition to helping us better understand the of neurodegeneration.}, }
@article {pmid14753657, year = {2003}, author = {Agar, J and Durham, H}, title = {Relevance of oxidative injury in the pathogenesis of motor neuron diseases.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {4}, pages = {232-242}, doi = {10.1080/14660820310011278}, pmid = {14753657}, issn = {1466-0822}, mesh = {Animals ; Antioxidants/chemistry/therapeutic use ; Disease Susceptibility ; Homeostasis/drug effects/*physiology ; Humans ; Motor Neuron Disease/drug therapy/metabolism/*physiopathology ; Oxidants/toxicity ; *Oxidative Stress ; Reactive Oxygen Species/metabolism/toxicity ; Superoxides/metabolism ; }, abstract = {Oxidative stress, which results from a complex interplay of pro- and anti-oxidant forces, is generally considered to be the major effector of accumulation of oxidatively modified protein accumulation in cells, although reduced degradation due to impairment of proteolytic activity could also contribute. The discovery that a familial lateral sclerosis (ALS) results from mutations in the gene encoding Cu/Zn superoxide dismutase a anti-oxidant enzyme, stimulated considerable evaluation of reactive oxygen species (ROS) generation and oxidative protein damage in both familial and sporadic forms of the disease. Mutations in SOD1 do not cause disease by compromising dismutating activity, but through some toxic gain of function. Although exacerbation of other copper-catalyzed enzymatic activities has been demonstrated in vitro, there is little evidence substantiating that this property is responsible for toxicity in vivo. Studies of ROS generation and oxidative damage in vivo have produced mixed results, but collectively are consistent with oxidative stress playing a secondary role in pathogenesis of the disease. Studies of post-mortem tissue from sporadic ALS patients has yielded more consistent evidence of accumulation of oxidative damage to proteins, lipids, and DNA, but the time course of accumulation cannot be determined and the initiating causes of the disease have not been identified. The interplay between motor neurons and glial cells is important in the clinical progression of both familial and sporadic motor neuron diseases and release of reactive oxygen and nitrogen species or cytokines from microglia could contribute to the demise of motor neurons. This review describes the general mechanisms of radical-mediated cellular damage followed by the evidence for and against the contribution of oxidative injury to the pathogenesis of motor neuron diseases.}, }
@article {pmid14753656, year = {2003}, author = {Figlewicz, DA and Orrell, RW}, title = {The genetics of motor neuron diseases.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {4}, pages = {225-231}, doi = {10.1080/14660820310011287}, pmid = {14753656}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/classification/genetics ; Animals ; Gangliosidoses, GM2/etiology/genetics ; Hereditary Sensory and Motor Neuropathy/genetics ; Humans ; Motor Neuron Disease/*genetics ; Muscular Atrophy, Spinal/classification/etiology/genetics ; Receptors, Androgen/*genetics ; Trinucleotide Repeats/*genetics ; }, abstract = {Motor neuron diseases may be divided into three categories: those with lower motor neuron involvement--spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA or Kennedy's disease); those with upper motor neuron involvement--primary lateral sclerosis (PLS) and the spastic paraplegias; and those with combined upper and lower motor neuron involvement--amyotrophic lateral sclerosis (ALS). Other familial motor neuron disorders include hereditary neuronopathies, GM2 gangliosidosis, and possibly the ALS/PD syndrome of Guam. The contribution of genetics to the etiopathogenesis of motor neuron considerably, accounting for a high percentage of spinal muscular atrophies, but only a small fraction of cases of ALS. The mode of inheritance also varies, with examples of autosomal dominant (AD), autosomal recessive (AR), or X-linked kindreds. (Tables 1 and 2).}, }
@article {pmid14753655, year = {2003}, author = {Grossman, A and Bradley, W}, title = {Psychosocial factors and cognition in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {4}, pages = {217-224}, doi = {10.1080/14660820310005554}, pmid = {14753655}, issn = {1466-0822}, mesh = {Acquired Immunodeficiency Syndrome/virology ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*psychology ; Chronic Disease/psychology ; Cognition/*physiology ; Cognition Disorders/diagnosis/etiology ; Coronary Disease ; Diagnostic Imaging ; Humans ; Personality ; *Psychology ; }, }
@article {pmid14750543, year = {2003}, author = {Kaufert, J and Koch, T}, title = {Disability or end-of-life? Competing narratives in bioethics.}, journal = {Theoretical medicine and bioethics}, volume = {24}, number = {6}, pages = {459-469}, pmid = {14750543}, issn = {1386-7415}, mesh = {Amyotrophic Lateral Sclerosis ; *Attitude to Death ; Casuistry ; *Disabled Persons ; *Ethics, Clinical ; Euthanasia, Passive/*ethics ; Humans ; *Narration ; *Quality of Life ; Social Perception ; Terminal Care/*ethics ; Ventilators, Mechanical ; }, abstract = {Bioethics, and indeed much ethical writing generally, makes its point through narratives. The religious parable no less than the medical teaching case uses a simple story to describe appropriate action or the application of a critical principle. While powerful, the telling story has limits. In this paper the authors describe a simple teaching case on "end-of-life" decision making that was ill received by its audience. The authors ill-received example, involving the disconnection of ventilation in a patient with ALS (Lou Gherig's Disease) was critiqued by audience members with long-term experience as ventilation users. In this case, the supposedly simple narrative of the presenters conflicted with the life histories of the audience. The lessons of this story, and the conflict that resulted, speak critically to the limits of simple teaching cases as well as the strengths of narrative analysis as a tool for the exploration of bioethical case histories.}, }
@article {pmid14739060, year = {2004}, author = {Emerit, J and Edeas, M and Bricaire, F}, title = {Neurodegenerative diseases and oxidative stress.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {58}, number = {1}, pages = {39-46}, doi = {10.1016/j.biopha.2003.11.004}, pmid = {14739060}, issn = {0753-3322}, mesh = {Animals ; Brain/*metabolism/pathology ; Cell Death/physiology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Oxidative Stress/*physiology ; }, abstract = {Oxidative stress is now recognized as accountable for redox regulation involving reactive oxygen species (ROS) and reactive nitrogen species (RNS). Its role is pivotal for the modulation of critical cellular functions, notably for neurons astrocytes and microglia, such as apoptosis program activation, and ion transport, calcium mobilization, involved in excitotoxicity. Excitotoxicity and apoptosis are the two main causes of neuronal death. The role of mitochondria in apoptosis is crucial. Multiple apoptotic pathways emanate from the mitochondria. The respiratory chain of mitochondria that by oxidative phosphorylation, is the fount of cellular energy, i.e. ATP synthesis, is responsible for most of ROS and notably the first produced, superoxide anion (O(2)(;-)). Mitochondrial dysfunction, i.e. cell energy impairment, apoptosis and overproduction of ROS, is a final common pathogenic mechanism in aging and in neurodegenerative disease such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Nitric oxide (NO(;)), an RNS, which can be produced by three isoforms of NO-synthase in brain, plays a prominent role. The research on the genetics of inherited forms notably ALS, AD, PD, has improved our understanding of the pathobiology of the sporadic forms of neurodegenerative diseases or of aging of the brain. ROS and RNS, i.e. oxidative stress, are not the origin of neuronal death. The cascade of events that leads to neurons, death is complex. In addition to mitochondrial dysfunction (apoptosis), excitotoxicity, oxidative stress (inflammation), the mechanisms from gene to disease involve also protein misfolding leading to aggregates and proteasome dysfunction on ubiquinited material.}, }
@article {pmid14720577, year = {2004}, author = {Greenberg, DA and Jin, K}, title = {VEGF and ALS: the luckiest growth factor?.}, journal = {Trends in molecular medicine}, volume = {10}, number = {1}, pages = {1-3}, doi = {10.1016/j.molmed.2003.11.006}, pmid = {14720577}, issn = {1471-4914}, support = {NS44921/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Apoptosis ; Humans ; Mice ; Neuroprotective Agents/pharmacology ; Signal Transduction ; Vascular Endothelial Growth Factor A/pharmacology/*physiology ; }, }
@article {pmid14720310, year = {2004}, author = {Przedborski, S}, title = {Programmed cell death in amyotrophic lateral sclerosis: a mechanism of pathogenic and therapeutic importance.}, journal = {The neurologist}, volume = {10}, number = {1}, pages = {1-7}, doi = {10.1097/01.nrl.0000106920.84668.37}, pmid = {14720310}, issn = {1074-7931}, support = {NS11766-27A1/NS/NINDS NIH HHS/United States ; NS38370/NS/NINDS NIH HHS/United States ; NS38586/NS/NINDS NIH HHS/United States ; NS42269/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Animals ; Apoptosis/*physiology ; Caspases/genetics ; DNA Fragmentation/genetics ; Genes, bcl-2/genetics ; Humans ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinases/genetics ; Motor Neurons/*pathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease of adulthood. Mounting evidence indicates that molecular components of the programmed cell death (PCD) machinery are implicated in the demise of motor neurons in this illness. PCD, rather than being passive, is an active mechanism of cell death tightly regulated by multiple molecular pathways.<br><br>REVIEW SUMMARY: Thus far, little is known about the etiology and the pathogenesis of ALS. However, several studies support the view that PCD is instrumental in ALS neurodegenerative process. Data from postmortem ALS specimens and from experimental models of ALS show that some dying motor neurons exhibit features reminiscent of apoptosis, a prominent morphologic form of PCD. In addition, many key molecular components of the PCD machinery are activated in ALS spinal cords. Supporting the significance of these alterations, genetic and pharmacological interventions aimed at mitigating these changes prolong survival and attenuate neurodegeneration in a mouse model of ALS.<br><br>CONCLUSIONS: The morphologic evidence of PCD in ALS remains an equivocal. However, the molecular evidence of PCD involvement in ALS is compelling. Moreover, preclinical studies in mice demonstrate the beneficial effects of targeting PCD on ALS-like neurodegeneration. The neurologist needs to be familiar with the concept of PCD and the potential significance of targeting PCD as neuroprotective strategies for ALS.}, }
@article {pmid14717615, year = {2004}, author = {Rogers, SJ and Williams, CS and Román, GC}, title = {Myelopathy in Sjögren's syndrome: role of nonsteroidal immunosuppressants.}, journal = {Drugs}, volume = {64}, number = {2}, pages = {123-132}, pmid = {14717615}, issn = {0012-6667}, mesh = {Clinical Trials as Topic ; Humans ; Immunosuppressive Agents/*therapeutic use ; Myelitis, Transverse/diagnosis/drug therapy/etiology ; Sjogren's Syndrome/complications/*drug therapy ; Spinal Cord/pathology ; Spinal Cord Diseases/diagnosis/*drug therapy/etiology ; }, abstract = {The incidence, aetiology and optimal treatment of CNS Sjögren's syndrome, including myelopathy associated with Sjögren's syndrome, are unknown at the present time. CNS Sjögren's syndrome is thought to be the result of an autoimmune vasculitis, but other mechanisms may be important. Spinal cord involvement in CNS Sjögren's syndrome may present as acute transverse myelitis, progressive myelitis, Brown-Séquard syndrome, neurogenic bladder or lower motor neurone disease. Optic nerve pathology frequently accompanies spinal cord involvement. Acute transverse myelitis has a high mortality and appears to be the most frequent form of spinal cord involvement in CNS Sjögren's syndrome, occurring in about 1% of all patients with Sjögren's syndrome. The patient's symptomatology and clinical course dictate current treatment of myelopathy. First-line treatment appears to be corticosteroid therapy. However, when the patient's condition fails to improve or deteriorates a nonsteroidal immunosuppressant agent should be considered. Agents used to treat myelopathy include cyclophosphamide, chlorambucil, azathioprine, ciclosporin (cyclosporin) and methotrexate in conjunction with corticosteroids. Most data exist as anecdotal reports. The agent of first choice, based on adverse effect profile and efficacy, appears to be cyclophosphamide given intravenously in pulse doses. Other nonsteroidal immunosuppressant agents should be considered, especially when lack of efficacy of, or intolerance to, cyclophosphamide exists in the patient's history. Glandular and other extraglandular symptoms may benefit concomitantly from the immunosuppressant treatment. In addition, when acute relief of symptomatology is needed, the patient may benefit from a trial of plasmapheresis or intravenous immunoglobulin. Infliximab (anti-tumour necrosis factor-alpha antibodies) has not been used as a treatment modality for myelopathy, but has shown some usefulness in the treatment of extraglandular symptoms, as well as peripheral nervous system manifestations of Sjögren's syndrome. This agent might be considered when all other treatment modalities have failed given the presumed importance of tumour necrosis factor in the pathogenesis of Sjögren's syndrome.}, }
@article {pmid14711010, year = {2003}, author = {Rotilio, G and Aquilano, K and Ciriolo, MR}, title = {Interplay of Cu,Zn superoxide dismutase and nitric oxide synthase in neurodegenerative processes.}, journal = {IUBMB life}, volume = {55}, number = {10-11}, pages = {629-634}, doi = {10.1080/15216540310001628717}, pmid = {14711010}, issn = {1521-6543}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Antioxidants/pharmacology ; Apoptosis ; Cell Line, Tumor ; Cysteine Endopeptidases/metabolism ; Humans ; Models, Biological ; Multienzyme Complexes/metabolism ; Mutation ; Neurodegenerative Diseases/*enzymology/genetics ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/*chemistry/metabolism ; Oxygen/metabolism ; Proteasome Endopeptidase Complex ; Superoxide Dismutase/*chemistry/metabolism ; Superoxides/metabolism ; }, abstract = {Reactive oxygen and nitrogen species (ROS and RNS) have been extensively recognized as important signaling molecules implicated in physiological processes such as gene expression, cell differentiation and immune activation. Nevertheless, continuous production of these species may produce oxidative and/or nitrosative stress resulting in cell damage and ultimately leading to cell death. Due to the high oxygen consumption and relative poor antioxidant defense, the central nervous system is highly susceptible to ROS- and RNS-mediated toxicity. Actually, the oxidative and nitrosative stress have been implicated in the pathogenesis of neurodegeneration of a large variety of neurological disorders. This review will cover some aspects of the involvement of ROS- and RNS-mediated apoptotic processes occurring in cellular models of familial amyotrophic lateral sclerosis (FALS), in particular the cases associated with mutations in SOD1, the gene encoding Cu,Zn superoxide dismutase (Cu,Zn SOD). A possible role for proteasome in the inhibition of neurodegenerative process by balancing ROS and RNS species is envisaged on the basis of evidence provided by results obtained from studies on this experimental model.}, }
@article {pmid14698606, year = {2004}, author = {Rao, SD and Weiss, JH}, title = {Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis.}, journal = {Trends in neurosciences}, volume = {27}, number = {1}, pages = {17-23}, doi = {10.1016/j.tins.2003.11.001}, pmid = {14698606}, issn = {0166-2236}, support = {AG 00836/AG/NIA NIH HHS/United States ; F31 NS 42570/NS/NINDS NIH HHS/United States ; NS 36548/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Communication/*physiology ; Glutamic Acid/metabolism ; Humans ; Models, Neurological ; Motor Neurons/*physiology ; Neuroglia/*physiology ; Reactive Oxygen Species/metabolism ; Spinal Cord/metabolism/pathology ; }, }
@article {pmid14683462, year = {2003}, author = {Pong, K and Zaleska, MM}, title = {Therapeutic implications for immunophilin ligands in the treatment of neurodegenerative diseases.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {2}, number = {6}, pages = {349-356}, doi = {10.2174/1568007033482652}, pmid = {14683462}, issn = {1568-007X}, mesh = {Animals ; Humans ; Immunophilins/chemistry/metabolism/*therapeutic use ; Immunosuppressive Agents/metabolism/therapeutic use ; Ligands ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {There is a significant unmet need for therapeutic agents in the treatment of neurodegenerative diseases. Given their clinical importance, prototypical molecules that clearly exhibit both neuroprotective and neuroregenerative activities have been highly sought after. The journey led to the exploitation of neurotrophins, a family of proteins that had extraordinary therapeutic properties in pre-clinical models of neurodegeneration. Although experimentally promising, clinical development of neurotrophins for various neurological indications, such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Parkinson's Disease was met with severe obstacles and setbacks, such as the inability to deliver these large proteins to target population of neurons, instability of the proteins, and non-specific activity. Immunophilins are proteins that act as receptors for immunosuppresant drugs, i.e. FK506 (tacrolimus), cyclosporin A, and rapamycin (sirolimus, Rapamune). Studies indicate immunophilins are expressed 10-100 fold higher in CNS and PNS tissue than in immune tissue. Subsequent studies revealed potent neuroprotective and neuroregenerative properties of immunophilin ligands in both culture and animal models. In contrast to neurotrophins, most immunophilin ligands are highly stable, small molecules that can readily cross the blood-brain barrier and are orally bioavailable. Taken together, these data prompted the development of nonimmunosuppressive immunophilin ligands with potent therapeutic activities, although the potency of select compounds has come into question in more recent studies. This review will examine the experimental evidence supporting the use of immunophilin ligands for the treatment of neurodegenerative diseases and the current progression of these molecules in clinical trials.}, }
@article {pmid14673212, year = {2003}, author = {Kesavapany, S and Li, BS and Pant, HC}, title = {Cyclin-dependent kinase 5 in neurofilament function and regulation.}, journal = {Neuro-Signals}, volume = {12}, number = {4-5}, pages = {252-264}, doi = {10.1159/000074627}, pmid = {14673212}, issn = {1424-862X}, mesh = {Alzheimer Disease/enzymology/etiology ; Animals ; Cells, Cultured ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*metabolism ; Disease Models, Animal ; Humans ; *MAP Kinase Kinase Kinase 1 ; MAP Kinase Kinase Kinases/metabolism ; Neurodegenerative Diseases/enzymology/etiology ; Neurofilament Proteins/chemistry/*metabolism ; Neurons/*enzymology ; Phosphorylation ; Signal Transduction/physiology ; }, abstract = {Neurofilaments are neuron-specific intermediate filaments. They are classed into three groups according to their molecular masses: neurofilament heavy, middle and light chains (NF-H, NF-M and NF-L). Neurofilaments assemble and form through the association of their central alpha-helical coiled-coil rod domains. NF-H and NF-M are distinct from NF-L as they contain a carboxyl-terminal tail domain, which appears to form connections with adjacent structures and other neurofilaments. Together with other axonal components such as microtubules, they form the dynamic axonal cytoskeleton. They maintain and regulate neuronal cytoskeletal plasticity through the regulation of neurite outgrowth, axonal caliber and axonal transport. Neurofilaments contain KSP repeats that are consensus motifs for the proline-directed kinases and are extensively phosphorylated in vivo, and their functions are thought to be regulated through their phosphorylation. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase, whose activity is restricted to the neuron through the neuronal-specific distribution of its activators p35 and p39. Cdk5 is the only kinase that affects the electrophoretic mobility of human NF-H and is thought to be the major neurofilament kinase. Cdk5 is involved in crosstalk with other signal transduction pathways such as the mitogen-activated protein kinase and myelin-associated glycoprotein pathways to influence the phosphorylation of neurofilaments and other cytoskeletal proteins. Both the hyperactivation of Cdk5 activity and subsequent hyperphosphorylation of neurofilaments and the microtubule-associated protein tau have been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we review the functions of neurofilaments and the significance of Cdk5 phosphorylation of neurofilaments.}, }
@article {pmid14673208, year = {2003}, author = {Nguyen, MD and Julien, JP}, title = {Cyclin-dependent kinase 5 in amyotrophic lateral sclerosis.}, journal = {Neuro-Signals}, volume = {12}, number = {4-5}, pages = {215-220}, doi = {10.1159/000074623}, pmid = {14673208}, issn = {1424-862X}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*etiology ; Animals ; Cell Cycle/physiology ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*metabolism ; Disease Models, Animal ; Humans ; Phosphorylation ; Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis is a neurological disorder that selectively affects motor neurons of brain and spinal cord. Emerging evidence indicates an involvement of the serine/threonine-cyclin-dependent kinase 5 (Cdk5) in the pathogenesis. Deregulation of Cdk5 by its truncated co-activators, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of cytosolic and cytoskeletal proteins and, possibly, through the induction of cell cycle regulators. The present paper reviews these findings and proposes new perspectives to decipher the mechanisms of neurodegeneration in amyotrophic lateral sclerosis induced by Cdk5.}, }
@article {pmid14673202, year = {2003}, author = {Mapelli, M and Musacchio, A}, title = {The structural perspective on CDK5.}, journal = {Neuro-Signals}, volume = {12}, number = {4-5}, pages = {164-172}, doi = {10.1159/000074617}, pmid = {14673202}, issn = {1424-862X}, support = {GP0097Y01/TI_/Telethon/Italy ; }, mesh = {Animals ; CDC2-CDC28 Kinases/chemistry/metabolism ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*chemistry/metabolism ; Enzyme Activation ; *Models, Molecular ; Nerve Tissue Proteins/*metabolism ; Protein Binding ; Structure-Activity Relationship ; }, abstract = {Cyclin-dependent kinase 5 (CDK5) plays an essential role in the development of the central nervous system during mammalian embryogenesis. In the adult, CDK5 is required for the maintenance of neuronal architecture. Its deregulation has profound cytotoxic effects and has been implicated in the development of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. In this review, we concentrate on the regulation of CDK5 activity, privileging a structural perspective based on a decade of structural analyses of different members of the CDK family, including CDK2 and CDK5. We review the activation mechanism of CDK5 and discuss its differences and similarities with that of CDK2 and of the other members of the CDK family.}, }
@article {pmid14661102, year = {2003}, author = {Sarchielli, P and Galli, F and Floridi, A and Floridi, A and Gallai, V}, title = {Relevance of protein nitration in brain injury: a key pathophysiological mechanism in neurodegenerative, autoimmune, or inflammatory CNS diseases and stroke.}, journal = {Amino acids}, volume = {25}, number = {3-4}, pages = {427-436}, doi = {10.1007/s00726-003-0028-6}, pmid = {14661102}, issn = {0939-4451}, mesh = {Animals ; Autoimmune Diseases/physiopathology ; Central Nervous System Diseases/etiology/*metabolism/physiopathology ; Humans ; Inflammation/physiopathology ; Nerve Degeneration/physiopathology ; Neurodegenerative Diseases/etiology/*metabolism/physiopathology ; Proteins/*metabolism ; Stroke/etiology/*metabolism/physiopathology ; }, abstract = {This review has focused on the evidence for the involvement of nitrative oxidation in certain neurodegenerative disorders (Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis), stroke, and inflammatory and autoimmune disorders (with particular attention devoted to multiple sclerosis). The relationship between protein peroxidation and pathological changes observed in the above disorders has been reported. Whereas many of the findings are from studies with animal models and autoptic specimens from human patients, few data are available from cerebrospinal fluid and blood samples of the patients at different times and disease stages. The participation of nitrative oxidation to the direct and indirect injury of neurons and other cells of the brain (i.e., oligodendrocytes, for multiple sclerosis) is clear; less evident is their relevance for the development and progression of these disorders.Further studies should be aimed to establish the clinical and prognostic value of peroxidative markers for the CNS diseases considered. This is fundamental for the development of therapeutic interventions antagonizing nitric oxide-related species damage.}, }
@article {pmid14657605, year = {2003}, author = {González De Aguilar, JL and René, F and Dupuis, L and Loeffler, JP}, title = {Neuroendocrinology of neurodegenerative diseases. Insights from transgenic mouse models.}, journal = {Neuroendocrinology}, volume = {78}, number = {5}, pages = {244-252}, doi = {10.1159/000074445}, pmid = {14657605}, issn = {0028-3835}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/*metabolism/physiopathology ; Neurosecretory Systems/*metabolism/physiopathology ; Parkinson Disease/metabolism ; }, abstract = {The nervous system plays a key role in the regulation of neuroendocrine axes and, in turn, the released neurohormones modulate the activity of different brain regions. Neurodegenerative diseases, which are known to affect specific neuronal populations, may provoke neuroendocrine dysfunctions that alter the intimate relationship between both systems. In addition, these modifications may influence the progression of the neurodegenerative process. In the present review, we summarise some of the endocrine changes characterising three major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Special attention is focused on the contribution of disease transgenic models to elucidate such alterations.}, }
@article {pmid14646121, year = {2004}, author = {Hasnain, SS}, title = {Synchrotron techniques for metalloproteins and human disease in post genome era.}, journal = {Journal of synchrotron radiation}, volume = {11}, number = {Pt 1}, pages = {7-11}, doi = {10.1107/s0909049503024166}, pmid = {14646121}, issn = {0909-0495}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Creutzfeldt-Jakob Syndrome/genetics/*metabolism ; Crystallography, X-Ray/*methods ; Humans ; Macromolecular Substances ; Metalloproteins/*chemistry/*metabolism ; Molecular Conformation ; Protein Binding ; Proteomics/methods ; Spectrometry, X-Ray Emission/*methods ; Structure-Activity Relationship ; Superoxide Dismutase/chemistry/*metabolism ; Superoxide Dismutase-1 ; *Synchrotrons ; }, abstract = {Metalloproteins make up some 30% of proteins in known genomes. Metalloproteins are a special class of proteins that utilise the unique properties of metal atoms in conjunction with the macromolecular assembly to perform life-sustaining processes. A number of metalloproteins are known to be involved in many disease states including ageing processes. The incorporation of the metal ion is a very tightly regulated process that, in vivo, very often requires specific chaperones to deliver and help incorporate the metal atom in the macromolecule. The lack of or inappropriate incorporation of metals along with genetic factors can lead to the mis-function of these proteins leading to disease. The mis-functions due to genetic alterations that lead to diseases like ALS (amyotrophic lateral sclerosis or motor neuron disease) and Creutzfeld Jacob disease (CJD) are now well recognised. Synchrotron radiation sources provide a unique set of structural tools, which in combination can prove extremely powerful in providing a comprehensive picture of these complex biological systems. In particular for metalloproteins, the combined use of X-ray crystallography, X-ray solution scattering and X-ray spectroscopy (XAFS) is extremely useful. We are currently engaged in a structural study where our aim is to characterize structurally and functionally metalloproteins and then transfer this knowledge to afford the problem of the mis-function of metalloproteins that lead to these terminal illnesses, either due to a gain of function/property or a loss of function/property. In this context, the benefits of adopting the 'philosophy' being developed for the structural genomics effort are highlighted.}, }
@article {pmid14649878, year = {2003}, author = {Jordán, J and Ceña, V and Prehn, JH}, title = {Mitochondrial control of neuron death and its role in neurodegenerative disorders.}, journal = {Journal of physiology and biochemistry}, volume = {59}, number = {2}, pages = {129-141}, pmid = {14649878}, issn = {1138-7548}, mesh = {Cell Death/*physiology ; Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/metabolism/*pathology/*physiopathology ; Neurons/pathology/*physiology ; }, abstract = {Genetic or functional mitochondrial alterations can result in the initiation of cell death programs that are believed to contribute to cell death in diabetes, ageing and neurodegenerative disorders. Mitochondria are being considered the main link between cellular stress signals activated during acute and chronic nerve cell injury, and the execution of nerve cell death. This second function of mitochondria is regulated by several families of proteins that can trigger an increase in permeability of the outer and/or inner mitochondrial membrane. One example of this is the formation of the mitochondrial permeability transition pore (MPTP). This process can trigger the release of cell death-inducing factors from mitochondria, as well as a dissipation of the mitochondrial transmembrane potential, depletion of ATP, and increased free radical formation. Among the factors released from mitochondria are cytochrome c, the apoptosis inductor factor (AIF), and caspases. We review the role of the MPTP in diverse physiological and pathological processes, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The design of drugs that could interfere with the functions of the MPTP could allow novel therapeutic approaches for the treatment of acute and chronic nerve cell injury.}, }
@article {pmid14645465, year = {2003}, author = {Leigh, PN and Abrahams, S and Al-Chalabi, A and Ampong, MA and Goldstein, LH and Johnson, J and Lyall, R and Moxham, J and Mustfa, N and Rio, A and Shaw, C and Willey, E and , }, title = {The management of motor neurone disease.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {74 Suppl 4}, number = {Suppl 4}, pages = {iv32-iv47}, pmid = {14645465}, issn = {0022-3050}, mesh = {Gastrostomy ; Genetic Counseling ; Humans ; Motor Neuron Disease/complications/*diagnosis/*therapy ; Neuroprotective Agents/therapeutic use ; Respiration, Artificial ; Riluzole/therapeutic use ; Terminal Care ; }, }
@article {pmid14640321, year = {2003}, author = {Lalonde, R and Strazielle, C}, title = {Neurobehavioral characteristics of mice with modified intermediate filament genes.}, journal = {Reviews in the neurosciences}, volume = {14}, number = {4}, pages = {369-385}, doi = {10.1515/revneuro.2003.14.4.369}, pmid = {14640321}, issn = {0334-1763}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*physiopathology ; Animals ; Anxiety ; Behavior, Animal ; Disease Models, Animal ; Humans ; Intermediate Filaments/chemistry/classification/drug effects/*genetics/metabolism ; Mice ; Mice, Transgenic/*physiology ; *Motor Activity ; Motor Neurons ; Mutation ; Neuropsychology ; *Psychomotor Performance ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Intermediate proteins comprise cytoskeletal elements that preserve the shape and structure of neurons. These proteins have been proposed to be involved in the onset and progression of amyotrophic lateral sclerosis (ALS), mainly characterized by motoneuron atrophy and paresis. In support of this hypothesis are the findings that genetically modified mice for intermediate filaments successfully mimic certain neuropathological aspects of ALS, such as reduced axonal caliber and retarded conduction speed in peripheral nerves, although often without leading to paresis. Nevertheless, even in those models with no overt phenotype, the involvement of intermediate proteins in motor function is underlined by the deficits in tests of balance and equilibrium revealed in mice containing transgenes for neurofilament of heavy molecular weight (NFH), alpha-internexin, peripherin, and vimentin. In addition, spatial learning was impaired in transgenic mice expressing transgenes for NFH and NFM, similar to the memory deficits reported in patients with ALS.}, }
@article {pmid14639006, year = {2003}, author = {Suzuki, T and Tsuzuki, K and Kameyama, K and Kwak, S}, title = {[Recent advances in the study of AMPA receptors].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {122}, number = {6}, pages = {515-526}, doi = {10.1254/fpj.122.515}, pmid = {14639006}, issn = {0015-5691}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Biological Transport ; Calcium ; Humans ; Motor Neurons/physiology ; RNA Editing ; Receptors, AMPA/analysis/chemistry/*physiology ; }, abstract = {As glutamate is a dominant excitatory neurotransmitter in the central nervous system, glutamate receptors, and especially AMPA receptors, are located ubiquitously in all brain areas. In this paper, we reviewed recent advances of studies on AMPA receptor functions. AMPA receptors are cation-conducting complexes composed of various combinations of four subunits (GluR1 to GluR4). The glutamine residue located in the pore-forming segment of GluR2 subunit (Q/R site) is changed to arginine by RNA editing at the pre mRNA stage in normal adult mammalian animal. The edited GluR2 subunit is a major determination of Ca(2+) permeability of the AMPA receptor; only edited GluR2-lacking receptor shows high-Ca(2+) permeability. The assembly of glutamate AMPA receptor subunit is not completely according to the stochastic theory. The heteromeric subunits assembly is more rapid than the homomeric assembly is. The transfer of AMPA receptor subunit to the plasma membrane is conducted in multiple ways. Many molecules that interact with the intracellular domain of AMPA receptor subunits are reported as the modulators of AMPA receptor subunit transfer. In the motoneuron of sporadic amyotrophic lateral sclerosis (ALS) patients, the efficiency of RNA editing at the GluR2 Q/R site is significantly decreased. Relative low level of edited GluR2 subunit expression is likely responsible for motoneuronal death in ALS. Recently, AMPA receptors in glial cells have been studied. Bergmann glial cells in cerebellum express Ca(2+)-permeable AMPA receptors. Conversion of these AMPA receptors to Ca(2+)-impermeable type receptors induces morphological and functional changes. Glioblastoma cells also express Ca(2+)-permeable AMPA receptors, and their conversion to Ca(2+)-impermeable receptors inhibits cell locomotion and induces apoptosis.}, }
@article {pmid14636160, year = {2003}, author = {Wood, JD and Beaujeux, TP and Shaw, PJ}, title = {Protein aggregation in motor neurone disorders.}, journal = {Neuropathology and applied neurobiology}, volume = {29}, number = {6}, pages = {529-545}, doi = {10.1046/j.0305-1846.2003.00518.x}, pmid = {14636160}, issn = {0305-1846}, mesh = {Animals ; Disease Models, Animal ; Humans ; Inclusion Bodies/*pathology ; Motor Neuron Disease/genetics/*pathology ; Mutation ; Protein Conformation ; Proteins/chemistry/*metabolism ; Superoxide Dismutase/genetics ; }, abstract = {Toxicity associated with abnormal protein folding and protein aggregation are major hypotheses for neurodegeneration. This article comparatively reviews the experimental and human tissue-based evidence for the involvement of such mechanisms in neuronal death associated with the motor system disorders of X-linked spinobulbar muscular atrophy (SBMA; Kennedy's disease) and amyotrophic lateral sclerosis (ALS), especially disease related to mutations in the superoxide dismutase (SOD1) gene. Evidence from transgenic mouse, Drosophila and cell culture models of SBMA, in common with other trinucleotide repeat expansion disorders, show protein aggregation of the mutated androgen receptor, and intraneuronal accumulation of aggregated protein, to be obligate mechanisms. Strong experimental data link these phenomena with downstream biochemical events involving gene transcription pathways (CREB-binding protein) and interactions with protein chaperone systems. Manipulations of these pathways are already established in experimental systems of trinucleotide repeat disorders as potential beneficial targets for therapeutic activity. In contrast, the evidence for the role of protein aggregation in models of SOD1-linked familial ALS is less clear-cut. Several classes of intraneuronal inclusion body have been described, some of which are invariably present. However, the lack of understanding of the biochemical basis of the most frequent inclusion in sporadic ALS, the ubiquitinated inclusion, has hampered research. The toxicity associated with expression of mutant SOD1 has been intensively studied however. Abnormal protein aggregation and folding is the only one of the four major hypotheses for the mechanism of neuronal degeneration in this disorder currently under investigation (the others comprise oxidative stress, axonal transport and cytoskeletal dysfunctions, and glutamatergic excitotoxicity). Whilst hyaline inclusions, which are strongly immunoreactive to SOD1, are linked to degeneration in SOD1 mutant mouse models, the evidence from human tissue is less consistent and convincing. A role for mutant SOD1 aggregation in the mitochondrial dysfunction associated with ALS, and in potentially toxic interactions with heat shock proteins, both leading to apoptosis, are supported by some experimental data. Direct in vitro data on mutant SOD1 show evidence for spontaneous oligomerization, but the role of such oligomers remains to be elucidated, and therapeutic strategies are less well developed for this familial variant of ALS.}, }
@article {pmid14635512, year = {2003}, author = {Funakoshi, H and Nakamura, T}, title = {[Neurotrophic factors and amyotrophic lateral sclerosis (ALS)--therapeutic potential of a new neurotrophic factor: HGF in ALS].}, journal = {No to shinkei = Brain and nerve}, volume = {55}, number = {10}, pages = {841-845}, pmid = {14635512}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Hepatocyte Growth Factor/*pharmacology/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/cytology/drug effects ; Nerve Growth Factors/*pharmacology ; Proto-Oncogene Proteins c-met/biosynthesis ; }, }
@article {pmid14621116, year = {2003}, author = {Simonds, AK}, title = {Home ventilation.}, journal = {The European respiratory journal. Supplement}, volume = {47}, number = {}, pages = {38s-46s}, doi = {10.1183/09031936.03.00029803}, pmid = {14621116}, issn = {0904-1850}, mesh = {Chronic Disease ; Female ; *Home Care Services ; Humans ; Long-Term Care ; Male ; Prognosis ; Pulmonary Disease, Chronic Obstructive/complications/mortality/*therapy ; *Quality of Life ; Respiration, Artificial/*methods ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/mortality/*therapy ; Risk Assessment ; Severity of Illness Index ; Survival Analysis ; Treatment Outcome ; }, abstract = {Home ventilation is a growth area. Rapid expansion during the 1990s was stimulated by the development of noninvasive ventilation (NIV) via a mask and the recognition that an increased number of patient groups can benefit. Although patients receiving NIV in the home outnumber those receiving invasive ventilation via tracheostomy, there is substantial variation in practice between European countries. Evidence that individuals who develop ventilatory failure as a consequence of chest wall disease or stable neuromuscular disease such as old poliomyelitis benefit from nocturnal NIV is overwhelming. Patients with progressive neuromuscular disease such as Duchenne muscular dystrophy and amyotrophic lateral sclerosis can also derive prolongation of life, palliation of symptoms and an improvement in quality of life. Home ventilation in chronic obstructive pulmonary disease (COPD) patients remains controversial. Multicentric randomised controlled trials of long-term oxygen therapy (LTOT) versus NIV plus LTOT in COPD have produced mixed results, although certain subgroups, e.g. those with recurrent infective exacerbations requiring short-term NIV, patients aged >65 yrs, and those with uncontrolled hypercapnia on LTOT or symptomatic nocturnal hypoventilation, may benefit. At the other end of the age spectrum, children as young as a few months can be successfully treated with noninvasive ventilation. Most work on paediatric home ventilation centres on children with congenital neuromuscular disease. Pressure preset bilevel ventilators are now the dominant form of ventilator in adults and children. Discharge planning is vital for the home ventilator patient and a sensible risk management strategy should be in place.}, }
@article {pmid14619409, year = {2003}, author = {de Paulis, T}, title = {ONO-2506. Ono.}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {4}, number = {7}, pages = {863-867}, pmid = {14619409}, issn = {1472-4472}, mesh = {Animals ; Caprylates/chemistry/*therapeutic use ; Clinical Trials as Topic/statistics &amp; numerical data ; Drugs, Investigational/chemistry/*therapeutic use ; Humans ; Nervous System Diseases/*drug therapy ; Technology, Pharmaceutical/methods ; }, abstract = {ONO-2506 is an enantiomeric, three carbon atom homolog of valproic acid under development by ONO Pharmaceutical for the potential treatment of stroke, as well as Alzheimer's and Parkinson's disease. The injectable formulation (Proglia) is undergoing phase II trials in the US and Japan for acute-phase cerebral infarction, and the oral formulation (Cereact) is in phase I trials in the UK for Alzheimer's disease (AD) and Parkinson's disease (PD). Japanese and European phase I trials for AD, PD and amyotropic lateral sclerosis (ALS) had commenced by March 2002 and phase II trials for ALS are underway in Europe.}, }
@article {pmid14612154, year = {2003}, author = {Kanai, Y and Hediger, MA}, title = {The glutamate and neutral amino acid transporter family: physiological and pharmacological implications.}, journal = {European journal of pharmacology}, volume = {479}, number = {1-3}, pages = {237-247}, doi = {10.1016/j.ejphar.2003.08.073}, pmid = {14612154}, issn = {0014-2999}, mesh = {Amino Acid Transport System X-AG/agonists/antagonists &amp; inhibitors/*physiology ; Amino Acid Transport Systems, Neutral/agonists/antagonists &amp; inhibitors/*physiology ; Animals ; Binding Sites/drug effects/physiology ; Biological Transport/drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/pharmacology ; Humans ; }, abstract = {The solute carrier family 1 (SLC1) is composed of five high affinity glutamate transporters, which exhibit the properties of the previously described system XAG-, as well as two Na+-dependent neutral amino acid transporters with characteristics of the so-called "ASC" (alanine, serine and cysteine). The SLC1 family members are structurally similar, with almost identical hydropathy profiles and predicted membrane topologies. The transporters have eight transmembrane domains and a structure reminiscent of a pore loop between the seventh and eighth domains [Neuron 21 (1998) 623]. However, each of these transporters exhibits distinct functional properties. Glutamate transporters mediate transport of L-Glu, L-Asp and D-Asp, accompanied by the cotransport of 3 Na+ and one 1 H+, and the countertransport of 1 K+, whereas ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. Given the high concentrating capacity provided by the unique ion coupling pattern of glutamate transporters, they play crucial roles in protecting neurons against glutamate excitotoxicity in the central nervous system (CNS). The regulation and manipulation of their function is a critical issue in the pathogenesis and treatment of CNS disorders involving glutamate excitotoxicity. Loss of function of the glial glutamate transporter GLT1 (SLC1A2) has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), resulting in damage of adjacent motor neurons. The importance of glial glutamate transporters in protecting neurons from extracellular glutamate was further demonstrated in studies of the slc1A2 glutamate transporter knockout mouse. The findings suggest that therapeutic upregulation of GLT1 may be beneficial in a variety of pathological conditions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) but not the glial glutamate transporters may be of therapeutic interest, allowing blockage of glutamate exit from neurons due to "reversed glutamate transport" of EAAC1, which will occur during pathological conditions, such as during ischemia after a stroke.}, }
@article {pmid14599431, year = {2003}, author = {Shaw, CA and Wilson, JM}, title = {Analysis of neurological disease in four dimensions: insight from ALS-PDC epidemiology and animal models.}, journal = {Neuroscience and biobehavioral reviews}, volume = {27}, number = {6}, pages = {493-505}, doi = {10.1016/j.neubiorev.2003.08.001}, pmid = {14599431}, issn = {0149-7634}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*physiopathology ; Animals ; Behavior, Animal/drug effects ; Central Nervous System/drug effects ; Cycas/*toxicity ; Dementia/etiology/*physiopathology ; Disease Models, Animal ; Disease Susceptibility ; Environmental Exposure ; Humans ; Mice ; Neurotoxicity Syndromes/*physiopathology ; Parkinson Disease/etiology/*physiopathology ; Plants, Toxic/chemistry ; Seeds/chemistry ; }, abstract = {The causal factor(s) responsible for sporadic neurological diseases are unknown and the stages of disease progression remain undefined and poorly understood. We have developed an animal model of amyotrophic lateral sclerosis-parkinsonism dementia complex which mimics all the essential features of the disease with the initial neurological insult arising from neurotoxins contained in washed cycad seeds. Animals fed washed cycad develop deficits in motor, cognitive, and sensory behaviors that correlate with the loss of neurons in specific regions of the central nervous system. The ability to recreate the disease by exposure to cycad allows us to extend the model in multiple dimensions by analyzing behavioral, cellular, and biochemical changes over time. In addition, the ability to induce toxin-based neurodegeneration allows us to probe the interactions between genetic and epigenetic factors. Our results show that the impact of both genetic causal and susceptibility factors with the cycad neurotoxins are complex. The article describes the features of the model and suggests ways that our understanding of cycad-induced neurodegeneration can be used to decipher and identify the early events in various human neurological diseases.}, }
@article {pmid14598376, year = {2004}, author = {Lariviere, RC and Julien, JP}, title = {Functions of intermediate filaments in neuronal development and disease.}, journal = {Journal of neurobiology}, volume = {58}, number = {1}, pages = {131-148}, doi = {10.1002/neu.10270}, pmid = {14598376}, issn = {0022-3034}, mesh = {Animals ; Humans ; Intermediate Filaments/*physiology ; Nervous System/*cytology/embryology ; Nervous System Diseases/*physiopathology ; Neurons/*physiology ; }, abstract = {Five major types of intermediate filament (IF) proteins are expressed in mature neurons: the three neurofilament proteins (NF-L, NF-M, and NF-H), alpha-internexin, and peripherin. While the differential expression of IF genes during embryonic development suggests potential functions of these proteins in axogenesis, none of the IF gene knockout experiments in mice caused gross developmental defects of the nervous system. Yet, deficiencies in neuronal IF proteins are not completely innocuous. Substantial developmental loss of motor axons was detected in mice lacking NF-L and in double knockout NF-M;NF-H mice, supporting the view of a role for IFs in axon stabilization. Moreover, the absence of peripherin resulted in approximately 30% loss of small sensory axons. Mice lacking NF-L had a scarcity of IF structures and exhibited a severe axonal hypotrophy, causing up to 50% reduction in conduction velocity, a feature that would be very detrimental for large animal species. Unexpectedly, the NF-M rather than NF-H protein turned out to be required for proper radial growth of large myelinated axons. Studies with transgenic mice suggest that some types of IF accumulations, reminiscent of those found in amyotrophic lateral sclerosis (ALS), can have deleterious effects and even cause neurodegeneration. Additional evidence for the involvement of IFs in pathogenesis came from the recent discovery of neurofilament gene mutations linked to ALS and Charcot-Marie-Tooth disease (CMT2E). Conversely, we discuss how certain types of perikaryal neurofilament aggregates might confer protection in motor neuron disease.}, }
@article {pmid14584974, year = {2003}, author = {}, title = {Xaliproden: SR 57746, SR 57746A, xaliproden hydrochloride, xaliprodene.}, journal = {Drugs in R&amp;D}, volume = {4}, number = {6}, pages = {386-388}, doi = {10.2165/00126839-200304060-00014}, pmid = {14584974}, issn = {1174-5886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Clinical Trials as Topic ; Humans ; Naphthalenes/*pharmacology/therapeutic use ; Orphan Drug Production ; Pyridines/*pharmacology/therapeutic use ; Receptor, Serotonin, 5-HT1A/*drug effects ; Serotonin Receptor Agonists/*pharmacology/therapeutic use ; }, abstract = {Xaliproden [SR 57746A, xaliprodene; Xaprila] is a compound that mimics the effects of nerve growth factor and is also a serotonin 5-HT1A receptor agonist. The drug was originated by Sanofi, and in mid-1999, Sanofi merged with Synthélabo to form Sanofi-Synthélabo. Phase III trials have been completed in patients with amyotrophic lateral sclerosis in Europe, the US and Canada. Xaliproden is at the phase II stage of clinical development for amyotrophic lateral sclerosis in Japan, where it also has orphan drug status for this indication.}, }
@article {pmid14583978, year = {2003}, author = {Parton, M and Mitsumoto, H and Leigh, PN}, title = {Amino acids for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD003457}, doi = {10.1002/14651858.CD003457}, pmid = {14583978}, issn = {1469-493X}, mesh = {Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; Threonine/*therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a progressive neuromuscular disease that causes disability and eventual death. Various amino acid preparations, the three branched-chain amino acids (L-leucine, L-valine and L-isoleucine) or, alternatively, L-threonine have been used as experimental therapy.<br><br>OBJECTIVES: To examine the efficacy of amino acid therapies in prolonging survival and/or slowing the progression of amyotrophic lateral sclerosis/motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2003), MEDLINE (from January 1966 to December 2002) and EMBASE (from January 1980 to December 2002) databases and reports of specialist conferences. Authors of known studies were contacted.<br><br>SELECTION CRITERIA: We included randomised or quasi-randomised trials of participants with a clinical diagnosis of amyotrophic lateral sclerosis/motor neuron disease treated with all combinations of amino acids. Our primary outcome measure was survival determined by a pooled hazard ratio of all studies. Our secondary outcome measures were (in order of priority): survival at six and 12 months, muscle strength, any validated rating scale of physical function, quality of life, proportion of patients completing therapy and proportion of patients reporting adverse events attributable to treatment.<br><br>DATA COLLECTION AND ANALYSIS: We identified six eligible trials and rejected a further seven because of incomplete data or inadequate duration. Eligible studies were rated for methodological quality and missing data sought from the authors. After this examination two studies were excluded from analysis. Our pooled survival analysis was performed by the Parmar method, other statistical calculations were done using the Review Manager 4.2 software package.<br><br>MAIN RESULTS: No benefit could be demonstrated for either branched-chain amino acids or L-threonine in improving survival in amyotrophic lateral sclerosis/motor neuron disease. Neither could we find evidence of an effect of either treatment on muscle strength or disability as measured by functional rating scales. No study assessed quality of life. Both branched-chain amino acids and L-threonine appeared well tolerated and caused a degree of adverse events comparable to that of the control medication.<br><br>REVIEWER'S CONCLUSIONS: There is no evidence to support a beneficial effect of either branched-chain amino acids or L-threonine in amyotrophic lateral sclerosis/motor neuron disease.}, }
@article {pmid14583939, year = {2003}, author = {Symington, A and Pinelli, J}, title = {Developmental care for promoting development and preventing morbidity in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD001814}, doi = {10.1002/14651858.CD001814}, pmid = {14583939}, issn = {1469-493X}, mesh = {Developmental Disabilities/*prevention &amp; control ; Humans ; Infant, Newborn ; *Infant, Premature ; Length of Stay ; Randomized Controlled Trials as Topic ; Respiration, Artificial ; Stress, Physiological/prevention &amp; control ; Treatment Outcome ; Weight Gain ; }, abstract = {BACKGROUND: Preterm infants experience a range of morbidity related to the immaturity of their organ systems and to concurrent disease states. An unfavourable environment in the neonatal intensive care unit (NICU) may compound this morbidity. Modification of the environment could minimize the iatrogenic effects. Developmental care is a broad category of interventions designed to minimize the stress of the NICU environment. These interventions may include one or more elements such as control of external stimuli (vestibular, auditory, visual, tactile), clustering of nursery care activities, and positioning or swaddling of the preterm infant. Individual strategies have also been combined to form programs, such as the 'Neonatal Individualized Developmental Care and Assessment Program' (NIDCAP) (Als 1986).<br><br>OBJECTIVES: In preterm infants, do developmental care interventions reduce neurodevelopmental delay, poor weight gain, length of hospital stay, length of mechanical ventilation, physiological stress and other clinically relevant adverse outcomes?<br><br>SEARCH STRATEGY: The Neonatal Review Group search strategy was utilized. Searches were made of MEDLINE from 1966 to July, 2003, and of CINAHL, The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003), and conference and symposia proceedings in the English language from 1990 to July, 2003. A list of all relevant articles was sent to two experts in the field to identify any omissions or additional unpublished studies.<br><br>SELECTION CRITERIA: Randomized trials in which elements of developmental care are compared to routine nursery care for infants < 37 weeks gestation and that measured clinically relevant outcomes. Reports were in English or a language for which a translator was available. Computerized searches were conducted and all potentially relevant titles and abstracts were extracted. Retrieved articles were assessed for relevance independently by two reviewers, based on predetermined criteria. Articles that met all criteria for relevance were assessed for methodological quality based on predetermined criteria. Articles judged to have the appropriate quality by both reviewers were included in the analysis.<br><br>DATA COLLECTION AND ANALYSIS: Data were extracted independently by the two authors. Meta-analyses were conducted for each intervention where the same outcome measures and/or instruments were used within comparable time points.<br><br>MAIN RESULTS: This review detected 32 eligible randomized controlled trials involving four major groups of developmental care interventions, 19 sub-groups and multiple clinical outcomes. The results of the review indicate that developmental care interventions demonstrate some benefit to preterm infants with respect to: improved short-term growth and feeding outcomes, decreased respiratory support, decreased length and cost of hospital stay, and improved neurodevelopmental outcomes to 24 months corrected age. These findings were based on two or three small trials for each outcome, and did not involve meta-analyses of more than two trials for any one outcome. Although a number of other benefits were demonstrated, those results were from single studies with small sample sizes. The lack of blinding of the assessors was a significant methodological flaw in half of the studies. The cost of the interventions and personnel was not considered in any of the studies.<br><br>REVIEWER'S CONCLUSIONS: Because of the inclusion of multiple interventions in most studies, the determination of the effect of any single intervention is difficult. Although there is evidence of some benefit of developmental care interventions overall, and no major harmful effects reported, there were a large number of outcomes for which no or conflicting effects were demonstrated. The single trials that did show a significant effect of an intervention on a major clinical outcome were based on small sample sizes, and the findings were often not supported in other small trials. Before a clear direction for practice can be supported, evidence demonstrating more consistent effects of developmental care interventions on important short- and long-term clinical outcomes is needed. The economic impact of the implementation and maintenance of developmental care practices should be considered by individual institutions.}, }
@article {pmid14582618, year = {2003}, author = {Koch, AL}, title = {Cell wall-deficient (CWD) bacterial pathogens: could amylotrophic lateral sclerosis (ALS) be due to one?.}, journal = {Critical reviews in microbiology}, volume = {29}, number = {3}, pages = {215-221}, doi = {10.1080/713610449}, pmid = {14582618}, issn = {1040-841X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*microbiology/therapy ; Animals ; Anti-Bacterial Agents/therapeutic use ; Cell Wall/metabolism ; Humans ; Insect Vectors/microbiology ; Insecta/microbiology ; L Forms/*pathogenicity/*physiology ; Osmotic Pressure ; Spirochaetales/isolation &amp; purification/pathogenicity ; }, abstract = {Recently, a number of diseases that had been thought previously to be caused by something other than an infectious agent are now known to be caused by bacteria. It now appears that it is not uncommon that bacteria, viruses, or fungi can cause diseases even when these organisms have not been detected or cultured. The most recent, well-publicized case is that of stomach ulcers; these are largely due to Helicobacter pylori infections. Here, the possibility is explored that amylotrophic lateral sclerosis (ALS) is caused by a cell wall-deficient microorganism.}, }
@article {pmid14577644, year = {2003}, author = {Nishida, Y}, title = {Elucidation of endemic neurodegenerative diseases--a commentary.}, journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences}, volume = {58}, number = {9-10}, pages = {752-758}, doi = {10.1515/znc-2003-9-1028}, pmid = {14577644}, issn = {0939-5075}, mesh = {Animals ; Copper/*deficiency ; Creutzfeldt-Jakob Syndrome/chemically induced/etiology ; Humans ; Manganese/adverse effects ; Manganese Poisoning ; *Metals ; Neurodegenerative Diseases/chemically induced/*etiology ; Parkinson Disease/etiology ; Prion Diseases/chemically induced/etiology ; Scrapie/chemically induced/etiology ; }, abstract = {Recent investigations of scrapie, Creutzfeldt-Jakob disease (CJD), and chronic wasting disease (CWD) clusters in Iceland, Slovakia and Colorado, respectively, have indicated that the soil in these regions is low in copper and higher in manganese, and it has been well-known that patients of ALS or Parkinson's disease were collectively found in the New Guinea and Papua islands, where the subterranean water (drinking water) contains much Al3+ and Mn2+ ions. Above facts suggest that these neurodegenerative diseases are closely related with the function of a metal ion. We have investigated the chemical functions of the metal ions in detail and established the unique mechanism of the oxygen activation by the transition metal ions such as iron and copper, and pointed out the notable difference in the mechanism among iron, aluminum and manganese ions. Based on these results, it has become apparent that the incorporation of Al(III) or Mn(II) in the cells induces the "iron-overload syndrome", which is mainly due to the difference in an oxygen activation mechanism between the iron ion and Al(III) or the Mn(II) ion. This syndrome highly promotes formation of hydrogen peroxide, and hydrogen peroxide thus produced can be a main factor to cause serious damages to DNA and proteins (oxidative stress), yielding a copper(II)- or manganese(II)-peptide complex and its peroxide adduct, which are the serious agents to induce the structural changes from the normal prion protein (PrP(c)) to abnormal disease-causing isoforms, PrP(Sc), or the formation of PrP 27-30 (abnormal cleavage at site 90 of the prion protein). It seems reasonable to consider that the essential origin for the transmissible spongiform encephalopathies (TSEs) should be the incorporation and accumulation of Al(III) and Mn(II) ions in the cells, and the sudden and explosive increase of scrapie and bovine spongiform encephalopathy (BSE) in the last decade may be partially due to "acid rain", because the acid rain makes Al(III) and Mn(II) ions soluble in the subterranean aquifers.}, }
@article {pmid14569202, year = {2003}, author = {Simpson, EP and Yen, AA and Appel, SH}, title = {Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Current opinion in rheumatology}, volume = {15}, number = {6}, pages = {730-736}, doi = {10.1097/00002281-200311000-00008}, pmid = {14569202}, issn = {1040-8711}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*physiopathology ; Antioxidants/*therapeutic use ; Female ; Humans ; Male ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Prognosis ; Risk Assessment ; Sensitivity and Specificity ; Severity of Illness Index ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis, or Lou Gehrig disease, is a progressive neurodegenerative disease of adult onset characterized by a loss of motor neurons in the spinal cord and motor cortex. In the last several years, substantial progress has been made in defining the pathogenesis of motor neuron injury and relationships between disease mechanisms and the selective vulnerability of the motor neuron in both familial and sporadic forms of amyotrophic lateral sclerosis.<br><br>RECENT FINDINGS: Current theories have shifted from a neuron-centered pathology to a focus on the interaction between motor neurons and glia, and their respective contributions to pathways implicated in amyotrophic lateral sclerosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of disease.<br><br>SUMMARY: This article reviews the clinical aspects of amyotrophic lateral sclerosis and potential mechanisms of disease pathogenesis in the context of recent data supporting a major role for oxidative stress throughout the disease course. Evidence suggesting an important role for intercellular signaling is emphasized.}, }
@article {pmid14559406, year = {2003}, author = {Krieger, C and Hu, JH and Pelech, S}, title = {Aberrant protein kinases and phosphoproteins in amyotrophic lateral sclerosis.}, journal = {Trends in pharmacological sciences}, volume = {24}, number = {10}, pages = {535-541}, doi = {10.1016/j.tips.2003.08.003}, pmid = {14559406}, issn = {0165-6147}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Apoptosis ; Disease Models, Animal ; Humans ; Phosphoproteins/genetics/*metabolism ; Phosphorylation ; Protein Kinases/biosynthesis/genetics/*metabolism ; }, }
@article {pmid14556719, year = {2003}, author = {Ciechanover, A and Brundin, P}, title = {The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.}, journal = {Neuron}, volume = {40}, number = {2}, pages = {427-446}, doi = {10.1016/s0896-6273(03)00606-8}, pmid = {14556719}, issn = {0896-6273}, mesh = {Animals ; Cysteine Endopeptidases/*metabolism/physiology ; Humans ; Multienzyme Complexes/*metabolism/physiology ; Neurodegenerative Diseases/enzymology/*metabolism ; Proteasome Endopeptidase Complex ; Signal Transduction/physiology ; Ubiquitin/*metabolism/physiology ; }, abstract = {The ubiquitin-proteasome system targets numerous cellular proteins for degradation. In addition, modifications by ubiquitin-like proteins as well as proteins containing ubiquitin-interacting and -associated motifs modulate many others. This tightly controlled process involves multiple specific and general enzymes of the system as well as many modifying and ancillary proteins. Thus, it is not surprising that ubiquitin-mediated degradation/processing/modification regulates a broad array of basic cellular processes. Moreover, aberrations in the system have been implicated, either as a primary cause or secondary consequence, in the pathogenesis of both inherited and acquired neurodegenerative diseases. Recent findings indicate that the system is involved in the pathogenesis of Parkinson's, Alzheimer's, Huntington's, and Prion diseases as well as amyotrophic lateral sclerosis. This raises hopes for a better understanding of the pathogenetic mechanisms involved in these diseases and for the development of novel, mechanism-based therapeutic modalities.}, }
@article {pmid14530974, year = {2004}, author = {Kanai, Y and Hediger, MA}, title = {The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {447}, number = {5}, pages = {469-479}, pmid = {14530974}, issn = {0031-6768}, mesh = {Amino Acid Transport System X-AG/*physiology ; Amino Acids, Neutral/*metabolism ; Animals ; Biological Transport/physiology ; Glutamic Acid/*metabolism ; Humans ; Multigene Family/physiology ; }, abstract = {The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.}, }
@article {pmid14519086, year = {2003}, author = {Baker, SK and Tarnopolsky, MA}, title = {Targeting cellular energy production in neurological disorders.}, journal = {Expert opinion on investigational drugs}, volume = {12}, number = {10}, pages = {1655-1679}, doi = {10.1517/13543784.12.10.1655}, pmid = {14519086}, issn = {1354-3784}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Coenzymes ; Creatine/metabolism/therapeutic use ; Disease Models, Animal ; Energy Metabolism/*drug effects ; Humans ; Huntington Disease/drug therapy ; Nervous System Diseases/*drug therapy/metabolism/*therapy ; Neuroprotective Agents/therapeutic use ; Ubiquinone/*analogs &amp; derivatives/metabolism/therapeutic use ; }, abstract = {The concepts of energy dysregulation and oxidative stress and their complicated interdependence have rapidly evolved to assume primary importance in understanding the pathophysiology of numerous neurological disorders. Therefore, neuroprotective strategies addressing specific bioenergetic defects hold particular promise in the treatment of these conditions (i.e., amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Friedreich's ataxia, mitochondrial cytopathies and other neuromuscular diseases), all of which, to some extent, share 'the final common pathway' leading to cell death through either necrosis or apoptosis. Compounds such as creatine monohydrate and coenzyme Q(10) offer substantial neuroprotection against ischaemia, trauma, oxidative damage and neurotoxins. Miscellaneous agents, including alpha-lipoic acid, beta-OH-beta-methylbutyrate, riboflavin and nicotinamide, have also been shown to improve various metabolic parameters in brain and/or muscle. This review will highlight the biological function of each of the above mentioned compounds followed by a discussion of their utility in animal models and human neurological disease. The balance of this work will be comprised of discussions on the therapeutic applications of creatine and coenzyme Q(10).}, }
@article {pmid14514986, year = {2003}, author = {Boillée, S and Peschanski, M and Junier, MP}, title = {The wobbler mouse: a neurodegeneration jigsaw puzzle.}, journal = {Molecular neurobiology}, volume = {28}, number = {1}, pages = {65-106}, pmid = {14514986}, issn = {0893-7648}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; *Disease Models, Animal ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Neurologic Mutants/*genetics ; Mutation/genetics ; Neurodegenerative Diseases/*genetics/pathology ; }, abstract = {Various mutations in humans and animals lead to the selective and progressive degeneration of motoneurons, resulting in muscular weakness, subsequent paralysis, and death (1-3). Amyotrophic lateral sclerosis (ALS) is the most common adult human motoneuron disease, but the vast majority of sporadic and familial cases of ALS are still of unknown origin (4). Murine models of motoneuron diseases, derived from spontaneous mutations in the colonies, have been known for half a century. Prior to the first identifications of the mutated proteins in human ALS, they have largely been used to explore the disease etiology. The chromosomal localization of these mutations does not favor a genetic similarity between these murine models and the few human forms of the disease for which the mutation or the chromosomal localization is known. Yet the fact that most human ALS cases are of unknown etiology and the recent discovery of molecules with no known role in motoneuron survival (5-7), indicate that these murine mutants may still contribute to the understanding of motoneuronal degenerative processes. This can be exemplified by the work performed on the wobbler mouse, one of the oldest and most extensively studied models, which is reviewed here.}, }
@article {pmid14504315, year = {2003}, author = {Horner, RD and Kamins, KG and Feussner, JR and Grambow, SC and Hoff-Lindquist, J and Harati, Y and Mitsumoto, H and Pascuzzi, R and Spencer, PS and Tim, R and Howard, D and Smith, TC and Ryan, MA and Coffman, CJ and Kasarskis, EJ}, title = {Occurrence of amyotrophic lateral sclerosis among Gulf War veterans.}, journal = {Neurology}, volume = {61}, number = {6}, pages = {742-749}, doi = {10.1212/01.wnl.0000069922.32557.ca}, pmid = {14504315}, issn = {1526-632X}, mesh = {Adult ; Age of Onset ; Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; Cohort Studies ; Female ; Humans ; Incidence ; Indian Ocean ; Male ; Middle Aged ; Persian Gulf Syndrome/*epidemiology ; Retrospective Studies ; Risk ; *Veterans ; *Warfare ; }, abstract = {BACKGROUND: In response to Gulf War veterans' concerns of high rates of ALS, this investigation sought to determine if Gulf War veterans have an elevated rate of ALS.<br><br>METHODS: A nationwide epidemiologic case ascertainment study design was used to ascertain all occurrences of ALS for the 10-year period since August 1990 among active duty military and mobilized Reserves, including National Guard, who served during the Gulf War (August 2, 1990, through July 31, 1991). The diagnosis of ALS was confirmed by medical record review. Risk was assessed by the age-adjusted, average, annual 10-year cumulative incidence rate.<br><br>RESULTS: Among approximately 2.5 million eligible military personnel, 107 confirmed cases of ALS were identified for an overall occurrence of 0.43 per 100,000 persons per year. A significant elevated risk of ALS occurred among all deployed personnel (RR = 1.92; 95% CL = 1.29, 2.84), deployed active duty military (RR = 2.15, 95% CL = 1.38, 3.36), deployed Air Force (RR = 2.68, 95% CL = 1.24, 5.78), and deployed Army (RR = 2.04; 95% CL = 1.10, 3.77) personnel. Elevated, but nonsignificant, risks were observed for deployed Reserves and National Guard (RR = 2.50; 95% CL = 0.88, 7.07), deployed Navy (RR = 1.48, 95% CL = 0.62, 3.57), and deployed Marine Corps (RR = 1.13; 95% CL = 0.27, 4.79) personnel. Overall, the attributable risk associated with deployment was 18% (95% CL = 4.9%, 29.4%).<br><br>CONCLUSIONS: Military personnel who were deployed to the Gulf Region during the Gulf War period experienced a greater post-war risk of ALS than those who were not deployed to the Gulf.}, }
@article {pmid14501843, year = {2003}, author = {Anderson, K and Talbot, K}, title = {Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling.}, journal = {Current opinion in neurology}, volume = {16}, number = {5}, pages = {595-599}, doi = {10.1097/01.wco.0000093102.34793.13}, pmid = {14501843}, issn = {1350-7540}, mesh = {Animals ; Disease Models, Animal ; Humans ; Motor Neurons/*metabolism/pathology ; Muscular Atrophy, Spinal/*genetics/pathology/therapy ; Ribonucleoproteins/*genetics ; }, abstract = {PURPOSE OF REVIEW: Many forms of spinal muscular atrophy, a pure lower motor neuron disease, have been characterized clinically but the molecular basis of most of these is unknown. In this article we review recent developments in our understanding of the spinal muscular atrophies and how this knowledge has revealed important new insights into the causes of motor neuron vulnerability which may ultimately lead to novel therapies for this untreatable group of disorders.<br><br>RECENT FINDINGS: The identification of the genetic basis of two forms of autosomal recessive spinal muscular atrophy has revealed that lower motor neurons appear to have a specific vulnerability to defects in RNA metabolism. Most notably, the survival motor neuron protein, deficient in the most common form of spinal muscular atrophy, plays a multifunctional role in ribonucleoprotein metabolism and pre-messenger RNA splicing. The role of this protein in motor neurons is currently under intense study. The identification of two other spinal muscular atrophy-causing genes has provided support for the central role of components of the RNA metabolic pathway in determining motor neuron survival.<br><br>SUMMARY: Understanding the molecular basis of lower motor neuron vulnerability in disorders such as spinal muscular atrophy will ultimately allow these disabling disorders to be treated. In addition we can expect to learn much about basic neuronal biology and about the pathways that are relevant to more common neurodegenerative disorders such as amyotrophic lateral sclerosis.}, }
@article {pmid13678536, year = {2003}, author = {Inoue, M and Sato, EF and Nishikawa, M and Park, AM and Kira, Y and Imada, I and Utsumi, K}, title = {Cross talk of nitric oxide, oxygen radicals, and superoxide dismutase regulates the energy metabolism and cell death and determines the fates of aerobic life.}, journal = {Antioxidants &amp; redox signaling}, volume = {5}, number = {4}, pages = {475-484}, doi = {10.1089/152308603768295221}, pmid = {13678536}, issn = {1523-0864}, mesh = {Aerobiosis ; Animals ; Cell Death ; *Energy Metabolism ; Humans ; Mitochondria/drug effects/enzymology/metabolism/pathology ; Neoplasms/drug therapy/pathology ; Nitric Oxide/*metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {Although oxygen is required for the energy metabolism in aerobic organisms, it generates reactive oxygen and nitrogen species that impair a wide variety of biological molecules, including lipids, proteins, and DNA, thereby causing various diseases. Because mitochondria are the major site of free radical generation, they are highly enriched with enzymes, such as Mn-type superoxide dismutase in matrix, and antioxidants including GSH on both sides of inner membranes, thus minimizing oxidative stress in and around this organelle. We recently showed that a cross talk of nitric oxide and oxygen radicals regulates the circulation, energy metabolism, reproduction, and remodeling of cells during embryonic development, and functions as a major defense system against pathogens. The present work shows that Cu/Zn-type superoxide dismutase, which has been postulated for a long time to be a cytosolic enzyme, also localizes bound to inner membranes of mitochondria, thereby minimizing oxidative stress in and around this organelle, while mitochondrial association decreases markedly with the variant types of the enzyme found in patients with familial amyotrophic lateral sclerosis. We also report that a cross talk of nitric oxide, superoxide, and molecular oxygen cooperatively regulates the fates of pathogens and their hosts and that oxidative stress in and around mitochondria also determines cell death in the development of animals and tissue injury caused by anticancer agents by some carnitine-inhibitable mechanism.}, }
@article {pmid13677809, year = {2003}, author = {Chan, S and Kaufmann, P and Shungu, DC and Mitsumoto, H}, title = {Amyotrophic lateral sclerosis and primary lateral sclerosis: evidence-based diagnostic evaluation of the upper motor neuron.}, journal = {Neuroimaging clinics of North America}, volume = {13}, number = {2}, pages = {307-326}, doi = {10.1016/s1052-5149(03)00018-2}, pmid = {13677809}, issn = {1052-5149}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*pathology ; *Evidence-Based Medicine ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Motor Neuron Disease/*diagnostic imaging/*pathology ; Motor Neurons/*diagnostic imaging/*pathology ; Tomography, Emission-Computed ; Tomography, Emission-Computed, Single-Photon ; Tomography, X-Ray Computed ; }, abstract = {Magnetic resonance imaging and MR spectroscopy are important tools in the diagnostic evaluation of patients with suspected motor neuron disease. Further investigation is needed to determine and to compare the utility of various neuroimaging markers for diagnosis and disease progression [112]. Newer MR tools, such as diffusion tensor imaging, magnetization transfer imaging, and functional MR imaging, have substantial promise as scientific and clinical tools in this ongoing endeavor.}, }
@article {pmid13129806, year = {2003}, author = {Miller, RG and Mitchell, JD and Lyon, M and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {3}, pages = {191-206}, pmid = {13129806}, issn = {1466-0822}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Databases as Topic ; Double-Blind Method ; Drug Evaluation ; Humans ; Motor Neuron Disease/classification/drug therapy/epidemiology/physiopathology ; Multicenter Studies as Topic ; Muscles/physiopathology ; Neuroprotective Agents/*therapeutic use ; Quality of Life ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*therapeutic use ; Risk ; Survival Analysis ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Riluzole 100 mg probably prolongs survival in patients with amyotrophic lateral sclerosis by about two months and the safety of the drug is not a major concern. The evidence from randomized controlled trials indicates that patients taking riluzole probably survive longer than patients taking placebo. The beneficial effects are very modest and the drug is expensive. Adverse effects from riluzole are relatively minor and for the most part reversible after stopping the drug. Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was November 2002.<br><br>SELECTION CRITERIA: Randomized trials of adults with diagnosis of amyotrophic lateral sclerosis (ALS), treated with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events.<br><br>We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio.<br><br>RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38).<br><br>CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with ALS. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease.}, }
@article {pmid13129799, year = {2003}, author = {Strong, M and Rosenfeld, J}, title = {Amyotrophic lateral sclerosis: a review of current concepts.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {3}, pages = {136-143}, doi = {10.1080/14660820310011250}, pmid = {13129799}, issn = {1466-0822}, mesh = {Age Factors ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics/physiopathology ; Cognition Disorders/etiology ; Dementia/*etiology ; Diagnosis, Differential ; Humans ; Neurobiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), once thought to be a rare neurodegenerative disease, affects between 1.2 and 1.8/100,000 individuals. This age-dependent disorder, similar to other major neurological disorders of the aging population (Alzheimer's and Parkinson's disease) is increasing in incidence at a rate which cannot be accounted for by population aging alone. Multiple clinical variants of ALS are now recognized which are associated with a spectrum of clinical outcomes from aggressive to rather indolent. Three variants of ALS are generally accepted, including the western Pacific type (often associated with dementia), familial (the majority of which are autosomal dominant in their inheritance) and classic sporadic ALS. Considerable biological heterogeneity underlies the disease process of ALS. By the time ALS is clinically evident, derangements at the cellular level in ALS are extensive and include alterations in the cytoskeleton, mitochondrial function, microglial activation, and the metabolism of reactive oxygenating species and glutamate. Our understanding of the genetic aspects of the disease continues to expand. These observations have led to the suggestion that multiple distinct etiologies may be responsible. Recent advances have also included the observation that cognitive decline may be present in a population of patients not previously recognised. Significant advances in both symptomatic and adjunctive therapy have resulted in prolonged quality and duration of life.}, }
@article {pmid12954195, year = {2003}, author = {Ichikawa, H}, title = {Hierarchy neural networks as applied to pharmaceutical problems.}, journal = {Advanced drug delivery reviews}, volume = {55}, number = {9}, pages = {1119-1147}, doi = {10.1016/s0169-409x(03)00115-7}, pmid = {12954195}, issn = {0169-409X}, mesh = {Animals ; *Neural Networks, Computer ; Predictive Value of Tests ; Swine, Miniature ; Technology, Pharmaceutical/*methods ; }, abstract = {Optimization and prediction are the main purposes in pharmaceutical application of the artificial neural networks (ANNs). To this end, hierarchy-type networks with the backpropagation learning method are most frequently used. This article reviews the basic operating characteristics of such networks. ANNs have outstanding abilities in both classification and fitting. The operation is basically carried out in a nonlinear manner. The nonlinearity brings forth merits as well as a small number of demerits. The reasons for the demerits are analyzed and their remedies are indicated. The mathematical relationships of ANN's operation and the ALS method as well as the multiregression analysis are reviewed. ANN can be regarded as a function that transforms an input vector to another (output) one. We examined the analytical formula for the partial derivative of this function with respect to the elements of the input vector. This is a powerful means to know the relationship between the input and the output. The reconstruction-learning method determines the minimum number of necessary neurons of the network and is useful to find the necessary descriptors or to trace the flow of information from the input to the output. Finally, the descriptor-mapping method was reviewed to find the nonlinear relationships between the output intensity and descriptors.}, }
@article {pmid12953386, year = {2003}, author = {Gerth van Wijk, R and van Cauwenberge, PB and Johansson, SG}, title = {[Revised terminology for allergies and related conditions].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {110}, number = {8}, pages = {328-331}, pmid = {12953386}, issn = {0028-2200}, mesh = {Europe ; Humans ; *Hypersensitivity/immunology ; Hypersensitivity, Delayed ; Hypersensitivity, Immediate ; Immunoglobulin E/immunology ; *Terminology as Topic ; }, abstract = {The European Academy of Allergology and Clinical Immunology has proposed a revised terminology for allergic and allergy-related reactions that can be used independently of target organ of patient age group. The proposed terminology is based on the present knowledge of the mechanisms which initiate and mediate allergic reactions. 'Hypersensitivity' is an umbrella term, 'allergy' involves a hypersensitivity reaction which is initiated by an immunological mechanism, and 'atopy' is an individual or familial tendency to produce IgE antibodies in response to low doses of allergens, and is accompanied by the typical symptoms or asthma, rhino-conjunctivitis or eczema/dermatitis. Each condition should be categorised als 'allergic/not allergic', and the allergic conditions should be further categorised as 'IgE-mediated/non IgE-mediated' (sometimes: 'IgE-associated'). Terms which are no longer in use include: 'idiosyncrasy' (this will now become 'hypersensitivity'); 'pseudo-allergy' ('non-allergic hypersensitivity'); 'extrinsic', 'intrinsic', 'endogenous' and 'exogenous asthma' ('allergic' (possibly 'IgE-mediated') and 'non-allergic asthma'); 'atopic eczema' ('atopic eczema/dermatitis syndrome'; 'allergic (possibly 'EgE-mediated') or 'non-allergic'); 'intrinsic' and 'cryptogenic variants of eczema' (non-allergic atopic eczema/dermatitis syndrom'); 'food intolerance' (non-allergic food hypersensitivity') and 'anaphylactoid reaction' ('non-allergic anaphylaxis').}, }
@article {pmid12946542, year = {2003}, author = {Litaker, JR and Chou, JY}, title = {Patterns of pharmacologic treatment of congestive heart failure in elderly nursing home residents and related issues: a review of the literature.}, journal = {Clinical therapeutics}, volume = {25}, number = {7}, pages = {1918-1935}, doi = {10.1016/s0149-2918(03)80196-0}, pmid = {12946542}, issn = {0149-2918}, mesh = {Aged ; Aged, 80 and over ; Angiotensin-Converting Enzyme Inhibitors/administration &amp; dosage/therapeutic use ; Cardiotonic Agents/administration &amp; dosage/therapeutic use ; Digoxin/administration &amp; dosage/therapeutic use ; Diuretics/administration &amp; dosage/therapeutic use ; Drug Utilization ; Heart Failure/*drug therapy ; Humans ; Nursing Homes ; }, abstract = {BACKGROUND: Congestive heart failure (CHF) is a serious clinical syndrome associated with increased morbidity, mortality, and health-related expenditure. In the United States, the incidence and prevalence of CHF have been shown to increase with age, particularly among the elderly (age >/=65 years). In addition, more elderly persons are living in or will be living in nursing homes. Given these trends, it is important to consider the quality of care, including pharmacologic treatment, received by elderly nursing home residents with a diagnosis of CHE There is currently a lack of clinical trial data on the pharmacologic treatment of CHF among elderly nursing home residents and, therefore, no standard of care. In lieu of clinical trial data, empiric studies based on nursing home populations may be useful.<br><br>OBJECTIVE: This article reviews empiric studies concerning the pharmacologic treatment of CHF in elderly nursing home residents.<br><br>METHODS: Empiric studies on the use of angiotensin-converting enzyme (ACE) inhibitors, digoxin, and diuretics in elderly nursing home residents with a diagnosis of CHF were identified through searches of MEDLINE, Cochrane Trials, and International Pharmaceutical Abstracts using the terms elderly, nursing home, geriatric, and heart failure. The search was limited to the past 11 years (1991-2002) to identify current patterns of treatment in the population of interest. Additional studies were identified through a manual search of the reference lists of the retrieved articles.<br><br>RESULTS: Thirteen empiric studies were identified: 9 examined ACE-inhibitor use, 4 digoxin use, and 7 diuretic use. The findings of these studies indicated that ACE inhibitors are underused, are often prescribed at clinically inefficient doses, and are used more often in "young" elderly nursing home residents (age 65-74 years). Among patients who received a prescription for digoxin, many did not have an appropriate indication (eg, no documented atrial fibrillation, normal sinus rhythm). Similarly, diuretics were found to be inappropriately prescribed to elderly nursing home residents for the treatment of CHF.<br><br>CONCLUSIONS: Based on the available empiric studies, elderly nursing home residents with a diagnosis of CHF do not appear to receive adequate treatment with ACE inhibitors, digoxin, or diuretics based on the recommendations of clinical or als or clinical guidelines. However, the clinical trials and clinical guidelines target the general elderly population and thus may not be applicable to elderly nursing home residents. Future research should explore factors influencing the pharmacologic treatment of CHF in elderly nursing home residents, and trials of new pharmacologic treatments for CHF should include elderly nursing home residents.}, }
@article {pmid12942157, year = {2003}, author = {Romano, G}, title = {Gene transfer in experimental medicine.}, journal = {Drug news &amp; perspectives}, volume = {16}, number = {5}, pages = {267-276}, doi = {10.1358/dnp.2003.16.5.829314}, pmid = {12942157}, issn = {0214-0934}, mesh = {Animals ; Clinical Trials as Topic/methods ; *Gene Transfer Techniques ; Genetic Therapy/adverse effects/statistics &amp; numerical data ; *Human Experimentation ; Humans ; }, abstract = {Gene transfer technology has many potential applications in medicine. Phase I and phase II gene-based clinical trials have been conducted for the treatment of cancer, monogenic disorders, some neurodegenerative illnesses, cardiopathies and infectious diseases. A phase I gene therapy clinical trial has recently been approved for the treatment of Parkinson's disease, while preclinical studies are in progress to develop gene-based interventions for the treatment of Alzheimer's disease and Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and diabetes type 1 and type 2. A number of gene transfer models have been generated for gene therapy and genetic immunization programs. Vector design is addressing several pressing issues in the matter of gene delivery improvement, stabilization of transgene expression and safety. This is necessary in order to achieve efficient gene-based therapeutic interventions. Indeed, considerable progress has been reported in the field of vector design, which has produced some encouraging results in clinical trials and preclinical studies. However, vector design should be further developed to allow for the successful application of gene transfer technology in therapy. This review summarizes the latest achievements and controversies in clinical trials and preclinical studies in the field of gene therapy.}, }
@article {pmid12939543, year = {2003}, author = {Shigeri, Y and Shimamoto, K}, title = {[Pharmacology of excitatory amino acid transporters (EAATs and VGLUTs)].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {122}, number = {3}, pages = {253-264}, doi = {10.1254/fpj.122.253}, pmid = {12939543}, issn = {0015-5691}, mesh = {Amino Acid Transport System X-AG/chemistry/genetics/*physiology ; Animals ; Drug Design ; Glutamic Acid/*metabolism/physiology ; Humans ; Learning ; Memory ; Neurodegenerative Diseases/etiology ; Neuronal Plasticity ; Synaptic Transmission ; }, abstract = {L-Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS). It contributes not only to fast synaptic neurotransmission but also to complex physiological processes like plasticity, learning, and memory. Glutamate is synthesized in the cytoplasm and stored in synaptic vesicles by a proton gradient-dependent uptake system (VGLUTs). Following its exocytotic release, glutamate activates different kinds of glutamate receptors and mediates excitatory neurotransmission. To terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels, glutamate is quickly removed by Na(+)-dependent glutamate transporters (EAATs). Recently, three vesicular glutamate transporters (VGLUT1-3) and five Na(+)-dependent glutamate transporters (EAAT1-5) were identified. VGLUTs and EAATs are thought to play important roles in neuronal disorders, such as amyotrophic lateral sclerosis, Alzheimer's disease, cerebral ischemia, and Huntington's disease. In this review, the development of new compounds to regulate the function of VGLUTs and EAATs will be described.}, }
@article {pmid12935309, year = {2003}, author = {Zhu, X and Perry, G and Smith, MA}, title = {Amyotrophic lateral sclerosis: a novel hypothesis involving a gained 'loss of function' in the JNK/SAPK pathway.}, journal = {Redox report : communications in free radical research}, volume = {8}, number = {3}, pages = {129-133}, doi = {10.1179/135100003225001494}, pmid = {12935309}, issn = {1351-0002}, support = {NS38648/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Free Radicals ; Guanine Nucleotide Exchange Factors/physiology ; Humans ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases/*physiology ; *Signal Transduction ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that mainly affects motor neurons. Despite intensive research efforts inspired by the mile-stone discovery linking the Cu/Zn superoxide dismutase 1 (SOD1) gene to a subset of familial cases, the mechanisms underlying disease pathogenesis are still largely unknown. Nonetheless, the recent finding of a second gene associated with familial form of the disease, ALS2, is likely to be of great help in elucidating the key pathways involved in motor neuron degeneration. Here, we provide evidence that the JNK/SAPK pathway plays a critical neuroprotective role in susceptible motor neurons in ALS. The involvement of the JNK/SAPK pathway integrates our knowledge about these two known genetic factors into a single pathogenic pathway involved in both sporadic and familial ALS.}, }
@article {pmid12909279, year = {2003}, author = {Carrí, MT and Ferri, A and Cozzolino, M and Calabrese, L and Rotilio, G}, title = {Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals.}, journal = {Brain research bulletin}, volume = {61}, number = {4}, pages = {365-374}, doi = {10.1016/s0361-9230(03)00179-5}, pmid = {12909279}, issn = {0361-9230}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Animals ; *Homeostasis ; Humans ; Metals/*metabolism ; Motor Neurons ; Nerve Degeneration/metabolism/*physiopathology ; *Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis is one of the most common neurodegenerative disorders, with an incidence of about 1/100,000. One of the typical features of this progressive, lethal disease, occurring both sporadically and as a familial disorder, is degeneration of cortical and spinal motor neurones. Present evidence indicates that loss of neurones in patients results from a complex interplay among oxidative injury, excitotoxic stimulation, dysfunction of critical proteins and genetic factors. This review focuses on existing evidence that oxidative stress is a major culprit in the pathogenesis of amyotrophic lateral sclerosis. An increase in reactive oxygen species and in products of oxidation has been observed both in post-mortem samples and in experimental models for ALS. This increase may be consequent to altered metabolism of copper and iron ions, that share the property to undergo redox cycling and generate reactive oxygen species. Metal-mediated oxidative stress would lead to several intracellular alterations and contribute to the induction of cell death pathways.}, }
@article {pmid12909079, year = {2003}, author = {Arundine, M and Tymianski, M}, title = {Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity.}, journal = {Cell calcium}, volume = {34}, number = {4-5}, pages = {325-337}, doi = {10.1016/s0143-4160(03)00141-6}, pmid = {12909079}, issn = {0143-4160}, support = {NS 39060/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Calcium/*metabolism/toxicity ; Calcium Signaling/physiology ; Glutamic Acid/physiology ; Guanylate Kinases ; Homeostasis/drug effects/physiology ; Humans ; Membrane Proteins/physiology ; Nerve Degeneration/metabolism/*physiopathology ; Nerve Tissue Proteins/physiology ; Neurodegenerative Diseases/metabolism/physiopathology ; Neurotoxins/*metabolism ; Nucleoside-Phosphate Kinase/metabolism ; Receptors, AMPA/chemistry/physiology ; Receptors, N-Methyl-D-Aspartate/chemistry/physiology ; }, abstract = {Excitotoxicity contributes to neuronal degeneration in many acute CNS diseases, including ischemia, trauma, and epilepsy, and may also play a role in chronic diseases, such as amyotrophic lateral sclerosis (ALS). Key mediators of excitotoxic damage are Ca ions (Ca(2+)), which under physiological conditions govern a multitude of cellular processes, including cell growth, differentiation, and synaptic activity. Consequently, homeostatic mechanisms exist to maintain a low intracellular Ca(2+) ion concentration so that Ca(2+) signals remain spatially and temporally localized. This permits multiple independent Ca-mediated signaling pathways to occur in the same cell. In excitotoxicity, excessive synaptic release of glutamate can lead to the disregulation of Ca(2+) homeostasis. Glutamate activates postsynaptic receptors, including the ionotropic N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) proprionate (AMPA), and kainate receptors. Upon their activation, these open their associated ion channel to allow the influx of Ca(2+) and Na(+) ions. Although physiological elevations in intracellular Ca(2+) are salient to normal cell functioning, the excessive influx of Ca(2+) together with any Ca(2+) release from intracellular compartments can overwhelm Ca(2+)-regulatory mechanisms and lead to cell death. Although Ca(2+) disregulation is paramount to neurodegeneration, the exact mechanism by which Ca(2+) ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca(2+)-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca(2+) entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca(2+) regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms.}, }
@article {pmid12893007, year = {2003}, author = {Zarkovic, K}, title = {4-hydroxynonenal and neurodegenerative diseases.}, journal = {Molecular aspects of medicine}, volume = {24}, number = {4-5}, pages = {293-303}, doi = {10.1016/s0098-2997(03)00024-4}, pmid = {12893007}, issn = {0098-2997}, mesh = {Aldehydes/immunology/*metabolism ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Immunohistochemistry ; Lipid Peroxidation/physiology ; Neurodegenerative Diseases/immunology/*metabolism ; Neurons/immunology/pathology ; Parkinson Disease/metabolism ; Rats ; }, abstract = {The development of oxidative stress, in which production of highly reactive oxygen species (ROS) overwhelms antioxidant defenses, is a feature of many neurological diseases: ischemic, inflammatory, metabolic and degenerative. Oxidative stress is increasingly implicated in a number of neurodegenerative disorders characterized by abnormal filament accumulation or deposition of abnormal forms of specific proteins in affected neurons, like Alzheimer's disease (AD), Pick's disease, Lewy bodies related diseases, amyotrophic lateral sclerosis (ALS), and Huntington disease. Causes of neuronal death in neurodegenerative diseases are multifactorial. In some familiar cases of ALS mutation in the gene for Cu/Zn superoxide dismutase (SOD1) can be identified. In other neurodegenerative diseases ROS have some, usually not clear, role in early pathogenesis or implications on neuronal death in advanced stages of illness. The effects of oxidative stress on "post-mitotic cells", such as neurons may be cumulative, hence, it is often unclear whether oxidative damage is a cause or consequence of neurodegeneration. Peroxidation of cellular membrane lipids, or circulating lipoprotein molecules generates highly reactive aldehydes among which one of most important is 4-hydroxynonenal (HNE). The presence of HNE is increased in brain tissue and cerebrospinal fluid of AD patients, and in spinal cord of ALS patients. Immunohistochemical studies show presence of HNE in neurofibrilary tangles and in senile plaques in AD, in the cytoplasm of the residual motor neurons in sporadic ALS, in Lewy bodies in neocortical and brain stem neurons in Parkinson's disease (PD) and in diffuse Lewy bodies disease (DLBD). Thus, increased levels of HNE in neurodegenerative disorders and immunohistochemical distribution of HNE in brain tissue indicate pathophysiological role of oxidative stress in these diseases, and especially HNE in formation of abnormal filament deposites.}, }
@article {pmid12873154, year = {2003}, author = {Festoff, BW and Suo, Z and Citron, BA}, title = {Prospects for the pharmacotherapy of amyotrophic lateral sclerosis : old strategies and new paradigms for the third millennium.}, journal = {CNS drugs}, volume = {17}, number = {10}, pages = {699-717}, pmid = {12873154}, issn = {1172-7047}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/pathology ; Animals ; Cell Death ; Drug Design ; Excitatory Amino Acid Antagonists/therapeutic use ; Glutamic Acid/metabolism ; Humans ; Neurons/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Riluzole/therapeutic use ; }, abstract = {Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly developing technologies if we are to discover pharmaceutical treatments that will help a significant population of patients with the disease. The focus of ALS research over the last 10 years has been on reactive oxygen species (ROS) and glutamate excitotoxicity, resulting in several clinical trials and the launch of the only drug currently available for the treatment of ALS, riluzole. Unfortunately, the therapeutic benefits have been minimal, at best, and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease course. By emphasising ROS and glutamate excitotoxicity, current ALS research has only partially been able to attenuate the rate of motor decline and neuronal loss associated with this illness. Clues to additional therapeutic potentialities will come from an increased understanding of the mode of cell death (apoptotic or other) and the pathways leading to neuronal demise. If death is apoptotic, inhibiting caspases may be useful. The regulatory modifications for cell death at the molecular level remain to be determined and exploited to prevent neuronal loss, although novel pathways have been recently elucidated that impact on protein aggregation and processing. Oxidative stress, seen in both familial and sporadic forms of ALS, may be only one post-translational mechanism likely to affect specific proteins essential for the health and stability of motor neurons. Protein cross-linking by transglutaminase paralleling that may lead to defects in proteasome function may also be a significant mechanism. The latest capabilities to screen protein changes in specific cells represent the kinds of advances needed to combat ALS in the third millennium.}, }
@article {pmid12871169, year = {2003}, author = {Avramut, M and Achim, CL}, title = {Immunophilins in nervous system degeneration and regeneration.}, journal = {Current topics in medicinal chemistry}, volume = {3}, number = {12}, pages = {1376-1382}, doi = {10.2174/1568026033451871}, pmid = {12871169}, issn = {1568-0266}, mesh = {Animals ; Cyclosporine/*therapeutic use ; Humans ; Immunophilins/*therapeutic use ; Nerve Regeneration/*physiology ; Nervous System Diseases/*drug therapy ; Neurons/*physiology ; Signal Transduction ; Tacrolimus/chemistry/*therapeutic use ; }, abstract = {Immunophilins are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their non- immunosuppressive analogs, which are collectively referred to as "immunophilin ligands" (IPL). Cyclosporin A binds to a class of IP called cyclophilins, whereas the receptors for FK506 and rapamycin belong to the family of FK506- binding proteins (FKBP). The latter are designated according to their molecular weight: FKBP12, 25, 52 etc. FKBP levels in the rat brain are up to 50 times higher than in the immune system. FKBP12 is associated with IP3 and ryanodine receptors present on the endoplasmic reticulum and plays a role in stabilizing calcium release. It has also been proposed to be a modulator of the TGFbeta receptor activity. Crush injury of facial or sciatic nerves in rat leads to markedly increased FKBP12 levels in the respective nerve nuclei and this increase is related to nerve regeneration. Cyclophilin A protects cells from death following expression of mutant Cu/ Zn superoxide dismutase, which is associated with familial amyotrophic lateral sclerosis. Our recent studies show that FKBP12 and FKBP52 are expressed in the human nervous system, especially in the substantia nigra- deep gray matter axis. In neurodegenerative diseases, FKBP12 levels increase in neurons situated in areas of pathology. This IP colocalizes with synaptophysin and alpha- synuclein, suggesting that it may become a novel marker of pathology. Immunophilins participate in axonal transport, synaptic vesicle assembly and may play a role in neuroprotection against abnormal protein aggregation, suggesting a potential avenue of therapeutic interventions.}, }
@article {pmid12870110, year = {2003}, author = {Gelinas, DF}, title = {Pulmonary function screening.}, journal = {Seminars in neurology}, volume = {23}, number = {1}, pages = {89-96}, doi = {10.1055/s-2003-40756}, pmid = {12870110}, issn = {0271-8235}, mesh = {Humans ; Neuromuscular Diseases/*complications/physiopathology ; Positive-Pressure Respiration ; Respiration Disorders/*diagnosis/etiology/physiopathology/*therapy ; Sleep Apnea Syndromes/etiology ; Sleep, REM ; Tracheostomy ; }, abstract = {Patients who suffer from neuromuscular diseases often have complications from respiratory insufficiencies. Some neuromuscular diseases, for example Landry Guillain-Barré syndrome, may only require temporary tracheal intubation; patients with other neuromuscular diseases, such as amyotrophic lateral sclerosis, may decide with the assistance of their doctor and family to opt for lifelong noninvasive ventilatory support. Other patients may only opt for noninvasive positive pressure ventilation. Respiratory dysfunction is caused by weakness of the upper airway muscles, which can lead to sleep apnea, abnormal swallow, and decreased respiratory muscle strength, as well as a decrease in total lung volume. Early respiratory changes in patients with neuromuscular disease are often best detected during sleep. During rapid eye movement sleep, there is a reduction in respiratory drive predisposing to hypopneas and apneas. The majority of neuromuscular patients with respiratory insufficiency may be monitored and treated in the outpatient setting, thus allowing them to remain in their homes.}, }
@article {pmid12849120, year = {2003}, author = {Isacson, O}, title = {The production and use of cells as therapeutic agents in neurodegenerative diseases.}, journal = {The Lancet. Neurology}, volume = {2}, number = {7}, pages = {417-424}, doi = {10.1016/s1474-4422(03)00437-x}, pmid = {12849120}, issn = {1474-4422}, mesh = {Animals ; Brain/pathology ; Brain Tissue Transplantation/*methods ; Cell Differentiation ; Fetal Tissue Transplantation/*methods ; Humans ; Neurodegenerative Diseases/*therapy ; Neurons/*transplantation ; Stem Cells/cytology ; }, abstract = {Although progressive neurodegenerative diseases have very different and highly specific causes, the dysfunction or loss of a vulnerable group of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. When a disease is diagnosed, the first step is to instigate protective measures to prevent further degeneration. However, most patients are symptom-free until almost all of the vulnerable cells have become dysfunctional or have died. There are known molecular mechanisms and processes in stem cells and progenitor cells that may be of use in the future design and selection of cell-based replacement therapies for neurological diseases. This review provides examples of conceptual and clinical problems that have been encountered in the development of cell-based treatments, and specific criteria for the effective use of cells in the future treatment of neurodegenerative diseases.}, }
@article {pmid12795519, year = {2003}, author = {Krivickas, LS}, title = {Amyotrophic lateral sclerosis and other motor neuron diseases.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {14}, number = {2}, pages = {327-345}, doi = {10.1016/s1047-9651(02)00119-5}, pmid = {12795519}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Diagnostic Imaging ; Electrodiagnosis/*methods ; Humans ; Motor Neuron Disease/*diagnosis ; Muscular Atrophy, Spinal/diagnosis ; Poliomyelitis/diagnosis ; }, abstract = {The anterior horn cell diseases, with the exception of polio, are progressive degenerative diseases of the motor neurons. These disorders include SMA types I to III in children and familial and sporadic ALS and its variants (PMA, PLS, and PBP), Kennedy's disease, and SMA type IV in adults. The electrodiagnostic study is a crucial step in the diagnostic process for all of these disorders. In general, motor NCS may be normal or reveal low CMAP amplitudes with relatively normal conduction velocities. Sensory NCS, except in the case of Kennedy's disease, are normal. The NEE is notable for the often abundant presence of abnormal spontaneous activity, including fibrillation potentials and positive sharp waves, fasciculation potentials, and complex repetitive discharges. Motor unit morphology is abnormal, with polyphasic motor units and large amplitude and duration MUAPs when the disease is slowly progressive. Recruitment in affected muscles is reduced with abnormally rapidly firing motor units. To diagnose a widespread disorder of the motor neurons, abnormalities must be present in multiple muscles with different nerve root and peripheral nerve innervation in multiple limbs. The Lambert Criteria and the El Escorial Criteria are the two most widely accepted sets of electrodiagnostic criteria for ALS. The electrodiagnostic diagnosis must be supported by appropriate history and physical examination findings and the exclusion, via neuroimaging and laboratory testing, of other diseases that may mimic a generalized disorder of the motor neurons.}, }
@article {pmid12795515, year = {2003}, author = {Shefner, JM and Gooch, CL}, title = {Motor unit number estimation.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {14}, number = {2}, pages = {243-260}, doi = {10.1016/s1047-9651(02)00130-4}, pmid = {12795515}, issn = {1047-9651}, mesh = {Action Potentials/physiology ; Cell Count/*methods ; Humans ; Motor Neurons/*pathology ; Neuromuscular Diseases/*pathology ; }, abstract = {Since its introduction 30 years ago, MUNE techniques have increasingly been refined and applied to a wide variety of neuromuscular disorders. Differences of opinion remain among MUNE investigators as to which method is best; however, statistical and MPS MUNE are currently the most widely used. Numerous methodologic issues remain, including the development of detailed universal standards for each technique and the implementation of modifications for the enhancement of reproducibility. These issues are the subjects of ongoing investigation. Despite technical variability, the MUNE values obtained using different methods show good agreement in studies of normal subjects and in patients with a variety of neurogenic processes. MUNE has been applied most successfully to patients with amyotrophic lateral sclerosis and to animal models of motor neuron disease, providing significant insight into the pathophysiology of these disorders. These techniques are increasingly being incorporated into clinical therapeutic trials. MUNE offers promise in the study of neuromuscular disease, enabling the collection of novel data in the living patient unobtainable by any other method.}, }
@article {pmid12792307, year = {2003}, author = {Rojas-Marcos, I and Rousseau, A and Keime-Guibert, F and Reñé, R and Cartalat-Carel, S and Delattre, JY and Graus, F}, title = {Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer.}, journal = {Medicine}, volume = {82}, number = {3}, pages = {216-223}, doi = {10.1097/01.md.0000076004.64510.ce}, pmid = {12792307}, issn = {0025-7974}, mesh = {Aged ; Antibodies, Neoplasm/immunology ; Antigens, Neoplasm/immunology ; Breast Neoplasms/*complications ; Female ; Genital Neoplasms, Female/*complications ; Humans ; Middle Aged ; Paraneoplastic Polyneuropathy/*complications/immunology ; Retrospective Studies ; }, abstract = {We conducted the current review of the paraneoplastic neurologic syndromes (PNSs) associated with gynecologic and breast carcinomas to describe their clinical and immunologic characteristics and their relative frequency. We retrospectively reviewed 92 patients whose serum was sent to our laboratories to detect onconeural antibodies and who were diagnosed as having PNSs associated with breast or gynecologic tumors. PNSs were defined as "definitive" and "possible" (atypical PNS, no onconeural antibodies, and no improvement after tumor treatment). Forty-nine patients had breast and 43 had gynecologic cancer. Sixty-three patients had onconeural antibodies (50 Yo-ab, 5 Hu-ab, 5 Ri-ab, and 3 amphiphysin-ab). Cerebellar ataxia represented 57 (62%) of all PNSs and was associated with anti-Yo in 88%. All Yo-abnegative patients had breast cancer; 4 of them had a mild cerebellar syndrome that improved after tumor treatment. Sensorypredominant neuropathies were present in 17 (18%) patients. Seven of them had Hu-ab (5) or amphiphysin-ab (2). Other PNSs were opsoclonus-myoclonus syndrome (4 cases, Ri-ab in 2), sensorimotor neuropathy (4 cases), paraneoplastic encephalomyelitis (4 cases, Ri-ab in 3), paraneoplastic retinopathy (2 cases), amyotrophic lateral sclerosis (2 cases), stiff-person syndrome (1 with amphiphysin-ab), and limbic encephalitis (1 case). All patients with gynecologic cancer presented definitive PNS, and onconeural antibodies were diagnosed in 93% of them. In contrast, 20% of PNSs associated with breast cancer were defined as possible and the incidence of onconeural antibodies was 51%, excluding the 2 patients with paraneoplastic retinopathy in whom antiretinal antibodies were not analyzed. In patients with possible PNS, a coincidental association between the tumor and the neurologic disorder cannot be excluded.}, }
@article {pmid12792141, year = {2003}, author = {Armon, C}, title = {An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis.}, journal = {Neuroepidemiology}, volume = {22}, number = {4}, pages = {217-228}, doi = {10.1159/000070562}, pmid = {12792141}, issn = {0251-5350}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; *Evidence-Based Medicine ; Humans ; *Risk Factors ; }, abstract = {An evidence-based medicine approach was applied to evaluate analytic studies of exogenous risk factors for amyotrophic lateral sclerosis (ALS) published since 1991. Classification systems for evaluating the literature and for drawing conclusions based on the class of available evidence were developed, modeled on those used by national societies. Considerations regarding the impact on the general public of confirming a role for putative risk factors were made explicit. There was evidence in support of smoking being a probable ('more likely than not') risk factor for ALS. Smoking has broad public health impact, no redeeming features, and is a modifiable risk factor. Evidence supported the conclusion that the following were probably not risk factors for ALS: trauma, physical activity, residence in rural areas and alcohol consumption. Evidence-based medicine methodology does not permit calculation of the magnitude of type I or type II errors in drawing these conclusions. New evidence may change these conclusions. Recommendations for future research include: draw on clinical trial methodology in designing future, confirmatory, case-control studies; consider utilizing cohort studies, recognizing the longer timelines for these to come to fruition; accord priority to investigating putative risk factors with greatest public health impact. Advances in study methodology may lead to development of finite research cycles for individual putative risk factors for sporadic ALS.}, }
@article {pmid12789618, year = {2003}, author = {Carter, GT and Krivickas, LS and Weydt, P and Weiss, MD and Miller, RG}, title = {Drug therapy for amyotrophic lateral sclerosis: Where are we now?.}, journal = {IDrugs : the investigational drugs journal}, volume = {6}, number = {2}, pages = {147-153}, pmid = {12789618}, issn = {1369-7056}, support = {HB133B980008/HB/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/etiology ; Animals ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Creatine/therapeutic use ; Cyclooxygenase Inhibitors/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {In the 60 years since Lou Gehrig died from amyotrophic lateral sclerosis (ALS) there have been numerous advances in our understanding of this disease. However, scant progress has been made regarding disease-altering treatments. Today most physicians still recommend vitamin E, which is the treatment Gehrig himself received. In this paper we will review what is currently known about the pathophysiology of ALS as well as the history of clinical trials in ALS. We indicate current and future directions in research and clinical trials, and also argue that a logical next step for clinical trials in ALS should be combination drug treatment.}, }
@article {pmid12787319, year = {2003}, author = {Dawbarn, D and Allen, SJ}, title = {Neurotrophins and neurodegeneration.}, journal = {Neuropathology and applied neurobiology}, volume = {29}, number = {3}, pages = {211-230}, doi = {10.1046/j.1365-2990.2003.00487.x}, pmid = {12787319}, issn = {0305-1846}, mesh = {Animals ; Humans ; Nerve Degeneration/pathology/*physiopathology ; *Nerve Growth Factors ; Neurodegenerative Diseases/drug therapy/pathology/*physiopathology ; Neurons/pathology/physiology ; Receptors, Nerve Growth Factor/chemistry/*physiology ; }, abstract = {There is growing evidence that reduced neurotrophic support is a significant factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In this review we discuss the structure and functions of neurotrophins such as nerve growth factor, and the role of these proteins and their tyrosine kinase (Trk) receptors in the aetiology and therapy of such diseases. Neurotrophins regulate development and the maintenance of the vertebrate nervous system. In the mature nervous system they affect neuronal survival and also influence synaptic function and plasticity. The neurotrophins are able to bind to two different receptors: all bind to a common receptor p75NTR, and each also binds to one of a family of Trk receptors. By dimerization of the Trk receptors, and subsequent transphosphorylation of the intracellular kinase domain, signalling pathways are activated. We discuss here the structure and function of the neurotrophins and how they have been, or may be, used therapeutically in AD, PD, Huntington's diseases, ALS and peripheral neuropathy. Neurotrophins are central to many aspects of nervous system function. However they have not truly fulfilled their therapeutic potential in clinical trials because of the difficulties of protein delivery and pharmacokinetics in the nervous system. With the recent elucidation of the structure of the neurotrophins bound to their receptors it will now be possible, using a combination of in silico technology and novel screening techniques, to develop small molecule mimetics with much improved pharmacotherapeutic profiles.}, }
@article {pmid12785280, year = {2003}, author = {Janakiraman, L}, title = {Pediatric Advanced Life Support (PALS): the current guidelines.}, journal = {Indian journal of pediatrics}, volume = {70 Suppl 1}, number = {}, pages = {S34-8}, pmid = {12785280}, issn = {0019-5456}, mesh = {Advanced Cardiac Life Support/*methods ; Airway Obstruction/therapy ; American Heart Association ; Arrhythmias, Cardiac/therapy ; Blood Circulation/physiology ; Child ; Heart Arrest/diagnosis/therapy ; Humans ; Pediatrics/*methods ; Poisoning/therapy ; *Practice Guidelines as Topic ; Respiratory Insufficiency/diagnosis/therapy ; Shock/diagnosis/therapy ; United States ; Wounds and Injuries/therapy ; }, abstract = {Every 5 years the American Heart Association (AHA) updates the Guidelines for CPR and Emergency Cardiovascular Care (ECC). The ECC Guidelines 2000 incorporates all the current consensus of experts, from not only a variety of disciplines, but also a variety of countries and cultures and is evidence based. The new Guidelines emphasize interventions to reduce the risk of sudden deaths, early identification of respiratory failure and shock and implementation of Advanced Life Support (ALS) to treat respiratory and cardiac arrest.}, }
@article {pmid12784672, year = {2002}, author = {Takahashi, H}, title = {[Pathology of neurodegenerative diseases: with special reference to Parkinson's disease and amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {42}, number = {11}, pages = {1085-1087}, pmid = {12784672}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Parkinson Disease/*pathology ; }, abstract = {The causes of Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are still unknown. Aging, environmental factors and genetic factors may be involved in the development of these illnesses, especially the sporadic phenotypes. The details of PD pathology have made remarkable advances in the last 5 years, after the discovery of mutation of the alpha-synuclein gene in families with PD: all of the Lewy bodies (Lewy filaments) in familial and sporadic PD contain the gene product alpha-synuclein. Further studies are necessary to elucidate the mechanisms underlying the development of PD, and to determine the therapeutic targets through which it may be possible to prevent the disease. With regard to the pathology of ALS, it is of great importance that in this disease, characteristic neuronal cytoplasmic inclusions (i.e., Bunina bodies and ubiquitinated inclusions) have been described in the lower motor neurons. At present, however, compared with the Lewy bodies in PD, much less is known about the profiles of the inclusions associated with ALS. Early identifications of the proteins that constitute these inclusions would be desirable if we are to elucidate the molecular pathology, and thus the mechanisms underlying ALS.}, }
@article {pmid12782245, year = {2003}, author = {Strong, MJ}, title = {The basic aspects of therapeutics in amyotrophic lateral sclerosis.}, journal = {Pharmacology &amp; therapeutics}, volume = {98}, number = {3}, pages = {379-414}, doi = {10.1016/s0163-7258(03)00040-8}, pmid = {12782245}, issn = {0163-7258}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/pathology ; Humans ; }, abstract = {Once thought to be a single pathological disease state, amyotrophic lateral sclerosis (ALS) is now recognized to be the limited phenotypic expression of a complex, heterogeneous group of biological processes, resulting in an unrelenting loss of motor neurons. On average, individuals affected with the disease live <5 years. In this article, the complex nature of the pathogenesis of ALS, including features of age dependency, environmental associations, and genetics, is reviewed. Once held to be uncommon, it is now clear that ALS is associated with a frontotemporal dementia and that this process may reflect disturbances in the microtubule-associated tau protein metabolism. The motor neuron ultimately succumbs in a state where significant disruptions in neurofilament metabolism, mitochondrial function, and management of oxidative stress exist. The microenvironment of the neuron becomes a complex milieu in which high levels of glutamate provide a source of chronic excitatory neurotoxicity, and the contributions of activated microglial cells lead to further cascades of motor neuron death, perhaps serving to propagate the disease once established. The final process of motor neuron death encompasses many features of apoptosis, but it is clear that this alone cannot account for all features of motor neuron loss and that aspects of a necrosis-apoptosis continuum are at play. Designing pharmacological strategies to mitigate against this process thus becomes an increasingly complex issue, which is reviewed in this article.}, }
@article {pmid12773898, year = {2003}, author = {Vercelletto, M and Belliard, S and Wiertlewski, S and Venisse, T and Magne, C and Duyckaerts, C and Damier, P}, title = {[Neuropsychological and scintigraphic aspects of frontotemporal dementia preceding amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {159}, number = {5 Pt 1}, pages = {529-542}, pmid = {12773898}, issn = {0035-3787}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Aphasia/diagnosis/etiology ; Atrophy/diagnostic imaging/pathology ; Dementia/*diagnosis/etiology ; Dentate Gyrus/diagnostic imaging/pathology ; Diagnosis, Differential ; Female ; *Frontal Lobe/diagnostic imaging/pathology ; Hippocampus/diagnostic imaging/pathology ; Humans ; Hypoglossal Nerve/diagnostic imaging/pathology ; Male ; Memory Disorders/diagnosis/etiology ; Middle Aged ; Neurons/diagnostic imaging/pathology ; Neuropsychological Tests ; Semantics ; *Temporal Lobe/diagnostic imaging/pathology ; Tomography, Emission-Computed, Single-Photon ; Tomography, X-Ray Computed ; }, abstract = {Between 1993 and 2001, we observed fifteen patients (ten men and five women, mean age 63 years) with frontotemporal dementia (FTD) which preceded signs of amyotrophic lateral sclerosis (ALS) which developed 21 months later. Mean disease duration in the fourteen deceased patients was 38 months. FTD associated with ALS is characterized by rapid course, predominance of disinhibited forms (orbito-basal), presence of aphasia with neologisms, and semantic memory disorders. Performed in all patients, single-photon emission computed tomography demonstrated a bifrontal pattern of low uptake, sometimes associated with low uptake in the anterior temporal region. In one patient, neuropathology revealed neuron atrophy and loss in the frontotemporal region, the anterior horns, and the hypoglossal nucleus. Ubiquitin-positive inclusions were visible in the dentate gyrus of the hippocampus and in the anterior horns. The dementia/ALS association is classically described is uncommon. It belongs to the FTD group since the Lund and Manchester consensus. Approximately 15 p.100 of patient with FTD can be expected to develop ALS. About 250 cases have been reported in the literature, half of them in the Pacific area where the incidence of ALS is high (55/100,000 inhabitants versus 1/100,000 in the rest of the world). Intermediary forms of FTD, semantic dementia, and progressive non-fluent aphasia are discussed since several cases of non-fluent progressive aphasia associated with ALS are reported in the literature. The links between these two degenerative diseases are discussed.}, }
@article {pmid12769802, year = {2003}, author = {Di Matteo, V and Esposito, E}, title = {Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {2}, number = {2}, pages = {95-107}, doi = {10.2174/1568007033482959}, pmid = {12769802}, issn = {1568-007X}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/metabolism/*therapeutic use ; Humans ; Parkinson Disease/*drug therapy/metabolism ; }, abstract = {Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.}, }
@article {pmid12769603, year = {2002}, author = {Iwasaki, Y and Ikeda, K and Kinoshita, M}, title = {Molecular and cellular mechanism of glutamate receptors in relation to amyotrophic lateral sclerosis.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {1}, number = {5}, pages = {511-518}, doi = {10.2174/1568007023339021}, pmid = {12769603}, issn = {1568-007X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Binding Sites/drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology/therapeutic use ; Glutamic Acid/metabolism ; Humans ; Receptors, Glutamate/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the central nervous system (CNS) with an unknown etiology. This disorder is characterized clinically by muscular weakness and wasting, and pathologically by selective degeneration of the corticospinal tracts and motor neurons of the brain stem and spinal cord. Median survival following onset is 3 to 5 years. Riluzole, an antiglutamatergic agent has been shown to have modest beneficial effects on survival. Glutamate is the main excitatory neurotransmitter in the CNS and excessive activation of glutamate receptors is excitotoxic to neurons. Glutamate receptor-mediated excitotoxicity has been proposed to explain the pattern of selective neuronal cell death and clinical manifestation of ALS. Activation of glutamate receptors leading to elevation of intracellular calcium may play a major role. This review will focus on the current understanding of the molecular and cellular mechanisms of glutamate receptors in relation to ALS.}, }
@article {pmid12757848, year = {2003}, author = {Liochev, SI and Fridovich, I}, title = {Mutant Cu,Zn superoxide dismutases and familial amyotrophic lateral sclerosis: evaluation of oxidative hypotheses.}, journal = {Free radical biology &amp; medicine}, volume = {34}, number = {11}, pages = {1383-1389}, doi = {10.1016/s0891-5849(03)00153-9}, pmid = {12757848}, issn = {0891-5849}, support = {R01 DK 59868/DK/NIDDK NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics ; Animals ; Free Radicals/*metabolism ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Oxidation-Reduction ; *Oxidative Stress ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {FALS-associated missense mutations of SOD1 exhibit a toxic gain of function that leads to the death of motor neurons. The explanations for this toxicity fall into two broad categories. One involves a gain of some oxidative activity, while the second involves a gain of protein: protein interactions. Among the postulated oxidative activities are the following: (i) peroxidase action; (ii) superoxide reductase action; and, (iii) the enhancement of production of O2- by partial reversal of the normal SOD activity, which then leads to increased formation of ONOO(-). We will herein concentrate on evaluating the relative merits of these oxidative hypotheses and consider whether the experiments with transgenic animals that purport to disprove these oxidative explanations really do so.}, }
@article {pmid12745611, year = {2003}, author = {Silani, V and Leigh, N}, title = {Stem therapy for ALS: hope and reality.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {1}, pages = {8-10}, pmid = {12745611}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*transplantation ; Nerve Regeneration/*physiology ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; }, abstract = {All are agreed that there is pressing need for an effective treatment for Amyotrophic Lateral Sclerosis (ALS; MND). Such treatment may derive from a combination of therapeutic strategies aimed at different aspects of the disorder, and might include drugs directed at the initial, intermediate or terminal cascade of events leading to cell death, as well as the use of stem cells to replace dead motor neurons, or to protect those that remain. The attraction of cell implantation or transplantation is that it might help to overcome the inability of the CNS to replace lost neurons. It is also clear that neural implantation will yield little benefit if the donor cells fail to integrate functionally into the recipient CNS circuitry. In this respect, ALS poses an especially difficult problem. The recent breakthroughs in stem cell research might nevertheless provide possibilities for neural implantation and cell replacement therapy for patients with ALS. The potential impact of these new approaches to neurodegenerative diseases has been emphasised by the many experiments using human foetal cell grafts in patients affected by Parkinson's and Huntington's disease. Clinical benefits in Parkinson's disease seem to be associated with integration of the donor cells into the recipient brain. Despite promising results, however, significant constraints have hampered the use of foetal cells for neural implantation and transplantation. Besides ethical concerns, the viability, purity, and final destiny of the foetal tissue have not been completely defined. Foetal cells are, in addition, post-mitotic and cannot be expanded or stored for long periods, necessitating close synchronisation of tissue donation and neurosurgery.}, }
@article {pmid12740985, year = {2000}, author = {Emeryk-Szajewska, B}, title = {Electrophysiologic diagnostics of very early stages of ALS.}, journal = {Supplements to Clinical neurophysiology}, volume = {53}, number = {}, pages = {116-125}, doi = {10.1016/s1567-424x(09)70146-1}, pmid = {12740985}, issn = {1567-424X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; *Electrodiagnosis ; Humans ; }, }
@article {pmid12737529, year = {2003}, author = {Rao, MV and Nixon, RA}, title = {Defective neurofilament transport in mouse models of amyotrophic lateral sclerosis: a review.}, journal = {Neurochemical research}, volume = {28}, number = {7}, pages = {1041-1047}, pmid = {12737529}, issn = {0364-3190}, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/*metabolism ; Animals ; *Axonal Transport ; Intermediate Filament Proteins/metabolism ; Mice ; Mice, Transgenic ; Mutation ; Neurofilament Proteins/*metabolism ; Neurons/metabolism ; Phenotype ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Neurofilament proteins synthesized in the cell body of neurons are assembled and transported into axons, where they influence axon radial growth, axonal transport, and nerve conduction velocities. In diseased states, neurofilaments accumulate in cell bodies and proximal axons of affected neurons, and these lesions are characteristic of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease type 2 (CMT2), and hereditary sensory motor neuropathy. Although the molecular mechanisms that contribute to these accumulations are not yet identified, transgenic mouse models are beginning to provide insight into the role of neurofilament transport in disease-related dysfunction of neurons. This review addresses axonal transport in mouse models of ALS and the special significance of neurofilament transport in this disease.}, }
@article {pmid12737523, year = {2003}, author = {Choi, IY and Lee, SP and Guilfoyle, DN and Helpern, JA}, title = {In vivo NMR studies of neurodegenerative diseases in transgenic and rodent models.}, journal = {Neurochemical research}, volume = {28}, number = {7}, pages = {987-1001}, pmid = {12737523}, issn = {0364-3190}, support = {P01AG1761702/AG/NIA NIH HHS/United States ; R01EB0031504/EB/NIBIB NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Magnetic Resonance Imaging ; *Magnetic Resonance Spectroscopy ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*diagnosis/metabolism ; Rats ; }, abstract = {In vivo magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide unique quality to attain neurochemical, physiological, anatomical, and functional information non-invasively. These techniques have been increasingly applied to biomedical research and clinical usage in diagnosis and prognosis of diseases. The ability of MRS to detect early yet subtle changes of neurochemicals in vivo permits the use of this technology for the study of cerebral metabolism in physiological and pathological conditions. Recent advances in MR technology have further extended its use to assess the etiology and progression of neurodegeneration. This review focuses on the current technical advances and the applications of MRS and MRI in the study of neurodegenerative disease animal models including amyotrophic lateral sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases. Enhanced MR measurable neurochemical parameters in vivo are described in regard to their importance in neurodegenerative disorders and their investigation into the metabolic alterations accompanying the pathogenesis of neurodegeneration.}, }
@article {pmid12733424, year = {2003}, author = {Gambetti, P and Parchi, P and Chen, SG}, title = {Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia.}, journal = {Clinics in laboratory medicine}, volume = {23}, number = {1}, pages = {43-64}, doi = {10.1016/s0272-2712(02)00065-3}, pmid = {12733424}, issn = {0272-2712}, mesh = {*Creutzfeldt-Jakob Syndrome/epidemiology/genetics/pathology ; Humans ; *Insomnia, Fatal Familial/epidemiology/genetics/pathology ; PrPSc Proteins/chemistry/metabolism ; }, abstract = {Studies on hereditary CJD and FFI have contributed greatly to the understanding of all forms of prion disease. Most importantly, they have provided strong support for the prion hypothesis [2]. The linkage of pathogenic PRNP mutations to human prion disease strengthens the notion that a change in PrP conformation is a key event that triggers the development of the disease. Although hereditary CJD and FFI account for only 10% of all cases of human prion disease, they provide a unique opportunity for studying disease pathogenesis initiated by perturbation in the PrP structure. An understanding of the events that accompany a change in PrP conformation has far-reaching implications for sCJD (the most common form of the disease) and for sporadic fatal insomnia. A wealth of available evidence indicates that a common pathway in disease pathogenesis may be shared by both the sporadic and the hereditary forms of prion disease, except that the initiating events are stochastic in the former, rather than predetermined by the presence of a germ-line mutation. In addition, investigations of hereditary CJD and FFI have provided plausible mechanisms of phenotypic heterogeneity in prion disease, a phenomenon analogous to the "prion strain" diversity in animal prion disease. Although many other neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's chorea are fairly homogeneous in disease phenotype, prion disease includes many clinically and pathologically distinct disease entities. In hereditary prion disease, the disease phenotype is likely to be determined by the combined effect of pathogenic mutations, codon 129 polymorphism, and the type of PrPSc. The pathogenic mutations include point mutations that are located mostly in the central and C-terminal region of PrP, and deletion and insertion mutations that are located in the N-terminal region. It is conceivable that these distinct types of mutations may result in differential changes in conformation or stability of PrP. The codon 129 polymorphism plays a twofold role in modulating the disease outcome. On the mutant allele, it determines the basic features of the disease phenotype--as in the case of FFI and CJD178--that result respectively from the coupling of M or V at codon 129 with the D178N mutation. On the normal allele, it may modulate the severity of the phenotype. A PrPSc subtype is encoded by the PRNP haplotype, and subsequently is generated by a conformational conversion process that transforms the cellular isoform to the pathogenic protein. The site for the formation of a specific PrPSc conformer and its accumulation in different brain regions are likely to contribute to the clinical features and pathologic lesions. The phenotypic homogeneity in other neurologic diseases, including Alzheimer's disease, may be due, in part, to the lack of a powerful genetic modifier such as the codon 129 polymorphism in the PrP gene, and the lack of the ability of affected gene products such as PrP to assume multiple protein conformations. Clearly, the remaining issue in the understanding of pathogenesis of prion disease is a detailed and accurate knowledge of the in vivo processes and conditions for the formation of PrPSc that inevitably lead to the development and expression of the disease. This knowledge will enable the development of a rational and effective strategy for therapeutic intervention.}, }
@article {pmid12728191, year = {2003}, author = {Mattson, MP}, title = {Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders.}, journal = {Neuromolecular medicine}, volume = {3}, number = {2}, pages = {65-94}, pmid = {12728191}, issn = {1535-1084}, mesh = {Animals ; Cell Death/drug effects/*physiology ; Cell Survival/drug effects/*physiology ; Central Nervous System/drug effects/*metabolism/physiopathology ; Humans ; Neurodegenerative Diseases/drug therapy/*physiopathology/prevention &amp; control ; Neurons/drug effects/*metabolism/pathology ; Neurotoxins/*pharmacology ; Oxidative Stress/drug effects/physiology ; Receptors, Glutamate/drug effects/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.}, }
@article {pmid12718737, year = {2003}, author = {Pong, K}, title = {Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics.}, journal = {Expert opinion on biological therapy}, volume = {3}, number = {1}, pages = {127-139}, doi = {10.1517/14712598.3.1.127}, pmid = {12718737}, issn = {1471-2598}, mesh = {Animals ; Antioxidants/metabolism/therapeutic use ; Humans ; *Molecular Mimicry ; Neurodegenerative Diseases/*enzymology/*therapy ; Oxidative Stress/*physiology ; Superoxide Dismutase/chemistry/*metabolism/*therapeutic use ; }, abstract = {Evidence of oxidative stress is apparent in both acute and chronic neurodegenerative diseases, such as stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Increased generation of reactive oxygen species simply overwhelm endogenous antioxidant defences, leading to subsequent oxidative damage and cell death. Tissue culture and animal models have been developed to mimic some of the biochemical changes and neuropathology found in these diseases. In doing so, it has been experimentally demonstrated that oxidative stress plays a critical role in neuronal cell death. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) have demonstrated therapeutic efficacy in models of neurodegeneration. However, delivery and stability issues have reduced the enthusiasm to clinically develop these proteins. Most recently, SOD mimetics, small molecules which mimic the activity of endogenous superoxide dismutase, have come to the forefront of antioxidant therapeutics. This review will examine the experimental evidence supporting the use of scavengers of superoxide anions in treating some neurodegenerative diseases, such as stroke, PD and ALS, but also the pitfalls that have met antioxidant molecules in clinical trials.}, }
@article {pmid12717675, year = {2003}, author = {Carod-Artal, FJ}, title = {[Neurological syndromes linked with the intake of plants and fungi containing a toxic component (I). Neurotoxic syndromes caused by the ingestion of plants, seeds and fruits].}, journal = {Revista de neurologia}, volume = {36}, number = {9}, pages = {860-871}, pmid = {12717675}, issn = {0210-0010}, mesh = {Administration, Oral ; Dementia/chemically induced ; Fungi/*metabolism ; Glycosides/adverse effects/metabolism ; Humans ; Magnetic Resonance Imaging ; Motor Neuron Disease/*etiology ; Neurotoxins/*adverse effects/*metabolism ; Parkinson Disease/etiology ; *Plants, Medicinal/adverse effects/classification/metabolism ; Spinal Cord Diseases/pathology ; }, abstract = {INTRODUCTION: A wide range of plants, seeds and fruits used for nutritional and medicinal purposes can give rise to neurotoxic symptoms.<br><br>DEVELOPMENT: We review the neurological pathology associated with the acute or chronic consumption of plants, seeds and fruits in human beings and in animals. Of the plants that can trigger acute neurotoxic syndromes in humans, some of the most notable include Mandragora officinalis, Datura stramonium, Conium maculatum (hemlock), Coriaria myrtifolia (redoul), Ricinus communis, Gloriosa superba, Catharanthus roseus, Karwinskia humboldtiana and Podophyllum pelatum. We also survey different neurological syndromes linked with the ingestion of vegetable foodstuffs that are rich in cyanogenic glycosides, Jamaican vomiting sickness caused by Blighia sapida, Parkinson dementia ALS of Guam island and exposition to Cycas circinalis, Guadeloupean parkinsonism and exposition to Annonaceae, konzo caused by ingestion of wild manioc and neurolathyrism from ingestion of Lathyrus sativus, the last two being models of motor neurone disease. Locoism is a chronic disease that develops in livestock feeding on plants belonging to Astragalus and Oxytropis sp., Sida carpinifolia and Ipomea carnea, which are rich in swainsonine, a toxin that inhibits the enzyme alpha mannosidase and induces a cerebellar syndrome.<br><br>CONCLUSIONS: The ingestion of neurotoxic seeds, fruits and plants included in the diet and acute poisoning by certain plants can give rise to different neurological syndromes, some of which are irreversible.}, }
@article {pmid12714052, year = {2003}, author = {Holz, RC and Bzymek, KP and Swierczek, SI}, title = {Co-catalytic metallopeptidases as pharmaceutical targets.}, journal = {Current opinion in chemical biology}, volume = {7}, number = {2}, pages = {197-206}, doi = {10.1016/s1367-5931(03)00033-4}, pmid = {12714052}, issn = {1367-5931}, support = {GM-56495/GM/NIGMS NIH HHS/United States ; }, mesh = {Amidohydrolases/antagonists &amp; inhibitors/metabolism ; Aminopeptidases/antagonists &amp; inhibitors/metabolism ; Animals ; Carboxypeptidases/antagonists &amp; inhibitors/metabolism ; Catalysis ; Humans ; Metalloendopeptidases/antagonists &amp; inhibitors/drug effects/*metabolism ; Protease Inhibitors/chemical synthesis/pharmacology ; }, abstract = {Understanding the reaction mechanism of co-catalytic metallopeptidases provides a starting point for the design and synthesis of new molecules that can be screened as potential pharmaceuticals. Many of the enzymes that contain co-catalytic metallo-active sites play important roles in cellular processes such as tissue repair, protein maturation, hormone level regulation, cell-cycle control and protein degradation. Therefore, these enzymes play central roles in several disease states including cancer, HIV, stroke, diabetes, bacterial infections, neurological processes, schizophrenia, seizure disorders, and amyotrophic lateral sclerosis. The mechanism of AAP, an aminopeptidase from Aeromonas proteolytica, is one of the best-characterized examples of a metallopeptidase containing a co-catalytic metallo-active site, although this enzyme is not a specific pharmaceutical target at this time. As a large majority of co-catalytic metallopeptidases contain active sites that are nearly identical to the one observed in AAP, the major steps of their catalytic mechanisms are likely to be very similar. With this in mind, it is possible to propose a general catalytic mechanism for the hydrolysis of amino acid substrates.}, }
@article {pmid12710507, year = {2002}, author = {Hanemann, CO and Ludolph, AC}, title = {Hereditary motor neuropathies and motor neuron diseases: which is which.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {4}, pages = {186-189}, doi = {10.1080/146608202760839003}, pmid = {12710507}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/etiology ; Animals ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/classification/*diagnosis/etiology ; Muscular Atrophy, Spinal/diagnosis/etiology ; Mutation ; Phenotype ; Syndrome ; }, abstract = {When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.}, }
@article {pmid12710506, year = {2002}, author = {Hardiman, O and Traynor, BJ and Corr, B and Frost, E}, title = {Models of care for motor neuron disease: setting standards.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {4}, pages = {182-185}, doi = {10.1080/146608202760839002}, pmid = {12710506}, issn = {1466-0822}, mesh = {Diagnosis, Differential ; Disability Evaluation ; Disease Progression ; Health Status Indicators ; Humans ; *Models, Nursing ; Motor Neuron Disease/diagnosis/*therapy ; Palliative Care ; Prognosis ; Reference Standards ; Terminal Care ; }, abstract = {Models of care for people with motor neuron disease (MND) must be designed in a patient-centered format, with an in-built flexibility and responsiveness that reflect the evolving nature of the condition. Diagnosis should be made as early as possible. Patients should have early access to centres with specialist knowledge of amyotrophic lateral sclerosis (ALS). Services should be flexible and responsive to the needs of the patient, and operate to best advantage when functioning as a coordinated team that cross-refers internally. Patients with ALS should be empowered to make rational end-of-life decisions based on maximizing quality of life and maintaining dignity. All models of care should be designed to cater for the sudden change from health to chronic illness, and should aim to provide a core of specialties that are patient-oriented, flexible and responsive. Ultimately, models of care should be assessed based on their outcomes.}, }
@article {pmid12710505, year = {2002}, author = {Silani, V and Fogh, I and Ratti, A and Sassone, J and Ciammola, A and Cova, L}, title = {Stem cells in the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {4}, pages = {173-181}, doi = {10.1080/146608202760839001}, pmid = {12710505}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Central Nervous System ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Mice ; Mice, Transgenic ; Motor Neurons ; Rats ; *Stem Cell Transplantation ; Stem Cells/*physiology ; }, abstract = {Until fairly recently, interest in stem cells was restricted to neurobiology studies on the principles of embryonic development. This situation has changed rapidly in the last few years when neuronal stems and precursors were isolated in vitro, thus allowing expansion and controlled differentiation of selective populations of neuronal cells. This theoretically unlimited reserve would then supply specific cells for transplantation in diseases characterized by widespread degeneration of selective cell populations as motor neurons in Amyotrophic Lateral Sclerosis (ALS). The recent evidence of cell transdifferentiation has further amplified the potential therapeutic use of stem cells. Stem cell technology is at an early stage but the desperate need for a therapy in ALS patients may legitimize clinical trials in absence of conclusive scientific evidence. This paper discusses the premises for stem cell therapy in ALS.}, }
@article {pmid12700323, year = {2003}, author = {Gourie-Devi, M and Nalini, A and Sandhya, S}, title = {Early or late appearance of "dropped head syndrome" in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {74}, number = {5}, pages = {683-686}, doi = {10.1136/jnnp.74.5.683}, pmid = {12700323}, issn = {0022-3050}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Female ; Head/*physiopathology ; Humans ; Male ; Middle Aged ; Muscle Weakness/etiology/*physiopathology ; Neck/physiopathology ; Posture/*physiology ; Syndrome ; Time Factors ; }, abstract = {BACKGROUND: "Dropped head syndrome" caused by neck extensor weakness has been reported in a variety of neuromuscular disorders. Previously published reports include isolated cases with amyotrophic lateral sclerosis (ALS). In this report, nine patients with ALS and dropped head syndrome seen during a 20 year period are described. PATIENTS AND INVESTIGATIONS: Between 1981 and 2000, 683 patients with ALS were diagnosed, based on El Escorial criteria. Nine of these had profound neck extensor weakness observed as an early feature, or developing during the later stages of the disease. The protocol for evaluation included detailed clinical history, neurological examination, electromyography, and nerve conduction studies. Investigations were undertaken to exclude malignancy, lymphoproliferative disorders, thyroid dysfunction, and collagen vascular disease.<br><br>RESULTS: The incidence of dropped head syndrome was 1.3%. The mean (SD) age of the affected patients was 53.3 (10.3) years (range 33 to 65), with an equal distribution of cases in the fourth to seventh decades. In six patients, head drop was an early feature (mean interval from onset of illness 11.6 months (range 3 to 24)); in three it was late (between three and eight years after onset). In five patients, mild neck flexor weakness was present in addition to severe extensor weakness. In all nine patients there were diffuse upper and lower motor neurone signs. None of the patients had difficulty in breathing but all had difficulty in swallowing and social embarrassment, both of which could be corrected by simple measures.<br><br>CONCLUSIONS: Dropped head syndrome is an important clinical sign and usually occurs as an early feature within the first one to two years after the onset of ALS. The cause of dropped head syndrome in these nine cases could be easily established as ALS by the presence of generalised signs.}, }
@article {pmid12692768, year = {2003}, author = {Bach, JR}, title = {Threats to "informed" advance directives for the severely physically challenged?.}, journal = {Archives of physical medicine and rehabilitation}, volume = {84}, number = {4 Suppl 2}, pages = {S23-8}, doi = {10.1053/apmr.2003.50243}, pmid = {12692768}, issn = {0003-9993}, mesh = {*Advance Directives ; Attitude to Health ; Decision Making ; Disabled Persons/*psychology/*rehabilitation ; Ethics, Medical ; Humans ; Informed Consent/*standards ; Life Support Care/psychology ; Neuromuscular Diseases/mortality/*psychology/*rehabilitation ; Patient Advocacy ; Patient Education as Topic/standards ; Patient Selection ; Personal Health Services ; Personal Satisfaction ; *Quality of Life ; Respiration, Artificial/*methods ; Self-Help Devices/*standards ; Terminal Care/psychology ; Withholding Treatment ; }, abstract = {The neuromuscular diseases, such as infantile spinal muscular atrophy, Duchenne's muscular dystrophy, and amyotrophic lateral sclerosis, are widely considered to be terminal illnesses. However, as with many neuromuscular and neurologic diseases, morbidity and mortality are caused by dysfunction of inspiratory, expiratory, and bulbar musculature. This article will discuss how inspiratory and expiratory musculature can be supported by simple, noninvasive means that are rarely considered when, as with the general population, individuals with disabilities are counseled about advance directives. Failure to use noninvasive aids almost invariably results in respiratory failure, intubation, and tracheostomy or death. When noninvasive aids are available, invasive measures referred to in advance directives (eg, intubation) are often needed only temporarily. Yet, ill-informed patients are often advised to refuse intubation and die or to be intubated and left to decide whether to undergo tracheostomy for long-term ventilatory support. Further, despite severe disability, ventilator users with neuromuscular disease report normal life satisfaction. Health care professionals, on the other hand, tend to ignore the patient's life satisfaction and consider quality of life measures not designed for the disabled to justify withholding life-saving interventions. Advance directives, although sometimes appropriate for patients with irretractable pain and advanced cancer, are inappropriate for patients with severe disability because of muscle weakness, and virtually no patients are appropriately counseled about all therapeutic options.}, }
@article {pmid12690044, year = {2003}, author = {van den Berg-Vos, RM and Visser, J and Franssen, H and de Visser, M and de Jong, JM and Kalmijn, S and Wokke, JH and van den Berg, LH}, title = {Sporadic lower motor neuron disease with adult onset: classification of subtypes.}, journal = {Brain : a journal of neurology}, volume = {126}, number = {Pt 5}, pages = {1036-1047}, doi = {10.1093/brain/awg117}, pmid = {12690044}, issn = {0006-8950}, mesh = {Adult ; Age of Onset ; Aged ; Cross-Sectional Studies ; Electrophysiology ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Neuron Disease/*classification/pathology ; Muscle Weakness/pathology ; Muscle, Skeletal/pathology ; Muscular Atrophy/pathology ; Statistics, Nonparametric ; }, abstract = {The discovery of the genetic basis of hereditary lower motor neuron disease (LMND) and the recognition of multifocal motor neuropathy as a distinct clinical entity necessitate a new classification of LMND. To this end, we studied the clinical and electrophysiological features of 49 patients with sporadic adult-onset LMND in a cross-sectional study. Disease duration was more than 4 years to exclude the majority of patients with amyotrophic lateral sclerosis. Based on the pattern of weakness, we identified three groups: 13 patients with generalized weakness (group 1); eight patients with symmetrical, distal muscle weakness (group 2); and 28 patients with non-generalized asymmetrical weakness of the arms in most patients (group 3). Group 3 could be subdivided into patients with weakness in predominantly the distal (group 3a) or the proximal (group 3b) muscle groups, both with disease progression to adjacent spinal cord segments. Distinctive features of group 1 were an older age at onset, more severe weakness and muscle atrophy, lower reflexes, greater functional impairment, more widespread abnormalities on concentric needle EMG, respiratory insufficiency and serum M-protein. In groups 2 and 3, concentric needle EMG findings also suggested a more widespread disease process. Retrospectively, the prognosis of sporadic adult-onset LMND appears to be favourable, because clinical abnormalities were still confined to one limb in most patients after a median disease duration of 12 years. We propose to classify the patients in the different subgroups as slowly progressive spinal muscular atrophy (group 1), distal spinal muscular atrophy (group 2), segmental distal spinal muscular atrophy (group 3a) and segmental proximal spinal muscular atrophy (group 3b). The described clinical phenotypes may help to distinguish between different LMND forms.}, }
@article {pmid12684997, year = {2003}, author = {Ishihara, K and Murakami, H and Ichikawa, H and Fukui, T and Kawamura, M}, title = {[A case of amyotrophic lateral sclerosis with dementia presenting long clinical course].}, journal = {No to shinkei = Brain and nerve}, volume = {55}, number = {2}, pages = {157-161}, pmid = {12684997}, issn = {0006-8969}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*psychology ; Atrophy ; Brain/pathology ; Dementia/complications/*psychology ; Humans ; Magnetic Resonance Imaging ; Male ; }, abstract = {We describe a patient with amyotrophic lateral sclerosis with dementia (ALS-D) displaying a long clinical course. A 68-year-old Japanese male with no family history of note was admitted complaining of severe dysarthria and dysphagia. At 63 years old, Pick's disease was diagnosed on the basis of abnormal behavior, such as "Denkfaulheit" and moria, and temporal lobe atrophy observed on magnetic resonance imaging (MRI). Five years after onset, dysarthria and dysphagia emerged, and gradually worsened. On admission, muscular weakness of the upper extremities, fasciculation, and exaggerated tendon stretch reflexes were noted. Needle electromyography performed on the left upper and lower extremities revealed neurogenic pattern changes. Based on these findings and clinical course, ALS-D was diagnosed. Due to severe bulbar palsy, verbal communication was impossible. However, neither specific symptoms of dementia nor abnormal behavior was demonstrated, although this latter had been observed 5 years ago, with only short-term memory impairment apparent. MRI disclosed severe knife-edge atrophy of bilateral temporal lobes, most prominently in the anterior regions. SPECT images revealed decreased uptake of tracer in bilateral inferior temporal lobes, predominantly on the left side. The patient died suddenly 4 months after admission, and post-mortem examination was not conducted. Total clinical course was about 8 years. Several cases of ALS-D have displayed similar clinical courses to the presented case. Some of these would also have initially been diagnosed as Pick's disease. We speculate that cases displaying psychiatric symptoms for several years and initially diagnosed as Pick's disease may finally be diagnosed as ALS-D upon the eventual emergence of motor symptoms(bulbar palsy).}, }
@article {pmid12684868, year = {2003}, author = {Weishaupt, JH and Neusch, C and Bähr, M}, title = {Cyclin-dependent kinase 5 (CDK5) and neuronal cell death.}, journal = {Cell and tissue research}, volume = {312}, number = {1}, pages = {1-8}, doi = {10.1007/s00441-003-0703-7}, pmid = {12684868}, issn = {0302-766X}, mesh = {Animals ; Cell Cycle ; *Cell Death ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/genetics/*metabolism ; Humans ; Neurons/*physiology ; Signal Transduction/physiology ; }, abstract = {Many neurological disorders like Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or stroke have in common a definite loss of CNS neurons due to apoptotic or necrotic neuronal cell death. Previous studies suggested that proapoptotic stimuli may trigger an abortive and, therefore, eventually fatal cell cycle reentry in postmitotic neurons. Neuroprotective effects of small molecule inhibitors of cyclin-dependent kinases (CDKs), which are key regulators of cell cycle progression, support the cell cycle theory of neuronal apoptosis. However, growing evidence suggests that deregulated CDK5, which is not involved in cell cycle control, rather than cell cycle relevant members of the CDK family, promotes neuronal cell death. Here we summarize the current knowledge about the involvement of CDK5 in neuronal cell death and discuss possible up- or downstream partners of CDK5. Moreover, we discuss potential therapeutic options that might arise from the identification of CDK5 as an important upstream element of neuronal cell death cascades.}, }
@article {pmid12678784, year = {2003}, author = {Wu, SN}, title = {Large-conductance Ca2+- activated K+ channels:physiological role and pharmacology.}, journal = {Current medicinal chemistry}, volume = {10}, number = {8}, pages = {649-661}, doi = {10.2174/0929867033457863}, pmid = {12678784}, issn = {0929-8673}, mesh = {Animals ; Electrophysiology ; Humans ; Large-Conductance Calcium-Activated Potassium Channels ; Potassium Channel Blockers/*pharmacology ; Potassium Channels, Calcium-Activated/chemistry/*drug effects/*physiology ; }, abstract = {Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels differ from most of other K(+) channels in that their activation is under dual control, i.e., activated by either increase in intracellular Ca(2+) or membrane depolarization. These channels, which are widely distributed in a variety of cells, can control Ca(2+) influx as well as a number of Ca(2+)-dependent physiological processes. In neurons or neuroendocrine cells, BK(Ca) channels are believed to play an important role in controlling hormonal secretion by altering the duration and frequency of action potentials. The activity of BK(Ca) channels functionally expressed in vascular endothelial cells can control K(+) efflux and affect intracellular Ca(2+) concentration. Experimental observations have revealed that a variety of compounds can directly modulate BK(Ca) channel activity. Epoxyeicosatrienoic acids, a metabolite of arachidonic acid, and the increase in intracellular cyclic GMP with vinpocetine or YC-1 can stimulate BK(Ca) channel activity. The increased activity of BK(Ca) channels thus serves as a negative feedback mechanism to limit Ca(2+) influx in excitable cells. Clotrimazole, an imidazole P-450 inhibitor used for the management of sickle cell anemia, can directly suppress BK(Ca) channel activity. Riluzole, a drug used for the treatment of amyotrophic lateral sclerosis, can directly enhance channel activity in neuroendocrine cells. This effect may explain its inhibitory action on excitatory neurotransmission. 2-Methoxyestradil, an endogenous metabolite of 17beta-estradiol, suppresses BK(Ca) channel activity, whereas resveratrol, a natural phytoalexin present in grapes and wine, directly stimulates BK(Ca) channel activity in vascular endothelial cells. These effects may be responsible for their actions on functional activities of endothelial cells. The fenamates, a family of nonsteroidal anti-inflammatory drugs, are also openers of BK(Ca) channels. Therefore, the modulation of BK(Ca) channel activity in excitable and non-excitable cells can be important for therapeutic interventions.}, }
@article {pmid12675260, year = {2002}, author = {Malaspina, A and Alimonti, D and Poloni, TE and Ceroni, M}, title = {Disease clustering: the example of ALS, PD, dementia and hereditary ataxias in Italy.}, journal = {Functional neurology}, volume = {17}, number = {4}, pages = {177-182}, pmid = {12675260}, issn = {0393-5264}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Cerebellar Ataxia/*epidemiology/*genetics ; Cluster Analysis ; Dementia/*epidemiology ; Humans ; Italy/epidemiology ; Parkinson Disease/*epidemiology ; }, abstract = {The "mini-epidemic" distribution of rare conditions (either sporadic, inherited or due to a transmissible agent) is frequently described as a cluster. Genetic abnormalities and environmental factors are usually investigated to explain the presence of a disease cluster. We have reported a cluster of amyotrophic lateral sclerosis (ALS) cases in a small area of central Italy, where an identical SOD1 gene mutation was found both in familial ALS (FALS) cases and in one apparently sporadic ALS individuals. Along with this cluster of ALS patients, we review important clusters of neurological disorders in Italy and discuss the importance of an accurate estimation of their regional/local prevalence. This approach is likely to facilitate molecular investigations, the search for environmental agents and the analysis of gene-environment interaction in disease presentation and development. The organisation of national registers that record, in particular, the geographical distribution of neurological disorders, might represent a good research strategy.}, }
@article {pmid12671941, year = {2003}, author = {Hawkes, C}, title = {Olfaction in neurodegenerative disorder.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {18}, number = {4}, pages = {364-372}, doi = {10.1002/mds.10379}, pmid = {12671941}, issn = {0885-3185}, mesh = {Apolipoprotein E4 ; Apolipoproteins E/genetics ; Female ; Humans ; Male ; Neurodegenerative Diseases/diagnosis/genetics/*physiopathology ; Olfaction Disorders/diagnosis/genetics/*physiopathology ; Olfactory Bulb/physiopathology ; Risk Factors ; Sex Factors ; Smell/genetics/*physiology ; }, abstract = {There has been an increase of interest in olfactory dysfunction since it was realised that anosmia was a common feature of idiopathic Parkinson's disease (PD) and Alzheimer-type dementia (AD). It is an intriguing possibility that the first sign of a disorder hitherto regarded as one of movement or cognition may be that of disturbed smell sense. In this review of PD, parkinsonian syndromes, essential tremor, AD, motor neurone disease (MND) and Huntington's chorea (HC) the following observations are made: 1). olfactory dysfunction is frequent and often severe in PD and AD; 2). normal smell identification in PD is rare and should prompt review of diagnosis unless the patient is female with tremor-dominant disease; 3). anosmia in suspected progressive supranuclear palsy and corticobasal degeneration is atypical and should likewise provoke diagnostic review; 4). hyposmia is an early feature of PD and AD and may precede motor and cognitive signs respectively; 5). subjects with anosmia and one ApoE-4 allele have an approximate 5-fold increased risk of later AD; 6). impaired smell sense is seen in some patients at 50% risk of parkinsonism; 7). smell testing in HC and MND where abnormality may be found, is not likely to be of clinical value; and 8). biopsy of olfactory nasal neurons shows non-specific changes in PD and AD and at present will not aid diagnosis.}, }
@article {pmid12666108, year = {2003}, author = {Rothstein, JD}, title = {Of mice and men: reconciling preclinical ALS mouse studies and human clinical trials.}, journal = {Annals of neurology}, volume = {53}, number = {4}, pages = {423-426}, doi = {10.1002/ana.10561}, pmid = {12666108}, issn = {0364-5134}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; *Disease Models, Animal ; Humans ; Mice ; *Mice, Transgenic ; }, }
@article {pmid12663085, year = {2003}, author = {Kikuchi, S and Shinpo, K and Takeuchi, M and Yamagishi, S and Makita, Z and Sasaki, N and Tashiro, K}, title = {Glycation--a sweet tempter for neuronal death.}, journal = {Brain research. Brain research reviews}, volume = {41}, number = {2-3}, pages = {306-323}, doi = {10.1016/s0165-0173(02)00273-4}, pmid = {12663085}, mesh = {Animals ; Cell Death/*physiology ; Glucose/metabolism ; Glycation End Products, Advanced/*metabolism ; Humans ; Nerve Tissue Proteins/metabolism ; Nervous System/*metabolism/pathology/physiopathology ; Neurodegenerative Diseases/*metabolism/pathology/physiopathology ; Neurons/*metabolism/pathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Glycation, one of the post-translational modifications of proteins, is a nonenzymatic reaction initiated by the primary addition of a sugar aldehyde or ketone to the amino groups of proteins. In the early stage of glycation, the synthesis of intermediates leading to the formation of Amadori compounds occurs. In the late stage, advanced glycation end products (AGE) are irreversibly formed after a complex cascade of reactions. Several AGEs have been characterized chemically, while other new compounds remain to be identified. To date, studies of the contribution of glycation to diseases have been primarily focused on its relationship to diabetes and diabetes-related complications. However, glucose-induced damage is not limited to diabetic patients. Although it does not cause rapid or remarkable cell damage, glycation advances slowly and accompanies every fundamental process of cellular metabolism. It has recently become clear that glycation also affects physiological aging and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Glycation alters the biological activity of proteins and their degradation processes. Protein cross-linking by AGE results in the formation of detergent-insoluble and protease-resistant aggregates. Such aggregates may interfere with both axonal transport and intracellular protein traffic in neurons. In addition, glycation reactions lead to the production of reactive oxygen species. Conversely, glycation is promoted by oxidative stress. We speculate on the presence of synergism between glycation and oxidative stress. In this review, we provide an outline of glycation and propose some possible mechanisms of its cytotoxicity and defense systems against it.}, }
@article {pmid12657369, year = {2003}, author = {Waldmeier, PC}, title = {Prospects for antiapoptotic drug therapy of neurodegenerative diseases.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {27}, number = {2}, pages = {303-321}, doi = {10.1016/S0278-5846(03)00025-3}, pmid = {12657369}, issn = {0278-5846}, mesh = {Alzheimer Disease/drug therapy/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Animals ; Apoptosis/*drug effects/physiology ; Brain Injuries/drug therapy/pathology ; Brain Ischemia/drug therapy/pathology ; Humans ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/pathology ; Spinal Cord Injuries/drug therapy/pathology ; }, abstract = {The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized. It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation. Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs. There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.}, }
@article {pmid12655642, year = {2003}, author = {Al-Chalabi, A and Miller, CC}, title = {Neurofilaments and neurological disease.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {25}, number = {4}, pages = {346-355}, doi = {10.1002/bies.10251}, pmid = {12655642}, issn = {0265-9247}, support = {G0000749/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Biological Transport/physiology ; Humans ; Intermediate Filaments/*metabolism/ultrastructure ; Mice ; Mice, Transgenic ; Mutation ; Nervous System Diseases/genetics/*metabolism/pathology ; Neurofilament Proteins/chemistry/genetics/*metabolism ; Neurons/metabolism/ultrastructure ; Protein Subunits/metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; tau Proteins/genetics ; }, abstract = {Neurofilaments are one of the major components of the neuronal cytoskeleton and are responsible for maintaining the calibre of axons. They are modified by post-translational changes that are regulated in complex fashions including by the interaction with neighbouring glial cells. Neurofilament accumulations are seen in several neurological diseases and neurofilament mutations have now been associated with Charcot-Marie-Tooth disease, Parkinson's disease and amyotrophic lateral sclerosis. In this review, we discuss the structure, normal function and molecular pathology of neurofilaments.}, }
@article {pmid12655070, year = {2003}, author = {Valentine, JS and Hart, PJ}, title = {Misfolded CuZnSOD and amyotrophic lateral sclerosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {100}, number = {7}, pages = {3617-3622}, pmid = {12655070}, issn = {0027-8424}, support = {R01 GM028222/GM/NIGMS NIH HHS/United States ; R01 NS039112/NS/NINDS NIH HHS/United States ; GM28222/GM/NIGMS NIH HHS/United States ; NS39112/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Models, Molecular ; Motor Neuron Disease/*enzymology/*genetics ; *Mutation ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Superoxide Dismutase/*genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5-10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper-zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.}, }
@article {pmid12644909, year = {2003}, author = {Potter, SZ and Valentine, JS}, title = {The perplexing role of copper-zinc superoxide dismutase in amyotrophic lateral sclerosis (Lou Gehrig's disease).}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {8}, number = {4}, pages = {373-380}, pmid = {12644909}, issn = {0949-8257}, support = {GM28222/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Humans ; Mutation ; Superoxide Dismutase/genetics/*physiology ; }, abstract = {The existence of a link between some cases of familial amyotrophic lateral sclerosis (FALS) and copper-zinc superoxide dismutase (CuZnSOD) has been understood for almost a decade. However, beyond the fact that mutations in CuZnSOD cause FALS by a toxic gain of function, the mechanism whereby specific mutations in the protein structure result in development of the disease has remained almost a complete mystery to date. We have undertaken a critical survey of in vitro characteristics of over 30 of the 90 different CuZnSOD mutant proteins that are known to cause FALS in order to determine the differences that exist between mutant and wild-type properties. As-isolated metal content analysis, SOD activity assays, and thermal stability determinations of a significant fraction of the mutants show that the FALS mutant SOD proteins can be classified distinctly into one of two groups. Members of the first group, termed wild-type-like, have physical properties and enzymatic activities that are strikingly similar to those of wild-type CuZnSOD. The second group, however, show aberrant metal content in the as-isolated forms, compromised SOD activities, and unusual DSC thermoscans. All mutations in the members of this second group occur in or near the metal binding sites of the protein and thus they are termed metal binding region mutants. We have also compared the relative rates of self-inactivation caused by reaction of the wild-type protein and several FALS-linked CuZnSOD mutants with hydrogen peroxide, as a measure of relative peroxidative activities. Results and implications of the role of CuZnSOD in FALS are discussed.}, }
@article {pmid12630951, year = {2003}, author = {Majoor-Krakauer, D and Willems, PJ and Hofman, A}, title = {Genetic epidemiology of amyotrophic lateral sclerosis.}, journal = {Clinical genetics}, volume = {63}, number = {2}, pages = {83-101}, doi = {10.1046/j.0009-9163.2002.00001.x}, pmid = {12630951}, issn = {0009-9163}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; Causality ; Female ; Humans ; Inheritance Patterns/genetics ; Male ; Mutation/genetics ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurological disorder, caused by the loss of motor neurons in the brain and spinal cord. Familial aggregation of ALS, with an age-dependent but high penetrance, is a major risk factor for ALS. Familial ALS (FALS) is clinically and genetically heterogeneous. Three genes and linkage to four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex). This review presents a tentative classification of the "major" ALS genes and ALS "susceptibility" genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors. Considering that mutations in ALS genes explain approximately 10% of familial as well as sporadic ALS, and most remaining cases of the discase are thought to result form the interaction of several genes and environmental factors, ALS is a paradigm for multifactorial discases.}, }
@article {pmid12595144, year = {2002}, author = {Robertson, J and Kriz, J and Nguyen, MD and Julien, JP}, title = {Pathways to motor neuron degeneration in transgenic mouse models.}, journal = {Biochimie}, volume = {84}, number = {11}, pages = {1151-1160}, doi = {10.1016/s0300-9084(02)00025-1}, pmid = {12595144}, issn = {0300-9084}, mesh = {Adult ; Animals ; Disease Models, Animal ; Humans ; Intermediate Filament Proteins/analysis ; *Membrane Glycoproteins ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Neurological ; Motor Neuron Disease/*genetics/pathology/physiopathology ; Nerve Degeneration/*genetics/pathology ; Nerve Tissue Proteins/analysis ; Peripherins ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder characterized by the selective loss of motor neurons. A pathological hallmark of both sporadic and familial ALS is the presence of abnormal accumulations of neurofilament and peripherin proteins in motor neurons. In the past decade, transgenic mouse approaches have been used to address the role of such cytoskeletal abnormalities in motor neuron disease and also to unravel the pathogenesis caused by mutations in the gene coding for superoxide dismutase 1 (SOD1) that account for ~20% of familial ALS cases. In mouse models, disparate effects could result from different types of intermediate filament (IF) aggregates. Perikaryal IF accumulations induced by the overexpression of any of the three wild-type neurofilament proteins were quite well tolerated by motor neurons. Indeed, perikaryal swellings provoked by NF-H overexpression can even confer protection against toxicity of mutant SOD1. Other types of IF aggregates seem neurotoxic, such as those found in transgenic mice overexpressing either peripherin or an assembly-disrupting NF-L mutant. Moreover, understanding the toxicity of SOD1 mutations has been surprisingly difficult. The analysis of transgenic mice expressing mutant SOD1 has yielded complex results, suggesting that multiple pathways may contribute to disease that include the involvement of non-neuronal cells.}, }
@article {pmid12590377, year = {2003}, author = {Morís, G and Vega, JA}, title = {[Neurotrophic factors: basis for their clinical application].}, journal = {Neurologia (Barcelona, Spain)}, volume = {18}, number = {1}, pages = {18-28}, pmid = {12590377}, issn = {0213-4853}, mesh = {Animals ; Brain Injuries/drug therapy ; Clinical Trials as Topic ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Nerve Growth Factors/metabolism/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/metabolism/therapeutic use ; Somatomedins/metabolism ; }, abstract = {Neurotrophic factors are molecules that regulate neuronal survival, nervous system plasticity and many other physiological functions of neuronal and glial cells, as well as some non-neuronal tissues. They have been involved in the etiopathogenesis of some neurodegenerative disorders, and some of them have been proposed as potential treatments for these diseases on the basis of in vitro experiments and animal models. The main neurotrophic factor families with potential therapeutic applications include the family of neurotrophins (NGF, BDNF or NT-3), GDNF and related neurotrophic factor, CNTF and the members of the IGF family. Some of these molecules have already been tested in clinical trials with contradictory results. One of the major challenges to their clinical use is the difficulty to deliver them into the central nervous system. Nevertheless, solid rational exists for the possible use of neurotrophic factors in the treatment of Alzheimer's and Parkinson's diseases, peripheral neuropathies or amyotrophic lateral sclerosis. This review compiles the essential aspects of neurotrophic factors and the current studies of their clinical relevance and therapeutic potentialities. Future directions for further research are also discussed.}, }
@article {pmid12575826, year = {2002}, author = {Dechant, G and Neumann, H}, title = {Neurotrophins.}, journal = {Advances in experimental medicine and biology}, volume = {513}, number = {}, pages = {303-334}, doi = {10.1007/978-1-4615-0123-7_11}, pmid = {12575826}, issn = {0065-2598}, mesh = {Animals ; Behavior/physiology ; Disease Models, Animal ; Humans ; Memory/physiology ; Models, Molecular ; Nerve Growth Factors/chemistry/genetics/*metabolism/therapeutic use ; Neurodegenerative Diseases/metabolism/therapy ; Neurons/metabolism ; Neuroprotective Agents/metabolism ; Neurotransmitter Agents/metabolism ; Receptors, Nerve Growth Factor/*metabolism ; Signal Transduction/physiology ; }, abstract = {Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. Target T cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.}, }
@article {pmid12570795, year = {2003}, author = {Campiani, G and Fattorusso, C and De Angelis, M and Catalanotti, B and Butini, S and Fattorusso, R and Fiorini, I and Nacci, V and Novellino, E}, title = {Neuronal high-affinity sodium-dependent glutamate transporters (EAATs): targets for the development of novel therapeutics against neurodegenerative diseases.}, journal = {Current pharmaceutical design}, volume = {9}, number = {8}, pages = {599-625}, doi = {10.2174/1381612033391261}, pmid = {12570795}, issn = {1381-6128}, mesh = {Amino Acid Transport System X-AG/metabolism/*physiology ; Animals ; Cell Membrane/metabolism ; Drug Design ; Glutamic Acid/*metabolism ; Humans ; Ligands ; Molecular Conformation ; Molecular Structure ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neurons/*metabolism ; Neuroprotective Agents/chemistry/*pharmacology/therapeutic use ; Receptors, Glutamate/metabolism ; Sodium/*metabolism ; }, abstract = {L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i). on the structure of its receptors, ii). on molecular biology and pharmacology of Glu transporters, and iii). on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.}, }
@article {pmid12570697, year = {2003}, author = {Monaco, EA and Vallano, ML}, title = {Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians.}, journal = {Current medicinal chemistry}, volume = {10}, number = {5}, pages = {367-379}, doi = {10.2174/0929867033368277}, pmid = {12570697}, issn = {0929-8673}, support = {NS40582/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cyclin-Dependent Kinases/*antagonists &amp; inhibitors/physiology ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Humans ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {The development of small molecule kinase inhibitors as potential cancer therapeutics is an area of intense interest, and a subset of these agents target cyclin-dependent kinase (CDK) activity. Ten distinct CDKs (1-9, 11), when paired with their cyclin activators, are integral to such diverse processes as cell cycle control, neuronal development, and transcriptional regulation. Mutation and/or aberrant expression of certain CDKs and their regulatory counterparts are associated with uncontrolled proliferation and tumorigenesis. As such, CDK selective inhibitors (CDKIs) that attenuate or prevent tumor growth have been developed. Recently, interest in the therapeutic potential of CDKIs has expanded to include neurodegenerative diseases, where dysregulated CDK activity has been linked to the pathogenesis of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke. Specifically, aberrant activation of cell cycle CDKs or CDK5 is associated with apoptosis and neuronal dysfunction in response to various neuronal stressors. To date, CDKIs have shown promise as neuroprotective agents in the research laboratory and, in the future, may prove useful in the neurology clinic.}, }
@article {pmid12564775, year = {2002}, author = {Shibata, N and Oda, H and Hirano, A and Kato, Y and Kawaguchi, M and Dal Canto, MC and Uchida, K and Sawada, T and Kobayashi, M}, title = {Molecular biological approaches to neurological disorders including knockout and transgenic mouse models.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {22}, number = {4}, pages = {337-349}, doi = {10.1046/j.1440-1789.2002.00449.x}, pmid = {12564775}, issn = {0919-6544}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Blotting, Southern ; Central Nervous System Diseases/*genetics ; *Disease Models, Animal ; Granuloma, Giant Cell/genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Mice ; Mice, Knockout ; Mice, Transgenic ; *Molecular Biology/methods ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Advances of molecular biology have provided a great variety of new approaches to research on human disorders. This article gives an outline of molecular biological approaches to analysis of neurological disorders such as giant cell glioblastoma (GGBM) and amyotrophic lateral sclerosis (ALS), and their respective animal models: p53 knockout mice for GGBM and mutant superoxide dismutase-1 transgenic mice for ALS. Genomic DNA extracted from fresh-frozen tissue is examined by Southern blotting for screening mutations in a certain gene. Polymerase chain reaction (PCR) products of a gene in genomic DNA are examined by single-stranded conformation polymorphism, sequencing and agarose gel electrophoresis for identifying mutations, and for preparing and evaluating DNA probes used in Southern blotting and DNA in situ hybridization (ISH). Total RNA from tissue is examined by northern blotting for quantifying and verifying a certain mRNA. Reverse transcription-PCR products of a certain mRNA in total RNA are examined by sequencing and agarose gel electrophoresis for preparing and evaluating cDNA probes used in northern blotting and mRNA ISH. Tissue total protein is immunoblotted for quantifying and verifying a certain protein, and for evaluating the specificity of antibodies used in western blotting and immunohistochemistry. Immunoprecipitates are immunoblotted for evaluating a profile of protein or other substances. Enzyme-linked immunosorbent assay is used for measuring tissue concentration of protein or other substances, and for determining titers of specific antibodies. By these procedures, chronological analysis of animal models for human diseases contribute to elucidating pathogenic mechanisms and exploiting new therapies. Noticing both the similarity and difference between human and animal disorders will help understand the nature of disease.}, }
@article {pmid12546990, year = {2003}, author = {Mathisen, PM}, title = {Gene discovery and validation for neurodegenerative diseases.}, journal = {Drug discovery today}, volume = {8}, number = {1}, pages = {39-46}, doi = {10.1016/s1359644602025400}, pmid = {12546990}, issn = {1359-6446}, mesh = {Adult ; Alzheimer Disease/drug therapy/metabolism/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Animals ; Humans ; *Neurodegenerative Diseases/drug therapy/genetics/physiopathology ; Parkinson Disease/epidemiology/metabolism/physiopathology ; Pharmacogenetics/*trends ; }, abstract = {Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.}, }
@article {pmid12541277, year = {2003}, author = {Li, CY and Sung, FC}, title = {Association between occupational exposure to power frequency electromagnetic fields and amyotrophic lateral sclerosis: a review.}, journal = {American journal of industrial medicine}, volume = {43}, number = {2}, pages = {212-220}, doi = {10.1002/ajim.10148}, pmid = {12541277}, issn = {0271-3586}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Bias ; Case-Control Studies ; Cohort Studies ; Confounding Factors, Epidemiologic ; Electromagnetic Fields/*adverse effects ; Humans ; Occupational Exposure/*adverse effects ; Risk Assessment ; }, abstract = {BACKGROUND: For the past two decades, there has been concern over electromagnetic exposure and human health. While most research has focused on cancer and reproductive outcomes, there is interest in the relationship between electromagnetic fields (EMF) and neurodegenerative diseases.<br><br>METHODS: We review epidemiological findings and evidence regarding the association between occupational exposure to power frequency EMFs and amyotrophic lateral sclerosis (ALS). Medline was searched for citations related to occupational hazards and ALS, literature reviews and epidemiological evaluations.<br><br>RESULTS: Nine out of the ten epidemiological studies that have been conducted on the risk of ALS in relation to occupational exposure to EMF show moderate to strong relative risk estimates that supported a link between them. Although data from these studies was consistent, the causal inference to a link between EMF exposure and ALS is restricted mainly due to the lack of direct information on EMF exposure and incomplete consideration of the other potential risk factors for ALS at workplaces. For instance, electric shock, in particular, is more common in electrical occupations than in any other occupations.<br><br>CONCLUSIONS: This review concludes that further studies should consider investigating the separate effect of EMF exposure and electrical shocks to make more specific interpretations. On-site measurements of EMF should be conducted to include information on EMF exposure from residences as well as workplaces to improve exposure assessment.}, }
@article {pmid12538963, year = {2002}, author = {Pellis, T}, title = {Training in BLS, ALS and the importance of early defibrillation.}, journal = {Minerva anestesiologica}, volume = {68}, number = {11}, pages = {797-804; discussion 805, 805-9; discussion 810}, pmid = {12538963}, issn = {0375-9393}, mesh = {Advanced Cardiac Life Support/*education ; Cardiopulmonary Resuscitation/*education ; *Electric Countershock ; Emergency Medicine/*education ; Humans ; Italy ; }, }
@article {pmid12534333, year = {2003}, author = {Dib, M}, title = {Amyotrophic lateral sclerosis: progress and prospects for treatment.}, journal = {Drugs}, volume = {63}, number = {3}, pages = {289-310}, pmid = {12534333}, issn = {0012-6667}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.}, }
@article {pmid12531867, year = {2003}, author = {Guégan, C and Przedborski, S}, title = {Programmed cell death in amyotrophic lateral sclerosis.}, journal = {The Journal of clinical investigation}, volume = {111}, number = {2}, pages = {153-161}, pmid = {12531867}, issn = {0021-9738}, support = {R01 NS38586/NS/NINDS NIH HHS/United States ; P50 NS038370/NS/NINDS NIH HHS/United States ; P50 NS38370/NS/NINDS NIH HHS/United States ; R29 NS37345/NS/NINDS NIH HHS/United States ; R01 NS042269/NS/NINDS NIH HHS/United States ; R01 NS038586/NS/NINDS NIH HHS/United States ; NS42269/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/*pathology ; Animals ; *Apoptosis ; Caspases/physiology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Proto-Oncogene Proteins c-bcl-2/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid12528305, year = {2002}, author = {Weydt, P and Weiss, MD and Möller, T and Carter, GT}, title = {Neuro-inflammation as a therapeutic target in amyotrophic lateral sclerosis.}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {3}, number = {12}, pages = {1720-1724}, pmid = {12528305}, issn = {1472-4472}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/immunology ; Animals ; Clinical Trials as Topic/statistics &amp; numerical data ; Drug Delivery Systems/*methods ; Humans ; Neurogenic Inflammation/*drug therapy/immunology ; Superoxide Dismutase/immunology ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuromuscular disease that destroys both upper and lower motor neurons, resulting in spasticity, diffuse muscular atrophy, weakness, and ultimately death from respiratory failure. It is presumed that in the vast majority of cases, ALS is acquired and occurs sporadically, although the exact etiology is unknown. Recent, emerging evidence suggests that neuro-inflammation may be a pathological characteristic of this disease; this could represent a potential therapeutic target for a pharmacological agent to help treat this severe disease. This article reviews the current research in this area and discusses theoretical and clinical ramifications of these recent findings.}, }
@article {pmid12519593, year = {2002}, author = {Hirst, A and Sloan, R}, title = {Benzodiazepines and related drugs for insomnia in palliative care.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD003346}, doi = {10.1002/14651858.CD003346}, pmid = {12519593}, issn = {1469-493X}, mesh = {Benzodiazepines/*therapeutic use ; Humans ; *Palliative Care ; Sleep Initiation and Maintenance Disorders/*drug therapy ; }, abstract = {BACKGROUND: Insomnia, a subjective complaint of poor sleep and associated impairment in daytime function, is a common problem. Currently, benzodiazepines are the most used pharmacological treatment for this complaint. They are considered helpful for occasional short-term use up to four weeks but longer term use is not advised due to potential problems regarding tolerance, dosing escalation, psychological addiction and physical dependence. There is no consensus on their utility in patients with progressive incurable conditions who may require assistance with sleep for many weeks as their condition deteriorates.<br><br>OBJECTIVES: To assess the effectiveness and safety of benzodiazepines or benzodiazepine receptor agonists such as Zolpidem, Zopiclone and Zaleplon for insomnia in palliative care.<br><br>SEARCH STRATEGY: Several electronic databases were searched including Cochrane PaPaS Group specialized register, Cochrane Library Issue 4, 2001, MEDLINE, EMBASE, BNI plus, CINAHL, BIOLOGICAL ABSTRACTS, PSYCINFO, CANCERLIT, HEALTHSTAR, WEB OF SCIENCE, SIGLE, Dissertation Abstracts, ZETOC and the MetaRegister of ongoing trials. These were searched from 1960 to 2001 or as much of this range as possible. Additional articles were sought by handsearching reference lists in standard textbooks and reviews in the field and by contacting academic centres in palliative care and pharmaceutical companies. There were no language restrictions.<br><br>SELECTION CRITERIA: Studies considered for inclusion were randomized controlled trials of adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition. (For example, cancers, AIDS, Motor Neurone Disease, Multiple Sclerosis, Parkinson's Disease, Chronic Obstructive Pulmonary Disease). There had to be an explicit complaint of insomnia in study participants, diagnosed by any of the three main classification systems (DSM-IV (APA 1994), ICSD (AASD 1990) or ICD (WHO 1992)), or as described in the study if it involved a subjective complaint of poor sleep. Studies had to compare a benzodiazepine or Zolpidem or Zopiclone or Zaleplon with placebo or active control for the treatment of insomnia. Any duration of therapy were considered.<br><br>DATA COLLECTION AND ANALYSIS: Abstracts were independently inspected by both reviewers, full papers were obtained where necessary. Where there was uncertainty advice was sought by a third (PW). Data extraction and quality assessments were undertaken independently by both reviewers.<br><br>MAIN RESULTS: No randomized controlled trials were identified meeting the a priori inclusion criteria. Thirty-seven studies were considered but all were excluded from the review.<br><br>REVIEWER'S CONCLUSIONS: Despite a comprehensive search no evidence from randomized controlled trials was identified. It was not possible to draw any conclusions regarding the use of benzodiazepines in palliative care.}, }
@article {pmid12512348, year = {2002}, author = {Orrell, RW and Schapira, AH}, title = {Mitochondria and amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {53}, number = {}, pages = {411-426}, doi = {10.1016/s0074-7742(02)53015-4}, pmid = {12512348}, issn = {0074-7742}, mesh = {Animals ; Brain/physiopathology ; Cell Line ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/*physiology ; Motor Neuron Disease/genetics/*physiopathology ; Organ Specificity ; Skin/physiopathology ; Spinal Cord/physiopathology ; }, }
@article {pmid12509691, year = {2002}, author = {Howard, RS and Orrell, RW}, title = {Management of motor neurone disease.}, journal = {Postgraduate medical journal}, volume = {78}, number = {926}, pages = {736-741}, pmid = {12509691}, issn = {0032-5473}, mesh = {Deglutition Disorders/etiology/therapy ; Humans ; Motor Neuron Disease/diagnosis/*therapy ; Neuroprotective Agents/therapeutic use ; Palliative Care/methods ; Respiration Disorders/etiology/therapy ; Respiration, Artificial/methods ; Riluzole/therapeutic use ; }, abstract = {Motor neurone disease is a progressive neurodegenerative disorder leading to severe disability and death. It is clinically characterised by mixed upper and lower motor neurone involvement affecting bulbar, limb, and respiratory musculature. Recent guidelines have established diagnostic criteria and defined management of the condition. In a proportion of familial amyotrophic lateral sclerosis there is a mutation in the gene encoding the enzyme copper/zinc superoxide dismutase 1; this has allowed mutation screening and generated considerable laboratory based research. The diagnosis must be given with care and consideration and close follow up is essential. Management involves a multidisciplinary team based in the hospital and the community. Riluzole is the only drug shown to have a disease modifying effect and has been approved by the National Institute for Clinical Excellence. The essence of care is good symptomatic management, including nutritional support with percutaneous endoscopic gastrostomy and ventilatory care with non-invasive ventilation. Palliative care should be introduced before the terminal stages after careful discussion with the patient and carers. Knowledge of this condition has grown dramatically recently with a parallel improvement in treatment and ability to deal with the most troublesome problems.}, }
@article {pmid12507415, year = {2003}, author = {Przedborski, S and Mitsumoto, H and Rowland, LP}, title = {Recent advances in amyotrophic lateral sclerosis research.}, journal = {Current neurology and neuroscience reports}, volume = {3}, number = {1}, pages = {70-77}, pmid = {12507415}, issn = {1528-4042}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/virology ; Animals ; Apoptosis/genetics/physiology ; Clinical Trials as Topic ; Disease Models, Animal ; HIV Infections/complications ; HIV-1 ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. Despite several genetic breakthroughs, the actual cause and mechanism of neurodegeneration in ALS remains a mystery. Nevertheless, recent scientific and clinical advances have led to the development of new therapeutic strategies for this progressive, fatal disorder. We review the progress of the most recent clinical trials in ALS, taking into account some of the hurdles encountered by these studies. We also discuss the potential role of retroviral infection as a cause or contributor to ALS, which is one of the most recent hypotheses for the pathogenesis of the disease. The genetic background of ALS is summarized and special attention is given to the newly identified ALS gene ALS2, and to those that are currently being investigated. The last part of this review is dedicated to the mutation in superoxide dismutase-1 (SOD1). The hypothesized deleterious mechanisms of mutant SOD1 are discussed, as well as the possibilities that the mutant protein activates the apoptotic cell death process and that these molecular alterations can be exploited to devise experimental neuroprotective therapies.}, }
@article {pmid12501701, year = {1998}, author = {Li, L}, title = {[Protective effects of schisanhenol, salvianolic acid A and SY-L on oxidative stress induced injuries of cerebral cells and their mechanisms].}, journal = {Sheng li ke xue jin zhan [Progress in physiology]}, volume = {29}, number = {1}, pages = {35-38}, pmid = {12501701}, issn = {0559-7765}, mesh = {Alzheimer Disease/metabolism ; Animals ; Caffeic Acids/*pharmacology ; *Cyclooctanes ; Drugs, Chinese Herbal/*pharmacology ; Free Radical Scavengers/*pharmacology ; Humans ; Lactates/*pharmacology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects ; Parkinson Disease/metabolism ; Polycyclic Compounds/*pharmacology ; }, abstract = {Oxidative stress may play an important role in neuronal degenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. These disorders make the elderly not being able to live normally and move freely. So it is necessary to find effective antioxidants to prevent or cure the aged persons from diseases related to neuronal degeneration. Schisanhenol (Sal) and salvianolic acid A (Sal A) are known antioxidants which were isolated from Chinese herbs respectively. SY-L is a totally synthetic new compound. The results showed that Sal, Sal A and SY-L significantly protect cerebral cells from the injuries induced by oxidative stress.}, }
@article {pmid12495570, year = {2002}, author = {Armon, C and Guiloff, RJ and Bedlack, R}, title = {Limitations of inferences from observational databases in amyotrophic lateral sclerosis: all that glitters is not gold.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {3}, pages = {109-112}, doi = {10.1080/146608202760834094}, pmid = {12495570}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Databases, Factual/*standards/*statistics &amp; numerical data ; Evidence-Based Medicine/*methods ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Retrospective Studies ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {Data from three observational databases have suggested that survival in patients with ALS who take riluzole is far greater than that reported in randomized controlled studies. This editorial discusses why therapeutic efficacy cannot be inferred from observational databases. Data in these databases cannot control for biases in treatment assignment or for differences in intensity of follow-up or supportive care. The retrospective riluzole data, as presented so far, have not demonstrated comparability between the treated and untreated groups across all known prognostic factors, including vital capacity at the start of the observation period. Furthermore, the similarity of untreated patients to historical cohorts likely reflects adverse selection. Optimization of analysis in retrospective studies may be accomplished by allowing full access to data to all interested parties.}, }
@article {pmid12486563, year = {2002}, author = {Flöel, A and Lohmann, H and Knecht, S}, title = {[Neuropsychological disorders in amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {73}, number = {12}, pages = {1144-1152}, doi = {10.1007/s00115-002-1383-3}, pmid = {12486563}, issn = {0028-2804}, mesh = {Aphasia/diagnosis/pathology/psychology ; Atrophy ; Dementia/*diagnosis/pathology/psychology ; Diagnostic Imaging ; Frontal Lobe/pathology ; Humans ; Motor Neuron Disease/*diagnosis/pathology/psychology ; *Neuropsychological Tests ; Pyramidal Tracts/pathology ; Temporal Lobe/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has traditionally been assumed to be a purely motor disturbance. It is now recognized that 2-5% of patients with ALS develop frontotemporal dementia. Additionally, neuropsychological analysis and functional imaging suggest that a proportion of patients with classical ALS also have neuropsychological impairment. On postmortem examination, ALS patients classified as not demented showed atrophy of the frontotemporal cortex. Conversely, in patients with frontotemporal dementia without known motor impairment, atrophy of spinal and bulbar neurons were found on postmortem examination. It is still not known whether patients with ALS and neuropsychological impairment form a distinct subgroup or if they are part of a continuous spectrum that runs from pure motor impairment to pure neuropsychological impairment.}, }
@article {pmid12482168, year = {2002}, author = {Krivickas, LS and Carter, GT}, title = {Amyotrophic lateral sclerosis: practical aspects of care.}, journal = {The journal of spinal cord medicine}, volume = {25}, number = {4}, pages = {274-276}, doi = {10.1080/10790268.2002.11753627}, pmid = {12482168}, issn = {1079-0268}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/*rehabilitation ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, }
@article {pmid12482167, year = {2002}, author = {Patel, SA and Maragakis, NJ}, title = {Amyotrophic lateral sclerosis: pathogenesis, differential diagnoses, and potential interventions.}, journal = {The journal of spinal cord medicine}, volume = {25}, number = {4}, pages = {262-273}, doi = {10.1080/10790268.2002.11753626}, pmid = {12482167}, issn = {1079-0268}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology/therapy ; Diagnosis, Differential ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease. The etiology is likely multifactorial, involving both genetic and environmental factors.<br><br>METHOD: Literature review.<br><br>FINDINGS: Motor neuron death is believed to arise from mutations in superoxide dismutase 1. Abnormal neurofilament metabolism, glutamate transporter dysfunction, and altered responses to growth factors may play a role. These discoveries have highlighted possible interventions, several of which have subsequently undergone human clinical trials. These include studies of antioxidants, antiglutamatergic agents, cyclooxygenase inhibitors, and various growth factors.<br><br>CONCLUSION: Findings are inconclusive, and further investigations are underway. At present, nonpharmacologic interventions such as nutritional support; physical, speech, and occupational therapy; and respiratory management offer the best means of improving quality of life for patients with ALS.}, }
@article {pmid12478466, year = {2002}, author = {Nguyen, MD and Mushynski, WE and Julien, JP}, title = {Cycling at the interface between neurodevelopment and neurodegeneration.}, journal = {Cell death and differentiation}, volume = {9}, number = {12}, pages = {1294-1306}, doi = {10.1038/sj.cdd.4401108}, pmid = {12478466}, issn = {1350-9047}, mesh = {Animals ; Apoptosis/genetics ; Cell Differentiation/genetics ; Central Nervous System/growth &amp; development/*metabolism/physiopathology ; Cyclin-Dependent Kinases/genetics/*metabolism ; Genes, cdc/physiology ; Humans ; Neurodegenerative Diseases/genetics/*metabolism ; Neurons/*metabolism/pathology ; Signal Transduction/genetics ; }, abstract = {The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycle-associated protein kinases, which are referred to as cyclin-dependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Ectopic expression of these proteins in neurons potently induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of non-membrane-associated proteins and possibly through the induction of cell cycle proteins. On the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint. Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but they likely conspire in leading neurons to their demise.}, }
@article {pmid12458964, year = {2002}, author = {Hu, JH and Krieger, C}, title = {Protein phosphorylation networks in motor neuron death.}, journal = {Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques}, volume = {59}, number = {}, pages = {71-109}, doi = {10.1007/978-3-0348-8171-5_3}, pmid = {12458964}, issn = {0071-786X}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Cell Death/physiology ; Humans ; Motor Neurons/*metabolism/pathology ; Phosphorylation ; Proteins/*metabolism ; }, abstract = {The disorder amyotrophic lateral sclerosis (ALS) is characterized by the death of specific groups of neurons, especially motor neurons, which innervate skeletal muscle, and neurons connecting the cerebral cortex with motor neurons, such as corticospinal tract neurons. There have been numerous attempts to elucidate why there is selective involvement of motor neurons in ALS. Recent observations have demonstrated altered activities and protein levels of diverse kinases in the brain and spinal cord of transgenic mice that overexpress a mutant superoxide dismutase (mSOD) gene that is found in patients with the familial form of ALS, as well as in patients who have died with ALS. These results suggest that the alteration of protein phosphorylation may be involved in the pathogenesis of ALS. The changes in protein kinase and phosphatase expression and activity can affect the activation of important neuronal neurotransmitter receptors such as NMDA receptors or other signaling proteins and can trigger, or modify, the process producing neuronal loss in ALS. These various kinases, phosphatases and signaling proteins are involved in many signaling pathways; however, they have close interactions with each other. Therefore, an understanding of the role of protein kinases and protein phosphatases and the molecular organization of protein phosphorylation networks are useful to determine the mechanisms of selective motor neuron death.}, }
@article {pmid12430012, year = {2002}, author = {Schloss, JV}, title = {Oxygen toxicity from plants to people.}, journal = {Planta}, volume = {216}, number = {1}, pages = {38-43}, doi = {10.1007/s00425-002-0905-3}, pmid = {12430012}, issn = {0032-0935}, support = {GM07775/GM/NIGMS NIH HHS/United States ; GM48568/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetolactate Synthase/metabolism ; Aldehyde-Lyases/metabolism ; Ascorbic Acid/metabolism ; Enterobacteriaceae/drug effects/metabolism ; Glutamate Decarboxylase/metabolism ; Humans ; Hydro-Lyases/metabolism ; Hydrogen Peroxide/metabolism ; Oxygen/adverse effects/*toxicity ; Peracetic Acid/metabolism ; Plants/*drug effects/metabolism ; Pyruvate Decarboxylase/metabolism ; Ribulose-Bisphosphate Carboxylase/metabolism ; }, abstract = {Over the past 30 years, acute oxygen toxicity in plants, mammals and enteric bacteria has been defined in terms of specific interactions of oxygen with a limited number of molecular targets. At least in the case of plants and mammals, response at the level of the whole organism is a consequence of oxygen's interaction with enzymes that should not exhibit oxygen sensitivity, ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) and glutamate decarboxylase (GAD). In enteric bacteria, inhibition of acetolactate synthase (ALS), or the production of peracetic acid by this enzyme, may be a contributing factor in the inactivation of dihydroxyacid dehydratase and loss of the ability to synthesize branched-chain amino acids under conditions of hyperbaric oxygen. The facile interaction of these enzymes with oxygen has questioned our fundamental understanding of their reaction mechanisms. Could these enzymes have radical mechanisms?}, }
@article {pmid12419463, year = {2002}, author = {Valentine, JS}, title = {Do oxidatively modified proteins cause ALS?.}, journal = {Free radical biology &amp; medicine}, volume = {33}, number = {10}, pages = {1314-1320}, doi = {10.1016/s0891-5849(02)01080-8}, pmid = {12419463}, issn = {0891-5849}, support = {GM28222/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*etiology ; Animals ; Copper/pharmacology ; Free Radicals ; Humans ; Mutation ; Neurodegenerative Diseases/enzymology/etiology ; Oxidative Stress ; Oxygen/*metabolism ; Superoxide Dismutase/metabolism ; Zinc/pharmacology ; }, abstract = {Over 90 individual mutations in SOD1 are known to cause familial amyotrophic lateral sclerosis (FALS). It is widely accepted that these mutations exert their toxic effects by a gain of function mechanism, but the nature of these toxic effects is as yet unknown. It has been proposed by several laboratories that reactions of FALS-mutant CuZnSOD are the source of elevated oxidative stress in CuZnSOD-linked FALS. It has also been proposed that aggregates of CuZnSOD are somehow involved in the disease. The hypothesis that aggregates of CuZnSOD cause ALS is particularly attractive because protein aggregates are frequently associated with other neurodegenerative diseases. Recent evidence increasingly suggests that protein aggregates containing CuZnSOD protein play a role in CuZnSOD-linked ALS, but it is not yet know why the aggregates form nor if the CuZnSOD proteins in the aggregates are cleaved, oxidized, demetallated, or otherwise covalently modified.}, }
@article {pmid12409815, year = {2002}, author = {Miller, RG}, title = {Role of fatigue in limiting physical activities in humans with neuromuscular diseases.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {81}, number = {11 Suppl}, pages = {S99-107}, doi = {10.1097/00002060-200211001-00011}, pmid = {12409815}, issn = {0894-9115}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis ; Electromyography/methods ; Fatigue Syndrome, Chronic/diagnosis ; Humans ; Magnetic Resonance Spectroscopy/methods ; Motor Activity ; *Muscle Fatigue ; Muscle, Skeletal/*metabolism ; *Neuromuscular Diseases/complications/diagnosis/metabolism ; Postpoliomyelitis Syndrome/diagnosis ; }, abstract = {New methods of examining both central and peripheral fatigue are now available. A broader understanding of the mechanisms of fatigue in healthy human subjects has begun to emerge. The mechanisms of fatigue in patients with various neuromuscular diseases are even more complex than in healthy persons. Examples of both central and peripheral fatigue in various neuromuscular diseases and other disorders are presented, including metabolic myopathy, chronic fatigue syndrome, postpolio syndrome, and amyotrophic lateral sclerosis.}, }
@article {pmid12395618, year = {2002}, author = {Stålberg, E and Erdem, H}, title = {Quantitative motor unit potential analysis in routine.}, journal = {Electromyography and clinical neurophysiology}, volume = {42}, number = {7}, pages = {433-442}, pmid = {12395618}, issn = {0301-150X}, mesh = {*Diagnostic Tests, Routine ; *Electromyography ; Evoked Potentials, Motor/*physiology ; Humans ; Motor Neuron Disease/*diagnosis/*physiopathology ; Motor Neurons/*physiology ; }, abstract = {This article is a review of the generation of the motor unit potential and modern techniques for its quantification. General comments are made on findings in neurogenic and myopathic conditions. Detailed examples are given from two pathological conditions, ALS and polymyositis. Quantitative parameters are presented and the usefulness of outliers compared to mean values is discussed.}, }
@article {pmid12394638, year = {2002}, author = {Cameron, A and Rosenfeld, J}, title = {Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {5}, number = {6}, pages = {631-643}, doi = {10.1097/00075197-200211000-00005}, pmid = {12394638}, issn = {1363-1950}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology/therapy ; Deglutition Disorders/etiology/therapy ; *Dietary Supplements ; *Enteral Nutrition ; Gastrostomy/methods ; Humans ; Motor Neuron Disease/complications/*physiopathology/therapy ; Nutrition Disorders/*etiology/prevention &amp; control/therapy ; Palliative Care ; Prognosis ; Respiratory Insufficiency/etiology ; }, abstract = {PURPOSE OF REVIEW: Aggressive nutritional intervention has become a cornerstone of treatment for many patients with neuromuscular diseases, in particular, motor neuron disease. Malnutrition is a common problem among patients with amyotrophic lateral sclerosis. Over the past decade, the recognition of nutrition as an independent, prognostic factor for survival and disease complications in amyotrophic lateral sclerosis has illustrated the importance of individualized nutritional management in symptomatic treatment. Paramount issues for nutritional management in amyotrophic lateral sclerosis include caloric supplementation, the diagnosis/treatment of dysphagia, and the timing/safety/efficacy of percutaneous endoscopic gastrostomy placement.<br><br>RECENT FINDINGS: In addition, many amyotrophic lateral sclerosis patients self-medicate with a variety of vitamins, herbs, and other dietary supplements. Outcome-based research for the use of nutraceuticals and functional foods in the treatment and prevention of amyotrophic lateral sclerosis and other neuromuscular diseases is in its early stages. In the past year, however, several interesting papers have been published that lend support to the use of dietary supplements as primary treatments for amyotrophic lateral sclerosis and other motor neuron disorders.<br><br>SUMMARY: Common or overlapping etiologies in disparate neurodegenerative diseases have led to the promise that optimal nutritional care and the appropriate use of dietary supplements in amyotrophic lateral sclerosis will have implications for the nutritional management of other degenerative conditions such as Parkinson's, Alzheimer's, and Huntington's disease. Furthermore, evidence supporting the efficacy of dietary supplements in amyotrophic lateral sclerosis may lend clues to the treatment of other neuromuscular disorders such as the muscular dystrophies.}, }
@article {pmid12393944, year = {2002}, author = {Fiscus, RR}, title = {Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells.}, journal = {Neuro-Signals}, volume = {11}, number = {4}, pages = {175-190}, doi = {10.1159/000065431}, pmid = {12393944}, issn = {1424-862X}, mesh = {Animals ; Apoptosis/*physiology ; Cell Survival/*physiology ; Central Nervous System Diseases/*enzymology/physiopathology ; Cyclic GMP/*metabolism ; Cyclic GMP-Dependent Protein Kinases/*metabolism ; Humans ; Nervous System/*enzymology/physiopathology ; Neurons/*enzymology ; Nitric Oxide/metabolism ; Signal Transduction/physiology ; }, abstract = {Our current understanding of nitric oxide (NO), cyclic GMP (cGMP) and protein kinase G (PKG) signaling pathways in the nervous systems has its origins in the early studies conducted on vascular tissues during the late 1970s and early to mid-1980s. The pioneering research into the NO/cGMP/PKG pathway in blood vessels conducted by the laboratories of Drs. Ferid Murad, Louis Ignarro and Robert Furchgott ultimately led to the awarding of the 1998 Nobel Prize in Physiology or Medicine to these three scientists. On the basis of further pioneering studies by Drs. John Garthwaite, Solomon Snyder, Steven Vincent and many other neuroscientists during the late 1980s and throughout the 1990s, it became recognized that NO serves as a neurotransmitter/neuromodulator in the central and peripheral nervous systems and that certain neural cells possess a cGMP signaling pathway similar to that in vascular smooth muscle cells. Although NO (at high concentrations) is toxic and thought to participate in neuronal cell death during stroke and neurodegenerative diseases (e.g. amyotrophic lateral sclerosis, Alzheimer's disease, HIV dementia and Parkinson's disease), recent evidence suggests that NO at low physiological concentrations can act as an antiapoptotic/prosurvival factor in certain neural cells (e.g. PC12 cells, motor neurons and neurons of dorsal root ganglia, hippocampus and sympathetic nerves). The antiapoptotic effects of NO are mediated, in part, by cGMP and a downstream target protein, PKG. Other cGMP-elevating factors (e.g. atrial and brain natriuretic peptides) and direct PKG activator (e.g. 8-bromo-cGMP) also have antiapoptotic effects which have been quantified by the new capillary electrophoresis with laser-induced fluorescence detector technology. Inhibition of soluble guanylyl cyclase and lowering of basal cGMP levels cause apoptosis in unstressed neural cells (NG108-15 and N1E-115 cells). The cGMP/PKG pathway appears to play an essential role in preventing activation of a proapoptotic pathway, thus promoting neural cell survival.}, }
@article {pmid12392798, year = {2002}, author = {Forloni, G and Terreni, L and Bertani, I and Fogliarino, S and Invernizzi, R and Assini, A and Ribizzi, G and Negro, A and Calabrese, E and Volonté, MA and Mariani, C and Franceschi, M and Tabaton, M and Bertoli, A}, title = {Protein misfolding in Alzheimer's and Parkinson's disease: genetics and molecular mechanisms.}, journal = {Neurobiology of aging}, volume = {23}, number = {5}, pages = {957-976}, doi = {10.1016/s0197-4580(02)00076-3}, pmid = {12392798}, issn = {0197-4580}, mesh = {Aged ; Alzheimer Disease/*genetics/*metabolism ; Amyloid/chemistry/metabolism ; Cysteine Endopeptidases/metabolism ; Humans ; Ligases/metabolism ; Membrane Proteins/chemistry/metabolism ; Multienzyme Complexes/metabolism ; Nerve Tissue Proteins/metabolism ; Parkinson Disease/*genetics/*metabolism ; Presenilin-1 ; Presenilin-2 ; Proteasome Endopeptidase Complex ; Protein Folding ; Synucleins ; Ubiquitin/metabolism ; *Ubiquitin-Protein Ligases ; }, abstract = {The accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. A causal role of protein aggregation was originally proposed in Alzheimer's disease (AD) where extracellular deposition of beta-amyloid (Abeta) is the main neuropathological feature. It is now believed that intracellular deposition of aggregated proteins may be relevant in Parkinson's disease (PD), amyotrophic lateral sclerosis and polyglutamine disorders. An impairment of ubiquitin-proteasome system (UPS) appears directly involved in these disorders. We reviewed the results on the role of protein misfolding in AD and PD and the influence of mutations associated with these diseases on the expression of amyloidogenic proteins. Results of genetic screening of familial cases of AD and PD are summarized. In the familial AD population (70 subjects) we found several mutations of the presenilin 1 (PS1) gene with a frequency of 12.8% and one mutation in the gene encoding the protein precursor of amyloid (APP) (1.4%). One mutation of Parkin in the homozygous form and two in the heterozygous form were identified in our PD population. We also reported data obtained with synthetic peptides and other experimental models, for evaluation of the pathogenic role of mutations in terms of protein misfolding.}, }
@article {pmid12392777, year = {2002}, author = {Esposito, E and Rotilio, D and Di Matteo, V and Di Giulio, C and Cacchio, M and Algeri, S}, title = {A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes.}, journal = {Neurobiology of aging}, volume = {23}, number = {5}, pages = {719-735}, doi = {10.1016/s0197-4580(02)00078-7}, pmid = {12392777}, issn = {0197-4580}, mesh = {Aged ; Antioxidants/*therapeutic use ; Brain/*metabolism ; Diet ; Humans ; Neurodegenerative Diseases/*diet therapy/*metabolism ; }, abstract = {Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. An increasing number of studies show that nutritional antioxidants (especially Vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor-kappaB (NF-kappaB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kappaB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.}, }
@article {pmid12387703, year = {2002}, author = {Moosmann, B and Behl, C}, title = {Antioxidants as treatment for neurodegenerative disorders.}, journal = {Expert opinion on investigational drugs}, volume = {11}, number = {10}, pages = {1407-1435}, doi = {10.1517/13543784.11.10.1407}, pmid = {12387703}, issn = {1354-3784}, mesh = {Animals ; Antioxidants/classification/pharmacology/*therapeutic use ; Free Radicals/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {Oxidative stress is a ubiquitously observed hallmark of neurodegenerative disorders. Neuronal cell dysfunction and cell death due to oxidative stress may causally contribute to the pathogenesis of progressive neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, as well as acute syndromes of neurodegeneration, such as ischaemic and haemorrhagic stroke. Neuroprotective antioxidants are considered a promising approach to slowing the progression and limiting the extent of neuronal cell loss in these disorders. The clinical evidence demonstrating that antioxidant compounds can act as protective drugs in neurodegenerative disease, however, is still relatively scarce. In the following review, the available data from clinical, animal and cell biological studies regarding the role of antioxidant neuroprotection in progressive neurodegenerative disease will be summarised, focussing particularly on Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The general complications in developing potent neuroprotective antioxidant drugs directed against these long-term degenerative conditions will also be discussed. The major challenges for drug development are the slow kinetics of disease progression, the unsolved mechanistic questions concerning the final causalities of cell death, the necessity to attain an effective permeation of the blood-brain barrier and the need to reduce the high concentrations currently required to evoke protective effects in cellular and animal model systems. Finally, an outlook as to which direction antioxidant drug development and clinical practice may be leading to in the near future will be provided.}, }
@article {pmid12387699, year = {2002}, author = {Jackson, M and Lladó, J and Rothstein, JD}, title = {Therapeutic developments in the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {11}, number = {10}, pages = {1343-1364}, doi = {10.1517/13543784.11.10.1343}, pmid = {12387699}, issn = {1354-3784}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Clinical Trials as Topic/statistics &amp; numerical data ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Technology, Pharmaceutical/*trends ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the selective death of motor neurones. The mechanisms and processes responsible for the selective loss of motor neurones are still unknown, however several hypotheses have been put forward, including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase-1 activity, axonal strangulation from cytoskeletal abnormalities, loss of trophic factor support and glutamate-mediated excitotoxicity. These theories are based on a better understanding of the genetics of amyotrophic lateral sclerosis and on biochemical and pathological analysis of post-mortem tissue. They have led to the development of appropriate animal and cell culture models, allowing the sequence of events in motor neuronal degeneration to be unravelled and potential therapeutic agents to be screened. Unfortunately, the majority of therapeutics found to be efficacious in the animal and cell culture models have failed in human trials. Riluzole is still the only proven therapy in humans, shown to extend survival of amyotrophic lateral sclerosis patients by approximately 3 months, but it has no effect on muscle strength. Other potential therapeutic approaches are being identified, including inhibition of caspase-mediated cell death, maintenance of mitochondrial integrity and energy production, regulation of glutamate homeostasis, reduction of inflammation and control of neurofilament synthesis. Hopefully, in the near future some new agents will be found that can alter the course of this devastating and fatal disease.}, }
@article {pmid12386499, year = {2002}, author = {Nolan, JP and De Latorre, FJ and Steen, PA and Chamberlain, DA and Bossaert, LL}, title = {Advanced life support drugs: do they really work?.}, journal = {Current opinion in critical care}, volume = {8}, number = {3}, pages = {212-218}, doi = {10.1097/00075198-200206000-00003}, pmid = {12386499}, issn = {1070-5295}, mesh = {Advanced Cardiac Life Support/*methods/mortality ; Animals ; Anti-Arrhythmia Agents/*administration &amp; dosage ; Critical Care/methods ; Dose-Response Relationship, Drug ; Epinephrine/administration &amp; dosage ; Female ; Fibrinolytic Agents/*administration &amp; dosage ; Heart Arrest/mortality/*therapy ; Humans ; Male ; Sensitivity and Specificity ; Survival Analysis ; Time Factors ; Treatment Outcome ; Vasoconstrictor Agents/*administration &amp; dosage ; Vasopressins/administration &amp; dosage ; }, abstract = {Basic life support and rapid defibrillation for ventricular fibrillation or pulseless ventricular tachycardia are the only two interventions that have been shown unequivocally to improve survival after cardiac arrest. Several drugs are advocated to treat cardiac arrest, but despite very encouraging animal data, no drug has been reliably proven to increase survival to hospital discharge after cardiac arrest. This review focuses on recent experimental and clinical data concerning the use of vasopressin, amiodarone, magnesium, and fibrinolytics during advanced life support (ALS). Animal data indicate that, in comparison with epinephrine (adrenaline), vasopressin produces better vital organ blood flow during cardiopulmonary resuscitation (CPR). These apparent advantages have yet to be converted into improved survival in large-scale trials of cardiac arrest in humans. Data from two prospective, randomized trials suggest that amiodarone may improve short-term survival after out-of-hospital ventricular fibrillation cardiac arrest. On the basis of anecdotal data, magnesium is recommended therapy for torsades de pointes and for shock-resistant ventricular fibrillation associated with hypomagnesemia. In the past, CPR has been a contraindication to giving fibrinolytics, but several studies have demonstrated the relative safety of fibrinolysis during and after CPR. Fibrinolytics are likely to be beneficial when cardiac arrest is associated with plaque rupture and fresh coronary thrombus or massive pulmonary embolism. Fibrinolysis may also improve cerebral microcirculatory perfusion once a spontaneous circulation has been restored. A planned, prospective, randomized trial may help to define the role of fibrinolysis during out-of-hospital CPR.}, }
@article {pmid12385592, year = {2002}, author = {Rao, AV and Balachandran, B}, title = {Role of oxidative stress and antioxidants in neurodegenerative diseases.}, journal = {Nutritional neuroscience}, volume = {5}, number = {5}, pages = {291-309}, doi = {10.1080/1028415021000033767}, pmid = {12385592}, issn = {1028-415X}, mesh = {Alzheimer Disease/pathology/physiopathology ; *Antioxidants/therapeutic use ; Brain/pathology/physiopathology ; Humans ; Motor Neuron Disease/pathology/physiopathology ; Neurodegenerative Diseases/pathology/*physiopathology/prevention &amp; control ; Oxidative Stress/*physiology ; Parkinson Disease/pathology/physiopathology ; }, abstract = {Neurodegenerative diseases (NDD) are a group of illness with diverse clinical importance and etiologies. NDD include motor neuron disease such as amyotrophic lateral sclerosis (ALS), cerebellar disorders, Parkinson's disease (PD), Huntington's disease (HD), cortical destructive Alzheimer's disease (AD) and Schizophrenia. Numerous epidemiological and experimental studies provide many risk factors such as advanced age, genetic defects, abnormalities of antioxidant enzymes, excitotoxicity, cytoskeletal abnormalities, autoimmunity, mineral deficiencies, oxidative stress, metabolic toxicity, hypertension and other vascular disorders. Growing body of evidence implicates free radical toxicity, radical induced mutations and oxidative enzyme impairment and mitochondrial dysfunction due to congenital genetic defects in clinical manifestations of NDD. Accumulation of oxidative damage in neurons either primarily or secondarily may account for the increased incidence of NDD such as AD, ALS and stroke in aged populations. The molecular mechanisms of neuronal degeneration remain largely unknown and effective therapies are not currently available. Recent interest has focused on antioxidants such as carotenoids and in particular lycopene, a potent antioxidant in tomatoes and tomato products, flavonoids and vitamins as potentially useful agents in the management of human NDD. The pathobiology of neurodegenerative disorders with emphasis on genetic origin and its correlation with oxidative stress of neurodegenerative disorders will be reviewed and the reasons as to why brain constitutes a vulnerable site of oxidative damage will be discussed. The article will also discuss the potential free radical scavenger, mechanism of antioxidant action of lycopene and the need for the use of antioxidants in the prevention of NDD.}, }
@article {pmid12373987, year = {2002}, author = {Eberhardie, C}, title = {Nutrition support in palliative care.}, journal = {Nursing standard (Royal College of Nursing (Great Britain) : 1987)}, volume = {17}, number = {2}, pages = {47-52; quiz 54-5}, doi = {10.7748/ns.17.2.47.s59}, pmid = {12373987}, issn = {0029-6570}, mesh = {Cachexia/etiology/therapy ; Decision Making ; Ethics, Nursing ; Humans ; Motor Neuron Disease/complications/therapy ; Neoplasms/complications/therapy ; Nutritional Support/*methods ; *Palliative Care ; }, abstract = {Nutrition is an important aspect of caring for patients with life-threatening illness. Good nutrition support is essential, not only for meeting the body's physical requirements but also because of associated social, cultural and psychological benefits for patients. The author uses examples from cancer and motor neurone disease to illustrate the nutrition needs, legal and ethical issues and specific symptoms that affect dietary intake in patients receiving palliative care.}, }
@article {pmid12373523, year = {2002}, author = {Kochman, A and Kośka, C and Metodiewa, D}, title = {Submolecular adventures of brain tyrosine: what are we searching for now?.}, journal = {Amino acids}, volume = {23}, number = {1-3}, pages = {95-101}, doi = {10.1007/s00726-001-0114-6}, pmid = {12373523}, issn = {0939-4451}, mesh = {*Brain Chemistry ; Dopamine/metabolism ; Free Radicals/metabolism ; Humans ; Molecular Structure ; Neurodegenerative Diseases/*metabolism ; Reactive Oxygen Species/metabolism ; Tyrosine/*chemistry/*metabolism ; }, abstract = {This overview summarizes recent findings on the role of tyrosyl radical (TyrO(*)) in the multitudinous neurochemical systems of brain, and theorizes on the putative role of TyrO(*) in neurological disorders [Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS)]. TyrO(*) and tyrosine per se can interact with reactive oxygen species (ROS) and reactive nitrogen species (RNS) via radical mechanisms and chain propagating reactions. The concentration of TyrO(*), ROS and RNS can increase dramatically under conditions of generalized stress: oxidative, nitrative or reductive as well, and this can induce damage directly (by lipid peroxidation) or indirectly (by proteins oxidation and/or nitration), potentially causing apoptotic neuronal cell death or autoschizis. Evidence of lesion-induced neuronal oxidative stress includes the presence of protein peroxides (TyrOOH), DT (o,o'-dityrosine) and 3-NT (3-nitrotyrosine). Mechanistic details of protein- and enzymatic oxidation/nitration in vivo remain unresolved, although recent in vitro data strongly implicate free radical pathways via TyrO(*). Nitration/denitration processes can be pathological, but they also may play: 1). a signal transduction role, because nitration of tyrosine residues through TyrO(*) formation can modulate, as well the phosphorylation (tyrosine kinases activity) and/or tyrosine hydroxylation (tyrosine hydroxylase inactivation), leading to consequent dopamine synthesis failure and increased degradation of target proteins, respectively; 2). a role of "blocker" for radical-radical reactions (scavenging of NO(*), NO(*)(2) and CO(3)(*-) by TyrO(*)); 3). a role of limiting factors for peroxynitrite formation, by lowering O(2)(*-) formation, which is strongly linked to the pathogenesis of neural diseases. It is still not known if tyrosine oxidation/nitration via TyrO(*) formation is 1). a footprint of generalized stress and neuronal disorders, or 2). an important part of O(2)(*-) and NO(*) metabolism, or 3). merely a part of integral processes for maintaining of neuronal homeostasis. The full answer to these questions should be of top research priority, as the problem of increased free radical formation in brain and/or imbalance of the ratios ROS/RNS/TyrO(*) may be all important in defining whether oxidative stress is the critical determinant of tissue and neural cell injury that leads to pathological end-points.}, }
@article {pmid12373010, year = {2002}, author = {De Benedetti, F and Meazza, C and Martini, A}, title = {Role of interleukin-6 in growth failure: an animal model.}, journal = {Hormone research}, volume = {58 Suppl 1}, number = {}, pages = {24-27}, doi = {10.1159/000064757}, pmid = {12373010}, issn = {0301-0163}, mesh = {Animals ; Endopeptidases/blood ; Growth Disorders/*etiology ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis/metabolism ; Interleukin-6/blood/genetics/*physiology ; Metabolic Clearance Rate ; Mice ; Mice, Transgenic ; Phosphopyruvate Hydratase/genetics ; Promoter Regions, Genetic ; Rats ; }, abstract = {Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50-70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.}, }
@article {pmid12365066, year = {1999}, author = {Armon, C}, title = {How can physicians and their patients with ALS decide to use the newly-available treatments to slow disease progression?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {1}, pages = {3-14}, doi = {10.1080/14660829952415945}, pmid = {12365066}, issn = {1466-0822}, mesh = {Acetates/therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy/economics/pathology/physiopathology ; Anticonvulsants/therapeutic use ; Clinical Trials as Topic ; *Cyclohexanecarboxylic Acids ; Disease Progression ; Gabapentin ; Growth Substances/*therapeutic use ; Humans ; Intercellular Signaling Peptides and Proteins/*therapeutic use ; Neuroprotective Agents/therapeutic use ; Quality of Life ; Riluzole/*therapeutic use ; Sickness Impact Profile ; *gamma-Aminobutyric Acid ; }, abstract = {The 1990s decade has seen the testing of treatments to slow disease progression in patients with ALS. Two such treatments (riluzole and myotrophin) have shown minimal or modest efficacy. Of these, riluzole has been approved for marketing in the United States, in Europe and in other countries. Patients and physicians who are trying to decide whether to use these treatments require background information: (a) to place these treatments in the context of other treatments; (b) to understand the outcome measures used; and (c) to understand the significance of the efficacy these treatments have shown. For example, in some cases treatment efficacy has been shown by some measures, but not others. This paper attempts to assist in this process. In addition, we attempt to show how to integrate objective data with relative or subjective factors, such as patient values, economic considerations, and the role of hope.}, }
@article {pmid12365061, year = {1999}, author = {Toepfer, M and Folwaczny, C and Klauser, A and Riepl, RL and Müller-Felber, W and Pongratz, D}, title = {Gastrointestinal dysfunction in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {1}, pages = {15-19}, doi = {10.1080/146608299300079484}, pmid = {12365061}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Breath Tests ; Carbon Dioxide/metabolism ; Contrast Media ; Digestive System/diagnostic imaging/*physiopathology ; Digestive System Physiological Phenomena ; Female ; Gastric Emptying/physiology ; Humans ; Male ; Middle Aged ; Radiography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of motor neurons. However, ALS has been recognized to involve several non-motor systems. Subclinical involvement of the autonomic system (i.e. of cardial or sudomotor regulation) has been described in ALS. Gastrointestinal motor dysfunction can occur in amyotrophic lateral sclerosis, even if patients do not complain of gastrointestinal symptoms. New techniques in non-invasive evaluation of gastrointestinal function showed delayed gastric emptying and delayed colonic transit times in patients with ALS.}, }
@article {pmid12362410, year = {2002}, author = {McGeer, PL and McGeer, EG}, title = {Inflammatory processes in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {26}, number = {4}, pages = {459-470}, doi = {10.1002/mus.10191}, pmid = {12362410}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/metabolism/*pathology/therapy ; Animals ; Disease Models, Animal ; Humans ; Inflammation/metabolism/*pathology ; }, abstract = {Neuroinflammation is a characteristic of pathologically affected tissue in several neurodegenerative disorders. These changes can be observed in the brainstem and spinal cord of amyotrophic lateral sclerosis (ALS) cases and in mouse models of the disease. They include an accumulation of large numbers of activated microglia and astrocytes, as well as small numbers of T cells, mostly adhering to postcapillary venules. Accompanying biochemical alterations include the appearance of numerous molecules characteristic of free-radical attack, the occurrence of proteins associated with activation of the complement cascade, and a sharp upregulation of the enzyme cyclooxygenase 2 (COX-2). Anti-inflammatory agents may have a role to play in treating ALS. COX-2 is a particularly attractive target because of its marked increase in ALS spinal cord.}, }
@article {pmid12362409, year = {2002}, author = {Heath, PR and Shaw, PJ}, title = {Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {26}, number = {4}, pages = {438-458}, doi = {10.1002/mus.10186}, pmid = {12362409}, issn = {0148-639X}, mesh = {Amino Acid Transport System X-AG/metabolism ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Excitatory Amino Acids/*physiology ; Glutamic Acid/*physiology ; Humans ; Motor Neurons/physiology ; Neural Pathways/pathology ; Neurotransmitter Agents/*physiology ; Receptors, AMPA/physiology ; Receptors, Glutamate/physiology ; Receptors, Kainic Acid/physiology ; Receptors, Metabotropic Glutamate/physiology ; Receptors, N-Methyl-D-Aspartate/physiology ; }, abstract = {Excitotoxicity may play a role in certain disorders of the motor system thought to be caused by environmentally acquired toxins, including lathyrism and domoic acid poisoning. Motor neurons appear to be particularly susceptible to toxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-kainate receptors. There is a body of evidence implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). Interference with glutamate-mediated toxicity is so far the only neuroprotective therapeutic strategy that has shown benefit in terms of slowing disease progression in ALS patients. Biochemical studies have shown decreased glutamate levels in central nervous system (CNS) tissue and increased levels in the cerebrospinal fluid (CSF) of ALS patients. CSF from ALS patients is toxic to neurons in culture, apparently via a mechanism involving AMPA receptor activation. There is evidence for altered expression and function of glial glutamate transporters in ALS, particularly excitatory amino acid transporter 2 (EAAT2). Abnormal splice variants of EAAT2 have been detected in human CNS. Mitochondrial dysfunction may contribute to excitotoxicity in ALS. Induction of neuronal nitric oxide synthase and cyclooxygenase 2 in ALS may also lead to significant interactions with regulation of the glutamate transmitter system. Certain features of motor neurons may predispose them to the neurodegenerative process in ALS, such as the cell size, mitochondrial activity, neurofilament content, and relative lack of certain calcium-binding proteins and molecular chaperones. Motor neurons appear vulnerable to toxicity mediated by calcium-permeable AMPA receptors. The relatively low expression of the glutamate receptor 2 (GluR2) AMPA receptor subunit and the high current density caused by the large number and density of cell surface AMPA receptors are potentially important factors that may predispose to such toxicity.}, }
@article {pmid12357010, year = {2002}, author = {Talbot, K}, title = {Motor neurone disease.}, journal = {Postgraduate medical journal}, volume = {78}, number = {923}, pages = {513-519}, pmid = {12357010}, issn = {0032-5473}, mesh = {Forecasting ; Humans ; Magnetic Resonance Imaging/methods ; Motor Neuron Disease/classification/*diagnosis/etiology/therapy ; Syndrome ; }, abstract = {Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS), is a neurodegenerative disorder of unknown aetiology. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Confirming the diagnosis may initially be difficult until the full clinical features are manifest. For all forms of the disease there is a significant differential diagnosis to consider, including treatable conditions, and therefore specialist neurological opinion should always be sought. Clear genetic inheritance has been demonstrated in a minority of patients with familial ALS but elucidation of the biological basis of genetic subtypes is also providing important information which may lead to treatments for sporadic forms of the disease. In the absence of curative or disease modifying therapy, management is supportive and requires a multidisciplinary approach. If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts.}, }
@article {pmid12354390, year = {2002}, author = {Xiong, ZQ and McNamara, JO}, title = {Fas(t) balls and Lou Gehrig disease. A clue to selective vulnerability of motor neurons?.}, journal = {Neuron}, volume = {35}, number = {6}, pages = {1011-1013}, doi = {10.1016/s0896-6273(02)00910-8}, pmid = {12354390}, issn = {0896-6273}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Animals ; Cell Death/genetics ; Central Nervous System/*metabolism/pathology/physiopathology ; Humans ; Motor Neurons/*metabolism/pathology ; Mutation/genetics ; Superoxide Dismutase/*deficiency/genetics ; Superoxide Dismutase-1 ; fas Receptor/genetics/*metabolism ; }, abstract = {The molecular basis of the selective death of motor neurons in amyotrophic lateral sclerosis (ALS) has been an enigma since its description by Charcot in 1869. In this issue of Neuron, demonstrate a motor neuron-specific death pathway which involves Fas and NO. Remarkably, motor neurons from mice carrying ALS-linked mutant forms of superoxide dismutase 1 (SOD1) exhibit an increased sensitivity to death triggered by Fas but not other insults. These data suggest new insights into the mechanisms of, and potential therapeutic strategies for, death of motor neurons in ALS.}, }
@article {pmid12237154, year = {2002}, author = {Knockaert, M and Greengard, P and Meijer, L}, title = {Pharmacological inhibitors of cyclin-dependent kinases.}, journal = {Trends in pharmacological sciences}, volume = {23}, number = {9}, pages = {417-425}, doi = {10.1016/s0165-6147(02)02071-0}, pmid = {12237154}, issn = {0165-6147}, mesh = {Animals ; Cyclin-Dependent Kinases/*antagonists &amp; inhibitors/physiology ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Humans ; Signal Transduction/drug effects/physiology ; }, abstract = {Cyclin-dependent kinases (CDKs) regulate the cell division cycle, apoptosis, transcription and differentiation in addition to functions in the nervous system. Deregulation of CDKs in various diseases has stimulated an intensive search for selective pharmacological inhibitors of these kinases. More than 50 inhibitors have been identified, among which >20 have been co-crystallized with CDK2. These inhibitors all target the ATP-binding pocket of the catalytic site of the kinase. The actual selectivity of most known CDK inhibitors, and thus the underlying mechanism of their cellular effects, is poorly known. Pharmacological inhibitors of CDKs are currently being evaluated for therapeutic use against cancer, alopecia, neurodegenerative disorders (e.g. Alzheimer's disease, amyotrophic lateral sclerosis and stroke), cardiovascular disorders (e.g. atherosclerosis and restenosis), glomerulonephritis, viral infections (e.g. HCMV, HIV and HSV) and parasitic protozoa (Plasmodium sp. and Leishmania sp.).}, }
@article {pmid12235840, year = {2001}, author = {Baba, M}, title = {[New trends in neuropathy practice: clinical approach to CIDP].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {41}, number = {12}, pages = {1210-1213}, pmid = {12235840}, issn = {0009-918X}, mesh = {Chronic Disease ; Electrodiagnosis ; Humans ; Polyneuropathies/classification/*diagnosis/physiopathology ; Reference Standards ; }, abstract = {Our recent study showed that the overall prevalence of CIDP was estimated as 2.2 per 100,000 population in Aomori Prefecture, in Northan Honshu of Japan. In our series of more than 80 cases with CIDP, a chronic acquired inflammatory demyelinating polyneuropathy, nearly 30% showed clear laterality of weakness, and electrophysiologic laterality or multifocality was apparent in almost all cases. Nearly 90% of patients were able to walk without walking aids or other assistance. Sixty% showed distal dominant muscular weakness. In 12 patients with age of onset under 15, pes cavus deformity was seen in 5. Two thirds complained numbness in the extremities during progressive phase. Four cases initially showed severe sensory ataxia associated with motor conduction block. It should be, thus, reminded that clinical spectrum of CIDP is enormously wide: chronic acquired demyelinating multiple mononeuropathy showing asymmetric involvement (Lewis-Summer syndrome) should be put on one side of the clinical presentation of CIDP. Multifocal motor neuropathy (MMN) is, on the other hand, an unique syndrome mimicking amyotrophic lateral sclerosis (ALS). There may be, however, true association syndrome of CIDP and ALS presenting both peripheral nerve demyelination and pyramidal sign with progressive bulbar involvement. Recently, several atypical varieties of CIDP showing only one-limb involvement, upper limb weakness rather than lower limb power loss, or proximal weakness, etc ... have been reported in the literature. To realize such clinical variations of chronic acquired demyelinating neuropathy is important for early diagnosis and commencement of treatment of CIDP. Clinical guideline for suspicion of CIDP could be useful for general physicians and neurologists unfamiliar to peripheral neuropathies.}, }
@article {pmid12235798, year = {2001}, author = {Sobue, G}, title = {[Molecular pathogenesis of motor neuron disease].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {41}, number = {12}, pages = {1070-1071}, pmid = {12235798}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Cysteine Endopeptidases/genetics ; Gene Expression Profiling ; Humans ; Multienzyme Complexes/genetics ; Proteasome Endopeptidase Complex ; Ubiquitin/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively involves motor neurons. About ninety percent of ALS patients are non-hereditary sporadic cases, the molecular pathogenesis of which is unknown. One of the effective approach to analyze the molecular pathology is to analyze the gene expression profiles of the neurons being involved in ALS and compare them to those of the intact neurons. The genes whose expression levels are specifically altered in ALS tissues are likely to be the candidate molecules which are related to the molecular pathogenesis of motor neuron degeneration. We have been examining the spinal cord tissues from the ALS and control autopsied cases by the methods of molecular indexing and cDNA microarray analysis. We have screened more than 10,000 genes, and obtained several novel genes the expression levels of which are altered in ALS tissues. We are now still ongoing to analyze the function of these genes as well as a role in pathophysiology in ALS.}, }
@article {pmid12235797, year = {2001}, author = {Takahashi, R}, title = {[Cell death protection by anti-apoptotic factor].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {41}, number = {12}, pages = {1067-1069}, pmid = {12235797}, issn = {0009-918X}, mesh = {*Apoptosis/drug effects ; Caspase Inhibitors ; Caspases/physiology ; Enzyme Inhibitors ; Humans ; Inhibitor of Apoptosis Proteins ; *Insect Proteins ; Neurodegenerative Diseases/drug therapy/etiology ; *Proteins ; X-Linked Inhibitor of Apoptosis Protein ; }, abstract = {Neurodegenerative disorders including ALS and Parkinson's disease are characterized by progressive loss of neuronal cell death. Apoptosis, a morphologically and biochemically defined form of cell death caused by active cellular signaling, has been long implicated in neurodegeneration. Recently, the basic molecular mechanism of apoptosis has been elucidated and a subset of cysteine proteases called caspases were shown to be the executioner of apoptosis. On the other hand, endogenous caspase inhibitor called inhibitor of apoptosis proteins (IAPs) were also identified. XIAP, the most potent apoptosis inhibitor among human IAPs, is shown to be direct and selective inhibitor for caspase-3, -7 and -9. We have very recently shown that XIAP has ubiquitin ligase activity which promotes the degradation of caspase-3 and this protease activity enhances the anti-apoptotic activity of XIAP. Regarding the involvement of apoptosis in neurodegenerative diseases, several lines of evidence indicated that caspases are involved in the pathogenesis of ALS and polyglutamine disease, suggesting the effectiveness of anti-apoptotic therapy for these diseases. Moreover, caspase-independent programmed cell death is also suggested to be involved in neurodegenerative disorders. Based on these findings, the therapeutic strategy for neurodegenerative disease should include both anti-apoptotic and anti-non-apoptotic cell death treatments.}, }
@article {pmid12235568, year = {2002}, author = {Tornero, D and Ceña, V and González- García, C and Jordán, J}, title = {[The role of the mitochondrial permeability transition pore in neurodegenerative processes].}, journal = {Revista de neurologia}, volume = {35}, number = {4}, pages = {354-361}, pmid = {12235568}, issn = {0210-0010}, mesh = {Animals ; Apoptosis ; Cell Death ; Humans ; Ion Channels/*physiology ; Mitochondria/*physiology ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Neurodegenerative Diseases/*physiopathology ; Second Messenger Systems ; Signal Transduction ; }, abstract = {AIMS: To review the role played by the mitochondrial permeability transition pore (MPTP) in different physiological and pathological processes.<br><br>METHOD: Both genetic and functional alterations in mitochondria can lead to errors that trigger programmed cell death, which in turn give rise to a number of diseases that affect the nervous system. Over the last few years the mitochondrion has been seen as the link between the different signalling pathways involved in some degenerative processes. The mitochondrion seems to play an important part in the cellular decision making that leads, irreversibly, toward the execution phase in cellular death processes. This being the case, the action would be mediated by the permeability of its membranes, through the formation of the mitochondrial permeability transition pore, and would involve phenomena such as the dissipation of the mitochondrial electrochemical potential and the release of substances from within it. These substances include apoptosis inducing factor (AIF), apoptosis protease activating factor 1 (apaf 1), cytochrome c and members of the protease family: the caspases. These alterations have been described in neurodegenerative pathologies such as Alzheimer s and Parkinson s disease, amyotrophic lateral sclerosis and transmissible spongiform encephalopaties.<br><br>CONCLUSIONS: Designing pharmaceutical products capable of interfering with the functions of MPTP would allow a better therapeutic approach in neurological pathologies.}, }
@article {pmid12218958, year = {2002}, author = {Noor, R and Mittal, S and Iqbal, J}, title = {Superoxide dismutase--applications and relevance to human diseases.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {8}, number = {9}, pages = {RA210-5}, pmid = {12218958}, issn = {1234-1010}, mesh = {Alzheimer Disease/enzymology ; Amyotrophic Lateral Sclerosis/enzymology ; Free Radicals ; Humans ; Oxidative Stress ; Parkinson Disease/enzymology ; Reactive Oxygen Species ; Superoxide Dismutase/metabolism/*physiology ; }, abstract = {Reactive oxygen species, such as superoxide radicals, are thought to underlie the pathogenesis of various diseases. Almost 3 to 10% of the oxygen utilized by tissues is converted to its reactive intermediates, which impair the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen. There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents. Among these, Cu, Zn superoxide dismutase (SOD1) is widely distributed and comprises 90% of the total SOD. This ubiquitous enzyme, which requires Cu and Zn for its activity, has great physiological significance and therapeutic potential. The present review describes the role of SODs, especially Cu, Zn SOD, in several diseases, such as familial amyotrophic lateral sclerosis (FALS), Parkinson's disease, Alzheimer's disease, dengue fever, cancer, Down's syndrome, cataract, and several neurological disorders. Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis. The mechanism by which mutant SOD1 causes the degeneration of motor neurons is not well understood. Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in several lines of FALS-SOD1 mice. Various observations and conclusions linking mutant SOD1 and FALS are discussed in this review in detail.}, }
@article {pmid12217627, year = {2002}, author = {Koutsilieri, E and Scheller, C and Tribl, F and Riederer, P}, title = {Degeneration of neuronal cells due to oxidative stress--microglial contribution.}, journal = {Parkinsonism &amp; related disorders}, volume = {8}, number = {6}, pages = {401-406}, doi = {10.1016/s1353-8020(02)00021-4}, pmid = {12217627}, issn = {1353-8020}, mesh = {Animals ; Humans ; Microglia/*metabolism/physiology ; Nerve Degeneration/*metabolism ; Neurons/*metabolism/pathology ; Oxidative Stress/*physiology ; }, abstract = {Various neurodegenerative disorders including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis have been causally linked to the generation of free radicals and oxidative stress. In this review, we discuss the implication of oxidative stress in neuronal death and point out the role of intracellular signaling pathways leading to activation of transcription factors associated with cell death and repair. In particular, the impact of microglia as contributors in promoting oxidative stress in neurodegeneration is highlighted. Finally, pivotal molecular targets for drug therapies of brain disorders are reported.}, }
@article {pmid12212984, year = {2002}, author = {Shneerson, JM and Simonds, AK}, title = {Noninvasive ventilation for chest wall and neuromuscular disorders.}, journal = {The European respiratory journal}, volume = {20}, number = {2}, pages = {480-487}, doi = {10.1183/09031936.02.00404002}, pmid = {12212984}, issn = {0903-1936}, mesh = {Humans ; Neuromuscular Diseases/mortality/*physiopathology/*therapy ; Outcome Assessment, Health Care ; *Respiration, Artificial ; Survival Rate ; Thoracic Diseases/mortality/*physiopathology/*therapy ; Thoracic Wall/*physiopathology ; }, abstract = {Neuromuscular and chest wall disorders are individually uncommon but together form an important group of conditions that can lead to chronic ventilatory failure. This is best recognised in scoliosis, kyphosis, following a thoracoplasty, in muscular dystrophies, such as Duchenne muscular dystrophy (DMD), and myotonic dystrophy, after poliomyelitis and with motor neurone disease (amyotrophic lateral sclerosis). If bulbar function is impaired, tracheostomy ventilation may be required, but in other situations, noninvasive ventilation is preferable. Positive pressure techniques using nasal and face masks are usually the first choice, but negative pressure ventilation is an alternative. There are no randomised-controlled trials regarding the indications for initiating noninvasive ventilation, but this is usually provided if there are symptoms due to nocturnal hypoventilation or right heart failure in the presence of a raised carbon dioxide tension in arterial blood (Pa,CO2) either at night or, more usually, in the daytime as well. There is no evidence that "prophylactic" ventilatory support is of benefit if this is provided before ventilatory failure has appeared. Careful selection of patients is required, especially in the presence of progressive neuromuscular disorders such as DMD and motor neurone disease. There are no randomised-controlled trials concerning the outcome of noninvasive ventilation in these conditions, but studies have shown an improved quality of life, physical activity and haemodynamics, normalisation of blood gases and slight improvement in other physiological measures, such as the vital capacity and maximal mouth pressures. Survival in chest wall disorders is approximately 90% at 1 yr and 80% at 5 yrs, and similar figures have been obtained in nonprogressive neuromuscular conditions. If, however, the underlying disorder is deteriorating, particularly if it involves the bulbar muscles, it may limit survival despite the provision of adequate noninvasive ventilatory support.}, }
@article {pmid12210822, year = {2002}, author = {Kirkitadze, MD and Bitan, G and Teplow, DB}, title = {Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies.}, journal = {Journal of neuroscience research}, volume = {69}, number = {5}, pages = {567-577}, doi = {10.1002/jnr.10328}, pmid = {12210822}, issn = {0360-4012}, support = {AG14366/AG/NIA NIH HHS/United States ; NS38328/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/chemistry/*metabolism ; Animals ; Humans ; Mice ; Mice, Transgenic ; Models, Neurological ; Neurodegenerative Diseases/*metabolism ; Protein Folding ; Protein Processing, Post-Translational ; }, abstract = {Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid deposition in the cerebral neuropil and vasculature. These amyloid deposits comprise predominantly fragments and full-length (40 or 42 residue) forms of the amyloid beta-protein (Abeta) organized into fibrillar assemblies. Compelling evidence indicates that factors that increase overall Abeta production or the ratio of longer to shorter forms, or which facilitate deposition or inhibit elimination of amyloid deposits, cause AD or are risk factors for the disease. In vitro studies have demonstrated that fibrillar Abeta has potent neurotoxic effects on cultured neurons. In vivo experiments in non-human primates have demonstrated that Abeta fibrils directly cause pathologic changes, including tau hyperphosphorylation. In concert with histologic studies revealing a lack of tissue injury in areas of the neuropil in which non-fibrillar deposits were found, these data suggested that fibril assembly was a prerequisite for Abeta-mediated neurotoxicity in vivo. Recently, however, both in vitro and in vivo studies have revealed that soluble, oligomeric forms of Abeta also have potent neurotoxic activities, and in fact, may be the proximate effectors of the neuronal injury and death occurring in AD. A paradigm shift is thus emerging that necessitates the reevaluation of the relative importance of polymeric (fibrillar) vs. oligomeric assemblies in the pathobiology of AD. In addition to AD, an increasing number of neurodegenerative disorders, including Parkinson's disease, familial British dementia, familial amyloid polyneuropathy, amyotrophic lateral sclerosis, and prion diseases, are associated with abnormal protein assembly processes. The archetypal features of the assembly-dependent neuropathogenetic effects of Abeta may thus be of relevance not only to AD but to these other disorders as well.}, }
@article {pmid12194501, year = {2002}, author = {Maier, CM and Chan, PH}, title = {Role of superoxide dismutases in oxidative damage and neurodegenerative disorders.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {8}, number = {4}, pages = {323-334}, doi = {10.1177/107385840200800408}, pmid = {12194501}, issn = {1073-8584}, mesh = {Aging/metabolism ; Alzheimer Disease/enzymology ; Amyotrophic Lateral Sclerosis/enzymology ; Animals ; Animals, Genetically Modified ; Brain Injuries/enzymology ; Humans ; Huntington Disease/enzymology ; Inflammation/enzymology ; Isoenzymes ; Mice ; Mice, Knockout ; Neurodegenerative Diseases/*enzymology ; Oxidative Stress ; Reperfusion Injury/enzymology ; Stroke/enzymology ; Superoxide Dismutase/*metabolism ; }, abstract = {In recent years, oxidative stress has been implicated in a variety of degenerative processes, diseases, and syndromes. Some of these include atherosclerosis, myocardial infarction, stroke, and ischemia/reperfusion injury; chronic and acute inflammatory conditions such as wound healing; central nervous system disorders such as forms of familial amyotrophic lateral sclerosis (ALS) and glutathione peroxidase-linked adolescent seizures; Parkinson's disease and Alzheimer's dementia; and a variety of other age-related disorders. Among the various biochemical events associated with these conditions, emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger, superoxide dismutase (SOD), as a common denominator. This review summarizes the function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities. Experimental evidence from laboratory animals that either overexpress (transgenics) or are deficient (knockouts) in antioxidant enzyme/protein levels and the genetic SOD mutations observed in some familial cases of ALS are also discussed.}, }
@article {pmid12174431, year = {2002}, author = {Portegies, P and Cohen, ES}, title = {[Possible etiological role retroviruses and enteroviruses in the development of amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {146}, number = {30}, pages = {1398-1400}, pmid = {12174431}, issn = {0028-2162}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/virology ; Antiretroviral Therapy, Highly Active ; Antiviral Agents/therapeutic use ; Disease Progression ; Enterovirus Infections/*complications/drug therapy ; HIV Infections/complications/drug therapy ; Humans ; Retroviridae Infections/*complications/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with unknown pathogenesis. Loss of motor neurons leads to progressive weakness and, finally, respiratory failure with a mean survival of 3 years. A possible causal role of a retroviral infection has recently been suggested by studies of 7 HIV-infected patients who developed a rapid progressive ALS-like disorder as the first manifestation of their HIV-infection. All patients stabilised or improved with antiretroviral therapy. Other research groups have published on the detection of enterovirus RNA in the spinal cords of ALS-patients, also suggesting a viral aetiology of the disease. The results of these neuro-virological studies warrant further research into the possible role of viral infections as a cause of ALS, as well as clinical trials with anti-retroviral and anti-enteroviral drugs in ALS.}, }
@article {pmid12170396, year = {2002}, author = {Pascuzzi, RM}, title = {ALS, motor neuron disease, and related disorders: a personal approach to diagnosis and management.}, journal = {Seminars in neurology}, volume = {22}, number = {1}, pages = {75-87}, doi = {10.1055/s-2002-33295}, pmid = {12170396}, issn = {0271-8235}, mesh = {Adolescent ; Adult ; Animals ; *Case Management ; Combined Modality Therapy ; Creatine/therapeutic use ; Diagnosis, Differential ; Diagnostic Tests, Routine ; Disease Models, Animal ; Enteral Nutrition ; Female ; Humans ; Male ; Mice ; Middle Aged ; Motor Neuron Disease/classification/*diagnosis/etiology/therapy ; Muscular Atrophy, Spinal/diagnosis ; Neurologic Examination ; Physical Therapy Modalities ; Quality of Life ; Respiration, Artificial ; Riluzole/therapeutic use ; Tracheostomy ; }, abstract = {Motor neuron disease, from diagnostic criteria, laboratory evaluation, communication with patients and their families, and the approach to long-term management represents a daunting challenge for many neurologists. Contained herein is a selective and biased discussion of several common dilemmas and questions that reflect recurring themes in the evaluation and management of patients with suspected motor neuron disease. The answers to these questions represent the author's opinions and are colored by personal experience, pearls graciously given to me by other experts in the field, and selected studies from the neuromuscular literature.}, }
@article {pmid12169227, year = {2002}, author = {Jankowsky, JL and Savonenko, A and Schilling, G and Wang, J and Xu, G and Borchelt, DR}, title = {Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development.}, journal = {Current neurology and neuroscience reports}, volume = {2}, number = {5}, pages = {457-464}, pmid = {12169227}, issn = {1528-4042}, mesh = {Alzheimer Disease/genetics/metabolism/therapy ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; *Disease Models, Animal ; Huntington Disease/genetics/therapy ; Mice ; Mice, Transgenic ; Motor Neuron Disease/genetics/pathology/therapy ; Mutation ; Nervous System/metabolism/*pathology ; Neurodegenerative Diseases/genetics/metabolism/*therapy ; Prion Diseases/genetics/metabolism/therapy ; Spinocerebellar Degenerations/genetics/metabolism/therapy ; Trinucleotide Repeats/genetics ; }, abstract = {Neurodegenerative diseases present an extraordinary challenge for medicine due to the grave nature of these illnesses, their prevalence, and their impact on individuals and caregivers. The most common of these age-associated chronic illnesses are Alzheimer's disease (AD) and Parkinson's disease (PD); other examples include the prion disorders, amyotrophic lateral sclerosis (ALS), and the trinucleotide (CAG) repeat diseases. All of these diseases are characterized by well-defined clinical syndromes with progressive courses that reflect the dysfunction and eventual loss of specific neuronal populations. Current therapies provide only symptomatic relief; none significantly alter the course of disease. We describe here how transgenic mice designed to model these diseases have substantially contributed to the identification and validation of many promising new therapies, and conversely how they have quickly and cost effectively eliminated several targets with unrealized expectations.}, }
@article {pmid12168685, year = {2002}, author = {Butterfield, DA and Castegna, A and Drake, J and Scapagnini, G and Calabrese, V}, title = {Vitamin E and neurodegenerative disorders associated with oxidative stress.}, journal = {Nutritional neuroscience}, volume = {5}, number = {4}, pages = {229-239}, doi = {10.1080/10284150290028954}, pmid = {12168685}, issn = {1028-415X}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Biological Availability ; Dyskinesias ; Humans ; Huntington Disease ; Intestinal Absorption ; Lipid Peroxidation ; Multiple Sclerosis ; *Neurodegenerative Diseases ; *Oxidative Stress ; Parkinson Disease ; *Vitamin E/administration &amp; dosage/chemistry/pharmacokinetics/physiology ; }, abstract = {Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.}, }
@article {pmid12151838, year = {2002}, author = {Rosso, SM and van Swieten, JC}, title = {New developments in frontotemporal dementia and parkinsonism linked to chromosome 17.}, journal = {Current opinion in neurology}, volume = {15}, number = {4}, pages = {423-428}, doi = {10.1097/00019052-200208000-00004}, pmid = {12151838}, issn = {1350-7540}, mesh = {*Chromosomes, Human, Pair 17 ; Dementia/*genetics ; Humans ; Parkinson Disease/*genetics ; Phenotype ; }, abstract = {PURPOSE OF REVIEW: The identification of tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has revealed invaluable information regarding the role of the tau protein in neurodegenerative disease. Over the past year several new mutations have been identified, and experimental studies have provided further insight into the mechanism of neurodegeneration due to tau mutations and possible interactions with amyloid pathology.<br><br>RECENT FINDINGS: Extensive clinical and pathological variation is seen in patients with different types of mutation, as well as in patients with the same mutation. Mutations may be found in patients with frontotemporal dementia (FTD), parkinsonism, progressive supranuclear palsy and corticobasal degeneration, justifying mutation analysis in familial cases of these disorders. Genetic heterogeneity exists in frontotemporal dementia, because a number of FTDP-17 families have neither tau mutations nor tau pathology. Genetic linkage has been found in familial FTD (chromosome 3), FTD with amyotrophic lateral sclerosis (9q21-q22), and FTD with inclusion body myopathy (9q13.3-p12). Tau deposits may consist of mainly mutated protein, or of mutated and wild-type protein in equal amounts, depending on the mutation. Recent animal studies show that amyloid-beta deposition may accelerate formation of neurofibrillary tangles.<br><br>SUMMARY: Hopefully, the identification of responsible genetic defects and associated proteins will be helpful in improving our understanding of the role of the tau protein in the common neurodegenerative process of frontotemporal degeneration.}, }
@article {pmid12146806, year = {2002}, author = {Graeber, MB and Moran, LB}, title = {Mechanisms of cell death in neurodegenerative diseases: fashion, fiction, and facts.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {12}, number = {3}, pages = {385-390}, pmid = {12146806}, issn = {1015-6305}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/pathology ; *Apoptosis ; Brain Ischemia/pathology ; Cell Death ; Creutzfeldt-Jakob Syndrome/pathology ; Humans ; Huntington Disease/pathology ; In Situ Nick-End Labeling/methods ; Neurodegenerative Diseases/*pathology ; Parkinson Disease/pathology ; Terminology as Topic ; }, abstract = {Apoptosis has become a most popular concept of cell death. However, the term is now so widely used and employed in such general terms in relation to neurological diseases that its application is very problematic. In addition, with the exception of developmental conditions, there is essentially no evidence of apoptosis fulfilling the criteria of its classical definition in any of the important human neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease. Importantly, a number of new cell death forms have been described in the literature and there is good reason to pay attention to these emerging concepts as they may provide a rationale for the development of disease-specific therapies.}, }
@article {pmid12138710, year = {2002}, author = {Hadano, S}, title = {[Causative genes for familial amyotrophic lateral sclerosis].}, journal = {Seikagaku. The Journal of Japanese Biochemical Society}, volume = {74}, number = {6}, pages = {483-489}, pmid = {12138710}, issn = {0037-1017}, mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; *Guanine Nucleotide Exchange Factors/genetics/physiology ; Humans ; Molecular Sequence Data ; Mutation ; Protein Structure, Tertiary ; *Superoxide Dismutase/genetics/physiology ; Superoxide Dismutase-1 ; }, }
@article {pmid12137643, year = {2002}, author = {Mitchell, JD and Wokke, JH and Borasio, GD}, title = {Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD002064}, doi = {10.1002/14651858.CD002064}, pmid = {12137643}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Randomized Controlled Trials as Topic ; Recombinant Proteins/therapeutic use ; }, abstract = {BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I have been postulated as possible disease modifying therapies for amyotrophic lateral sclerosis. Randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis to date have yielded conflicting results.<br><br>OBJECTIVES: The main objective of this review was to examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Occurrence of adverse events has also been reviewed.<br><br>SEARCH STRATEGY: A search was carried out using the Cochrane Neuromuscular Disease Group register for randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Enquiries were also made of authors of randomised clinical trials as well as the manufacturers of recombinant human insulin-like growth factor I regarding any other randomised clinical trials which had not yet been published.<br><br>SELECTION CRITERIA: Types of studies: all randomised controlled clinical trials involving recombinant human insulin-like growth factor I treatment of amyotrophic lateral sclerosis.<br><br>TYPES OF PARTICIPANTS: Adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. Types of interventions: Treatment with recombinant human insulin-like growth factor I or placebo. Types of outcome measures: Primary: Change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score with 0.1mg/kg/day of recombinant human insulin-like growth factor I after nine months treatment. Secondary: Change in AALSRS with recombinant human insulin like growth factor I 0.1mg/kg/day and 0.05mg/kg/day at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomised clinical trials. Each reviewer graded them for methodological quality. Data were extracted and entered by the lead reviewer and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs.<br><br>MAIN RESULTS: The primary outcome measure was change in disease progression as determined by the Appel ALS Rating Scale total score with 0.1 mg/kg/day of recombinant human insulin-like growth factor I subcutaneously after nine months treatment. The level of significance was lower in the European trial which compared 59 patients on placebo with 124 on insulin-like growth factor I 0.1 mg/kg/day (weighted mean difference -3.30, 95%CI -8.68 to 2.08) than in the North American trial which compared 90 patients on placebo with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day 89 patients and 87 patients on 0.1mg/kg/day (weighted mean difference -6.00, 95%CI -10.99 to -1.01). The combined analysis from both randomised clinical trials showed a weighted mean difference of -4.75 (95% CI -8.41 to -1.09) favouring the treated group. The secondary outcome measures showed similar trends favouring recombinant human insulin-like growth factor I but these did not reach significance at the five per cent level. Similarly the data with the 0.05mg/kg/day dose showed trends favouring recombinant human insulin-like growth factor I at all time points but did not reach significance at the five per cent level at any point. Evaluation of adverse events showed an increased risk of injection site reactions/inflammation with recombinant human insulin-like growth factor I (relative risk 2.53, 95% CI 1.40 to 4.59). The drug was otherwise safe and well tolerated.<br><br>REVIEWER'S CONCLUSIONS: Recombinant human insulin-like growth factor I may be modestly effective but the evidence currently available is insufficient for a definitive assessment. Further randomised clinical trials need to be done.}, }
@article {pmid12137229, year = {2002}, author = {Schapira, AH}, title = {Primary and secondary defects of the mitochondrial respiratory chain.}, journal = {Journal of inherited metabolic disease}, volume = {25}, number = {3}, pages = {207-214}, pmid = {12137229}, issn = {0141-8955}, mesh = {Animals ; DNA, Mitochondrial/biosynthesis/*genetics ; *Electron Transport ; Humans ; Mitochondria/*metabolism ; Mutation ; Neurodegenerative Diseases/genetics ; RNA, Transfer/genetics ; }, abstract = {Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.}, }
@article {pmid12134639, year = {2002}, author = {Christen, Y}, title = {[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases].}, journal = {Journal de la Societe de biologie}, volume = {196}, number = {1}, pages = {85-94}, pmid = {12134639}, issn = {1295-0661}, mesh = {Aging ; Alzheimer Disease/genetics ; Amyloid beta-Peptides/genetics ; Dementia/genetics ; Humans ; *Mutation ; Neurodegenerative Diseases/*genetics ; Proteins/*genetics ; }, abstract = {Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.}, }
@article {pmid12133810, year = {2002}, author = {Clark, JE and Brennan, A and Ramesh, TM and Heywood, JA}, title = {Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {7}, number = {}, pages = {c83-96}, doi = {10.2741/A762}, pmid = {12133810}, issn = {1093-9946}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Chemistry, Pharmaceutical/economics/*trends ; Cooperative Behavior ; *Drug Design ; Drug Industry/economics/trends ; Foundations/trends ; Humans ; *Orphan Drug Production/economics ; Research Support as Topic/economics/trends ; }, abstract = {As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.}, }
@article {pmid12127321, year = {2002}, author = {Shimizu, A and Nakanishi, T and Kishikawa, M and Miyazaki, A}, title = {Detection and identification of protein variants and adducts in blood and tissues: an application of soft ionization mass spectrometry to clinical diagnosis.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {776}, number = {1}, pages = {15-30}, doi = {10.1016/s1570-0232(02)00031-4}, pmid = {12127321}, issn = {1570-0232}, mesh = {Amino Acid Sequence ; Blood ; Chromatography, Liquid/methods ; Diagnosis ; Hemoglobins/*analysis ; Humans ; Mass Spectrometry/*methods ; Prealbumin/*analysis ; Superoxide Dismutase/*analysis/blood ; }, abstract = {The detection and identification of protein variants and abnormally increased modified proteins are important for clinical diagnosis. We applied soft ionization mass spectrometry (MS) to analyze proteins in blood and tissues from various patients. Over the past 8 years, we diagnosed 132 cases (55 kinds) of variant proteins including hemoglobin (Hb), transthyretin (TTR), and Cu/Zn-superoxide dismutase (SOD-1), using MS as the leading technology. Of these variants, eight were new, and nine were the first cases in Japan. Some abnormal Hb cause diseases, and most of them cause erroneous levels of glycated Hb, HbA1c, i.e., a popular index of diabetes. Most of the variant TTR causes amyloidotic polyneuropathy. Variant SOD-1 causes amyotrophic lateral sclerosis. We first showed that immunoprecipitation by a specific antiserum is a reliable and simple method to prepare protein from sera and tissues for analysis by matrix-assisted laser desorption time-of-flight MS, and liquid chromatography-electrospray ionization MS (LC-ESI-MS). The use of this technology has become widespread. Using an immunoprecipitated target protein and LC-ESI-MS, we showed that the ratios of tetra-, di- and a-sialo-transferrin from two cases of congenital glycoprotein deficient syndrome were clearly distinguishable from those of control samples. We first reported a unique modified form of TTR, that is, S-sulfonated TTR, which increased markedly and specifically in three cases with molibdenum cofactor deficiency. We proposed that S-sulfonated TTR is a useful marker for screening this disease. ESI-MS was successfully used for the accurate determination of HbA1c, and we clarified the extent of discrepancies between the HbA1c value measured by conventional methods and the accurate values for samples containing various Hb variants determined by the MS method.}, }
@article {pmid12126755, year = {2002}, author = {Zelko, IN and Mariani, TJ and Folz, RJ}, title = {Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.}, journal = {Free radical biology &amp; medicine}, volume = {33}, number = {3}, pages = {337-349}, doi = {10.1016/s0891-5849(02)00905-x}, pmid = {12126755}, issn = {0891-5849}, support = {HL31992/HL/NHLBI NIH HHS/United States ; HL55166/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Evolution, Molecular ; Gene Expression Regulation, Enzymologic/*physiology ; Humans ; Multigene Family/*genetics ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Superoxide dismutases are an ubiquitous family of enzymes that function to efficiently catalyze the dismutation of superoxide anions. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC 1.15.1.1), was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or Mn-SOD (EC 1.15.1.1), exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC 1.15.1.1), is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces. What role(s) these SODs play in both normal and disease states is only slowly beginning to be understood. A molecular understanding of each of these genes has proven useful toward the deciphering of their biological roles. For example, a variety of single amino acid mutations in SOD1 have been linked to familial amyotrophic lateral sclerosis. Knocking out the SOD2 gene in mice results in a lethal cardiomyopathy. A single amino acid mutation in human SOD3 is associated with 10 to 30-fold increases in serum SOD3 levels. As more information is obtained, further insights will be gained.}, }
@article {pmid12117078, year = {2002}, author = {Te, AE}, title = {A modern rationale for the use of phenoxybenzamine in urinary tract disorders and other conditions.}, journal = {Clinical therapeutics}, volume = {24}, number = {6}, pages = {851-61; discussion 837}, doi = {10.1016/s0149-2918(02)80003-0}, pmid = {12117078}, issn = {0149-2918}, mesh = {Adrenergic alpha-Antagonists/adverse effects/pharmacokinetics/*therapeutic use ; Animals ; Clinical Trials as Topic ; Half-Life ; Humans ; Male ; Phenoxybenzamine/adverse effects/pharmacokinetics/*therapeutic use ; Prostatic Hyperplasia/*drug therapy ; Rats ; Tissue Distribution ; Urinary Tract Infections/*drug therapy ; }, abstract = {BACKGROUND: Phenoxybenzamine (PBZ) is a nonselective, irreversible alpha-adrenergic receptor antagonist that is approved for the treatment of diaphoresis and hypertension associated with pheochromocytoma. It may also be useful in several chronic conditions whose pathogenesis is mediated or affected by alpha-adrenergic stimulation, such as lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH) and neurogenic bladder (eg, secondary to myelomeningocele and in sphincter dyssynergia and autonomic dysreflexia); in an adjunctive role after urogenital surgery or brachytherapy by relieving symptoms associated with increased alpha-adrenergic tone; and in the treatment of complex regional pain syndrome (CRPS) and prostatitis. However, carcinogenic concerns may have limited its potential application.<br><br>OBJECTIVE: The purpose of this article is to reassess the usefulness and contemporary application of PBZ for the control of urinary tract symptoms associated with BPH and neurogenic bladder, after urogenital surgery and brachytherapy, and in certain other conditions (eg, CRPS, prostatitis).<br><br>METHODS: A search of literature published from 1966 to 2002 was performed on MEDLINE using the search terms phenoxybenzamine, alpha-adrenergic blockers, benign prostatic hyperplasia, neurogenic bladder, urinary retention, and complex regional pain<br><br>RESULTS: Despite concerns about possible carcinogenicity, no reports of drug-related tumors have been made since PBZ's introduction in 1953. Investigators have used PBZ in off-label trials to alleviate symptoms of a variety of conditions that cause urinary retention. In adult male patients with retention due to inguinal hernioplasty and female patients with retention caused by vaginal repair, as well as in pediatric patients with myelomeningocele, treatment with PBZ improved bladder function and, in the patients with myelomeningocele, was associated with reduced incidence of urinary tract infection. Larger tri- als of PBZ in men with BPH produced significant urinary symptom relief (P < 0.05 in 2 studies). Moreover, studies suggest that PBZ may be useful in alleviating pain due to trauma and CRPS. The most common adverse events appear to be dizziness, impotence and ejaculatory dysfunction, and nasal stuffiness.<br><br>CONCLUSIONS: No drug-related tumors in humans have been reported after -50 years of clinical experience with PBZ. Clinical trials have demonstrated that it can relieve symptoms in patients with BPH and other urologic and pain-related conditions.}, }
@article {pmid12093078, year = {2002}, author = {Trojanowski, JQ and Ishihara, T and Higuchi, M and Yoshiyama, Y and Hong, M and Zhang, B and Forman, MS and Zhukareva, V and Lee, VM}, title = {Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam.}, journal = {Experimental neurology}, volume = {176}, number = {1}, pages = {1-11}, doi = {10.1006/exnr.2002.7940}, pmid = {12093078}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/genetics/*pathology ; Animals ; Comorbidity ; Dementia/epidemiology/genetics/*pathology ; *Disease Models, Animal ; Disease Progression ; Guam/epidemiology/ethnology ; Humans ; Mice ; Mice, Transgenic ; Parkinsonian Disorders/epidemiology/genetics/*pathology ; Tauopathies/epidemiology/genetics/*pathology ; }, abstract = {Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.}, }
@article {pmid12085093, year = {2002}, author = {Wong, PC and Cai, H and Borchelt, DR and Price, DL}, title = {Genetically engineered mouse models of neurodegenerative diseases.}, journal = {Nature neuroscience}, volume = {5}, number = {7}, pages = {633-639}, doi = {10.1038/nn0702-633}, pmid = {12085093}, issn = {1097-6256}, support = {AG05146/AG/NIA NIH HHS/United States ; AG07914/AG/NIA NIH HHS/United States ; AG10480/AG/NIA NIH HHS/United States ; AG10491/AG/NIA NIH HHS/United States ; AG14248/AG/NIA NIH HHS/United States ; NS07435/NS/NINDS NIH HHS/United States ; NS10580/NS/NINDS NIH HHS/United States ; NS20471/NS/NINDS NIH HHS/United States ; NS37145/NS/NINDS NIH HHS/United States ; NS37771/NS/NINDS NIH HHS/United States ; NS38065/NS/NINDS NIH HHS/United States ; NS38377/NS/NINDS NIH HHS/United States ; NS40014/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics ; Animals ; Cell Survival ; *Disease Models, Animal ; Mice ; Motor Neuron Disease/genetics ; Motor Neurons/pathology ; Neurodegenerative Diseases/*genetics ; Superoxide Dismutase/*genetics ; }, abstract = {Recent research has significantly advanced our understanding of the molecular mechanisms of neurodegenerative diseases, including Alzheimer's disease (AD) and motor neuron disease. Here we emphasize the use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets. In motor neuron diseases, Cu/Zn superoxide dismutase and survival motor neuron mouse models are useful in testing disease mechanisms and therapeutic strategies for amyotrophic lateral sclerosis (ALS) and spinal motor atrophy, respectively, but the mechanisms that account for selective motor neuron loss remain uncertain. We anticipate that, in the future, therapies based on understanding disease mechanisms will be identified and tested in mouse model systems.}, }
@article {pmid12076984, year = {2002}, author = {Liu, B and Gao, HM and Wang, JY and Jeohn, GH and Cooper, CL and Hong, JS}, title = {Role of nitric oxide in inflammation-mediated neurodegeneration.}, journal = {Annals of the New York Academy of Sciences}, volume = {962}, number = {}, pages = {318-331}, doi = {10.1111/j.1749-6632.2002.tb04077.x}, pmid = {12076984}, issn = {0077-8923}, mesh = {Animals ; Cells, Cultured ; Cytokines/metabolism ; Humans ; Inflammation/*physiopathology ; Lipopolysaccharides/metabolism ; Narcotics/metabolism ; *Nerve Degeneration ; Neurodegenerative Diseases/*metabolism ; Neuroglia/metabolism ; Neurons/*metabolism ; Nitric Oxide/*metabolism ; }, abstract = {Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.}, }
@article {pmid12076411, year = {2002}, author = {Miller, RG and Mitchell, JD and Lyon, M and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD001447}, doi = {10.1002/14651858.CD001447}, pmid = {12076411}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was May, 2001 SELECTION CRITERIA: Types of studies: randomized trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio.<br><br>MAIN RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38).<br><br>REVIEWER'S CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with amyotrophic lateral sclerosis. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease.}, }
@article {pmid12069110, year = {2002}, author = {Beal, MF}, title = {Coenzyme Q10 as a possible treatment for neurodegenerative diseases.}, journal = {Free radical research}, volume = {36}, number = {4}, pages = {455-460}, doi = {10.1080/10715760290021315}, pmid = {12069110}, issn = {1071-5762}, support = {AG12992/AG/NIA NIH HHS/United States ; AG14390/AG/NIA NIH HHS/United States ; NS38180/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*therapeutic use ; Coenzymes ; Cytoprotection ; Dietary Supplements ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*drug therapy ; Ubiquinone/*analogs &amp; derivatives/*therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.}, }
@article {pmid12061943, year = {2002}, author = {Lechtzin, N and Rothstein, J and Clawson, L and Diette, GB and Wiener, CM}, title = {Amyotrophic lateral sclerosis: evaluation and treatment of respiratory impairment.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {1}, pages = {5-13}, doi = {10.1080/146608202317576480}, pmid = {12061943}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology/therapy ; Humans ; Positive-Pressure Respiration ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/*diagnosis/etiology/*therapy ; *Respiratory Mechanics ; Respiratory Muscles/physiopathology ; Respiratory Therapy ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) invariably develop respiratory muscle weakness and most die from pulmonary complications. There are numerous tests available to evaluate respiratory status in ALS and it is important to understand their various advantages and limitations. Forced vital capacity (FVC) is commonly used but can remain normal despite substantial inspiratory muscle weakness. Maximal pressures measured at the mouth are useful for excluding weakness if they are normal but are difficult to interpret if abnormal. Invasive testing, such as measurement of transdiaphragmatic pressure, provides an accurate measure of inspiratory strength but is not readily available and is not practical for serial measures. There are supportive respiratory techniques that have been shown to benefit patients with ALS. Clinicians should be familiar with these interventions, including mechanically assisted coughing, non-invasive ventilation and tracheostomy with mechanical ventilation. Observational studies have demonstrated improved survival and quality of life with noninvasive ventilation. Tracheostomy with long-term mechanical ventilation is not frequently used but can be an important component of care for ALS. This review describes an approach to respiratory evaluation and care of patients with ALS.}, }
@article {pmid12052096, year = {2002}, author = {Ginsberg, G and Lowe, S}, title = {Cost effectiveness of treatments for amyotrophic lateral sclerosis: a review of the literature.}, journal = {PharmacoEconomics}, volume = {20}, number = {6}, pages = {367-387}, pmid = {12052096}, issn = {1170-7690}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*economics/*therapy ; Cost-Benefit Analysis ; Drug Costs ; Excitatory Amino Acid Antagonists/*economics/therapeutic use ; Forecasting ; Humans ; Insulin-Like Growth Factor I/*economics/therapeutic use ; Quality-Adjusted Life Years ; Respiration, Artificial/*economics/methods ; Riluzole/*economics/therapeutic use ; Risk Factors ; Survival Rate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a difficult to diagnose, fatal, progressive degenerative disease with an average survival time of 2 to 5 years. Percutaneous endoscopic gastrotomy (PEG) and bi-level intermittent positive pressure (BIPAP) ventilation may be the major interventions leading to longer survival of patients with ALS. Riluzole has been shown to have modest effects on survival (as opposed to functional) gains and is currently the only drug approved for the treatment of ALS. There is conflicting evidence with regard to the ability of recombinant human insulin-like growth factor (rhIGF-I) to retard ALS progression. Mechanical ventilation (via a tracheostomy tube) is expensive, but is widely used in later stage patients with ALS in the US. A review of nine cost-effectiveness studies of riluzole and one of rhIGF-I found the following: drug costs and survival gains are the major drivers of cost effectiveness; survival gains are estimated from truncated databases with a high degree of uncertainty; more accurate stage-specific utility weights based on patients who agreed to treatment are needed; case incidence-based evaluations should be carried out; cost-effectiveness ratios are insensitive to discount rates; employment and caregiver issues or externalities have been widely ignored; threshold acceptance cost-effectiveness values are ill-defined and evaluations are not generalisable to other countries because of cost and treatment style differences. On account of the high degree of uncertainty pertaining to survival gains and the relatively high costs per life years or quality-adjusted life-years gained, and while acknowledging that not every therapy has to be cost effective (e.g. orphan drugs), it is still inconclusive as to whether or not riluzole or rhIGF-1 can be considered as cost-effective therapies for ALS.}, }
@article {pmid12048038, year = {2002}, author = {Wolpaw, JR and Birbaumer, N and McFarland, DJ and Pfurtscheller, G and Vaughan, TM}, title = {Brain-computer interfaces for communication and control.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {113}, number = {6}, pages = {767-791}, doi = {10.1016/s1388-2457(02)00057-3}, pmid = {12048038}, issn = {1388-2457}, mesh = {Brain Diseases/*rehabilitation ; *Communication Aids for Disabled ; *Computer Systems ; Electroencephalography/*instrumentation ; Humans ; User-Computer Interface ; }, abstract = {For many years people have speculated that electroencephalographic activity or other electrophysiological measures of brain function might provide a new non-muscular channel for sending messages and commands to the external world - a brain-computer interface (BCI). Over the past 15 years, productive BCI research programs have arisen. Encouraged by new understanding of brain function, by the advent of powerful low-cost computer equipment, and by growing recognition of the needs and potentials of people with disabilities, these programs concentrate on developing new augmentative communication and control technology for those with severe neuromuscular disorders, such as amyotrophic lateral sclerosis, brainstem stroke, and spinal cord injury. The immediate goal is to provide these users, who may be completely paralyzed, or 'locked in', with basic communication capabilities so that they can express their wishes to caregivers or even operate word processing programs or neuroprostheses. Present-day BCIs determine the intent of the user from a variety of different electrophysiological signals. These signals include slow cortical potentials, P300 potentials, and mu or beta rhythms recorded from the scalp, and cortical neuronal activity recorded by implanted electrodes. They are translated in real-time into commands that operate a computer display or other device. Successful operation requires that the user encode commands in these signals and that the BCI derive the commands from the signals. Thus, the user and the BCI system need to adapt to each other both initially and continually so as to ensure stable performance. Current BCIs have maximum information transfer rates up to 10-25bits/min. This limited capacity can be valuable for people whose severe disabilities prevent them from using conventional augmentative communication methods. At the same time, many possible applications of BCI technology, such as neuroprosthesis control, may require higher information transfer rates. Future progress will depend on: recognition that BCI research and development is an interdisciplinary problem, involving neurobiology, psychology, engineering, mathematics, and computer science; identification of those signals, whether evoked potentials, spontaneous rhythms, or neuronal firing rates, that users are best able to control independent of activity in conventional motor output pathways; development of training methods for helping users to gain and maintain that control; delineation of the best algorithms for translating these signals into device commands; attention to the identification and elimination of artifacts such as electromyographic and electro-oculographic activity; adoption of precise and objective procedures for evaluating BCI performance; recognition of the need for long-term as well as short-term assessment of BCI performance; identification of appropriate BCI applications and appropriate matching of applications and users; and attention to factors that affect user acceptance of augmentative technology, including ease of use, cosmesis, and provision of those communication and control capacities that are most important to the user. Development of BCI technology will also benefit from greater emphasis on peer-reviewed research publications and avoidance of the hyperbolic and often misleading media attention that tends to generate unrealistic expectations in the public and skepticism in other researchers. With adequate recognition and effective engagement of all these issues, BCI systems could eventually provide an important new communication and control option for those with motor disabilities and might also give those without disabilities a supplementary control channel or a control channel useful in special circumstances.}, }
@article {pmid12044443, year = {2002}, author = {Wyss, M and Schulze, A}, title = {Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?.}, journal = {Neuroscience}, volume = {112}, number = {2}, pages = {243-260}, doi = {10.1016/s0306-4522(02)00088-x}, pmid = {12044443}, issn = {0306-4522}, mesh = {Administration, Oral ; Animals ; Arteriosclerosis/*prevention &amp; control ; Creatine/*administration &amp; dosage/*metabolism ; Dietary Supplements ; Female ; Humans ; Male ; Metabolism, Inborn Errors/drug therapy/metabolism ; Nervous System Diseases/*prevention &amp; control ; }, abstract = {Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.}, }
@article {pmid12043837, year = {2001}, author = {Schwartz, M}, title = {Harnessing the immune system for neuroprotection: therapeutic vaccines for acute and chronic neurodegenerative disorders.}, journal = {Cellular and molecular neurobiology}, volume = {21}, number = {6}, pages = {617-627}, pmid = {12043837}, issn = {0272-4340}, mesh = {Acute Disease ; Animals ; Autoantigens/*immunology ; Chronic Disease ; Humans ; Immune System/*drug effects/immunology ; Immunotherapy, Active/methods/*trends ; Inflammation/drug therapy/immunology ; Neurodegenerative Diseases/*drug therapy/immunology/physiopathology ; Neuroprotective Agents/*immunology ; T-Lymphocytes/*drug effects/immunology ; }, abstract = {Nerve injury causes degeneration of directly injured neurons and the damage spreads to neighboring neurons. Research on containing the damage has been mainly pharmacological, and has not recruited the immune system. We recently discovered that after traumatic injury to the central nervous system (spinal cord or optic nerve), the immune system apparently recognizes certain injury-associated self-compounds as potentially destructive and comes to the rescue with a protective antiself response mediated by a T-cell subpopulation that can recognize self-antigens. We further showed that individuals differ in their ability to manifest this protective autoimmunity, which is correlated with their ability to resist the development of autoimmune diseases. This finding led us to suggest that the antiself response must be tightly regulated to be expressed in a beneficial rather than a destructive way. In seeking to develop a neuroprotective therapy by boosting the beneficial autoimmune response to injury-associated self-antigens, we looked for an antigen that would not induce an autoimmune disease. Candidate vaccines were the safe synthetic copolymer Cop-1, known to cross-react with self-antigens, or altered myelin-derived peptides. Using these compounds as vaccines, we could safely boost the protective autoimmune response in animal models of acute and chronic insults of mechanical or biochemical origin. Since this vaccination is effective even when given after the insult, and because it protects against the toxicity of glutamate (the most common mediator of secondary degeneration), it can be used to treat chronic neurodegenerative disorders such as glaucoma, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid12042066, year = {2002}, author = {Llanos, RM and Mercer, JF}, title = {The molecular basis of copper homeostasis copper-related disorders.}, journal = {DNA and cell biology}, volume = {21}, number = {4}, pages = {259-270}, doi = {10.1089/104454902753759681}, pmid = {12042066}, issn = {1044-5498}, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Biological Transport ; Copper/*metabolism ; *Hepatolenticular Degeneration/genetics/metabolism ; Homeostasis ; Humans ; *Menkes Kinky Hair Syndrome/genetics/metabolism ; Oxidative Stress ; Prion Diseases/genetics/metabolism ; }, abstract = {Copper is an essential trace element that can be extremely toxic in excess due to the pro-oxidant activity of copper ions. Inherited disorders of copper transport, Menkes disease (copper deficiency), and Wilson disease (copper toxicosis) are caused by mutations of two closely related Cu transporting-ATPases, and demonstrate the essentiality and potential toxicity of copper. Other copper toxicosis conditions in humans and animals have been described, but are not well understood at a molecular level. Copper homeostatic mechanisms are being discovered. One such mechanism is copper-induced trafficking of the Cu-ATPases, which allows cells to provide copper to secreted cupro-proteins but also to efflux excess copper. Oxidative damage induced by copper may be involved in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, familial amyotrophic lateral sclerosis, and prion diseases.}, }
@article {pmid12041880, year = {2001}, author = {Vinceti, M and Wei, ET and Malagoli, C and Bergomi, M and Vivoli, G}, title = {Adverse health effects of selenium in humans.}, journal = {Reviews on environmental health}, volume = {16}, number = {4}, pages = {233-251}, doi = {10.1515/reveh.2001.16.4.233}, pmid = {12041880}, issn = {0048-7554}, mesh = {Biomarkers/analysis ; Environmental Exposure/*adverse effects/analysis ; Humans ; Maximum Allowable Concentration ; Selenium/*adverse effects/analysis ; }, abstract = {Epidemiologic studies and case reports have shown that chronic exposure to selenium compounds is associated with several adverse health effects in humans. An early toxic effect of selenium is on endocrine function, particularly on the synthesis of thyroid hormones following dietary exposure of around 300 micrograms Se/d, and on the metabolism of growth hormone and insulin-like growth factor-1. Other adverse effects of selenium exposure can be the impairment of natural killer cells activity and at higher levels, hepatotoxicity and gastrointestinal disturbances. Dermatologic effects, such as nail and hair loss and dermatitis, occur after exposure to high levels of environmental selenium. Assessing the toxicity and morbidity after long-term exposure to environmental selenium is difficult: neurotoxicity, particularly the degeneration of motor neurons leading to increased risk of amyotrophic lateral sclerosis, might occur after chronic exposure to both organic and inorganic selenium compounds. The results of laboratory investigations and cohort studies suggest that selenium species exhibit a bivalent effect in cancer, either increasing or decreasing risk. Current environmental selenium exposure limits appear to be inadequate for averting adverse health effects.}, }
@article {pmid12028651, year = {2002}, author = {Lindal, S}, title = {Mitochondria and neurodegenerative diseases--is there a link? The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis (ALS).}, journal = {Ultrastructural pathology}, volume = {26}, number = {1}, pages = {1-2}, doi = {10.1080/01913120252934251}, pmid = {12028651}, issn = {0191-3123}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/*pathology ; Humans ; Mitochondria, Muscle/metabolism/*ultrastructure ; Mitochondrial Myopathies/*complications/metabolism/*pathology ; }, }
@article {pmid12020475, year = {2002}, author = {Morrison, KE}, title = {Therapies in amyotrophic lateral sclerosis-beyond riluzole.}, journal = {Current opinion in pharmacology}, volume = {2}, number = {3}, pages = {302-309}, doi = {10.1016/s1471-4892(02)00169-8}, pmid = {12020475}, issn = {1471-4892}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology/physiopathology ; Animals ; Cell Hypoxia/physiology ; Disease Models, Animal ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Several mechanisms have been proposed to account for the progressive motor neurone death evident in amyotrophic lateral sclerosis. These include oxidative stress, neurofilament damage, mitochondrial abnormalities, glutamate-mediated excitotoxicity and altered responses to hypoxia. Current quests for therapies involve studying combinations of agents that act by various mechanisms and evaluating stem-cell therapies in model systems. High-throughput cell-culture screening systems are also being developed. The goal for therapy is to define agents that clearly prevent progression of, and it is hoped even reverse, motor neurone loss.}, }
@article {pmid12019785, year = {2002}, author = {Bruijn, LI}, title = {Amyotrophic lateral sclerosis: from disease mechanisms to therapies.}, journal = {BioTechniques}, volume = {32}, number = {5}, pages = {1112, 1114, 1116 passim}, doi = {10.2144/02325dd01}, pmid = {12019785}, issn = {0736-6205}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/*physiopathology ; Animals ; Disease Models, Animal ; *Drug Design ; Genomics ; Humans ; }, }
@article {pmid11996516, year = {2001}, author = {Brighina, L and Sala, G and Ceresa, C and Tremolizzo, L and Ferrarese, C}, title = {Recent advances in the therapy of amyotrophic lateral sclerosis: focus on excitotoxicity.}, journal = {Functional neurology}, volume = {16}, number = {4 Suppl}, pages = {189-202}, pmid = {11996516}, issn = {0393-5264}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Clinical Trials as Topic ; Humans ; Nerve Growth Factors/therapeutic use ; Neurology/*trends ; Neurotoxins/antagonists &amp; inhibitors/*metabolism ; Research Design ; }, }
@article {pmid11996515, year = {2001}, author = {Carrì, MT and Ferri, A and Casciati, A and Celsi, F and Ciriolo, MR and Rotilio, G}, title = {Copper-dependent oxidative stress, alteration of signal transduction and neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Functional neurology}, volume = {16}, number = {4 Suppl}, pages = {181-188}, pmid = {11996515}, issn = {0393-5264}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*physiopathology ; Animals ; Copper/*physiology ; Humans ; Nerve Degeneration/*etiology/physiopathology ; Oxidative Stress/*physiology ; Signal Transduction/*physiology ; }, }
@article {pmid11996514, year = {2001}, author = {Ceroni, M and Curti, D and Alimonti, D}, title = {Amyotrophic lateral sclerosis and SOD1 gene: an overview.}, journal = {Functional neurology}, volume = {16}, number = {4 Suppl}, pages = {171-180}, pmid = {11996514}, issn = {0393-5264}, mesh = {Amino Acids/blood ; Amyotrophic Lateral Sclerosis/blood/*genetics/physiopathology ; Codon ; Humans ; Mutation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid11996512, year = {2001}, author = {Beal, MF}, title = {Mitochondria and oxidative damage in amyotrophic lateral sclerosis.}, journal = {Functional neurology}, volume = {16}, number = {4 Suppl}, pages = {161-169}, pmid = {11996512}, issn = {0393-5264}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/*metabolism/*pathology ; Oxidation-Reduction ; Permeability ; }, }
@article {pmid11978481, year = {2002}, author = {Beal, MF}, title = {Oxidatively modified proteins in aging and disease.}, journal = {Free radical biology &amp; medicine}, volume = {32}, number = {9}, pages = {797-803}, doi = {10.1016/s0891-5849(02)00780-3}, pmid = {11978481}, issn = {0891-5849}, mesh = {Aging/*physiology ; Humans ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Peroxynitrous Acid/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {There is a large body of evidence implicating oxidative damage in the pathogenesis of both normal aging and neurodegenerative diseases. Oxidative damage to proteins has been well established. Although there are a large number of potential oxidative modifications only a few have been systematically studied. The most frequently studied marker of oxidative damage to proteins is protein carbonyl groups. 3-Nitrotyrosine is thought to be a relatively specific marker of oxidative damage mediated by peroxynitrite. Increased concentrations of both protein carbonyls and 3-nitrotyrosine have been documented in both normal aging as well as in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These findings help to provide a rationale for trials of antioxidants in neurodegenerative diseases.}, }
@article {pmid11972141, year = {2002}, author = {Nguimfack Mbodie, PC}, title = {[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?].}, journal = {L'Encephale}, volume = {28}, number = {2}, pages = {147-153}, pmid = {11972141}, issn = {0013-7006}, mesh = {Environment ; Free Radicals/*metabolism ; Glutamates/*metabolism ; Humans ; Neurotoxins/*metabolism ; Schizophrenia/*etiology/*metabolism ; Systems Theory ; }, abstract = {The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.}, }
@article {pmid11967639, year = {2002}, author = {Dib, M and Garrel, C and Favier, A and Robin, V and Desnuelle, C}, title = {Can malondialdehyde be used as a biological marker of progression in neurodegenerative disease?.}, journal = {Journal of neurology}, volume = {249}, number = {4}, pages = {367-374}, doi = {10.1007/s004150200025}, pmid = {11967639}, issn = {0340-5354}, mesh = {Animals ; Biomarkers/blood ; Disease Progression ; Humans ; Malondialdehyde/*blood ; Neurodegenerative Diseases/*blood ; Oxidative Stress/physiology ; }, abstract = {There is a large body of evidence that free radical-mediated oxidative damage is involved in the pathogenesis of neurodegenerative disease. Although it is unlikely that markers of such damage will have any diagnostic value, they might be of considerable interest in following disease progression and monitoring the efficacy of different treatments. Among such markers, there is evidence for the elevation of peripheral malondialdehyde levels in several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. The measurement of malondialdehyde levels, which is both simple and cheap to perform, can and should be incorporated into future clinical trials. This will allow a clearer picture to emerge as to whether malondialdehyde can be considered as a marker for the evolution of these diseases.}, }
@article {pmid11939461, year = {2002}, author = {Poulsen, DJ and Harrop, JS and During, MJ}, title = {Gene therapy for spinal cord injury and disease.}, journal = {The journal of spinal cord medicine}, volume = {25}, number = {1}, pages = {2-9}, doi = {10.1080/10790268.2002.11753594}, pmid = {11939461}, issn = {1079-0268}, mesh = {*Genetic Therapy ; Humans ; Spinal Cord Diseases/*genetics/pathology/*therapy ; Spinal Cord Injuries/*genetics/pathology/*therapy ; }, abstract = {An incomplete understanding of the pathological processes involved in neurodegeneration and dysfunction of spinal cord injuries and diseases makes these disorders difficult to treat. Repair of damaged or genetically impaired spinal cord also has been limited by the complexity, cellular heterogeneity, and relative inaccessibility of the tissue. Thus, therapeutic options for the treatment of either chronic spinal cord diseases such as amyotrophic lateral sclerosis or acute spinal cord injuries have been rather limited. Potential new therapeutic targets are being identified as our understanding of the molecular pathology involved in neural injury and regeneration increases. Recent advances in gene transfer techniques have made gene therapy a more realistic and viable strategy for the treatment of a broad range of spinal cord disorders. This review summarizes the current state of knowledge regarding the limitations and recent advances in gene therapy and potential application of this technology toward spinal cord injury and disease.}, }
@article {pmid11928897, year = {2001}, author = {Rafałowska, J}, title = {Are all new data referring to amyotrophic lateral sclerosis certain? Some doubts.}, journal = {Folia neuropathologica}, volume = {39}, number = {4}, pages = {261-264}, pmid = {11928897}, issn = {1641-4640}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Humans ; Motor Neurons/enzymology/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Progress in molecular investigations presents new data facilitating the recognition of pathogenic mechanisms of numerous nervous system diseases, among them amyotrophic lateral sclerosis (ALS). Molecular studies of ALS are mainly concentrated on genetic search, excitotoxicity and astrocytic participation, pathology of neurofilaments, apoptosis, trophic factors, and selective motoneurone degeneration. In literature part of the results of these investigations are presented as certainty but some doubts exist. Problems of the role of the superoxide dismutase (SOD-1) mutation gene and free radical scavenging and selective vulnerability and death of motor neurone cells in ALS are mentioned.}, }
@article {pmid11928679, year = {2001}, author = {Sińczuk-Walczak, H}, title = {[Nervous system disorders induced by occupational exposure to aluminium compounds: a literature review].}, journal = {Medycyna pracy}, volume = {52}, number = {6}, pages = {479-481}, pmid = {11928679}, issn = {0465-5893}, mesh = {Aluminum/*adverse effects ; Alzheimer Disease/chemically induced ; Amyotrophic Lateral Sclerosis/chemically induced ; Central Nervous System Diseases/*chemically induced ; Dementia/chemically induced ; Humans ; Neurobehavioral Manifestations ; Occupational Exposure/*adverse effects ; Risk Factors ; }, abstract = {This is a review of the literature on the effect of aluminum (Al) and its compounds on the nervous system. The role of aluminum in etiology of some degenerative diseases of the nervous system, e.g. Alzheimer disease, amyotrophic lateral sclerosis or dementia, is presented. The special attention was turned to the effects of aluminum on the nervous system functions in persons occupationally exposed to metal-containing dusts and fumes, manifested mostly by neurobehavioral disorders and changes in the brain bioelectric functions and less frequently pronounced by clinical neurological symptoms.}, }
@article {pmid11924029, year = {2001}, author = {Arnulf, I and Derenne, JP}, title = {[Respiratory disorders during sleep in degenerative diseases of the brain stem].}, journal = {Revue neurologique}, volume = {157}, number = {11 Pt 2}, pages = {S148-51}, pmid = {11924029}, issn = {0035-3787}, mesh = {*Brain Stem/physiopathology ; Humans ; Neurodegenerative Diseases/*diagnosis/physiopathology ; Polysomnography ; Sleep Apnea, Central/*diagnosis/physiopathology ; Sleep, REM/physiology ; }, abstract = {Sleep-disordered breathing may be present in patients with degenerative diseases affecting the brainstem. Indeed, this last structure contains the executive system of rapid eye movement (REM) sleep (tegmentum of the pons), of respiratory drive (medulla oblongata and pons) and motor neurons of upper airways dilators (fifth, seventh, ninth, tenth and twelfth cranial roots). Patients with Parkinson's disease suffer frequently from insomnia, partly caused by nocturnal motor disability, and from REM sleep behavior disorder. In 20 percent of the patients, excessive daytime sleepiness is caused by a sleep apnea syndrome, with a partly levodopa-dependent upper airway dysfunction. In 40 percent of the patients, sleepiness mimics a secondary narcolepsy and may be associated with hypnagogic hallucinations. During supranuclear palsy, REM sleep is progressively curtailed with rare sleep-disordered breathing. Patients with multiple systemic atrophy may present a nocturnal stridor caused by laryngeal palsy and benefit from tracheotomy or continuous nasal positive airway pressure. Seldom sleep and respiratory studies in genetic ataxic diseases suggest a normal respiratory drive, occasional diaphragmatic dysfunction and night hypopneas. During amyotrophic lateral sclerosis, the progressive loss of phrenic nerve leads to a diaphragmatic dysfunction, dyspnea and a lesser survival. Adequate ventilation is jeopardized during REM sleep with a consequent loss of this state.}, }
@article {pmid11924004, year = {2001}, author = {Chritin, M and Besson, G and Mallaret, M and Savasta, M}, title = {[Amyotrophic lateral sclerosis and animal models].}, journal = {Revue neurologique}, volume = {157}, number = {11 Pt 1}, pages = {1351-1361}, pmid = {11924004}, issn = {0035-3787}, mesh = {Animals ; Animals, Genetically Modified ; Brain/pathology ; Disease Models, Animal ; Humans ; Motor Neuron Disease/mortality/*pathology ; Motor Neurons/pathology ; Spinal Cord/pathology ; Survival Rate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which affects cortical, bulbar and spinal motoneurones. The cause of the disease, probably due to several factors, is still unknown and the survival delay of patients with ALS generally does not exceed 3-5 years. Animals models provide a unique opportunity to study pathological features and to evaluate potential therapeutic effects of news treatments. Natural disease models, neurotoxins or viral-induced models and more recently transgenic models with genetic anomalies mimicking those found in ALS patients have been extensively studied. This review summarizes the most relevant clinical and pathological advances issuing from these animal studies.}, }
@article {pmid11914415, year = {2002}, author = {Cox, PA and Sacks, OW}, title = {Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam.}, journal = {Neurology}, volume = {58}, number = {6}, pages = {956-959}, doi = {10.1212/wnl.58.6.956}, pmid = {11914415}, issn = {0028-3878}, mesh = {Alzheimer Disease/chemically induced/epidemiology ; Amino Acids, Diamino/adverse effects ; Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Animals ; *Chiroptera ; Cyanobacteria Toxins ; Cycas/*adverse effects ; Cycasin/adverse effects ; Diet/*adverse effects ; Female ; Guam/epidemiology ; Humans ; Incidence ; Male ; Native Hawaiian or Other Pacific Islander ; Parkinson Disease/epidemiology ; Parkinson Disease, Secondary/chemically induced ; Plants, Toxic/adverse effects ; Seeds/adverse effects ; }, abstract = {The Chamorro people of Guam have been afflicted with a complex of neurodegenerative diseases (now known as ALS-PDC) with similarities to ALS, AD, and PD at a far higher rate than other populations throughout the world. Chamorro consumption of flying foxes may have generated sufficiently high cumulative doses of plant neurotoxins to result in ALS-PDC neuropathologies, since the flying foxes forage on neurotoxic cycad seeds.}, }
@article {pmid11913521, year = {2002}, author = {Balcar, VJ}, title = {Molecular pharmacology of the Na+-dependent transport of acidic amino acids in the mammalian central nervous system.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {25}, number = {3}, pages = {291-301}, doi = {10.1248/bpb.25.291}, pmid = {11913521}, issn = {0918-6158}, mesh = {Animals ; Biological Transport ; Central Nervous System/*metabolism ; Glutamic Acid/*metabolism ; Humans ; Sodium/*metabolism ; }, abstract = {The Na+-dependent transport of L-glutamate (GluT) has been identified in brain tissue more than thirty years ago. Neurochemical studies, performed in various experimental models during 1970's, defined the basic rules for the selection or synthesis of GluT-specific substrates and inhibitors. The protein molecules (transporters) that mediate the translocation of the substrates across the plasma membrane have been cloned and studied during the last ten years. The sites on the transporters that bind the substrates favour glutamate-like or aspartate-like molecules with one positively charged and two negatively charged ionised groups. Substituents at C3 and C4 are often tolerated but substitutions at C2 or alterations of the ionisable groups usually impede the binding. The substrate binding sites display an "anomalous" selectivity towards stereoisomers. These structural requirements are shared by all Na+-dependent glutamate transporters thus making the design of transporter-selective ligands a challenging task. Moreover, the molecular mechanisms of the transport have not yet been adequately elucidated. Data from a wide variety of experimental studies strongly indicate that Na+-dependent GluT regulates the functioning of the glutamatergic excitatory synapses-the most important rapid inter-neuronal signalling system in the mammalian brain. Altered structural and/or functional properties of the Na+-dependent glutamate transporters have been implicated in the damage to the brain tissue following cerebral ischaemia and in the progressive loss of neurons in conditions such as Alzheimer dementia and amyotrophic lateral sclerosis. Furthermore, it seems that fine-tuning of glutamatergic neurotransmission by regulating the Na+-dependent GluT could be useful in the therapy of schizophrenia.}, }
@article {pmid11912105, year = {2002}, author = {Shaw, PJ}, title = {Toxicity of CSF in motor neurone disease: a potential route to neuroprotection.}, journal = {Brain : a journal of neurology}, volume = {125}, number = {Pt 4}, pages = {693-694}, doi = {10.1093/brain/awf138}, pmid = {11912105}, issn = {0006-8950}, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Cerebrospinal Fluid Proteins/metabolism/*toxicity ; Humans ; Microglia/drug effects/metabolism ; Minocycline/*therapeutic use ; Motor Neuron Disease/*cerebrospinal fluid/*drug therapy/physiopathology ; Motor Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*therapeutic use ; Neurotoxins/metabolism/*toxicity ; Oxidative Stress/drug effects/physiology ; Spinal Cord/*drug effects/metabolism/physiopathology ; }, }
@article {pmid11911667, year = {2002}, author = {Smyth, PG and Berman, SA}, title = {Markers of apoptosis: methods for elucidating the mechanism of apoptotic cell death from the nervous system.}, journal = {BioTechniques}, volume = {32}, number = {3}, pages = {648-50, 652, 654 passim}, doi = {10.2144/02323dd02}, pmid = {11911667}, issn = {0736-6205}, mesh = {Animals ; Apoptosis/*physiology ; Biomarkers ; Cytological Techniques/*methods ; Humans ; Nervous System/*cytology ; Neurodegenerative Diseases/*pathology ; }, abstract = {Apoptosis is a highly conserved energy-requiring program for non-inflammatory cell death that is important in both normal physiology and disease. Numerous techniques have been used to study apoptosis. In the nervous system, apoptosis is necessary for normal development, but it also occurs in many acute and chronic pathologic conditions. This review places commonly used markers of apoptosis and their detection in the context of what is now known about the process of apoptosis. We review the potential role of apoptosis in nervous system and neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis). We then describe important morphological, immunocytochemical, and molecular genetic markers for apoptosis, including proteases, signal transduction molecules, and mitochondrial proteins. The possibility of manipulating apoptosis therapeutically in conditions of too many or too few cells is under active investigation.}, }
@article {pmid11908237, year = {2002}, author = {Murray, B and Mitsumoto, H}, title = {Drug therapy in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {88}, number = {}, pages = {63-82}, pmid = {11908237}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Excitatory Amino Acid Antagonists/*therapeutic use ; Genetic Therapy ; Humans ; Immunotherapy ; Nerve Growth Factors/*therapeutic use ; }, }
@article {pmid11908236, year = {2002}, author = {Bromberg, MB}, title = {Diagnostic criteria and outcome measurement of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {88}, number = {}, pages = {53-62}, pmid = {11908236}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; *Disability Evaluation ; Electrodiagnosis/*standards ; Humans ; Treatment Outcome ; }, abstract = {ALS is a most challenging disease. Accurate diagnostic criteria are well along in refinement, and experience with patients who are at the limits of the criteria should be presented to increase our comfort with the limits of ALS or motor neuron disease. As our understanding of the pathophysiology is further refined, there will be new drugs to test. It will be important to have sensitive clinical and electrophysiologic measures available to detect changes in the rate of progression. When effective drugs are identified, they will, in addition to helping patients, lend support to proposed mechanisms. Charcot would be impressed with our advances in the ability to detect and follow upper and lower motor neuron loss, but would urge us to press on in our clinical endeavors.}, }
@article {pmid11908235, year = {2002}, author = {Shefner, JM and Gooch, CL}, title = {Motor unit number estimation in neurologic disease.}, journal = {Advances in neurology}, volume = {88}, number = {}, pages = {33-52}, pmid = {11908235}, issn = {0091-3952}, mesh = {Action Potentials ; Cell Count/*methods ; Humans ; Motor Neurons/*pathology/physiology ; Neuromuscular Diseases/*pathology ; }, abstract = {Since its introduction 30 years ago, MUNE technologies have been increasingly refined and applied to a wide variety of neuromuscular disorders. Differences of opinion remain among MUNE investigators as to which method should be used; however, statistical and MPS MUNE currently enjoy the most widespread use. A number of methodological issues remain, including the development of detailed universal standards for each technique and modifications for the further enhancement of reproducibility. These issues are the subject of ongoing investigation. However, despite technical variability, the MUNE values obtained with different methods show good agreement, both in studies of healthy subjects and in patients with a variety of neurogenic processes. MUNE has been most successfully applied to patients with ALS and in animal models of motor neuron disease, providing significant insight into the pathophysiology of these disorders. These techniques are being increasingly incorporated into clinical therapeutic trials. MUNE is a technology offering important promise in the study of neuromuscular disease, enabling the collection of novel data in the living patient unobtainable by any other method.}, }
@article {pmid11908227, year = {2002}, author = {Siddique, T and Lalani, I}, title = {Genetic aspects of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {88}, number = {}, pages = {21-32}, pmid = {11908227}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/classification/etiology/*genetics ; Humans ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid11908220, year = {2002}, author = {Simpson, EP and Mosier, D and Appel, SH}, title = {Mechanisms of disease pathogenesis in amyotrophic lateral sclerosis. A central role for calcium.}, journal = {Advances in neurology}, volume = {88}, number = {}, pages = {1-19}, pmid = {11908220}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*physiopathology ; Calcium/*physiology ; Humans ; Mitochondria/physiology ; Oxidative Stress ; }, }
@article {pmid11898584, year = {2002}, author = {Kaufmann, P and Mitsumoto, H}, title = {Amyotrophic lateral sclerosis: objective upper motor neuron markers.}, journal = {Current neurology and neuroscience reports}, volume = {2}, number = {1}, pages = {55-60}, pmid = {11898584}, issn = {1528-4042}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism/physiopathology ; *Biomarkers ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Magnetoencephalography ; Motor Neurons/*metabolism/physiology ; Tomography, Emission-Computed ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis. It is based on the combination of both upper and lower motor neuron signs in the neurologic examination. With several new therapeutic agents on the horizon, effective and objective disease markers for diagnosis and surrogate outcome measures in clinical trials are crucial. Whereas the presence of lower motor neuron signs on neurologic examination can be ascertained by electromyography, there is no widely accepted marker for upper motor neuron involvement. Neuroimaging changes of the corticospinal tract in ALS patients have been studied using magnetic resonance (MR) imaging, but appear to lack sensitivity and specificity. MR spectroscopy, a technique that allows one to evaluate biochemical tissue composition in vivo, has been widely used to establish the progressive decrease in N-acetylaspartate, a marker of neuronal integrity, in the course of ALS. More recently, diffusion tensor imaging, a newer MR technique, has demonstrated changes in diffusivity along the corticospinal tract in ALS patients. Metabolic aspects in the brains of ALS patients have been evaluated using positron emission tomography. Transcranial magnetic stimulation is a more established technique that evaluates the neurophysiologic integrity of upper motor neurons in ALS. This article reviews the progress that has been made over the past two decades towards establishing valid diagnostic and natural history markers of upper motor neuron involvement in ALS.}, }
@article {pmid11898502, year = {2001}, author = {Shaw, CE and al-Chalabi, A and Leigh, N}, title = {Progress in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {1}, number = {1}, pages = {69-76}, pmid = {11898502}, issn = {1528-4042}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/genetics/*pathology ; Environment ; Humans ; Motor Neurons/pathology ; Virus Diseases/complications ; }, abstract = {This decade has seen the discovery of one cause for amyotrophic lateral sclerosis (ALS)--mutations in the copper/zinc superoxide dismutase (SOD1) gene. Mutant SOD1 has provided an invaluable tool for transgenic and cellular experiments designed to elicit the biochemical pathways that are disturbed in ALS. We highlight recent advances in ALS research, including diagnostic issues, new loci for ALS genes, and progress in understanding the toxicity of mutant SOD1. The evidence for persistant viral infection, glutamate-mediated excitotoxicity, oxidative stress, altered neurofilament and peripherin expression, disrupted axonal transport, neurotrophin deficiency, and mitochondrial dysfunction are critically reviewed. As yet, no consensus has been achieved on the pathways that lead to selective neuronal death, and the underlying causes are still unknown in the vast majority of patients. Further clues about genetic susceptibility and environmental triggers are urgently needed so that more effective treatments for ALS can be developed, with the ultimate goal being prevention.}, }
@article {pmid11895127, year = {2001}, author = {Tabner, BJ and Turnbull, S and El-Agnaf, O and Allsop, D}, title = {Production of reactive oxygen species from aggregating proteins implicated in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.}, journal = {Current topics in medicinal chemistry}, volume = {1}, number = {6}, pages = {507-517}, doi = {10.2174/1568026013394822}, pmid = {11895127}, issn = {1568-0266}, mesh = {Alzheimer Disease/chemically induced/metabolism ; Amyloid beta-Peptides/adverse effects/chemistry/metabolism ; Electron Spin Resonance Spectroscopy ; Humans ; Nerve Tissue Proteins/adverse effects/chemistry/*metabolism ; Neurodegenerative Diseases/chemically induced/*metabolism ; Parkinson Disease/metabolism ; Parkinson Disease, Secondary/chemically induced ; Reactive Oxygen Species/*metabolism ; Synucleins ; alpha-Synuclein ; }, abstract = {The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), motor neurone disease and the 'prion' dementias. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the beta-amyloid (Abeta), which accumulates in the brain in AD, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown recently that solutions of Abeta liberate readily detectable amounts of hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). We have also obtained similar results with alpha-synuclein, which accumulates in Lewy bodies in PD. Our data suggest that hydrogen peroxide accumulates during Abeta or alpha-synuclein incubation and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, we now support the idea that one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD, PD, and possibly some other protein conformational diseases, could be the direct production of ROS during formation of the abnormal protein aggregates. This hypothesis suggests a novel approach to the therapy of this group of diseases.}, }
@article {pmid11895124, year = {2001}, author = {Adams, JD and Klaidman, LK and Chang, ML and Yang, J}, title = {Brain oxidative stress--analytical chemistry and thermodynamics of glutathione and NADPH.}, journal = {Current topics in medicinal chemistry}, volume = {1}, number = {6}, pages = {473-482}, doi = {10.2174/1568026013394778}, pmid = {11895124}, issn = {1568-0266}, mesh = {Animals ; Brain/anatomy &amp; histology/*metabolism ; Brain Chemistry ; Chemistry Techniques, Analytical ; Glutathione/analysis/metabolism ; Humans ; NADP/analysis/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Thermodynamics ; }, abstract = {Oxidative stress occurs in the brain due to stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, trauma, aging and other conditions. Analysis of the effects of oxidative stress can involve quantitation of brain GSH, GSSG, NADPH and NADP. Reliable and rapid assays have been developed for these compounds and will be presented in detail. The assays have been used to analyze the effects of brain oxidative stress. Thermodynamic calculations can be performed to find the observed electrochemical potentials of the GSSG/GSH and the NADP/NADPH couples during oxidative stress. The biochemical consequences of these thermodynamic changes in the cell will be discussed as well as the defense mechanisms available to the cell to recover from oxidative stress.}, }
@article {pmid11884366, year = {2002}, author = {Lopez, MF and Melov, S}, title = {Applied proteomics: mitochondrial proteins and effect on function.}, journal = {Circulation research}, volume = {90}, number = {4}, pages = {380-389}, doi = {10.1161/hh0402.105757}, pmid = {11884366}, issn = {1524-4571}, support = {AG18679/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Databases, Protein ; Electrophoresis, Gel, Two-Dimensional ; Heart/*physiology ; Humans ; Mass Spectrometry ; Mitochondria, Heart/*metabolism ; Mitochondrial Diseases/metabolism ; Mitochondrial Proteins/*metabolism ; Proteome/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The identification of a majority of the polypeptides in mitochondria would be invaluable because they play crucial and diverse roles in many cellular processes and diseases. The endogenous production of reactive oxygen species (ROS) is a major limiter of life as illustrated by studies in which the transgenic overexpression in invertebrates of catalytic antioxidant enzymes results in increased lifespans. Mitochondria have received considerable attention as a principal source---and target---of ROS. Mitochondrial oxidative stress has been implicated in heart disease including myocardial preconditioning, ischemia/reperfusion, and other pathologies. In addition, oxidative stress in the mitochondria is associated with the pathogenesis of Alzheimer's disease, Parkinson's disease, prion diseases, and amyotrophic lateral sclerosis (ALS) as well as aging itself. The rapidly emerging field of proteomics can provide powerful strategies for the characterization of mitochondrial proteins. Current approaches to mitochondrial proteomics include the creation of detailed catalogues of the protein components in a single sample or the identification of differentially expressed proteins in diseased or physiologically altered samples versus a reference control. It is clear that for any proteomics approach prefractionation of complex protein mixtures is essential to facilitate the identification of low-abundance proteins because the dynamic range of protein abundance within cells has been estimated to be as high as 10(7). The opportunities for identification of proteins directly involved in diseases associated with or caused by mitochondrial dysfunction are compelling. Future efforts will focus on linking genomic array information to actual protein levels in mitochondria.}, }
@article {pmid11881740, year = {2001}, author = {Beckman, JS and Estévez, AG and Crow, JP and Barbeito, L}, title = {Superoxide dismutase and the death of motoneurons in ALS.}, journal = {Trends in neurosciences}, volume = {24}, number = {11 Suppl}, pages = {S15-20}, doi = {10.1016/s0166-2236(00)01981-0}, pmid = {11881740}, issn = {0166-2236}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Cell Death ; Humans ; Motor Neurons/*enzymology/*pathology ; Superoxide Dismutase/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal disease that is characterized by the relentless death of motoneurons. Mutations to Cu-Zn superoxide dismutase (SOD), though occurring in just 2-3% of individuals with ALS, remain the only proven cause of the disease. These mutations structurally weaken SOD, which indirectly decreases its affinity for Zn. Zn-deficient SOD induces apoptosis in motoneurons through a mechanism involving peroxynitrite. Importantly, Zn-deficient wild-type SOD is just as toxic as Zn-deficient ALS mutant SOD, suggesting that the loss of Zn from wild-type SOD could be involved in the other 98% of cases of ALS. Zn-deficient SOD could therefore be an important therapeutic target in all forms of ALS.}, }
@article {pmid11876200, year = {1998}, author = {Schuerger, AC}, title = {Microbial contamination of advanced life support (ALS) systems poses a moderate threat to the long-term stability of space-based bioregenerative systems.}, journal = {Life support &amp; biosphere science : international journal of earth space}, volume = {5}, number = {3}, pages = {325-337}, pmid = {11876200}, issn = {1069-9422}, mesh = {*Ecological Systems, Closed ; *Environmental Microbiology ; Humans ; Hydroponics ; *Life Support Systems ; Plant Diseases ; Plants/microbiology ; *Space Flight ; *Weightlessness ; }, abstract = {Microbial contamination of terrestrial hydroponic plant-growing systems provides an effective analogue for studying microbial contamination issues for space-based advanced life support (ALS) systems. If aggressive root or foliar pathogens are introduced into ALS hydroponic systems, severe epidemics are probable. Greater than 80% of the reported outbreaks of root pathogens in terrestrial hydroponic systems describe epidemics caused by fungal species of Fusarium, Phytophthora, and Pythium. However, it is likely that a comprehensive sanitation and quarantine program for space-based ALS modules will prevent contamination by Phytophthora and Pythium spp. because these pathogens are general soilborne. However, Fusarium spp. are typically airborne, can grow saprophytically on diverse substrates, and have been common contaminants of American spacecraft. If comprehensive sanitation and quarantine programs are established for space-based ALS modules, then the threat of pathogen introductions into these systems will be significantly mitigated. Microbial contamination studies in spacecraft over the last 30 years indicate that a high diversity of bacteria, fungi, and actinomycetes are commonly carried on board probably via clothing, equipment, air currents during spacecraft handling and loading, food, and the astronauts themselves. Species of Alternaria, Aspergillus, Botrytis, Candida, Cephalosporium, Cladosporium, Fusarium, Mucor, Penicillium, Phoma, and Trichoderma were the most prevalent fungi recovered, and species of Bacillus, Escherichia, Klebsiella, Micrococcus, Pseudomonas, Staphylococcus, and Streptococcus were the most prevalent bacteria recovered from spacecraft. Most of these genera contain species that have been reported as plant pathogens. Strict quarantine procedures were not effective in preventing contamination of spacecraft during these missions. Research must be initiated to better understand how microorganisms interact with plants and animals in microgravity environments because microbial contamination of spacecraft and ALS modules cannot be avoided. An integrated pest management (IPM) program likely will be developed for managing plant disease outbreaks in space-based ALS systems.}, }
@article {pmid11870681, year = {2002}, author = {Hand, CK and Rouleau, GA}, title = {Familial amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {25}, number = {2}, pages = {135-159}, doi = {10.1002/mus.10001}, pmid = {11870681}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Apoptosis ; Copper/metabolism/poisoning ; Genetic Linkage ; Glutamic Acid/physiology ; Humans ; Mutation ; Neurofilament Proteins/genetics ; Oxidative Stress ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {The increasing complexity of the pathways implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) has stimulated intensive research in many directions. Genetic analysis of familial ALS has yielded six loci and one disease gene (SOD1), initially suggesting a role for free radicals in the disease process, although the mechanisms through which the mutant exerts toxicity and results in selective motor neuron death remain uncertain. Numerous studies have focused on structural elements of the affected cell, emphasizing the role of neurofilaments and peripherin and their functional disruption in disease. Other topics examined include cellular homeostasis of copper and calcium, particularly in the context of oxidative stress and the processes of protein aggregation, glutamate excitotoxicity, and apoptosis. It has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies. This study discusses the main areas of investigation and reviews the findings.}, }
@article {pmid11854102, year = {2001}, author = {Borasio, GD and Voltz, R and Miller, RG}, title = {Palliative care in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {19}, number = {4}, pages = {829-847}, doi = {10.1016/s0733-8619(05)70049-9}, pmid = {11854102}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Deglutition Disorders/etiology ; Dysarthria/etiology ; Dyspnea/etiology ; Humans ; Hypoventilation/etiology ; Muscle Weakness/etiology ; Pain/etiology ; *Palliative Care ; Quality of Life ; Sialorrhea/etiology ; Sleep Wake Disorders/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease in adults. The clinical picture consists of generalized fasciculations, progressive atrophy and weakness of the skeletal muscles, spasticity and pyramidal tract signs, dysarthria, dysphagia, and dyspnea. Pseudobulbar affect is common. Disease-specific treatment options are still unsatisfactory. Therapeutic nihilism is not justified as a large array of palliative measures available to enhance the quality of life of patients and their families. Because of its clinical characteristics, ALS represents a paradigm for palliative care in neurological diseases. Numerous projects are being undertaken worldwide in an effort to enlarge the evidence base for palliative interventions in ALS. Palliative care in ALS is a multidisciplinary effort requiring careful coordination. An open and empathic disclosure of the diagnosis is essential. Nutritional deficiency caused by dysphagia can be relieved by a percutaneous endoscopic gastrostomy. Respiratory insufficiency can be effectively treated by non-invasive home mechanical ventilation. The terminal phase of the disease should be discussed at the latest when symptoms of dyspnea appear, in order to prevent unwarranted fears of "choking to death." Psychological and spiritual care of patients and families are important. Collaboration with hospice institutions and completion of advance directives can be of invaluable help in the terminal phase.}, }
@article {pmid11854007, year = {2002}, author = {Smith, DS and Tsai, LH}, title = {Cdk5 behind the wheel: a role in trafficking and transport?.}, journal = {Trends in cell biology}, volume = {12}, number = {1}, pages = {28-36}, doi = {10.1016/s0962-8924(01)02181-x}, pmid = {11854007}, issn = {0962-8924}, mesh = {Animals ; Biological Transport, Active/physiology ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/metabolism/*physiology ; Cytoskeleton/*metabolism ; Humans ; Membranes/physiology ; Neurodegenerative Diseases/*metabolism ; Neurons/*physiology ; Neurotransmitter Agents/physiology ; Protein Transport/physiology ; Signal Transduction/*physiology ; Synapses/physiology ; }, abstract = {Cdk5, a serine/threonine kinase in the cyclin-dependent kinase (Cdk) family, is an important regulator of neuronal positioning during brain development. Cdk5 might also play a role in synaptogenesis and neurotransmission. Loss of Cdk5 in mice is perinatal lethal, and overactive Cdk5 induces apoptosis in cultured cells, indicating that strict regulation of kinase activity is crucial. Indeed, activity depends on the stability of activating partners, subcellular localization and the phosphorylation state of the enzyme itself. Deregulated kinase activity has been linked to neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review focuses on links between Cdk5 activity and components of cytoskeletal, membrane and adhesion systems that allow us to postulate a role for Cdk5 in directing intracellular traffic in neurons.}, }
@article {pmid11850111, year = {2002}, author = {Menzies, FM and Ince, PG and Shaw, PJ}, title = {Mitochondrial involvement in amyotrophic lateral sclerosis.}, journal = {Neurochemistry international}, volume = {40}, number = {6}, pages = {543-551}, doi = {10.1016/s0197-0186(01)00125-5}, pmid = {11850111}, issn = {0197-0186}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Homeostasis/physiology ; Humans ; Mitochondria/*metabolism/pathology/ultrastructure ; }, abstract = {The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.}, }
@article {pmid11847479, year = {2001}, author = {Ghezzi, P and Mennini, T}, title = {Tumor necrosis factor and motoneuronal degeneration: an open problem.}, journal = {Neuroimmunomodulation}, volume = {9}, number = {4}, pages = {178-182}, doi = {10.1159/000049024}, pmid = {11847479}, issn = {1021-7401}, mesh = {Animals ; Antibodies, Monoclonal/adverse effects/immunology/therapeutic use ; Apoptosis/drug effects/physiology ; Autoimmune Diseases/immunology/metabolism/therapy ; Cells, Cultured/drug effects ; Contraindications ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/immunology/therapy ; Gene Expression Regulation/physiology ; Humans ; Inflammation/metabolism ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; Motor Neuron Disease/enzymology/genetics/immunology/metabolism/therapy ; Motor Neurons/*pathology ; Multiple Sclerosis/immunology/metabolism/therapy ; NF-kappa B/metabolism ; Nerve Degeneration/*metabolism/pathology ; Nerve Growth Factors/pharmacology ; Neuronal Ceroid-Lipofuscinoses/genetics/metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Oxidative Stress ; Rats ; Receptors, Tumor Necrosis Factor/drug effects/physiology ; Signal Transduction ; Superoxide Dismutase/deficiency/genetics ; Tumor Necrosis Factor-alpha/immunology/pharmacology/*physiology/therapeutic use ; }, abstract = {Tumor necrosis factor (TNF) has been implicated in the pathogenesis of various central nervous system diseases with an inflammatory component. Elevated TNF levels were observed in animal models of motor neuron disease (MND), and activation of the TNF system has been reported in patients with amyotrophic lateral sclerosis (ALS). The easy availability of scientific reports to the layman through the web, often based only on the abstracts, has prompted many patients to ask whether anti-TNF therapy might be beneficial in ALS. This review discusses the possible role of TNF in motoneuronal degeneration. Although TNF is mostly regarded as neurotoxic cytokine, there are reports of a neuroprotective and neurotrophic action. Studies with animal models of ALS are not sufficient to show whether TNF has a pathogenic or a protective role in MND though anti-TNF antibodies have shown protective effects in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). On the other hand, while TNF-deficient mice are protected from EAE, anti-TNF antibodies worsen the disease in MS patients, suggesting caution in extrapolating preliminary basic studies to the patient.}, }
@article {pmid11817274, year = {2001}, author = {de Carvalho, M and Johnsen, B and Fuglsang-Frederiksen, A}, title = {Medical technology assessment. Electrodiagnosis in motor neuron diseases and amyotrophic lateral sclerosis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {31}, number = {5}, pages = {341-348}, doi = {10.1016/s0987-7053(01)00272-6}, pmid = {11817274}, issn = {0987-7053}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Diagnosis, Differential ; Disease Progression ; *Electromyography/methods/standards ; Humans ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/physiology ; Muscle Denervation ; Nerve Regeneration ; Neuromuscular Diseases/diagnosis ; Prognosis ; Quality Control ; }, abstract = {In motor neuron diseases/amyotrophic lateral sclerosis (MND-ALS), electrodiagnostic techniques are essential in supporting the diagnosis and excluding other conditions that clinically resemble MND-ALS. Electrodiagnostic techniques can also monitor disease progression and provide prognostic information. Electromyography has an important role in the diagnosis of MND-ALS, but some drawbacks should be borne in mind. Although internationally accepted electrophysiological criteria have been defined to support MND-ALS diagnosis, differences in different laboratories can raise unexpected difficulties in application of diagnosis criteria. Much work needs to be done to increase standardisation of the electrodiagnosis of MND-ALS in order to improve quality. Differential diagnosis with motor axonal neuropathies may be particularly difficult. EMG is an essential tool for the early diagnosis of MND-ALS, which increases potential benefit of therapeutic interventions. A wide discussion among neurophysiologists from different schools could create a sound consensus on early diagnosis of MND-ALS.}, }
@article {pmid11815275, year = {2002}, author = {Newbery, HJ and Abbott, CM}, title = {Of mice, men and motor neurons.}, journal = {Trends in molecular medicine}, volume = {8}, number = {2}, pages = {88-92}, doi = {10.1016/s1471-4914(02)02283-9}, pmid = {11815275}, issn = {1471-4914}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology/therapy ; Animals ; Cytoskeleton/metabolism ; *Disease Models, Animal ; Endothelial Growth Factors/genetics/physiology ; Genetic Therapy/trends ; Humans ; Lymphokines/genetics/physiology ; Mice ; Mice, Mutant Strains ; Mice, Transgenic ; Motor Neurons/metabolism/*pathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {The use of mouse models has been of particular importance in studying the pathogenesis of amyotrophic lateral sclerosis. Here, we describe both transgenic and classical mutants for which the genetic lesion is known. We draw attention, wherever possible, to pathological factors common to multiple models.}, }
@article {pmid11809124, year = {2001}, author = {Stewart, A and Sandercock, J and Bryan, S and Hyde, C and Barton, PM and Fry-Smith, A and Burls, A}, title = {The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.}, journal = {Health technology assessment (Winchester, England)}, volume = {5}, number = {2}, pages = {1-97}, doi = {10.3310/hta5020}, pmid = {11809124}, issn = {1366-5278}, mesh = {Cost-Benefit Analysis ; Humans ; Incidence ; Motor Neuron Disease/*drug therapy/epidemiology ; Neuroprotective Agents/adverse effects/*economics/*therapeutic use ; Prevalence ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*economics/*therapeutic use ; Technology Assessment, Biomedical ; Treatment Outcome ; United Kingdom/epidemiology ; }, }
@article {pmid11808267, year = {2001}, author = {Shiote, M and Abe, K}, title = {[Amyotrophic lateral sclerosis].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {59 Suppl 8}, number = {}, pages = {490-494}, pmid = {11808267}, issn = {0047-1852}, mesh = {*Amyotrophic Lateral Sclerosis ; Female ; Humans ; Male ; }, }
@article {pmid11801324, year = {2002}, author = {Patzke, H and Tsai, LH}, title = {Cdk5 sinks into ALS.}, journal = {Trends in neurosciences}, volume = {25}, number = {1}, pages = {8-10}, doi = {10.1016/s0166-2236(00)02000-2}, pmid = {11801324}, issn = {0166-2236}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Animals ; Cell Death/*physiology ; Central Nervous System/*metabolism/pathology/physiopathology ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*metabolism ; Cytoskeleton/metabolism/pathology ; Disease Models, Animal ; Humans ; Mice ; Motor Neurons/*metabolism/pathology ; Nerve Tissue Proteins/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Recent research points to an involvement of deregulated cdk5 activity in the pathogenesis of mutant SOD1-mediated disease. In addition, inhibition of this activity might promote motor neuron survival. These observations have opened the door to further research into the role of cdk5 in ALS and other neurodegenerative diseases.}, }
@article {pmid11784953, year = {2001}, author = {Grippo, J and Grippo, T}, title = {[Channelopathies in neurology].}, journal = {Revista de neurologia}, volume = {33}, number = {7}, pages = {643-647}, pmid = {11784953}, issn = {0210-0010}, mesh = {Humans ; Ion Channels/*metabolism ; Migraine Disorders/metabolism ; Movement Disorders/genetics/*metabolism ; Muscles/metabolism ; Nervous System Diseases/genetics/*metabolism ; Neurons/metabolism ; Periodicity ; }, abstract = {INTRODUCTION: The main function of ionic channels are the conduction, recognition and selection of specific ions. They open and close in respond answer to electrical, mechanical and chemical stimulus, acting in the excitation or transmission of diverse tissues.<br><br>DEVELOPMENT: The clinical and molecular manifestations of channelophathies are varied and use to shown up in continuous or paroxystic ways. Alteration of Ca channels cause muscle dysfunction periodic paralysis with or without potassium changes, myasthenia or myasthenic disorders, like Lambert Eaton syndrome, amyotrophic lateral sclerosis, Central Core disease, malignant hyperthermia. Cl and Na channels alterations produce myotonic diseases: Thomsen, Becker and paramyothonies, potassium sensible paralysis, fluctuant congenital myotonic, Andersen s syndrome. Channelopathies also produce various episodic ataxia type 1, type 2, spinocerebellar 6 and familial hemiplegic migraine. Abnormal paroxystic movements are present as channelophaties: episodic nocturnal dystonia, paroxystic dyskinesia. In some families are associates abnormal episodic movements and epilepsy. Several epileptic syndromes are also related with channels dysfunction: frontal lobe nocturnal epilepsy, choreoatetosis epilepsy, benign neonatal convulsions, generalized epilepsy with febrile convulsions plus.<br><br>CONCLUSIONS: Voltage gated channels dysfunction are related to diseases with episodic phenomena or permanent conditions on muscle or neuronal tissues, with clinical and genetic heterogenous manifestations.}, }
@article {pmid11771766, year = {2001}, author = {McGeer, PL}, title = {COX-2 and ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {3}, pages = {121-122}, doi = {10.1080/146608201753275562}, pmid = {11771766}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*enzymology ; Animals ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/therapeutic use ; Humans ; Isoenzymes/antagonists &amp; inhibitors/*biosynthesis ; Membrane Proteins ; Prostaglandin-Endoperoxide Synthases/*biosynthesis ; RNA, Messenger/biosynthesis ; Spinal Cord/enzymology ; }, }
@article {pmid11766772, year = {2001}, author = {Strong, MJ}, title = {Progress in clinical neurosciences: the evidence for ALS as a multisystems disorder of limited phenotypic expression.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {28}, number = {4}, pages = {283-298}, doi = {10.1017/s0317167100001505}, pmid = {11766772}, issn = {0317-1671}, mesh = {Amyotrophic Lateral Sclerosis/classification/drug therapy/*genetics/*physiopathology ; Animals ; Humans ; Neurosciences/*trends ; Phenotype ; }, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a unique neurodegeneration disorder in which motor neurons are selectively vulnerable to a single disease process. Our current understanding of ALS, however, suggests that this is far too limited an approach. While motor neuron degeneration remains the central component to this process, there is considerable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial variants of ALS for which unique genetic linkage has been identified is increasing, attesting further to the biological heterogeneity of the disorder. At the cellular level, derangements in cytoskeletal protein and glutamate metabolism, mitochondrial function, and in glial interactions are clearly evident. When considered in this fashion, ALS can be justifiably considered a disorder of multiple biological processes sharing in common the degeneration of motor neurons.}, }
@article {pmid11759391, year = {2001}, author = {Sela, B}, title = {[Role of caspases in neural degeneration in amyotrophic lateral sclerosis].}, journal = {Harefuah}, volume = {140}, number = {11}, pages = {1100-4, 1115}, pmid = {11759391}, issn = {0017-7768}, mesh = {Caspase 1/metabolism ; Caspase 2 ; Caspases/*metabolism ; Humans ; Motor Neuron Disease/enzymology/*physiopathology ; Nerve Degeneration/*physiopathology ; Signal Transduction ; }, abstract = {Animal model of the motor neuron disease amyotrophic lateral sclerosis (ALS), has implicated apoptotis in the neuronal degeneration evident in this disease. Mice showing ALS-like symptoms, as well as several human families with ALS, have a missense mutation in the gene coding for DOD-1. A defective enzyme enhances neuronal cell death by activating interleukin converting enzyme (ICE), an initia of apoptosis. The role of caspase-1 and caspase-3 in the apoptotic process is apparent and the use of the caspase inhibitor zVAD-fink demonstrated some promise in slowing neural death by apoptosis and prolonging life in mice with ALS-like symptoms. We discuss the possible mechanisms of caspase enzymes cascade activation and their central role in apoptosis and possibly in neural death.}, }
@article {pmid11745983, year = {2001}, author = {Benditt, JO and Smith, TS and Tonelli, MR}, title = {Empowering the individual with ALS at the end-of-life: disease-specific advance care planning.}, journal = {Muscle &amp; nerve}, volume = {24}, number = {12}, pages = {1706-1709}, doi = {10.1002/mus.1208}, pmid = {11745983}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*therapy ; Humans ; *Living Wills ; *Patient Rights ; Power, Psychological ; United States ; }, }
@article {pmid11744509, year = {2001}, author = {Ahlbom, IC and Cardis, E and Green, A and Linet, M and Savitz, D and Swerdlow, A and , }, title = {Review of the epidemiologic literature on EMF and Health.}, journal = {Environmental health perspectives}, volume = {109 Suppl 6}, number = {Suppl 6}, pages = {911-933}, pmid = {11744509}, issn = {0091-6765}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*etiology ; Brain Neoplasms/etiology ; Breast Neoplasms/etiology ; Cardiovascular Diseases/etiology ; Child ; Child, Preschool ; Chronic Disease ; Confounding Factors, Epidemiologic ; Depression/etiology ; Electromagnetic Fields/*adverse effects ; Environmental Exposure ; Epidemiologic Studies ; Female ; Humans ; Infant ; Infant, Newborn ; Leukemia/*etiology ; Male ; Middle Aged ; Neoplasms/etiology ; *Occupational Exposure ; Pregnancy ; Reproducibility of Results ; Research Design ; Risk Assessment ; Suicide ; }, abstract = {Exposures to extremely low-frequency electric and magnetic fields (EMF) emanating from the generation, transmission, and use of electricity are a ubiquitous part of modern life. Concern about potential adverse health effects was initially brought to prominence by an epidemiologic report two decades ago from Denver on childhood cancer. We reviewed the now voluminous epidemiologic literature on EMF and risks of chronic disease and conclude the following: a) The quality of epidemiologic studies on this topic has improved over time and several of the recent studies on childhood leukemia and on cancer associated with occupational exposure are close to the limit of what can realistically be achieved in terms of size of study and methodological rigor. b) Exposure assessment is a particular difficulty of EMF epidemiology, in several respects: i) The exposure is imperceptible, ubiquitous, has multiple sources, and can vary greatly over time and short distances. ii) The exposure period of relevance is before the date at which measurements can realistically be obtained and of unknown duration and induction period. iii) The appropriate exposure metric is not known and there are no biological data from which to impute it. c) In the absence of experimental evidence and given the methodological uncertainties in the epidemiologic literature, there is no chronic disease for which an etiological relation to EMF can be regarded as established. d) There has been a large body of high quality data for childhood cancer, and also for adult leukemia and brain tumor in relation to occupational exposure. Among all the outcomes evaluated in epidemiologic studies of EMF, childhood leukemia in relation to postnatal exposures above 0.4 microT is the one for which there is most evidence of an association. The relative risk has been estimated at 2.0 (95% confidence limit: 1.27-3.13) in a large pooled analysis. This is unlikely to be due to chance but, may be, in part, due to bias. This is difficult to interpret in the absence of a known mechanism or reproducible experimental support. In the large pooled analysis only 0.8% of all children were exposed above 0.4 microT. Further studies need to be designed to test specific hypotheses such as aspects of selection bias or exposure. On the basis of epidemiologic findings, evidence shows an association of amyotrophic lateral sclerosis with occupational EMF exposure although confounding is a potential explanation. Breast cancer, cardiovascular disease, and suicide and depression remain unresolved.}, }
@article {pmid11738189, year = {2001}, author = {Eisen, A and Swash, M}, title = {Clinical neurophysiology of ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {112}, number = {12}, pages = {2190-2201}, doi = {10.1016/s1388-2457(01)00692-7}, pmid = {11738189}, issn = {1388-2457}, mesh = {Action Potentials ; Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Cell Count ; Electromyography ; Humans ; Motor Cortex/physiopathology ; Motor Neurons/pathology/physiology ; Nervous System/*physiopathology ; Neural Conduction ; Neurons, Afferent/physiology ; Respiration ; }, abstract = {The neurophysiology of amyotrophic lateral sclerosis is important not only in relation to diagnosis, but also in the development of methods to follow progress, and the effects of putative therapies, in the disease. Quantitative techniques can be applied to the measurement of reinnervation using needle electromyogram. The methodology of motor unit number estimation may be useful in measuring loss of functioning motor units in groups of patients but variability in the measurement using current methods limits its sensitivity in the evaluation of individual patients. Conventional neurophysiological measurements, expressed as a multimetric index, may be useful in assessing progress. The cortical and upper motor neuron system can be assessed using transcortical magnetic stimulation protocols, and cortical excitability may be measured by the peristimulus histogram method. In this review the advantages, limitations and promise of these various methods is discussed, in order to indicate the direction for further neurophysiological studies in this disorder.}, }
@article {pmid11732281, year = {2001}, author = {Bak, MI and Domzał-Stryga, A and Królicki, L and Kwieciński, H}, title = {[Proton MR spectroscopy studies of the brain in ALS patients].}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {61-70}, pmid = {11732281}, issn = {0028-3843}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; Aspartic Acid/metabolism ; Brain/*pathology ; Disease Progression ; Female ; Frontal Lobe/pathology ; Humans ; *Magnetic Resonance Spectroscopy ; Male ; Motor Cortex/pathology ; Protons ; Severity of Illness Index ; }, abstract = {Nuclear magnetic resonance spectroscopy (MRS) has an ability to measure brain metabolites noninvasively in vivo. The content of N-acetyl-aspartate (NAA) is used as a biochemical marker of neuronal integrity and viability. In amyotrophic lateral sclerosis (ALS) patients the degeneration and neuronal loss of motor cortex was reported. The presence of these changes can lead to the decrease of NAA. The aim of this study was to evaluate the neurochemical status of motor cortex (by using 1H-MRS) in 11 patients with clinically definite or probable forms of ALS (according to the El Escorial criteria). These data were compared with MRS results from 4 healthy controls. The mean NAA/(Cr + PCr) values were decreased by 19% (p < 0.05) when compared with controls. In 4 ALS patients the NAA/(Cr + PCr) ratio was decreased by 31% (p < 0.05) and these patients had rapidly progressing disease. In other 7 ALS patients, we found that NAA/(Cr + PCr) was decreased by 10% (p < 0.05) and they showed less advanced neurological symptoms. 1H-MRS of the motor cortex can be a new diagnostic tool in ALS and it might help to monitor the progress of the disease.}, }
@article {pmid11732280, year = {2001}, author = {Kwieciński, H}, title = {[Symptomatic treatment and palliative care of ALS].}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {51-59}, pmid = {11732280}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Pain Management ; *Palliative Care ; Positive-Pressure Respiration ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, affecting upper and lower motor neurons, which eventually progresses to respiratory deterioration and death in most of the patients. Only one drug, riluzole, has been approved for the treatment of ALS. The drug has a benefit, prolonging life by 3-6 months, but the disease progresses inexorably, with no better quality of life. The fundamental role of medicine is sometimes to cure, but always to bring comfort. In current situation, ALS patients need adequate palliative care more than anything else. Prognosis and treatment options should be discussed with the patient and the relatives, but full information about the prognosis may deprive the patient of hope. However, disclosure of the prognosis is necessary to obtain informed consent for management decisions such as tracheostomy and artificial ventilation. Nasal positive-pressure ventilation (BiPAP) is an alternative to tracheostomy, at least for some patients without advanced bulbar impairment. Nutritional status in patients who cannot swallow can be efficiently improved by a percutaneous endoscopic gastrostomy. (PEG).}, }
@article {pmid11732279, year = {2001}, author = {Münch, C and Ludolph, AC}, title = {Pharmacological treatment of ALS.}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {41-50}, pmid = {11732279}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Clinical Trials as Topic ; Humans ; Motor Neurons/pathology ; Neuroprotective Agents/*therapeutic use ; Point Mutation/genetics ; Riluzole/*therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from chronic and selective loss of motor neurons in the brain and spinal cord. In 1993, the etiology of ALS has been clarified for a small sub-group of patients with an autosomal-dominant form of this disease. About 10 percent of familial ALS patients have been associated with more than 50 mutations of the gene of the Cu/Zn superoxide dismutase (SOD1). Mutations in the SOD1 gene account for 1 percent of all ALS patients and have therefore limited epidemological and clinical relevance; however, they are of fundamental importance for the understanding of the ALS pathogenesis, and the development of neuroprotective strategies. In two double-blind and placebo-controlled studies the membrane stabilisator riluzole has been shown to be the first neuroprotective compound with a significant effect on survival of ALS patients. The neuroprotective approach reduced therapeutic nihilism in ALS and is a first step in the treatment of this devastating disease.}, }
@article {pmid11732278, year = {2001}, author = {Silani, V and Braga, M and Cardin, V and Scarlato, G}, title = {The pathogenesis of ALS: implications for treatment strategies.}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {25-39}, pmid = {11732278}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*physiopathology ; Clinical Trials as Topic ; Glutamic Acid/metabolism ; Humans ; Neurotoxins/metabolism ; }, abstract = {Besides the free radical hypothesis raised by the identification of Superoxide Dismutase I mutations in a subset of familiar Amyotrophic Lateral Sclerosis (ALS) patients, three etiopathogenic hypotheses for sporadic ALS, namely autoimmune, neurofilament, and glutamate toxicity, have attracted interest in the last few years. The role of autoimmunity in ALS has been seriously questioned. The excitotoxic hypothesis for ALS spurred two clinical trials with riluzole. The results of both studies showed a modest benefit in prolonging survival that was statistically significant. Riluzole was the first drug made available for ALS patients. It began a new era in both basic and clinical research. Various human recombinant neurotrophic molecules (CNTF, BDNF, IGF-I) were administered to ALS patients. IGF-I slowed the progression of functional impairment in patients with ALS with no adverse effects. The recent demonstration of the specific viral echovirus 7 RNA sequences in the spinal cord of ALS patients refocused research on the viral hypothesis of the disease and antiviral drugs are ready to be used in clinical settings. New treatment strategies are today under study: intrathecal infusion with BDNF, intrathecal capsules for neurotrophic factor secretion or in vivo gene therapy using viral vectors. New research findings are, more than for other diseases, immediately transferred to clinical ground for the desperate need of a curative treatment of the patients affected by ALS.}, }
@article {pmid11732276, year = {2001}, author = {Domitrz, I and Jedrzejowska, M and Lipowska, M and Siddique, T and Kwieciński, H}, title = {[Kennedy's disease: expansion of the CAG trinucleotide].}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {107-114}, pmid = {11732276}, issn = {0028-3843}, mesh = {Humans ; Motor Neurons/pathology ; Muscular Atrophy, Spinal/*genetics ; Point Mutation/genetics ; Trinucleotide Repeat Expansion/*genetics ; X Chromosome/genetics ; }, abstract = {Kennedy's disease is a rare X-linked spinal and bulbar muscular atrophy (SBMA). A degenerative process of the motor neurons is associated with an increase in the number of CAG repeats encoding a polyglutamine stretch within the androgen receptor. Despite a distinctive clinical phenotype, SBMA can be misdiagnosed, usually due to the lack of clear family history. Accurate diagnosis is important for genetic counseling and because alternative diagnosis of amyotrophic lateral sclerosis usually means much worse prognosis. We report 2 unrelated patients with Kennedy's disease in whom the clinical diagnosis was confirmed by showing the CAG repeat expansion.}, }
@article {pmid11732268, year = {2001}, author = {Iłzecka, J}, title = {[Superoxide dismutase-1 (SOD-1) gene mutation-dependent mechanisms of neural degeneration in amyotrophic lateral sclerosis].}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {3}, pages = {461-469}, pmid = {11732268}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/pathology ; Excitatory Amino Acid Transporter 2/genetics/metabolism ; Glutamic Acid/genetics/metabolism ; Humans ; Motor Neurons/pathology ; Nerve Degeneration/*genetics/pathology ; Point Mutation/*genetics ; RNA, Messenger/genetics ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving motor neuron degeneration, occurring in sporadic and familial forms. Mutations in Cu/Zn superoxide dismutase gene (SOD-1) play a key role in the pathogenesis of the familial form in which it is present in about 20%. The mechanisms by which the mutated enzyme produces the disease are not sufficiently know. The following hypothesis are considered: oxidative damage, disorganization of neurofilaments, toxic action of intracellular aggregates, disturbed mechanisms of protein synthesis or degradation, and increased glutamic acid toxicity due to damage of EAAT 2 mRNA, transporter of this acid. It is supposed that motor neuron death is due to various mechanisms caused by SOD-1 enzyme mutations. Pathological changes suggest that biochemical processes leading to neurodegeneration in familial ALS form related or unrelated to SOD-1 mutation, and in sporadic form may be very similar.}, }
@article {pmid11724913, year = {2001}, author = {Cluskey, S and Ramsden, DB}, title = {Mechanisms of neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Molecular pathology : MP}, volume = {54}, number = {6}, pages = {386-392}, pmid = {11724913}, issn = {1366-8714}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Animals ; Copper/metabolism ; Cytoplasm/metabolism ; Glutamic Acid/metabolism ; Humans ; Mice ; Mice, Transgenic ; Middle Aged ; Mitochondria/metabolism ; Models, Animal ; Mutation ; *Nerve Degeneration ; Neurofilament Proteins/metabolism ; Neurons/metabolism ; Oxidative Stress ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common variant of motor neurone disease affecting adults that usually strikes during mid to late life. Its aetiology is still poorly understood, although a major breakthrough came with the discovery that mutations in the Cu/Zn superoxide dismutase (SOD1) gene affect approximately 20% of patients with familial ALS. Experiments using both transgenic mice and ALS tissues have been useful in delineating other genetic defects in ALS. However, because only a subset of cases can be attributed to one particular molecular defect (such as mutation of SOD1 or the gene encoding neurofilament H), the aetiology of ALS is likely to be multifactorial. This review discusses the major mechanisms of neurodegeneration in ALS, such as oxidative stress, glutaminergic excitotoxicity, damage to vital organelles, and aberrant protein aggregation.}, }
@article {pmid11719252, year = {2001}, author = {Gallo, JM}, title = {Kennedy's disease: a triplet repeat disorder or a motor neuron disease?.}, journal = {Brain research bulletin}, volume = {56}, number = {3-4}, pages = {209-214}, doi = {10.1016/s0361-9230(01)00575-5}, pmid = {11719252}, issn = {0361-9230}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; Muscular Atrophy, Spinal/*classification/*genetics ; Neurofilament Proteins/genetics ; Peptides/genetics ; Receptors, Androgen/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tubulin/genetics ; }, abstract = {Two definite genetic causes of adult motor neuron degeneration have been identified to date: CAG repeat expansion in the androgen receptor gene in Kennedy's disease and point mutations in the SOD1 gene, encoding the enzyme, Cu/Zn superoxide dismutase, in some familial forms of amyotrophic lateral sclerosis. Although both have unrelated genetic causes, Kennedy's disease and SOD1-linked amyotrophic lateral sclerosis share several pathogenic features. First, expanded androgen receptor and mutant Cu/Zn superoxide dismutase have a propensity to aggregate into insoluble complexes and form inclusion bodies in affected neurons. Deposits of mutant proteins could be detrimental to neuronal viability by interfering with the normal housekeeping functions of chaperones and of the ubiquitin/proteasome system. Secondly, cytoskeletal function may be impaired in both diseases as decreased transactivational activity of expanded androgen receptor may cause an abnormal pattern of tubulin expression in motor neurons in Kennedy's disease and disruption of neurofilament organisation is a hallmark of amyotrophic lateral sclerosis. The concept of activation of overlapping cell death cascades by two distinct genetic defects could help elucidating downstream pathogenic processes and may provide novel targets for pharmacological intervention or gene therapy for the treatment of motor neuron disorders.}, }
@article {pmid11719130, year = {2001}, author = {Kloeck, WG}, title = {The 9 ALS triads--an alphabetical checklist for advanced life support providers.}, journal = {Resuscitation}, volume = {50}, number = {1}, pages = {57-60}, doi = {10.1016/s0300-9572(00)00368-3}, pmid = {11719130}, issn = {0300-9572}, mesh = {Humans ; Life Support Care/*instrumentation ; Resuscitation/*education/*instrumentation ; Teaching/methods ; *Teaching Materials ; }, abstract = {The successful outcome of a resuscitation attempt relies frequently on the performance of many advanced life support interventions. A checklist of 27 procedures, following an alphabetical sequence, is presented as an educational memory aid for healthcare providers.}, }
@article {pmid11715057, year = {2001}, author = {Cleveland, DW and Rothstein, JD}, title = {From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS.}, journal = {Nature reviews. Neuroscience}, volume = {2}, number = {11}, pages = {806-819}, doi = {10.1038/35097565}, pmid = {11715057}, issn = {1471-003X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology/therapy ; Animals ; Astrocytes/physiology ; Caspase 3 ; Caspases/metabolism ; Cell Death ; Copper/metabolism ; Endothelial Growth Factors/genetics/metabolism ; Humans ; Lymphokines/genetics/metabolism ; Models, Molecular ; Models, Neurological ; Motor Neurons/*physiology ; Neurofilament Proteins/genetics/metabolism ; Oxidation-Reduction ; Protein Structure, Tertiary ; Superoxide Dismutase/chemistry/*genetics/metabolism ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; Zinc/metabolism ; }, }
@article {pmid11699892, year = {2001}, author = {Martin-Rendon, E and Azzouz, M and Mazarakis, ND}, title = {Lentiviral vectors for the treatment of neurodegenerative diseases.}, journal = {Current opinion in molecular therapeutics}, volume = {3}, number = {5}, pages = {476-481}, pmid = {11699892}, issn = {1464-8431}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Genetic Therapy/adverse effects/*methods/trends ; *Genetic Vectors ; Humans ; Huntington Disease/therapy ; Lentivirus/*genetics ; Nervous System/metabolism ; Neurodegenerative Diseases/*therapy ; Parkinsonian Disorders/therapy ; Safety ; }, abstract = {A number of potential gene therapy applications in the adult nervous system include neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. During the last five years, lentiviral vectors have developed into extremely efficient gene transfer vehicles to the nervous system, revealing a wide range of possibilities for the treatment or such disorders. This review describes the most important and recent advances in the development of lentiviral vectors as well as the demonstration of proof-of-principle in animal models of human neurodegenerative diseases.}, }
@article {pmid11694248, year = {2001}, author = {Leung, KC and Ho, KK}, title = {Measurement of growth hormone, insulin-like growth factor I and their binding proteins: the clinical aspects.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {313}, number = {1-2}, pages = {119-123}, doi = {10.1016/s0009-8981(01)00662-3}, pmid = {11694248}, issn = {0009-8981}, mesh = {Adult ; Growth Hormone/*blood/deficiency ; Humans ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor I/*metabolism ; }, abstract = {BACKGROUND: Growth hormone (GH) secreted from the pituitary stimulates the production of insulin-like growth factor I (IGF-I) from the liver and extrahepatic tissues, which in turn regulates tissue proliferation and differentiation in an endocrine or autocrine/paracrine manner. Both GH and IGF-I circulates as complexes with specific binding proteins. The GH binding protein (GHBP) corresponds to the extracellular, ligand-binding domain of the GH receptors in tissues and its serum concentration may reflect the status of the tissue receptors. Most serum IGF-I associates with IGF binding protein 3 (IGFBP-3) and another protein, the acid labile subunit (ALS). Like IGF-I, serum concentrations of IGFBP-3 and ALS are tightly regulated by GH. GH secretion (both spontaneous and stimulated), IGF-I, IGFBP-3, and ALS have been assessed as potential biochemical markers for diagnosis of GH-related disorders.<br><br>CONCLUSIONS: In acromegaly, IGF-I is the most reliable marker. The peak GH response to insulin tolerance test is the diagnostic test of choice, GH deficiency. GHBP has no diagnostic value in acromegaly or GH deficiency. However, it may be a potential biochemical marker for GH insensitivity syndrome as serum GHBP concentrations are undetectable or reduced in >75% of these patients. Other biochemical tests may also prove to be useful in these disorders, but require further validation.}, }
@article {pmid11687124, year = {2001}, author = {Symington, A and Pinelli, J}, title = {Developmental care for promoting development and preventing morbidity in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD001814}, doi = {10.1002/14651858.CD001814}, pmid = {11687124}, issn = {1469-493X}, mesh = {Developmental Disabilities/*prevention &amp; control ; Humans ; Infant, Newborn ; *Infant, Premature ; Length of Stay ; Randomized Controlled Trials as Topic ; Respiration, Artificial ; Stress, Physiological/prevention &amp; control ; Treatment Outcome ; Weight Gain ; }, abstract = {BACKGROUND: Preterm infants experience a range of morbidity related to the immaturity of their organ systems and to concurrent disease states. An unfavourable environment in the neonatal intensive care unit (NICU) may compound this morbidity. Modification of the environment could minimize the iatrogenic effects. Developmental care is a broad category of interventions designed to minimize the stress of the NICU environment. These interventions may include one or more elements such as control of external stimuli (vestibular, auditory, visual, tactile), clustering of nursery care activities, and positioning or swaddling of the preterm infant. Individual strategies have also been combined to form programs, such as the 'Neonatal Individualized Developmental Care and Assessment Program' (NIDCAP) (Als 1986).<br><br>OBJECTIVES: In preterm infants, do developmental care interventions reduce neurodevelopmental delay, poor weight gain, length of hospital stay, length of mechanical ventilation, physiological stress and other clinically relevant adverse outcomes?<br><br>SEARCH STRATEGY: The Neonatal Review Group search strategy was utilized. Searches were made of Medline from 1966 to July, 2000, and of CINAHL, The Cochrane Library, and conference and symposia proceedings in the English language from 1990 to July, 2000. A list of all relevant articles was sent to two experts in the field to identify any omissions or additional unpublished studies.<br><br>SELECTION CRITERIA: Randomized trials in which elements of developmental care are compared to routine nursery care for infants < 37 weeks gestation and that measured clinically relevant outcomes. Reports were in English or a language for which a translator was available. Computerized searches were conducted and all potentially relevant titles and abstracts were extracted. Retrieved articles were assessed for relevance independently by two reviewers, based on predetermined criteria. Articles that met all criteria for relevance were assessed for methodological quality based on predetermined criteria. Articles judged to have the appropriate quality by both reviewers were included in the analysis.<br><br>DATA COLLECTION AND ANALYSIS: Data were extracted independently by the two authors. Meta-analyses were conducted for each intervention where the same outcome measures and/or instruments were used within comparable time points.<br><br>MAIN RESULTS: This review detected 31 eligible randomized controlled trials involving four major groups of developmental care interventions, 19 sub-groups and multiple clinical outcomes. The results of the review indicate that developmental care interventions demonstrate some benefit to preterm infants with respect to: improved short-term growth outcomes, decreased respiratory support, decreased length and cost of hospital stay, and improved neurodevelopmental outcomes to 24 months corrected age. These findings were based on two or three small trials for each outcome, and did not involve meta-analyses of more than two trials for any one outcome. Although a number of other benefits were demonstrated, those results were from single studies with small sample sizes. The lack of blinding of the assessors was a significant methodological flaw in half of the studies. The cost of the interventions and personnel was not considered in any of the studies.<br><br>REVIEWER'S CONCLUSIONS: Because of the inclusion of multiple interventions in most studies, the determination of the effect of any single intervention is difficult. Although there is evidence of some benefit of developmental care interventions overall, and no major harmful effects reported, there were a large number of outcomes for which no or conflicting effects were demonstrated. The single trials that did show a significant effect of an intervention on a major clinical outcome were based on small sample sizes, and the findings were often not supported in other small trials. Before a clear direction for practice can be supported, evidence demonstrating more consistent effects of developmental care interventions on important short- and long-term clinical outcomes is needed. The economic impact of the implementation and maintenance of developmental care practices should be considered by individual institutions.}, }
@article {pmid11687111, year = {2001}, author = {Miller, RG and Mitchell, JD and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD001447}, doi = {10.1002/14651858.CD001447}, pmid = {11687111}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis (ALS) in some countries but not others. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials and other experts in the field. The most recent search was conducted in June 1999.<br><br>SELECTION CRITERIA: Types of studies: randomized trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of ALS Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: per cent mortality at 12 months with riluzole 100 mg Secondary: per cent mortality as a function of time with 100 mg and with all doses of riluzole, scales of neurologic function, quality of life, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by the other two. We obtained some missing data from investigators. We performed meta-analyses with RevMan software using a fixed effects model.<br><br>MAIN RESULTS: The two eligible trials included a total of 794 riluzole treated patients and 320 placebo treated patients. The methodological quality was acceptable and the trials were easily comparable. There were significant differences between the riluzole and placebo groups of both trials, in terms of the primary outcome measure, which was per cent mortality at 12 months with the 100 mg dose of riluzole. The odds ratio for the combined studies was 0.57 (95%CI 0.41 to 0.80) at 12 months. In the secondary outcome measures, there was a survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. Pooled data from the 50, 100 and 200mg dose groups in the larger trial showed a lower per cent mortality with riluzole compared to placebo only at 12 months (odds ratio (OR) 0.64, 95% CI 0.47 to 0.88). There was no beneficial effect on bulbar function, or muscle strength. There were scant data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference (WMD) 35.5 days, 95% CI 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (WMD 2.65, 95% CI 1.51 to 4.65).<br><br>REVIEWER'S CONCLUSIONS: Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with ALS.}, }
@article {pmid17974446, year = {1995}, author = {Alcaz, S and Apostolski, S}, title = {[Frontal lobe dysfunction in ALS].}, journal = {Srpski arhiv za celokupno lekarstvo}, volume = {123}, number = {9-10}, pages = {266-270}, pmid = {17974446}, issn = {0370-8179}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Dementia/*complications ; Frontal Lobe/*physiopathology ; Humans ; }, abstract = {We present the facts on kind and frequency of disorder of high cortical functions in amyotrophic lateral sclerosis. It was considered for a long time that this disease affects selectively motor neurons. The signs of degeneration found in other structures and associated signs of other neurological disorders brought the diagnosis of amyotrophic lateral sclerosis under suspicion. However, the specific type of degenerative dementia is nowadays more frequently discovered in patients with amyotrophic lateral sclerosis. The nosological status of motor neuron disease with dementia is still controversial. There is a possibility of a new clinical entity or a variant of motor neuron disease. Taking into account the fact that pathological changes of motor neurons and the natural history of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis with dementia are not essentially different, as well as the fact that frontal dysfunction is detected in non-demented patients with amyotrophic lateral sclerosis, the authors consider that we are facing a variant of well-known disease of motor neuron.}, }
@article {pmid11980064, year = {1991}, author = {Siddique, T and Hu, P and Hentati, A and Deng, G and Hung, WY and McInnis, MG and Warren, AC and Rimmler, J and Antonarakis, S and Pericak-Vance, MA}, title = {A molecular genetic approach to amyotrophic lateral sclerosis.}, journal = {International journal of neurology}, volume = {25-26}, number = {}, pages = {60-69}, pmid = {11980064}, issn = {0020-7446}, mesh = {Amyotrophic Lateral Sclerosis/classification/*genetics/physiopathology ; Animals ; Genetic Linkage/genetics ; Humans ; }, abstract = {Disorders of the motor neurons may affect both the upper and lower neurons, primarily the lower motor neurons as in the spinal muscular atrophies are primarily the upper motor neurons as in the familial spastic paraplegias. Amyotrophic lateral sclerosis is a degenerative disorder of the motor neuron that results in paralysis and wasting of voluntary muscles. Large motor neurons in the cerebral cortex, brain stem and spinal cord degenerate or are lost. Hyaline inclusions may be seen in the cytoplasm of surviving motor neurons. Acute axonal degeneration of peripheral motor fibers occurs at all levels, including the distal axon. Subclinical involvement of the spinecerebellar tracts, posterior column and Clarke's column as well as loss of large neurons in the dorsal root ganglia and neurons of oculomotor nuclei has been reported. The average duration of life onset of symptoms of amyotrophic lateral sclerosis is three years and ninety per cent of patients died within 5 years. The basic mechanism of disease in amyotrophic lateral sclerosis remains unknown. There is no known treatment that will prevent, reverse or otherwise alter the course of the disease. Autosomal dominant and autosomal recessive forms of amyotrophic lateral sclerosis are genetic models of amyotrophic lateral sclerosis which may provide insight into the disease mechanism of sporadic amyotrophic lateral sclerosis, five to ten percent of adult cases of amyotrophic lateral sclerosis with early onset of symptoms and a more benign course. It is conceivable that both genetic and sporadic forms of amyotrophic lateral sclerosis result from failure of the same or similar neuronal mechanism triggered by defective genes and by an environment agent in sporadic amyotrophic lateral sclerosis.}, }
@article {pmid14242031, year = {1965}, author = {BRODY, JA and HADLOW, WJ and HOTCHIN, J and JOHNSON, RT and KOPROWSKI, H and KURLAND, LT}, title = {SOVIET SEARCH FOR VIRUSES THAT CAUSE CHRONIC NEUROLOGIC DISEASES IN THE U.S.S.R.}, journal = {Science (New York, N.Y.)}, volume = {147}, number = {3662}, pages = {1114-1116}, doi = {10.1126/science.147.3662.1114}, pmid = {14242031}, issn = {0036-8075}, mesh = {*Amyotrophic Lateral Sclerosis ; *Encephalitis ; *Encephalitis, Arbovirus ; *Epidemiology ; Humans ; *Multiple Sclerosis ; *Nervous System Diseases ; USSR ; *Virus Diseases ; *Viruses ; }, }
@article {pmid14186560, year = {1964}, author = {HABERLANDT, WF}, title = {[RECENT RESULTS OF MEDICAL GENETICS, ESPECIALLY IN THE NEUROPSYCHIATRIC SECTOR].}, journal = {Wiener klinische Wochenschrift}, volume = {76}, number = {}, pages = {165-170}, pmid = {14186560}, issn = {0043-5325}, mesh = {*Amyotrophic Lateral Sclerosis ; *Ataxia ; *Bulbar Palsy, Progressive ; *Cerebellar Diseases ; *Chromosome Aberrations ; *Down Syndrome ; *Genetics, Medical ; Humans ; *Mental Disorders ; *Nervous System Diseases ; *Phenylketonurias ; *Trisomy ; }, }
@article {pmid14066107, year = {1963}, author = {WISE, RP}, title = {MUSCLE DISORDERS AND THE RELAXANTS.}, journal = {British journal of anaesthesia}, volume = {35}, number = {}, pages = {558-564}, doi = {10.1093/bja/35.9.558}, pmid = {14066107}, issn = {0007-0912}, mesh = {*Amyotrophic Lateral Sclerosis ; *Bronchial Neoplasms ; *Collagen Diseases ; Humans ; *Hyperthyroidism ; *Muscle Relaxants, Central ; *Muscular Diseases ; *Muscular Dystrophies ; *Myasthenia Gravis ; *Myotonic Dystrophy ; *Paralyses, Familial Periodic ; *Porphyrias ; *Preanesthetic Medication ; }, }
@article {pmid14146307, year = {1963}, author = {BOSHES, B and BRUMLIK, J and BLONSKY, E}, title = {CLINICAL NEUROLOGY.}, journal = {Progress in neurology and psychiatry}, volume = {18}, number = {}, pages = {167-223}, pmid = {14146307}, issn = {0079-6506}, mesh = {*Amyotrophic Lateral Sclerosis ; *Behcet Syndrome ; *Brain Neoplasms ; *Collagen Diseases ; *Cranial Nerves ; *Extrapyramidal Tracts ; *Genetics, Medical ; *Headache ; Humans ; *Leprosy ; *Lupus Erythematosus, Systemic ; *Multiple Sclerosis ; *Muscular Diseases ; *Myocardial Infarction ; *Neoplasms ; *Neuralgia ; *Neurology ; *Parasitic Diseases ; *Sarcoidosis ; *Spinal Cord Neoplasms ; *Toxicology ; *Tuberculoma ; *Vascular Diseases ; *Virus Diseases ; }, }
@article {pmid14123706, year = {1963}, author = {ZANOLI, R and ROMAGNOLI, C and TRABUCCHI, L}, title = {[THE CERVICAL SPINAL CORD AND SPONDYLOARTHROSIS].}, journal = {La Chirurgia degli organi di movimento}, volume = {52}, number = {}, pages = {93-145}, pmid = {14123706}, issn = {0009-4749}, mesh = {*Amyotrophic Lateral Sclerosis ; *Cervical Cord ; *Cervical Vertebrae ; Humans ; *Hypoxia ; *Intervertebral Disc Displacement ; *Multiple Sclerosis ; *Neurologic Manifestations ; *Pathology ; *Spinal Cord ; *Spinal Cord Compression ; *Spinal Cord Injuries ; *Spinal Diseases ; }, }
@article {pmid11687039, year = {2001}, author = {Ducharme, F}, title = {Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD003133}, doi = {10.1002/14651858.CD003133}, pmid = {11687039}, issn = {1469-493X}, mesh = {Administration, Inhalation ; Adolescent ; Adult ; Anti-Asthmatic Agents/*therapeutic use ; Anti-Inflammatory Agents/*therapeutic use ; Asthma/*drug therapy ; Child ; Child, Preschool ; Chronic Disease ; Drug Therapy, Combination ; Humans ; Leukotriene Antagonists/*therapeutic use ; Steroids ; }, abstract = {BACKGROUND: Anti-leukotriene (AL) agents are being considered as "add-on" therapy to inhaled corticosteroids (ICS), in chronic asthma.<br><br>OBJECTIVES: To examine the safety and efficacy of daily AL plus ICS compared to ICS alone, and determine the corticosteroid-sparing effect of AL when added to ICS in chronic asthma.<br><br>SEARCH STRATEGY: We searched Medline, Embase, Cinahl (all up to 2001), reference lists of review articles and trials, contacted international headquarters of AL manufacturers and ATS meeting abstracts (1998-2000).<br><br>SELECTION CRITERIA: Randomised placebo-controlled trials of asthmatics aged 2 years and older lasting at least one month.<br><br>DATA COLLECTION AND ANALYSIS: Two reviewers assessed quality and extracted data independently. Trials were grouped by asthma control at baseline (symptomatic or well-controlled) and dose of ICS in the control group (same or double).<br><br>MAIN RESULTS: Of 336 citations, 11 trials (only adults) met inclusion criteria. Six were published in full-text, eight were high quality. Daily dose of ICS was 300-2000 mcg beclomethasone-equivalent. In symptomatic adults, AL (at 2-4 times licensed dose) combined with ICS reduced the number of patients with exacerbations that required systemic corticosteroids, compared to ICS alone [Relative Risk (RR) = 0.34; 95% Confidence Interval (CI) 0.13, 0.88]. This equates to 20 patients (95% CI 1,100 patients) treated to prevent one needing systemic corticosteroids. There was no difference in side effects. No trials tested the efficacy of licensed doses of ALs as add-on to ICS. In symptomatic adults, addition of zafirlukast to ICS did not reduce the number of exacerbations requiring systemic corticosteroids, compared to doubled dose ICS [RR= 1.39; 95% CI: 0.63, 3.08)]. There were no differences in any other measure of outcome. Higher doses of zafirlukast than currently licensed were associated with increased risk of liver enzyme elevation. In ICS-sparing trials of AL agents there was no difference in ICS dose after 12-16 weeks [Weighted Mean Difference (WMD) 1.9% change; 95% CI -3.5, 7.3], and no difference in lowest tolerated dose of ICS [WMD= 44 mcg/d; 95% CI -59, 148)].<br><br>REVIEWER'S CONCLUSIONS: Used as add-on therapy to inhaled corticosteroids, high dose anti-leukotrienes reduced exacerbations, but there is no evidence to support their use at currently licensed doses. There is insufficient evidence to indicate whether they confer benefit over doubling the dose of corticosteroids. There is no evidence that they have any significant inhaled corticosteroid-sparing effect.}, }
@article {pmid11686950, year = {2001}, author = {Henderson-Smart, DJ and Bhuta, T and Cools, F and Offringa, M}, title = {Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD000104}, doi = {10.1002/14651858.CD000104}, pmid = {11686950}, issn = {1469-493X}, mesh = {Chronic Disease ; *High-Frequency Ventilation ; Humans ; Infant, Newborn ; Infant, Premature ; *Intermittent Positive-Pressure Ventilation ; Lung Diseases/*prevention &amp; control ; Randomized Controlled Trials as Topic ; Respiratory Distress Syndrome, Newborn/therapy ; }, abstract = {BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies.<br><br>OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects.<br><br>SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language.<br><br>SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life.<br><br>DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. 95% confidence intervals were used.<br><br>MAIN RESULTS: Meta-analysis of the eight eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and a significant reduction in CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group (six trials, summary RR 0.73 (0.57, 0.93). There is a significant increase in severe (grades 3 &amp; 4) intraventricular hemorrhage (IVH) and in any pulmonary air leak syndrome [summary RR 1.19 (1.03, 1.38)] in the HFOV group. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of six trials where a high volume strategy (HVS) was used for HFOV, this is associated with significantly lower rates of CLD in survivors at 28-30 days [three trials, summary RR 0.53 (0.36, 0.76)], of 'death or CLD at 28-30 days' [three trials, summary RR 0.56 (0.40, 0.77) and oxygen use at 36-37 weeks postmenstrual age or discharge [five trials, summary RR 0.72 (0.56, 0.93)]. There were no overall differences in the rates of IVH or PVL. One trial suggests that HFOV may reduce the cost of in-hospital care. In this group of trials HFOV is associated with a strong trend for an increased rate of gross pulmonary ALS (four trials, summary RR 1.54 (0.98, 2.42)] In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of periventricular leukomalacia (PVL) [summary RR 1.64 (1.02, 2.64).<br><br>REVIEWER'S CONCLUSIONS: Benefits of HFOV in terms of CLD appear to be outweighed by concerns about increased rates of pulmonary air leak and severe IVH. Until these issues are resolved HFOV cannot be recommended as the routine method of giving mechanical ventilation to preterm infants with RDS. Future trials should target very preterm infants who are at most risk of CLD and infants should be randomized in gestational age strata. Important long term pulmonary and neurodevelopmental outcomes should be measured and reported. Economic effects should be assessed.}, }
@article {pmid11684886, year = {2001}, author = {Strasburger, CJ and Bidlingmaier, M and Wu, Z and Morrison, KM}, title = {Normal values of insulin-like growth factor I and their clinical utility in adults.}, journal = {Hormone research}, volume = {55 Suppl 2}, number = {}, pages = {100-105}, doi = {10.1159/000063484}, pmid = {11684886}, issn = {0301-0163}, mesh = {Acromegaly/blood/diagnosis/drug therapy ; Adult ; Endocrinology/*methods ; Growth Hormone/adverse effects/therapeutic use ; Human Growth Hormone/deficiency ; Humans ; Insulin-Like Growth Factor I/*analysis ; Reference Values ; Safety ; }, abstract = {The concentration of circulating insulin-like growth factor I (IGF-I) is a potential marker for growth hormone (GH) deficiency in adults. Indeed, researchers have shown that IGF-I levels are of greater diagnostic value than other possible markers, such as IGF-binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS). Accurate age-matched normative data are essential to give patient data diagnostic meaning. Such data are assay specific and must exclude those individuals with certain confounding medical conditions. Post-diagnosis, monitoring of IGF-I and IGFBP-3 levels can be used to assess the efficacy and safety of GH replacement therapy. Furthermore, IGF-I levels, and possibly ALS levels, can be used to aid the diagnosis and monitoring of acromegaly. For example, acromegaly can be excluded in patients with normal IGF-I levels if liver failure and malnutrition/malabsorption are ruled out.}, }
@article {pmid11684881, year = {2001}, author = {Baxter, RC}, title = {Inhibition of the insulin-like growth factor (IGF)-IGF-binding protein interaction.}, journal = {Hormone research}, volume = {55 Suppl 2}, number = {}, pages = {68-72}, doi = {10.1159/000063479}, pmid = {11684881}, issn = {0301-0163}, mesh = {Animals ; Humans ; Insulin-Like Growth Factor Binding Proteins/antagonists &amp; inhibitors/*metabolism ; Kinetics ; Somatomedins/antagonists &amp; inhibitors/*metabolism ; }, abstract = {A family of six insulin-like growth factor (IGF) binding proteins transport IGFs in the circulation and regulate their extravascular distribution. The acid-labile subunit (ALS) combines with IGF-binding protein (IGFBP)-3 or IGFBP-5 to form abundant and stable heterotrimeric IGF-transporting complexes which are confined to the circulation. The factors that determine ALS dissociation, and regulate IGF and IGFBP passage out of the circulation, are poorly understood. Binary IGF-IGFBP complexes have high affinities and slow dissociation rates, which may be accelerated by partial IGFBP proteolysis and interaction with glycosaminoglycans. IGFBPs can interfere in IGF analyses, so removal of IGFBPs, and minimization of their influence in IGF assays, is essential to ensure valid quantification of IGFs.}, }
@article {pmid11684877, year = {2001}, author = {Monson, JP}, title = {Biochemical markers of individual response to growth hormone replacement in adults.}, journal = {Hormone research}, volume = {55 Suppl 2}, number = {}, pages = {49-54}, doi = {10.1159/000063475}, pmid = {11684877}, issn = {0301-0163}, mesh = {*Biomarkers ; Growth Hormone/administration &amp; dosage/adverse effects/*therapeutic use ; *Hormone Replacement Therapy ; Humans ; Outcome Assessment, Health Care/*methods ; }, abstract = {Options for determining the response to growth hormone (GH) replacement in adults include symptomatic response, changes in body composition and measurement of biochemical markers of GH action. It has become apparent from various studies and during routine clinical practice that abnormal elevation of serum markers of GH action during GH therapy may not be associated with either adverse symptoms or abnormalities in body composition, thereby limiting the value of subjective assessment and physical characteristics as safety markers of over-treatment. Candidate biochemical markers include insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS), and markers of bone remodelling. No single measurement provides an ideal index of adequacy of GH replacement. Serum IGF-I has the greatest utility during GH dose titration as it is more sensitive to changes in GH status than IGFBP-3 and ALS, and is also more sensitive to excessive GH replacement. IGF-I, therefore, provides an important safety marker. Furthermore, changes in IGF-I correlate with improvements in body composition. Changes in circulating insulin and leptin occur during GH therapy, but are significantly influenced by changes in body fat and its distribution and do not provide useful information upon which to gauge responsiveness to GH. Markers of bone remodelling are an important indicator of GH action within individuals, but exhibit wide inter-individual variation which limits their usefulness in defining relative GH responsiveness.}, }
@article {pmid11679167, year = {2001}, author = {Costa, V and Moradas-Ferreira, P}, title = {Oxidative stress and signal transduction in Saccharomyces cerevisiae: insights into ageing, apoptosis and diseases.}, journal = {Molecular aspects of medicine}, volume = {22}, number = {4-5}, pages = {217-246}, doi = {10.1016/s0098-2997(01)00012-7}, pmid = {11679167}, issn = {0098-2997}, mesh = {Aging/*metabolism ; Animals ; *Apoptosis ; Disease ; Humans ; *Oxidative Stress ; Saccharomyces cerevisiae/*metabolism/physiology ; *Signal Transduction ; }, abstract = {In yeast, as in higher eukaryotes, reactive oxygen species are produced as normal by-products of cellular metabolism. Under physiological conditions, the cell defence mechanisms are able to avoid molecular damages. This balance is disturbed when yeast cells are exposed to diverse environmental stress conditions, such as the presence of oxidants, heat shock, ethanol and metal ions. The increased production of reactive oxygen species is sensed by the cell, leading to the induction of defence mechanisms - the oxidative stress response. The present review discusses the mechanisms by which reactive oxygen species are sensed and the signalling pathways that are coupled with changes in genomic expression programs. Yeast has been used as an eukaryotic cell system to characterise the molecular mechanisms underlying the oxidative stress response. Furthermore, yeast has been utilised to elucidate the role of oxidative stress in ageing, apoptosis, and diseases, such as familial amyotrophic lateral sclerosis and Friedreich's ataxia.}, }
@article {pmid11676990, year = {2001}, author = {Karitzky, J and Ludolph, AC}, title = {Imaging and neurochemical markers for diagnosis and disease progression in ALS.}, journal = {Journal of the neurological sciences}, volume = {191}, number = {1-2}, pages = {35-41}, doi = {10.1016/s0022-510x(01)00628-1}, pmid = {11676990}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/metabolism ; Biomarkers/analysis ; *Diagnostic Imaging/methods ; Disease Progression ; Genetic Testing ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Male ; Middle Aged ; Sensitivity and Specificity ; Tomography, Emission-Computed ; }, abstract = {Based on the development of a transgenic animal model, an increasing number of experimental strategies have revealed the potential to modify the selective degeneration of motor neurons, a feature unique to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The translation of this success into therapeutic effects in human diseases is a challenge of the future. For this purpose, tools must be developed which serve as diagnostic and surrogate markers for diagnosis and disease progression. Currently, to understand the pathogenesis of the spinal cord disease, the focus remains on more traditional electrodiagnostic techniques. For the characterization of the involvement of brain structures, imaging techniques are increasingly explored. This review focuses on the use of imaging techniques as surrogate markers for the involvement of the brain in motor neuron disorders, but also tries to point out that the final goal will be the development of cheap biochemical markers for the screening of populations at risk.}, }
@article {pmid11675875, year = {2001}, author = {Urushitani, M and Shimohama, S}, title = {The role of nitric oxide in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {2}, pages = {71-81}, doi = {10.1080/146608201316949415}, pmid = {11675875}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Cell Death ; Free Radical Scavengers/metabolism ; Humans ; Motor Neurons/physiology ; Neuroprotective Agents/metabolism ; Nitric Oxide/*metabolism ; Signal Transduction/physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuronal death. The cause of ALS is unclear, but accumulating evidence, such as the insufficient clearance of glutamate through the glutamate transporter, and the specific distribution of Ca2+-permeable AMPA receptors in spinal motor neurons, indicates that glutamate-induced neurotoxicity is involved in its pathogenesis. Interestingly, nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor (EDRF), was found to be a pivotal inducer of glutamate-induced neuronal death. NO is generated by nitric oxide synthase (NOS), of which there are three subtypes: neuronal NOS expressed mainly in neurons, inducible NOS in astroglia, and endothelial NOS in vessels. NO-related toxicity is caused by peroxynitrite, formed by the reaction of NO with superoxide anions, resulting in the nitration of tyrosine residues in neurofilaments, irreversible inhibition of the mitochondrial respiratory chain, and inhibition of the glutamate transporter. Clinically, the axonal spheroids of motor neurons are reported to be immunoreactive to anti-nitrotyrosine antibody, and there are elevated levels of the metabolites of NO in the cerebrospinal fluid of ALS patients. Since physiologically normal motor neurons express limited amounts of neuronal NOS, the source of NO is considered to be non-motor neurons expressing neuronal NOS, astroglia expressing inducible NOS, or motor neurons themselves inducing neuronal NOS. Conversely, neurons containing neuronal NOS are known to be resistant to toxic stimuli, which raises the possibility that such neurons are protected by NO. Several mechanisms have been reported to mediate the NO-related neuroprotection, including cyclic guanosine 3',5'-monophosphate (cyclic GMP), a downstream product of NO generation. This review summarizes previous studies on NO, focusing on its dual functions of neurotoxicity or neuroprotection, and discusses the putative roles of NO in relation to the pathogenesis of ALS.}, }
@article {pmid11673410, year = {2001}, author = {Clarke, G and Lumsden, CJ and McInnes, RR}, title = {Inherited neurodegenerative diseases: the one-hit model of neurodegeneration.}, journal = {Human molecular genetics}, volume = {10}, number = {20}, pages = {2269-2275}, doi = {10.1093/hmg/10.20.2269}, pmid = {11673410}, issn = {0964-6906}, mesh = {Cell Death ; Humans ; *Models, Neurological ; Neurodegenerative Diseases/*genetics ; }, abstract = {The clinical manifestations of inherited neurodegenerative diseases are often delayed for periods from years to decades. This observation has led to the idea that, in these disorders, neurons die from cumulative damage. A critical prediction of the cumulative damage hypothesis is that the probability of neuronal death increases with age. However, we recently demonstrated, in 17 examples of neurodegeneration, that the kinetics of neuronal death appear to be exponential. These examples include both monogenic disorders, such as photoreceptor degenerations, as well as others that are partly or entirely acquired (such as the clinical phase of parkinsonism and retinal detachment). Exponential kinetics indicate that (i) the risk of death is constant, (ii) death occurs randomly in time and (iii) the death of each neuron is independent of other neurons. We use the term 'one-hit model' to refer to the single catastrophic intracellular biochemical event, analogous to radioactive decay, which leads to neuronal death in the diseases we analyzed. Here, we examine the major features and implications of the one-hit model and provide preliminary evidence that amyotrophic lateral sclerosis also appears to fit this model. We also discuss a testable biochemical hypothesis, the mutant steady-state hypothesis, that we proposed to account for the one-hit model. Finally, we explore six unresolved issues that appear to challenge this model. The one-hit model appears to capture a novel principle underlying many neurodegenerations. Our findings suggest that any consideration of the biochemical basis of neurodegeneration must include a meticulous examination of the kinetics of cell death.}, }
@article {pmid11668883, year = {2001}, author = {Charles, T and Swash, M}, title = {Amyotrophic lateral sclerosis: current understanding.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {33}, number = {5}, pages = {245-253}, doi = {10.1097/01376517-200110000-00005}, pmid = {11668883}, issn = {0888-0395}, mesh = {Drug Approval ; England ; Humans ; Motor Neuron Disease/drug therapy/etiology/*nursing ; Riluzole/therapeutic use ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or motor neuron disease (MND) as it is usually termed in the United Kingdom, is a fatal degenerative disease resulting in progressive weakness and wasting of voluntary muscles. The disease is caused by degeneration of upper motor neurons in the motor cortex and of lower motor neurons in the brainstem and spinal cord. This combined loss of function causes spastic paralysis, flaccid muscle weakness, wasting, and fasciculations. The disease process spares the sensory, autonomic, and oculomotor neurons. ALS is the most common of the MND syndromes in adults. Although the cause of ALS is unknown, there is evidence that the excitatory neurotransmitter glutamate plays an important role in neuronal cell death in the disease. Several risk factors, such as exposure to welding and soldering, inhalation of lead vapor, exposure to chemicals, and electrical trauma are postulated as contributing to the pathogenesis of ALS. About 90% of all ALS patients have the sporadic form. Approximately 20% of all familial ALS cases are associated with mutations of the copper/zinc superoxide dismutase-1 gene. What is not clear is what factors contribute to the causation of the more common sporadic cases. The drug riluzole has neuroprotective effects in ALS and is the only disease-specific treatment available to date. Riluzole has been approved by the National Institute for Clinical Excellence for use in the National Health Service of the United Kingdom. Other treatments are aimed at managing the devastating symptoms of ALS.}, }
@article {pmid11600812, year = {2001}, author = {Siegsmund, M and Musial, A and Weiss, J and Alken, P}, title = {[Ldr brachytherapy, a minimally invasive alternative in the treatment of organ-confined prostate cancer].}, journal = {Onkologie}, volume = {24 Suppl 5}, number = {}, pages = {46-50}, doi = {10.1159/000055186}, pmid = {11600812}, issn = {0378-584X}, mesh = {*Brachytherapy ; Clinical Trials as Topic ; Humans ; Male ; Neoplasm Staging ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/mortality/pathology/*radiotherapy ; Radiotherapy Dosage ; }, abstract = {LDR Brachytherapy, a Minimally Invasive Alternative in the Treatment of Organ-Confined Prostate Cancer In den letzten Jahren erlebte die Brachytherapie mit permanenten Implantaten beim organbegrenzten Prostatakarzinom besonders in den USA, wo im Jahre 1999 mehr als 40 000 Implantationen durchgeführt wurden, eine Renaissance. Mit einer gewissen Verzögerung nimmt die Popularität dieser Methode auch in Europa immer mehr zu. Dies, obwohl die Brachytherapie keine absolut neue Methode in der Behandlung des Prostatakarzinoms ist, sie hat im Gegenteil eine lange Tradition.}, }
@article {pmid11599635, year = {2001}, author = {Halliwell, B}, title = {Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment.}, journal = {Drugs &amp; aging}, volume = {18}, number = {9}, pages = {685-716}, pmid = {11599635}, issn = {1170-229X}, mesh = {Animals ; Antioxidants/metabolism/*therapeutic use ; Brain/drug effects/metabolism/pathology ; Free Radicals/adverse effects/*metabolism ; Humans ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/etiology/metabolism ; Oxidative Stress ; }, abstract = {Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.}, }
@article {pmid11596474, year = {2001}, author = {Aoki, M and Nagai, M and Kato, M and Itoyama, Y}, title = {[ALS models by transgenic animals].}, journal = {No to shinkei = Brain and nerve}, volume = {53}, number = {9}, pages = {799-807}, pmid = {11596474}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Animals ; *Animals, Genetically Modified ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Point Mutation ; Rats ; Superoxide Dismutase/*genetics ; }, }
@article {pmid11585669, year = {2001}, author = {Newbery, HJ and Abbott, CM}, title = {Of mice, men and motor neurons.}, journal = {Trends in genetics : TIG}, volume = {17}, number = {10}, pages = {S2-6}, doi = {10.1016/s0168-9525(01)02459-3}, pmid = {11585669}, issn = {0168-9525}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Disease Models, Animal ; Endothelial Growth Factors/genetics ; Humans ; Lymphokines/genetics ; Mice ; Mice, Knockout ; Mice, Mutant Strains ; Mice, Transgenic ; Motor Neuron Disease/enzymology/*genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {The use of mouse models has been of particular importance in studying the pathogenesis of amyotrophic lateral sclerosis. Here, we describe both transgenic and classical mutants for which the genetic lesion is known. We draw attention, wherever possible, to pathological factors common to multiple models.}, }
@article {pmid11579422, year = {2001}, author = {Orth, M and Schapira, AH}, title = {Mitochondria and degenerative disorders.}, journal = {American journal of medical genetics}, volume = {106}, number = {1}, pages = {27-36}, doi = {10.1002/ajmg.1425}, pmid = {11579422}, issn = {0148-7299}, mesh = {Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Alzheimer Disease/genetics ; Cell Nucleus/metabolism ; Hepatolenticular Degeneration/genetics ; Humans ; Huntington Disease/genetics ; Mitochondria/metabolism ; Mitochondrial Diseases/*diagnosis/*genetics ; Mutation ; Neurodegenerative Diseases/*diagnosis/*genetics ; Oxygen/metabolism ; Parkinson Disease/genetics ; Phosphorylation ; Spastic Paraplegia, Hereditary/genetics ; }, abstract = {In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.}, }
@article {pmid11571217, year = {2001}, author = {Le Forestier, N and Maisonobe, T and Piquard, A and Rivaud, S and Crevier-Buchman, L and Salachas, F and Pradat, PF and Lacomblez, L and Meininger, V}, title = {Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature.}, journal = {Brain : a journal of neurology}, volume = {124}, number = {Pt 10}, pages = {1989-1999}, doi = {10.1093/brain/124.10.1989}, pmid = {11571217}, issn = {0006-8950}, mesh = {Adult ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Motor Neuron Disease/*classification/diagnosis/pathology/*physiopathology ; Motor Neurons/pathology/physiology ; Prospective Studies ; }, abstract = {The question of whether primary lateral sclerosis (PLS) is a nosological entity distinct from amyotrophic lateral sclerosis (ALS) has been the subject of controversy since it was first described in the nineteenth century. PLS has been defined as a rare, non-hereditary disease characterized by progressive spinobulbar spasticity, related to the selective loss of precentral pyramidal neurones, with secondary pyramidal tract degeneration and preservation of anterior horn motor neurones. In the recent clinical literature, the frontier between ALS and neurodegenerative disease remains poorly defined. We studied 20 patients with a diagnosis of PLS. We carried out a variety of tests in order to determine the presence of a more diffuse neurodegenerative process. We also performed a longitudinal electrophysiological evaluation. Our clinical, electrophysiological and pathological investigations provide evidence that the disease has a heterogeneous clinical presentation and that degeneration is not restricted to the central motor system.}, }
@article {pmid11569536, year = {2001}, author = {González Deniselle, MC and González, SL and De Nicola, AF}, title = {Cellular basis of steroid neuroprotection in the wobbler mouse, a genetic model of motoneuron disease.}, journal = {Cellular and molecular neurobiology}, volume = {21}, number = {3}, pages = {237-254}, pmid = {11569536}, issn = {0272-4340}, mesh = {Animals ; Disease Models, Animal ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/*drug therapy/*genetics/pathology ; Neuroprotective Agents/*pharmacology ; Pregnatrienes/*pharmacology ; }, abstract = {1. The Wobbler mouse suffers an autosomal recessive mutation producing severe motoneuron degeneration and astrogliosis in the spinal cord. It has been considered a suitable model of human motoneuron disease, including the sporadic form of amyotrophic lateral sclerosis (ALS). 2. Evidences exist demonstrating increased oxidative stress in the spinal cord of Wobbler mice, whereas antioxidant therapy delayed neurodegeneration and improved muscle trophism. 21-Aminosteroids are glucocorticoid-derived hydrophobic compounds with antioxidant potency 3 times higher than vitamin E and 100 times higher than methylprednisolone. They do not bind to intracellular receptors, and prevent lipid peroxidation by insertion into membrane lipid bilayers. 3. In common with the spinal cord of ALS patients, Wobbler mice present astrocytosis with hyperexpression of glial fibrillary acidic protein (GFAP), and increased expression of nitric oxide synthase (NOS) and growth-associated protein (GAP-43) in motoneurons. Here, we review our studies on the effects of a 21-aminosteroid on GFAP, NOS, and GAP-43. 4. First, we showed that 21-aminosteroid treatment further increased GFAP-expressing astrocytes in gray matter of the Wobbler spinal cord. This effect may provide neuroprotection if one considers a trophic and beneficial function of astrocytes during the course of degeneration. Other neuroprotectans used in Wobbler mice (T-588) also increased pre-existing astrocytosis. 5. Second, histochemical determination of NADPH-diaphorase, a parameter indicative of neuronal NOS activity, showed that the 21-aminosteroid down-regulated the high activity of this enzyme in ventral horn motoneurons. Therefore, suppression of nitric oxide by decreasing NADPH-diaphorase (NOS) activity may provide neuroprotection considering that excess NO is highly toxic to motoneurons. 6. Finally, 21-aminosteroid treatment significantly attenuated the aberrant expression of both GAP-43 protein and mRNA in Wobbler motoneurons. Hyperexpression of GAP-43 possibly indicated abnormal synaptogenesis, denervation, and muscle atrophy, parameters which may return to normal following antioxidant steroid treatment. 7. Besides 21-aminosteroids, other steroids also behave as neuroprotectans. In this regard, degenerative diseases may constitute potential targets of these hormones, based on the fact that the spinal cord expresses in a regional and cell-specific fashion, receptors for androgens. progesterone, adrenal steroids, and estrogens.}, }
@article {pmid11554556, year = {2001}, author = {Klein, RC and Castellino, FJ}, title = {Activators and inhibitors of the ion channel of the NMDA receptor.}, journal = {Current drug targets}, volume = {2}, number = {3}, pages = {323-329}, doi = {10.2174/1389450013348290}, pmid = {11554556}, issn = {1389-4501}, mesh = {Animals ; Excitatory Amino Acid Agonists/*pharmacology ; Excitatory Amino Acid Antagonists/*pharmacology ; Humans ; Ion Channels/*agonists/*antagonists &amp; inhibitors ; Receptors, N-Methyl-D-Aspartate/*agonists/*antagonists &amp; inhibitors ; }, abstract = {The involvement of the glutamate-glycine activated ion channels of the NMDA receptor in various neurophysiological processes has made this ion channel the focus of intense research. The excessive release of glutamate in a variety of neuronal hypoxic conditions implicates the NMDA receptor in a number of neuropatholological states, such as stroke, chronic pain, Parkinson's disease, Alzheimer's disease, ALS, and epilepsy, among others, thus making this receptor a prime drug target candidate. A variety of agents are known to be effective in opening and closing of the ion channels of this receptor, among the latter group of agents is the peptidic conantokins. Through the use of electrophysiological measurements with a number of cell types containing natural and recombinant subunits of the NMDA receptor, much knowledge is evolving regarding the mechanism of action of activators and inhibitors of the NMDA receptor ion channels. In addition, structure-function studies of the conantokins in these systems have been revealing in terms of their complimentary sites on the NMDA receptor. These relationships serve as the main focus of this review.}, }
@article {pmid11545263, year = {2001}, author = {Brandt, R}, title = {Cytoskeletal mechanisms of neuronal degeneration.}, journal = {Cell and tissue research}, volume = {305}, number = {2}, pages = {255-265}, doi = {10.1007/s004410000334}, pmid = {11545263}, issn = {0302-766X}, mesh = {Alzheimer Disease/genetics/metabolism/pathology/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; Cytoskeleton/metabolism/pathology/*physiology ; Humans ; Nerve Degeneration/genetics/metabolism/pathology/*physiopathology ; tau Proteins/genetics/metabolism/physiology ; }, abstract = {The cytoskeleton is the major intracellular determinant of neuronal morphology and is required for fundamental processes during the development and maintenance of a neuron. Thus, it is not surprising that many neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (motor neuron disease) are characterized by typical abnormalities in the organization of the cytoskeleton. However, the role of the cytoskeletal changes during the development of the disease, e.g., whether they have a causative role during neuronal degeneration or represent an epiphenomenon of neurons that degenerate by other means, is still disputed. In this review, recent results on the development and the role of cytoskeletal abnormalities during neurodegenerative diseases are discussed and a mechanistic framework for the involvement of cytoskeletal changes during neurodegenerative processes is presented.}, }
@article {pmid11542677, year = {1999}, author = {Finstein, MS and Strom, PF and Hogan, JA and Cowan, RM}, title = {Composting on Mars or the Moon: I. Comparative evaluation of process design alternatives.}, journal = {Life support &amp; biosphere science : international journal of earth space}, volume = {6}, number = {3}, pages = {169-179}, pmid = {11542677}, issn = {1069-9422}, mesh = {*Biodegradation, Environmental ; Conservation of Natural Resources ; *Ecological Systems, Closed ; Fermentation ; Humans ; Hydrogen-Ion Concentration ; *Life Support Systems ; Mars ; Moon ; Oxygen/metabolism ; Temperature ; Waste Management/*methods ; Water ; }, abstract = {As a candidate technology for treating solid wastes and recovering resources in bioregenerative Advanced Life Support, composting potentially offers such advantages as compactness, low mass, near ambient reactor temperatures and pressures, reliability, flexibility, simplicity, and forgiveness of operational error or neglect. Importantly, the interactions among the physical, chemical, and biological factors that govern composting system behavior are well understood. This article comparatively evaluates five Generic Systems that describe the basic alternatives to composting facility design and control. These are: 1) passive aeration; 2) passive aeration abetted by mechanical agitation; 3) forced aeration--O2 feedback control; 4) forced aeration--temperature feedback control; 5) forced aeration--integrated O2 and temperature feedback control. Each of the five has a distinctive pattern of behavior and process performance characteristics. Only Systems 4 and 5 are judged to be viable candidates for ALS on alien worlds, though which is better suited in this application is yet to be determined.}, }
@article {pmid11532157, year = {2001}, author = {Sathasivam, S and Ince, PG and Shaw, PJ}, title = {Apoptosis in amyotrophic lateral sclerosis: a review of the evidence.}, journal = {Neuropathology and applied neurobiology}, volume = {27}, number = {4}, pages = {257-274}, doi = {10.1046/j.0305-1846.2001.00332.x}, pmid = {11532157}, issn = {0305-1846}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; *Apoptosis ; Humans ; Motor Neurons/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the upper and lower motor neurones of the central nervous system. Recently, a lot of interest has been generated by the possibility that a mechanism of programmed cell death, termed apoptosis, is responsible for the motor neurone degeneration in this condition. Apoptosis is regulated through a variety of different pathways which interact and eventually lead to controlled cell death. Apart from genetic regulation, factors involved in the control of apoptosis include death receptors, caspases, Bcl-2 family of oncoproteins, inhibitor of apoptosis proteins (IAPs), inhibitors of IAPs, the p53 tumour suppressor protein and apoptosis-related molecules. The first part of this article will give an overview of the current knowledge of apoptosis. In the second part of this review, we will examine in detail the evidence for and against the contribution of apoptosis in motor neurone cell death in ALS, looking at cellular-, animal- and human post-mortem tissue-based models. In a chronic neurodegenerative disease such as ALS, conclusive evidence of apoptosis is likely to be difficult to detect, given the rapidity of the apoptotic cell death process in relation to the relatively slow time course of the disease. Although a complete picture of motor neurone death in ALS has not been fully elucidated, there is good and compelling evidence that a programmed cell death pathway operates in this disorder. The strongest body of evidence supporting this comes from the findings that, in ALS, changes in the levels of members of the Bcl-2 family of oncoproteins results in a predisposition towards apoptosis, there is increased expression or activation of caspases-1 and -3, and the dying motor neurones in human cases exhibit morphological features reminiscent of apoptosis. Further supporting evidence comes from the detection of apoptosis-related molecules and anti-Fas receptor antibodies in human cases of ALS. However, the role of the p53 protein in cell death in ALS is at present unclear. An understanding of the mechanism of programmed cell death in ALS may provide important clues for areas of potential therapeutic intervention for neuroprotection in this devastating condition.}, }
@article {pmid11527091, year = {2001}, author = {Savage, MO and Camacho-Hübner, C and Dunger, DB and Ranke, MB and Ross, RJ and Rosenfeld, RG}, title = {Is there a medical need to explore the clinical use of insulin-like growth factor I?.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {11 Suppl A}, number = {}, pages = {S65-9}, doi = {10.1016/s1096-6374(01)80011-3}, pmid = {11527091}, issn = {1096-6374}, mesh = {Clinical Trials as Topic ; Gene Deletion ; Growth Disorders/*drug therapy/physiopathology ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/deficiency/genetics/*therapeutic use ; Metabolic Diseases/*drug therapy/metabolism ; Nervous System Diseases/*drug therapy/metabolism/physiopathology ; Osteoporosis/*drug therapy/metabolism/physiopathology ; Receptors, Somatotropin/deficiency ; }, abstract = {Cloning of the insulin-like growth factor I (IGF-I) gene led to the development in 1987 of recombinant IGF-I available for clinical use. Trials were started targeting endocrine, metabolic and neurological disorders, and beneficial results have been demonstrated in IGF-I deficiency states caused by IGF-I gene deletion and growth hormone (GH) receptor deficiency, type 1 and type 2 diabetes mellitus, and severe insulin resistance syndromes. Results of equivocal benefit have also been reported in osteoporosis and amyotrophic lateral sclerosis. Recent encouraging data using the IGF-I-IGF-binding protein 3 (IGFBP-3) complex in diabetes mellitus suggest that this preparation may eventually replace recombinant free IGF-I. The lack of an established therapeutic indication for IGF-I has resulted in its supplies being severely limited. It will probably be decided during the next decade whether use of IGF-I or the IGF-I-IGFBP-3 complex becomes firmly established as an accepted endocrine therapy.}, }
@article {pmid11527090, year = {2001}, author = {Morrison, KM and Wu, Z and Bidlingmaier, M and Strasburger, CJ}, title = {Findings and theoretical considerations on the usefulness of the acid-labile subunit in the monitoring of acromegaly.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {11 Suppl A}, number = {}, pages = {S61-3}, doi = {10.1016/s1096-6374(01)80010-1}, pmid = {11527090}, issn = {1096-6374}, mesh = {Acromegaly/*blood/diagnosis/*drug therapy ; Animals ; Biomarkers/blood ; Carrier Proteins/*blood ; Glycoproteins/*blood ; Human Growth Hormone/analogs &amp; derivatives/*therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Predictive Value of Tests ; Receptors, Somatotropin/*antagonists &amp; inhibitors ; }, abstract = {Growth hormone (GH) action induces a variety of biochemical factors of which insulin-like growth factor I (IGF-I) is conventionally measured for the diagnosis and monitoring of GH-related disorders such as GH deficiency or acromegaly. IGF-I circulates predominantly as a ternary complex with IGF-binding protein 3 (IGFBP-3) and the acid labile subunit (ALS). In the treatment of active acromegaly with the GH receptor antagonist pegvisomant, ALS showed a closer correlation with the change in ring size, measured as a clinical indicator of disease activity, than did IGF-I or IGFBP-3. ALS thus seems to be a clinically useful marker of disease activity in acromegaly.}, }
@article {pmid11524608, year = {2001}, author = {Bruno, V and Battaglia, G and Copani, A and D'Onofrio, M and Di Iorio, P and De Blasi, A and Melchiorri, D and Flor, PJ and Nicoletti, F}, title = {Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {21}, number = {9}, pages = {1013-1033}, doi = {10.1097/00004647-200109000-00001}, pmid = {11524608}, issn = {0271-678X}, mesh = {Animals ; Brain Diseases/*drug therapy ; Humans ; Neuroprotective Agents/*pharmacology ; Receptors, Metabotropic Glutamate/*agonists/*antagonists &amp; inhibitors ; }, abstract = {Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.}, }
@article {pmid11490451, year = {2001}, author = {Andersen, PM}, title = {[Genetics of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {101}, number = {3}, pages = {54-63}, pmid = {11490451}, issn = {1997-7298}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/physiopathology ; Atrophy/pathology/physiopathology ; Chromosomes, Human, Pair 21/genetics ; DNA Mutational Analysis ; Female ; Gene Expression ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/pathology/physiopathology ; Paresis/physiopathology ; Point Mutation/genetics ; Superoxide Dismutase/genetics ; }, }
@article {pmid11474839, year = {2001}, author = {Elliott, JL}, title = {Zinc and copper in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {25}, number = {6}, pages = {1169-1185}, doi = {10.1016/s0278-5846(01)00185-3}, pmid = {11474839}, issn = {0278-5846}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*etiology/genetics ; Animals ; Copper/metabolism/*physiology ; Humans ; Superoxide Dismutase/chemistry/genetics/metabolism/*physiology ; Superoxide Dismutase-1 ; Zinc/metabolism/*physiology ; }, abstract = {1. Missense mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1) are responsible for causing one form of familial amyotrophic lateral sclerosis (FALS) linked to chromosome 21q. 2. Mutant SOD1-induced disease is clearly related to a toxic gain of function for the abnormal enzyme, and recent work has begun to investigate the mechanisms underlying this toxicity. In addition to its well known and likely beneficial dismutase activity, wild type SOD1 also possesses the ability to participate in other enzymatic reactions that may be injurious to cells including peroxidation or nitration. 3. Many of the SOD1 mutations associated with FALS appear to increase the likelihood that the enzyme will perform either one of these potentially harmful functions resulting in increased hydroxyl radical formation or the addition of nitro groups to tyrosine residues within cellular proteins.}, }
@article {pmid11470959, year = {2001}, author = {Duff, K and Rao, MV}, title = {Progress in the modeling of neurodegenerative diseases in transgenic mice.}, journal = {Current opinion in neurology}, volume = {14}, number = {4}, pages = {441-447}, doi = {10.1097/00019052-200108000-00003}, pmid = {11470959}, issn = {1350-7540}, mesh = {Animals ; Brain/pathology ; *Disease Models, Animal ; Heredodegenerative Disorders, Nervous System/*genetics/pathology ; Humans ; Mice ; Mice, Transgenic ; *Models, Genetic ; }, abstract = {Transgenic mouse models exist for the major neurodegenerative diseases, including Alzheimer's disease, tauopathy and amyotrophic lateral sclerosis. Although many of the mice do not completely replicate the human disease they are intended to model, they have provided insight into the mechanisms that underlie disease etiology. In the case of the Alzheimer's disease and amyotrophic lateral sclerosis models, the mice have also provided a therapeutic testing ground for the testing of agents that have been shown to have considerable clinical promise.}, }
@article {pmid11467101, year = {2001}, author = {Carter, GT and Rosen, BS}, title = {Marijuana in the management of amyotrophic lateral sclerosis.}, journal = {The American journal of hospice &amp; palliative care}, volume = {18}, number = {4}, pages = {264-270}, doi = {10.1177/104990910101800411}, pmid = {11467101}, issn = {1049-9091}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy/physiopathology/psychology ; Cannabis/*therapeutic use ; Drug and Narcotic Control/legislation &amp; jurisprudence ; Evidence-Based Medicine ; Humans ; Patient Selection ; *Phytotherapy ; Treatment Outcome ; }, abstract = {Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted.}, }
@article {pmid11467056, year = {2000}, author = {Ikemoto, A and Hirano, A and Akiguchi, I}, title = {Neuropathology of amyotrophic lateral sclerosis with extra-motor system degeneration: characteristics and differences in the molecular pathology between ALS with dementia and Guamanian ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {2}, pages = {97-104}, doi = {10.1080/14660820050515395}, pmid = {11467056}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Dementia/*pathology ; Diagnosis, Differential ; Humans ; Inclusion Bodies/pathology ; Motor Neurons/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is classified into distinct subtypes mainly based on clinicopathological features, in addition to epidemiologic and genetic backgrounds. In addition to sporadic ALS with classical pathology, characteristics in the clinical features, in the histological findings and their topographical distribution, and in the molecular pathology, especially the intracytoplasmic neuronal inclusions, enable us to identify the following subtypes: ALS with dementia (ALS-D), ALS in the Western Pacific, ALS with multi-system degeneration, familial ALS, and superoxide dismutase 1-linked ALS. These subtypes not infrequently exhibit various types of extra-motor system degeneration, and even multi-system pathology. Some of the subtypes (for instance ALS-D or familial ALS) can be deduced, to a certain extent, from characteristic neuronal inclusions such as ALS-type ubiquitinated inclusions, Lewy body-like hyaline inclusions (LBHIs), or ubiquitinated intracytoplasmic neuronal inclusions as typically seen in the dentate fascia. The purpose of this article is to clarify the molecular pathogenesis of the cerebral cortex in ALS-D and Guamanian ALS and parkinsonism-dementia complex (PDC), in order to elucidate the relationship and distinction between these two subtypes. As indicated previously, investigations on ubiquitin-immunoreactivity in the hippocampus further support the view that the pathology of G-ALS/PDC may be that of a tau-related tangle disorder, whilst ALS-D has a feature of the motor neuron disease type-frontotemporal dementia.}, }
@article {pmid11467055, year = {2000}, author = {Desport, JC and Preux, PM and Truong, CT and Courat, L and Vallat, JM and Couratier, P}, title = {Nutritional assessment and survival in ALS patients.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {2}, pages = {91-96}, doi = {10.1080/14660820050515386}, pmid = {11467055}, issn = {1466-0822}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diet therapy/*mortality ; Gastrostomy ; Humans ; Middle Aged ; *Nutrition Assessment ; Nutrition Disorders/drug therapy/mortality ; Prognosis ; Retrospective Studies ; }, abstract = {Malnutrition, present in 16-50% of ALS patients, is an independent prognostic factor for worsened survival. It is caused primarily by swallowing dysfunction, resulting from involvement of the lower sets of cranial nerves, but hypermetabolism is also implicated. Malnutrition itself can produce neuromuscular weakness and adversely affect patients' quality of life, thereby creating a vicious circle. The nutritional status of ALS patients can be assessed with dietary review and measurements of weight (W) and height (H). A body mass index (BMI = W/H2) below 18.5-20 kg/m2 indicates a state of malnutrition. Dietary counselling is important, but rapidly becomes insufficient, particularly in bulbar-onset ALS, where enteral nutritional support is then necessary. Percutaneous endoscopic gastrostomy tube placement is well tolerated, and provides more efficient enteral nutrition than nasogastric tube feeding. Enteral nutrition support can improve the respiratory status of ALS patients. The effect on survival remains to be confirmed.}, }
@article {pmid11467054, year = {2000}, author = {Gaudette, M and Hirano, M and Siddique, T}, title = {Current status of SOD1 mutations in familial amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {2}, pages = {83-89}, doi = {10.1080/14660820050515377}, pmid = {11467054}, issn = {1466-0822}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*genetics ; Humans ; *Point Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Twenty percent of cases of familial amyotrophic lateral sclerosis (FALS) have identifiable mutations in the gene for Cu, Zn superoxide dismutase (SOD1) located on the long arm of chromosome 21. SOD1 mutations are thought to cause a yet unknown toxic gain of function resulting in motor neuron damage. Seventy-one mutations, located in all five exons of SOD1, have been reported. Identified mutations are predominantly heterozygous mis-sense mutations, although rare nonsense mutations, deletions, and insertions exist. While gene dosage has an effect on the age of onset, genotoype/phenotype correlation is better defined for progression of symptoms than for disease onset.}, }
@article {pmid11467053, year = {2000}, author = {Gooch, CL and Harati, Y}, title = {Motor unit number estimation, ALS and clinical trials.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {2}, pages = {71-82}, doi = {10.1080/14660820050515368}, pmid = {11467053}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Cell Count/*methods ; Clinical Trials as Topic/*methods ; Humans ; Motor Neurons/*pathology ; }, abstract = {Motor unit number estimation (MUNE) techniques have evolved substantially over the past decade and have been applied, with increasing frequency, to the study of amyotrophic lateral sclerosis (ALS). As major clinical therapeutic trials in motor neuron disease continue to appear, the need for a clear quantitative method of following motor unit physiology in the living subject grows ever more pressing. In this article, we review the major modern techniques of MUNE and the data supporting their reproducibility and utility in patients with ALS, with particular attention to their role in evaluating the efficacy of new therapeutic interventions.}, }
@article {pmid11467047, year = {2000}, author = {Swash, M and Desai, J}, title = {Motor neuron disease: classification and nomenclature.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {2}, pages = {105-112}, doi = {10.1080/14660820050515403}, pmid = {11467047}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/classification ; Animals ; Bulbar Palsy, Progressive/classification ; Humans ; Motor Neuron Disease/*classification ; Muscular Atrophy, Spinal/classification ; *Terminology as Topic ; }, abstract = {The classification and nomenclature of motor neuron disease, whether sporadic or familial, is confused. For example, both the sporadic and familial motor neuron diseases are phenotypically heterogeneous and, in familial ALS, phenotypic heterogeneity correlates only weakly with different underlying mutations in the SOD1 gene. We propose a classification which is based on underlying causative mechanisms, where these are known, but which also recognizes different clinical phenotypes when the cause is unknown. This classification is flexible, and allows reattribution of clinical syndromes when their causation is understood. Currently uncertain associations--for example, a possible association of ALS with cancer--are given tentative recognition in this classification. In addition, this new classification recognizes geographical clustering and descriptions of unusual motor neuron disorder phenotypes of unknown origin in different parts of the world.}, }
@article {pmid11466960, year = {2000}, author = {Pioro, EP}, title = {Antioxidant therapy in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {5-12; discussion 13-5}, doi = {10.1080/14660820050515656}, pmid = {11466960}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Antioxidants/*therapeutic use ; Humans ; }, }
@article {pmid11466959, year = {2000}, author = {Brooks, BR and Juhasz-Poscine, K and Waclawik, A and Sanjak, M and Belden, D and Roelke, K and Parnell, J and Weasler, C}, title = {Mosaic chemotherapy strategies for developing ALS/MND therapeutic approaches: beta-2 adrenergic agonists.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {45-53; discussion 53-4}, pmid = {11466959}, issn = {1466-0822}, support = {M01 RR03186/RR/NCRR NIH HHS/United States ; }, mesh = {Adrenergic beta-2 Receptor Agonists ; Adrenergic beta-Agonists/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Clenbuterol/*therapeutic use ; Humans ; }, }
@article {pmid11466958, year = {2000}, author = {Smith, RG and Appel, SH}, title = {Immunosuppression and anti-inflammatory agents in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {33-42; discussion 42-3}, pmid = {11466958}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*immunology/metabolism ; Anti-Inflammatory Agents/*therapeutic use ; Humans ; Immunosuppressive Agents/*therapeutic use ; Prostaglandin-Endoperoxide Synthases/metabolism ; }, }
@article {pmid11466956, year = {2000}, author = {Appel, SH and Beers, D and Smith, RG and Wilson, JE}, title = {Altered calcium homeostasis in ALS as a target for therapy.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {27-32}, pmid = {11466956}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Calcitriol/*therapeutic use ; Calcium/*metabolism ; Calcium Channel Agonists/*therapeutic use ; Homeostasis/drug effects/physiology ; Humans ; }, }
@article {pmid11466954, year = {2000}, author = {Strong, MJ and Pattee, GL}, title = {Creatine and coenzyme Q10 in the treatment of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {17-20}, doi = {10.1080/14660820050515665}, pmid = {11466954}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Antioxidants/*therapeutic use ; Coenzymes ; Creatine/*therapeutic use ; Humans ; Ubiquinone/analogs &amp; derivatives/*therapeutic use ; }, }
@article {pmid11465930, year = {2001}, author = {Miller, RG}, title = {Examining the evidence about treatment in ALS/MND.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {1}, pages = {3-7}, doi = {10.1080/146608201300079355}, pmid = {11465930}, issn = {1466-0822}, mesh = {Clinical Trials as Topic ; Critical Care ; Excitatory Amino Acid Antagonists/adverse effects/therapeutic use ; Humans ; Motor Neuron Disease/diagnosis/mortality/*therapy ; Palliative Care ; Practice Guidelines as Topic ; Riluzole/adverse effects/therapeutic use ; Survival Rate ; }, abstract = {The application of evidence-based medicine to the treatment of patients with amyotrophic lateral sclerosis (ALS) is just beginning. A small number of systematic reviews analyzing the pertinent evidence, grading the methodology and formulating recommendations to guide clinical decision-making have begun to appear. The American Academy of Neurology practice parameters for informing the patient and managing nutritional and respiratory issues and palliative care are discussed. In addition, the first systematic review in the field of ALS/MND from the Cochrane collaboration concerns riluzole treatment and this meta-analysis is also described. Some of the most important recommendations that have the potential to significantly prolong survival and enhance quality of life are the early institution of percutaneous endoscopic gastrostomy for patients with significant dysphagia, and the initiation of non-invasive positive pressure ventilation for patients with symptoms of early respiratory insufficiency. Assertive treatment of pain and dyspnea are also strongly recommended for patients with ALS. The North American ALS patient database, ALS C.A.R.E., is also described as a methodology for measuring clinical outcomes, and some early results are presented. The evidence on riluzole indicates effectiveness in prolonging survival with a good safety profile.}, }
@article {pmid11465927, year = {2001}, author = {Silani, V and Braga, M and Botturi, A and Cardin, V and Bez, A and Pizzuti, A and Scarlato, G}, title = {Human developing motor neurons as a tool to study ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S69-76}, doi = {10.1080/146608201750138594}, pmid = {11465927}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*pathology ; Cells, Cultured ; Humans ; Motor Neurons/*cytology/*physiology ; }, abstract = {Defining the basis of the selective cell vulnerability of human motor neurons (hMNs) represents a crucial step in revealing the pathogenesis of amyotrophic lateral sclerosis (ALS). Tissue culture models offer an ideal system for identification of the hMN-specific features at the single cell level. Purified hMNs and astrocytes can today be isolated from the anterior horn of the human embryonic spinal cord. Cultures can be studied at the single cell level using cDNA/mRNA amplification techniques. The effects of molecules affecting hMN survival, neurite extension, and metabolism can be tested in vitro and the expression of selective genes assayed using DNA microarray technology. Crucial information of immediate clinical application for the treatment of patients affected by ALS can be derived after testing the efficacy of candidate pharmaceutical molecules using in vitro cell models. Adult nervous tissue or progenitor cells derived from different regions of the nervous system may be used as an alternative source of human neuronal cells. HMNs in culture, combined with the application of adequate technology, can contribute greatly to identifying the primitive critical events responsible for the cell degeneration observed in ALS, bypassing the intrinsic limitations of the non-human models of the disease.}, }
@article {pmid11465926, year = {2001}, author = {Beck, M and Karch, C and Wiese, S and Sendtner, M}, title = {Motoneuron cell death and neurotrophic factors: basic models for development of new therapeutic strategies in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S55-68}, pmid = {11465926}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Animals ; Cell Death/drug effects/*physiology ; Humans ; Motor Neurons/*pathology/physiology ; Nerve Growth Factors/physiology/*therapeutic use ; }, abstract = {Motoneurons are generated in excess during embryonic development of higher vertebrates. In the lumbar spinal cord of the developing rat, about 6000 motoneurons are present at embryonic day 14. These neurons grow out axons which make contact with their target tissue, the skeletal muscle. About 50% of the motoneurons are lost during a critical period from embryonic day 14 until postnatal day 3. This process, which is called physiological motoneuron cell death, has been the focus of research aiming at the identification of neurotrophic factors which regulate motoneuron survival during this developmental period. Motoneuron cell death can also be observed in vitro when the motoneurons are isolated from the embryonic avian or rodent spinal cord. These isolated motoneurons and other types of primary neurons have been a useful tool for studying basic mechanisms underlying neuronal degeneration during development and under pathophysiological conditions in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Accumulating evidence from such studies suggests that some specific requirements of motoneurons for survival and proper function may change during development. These findings might be relevant for understanding the pathophysiological processes underlying ALS and thus could contribute to the development of new therapeutic strategies.}, }
@article {pmid11465925, year = {2001}, author = {Appel, SH and Beers, D and Siklos, L and Engelhardt, JI and Mosier, DR}, title = {Calcium: the Darth Vader of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S47-54}, pmid = {11465925}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Calcium/*metabolism ; Humans ; Motor Neurons/metabolism/pathology ; }, abstract = {Motor neuron dysfunction and loss in amyotrophic lateral sclerosis (ALS) have been attributed to several different mechanisms, including increased intracellular calcium, glutamate excitotoxicity, oxidative stress and free radical damage, mitochondrial dysfunction, and neurofilament aggregation and dysfunction of transport mechanisms. These alterations are not mutually exclusive, and increased calcium could be a common denominator. Furthermore, the selective vulnerability of spinal motor neurons and the relative sparing of eye motor neurons represent striking features of both sporadic and familial ALS. Here we review the evidence that calcium homeostasis is altered in ALS, and that low levels of the calcium binding proteins parvalbumin and calbindin-D28K contribute to selective vulnerability by decreasing the ability of motor neurons to handle an increased calcium load, with cell injury and death as the consequence.}, }
@article {pmid11465923, year = {2001}, author = {Andersen, PM}, title = {Genetics of sporadic ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S37-41}, doi = {10.1080/14660820152415726}, pmid = {11465923}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genetic Predisposition to Disease ; Humans ; Superoxide Dismutase/*genetics ; }, abstract = {The only known gene to be involved in ALS is the CuZn-superoxide dismutase (CuZn-SOD) gene. Since 1993, 89 disease-associated mutations have been found in this gene, 14 of them in cases with apparently sporadic ALS. Most frequent are the D90A (most often with recessive inheritance, but a few with dominant inheritance) and the I113T (dominant inheritance with variable penetrance). Statistical and genealogical evidence suggest that quite a number of diagnosed sporadic cases may in fact be familial cases in pedigrees with very low disease penetrance.}, }
@article {pmid11465922, year = {2001}, author = {Borasio, GD}, title = {Palliative care in ALS: searching for the evidence base.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S31-5}, pmid = {11465922}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; *Evidence-Based Medicine ; Humans ; Palliative Care/*standards ; *Quality of Life ; }, abstract = {The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a challenge for the neurologist. Most of the disabilities from progressive disease can be effectively relieved by symptomatic treatment. Prognosis and treatment options should be openly discussed with patient and relatives. Adequate assistance and palliative treatment in the terminal phase are of paramount importance. Unfortunately, training in communication skills for young doctors and evidence-based recommendations for palliative care are insufficient at present. In addition, new data from a randomized study question the concept of "health-related quality of life" and favor an individualized approach to the definition of quality of life in ALS.}, }
@article {pmid11465921, year = {2001}, author = {Swash, M}, title = {ALS 2000: the past points to the future.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S3-9}, pmid = {11465921}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*pathology ; Cell Death ; Humans ; }, abstract = {In this introductory review a number of issues concerning the direction of future research in ALS are addressed in relation to current understanding of this disorder and its treatment. The importance of understanding the pathways leading to motor neuron dysfunction and death is emphasized. Contemporary epidemiology, understandably focussed on genetic markers for familial ALS, needs to be widened to include as yet undocumented susceptibility-related genetic traits. Potential avenues for therapy are considered, and the fundamental contemporary issue of clinical measurement is discussed. Neglected aspects of contemporary research, including disturbed axoplasmic flow, are brought to attention. The role of experiment derived from clinical observation, and vice versa, is described by reference to a number of past and recent contributions to the understanding of ALS.}, }
@article {pmid11465920, year = {2001}, author = {Nobile-Orazio, E and Carpo, M and Meucci, N}, title = {Are there immunologically treatable motor neuron diseases?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S23-30}, pmid = {11465920}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/complications/*immunology/*therapy ; Humans ; Immunosuppressive Agents/*therapeutic use ; Lymphoma/complications ; Paraneoplastic Polyneuropathy/complications/*immunology/*therapy ; Paraproteinemias/complications ; }, abstract = {Several studies have addressed the issue of a possible immunological involvement in the pathogenesis of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), particularly when the disease was associated with cancer, lymphoma or other monoclonal gammopathies or with the presence of serum antibodies to neural antigens. The hypothesis of the existence of immunologically treatable MND was reinforced by the occasional report of MND patients responding to immune or cytostatic therapies and by the identification among those with a purely lower motor neuron syndrome (LMNS) of a motor neuropathy, presently known as multifocal motor neuropathy (MMN), which almost invariably responded to immune therapies. These observations have led to several attempts to treat patients with MND or LMNS, either idiopathic or associated with the above mentioned conditions, with a number of immune or cytostatic therapies. The aim of this review is to verify whether the available data provide enough evidence to support the concept of dysimmune MND and to justify the use in these patients of potentially harmful immune cytostatic therapies.}, }
@article {pmid11465919, year = {2001}, author = {Munsat, TL}, title = {Slowing down ALS--is this good or bad?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S19-22}, pmid = {11465919}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/psychology ; Cost-Benefit Analysis ; Humans ; Neuroprotective Agents/economics/*therapeutic use ; Quality of Life ; Riluzole/economics/*therapeutic use ; }, abstract = {The availability of a drug that provides modest relief in ALS without altering its inevitable progression and end, has posed new ethical and economic problems for patients, caregivers and physicians. Early evidence suggests that riluzole does provide a short additional quality of life and economic benefit for patient and society. However, there is a clear need for additional therapies, even if the benefit is minor.}, }
@article {pmid11465918, year = {2001}, author = {Meininger, V}, title = {Clinical trials: the past, a lesson for the future.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S15-8}, doi = {10.1080/14660820152415681}, pmid = {11465918}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*trends ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Numerous drugs have been tested in amyotrophic lateral sclerosis with the expectation both that they will treat patients and improve our understanding of some of the basic mechanisms of the disease. Most of these trials were considered to be negative. Careful analysis of the trials does not allow us to clearly discard any of the tested drugs, or any of the suspected mechanisms. Expectations for the future are that: a) we need to be realistic about what to expect; b) we have to define clearly our end-points; c) we have to calculate the expected power before the trials, not after; and d) we have to improve our understanding of the pharmacology.}, }
@article {pmid11465917, year = {2001}, author = {Mitsumoto, H}, title = {Clinical trials: present and future.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S10-4}, doi = {10.1080/14660820152415672}, pmid = {11465917}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic/*trends ; Enzyme Inhibitors/*therapeutic use ; Humans ; }, abstract = {The past decade has seen a major expansion of clinical trials in amyotrophic lateral sclerosis (ALS). However, the perfectly-designed ALS trial remains elusive. Attempts to track the progression of the disease are affected by continual improvements in the care of patients. Comparing the effectiveness of different drugs is difficult because different primary endpoints are used in different studies. We also need to decide how much benefit we are aiming to achieve when studying a new treatment. The interpretation of animal models has also proved problematic, with results not being replicated in human studies. Moreover, promising phase I/II trial results have often not been confirmed by phase III studies. Our patients, meanwhile, are anxious to try any medication that may help. The ALS research community has learned a great deal from past trials and this will be greatly beneficial when evaluating the novel and combination therapies currently being developed. Effort must also be directed towards the search for objective markers for ALS.}, }
@article {pmid11465018, year = {2000}, author = {Watanabe, Y and Kato, S and Adachi, Y and Nakashima, K}, title = {Frameshift, nonsense and non amino acid altering mutations in SOD1 in familial ALS: report of a Japanese pedigree and literature review.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {4}, pages = {251-258}, doi = {10.1080/14660820050515070}, pmid = {11465018}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Codon, Nonsense ; Family Health ; Female ; Frameshift Mutation ; Humans ; Japan ; Male ; Middle Aged ; *Mutation ; Pedigree ; Point Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {We demonstrated the clinical characteristics of each member of a family from Oki Island in western Japan, whose members have familial amyotrophic lateral sclerosis (FALS) with a 2-base pair (bp) deletion at codon 126 of Cu/Zn superoxide dismutase (SOD1) gene. Mean disease duration among the Oki family members was about 2 years. Long-term survivors with respiratory support presented disturbances in eye movement and urination toward the end stages of the disease. In addition, we focused on in-vitro instabilities in the frameshift and nonsense mutations, including the 2-bp deletion, as well as some deletional, insertional and intronic mutations. These mutations were all found within exon 4, exon 5 and intron 4. As for the durations of illness, there were no significant differences between FALS patients with these SOD1 mutations and those with point mutations, although the former cases were likely to have shorter disease durations. In cell culture experiments, SOD1 proteins with frameshift and nonsense mutations were extremely unstable and showed very short half-lives. We postulated that the in-vitro instability of the mutant SOD1 might be related to the pathogenesis of FALS, e.g. through the mechanism of copper release.}, }
@article {pmid11465017, year = {2000}, author = {Mitchell, JD}, title = {Amyotrophic lateral sclerosis: toxins and environment.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {4}, pages = {235-250}, doi = {10.1080/14660820050515061}, pmid = {11465017}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/genetics ; Hazardous Substances/*adverse effects ; Humans ; Risk Factors ; }, abstract = {The role of environmental influences in the aetiopathogenesis of amyotrophic lateral sclerosis (ALS) has exercised minds since the 19th century. Despite strong hunches that environmental agents might be implicated in the causation of ALS, research seeking more objective evidence has generally yielded results which have been confusing and difficult to understand in terms of a unitary aetiological hypothesis. This review attempts to draw this evidence together in the context of a semi-systematic review of the literature. Potential physical influences are described as well as the better known chemical factors. The interface with recent advances in molecular genetics is reviewed as well as foci of ALS variants as they occur in localized areas in various parts of the world. There is a discussion of large and small area geographical clustering and the review concludes by presenting a general view of the possible significance of these--at times--confusing pointers in the context of other current theories of the aetiology of ALS.}, }
@article {pmid11465016, year = {2000}, author = {Xu, Z}, title = {Mechanism and treatment of motoneuron degeneration in ALS: what have SOD1 mutants told us?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {4}, pages = {225-234}, doi = {10.1080/14660820050515052}, pmid = {11465016}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; Humans ; Motor Neurons/enzymology/pathology ; Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron degeneration, skeletal muscle atrophy, paralysis and death. The identification of mutations in Cu,Zn superoxide dismutase (SOD1) as a genetic cause of this disease has led to the creation of a number of in-vitro and in-vivo models. Experiments have been carried out in these model systems to address fundamental questions related to the disease: (1) what is the nature of toxicity of the mutated SOD1? (2) what are the cellular targets and pathways that lead to neuronal degeneration? (3) what makes motoneurons particularly vulnerable to the toxicity of the mutant enzyme? and (4) are there effective treatments for ALS based on current hypotheses regarding the disease mechanism? Current research on these questions is reviewed.}, }
@article {pmid11464952, year = {2000}, author = {Ono, S}, title = {The skin in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {3}, pages = {191-199}, doi = {10.1080/14660820050515188}, pmid = {11464952}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*pathology ; Elasticity ; Humans ; Skin/*pathology ; }, abstract = {It has been repeatedly noted, but never as yet fully explained, that patients with ALS do not develop bedsores even at the terminal stage. Furthermore, the skin of ALS patients feels supple, like tanned leather, and loses elasticity. When the skin is stretched, it returns only sluggishly to its original position. We termed this property of skin 'delayed return phenomenon (DRP)'; it is usually seen more than 2 1/2 years after the onset of symptoms. Though it is thought that phenomena such as DRP and the absence of bedsores are characteristic of this disease, little attention has been paid to these unique features in ALS patients. In this review we summarize recent developments in research on skin from ALS patients, which may give insight into the possible mechanisms and pathogenesis underlying this disorder.}, }
@article {pmid11464951, year = {2000}, author = {Swerdlow, RH and Parks, JK and Pattee, G and Parker, WD}, title = {Role of mitochondria in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {3}, pages = {185-190}, doi = {10.1080/14660820050515179}, pmid = {11464951}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Free Radicals/metabolism ; Humans ; Mitochondria/*metabolism/pathology ; }, abstract = {Neurodegeneration in amyotrophic lateral sclerosis (ALS) is characterized by the specific loss of central and peripheral motor neurons. While this pattern of neuronal demise gives rise to a distinct clinical syndrome, at the cellular and molecular level ALS pathology is similar to that seen in other neurodegenerative diseases. In particular, mitochondrial dysfunction in ALS is reminiscent of that observed in Alzheimer's and Parkinson's diseases. Mitochondria in persons with ALS demonstrate impaired electron transport, increased free radical generation, and an inability to adequately buffer cytosolic calcium shifts. These abnormalities are probably systemic and potentially due to mutation of mitochondrial DNA.}, }
@article {pmid11464950, year = {2000}, author = {Kato, S and Takikawa, M and Nakashima, K and Hirano, A and Cleveland, DW and Kusaka, H and Shibata, N and Kato, M and Nakano, I and Ohama, E}, title = {New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {3}, pages = {163-184}, doi = {10.1080/14660820050515160}, pmid = {11464950}, issn = {1466-0822}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Astrocytes/enzymology/pathology ; Humans ; Inclusion Bodies/enzymology/pathology ; Mutation ; Neurons/enzymology/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Approximately 5-10% of ALS is familial. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. The neuronal Lewy-body-like hyaline inclusion (LBHI) and astrocytic hyaline inclusion (Ast-HI) are morphological hallmarks of certain SOD1-linked FALS patients with SOD1 gene mutant and transgenic mice expressing human SOD1 with G85R mutation. From the detailed immunohistochemical analyses, the essential common protein of both inclusions is SOD1. Ultrastructurally, both inclusions consist of granule-coated fibrils 15-25 nm in diameter. Based on the immuno-electron microscopical finding that these abnormal granule-coated fibrils are positive for SOD1, the formation (or aggregation) of the abnormal fibrils containing SOD1 would be essential evidence in diseases caused by various SOD1 mutations. The granule-coated fibrils are also modified by advanced glycation end products (AGEs). The AGEs themselves are insoluble molecules with direct toxic effects on cells. AGE formation of SOD1 composing the granule-coated fibrils (probable AGE-modified mutant SOD1) may amplify their aggregation and produce a more marked toxicity.}, }
@article {pmid11464949, year = {2000}, author = {Shibata, N and Hirano, A and Yamamoto, T and Kato, Y and Kobayashi, M}, title = {Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {3}, pages = {143-161}, doi = {10.1080/14660820050515151}, pmid = {11464949}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; Mice ; Mice, Transgenic ; *Point Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron system involvement, and is epidemiologically subclassified into sporadic, familial and endemic forms. About 20% of ALS families are associated with mutations in the gene for superoxide dismutase-1 (SOD1) encoded on chromosome 21q22.1. Several studies have pointed to a variety of functions of mutant SOD1, which has enhanced catalytic activity of the peroxynitrite-mediated tyrosine nitration, readily releases the reactive Cu ions, induces apoptotic cell death, has enhanced peroxidase activity, damages the mitochondria to release Ca2+, and forms SOD1-containing aggregates in the cytoplasm. Many of these studies have obtained evidence for increased oxidative damage in ALS. On the other hand, some reports disagree with oxidative damage involvement in SOD1 mutant ALS. In considering the findings of increased oxidative damage in mutant SOD1-expressing transgenic mice, it should be remembered that overexpression of mutant SOD1 may enhance oxidative stress generation from this enzyme. In this review, we present the clinicopathological features of SOD1 mutant familial ALS and its transgenic mouse model, and also discuss SOD1 mutation-related neurotoxicity, including SOD1 protein aggregation and post-translational protein modification.}, }
@article {pmid11464945, year = {2000}, author = {Pioro, EP}, title = {Proton magnetic resonance spectroscopy (1H-MRS) in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S7-16}, doi = {10.1080/14660820052415772}, pmid = {11464945}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; Magnetic Resonance Spectroscopy/*methods ; Protons ; }, abstract = {Establishing the presence of upper motor neuron (UMN) pathology is essential for an accurate and definite diagnosis of ALS. However, clinical identification of UMN dysfunction can be difficult in early disease or if lower motor neuron signs are prominent. A routine technique such as magnetic resonance imaging is usually normal and non-specific. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive neuroimaging technique that has successfully demonstrated evidence of neuronal abnormalities in motor regions of the brain in ALS. This review discusses the advantages and limitations of employing 1H-MRS as an investigative tool in the diagnosis of ALS.}, }
@article {pmid11464944, year = {2000}, author = {Shaw, PJ and Williams, R}, title = {Serum and cerebrospinal fluid biochemical markers of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S61-7}, pmid = {11464944}, issn = {1466-0822}, mesh = {*Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; Biomarkers ; Humans ; }, abstract = {To date there is no satisfactory serum or cerebrospinal fluid (CSF) metabolic marker with which to identify patients with ALS. The goal of finding a suitable marker will be more feasible following the identification of defined subgroups of patients with ALS. Some aspects of neurotransmitter chemistry in CSF seem worthy of further investigation, in particular, clarification of whether there is a significant elevation of CSF glutamate in a subgroup of patients and whether there are robust alterations in the noradrenaline transmitter system. It seems unlikely, in the face of present evidence, that the presence of aberrant exitatory amino acid transporter 2 transcripts in CSF will prove to be a useful marker of ALS. Increased levels of 3-nitrotyrosine and neurofilament light in CSF, while not entirely disease-specific for ALS, may nevertheless prove useful confirmatory markers of the disease and its progression.}, }
@article {pmid11464943, year = {2000}, author = {Robberecht, W}, title = {Genetic markers of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S57-9}, pmid = {11464943}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; *Genetic Markers ; Humans ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {As a result of the advances made in the field of molecular and population genetics, it is anticipated that several genes underlying ALS or predisposing to ALS might be identified in the near future. This will enable physicians to establish a diagnosis of ALS based on molecular findings in addition to clinical and electrophysiological findings. At present, mutations in the gene encoding for the free radical scavenging enzyme, superoxide dismutase (SOD1), is the only basis for a molecular diagnosis. Other mutations are under investigation and confirmed results are eagerly awaited.}, }
@article {pmid11464942, year = {2000}, author = {Weber, M and Eisen, A}, title = {Peristimulus time histograms (PSTHs)--a marker for upper motor neuron involvement in ALS?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S51-6}, doi = {10.1080/14660820052415826}, pmid = {11464942}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electric Stimulation ; Humans ; *Magnetics ; Motor Neurons/*physiology ; Neural Conduction ; Sensitivity and Specificity ; }, abstract = {Upper motor neuron involvement in ALS has been widely studied by means of transcranial magnetic stimulation and various imaging methods, such as magnetic resonance imaging, proton emission tomography, single photon emission computer tomography and magnetic resonance spectroscopy. Although almost all of these methods have detected 'abnormalities' of the motor cortex, no method has yet proven to be capable of monitoring disease progression. We and others have used peristimulus time histograms (PSTH) to evaluate corticomotoneuronal dysfunction. The primary peak (PP) in the PSTH reflects the initial rising phase of the excitatory post-synaptic potential evoked at the anterior horn cell by converging corticomotoneurons. In ALS, the PP is delayed in onset, increased in duration, and desynchronized. These abnormalities become more pronounced over time. Delayed PPs also occur more frequently in non-hereditary ALS (nHALS) with disease progression and are a hallmark of the autosomal recessively inherited D90A Cu-Zn SOD mutation. Evidence indicates that in this particular mutation, as well as in nHALS, the fast-conducting monosynaptic pathway originating from large pyramidal Betz cells is preferentially lost, whereas a slow-conducting pathway seems to be spared. This is most likely due to the enormous metabolic demand of the large pyramidal cells, which may explain the selective vulnerability of the most recent phylogenetic system to develop in the human nervous system.}, }
@article {pmid11464941, year = {2000}, author = {Pouget, J and Trefouret, S and Attarian, S}, title = {Transcranial magnetic stimulation (TMS): compared sensitivity of different motor response parameters in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S45-9}, doi = {10.1080/14660820052415817}, pmid = {11464941}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electric Stimulation ; *Evoked Potentials, Motor ; Humans ; Motor Neurons/*physiology ; Sensitivity and Specificity ; *Transcranial Magnetic Stimulation ; }, abstract = {Owing to the low sensitivity of clinical signs in assessing upper motor neuron (UMN) involvement in ALS, there is a need for investigative tools capable of detecting abnormal function of the pyramidal tract. Transcranial magnetic stimulation (TMS) may contribute to the diagnosis by reflecting a UMN dysfunction that is not clinically detectable. Several parameters for the motor responses to TMS can be evaluated with different levels of significance in healthy subjects compared with ALS patients. The central motor conduction time, however, is not sensitive in detecting subclinical UMN defects in individual ALS patients. The amplitude of the motor evoked potential (MEP), expressed as the percentage of the maximum wave, also has a low sensitivity. In some cases, the corticomotor threshold is decreased early in the disease course as a result of corticomotor neuron hyperexcitability induced by glutamate. Later, the threshold increases, indicating a loss of UMN. In our experience, a decreased silent period duration appears to be the most sensitive parameter when using motor TMS in ALS. TMS is also a sensitive technique for investigating the corticobulbar tract, which is difficult to study by other methods. TMS is a widely available, painless and safe technique with a good sensitivity that can visualize both corticospinal and corticobulbar tract abnormalities. The sensitivity can be improved further by taking into account the several MEP parameters, including latency and cortical silent period decreased duration.}, }
@article {pmid11464940, year = {2000}, author = {Olney, RK and Lomen-Hoerth, C}, title = {Motor unit number estimation (MUNE): how may it contribute to the diagnosis of ALS?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S41-4}, doi = {10.1080/146608200300079473}, pmid = {11464940}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Cell Count ; Electrophysiology/*methods ; Humans ; Motor Neurons/cytology/*physiology ; }, abstract = {Motor unit number estimation (MUNE) is a type of electrophysiological technique that measures the approximate number of lower motor neurons (LMNs) innervating a single muscle or a small group of muscles. Low MUNE counts provide evidence of LMN degeneration, but a single MUNE study does not determine if this loss is ongoing, recent or remote in time. Sequential change of MUNE count provides evidence for ongoing degeneration. Furthermore, sequential change in MUNE from a normal to abnormally low count provides evidence for progressive spread of signs within a region or to another region. MUNE has no established ability to identify other diseases that may provide a non-ALS explanation for the signs of LMN degeneration. If MUNE studies were to be incorporated into a future revision of the diagnostic criteria for ALS, prospective studies will be important to define more clearly the sensitivity and specificity of MUNE in patients with ALS and in patients with weakness that does not involve LMN degeneration. In addition to its potential contributions toward the diagnosis of ALS, MUNE may have greater potential in quantifying the rate of progression in studies of the natural history of ALS and the response to experimental treatment.}, }
@article {pmid11464939, year = {2000}, author = {Tröger, M and Dengler, R}, title = {The role of electromyography (EMG) in the diagnosis of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S33-40}, doi = {10.1080/14660820052415808}, pmid = {11464939}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; *Electromyography ; Humans ; }, abstract = {Electromyography (EMG) plays a key role in the diagnostic evaluation of ALS. This paper deals with the contribution of conventional needle EMG and electroneurography to the neurophysiological assessment of ALS. In addition, special EMG techniques such as single fibre EMG and macro EMG are discussed as they mirror the decline of the number of motor units during the disease process and the remodelling capacity of the surviving motor units.}, }
@article {pmid11464938, year = {2000}, author = {Shiozawa, Z and Shindo, K and Ohta, E and Ohushi, K and Nagamatsu, M and Nagasaka, T}, title = {A concise overview of recent breakthroughs in imaging of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S3-6}, doi = {10.1080/14660820052415763}, pmid = {11464938}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; *Tomography, Emission-Computed ; *Tomography, Emission-Computed, Single-Photon ; }, abstract = {Numerous attempts have been made to visualize the motor cortex and pyramidal tract lesions in patients with ALS using magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). This paper briefly reviews the applicability of these imaging modalities in ALS.}, }
@article {pmid11464937, year = {2000}, author = {Brooks, BR and Bushara, K and Khan, A and Hershberger, J and Wheat, JO and Belden, D and Henningsen, H}, title = {Functional magnetic resonance imaging (fMRI) clinical studies in ALS--paradigms, problems and promises.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S23-32}, doi = {10.1080/14660820052415790}, pmid = {11464937}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Humans ; *Magnetic Resonance Imaging ; }, abstract = {Functional magnetic resonance imaging (fMRI) provides high-resolution, non-invasive estimates of neural activity detected by a blood oxygen level dependent signal by assessing the increase in blood flow to the local vasculature that accompanies neural activity in the brain. fMRI studies with standard hand motor test (index-thumb opposition, ITO, or pinch) in ALS patients show good test-retest reliability and similar amplitude of signals in ALS patients compared with control subjects. Isometric force can be performed with careful control for the force exerted, recruitment of other muscles and motion artefact. The volume (number of voxels above threshold) of sensorimotor and cerebellar cortex activated by ITO is reproducibly larger in ALS patients compared with control subjects. Imagined movements in ALS have been studied, as in amputees, and larger volumes are activated in ALS patients with imagined movements as well, compared with control subjects. fMRI studies in ALS patients evaluating cortical activation during pure somatosensory stimulation cutaneous stimulation of the hand to elicit the palmomental response and cutaneous stimulation of the sole to elicit the plantar response - indicate that ALS patients activate a significantly smaller volume of the contralateral sensorimotor cortex compared to control subjects. No statistically significant difference was seen in other areas, including the ipsilateral cerebellum and the contralateral thalamus. An anterior shift in the volume of cortex activated by these paradigms occurs in ALS patients, with a volume of activation, anteriorly, not activated in control subjects. fMRI studies will complement other clinical neurophysiological and neuroimaging techniques in our future attempts to solve the riddle of ALS and other motor neuron diseases.}, }
@article {pmid11464936, year = {2000}, author = {Turner, MR and Leigh, PN}, title = {Positron emission tomography (PET)--its potential to provide surrogate markers in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S17-22}, doi = {10.1080/14660820052415781}, pmid = {11464936}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging ; Humans ; *Tomography, Emission-Computed ; }, abstract = {Positron emission tomography (PET) has enabled us to study the human brain with unrivalled sensitivity, and has already established its place in the research of neurological conditions such as Parkinson's disease and epilepsy. PET has been used as a tool in the study of patients with motor neuron disease (MND) for well over ten years now, but its potential in diagnosis and to identify surrogate markers of disease expression (phenotype) and progression has yet to be fully realized. The early studies using 2-18fluoro-2-deoxy-D-glucose to measure regional changes in cerebral metabolic rate for glucose gave the first clues to the more widespread involvement of the brain in MND. Later studies exploited the development of activation studies using 15O-containing tracers, which allowed correlation with neuropsychological measures, and the refinement of mapping techniques to delineate the extra-motor areas involved in the disease process. More recently, studies involving ligands such as 11C-flumazenil have allowed the exploration of functional reorganisation in MND, and inhibitory interneuronal pathways which may be crucial in modulation of disease expression. In the future new ligands will be applied in combination with other modalities of investigation (multimodal magnetic resonance imaging; neurophysiological studies) in order to understand the pathophysiology of this heterogeneous condition. Although the potential of PET has not yet been realized in ALS, it is likely to play a part in defining new diagnostic and surrogate markers of disease extent and severity.}, }
@article {pmid11464934, year = {2000}, author = {Brooks, BR}, title = {Versailles minimal dataset for diagnosis of ALS: a distillate of the 2nd Consensus Conference on accelerating the diagnosis of ALS. Versailles 2nd Consensus Conference participants.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S79-81}, doi = {10.1080/14660820050515629}, pmid = {11464934}, issn = {1466-0822}, mesh = {Diagnosis, Differential ; Diagnostic Imaging ; Humans ; Motor Neuron Disease/*diagnosis ; Neurologic Examination ; Patient Care Team ; Practice Guidelines as Topic ; Prognosis ; }, abstract = {The 2nd Consensus Conference (Versailles) recommended that an ALS knowledge-base for initial healthcare providers, diagnosing neurologists and confirming neurologists should be defined to include a simplified version of diagnostic criteria less formal than the World Federation of Neurology El Escorial Revisted Criteria ('ALS diagnosis - An algorithm'), a set of rules concerning red flags which should increase the suspicion of ALS as the diagnosis and minimize the time between suspicion and referral for confirmation of diagnosis ('ALS axioms of referral'), as well as a site of symptom onset-specific checklist of minimal clinical examination, neuroimaging, electrodiagnostic, pulmonary function and laboratory test information required to confirm the diagnosis of ALS ('Versailles minimal dataset'). Although introductory discussions addressed the advantages and disadvantages of earlier diagnosis, false-positive or false-negative diagnosis, the frequency of follow-up and what potential biological markers to be followed, these issues will have to be further evaluated at future consensus conferences.}, }
@article {pmid11464926, year = {2000}, author = {Eisen, A and Weber, M}, title = {Neurophysiological evaluation of cortical function in the early diagnosis of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S47-51}, doi = {10.1080/14660820052415907}, pmid = {11464926}, issn = {1466-0822}, mesh = {Anterior Horn Cells/physiology ; Electroencephalography ; Electromyography ; Glutamic Acid/physiology ; Humans ; Interneurons/physiology ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/*physiology ; Muscle, Skeletal/*innervation ; Synaptic Transmission/*physiology ; }, abstract = {The corticomotoneuronal system is selectively vulnerable in amyotrophic lateral sclerosis (ALS). In the past it has been difficult to evaluate the upper motor neuron component of this system. Recent studies using functional imaging and neurophysiological methods are now available as potential surrogate markers in the early diagnosis of ALS. We have used peristimulus time histograms (PSTHs) to evaluate the integrity of the motor cortex in ALS and in particular the cortical colonies that synapse with single anterior horn cells. The motor cortex in ALS becomes hyperexcitable early in the course of the disease and this may persist for some time. This is reflected in the PSTH by a desynchronized, complex response. Evidence indicates that this prime abnormality in ALS is supraspinal in origin and probably due to increased repetitive firing of the corticomotoneuron. The hyperexcitability is likely to be due to a combination of increased excitation at the level of the motor cortex and decreased inhibition due to dysfunction of the cortical inhibitory interneurones that modulate the output of the corticomotoneurone.}, }
@article {pmid11464924, year = {2000}, author = {Andersen, PM}, title = {Genetic factors in the early diagnosis of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S31-42}, doi = {10.1080/14660820052415899}, pmid = {11464924}, issn = {1466-0822}, mesh = {Gene Frequency/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Testing ; Genotype ; Humans ; Motor Neuron Disease/diagnosis/*genetics ; Mutation/genetics ; Pedigree ; Penetrance ; Superoxide Dismutase/genetics ; }, abstract = {The frequency of familial amyotrophic lateral sclerosis (ALS) is usually reported as 5-10% of all ALS cases. This figure is probably an underestimate, primarily due to inadequate recording of family history in the patients' charts, and to the not infrequent occurrence of reduced disease penetrance in pedigrees with familial ALS. The true familial ALS frequency may be at least double this. Familial ALS is heterogenetic. The only known ALS-causing gene is the CuZn-superoxide dismutase gene (CuZn-SOD). Mutations in this gene account for a fifth of all familial ALS cases and a few percent of apparent sporadic ALS cases. Genetic testing for CuZn-SOD mutations can help confirm a diagnosis of ALS, especially in cases with atypical features that have been reported in some cases with CuZn-SOD mutations. Genetic testing should only be performed after thorough clinical examination and in cases with a proven or uncertain family history of ALS. It is not warranted in cases with no proven family history for three generations, unless the patient shows the characteristic phenotype associated with recessive inheritance of the D90A CuZn-SOD mutation.}, }
@article {pmid11464923, year = {2000}, author = {Brooks, BR}, title = {Problems in shortening the time to confirmation of ALS diagnosis: lessons from the 1st Consensus Conference, Chicago, May 1998.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S3-7}, doi = {10.1080/146608200300079987}, pmid = {11464923}, issn = {1466-0822}, support = {M01 RR03186/RR/NCRR NIH HHS/United States ; }, mesh = {Diagnostic Imaging ; Electromyography ; Humans ; Motor Neuron Disease/*diagnosis/therapy ; Neurologic Examination ; Patient Care Team ; Practice Guidelines as Topic ; }, abstract = {The 2nd Consensus Conference (Versailles) on the early diagnosis of amyotrophic lateral sclerosis (ALS) developed themes identified at the 1st Consensus Conference (Chicago) on defining optimal management in ALS. These themes included describing the problems and limitations in current diagnostic practices, identifying consequences of early diagnosis on patient management, establishing recommendations to help healthcare personnel achieve the early diagnosis and proposing solutions to facilitate early diagnosis of ALS. Lessons from the ISIS Survey and the 1st Consensus Conference focused on the variability of the first-contact physician, supply factors for specialists and variability of application of medical techniques. The recently introduced concept of 'ALS health states or stages' was reviewed in terms of ongoing and potential prospective studies. The relative contribution of neuroimaging or clinical neurophysiological investigations to accelerating the diagnosis of ALS in clinical practice was debated. The role of a common ALS knowledge-base among patients, initial healthcare providers, diagnosing neurologists and confirming neurologists was critically appraised with regard to simplified 'ALS diagnostic algorithm', 'ten aphorisms in the diagnosis of ALS' and 'ALS axioms of referral'. Refining this ALS knowledge-base is required to identify a minimum dataset required for the evaluation and diagnosis of ALS.}, }
@article {pmid11464851, year = {2000}, author = {Mitsumoto, H and Del Bene, M}, title = {Improving the quality of life for people with ALS: the challenge ahead.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {5}, pages = {329-336}, doi = {10.1080/146608200300079464}, pmid = {11464851}, issn = {1466-0822}, mesh = {Attitude to Health ; Caregivers ; Enteral Nutrition ; Exercise ; Family ; Hospice Care ; Humans ; Motor Neuron Disease/psychology/rehabilitation/*therapy ; Patient Care Team ; *Quality of Life ; }, abstract = {In tandem with recent progress in basic and clinical research in amyotrophic lateral sclerosis (ALS), clinical care and management has improved substantially. Key processes and practices have been established and are specified in current ALS Practice Parameters; the international ALS databases identify the current status of care and management given by physicians. A number of prospective clinical management research studies are now well underway to establish the effective utility of enteral feeding, assistive ventilatory device, and exercise in patients with ALS. One of the main research objectives in the clinical management of ALS is to improve patients' quality of life. For patients with ALS, only comprehensive multidisciplinary care can effectively improve their overall quality of life from diagnosis to death. This paper will briefly review a number of factors that must be considered if we are to improve the quality of life for these patients, including comprehensive medical management, patient education, the importance of hope, the role of the health care professional, and the patients themselves.}, }
@article {pmid11464850, year = {2000}, author = {Bajaj, NP}, title = {Cyclin-dependent kinase-5 (CDK5) and amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {5}, pages = {319-327}, doi = {10.1080/146608200300079563}, pmid = {11464850}, issn = {1466-0822}, mesh = {Animals ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*metabolism ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/*pathology/*physiopathology ; Neurofilament Proteins/metabolism ; Phosphorylation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Cyclin-dependent kinase-5 (CDK5) is a serine-threonine protein kinase that has been implicated in a number of physiological processes in nerve and muscle cells, including neurogenesis, neuritic outgrowth, axonal transport of membrane-bound organelles and myogenesis. CDK5 has also been shown to phosphorylate the important cytoskeletal proteins, neurofilament and tau, both in vitro and in cells. The latter has prompted study into the potential role of CDK5 in the hyperphosphorylation of these proteins as part of the neuropathology seen in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. More recently, increasing evidence has suggested a role for CDK5 in cellular apoptosis. Apoptosis has been implicated as the final common pathway of cell death in a number of neurodegenerative diseases including ALS. This article sets out to review the physiological and pathological roles ascribed to CDK5 and the possible relevance thereof to the pathogenesis of ALS.}, }
@article {pmid11464849, year = {2000}, author = {Mazzini, L and Balzarini, C}, title = {An overview of H-reflex studies in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {5}, pages = {313-318}, doi = {10.1080/146608200300079554}, pmid = {11464849}, issn = {1466-0822}, mesh = {Electrophysiology/methods ; *H-Reflex ; Humans ; Motor Neuron Disease/*diagnosis/*physiopathology ; Motor Neurons/physiology ; Presynaptic Terminals/physiology ; }, abstract = {H-reflex methods were used to investigate motor neuron excitability and the basic physiology of segmental spinal reflexes. While many studies have been performed using these electrophysiological techniques, in both normal subjects and patients with different neurological diseases, few studies have focused on patients affected by amyotrophic lateral sclerosis (ALS). This article reviews the various electrophysiological techniques which use H-reflex to study the physiology of segmental spinal reflexes in motor neuron diseases. Their possible applications for elucidating pathophysiological mechanisms in ALS and for monitoring the disease during clinical trials are discussed.}, }
@article {pmid11464848, year = {2000}, author = {Doble, A and Kennel, P}, title = {Animal models of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {5}, pages = {301-312}, doi = {10.1080/146608200300079545}, pmid = {11464848}, issn = {1466-0822}, mesh = {Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; Motor Neuron Disease/*physiopathology/therapy ; Motor Neurons/drug effects/pathology ; Neurotoxins/toxicity ; Superoxide Dismutase/genetics ; }, abstract = {Animal models of human disease are important in unravelling the pathophysiology of the condition, for exploring the natural history of disease and for evaluating potential therapies. The development of animal models of human neurodegenerative disease such as ALS is particularly challenging, given the paucity of knowledge of their aetiology and the organizational specificity of the human motor system. Nonetheless, a range of spontaneously occurring, experimentally produced, or genetically engineered models of ALS are now available. Although not always a perfect replica of the ALS disease, these models are shown to be of outstanding importance for investigations of the mechanisms of dysfunction/death of motor neurons in vivo. This is particularly true for the transgenic mouse models expressing superoxide dismutase or cytoskeletal proteins. This approach has provided an unparalleled opportunity for testing of potential pharmacological or gene therapies, and it can be expected that the results of these studies will be translated into the clinical advances of the next years.}, }
@article {pmid11464847, year = {2000}, author = {Brooks, BR and Miller, RG and Swash, M and Munsat, TL and , }, title = {El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {5}, pages = {293-299}, doi = {10.1080/146608200300079536}, pmid = {11464847}, issn = {1466-0822}, mesh = {Diagnosis, Differential ; Electrophysiology/methods ; Humans ; Motor Neuron Disease/*diagnosis/pathology/physiopathology ; Motor Neurons/pathology/physiology ; Nerve Degeneration ; }, }
@article {pmid11464472, year = {2000}, author = {Moriwaka, F and Tashiro, K}, title = {[The advance in the research and therapeutic trials of amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {40}, number = {12}, pages = {1258-1260}, pmid = {11464472}, issn = {0009-918X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/etiology ; Controlled Clinical Trials as Topic ; Drug Design ; Excitatory Amino Acids/metabolism ; Humans ; Naphthalenes/therapeutic use ; Neuroprotective Agents/pharmacology/therapeutic use ; Practice Guidelines as Topic ; Pyridines/therapeutic use ; Riluzole/pharmacology/therapeutic use ; }, abstract = {The research concerning with the pathogenesis of amyotrophic lateral sclerosis (ALS) has been in steady progress in the last 10 years, including discovery of SOD mutation in familial ALS. Riluzole, by its inhibiting excitatory amino acid release, is the only drug, which has been demonstrated the neuroprotective activity in the randomised double-blind placebo-controlled clinical trials in patients with ALS, although many other clinical therapeutic trials for ALS patients has been carried out. We discussed the clinical trials being the under way, especially SR57746A, (1-[2-(naphth-2-yl)ethy]-4-(3-trifluoromethyl phenyl)-1, 2, 5, 6-tetrahydro-pyridine, hydrochloride), a non-peptide compound which has been shown to exhibit a wide range of neurotrophic effects both in vitro and in vivo, and its phase II study in Japan and two kinds of phase III studies ongoing in the United States, Canada and Europe. We also introduced the clinical guideline for practice and care of ALS patients proposed by American Academy of Neurology, expecting to establish clinical guideline to be applicable to Japanese cases.}, }
@article {pmid11462792, year = {2001}, author = {Imam, SZ and el-Yazal, J and Newport, GD and Itzhak, Y and Cadet, JL and Slikker, W and Ali, SF}, title = {Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts.}, journal = {Annals of the New York Academy of Sciences}, volume = {939}, number = {}, pages = {366-380}, doi = {10.1111/j.1749-6632.2001.tb03646.x}, pmid = {11462792}, issn = {0077-8923}, mesh = {Animals ; Antioxidants/pharmacology ; Biomarkers/analysis ; Dopamine/*metabolism ; Dopamine Agents/*toxicity ; Enzyme Inhibitors/pharmacology ; Humans ; Indazoles/pharmacology ; Methamphetamine/*toxicity ; Nitrates/*metabolism ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Nitric Oxide Synthase Type I ; PC12 Cells ; Rats ; Tyrosine/*analogs &amp; derivatives/*drug effects/metabolism ; }, abstract = {Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.}, }
@article {pmid11462390, year = {2001}, author = {Kurosawa, K}, title = {[Amyotrophic lateral sclerosis].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {33}, pages = {178-180}, pmid = {11462390}, mesh = {*Amyotrophic Lateral Sclerosis ; Female ; Humans ; Male ; }, }
@article {pmid11460829, year = {2001}, author = {Orrell, RW and Figlewicz, DA}, title = {Clinical implications of the genetics of ALS and other motor neuron diseases.}, journal = {Neurology}, volume = {57}, number = {1}, pages = {9-17}, doi = {10.1212/wnl.57.1.9}, pmid = {11460829}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Animals ; Gene Deletion ; Humans ; Motor Neuron Disease/diagnosis/*genetics ; Mutation, Missense ; Trinucleotide Repeats ; }, abstract = {Genetic mutations have been identified in the major motor neuron diseases, including ALS, spinal muscular atrophy, bulbospinal muscular atrophy (Kennedy's disease), the hereditary spastic paraplegias, and rarer conditions such as GM2 gangliosidosis (hexosaminidase A deficiency). These include mutations in the SOD1 gene, deletions of the telomeric copy of the SMN gene, expansions of the trinucleotide repeat region in the first exon of the androgen receptor gene, other rare mutations, and diseases where linkage has been established but the gene not identified. Identification of one of these genetic abnormalities will allow specific diagnosis in patients. Because cure is not yet available, presymptomatic testing is seldom indicated; in such cases, careful counseling is appropriate.}, }
@article {pmid11442328, year = {2001}, author = {Fink, JK}, title = {Progressive spastic paraparesis: hereditary spastic paraplegia and its relation to primary and amyotrophic lateral sclerosis.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {199-207}, doi = {10.1055/s-2001-15265}, pmid = {11442328}, issn = {0271-8235}, support = {R01NS33645/NS/NINDS NIH HHS/United States ; R01NS36177/NS/NINDS NIH HHS/United States ; R01NS38713/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications/pathology/*physiopathology ; Heredodegenerative Disorders, Nervous System/*complications/pathology/*physiopathology ; Humans ; Motor Neuron Disease/*complications/pathology/*physiopathology ; Paraparesis, Spastic/*complications/pathology/*physiopathology ; }, abstract = {The syndrome of insidiously progressive spastic weakness of both legs occurs in a number of etiologically distinct disorders including hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and sometimes in amyotrophic lateral sclerosis (ALS). This review summarizes the clinical and pathologic relationship between these disorders.}, }
@article {pmid11442326, year = {2001}, author = {Verma, A and Bradley, WG}, title = {Atypical motor neuron disease and related motor syndromes.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {177-187}, doi = {10.1055/s-2001-15263}, pmid = {11442326}, issn = {0271-8235}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/*diagnosis/*physiopathology ; Motor Neurons/physiology ; Syndrome ; Time Factors ; }, abstract = {There is an imperative need for the early diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) in the current era of emerging treatments. When evaluating the patient with ALS/MND, the neurologist must consider a number of other motor neuron disorders and related motor syndromes that may have clinical features resembling ALS/MND. The revised Airlie House-El Escorial diagnostic criteria have been established through the consensus of experts meeting at workshops. However, by definition, using these criteria a patient is likely to have fairly advanced disease at the time of a definitive ALS/MND diagnosis. The reasons for the difficulty in making an early ALS/MND diagnosis are several. No surrogate diagnostic marker currently exists for ALS/MND. ALS/MND at its onset is heterogeneous in clinical presentation, its clinical course is variable, and several clinical variants are recognized. In addition, certain motor syndromes, such as monomelic amyotrophy, postpolio muscular atrophy, and multifocal motor neuropathy, can clinically mimic ALS/MND. Therefore, not only may the diagnosis of ALS/MND be clinically missed in the early stages, but worse, the patient may be wrongly labeled as having ALS/MND. The diagnosis of ALS/MND requires a combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Motor syndromes in which the deficit is restricted to the UMN or LMN through the entire course of the disease are described as atypical MND in this review. Approximately 5% of patients with ALS/MND have overt dementia with a characteristic frontal affect. ALS/MND with parkinsonism and dementia is rare outside the western Pacific region. The clinical course of motor disorder in these overlap syndromes does not differ from that in typical ALS/MND.}, }
@article {pmid11442325, year = {2001}, author = {Turner, MR and Parton, MJ and Leigh, PN}, title = {Clinical trials in ALS: an overview.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {167-175}, doi = {10.1055/s-2001-15262}, pmid = {11442325}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Meta-Analysis as Topic ; Research Design ; Riluzole/therapeutic use ; }, abstract = {Clinical trials in amyotrophic lateral sclerosis (ALS) have been conducted for over half a century now and have incorporated a wide variety of drugs. Most of these trials have had negative results and a cure remains elusive. The explosion in our understanding of molecular biology and parallel developments in clinical epidemiology have opened up a vast number of novel therapeutic strategies. However, advances in statistical analysis, computing, and global communications have also put greater pressure on scientific investigators to improve the design and implementation of clinical trials so that they permit rigorous testing of hypotheses within a solid ethical framework. This article documents the first published trial for all drugs tried clinically in the treatment of ALS, focusing in more detail on the large, multicenter trials of recent years, namely those involving riluzole, ciliary neurotrophic factor, insulin-like growth factor-I, brain-derived neurotrophic factor, and SR57746A. The problems in the design of trials in ALS are discussed, including the selection of end points and surrogate markers of disease progression, and the major parameters in ALS assessment are reviewed.}, }
@article {pmid11442324, year = {2001}, author = {Borasio, GD and Miller, RG}, title = {Clinical characteristics and management of ALS.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {155-166}, doi = {10.1055/s-2001-15268}, pmid = {11442324}, issn = {0271-8235}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Hospice Care ; Humans ; Palliative Care ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of degenerative motor neuron disease in adulthood. The clinical picture was accurately described by Charcot over 125 years ago and consists of generalized fasciculations, progressive atrophy and weakness of the skeletal muscles, spasticity and pyramidal tract signs, dysarthria, dysphagia, and dyspnea. Pseudobulbar affect is common. Disease-specific treatment options are still unsatisfactory. However, therapeutic nihilism is not justified as a large array of palliative measures is available to enhance the quality of life of patients and their families. Palliative care in ALS is a multidisciplinary effort requiring careful coordination. An open and frank disclosure of the diagnosis is of paramount importance. Nutritional deficiency due to pronounced dysphagia can be relieved by a percutaneous endoscopic gastrostomy. Respiratory insufficiency can be effectively treated by noninvasive home mechanical ventilation. The terminal phase of the disease should be discussed, at the latest, when symptoms of dyspnea appear in order to prevent unwarranted fears of "choking to death." Collaboration with hospice and completion of advance directives can be of invaluable help in the terminal phase.}, }
@article {pmid11442323, year = {2001}, author = {Eisen, A}, title = {Clinical electrophysiology of the upper and lower motor neuron in amyotrophic lateral sclerosis.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {141-154}, doi = {10.1055/s-2001-15261}, pmid = {11442323}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Electromyography ; Electrophysiology ; Excitatory Postsynaptic Potentials/physiology ; Humans ; Motor Cortex/physiopathology ; Motor Neurons/*physiology ; Muscle, Skeletal/physiopathology ; Neural Conduction/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Electrophysiology is important in amyotrophic lateral sclerosis (ALS). It helps in the assessment of disease severity and rate of progression, and it plays a role in evaluating the efficacy of therapeutic trials. Presently, electrophysiology is the only means of confirming suspected ALS, and this has been incorporated into the El Escorial criteria. Needle electromyography identifies disease in clinically "unaffected muscles" including bulbar musculature, confirms involvement of anterior horn cells, and can detect early involvement of respiratory muscles (intercostals and diaphragm). Conduction studies are imperative to rule out motor neuropathy with multifocal conduction block. Various techniques (cortical threshold, cortical silent period, double stimulation) employing transcranial magnetic stimulation have demonstrated that the motor cortex in ALS is hyperexcitable. Central motor conduction is normal in ALS but uniquely slow in the D9OA SOD1 mutation. Using peristimulus time histograms (PSTHs) it is possible to estimate the size of a unitary excitatory postsynaptic potential (EPSP). In ALS the EPSP is typically desynchronized. With time it becomes reduced in amplitude and a slow conducting component becomes recognizable in the primary peak of the PSTH. This reflects conduction through a slow motor pathway. Abnormalities of the PSTH are not seen in Kennedy's disease, implying that the changes seen in ALS are due to supraspinal mechanisms.}, }
@article {pmid11442322, year = {2001}, author = {Brown, RH and Robberecht, W}, title = {Amyotrophic lateral sclerosis: pathogenesis.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {131-139}, doi = {10.1055/s-2001-15260}, pmid = {11442322}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Animals ; Humans ; Mice ; Motor Neurons/physiology ; Mutation/genetics ; Neurons/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by motor neuron degeneration. A subgroup of familial cases arises from mutations in the gene encoding cytosolic superoxide dismutase (SOD1). This review considers insight now being gained into ALS pathogenesis from the study of mutant SOD1 protein and its possible mechanisms of adverse effect on nerve cells. Also discussed are the status of other genetic forms of ALS and the elusive question of why this disorder so specifically targets motor neurons. Ultimately, it is hoped that insights from these types of studies will improve the prospects for developing meaningful therapies of ALS.}, }
@article {pmid11436263, year = {2001}, author = {Turner, M}, title = {The treatment of motor neurone disease.}, journal = {The Practitioner}, volume = {245}, number = {1623}, pages = {530-2, 536-8}, pmid = {11436263}, issn = {0032-6518}, mesh = {Analgesics/therapeutic use ; Enteral Nutrition ; Humans ; Motor Neuron Disease/drug therapy/*therapy ; Neuroprotective Agents/therapeutic use ; Patient Care Management ; Patient Education as Topic ; Physical Therapy Modalities ; Physician's Role ; Riluzole/therapeutic use ; }, }
@article {pmid11432802, year = {2001}, author = {Smith, DS and Greer, PL and Tsai, LH}, title = {Cdk5 on the brain.}, journal = {Cell growth &amp; differentiation : the molecular biology journal of the American Association for Cancer Research}, volume = {12}, number = {6}, pages = {277-283}, pmid = {11432802}, issn = {1044-9523}, mesh = {Alzheimer Disease/enzymology ; Animals ; Axons/physiology ; Brain/*enzymology ; Cell Movement/physiology ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*metabolism/physiology ; Humans ; Neurons/enzymology/physiology ; *Signal Transduction ; }, abstract = {Mammalian brains are highly compartmentalized into groups of functionally specialized neurons. Cell migration and neurite outgrowth must be tightly orchestrated to achieve this level of organization. A small serine/threonine kinase that shows homology to cyclin-dependent kinases (Cdks) has emerged as an important regulator of neuronal migration. Cdk5, unlike other Cdks, is not regulated by cyclins, and its activity is primarily detected in postmitotic neurons in developing and adult nervous systems. This review describes work indicating that Cdk5 links extracellular signaling pathways and cytoskeletal/membrane systems to direct neuronal migration, axon growth, and possibly neurosecretion. Despite its importance, unchecked Cdk5 activity is toxic to neurons, and may underlie some of the pathologies associated with neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid11431138, year = {2001}, author = {Boisclair, YR and Rhoads, RP and Ueki, I and Wang, J and Ooi, GT}, title = {The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system.}, journal = {The Journal of endocrinology}, volume = {170}, number = {1}, pages = {63-70}, doi = {10.1677/joe.0.1700063}, pmid = {11431138}, issn = {0022-0795}, support = {DK-51624/DK/NIDDK NIH HHS/United States ; }, mesh = {Adult ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/chemistry/genetics/*physiology ; Glycoproteins/chemistry/genetics/*physiology ; Growth Hormone/deficiency/metabolism ; Humans ; Insulin/metabolism ; Liver/*metabolism ; Mice ; Mice, Knockout ; Models, Animal ; Rats ; Somatomedins/*physiology ; }, abstract = {The insulin-like growth factors-I and -II (IGFs) are involved in a wide array of cellular processes such as proliferation, prevention of apoptosis, and differentiation. Most of these effects are mediated by the IGF-I receptor, although at higher IGF concentrations the insulin receptor can also be activated. As the expression of both the IGFs and their receptors is widespread, IGFs are thought to have autocrine/paracrine modes of actions also, particularly during foetal life. The endocrine component of the IGF system is recognised to be important after birth, with IGF-I mediating many of the effects of growth hormone (GH), and linking anabolic processes to nutrient availability. Consideration of ligands and receptors, however, is insufficient to provide a complete understanding of the biology of IGF. This is because IGFs are found in binary complexes of 40-50 kDa with members of a family of IGF-binding proteins (IGFBPs-1 to -6) in all biological fluids. In addition, in postnatal serum, most IGFs are sequestered into ternary complexes of 150 kDa consisting of one molecule each of IGF, IGFBP-3 or IGFBP-5, and acid-labile subunit (ALS). Despite evidence that ALS plays an important role in the biology of circulating IGFs, it has received only limited attention relative to the other components of the IGF system. This review provides an overview on the current knowledge of ALS protein and gene structure, organisation and regulation by hormones, and insights from novel animal models such as the ALS knockout mice.}, }
@article {pmid11424902, year = {2001}, author = {Danysz, W}, title = {Neurotoxicity as a mechanism for neurodegenerative disorders: basic and clinical aspects.}, journal = {Expert opinion on investigational drugs}, volume = {10}, number = {5}, pages = {985-989}, doi = {10.1517/13543784.10.5.985}, pmid = {11424902}, issn = {1354-3784}, mesh = {Alzheimer Disease/*etiology ; Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Humans ; Levodopa/toxicity ; Nerve Growth Factor/toxicity ; Neuroprotective Agents/pharmacology ; Nicotine/pharmacology ; Parkinson Disease/*etiology ; }, abstract = {This three day meeting focused on chronic neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods.}, }
@article {pmid11424053, year = {2001}, author = {Calzada Sierra, DJ}, title = {[Bioethical considerations in the approach to patients with amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {32}, number = {10}, pages = {952-957}, pmid = {11424053}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/therapy ; *Bioethics ; Cost of Illness ; Euthanasia/ethics ; Humans ; Palliative Care/ethics ; Physician-Patient Relations ; Quality of Life ; }, abstract = {INTRODUCTION: The traditional doctor-patient relation has become a great bioethical challenge due to the advances in science in recent years. This is particularly true when patients suffer diseases such as amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a relentless course and in spite of modern treatment 50% of the patients die within three years of first having symptoms of the disease. It therefore causes great psychological and social impact.<br><br>OBJECTIVE: To analyze the great bioethical challenge which arises when diagnosing and treating a patient with ALS.<br><br>DEVELOPMENT: In this paper we analyze the doctor-patient relationship, the principles of doing no harm and of being beneficial, and more modern concepts such as informed consent, biomedical investigations and euthanasia, as well as the importance of palliative medicine and rehabilitation to alleviate suffering and improve quality of life. Biomedical investigations should conform to the relevant national and international rules. We discuss the right of patients to be given truthful information.<br><br>CONCLUSIONS: We recommend better training of doctors in all aspects of attention to these patients, with emphasis on the diagnosis and importance of rehabilitation, palliative medicine and the management of psychological aspects. Biomedical investigations should fulfil current regulations. We recommend discretion, complete or partial, with regard to information given to the patients and their relatives so as not to cause despair.}, }
@article {pmid11417073, year = {2001}, author = {Benders, NA and Wijnberg, ID and van der Kolk, JH}, title = {[Equine motor neuron disease: a review based on a case report].}, journal = {Tijdschrift voor diergeneeskunde}, volume = {126}, number = {11}, pages = {376-380}, pmid = {11417073}, issn = {0040-7453}, mesh = {Animals ; Electromyography/veterinary ; Female ; Horse Diseases/*diagnosis/pathology ; Horses ; Motor Neuron Disease/diagnosis/pathology/*veterinary ; Muscular Atrophy/veterinary ; Prognosis ; Vitamin E/blood ; }, abstract = {A 10-year-old, non-pregnant Dutch Warmblood mare was referred to the Department of Equine Science because of chronic weight loss, despite good appetite, and dullness. Clinical examination revealed muscle atrophy, trembling of the limb muscles, an abnormal stance in which all four limbs were placed under the body, and an abnormal low head carriage. The plasma vitamin E concentration was markedly decreased (0.2 mumol/l), the electromyographic (EMG) examination was consistent with denervation, and the oral glucose absorption test was below the reference value (40% increase over the resting glucose level). Because of the clinical diagnosis of equine motor neuron disease (EMND), the horse was euthanazed and post-mortem examination confirmed this diagnosis. Based on the similarity in pathological findings, EMND can be compared to amyotrophic lateral sclerosis (ALS) in humans. However, in horses, only the lower motor neurons and occasionally some nuclei of the cranial nerves are affected. Because of the low plasma vitamin E concentration found in horses with EMND, an absolute or a relative antioxidant deficiency can be involved in the pathogenesis. In general, it is a progressive disease process and stabilization of the situation is the best feasible result. There is no specific therapy other than vitamin E supplementation and the prognosis is poor.}, }
@article {pmid11406080, year = {2001}, author = {Sethi, D and Kwan, I and Kelly, AM and Roberts, I and Bunn, F}, title = {Advanced trauma life support training for ambulance crews.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD003109}, doi = {10.1002/14651858.CD003109}, pmid = {11406080}, issn = {1469-493X}, mesh = {Controlled Clinical Trials as Topic ; Emergency Medical Technicians/*education ; Humans ; *Life Support Care ; Randomized Controlled Trials as Topic ; Traumatology/*education ; }, abstract = {BACKGROUND: There is an increasing global burden of disease from injuries. Models of trauma care initially developed in high-income countries are also being adopted in low and middle-income countries (LMIC). Amongst these ambulance crews with Advanced Life Support (ALS) training are being promoted in LMIC as a strategy for improving outcomes for victims of trauma. However there is controversy as to the effectiveness of this health service intervention, and the evidence has yet to be rigorously appraised.<br><br>OBJECTIVES: To quantify the effectiveness of ambulance crews with ALS training versus crews with any other level of training in reducing mortality and morbidity in trauma patients.<br><br>SEARCH STRATEGY: We searched the Cochrane Controlled Trial Register (CCTR), the specialised register of the Cochrane Injuries Group, MEDLINE, EMBASE, CINAHL, PubMed and the National Research Register. We checked references of background papers and contacted authors to identify additional published or unpublished data.<br><br>SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials and controlled before-and-after studies comparing effectiveness of ambulance crews with ALS training versus crews with any other levels of training in reducing mortality and morbidity in trauma patients. Studies which compared crews staffed by physicians versus others were excluded.<br><br>DATA COLLECTION AND ANALYSIS: Two reviewers independently applied eligibility criteria to trial reports for inclusion and extracted data.<br><br>MAIN RESULTS: We found one randomised controlled trial, which included 16 trauma cases. However, outcome data were added to the main non-randomised cohort in the analysis, and data on these 16 cases are not yet available.<br><br>REVIEWER'S CONCLUSIONS: In the absence of evidence of the effectiveness of advanced life support, strong argument could be made that it should not be promoted outside the context of a properly concealed and otherwise rigorously conducted randomised controlled trial.}, }
@article {pmid11405387, year = {2001}, author = {Brody, JA and Grant, MD}, title = {Age-associated diseases and conditions: implications for decreasing late life morbidity.}, journal = {Aging (Milan, Italy)}, volume = {13}, number = {2}, pages = {64-67}, doi = {10.1007/BF03351527}, pmid = {11405387}, issn = {0394-9532}, support = {5T32 AG00231-03/AG/NIA NIH HHS/United States ; AG12875/AG/NIA NIH HHS/United States ; }, mesh = {Age of Onset ; Aged ; *Aging ; Cause of Death/*trends ; Chronic Disease/*mortality ; Humans ; }, abstract = {We discuss two types of age-associated diseases; aging-dependent such as Alzheimer's disease and congestive heart failure which increase logarithmically with age, versus age-dependent such as multiple sclerosis and amyotrophic lateral sclerosis which occur at proscribed ages, and then occurrence of new cases ceases or diminishes with further aging. Prevention strategies with both types emphasize postponement or delay of onset. The non-fatal aging-dependent diseases and conditions are an accumulating burden as we age, and increase overall morbidity in late years. These include Alzheimer's disease and other dementias, Parkinson's disease, loss of vision and hearing, incontinence, osteoporosis and hip fracture, osteoarthritis and depression. With mortality postponed, we will be living for many years at old and vulnerable ages. Life's quality will be reasonable for most. Still, increasing the chance that all will experience this desirable outcome requires pursuing the means to delay the onset of the physical and social events which we categorize as the non-fatal aging-dependent diseases and conditions. We must recognize that each added year occurs at the tip of an exponential curve where risk is maximal.}, }
@article {pmid11400322, year = {2001}, author = {Sobue, G}, title = {[Molecular pathogenesis of motor neuron diseases].}, journal = {Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology}, volume = {21}, number = {1}, pages = {21-25}, pmid = {11400322}, issn = {1340-2544}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; Mice ; Mice, Transgenic ; Muscular Atrophy/*genetics ; }, abstract = {Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are representative motor neuron diseases in which selective neuronal degeneration occurs. In this paper, some molecular aspects are discussed related to the pathogenesis of the neuronal degeneration. SBMA is a an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA), and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders very likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. In SBMA, nuclear inclusions (NIs) containing mutant AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as CREB or creb-binding protein (CBP) sequestrated in NIs, may alter the major intracellular transcriptional signal transduction and ultimately may result in neuronal degeneration. The components in the ubiquitin-proteasome pathway also colocalized in NIs and contribute to the path-ogenesis of SBMA. We generated two types of transgenic mice expressing 239Q under the control of human AR promoter and full-size AR containing 97Q. Marked neurological symptoms and extensive nuclear inclusions were observed in both transgenic lines, but there was no neuronal cell death, suggesting that major neurological phenotype was due to neuronal dysfunction instead of neuronal cell death. As for the therapeutic strategies, the overexpression of Hsp70 and Hsp40 chaperones acted together to protect a cultured neuronal cell model of SBMA from inclusion formation and cell death by mutant AR with expanded polyglutamine tract. In regard to ALS, we are screening the gene expression profiles of the motor neurons from the human ALS and SOD transgenic mouse spinal cord. Motor neurons were microdissected from the spinal cord samples by a lazer-captured microdissection system. Gene expression profiles were screened by cDNA microarray and molecular indexing. Several new molecules were cloned and characterized for their function and relation to neuronal cell dysfunction. Some molecules characterized in this procedure were briefly described.}, }
@article {pmid11396674, year = {2001}, author = {Yase, Y and Yoshida, S and Kihira, T and Wakayama, I and Komoto, J}, title = {Kii ALS dementia.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {21}, number = {2}, pages = {105-109}, doi = {10.1046/j.1440-1789.2001.00303.x}, pmid = {11396674}, issn = {0919-6544}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/genetics/pathology ; Brain/pathology ; Dementia/*epidemiology/genetics/pathology ; Humans ; Japan/epidemiology ; }, abstract = {Epidemiological surveys in the foci of ALS of the Kii Peninsula of Japan started in the early 1960s. Continuous surveys conducted for decades revealed that there have been two foci in the Kii Peninsula: one in Kozagawa in the southern part, and the other in Hobara in the south-east. Clinically, ALS patients of the Kii foci occasionally showed parkinsonian features or dementia that have not been reported in the sporadic form of ALS. Neuropathologically, numerous NFT that are identical to those of Alzheimer's disease were observed in the cerebral cortex and in the brainstem nuclei. To elucidate the etiopathogenesis of this unique form of ALS, an analysis was conducted of the environment in the focus areas and of the specimens from the patients with ALS. It was hypothesized that the long exposure of these environments to low calcium and magnesium, and an excess of aluminum and manganese in the drinking water and the soil, might lead to the deposition of some trace elements in the CNS, eventually causing neuronal degeneration and death.}, }
@article {pmid11388661, year = {2001}, author = {Apfel, SC}, title = {Neurotrophic factor therapy--prospects and problems.}, journal = {Clinical chemistry and laboratory medicine}, volume = {39}, number = {4}, pages = {351-355}, doi = {10.1515/CCLM.2001.055}, pmid = {11388661}, issn = {1434-6621}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Nerve Growth Factors/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Peripheral Nervous System Diseases/drug therapy ; }, abstract = {Over the past 15 years neurotrophic factors have generated considerable excitement for their potential as therapy for a wide variety of degenerative neurological disorders, for which there is currently no treatment. The first part of this period was marked by the discovery, characterization, and cloning of many new growth factors, and by successful testing of these factors in animal models of neurological disease. In recent years the biotechnology industry and pharmaceutical industry have attempted to replicate the success of the animal studies in clinical trials. Although some studies have demonstrated moderate efficacy, for the most part the clinical trials have been less successful at demonstrating the therapeutic efficacy of this new class of drugs. For example, nerve growth factor appeared to be efficacious in two phase II clinical trials for peripheral neuropathy, but failed in a large scale phase III trial. Ciliary neurotrophic factor, brain derived neurotrophic factor and insulin like growth factor-1 have all been tested in clinical trials for the treatment of amyotrophic lateral sclerosis, with at best, variable indications of efficacy. Nevertheless, there are still many reasons to be optimistic that some of these agents may be useful clinically. Many technical and pharmacological issues remain to be adequately addressed, before neurotrophic factors can live up to their potential. Our collective experience with them has re-adjusted previously wild expectations, so that they are now much more realistic. This is necessary and beneficial for the maturation of this field of study.}, }
@article {pmid11386269, year = {2001}, author = {Rowland, LP and Shneider, NA}, title = {Amyotrophic lateral sclerosis.}, journal = {The New England journal of medicine}, volume = {344}, number = {22}, pages = {1688-1700}, doi = {10.1056/NEJM200105313442207}, pmid = {11386269}, issn = {0028-4793}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Environment ; Genetic Predisposition to Disease ; Humans ; Motor Neurons/pathology/physiology ; Mutation ; Suicide, Assisted ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, }
@article {pmid11382189, year = {2000}, author = {Anneser, J}, title = {Molecular basis of treatment in motor neurone disease.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {21}, number = {5 Suppl}, pages = {S913-8}, doi = {10.1007/s100720070003}, pmid = {11382189}, issn = {1590-1874}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology/virology ; Animals ; Central Nervous System Viral Diseases/complications/genetics/physiopathology ; Glutamic Acid/genetics/*metabolism ; Humans ; Nerve Growth Factors/*therapeutic use ; Neurofilament Proteins/*genetics/metabolism ; Oxidative Stress/drug effects/*genetics ; Receptors, Glutamate/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {The pathways leading to motorneuron degeneration in amyotrophic lateral sclerosis (ALS) are complex. Excitotoxicity, oxidative damage and, maybe, abnormal aggregation of neurofilaments are key events on which therapeutical strategies can be designed. This paper reviews current knowledge on these strategies. Even though we should be aware that appropriate management of disease symptoms remains the most effective therapeutical intervention, understanding the pathophysiology of ALS is essential for developing new therapies.}, }
@article {pmid11375746, year = {2001}, author = {Sayre, LM and Smith, MA and Perry, G}, title = {Chemistry and biochemistry of oxidative stress in neurodegenerative disease.}, journal = {Current medicinal chemistry}, volume = {8}, number = {7}, pages = {721-738}, doi = {10.2174/0929867013372922}, pmid = {11375746}, issn = {0929-8673}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; DNA, Mitochondrial/chemistry/genetics ; Humans ; Huntington Disease/genetics/metabolism ; Lewy Body Disease/metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Parkinson Disease/metabolism ; Proteins/chemistry/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The age-related neurodegenerative diseases exemplified by Alzheimer&amp;hyp;s disease (AD), Lewy body diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington&amp;hyp;s disease are characterized by the deposition of abnormal forms of specific proteins in the brain. Although several factors appear to underlie the pathological depositions, the cause of neuronal death in each disease appears to be multifactorial. In this regard, evidence in each case for a role of oxidative stress is provided by the finding that the pathological deposits are immunoreactive to antibodies recognizing protein side-chains modified either directly by reactive oxygen or nitrogen species, or by products of lipid peroxidation or glycoxidation. Although the source(s) of increased oxidative damage are not entirely clear, the findings of increased localization of redox-active transition metals in the brain regions most affected is consistent with their contribution to oxidative stress. It is tempting to speculate that free radical oxygen chemistry plays a pathogenetic role in all these neurodegenerative conditions, though it is as yet undetermined what types of oxidative damage occur early in pathogenesis, and what types are secondary manifestations of dying neurons. Delineation of the profile of oxidative damage in each disease will provide clues to how the specific neuronal populations are differentially affected by the individual disease conditions.}, }
@article {pmid11374089, year = {2001}, author = {Bak, TH and Hodges, JR}, title = {Motor neurone disease, dementia and aphasia: coincidence, co-occurrence or continuum?.}, journal = {Journal of neurology}, volume = {248}, number = {4}, pages = {260-270}, doi = {10.1007/s004150170199}, pmid = {11374089}, issn = {0340-5354}, mesh = {Aphasia/complications/*etiology/physiopathology ; Cognition Disorders/etiology/physiopathology ; Comorbidity ; Dementia/complications/*etiology/physiopathology ; Disease Progression ; Frontal Lobe/pathology ; Genetic Predisposition to Disease ; Humans ; Memory Disorders/etiology/physiopathology ; Motor Neuron Disease/complications/*physiopathology ; Severity of Illness Index ; Terminology as Topic ; }, abstract = {Cognitive, and particularly aphasic, symptoms associated with motor neurone disease (MND) are still frequently described as rare and "recently discovered". This review demonstrates that the association between MND and dementia was described and recognised as an entity as early as 1929, and its close relationship to Pick's disease was postulated in 1932. Changes in language production and comprehension were also observed by early authors, although they were rarely described as aphasia. The striking similarity to the contemporary descriptions is, however, sometimes obscured by diverging terminology. The syndromes of MND/dementia and MND/aphasia are well established but represent a comparatively small subgroup of MND. In addition, subtle cognitive alterations have also been reported in non-demented MND patients; most studies have found evidence of frontal-executive dysfunction, similar in pattern, but much milder than in patients with frank MND/dementia. These findings are strengthened further by post-mortem studies demonstrating pathological changes in the frontal lobes, and functional neuroimaging studies, showing reduced frontal activation. The issue of whether memory, visuospatial skills and language are affected in non-demented subjects remains, however, controversial. Further studies are required to establish whether MND/dementia and MND/aphasia form separate disease entities or can be viewed as extreme forms of a cognitive deficit characteristic of MND in general.}, }
@article {pmid11369436, year = {2001}, author = {Danbolt, NC}, title = {Glutamate uptake.}, journal = {Progress in neurobiology}, volume = {65}, number = {1}, pages = {1-105}, doi = {10.1016/s0301-0082(00)00067-8}, pmid = {11369436}, issn = {0301-0082}, mesh = {ATP-Binding Cassette Transporters/chemistry/isolation &amp; purification/*metabolism ; Amino Acid Transport System X-AG ; Anesthetics/pharmacology ; Animals ; Bone and Bones/metabolism ; Brain/embryology/growth &amp; development/*metabolism ; Carrier Proteins/metabolism ; Ethanol/pharmacology ; Extracellular Space/metabolism ; Female ; Gene Expression Regulation ; Glutamic Acid/*metabolism ; Glutamine/metabolism ; HIV Infections/metabolism ; Hepatic Encephalopathy/metabolism ; Humans ; Intracellular Fluid/metabolism ; Ion Channel Gating ; Ion Channels/metabolism ; Ion Transport ; Ischemia/metabolism ; Male ; Mammals/metabolism ; Mercury Poisoning/metabolism ; Monocarboxylic Acid Transporters ; Nerve Tissue Proteins/chemistry/isolation &amp; purification/*metabolism ; Nervous System Diseases/metabolism ; Neuroglia/metabolism ; Neurons/drug effects/metabolism ; Neurotransmitter Agents/metabolism ; Organ Specificity ; Placenta/metabolism ; Potassium/metabolism ; Pregnancy ; Protein Conformation ; Rats ; Receptors, Glutamate/chemistry/classification/drug effects/*metabolism ; Sodium/metabolism ; Synapses/physiology ; Synaptic Transmission/drug effects/physiology ; Viscera/metabolism ; }, abstract = {Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.}, }
@article {pmid11357946, year = {2001}, author = {Tarnopolsky, MA and Beal, MF}, title = {Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders.}, journal = {Annals of neurology}, volume = {49}, number = {5}, pages = {561-574}, pmid = {11357946}, issn = {0364-5134}, mesh = {Animals ; Creatine/*therapeutic use ; Energy Metabolism/*drug effects ; Humans ; Nervous System Diseases/*drug therapy ; }, abstract = {Substantial evidence indicates that bioenergetic dysfunction plays either a primary or secondary role in the pathophysiology of cell death in neurodegenerative and neuromuscular disorders, and even in normal aging. Agents that ameliorate bioenergetic defects may therefore be useful in therapy. Creatine, which increases muscle and brain phosphocreatine concentrations, and may inhibit the activation of the mitochondrial permeability transition, protects against neuronal degeneration in transgenic murine models of amyotrophic lateral sclerosis and Huntington's disease and in chemically mediated neurotoxicity. Initial studies of creatine use in humans appear promising; however, further long-term, well-designed trials are needed. Coenzyme Q10, Gingko biloba, nicotinamide, riboflavin, carnitine, lipoic acid, and dichloroacetate are other agents which may have beneficial effects on energy metabolism, but the preclinical and clinical evidence for efficacy in neurological diseases remains limited. These compounds are widely used as dietary supplements; however, they must be subjected to rigorous evaluation through randomized, double-blinded trials to establish efficacy, cost-effectiveness and safety in neurological disorders.}, }
@article {pmid11346364, year = {2001}, author = {Bowen, BC and Bradley, WG}, title = {Amyotrophic lateral sclerosis: the search for a spectroscopic marker of upper motoneuron involvement.}, journal = {Archives of neurology}, volume = {58}, number = {5}, pages = {714-716}, doi = {10.1001/archneur.58.5.714}, pmid = {11346364}, issn = {0003-9942}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Biomarkers ; Brain/physiopathology ; Humans ; *Magnetic Resonance Spectroscopy ; Motor Neurons/physiology ; Pyramidal Tracts/physiopathology ; }, }
@article {pmid11345011, year = {2001}, author = {Jackson, CE and Rosenfeld, J}, title = {Motor neuron disease.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {12}, number = {2}, pages = {335-52, ix-x}, pmid = {11345011}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/rehabilitation ; Antiviral Agents/*administration &amp; dosage ; Clinical Trials as Topic ; Combined Modality Therapy ; Humans ; Motor Neuron Disease/diagnosis/drug therapy/rehabilitation ; Neuroprotective Agents/*administration &amp; dosage ; Physical Therapy Modalities/methods ; Prognosis ; Riluzole/*administration &amp; dosage ; }, abstract = {Motor neuron disease refers to a spectrum of disorders resulting from degeneration of the upper or lower motor neurons or both. Amyotrophic lateral sclerosis is the most common form of motor neuron disease, in which patients demonstrate evidence of both anterior horn cell (lower motor neuron) and corticospinal tract (upper motor neuron) dysfunction. Several theories regarding the pathogenesis of amyotrophic lateral sclerosis have emerged, including glutamate excitotoxicity, free radical oxidative stress, cytoskeletal abnormalities, a deficiency of neurotrophic factor, autoimmunity, apoptosis, and viral infection. Numerous clinical trials have been completed based on these possible mechanisms of the disease propagation including treatment with antiglutamate agents, anti-oxidants, immunosuppressants, and neurotrophic factors. Several of these trials have shown modest effects in slowing the disease course. None, however, have yielded marked benefit in arresting disease progression. The most significant effect in abating disease progression has been our use and understanding of aggressive symptomatic therapy to reduce disability, enhance quality of life, and improve prognosis.}, }
@article {pmid11329733, year = {2001}, author = {Racek, J and Holecek, V and Sedlácek, D and Panzner, P}, title = {[Free radicals in immunology and infectious diseases].}, journal = {Epidemiologie, mikrobiologie, imunologie : casopis Spolecnosti pro epidemiologii a mikrobiologii Ceske lekarske spolecnosti J.E. Purkyne}, volume = {50}, number = {2}, pages = {87-91}, pmid = {11329733}, issn = {1210-7913}, mesh = {Aging/immunology ; Autoimmune Diseases/*immunology ; Free Radicals/*immunology ; Humans ; Hypersensitivity/*immunology ; Infections/*immunology ; Physical Exertion ; }, abstract = {Free radicals contribute significantly in modification of immune processes and inflammatory reactions. They are produced by activated phagocytes which use them for killing microorganisms. Free radicals facilitate production of cytokines, which are important as modifiers of inflammatory reactions. Formation of free radicals is influenced by antioxidants which can thus modify the intensity of inflammatory reaction and immune response. The authors describe in detail the contribution of free radicals in etiology and pathogenesis of autoimmune diseases including rheumatoid arthritis, multiple sclerosis or amyotrophic lateral sclerosis. The role of free radicals and modifying influence of antioxidants in viral, bacterial, parasitic and mycotic diseases is described in the second part of the review. Finally, influence of free radicals and antioxidants on immunity changes in patients with malignant tumours, during aging and physical exercise is discussed.}, }
@article {pmid11328670, year = {2001}, author = {Macmillan-Crow, LA and Cruthirds, DL}, title = {Invited review: manganese superoxide dismutase in disease.}, journal = {Free radical research}, volume = {34}, number = {4}, pages = {325-336}, doi = {10.1080/10715760100300281}, pmid = {11328670}, issn = {1071-5762}, mesh = {Animals ; Apoptosis ; Humans ; Mice ; Mice, Knockout ; Mitochondria/*enzymology ; Neoplasms/*enzymology ; Nitrates/pharmacology ; Organ Transplantation/*adverse effects ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*enzymology ; Superoxide Dismutase/deficiency/*physiology ; Superoxides/metabolism ; }, abstract = {Manganese superoxide dismutase (MnSOD) is essential for life as dramatically illustrated by the neonatal lethality of mice that are deficient in MnSOD. In addition, mice expressing only 50% of the normal compliment of MnSOD demonstrate increased susceptibility to oxidative stress and severe mitochondrial dysfunction resulting from elevation of reactive oxygen species. Thus, it is important to know the status of both MnSOD protein levels and activity in order to assess its role as an important regulator of cell biology. Numerous studies have shown that MnSOD can be induced to protect against pro-oxidant insults resulting from cytokine treatment, ultraviolet light, irradiation, certain tumors, amyotrophic lateral sclerosis, and ischemia/reperfusion. In addition, overexpression of MnSOD has been shown to protect against pro-apoptotic stimuli as well as ischemic damage. Conversely, several studies have reported declines in MnSOD activity during diseases including cancer, aging, progeria, asthma, and transplant rejection. The precise biochemical/molecular mechanisms involved with this loss in activity are not well understood. Certainly, MnSOD gene expression or other defects could play a role in such inactivation. However, based on recent findings regarding the susceptibility of MnSOD to oxidative inactivation, it is equally likely that post-translational modification of MnSOD may account for the loss of activity. Our laboratory has recently demonstrated that MnSOD is tyrosine nitrated and inactivated during human kidney allograft rejection and human pancreatic ductal adenocarcinoma. We have determined that peroxynitrite (ONOO-) is the only known biological oxidant competent to inactivate enzymatic activity, to nitrate critical tyrosine residues, and to induce dityrosine formation in MnSOD. Tyrosine nitration and inactivation of MnSOD would lead to increased levels of superoxide and concomitant increases in ONOO- within the mitochondria which, could lead to tyrosine nitration/oxidation of key mitochondrial proteins and ultimately mitochondrial dysfunction and cell death. This article assesses the important role of MnSOD activity in various pathological states in light of this potentially lethal positive feedback cycle involving oxidative inactivation.}, }
@article {pmid11328326, year = {2001}, author = {Léger, JM and Salachas, F}, title = {Diagnosis of motor neuropathy.}, journal = {European journal of neurology}, volume = {8}, number = {3}, pages = {201-208}, doi = {10.1046/j.1468-1331.2001.00136.x}, pmid = {11328326}, issn = {1351-5101}, mesh = {Acute Disease ; Chronic Disease ; Guillain-Barre Syndrome/diagnosis ; Humans ; Motor Neuron Disease/*diagnosis ; Nervous System Diseases/diagnosis ; Peripheral Nervous System Diseases/diagnosis ; Poliomyelitis/diagnosis ; Porphyria, Acute Intermittent/diagnosis ; }, abstract = {Motor neuropathy is a clinical entity which leads to consideration of a wide spectrum of peripheral nerve disorders. Firstly, it may be distinguished from other causes of peripheral motor involvement such as muscle diseases and disorders of the neuromuscular junction. Secondly, it may be discussed in two different forms: acute and chronic. Acute chronic neuropathies are mainly observed in Guillain-Barré syndrome, in which electrophysiological studies allow us to recognize the classical demyelinating form and the axonal form. The other causes of acute motor neuropathy are mainly poliomyelitis and porphyrias. Chronic motor neuropathies are mainly observed in motor neuron diseases, mainly amyotrophic lateral sclerosis, but also Kennedy's disease and other lower motor neuron diseases which may be inherited or acquired. The other causes are multifocal motor neuropathy and the predominantly motor forms of chronic inflammatory demyelinating polyneuropathy. The characterization of these different types of chronic neuropathy is of major importance because of the therapeutic consequences which may lead to the proposal of specific treatments.}, }
@article {pmid11327325, year = {2000}, author = {Rotilio, G and Carrì, MT and Rossi, L and Ciriolo, MR}, title = {Copper-dependent oxidative stress and neurodegeneration.}, journal = {IUBMB life}, volume = {50}, number = {4-5}, pages = {309-314}, doi = {10.1080/713803724}, pmid = {11327325}, issn = {1521-6543}, mesh = {Alzheimer Disease/etiology/metabolism ; Amyotrophic Lateral Sclerosis/etiology/metabolism ; Animals ; Apoptosis ; Copper/*metabolism ; Hepatolenticular Degeneration/etiology/metabolism ; Humans ; Menkes Kinky Hair Syndrome/etiology/metabolism ; Models, Neurological ; Nerve Degeneration/*etiology/metabolism ; Neurodegenerative Diseases/etiology/metabolism ; *Oxidative Stress ; Prion Diseases/etiology/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Copper is an essential trace element, but its redox reactivity leads to risks of damage to cell and tissues. These are well exemplified by several forms of neurodegenerative diseases, either arising as inherited disorders of copper metabolism, such as Menkes' and Wilson's disease, or as conformational diseases such as Alzheimer's disease and prion diseases. This review will cover some aspects of the involvement of copper-mediated oxidative stress in degenerative processes in the central nervous system, with special focus on the familial form of amyotrophic lateral sclerosis (FALS). Furthermore, a possible role of copper reactivity in inducing critical steps in the apoptotic pathways leading to neurodegeneration is envisaged.}, }
@article {pmid11304046, year = {2001}, author = {Shibata, N}, title = {Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {21}, number = {1}, pages = {82-92}, doi = {10.1046/j.1440-1789.2001.00361.x}, pmid = {11304046}, issn = {0919-6544}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*pathology ; Animals ; *Disease Models, Animal ; Mice ; *Mice, Transgenic ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Familial amyotrophic lateral sclerosis (ALS) with mutations in the gene for superoxide dismutase-1 (SOD1) is clinicopathologically reproduced by transgenic mice expressing mutant forms of SOD1 detectable in familial ALS patients. Motor neuron degeneration associated with SOD1 mutation has been thought to result from a novel neurotoxicity of mutant SOD1, but not from a reduction in activity of this enzyme, based on autosomal dominant transmission of SOD1 mutant familial ALS and its transgenic mouse model, clinical severity of the ALS patients independent to enzyme activity, no ALS-like disease in SOD1 knockout or wild-type SOD1-overexpressing mice, and clinicopathological severity of mutant SOD1 transgenic mice dependent on transgene copy numbers. Proposed mechanisms of motor neuron degeneration such as oxidative injury, peroxynitrite toxicity, cytoskeletal disorganization, glutamate excitotoxicity, disrupted calcium homeostasis, SOD1 aggregation, carbonyl stress and apoptosis have been discussed. Intracytoplasmic vacuoles, indicative of increased oxidative damage to the mitochondria and endoplasmic reticulum, in the neuropil and motor neurons appear in high expressors of mutant SOD1 transgenic mice but not in low expressors of the mice or familial ALS patients, suggesting that overexpression of mutant SOD1 in mice may enhance oxidative stress generation from this enzyme. Thus, transgenic mice carrying small transgene copy numbers of mutant SOD1 would provide a beneficial animal model for SOD1 mutant familial ALS. Such a model would contribute to elucidating the pathomechanism of this disease and establishing new therapeutic agents.}, }
@article {pmid11304045, year = {2001}, author = {Kato, S and Nakashima, K and Horiuchi, S and Nagai, R and Cleveland, DW and Liu, J and Hirano, A and Takikawa, M and Kato, M and Nakano, I and Sakoda, S and Asayama, K and Ohama, E}, title = {Formation of advanced glycation end-product-modified superoxide dismutase-1 (SOD1) is one of the mechanisms responsible for inclusions common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutation, and transgenic mice expressing human SOD1 gene mutation.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {21}, number = {1}, pages = {67-81}, doi = {10.1046/j.1440-1789.2001.00359.x}, pmid = {11304045}, issn = {0919-6544}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Glycation End Products, Advanced/*metabolism ; Humans ; Inclusion Bodies/*enzymology/pathology ; Mice ; Mice, Transgenic ; Mutation ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) are morphological hallmarks of certain familial amyotrophic lateral sclerosis (FALS) patients with superoxide dismutase-1 (SOD1) gene mutations, and transgenic mice expressing the human SOD1 gene mutation. The ultrastructure of inclusions in both diseases is identical: the essential common constituents are granule-coated fibrils approximately 15-25nm in diameter and granular materials. Detailed immunohistochemical analyses have shown that the essential common protein of the inclusions in both diseases is an SOD1 protein. This finding, together with the immunoelectron microscopy finding that the abnormal granule-coated fibrils comprising the inclusions are positive for SOD1, indicates that these granule-coated fibrils containing SOD1 are important evidence for mutant SOD1-linked disease in human and mouse. For immunoelectron microscopy, the granule-coated fibrils are modified by advanced glycation endproducts (AGE) such as N(epsilon)-carboxymethyl lysine, pyrraline and pentosidine (Maillard reaction). Based on the fact that AGE themselves are insoluble molecules with direct cytotoxic effects, the granule-coated fibrils and granular materials are not digested by the lysosomal and ubiquitin systems. The neurons and astrocytes of the normal individuals and non-transgenic mice show no significant immunoreactivity for AGE. Considered with the mutant-SOD1 aggregation toxicity, a portion of the SOD1 comprising both types of the inclusion is modified by the AGE, and the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e. granule-coated fibril formation).}, }
@article {pmid11295106, year = {2001}, author = {Martin, LJ}, title = {Neuronal cell death in nervous system development, disease, and injury (Review).}, journal = {International journal of molecular medicine}, volume = {7}, number = {5}, pages = {455-478}, pmid = {11295106}, issn = {1107-3756}, support = {AG16282/AG/NIA NIH HHS/United States ; NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; *Cell Death ; Humans ; Microscopy, Electron ; Models, Biological ; Necrosis ; Nervous System/*cytology/growth &amp; development ; Nervous System Diseases/*pathology ; Neurons/*cytology/ultrastructure ; }, abstract = {Neuronal death is normal during nervous system development but is abnormal in brain and spinal cord disease and injury. Apoptosis and necrosis are types of cell death. They are generally considered to be distinct forms of cell death. The re-emergence of apoptosis may contribute to the neuronal degeneration in chronic neurodegenerative disease, such as amyotrophic lateral sclerosis and Alzheimer's disease, and in neurological injury such as cerebral ischemia and trauma. There is also mounting evidence supporting an apoptosis-necrosis cell death continuum. In this continuum, neuronal death can result from varying contributions of coexisting apoptotic and necrotic mechanisms; thus, some of the distinctions between apoptosis and necrosis are becoming blurred. Cell culture and animal model systems are revealing the mechanisms of cell death. Necrosis can result from acute oxidative stress. Apoptosis can be induced by cell surface receptor engagement, growth factor withdrawal, and DNA damage. Several families of proteins and specific biochemical signal-transduction pathways regulate cell death. Cell death signaling can involve plasma membrane death receptors, mitochondrial death proteins, proteases, kinases, and transcription factors. Players in the cell death and cell survival orchestra include Fas receptor, Bcl-2 and Bax (and their homologues), cytochrome c, caspases, p53, and extracellular signal-regulated protein kinases. Some forms of cell death require gene activation, RNA synthesis, and protein synthesis, whereas others forms are transcriptionally-translationally-independent and are driven by posttranslational mechanisms such as protein phosphorylation and protein translocation. A better understanding of the molecular mechanisms of neuronal cell death in nervous system development, injury and disease can lead to new therapeutic approaches for the prevention of neurodegeneration and neurological disabilities and will expand the field of cell death biology.}, }
@article {pmid11286882, year = {2001}, author = {Hoyer, LL}, title = {The ALS gene family of Candida albicans.}, journal = {Trends in microbiology}, volume = {9}, number = {4}, pages = {176-180}, doi = {10.1016/s0966-842x(01)01984-9}, pmid = {11286882}, issn = {0966-842X}, support = {AI39441/AI/NIAID NIH HHS/United States ; DE14158/DE/NIDCR NIH HHS/United States ; }, mesh = {Candida albicans/*genetics/metabolism/*pathogenicity ; Candidiasis/microbiology ; Fungal Proteins/*genetics/*metabolism ; Gene Expression Regulation, Fungal ; *Genes, Fungal ; Humans ; Multigene Family ; }, abstract = {The ALS gene family of Candida albicans encodes large cell-surface glycoproteins that are implicated in the process of adhesion to host surfaces. ALS genes are also found in other Candida species that are isolated from cases of clinical disease. Genes in the ALS family are differentially regulated by physiologically relevant mechanisms. ALS genes exhibit several levels of variability including strain- and allele-specific size differences for the same gene, strain-specific differences in gene regulation, the absence of particular ALS genes in certain isolates, and additional ALS coding regions in others. The differential regulation and genetic variability of the ALS genes results in a diverse cell-surface Als protein profile that is also affected by growth conditions. The ALS genes are one example of a gene family associated with pathogenicity mechanisms in C. albicans and other Candida species.}, }
@article {pmid11286045, year = {2000}, author = {Pasetti, C and Zanini, G}, title = {The physician-patient relationship in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {21}, number = {5}, pages = {318-323}, doi = {10.1007/s100720070070}, pmid = {11286045}, issn = {1590-1874}, mesh = {Amyotrophic Lateral Sclerosis/psychology/rehabilitation/*therapy ; Disease Progression ; Humans ; *Physician-Patient Relations ; }, abstract = {The principal models of the physician-patient relationship are analysed in terms of their historical development. An outline is given of the clinical, psychological and ethical particularities of the approach to patients with amyotrophic lateral sclerosis. The peculiarities of this disease are so exclusive that they do not resemble other progressive diseases with a negative prognosis, and therefore require an equally exclusive approach to the physician-patient relationship. This approach should not only be informative, scientific and interpretative-deliberative, but must simultaneously be founded on a solid therapeutic alliance aimed at seeking the best interests of the patients while respecting their autonomy as well as their "good" (not only in the sense of physical well-being, but also in terms of respect for their personal values). This is the only way to confront the conflicts that inevitably arise (especially in advanced stages of the disease) without the risks associated with a desire to escape or to adopt extreme solutions (such as euthanasia and therapeutic insistence) and without the risk of burn-out.}, }
@article {pmid11284995, year = {2001}, author = {Skvortsova, VI and Limborska, SA and Slominsky, PA and Levitskaya, NI and Levitsky, GN and Shadrina, MI and Kondratyeva, EA}, title = {Sporadic ALS associated with the D90A Cu,Zn superoxide dismutase mutation in Russia.}, journal = {European journal of neurology}, volume = {8}, number = {2}, pages = {167-172}, doi = {10.1046/j.1468-1331.2001.00186.x}, pmid = {11284995}, issn = {1351-5101}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; Female ; Genes, Recessive ; Heterozygote ; Homozygote ; Humans ; Male ; Middle Aged ; *Mutation ; Pedigree ; Superoxide Dismutase/*genetics ; }, abstract = {Twenty blood samples from Russian patients (Moscow) with idiopathic motor neurone disease were analysed for mutations in the Cu,Zn superoxide dismutase (Cu,Zn SOD) gene. Two patients (10%) with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease-related mutation. One patient appears to have autosomal recessive adult-onset ALS associated with homozygosity for D90A and presents the characteristic phenotype of very slowly ascending paresis with both lower and upper motor neurone signs. Another patient, heterozygous for D90A, presents ALS with lumbar onset and rapid progression. This is the first report of a Cu,Zn SOD mutation in ALS in Russia.}, }
@article {pmid11284281, year = {2001}, author = {Opstelten, FW and Boon, AJ}, title = {[Suspected amyotrophic lateral sclerosis? Don't forget diagnostic imaging of the spine].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {145}, number = {11}, pages = {505-509}, pmid = {11284281}, issn = {0028-2162}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Diagnosis, Differential ; Humans ; *Magnetic Resonance Imaging ; Male ; Muscle Weakness/etiology ; Neurologic Examination ; Polyradiculopathy/etiology ; Spinal Cord Compression/etiology ; Spinal Stenosis/*diagnosis/diagnostic imaging ; Spine/diagnostic imaging/*pathology ; *Tomography, X-Ray Computed ; }, abstract = {Two patients, men aged 35 and 72 years, had progressive muscle weakness, lower motor neuron signs in all extremities and upper motor neuron signs in the legs. There were no major sensory signs on examination. The clinical picture very much resembled amyotrophic lateral sclerosis (ALS), although there were never brain stem signs. Myelopathy and polyradiculopathies caused by a tandem cervical and lumbar spinal stenosis explained the clinical picture. Cervical MRI and lumbar CT confirmed this diagnosis. Laminectomy was done, after which both patients remained with unchanged symptoms. Tandem spinal stenosis should be part of the differential diagnosis of ALS. Imaging of the spine is necessary to confirm this diagnosis, and in the absence of bulbar signs always necessary prior to the diagnosis of ALS.}, }
@article {pmid11283461, year = {2001}, author = {Portet, F and Touchon, J and Camu, W}, title = {[Amyotrophic lateral sclerosis and cognitive disorders: review and analysis of the literature].}, journal = {Revue neurologique}, volume = {157}, number = {2}, pages = {139-150}, pmid = {11283461}, issn = {0035-3787}, mesh = {Cognition Disorders/*etiology ; Dementia/classification/*complications/physiopathology ; Humans ; Motor Neuron Disease/genetics/*physiopathology/*psychology ; Superoxide Dismutase/genetics ; }, abstract = {In the last ten years, the syndromic nature of amyotrophic lateral sclerosis (ALS) has become more accepted. Together with upper and lower motor neuron signs, sensory or cognitive impairment are not uncommon. The frequency of a multidegenerative profile in ALS with SOD1 mutations is also an argument for this. We reviewed the literature about:}, }
@article {pmid11280030, year = {2001}, author = {Bush, AI and Goldstein, LE}, title = {Specific metal-catalysed protein oxidation reactions in chronic degenerative disorders of ageing: focus on Alzheimer's disease and age-related cataracts.}, journal = {Novartis Foundation symposium}, volume = {235}, number = {}, pages = {26-38; discussion 38-43}, doi = {10.1002/0470868694.ch4}, pmid = {11280030}, issn = {1528-2511}, mesh = {Aging/*metabolism ; Alzheimer Disease/*metabolism/physiopathology/therapy ; Cataract/*metabolism/physiopathology/therapy ; Chronic Disease ; Humans ; Metalloproteins/*metabolism/physiology ; Neurodegenerative Diseases/physiopathology/therapy ; Oxidation-Reduction ; }, abstract = {Abnormalities of protein aggregation and deposition may play an important role in the pathophysiology of a diverse set of chronically progressive degenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and age-related cataracts. We propose that aberrant metalloprotein reactions may be a common denominator in these diseases. In these instances, an abnormal reaction between a protein and redox active metal ions (especially copper or iron) promotes the generation of reactive oxygen species, and possibly, protein radicalization. These products then lead to chemical modification of the protein, alterations in protein structure and solubility, and oxidative damage to surrounding tissue. In this review, we explore these ideas by focusing on two common diseases of ageing, Alzheimer's disease and age-related cataracts. Understanding the metalloprotein biochemistry in both diseases may lead to a better understanding of the underlying pathophysiology in both disorders and suggest novel targets for therapeutic agents.}, }
@article {pmid11268031, year = {2001}, author = {Eisen, A and Weber, M}, title = {The motor cortex and amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {24}, number = {4}, pages = {564-573}, doi = {10.1002/mus.1042}, pmid = {11268031}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*pathology/*physiopathology ; Diagnosis, Differential ; Disease Progression ; Electric Stimulation ; Humans ; Magnetic Resonance Imaging ; Motor Cortex/diagnostic imaging/*pathology/physiopathology ; Motor Neurons/pathology ; Neural Conduction ; Peripheral Nerves/physiopathology ; Tomography, Emission-Computed ; }, abstract = {On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.}, }
@article {pmid11253364, year = {2000}, author = {Mattson, MP}, title = {Apoptosis in neurodegenerative disorders.}, journal = {Nature reviews. Molecular cell biology}, volume = {1}, number = {2}, pages = {120-129}, doi = {10.1038/35040009}, pmid = {11253364}, issn = {1471-0072}, mesh = {Animals ; *Apoptosis ; Brain/*pathology ; Calcium/metabolism ; Caspases/metabolism ; Homeostasis ; Humans ; Mitochondria/physiology ; Neurodegenerative Diseases/*pathology/physiopathology ; Neurons/*pathology/physiology ; Stroke/*pathology/physiopathology ; }, abstract = {Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death--apoptosis--involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.}, }
@article {pmid11250060, year = {2001}, author = {Cotterill, RM}, title = {Cooperation of the basal ganglia, cerebellum, sensory cerebrum and hippocampus: possible implications for cognition, consciousness, intelligence and creativity.}, journal = {Progress in neurobiology}, volume = {64}, number = {1}, pages = {1-33}, doi = {10.1016/s0301-0082(00)00058-7}, pmid = {11250060}, issn = {0301-0082}, mesh = {Animals ; Basal Ganglia/anatomy &amp; histology/*physiology ; Cerebellum/anatomy &amp; histology/*physiology ; Cerebral Cortex/anatomy &amp; histology/*physiology ; Cognition/*physiology ; Consciousness/*physiology ; *Creativity ; Hippocampus/anatomy &amp; histology/*physiology ; Humans ; Intelligence/*physiology ; Nerve Net/anatomy &amp; histology/*physiology ; }, abstract = {It is suggested that the anatomical structures which mediate consciousness evolved as decisive embellishments to a (non-conscious) design strategy present even in the simplest unicellular organisms. Consciousness is thus not the pinnacle of a hierarchy whose base is the primitive reflex, because reflexes require a nervous system, which the single-celled creature does not possess. By postulating that consciousness is intimately connected to self-paced probing of the environment, also prominent in prokaryotic behavior, one can make mammalian neuroanatomy amenable to dramatically straightforward rationalization. Muscular contraction is the nervous system's only externally directed product, and the signaling routes which pass through the various brain components must ultimately converge on the motor areas. The function of several components is still debatable, so it might seem premature to analyze the global operation of the circuit these routes constitute. But such analysis produces a remarkably simple picture, and it sheds new light on the roles of the individual components. The underlying principle is conditionally permitted movement, some components being able to veto muscular contraction by denying the motor areas sufficient activation. This is true of the basal ganglia (BG) and the cerebellum (Cb), which act in tandem with the sensory cerebrum, and which can prevent the latter's signals to the motor areas from exceeding the threshold for overt movement. It is also true of the anterior cingulate, which appears to play a major role in directing attention. In mammals, the result can be mere thought, provided that a second lower threshold is exceeded. The veto functions of the BG and the Cb stem from inhibition, but the countermanding disinhibition develops at markedly different rates in those two key components. It develops rapidly in the BG, control being exercised by the amygdala, which itself is governed by various other brain regions. It develops over time in the Cb, thereby permitting previously executed movements that have proved advantageous. If cognition is linked to overt or covert movement, intelligence becomes the ability to consolidate individual motor elements into more complex patterns, and creativity is the outcome of a race-to-threshold process which centers on the motor areas. Amongst the ramifications of these ideas are aspects of cortical oscillations, phantom limb sensations, amyotrophic lateral sclerosis (ALS) the difficulty of self-tickling and mirror neurons.}, }
@article {pmid11249671, year = {1999}, author = {Abicht, A and Lochmüller, H}, title = {Technology evaluation: CRIB (CNTF delivery) CytoTherapeutics Inc.}, journal = {Current opinion in molecular therapeutics}, volume = {1}, number = {5}, pages = {645-650}, pmid = {11249671}, issn = {1464-8431}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Biotechnology ; Cell Transplantation ; Ciliary Neurotrophic Factor/*genetics ; *Gene Transfer Techniques ; Genetic Therapy/adverse effects/*methods ; Humans ; Huntington Disease/therapy ; Transplantation, Heterologous ; }, abstract = {To achieve continuous, site-specific delivery of therapeutic molecules to the central nervous system (CNS), a new therapeutic approach was developed combining in vitro gene transfer with a new delivery device. Xenogenic cells genetically modified to secrete specific bioactive substances were encapsulated into polymer-based fibers. A semipermeable membrane allows for passage of nutrients and cell-released therapeutic agents, but restricts inward diffusion of larger molecules and cells of the host's immune system, thus facilitating xenograft survival. This novel technique was successfully tested for the in vitro and in vivo delivery of various therapeutic agents, including neurotrophic factors, neurotransmitters and hormones. Phase I clinical trials were reported for the treatment of amyotrophic lateral sclerosis (ALS) and chronic cancer pain.}, }
@article {pmid11241580, year = {2001}, author = {Gadea, A and López-Colomé, AM}, title = {Glial transporters for glutamate, glycine and GABA I. Glutamate transporters.}, journal = {Journal of neuroscience research}, volume = {63}, number = {6}, pages = {453-460}, doi = {10.1002/jnr.1039}, pmid = {11241580}, issn = {0360-4012}, mesh = {ATP-Binding Cassette Transporters/*metabolism ; Amino Acid Transport System X-AG ; Animals ; Glutamic Acid/*metabolism ; Glycine/*metabolism ; Humans ; Neuroglia/*metabolism ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {The termination of chemical neurotransmission in the CNS involves the rapid removal of neurotransmitter from synapses by specific transport systems. Such mechanism operates for the three major amino acid neurotransmitters glutamate, gamma-aminobutyric acid (GABA) and glycine. To date, five different high-affinity Na(+)-dependent glutamate (Glu) transporters have been cloned: GLT1, GLAST, EAAC1, EAAT4 and EAAT5. The first two are expressed mainly by glial cells, and seem to be the predominant Glu transporters in the brain. A major function of Glu uptake in the nervous system is to prevent extracellular Glu concentrations from raising to neurotoxic levels in which glial transporters seem to play a critical role in protecting neurons from glutamate-induced excitotoxicity. Under particular conditions, glial GluTs have been shown to release Glu by reversal of activity, in a Ca(2+)--and energy-independent fashion. Furthermore, an activity of these transporters as ion channels or transducing units coupled to G-proteins has recently been reported. The localization, stoichiometry, and regulation of glial GluTs are outlined, as well as their possible contributions to nervous system diseases as ALS, AD and ischemic damage.}, }
@article {pmid11239414, year = {2001}, author = {Julien, JP}, title = {Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.}, journal = {Cell}, volume = {104}, number = {4}, pages = {581-591}, doi = {10.1016/s0092-8674(01)00244-6}, pmid = {11239414}, issn = {0092-8674}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*genetics/*metabolism ; Animals ; Apoptosis ; Cell Death ; Copper/metabolism ; Cytoskeleton/chemistry/genetics ; Humans ; Mice ; Mitochondria/metabolism ; Models, Biological ; Motor Neurons/pathology ; Mutation, Missense ; Neurofilament Proteins/metabolism ; Risk Factors ; Superoxide Dismutase/chemistry/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid11228742, year = {1999}, author = {Kaltschmidt, B and Sparna, T and Kaltschmidt, C}, title = {Activation of NF-kappa B by reactive oxygen intermediates in the nervous system.}, journal = {Antioxidants &amp; redox signaling}, volume = {1}, number = {2}, pages = {129-144}, doi = {10.1089/ars.1999.1.2-129}, pmid = {11228742}, issn = {1523-0864}, mesh = {Animals ; Humans ; NF-kappa B/biosynthesis/*metabolism ; Nervous System/*metabolism ; Oxidants/*physiology ; Reactive Oxygen Species/*physiology ; }, abstract = {Nuclear factor kappa B (NF-kappa B) is a transcription factor crucially involved in glial and neuronal function. NF-kappa B is ubiquitously distributed within the nervous system, and its inducible activity can be discerned from constitutive activity. Prototypic inducible NF-kappa B in the nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory I kappa B-alpha molecule. A number of signals from the cell surface can lead to rapid activation of NK-kappa B, thus releasing the inhibition by I kappa B. This activates translocation of NF-kappa B to the nucleus, where it binds to kappa B motifs of target genes and activates transcription. Previous findings have identified reactive oxygen intermediates (ROI) as a common denominator of NF-kappa B activating signals. More specifically, hydrogen peroxide (H2O2) might be used as second messenger in the NF-kappa B system, despite its cytotoxicity. Analysis of pathways leading to NF-kappa B activation in the nervous system has identified a number of ROI-dependent pathways such as cytokine- and neurotrophin-mediated activation, glutamatergic signal transduction, and various diseases with crucial ROI involvement (e.g., Alzheimer's disease, Parkinson's disease, experimental autoimmune encephalomyelitis, multiple sclerosis, amyotrophic lateral sclerosis, and injury). A number of NF-kappa B-specific target genes contribute to the production of ROI or are involved in detoxification of ROIs. In this review, possible mechanisms and regulatory pathways of ROI-mediated NF-kappa B activation are discussed.}, }
@article {pmid11223575, year = {2001}, author = {Clostre, F}, title = {[Mitochondria: recent pathophysiological discoveries and new therapeutic perspectives].}, journal = {Annales pharmaceutiques francaises}, volume = {59}, number = {1}, pages = {3-21}, pmid = {11223575}, issn = {0003-4509}, mesh = {Animals ; Apoptosis/physiology ; Humans ; Mitochondria/genetics/pathology/*physiology ; Nerve Degeneration/pathology ; }, abstract = {Until about a decade ago, few researchers in clinical or evolutionary biology paid much attention to mitochondria. But over the years, as technological advances in molecular biology made nuclear functions more accessible to them, interest in mitochondria began to revive. First, geneticists started tracing certain rare inherited disorders to mutations in the mitochondria's circular genome. More recently, other researchers have speculated that mitochondria might contribute to aging, either by releasing tissue-damaging reactive oxygen molecules or by impairing and depriving the cell of the energy it needs to function. One the most important recent developments has been the recognition that mitochondria play a central role in the regulation of programmed cell death, or apoptosis. Now, we know that mitochondria play a decisive role in life-death decisions for the cell and may choose between the apoptotic and necrotic pathways. Mitochondria can trigger cell death in a number of ways: by disrupting electron transport and energy metabolism, by activating the mitochondrial permeability transition, by releasing and/or activating proteins that mediate apoptosis. Any or all of these mechanisms may help to explain how mitochondrial defects contribute to the pathogenesis of neuronal death or dysfunction in ischemia/reperfusion injury as well as in human degenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. This has opened up new avenues for understanding the pathogenesis of neurodegeneration and may lead to new and more effective therapeutic approaches to these diseases.}, }
@article {pmid11212310, year = {1999}, author = {Becker, DA}, title = {Diagnostic and therapeutic applications of azulenyl nitrone spin traps.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {56}, number = {7-8}, pages = {626-633}, doi = {10.1007/s000180050457}, pmid = {11212310}, issn = {1420-682X}, support = {NS38221-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/metabolism/pathology ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Azulenes ; Brain Ischemia/diagnosis/drug therapy/metabolism/pathology ; Disease Models, Animal ; Dopamine/metabolism ; Humans ; Neuroprotective Agents/chemistry/metabolism/*therapeutic use ; Nitrogen Oxides/metabolism/pharmacology/*therapeutic use ; Oxidative Stress ; Parkinson Disease/diagnosis/drug therapy/metabolism/pathology ; Retinal Ganglion Cells/drug effects/metabolism/pathology/physiology ; Sesquiterpenes/metabolism/pharmacology/*therapeutic use ; *Spin Trapping ; Stroke/diagnosis/drug therapy/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Azulenyl nitrones have been recently demonstrated to constitute a new class of nitrone-based spin traps with the unprecedented capacity to tag free radicals by yielding characteristically colored and highly visible diamagnetic (and paramagnetic) spin adducts. In addition, a comparison of the oxidation potentials of azulenyl nitrones such as 1 and congeners to those of conventional nitrone spin traps previously investigated as potential antioxidant therapeutics such as N-tert-butyl-alpha-phenylnitrone and its related ortho-sodium sulfonate reveals that the azulene-derived spin traps are far more readily oxidized. These special features render azulenyl nitrones of interest with regard to both their distinct ability to engender the convenient use of colorimetric detection to monitor free radical-mediated oxidative stress in biological systems, and to their potentially enhanced efficacy as neuroprotective antioxidants vs. those conventional nitrone spin traps earlier examined as such. Herein is reported an overview of recent developments pertaining to the use of azulenyl nitrones in the detection of oxidative stress in animal models of amyotrophic lateral sclerosis and stroke, and to their neuroprotective activity in animal models of Parkinson's disease, stroke and neurodegeneration within the retina.}, }
@article {pmid11211839, year = {2000}, author = {Liu, Z and Chen, J}, title = {[The research advance of brain derived neurotrophic factor].}, journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}, volume = {17}, number = {4}, pages = {454-6, 460}, pmid = {11211839}, issn = {1001-5515}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/chemistry/pharmacology/*physiology ; Central Nervous System Diseases/drug therapy/physiopathology ; Genetic Therapy ; Neurons/physiology ; }, abstract = {Recent research advances in neuroscience show that neurotrophic factors are proteins that affect selectively various kinds of neurons of CNS and PNS. Brain derived neurotrophic factor (BDNF) is another neurotrophic factor that was first reported by Barde, a German chemist, thirty years later after the nerve growth factor had been found out. BDNF plays an important role in the growth, development, differentiation, maintenance and regeneration of various types of neurons in the CNS and has potential application to the treatment of brain injury and neurodegenerative diseases such as Alzheimer's disease, Parkinson's syndrome, Huntington's chorea and amyotrophic lateral sclerosis. In this paper, the structure, function and potential clinical application of BDNF were reviewed.}, }
@article {pmid11205563, year = {2000}, author = {Marés-Segura, R}, title = {[Spinal cord paraneoplastic syndromes].}, journal = {Revista de neurologia}, volume = {31}, number = {12}, pages = {1219-1223}, pmid = {11205563}, issn = {0210-0010}, mesh = {Antibodies, Neoplasm/immunology ; Autoantibodies/immunology ; Breast Neoplasms/complications/immunology ; Carcinoma, Small Cell/complications/immunology ; Demyelinating Autoimmune Diseases, CNS/etiology/immunology ; Disease Progression ; Female ; Humans ; Lung Neoplasms/complications/immunology ; Male ; Motor Neuron Disease/etiology/immunology ; Muscle Rigidity/etiology/immunology ; Myelitis/etiology ; Myelitis, Transverse/etiology/immunology ; Neoplasms, Unknown Primary/diagnosis ; Paraneoplastic Syndromes, Nervous System/*etiology/immunology ; Paraproteins/immunology ; Sensation Disorders/etiology/immunology ; Stiff-Person Syndrome/etiology/immunology ; }, abstract = {OBJECTIVE: We reviewed the bibliography of various paraneoplastic syndromes which may show spinal involvement.<br><br>DEVELOPMENT: Paraneoplastic sensory neuropathy, myelitis and rigidity syndromes may present alone or as part of a generalized syndrome of paraneoplastic encephalomyelitis/sensory neuronopathy, usually associated with small cell cancer of the lung and anti-Hu antibodies. Amyotrophic lateral sclerosis and subacute necrotizing myelopathy of paraneoplastic origin are very rare, although casual association of these conditions with cancer cannot be ruled out. Subacute motor neuronopathy is linked to lymphoproliferative syndromes and breast cancer has been reported associated with cases of primary lateral sclerosis and the stiff man syndrome.<br><br>CONCLUSIONS: Various conditions of paraneoplastic origin may affect the spinal cord. Neurological symptoms may precede the diagnosis of neoplasia, are serious and do not usually respond to either immunosuppressive treatment or treatment of the underlying neoplasm, although there are exceptions. The presence of specific antibodies in some cases facilitates early diagnosis and shows the importance of immune mechanisms in these diseases. The paraneoplastic motor neuron syndromes may present atypically: at early or late age, be of slow evolution and associated with raised protein levels of the cerebrospinal fluid or with paraproteinemia.}, }
@article {pmid11200703, year = {2000}, author = {Mitchell, JD}, title = {Guidelines in motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS)--from diagnosis to patient care.}, journal = {Journal of neurology}, volume = {247}, number = {}, pages = {7-12}, pmid = {11200703}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Clinical Trials as Topic ; Humans ; Legislation, Medical ; Motor Neuron Disease/*diagnosis/*therapy ; Outcome Assessment, Health Care ; *Practice Guidelines as Topic ; }, abstract = {This paper reviews the scope of current guidelines in motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) and examines issues which have arisen in the preparation of these documents. The review concludes with an evaluation of the impact of the guidelines which have been produced to date and looks towards potential future developments in this area.}, }
@article {pmid11200702, year = {2000}, author = {Robberecht, W}, title = {Genetics of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {247}, number = {}, pages = {2-6}, pmid = {11200702}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Apolipoproteins E/genetics ; Humans ; Mutation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The genetic cause of amyotrophic lateral sclerosis (ALS) is known in a minority of cases. Mutations in SOD1, the gene encoding a superoxide dismutase on chromosome 21, are indeed found in 20% of familial ALS patients, who constitute only 5 or 10% of all ALS patients. In rare cases, a mutation in NFH, the gene encoding the heavy subunit of neurofilament, is present. Familial ALS has been linked to other loci but the genes involved remain to be identified. A genetic component is also thought to at least contribute to the pathogenesis of sporadic ALS. Their identification is now possible thanks to progress in molecular genetics.}, }
@article {pmid11200701, year = {2000}, author = {Meininger, V and Lacomblez, L and Salachas, F}, title = {What has changed with riluzole?.}, journal = {Journal of neurology}, volume = {247}, number = {}, pages = {19-22}, pmid = {11200701}, issn = {0340-5354}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Glutamic Acid ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Riluzole, after two significant trials, was introduced as the first standard treatment of amyotrophic lateral clerosis (ALS) in the early 95'. After 5 years what has changed in the field of ALS? In the field of basic science, riluzole as an active drug has largely contributed to stimulate the research of the possible role of glutamate in the genesis of ALS. However, the apparent simplicity of the relation between the drug and its mechanisms has to modulated in the light of the negativity of other trials (gabapentin) and the display of other mechanisms of the disease and of the compound. Possible relation with other putative mechanisms of ALS, as oxydative stress or growth factors, could be (and probably are) also involved. In the field of its activity, riluzole has an impact on the survival rate which has been largely debated. Comparison with historical databases are supporting the results of the two initial trials. Other information have been published supporting the probable activity of the drug on the muscle strength decline, a controversial matter. They strengthen the initial data and give additional reasons to use riluzole as a standard treatment of patients. In the field of the daily care, riluzole provided a real and unique hope for ALS sufferers. Even if its activity is not as complete as patients would have expected, it provides a hope for slowing down the rate of evolution and abolishes the myth of "no hope, no cure" which was the leitmotiv of patients care until recently. We have to better define the mode of administration with regard to the clinical status of the patients (respiratory disorders, fatigue, stiffness). In the field of care givers, riluzole was one major factor which provided the basis for national and international collaborations either for therapeutic trials or for standard of care. It made possible large collaborative programs in and among many countries. We do hope that this impulse will continue and be stimulated by additional results both in the field of basic science and clinical research.}, }
@article {pmid11200700, year = {2000}, author = {Ludolph, AC}, title = {Treatment of amyotrophic lateral sclerosis--what is the next step?.}, journal = {Journal of neurology}, volume = {247}, number = {}, pages = {13-18}, pmid = {11200700}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/prevention &amp; control/*therapy ; Animals ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable. However, recent evidence in both experimental animals and men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of drugs is still small, this progress cannot only be seen as a success of the present but must also be acknowledged as a basis for future developments. How will future studies be designed? They will have to take into account that the disease presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have been shown to be effective in transgenic animal models. This also implies that we are likely to use a combination of therapies and we will try to treat patients early. The latter will be associated with the demand for a novel clinical attitude toward the diagnosis of the disease and the development of novel markers for both the preclinical period and the longitudinal course of the disease.}, }
@article {pmid11198744, year = {2000}, author = {Hardiman, O}, title = {Pitfalls in the diagnosis of motor neurone disease.}, journal = {Hospital medicine (London, England : 1998)}, volume = {61}, number = {11}, pages = {767-771}, doi = {10.12968/hosp.2000.61.11.1461}, pmid = {11198744}, issn = {1462-3935}, mesh = {Diagnosis, Differential ; *Diagnostic Errors ; Humans ; Magnetic Resonance Imaging ; Motor Neuron Disease/*diagnosis/physiopathology ; Muscular Atrophy, Spinal/diagnosis ; Myositis, Inclusion Body/diagnosis ; Nervous System/physiopathology ; Polyneuropathies/diagnosis ; Postpoliomyelitis Syndrome/diagnosis ; Spinal Cord Diseases/diagnosis ; Thyrotoxicosis/diagnosis ; }, abstract = {Motor neurone disease is characterized by progressive degeneration of upper and lower motor neurones with preservation of cognition. Recognition of classical motor neurone disease is not difficult, but during the early stages both false positive and false negative diagnoses are common. Careful examination, frequent follow-up and ancillary tests are necessary to avoid erroneous diagnoses.}, }
@article {pmid11193803, year = {2000}, author = {Trojanowski, JQ and Lee, VM}, title = {"Fatal attractions" of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders.}, journal = {Annals of the New York Academy of Sciences}, volume = {924}, number = {}, pages = {62-67}, doi = {10.1111/j.1749-6632.2000.tb05561.x}, pmid = {11193803}, issn = {0077-8923}, mesh = {Alzheimer Disease/*metabolism/*pathology ; Brain Chemistry/physiology ; Humans ; Nerve Degeneration/metabolism/pathology ; Nerve Tissue Proteins/*metabolism ; Synucleins ; tau Proteins/*metabolism ; }, abstract = {Abnormal protein-protein interactions that result in the formation of intracellular and extracellular aggregates of proteinacious fibrils are common neuropathological features of many, albeit diverse, neurodegenerative disorders, such as sporadic and familial Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion encephalopathies. Indeed, increasing evidence suggests that abnormal protein-protein interactions and/or the lesions that result from the aggregation of pathological protein fibrils could play a mechanistic role in the dysfunction and death of neurons or glial cells in neurodegenerative diseases. Here we propose that "fatal attractions" between brain proteins are the key pathological events underlying Alzheimer's disease and a large number of other seemingly diverse neurodegenerative disorders. This hypothesis predicts that the abnormal interaction between normal brain proteins alters their conformation and promotes the assembly of these pathological conformers into filaments that progressively accumulate as intracellular or extracellular fibrous deposits in the central nervous system. Further, the transformation of the normal proteins into pathological conformers is predicted to result in losses of critical functions, and the disease proteins or their progressive accumulation into filamentous aggregates are predicted to acquire neurotoxic properties, all of which culminate in the dysfunction and death of affected brain cells. Thus, the "fatal attractions" hypothesis describes a plausible unifying mechanism that accounts for the onset/progression of Alzheimer's disease and a large number of other seemingly unrelated neurodegenerative disorders characterized neuropathologically by filamentous brain lesions formed by different proteins.}, }
@article {pmid11174039, year = {2001}, author = {Armon, C}, title = {Environmental risk factors for amyotrophic lateral sclerosis.}, journal = {Neuroepidemiology}, volume = {20}, number = {1}, pages = {2-6}, doi = {10.1159/000054751}, pmid = {11174039}, issn = {0251-5350}, mesh = {Environmental Pollution/adverse effects ; Humans ; Motor Neuron Disease/epidemiology/*etiology ; Risk Factors ; *Social Environment ; }, abstract = {In order to evaluate reported associations of environmental risk factors with amyotrophic lateral sclerosis (ALS), consideration is given first to robust clinical and epidemiologic observations. These are observations which have persisted in time, have been replicated consistently and likely reflect the reality of the disease. Sporadic, familial and Western Pacific ALS are considered. In contrast, other associations appear to have emerged due to chance, sometimes compounded by faulty study design, and have dissipated once greater attention was given to methodological rigor. Current data suggest that there are no robust environmental risk factors for sporadic ALS.}, }
@article {pmid11173971, year = {2001}, author = {Davis, KM and Wu, JY}, title = {Role of glutamatergic and GABAergic systems in alcoholism.}, journal = {Journal of biomedical science}, volume = {8}, number = {1}, pages = {7-19}, doi = {10.1007/BF02255966}, pmid = {11173971}, issn = {1021-7770}, support = {NS37851/NS/NINDS NIH HHS/United States ; }, mesh = {Alcoholism/*physiopathology ; Brain Chemistry/drug effects ; Ethanol/pharmacology ; Humans ; Receptors, GABA/drug effects/*physiology ; Receptors, Glutamate/drug effects/*physiology ; }, abstract = {The pharmacological effects of ethanol are complex and widespread without a well-defined target. Since glutamatergic and GABAergic innervation are both dense and diffuse and account for more than 80% of the neuronal circuitry in the human brain, alterations in glutamatergic and GABAergic function could affect the function of all neurotransmitter systems. Here, we review recent progress in glutamatergic and GABAergic systems with a special focus on their roles in alcohol dependence and alcohol withdrawal-induced seizures. In particular, NMDA-receptors appear to play a central role in alcohol dependence and alcohol-induced neurological disorders. Hence, NMDA receptor antagonists may have multiple functions in treating alcoholism and other addictions and they may become important therapeutics for numerous disorders including epilepsy, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's chorea, anxiety, neurotoxicity, ischemic stroke, and chronic pain. One of the new family of NMDA receptor antagonists, such as DETC-MESO, which regulate the redox site of NMDA receptors, may prove to be the drug of choice for treating alcoholism as well as many neurological diseases.}, }
@article {pmid11173059, year = {2001}, author = {Maimone, D and Dominici, R and Grimaldi, LM}, title = {Pharmacogenomics of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {413}, number = {1}, pages = {11-29}, doi = {10.1016/s0014-2999(00)00939-0}, pmid = {11173059}, issn = {0014-2999}, mesh = {Alzheimer Disease/drug therapy/genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Animals ; Apoptosis ; Genetic Predisposition to Disease ; Humans ; Inflammation/pathology ; Nerve Growth Factors/genetics/metabolism/therapeutic use ; Neurodegenerative Diseases/drug therapy/*genetics/*metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Neurotransmitter Agents/metabolism ; Oxidative Stress ; Parkinson Disease/drug therapy/genetics/metabolism/pathology ; *Pharmacogenetics ; Polymorphism, Genetic ; }, abstract = {Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.}, }
@article {pmid11149699, year = {2000}, author = {Nestor, P and Hodges, J}, title = {Non-Alzheimer dementias.}, journal = {Seminars in neurology}, volume = {20}, number = {4}, pages = {439-446}, doi = {10.1055/s-2000-13176}, pmid = {11149699}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/complications/pathology/physiopathology ; Aphasia, Primary Progressive/etiology/pathology/physiopathology ; Brain/*pathology/*physiopathology ; Dementia/complications/*pathology/physiopathology ; Humans ; Lewy Body Disease/pathology/physiopathology/psychology ; Movement Disorders/etiology/pathology/physiopathology ; }, abstract = {The past decade has seen a considerable resurgence of interest in non-Alzheimer forms of neurodegenerative dementia. Advances in our understanding and classification of these conditions have taken place over a diverse range of disciplines: from genetics and immunohistochemistry to neuropsychology and psychiatry. The aim of this article is to review, from a clinician's perspective, our current understanding of the major degenerative dementias that fall into the differential diagnosis of Alzheimer's disease. The clinical variants of frontotemporal dementia (semantic dementia, progressive nonfluent aphasia, and dementia of a frontal type), amyotrophic lateral sclerosis associated dementia, corticobasal degeneration, and dementia with Lewy bodies are considered.}, }
@article {pmid11141633, year = {2000}, author = {Hamilton, SR}, title = {Neuro-ophthalmology of movement disorders.}, journal = {Current opinion in ophthalmology}, volume = {11}, number = {6}, pages = {403-407}, doi = {10.1097/00055735-200012000-00004}, pmid = {11141633}, issn = {1040-8738}, mesh = {Humans ; Movement Disorders/*complications/diagnosis/therapy ; Neurology/*methods ; Ocular Motility Disorders/diagnosis/*etiology/therapy ; Ophthalmology/*methods ; Visual Perception ; }, abstract = {Movement disorders are a diverse group of neurologic disorders that share in common the frequent development of clinical abnormalities in ocular motility or visual perception. This article reviews the recent literature pertaining to the neuro-ophthalmologic advances in the basal ganglia disorders (Parkinson disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and Huntington disease), the spinocerebellar ataxias and episodic ataxias, amyotrophic lateral sclerosis, benign essential blepharospasm, hemifacial spasm, and Tourette syndrome.}, }
@article {pmid11135279, year = {2000}, author = {Brown, WF and Doherty, TJ and Chan, M and Andres, A and Provost, SM}, title = {Human motor units in health and disease.}, journal = {Muscle &amp; nerve. Supplement}, volume = {9}, number = {}, pages = {S7-18}, doi = {10.1002/1097-4598(2000)999:9&lt;::aid-mus4&gt;3.0.co;2-o}, pmid = {11135279}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Electromyography ; Humans ; Motor Neurons/*physiology ; Muscle, Skeletal/*innervation/*physiology ; }, abstract = {Recent advances in clinical neurophysiology have made it possible to non-invasively stimulate single motor axons and determine the physiological characteristics of the associated motor units. Some motor units lend themselves to longitudinal studies of their electrical and contractile characteristics. The former include the conduction velocities of their motor axons and the sizes and shapes of their motor unit action potentials and the latter such contractile characteristics of the motor unit as their contractile speeds, twitch and tetanic tensions, and resistance to fatigue. The feasibility of serially examining the same motor unit has made it possible to study the responses of single motor units to conditioning as well as changes in the responses of single motor units to diseases such as amyotrophic lateral sclerosis. The non-invasive character of these approaches offers an attractive means of studying the responses of single human cells, in these cases motor neurons, in health and disease.}, }
@article {pmid11131547, year = {2000}, author = {Bohn, MC and Connor, B and Kozlowski, DA and Mohajeri, MH}, title = {Gene transfer for neuroprotection in animal models of Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Novartis Foundation symposium}, volume = {231}, number = {}, pages = {70-89; discussion 89-93}, doi = {10.1002/0470870834.ch5}, pmid = {11131547}, issn = {1528-2511}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Disease Models, Animal ; *Gene Transfer Techniques ; *Genetic Therapy ; Glial Cell Line-Derived Neurotrophic Factor ; *Nerve Growth Factors ; Nerve Tissue Proteins/genetics ; *Neuroprotective Agents ; Parkinsonian Disorders/*therapy ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MN) and dopaminergic (DA) neurons, neurons which selectively die in amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). GDNF gene delivery has been studied in rodent models of ALS and PD. In a mouse model of ALS, implantation of myoblasts retrovirally transduced with GDNF into hindlimb muscles at 6 weeks of age, i.e. prior to the onset of disease symptoms, increased the number of large MNs that maintained projections to treated muscles at 18 weeks of age. GDNF-treated mice also performed better on tests of motor function and had a delayed onset of disease. In a progressive degeneration rat model of PD, effects of in vivo GDNF gene therapy using an adenoviral vector (AdGDNF) were studied in young and aged rats. AdGDNF protected DA neurons against the neurotoxin, 6-hydroxydopamine (6-OHDA), and was effective whether injected either before or after 6-OHDA damage had commenced. However, if AdGDNF was injected prior to 6-OHDA, it was most effective in protecting against DA-dependent changes in the brain when injected near the terminals of the DA neurons. In contrast, if 6-OHDA damage had already commenced, AdGDNF was most effective if injected near the DA soma. These studies suggest that GDNF gene delivery into specific sites in the CNS or into muscle where MNs have access to secreted GDNF may slow the progression of PD and ALS, respectively. Neurotrophic factor gene therapy offers novel interventions not only for PD and ALS, but also other neurodegenerative diseases and injuries to the nervous system.}, }
@article {pmid11130970, year = {2000}, author = {Nicholson, SJ and Witherden, AS and Hafezparast, M and Martin, JE and Fisher, EM}, title = {Mice, the motor system, and human motor neuron pathology.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {11}, number = {12}, pages = {1041-1052}, doi = {10.1007/s003350010205}, pmid = {11130970}, issn = {0938-8990}, mesh = {Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/genetics/metabolism/*pathology ; Superoxide Dismutase/genetics ; }, abstract = {Motor neurons are among some of the most unusual cells in the body becaue of their immense size and their role as the critical link between the motor centers of the brain and the muscles. In addition to their intrinsic biological interest, it is vital that we gain a better understanding of these cells and their pathology, since motor neuron degenerative diseases are lethal disorders that affect young and old and are relatively common. For example, one form of spinal muscular atrophy (SMA) is the most common genetic killer of children in the developed world. Amyotrophic lateral sclerosis (ALS), another form of motor neuron degeneration, is the third most common neurodegenerative cause of adult death, after Alzheimer's disease and Parkinson's disease, and is significantly more common than multiple sclerosis (Motor Neurone Disease Association 1998). Currently, approximately 1 in 500 people in England and Wales who die have a form of motor neuron disease (Motor Neurone Disease Association 1998). Each year, 5000 Americans are diagnosed with ALS, and of these, 10% are under 40 years old. Mouse models of motor neuron degeneration are essential for understanding the causes and mechanisms of motor neuron pathology. These mice are yielding important information that will ultimately lead to treatments and potentially cures for these diseases.}, }
@article {pmid11128605, year = {2000}, author = {Offen, D and Elkon, H and Melamed, E}, title = {Apoptosis as a general cell death pathway in neurodegenerative diseases.}, journal = {Journal of neural transmission. Supplementum}, volume = {}, number = {58}, pages = {153-166}, doi = {10.1007/978-3-7091-6284-2_13}, pmid = {11128605}, issn = {0303-6995}, mesh = {Alzheimer Disease/genetics/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Animals ; *Apoptosis ; Humans ; Huntington Disease/physiopathology ; Neurodegenerative Diseases/genetics/*physiopathology ; Parkinson Disease/physiopathology ; Peptides/genetics ; Prion Diseases/physiopathology ; }, abstract = {Neurodegenerative processes are generally characterized by the long-lasting course of neuronal death and the selectivity of the neuronal population or brain structure involved in the lesion. Two main common forms of cell death that have been described in neurons as in other vertebrate tissues i.e., necrosis and apoptosis. Necrosis is the result of cellular "accidents", such as those occurring in tissues subjected to chemical trauma. The necrotizing cells swell, rupture and provoke an inflammatory response. Apoptosis, on the other hand, is dependent on the cell's "decision" to commit suicide and die, and therefore is referred to as "programmed cell death" (PCD). The course of apoptotic death is characterized by a massive morphological change, including cell shrinkage, nuclear (chromosome) condensation and DNA degradation. Activation of PCD in an individual cell is based on its own internal metabolism, environment, developmental background and its genetic information. Such a situation occurs in most of the neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis (ALS). In these pathological situations, specific neurons undergo apoptotic cell death characterized by DNA fragmentation, increased levels of pro-apoptotic genes and "apoptotic proteins" both, in human brain and in experimental models. It is of utmost importance to conclusively determine the mode of cell death in neurodegenerative diseases, because new "anti-apoptotic" compounds may offer a means of protecting neurons from cell death and of slowing the rate of cell degeneration and illness progression.}, }
@article {pmid11098292, year = {2000}, author = {Robberecht, W and Van Den Bosch, L and Vleminckx, V}, title = {Amyotrophic lateral sclerosis: pathogenesis.}, journal = {Acta neurologica Belgica}, volume = {100}, number = {3}, pages = {181-187}, pmid = {11098292}, issn = {0300-9009}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; Animals ; Humans ; Mice ; Mice, Transgenic ; Mutation/*genetics ; Neurofilament Proteins/genetics ; Oxidative Stress/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid11096437, year = {2000}, author = {Alisky, JM and Davidson, BL}, title = {Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases.}, journal = {Human gene therapy}, volume = {11}, number = {17}, pages = {2315-2329}, doi = {10.1089/104303400750038435}, pmid = {11096437}, issn = {1043-0342}, mesh = {Amyotrophic Lateral Sclerosis/etiology/pathology/*therapy ; Animals ; Calbindins ; Drug Delivery Systems/methods ; Genetic Therapy/*methods ; Genetic Vectors/administration &amp; dosage/genetics ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/pathology/therapy ; Proto-Oncogene Proteins c-bcl-2/physiology ; S100 Calcium Binding Protein G/physiology ; Superoxide Dismutase/genetics ; }, abstract = {There are several incurable diseases of motor neuron degeneration, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditary spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Advances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting disease progression. Nonviral preparations and recombinant adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses may ultimately transduce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramuscular injection, or cell-based therapies. Studies using transgenic mice expressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin, bcl-2, and growth factors. These same molecules promoted neuronal survival in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atrophy. Finally, it may be possible to repopulate lost corticospinal and lower motor neurons by transplanting stem cells or stimulating native progenitor populations. The challenge ahead is to translate these basic science breakthroughs into workable clinical practice.}, }
@article {pmid11094907, year = {1999}, author = {Carter, GT and Bednar-Butler, LM and Abresch, RT and Ugalde, VO}, title = {Expanding the role of hospice care in amyotrophic lateral sclerosis.}, journal = {The American journal of hospice &amp; palliative care}, volume = {16}, number = {6}, pages = {707-710}, doi = {10.1177/104990919901600607}, pmid = {11094907}, issn = {1049-9091}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Disease Progression ; Home Care Services ; Hospice Care/*organization &amp; administration/psychology ; Humans ; Needs Assessment ; Patient Admission ; Patient Selection ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, ultimately fatal, motor neuron disease that poses a myriad of clinical and end-of-life problems. The needs of advanced ALS patients are well suited to the interdisciplinary, multi-modality setting of hospice, where comprehensive palliative strategies may ease suffering and allow the patient to die with dignity in the home. Unfortunately, hospice services are far underutilized in this setting. There is a great need to increase awareness of both patients and clinicians regarding the effectiveness of hospice in the care of advanced ALS patients.}, }
@article {pmid11090860, year = {2000}, author = {Hurko, O and Walsh, FS}, title = {Novel drug development for amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {21-28}, doi = {10.1016/s0022-510x(00)00419-6}, pmid = {11090860}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Drug Design ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has become an increasingly attractive area for the pharmaceutical industry, the most experimentally tractable of the neurodegenerative diseases. Mechanisms underlying cell death in ALS are likely to be important in more common but more complex disorders. Riluzole, the only drug launched for treatment ALS is currently undergoing industrial trials for Alzheimer's, Parkinson's, Huntington disease, stroke and head injury. Other compounds in Phase III testing for ALS (mecamserin, xaliproden, gabapentin) are also in trials for other neurodegenerative disorders. Mechanisms of action of these advanced compounds are limited to glutamate antagonism, direct or indirect growth factor activity, as well as GABA agonism and interaction with calcium channels. A broader range of mechanisms is represented by compounds in Phase I trials: glutamate antagonism (dextramethorphan/p450 inhibitor; talampanel), growth factors (leukemia inhibiting factor; IL-1 receptor; encapsulated cells secreting CNTF) and antioxidants (TR500, a glutathione-repleting agent; recombinant superoxide dismutase; procysteine.) An even broader range of mechanisms is being explored in preclinical discovery programs. Recognition of the difficulties associated with delivery of protein therapeutics to the CNS has led to development of small molecules interacting either with neurotrophin receptors or with downstream intracellular signalling pathways. Other novel drug targets include caspaces, protein kinases and other molecules influencing apoptosis. High-throughput screens of large libraries of small molecules yield lead compounds that are subsequently optimized by chemists, screened for toxicity, and validated before a candidate is selected for clinical trials. The net is cast wide in early discovery efforts, only about 1% of which result in useful drugs at the end of a decade-long process. Successful discovery and development of novel drugs will increasingly depend on collaborative efforts between the academy and industry.}, }
@article {pmid11090859, year = {2000}, author = {Neary, D and Snowden, JS and Mann, DM}, title = {Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS).}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {15-20}, doi = {10.1016/s0022-510x(00)00425-1}, pmid = {11090859}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/psychology ; Brain/*pathology ; Cognition Disorders/*pathology/psychology ; Humans ; Language Disorders/pathology/psychology ; Memory Disorders/pathology/psychology ; }, abstract = {A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.}, }
@article {pmid11090858, year = {2000}, author = {Julien, JP and Beaulieu, JM}, title = {Cytoskeletal abnormalities in amyotrophic lateral sclerosis: beneficial or detrimental effects?.}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {7-14}, doi = {10.1016/s0022-510x(00)00422-6}, pmid = {11090858}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cytoskeleton/genetics/*pathology ; Disease Models, Animal ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/*pathology ; Nerve Degeneration/genetics/pathology ; }, abstract = {Cytoskeletal abnormalities have been reported in cases of amyotrophic lateral sclerosis (ALS) including abnormal inclusions containing neurofilaments (NFs) and/or peripherin, reduced mRNA levels for the NF light (NF-L) protein and mutations in the NF heavy (NF-H) gene. Recently, transgenic mouse approaches have been used to address whether cytoskeletal changes may contribute to motor neuron disease. Mice lacking one of the three NF subunits are viable and do not develop motor neuron disease. Nonetheless, mice with null mutations for NF-L or for both NF-M and NF-H genes developed severe atrophy of ventral and dorsal root axons. The atrophic process is associated with hind limb paralysis during aging in mice deficient for both NF-M and NF-H proteins. The overexpression in mice of transgenes coding for wild-type or mutant NF proteins can provoke abnormal NF accumulations, axonal atrophy and sometimes motor dysfunction. However, the perikaryal NF accumulations are generally well tolerated by motor neurons and, except for expression of a mutant NF-L transgene, they did not provoke massive motor neuron death. Increasing the levels of perikaryal NF proteins may even confer protection in motor neuron disease caused by ALS-linked mutations in the superoxide dismutase (SOD1). In contrast, the overexpression of wild-type peripherin, a type of IF gene upregulated by inflammatory cytokines, provoked the formation of toxic IF inclusions with the high-molecular-weight NF proteins resulting in the death of motor neurons during aging. These results together with the detection of peripherin inclusions at early stage of disease in mice expressing mutant SOD1 suggest that IF inclusions containing peripherin may play a contributory role in ALS pathogenesis.}, }
@article {pmid11090857, year = {2000}, author = {Rowland, LP}, title = {Six important themes in amyotrophic lateral sclerosis (ALS) research, 1999.}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {2-6}, doi = {10.1016/s0022-510x(00)00428-7}, pmid = {11090857}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Genetic Therapy/trends ; Humans ; Mice ; }, abstract = {My assignment was to identify the 6 most important ALS papers published in 1999 but, great to relate, there were too many excellent candidates. Rather than confining the search to individual papers, six major themes seemed appropriate for discussion: 1) The study of transgenic mice that carry a mutated human gene for superoxide dismutase-1 (SOD1) has led to many far-reaching advances in ALS research. The mice are regarded as the best test system to evaluate potential therapies, including creatine. Inconsistencies between efficacy in mice and people are noted, however. 2) Transgenic mice have also been used to evaluate the role of glutamate toxicity in the pathogenesis of ALS, a dominant theory. 3) The role of mitochondria in the pathogenesis of ALS is gathering increasing attention. 4) The role of neurofilaments in the pathogenesis of ALS has provided new twists in mice and people. 5) Motor neuropathy is the most important differential diagnosis of ALS. 6) Gene therapy, as exemplified by the use of stem cells, has been applied successfully to animal models of other inherited diseases of the central nervous system.}, }
@article {pmid11085837, year = {2000}, author = {Tarnopolsky, MA}, title = {Potential benefits of creatine monohydrate supplementation in the elderly.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {3}, number = {6}, pages = {497-502}, doi = {10.1097/00075197-200011000-00013}, pmid = {11085837}, issn = {1363-1950}, mesh = {Aged ; Aging/drug effects/*physiology ; Creatine/*administration &amp; dosage/metabolism ; *Dietary Supplements ; Exercise/*physiology ; Humans ; Muscle, Skeletal/*drug effects/metabolism ; Proteins/*metabolism ; Sports/physiology ; }, abstract = {Creatine plays a role in cellular energy metabolism and potentially has a role in protein metabolism. Creatine monohydrate supplementation has been shown to result in an increase in skeletal muscle total and phosphocreatine concentration, increase fat-free mass, and enhance high-intensity exercise performance in young healthy men and women. Recent evidence has also demonstrated a neuroprotective effect of creatine monohydrate supplementation in animal models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and after ischemia. A low total and phosphocreatine concentration has been reported in human skeletal muscle from aged individuals and those with neuromuscular disorders. A few studies of creatine monohydrate supplementation in the elderly have not shown convincing evidence of a beneficial effect with respect to muscle mass and/or function. Future studies will be required to address the potential for creatine monohydrate supplementation to attenuate age-related muscle atrophy and strength loss, as well as to protect against age-dependent neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.}, }
@article {pmid11074787, year = {2000}, author = {Bedlack, RS and Strittmatter, WJ and Morgenlander, JC}, title = {Apolipoprotein E and neuromuscular disease: a critical review of the literature.}, journal = {Archives of neurology}, volume = {57}, number = {11}, pages = {1561-1565}, doi = {10.1001/archneur.57.11.1561}, pmid = {11074787}, issn = {0003-9942}, mesh = {Alleles ; Amyloid Neuropathies/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Apolipoproteins E/genetics/*metabolism ; Dementia/metabolism ; Diabetic Neuropathies/metabolism ; Disease Progression ; HIV Infections/complications/metabolism ; Humans ; Motor Neuron Disease/metabolism ; Myositis, Inclusion Body/metabolism ; Neuromuscular Diseases/*metabolism ; Parkinson Disease/metabolism ; Prognosis ; Research Design ; Risk ; }, abstract = {Molecular mechanisms that alter the incidence and rate of neuromuscular disease progression are, in many cases, only partially understood. Several recent studies have asked whether apolipoprotein E (apoE for the protein, APOE for the gene) influences these aspects of specific neuromuscular disorders, as it does in central nervous system disorders such as Alzheimer disease. Although these studies are open to methodological criticism, several interesting trends have emerged. First, the APOE4 allele seems to be associated with an increased risk for developing certain neuromuscular diseases, including diabetic neuropathy and human immunodeficiency viral neuropathy. Second, this allele appears to be associated with faster progression of some neuromuscular diseases, including diabetic neuropathy and possibly motor neuron disease. Third, the APOE2 allele seems to confer protection against developing certain neuromuscular diseases, including the amyotrophic lateral sclerosis (ALS)/parkinsonism/dementia complex of Guam. Finally, this allele is associated with a better prognosis in neuromuscular diseases such as motor neuron disease. The effect of various APOE alleles on neuromuscular diseases therefore parallels their influence on central nervous system diseases. Arch Neurol. 2000;57:1561-1565}, }
@article {pmid11063050, year = {2000}, author = {Eldadah, BA and Faden, AI}, title = {Caspase pathways, neuronal apoptosis, and CNS injury.}, journal = {Journal of neurotrauma}, volume = {17}, number = {10}, pages = {811-829}, doi = {10.1089/neu.2000.17.811}, pmid = {11063050}, issn = {0897-7151}, support = {1RO1NS36537/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*physiology ; Brain Injuries/*metabolism/pathology/physiopathology ; Brain Ischemia/metabolism/pathology/physiopathology ; Caspases/*metabolism ; Humans ; Nerve Degeneration/*metabolism/pathology/physiopathology ; Neurodegenerative Diseases/metabolism/pathology/physiopathology ; Signal Transduction/*physiology ; Spinal Cord Injuries/*metabolism/pathology/physiopathology ; }, abstract = {Caspases are a family of mammalian proteases related to the ced-3 gene of Caenorhabditis elegans. They mediate many of the morphological and biochemical features of apoptosis, including structural dismantling of cell bodies and nuclei, fragmentation of genomic DNA, destruction of regulatory proteins, and propagation of other pro-apoptotic molecules. Based on their substrate specificities and DNA sequence homologies, the 14 currently identified caspases may be divided into three groups: apoptotic initiators, apoptotic executioners, and inflammatory mediators. Caspases are activated through two principal pathways, known as the "extrinsic pathway," which is initiated by cell surface death receptor ligation, and the intrinsic pathway, which arises from mitochondria. Endogenous inhibitors, such as the inhibitors of apoptosis (IAP) family, modulate caspase activity at various points within these pathways. Upon activation, caspases appear to play an important role in sequelae of traumatic brain injury, spinal cord injury, and cerebral ischemia. In addition, they may also play a role in mediating cell death in chronic neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. This article reviews the current literature on the role of caspases in acute and chronic CNS injury, and provides evidence for the potential therapeutic use of caspase inhibitors in the setting of these conditions.}, }
@article {pmid11062847, year = {2000}, author = {Alimonti, D and Malaspina, A and Poloni, TE and Ceroni, M}, title = {Genotype-phenotype correlation in familial amyotrophic lateral sclerosis with SOD1 mutation.}, journal = {Functional neurology}, volume = {15}, number = {3}, pages = {177-191}, pmid = {11062847}, issn = {0393-5264}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics ; Gene Expression/genetics ; Genotype ; Humans ; Phenotype ; Point Mutation/*genetics ; Superoxide Dismutase/*genetics/*metabolism ; }, }
@article {pmid11060751, year = {2000}, author = {Jain, KK}, title = {Evaluation of memantine for neuroprotection in dementia.}, journal = {Expert opinion on investigational drugs}, volume = {9}, number = {6}, pages = {1397-1406}, doi = {10.1517/13543784.9.6.1397}, pmid = {11060751}, issn = {1354-3784}, mesh = {Alzheimer Disease/prevention &amp; control ; Animals ; Dementia/*prevention &amp; control ; Humans ; Memantine/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.}, }
@article {pmid11059071, year = {2000}, author = {Busljeta, I and Gomzi, M and Trosić, I}, title = {[Biological effects of nonionizing radiation: low frequency electromagnetic fields].}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {51}, number = {1}, pages = {35-51}, pmid = {11059071}, issn = {0004-1254}, mesh = {Animals ; Electromagnetic Fields/*adverse effects ; Humans ; }, abstract = {This article reviews various studies on effects of electric and magnetic fields of extremely low frequencies on human health and gives an overview of residential and occupational exposure to different sources, currently established exposure limitations, and protection measures. Throughout the evolution biological systems adapted to natural electric and magnetic fields. Only hundred years ago human exposure to radiation was limited to electric and magnetic fields arising either from extraterrestrial or terrestrial sources, yet both natural. For the past fifty years there has been large growth of artificial sources of electric and magnetic fields, especially with frequencies of 50 and 60 Hz (power generating and distribution systems). The concern about long-term exposure to artificial fields and possible adverse effects on human health has been entirely justified and led to numerous intensive epidemiological and laboratory studies. Results of several epidemiological studies confirm the connection between exposure to electric and magnetic fields of extremely low frequencies (up to 300 Hz) and increased risk of leukemia and brain tumor in children and adults. In addition, the risk of breast cancer in occupationally exposed population has increased. Laboratory studies on animal models, in vitro systems, and human volunteers did not confirm this connection. There is a growing interest in investigation of other possible adverse health effects such as neurodegenerative diseases (Alzheimer's disease and other forms of dementia, amyotrophic lateral sclerosis), cardiovascular disorders (arrhythmias and acute myocardial infarction), psychiatric disorders, and electrosensitivity.}, }
@article {pmid11051298, year = {2000}, author = {Mastrianni, JA and Roos, RP}, title = {The prion diseases.}, journal = {Seminars in neurology}, volume = {20}, number = {3}, pages = {337-352}, doi = {10.1055/s-2000-9396}, pmid = {11051298}, issn = {0271-8235}, mesh = {Amyloid/genetics ; Brain/pathology/physiopathology ; Creutzfeldt-Jakob Syndrome/pathology ; Diagnosis, Differential ; Genetic Counseling/trends ; Gerstmann-Straussler-Scheinker Disease/genetics/pathology ; Humans ; Mutation/physiology ; Phenotype ; Prion Diseases/epidemiology/*genetics/*pathology ; Prion Proteins ; Prions/genetics/metabolism ; Protein Precursors/genetics ; }, abstract = {The prion diseases constitute an unusual group of neurodegenerative disorders. Although they are similar in many ways to other more common diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, they are set apart on the basis of their transmissible nature. In addition to the unique feature of transmissibility, the prion diseases demonstrate that the expression of diverse disease phenotypes is possible from a common etiologic factor. This review provides the reader with a basic understanding of the nature of prions and highlights the clinical and pathologic features of these fascinating diseases.}, }
@article {pmid11050436, year = {2000}, author = {Raha, S and Robinson, BH}, title = {Mitochondria, oxygen free radicals, disease and ageing.}, journal = {Trends in biochemical sciences}, volume = {25}, number = {10}, pages = {502-508}, doi = {10.1016/s0968-0004(00)01674-1}, pmid = {11050436}, issn = {0968-0004}, mesh = {Aging/*physiology ; Disease ; Electron Transport Complex I ; Electron Transport Complex III/*metabolism ; Humans ; Metabolism, Inborn Errors/metabolism ; Mitochondria/*metabolism ; NADH, NADPH Oxidoreductases/deficiency/*metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxides/metabolism ; }, abstract = {Superoxide is generated by the mitochondrial respiratory chain. The transformation of this superoxide into hydrogen peroxide and, under certain conditions, then into hydroxyl radicals is important in diseases where respiratory chain function is abnormal or where superoxide dismutase function is altered, as in amyotrophic lateral sclerosis. In addition, these reactive oxygen species can influence the ageing process through mechanisms involving mutagenesis of mtDNA or increased rates of shortening of telomeric DNA.}, }
@article {pmid11037194, year = {2000}, author = {Mitsuyama, Y}, title = {Dementia with motor neuron disease.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {20 Suppl}, number = {}, pages = {S79-81}, doi = {10.1046/j.1440-1789.2000.00302.x}, pmid = {11037194}, issn = {0919-6544}, mesh = {Dementia/*complications/*pathology/physiopathology ; Diagnosis, Differential ; Disease Progression ; Humans ; Motor Neuron Disease/*complications/*pathology/physiopathology ; Nerve Degeneration/pathology/physiopathology ; Spinal Cord/pathology/physiopathology ; }, abstract = {Dementia with motor neuron disease has been described as a new clinicopathologic entity and more than 100 cases have been reported in Japan since 1964. The clinicopathologic criteria in the diagnosis of dementia with motor neuron disease are: (i) frontotemporal lobe-type dementia with insidious onset, mostly in the presenile period; (ii) neurogenic muscular wasting during the course of the illness (amyotrophic lateral sclerosis- or SPMA-like symptoms); (iii) duration from the onset of illness to death of 2-5 years (average, 30.6 months); (iv) both extrapyramidal symptoms and definite sensory deficits are present less commonly; (v) no characteristic abnormalities in the cerebrospinal fluid or electroencephalogram on screening; (vi) no known parental consanguinity or familial occurrence; and (vii) non-specific, mild to slight degenerative changes in the frontotemporal cortex, hypoglossal nuclei and spinal cord, and frequently in the substantia nigra. Dementia with motor neuron disease is characterized by ubiquitin-immunoreactive intraneuronal inclusions in cortical layer II and hippocampal dentate granule cells.}, }
@article {pmid11034730, year = {2000}, author = {Symington, A and Pinelli, J}, title = {Developmental care for promoting development and preventing morbidity in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD001814}, doi = {10.1002/14651858.CD001814}, pmid = {11034730}, issn = {1469-493X}, mesh = {Developmental Disabilities/*prevention &amp; control ; Humans ; Infant, Newborn ; *Infant, Premature ; Length of Stay ; Randomized Controlled Trials as Topic ; Respiration, Artificial ; Stress, Physiological/prevention &amp; control ; Treatment Outcome ; Weight Gain ; }, abstract = {BACKGROUND: Preterm infants experience a range of morbidity related to the immaturity of their organ systems and to concurrent disease states. An unfavourable environment in the neonatal intensive care unit (NICU) may compound this morbidity. Modification of the environment could minimize the iatrogenic effects. Developmental care is a broad category of interventions designed to minimize the stress of the NICU environment. These interventions may include one or more elements such as control of external stimuli (vestibular, auditory, visual, tactile), clustering of nursery care activities, and positioning or swaddling of the preterm infant. Individual strategies have also been combined to form programs, such as the 'Neonatal Individualized Developmental Care and Assessment Program' (NIDCAP) (Als 1986).<br><br>OBJECTIVES: In preterm infants, do developmental care interventions reduce neurodevelopmental delay, poor weight gain, length of hospital stay, length of mechanical ventilation, physiological stress and other clinically relevant adverse outcomes?<br><br>SEARCH STRATEGY: The Neonatal Review Group search strategy was utilized. Searches were made of Medline from 1966 to July, 2000, and of CINAHL, The Cochrane Library, and conference and symposia proceedings in the English language from 1990 to July, 2000. A list of all relevant articles was sent to two experts in the field to identify any omissions or additional unpublished studies.<br><br>SELECTION CRITERIA: Randomized trials in which elements of developmental care are compared to routine nursery care for infants < 37 weeks gestation and that measured clinically relevant outcomes. Reports were in English or a language for which a translator was available. Computerized searches were conducted and all potentially relevant titles and abstracts were extracted. Retrieved articles were assessed for relevance independently by two reviewers, based on predetermined criteria. Articles that met all criteria for relevance were assessed for methodological quality based on predetermined criteria. Articles judged to have the appropriate quality by both reviewers were included in the analysis.<br><br>DATA COLLECTION AND ANALYSIS: Data were extracted independently by the two authors. Meta-analyses were conducted for each intervention where the same outcome measures and/or instruments were used within comparable time points.<br><br>MAIN RESULTS: This review detected 31 eligible randomized controlled trials involving four major groups of developmental care interventions, 19 sub-groups and multiple clinical outcomes. The results of the review indicate that developmental care interventions demonstrate some benefit to preterm infants with respect to: improved short-term growth outcomes, decreased respiratory support, decreased length and cost of hospital stay, and improved neurodevelopmental outcomes to 24 months corrected age. These findings were based on two or three small trials for each outcome, and did not involve meta-analyses of more than two trials for any one outcome. Although a number of other benefits were demonstrated, those results were from single studies with small sample sizes. The lack of blinding of the assessors was a significant methodological flaw in half of the studies. The cost of the interventions and personnel was not considered in any of the studies.<br><br>REVIEWER'S CONCLUSIONS: Because of the inclusion of multiple interventions in most studies, the determination of the effect of any single intervention is difficult. Although there is evidence of some benefit of developmental care interventions overall, and no major harmful effects reported, there were a large number of outcomes for which no or conflicting effects were demonstrated. The single trials that did show a significant effect of an intervention on a major clinical outcome were based on small sample sizes, and the findings were often not supported in other small trials. Before a clear direction for practice can be supported, evidence demonstrating more consistent effects of developmental care interventions on important short- and long-term clinical outcomes is needed. The economic impact of the implementation and maintenance of developmental care practices should be considered by individual institutions.}, }
@article {pmid11033335, year = {2000}, author = {Bär, PR}, title = {Motor neuron disease in vitro: the use of cultured motor neurons to study amyotrophic lateral sclerosis.}, journal = {European journal of pharmacology}, volume = {405}, number = {1-3}, pages = {285-295}, doi = {10.1016/s0014-2999(00)00560-4}, pmid = {11033335}, issn = {0014-2999}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Cell Death ; Cells, Cultured ; Humans ; Motor Neuron Disease/*pathology ; Motor Neurons/*pathology/ultrastructure ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease in which motor neurons in the nervous system die. The cause is unknown, and no effective treatment exists. Mutations in the gene for superoxide dismutase found in a subpopulation have led to an animal model, but research with these mice has not produced complete insight into the disease mechanism. Studies with isolated motor neurons may produce important information. This review discusses approaches to culture motor neurons - single cells, cocultured with other cells, and in intact preparations, such as the spinal or cortical slice. Motor neurons in monoculture are suitable for acute but not for chronic studies, whereas cocultures and slices survive up to months and are used for chronic studies. Results with toxic substances believed to play a role in the disease, such as oxidants and glutamate, and of studies where the energy status of the cells is manipulated, are presented.}, }
@article {pmid11032970, year = {2000}, author = {Goldstein, S and Lestage, P}, title = {Chemical and pharmacological aspects of heteroaryl-nitrones.}, journal = {Current medicinal chemistry}, volume = {7}, number = {12}, pages = {1255-1267}, doi = {10.2174/0929867003374183}, pmid = {11032970}, issn = {0929-8673}, mesh = {Nitrogen Oxides/*chemistry/*pharmacology ; }, abstract = {Radical induced oxidative damage is extremely harmful to tissues and organs due to molecular modifications brought to polyunsaturated membrane lipids, proteins and nucleic acids. Oxidative stress is believed to be one of the pathophysiological mechanisms that operate in neurodegenerative disorders such as cerebral ischemias, amyotrophic lateral sclerosis, Parkinson s and Alzheimer s diseases. Nitrones oppose oxidative challenges by virtue of their ability to trap very rapidly oxygen or carbon centered radicals thus generating nitroxide radical species which are more stable and biochemically less harmful than the original radical. However the operational mechanism of nitrones might also go beyond direct scavenging of radicals. The chemical and pharmacological properties of nitrones depend strongly on the connectivity as well as on the type and position of the substituents in the compound's architecture. Heteroaryl-nitrones are known, but except for a few cases (for example pyridyl-nitrones) no particular attention has been given to this class of molecules. The following review is a survey of the literature reports on this subject from 1980 to 1999. The structures were classified according to the heterocyclic substituent on the nitrone double bond, and documented pharmaceutical features were emphasized. Whenever possible heteroaromatic and related aromatic nitrones were compared.}, }
@article {pmid11026975, year = {2000}, author = {Haefliger, IO and Fleischhauer, JC and Flammer, J}, title = {In glaucoma, should enthusiasm about neuroprotection be tempered by the experience obtained in other neurodegenerative disorders?.}, journal = {Eye (London, England)}, volume = {14 (Pt 3B)}, number = {}, pages = {464-472}, doi = {10.1038/eye.2000.132}, pmid = {11026975}, issn = {0950-222X}, mesh = {Apoptosis ; Glaucoma/complications/*drug therapy/pathology ; Humans ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/*therapeutic use ; Optic Nerve Diseases/*drug therapy/etiology/pathology ; Retinal Ganglion Cells/pathology ; }, abstract = {Some in vitro and in vivo evidence, as well as rare observations in human eyes with glaucoma, suggests that retinal ganglion cells could be lost by apoptosis during the course of glaucomatous optic neuropathy. There exist also observations indicating that in the vitreous of patients with glaucoma it is possible to measure an increased concentration of glutamate (an excitotoxic amino acid known to induce neuronal apoptosis in animal models). These observations, among others, suggest the possibility of an excitotoxicity mechanism in the pathogenesis of glaucoma and as a consequence the potential for a neuroprotective approach to treating this disorder. Amazingly, not only in glaucoma but also in other neurodegenerative disorders (Parkinson's disease, amyotrophic lateral sclerosis, stroke, etc.) it has been postulated that neurons could be lost through an excitotoxic mechanism. In these non-glaucomatous disorders, quite a large number of clinical trials have already been conducted to determine the potential benefit of different neuroprotective therapies. Unfortunately, with a few rare exceptions, the results of these clinical studies have been very disappointing (in contrast to encouraging results obtained in preclinical trials). The experience acquired in other neurodegenerative disorders should probably be kept in mind when addressing the question of neuroprotection in glaucoma. In particular, the hope raised by preclinical studies showing that drugs could have a beneficial effect on the survival of retinal ganglion cells should certainly be tempered until such an effect is confirmed by clinical trials conducted in patients with glaucoma.}, }
@article {pmid11014725, year = {2000}, author = {Honig, LS and Rosenberg, RN}, title = {Apoptosis and neurologic disease.}, journal = {The American journal of medicine}, volume = {108}, number = {4}, pages = {317-330}, doi = {10.1016/s0002-9343(00)00291-6}, pmid = {11014725}, issn = {0002-9343}, support = {5P30-AG12300/AG/NIA NIH HHS/United States ; 5R01-DK45923/DK/NIDDK NIH HHS/United States ; }, mesh = {Apoptosis/*physiology ; Cellular Senescence/physiology ; Humans ; Necrosis ; Nervous System Diseases/pathology/*physiopathology ; }, abstract = {Many neurological disorders involve cell death. During development of the nervous system, cell death is a normal feature. Elimination of substantial numbers of initially generated cells enables useful pruning of "mismatched" or excessive cells produced by exuberance during the proliferative and migratory phases of development. Such cell death, occurring by "programmed" pathways, is termed apoptosis. In mature organisms, cells die in two major fashions, either by necrosis or apoptosis. In the adult nervous system, because there is little cell production during adulthood, there is little normal cell death. However, neurological disease is often associated with significant neural cell death. Acute disorders, occurring over minutes to hours, such as brain trauma, infarction, hemorrhage, or infection, prominently involve cell death, much of which is by necrosis. Chronic disorders, with relatively slow central nervous system degeneration, may occur over years or decades, but may involve cell losses. Such disorders include motor neuron diseases such as amyotrophic lateral sclerosis (ALS), cerebral dementing disorders such as Alzheimer's disease and frontotemporal dementia, and a variety of degenerative movement disorders including Parkinson's disease, Huntington's disease, and the inherited ataxias. There is evidence that the mechanism of neuronal cell death in these disorders may involve apoptosis. Direct conclusive evidence of apoptosis is scarce in these chronic disorders, because of the swiftness of cell death in relation to the slowness of the disease. Thus, at any particular time point of assessment, very few cells would be expected to be undergoing death. However, it is clearly of importance to define the type of cell death in these disorders. Of significance is that while treating the underlying causes of these conditions is an admirable goal, it may also be possible to develop productive therapies based on alleviating the process of cell death. This is particularly likely if this cell loss is through apoptosis, a programmed process for which the molecular cascade is increasingly understood. This article reviews our understanding of apoptosis in the nervous system, concentrating on its possible roles in chronic neurodegenerative disorders.}, }
@article {pmid11008289, year = {2000}, author = {Jordán, J and Galindo, MF and Ceña, V and González-García, C}, title = {[Cysteine proteinase and neurodegeneration].}, journal = {Revista de neurologia}, volume = {31}, number = {4}, pages = {333-340}, pmid = {11008289}, issn = {0210-0010}, mesh = {Apoptosis/physiology ; Caspases/classification/metabolism ; Cysteine Endopeptidases/*metabolism ; Humans ; Membrane Proteins/metabolism ; Nerve Growth Factor/physiology ; Neurodegenerative Diseases/*enzymology ; Receptors, Tumor Necrosis Factor/metabolism ; fas Receptor/metabolism ; }, abstract = {OBJECTIVE: This is a review of the part played by the cysteine proteases in different physiological and pathological processes.<br><br>DEVELOPMENT: Apoptotic processes have a crucial function in control of the number of cells in multicellular organisms, both during development and throughout life. Alterations in these are closely related to different pathological processes, from cancer (with fewer apoptotic processes) to the degenerative disorders in which apoptosis is increased. Although the stimuli which may induce apoptosis are very varied, the apoptotic phenotypes are similar. Different metabolic routes are involved in apoptosis and in these changes, both in transcription and postranscription. The latter form the basis of this paper. We review the role of the cysteine protease family, in which the caspases and calpains are the best representatives, which have been related to different degenerative models. In this review we describe the stimuli and cascades of intracellular signalling which occur on activation.<br><br>CONCLUSION: These proteases are involved in many situations involving the development and maintenance of the number of cells in the tissues, both physiological and pathological. They may be considered to be possible therapeutic targets in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea.}, }
@article {pmid11003783, year = {2000}, author = {Daube, JR}, title = {Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders.}, journal = {Muscle &amp; nerve}, volume = {23}, number = {10}, pages = {1488-1502}, doi = {10.1002/1097-4598(200010)23:10&lt;1488::aid-mus4&gt;3.0.co;2-e}, pmid = {11003783}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electrophysiology ; Humans ; Motor Neuron Disease/*diagnosis/*physiopathology ; Muscles/*physiopathology ; Neural Conduction/physiology ; }, abstract = {The clinical electrodiagnostic medicine (EDX) consultant asked to assess patients with suspected amyotrophic lateral sclerosis (ALS) has a number of responsibilities. Among the most important is to provide a clinical assessment in conjunction with the EDX study. The seriousness of the diagnoses and their enormous personal and economic impact require a high-quality EDX study based on a thorough knowledge of and experience with motor neuron diseases (MNDs) and related disorders. Clinical evaluation will help determine which of the EDX tools available to the EDX consultant should be applied in individual patients. Although electromyography (EMG) and nerve conduction study are the most valuable, each of the following may be helpful in the assessment of selected patients based on their clinical findings: repetitive nerve stimulation, motor unit number estimate, single-fiber EMG, somatosensory evoked potential, autonomic function test, and polysomnography. The pertinent literature on these is reviewed in this monograph. The selection and application of these EDX tools depend on a thorough knowledge of the MNDs and related disorders.}, }
@article {pmid10997531, year = {2000}, author = {Young, WF}, title = {Cervical spondylotic myelopathy: a common cause of spinal cord dysfunction in older persons.}, journal = {American family physician}, volume = {62}, number = {5}, pages = {1064-70, 1073}, pmid = {10997531}, issn = {0002-838X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Cervical Vertebrae ; Diagnosis, Differential ; Humans ; Hypesthesia/etiology ; Magnetic Resonance Imaging ; Muscle Weakness/etiology ; Neck Pain/etiology ; Neuralgia/etiology ; Neurosurgical Procedures ; Patient Education as Topic ; Spinal Cord/*physiopathology ; Spinal Osteophytosis/*complications/*diagnosis/physiopathology ; Teaching Materials ; Tomography, X-Ray Computed ; }, abstract = {Cervical spondylotic myelopathy is the most common cause of spinal cord dysfunction in older persons. The aging process results in degenerative changes in the cervical spine that, in advanced stages, can cause compression of the spinal cord. Symptoms often develop insidiously and are characterized by neck stiffness, arm pain, numbness in the hands, and weakness of the hands and legs. The differential diagnosis includes any condition that can result in myelopathy, such as multiple sclerosis, amyotrophic lateral sclerosis and masses (such as metastatic tumors) that press on the spinal cord. The diagnosis is confirmed by magnetic resonance imaging that shows narrowing of the spinal canal caused by osteophytes, herniated discs and ligamentum flavum hypertrophy. Choice of treatment remains controversial, surgical procedures designed to decompress the spinal cord and, in some cases, stabilize the spine are successful in many patients.}, }
@article {pmid10989656, year = {1999}, author = {Beal, MF}, title = {Mitochondria, NO and neurodegeneration.}, journal = {Biochemical Society symposium}, volume = {66}, number = {}, pages = {43-54}, doi = {10.1042/bss0660043}, pmid = {10989656}, issn = {0067-8694}, support = {AG11337/AG/NIA NIH HHS/United States ; NS16367/NS/NINDS NIH HHS/United States ; NS31579/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/drug therapy/*physiopathology ; Nitric Oxide/*physiology ; }, abstract = {A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.}, }
@article {pmid10979548, year = {2000}, author = {Jankowicz, E and Drozdowski, W and Halicka, D}, title = {[Frontotemporal dementias].}, journal = {Neurologia i neurochirurgia polska}, volume = {34}, number = {3}, pages = {553-564}, pmid = {10979548}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/complications/physiopathology ; Dementia/*diagnosis/etiology/*physiopathology ; Diagnosis, Differential ; Frontal Lobe/*pathology/*physiopathology ; Humans ; Motor Neuron Disease/complications/physiopathology ; Pick Disease of the Brain/physiopathology ; Temporal Lobe/*pathology/*physiopathology ; }, abstract = {Frontotemporal dementias are the second largest degenerative dementia group after Alzheimer's disease. It is a clinical syndrome corresponding to at least three histological entities: Pick's disease, non-specific frontotemporal degeneration, frontal lobe abnormalities associated with motor neuron disease. There are four group of symptoms in the clinical description of FTD: behavioural disorder, affective symptoms, speech disorders, neurological signs. FTD is associated with primary degeneration of the frontal and temporal lobes. Histologically there was neuronal loss, microvacuolation, tau- and ubiquitin-immunoreactive inclusions. The ballooned cortical neurons and tau- and ubiquitin-immunoreactive, argyrophilic inclusions have been called Pick-type histology. There are many descriptions of association of FTD and Pick's disease with motor neuron disease and amyotrophic lateral sclerosis. Histological changes were similar to cortical ones. In this study, we described clinical characteristic features of frontotemporal dementia and difficulties in its identification. The distinctive histopathological pattern in the FTD patients and its value to differentiate frontotemporal degeneration from other degenerative dementias is discussed.}, }
@article {pmid10979314, year = {2000}, author = {Ikeda, K}, title = {[Where fronto-temporal dementia should be placed in the history of Pick's disease and related disorders].}, journal = {Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica}, volume = {102}, number = {6}, pages = {529-542}, pmid = {10979314}, issn = {0033-2658}, mesh = {*Dementia/classification/pathology ; *Frontal Lobe/pathology ; Humans ; *Pick Disease of the Brain/pathology ; *Temporal Lobe/pathology ; }, abstract = {Pick syndrome, non-Alzheimer type dementia with primary degeneration in the anterior portion of the brain, has been shown to include several disease-entities besides classic Pick's disease. Fronto-temporal dementia (FTD) proposed by Lund &amp; Manchester group is a concept that includes Pick's disease, and its "clinical diagnostic features" are useful because they distinguish dementia with frontal and anterior temporal involvement from Alzheimer type dementia. FTD is classified into three types, the frontal lobe degeneration (FLD) type, Pick type and motor neuron disease (MND) type, and neuropathological diagnostic features of each type are presented. In Japan, however, cases neuropathologically corresponding to the FLD type, which has mild frontal dominant degeneration with heavy heredity, have not been previously reported. Classic Japanese Pick's disease is consistent with Pick type, however, cases of Pick's disease with and without Pick body exist in nearly the same number in Japan. The latter may include heterogeneous types, which should be elucidated. MND type corresponds to Japanese cases, called Yuasa-Mitsuyama disease or dementia with motor neuron disease, and could be actually diagnosed because such patients do not exhibit severe personality change and accompany symptoms of amyotrophic lateral sclerosis or spinal progressive muscular atrophy in their clinical course. In addition, Pick syndrome includes progressive subcortical gliosis, corticobasal degeneration, basophilic inclusion body disease and fronto-temporal dementia with parkinsonism linked chromosome 17. Progressive aphasia and semantic dementia are neuropsychologically important concepts, however, they are symptom-complex and are dominated only by where the degeneration begins and how it progresses. They should not be confused with pathologically confirmed disease-entities.}, }
@article {pmid10970056, year = {2000}, author = {Al-Chalabi, A and Leigh, PN}, title = {Recent advances in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {13}, number = {4}, pages = {397-405}, doi = {10.1097/00019052-200008000-00006}, pmid = {10970056}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics/physiopathology/therapy ; Genetic Linkage ; Humans ; Mutation/physiology ; Neurology/*trends ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.}, }
@article {pmid10965511, year = {2000}, author = {Behl, C and Moosmann, B and Manthey, D and Heck, S}, title = {The female sex hormone oestrogen as neuroprotectant: activities at various levels.}, journal = {Novartis Foundation symposium}, volume = {230}, number = {}, pages = {221-34; discussion 234-8}, doi = {10.1002/0470870818.ch16}, pmid = {10965511}, issn = {1528-2511}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid beta-Protein Precursor/metabolism ; Antioxidants/*metabolism ; Estradiol/metabolism ; Estrogens/*metabolism ; Female ; Glutamates/metabolism ; Humans ; Neuroprotective Agents/*metabolism ; Oxidative Stress ; }, abstract = {The female sex hormone oestradiol (oestrogen) is a steroidal compound that binds to specific intracellular receptors which act as transcription factors. Oestrogen displays many of its effects by the classical mode of action through receptor binding, transactivation and binding to consensus oestrogen response elements on DNA. Although the primary role of oestrogen as an ovarian steroid was thought to be the regulation of sex differentiation and maturation, since oestrogen receptors are expressed in a variety of other tissues besides sex organs, oestrogen is believed to exert multiple activities in several target sites throughout the body, including the nervous system. In the brain oestrogens have multiple activities. Potential neuroprotective functions of oestrogens are being intensively studied and it is becoming increasingly clear that oestrogens are (1) neuroprotective hormones acting via oestrogen receptor-dependent pathways at the genomic level and (2) neuroprotective steroidal structures acting independently of the activation of specific oestrogen receptors. One striking activity of the molecule oestradiol is its intrinsic antioxidant activity which makes it a potential chemical shield for neurons. Nerve cells frequently encounter oxidative challenges during the normal physiology, but also under pathophysiological conditions. Oxidative stress has been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. It is important to stress that the antioxidant neuroprotective activity of oestrogens is independent of oestrogen receptor activation, since oestrogen derivatives and aromatic alcohols that do not bind to oestrogen receptors share the same antioxidant neuroprotective activity. Although this effect of oestrogens can clearly be separated from oestrogen receptor binding, oestrogens may interact with intracellular signalling pathways, such as the mitogen activated protein kinase, cyclic AMP pathways, and with the activity of the redox-sensitive transcription factor NF-kappa B.}, }
@article {pmid10961426, year = {2000}, author = {Albers, DS and Beal, MF}, title = {Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease.}, journal = {Journal of neural transmission. Supplementum}, volume = {59}, number = {}, pages = {133-154}, doi = {10.1007/978-3-7091-6781-6_16}, pmid = {10961426}, issn = {0303-6995}, mesh = {Aging/*physiology ; Humans ; Mitochondrial Myopathies/*etiology ; Neurodegenerative Diseases/*complications/physiopathology ; *Oxidative Stress ; }, abstract = {A major risk factor for neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) is aging. Two processes that have been implicated in aging are free radical-induced oxidative damage and mitochondrial dysfunction. A progressive impairment of mitochondrial function and/or increased oxidative damage has been suggested to play critical roles in the pathogenesis of these neurodegenerative diseases. For example, decreased complex I activity, increased oxidative damage and altered activities of antioxidant defense enzymes have been demonstrated in PD. In AD, decrements in complex IV activity and increased oxidative damage have been reported. Reductions in complex II activity, increased cortical lactate levels and oxidative damage have been described in HD. Some familial ALS cases are associated with mutations in the gene for Cu,Zn superoxide dismutase (SOD1) while increased oxidative damage is observed in sporadic ALS. Studies in PSP have demonstrated regionally specific reductions in brain and muscle mitochondrial function, hypofrontality and increased oxidative damage. Altogether, the age-dependent onset and progressive course of these neurodegenerative diseases may ultimately highlight an association between aging, mitochondrial impairment and oxidative stress.}, }
@article {pmid10951106, year = {2000}, author = {Stuerenburg, HJ}, title = {The roles of carnosine in aging of skeletal muscle and in neuromuscular diseases.}, journal = {Biochemistry. Biokhimiia}, volume = {65}, number = {7}, pages = {862-865}, pmid = {10951106}, issn = {0006-2979}, mesh = {Aging/*physiology ; Antioxidants ; Carnosine/*physiology ; Humans ; Muscle, Skeletal/*physiology ; Neuromuscular Diseases/*physiopathology ; Oxidative Stress ; }, abstract = {Skeletal muscles undergo specific alterations that are related to the aging process. The incidence of several neuromuscular diseases (e.g., amyotrophic lateral sclerosis (ALS), myasthenia gravis, polymyositis, drug-induced myopathies, late-onset mitochondrial myopathy) is age-related. The increased sensitivity to disease of aging muscle represents an additional age-related negative influence in the presence of existing risk factors (such as a genetic predisposition). The potential significance of carnosine lies on one hand in its possible influence on specific physiological changes in muscle associated with the aging process, and on the other in its effect on oxidative stress and the antioxidative system in specific neuromuscular diseases such as ALS or polymyositis.}, }
@article {pmid10942700, year = {2000}, author = {Missiaen, L and Robberecht, W and van den Bosch, L and Callewaert, G and Parys, JB and Wuytack, F and Raeymaekers, L and Nilius, B and Eggermont, J and De Smedt, H}, title = {Abnormal intracellular ca(2+)homeostasis and disease.}, journal = {Cell calcium}, volume = {28}, number = {1}, pages = {1-21}, doi = {10.1054/ceca.2000.0131}, pmid = {10942700}, issn = {0143-4160}, mesh = {Animals ; Calcium/*metabolism ; Calcium Channels/genetics ; Calcium Channels, L-Type/genetics ; Calcium Metabolism Disorders/*metabolism ; Calcium Signaling ; Calcium-Binding Proteins/metabolism ; Calcium-Transporting ATPases/genetics ; Homeostasis ; Humans ; Inositol 1,4,5-Trisphosphate Receptors ; Mice ; Models, Biological ; Muscle Contraction ; *Mutation ; Receptors, Cytoplasmic and Nuclear/genetics ; Ryanodine Receptor Calcium Release Channel/genetics ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; TRPC Cation Channels ; }, abstract = {A whole range of cell functions are regulated by the free cytosolic Ca(2+)concentration. Activator Ca(2+)from the extracellular space enters the cell through various types of Ca(2+)channels and sometimes the Na(+)/Ca(2+)-exchanger, and is actively extruded from the cell by Ca(2+)pumps and Na(+)/Ca(2+)-exchangers. Activator Ca(2+)can also be released from internal Ca(2+)stores through inositol trisphosphate or ryanodine receptors and is taken up into these organelles by means of Ca(2+)pumps. The resulting Ca(2+)signal is highly organized in space, frequency and amplitude because the localization and the integrated free cytosolic Ca(2+)concentration over time contain specific information. Mutations or functional abnormalities in the various Ca(2+)transporters, which in vitro seem to induce trivial functional alterations, therefore, often lead to a plethora of diseases. Skeletal-muscle pathology can be caused by mutations in ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central-core disease), dihydropyridine receptors (familial hypokalemic periodic paralysis, malignant hyperthermia, muscular dysgenesis) or Ca(2+)pumps (Brody disease). Ca(2+)-pump mutations in cutaneous epidermal keratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hailey-Hailey) and hearing/vestibular problems respectively. Mutated Ca(2+)channels in the photoreceptor plasma membrane cause vision problems. Hemiplegic migraine, spinocerebellar ataxia type-6, one form of episodic ataxia and some forms of epilepsy can be due to mutations in plasma-membrane Ca(2+)channels, while antibodies against these channels play a pathogenic role in all patients with the Lambert-Eaton myasthenic syndrome and may be of significance in sporadic amyotrophic lateral sclerosis. Brain inositol trisphosphate receptors have been hypothesized to contribute to the pathology in opisthotonos mice, manic-depressive illness and perhaps Alzheimer's disease. Various abnormalities in Ca(2+)-handling proteins have been described in heart during aging, hypertrophy, heart failure and during treatment with immunosuppressive drugs and in diabetes mellitus. In some instances, disease-causing mutations or abnormalities provide us with new insights into the cell biology of the various Ca(2+)transporters.}, }
@article {pmid10935845, year = {1998}, author = {Rachele, MG and Mascia, V and Tacconi, P and Dessi, N and Marrosu, F and Giagheddu, M}, title = {Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy.}, journal = {Italian journal of neurological sciences}, volume = {19}, number = {2}, pages = {97-100}, pmid = {10935845}, issn = {0392-0461}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; *Family Health ; Female ; Humans ; Italy/epidemiology ; Middle Aged ; *Spouses ; }, abstract = {A conjugal case of amyotrophic lateral sclerosis (ALS) observed in Sardinia, Italy is reported. This is believed to be the ninth such observation described in the literature. The couple had lived together for 38 years in a house adjacent to the distillery they owned. No exogenous factors were revealed which could explain the genesis of the disease in either patients. Particularly, exposure to alcohol does not appear to have been involved in causing ALS. On the basis of statistical and epidemiological evaluations, the most likely explanation is that this association was purely coincidental.}, }
@article {pmid10935441, year = {2000}, author = {Nakano, I}, title = {Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia).}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {20}, number = {1}, pages = {68-75}, doi = {10.1046/j.1440-1789.2000.00272.x}, pmid = {10935441}, issn = {0919-6544}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Dementia/*pathology ; Humans ; }, abstract = {Frontotemporal dementia (FTD) with motor neuron disease means amyotrophic lateral sclerosis (ALS) with dementia. In the cerebrum of this condition, the medial cortex of the rostral temporal lobe is constantly and most remarkably involved. Another constant and quite characteristic lesion is neuronal loss localized to the CA1-subiculum transitional area at the level of the pes hippocampi. The rostral portion of the parahippocampal gyrus, and the amygdaloid nucleus are also involved. Ubiquitinated intracytoplasmic inclusions are seen in the dentate granule cells and parahippocampal gyrus neurons. Some cases of ALS without dementia show the identical temporal lobe degeneration as well as the cortical ubiquitinated inclusions, thus raising the possibility of overlooked dementia or premature death of the patients. Similarly, recently proposed motor neuron disease-inclusion dementia may be a forme fruste of ALS with dementia.}, }
@article {pmid10935248, year = {2000}, author = {López-Pousa, S and Serra-Mestres, J and Lozano-Gallego, M and Tron-Estrada, A and Vilalta-Franch, J and Garre-Olmo, J and Camps-Rovira, G and Hernández-Ferrándiz, M and Mariscot-Bas, C and Llinàs-Reglà, J and Pujol-Gómez, C}, title = {[Integrated program of psychogeriatric care].}, journal = {Revista de neurologia}, volume = {30}, number = {12}, pages = {1181-1187}, pmid = {10935248}, issn = {0210-0010}, mesh = {Aged ; Ambulatory Care ; Dementia/diagnosis/*rehabilitation ; Health Services for the Aged/*organization &amp; administration ; Humans ; Psychotherapy ; Residential Treatment ; Social Support ; Spain ; }, abstract = {INTRODUCTION: At the present time there is considerable controversy over the course to follow in attention to patients with psychogeriatric disorders. Rapid diagnosis and maintaining the patients in their homes are the basic objectives of the policy of sharing responsibility among those involved.<br><br>DEVELOPMENT: We review the bibliography and suggest a form of attention based on experience acquired in the dementia evaluation unit of the Programme Vida als Anys of the Generalitat de Catalunya. The model described is based on making the diagnosis in the patient's home, giving support to the family and integrating the patient into a follow-up unit, with a person responsible for evaluating and resolving the needs of both patient and family as they arise. In order to carry out this programme, the attention must be given by multidiscliplinary units with the necessary resources.}, }
@article {pmid10934934, year = {2000}, author = {Martić, V}, title = {[Motor neuron disease: primary lateral sclerosis and amyotrophic lateral sclerosis].}, journal = {Vojnosanitetski pregled}, volume = {57}, number = {2}, pages = {205-208}, pmid = {10934934}, issn = {0042-8450}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/*diagnosis ; Prognosis ; }, abstract = {AIM: Primary lateral sclerosis and amyotrophic lateral sclerosis are amongst motor neuron diseases. Differences between these two disorders are stressed by this paper.<br><br>SOURCE OF DATA: Articles pertinent to this subject from the past 10 years.<br><br>CONCLUSION: Both disorders are of neurodegenerative pathogenesis, and motor neurons are selectively involved. Unless only motor neurons from central nervous system are involved in primary lateral sclerosis, in amyotrophic lateral sclerosis motor neurons are involved both in central and in peripheral nervous system. Clinical neurophysiological and radiological features are helpful in differential diagnosis of these diseases. Primary lateral sclerosis has better prognosis and much higher survival rate.}, }
@article {pmid10931172, year = {2000}, author = {Schulz, JB and Lindenau, J and Seyfried, J and Dichgans, J}, title = {Glutathione, oxidative stress and neurodegeneration.}, journal = {European journal of biochemistry}, volume = {267}, number = {16}, pages = {4904-4911}, doi = {10.1046/j.1432-1327.2000.01595.x}, pmid = {10931172}, issn = {0014-2956}, mesh = {Alzheimer Disease/physiopathology ; Animals ; Friedreich Ataxia/physiopathology ; Glutathione/*metabolism ; Humans ; Mitochondria/metabolism ; Motor Neuron Disease/physiopathology ; Nerve Degeneration/*physiopathology ; Oxidative Stress/*physiology ; Parkinson Disease/physiopathology ; }, abstract = {There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.}, }
@article {pmid10929249, year = {2000}, author = {Borasio, GD and Voltz, R}, title = {[Patient consultation and palliative care in neurology, e.g. in amyotrophic lateral sclerosis].}, journal = {Der Internist}, volume = {41}, number = {7}, pages = {627-632}, doi = {10.1007/s001080050580}, pmid = {10929249}, issn = {0020-9554}, mesh = {*Advance Directives ; Amyotrophic Lateral Sclerosis/*psychology/*therapy ; Counseling ; Family Therapy/methods ; Germany ; Humans ; Palliative Care/*methods ; *Physician-Patient Relations ; Terminal Care/methods ; }, }
@article {pmid10923991, year = {2000}, author = {Johnson, WG}, title = {Late-onset neurodegenerative diseases--the role of protein insolubility.}, journal = {Journal of anatomy}, volume = {196 (Pt 4)}, number = {Pt 4}, pages = {609-616}, pmid = {10923991}, issn = {0021-8782}, mesh = {Adult ; Aged ; Alzheimer Disease/metabolism ; Amyloid/*metabolism ; Basal Ganglia/metabolism ; Chemical Precipitation ; Down Syndrome/metabolism ; Heredodegenerative Disorders, Nervous System/*etiology/metabolism ; Humans ; Middle Aged ; Multiple System Atrophy/metabolism ; Mutation ; Nerve Tissue Proteins/metabolism ; Parkinson Disease/metabolism ; Solubility ; Synucleins ; alpha-Synuclein ; tau Proteins/genetics/metabolism ; }, abstract = {Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha-synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way. Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases.}, }
@article {pmid10912519, year = {2000}, author = {Boisclair, YR and Hurst, KR and Ueki, I and Tremblay, ML and Ooi, GT}, title = {Regulation and role of the acid-labile subunit of the 150-kilodalton insulin-like growth factor complex in the mouse.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {14}, number = {7}, pages = {562-566}, doi = {10.1007/s004670000333}, pmid = {10912519}, issn = {0931-041X}, support = {DK-51624-01A1/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Blood/metabolism ; Carrier Proteins/chemistry/genetics/*physiology ; Gene Expression Regulation, Developmental ; Glycoproteins/chemistry/genetics/*physiology ; Mice/*physiology ; Mice, Knockout/genetics ; Molecular Weight ; Somatomedins/metabolism ; }, abstract = {After birth, the acid-labile subunit (ALS) associates in the circulation with insulin-like growth factor (IGF)-I or -II and with IGF binding protein-3 (IGFBP-3) to form a 150-kilodalton complex. This association leads to the retention of IGFs in the vascular system and promotes their endocrine actions. ALS is synthesized almost exclusively in liver, and both hepatic ALS mRNA and circulating levels are increased by growth hormone (GH). Three major areas of study were pursued to better understand the regulation of ALS synthesis and its role in the circulating IGF system. First, the mouse ALS gene was isolated and shown to be organized into two exons and a single intron on chromosome 17. Second, using transient transfection studies in the rat H4-II-E hepatoma cell line and primary rat hepatocytes, the region of the mouse promoter that is responsive to GH was mapped to a nine-base pair cis-element resembling a gamma-interferon-activated sequence. The activation of the mouse ALS gene by GH is mediated by the binding of STAT5 isoforms to this sequence. Finally, an ALS knockout model was created by inactivating the ALS gene in mouse embryonic stem cells. Mice that are homozygous for the mutation grow at a slower rate after birth. This growth depression is associated with large decreases in the plasma concentrations of both IGF-I and IGFBP-3, indicating the critical role of ALS in the regulation of circulating levels of these proteins. Studies of this model will lead to a better understanding of the circulating IGF system.}, }
@article {pmid10906800, year = {2000}, author = {Weiss, JH and Sensi, SL}, title = {Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration.}, journal = {Trends in neurosciences}, volume = {23}, number = {8}, pages = {365-371}, doi = {10.1016/s0166-2236(00)01610-6}, pmid = {10906800}, issn = {0166-2236}, support = {AG00836/AG/NIA NIH HHS/United States ; NS30884/NS/NINDS NIH HHS/United States ; NS36548/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain Chemistry/physiology ; Calcium/*metabolism ; Humans ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/metabolism ; Receptors, AMPA/*metabolism ; Receptors, Kainic Acid/*metabolism ; Zinc/*metabolism ; }, abstract = {Neurological diseases, including global ischemia, Alzheimer's disease and amyotrophic lateral sclerosis, are characterized by selective patterns of neurodegeneration. Most studies of potential glutamate-receptor-mediated contributions to disease have focused on the highly Ca2+-permeable and widely distributed NMDA-receptor channel. However, an alternative hypothesis is that the presence of AMPA- or kainate-receptor channels that are directly permeable to Ca2+ ions (Ca-A/K-receptor channels) is of greater significance to the neuronal loss seen in these conditions. Besides a restricted distribution and high Ca2+ permeability, two other factors make Ca-A/K receptors appealing candidate contributors to selective injury: their high permeability to Zn2+ ions and the possibility that their numbers increase in disease-associated conditions. Further characterization of the functions of these channels should result in new approaches to treatment of these conditions.}, }
@article {pmid10885984, year = {2000}, author = {Sturtevant, J}, title = {Applications of differential-display reverse transcription-PCR to molecular pathogenesis and medical mycology.}, journal = {Clinical microbiology reviews}, volume = {13}, number = {3}, pages = {408-427}, pmid = {10885984}, issn = {0893-8512}, mesh = {Animals ; Cell Cycle ; Cell Differentiation ; Cloning, Molecular ; Gene Expression ; Humans ; *Mycology ; Reverse Transcriptase Polymerase Chain Reaction/*methods ; Virulence ; }, abstract = {The host-fungus interaction is characterized by changes in gene expression in both host and pathogen. Differential-display reverse transcription PCR (DDRT-PCR) is a PCR-based method that allows extensive analysis of gene expression among several cell populations. Several limitations and drawbacks to this procedure have now been addressed, including the large number of false-positive results and the difficulty in confirming differential expression. Modifications that simplify the reaction time, allow the use of minute quantities of RNA, or address unusual species- or gene-specific sequences have been reported. DDRT-PCR has been used to address biological questions in mammalian systems, including cell differentiation, cell activation, cell stress, and identification of drug targets. In microbial pathogenesis and plant pathogenesis, DDRT-PCR has allowed the identification of virulence factors, genes involved in cell death, and signaling genes. In Candida albicans, DDRT-PCR studies identified TIF-2, which may play a role in the upregulation of phospholipases, and the stress-related genes, CIP1 and CIP2. In Histoplasma capsulatum and C. albicans, genes involved in the host-pathogen interaction, including a member of the 100-kDa family in Histoplasma and an ALS and 14-3-3 gene in Candida, were potentially identified by DDRT-PCR. Although very few reports have been published in medical mycology, studies in mammalian, nonfungal microbial, and plant pathogen systems are easily applied to basic questions in fungal pathogenesis and antifungal therapeutics.}, }
@article {pmid10865571, year = {1999}, author = {Houde, SC and Mangolds, V}, title = {Amyotrophic lateral sclerosis: a team approach to primary care.}, journal = {Clinical excellence for nurse practitioners : the international journal of NPACE}, volume = {3}, number = {6}, pages = {337-345}, pmid = {10865571}, issn = {1085-2360}, mesh = {Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology/psychology/*therapy ; Diagnosis, Differential ; Family/psychology ; Humans ; Job Description ; Nurse Practitioners/*organization &amp; administration ; Patient Care Team/*organization &amp; administration ; Primary Health Care/*methods ; Quality of Life ; Social Support ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes degeneration of motor neurons and results in death. The most frequent presenting symptom of patients with ALS is muscle weakness. The role of the nurse practitioner (NP) in the diagnosis and management of ALS is multifaceted. The NP could serve as the coordinator of care provided by a multidisciplinary team or as a member of the team. The coordinator of the team may vary depending on the individual needs of the patient with ALS and the stage of illness. Muscle weakness and spasticity, respiratory difficulties, and speech and swallowing problems are frequently encountered problems needing intervention. The role of the NP is important in providing symptomatic relief for the patient, and essential in providing education and psychosocial support for the patient and family caregivers. This article reviews the pathophysiology, assessment, management, and recent advances in research related to ALS. The challenging role of the NP in improving the quality of life of patients with ALS and their families is discussed.}, }
@article {pmid10859496, year = {2000}, author = {Torrey, EF and Miller, J and Rawlings, R and Yolken, RH}, title = {Seasonal birth patterns of neurological disorders.}, journal = {Neuroepidemiology}, volume = {19}, number = {4}, pages = {177-185}, doi = {10.1159/000026253}, pmid = {10859496}, issn = {0251-5350}, mesh = {Central Nervous System Diseases/*epidemiology/etiology ; Female ; Humans ; Pregnancy ; Prenatal Exposure Delayed Effects ; Risk Factors ; *Seasons ; }, abstract = {Existing seasonal birth studies were reviewed for multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, cerebral palsy, congenital malformations of the central nervous system and mental retardation. Epilepsy appears to have the most consistent pattern, with an excess of births in winter and a deficit in September. MS, ALS and possibly Parkinson's disease appear to have an excess of spring births. Studies of cerebral palsy are not conclusive, although there are suggestions that there may be an excess of summer births. The findings for Alzheimer's disease, congenital malformations of the central nervous system, and mental retardation are contradictory and insufficient to draw any conclusions.}, }
@article {pmid10856939, year = {2000}, author = {Beal, MF}, title = {Energetics in the pathogenesis of neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {23}, number = {7}, pages = {298-304}, doi = {10.1016/s0166-2236(00)01584-8}, pmid = {10856939}, issn = {0166-2236}, mesh = {Animals ; Cell Death/*genetics ; DNA, Mitochondrial/*genetics ; Humans ; Mitochondria/*genetics ; Necrosis ; Neurodegenerative Diseases/*genetics/therapy ; }, abstract = {Mitochondria have been linked to both necrotic and apoptotic cell death, which are thought to have a major role in the pathogenesis of neurodegenerative diseases. Recent evidence shows that nuclear gene defects affecting mitochondrial function have a role in the pathogenesis of Friedreich's ataxia, Wilson's disease and hereditary spastic paraplegia. There is also accumulating evidence that mitochondrial dysfunction might have a role in the pathogenesis of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease. If this is so, a number of therapeutic targets are implicated that might result in novel treatments for neurodegenerative diseases.}, }
@article {pmid10845068, year = {2000}, author = {Cowan, WM and Harter, DH and Kandel, ER}, title = {The emergence of modern neuroscience: some implications for neurology and psychiatry.}, journal = {Annual review of neuroscience}, volume = {23}, number = {}, pages = {343-391}, doi = {10.1146/annurev.neuro.23.1.343}, pmid = {10845068}, issn = {0147-006X}, mesh = {Animals ; Humans ; Memory ; Mental Disorders/genetics ; Nervous System Diseases/genetics ; Neurodegenerative Diseases/genetics ; Neurology/*trends ; Neurosciences/*trends ; Prefrontal Cortex/physiopathology ; Psychiatry/*trends ; Schizophrenia/physiopathology ; Schizophrenic Psychology ; }, abstract = {One of the most significant developments in biology in the past half century was the emergence, in the late 1950s and early 1960s, of neuroscience as a distinct discipline. We review here factors that led to the convergence into a common discipline of the traditional fields of neurophysiology, neuroanatomy, neurochemistry, and behavior, and we emphasize the seminal roles played by David McKenzie Rioch, Francis O Schmitt, and especially Stephen W Kuffler in creating neuroscience as we now know it. The application of the techniques of molecular and cellular biology to the study of the nervous system has greatly accelerated our understanding of the mechanisms involved in neuronal signaling, neural development, and the function of the major sensory and motor systems of the brain. The elucidation of the underlying causes of most neurological and psychiatric disorders has proved to be more difficult; but striking progress is now being made in determining the genetic basis of such disorders as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and a number of ion channel and mitochondrial disorders, and a significant start has been made in identifying genetic factors in the etiology of such disorders as manic depressive illness and schizophrenia. These developments presage the emergence in the coming decades of a new nosology, certainly in neurology and perhaps also in psychiatry, based not on symptomatology but on the dysfunction of specific genes, molecules, neuronal organelles and particular neural systems.}, }
@article {pmid10842583, year = {1999}, author = {Stracher, A}, title = {Calpain inhibitors as therapeutic agents in nerve and muscle degeneration.}, journal = {Annals of the New York Academy of Sciences}, volume = {884}, number = {}, pages = {52-59}, doi = {10.1111/j.1749-6632.1999.tb08635.x}, pmid = {10842583}, issn = {0077-8923}, mesh = {Animals ; Glycoproteins/pharmacology/*therapeutic use ; Hair Cells, Auditory/drug effects ; Haplorhini ; Hearing Loss, Noise-Induced/*drug therapy/prevention &amp; control ; Leupeptins/pharmacology/*therapeutic use ; Mice ; Mice, Inbred C57BL ; Muscular Dystrophy, Animal/*drug therapy ; Nerve Degeneration/*drug therapy ; Spiral Ganglion/drug effects ; }, abstract = {It seems plausible to hypothesize that in all forms of neurodegeneration or other forms of tissue degeneration, a common pathway exists that, when deciphered, could lead to our understanding of a variety of diseases that result in tissue necrosis, as well as offer potential for therapeutic intervention. In recent years progress toward elucidating this common pathway has been accelerated through the studies of a number of laboratories, including our own, on the role of the protease calpain in this process. Thus, in a variety of disorders, such as stroke, spinal cord injury, traumatic nerve injury, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, muscular dystrophy, cataract formation, unregulated calpain proteolysis, initiated via dysregulation of calcium ion homeostasis, participates in the pathogenesis and is a potentially unifying mechanistic event. In order to demonstrate the feasibility of the approach we have taken in using the calpain inhibitor leupeptin as a therapeutic agent, I will describe two areas of research in which we have been engaged over the past 20 years. One is our long-standing interest in muscular dystrophy. The other is of more recent vintage, and involves the use of calpain inhibitors to protect sensory hair cells and spiral ganglion neurons from damage associated with acoustic trauma, this latter in collaboration with Dr. R. Salvi at SUNY-Buffalo and Dr. A. Shulman at SUNY-Downstate.}, }
@article {pmid10840479, year = {2000}, author = {Allison, SP and Rawlings, J and Field, J and Bean, N and Stephen, AD}, title = {Nutrition in the elderly hospital patient Nottingham studies.}, journal = {The journal of nutrition, health &amp; aging}, volume = {4}, number = {1}, pages = {54-57}, pmid = {10840479}, issn = {1279-7707}, mesh = {Aged ; *Aging ; Body Temperature Regulation ; Femoral Fractures/epidemiology ; *Hospitalization ; Humans ; Motor Neuron Disease/therapy ; *Nutritional Status ; Nutritional Support ; Protein-Energy Malnutrition/epidemiology/physiopathology/therapy ; United Kingdom ; }, abstract = {Forty percent of elderly hospital admissions in the UK are undernourished, half severely so. Most continue to lose weight in hospital. not only because of disease, but also because of failure to identify and treat malnutrition and due to shortcomings in hospital food provision, upon which most patients depend for their nutritional care. Our studies have shown that more than 40% of food set before patients is left, and therefore wasted. This means that elderly patients are taking less than 70% of their energy (30-35 kcal/kg/day), and protein (1 dram/kg/day) requirements. Catering strategies, such as provision of smaller volume, high energy and protein density meals with snacks and, if necessary, proprietary oral supplements, have been shown not only to improve nutritional status of patients, but to result in improved clinical outcome. Our work has shown a relationship between malnutrition and loss of thermoregulation, which is reversed by appropriate feeding. We have also described the beneficial effects of overnight nasogastric tube feeding in undernourished patients with fractured femur. Like others, we have used a percutaneous endoscopic gastrostomy in the management of elderly patients with cerebrovascular and motor neurone disease, and have published audits of outcome in this field.}, }
@article {pmid10836614, year = {2000}, author = {Hardiman, O}, title = {Symptomatic treatment of respiratory and nutritional failure in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {247}, number = {4}, pages = {245-251}, doi = {10.1007/s004150050578}, pmid = {10836614}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Humans ; Nutrition Disorders/physiopathology/*therapy ; Nutritional Support ; Palliative Care ; Respiratory Insufficiency/physiopathology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by death of upper and lower motor neurones. Nutritional and respiratory failure occurs in most patients with ALS. Nutritional failure occurs primarily as a result of dysphagia, although malnutrition may also develop in the absence of clinically apparent dysphagia. The optimal management of nutrition in early ALS has not been established. In later stages of the disease, parenteral nutritional support using percutaneous endoscopic gastrostomy confers a significant survival benefit in selected patients. Respiratory failure occurs as a result of bulbar, cervical and thoracic loss of motor neurones. Inspiratory muscles are preferentially affected. Management of respiratory failure includes the use of strategies that limit aspiration pneumonia, the reduction in secretions, and positioning of the patient to a maximal mechanical advantage. Use of non-invasive positive pressure ventilation in appropriate patients significantly enhances survival. The decision to undertake invasive mechanical ventilation should be made prior to the development of symptoms that might warrant this intervention. The progressive nature of the condition should be taken into account when such a decision is discussed with the patient and carer. Further studies are required to determine the optimal nutritional requirements of patients with ALS, and to elucidate the physiological changes involved in the decline in respiratory function.}, }
@article {pmid10819049, year = {2000}, author = {Grigor'ev, IuG}, title = {[Delayed biological effect of electromagnetic fields action].}, journal = {Radiatsionnaia biologiia, radioecologiia}, volume = {40}, number = {2}, pages = {217-225}, pmid = {10819049}, issn = {0869-8031}, mesh = {Animals ; Electromagnetic Fields/*adverse effects ; Humans ; Neoplasms/*etiology ; Neoplasms, Experimental/etiology ; Nervous System Diseases/*etiology ; Time Factors ; }, abstract = {The real possibility of the development of remote effects in people after longterm EMF-exposure was presented in the world scientific literature. Many authors decided that there is connection between long-term EMF-exposure and development of the breast cancer, brain tumours, leukaemia and neurodegenerative diseases (Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis). The analysis of up-to-date publications leads us to the conclusion that this problem is actual and further researches of conditions provoking development of last-term effects are required.}, }
@article {pmid10812965, year = {2000}, author = {Froestl, W}, title = {Receptors in neurodegenerative diseases.}, journal = {Pharmaceutica acta Helvetiae}, volume = {74}, number = {2-3}, pages = {247-251}, doi = {10.1016/s0031-6865(99)00035-7}, pmid = {10812965}, issn = {0031-6865}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuropeptides/*physiology ; Receptors, Neuropeptide/chemistry/*drug effects ; }, abstract = {The ability of trophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases, such as Alzheimer's, Huntington's and Parkinson's disease, of amyotrophic lateral sclerosis and peripheral sensory neuropathies. Recent biological data on the neutrotrophins NGF and BDNF, on GDNF, CNTF and IGF-I are discussed together with first results from clinical trials. Literature is presented on the three-dimensional structures of these trophic factors and on models proposed for ligand-receptor interactions. Substantial progress has been made in the understanding of the mechanisms of apoptosis. The cascade consisting of interaction of apoptosis-inducing ligands with death receptors, the coupling of this complex to adaptor proteins via death domains, the further recruitment of procaspases via death effector or caspase recruitment domains and the execution of cell death via the effector caspases is briefly outlined.}, }
@article {pmid10809401, year = {2000}, author = {Krüger, R and Müller, T and Riess, O}, title = {Involvement of alpha-synuclein in Parkinson's disease and other neurodegenerative disorders.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {107}, number = {1}, pages = {31-40}, doi = {10.1007/s007020050002}, pmid = {10809401}, issn = {0300-9564}, mesh = {Alzheimer Disease/genetics/metabolism/pathology ; Humans ; Nerve Degeneration/genetics/metabolism/pathology ; Nerve Tissue Proteins/*genetics/*metabolism ; Parkinson Disease/genetics/*metabolism/*pathology ; Synucleins ; alpha-Synuclein ; }, abstract = {A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the alpha-synuclein gene in autosomal dominant Parkinson's disease (PD). Alpha-synuclein is the main component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a fragment of alpha-synuclein (NAC) is the second major component of amyloid plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of alpha-synuclein in affected brain regions. This may indicate that these disorders partially share common pathogenic mechanisms. Recent data provide first insights into the physiological function of alpha-synuclein and support the concept of an essential role of alpha-synuclein in neurodegeneration. Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration and of the pathophysiological function of alpha-synuclein in particular may influence future development of therapeutic strategies in neurodegenerative disorders.}, }
@article {pmid10796796, year = {2000}, author = {Miller, RG and Mitchell, JD and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD001447}, doi = {10.1002/14651858.CD001447}, pmid = {10796796}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Riluzole/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis (ALS) in some countries but not others. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials and other experts in the field. The most recent search was conducted in June 1999.<br><br>SELECTION CRITERIA: Types of studies: randomized trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of ALS Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: per cent mortality at 12 months with riluzole 100 mg Secondary: per cent mortality as a function of time with 100 mg and with all doses of riluzole, scales of neurologic function, quality of life, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by the other two. We obtained some missing data from investigators. We performed meta-analyses with RevMan software using a fixed effects model.<br><br>MAIN RESULTS: The two eligible trials included a total of 794 riluzole treated patients and 320 placebo treated patients. The methodological quality was acceptable and the trials were easily comparable. There were significant differences between the riluzole and placebo groups of both trials, in terms of the primary outcome measure, which was per cent mortality at 12 months with the 100 mg dose of riluzole. The odds ratio for the combined studies was 0.57 (95%CI 0.41 to 0.80) at 12 months. In the secondary outcome measures, there was a survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. Pooled data from the 50, 100 and 200mg dose groups in the larger trial showed a lower per cent mortality with riluzole compared to placebo only at 12 months (odds ratio (OR) 0.64, 95% CI 0.47 to 0.88). There was no beneficial effect on bulbar function, or muscle strength. There were scant data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference (WMD) 35.5 days, 95% CI 5.9 to 65. 0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (WMD 2.65, 95% CI 1.51 to 4.65).<br><br>REVIEWER'S CONCLUSIONS: Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with ALS.}, }
@article {pmid10796129, year = {2000}, author = {Henderson-Smart, DJ and Bhuta, T and Cools, F and Offringa, M}, title = {Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD000104}, doi = {10.1002/14651858.CD000104}, pmid = {10796129}, issn = {1469-493X}, mesh = {*High-Frequency Ventilation ; Humans ; Infant, Newborn ; Infant, Premature ; *Intermittent Positive-Pressure Ventilation ; Randomized Controlled Trials as Topic ; Respiratory Distress Syndrome, Newborn/*therapy ; }, abstract = {BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 seconds. This has been shown to result in less lung injury in experimental studies.<br><br>OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects.<br><br>SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching by the Cochrane Collaboration, mainly in the English language. Expert informant's search in the Japanese language was made by Prof. Y. Ogawa.<br><br>SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life.<br><br>DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated.<br><br>MAIN RESULTS: Meta-analysis of the six eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group. However, there are trends towards increases in severe (grades 3 &amp; 4) intraventricular hemorrhage (IVH) and in periventricular leukomalacia (PVL) in the HFOV group. HFOV results in a small increase in any air leak syndrome (ALS), [summary RR 1.20 (1.03, 1.39)]. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of four trials where a high volume strategy (HVS) was used, HFOV results in more favourable pulmonary outcomes. There are significantly lower rates of CLD in survivors at 28-30 days [summary RR 0.53 (0.36, 0.76)] and of 'death or CLD at 28-30 days' [summary RR 0.56 (0.40, 0.77) with a non-significant trend towards a reduction in oxygen use at 36-37 weeks postmenstrual age or discharge [summary RR 0.74 (0.55, 1.01)]. There were no differences in the rates of IVH or PVL. Of the four trials in the subgroup using surfactant routinely, three also used the HVS. The trends in results were similar with surfactant to those for the HVS subgroup analysis. One trial suggests that HFOV may reduce the cost of in-hospital care. In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of PVL [summary RR 1.64 (1.02, 2.64).<br><br>REVIEWER'S CONCLUSIONS: The overall meta-analyses is dominated by the large HIFI study which did not use the HVS recommended on the basis of animal studies, and in which surfactant was not available. Studies which used HVS have shown some benefits in short term measures of CLD without an in}, }
@article {pmid10795884, year = {2000}, author = {Silani, V and Braga, M and Ciammola, A and Cardin, V and Scarlato, G}, title = {Motor neurones in culture as a model to study ALS.}, journal = {Journal of neurology}, volume = {247 Suppl 1}, number = {}, pages = {I28-36}, doi = {10.1007/s004150050554}, pmid = {10795884}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Astrocytes ; Calcium/metabolism ; Cell Survival ; Culture Techniques ; Disease Models, Animal ; Glutamic Acid/adverse effects/metabolism ; Humans ; Mitochondria/physiology ; Motor Neurons/*pathology ; Point Mutation ; Rats ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Defining the basis of the selective cell vulnerability of motor neurones (MN) represents the key issue in amyotrophic lateral sclerosis (ALS), and tissue culture models are the ideal system for the identification of the MN specific features at the single cell level. Neurone-astrocyte metabolic interactions, which have a critical role in MN through glutamatergic toxicity, have been mostly defined in vitro. Ca++ metabolism, which appears to play a critical role in inducing MN loss in ALS, has been successfully studied using in vitro cell models. Furthermore, primary cultures demonstrated that apoptotic or necrotic death of neurones after injury depends upon the cell energetic status. Superoxide dismutase- (SOD-1) mutations were successfully expressed in cultured rodent MNs, providing a critical assay to sequence the molecular processes responsible for MN degeneration due to the identified genetic defect. The recent identification of genes that separate humans from apes further increases the value of the human in vitro models to better understand specific human cellular properties. Purified human MNs and astrocytes can today be obtained from the human embryonic spinal cord anterior horns. Interactions at the single cell level can be dissected using the cDNA amplification techniques. The effects of molecules affecting MN survival, neurite extension, and metabolism can easily be defined in vitro, gaining a critical mass of information of immediate clinical application in the treatment of patients affected by ALS. Understanding the properties of human MNs in vitro represents today a significant and critical tool that can easily be reached after extension of the available knowledge from non-primate to human research. Human MN culture studies can greatly contribute to identifying the primitive critical cellular events responsible for the MN degeneration observed in ALS and to gaining crucial information on new therapeutical agents.}, }
@article {pmid10795883, year = {2000}, author = {Shaw, PJ and Eggett, CJ}, title = {Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {247 Suppl 1}, number = {}, pages = {I17-27}, pmid = {10795883}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Calcium-Binding Proteins/metabolism ; Cytoskeleton ; Glutamic Acid/metabolism ; Humans ; Mitochondria/physiology ; Motor Neurons/*pathology/physiology ; Nerve Degeneration ; Point Mutation ; Receptors, Glutamate/physiology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.}, }
@article {pmid10795882, year = {2000}, author = {Ludolph, AC and Meyer, T and Riepe, MW}, title = {The role of excitotoxicity in ALS--what is the evidence?.}, journal = {Journal of neurology}, volume = {247 Suppl 1}, number = {}, pages = {I7-16}, doi = {10.1007/s004150050552}, pmid = {10795882}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology ; Animals ; Disease Models, Animal ; Glutamic Acid/adverse effects/metabolism ; Humans ; Hypoxia ; Motor Neurons/pathology ; Nerve Degeneration ; Neurotoxins/*adverse effects ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {It is well accepted that excitotoxic mechanisms contribute to the pathogenesis of acute neuronal death in stroke, epilepsy, or brain trauma. It is less widely acknowledged that excitotoxic mechanisms play a role in the pathogenesis of chronic neurological disorders, in particular neurodegenerative diseases. However, evidence is accumulating that this mechanism is indeed part of the pathogenesis of late-onset neurodegenerative diseases. One of the clinical examples may be amyotrophic lateral sclerosis, a disease in which antiexcitotoxic strategies have neuroprotective effects in both, an established animal model and in man. In addition, there is accumulating neuropathological, pathobiochemical and pathophysiological evidence which indicates that excitotoxic mechanisms are part of the pathogenesis of the human disease and consequently part of the mechanisms explaining selective vulnerability ("pathoclisis") in the human motor system.}, }
@article {pmid10795881, year = {2000}, author = {Robberecht, W}, title = {Oxidative stress in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {247 Suppl 1}, number = {}, pages = {I1-6}, doi = {10.1007/s004150050551}, pmid = {10795881}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Humans ; Motor Neurons/enzymology/pathology ; *Oxidative Stress ; Point Mutation ; Reactive Oxygen Species ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {The pathogenesis of amyotrophic lateral sclerosis is poorly understood. In one or two percentage of patients, mutations in the SOD1 gene are known to underly the disease. Even in these cases, the mechanism of cell death remains unclear. Most researchers agree that damage by reactive oxygen species is involved in this process, but whether the latter plays a primary role or is an epiphenomenon is uncertain. As evidence for oxidative stress is not only found in mutant SOD1-related familial amyotrophic lateral sclerosis, but also in sporadic amyotrophic lateral sclerosis, it is tempting to speculate that a similar mechanism is at work in both forms of the disease.}, }
@article {pmid10791091, year = {1999}, author = {Iwasaki, Y and Ikeda, K}, title = {[Cotreatment of amyotrophic lateral sclerosis patients].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {39}, number = {12}, pages = {1253-1255}, pmid = {10791091}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drug Therapy, Combination ; Humans ; Mice ; Nerve Growth Factors/administration &amp; dosage ; Neuroprotective Agents/*administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {In the treatment of cancers and infectious diseases, several drugs are administered simultaneously. Riluzole is a only drug which prolongs survival in amyotrophic lateral sclerosis (ALS) patients, however its effect is modest. We review the preclinical data supporting combination treatment for ALS and discuss the possible combination treatment in patients with ALS. In vitro studies showed favorable results in combination of neurotrophic factors. The combination of BDNF and GDNF reduced motor neuron death after axotomy for more than either factor alone. CNTF and BDNF combination treatment in wobbler mice arrested paw deformity. In the treatment of ALS, riluzole is the only drug available by prescription. When combination treatment is considered in ALS, the most effective combination need to be addressed.}, }
@article {pmid10768651, year = {2000}, author = {Chosidow, O and Doppler, V and Bensimon, G and Joly, P and Salachas, F and Lacomblez, L and Prost, C and Camu, W and Francès, C and Herson, S and Meininger, V}, title = {Bullous pemphigoid and amyotrophic lateral sclerosis: a new clue for understanding the bullous disease?.}, journal = {Archives of dermatology}, volume = {136}, number = {4}, pages = {521-524}, doi = {10.1001/archderm.136.4.521}, pmid = {10768651}, issn = {0003-987X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/etiology/pathology ; Autoantibodies/blood ; Autoantigens/immunology ; *Carrier Proteins ; Collagen/immunology ; *Cytoskeletal Proteins ; Drug Therapy, Combination ; Dystonin ; Fatal Outcome ; Female ; Humans ; Immunoblotting ; Male ; Middle Aged ; *Nerve Tissue Proteins ; *Non-Fibrillar Collagens ; Pemphigoid, Bullous/*diagnosis/drug therapy/etiology/pathology ; Recurrence ; Collagen Type XVII ; }, abstract = {BACKGROUND: Bullous pemphigoid (BP) occurs in many patients with multiple sclerosis. Isolated cases of BP in patients with other neurological disorders further support a pathogenic association between cutaneous and neurological diseases. Any description of BP in patients with amyotrophic lateral sclerosis is lacking.<br><br>OBSERVATIONS: We studied a French population of 168 patients with typical amyotrophic lateral sclerosis. Among these, 3 had clinical and histological features of BP. The mean age of the patients was 54 years. None was known to have autoimmune disorders. Results of immunoblot analysis disclosed both anti-BP antigen 1 and anti-BP antigen 2 antibodies.<br><br>CONCLUSIONS: Bullous pemphigoid seems to be unexpectedly associated with amyotrophic lateral sclerosis. On the basis of the cases presented herein, we discuss the epidemiological significance of the association and the possible interrelation between BP antigen 1 and neurofilaments in the pathogenesis of both disorders.}, }
@article {pmid10742999, year = {2000}, author = {González-Lorenzo, F and Díaz-Lobato, S}, title = {[Mechanical ventilation in patients with amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {30}, number = {1}, pages = {61-64}, pmid = {10742999}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Chronic Disease ; Equipment Design ; Humans ; Quality of Life ; Respiration, Artificial/*instrumentation ; Respiratory Insufficiency/etiology/*therapy ; Terminal Care ; }, abstract = {In the final stage of amyotrophic lateral sclerosis, the majority of patients develop chronic respiratory failure. If these patients are not informed about the acute respiratory insufficiency, they run the risk of having to be intubated and stay in Intensive Care Unit over a long term; many of them die of respiratory failure without being informed about the available options. Prognosis and treatment options should be discussed with the patient and family. Their informed consent to prolonged mechanical ventilation of the lungs and stopped it under certain circumstances would be obtained before the condition progress to critical. The non invasive artificial home ventilation has led to advances in the management of patients with amyotrophic lateral sclerosis, as a longer period of survival with a higher level of quality of life. We also have analyzed ethical and social aspects and the results of long term mechanical ventilation in the literature.}, }
@article {pmid10742195, year = {2000}, author = {Bush, AI}, title = {Metals and neuroscience.}, journal = {Current opinion in chemical biology}, volume = {4}, number = {2}, pages = {184-191}, doi = {10.1016/s1367-5931(99)00073-3}, pmid = {10742195}, issn = {1367-5931}, mesh = {Alzheimer Disease/metabolism ; Animals ; Brain/*metabolism ; Cataract/metabolism ; Humans ; Metals/*metabolism ; Mitochondrial Encephalomyopathies/metabolism ; Motor Neuron Disease/metabolism ; Parkinson Disease/metabolism ; Prion Diseases/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Data are now rapidly accumulating to show that metallochemical reactions might be the common denominator underlying Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases, cataracts, mitochondrial disorders and Parkinson's disease. In these disorders, an abnormal reaction between a protein and a redox-active metal ion (copper or iron) promotes the formation of reactive oxygen species or radicalization. It is especially intriguing how the powerful catalytic redox activity of antioxidant Cu/Zn-superoxide dismutase can convert into a pro-oxidant activity, a theme echoed in the recent proposal that Abeta and PrP, the proteins respectively involved in Alzheimer's disease and prion diseases, possess similar redox activities.}, }
@article {pmid10736372, year = {2000}, author = {Meldrum, BS}, title = {Glutamate as a neurotransmitter in the brain: review of physiology and pathology.}, journal = {The Journal of nutrition}, volume = {130}, number = {4S Suppl}, pages = {1007S-15S}, doi = {10.1093/jn/130.4.1007S}, pmid = {10736372}, issn = {0022-3166}, mesh = {Animals ; Brain/*physiology/physiopathology ; Glutamic Acid/*physiology ; Humans ; Nerve Degeneration/physiopathology ; Nervous System Diseases/drug therapy/physiopathology ; Neurotransmitter Agents/*physiology ; Reference Values ; }, abstract = {Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.}, }
@article {pmid10721755, year = {2000}, author = {Sliwa, JA}, title = {Neuromuscular rehabilitation and electrodiagnosis. 1. Central neurologic disorders.}, journal = {Archives of physical medicine and rehabilitation}, volume = {81}, number = {3 Suppl 1}, pages = {S3-12; quiz S36-44}, pmid = {10721755}, issn = {0003-9993}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*rehabilitation ; Electrodiagnosis ; Humans ; Multiple Sclerosis/*diagnosis/physiopathology/*rehabilitation ; Muscle Fatigue ; Parkinson Disease/*diagnosis/physiopathology/*rehabilitation ; Patient Care Planning ; }, abstract = {This self-directed learning module highlights the medical treatment and rehabilitation intervention of certain central neurologic disorders encountered in physiatric practice. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article contains sections on multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Information covered in these sections includes discussions of the current medical management and the benefits of comprehensive rehabilitation and interventions for specific impairments seen in these conditions.}, }
@article {pmid10716663, year = {1999}, author = {Cole, N and Siddique, T}, title = {Genetic disorders of motor neurons.}, journal = {Seminars in neurology}, volume = {19}, number = {4}, pages = {407-418}, doi = {10.1055/s-2008-1040855}, pmid = {10716663}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Humans ; Motor Neuron Disease/*genetics ; Muscular Atrophy, Spinal/genetics ; Muscular Disorders, Atrophic/genetics ; }, abstract = {Disorders of the motor neuron are etiologically and clinically heterogeneous and cause serious disability and death. Whereas mendelian inheritance can be demonstrated in a subset of these disorders, the genetic contribution to the sporadic forms of motor neuron degeneration are not well understood. In families with spinal muscular atrophy, Kennedy disease and amyotrophic lateral sclerosis, genetic linkage analysis and positional cloning have proven to be extremely productive. The genetics of these neurodegenerative disorders are reviewed.}, }
@article {pmid10677867, year = {2000}, author = {Orrell, RW}, title = {Amyotrophic lateral sclerosis: copper/zinc superoxide dismutase (SOD1) gene mutations.}, journal = {Neuromuscular disorders : NMD}, volume = {10}, number = {1}, pages = {63-68}, doi = {10.1016/s0960-8966(99)00071-1}, pmid = {10677867}, issn = {0960-8966}, mesh = {Amino Acid Sequence/genetics ; Amyotrophic Lateral Sclerosis/*genetics ; Base Sequence/genetics ; Humans ; Mutation/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Mutations of the SOD1 gene, encoding the enzyme copper/zinc superoxide dismutase, have been identified in around 20% of patients with familial amyotrophic lateral sclerosis (ALS), and also in patients with apparently sporadic ALS. The table documents the mutations identified and published to date, and references clinical and pathological descriptions of the patients and families with individual mutations. The table includes 63 different mutations of SOD1 at 43 codons, three intronic sites, and two in the 3' untranslated region. Most of the mutations are heterozygotes, with autosomal dominant inheritance, but a small number of individuals appear to be sporadic, or are homozygotes with autosomal dominant recessive inheritance.}, }
@article {pmid10693255, year = {2000}, author = {Antoine, JC and Honnorat, J}, title = {[Anti-neuronal antibodies and central nervous system diseases: contribution to diagnosis and pathophysiology].}, journal = {Revue neurologique}, volume = {156}, number = {1}, pages = {23-33}, pmid = {10693255}, issn = {0035-3787}, mesh = {Antibodies/*immunology ; *Central Nervous System Diseases/diagnosis/immunology/physiopathology ; Female ; Humans ; Male ; Neurons/*immunology ; }, abstract = {Antibodies against antigens found in the central nervous system have been evidenced in several neurological diseases. The most well-known are associated with paraneoplastic neurological diseases (Anti-Hu, Yo, Ri amphiphysin, Tr, CV2 and Ta antibodies). Some of these antibodies are specific for certain types of cancer or neurological syndromes and are highly useful diagnostic tools for the clinician. They have contributed to the hypothesis that these paraneoplastic neurological syndromes involve autoimmune cross reactions between tumoral and nervous system antigens. They are however most unlikely pathogenic on their own. Anti voltage-dependent calcium channel antibodies associated with Lambert-Eaton syndrome which is paraneoplastic in only 60 p. 100 of the cases are also observed in cases of paraneoplastic cerebellar atrophy. Anti-GAD antibodies are seen in non-paraneoplastic stiff man syndrome and in certain progressive cerebellar atrophies. Antibodies reacting with different glutamate receptors are detected in different neurological diseases including Rasmussen's encephalitis. Finally, antibodies are described in diverse conditions such as amyotrophic lateral sclerosis, Sydeham chorea or Gilles de la Tourette syndrome. The significance of the antibodies observed outside the context of paraneoplastic syndromes is not well understood, but the anti-GAD antibodies associated with progressive cerebellar disorders and autoimmune polyendocrinopathies could be an expression of the autoimmune nature of certain neurological degenerative processes affecting the central nervous system.}, }
@article {pmid10691289, year = {1999}, author = {Mattson, MP and Duan, W and Chan, SL and Camandola, S}, title = {Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders.}, journal = {Journal of molecular neuroscience : MN}, volume = {13}, number = {1-2}, pages = {17-30}, pmid = {10691289}, issn = {0895-8696}, mesh = {Animals ; *Apoptosis ; Apoptosis Regulatory Proteins ; Carrier Proteins/*metabolism ; Humans ; *Intracellular Signaling Peptides and Proteins ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified as the product of a gene upregulated in prostate tumor cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase Czeta, Bcl-2, and caspase-8. A rapid increase in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction. The mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-kappaB and suppression of Bcl-2 expression and/or function. Studies of postmortem tissues from patients and animal models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis, have documented increased levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process. Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration. A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.}, }
@article {pmid10689460, year = {1999}, author = {Eisen, A and Nakajima, M and Stewart, H and Weber, M}, title = {Excitability of the motor cortex in amyotrophic lateral sclerosis.}, journal = {Electroencephalography and clinical neurophysiology. Supplement}, volume = {50}, number = {}, pages = {175-182}, pmid = {10689460}, issn = {0424-8155}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Motor Cortex/*physiopathology ; }, }
@article {pmid10685504, year = {1999}, author = {Nishida, Y and Nishino, S}, title = {Contribution of a metal-peroxide adduct to neurodegeneration is due to its oxidative protease activity.}, journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences}, volume = {54}, number = {12}, pages = {1107-1114}, doi = {10.1515/znc-1999-1217}, pmid = {10685504}, issn = {0939-5075}, mesh = {*Aging ; Amyloid Precursor Protein Secretases ; Amyloid beta-Protein Precursor/chemistry/*metabolism ; Animals ; Aspartic Acid Endopeptidases ; Base Sequence ; Endopeptidases/*metabolism ; Humans ; Metals/chemistry/*metabolism ; Molecular Sequence Data ; Nerve Degeneration/enzymology/*metabolism ; Peroxides/chemistry/*metabolism ; }, abstract = {Many hypotheses have been developed to explain aging and age-related neurodegenerative disorders; one of the most compelling is the role of oxidative stress to induce changes in protease activity in brains of patients of Alzheimer's disease and prion disease. At the moment however, there is no clear answer how protein degradation may be achieved in the brain. We have observed that several metal compounds can degrade proteins in the presence of hydrogen peroxide, and elucidated the reaction scheme based on the new theoretical point for the reactivity of a metal-peroxide adduct with eta 1-coordination mode. In this article we would like to point out the importance of a copper(II)-peroxide adduct to promote neurodegenerative diseases such as prion disease and amyotrophic lateral sclerosis through its oxidative protease function.}, }
@article {pmid10684590, year = {2000}, author = {Gurney, ME}, title = {What transgenic mice tell us about neurodegenerative disease.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {22}, number = {3}, pages = {297-304}, doi = {10.1002/(SICI)1521-1878(200003)22:3&lt;297::AID-BIES12&gt;3.0.CO;2-I}, pmid = {10684590}, issn = {0265-9247}, mesh = {Alzheimer Disease/genetics/physiopathology ; Animals ; Humans ; Mice ; *Mice, Transgenic ; Motor Neuron Disease/genetics/physiopathology ; Neurodegenerative Diseases/*genetics/*physiopathology ; Trinucleotide Repeats ; }, abstract = {The recent broad advance in our understanding of human neurodegenerative diseases is based on the application of a new molecular approach. Through linkage analysis, the genes responsible for Huntington's disease, the spinocerebellar ataxias, and familial forms of Alzheimer's disease and amyotrophic lateral sclerosis (ALS) have been identified and cloned. The characterization of pathogenic mutations in such genes allows the creation of informative transgenic mouse models as, without exception, the genetic forms of adult neurodegenerative disease are due to toxicity of the mutant protein. Transgenic models provide insight into the oxidative mechanisms in ALS pathogenesis, the pathogenicity of expanded polyglutamine tracts in CAG triplet repeat disorders, and amyloidogenesis in Alzheimer's disease. Although such models have their limitations, they currently provide the best entry point for the study of human neurodegenerative diseases.}, }
@article {pmid10652752, year = {1999}, author = {Cabrera-Gómez, JA and López-Saura, P}, title = {[Recent advances in the treatment the nervous system disorders with interferon-alpha].}, journal = {Revista de neurologia}, volume = {29}, number = {12}, pages = {1225-1235}, pmid = {10652752}, issn = {0210-0010}, mesh = {Central Nervous System Diseases/*drug therapy ; Humans ; Interferon-alpha/*therapeutic use ; }, abstract = {INTRODUCTION: The interferons (IFN) have had considerable effect on the course of relapses and the natural course of the disability of patients with multiple sclerosis (MS). However, the effects of IFN in other neurological disorders are little known.<br><br>OBJECTIVES: To review the literature on the experimental and clinical applications of the IFN in disorders of the nervous system excluding MS.<br><br>DEVELOPMENT: We reviewed studies of the applications of the IFN in viral diseases (experimental and human rabies, herpes zoster, herpes virus, non-herpetic meningoencephalitic viruses, HTLV-I myelopathy, arbovirus in animals, subacute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy); supposedly viral diseases (Reye's syndrome), continuous partial epilepsy (Kojewnikoff's syndrome); prion diseases (Creutzfeldt-Jakob disease); degenerative-hereditary diseases (amyotrophic lateral sclerosis, Alzheimer's disease, schizophrenia, Sturge-Weber-Dimitri syndrome); immuno-allergic disorders (experimental myasthenia gravis, chronic inflammatory demyelinating polyneuropathy-CIDP-); Landry-Guillain-Barr&#xe9;-Strohl syndrome, polyneuropathy associated with IgM monoclonal gammapathy; tumour disorders (benign and malignant primary tumours of the brain, metastatic tumours, meningeal carcinomatosis, extra-intracranial haemangiomas, meningiomas), and other causes (cuban epidemic neuropathy, neuro-Bec&#xe7;et).<br><br>CONCLUSIONS: Disorders of the nervous system in which IFN may be used in a clinical trial include: herpes zoster and herpes simplex infections, HTLV-I myelopathy; subacute sclerosing leukoencephalopathy, continuous partial epilepsy (Kojewnicoff's syndrome), intra-extracranial haemangiomas, CIDP, polyneuropathy associated with IgM gamma monoclonal disorder, malignant primary tumours, recurrent meningiomas, some cerebral metastases, Beh&#xe7;et's disease and schizophrenia.}, }
@article {pmid10643818, year = {1999}, author = {Weber, GF}, title = {Final common pathways in neurodegenerative diseases: regulatory role of the glutathione cycle.}, journal = {Neuroscience and biobehavioral reviews}, volume = {23}, number = {8}, pages = {1079-1086}, doi = {10.1016/s0149-7634(99)00041-x}, pmid = {10643818}, issn = {0149-7634}, mesh = {Animals ; Glutathione/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Reactive Oxygen Species/physiology ; }, abstract = {Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of final common pathways which characterize frequently occurring cellular responses to disruption of homeostasis. The clinical presentation and common patho-biochemistry of reactive oxygen intermediates of Guam's disease have suggested that such pathways may be operative in three major neurodegenerative disorders: Alzheimer's dementia, amyotrophic lateral sclerosis and Parkinson's disease. A candidate-signaling pathway in this regard is characterized by the cascade arachidonic acid/HPETE/*OH/cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB. This sequence may lead to apoptosis as well as long-term potentiation and memory and constitutes a biochemical correlate to excitotoxicity. The predominant control of *OH release from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a central biochemical process that is also intimately associated with the synthesis of the neurotransmitters glutamate and GABA and is connected to energy metabolism. Modifications in the activity of the glutathione cycle may provide treatment options.}, }
@article {pmid10637819, year = {1999}, author = {Puls, I and Beck, M and Giess, R and Magnus, T and Ochs, G and Toyka, KV}, title = {[Clenbuterol in amyotrophic lateral sclerosis. No indication for a positive effect].}, journal = {Der Nervenarzt}, volume = {70}, number = {12}, pages = {1112-1115}, doi = {10.1007/s001150050548}, pmid = {10637819}, issn = {0028-2804}, mesh = {Adrenergic beta-Agonists/adverse effects/*therapeutic use ; Clenbuterol/adverse effects/*therapeutic use ; Humans ; Motor Neuron Disease/diagnosis/*drug therapy ; Neurologic Examination/drug effects ; Treatment Failure ; }, abstract = {The anabolic effects of clenbuterol have been recognized for a long time. Clenbuterol augments the expression of specific muscle proteins with a differential effect on type I and type II fibres. Furthermore, clenbuterol induces the synthesis of endogenous nerve growth factor (NGF) and may itself be a myotrophic factor released by neuron endings. Side effects include tremor and headache and dose dependent abnormalities of laboratory values (hypokalemia, hypoglycemia). After long-term medication increasing fatigue of muscles has been observed. Decreased expression of beta 2-adrenergic receptors may limit the expected functional improvement. The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved. Controlled treatment trials are warranted to assess this question.}, }
@article {pmid10637812, year = {1999}, author = {Dichgans, J and Schulz, JB}, title = {[Aging in parts? Systemic aging of the nervous system].}, journal = {Der Nervenarzt}, volume = {70}, number = {12}, pages = {1072-1081}, doi = {10.1007/s001150050541}, pmid = {10637812}, issn = {0028-2804}, mesh = {Animals ; Cellular Senescence/genetics/*physiology ; Central Nervous System/pathology ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/genetics/pathology/*physiopathology ; Neurons/pathology/physiology ; }, abstract = {Neurons of the central nervous system in general do not multiply after birth. Therefore, no replacement or biological renewal of individual cells affected by aging or death is possible. Morphological changes occurring in the aging brain are found substantially more pronounced in neurodegenerative diseases. Systemic degenerations of selective brain areas in these disorders, e.g. in Alzheimer's, Parkinson's, Huntington's disease or in amyotrophic lateral sclerosis, may be considered as models of accelerated aging and may allow to study the genetic and environmental influences of selective aging and cell death in modules of the central nervous system. Although neurodegenerative diseases are disparate disorders on the basis of their symptomatology and the anatomic distribution of pathologic lesions, they actually share key attributes with respect to biochemical and cellular determinants of selective vulnerability. Most strikingly, many show a conversion of disease specific and only recently identified proteins into unsoluble aggregates which form intra- or extracellular deposits. These protein aggregates may, over time, affect neuronal function, eventually leading to neurodegeneration and neurodegenerative pathology. The pathological process is counterbalanced by protective mechanisms that may loose their efficacy during normal aging. This could explain the late onset of even the inherited neurodegenerative disorders. Since the expression of disease-specific proteins is often not restricted to the affected brain areas (as exemplified by the expression of polyglutamine containing proteins in trinucleotide repeat disorders in non-affected brain areas and even outside the brain), the anatomical specificity of the degenerative process may be determined by associated binding proteins. Therapeutic strategies include the reinforcement of physiological defense mechanisms and intervention at early phases of the pathological biochemistry of disease specific proteins.}, }
@article {pmid10636117, year = {2000}, author = {Karpati, G and Dalakas, MC}, title = {Viral hide-and-seek in sporadic ALS: a new challenge.}, journal = {Neurology}, volume = {54}, number = {1}, pages = {6-7}, doi = {10.1212/wnl.54.1.6}, pmid = {10636117}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*virology ; Enterovirus/*genetics ; Humans ; RNA, Viral/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; }, }
@article {pmid10634430, year = {2000}, author = {Worrall, BB and Rowland, LP and Chin, SS and Mastrianni, JA}, title = {Amyotrophy in prion diseases.}, journal = {Archives of neurology}, volume = {57}, number = {1}, pages = {33-38}, doi = {10.1001/archneur.57.1.33}, pmid = {10634430}, issn = {0003-9942}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Creutzfeldt-Jakob Syndrome/genetics/*pathology ; *Family Health ; Genetic Predisposition to Disease ; Gerstmann-Straussler-Scheinker Disease/genetics/pathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis was once thought to be caused by persistent viral infection, partly because some patients with transmissible Creutzfeldt-Jakob disease showed prominent amyotrophy. However, in the past 15 years there has been little interest in the amyotrophy in prion diseases, and the possible link to amyotrophic lateral sclerosis has been eschewed. We analyzed case reports of prion disease published after 1968 for evidence of amyotrophy. We defined amyotrophy as clinically evident fasciculation buttressed by electromyographic results in some cases. We sought evidence of motor neuron degeneration at autopsy. Prion disease was proved by transmissibility, immunohistochemistry demonstration of protease-resistant prion protein, or finding a mutation in the prion protein gene. Amyotrophy was noted in 27 patients: 13 with sporadic Creutzfeldt-Jakob disease, 2 with familial Creutzfeldt-Jakob disease, and 12 with Gerstmann-Sträussler-Scheinker disease. Of the 27, 23 showed clinical fasciculation and 10 had electromyographic evidence of denervation. The spinal cord was examined in 8 patients: 6 showed loss of motor neurons, 1 showed vacuolation of motor neurons, and 1 reported no abnormalities. Another 23 patients had typical histopathological characteristics but lacked molecular or biochemical proof of prion disease. The total number of patients with amyotrophy and proven prion disease that we identified was 50. This case review supports the belief that amyotrophy is occasionally a prominent feature of Creutzfeldt-Jakob disease and underscores the importance of documenting lower motor neuron function and the crucial role of examining the spinal cord at autopsy in cases of prion disease.}, }
@article {pmid10631655, year = {1999}, author = {Bradley, WG}, title = {Biological markers in amyotrophic lateral sclerosis: help or hindrance?.}, journal = {Journal of neurology}, volume = {246 Suppl 3}, number = {}, pages = {III13-5}, pmid = {10631655}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism/physiopathology/therapy ; Biomarkers ; Clinical Trials as Topic ; Disease Progression ; Humans ; }, abstract = {Biological markers play an important role in the development of the understanding of a disease, its diagnosis and treatment. This is particularly true of amyotrophic lateral sclerosis (ALS) at this time. We need better biological markers for the diagnosis, for improved understanding of the underlying pathogenetic mechanisms, and for assistance in new drug development. This review of currently available biological and surrogate markers in ALS discusses novel approaches to the use of such markers, and new drugs for the treatment of ALS.}, }
@article {pmid10631653, year = {1999}, author = {Eisen, A}, title = {How to improve the diagnostic process.}, journal = {Journal of neurology}, volume = {246 Suppl 3}, number = {}, pages = {III6-9}, pmid = {10631653}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Family Practice/methods ; Humans ; *Quality of Health Care ; Time Factors ; }, abstract = {The existing therapeutic options for treating amyotrophic lateral sclerosis (ALS) are relatively limited but, as therapies improve, there will be a need for early diagnosis of this rare but fatal neurogenerative disorder. Early diagnosis not only requires the utility of a good biological marker, it also requires medical personnel who are experienced to consider/establish a diagnosis of ALS. In many countries, diagnosis of ALS follows a three-step process involving the family physician/practitioners, a community neurologist and an ALS specialist. This process is cumbersome and as the number of cases seen by the first two doctors is extremely small, their awareness is consequently low. There is an urgent need to improve the awareness of ALS in the family physicians but also within the general population. A number of elements which probably contribute to delays in achieving an early diagnosis of ALS will be discussed in this paper with the view of identifying how the diagnostic process can be improved.}, }
@article {pmid10630682, year = {1999}, author = {Bredt, DS}, title = {Endogenous nitric oxide synthesis: biological functions and pathophysiology.}, journal = {Free radical research}, volume = {31}, number = {6}, pages = {577-596}, doi = {10.1080/10715769900301161}, pmid = {10630682}, issn = {1071-5762}, mesh = {Animals ; Brain/metabolism ; Calcium Channels/metabolism ; Humans ; Muscle, Skeletal/metabolism ; Neurons/metabolism ; Nitric Oxide/metabolism/*physiology ; Nitric Oxide Synthase/*physiology ; }, abstract = {Modern molecular biology has revealed vast numbers of large and complex proteins and genes that regulate body function. By contrast, discoveries over the past ten years indicate that crucial features of neuronal communication, blood vessel modulation and immune response are mediated by a remarkably simple chemical, nitric oxide (NO). Endogenous NO is generated from arginine by a family of three distinct calmodulin- dependent NO synthase (NOS) enzymes. NOS from endothelial cells (eNOS) and neurons (nNOS) are both constitutively expressed enzymes, whose activities are stimulated by increases in intracellular calcium. Immune functions for NO are mediated by a calcium-independent inducible NOS (iNOS). Expression of iNOS protein requires transcriptional activation, which is mediated by specific combinations of cytokines. All three NOS use NADPH as an electron donor and employ five enzyme cofactors to catalyze a five-electron oxidation of arginine to NO with stoichiometric formation of citrulline. The highest levels of NO throughout the body are found in neurons, where NO functions as a unique messenger molecule. In the autonomic nervous system NO functions NO functions as a major non-adrenergic non-cholinergic (NANC) neurotransmitter. This NANC pathway plays a particularly important role in producing relaxation of smooth muscle in the cerebral circulation and the gastrointestinal, urogenital and respiratory tracts. Dysregulation of NOS activity in autonomic nerves plays a major role in diverse pathophysiological conditions including migraine headache, hypertrophic pyloric stenosis and male impotence. In the brain, NO functions as a neuromodulator and appears to mediate aspects of learning and memory. Although endogenous NO was originally appreciated as a mediator of smooth muscle relaxation, NO also plays a major role in skeletal muscle. Physiologically muscle-derived NO regulates skeletal muscle contractility and exercise-induced glucose uptake. nNOS occurs at the plasma membrane of skeletal muscle which facilitates diffusion of NO to the vasculature to regulate muscle perfusion. nNOS protein occurs in the dystrophin complex in skeletal muscle and NO may therefore participate in the pathophysiology of muscular dystrophy. NO signalling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signalling is largely regulated at the level of NO biosynthesis. Acute control of nNOS activity is mediated by allosteric enzyme regulation, by posttranslational modification and by subcellular targeting of the enzyme. nNOS protein levels are also dynamically regulated by changes in gene transcription, and this affords long-lasting changes in tissue NO levels. While NO normally functions as a physiological neuronal mediator, excess production of NO mediates brain injury. Overactivation of glutamate receptors associated with cerebral ischemia and other excitotoxic processes results in massive release of NO. As a free radical, NO is inherently reactive and mediates cellular toxicity by damaging critical metabolic enzymes and by reacting with superoxide to form an even more potent oxidant, peroxynitrite. Through these mechanisms, NO appears to play a major role in the pathophysiology of stroke, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid10621940, year = {1999}, author = {Akaike, A}, title = {[Neuronal response to radical stress].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {114}, number = {5}, pages = {273-279}, doi = {10.1254/fpj.114.273}, pmid = {10621940}, issn = {0015-5691}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Cell Death ; Glutamates/physiology ; Humans ; Motor Neurons/physiology ; Neurons/*physiology ; Oxidative Stress/*physiology ; Parkinson Disease/pathology ; Reactive Oxygen Species ; }, abstract = {Glutamate and reactive oxygen species including nitric oxide (NO) and superoxide anion (O2.-) have been postulated to play pivotal roles in the pathogenesis of the neuronal cell loss that is associated with several neurological disease states including Parkinson's disease and amyotrophic lateral sclerosis. In mesencephalic cultures, nondopaminergic neurons but not dopaminergic neurons are susceptible to NO cytotoxicity, although both types of neurons are damaged by glutamate. Methylphenylpyridium ion (MPP+) selectively enhances glutamate and NO cytotoxicity against dopaminergic neurons of mesencephalic cultures. It is suggested that glutathione plays an important role in the expression of NO-mediated glutamate cytotoxicity in dopaminergic neurons. In cultured spinal neurons, glutamate coadministered with the glutamate transporter inhibitor selectively damages motor neurons. Motor neurons are injured by NO, whereas nonmotor neurons are protected by NO through the guanylyl cyclase-cGMP cascade. It is suggested that selective motor neuronal death caused by chronic low-level exposure to glutamate is mediated by the formation of NO in nonmotor neurons. It is possible that neurotoxicity induced by NO and O2.- associated with neurodegenerative disorders is regulated by intracellular defense systems such as glutathione and cGMP.}, }
@article {pmid10617331, year = {1999}, author = {Baker, DJ}, title = {Management of respiratory failure in toxic disasters.}, journal = {Resuscitation}, volume = {42}, number = {2}, pages = {125-131}, doi = {10.1016/s0300-9572(99)00098-2}, pmid = {10617331}, issn = {0300-9572}, mesh = {*Disasters ; Emergency Medical Services ; Emergency Service, Hospital ; Environmental Exposure ; Hazardous Substances/*poisoning ; Humans ; Respiratory Insufficiency/*chemically induced/therapy ; }, abstract = {Accidental or deliberate release of toxic substances may be a cause of mass casualties, some of which may involve partial or complete respiratory failure. Life support measures may be delayed by the need for containment of the toxic release and decontamination. Advanced life support (ALS) may be provided in such circumstances using the TOXALS protocol. With proper training and equipment, emergency medical personnel can provide effective prehospital care during decontamination of chemical casualties.}, }
@article {pmid10601567, year = {2000}, author = {Martin, LJ and Price, AC and Kaiser, A and Shaikh, AY and Liu, Z}, title = {Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review).}, journal = {International journal of molecular medicine}, volume = {5}, number = {1}, pages = {3-13}, doi = {10.3892/ijmm.5.1.3}, pmid = {10601567}, issn = {1107-3756}, support = {NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Apoptosis/genetics ; Autoimmunity/immunology ; DNA Damage ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.}, }
@article {pmid10598368, year = {1999}, author = {Bélec, L}, title = {[The hypothesis of infectious etiology for idiopathic nervous system diseases: from the postulates of Koch to the criteria of Hill].}, journal = {Clinical and experimental pathology}, volume = {47}, number = {5}, pages = {207-213}, pmid = {10598368}, issn = {1292-7953}, mesh = {Bacterial Infections/*complications ; Humans ; Nervous System Diseases/*microbiology/virology ; Virus Diseases/*complications ; Whipple Disease/microbiology ; }, abstract = {The evaluation of the hypothesis of an infectious etiology to some neurological diseases comprises four different situations. First, numerous neurological diseases have an obvious infectious etiology (encephilitis, meningoencephilitis). Second, some neurological disorders were primarily suspected to be have an infectious etiology, but the causative microorganism was discovered either longtime after the princeps description of the disease (neurologic Whipple disease, due to Tropheryma whippelii), or at the same time (tropical spastic para-paresis secondary to HTLV-I infection). Third, for other neurological diseases, an infectious etiology that was not suspected at time of their anatomoclinic descriptions, was further demonstrated in the context of a generally complex physiopathology (Guillain-Barré syndrome and infection by Campylobacter jejuni). Finally, some idiopathic neurological diseases could be related to well known or yet unknown microorganisms, in association with some environmental factors, and with a particular genetic or acquired susceptibility of the host. The evaluation of an infectious etiology to these idiopathic neurological disorders must be envisioned according to 3 possibilities: 1) generally, the neurological disease is well defined, but its etiology remains unknown and an infectious hypothesis could be relevant (multiple sclerosis, post-polio syndrome, amyotrophic lateral sclerosis); 2) sometimes, a microorganism that is not associated with a known disease, and then qualified as "orphelin", could be associated with neurological disorders (spumaretrovirus); 3) finally, a new neurological disease could be associated with a known or yet unknown microorganism, directly or indirectly. In conclusion, some idiopathic neurological diseases could have an infectious etiology, with physiopathologic, diagnostic, prophylactic (vaccination) and therapeutic (use of anti-infectious drugs) consequences.}, }
@article {pmid10595505, year = {1999}, author = {Cleveland, DW}, title = {From Charcot to SOD1: mechanisms of selective motor neuron death in ALS.}, journal = {Neuron}, volume = {24}, number = {3}, pages = {515-520}, doi = {10.1016/s0896-6273(00)81108-3}, pmid = {10595505}, issn = {0896-6273}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics/physiopathology ; Cell Death ; Humans ; Models, Neurological ; Motor Neurons/*physiology ; Mutation/physiology ; Neurology/trends ; Superoxide Dismutase/chemistry/*genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid10594838, year = {1999}, author = {Oda, Y}, title = {Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system.}, journal = {Pathology international}, volume = {49}, number = {11}, pages = {921-937}, doi = {10.1046/j.1440-1827.1999.00977.x}, pmid = {10594838}, issn = {1320-5463}, mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Central Nervous System/*enzymology ; Choline O-Acetyltransferase/*chemistry/genetics/*metabolism ; Cholinergic Fibers/enzymology ; Humans ; Molecular Sequence Data ; Neurodegenerative Diseases/*enzymology ; Presynaptic Terminals/*enzymology/pathology ; Sequence Homology, Amino Acid ; }, abstract = {Choline acetyltransferase (ChAT), the enzyme responsible for the biosynthesis of acetylcholine, is presently the most specific indicator for monitoring the functional state of cholinergic neurones in the central and peripheral nervous systems. ChAT is a single-strand globular protein. The enzyme is synthesized in the perikaryon of cholinergic neurones and transported to the nerve terminals probably by both slow and rapid axoplasmic flows. ChAT exists in at least two forms in cholinergic nerve terminals: (i) soluble; and (ii) non-ionically membrane-bound forms. Multiple mRNA species of ChAT (R-, N-and M-types) are transcribed from different promoter regions and produced by different splicing in the mouse, rat, and human. All transcripts encode the same ChAT protein in rodents, while in human M-type mRNA has the capability to generate both large and small forms of ChAT proteins and R-and N-types ChAT mRNA generate a small form, which corresponds to the rodent ChAT. The genomic structure of ChAT is unique compared with other enzymes for neurotransmitters. The first intron of the ChAT gene encompasses the open reading frame encoding another protein, vesicular acetylcholine transporter (VAChT), which is responsible for the transportation of acetylcholine from the cytoplasm into the synaptic vesicles. The expressions of ChAT and VAChT appear to be coordinately regulated by multiple regulatory elements in cholinergic neurones. Immunohistochemical and in situ hybridization studies have revealed the localization of cholinergic neurones in the central nervous system: the medial septal nucleus, the nucleus of the diagonal band of Broca, the basal nucleus of Meynert, the caudate nucleus, the putamen, the nucleus accumbens, the pedunculopontine tegmental nucleus, the laterodorsal tegmental nucleus, the medial habenular nucleus, the parabigeminal nucleus, some cranial nerve nuclei, and the anterior horn of the spinal cord. Focally distributed cholinergic neurones project fibers to many areas in the central nervous system and construct a complicated cholinergic network, playing an important role in neuropsychic activities, such as learning, memory, arousal, sleep and movement. Central cholinergic neurones are involved in several neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, in which disturbance of the central cholinergic system does not appear to be closely related to the etiology, but rather to the development of clinical symptoms. In addition, abnormalities of ChAT in the brain have been recently demonstrated in schizophrenia and sudden infant death syndrome.}, }
@article {pmid10540029, year = {1999}, author = {Swash, M and Desai, J and Misra, VP}, title = {What is primary lateral sclerosis?.}, journal = {Journal of the neurological sciences}, volume = {170}, number = {1}, pages = {5-10}, doi = {10.1016/s0022-510x(99)00184-7}, pmid = {10540029}, issn = {0022-510X}, mesh = {Diagnosis, Differential ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/physiopathology ; Neurology/trends ; }, abstract = {Primary lateral sclerosis (PLS) is a rare degenerative disorder of the upper motor neuron. Its nosological status and relationship to other motor neuron syndromes, especially amyotrophic lateral sclerosis (ALS), is uncertain. Diagnostic criteria have been proposed. We discuss the history of this rare clinical disorder, its relationship to the motor neuron disease syndrome, and reports of overlapping clinico-pathological conditions. Two patients with the clinical syndrome of PLS are described to illustrate current understanding of the clinical, laboratory, and neurophysiological features.}, }
@article {pmid10540027, year = {1999}, author = {Strong, MJ}, title = {Neurofilament metabolism in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {170-177}, doi = {10.1016/s0022-510x(99)00241-5}, pmid = {10540027}, issn = {0022-510X}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Cell Aggregation/genetics/physiology ; Humans ; Mice ; Neurofilament Proteins/genetics/*metabolism ; Nitric Oxide Synthase/genetics/*metabolism ; Nitric Oxide Synthase Type I ; Nitric Oxide Synthase Type II ; }, abstract = {Although the role of intraneuronal neurofilamentous aggregates in the pathogenesis of ALS is unknown, their presence forms a key neuropathological hallmark of the disease process. Conversely, the experimental induction of neurofilamentous aggregates in either neurotoxic or transgenic mice gives rise to motor system degeneration. To determine whether alterations in the physiochemical properties of NF are present in sporadic ALS, we purified NF subunit proteins from cervical spinal cord of ALS and age-matched control patients. The cytoskeleton-enriched, Triton X-100 insoluble fraction was further separated into individual NF subunits using hydroxyapatite HPLC. We observed no differences between control and ALS in the characteristics of NFH, including migration patterns on 2D-IEF, sensitivity to E. coli, alkaline phosphatase mediated dephosphorylation, peptide mapping, or proteolysis (calpain, calpain/calmodulin mediated, phosphorylated or dephosphorylated NFH). NFL showed no differences in 2D-IEF migration patterns, peptide mapping, or the extent of NFL nitrotyrosine immunoreactivity in either the Triton soluble or insoluble fractions. The latter observation demonstrated that NFL nitration is a ubiquitous occurrence in neurons and suggests that NFL might function as a sink for free reactive nitrating species. In contrast to the lack of differences in the post-translational processing of NF in ALS, we did observe a selective suppression of NFL steady state mRNA levels in the limb innervating lateral motor neuron column of ALS. This occurred in the absence of modifications in NFH, NFM or neuronal nitric oxide synthase (Type I NOS; nNOS) steady state mRNA levels. Coupled with previous observations of nNOS immunoreactivity co-localizing with NF aggregates in ALS motor neurons, this suggests activation of the nNOS enzyme complex in ALS, which would be predicted to contribute directly to the generation of reactive nitrating species. Given this, the isolated suppression of NFL steady state mRNA levels in ALS may indicate that ALS motor neurons are at an intrinsic deficit in the ability to buffer free reactive nitrating species.}, }
@article {pmid10540026, year = {1999}, author = {Silani, V and Ciammola, A and Pizzuti, A and Cardin, V and Scarlato, G}, title = {Motor neurone metabolism.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {161-169}, doi = {10.1016/s0022-510x(99)00240-3}, pmid = {10540026}, issn = {0022-510X}, mesh = {Animals ; Anterior Horn Cells/cytology/*metabolism ; Astrocytes/cytology/*metabolism ; Cells, Cultured ; Humans ; Motor Neuron Disease/metabolism ; Motor Neurons/cytology/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {The cell and molecular mechanisms which determine the motor neurone (MN) phenotype are unclear. Tissue culture models offer a unique system for the study of a wide variety of MN features. For instance, since the neurone-astrocyte metabolic interactions play a critical role in the selective MN loss observed in amyotrophic lateral sclerosis (ALS), the glutamatergic MN toxicity could be reanalyzed in vitro, after a careful evaluation of the role of astrocytes. Ca(2+) appears to be important in inducing MN loss from in vitro studies. It was shown primarily in culture that apoptotic or necrotic death of neurones after injury depends upon the cell energetic status. Also, SOD-1 mutations were successfully expressed in cultured MNs, providing a critical assay to sequence the molecular processes responsible for MN degeneration due to an identified genetic defect. Purified human developing MNs and astrocytes were recently obtained from the spinal cord anterior horn. The effects of molecules affecting MN survival, neurite extension, and metabolism can easily be tested in long-term cultures. Interactions at the single cell level can be studied today using a series of RNA amplification techniques. Understanding the properties of human MNs in vitro may represent a critical tool in defining regional metabolic changes that could constitute the first pathogenic event of cell degeneration in ALS.}, }
@article {pmid10540001, year = {1999}, author = {Miller, RG and Munsat, TL and Swash, M and Brooks, BR}, title = {Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {2-12}, doi = {10.1016/s0022-510x(99)00209-9}, pmid = {10540001}, issn = {0022-510X}, mesh = {*Amyotrophic Lateral Sclerosis ; Clinical Trials as Topic/*methods/statistics &amp; numerical data ; Humans ; Quality of Life ; }, abstract = {BACKGROUND: In 1994 consensus guidelines were developed for conducting clinical trials in ALS. With growing experience in clinical trials, it has become clear that a number of further guidelines were needed.<br><br>METHODS: Under the auspices of the World Federation of Neurology Committee on Research, a multinational group of neurologists, statisticians, patient advocates, representatives from the pharmaceutical industry as well as regulatory agencies developed consensus about a number of revisions to the existing guidelines during a 2 day conference in April 1998.<br><br>RESULTS: Expanded areas of focus include greater protection of patient rights, more detailed guidelines for outcome measures statistical analyses, disclosure of study results and improved interaction between investigators and the corporate sector.<br><br>COMMENT: Substantial progress has been made in standardizing and improving the quality of clinical trials in ALS through these consensus guidelines.}, }
@article {pmid10592440, year = {1999}, author = {Van den Berghe, G}, title = {Growth hormone secretagogues in critical illness.}, journal = {Hormone research}, volume = {51 Suppl 3}, number = {}, pages = {21-28}, doi = {10.1159/000053158}, pmid = {10592440}, issn = {0301-0163}, mesh = {Animals ; *Critical Illness ; *Growth Hormone-Releasing Hormone/pharmacology/therapeutic use ; Human Growth Hormone/*metabolism/*physiology ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/metabolism ; Oligopeptides/pharmacology/therapeutic use ; Pituitary Hormones, Anterior/metabolism ; }, abstract = {Alterations within the somatotropic axis occurring during the course of critical illness follow a biphasic pattern. The initial stress response consists of activated growth hormone (GH) release whereas circulating levels of GH-dependent insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 fall and IGFBP-1 concentrations rise. In contrast, in the chronic intensive care-dependent phase of severe illness, pulsatile GH secretion substantially decreases whereas the non-pulsatile fraction remains relatively elevated, resulting in an abnormally flat GH secretory pattern and low-normal mean nocturnal GH serum concentrations. Specifically the reduced amount of GH released in pulses is found to be related to low circulating levels of IGF-I, IGFBP-3 and acid-labile subunit (ALS), which suggests that a relative hyposomatotropism may participate in the pathogenesis of the wasting syndrome distinctively in the chronic phase of critical illness. The relative hyposomatotropism seems at least in part of hypothalamic origin since the whole somatotropic axis has been found to be very responsive to continuous infusion of GH releasing peptide (GHRP), administered alone or in combination with GH releasing hormone (GHRH), as evidenced by reactivated pulsatile GH secretion followed by substantial increases in circulating levels of IGF-I, IGFBP-3 and ALS. GHRH alone, however, is unable to exert the same effect, which may point to an underlying reduced availability of the endogenous ligand for the GHRP receptor. The presence of considerable responsiveness to restored endogenous pulsatile GH secretion using GHRPs not only further delineates the distinct pathophysiological paradigm of the chronic phase of critical illness, as opposed to the acute phase, which is thought to be primarily a condition of GH resistance, but may also have important therapeutic consequences. Recent data revealed that this novel strategy evokes metabolic improvement related to the balanced endocrine responses. Whether GH secretagogues also enhance clinical recovery of protracted critically ill patients remains to be elucidated.}, }
@article {pmid10590895, year = {1999}, author = {Bromberg, MB}, title = {Pathogenesis of amyotrophic lateral sclerosis: a critical review.}, journal = {Current opinion in neurology}, volume = {12}, number = {5}, pages = {581-588}, doi = {10.1097/00019052-199910000-00012}, pmid = {10590895}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/physiopathology ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/physiology ; Sex Characteristics ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease with unknown pathogenesis. It is a relatively common disorder of adults (2-4 per 100,000 incidence) and leads to death from respiratory failure. There is no cure at this time, and available treatment and management can at best extend survival to a modest degree. Increasing our understanding of the pathogenesis of this disease is essential to the development of more effective treatments. The level of research interest is very high, and yearly reviews of the literature are helpful in assessing progress.}, }
@article {pmid10589531, year = {1999}, author = {Shaw, PJ}, title = {Calcium, glutamate, and amyotrophic lateral sclerosis: more evidence but no certainties.}, journal = {Annals of neurology}, volume = {46}, number = {6}, pages = {803-805}, pmid = {10589531}, issn = {0364-5134}, mesh = {Calcium/*metabolism ; Excitatory Amino Acid Transporter 2 ; Glutamic Acid/*metabolism ; Humans ; Motor Neuron Disease/metabolism/*physiopathology ; Receptors, AMPA/physiology ; Receptors, Glutamate/metabolism ; Receptors, Neurotransmitter/metabolism ; }, }
@article {pmid10583431, year = {1999}, author = {Schapira, AH and Cock, HR}, title = {Mitochondrial myopathies and encephalomyopathies.}, journal = {European journal of clinical investigation}, volume = {29}, number = {10}, pages = {886-898}, doi = {10.1046/j.1365-2362.1999.00540.x}, pmid = {10583431}, issn = {0014-2972}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {DNA, Mitochondrial/*genetics ; Humans ; Mitochondrial Encephalomyopathies/*genetics/metabolism/*physiopathology ; Mitochondrial Myopathies/*genetics/metabolism/*physiopathology ; Oxidative Phosphorylation ; Point Mutation ; }, abstract = {Defects of mitochondrial metabolism result in a wide variety of human disorders, which can present at any time from infancy to late adulthood and involve virtually any tissue either alone or in combination. Abnormalities of the electron transport and oxidative phosphorylation (OXPHOS) system are probably the most common cause of mitochondrial diseases. Thirteen of the protein subunits of OXPHOS are encoded by mitochondrial DNA (mtDNA) and mutations of this genome are important causes of OXPHOS deficiency. The link between genotype and phenotype with respect to mtDNA mutations is not clear: the same mutation may result in a variety of phenotypes, and the same phenotype may be seen with a variety of different mtDNA mutations. The pathogenesis of mtDNA mutations is unclear although OXPHOS and ATP deficiency, and free radical generation, are thought to contribute to tissue dysfunction. There is now strong evidence for mitochondrial dysfunction in neurodegenerative disorders. In some cases, e.g. Friedreich's ataxia, hereditary spastic paraplegia, this is a result of a mutation of a nuclear gene encoding a mitochondrial protein, whilst in others, e.g. Huntington's disease, amyotrophic lateral sclerosis, the OXPHOS defect is secondary to events induced by a mutation in a nuclear gene encoding a non-mitochondrial protein. In yet a third group, e.g. Parkinson's disease, Alzheimer's disease, the relationship of the mitochondrial defect to aetiology and pathogenesis is unclear.}, }
@article {pmid10570736, year = {1999}, author = {Sivak, ED and Shefner, JM and Sexton, J}, title = {Neuromuscular disease and hypoventilation.}, journal = {Current opinion in pulmonary medicine}, volume = {5}, number = {6}, pages = {355-362}, doi = {10.1097/00063198-199911000-00006}, pmid = {10570736}, issn = {1070-5287}, mesh = {Acute Disease ; Chronic Disease ; Dyspnea/etiology ; Fatigue/etiology ; Humans ; Hypercapnia/etiology ; Hypoxia/etiology ; Muscle Weakness/etiology ; Neuromuscular Diseases/*complications ; Randomized Controlled Trials as Topic ; Respiration Disorders/etiology ; Respiration, Artificial ; Respiratory Insufficiency/etiology ; Respiratory Mechanics/physiology ; Respiratory Muscles/physiopathology ; Sleep Apnea, Central/*etiology/therapy ; Sleep Wake Disorders/etiology ; Tachycardia/etiology ; Vital Capacity/physiology ; }, abstract = {Alveolar hypoventilation associated with neuromuscular disease can occur in acute and chronic forms. In the acute form, progressive weakness of respiratory muscles leads to rapid reduction in vital capacity followed by respiratory failure with hypoxemia and hypercarbia. Symptoms are those of acute respiratory failure, including dyspnea, tachypnea, and tachycardia. In the chronic form, impairment of the respiratory muscles affects mechanical properties of the lungs and chest wall, decreases the ability to clear secretions, and eventually may alter the function of the central respiratory centers. Symptoms include orthopnea, fatigue, disturbed sleep, and hypersomnolence. Treatment and outcome of the disease's chronic form are dependent on the underlying clinical cause of the alveolar hypoventilation. For chronic but stable diseases such as old polio, quadriplegia, or kyposcoliosis, mechanical support of minute ventilation can reverse symptoms. For chronic and progressive disease such as muscular dystrophy and amyotrophic lateral sclerosis, mechanical support of minute ventilation provides only symptomatic relief and is usually associated with deterioration to the point of complete ventilator dependency for survival. For the chronic progressive forms of alveolar hypoventilation, there is currently a need for quality randomized controlled clinical trials to define physiologic indicators and appropriate timing for mechanical support of minute ventilation.}, }
@article {pmid10560642, year = {1999}, author = {Smithson, WH}, title = {Integrating the algorithm into community practice.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S63-6; discussion S67-71}, pmid = {10560642}, issn = {0028-3878}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis ; *Community Health Services ; Decision Making ; *Family Practice ; Humans ; *Primary Health Care ; }, abstract = {The success of integrating an algorithm of care for amyotrophic lateral sclerosis (ALS) into community practice depends on highlighting the benefits to patients and families and demonstrating those benefits to clinicians and service providers. The key issues in providing care for patients with ALS are the delay in establishing a diagnosis, variable access to necessary multidisciplinary services in health and social care, the need for further research to improve the prognosis, and increasing the level of information about ALS among professionals. Achieving an accurate diagnosis as soon as possible can enable focused services to be available earlier and can enable a management plan to be drawn up in anticipation of clinical deterioration. In view of the low incidence of the condition, it may be prudent to include ALS education as part of a broader neurologic educational initiative. Voluntary organizations, patients and their families, specialist liaison nurses, and pressure groups can all be powerful influences on the provision of health care and public/professional education. Adoption of the algorithm into community practice is likely to be a gradual process, involving a number of different approaches. The only general guidance is to carefully consider the key messages and their intended target audiences.}, }
@article {pmid10560641, year = {1999}, author = {Swash, M}, title = {An algorithm for ALS diagnosis and management.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S58-62}, pmid = {10560641}, issn = {0028-3878}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Decision Trees ; Humans ; }, abstract = {The diagnosis of ALS is often delayed, probably largely because the disease is relatively uncommon. A practical approach to diagnosis, with a simple algorithm for investigation, might improve diagnostic sensitivity in the early stages of the disease. It is clear that the first step in the diagnostic algorithm must be referral to a neurologist, which implies recognition by the primary care physician that the illness is neurologic in origin. It is the role of the neurologist to make the diagnosis, to confirm it beyond all reasonable doubt, to exclude other treatable conditions, and to inform the patient and the family of the diagnosis in a timely, honest, and compassionate way. Definition of different disease stages allows a model of the process of care to be formulated and indicates the time points at which intervention may be possible. There are two pathways to diagnosis of ALS, which overlap to a considerable extent. Diagnosis by positive criteria is limited by the absence of a specific diagnostic test, whereas diagnosis by exclusion of other disorders may introduce delay that can be tempered only by efficiency in the investigative pathway. The imperative necessity for diagnostic review is perhaps the most important aspect of the diagnosis of ALS, in view of the increasing recognition of the need for early diagnosis, and when an effective therapy becomes available, this process of review will become more important, albeit more difficult.}, }
@article {pmid10560640, year = {1999}, author = {Brooks, BR}, title = {Earlier is better: the benefits of early diagnosis.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S53-4; discussion S55-7}, pmid = {10560640}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Employment/*statistics &amp; numerical data ; Humans ; *Quality of Life ; }, abstract = {The concept of earlier diagnosis of amyotrophic lateral sclerosis (ALS) requires in-depth investigation of its benefits and consequences. First, how good must a treatment be before ALS is determined to be a treatable condition? Analogy with cancer therapy suggests that a good quality of life after treatment is an essential feature of a "good" therapy. Survival in some diseases may be prolonged without a significant improvement in the patient's quality of life. Neurologists need to be clear about what they are trying to achieve in prolonging survival and maintaining a good quality of life for their patients with ALS. Second, can early diagnosis extend apparent survival in the absence of a therapeutic intervention that significantly affects the disease process? Earlier diagnosis on the basis of confirmed clinical signs and earlier institution of therapy may lead to a perception of improved survival, which is greater in young ALS patients. Third, can early diagnosis provide a benefit through prolongation of the time the patient remains able to work? Any therapeutic intervention to slow the early stages of the disease would benefit patients who wanted to maintain their self-esteem by continuing to work. Finally, earlier diagnosis of ALS requires decisions to be made concerning the acceptable rate of misdiagnosis, which at present reaches 10% false-positive and up to 44% false-negative.}, }
@article {pmid10560639, year = {1999}, author = {Cashman, NR}, title = {Do the benefits of currently available treatments justify early diagnosis and announcement? Arguments for.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S50-2; discussion S55-7}, pmid = {10560639}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Humans ; Neuroprotective Agents/*administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {Both a biologic imperative and an ethical imperative exist for providing the diagnosis of amyotrophic lateral sclerosis (ALS) as soon as possible and involving patients and their families in therapeutic decisions. The participation of excitotoxic mechanisms in ALS and the availability of riluzole, which may slow the rate of progression of ALS, provide the biologic rationale for early therapy in ALS. A neuroprotective agent, such as riluzole, is more effective at an early stage of disease, when more undamaged neurons remain. The development of effective therapy for ALS also provides the ethical basis for early announcement of diagnosis. When no primary treatment was available, an accepted approach was one of "protecting" the patient from the diagnosis, which was one of exclusion, requiring almost 100% certainty before announcement. The availability of a primary therapy, albeit not a cure, means that a diagnosis of ALS can now be offered as the most likely diagnosis with 90-95% certainty. The logical corollary of this new model is that patients must be involved immediately, to help decide when therapy is appropriate and to balance the relative personal significance of therapeutic gains versus adverse effects.}, }
@article {pmid10560638, year = {1999}, author = {Ludolph, AC and Riepe, MW}, title = {Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic lateral sclerosis? Arguments against.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S46-9; discussion S55-7}, pmid = {10560638}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Animals ; Humans ; Neuroprotective Agents/*adverse effects ; Riluzole/*adverse effects ; }, abstract = {Recent in vitro and experimental animal studies strongly indicate that motor neuron diseases, like other neurodegenerative diseases, may be preceded by a long preclinical period. Clinical studies have suggested that the beneficial effects of neuroprotection in human amyotrophic lateral sclerosis (ALS) may be due to a preferential effect on early phases of the disease. However, the aim of this article is to review the potential arguments that there is no justification for early neuroprotective treatment of ALS. Controversies concerning the clinical neuroprotective effects of riluzole in mice and humans exist. Side effects of riluzole are emphasized and the data that appear to indicate that ALS has a long preclinical period are questioned. On the basis of these doubts and skepticisms, we conclude that it may be premature to treat ALS early without addressing the major objections in future studies in a controlled manner.}, }
@article {pmid10560637, year = {1999}, author = {Brooks, BR}, title = {What are the implications of early diagnosis? Maintaining optimal health as long as possible.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S43-5; discussion S55-7}, pmid = {10560637}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Disease Progression ; Humans ; Neuroprotective Agents/*administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {As yet, there is no staging system for amyotrophic lateral sclerosis (ALS). One early attempt to define disease stages consisted of post-hoc analysis of the international, placebo-controlled, clinical trials of riluzole. In this analysis, five health states were defined for ALS (mild, moderate, severe, terminal, death) to determine whether therapeutic intervention with riluzole could favorably influence the time spent in the different stages. The time spent in the mild and moderate disease states (taken together) was considerably longer in patients treated with riluzole than in those treated with placebo (317 days compared with 242 days). Riluzole did not influence the median time in the mild, severe, or terminal ALS stages but did slightly shorten the time in the moderate ALS stage compared with placebo. In all the ALS stages, the 75th percentile of time in that state appeared to be extended. Survival analysis indicated that the relative risk was less than 1.0 with riluzole treatment in the moderate, severe, and terminal health states but not in the mild health state, when it remained at 1.0. The time to failure was longer in patients in the moderate, severe, and terminal ALS stages but was significantly longer only in the moderate ALS stage. These findings indicate that future studies of therapeutic intervention should examine rigorously defined stages of disease to examine end points other than death. The development of a staging system, analogous to the ones used in oncology, has implications for the concept of early diagnosis.}, }
@article {pmid10560636, year = {1999}, author = {Silani, V and Borasio, GD}, title = {Honesty and hope: announcement of diagnosis in ALS.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S37-9; discussion S40-2}, pmid = {10560636}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Humans ; *Physician-Patient Relations ; *Truth Disclosure ; }, abstract = {Informing patients and their families about a diagnosis such as amyotrophic lateral sclerosis (ALS) is a daunting task for any physician. The way the diagnosis is communicated will have a major impact on the physician-patient relationship and the attitude of the patient toward the disease and toward symptomatic treatment measures. Breaking the news can be truly defined as the starting point of palliative care in ALS. It is an ongoing information process which, by its nature, escapes narrow definitions or standardization attempts. Nevertheless, a number of techniques exist to facilitate the process and ease the burden for physicians, patients, and families. We believe that the terminal phase should be discussed at the latest when first respiratory symptoms appear, to prevent unwarranted fears of "choking to death."}, }
@article {pmid10560635, year = {1999}, author = {Strong, MJ}, title = {Simplifying the approach: what can we do?.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S31-4; discussion S35-6}, pmid = {10560635}, issn = {0028-3878}, mesh = {Adult ; Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; Decision Making ; Electromyography ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; }, abstract = {Although it is desirable to simplify the diagnosis of amyotrophic lateral sclerosis (ALS), it is not obvious how to achieve this. Although a simplified electrophysiologic approach can be easily performed, interpretation of the results in a complex differential diagnosis is far from simple. Genetic screening may potentially be useful but is still in its infancy, even in familial ALS. Spasticity scales are most informative when greater degrees of spasticity are present, but usually these cases can also be identified clinically. It is difficult to envisage simplifying the scales because bedside rating scales are inherently not good at the mild end of the spectrum. Although MRI may prove to be useful in simplifying the diagnostic procedure, at present the numbers of patients studied are too small and the findings not sufficiently specific. Among the major issues that must be decided are whether any of the newer diagnostic techniques are sufficiently reliable, sensitive, and specific to allow any further simplification, and whether paraclinical tests are acceptable surrogates for clinical phenomena. The diagnostic approach of moving a possible diagnosis of ALS into the category of probable ALS earlier by giving more weight to electrophysiologic findings appears to be the only option, together with a more rigorous approach to excluding disorders known to mimic ALS. The problem lies less in the specialist reaching a correct diagnosis than at the level of initial evaluation, where the suspicion of ALS may be raised in only 27-40% of cases.}, }
@article {pmid10560634, year = {1999}, author = {Belsh, JM}, title = {Diagnostic challenges in ALS.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S26-30; discussion S35-6}, pmid = {10560634}, issn = {0028-3878}, mesh = {Adult ; Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis ; Bulbar Palsy, Progressive/*diagnosis ; Diagnosis, Differential ; Humans ; Muscular Atrophy, Spinal/*diagnosis ; }, abstract = {Although the essential requirements for diagnosis of amyotrophic lateral sclerosis (ALS) are clearly defined by the El Escorial criteria, many physicians, including neurologists, still miss the diagnosis. Physician misdiagnosis of ALS relates to lack of knowledge about ALS and skill and to diagnostic difficulty. The differential diagnosis must exclude nonmotor neuron diseases and other adult-onset motor neuron diseases with restricted presentations, e.g., progressive bulbar palsy (pure bulbar), progressive muscular atrophy (pure lower motor neuron) and primary lateral sclerosis (pure upper motor neuron), ALS-like syndromes and ALS variants, and adult-onset spinal muscular atrophies. Although the diagnosis of ALS remains a clinical one, laboratory testing can be used to exclude other diseases and to confirm the diagnosis. Such tests include EMG and nerve conduction studies, MRI and CT of the spine and brain, identification of biochemical markers in blood and CSF, and muscle or nerve biopsy. Genetic testing can identify gene defects in some types of familial ALS and in certain other inherited motor neuron diseases that mimic ALS. At present there is no widely accepted protocol for laboratory testing in cases of suspected ALS, but it is hoped that laboratory tests will improve in the future to facilitate earlier confirmation of a diagnosis of ALS. However, correct and early diagnosis of ALS can only be achieved when the first, second, or third physician who sees the patient knows about ALS and includes it in a differential diagnosis.}, }
@article {pmid10560633, year = {1999}, author = {Hillel, A and Dray, T and Miller, R and Yorkston, K and Konikow, N and Strande, E and Browne, J}, title = {Presentation of ALS to the otolaryngologist/head and neck surgeon: getting to the neurologist.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S22-5; discussion S35-6}, pmid = {10560633}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*surgery ; Female ; Gastrostomy ; Humans ; Laryngectomy ; Middle Aged ; *Neurology ; *Otolaryngology ; *Referral and Consultation ; }, abstract = {Patients with early symptoms of bulbar amyotrophic lateral sclerosis (ALS) are usually referred to the otolaryngologist without a diagnosis. Careful examination of the speech quality and a physical exam, including the vocal cords, should be undertaken. The emotional state of the patient should be considered, and a diagnosis should not be offered before a neurologic consultation has been obtained. Patients with late symptoms of bulbar ALS almost always present with both significant speech and swallowing abnormalities. Evaluation can be difficult because many abnormalities are found on examination. Advanced progression of symptoms is a clear indication for rapid referral to a neurologist if a diagnosis has not already been made. Supportive and symptomatic care should be offered to the patient immediately. The University of Washington Neuromuscular Clinic for Speech and Swallowing Disorders has seen 600 new neurologic patients since 1986, 211 of whom were ALS patients. The introduction of percutaneous gastrostomy has greatly changed the management of ALS patients, and 75 patients have undergone this procedure (32% because of inadequate swallowing, 68% for declining vital capacity). Medical management to improve symptoms may be indicated before surgery. Surgical options for patients with late salivary presentation are uncommon and include removal of the submaxillary glands, tracheostomy, and laryngeal or salivary diversion procedures. Laryngectomy or laryngeal diversion procedures are only very rarely indicated. Although tracheostomy usually interferes with swallowing and worsens aspiration, it may rarely be indicated in patients with late airway presentation for glottic narrowing or artificial respiratory support. Symptomatic management of patients with bulbar ALS is usually best undertaken by a multidisciplinary clinic that can provide a physically and psychologically supportive environment.}, }
@article {pmid10560632, year = {1999}, author = {Gelinas, D}, title = {Conceptual approach to diagnostic delay in ALS: a United States perspective.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S17-9; discussion S20-1}, pmid = {10560632}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; *Critical Pathways ; Humans ; Neurology ; Primary Health Care ; *Referral and Consultation ; Time Factors ; United States ; }, abstract = {The mean time from onset of symptoms to confirmation of diagnosis of amyotrophic lateral sclerosis (ALS) in the United States, as elsewhere, is 16-18 months. Delays may arise from the complex referral pathway, caused at least in part by the multiple types of insurance and health-care services available in the United States and also because physicians sometimes attempt to avoid medicolegal responsibility for a very undesirable diagnosis. In addition, initial symptoms are often intermittent and nonspecific and may be denied or not recognized by the patient. In the United States, the primary care physician is increasingly viewed by health maintenance organizations as a gatekeeper, with incentives to keep the diagnosis within the primary care realm. This may lead to misdiagnosis and inappropriate referral. Even after the patient reaches a neurologist, the differential diagnosis of ALS is large and may involve many tests, all of which may incur scheduling and reporting delays. Reluctance to give a bad diagnosis before it is absolutely certain may also cause delay. Delays after diagnosis may be the result of health insurance constraints, the prejudices of the neurologist in favor of or against particular therapies, and the patient's willingness to accept or ability to pay for therapy. Many of these delays may be lessened by both professional and lay educational initiatives to raise awareness of the symptoms of ALS and encourage more rapid presentation and referral to the neurologist. The availability of credible treatment options would undoubtedly encourage physicians to have hope and to seek an earlier diagnosis.}, }
@article {pmid10560629, year = {1999}, author = {Brooks, BR}, title = {Defining optimal management in ALS: from first symptoms to announcement.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S1-3; discussion S20-1}, pmid = {10560629}, issn = {0028-3878}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; *Critical Pathways ; Decision Trees ; Humans ; }, abstract = {The advances in treatment for amyotrophic lateral sclerosis (ALS) have demonstrated the need to diagnose this disease precisely and directly. Two international initiatives, at El Escorial in 1990 and at Airlie House in 1998, have grappled with the clinical and laboratory elements that may accelerate the diagnostic process. Shortly after the Airlie House meeting in 1998, an international group of clinical neurologists met to discuss optimal management strategies in ALS. The goals were to examine current diagnosis and treatment pathways and to attempt to devise an algorithm that would foster early diagnosis, thus enhancing the possibility of optimal treatment.}, }
@article {pmid10555188, year = {1999}, author = {Kobayashi, M and Ikeda, K and Kinoshita, M and Iwasaki, Y}, title = {Amyotrophic lateral sclerosis with supranuclear ophthalmoplegia and rigidity.}, journal = {Neurological research}, volume = {21}, number = {7}, pages = {661-664}, doi = {10.1080/01616412.1999.11740994}, pmid = {10555188}, issn = {0161-6412}, mesh = {Autopsy ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*complications/pathology ; Muscle Rigidity/*complications/pathology ; Neck Muscles ; Supranuclear Palsy, Progressive/*complications/pathology ; }, abstract = {Ophthalmoplegia is rarely reported in patients with amyotrophic lateral sclerosis (ALS). We describe a patient with sporadic ALS, who had developed progressive external ophthalmoplegia of supranuclear origin and rigidity in the neck. Autopsy findings showed histopathological abnormalities consistent with ALS. In addition to these findings, there was neuronal loss and gliosis in the putamina and globi pallidi, and gliosis in the periaqueductal gray matter. Our case appears to raise the possibility that ALS comprises a heterogenous group of disorders.}, }
@article {pmid10551448, year = {1999}, author = {Green, SL and Tolwani, RJ}, title = {Animal models for motor neuron disease.}, journal = {Laboratory animal science}, volume = {49}, number = {5}, pages = {480-487}, pmid = {10551448}, issn = {0023-6764}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; *Disease Models, Animal ; Dogs ; Genetic Engineering ; Horses ; Humans ; Mice ; *Motor Neuron Disease/genetics/pathology ; }, abstract = {Motor neuron disease is a general term applied to a broad class of neurodegenerative diseases that are characterized by fatally progressive muscular weakness, atrophy, and paralysis attributable to loss of motor neurons. At present, there is no cure for most motor neuron diseases, including amyotrophic lateral sclerosis (ALS), the most common human motor neuron disease--the cause of which remains largely unknown. Animal models of motor neuron disease (MND) have significantly contributed to the remarkable recent progress in understanding the cause, genetic factors, and pathologic mechanisms proposed for this class of human neurodegenerative disorders. Largely driven by ALS research, animal models of MND have proven their usefulness in elucidating potential causes and specific pathogenic mechanisms, and have helped to advance promising new treatments from "benchside to bedside." This review summarizes important features of selected established animal models of MND: genetically engineered mice and inherited or spontaneously occurring MND in the murine, canine, and equine species.}, }
@article {pmid10545780, year = {1999}, author = {Wiederholt, WC}, title = {Neuroepidemiologic research initiatives on Guam: past and present.}, journal = {Neuroepidemiology}, volume = {18}, number = {6}, pages = {279-291}, doi = {10.1159/000026223}, pmid = {10545780}, issn = {0251-5350}, support = {AG14382/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Dementia/epidemiology/etiology/genetics/history ; Guam/epidemiology ; History, 20th Century ; Humans ; Neurodegenerative Diseases/*epidemiology/genetics/*history ; Parkinson Disease/complications/epidemiology/genetics/history ; }, abstract = {Since the middle of this century, a remarkable concentration of cases of neurodegenerative disease(s), referred to as amyotrophic lateral sclerosis and Parkinson-dementia complex (ALS/PDC), has been recognized among Chamorro natives of Guam. Intense investigations over the last 4 decades have failed to determine the etiology of these invariably fatal diseases. Over the same time period, the incidence of ALS has decreased dramatically, the incidence of PDC has decreased, but to a lesser degree, and age at onset has shifted to a later age by about 1 decade. Almost 50% of demented patients present without the classical Parkinsonian features of PDC, and the morphological picture has changed. Results of past and present research initiatives are reviewed.}, }
@article {pmid10542672, year = {1998}, author = {Forshew, DA}, title = {Therapeutic advances: new hope for patients with ALS.}, journal = {Nursing spectrum (D.C./Baltimore metro ed.)}, volume = {8}, number = {25}, pages = {12-14}, pmid = {10542672}, issn = {1098-9153}, mesh = {Acetates/therapeutic use ; Aged ; *Amines ; Amyotrophic Lateral Sclerosis/*diagnosis/etiology/*therapy ; *Cyclohexanecarboxylic Acids ; GABA Agonists/therapeutic use ; Gabapentin ; Humans ; Long-Term Care ; Neuroprotective Agents/therapeutic use ; Patient Education as Topic ; Riluzole/therapeutic use ; *gamma-Aminobutyric Acid ; }, }
@article {pmid10529787, year = {1999}, author = {Schwartz, M and Yoles, E and Levin, LA}, title = {'Axogenic' and 'somagenic' neurodegenerative diseases: definitions and therapeutic implications.}, journal = {Molecular medicine today}, volume = {5}, number = {11}, pages = {470-473}, doi = {10.1016/s1357-4310(99)01592-0}, pmid = {10529787}, issn = {1357-4310}, mesh = {Axonal Transport ; Axons/pathology ; Cell Death ; Humans ; Ischemia/pathology ; *Models, Neurological ; Nerve Degeneration/classification/*pathology ; Neurodegenerative Diseases/*classification/drug therapy/pathology/prevention &amp; control ; Neurons/pathology ; Neuroprotective Agents/therapeutic use ; Neurotoxins/adverse effects ; Signal Transduction ; }, abstract = {Neurodegenerative diseases are characterized by a relentless loss of specific groups of neuronal subtypes. Many of these diseases share similar molecular mechanisms and extracellular mediators of neuronal loss. We now suggest that neurodegeneration originating in the neuronal cell bodies (e.g. in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) should be distinguished from that originating in the axons (e.g. in glaucoma, certain peripheral neuropathies and spinal stenosis). We propose that the former group of diseases be defined as 'somagenic' and the latter as 'axogenic'. Although axogenic disorders may share common symptoms and mediators of toxicity with somagenic disorders, they have distinct temporal, subcellular and signal-transduction features. We further suggest that, by adopting this classification of disorders based on pathophysiological processes, we will come to recognize additional diseases (in particular, those defined as axogenic) as being neurodegenerative and therefore possibly amenable to neuroprotective therapy.}, }
@article {pmid10529749, year = {1999}, author = {Comi, G and Rovaris, M and Leocani, L}, title = {Review neuroimaging in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {6}, number = {6}, pages = {629-637}, doi = {10.1046/j.1468-1331.1999.660629.x}, pmid = {10529749}, issn = {1351-5101}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Central Nervous System/pathology ; Humans ; Magnetic Resonance Imaging ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic degenerative disorder of unknown etiology affecting the motor system. Conventional and non-conventional neuroimaging techniques can provide essential help both to increase the confidence in ALS diagnosis and to assess the disease evolution. Signal abnormalities at the level of the motor cortex and the corticospinal tract on conventional T2-weighted magnetic resonance (MR) images are a potentially useful marker of ALS pathology. However, the prognostic value of these conventional MR abnormalities is still hampered by their low pathological specificity. Non-conventional MR techniques with a higher pathological specificity, such as MR spectroscopy, magnetization transfer imaging and diffusion-weighted imaging, seem to have some potential not only for ALS diagnosis, but also for monitoring disease evolution either naturally or when modified by experimental treatments.}, }
@article {pmid10527800, year = {1999}, author = {Elliott, JL}, title = {Experimental models of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {6}, number = {5}, pages = {310-320}, doi = {10.1006/nbdi.1999.0266}, pmid = {10527800}, issn = {0969-9961}, support = {NS01853/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Motor Neuron Disease/pathology/*physiopathology ; Motor Neurons/pathology/physiology ; Nerve Growth Factors/physiology ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by the progressive loss of motor neurons, leading to profound weakness and eventual death of affected individuals. For the vast majority of patients with ALS, the etiology of the disorder is unknown, and although multiple clinical trials of various therapeutic agents have been undertaken, truly effective therapy is not currently available for the disease. The selection of treatments used in ALS clinical trials frequently has its basis in promising data obtained from experimental model systems in which the proposed agent has shown some effect in protecting motor neurons from a particular insult. The likelihood of a successful clinical outcome for a given treatment in ALS would therefore depend on two principal factors, including the similarity of the model to the disease and the biologic action of the potential therapeutic agent. Partly because early experimental models of ALS failed to replicate the disease process, treatment success in these models did not carry over into human trials. Recently, however, a variety of newer model systems have been developed and utilized to investigate motor neuron degeneration as related to ALS. For example, in this issue, Corse et al. use a rat spinal cord organotypic slice subjected to glutamate excitotoxicity as a model system to test the effectiveness of neurotrophic factors in preventing motor neuron degeneration. This review will assess the strengths and weaknesses of differing ALS model systems that have been used to preclinically test potential drug efficacy in ALS.}, }
@article {pmid10525999, year = {1999}, author = {Oyanagi, K and Wada, M}, title = {Neuropathology of parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam: an update.}, journal = {Journal of neurology}, volume = {246 Suppl 2}, number = {}, pages = {II19-27}, pmid = {10525999}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Brain/pathology ; Dementia/*pathology ; Guam ; Humans ; Parkinsonian Disorders/*pathology ; Spinal Cord/pathology ; }, abstract = {A comparative study was performed to investigate the differences and similarities of the neuropathological findings in the parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) of Guam, progressive supranuclear palsy and classic ALS. Based on the findings, it is proposed that (a) PDC is a discrete disease entity, (b) NFTs in Chamorro ALS are merely a background feature widely distributed in this population, (c) Chamorro ALS is a disease combined with classic ALS and neurofibrillary degeneration, (d) thus a subtype of "Guam ALS" is not present, and (e) PDC and ALS of Guam are different diseases.}, }
@article {pmid10525998, year = {1999}, author = {Murakami, N}, title = {Parkinsonism-dementia complex on Guam - overview of clinical aspects.}, journal = {Journal of neurology}, volume = {246 Suppl 2}, number = {}, pages = {II16-8}, pmid = {10525998}, issn = {0340-5354}, mesh = {Age of Onset ; Dementia/*physiopathology ; Female ; Guam ; Humans ; Male ; Middle Aged ; Parkinsonian Disorders/*physiopathology ; }, abstract = {Parkinsonism-dementia complex (PDC) is the second most common neurodegenerative disorder in Guam, after amyotrophic lateral sclerosis (ALS). PDC was first described by Hirano 1961. A familial appearance is seen among some PDC cases, which may also include ALS, and vice versa, but subsequent research including pedigree analysis, prospective case control registries, and the search for specific gene markers has failed to yield a satisfactory genetic explanation. Important diagnostic indicators of the illness include rigido-akinetic type Parkinsonism and severe dementia.In PDC, rigidity is so marked that postural deformities such as a generally flexed posture become rather prominent. Gait disturbances are a common initial symptom. Hyperreflexia and spinal muscular atrophy, developing mainly in the distal extremities, are frequently observed. These mixed-syndrome patients can be seen as clear support for the view that Guam ALS and PDC constitute a single mixed disease entity with a spectrum of clinical expression. The present paper offers an overview and description of the clinical features of PDC.}, }
@article {pmid10525172, year = {1999}, author = {Torreilles, F and Salman-Tabcheh, S and Guérin, M and Torreilles, J}, title = {Neurodegenerative disorders: the role of peroxynitrite.}, journal = {Brain research. Brain research reviews}, volume = {30}, number = {2}, pages = {153-163}, doi = {10.1016/s0165-0173(99)00014-4}, pmid = {10525172}, mesh = {Alzheimer Disease/physiopathology ; Animals ; Central Nervous System/*physiopathology ; Humans ; Inflammation ; Motor Neuron Disease/physiopathology ; Multiple Sclerosis/physiopathology ; Neurodegenerative Diseases/pathology/*physiopathology ; Neurons/pathology/physiology ; Nitrates/*physiology ; Oxidants ; Parkinson Disease/physiopathology ; }, abstract = {Inflammatory reaction is thought to be an important contributor to neuronal damage in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and the parkinsonism dementia complex of Guam. Among the toxic agents released in brain tissues by activated cells, we focus attention in this review on peroxynitrite, the product of the reaction between nitric oxide (NO) and superoxide. Peroxynitrite is a strong oxidizing and nitrating agent which can react with all classes of biomolecules. In the CNS it can be generated by microglial cells activated by pro-inflammatory cytokines or beta-amyloid peptide (beta-A) and by neurons in three different situations: hyperactivity of glutamate neurotransmission, mitochondrial dysfunction and depletion of L-arginine or tetrahydrobiopterin. The first two situations correspond to cellular responses to an initial neuronal injury and the peroxynitrite formed only exacerbates the inflammatory process, whereas in the third situation the peroxynitrite generated directly contributes to the initiation of the neurodegenerative process.}, }
@article {pmid10516713, year = {1999}, author = {Wyman, T and Rohrer, D and Kirigiti, P and Nichols, H and Pilcher, K and Nilaver, G and Machida, C}, title = {Promoter-activated expression of nerve growth factor for treatment of neurodegenerative diseases.}, journal = {Gene therapy}, volume = {6}, number = {10}, pages = {1648-1660}, doi = {10.1038/sj.gt.3300989}, pmid = {10516713}, issn = {0969-7128}, support = {DK53462/DK/NIDDK NIH HHS/United States ; HL42358/HL/NHLBI NIH HHS/United States ; RR00163/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism ; Brain Tissue Transplantation ; Carcinoembryonic Antigen/genetics ; Cell Line ; Endothelial Growth Factors/genetics ; Fetal Tissue Transplantation ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Humans ; Lac Operon ; Lymphokines/genetics ; Metallothionein/genetics ; Nerve Growth Factor/*genetics ; Neurodegenerative Diseases/metabolism/*therapy ; *Promoter Regions, Genetic ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {Genetic transfer approaches have received recent consideration as potential treatment modalities for human central and peripheral nervous system (CNS and PNS, respectively) neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Transplantation of genetically modified cells into the brain represents a promising strategy for the delivery and expression of specific neurotrophic factors, neurotransmitter-synthesizing enzymes, and cellular regulatory proteins for intervention in neurodegenerative diseases. The use of specific regulatable promoters may also provide potential control of gene expression required for dose-specific or time-specific therapeutic strategies. In this article, we review the potential use of activated promoters in ex vivo systems for the potential genetic therapy of neurodegenerative disorders, and then describe our own studies using the zinc-inducible metallothionein promoter for the regulated expression of nerve growth factor (NGF) in rodent brain transplants.}, }
@article {pmid10512489, year = {1999}, author = {Sims, KD and Robinson, MB}, title = {Expression patterns and regulation of glutamate transporters in the developing and adult nervous system.}, journal = {Critical reviews in neurobiology}, volume = {13}, number = {2}, pages = {169-197}, doi = {10.1615/critrevneurobiol.v13.i2.30}, pmid = {10512489}, issn = {0892-0915}, support = {MH11977/MH/NIMH NIH HHS/United States ; NS29828/NS/NINDS NIH HHS/United States ; NS36465/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Aspartic Acid/*metabolism/physiology ; Biological Transport/physiology ; Central Nervous System/*growth &amp; development/*physiology ; *Gene Expression ; Glutamic Acid/*metabolism/physiology ; Humans ; }, abstract = {Glutamate and aspartate are the primary excitatory neurotransmitters in the mammalian central nervous system and have also been implicated as mediators of excitotoxic neuronal injury and death. The precise control of extracellular glutamate and aspartate is crucial to the maintenance of normal synaptic transmission and the prevention of excitotoxicity following acute insults to the brain, such as stroke or head trauma, or during the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis. The removal of excitatory amino acids (EAAs) from the extracellular space is primarily mediated by a family of sodium-dependent glutamate transporters. These transporters use the sodium electrochemical gradients of the cell to actively concentrate EAAs in both neurons and glia. Five members of this transporter family have been cloned recently and include both 'glial'-specific and 'neuron'-specific subtypes. Although these subtypes share many common functional properties, there are considerable differences in developmental expression, chronic and acute regulation by cellular signaling pathways, and contribution to disease processes among the subtypes. In this review recent studies of glutamate transporter expression, regulation, function, and pathological relevance are summarized, and some of the discrepancies and unexpected results common to any rapidly progressing field are discussed.}, }
@article {pmid10508735, year = {1999}, author = {Julien, JP}, title = {Neurofilament functions in health and disease.}, journal = {Current opinion in neurobiology}, volume = {9}, number = {5}, pages = {554-560}, doi = {10.1016/S0959-4388(99)00004-5}, pmid = {10508735}, issn = {0959-4388}, mesh = {Animals ; Gene Targeting ; Health ; Neurodegenerative Diseases/*physiopathology ; Neurofilament Proteins/*physiology ; }, abstract = {Transgenic approaches have recently been used to investigate the functions of neuronal intermediate filaments. Gene knockout studies have demonstrated that neurofilaments are not required for axogenesis and that individual neurofilament proteins play distinct roles in filament assembly and in the radial growth of axons. The involvement of neurofilaments in disease is supported by the discovery of novel mutations in the neurofilament heavy gene from cases of amyotrophic lateral sclerosis and by reports of neuronal death in mouse models expressing neurofilament and alpha-internexin transgenes. However, mouse studies have shown that axonal neurofilaments are not required for pathogenesis caused by mutations in superoxide dismutase and that increasing perikaryal levels of neurofilament proteins may even confer protection in this disease.}, }
@article {pmid10494326, year = {1999}, author = {Vermeulen, M and de Haan, RJ}, title = {[New therapies in neurology, but who benefits?].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {143}, number = {35}, pages = {1764-1766}, pmid = {10494326}, issn = {0028-2162}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Antiviral Agents/therapeutic use ; Carbamates/therapeutic use ; Humans ; Interferon-beta/therapeutic use ; Migraine Disorders/drug therapy ; Multiple Sclerosis/drug therapy ; Nervous System Diseases/*drug therapy ; Netherlands ; Neuroprotective Agents/therapeutic use ; Outcome Assessment, Health Care/*methods ; *Phenylcarbamates ; Riluzole/therapeutic use ; Rivastigmine ; Sumatriptan/therapeutic use ; Vasoconstrictor Agents/therapeutic use ; }, abstract = {In recent years several new treatments have been introduced in neurology, sumatriptan in migraine, riluzole in amyotrophic lateral sclerosis, interferon-beta in multiple sclerosis and rivastigmine in Alzheimer's disease. Doubts exist on the effects on functional outcome of these new treatments. Hardly effective drugs are not forced on physicians by the pharmaceutical industry, since physicians are involved in decisions from phase I studies to the final approval of the drugs. The problem is, however, that in clinical studies emphasis is still on statistically significant differences rather than on meaningful differences in the functional status of patients. In conclusion, in clinical studies outcome measures should be chosen more carefully and there is a need for sensitive linear functional scales.}, }
@article {pmid10480639, year = {1999}, author = {Waggie, KS and Kahle, PJ and Tolwani, RJ}, title = {Neurons and mechanisms of neuronal death in neurodegenerative diseases: a brief review.}, journal = {Laboratory animal science}, volume = {49}, number = {4}, pages = {358-362}, pmid = {10480639}, issn = {0023-6764}, mesh = {Animals ; *Apoptosis ; Disease Models, Animal ; Humans ; Mutation ; Neurodegenerative Diseases/genetics/*pathology/therapy ; Neurons/*pathology ; }, abstract = {BACKGROUND AND PURPOSE: Degenerative diseases of the central nervous system are a heterogenous group of slowly progressive disorders. A common feature of this group, which includes Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, is gradual loss of specific populations of neurons.<br><br>METHODS: A series of reports about neurodegenerative diseases and their relevant animal models, as well as a brief overview of the normal neuron and mechanisms of neuronal degeneration and death, is presented.<br><br>CONCLUSION: Study of the aforementioned animal models, spontaneously occurring and experimentally induced, have provided important insights into the pathogenesis of these disorders and the development of effective therapeutic strategies.}, }
@article {pmid10465680, year = {1999}, author = {Parsons, CG and Danysz, W and Quack, G}, title = {Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data.}, journal = {Neuropharmacology}, volume = {38}, number = {6}, pages = {735-767}, doi = {10.1016/s0028-3908(99)00019-2}, pmid = {10465680}, issn = {0028-3908}, mesh = {Animals ; Brain/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Excitatory Amino Acid Antagonists/*adverse effects/pharmacokinetics ; Humans ; Learning/drug effects ; Memantine/*adverse effects/pharmacokinetics ; Neuroprotective Agents/adverse effects/pharmacokinetics ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors ; }, abstract = {N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson's disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine's moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine.}, }
@article {pmid10463350, year = {1999}, author = {Bouche, P and Le Forestier, N and Maisonobe, T and Fournier, E and Willer, JC}, title = {Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy.}, journal = {Journal of neurology}, volume = {246}, number = {7}, pages = {520-525}, doi = {10.1007/s004150050397}, pmid = {10463350}, issn = {0340-5354}, mesh = {Diagnosis, Differential ; Disease Progression ; Electromyography ; Humans ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/*physiology ; Neural Conduction ; Peripheral Nervous System Diseases/diagnosis/physiopathology ; Severity of Illness Index ; }, abstract = {Motor neuron disease (MND) is a group of disorders in which there is degeneration of upper and lower motor neurons to a variable degree. Amyotrophic lateral sclerosis is the most frequent form of the disease, presenting with both upper and lower motor neuron involvement. Frequently, especially in the early stages of the disease, only lower motor neuron signs are present. In these conditions, some pure motor neuropathies may resemble MND. The diagnosis is of importance because some of these motor neuropathies are "dysimmune" disorders and may respond to immune therapies. In such diseases the multifocal motor neuropathy with conduction block appears to be the more frequent. In MND and pure motor neuropathies, the electrophysiological examination is the most decisive test. In MND, it is of diagnostic importance. In addition, it is useful in the assessment of disease severity and progression, in the evaluation of therapeutic trials and in the understanding of etiopathogenesis of the disease. In pure motor neuropathies, the presence of conduction block leads to immune treatment with good response in more than 50% of the cases.}, }
@article {pmid10463257, year = {1999}, author = {Iwanowski, L}, title = {[Amyotrophic lateral sclerosis].}, journal = {Neurologia i neurochirurgia polska}, volume = {33}, number = {2}, pages = {445-450}, pmid = {10463257}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Bromocriptine/*therapeutic use ; Dopamine Agonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Retrospective Studies ; Riluzole/*therapeutic use ; }, abstract = {The literature on amyotrophic lateral sclerosis from the years 1995/96 is reviewed including the topics of the World Congress of Neurology in Buenos Aires in September 1997. The problems of a) changed criteria of diagnosis and course of SLA after the time of the first definitions by classical neurological authors, b) the concepts concerning the aetiology and mechanisms of the disease, c) the present studies on drugs and their tentative clinical applications are discussed.}, }
@article {pmid10461542, year = {1999}, author = {Kisby, GE and Kabel, H and Hugon, J and Spencer, P}, title = {Damage and repair of nerve cell DNA in toxic stress.}, journal = {Drug metabolism reviews}, volume = {31}, number = {3}, pages = {589-618}, doi = {10.1081/dmr-100101937}, pmid = {10461542}, issn = {0360-2532}, support = {NS19611/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Carcinogens/toxicity ; Cycadopsida/toxicity ; DNA Damage/*drug effects ; DNA Repair/*drug effects/physiology ; Gene Expression/drug effects ; Humans ; Methylazoxymethanol Acetate/analogs &amp; derivatives/toxicity ; Neurodegenerative Diseases/chemically induced/*genetics ; Stress, Physiological/genetics ; }, abstract = {It is generally agreed that ALS/PDC is triggered by a disappearing environmental factor peculiar to the lifestyle of people of the western Pacific (i.e., Guam, Irian Jaya, Indonesia, and the Kii Peninsula of Japan). A strong candidate is the cycad plant genotoxin cycasin, the beta-D-glucoside of methylazoxymethanol (MAM). We propose that prenatal or postnatal exposure to low levels of cycasin/MAM may damage neuronal DNA, compromise DNA repair, perturb neuronal gene expression, and irreversibly alter cell function to precipitate a slowly evolving disease ("slow-toxin" hypothesis). In support of our hypothesis, we have demonstrated the following: 1. DNA from postmitotic rodent central nervous system neurons is particularly sensitive to damage by MAM. 2. MAM reduces DNA repair in human and rodent neurons, whereas DNA-repair inhibitors potentiate MAM-induced DNA damage and toxicity in mature rodent nervous tissue. 3. Human neurons (SY5Y neuroblastoma) that are deficient in DNA repair are susceptible to MAM-induced cytotoxicity and DNA damage, whereas overexpression of DNA repair in similar cells is protective. 4. MAM alters gene expression in SY5Y human neuroblastoma cells and, in the presence of DNA damage and reduced DNA repair, enhances glutamate-modulated expression of tau mRNA in rat primary neurons; the corresponding protein (TAU) is elevated in ALS/PDC and Alzheimer's disease. These findings support a direct relationship between MAM-induced DNA damage and neurotoxicity and suggest the genotoxin may operate in a similar manner in vivo. More broadly, a combination of genotoxin-induced DNA damage (via exogenous and/or endogenous agents) and disturbed DNA repair may be important contributing factors in the slow and progressive degeneration of neurons that is characteristic of sporadic neurodegenerative disease. Preliminary studies demonstrate that DNA repair is reduced in the brain of subjects with western Pacific ALS/PDC, ALS, and Alzheimer's disease, which would increase the susceptibility of brain tissue to DNA damage by endogenous/exogenous genotoxins. Interindividual differences in the extent of prior exposure to DNA-damaging agents and/or the efficiency of its repair might produce population variety in the rate of damage accumulation and explain the susceptibility of certain individuals to sporadic neurodegenerative disease. Studies are underway using DNA-repair proficient and deficient neuronal cell cultures and mutant mice to explore gene-environment interplay with respect to MAM treatment, DNA damage, and DNA repair, and the age-related appearance of neurobehavioral and neuropathological compromise.}, }
@article {pmid10453774, year = {1999}, author = {Francis, K and Bach, JR and DeLisa, JA}, title = {Evaluation and rehabilitation of patients with adult motor neuron disease.}, journal = {Archives of physical medicine and rehabilitation}, volume = {80}, number = {8}, pages = {951-963}, doi = {10.1016/s0003-9993(99)90089-8}, pmid = {10453774}, issn = {0003-9993}, mesh = {Activities of Daily Living ; Adult ; Amyotrophic Lateral Sclerosis/classification/diagnosis/epidemiology/etiology/psychology/rehabilitation ; Communication ; Death ; Female ; Humans ; Male ; Motor Neuron Disease/classification/*diagnosis/epidemiology/etiology/psychology/*rehabilitation ; Psychology, Social ; }, abstract = {Adult motor neuron disease (amyotrophic lateral sclerosis [ALS]) is a neurodegenerative disorder characterized by loss of motor neurons in the cortex, brain stem, and spinal cord, manifested by upper and lower motor neuron signs and symptoms affecting bulbar, limb, and respiratory musculature. Clinically, the disease course is characterized by progressive weakness, atrophy, spasticity, dysarthria, dysphagia, and respiratory compromise, ultimately resulting in death or mechanical ventilation in the vast majority of patients. Patterns of presentation and pathological features of the disease, along with clinical and electrophysiologic criteria for diagnosis, are discussed in this review. Since 8% to 22% of patients survive more than 10 years without ventilator use, meticulous medical and rehabilitation management is extremely important to ensure optimal health and quality of life in these patients. Major issues in the care of individuals with ALS include weakness and spasticity, impairments in activities of daily living and mobility, communication deficits and dysphagia in those with bulbar involvement, respiratory compromise, fatigue and sleep disorders, pain, and psychosocial distress. Research in ALS changes rapidly, but is currently focused on potential etiologic factors such as glutamate excitotoxicity, role of oxidative stress, autoimmunity to calcium channels, and cytoskeletal abnormalities, as well as related treatment initiatives including glutamate modulators, neurotrophic factors, antioxidants, antiapoptotic factors, and gene therapy. Recently, mutations in the gene encoding Cu/Zn superoxide dismutase were identified in a subset of familial ALS patients. Riluzole, a glutamate antagonist and Na-channel blocker, became the only drug currently approved for treatment of ALS after studies showed a small positive effect on survival. Until a definitive treatment or cure for ALS is found, the multifaceted rehabilitation team approach remains the best hope for improving health and survival in this devastating illness.}, }
@article {pmid10448978, year = {1999}, author = {Kalra, S and Arnold, DL and Cashman, NR}, title = {Biological markers in the diagnosis and treatment of ALS.}, journal = {Journal of the neurological sciences}, volume = {165 Suppl 1}, number = {}, pages = {S27-32}, doi = {10.1016/s0022-510x(99)00023-4}, pmid = {10448978}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*therapy ; Aspartic Acid/analogs &amp; derivatives/analysis ; Biomarkers/*analysis ; Brain/metabolism ; Creatine/analysis ; Disease Progression ; Electromyography ; Humans ; Magnetic Resonance Imaging ; Monitoring, Physiologic ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Tomography, Emission-Computed ; }, abstract = {The care of patients with amyotrophic lateral sclerosis (ALS), which has classically focused on treatment of symptomatology, has now entered an encouraging new era of therapy targeted at the pathophysiology of the disease. However, an objective measure of disease progression and therapeutic response is sorely needed. Quantitative neuromuscular examinations, measurement of pulmonary function, disability scales, and even survival, are limited by variability due to a number of poorly controlled factors. Quantitative electromyography, positron emission tomography scanning, and magnetic cortical stimulation, provide potential objective indicators of disease progression, but require a large number of patients and a long observation period for adequate statistical power. We have examined the role of magnetic resonance spectroscopic imaging in detecting acute changes in motor cortical metabolism in response to riluzole therapy. N-acetylaspartate (NAA), the most prominent signal in proton spectra of normal brain, is a neuron-specific molecule. ALS patients were found to experience a significant increase in the NAA/creatine ratio within 3 weeks of initiation of riluzole therapy. As glutamate can trigger the generation of reactive oxygen species in neurons, we speculate that acute changes in NAA levels may reflect oxidative injury to mitochondria where NAA is synthesised. The advent of a useful test for upper motor neuron metabolic compromise may provide an objective, non-invasive, short duration measure with which to screen the efficacy of potential therapeutic agents for ALS.}, }
@article {pmid10448050, year = {1999}, author = {Waggoner, DJ and Bartnikas, TB and Gitlin, JD}, title = {The role of copper in neurodegenerative disease.}, journal = {Neurobiology of disease}, volume = {6}, number = {4}, pages = {221-230}, doi = {10.1006/nbdi.1999.0250}, pmid = {10448050}, issn = {0969-9961}, support = {DK44464/DK/NIDDK NIH HHS/United States ; HL41536/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/metabolism/physiology ; Alzheimer Disease/enzymology/metabolism/pathology ; Amino Acid Sequence ; Amyloid beta-Peptides/metabolism/physiology ; Amyotrophic Lateral Sclerosis/enzymology/metabolism/pathology ; Animals ; Carrier Proteins/metabolism/physiology ; *Cation Transport Proteins ; Ceruloplasmin/deficiency/metabolism/physiology ; Copper/*metabolism/*physiology ; Copper-Transporting ATPases ; Hepatolenticular Degeneration/enzymology/metabolism/pathology ; Humans ; Menkes Kinky Hair Syndrome/enzymology/metabolism/pathology ; Mice ; Molecular Sequence Data ; Neurodegenerative Diseases/enzymology/*metabolism/pathology ; Prion Diseases/metabolism/pathology ; Prions/metabolism/physiology ; *Recombinant Fusion Proteins ; Sequence Homology, Amino Acid ; }, abstract = {Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.}, }
@article {pmid10442571, year = {1999}, author = {Hall, K and Hilding, A and Thorén, M}, title = {Determinants of circulating insulin-like growth factor-I.}, journal = {Journal of endocrinological investigation}, volume = {22}, number = {5 Suppl}, pages = {48-57}, pmid = {10442571}, issn = {0391-4097}, mesh = {Aging/blood ; Blood Proteins/*metabolism ; *Hormone Replacement Therapy ; Human Growth Hormone/*therapeutic use ; Humans ; Insulin-Like Growth Factor I/*metabolism ; Molecular Weight ; Nutritional Status ; Protein Isoforms/*metabolism ; }, abstract = {Total IGF-I level in serum is a sensitive index during growth hormone (GH) replacement therapy of adults, since GH stimulates the hepatic expressions of both insulin-like growth factor (IGF-I) and acid-labile subunit (ALS) and the major part of IGF-I in the circulation is found in a ternary complex together with ALS and IGFBP-3. However, other regulators of the proteins constituting the ternary complex may influence IGF-I levels. In healthy subjects the serum IGF-I levels are low at birth, rise during childhood, with peak levels during puberty, and decline with increasing age. This pattern has been attributed to the age-dependent GH production, but it is unknown whether the wide range of IGF-I levels within each age interval is due to GH production or GH sensitivity. In elderly twins approximately 60% of IGF-I levels are genetically determined. The remaining environmental dependency of IGF-I is partly due to nutrition. Both caloric and protein content of the diet is of importance. Thus, low IGF-I levels are found in GH deficient patients as well as in patients with GH resistance due to malnutrition or GH receptor defects. It is essential that IGF-I determination is performed by assays in which IGFBPs do not interfere, and that IGF-I concentration is evaluated in relation to age, i.e. expressed in SD score, and the number of individuals constituting the reference intervals improves the sensitivity and specificity. Although determination of IGF-I is recommended in assessing GH deficiency in children, its diagnostic value in patients with adult onset of GH deficiency is not agreed upon. In the age group above 40-80 years many patients with pituitary/hypothalamic disorders and GH peaks below 3 microg/l during provocation tests have normal IGF-I levels. It is not clarified, whether the IGF-I levels within normal range for age is due to endogenous basal GH production being sufficient or other factors stimulating IGF-I, IGFBP-3 or ALS expressions.}, }
@article {pmid10442086, year = {1999}, author = {Chabrier, PE and Demerlé-Pallardy, C and Auguet, M}, title = {Nitric oxide synthases: targets for therapeutic strategies in neurological diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {55}, number = {8-9}, pages = {1029-1035}, doi = {10.1007/s000180050353}, pmid = {10442086}, issn = {1420-682X}, mesh = {Alzheimer Disease/drug therapy/enzymology ; Amidines/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/enzymology ; Animals ; Benzylamines/pharmacology/therapeutic use ; Brain Injuries/drug therapy ; Brain Ischemia/drug therapy ; Enzyme Induction ; Humans ; Huntington Disease/drug therapy/enzymology ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; Nerve Degeneration/*drug therapy/metabolism/prevention &amp; control ; Nerve Tissue Proteins/*antagonists &amp; inhibitors ; Nervous System Diseases/*drug therapy ; Nitric Oxide/adverse effects/physiology ; Nitric Oxide Synthase/*antagonists &amp; inhibitors ; Nitric Oxide Synthase Type I ; Organ Specificity ; Polymethacrylic Acids/pharmacology ; Pyrazines/pharmacology/therapeutic use ; Thiophenes/pharmacology/therapeutic use ; }, abstract = {Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.}, }
@article {pmid10436336, year = {1999}, author = {Bak, TH and Hodges, JR}, title = {Cognition, language and behaviour in motor neurone disease: evidence of frontotemporal dysfunction.}, journal = {Dementia and geriatric cognitive disorders}, volume = {10 Suppl 1}, number = {}, pages = {29-32}, doi = {10.1159/000051208}, pmid = {10436336}, issn = {1420-8008}, mesh = {*Behavior ; Cognition/*physiology ; Frontal Lobe/*physiopathology ; Humans ; *Language ; Motor Neuron Disease/physiopathology/*psychology ; Temporal Lobe/*physiopathology ; }, abstract = {Cognitive symptoms accompanying motor neurone disease (MND) have been recognized and described since the late 19th century. Numerous reports from Europe, North America and Japan suggest existence of a syndrome that can be described as MND/dementia. Typically, psychiatric and cognitive changes, strongly reminiscent of frontotemporal dementia, precede the occurrence of the classical signs and symptoms of MND by several months. In a small number of patients a similar picture can be heralded by a progressive aphasia leading ultimately to mutism. While the syndromes of MND/dementia and MND/aphasia constitute a comparatively small group, subtle but consistent cognitive alterations have also been observed in the majority of nondemented MND patients. Although generally much less pronounced, their pattern, affecting mostly frontal-executive functions, resembles that of MND/dementia. Postmortem examination results, describing pathological changes in the frontal lobes, and functional neuroimaging studies, showing abnormal pattern of frontal activation, add more weight to the hypothesis linking MND to the frontotemporal dementia.}, }
@article {pmid10434670, year = {1999}, author = {Nakashima, K}, title = {[ALS-related syndromes due to exogenous toxins].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {347-349}, pmid = {10434670}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology ; Diagnosis, Differential ; Humans ; Plants/toxicity ; Toxins, Biological/toxicity ; Trace Elements/toxicity ; }, }
@article {pmid10434669, year = {1999}, author = {Iwasaki, Y and Ichikawa, Y and Ikeda, K}, title = {[Concurrence of familial ALS with Ribbing's disease].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {343-346}, pmid = {10434669}, mesh = {Amyotrophic Lateral Sclerosis/complications/*genetics ; Camurati-Engelmann Syndrome/*complications/genetics ; Chromosomes, Human, Pair 21 ; Diagnosis, Differential ; Female ; Genes, Dominant ; Humans ; Middle Aged ; Mutation ; Prognosis ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid10434667, year = {1999}, author = {Kuzuhara, S}, title = {[ALS and parkinsonism-dementia complex of Kii peninsula].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {335-338}, pmid = {10434667}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology ; Brain/pathology ; *Dementia/complications/epidemiology ; Diagnosis, Differential ; Humans ; Japan/epidemiology ; *Parkinson Disease/complications/epidemiology ; Prognosis ; }, }
@article {pmid10434666, year = {1999}, author = {Kuzuhara, S}, title = {[ALS and parkinsonism-dementia complex of Guam and western Pacific].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {330-334}, pmid = {10434666}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology ; *Dementia/complications/epidemiology ; Diagnosis, Differential ; Guam/epidemiology ; Humans ; *Parkinson Disease/complications/epidemiology ; Prognosis ; }, }
@article {pmid10434665, year = {1999}, author = {Yuasa, R}, title = {[Amyotrophic lateral sclerosis with dementia].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {326-329}, pmid = {10434665}, mesh = {*Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Dementia/complications/physiopathology ; Frontal Lobe/pathology ; Motor Neurons/pathology ; Prognosis ; Temporal Lobe/pathology ; }, }
@article {pmid10434664, year = {1999}, author = {Warita, H and Abe, K}, title = {[Juvenile ALS].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {323-325}, pmid = {10434664}, mesh = {Adolescent ; Adult ; Age of Onset ; *Amyotrophic Lateral Sclerosis/classification/genetics ; Child ; Child, Preschool ; Diagnosis, Differential ; Humans ; Prognosis ; }, }
@article {pmid10434663, year = {1999}, author = {Abe, K}, title = {[Autosomal dominant ALS].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {320-322}, pmid = {10434663}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Chromosomes, Human, Pair 21 ; *Genes, Dominant ; Humans ; Point Mutation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid10434662, year = {1999}, author = {Manabe, Y and Abe, K}, title = {[Sporadic ALS].}, journal = {Ryoikibetsu shokogun shirizu}, volume = {}, number = {27 Pt 2}, pages = {316-319}, pmid = {10434662}, mesh = {ATP-Binding Cassette Transporters ; Amino Acid Transport System X-AG ; *Amyotrophic Lateral Sclerosis/diagnosis/etiology ; Diagnosis, Differential ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/pathology ; Prognosis ; }, }
@article {pmid10433655, year = {1999}, author = {Ross, AP}, title = {Neurologic degenerative disorders.}, journal = {The Nursing clinics of North America}, volume = {34}, number = {3}, pages = {725-742}, pmid = {10433655}, issn = {0029-6465}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/physiopathology/*therapy ; Humans ; Multiple Sclerosis/classification/*diagnosis/physiopathology/*therapy ; Myasthenia Gravis/*diagnosis/physiopathology/*therapy ; Parkinson Disease/*diagnosis/physiopathology/*therapy ; Voluntary Health Agencies ; }, abstract = {Neurologic degenerative disorders pose challenges to patients, their families, and health care professionals who care for them. In recent years there have been many advances in the diagnosis and management of neurologic degenerative diseases. Multiple sclerosis, myasthenia gravis, Parkinson's disease, and amyotrophic lateral sclerosis are discussed.}, }
@article {pmid10425565, year = {1999}, author = {Kato, S and Saito, M and Hirano, A and Ohama, E}, title = {Recent advances in research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations: neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions.}, journal = {Histology and histopathology}, volume = {14}, number = {3}, pages = {973-989}, doi = {10.14670/HH-14.973}, pmid = {10425565}, issn = {0213-3911}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/*pathology ; Animals ; Astrocytes/*cytology ; Humans ; Hyalin ; Lewy Bodies/*pathology ; *Mutation ; Neurons/*pathology ; Research ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Of all patients with ALS, approximately 5%-10% of them are familial and most of the others are sporadic. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. FALS is neuropathologically classified into two subtypes: classical FALS in which degeneration is restricted to only motor neurons and FALS which is characterized by the degeneration of the posterior column in addition to the lesion of the motor neuron system. The neuronal Lewy body-like hyaline inclusion (LBHI) is a characteristic neuropathological marker of mutant SOD1-linked FALS with posterior column involvement. Inclusions similar to the neuronal LBHIs have been discovered in astrocytes in certain patients with FALS exhibiting SOD1 gene mutations. The purpose of this review is to discuss the novel neuropathological significance of the astrocytic hyaline inclusions (Ast-HIs) and neuronal LBHIs in brain tissues from individuals with the posterior-column-involvement-type FALS with SOD1 gene mutations. In hematoxylin and eosin preparations, both Ast-HIs and neuronal LBHIs are eosinophilic inclusions and sometimes show eosinophilic cores with paler peripheral halos. Immunohistochemically, both inclusions are intensely positive for SOD1. At the ultrastructural level, both inclusions consist of approximately 15-25 nm-sized granule-coated fibrils and granular materials. Immunoelectron microscopically, these abnormal granule-coated fibrils and granular materials are positive for SOD1. Therefore, the FALS disease process originating from SOD1 gene mutations occurs in astrocytes as well as neurons and is involved in the formation of both inclusions.}, }
@article {pmid10422476, year = {1999}, author = {Kohler, A and Genoud, D and Magistris, MR}, title = {[Amyotrophic lateral sclerosis].}, journal = {Revue medicale de la Suisse romande}, volume = {119}, number = {6}, pages = {497-502}, pmid = {10422476}, issn = {0035-3655}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/psychology/*therapy ; Diagnosis, Differential ; Disease Progression ; Electromyography ; Humans ; Patient Education as Topic ; Quality of Life ; }, }
@article {pmid10416039, year = {1999}, author = {Beal, MF}, title = {Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases.}, journal = {BioFactors (Oxford, England)}, volume = {9}, number = {2-4}, pages = {261-266}, doi = {10.1002/biof.5520090222}, pmid = {10416039}, issn = {0951-6433}, support = {NS16367/NS/NINDS NIH HHS/United States ; NS31579/NS/NINDS NIH HHS/United States ; P01 AG12992/AG/NIA NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Antioxidants/*therapeutic use ; Coenzymes ; Humans ; Huntington Disease/blood/drug therapy ; Lactates/blood ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/blood/drug therapy ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives/blood/therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases.}, }
@article {pmid10409881, year = {1999}, author = {Mattle, HP}, title = {[New drugs in neurology].}, journal = {Praxis}, volume = {88}, number = {18}, pages = {827-834}, pmid = {10409881}, issn = {1661-8157}, mesh = {Adult ; Aged ; Central Nervous System Agents/adverse effects/*therapeutic use ; Central Nervous System Diseases/*drug therapy/etiology ; Female ; Humans ; Male ; Treatment Outcome ; }, abstract = {This article reviews new drugs and recent knowledge or indications for old drugs for the treatment of neurological disorders. Drugs for disorders such as migraine, epilepsy, Parkinson's disease, Alzheimer's disease, ischemic stroke, amyotrophic lateral sclerosis and multiple sclerosis are considered.}, }
@article {pmid10399861, year = {1999}, author = {Donaghy, M}, title = {Classification and clinical features of motor neurone diseases and motor neuropathies in adults.}, journal = {Journal of neurology}, volume = {246}, number = {5}, pages = {331-333}, doi = {10.1007/s004150050358}, pmid = {10399861}, issn = {0340-5354}, mesh = {Adult ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/*classification/diagnosis/*physiopathology ; Motor Neurons/physiology ; Neural Conduction/physiology ; }, abstract = {The term motor neurone disease encompasses combined upper and lower motor neurone disorders (amyotrophic lateral sclerosis), pure lower motor neurone disorders (spinal muscular atrophies, multifocal motor neuropathies, post irradiation lumbosacral radiculopathy, post-polio syndrome, hereditary bulbar palsy) and pure upper motor neurone disorders (primary lateral sclerosis, hereditary spastic paraplegia, neurolathyrism, Konzo). The chief clinical and electrophysiological criteria for these different disorders are discussed, with particular attention to diagnostically distinctive characteristics of each. Age of onset, and inheritance are considered as additional diagnostic features.}, }
@article {pmid10399726, year = {1999}, author = {Potemkowski, A and Honczarenko, K and Fabian, A}, title = {[Clinical course and epidemiological analysis of amyotrophic lateral sclerosis in Szczecin in 1986-1995].}, journal = {Neurologia i neurochirurgia polska}, volume = {33}, number = {1}, pages = {71-78}, pmid = {10399726}, issn = {0028-3843}, mesh = {Adult ; Age Distribution ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; Female ; Humans ; Male ; Middle Aged ; Poland/epidemiology ; Retrospective Studies ; Risk Factors ; Severity of Illness Index ; Sex Distribution ; Time Factors ; }, abstract = {49 patients diagnosed as amyotrophic lateral sclerosis (ALS), hospitalized between 1986-1995, inhabitants of Szczecin-City were included in this study. ALS was diagnosed according to WFN criteria. The control group consisted of 60 people. Men:women ratio was 1.57:1. The mean age at ALS onset was 53.2 years. The disease was most often present between 51 and 60 years. Only one ALS patient was observed in the group of patients aged 21-30 and in the group of individuals older than 70 years. ALS incidence was 0.9 per 100,000 inhabitants and its prevalence in 1995 was 2.7 per 100,000 inhabitants. The mean duration was 30.8 months and was slightly higher in women. The shortest duration was observed in the bulbar form of ALS--21 months. Patients with ALS had been exposed to head trauma and contact with animals more often than the average population. There is no difference between Szczecin and previously analysed Polish cities in the considered epidemiological parameters. No discrepancies of clinical picture and course of the disease were found in comparison with other reported by other authors.}, }
@article {pmid10377809, year = {1999}, author = {Saito, T}, title = {[Mechanical ventilation for amyotrophic lateral sclerosis--Making a comparison between hospital and home care].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {39}, number = {1}, pages = {70-71}, pmid = {10377809}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Home Care Services, Hospital-Based ; Humans ; Informed Consent ; *Intermittent Positive-Pressure Ventilation ; *Length of Stay ; Long-Term Care ; Quality of Life ; }, abstract = {In Japan, the traditional method of mechanical ventilation (MV) used for patients with amyotrophic lateral sclerosis (ALS) has been positive pressure ventilation with tracheostomy (PPV). Survival after starting PPV can be for many years. The purpose of our study is to report our findings on 25 patients (22.5%) using PPV for thirteen years. A total of 91 ALS patients without PPV died during in past thirteen years. Four patients with PPV lived at home and their families usually served as primary caregivers. Other five patients with PPV lived in our hospital, because they were lacked willing, competent or available caregivers at home, and they had not sufficient informed consent about use of mechanical ventilation or not. The quality of MV care provided by properly trained family members and home helper was as good as care provided by home-visited nurse. Quality of life in ALS patients with home MV were significantly increased comparing to hospital MV. Few patients chose nasal intermittent PPV. Most patients with ALS do not want to use MV. They need assistance with palliative care and planning for emergencies, so that PPV can be avoided when respiratory failure occurs. Before a decision is made to use PPV, the patient with ALS and family should understand that death related to ALS can be prevented with home MV and good care. However, if PPV is used, ongoing tracheal suctioning will be required, immobility will progress, or needed resources and cost are high, with the result that family might be burdened with heavy responsibility. Thorough informed consent are necessary.}, }
@article {pmid10377806, year = {1999}, author = {Kusaka, H}, title = {[Neuropathology of the motor neuron disease--Bunina body].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {39}, number = {1}, pages = {65-66}, pmid = {10377806}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Humans ; Inclusion Bodies/*pathology ; Motor Neuron Disease/*pathology ; Motor Neurons/*cytology ; Rats ; }, abstract = {Bunina body is known to occur in cases of sporadic amyotrophic lateral sclerosis (ALS), ALS with dementia (a so-called Mitsuyama type), and Guamanian ALS, and seems to lend a diagnostic priority to the presence of Bunina bodies. Absence of Bunina body in a subset of familial ALS with posterior column and spinocerebellar tract involvement or motor neuron disease with basophilic inclusion also adds credence to the specificity of Bunina body in ALS. However, despite its bright eosinophilia, distinct expression of cystatin C, and conspicuous ultrastructure, the origin of Bunina body is still unknown and remain several unsolved problems. Bunina bodies are usually seen within the cytoplasm or dendrites of degenerated and/or sometimes normal-looking large neurons. However, so far, no Bunina body has been found within the axoplasm. Bunina bodies are mainly distributed in the lower motor neurons. Only a single report described it in the Betz cell. Furthermore, several recent studies have revealed the occurrence in neurons which are so far considered to be exempt from the pathology of ALS, i.e. the oculomotor nucleus, Onufurowicz's nucleus, Clarke's nucleus, reticular formation of the brain stem, and subthalamic nucleus. In addition to the occurrence in neurons other than motor neurons, ultrastructurally similar or identical inclusions are reported in neurons of aged rats, the olfactory bulb of aged human, the spinal cord of a patient without ALS, and gangliocytoma. Bunina body probably represents a facet of the degenerating process of a neuron. A high incidence in ALS, particularly in lower motor neurons, awaits a further study of the pathogenesis of Bunina body.}, }
@article {pmid10377805, year = {1999}, author = {Kohara, N}, title = {[Abnormal hyperexcitability in ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {39}, number = {1}, pages = {61-64}, pmid = {10377805}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Electromyography ; Electrophysiology ; Evoked Potentials ; Fasciculation ; Humans ; Motor Neurons/*physiology ; Neuromuscular Junction/physiopathology ; Synaptic Transmission ; }, abstract = {The defect of neuromuscular transmission is one of the important signs in ALS. The amplitude of a single motor unit potential from patients with ALS often decrease during tonic voluntary contraction. This phenomenon is closely correlated with fatigue seen in the patient. Overfunctioning of Ach release in the nerve terminal might cause the failure of neuromuscular transmission in ALS. Fasciculations is an another characteristic sign and considered mainly to be peripheral axons in origin. It is postulated that the dysfunction of potassium channel in ALS axons makes the hyperexcitability of the axon membrane, causing fasciculations. Magnetic cortical stimulation sometimes evokes the same potentials as fasciculations, implying the hyperexcitability might be present also in spinal motoneurons or even in pyramidal neurons in ALS. All of these findings lead to the hypothesis that hyperexcitability or overactivity of central and peripheral motoneurons is an essential feature in ALS.}, }
@article {pmid10377784, year = {1999}, author = {Shimohama, S and Sawada, H and Kihara, T and Urushitani, M}, title = {[Neuronal cell death in neurodegenerative disorders and oxidative stress].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {39}, number = {1}, pages = {4-6}, pmid = {10377784}, issn = {0009-918X}, mesh = {Cell Death ; Humans ; Neurodegenerative Diseases/*etiology/pathology ; Neurons/*physiology ; *Oxidative Stress ; }, abstract = {Mechanisms of the process of neuronal degeneration in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD) remain unsolved. Oxidative stress might be a possible mechanism of neuronal cell death. Glutamate is an excitatory amino acid and its excessive release can cause intracellular calcium influx, activation of calcium-dependent enzymes such as nitric oxide (NO) synthase (NOS), and production of toxic oxygen radicals. Excessive release of glutamate, therefore, can be used as a model of experimental oxidative stress. Continuous exposure to low levels of glutamate potentiates selective motor neuronal death mediated by NO, which inversely protects nonmotor neurons through the guanylyl cyclase-cGMP cascade. Mesencephalic dopaminergic neurons are resistant to cytotoxicity induced by NO. The protecting mechanism from NO neurotoxicity in dopaminergic neurons is based on inhibition of conversion of NO to peroxynitrite anion, and is possibly due to suppression of superoxide anion production. Dopamine D 2 agonists provide protection mediated not only by the inhibition of dopamine turnover but also via D 2-type dopamine receptor stimulation and the subsequent synthesis of proteins that scavenge free radicals. In addition, nicotinic receptor stimulation may be able to protect neurons from oxidative stress induced by A beta.}, }
@article {pmid10376049, year = {1999}, author = {Avila, PC and Shusterman, DJ}, title = {Work-related asthma and latex allergy. Sorting out the types, causes, and consequences.}, journal = {Postgraduate medicine}, volume = {105}, number = {7}, pages = {39-46}, doi = {10.3810/pgm.1999.06.621}, pmid = {10376049}, issn = {0032-5481}, mesh = {Adult ; Asthma/diagnosis/epidemiology/*etiology/immunology ; Humans ; Latex Hypersensitivity/*complications ; Occupational Diseases/diagnosis/epidemiology/*etiology/immunology ; Risk Factors ; United States/epidemiology ; }, abstract = {Work-related asthma now has clear definitions based on criteria agreed upon by the American College of Chest Physicians. The clinician should suspect occupational asthma, irritant-induced asthma, or work-aggravated asthma in adults with new-onset asthma or asthma symptoms that worsen during work, after work (late allergic response), or over the course of workdays. The possible cause should be sought, and a skin test or immunoassay should be performed, if possible,to he;lp detect sensation. Workup als o includes objective documentation of worsening of symptoms and airway obstruction during occupational exposure. If this information is inconclusive, an inhalation challenge may be considered. Medical management is the same as for nonoccupational asthma, but cessation of exposure to the specific agent is necessary to improve long-term diagnosis. Latex allergy and latex-induced asthma are becoming more common in the workplace, particularly in the healthcare field. No commercially available standard serum or skin test are available for diagnosis. The principal treatment is avoidance of latex, which can be achieved in most cases without extensive changes to the workplace.}, }
@article {pmid10354791, year = {1999}, author = {Meyer, M and Rasmussen, JZ}, title = {[Neuronal growth factors--neurotrophins].}, journal = {Ugeskrift for laeger}, volume = {161}, number = {14}, pages = {2063-2070}, pmid = {10354791}, issn = {0041-5782}, mesh = {Cell Communication ; Cell Differentiation ; Central Nervous System/embryology/metabolism/*physiology ; Central Nervous System Diseases/drug therapy/metabolism/physiopathology ; Growth Substances/metabolism/*physiology ; Humans ; Models, Neurological ; Nerve Growth Factors/metabolism/*physiology ; Neurodegenerative Diseases/drug therapy/metabolism/*physiopathology ; Neuronal Plasticity ; Neurons/metabolism/*physiology ; Peripheral Nervous System/embryology/metabolism/*physiology ; Peripheral Nervous System Diseases/drug therapy/metabolism/physiopathology ; Receptors, Growth Factor/metabolism/*physiology ; Receptors, Nerve Growth Factor/metabolism/*physiology ; }, abstract = {Neurotrophic factors are polypeptides primarily known to regulate the survival and differentiation of nerve cells during the development of the peripheral and central nervous systems. The neurotrophic factors act via specific receptors after retrograde axonal transport from the nerve fibre target areas back to the cell bodies, and locally through autocrine and paracrine mechanisms linked to nerve cell activity. In the mature nervous system, neurotrophic factors maintain morphological and neurochemical characteristics of nerve cells and promote activity-dependent dynamic/plastic changes in the synaptic contacts between nerve cells by strengthening functionally active synaptic connections. Induction and increased production of neurotrophic factors in relation to neural injuries are thought to serve protective and reparative purposes. Specific neurotrophic factors have thus been shown to protect nerve cells in a number of experimental models for neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis, just as specific neurotrophic factors have been shown to stimulate regenerative growth of both peripheral and central nerve fibres. Today, problems with continuous and localized delivery of specific neurotrophins or combinations thereof into the nervous system appear to be the most important obstacle for more widespread clinical application.}, }
@article {pmid10349335, year = {1998}, author = {Kakizuka, A}, title = {[Recent progress in the research field on triplet repeat diseases].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {38}, number = {12}, pages = {988-992}, pmid = {10349335}, issn = {0009-918X}, mesh = {Animals ; Apoptosis ; Humans ; Mice ; Mice, Transgenic ; *Neurodegenerative Diseases/genetics ; Peptides/genetics/physiology ; *Trinucleotide Repeats ; }, abstract = {At present, 8 inherited neurodegenerative disorders (e.g. Huntington disease, Machado-Joseph disease, etc.) are identified to be caused by the polyglutamine-coding CAG triplet expansions in the responsible genes. These disorders commonly demonstrate dominant inheritance, if autosomal, and late onset of their manifestations. Interestingly, the longer expansions result in earlier onset and more severe clinical manifestations. Proteins containing expanded polyglutamine repeats appear to precipitate by self-aggregation, and as a result produce a core disease-related phenotype: neuronal cell death or degeneration. Given that polyglutamine aggregation might be central in neurodegeneration, the parameters that determine the feasibility of the polyglutamines to aggregate would determine the age of onset and the clinical severity. These parameters are postulated to be the concentration and the length of polyglutamines, which is supported by clinical and experimental observations. The stronger neuronal degenerations are always accompanied by the longer polyglutamine stretches and by the higher concentration of the expanded polyglutamines. In other neurodegenerative disorders, such as Alzheimer disease, prion disease, Parkinson disease and amyotrophic lateral sclerosis, precipitation of abnormal proteins is also now considered to play a key role. These observations might lead to the elucidation of universal mechanisms for neurodegeneration and to treatments effective for many neurodegenerative disorders.}, }
@article {pmid10349332, year = {1998}, author = {Kimura, J}, title = {[Therapy oriented neurology from repair to remedy].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {38}, number = {12}, pages = {969-973}, pmid = {10349332}, issn = {0009-918X}, mesh = {Afferent Pathways ; Botulinum Toxins/*therapeutic use ; Cyclooxygenase Inhibitors/therapeutic use ; Humans ; Immunization, Passive ; Multicenter Studies as Topic ; Muscular Diseases/*therapy ; *Nerve Block/methods ; Neurology ; Peripheral Nervous System Diseases/therapy ; }, abstract = {In addition to the traditional preoccupation for accurate localization of lesions, a new trend in our discipline emphasizes therapeutic approaches to various neurological disorders. This review summarizes the result of multi-center trials that we personally participated during the past decade to present an overview of the current thought in the area of our interest. The disorders in question include dystonia, chronic inflammatory demeyelinating polyneuropathy, myoclonic epilepsy, diabetic polyneuropathy, amyotrophic lateral sclerosis, and experimental allergic neuritis. These results and other equally encouraging data suggest that we are not necessarily fighting a loosing battle in dealing with these incapacitating diseases, even though our effort often falls short of achieving a complete cure. In formulating a list of differential diagnosis, we must always entertain the possibility of remedy as the eventual goal of our clinical practice.}, }
@article {pmid10335495, year = {1999}, author = {Ludolph, AC and Meyer, T and Riepe, MW}, title = {Antiglutamate therapy of ALS--which is the next step?.}, journal = {Journal of neural transmission. Supplementum}, volume = {55}, number = {}, pages = {79-95}, doi = {10.1007/978-3-7091-6369-6_8}, pmid = {10335495}, issn = {0303-6995}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Forecasting ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/drug therapy ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable for a long time. However, recent evidence in men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of the drugs is still small, this progress cannot only be seen as a success of the present but most also be acknowledged as a starting point for the future. How will these future studies look like? They will have to take into account that ALS presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have recently been shown to be effective in a transgenic animal model. This also implies that we are likely to use combination therapies and have to try to treat patients early. The latter will be necessarily connected with the demand for a novel clinical attitude to the diagnosis of the disease.}, }
@article {pmid10334661, year = {1999}, author = {Doble, A}, title = {The role of excitotoxicity in neurodegenerative disease: implications for therapy.}, journal = {Pharmacology &amp; therapeutics}, volume = {81}, number = {3}, pages = {163-221}, doi = {10.1016/s0163-7258(98)00042-4}, pmid = {10334661}, issn = {0163-7258}, mesh = {AIDS Dementia Complex/etiology ; Amyotrophic Lateral Sclerosis/etiology ; Calcium/*metabolism ; Excitatory Amino Acids/*physiology ; Glutamic Acid/metabolism/*toxicity ; Humans ; N-Methylaspartate/physiology ; Neurodegenerative Diseases/drug therapy/*etiology/physiopathology ; Neurotransmitter Agents/*antagonists &amp; inhibitors ; }, abstract = {Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand-gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation. In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well-established experimentally, both in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurological sequelae of stroke, and there now seems to be little doubt that such a process is indeed a determining factor in the extent of the lesions observed. Several clinical trials have evaluated the potential of antiglutamate drugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex, several lines of circumstantial evidence suggest that excitotoxicity may contribute to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are examples of neurodegenerative diseases where mitochondrial dysfunction may sensitise specific populations of neurones to excitotoxicity from synaptic glutamic acid. The first clinical trials aimed at providing neuroprotection with antiglutamate drugs are currently in progress for these two diseases.}, }
@article {pmid10331091, year = {1999}, author = {Seal, RP and Amara, SG}, title = {Excitatory amino acid transporters: a family in flux.}, journal = {Annual review of pharmacology and toxicology}, volume = {39}, number = {}, pages = {431-456}, doi = {10.1146/annurev.pharmtox.39.1.431}, pmid = {10331091}, issn = {0362-1642}, mesh = {Amino Acid Transport Systems ; Animals ; Biological Transport/physiology ; Carrier Proteins/genetics/*metabolism ; Excitatory Amino Acids/*metabolism ; Glutamic Acid/metabolism ; Humans ; Nervous System Diseases/drug therapy/metabolism ; Signal Transduction/physiology ; }, abstract = {As the most predominant excitatory neurotransmitter, glutamate has the potential to influence the function of most neuronal circuits in the central nervous system. To limit receptor activation during signaling and prevent the overstimulation of glutamate receptors that can trigger excitotoxic mechanisms and cell death, extracellular concentrations of excitatory amino acids are tightly controlled by transport systems on both neurons and glial cells. L-Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory amino acids may contribute to the neurodegeneration seen in a variety of conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To establish the contributions of carrier systems to the etiology of neurological disorders, and to consider their potential utility as therapeutic targets, a detailed understanding of transporter function and pharmacology is required. This review summarizes current knowledge of the structural and functional diversity of excitatory amino acid transporters and explores how they might serve as targets for drug design.}, }
@article {pmid10319403, year = {1999}, author = {Zavalishin, IA and Zakharova, MN}, title = {[Amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {99}, number = {4}, pages = {60-64}, pmid = {10319403}, issn = {1997-7298}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*etiology ; Female ; Humans ; Male ; }, }
@article {pmid10229967, year = {1999}, author = {González-Fraguela, ME and Castellano-Benítez, O and González-Hoyuela, M}, title = {[Oxidative stress in neurodegeneration].}, journal = {Revista de neurologia}, volume = {28}, number = {5}, pages = {504-511}, pmid = {10229967}, issn = {0210-0010}, mesh = {Aging/physiology ; Antioxidants/metabolism ; Cell Death/physiology ; Free Radicals/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {INTRODUCTION: The aetiology of the neuronal death which occurs in neurodegenerative diseases is still unknown. These disorders are of insidious onset and follow an inexorable, gradually progressive course. The best known and most frequent are Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).<br><br>DEVELOPMENT: Advances in molecular genetics and neurobiochemistry towards the understanding of processes involved in cell death, suggest the association of phenomena of excito-toxicity and oxidation damage in the selective degeneration of neuronal populations, characteristic of these disorders.<br><br>CONCLUSION: The evidence presented here suggests that the species reactive to oxygen (SRO) play a direct part in the aetiology and/or pathogenesis of neurodegenerative disorders, although it is still very difficult to establish whether these reactive species represent the primary etiological factor, or are toxic products secondary to tissue damage.}, }
@article {pmid10226799, year = {1999}, author = {Bereket, A and Lang, CH and Wilson, TA}, title = {Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus.}, journal = {Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme}, volume = {31}, number = {2-3}, pages = {172-181}, doi = {10.1055/s-2007-978716}, pmid = {10226799}, issn = {0018-5043}, mesh = {Diabetes Mellitus, Type 1/*metabolism ; Human Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Insulin-Like Growth Factor II/metabolism ; }, abstract = {The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.}, }
@article {pmid10226049, year = {1999}, author = {Sayre, LM and Perry, G and Smith, MA}, title = {Redox metals and neurodegenerative disease.}, journal = {Current opinion in chemical biology}, volume = {3}, number = {2}, pages = {220-225}, doi = {10.1016/S1367-5931(99)80035-0}, pmid = {10226049}, issn = {1367-5931}, mesh = {Amyloid beta-Peptides/metabolism ; Homeostasis ; Humans ; Metals/*metabolism ; Neurodegenerative Diseases/enzymology/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Superoxide Dismutase/metabolism ; }, abstract = {Multiple lines of evidence implicate redox-active transition metals as mediators of oxidative stress in neurodegenerative diseases. Among the recent research discoveries is the finding that transition metals bind to proteins associated with neurodegeneration, including the prion protein. Whereas binding in the latter case may serve an antioxidant function, adventitious binding of metals to other proteins appears to preserve their catalytic redox activity in a manner that disturbs free radical homeostasis. Alterations in the levels of copper- and iron-containing metalloenzymes, involved in processing partially reduced oxygen species, are also likely to contribute to altered redox balance in neurodegenerative diseases. Nonetheless, even in familial forms of amyotrophic lateral sclerosis linked to mutations in superoxide dismutase, it is unclear whether an altered enzyme activity or, indirectly, a disturbance in transition-metal homeostasis is involved in the disease pathogenesis.}, }
@article {pmid10223093, year = {1999}, author = {Mackin, GA}, title = {Optimizing care of patients with ALS. Steps to early detection and improved quality of life.}, journal = {Postgraduate medicine}, volume = {105}, number = {4}, pages = {143-6, 151-6}, doi = {10.3810/pgm.1999.04.676}, pmid = {10223093}, issn = {0032-5481}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/psychology/*therapy ; Diagnosis, Differential ; Humans ; Neuroprotective Agents/therapeutic use ; Patient Care Team ; Quality of Life ; Riluzole/therapeutic use ; }, abstract = {Primary care physicians should be alert for early, purely motor neurologic signs and symptoms of ALS, a progressive and ultimately fatal motor neuron disease. Because many neuromuscular disorders mimic ALS, careful differential diagnosis is essential. All patients with signs of motor neuron dysfunction need prompt referral to a neurologist at a regional ALS care center to ensure that they receive an accurate diagnosis and disease-specific multidisciplinary care. Once the diagnosis is confirmed, primary care physicians should work closely with the ALS center to ensure continuity of care and provide emotional support for both patient and family. Patients may also benefit from enrollment in treatment trials and the ALS CARE database. Riluzole, the only medication approved for treatment of ALS, has been shown to slow disease progression and prolong survival. Such benefits have provided new hope to patients and have spurred investigators to search for other, more effective medications for use alone or in combination.}, }
@article {pmid10220104, year = {1999}, author = {Eisen, A and Weber, M}, title = {Treatment of amyotrophic lateral sclerosis.}, journal = {Drugs &amp; aging}, volume = {14}, number = {3}, pages = {173-196}, pmid = {10220104}, issn = {1170-229X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antioxidants/*therapeutic use ; Calcium Channel Blockers/therapeutic use ; Clinical Trials as Topic ; Excitatory Amino Acid Agents/*therapeutic use ; Forecasting ; Genetic Therapy ; Growth Substances/therapeutic use ; Humans ; Immunotherapy ; Nerve Growth Factors/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {Survival of patients with amyotrophic lateral sclerosis (ALS) is improving. Timely and more frequent implementation of bimodal passive airway pressure (BIPAP) and percutaneous endoscopically placed gastrostomy (PEG) may be the major factors impacting on longer survival. However, several drugs recently subjected to rigorous clinical trials have demonstrated significant results or encouraging trends. ALS is a complex disease in which aging neurons are subjected to a variety of susceptibility genes, most of which remain to be discovered, that interact with equally unrecognised environmental factors. This makes it unlikely that a single therapeutic agent will be of value. The thrust must be on polypharmacy. The 'cocktail' that will eventually be of greatest benefit has yet to be formulated. It might contain glutamate N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists, antioxidants or a combination of trophic factors and neuroprotective agents. This statement is made with the understanding that the aetiopathogenesis of ALS is far from clear. Drug delivery is a problem and better delivery systems are needed. The efficacy of some of the medications that presently only induce modest benefit may be improved by liposomal packaging, use of a patch or inhalation delivery or intraventricular pump reservoirs. There is a great need to develop an early marker of ALS and sensitive reproducible measures of disease progression. This will curtail the present need for large, lengthy and very expensive clinical trials. The new millennium will see the advent of targeted therapy using viral vectors which can deliver replacement genes, trophic factors and other drugs to degenerating neurons; transplantation of neural progenitor cells which can become mature functioning neurons; anti-apoptotic agents which will allow neurons to survive longer; and mechanisms that can protect the telomerase maintenance system which is so crucial in the immortalisation of cells.}, }
@article {pmid10213726, year = {1999}, author = {Shaw, PJ}, title = {Motor neurone disease.}, journal = {BMJ (Clinical research ed.)}, volume = {318}, number = {7191}, pages = {1118-1121}, pmid = {10213726}, issn = {0959-8138}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Clinical Trials as Topic ; Glutamic Acid/physiology ; Humans ; Motor Neuron Disease/*etiology/genetics/pathology/therapy ; Nerve Degeneration ; Oxidative Stress ; }, }
@article {pmid10193591, year = {1999}, author = {Walling, AD}, title = {Amyotrophic lateral sclerosis: Lou Gehrig's disease.}, journal = {American family physician}, volume = {59}, number = {6}, pages = {1489-1496}, pmid = {10193591}, issn = {0002-838X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/etiology/therapy ; Female ; Humans ; Male ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly called Lou Gehrig's disease, is a progressive neuromuscular condition characterized by weakness, muscle wasting, fasciculations and increased reflexes. Approximately 30,000 Americans currently have the disease. The annual incidence rate is one to two cases per 100,000. The disease is most commonly diagnosed in middle age and affects more men than women. It usually presents with problems in dexterity or gait resulting from muscle weakness. Difficulty in speaking or swallowing is the initial symptom in the bulbar form of the disease. Over a period of months or years, patients with ALS develop severe, progressive muscular weakness and other symptoms caused by loss of function in both upper and lower motor neurons. Sphincter control, sensory function, intellectual abilities and skin integrity are preserved. Patients become completely disabled, often requiring ventilatory support and gastrostomy. Death usually occurs within five years of diagnosis and is attributed to respiratory failure or cachexia. The etiology of the disease is unknown. Current research is focused on abnormalities of neuronal cell metabolism involving glutamate and the role of potential neurotoxins and neurotrophic factors. New drugs are being developed based on these theories. Current management involves aggressive, individualized alleviation of symptoms and complications.}, }
@article {pmid10191634, year = {1999}, author = {Suzuki, H}, title = {[Apoptosis and neurotrophic factors].}, journal = {No to hattatsu = Brain and development}, volume = {31}, number = {2}, pages = {129-134}, pmid = {10191634}, issn = {0029-0831}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; *Apoptosis ; Brain-Derived Neurotrophic Factor/*physiology/therapeutic use ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Motor Neuron Disease/genetics/physiopathology ; Muscular Atrophy/genetics ; *Nerve Growth Factors ; Nerve Tissue Proteins/metabolism ; }, abstract = {Neurotrophic factors are endogenous soluble proteins regulating development, differentiation, and survival of neurons. They are secreted from target cells or surrounding glial cells and act on the neurons via their receptors on the cell membranes. Several factors are reported to promote survival of motor neurons in vitro and to rescue developing motor neurons from naturally occurring cell death. Administration of the factors has also been shown to rescue motor neurons from degeneration after axotomy in adult as well as neonatal rodents. On the basis of these lines of evidence, neurotrophic factors have been considered to be potential candidates for drugs alleviating human motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Although some factors such as ciliary neurotrophic factor and brain-derived neurotrophic factor slowed down the disease progression in animal models of motor neuron disease, phase III clinical trials showed no therapeutic effects for ALS patients treated with these factors. There may be some reasons for this lack of success in humans. Several important issues remain to be resolved such as the drug delivery systems for neurotrophic factors and combination of neurotrophic factors with complementary effects.}, }
@article {pmid10190269, year = {1999}, author = {Miller, RG}, title = {Carrell-Krusen Symposium invited lecture. Clinical trials in motor neuron diseases.}, journal = {Journal of child neurology}, volume = {14}, number = {3}, pages = {173-179}, doi = {10.1177/088307389901400308}, pmid = {10190269}, issn = {0883-0738}, mesh = {Acetates/therapeutic use ; Adolescent ; Adult ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Brain-Derived Neurotrophic Factor/therapeutic use ; Child ; Child, Preschool ; Clinical Trials as Topic/*standards ; *Cyclohexanecarboxylic Acids ; Excitatory Amino Acid Antagonists/therapeutic use ; Female ; Gabapentin ; Glutamic Acid/drug effects ; Guidelines as Topic/*standards ; Humans ; Infant ; Insulin-Like Growth Factor I/therapeutic use ; Male ; Mice ; Middle Aged ; Motor Neuron Disease/*drug therapy/genetics ; Muscular Atrophy, Spinal/diagnosis/*drug therapy/genetics ; Nerve Growth Factors/therapeutic use ; Outcome Assessment, Health Care/organization &amp; administration ; Postpoliomyelitis Syndrome/drug therapy ; Riluzole/therapeutic use ; *gamma-Aminobutyric Acid ; }, abstract = {Although there is no truly effective disease-specific therapy for any of the motor neuron diseases, rapid progress in our understanding of the pathophysiology of some of these disorders is being made. In addition to progress in neuroscience, clinical trials of agents that appear to slow the progress of at least one of these diseases, amyotrophic lateral sclerosis, are beginning to show promising results. The first clinical trials in spinal muscular atrophy are currently underway. A number of other developments have raised the quality of clinical trials, which should improve their productivity and efficiency in the future.}, }
@article {pmid10188205, year = {1999}, author = {Whitcomb, CE}, title = {An introduction to ALS-inhibiting herbicides.}, journal = {Toxicology and industrial health}, volume = {15}, number = {1-2}, pages = {231-239}, doi = {10.1191/074823399678846592}, pmid = {10188205}, issn = {0748-2337}, mesh = {Acetolactate Synthase/*drug effects/metabolism ; Animals ; Drug Resistance ; Environmental Monitoring ; Herbicides/*pharmacology ; Pest Control ; Pesticide Residues/adverse effects ; *Plant Physiological Phenomena ; }, abstract = {Herbicides that inhibit acetolactate synthase (ALS), the enzyme common to the biosynthesis of the branch-chain amino acids (valine, leucine, and isoleucine), affect many species of higher plants as well as bacteria, fungi, yeasts, and algae. The novel mechanism of action attributed to ALS inhibitors, their effect on the reproduction of some plant species, their potency at extremely low concentrations, and the rapid evolution of resistance to these herbicides in some plants and microorganisms are characteristics that set ALS inhibitors apart from their predecessors. This class of chemicals affects seedling growth. Older plants exhibit varied signs of malformation, stunting, and reduced seed production. These herbicides are so potent that they can affect plants at levels that are undetectable by any standard chemical protocol. Weeds quickly become resistant to ALS inhibitors, presumably because these herbicides have a single mode of action and because many have long residual activity. Concern now is directed towards developing the technology to detect very low concentrations of ALS inhibitors in the environment and their indirect effects on plant and animal health.}, }
@article {pmid10093924, year = {1999}, author = {Lyons, TJ and Gralla, EB and Valentine, JS}, title = {Biological chemistry of copper-zinc superoxide dismutase and its link to amyotrophic lateral sclerosis.}, journal = {Metal ions in biological systems}, volume = {36}, number = {}, pages = {125-177}, pmid = {10093924}, issn = {0161-5149}, support = {DK46828/DK/NIDDK NIH HHS/United States ; GM28222/GM/NIGMS NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Enzyme Activation ; Humans ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Mutation ; Oxidation-Reduction ; Protein Conformation ; *Superoxide Dismutase/chemistry/genetics/metabolism ; }, }
@article {pmid10093584, year = {1999}, author = {Siemers, E}, title = {Multiple system atrophy.}, journal = {The Medical clinics of North America}, volume = {83}, number = {2}, pages = {381-392}, doi = {10.1016/s0025-7125(05)70110-3}, pmid = {10093584}, issn = {0025-7125}, mesh = {Brain/pathology ; Cognition Disorders/etiology ; Humans ; Multiple System Atrophy/complications/*diagnosis/pathology ; }, abstract = {MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid10092700, year = {1999}, author = {Polkey, MI and Lyall, RA and Davidson, AC and Leigh, PN and Moxham, J}, title = {Ethical and clinical issues in the use of home non-invasive mechanical ventilation for the palliation of breathlessness in motor neurone disease.}, journal = {Thorax}, volume = {54}, number = {4}, pages = {367-371}, pmid = {10092700}, issn = {0040-6376}, mesh = {Dyspnea/*etiology/*therapy ; *Ethics, Medical ; Humans ; Life Expectancy ; Motor Neuron Disease/*complications ; *Palliative Care ; Quality of Life ; *Respiration, Artificial ; }, }
@article {pmid10080385, year = {1999}, author = {Mufson, EJ and Kroin, JS and Sendera, TJ and Sobreviela, T}, title = {Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {57}, number = {4}, pages = {451-484}, doi = {10.1016/s0301-0082(98)00059-8}, pmid = {10080385}, issn = {0301-0082}, support = {AG09466/AG/NIA NIH HHS/United States ; AG10161/AG/NIA NIH HHS/United States ; AG10668/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Axonal Transport ; Central Nervous System/cytology/*metabolism/pathology ; Fibroblast Growth Factors/administration &amp; dosage/metabolism ; Humans ; Nerve Growth Factors/administration &amp; dosage/*metabolism/pharmacology ; Nerve Tissue Proteins/administration &amp; dosage/*metabolism/pharmacology ; Neurodegenerative Diseases/metabolism/*therapy ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pons. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.}, }
@article {pmid10079842, year = {1998}, author = {Wong, PC and Borchelt, DR and Lee, MK and Pardo, CA and Thinakaran, G and Martin, LJ and Sisodia, SS and Price, DL}, title = {Familial amyotrophic lateral sclerosis and Alzheimer's disease. Transgenic models.}, journal = {Advances in experimental medicine and biology}, volume = {446}, number = {}, pages = {145-159}, pmid = {10079842}, issn = {0065-2598}, support = {AG 05146/AG/NIA NIH HHS/United States ; NS 10580/NS/NINDS NIH HHS/United States ; NS 20471/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/*physiopathology ; Amyloid beta-Protein Precursor/genetics/*physiology ; Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Genetic Diseases, Inborn ; Humans ; Mice ; Mice, Transgenic ; Mutagenesis ; Superoxide Dismutase/genetics/*physiology ; Superoxide Dismutase-1 ; }, }
@article {pmid10079828, year = {1999}, author = {Carrì, MT and Battistoni, A and Ferri, A and Gabbianelli, R and Rotilio, G}, title = {A study of the dual role of copper in superoxide dismutase as antioxidant and pro-oxidant in cellular models of amyotrophic lateral sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {448}, number = {}, pages = {205-213}, doi = {10.1007/978-1-4615-4859-1_18}, pmid = {10079828}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; *Antioxidants ; Copper/*physiology ; Humans ; Models, Biological ; Oxidants/*physiology ; Superoxide Dismutase/genetics/*physiology ; }, }
@article {pmid10079827, year = {1999}, author = {Valentine, JS and Hart, PJ and Gralla, EB}, title = {Copper-zinc superoxide dismutase and ALS.}, journal = {Advances in experimental medicine and biology}, volume = {448}, number = {}, pages = {193-203}, doi = {10.1007/978-1-4615-4859-1_17}, pmid = {10079827}, issn = {0065-2598}, support = {GM28222/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; *Copper ; Humans ; Mutation ; Superoxide Dismutase/chemistry/genetics/*physiology ; *Zinc ; }, }
@article {pmid10076028, year = {1999}, author = {Heales, SJ and Bolaños, JP and Stewart, VC and Brookes, PS and Land, JM and Clark, JB}, title = {Nitric oxide, mitochondria and neurological disease.}, journal = {Biochimica et biophysica acta}, volume = {1410}, number = {2}, pages = {215-228}, doi = {10.1016/s0005-2728(98)00168-6}, pmid = {10076028}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/etiology ; Astrocytes/metabolism/pathology ; Cell Death ; Electron Transport/genetics ; Glutamic Acid/metabolism ; Humans ; Mitochondria/*metabolism/pathology ; Nervous System Diseases/*etiology/genetics ; Neurodegenerative Diseases/etiology/genetics ; Neurons/metabolism/pathology ; Nitrates/metabolism ; Nitric Oxide/*metabolism ; Permeability ; }, abstract = {Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state. Within the brain, the susceptibility of different brain cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage. Thus neurones, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules. Following cytokine exposure, astrocytes can increase NO generation, due to de novo synthesis of the inducible form of nitric oxide synthase (NOS). Whilst the NO/ONOO- so formed may not affect astrocyte survival, these molecules may diffuse out to cause mitochondrial damage, and possibly cell death, to other cells, such as neurones, in close proximity. Evidence is now available to support this scenario for neurological disorders, such as multiple sclerosis. In other conditions, such as ischaemia, increased availability of glutamate may lead to an activation of a calcium-dependent nitric oxide synthase associated with neurones. Such increased/inappropriate NO formation may contribute to energy depletion and neuronal cell death. The evidence available for NO/ONOO--mediated mitochondrial damage in various neurological disorders is considered and potential therapeutic strategies are proposed.}, }
@article {pmid10047920, year = {1999}, author = {Hernández Borge, J and García González, L and Martín Arroyo Caballero, JA and Ruiz Avalos, A}, title = {[Acute respiratory failure as the presentation of amyotrophic lateral sclerosis. Apropos a case].}, journal = {Archivos de bronconeumologia}, volume = {35}, number = {1}, pages = {48-50}, doi = {10.1016/s0300-2896(15)30324-0}, pmid = {10047920}, issn = {0300-2896}, mesh = {Acute Disease ; Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Fatal Outcome ; Humans ; Hypercapnia/diagnosis/etiology ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/etiology ; Respiratory Insufficiency/*diagnosis/etiology ; }, abstract = {We report the case of a 61-year-old man with amyotrophic lateral sclerosis presenting with respiratory failure requiring long-term mechanical ventilation. Diagnostic difficulties are discussed along with the circumstances that give rise to suspicion of neuromuscular disease in a context of respiratory failure of unknown cause. The patient is at present in stable condition after 6 months of domiciliary mechanical ventilation. The treatment options in such cases and their indications are discussed.}, }
@article {pmid10023133, year = {1999}, author = {Cruz, DC and Nelson, LM and McGuire, V and Longstreth, WT}, title = {Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-based case-control study.}, journal = {Neuroepidemiology}, volume = {18}, number = {2}, pages = {101-110}, doi = {10.1159/000069413}, pmid = {10023133}, issn = {0251-5350}, support = {R01 NS031964/NS/NINDS NIH HHS/United States ; R01NS27889/NS/NINDS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*genetics ; Case-Control Studies ; Female ; Fractures, Bone/*epidemiology ; Humans ; Male ; Middle Aged ; Population Surveillance ; }, abstract = {This population-based case-control study was conducted in three counties in western Washington state (USA) between 1990 and 1994 to assess the association between amyotrophic lateral sclerosis (ALS) and several hypothesized risk factors, including a family history of neurodegenerative diseases, physical trauma (fractures, electrical shocks, and surgeries), rural residence, travel, and medical history. One hundred seventy-four cases with ALS, newly diagnosed by neurologists, were identified through several case-finding methods. Two controls (n = 348), who were matched to each case by gender and age (+/-5 years), were identified through random digit telephone dialing or Medicare lists. Exposure data were collected through structured in-person interviews. A greater proportion of cases (2. 3%) than controls (0.9%) reported a first-degree relative with ALS, resulting in an odds ratio of 3.1 (95% CI, 0.6-15.7). For a positive family history of ALS among second-degree relatives, the odds ratio was 4.0 (95% CI, 1.0-16.6). Overall, reports of first- or second-degree relatives with ALS yielded a significantly elevated odds ratio of 3.3 (95% CI, 1.1-9.9). No association was found with a family history of Alzheimer's disease or Parkinson's disease, or with a family history of the neurodegenerative diseases as a group. No significant associations were demonstrated for any of the other factors analyzed, including a history of fractures, electrical shocks, or surgeries, a history of residence in rural areas, a history of travel to areas in the western Pacific where ALS is endemic, and a medical history of polio, polio immunization, or tetanus immunization.}, }
@article {pmid9989458, year = {1999}, author = {Cookson, MR and Shaw, PJ}, title = {Oxidative stress and motor neurone disease.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {9}, number = {1}, pages = {165-186}, pmid = {9989458}, issn = {1015-6305}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Apoptosis ; Calcium/metabolism ; Humans ; Hydroxyl Radical/metabolism ; Mitochondria/metabolism ; Motor Neuron Disease/enzymology/*metabolism/pathology/therapy ; Motor Neurons/metabolism/pathology ; Mutation ; Neurofilament Proteins/metabolism ; Oxidative Stress/*physiology ; Proteins/metabolism ; Superoxide Dismutase/genetics/metabolism/*physiology ; Superoxide Dismutase-1 ; }, abstract = {The effects of oxidative stress within post mitotic cells such as neurones may be cumulative, and injury by free radical species is a major potential cause of the age-related deterioration in neuronal function seen in several neurodegenerative diseases. There is strong evidence that oxidative stress plays an important role in the pathogenesis of motor neurone disease (MND). Point mutations in the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) are found in some pedigrees with the familial form of MND. How mutations in this ubiquitous enzyme cause the relatively selective cell death of specific groups of motor neurones is not clear, although a number of hypotheses have been forwarded. These include (1) the formation of hydroxyl radicals, (2) the catalysis of reactions of the nitrogen centred oxidant species peroxynitrite, (3) toxicity of copper or zinc and (4) protein aggregation. Some experimental support for these different hypotheses has been produced by manipulating cells in culture to express the mutant SOD1 proteins and by generating transgenic mice which over-express mutant SOD1. Observations in these model systems are, in some cases at least, supported by observations made on pathological material from patients with similar SOD1 mutations. Furthermore, there are reports of evidence of free radical mediated damage to neurones in the sporadic form of MND. Several lines of evidence suggest that alterations in the glutamatergic neurotransmitter system may also play a key role in the injury to motor neurones in sporadic MND. There are several important subcellular targets, which may be preferentially impaired within motor neurones, including neurofilament proteins and mitochondria. Future research will need to identify the aspects of the molecular and physiological phenotype of human motor neurones that makes them susceptible to degeneration in MND, and to identify those genetic and environmental factors which combine to cause this disease in individuals and in familial pedigrees.}, }
@article {pmid9974153, year = {1999}, author = {Morrison, BM and Morrison, JH}, title = {Amyotrophic lateral sclerosis associated with mutations in superoxide dismutase: a putative mechanism of degeneration.}, journal = {Brain research. Brain research reviews}, volume = {29}, number = {1}, pages = {121-135}, doi = {10.1016/s0165-0173(98)00049-6}, pmid = {9974153}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; Mice ; Mice, Transgenic/genetics ; Mutation/*physiology ; Nerve Degeneration/*genetics ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurologic disease that rapidly progresses from mild motor symptoms to severe motor paralysis and premature death. Until recently, there were few substantive studies conducted on the pathogenesis of the disease. With the genetic linkage of mutations in the superoxide dismutase (SOD-1) gene with familial ALS patients, new avenues for study have become available including transgenic mice and culture models. Although not yet providing a complete picture of the disease mechanism, studies utilizing these model systems have greatly advanced our understanding of the mechanism of degeneration and should eventually lead to putative therapeutic agents. In this review, we will present the important findings from these model systems, provide a framework in which to evaluate these findings, and speculate on the mechanism of degeneration initiated by the mutations in SOD-1.}, }
@article {pmid9974149, year = {1999}, author = {Cassarino, DS and Bennett, JP}, title = {An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration.}, journal = {Brain research. Brain research reviews}, volume = {29}, number = {1}, pages = {1-25}, doi = {10.1016/s0165-0173(98)00046-0}, pmid = {9974149}, support = {NS34299/NS/NINDS NIH HHS/United States ; NS35325/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell Death/physiology ; Cell Nucleus/*physiology ; Humans ; Mitochondria/metabolism/*physiology ; Mutation/*physiology ; Neurodegenerative Diseases/*physiopathology ; Oxidative Stress/*physiology ; }, abstract = {There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's disease and amyotrophic lateral sclerosis. Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death in numerous model systems. Although protective nuclear responses such as antioxidant enzymes and bcl-2 may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and clearly points out many potential therapeutic targets for preventing or ameliorating these diseases.}, }
@article {pmid9951030, year = {1998}, author = {Borrás-Blasco, J and Plaza-Macías, I and Navarro-Ruiz, A and Perís-Martí, J and Antón-Cano, A}, title = {[Riluzole as a treatment for amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {27}, number = {160}, pages = {1021-1027}, pmid = {9951030}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {INTRODUCTION: The Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by the selective degeneracy of the superior motoneurons of the cortex motor and of the inferior motoneurons at level of the encephalic trunk and spinal marrow. Exist sporadic and familiar forms, being estimated an incidence of 1-2 cases by 100,000 inhabitants. The cause of the neuronal degeneracy is yet unknown, being implied, between other mechanisms, the glutamic exotoxicity is the responsible for the death neuronal. The riluzol is a benzothiazole derivative whose neuroprotector mechanism still it has not been totally clarified, though seems that reduces the neuroexcitatory action of the glutamic acid blocking his transmission.<br><br>DEVELOPMENT: Two clinical trials have been accomplished with similar characteristics: multicentre, randomized, double blind, and placebo-controlled. Between both studies have been included more than 1,100 patient, obtained significant statistic results in the prolongation of the survival time, however this effect was not going accompanied of an improvement in the muscular force neither of the pulmonary capacity, what is translated in which the riluzol does not modify the quality of life of the patient. The drug presents good tolerance and mild adverse effects and as consequence of this in 1996, the FDA approved his marketing and utilization in the treatment of the ALS. The approval of the riluzol as first agent for the treatment of the ALS has raised an important number of problems about the efficiency and cost of the treatment.<br><br>CONCLUSION: Though its benefits are modest, it is considered a starting point in the pharmacotherapy of the ALS.}, }
@article {pmid9949861, year = {1998}, author = {Wagey, RT and Krieger, C}, title = {Abnormalities of protein kinases in neurodegenerative diseases.}, journal = {Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques}, volume = {51}, number = {}, pages = {133-183}, doi = {10.1007/978-3-0348-8845-5_4}, pmid = {9949861}, issn = {0071-786X}, mesh = {Alzheimer Disease/enzymology ; Amyotrophic Lateral Sclerosis/enzymology ; Animals ; Apoptosis ; Brain/*enzymology/physiopathology ; Humans ; Neurodegenerative Diseases/*enzymology/physiopathology ; Protein Kinases/*metabolism ; Spinal Cord/*enzymology/physiopathology ; }, abstract = {In neurodegenerative diseases such as ALS and AD there is evidence for abnormal regulation of protein kinases. In these diseases, altered activities and protein levels of several specific kinases suggest that abnormal phosphorylation is present and this aberrant phosphorylation may be involved in the pathogenesis of these diseases. The observation that regulation of the NMDA receptor ion channel is altered in tissue from ALS patients may arise from the abnormal phosphorylation state of the protein kinase regulating NMDA receptor function. Whether the abnormalities of these protein kinases is a primary event leading to altered receptor regulation or vice versa is still poorly understood. The seemingly multiple pathogenic mechanisms of ALS and AD create complexity in assessing a primary cause that may lead to cell death. The mechanisms causing cell death (apoptosis or necrosis) may be overlapping with integrated events among the components interacting and contributing to a final pathway for neuron death. Thus, evidence of impairment in protein kinase signalling in these diseases may be a primary cause, a secondary event, or a compensatory mechanism. To further study this issue, different model systems could be beneficial to obtain a better understanding of these diseases.}, }
@article {pmid9932448, year = {1998}, author = {Estévez, AG and Spear, N and Manuel, SM and Barbeito, L and Radi, R and Beckman, JS}, title = {Role of endogenous nitric oxide and peroxynitrite formation in the survival and death of motor neurons in culture.}, journal = {Progress in brain research}, volume = {118}, number = {}, pages = {269-280}, doi = {10.1016/s0079-6123(08)63214-8}, pmid = {9932448}, issn = {0079-6123}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Apoptosis ; Brain-Derived Neurotrophic Factor/pharmacology ; Cell Death ; Cell Survival/drug effects/physiology ; Humans ; Motor Neurons/cytology/drug effects/*metabolism ; Nitrates/metabolism/*physiology ; Nitric Oxide/biosynthesis/*physiology ; Superoxide Dismutase/genetics ; Tyrosine/analogs &amp; derivatives/physiology ; }, abstract = {Motor neuron survival is highly dependent on trophic factor supply. Deprivation of trophic factors results in induction of neuronal NOS, which is also found in pathological conditions. Growing evidence suggests that motor neuron degeneration involves peroxynitrite formation. Trophic factors modulate peroxynitrite toxicity (Estévez et al., 1995; Shin et al., 1996; Spear et al., 1997). Whether a trophic factor prevents or potentiates peroxynitrite toxicity depends upon when the cells are exposed to the trophic factor (Table 1). These results strongly suggest that a trophic factor that can protect neurons under optimal conditions, but under stressful conditions can increase cell death. In this context, it is possible that trophic factors or cytokines produced as a response to damage may potentiate rather than prevent motor neuron death. A similar argument may apply to the therapeutic administration of trophic factors to treat neurodegenerative diseases. Similarly, the contrasting actions of NO on motor neurons may have important consequences for the potential use of nitric oxide synthase inhibitors in the treatment of ALS and other related neurodegenerative diseases.}, }
@article {pmid9922416, year = {1999}, author = {Young, KD and Seidel, JS}, title = {Pediatric cardiopulmonary resuscitation: a collective review.}, journal = {Annals of emergency medicine}, volume = {33}, number = {2}, pages = {195-205}, doi = {10.1016/s0196-0644(99)70394-x}, pmid = {9922416}, issn = {0196-0644}, mesh = {Age Distribution ; *Cardiopulmonary Resuscitation ; Child ; Heart Arrest/complications/*mortality/*therapy ; Humans ; Outcome Assessment, Health Care ; Research ; }, abstract = {Little information is available about the effects of CPR in children, although it is known that the outcomes are dismal. Examples of unanswered questions include which advanced life support (ALS) procedures should be performed out-of-hospital, whether high-dose epinephrine improves survival, and the true prevalence of ventricular fibrillation as a presenting rhythm. Children differ from adults as to the cause and pathophysiology of cardiopulmonary arrest, but prehospital EMS and hospital resuscitation teams were initially designed for the care of adults. Because pediatric cardiopulmonary arrest is rare, prospective data are difficult to gather, and there are few large published studies. The purpose of this collective review was to review the current body of knowledge regarding survival rates and outcomes in pediatric CPR and, based on this review, to outline a course for future research.}, }
@article {pmid9894144, year = {1998}, author = {Carter, GT and Miller, RG}, title = {Comprehensive management of amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {9}, number = {1}, pages = {271-84, viii-ix}, pmid = {9894144}, issn = {1047-9651}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/physiopathology/psychology/*therapy ; Comprehensive Health Care/*organization &amp; administration ; Disease Progression ; Humans ; Patient Care Planning/*organization &amp; administration ; Patient Care Team/*organization &amp; administration ; Physical and Rehabilitation Medicine ; Terminal Care/organization &amp; administration ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease that poses a myriad of clinical problems. Patients with ALS are best treated in a multidisciplinary setting involving physicians, clinical nursing specialists, and physical, occupational, speech, and respiratory therapists, as well as psychologists and social workers. Palliative and rehabilitative strategies may ease suffering, while new treatments provide hope for effective treatment of this disease.}, }
@article {pmid9890561, year = {1999}, author = {Bohn, MC}, title = {A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy.}, journal = {Biochemical pharmacology}, volume = {57}, number = {2}, pages = {135-142}, doi = {10.1016/s0006-2952(98)00280-9}, pmid = {9890561}, issn = {0006-2952}, support = {NS31957/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Dopamine/physiology ; *Genetic Therapy ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Motor Neuron Disease/drug therapy ; Nerve Growth Factors/genetics/*metabolism ; Nerve Tissue Proteins/genetics/*metabolism/therapeutic use ; Neuroglia/*metabolism ; Neurons/physiology ; Parkinson Disease/drug therapy ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) was identified as a consequence of the hypothesis that glia secrete factors that influence growth and differentiation of specific classes of neurons. Glia are a likely source of additional neurotrophic factors; however, this strategy has not been applied extensively. The discovery of GDNF in 1993 led to an abundance of studies that within only a few years qualified GDNF as a bona fide neurotrophic factor. Of particular interest are studies demonstrating the effectiveness of GDNF protein in ameliorating neurodegeneration in animal models of Parkinson's disease and amyotrophic lateral sclerosis (ALS). It remains to be determined whether GDNF will be an effective therapy in humans with these diseases. However, since these diseases are slowly progressive and the CNS relatively inaccessible, the delivery of GDNF as a therapeutic molecule to the CNS in a chronic manner is problematic. Studies addressing this problem are applying viral vector mediated transfer of the GDNF gene to the CNS in order to deliver biosynthesized GDNF to a specific location in a chronic manner. Recent studies suggest that these GDNF gene therapy approaches are effective in rat models of Parkinson's disease. These studies are reviewed in the context of what developments will be needed in order to apply GDNF gene therapy to the clinic.}, }
@article {pmid9876873, year = {1998}, author = {Facchinetti, F and Dawson, VL and Dawson, TM}, title = {Free radicals as mediators of neuronal injury.}, journal = {Cellular and molecular neurobiology}, volume = {18}, number = {6}, pages = {667-682}, pmid = {9876873}, issn = {0272-4340}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Brain/pathology/*physiopathology ; Brain Ischemia/*physiopathology ; Free Radicals ; Humans ; Neurodegenerative Diseases/*physiopathology ; Neurons/cytology/*physiology ; *Oxidative Stress ; Parkinson Disease/physiopathology ; Spinal Cord/pathology/*physiopathology ; Superoxide Dismutase/genetics ; }, abstract = {1. Free radicals may play an important role in several pathological conditions of the central nervous system (CNS) where they directly injure tissue and where their formation may also be a consequence of tissue injury. 2. Free radicals produce tissue damage through multiple mechanisms, including excito-toxicity, metabolic dysfunction, and disturbance of intracellular homeostasis of calcium. 3. Oxidative stress can significantly worsen acute insults, such as ischemia, as well as chronic neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease. 4. For instance, recent findings suggest a causal role for chronic oxidative stress in familial ALS, as this disease is linked to missence mutations of the copper/zinc superoxide dismutase (SOD). 5. Thus, therapeutic approaches which limit oxidative stress may be potentially beneficial in several neurological diseases.}, }
@article {pmid9851659, year = {1998}, author = {Kurek, JB and Radford, AJ and Crump, DE and Bower, JJ and Feeney, SJ and Austin, L and Byrne, E}, title = {LIF (AM424), a promising growth factor for the treatment of ALS.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S106-13}, doi = {10.1016/s0022-510x(98)00208-1}, pmid = {9851659}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Drug Delivery Systems ; Growth Inhibitors/chemistry/physiology/*therapeutic use ; Humans ; *Interleukin-6 ; Leukemia Inhibitory Factor ; Lymphokines/chemistry/physiology/*therapeutic use ; Mice ; Mice, Neurologic Mutants ; Muscle, Skeletal/drug effects/physiology ; Nervous System/drug effects ; Neurons/drug effects ; Receptors, Cytokine/metabolism ; Regeneration/drug effects ; Signal Transduction ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.}, }
@article {pmid9851646, year = {1998}, author = {Swash, M}, title = {Early diagnosis of ALS/MND.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S33-6}, doi = {10.1016/s0022-510x(98)00215-9}, pmid = {9851646}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/genetics ; Diagnosis, Differential ; Electromyography ; Humans ; Middle Aged ; Prognosis ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics ; Time Factors ; }, abstract = {With the advent of a specific biological therapy for ALS there is an increasing imperative for early diagnosis. As new, more effective therapies become available, this will become more important. It is intuitively probable that early therapy will prevent disability in this otherwise relentlessly progressive disorder. The difficulties posed by this need for early diagnosis in clinical practice are discussed.}, }
@article {pmid9851643, year = {1998}, author = {Rowland, LP}, title = {Diagnosis of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S6-24}, doi = {10.1016/s0022-510x(98)00193-2}, pmid = {9851643}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Atrophy/diagnosis ; Central Nervous System Diseases/diagnosis ; Cervical Vertebrae ; Diagnosis, Differential ; Electromyography ; Fasciculation/diagnosis ; Humans ; Infections/diagnosis ; Lymphoproliferative Disorders/complications ; Motor Neuron Disease/diagnosis ; Myositis, Inclusion Body/diagnosis ; Neuromuscular Diseases/diagnosis ; Paraneoplastic Syndromes/diagnosis ; Peripheral Nervous System Diseases/diagnosis ; Spinal Osteophytosis/diagnosis ; Thyrotoxicosis/diagnosis ; beta-N-Acetylhexosaminidases/deficiency ; }, abstract = {This review of the differential diagnosis of amyotrophic lateral sclerosis focuses on two themes. The first is practical, how to establish the diagnosis based primarily on clinical findings buttressed by electrodiagnosis. The main considerations are multifocal motor neuropathy and cervical spondylotic myelopathy. The second theme is the relationship of motor neuron disease to other conditions, including benign fasciculation (Denny-Brown, Foley syndrome), paraneoplastic syndromes, lymphoproliferative disease, radiation damage, monomelic amyotrophy (Hirayama syndrome), as well as an association with parkinsonism, dementia and multisystem disorders of the central nervous system.}, }
@article {pmid9850924, year = {1998}, author = {McGeer, PL and McGeer, EG}, title = {Mechanisms of cell death in Alzheimer disease--immunopathology.}, journal = {Journal of neural transmission. Supplementum}, volume = {54}, number = {}, pages = {159-166}, doi = {10.1007/978-3-7091-7508-8_15}, pmid = {9850924}, issn = {0303-6995}, mesh = {Alzheimer Disease/*immunology/*pathology ; Astrocytes/pathology ; Brain/immunology/*pathology ; Humans ; Inflammation ; Microglia/pathology ; Models, Immunological ; Models, Neurological ; Neurons/pathology ; Parkinson Disease/immunology/pathology ; }, abstract = {Lesions in such chronic neurodegenerative disorders as Alzheimer disease, Parkinson disease, the parkinsonism dementia complex of Guam and amyotrophic lateral sclerosis have associated with them a variety of proteins known to be involved in inflammatory processes. This is particularly true of Alzheimer disease where inflammatory reactions are thought to be important contributors to the neuronal loss. They include complement proteins, complement inhibitors, acute phase reactants, inflammatory cytokines, proteases and protease inhibitors. Studies of cultured human astrocytes and microglia, obtained from postmortem brain, have established that nearly all of these proteins are produced by one or another of these cell types. Human neurons also produce many inflammatory proteins and their inhibitors, creating complex interactions. Accumulations of amyloid and extracellular tangles apparently act as irritants, causing the activation of complement, the initiation of reactive changes in microglia, and the release of potentially neurotoxic products. Such products include the membrane attack complex, oxygen free radicals and excess glutamate. Twenty epidemiological studies that have been published to data indicate that populations taking antiinflammatory drugs have a significantly reduced prevalence of Alzheimer disease or a slower mental decline. One small clinical trial with indomethacin showed arrest of the disease over a 6 month period. Therapeutic intervention in key inflammatory processes holds great promise for the amelioration of Alzheimer disease and possibly other neurodegenerative disorders.}, }
@article {pmid9842550, year = {1998}, author = {Okamoto, K}, title = {[Hippocampal pathology in dementia patients with amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {50}, number = {10}, pages = {915-922}, pmid = {9842550}, issn = {0006-8969}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*pathology ; Dementia/complications/*pathology ; Entorhinal Cortex/chemistry/pathology ; Female ; Frontal Lobe/*pathology ; Hippocampus/*pathology ; Humans ; Male ; Middle Aged ; Temporal Lobe/*pathology ; Ubiquitins/analysis ; }, }
@article {pmid9840894, year = {1998}, author = {McComas, AJ}, title = {1998 ISEK Congress Keynote Lecture: Motor units: how many, how large, what kind? International Society of Electrophysiology and Kinesiology.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {8}, number = {6}, pages = {391-402}, doi = {10.1016/s1050-6411(98)00020-0}, pmid = {9840894}, issn = {1050-6411}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Child ; Electromyography ; Humans ; Middle Aged ; Motor Neurons/cytology/*physiology ; Muscle Contraction/*physiology ; Muscle Fibers, Skeletal/cytology/physiology ; Muscle, Skeletal/cytology/innervation/*physiology ; Neuromuscular Diseases/pathology/physiopathology ; }, abstract = {There are now at least nine methods for motor unit number estimation (MUNE) in living human muscles. All methods are based on the comparison of an average single motor unit potential (or twitch) with the response of the whole muscle. Such estimations have been performed for proximal and distal muscles of the arm and leg in healthy subjects and in patients with various neuromuscular disorders. In healthy subjects there is a loss of motor units which is most evident in distal muscles and after the age of 60 years. Substantial losses of motor units have been measured in patients with ALS, post-polio symptoms, and diabetic peripheral neuropathies. In contrast, normal MUNEs have been found in approximately half of patients with persisting obstetric brachial palsies. The sizes of motor units show considerable variations within the same muscle and also between muscles; very large units are usually present in severe partial denervation. Although many motor unit properties are largely governed by motoneurons, some exhibit less plasticity in humans than in other mammals.}, }
@article {pmid9834544, year = {1998}, author = {Hauw, JJ and Seilhean, D and Colle, MA and Hogenhuys, J and Duyckaerts, C}, title = {[Neuropathologic markers in degenerative dementias].}, journal = {Revue neurologique}, volume = {154 Suppl 2}, number = {}, pages = {S50-64}, pmid = {9834544}, issn = {0035-3787}, mesh = {Biomarkers ; Humans ; Nerve Degeneration/metabolism/*pathology/psychology ; }, abstract = {The number of neuropathological markers used for the diagnosis of degenerative dementias is rapidly increasing, and this is somewhat confusing: some lesions described a long time ago, such as ballooned cells, proved to be less specific than they were supposed to be; this is also the case for Lewy bodies, that have been recognised in a larger spectrum of disorders than thought a few years ago. On the contrary, for an increasing number of neuropathologists, Pick bodies are now mandatory for the diagnosis of Pick disease, and this contrasts with the prevalent opinions of the late sixties or seventies. There are a number of reasons for the changing significance of neuropathological markers. Three of them can be easily identified: 1) the burst of immunohistochemistry into neuropathology allowed an easier recognition, a better delineation and new pathophysiological approaches to old lesions, and a dramatic increase in the description of new markers, especially in glial cells; 2) in some conditions characterized by the number and distribution of some lesions rather than by their mere presence, such as aging and Alzheimer disease, a better neuroanatomical point of view permitted new insights into the concept of disease versus age-related changes; 3) more accurate clinicopathologic correlations showed clearly the need of grouping or lumping together some entities: for example, obvious relationship aroused between progressive supranuclear palsy and corticobasal degeneration; in contrast, distinguishing different disorders in the frontal lobe dementias grouped together into "Pick disease" was felt necessary. This review summarizes the main criteria for identification, and the presumed meaning of the chief markers indicating the presence of abnormally phosphorylated tau proteins, A beta peptides, and PrP proteins. Abnormally phosphorylated tau proteins can be stored in the neurons, and participate in the constitution of many lesions (neurofibrillary tangles, neuropil threads, abnormal processes of the crown of neuritic senile plaques, Pick bodies, granulo-vacuolar degeneration, argyrophilic grains). When seen in neuroglia, they are the chief constituents of various lesions that affect mainly astrocytes (abnormal tufts of fibres, astrocytic plaques, thorn-shaped astrocytes, spiny astrocytes) and also oligodendrocytes (oligodendroglial threads and coils, glial cytoplasmic inclusions). A beta peptides, in "preamyloid" and amyloid conformations, can be seen in the extracellular space (plaques, of the neuritic or non-neuritic varieties, diffuse, focal and granular deposits) and in the vascular walls (amyloid angiopathies). Some PrP deposits are also of the amyloid variety (kuru type, multicentric or florid plaques), but immunohistochemistry, far more sensitive than conventional studies, revealed a number of other lesions (perivacuolar, neuronal, "synaptic" deposits...). Numerous markers are easily detected by ubiquitin immunohistochemistry. Lewy bodies, Pick bodies, neurofibrillary tangles had already be identified by other methods. In contrast, some ubiquitin-positive inclusions are shown, by this technique only, in amyotrophic lateral sclerosis and other conditions which were thus related to this disease. Finally, this review deals with two classic markers, ballooned cells ("Pick cells") and spongiosis seen in disorders due to non conventional agents or prions (spongiform encephalopathies).}, }
@article {pmid9810774, year = {1998}, author = {Ferencík, M and Novák, M and Mikula, I and Sokol, J}, title = {[Prionoses--neurodegenerative diseases caused by prions, offectious proteinaceous molecules].}, journal = {Bratislavske lekarske listy}, volume = {99}, number = {8-9}, pages = {486-498}, pmid = {9810774}, issn = {0006-9248}, mesh = {Animals ; Humans ; *Prion Diseases/diagnosis/transmission/veterinary ; *Prions ; Zoonoses ; }, abstract = {Prionoses are a group of human and animal neurodegenerative diseases caused by prions, infectious pathogens that differ from bacteria, fungi, parasites, viroids, and viruses. Despite intensive searches over the past three decades, no nucleic acid has been found within prions and considerable experimental data argue that prions are composed exclusively of proteins (glycoproteins). Normal prion protein (PrPC) is encoded by a gene present in all nuclear cells of humans and other mammals but is constitutively expressed mainly in neurons. PrPC is protease sensitive and nonpathogenic but it can be modified to the pathological and protease resistant form designated PrPSC which is essential for infectivity. Prion diseases are manifested as infectious, genetic, or sporadic disorders and are also named as transmissible spongiform encephalopathies (TSE). TSE culminate with a progressive and fatal degeneration of the CNS. The human prionoses include Creutzfeldt-Jakob disease (CJD), kuru, Gerstman-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). In mammals, more than 15 different species have been described to suffer from prion disorders till now. Scrapie of sheep and goats is the oldest and the most studied of the prion diseases. Bovine spongiform encephalopathy (BSE) and transmissible mink encephalopathy are thought to result from the feeding of scrapie-infected animal products, whereas BSE has been identified in transmission to mice, domestic cats, two exotic species of ruminant, and monkey. More than 20 cases of clinically and pathologically atypical form of CJD, referred to as "new variant" CJD (vCJD) have been recognized in unusually young people in the United Kingdom. There is a strong evidence that the same prion strain is involved in both BSE and vCJD. It suggest the breaking of species barrier which results by spreading of BSE to humans, putatively by dietary exposure. Understanding the function of prion proteins and their modification to the pathological form may give new insight into the etiologic and pathogenic mechanisms also other diseases caused by aberrant proteins, including Alzheimer' disease, amyotrophic lateral sclerosis, and Parkinson's disease. (Tab. 4, Fig. 3, Ref. 76.)}, }
@article {pmid9804539, year = {1998}, author = {Price, DL and Sisodia, SS and Borchelt, DR}, title = {Genetic neurodegenerative diseases: the human illness and transgenic models.}, journal = {Science (New York, N.Y.)}, volume = {282}, number = {5391}, pages = {1079-1083}, doi = {10.1126/science.282.5391.1079}, pmid = {9804539}, issn = {0036-8075}, support = {NS 10580/NS/NINDS NIH HHS/United States ; NS 20471/NS/NINDS NIH HHS/United States ; NS 37145/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism/pathology ; Amino Acid Sequence ; Amyloid beta-Protein Precursor/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Disease Models, Animal ; Humans ; Huntington Disease/genetics/metabolism/pathology ; Mice ; *Mice, Transgenic ; Molecular Sequence Data ; Neurodegenerative Diseases/*genetics/metabolism/pathology ; Peptides/genetics ; Trinucleotide Repeats ; }, abstract = {Review The neurodegenerative disorders, a heterogeneous group of chronic progressive diseases, are among the most puzzling and devastating illnesses in medicine. Some of these disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, the prion diseases, and Parkinson's disease, can occur sporadically and, in some instances, are caused by inheritance of gene mutations. Huntington's disease is acquired in an entirely genetic manner. Transgenic mice that express disease-causing genes recapitulate many features of these diseases. This review provides an overview of transgenic mouse models of familial amyotrophic lateral sclerosis, familial Alzheimer's disease, and Huntington's disease and the emerging insights relevant to the underlying molecular mechanisms of these diseases.}, }
@article {pmid9804538, year = {1998}, author = {Hardy, J and Gwinn-Hardy, K}, title = {Genetic classification of primary neurodegenerative disease.}, journal = {Science (New York, N.Y.)}, volume = {282}, number = {5391}, pages = {1075-1079}, doi = {10.1126/science.282.5391.1075}, pmid = {9804538}, issn = {0036-8075}, mesh = {Alzheimer Disease/classification/genetics/pathology ; Brain/pathology ; Genes, Dominant ; Humans ; Mutation ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*classification/*genetics/pathology ; Parkinson Disease/classification/genetics/pathology ; Peptides/genetics/metabolism ; Synucleins ; Trinucleotide Repeats ; tau Proteins/genetics ; }, abstract = {Review During the past 10 years (the "decade of the brain"), some of the genetic causes of many of the primary neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, and many ataxic syndromes, have been found. These breakthroughs mean that for many of these diseases we now know the initiating trigger as well as the final outcome. These diseases have many pathological mechanisms in common, and there may be relatively few pathways to neuronal death seen in these disorders. Thus, treatment strategies developed for a particular disease may be found to have efficacy in more than one disorder.}, }
@article {pmid9804382, year = {1998}, author = {Julien, JP and Couillard-Després, S and Meier, J}, title = {Transgenic mice in the study of ALS: the role of neurofilaments.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {8}, number = {4}, pages = {759-769}, pmid = {9804382}, issn = {1015-6305}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Humans ; Mice ; Mice, Transgenic/*genetics ; Mutation/physiology ; Neurofilament Proteins/*genetics/*physiology ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder of multiple etiologies that affects primarily motor neurons in the brain and spinal cord. Abnormal accumulations of neurofilaments (NFs) in motor neurons and a down-regulation of mRNA for the NF light subunit (NF-L) are associated with ALS, but it remains unclear to what extent these NF perturbations contribute to human disease. Transgenic mouse studies demonstrated that overexpression of normal and mutant NF proteins can sometimes provoke a motor neuronopathy characterized by the presence of abnormal NF accumulations resembling those found in ALS. Remarkably, the motor neuronopathy in transgenic mice overexpressing human NF heavy (NF-H) subunits was rescued by the co-expression of a human NF-L transgene at levels that restored a correct stoichiometry of NF-L to NF-H subunits. Transgenic approaches have also been used to investigate the role of NFs in disease caused by Cu/Zn superoxide dismutase (SOD1) mutations, which is responsible for approximately 2% cases of ALS. Studies with transgenic mice expressing low levels of a fusion NF-H/lacZ protein, in which NFs are withheld from the axonal compartment, suggested that axonal NFs are not toxic intermediates required for SOD1-mediated disease. On the contrary, overexpression of human NF-H proteins was found to confer an effective protection against mutant SOD1 toxicity in transgenic mice, a phenomenon that may be due to the ability of NF proteins to chelate calcium. In conclusion, transgenic studies showed that disorganized NFs can sometimes have noxious effects resulting in neuronopathy. However, in the context of motor neuron disease caused by mutant SOD1, there is emerging evidence that NF proteins rather play a protective role.}, }
@article {pmid9804381, year = {1998}, author = {Borchelt, DR and Wong, PC and Sisodia, SS and Price, DL}, title = {Transgenic mouse models of Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {8}, number = {4}, pages = {735-757}, pmid = {9804381}, issn = {1015-6305}, support = {AG 14248/AG/NIA NIH HHS/United States ; NS 37145/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*genetics/*pathology ; Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Animals ; Humans ; Mice ; Mice, Transgenic/*genetics ; }, abstract = {Over the past several years, there has been enormous progress in generating transgenic mice that model aspects of human neurodegenerative diseases. These studies build upon the efforts of molecular geneticists who have identified a number of genes that, when mutated, cause familial forms of these diseases. In this review, we focus on the mutations that cause familial forms of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), and transgenic mouse models that develop clinical and pathological abnormalities resembling those occurring in the human diseases.}, }
@article {pmid9791781, year = {1998}, author = {Neatherlin, JS}, title = {Management of amyotrophic lateral sclerosis with riluzole.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {30}, number = {4}, pages = {257-260}, doi = {10.1097/01376517-199808000-00007}, pmid = {9791781}, issn = {0888-0395}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/nursing ; Humans ; Information Services ; Neuroprotective Agents/pharmacology/*therapeutic use ; Patient Selection ; Riluzole/pharmacology/*therapeutic use ; Self-Help Groups ; }, abstract = {In summary, riluzole is a recently-released drug for the treatment of ALS. While it will not cure the disease, it does prolong survival time and ventilator-free time. Riluzole has few adverse effects, but liver enzymes should be watched closely for elevations.}, }
@article {pmid9786609, year = {1998}, author = {Delanty, N and Dichter, MA}, title = {Oxidative injury in the nervous system.}, journal = {Acta neurologica Scandinavica}, volume = {98}, number = {3}, pages = {145-153}, doi = {10.1111/j.1600-0404.1998.tb07285.x}, pmid = {9786609}, issn = {0001-6314}, mesh = {Central Nervous System Diseases/physiopathology ; Free Radicals ; Humans ; Lipid Peroxidation/*physiology ; Nervous System/physiopathology ; Nervous System Diseases/*physiopathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {A free radical is a highly reactive chemical species that can react with organic macromolecules leading to cell and tissue damage and consequent functional disruption. Free radical or oxidative injury is increasingly recognized as an important factor in the pathophysiology of many human diseases, including those that affect the nervous system. This review summarizes important evidence implicating oxidative injury in the pathogenesis and progression of many important neurological disorders, including cerebrovascular disease, epilepsy, amyotrophic lateral sclerosis, and Huntington's disease. Results of controlled clinical trials of various antioxidant therapies in neurological disease performed to date are also highlighted.}, }
@article {pmid9773096, year = {1998}, author = {Nieoullon, A}, title = {[Cellular bases of neurodegenerative processes].}, journal = {Therapie}, volume = {53}, number = {1}, pages = {21-29}, pmid = {9773096}, issn = {0040-5957}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; *Apoptosis ; Brain/*pathology/physiopathology ; Humans ; Huntington Disease/pathology ; Neurodegenerative Diseases/*genetics/*pathology/physiopathology ; Neurons/*pathology/physiology ; }, abstract = {Neurodegenerative processes are generally characterized by the long-lasting course of neuronal death and the selectivity of the neuronal population or brain structure involved in the lesion. This is the case for Alzheimer's, Parkinson's or Huntington's diseases, or amyotrophic lateral sclerosis (ALS). The reasons for such a specificity are largely unknown as are generally the mechanisms of the diseases. One common feature of these diseases, however, is that the neuronal death is thought to involve apoptosis, at least partly. Interestingly, apoptosis in the brain would involve specific gene products similar to that identified in the nematode c. elegans, partly corresponding in mammals to ICE-related compounds and Bcl2 protein. The involvement of calcium as well as of oxydative stress mechanisms in such neuronal death is to be fully proved but putative modulation by external signals (such as those provided through trophic factors or even neurotransmitters) represents an interesting way to validate the current hypothesis of neuronal death in neurodegenerative diseases in humans.}, }
@article {pmid9769023, year = {1998}, author = {McGeer, PL and McGeer, EG}, title = {Glial cell reactions in neurodegenerative diseases: pathophysiology and therapeutic interventions.}, journal = {Alzheimer disease and associated disorders}, volume = {12 Suppl 2}, number = {}, pages = {S1-6}, pmid = {9769023}, issn = {0893-0341}, mesh = {Alzheimer Disease/drug therapy/immunology ; Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Complement Activation/drug effects/immunology ; Cytokines/physiology ; Humans ; Indomethacin/therapeutic use ; Inflammation Mediators/*physiology ; Microglia/drug effects/immunology ; Neurodegenerative Diseases/drug therapy/*immunology ; Neuroglia/drug effects/*immunology ; Parkinson Disease/drug therapy/immunology ; }, abstract = {A variety of proteins known to be involved in inflammatory processes are associated with lesions in chronic neurodegenerative disorders such as Alzheimer disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This is particularly true of AD, in which inflammatory reactions are believed to be important contributors to the neuronal loss. Inflammatory proteins associated with AD include complement proteins, complement inhibitors, acute-phase reactants, inflammatory cytokines, proteases, and protease inhibitors. Studies of cultured human astrocytes and microglia obtained from postmortem brain have established that almost all of these proteins are produced by one or the other of these two cell types. Human neurons also produce many inflammatory proteins and their inhibitors, creating complex interactions. Accumulations of amyloid, extracellular tangles, or Lewy bodies apparently act as irritants, causing the activation of complement, the initiation of reactive changes in microglia, and the release of potentially neurotoxic products such as the membrane attack complex, oxygen free radicals, and excess glutamate. A number of epidemiologic studies indicate that populations taking anti-inflammatory drugs have a sharply reduced prevalence of AD. One small clinical trial with indomethacin showed arrest of the disease over a 6-month period. Therapeutic intervention in key inflammatory processes holds great promise for the amelioration of AD and possibly other neurodegenerative disorders.}, }
@article {pmid9765899, year = {1998}, author = {de Belleroche, J and Orrell, RW and Virgo, L and Habgood, J and Gardiner, IM and Malaspina, A and Kaushik, N and Mitchell, J and Greenwood, J}, title = {Copper, zinc superoxide dismutase (SOD1) and its role in neuronal function and disease with particular relevance to motor neurone disease/amyotrophic lateral sclerosis.}, journal = {Biochemical Society transactions}, volume = {26}, number = {3}, pages = {476-480}, doi = {10.1042/bst0260476}, pmid = {9765899}, issn = {0300-5127}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Humans ; Isoenzymes/genetics/metabolism ; Motor Neuron Disease/*enzymology/genetics ; *Point Mutation ; Protein Structure, Secondary ; Superoxide Dismutase/*genetics/*metabolism ; }, }
@article {pmid9762518, year = {1998}, author = {McGeer, EG and McGeer, PL}, title = {The importance of inflammatory mechanisms in Alzheimer disease.}, journal = {Experimental gerontology}, volume = {33}, number = {5}, pages = {371-378}, doi = {10.1016/s0531-5565(98)00013-8}, pmid = {9762518}, issn = {0531-5565}, mesh = {Alzheimer Disease/*metabolism ; Humans ; Inflammation/*metabolism ; Inflammation Mediators/*metabolism ; }, abstract = {Lesions in such chronic neurodegenerative disorders as Alzheimer disease (AD), Parkinson disease, the parkinsonism dementia complex of Guam, and amyotrophic lateral sclerosis have associated with them a variety of proteins known to be involved in inflammatory processes. This is particularly true of AD, where inflammatory reactions are thought to be important contributors to the neuronal loss. Proteins present include complement proteins, complement inhibitors, acute phase reactants, inflammatory cytokines, proteases, and protease inhibitors. Studies of cultured human astrocytes and microglia, obtained from postmortem brain, have established that nearly all of these proteins are produced by one or another of these cell types. Human neurons also produce many inflammatory proteins and their inhibitors, creating complex interactions. Accumulations of amyloid and extracellular tangles apparently act as irritants, causing the activation of complement, the initiation of reactive changes in microglia, and the release of potentially neurotoxic products. Such products include the membrane attack complex, oxygen free radicals, and excess glutamate. Twenty epidemiological studies that have been published to date indicate that populations taking antiinflammatory drugs have a significantly reduced prevalence of AD or a slower mental decline. One small clinical trial with indomethacin showed arrest of the disease over a six-month period. Therapeutic intervention in key inflammatory processes holds great promise for the amelioration of AD and possibly other neurodegenerative disorders.}, }
@article {pmid9757416, year = {1998}, author = {Kuhlenbäumer, G and Bocchicchio, M and Kress, W and Young, P and Oberwittler, C and Stögbauer, F}, title = {[X-chromosomal recessive spinobulbar muscular atrophy (Kennedy type). Description of a family, clinical aspects, molecular genetics, differential diagnosis and therapy].}, journal = {Der Nervenarzt}, volume = {69}, number = {8}, pages = {660-665}, doi = {10.1007/s001150050325}, pmid = {9757416}, issn = {0028-2804}, mesh = {Diagnosis, Differential ; Genes, Recessive/*genetics ; Humans ; *Medulla Oblongata ; Muscular Atrophy, Spinal/diagnosis/*genetics ; Neurologic Examination ; Pedigree ; Receptors, Androgen/genetics ; Sex Chromosome Aberrations/diagnosis/*genetics ; Syndrome ; Trinucleotide Repeats/genetics ; *X Chromosome ; }, abstract = {The Kennedy-Syndrome is a X-linked recessive bulbospinal muscular atrophy, in some cases associated with endocrinological disturbances such as androgen resistance and diabetes mellitus. The age of onset is usually between 20 and 40. Presenting symptoms are proximal flaccid weakness, fasciculations, cramps or tremor. Disease progression is usually slow and live expectancy is normal. It is important to distinguish the Kennedy-Syndrome from amyotrophic lateral sclerosis, spinal muscular atrophy, muscular dystrophies and other types of motor neuron disease. Kennedy disease is caused by an expanded trinucleotide repeat in the androgen receptor gene. Genetic analysis allows a precise-diagnosis on an individual basis and reliable genetic counselling. An effective medical treatment does not yet exist.}, }
@article {pmid9752717, year = {1998}, author = {Julien, JP and Mushynski, WE}, title = {Neurofilaments in health and disease.}, journal = {Progress in nucleic acid research and molecular biology}, volume = {61}, number = {}, pages = {1-23}, doi = {10.1016/s0079-6603(08)60823-5}, pmid = {9752717}, issn = {0079-6603}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Axons/physiology ; Humans ; Intermediate Filaments/genetics/*metabolism/*ultrastructure ; Mice ; Mice, Transgenic ; Neurofilament Proteins/*genetics/*metabolism ; Parkinson Disease/pathology ; Sequence Deletion ; }, abstract = {This article reviews current knowledge of neurofilament structure, phosphorylation, and function and neurofilament involvement in disease. Neurofilaments are obligate heteropolymers requiring the NF-L subunit together with either the NF-M or the NF-H subunit for polymer formation. Neurofilaments are very dynamic structures; they contain phosphorylation sites for a large number of protein kinases, including protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase 5 (Cdk5), extracellular signal regulated kinase (ERK), glycogen synthase kinase-3 (GSK-3), and stress-activated protein kinase gamma (SAPK gamma). Most of the neurofilament phosphorylation sites, located in tail regions of NF-M and NF-H, consist of the repeat sequence motif, Lys-Ser-Pro (KSP). In addition to the well-established role of neurofilaments in the control of axon caliber, there is growing evidence based on transgenic mouse studies that neurofilaments can affect the dynamics and perhaps the function of other cytoskeletal elements, such as microtubules and actin filaments. Perturbations in phosphorylation or in metabolism of neurofilaments are frequently observed in neurodegenerative diseases. A down-regulation of mRNA encoding neurofilament proteins and the presence of neurofilament deposits are common features of human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Although the extent to which neurofilament abnormalities contribute to pathogenesis in these human diseases remains unknown, emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in the NF-H gene of some ALS eases, suggests that disorganized neurofilaments can provoke selective degeneration and death of neurons. An interference of axonal transport by disorganized neurofilaments has been proposed as one possible mechanism of neurofilament-induced pathology. Other factors that can potentially lead to the accumulation of neurofilaments will be discussed as well as the emerging evidence for neurofilaments as being possible targets of oxidative damage by mutations in the superoxide dismutase enzyme (SOD1); such mutations are responsible for approximately 20% of familial ALS cases.}, }
@article {pmid9749572, year = {1998}, author = {Langston, JW}, title = {Epidemiology versus genetics in Parkinson's disease: progress in resolving an age-old debate.}, journal = {Annals of neurology}, volume = {44}, number = {3 Suppl 1}, pages = {S45-52}, doi = {10.1002/ana.410440707}, pmid = {9749572}, issn = {0364-5134}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects ; Aging/pathology ; *Environmental Health ; Humans ; Mutation ; Parkinson Disease/*epidemiology/genetics ; Risk Factors ; Twin Studies as Topic ; }, abstract = {Determining the relative contributions of environment and heredity to the cause of Parkinson's disease (PD) is more than an academic issue because its resolution dictates future research directions to an enormous degree. This article reviews new advances on both sides of this equation. The recent identification of the genetic mutation responsible for parkinsonism in a large Italian kindred is likely to provide exciting new research opportunities but the mutation does not appear to be responsible for the vast majority of PD. A large twin study also points away from genetic influences as important, at least in patients with disease beginning after the age of 50 years. On the other hand, genetic influences loom large in younger-onset disease. With regard to the environment, epidemiologic studies have provided only broad, thought-tantalizing clues to the cause of the disease. Although rural living, well-water consumption, and exposure to pesticides have emerged as potential risk factors, identification of specific agents is lacking, and aging remains as the only unequivocal risk factor for the disease. The surprisingly strong inverse relationship between cigarette smoking and PD provides an intriguing lead, but novel experimental avenues to pursue this observation are not readily obvious. The amyotrophic lateral sclerosis/dementia/parkinsonism complex in the western Pacific suggests the possibility of long-latency toxins, but pinning down a specific causative agent for this syndrome has eluded investigators to date. Despite the many obstacles ahead, however, research on PD appears to be more robust than ever, and our quest to find its cause appears to be under a full head of steam as we approach the 21st century.}, }
@article {pmid9749571, year = {1998}, author = {Morrison, BM and Hof, PR and Morrison, JH}, title = {Determinants of neuronal vulnerability in neurodegenerative diseases.}, journal = {Annals of neurology}, volume = {44}, number = {3 Suppl 1}, pages = {S32-44}, doi = {10.1002/ana.410440706}, pmid = {9749571}, issn = {0364-5134}, support = {AG05138/AG/NIA NIH HHS/United States ; AG06647/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Humans ; Nerve Degeneration/*pathology ; Neurons/*pathology ; }, abstract = {Selective neuronal vulnerability can be defined anatomically by the differential vulnerability of circuits and neurochemically by the vulnerability of neurons that differentially express particular proteins. The anatomic perspective is exemplified by the vulnerability of the nigrostriatal projection in Parkinson's disease (PD), the degeneration of upper and lower motor neurons in amyotrophic lateral sclerosis (ALS), and the preferential loss of long corticocortical projections in Alzheimer's disease (AD). The neurochemical perspective is reflected in the heightened vulnerability of neurons that normally express high somatodendritic levels of neurofilament (eg, entorhinal and association cortices in AD, the spinal cord in a mouse model of ALS, and the retina in a primate model of glaucoma), as well as the reduced vulnerability of neurons that express calcium-binding proteins (eg, neocortex of AD patients, the spinal cord and brainstem of ALS patients, and the spinal cord of a mouse model of ALS). By combining neurochemical and anatomic correlates of vulnerability, an integrated view of vulnerable neurons is emerging in which characteristics of vulnerable neurons appear to transcend both brain region and disease state, suggesting that neurodegenerative disorders share common mechanisms of degeneration.}, }
@article {pmid9747930, year = {1998}, author = {Matheron, L and Barrau, K and Blin, O}, title = {Disease management: the example of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {245 Suppl 2}, number = {}, pages = {S20-8; discussion S29}, doi = {10.1007/pl00014806}, pmid = {9747930}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Disease Management ; Humans ; }, abstract = {Disease management is defined as any medical or pharmaceutical intervention designed to improve both outcomes for the patient and overall cost-effectiveness of the health plan. Disease management focuses on the patient throughout the entire course of the disease, involving both health providers and third-party payers. It requires structured management of change, inter- and intra-professional communication and access to information, identification of pertinent economic and clinical outcomes, and the establishment of guidelines, computerized systems and quality assurance. The concept of disease management remains controversial, primarily because its effectiveness is untested. Furthermore, if only economic outcomes are considered, ethical problems such as the selection of populations (for example, the exclusion from health care of people deemed 'too old') will emerge. As a model of neurodegenerative disease, amyotrophic lateral sclerosis (ALS) is a suitable condition for disease management. Many possible targets for disease management initiatives in ALS can be defined, including training, communication, education, guidelines for diagnosis, follow-up, clinical trials and treatments. Medico-economic studies need to be improved if accreditation is planned. Much remains to be done to improve the therapy and disease management of ALS. However, the identification of optimal treatment will improve care of ALS patients, particularly in less affluent countries.}, }
@article {pmid9747929, year = {1998}, author = {Silani, V and Kasarskis, EJ and Yanagisawa, N}, title = {Nutritional management in amyotrophic lateral sclerosis: a worldwide perspective.}, journal = {Journal of neurology}, volume = {245 Suppl 2}, number = {}, pages = {S13-9; discussion S29}, doi = {10.1007/pl00014805}, pmid = {9747929}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cross-Cultural Comparison ; Humans ; *Nutritional Support ; }, abstract = {Although respiratory failure is the primary cause of death in patients with amyotrophic lateral sclerosis (ALS), the management of nutritional status is important to enhancing the quality of life and optimising the timing of interventive techniques. Progressively weakening muscles impair the patient's ability to eat, and nearly all patients with ALS develop severe dysphagia. If nutritional support is not provided, food and fluid consumption may be greatly restricted, leading to weight loss and malnutrition. This may be compounded by impaired respiratory functions, which place increased energy demands on the patient. This paper describes the nutritional needs of ALS patients from a worldwide and cross-cultural perspective. In particular, the differences between a paternalistic and a patient-centred approach to treatment are addressed. The need for further study into the nutritional status of ALS patients and the issue of parenteral and enteral nutritional therapy, particularly percutaneous endoscopic gastrostomy, are discussed.}, }
@article {pmid9747928, year = {1998}, author = {Borasio, GD and Gelinas, DF and Yanagisawa, N}, title = {Mechanical ventilation in amyotrophic lateral sclerosis: a cross-cultural perspective.}, journal = {Journal of neurology}, volume = {245 Suppl 2}, number = {}, pages = {S7-12; discussion S29}, doi = {10.1007/s004150050641}, pmid = {9747928}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Cross-Cultural Comparison ; Humans ; *Respiration, Artificial ; }, abstract = {Mechanical ventilation is known to be an effective means of relieving symptoms of chronic hypoventilation and prolonging life in patients with amyotrophic lateral sclerosis (ALS). Various methods of mechanical ventilation are available to patients with ALS. However, attitudes towards mechanical ventilation in ALS vary widely across different cultures, and even within a given medical system. This article describes differences and similarities between a North American, a European and a Japanese approach, based on the respective medical and cultural traditions. The common goal is to provide optimal palliative care to patients with ALS.}, }
@article {pmid9747927, year = {1998}, author = {Russell, JA}, title = {Ethical considerations in disease management of amyotrophic lateral sclerosis: a cross-cultural, worldwide perspective.}, journal = {Journal of neurology}, volume = {245 Suppl 2}, number = {}, pages = {S4-6; discussion S29}, doi = {10.1007/pl00014808}, pmid = {9747927}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cross-Cultural Comparison ; Cultural Diversity ; Disclosure ; *Ethics, Medical ; Humans ; Internationality ; Personal Autonomy ; Resource Allocation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is universally fatal. Technological advances have provided a means to impact upon, without radically improving, the natural history of the disease. In addition, we now have the capability of potentially identifying patients who are pre-symptomatic carriers of the rare heritable forms of the disease. These capabilities provide the basis for the numerous ethical dilemmas that face patients, physicians, and agencies responsible for health care expenditures; dilemmas that can only be amplified between cultures. This paper attempts to address some of the major ethical issues germane to the care of ALS patients. It discusses the emergence of autonomy as the reigning principle of medical ethics in the United States and its potential conflict with the ethical dilemma of limited resource allocation. Finally, it attempts to compare and contrast, in an admittedly anecdotal and fragmentary fashion, the perspective of other cultures regarding the care of ALS patients.}, }
@article {pmid9745361, year = {1998}, author = {Trotti, D and Danbolt, NC and Volterra, A}, title = {Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?.}, journal = {Trends in pharmacological sciences}, volume = {19}, number = {8}, pages = {328-334}, doi = {10.1016/s0165-6147(98)01230-9}, pmid = {9745361}, issn = {0165-6147}, support = {754/TI_/Telethon/Italy ; }, mesh = {Animals ; Biological Transport ; Glutamates/adverse effects/*metabolism/*physiology ; Humans ; Neurodegenerative Diseases/pathology ; Oxidation-Reduction ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Receptors, Glutamate/metabolism ; }, abstract = {Increasing evidence indicates that glutamate transporters are vulnerable to the action of biological oxidants, resulting in reduced uptake function. This effect could contribute to the build-up of neurotoxic extracellular glutamate levels, with major pathological consequences. Specific 'redox-sensing' elements, consisting of cysteine residues, have been identified in the structures of at least three transporter subtypes (GLT1, GLAST and EAAC1) and shown to regulate transport rate via thiol-disulphide redox interconversion. In this article, Davide Trotti, Niels Danbolt and Andrea Volterra discuss these findings in relation to the emerging view that in brain diseases oxidative and excitotoxic mechanisms might often operate in tight conjunction to induce neuronal damage. In particular, they review evidence suggesting a possible involvement of oxidative alterations of glutamate transporters in specific pathologies, including amyotrophic lateral sclerosis, Alzheimer's disease, brain trauma and ischaemia.}, }
@article {pmid9741578, year = {1998}, author = {Squadrito, GL and Pryor, WA}, title = {Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide.}, journal = {Free radical biology &amp; medicine}, volume = {25}, number = {4-5}, pages = {392-403}, doi = {10.1016/s0891-5849(98)00095-1}, pmid = {9741578}, issn = {0891-5849}, mesh = {Carbon Dioxide/*chemistry ; Free Radical Scavengers ; Free Radicals ; Nitrates/*chemistry ; Nitric Oxide/*chemistry ; Oxidation-Reduction ; Superoxides/*chemistry ; }, abstract = {The roles of superoxide (O2.-), peroxynitrite, and carbon dioxide in the oxidative chemistry of nitric oxide (.NO) are reviewed. The formation of peroxynitrite from .NO and O2.- is controlled by superoxide dismutase (SOD), which can lower the concentration of superoxide ions. The concentration of CO2 in vivo is high (ca. 1 mM), and the rate constant for reaction of CO2 with -OONO is large (pH-independent k = 5.8 x 10(4) M(-l)s(-1)). Consequently, the rate of reaction of peroxynitrite with CO2 is so fast that most commonly used scavengers would need to be present at very high, near toxic levels in order to compete with peroxynitrite for CO2. Therefore, in the presence of physiological levels of bicarbonate, only a limited number of biotargets react directly with peroxynitrite. These include heme-containing proteins such as hemoglobin, peroxidases such as myeloperoxidase, seleno-proteins such as glutathione peroxidase, proteins containing zinc-thiolate centers such as the DNA-binding transcription factors, and the synthetic antioxidant ebselen. The mechanism of the reaction of CO2 with OONO produces metastable nitrating, nitrosating, and oxidizing species as intermediates. An analysis of the lifetimes of the possible intermediates and of the catalysis of peroxynitrite decompositions suggests that the reactive intermediates responsible for reactions with a variety of substrates may be the free radicals .NO2 and CO3.-. Biologically important reactions of these free radicals are, for example, the nitration of tyrosine residues. These nitrations can be pathological, but they also may play a signal transduction role, because nitration of tyrosine can modulate phosphorylation and thus control enzymatic activity. In principle, it might be possible to block the biological effects of peroxynitrite by scavenging the free radicals .NO2 and CO3.-. Because it is difficult to directly scavenge peroxynitrite because of its fast reaction with CO2, scavenging of intermediates from the peroxynitrite/CO2 reaction would provide an additional way of preventing peroxynitrite-mediated cellular effects. The biological effects of peroxynitrite also can be prevented by limiting the formation of peroxynitrite from .NO by lowering the concentration of O2.- using SOD or SOD mimics. Increased formation of peroxynitrite has been linked to Alzheimer's disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, and other diseases.}, }
@article {pmid9739520, year = {1998}, author = {Tsuzaka, K and Mitsumoto, H}, title = {[Neurotrophic factor treatment in amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {50}, number = {7}, pages = {625-630}, pmid = {9739520}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain-Derived Neurotrophic Factor/*therapeutic use ; Ciliary Neurotrophic Factor ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Nerve Growth Factors/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; }, }
@article {pmid9739519, year = {1998}, author = {Kinoshita, M and Ikeda, K}, title = {[Treatment with lecithinized superoxide dismutase in amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {50}, number = {7}, pages = {615-624}, pmid = {9739519}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Mice ; Mutation ; *Phosphatidylcholines ; Rats ; Recombinant Proteins/therapeutic use ; Superoxide Dismutase/chemistry/genetics/*therapeutic use ; }, }
@article {pmid9729418, year = {1998}, author = {Qian, ZM and Wang, Q}, title = {Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders.}, journal = {Brain research. Brain research reviews}, volume = {27}, number = {3}, pages = {257-267}, doi = {10.1016/s0165-0173(98)00012-5}, pmid = {9729418}, mesh = {Animals ; Antigens, Neoplasm ; Brain/*metabolism ; Carrier Proteins/*biosynthesis ; Ceruloplasmin/biosynthesis ; Humans ; Iron/metabolism/*pharmacokinetics ; Melanoma-Specific Antigens ; Neoplasm Proteins/biosynthesis ; Nerve Tissue Proteins/*biosynthesis ; Neurodegenerative Diseases/*metabolism ; Receptors, Cell Surface/biosynthesis ; }, abstract = {New findings on the role of LfR (lactotransferrin receptor), MTf (melanotransferrin), CP (ceruloplasmin) and DCT1 (Divalent Cation Transporter) in brain iron transport, obtained during the past 3 years, are important advances in the fields of physiology and pathophysiology of brain iron metabolism. According to these findings, disruption in the expression of these proteins in the brain is probably one of the important causes of the altered brain iron metabolism in age-related neurodegenerative diseases, including Parkinson's Disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the involvement of LfR, MTf and DCT1 in iron uptake by and CP in iron egress from different types of brain cells as well as control mechanisms of expression of these proteins in the brain are critical for elucidating the causes of excessive accumulation of iron in the brain and neuronal death in neurodegenerative diseases.}, }
@article {pmid9728338, year = {1998}, author = {Gurney, ME and Liu, R and Althaus, JS and Hall, ED and Becker, DA}, title = {Mutant CuZn superoxide dismutase in motor neuron disease.}, journal = {Journal of inherited metabolic disease}, volume = {21}, number = {5}, pages = {587-597}, pmid = {9728338}, issn = {0141-8955}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/*enzymology/*genetics ; Superoxide Dismutase/*genetics ; }, abstract = {CuZn superoxide dismutase (CuZn SOD) is one of several antioxidant enzymes that defend the cell against damage by oxygen free radicals. Mutations of the SOD1 gene encoding CuZn SOD are found in patients with familial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic disease that is caused by the death of motor neurons in cortex, brainstem and spinal cord. The disease can be reproduced in transgenic mice by expression of mutant human CuZn SOD. Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance the generation of oxygen radicals by the mutant enzyme. Thus, mutation converts a protective, antioxidant enzyme into a destructive, prooxidant form that catalyses free radical damage to which motor neurons are selectively vulnerable. Recent studies of neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms (copper chelation therapy, dietary antioxidants, and coexpression of bcl-2) delays disease onset but does not extend disease duration. In contrast, inhibition of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of an inhibitor of caspase-1) has no effect on disease onset but extends survival by increasing the duration of symptomatic disease. Thus, neuroprotective agents differentially target the processes underlying disease initiation and propagation.}, }
@article {pmid9723527, year = {1998}, author = {Hale, D and Gottschalk, R and Maki, T and Monaco, AP}, title = {Use of pharmacologic immunosuppression to augment the specific unresponsiveness (tolerance) to skin allografts induced by donor-specific bone marrow in antilymphocyte serum-treated mice: the unique effect of sirolimus.}, journal = {Transplantation proceedings}, volume = {30}, number = {5}, pages = {2432-2434}, doi = {10.1016/s0041-1345(98)00676-9}, pmid = {9723527}, issn = {0041-1345}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Cytokines/biosynthesis/genetics ; Immunosuppression Therapy/*methods ; Immunosuppressive Agents/*therapeutic use ; Lymphocytes/immunology ; Mice ; Mice, Inbred Strains ; Polyenes/*therapeutic use ; Sirolimus ; Skin Transplantation/*immunology ; Transcription, Genetic ; Transplantation, Homologous ; }, abstract = {Tolerance produced with ALS treatment, DSBM, and sirolimus involves multiple mechanisms of a specific and nonspecific nature. In eventual clinical application for tolerance induction, sirolimus (rapamycin) has great potential for augmenting the tolerogenicity of the ALS/BM regimen.}, }
@article {pmid9723164, year = {1998}, author = {Morrison, BM and Morrison, JH and Gordon, JW}, title = {Superoxide dismutase and neurofilament transgenic models of amyotrophic lateral sclerosis.}, journal = {The Journal of experimental zoology}, volume = {282}, number = {1-2}, pages = {32-47}, pmid = {9723164}, issn = {0022-104X}, support = {AG 10520/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*physiopathology ; Animals ; Disease Models, Animal ; Humans ; Isoenzymes/*metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/*enzymology/pathology ; Neurofilament Proteins/*metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurologic disease characterized by progressive motor dysfunction that leads to paralysis and eventually death. There are numerous hypotheses for the pathogenesis of this disease, but the mechanisms of degeneration were difficult to investigate before the development of animal models. Transgenic mice with alterations in either the superoxide dismutase (SOD-1) or neurofilament genes display motor neuron pathology and deficits in motor function and, therefore, provide animal models for the study of ALS neurodegeneration. Using these animal models, as well as several in vitro models, researchers have made rapid progress during the last several years toward understanding the cause and mechanism of ALS neurodegeneration. These studies have demonstrated that motor neuron degeneration in ALS may be secondary to a number of causes, including neurofilament disruption, mutations in SOD-1, and glutamate excitotoxicity. Although each of these mechanisms can cause motor neuron degeneration by itself, studies of transgenic mice have indicated several points at which these mechanisms may interact, suggesting that they are components of one general mechanism of neurodegeneration.}, }
@article {pmid9714810, year = {1998}, author = {Beal, MF}, title = {Mitochondrial dysfunction in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta}, volume = {1366}, number = {1-2}, pages = {211-223}, doi = {10.1016/s0005-2728(98)00114-5}, pmid = {9714810}, issn = {0006-3002}, support = {NS10828/NS/NINDS NIH HHS/United States ; NS16763/NS/NINDS NIH HHS/United States ; NS31579/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/etiology ; Amyotrophic Lateral Sclerosis/etiology ; Animals ; Energy Metabolism/*genetics ; Friedreich Ataxia/etiology ; Humans ; Huntington Disease/etiology ; Mitochondria/enzymology/*physiology ; Neurodegenerative Diseases/*etiology/*genetics/therapy ; Oxidative Stress/genetics ; }, abstract = {A potential pivotal role for mitochondrial dysfunction in neurodegenerative diseases is gaining increasing acceptance. Mitochondrial dysfunction leads to a number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Neurodegenerative diseases of widely disparate genetic etiologies may share mitochondrial dysfunction as a final common pathway. Recent studies using cybrid cell lines suggest that sporadic Alzheimer's disease is associated with a deficiency of cytochrome oxidase. Friedreich's ataxia is caused by an expanded GAA repeat resulting in dysfunction of frataxin, a nuclear encoded mitochondrial protein involved in mitochondrial iron transport. This results in increased mitochondrial iron and oxidative damage. Familial amyotrophic lateral sclerosis is associated with point mutations in superoxide dismutase, which may lead to increased generation of free radicals and thereby contribute to mitochondrial dysfunction. Huntington's disease (HD) is caused by an expanded CAG repeat in an unknown protein termed huntingtin. The means by which this leads to energy impairment is unclear, however studies in both HD patients and a transgenic mouse model show evidence of bioenergetic defects. Mitochondrial dysfunction leads to oxidative damage which is well documented in several neurodegenerative diseases. Therapeutic approaches include methods to buffer intracellular ATP and to scavenge free radicals.}, }
@article {pmid9711902, year = {1998}, author = {Keller, JN and Mattson, MP}, title = {Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system.}, journal = {Reviews in the neurosciences}, volume = {9}, number = {2}, pages = {105-116}, doi = {10.1515/revneuro.1998.9.2.105}, pmid = {9711902}, issn = {0334-1763}, mesh = {Animals ; Cell Death/drug effects/physiology ; Central Nervous System/*metabolism/*pathology ; Humans ; Lipid Peroxidation/*physiology ; Models, Neurological ; Signal Transduction/drug effects/*physiology ; }, abstract = {Free radicals are known to occur as natural by-products under physiological conditions and have been implicated in the neuronal loss observed in a variety of neuropathological conditions including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and ischemia. Oxyradical-induced cytotoxicity arises from both chronic and acute increases in reactive oxygen species which give rise to subsequent lipid peroxidation (LP). By reacting with polyunsaturated fatty acids in the the various cellular membranes, oxyradicals such as hydroxyl (OH.) and peroxynitrite (ONOO) give rise to a variety of lipid peroxidation products (LPP), including 4-hydroxynonenal (HNE) and malondialdehyde (MD). Once formed, these peroxidation metabolites have been demonstrated to have relatively long half-lives within cells (minutes to hours), allowing for multiple interactions with cellular components. Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous neurodegenerative conditions. Data supporting this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD, ALS, PD, and ischemia. Secondly, direct application of LPP, either in vivo or in vitro, has been shown to be cytotoxic and mimic neuronal alterations observed in neuropathological conditions. Furthermore, prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety of neurodegenerative paradigms. Additionally, LP and LPP have been implicated in the modulation of a wide array of activities within the central nervous system including long term potentiation, neurite outgrowth, and proliferation. Understanding the mechanism(s) and involvement of LP in these processes will greatly enhance the understanding of oxyradical and ion homeostasis in neurophysiological and neuropathological conditions. The focus of this review is to describe the process by which lipid peroxidation occurs and establish a framework for its involvement in the central nervous system.}, }
@article {pmid9690754, year = {1998}, author = {Ajdacic-Gross, V and Wang, J and Gutzwiller, F}, title = {Season of birth in amyotrophic lateral sclerosis.}, journal = {European journal of epidemiology}, volume = {14}, number = {4}, pages = {359-361}, pmid = {9690754}, issn = {0393-2990}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; *Birth Rate ; Chi-Square Distribution ; Female ; Humans ; Infant, Newborn ; Models, Statistical ; Pregnancy ; Risk Factors ; *Seasons ; Switzerland/epidemiology ; }, abstract = {While studying birth cohort issues, the authors focused also on the seasons of birth in amyotrophic lateral sclerosis (ALS). The analyses were based on computerized death records of Swiss mortality statistics 1969-1993. The results confirm an excess of births in spring months. They suggest that risk factors in ALS can be acquired very early in life, thus introducing a long latency period.}, }
@article {pmid9683997, year = {1997}, author = {Price, DL and Wong, PC and Borchelt, DR and Pardo, CA and Thinakaran, G and Doan, AP and Lee, MK and Martin, LJ and Sisodia, SS}, title = {Amyotrophic lateral sclerosis and Alzheimer disease. Lessons from model systems.}, journal = {Revue neurologique}, volume = {153}, number = {8-9}, pages = {484-495}, pmid = {9683997}, issn = {0035-3787}, support = {AG 05146/AG/NIA NIH HHS/United States ; NS 10580/NS/NINDS NIH HHS/United States ; NS 20471/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease/genetics/pathology/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; Disease Models, Animal ; Dogs ; Humans ; Mice ; Mice, Transgenic ; }, abstract = {The human neurodegenerative diseases, including motor neuron disease and Alzheimer's disease (AD), are characterized by a selective involvement of certain regions of the brain/spinal cord and selected populations of neurons. Sporadic amyotrophic lateral sclerosis (ALS) is an age-associated disease with cytoskeletal abnormalities and death of motor neurons; familial ALS (FALS), an autosomal dominant disease linked to mutations in superoxide dismutase 1 (SOD1), is manifested by inclusions and degeneration of motor neurons. Autosomal dominant familial AD (FAD), linked to mutations in presenilin (PS1 and PS2) genes or the amyloid precursor protein (APP) gene, shows brain abnormalities (e.g., neurofibrillary tangles, deposits of .-amyloid A., and death of subsets of neurons) similar to those that occur in sporadic AD, the risk of which is enhanced by the presence of one or two copies of apolipoprotein E4 (apoE4) alleles. To examine the mechanisms of these diseases, investigators have used a variety of animal models, including experimentally produced, spontaneously occurring, or genetically engineered models of disease. Studies of models of degeneration of motor neurons (axotomy) and cytoskeletal abnormalities seen in motor neuron disease (i.e., axonopathy induced by .,.'-iminodipropionitrile (IDPN), hereditary canine spinal muscular atrophy (HCSMA), and neurofilament NF transgenic Tg mice) have demonstrated that NF-filled swellings of axons are related to alterations in the biology of NF transport. Tg mice with SOD1 mutations, which develop the clinical features of FALS, show selective degeneration of motor neurons, which is attributed to the acquisition of toxic properties by mutant SOD1. Models of AD include: aged monkeys that show both cognitive/memory deficits and cellular abnormalities (amyloid deposition/cytoskeletal abnormalities of neurons) in cortex and hippocampus; and Tg mice that express mutant human FAD-linked genes (i.e., APP and PS1) and show increased levels of A.42, amyloid deposits, dystrophic neurites, and local responses of astrocytes and microglia. This review discusses the behavioral/neuropathological features of AD, the results of investigations of mechanisms of disease in model systems, and potential utility of some of these models for testing new therapies.}, }
@article {pmid9681637, year = {1998}, author = {Gonatas, NK and Gonatas, JO and Stieber, A}, title = {The involvement of the Golgi apparatus in the pathogenesis of amyotrophic lateral sclerosis, Alzheimer's disease, and ricin intoxication.}, journal = {Histochemistry and cell biology}, volume = {109}, number = {5-6}, pages = {591-600}, doi = {10.1007/s004180050257}, pmid = {9681637}, issn = {0948-6143}, support = {NS 05572/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*pathology ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Golgi Apparatus/*pathology ; Humans ; Immunohistochemistry ; Ricin/*toxicity ; }, abstract = {Several diseases involving a variety of cells and tissues are associated with defective enzymes of the Golgi apparatus (GA). An intact GA of neurons is crucial for the physiological function of axons and presynaptic terminals since proteins destined for fast axoplasmic transport are processed by the organelle. Despite the obvious importance of the GA of neurons, its function and involvement in pathological reactions have not been studied systematically. The purpose of this paper is to draw attention to the contribution of the neuronal GA in pathology using two paradigms: (1) the involvement of the neuronal GA in the pathogeneses of amyotrophic lateral sclerosis (ALS), in an animal model of ALS, and in Alzheimer's disease; and (2) the elucidation of a retrograde transport pathway involving the neuronal transgolgi network, in vitro and in vivo, and the participation of this pathway in the toxicity and/or endocytosis of ricin and other toxic or non-toxic ligands.}, }
@article {pmid9671259, year = {1998}, author = {Martin, LJ and Al-Abdulla, NA and Brambrink, AM and Kirsch, JR and Sieber, FE and Portera-Cailliau, C}, title = {Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis.}, journal = {Brain research bulletin}, volume = {46}, number = {4}, pages = {281-309}, doi = {10.1016/s0361-9230(98)00024-0}, pmid = {9671259}, issn = {0361-9230}, support = {NS20020/NS/NINDS NIH HHS/United States ; NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*physiology ; *Axotomy ; Brain Ischemia/*pathology/physiopathology ; Cell Death/physiology ; Necrosis ; Nerve Degeneration/*physiopathology ; Neurons/physiology ; Neurotoxins/*pharmacology ; }, abstract = {In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult-onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N-methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitotoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in nonneuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.}, }
@article {pmid9666049, year = {1998}, author = {Riggs, JE}, title = {Aging, increasing genomic entropy, and neurodegenerative disease.}, journal = {Neurologic clinics}, volume = {16}, number = {3}, pages = {757-770}, doi = {10.1016/s0733-8619(05)70093-1}, pmid = {9666049}, issn = {0733-8619}, mesh = {Aged ; Aged, 80 and over ; Aging/*genetics/*physiology ; *Genome ; Humans ; Models, Biological ; Neurodegenerative Diseases/genetics ; }, abstract = {The genome, as biologic information, can be conceptualized in terms of entropy. The second law of thermodynamics dictates that entropy must increase over time. Consequently, aging can be viewed as increasing genomic entropy. Genetic instability is the biophysical correlate of increasing genomic entropy. Rates of increasing genomic entropy can be determined from age-specific mortality rate dynamics (e.g., Parkinson's disease and amyotrophic lateral sclerosis). These observations are consistent with a model of neurodegenerative disease as a manifestation of increasing genomic entropy with aging.}, }
@article {pmid9666035, year = {1998}, author = {Riggs, JE}, title = {The aging population: implications for the burden of neurologic disease.}, journal = {Neurologic clinics}, volume = {16}, number = {3}, pages = {555-560}, doi = {10.1016/s0733-8619(05)70079-7}, pmid = {9666035}, issn = {0733-8619}, mesh = {Aged ; Aged, 80 and over ; *Aging ; *Brain Diseases ; Female ; Humans ; Male ; Quality of Life ; }, abstract = {The aging population has had a significant impact upon the societal burden of several neurologic disorders, such as Alzheimer's disease, primary malignant brain tumor, Parkinson's disease, and amyotrophic lateral sclerosis. The increased burden is the result of more than just the dramatically increasing number of elderly individuals. This profound demographic change in the age structure of populations in developed nations is primarily the result of increasing survival. This differential survival over time, and its corresponding less selective culling effect on the surviving population gene pool, is an additional explanation for the observed increasing frequency of several neurologic diseases associated with senescence.}, }
@article {pmid9655946, year = {1998}, author = {Chipman, D and Barak, Z and Schloss, JV}, title = {Biosynthesis of 2-aceto-2-hydroxy acids: acetolactate synthases and acetohydroxyacid synthases.}, journal = {Biochimica et biophysica acta}, volume = {1385}, number = {2}, pages = {401-419}, doi = {10.1016/s0167-4838(98)00083-1}, pmid = {9655946}, issn = {0006-3002}, mesh = {Acetolactate Synthase/chemistry/genetics/*metabolism ; Amino Acid Sequence ; Binding Sites ; Hydroxy Acids/*metabolism ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Sequence Alignment ; }, abstract = {Two groups of enzymes are classified as acetolactate synthase (EC 4. 1.3.18). This review deals chiefly with the FAD-dependent, biosynthetic enzymes which readily catalyze the formation of acetohydroxybutyrate from pyruvate and 2-oxobutyrate, as well as of acetolactate from two molecules of pyruvate (the ALS/AHAS group). These enzymes are generally susceptible to inhibition by one or more of the branched-chain amino acids which are ultimate products of the acetohydroxyacids, as well as by several classes of herbicides (sulfonylureas, imidazolinones and others). Some ALS/AHASs also catalyze the (non-physiological) oxidative decarboxylation of pyruvate, leading to peracetic acid; the possible relationship of this process to oxygen toxicity is considered. The bacterial ALS/AHAS which have been well characterized consist of catalytic subunits (around 60 kDa) and smaller regulatory subunits in an alpha2beta2 structure. In the case of Escherichia coli isozyme III, assembly and dissociation of the holoenzyme has been studied. The quaternary structure of the eukaryotic enzymes is less clear and in plants and yeast only catalytic polypeptides (homologous to those of bacteria) have been clearly identified. The presence of regulatory polypeptides in these organisms cannot be ruled out, however, and genes which encode putative ALS/AHAS regulatory subunits have been identified in some cases. A consensus sequence can be constructed from the 21 sequences which have been shown experimentally to represent ALS/AHAS catalytic polypeptides. Many other sequences fit this consensus, but some genes identified as putative 'acetolactate synthase genes' are almost certainly not ALS/AHAS. The solution of the crystal structures of several thiamin diphosphate (ThDP)-dependent enzymes which are homologous to ALS/AHAS, together with the availability of many amino acid sequences for the latter enzymes, has made it possible for two laboratories to propose similar, reasonable models for a dimer of catalytic subunits of an ALS/AHAS. A number of characteristics of these enzymes can now be better understood on the basis of such models: the nature of the herbicide binding site, the structural role of FAD and the binding of ThDP-Mg2+. The models are also guides for experimental testing of ideas concerning structure-function relationships in these enzymes, e.g. the nature of the substrate recognition site. Among the important remaining questions is how the enzyme suppresses alternative reactions of the intrinsically reactive hydroxyethylThDP enamine formed by the decarboxylation of the first substrate molecule and specifically promotes its condensation with 2-oxobutyrate or pyruvate.}, }
@article {pmid9652189, year = {1998}, author = {Connolly, GP}, title = {Fibroblast models of neurological disorders: fluorescence measurement studies.}, journal = {Trends in pharmacological sciences}, volume = {19}, number = {5}, pages = {171-177}, doi = {10.1016/s0165-6147(98)01202-4}, pmid = {9652189}, issn = {0165-6147}, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Calcium/metabolism ; Cells, Cultured ; Central Nervous System Diseases/diagnosis/*physiopathology ; Fibroblasts/pathology/*physiology ; Humans ; Lesch-Nyhan Syndrome/physiopathology ; Lysosomal Storage Diseases/physiopathology ; Mitochondrial Myopathies/physiopathology ; Potassium Channels/physiology ; Skin/*physiopathology ; Spectrometry, Fluorescence/methods ; }, abstract = {Biochemical studies of human fibroblasts from patients with neurological disorders have revealed a wealth of information on how such disorders occur. In this review, Gerald Connolly describes how recently developed fluorescence video imaging techniques have been used to study the physiology of skin fibroblasts isolated from patients with certain neurological disorders, including those produced by Alzheimer's disease, Lesch-Nyhan syndrome, mitochondrial disorders, amyotrophic lateral sclerosis and lysosomal disorders. The results of these studies indicate disruptions in cell homeostasis, particularly specific changes in Ca2+ homeostasis and autofluorescence, which mirror changes thought to occur in the CNS of neurologically impaired patients. More extensive studies of these 'systemic changes' using new fluorescent indicators, combined with advances in imaging techniques, are predicted to increase the potential usefulness of human skin fibroblasts as experimental models and to help diagnose and treat neurological disorders.}, }
@article {pmid9647296, year = {1998}, author = {Bajaj, NP and Irving, NG and Leigh, PN and Miller, CC}, title = {Alzheimer's disease, amyotrophic lateral sclerosis, and transgenic mice.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {64}, number = {6}, pages = {711-715}, doi = {10.1136/jnnp.64.6.711}, pmid = {9647296}, issn = {0022-3050}, mesh = {Alzheimer Disease/complications/*diagnosis/genetics ; Amyotrophic Lateral Sclerosis/*diagnosis/genetics ; Animals ; Astrocytes/pathology ; Cognition Disorders/etiology ; Disease Models, Animal ; Mice ; *Mice, Transgenic ; Motor Neuron Disease/diagnosis/genetics ; }, }
@article {pmid9642748, year = {1998}, author = {Berkhoff, M and Sturzenegger, M and Spiegel, R and Rösler, KM and Hess, CW}, title = {[X-chromosomal bulbospinal muscular atrophy (Kennedy syndrome)].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {128}, number = {21}, pages = {817-823}, pmid = {9642748}, issn = {0036-7672}, mesh = {Adult ; Diagnosis, Differential ; Female ; Genes, Recessive/*genetics ; Genetic Carrier Screening ; Genetic Counseling ; Humans ; Male ; Middle Aged ; Muscular Atrophy/diagnosis/*genetics ; Nystagmus, Pathologic/diagnosis/genetics ; Pedigree ; Sex Chromosome Aberrations/diagnosis/*genetics ; *X Chromosome ; }, abstract = {Two brothers with slowly progressive weakness and congenital nystagmus are presented. DNA analysis confirmed X-linked recessive bulbospinal muscular atrophy (XBSMA, Kennedy's disease) by demonstration of increased size of a CAG-triplet repeat on the androgen receptor gene on the X-chromosome. XBSMA is characterized by almost symmetrical muscular atrophy, weakness and fasciculations predominantly of bulbar, facial and proximal muscles of the extremities, with onset in the third to fifth decade. Tendon reflexes are depressed and pyramidal signs are absent. Sensory symptoms are clinically rare, but sensory nerve action potentials are frequently abnormal. Additional symptoms are important for differential diagnosis, and include postural tremor, gynecomastia, diabetes mellitus, testicular atrophy and impotence. Differentiation of this hereditary disorder from treatable conditions such as multifocal motor neuropathy or amyotrophic lateral sclerosis is essential. Though life expectancy is normal, patients become disabled in the course of the disease and need supportive care. Periodic testing for diabetes is recommended, and genetic counseling should be provided for patients and their relatives.}, }
@article {pmid9642676, year = {1998}, author = {Nagata, Y and Fujita, K and Yamauchi, M and Kato, T and Ando, M and Honda, M}, title = {Neurochemical changes in the spinal cord in degenerative motor neuron diseases.}, journal = {Molecular and chemical neuropathology}, volume = {33}, number = {3}, pages = {237-247}, doi = {10.1007/BF02815185}, pmid = {9642676}, issn = {1044-7393}, mesh = {Animals ; Humans ; Motor Neuron Disease/*metabolism ; Neurodegenerative Diseases/*metabolism ; Neurotransmitter Agents/metabolism ; Spinal Cord/*metabolism ; }, abstract = {Human amyotrophic lateral sclerosis (ALS), a typical motor neuron disease, is characterized pathologically by selective degenerative loss of motoneurons in the CNS. We have demonstrated significant reductions of neurotransmitter-related factors, such as acetylcholine-(ACh)-synthesizing enzyme activity and glutamate and aspartate contents in the ALS, compared to the non-ALS spinal cord obtained at autopsy. We have also shown considerable reductions in activities of cytochrome-c oxidase (CO), an enzyme contributing to aerobic energy production, and transglutaminase (TG), a Ca(2+)-dependent marker enzyme for tissue degeneration, in the ALS spinal cord. We found marked increases in fragmented glial fibrillary acidic protein (GFAP), a filamentous protein specifically associated with reactive astrocytes, in the ALS spinal cord relative to non-ALS tissue. These biochemical results corresponded well to pathomor-phological neuronal degenerative loss and reactive proliferation of astroglial components in the ALS spinal cord tissue. However, these results only indicate the final pathological and biochemical outcomes of ALS, and it is difficult to follow up cause and process in the ALS spinal cord during progression of the disease. Therefore, we used an animal model closely resembling human ALS, motor neuron degeneration (Mnd) mutant mice, a subline of C57BL/6 that shows late-onset progressive degeneration of lower motor neurons with paralytic gait beginning around 6.5 mo of age, to follow the biochemical and pathological alterations during postnatal development. We detected significant decreases in CO activity during early development and in activity of superoxide dismutase (SOD), an antioxidant enzyme, in later stages in Mnd mutant spinal cord tissue. TG activity in the Mnd spinal cord showed gradual increases during early development reaching a maximum at 5 mo, and then tending to decrease thereafter. Amounts of fragmented GFAPs increased continuously during postnatal development in Mnd spinal cord. These biochemical changes were observed prior to the appearance of clinical motor dysfunctions in the Mnd mutant mice. Such biochemical analyses using appropriate animal models will be useful for inferring the origin and progression of human ALS.}, }
@article {pmid9634206, year = {1998}, author = {Ince, PG and Lowe, J and Shaw, PJ}, title = {Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology.}, journal = {Neuropathology and applied neurobiology}, volume = {24}, number = {2}, pages = {104-117}, doi = {10.1046/j.1365-2990.1998.00108.x}, pmid = {9634206}, issn = {0305-1846}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*classification/etiology/pathology ; Animals ; Diagnosis, Differential ; Free Radicals ; Glutamic Acid/metabolism ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/etiology/genetics ; Ubiquitins/metabolism ; }, abstract = {The classification of amyotrophic lateral sclerosis (ALS) is reconsidered in the light of developments in the molecular pathogenesis and histopathology of the condition. A current view is encapsulated in the El Escorial World Federation of Neurology criteria for the diagnosis of ALS. While intended for research purposes, use of these criteria for entry into clinical trials may result in the exclusion of some patient groups with related disorders that are likely to share aetiological mechanisms but which are not classified as 'definite ALS' or 'probable ALS'. The relationship between ALS and the more restricted motor disorders of progressive lateral sclerosis and progressive muscular atrophy, together with cerebral degenerations including ALS-dementia and ALS-related frontal lobe dementia, are reviewed. The possibility is raised that they all represent syndromic manifestations of a similar pathogenetic cascade whose clinical phenotype depends upon the anatomical selectivity of involvement in each individual. The new evidence regarding the central role of oxidative stress and abnormal glutamatergic neurotransmission in familial and sporadic ALS seem applicable across these disorders. New evidence regarding the molecular pathology of inclusion bodies in these various syndromes, including ubiquitinated inclusions and hyaline conglomerate inclusions, shows striking similarities between them. Marked differences in the anatomical distribution of lesions determine the predominance and type of motor and cognitive features in each syndrome. This concept of a clinicopathological spectrum is potentially of equal relevance to other late onset neurodegenerative disorders including multisystem atrophies, the Lewy body disorders and various manifestations of Alzheimer's disease. It will gain increasing importance as therapies evolve from the symptomatic to those directed at underlying pathogenetic events.}, }
@article {pmid9625304, year = {1998}, author = {Galassi, G and Gentilini, M and Ferrari, S and Ficarra, G and Zonari, P and Mongiardo, N and Tommelleri, G and Di Rienzo, B}, title = {Motor neuron disease and HIV-1 infection in a 30-year-old HIV-positive heroin abuser: a causal relationship?.}, journal = {Clinical neuropathology}, volume = {17}, number = {3}, pages = {131-135}, pmid = {9625304}, issn = {0722-5091}, mesh = {Acquired Immunodeficiency Syndrome/*complications/pathology ; Adult ; Atrophy ; HIV Seropositivity/*complications/pathology ; Heroin Dependence/*complications/pathology ; Humans ; Male ; Motor Neuron Disease/etiology/*pathology ; }, abstract = {Although human retroviruses seem plausible agents of motor neuron diseases, there are only few reports of patients infected by the human immunodeficiency virus, with documented motor neuron disorder. That retroviral infections may cause motor neuron pathology by various mechanisms in animals and humans is known. Neurological symptoms potentially attributed to damage of lower motor neurons are often described during the course of HIV-1 infection and AIDS, however, it is often difficult to establish whether the disorder is primarily affecting the perikarya of lower motor neurons, or whether it is due to a focal proximal axonopathy, or to a dying-back process. We report a 30-year-old heroin abuser, HIV-1 positive, who presented a rapidly progressive limb weakness, muscle wasting, and bulbar signs, in absence of sensory loss of cerebellar and pyramidal signs. Imaging studies were negative. CSF showed increased protein content, negative cytology, and no oligoclonal bands. Serum protein electrophoresis, urinary heavy metal, and viral researches were negative. CD4 cells were counted 340 mm3 with a CD4-CD8 ratio equal to 0.4. Electrophysiology showed acute and chronic neurogenic changes, confirmed by muscle biopsy. Conduction studies along motor and sensory nerves fell within normal range. Biopsy of sural nerve revealed mild myelinated and unmyelinated fiber loss, occasional degeneration and regeneration, unremarkable inflammation. Despite treatment with AZT, zalcitabine, and steroids, the patient died after 3-month illness. Neuropathology showed normal cortical cell Betz's, and hemispheric white matter. Brain stem motor nuclei (inferior olival, dorsal motor of the vagus, hypoglossal) showed atrophy and intracytoplasmatic lipofuscin accumulation. Vacuolization, central chromatolysis, and neuronophagia were rarely seen. As associated pathology, in the fourth ventricle there were two small subependymal foci of demyelination, with reactive astrocytes and vascular proliferation. A possible crucial role of the HIV-1 infection in the development and progression of our patient's illness is considered in view of the known altered immunity proved in MND and ALS cases.}, }
@article {pmid9612802, year = {1998}, author = {Chang, TM and Prakash, S}, title = {Therapeutic uses of microencapsulated genetically engineered cells.}, journal = {Molecular medicine today}, volume = {4}, number = {5}, pages = {221-227}, doi = {10.1016/s1357-4310(98)01246-5}, pmid = {9612802}, issn = {1357-4310}, mesh = {Animals ; Biotechnology ; Capsules ; *Cell Transplantation ; *Genetic Engineering ; Genetic Therapy/*methods ; Humans ; Rats ; Renal Insufficiency/therapy ; }, abstract = {Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.}, }
@article {pmid9606682, year = {1998}, author = {Schönhofer, B and Köhler, D}, title = {[Therapeutic strategies in respiratory insufficiency in amyotrophic lateral sclerosis. Possibilities and limits].}, journal = {Der Nervenarzt}, volume = {69}, number = {4}, pages = {312-319}, doi = {10.1007/s001150050276}, pmid = {9606682}, issn = {0028-2804}, mesh = {Advance Directives/legislation &amp; jurisprudence ; Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Informed Consent/legislation &amp; jurisprudence ; *Palliative Care/legislation &amp; jurisprudence ; Respiratory Insufficiency/*therapy ; *Respiratory Therapy ; Terminal Care/legislation &amp; jurisprudence ; }, abstract = {In the final stage of amyotrophic lateral sclerosis (ALS) the majority of patients develop chronic respiratory failure due to respiratory muscle weakness. The interaction between the patient with ALS and the physician should be characterized by continuous communication, especially with respect to the prospect of ventilatory failure and for support. The patient and his family must be informed thoroughly about the natural history and the prognosis of ALS, depending on the individual disease process. Already in the early stage of the disease coping strategies should be discussed so that imminent respiratory emergencies can be handled. If ALS patients are not informed about the acute respiratory insufficiency they run the risk of having to be intubated and mechanically ventilated over a long term. If dyspnea and hypersecretion dominate the final stage of ALS, the therapeutic strategy consists of the administration of morphine, insufflation of oxygen and bronchoscopic suction. Mechanical ventilation should only be initiated in the exceptional case. However, if dyspnea occurs in the early stage of the disease, when there is no bulbar paralysis and peripheral muscle function is intact, then noninvasive mechanical ventilation via mask may improve the quality of life substantially. Nevertheless, invasive mechanical ventilation via a tracheostomy should be avoided.}, }
@article {pmid9592986, year = {1998}, author = {Cimino, G and Rapanotti, MC and Sprovieri, T and Elia, L}, title = {ALL1 gene alterations in acute leukemia: biological and clinical aspects.}, journal = {Haematologica}, volume = {83}, number = {4}, pages = {350-357}, pmid = {9592986}, issn = {0390-6078}, mesh = {Acute Disease ; Chromosomes, Human, Pair 4 ; Chromosomes, Human, Pair 6 ; Chromosomes, Human, Pair 9 ; DNA-Binding Proteins/*genetics ; Histone-Lysine N-Methyltransferase ; Humans ; Leukemia/diagnosis/*genetics ; Myeloid-Lymphoid Leukemia Protein ; *Proto-Oncogenes ; *Transcription Factors ; Translocation, Genetic ; Zinc Fingers ; }, abstract = {BACKGROUND AND OBJECTIVE: The ALL1 gene, also referred to as MLL, HRX or Htrx1, is interrupted in the vast majority of translocations involving the chromosome band 11q23. Alterations in this gene are reported in approximately 5-10% of acute leukemias (AL) and characterize different leukemic subtypes such as infant (< 12 months of age) AL, topoisomerase II inhibitors-related (TR) AL and a small subset of de novo AML and ALL. Distinguishing features of ALL1 alterations include the striking heterogeneity of its recombinations, i.e., more than 30 chromosome partners have been described in ALL1 rearrangements, and the lack of association with a definite lineage. The objective of this article is to review the biological and structural properties of ALL1 gene and its various fusion proteins, and to discuss the clinical relevance of these lesions with special emphasis on their role in molecular diagnosis and monitoring of minimal residual disease.<br><br>The material examined in the present review includes data published by the authors in this field, articles and abstracts published in journals covered by the Science Citation Index and Medline, as well as some more recent personal unpublished observations.<br><br>STATE OF THE ART: The ALL1 gene spans approximately 90 kb of DNA in length, and consists of 36 exons, ranging in size from 65 bp to 4249 bp. ALL1 codifies for a major transcript of approximately or equal to 15 kb. It encodes a protein of more than 3910 amino acids, containing three regions sharing sequence homology with the Drosophila trithorax gene. These homologies suggest that ALL1 is a transcription factor controlling development and/or differentiation of human cells. To date, twelve ALL1 partner genes have been characterized which are involved in the following translocations: t(4;11), t(9;11), t(6;11), t(11;19), t(1;11) t(10;11), t(11;16), t(11;17) and t(X;11). Since all these genes do not share relevant homologies among each other, their putative role in ALL1 activation still remains to be clarified. The analysis of ALL1 breakpoint cluster region (bcr) shows that several DNA motifs implicated in illegitimate recombination events are located within the bcr. Thus, mapping of breakpoints in the different subtypes of ALL1 +ve leukemia may help in understanding the events leading to translocations in human ALs. In this respect, data on ALL1 breakpoint localization suggest that similar pathogenetic mechanisms may underlie infant and TR AL and that these events might differ from those occurring in de novo AL. The availability of this molecular marker provides a new tool for diagnostic purposes and characterization of ALs and for monitoring of minimal residual disease. To date, the prognostic value of ALL1 rearrangements has been clearly demonstrated for infant ALs only, whereas the clinical relevance of ALL1 rearrangements in the other leukemic subtypes needs further evaluation by future prospective studies on a larger number of patients homogeneously treated. As concerning studies on minimal residual disease, data on PCR monitoring of the ALL1/AF4 fusion transcript, resulting from the t(4;11) translocation, show the clinical relevance of this molecular test in predicting outcome and, as a consequence, in designing individual post-remission therapies.<br><br>PERSPECTIVES: It is expected that future studies will provide more detailed information regarding either the normal ALL1 function and/or the leukemogenic effect of ALL1 alterations, together with a better definition of the prognostic relevance of the hybrid proteins formed by this gene at diagnosis and during remission of disease.}, }
@article {pmid9564180, year = {1998}, author = {Harris, ED}, title = {Amyotrophic lateral sclerosis: a lesson in deficiency diseases.}, journal = {Nutrition reviews}, volume = {56}, number = {3}, pages = {81-84}, doi = {10.1111/j.1753-4887.1998.tb01698.x}, pmid = {9564180}, issn = {0029-6643}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Animals ; Humans ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-dependent degeneration of motor neurons in the central nervous system. ALS is not caused by faulty nutrition. Recent data suggest that ALS could be an oxidative neurotoxicity induced by a mutation in the SOD1 protein. This finding extends beyond the simple loss of an antioxidant enzyme.}, }
@article {pmid9563578, year = {1998}, author = {Bromberg, MB}, title = {Electrodiagnostic studies in clinical trials for motor neuron disease.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {15}, number = {2}, pages = {117-128}, doi = {10.1097/00004691-199803000-00004}, pmid = {9563578}, issn = {0736-0258}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Clinical Trials as Topic ; Disease Progression ; *Electrodiagnosis ; Electromyography ; Humans ; Magnetics ; Motor Neuron Disease/*diagnosis/pathology/physiopathology ; Motor Neurons/pathology ; }, abstract = {Motor neuron disease (MND) is a group of neurodegenerative disorders characterized by death of upper motor neurons (UMN) and lower motor neurons (LMN). Clinical study of UMN loss is limited, but electrodiagnostic studies can be used readily to assess the functional state of LMN. Electrodiagnostic studies are regularly used in making the diagnosis of amyotrophic lateral sclerosis (ALS) and other forms of MND. They can also be used to follow disease progression and serve as end point measures in drug trials. In this role, electrodiagnostic studies can provide specific information not readily available from measurement of muscle strength or clinical functional scales. This article emphasizes the primary pathologic and secondary physiologic changes that take place after LMN loss and how they can be assessed by electrodiagnostic studies. It reviews the uses of routine electrodiagnostic studies for the diagnosis of MND but focuses on how special electrodiagnostic studies can be used as end point measures in drug trials.}, }
@article {pmid9562996, year = {1998}, author = {Maertens de Noordhout, A}, title = {[Applications of cortical magnetic stimulation].}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {28}, number = {1}, pages = {9-30}, doi = {10.1016/s0987-7053(97)89575-5}, pmid = {9562996}, issn = {0987-7053}, mesh = {Animals ; Cerebral Cortex/*physiology ; *Electromagnetic Fields ; Humans ; *Magnetoencephalography ; Motor Cortex/physiology ; }, abstract = {In the last decade, a new electrophysiological tool has become available since the development of painless magnetic stimulators able to activate the primary motor cortex and the motor roots in conscious man. Therefore, it became possible to measure the conduction time within fast-conducting central motor pathways by substracting from the total latency of muscle responses elicited by cortical stimuli the conduction time in peripheral nerves. This technique proved sensitive enough to illustrate early abnormalities of central motor conduction in various neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, cervical spondylotic myelopathy, degenerative ataxias or hereditary spastic paraplegias. When recorded early after stroke, motor evoked potentials are also a valuable tool to predict functional outcome. They can also illustrate subtle pathophysiological disturbances in diseases where there is no direct involvement of central motor pathways such as Parkinson's disease, dystonia or epilepsy. Magnetic cortical stimulation also offers unique opportunities to explore intracerebral inhibitory and excitatory circuits and mechanisms of brain plasticity. The recent development of rapid rate stimulators also enables functional studies of non-motor cerebral regions such as visual or frontal cortices. Moreover, rapid rate stimulation seems useful in the treatment of drug-resistant depression but the safety of this procedure, particularly with regard to the production of seizures or kindling, remains to be fully documented.}, }
@article {pmid9562665, year = {1998}, author = {Jackson, CE and Bryan, WW}, title = {Amyotrophic lateral sclerosis.}, journal = {Seminars in neurology}, volume = {18}, number = {1}, pages = {27-39}, doi = {10.1055/s-2008-1040859}, pmid = {9562665}, issn = {0271-8235}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/therapy ; Education, Medical, Continuing ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with evidence of both anterior horn cell and corticospinal tract degeneration. The incidence of ALS is 1 to 2.5 cases per 100,000 population and the disease occurs primarily in adult life. The etiology of sporadic ALS remains unknown, although 5 to 10% of cases are familial. The diagnosis of ALS requires the presence of both upper and lower motor neuron findings and progressive motor dysfunction. Several theories regarding the pathogenesis of ALS have emerged including glutamate excitotoxicity, free radical oxidative stress, neurofilament accumulation, and autoimmunity. Clinical trials involving antiglutamate agents, antioxidants, immunosuppressants, and growth factors have shown no substantial benefit in slowing progression, with death usually occurring 2 to 5 years following the onset of symptoms. The management of ALS patients requires a multidisciplinary team that can provide the numerous medical and physical interventions necessary to treat weakness and fatigue, bulbar dysfunction, spasticity and pain, depression, and respiratory failure.}, }
@article {pmid9551785, year = {1998}, author = {Taylor, CP and Gee, NS and Su, TZ and Kocsis, JD and Welty, DF and Brown, JP and Dooley, DJ and Boden, P and Singh, L}, title = {A summary of mechanistic hypotheses of gabapentin pharmacology.}, journal = {Epilepsy research}, volume = {29}, number = {3}, pages = {233-249}, doi = {10.1016/s0920-1211(97)00084-3}, pmid = {9551785}, issn = {0920-1211}, mesh = {Acetates/pharmacokinetics/*pharmacology/*therapeutic use ; *Amines ; Analgesics/pharmacology/therapeutic use ; Animals ; Anti-Anxiety Agents/administration &amp; dosage/therapeutic use ; Anticonvulsants/pharmacology/therapeutic use ; Brain/drug effects/physiology ; Calcium Channels/chemistry/drug effects/physiology ; *Cyclohexanecarboxylic Acids ; Gabapentin ; Humans ; Models, Neurological ; Neuroprotective Agents/pharmacology/therapeutic use ; Neurotransmitter Agents/physiology ; Pain ; Sodium Channels/physiology ; Synapses/drug effects/physiology ; Tissue Distribution ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).}, }
@article {pmid9546290, year = {1998}, author = {Mann, DM}, title = {Dementia of frontal type and dementias with subcortical gliosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {8}, number = {2}, pages = {325-338}, pmid = {9546290}, issn = {1015-6305}, mesh = {Cerebral Cortex/*pathology ; Dementia/*pathology ; Frontal Lobe/*pathology ; Gliosis/*pathology ; Humans ; Language Disorders/pathology ; Motor Neuron Disease/pathology ; }, abstract = {The group of Frontotemporal dementias (FTD) is composed of non-Alzheimer forms of dementia characterized clinically by behavioural and personality change leading to apathy and mutism. The disorder is associated with a progressive atrophy of the frontal, anterior temporal and anterior parietal lobes of the brain with several types of underlying pathology. One type (frontal lobe degeneration) is characterized by a microvacuolar degeneration of the outer cortical laminae along with a mild and mainly subpial gliosis and a loss of nerve cells, mostly from layers II and III. Another type shows transcortical tissue cavitation and florid gliosis with neuronal degeneration characterized by the presence of tau and ubiquitin positive inclusion bodies and alpha beta-crystallin-positive ballooned neurones: such changes have been termed 'Pick-type histology', and form the basis for the modern definition of 'Pick's disease'. The aetiological relationship between these two histological types is presently unknown. Both histologies can be differently distributed topographically throughout the brain to produce syndromes of progressive language disorder, when affecting bitemporal lobes or the left hemisphere preferentially, or progressive apraxia when parietal and motor regions are involved. Either pathology can be combined with or overlaps with that of classical motor neurone disease to produce motor neurone disease dementia. The underlying cause of FTD is unknown but genetic factors are strongly implicated. About half of cases show a previous family history of a similar disorder. In several families bearing a FTD clinical and pathological phenotype, linkage to chromosome 17 has been established but the pathology of this group appears distinctive and its relation to other forms of FTD awaits further elucidation. It is still possible that the many clinical and pathological variants of FTD may reflect different phenotypic expressions of a particular genetic change(s) at a single locus on this chromosome.}, }
@article {pmid9539113, year = {1998}, author = {Bai, G and Lipton, SA}, title = {Aberrant RNA splicing in sporadic amyotrophic lateral sclerosis.}, journal = {Neuron}, volume = {20}, number = {3}, pages = {363-366}, doi = {10.1016/s0896-6273(00)80979-4}, pmid = {9539113}, issn = {0896-6273}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; RNA Splicing/*physiology ; RNA, Messenger/genetics ; }, }
@article {pmid9513930, year = {1997}, author = {Durlach, J and Bac, P and Durlach, V and Durlach, A and Bara, M and Guiet-Bara, A}, title = {Are age-related neurodegenerative diseases linked with various types of magnesium depletion?.}, journal = {Magnesium research}, volume = {10}, number = {4}, pages = {339-353}, pmid = {9513930}, issn = {0953-1424}, mesh = {*Aging ; Amyotrophic Lateral Sclerosis/epidemiology ; Dementia/epidemiology ; Humans ; Magnesium/therapeutic use ; Magnesium Deficiency/*complications/drug therapy ; Neurodegenerative Diseases/*etiology ; Parkinson Disease/epidemiology ; }, abstract = {Age-related human neurodegenerative diseases are a major social and medical problem. It is therefore logical to take into consideration every theory with an overall approach to neurodegenerative diseases. This environmental proposal relies mainly on data concerning the Western Pacific amyotrophic lateral sclerosis-Parkinsonism-dementia complex (WP ALS-PD) considered as 'a prototypal human neurodegenerative disease' and on extrapolation from it to the bulk of neurodegenerative diseases (NDD). NDD would be due to an accelerated ageing process in certain populations of neurons due to the noxious synergy of (1) increased environmental slow deleterious factors (such as slow toxins) and of (2) decreased environmental protective factors (Mg deficient intake particularly). First, it was observed that three apparently dissimilar conditions occurred at extraordinary high rates in the Guam area: motoneuron disease (ALS), Parkinson's disease (P) and Alzheimer's-like dementia (D). Next, several other foci of endemic ALS-PD were found in Asia and Oceania in three Western Pacific population groups. These included the Chamorro people in Mariana Islands (Guam and Rota), the Auyu and Jakai people of West New Guinea and the Japanese residents of the Kii peninsula (Honshu island). The post-Second World War decline of the occurrence of WP ALS-PD in all three high incidence disease foci coupled with the absence of demonstrable heritable or transmissible factors had led to focus the search for the cause of this degenerative disease on nontransmissible environmental factors that are disappearing as the susceptible population groups acculturate to modern way. Epidemiologic study has shown that preference for traditional Chamorro food is the only one of 23 tested variables significantly associated with an increased risk for PD. An early suggestion incriminated the toxic seed of the false sago palm (Cycas circinalis L) which was used in traditional food and medicine. Laboratory investigation of cycad seed revealed the presence of various toxins and particularly of an 'unusual' non protein aminoacid: L-BMAA (beta-N-methylamino-L-alanine), an excitotoxic aminoacid. This slow toxin presents some structural similarity to another 'unusual' excitotoxic aminoacid: L-BOAA (beta-N-oxalyl-amino-L-alanine), an exogenous neurotoxin present in the grass pea (Lathyrus sativus) whose excessive consumption may cause lathyrism. The excitotoxicity of both L-BMAA and L-BOAA mainly concerns non-NMDA receptors. The neurotoxicity of these aminoacids varies with experimental models failing to induce an experimental model akin to WP ALS-PD or displaying many of the motor-system and behavioral changes of WP ALS-PD. It may be due to the presence of physiological levels of bicarbonate or of various toxic cofactors: bio-organic such as cycasin or inorganic such as pollutant metals e.g. aluminum or manganese, together with the lack of protective factors (e.g. calcium and magnesium deficiencies). Combined Al intoxication with Ca-Mg deficiencies is a reasonable model to investigate the pathogenesis of neurodegenerative diseases and eventually to screen their treatments. It may also be considered as a model of magnesium deficit, but it does not concern simple magnesium deficiency reversible with mere oral physiological magnesium supplementation. Magnesium deficiency cannot result in neurodegenerative disease. Combined Al intoxication with Ca-Mg deficiencies is not reversible through physiological oral magnesium supplementation. It therefore constitutes a type of experimental magnesium depletion model, instrumental in the investigation of the pathogenesis of magnesium depletion and in the screening of its still unknown possible treatments. (ABSTRACT TRUNCATED)}, }
@article {pmid9512453, year = {1998}, author = {Andersen, JK}, title = {Use of genetically engineered mice as models for exploring the role of oxidative stress in neurodegenerative diseases.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {3}, number = {}, pages = {c8-16}, doi = {10.2741/a259}, pmid = {9512453}, issn = {1093-9946}, support = {P01AG09793/AG/NIA NIH HHS/United States ; R29AG1241/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Disease Models, Animal ; Genetic Engineering/*methods ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*pathology ; Oxidative Stress/*physiology ; }, abstract = {A growing body of evidence has suggested that oxidative stress may play a major role in the degeneration of neurons associated with several neurological diseases of aging including ALS, Parkinson's, and Alzheimer's disease; this has been the topic of numerous previous reviews and opinion papers (e.g. 1-10). The ability to construct genetically engineered mouse lines containing targeted mutations has done much to aid in the assessment of the role of reactive oxygen species (ROS) in both the initiation as well as the progression of these diseases and has markedly advanced research in the field. Most importantly, the creation of genetic animal models has strengthened the argument that antioxidants may be a useful therapy in the treatment of these types of disorders.}, }
@article {pmid9498191, year = {1997}, author = {Kuba, GB and Kroll, P}, title = {[Pseudotumor cerebri and pregnancy--a case report].}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {211}, number = {6}, pages = {395-397}, doi = {10.1055/s-2008-1035154}, pmid = {9498191}, issn = {0023-2165}, mesh = {Adult ; Cesarean Section ; Female ; Follow-Up Studies ; Humans ; Infant, Newborn ; Papilledema/diagnosis ; Pregnancy ; Pregnancy Complications/*diagnosis ; Pseudotumor Cerebri/*diagnosis ; Refraction, Ocular ; Visual Acuity ; }, abstract = {BACKGROUND: Indications for section caesarean or interruption in ophthalmologic diseases are discussed controversially in the literature and are often overemphasized.<br><br>CASE REPORT: A 34-year-old VII-gravida VI-para consulted our clinic for the first time in her 14th week of pregnancy because of bilateral papilledema. There was no indication for EPH-gestosis, neurological examination als well as MRT were normal. In control examinations--first every 3 weeks, then with the beginning of the 30th week of pregnancy every week--the clinical course was uneventful: visual acuity remained on both sides 1.0, on the right eye more than on the left eye the discs appeared prominent with hazy margins, the blind spot was enlarged on the right eye more than on the left eye. Furthermore there was intermittent myopia. In the 37th week of pregnancy section caesarean was performed because of gynecological indications. At the last examination, 4 weeks later, there was a nearly complete restitution ad integrum.<br><br>CONCLUSION: Indications for section caesarean or interruption in patients with papilledema due to pseudotumor cerebri will be discussed with the literature.}, }
@article {pmid9495562, year = {1997}, author = {Bains, JS and Shaw, CA}, title = {Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death.}, journal = {Brain research. Brain research reviews}, volume = {25}, number = {3}, pages = {335-358}, doi = {10.1016/s0165-0173(97)00045-3}, pmid = {9495562}, mesh = {Animals ; Cell Death/*physiology ; Glutathione/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Oxidative Stress/*physiology ; }, abstract = {Oxidative stress has been implicated in both normal aging and in various neurodegenerative disorders and may be a common mechanism underlying various forms of cell death including necrosis, apoptosis, and excitotoxicity. In this review, we develop the hypothesis that oxidative stress-mediated neuronal loss may be initiated by a decline in the antioxidant molecule glutathione (GSH). GSH plays multiple roles in the nervous system including free radical scavenger, redox modulator of ionotropic receptor activity, and possible neurotransmitter. GSH depletion can enhance oxidative stress and may also increase the levels of excitotoxic molecules; both types of action can initiate cell death in distinct neuronal populations. Evidence for a role of oxidative stress and diminished GSH status is presented for Lou Gehrig's disease (ALS), Parkinson's disease, and Alzheimer's disease. Potential links to the Guamanian variant of these diseases (ALS-PD complex) are discussed. In context to the above, we provide a GSH-depletion model of neurodegenerative disorders, suggest experimental verifications of this model, and propose potential therapeutic approaches for preventing or halting these diseases.}, }
@article {pmid9469581, year = {1998}, author = {Ariga, T and Jarvis, WD and Yu, RK}, title = {Role of sphingolipid-mediated cell death in neurodegenerative diseases.}, journal = {Journal of lipid research}, volume = {39}, number = {1}, pages = {1-16}, pmid = {9469581}, issn = {0022-2275}, support = {CA-09380/CA/NCI NIH HHS/United States ; NS-11853/NS/NINDS NIH HHS/United States ; NS-26994/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Gangliosides/physiology ; Glycolipids/physiology ; Humans ; Lipids/physiology ; Neurodegenerative Diseases/*pathology ; Second Messenger Systems ; Sphingolipids/*physiology ; }, abstract = {The metazoan nervous system gives rise intradevelopmentally to many more neurons than ultimately survive in the adult. Such excess cells are eliminated through programmed cell death or apoptosis. As is true for cells of other lineages, neuronal survival is sustained by an array of growth factors, such that withdrawal of neurotrophic support results in apoptotic cell death. Apoptosis is therefore believed to represent a beneficial process essential to normal development of central and peripheral nervous system (CNS and PNS) structures. Although the initiation of neuronal apoptosis in response to numerous extracellular agents has been widely reported, the regulatory mechanisms underlying this mode of cell death remain incompletely understood. In recent years, the contribution of lipid-dependent signaling systems, such as the sphingomyelin pathway, to regulation of cell survival has received considerable attention, leading to the identification of lethal functions for the lipid effectors ceramide and sphingosine in both normal and pathophysiological conditions. Moreover, the apoptotic capacities of several cytotoxic receptor systems (e.g., CD120a, CD95) and many environmental stresses (e.g., ionizing radiation, heat-shock, oxidative stress) are now known to derive from the activation of multiple signaling cascades by ceramide or, under some circumstances, by sphingosine. Inappropriate initiation of apoptosis has been proposed to underlie the progressive neuronal attrition associated with various neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders that are characterized by the gradual loss of specific populations of neurons. In such pathophysiological states, neuronal cell death can result in specific disorders of movement and diverse impairments of CNS and PNS function. In some autoimmune neurological diseases such as Guillain-Barré syndrome, demyelinating polyneuropathy, and motoneuron disease, persistent immunological attack of microvascular endothelial cells by glycolipid-directed autoantibodies may lead to extensive cellular damages, resulting in increased permeability across brain-nerve barrier (BNB) and/or blood-brain barrier (BBB).}, }
@article {pmid9430996, year = {1997}, author = {Horiuchi, M and Sugihara, H and Fujisawa, K and Abe, M and Tadokoro, M}, title = {[An autopsy case of amyotrophic lateral screlosis (ALS): magnetic resonance imaging and pathological findings of the pyramidal tract].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {37}, number = {9}, pages = {810-816}, pmid = {9430996}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Female ; Humans ; *Magnetic Resonance Imaging ; Middle Aged ; Pyramidal Tracts/*pathology ; }, abstract = {A 59-year-old woman was diagnosed as amyotrophic lateral screlosis (ALS) on the basis of neurological and electromyographical findings, and died after about 4 years course. Magnetic resonance imaging (MRI) on coronal planes through the internal capsule revealed high signal area almost limited to the pyramidal tract; the high signal area was more restricted in proton weighted imaging than in T2 weighted imaging. Histological lesion of the precentral gyrus was slight, while loss of myelinated fibers in the posterior limb of the internal capsule was remarkable. Extent of the pathological lesion in the posterior limb of the internal capsule well corresponded to the high signal area in proton weighted imaging. Comparison of the pyramidal tract pathology in the corona radiata and the internal capsule in Klüver-Barrera preparations with the MRI findings obtained 2 years and 8 months before the autopsy suggests us that the T2 weighted imaging of ALS brains may detect involvement of the pyramidal tract as early as or even earlier than histological changes become manifest.}, }
@article {pmid9441250, year = {1997}, author = {Bachus, R and Claus, A and Meyer, T and Riepe, M and Ludolph, AC}, title = {[Molecular biology findings in amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {68}, number = {10}, pages = {785-791}, doi = {10.1007/s001150050195}, pmid = {9441250}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; DNA Mutational Analysis ; Excitatory Amino Acids/physiology ; Humans ; Motor Neurons/physiology ; Reactive Oxygen Species ; Superoxide Dismutase/genetics ; }, abstract = {At presently, the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are unknown. In recent years, the genetic background of hereditary motor neuron diseases has been partly defined. In particular, these advances represent an opportunity to improve our understanding of the pathogenesis of the familial and sporadic forms of ALS and thus provide a basis for rational therapeutic approaches. In this article, recent findings on the pathogenesis of the familial form of ALS and their implications for the sporadic form are discussed.}, }
@article {pmid9424550, year = {1997}, author = {Conradi, S and Ronnevi, LO}, title = {[Improved knowledge resulted in better care of ALS].}, journal = {Lakartidningen}, volume = {94}, number = {48}, pages = {4484-6, 4489-92}, pmid = {9424550}, issn = {0023-7205}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Clinical Competence ; Humans ; Patient Care Team ; Riluzole/therapeutic use ; }, abstract = {An example of the substantial advances in the management and treatment of patients with amyotrophic lateral sclerosis (ALS) in recent years is the introduction in 1996 of Riluzole, the first drug with verified effect on the disease course. The article consists in a review of recent advances in our knowledge of the pathogenic mechanisms, diagnosis, management and treatment of ALS.}, }
@article {pmid9420085, year = {1998}, author = {Pirotte, B and Krischek, B and Levivier, M and Bolyn, S and Brucher, JM and Brotchi, J}, title = {Diagnostic and microsurgical presentation of intracranial angiolipomas. Case report and review of the literature.}, journal = {Journal of neurosurgery}, volume = {88}, number = {1}, pages = {129-132}, doi = {10.3171/jns.1998.88.1.0129}, pmid = {9420085}, issn = {0022-3085}, mesh = {Aged ; Angiolipoma/complications/*diagnosis/pathology/*surgery ; Brain Neoplasms/complications/*diagnosis/pathology/*surgery ; Diagnosis, Differential ; Female ; Humans ; Magnetic Resonance Imaging ; Microsurgery ; Tomography, X-Ray Computed ; }, abstract = {Angiolipomas (ALs) are hamartomas composed of abnormally differentiated vessels and mature adipose tissue. Although they are most commonly found in peripheral tissues, ALs sometimes grow in the spinal epidural space. Intracranial ALs (ICALs) are rare: only seven cases have been reported in the literature. The authors describe the case of a 70-year-old woman who presented with ocular symptoms from a clinically and radiologically progressing parasellar ICAL. The radiological as well as the microsurgical findings are illustrated and compared with the seven previously published cases. The most frequent location of ALs is the skull base, especially the parasellar region. Other ICALs were diagnosed as components of cerebral arteriovenous malformations and were not symptomatic by themselves. Neuroradiological studies of ICALs usually demonstrate the characteristics of both adipose and vascular tissues. However, a review of the literature shows that the diagnosis had not been suspected preoperatively in any of the cases. Operative descriptions emphasize that most neurosurgeons were caught off guard by the profuse bleeding and the unusual relationship of this unexpected lesion to the cavernous sinus, so that removal was rarely complete. The authors conclude that preoperative diagnosis of ICALs is achievable based on magnetic resonance analysis, which should help optimize the microsurgical management of these lesions.}, }
@article {pmid9419064, year = {1997}, author = {Hayashi, H}, title = {Ventilatory support: Japanese experience.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S97-100}, doi = {10.1016/s0022-510x(97)00254-2}, pmid = {9419064}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Japan ; Long-Term Care ; *Respiration, Artificial ; }, abstract = {Paternalism is a predominant pattern in the social and behavioural climate of medical practice in Japan. Recognition of the sanctity of life is the first principle guiding medical ethics. This principle is an important factor in considering the management of patients with ALS in Japan. Following discussion of these principles in the application of ventilatory support to patients with ALS among the Ministry of Health and Welfare of Japan (MHWJ), the Japan ALS Association (JALSA) and ALS patients and families in the Tokyo Metropolitan Neurological Hospital (TMNH), I have concluded that the development of ventilatory failure in ALS in the Japanese context should not be regarded as the endpoint of the disease but merely one of its impairments. Ventilatory support, considered in this context, can extend the life of an ALS patient.}, }
@article {pmid9419063, year = {1997}, author = {Smyth, A and Riedl, M and Kimura, R and Olick, R and Siegler, M}, title = {End of life decisions in amyotrophic lateral sclerosis: a cross-cultural perspective.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S93-6}, doi = {10.1016/s0022-510x(97)00253-0}, pmid = {9419063}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Cross-Cultural Comparison ; Humans ; Terminal Care ; }, abstract = {In an era where life-sustaining technology offers physicians unprecedented powers to prolong survival in terminal illness, the question of how end of life decisions are made has become a major subject of study and debate. Amyotrophic lateral sclerosis (ALS) is a disease in which physical ability declines while mental capacity most often remains intact. Since most patients with ALS die of respiratory failure, a distinguishing feature of this disease is whether a patient is offered and accepts a chance to go on long-term mechanical ventilation. This unusual feature makes ALS a compelling model for studying end of life decisions in different countries. This paper reviews the literature and presents preliminary data on how end of life decisions in ALS are made in the US, Great Britain, and Japan. We address this issue by examining how cultural differences in truth-telling and informed consent, societal differences in attitudes toward the use of artificial life support, and legal differences in the role and status of advance directives in each country influenced decisions in the following three groups of patients: (1) the mentally competent; (2) mentally incompetent patients who previously completed advance directives when competent; and (3) mentally incompetent patients who have not provided advance guidance about their wishes.}, }
@article {pmid9419057, year = {1997}, author = {Gurney, ME}, title = {The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S67-73}, doi = {10.1016/s0022-510x(97)00247-5}, pmid = {9419057}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Humans ; Mice ; Mice, Transgenic/genetics/*physiology ; Motor Neuron Disease/drug therapy/genetics ; Superoxide Dismutase/genetics ; }, abstract = {The discovery of mutations in the human SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,Zn SOD) in patients with familial amyotrophic lateral sclerosis (ALS) has made possible the development of etiological models of the disease. Expression of mutant SOD1 genes in transgenic mice causes a progressive paralytic disease whose general features resemble ALS in humans. We have used the transgenic model to explore etiological mechanisms and to screen potential therapeutics. Our results and those of others show that familial ALS mutations cause a gain-of-function in Cu,Zn SOD that enhances the generation of damaging oxygen radicals. This may render motor neurons sensitive to the excitotoxic effects of ambient glutamate, as a putative glutamatergic inhibitor such as riluzole has therapeutic efficacy both in the transgenic model and in human ALS. This finding highlights the utility of the SOD1-G93A transgenic mouse model for preclinical drug studies in ALS.}, }
@article {pmid9419054, year = {1997}, author = {Pioro, EP}, title = {MR spectroscopy in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S49-53}, doi = {10.1016/s0022-510x(97)00244-x}, pmid = {9419054}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; *Magnetic Resonance Imaging ; *Magnetic Resonance Spectroscopy ; Motor Neuron Disease/*pathology ; }, abstract = {Proton magnetic resonance spectroscopy (1H-MRS) and proton magnetic resonance spectroscopic imaging (1H-MRSI) have been used to identify neuronal dysfunction and/or loss in vivo in patients with various neurological diseases, including amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Both long and short echo time (TE) proton spectroscopy reveal the brain metabolites choline (Cho), creatine/phosphocreatine (Cr), and N-acetyl (NA) groups. Because NA groups are localized to mature neurons and Cr is homogeneously distributed throughout the brain, the NA/Cr ratio is considered an index of neuronal integrity. Long TE proton spectroscopic studies have revealed significantly decreased NA/Cr values in the sensorimotor cortex and brainstem of patients with ALS, consistent with neuronal dysfunction and/or loss. The amount of NA/Cr decrease appears to be directly proportional to the degree of clinical upper motor neuron deficit. Short TE 1H-MRS and 1H-MRSI also reveal other metabolites such as glutamate (Glu) and glutamine (Gln), which have been implicated in the ALS/MND disease process. Preliminary results of short TE 1H-MRSI of the medulla in patients with ALS/MND have revealed significantly decreased NA/Cr values and abnormally elevated Glu+Gln/Cr ratios, compared to control individuals. The latter values were higher in patients with more rapid disease. Although it is unclear whether the elevation of Glu+Gln/Cr precedes or follows the neuronal (and axonal) degeneration in the medulla of these patients, its occurrence provides in vivo evidence of abnormal glutamate metabolism in the CNS parenchyma of patients with ALS/MND.}, }
@article {pmid9419050, year = {1997}, author = {Borasio, GD}, title = {Amyotrophic lateral sclerosis: lessons in trial design from recent trials.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S23-8}, doi = {10.1016/s0022-510x(97)00240-2}, pmid = {9419050}, issn = {0022-510X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/mortality/psychology ; Clinical Trials as Topic/*methods ; Disease Progression ; Humans ; *Research Design ; }, abstract = {The recent history of clinical trials in ALS is marked by a great diversity in trial design. This has limited the comparability of the trial results, and has resulted in intense discussions about which parameters should or should not be evaluated when testing a new drug for ALS. This article discusses, without any claim to completeness, some aspects of trial design in relation to past, ongoing and future ALS trials, including: choice of endpoints, measurement of disease progression, assessment of quality of life, placebo-controlled trials, open-label trials, collaboration with the industry, and methods for investigating mechanisms of action of experimental drugs.}, }
@article {pmid9402548, year = {1997}, author = {Borasio, GD and Voltz, R}, title = {Palliative care in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {244 Suppl 4}, number = {}, pages = {S11-7}, doi = {10.1007/pl00007719}, pmid = {9402548}, issn = {0340-5354}, mesh = {Advance Directives ; Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Anxiety/prevention &amp; control ; Coma/etiology ; Deglutition Disorders/therapy ; Dysarthria/rehabilitation/therapy ; Dyspnea/etiology/therapy ; Gastrostomy/psychology ; Humans ; Hypercapnia/etiology ; Nutrition Disorders/prevention &amp; control ; *Palliative Care ; Physician-Patient Relations ; Respiratory Therapy ; Societies ; *Terminal Care ; Truth Disclosure ; }, abstract = {The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a challenge for the neurologist. Most disabilities associated with progressive disease can be ameliorated by symptomatic treatment. Prognosis and treatment options should be openly discussed with the patient and his/her relatives. Nutritional deficiency due to pronounced dysphagia can be efficiently relieved by a percutaneous enterogastrostomy. Respiratory insufficiency can be treated by non-invasive ventilation at home, provided the familial environment is supportive. Adequate assistance and palliative treatment in the terminal phase is of paramount importance.}, }
@article {pmid10187031, year = {1998}, author = {Bissell, RA and Eslinger, DG and Zimmerman, L}, title = {The efficacy of advanced life support: a review of the literature.}, journal = {Prehospital and disaster medicine}, volume = {13}, number = {1}, pages = {77-87}, pmid = {10187031}, issn = {1049-023X}, mesh = {Emergency Medical Services/methods/*standards ; Heart Arrest/mortality/therapy ; Humans ; Life Support Care/methods/*standards ; *Quality of Health Care ; Seizures/mortality/therapy ; Survival Rate ; United States ; Wounds and Injuries/mortality/therapy ; }, abstract = {INTRODUCTION: Jurisdictions throughout the United States and some other parts of the world have invested substantial time and resources into creating and sustaining a prehospital advanced life support (ALS) system without knowing whether the efficacy of ALS-level care had been validated scientifically. In recent years, it has become fashionable for speakers before large audiences to declare that there is no scientific evidence for the clinical effectiveness of ALS-level care in the out-of-hospital setting. This study was undertaken to evaluate the evidence that pertains to the efficacy of ALS-level care in the current scientific literature.<br><br>METHODS: An extensive review of the available literature was accomplished using computerized and manual means to identify all applicable articles from 1966 to October, 1995. Selected articles were read, abstracted, analyzed, and compiled. Each article also was categorized as presenting evidence supporting or refuting the clinical efficacy of ALS-level care, and a list was constructed that pointed to where the preponderance of the evidence lies.<br><br>RESULTS: Research in this field differs widely in terms of methodological sophistication. Of the 51 articles reviewed, eight concluded that ALS-level care is not any more effective than is basic life support, seven concluded that it is effective in some applications but not for others, and the remainder demonstrated effectiveness. The strongest support for ALS-level care was in the area of responses to victims of cardiac arrest, whereas somewhat more divergent findings related to trauma or non condition-specific studies.<br><br>CONCLUSIONS: While not unanimous, the predominant finding of recent research into the clinical effectiveness of advanced life support demonstrates improved effectiveness over basic life support for patients with certain pathologies. More outcomes-based research is needed.}, }
@article {pmid9369999, year = {1997}, author = {Aschner, M}, title = {Astrocyte metallothioneins (MTs) and their neuroprotective role.}, journal = {Annals of the New York Academy of Sciences}, volume = {825}, number = {}, pages = {334-347}, doi = {10.1111/j.1749-6632.1997.tb48445.x}, pmid = {9369999}, issn = {0077-8923}, support = {ES 07331/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/cytology/pathology/*physiology ; Brain Diseases/pathology/*physiopathology ; Humans ; Metallothionein/*physiology ; Methylmercury Compounds/toxicity ; Models, Neurological ; *Neuroprotective Agents ; Neurotoxins/toxicity ; }, abstract = {I have briefly detailed in this review the role of astrocytes in MeHg neurotoxicity, emphasizing the mechanisms and significance of astrocytic swelling in neuropathological conditions. I have also described the functions of brain MTs and have reported recent observations on their propensity to attenuate cytotoxicity. While it is unclear why three different MT genes are expressed in the brain, this redundancy should allow for greater accumulation of MTs under stressful conditions compared to its accumulation if only a single gene was present. Another explanation may be that genes encoding functionally identical MTs might be regulated independently, thus permitting cell-specific MT expression. Finally, each of the three MT isoforms may have distinct functions. As discussed herein, astrocytic MTs afford protection from the acute cytotoxic effects of MeHg, reversing the effect of this organometal on RVD and inhibition of taurine release. Whether other vital cellular functions are protected by MTs will have to await future studies, as will the mechanisms associated with MT-induced cellular protection. That the resistance to heavy metal toxicity is closely related to the cellular ability to synthesize MTs, raises interesting questions regarding the potential involvement of heavy metals in neurodegenerating (amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) under conditions of compromised MT synthesis. Future studies on the expression and regulation of MT genes are likely to culminate in novel strategies for manipulating intracellular MT levels, providing insight to their role in both health and disease.}, }
@article {pmid9345852, year = {1997}, author = {Sagot, Y and Vejsada, R and Kato, AC}, title = {Clinical and molecular aspects of motoneurone diseases: animal models, neurotrophic factors and Bcl-2 oncoprotein.}, journal = {Trends in pharmacological sciences}, volume = {18}, number = {9}, pages = {330-337}, doi = {10.1016/s0165-6147(97)01094-8}, pmid = {9345852}, issn = {0165-6147}, mesh = {Animals ; Genes, bcl-2/genetics/*physiology ; Humans ; Motor Neuron Disease/genetics/*metabolism/*physiopathology ; Neurotransmitter Agents/*physiology ; }, abstract = {Animal models of motor neurone disease (MND) are being increasingly used for screening molecules with clinical potential. A number of different treatments to decrease the progression of neuronal cell loss have been proposed; these include: Bcl-2 (B-cell leukaemia oncogene-2), neurotrophic factors, glutamate receptor inhibitors and Ca2+ channel antagonists. In this review Yves Sagot, Richard Vejsada and Ann C. Kato focus on the effects of neurotrophic factors and Bcl-2, both of which have been shown to prevent cell death in various experimental paradigms. Studies performed in animal models of MND have confirmed the potential of these molecules to support motoneurone survival. Some of them have been shown to act in synergy and these results are discussed in the context of molecular mechanisms leading to collaborative and synergistic activities, and also with respect to presumptive subpopulations of motoneurones, which express diverse receptors for neurotrophic factors. Finally, the current status of clinical trials for amyotrophic lateral sclerosis using neurotrophic factors will be discussed, as well as recent reports that neurotrophic factors can exert adverse effects on neuronal survival.}, }
@article {pmid9329677, year = {1997}, author = {Buée, L and Hof, PR and Delacourte, A}, title = {Brain microvascular changes in Alzheimer's disease and other dementias.}, journal = {Annals of the New York Academy of Sciences}, volume = {826}, number = {}, pages = {7-24}, doi = {10.1111/j.1749-6632.1997.tb48457.x}, pmid = {9329677}, issn = {0077-8923}, support = {AG05138/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aging ; Alzheimer Disease/*pathology ; Amyloid/analysis ; Brain/*blood supply/pathology ; Dementia, Vascular/*pathology ; Heparan Sulfate Proteoglycans/analysis ; Humans ; Microcirculation ; Neurofibrillary Tangles/pathology ; }, abstract = {Vasculopathy in Alzheimer's disease (AD) may represent an important pathogenetic factor of this disorder. In the present study, microvasculature was studied by immunohistochemistry using a monoclonal antibody against a vascular heparan sulfate proteoglycan. Vascular changes were consistently observed in AD and included decrease in vascular density, presence of atrophic and coiling vessels, and glomerular loop formations. The laminar and regional distribution of these vascular alterations was correlated with the presence of neurofibrillary tangles. However, vascular changes may also follow neuronal loss. Vascular density may be related to a decrease in brain metabolism. Furthermore, one of the main features of AD is the presence of amyloid deposits within brain parenchyma and blood vessel walls. It is not yet clear whether amyloid components are derived from the blood or the central nervous system. Because AD is clearly heterogeneous, based on clinical and genetic data, evidence for either a brain or peripheral origin is discussed. Microvasculature was also analyzed in other neurodegenerative disorders devoid of amyloid deposits including amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam and Pick's disease. In conclusion, if vasculopathy in neurodegenerative disorders is not directly involved in pathogenesis, it may act synergistically with other pathogenetic mechanisms including genetic and environmental factors. This aspect of pathology is particularly interesting in view of its accessibility to therapeutic interventions.}, }
@article {pmid9341570, year = {1997}, author = {Brown, RH}, title = {Amyotrophic lateral sclerosis. Insights from genetics.}, journal = {Archives of neurology}, volume = {54}, number = {10}, pages = {1246-1250}, doi = {10.1001/archneur.1997.00550220050013}, pmid = {9341570}, issn = {0003-9942}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology/therapy ; Cell Death ; Humans ; Motor Neuron Disease/genetics/pathology/physiopathology ; Motor Neurons/physiology ; Mutation ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is among the most dire neurological diseases. The essential clinical feature of the disorder is relentless, lethal paralysis, usually beginning in midadult years. The disease is caused by a slow, progressive loss of motor neurons in the brain and spinal cord. It usually begins focally and then spreads. In most cases, there is concurrent involvement of corticospinal (upper) and spinal (lower) motor neurons, although in some instances the spinal motor neuron features predominate. Involvement of the spinal motor neurons produces muscle denervation of the affected muscles and fasciculations, followed by muscle atrophy. When corticospinal motor neurons degenerate, the weakness is accompanied by spasticity. The mean age at onset of ALS is 55 years; the mean duration is about 4 years. The incidence of new cases is approximately 1 per 100,000 population. The total number of cases is about 5 per 100,000 population. In the United States, it is estimated that there are 20,000 to 30,000 cases. About 10% of cases are inherited as an autosomal dominant trait; familial and sporadic ALS are clinically indistinguishable.}, }
@article {pmid9339959, year = {1997}, author = {Thatte, U and Dahanukar, S}, title = {Apoptosis: clinical relevance and pharmacological manipulation.}, journal = {Drugs}, volume = {54}, number = {4}, pages = {511-532}, pmid = {9339959}, issn = {0012-6667}, mesh = {Acquired Immunodeficiency Syndrome/genetics/immunology ; Apoptosis/drug effects/*genetics/immunology ; Autoimmune Diseases/genetics/immunology ; Cell Division/drug effects/*genetics/immunology ; Cell Survival/genetics/immunology ; Gene Expression Regulation/*genetics/immunology ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Hematopoietic Cell Growth Factors/*pharmacology ; Humans ; Inflammation/genetics/immunology ; Interleukin-3/pharmacology ; Neoplasms/genetics/immunology ; Neurodegenerative Diseases/genetics/immunology ; Promoter Regions, Genetic/genetics ; Virus Diseases/genetics/immunology ; }, abstract = {Apoptosis, often synonymously used with the term 'programmed cell death', is an active, genetically controlled process that removes unwanted or damaged cells. Suppression, overexpression or mutation of a number of genes which orchestrate the apoptotic process are associated with disease. The diseases in which apoptosis has been implicated can be grouped into 2 broad groups: those in which there is increased cell survival (i.e. associated with inhibition of apoptosis) and those in which there is excess cell death (where apoptosis is overactive). Diseases in which there is an excessive accumulation of cells include cancer, autoimmune disorders and viral infections. Deprivation of trophic factors is known to induce apoptosis in cells dependent on them for survival. This fact has been exploited in the use of antiandrogens or antiestrogens in the management of prostate or breast cancer. Haemopoietic growth factors like granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin-3 prevent apoptosis in target cells and modulation of levels of these factors has been tried in the prevention of chemotherapy-induced myelosuppression. Until recently, it was thought that cytotoxic drugs killed target cells directly by interfering with some life-maintaining function. However, of late, it has been shown that exposure to several cytotoxic drugs with disparate mechanisms of action induces apoptosis in both malignant and normal cells. Physiological regulation of cell death is essential for the removal of potentially autoreactive lymphocytes during development and the removal of excess cells after the completion of an immune response. Recent work has clearly demonstrated that dysregulation of apoptosis may underlie the pathogenesis of autoimmune diseases by allowing abnormal autoreactive lymphocytes to survive. AIDS and neurodegenerative disorders like Alzheimer's or Parkinson's disease represent the most widely studied group of disorders where an excess of apoptosis has been implicated. Amyotrophic lateral sclerosis, retinitis pigmentosa, epilepsy and alcoholic brain damage are other neurological disorders in which apoptosis has been implicated. Apoptosis has been reported to occur in conditions characterised by ischaemia, e.g. myocardial infarction and stroke. The liver is a site where apoptosis occurs normally. This process has also been implicated in a number of liver disorders including obstructive jaundice. Hepatic damage due to toxins and drugs is also associated with apoptosis in hepatocytes. Apoptosis has also been identified as a key phenomenon in some diseases of the kidney, i.e. polycystic kidney, as well as in disorders of the pancreas like alcohol-induced pancreatitis and diabetes.}, }
@article {pmid9337068, year = {1997}, author = {Multhaup, G and Ruppert, T and Schlicksupp, A and Hesse, L and Beher, D and Masters, CL and Beyreuther, K}, title = {Reactive oxygen species and Alzheimer's disease.}, journal = {Biochemical pharmacology}, volume = {54}, number = {5}, pages = {533-539}, doi = {10.1016/s0006-2952(97)00062-2}, pmid = {9337068}, issn = {0006-2952}, mesh = {Aging ; Alzheimer Disease/genetics/*metabolism/pathology ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Brain/metabolism/pathology ; Humans ; Oxidative Stress ; *Reactive Oxygen Species ; Superoxide Dismutase/metabolism ; }, abstract = {Although a consensus that Alzheimer's disease (AD) is a single disease has not been reached yet, the involvement of the amyloid precursor protein (APP) and betaA4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of betaA4 in cell cultures, and the findings that aggregation of betaA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals may be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS may be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.}, }
@article {pmid9322693, year = {1997}, author = {Zalstein, S and Cameron, PA}, title = {Helicopter emergency medical services: their role in integrated trauma care.}, journal = {The Australian and New Zealand journal of surgery}, volume = {67}, number = {9}, pages = {593-598}, doi = {10.1111/j.1445-2197.1997.tb04604.x}, pmid = {9322693}, issn = {0004-8682}, mesh = {Air Ambulances/*standards ; Clinical Competence ; Delivery of Health Care, Integrated/*organization &amp; administration ; Emergency Medical Services/*organization &amp; administration ; Health Services Accessibility ; Humans ; Life Support Care/standards ; Outcome Assessment, Health Care ; Regional Medical Programs/organization &amp; administration ; Triage/organization &amp; administration ; Wounds and Injuries/mortality/*therapy ; }, abstract = {The role of helicopters in trauma management must be considered in the context of the provision of sophisticated, high-quality trauma care. The present review examines the evolution of systems of trauma care, the value of advanced life support (ALS), and the role of the Helicopter Emergency Medical Service (HEMS) in improving outcomes. Comparison is made of outcomes of patients managed by HEMS and road ambulances, and important aspects of HEMS including staffing and safety are discussed. There is a role for HEMS as part of a modern trauma system, in particular in bringing ALS skills and access to expert medical care to the rural accident scene or hospital at distances of up to 160 km. It is of greatest value when it is integrated into a well-organized ambulance service and emergency system with good triage and close medical supervision.}, }
@article {pmid9311102, year = {1997}, author = {Hörtnagl, H and Hellweg, R}, title = {Pathophysiological aspects of human neurodegenerative diseases.}, journal = {Wiener klinische Wochenschrift}, volume = {109}, number = {16}, pages = {623-635}, pmid = {9311102}, issn = {0043-5325}, mesh = {Amyloid beta-Peptides/physiology ; Apoptosis/genetics/physiology ; Brain/physiopathology ; Chromosome Mapping ; Cytokines/physiology ; Excitatory Amino Acids/physiology ; Genetic Linkage/genetics ; Humans ; Nerve Growth Factors/physiology ; Neurodegenerative Diseases/genetics/*physiopathology ; Reactive Oxygen Species/metabolism ; Risk Factors ; }, abstract = {This review summarizes the most intriguing topical pathophysiological theories that contribute to current molecular understanding of the most important adult-onset human neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The pathophysiological aspects discussed include genetic linkages, involvement of cytokines and excitotoxic amino acids, contribution of oxidative stress, roles of neurotrophic factors and beta-amyloid deposition, the significance of apoptotic cell death and possible risk factors. An attempt is made to point out common characteristics of these neurodegenerative diseases. Present knowledge of the pathophysiological background of these diseases may provide an encouraging basis for the development of new therapeutic strategies which actually interact with the cascade of neurodegeneration and go beyond the mere pharmacological substitution of neurotransmitter deficits.}, }
@article {pmid9311004, year = {1997}, author = {Maeda, T and Kurahashi, K and Matsunaga, M and Inoue, K and Inoue, M}, title = {[On intra-familial clinical diversities of a familial amyotrophic lateral sclerosis with a point mutation of Cu/Zn superoxide dismutase (Asn 86-Ser].}, journal = {No to shinkei = Brain and nerve}, volume = {49}, number = {9}, pages = {847-851}, pmid = {9311004}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/enzymology/*genetics ; Family Health ; Female ; Humans ; Male ; Middle Aged ; Pedigree ; *Point Mutation ; Superoxide Dismutase/*genetics ; }, abstract = {In a familial amyotrophic lateral sclerosis (FALS) with SOD-1 mutation (Asn 86-Ser), there were intra-familial clinical diversities. The proband, a daughter patient, shows a mild clinical course of 16 years. Her father died of respiratory failure in 3 years. His initial symptom was weakness of upper extremity. The daughter's first symptom was that of lower extremities. Her respiratory-assist started after 9 years from the onset. She is alive under whole-day respiratory assist while she had been taking nutrients per os for 15 years. Her abilities of swallowing remain, even more dependent of tube-feeding (15 years after the onset). The fact of the presence of intra-familial clinical varieties with SOD-1 mutation in FALS suggests that the mutation is not an exclusive factor to determine the clinical phenotype, age of the onset and rapidity of illness of FALS associated with SOD-1 mutation. We collect reports of FALS with SOD-1 mutation which have similar diversities of intra-familial clinical manifestations as our family. Varieties of intra-familial clinical manifestations of motor neuron disease are shown in 9 families with SOD-1 mutation. The genetic error appears to have a limit, and is not a exclusive cause of FALS. However, we should not underestimate the significance of the discovery of a gene, since it might offer a clue to still unanswered riddle of ALS pathogenesis.}, }
@article {pmid9309687, year = {1997}, author = {Schulz, JB and Matthews, RT and Klockgether, T and Dichgans, J and Beal, MF}, title = {The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases.}, journal = {Molecular and cellular biochemistry}, volume = {174}, number = {1-2}, pages = {193-197}, pmid = {9309687}, issn = {0300-8177}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism/pharmacology ; Animals ; Disease Models, Animal ; Dopamine Agents/metabolism/pharmacology ; Hydroxyl Radical/metabolism ; Mice ; Mitochondria/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Nitric Oxide/*metabolism ; Nitro Compounds ; Primates ; Propionates/metabolism/pharmacology ; Rats ; }, abstract = {Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.}, }
@article {pmid9449038, year = {1997}, author = {Gelato, MC and Frost, RA}, title = {IGFBP-3. Functional and structural implications in aging and wasting syndromes.}, journal = {Endocrine}, volume = {7}, number = {1}, pages = {81-85}, pmid = {9449038}, issn = {1355-008X}, support = {2507RR0573619/RR/NCRR NIH HHS/United States ; DK-49316/DK/NIDDK NIH HHS/United States ; T32-DK-07521/DK/NIDDK NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Aging/blood ; Female ; *Frail Elderly ; Humans ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Male ; Middle Aged ; Wasting Syndrome/blood ; }, abstract = {Over the last several years, the authors have studied the relationship of insulin-like growth factors (IGFs) and the insulin-like growth factor binding proteins (IGFBPs) in the circulation in a number of clinical settings. Patterns have emerged that seem to be characteristic of various conditions. In aging, there are marked decreases in IGF-I and -II, normal levels of IGFBP-3, and marked increases in IGFBP-1 in serum. Using ligand blotting and an IGFBP-3 proteolysis assay, BP-3 is intact. Based on native gel electrophoresis, IGFBP-1 is in its most highly phosphorylated state in those elders who have high IGFBP-1 levels. This pattern is slightly different in catabolic conditions such as AIDS (wasting in adults; failure to thrive in children), uncontrolled diabetes mellitus, trauma, and severe burns. In these conditions, serum levels of IGF-I and -II are markedly diminished, IGFBP-3 levels are also decreased, and IGFBP-1 levels are markedly increased. In addition, there is increased proteolysis of IGFBP-3 (AIDS failure to thrive, uncontrolled diabetes mellitus) and disruption of the ternary complex with decreased levels of ALS (AIDS wasting and burns). IGFBP-1 is in its most highly phosphorylated state in all catabolic conditions studied. Thus, the alterations in the circulating levels of IGFs and the changes in the physical state of the IGFBPs may lead to decreased anabolic activity and be a part of the mechanism of increased catabolism and wasting.}, }
@article {pmid9266721, year = {1997}, author = {Bredesen, DE and Ellerby, LM and Hart, PJ and Wiedau-Pazos, M and Valentine, JS}, title = {Do posttranslational modifications of CuZnSOD lead to sporadic amyotrophic lateral sclerosis?.}, journal = {Annals of neurology}, volume = {42}, number = {2}, pages = {135-137}, doi = {10.1002/ana.410420202}, pmid = {9266721}, issn = {0364-5134}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics/physiopathology ; Animals ; Dimerization ; Humans ; Mice ; Mice, Transgenic ; Models, Molecular ; Mutation ; Protein Conformation ; *Protein Processing, Post-Translational ; Superoxide Dismutase/chemistry/*genetics/*metabolism ; }, }
@article {pmid9246719, year = {1997}, author = {Doré, S and Kar, S and Quirion, R}, title = {Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {20}, number = {8}, pages = {326-331}, doi = {10.1016/s0166-2236(96)01036-3}, pmid = {9246719}, issn = {0166-2236}, mesh = {Humans ; Insulin-Like Growth Factor I/*pharmacology ; Nerve Degeneration/*physiology ; Nervous System Diseases/*drug therapy ; }, abstract = {Insulin-like growth factor-I (IGF-I) is a pleiotropic protein that acts on many tissues and organs. As it is one of the major trophic factors in the circulation, its actions in peripheral tissues are well established. It has been used for the treatment of several diseases, including growth deficiency, osteoporosis, catabolic disorders and diabetes. Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurones and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS), a degenerative disease of the motoneurones. We review briefly here experimental and clinical information that suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS, Alzheimer's disease, various neuropathies and brain trauma. The rather unique propensity of IGF-I to act on a variety of neuronal cells might provide a general means of reducing or slowing down neuronal losses that occur following various brain insults.}, }
@article {pmid9227949, year = {1997}, author = {Ross, MA}, title = {Acquired motor neuron disorders.}, journal = {Neurologic clinics}, volume = {15}, number = {3}, pages = {481-500}, doi = {10.1016/s0733-8619(05)70330-3}, pmid = {9227949}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/diagnosis/*etiology/therapy ; Neurologic Examination ; Palliative Care ; Poliomyelitis/complications/diagnosis/therapy ; Postpoliomyelitis Syndrome/diagnosis/etiology/therapy ; Prognosis ; }, abstract = {The acquired motor neuron disorders are a heterogeneous group of conditions in which motor neuron degeneration or dysfunction produces the predominant manifestation of weakness, while the sensory system is clinically spared. The disorders most commonly seen in clinical practice are amyotrophic lateral sclerosis, late manifestations of poliomyelitis, and lower motor neuron syndromes, including motor neuropathy. Less often, acquired motor neuron disorders may complicate metabolic, toxic, or systemic disorders. The pathogenesis of most acquired motor neuron disorders is poorly understood, and treatment is mainly supportive; however clues to understanding the pathogenesis of amyotrophic lateral sclerosis are emerging, and new pharmacologic therapies are available. There is a growing sense of hope that combinations of drugs that are currently being tested may impact the survival of amyotrophic lateral sclerosis.}, }
@article {pmid10420924, year = {1997}, author = {Zazpe, A and Del Río, J}, title = {[Neurotrophins. II: therapeutic potential].}, journal = {Revista de medicina de la Universidad de Navarra}, volume = {41}, number = {3}, pages = {180-184}, pmid = {10420924}, issn = {0556-6177}, mesh = {Alzheimer Disease/*drug therapy ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Apoptosis/drug effects ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Mice ; Mice, Neurologic Mutants ; Nerve Degeneration/drug therapy ; Nerve Growth Factors/pharmacology/physiology/*therapeutic use ; Neurons/drug effects/pathology ; Parkinson Disease/*drug therapy ; }, abstract = {Neurodegenerative diseases are highly devastating disorders characterized by the damage and loss of discrete neuronal populations. Until recently, it was assumed that the ability of the central nervous system to recover from injury was extremely limited. However, many "in vitro" and "in vivo" studies have shown that neurotrophic factor are able to prevent or inhibit neuronal cell death induced by a variety of insults. Accordingly, trophic factors may represent a new tool for treating neuronal injury and death in a variety of neurodegenerative diseases. In his review, the therapeutic possibilities of neurotrophins in the treatment of Parkinson's disease, Alzheimer disease and amyotrophic lateral sclerosis are analysed.}, }
@article {pmid9280754, year = {1997}, author = {Hira, NK and Marciniak, MM and Penner, SL}, title = {Ophthalmomyiasis interna posterior and pigmentary retinopathy of Guam.}, journal = {Journal of the American Optometric Association}, volume = {68}, number = {7}, pages = {452-458}, pmid = {9280754}, issn = {0003-0244}, mesh = {Aged ; Animals ; Diagnosis, Differential ; *Diptera ; Eye Infections, Parasitic/*etiology/pathology ; Fluorescein Angiography ; Fundus Oculi ; Guam ; Humans ; Larva ; Male ; Myiasis/*etiology/pathology ; Retina/parasitology/*pathology ; Retinitis Pigmentosa/*parasitology/pathology ; Retrospective Studies ; }, abstract = {BACKGROUND: Ophthalmomyiasis is ocular invasion by a fly larva. In the United States, only two cases of bilateral subretinal ophthalmomyiasis have been reported in the literature. Subretinal invasion by the fly larva results in characteristic ophthalmoscopic and angiographic findings. Recently, similar subretinal changes have been associated with amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS-PDC) in the Chamorro population of Guam. This pigmentary retinopathy of Guam (PROG) is generally bilateral in presentation, whereas ophthalmomyiasis is generally unilateral. While PROG has been associated with neurologic findings, ophthalmomyiasis interna posterior (OIP) has not.<br><br>CASE REPORT: A case of a 65-year-old Asian man with bilateral subretinal changes is described. Similarities and differences between ophthalmomyiasis and the pigmentary retinopathy of Guam are discussed.<br><br>CONCLUSIONS: Because PROG has been associated with ALS-PDC, a neurologic evaluation should be included in the workup of patients suspected of having OIP or PROG.}, }
@article {pmid9262052, year = {1997}, author = {Chou, SM}, title = {Neuropathology of amyotrophic lateral sclerosis: new perspectives on an old disease.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {96}, number = {7}, pages = {488-498}, pmid = {9262052}, issn = {0929-6646}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Inclusion Bodies/ultrastructure ; Motor Neurons/*pathology/ultrastructure ; Pyramidal Tracts/*pathology/ultrastructure ; }, abstract = {Recent discoveries on linkage of the gene mutation of an enzyme, copper/zinc superoxide dismutase 1 (SOD-1), to familial amyotrophic lateral sclerosis (ALS) (which constitutes about 1% of all ALS cases) and several transgenic mouse models of ALS have shed light on potential pathogenetic processes involved in this disease. Any speculation as to the pathogenesis of ALS must reflect the unique neurobiology of motor neurons. The most distinctive aspects of motor neurons are their asymmetry, large size, and enormously elongated and thick axons. These characteristics also contribute to their vulnerability to ALS. The determinants of these unique properties are the intermediate cytoskeletal filaments, and the neurofilaments of motor neurons. This characteristic is not exclusive to motor neurons and is shared with other neurons with long axons, including some sensory neurons that are also involved in ALS. The histopathology of the early stages of ALS overwhelmingly suggests that accumulation and aggregation of neurofilaments within motor neurons is intimately related to the morphogenesis of the unique cytoplasmic inclusions, and plays a central role in the pathogenesis of the disease. Understanding of the causal relationship and the morphogenesis of inclusion bodies is critical in any attempt to reverse this complex disease process, which potentially involves the neurotoxic effects of free radicals (nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite, etc) on neurofilaments. By emphasizing the unique make-up of motor neurons, this review intends to reevaluate and reinterpret the basic neuropathology of ALS in the light of recent molecular genetic-data.}, }
@article {pmid9224806, year = {1997}, author = {Gegelashvili, G and Schousboe, A}, title = {High affinity glutamate transporters: regulation of expression and activity.}, journal = {Molecular pharmacology}, volume = {52}, number = {1}, pages = {6-15}, doi = {10.1124/mol.52.1.6}, pmid = {9224806}, issn = {0026-895X}, mesh = {Animals ; Arachidonic Acid/metabolism ; Chromosome Mapping ; Free Radicals ; *Gene Expression Regulation ; Humans ; Protein Processing, Post-Translational ; Receptors, Glutamate/*genetics/metabolism ; Second Messenger Systems ; }, abstract = {L-Glutamic acid is a major excitatory neurotransmitter in the mammalian central nervous system. The termination of the glutamatergic transmission and the clearance of the excessive, neurotoxic concentrations of glutamate is ensured by a high affinity glutamate uptake system. Four homologous types of Na/K-dependent high affinity glutamate transporters, glutamate/aspartate transporter, glutamate transporter 1, excitatory amino acid carrier 1, and excitatory amino acid transporter 4, have recently been cloned and were assigned to a separate gene family, together with two neutral amino acid carriers, alanine/serine/cysteine transporter 1/serine/alanine/threonine transporter and adipocyte amino acid transporter. The genomic organization of these transporters is still under investigation. Very little is known about the nature of the factors and molecular mechanisms that regulate developmental, regional, and cell type-specific expression of the glutamate transporters and their aberrant functioning in neurodegenerative diseases (e.g., amyotrophic lateral sclerosis and Alzheimer's disease). Some experimental conditions (e.g., ischemia, corticostriatal lesions, hyperosmolarity, culturing conditions) and several naturally occurring and synthetic compounds (e.g., glutamate receptor agonists, dopamine, alpha1- and beta-adrenergic agonists, cAMP, phorbol esters, arachidonic acid, nitric oxide, oxygen free radicals, amyloid beta-peptide, tumor necrosis factor-alpha, glucocorticosteroids, unidentified neuronal factors) affect the molecular expression and activity of glutamate transporters. Further elucidation of the molecular events that link epigenetic signals with transcriptional and post-transcriptional mechanisms (e.g., alternative splicing, translation and post-translational modifications) is crucial for the development of selective pharmacological tools and strategies interfering with the expression of the individual glutamate transporters.}, }
@article {pmid9190105, year = {1997}, author = {}, title = {Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death.}, journal = {Dysphagia}, volume = {12}, number = {3}, pages = {174-175}, pmid = {9190105}, issn = {0179-051X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*mortality ; Cause of Death ; Deglutition Disorders/diagnosis/etiology/mortality ; Female ; Humans ; Male ; *Nutritional Status ; Oropharynx/physiopathology ; Prognosis ; }, }
@article {pmid9312837, year = {1997}, author = {Lechner-Scott, J and Steck, AJ and Scott, RJ}, title = {[Genetic studies in neurology].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {127}, number = {26}, pages = {1141-1153}, pmid = {9312837}, issn = {0036-7672}, mesh = {Genetic Markers/genetics ; Genetic Testing ; Humans ; Nervous System Diseases/diagnosis/*genetics ; Neurologic Examination ; Pedigree ; Trinucleotide Repeats/genetics ; }, abstract = {The use of either direct or indirect genetic analyses in neurology is becoming ever greater as more genes are identified thanks to the human genome project. Often the methodologies are complex and difficult to understand. The aim of this review is to present various approaches to molecular diagnosis using several different inherited neurological diseases as examples. These include inherited mitochondriopathies, monogenetic disorders like trinucleotid repeat instability syndromes, duplication anomalies and specific point mutations as well as heterogenetic diseases such as limb girdle dystrophy and familial amyotrophic lateral sclerosis. Possible pathogenetic implications can now be proposed as the basis of new therapeutic modalities.}, }
@article {pmid9296165, year = {1997}, author = {Moulard, B and Camu, W and Malafosse, A and Billiard, M and Baldy-Moulinier, M}, title = {[Clinical study of familial forms of amyotrophic lateral sclerosis. Review of the literature].}, journal = {Revue neurologique}, volume = {153}, number = {5}, pages = {314-324}, pmid = {9296165}, issn = {0035-3787}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/diagnosis/*genetics/physiopathology ; Causality ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons. The disease is possibly due to several factors, including a genetic one. This is supported by the existence of 5 to 10 p. 100 familial cases. In these pedigrees, the transmission is autosomal dominant, with a high penetrance (> 90 p. 100). We studied the phenotypes of these familial cases, in reviewing the literature on familial ALS (FALS). It has been noted that FALS are heterogeneous, with different age of onset, site of onset and disease duration. Moreover, in FALS, onset is earlier than in the sporadic form (48 vs 60 years, as usually reported in the literature). We also frequently noted sensory disorders (20 p. 100), onset on the lower limbs (46 p. 100) and decreased or absent ankle-jerks (75 p. 100) in FALS patients.}, }
@article {pmid9226998, year = {1997}, author = {Louvel, E and Hugon, J and Doble, A}, title = {Therapeutic advances in amyotrophic lateral sclerosis.}, journal = {Trends in pharmacological sciences}, volume = {18}, number = {6}, pages = {196-203}, doi = {10.1016/s0165-6147(97)01062-6}, pmid = {9226998}, issn = {0165-6147}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics/physiopathology ; Animals ; Antioxidants/pharmacology/therapeutic use ; Clinical Trials as Topic/trends ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/pharmacology/therapeutic use ; Free Radicals/adverse effects ; Gene Expression Regulation, Enzymologic/drug effects/genetics ; Humans ; Immunosuppressive Agents/pharmacology/therapeutic use ; Mutation/genetics ; Nerve Growth Factors/pharmacology/therapeutic use ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and rapidly fatal neurodegenerative disease in which both upper and lower motoneurones are involved. The recent discovery of mutations affecting the superoxide dismutase (SOD) gene has given impetus to research on the role of oxidative stress in the pathogenesis of familial ALS, while further evidence for a role of excitotoxicity in the disease process has arisen. In this review, Erik Louvel, Jacques Hugon and Adam Doble discuss these findings and, in addition, describe how a number of large, well-controlled clinical trials have taken place to test potential therapies suggested by different aetiological hypotheses, including immunosuppressive therapies, neurotrophic factors, antioxidants and anti-excitotoxic drugs. These trials have led to the first modest steps in the treatment of this devastating neurological disease.}, }
@article {pmid9189030, year = {1997}, author = {Rowland, LP}, title = {Paraneoplastic primary lateral sclerosis and amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {41}, number = {6}, pages = {703-705}, doi = {10.1002/ana.410410605}, pmid = {9189030}, issn = {0364-5134}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; History, 20th Century ; Humans ; *Motor Neuron Disease ; Neurology/history ; *Paraneoplastic Syndromes ; United States ; }, }
@article {pmid9184716, year = {1997}, author = {Wagner, ML and Landis, BE}, title = {Riluzole: a new agent for amyotrophic lateral sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {31}, number = {6}, pages = {738-744}, doi = {10.1177/106002809703100614}, pmid = {9184716}, issn = {1060-0280}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Drug Interactions ; Humans ; Neuroprotective Agents/adverse effects/pharmacokinetics/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole ; Thiazoles/adverse effects/pharmacokinetics/*therapeutic use ; }, abstract = {OBJECTIVE: To provide a comprehensive review of riluzole, including its mechanism of action, pharmacokinetics, adverse drug reactions, drug interactions, efficacy, and administration. A brief review of amyotrophic lateral sclerosis (ALS) is also included.<br><br>DATA SOURCES: A computerized search of the MEDLINE database in May 1996 was used to identify publications regarding ALS, riluzole, and metabolism by CYP1A2. Manufacturer's information on riluzole was used when there was no primary literature.<br><br>DATA SYNTHESIS: Riluzole is approximately 90% absorbed following an oral dose. Its bioavailability is 60%. Peak concentrations occur within 1-1.5 hours of administration. Riluzole extensively binds to lipoproteins and albumin. This agent primarily undergoes CYP1A2 hydroxylation and glucuronidation, after which it is eliminated by the kidneys. Clearance is reduced in native Japanese healthy subjects and may be reduced in patients with hepatic impairment. Two trials with a total of 1114 patients addressed the efficacy of riluzole in ALS. Riluzole extended the time to tracheostomy or death, and the effect was greatest with dosages of 100 mg/d or greater. No effect on patients' symptoms or global assessment was detected at 18 or 21 months. Several flaws in these trials have led to questions concerning the validity of these results. The most commonly reported adverse effects of riluzole have been transient elevation of liver enzyme concentrations (2-5 times the upper limit of normal), worsening of asthenia, nausea, vomiting, diarrhea, anorexia, dizziness, vertigo, somnolence, and mouth paresthesia. Not as commonly reported, but still very serious, is neutropenia, which occurred in 3 of 4000 patients.<br><br>CONCLUSIONS: Although the benefits of riluzole are questionable and it is expensive, this agent may extend the time to tracheostomy or death in patients with ALS. At present, this is the only agent approved for the treatment of ALS and should be made available for these patients.}, }
@article {pmid9296143, year = {1997}, author = {Petiot, P and Vial, C and de Saint Victor, JF and Charles, N and Carrier, H and Depierre, P and Bady, B}, title = {[Dropped head syndrome: diagnostic discussion apropos of 3 cases].}, journal = {Revue neurologique}, volume = {153}, number = {4}, pages = {251-255}, pmid = {9296143}, issn = {0035-3787}, mesh = {Aged ; Female ; *Head ; Humans ; Male ; Middle Aged ; Muscle Weakness ; Muscular Diseases/*diagnosis ; Neck Muscles/*physiopathology ; Neuromuscular Diseases/*diagnosis ; Syndrome ; }, abstract = {We report three cases presenting mainly with neck extensor weakness, or dropped head syndrome, revealing respectively myasthenia gravis, amyotrophic lateral sclerosis and non-inflammatory neck extensors myopathy. We discuss the different diagnosis of this rare syndrome and this late onset localized myopathy of unknown etiology.}, }
@article {pmid9181475, year = {1997}, author = {Tsirka, SE}, title = {Clinical implications of the involvement of tPA in neuronal cell death.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {75}, number = {5}, pages = {341-347}, doi = {10.1007/s001090050119}, pmid = {9181475}, issn = {0946-2716}, mesh = {Animals ; Bone Marrow Transplantation ; Brain/cytology/metabolism/pathology ; *Cell Death ; Humans ; Ischemia/pathology ; Mice ; Microglia/physiology ; Nerve Degeneration ; Neurons/*physiology ; Neurotoxins ; Serine Endopeptidases/metabolism ; Tissue Plasminogen Activator/*physiology ; }, abstract = {Tissue plasminogen activator (tPA), the serine protease that converts inactive plasminogen to the protease plasmin, was recently shown to mediate neurodegeneration in the mouse hippocampus. Mice deficient in tissue plasminogen activator (tPA) display a dramatic resistance to a paradigm of excitotoxic neuronal death that involves intrahippocampal injection of the excitotoxin. This model is thought to reproduce the mechanism of neuronal death observed during acute (such as ischemic stroke) and degenerative (such as amyotrophic lateral sclerosis) diseases of the nervous system. The requirement for the proteolytic activity of tPA to mediate neuronal death is acute in the adult mouse. Serine protease inhibitors, specific for tPA or the tPA/plasmin proteolytic cascade, are effective in conferring extensive neuroprotection following the excitotoxic injection. These findings suggest possible new ways for interfering with the neuronal death observed in the hippocampus as a result of excitotoxicity. In addition, tPA is produced in the hippocampus primarily by microglial cells, which become activated in response to the neuronal injury. Blocking microglial activation has been shown in other injury paradigms to protect against neuronal death, therefore suggesting another way to retard neurodegeneration in the CNS. Furthermore, after the insult has been inflicted and in the presence of a compromised blood-brain barrier macrophages (cells deriving from the same lineage as microglia) migrate into the brain, where they are thought to contribute to the neuronal cell loss by secreting neurotoxic molecules. If these macrophages/microglia expressed, however, a tPA inhibitor, rather than the possibly neurotoxic tPA, they might be able to protect the neurons from dying.}, }
@article {pmid9178169, year = {1997}, author = {Dengler, R and Tröger, M}, title = {Impact of riluzole on the relationship between patient and physician.}, journal = {Journal of neurology}, volume = {244 Suppl 2}, number = {}, pages = {S30-2}, pmid = {9178169}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*psychology ; Attitude ; Disease Progression ; Emotions ; Humans ; Neuroprotective Agents/*therapeutic use ; *Physician-Patient Relations ; Physicians/*psychology ; Riluzole ; Thiazoles/*therapeutic use ; }, abstract = {To date, there has been little systematic research on the patient-physician relationship in amyotrophic lateral sclerosis (ALS). Important factors in this relationship are the emotional state, or mood, of the patients and their expectations of successful therapeutic intervention. In many patients there is a gradual deterioration of mood with disease progression-a view supported by studies comparing the initial and late phases of the disease. The few studies examining patients' expectations of therapy revealed a strong desire to be informed about the disease and its course without destroying every hope. In the later stages of the disease patients expected compassion and help with immediate problems. To our knowledge there has been no systematic study on the attitude of physicians towards ALS patients. The lack of effective treatment and the wish to avoid full information about the poor prognosis are almost unique problems involved in dealing with ALS patients. The new option to treat with a drug that slows disease progression provides some alleviation for the physician. Riluzole, at least, partially meets this expectation. Although its efficacy is too limited to satisfy fully the wishes of patients and physicians, it is the first available drug that has been shown to slow disease progression. Thus, it may bring to an end the feeling that there is nothing that can be done for these patients. In our experience this provides relevant alleviation in the management of ALS patients.}, }
@article {pmid9178168, year = {1997}, author = {Swash, M}, title = {Health outcome and quality-of-life measurements in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {244 Suppl 2}, number = {}, pages = {S26-9}, pmid = {9178168}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/therapy ; Humans ; *Quality of Life ; Treatment Outcome ; }, abstract = {Quality of life has been used as a primary outcome measure in the treatment of cancer and cardiovascular disease, and as a secondary outcome measure in therapy of Parkinson's disease. However, it has been relatively neglected in studies of amyotrophic lateral sclerosis (ALS). Although there is need for the development of an ALS-specific quality-of-life measure, it will be necessary, nonetheless, to continue to use generic measures in order to ensure comparability of measurement between disease states. An argument is put forward for the use of quality-of-life measures as a primary end-point in future clinical trials in ALS. A distinction is drawn between the demonstration of biological efficacy and clinically useful benefit. The most likely instruments to prove useful are briefly discussed.}, }
@article {pmid9178165, year = {1997}, author = {Shaw, PJ and Ince, PG}, title = {Glutamate, excitotoxicity and amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {244 Suppl 2}, number = {}, pages = {S3-14}, pmid = {9178165}, issn = {0340-5354}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Excitatory Amino Acid Antagonists/*pharmacology ; Glutamic Acid/*drug effects/*metabolism ; Humans ; Neuroprotective Agents/*pharmacology ; Receptors, Glutamate/drug effects/metabolism ; Riluzole ; Thiazoles/*pharmacology ; }, abstract = {The "glutamate hypothesis" is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and CI-, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of "downstream" events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.}, }
@article {pmid9125397, year = {1997}, author = {Niizato, K and Tsuchiya, K and Tominaga, I and Kato, Y and Ikeda, K}, title = {Pick's disease with amyotrophic lateral sclerosis (ALS): report of two autopsy cases and literature review.}, journal = {Journal of the neurological sciences}, volume = {148}, number = {1}, pages = {107-112}, doi = {10.1016/s0022-510x(96)00315-2}, pmid = {9125397}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/pathology ; Dementia/*complications/pathology ; Fatal Outcome ; Female ; Humans ; Male ; Middle Aged ; }, abstract = {We report the findings in two autopsy cases of Pick's disease with amyotrophic lateral sclerosis (ALS). Both presented severe cortical degeneration and subcortical gliosis of temporal lobes, as well as the neuropathological characteristics of ALS. As such cases are rare, we present the clinical and pathological findings in detail and a review the relevant literature.}, }
@article {pmid9210248, year = {1997}, author = {Abe, K}, title = {Clinical and molecular analysis of neurodegenerative diseases.}, journal = {The Tohoku journal of experimental medicine}, volume = {181}, number = {4}, pages = {389-409}, doi = {10.1620/tjem.181.389}, pmid = {9210248}, issn = {0040-8727}, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/enzymology/genetics ; DNA/genetics ; Female ; Humans ; Male ; Membrane Proteins/genetics ; Minisatellite Repeats ; Mutation ; Nervous System Diseases/*genetics/metabolism/pathology ; Pedigree ; Presenilin-1 ; Spinocerebellar Degenerations/genetics ; Superoxide Dismutase/genetics ; Trinucleotide Repeats ; }, abstract = {Clinical and molecular analyses of neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 1 (SCA1) were performed. In the present study, a Japanese family of AD with an Ala285Val substitution in exon 8 of the presenilin-1 (PS-1) gene was found. This family was characterized by relatively late onset (mean age at 50 years) in familial AD with PS-1 gene mutation and by absence of myoclonus, seizure or paratonia. Magnetic resonance image (MRI) study showed marked linear signal abnormalities in white matter of parietoocctipital lobes, suggesting a presence of cortical amyloid angiopathy of the patient with PS-1 gene mutation. Clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene were reported. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and Babinski sign was not observed in any cases. Bulbar palsy was frequent with a mutation, but not present with another mutation. SOD activity of red blood cells was generally reduced with minor variations. CAG trinucleotide repeat expansion was analyzed in 25 families with hereditary ataxia of Menzel type in the northeast of Japan. Twenty of 38 patients in 12 families had expanded allele for spinocerebellar ataxia type 1 (SCA1). Study of the number of CAG repeats in various tissues showed no differences in the repeat length in lymphocytes, muscle or brain; sperm, however, showed an obvious expansion. This may be a clue to a possible mechanism for the molecular basis of paternal anticipation of the disease. These results suggest that clinical features of some familial cases of neurodegenerative diseases such as AD, ALS, and SCA1 are well correlated with their genetic mutations.}, }
@article {pmid9172907, year = {1997}, author = {Robles, A and Vilariño, I and Sesar, A and Pardellas, H and Cacabelos, P and Noya, M}, title = {[Progressive degenerative aphasia: clinical and neuroradiological observations in 18 cases].}, journal = {Revista de neurologia}, volume = {25}, number = {140}, pages = {505-512}, pmid = {9172907}, issn = {0210-0010}, mesh = {Age of Onset ; Aged ; Aphasia/*etiology ; Atrophy/complications/diagnosis/physiopathology ; Frontal Lobe/*physiopathology ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Neuron Disease/complications/diagnosis/physiopathology ; Retrospective Studies ; Temporal Lobe/*physiopathology ; Tomography, X-Ray Computed ; }, abstract = {INTRODUCTION: In some types of degenerative dementia aphasia is the main disorder. In primary progressive aphasia. (PPA) atrophy is limited to the dominant peri-sylvan region. We present 18 cases of progressive aphasia of degenerative origin, with or without dementia.<br><br>MATERIAL AND METHODS: We describe the clinical and neuro-radiological findings in 3 patients with 'aphasic dementia and motor neuron disease (ADMND)', 7 with 'semantic dementia' (DS), and 4 with 'fronto-temporal dementia' with 'marked non-fluent aphasia' (AFTD). Criteria published in recent years were used.<br><br>RESULTS: In patients with ADMND non-fluent aphasia progressed to global aphasia, with dementia occurring after 2-9 months, and death after an average of 17 months. In cases with SD, initial anomic aphasia progressed to transcortical sensory or global aphasia, and in patients with AFTD, Broca's aphasia or motor transcortical aphasia progressed to global aphasia. Seven of these patients had been initially diagnosed as having PPA and became demented after two years or more. In most of the cases the cognitive disorder had the characteristics of fronto-temporal dementia. All cases had cortical atrophy or asymmetrical cortical or cortico-subcortical atrophy. The 4 cases of non-fluent PPA were not demented after 21 months-6 years of illness, and showed perisylvan and left fronto-temporopolar atrophy.<br><br>CONCLUSIONS: The PPA may correspond to the initial form of at least three varieties of dementia, usually the fronto-temporal type. Dementia occurs after two years or more, except in patients with motor neurone disease, when there is a latent period of less than one year.}, }
@article {pmid9112583, year = {1997}, author = {Hetta, J and Jansson, I}, title = {Sleep in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {244}, number = {4 Suppl 1}, pages = {S7-9}, pmid = {9112583}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Sleep/*physiology ; }, abstract = {Amyotrophic lateral sclerosis can be associated with profound sleep disturbances resulting from factors such as reduced mobility, muscle cramps, swallowing problems and anxiety. Although few studies have examined sleep patterns in ALS, disease-related symptoms such as restless legs and increased myoclonic activity can disturb both the initiation and maintenance of sleep. In addition, sleep-disordered breathing, exhibiting as hypoventilation, has been reported in patients with ALS. Interference with sleep patterns may produce daytime symptoms and activities of daily living can be further affected by an increased incidence of depression. Pharmacotherapy of sleep disturbance should be directed at the underlying cause and when hypnotics are required these should be short acting to minimise the carry-over effect into daytime.}, }
@article {pmid9111507, year = {1997}, author = {Tu, PH and Gurney, ME and Julien, JP and Lee, VM and Trojanowski, JQ}, title = {Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {76}, number = {4}, pages = {441-456}, pmid = {9111507}, issn = {0023-6837}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/etiology/pathology ; Animals ; Humans ; Mice ; *Mice, Transgenic ; Neurofibrils/*pathology ; *Oxidative Stress ; *Point Mutation ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain stem. About 10% of all ALS cases are familial (FALS), inherited in an autosomal dominant manner. One fifth of FALS patients carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several lines of transgenic mice have been engineered to express mutant forms of the SOD1 gene that are linked to FALS. Significantly, many of these transgenic lines of mice develop a motor neuron disease (MND) that resembles human FALS. Oxidative stress induced by human SOD1 mutations is believed to play an important role in the pathogenesis of FALS and the FALS-like MND seen in the mutant SOD1 transgenic mice. For example, two lines of these mice showed prominent degeneration of mitochondria and endoplasmic reticulum in spinal cord neurons. Furthermore, recent studies have shown that neurofilament (NF)-rich spheroids. Lewy body-like NF inclusions, altered ubiquitin immunoreactivity, and Golgi fragmentation occur in the spinal cord motoneurons of these mutant SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities of human ALS, mutant SOD1 transgenic mice provide a useful model for studies designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice that overexpress NF proteins also develop a clinical and pathologic phenotype similar to human MND, and polymorphisms in an NF gene have been linked to patients with ALS. Collectively, these observations implicate NF protein abnormalities in the pathogenesis of this disorder. Accordingly, this review summarizes recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease.}, }
@article {pmid9092140, year = {1997}, author = {Binzer, MN and Gredal, O and Brøndum-Nielsen, K and Andersen, PM}, title = {[Amyotrophic lateral sclerosis and superoxide dismutase--a review].}, journal = {Ugeskrift for laeger}, volume = {159}, number = {11}, pages = {1593-1596}, pmid = {9092140}, issn = {0041-5782}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Humans ; Mutation ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {The recent observation that mutations in cytosolic CuZn-superoxide dismutase (CuZn-SOD) are associated with amyotrophic lateral sclerosis (ALS) suggests that the disease arises from a perturbation of the homeostasis of free radicals resulting in neuronal degeneration by reactive oxygen species. The stability is altered in these mutant molecules, but without necessarily reducing the specific activity of the CuZn-SOD molecule. Substantial evidence argues that the disease arises not from the loss of CuZn-SOD function, but rather from an adverse or novel property of the mutant enzyme molecule. The mechanism for this acquired adverse function is, as yet, completely unknown. SOD research is an important step for a better understanding of the pathogenesis of ALS.}, }
@article {pmid9126161, year = {1997}, author = {Davidson, BL and Bohn, MC}, title = {Recombinant adenovirus: a gene transfer vector for study and treatment of CNS diseases.}, journal = {Experimental neurology}, volume = {144}, number = {1}, pages = {125-130}, doi = {10.1006/exnr.1996.6398}, pmid = {9126161}, issn = {0014-4886}, support = {HD 33531/HD/NICHD NIH HHS/United States ; NS 34568/NS/NINDS NIH HHS/United States ; NS31957/NS/NINDS NIH HHS/United States ; }, mesh = {Adenoviridae/*genetics ; Animals ; Central Nervous System Diseases/*physiopathology/*therapy ; *Gene Transfer Techniques ; *Genetic Vectors ; Humans ; *Recombination, Genetic ; }, abstract = {Gene transfer to the CNS with recombinant adenoviral vectors is a relatively recent event. In initial reports it was clearly demonstrated that adenoviral vectors can transfer genetic material to multiple cell types within the CNS. The relative ease in generating recombinant adenovirus (Ad) led to feasibility studies in the CNS with application to animal models of inherited disease, neurodegenerative diseases (e.g., Parkinson's and amyotrophic lateral sclerosis), and cerebrovascular disease. In combination with Ad gene transfer to peripheral tissues, these experiments have identified specific limitations and directed further research to improve vector design, formulation, and delivery.}, }
@article {pmid9282413, year = {1997}, author = {}, title = {Riluzole for amyotrophic lateral sclerosis.}, journal = {Drug and therapeutics bulletin}, volume = {35}, number = {2}, pages = {11-12}, doi = {10.1136/dtb.1997.35211}, pmid = {9282413}, issn = {0012-6543}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole ; Thiazoles/*therapeutic use ; }, abstract = {Around one in 20,000 adults in the UK will develop amyotrophic lateral sclerosis, the commonest variant of motor neurone disease. Riluzole (Rilutek-Rhône-Poulenc Rorer) was launched in the UK in August 1996 as "the first anti-excitotoxic agent proven to extend life in amyotrophic lateral sclerosis". We review the clinical data on the effectiveness of riluzole and assess its place in the management of amyotrophic lateral sclerosis, a condition that is invariably fatal and has a median survival time from symptom onset of about 2.5 years.}, }
@article {pmid11370073, year = {1997}, author = {Jokelainen, M}, title = {[Pharmacotherapy of amyotrophic lateral sclerosis].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {113}, number = {6}, pages = {513-516}, pmid = {11370073}, issn = {0012-7183}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy ; Anti-Anxiety Agents/administration &amp; dosage ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Morphine/administration &amp; dosage ; Neuroprotective Agents/*adverse effects ; Prognosis ; Riluzole/*therapeutic use ; Severity of Illness Index ; Terminal Care ; }, }
@article {pmid9686247, year = {1997}, author = {Taylor, CP}, title = {Mechanisms of action of gabapentin.}, journal = {Revue neurologique}, volume = {153 Suppl 1}, number = {}, pages = {S39-45}, pmid = {9686247}, issn = {0035-3787}, mesh = {Acetates/metabolism/*pharmacology ; *Amines ; Animals ; Anticonvulsants/metabolism/*pharmacology ; *Cyclohexanecarboxylic Acids ; Drug Interactions ; Gabapentin ; Humans ; Neurotransmitter Agents/metabolism ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.}, }
@article {pmid9380959, year = {1997}, author = {Barthlen, GM}, title = {Nocturnal respiratory failure as an indication of noninvasive ventilation in the patient with neuromuscular disease.}, journal = {Respiration; international review of thoracic diseases}, volume = {64 Suppl 1}, number = {}, pages = {35-38}, doi = {10.1159/000196734}, pmid = {9380959}, issn = {0025-7931}, mesh = {Adrenergic Uptake Inhibitors/therapeutic use ; Amyotrophic Lateral Sclerosis/complications ; Cyanosis/etiology ; Headache/etiology ; Humans ; Hypertension/etiology ; Intermittent Positive-Pressure Ventilation ; Muscle Contraction/physiology ; Muscular Dystrophies/complications ; Myasthenia Gravis/complications ; Myotonic Dystrophy/complications ; Neuromuscular Diseases/*complications/physiopathology ; Oxygen Inhalation Therapy ; Polycythemia/etiology ; Polysomnography ; Positive-Pressure Respiration/methods ; Postpoliomyelitis Syndrome/complications ; Protriptyline/therapeutic use ; Psychomotor Agitation/etiology ; Respiration ; Respiratory Insufficiency/diagnosis/*etiology/physiopathology/therapy ; Sleep/physiology ; Sleep Apnea Syndromes/diagnosis/*etiology/physiopathology/therapy ; Sleep Initiation and Maintenance Disorders/etiology ; Sleep Stages ; Snoring/etiology ; Tracheostomy ; }, abstract = {Patients with neuromuscular disease may suffer from nocturnal respiratory failure despite normal daytime respiratory function. The physiological reduction in muscle tone during sleep may be life-threatening in a patient with impaired muscle strength. Nocturnal respiratory failure may occur in patients with the postpolio syndrome, amyotrophic lateral sclerosis, myasthenia gravis, myotonic dystrophy, and muscular dystrophy. Diagnosis of obstructive, central and mixed apneas, hypopneas, and hypoventilation is best made using polysomnography. Therapeutic options include noninvasive ventilation such as continuous positive airway pressure, bilevel positive airway pressure, intermittent positive pressure ventilation and, rarely, tracheostomy, oxygen, or protriptyline. Evaluation by a sleep specialist should be initiated in any neuromuscular patient with nocturnal symptoms such as air hunger, intermittent snoring or breathing, orthopnea, cyanosis, restlessness, and insomnia. Daytime symptoms may include morning drowsiness, headaches and excessive daytime sleepiness. Polycythemia, hypertension, and signs of heart failure may also be seen. Effective treatment is available, and may improve the quality of life, and possibly increase survival.}, }
@article {pmid9380813, year = {1997}, author = {Brola, W and Szafraniec, L}, title = {[Pathologic laughing and crying in neurologic disorders].}, journal = {Przeglad lekarski}, volume = {54}, number = {5}, pages = {356-359}, pmid = {9380813}, issn = {0033-2240}, mesh = {*Crying/psychology ; Humans ; *Laughter/psychology ; Mood Disorders/*etiology/psychology ; Multiple Sclerosis/psychology ; Nervous System Diseases/*complications/psychology ; }, abstract = {Affective disorders are complications of many nervous system diseases. Pathological laughing and crying may accompany cerebrovascular lesions, multiple sclerosis, ALS, Alzheimer disease or cerebral tumours. Precise mechanisms of how these disorders arise are still unknown. Reviews of the literature were been accomplished in the article where, taking the examples of stroke and multiple sclerosis, have been discussed: the clinic picture, pathogenesis in neuroanatomic and neurophysiologic aspects as well as diagnostic criteria and the treatment of uncontrolled pathological laughing and/or crying.}, }
@article {pmid9361293, year = {1997}, author = {Cuajungco, MP and Lees, GJ}, title = {Zinc metabolism in the brain: relevance to human neurodegenerative disorders.}, journal = {Neurobiology of disease}, volume = {4}, number = {3-4}, pages = {137-169}, doi = {10.1006/nbdi.1997.0163}, pmid = {9361293}, issn = {0969-9961}, mesh = {Animals ; Brain/*metabolism ; Humans ; Neurodegenerative Diseases/*chemically induced ; Zinc/*metabolism ; }, abstract = {Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.}, }
@article {pmid9300664, year = {1997}, author = {Kola, I and Hertzog, PJ}, title = {Animal models in the study of the biological function of genes on human chromosome 21 and their role in the pathophysiology of Down syndrome.}, journal = {Human molecular genetics}, volume = {6}, number = {10}, pages = {1713-1727}, doi = {10.1093/hmg/6.10.1713}, pmid = {9300664}, issn = {0964-6906}, mesh = {Animals ; Bone and Bones/diagnostic imaging/pathology ; *Chromosome Mapping ; *Chromosomes, Human, Pair 21 ; Disease Models, Animal ; Down Syndrome/*genetics/pathology/*physiopathology ; Genetic Markers ; Humans ; Mice ; Mice, Transgenic ; Radiography ; }, abstract = {Human chromosome 21 is the smallest human autosome and many important genetic/familial disorders map to this chromosome, e.g., familial amyotrophic lateral sclerosis (FALS), Down syndrome, Alzheimer's disease and some cases of Ewings sarcoma. Hence, the identification of genes localised to this chromosome and studies on their normal biological function and their role in disease is gaining momentum. The use of animal models to generate gain- and loss-of-function mutations is an important element of these studies on functionality/pathology and has yielded powerful insights. However, no animal model has yet been generated that exactly models any of the disorders associated with this chromosome. The major utility of the animal models has been to illuminate the biological functions of genes and the causation of pathophysiology of diseases associated with genes on this chromosome.}, }
@article {pmid9266433, year = {1997}, author = {Tatton, WG and Chalmers-Redman, RM and Ju, WY and Wadia, J and Tatton, NA}, title = {Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription.}, journal = {Journal of neural transmission. Supplementum}, volume = {49}, number = {}, pages = {245-268}, doi = {10.1007/978-3-7091-6844-8_25}, pmid = {9266433}, issn = {0303-6995}, mesh = {Alzheimer Disease/drug therapy/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Animals ; *Apoptosis ; Brain/metabolism/pathology ; Brain Diseases/*drug therapy/metabolism/*pathology ; Cerebrovascular Disorders/drug therapy/pathology ; Humans ; Mitochondria/metabolism ; Models, Neurological ; Necrosis ; Neurons/pathology ; Parkinson Disease/drug therapy/pathology ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Retinal Diseases/drug therapy/pathology ; Superoxide Dismutase/genetics/metabolism ; Transcription, Genetic/*drug effects ; bcl-2-Associated X Protein ; }, abstract = {Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.}, }
@article {pmid9266431, year = {1997}, author = {Siddique, T and Nijhawan, D and Hentati, A}, title = {Familial amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission. Supplementum}, volume = {49}, number = {}, pages = {219-233}, doi = {10.1007/978-3-7091-6844-8_23}, pmid = {9266431}, issn = {0303-6995}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/pathology ; Animals ; Chromosome Mapping ; Chromosomes, Human, Pair 2 ; Chromosomes, Human, Pair 21 ; Exons ; Genes, Dominant ; Genes, Recessive ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; *Mutation ; Nerve Degeneration ; Point Mutation ; Sequence Deletion ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis is sporadic in ninety percent of cases and familial (FALS) in ten percent. Both forms of FALS whether transmitted as an autosomal dominant (DFALS) or as an autosomal recessive (RFALS) trait is genetically heterogeneous. The locus for one form of RFALS maps to chromosome 2q33. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) gene which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.}, }
@article {pmid9266412, year = {1997}, author = {Lindholm, D}, title = {Models to study the role of neurotrophic factors in neurodegeneration.}, journal = {Journal of neural transmission. Supplementum}, volume = {49}, number = {}, pages = {33-42}, doi = {10.1007/978-3-7091-6844-8_4}, pmid = {9266412}, issn = {0303-6995}, mesh = {Alzheimer Disease/pathology/physiopathology ; Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Animals ; Brain/*pathology/physiopathology ; Disease Models, Animal ; Humans ; Mice ; Mice, Neurologic Mutants ; Models, Neurological ; Motor Neurons/pathology ; Nerve Growth Factors/biosynthesis/*physiology ; Nervous System Diseases/*pathology/*physiopathology ; Parkinson Disease/pathology/physiopathology ; }, abstract = {The physiological functions of neurotrophic factors, such as nerve growth factor (NGF), in supporting the survival and differentiation of specific neurons during early development has in many cases been well established. Recent studies have shown that neurotrophic factors can also protect vulnerable neurons against a variety of mechanical and chemical injuries. The role and the effects of neurotrophic factors in various neurological diseases are however less known. Neurodegenerative diseases such as Parkinson and Alzheimer's diseases as well as amyotrophic lateral sclerosis (ALS) are characterized by an impaired function and ultimate loss of specific populations of neurons. The study of the ethiology and molecular biology of these diseases has for a long time been hampered by the lack of good animal models mimicked part of the human disease in experimental animals. Here we will discuss some of the current approaches taken in these studies as well as address the important question of the possible beneficial effect of neurotrophic factors in alleviating the symptoms and possibly retarding the course of neurodegenerative diseases.}, }
@article {pmid9252791, year = {1997}, author = {Pasquier, F and Petit, H}, title = {Frontotemporal dementia: its rediscovery.}, journal = {European neurology}, volume = {38}, number = {1}, pages = {1-6}, doi = {10.1159/000112894}, pmid = {9252791}, issn = {0014-3022}, mesh = {Alzheimer Disease/diagnosis ; Cognition Disorders ; *Dementia/classification/diagnosis/epidemiology/etiology/history ; Diagnosis, Differential ; Female ; Frontal Lobe/pathology ; History, 19th Century ; History, 20th Century ; Humans ; Male ; Prevalence ; Temporal Lobe/pathology ; }, abstract = {Frontotemporal dementia (FTD) is the second most frequent degenerative cause of dementia. Although described for more than a century, it remains often misdiagnosed, mistaken for Alzheimer's disease or psychiatric disorders, which is prejudicial to care and research. It is a clinical syndrome corresponding to at least three histological entities: (1) Pick's disease, (2) non-specific frontotemporal degeneration, (6 times more frequent), and (3) frontal lobe abnormalities associated with motor neurone disease. It never corresponds to Alzheimer pathology. It must be suspected in patients with behavioural dyscontrol predating memory impairment, without spatial disorientation and normal EEG.}, }
@article {pmid9181045, year = {1997}, author = {Multhaup, G}, title = {Amyloid precursor protein, copper and Alzheimer's disease.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {51}, number = {3}, pages = {105-111}, doi = {10.1016/s0753-3322(97)86907-7}, pmid = {9181045}, issn = {0753-3322}, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Copper/*metabolism ; Humans ; Hydroxyl Radical/metabolism ; }, abstract = {Although a consensus that Alzheimer's disease (AD) is a single disease has not yet been reached, the involvement of the amyloid precursor protein (APP) and beta A4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of beta A4 in cell cultures, and the findings that aggregation of beta A4 can be induced by metal-catalyzed oxidation and that free oxygen radicals might be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS might be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.}, }
@article {pmid9130818, year = {1997}, author = {Mitake, S and Ojika, K and Hirano, A}, title = {Hirano bodies and Alzheimer's disease.}, journal = {The Kaohsiung journal of medical sciences}, volume = {13}, number = {1}, pages = {10-18}, pmid = {9130818}, issn = {1607-551X}, mesh = {Alzheimer Disease/metabolism/*pathology/physiopathology ; Hippocampus/physiopathology/*ultrastructure ; Humans ; Immunohistochemistry ; Inclusion Bodies/*chemistry ; Neuropeptides/analysis ; }, abstract = {Hirano bodies are refractile eosinophilic rod-like structures, initially observed in Guamanian (Chamorro) patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex. Subsequent investigations revealed that Hirano bodies have a distinct topographic distribution in the hippocampus, and that their number increases in the pyramidal layer of Sommer's sector but not in the stratum lacunosum with advancing age. Since patients with Alzheimer's disease (AD) have significantly more Hirano bodies than normal subjects in the same age range, the inclusions appear seem to be of relevance in this disease. Immunohistochemical and electron microscopic studies have demonstrated that the main components of Hirano bodies are abnormal micro-filaments, and that not only molecules associated with cell cytoskeleton, but also some stress-related proteins and growth factors such as beta-amyloid precursor protein, hippocampal cholinergic neurostimulating peptide (HCNP), transforming growth factor beta 3 are present in Hirano bodies. The accumulation of HCNP in Hirano bodies suggests that patients bearing these inclusions may have a disturbance of the septohippocampal cholinergic system, considered to be of importance for le arning and memory formation, and hence be related to the memory impairment of AD.}, }
@article {pmid9125377, year = {1997}, author = {Peltékian, E and Parrish, E and Bouchard, C and Peschanski, M and Lisovoski, F}, title = {Adenovirus-mediated gene transfer to the brain: methodological assessment.}, journal = {Journal of neuroscience methods}, volume = {71}, number = {1}, pages = {77-84}, doi = {10.1016/s0165-0270(96)00128-8}, pmid = {9125377}, issn = {0165-0270}, mesh = {Adenoviridae/*genetics/immunology/pathogenicity ; Adult ; Animals ; Brain/immunology/*metabolism/pathology ; Brain Diseases/therapy ; Brain Neoplasms/therapy ; Cell Death ; Cells, Cultured ; Defective Viruses/*genetics/immunology/pathogenicity ; Genetic Therapy/adverse effects/*methods ; Genetic Vectors/administration &amp; dosage/adverse effects/*genetics/immunology ; Humans ; Injections, Intraventricular ; Nerve Degeneration ; Retroviridae/genetics ; Safety ; Transfection/*methods ; }, abstract = {The purpose of this short review is to analyse major advantages and limitations of the adenovirus (Ad), specifically with relevance to its use as a vector for gene transfer to the brain. The characteristics of Ad transduction include: the relative absence of cell type specificity; the limited spatial spread of the virus; and the long-term expression of the transgene. In the central nervous system, in contrast to that which occurs in other organs, Ad transduction in the adult does not systematically provoke cell death. Nevertheless, a proportion of the transduced cells do die, and this represents a conspicuous problem. Mechanisms leading to cell death in the brain may include immune rejection and inflammation-related toxicity, although this would not explain all of the results, and direct toxicity related to either inappropriate preparation or the transduction itself. Taking into account uncertainties concerning the innocuousness of Ad transduction, it may seem unwise to envisage Ad gene therapy for diseases that are not life-threatening and/or benefit from adequate drug or surgical treatments (e.g. Parkinson's disease or epilepsy). Ad vectors may not be easily used either in diseases displaying major immune dysfunction (e.g. multiple sclerosis). In contrast, malignant brain tumors and numerous neurodegenerative diseases (such as Huntington's, Alzheimer's diseases or amyotrophic lateral sclerosis) are directly life-threatening and deprived of any adequate treatment. They may be appropriate targets for Ad-mediated gene therapy, once both the vector and the gene of interest have been defined and optimized.}, }
@article {pmid9086359, year = {1997}, author = {Moriwaka, F}, title = {[Amyotrophic lateral sclerosis].}, journal = {[Hokkaido igaku zasshi] The Hokkaido journal of medical science}, volume = {72}, number = {1}, pages = {21-25}, pmid = {9086359}, issn = {0367-6102}, mesh = {Adult ; Amino Acids, Branched-Chain/administration &amp; dosage ; Amyotrophic Lateral Sclerosis/etiology/*therapy ; Animals ; Autoimmunity ; Double-Blind Method ; Excitatory Amino Acid Antagonists/administration &amp; dosage ; Glutamic Acid/toxicity ; Humans ; Nerve Growth Factors ; Nerve Tissue Proteins/therapeutic use ; Point Mutation ; Randomized Controlled Trials as Topic ; Riluzole ; Superoxide Dismutase/genetics ; Thiazoles/administration &amp; dosage ; Threonine/administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal illness characterized by upper and lower motor neuron degeneration of adults. Recently, many advances are being made in our understanding of the pathogenesis of ALS, which are the role of autoimmunity, the glutamate excitotoxicity, the neurotrophic factor and the defined mutation of superoxide dismutase in familial ALS cases. The therapeutic trials have been carried out more commonly based on the putative pathogenesis described. Among them, riluzole, antiglutamate agent, is proved to have the survival advantage in a controlled double-blind randomized study. These current putative pathogenesis and therapeutic trials of ALS are discussed.}, }
@article {pmid8997453, year = {1997}, author = {Knight, JA}, title = {Reactive oxygen species and the neurodegenerative disorders.}, journal = {Annals of clinical and laboratory science}, volume = {27}, number = {1}, pages = {11-25}, pmid = {8997453}, issn = {0091-7370}, mesh = {Aging/physiology ; Antioxidants ; Humans ; Ischemia/metabolism ; Lipid Peroxidation/physiology ; Macrophages/metabolism ; Mitochondrial Encephalomyopathies/physiopathology ; Nervous System Diseases/*etiology/physiopathology ; Nitric Oxide/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The major neurodegenerative disorders include Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis. Although their etiology and pathogenesis are unknown, numerous recent studies suggest that oxygen-derived free radicals play an important role. Furthermore, these reactive oxygen species are probably important in brain ischemia and reperfusion, Down's syndrome, and the mitochondrial encephalopathies. In this review, evidence for oxygen-derived free radicals in the pathogenesis of these disorders is discussed.}, }
@article {pmid9201563, year = {1996}, author = {Clark, W and Kendall, MJ}, title = {Therapeutic advances: riluzole for the treatment of motor neurone disease.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {21}, number = {6}, pages = {373-376}, doi = {10.1111/j.1365-2710.1996.tb00035.x}, pmid = {9201563}, issn = {0269-4727}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Asthenia/chemically induced ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Health Care Costs ; Humans ; Quality of Life ; Riluzole ; Survivors ; Thiazoles/adverse effects/*therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic laterial sclerosis is a fatal neurogenerative disorder, for which only symptomatic treatment was previously available. Riluzole was recently launched in the U.S.A. and Europe. This is the first drug to produce a modest increase in survival (approximately 3 months) in patients with this disease. Unfortunately, treatment causes a number of side-effects of which asthenia is particularly troublesome. Between 10 and 20 per cent of patients can be expected to withdraw from treatment due to these adverse effects. Data on the real time survival advantage and quality of life that can be expected whilst on treatment are needed to identify the place of riluzole in the management of this distressing disease.}, }
@article {pmid9082189, year = {1996}, author = {Abel, A and Danek, A and Borasio, GD and Witt, TN}, title = {[X chromosomal bulbospinal neuropathy (X-BSN, Kennedy syndrome): an illness with repetitive triplet sequences. Case report, differential diagnosis and molecular genetics aspects].}, journal = {Der Nervenarzt}, volume = {67}, number = {12}, pages = {1011-1019}, doi = {10.1007/s001150050084}, pmid = {9082189}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Bulbar Palsy, Progressive/diagnosis/*genetics ; Genetic Carrier Screening ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/*genetics ; Neurologic Examination ; Pedigree ; Phenotype ; Receptors, Androgen/genetics ; Sex Chromosome Aberrations/*genetics ; Trinucleotide Repeats/*genetics ; *X Chromosome ; }, abstract = {X-chromosomal recessive bulbospinal neuronopathy (X-BNS, Kennedy's disease) is an important differential diagnosis of amyotrophic lateral sclerosis. We present the data of ten own patients along with a review of the literature on this uncommon disease which is caused by an expanded CAG-repeat in the androgen receptor gene. This mutation probably affects the transcription regulating activity of the androgen receptor in neurons. Signs and symptoms of X-BSN can be derived from partial insensitivity for androgens and a mixed, mainly motor neuronopathy. The clinical diagnosis is based on: 1. lower motor neuron weakness of bulbar and proximal limb muscles with onset in the third to fifth decade, 2. cramps and pronounced fasciculations, particularly of facial muscles, 3. postural tremor, 4. diminished or absent sensory action potentials inspite of only minor sensory impairment, 5. gynecomastia, and 6. infertility, diabetes mellitus and hyperlipoproteinemia in a minority of cases. Unlike amyotrophic lateral sclerosis, disease progression is slow with barely shortened life expectancy, which should be stressed in patient counselling. Causal treatment is as yet unavailable but several aspects of palliative medicine should be considered.}, }
@article {pmid9044576, year = {1996}, author = {Ferrer, I}, title = {[Motor neuron diseases: a type of programmed cell death?].}, journal = {Neurologia (Barcelona, Spain)}, volume = {11 Suppl 5}, number = {}, pages = {7-13}, pmid = {9044576}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Apoptosis ; *Cell Death ; Humans ; Lewy Bodies ; Motor Neuron Disease/*physiopathology ; Motor Neurons/ultrastructure ; Muscular Atrophy, Spinal/physiopathology ; Spinal Muscular Atrophies of Childhood/physiopathology ; }, abstract = {Motor neuron diseases in humans, which include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophies (SMAs), are characterized by motorneuron loss and chromatolysis in some or many remaining cells of the anterior horn of the spinal cord. Motorneurons are filled with phosphorylated neurofilaments, and ubiquitinated filamentous and granular inclusions which conform Lewy-like bodies in ALS patients. In addition, axonal balloonings filled with phosphorylated neurofilaments are usually observed in ALS patients with predominant signs of spinal motor neuron deficits and rapid clinical course. SMAs also occur in other species. Loss of motorneurons and chromatolytic cells filled with phosphorylated neurofilaments are the main pathologic findings in the ventral horn. In both humans and animals, loss of synaptic afferents is found in chromatolytic cells but not in normally-appearing motorneurons, thus suggesting that loss of synapses is a later event in motor neuron disease. These morphological features, together with the lack of c-Jun/AP-1 immunostaining and lack of staining with the method of in situ labelling of nuclear DNA fragmentation of dying cells, are different from those found during the process of naturally occurring (programmed) cell death in normal development. Although deletions in the SMN and NAIP genes located in 5q are found in patients with SMA, the cell death programme in SMA should not be considered as a mere persistence or reactivation of naturally occurring (programmed) cell death during normal development.}, }
@article {pmid9044573, year = {1996}, author = {Pou, A}, title = {[Juvenile and adult forms of spinal muscular atrophies].}, journal = {Neurologia (Barcelona, Spain)}, volume = {11 Suppl 5}, number = {}, pages = {43-57}, pmid = {9044573}, issn = {0213-4853}, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Chromosomes, Human, Pair 2 ; Chromosomes, Human, Pair 21 ; Chromosomes, Human, Pair 5 ; Exons ; Humans ; Muscular Atrophy, Spinal/enzymology/*genetics ; Pedigree ; Superoxide Dismutase/metabolism ; X Chromosome ; }, abstract = {We propose a classification system for spinal muscular atrophies (SMA) based on the distribution of clinical signs, paresis and atrophy, as well as on the location of the responsible gene and the resulting enzyme deficiency, whenever these are known. This highly practical classification system encompasses three large SMA groups, as follows. A) Generalized forms, many of which are hereditary, are generally transmitted in a recessive autosomal manner. The course of disease is more severe when symptoms manifest early. Patients whose symptoms first occur after the first year of life often reach adolescence and even adulthood, confirming a highly apparent congruence of intermediate and pseudomyopathic juvenile forms. The same genetic defect, deletion in the 5q11-13.3 locus, that is responsible for acute infantile SMA has been demonstrated in both the aforementioned forms. B) Focal forms are restricted and often isolated cases; when they are hereditary, the genetic profile is highly heterogeneous. Though the disease will not necessarily evolve, it may progress to a generalized form. Focal forms may be symetric, assymetric, spinal-bulbar or multisegmental. The genetic abnormality has been identified for only some forms, such as chronic bulbar-spinal amyotrophy linked to the X-chromosome, at whose location, Xq11, the androgenic receptor is found. C) Amyotrophic lateral sclerosis (ALS) manifests clinically in a variety of ways and may be isolated, familial, juvenile or associated. Familial ALS is related to a gene defect in the 21q22.1 location that codifies for the superoxide dismutase enzyme. One juvenile form of ALS is related to a defect in the 2q33-35 chromosome. Any type of SMA can be related to degenerative neuronal disease of the central nervous system, especially juvenile ALS with generalized SMA, although such a link is at present merely an attractive hypothesis. Specific bibliographic references are given for each SMA form. Figures are provided to illustrate most of the SMA forms included in this classification system, the patients being at this time older adolescents and adults whose disease has been in evidence over many years.}, }
@article {pmid9044571, year = {1996}, author = {Espadaler-Gamissans, JM}, title = {[Electrophysiologic assessment in motor neuron diseases].}, journal = {Neurologia (Barcelona, Spain)}, volume = {11 Suppl 5}, number = {}, pages = {20-28}, pmid = {9044571}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electromyography ; Humans ; *Motor Neurons ; Muscle, Skeletal ; Muscular Atrophy, Spinal/*diagnosis/*physiopathology ; }, abstract = {Electrophysiologic assessment is an important diagnostic tool in motor neuron diseases, contributing on occasions to define a patient's prognosis and clinical course as well as to further our understanding of the disease itself. The advent of motor cortex stimulation techniques facilitates the study of impaired descending motor pathways in predominantly upper motor neuron forms of amyotrophic lateral sclerosis. The most important feature of this technique is the decrease in amplitude of muscle responses to cortical stimuli, as a reflection of upper and lower motor neuron death. Coaxial needle electromyography (EMG) affords data on muscle fiber denervation as well as alterations in motor unit potentials, whose amplitude and duration increase. Motor and sensory nerve conduction velocities are preserved: single fiber and macro-EMG studies reveal changes suggestive of collateral sprouting of distal axons in surviving motor units in a compensatory reinnervation process. None of these techniques, however, provides a direct measure of the number of motor units present in a muscle, information that would be an essential aid in following the natural course of such diseases as well as assessing the efficacy of experimental treatments. Several techniques for estimating the number of motor units have been put forth, although none has been widely accepted. We describe the techniques proposed, weighing the advantages and disadvantages of each. At present it is impossible to tell which technique best estimates the real number of motor units present.}, }
@article {pmid9044569, year = {1996}, author = {Pou, A}, title = {[Motor neuron diseases. Present].}, journal = {Neurologia (Barcelona, Spain)}, volume = {11 Suppl 5}, number = {}, pages = {1-6}, pmid = {9044569}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/*physiopathology ; Apoptosis ; Humans ; Motor Neuron Disease/diagnosis/genetics/*physiopathology ; Muscular Atrophy, Spinal/diagnosis/genetics/*physiopathology ; Superoxide Dismutase/genetics ; }, abstract = {Recent progress in our understanding of motor neuron diseases, particularly those of degenerative pathogenesis such as spinal muscular atrophies (SMA) and amyotrophic lateral sclerosis (ALS), have to be described as historic. They are essentially of three types: 1) In first place are advances afforded by molecular genetics both in SMA (with the discovery of survival motor neurons and neuronal apoptosis inhibitor protein, which are markers of the disease and their pathogenetic mechanism) and in ALS (with the discovery of the super oxide dismutase [SOD1] gene, involved in the genesis of familial forms of ALS and other types of SMA such as certain forms of familial juvenile ALS, bulbar-spinal atrophy with gynecomasty and others). 2) In second place are biological data detailing the mechanisms of neuron death, whether programed or not, and emphasizing the importance of the so-called trophic or neurotrophin factors-whether nerve growth factor, brain-derived-neurotrophic factor, neurotrophin-3 or others whose effect of preventing neuron death has been demonstrated in vitro-as well as that of other substances such as Ca(2+)-activated neutral protease, which stabilizes synapses during development. It is assumed that one or another of these data will lead to therapeutic strategies for blocking the cascade of events that lead to neuron degeneration. 3) Finally, the strong impact of neuroimmunology in the field of neuromuscular pathology has been of interest mainly in neurogenic diseases marked purely and essentially be motor expression. As markers and pathogens, antiganglioside antibodies must necessarily be determined at this time in such entities as multifocal motor neuropathy, Guillain-Barré syndrome, acute axon motor neuropathy, Miller-Fisher syndrome and others, as their presence can inform therapeutic approaches. These three aspects and others currently under discussion will be treated in this course. At the same time the basic diagnostic aspects of motor neuron diseases will be emphasized: electrophysiologic assessment, on the one hand, and clinical features on the other. Establishing an exhaustive classification of SMA, from the earliest forms of infancy to adult types, is of great priority, as is exposing the full range of SMA according to whether distal or proximal predominance of atrophy is present. Our current understanding of the field is summarized in ten chapters on degenerative motor neuron diseases.}, }
@article {pmid9011143, year = {1996}, author = {Rowland, LP}, title = {Controversies about amyotrophic lateral sclerosis.}, journal = {Neurologia (Barcelona, Spain)}, volume = {11 Suppl 5}, number = {}, pages = {72-74}, pmid = {9011143}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/*therapy ; Chelation Therapy ; Humans ; Peripheral Nerves/physiopathology ; Thiamine/therapeutic use ; Venoms/therapeutic use ; Vitamin B 12/therapeutic use ; }, abstract = {Controversy regarding amyotrophic lateral sclerosis (ALS) concerns aspects of relatively little consequence (such as the role of lead intoxication or trauma in the pathogenesis of the disease) and others of greater relevance, particularly the two following questions regarding treatment options: 1) Are we in a new era of therapy for ALS? Prior to the 1990's no controlled study showed consistent benefit from any of the treatments tried. We have now had announcements of benefit for four entirely different agents: riluzole, insulin-like growth hormone, brain derived neurotrophic hormone and gabapentin. The benefit, at most, is marginal or questionable. The effect is of statistical significance but of little clinical relevance, and 2) what is the role of peripheral nerves in ALS? The syndrome of multifocal motor neuropathy and conduction block (MMNCB) shares some clinical data (active tendon jerks in weak, wasted and fasciculating muscles) and pathological features (anterior horn cell loss and glions) with "typical" ALS. This is relevant because MMNCB is reversible with immunoglobulin therapy. The rigid separation between ALS (a disease of the motor neuron perikaryon) and MMNCB (a disease of the motor neuron axon) is no longer tenable.}, }
@article {pmid9007410, year = {1996}, author = {Hosler, BA and Brown, RH}, title = {Superoxide dismutase and oxygen radical neurotoxicity.}, journal = {Current opinion in neurology}, volume = {9}, number = {6}, pages = {486-491}, doi = {10.1097/00019052-199612000-00016}, pmid = {9007410}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Animals ; Cell Death/genetics ; DNA Mutational Analysis ; Humans ; Hydroxyl Radical/metabolism ; Mice ; Motor Neurons/enzymology ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/deficiency/*genetics ; }, abstract = {Although reactive oxygen species are natural metabolic products, they can be toxic to cells and are implicated in some neurodegenerative disease. Cytosolic Cu, Zn superoxide dismutase normally defends against damage by reactive oxygen species; however, mutant forms of the enzyme might instead contribute to damage of motor neurons n some amyotrophic lateral sclerosis patients. Possible mechanisms of oxidative injury to neurons are discussed with reference to cytosolic Cu, Zn superoxide dismutase mutations and other factors which might enhance oxygen radical toxicity.}, }
@article {pmid8998034, year = {1996}, author = {Kent, MA}, title = {The ethical arguments concerning the artificial ventilation of patients with motor neurone disease.}, journal = {Nursing ethics}, volume = {3}, number = {4}, pages = {317-328}, doi = {10.1177/096973309600300405}, pmid = {8998034}, issn = {0969-7330}, mesh = {Cost of Illness ; Disclosure ; *Ethics, Nursing ; *Home Care Services ; Humans ; Internationality ; Motor Neuron Disease/*therapy ; Paternalism ; *Patient Advocacy ; Patient Selection ; *Personal Autonomy ; Resource Allocation ; *Respiration, Artificial ; United Kingdom ; *Withholding Treatment ; }, abstract = {This paper focuses on the ethical dilemmas created by advanced technology that would allow patients with motor neurone disease to be sustained by artificial ventilation. The author attempts to support the patient's right to informed choice, arguing from the perspective of autonomy as a first order principle. The counter arguments of caregiver burden and financial restraints are analysed. In the UK, where active euthanasia is not legalized, the dilemma of commencing ventilation is seen to be outweighed by the problems of withdrawing this treatment. The lack of accurate data and protocols that would clarify the current situation is emphasized and the conclusion takes the form of a recommendation for further research.}, }
@article {pmid8971099, year = {1996}, author = {Radunovíc, A and Leigh, PN}, title = {Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {61}, number = {6}, pages = {565-572}, pmid = {8971099}, issn = {0022-3050}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Genotype ; Humans ; Mutation/*genetics ; Superoxide Dismutase/*genetics ; }, }
@article {pmid8959995, year = {1996}, author = {Doble, A}, title = {The pharmacology and mechanism of action of riluzole.}, journal = {Neurology}, volume = {47}, number = {6 Suppl 4}, pages = {S233-41}, doi = {10.1212/wnl.47.6_suppl_4.233s}, pmid = {8959995}, issn = {0028-3878}, mesh = {Animals ; Excitatory Amino Acid Antagonists/*pharmacology ; Rats ; Riluzole ; Thiazoles/*pharmacology ; }, abstract = {The excitotoxic hypothesis of neurodegeneration has stimulated much interest in the possibility of using compounds that will block excitotoxic processes to treat neurologic disorders. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS. Riluzole inhibits the release of glutamic acid from cultured neurons, from brain slices, and from corticostriatal neurons in vivo. It is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors. In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed. In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.}, }
@article {pmid8959993, year = {1996}, author = {Leigh, PN and Meldrum, BS}, title = {Excitotoxicity in ALS.}, journal = {Neurology}, volume = {47}, number = {6 Suppl 4}, pages = {S221-7}, doi = {10.1212/wnl.47.6_suppl_4.221s}, pmid = {8959993}, issn = {0028-3878}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; Neurotoxins/*metabolism ; }, }
@article {pmid8959992, year = {1996}, author = {Jerusalem, F and Pohl, C and Karitzky, J and Ries, F}, title = {ALS.}, journal = {Neurology}, volume = {47}, number = {6 Suppl 4}, pages = {S218-20}, doi = {10.1212/wnl.47.6_suppl_4.218s}, pmid = {8959992}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Humans ; }, abstract = {The cause of ALS is not known but there are four main hypotheses about its etiology. First, an excess of extracellular glutamate in the CNS of patients with ALS resulting from a defect in glutamate reuptake may have excitotoxic effects on motor neurons. Clinical trials suggest the antiglutamate agent riluzole improves survival of patients with the disease. Second, ALS may be an autoimmune disease, but immunologically-based treatments have been unsuccessful. The third hypothesis is that ALS results from a lack of neurotrophic growth factors. Preliminary results from clinical trials indicate recombinant human insulin-like growth factor I offers therapeutic promise. Finally, familial ALS is sometimes linked to a gene encoding a Cu/Zn-binding superoxide dismutase; the mutations in ALS are thought to result in gain of function of dismutase activity. The involvement of superoxide dismutase in sporadic ALS is unclear.}, }
@article {pmid8957007, year = {1996}, author = {Vincent, A and Drachman, DB}, title = {Amyotrophic lateral sclerosis and antibodies to voltage-gated calcium channels--new doubts.}, journal = {Annals of neurology}, volume = {40}, number = {5}, pages = {691-693}, doi = {10.1002/ana.410400502}, pmid = {8957007}, issn = {0364-5134}, mesh = {Amyotrophic Lateral Sclerosis/blood/*immunology ; Autoantibodies/*blood ; Calcium Channels/*immunology ; Calcium Channels, L-Type ; Endopeptidases/*blood ; Humans ; Immunoglobulin Fab Fragments ; Immunoglobulin G/*blood ; }, }
@article {pmid8950969, year = {1996}, author = {Hasegawa, T and Abe, K and Aoki, M and Itoyama, Y}, title = {[Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations in Japan].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {54}, number = {11}, pages = {3157-3162}, pmid = {8950969}, issn = {0047-1852}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; Japan ; Mutation ; Superoxide Dismutase/genetics ; }, }
@article {pmid8944624, year = {1996}, author = {Beckman, JS and Koppenol, WH}, title = {Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.}, journal = {The American journal of physiology}, volume = {271}, number = {5 Pt 1}, pages = {C1424-37}, doi = {10.1152/ajpcell.1996.271.5.C1424}, pmid = {8944624}, issn = {0002-9513}, support = {HL-46407/HL/NHLBI NIH HHS/United States ; HL-48676/HL/NHLBI NIH HHS/United States ; NS-24338/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Arteriosclerosis/physiopathology ; Endothelium, Vascular/physiology ; Humans ; Models, Biological ; Muscle, Smooth, Vascular/physiology ; Neurons/physiology ; Nitrates/*metabolism ; Nitric Oxide/*metabolism ; Oxyhemoglobins/metabolism ; *Second Messenger Systems ; Superoxide Dismutase/metabolism ; Superoxides/*metabolism ; Synapses/physiology ; }, abstract = {Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.}, }
@article {pmid8923496, year = {1996}, author = {Chokroverty, S}, title = {Sleep and degenerative neurologic disorders.}, journal = {Neurologic clinics}, volume = {14}, number = {4}, pages = {807-826}, doi = {10.1016/s0733-8619(05)70286-3}, pmid = {8923496}, issn = {0733-8619}, mesh = {Aged ; Alzheimer Disease/physiopathology ; Cerebellar Diseases/physiopathology ; Dystonia Musculorum Deformans/physiopathology ; Humans ; Huntington Disease/physiopathology ; Motor Neuron Disease/physiopathology ; Nervous System Diseases/diagnosis/*physiopathology/therapy ; Parkinson Disease/physiopathology ; Shy-Drager Syndrome/physiopathology ; Sleep/*physiology ; Sleep Wake Disorders/physiopathology/therapy ; Supranuclear Palsy, Progressive/physiopathology ; Tourette Syndrome/physiopathology ; }, abstract = {This article summarizes sleep disturbances in a variety of neuro-degenerative diseases, including Parkinson's disease, multiple system atrophy, and amyotrophic lateral sclerosis. Sleep complaints in these conditions include insomnia, hypersomnia, abnormal motor activity and behavior during sleep, sleep-related breathing problems, and circadian rhythm sleep disturbances. Clinical examination followed in selected cases by polysomnographic, multiple sleep latency, and other laboratory tests is essential for correct diagnosis and treatment of these sleep disturbances.}, }
@article {pmid8983715, year = {1996}, author = {Jiménez-Jiménez, FJ and García-Ruiz, PJ and de Bustos, F}, title = {[Calcium, neuronal death and neurological disease].}, journal = {Revista de neurologia}, volume = {24}, number = {134}, pages = {1199-1209}, pmid = {8983715}, issn = {0210-0010}, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Brain/physiopathology ; Brain Ischemia/physiopathology ; Calcium Channels/*physiology ; *Cell Death ; Epilepsy/physiopathology ; Humans ; Huntington Disease/physiopathology ; *Nerve Degeneration ; Neurons/*physiology ; Parkinson Disease/physiopathology ; }, abstract = {Calcium ion (Ca2+) plays a role in several important functions in the central nervous system such as production of action potentials, neurotransmitter release, or neuronal plasticity, etc. However, its excessive influx to neurons due to failure of the mechanisms implicated in the regulation of its intracellular concentration (Ca(2+)-channels, calcium binding proteins), leads to a cascade of events which causes cytotoxicity and neuronal death. Ca2+ mediated toxicity has been implicated in the pathogenesis of neurodegenerative diseases (Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, Huntington's), brain ischemia, epilepsy, cranial trauma, and AIDS-dementia complex. In this article we review the current status of this topic.}, }
@article {pmid8944317, year = {1996}, author = {Price, DL and Becher, MW and Wong, PC and Borchelt, DR and Lee, MK and Sisodia, SS}, title = {Inherited neurodegenerative diseases and transgenic models.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {6}, number = {4}, pages = {467-480}, doi = {10.1111/j.1750-3639.1996.tb00876.x}, pmid = {8944317}, issn = {1015-6305}, support = {AG 05146/AG/NIA NIH HHS/United States ; NS 07179/NS/NINDS NIH HHS/United States ; NS 20471/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*genetics/pathology ; Amyloid beta-Peptides/genetics ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Ataxin-1 ; Ataxins ; Brain/*pathology ; Chromosomes, Human, Pair 21 ; Humans ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Nuclear Proteins/genetics ; Spinocerebellar Degenerations/*genetics/pathology ; Superoxide Dismutase/genetics ; Trinucleotide Repeats ; }, abstract = {In recent years, the identification of mutations in specific genes in several inherited neurodegenerative disorders, combined with advances in the field of transgenic methods, has provided neuroscientists and neuropathologists with information and strategies to develop transgenic (Tg) models to study human diseases. These approaches have proved to be extraordinarily useful in modeling familial forms of amyotrophic lateral sclerosis (FALS) and Alzheimer's disease (FAD) and the spectrum of triplet-repeat disorders. Investigations of these models have begun to provide new insights into the roles of disease-specific mutant proteins and the pathogenic mechanisms of disease as well as opportunities to test therapeutic interventions.}, }
@article {pmid8937834, year = {1996}, author = {Rothstein, JD}, title = {Therapeutic horizons for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurobiology}, volume = {6}, number = {5}, pages = {679-687}, doi = {10.1016/s0959-4388(96)80103-6}, pmid = {8937834}, issn = {0959-4388}, support = {NS33958/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; Animals ; Antioxidants/therapeutic use ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Mice ; Mice, Transgenic ; Motor Neuron Disease/epidemiology/therapy ; Motor Neurons/pathology/physiology ; Nerve Degeneration ; Nerve Growth Factors/therapeutic use ; Nerve Regeneration ; Superoxide Dismutase/biosynthesis/genetics ; }, abstract = {Recent theories on the pathogenesis of motor neuron disease and research on motor neuron injury have resulted in new putative therapies, which include treatment with various neurotrophic factors, antioxidants and anti-excitotoxicity agents. Clinical and preclinical studies have now provided the first agents that reproducibly alter the course of amyotrophic lateral sclerosis.}, }
@article {pmid8930947, year = {1996}, author = {Bruijn, LI and Cleveland, DW}, title = {Mechanisms of selective motor neuron death in ALS: insights from transgenic mouse models of motor neuron disease.}, journal = {Neuropathology and applied neurobiology}, volume = {22}, number = {5}, pages = {373-387}, doi = {10.1111/j.1365-2990.1996.tb00907.x}, pmid = {8930947}, issn = {0305-1846}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Death/physiology ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/metabolism/*pathology ; Motor Neurons/*physiology/ultrastructure ; Superoxide Dismutase/metabolism ; }, abstract = {Concerning the mechanism(s) of disease underlying amyotrophic lateral sclerosis (ALS), transgenic mouse models have provided (i) a detailed look at the pathogenic progression of disease, (ii) a tool for testing hypotheses concerning the mechanism of neuronal death, and (iii) a host appropriate for testing therapeutic strategies. Thus far, these efforts have proved that mutation in a neurofilament subunit can cause progressive disease displaying both selective motor neuron death and aberrant neurofilament accumulation similar to that reported in human disease. Additional mice expressing point mutations in the cytoplasmic enzyme superoxide dismutase (SOD1), the only known cause of ALS, have proved that disease arises from a toxic property of the mutant enzyme rather than loss of enzymatic activity.}, }
@article {pmid8914431, year = {1996}, author = {Suzuki, K}, title = {[Neurological disorders associated with impaired glucose tolerance].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {54}, number = {10}, pages = {2704-2708}, pmid = {8914431}, issn = {0047-1852}, mesh = {Autonomic Nervous System Diseases/*etiology ; Diabetes Complications ; Glucose Intolerance/*complications ; Humans ; Peripheral Nervous System Diseases/etiology ; }, abstract = {The clinical relevance of neurological disorders associated with impaired glucose tolerance(IGT) is reviewed. In this review some neurological diseases, such as, myotonic dystrophy, Crow-Fukase syndrome, Wolfram syndrome (DIDMOAD), Friedreich ataxia, spinal muscular atrophy of the Kennedy-Alter-Sung type, amyotrophic lateral sclerosis, Parkinson-dementia, and MELAS are discussed in relation to, glucose intolerance. Although the etiology of these disorders still remains an enigma, MELAS was caused by an A-to-G mutation at nucleotide position 3243 of the mitochondria genome. An association of "diabetic neuropathy" with IGT appears to be negative. Peripheral nerve function did not differ between IGT and control subjects, whereas autonomic nerve function deviated; an abnormal expiration to inspiration ratio of R-R interval was significantly more common in IGT than in control subjects. In conclusion, diabetes, but not IGT, is associated with peripheral nerve dysfunction.}, }
@article {pmid8911742, year = {1996}, author = {Hughes, RA and O'Leary, PD}, title = {Neurotrophic factors and the development of drugs to promote motoneuron survival.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {23}, number = {10-11}, pages = {965-969}, doi = {10.1111/j.1440-1681.1996.tb01150.x}, pmid = {8911742}, issn = {0305-1870}, mesh = {Cell Survival/drug effects ; Drug Design ; Humans ; Motor Neurons/*cytology/*drug effects ; Nerve Growth Factors/pharmacology/physiology ; Nerve Tissue Proteins/*pharmacology/*physiology ; }, abstract = {1. During embryonic development, neuronal populations undergo a period of naturally occurring cell death. In the vertebrate, the survival of neurons during this period is dependent upon specific neurotrophic factors. Recent advances in in vitro and in vivo assays have led to the identification of a number of neurotrophic factors for spinal motoneurons, including brain-derived neurotrophic factor, ciliary neurotrophic fibroblast growth factors, insulin-like growth factors and glial-derived neurotrophic factor. 2. The presence of multiple trophic factors promoting motoneuron survival suggests either that there is significant functional redundancy between the factors or that they act in concert to produce their effects. 3. In addition to their physiological role, neurotrophic factors show tremendous clinical potential for the treatment of human neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, because they are poorly absorbed across biological membranes and are unstable in plasma, the recombinant neurotrophic factors themselves are not optimally suited as drugs. One means to circumvent these problems is to use the known three-dimensional structures of these factors as templates to design low molecular weight compounds that retain neurotrophic activity but exhibit better pharmacokinetic properties.}, }
@article {pmid8906612, year = {1996}, author = {Liu, D}, title = {The roles of free radicals in amyotrophic lateral sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {7}, number = {3}, pages = {159-167}, pmid = {8906612}, issn = {0895-8696}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/enzymology/genetics/*physiopathology ; Animals ; Apoptosis ; Brain/pathology/physiopathology ; DNA/metabolism ; Free Radicals/metabolism ; Humans ; Mice ; Mice, Transgenic ; Models, Neurological ; Neurons/pathology/physiology ; Superoxide Dismutase/*genetics/metabolism ; Superoxides/metabolism ; }, abstract = {The mutations of the Cu,Zn superoxide dismutase (Cu,Zn-SOD) gene observed in amyotrophic lateral sclerosis (ALS) patients suggest that free radicals play a role in this fatal disease. Free radicals trigger oxidative damage to proteins, membrane lipids, and DNA, thereby destroying neurons. Mutations of the SOD gene may reduce its superoxide dismutase activity, thereby elevating free radical levels. In addition, the mutant SOD protein may function as a peroxidase to oxidize cellular components, and it may also react with peroxynitrite-a product of the reaction between superoxide and nitric oxide-to ultimately form nitrate proteins. The selective degeneration of motor neurons in ALS may be caused by the high level of Cu,Zn-SOD present in and the large number of glutamatergic synapses projecting to these neurons. Free radical-triggered and age-accumulated oxidation may modify the program controlling motor neuron death, thereby initiating apoptosis of motor neurons in young adults.}, }
@article {pmid8891467, year = {1996}, author = {Bryson, HM and Fulton, B and Benfield, P}, title = {Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis.}, journal = {Drugs}, volume = {52}, number = {4}, pages = {549-563}, pmid = {8891467}, issn = {0012-6667}, mesh = {Administration, Oral ; Animals ; Antiparkinson Agents/pharmacokinetics/pharmacology/*therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Tolerance ; Excitatory Amino Acid Antagonists/pharmacokinetics/pharmacology/*therapeutic use ; Humans ; In Vitro Techniques ; Mice ; Motor Neuron Disease/*drug therapy/mortality ; Multicenter Studies as Topic ; Neuroprotective Agents/pharmacokinetics/pharmacology/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole ; Sodium Channels/drug effects ; Thiazoles/blood/pharmacokinetics/pharmacology/*therapeutic use ; Treatment Outcome ; }, abstract = {Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.}, }
@article {pmid8891076, year = {1996}, author = {Rubio, A and Steinberg, K and Figlewicz, DA and MacDonald, ME and Greenamyre, T and Hamill, R and Shoulson, I and Powers, JM}, title = {Coexistence of Huntington's disease and familial amyotrophic lateral sclerosis: case presentation.}, journal = {Acta neuropathologica}, volume = {92}, number = {4}, pages = {421-427}, doi = {10.1007/s004010050539}, pmid = {8891076}, issn = {0001-6322}, support = {AG08665/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications/*pathology ; Humans ; Huntington Disease/*complications/*pathology ; Male ; Pedigree ; }, abstract = {We present the clinical, molecular genetic and neuropathological findings of an 81-year-old man with concurrent Huntington's disease (HD) and familial amyotrophic lateral sclerosis (FALS). His mother had been diagnosed clinically as having ALS. There was no known family history of HD, but a maternal uncle had died in a chronic care psychiatric hospital. The diagnosis of HD in the patient was suspected at age 66, after 8 years of personality change, hallucinations, agitation, cognitive decline and choreoathetosis. No symptoms of motor neuron disease were noticed at that time, but progressive weakness developed later. Postmortem examination revealed cerebral atrophy, marked atrophy of basal ganglia (grade 3), and atrophy of brain stem and spinal cord. The neostriatum displayed massive neuronal loss and gliosis. The neocortex showed changes characteristic of Alzheimer's disease. Pathological lesions also included loss of neurons and gliosis in the anterior horns, Clarke's columns and the hypoglossal nuclei; degeneration of the lateral corticospinal tracts, dorsal spinocerebellar tracts and fasciculus gracilis; and rare Bunina bodies and ubiquitin-positive filamentous skeins in motor-neuron perikarya. Molecular analysis demonstrated chromosome 4p16.3 expansion of trinucleotide repeats characteristic of HD. Analysis of Cu,Zn superoxide dismutase gene and heavy neurofilament subunit gene failed to demonstrate mutations. The concurrence of HD and FALS in our patient and three previously reported cases did not appear to be associated with cosegregation in other family members.}, }
@article {pmid8891072, year = {1996}, author = {Ince, PG and Shaw, PJ and Slade, JY and Jones, C and Hudgson, P}, title = {Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes.}, journal = {Acta neuropathologica}, volume = {92}, number = {4}, pages = {395-403}, doi = {10.1007/s004010050535}, pmid = {8891072}, issn = {0001-6322}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; *Exons ; Female ; Humans ; Immunohistochemistry ; *Mutation ; Pedigree ; Superoxide Dismutase/*genetics ; }, abstract = {Detailed molecular pathology studies and clinicopathological phenotyping of familial amyotrophic lateral sclerosis (FALS) with characterised mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) will yield important insights into the pathogenesis of motor neuron degeneration. An autopsy case is described with the mutation E100G (exon 4) of the SOD1 gene in which full neuropathological examination including immunocytochemistry of ubiquitin and neurofilament epitopes was performed. The case falls into the category of "amyotrophic lateral sclerosis (ALS) with posterior column involvement." Critical analysis of the findings indicates a truly multisystem disorder in which ascending sensory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system. Abnormal neurofilament phosphorylation was not a prominent feature. Ubiquitinated neuronal inclusions were infrequent except in the hippocampal denate granule cells where they were indistinguishable from sporadic cases of ALS-dementia. The motor cortex was preserved despite severe distal axonal loss in the corticospinal tract. These findings suggest a primary failure of axonal maintainance affecting several neuronal groups with long projecting axons. The differences and similarities compared to previously reported case with I113T (exon 4) and A4T (exon 1) mutations are discussed. Findings related to inflammatory cell infiltration, ubiquitination and neurofilament phosphorylation are discussed with reference to the pathogenesis of sporadic ALS.}, }
@article {pmid8858062, year = {1996}, author = {Mitsumoto, H and Olney, RK}, title = {Drug combination treatment in patients with ALS: current status and future directions.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S103-7}, doi = {10.1212/wnl.47.4_suppl_2.103s}, pmid = {8858062}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Drug Combinations ; Fibroblast Growth Factor 2/therapeutic use ; Humans ; }, }
@article {pmid8858055, year = {1996}, author = {Brooks, BR}, title = {Natural history of ALS: symptoms, strength, pulmonary function, and disability.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S71-81; discussion S81-2}, doi = {10.1212/wnl.47.4_suppl_2.71s}, pmid = {8858055}, issn = {0028-3878}, support = {M01RR03186/RR/NCRR NIH HHS/United States ; }, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Female ; Humans ; Male ; }, }
@article {pmid8858053, year = {1996}, author = {Hirano, A}, title = {Neuropathology of ALS: an overview.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S63-6}, doi = {10.1212/wnl.47.4_suppl_2.63s}, pmid = {8858053}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; }, }
@article {pmid8858052, year = {1996}, author = {Cleveland, DW and Bruijn, LI and Wong, PC and Marszalek, JR and Vechio, JD and Lee, MK and Xu, XS and Borchelt, DR and Sisodia, SS and Price, DL}, title = {Mechanisms of selective motor neuron death in transgenic mouse models of motor neuron disease.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S54-61; discussion S61-2}, doi = {10.1212/wnl.47.4_suppl_2.54s}, pmid = {8858052}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; *Cell Death ; Mice ; Mice, Transgenic ; Motor Neuron Disease/genetics/*metabolism ; Neurofilament Proteins/metabolism ; }, abstract = {To examine the mechanism(s) of disease underlying ALS, transgenic mouse models have been constructed that express aberrant neurofilaments or mutations in the abundant, cytoplasmic enzyme superoxide dismutase 1 (SOD1). In addition to progressive weakness arising from selective motor neuron death, mice expressing a modest level of a point mutant in neurofilament subunit NF-L show most of the pathologic hallmarks observed in familial and sporadic ALS, including perikaryal proximal axonal swellings, axonal degeneration, and severe skeletal muscle atrophy. Additional mice expressing familial ALS-linked mutations in the cytoplasmic enzyme SOD1, the only proven cause of ALS and which accounts for approximately 20% of familial disease, have demonstrated that at least one mutation causes disease through acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity. These animals not only provide a detailed look at the pathogenic progression of disease, but also represent a tool for testing hypotheses concerning the specific mechanism(s) of neuronal death and for testing therapeutic strategies.}, }
@article {pmid8858050, year = {1996}, author = {Smith, RG and Siklos, L and Alexianu, ME and Engelhardt, JI and Mosier, DR and Colom, L and Habib Mohamed, A and Appel, SH}, title = {Autoimmunity and ALS.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S40-5; discussion S45-6}, doi = {10.1212/wnl.47.4_suppl_2.40s}, pmid = {8858050}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; *Autoimmunity ; Humans ; Mice ; }, abstract = {Significant evidence has accrued suggesting that antibodies to voltage-gated calcium channel are observed in at least some patients with sporadic ALS (SALS) and that such antibodies alter the function of these ion channels in vitro and in vivo. Further, passive transfer of these immunoglobulin-containing fractions into mice produces changes at the neuromuscular junction that are very similar to changes observed in patients with SALS. These changes reflect local alterations in intracellular Ca2+ homeostasis and, in animal models, may also evidence early changes of motoneuron injury, such as Golgi apparatus swelling and fragmentation. Although not yet documented to induce motoneuron death in vivo, SALS immunoglobulins induce Ca(2+)-dependent apoptosis in a differentiated motoneuron hybrid cell line via a mechanism that involves oxidative injury. SALS immunoglobulin-mediated apoptosis in these cells is regulated by the presence of the same calcium-binding proteins that may modulate selective motoneuron vulnerability in SALS.}, }
@article {pmid8858049, year = {1996}, author = {Bredesen, DE and Wiedau-Pazos, M and Goto, JJ and Rabizadeh, S and Roe, JA and Gralla, EB and Ellerby, LM and Valentine, JS}, title = {Cell death mechanisms in ALS.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S36-8; discussion S38-9}, doi = {10.1212/wnl.47.4_suppl_2.36s}, pmid = {8858049}, issn = {0028-3878}, support = {AG12282/AG/NIA NIH HHS/United States ; DK46828/DK/NIDDK NIH HHS/United States ; GM28222/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; *Cell Death ; Humans ; Superoxide Dismutase/metabolism ; }, abstract = {Mutations in copper-zinc superoxide dismutase (CuZnSOD) that are associated with familial ALS (FALS) are dominant, gain-of-function mutations, but the nature of the function gained has not been identified. In addition to catalyzing the dismutation of superoxide, copper-zinc superoxide dismutase also displays peroxidase activity. Whereas mutants A4V and G93A retained superoxide dismutase activity, they demonstrated a markedly enhanced copper-dependent peroxidase activity in comparison with that of the wild type enzyme as detected by the spin trap 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) in electron paramagnetic resonance measurements. Two copper chelators, diethyldithiocarbamate and penicillamine, inhibited the mutants' peroxidase activity, but not that of the wild type enzyme, at stoichiometric concentrations; furthermore, these copper chelators enhanced neural survival in a cell-culture model of ALS but did not alter survival of cells expressing only wild type copper-zinc superoxide dismutase. These observations suggest that oxidative reactions catalyzed by mutant copper-zinc superoxide dismutases may initiate the neuropathologic changes of FALS.}, }
@article {pmid8858048, year = {1996}, author = {Siddique, T and Nijhawan, D and Hentati, A}, title = {Molecular genetic basis of familial ALS.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S27-34; discussion S34-5}, doi = {10.1212/wnl.47.4_suppl_2.27s}, pmid = {8858048}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Humans ; Mice ; Mutation ; Superoxide Dismutase/metabolism ; }, abstract = {Familial amytrophic lateral sclerosis (FALS) is transmitted in a mendelian fashion as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait. Both DFALS and RFALS are genetically heterogeneous. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) which is coded on chromosome 21. The locus for one form of RFALS maps to chromosome 2q33. Forty-six mutations in the SOD1 gene have been reported in DFALS families. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Several possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.}, }
@article {pmid8964701, year = {1996}, author = {Jappe, U and Hölzle, E and Ring, J}, title = {[Parry-Romberg syndrome. Summary and new knowledge based on an unusual case].}, journal = {Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete}, volume = {47}, number = {8}, pages = {599-603}, doi = {10.1007/s001050050475}, pmid = {8964701}, issn = {0017-8470}, mesh = {Adipose Tissue/pathology ; Atrophy ; Autonomic Nerve Block ; Facial Hemiatrophy/*diagnosis/therapy ; Female ; Functional Laterality ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Muscular Atrophy/diagnosis/therapy ; Skin/pathology ; }, abstract = {A 52 year old female with Parry-Romberg syndrome presented with gradual atrophy of the subcutaneous fat and muscle on her chest and back. The disease process was limited to the C3 to T2 dermatomes on the right side. In addition, there was muscle atrophy of the right arm and extending down the back to T10, als well as right sided paralysis of the diaphragm. Sympathetic nerve blockage reduced pain and hyperesthesia; no progression was seen over several months using NMR to monitor the patient. The Parry-Romberg syndrome has been defined in many ways; in view of this unusual case, we review the literature, attempting to provide a more accurate case definition.}, }
@article {pmid8899672, year = {1996}, author = {Feenberg, AL and Licht, JM and Kane, KP and Moran, K and Smith, RA}, title = {The online patient meeting.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {129-131}, doi = {10.1016/0022-510x(96)00093-7}, pmid = {8899672}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Computer Communication Networks/*trends ; Humans ; Microcomputers ; Self-Help Groups/*trends ; Sick Role ; }, abstract = {Studies have shown the importance of social support for health, and the value of patient support groups. Today we are seeing a further development of the idea of the patient meeting: online discussions on the internet and other computer networks. This paper reports on the online activities of patients with amyotrophic lateral sclerosis. The paper explores key questions in the evaluation of online patient meetings, such as the ability of patients to discuss their problems frankly, the availability and accuracy of advice, the spread and control of rumours.}, }
@article {pmid8899658, year = {1996}, author = {Gorman, AM and McGowan, A and O'Neill, C and Cotter, T}, title = {Oxidative stress and apoptosis in neurodegeneration.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {45-52}, doi = {10.1016/0022-510x(96)00097-4}, pmid = {8899658}, issn = {0022-510X}, mesh = {Apoptosis/*physiology ; Humans ; Nerve Degeneration/*physiology ; Nervous System Diseases/*metabolism/pathology ; Oxidative Stress/*physiology ; }, abstract = {The pathogenesis of neurodegenerative diseases such as Parkinson's diseases, amyotrophic lateral sclerosis and Alzheimer's disease is unknown. These diseases are characterized by a slow, progressive loss of particular subsets of neurons. Much evidence has accumulated which supports the hypothesis that oxidative stress and damage by free radicals may play an important part in these diseases. In particular recent studies with the inherited form of amyotrophic lateral sclerosis have revealed mutations in the superoxide dismutase gene, which is one of the cell's main defence mechanisms against oxidative stress. These findings suggest a direct link between oxidative stress and the development of a neurodegenerative disease.}, }
@article {pmid8899652, year = {1996}, author = {Cudkowicz, ME and Brown, RH}, title = {An update on superoxide dismutase 1 in familial amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {10-15}, doi = {10.1016/0022-510x(96)00084-6}, pmid = {8899652}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics ; Humans ; Mutation ; Superoxide Dismutase/*genetics ; }, }
@article {pmid8708678, year = {1996}, author = {Román, GC}, title = {Neuroepidemiology of amyotrophic lateral sclerosis: clues to aetiology and pathogenesis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {61}, number = {2}, pages = {131-137}, pmid = {8708678}, issn = {0022-3050}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis/etiology/mortality/physiopathology ; Brain/*physiopathology ; Cycasin/adverse effects ; Environmental Pollution/adverse effects ; Female ; Guam/epidemiology ; Humans ; Incidence ; Iron/adverse effects ; Male ; Middle Aged ; *Motor Neuron Disease/epidemiology/etiology/physiopathology ; Prevalence ; Risk Factors ; Survival Rate ; }, }
@article {pmid8998942, year = {1996}, author = {Tschäpe, H}, title = {[The distribution of antibiotically-resistant organisms in the environment with special attention to salmonellae].}, journal = {DTW. Deutsche tierarztliche Wochenschrift}, volume = {103}, number = {7}, pages = {273-277}, pmid = {8998942}, issn = {0341-6593}, mesh = {Animals ; Bacteria/*drug effects/genetics/growth &amp; development ; Drug Resistance, Microbial/genetics ; *Environmental Microbiology ; Gene Transfer, Horizontal ; Humans ; Salmonella/*drug effects/genetics/growth &amp; development ; Streptothricins/pharmacology ; }, abstract = {Antibiotic resistant determinants (R) prevail in environmental bacteria independent of antibiotic application in human and veterinary medicine als well as in agriculture. Due to horizontal gene transfer (plasmids) the spread of R. determinants to pathogenic bacteria occur in relation to selection pressure. Since salmonella bacteria have been found to persist in environmental habitats for a long time they will serve as recipients as a reservoir (donors).}, }
@article {pmid8965091, year = {1996}, author = {de Belleroche, J and Orrell, RW and Virgo, L}, title = {Amyotrophic lateral sclerosis: recent advances in understanding disease mechanisms.}, journal = {Journal of neuropathology and experimental neurology}, volume = {55}, number = {7}, pages = {747-757}, pmid = {8965091}, issn = {0022-3069}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/etiology/genetics/*physiopathology ; Animals ; Humans ; Isoenzymes/genetics ; Molecular Sequence Data ; Mutation ; Neurology/*trends ; Pedigree ; Superoxide Dismutase/genetics ; }, }
@article {pmid8916290, year = {1996}, author = {Lapchak, PA}, title = {Therapeutic potentials for glial cell line-derived neurotrophic factor (GDNF) based upon pharmacological activities in the CNS.}, journal = {Reviews in the neurosciences}, volume = {7}, number = {3}, pages = {165-176}, doi = {10.1515/revneuro.1996.7.3.165}, pmid = {8916290}, issn = {0334-1763}, mesh = {Animals ; Central Nervous System/*drug effects ; Dopamine/physiology ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Injections, Intraventricular ; Mice ; Nerve Degeneration/drug effects ; Nerve Growth Factors/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; Oxidopamine/antagonists &amp; inhibitors ; Rats ; }, abstract = {Since the discovery of the novel neurotrophic factor GDNF in 1993 [25], the molecule has received a great deal of attention from neuroscientists studying all aspects of neurotrophic factor physiology and pharmacology. GDNF instantly became a focus of basic research when it was discovered that GDNF was a potent neurotrophic factor for at least two diverse neuronal populations including dopaminergic neurons and motor neurons [25,47] magnitude. A comprehensive review of the pharmacology of GDNF and hypotheses concerning its possible clinical uses is presented. Based upon our current knowledge of GDNF's pharmacology, it appears that the molecule may be useful in the treatment of neurodegenerative diseases, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MND) and cholinergic deficit-related dementia.}, }
@article {pmid8853449, year = {1996}, author = {Donaghy, AJ and Baxter, RC}, title = {Insulin-like growth factor bioactivity and its modification in growth hormone resistant states.}, journal = {Bailliere's clinical endocrinology and metabolism}, volume = {10}, number = {3}, pages = {421-446}, doi = {10.1016/s0950-351x(96)80560-x}, pmid = {8853449}, issn = {0950-351X}, mesh = {Human Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Proteins/blood/*metabolism ; Insulin-Like Growth Factor I/*metabolism ; Metabolic Diseases/metabolism/*physiopathology ; }, abstract = {Acquired growth hormone (GH) resistance is an increasingly recognized feature of catabolic states. Low circulating levels of the insulin-like growth factors (IGF-I and II) have been shown to be associated with changes in the IGF binding proteins (IGFBP-1 to -6) that may significantly impact on IGF bioactivity. IGFBP-3 binds IGF and a third glycoprotein, the acid labile subunit (ALS), to form a stable 150 kDa ternary complex that serves as an intravascular store for IGFs and prolongs IGF half-life. IGFBP-1 is present at much lower concentration in serum but levels fluctuate acutely, suggesting regulation of IGF bioactivity in response to short-term metabolic changes. The function of IGFBP-2 remains unclear, but studies suggest that this protein may act as an alternative carrier for IGF when IGFBP-3 levels are low. Multiple regulatory influences on circulating IGFBP levels have been identified but three appear prominent. Nutritional influences, in particular substrate availability, appear to be a central regulatory influence on IGFBP levels in catabolic states. Low substrate availability increases IGFBP-1 levels acutely and decreases IGFBP-3 and IGFBP-2 levels in the intermediate term, with each of these changes likely to further limit IGF bioactivity. End organ failure, particularly of liver and kidney significantly affects production and clearance rates of the circulating IGFBPs and may contribute to the catabolism frequently seen in these states. Severe protein catabolism often accompanies malignancy and chronic sepsis and it is likely that additional ill-defined factors influence IGF bioactivity in this setting. Recent studies have identified post-translational modifications to the IGFBPs such as proteolysis and phosphorylation, which appear to further impact on IGF bioactivity. The relative contributions of these changes to the overall impairment of IGF bioactivity in GH-resistant states remains to be fully elucidated.}, }
@article {pmid8811995, year = {1996}, author = {Neary, D and Snowden, J}, title = {Fronto-temporal dementia: nosology, neuropsychology, and neuropathology.}, journal = {Brain and cognition}, volume = {31}, number = {2}, pages = {176-187}, doi = {10.1006/brcg.1996.0041}, pmid = {8811995}, issn = {0278-2626}, mesh = {Atrophy/physiopathology ; Cerebral Cortex/physiopathology ; Dementia/*physiopathology ; Frontal Lobe/*physiopathology ; Humans ; Motor Neuron Disease/physiopathology ; Temporal Lobe/*physiopathology ; }, abstract = {Fronto-temporal dementia is the commonest clinical manifestation of fronto-temporal lobar atrophy. It is associated with three types of underlying histology: microvacuolation or spongiosus (frontal lobe degeneration type), gliosis with or without inclusion bodies and swollen neurones (Pick-type), and motor neurone disease type. The clinical disorder presents in the presenium, is highly familial and is characterized by profound personality change, social incompetence and stereotypic ritualistic behavior. Language becomes attenuated, culminating in total mutism. Visuo-spatial skills are strikingly preserved. The electroencephalogram is normal and structural and functional imaging reflect fronto-temporal lobar atrophy. In a minority of cases the amyotrophic form of motor neurone disease coexists with fronto-temporal dementia and has a rapid and brief duration of illness. Phenotypic characterization of patients at each level of description: clinical, anatomical, and histological, provides a foundation for the molecular genetic studies which ought to shed light on the etiology of this form of focal cerebral degeneration.}, }
@article {pmid8809921, year = {1996}, author = {Bircher, N and Otto, C and Babbs, C and Braslow, A and Idris, A and Keil, JP and Kaye, W and Lane, J and Morioka, T and Roese, W and Wik, L}, title = {Future directions for resuscitation research. II. External cardiopulmonary resuscitation basic life support.}, journal = {Resuscitation}, volume = {32}, number = {1}, pages = {63-75}, doi = {10.1016/0300-9572(95)00935-3}, pmid = {8809921}, issn = {0300-9572}, mesh = {Cardiopulmonary Resuscitation/education/*methods ; *Emergency Medical Services ; *Forecasting ; Guidelines as Topic ; Humans ; *Research ; }, abstract = {In sudden cardiac deaths outside hospitals, the present performance of external cardiopulmonary resuscitation-basic life support (CPR-BLS), as a bridge to advanced life support (ALS) attempts for restoration of spontaneous circulation (ROSC), still yields suboptimal results. Therefore, future education research should develop more effective, simpler and quicker ways to enable everyone to acquire the necessary BLS skills. Individualized self-training by lay persons is being revived. Although airway control and direct mouth-to-mouth ventilation skills are difficult to acquire, they must continue to be taught to the lay public and health professionals, primarily for use on relatives and friends where infection risk is not a problem. In children and trauma victims, steps A and B alone may be lifesavers. The best way to ventilate and oxygenate during the initiation of brief external CPR-BLS should be re-evaluated. There is a great difference between animals and humans in the behavior of the airway and thorax during coma, and thus in the need for added positive pressure ventilation. During chest compressions in humans, steps A and B are needed. Details deserve re-evaluation. The low perfusion pressures (borderline blood flows) produced by standard external CPR remain the most serious limitation of this method. In spite of extensive efforts so far, novel laboratory research to remedy this limitation is important for the development of more effective emergency artificial circulation. The results of such studies are greatly influenced by different details in animal models. Active compression-decompression (ACD) external CPR, also called 'push-pull' CPR, with a plunger-type device used by hand or a machine, and intermittent abdominal compression (IAC) external CPR are both promising modifications of standard external CPR. Both need further experimental and clinical clarification. For BLS, developing a more effective purely manual CPR-BLS method for help in rapid ROSC should be given high priority. Portable external CPR machines need improvements. They will serve for bridging ROSC-resistant cases through transport and ALS attempts, primarily by freeing the hands of health professionals for more effective sophisticated ALS measures.}, }
@article {pmid8687473, year = {1996}, author = {Eizirik, DL and Spencer, P and Kisby, GE}, title = {Potential role of environmental genotoxic agents in diabetes mellitus and neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {51}, number = {12}, pages = {1585-1591}, doi = {10.1016/0006-2952(95)02433-6}, pmid = {8687473}, issn = {0006-2952}, support = {NS-19611/NS/NINDS NIH HHS/United States ; }, mesh = {Diabetes Mellitus/*chemically induced ; *Environmental Exposure ; Nerve Degeneration ; Pancreas/drug effects ; Risk Factors ; Toxins, Biological/*pharmacology ; }, abstract = {Epidemiological data suggest that environmental genotoxins are risk factors for some forms of diabetes mellitus and neurodegenerative diseases. The present commentary focuses on mechanisms involved in genotoxin-induced pancreatic beta-cell and neuronal damage. These two cell types seem to share a similar vulnerability to different forms of DNA damage, and the long-term consequences of repeated genotoxic insults to post-mitotic neurons or slowly proliferating beta-cells remain to be clarified. One intriguing possibility is that genotoxins could act as "slow" toxins in these cells, triggering a cascade of cellular events, which culminates in progressive cell dysfunction and loss. Indeed, exposure to mutagenic nitroso agents such as streptozotocin and cycasin induces long-lasting damage to both beta -cells and neurons. These data on cycasin, a toxin obtained from the cycad plant (Cycas spp.), are of special interest, since this agent may be implicated in both amyotrophic lateral sclerosis/Parkinson dementia complex and diabetes mellitus in the western Pacific area. Future studies are required to sort out the interactions between different genotoxic agents, viral infections, and cellular repair mechanisms on cellular survival and function. Moreover, further epidemiological studies are needed to clarify the role of N-nitrosoureas in diabetes mellitus and neurodegenerative diseases in populations with different genetic backgrounds. Answers to these questions may provide useful information on the pathogenesis of these devastating diseases, and open the possibility for their primary prevention.}, }
@article {pmid8811421, year = {1996}, author = {Dawson, VL and Dawson, TM}, title = {Nitric oxide neurotoxicity.}, journal = {Journal of chemical neuroanatomy}, volume = {10}, number = {3-4}, pages = {179-190}, doi = {10.1016/0891-0618(96)00148-2}, pmid = {8811421}, issn = {0891-0618}, support = {NS01578/NS/NINDS NIH HHS/United States ; NS22643/NS/NINDS NIH HHS/United States ; NS33142/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurotoxins/*toxicity ; Nitric Oxide/physiology/*toxicity ; }, abstract = {Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.}, }
@article {pmid8827179, year = {1996}, author = {Brooks, BR}, title = {Clinical epidemiology of amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {14}, number = {2}, pages = {399-420}, doi = {10.1016/s0733-8619(05)70264-4}, pmid = {8827179}, issn = {0733-8619}, support = {M01RR03186/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/economics/*epidemiology/etiology ; Case-Control Studies ; Cohort Effect ; Female ; Global Health ; Humans ; Incidence ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/epidemiology ; Palliative Care/trends ; Prevalence ; Registries ; Risk Factors ; Treatment Outcome ; }, abstract = {The introduction of palliative therapies in amyotrophic lateral sclerosis (ALS) will alter the epidemiology of ALS as it is known now. Although incidence rates will remain unchanged in the near future, prevalence rates will likely increase dramatically. Better understanding of the age-specific presentation of motor neuron diseases worldwide will shed light on the vexing questions concerning the variable incidence rates in some countries and apparent incidence gradients in North America and Europe.}, }
@article {pmid8675141, year = {1996}, author = {Heene, R and Kolander, D and Knisatschek, H}, title = {[Chronic progressive spinobulbar spasticity (primary lateral sclerosis)].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {64}, number = {5}, pages = {192-203}, doi = {10.1055/s-2007-996385}, pmid = {8675141}, issn = {0720-4299}, mesh = {Aged ; Brain Stem/pathology/physiopathology ; Diagnostic Imaging ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/pathology/physiopathology ; Muscle Spasticity/*diagnosis/pathology/physiopathology ; Nerve Degeneration ; Neurologic Examination ; Pyramidal Tracts/pathology/physiopathology ; }, abstract = {This paper presents an account of chronic-progressive Spinobulbar Spasticity (SBS) or Primary Lateral Sclerosis (PLS), a rare syndrome involving degeneration of the upper motoneuron, on the basis of 6 clinically examined cases. Individuals of both sexes can be affected. Onset of the syndrome occurs around the age of 54, but may sometimes be before 50. Early symptoms of the disease are spasticity on one leg and disturbance of motor skills in one hand. The symptoms generalize within two to three years into tetraspasticity accentuated in the legs, accompanied by pseudo-bulbar dysarthria and dysphagia, which, however, may also be present at the onset of the disease. Compulsive laughing and crying, optokinetic disturbances and facial stiffness develop as additional, though inconstant symptoms. Disease courses of 25 years were observed. Therapy is symptomatic. Fasciculation and muscular atrophy, which would indicate a transition to Amyotrophic Lateral Sclerosis (ALS), were not observed even if the disease was of longstanding. SBS differs from spastic spinal paralysis by virtue of its greater mean age of incidence, its tetraspasticity in conjunction with pseudobulbar signs, and-so far as can be established to date-its apparent non-hereditariness. An influence of exotoxic factors has not been demonstrated so far. The clinical syndrome results from a selective degeneration of the corticospinal and cortico-bulbar tracts up to the motor cortex, where loss of original pyramidal cells has been shown to occur (Pringle et al., 1992). The paper includes a survey of the clinical and neuropathological findings in cases of SBS published so far. Extensive anamnestic and clinical records including TCMS-studies, PET and NMR-CT scans performed in the parasagittal plane are essential for early diagnosis of the syndrome.}, }
@article {pmid8672298, year = {1996}, author = {Hayashi, H}, title = {[To disclose to the patients the diagnosis and information about the likely course of amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {48}, number = {5}, pages = {409-415}, pmid = {8672298}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Ethics, Medical ; Humans ; Physician's Role ; Physician-Patient Relations ; Professional-Family Relations ; Respiratory Paralysis/etiology ; *Truth Disclosure ; }, }
@article {pmid8780963, year = {1996}, author = {Strong, MJ and Grace, GM and Orange, JB and Leeper, HA}, title = {Cognition, language, and speech in amyotrophic lateral sclerosis: a review.}, journal = {Journal of clinical and experimental neuropsychology}, volume = {18}, number = {2}, pages = {291-303}, doi = {10.1080/01688639608408283}, pmid = {8780963}, issn = {1380-3395}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/psychology ; Anterior Horn Cells/physiology ; Brain Mapping ; Cerebral Cortex/physiopathology ; Cognition Disorders/*diagnosis/physiopathology/psychology ; Female ; Humans ; Language Disorders/*diagnosis/physiopathology/psychology ; Male ; Middle Aged ; Speech Disorders/*diagnosis/physiopathology/psychology ; Spinal Cord/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disorder manifesting as a relentless loss of motor capabilities and, ultimately, death. Traditionally thought to affect solely the lower motor neurons and corticospinal tracts, recent studies suggest that the pathogenic process of ALS is more extensive, involving dysfunction of cortical grey and white matter with clinical correlates of impairment in cognition and language. The impact of speech and motor deficits are discussed in relation to the issues of assessment of cognition and language. Three case studies are presented for illustrative purposes. Finally, direction for future research to investigate cognitive dysfunction in ALS are presented.}, }
@article {pmid8763652, year = {1996}, author = {Hugon, J and Vallat, JM and Dumas, M}, title = {[Role of glutamate and excitotoxicity in neurologic diseases].}, journal = {Revue neurologique}, volume = {152}, number = {4}, pages = {239-248}, pmid = {8763652}, issn = {0035-3787}, mesh = {Acute Disease ; Chronic Disease ; Glutamic Acid/*physiology ; Humans ; Nervous System Diseases/*etiology/physiopathology ; Receptors, Glutamate/classification/physiology ; }, abstract = {Glutamate is one of the major excitatory neurotransmitter in the central nervous system. Glutamate acts on 4 different post synaptic receptors; NMDA (N-Methyl-D-aspartate) AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), Kainate and metabotropic receptors. The three former receptors are linked to membrane ion channels whereas metabotropic receptors are coupled with a G protein. Glutamate is involved in the physiologic processes of learning, memory and motricity. Glutamate is also a potent neurotoxin responsible for toxic neuronal death of post synaptic neurons. This action has been denominated excitotoxicity and occurs as a consequence of a prolonged or a strong activation of glutamate post-synaptic receptors. The rise in intracellular calcium seems to play a major role in the pathological events following excitotoxicity. The pathophysiology of several acute or chronic neurological disorders has been linked to excitotoxicity. This excitotoxic process could be present in acute neuronal death observed in stroke, hypoglycemia and traumatisms of the central nervous system and in chronic neuronal degeneration observed in Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease and neuro AIDS. A better knowledge of the cellular events induced by excitotoxicity will allow to consider new therapeutic approaches in various neurological disorders.}, }
@article {pmid8737922, year = {1996}, author = {Love, S}, title = {The search for a transmissible agent in ALS.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {6}, number = {2}, pages = {99-100}, doi = {10.1111/j.1750-3639.1996.tb00789.x}, pmid = {8737922}, issn = {1015-6305}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*virology ; Animals ; Brain/*pathology/virology ; Creutzfeldt-Jakob Syndrome/pathology/transmission ; Humans ; Primates ; Viruses/isolation &amp; purification ; }, }
@article {pmid8936348, year = {1996}, author = {Krieger, C and Lanius, RA and Pelech, SL and Shaw, CA}, title = {Amyotrophic lateral sclerosis: the involvement of intracellular Ca2+ and protein kinase C.}, journal = {Trends in pharmacological sciences}, volume = {17}, number = {3}, pages = {114-120}, doi = {10.1016/0165-6147(96)10004-3}, pmid = {8936348}, issn = {0165-6147}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*metabolism ; Calcium/*metabolism ; Humans ; Protein Kinase C/*metabolism ; Receptors, Glutamate/metabolism ; }, abstract = {The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is characterized by the selective death of motoneurones and corticospinal tract neurones. Abnormalities in excitatory amino acids and their receptors, as well as disordered function of voltage-dependent Ca2+ channels and superoxide dismutase have been reported in ALS patients. Furthermore, the activity of protein kinase C (PKC), a Ca2+, phospholipid-dependent enzyme, is also substantially increased in tissue from ALS patients, suggesting that alterations in intracellular free Ca2+ may be central to many of the diverse pathogenic mechanisms potentially responsible for ALS as discussed here by Charles Krieger and colleagues. Increased PKC activity, in turn, may have direct or indirect effects on neuronal viability and influence the pathogenic process in ALS by modifying the phosphorylation of voltage-dependent Ca2+ channels, neurotransmitter receptors and structural proteins.}, }
@article {pmid8742391, year = {1996}, author = {Tamayo, JA and Ojea, T and Padilla, F and Fernández, O}, title = {[Frontal dementia-motor neuron disease: a case report and literature review].}, journal = {Revista de neurologia}, volume = {24}, number = {127}, pages = {287-289}, pmid = {8742391}, issn = {0210-0010}, mesh = {Dementia/*complications/diagnosis/*physiopathology ; Diagnosis, Differential ; Female ; Frontal Lobe/*physiopathology ; Humans ; Middle Aged ; Motor Neuron Disease/*complications/diagnosis ; }, abstract = {The association between frontal dementia and motor neurone disease has been known for years now although its existence as a nosologic entity in its own right is still subject to debate. Lack of strict histological criteria and inspecificity in complementary tests which might otherwise lend weight to such a diagnosis prevent our considering it as much more than a mere clinical syndrome. We present here the case of a 56 year old female patient who developed a type of dementia with frontal characteristics associated with motor neurone disease. We discuss the clinical picture and review the relevant literature.}, }
@article {pmid8695148, year = {1996}, author = {Martí-Fàbregas, J and Pradas, J}, title = {[Amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {11}, number = {3}, pages = {99-108}, pmid = {8695148}, issn = {0213-4853}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Autoimmunity ; Axons ; Free Radicals ; Glutamates/physiology ; Humans ; Incidence ; Spain/epidemiology ; Terminology as Topic ; }, abstract = {Several aspects of amyotrophic lateral sclerosis are reviewed, with special emphasis on arguments based on etiological and pathogenic theories currently in vogue: free radicals, glutamate-induced toxic excitation, trophic factors, autoimmunity and axon transport. Each of these theories has inspired therapeutic trials, some of which are already completed and others are still in progress. More than one neurodegenerative mechanism may be involved in amyotrophic lateral sclerosis, meaning that it might be necessary to combine several drugs in future trials.}, }
@article {pmid8820402, year = {1996}, author = {Muller, U and Graeber, MB}, title = {Neurogenetic diseases: molecular diagnosis and therapeutic approaches.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {74}, number = {2}, pages = {71-84}, pmid = {8820402}, issn = {0946-2716}, mesh = {Genetic Diseases, Inborn/*diagnosis/etiology/genetics/therapy ; Genetic Therapy ; Humans ; Nervous System Diseases/*diagnosis/etiology/genetics/therapy ; Tissue Transplantation ; }, abstract = {A neurogenetic disorder is defined as a clinical disease caused by a defect in one or more genes which affect the differentiation and function of the neuroectoderm and its derivatives. Genetic findings in various neurogenetic disorders are discussed. Huntington disease, spinobulbar muscular atrophy, and the autosomal dominant cerebellar ataxias are examples of autosomal dominant disorders caused by the expansion of trinucleotides (CAG) within disease genes. The CAG expansions appear to result in a gain of gene function. Prenatal, presymptomatic, and differential diagnostic tests are based on the detection of the repeat expansions. Point mutations within disease genes result in many additional neurogenetic disorders. An autosomal dominant form of amyotrophic lateral sclerosis and various types of craniosynostotic syndromes are described. The mutations in the disease genes also appear to result in a gain of gene function. Molecular diagnosis in these disorders is based on the direct examination of the mutated gene by methods such as single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct DNA sequencing. In many neurogenetic disorders the disease gene has not yet been identified. Here molecular diagnosis relies on indirect approaches based on methods such as the analysis of linkage and of allelic association. Hereditary forms of dystonia are presented as examples. Common sporadic neurological disorders such as Alzheimer and Parkinson diseases frequently have multifactorial causes. Investigations into the molecular basis and the development of diagnostic tests in these two important diseases are discussed. At present no curative therapies exist in neurogenetic disorders. Gene therapeutic approaches, however, provide promise for a cure in at least some of these diseases. Basic principles of gene therapy are explained and attempts at gene therapy in Alzheimer and Parkinson diseases are described. Finally, some of the many obstacles are summarized that must be overcome before gene therapy becomes feasible in most monogenic neurological diseases.}, }
@article {pmid9281286, year = {1996}, author = {Barkhatova, VP and Zavalishin, IA and Kostiuk, AV and Demina, EG and Moskvitina, TA}, title = {[Neurotransmitter changes in amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {96}, number = {4}, pages = {78-85}, pmid = {9281286}, issn = {1997-7298}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Catecholamines/analysis ; Chromatography, High Pressure Liquid ; Chronic Disease ; Female ; Humans ; Male ; Middle Aged ; Neurotransmitter Agents/*analysis ; }, abstract = {The results of investigation concerning both total and cerebral catecholamine metabolism indices in 78 patients with amyotrophic lateral sclerosis (ALS) are presented. The considerable elevation of both blood and liquor norepinephrine level as well as of blood epinephrine concentration was observed together with acute decrease of platelet MAO B activity. The conclusion was made about the participation of catecholamines in exitotoxic mechanisms of motor neurons systems death which was quite characteristic for ALS development. A short literary review was presented concerning the role of neurotransmitters in regulation of motor functions. The neurochemical disturbances which may result in release of exitotoxic mechanisms of ALS were considered too. The consideration of data obtained as well as the analysis of modern conceptions of ALS pathogenesis enable both to determine some ways of ALS pathogenetic therapy and to define the basic directions of further investigations.}, }
@article {pmid9246496, year = {1996}, author = {Siddique, T}, title = {ALS: molecular clues to the jigsaw puzzle of neuronal degeneration.}, journal = {Cold Spring Harbor symposia on quantitative biology}, volume = {61}, number = {}, pages = {699-708}, pmid = {9246496}, issn = {0091-7451}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*pathology ; Animals ; Humans ; Mice ; Mice, Transgenic ; Nerve Degeneration/*physiology ; Superoxide Dismutase/deficiency/genetics/metabolism ; }, }
@article {pmid9044305, year = {1996}, author = {Fujii, J and Myint, T and Okado, A and Kaneto, H and Taniguchi, N}, title = {Oxidative stress caused by glycation of Cu,Zn-superoxide dismutase and its effects on intracellular components.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {11 Suppl 5}, number = {}, pages = {34-40}, doi = {10.1093/ndt/11.supp5.34}, pmid = {9044305}, issn = {0931-0509}, mesh = {Amyotrophic Lateral Sclerosis/etiology ; Animals ; Baculoviridae/genetics ; Binding Sites ; DNA Fragmentation ; Glycosylation ; Humans ; Models, Biological ; Mutagenesis, Site-Directed ; Oxidative Stress/*physiology ; Peptide Fragments/chemistry/metabolism ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/genetics/metabolism ; Superoxide Dismutase/chemistry/genetics/*metabolism ; }, abstract = {It is now evident that the redox state of the cell is a pivotal determinant of the fate of cells. Extensive production of reactive oxygen species (ROI) causes necrotic cell death. Even transient or localized production of ROI may mediate a signal for apoptotic cell death, whereas small amounts of ROI function as an intracellular messenger of some growth stimulants. Accumulating evidence supports the concept that decreases in Cu,Zn-superoxide dismutase (SOD) activity causes apoptotic cell death in neuronal cells. Our data using mutant Cu,Zn-SOD related to familial amyotrophic lateral sclerosis (FALS) suggest that glycation itself and ROI produced from the glycated proteins are involved in many diseases, including diabetic complications. Glycation of important cellular components, including lipid, DNA and proteins, induces dysfunction of these components. Mutant proteins in patients with various hereditary diseases would be destabilized by the glycation reaction, as shown in the case of mutant Cu,Zn-SODs, thereby hyperglycaemic conditions would trigger the onset of some hereditary diseases such as FALS and Alzheimer's disease. Glycation, particularly of antioxidative enzymes, would enhance production of ROI, resulting in oxidative damage to the cells.}, }
@article {pmid9012212, year = {1996}, author = {Schmidbauer, M and Hainfellner, JA and Budka, H}, title = {[Sporadic juvenile amyotrophic lateral sclerosis with neuronal basophil inclusion bodies--a nosologic entity?].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {201-202}, pmid = {9012212}, issn = {0043-5341}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/classification/diagnosis/*pathology ; Brain/pathology ; Child ; Cytoskeleton/pathology ; Diagnosis, Differential ; Humans ; Inclusion Bodies/*pathology ; Motor Neurons/pathology ; Spinal Cord/pathology ; }, abstract = {Among the very few cases of juvenile sporadic amyotrophic lateral sclerosis (ALS), 6 cases with neuronal basophilic inclusion bodies (BI) and clinical features uncommon to "classical" adult sporadic ALS have been reported. We present here two further cases and review the relevant literature. There are clinical and neuropathological similarities of systemic degeneration between juvenile cases with or without BI and juvenile and adult sporadic ALS when the latter is allowed to run a protracted course in patients on respirators. Because of overlapping topology and neuronal cytoskeletal pathology, the nosologic distinction within the ALS spectrum is questionable.}, }
@article {pmid9012210, year = {1996}, author = {Bernat, E}, title = {[Legal limits of assisted death: exemplified by amyotrophic lateral sclerosis].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {195-198}, pmid = {9012210}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Austria ; *Ethics, Medical ; Euthanasia, Passive/*legislation &amp; jurisprudence ; Humans ; Life Support Care/*legislation &amp; jurisprudence ; Suicide, Assisted/legislation &amp; jurisprudence ; Terminal Care/legislation &amp; jurisprudence ; Treatment Refusal/legislation &amp; jurisprudence ; }, abstract = {The article discusses the question to what extent the physician may offer aid in dying to the terminally ill patient. The author comes to the conclusion that the withdrawal of artificial ventilation (after application of anesthesia) is allowed and even a physician's duty if the patient refuses further ventilation. Because the competent patient may refuse treatment at any time, a doctor's willful disregard of his patient's right to self-determination could also be regarded as battery [section 110 Penal Code).}, }
@article {pmid9012209, year = {1996}, author = {Meran, JG and Hamm, M and Ganser, A}, title = {[Patient education--support--help with decisions: ethical aspects in treatment of amyotrophic lateral sclerosis].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {190-194}, pmid = {9012209}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; *Ethics, Medical ; Euthanasia ; Euthanasia, Passive ; Humans ; *Palliative Care ; *Patient Education as Topic ; *Physician-Patient Relations ; Respiratory Insufficiency/psychology/therapy ; *Sick Role ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) develop progressive, degenerative loss of muscle function while retaining mental capacity. This implies special problems of patient information, which should be phase-adapted and patient centered. The difficult task of the physicians requires to provide sufficient information, to enable shared decision-making, without leaving the patient alone. Respiratory failure due to loss of muscle function is often the limiting problem. However, the possible option of ventilatory support opens the question when to stop treatment. It is most important to differentiate between intended mercy-killing and foregoing treatment due to the patient's wish. Discontinuation of treatment is morally justifiable, even required, if the patient refuses further treatment. Advance directives may be helpful to make decisions according to patients' preferences in time.}, }
@article {pmid9012207, year = {1996}, author = {Zeitlhofer, J}, title = {[Clinical aspects of amyotrophic lateral sclerosis].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {182-185}, pmid = {9012207}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Autoimmune Diseases/diagnosis/physiopathology ; Bulbar Palsy, Progressive/diagnosis/physiopathology ; Diagnosis, Differential ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/physiology ; Muscle Spasticity/diagnosis/physiopathology ; Neurologic Examination ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a progressive degenerative disease of upper and lower motor neurons with a prevalence of 4.3/100.000. The clinical symptoms include peripheral weakness and central spastic paresis and bulbar paralysis (weakness of mimic muscles, atrophy of the tongue, dysarthria). The prognosis leads to death within a few years. Pathogenetic factors are free O2-radicals, a disturbance of glutamate-metabolism, abnormal accumulation of neuronal proteins and autoimmunological mechanisms.}, }
@article {pmid8988464, year = {1996}, author = {Kuhn, W and Müller, T}, title = {The clinical potential of Deprenyl in neurologic and psychiatric disorders.}, journal = {Journal of neural transmission. Supplementum}, volume = {48}, number = {}, pages = {85-93}, doi = {10.1007/978-3-7091-7494-4_8}, pmid = {8988464}, issn = {0303-6995}, mesh = {Adult ; Aged ; Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Antidepressive Agents/therapeutic use ; Antipsychotic Agents/therapeutic use ; Child ; Clinical Trials as Topic ; Cross-Over Studies ; Depression/drug therapy ; Double-Blind Method ; Humans ; Mental Disorders/*drug therapy ; Middle Aged ; Monoamine Oxidase Inhibitors/therapeutic use ; Narcolepsy/drug therapy ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Nootropic Agents/*therapeutic use ; Parkinson Disease, Secondary/drug therapy ; Schizophrenia/drug therapy ; Selegiline/*therapeutic use ; Supranuclear Palsy, Progressive/drug therapy ; Tourette Syndrome/drug therapy ; Treatment Outcome ; }, abstract = {This article reviews the results of clinical studies with Deprenyl in various neurologic and psychiatric disorders except Parkinson's disease. Promising results could be observed both in narcolepsy in a dose of at least 20 mg/day in three different trials and in one study of Tourette's syndrome including attention hyperactivity disorders using an average dosis of 8.1 mg/ day. Controversial results were reported for Alzheimer's disease. On the one hand significant improvement of cognitive functions was found by various authors. On the other hand in a more recent study no effect on the progression of the disease could be observed. For depression a higher dosage of deprenyl between 30 to 60 mg/day appears to be necessary for effective treatment. No positive results were found in amyotrophic lateral sclerosis and in tardive dyskinesias.}, }
@article {pmid8950621, year = {1996}, author = {Baxter, RC}, title = {The role of insulin-like growth factors and their binding proteins in tumor hypoglycemia.}, journal = {Hormone research}, volume = {46}, number = {4-5}, pages = {195-201}, doi = {10.1159/000185023}, pmid = {8950621}, issn = {0301-0163}, mesh = {Humans ; Hypoglycemia/drug therapy/*etiology ; Insulin/blood ; Insulin-Like Growth Factor Binding Protein 3/physiology ; Insulin-Like Growth Factor Binding Proteins/*physiology ; Insulin-Like Growth Factor I/*physiology ; Insulin-Like Growth Factor II/*physiology ; Neoplasms/*complications/physiopathology ; }, abstract = {Tumors of nonislet cell origin may overexpress insulin-like growth factor (IGF)-II, leading to hypoglycemia with suppressed serum insulin levels (NICTH). Most of the serum IGF-II in NICTH patients is in precursor forms of 10-15 kD, and may be abnormally glycosylated. In NICTH, IGFs and IGF-binding protein-3 (IGFBP-3) are mainly found in binary complexes of 50-60 kD, instead of the normal ternary complex of about 140 kD with the acid-labile subunit (ALS). Factors contributing to the defect are: (1) low ALS levels, secondary to suppressed growth hormone (GH); (2) defective IGFBP-3 binding to ALS; (3) reduced ability of pro-IGF-II forms to complex normally, and (4) very high levels of other IGFBPs, including IGFBP-2 and IGFBP-6, which might limit the formation of complexes with IGFBP-3. While both GH and glucocorticoids can restore normoglycemia and increase high-molecular-weight IGFBP-3 complexes, corticosteroid treatment suppresses tumor IGF-II, whereas GH can restore normoglycemia despite continuing high IGF-II levels. Both treatments increase serum ALS, IGFBP-3, and IGF-I levels, and decrease IGFBP-2, whereas IGFBP-6 is unaffected. The reversal of hypoglycemia, by surgery, GH, or glucocorticoid treatment, is always accompanied by improved ternary complex formation, emphasizing the importance of the components of this complex, in particular ALS, in normal blood sugar regulation.}, }
@article {pmid8875253, year = {1996}, author = {Siddique, T and Deng, HX}, title = {Genetics of amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {5 Spec No}, number = {}, pages = {1465-1470}, doi = {10.1093/hmg/5.supplement_1.1465}, pmid = {8875253}, issn = {0964-6906}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Chromosomes, Human, Pair 21 ; Copper ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Superoxide Dismutase/*genetics ; Zinc ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by degeneration of motor neurons in the brain and spinal cord. Identification of mutations in the gene for Cu,Zn superoxide dismutase (SOD1) in a subset of ALS families made it possible to develop a transgenic mouse model of ALS and to investigate its pathogenesis. These investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals. Conformational change in the mutant SOD1 protein, especially the distortion of the 'rim' of the electrostatic guidance channel may be central to this toxic gain of function and to the pathogenesis of ALS.}, }
@article {pmid8873431, year = {1996}, author = {Hugon, J}, title = {Riluzole and ALS therapy.}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {185-187}, pmid = {8873431}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Double-Blind Method ; Excitatory Amino Acid Antagonists/*therapeutic use ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/drug effects/physiology ; Neurologic Examination ; Riluzole ; Survival Analysis ; Thiazoles/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder clinically characterized by progressive muscle weakness, amyotrophy, fasciculations and signs of corticospinal tract deficits. The cause is unknown but several hypotheses are currently proposed. In familial forms of ALS, a mutation of the Cu-Zn superoxide dismutase gene was reported in some patients. Autoimmunity and neurofilament dysfunction were also observed. The last hypothesis is linked to excitotoxicity. This cellular phenomenon is associated with the overstimulation of glutamate post-synaptic receptors, leading to neuronal degeneration. Abnormal glutamate metabolism was also discovered in ALS patients. In these conditions, riluzole, a pharmacological agent that reduces glutamate release from nerve terminals, was administered to ALS patients. Riluzole is an anti-convulsant and a neuroprotective agent and specifically blocks sodium channels in their inactivated states. In a recent double blind placebo controlled study, riluzole was given to 77 patients (placebo 78 patients). After 1 year of treatment 58% of the placebo-treated patients were still alive compared to 74% of patients treated with riluzole. The prolonged survival was significant in the overall population and in the bulbar-onset group.}, }
@article {pmid8866125, year = {1996}, author = {Price, DL and Koliatsos, VE and Wong, PC and Pardo, CA and Borchelt, DR and Lee, MK and Cleveland, DW and Griffin, JW and Hoffman, PN and Cork, LC and Sisodia, SS}, title = {Motor neuron disease and model systems: aetiologies, mechanisms and therapies.}, journal = {Ciba Foundation symposium}, volume = {196}, number = {}, pages = {3-13; discussion 13-7}, doi = {10.1002/9780470514863.ch2}, pmid = {8866125}, issn = {0300-5208}, support = {AG 05146/AG/NIA NIH HHS/United States ; NS 20471/NS/NINDS NIH HHS/United States ; NS 27036/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Disease Models, Animal ; Humans ; Mice ; Motor Neuron Disease/etiology/physiopathology/*therapy ; Rats ; }, abstract = {The phenotypes of many neurological diseases, including motor neuron disease (amyotrophic lateral sclerosis; ALS) and Alzheimer's disease (AD), are determined by the vulnerabilities of populations of nerve cells and the character/ evolution of cellular abnormalities. Because different cell types respond selectively to individual trophic factors, these factors may be useful in ameliorating pathology in cells that express their cognate receptors. To test therapies for ALS and AD, investigators require model systems. Although there are a variety of models of ALS, two models are particularly attractive: transgenic mice that express human superoxide dismutase 1 (SOD-1) mutations linked to familial ALS develop paralysis associated with a gain of adverse property of the mutant SOD; and axotomy of facial axons in neonatal rats, a manipulation that causes retrograde cell degeneration, which can be ameliorated by several trophic factors.}, }
@article {pmid8861020, year = {1996}, author = {Mayer, RJ and Tipler, C and Arnold, J and Laszlo, L and Al-Khedhairy, A and Lowe, J and Landon, M}, title = {Endosome-lysosomes, ubiquitin and neurodegeneration.}, journal = {Advances in experimental medicine and biology}, volume = {389}, number = {}, pages = {261-269}, doi = {10.1007/978-1-4613-0335-0_33}, pmid = {8861020}, issn = {0065-2598}, mesh = {Animals ; Bioreactors ; Endosomes/*physiology ; Humans ; Lysosomes/*physiology ; Nerve Degeneration/*physiology ; Nerve Tissue Proteins/*analysis ; Nervous System Diseases/etiology/metabolism/*physiopathology ; Prion Diseases/metabolism/physiopathology/transmission ; Ubiquitins/*analysis ; }, abstract = {Before the advent of ubiquitin immunochemistry and immunogold electron microscopy, there was no known intracellular molecular commonality between neurodegenerative diseases. The application of antibodies which primarily detect ubiquitin protein conjugates has shown that all of the human and animal idiopathic and transmissible chronic neurodegenerative diseases, (including Alzheimer's disease (AD), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD) and scrapie) are related by some form of intraneuronal inclusion which contains ubiquitin protein conjugates. In addition, disorders such as Alzheimer's disease, CJD and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins which may be associated with cytoskeletal reorganisation. Although our knowledge about these diseases is increasing, they remain largely untreatable. Recently, attention has focused on the mechanisms of production of different types of amyloid and the likely involvement within cells of the endosome-lysosome system, organelles which are immuno-positive for ubiquitin protein conjugates. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials or their precursors which subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Such common features of the disease processes give new direction to therapeutic intervention.}, }
@article {pmid8848783, year = {1996}, author = {Ejima, A and Watanabe, C and Koyama, H and Satoh, H}, title = {Analysis of trace elements in the central nerve tissues with inductively coupled plasma-mass spectrometry.}, journal = {The Tohoku journal of experimental medicine}, volume = {178}, number = {1}, pages = {1-10}, doi = {10.1620/tjem.178.1}, pmid = {8848783}, issn = {0040-8727}, mesh = {Adult ; Aged ; Animals ; Female ; Humans ; Infant, Newborn ; Male ; *Mass Spectrometry ; Middle Aged ; Nerve Tissue/*chemistry ; Trace Elements/*analysis ; }, abstract = {To investigate the roles of various elements in neurological disorders, multi-element analysis of limited quantities of samples in the central nervous system is required. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis suits this requirement, but spectral and non-spectral interferences are inevitable. We studied correction methods for the non-spectral interferences by analyzing signals of 21 elements in various concentrations of HNO3 as well as 5 major elements (Na, K, P, Ca, and Cl). Using internal standards, the interferences caused by the major elements were corrected, but the interferences caused by HNO3 were impossible to correct for the elements with high ionization potentials. Thus, we decided to use a standard addition method to correct these interferences. The spectral interferences on Mn and Fe rising from HNO3 or major elements were compared with the signals of samples. Although the interferences on Mn were negligible, those on Fe were considerable and careful blank subtraction were needed. We measured concentrations of elements in the spinal cord of 4 controls and a patient with amyotrophic lateral sclerosis (ALS) using the standard addition method. The concentrations of Mn, Se, Fe, and Zn in the controls were nearly the same as previously reported values, whereas Mn concentrations in the ALS patient were higher.}, }
@article {pmid8833441, year = {1996}, author = {Lee, MK and Cleveland, DW}, title = {Neuronal intermediate filaments.}, journal = {Annual review of neuroscience}, volume = {19}, number = {}, pages = {187-217}, doi = {10.1146/annurev.ne.19.030196.001155}, pmid = {8833441}, issn = {0147-006X}, support = {NS 27036/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport ; Axons/physiology ; Humans ; Intermediate Filaments/*physiology/ultrastructure ; Invertebrates ; Mammals ; Mice ; Mice, Transgenic ; Neurofilament Proteins/biosynthesis/*physiology ; Neurons/*physiology/ultrastructure ; Vertebrates ; }, abstract = {Neurofilaments (NFs) are the most abundant structural components in large-diameter myelinated axons. Assembled as obligate heteropolymers requiring NF-L and substoichiometric amounts of NF-M and/or NF-H, NF investment into axons is essential for establishment of axonal caliber, itself a key determinant of conduction velocity. Use of transgenic mice to increase axonal accumulation of NFs or to express mutant NFs subunits has proven that aberrant organization or assembly of NFs is sufficient to cause disease arising from selective dysfunction and degeneration of motor neurons. Because aberrant accumulation of NFs is a common pathology in a series of motor neuron diseases-including amyotrophic lateral sclerosis-NF misaccumulation, and the resultant disruption in axonal transport, is probably a key intermediate in the pathogenesis of these diseases.}, }
@article {pmid8792146, year = {1996}, author = {Taylor, CG and Stasi, R and Bastianelli, C and Venditti, A and Del Poeta, G and Amadori, S and Sargent, J}, title = {Diagnosis and classification of the acute leukemias: recent advances and controversial issues.}, journal = {Hematopathology and molecular hematology}, volume = {10}, number = {1-2}, pages = {1-38}, pmid = {8792146}, issn = {1082-8893}, mesh = {Acute Disease ; Biotechnology/*trends ; Histocytochemistry ; Humans ; Immunophenotyping ; Karyotyping ; Leukemia/classification/*diagnosis/physiopathology ; Leukemia, Myeloid/diagnosis ; Microscopy, Electron ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; }, abstract = {Although morphology and cytochemistry continue to be the mainstay of the diagnosis of acute leukemia (AL), new developments in immunophenotyping, cytogenetics, molecular biology, and in vitro assays have dramatically improved our understanding of this disease and enabled the identification of entities with distinct clinico-biologic features. Immunophenotyping is essential for diagnosing and subclassifying acute lymphoblastic leukemia (ALL) and is also very helpful in certain types of acute myeloid leukemias (AML), such as AML with minimal differentiation or acute megakaryoblastic leukemia. Cytogenetic findings are clinically relevant for diagnosis and prognosis. Nonrandom chromosomal abnormalities such as t(15;17)(q22;q12) or t(1;19)(q23;p13) have been so closely associated with distinct types of acute leukemias that their recognition can allow diagnosis independent of the other criteria. Molecular analysis is a powerful method in the assessment of the malignant potential, clonality, and classification of the ALs. It has become clear that in some leukemias a proportion of patients exhibit the biologically relevant molecular defect in the absence of a karyotypic equivalent. On the other hand apparently uniform chromosomal abnormalities such as the t(1;19), t(9;22), t(8;14), or t(15;17) may differ at the molecular level. In vitro assays can evaluate the growth pattern and cell-cycle kinetics of leukemic cells, as well as their sensitivity to therapeutic agents. All these data are relevant to the management of AL. Because the French-American-British (FAB) classification does not fully correlate with much of this new information, alternative classifications have been proposed. In this review we concentrate on recent diagnostic contributions resulting from advances in biotechnology and discuss some of the points that arouse controversy in the single classifications.}, }
@article {pmid8743979, year = {1996}, author = {Romero, FJ}, title = {Antioxidants in peripheral nerve.}, journal = {Free radical biology &amp; medicine}, volume = {20}, number = {7}, pages = {925-932}, doi = {10.1016/0891-5849(95)02183-3}, pmid = {8743979}, issn = {0891-5849}, mesh = {Alcoholism/complications ; Animals ; Antioxidants/*metabolism ; Diabetic Neuropathies/metabolism ; Humans ; Oxidative Stress/*physiology ; Peripheral Nerves/*metabolism ; Peripheral Nervous System Diseases/etiology/metabolism ; }, abstract = {Oxidative stress and antioxidants have been related in a wide variety of ways with nervous tissue. This review attempts to gather the most relevant information related to a) the antioxidant status in non pathologic nervous tissue; b) the hypothesis and evidence for oxidative stress (considered as the disequilibrium between prooxidants and antioxidants in the cell) as the responsible mechanism of diverse neurological diseases; and c) the correlation between antioxidant alterations and neural function, in different experimental neuropathies. Decreased antioxidant availability has been observed in different neurological disorders in the central nervous system, for example, Parkinson's disease, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, cerebral ischaemia, etc. Moreover, the experimental manipulation of the antioxidant defense has led in some cases to interesting experimental models in which electrophysiological alterations are associated with the metabolic modifications induced. In view of the electrophysiological and biochemical effects of some protein kinase C inhibitors on different neural experimental models, special attention is dedicated to the role of this kinase in peripheral nervous tissue. The nervous tissue, central as well as peripheral, has two main special features that are certainly related to its antioxidant metabolism: the lipid-enriched membrane and myelin sheaths, and cellular excitability. The former explains the importance of the glutathione (GSH)-conjugating activity towards 4-hydroxy-nonenal, a biologically active product of lipid peroxidation, present in nervous tissue and in charge of its inactivation. The impairment of the latter by oxidative damage or experimental manipulation of antioxidant metabolism is discussed. Work on different experimental neuropathies from author's laboratory has been primarily used to provide information about the involvement of free radical damage and antioxidants in peripheral nerve metabolic and functional impairment.}, }
@article {pmid8741231, year = {1996}, author = {Festoff, BW}, title = {Amyotrophic lateral sclerosis: current and future treatment strategies.}, journal = {Drugs}, volume = {51}, number = {1}, pages = {28-44}, pmid = {8741231}, issn = {0012-6667}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Apoptosis/drug effects ; Ciliary Neurotrophic Factor ; Clinical Trials as Topic ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Nerve Tissue Proteins/therapeutic use ; Riluzole ; Thiazoles/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, enigmatic disorder characterised by relentless progression of muscle wasting and weakness until death ensues due to respiratory muscle failure. Intellectual functions are usually spared. ALS, known also as motor neuron disease (MND) in the UK, maladie de Charcot in France and Lou Gehrig's disease in the US, is usually sporadic, but between 5 and 10% of all cases are hereditary, usually inherited as autosomal dominant. Previously thought to be untreatable, as well as incurable, just in the last 3 years ALS has been the greatest clinical application of recent exciting break-throughs in preclinical neurobiology research. Although definitive information regarding the cause(s) and pathogenesis of ALS still escapes us, meaningful demonstration of intercession in the downhill course with specific therapy has been suggested, giving reason to be hopeful, if cautiously and critically optimistic. This review focuses on the recent work from the fields of growth/trophic factors, glutamate/neurotoxicity, neuroprotection and proteases and inhibitors, as well as the approaches to measuring specific effects in patients with the illness. It ends with a eye to the horizon, and the future, and where ALS treatment strategies may be heading after the millennium.}, }
@article {pmid8734302, year = {1996}, author = {Jenner, P}, title = {Oxidative stress in Parkinson's disease and other neurodegenerative disorders.}, journal = {Pathologie-biologie}, volume = {44}, number = {1}, pages = {57-64}, pmid = {8734302}, issn = {0369-8114}, mesh = {Alzheimer Disease/*metabolism ; Basal Ganglia Diseases/*metabolism ; Cell Death/physiology ; Dihydroxyphenylalanine/*therapeutic use ; Dopamine Agents/*therapeutic use ; Glutathione/metabolism ; Humans ; Oxidative Stress/*physiology ; Parkinson Disease/drug therapy/*metabolism ; }, abstract = {The cause of cell death in neurodegenerative diseases remains unknown but the formation of free radicals and the occurrence of oxidative stress may be a common component of many, if not all, such disorders. For example, in substantia nigra in Parkinson's diseases key alterations occur, in iron handling, mitochondrial function and antioxidant defences, particularly reduced glutathione. These indices of oxidative stress are accompanied by evidence of free radical mediated damage in the form of increased lipid peroxidation and oxidation of DNA bases. The alterations in oxidative stress occurring in Parkinson's disease appear not be related to the administration of L-DOPA. Some alterations of oxidative stress are found in other basal ganglia in degenerative disorders (multiple system atrophy, progressive supranuclear palsy, Huntington's disease) but these have not been investigated to the same extent. Similarly, examination of biochemical changes occurring in Alzheimer's disease, motor neurone disease and diabetic neuropathy also suggest the involvement of free radical mediated mechanisms as a component of neurodegeneration. It is probable that irrespective of the primary cause of individual neurodegenerative disorder, the onset of oxidative stress is a common mechanism by which neuronal death occurs and which contributes to disease progression. Clearly, therapeutic strategies aimed at limiting free radical production and oxidative stress and/or damage may slow the advance of neurodegenerative disease.}, }
@article {pmid8734301, year = {1996}, author = {Gurney, ME and Cutting, FB and Zhai, P and Andrus, PK and Hall, ED}, title = {Pathogenic mechanisms in familial amyotrophic lateral sclerosis due to mutation of Cu, Zn superoxide dismutase.}, journal = {Pathologie-biologie}, volume = {44}, number = {1}, pages = {51-56}, pmid = {8734301}, issn = {0369-8114}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/prevention &amp; control ; Animals ; Chromosome Aberrations/*genetics ; Chromosome Disorders ; *Chromosomes, Human, Pair 21 ; Excitatory Amino Acid Antagonists ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Riluzole ; Superoxide Dismutase/*genetics ; Thiazoles/therapeutic use ; Vitamin E/therapeutic use ; }, abstract = {Oxidative mechanisms of damage have been implicated indirectly in the damage to brain tissue caused acutely by ischemia or chronically by neurodegenerative diseases. A direct link between pathogenesis and antioxidant enzyme systems has come from studies of a genetic form of amyotrophic lateral sclerosis (ALS). ALS causes the degeneration of motor neurons in cortex, brainstem and spinal cord with consequent progressive paralysis and death. The disease occurs in both sporadic and familial forms. Some 20% of kindreds in which ALS is inherited in an autosomal dominant fashion have mutations in the gene (SOD1) encoding Cu, Zn superoxide dismutase (SOD). Several SOD1 mutations have been shown by ourselves and others to cause motor neuron disease when expressed at high levels in transgenic mice, whereas transgenic mice expressing comparable amounts of wild-type human SOD do not show clinical disease. Thus, we have argued that motor neuron disease is caused by gain-of-function mutations in the human SOD1 gene. Our current experiments investigate the link between mutation of SOD1 and oxidative pathways of damage.}, }
@article {pmid8725383, year = {1996}, author = {Simonian, NA and Coyle, JT}, title = {Oxidative stress in neurodegenerative diseases.}, journal = {Annual review of pharmacology and toxicology}, volume = {36}, number = {}, pages = {83-106}, doi = {10.1146/annurev.pa.36.040196.000503}, pmid = {8725383}, issn = {0362-1642}, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Apoptosis/physiology ; Arachidonic Acid/metabolism ; Electron Transport ; Endopeptidases/metabolism ; Enzyme Activation ; Free Radicals/adverse effects/metabolism ; Humans ; Mitochondria/metabolism ; Necrosis/physiopathology ; Nerve Degeneration/*physiology ; Nitric Oxide/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Parkinson Disease/physiopathology ; }, abstract = {Oxidative stress refers to the cytopathologic consequences of a mismatch between the production of free radicals and the ability of the cell to defend against them. Growing data from experimental models and human brain studies suggest oxidative stress may play an important role in neuronal degeneration in diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Mitochondrial oxidative metabolism, nitric oxide, phospholipid metabolism, and proteolytic pathways are potential sources of intracellular free radicals. Alterations in free radical defense systems may also contribute to oxidative stress. A net increase in reactive oxygen species can produce damage to lipids, proteins, and DNA and induce necrosis or apoptosis. Elucidating the pathways important in the production of and defense from free radicals may be important in devising new pharmacologic strategies to slow or halt neuronal degeneration.}, }
@article {pmid8587178, year = {1996}, author = {Yase, Y}, title = {[Amyotrophic lateral sclerosis--causative role of trace elements].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {54}, number = {1}, pages = {123-128}, pmid = {8587178}, issn = {0047-1852}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism ; Animals ; Bone and Bones/metabolism ; Central Nervous System/metabolism ; Humans ; *Trace Elements/adverse effects/deficiency ; }, abstract = {Although numerous hypotheses have been proposed for the cause of amyotrophic lateral sclerosis (ALS), conclusive decision still remains vague. Recent epidemiological investigation disclosed an aggregation of ALS cases in the Western Pacific, including the Kii Peninsula of Japan, the island of Guam in Marianas and West New Guinea. Extensive environmental studies in these foci indicated an important role of trace elements in ALS etiology. It is postulated that chronic environment deficiencies of calcium and magnesium may provoke secondary hyperparathyroidism, resulting in increased intestinal absorption of toxic metals under the presence of excess levels of divalent or trivalent cations and lead to the mobilization of calcium and metals from the bone and deposition of these elements in nervous tissue. This hypothesis, called metal-induced calcifying degeneration of CNS, has been supported by experimental studies using several animal species.}, }
@article {pmid8838230, year = {1995}, author = {Aguilera, AJ}, title = {Molecular genetic advances in neurodegenerative disorders.}, journal = {Clinics in laboratory medicine}, volume = {15}, number = {4}, pages = {915-926}, pmid = {8838230}, issn = {0272-2712}, mesh = {Alzheimer Disease/etiology/genetics/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; DNA Mutational Analysis ; Genetics, Medical ; Humans ; Huntington Disease/genetics/pathology ; Nerve Degeneration ; Nervous System Diseases/*diagnosis/genetics/therapy ; }, abstract = {Advances in molecular genetics have had a major impact on our understanding of the pathogenesis of neurologic disorders. This article discusses molecular genetic contributions to our knowledge of Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, as well as their implications for diagnosis and treatment. Specific, sensitive testing for Huntington's disease is now possible; elucidation of the pathogenesis of familial amyotrophic lateral sclerosis has been achieved and has launched promising drug trials; and the heterogeneity and pathogenetic complexity of Alzheimer's disease have been revealed.}, }
@article {pmid8805422, year = {1995}, author = {Brown, RH}, title = {Superoxide dismutase in familial amyotrophic lateral sclerosis: models for gain of function.}, journal = {Current opinion in neurobiology}, volume = {5}, number = {6}, pages = {841-846}, doi = {10.1016/0959-4388(95)80114-6}, pmid = {8805422}, issn = {0959-4388}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Humans ; Models, Neurological ; Superoxide Dismutase/*physiology ; }, }
@article {pmid8752463, year = {1995}, author = {Murakami, N and Yoshida, M}, title = {[Reappraisal of amyotrophic lateral sclerosis with dementia].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1560-1562}, pmid = {8752463}, issn = {0009-918X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/pathology ; Atrophy ; Dementia/*etiology ; Diagnosis, Differential ; Female ; Frontal Lobe/pathology/physiopathology ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) with dementia is characterized by rapidly progressive dementia and motor neuron involvement. The age at onset in 12 sporadic cases ranged from 43 years to 78 years. The initial symptoms are dementia, such as uninhibited behavior and personality change in most patients. Both dementia and motor neuron involvement appear within 1 or 2 years of the onset. The clinical picture of motor neuron disturbance was bulbar-type ALS. In ALS-dementia, lower motor neuron sign is predominant than upper motor neuron sign. The pattern of dementia indicated impaired frontal lobe function, confirmed by frontal sign such as perseveration, forced grasping and utilization behavior. These neurological signs are significant in association with the frontal lesion on CT, MRI and single photon emission computed tomography. The pathological findings show frontotemporal atrophy, mild non-specific neuronal loss of cortical superficial layer, fibrous gliosis of subcortical white matter, degeneration of substantia nigra and motor neuron involvement. The clinicopathological findings resembled those of dementia of frontal type and are distinct from those of Alzheimer's disease. We thus consider that the combination of motor neuron disease and dementia is a new clinicopathological entity, quite distinct from ALS or other dementias, as Yuasa and Mitsuyama proposed earlier.}, }
@article {pmid8752462, year = {1995}, author = {Tayama, N}, title = {[Dysphagia in amyotrophic lateral sclerosis--the mechanism and managements].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1557-1559}, pmid = {8752462}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology/*prevention &amp; control ; Humans ; *Laryngectomy ; Pneumonia, Aspiration/etiology/prevention &amp; control ; Prognosis ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) raises progressive dysphagia that causes aspiration. This diseases affects oral phase first and then pharyngeal phase of swallowing. Aspiration pneumonia by dysphagia becomes major problem from clinical aspect to cause aggravation of vital prognosis. We explain the mechanism of dysphagia from deglutition dynamics and discuss the clinical managements. Several functional operations such as cricopharyngeal myotomy, laryngeal suspension and so forth, have been applied to prevent aspiration, with satisfactory results in cases with mild dysphagia. However, in cases of ALS patients with severe aspiration, the results are poor. Then we have to divide airway from digestive tract completely to prevent aspiration by laryngectomy. However, the larynx is a multi-functional organ, loss of the larynx does improve the swallowing but loose phonatory function. We need to evaluate a deglutition function before starting of treatments of dysphagia. Besides, we also need to put hopes and life style of patients in consideration. We have to be very careful to choose the way of surgical treatment and the time of operation. We can conclude that laryngectomy is useful for vital prognosis and amelioration of QOL in ALS patients.}, }
@article {pmid8752461, year = {1995}, author = {Yagishita, A}, title = {[MR imaging of the brain of amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1554-1556}, pmid = {8752461}, issn = {0009-918X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Brain/*pathology/physiopathology ; Female ; Humans ; *Magnetic Resonance Imaging ; Male ; Middle Aged ; Nerve Degeneration ; }, abstract = {To investigate imaging characteristics of amyotrophic lateral sclerosis (ALS), the author reviewed magnetic resonance (MR) images of the brain of 50 ALS patients. MR images demonstrated abnormal foci in the internal capsule in nine patients, representing degeneration of the corticospinal tract (CST). These foci were hyperintense relative to cortical gray matter on T2-weighted images and still hyperintense relative to white matter on proton-density-weighted images. In contrast, normal hyperintense foci in the internal capsule representing fibers of the CST were isointense to gray matter on T2-weighted images and iso- or hypointense to white matter on proton-density-weighted images. T2-weighted images showed low signal within the motor cortex in three patients, indicating degeneration of the cortex. The images also demonstrated hyperintense lesions in the white matter of the precentral gyri in all of them, indicating degeneration of the CST. Other studies, however, reported that low signal within the motor cortex in aged normal controls was frequently observed. Therefore, the low signal was a useful finding only for young ALS patients. T2-weighted images of a patient showed hyperintense lesions in the body of the corpus callosum, representing degeneration of the commissural fibers interconnecting the motor cortices bilaterally.}, }
@article {pmid8752460, year = {1995}, author = {Chen, KM}, title = {[Disappearance of ALS from Guam: implications for exogenous causes].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1549-1553}, pmid = {8752460}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; Animals ; Ecology ; Genetics, Population ; Guam/epidemiology ; Humans ; Nutritional Status ; Risk Factors ; Socioeconomic Factors ; }, abstract = {The author reports the disappearance of amyotrophic lateral sclerosis (ALS) from Guam over past 30 years, which coincided with rapid changes in the ecology, socioeconomy, and westernization of the life style. This slow but steady decline is believed to be the consequences of radical changes from food collection to wage-based life style and dietary improvement in recent years and elimination of exogenous factors. Those risk factor(s) are believed to be the environmental trace metals which must have triggered the accelerated oxidative stresses in the motor neurons of genetically susceptible population. Changing Epidermiology: 1. The annual incidence of 70/100,000 in 1960s down to 7/100,000 in 1990s, and remained unchanged for past 15 years. 2. Upward shift of age at onset by 10 years and at death by 8 years and even out of sex ratio. 3. Birth cohort analysis showed less risks for those born after 1920. No ALS cases born after 1945. 4. No increase in the incidence of ALS among non-Chamorros transients of Guam and Marianas during W.W.II. 5. Long-term resident non-Charmorro and half-Chamorros on Guam are also affected. 6. Charmorro migrants to U.S. Mainland are affected after long absence from Guam. 7. Incubation period for both ways is estimated to be 18 approximately 20 years. 8. Other forms of dementias like Alzheimer disease (AD) and vascular dementias are on the rise and the leading cause of death is cerebro- and cardiovascular diseases. 9. ALS is also declining in past 10 approximately 15 years in Kii peninsula, and West New Guinea. Changing Ecology of Guam: 1. One third of Island land was used for construction of huge military bases after W.W.II. 2. Urbanization of villages including concrete houses, deep well water supply, sewage, and electrification. 3. Tourism boom: high-rise hotels, development of 7 golf courses and other recreational facilities resulted in loss of flora and erosions of soil. Socioeconomic Changes: 1. Shift in population demography; Efflux of Chamorros and influx of aliens; Chamorros less than 50% by 1990. 2. Tourists passed 1 million in 1994. 3. Automobiles 1 car/1.5 person. 4. Westernization: After W.W.II, almost free access to Military Commissary for imported food and appliances. 5. Life style: from food collection to wage-based society. Genetic Studies: 1. Familial aggregations, but no clear-cut Mendelian inheritance. 2. Segregation analysis: no absolute genetic or environmental cause but additive gene component may play a role in genetic susceptibility and basis for geographical clustering. 3. Absence of Apo-E or Mu/Zn SOD genes. 4. Recent discovery of mtDNA Complex I deficiency in Parkinsonism-dementia cases suggests mitochondrial DNA abnormality. Comparative Environmental Studies: 1. Environmental studies in three hyperendemic areas in the Western Pacific--Kii, Marianas, and west New Guinea, where strikingly high incidences of ALS is known to occur, found the identical geochemical environment--low Ca, Mg, and Zn and high A1, Mn, Fe, Si, in the garden soil and drinking water. 2. Exogenous etiologic factors that are absent from primitive culture of Auyu and Jackai tribes in West New Guinea were eliminated. 3. Cycad neurotoxicity has been excluded. 4. Suspected exogenous agents that are common in these 3 hyperendemic areas are (a) locally grown vegetables, starchy roots, and reef fish; (b) surface water containing soluble organic minerals from red laterites; (c) rain water that is chemically pure and lack of essential minerals. Pathogenic Speculation: Chronic dietary deficiency since birth in Ca, Mg and Zn induced excessive absorption of divalent cations which accelerates oxidant-mediated neuronal degenerations in a genetically susceptible population. The process is probably carried through interactions between cytoskeletal abnormality of the neuron, aging process, abnormal proteins, and mitochondrial dysfunction.}, }
@article {pmid8752459, year = {1995}, author = {Nakano, R}, title = {[Familial amyotrophic lateral sclerosis and mutations in the Cu/Zn superoxide dismutase gene].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1546-1548}, pmid = {8752459}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Animals ; Chromosomes, Human, Pair 21/genetics ; Free Radicals ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/physiology ; *Mutation ; Nerve Degeneration ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder affecting primarily upper and lower motor neurons. In all cases of ALS, approximately 5-10% of cases are familial (FALS). Missense mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been demonstrated in some families of FALS since 1993. We have also identified a novel missense mutation (substitution of Thr for Ala4) in exon 1 in a Japanese FALS family, and clarified the pathological findings of a patient in this family were typical of FALS with posterior column involvement. However, the mechanism by which the mutations in SOD1 lead to ALS is unknown. It is now clear that the mutations in SOD1 reduce total SOD activities only by 30-60%, and there is doubt whether a reduction in enzymatic function of this magnitude suffices to cause the neuronal loss. Recently, transgenic mice expressing the mutant SOD1 demonstrate motor neuron degeneration despite an increased level of SOD activity. The process of motor neuron degeneration in FALS might be mediated by some novel functions of the mutant SOD1 protein.}, }
@article {pmid8752458, year = {1995}, author = {Takahashi, R}, title = {[Deficiency of human ciliary neurotropic factor (CNTF) is not causally related to amyotrophic lateral sclerosis (ALS)].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1543-1545}, pmid = {8752458}, issn = {0009-918X}, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Ciliary Neurotrophic Factor ; Genotype ; Humans ; Mice ; Mice, Knockout ; Mutation ; Nerve Tissue Proteins/*deficiency/genetics ; RNA, Messenger/genetics ; }, abstract = {Ciliary neurotrophic factor (CNTF) promotes the survival of motor neurons in vitro and in vivo. A recent report showed that disruption of the CNTF gene in mice caused motor neuron degeneration. We have found a null mutation in the human CNTF gene. The mutated allele shows a G to A transition producing a new splice acceptor site and the resulting mRNA species codes for an aberrant protein. Analysis of tissue samples demonstrated that the mutated allele expressed only the mutated mRNA species. In 391 Japanese people tested, 61.9% were normal homozygotes, 35.8% heterozygotes and 2.3% mutant homozygotes. The distribution of the three genotypes is similar in healthy and neurological disease subjects including ALS patients. Our findings indicate that CNTF deficiency is not causally related to ALS.}, }
@article {pmid8815363, year = {1995}, author = {Vanacore, N and Corsi, L and Fabrizio, E and Bonifati, V and Meco, G}, title = {[Relationship between exposure to environmental toxins and motor neuron disease: a case report].}, journal = {La Medicina del lavoro}, volume = {86}, number = {6}, pages = {522-533}, pmid = {8815363}, issn = {0025-7818}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/chemically induced ; Animals ; Cats ; Environmental Pollutants/*adverse effects ; Humans ; Lead Poisoning/etiology ; Male ; Mercury Poisoning/etiology ; Metals/*adverse effects ; Middle Aged ; Motor Neuron Disease/*chemically induced ; Occupational Diseases/*chemically induced ; Occupations ; Primates ; Rats ; Risk Factors ; Solvents/*adverse effects ; Time Factors ; }, abstract = {A case is reported of amyotrophic lateral sclerosis with occupational exposure to solvents and metals. The environmental toxin theory of motorneuron disease, including aspects of epidemiological, clinical, experimental and individual susceptibility is discussed. An overall evaluation of animal and human data was made using a methodological approach developed by the International Agency for Research on Cancer and a Scandinavian group of experts. It is concluded that there is a probable linkage between metals/solvents exposure and motorneuron disease.}, }
@article {pmid8745627, year = {1995}, author = {Vercelletto, M and Bertout, C and Geffriaud, J and Labat, JJ and Magne, C and Fève, JR}, title = {[Frontal type dementia and amyotrophic lateral sclerosis. 3 cases with (HmPAO Tc99m) single-photon emission tomography study].}, journal = {Revue neurologique}, volume = {151}, number = {11}, pages = {640-647}, pmid = {8745627}, issn = {0035-3787}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnostic imaging/physiopathology ; Dementia/*complications/diagnostic imaging/physiopathology ; *Frontal Lobe ; Humans ; Male ; *Organotechnetium Compounds ; *Oximes ; Technetium Tc 99m Exametazime ; *Tomography, Emission-Computed, Single-Photon ; }, abstract = {Three cases of rapid onset neuropsychological frontal dementia preceded the development of sporadic amyotrophic lateral sclerosis by 12 to 24 months. HmPAO Tc99m scintigraphy demonstrated hypoactivity in the cortex, predominantly in the frontal region. Three hypotheses are discussed: 1) coincidence between two degenerative diseases, Alzheimer's disease or Pick's disease and ALS; 2) an amyotrophic form of Creutzfeld Jakob disease; 3) pre-senile dementia associated with a motoneuron disease, a clinical pathology entity recently described by Mitzuyama.}, }
@article {pmid8599726, year = {1995}, author = {Apfel, SC and Kessler, JA}, title = {Neurotrophic factors in the therapy of peripheral neuropathy.}, journal = {Bailliere's clinical neurology}, volume = {4}, number = {3}, pages = {593-606}, pmid = {8599726}, issn = {0961-0421}, mesh = {Diabetic Neuropathies ; Humans ; Insulin-Like Growth Factor I ; Insulin-Like Growth Factor II ; Nerve Growth Factors/therapeutic use ; Peripheral Nervous System Diseases/drug therapy/*etiology ; Receptors, Growth Factor/physiology ; }, abstract = {Neurotrophic factors are proteins that promote the survival and differentiation of specific populations of neurones. With the successful cloning and large-scale production of many different neurotrophic factors, it has become practical to consider their application in the treatment of neurological disease. Several groups of neurotrophic factors hold particular promise for the therapy of peripheral nervous system disease in the near future. These include the neurotrophin gene family, cytokines such as CNTF and the IGF family. Evidence is accumulating that an abnormal availability of some of these factors may contribute towards the pathophysiology of some types of neuropathy, most notably diabetic neuropathy. Pre-clinical studies in animal models have demonstrated the likely efficacy of factors such as NGF for small-fibre sensory neuropathy, BDNF, CNTF and IGF-I for motor neurone disease, and NT-3 for large-fibre neuropathy. Clinical trials of several growth factors are currently underway for the treatment of peripheral nerve disease, and other clinical trials are currently being planned.}, }
@article {pmid8599725, year = {1995}, author = {Sendtner, M}, title = {Molecular biology of neurotrophic factors.}, journal = {Bailliere's clinical neurology}, volume = {4}, number = {3}, pages = {575-591}, pmid = {8599725}, issn = {0961-0421}, mesh = {Animals ; Humans ; Insulin-Like Growth Factor I/cerebrospinal fluid ; Insulin-Like Growth Factor II/cerebrospinal fluid ; Mice ; Nerve Growth Factors/*therapeutic use ; Peripheral Nervous System Diseases/drug therapy ; RNA, Messenger ; Rats ; Receptors, Growth Factor/*physiology ; }, abstract = {The survival and functional maintenance of spinal motoneurones and of peripheral neurones, such as sensory, sympathetic and parasympathetic neurones, has been shown to depend on neurotrophic factors, both during the period of developmental cell death and in adulthood. A variety of such factors has been identified over recent years, among them factors of the NGF gene family, for example BDNF, NT-3, NT-4/5 and NT-6, and factors such as CNTF and LIF acting on neuronal target cells via receptor components shared with cytokines such as IL-6. In addition, pluripotent mitogens, such as IGF-I and IGF-II can support the survival of a variety of neuronal cell types, including spinal motoneurones both in cell culture and in vivo. The establishment of mice in which the genes for these factors and their receptors have been inactivated by homologous recombination has been a major step in the understanding of their physiological function. It is not clear so far whether or not similar gene defects in human are associated with any neurological disease. However, some of these factors have been demonstrated to be effective in animal models of neuropathy and motoneurone disorders, so that first clinical trials using these factors for symptomatic treatment of amyotrophic lateral sclerosis (ALS) and peripheral neuropathies have already been initiated.}, }
@article {pmid8592323, year = {1995}, author = {de Belleroche, J and Orrell, R and King, A}, title = {Familial amyotrophic lateral sclerosis/motor neurone disease (FALS): a review of current developments.}, journal = {Journal of medical genetics}, volume = {32}, number = {11}, pages = {841-847}, pmid = {8592323}, issn = {0022-2593}, mesh = {Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/classification/epidemiology/*genetics ; Animals ; Chromosomes, Human, Pair 21/genetics ; Ciliary Neurotrophic Factor ; Disease Models, Animal ; Female ; Genes, Dominant ; Genetic Linkage ; Genetic Testing ; Humans ; Infant ; Intermediate Filaments/pathology ; Male ; Mice ; Middle Aged ; Motor Neurons/pathology ; Nerve Tissue Proteins/deficiency/genetics ; Neurofilament Proteins/analysis ; Pedigree ; Point Mutation ; Superoxide Dismutase/chemistry/*deficiency/genetics ; }, }
@article {pmid8573963, year = {1995}, author = {Cory, PR and Gidal, Be}, title = {Potential use of gabapentin and lamotrigine.}, journal = {The Annals of pharmacotherapy}, volume = {29}, number = {11}, pages = {1160-1161}, doi = {10.1177/106002809502901116}, pmid = {8573963}, issn = {1060-0280}, mesh = {Acetates/pharmacology/*therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anticonvulsants/pharmacology/*therapeutic use ; Clinical Trials as Topic ; *Cyclohexanecarboxylic Acids ; Drugs, Investigational/pharmacology/therapeutic use ; Gabapentin ; Humans ; Lamotrigine ; Triazines/pharmacology/*therapeutic use ; *gamma-Aminobutyric Acid ; }, abstract = {Based on the proposed neurotoxic etiology of ALS and possible actions of gabapentin and lamotrigine, there is some reason to hope for a beneficial response when using these agents in patients with ALS. However, because of the lack of evidence supporting this use, the cost of treatment, and the risk of adverse effects, there is no rationale for this use before larger, controlled clinical trials are completed.}, }
@article {pmid8560109, year = {1995}, author = {Zaritsky, A and Nadkarni, V and Hazinski, MF and Foltin, G and Quan, L and Wright, J and Fiser, D and Zideman, D and O'Malley, P and Chameides, L}, title = {Recommended guidelines for uniform reporting of pediatric advanced life support: the Pediatric Utstein Style. A statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council.}, journal = {Resuscitation}, volume = {30}, number = {2}, pages = {95-115}, doi = {10.1016/0300-9572(95)00884-v}, pmid = {8560109}, issn = {0300-9572}, mesh = {Child ; Data Collection/standards ; *Emergency Medical Services ; Europe ; Humans ; *Life Support Care ; *Pediatrics ; Records/standards ; *Resuscitation ; Terminology as Topic ; United States ; }, abstract = {This consensus document is an attempt to provide an organized method of reporting pediatric ALS data in out-of-hospital, emergency department, and in-hospital settings. For this methodology to gain wide acceptance, the task force encourages development of a common data set for both adult and pediatric ALS interventions. In addition, every effort should be made to ensure that consistent definitions are used in all age groups. As health care changes, we will all be challenged to document the effectiveness of what we currently do and show how new interventions or methods of treatment improve outcome and/or reduce cost. Only through collaborative research will we obtain the necessary data. For these reasons, and to improve the quality of care and patient outcomes, it is the hope of the task force that clinical researchers will follow the recommendations in this document. It is recognized that further refinements of this statement will be needed; these recommendations will improve only when researchers, clinicians, and EMS personnel use them, work with them, and modify them. Suggestions, recommendations, and other comments aimed at improving the reporting of pediatric resuscitation should be sent to Arno Zaritsky, MD, Eastern Virginia Medical School, Children's Hospital of The King's Daughter, Division of Critical Care Medicine, 601 Children's Lane, Norfolk, VA 23507.}, }
@article {pmid7671387, year = {1995}, author = {Zaritsky, A and Nadkarni, V and Hazinski, MF and Foltin, G and Quan, L and Wright, J and Fiser, D and Zideman, D and O'Malley, P and Chameides, L}, title = {Recommended guidelines for uniform reporting of pediatric advanced life support: the pediatric Utstein Style. A statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council. Writing Group.}, journal = {Circulation}, volume = {92}, number = {7}, pages = {2006-2020}, doi = {10.1161/01.cir.92.7.2006}, pmid = {7671387}, issn = {0009-7322}, mesh = {Child ; Data Collection/standards ; *Emergency Medical Services ; Europe ; Humans ; *Life Support Care ; *Pediatrics ; Records/standards ; *Resuscitation ; Terminology as Topic ; United States ; }, abstract = {This consensus document is an attempt to provide an organized method of reporting pediatric ALS data in out-of-hospital, emergency department, and in-hospital settings. For this methodology to gain wide acceptance, the task force encourages development of a common data set for both adult and pediatric ALS interventions. In addition, every effort should be made to ensure that consistent definitions are used in all age groups. As health care changes, we will all be challenged to document the effectiveness of what we currently do and show how new interventions or methods of treatment improve outcome and/or reduce cost. Only through collaborative research will we obtain the necessary data. For these reasons, and to improve the quality of care and patient outcomes, it is the hope of the task force that clinical researchers will follow the recommendations in this document. It is recognized that further refinements of this statement will be needed; these recommendations will improve only when researchers, clinicians, and EMS personnel use them, work with them, and modify them. Suggestions, emendations, and other comments aimed at improving the reporting of pediatric resuscitation should be sent to Arno Zaritsky, MD, Eastern Virginia Medical School, Children's Hospital of the King's Daughter, Division of Critical Care Medicine, 601 Children's Lane, Norfolk, VA 23507.}, }
@article {pmid7567346, year = {1995}, author = {Zaritsky, A and Nadkarni, V and Hazinski, MF and Foltin, G and Quan, L and Wright, J and Fiser, D and Zideman, D and O'Malley, P and Chameides, L}, title = {Recommended guidelines for uniform reporting of pediatric advanced life support: the pediatric Utstein style. A statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council.}, journal = {Pediatrics}, volume = {96}, number = {4 Pt 1}, pages = {765-779}, pmid = {7567346}, issn = {0031-4005}, mesh = {Child ; Data Collection/standards ; *Emergency Medical Services ; Europe ; Humans ; *Life Support Care ; *Pediatrics ; Records/standards ; *Resuscitation ; Terminology as Topic ; United States ; }, abstract = {This consensus document is an attempt to provide an organized method of reporting pediatric ALS data in out-of-hospital, emergency department, and in-hospital settings. For this methodology to gain wide acceptance, the task force encourages development of a common data set for both adult and pediatric ALS interventions. In addition, every effort should be made to ensure that consistent definitions are used in all age groups. As health care changes, we will all be challenged to document the effectiveness of what we currently do and show how new interventions or methods of treatment improve outcome and/or reduce cost. Only through collaborative research will we obtain the necessary data. For these reasons, and to improve the quality of care and patient outcomes, it is the hope of the task force that clinical researchers will follow the recommendations in this document. It is recognized that further refinements of this statement will be needed; these recommendations will improve only when researchers, clinicians, and EMS personnel use them, work with them, and modify them. Suggestions, emendations, and other comments aimed at improving the reporting of pediatric resuscitation should be sent to Arno Zaritsky, MD, Eastern Virginia Medical School, Children's Hospital of The King's Daughter, Division of Critical Care Medicine, 601 Children's Lane, Norfolk, VA 23507.}, }
@article {pmid7476305, year = {1995}, author = {Baxter, RC}, title = {Insulin-like growth factor binding proteins as glucoregulators.}, journal = {Metabolism: clinical and experimental}, volume = {44}, number = {10 Suppl 4}, pages = {12-17}, doi = {10.1016/0026-0495(95)90215-5}, pmid = {7476305}, issn = {0026-0495}, mesh = {Blood Glucose/*metabolism ; Humans ; Hypoglycemia/metabolism ; Insulin-Like Growth Factor Binding Protein 1/physiology ; Insulin-Like Growth Factor Binding Proteins/*physiology ; }, abstract = {Circulating insulin-like growth factors (IGFs) represent an important pool of potential hypoglycemic activity, which is largely inhibited by their sequestration in a heterotrimeric complex comprising growth factor, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Less than 1% of total IGFs circulate in the free form, yet even this amount might contribute significantly to circulating insulin-like activity. The ternary binding protein complex appears to inhibit insulin-like activity of bound IGFs by preventing their egress from the circulation. Although the integrity of this complex might be affected by limited proteolysis of IGFBP-3 in pregnancy and catabolic conditions, the evidence that this increases IGF bioavailability, and thus hypoglycemic potential, is as yet unclear. However, in patients with IGF-II-secreting tumors, hypoglycemia may result from a failure of the ternary complex to adequately sequester the IGFs. Improvement in complex formation, by treatment with corticosteroids or growth hormone, alleviates the hypoglycemia, even if (as seen with growth hormone treatment) IGF-II hypersecretion persists. In these patients, blood glucose levels are inversely correlated with IGFBP-2 levels, suggesting that this protein might play a part in transporting IGFs to their target tissues. Conversely, ALS levels correlate positively with blood glucose, emphasizing the importance of the ternary complex in preventing hypoglycemia. Unlike the other IGF-binding proteins, IGFBP-1 is acutely regulated in the circulation, in a manner consistent with its acting as a glucose counterregulator. It might act in this way by inhibiting the activity of free IGFs in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7486597, year = {1995}, author = {Trembly, B}, title = {Clinical potential for the use of neuroprotective agents. A brief overview.}, journal = {Annals of the New York Academy of Sciences}, volume = {765}, number = {}, pages = {1-20; discussion 26-7}, doi = {10.1111/j.1749-6632.1995.tb16554.x}, pmid = {7486597}, issn = {0077-8923}, mesh = {Animals ; Brain Diseases/*drug therapy ; Brain Injuries/*drug therapy ; Brain Ischemia/*drug therapy ; Calcium Channel Blockers/therapeutic use ; Cerebrovascular Disorders/*drug therapy ; Epilepsy/drug therapy ; Humans ; Hypothermia/drug therapy/physiopathology ; Ischemic Attack, Transient/drug therapy ; Neuroprotective Agents/*therapeutic use ; Neurosurgery ; Nimodipine/therapeutic use ; Postoperative Complications/drug therapy ; Spinal Cord Injuries/*drug therapy ; Subarachnoid Hemorrhage/*drug therapy ; }, abstract = {"Stroke treatment seems to be entering a golden age ...." Fisher's observation not only applies to ischemic stroke, but to all the conditions described above, and in the future, possibly (and quite speculatively), to other neurologic diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, even radiation therapy and Bell's palsy. Physicians must sharpen their criteria for decisions regarding therapy and must" ... be prepared to accept what is actually known from scientific data ... rather than to rely on instinct, clinical impression, or the need to do something rather than nothing."}, }
@article {pmid9415162, year = {1995}, author = {Yuen, EC and Mobley, WC}, title = {Therapeutic applications of neurotrophic factors in disorders of motor neurons and peripheral nerves.}, journal = {Molecular medicine today}, volume = {1}, number = {6}, pages = {278-286}, doi = {10.1016/s1357-4310(95)91189-8}, pmid = {9415162}, issn = {1357-4310}, support = {AG08938/AG/NIA NIH HHS/United States ; AG10672/AG/NIA NIH HHS/United States ; NS24054/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Clinical Trials as Topic ; Cytokines/therapeutic use ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Insulin-Like Growth Factor II/therapeutic use ; Motor Neuron Disease/*drug therapy/physiopathology ; Nerve Growth Factors/*therapeutic use ; Peripheral Nervous System Diseases/*drug therapy/physiopathology ; }, abstract = {Research in the past few years has produced exciting progress in our understanding of neurotrophic factors. Robust effects of neurotrophic factors on neuronal survival and differentiation in animal studies have encouraged initiation of clinical trials for diseases of the human nervous system. In this article, the data for the actions of neurotrophic factors and the rationale for their use in clinical trials are reviewed. Recent data demonstrating efficacy of insulin-like growth factor 1 in amyotrophic lateral sclerosis suggest that neurotrophic factors can be used to treat neurological disease.}, }
@article {pmid8714677, year = {1995}, author = {Julien, JP}, title = {A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire}, volume = {73}, number = {9-10}, pages = {593-597}, doi = {10.1139/o95-064}, pmid = {8714677}, issn = {0829-8211}, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/etiology/*physiopathology/therapy ; Animals ; Axonal Transport ; Gene Expression Regulation/physiology ; Genetic Variation ; Humans ; Mice ; Mice, Transgenic ; Neurofilament Proteins/chemistry/*physiology ; Structure-Activity Relationship ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of motor neurons, characterized by abnormal accumulation of neurofilaments (NFs) in perikarya and proximal axons. Two lines of evidence suggest that neurofilament accumulation can play a crucial role in ALS pathogenesis. First, transgenic mouse models overexpressing NF proteins were found to develop motor neuron degeneration and, second, variant alleles of the NF heavy-subunit (NF-H) gene have been found in some human ALS patients. Our axonal transport studies with transgenic mice overexpressing the human NF-H gene, a model of ALS, revealed defects of intracellular transport not only for neurofilament proteins but also for other cytoskeletal proteins and organelles such as mitochondria. Therefore, we propose that neurofilament accumulation in mice causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS.}, }
@article {pmid8580551, year = {1995}, author = {Eisen, A}, title = {Amyotrophic lateral sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {34}, number = {9}, pages = {824-832}, doi = {10.2169/internalmedicine.34.824}, pmid = {8580551}, issn = {0918-2918}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/physiopathology/therapy ; Animals ; Humans ; }, abstract = {The final cascade of amyotrophic lateral sclerosis (ALS) coincides with the onset of clinical neurological deficits and involves multifactorial interactive mechanisms. These terminal events include excitotoxicity, free radical accumulation and possibly immunological disturbances. They are probably predated by months or years by thus far unidentified triggers. Selective vulnerability of the corticomotneuronal system in ALS is likely due to degradation of several gene products essential to transmitter, receptor and nerve growth factor maintenance specific to this functional system. Therapeutic strategies involve neuroprotection, symptomatic and combination neuronal therapy targeted to the final cascade of ALS.}, }
@article {pmid7668820, year = {1995}, author = {Beal, MF}, title = {Aging, energy, and oxidative stress in neurodegenerative diseases.}, journal = {Annals of neurology}, volume = {38}, number = {3}, pages = {357-366}, doi = {10.1002/ana.410380304}, pmid = {7668820}, issn = {0364-5134}, support = {NS16367/NS/NINDS NIH HHS/United States ; NS31579/NS/NINDS NIH HHS/United States ; NS32365/NS/NINDS NIH HHS/United States ; }, mesh = {*Aging ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; *Energy Metabolism ; Humans ; Huntington Disease/metabolism/physiopathology ; Mitochondria/metabolism/physiology ; *Nerve Degeneration ; Nervous System Diseases/metabolism/*physiopathology ; *Oxidative Stress ; Receptors, N-Methyl-D-Aspartate/metabolism/physiology ; }, abstract = {The etiology of neurodegenerative diseases remains enigmatic; however, evidence for defects in energy metabolism, excitotoxicity, and for oxidative damage is increasingly compelling. It is likely that there is a complex interplay between these mechanisms. A defect in energy metabolism may lead to neuronal depolarization, activation of N-methyl-D-aspartate excitatory amino acid receptors, and increases in intracellular calcium, which are buffered by mitochondria. Mitochondria are the major intracellular source of free radicals, and increased mitochondrial calcium concentrations enhance free radical generation. Mitochondrial DNA is particularly susceptible to oxidative stress, and there is evidence of age-dependent damage and deterioration of respiratory enzyme activities with normal aging. This may contribute to the delayed onset and age dependence of neurodegenerative diseases. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Potential therapeutic approaches include glutamate release inhibitors, excitatory amino acid antagonists, strategies to improve mitochondrial function, free radical scavengers, and trophic factors. All of these approaches appear promising in experimental studies and are now being applied to human studies.}, }
@article {pmid7489816, year = {1995}, author = {MacLean, HE and Warne, GL and Zajac, JD}, title = {Defects of androgen receptor function: from sex reversal to motor neurone disease.}, journal = {Molecular and cellular endocrinology}, volume = {112}, number = {2}, pages = {133-141}, doi = {10.1016/0303-7207(95)03608-a}, pmid = {7489816}, issn = {0303-7207}, mesh = {Breast Neoplasms, Male/genetics ; Disorders of Sex Development/*genetics ; Female ; Humans ; Infertility, Male/genetics ; Male ; Motor Neuron Disease/*genetics ; *Mutation ; Prostatic Neoplasms/genetics ; Receptors, Androgen/*genetics/*physiology ; }, abstract = {The androgen receptor (AR) is a ligand-dependent DNA transcription factor that binds androgens which cause masculinisation of the developing male fetus. Classical abnormalities of receptor function result in the syndrome of androgen resistance, with resultant failure of normal male differentiation. In more recent years, however, mutations in the AR gene have been described in a number of diverse clinical conditions, from male infertility to prostate and breast cancer through to a form of motor neurone disease (Kennedy's disease). This review discusses the various AR gene mutations found in androgen insensitivity syndrome (AIS) and the other conditions described above, and relates how different mutations, or disruption of different functional domains, contributes to the various phenotypes. Mutations that cause complete AIS usually disrupt the DNA or steroid binding ability of the receptor. In partial AIS, mutations generally decrease receptor affinity for ligand, affect thermostability of the protein, or affect the ability of the receptor to activate transcription of responsive genes. Isolated mutations occur in the steroid binding domain of the receptor in prostate cancer, and many cancers have an identical mutation. Similarly, in the two cases of male breast cancer in which AR gene mutations have been described, the mutations in the DNA binding domain of the receptor are alike. In Kennedy's disease a trinucleotide repeat expansion occurs in exon A of the AR gene, which appears to affect ability of the receptor to bind ligand and activate transcription, although the mechanism of neuronal degeneration remains unknown.}, }
@article {pmid7582045, year = {1995}, author = {Wong, PC and Borchelt, DR}, title = {Motor neuron disease caused by mutations in superoxide dismutase 1.}, journal = {Current opinion in neurology}, volume = {8}, number = {4}, pages = {294-301}, doi = {10.1097/00019052-199508000-00008}, pmid = {7582045}, issn = {1350-7540}, support = {AG 05146/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Cell Line ; *DNA Mutational Analysis ; Genes, Dominant/genetics ; Humans ; Isoenzymes/*genetics ; Mice ; Mice, Transgenic ; Nerve Degeneration/genetics ; Phenotype ; Superoxide Dismutase/*genetics ; }, abstract = {A subset of pedigrees with dominant inheritance of familial amyotrophic lateral sclerosis have mutations in superoxide dismutase 1. Initial studies suggested that disease-linked mutations impaired superoxide dismutase 1 activity, which is consistent with the notion that disease results from increased oxidative injury. However, results of recent cell culture and transgenic studies demonstrate that mutant proteins retaining high levels of superoxide dismutase 1 activity cause motor neuron degeneration; elevating the level of wild-type superoxide dismutase 1 does not cause disease. These findings suggest that the familial amyotrophic lateral sclerosis phenotype may occur through other mechanisms that can now be explored in model systems.}, }
@article {pmid9415157, year = {1995}, author = {Morrison, KE}, title = {Mechanisms in motor neurone disease: clues from genetic studies.}, journal = {Molecular medicine today}, volume = {1}, number = {4}, pages = {195-201}, doi = {10.1016/s1357-4310(95)91930-9}, pmid = {9415157}, issn = {1357-4310}, mesh = {Brain/physiopathology ; Free Radicals ; Humans ; Models, Neurological ; Motor Neuron Disease/etiology/*genetics/*physiopathology/therapy ; Muscle Fibers, Skeletal/physiology ; Point Mutation ; Spinal Cord/physiopathology ; Superoxide Dismutase/*genetics ; }, abstract = {Motor neurone disease is a rapidly progressive neurodegenerative disorder, characterized by muscular weakness and wasting with fasciculation and by spasticity. While most cases are sporadic, approximately 10% are inherited in an autosomal dominant mode. Recently, mutations in the gene encoding the free-radical scavenging enzyme superoxide dismutase-1 have been found to segregate with the disorder in 20% of familial cases. This is an exciting development, as free radical damage has long been implicated in the pathogenesis of motor neurone disease and it raises the possibility of novel therapeutic approaches in this otherwise fatal condition.}, }
@article {pmid8521630, year = {1995}, author = {Kato, S and Oda, M and Murahashi, M and Suda, N}, title = {Motor neuron disease with involvement of the pallido-luysio-nigral system and mesencephalic tegmentum.}, journal = {Clinical neuropathology}, volume = {14}, number = {4}, pages = {241-244}, pmid = {8521630}, issn = {0722-5091}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Atrophy/pathology ; Brain/*pathology ; Corpus Striatum/pathology ; Fatal Outcome ; Globus Pallidus/pathology ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*pathology ; Nerve Degeneration/*physiology ; Tegmentum Mesencephali/*pathology ; Thalamic Nuclei/pathology ; }, abstract = {A rare case of motor neuron disease and involvement of the pallido-luysio-nigral system and brainstem tegmentum is presented. A 51-year-old man developed progressive muscle atrophy with fasciculation predominantly in the shoulder girdle, upper arms, upper back, and neck in addition to hyperreflexia and a positive Chaddock reflex. He also had retinitis pigmentosa, high arched palate, and mild hand tremor. He eventually developed bulbar palsy and died of paralysis of the respiratory muscles 11 years after the onset of his illness. Neuropathological examinations showed prominent neuronal loss and gliosis in the pallido-luysio-nigral system and the tegmentum of the brainstem in addition to the simultaneous involvement of the upper and lower motor neurons. This patient and 6 similar patients are discussed in relation to pallido-luysio-nigral atrophy and the topographic distribution of degeneration in amyotrophic lateral sclerosis.}, }
@article {pmid7783764, year = {1995}, author = {Eisen, A}, title = {Amyotrophic lateral sclerosis is a multifactorial disease.}, journal = {Muscle &amp; nerve}, volume = {18}, number = {7}, pages = {741-752}, doi = {10.1002/mus.880180711}, pmid = {7783764}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/*physiopathology ; Animals ; Chromosome Mapping ; Chromosomes, Human, Pair 21 ; Glutamic Acid/physiology/toxicity ; Humans ; Mutation ; Nerve Growth Factors/biosynthesis/genetics/therapeutic use ; Neurofilament Proteins/genetics ; Neurotoxins/toxicity ; Receptors, N-Methyl-D-Aspartate/genetics/physiology ; Second Messenger Systems ; Signal Transduction ; Species Specificity ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is probably biphasic. An initial trigger(s) is followed by a terminal cascade coinciding with the onset of neurological deficits. The terminal cascade involves interactive multifactorial pathogenic mechanisms. Aging must play a crucial role leading to multiple defective or degraded gene products accumulating with progressing years. This in turn leads to failure of receptor integrity and resulting excitotoxicity, free radical accumulation, failure of neurotrophism, and possibly immunological disturbances. These events are predated by months or years by a trigger which is also likely to be multifactorial and cumulative. Evidence suggests that environmental factors may be important triggers. Failure of specific glutamate transporters and calcium binding proteins may account for selective vulnerability of the corticomotoneuronal system. It is postulated that in ALS the primary target cell is the corticomotoneuron or the local circuit interneurons which modulate its activity. Glia cells may play an important role in the demise of the corticomotoneuronal cell. The disordered corticomotoneuron induces excessive excitatory transmitter (glutamate?) release at the corticomotoneuronal-spinal-motoneuronal synapse resulting in the subsequent demise of this neuron.}, }
@article {pmid7655341, year = {1995}, author = {Ebadi, M and Iversen, PL and Hao, R and Cerutis, DR and Rojas, P and Happe, HK and Murrin, LC and Pfeiffer, RF}, title = {Expression and regulation of brain metallothionein.}, journal = {Neurochemistry international}, volume = {27}, number = {1}, pages = {1-22}, doi = {10.1016/0197-0186(94)00164-p}, pmid = {7655341}, issn = {0197-0186}, support = {ES03949/ES/NIEHS NIH HHS/United States ; }, mesh = {Amino Acids/analysis ; Animals ; Base Sequence ; Brain/growth &amp; development/*metabolism/ultrastructure ; *Gene Expression Regulation ; Humans ; Metallothionein/analysis/chemistry/*genetics/metabolism ; Molecular Sequence Data ; Neurons/chemistry/metabolism/ultrastructure ; RNA, Messenger/analysis ; Zinc/analysis/chemistry/metabolism ; }, abstract = {Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These "vesicular" pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guillaine-Barré syndrome, hepatic encephalopathy, multiple sclerosis, Parkinson's disease, Pick's disease, retinitis pigmentosa, retinal dystrophy, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT isoforms and other low molecular weight zinc-binding proteins in these conditions, diseases, disorders, or syndromes is being delineated at this time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytokine-induced induction of MT provides a long-lasting protection to avert oxidative damage.}, }
@article {pmid7482387, year = {1995}, author = {Doble, A}, title = {Excitatory amino acid receptors and neurodegeneration.}, journal = {Therapie}, volume = {50}, number = {4}, pages = {319-337}, pmid = {7482387}, issn = {0040-5957}, mesh = {AIDS Dementia Complex/metabolism ; Animals ; Central Nervous System/injuries/metabolism ; Cerebrovascular Disorders/metabolism ; Glutamic Acid/metabolism ; Humans ; *Nerve Degeneration ; Receptors, Glutamate/classification/*metabolism ; }, abstract = {This review describes recent advances in our understanding of the pharmacology of excitatory amino acid receptors, and the application of this knowledge to the unravelling of the aetiology of neurodegenerative diseases, and to their therapy. Ionotropic excitatory amino acid receptors can be divided into two large families, the NMDA receptor family, and the AMPA/kainate receptor family. Receptor cloning studies have shown there to be a large number of potential subtypes of receptors in both these families. Antagonists have been developed for the NMDA receptor which can interact with at least four independent drug recognition sites on the receptor. For the AMPA/kainate receptor, two classes of antagonist have so far been identified. Reasonably potent, selective and brain-penetrating antagonists now exist for virtually all these sites, and compounds inhibiting the release of glutamic acid presynaptically have also been identified, such as riluzole. The ability of glutamic acid to kill neurons (excitotoxicity) seems to be mediated, in most cases, by an interaction with NMDA receptors, leading to an uncontrollable rise in intracellular calcium concentrations and thence cell lysis and death. The setting-up of glutamatergic loops seems to be a key process in the maintenance, spread and amplification of neurodegenerative foci. The existence of such processes has been amply demonstrated in animal models of stroke, in which both NMDA and AMPA/kainate receptor antagonists have neuroprotective effects. Clinical trials are underway with NMDA receptor antagonists in stroke. Excitotoxic mechanisms probably also contribute to pathology in head trauma and viral encephalopathy. Ingestion of excitatory amino acids may play a role in neurological conditions of dietary aetiology, such as neurolathyrism and domoic acid intoxication. For chronic neurodegenerative diseases, the role of excitatory amino acids is much less clear, although there is some evidence for the existence of excitotoxic mechanisms in amyotrophic lateral sclerosis. Evidence from animal models suggests that drugs that block glutamatergic neurotransmission might be beneficial in Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis, but the relevance of these animal models to the human pathology is not clear. However, preliminary clinical results suggest riluzole to be efficacious in prolonging survival in amyotrophic lateral sclerosis, and certain weak NMDA receptor antagonists are currently used in the treatment of Parkinson's disease. The next few years could witness a breakthrough in the treatment of neurological conditions as drugs that interfere with glutamatergic transmission become available for clinical use.}, }
@article {pmid8521632, year = {1995}, author = {Yoshida, M and Okuda, S and Murakami, N and Hashizume, Y and Sobue, G}, title = {[Two siblings of familial amyotrophic lateral sclerosis with multisystemic degeneration characterized by mild involvement of the middle root zone of the posterior column, Clarke's nuclei and spinocerebellar tract].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {6}, pages = {589-599}, pmid = {8521632}, issn = {0009-918X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Fatal Outcome ; Humans ; Male ; Middle Aged ; Spinal Cord/*pathology ; Spinal Nerve Roots/*pathology ; Spinocerebellar Degenerations/*pathology ; }, abstract = {The aim of this study is to clarify the clinicopathological characteristics of the multisystem degeneration seen in two male siblings with familial amyotrophic lateral sclerosis (FALS). A similar neurological disorder affected their elder sister and paternal uncle, but not their parents. The older brother (case 1) developed muscular weakness at 50 years of age and the younger brother (case 2), at 42 years of age. The duration of illness was 19 months in case 1 and 31 months in case 2. The clinical picture was the common (suspended) form in case 1 and the pseudopolyneuritic form in case 2. Pyramidal tract sign was obscure in both cases and cerebellar sign, sensory disturbance, sphincter disturbance and oculomotor palsy were not observed in either case. Neuropathological examination revealed similar findings in the two cases: 1) marked loss of lower motor neurons in the spinal anterior horn and motor nuclei of the lower brain stem in both cases, with neuronal loss of Onuf's nuclei in case 2; 2) very mild involvement in Clarke's nuclei, the dorsal and ventral spinocerebellar tracts and the middle root zone of the posterior column; 3) relatively well preserved Betz cells in the upper motor cortex with the appearance of a few macrophages, and mild changes in the pyramidal tract of the spinal cord; and 4) mild degenerative changes in the pallidoluysian system and the dentatorubral system. The most characteristic pathological findings common to both cases were the extremely mild involvement of the middle root zone of the posterior column, Clarke's nuclei and spinocerebellar tracts. The pattern of lower motor neuron system degeneration paralleled the development of clinical features. Genetic studies demonstrated no mutations in exons 1, 2 and 4 of Cu/Zn-binding superoxide dismutase gene. We emphasized the existence of mild involvement of middle root zone of posterior column, Clarke's nuclei and spinocerebellar tract in FALS with multisystemic degeneration.}, }
@article {pmid7605680, year = {1995}, author = {Takahashi, H}, title = {[Familial amyotrophic lateral sclerosis with or without mutation of the Cu/Zn superoxide dismutase gene].}, journal = {No to shinkei = Brain and nerve}, volume = {47}, number = {6}, pages = {535-541}, pmid = {7605680}, issn = {0006-8969}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Female ; Humans ; Middle Aged ; Mutation ; Superoxide Dismutase/*genetics ; }, }
@article {pmid7605679, year = {1995}, author = {Nakano, R and Tsuji, S}, title = {[Familial amyotrophic lateral sclerosis and a mutation of Cu/Zn superoxide dismutase gene].}, journal = {No to shinkei = Brain and nerve}, volume = {47}, number = {6}, pages = {529-534}, pmid = {7605679}, issn = {0006-8969}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*genetics ; Free Radicals ; Humans ; Molecular Sequence Data ; Motor Neurons/physiology ; Mutation ; Superoxide Dismutase/*genetics ; }, }
@article {pmid7583675, year = {1995}, author = {Higgins, LS and Cordell, B}, title = {Genetically engineered animal models of human neurodegenerative diseases.}, journal = {Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration}, volume = {4}, number = {2}, pages = {117-129}, doi = {10.1006/neur.1995.0015}, pmid = {7583675}, issn = {1055-8330}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Animals, Genetically Modified ; Central Nervous System Diseases/*genetics ; Disease Models, Animal ; Fragile X Syndrome/genetics ; *Genetic Engineering ; Humans ; Nerve Degeneration/*genetics ; Virus Diseases/genetics ; }, abstract = {The influence of a single gene, engineered to be normally or abnormally expressed, can be evaluated in vivo through the development of transgenic animals. Application of this approach in the study of human neurological problems is contributing to an increased understanding of the pathogenic components operative in a variety of disorders. These include Alzheimer's disease, prion encephalopathies, motor neuron disease such as amyotrophic lateral sclerosis, and fragile X syndrome, as well as a number of viral-mediated neurological disorders. These transgenic animals can also serve as models to investigate the possible involvement of additional genetic and environmental factors on the disease state. Moreover, transgenic animals can be used in the development of intervention strategies. The application of this powerful and increasingly popular tool to investigate neurodegenerative disorders is reviewed.}, }
@article {pmid7576866, year = {1995}, author = {Lo, AC and Houenou, LJ and Oppenheim, RW}, title = {Apoptosis in the nervous system: morphological features, methods, pathology, and prevention.}, journal = {Archives of histology and cytology}, volume = {58}, number = {2}, pages = {139-149}, doi = {10.1679/aohc.58.139}, pmid = {7576866}, issn = {0914-9465}, support = {HD 29435/HD/NICHD NIH HHS/United States ; NS 20402/NS/NINDS NIH HHS/United States ; NS 31380/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*physiology ; Humans ; Models, Biological ; Necrosis ; *Nervous System Physiological Phenomena ; }, abstract = {For nearly 70 years apoptosis has been known to be a form of cell death distinct from necrosis as well as an important regressive event during the normal development of the nervous system. For example, in the chick, mouse, rat and human approximately 50% of postmitotic neurons die naturally during embryonic or fetal development. It is generally accepted that neurons die during this period by apoptosis. After the period of naturally occurring cell death, the surviving neurons may undergo degeneration and death due to injury or disease later either during development or in adulthood. Recently, apoptosis has been suggested to be involved in the abnormal neuronal death that occurs following axonal injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's. Although little is known about the etiology of these diseases, progress is steadily being made toward understanding their underlying mechanisms. For diseases of spinal motoneurons, during the past two years gene mutations have been identified in patients with familial amyotrophic lateral sclerosis or spinal muscular atrophy. Furthermore, a number of in vitro, in vivo, and mutant animal models have been developed in order to study the factors which control motoneuron survival and/or death. Here, we review the morphological differences between necrotic and apoptotic cell death and some of the methods used to differentiate the two pathways. We also discuss motoneuron cell death during development, following injury and in disease, and its prevention by different agents, including neurotrophic factors.}, }
@article {pmid7611634, year = {1995}, author = {Okumura, H and Kurland, LT and Waring, SC}, title = {Amyotrophic lateral sclerosis and polio: is there an association?.}, journal = {Annals of the New York Academy of Sciences}, volume = {753}, number = {}, pages = {245-256}, doi = {10.1111/j.1749-6632.1995.tb27551.x}, pmid = {7611634}, issn = {0077-8923}, mesh = {*Amyotrophic Lateral Sclerosis ; Case-Control Studies ; Guam ; Humans ; Minnesota ; Motor Neuron Disease ; *Postpoliomyelitis Syndrome ; }, abstract = {Because polio and ALS are both manifestations of anterior horn cell disease, consideration of some etiologic or pathogenetic relationship continues to recur. Studies that show an association are infrequent and are greatly outnumbered by negative reports in spite of possible journal bias to report positive results. Our limited studies in Guam and Rochester, Minnesota, have added to the negative list, and support the conclusion that there is no etiologic association of these two distinct diseases. The role, if any, of nonparalytic polio and polio vaccines with respect to ALS is not clear. With such a high proportion of the population having antibodies to polio, it may not be feasible to differentiate ALS with respect to the presence or absence of polio antibodies. Although the results to date do not support a polio-ALS relationship, further long-term studies are desirable for both the classical and the Western Pacific forms of ALS with respect to past polio outbreaks and, for the future, the unknown effect of polio vaccines on the incidence of ALS.}, }
@article {pmid8968216, year = {1995}, author = {Kornberg, AJ and Pestronk, A}, title = {Chronic motor neuropathies: diagnosis, therapy, and pathogenesis.}, journal = {Annals of neurology}, volume = {37 Suppl 1}, number = {}, pages = {S43-50}, doi = {10.1002/ana.410370706}, pmid = {8968216}, issn = {0364-5134}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Antibody Specificity ; Antigens/immunology ; Autoantibodies/blood/immunology ; *Autoimmune Diseases/diagnosis/etiology/therapy ; Chronic Disease ; Cyclophosphamide/therapeutic use ; Diagnosis, Differential ; Female ; G(M1) Ganglioside/immunology ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Middle Aged ; Neural Conduction ; *Neuromuscular Diseases/diagnosis/etiology/immunology/therapy ; }, abstract = {Pure motor neuropathy syndromes resemble amyotrophic lateral sclerosis variants with no upper motor neuron signs. Their identification is important, as, in contrast to amyotrophic lateral sclerosis, they are often immune mediated and treatable. Typically the immune-mediated motor neuropathy syndromes are distal and asymmetrical and progress slowly. The clinical features may help alert the clinician to the diagnosis, but other ancillary evidence such as abnormalities on electrophysiological testing and the presence of serum autoantibodies to neural antigens are helpful in making the diagnosis more secure. Electrophysiological abnormalities include not only motor conduction block but also other evidence of a demyelinative process such as prolonged distal latencies or F-wave abnormalities. High-titer anti-GM1 antibodies occur frequently but more specific patterns of reactivity may be especially helpful. Treatment of these motor neuropathy syndromes includes cyclophosphamide, which we use in combination with plasma exchange, and in some patients, human immune globulin. Clinical responses to therapy may occur within the first 2 to 4 months in patients with motor neuropathy syndromes with demyelinative features, but only become obvious 6 months or later after starting treatment in patients with predominantly axonal disorders.}, }
@article {pmid7739643, year = {1995}, author = {al-Chalabi, A and Powell, JF and Leigh, PN}, title = {Neurofilaments, free radicals, excitotoxins, and amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {18}, number = {5}, pages = {540-545}, doi = {10.1002/mus.880180511}, pmid = {7739643}, issn = {0148-639X}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Conserved Sequence ; Free Radicals ; Humans ; Molecular Sequence Data ; Neurofilament Proteins/genetics/*physiology ; Neurotoxins/*metabolism ; }, abstract = {There is increasing evidence implicating abnormalities of neurofilament function in the pathogenesis of amyotrophic lateral sclerosis (ALS). The observation that the P2 blood protein phenotype is overrepresented in patients with ALS is potentially important, but needs confirmation. It should be shown that this segregation is selective for ALS. If it is, the implications outlined in Meyer's hypothesis will need to be explored, bearing in mind that much of the evidence implicating excitotoxins, free radicals, and neurofilaments in familial and sporadic ALS is still circumstantial. Thus the identification of candidate genes, the pursuit of large segregation studies, and identification of specific point mutations, remain key goals in ALS research.}, }
@article {pmid7739642, year = {1995}, author = {Meyer, MA and Potter, NT}, title = {Sporadic ALS and chromosome 22: evidence for a possible neurofilament gene defect.}, journal = {Muscle &amp; nerve}, volume = {18}, number = {5}, pages = {536-539}, doi = {10.1002/mus.880180510}, pmid = {7739642}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; *Chromosomes, Human, Pair 22 ; Humans ; *Mutation ; Neurofilament Proteins/*genetics ; }, abstract = {ALS is associated with the P2 blood group phenotype. Molecular evidence now shows the gene encoding this antigen to be on the long arm of human chromosome 22 near the newly discovered gene for heavy neurofilament (NF-H). Since an ALS-type condition can be generated in transgenic mice expressing the human NF-H gene, and since the gene for the CNTF-related cytokine leukemia inhibitory factor (LIF) is located adjacent to this gene, it is hypothesized that a defect on the chromosome 22 band region q12 is involved in the pathogenesis of sporadic ALS.}, }
@article {pmid7602783, year = {1995}, author = {Fujii, J and Suzuki, K and Taniguchi, N}, title = {[Physiological significance of superoxide dismutase isozymes].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {53}, number = {5}, pages = {1227-1231}, pmid = {7602783}, issn = {0047-1852}, mesh = {Amyotrophic Lateral Sclerosis/etiology ; Diabetes Mellitus/etiology ; Down Syndrome/etiology ; Free Radical Scavengers ; Humans ; Isoenzymes/deficiency/genetics/*physiology ; Mutation ; Neoplasms/etiology ; Superoxide Dismutase/deficiency/genetics/*physiology ; }, abstract = {Superoxide dismutases (SODs) scavenge superoxide anion and participate in an essential role as a defense system against oxidative stress in body. Cu,Zn-SOD is localized at cytoplasm. A defect in the Cu,Zn-SOD gene has been demonstrated in some cases of familial amyotrophic lateral sclerosis. Trisomy of chromosome 21 in Down's syndrome increases the level of this isozyme and causes the disease. Inactivation of Cu,Zn-SOD by glycation under hyperglycemic conditions may also be a critical factor for diabetic complication. The expression of the second isozyme, Mn-SOD localized at mitochondrial matrix, is regulated in a complex manner by many stimulants such as interleukin-1, -6, tumor necrosis factor, lipopolysaccharide, and tumor promoters phorbol ester (TPA) and okadaic acid. This isozyme seems to work as a defense mechanism against damage during inflammatory responses. The third isozyme, extracellular SOD, is highly glycosylated and has affinity for heparin sulfate. This may participate in scavenging superoxide in plasma and, therefore, missense mutation in heparin binding domain increases the serum level of this isozyme, although the physiological role is not clearly understood yet.}, }
@article {pmid7595629, year = {1995}, author = {Bergeron, C}, title = {Oxidative stress: its role in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {81-84}, doi = {10.1016/0022-510x(95)00071-9}, pmid = {7595629}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*physiopathology ; Humans ; Oxidative Stress/genetics/*physiology ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {The discovery of mutations in the Cu,Zn superoxide dismutase gene in familial ALS implicates oxidative stress in the pathogenesis of this disorder. Recent findings further suggest that oxidative stress may also be present in the more common sporadic form of the disease. The possible sources of oxidative stress in ALS are reviewed, and the participation of this disease mechanism to motorneuron death is discussed.}, }
@article {pmid7595601, year = {1995}, author = {Festoff, BW and Yang, SX and Vaught, J and Bryan, C and Ma, JY}, title = {The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies.}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {114-121}, doi = {10.1016/0022-510x(95)00080-l}, pmid = {7595601}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Humans ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Mice ; Neuromuscular Agents/*therapeutic use ; Signal Transduction/drug effects/*physiology ; Somatomedins/metabolism/*physiology/*therapeutic use ; }, abstract = {Because of its multi-faceted potential as a neurotrophic factor, insulin-like growth factor I (IGF-I) has been given to hundreds of ALS patients world-wide. Unlike some patients with post-polio syndrome and fragile elderly males, it is unclear whether any of these patients possess disturbances in IGF signaling. We found that about 25% of ALS patients in a controlled trial of human growth hormone (hGH) had lower or higher than normal IGF-I serum levels. Many ALS patients do have some of the characteristics of type II diabetes mellitus, where IGF-I therapy is also under way. In addition, in type I diabetes significant increase in a circulating molecule that binds IGF-I, IGF-I binding protein 1 (IGFBP-1), occurs along with reduced IGF-I, when neuropathic complications are prominent. We have studied the response of IGFBPs in ALS patients to subcutaneous rhIGF-I and found transient induction of IGFBP-1. Studies related to the IGFBPs have not been done in familial ALS (FALS) patients. However, the gene for another IGFBP, BP-2, co-localizes with the gene for juvenile ALS (ALSJ) on chromosome 2. IGF-I has been given to several models of motor neuron degeneration in the mouse, including motor neuron disease and wobbler, with beneficial effects. However, it is also not known whether any accepted genetic mouse model of motor neuron degeneration possesses any disturbance in the IGF signaling system.}, }
@article {pmid7595596, year = {1995}, author = {}, title = {World Federation of Neurology Research Group on Neuromuscular Diseases Subcommittee on Motor Neuron Disease. Airlie House guidelines. Therapeutic trials in amyotrophic lateral sclerosis. Airlie House "Therapeutic Trials in ALS" Workshop Contributors.}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {1-10}, pmid = {7595596}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Clinical Trials as Topic/*standards ; Humans ; }, }
@article {pmid7724960, year = {1995}, author = {Waespe, W and Vogel Wigger, BM and Bächli, E and Boltshauser, E}, title = {[Differential diagnostic aspects of progressive spastic paraplegia in adults with emphasis on neurometabolic diseases].}, journal = {Praxis}, volume = {84}, number = {16}, pages = {473-477}, pmid = {7724960}, issn = {1661-8157}, mesh = {Adrenoleukodystrophy/diagnosis ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis ; Avitaminosis/diagnosis ; Brain Diseases, Metabolic/*diagnosis ; Diagnosis, Differential ; Humans ; Leukodystrophy, Metachromatic/diagnosis ; Lipid Metabolism, Inborn Errors/diagnosis ; Multiple Sclerosis/diagnosis ; Optic Atrophies, Hereditary/diagnosis ; Paraplegia/*diagnosis ; Spastic Paraplegia, Hereditary/diagnosis ; }, abstract = {The differential diagnosis of a progressive spastic paraparesis in the young adult is broad and includes rare neuro-metabolic diseases like cerebro-tendinous xanthomatosis, adrenomyeloneuropathy and hypovitaminosis. Their clinical presentation as well as the result of paraclinical examinations can be similar to those of multiple sclerosis. The early recognition of these diseases is important, because a dietary regimen may reduce the severity and progression of symptoms and signs and genetic counselling can be important. The relevant biochemical examinations for their detection are discussed. These neuro-metabolic diseases have to be differentiated from other neuro-degenerative diseases like amyotrophic lateral sclerosis and hereditary spastic paraplegias.}, }
@article {pmid7788066, year = {1995}, author = {Goonetilleke, A}, title = {Current therapies in motor neurone disease.}, journal = {British journal of hospital medicine}, volume = {53}, number = {7}, pages = {314-317}, pmid = {7788066}, issn = {0007-1064}, mesh = {Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; Clinical Trials as Topic ; Gangliosides/therapeutic use ; Humans ; Motor Neuron Disease/chemically induced/*drug therapy ; Neurotoxins/toxicity ; Thyrotropin-Releasing Hormone/therapeutic use ; }, abstract = {Motor neurone disease (MND) is a fatal neurological disorder, characterised by progressive weakness and wasting of muscles. The variety of hypotheses for its aetiopathogenesis are reflected in the large number of drugs tried in an attempt to modify disease progression. Although MND was first described by Charcot in the 1870s, there is as yet no known cure for the disease.}, }
@article {pmid7710370, year = {1995}, author = {Rosenberg, RN and Iannaccone, ST}, title = {The prevention of neurogenetic disease.}, journal = {Archives of neurology}, volume = {52}, number = {4}, pages = {356-362}, doi = {10.1001/archneur.1995.00540280038016}, pmid = {7710370}, issn = {0003-9942}, mesh = {Alzheimer Disease/diagnosis/genetics ; Base Sequence ; Brain Diseases/diagnosis/*genetics/prevention &amp; control ; DNA/genetics ; Fragile X Syndrome/diagnosis/genetics ; Genetic Markers ; Hereditary Sensory and Motor Neuropathy/diagnosis/genetics ; Humans ; Huntington Disease/diagnosis/genetics ; Molecular Sequence Data ; Muscular Dystrophies/diagnosis/genetics ; Myotonic Dystrophy/diagnosis/genetics ; Neurofibromatosis 1/diagnosis/genetics ; Neuromuscular Diseases/diagnosis/*genetics/prevention &amp; control ; Repetitive Sequences, Nucleic Acid ; Spinocerebellar Degenerations/diagnosis/genetics ; Tay-Sachs Disease/diagnosis/genetics ; }, abstract = {A significant number of major neurogenetic diseases have been defined at the molecular level in recent years, making it possible to determine precisely the genotype for familial Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dominantly inherited ataxia, Charcot-Marie-Tooth disease, myotonic muscular dystrophy, Duchenne-Becker muscular dystrophy, familial amyotrophic lateral sclerosis, and neurofibromatosis. This information has made it possible to identify the abnormal genotype of at-risk persons for these diseases and for at-risk pregnancies for several of them. Precise molecular diagnoses are thus possible using applied molecular markers. Prevention of disease can be achieved using these molecular markers with genetic counseling and appropriate family planning. Significant progress is being made in this regard with Tay-Sachs disease, Huntington's disease, the dominantly inherited ataxias, and the muscular dystrophies. Further, this molecular genotyping will be of indispensible value to families with these diseases when somatic cell gene therapy becomes available. The field of molecular neurogenetics is moving forward rapidly, and advances in gene identification for these diseases will lead in the near future to the means to prevent many of them.}, }
@article {pmid7671442, year = {1995}, author = {Walum, E and Eriksson, G and Peterson, A and Holme, E and Larsson, NG and Eriksson, C and el-Shamy, W}, title = {Use of primary cultures and continuous cell lines to study effects on astrocytic regulatory functions.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {22}, number = {4}, pages = {284-287}, doi = {10.1111/j.1440-1681.1995.tb01996.x}, pmid = {7671442}, issn = {0305-1870}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Astrocytes/*cytology/drug effects/physiology ; Biological Transport, Active ; Cell Line ; Cells, Cultured ; Energy Metabolism ; Glutamic Acid/*metabolism ; Metals/toxicity ; Oxygen Consumption/physiology ; Rats ; Solvents/toxicity ; }, abstract = {1. Current opinions on the mechanisms for glutamate-mediated neurotoxicity are reviewed. The protective role of astrocytic high-affinity glutamate transport is also discussed. 2. Low-density seeding of primary astrocytes from rat hemispheres was found to result in the development of reactive-like astrocytes. Typical glial signs of amyotrophic lateral sclerosis (ALS) could not be induced in astrocyte cultures by serum from ALS-patients. 3. Glutamate (100 mumol/L) was found to induce an increase in respiratory activity in primary cultures of astrocytes. This stimulation appeared to be related to the co-transport of Na2+ with glutamate and a resulting activation of Na2+/K(+)-ATPase. Both basal respiration and glutamate-stimulated oxygen consumption was inhibited by organic solvents. 4. Preliminary results show that heavy metals cause an increase in the mitochondrial DNA content at concentrations that have no effect on growth rate or morphology in a glial cell line. This increase was accompanied by an inhibition of oxygen consumption and an increased production of lactate at unaltered ATP levels.}, }
@article {pmid7614764, year = {1995}, author = {Konagaya, M and Sakai, M and Iida, M and Hashizume, Y}, title = {[An autopsied case of dominantly affecting upper motor neuron with atrophy of the frontal and temporal lobes--with special reference to primary lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {4}, pages = {384-390}, pmid = {7614764}, issn = {0009-918X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*pathology ; Atrophy ; Female ; Frontal Lobe/*pathology ; Humans ; Male ; Middle Aged ; Motor Neurons/*pathology ; Temporal Lobe/*pathology ; }, abstract = {In this paper, the autopsy findings of a 78-year-old man mimicking primary lateral sclerosis (PLS) are reported. His clinical symptoms were slowly progressive spasticity, pseudobulbar palsy and character change. He died of sepsis 32 months after protracting the disease. The autopsy revealed severe atrophy of the frontal and temporal lobes. The histological findings were severe neuronal loss with gliosis in the precentral gyrus and left temporal lobe tip, loss of Betz cell, prominent demyelination throughout of the corticospinal tract, axonal swelling in the cerebral peduncule, severe degeneration of the amygdala, mild degeneration of the Ammon horn, normal substantia nigra, a few neuronal cells with central chromatolysis in the facial nerve nucleus and very mild neuronal cell loss in the spinal anterior horn. The anterior horn cell only occasionally demonstrated Bunina body by H &amp; E and cystatin-C stainings, as well as, skein-like inclusion by ubiquitin staining. Thus, this is a case of uncommon amyotrophic lateral sclerosis (ALS) dominantly affecting the upper motor neuron including the motor cortex and temporal limbic system. In analysis of nine cases of putative primary lateral sclerosis in the literature, six cases showed loss of Betz cell in the precentral gyrus, and four cases very mild involvement of the lower motor neuron such as central chromatolysis and eosinophilic inclusion body. Degeneration of the limbic system was observed in two cases. We indicated a possible subgroup with concomitant involvement in the motor cortex and temporal lobe in motor neuron disease dominantly affecting the upper motor neuron.}, }
@article {pmid7889564, year = {1995}, author = {Brown, RH}, title = {Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice.}, journal = {Cell}, volume = {80}, number = {5}, pages = {687-692}, doi = {10.1016/0092-8674(95)90346-1}, pmid = {7889564}, issn = {0092-8674}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/pathology ; Animals ; Cell Death ; Cytoskeleton/pathology ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*pathology ; Mutation ; Neurofilament Proteins/genetics/physiology ; Superoxide Dismutase/*genetics/metabolism ; }, }
@article {pmid7763331, year = {1995}, author = {Stephan, KM and Dettmers, C and Frackowiak, RS}, title = {[Organization and reorganization of the human cortex].}, journal = {Arzneimittel-Forschung}, volume = {45}, number = {3A}, pages = {390-393}, pmid = {7763331}, issn = {0004-4172}, mesh = {Brain Diseases/pathology/physiopathology ; Humans ; Motor Cortex/anatomy &amp; histology/pathology/*physiology ; Neuronal Plasticity/physiology ; Tomography, Emission-Computed ; }, abstract = {The potential mechanisms underlying recovery and reorganisation of the motor cortex are described on the basis of functional imaging studies. These were performed in normal subjects and patients over the past years by the Hammersmith group. The mechanisms of motor learning are discussed and altered patterns of activation after suffering from stroke, amyotrophic lateral sclerosis and amputation are described. The potential role of ispilateral cortical representation in the primary motor cortex, as well as the role of opercular premotor cortex, insular cortex and inferior parietal cortex are discussed.}, }
@article {pmid7638462, year = {1995}, author = {Bach, JR}, title = {Respiratory muscle aids for the prevention of pulmonary morbidity and mortality.}, journal = {Seminars in neurology}, volume = {15}, number = {1}, pages = {72-83}, doi = {10.1055/s-2008-1041010}, pmid = {7638462}, issn = {0271-8235}, mesh = {Humans ; Lung Diseases/epidemiology/*etiology/mortality/*prevention &amp; control ; Neuromuscular Diseases/*complications/physiopathology/therapy ; Respiration, Artificial/*instrumentation ; Respiratory Muscles/*physiopathology ; *Ventilators, Mechanical ; }, abstract = {The great majority of individuals with ventilatory failure due to paralytic syndromes can be managed entirely by noninvasive inspiratory and expiratory muscle aids. When the equipment is properly used, individuals may eventually become dependent on noninvasive IPPV 24 hours a day without ever being hospitalized, intubated, tracheostomized, or bronchoscoped. The use of noninvasive respiratory muscle aids eliminates the need for "crisis" decision making about whether or not to "go on a respirator." Use of respiratory muscle aids by ALS patients familiarizes them with ventilator dependency before any decision about tracheostomy needs to be made. These methods enhance quality of life in many ways, including permitting the use of GPB for security in the event of ventilator failure. They can also drastically decrease cost and optimize psychosocial functioning. These techniques should become part of the therapeutic armamentarium of every physician who treats patients with generalized neuromuscular disorders who have the potential to develop ventilatory insufficiency, mucus plugging, or both.}, }
@article {pmid7877963, year = {1995}, author = {Rowland, LP}, title = {Amyotrophic lateral sclerosis: human challenge for neuroscience.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {92}, number = {5}, pages = {1251-1253}, pmid = {7877963}, issn = {0027-8424}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Humans ; Mice ; Mice, Transgenic ; Superoxide Dismutase/*genetics ; }, }
@article {pmid7788965, year = {1995}, author = {Grisold, W and Drlicek, M and Liszka-Setinek, U and Wondrusch, E}, title = {Anti-tumour therapy in paraneoplastic neurological disease.}, journal = {Clinical neurology and neurosurgery}, volume = {97}, number = {1}, pages = {106-111}, doi = {10.1016/0303-8467(95)00003-3}, pmid = {7788965}, issn = {0303-8467}, mesh = {Antineoplastic Agents/administration &amp; dosage ; Autoantibodies/analysis ; Autoimmune Diseases/immunology/*therapy ; Brain/immunology ; Combined Modality Therapy ; Humans ; Immunosuppressive Agents/administration &amp; dosage ; Lambert-Eaton Myasthenic Syndrome/immunology/therapy ; Nervous System Diseases/immunology/*therapy ; Neurologic Examination ; Paraneoplastic Syndromes/immunology/*therapy ; Prognosis ; }, abstract = {Paraneoplastic neurological syndromes have attracted attention in recent years. Detection of auto-antibodies directed against CNS and PNS structures have suggested an autoimmune etiology. This review is based on reports from the past 10 years and summarizes the therapeutic results in 258 patients suffering from paraneoplastic neurological disease including paraneoplastic encephalomyelitis, sensory neuronopathy, cerebellar degeneration, motor neurone disease and stiff man syndrome. The results show that in some entities such as Lambert-Eaton syndrome successful treatment can be expected. In other syndromes such as subacute sensory neuronopathy or paraneoplastic cerebellar degeneration therapeutic success varies from 5 to 10%.}, }
@article {pmid9021260, year = {1995}, author = {Brooks, BR}, title = {Emerging directions in ALS therapeutics: palliative therapies at the advent of the twenty-first century.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {386-392}, pmid = {9021260}, issn = {1065-6766}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; }, }
@article {pmid9021259, year = {1995}, author = {Pioro, EP and Mitsumoto, H}, title = {Animal models of ALS.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {375-385}, pmid = {9021259}, issn = {1065-6766}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; *Disease Models, Animal ; Dogs ; Humans ; Mice ; }, abstract = {Animal models of amyotrophic lateral sclerosis (ALS) provide a unique opportunity to study this incurable and fatal human disease both clinically and pathologically. This is particularly true for certain pathological and therapeutic studies that are impractical or impossible to perform in human patients. Nonetheless, postmortem ALS tissue remains the "gold standard" against which pathologic findings in animal models must be compared. Four natural disease models have been most extensively studied, including three mouse models: motor neuron degeneration (Mnd), progressive motor neuronopathy (pmn), wobbler, and one canine model: hereditary canine spinal muscular atrophy (HCSMA). The wobbler mouse has been the most extensively studied of these models with analyses of clinical, pathological (perikaryon, axon, muscle), and biochemical features. Experimentally induced ALS animal models have allowed controlled testing of various neurotoxic, viral and immune-mediated mechanisms. Molecular techniques have recently generated mouse models in which genes relevant to the human disease or motor neuron biology have been manipulated. The most clinically relevant of these is a transgenic mouse overexpressing the mutated SOD1 gene of FALS patients, which has already provided significant insights into mechanisms of motor neuron degeneration in this disease. Because no single animal model perfectly reflects all the clinical and pathological characteristics of ALS, study of selected features from the most relevant models will contribute to a better understanding of the pathogenesis and/or etiology of this disease.}, }
@article {pmid9021258, year = {1995}, author = {Appel, SH and Smith, RG and Alexianu, M and Siklos, L and Engelhardt, J and Colom, LV and Stefani, E}, title = {Increased intracellular calcium triggered by immune mechanisms in amyotrophic lateral sclerosis.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {368-374}, pmid = {9021258}, issn = {1065-6766}, support = {NS343186/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/immunology/*metabolism ; Animals ; Calcium/*metabolism ; Humans ; Mice ; }, abstract = {Although the causes of motor neuron degeneration and death in amyotrophic lateral sclerosis (ALS) is unknown, recent evidence suggests a prominent role for increased intracellular calcium, possibly triggered by autoimmune mechanisms. The presence in ALS patients of paraproteinemias, lymphomas, lymphoid cells in the central nervous system (CNS) and the availability of animal models of immune-mediated motor neuron disease provide circumstantial evidence for autoimmunity. Direct evidence derives from the demonstration that ALS IgGs bind to voltage-gated calcium channels in 75% of sporadic cases, but not in familial ALS cases, and that ALS IgGs increase N-type and P-type calcium currents in neuronal cells and in lipid bilayers. These same ALS IgGs are cytotoxic for a motor neuron cell line (VSC 4.1) in vitro. In addition, following passive transfer to mice in vivo, ALS IgGs produce ultrastructural and calcium changes in synaptic vesicles and mitochondria of motor axon terminals, as well as in rough endoplasmic reticulum and Golgi complex of motor neuron perikarya, but not in sensory neurons or Purkinje cells. The reason for the selective vulnerability of motor neurons is not clearly defined, but a prominent possibility is the physiological absence in motor neurons of the calcium-binding proteins calbindin-D28k and parvalbumin. These studies emphasize the central role of increased intracellular calcium in motor neuron cell death in sporadic ALS, and the role of autoimmunity in triggering such increases.}, }
@article {pmid9021257, year = {1995}, author = {Salazar-Grueso, EF and Roos, RP}, title = {Amyotrophic lateral sclerosis and viruses.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {360-367}, pmid = {9021257}, issn = {1065-6766}, support = {1 P01 NS21442/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*virology ; DNA Viruses/*physiology ; Humans ; RNA Viruses/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease of unknown etiology. A number of theories have been pursued to explain the cause of ALS, including viral infection. This review examines the evidence implicating viruses in the pathogenesis of ALS, as well as current studies of naturally occurring and experimental models of virus-induced motor neuron disease (MND). The association of viruses and ALS remains to be established. The study of animal models of virus-induced MND may shed light on processes relevant to the etiology of ALS.}, }
@article {pmid9021256, year = {1995}, author = {Rothstein, JD}, title = {Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {348-359}, pmid = {9021256}, issn = {1065-6766}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Glutamic Acid/metabolism ; Humans ; Nerve Degeneration/*physiology ; Neurotransmitter Agents/metabolism/*toxicity ; }, abstract = {The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but several observations suggest that glutamate could participate in selective motor neuron degeneration. Extracellular levels of glutamate are elevated in ALS. Synaptic concentrations of glutamate are regulated by high-affinity glutamate transport, and defects in glutamate transport have also been observed in ALS tissue. Three sodium-dependent glutamate transporters have now been identified: a neuronal transporter EAAC1, and two astroglial transporters GLT-1 and GLAST. The defect in glutamate transport in ALS appears to be relatively specific for the GLT-1 subtype. The role of chronic excess glutamate and glutamate transporter loss has been investigated in experimental paradigms, where it was found that excitotoxicity could account for selective motor neuron degeneration. These culture paradigms have demonstrated that motor neurons are sensitive to glutamate toxicity via non-NMDA receptors and that various agents (e.g., antioxidants, glutamate release inhibitors, non-NMDA receptor antagonists) can be neuroprotective. These experimental studies will provide a basis for understanding the primary and secondary role of glutamate in motor neuron death and will provide important insight into possible therapeutic interventions.}, }
@article {pmid9021255, year = {1995}, author = {Siddique, T and Hentati, A}, title = {Familial amyotrophic lateral sclerosis.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {338-347}, pmid = {9021255}, issn = {1065-6766}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; Mutation/genetics ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is inherited in ten percent of cases as a Mendelien trait. Familial ALS (FALS) is genetically heterogeneous and transmitted either as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait. Fifteen percent of DFALS families have mutations in the gene for Cu,Zn superoxide dismutase (SOD1) which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Several observations suggest that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed. The role of eventual neurofilament involvement in the pathogenesis of ALS is also discussed. The locus for one form of RFALS has been mapped to chromosome 2q33. FALS can also be associated with dementia and the gene locus for one form of hereditary ALS-dementia syndrome maps to chromosome 17q21-22.}, }
@article {pmid9021252, year = {1995}, author = {Bradley, WG}, title = {Overview of motor neuron disease: classification and nomenclature.}, journal = {Clinical neuroscience (New York, N.Y.)}, volume = {3}, number = {6}, pages = {323-326}, pmid = {9021252}, issn = {1065-6766}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Motor Neuron Disease/*classification ; Terminology as Topic ; }, abstract = {Amyotrophic lateral sclerosis (ALS), although a disease that has been well recognized for nearly 150 years, still causes problems of diagnosis and management, as there is no definitive diagnostic test, and the disease is pleomorphic. Research criteria were developed for the categorization of definite, probable, and possible ALS at the El Escorial Workshop (published in 1994). The principal features are upper and lower motor neuron signs at several levels of the neuraxis, without involvement of other neurological systems. Separation of ALS or motor neuron disease (MND) from the spinal muscular atrophies or hereditary spastic paraplegia can be difficult. The relatively rapid progression to death in an average of 5 years is one of the hallmarks of ALS. However, some cases are relatively more benign. The recent finding that mutations of the SOD1 gene underlie about 20% of familial cases of ALS has allowed the recognition that all phenotypes can occur in different members of the same family with the same mutation, clarifying earlier suggestions that different phenotypes represent different diseases. Until the cause and cure of ALS are found, neurologists and rehabilitation specialists must continue to provide essential support for patients with this devastating disease.}, }
@article {pmid8817667, year = {1995}, author = {Lee, CY and Rechler, MM}, title = {Formation of 150-kDa binary complexes of insulin-like growth factor binding protein-3 and the acid-labile subunit in vitro and in vivo.}, journal = {Progress in growth factor research}, volume = {6}, number = {2-4}, pages = {241-251}, doi = {10.1016/0955-2235(95)00014-3}, pmid = {8817667}, issn = {0955-2235}, mesh = {Animals ; Carrier Proteins/*metabolism ; Endopeptidases/metabolism ; Glycoproteins/*metabolism ; In Vitro Techniques ; Insulin-Like Growth Factor Binding Protein 3/*metabolism ; Insulin-Like Growth Factor I/metabolism ; Molecular Weight ; Protein Conformation ; Rats ; Somatomedins/*metabolism ; }, abstract = {Adult rat serum contains two types of 150-kDa IGFBP complexes: ternary complexes containing bound IGF-I, intact IGFBP-3 and the acid-labile subunit (ALS), and binary complexes that contain ALS and proteolytically-nicked IGFBP-3 but which lack bound IGF. We present evidence that the binary complexes containing proteolytically-nicked IGFBP-3 can be formed in two ways: by direct association of IGFBP-3 with ALS in the absence of IGF, and by proteolysis of IGFBP-3 within 150-kDa ternary complexes, resulting in increased dissociation of IGF-I. The relative contributions of the two mechanisms is unknown. Preliminary results indicate that binary complexes also can form in vivo. Proteolysis of IGFBP-3 in the 150-kDa ternary complex provides a regulatable mechanism by which IGF-I may be mobilized from the circulating reservoir of 150-kDa complexes to the tissues.}, }
@article {pmid8817659, year = {1995}, author = {Scharf, JG and Ramadori, G and Braulke, T and Hartmann, H}, title = {Cellular localization and hormonal regulation of biosynthesis of insulin-like growth factor binding proteins and of the acid-labile subunit within rat liver.}, journal = {Progress in growth factor research}, volume = {6}, number = {2-4}, pages = {175-180}, doi = {10.1016/0955-2235(95)00031-3}, pmid = {8817659}, issn = {0955-2235}, mesh = {Animals ; Carrier Proteins/*biosynthesis ; Glycoproteins/*biosynthesis ; Insulin/physiology ; Insulin-Like Growth Factor Binding Protein 3/*biosynthesis ; Liver/*metabolism ; Models, Biological ; Rats ; Somatomedins/*metabolism ; Tissue Distribution ; }, abstract = {In the circulation, most of the IGFs are bound to a high molecular weight binding protein complex of 150 kDa that consists of IGF-I (or IGF-II), IGFBP-3 and the acid-labile subunit (ALS). Within rat liver, individual components of the 150 kDa complex are synthesized in different cellular compartments. ALS expression is localized in hepatocytes, but not in non-parenchymal cells. IGFBP-3 mRNA, however, is exclusively expressed in non-parenchymal and among them in endothelial and Kupffer cells. Co-cultures of hepatocytes and Kupffer cells were used as a model to study the hormonal regulation of biosynthesis of the components of the 150 kDa complex. Although expressed in different liver cell populations IGFBP-3 and ALS were regulated synergistically. Insulin stimulated both the expression of ALS and IGFBP-3 in co-cultures in a dose-dependent manner, while expression of IGFBP-I was decreased. Regulation of IGFBP-3 synthesis of Kupffer cells required a mediator that is secreted by hepatocytes, since IGFBP-3 expression in cultures of pure Kupffer cells did not respond to the stimulating effect of insulin.}, }
@article {pmid8817656, year = {1995}, author = {Ooi, GT and Cohen, FJ and Hsieh, S and Seto, D and Rechler, MM and Boisclair, YR}, title = {Structure and regulation of the ALS gene.}, journal = {Progress in growth factor research}, volume = {6}, number = {2-4}, pages = {151-157}, doi = {10.1016/0955-2235(95)00024-0}, pmid = {8817656}, issn = {0955-2235}, mesh = {Animals ; Carrier Proteins/*genetics ; Chromosome Mapping ; *Gene Expression Regulation ; Glycoproteins/*genetics ; Humans ; Mice ; Rats ; Somatomedins/*physiology ; }, abstract = {The mouse ALS gene spans at least 6 kb. It contains 2 exons which encode a protein highly homologous to human and rat ALS. It was localized to mouse chromosome 17 by flourescent in situ hybridization. The 5' flanking region lacks a TATA box but contains GC boxes that may be recognised by transcription factors such as Spl. Hepatic ALS mRNA is decreased in rats following hypophysectomy, and restored by stimulated ALS promoter activity in a rat hepatoma cell line, but not in 3T3-F442A mouse preadipocyte fibroblasts, suggesting that utilisation of the ALS promoter is cell-type specific. The rat hepatoma system is a promising system to study the regulation of ALS gene expression, and the signalling pathways of CH regulation.}, }
@article {pmid8787247, year = {1995}, author = {Rowland, LP}, title = {Amyotrophic lateral sclerosis with paraproteins and autoantibodies.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {93-105; discussion 107-11}, pmid = {8787247}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; Antibodies, Monoclonal ; *Autoantibodies ; Humans ; Motor Neuron Disease/*metabolism ; Paraproteins/*metabolism ; }, }
@article {pmid8787246, year = {1995}, author = {Mitsumoto, H and Pioro, EP}, title = {Animal models of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {73-87; discussion 89-91}, pmid = {8787246}, issn = {0091-3952}, mesh = {Aluminum/toxicity ; Amyotrophic Lateral Sclerosis/*metabolism/*physiopathology ; Animals ; *Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neuron Disease/*physiopathology ; *Neurotoxins ; }, }
@article {pmid8787245, year = {1995}, author = {Rothstein, JD}, title = {Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {7-20; discussion 21-7}, pmid = {8787245}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; Glutamic Acid/*metabolism ; Humans ; Models, Biological ; Neurotoxins/*metabolism/*toxicity ; Neurotransmitter Agents/metabolism ; Receptors, Glutamate/metabolism ; }, abstract = {A large number of studies have documented abnormalities of glutamate metabolism in ALS patients or in postmortem ALS tissue. These abnormalities include altered synthetic enzymes, tissue glutamate levels, transporter proteins, and postsynaptic receptors, as well as the presence of potentially toxic agonists. As yet, there is no hypothesis effectively linking all the observations to one central defect. Furthermore, it is not clear if the various abnormalities in glutamate systems represent a primary defect or a secondary response. For example, defects of glutamate transport subtypes could reflect the primary loss of the proteins or the secondary effect of another toxic insult. Nevertheless, experimental paradigms suggest that, even if secondary, glutamate could contribute to the death of motor neurons. Therefore, interventions to minimize the toxicity of glutamate (e.g., receptor antagonists, release inhibitors, or antioxidants) could partially ameliorate the degeneration of motor neurons. This has been observed experimentally in cultured motor neurons. More importantly, a small study with riluzole suggests that glutamate-acting drugs could alter the progression of the disease. Future studies with riluzole and other glutamate-acting agents will evaluate this possibility.}, }
@article {pmid8787244, year = {1995}, author = {Seagar, MJ and Martin-Moutot, N and Leveque, C and Marqueze, B and Pouget, J}, title = {Anti-calcium channel autoantibodies in amyotrophic lateral sclerosis. A review of the evidence.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {67-72}, pmid = {8787244}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Animals ; *Autoantibodies ; Calcium Channels/*drug effects/*immunology ; Molecular Structure ; }, }
@article {pmid8787243, year = {1995}, author = {Drachman, DB and Fishman, PS and Rothstein, JD and Motomura, M and Lang, B and Vincent, A and Mellits, ED}, title = {Amyotrophic lateral sclerosis. An autoimmune disease?.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {59-65}, pmid = {8787243}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Antibodies ; *Autoimmunity ; Disease Models, Animal ; Immunosuppression Therapy ; }, }
@article {pmid8787242, year = {1995}, author = {Appel, SH and Smith, RG and Alexianu, MF and Engelhardt, JI and Stefani, E}, title = {Autoimmunity as an etiological factor in sporadic amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {47-57}, pmid = {8787242}, issn = {0091-3952}, support = {NS33186/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Animals ; Antibodies ; *Autoimmunity ; Calcium Channels/immunology ; Humans ; Inflammation ; Motor Neuron Disease/*etiology ; }, }
@article {pmid8787241, year = {1995}, author = {Hosler, BA and Brown, RH}, title = {Copper/zinc superoxide dismutase mutations and free radical damage in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {41-46}, pmid = {8787241}, issn = {0091-3952}, support = {1P01NS31248/NS/NINDS NIH HHS/United States ; NS31248-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Cell Death ; Copper/*metabolism ; Free Radicals/metabolism ; Humans ; Mutation ; Superoxide Dismutase/*genetics ; Zinc/*metabolism ; }, }
@article {pmid8787240, year = {1995}, author = {Pinelli, P and Pisano, F and Miscio, G}, title = {The possible role of a secondary pathogenetic factor in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {29-40}, pmid = {8787240}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; *Autoimmunity ; *Electroencephalography ; Glutamic Acid/*metabolism ; Humans ; Time Factors ; }, }
@article {pmid8787238, year = {1995}, author = {Blin, O}, title = {Should N-methyl-D-aspartate or non-N-methyl-D-aspartate glutamate receptor antagonist be used in amyotrophic lateral sclerosis?.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {259-261}, pmid = {8787238}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Models, Animal ; Excitatory Amino Acid Antagonists ; Humans ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors ; }, }
@article {pmid8787237, year = {1995}, author = {Hugon, J}, title = {Excitotoxic blocking strategies in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {245-52; discussion 253-8}, pmid = {8787237}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Anticonvulsants/pharmacology ; Humans ; Lamotrigine ; *Neurotoxins ; Presynaptic Terminals/*drug effects/*metabolism ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors ; Threonine/pharmacology ; Triazines/pharmacology ; }, }
@article {pmid8787236, year = {1995}, author = {Askanas, V}, title = {Neurotrophic factors and amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {241-244}, pmid = {8787236}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain-Derived Neurotrophic Factor ; Cells, Cultured/drug effects ; Motor Neurons/*drug effects ; Nerve Growth Factors/*pharmacology ; Nerve Tissue Proteins/pharmacology ; }, }
@article {pmid8787235, year = {1995}, author = {Henderson, CE}, title = {Neurotrophic factors as therapeutic agents in amyotrophic lateral sclerosis. Potential and pitfalls.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {235-240}, pmid = {8787235}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Motor Neuron Disease/*drug therapy ; Nerve Growth Factors/*adverse effects/*physiology/*therapeutic use ; Treatment Outcome ; }, }
@article {pmid8787233, year = {1995}, author = {Azulay, JP}, title = {The design of clinical trials in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {225-227}, pmid = {8787233}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Clinical Trials as Topic ; Electrophysiology ; Humans ; Motor Neuron Disease/*therapy ; *Research Design ; }, }
@article {pmid8787232, year = {1995}, author = {Conradi, S and Ronnevi, LO}, title = {Megaslope, natural course, and historical controls in amyotrophic lateral sclerosis trials.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {219-224}, pmid = {8787232}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology/*therapy ; Clinical Trials as Topic ; Humans ; Linear Models ; Motor Neuron Disease/*diagnosis/*physiopathology/*therapy ; Research Design ; Statistics as Topic ; }, }
@article {pmid8787231, year = {1995}, author = {Munsat, TL}, title = {Issues in amyotrophic lateral sclerosis clinical trial design.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {209-218}, pmid = {8787231}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Clinical Trials as Topic ; Humans ; Motor Neuron Disease/*therapy ; Quality of Life ; *Research Design ; Statistics as Topic ; }, }
@article {pmid8787230, year = {1995}, author = {Meininger, V and Bensimon, G and Lacomblez, L and Salachas, F}, title = {Natural history of amyotrophic lateral sclerosis. A discussion.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {199-207}, pmid = {8787230}, issn = {0091-3952}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; *Diagnosis, Differential ; Follow-Up Studies ; Humans ; Motor Activity ; Motor Neuron Disease/*diagnosis/*physiopathology ; Respiration ; }, }
@article {pmid8787229, year = {1995}, author = {Guiloff, RJ and Goonetilleke, A}, title = {Natural history of amyotrophic lateral sclerosis. Observations with the Charing Cross Amyotrophic Lateral Sclerosis Rating Scales.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {185-198}, pmid = {8787229}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; *Diagnosis, Differential ; Humans ; Motor Activity ; Motor Neuron Disease/*diagnosis/*physiopathology ; Prognosis ; }, abstract = {Natural history data increase the descriptive knowledge about amyotrophic lateral sclerosis (ALS), help define primary outcome variables and numbers of patients needed on clinical trials, and may give valuable predictive information. Global scores do not adequately represent the clinical variability of ALS. The Charing Cross Quantitative and Qualitative ALS Rating Scales assess disease severity and progression by validated regional scores (bulbar, respiration, upper limb, lower limb) and activities of daily living. The main stages in the development of these scales are summarized. Interval, or quantitative, scales provide accurate and sensitive measurements of the evolution of the disease and are useful for phase II therapeutic trials. The deterioration rates of regional scores in individual patients may not be linear. Rates of disease progression in ALS vary (1) among patients, (2) among topographical regions within a single patient, and (3) at different stages of the disease in a single region in the same patient. The deterioration rates of the regional scores of an ALS population depend critically on whether deaths are included or excluded from the population mean scores. Qualitative scales with simple scores are best suited for large-scale, phase III trials and for life table analysis of times to failure.}, }
@article {pmid8787228, year = {1995}, author = {Brooks, BR and Shodis, KA and Lewis, DH and Rawling, JD and Sanjak, M and Belden, DS and Hakim, H and DeTan, Y and Gaffney, JM}, title = {Natural history of amyotrophic lateral sclerosis. Quantification of symptoms, signs, strength, and function.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {163-184}, pmid = {8787228}, issn = {0091-3952}, support = {M01RR03186/RR/NCRR NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; *Diagnosis, Differential ; Humans ; Motor Activity ; *Neurophysiology ; Reflex/physiology ; Time Factors ; }, }
@article {pmid8787227, year = {1995}, author = {Cambier, J and Serratrice, J}, title = {Clues to the diagnosis of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {161-162}, pmid = {8787227}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; *Fasciculation ; Humans ; Motor Neuron Disease/*diagnosis ; *Muscle Weakness ; }, }
@article {pmid8787226, year = {1995}, author = {Swash, M}, title = {The diagnosis of amyotrophic lateral sclerosis. A discussion.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {157-160}, pmid = {8787226}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; *Fasciculation ; Humans ; Motor Neuron Disease/*diagnosis ; }, }
@article {pmid8787225, year = {1995}, author = {Ben Hamida, M and Hentati, F}, title = {Atypical amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {153-155}, pmid = {8787225}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Ganglia, Sensory/*physiopathology ; Genetic Diseases, Inborn ; Humans ; }, }
@article {pmid8787224, year = {1995}, author = {Pouget, J and Azulay, JP and Billé-Turc, F and Sangla, I and Serratrice, GT}, title = {The diagnosis of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {143-152}, pmid = {8787224}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Bulbar Palsy, Progressive/*diagnosis ; Cognition ; Evoked Potentials ; Eye Movements ; Ganglia, Sensory/physiopathology ; Humans ; Motor Neuron Disease/*diagnosis ; }, }
@article {pmid8787223, year = {1995}, author = {Pellissier, JF and Baêta, AM and Figarella-Branger, D}, title = {Neuropathology of the cortex in amyotrophic lateral sclerosis with dementia.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {139-141}, pmid = {8787223}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Cell Count ; Cerebral Cortex/*pathology ; Dementia/*pathology ; Humans ; Neurons/pathology ; }, }
@article {pmid8787221, year = {1995}, author = {Eisen, AA}, title = {Amyotrophic lateral sclerosis. A multifactorial disease.}, journal = {Advances in neurology}, volume = {68}, number = {}, pages = {121-134}, pmid = {8787221}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*etiology/*metabolism ; *Genetic Diseases, Inborn ; Glutamic Acid/*metabolism ; Humans ; Nerve Growth Factors/metabolism ; Risk Factors ; *Second Messenger Systems ; }, }
@article {pmid8660387, year = {1995}, author = {Davies, KJ}, title = {Oxidative stress: the paradox of aerobic life.}, journal = {Biochemical Society symposium}, volume = {61}, number = {}, pages = {1-31}, doi = {10.1042/bss0610001}, pmid = {8660387}, issn = {0067-8694}, mesh = {Antioxidants/metabolism ; DNA Damage ; Humans ; *Oxidative Stress ; Oxygen/metabolism ; Radioactive Pollutants ; Reactive Oxygen Species ; Superoxide Dismutase/metabolism ; }, abstract = {The paradox of aerobic life, or the 'Oxygen Paradox', is that higher eukaryotic aerobic organisms cannot exist without oxygen, yet oxygen is inherently dangerous to their existence. This 'dark side' of oxygen relates directly to the fact that each oxygen atom has one unpaired electron in its outer valence shell, and molecular oxygen has two unpaired electrons. Thus atomic oxygen is a free radical and molecular oxygen is a (free) bi-radical. Concerted tetravalent reduction of oxygen by the mitochondrial electron-transport chain, to produce water, is considered to be a relatively safe process; however, the univalent reduction of oxygen generates reactive intermediates. The reductive environment of the cellular milieu provides ample opportunities for oxygen to undergo unscheduled univalent reduction. Thus the superoxide anion radical, hydrogen peroxide and the extremely reactive hydroxyl radical are common products of life in an aerobic environment, and these agents appear to be responsible for oxygen toxicity. To survive in such an unfriendly oxygen environment, living organisms generate--or garner from their surroundings--a variety of water- and lipid-soluble antioxidant compounds. Additionally, a series of antioxidant enzymes, whose role is to intercept and inactivate reactive oxygen intermediates, is synthesized by all known aerobic organisms. Although extremely important, the antioxidant enzymes and compounds are not completely effective in preventing oxidative damage. To deal with the damage that does still occur, a series of damage removal/repair enzymes, for proteins, lipids and DNA, is synthesized. Finally, since oxidative stress levels may vary from time to time, organisms are able to adapt to such fluctuating stresses by inducing the synthesis of antioxidant enzymes and damage removal/repair enzymes. In a perfect world the story would end here; unfortunately, biology is seldom so precise. The reality appears to be that, despite the valiant antioxidant and repair mechanisms described above, oxidative damage remains an inescapable outcome of aerobic existence. In recent years oxidative stress has been implicated in a wide variety of degenerative processes, diseases and syndromes, including the following: mutagenesis, cell transformation and cancer; atherosclerosis, arteriosclerosis, heart attacks, strokes and ischaemia/reperfusion injury; chronic inflammatory diseases, such as rheumatoid arthritis, lupus erythematosus and psoriatic arthritis; acute inflammatory problems, such as wound healing; photo-oxidative stresses to the eye, such as cataract; central-nervous-system disorders, such as certain forms of familial amyotrophic lateral sclerosis, certain glutathione peroxidase-linked adolescent seizures, Parkinson's disease and Alzheimer's dementia; and a wide variety of age-related disorders, perhaps even including factors underlying the aging process itself. Some of these oxidation-linked diseases or disorders can be exacerbated, perhaps even initiated, by numerous environmental pro-oxidants and/or pro-oxidant drugs and foods. Alternatively, compounds found in certain foods may be able to significantly bolster biological resistance against oxidants. Currently, great interest centres on the possible protective value of a wide variety of plant-derived antioxidant compounds, particularly those from fruits and vegetables.}, }
@article {pmid8585475, year = {1995}, author = {McComas, AJ and Miller, RG and Gandevia, SC}, title = {Fatigue brought on by malfunction of the central and peripheral nervous systems.}, journal = {Advances in experimental medicine and biology}, volume = {384}, number = {}, pages = {495-512}, doi = {10.1007/978-1-4899-1016-5_38}, pmid = {8585475}, issn = {0065-2598}, mesh = {Central Nervous System Diseases/*physiopathology ; Humans ; Multiple Sclerosis/physiopathology ; Muscle Fatigue/*physiology ; Neuromuscular Diseases/*physiopathology ; Peripheral Nervous System Diseases/*physiopathology ; Time Factors ; }, abstract = {Increased fatigability necessarily occurs in every patient with muscle weakness, regardless of whether the latter is due to a central or peripheral neurological disorder. The tendency for disuse to increase fatigability, as a secondary phenomenon, must also be considered; disuse affects both motoneuron recruitment and the biochemical and physiological properties of the muscle fibers. In recent studies impaired recruitment has been observed in postpolio patients, while patients with multiple sclerosis or spinal cord injury have shown, in addition, altered neuromuscular function. Findings are also presented in ALS and the chronic fatigue syndrome. In general, the most dramatic increases in fatigability take place in disorders of the peripheral nervous system and almost any cell component can be incriminated. There is a need to study fatigability systematically in neurology and rehabilitation.}, }
@article {pmid7796839, year = {1995}, author = {Aebischer, P and Kato, AC}, title = {Treatment of amyotrophic lateral sclerosis using a gene therapy approach.}, journal = {European neurology}, volume = {35}, number = {2}, pages = {65-68}, doi = {10.1159/000117095}, pmid = {7796839}, issn = {0014-3022}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Capsules ; Cell Line ; Ciliary Neurotrophic Factor ; *Genetic Therapy ; Humans ; Nerve Growth Factors/therapeutic use ; Nerve Tissue Proteins/genetics/therapeutic use ; Polymers ; }, abstract = {Neurotrophic factors which act on motor neurons may provide an efficient treatment for amyotrophic lateral sclerosis. In order to overcome the difficulty of administering proteins into the central nervous system, it is possible to use a gene therapy approach, i.e. the polymer encapsulation of cells which have been genetically engineered to release one of these neurotrophic factors. The polymer-encapsulated cells can be implanted subcutaneously or even intrathecally and permit continuous, slow release of proteins. There is no rejection of the cells due to their isolation by a semi-permeable membrane, no risk of tumor formation and the polymer device can be removed in the event of a problem.}, }
@article {pmid7778388, year = {1995}, author = {Iakhno, NN and Shtul'tan, DR and Elkin, MN and Zakharov, VV}, title = {[The amyotrophic lateral sclerosis syndrome--frontal-type dementia].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {95}, number = {1}, pages = {20-23}, pmid = {7778388}, issn = {1997-7298}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/psychology ; Chronic Disease ; Dementia/*diagnosis/etiology/psychology ; Diagnosis, Differential ; *Frontal Lobe ; Humans ; Male ; Middle Aged ; Psychopathology ; Syndrome ; }, abstract = {The article presents analysis of clinical case of and review of literature on "ALS-dementia complex", a combination of ALS syndrome and dementia predominantly of frontal lobe type. The review of literature contains discussion on the problem of lobe dementia, analysis of relation of ALS-dementia syndrome and the following diseases: Alzheimer, Pick, Creutzfeldt-Jakob, Lewy bodies, Charcot (classic type), multisystem degeneration. Polymorphism of ALS-dementia complex and the possibilities of its differential diagnosis are considered.}, }
@article {pmid7742172, year = {1995}, author = {Williams, LR}, title = {Oxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment.}, journal = {Cerebrovascular and brain metabolism reviews}, volume = {7}, number = {1}, pages = {55-73}, pmid = {7742172}, issn = {1040-8827}, mesh = {Aging/*physiology ; Animals ; Humans ; *Nerve Degeneration ; Nerve Growth Factors/*therapeutic use ; Nervous System Diseases/etiology ; *Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.}, }
@article {pmid7618430, year = {1995}, author = {Robberecht, W}, title = {New treatment strategies in amyotrophic lateral sclerosis: solutions or illusions?.}, journal = {Acta neurologica Belgica}, volume = {95}, number = {2}, pages = {65-69}, pmid = {7618430}, issn = {0300-9009}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Antioxidants/therapeutic use ; Autoimmune Diseases/metabolism ; Excitatory Amino Acid Antagonists ; Free Radicals/toxicity ; Glutamates/metabolism ; Humans ; Nerve Growth Factors/metabolism ; Nerve Tissue Proteins/metabolism/therapeutic use ; }, }
@article {pmid7598450, year = {1995}, author = {Smith, RG and Appel, SH}, title = {Molecular approaches to amyotrophic lateral sclerosis.}, journal = {Annual review of medicine}, volume = {46}, number = {}, pages = {133-145}, doi = {10.1146/annurev.med.46.1.133}, pmid = {7598450}, issn = {0066-4219}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/mortality/physiopathology ; Autoimmune Diseases/genetics/mortality/physiopathology ; Free Radicals ; Glutamic Acid/physiology ; Humans ; Isoenzymes/genetics ; Motor Neurons/physiology ; Mutation ; Nerve Degeneration/genetics/physiology ; Phenotype ; Superoxide Dismutase/genetics ; Survival Rate ; }, abstract = {New discoveries are expanding our knowledge of mechanisms involved in amyotrophic lateral sclerosis (ALS) pathogenesis. Some recent advances in our understanding of motoneuron death in familial ALS (fALS) and sporadic ALS (sALS) are reviewed, with emphasis on molecular similarities that may further unite these phenotypically linked diseases.}, }
@article {pmid7482223, year = {1995}, author = {Antel, JP and Cashman, NR}, title = {Immunological findings in amyotrophic lateral sclerosis.}, journal = {Springer seminars in immunopathology}, volume = {17}, number = {1}, pages = {17-28}, pmid = {7482223}, issn = {0344-4325}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Humans ; }, }
@article {pmid7475893, year = {1995}, author = {Bowling, AC and Beal, MF}, title = {Bioenergetic and oxidative stress in neurodegenerative diseases.}, journal = {Life sciences}, volume = {56}, number = {14}, pages = {1151-1171}, doi = {10.1016/0024-3205(95)00055-b}, pmid = {7475893}, issn = {0024-3205}, support = {5P 50 AG-05134/AG/NIA NIH HHS/United States ; NS-16367/NS/NINDS NIH HHS/United States ; P01 AG-11337/AG/NIA NIH HHS/United States ; }, mesh = {Aging ; Alzheimer Disease/etiology/metabolism ; Amyotrophic Lateral Sclerosis/etiology/metabolism ; Animals ; DNA, Mitochondrial/genetics ; *Energy Metabolism ; Humans ; Huntington Disease/etiology/metabolism ; Mitochondria/physiology ; Mutation ; Nervous System Diseases/*etiology/metabolism/pathology ; *Oxidative Stress ; Parkinson Disease/etiology/metabolism ; }, abstract = {Aging is a major risk factor for several common neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Recent studies have implicated mitochondrial dysfunction and oxidative stress in the aging process and also in the pathogenesis of neurodegenerative diseases. In brain and other tissues, aging is associated with progressive impairment of mitochondrial function and increased oxidative damage. In PD, several studies have demonstrated decreased complex I activity, increased oxidative damage, and altered activities of antioxidant defense systems. Some cases of familial ALS are associated with mutations in the gene for Cu, Zn superoxide dismutase (Cu, Zn SOD) and decreased Cu, Zn SOD activity, while in sporadic ALS oxidative damage may be increased. Defects in energy metabolism and increased cortical lactate levels have been detected in HD patients. Studies of AD patients have identified decreased complex IV activity, and some patients with AD and PD have mitochondrial DNA mutations. The age-related onset and progressive course of these neurodegenerative diseases may be due to a cycling process between impaired energy metabolism and oxidative stress.}, }
@article {pmid7847672, year = {1994}, author = {Lipton, SA}, title = {AIDS-related dementia and calcium homeostasis.}, journal = {Annals of the New York Academy of Sciences}, volume = {747}, number = {}, pages = {205-224}, doi = {10.1111/j.1749-6632.1994.tb44411.x}, pmid = {7847672}, issn = {0077-8923}, support = {EY05477/EY/NEI NIH HHS/United States ; EY09024/EY/NEI NIH HHS/United States ; HD29587/HD/NICHD NIH HHS/United States ; }, mesh = {AIDS Dementia Complex/drug therapy/pathology/*physiopathology ; Astrocytes/physiology ; Calcium/*physiology ; Calcium Channel Blockers/pharmacology ; Central Nervous System/pathology ; HIV Envelope Protein gp120/pharmacology ; Homeostasis ; Humans ; Monocytes/physiology ; Nerve Degeneration ; Oligodendroglia/physiology ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/physiology ; }, abstract = {Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.}, }
@article {pmid7996280, year = {1994}, author = {Hintz, HF}, title = {Nutrition and equine performance.}, journal = {The Journal of nutrition}, volume = {124}, number = {12 Suppl}, pages = {2723S-2729S}, doi = {10.1093/jn/124.suppl_12.2723S}, pmid = {7996280}, issn = {0022-3166}, mesh = {Amino Acids/administration &amp; dosage ; Animal Feed ; *Animal Nutritional Physiological Phenomena ; Animals ; Dietary Proteins/administration &amp; dosage ; Energy Intake ; Energy Metabolism ; Horses/*physiology ; *Physical Conditioning, Animal ; Vitamin E/administration &amp; dosage ; }, abstract = {Some aspects of energy, protein and vitamin E nutrition of the performance horse are discussed. The amount, dietary source and time of ingestion of energy before exercise can influence performance. In 1989 the National Research Council (NRC) increased their estimates of energy required by racehorses. Recent studies indicate that the increase was reasonable. Many factors, however, can influence energy requirements. Therefore, the best measure would be body weight and composition of the horse. A proper balance of soluble carbohydrate, fiber, fat and protein is essential. Some guidelines are presented. The amount and type energy source given before exercise can influence level of plasma glucose and free fatty acids during exercise, but the effects of these changes in the concentration of metabolites remains to be determined. There is no evidence that increased dietary concentrations of protein are needed and, in fact, may impair performance. Supplemental histidine (to enhance carnosine levels) or carnitine appear to be of limited value for horses fed conventional diets. Dietary concentrations of vitamin E less than the 80 IU/kg recommended by NRC seem to adequately protect against exercise-induced peroxidation. The NRC value may be justified on the basis of immune response, but further studies are needed. Vitamin E has been shown to be involved with familial equine degenerative myeloencephalopathy and may be involved with equine motor neuron disease, a condition considered to be similar to amyotrophic lateral sclerosis in humans.}, }
@article {pmid7867282, year = {1994}, author = {Kaplan, LM and Hollander, D}, title = {Respiratory dysfunction in amyotrophic lateral sclerosis.}, journal = {Clinics in chest medicine}, volume = {15}, number = {4}, pages = {675-681}, pmid = {7867282}, issn = {0272-5231}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Female ; Humans ; Male ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/*physiopathology/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the voluntary motor system. Involvement of the respiratory system is inevitable and leads to the development of respiratory failure, the usual cause of death in this disorder. ALS at present is incurable, and only symptomatic treatment is available. This article presents guidelines for the recognition and management of respiratory failure.}, }
@article {pmid7866588, year = {1994}, author = {Olanow, CW and Arendash, GW}, title = {Metals and free radicals in neurodegeneration.}, journal = {Current opinion in neurology}, volume = {7}, number = {6}, pages = {548-558}, doi = {10.1097/00019052-199412000-00013}, pmid = {7866588}, issn = {1350-7540}, mesh = {Alzheimer Disease/*etiology/physiopathology ; Amyotrophic Lateral Sclerosis/*etiology/physiopathology ; Animals ; Cell Death/physiology ; Free Radicals/*adverse effects ; Humans ; Metals/*adverse effects ; Nerve Degeneration/physiology ; Oxidative Stress/physiology ; Parkinson Disease/*etiology/physiopathology ; }, abstract = {Substantial evidence has accumulated implicating metals and free radicals in the pathogenesis of the major neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Metal-induced oxidant stress can damage critical biological molecules and initiate a cascade of events including mitochondrial dysfunction, excitotoxicity, and a rise in cytosolic free calcium, leading to cell death. In Parkinson's disease and Alzheimer's disease there is evidence of oxidative stress in affected brain regions, as indicated by increased metal accumulation (which promotes free radical formation), decreased antioxidant levels (which protect against free radical formation), and oxidative damage. Recently, studies of the familial form of amyotrophic lateral sclerosis have detected mutations in the gene that encodes superoxide dismutase, which is one of the body's primary oxidant defense mechanisms. Mice that are transfected with the human mutant superoxide dismutase gene develop an amyotrophic lateral sclerosis syndrome. These studies demonstrate that oxidant stress can initiate the development of a chronic progressive neurodegenerative disorder.}, }
@article {pmid7529039, year = {1994}, author = {Kelly, M and Cats, M}, title = {Hospice care in motor neurone disease.}, journal = {Nursing standard (Royal College of Nursing (Great Britain) : 1987)}, volume = {9}, number = {9}, pages = {30-32}, doi = {10.7748/ns.9.9.30.s40}, pmid = {7529039}, issn = {0029-6570}, mesh = {Brain/physiopathology ; *Hospice Care ; Humans ; Motor Neuron Disease/*nursing/physiopathology ; Motor Neurons/physiology ; *Palliative Care ; Spinal Cord/physiopathology ; }, abstract = {Motor neurone disease is not automatically linked in people's minds with palliative care and the hospice movement, but an increasing number of people with the condition are benefiting from the services offered by hospices. The authors review what these services entail, and explain how they can help patients and families cope with this distressing illness.}, }
@article {pmid7832434, year = {1994}, author = {Chiueh, CC and Wu, RM and Mohanakumar, KP and Sternberger, LM and Krishna, G and Obata, T and Murphy, DL}, title = {In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia.}, journal = {Annals of the New York Academy of Sciences}, volume = {738}, number = {}, pages = {25-36}, doi = {10.1111/j.1749-6632.1994.tb21786.x}, pmid = {7832434}, issn = {0077-8923}, mesh = {Animals ; Antioxidants/pharmacology ; Basal Ganglia/drug effects/*metabolism/pathology ; Corpus Striatum/drug effects/*metabolism ; Dopamine/*metabolism ; Free Radical Scavengers ; Free Radicals/metabolism ; Humans ; Hydroxyl Radical/analysis/*metabolism ; *MPTP Poisoning ; Melanins/biosynthesis ; Nerve Degeneration/drug effects ; Parkinson Disease/*drug therapy/*metabolism ; Rats ; Salicylates ; Selegiline/pharmacology/therapeutic use ; Substantia Nigra/drug effects/*metabolism/pathology ; }, abstract = {The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid9216981, year = {1994}, author = {Price, DL and Cleveland, DW and Koliatsos, VE}, title = {Motor neurone disease and animal models.}, journal = {Neurobiology of disease}, volume = {1}, number = {1-2}, pages = {3-11}, doi = {10.1006/nbdi.1994.0002}, pmid = {9216981}, issn = {0969-9961}, support = {AG 05146/AG/NIA NIH HHS/United States ; NS 20471/NS/NINDS NIH HHS/United States ; NS 27036/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Disease Models, Animal ; Dogs ; Mice ; Motor Neuron Disease/*physiopathology ; Nerve Degeneration ; Rats ; }, }
@article {pmid7996698, year = {1994}, author = {Yoshino, H}, title = {[Immunological aspects of amyotrophic lateral sclerosis].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {52}, number = {11}, pages = {2984-2989}, pmid = {7996698}, issn = {0047-1852}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Autoantibodies/analysis ; Calcium Channels/immunology ; G(M1) Ganglioside/immunology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating human neurologic disorder which causes atrophy and weakness of skeletal muscles leading to death. Although pathogenesis of most cases of ALS is not known yet, large number of evidence suggest autoimmune mechanisms through clinical, pathological, and laboratory findings, for example, high frequency of the presence of serum monoclonal gammopathy, association of thyroid diseases, and lymphocytic infiltration of brain and spinal cord tissues of patients. Especially recent findings of IgG antibodies against calcium channels and IgM anti-GM1 antibodies are important to elucidate the pathogenesis of ALS. Although conventional immunotherapy may not be effective, multifocal motor neuropathy (MMN) which simulates ALS should be carefully examined because MMN is a treatable disorder.}, }
@article {pmid7996680, year = {1994}, author = {Tabira, T}, title = {[Target antigens in neuroimmunological diseases].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {52}, number = {11}, pages = {2855-2860}, pmid = {7996680}, issn = {0047-1852}, mesh = {Autoantigens/*immunology ; Autoimmune Diseases/*immunology ; Humans ; Nervous System Diseases/*immunology ; }, abstract = {Target antigens in neuroimmunological diseases were reviewed. These are; ple21 in limbic encephalitis; PCD17, CDR62, CDR34, and CZF in paraneoplastic cerebellar degeneration; one of the anion transporters band 3 in chorea-acanthocytosis; visinin-like substance in cancer-associated retinopathy (CAR syndrome); myelin basic protein (MBP) and proteolipid protein (PLP) in acute disseminated encephalomyelitis; MBP, PLP and myelin-oligodendrocyte glycoprotein (MOG) in multiple sclerosis; glutamic acid decarboxylase in stiff-man syndrome; GM1 ganglioside in amyotrophic lateral sclerosis; peripheral nerve K+ channel in Isaacs syndrome; synaptotagmin in Lambert-Eaton syndrome; acetylcholine receptor in myasthenia gravis; GM1 ganglioside in Guillain-Barré syndrome; GQ1b ganglioside in Fisher syndrome; myelin-associated glycoprotein in IgM paraproteinemic neuropathy; HuD in paraneoplastic sensory neuropathy; and tRNA and HSP65 in polymyositis.}, }
@article {pmid7845336, year = {1994}, author = {Wilson, GN}, title = {Atypical inheritance: new horizons for neurology.}, journal = {Neurologic clinics}, volume = {12}, number = {4}, pages = {663-681}, pmid = {7845336}, issn = {0733-8619}, support = {HD-26324/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Chromosome Aberrations/*genetics ; Chromosome Disorders ; Gene Deletion ; Gene Expression Regulation/physiology ; Humans ; Mosaicism/genetics ; Nervous System Diseases/*genetics ; }, abstract = {Rediscovery of Mendel's laws produced an enthusiastic new discipline at the turn of this century. The eugenics movement had many disciples in the United States, and it should be noted that the term "final solution" was first used by the National Association of Charities and Corrections in the 1920s. American advocates of eugenics accomplished mass sterilization of retarded individuals and the prohibition of Jewish immigration from Germany during World War II. It is interesting that the close of this century has produced a similar revolution in genetics. These newer genetic mechanisms expose the major fallacy of eugenics: traits may be genetic without showing obvious familial transmission. Sanctions against reproduction or immigration thus will have little effect on the gene pool. The clinical implications of atypical inheritance are enormous. Almost every medical disorder must be reinvestigated for evidence of subtle chromosome changes, for worsening in progressive generations, and for influence of parental origin. The classical Mendelian model taught that extreme and rare phenotypes shed light on more frequent ones, hence the definition of genes responsible for hypercholesterolemia, for Alzheimer disease, and for amyotrophic lateral sclerosis. Atypical inheritance mechanisms further enhance this approach, bringing all of neurology under the light of genetic technology. The lure for the practitioner, then, is not the hyperbole of molecular biology; it is the need for a seasoned hand so emphasized by Huntington's disease and the duty to protect the next century from disasters of the current one.}, }
@article {pmid7943166, year = {1994}, author = {Gonatas, NK}, title = {Rous-Whipple Award Lecture. Contributions to the physiology and pathology of the Golgi apparatus.}, journal = {The American journal of pathology}, volume = {145}, number = {4}, pages = {751-761}, pmid = {7943166}, issn = {0002-9440}, support = {NS-05572/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology ; Animals ; Antibodies ; Endocytosis ; Golgi Apparatus/metabolism/*physiology/*ultrastructure ; Humans ; Lectins ; Microtubules/physiology ; Mitosis/physiology ; Motor Neurons/physiology/ultrastructure ; Organelles/ultrastructure ; *Receptors, Cell Surface ; Receptors, Fibroblast Growth Factor ; Sialoglycoproteins/genetics/metabolism ; Toxins, Biological ; }, abstract = {The importance of the Golgi apparatus in the transport, processing, and targeting of proteins destined for secretion, plasma membranes, and lysosomes has emerged from numerous studies. In this paper we review studies from our laboratory dealing with 1) the Golgi apparatus during mitosis and the role of microtubules in maintaining the structure of the organelle, 2) the endocytosis of antibodies, exogenous lectins, and toxins into the Golgi apparatus of several cells including neurons in vivo and in vitro, 3) the traffic of MG-160, a membrane sialoglycoprotein of the medial cisternae of the Golgi apparatus, from the trans-Golgi network to the Golgi cisternae, and 4) the involvement of the Golgi apparatus of motor neurons in the pathogenesis of amyotrophic lateral sclerosis. We conclude with a summary of ongoing work on the primary structure of MG-160 and introduce evidence suggesting that this intrinsic membrane protein of the Golgi apparatus may be involved in the regulation of endogenous, autocrine, basic fibroblast growth factor. We hope that this review will stimulate studies on the Golgi apparatus of neurons, which may lead to the discovery of neuron-specific properties of this important organelle and its involvement in the pathogenesis of neurodegenerative disorders.}, }
@article {pmid7849532, year = {1994}, author = {Lindvall, O and Odin, P}, title = {Clinical application of cell transplantation and neurotrophic factors in CNS disorders.}, journal = {Current opinion in neurobiology}, volume = {4}, number = {5}, pages = {752-757}, doi = {10.1016/0959-4388(94)90019-1}, pmid = {7849532}, issn = {0959-4388}, mesh = {Animals ; Central Nervous System Diseases/*therapy ; Humans ; Nerve Degeneration ; Nerve Growth Factors ; Nerve Tissue Proteins/*therapeutic use ; *Neurons/*transplantation ; Parkinson Disease/surgery ; }, abstract = {Cell transplantation and administration of neurotrophic factors are now being explored as new therapeutic strategies to restore and preserve function in the diseased human central nervous system. Neural grafts show long-term survival and restore function in patients with Parkinson's disease, but the symptomatic relief needs to be increased. Cell transplantation also seems justified in patients with Huntington's disease and, possibly, in demyelinating disorders. Clinical trials with neurotrophic factors have been initiated in amyotrophic lateral sclerosis, dementia and Huntington's disease, and may later be started in Parkinson's disease and after acute brain insults. However, it remains to be shown if neurotrophic factors can rescue damaged cells in the brain and spinal cord of patients with these disorders.}, }
@article {pmid8090715, year = {1994}, author = {Luft, R}, title = {The development of mitochondrial medicine.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {91}, number = {19}, pages = {8731-8738}, pmid = {8090715}, issn = {0027-8424}, mesh = {Aging ; DNA, Mitochondrial/*genetics ; Humans ; Mitochondria/*physiology ; Mitochondrial Encephalomyopathies ; *Mitochondrial Myopathies ; Oxidative Phosphorylation ; }, abstract = {Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.}, }
@article {pmid8055404, year = {1994}, author = {Krueger, G}, title = {Amyotrophic lateral sclerosis: is excitotoxicity the key?.}, journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne}, volume = {151}, number = {4}, pages = {441-443}, pmid = {8055404}, issn = {0820-3946}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Female ; Humans ; Male ; Receptors, N-Methyl-D-Aspartate/*physiology ; }, }
@article {pmid7952856, year = {1994}, author = {Morrison, KE and Harding, AE}, title = {Disorders of the motor neurone.}, journal = {Bailliere's clinical neurology}, volume = {3}, number = {2}, pages = {431-445}, pmid = {7952856}, issn = {0961-0421}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Chromosome Mapping ; Disease Models, Animal ; Humans ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/*genetics ; Muscular Atrophy, Spinal/classification/genetics/veterinary ; }, abstract = {The spinal muscular atrophies (SMAs) are defined as a group of inherited disorders sharing the common pathological feature of degeneration of the anterior horn cells of the spinal cord and, in some cases, additionally of the bulbar motor nuclei. They are classified according to clinical features, including severity and distribution of muscle weakness and on their modes of inheritance. The SMAs are not uncommon: SMA type I (severe, acute infantile SMA) alone has a gene frequency in the UK estimated at 0.006. Together they represent a significant source of morbidity and mortality. Over the past 3 years, two major advances have been made towards understanding the molecular basis of these clinically heterogeneous disorders. First, in 1990, it was reported that all three forms of childhood-onset proximal SMA were linked to probes mapping to the proximal long arm of chromosome 5. Significant progress has been made towards isolating the gene or genes responsible, and a protocol for prenatal disease prediction in families with a previously severely affected child has been established. Second, in 1991, the molecular defect in adult-onset X-linked spinal and bulbar muscular atrophy was defined as an expansion of a (CAG)n trinucleotide repeat which encodes a string of glutamine residues in the first exon of the androgen receptor. Little progress has been made in elucidating the molecular pathology of the other SMAs. None of them has been linked to chromosome 5q markers, or indeed to markers elsewhere; the conditions are rare and pedigrees generally small. When the gene (or genes) on proximal 5q underlying SMA types I, II and III is cloned, mutations in this can then be sought in the other SMAs. The product of the chromosome 5q gene presumably plays a crucial role in maintaining the integrity of motor neurones, so determination of its structure and function may well have consequences far beyond those pertaining to the inherited SMAs. The identification of pathogenic mutations in the SOD-1 gene in familial amyotrophic lateral sclerosis is of great interest, although it is not clear that similar mechanisms contribute to the more common sporadic form of the disease.}, }
@article {pmid7952238, year = {1994}, author = {Rowland, LP}, title = {Amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {7}, number = {4}, pages = {310-315}, doi = {10.1097/00019052-199408000-00006}, pmid = {7952238}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology ; Clinical Trials as Topic ; Excitatory Amino Acid Antagonists ; Humans ; Immunization, Passive ; Motor Neuron Disease/drug therapy/etiology ; Neurologic Examination/drug effects ; Riluzole ; Thiazoles/adverse effects/therapeutic use ; }, abstract = {Therapeutic trials for amyotrophic lateral sclerosis have attracted much attention, but no drug tested has been effective yet. Three major theories of pathogenesis form the basis for these trials: autoimmunity, chronic excitotoxic stimulation due to accumulation of glutamate, and, in the familial form, peroxidation due to subnormal activity of superoxide dismutase. In striking contrast to the negative results of all of the other drug trials, riluzole (a glutamate antagonist) was said to benefit patients with bulbar onset but not those with spinal onset. Problems with the original trial may be clarified by other studies now in progress. The most optimistic news is the response to therapy of multifocal motor neuropathy, a disorder that clinically resembles motor neuron disease. This year, three groups reported benefit from intravenous immunoglobulin therapy.}, }
@article {pmid7964863, year = {1994}, author = {Müller, U and Graeber, MB and Haberhausen, G and Köhler, A}, title = {Molecular basis and diagnosis of neurogenetic disorders.}, journal = {Journal of the neurological sciences}, volume = {124}, number = {2}, pages = {119-140}, doi = {10.1016/0022-510x(94)90318-2}, pmid = {7964863}, issn = {0022-510X}, mesh = {Animals ; Base Sequence ; Humans ; *Molecular Biology ; Molecular Sequence Data ; Mutation ; Nervous System Diseases/*diagnosis/*genetics ; }, abstract = {Over the past few years, molecular neurogenetics has developed into one of the most promising and active research fields. The new discipline applies modern molecular genetic techniques to the investigation of classical neurological disorders. In the following article, a definition of neurogenetic disease is introduced, the molecular basis of four groups of neurogenetic disorders is described and recent diagnostic developments are presented. The first group of diseases is caused by trinucleotide expansions. "Expanding" trinucleotide repeats were not known to occur in any species until about three years ago. Today, disorders such as Huntington's disease, spinocerebellar ataxia type 1, fragile X mental retardation, spinobulbar muscular atrophy and myotonic dystrophy are all known to be caused by the expansion of trinucleotides. The second group is characterized by chromosomal deletions or uniparental disomies. Lissencephaly and the Miller-Dieker syndrome, Prader-Willi and Angelman syndromes and Duchenne and Becker muscular dystrophies belong to this category. The third group includes those neurogenetic disorders that are mainly caused by point mutations such as the X-linked leukodystrophies, including Pelizaeus-Merzbacher disease and adrenoleukodystrophy, Charcot-Marie-Tooth syndrome type 1, familial forms of amyotrophic lateral sclerosis, several types of craniosynostoses and some CNS tumor syndromes. Finally, Alzheimer's and Parkinson's disease are discussed as representatives of group four, i.e. genetically heterogeneous neurological disorders.}, }
@article {pmid7957485, year = {1994}, author = {Chute, DL and Bliss, ME}, title = {ProsthesisWare: concepts and caveats for microcomputer-based aids to everyday living.}, journal = {Experimental aging research}, volume = {20}, number = {3}, pages = {229-238}, doi = {10.1080/03610739408253969}, pmid = {7957485}, issn = {0361-073X}, mesh = {Aged ; Cognition/physiology ; Humans ; *Microcomputers ; Movement/physiology ; *Prosthesis Design ; *Software ; Therapy, Computer-Assisted ; }, abstract = {Two main approaches have been taken in using the microcomputer as an aid to the elderly for everyday living. The first strategy is often termed cognitive rehabilitation and uses the computer as a tutor for the training or retraining of such general cognitive skills as memory or attention. The strength of this strategy is that it is inexpensive and deliverable; its weakness is that it is ineffective for many people because it requires plasticity and the ability to generalize to real-life situations. The second strategy, termed ProsthesisWare, uses the computer as a prosthetic or augmentative device for any deficiencies in cognitive or motor abilities. The strength of the ProsthesisWare approach is that it can be effective in providing compensation and in maintaining the independent home environment that most people desire; its weakness is that it requires acceptance, maintenance, and idiosyncratic customization. As an illustration of the ProsthesisWare program. SpeechWare is presented. This software serves as a prosthetic aid for those who, as a result of stroke, amyotrophic lateral sclerosis, or other neurological impairment, have lost the ability to communicate and who may also have severe motor impairments. SpeechWare also includes telephone, distance electronic, and written communication functions as well as basic control of household appliances and environment.}, }
@article {pmid7834016, year = {1994}, author = {Uchida, Y}, title = {Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases.}, journal = {Biological signals}, volume = {3}, number = {4}, pages = {211-215}, doi = {10.1159/000109547}, pmid = {7834016}, issn = {1016-0922}, mesh = {Adult ; Alzheimer Disease/metabolism/pathology ; Astrocytes/metabolism/pathology ; Basal Ganglia Diseases ; Brain/*metabolism/pathology ; Brain Diseases/*metabolism/pathology ; Growth Inhibitors/analysis/metabolism ; Humans ; Immunohistochemistry ; Metallothionein ; Metallothionein 3 ; Nerve Tissue Proteins/analysis/*metabolism ; Neurons/*metabolism/pathology ; Spinal Cord/*metabolism/pathology ; }, abstract = {Growth-inhibitory factor (GIF), which is deficient in the Alzheimer's disease brain, is a 68-amino-acid metallothionein-like protein. GIF is expressed in the central nervous system but not in peripheral tissues including dorsal root ganglion. GIF is immunocytochemically distributed in Bergmann's glia in the cerebellum and astrocytes in the neocortex, hippocampus, striatum, brain stem, and spinal cord. Strong GIF immunoreactivity is localized in astrocyte cell bodies and fine long processes, which are closely associated with neural perikarya and dendrites, such as layers 2-6 of cerebral gray matter, the molecular layer of the dentate gyrus, the pyramidal layer of the hippocampus and spinal gray matter. GIF is induced in reactive astrocytes in the cerebral cortex in cases of meningitis and Creutzfeldt-Jakob disease or in reactive astrocytes surrounding old cerebral infarcts. On the other hand, GIF is reduced in the subset of reactive astrocytes in lesioned areas of degenerative diseases such as Alzheimer's disease, multiple-system atrophy, Parkinson's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. Reduction of GIF is correlated with neuronal loss. Thus, perturbation in normal neuroglial interaction in degenerative diseases may lead to a reduction of GIF in reactive astrocytes.}, }
@article {pmid7807144, year = {1994}, author = {Shaw, PJ}, title = {Excitotoxicity and motor neurone disease: a review of the evidence.}, journal = {Journal of the neurological sciences}, volume = {124 Suppl}, number = {}, pages = {6-13}, doi = {10.1016/0022-510x(94)90170-8}, pmid = {7807144}, issn = {0022-510X}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Motor Neuron Disease/*physiopathology ; Receptors, Glutamate/*physiology ; }, abstract = {Excitotoxic mechanisms have a well established role in the pathogenesis of neuronal injury following acute CNS insults such as ischaemia and trauma. Their role in the selective cell death which occurs in chronic neurodegenerative disorders such as motor neurone disease (MND) is more speculative. The traditional classification of glutamate receptor subtypes which mediate excitotoxicity requires modification in the light of new molecular data. There is much greater structural and functional diversity in this receptor family than previously envisaged and it is quite possible that specific populations of neurones will be characterised by a unique profile of glutamate receptor subtypes which may be a factor determining their selective vulnerability. The molecular mechanisms underlying excitotoxic neuronal injury are still being elucidated but it is clear that the cascade of events resulting from elevation of intracellular free calcium is likely to play a major role. As well as being a primary mechanism of neuronal injury, excitotoxicity can secondarily damage neurones whose energy metabolism is impaired from some primary pathological process. The 8 lines of evidence that primary or secondary excitotoxic mechanisms may be involved in the selective neuronal injury of MND are discussed. The evidence, while still circumstantial, is sufficient to warrant further research effort in this field, not least because the emergence of pharmacological agents which modify specific aspects of excitatory amino acid neurotransmission offer the possibility of therapeutic intervention in MND.}, }
@article {pmid7807140, year = {1994}, author = {Lowe, J}, title = {New pathological findings in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {124 Suppl}, number = {}, pages = {38-51}, doi = {10.1016/0022-510x(94)90175-9}, pmid = {7807140}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Inclusion Bodies/*pathology/ultrastructure ; Microscopy, Electron ; Motor Neuron Disease/pathology ; }, abstract = {There have been recent developments in the pathology of sporadic ALS. A new filamentous neuronal inclusion body in ALS detected by immunohistochemical localisation of the protein ubiquitin has been characterised at the light microscopic and ultrastructural level and appears specific for the disease. The molecular composition of underlying filaments remains unresolved but the quest for this is a major aim in ALS research. Despite being a progressive degenerative process which primarily affects motor systems, ALS is now recognised to involve several non-motor systems and in long survivors affects many subcortical structures. There is also accumulating evidence that the neurodegenerative process underlying ALS may present as a non-motor clinical syndrome, particularly as a frontal lobe dementia with characteristic inclusions present in the non-motor cortex. Considering ALS as a multisystem disease rather than simply a disease of motor neurones has major implications for research into pathogenesis.}, }
@article {pmid7807137, year = {1994}, author = {Strong, MJ}, title = {Aluminum neurotoxicity: an experimental approach to the induction of neurofilamentous inclusions.}, journal = {Journal of the neurological sciences}, volume = {124 Suppl}, number = {}, pages = {20-26}, doi = {10.1016/0022-510x(94)90172-4}, pmid = {7807137}, issn = {0022-510X}, mesh = {Aluminum/*toxicity ; Animals ; Humans ; Inclusion Bodies/metabolism/pathology ; Nervous System Diseases/*chemically induced/metabolism/pathology ; Neurofilament Proteins/drug effects/*metabolism ; }, abstract = {Acute or chronic aluminum neurotoxicity experiments in the rabbit suggest that aluminum can induce phosphorylation of neurofilamentous proteins. This may result in abnormal resistance to degradation or transport of neurofilament protein and so to the accumulation of neurofilaments in abnormal cells. The possible importance of this process in ALS is considered in relation to the neurofilamentous abnormalities characteristic of intraneuronal inclusions in ALS and in other neurodegenerative disorders.}, }
@article {pmid7807136, year = {1994}, author = {Appel, SH and Smith, RG and Engelhardt, JI and Stefani, E}, title = {Evidence for autoimmunity in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {124 Suppl}, number = {}, pages = {14-19}, doi = {10.1016/0022-510x(94)90171-6}, pmid = {7807136}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Autoimmune Diseases/*immunology/pathology ; Disease Models, Animal ; Humans ; }, abstract = {Although the etiology and pathogenesis of ALS is unknown, increasing evidence supports a role for autoimmune mechanisms in motoneuron degeneration and death. An animal model, experimental autoimmune gray matter disease, can be induced by the inoculation of spinal cord gray matter. The experimental disease is characterized by weakness secondary to the loss of upper and lower motoneurons, accompanied by inflammatory foci within the spinal cord, and IgG at the neuromuscular junction and within UMN and LMN. In human ALS, IgG is present within the UMN and LMN, and T-lymphocytes and activated microglia have been identified within spinal cord gray matter and motor cortex. ALS IgG can passively transfer physiological changes of the neuromuscular junction to mice resulting in enhanced release of acetylcholine. The ALS IgG selectively interact with calcium channels and alter channel function. These data suggest a potential role for autoimmune mechanisms in the destruction and loss of motoneurons in ALS.}, }
@article {pmid8158117, year = {1994}, author = {Wu, D and Hersh, LB}, title = {Choline acetyltransferase: celebrating its fiftieth year.}, journal = {Journal of neurochemistry}, volume = {62}, number = {5}, pages = {1653-1663}, doi = {10.1046/j.1471-4159.1994.62051653.x}, pmid = {8158117}, issn = {0022-3042}, support = {AG05893/AG/NIA NIH HHS/United States ; AG08013/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/enzymology ; Amyotrophic Lateral Sclerosis/enzymology ; Animals ; Brain/*enzymology ; Choline O-Acetyltransferase/biosynthesis/deficiency/*metabolism ; Cloning, Molecular ; Humans ; Protein Biosynthesis ; Protein Processing, Post-Translational ; RNA, Messenger/metabolism ; Schizophrenia/enzymology ; Transcription, Genetic ; }, abstract = {It is well known that the regulation of choline acetyltransferase (ChAT) activity under physiological and pathological conditions is important for the development and neuronal activities of cholinergic systems involved in many fundamental brain functions. This review focuses on recent progress in understanding the regulation of ChAT at the levels of both the protein and the mRNA. A deficiency in ChAT activity has been reported for neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, and schizophrenia. Although a major feature of ChAT regulation is likely to involve the spatial and temporal control of transcription, regulation of expression can also be at the level of RNA processing, transport/translocation, turnover, or translation. In addition, there is increasing evidence that ChAT might be regulated at the posttranslational level by compartmentation and/or covalent modification, i.e., phosphorylation, as well as noncovalent modification (protein-protein interaction, etc.). Synaptic activity and the state of neuronal transmission may also involve the regulation of ChAT at different levels via both positive and negative feedback loops, as was demonstrated in the characterization of two ChAT mutant Drosophila strains. Clearly, identification of cholinergic-specific elements and the characterization of the trans-acting factors that bind to them represent an important area of future research. Equally important is research on the mechanisms governing ChAT as an enzymatic entity. The future should be an exciting time during which we look forward to the elucidation of the cholinergic signal and its regulation as well as the determination of the three-dimensional structure of the enzyme.}, }
@article {pmid8042756, year = {1994}, author = {Diefenbach, C and Buzello, W}, title = {[Muscle relaxation in patients with neuromuscular diseases].}, journal = {Der Anaesthesist}, volume = {43}, number = {5}, pages = {283-288}, doi = {10.1007/s001010050059}, pmid = {8042756}, issn = {0003-2417}, mesh = {*Anesthesia/adverse effects ; Humans ; *Muscle Relaxants, Central/adverse effects ; *Neuromuscular Blocking Agents/adverse effects ; Neuromuscular Diseases/classification/*complications/physiopathology ; }, abstract = {The classification of neuromuscular diseases with regard to the use of muscle relaxants is based on the localisation of the particular abnormality. Three types of syndromes can be differentiated: (1) denervation states; (2) disturbances of neuromuscular transmission; and (3) intracellular disease. Succinylcholine should be avoided in all types of denervation syndrome due to the possibility of life-threatening hyperkalaemia. The time frame during which succinylcholine must be avoided following a traumatic denervation or burn begins 24 h after the event. The exact period of risk is unknown, but a duration of 6 months can be considered the absolute minimum. Patients may display increased sensitivity to non-depolarising muscle relaxants following damage to the second motoneuron (e.g., amyotrophic lateral sclerosis), whereas in diseases of the first motoneuron (e.g., cerebral apoplexy), increased resistance to muscle relaxants may be observed in the affected parts of the body. In diseases of the neuromuscular junction (myasthenia gravis) there is increased sensitivity to non-depolarising muscle relaxants. No complications have been described following the use of succinylcholine in these patients, however, the use of reversal agents may lead to prolongation of the effect of succinylcholine. Patients with a primary myopathy may display increased sensitivity to non-depolarising muscle relaxants. The use of drugs with acetylcholine-like actions (succinylcholine, reversal agents) should be avoided due to the danger of triggering muscle spasms in patients with myotonic disease and the risk of rhabdomyolysis in patients with dystrophic muscle disease. Irrespective of the type of muscle disease present, titration of the dose of muscle relaxant should always be done using a nerve stimulator.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7999315, year = {1994}, author = {Lipton, SA}, title = {HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists.}, journal = {Molecular neurobiology}, volume = {8}, number = {2-3}, pages = {181-196}, pmid = {7999315}, issn = {0893-7648}, support = {EY05477/EY/NEI NIH HHS/United States ; EY09024/EY/NEI NIH HHS/United States ; HD29587/HD/NICHD NIH HHS/United States ; }, mesh = {AIDS Dementia Complex/*drug therapy/physiopathology ; Adult ; Astrocytes/pathology/virology ; Brain/*pathology ; Calcium Channel Blockers/*therapeutic use ; Child ; Cytokines/biosynthesis ; HIV Envelope Protein gp120/toxicity ; HIV-1/pathogenicity/*physiology ; Humans ; Macrophages/physiology/virology ; Models, Biological ; Monocytes/drug effects/physiology/virology ; N-Methylaspartate/*antagonists &amp; inhibitors ; Nervous System Diseases/pathology/physiopathology ; Neurons/drug effects/pathology/physiology ; Receptors, N-Methyl-D-Aspartate/physiology ; }, abstract = {Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.}, }
@article {pmid8047225, year = {1994}, author = {Hausmanowa-Petrusewicz, I}, title = {[Conduction bloc in peripheral nerves. Facts and hypotheses].}, journal = {Neurologia i neurochirurgia polska}, volume = {28}, number = {2}, pages = {157-166}, pmid = {8047225}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Demyelinating Diseases/physiopathology ; Diagnosis, Differential ; Humans ; Median Nerve/physiopathology ; Nerve Fibers ; Peripheral Nerves/*physiopathology ; Peripheral Nervous System Diseases/diagnosis/*physiopathology ; Polyradiculoneuropathy/immunology ; }, abstract = {In the terminological dictionary of the AAEE conduction block is defined as inability of impulse to pass through a certain point in nerve fibre, although conduction is preserved below that point. Conduction block is manifested as a quantitatively corresponding drop of the amplitude and area of motor evoked potential (MEP) in the distal part in relation to the values of these parameters proximal to the block. Excessive desynchronization of conduction in nerve fibres and certain technical factors should be excluded. Multifocal conduction block is found in many neuropathies, particularly purely motor ones. The probable mechanisms responsible for the difference between motor and sensory nerve fibres with respect to their susceptibility to block development have been discussed. The understanding of conduction block could have important clinical implications, especially in the differential diagnosis of chronic demyelinative neuropathies, in the selection of immunological research methods, in the choice of treatment and prognostication of possible improvement (e.g. in the Guillain-Barre syndrome). Purely motor neuropathy with multifocal conduction block may simulate amyotrophic lateral sclerosis. The development of block in neuropathies is associated frequently with increased level of antibodies against GM1 and the interrelation between these phenomena is not known; the development of block may be due to deposition of GM1 antibodies in internodes or Ranvier's nodes with production of demyelination or with damage to ion channels. Although the concept of conduction block has been introduced in electroneurographic diagnosis there are still many doubts as to the correctness of diagnostic criteria, indispensable technical conditions, and also to the basic problems, such as e.g. 1) is conduction block really limited to acquired neuropathies (its possible occurrence in congenital neuropathies is discussed), 2) why is conduction block not reflecting clinical improvement, 3) in what degree is block reflecting the loss of motor units. These questions are discussed by the author in the light of literature reports and own experience.}, }
@article {pmid7913990, year = {1994}, author = {Langauer-Lewowicka, H}, title = {[Aluminum neurotoxicity].}, journal = {Neurologia i neurochirurgia polska}, volume = {28}, number = {2}, pages = {221-226}, pmid = {7913990}, issn = {0028-3843}, mesh = {Aluminum/analysis/*toxicity ; Alzheimer Disease/etiology ; Brain Diseases/*etiology ; Environment ; Humans ; Neurotransmitter Agents/metabolism ; Protein Synthesis Inhibitors ; Renal Dialysis/adverse effects ; Renal Insufficiency/therapy ; }, abstract = {Adverse health effects of aluminium (Al), especially its possible role in aetiology of some human neurodegenerative disorders, e.g. dialysis encephalopathy syndrome, Alzheimer disease, amyotrophic lateral sclerosis of Guam, dementia, are presented. The influence of Al on brain protein synthesis is discussed. The author pays attention to the health risk connected with growing amount of Al in our ecosystem.}, }
@article {pmid7838303, year = {1994}, author = {Lindsay, RM}, title = {Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor.}, journal = {Neurobiology of aging}, volume = {15}, number = {2}, pages = {249-251}, doi = {10.1016/0197-4580(94)90124-4}, pmid = {7838303}, issn = {0197-4580}, mesh = {Animals ; Ciliary Neurotrophic Factor ; Humans ; Nerve Degeneration/physiology ; Nerve Growth Factors/*physiology/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; Nervous System Diseases/*drug therapy/*physiopathology ; Receptors, Nerve Growth Factor/physiology ; }, abstract = {The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.}, }
@article {pmid7838302, year = {1994}, author = {Messer, A}, title = {Mutant mouse models of ALS.}, journal = {Neurobiology of aging}, volume = {15}, number = {2}, pages = {247-248}, doi = {10.1016/0197-4580(94)90123-6}, pmid = {7838302}, issn = {0197-4580}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Mice ; *Mice, Neurologic Mutants ; Nerve Degeneration/physiology ; }, }
@article {pmid8208338, year = {1994}, author = {Hirano, A}, title = {Hirano bodies and related neuronal inclusions.}, journal = {Neuropathology and applied neurobiology}, volume = {20}, number = {1}, pages = {3-11}, doi = {10.1111/j.1365-2990.1994.tb00951.x}, pmid = {8208338}, issn = {0305-1846}, mesh = {Animals ; Humans ; Inclusion Bodies/physiology/*ultrastructure ; Nervous System/pathology/ultrastructure ; Nervous System Diseases/pathology ; Neurons/*ultrastructure ; }, abstract = {Hirano bodies are bright eosinophilic intracytoplasmic inclusions which have a highly characteristic crystalloid fine structure. They occur preferentially in the neuronal processes of the CA1 area in Ammon's horn in a wide variety of conditions, especially amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam, Alzheimer's disease, Pick's disease and 'normal' elderly individuals. Hirano bodies contain epitopes of actin, actin-associated proteins, tau, middle molecular weight neurofilaments subunit and a C-terminal fragment of beta-amyloid precursor protein. In addition to the CA1 area of Ammon's horn, they have also been identified in many other areas of the nervous system in humans and various experimental animals. Although usually observed in neurons, Hirano bodies may also be present in other cell types. It is the consensus that Hirano bodies in the pyramidal layer of CA1 originate largely from an age-related alteration of the microfilamentous system.}, }
@article {pmid8264698, year = {1994}, author = {Lange, DJ}, title = {AAEM minimonograph #41: neuromuscular diseases associated with HIV-1 infection.}, journal = {Muscle &amp; nerve}, volume = {17}, number = {1}, pages = {16-30}, doi = {10.1002/mus.880170104}, pmid = {8264698}, issn = {0148-639X}, mesh = {Acute Disease ; Axons ; Chronic Disease ; Cytomegalovirus Infections/complications ; Demyelinating Diseases/etiology/therapy ; HIV Infections/*complications ; Humans ; Muscular Diseases/complications ; Neuromuscular Diseases/*etiology/therapy ; Peripheral Nervous System Diseases/etiology/microbiology ; Spinal Nerve Roots ; }, abstract = {Neuromuscular diseases occur in as many as 50% of patients infected with human immunodeficiency virus type 1 (HIV-1). All forms of neuromuscular disease have been reported, including axonal neuropathy, demyelinating neuropathy, mononeuropathy multiplex, polyradiculitis, ALS-like syndromes, disorders of neuromuscular transmission, myopathy, and toxic neuropathies due to medication side effects. Neuromuscular disease is often the presenting manifestation of HIV-1 infection. Infection with cytomegalovirus (CMV) is associated with different types of neuropathy including mononeuritis multiplex and polyradiculopathy. There is effective treatment for many of the associated disorders including chronic inflammatory demyelinating neuropathy, CMV-mediated neuropathies, and myopathy. Treatment of CMV-mediated mononeuropathy multiplex may be life saving. The different neuromuscular syndromes associated with different stages of HIV-1 infection may be due, in part, to different levels of immunocompetence.}, }
@article {pmid8008989, year = {1994}, author = {Sherman, MS and Paz, HL}, title = {Review of respiratory care of the patient with amyotrophic lateral sclerosis.}, journal = {Respiration; international review of thoracic diseases}, volume = {61}, number = {2}, pages = {61-67}, doi = {10.1159/000196308}, pmid = {8008989}, issn = {0025-7931}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Humans ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/physiopathology/*therapy ; Respiratory Therapy ; }, abstract = {Respiratory failure is the leading cause of death in patients with amyotrophic lateral sclerosis (ALS). We review the physiology of respiratory compromise in ALS and techniques of monitoring respiratory function. Treatment options, including pharmacologic interventions, aspiration precautions, and invasive and noninvasive modes of mechanical ventilation are reviewed. Our clinical experience with respiratory failure in ALS demonstrates significantly prolonged survival in subjects who elect to receive noninvasive mechanical ventilation (19.25 vs. 80.4 days, p < 0.01). Four of 18 patients who elected to receive noninvasive ventilation decided to discontinue treatment. Four of 13 patients who were receiving mechanical ventilation elected to discontinue life support. The decision to utilize these modalities must be made with realistic considerations of the patient's quality of life.}, }
@article {pmid7981631, year = {1994}, author = {Patterson, D and Warner, HR and Fox, LM and Rahmani, Z}, title = {Superoxide dismutase, oxygen radical metabolism, and amyotrophic lateral sclerosis.}, journal = {Molecular genetic medicine}, volume = {4}, number = {}, pages = {79-118}, doi = {10.1016/b978-0-12-462004-9.50007-4}, pmid = {7981631}, issn = {1057-2805}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Base Sequence ; Chromosome Mapping ; Chromosomes, Human, Pair 21 ; Codon ; Free Radicals/metabolism ; Humans ; Peroxides/metabolism ; *Point Mutation ; Superoxide Dismutase/*genetics/metabolism ; }, }
@article {pmid7925318, year = {1994}, author = {Goonetilleke, A and de Belleroche, J and Guiloff, RJ}, title = {Motor neurone disease.}, journal = {Essays in biochemistry}, volume = {28}, number = {}, pages = {27-45}, pmid = {7925318}, issn = {0071-1365}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/metabolism/pathology/therapy ; Brain/metabolism/pathology ; Carbohydrate Sequence ; Female ; Humans ; Male ; Molecular Sequence Data ; Motor Neurons/pathology ; Nerve Degeneration ; Spinal Cord/metabolism/pathology ; }, abstract = {Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.}, }
@article {pmid7705221, year = {1994}, author = {Lipton, SA}, title = {Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists.}, journal = {Developmental neuroscience}, volume = {16}, number = {3-4}, pages = {145-151}, doi = {10.1159/000112101}, pmid = {7705221}, issn = {0378-5866}, mesh = {AIDS Dementia Complex/*drug therapy/*pathology ; Calcium Channel Blockers/*therapeutic use ; HIV Infections/complications/*pathology ; *HIV-1 ; Humans ; N-Methylaspartate/*antagonists &amp; inhibitors ; Neurons/*physiology ; }, abstract = {A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.}, }
@article {pmid7532612, year = {1994}, author = {Baxter, RC}, title = {Insulin-like growth factor binding proteins in the human circulation: a review.}, journal = {Hormone research}, volume = {42}, number = {4-5}, pages = {140-144}, doi = {10.1159/000184186}, pmid = {7532612}, issn = {0301-0163}, mesh = {Adult ; Animals ; Biological Availability ; Carrier Proteins/*blood/chemistry ; Humans ; Infant, Newborn ; Insulin/metabolism ; Insulin-Like Growth Factor Binding Proteins ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor II/metabolism ; Molecular Structure ; Somatomedins/*metabolism ; }, abstract = {The actions and bioavailability of the insulin-like growth factors (IGFs) are regulated by a family of six IGF binding proteins. IGFBP-3, the major circulating IGFBP, is unique in combining with a glycoprotein, the acid-labile subunit (ALS), to form a ternary complex with IGF-I or IGF-II. Each component of this trimer is growth hormone-dependent, and the hypoglycemic potential of circulating IGFs appears neutralized in this form. IGFs in the complex have a greatly extended circulating half-life, their stability being conferred by the presence of ALS, which is itself very stable in the circulation. IGFBP-1 does not appear to be a carrier of IGFs, but to act as an acute modulator of their metabolic activities. In this role it can be viewed as an insulin counter-regulator, blocking 'free' insulin-like activity during fasting or hypoglycemia. IGF-I administration causes complex changes in circulating IGFBPs, so that a detailed knowledge of their regulation is essential if the therapeutic potential of IGF-I is to be optimised.}, }
@article {pmid7497973, year = {1994}, author = {Jokelainen, M}, title = {[Hope for amyotrophic lateral sclerosis?].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {110}, number = {16}, pages = {1499-1501}, pmid = {7497973}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*immunology ; Autoantibodies ; Calcium Channels/immunology ; Humans ; Immune Tolerance ; Immunoglobulin G ; }, }
@article {pmid8250524, year = {1993}, author = {Martin, JB}, title = {Molecular genetics in neurology.}, journal = {Annals of neurology}, volume = {34}, number = {6}, pages = {757-773}, doi = {10.1002/ana.410340603}, pmid = {8250524}, issn = {0364-5134}, mesh = {Chromosome Mapping ; Humans ; *Molecular Biology ; Nervous System Diseases/*genetics ; }, abstract = {There has been remarkable progress in the identification of mutations in genes that cause inherited neurological disorders. Abnormalities in the genes for Huntington disease, neurofibromatosis types 1 and 2, one form of familial amyotrophic lateral sclerosis, fragile X syndrome, myotonic dystrophy, Kennedy syndrome, Menkes disease, and several forms of retinitis pigmentosa have been elucidated. Rare disorders of neuronal migration such as Kallmann syndrome, Miller-Dieker syndrome, and Norrie disease have been shown to be due to specific gene defects. Several muscle disorders characterized by abnormal membrane excitability have been defined as mutations of the muscle sodium or chloride channels. These advances provide opportunity for accurate molecular diagnosis of at-risk individuals and are the harbinger of new approaches to therapy of these diseases.}, }
@article {pmid8248295, year = {1993}, author = {McComas, AJ and Galea, V and de Bruin, H}, title = {Motor unit populations in healthy and diseased muscles.}, journal = {Physical therapy}, volume = {73}, number = {12}, pages = {868-877}, doi = {10.1093/ptj/73.12.868}, pmid = {8248295}, issn = {0031-9023}, mesh = {Adaptation, Physiological ; Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Bias ; Child ; Diagnosis, Computer-Assisted/instrumentation/*methods ; Electric Stimulation/instrumentation/*methods ; Electromyography/instrumentation/*methods ; Evaluation Studies as Topic ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*physiology ; Muscles/anatomy &amp; histology/*innervation ; Neuromuscular Diseases/classification/diagnosis/*pathology ; Severity of Illness Index ; }, abstract = {The numbers of functioning motor units can be estimated in proximal and distal muscles of human limbs by an electrophysiological technique in which the mean sizes of the motor unit potentials are compared with the maximum M-waves of the same muscles. Although manual methods of estimation have been used successfully in the past, the introduction of automated techniques has brought considerable advantages, including greater objectivity and reduced contamination of the results by "alternation." In healthy subjects, the intrinsic muscles of the hand have approximately 100 motor units each, and the biceps brachii muscle has only slightly more. With advancing age, there is a loss of motor units, which appears to be more pronounced in distal muscles. The motor unit estimating methodology has been found to be of value in the diagnosis and assessment of patients suspected of having muscle denervation. In amyotrophic lateral sclerosis, the mean rate of motor unit loss is swift, whereas in late-onset cases of spinal muscular atrophy, the reduction in the motor unit population does not appear to progress. In only the most rapidly deteriorating cases of post-polio syndrome is it possible to demonstrate further loss of motor units. In all of these denervating disorders, and in peripheral neuropathies, the importance of collateral reinnervation as a compensatory mechanism is emphasized.}, }
@article {pmid8121888, year = {1993}, author = {Uysal, A and Kaaden, OR}, title = {[Handling of unconventional pathogens].}, journal = {Der Pathologe}, volume = {14}, number = {6}, pages = {351-354}, pmid = {8121888}, issn = {0172-8113}, mesh = {Autopsy/methods ; Brain/microbiology/*pathology ; Creutzfeldt-Jakob Syndrome/pathology/*prevention &amp; control/transmission ; Histological Techniques ; Humans ; *Infectious Disease Transmission, Patient-to-Professional ; Prion Diseases/pathology/*prevention &amp; control/transmission ; Risk Factors ; Specimen Handling/methods ; Sterilization/*methods ; }, abstract = {This article summarizes decontamination problems in handling transmissible spongiform encephalopathies (TSE) in the field of human pathology. The combination of chemical (i.e. 1 M NaOH, 1 h, room temperature) and physical (i.e. autoclaving for 30 min at 131 degrees C) decontamination methods was proven to be suitable for instruments and other materials. Als for the autopsy of suspected TSE patients, safety measures have to be taken. The brain preparation, in particular, represents a considerable risk which must be minimized by appropriate safety measures. Conventional formaldehyde fixation does not decontaminate tissues! Embedding, cutting, deparaffinization and processing or staining have to be done with cautions; members of staff must be aware of the danger. After the handling of suspect materials, the hands should be washed without brushing the skin. In the case of percutaneous inoculation the injury must be decontaminated immediately using iodine- or phenol-containing preparations, 0.5 M NaOH or 1:3000 potassium permanganate.}, }
@article {pmid8106826, year = {1993}, author = {Tidwell, J}, title = {Pulmonary management of the ALS patient.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {25}, number = {6}, pages = {337-342}, doi = {10.1097/01376517-199312000-00003}, pmid = {8106826}, issn = {0888-0395}, mesh = {Advance Directives ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/physiopathology/therapy ; Diagnosis, Differential ; Ethics, Nursing ; Humans ; Male ; Middle Aged ; Respiration, Artificial ; Respiratory Paralysis/etiology/*nursing/physiopathology/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic progressive motor neuron disease with a poor prognosis which eventually weakens and paralyzes the respiratory muscles. ALS is characterized by progressive degeneration of both cortical and alpha motor neurons of the final common pathway. Early symptoms usually begin with alpha motor neuron involvement and then progress to include cortical motor neuron involvement. Degeneration of respiratory nerve centers in the anterior horn at the C3-C5 levels results in respiratory muscle fatigue, respiratory failure and eventually death. Treatment consists of preventing respiratory complications and supporting lung function for as long as possible. One case example of a critically ill patient with ALS highlights nursing concerns. With advanced directives and durable power of attorney, the patient now has better means available for making known the decision of whether to accept or reject mechanical ventilation.}, }
@article {pmid8313244, year = {1993}, author = {Eisen, A and Krieger, C}, title = {Pathogenic mechanisms in sporadic amyotrophic lateral sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {20}, number = {4}, pages = {286-296}, pmid = {8313244}, issn = {0317-1671}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/pathology ; Humans ; }, abstract = {In recognition of the 100th anniversary of Charcot's death we have reviewed possible pathogenic mechanisms in amyotrophic lateral sclerosis (ALS). Advances in the last 5 years in molecular biology and genetics have identified mutations in the cytosolic dismutase (SOD1) gene in some patients with familial ALS raising the possibility that oxidative stress may be involved in the pathogenesis. An excitotoxic pathogenesis has been implicated based on elevated plasma and CSF levels of amino acids and altered contents of amino acids in the nervous system of ALS patients and changes in the number of excitatory amino acid receptors. ALS sera containing antibodies to L-type calcium channels and the development of immune mediated lower and upper and lower motor neuron models have revitalized research efforts focusing on an immune basis for ALS. Other pathogenic mechanisms which have been the subject of recent research include elemental toxicity, apoptosis and programmed cell death and possibly a deficiency or abnormality in growth factors. Pathogenic processes for ALS must account for an increasing incidence of ALS, male preponderance, and the selective vulnerability of the cortico-motoneuronal system.}, }
@article {pmid8282084, year = {1993}, author = {Lewis, ME and Neff, NT and Contreras, PC and Stong, DB and Oppenheim, RW and Grebow, PE and Vaught, JL}, title = {Insulin-like growth factor-I: potential for treatment of motor neuronal disorders.}, journal = {Experimental neurology}, volume = {124}, number = {1}, pages = {73-88}, doi = {10.1006/exnr.1993.1177}, pmid = {8282084}, issn = {0014-4886}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Cell Survival ; Humans ; Insulin-Like Growth Factor I/pharmacology/*therapeutic use ; Models, Biological ; Molecular Sequence Data ; Motor Neuron Disease/*drug therapy/physiopathology ; Motor Neurons/cytology/drug effects/physiology ; Nervous System/drug effects ; Nervous System Physiological Phenomena ; Receptor, IGF Type 1/physiology ; }, abstract = {Motor neuronal disorders, such as the loss of spinal cord motor neurons in amyotrophic lateral sclerosis or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. Normally, such proteins do not cross the blood-brain barrier, but spinal cord motor neuron axons and nerve terminals lie outside the barrier and thus may be targeted by systemic administration of protein growth factors. Insulin-like growth factor-I (IGF-I) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies.}, }
@article {pmid8282083, year = {1993}, author = {Seeburger, JL and Springer, JE}, title = {Experimental rationale for the therapeutic use of neurotrophins in amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {124}, number = {1}, pages = {64-72}, doi = {10.1006/exnr.1993.1176}, pmid = {8282083}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Brain-Derived Neurotrophic Factor ; Humans ; Motor Neurons/drug effects/*physiology ; Nerve Growth Factors/pharmacology/physiology/*therapeutic use ; Nerve Tissue Proteins/pharmacology/therapeutic use ; Neurotrophin 3 ; Receptors, Nerve Growth Factor/drug effects/physiology ; }, abstract = {Current therapeutic efforts to treat chronic and progressive neurodegenerative disease include, for the first time, attempts to regenerate affected nervous tissue using neurotrophic factors. The rationale for using trophic factors includes the understanding that they support neuronal survival and regrowth processes. The potential benefits of trophic factor therapy will be no more realized in the near future than in the treatment of amyotrophic lateral sclerosis (ALS). ALS is pathologically characterized by the selective degeneration of specific populations of cranial and spinal motoneurons. Evidence for the existence of factors that support motoneurons has come from studies demonstrating that motoneurons receive trophic influences from various tissues, both central and peripheral, within their local environment. Although the identity of these putative tissue-derived factors has remained enigmatic, recent studies have demonstrated that several previously characterized trophic factors exhibit trophic influences on motoneurons. Among these are several members of the neurotrophin family, most notably brain-derived neurotrophic factor. These neurotrophins meet most of the criteria to be considered motoneuron trophic factors: they are locally available to motoneurons in vivo; motoneurons express specific receptors for these factors; and exogenous application of these factors mimicks the effects of the uncharacterized endogenous agents. The clinical use of these factors for the treatment of ALS, therefore, appears to be scientifically justified.}, }
@article {pmid8282067, year = {1993}, author = {Appel, SH and Smith, RG}, title = {Can neurotrophic factors prevent or reverse motoneuron injury in amyotrophic lateral sclerosis?.}, journal = {Experimental neurology}, volume = {124}, number = {1}, pages = {100-102}, doi = {10.1006/exnr.1993.1180}, pmid = {8282067}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology/physiopathology ; Animals ; Growth Substances/*therapeutic use ; Humans ; Motor Neurons/drug effects/*pathology ; Nerve Growth Factors/*therapeutic use ; }, }
@article {pmid8232960, year = {1993}, author = {Cornblath, DR and Kurland, LT and Boylan, KB and Morrison, L and Radhakrishnan, K and Montgomery, M}, title = {Conjugal amyotrophic lateral sclerosis: report of a young married couple.}, journal = {Neurology}, volume = {43}, number = {11}, pages = {2378-2380}, doi = {10.1212/wnl.43.11.2378}, pmid = {8232960}, issn = {0028-3878}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*physiopathology ; Female ; Humans ; Male ; Marriage ; Time Factors ; }, abstract = {We report a 38-year-old nurse who developed amyotrophic lateral sclerosis (ALS) beginning in September 1990. In May 1991, her 38-year-old husband developed dysarthria, which progressed to typical ALS. This is the fourth report in the literature of conjugal ALS occurring outside of Guam. Although this event is most likely due to coincidence, exogenous agents should be considered in the etiology of ALS.}, }
@article {pmid7902065, year = {1993}, author = {Edwards, RH}, title = {Neural degeneration and the transport of neurotransmitters.}, journal = {Annals of neurology}, volume = {34}, number = {5}, pages = {638-645}, doi = {10.1002/ana.410340504}, pmid = {7902065}, issn = {0364-5134}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Biological Transport ; Cell Membrane/metabolism ; Humans ; Nerve Degeneration/*physiology ; Neurotransmitter Agents/*metabolism ; Parkinson Disease/metabolism ; Parkinson Disease, Secondary/*metabolism ; }, abstract = {A number of neurodegenerative diseases selectively affect distinct neuronal populations, but the mechanisms responsible for selective cell vulnerability have generally remained unclear. The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces the selective degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson's disease. The plasma membrane dopamine transporter mediates this selective toxicity through accumulation of the active metabolite N-methyl-4-phenylpyridinium (MPP+). In contrast, the vesicular amine transporter protects against this form of injury by sequestering the toxin from its primary site of action in mitochondria. Together with the identification of defects in glutamate transport from patients with amyotrophic lateral sclerosis, these observations suggest that neurotransmitter transport may have a major role in neurodegenerative disease. The recent cloning of cDNAs encoding these transport proteins will help to explore this hypothesis.}, }
@article {pmid7507613, year = {1993}, author = {Olanow, CW}, title = {A radical hypothesis for neurodegeneration.}, journal = {Trends in neurosciences}, volume = {16}, number = {11}, pages = {439-444}, doi = {10.1016/0166-2236(93)90070-3}, pmid = {7507613}, issn = {0166-2236}, mesh = {Animals ; *Free Radicals ; Humans ; Nerve Degeneration/*physiology ; Superoxide Dismutase/genetics/*physiology ; }, abstract = {Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis (FALS). SOD clears superoxide radical and is one of the body's principal defense mechanisms against oxygen toxicity. The finding of SOD variants in FALS is consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS, and possibly to the pathogenesis of other neurodegenerative disorders such as Parkinson's disease, in which there is substantial evidence of oxidant stress. The implication of free radicals in the pathogenesis of neurodegenerative disorders raises the possibility that antioxidants might provide neuroprotective therapy.}, }
@article {pmid8229065, year = {1993}, author = {Appel, SH and Smith, RG and Engelhardt, JI and Stefani, E}, title = {Evidence for autoimmunity in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {118}, number = {2}, pages = {169-174}, doi = {10.1016/0022-510x(93)90106-9}, pmid = {8229065}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Autoimmune Diseases/*immunology/pathology ; Humans ; Mice ; }, abstract = {Although the etiology and pathogenesis of ALS is unknown, increasing evidence supports a role for autoimmune mechanisms in motoneuron degeneration and death. An animal model, experimental autoimmune gray matter disease, can be induced by the inoculation of spinal cord gray matter. The experimental disease is characterized by weakness secondary to the loss of upper and lower motoneurons, accompanied by inflammatory foci within the spinal cord, and IgG at the neuromuscular junction and within UMN and LMN. In human ALS, IgG is present within the UMN and LMN, and T-lymphocytes and activated microglia have been identified within spinal cord gray matter and motor cortex. ALS IgG can passively transfer physiological changes of the neuromuscular junction to mice resulting in enhanced release of acetylcholine. The ALS IgG selectively interact with calcium channels and alter channel function. These data suggest a potential role for autoimmune mechanisms in the destruction and loss of motoneurons in ALS.}, }
@article {pmid8186693, year = {1993}, author = {Henderson, CE and Bloch-Gallego, E and Camu, W and Gouin, A and Lemeulle, C and Mettling, C}, title = {Motoneuron survival factors: biological roles and therapeutic potential.}, journal = {Neuromuscular disorders : NMD}, volume = {3}, number = {5-6}, pages = {455-458}, doi = {10.1016/0960-8966(93)90096-3}, pmid = {8186693}, issn = {0960-8966}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Animals ; Cell Death ; *Cell Survival ; Humans ; Motor Neurons/*cytology/physiology ; Muscular Atrophy, Spinal/pathology/physiopathology/therapy ; Nerve Growth Factors/*physiology/therapeutic use ; Spinal Cord/*cytology/pathology/physiology ; }, abstract = {The existence of factors that promote motoneuron survival in the spinal cord at critical stages of development was first deduced 50 yr ago. The large amount of work that has been put into characterizing such factors reflects both their biological importance and the hope that such molecules may be used therapeutically to slow motoneuron death in pathologies such as the spinal muscular atrophies and amyotrophic lateral sclerosis. Since 1990, several factors have been shown to have in vitro and/or in vivo activities that suggest they play a role in regulating motoneuron survival. Their physiological functions during motoneuron development are probably different and complementary. Several of them seem reasonable candidates for preclinical development, but many crucial experiments remain to be done.}, }
@article {pmid8332139, year = {1993}, author = {Chou, SM and Norris, FH}, title = {Amyotrophic lateral sclerosis: lower motor neuron disease spreading to upper motor neurons.}, journal = {Muscle &amp; nerve}, volume = {16}, number = {8}, pages = {864-869}, doi = {10.1002/mus.880160810}, pmid = {8332139}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Axons/ultrastructure ; Humans ; *Models, Neurological ; Motor Cortex/physiopathology ; Motor Neuron Disease/*physiopathology ; }, abstract = {Contrary to the recently reemphasized notion that the primary neuron involved in amyotrophic lateral sclerosis (ALS) is the cortical (upper) motor neuron (UMN), we believe that the lower motor neuron (LMN) is primarily involved by the retrograde transport of pathogens from neuromuscular junctions, and the disease process spreads monosynaptically to the UMN. Pathologically and epidemiologically, the LMN hypothesis is more logical than the UMN in light of the recent understanding of neuroaxonal transport systems, particularly in regard to anterograde cytoskeleton transport and the kinetics of the force promoting slow axonal transport. By correlating the early pathologic findings, i.e., the swelling of the initial axons and formation of intracytoplasmic inclusions in the LMN, ALS may be regarded as a disease of axonal transport, especially its slow component (SCa). Therapeutic intervention to facilitate SCa should be attempted in ALS.}, }
@article {pmid8302496, year = {1993}, author = {}, title = {Mutations in the copper- and zinc-containing superoxide dismutase gene are associated with "Lou Gehrig's disease".}, journal = {Nutrition reviews}, volume = {51}, number = {8}, pages = {243-245}, doi = {10.1111/j.1753-4887.1993.tb03114.x}, pmid = {8302496}, issn = {0029-6643}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Chromosomes, Human, Pair 21 ; Humans ; *Mutation ; Superoxide Dismutase/*genetics ; }, abstract = {Recent genetic analyses of patients with a familial, chromosome 21-linked form of amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, suggest that mutations in the cytosolic copper/zinc superoxide dismutase (SOD1) gene may be involved in development of the disease. Although no functional disturbance of SOD1 activity has yet been identified, altered free radical protection may contribute to the destruction of motor neurons. The role of antioxidant status needs to be investigated as a possible preventive and therapeutic intervention for ALS.}, }
@article {pmid7691004, year = {1993}, author = {Isacson, O}, title = {On neuronal health.}, journal = {Trends in neurosciences}, volume = {16}, number = {8}, pages = {306-308}, doi = {10.1016/0166-2236(93)90104-t}, pmid = {7691004}, issn = {0166-2236}, mesh = {*Health ; Humans ; Nerve Degeneration/physiology ; Nervous System Diseases/*physiopathology ; }, abstract = {Many recent studies of the degeneration, neuroprotection and regeneration of CNS neurons have departed from previous dichotomous descriptions of neurons as either dead or alive. In this brief article aspects of neuronal health are examined by outlining ways to assess both neuronal resilience and vulnerability to common forms of structural brain insults. According to this theory of neuronal health, neurons exist in a dynamic equilibrium that spans a spectrum of cellular existence, constantly influenced by both extracellular physiological changes and intracellular mechanisms designed to react to external stimuli while maintaining structural integrity. The spectrum between particularly resilient and vulnerable neuronal states is illustrated by experiments in vivo that examine trophic and metabolic fluctuations influencing the likelihood of neuronal death after neuronal insults. Studies show that adult CNS neurons can be protected in vivo by trophic agents or other pharmacological interventions against structural and toxic damage. Conversely, low-level neuronal impairment due to genetic or physiological perturbations can predispose neurons to demise by insults that normally would not cause cell death. The experimental approaches described may help in the study of neuronal pathophysiology, and in investigations towards new treatments for the neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.}, }
@article {pmid8325256, year = {1993}, author = {Spencer, PS and Ludolph, AC and Kisby, GE}, title = {Neurologic diseases associated with use of plant components with toxic potential.}, journal = {Environmental research}, volume = {62}, number = {1}, pages = {106-113}, doi = {10.1006/enrs.1993.1095}, pmid = {8325256}, issn = {0013-9351}, support = {NS 19611/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Nervous System Diseases/*chemically induced ; *Plants, Toxic/chemistry ; }, abstract = {Epidemics of neurotoxic disease in developing regions of the world are often associated with dietary dependence on plant components with inherent toxic potential or which have spoiled and become contaminated with mycotoxins. Diseases triggered by plant toxins include lathyrism and cassavism, types of irreversible spastic parapareses associated with staple diets of grass pea and bitter cassava root, respectively. Mildewed sugarcane poisoning, an encephalopathy and tardive dystonia, illustrates the neurotoxic effects of a widely distributed plant and fungal toxin. Food and medicinal use of the neurotoxic cycad plant is thought to have a role in the etiology of western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia. Plant-associated neurotoxicity is a significant and preventable cause of morbidity in certain regions of Africa, Asia, and Oceania.}, }
@article {pmid7691501, year = {1993}, author = {Faulds, D and Goa, KL and Benfield, P}, title = {Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders.}, journal = {Drugs}, volume = {45}, number = {6}, pages = {953-1040}, pmid = {7691501}, issn = {0012-6667}, mesh = {Arthritis, Rheumatoid/drug therapy ; Clinical Trials as Topic ; Cyclosporine/administration &amp; dosage/pharmacokinetics/pharmacology/*therapeutic use ; Diabetes Mellitus, Type 1/drug therapy ; Digestive System Diseases/drug therapy ; Eye Diseases/drug therapy ; Humans ; Immune System Diseases/*drug therapy ; Nephrotic Syndrome/drug therapy ; Nervous System Diseases/drug therapy ; Skin Diseases/drug therapy ; }, abstract = {Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological factor, and this is the focus of the present review. In patients with severe disease refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behçet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid8401784, year = {1993}, author = {Neary, D and Snowden, JS and Mann, DM}, title = {The clinical pathological correlates of lobar atrophy.}, journal = {Dementia (Basel, Switzerland)}, volume = {4}, number = {3-4}, pages = {154-159}, doi = {10.1159/000107315}, pmid = {8401784}, issn = {1013-7424}, mesh = {Aphasia/pathology/psychology ; Atrophy ; Dementia/*pathology/psychology ; Frontal Lobe/*pathology ; Humans ; Motor Neuron Disease/pathology/psychology ; Temporal Lobe/*pathology ; }, abstract = {Three clinical syndromes associated with fronto-temporal cerebral atrophy, studied in one centre are discussed: dementia of frontal type (DFT), DFT and motor neurone disease (MND) and progressive aphasia (PA). The pathological findings in DFT (13 brains), DFT and MND (5 brains) and PA (5 brains) permit a number of clinical pathological groupings. The nosological status of fronto-temporal atrophy is discussed with reference to the literature and it is suggested that a common underlying pathology, including Picks disease as strictly defined by the presence of inclusion bodies, underlies the clinical syndromes, each being determined by the anatomical distribution of the pathology.}, }
@article {pmid8472072, year = {1993}, author = {Scano, G and Gigliotti, F and Duranti, R and Gorini, M and Fanelli, A and Marconi, G}, title = {Control of breathing in patients with neuromuscular diseases.}, journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace}, volume = {48}, number = {1}, pages = {87-91}, pmid = {8472072}, issn = {1122-0643}, mesh = {Humans ; Motor Neuron Disease/physiopathology ; Muscular Diseases/physiopathology ; Neuromuscular Diseases/*physiopathology ; Polyradiculoneuropathy/physiopathology ; Respiration/*physiology ; }, abstract = {We reviewed the studies devoted to investigate the control of breathing in patients with neuromuscular diseases. Neural respiratory drive has been assessed in terms of minute ventilation and mouth occlusion pressure (P0.1) in patients with several types of neuromuscular affections (amyotrophic lateral sclerosis, poliomyelitis and post-polio syndrome, Guillain Barré syndrome, muscular dystrophies, inflammatory muscle diseases). More recently we have used electromyographic activity of diaphragm to evaluate neural drive in patients with myasthenia gravis and muscular dystrophies. The results of these studies seem to indicate that patients with myasthenia gravis are not likely to have a decreased respiratory drive, the disorder in neuromuscular transmission being probably the reason for the apparent decrease in diaphragmatic neural activation during hypercapnic stimulation. Increase in neural afferent information from lung and/or rib cage might explain both the increased neural respiratory drive and the faster breathing observed in patients with neuromuscular disease.}, }
@article {pmid8457886, year = {1993}, author = {Smith, RG and Engelhardt, JI and Tajti, J and Appel, SH}, title = {Experimental immune-mediated motor neuron diseases: models for human ALS.}, journal = {Brain research bulletin}, volume = {30}, number = {3-4}, pages = {373-380}, doi = {10.1016/0361-9230(93)90268-g}, pmid = {8457886}, issn = {0361-9230}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; *Disease Models, Animal ; Guinea Pigs ; Humans ; Motor Neuron Disease/*immunology ; }, abstract = {Amyotrophic lateral sclerosis is an idiopathic, ultimately fatal disease, clinically manifest as progressive weakness and spasticity, associated with the loss of motoneurons. Circumstantial evidence supports a role for autoimmune processes in the progression of this human disorder. Two immune-mediated animal models have been developed in our laboratory for motor neuron loss. Experimental autoimmune motor neuron disease is a lower motor syndrome induced in guinea pigs by the repeated injection of a purified bovine spinal motor neuron antigen. Affected animals demonstrate extremity weakness, associated with electromyographic and morphologic evidence of denervation, a loss of spinal cord motor neurons, high antibody titers against motor neurons, and localization of IgG immunoreactivity to the neuromuscular junction and motor neuron cytoplasm. Experimental autoimmune grey matter disease is a more acute and severe disorder involving both upper and lower motor neurons, induced in guinea pigs by inoculation of a bovine ventral spinal cord homogenate, in which scattered foci of denervation are observed in the motor cortex and ventral spinal cord. Similarities between these diseases and human ALS are reviewed.}, }
@article {pmid8423066, year = {1993}, author = {McGeer, PL and Kawamata, T and Walker, DG and Akiyama, H and Tooyama, I and McGeer, EG}, title = {Microglia in degenerative neurological disease.}, journal = {Glia}, volume = {7}, number = {1}, pages = {84-92}, doi = {10.1002/glia.440070114}, pmid = {8423066}, issn = {0894-1491}, mesh = {Antigens, Surface/metabolism ; Complement Membrane Attack Complex/metabolism ; Humans ; Ligands ; *Nerve Degeneration ; Nerve Tissue Proteins/metabolism ; Nervous System Diseases/metabolism/*pathology ; Neuroglia/metabolism/*physiology ; }, abstract = {Microglia express many leukocyte surface antigens which are upregulated in such chronic degenerative neurological diseases as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). These surface antigens include leukocyte common antigen, immunoglobulin Fc receptors, MHC class I and class II glycoproteins, beta 2-integrins, and the vitronectin receptor. Ligands for these receptors are also found. They include immunoglobulins, complement proteins of the classical pathway, T lymphocytes of the cytotoxic/suppressor and helper/inducer classes, and vitronectin. T lymphocytes marginate along capillary venules, with some penetrating into the tissue matrix. Immunoglobulins and complement proteins are synthesized locally in brain, although they may also come from the bloodstream if the blood-brain barrier is compromised. The membrane attack complex, which is formed from C5b-9, the terminal components of complement, has been identified in AD and multiple sclerosis brain tissue. In addition, proteins designed to defend against bystander lysis caused by the membrane attack complex, including protectin, C8 binding protein, clusterin, and vitronectin, are associated with damaged neuronal processes in AD. Autodestruction may play a prominent part in these 2 diseases.}, }
@article {pmid8407246, year = {1993}, author = {Neumann-Haefelin, D and Fleps, U and Renne, R and Schweizer, M}, title = {Foamy viruses.}, journal = {Intervirology}, volume = {35}, number = {1-4}, pages = {196-207}, doi = {10.1159/000150310}, pmid = {8407246}, issn = {0300-5526}, mesh = {Animals ; Humans ; Retroviridae Infections/*microbiology ; *Spumavirus/genetics/physiology ; }, abstract = {Foamy viruses share complex genome organization with lentiviruses and certain oncoviruses. The open reading frame 3' of env encodes a transcriptional transactivator. Distinct responsive sequences were identified in the long terminal repeats (LTRs) of simian (SFV-1 and SFV-3) and human foamy viruses (HFV). Transactivation of heterologous LTRs was described including those of simian and human immunodeficiency viruses. Foamy viruses persist for the whole lifetime in infected hosts (primates, cats, hamsters, cattle, and probably other mammals). The virus may be orally shed and transmitted, while being latent in various internal organs. Selective viral gene expression in the brains of mice transgenic for HFV has suggested a particular relationship to neural tissue. In latently SFV-3-infected cultured cells, methylation of proviral DNA is apparently involved in the control of latency. Demethylation as well as transfection with the transactivator were shown to be instrumental in viral reactivation. Natural infections with foamy viruses are common, elicit strong immune responses, and seem to be asymptomatic in nonhuman primates. Detection of such infections, however, may not be a triviality in man. While accidental transmission of foamy viruses to man is well documented, reported seroprevalence in human populations and the association of HFV with specific pathology (e.g. thyroiditis de Quervain, amyotrophic lateral sclerosis, and Graves' disease) are controversial and remain to be proven.}, }
@article {pmid8375434, year = {1993}, author = {Uitti, RJ and Calne, DB}, title = {Pathogenesis of idiopathic parkinsonism.}, journal = {European neurology}, volume = {33 Suppl 1}, number = {}, pages = {6-23}, doi = {10.1159/000118533}, pmid = {8375434}, issn = {0014-3022}, mesh = {Alzheimer Disease/etiology/pathology ; Amyotrophic Lateral Sclerosis/etiology/pathology ; Brain/pathology ; Environmental Exposure/adverse effects ; Humans ; Lewy Bodies/ultrastructure ; Parkinson Disease/*etiology/pathology ; Risk Factors ; }, abstract = {Idiopathic parkinsonism (Parkinson's disease) makes up the largest diagnostic subgroup of patients with parkinsonism. Various hypotheses exist regarding the pathogenesis of idiopathic parkinsonism: these include genetic predilection aging, environmental factors, oxidative stress, excitotoxicity, autoimmunity, and trauma. We suggest that the pathogenesis of idiopathic parkinsonism is likely to be multifactorial, deriving from environmental factor(s) acting upon a genetically predisposed individual. Because of the compelling evidence indicating common clinical and pathological findings in idiopathic parkinsonism, Alzheimer's disease, and amyotrophic lateral sclerosis, we believe that these conditions result from pathological processes with more similarity than diversity. A primary glutamatergic cell neocortical abnormality provides an attractive unifying explanation which may explain the overlapping abnormalities found in idiopathic parkinsonism, Alzheimer's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid8348920, year = {1993}, author = {Müller, M and Vieregge, P and Reusche, E and Ogomori, K}, title = {Amyotrophic lateral sclerosis and frontal lobe dementia in Alzheimer's disease. Case report and review of the literature.}, journal = {European neurology}, volume = {33}, number = {4}, pages = {320-324}, doi = {10.1159/000116962}, pmid = {8348920}, issn = {0014-3022}, mesh = {Alzheimer Disease/*diagnosis/pathology ; Amyotrophic Lateral Sclerosis/*diagnosis/pathology ; Atrophy ; Brain/pathology ; Diabetic Neuropathies/diagnosis/pathology ; Female ; Frontal Lobe/*pathology ; Humans ; Middle Aged ; Neurofibrillary Tangles/ultrastructure ; Neurologic Examination ; Neuropsychological Tests ; Spinal Cord/pathology ; }, abstract = {Clinicopathological data of a woman with a 3-year course of concurrent amyotrophic lateral sclerosis and dementia are presented. Dementia had occurred at time of onset of motor disturbances and presented as typical frontal lobe dementia. Pathology confirmed motor neuron disease of amyotrophic lateral sclerosis and frontal lobe atrophy. Multiple senile plaques were distributed cortically and in the hippocampus, where diffuse spread of neurofibrillary tangles was seen. Hence, this Alzheimer's dementia in a patient with sporadic amyotrophic lateral raises the question of a possible association between the two conditions.}, }
@article {pmid8269084, year = {1993}, author = {Lowe, J and Mayer, RJ and Landon, M}, title = {Ubiquitin in neurodegenerative diseases.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {3}, number = {1}, pages = {55-65}, doi = {10.1111/j.1750-3639.1993.tb00726.x}, pmid = {8269084}, issn = {1015-6305}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Brain Chemistry ; Humans ; Immunohistochemistry ; Intermediate Filaments/pathology ; Nervous System Diseases/*metabolism/pathology ; Neuroglia/metabolism/pathology ; Prion Diseases/metabolism/pathology ; Ubiquitins/analysis/*metabolism ; tau Proteins/metabolism ; }, abstract = {Immunochemical staining to detect ubiquitin has become an essential technique in evaluating neurodegenerative processes. Age related staining is seen in myelin, in nerve processes in lysosome-related dense bodies, and in corpora amylacea. There is a constant association between filamentous inclusions and the presence of ubiquitin. Intermediate filaments associated with ubiquitin, alpha B crystallin and enzymes of the ubiquitin pathway are the basis of Lewy bodies and Rosenthal fibres, as well as related bodies outside the nervous system. Neurofibrillary tangles in diverse diseases are associated with ubiquitin as are several other tau containing inclusions in both neurones and glia. Inclusions in motor neurones and non-motor cortex characterizing amyotrophic lateral sclerosis (ALS) and certain related forms of frontal lobe dementia can only be readily detected by anti-ubiquitin. Anti-ubiquitin also identifies both filamentous and lysosomal structures in neuronal processes as well as in some swollen neurones. Involvement of ubiquitin-containing elements of the lysosomal system appears important in pathogenesis of prion encephalopathies. Despite great advances in understanding cell biology of the ubiquitin pathway there are as yet few insights into the precise role played by ubiquitin in neuronal disease.}, }
@article {pmid8062675, year = {1993}, author = {Kuisma, M and Jokelainen, M and Saarinen, K}, title = {[Respiratory insufficiency in amyotrophic lateral sclerosis].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {109}, number = {12}, pages = {1045-1050}, pmid = {8062675}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Respiratory Function Tests ; Respiratory Insufficiency/diagnosis/*etiology/therapy ; }, }
@article {pmid8062674, year = {1993}, author = {Ignatius, J}, title = {[Free radicals as a cause of amyotrophic lateral sclerosis?].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {109}, number = {12}, pages = {1041-1043}, pmid = {8062674}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Chromosomes, Human, Pair 21 ; Free Radicals ; Humans ; Mutation ; Superoxide Dismutase/genetics ; }, }
@article {pmid7712626, year = {1993}, author = {Serratrice, G}, title = {Motor neuropathies and antiglycolipid antibodies.}, journal = {Clinical and experimental neurology}, volume = {30}, number = {}, pages = {25-32}, pmid = {7712626}, issn = {0196-6383}, mesh = {Antibodies/*analysis/immunology ; Antibody Specificity ; Demyelinating Diseases/immunology/physiopathology ; G(M1) Ganglioside/immunology ; Glycolipids/*immunology ; Humans ; Motor Neuron Disease/*immunology/physiopathology ; Neural Conduction ; }, abstract = {This paper describes patients with demyelinating motor neuropathies associated with conduction blocks, pure motor neuropathies and intermediate forms with resemblances to amyotrophic lateral sclerosis, in persons with raised titres of anti-GM1 antibodies. The specificity of the abnormal anti-GM1 antibody titres is discussed, and the possibilities of immunosuppressive therapy mentioned.}, }
@article {pmid7679235, year = {1993}, author = {Appel, SH}, title = {Excitotoxic neuronal cell death in amyotrophic lateral sclerosis.}, journal = {Trends in neurosciences}, volume = {16}, number = {1}, pages = {3-5}, doi = {10.1016/0166-2236(93)90039-o}, pmid = {7679235}, issn = {0166-2236}, mesh = {Amino Acids/toxicity ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Cell Death/drug effects ; Humans ; Neurons/*drug effects ; Neurotoxins/*toxicity ; }, }
@article {pmid7505706, year = {1993}, author = {Oliver, D}, title = {Ethical issues in palliative care--an overview.}, journal = {Palliative medicine}, volume = {7}, number = {4 Suppl}, pages = {15-20}, doi = {10.1177/0269216393007004S04}, pmid = {7505706}, issn = {0269-2163}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Ethics, Medical ; Humans ; Motor Neuron Disease/*therapy ; Palliative Care/*standards ; Patient Care Planning/standards ; Terminal Care/standards ; Truth Disclosure ; }, abstract = {There are many ethical decisions to be made during palliative care of a patient with motor neurone disease. These may concern the physical and psychosocial care of the patient and will become highlighted when death approaches. By close involvement of the patient and his/her family with the interdisciplinary team the most appropriate decisions on the patient's care can be made.}, }
@article {pmid1487752, year = {1992}, author = {Kurland, LT and Radhakrishnan, K and Smith, GE and Armon, C and Nemetz, PN}, title = {Mechanical trauma as a risk factor in classic amyotrophic lateral sclerosis: lack of epidemiologic evidence.}, journal = {Journal of the neurological sciences}, volume = {113}, number = {2}, pages = {133-143}, doi = {10.1016/0022-510x(92)90241-c}, pmid = {1487752}, issn = {0022-510X}, support = {AR30582/AR/NIAMS NIH HHS/United States ; NS17750/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*epidemiology/*etiology ; Epidemiologic Methods ; Humans ; Male ; Risk Factors ; Wounds and Injuries/*complications ; }, abstract = {We have examined the relationship between mechanical injuries and the subsequent development of classic amyotrophic lateral sclerosis (ALS) through a critical review of the literature. Only prospective evaluation of a large cohort of trauma victims can provide an unbiased answer to this controversy. However, such an evaluation would be prohibitively expensive, and the results would not be available in our lifetime. The results of retrospective case-control studies are conflicting in part because of biases in the selection of patients and controls, poor definition of the nature and extent of the trauma and its chronological relationship to the onset of ALS, and a non-uniform approach to the collection of antecedent information. More rigorously designed studies show no association of ALS to antecedent trauma. The existing data thus do not suggest that mechanical trauma is a risk factor for ALS. Future case-control studies should conform to a standardized methodology. The critical analysis presented here of the research on the purported connection between mechanical injury and ALS may serve as a model for the evaluation of the role of trauma in other chronic diseases. Application of these methodological principles may bring increased scientific rigor to assessing the frequently litigated question of what constitutes a true trauma sequela.}, }
@article {pmid1344205, year = {1992}, author = {Kew, J and Leigh, N}, title = {Dementia with motor neurone disease.}, journal = {Bailliere's clinical neurology}, volume = {1}, number = {3}, pages = {611-626}, pmid = {1344205}, issn = {0961-0421}, mesh = {Alzheimer Disease/complications/pathology ; Brain/pathology ; Chromosome Aberrations ; Chromosome Disorders ; Dementia/*complications/pathology ; Humans ; Motor Neuron Disease/*complications/genetics/pathology ; }, }
@article {pmid1344203, year = {1992}, author = {Gustafson, L and Brun, A and Passant, U}, title = {Frontal lobe degeneration of non-Alzheimer type.}, journal = {Bailliere's clinical neurology}, volume = {1}, number = {3}, pages = {559-582}, pmid = {1344203}, issn = {0961-0421}, mesh = {Cerebrovascular Circulation ; Cognition Disorders/etiology/pathology ; Dementia/complications/diagnosis/*pathology ; Frontal Lobe/*pathology ; Humans ; Language Disorders/etiology/pathology ; Magnetic Resonance Imaging ; Pedigree ; Regional Blood Flow ; Tomography, X-Ray Computed ; }, abstract = {In a longitudinal prospective study of dementias, several hundred cases have been examined from a clinical, brain imaging, neurochemical and neuropathological point of view. Frontal lobe degeneration of non-Alzheimer type (FLD) was the second most common primary degenerative dementia found in about 10% of the material. FLD has a consistent pathology and a characteristic clinical picture, which have been described by several independent research groups. The cortical degeneration mainly involves frontal or frontotemporal grey matter, without the circumscribed or knife-blade atrophy seen in Pick's disease. The degeneration involves predominantly frontal areas, including the insula and cingulate gyrus in its anterior parts. The striate body is normal or only slightly altered. The pathological changes are non-specific, with neuronal loss, slight gliosis and spongiosis but none or few senile plaques, tangles, congophilic vessels or Pick cells. Pathological changes are in some respects similar to those in amyotrophic lateral sclerosis. FLD is a slowly progressive dementia with personality changes, lack of insight, disinhibition, stereotypy and later apathy. There is also progressive dynamic aphasia which ends in mutism and amimia. Memory, spatial ability and receptive language functions are comparatively spared. Psychotic symptoms, emotional reactions, hypochondriasis and a Klüver-Bucy-like syndrome are sometimes observed. Electroencephalography is normal, at least during the early stage, while functional brain imaging such as regional cerebral blood flow reflects the frontal pathology. It is possible to achieve early diagnosis and differentiation from Alzheimer's disease and cerebrovascular dementia by clinical examination with neuropsychological assessment supported by brain imaging, and in the future probably various biological markers. The aetiology is unknown but there is a positive family history for dementia of similar type in about 50% of post-mortem verified cases.}, }
@article {pmid1335040, year = {1992}, author = {Swash, M and Schwartz, MS}, title = {What do we really know about amyotrophic lateral sclerosis?.}, journal = {Journal of the neurological sciences}, volume = {113}, number = {1}, pages = {4-16}, doi = {10.1016/0022-510x(92)90258-m}, pmid = {1335040}, issn = {0022-510X}, mesh = {*Amyotrophic Lateral Sclerosis/complications/etiology/genetics ; Autoimmunity ; Dementia/complications ; Electrophysiology ; Humans ; Inclusion Bodies/ultrastructure ; Models, Neurological ; Movement Disorders/classification ; Nervous System/drug effects ; Poliomyelitis/complications ; Prognosis ; Risk Factors ; Spinal Cord/pathology/physiopathology ; }, abstract = {The cause of amyotrophic lateral sclerosis is unknown. In this review clinical and scientific data that are pertinent to understanding this disease are reviewed. There are currently several major controversies concerning the possible role of immunological factors, genetic factors, environmental toxins, and viral infection in pathogenesis. These concepts must be considered in relation to what is known about the disease in all its aspects, including epidemiological data, information on the classical and molecular pathology of the disease, and on associated involvement of other systems, e.g., the spinocerebellar pathways and frontal dementia. Only when all this information is assimilated can full understanding of the disease and, hopefully, a logical approach to treatment and prevention, be achieved.}, }
@article {pmid1307392, year = {1992}, author = {Kovindha, A and Sa-Gnuanmitra, P}, title = {Post-polio syndrome: a review and case report.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {75}, number = {11}, pages = {666-669}, pmid = {1307392}, issn = {0125-2208}, mesh = {Adult ; Atrophy ; Electromyography ; Exercise Therapy ; Hand/pathology ; Humans ; Leg/pathology ; Male ; Muscle Denervation ; Postpoliomyelitis Syndrome/*diagnosis/rehabilitation ; Thailand ; }, abstract = {A 21-year-old Thai man presented with progressive weakness and atrophy of both hands for 2 years. His left leg was atrophic and weak secondary to poliomyelitis since he was 8 months old. Physical examination showed that there was atrophy of both hands and forearms as well as left leg. Sensation was normal. Deep tendon reflexes were normal except for hyporeflexia of left leg. EMG showed chronic denervation pattern in the recent atrophic muscles and in normal power muscles. Motor and sensory nerve conductions were normal. Biopsy of forearm muscle revealed degeneration and fibrosis of muscle fibers. These findings were compatible with post-polio syndrome (PPS) which presents in patients with late paralysis following poliomyelitis. It is not a form of amyotrophic lateral sclerosis although some clinical similarities exist. Weakness from PPS may lead to musculoskeletal pain and increased functional disability. Proper rehabilitation program is to maintain his functional status and allow him to continue to live as independently as possible by regular exercise without stressing joints and muscles.}, }
@article {pmid1469439, year = {1992}, author = {Mazzarello, P and Poloni, M and Spadari, S and Focher, F}, title = {DNA repair mechanisms in neurological diseases: facts and hypotheses.}, journal = {Journal of the neurological sciences}, volume = {112}, number = {1-2}, pages = {4-14}, doi = {10.1016/0022-510x(92)90125-5}, pmid = {1469439}, issn = {0022-510X}, mesh = {Animals ; *DNA Repair ; DNA Replication ; Humans ; Nervous System Diseases/enzymology/*metabolism ; }, abstract = {DNA repair mechanisms usually consist of a complex network of enzymatic reactions catalyzed by a large family of mutually interacting gene products. Thus deficiency, alteration or low levels of a single enzyme and/or of auxiliary proteins might impair a repair process. There are several indications suggesting that some enzymes involved both in DNA replication and repair are less abundant if not completely absent in stationary and non replicating cells. Postmitotic brain cell does not replicate its genome and has lower levels of several DNA repair enzymes. This could impair the DNA repair capacity and render the nervous system prone to the accumulation of DNA lesions. Some human diseases clearly characterized by a DNA repair deficiency, such as xeroderma pigmentosum, ataxia-telangiectasia and Cockayne syndrome, show neurodegeneration as one of the main clinical and pathological features. On the other hand there is evidence that some diseases characterized by primary neuronal degeneration (such as amyotrophic lateral sclerosis and Alzheimer disease) may have alterations in the DNA repair systems as well. DNA repair thus appears important to maintain the functional integrity of the nervous system and an accumulation of DNA damages in neurons as a result of impaired DNA repair mechanisms may lead to neuronal degenerations.}, }
@article {pmid1392132, year = {1992}, author = {Harding, AE}, title = {Molecular genetics and clinical aspects of inherited disorders of nerve and muscle.}, journal = {Current opinion in neurology and neurosurgery}, volume = {5}, number = {5}, pages = {600-604}, pmid = {1392132}, issn = {0951-7383}, mesh = {Amyloidosis/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Chromosome Aberrations/genetics ; Chromosome Disorders ; Genes, Dominant/genetics ; Genes, Recessive/genetics ; Hereditary Sensory and Motor Neuropathy/genetics ; Humans ; *Molecular Biology ; Muscular Atrophy, Spinal/genetics ; Muscular Diseases/genetics ; Neuromuscular Diseases/*genetics ; }, abstract = {Rapid progress has been made in elucidating the molecular genetic basis of several neuromuscular disorders in the past year. Candidate genes have been identified or analysed in hereditary motor and sensory neuropathy (HMSN) type I, X-linked bulbospinal neuronopathy and non-dystrophic myotonic disorders, and further mutations causing amyloidosis have been identified. A familial amyotrophic lateral sclerosis (ALS) locus maps to chromosome 21 in some families, and the chronic childhood spinal muscular atrophy (SMA), facioscapulohumeral muscular dystrophy (FSHD) and malignant hyperthermia loci have been localized more precisely.}, }
@article {pmid1327304, year = {1992}, author = {Jubelt, B}, title = {Motor neuron diseases and viruses: poliovirus, retroviruses, and lymphomas.}, journal = {Current opinion in neurology and neurosurgery}, volume = {5}, number = {5}, pages = {655-658}, pmid = {1327304}, issn = {0951-7383}, mesh = {Animals ; HIV/pathogenicity ; Human T-lymphotropic virus 1/pathogenicity ; Human T-lymphotropic virus 2/pathogenicity ; Humans ; Lymphoma/*immunology ; Motor Neuron Disease/*immunology/microbiology ; Motor Neurons/immunology/microbiology ; Paraneoplastic Syndromes/*immunology ; Poliomyelitis/*immunology/microbiology ; Poliovirus/pathogenicity ; Retroviridae Infections/*immunology/microbiology ; }, abstract = {The viral theory of motor neuron disease (MND) has been rejuvenated in the last 5 years for several reasons. First, it is now recognized that enteroviruses and picornaviruses similar to poliovirus can persist and induce immune-mediated diseases. In some picornavirus animal models, the immune-mediated disease can occur and continue long after the infectious virus has been cleared, and in some cases of human MND an immune-mediated disease may occur. Second, the human retroviruses human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus (HTLV) have caused isolated MND syndromes. Neither of these two specific viruses appear to be 'the amyotrophic lateral sclerosis (ALS) retrovirus', because they cause a plethora of neurologic syndromes unrelated to MND. Retroviruses of mice, however, can cause MND and lymphomas, and because there is an increased incidence of lymphomas in ALS patients, it has been suggested that retroviruses are another possible viral agent of human MND.}, }
@article {pmid1338180, year = {1992}, author = {Piccoli, F and La Bella, V and Guarneri, R}, title = {New insights on the pathogenesis of neurodegenerative disorders.}, journal = {Acta neurologica}, volume = {14}, number = {4-6}, pages = {455-468}, pmid = {1338180}, issn = {0001-6276}, mesh = {Animals ; Disease Models, Animal ; Haplorhini ; Humans ; Models, Neurological ; *Nerve Degeneration/drug effects/genetics/physiology ; Nervous System Diseases/*etiology/pathology ; Neuronal Plasticity ; Neurotoxins/pharmacology/toxicity ; Plants, Toxic ; Rats ; Receptors, Neurotransmitter/drug effects/physiology ; Synaptic Transmission/drug effects ; }, abstract = {In the last few years, an increasing amount of studies have been dedicated to the etiopathogenesis of age-related neurodegenerative disorders, such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. The discovery of synthetic, as well as natural molecules, able to reproduce in the animals biochemical and morphological alterations of neurodegenerative disorders, has provided a major impetus to the "environmental" hypothesis of neurodegeneration. In this review, following a brief description of the ability of the nervous system to counteract the degenerative process, the main neurotoxic-based animal models for neurodegeneration are examined. These might give us interesting clues for understanding the pathogenetic mechanism(s) of neurodegenerative process.}, }
@article {pmid1389560, year = {1992}, author = {Oyanagi, K and Ikuta, F}, title = {[The quantitative investigations on the neuronal loss in ALS].}, journal = {No to shinkei = Brain and nerve}, volume = {44}, number = {6}, pages = {533-545}, pmid = {1389560}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Brain Stem/pathology ; Cerebral Cortex/pathology ; Humans ; Motor Neurons/*pathology ; Neural Pathways/pathology ; Spinal Cord/pathology ; }, }
@article {pmid1389558, year = {1992}, author = {Nakano, I}, title = {[Neuropathology of classical and several other types of amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {44}, number = {6}, pages = {495-503}, pmid = {1389558}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics/*pathology ; Dementia/etiology ; Family Health ; Humans ; Motor Neurons/pathology ; Nervous System/*pathology ; }, }
@article {pmid1389557, year = {1992}, author = {Mannen, T}, title = {[Amyotrophic lateral sclerosis--its problem].}, journal = {No to shinkei = Brain and nerve}, volume = {44}, number = {6}, pages = {492-494}, pmid = {1389557}, issn = {0006-8969}, mesh = {Amino Acids, Diamino/metabolism ; *Amyotrophic Lateral Sclerosis/etiology/immunology/metabolism ; Autoimmune Diseases/etiology/immunology/metabolism ; Cyanobacteria Toxins ; Humans ; N-Methylaspartate/metabolism ; }, }
@article {pmid1327025, year = {1992}, author = {Takahashi, H and Ikuta, F}, title = {[Bunina body in amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {44}, number = {6}, pages = {525-532}, pmid = {1327025}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Anterior Horn Cells/metabolism/ultrastructure ; Humans ; Immunohistochemistry ; Inclusion Bodies/metabolism/*ultrastructure ; Microscopy, Electron ; Motor Neurons/metabolism/*pathology/ultrastructure ; }, }
@article {pmid1637043, year = {1992}, author = {Duncan, MW}, title = {beta-Methylamino-L-alanine (BMAA) and amyotrophic lateral sclerosis-parkinsonism dementia of the western Pacific.}, journal = {Annals of the New York Academy of Sciences}, volume = {648}, number = {}, pages = {161-168}, doi = {10.1111/j.1749-6632.1992.tb24534.x}, pmid = {1637043}, issn = {0077-8923}, mesh = {Amino Acids, Diamino/*toxicity ; Amyotrophic Lateral Sclerosis/chemically induced/*etiology ; Cyanobacteria Toxins ; Diet ; Guam/epidemiology ; Humans ; Neurotoxins/*toxicity ; Parkinson Disease, Secondary/chemically induced/*etiology ; Risk Factors ; }, }
@article {pmid1322079, year = {1992}, author = {Spencer, PS and Ludolph, AC and Kisby, GE}, title = {Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties?.}, journal = {Annals of the New York Academy of Sciences}, volume = {648}, number = {}, pages = {154-160}, doi = {10.1111/j.1749-6632.1992.tb24533.x}, pmid = {1322079}, issn = {0077-8923}, support = {NS19611/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/etiology ; Amyotrophic Lateral Sclerosis/etiology ; Animals ; Brain/metabolism ; Brain Diseases/*chemically induced/metabolism ; Energy Metabolism ; Environmental Pollutants/*toxicity ; Glutamates/metabolism ; Humans ; Neurotoxins/*toxicity ; Parkinson Disease/etiology ; Receptors, Glutamate ; Receptors, Neurotransmitter/metabolism ; Spinal Cord/metabolism ; Spinal Cord Diseases/*chemically induced/metabolism ; }, abstract = {At the present time, it seems unlikely that progressive neurodegenerative diseases, such as ALS, Parkinson's disease, and dementia of the Alzheimer type, are triggered by environmental agents with excitotoxic potential. These include excitotoxic agents that behave as glutamate agonists or disrupt energy metabolism: both types elicit permanent but self-limiting neuronal diseases with patterns of neuronal deficit that reflect selective chemical exposure (MPP+ and parkinsonism), differential susceptibility to energy dysmetabolism (NPA and dystonia), or the distribution of glutamate-receptors (domoic acid and memory loss). If environmental agents play an etiologic role in progressive neurodegenerative diseases, they are likely to target a critical, irreplaceable neuronal molecule that is required to maintain long-term neuronal integrity.}, }
@article {pmid1619777, year = {1992}, author = {Yase, Y}, title = {[The etiopathogenesis of amyotrophic lateral sclerosis--recent development].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {50}, number = {4}, pages = {900-906}, pmid = {1619777}, issn = {0047-1852}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/genetics ; Humans ; Pacific Islands/epidemiology ; }, abstract = {In spite of extensive studies of amyotrophic lateral sclerosis (ALS) for the past decades, its cause still remains obscure. Based on the clinicopathological observations and experimental studies of sporadic and endemic ALS cases, etiologic hypothesis encompass a wide range of postulated pathophysiological mechanisms in the various fields. Reviewing briefly these, recent concern on genetic hypothesis, of familial ALS, background of case aggregation in the Western Pacific and immune hypothesis has been discussed. Although there is no unifying theory explanatory for ALS process at present, accumulated results through basic and clinical neurological science may provide a better understanding for the pathogenesis of ALS.}, }
@article {pmid1517745, year = {1992}, author = {Hasegawa, K and Kowa, H and Yagishita, S}, title = {Extrapyramidal system involvement in motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {108}, number = {2}, pages = {137-148}, doi = {10.1016/0022-510x(92)90044-l}, pmid = {1517745}, issn = {0022-510X}, mesh = {Aged ; Basal Ganglia/pathology ; Brain/*pathology ; Brain Stem/pathology ; Female ; Globus Pallidus/pathology ; Humans ; Male ; Medulla Oblongata/pathology ; Mesencephalon/pathology ; Middle Aged ; Motor Neurons/*pathology/physiology ; Nerve Degeneration ; Neuromuscular Diseases/*pathology/physiopathology ; Neurons/pathology ; Spinal Cord/*pathology ; Substantia Nigra/pathology ; Thalamic Nuclei/pathology ; }, abstract = {Three cases of motor neuron disease (MND), in which neuropathological findings were atypical, are reported. The first case manifested widespread and severe degeneration of the spinal cord, as in spinal fibrosis. Case 2 revealed severe degeneration of the pyramidal tract with many spheroids, which made it difficult to differentiate from primary amyotrophic lateral sclerosis. The last case revealed degeneration of the nigro-pallido-luysian system, even though no clinical manifestation of extrapyramidal and/or cerebellar symptoms had been noted throughout the clinical course. In MND, degeneration might occur in various locations other than the motor system.}, }
@article {pmid1628448, year = {1992}, author = {Yoshida, M and Murakami, N and Hashizume, Y and Itoh, E and Takahashi, A}, title = {[A clinicopathological study of two respirator-aided long-survival cases of amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {32}, number = {3}, pages = {259-265}, pmid = {1628448}, issn = {0009-918X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*pathology/therapy ; Brain/pathology ; Humans ; Male ; Middle Aged ; Neurons/pathology ; Prognosis ; Spinal Cord/pathology ; *Ventilators, Mechanical ; }, abstract = {We reported two respirator-aided 10-year-survival male patients with sporadic amyotrophic lateral sclerosis (ALS). Their ages at onset were 54 and 52, clinical features common in both cases, the durations to tracheotomy 32 months and 27 months respectively, and the durations for respiratory support over 8 years in both cases. There were normal external ocular movement, normal pelvic sphincter function, normal sensory system and no bed sores throughout 10 years of illness. The brain weighted 1,295 g in case 1 and 1,430 g in case 2, being normal macroscopically. The spinal cord was slightly wasted with atrophic anterior roots. The histopathological study demonstrated the typical pattern of ALS in spite of the prolonged survival with artificial respiration. Neuronal loss and gliosis of the motor nuclei in the spinal cord and brainstem were more striking than those of the natural course. Neither hypertrophic astrocyte, central chromatolysis nor neuronophagia was observed. This finding suggested inactive condition of the degeneration. The pattern of white matter degeneration in the cord indicated some pallor of anterior and lateral columns, severe pallor of pyramidal tracts and intact posterior column and spinocerebellar tracts. The giant pyramidal cells in the precentral gyrus were lost in both cases. Pyramidal degeneration was traceable up to the cerebral peduncles in the case 2 and undetectable in that portion in the case 1. On the other hand, the extraocular muscle nuclei, the Onuf's nuclei, the dorsal motor nucleus of the vagus nerve, intermediolateral and Clarke's nuclei were relatively preserved, though no cell count was done in Clarke's nuclei and Onuf's nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1583817, year = {1992}, author = {Hirano, A}, title = {Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam: immunohistochemical studies.}, journal = {The Keio journal of medicine}, volume = {41}, number = {1}, pages = {6-9}, doi = {10.2302/kjm.41.6}, pmid = {1583817}, issn = {0022-9717}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Biomarkers ; Dementia/*metabolism ; Guam ; Humans ; Immunohistochemistry ; Parkinson Disease/*metabolism ; }, abstract = {The incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) among the Chamorros in Guam is remarkably high. The patients with ALS have clinical and pathological characteristics similar to those in other parts of the world. The PDC patients display parkinsonism and progressive dementia and show a characteristic neuronal loss in certain parts of the central nervous system such as the hippocampus and substantia nigra. The Guamanian patients with ALS and PDC commonly have widespread Alzheimer's neurofibrillary changes, but without the associated senile plaques. We have applied immunohistochemical procedures to examine the expression of marker substances in Guamanian ALS and PDC. The markers studied include tau protein, ubiquitin, beta proteins, synaptophysin, calcineurin, Met-enkephalin, substance P and tyrosine hydroxylase. The results were compared with the findings in patients with Alzheimer's disease, Parkinson's disease, sporadic ALS and familial ALS.}, }
@article {pmid1373920, year = {1992}, author = {Lowrie, MB and Vrbová, G}, title = {Dependence of postnatal motoneurones on their targets: review and hypothesis.}, journal = {Trends in neurosciences}, volume = {15}, number = {3}, pages = {80-84}, doi = {10.1016/0166-2236(92)90014-y}, pmid = {1373920}, issn = {0166-2236}, mesh = {Animals ; Humans ; Motor Neurons/*physiology ; Nervous System/*growth &amp; development ; }, abstract = {Motoneurones are known to die (1) during embryonic development (naturally occurring cell death), (2) early in postnatal development after axonal injury, and (3) as a consequence of disease, such as spinal muscular atrophy or (in later life) amyotrophic lateral sclerosis. Naturally occurring motoneurone death has been extensively investigated, and interaction with the target muscle has emerged as an important factor for survival of embryonic motoneurones. Evidence that this target dependence of motoneurones continues postnatally is discussed in this review, as is the possible nature of the retrograde signal from the muscle. An explanation for the role of the muscle in motoneurone survival is also proposed, which may be applicable in situations where motoneurone death occurs postnatally. This proposal takes into account the changing functional demands imposed on motoneurones as a result of the gradual maturation of the CNS, and suggests that during development the muscle induces the motoneurones to become competent to carry out these requirements.}, }
@article {pmid1571856, year = {1992}, author = {Eisen, A and Calne, D}, title = {Amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease: phylogenetic disorders of the human neocortex sharing many characteristics.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {19}, number = {1 Suppl}, pages = {117-123}, pmid = {1571856}, issn = {0317-1671}, mesh = {Alzheimer Disease/genetics/*physiopathology ; Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Cerebral Cortex/*physiopathology ; Humans ; Parkinson Disease/genetics/*physiopathology ; Phylogeny ; }, abstract = {Features common to amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are reviewed. Shared epidemiological aspects include an increasing frequency which is proportional for each disease. We draw attention to geographic non-uniform distribution which, for ALS and PD, correlates positively with latitude. Clinical and pathological overlap occurs in the same patients, and in members of the same family. A high early morning plasma cysteine/sulphate ratio possibly related to the development of proteinacious inclusions, as well as ubiquinated neuronal inclusions, characterize ALS, PD and AD. HLA-DR (the human group II major histocompatibility class) staining is marked in ALS, PD and AD and may represent autoimmunity-incited by-products of neuronal degeneration. Based upon demonstrated glutaminergic connections between the neocortex and anterior horn cells, the entorhinal cortex and the basal ganglia we hypothesize that ALS, AD and PD are phylogenetic disturbances of the neocortical cell. The postsynaptic neuron may degenerate secondarily to anterograde effects of deranged glutamate metabolism. Future therapeutic strategies should be directed to agents that decrease transmission induced by excitatory amino-acids.}, }
@article {pmid1549143, year = {1992}, author = {Eisen, A and Kim, S and Pant, B}, title = {Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron?.}, journal = {Muscle &amp; nerve}, volume = {15}, number = {2}, pages = {219-224}, doi = {10.1002/mus.880150215}, pmid = {1549143}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/pathology ; Animals ; Anterior Horn Cells/physiology ; Disease Models, Animal ; Electromyography ; Haplorhini ; Humans ; Motor Neurons/*pathology/physiology ; Phylogeny ; }, abstract = {It is proposed that the primary cell involved in amyotrophic lateral sclerosis (ALS) is the corticomotoneuron. The spinal motoneuron becomes affected as a result of antegrade effects. This hypothesis does not negate most of the presently popular theories regarding the pathogenesis of ALS, but directs focus to one cell type--the corticomotoneuron. It takes cognizance of the complex, monosynaptic, corticomotoneuronal-spinomotoneuronal connections that have evolved in primates, and especially in man. It might explain the lack of any natural or thus far induced animal model which closely mimics the human disease. Threshold measurements to transcotical magnetic stimulation might be used to test the hypothesis. Replication of ALS in an animal is only likely to succeed in a nonhuman primate.}, }
@article {pmid1554521, year = {1992}, author = {Majkowski, J}, title = {Long-term treatment of amyotrophic lateral sclerosis with phthalazinol.}, journal = {Advances in second messenger and phosphoprotein research}, volume = {25}, number = {}, pages = {409-416}, pmid = {1554521}, issn = {1040-7952}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Male ; Phosphodiesterase Inhibitors/administration &amp; dosage/*therapeutic use ; Phthalazines/administration &amp; dosage/*therapeutic use ; }, }
@article {pmid1490424, year = {1992}, author = {Perl, DP and Good, PF}, title = {Aluminium and the neurofibrillary tangle: results of tissue microprobe studies.}, journal = {Ciba Foundation symposium}, volume = {169}, number = {}, pages = {217-27; discussion 227-36}, doi = {10.1002/9780470514306.ch13}, pmid = {1490424}, issn = {0300-5208}, support = {AG-05138/AG/NIA NIH HHS/United States ; AG-08802/AG/NIA NIH HHS/United States ; ES-00928/ES/NIEHS NIH HHS/United States ; }, mesh = {Aluminum/*metabolism ; Alzheimer Disease/metabolism ; Hippocampus/metabolism ; Humans ; Lasers ; Neurofibrillary Tangles/*metabolism ; Neurons/metabolism ; }, abstract = {Despite the contradictory results of studies attempting to compare the bulk brain tissue aluminium content of specimens from Alzheimer's disease patients and controls, microprobe studies from our laboratory have consistently documented evidence of selective accumulation of the element within the neurofibrillary tangle-bearing cells associated with this condition. Laser microprobe mass analysis (a highly sensitive and precise technique for trace elemental microprobe analysis) has now demonstrated that the most prominent aluminium accumulations occur within the neurofibrillary tangle itself. Similar findings have been obtained from microprobe studies of the neurofibrillary tangles which are a characteristic feature of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. Although the intraneuronal localization of aluminium in the Guam-derived specimens is similar to that of Alzheimer's disease, the concentration of aluminium is considerably higher than is encountered in Alzheimer's disease specimens. We conclude that aluminium is an integral component of the neurofibrillary tangle and raise the possibility that the cross-linking properties of this highly reactive metal may stabilize the constituent cytoskeletal proteins which make up this pathological structure.}, }
@article {pmid1490420, year = {1992}, author = {Wisniewski, HM and Wen, GY}, title = {Aluminium and Alzheimer's disease.}, journal = {Ciba Foundation symposium}, volume = {169}, number = {}, pages = {142-54; discussion 154-64}, doi = {10.1002/9780470514306.ch9}, pmid = {1490420}, issn = {0300-5208}, mesh = {Aluminum/*adverse effects ; Alzheimer Disease/*chemically induced/pathology ; Animals ; Brain Diseases/chemically induced/pathology ; Humans ; Risk Factors ; }, abstract = {The hypothesis that aluminium (Al) is a cause of (or a risk factor in) the development of beta-amyloid plaques and neurofibrillary tangles (NFT) and dementia in Alzheimer's disease (AD) is based on studies by Wisniewski et al, Klatzo et al and Terry &amp; Peña in 1965 that showed that injection of experimental animals with Al compounds induces the formation of NFT. Other publications revealed that Al affects cognitive functions in experimental animals and humans undergoing dialysis for renal failure. Electron probe and laser microprobe mass analysis (LAMMA) studies have demonstrated the presence of Al in NFT and cores of amyloid stars and nuclei of neurons in AD patients. Other studies have indicated the association between amyotrophic lateral sclerosis/Guam parkinsonism-dementia complex and Al in the environment. A recent report suggests that the chelating agent desferrioxamine slows the rate of cognitive decline in AD patients. Extensive studies of the pathology of AD and Al-induced encephalopathy by our group and others indicate that Al does not cause Alzheimer's disease neuropathology. However, under certain conditions, cognition can be affected when Al enters the brain. Therefore, for individuals with renal failure or undergoing dialysis or individuals with a damaged blood-brain barrier, the intake of Al should be controlled.}, }
@article {pmid1356048, year = {1992}, author = {Swash, M and Leigh, N}, title = {Criteria for diagnosis of familial amyotrophic lateral sclerosis. European FALS Collaborative Group.}, journal = {Neuromuscular disorders : NMD}, volume = {2}, number = {1}, pages = {7-9}, doi = {10.1016/0960-8966(92)90020-7}, pmid = {1356048}, issn = {0960-8966}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/genetics ; Humans ; }, abstract = {Clinical criteria for the diagnosis of motor neuron disease, agreed at the inaugural meeting of the European Familial Amyotrophic Lateral Sclerosis Collaborative Group, are described. The criteria are derived from those developed for the study of sporadic amyotrophic lateral sclerosis, and allow the inclusion of certain recognized clinical sub-types of familial amyotrophic lateral sclerosis. They will require testing for consistency and sensitivity.}, }
@article {pmid1340912, year = {1992}, author = {Hausmanowa-Petrusewicz, I}, title = {Role of electromyography in the diagnosis of motor neuron disorders.}, journal = {Neuropatologia polska}, volume = {30}, number = {3-4}, pages = {187-197}, pmid = {1340912}, issn = {0028-3894}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Branchial Region/physiopathology ; Electromyography/*methods ; Female ; Humans ; Male ; Motor Neuron Disease/*diagnosis/physiopathology ; Muscles/physiopathology ; Muscular Atrophy, Spinal/*diagnosis/physiopathology ; }, abstract = {Programming of electromyographic examination in motor neuron diseases is discussed taking into account application of appropriate techniques. The difficulties of correct interpretation of results are stressed. The stages of disintegration and reintegration of affected motor units are described as well as compensatory changes of surviving motor units. A detailed description of EMG dynamics of amyotrophic lateral sclerosis, late post-polio syndrome and of childhood spinal muscular atrophy is given.}, }
@article {pmid1281433, year = {1992}, author = {Jusić, A and Ries, M and Sostarko, M}, title = {Amyotrophic lateral sclerosis.}, journal = {Neurologia croatica : glasilo Udruzenja neurologa Jugoslavije = official journal of Yugoslav Neurological Association}, volume = {41}, number = {4}, pages = {213-226}, pmid = {1281433}, issn = {0353-8842}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Diagnosis, Differential ; Humans ; Palliative Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinical entity differentiated during the last few years into definite, probable, possible and suspected ALS. There are many hypotheses trying to explain its genesis: slow virus hypothesis, trace elements, immunologic and trophic factors, excitotoxins, metabolic influences, DNA anomalies, and so on. It is necessary to differentiate ALS like syndromes and ALS variants. Some of the ALS like syndromes can be treated. Only the disease elaborated like that may be submitted to clinical therapeutical trials or molecular-genetic research. Palliative therapy is still necessary. It does not prolong life, it makes its quality better.}, }
@article {pmid1817796, year = {1991}, author = {Yoshida, S}, title = {[Environmental factors in western Pacific foci of ALS and a possible pathogenetic role of aluminum (Al) in motor neuron degeneration].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {31}, number = {12}, pages = {1310-1312}, pmid = {1817796}, issn = {0009-918X}, mesh = {Aluminum/*adverse effects ; Amyotrophic Lateral Sclerosis/epidemiology/*etiology ; *Environment ; Guam/epidemiology ; Humans ; Japan/epidemiology ; Motor Neurons/*drug effects/physiology ; Nerve Degeneration/*drug effects ; Pacific Ocean ; Risk Factors ; }, abstract = {Recent decline in incidence rates of ALS in Guam and the Kii Peninsula of Japan strongly implicates environmental factors rather than inheritance in its causation. Environmental studies in Western Pacific foci showed identical mineral compositions in the soils and drinking water, i.e., extremely low calcium (Ca) and magnesium (Mg) and high aluminum (Al) and manganese (Mn). Series of trace-elemental analyses of the CNS tissue of ALS patients have revealed a high contents of Al and Ca with significant positive correlations between Al and Ca and/or between Ca and Mn, suggesting the prolonged exposure to these trace environment to cause abnormal mineral metabolism detrimental to neurons. Using electron energy loss spectrometry (EELS), Al was found to accumulate within DNA-containing chromatins and rRNA-containing cellular components, i.e., nucleolus, heterochromatin, rough endoplasmic reticulum, in lumbar motor neurons of ALS. Thus, Al may preferentially bind to nucleic acids and cause a progressive inhibition of the protein synthesis of rRNA and the transcription or gene modulation of DNA, leading to neuronal degeneration.}, }
@article {pmid1817791, year = {1991}, author = {Mannen, T}, title = {[Neuropathology of Onuf's nucleus].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {31}, number = {12}, pages = {1281-1285}, pmid = {1817791}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Anterior Horn Cells/*pathology ; Humans ; Poliomyelitis/pathology ; Sacrococcygeal Region ; Shy-Drager Syndrome/pathology ; Spinal Cord/*pathology ; }, abstract = {Onuf's nucleus is a small motoneuron group in S2 anterior horn, which was described by Onufrowicz in 1900. He suggested that the motoneurons in the nucleus innervated striated muscles involved in election and ejaculation. The nucleus is readily shown by the K-B stain on account of its pale staining background which is sharply demarcated from the surrounding network of fine myelinated fibers. However, neuropathological descriptions of the nucleus are very rare. Pons-Tortella et al reported the sparing of this nucleus in acute anterior poliomyelitis. In 1977. We reported that Onuf's nucleus were well preserved in cases with ALS, in which the function of bladder and rectal sphincters is often intact until the latest stage of the illness. On the control , Shy-Drager syndrome showed severe degeneration of Onuf's nucleus. The patients with Shy-Drager syndrome showed clinically evident urinary and/or fecal incontinence. Combination of these clinical and pathological findings led to conclusion that Onuf's nucleus innervates the striated muscles of the sphincters. In 1990, Iwatsubo et al studied corticofugal projections to the motoneurons with Nauta-Gygax's technique in a patient with cerebral infarction. They verified that the oculomotor and abducens nuclei and Onuf's nucleus do not receive direct cortical projections. These motoneurons are characteristically spared in ALS. For the studies on ALS, it is important to know what differences between Onuf's nucleus and other motoneuron groups in anterior horn are biochemically and physiologically.}, }
@article {pmid1764852, year = {1991}, author = {Wolf, HK and Crain, BJ and Siddique, T}, title = {Degeneration of the substantia nigra in familial amyotrophic lateral sclerosis.}, journal = {Clinical neuropathology}, volume = {10}, number = {6}, pages = {291-296}, pmid = {1764852}, issn = {0722-5091}, support = {5K07S00960//PHS HHS/United States ; AG-05128/AG/NIA NIH HHS/United States ; NS21442/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*pathology ; Family Health ; Gliosis/etiology/*pathology ; Humans ; Macrophages ; Male ; Pigmentation ; *Substantia Nigra ; }, abstract = {We have studied a large family with familial amyotrophic lateral sclerosis (FALS) and examined the brain and spinal cord of a 40-year-old male family member at autopsy three years after clinical onset of the disease. The most unusual finding was a severe degree of neuronal loss of the substantia nigra accompanied by gliosis and numerous pigment-laden macrophages. There was marked degeneration of the upper and lower motor neurons and the corticospinal tracts. In addition, there was an unusually severe degree of diffuse degeneration throughout the anterolateral columns of the spinal cord. The posterior columns and Clarke's nucleus were not involved. Nigral degeneration has rarely been reported in FALS. The findings in this case emphasize the great variability of morphologic changes encountered in FALS and raise the question of a relationship between FALS and extrapyramidal disorders such as Parkinson's disease. We conclude that careful postmortem examinations of further cases of FALS are needed to fully define the extent of degenerative changes in this disease.}, }
@article {pmid1842454, year = {1991}, author = {Meiri, H and Banin, E and Roll, M}, title = {Aluminum ingestion--is it related to dementia?.}, journal = {Reviews on environmental health}, volume = {9}, number = {4}, pages = {191-205}, doi = {10.1515/reveh.1991.9.4.191}, pmid = {1842454}, issn = {0048-7554}, mesh = {Aluminum/*adverse effects/analysis/chemistry/*pharmacokinetics ; Alzheimer Disease/*chemically induced ; Animals ; Brain/drug effects/metabolism ; Cats ; Cooking and Eating Utensils ; Diet/adverse effects ; Humans ; Infant ; Infant Food/analysis ; *Intestinal Absorption ; Mice ; Pharmaceutical Preparations/chemistry ; Rats ; Tea/chemistry ; }, abstract = {Elevated levels of aluminum in brain tissue have been found in demented patients with Alzheimer's disease, with ALS-PD complex of Guam and with dialysis encephalopathy. A possible etiological relationship between enhanced aluminum exposure and impaired mental function was suggested both for ALS-PD of Guam (a region where high contents of aluminum in water are found) and for dialysis encephalopathy which appears in dialyzed patients exposed to high doses of aluminum in medications and in dialysate fluid. The role of aluminum in Alzheimer's disease is not known as is the question of life-long aluminum accumulation in healthy human beings. In this review we have limited ourselves to the issue of oral aluminum ingestion and the possible neurotoxic consequences of such exposure. The following topics are summarized: 1. Physiological mechanisms involved in ingestion and intestinal absorption of aluminum and the influences of pH and available organic complexing agents on these processes. 2. Effects of an aluminum-enriched diet on behavior and on brain metabolism. 3. Dietary sources of aluminum and elevated loads of this substance due to prolonged intake of aluminum-containing medications. The main conclusion of this summary is that aluminum is absorbed and may accumulate in different organs in both adults and infants. Two groups seem to be at particular risk for aluminum related toxicity: people with chronic renal failure treated with aluminum-containing medications and pre-term infants fed on aluminum containing formulate. It seems probable that at least upon short term exposure the healthy human body can defend itself adequately from aluminum's toxic effects. However, not enough information is available on possible effects of life-long exposure to aluminum in the environment, diet and medications, which over decades may lead to accumulation of this substance with expressions of toxicity. Therefore, the question of aluminum's relevance to dementive diseases cannot yet be adequately answered.}, }
@article {pmid1724684, year = {1991}, author = {Barker, R}, title = {Substance P and neurodegenerative disorders. A speculative review.}, journal = {Neuropeptides}, volume = {20}, number = {2}, pages = {73-78}, doi = {10.1016/0143-4179(91)90054-m}, pmid = {1724684}, issn = {0143-4179}, mesh = {Alzheimer Disease/etiology ; Amyotrophic Lateral Sclerosis/etiology ; Autoimmunity ; Central Nervous System Diseases/*etiology ; Humans ; Parkinson Disease/etiology ; Substance P/deficiency/immunology/*physiology ; }, abstract = {The causes of the neurodegenerative disorders of Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are unknown. It is proposed that all these disorders result primarily from a loss of trophic peptidergic neurotransmitter, possibly Substance P (SP). This loss in turn produces the classical neuronal degeneration seen in each of these diseases and occurs due to a combination of natural aging and chronic autoimmune destruction following a viral infection of the CNS, early in life. The loss is therefore slow and by the time of clinical presentation the inflammatory process is disappearing as the antigenic stimulus lessens with its removal. The implications of the theory in terms of future research and therapy are briefly discussed.}, }
@article {pmid1939490, year = {1991}, author = {Wiederkehr, F}, title = {Analysis of cerebrospinal fluid proteins by electrophoresis.}, journal = {Journal of chromatography}, volume = {569}, number = {1-2}, pages = {281-296}, doi = {10.1016/0378-4347(91)80234-4}, pmid = {1939490}, mesh = {Antibodies/cerebrospinal fluid ; Cerebrospinal Fluid Proteins/*analysis/isolation &amp; purification ; Electrophoresis/*methods ; Electrophoresis, Gel, Two-Dimensional ; Humans ; Isoelectric Focusing ; }, abstract = {The cerebrospinal fluid (CSF) is a specific ultrafiltrate of plasma, which surrounds the brain and spinal cord. The study of its proteins and their alteration may yield useful information on several neurological diseases. By using various electrophoretic separation techniques, several CSF proteins have been identified derived from plasma or from brain. Different one-dimensional methods, such as agarose gel electrophoresis and isoelectric focusing, are of similar value in identifying the non-specific oligoclonal bands, which are mainly helpful in the diagnosis of multiple sclerosis and other inflammatory diseases. Isoelectric focusing has a greater resolution than other one-dimensional methods, and it yields additional data about disease-associated proteins occurring in Alzheimer's disease, Huntington's chorea and amyotrophic lateral sclerosis. Silver-stained two-dimensional gels provide more information about the complex protein composition of CSF, particularly about proteins produced in the brain, such as apolipoprotein E and neuron-specific enolase. For the detection of oligoclonal antibodies, the investigation of protein changes revealed by Parkinson's disease, schizophrenia and Creutzfeldt-Jakob disease, and the analysis of CSF immune complexes, two-dimensional electrophoresis has a greater sensitivity.}, }
@article {pmid1769159, year = {1991}, author = {Terao, S and Sobue, G and Mukai, E and Murakami, N and Hashizume, Y}, title = {[A clinicopathological study of familial amyotrophic lateral sclerosis with special reference to the mode of motoneuron loss in the spinal ventral horn].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {31}, number = {9}, pages = {960-969}, pmid = {1769159}, issn = {0009-918X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Anterior Horn Cells/pathology ; Family Health ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*pathology ; Spinal Cord/*pathology ; }, abstract = {The authors analyzed clinicopathologically eight patients with familial amyotrophic lateral sclerosis (F-ALS). We performed the morphometric analysis on size and topographical distribution of the fourth lumbar spinal ventral horn cells, and correlated thus obtained results with the clinical, genetic and neuropathological features of these cases. The patients were consisted of six men and two women with age ranged between 40 and 58 years old. Six cases among them were involved predominantly in the lower-legs with generalized hyporeflexia and no Babinski's sign, which were compatible with the "pseudopolyneuritic" as a clinical form. Two other cases were involved in the upper limbs as the initial symptom and were considered to be "common form". Pathologically, five cases showed multiple system degenerations including the middle root zone of the posterior columns, Clarke's nuclei and posterior spinocerebellar tracts as well as the ventral horns and pyramidal tracts, which were designated as the form of "multiple system degeneration". In addition, three in these five cases were also associated with an extensive neuron loss and marked gliosis in the Onuf's nuclei, subthalamic, red and cerebellar dentate nuclei, suggesting that the involvement in certain F-ALS cases with a form of multiple system degeneration is more extensive in topography than ever believed. In other three cases, the neuronal degenerations were considerably restricted in the somatic motor efferent system, which were consistent with the classical pathology of the sporadic ALS, and were designated as "classical form". Five of seven cases showed a severe motoneuron loss in both the large and small neurons in the ventral horn. These five cases were heterogeneous in the pathological forms "multiple system degeneration" or "classical", but all were "pseudopolyneuritic" in clinical form. Moreover, these extensive motor neuron loss including small ones in the spinal ventral horn was similarly observed in the sporadic pseudopolyneuritic form of ALS cases. In two cases of F-ALS with "common" in clinical form, large motoneurons were fairly well preserved as are in the common form of sporadic ALS cases. Our tentative conclusion is that mode of motoneuron loss in the spinal ventral horn of F-ALS is more correlated to the clinical manifestations rather than the pathological or genetic background.}, }
@article {pmid1933684, year = {1991}, author = {McGeer, PL and McGeer, EG and Kawamata, T and Yamada, T and Akiyama, H}, title = {Reactions of the immune system in chronic degenerative neurological diseases.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {18}, number = {3 Suppl}, pages = {376-379}, doi = {10.1017/s0317167100032479}, pmid = {1933684}, issn = {0317-1671}, mesh = {Alzheimer Disease/*immunology ; Amyotrophic Lateral Sclerosis/*immunology ; Chronic Disease ; Humans ; Immune System/*metabolism ; Immunity, Cellular ; Immunohistochemistry ; Proteins/immunology/metabolism ; }, abstract = {Elements consistent with a cell mediated immune response were identified immunohistochemically in amyotrophic lateral sclerosis (ALS) spinal cord and Alzheimer disease (AD) hippocampus. T helper/inducer and cytotoxic/suppressor lymphocytes were detected in affected tissues in both diseases. In addition, abundant reactive microglia were found expressing the major histocompatibility glycoproteins HLA-A,B,C and HLA-DR, as well as receptors for the Fc chain (Fc gamma R1), for complement 3 and 4, and for vitronectin. In AD, the complement proteins C1q, C4d, C3d and C5b-9 were found on dystrophic neurites, neuropile threads and some neurofibrillary tangles. In ALS, the only complement proteins identified were C4d and C3d. The integrin ligands vitronectin and ICAM-1 were also identified in affected tissues in both diseases.}, }
@article {pmid1921949, year = {1991}, author = {Adams, RD and Salam-Adams, M}, title = {Chronic nontraumatic diseases of the spinal cord.}, journal = {Neurologic clinics}, volume = {9}, number = {3}, pages = {605-623}, pmid = {1921949}, issn = {0733-8619}, mesh = {Chronic Disease ; Humans ; Spinal Cord Diseases/*diagnosis/etiology/therapy ; }, abstract = {This article reviews common chronic diseases of the spinal cord such as spinal multiple sclerosis, cervical spondylosis, and motor system diseases, including amyotrophic lateral sclerosis. Secondary epidural and meningeal tumors and syringomyelia are also discussed.}, }
@article {pmid1894143, year = {1991}, author = {Spencer, PS and Kisby, GE and Ludolph, AC}, title = {Long-latency neurodegenerative disease in the western Pacific.}, journal = {Geriatrics}, volume = {46 Suppl 1}, number = {}, pages = {37-42}, pmid = {1894143}, issn = {0016-867X}, support = {NS 19611/NS/NINDS NIH HHS/United States ; }, mesh = {Biomarkers ; Cycasin ; Guam ; Humans ; Indonesia ; Japan ; *Nerve Degeneration ; Nervous System Diseases/*chemically induced/metabolism ; Neuromuscular Diseases/chemically induced ; *Neurotoxins ; *Plant Extracts ; Reaction Time ; }, abstract = {The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototypical neurodegenerative disorder found among inhabitants of Guam, New Guinea (Irian Jaya, Indonesia) and Japan (Kii Peninsula, Honshu). Nonviral environmental factors peculiar to the affected populations seem to play a prominent etiologic role. Although cause-effect relationships cannot be established by epidemiologic studies alone, we have shown in all three affected population groups that individuals develop the amyotrophic lateral sclerosis variant of this disorder after heavy exposure to the raw or incompletely detoxified seed of neurotoxic cycad plants. Since long periods may elapse between cycad exposure and the appearance of neurological disease in humans, cycads may harbor a "slow toxin" that causes the postmitotic neuron to undergo slow irreversible degeneration. Two cycad neurotoxins are recognized, one of which (cycasin) is known to have long-latency effects (tumorigenesis) on mitotic neurons and replicating cells in other tissues. This paper explores the possible relationship between tumorigenesis and long-latency neurotoxicity, and discusses possible biologic markers of cycad exposure and subclinical neurodegenerative disease.}, }
@article {pmid1866020, year = {1991}, author = {Leone, M}, title = {Parental sex effect in familial amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {41}, number = {8}, pages = {1292-1294}, doi = {10.1212/wnl.41.8.1292}, pmid = {1866020}, issn = {0028-3878}, mesh = {Adult ; Aged ; Aging/physiology ; Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; *Fathers ; Female ; Humans ; Male ; Middle Aged ; *Mothers ; }, abstract = {Since a parental sex effect has been reported in Huntington's disease, we looked to see whether a similar effect is apparent in adult (autosomal dominant) familial ALS. We analyzed the data for 145 patients, with an onset age range of 20 to 68 years and a known affected parent (AP), from 52 families described in the literature. There was a significant increase in the percentage of patients inheriting the gene from an affected mother as a function of the age at onset. There was also a significant correlation between AP and offspring age at onset only when the AP was the mother.}, }
@article {pmid1721746, year = {1991}, author = {Lindvall, O}, title = {Prospects of transplantation in human neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {14}, number = {8}, pages = {376-384}, doi = {10.1016/0166-2236(91)90167-s}, pmid = {1721746}, issn = {0166-2236}, mesh = {Animals ; Brain Tissue Transplantation/*physiology ; Humans ; Huntington Disease/therapy ; Nerve Degeneration/*physiology ; Nervous System Diseases/*therapy ; Parkinson Disease/therapy ; }, abstract = {Over the past decade experimental data obtained from animals have suggested that restoration or preservation of function through cell transplantation into the CNS might be developed into a useful therapeutic approach in human neurodegenerative disorders. Clinical trials in patients with Parkinson's disease have provided evidence that grafts of fetal dopaminergic neurons can survive and induce functional effects in the human brain, but no treatment based on transplantation is available yet. Initiation of studies of patients with striatal neural grafts in Huntington's disease is supported by findings in animal models, and is motivated by the lack of therapy and the severity of the symptoms in this disorder. Application of cell transplantation to other neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and hereditary ataxia is definitely premature. Further progress can be made only by systematic studies in animals of the scientific issues that can now be defined, but will also require clinical trials in a few well-monitored patients.}, }
@article {pmid1721741, year = {1991}, author = {Clowry, G and Sieradzan, K and Vrbová, G}, title = {Transplants of embryonic motoneurones to adult spinal cord: survival and innervation abilities.}, journal = {Trends in neurosciences}, volume = {14}, number = {8}, pages = {355-357}, doi = {10.1016/0166-2236(91)90162-n}, pmid = {1721741}, issn = {0166-2236}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Brain Tissue Transplantation/*physiology ; Fetal Tissue Transplantation/*physiology ; Graft Survival/physiology ; Humans ; Motor Neurons/*transplantation ; Muscles/innervation ; Spinal Cord/*physiology ; }, abstract = {One goal of transplantation experiments involving damaged spinal cords is to reconstruct a functional innervation to muscles in the periphery. Embryonic spinal cord grafts have been shown to survive transplantation into adult spinal cord lacking motoneurones. Motoneurones from the graft appear to be able to innervate muscle tissue by being encouraged to grow across a bridge of peripheral nerve. Integration of grafted motoneurones appears to involve their migration from the graft into the host ventral horn, thus replacing depleted host neurones. These results suggest possible strategies of research that might lead to treatments of spinal cord injuries and disorders in which motoneurone loss occurs, such as amyotrophic lateral sclerosis, spinal muscular atrophies and poliomyelitis.}, }
@article {pmid1658239, year = {1991}, author = {Kihira, T and Yoshida, S and Uebayashi, Y and Yase, Y and Yoshimasu, F}, title = {Involvement of Onuf's nucleus in ALS. Demonstration of intraneuronal conglomerate inclusions and Bunina bodies.}, journal = {Journal of the neurological sciences}, volume = {104}, number = {2}, pages = {119-128}, doi = {10.1016/0022-510x(91)90300-v}, pmid = {1658239}, issn = {0022-510X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*pathology ; Brain/*pathology/ultrastructure ; Female ; Humans ; Inclusion Bodies/*ultrastructure ; Male ; Middle Aged ; Neurons/pathology/ultrastructure ; Spinal Cord/*pathology/ultrastructure ; }, abstract = {Onuf's nucleus of 3 ALS cases was examined histologically, morphometrically and for metal content. Case 1 showed conglomerate inclusions (CIs), cases 2 and 3 showed Bunina bodies in Onuf's nucleus. Electron microscopy showed that CIs were intracytoplasmic accumulations of 10 nm neurofilaments with discrete borders. Onuf's neurons in ALS showed a significant decrease (P less than 0.001) in the cytoplasmic, nuclear and nucleolar areas in comparison with neurons of age-matched controls and elderly controls. Metal analysis of the sacral spinal cords by alpha particle-excited X-ray fluorescence analysis (PIXE) showed relatively high Al levels in the ALS cases compared with controls. Morin staining revealed intense green fluorescence (indicating Al) in the nucleoli and cytoplasm of the CI-containing neurons, but not in the CIs themselves. The appearance of CIs or Bunina bodies and neuronal atrophy in Onuf's nucleus seems to indicate that this structure is also involved in the disease process of ALS, although it is less vulnerable than most other motor ganglia.}, }
@article {pmid1922165, year = {1991}, author = {McComas, AJ}, title = {Invited review: motor unit estimation: methods, results, and present status.}, journal = {Muscle &amp; nerve}, volume = {14}, number = {7}, pages = {585-597}, doi = {10.1002/mus.880140702}, pmid = {1922165}, issn = {0148-639X}, mesh = {Computers ; Electric Stimulation ; Electronic Data Processing ; Electrophysiology ; Humans ; *Motor Neurons ; Muscles/*innervation ; Neuromuscular Diseases/*diagnosis ; }, abstract = {The renewed interest in motor unit estimation (counting) has coincided with the introduction of computer-based methodology and with the application of the technique to proximal as well as distal muscles. The advantages and disadvantages of the different methods are considered, together with the assumptions inherent in this type of examination. In normal subjects, the extensor digitorum brevis (EDB) muscle has approximately 200 motor units while each of the intrinsic muscles of the hand has about 100 units; larger muscles in the limbs contain greater numbers of units. Beyond the age of 60 years, there is a decline in the number of functioning motor units in both proximal and distal muscles. In denervating disorders, motor unit estimation is useful for diagnosis and assessment; abnormal values may often be observed in muscles judged clinically to be unaffected. Serial studies have enabled the rate of motor unit loss to be determined in ALS and in spinal muscular atrophy. Depletion of motor units has also been found following upper motoneuron lesions caused by injury to the spinal cord or by cerebral hemorrhage; trans-synaptic dysfunction has been presumed responsible. Rather surprisingly, reduced numbers of motor units have been observed in a variety of myopathic disorders; of these, the most consistent abnormalities have been reported in myotonic muscular dystrophy.}, }
@article {pmid2041595, year = {1991}, author = {Spencer, PS and Kisby, GE and Ludolph, AC}, title = {Slow toxins, biologic markers, and long-latency neurodegenerative disease in the western Pacific region.}, journal = {Neurology}, volume = {41}, number = {5 Suppl 2}, pages = {62-6; discussion 66-8}, doi = {10.1212/wnl.41.5_suppl_2.62}, pmid = {2041595}, issn = {0028-3878}, support = {NS 19611/NS/NINDS NIH HHS/United States ; }, mesh = {Biomarkers ; Cycasin ; Guam ; Humans ; Indonesia ; Japan ; *Nerve Degeneration ; Nervous System Diseases/*chemically induced/metabolism ; Neuromuscular Diseases/chemically induced ; *Neurotoxins ; *Plant Extracts ; Reaction Time ; }, abstract = {The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototypical neurodegenerative disorder found among inhabitants of Guam, New Guinea (Irian Jaya, Indonesia) and Japan (Kii Peninsula, Honshu). Nonviral environmental factors peculiar to the affected populations seem to play a prominent etiologic role. Although cause-effect relationships cannot be established by epidemiologic studies alone, we have shown in all three affected population groups that individuals develop the amyotrophic lateral sclerosis variant of this disorder after heavy exposure to the raw or incompletely detoxified seed of neurotoxic cycad plants. Since long periods may elapse between cycad exposure and the appearance of neurological disease in humans, cycads may harbor a "slow toxin" that causes the postmitotic neuron to undergo slow irreversible degeneration. Two cycad neurotoxins are recognized, one of which (cycasin) is known to have long-latency effects (tumorigenesis) on mitotic neurons and replicating cells in other tissues. This paper explores the possible relationship between tumorigenesis and long-latency neurotoxicity, and discusses possible biologic markers of cycad exposure and subclinical neurodegenerative disease.}, }
@article {pmid1867841, year = {1991}, author = {Heifer, U}, title = {[Blood alcohol concentration and effect, traffic medicine characteristics and legal traffic relevance of alcohol limit values in road traffic].}, journal = {Blutalkohol}, volume = {28}, number = {3}, pages = {121-145}, pmid = {1867841}, issn = {0006-5250}, mesh = {Accidents, Traffic/*legislation &amp; jurisprudence/prevention &amp; control ; Alcohol Drinking/blood/*legislation &amp; jurisprudence/prevention &amp; control ; Alcoholic Intoxication/*blood/prevention &amp; control ; Automobile Driving/*legislation &amp; jurisprudence ; Ethanol/*blood ; Humans ; Metabolic Clearance Rate ; Risk Factors ; }, abstract = {Since the expert report of the Federal Health Office (FHO) in 1966 (also compare FHO expert report 1977) numerous papers about the influence of small doses of alcohol on driving ability have been published (see Blood Alcohol, Alcohol, Drugs and Behavior). These papers emphasise the possibility to prove an acute influence on the central nervous system of man with characteristic consequences for his readiness to perform and his general effectiveness with regard to the safe conduct of a vehicle above a concentration of blood alcohol from 0.2 to 0.3% upwards. This experimentally observed increase in knowledge which conforms with jurisdiction i.e. assuming the possibility of alcohol-effected reduced driving ability above 0.3% in individual cases, -however, does not include a regular capability to detect a reduced driving ability for a range in blood alcohol concentration of 0.3% to 1.0% (see opinion of the directors and boards in the German Society for Legal Medicin, 1984). From All presentations the following conclusions may be drawn regarding the level and traffic medicals als well as psychophysical relevance and the forensic importance of alcohol threshold values in road traffic: 1. The 0.0% would be consistent. Each trace of blood alcohol can influence driving ability. Such a limit would, however, be linked to an intolerable cover-up-level. 2. The threshold level to prove the effect of alcohol lies at 0.3% to 0.4% as a basic value (jurisdiction = 0.3%). This level must definitely be regarded as preventing traffic accidents. FREUDENBERG, 1966: At 0.4% the relative probability to become involved a lethal traffic accident is 2.1 times higher than the sober value. BORKENSTEIN, 1964/74: At 0.4% the relative probability to cause an accident is not significantly higher than the sober value. A blood alcohol concentration of 0.4% may be proven by an analytical average value of 0.5% (safety margin: 0.1%). From legal and traffic medical viewpoint nothing contradicts the intention to establish an abstract danger ceiling at 0.4 + 0.1% = 0.5% linked to unlawful behaviour and the prohibition to drive. 3. The danger ceiling presently in operation contains a basic value of 0.6 to 0.7% and a safety margin of 0.15% = 0.8%. At 0.6 to 0.7% the majority of drivers are unable to participate in the traffic. FREUDENBERG, 1966: At 0.7% the relative possibility to become involved in an traffic accident is 3.7 times higher als compared to the sober value. BORKENSTEIN: At 0.7% the relative probability to cause an accident in increased 2.7 times.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid2012508, year = {1991}, author = {Calne, DB and Zigmond, MJ}, title = {Compensatory mechanisms in degenerative neurologic diseases. Insights from parkinsonism.}, journal = {Archives of neurology}, volume = {48}, number = {4}, pages = {361-363}, doi = {10.1001/archneur.1991.00530160025009}, pmid = {2012508}, issn = {0003-9942}, mesh = {Animals ; Dopamine/pharmacology/physiology ; Humans ; Parkinson Disease/drug therapy/*physiopathology ; Substantia Nigra/drug effects ; }, abstract = {In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projection increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa.}, }
@article {pmid1650241, year = {1991}, author = {Miller, BL}, title = {A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatine and choline.}, journal = {NMR in biomedicine}, volume = {4}, number = {2}, pages = {47-52}, doi = {10.1002/nbm.1940040203}, pmid = {1650241}, issn = {0952-3480}, mesh = {Aspartic Acid/*analogs &amp; derivatives/chemistry ; Brain Chemistry/*physiology ; Choline/*chemistry ; Creatine/*chemistry ; Humans ; Magnetic Resonance Spectroscopy/methods ; Phosphocreatine/chemistry ; Protons ; }, abstract = {The structure and function of the chemicals contributing to the three main peaks seen with 1H NMR spectroscopy, N-acetyl-L-aspartate (NAA), creatine/phosphocreatine (Cr), and choline-containing compounds (Cho) is reviewed and the changes seen with these compounds in various disease states are briefly outlined. NAA is present within neurons although its biological function is largely unknown. NAA is elevated in several degenerative neurological conditions including amyotrophic lateral sclerosis and canavan disease, and in high concentrations it may behave like a neurotoxin. The creatine peak seen with 1H NMR spectroscopy consists of creatine and phosphocreatine which serve as a reserve for high-energy phosphates in the cytosol of muscle and neurons. They also buffer cellular ATP/ADP. The Cho peak seen with 1H NMR consists of a complex mixture of Cho-containing compounds. Cho is a precursor for the neurotransmitter acetylcholine and for the membrane constituent phosphatidylcholine. Future studies of changes seen in the Cho peak with stroke, degenerative dementia, drug intake, and infectious and neoplastic brain masses will be of great interest.}, }
@article {pmid2008740, year = {1991}, author = {Hansen, PR and Werdelin, LM}, title = {[Amyotrophic lateral sclerosis: an autoimmune disease?].}, journal = {Ugeskrift for laeger}, volume = {153}, number = {8}, pages = {565-566}, pmid = {2008740}, issn = {0041-5782}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*immunology ; Antibodies, Monoclonal/analysis ; Autoimmune Diseases/*immunology ; Gangliosides/immunology ; Humans ; Immunoglobulin M/analysis ; Immunosuppressive Agents/administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis is characterized by degeneration of the motor neurones in the central nervous system and, as a rule, the condition results in rapid incapacity and death. The etiology is unknown but experimental results from recent years suggest that immunological mechanisms are of pathophysiological significance. Gangliosides constitute an important membrane component in nerve tissue and the majority of patients probably have high titres of circulation polyclonal IgM-antibodies to these compounds, particularly gangliosides GM1 and GD1a. The antibody titre appears to be correlated with the clinical condition and selective immune suppression (e.g. with cyclophosphamide) may possibly be of therapeutic value.}, }
@article {pmid1988760, year = {1991}, author = {Williams, DB and Windebank, AJ}, title = {Motor neuron disease (amyotrophic lateral sclerosis).}, journal = {Mayo Clinic proceedings}, volume = {66}, number = {1}, pages = {54-82}, doi = {10.1016/s0025-6196(12)61175-6}, pmid = {1988760}, issn = {0025-6196}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology/pathology/therapy ; Animals ; Female ; Global Health ; Humans ; Male ; Micronesia/epidemiology ; }, abstract = {Amyotrophic lateral sclerosis is an insidiously developing, adult-onset, progressive anterior horn cell degeneration with associated degeneration of descending motor pathways. It has been recognized as an important clinical syndrome since the middle of the 19th century. Despite increasing clinical and research interest in this condition, its cause remains obscure, even in the broadest terms. Epidemiologic characteristics of the disease have been interpreted as evidence of both genetic and environmental causes. A major change in the view of this disease is the widely developing perception that it is a disease of elderly persons more than of middle-aged adults as was previously taught. Etiologic hypotheses encompass a broad range of postulated pathophysiologic mechanisms, and we review these in detail. The clinical limits of the disease can now be better defined by using modern diagnostic techniques. Although interest in supportive symptomatic therapy is growing, no intervention has yet been shown to modify the biologically determined motor system degeneration.}, }
@article {pmid1956586, year = {1991}, author = {Yasui, M and Yase, Y and Ota, K and Mukoyama, M and Adachi, K}, title = {High aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula, Japan: two case reports.}, journal = {Neurotoxicology}, volume = {12}, number = {2}, pages = {277-283}, pmid = {1956586}, issn = {0161-813X}, mesh = {Aged ; Aged, 80 and over ; Aluminum/*metabolism ; Amyotrophic Lateral Sclerosis/epidemiology/*metabolism/pathology ; Calcium/metabolism ; Central Nervous System/*metabolism ; Female ; Humans ; Japan/epidemiology ; Magnesium/metabolism ; Middle Aged ; }, abstract = {We report two cases of amyotrophic lateral sclerosis (ALS), in which metal analysis revealed markedly higher aluminum concentration in the central nervous system (CNS) as well as higher calcium and lower magnesium concentration and higher Ca/Mg ratios compared with controls. Case 1 was a 55-year-old housewife and total duration of illness was 2 years and 2 mon from onset of clinical symptom. Case 2 was a 80-year-old woman and total duration of illness was 10 mon. Results showed that neither were exposed to toxic environments nor any neurologic disease in the past history. Postmortem examination disclosed motor neuron death and degeneration of pyramidal tracts. The significance of metal metabolism in pathogenesis of amyotrophic lateral sclerosis is discussed.}, }
@article {pmid1906674, year = {1991}, author = {Spencer, PS and Allen, CN and Kisby, GE and Ludolph, AC and Ross, SM and Roy, DN}, title = {Lathyrism and western Pacific amyotrophic lateral sclerosis: etiology of short and long latency motor system disorders.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {287-299}, pmid = {1906674}, issn = {0091-3952}, support = {NS 19611/NS/NINDS NIH HHS/United States ; }, mesh = {*Amino Acids, Diamino ; Amyotrophic Lateral Sclerosis/chemically induced/*etiology/physiopathology ; Humans ; Lathyrism/chemically induced/*etiology/physiopathology ; Nerve Degeneration ; Nervous System Diseases/chemically induced/physiopathology ; Neuromuscular Diseases/chemically induced/*etiology/physiopathology ; Neurons/drug effects ; Pacific Islands ; Plants, Toxic ; Reaction Time ; beta-Alanine/analogs &amp; derivatives ; }, }
@article {pmid1853781, year = {1991}, author = {Brooks, BR and Sufit, RL and DePaul, R and Tan, YD and Sanjak, M and Robbins, J}, title = {Design of clinical therapeutic trials in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {521-546}, pmid = {1853781}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/complications/pathology/*therapy ; Cell Survival ; *Clinical Trials as Topic ; Extremities/physiopathology ; Female ; Humans ; Isometric Contraction ; Male ; Motor Neurons/pathology ; Muscles/physiopathology ; Research Design ; Severity of Illness Index ; Sex Characteristics ; Statistics as Topic ; Terminology as Topic ; }, }
@article {pmid1853780, year = {1991}, author = {Munsat, TL and Hollander, D and Andres, P and Finison, L}, title = {Clinical trials in ALS: measurement and natural history.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {515-519}, pmid = {1853780}, issn = {0091-3952}, support = {NS24623/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; *Clinical Trials as Topic ; Humans ; Isometric Contraction ; Muscles/physiopathology ; Neurology/methods ; Severity of Illness Index ; }, }
@article {pmid1853774, year = {1991}, author = {Appel, SH and Engelhardt, JI and García, J and Stefani, E}, title = {Autoimmunity and ALS: a comparison of animal models of immune-mediated motor neuron destruction and human ALS.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {405-412}, pmid = {1853774}, issn = {0091-3952}, support = {R01-AR38970/AR/NIAMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Autoimmune Diseases/pathology/physiopathology ; Autoimmunity/*physiology ; Cell Survival ; Disease Models, Animal ; Humans ; Immunization, Passive ; Inflammation ; *Motor Neurons/pathology ; Neuromuscular Diseases/*immunology/pathology/physiopathology ; Neuromuscular Junction/physiopathology ; Tissue Distribution ; }, }
@article {pmid1853764, year = {1991}, author = {Rowland, LP}, title = {Ten central themes in a decade of ALS research.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {3-23}, pmid = {1853764}, issn = {0091-3952}, support = {NS11766/NS/NINDS NIH HHS/United States ; RR-000645/RR/NCRR NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Motor Neurons ; Neurology/*trends ; Neuromuscular Diseases/etiology/pathology/physiopathology ; Neurosciences ; *Research ; }, }
@article {pmid1853761, year = {1991}, author = {Kurtzke, JF}, title = {Risk factors in amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {245-270}, pmid = {1853761}, issn = {0091-3952}, mesh = {Adult ; Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/epidemiology/*etiology/mortality ; Demography ; Global Health ; Humans ; Incidence ; Middle Aged ; Motor Neurons ; Neuromuscular Diseases/mortality ; Prevalence ; Racial Groups ; Risk Factors ; Sex Factors ; Space-Time Clustering ; Wounds and Injuries/complications ; }, }
@article {pmid1822786, year = {1991}, author = {Clowry, G and Sieradzan, K and Vrbová, G}, title = {Grafts of embryonic tissue into spinal cord: a possible strategy for treating neuromuscular disorders.}, journal = {Neuromuscular disorders : NMD}, volume = {1}, number = {2}, pages = {87-92}, doi = {10.1016/0960-8966(91)90054-v}, pmid = {1822786}, issn = {0960-8966}, mesh = {*Fetal Tissue Transplantation ; Humans ; Neuromuscular Diseases/*therapy ; Spinal Cord/*physiology ; Spinal Cord Injuries/therapy ; }, abstract = {The article describes various approaches used to bring about repair of damaged spinal cord by using embryonic grafts of neuronal tissue. One approach is to stimulate the host's neuronal elements to grow and regenerate. Indeed embryonic grafts have been found to reduce the effects of spinal cord injury, and promote regrowth of axons across a lesion site at least to a limited extent. Attempts have also been made to restore the loss of supraspinal influences with grafts from embryonic brain, and transplants of aminergic neurones have been shown to compensate for the loss of aminergic supraspinal inputs. Finally, it is possible to replace loss of highly specialised cells such as motoneurones by grafts of embryonic spinal cord. Grafted embryonic motoneurones are able to survive within adult host cord although both their chances of survival and maturation seem improved by prior depletion of the host motoneurones. They are able to innervate a skeletal muscle via its peripheral nerve if this is co-implanted at the site of grafting but no axon growth has yet been detected into the host ventral root. However, grafted embryonic neurones are able to migrate away from the graft to sites once occupied by missing motoneurones in the host anterior horn. Within the context of the treatment of neuromuscular disease, the research described suggests possible stratagems for the treatment of disorders such as amyotrophic lateral sclerosis, spinal muscular atrophies or poliomyelitis either by employing grafts that could release neuroactive substances which might prevent existing cells from dying, or even by replacing missing motoneurones with transplanted embryonic motoneurones.}, }
@article {pmid1822341, year = {1991}, author = {Emery, AE}, title = {Population frequencies of neuromuscular diseases--II. Amyotrophic lateral sclerosis (motor neurone disease).}, journal = {Neuromuscular disorders : NMD}, volume = {1}, number = {5}, pages = {323-325}, doi = {10.1016/0960-8966(91)90117-b}, pmid = {1822341}, issn = {0960-8966}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Humans ; *Motor Neurons ; Neuromuscular Diseases/*epidemiology ; Prevalence ; }, abstract = {A summary of the world literature on the prevalence of amyotrophic lateral sclerosis (motor neurone disease) has been carried out. Excluding those particular isolates with especially high prevalences (e.g. Guam and the Kii Peninsula of Japan), the mean prevalence among both sexes in other populations is around 41.6 x 10(-6) or 1 in 24,000.}, }
@article {pmid1775824, year = {1991}, author = {Grégoire, N and Serratrice, G}, title = {[Risk factors in amyotrophic lateral sclerosis. Initial results apropos of 35 cases].}, journal = {Revue neurologique}, volume = {147}, number = {11}, pages = {706-713}, pmid = {1775824}, issn = {0035-3787}, mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/genetics ; Epidemiologic Methods ; Female ; France/epidemiology ; Humans ; Male ; Medical History Taking ; Middle Aged ; Retrospective Studies ; Risk Factors ; Sports ; Wounds and Injuries/epidemiology ; }, abstract = {A retrospective study of endogenous and exogenous risk factors in amyotrophic lateral sclerosis (ALS) was conducted in 35 ALS patients and 35 healthy controls, using guided questioning. No significant correlation was detected between the disease and most of the environmental factors explored. A significant difference (p less than 0.05) was found between patients and controls in only two parameters: 1) occurrence of injuries during the year that preceded the diagnosis of ALS (usually localized to the limbs), and 2) regular practice of sports in adulthood. It appeared that injuries often revealed but could not be considered as a possible cause of the disease. Analysis of the sport activities was not sufficient for a definite conclusion. On the other hand, 11 p. 100 of ALS patients had a family history of ALS, and 25 p. 100 (as against 8 p. 100 of controls) had a history of degenerative disease of the nervous system. These results should lead to a reconsideration of genetic factors or to a search for exposure of several members of the same family to toxic or infectious environmental factors.}, }
@article {pmid1754703, year = {1991}, author = {Zuber, M and Alperovitch, A}, title = {[Parkinson's disease and environmental factors].}, journal = {Revue d'epidemiologie et de sante publique}, volume = {39}, number = {4}, pages = {373-387}, pmid = {1754703}, issn = {0398-7620}, mesh = {Case-Control Studies ; Developing Countries ; Diet ; Environmental Pollutants/*toxicity ; *Epidemiologic Methods ; Humans ; Parkinson Disease/epidemiology/*etiology ; Rural Population ; Smoking/adverse effects ; Virus Diseases/complications ; Water Pollution, Chemical ; }, abstract = {The etiology of the nigrostriatal pathway degeneration in Parkinson's disease (PD) is unknown but there is a growing pool of evidence that environmental factors may be involved in the genesis of this disorder. The discovery of the N-Methyl 4-Phenyl 1,2,3,6-Tetrahydro-Pyridine (MPTP)-induced injury in late 1970s provided the first experimental model of PD and stimulated dramatically the epidemiological research. An excitotoxic amino acid contained in Cycadales, which is thought to be responsible for the amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam, provides another example of toxin-induced parkinsonism. This amino acid is present in most seeds common in the Western diet. In developed countries, prevalence of PD is 2 to 5 times as high than in developing countries. PD patients in developed countries are more likely than controls to have lived in rural environment. Case control studies have suggested that this positive association is possibly related to pesticides and herbicides exposures or well water drinking. Dietary surveys are now going on and several hypothesis are tested including high MPTP-structural analogs or seeds consumption in PD patients and low antioxidants consumption. The negative association between smoking habits and PD has been recognized for more than 20 years. There is evidence that this association is not an artefact due to the disease affecting smoking habits. Its origin is unknown but it could provide important aetiological clues for PD. The most recent hypothesis concerning the relationships between these environmental factors and PD are reviewed and pertinent suitable surveys for the future are discussed.}, }
@article {pmid1754009, year = {1991}, author = {Als, H}, title = {Neurobehavioral organization of the newborn: opportunity for assessment and intervention.}, journal = {NIDA research monograph}, volume = {114}, number = {}, pages = {106-116}, pmid = {1754009}, issn = {1046-9516}, support = {P30 HD-18655/HD/NICHD NIH HHS/United States ; R01 HD-18654/HD/NICHD NIH HHS/United States ; R01 HD-18761/HD/NICHD NIH HHS/United States ; }, mesh = {Behavior ; Brain/physiology ; Humans ; Infant ; Infant, Newborn/physiology/*psychology ; Infant, Premature ; }, abstract = {A functional model has been formulated that attempts to specify the behavioral subsystems of functioning that exemplify in their respective interplay an infant's individuality of behavioral functioning in the manner in which they move from stable to disorganized functioning and in the flexibility with which they maintain organized functioning in the face of varied exogenous and endogenous events. Based on this model, Als and colleagues have attempted to develop systematic assessments, the APIB and the K-Box Paradigm, to quantify the degree of differentiation and modulation of these behaviorally defined subsystems of functioning. It is hypothesized that the differences documented via these assessments are brain based (i.e., part of the child's biological makeup, which is influenced by the intrauterine and extrauterine environment, be it sensory and/or drug exposure, and which shows a recognizable pattern along a definable trajectory).}, }
@article {pmid1749211, year = {1991}, author = {Williams, AC and Steventon, GB and Sturman, S and Waring, RH}, title = {Hereditary variation of liver enzymes involved with detoxification and neurodegenerative disease.}, journal = {Journal of inherited metabolic disease}, volume = {14}, number = {4}, pages = {431-435}, pmid = {1749211}, issn = {0141-8955}, mesh = {Animals ; Humans ; Inactivation, Metabolic/*physiology ; Liver/*enzymology ; Nervous System Diseases/*enzymology/genetics ; }, abstract = {Enzymes involved with the metabolic transformation of xenobiotics have recently been studied in patients with the neurodegenerative diseases, Alzheimer's disease, Parkinson's disease and motor neurone disease. Defects were detected in sulphur pathways and also, in the case of Parkinson's disease, in monoamine oxidase B. The possibility exists that the ability to cope safely with endogenous and exogenous substances which have neurotoxic properties is important in the pathogenesis of these diseases. Potentially such individuals could be identified preclinically and these diseases postponed by reduction in the load of toxin or modification of the relevant enzymic activity.}, }
@article {pmid1745432, year = {1991}, author = {Anger, WK}, title = {Animal test systems to study behavioral dysfunctions of neurodegenerative disorders.}, journal = {Neurotoxicology}, volume = {12}, number = {3}, pages = {403-413}, pmid = {1745432}, issn = {0161-813X}, support = {NS-19611/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/psychology ; Animals ; Behavior, Animal/physiology ; Cognition Disorders/*physiopathology ; Disease Models, Animal ; *Nerve Degeneration ; Nervous System Diseases/chemically induced/*psychology ; }, abstract = {The Eighth International Neurotoxicology Conference, Role of Toxicants in Neurological Disorders (1990), evaluated the evidence that chemical exposures may play a role in the development of neurodegenerative disorders. This article describes the major neurodegenerative disorders (Amyotrophic Lateral Sclerosis, Huntington disease, Parkinson disease, and Alzheimer disease) addressed at the conference, followed by a description of test systems or models developed to study behavioral aspects of these disorders in animals. However, due to the complexity of the disorders and the species in which they are found, fully-developed models in animals of neurodegenerative disorders are lacking. This suggests the need for a clear strategy for selecting behavioral tests in animals to study aspects of any neurodegenerative disorders. Such a strategy is here exemplified for Alzheimer disease (AD) as a prototypical neurodegenerative disorder. Since an animal model cannot provide the full range of effects of human neurodegenerative diseases, particularly AD which produces incompletely characterized cognitive deficits, a rodent model must at this time be drawn from multiple sources, including: (1) Tests currently used to identify in rodents deficits associated with AD; (2) tests to identify Alzheimer-related signs in patients; and, (3) tests that relate to theoretical constructs of human and animal cognition. A battery that draws from those sources could include tests of: (a) Spatial learning and memory (Morris Water Maze and Radial Arm Maze), (b) delayed recall match-to-sample; (c) serial response learning; and, (d) visual discrimination (e.g., vertical vs. horizontal stimuli). This battery will identify behavioral changes characteristic of early-, middle- and late-stage AD, afford the potential to relate the findings to theoretical constructs of cognition, and evaluate learning capabilities not previously studied in rodent models of neurodegenerative disorders.}, }
@article {pmid1745428, year = {1991}, author = {Garruto, RM}, title = {Pacific paradigms of environmentally-induced neurological disorders: clinical, epidemiological and molecular perspectives.}, journal = {Neurotoxicology}, volume = {12}, number = {3}, pages = {347-377}, pmid = {1745428}, issn = {0161-813X}, mesh = {Aluminum/adverse effects/toxicity ; Alzheimer Disease/chemically induced ; Amyotrophic Lateral Sclerosis/chemically induced ; Animals ; *Environmental Exposure ; Humans ; Nervous System Diseases/*chemically induced/epidemiology/pathology ; Pacific Islands/epidemiology ; Parkinson Disease, Secondary/chemically induced ; }, abstract = {During the past quarter century biomedical scientists have begun to recognize the unique opportunities for studying disease etiology and mechanisms of pathogenesis in non-Western anthropological populations with focal, endemic diseases. Such natural experiments as they are called, are important paradigms for solving etiological and epidemiological problems of widespread medical significance, with an ultimate goal towards treatment and prevention. The systematic search for etiological factors and mechanisms of pathogenesis of neurodegenerative disorders is perhaps nowhere better exemplified than in the western Pacific. During the past three decades, the opportunistic and multidisciplinary study of hyperendemic foci of amyotrophic lateral sclerosis and parkinsonism-dementia which occur in different cultures, in different ecological zones and among genetically divergent populations have served as natural models that have had a major impact on our thinking and enhanced our understanding of these and other neurodegenerative disorders such as Alzheimer disease and the process of early neuronal aging. Our cross-disciplinary approach to these intriguing neurobiological problems and the accumulated epidemiological, genetic, cellular and molecular evidence strongly implicates environmental factors in their causation, specifically the role of aluminum and its interaction with calcium in neuronal degeneration. As a direct consequence of our studies in these Pacific populations, we have undertaken the long-term development of experimental models of neuronal degeneration, in an attempt to understand the cellular and molecular mechanisms by which these toxicants affect the central nervous system. Our experimental studies have resulted in the establishment of an aluminum-induced chronic myelopathy in rabbits and the development of neurofilamentous lesions after low-dose aluminum administration in cell culture. These studies clearly demonstrate the philosophy that chronic rather than acute experimental models of toxicity are necessary in order to enhance our understanding of human neurodegenerative disorders with long-latency and slow progression. Finally, the ultimate significance of these Pacific paradigms may well depend on our ability to comprehensively evaluate and synthesize the growing body of relevant scientific data from other human disorders and from widely divergent academic fields, as well as our ability to recognize emerging new models in nature.}, }
@article {pmid1745427, year = {1991}, author = {Reuhl, KR}, title = {Delayed expression of neurotoxicity: the problem of silent damage.}, journal = {Neurotoxicology}, volume = {12}, number = {3}, pages = {341-346}, pmid = {1745427}, issn = {0161-813X}, mesh = {Aging/drug effects ; Animals ; Humans ; Nervous System Diseases/*chemically induced ; Time Factors ; }, abstract = {A prolonged period of latency between toxic exposure and disease is a recognized phenomenon in oncology, but is a relatively new concept in neurotoxicology. Suggestions that exposure to neurotoxic compounds may be followed years or decades later by clinically evident neurological disease have received considerable anecdotal support but little empirical evidence. In recent years, evidence has emerged linking environmental factors to several neurodegenerative diseases, including amyotrophic lateral sclerosis and the Parkinsonism-dementia complex. While these diseases have not been definitively demonstrated to arise from exposure to toxins or toxicants, nevertheless the possibility exists that xenobiotic exposure could lead to neurological conditions possessing a period of clinical "silence" prior to expression. Detection of such damage using standard toxicology testing protocols poses a major challenge. Lessons learned from neurodegenerative diseases can be profitably applied to the study of the long-term effects of xenobiotics on the brain and elucidation of the role of aging on the expression of neurotoxicity.}, }
@article {pmid1745426, year = {1991}, author = {Calne, DB}, title = {Neurotoxins and degeneration in the central nervous system.}, journal = {Neurotoxicology}, volume = {12}, number = {3}, pages = {335-339}, pmid = {1745426}, issn = {0161-813X}, mesh = {Animals ; Central Nervous System Diseases/*chemically induced ; Humans ; Nerve Degeneration/*drug effects ; Neurotoxins/adverse effects ; }, abstract = {Numerous examples exist where neurotoxins have been shown to induce selective death of certain groups of nerve cells. While the peripheral nerves are particularly vulnerable, neurotoxins are also capable of generating models of the major degenerative disorders of the central nervous system: dementia of Alzheimer's type, Parkinsonism, and amyotrophic lateral sclerosis. Important organic toxins, in this context, include certain pyridines, amines, aminoacids, nitriles, hexacarbons, and sulphides. Inorganic toxins include free radicals and certain metals. Toxins may also be classified according to their origin--exogenous or endogenous. This review will not consider neurological damage that can result from exposure to alcohol, or neurological adverse reactions to medications.}, }
@article {pmid1713013, year = {1991}, author = {Engel, WK}, title = {RNA metabolism in relation to amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {125-153}, pmid = {1713013}, issn = {0091-3952}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/microbiology ; Female ; Humans ; Male ; Paraplegia/microbiology ; RNA/*metabolism ; RNA, Viral/physiology ; Retroviridae/genetics ; Uridine Monophosphate/metabolism ; }, }
@article {pmid1677233, year = {1991}, author = {Plaitakis, A}, title = {Altered glutamatergic mechanisms and selective motor neuron degeneration in amyotrophic lateral sclerosis: possible role of glycine.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {319-326}, pmid = {1677233}, issn = {0091-3952}, support = {NS-11631/NS/NINDS NIH HHS/United States ; NS-16871/NS/NINDS NIH HHS/United States ; RR-71/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Glutamates/metabolism ; Glutamic Acid ; Glutamine/*physiology ; Glycine/*physiology ; Humans ; Motor Neurons/metabolism/pathology/*physiology ; *Nerve Degeneration ; Synaptic Transmission/drug effects ; }, }
@article {pmid1672467, year = {1991}, author = {Henny, C and Regli, F}, title = {[Amyotrophic lateral sclerosis. Focal points].}, journal = {Revue medicale de la Suisse romande}, volume = {111}, number = {1}, pages = {9-16}, pmid = {1672467}, issn = {0035-3655}, mesh = {Amyotrophic Lateral Sclerosis/etiology/pathology/*physiopathology ; Anterior Horn Cells/pathology ; Central Nervous System/*pathology ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; Neuropeptides/physiology ; Neurotransmitter Agents/physiology ; Peripheral Nerves/*pathology ; }, }
@article {pmid1668896, year = {1991}, author = {Mayer, RJ and Lowe, J and Landon, M and McDermott, H and László, L}, title = {The role of protein ubiquitination in neurodegenerative disease.}, journal = {Acta biologica Hungarica}, volume = {42}, number = {1-3}, pages = {21-26}, pmid = {1668896}, issn = {0236-5383}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Brain Diseases/*metabolism ; Carrier Proteins/metabolism ; Humans ; Immunohistochemistry ; Inclusion Bodies/metabolism ; Ubiquitins/*metabolism ; }, abstract = {Ubiquitin immunocytochemistry with an antiserum which reacts with ubiquitin-protein conjugates demonstrates the presence of ubiquitinated proteins in filamentous inclusions found in neurones in the major human neurodegenerative diseases, i.e. Alzheimer's disease, diffuse Lewy body disease, motor neurone disease. Ubiquitin immunohistochemistry has revolutionized the neuropathological diagnosis of dementia showing that diffuse Lewy body disease is not, as previously supposed, a rare cause of dementia. The filamentous inclusions in neurones in the human neurodegenerative diseases can be divided into at least two types based on recent immunocytochemical studies. We have shown that a ubiquitin-carboxyl terminal hydrolase is present in Lewy bodies but not in neurofibrillary tangles in Alzheimer's disease. This observation is significant since it indicates that molecular pathological mechanisms in neurones in diffuse Lewy body disease are fundamentally different to Alzheimer's disease. Ubiquitin-protein conjugates are also found in vacuoles in areas of granulovacuolar degeneration in hippocampal neurones in Alzheimer's disease and in granulovacuoles in neurones of scrapie infected mouse brain. These locations suggest that ubiquitinated protein are present in the lysosome-related system of neurones. We have recently shown that ubiquitin-protein conjugates are indeed enriched some 12-fold in the lysosomes of normal fibroblasts and lymphocytes.}, }
@article {pmid1649547, year = {1991}, author = {Hirano, A}, title = {Cytopathology of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {91-101}, pmid = {1649547}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/metabolism/*pathology ; Cell Survival ; Cytoplasmic Granules/ultrastructure ; Dementia/complications ; Guam ; Humans ; Intermediate Filaments/ultrastructure ; Longitudinal Studies ; Motor Neurons ; Neuromuscular Diseases/complications ; Neurons/metabolism/pathology ; Survival Analysis ; Ubiquitins/metabolism ; }, }
@article {pmid2269964, year = {1990}, author = {Kennedy, PG}, title = {On the possible role of viruses in the aetiology of motor neurone disease: a review.}, journal = {Journal of the Royal Society of Medicine}, volume = {83}, number = {12}, pages = {784-787}, pmid = {2269964}, issn = {0141-0768}, mesh = {Adult ; Animals ; Disease Models, Animal ; Humans ; Incidence ; Mice ; *Motor Neurons ; Neuromuscular Diseases/epidemiology/*microbiology ; Poliomyelitis/complications ; Virus Diseases/*complications ; }, }
@article {pmid2276102, year = {1990}, author = {Hudson, AJ and Rice, GP}, title = {Similarities of guamanian ALS/PD to post-encephalitic parkinsonism/ALS: possible viral cause.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {17}, number = {4}, pages = {427-433}, doi = {10.1017/s0317167100031024}, pmid = {2276102}, issn = {0317-1671}, mesh = {Amyotrophic Lateral Sclerosis/*microbiology ; Dementia/complications ; Guam ; Humans ; Parkinson Disease, Postencephalitic/*microbiology ; }, abstract = {Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilN1 strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD.}, }
@article {pmid2075175, year = {1990}, author = {Martinius, J}, title = {[Changes in diagnostic and therapeutic viewpoints: biological psychiatry aspects].}, journal = {Praxis der Kinderpsychologie und Kinderpsychiatrie}, volume = {39}, number = {9-10}, pages = {353-357}, pmid = {2075175}, issn = {0032-7034}, mesh = {Adolescent ; Autistic Disorder/etiology/therapy ; Child ; Combined Modality Therapy ; Humans ; Neurocognitive Disorders/*etiology/therapy ; }, abstract = {The beginnings of child als adolescent psychiatry were dominated by biological thinking. Due to its unidirectionality it was bound to fail. Instead, psychological and social conditions for the development of psychic disturbances gained recognition and preference. Child and adolescent psychiatry presently favours a synthesis of all conditions, including the biological ones. Early infantile autism is taken as an example for a change of views towards a primary biological causation, with all consequences for diagnosis and treatment. Change in child and adolescent psychiatry means development and synthesis of all components.}, }
@article {pmid2233870, year = {1990}, author = {Bradley, WG}, title = {Critical review of gangliosides and thyrotropin-releasing hormone in peripheral neuromuscular diseases.}, journal = {Muscle &amp; nerve}, volume = {13}, number = {9}, pages = {833-842}, doi = {10.1002/mus.880130910}, pmid = {2233870}, issn = {0148-639X}, mesh = {Chronic Disease ; Dose-Response Relationship, Drug ; Gangliosides/*therapeutic use ; Humans ; Neuromuscular Diseases/*drug therapy ; Thyrotropin/*physiology ; }, abstract = {The lack of effective therapy for many of the chronic neuromuscular diseases such as amyotrophic lateral sclerosis, hereditary motor sensory neuropathy (Charcot-Marie-Tooth disease), spinocerebellar degenerations and idiopathic polyneuropathy has led to a search for substances that may stimulate peripheral nerve regeneration. Two such agents that have been proposed are gangliosides (mixed purified bovine brain gangliosides, Cronassial) and thyrotropin releasing factor (TRH). Studies on both of these agents were initially reported with enthusiasm to be successful, but later double-blind controlled studies have failed to confirm these findings. This review provides critical analysis of the designs of studies of potentially effective agents in chronic neuromuscular diseases, and emphasizes the power of the placebo response, and the importance of designing placebos which are indistinguishable from the trial medication other than in the active effect.}, }
@article {pmid2256793, year = {1990}, author = {Beauvais, P and Billette de Villemeur, T and Richardet, JM}, title = {[Probable amyotrophic lateral sclerosis. An unusual case. Review of the literature].}, journal = {Archives francaises de pediatrie}, volume = {47}, number = {7}, pages = {519-522}, pmid = {2256793}, issn = {0003-9764}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Child ; Humans ; Male ; }, abstract = {A case of neurological disease in a 11 year-old boy is described. The disease began early in life and had recently progressed to paraplegia with pyramidal tract dysfunction, generalized muscle atrophy and numerous fasciculations. The association of pyramidal tract and peripheral dysfunction led to the diagnosis of amyotrophic lateral sclerosis, despite some unusual features. A review of literature data concerning the juvenile and infantile types of the disease is presented, emphasizing the heterogeneity of the disease.}, }
@article {pmid2201483, year = {1990}, author = {Howland, RH}, title = {Schizophrenia and amyotrophic lateral sclerosis.}, journal = {Comprehensive psychiatry}, volume = {31}, number = {4}, pages = {327-336}, doi = {10.1016/0010-440x(90)90039-u}, pmid = {2201483}, issn = {0010-440X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications ; Humans ; Male ; Middle Aged ; Neurocognitive Disorders/*complications ; Schizophrenia/*complications ; Schizophrenia, Paranoid/complications ; *Schizophrenic Psychology ; }, abstract = {Schizophrenia and amyotrophic lateral sclerosis (ALS) are central nervous system (CNS) disorders of unknown etiology. The association of these two disorders has been infrequently reported in the literature, but is not a rare occurrence. Various neuromuscular abnormalities involving the alpha-motor neuron have been described in some patients with schizophrenia. This report reviews the literature on schizophrenia, psychosis, and ALS and describes two additional cases of schizophrenia associated with ALS. The possibility that the neuromuscular dysfunction in schizophrenia may predispose to ALS and provide an explanation for the association of these two disorders is discussed. Additional research data are needed to test this hypothesis.}, }
@article {pmid2197055, year = {1990}, author = {Hewitt, CD and Savory, J and Wills, MR}, title = {Aspects of aluminum toxicity.}, journal = {Clinics in laboratory medicine}, volume = {10}, number = {2}, pages = {403-422}, pmid = {2197055}, issn = {0272-2712}, support = {ESO4464/ES/NIEHS NIH HHS/United States ; }, mesh = {Aluminum/metabolism/*toxicity ; Brain Diseases/etiology ; Chronic Kidney Disease-Mineral and Bone Disorder/etiology ; Environmental Exposure ; Humans ; Kidney Failure, Chronic/metabolism ; Renal Dialysis/adverse effects ; }, abstract = {Aluminum is the most abundant metal in the earth's crust. The widespread occurrence of aluminum, both in the environment and in foodstuffs, makes it virtually impossible for man to avoid exposure to this metal ion. Attention was first drawn to the potential role of aluminum as a toxic metal over 50 years ago, but was dismissed as a toxic agent as recently as 15 years ago. The accumulation of aluminum, in some patients with chronic renal failure, is associated with the development of toxic phenomena; dialysis encephalopathy, osteomalacic dialysis osteodystrophy, and an anemia. Aluminum accumulation also occurs in patients who are not on dialysis, predominantly infants and children with immature or impaired renal function. Aluminum has also been implicated as a toxic agent in the etiology of Alzheimer's disease, Guamiam amyotrophic lateral sclerosis, and parkinsonism-dementia.}, }
@article {pmid2189083, year = {1990}, author = {Evans, BK and Fagan, C and Arnold, T and Dropcho, EJ and Oh, SJ}, title = {Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy.}, journal = {Neurology}, volume = {40}, number = {6}, pages = {960-962}, doi = {10.1212/wnl.40.6.960}, pmid = {2189083}, issn = {0028-3878}, mesh = {Aged ; Carcinoma, Renal Cell/*surgery ; Humans ; Kidney Neoplasms/*surgery ; Male ; *Motor Neurons ; *Nephrectomy ; Neuromuscular Diseases/*etiology/surgery ; Paraneoplastic Syndromes/*etiology/surgery ; }, abstract = {A 74-year-old man had a paraneoplastic motor neuron disease mimicking amyotrophic lateral sclerosis. He had an elevated erythrocyte sedimentation rate, other laboratory abnormalities, and a previously undiagnosed renal cell carcinoma. Four months after nephrectomy, his strength had improved and he had no fasciculations. Seven other patients with cancer and motor neuron disease improved or stabilized after tumor treatment. Even though it is rare, paraneoplastic motor neuron disease is important to diagnose because it may be treatable.}, }
@article {pmid2113462, year = {1990}, author = {Nix, WA and Pfeifer, B and Vogt, T}, title = {[Methodology and diagnostic possibilities of macro-EMG. II. Diagnostic possibilities].}, journal = {EEG-EMG Zeitschrift fur Elektroenzephalographie, Elektromyographie und verwandte Gebiete}, volume = {21}, number = {2}, pages = {96-102}, pmid = {2113462}, issn = {0012-7590}, mesh = {Electromyography/*methods ; Humans ; Neuromuscular Diseases/*diagnosis ; }, abstract = {The macro-EMG can be recorded with a modified single fiber or concentric needle. The two needles attain different results with smaller potentials values for the concentric needle type. For the single fiber type normal data are given for the EDC and tibialis anterior muscle. These data are compared with previously published results and their statistical evaluation. The concentric needle type can be used for scanning EMG. In addition potential stability can be examined in different parts of the MU using the unblanketing principle. A further novel use for macro-EMG is simultaneous single motor unit twitch recording to compare mechanical and electrical MU activity. In normal muscle the electrical signal is positively correlated with twitch force. In diseased muscle like ALS twitch is dissociated from electrical potential size. Macro-EMG allows to quantify MU size, a prerequisite to follow up dynamic changes in muscle. Improved computer programs in commercially available EMG-machines will help to introduce this method into clinical EMG laboratories as a useful addition to increase the diagnostic yield of EMG.}, }
@article {pmid2190313, year = {1990}, author = {Frey, FJ}, title = {[Cyclosporin in autoimmune diseases].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {120}, number = {21}, pages = {772-786}, pmid = {2190313}, issn = {0036-7672}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Anemia, Aplastic/drug therapy ; Arthritis, Rheumatoid/drug therapy ; Autoimmune Diseases/*drug therapy ; Clinical Trials as Topic ; Cyclosporins/adverse effects/*therapeutic use ; Diabetes Mellitus, Type 1/drug therapy ; Graves Disease/drug therapy ; Humans ; Liver Cirrhosis, Biliary/drug therapy ; Multiple Sclerosis/drug therapy ; Myasthenia Gravis/drug therapy ; Nephrosis, Lipoid/drug therapy ; Psoriasis/drug therapy ; Sjogren's Syndrome/drug therapy ; Uveitis/drug therapy ; }, abstract = {The efficacy of cyclosporine (Sandimmun) is well established in the field of organ transplantation. More recently, prospective controlled trials were performed in patients with other diseases. The efficacy of cyclosporine for the following clinical entities was proven by the trials: endogenous uveitis, rheumatoid arthritis, Sjögren's syndrome, myasthenia gravis, psoriasis and Crohn's disease. Furthermore, there is evidence from a controlled trial of some benefit for patients with aplastic anemia. The proteinuria of patients with glomerulonephritis was reduced by cyclosporine, though no improvement in glomerular filtration rate was observed. Large controlled trials in patients with multiple sclerosis or amyotrophic lateral sclerosis revealed a beneficial effect on some clinical parameters. Nevertheless, cyclosporine cannot be recommended for these patients at the present time, since the ratio between the (slight) beneficial effects and the side effects was unfavourable. In patients with primary biliary cirrhosis, cholestasis slightly diminished after the administration of cyclosporine. Whether this improvement in laboratory parameters predicts an improved outcome in patients with primary biliary cirrhosis has yet to be demonstrated. Some patients with recently diagnosed insulin dependent diabetes needed no further insulin therapy as long as cyclosporine was administered. This is an observation of tremendous potential practical relevance for the future, when methodology may be available for diagnosing autoimmune destruction of beta-cells before clinically overt diabetes is present. Cyclosporine combined with prednisone was slightly more efficacious in patients with Graves' ophthalmopathy than prednisone alone. For all other autoimmune diseases, no controlled studies with cyclosporine are available at the present time. The most important side effects of cyclosporine are renal dysfunction, hypertension, gout, tremor, gingival hyperplasia and hypertrichosis. These side effects are manageable by appropriate dosage of cyclosporine and prophylactic measures. Side effects caused interruption of cyclosporine therapy in less than 5% of the patients. Thus, cyclosporine appears to be an efficacious new agent for treatment of some groups of patient with immune diseases.}, }
@article {pmid2140182, year = {1990}, author = {Tommasi-Davenas, C and Vighetto, A and Confavreux, C and Aimard, G}, title = {[Causes of paralysis of the hypoglossal nerve. Apropos of 32 cases].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {19}, number = {18}, pages = {864-868}, pmid = {2140182}, issn = {0755-4982}, mesh = {Adolescent ; Adult ; Aged ; Central Nervous System Diseases/complications ; Cerebral Ventricle Neoplasms/complications/metabolism ; Cranial Nerve Diseases/etiology ; Cranial Nerve Neoplasms/complications/secondary ; Craniocerebral Trauma/complications ; Female ; Humans ; *Hypoglossal Nerve ; Male ; Middle Aged ; Neoplasms/*complications/pathology ; Paralysis/*etiology ; Retrospective Studies ; Vascular Diseases/complications ; }, abstract = {Thirty-two consecutive cases of hypoglossal nerve palsy (excluding syringomyelia and amyotrophic lateral sclerosis) collected between 1971 and 1987 were reviewed. The XIIth nerve palsy was clinically isolated in 8 cases, associated with other cranial nerve palsies in 16 cases and with long tracts involvement in 8 cases. Seventeen cases were related to tumours. Malignant tumours were predominant, especially middle and posterior fossa bone metastases. Carcinomatous meningitis and brainstem glioma were also found, as well as lymphoproliferative disorders and benign tumours such as chemodectoma and neurinoma. A vascular origin was established in 6 cases, related to vertebrobasilar infarct, truncular ischaemia and internal carotid dissection. The paralysis was consecutive to head or neck trauma in 4 cases and to various inflammatory processes in 4 other cases. The last case was caused by Chiari's malformation. To our knowledge, this is the first aetiological review of XIIth nerve palsy in the literature.}, }
@article {pmid2194313, year = {1990}, author = {Munsat, TL and Hollander, D}, title = {Excitotoxins and amyotrophic lateral sclerosis.}, journal = {Therapie}, volume = {45}, number = {3}, pages = {277-279}, pmid = {2194313}, issn = {0040-5957}, mesh = {Amino Acids, Diamino/*pharmacology ; Amyotrophic Lateral Sclerosis/*metabolism ; Excitatory Amino Acid Antagonists ; Glutamates/metabolism/therapeutic use ; Humans ; Neurotoxins/*pharmacology ; }, abstract = {Recent data suggest that amiotrophic lateral sclerosis (ALS) could be the result of motoneuron damage induced by endogenous or exogenous excitotoxins, and especially by excitatory amino acids (EAA). Three main sources support this hypothesis: 1) The induction of experimental models of motor neuron disease by 2 excitotoxins (BOAA and BMAA). 2) Evidence of disordered glutamate metabolism in ALS. 3) Data suggesting that EAAs may be a factor in the pathogenesis of other degenerative neurologic diseases (Huntington disease and Alzheimer disease). This new "excitotoxin hypothesis" of ALS is of particular interest as several effective antiglutamate agents are now available for human therapeutic trials.}, }
@article {pmid1974426, year = {1990}, author = {Turski, L}, title = {[The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences].}, journal = {Arzneimittel-Forschung}, volume = {40}, number = {5}, pages = {511-514}, pmid = {1974426}, issn = {0004-4172}, mesh = {Amino Acids/physiology ; Animals ; Humans ; Nervous System Diseases/physiopathology ; Neurotransmitter Agents/physiology ; Receptors, N-Methyl-D-Aspartate ; Receptors, Neurotransmitter/*physiology ; }, abstract = {Amino acids such as L-glutamate und L-aspartate are major excitatory neurotransmitters in the mammalian central nervous system (CNS) and potential neurotoxins (excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e. N-methyl-D-aspartate- (NMDA), kainate- and quisqualate-receptors. In this review interest is focused primarily on the NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the NMDA-receptor-ionophore complex has an agonist binding site for glutamate, NMDA and related EAAs which is coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for glycine, phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the NMDA receptor. An additional polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of NMDA-mediated neurotransmission may have antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of NMDA-receptor antagonists in neurological diseases such as hypoxia/ischemia, hypoglycemia, epilepsy and chronic neurodegenerative disorders (Huntington's, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, and AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2157280, year = {1990}, author = {Meier, T and Meyer, M}, title = {[Peripheral neuropathy with monoclonal gammopathy].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {120}, number = {12}, pages = {417-425}, pmid = {2157280}, issn = {0036-7672}, mesh = {Demyelinating Diseases/etiology/physiopathology ; Diagnosis, Differential ; Humans ; *Immunoglobulin M ; Immunoglobulin kappa-Chains ; Male ; Middle Aged ; Neural Conduction ; Paraproteinemias/*complications ; Peripheral Nervous System Diseases/diagnosis/*etiology ; }, abstract = {The case is reported of a patient with IgM-kappa paraproteinemia and polyneuropathy (PN) with very slow nerve conduction velocities. The association of demyelinating PN with severely decreased nerve conduction velocities and an IgM-kappa paraprotein usually suggests the diagnosis of monoclonal gammopathy of undetermined significance (MGUS), but less often of clinically manifest macroglobulinemia. Demyelinating PN with IgG-lambda- or IgA-lambda paraproteinemia occurs often in the uncommon but readily treatable osteosclerotic myeloma. A monoclonal protein combined with peripheral neuropathy involving predominant pain, temperature and autonomic loss (small fibre neuropathy) is by and large pathognomonic for primary systemic amyloidosis or amyloidosis associated with multiple myeloma or Waldenström's macroglobulinemia. Mild sensorimotor axonal polyneuropathy is an unspecific syndrome found in all gammopathies. It is important to differentiate between paraproteinemia with clinically pure chronic sensory PN and paraneoplastic sensory polyneuropathy. Unlike amyotrophic lateral sclerosis (ALS), paraproteinemias associated with a motor neuron disease-like syndrome sometimes evolve unusually slowly and exhibit neurophysiologically subclinical lesions of sensory nerve fibers. Mononeuropathy or multifocal neuropathy with a monoclonal protein is typical of cryoglobulinemia. Demyelinating PN of osteosclerotic myelomas presenting with one or a small number of bone lesions usually regress after excision or irradiation of the plasma cell proliferations. Immunosuppressants and plasmapheresis in the treatment of the demyelinating IgM-kappa neuropathies, of paraproteinemia with the motor neuron disease-like syndrome, and of mononeuropathy or multifocal neuropathy with cryoglobulinemia, are of doubtful value.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2408129, year = {1990}, author = {el Alaoui-Faris, M and Medejel, A and al Zemmouri, K and Yahyaoui, M and Chkili, T}, title = {[Amyotrophic lateral sclerosis syndrome of syphilitic origin. 5 cases].}, journal = {Revue neurologique}, volume = {146}, number = {1}, pages = {41-44}, pmid = {2408129}, issn = {0035-3787}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/drug therapy/*etiology/physiopathology ; Cerebrospinal Fluid/analysis ; Cerebrospinal Fluid Proteins/analysis ; Female ; Follow-Up Studies ; Humans ; Lymphocytosis/cerebrospinal fluid ; Male ; Middle Aged ; Neurosyphilis/*complications ; Penicillin G/therapeutic use ; Syndrome ; Syphilis Serodiagnosis ; }, abstract = {We studied 5 cases of syphilitic lateral amyotrophic sclerosis. The diagnosis was based on the presence of a lymphocytic reaction in the CSF and positive VDRL and TPHA reactions in both blood and CSF. Clinically, the disease affected the arms in 3 cases and produced paraplegia in 2 cases. The gradual extension of amyotrophy over several months, the diffusion of electromyographic abnormalities and the finding of spinal cord atrophy at myelography and CT suggested a subacute ischemic mechanism with meningo-myelic arteritis involving the anterior horns. After treatment with penicillin G in high doses, the outcome was constantly favourable, with improvement of motor deficit in 4 cases and stabilisation in 1 case in a 5 to 13 years' follow-up.}, }
@article {pmid2404216, year = {1990}, author = {Armon, C and Daube, JR and Windebank, AJ and Kurland, LT}, title = {How frequently does classic amyotrophic lateral sclerosis develop in survivors of poliomyelitis?.}, journal = {Neurology}, volume = {40}, number = {1}, pages = {172-174}, doi = {10.1212/wnl.40.1.172}, pmid = {2404216}, issn = {0028-3878}, support = {NS 17750/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Female ; Humans ; Poliomyelitis/*complications ; United States ; }, abstract = {There is a paucity of reports of classic amyotrophic lateral sclerosis (ALS) developing in survivors of paralytic poliomyelitis. We describe a patient with classic ALS and an antecedent paralytic disease thought to have been poliomyelitis from which she recovered completely. If the paucity of ALS preceded by true poliomyelitis is not merely a matter of underreporting, antecedent paralytic poliomyelitis may have a protective role against the development of ALS. This has implications relevant to pathogenesis and to projected secular trends of ALS incidence since the introduction of poliomyelitis vaccines. There is a need to establish the incidence of cases of classic ALS in patients with antecedent poliomyelitis.}, }
@article {pmid2403478, year = {1990}, author = {Safar, P and Abramson, NS and Angelos, M and Cantadore, R and Leonov, Y and Levine, R and Pretto, E and Reich, H and Sterz, F and Stezoski, SW}, title = {Emergency cardiopulmonary bypass for resuscitation from prolonged cardiac arrest.}, journal = {The American journal of emergency medicine}, volume = {8}, number = {1}, pages = {55-67}, doi = {10.1016/0735-6757(90)90298-e}, pmid = {2403478}, issn = {0735-6757}, support = {NS15295/NS/NINDS NIH HHS/United States ; NS24446/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Cardiopulmonary Bypass ; Dogs ; Emergencies ; Heart Arrest/*therapy ; Life Support Care ; *Resuscitation ; Time Factors ; }, abstract = {After cardiac arrest (no flow) of more than approximately 5 minutes' duration, standard external cardiopulmonary resuscitation (CPR) basic, advanced, and prolonged life support (BLS, ALS, PLS) do not reliably produce cerebral and coronary perfusion pressures to maintain viability and achieve stable spontaneous normotension; nor do they provide prolonged control over pressure, flow, composition, and temperature of blood. Since these capabilities are often needed to achieve conscious survival, emergency closed-chest cardiopulmonary bypass (CPB) by veno-arterial pumping via oxygenator is presented in this review as a potential addition to ALS-PLS for selected cases. In six dog studies by the Pittsburgh group (n = 221; 1982 through 1988), all 179 dogs that received CPB after prolonged cardiac arrest (no flow) or after CPR (low flow) states had restoration of stable spontaneous circulation. The use of CPB enhanced survival and neurological recovery over those achieved with CPR-ALS attempts only. With CPB and standard intensive care, it was possible to reverse normothermic ventricular fibrillation (VF) cardiac arrest (no flow) of up to 15 minutes and to achieve survival without neurologic deficit; VF of 20 minutes to achieve survival but with neurologic deficit; and VF of 30 minutes to achieve transient restoration of spontaneous circulation followed by secondary cardiac death. CPB could restore stable spontaneous circulation after ice water submersion of up to 90 minutes. Other groups' laboratory and clinical results agree with these findings in general. Clinical feasibility trials are needed to work out logistic problems and to meet clinical challenges. Future possibilities for emergency CPB require further research and development.}, }
@article {pmid2190115, year = {1990}, author = {Dubrovsky, B and Filipini, D}, title = {Neurobiological aspects of the pelvic floor muscles involved in defecation.}, journal = {Neuroscience and biobehavioral reviews}, volume = {14}, number = {2}, pages = {157-168}, doi = {10.1016/s0149-7634(05)80216-7}, pmid = {2190115}, issn = {0149-7634}, support = {1RO-IAM-3487701/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Biological Evolution ; Defecation/*physiology ; Fecal Incontinence/physiopathology ; Humans ; Mammals/*growth &amp; development ; Muscles/anatomy &amp; histology/innervation/*physiology ; Perineum/anatomy &amp; histology/innervation/*physiology ; Posture ; }, abstract = {Neurobiological aspects of the organization of pelvic floor musculature are reviewed. Evolutionary considerations on the origin of these muscles indicate that they develop with specific attachments and function, i.e., do not derive from preexisting muscles such as the ones from the tail. Anatomically, pelvic floor muscles can be divided into 1) true sphincters and related muscles and 2) muscles which flank the visceral outlets. While in quadrupedal mammals the EAS behaves as a fast twitch muscle, in man this muscle has slow twitch characteristics. Like some epaxial muscles the EAS has a strong connectivity with its surrounding skin. In further analogy with some epaxial muscle the EAS, although endowed with muscle spindles, is devoid of the phasic, monosynaptic component of the stretch reflex. Onuf's nucleus which innervates pelvic floor muscles receives an important group of suprasegmental afferents including, probably, direct corticospinal fibers. Pelvic floor muscles play a fundamental role in signaling arrival of feces to the perineum. While sphincteric activity is important for continence, other mechanisms such as the anorectal angle and anal cushions are also of relevance. Although emphasis has been put on motor factors, fecal incontinence can also result from impairments in sensory mechanisms of the anorectal system. In diseases like amyotrophic lateral sclerosis, Werdnig Hoffman's and others there is selective sparing of neuropathology in Onuf's nucleus. In contrast, the nucleus is affected in some autonomic visceromotor neuronal disorders, e.g., Shy Drager syndrome, Fabry's disease. It has been suggested that Onuf's nucleus occupies an intermediate position between visceral and somatic nuclei.}, }
@article {pmid2138268, year = {1990}, author = {Mühlenberg, W}, title = {[High aluminum concentrations in well water of southern Lower Saxony sandy soil areas caused by acid precipitation--evaluation from the public health and ecologic viewpoint].}, journal = {Das Offentliche Gesundheitswesen}, volume = {52}, number = {1}, pages = {1-8}, pmid = {2138268}, issn = {0029-8573}, mesh = {Acid Rain/*adverse effects ; Germany, West ; Humans ; Hydrogen-Ion Concentration ; Water Pollution, Chemical/*analysis ; Water Supply/*analysis ; }, abstract = {Decades of acid precipitation have caused soil acidification in regions with low neutralizing capacity of industrial countries, thus mobilizing aluminium from clay minerals into soil solution and ground water. In the southern sandy heath-land of Lower Saxony all the wells with pH values lower than 4.5 showed aluminium contents higher than 2.0 mg/l. 66.7% of the specimens within the pH-range 4.5 to 5.0 and 20% of the specimens within the pH-range 5.0 to 5.5 had aluminium levels of more than 0.2 mg/l, that is the maximum permissible limit value of the drinking water regulation. High contents of aluminium in drinking water are objectionable from the hygienic point of view, as they may cause intoxications in infants and patients with impaired renal function. In addition to this, the involvement of aluminium in the pathogenesis of severe degenerative disorders of the central nervous system cannot be excluded, such as Alzheimers disease, amyotrophic lateral sclerosis and Parkinsons dementia.}, }
@article {pmid2130665, year = {1990}, author = {Rapport, MM}, title = {Implications of altered brain ganglioside profiles in amyotrophic lateral sclerosis (ALS).}, journal = {Acta neurobiologiae experimentalis}, volume = {50}, number = {4-5}, pages = {505-513}, pmid = {2130665}, issn = {0065-1400}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Brain/physiopathology ; *Brain Chemistry ; Cerebral Cortex/chemistry ; Gangliosides/*analysis/physiology ; Reference Values ; }, abstract = {Rapport et al. (11) reported that marked aberrations in brain ganglioside profiles were present in 17 of 21 patients with ALS. The aberrations were detected both in motor cortex and in unexpected regions such as frontal, temporal, and parahippocampal gyrus cortex. These results suggest that some underlying pathological process in ALS also occurs in some neurons that are less vulnerable than motor neurons to consequent deterioration. Since gangliosides are major membrane constituents whose carbohydrate residues establish structural configurations on the external face of the cell membrane, it is highly probable that aberrant ganglioside patterns reflect alterations in receptor structure and function. Receptors are inherently cell specific and the specificity would account for differences in response of sensory and motor neurons to the pathological process in ALS. An apparent absence of similar ganglioside aberrations in spinal cord suggests that the primary pathology is in the brain. Such aberrations are not seen in Alzheimer's disease. If receptor functions are altered in ALS, what ligands might be involved? A major consideration is neurotrophic hormones (2). Gangliosides are known to modulate the effect of nerve growth factor in some in vitro systems and very recent evidence implicates protein kinase activation as an important mechanism.}, }
@article {pmid1980020, year = {1990}, author = {Askmark, H and Aquilonius, SM and Gillberg, PG}, title = {Neuropharmacology of amyotrophic lateral sclerosis.}, journal = {Progress in brain research}, volume = {84}, number = {}, pages = {371-380}, doi = {10.1016/s0079-6123(08)60920-6}, pmid = {1980020}, issn = {0079-6123}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Humans ; Neurons/*physiology ; Neurotransmitter Agents/physiology ; Spinal Cord/physiology/*physiopathology ; }, }
@article {pmid1690486, year = {1990}, author = {Dreikorn, K and Richter, R and Schönhöfer, PS}, title = {[Conservative, non-hormonal treatment of benign prostatic hyperplasia].}, journal = {Der Urologe. Ausg. A}, volume = {29}, number = {1}, pages = {8-16; discussion 17-8}, pmid = {1690486}, issn = {0340-2592}, mesh = {Adrenergic alpha-Antagonists/therapeutic use ; Anticholesteremic Agents/therapeutic use ; Humans ; Male ; Palliative Care/methods ; Plant Extracts/therapeutic use ; Prostatic Hyperplasia/*therapy ; Tissue Extracts/therapeutic use ; Urinary Bladder Neck Obstruction/therapy ; }, abstract = {The indications for and efficacy of non-hormonal drugs in the treatment of benign prostatic hyperplasia (BPH) are the subject of some controversy. However, a critical evaluation of the available literature shows that no clinically relevant reduction of prostatic size has been reached with any drug tested so far. It is suggested that alpha-adrenergic blockers exert a beneficial effect by reducing the "dynamic" component associated with prostatic obstruction. The application of objective criteria has not shown cholesterol-lowering and phytotherapeutic drugs to have any significant and clinically relevant advantage over placebos. The evaluation of drug therapy in BPH patients is complicated by the fact that the obstructive signs are masked by irritative symptoms ("prostatism", "unstable bladder"), the causes of which are also unknown. A causal drug therapy should have an impact on biochemically and/or biologically confirmed changes that are responsible for the development of BPH. Als long as the cause of BPH remains unknown, drugs cannot fulfil these requirements. The efficacy of drug therapy in patients with BPH can only, therefore, be evaluated in double blind controlled studies including modern urodynamic investigations. However, these standards should also be applied to the decision as to whether operative treatment is indicated and to evaluation of the results.}, }
@article {pmid2697901, year = {1989}, author = {Bonduelle, M}, title = {[Amyotrophic lateral sclerosis. In search of its etio-pathogenic mechanisms].}, journal = {Recenti progressi in medicina}, volume = {80}, number = {12}, pages = {659-664}, pmid = {2697901}, issn = {0034-1193}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/immunology/physiopathology/therapy ; Humans ; }, abstract = {The etiological problem of ALS has still not been resolved although a large amount of work, more and more technical, has been devoted in the fields of immunology, virology, environment and genetics. This research is related to spinal amyotrophies in general--to motor neuron diseases--and it is only as an analogy or as a model that the results may be used in the specific case of ALS. The genetic hypothesis of ALS is suggested by family cases (in adults) and seems to be linked to Parkinson and Alzheimer diseases; all of these are 'degenerative' nervous diseases and there are examples of their association. Research is being done in anatomy, embryogenesis, neurochemistry, molecular genetics to investigate the pathophysiology of neuron considered the only way to develop a specific therapy. The treatment, although still symptomatic, is improving due to technical progress in management.}, }
@article {pmid2686140, year = {1989}, author = {Hansen, PR}, title = {[Autoimmune neuropathy].}, journal = {Ugeskrift for laeger}, volume = {151}, number = {44}, pages = {2870-2873}, pmid = {2686140}, issn = {0041-5782}, mesh = {Autoantibodies/analysis ; Chronic Disease ; Demyelinating Diseases/immunology ; Humans ; Immunoglobulin M/analysis ; Nervous System Diseases/*immunology ; }, abstract = {Chronic progressive polyneuropathy is frequently cryptogenic but occurs in association with monoclonal gammopathy. In cases of this type, a relatively mild, mainly axonal sensomotor neuropathy is frequently present and may be difficult to distinguish from carcinomatous neuropathy in malignant conditions without the presence of the M-component. In benign essential gammopathy (MGUS) with an M-component of IgM-kappa class, the neuropathy is frequently demyelinizing and the paraprotein reacts specifically with carbohydrate determinants in myelin-associated glycoprotein (MAG) and other glycoproteins and glycolipids in peripheral nerve tissue. Demonstration is undertaken by immune fluorescence investigation (eg on skin biopsy material) whereas serological diagnosis involves difficulties. There is much evidence to suggest that the autoimmune reaction is of significance for the development of nerve damage and uncontrolled trials have shown beneficial effects of immune suppression including plasmapherisis. The latter treatment should be considered in the Guillain-Barré syndrome, neuropathy and HIV-infection and also in motor neurone disease and IgM-MGUS, in which autoimmunological mechanisms may also be of pathophysiological significance.}, }
@article {pmid2673004, year = {1989}, author = {Drachman, DB and Kuncl, RW}, title = {Amyotrophic lateral sclerosis: an unconventional autoimmune disease?.}, journal = {Annals of neurology}, volume = {26}, number = {2}, pages = {269-274}, doi = {10.1002/ana.410260214}, pmid = {2673004}, issn = {0364-5134}, support = {1 RO1 NS23719/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/classification/*immunology ; Autoantibodies/immunology ; Autoimmune Diseases/*immunology ; Gangliosides/*immunology ; Humans ; }, abstract = {The possibility of an autoimmune mechanism of pathogenesis in amyotrophic lateral sclerosis has long been considered, but the evidence to support a conventional autoimmune process, reviewed here, is inconclusive. However, antibodies that react in vitro with gangliosides have recently been found in sera of a large majority of patients with classical amyotrophic lateral sclerosis and other motor neuron syndromes. A working hypothesis is proposed, suggesting how antibodies might be related to the disease process. The hypothesis attempts to account for (1) a pathogenic role of antibodies directed against the carbohydrate components of glycolipids, (2) the selectivity of the process for motor neurons, (3) an antibody-mediated mechanism that could result in apparently degenerative neuropathological changes without signs of inflammation, and (4) a type of autoimmune response that is extremely difficult to suppress by conventional means. Although the evidence for this hypothesis is by no means complete, its critical features are all testable.}, }
@article {pmid2671267, year = {1989}, author = {Sillevis Smitt, PA and de Jong, JM}, title = {Animal models of amyotrophic lateral sclerosis and the spinal muscular atrophies.}, journal = {Journal of the neurological sciences}, volume = {91}, number = {3}, pages = {231-258}, doi = {10.1016/0022-510x(89)90056-7}, pmid = {2671267}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/etiology/*physiopathology ; *Disease Models, Animal ; Muscular Atrophy, Spinal/chemically induced/etiology/*physiopathology ; }, abstract = {The causes of human amyotrophic lateral sclerosis (ALS) and the spinal muscular atrophies (SMA) are, almost without exception, unknown. This ignorance has stimulated the search for animal models to obtain insight into the etiology, pathogenesis and biochemical mechanisms underlying the human disorders. None of the 38 animal models, described in this review, provides an exact animal copy of a specific human motor neuron disease. Most of the models reproduce certain structural or physiological aspects of their human counterparts. The various experimental models can be classified according to the pathogenetic mechanism involved and according to the structural changes observed. Models based on experimentally induced disease, include heavy metals and trace elements (lead intoxication in guinea pigs, rabbits, rats, cats and primates; mercury intoxication in rats; aluminium intoxication in rabbits; swayback in goat kids; calcium and magnesium deficient rabbits and primates and calcium deficient cynomolgus monkeys), toxins (IDPN, vincristine, vinblastine, podophyllotoxin, colchicine, maytansine, maytanprine, L-BMAA, lectins, adriamycin), nutritional factors (ascorbic acid deficient guinea pigs), virus infection (spongiform polioencephalomyelitis, attenuated poliovirus, lactate dehydrogenase-elevating virus), and immunological factors (immunization with motor neurons). Hereditary models comprise hereditary canine spinal muscular atrophy, hereditary neurogenic amyotrophy in the pointer dog, Stockard paralysis, Swedish Lapland dog paralysis, "wobbler" mouse, "shaker" calf, and hereditary spinal muscular atrophy in zebra foals, crossbred rabbits,}, }
@article {pmid2660234, year = {1989}, author = {Meininger, V}, title = {[Treatment of amyotrophic lateral sclerosis].}, journal = {La Revue du praticien}, volume = {39}, number = {14}, pages = {1237-1240}, pmid = {2660234}, issn = {0035-2640}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/physiopathology/*therapy ; Humans ; }, }
@article {pmid2563937, year = {1989}, author = {Miller, SC and Warnick, JE}, title = {Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens.}, journal = {Archives of neurology}, volume = {46}, number = {3}, pages = {330-335}, doi = {10.1001/archneur.1989.00520390096025}, pmid = {2563937}, issn = {0003-9942}, support = {NS-21312/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Androgens/pharmacology ; Animals ; Humans ; Neurotransmitter Agents/pharmacology ; Rats ; Receptors, Neurotransmitter/metabolism ; Receptors, Thyrotropin-Releasing Hormone ; Sex Factors ; Spinal Cord/drug effects ; Thyrotropin-Releasing Hormone/administration &amp; dosage/pharmacology/*therapeutic use ; }, abstract = {Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). Clinical studies have been divided on the efficacy of protirelin (TRH) despite strong experimental findings that are consistent with a role for the peptide in ALS. Recent findings provide evidence of a gender-related specificity in the ability of protirelin to potentiate the monosynaptic reflex. While castration in male neonatal rats lowered the sensitivity to protirelin, testosterone treatment restored that sensitivity. An examination of the clinical studies reveals a failure either to identify patients' sex or to separate the results on the basis of sex. These findings provide convincing evidence for the potential efficacy of protirelin in ALS if the patient's sex and underlying hormonal status are taken into account.}, }
@article {pmid2538809, year = {1989}, author = {Massey, EW}, title = {Hand weakness in elderly patients.}, journal = {Postgraduate medicine}, volume = {85}, number = {4}, pages = {59-60, 63-5, 70}, doi = {10.1080/00325481.1989.11700614}, pmid = {2538809}, issn = {0032-5481}, mesh = {Aged ; Diagnosis, Differential ; Hand/innervation/*physiopathology ; Humans ; Motor Neurons/physiology ; Neuromuscular Diseases/diagnosis ; Peripheral Nervous System Diseases/diagnosis ; }, abstract = {Weakness of the hand is a common problem in the elderly. When joint and vascular diseases have been ruled out, a systematic anatomic approach to the possible neurologic causes can be used to sort through nonspecific symptoms and the complexity of hand anatomy. Syndromes of the peripheral nerves supplying the hand (ie, median, ulnar, radial) are common and are generally caused by compression of these nerves in their pathway through the elbow, forearm, or wrist. Other common causes of hand weakness include lower motor neuron syndromes involving the brachial plexus; cervical radiculopathy amyotrophic lateral sclerosis; and myasthenia gravis. Along with a careful history and physical examination, several tests are helpful in discerning the nature and location of lesions. Electromyography, magnetic resonance imaging, computed tomography, and myelography may all be used to exclude or support a diagnosis.}, }
@article {pmid2694031, year = {1989}, author = {Cawte, J and Kilburn, C and Florence, M}, title = {Motor neurone disease of the western Pacific: do the foci extend to Australia?.}, journal = {Neurotoxicology}, volume = {10}, number = {2}, pages = {263-270}, pmid = {2694031}, issn = {0161-813X}, mesh = {Australia/epidemiology ; Diet/adverse effects ; Genetic Predisposition to Disease ; Humans ; Manganese Poisoning ; *Motor Neurons ; Native Hawaiian or Other Pacific Islander/genetics ; Neuromuscular Diseases/chemically induced/*ethnology ; }, abstract = {Hyperendemic foci of motor neurone disease, and other neurodegenerative disorders, are located in the western Pacific area, in the Japanese of the Kii Peninsula of Honshu Island, the Chamorros of the Mariana Islands, the Auyu and Jakai of West New Guinea. It is suspected that there is a common aetiologic pathway from toxic metal and essential minerals in these three foci. A fourth focus of motor neurone disease occurs in an isolated tribal group living on the same Pacific longitude, at Angurugu on Groote Eylandt in the Gulf of Carpentaria, Northern Australia. This environment is also characterized by local ecological extremes, including low calcium and iron, and high manganese. The "Angurugu syndrome", described in this paper, shows dysfunction of motor neurones, including upper and lower motor, cerebellar, extrapyramidal and cranial nerves, especially oculomotor. About half the cases emerge in adult life. The others are evident in early childhood. The syndrome is viewed not as simple manganism but as manganism synergistic with accompanying mineral changes. No autopsy studies have been carried out. This paper suggests that this syndrome incurs a loss of the neurotransmitter dopamine. A case study is presented that indicates the unusual range of symptoms, including ataxia, and partial relief by L Dopa (Sinemet).}, }
@article {pmid2662342, year = {1989}, author = {Chazot, F and Tabaraud, F and Boulesteix, JM and Hugon, J and Vallat, JM and Dumas, M}, title = {[Epidemiology of amyotrophic lateral sclerosis in the Limousin area].}, journal = {Revue neurologique}, volume = {145}, number = {5}, pages = {408-410}, pmid = {2662342}, issn = {0035-3787}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*epidemiology ; France ; Humans ; Prospective Studies ; Retrospective Studies ; }, abstract = {Several epidemiologic studies of amyotrophic lateral sclerosis have shown a uniform repartition over the world. We report the results of a retrospective study and the preliminary results of a prospective study carried out in the Limousin area. The mean incidence per/year is 0.97/100,000 in the retrospective study and 1.3/100,000 in the prospective study. Such data are similar to those previously reported. The two major findings are the high frequency of bulbar palsy and the high mean age of the patients. This can be associated with the high mean age of the population in the Limousin area as compared to other regions.}, }
@article {pmid2662216, year = {1989}, author = {Vassilopoulos, D}, title = {The genetics of motor neurone disease.}, journal = {Progress in clinical and biological research}, volume = {306}, number = {}, pages = {91-104}, pmid = {2662216}, issn = {0361-7742}, mesh = {Amyotrophic Lateral Sclerosis/classification/epidemiology/etiology/*genetics ; Family Health ; Genetic Counseling ; Genetic Markers ; Humans ; *Motor Neurons ; Neuromuscular Diseases/classification/epidemiology/etiology/*genetics ; Twins ; }, }
@article {pmid2660221, year = {1989}, author = {Goulon, M and Goulon-Goëau, C}, title = {[Amyotrophic lateral sclerosis and respiratory assistance].}, journal = {Revue neurologique}, volume = {145}, number = {4}, pages = {293-298}, pmid = {2660221}, issn = {0035-3787}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Child ; Female ; Humans ; Male ; Middle Aged ; *Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/etiology ; Tracheotomy ; }, abstract = {Respiratory insufficiency of restrictive origin, often aggravated by obstructive disorders, is constant in amyotrophic lateral sclerosis (ALS), and is usually progressive. Respiratory distress may be life-threatening while the neurologic disease is still limited. Furthermore, the diagnosis of ALS is not always obvious when urgent therapeutic decisions have to be made. Results are reported in 16 patients with ALS treated by assisted ventilation: 14 by endotracheal and 2 by nasobuccal routes. Transient improvement in respiratory function in 9 patients allowed partial return of spontaneous respiration. Known mean duration of course (n = 14) from first sign to death (12 cases) or last control (2 cases) was 3 years 3 months (1 to 9 years). Survival from tracheotomy to death or last control (July 1988 in 12 cases) was 12 months (3 to 48 months). These patients can now return home under the care of associations providing respirators.}, }
@article {pmid2646683, year = {1989}, author = {Mathe, JF and Fève, JR and Labat, JJ and De Kersaint Gilly, A and Potagas, C and Dubois, C}, title = {[Ischemia of the anterior horn of the spinal cord].}, journal = {Revue neurologique}, volume = {145}, number = {1}, pages = {60-64}, pmid = {2646683}, issn = {0035-3787}, mesh = {Adolescent ; *Anterior Horn Cells ; Female ; Humans ; Ischemia/diagnosis/*etiology ; Male ; Middle Aged ; *Motor Neurons ; Spinal Cord/*blood supply ; }, abstract = {Ischemia of the motoneurons in the anterior horn is a well known pathological entity. Their clinical signs and symptoms are similar to those of amyotrophic lateral sclerosis. Evidence by selective angiography of angiomas of the spinal cord or compression or deviation of Adamkiewicz artery may be suggestive of an initial vascular lesion. Various data (knowledge of development or lesions during experimental ischemia, selective electrophysiologic analysis of anterior horn neurons, evidence of precise circumstances of spinal vascular disorder or spinal arteriography) suggest that anterior horn ischemia is a multiple aspect phenomenon. Our 4 cases illustrate this hypothesis and demonstrate under confirmed vascular circumstances the different clinical aspects of anterior horn ischemic lesions. In addition to typical amyotrophic paralysis unusual or misleading symptoms may occur such as claudication, paroxysmal contractures or progressive spastic paraparesis. Investigations required and possible treatment of the lesions are simplified by awareness of these various clinical aspects.}, }
@article {pmid2646678, year = {1989}, author = {Maertens de Noordhout, A and Rothwell, JC and Day, BL and Thompson, PD and Delwaide, PJ and Marsden, CD}, title = {[Percutaneous electric and magnetic stimulation of the motor cortex in man. Physiological aspects and clinical applications].}, journal = {Revue neurologique}, volume = {145}, number = {1}, pages = {1-15}, pmid = {2646678}, issn = {0035-3787}, mesh = {Central Nervous System Diseases/*physiopathology ; Electric Stimulation ; Electromyography ; Humans ; Magnetics ; Motor Cortex/*physiology/physiopathology ; Muscle Contraction ; Neural Conduction ; }, abstract = {The new techniques of percutaneous electric and magnetic stimulation of the motor cortex in conscious man provide a unique opportunity of functional testing of the central motor pathways. These techniques seem to be safe and no immediate or delayed adverse reactions have been reported. The physiological studies so far performed suggest that the structures which are preferentially excited by these methods are the fast conducting pyramidal neurones. It has been shown that a single cortical stimulus is able to activate spinal motoneurones repeatedly. This phenomenon can easily be explained if the cortical stimulus generates multiple descending volleys in the central motor pathways. By comparison with experiments of stimulation of the exposed motor cortex in animals, it is likely that electric brain stimulation directly activates the axons of the pyramidal neurons at their origin and to a lesser extent also recruits these neurons transsynaptically, via some cortical interneurones. Magnetic stimulation of the brain at the vertex seems to act mostly by the latter mechanism. These different modes of action of the two methods of cortical stimulation explain the latency differences of the EMG responses obtained with either technique. Increased excitability of the spinal motoneurones and the existence of multiple descending volleys in response to a single cortical stimulus result in shortening of the latencies and greater amplitude of the responses recorded during voluntary contraction of the target muscle. Stimulation of the motor cortex has been used in pilot studies conducted on patients suffering from various disorders of the central motor pathways, such as multiple sclerosis, cervical spondylosis, motor neurone disease or stroke. The sensitivity of the technique looks promising. In M.S., the EMG responses usually show an increased central conduction latency, a reduced amplitude and a prolonged duration. The severity of the electrophysiological abnormalities is not very well correlated with clinical weakness, but the correlations seems to be better with hyperreflexia and the presence of brisk finger flexor jerks. The same abnormalities are observed in cervical spondylosis, although to a lesser extent. In motor neurone disease, the responses have a moderately increased latency and their size and duration are markedly reduced. Patients with acute hemispheric stroke usually show absent responses on the contralateral side. Finally, electric cortical stimulation can be very useful in monitoring the functional integrity of descending motor tracts during surgical operations performed on the spinal cord.}, }
@article {pmid2561585, year = {1989}, author = {Cruz Martínez, A and Lara, M and Villoslada, C}, title = {[Peripheral neuropathy in HIV infection].}, journal = {Archivos de neurobiologia}, volume = {52 Suppl 1}, number = {}, pages = {79-92}, pmid = {2561585}, issn = {0004-0576}, mesh = {Acquired Immunodeficiency Syndrome/*complications ; Adult ; Biopsy ; Female ; Humans ; Male ; Middle Aged ; Peripheral Nervous System Diseases/*etiology/pathology/physiopathology/therapy ; }, abstract = {Neuropathy may complicate all stages of human immunodeficiency virus infection (HIV). Different types of peripheral neuropathy and myelopathy have been reported associated with HIV infection: sensory symmetrical polyneuropathy, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, sensory ataxic neuropathy (ganglioneuronitis), cauda equina syndrome, amyotrophic lateral sclerosis, spastic paraparesia, and subclinical neuropathy diagnosed by electrophysiologic study. We describe the main clinical, electrophysiological and pathological features in these different types of neuropathy and comment their pathogenesis and treatment. Results in our series of twenty-two patients are also reported. In this series we want to underline three cases in which a chronic demyelinating polyneuropathy was the first manifestation of HIV infection. Thus, patients with predominantly motor demyelinating neuropathies and suspicious risk factors should be screened for silent HIV infection.}, }
@article {pmid2557642, year = {1989}, author = {Mayer, RJ and Lowe, J and Lennox, G and Doherty, F and Landon, M}, title = {Intermediate filaments and ubiquitin: a new thread in the understanding of chronic neurodegenerative diseases.}, journal = {Progress in clinical and biological research}, volume = {317}, number = {}, pages = {809-818}, pmid = {2557642}, issn = {0361-7742}, mesh = {Chronic Disease ; Cytoskeleton/*analysis ; Humans ; Intermediate Filaments/*analysis ; *Nerve Degeneration ; Nervous System Diseases/*metabolism/physiopathology ; Ubiquitins/*analysis ; }, abstract = {We have recently shown that there is a previously unsuspected link between the intracellular inclusions seen in several major chronic human degenerative diseases, including neurodegenerative diseases: the inclusions showing ubiquitin immunoreactivity. The conditions include Parkinson's disease, motor neurone disease, Alzheimer's disease, Pick's disease, and alcoholic liver disease as well as cerebellar astrocytomas and a myopathy. The inclusions found in these diseases are reported to contain intermediate filaments: neurofilaments are associated with Lewy bodies in Parkinson's disease, Pick's bodies in Pick's disease and neurofibrillary tangles in Alzheimer's disease, cytokeratins are found in Mallory bodies in alcoholic liver disease, glial fibrillary acidic proteins and vimentin are found in Rosenthal fibres in astrocytomas, and desmin is found in cytoplasmic bodies in cytoplasmic body myopathy. Therefore five classes of intermediate filaments are found in inclusions which also contain ubiquitin immunoreactivity; we have also shown that ubiquitin immunoreactivity is present in vesicles in some areas of granulovacuolar degeneration in Alzheimer's disease. Protein ubiquitination is considered a signal for extralysosomal protein degradation, (although ubiquitination may have several other important functions). We have recently shown that intermediate filaments are involved in protein sequestration before degradation by lysosomally mediated autophagy: therefore intermediate filament-containing ubiquitinated inclusions may be the hallmarks of cellular attempts to eliminate pathogenic insults by the activation of both extralysosomal and lysosomal mechanisms of intracellular protein degradation. We have recently been able to reproduce, at least in part, some of the clinical observations in tissue culture cells. Ubiquitinated protein conjugates accumulate in lysosomes in fibroblasts treated with the lysosomal cysteine protease inhibitor E-64, which may mimic aspects of granulovacuolar degeneration.}, }
@article {pmid2497685, year = {1989}, author = {Brooks, BR}, title = {A summary of the current position of TRH in ALS therapy.}, journal = {Annals of the New York Academy of Sciences}, volume = {553}, number = {}, pages = {431-461}, pmid = {2497685}, issn = {0077-8923}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Research Design ; Thyrotropin-Releasing Hormone/adverse effects/*therapeutic use ; }, abstract = {The critical points that must be addressed in evaluating ergotropic drugs are exemplified by the current morass of positive and negative results that have been obtained in clinical investigations of TRH or its analogues. Appropriate subject selection is crucial. These patients may have bulbar symptoms, and those features of ALS should be specifically assayed for treatment effects relative to placebo. Gender-specific effects of TRH need to be accounted for in study design. In addition, electrophysiological techniques such as single fiber density may help determine the responsiveness of patients to TRH or its analogues. The clinical significance of an increase in fiber density following TRH or other drugs should be determined, as it will provide insight into the state of motor neurons in the spinal cord of patients with ALS and possibly could be important in determining those who may respond to TRH if such a response is possible. Clinical studies have quite clearly shown conflicting results. Basic studies, however, have shown that response to TRH is state dependent, that is, whether the patient is male or female. Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues.}, }
@article {pmid2497684, year = {1989}, author = {Brooke, MH}, title = {Thyrotropin-releasing hormone in ALS. Are the results of clinical studies inconsistent?.}, journal = {Annals of the New York Academy of Sciences}, volume = {553}, number = {}, pages = {422-430}, doi = {10.1111/j.1749-6632.1989.tb46663.x}, pmid = {2497684}, issn = {0077-8923}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Humans ; Thyrotropin-Releasing Hormone/*therapeutic use ; }, abstract = {The results of the various studies and an analysis of the methodology are presented in TABLE 1. As can be seen, there was no "perfect" study. In five of the studies enough information was presented with regard to the measurements and the behavior of control patients that a statistical analysis could be performed. Three of the studies showed a transient, statistically significant effect in at least some muscles. The two studies that demonstrated no such effect both used TRH in very small doses. It therefore seems reasonable to conclude that the effect of TRH in ALS is a definite, acute, and transient response. The cause of this response, however, has not been documented, and whether it is associated with an effect of the drug on the disease process remains to be seen.}, }
@article {pmid2493673, year = {1989}, author = {Bouche, P and Castaigne, P and Meininger, V}, title = {[Management of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {145}, number = {1}, pages = {49-54}, pmid = {2493673}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Delivery of Health Care ; Health Services ; Humans ; Long-Term Care ; Time Factors ; }, abstract = {There is no specific treatment for patients with amyotrophic lateral sclerosis. Nevertheless several associations of patients have been created to stimulate the research to find the causes and treatments of the disease and to help the patients. In spite of the absence of a specific treatment, new symptomatic therapeutic resources have been recently introduced in order to modify the management and in some cases to improve the condition of patients with ALS. Among these resources, it is worth outlining those which are devoted to the medulla trouble such as the permanent gastric tubes. The respiratory insufficiency is an early phenomenon and is considered the main prognostic factor. Its management should become soon one of the main therapeutic targets. In some countries the indications of devices for respiratory assistance at home are not rare. It is not impossible that in a near future we shall propose such devices to our patients. Beside these therapeutic resources which are difficult to manage, there are numerous drugs used to improve spasticity, cramps or drooling. Physiotherapy and speech therapy are of great importance. The management of such patients needs the cooperation of all the medical and paramedical members and the family whose role is essential.}, }
@article {pmid2471992, year = {1989}, author = {Sarnat, HB and Jacob, P and Jiménez, C}, title = {[Spinal muscular atrophy: disappearance of RNA fluorescence of degenerating motor neurons. An acridine orange study].}, journal = {Revue neurologique}, volume = {145}, number = {4}, pages = {305-311}, pmid = {2471992}, issn = {0035-3787}, mesh = {Acridine Orange ; Child, Preschool ; Female ; Fluorescence ; Humans ; Infant ; Infant, Newborn ; Male ; Motor Neurons/*analysis ; Muscular Atrophy, Spinal/*genetics ; RNA/*analysis/genetics ; Spinal Muscular Atrophies of Childhood/*genetics/pathology ; Transcription, Genetic ; }, abstract = {The histochemical distribution of nucleic acids has been studied in degenerating motor neurons of 9 children who died with spinal muscular atrophy, using the fluorochrome acridine orange. Ribonucleic acid (RNA) fluorescence disappeared abruptly from involved motor neurons without chromatolysis, attenuation of intensity, or other intermediate transitions that follow axotomy or hypoxic insults. We found a nearly identical pattern in 3 adults with amyotrophic lateral sclerosis. The findings in older subjects are complicated, however, by the presence of cytoplasmic lipofuscin. The autofluorescence of this pigment is inhibited by acridine orange. Our results support the hypothesis that spinal muscular atrophy is a disturbance of the genetically coded mechanism that arrests the programmed physiological death of surplus motor neuroblasts after a certain time in embryonic life, so that the normal lethal developmental process becomes pathological by persisting postnatally. A failure of RNA transcription seems to be primary and results in a failure of synthesis of neurotransmitters, of enzymes, and of cytoplasmic proteins. Consequent inanition leads to cell death.}, }
@article {pmid3069072, year = {1988}, author = {Beauvais, P and Roubergue, A and de Villemeur, TB and Richardet, JM}, title = {[Progressive bulbopontine paralysis in children].}, journal = {Archives francaises de pediatrie}, volume = {45}, number = {9}, pages = {653-655}, pmid = {3069072}, issn = {0003-9764}, mesh = {Bulbar Palsy, Progressive/genetics/*physiopathology ; Child ; Child, Preschool ; Female ; Humans ; Male ; Time Factors ; }, abstract = {A case of pons-bulbar palsy in a 10 year-old girl is reported. The authors insist on the fact that motor cranial nerve nuclear dysfunction was isolated, without any pyramidal tract disorder. They also emphasize the slow course of the disease, which after one year of quick progression was stable for the next 5 years. Nineteen identical cases were found in the literature. From this nosographic group, one must exclude patients with associated lateral spinal tract dysfunction: these patients must be discussed with the juvenile or infantile amyotrophic lateral sclerosis group. The heterogeneity of the pons-bulbar paralysis group is also underlined: the course may be quickly fatal or, on the contrary, protracted for a long time; genetic transmission is also quite variable.}, }
@article {pmid3062085, year = {1988}, author = {Pascuzzi, RM}, title = {Amyotrophic lateral sclerosis.}, journal = {Indiana medicine : the journal of the Indiana State Medical Association}, volume = {81}, number = {7}, pages = {607-612}, pmid = {3062085}, issn = {0746-8288}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*physiopathology ; Humans ; Motor Neurons/physiopathology ; }, }
@article {pmid3043614, year = {1988}, author = {Neau, JP and Robert, R and Antoun, S and Pourrat, O and Gil, R and Lefevre, JP}, title = {[Diaphragmatic paralysis disclosed by acute respiratory failure. Apropos of a case of amyotrophic lateral sclerosis and review of the literature].}, journal = {La Revue de medecine interne}, volume = {9}, number = {3}, pages = {260-262}, doi = {10.1016/s0248-8663(88)80091-2}, pmid = {3043614}, issn = {0248-8663}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Humans ; Male ; Respiratory Insufficiency/*etiology ; Respiratory Paralysis/complications/*etiology ; }, abstract = {A case of acute respiratory failure revealing amyotrophic lateral sclerosis is reported. The other neurological diseases with diaphragmatic paralysis are recalled.}, }
@article {pmid3062350, year = {1988}, author = {Jones, KJ}, title = {Steroid hormones and neurotrophism: relationship to nerve injury.}, journal = {Metabolic brain disease}, volume = {3}, number = {1}, pages = {1-18}, pmid = {3062350}, issn = {0885-7490}, support = {6 507 RR05266-24/RR/NCRR NIH HHS/United States ; }, mesh = {Androgens/*pharmacology ; Animals ; Estradiol/*pharmacology ; Female ; Male ; Neurons/*drug effects ; *Trauma, Nervous System ; Ventromedial Hypothalamic Nucleus/cytology/drug effects ; }, abstract = {Current data on the neurotrophic effects of steroid hormones suggest that, in brain and spinal cord regions containing receptor systems, steroids act at the level of RNA and protein synthesis to effect metabolic changes associated with nerve-cell survival, elaboration/maintenance of dendritic and axonal processes, synaptogenesis, and neurotransmission. While many of these effects appear to be associated with the neuroanatomical systems involved in the endocrine and behavioral aspects of reproduction, evidence does exist for similar neurotrophic effects outside the reproductive sphere. Both estrogens and androgens appear to exert this stimulatory, growthlike effect on target neurons. The effects of progesterone are not discussed in this review because relatively little information is available regarding the independent effects of progesterone on the brain. We have just completed a study (Jones et al., 1987b) which suggests that progesterone may act independently in the brain to affect protein synthesis. A number of conclusions concerning the mechanism of steroid action in producing trophic effects on neurons can be drawn. First, the time course of hormone action is similar to that found in nonneural target tissue, such as the uterus. Second, steroid hormones act on neurons through receptor-mediated genomic activation. Third, this effect on the genome appears to be at the level of both transcription and translation. Fourth, there is brain-region specificity in the gene products resulting from steroid hormone administration. Finally, short-term exposure to estrogens or androgens generally results in an anabolic response within target neurons. The brain and spinal cord, injured either by disease or by experimentally induced trauma, is responsive in a reparative manner to exogenous and/or endogenous gonadal steroid hormones. The mechanism underlying this therapeutic role of steroids on damaged neurons is not known but has been postulated to involve direct action of steroid hormones or target neurons. It has been hypothesized that two diseases, Alzheimer's and ALS, may be related to steroid hormone/receptor deficiencies. In this regard, Appel (1981) has suggested that putative "neurotrophic hormones" acting at the synapse may be critical in maintaining the neural networks affected in ALS, Alzheimer's disease, and parkinsonism. Extending that hypothesis to include direct action of such putative hormones within the cell body and at the level of the genome, the evidence presented in this discussion would argue that possible candidates could be gonadal steroids.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid3277599, year = {1988}, author = {Mitsumoto, H and Hanson, MR and Chad, DA}, title = {Amyotrophic lateral sclerosis. Recent advances in pathogenesis and therapeutic trials.}, journal = {Archives of neurology}, volume = {45}, number = {2}, pages = {189-202}, doi = {10.1001/archneur.1988.00520260077025}, pmid = {3277599}, issn = {0003-9942}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/etiology/metabolism ; Animals ; Diagnosis, Differential ; Disease Models, Animal ; Humans ; }, abstract = {We reviewed the current status of pathogenesis and therapeutic trials in amyotrophic lateral sclerosis (ALS). Clinical studies have identified several rare but definable causes for apparent ALS. Certain clinical features previously considered unlikely to occur in ALS are found on careful examination. Epidemiologic surveillance and recent studies of neurotoxic plant seeds used in Guam have shed light on the pathogenesis of endemic ALS. Extensive analyses of biochemical, metabolic, immunologic, viral, and toxic factors have provided provocative results requiring further studies. Reflecting on some of these hypotheses, therapeutic trials have been performed more vigorously than ever. Amyotrophic lateral sclerosis is now investigated at the molecular genetic level. Human autopsy and experimental animal studies have expanded our understanding of basic mechanisms involving motoneuronal degeneration. In the future, we must continue a relentless search for the pathogenesis of ALS, prospective clinical studies to define the limits of ALS, and well-designed, controlled therapeutic trials.}, }
@article {pmid2465598, year = {1988}, author = {Kurland, LT}, title = {Amyotrophic lateral sclerosis and Parkinson's disease complex on Guam linked to an environmental neurotoxin.}, journal = {Trends in neurosciences}, volume = {11}, number = {2}, pages = {51-54}, doi = {10.1016/0166-2236(88)90163-4}, pmid = {2465598}, issn = {0166-2236}, mesh = {Amino Acids, Diamino/*toxicity ; Amyotrophic Lateral Sclerosis/*chemically induced/epidemiology ; Cyanobacteria Toxins ; Guam ; Humans ; *Neurotoxins ; Parkinson Disease, Secondary/*chemically induced/epidemiology ; *Plant Poisoning ; }, }
@article {pmid3285771, year = {1988}, author = {Stewart, SS and Appel, SH}, title = {Trophic factors in neurologic disease.}, journal = {Annual review of medicine}, volume = {39}, number = {}, pages = {193-201}, doi = {10.1146/annurev.me.39.020188.001205}, pmid = {3285771}, issn = {0066-4219}, mesh = {Alzheimer Disease/*etiology ; Amyotrophic Lateral Sclerosis/*etiology ; Humans ; *Nerve Growth Factors ; Parkinson Disease/*etiology ; }, abstract = {Recent studies suggest that diffusible factors released by neural targets enhance the survival, growth, and differentiation of neurons both peripherally and in the central nervous system. Evidence for such trophic factors exists for many of the neural systems involved in the degenerative neurologic diseases Alzheimer's disease, parkinsonism, and amyotrophic lateral sclerosis. It is our hypothesis that for each of these disorders there is both a primary insult and a secondary effect. The primary insult may have multiple etiologies, but the secondary effect is the result of retrograde degeneration. Such retrograde degeneration occurs because of an impairment of trophic factor function or an inadequacy of trophic effects to keep pace with the primary destructive process. Accordingly, it may be possible to exploit such trophic mechanisms to define further the pathobiology of neural degeneration and to develop specific treatments for currently incurable illnesses.}, }
@article {pmid3068777, year = {1988}, author = {Schoenen, J}, title = {[Amyotrophic lateral sclerosis. Physiopathology and experimental models. Chemical neuroanatomy of the human spinal cord: applications to pathologic cases including amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {144}, number = {11}, pages = {664-671}, pmid = {3068777}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Humans ; Spinal Cord/analysis/*pathology ; }, abstract = {The purpose of this paper is to illustrate the advantages of the chemo-morphological approach in the study of pathological material. On one hand, the analysis of selected pathological cases (amputations, spinal transections) is able to provide invaluable information concerning the cells of origin of certain spinal transmitters in the human being. On the other hand, chemical neuropathology allows a more precise identification of the neuronal nets or types that are involved in a disease process. This advantage is underlined by studies performed in amyotrophic lateral sclerosis. In this condition, certain modifications, such as the reductions of acetylcholinesterase, choline acetyltransferase, cholinergic muscarinic, glycine or TRH receptors, are probably a consequence of motoneuron degeneration. In contradistinction, other findings, such as specific metabolic changes of motoneurons or early disappearance of SP-containing fibers in lamina IX, might be relevant for the pathogenesis of the disease.}, }
@article {pmid3068774, year = {1988}, author = {Rowland, LP}, title = {Research progress in motor neuron diseases.}, journal = {Revue neurologique}, volume = {144}, number = {11}, pages = {623-629}, pmid = {3068774}, issn = {0035-3787}, support = {NS-11766/NS/NINDS NIH HHS/United States ; RR-00645/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; *Motor Neurons ; *Neuromuscular Diseases ; }, abstract = {The cause of amyotrophic lateral sclerosis is not known. However, there is increasing evidence that the syndrome has more than one cause. Many of the different categories of causation are dealt with in the papers presented in this symposium - including genetic and acquired forms, and multiple categories within those two major classes. The diversity of different causes gives hope that progress in one field will be followed by elucidation of other fields. As examples, there has been progress in understanding the genetic forms due to hexosaminidase deficiency and molecular genetics is being applied to other heritable motor neuron diseases. Among acquired diseases, in different parts of the world, there has been new evidence that persistent viral infection may be important, that dietary constituents may be important, and that paraproteinemia may be important.}, }
@article {pmid2965893, year = {1988}, author = {Oyanagi, K and Ikuta, F}, title = {[Morphometric investigation on the neostriatum and spinal cord in extrapyramidal degenerative diseases and amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {40}, number = {1}, pages = {47-54}, pmid = {2965893}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Basal Ganglia Diseases/*pathology ; Corpus Striatum/*pathology ; Humans ; Huntington Disease/pathology ; Nerve Degeneration ; Spinal Cord/*pathology ; Supranuclear Palsy, Progressive/pathology ; }, }
@article {pmid3140337, year = {1987}, author = {Hudson, AJ}, title = {Outpatient management of amyotrophic lateral sclerosis.}, journal = {Seminars in neurology}, volume = {7}, number = {4}, pages = {344-351}, doi = {10.1055/s-2008-1041435}, pmid = {3140337}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/therapy ; Deglutition ; Enteral Nutrition ; Humans ; Lung Diseases/etiology/therapy ; *Outpatient Clinics, Hospital ; }, abstract = {The patient with ALS can be managed almost entirely as an outpatient by a team consisting of a nurse, physiotherapist, occupational therapist, speech pathologist, nutritionist, respirologist, social worker, and certain other consultants from time to time. The team's goal is to maintain physical function and extend the useful life of the patient through the skills that the team members are trained to provide. Pulmonary function tests, especially spirometry, should be done at regular intervals and a modified barium swallow should also be done at least once in cases with dysphagia. It is possible with these tests to anticipate and even correct a number of hazards, such as upper airway obstruction and aspiration. Some patients are candidates for gastrostomy and tympanic and chorda tympani neurectomy, but full knowledge of their pulmonary function is essential before undertaking any operative procedure. Death in ALS is due to pulmonary failure and the choice of respirator care requires careful deliberation with the family. The neurologist and ALS team should work in close cooperation with the home care personnel in the patient's own community. Does the care of the ALS patient in any way affect survival? In the attempt to answer this question we have estimated the survival of ALS patients in southwestern Ontario, most of whom have visited our clinic over the period of 1978 to 1985, inclusive. As shown in Figure 4, there was an apparent decline in the annual mortality rate over this period, although there was no significant change in the incidence of ALS in this region.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2449630, year = {1987}, author = {Saper, CB and Wainer, BH and German, DC}, title = {Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer's disease.}, journal = {Neuroscience}, volume = {23}, number = {2}, pages = {389-398}, doi = {10.1016/0306-4522(87)90063-7}, pmid = {2449630}, issn = {0306-4522}, support = {NS17661/NS/NINDS NIH HHS/United States ; NS20030/NS/NINDS NIH HHS/United States ; NS22835/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*physiopathology ; Animals ; *Axonal Transport ; Brain Diseases/*physiopathology ; Communicable Diseases/physiopathology ; Humans ; *Nerve Degeneration ; Tetanus Toxin/metabolism ; }, abstract = {Neurons depend upon the processes of axonal and transneuronal transport for intra- and intercellular communication and trophic support. Experimental studies in the last decade have elucidated the mechanisms underlying these processes, and provided evidence for their role in the spread of viral and toxic diseases through the nervous system. Recent advances in neuroanatomy, and in the pathological study of certain degenerative conditions, such as Alzheimer's disease, suggest that the same principles may underlie the anatomical specificity of cell loss in a variety of system degenerations. In Alzheimer's disease, as well as in olivo-ponto-cerebellar atrophy, progressive supranuclear palsy, amyotrophic lateral sclerosis, primary autonomic failure of the Shy-Drager type, and other system degenerations, the main feature that marks the affected populations of neurons is their anatomical interconnectivity. We consider here the possibility that, in these conditions, the processes of axonal and transneuronal transport may subserve the transmission from neuron to neuron of a toxic or infectious agent, or alternatively that the diseases may result from the failure of normal transport of a trophic agent. This hypothesis not only provides a unifying framework in which to view a variety of seemingly disparate conditions, but also suggests certain approaches to identifying the causative agents.}, }
@article {pmid3313811, year = {1987}, author = {Gold, BG}, title = {The pathophysiology of proximal neurofilamentous giant axonal swellings: implications for the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Toxicology}, volume = {46}, number = {2}, pages = {125-139}, doi = {10.1016/0300-483x(87)90123-5}, pmid = {3313811}, issn = {0300-483X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Axons/drug effects/*physiopathology ; Cytoskeleton/*physiopathology ; Electrophysiology ; Hexanones/pharmacology ; Humans ; Intermediate Filaments/drug effects/*physiopathology ; Nitriles/pharmacology ; }, abstract = {Neurofilamentous giant axonal swellings are observed in a number of human disorders, although they can manifest at different locations (i.e. proximal or distal) along the axon. Recent advances in understanding the pathogenesis of these changes has resulted from correlations of ultrastructural changes with abnormalities in the axonal transport of neurofilament proteins in experimental models produced by toxic chemicals. Using single, high doses of either acrylamide or 2,5-hexanedione, a reduction in neurofilament transport has been shown in the rat sciatic nerve. In contrast to the distal axonal swellings observed upon repeated exposures to these agents, modest proximal axonal swellings containing increased neurofilament content are found following high dose exposures. Thus, regardless of the location of swelling production, a defect in slow transport appears to underlie swelling formation. beta,beta'-Iminodipropionitrile (IDPN) produces proximal neurofilamentous giant axonal swellings which are indistinguishable from those observed in some patients with amyotrophic lateral sclerosis (ALS). Although not a model for ALS, IDPN provides a means to study the functional consequences of proximal giant axonal swellings. Intracellular recordings from IDPN-intoxicated cats reveal a number of abnormalities which may have electrophysiological counterparts in ALS, suggesting that the swellings may be important in the expression of the disease. Although axonal degeneration is rarely observed in the cat, perikaryal recordings reveal a number of alterations which are strikingly similar to those obtained from chromatolytic motor neurons following nerve transection. A perturbation of "trophic" signals from the periphery may be involved in the generation of axotomy-like changes in IDPN-intoxicated cats.}, }
@article {pmid3124710, year = {1987}, author = {}, title = {Current status of thyrotropin-releasing hormone therapy in amyotrophic lateral sclerosis. Committee on Health Care Issues, American Neurological Association.}, journal = {Annals of neurology}, volume = {22}, number = {4}, pages = {541-543}, doi = {10.1002/ana.410220416}, pmid = {3124710}, issn = {0364-5134}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Double-Blind Method ; Humans ; Thyrotropin-Releasing Hormone/adverse effects/metabolism/*therapeutic use ; }, }
@article {pmid3323409, year = {1987}, author = {Sears, TA}, title = {Structural changes in intercostal motoneurones following axotomy.}, journal = {The Journal of experimental biology}, volume = {132}, number = {}, pages = {93-109}, doi = {10.1242/jeb.132.1.93}, pmid = {3323409}, issn = {0022-0949}, mesh = {Animals ; Axons/physiology ; Humans ; Intercostal Nerves/*anatomy &amp; histology ; Motor Neurons/pathology/physiology/*ultrastructure ; Nerve Degeneration ; Neuromuscular Diseases/*etiology ; Thoracic Nerves/*anatomy &amp; histology ; }, abstract = {Motoneurone disease (MND or amyotrophic lateral sclerosis) is a paralysing disease of unknown cause involving progressive, widespread muscle atrophy due to degeneration of spinal and other motoneurones and an accompanying loss of Betz cells in the motor cortex. A current hypothesis attributes the disease to the loss of a muscle-derived neurotrophic factor acting in concert with the normal age-related deterioration and loss of motoneurones. The roots of this hypothesis are traced through research based mainly on the developing neuromuscular system, and in particular on the age-related processes of natural motoneurone death during embryogenesis: the neonatal reduction of polyneuronal innervation and the age-dependent variations in motor nerve terminal sprouting in response to partial denervation. A consideration of the disease process itself in association with the review of earlier work provide the background for the present work which reexamines ultrastructurally the chromatolytic and later responses to axotomy and the muscle-dependent factors responsible for the reformation of the Nissl bodies.}, }
@article {pmid3318745, year = {1987}, author = {Morita, K and Kaiya, H and Ikeda, T and Namba, M}, title = {Presenile dementia combined with amyotrophy: a review of 34 Japanese cases.}, journal = {Archives of gerontology and geriatrics}, volume = {6}, number = {3}, pages = {263-277}, doi = {10.1016/0167-4943(87)90026-4}, pmid = {3318745}, issn = {0167-4943}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Dementia/*complications/diagnosis ; Diagnosis, Differential ; Electroencephalography ; Humans ; Male ; Middle Aged ; }, abstract = {Thirty-four Japanese cases exhibiting presenile dementia combined with amyotrophy were reviewed with four case reports. The clinical feature of dementia was generally unspecific and could not be clearly diagnosed as Pick's disease or Alzheimer's disease. But most of these patients did not exhibit manifest visual agnosia or apraxia suggesting 'posterior dementia'. Brain CTs showed mild diffuse atrophy with non-circumscribed fronto-temporal accentuation. PSD (periodic synchronous discharge on EEG) as seen in Creutzfeldt-Jakob disease (CJD) was not noted in any of these cases. Although individual neurological findings were not contradictory to amyotrophy lateral sclerosis (ALS), the clinicopathologic findings, on the whole, could be regarded as indicative of an atypical spinal progressive muscular atrophy. The brain pathology lacked specific changes. A mild to moderate degree of glial proliferation, subcortical gliosis and a moderate spongy state of the upper cortical layers were seen mainly in the fronto-temporal area. Nigral degeneration was observed in half of the cases. No Pick's cells, Pick's balls, Alzheimer's neurofibrillary changes or senile plaques were observed except in two cases, in whom it could be regarded as physiological. Brain weight was lighter than that of normal Japanese but heavier than that of Pick's disease, Alzheimer's disease or CJD. The brain pathology was similar to that of progressive subcortical gliosis. We have concluded that the disease under discussion might be a new disease entity.}, }
@article {pmid3315142, year = {1987}, author = {Spencer, PS}, title = {Guam ALS/parkinsonism-dementia: a long-latency neurotoxic disorder caused by "slow toxin(s)" in food?.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {14}, number = {3 Suppl}, pages = {347-357}, doi = {10.1017/s0317167100037732}, pmid = {3315142}, issn = {0317-1671}, support = {NS19611/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*epidemiology/etiology/physiopathology ; Amyotrophic Lateral Sclerosis/*epidemiology/etiology/physiopathology ; *Diet ; Guam ; Humans ; Lathyrism/physiopathology ; Neurotoxins/adverse effects ; Parkinson Disease, Secondary/chemically induced/*epidemiology/physiopathology ; *Plants, Toxic ; }, abstract = {Parkinsonism (P) with progressive dementia (D) of the Alzheimer type is recognized as a clinical variant of a form of amyotrophic lateral sclerosis (ALS) that has occurred in high incidence among the Chamorro people of the islands of Guam and Rota in the Marianas chain of Micronesia. The declining annual incidence, upward shifting of the age of onset, narrowing of the sex ratio, and occurrence of the disease among non-Chamorros, point to a disappearing environmental causation peculiar to the traditional culture of these islands. Evidence is presented in support of the proposal that heavy use of certain toxic plants, notably cycads, a traditional source of food and medicine for the Chamorro people, plays an important etiological role. Clinical and epidemiological approaches are offered to test for a relationship between ALS/P-D and long-latency plant toxicity.}, }
@article {pmid3306367, year = {1987}, author = {Bradley, WG}, title = {Recent views on amyotrophic lateral sclerosis with emphasis on electrophysiological studies.}, journal = {Muscle &amp; nerve}, volume = {10}, number = {6}, pages = {490-502}, doi = {10.1002/mus.880100603}, pmid = {3306367}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Anterior Horn Cells/*physiology ; Electrophysiology ; Humans ; Motor Neurons/*physiology ; Muscles/*physiopathology ; Neuromuscular Diseases/physiopathology ; Poliomyelitis/complications ; }, abstract = {Peripheral electrophysiological studies are of particular value of elucidating the anatomy and pathophysiology of neuromuscular diseases, but they can also help in providing clues to the etiology of the disease. Recent studies of the motor units in chronic denervating conditions including amyotrophic lateral sclerosis (ALS) are reviewed. These indicate that reinnervation is a relatively active process which compensates for the progressive loss of motoneurons in ALS until more than 50% of the motoneurons have died. There seems to be no predilection for death of motoneurons of any particular size in ALS. Fasciculations may arise both proximally and distally. The dying-back change is not a major feature of ALS. These and other data cast doubt on the etiological theories that ALS arises from premature aging of motoneurons, deficiency of motoneuron trophic factors, or an inhibitor of a motoneuronal sprouting factor, and point to the need to study metabolic changes intrinsic to the motoneuron in ALS.}, }
@article {pmid2438109, year = {1987}, author = {Sieb, JP and Jerusalem, F and Fresmann, J}, title = {[Symptomatic therapy in amyotrophic lateral sclerosis].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {112}, number = {19}, pages = {769-772}, doi = {10.1055/s-2008-1068139}, pmid = {2438109}, issn = {0012-0472}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Humans ; Palliative Care/*methods ; Terminal Care/methods ; }, }
@article {pmid11681402, year = {1987}, author = {Sanjak, M and Reddan, W and Brooks, BR}, title = {Role of muscular exercise in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {5}, number = {2}, pages = {251-68, vi}, pmid = {11681402}, issn = {0733-8619}, mesh = {Adult ; Energy Metabolism/physiology ; Exercise/*physiology ; Female ; Humans ; Isometric Contraction/physiology ; Male ; Middle Aged ; Motor Neuron Disease/physiopathology/*rehabilitation ; Motor Neurons/physiology ; Muscle Denervation/rehabilitation ; Oxygen Consumption/physiology ; *Physical Therapy Modalities ; }, abstract = {The general, systemic, and specific neuromuscular adaptation to physical exercise and training in healthy individuals is reviewed with application to individuals with neuromuscular disease in general and ALS in particular. A pilot study utilizing patients with ALS suggests the cardiopulmonary response to acute exercise is similar to normal individuals. However, a case study of a training response suggests the success of neuromuscular adaptation will be dependent upon the degree of motor neuron involvement.}, }
@article {pmid11681401, year = {1987}, author = {DePaul, R and Abbs, JH}, title = {Manifestations of ALS in the cranial motor nerves: dynametric, neuropathologic, and speech motor data.}, journal = {Neurologic clinics}, volume = {5}, number = {2}, pages = {231-50, v-vi}, pmid = {11681401}, issn = {0733-8619}, support = {HD-03352/HD/NICHD NIH HHS/United States ; NS-13274/NS/NINDS NIH HHS/United States ; }, mesh = {Cranial Nerve Diseases/*diagnosis/pathology/physiopathology ; Cranial Nerves/pathology/physiopathology ; Dysarthria/*diagnosis/pathology/physiopathology ; Humans ; Motor Neuron Disease/*diagnosis/pathology/physiopathology ; Motor Neurons/pathology/*physiology ; }, abstract = {Although our knowledge of ALS manifestations in the cranial motor nerves is limited, available retrospective and prospective reports, including associated neuropathology in the cranial motor nerves, clearly indicate fruitful directions for additional biologically based studies. These data further demonstrate that the brain stem, with multiple discrete motoneuron groups, is amenable to parallel behavioral, anatomic, histochemical, and pharmacologic analyses as a means to enhance clinical diagnosis and management of ALS. Moreover, the contribution of such studies to the further understanding of the underlying mechanisms of ALS may be of even greater potential.}, }
@article {pmid3550594, year = {1987}, author = {Neal, GD and Clarke, LR}, title = {Neuromuscular disorders.}, journal = {Otolaryngologic clinics of North America}, volume = {20}, number = {1}, pages = {195-201}, pmid = {3550594}, issn = {0030-6665}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications ; Child ; Female ; Humans ; Infant, Newborn ; Male ; Myasthenia Gravis/complications ; Neuromuscular Diseases/*complications ; Otorhinolaryngologic Diseases/*etiology ; }, abstract = {Laryngeal innervation and the functional disorders associated with lower motor neuron paralyses are reviewed. Causes of diffuse denervation, such as drug toxicities and demyelinating disease, are also discussed. Symptoms and treatment of myasthenia gravis, amyotrophic lateral sclerosis, and botulism are discussed as examples of neuromuscular blockade at various levels.}, }
@article {pmid3550417, year = {1987}, author = {Braun, SR}, title = {Respiratory system in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {9-31}, pmid = {3550417}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology/therapy ; Biomechanical Phenomena ; Cough/physiopathology ; Humans ; Respiration ; Respiration, Artificial/methods ; Respiratory Function Tests ; Respiratory Insufficiency/diagnosis/physiopathology/therapy ; Respiratory Muscles/physiopathology ; Respiratory System/*physiopathology ; }, abstract = {Failure of the respiratory system is the most common cause of death in amyotrophic lateral sclerosis. This is due to weakened respiratory musculature resulting in respiratory failure, ineffective cough, and failure to protect the lungs from aspiration. Treatment is only supportive at present, but mechanical ventilation with either negative or positive pressure offer some life-extending possibilities. The respiratory system should be closely monitored as early identification of problems may allow better insight into the immediate prognosis.}, }
@article {pmid3550416, year = {1987}, author = {Mitchell, JD}, title = {Heavy metals and trace elements in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {43-60}, pmid = {3550416}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism ; Animals ; Female ; Humans ; Lead Poisoning/complications/metabolism ; Male ; Mercury Poisoning/complications/metabolism ; Metals/*poisoning ; Occupational Diseases/complications/metabolism ; Trace Elements/deficiency/metabolism/*poisoning ; }, abstract = {The first descriptions of the clinical picture of ALS arose from knowledge of the toxic effects of lead on the nervous system. The place of lead in the etiology of ALS remains controversial over 150 years later. More recently, trace element studies have provided a novel approach in our attempts to demonstrate a fundamental metabolic abnormality in motor neurons. The evidence that has been presented in this general area is reviewed in this article.}, }
@article {pmid3550415, year = {1987}, author = {Melmed, S and Braunstein, GD}, title = {Endocrine function in amyotrophic lateral sclerosis. A review.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {33-42}, pmid = {3550415}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*physiopathology ; Calcium/physiology ; Endocrine Glands/*physiopathology ; Female ; Humans ; Hypothalamo-Hypophyseal System/physiopathology ; Male ; Ovary/physiopathology ; Pancreas/physiopathology ; Testis/physiopathology ; Thyroid Gland/physiopathology ; }, abstract = {Endocrine and metabolic disturbances found in patients with ALS are reviewed. Pancreatic function, carbohydrate tolerance, calcium metabolism, testicular and ovarian thyroid and pituitary function are discussed. It is difficult to interpret these various metabolic dysfunctions as being either an epiphenomenon of ALS or possibly a clue to etiology of the disease. The data are reviewed and interpreted with these constraints.}, }
@article {pmid3550414, year = {1987}, author = {Andres, PL and Thibodeau, LM and Finison, LJ and Munsat, TL}, title = {Quantitative assessment of neuromuscular deficit in ALS.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {125-141}, pmid = {3550414}, issn = {0733-8619}, support = {MO1RR000054/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Humans ; Muscle Contraction ; Muscles/*physiopathology ; Neurologic Examination/methods ; Time Factors ; }, abstract = {Several criteria must be met in developing a test battery forr ALS. First, the test items should be designed to answer the specific questions being asked. If questions involve the amount and rate of deterioration, then the test items should generate interval data and show evidence that they reflect change in the disease itself. Second, the reliability of the test items should be carefully determined. Are the variances due to testing errors such as inconsistent positioning or changes in verbal instructions; or do they reflect human performance variation? Third, the test items must be sensitive to small changes, and one must be able to test the very strong as well as the severely debilitated patient. The TQNE was designed to measure degree of disease progression in ALS. The major portion of the protocol consists of isometric force measurement using an electronic strain gauge. Other quantitative segments include tests of pulmonary function, speech rates, and timed activities. Using z-score transformations, we have summarized these test items into five megascores: pulmonary function, bulbar function, timed hand activities, arm strength, and leg strength. Megascores have been used to characterize the natural history of the disease and to judge therapeutic efficacy. Quantitative methods to measure deficit in neuromuscular disease lag far behind other technologic advances in medical research. Future advances in the measurement of neuromuscular deficit depend on the commitment of researchers to invest the time and resources necessary to develop more sensitive and reliable testing techniques.}, }
@article {pmid3104751, year = {1987}, author = {Munsat, TL and Taft, J and Kasdon, D}, title = {Intrathecal thyrotropin-releasing hormone in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {159-170}, pmid = {3104751}, issn = {0733-8619}, support = {MO1RR00054/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*drug therapy ; Drug Evaluation ; Humans ; Infusion Pumps ; Injections, Spinal ; Kinetics ; Thyrotropin-Releasing Hormone/*administration &amp; dosage/adverse effects/metabolism ; Time Factors ; }, abstract = {Thyrotropin releasing hormone (TRH) has potential therapeutic applications in amyotrophic lateral sclerosis (ALS) and related diseases because of its function as a neuroregulator of the anterior horn cell. However, its therapeutic potential, and that of other neuropeptides, is reduced by the blood-brain barrier that limits access to neuronal cells. We have thus explored the direct intrathecal administration of TRH in ALS, with both short-term boluses and infusions and chronic constant infusions. Our experience suggests that this approach is safe, has high patient acceptance, and is worthy of more careful evaluation.}, }
@article {pmid3556088, year = {1987}, author = {Price, DL and Cork, LC and Struble, RG and Kitt, CA and Walker, LC and Powers, RE and Whitehouse, PJ and Griffin, JW}, title = {Dysfunction and death of neurons in human degenerative neurological diseases and in animal models.}, journal = {Ciba Foundation symposium}, volume = {126}, number = {}, pages = {30-48}, doi = {10.1002/9780470513422.ch3}, pmid = {3556088}, issn = {0300-5208}, support = {NS 07179/NS/NINDS NIH HHS/United States ; NS 10580/NS/NINDS NIH HHS/United States ; NS 15721/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Basal Ganglia Diseases/pathology/physiopathology ; Brain Diseases/pathology/physiopathology ; Cell Survival ; Cerebral Cortex ; Humans ; Motor Neurons/pathology/physiology ; *Nerve Degeneration ; Nervous System Diseases/*pathology/physiopathology ; Neuromuscular Diseases/pathology/physiopathology ; Neurons/*pathology/physiology ; }, abstract = {The human neurological disorders--amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)--share certain features: they occur in later stages of adult life; are slowly progressive; and involve specific groups of nerve cells. Different clinical syndromes result from dysfunction and death of these specific groups of neurons. In ALS, patients are weak due to disease of motor neurons in the spinal cord. The clinical features of PD, e.g. slow movements, tremor and rigidity, are attributed, in part, to degeneration of dopaminergic neurons of the substantia nigra. Impairments of cognition and memory in AD result from disease of neurons in a number of regions, including brainstem, basal forebrain, amygdala, hippocampus, and neocortex. In each of these diseases, affected neurons exhibit abnormalities of the neuronal cytoskeleton: in ALS, neurofilaments accumulate and distend proximal motor axons; in PD, nigral perikarya show Lewy bodies-intracytoplasmic inclusions containing neurofilament antigens; in AD, neurons develop neurofibrillary tangles, Hirano bodies, granulovacuolar degeneration and filament-filled neurites in plaques. Certain features of ALS, PD and AD are recapitulated in animal models, three of which are described in this review. Hereditary canine spinal muscular atrophy (HCSMA), a dominantly inherited motor neuron disease, shows many clinical and pathological features in common with ALS, including weakness, muscle atrophy, neurofilamentous swellings of proximal axons, impaired transport of neurofilament proteins, and degeneration of motor neurons. In primates, intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome due to injury of nigral dopaminergic neurons and associated denervation of the striatum. Finally, aged macaques exhibit memory deficits, and their cerebral cortices show senile plaques and filament-filled neurites derived from a variety of transmitter-specific populations of nerve cells. In human diseases, the causes and mechanisms leading to dysfunction and death of nerve cells are unknown. Investigators have begun using a variety of techniques derived from neurobiology to study animal models in an effort to clarify the mechanisms, evolutions, and consequences of structural-chemical abnormalities occurring in different neuronal systems implicated in human disease. Understanding such processes in these models should provide important new insights into the pathogeneses of similar processes occurring in ALS, PD and AD.}, }
@article {pmid3556087, year = {1987}, author = {Agid, Y and Blin, J}, title = {Nerve cell death in degenerative diseases of the central nervous system: clinical aspects.}, journal = {Ciba Foundation symposium}, volume = {126}, number = {}, pages = {3-29}, doi = {10.1002/9780470513422.ch2}, pmid = {3556087}, issn = {0300-5208}, mesh = {Adult ; Cell Survival ; Central Nervous System Diseases/complications/*pathology ; Humans ; Models, Neurological ; *Nerve Degeneration ; Neurons/*pathology ; Time Factors ; }, abstract = {The origin of degenerative diseases of the central nervous system lies in genetic and acquired disorders. Analysis of the clinical characteristics of diseases affecting specific neuronal systems may help us to understand their pathogenesis. The stereotyped symptomatology characteristic of most degenerative diseases results from neuronal death in specific pathways: pyramidal tract and motor neurons in amyotrophic lateral sclerosis, nigrostriatal dopamine system in Parkinson's disease, posterior and lateral columns of the spinal cord in Friedreich's ataxia, etc. This suggests that these neurons are sensitive to pathological processes that are still unknown. Progression of the disease, whether linear or not, is slow, but it is more rapid than similar effects due to ageing. This indicates either that the environmental cause of degeneration (if it exists) is continuously present or that a vital process has been once and for all disrupted, perhaps at the level of the genome, causing insufficient production of essential proteins, or accumulation of eventually toxic metabolites. Symptoms generally appear during adulthood, i.e. after normal differentiation has taken place, and after a considerable number of neurons have already been damaged. The initiation of neuronal death precedes the appearance of the first symptoms.}, }
@article {pmid3316495, year = {1987}, author = {Perl, DP and Good, PF}, title = {The association of aluminum Alzheimer's disease, and neurofibrillary tangles.}, journal = {Journal of neural transmission. Supplementum}, volume = {24}, number = {}, pages = {205-211}, pmid = {3316495}, issn = {0303-6995}, mesh = {Aluminum/*adverse effects ; Alzheimer Disease/*chemically induced ; Animals ; Brain/drug effects ; Humans ; Motor Neurons/drug effects ; Nerve Degeneration/drug effects ; Nervous System Diseases/chemically induced ; Neurofibrils/*drug effects ; Rabbits ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disease characterized by the development of large numbers of neurofibrillary tangles in certain neuronal populations. Aluminum salts inoculated into experimental animals produce neurofilamentous lesions which are similar, but not identical, to the neurofibrillary tangle of Alzheimer's disease. Although a few reports suggest evidence of increased amounts of aluminum in the brains of Alzheimer's disease victims, such bulk analysis studies have been difficult to replicate. Using scanning electron microscopy with x-ray spectrometry, we have identified accumulations of aluminum in neurofibrillary tangle-bearing neurons of Alzheimer's disease. Similar accumulations have been identified in the neurofibrillary tangle-bearing neurons found in the brains of indigenous natives of Guam who suffer from parkinsonism with dementia and from amyotrophic lateral sclerosis. This ongoing research still cannot ascribe a causal role of aluminum in the pathogenesis of the neurofibrillary tangle; however, it does suggest that environmental factors may play an important part in the formation of this abnormality.}, }
@article {pmid2437770, year = {1987}, author = {Henderson, CE}, title = {Neurite-promoting factors for spinal neurons: their possible importance for the understanding of amyotrophic lateral sclerosis and the spinal muscular atrophies.}, journal = {Advances in experimental medicine and biology}, volume = {209}, number = {}, pages = {59-64}, doi = {10.1007/978-1-4684-5302-7_9}, pmid = {2437770}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Axonal Transport ; Cell Survival ; Chick Embryo ; Denervation ; Humans ; Motor Neurons/*physiopathology ; Muscles/*analysis ; Muscular Atrophy/*physiopathology ; Nerve Growth Factors/*physiology ; Neuromuscular Junction/*physiopathology ; Rats ; }, }
@article {pmid3008639, year = {1986}, author = {Goldman, JE and Yen, SH}, title = {Cytoskeletal protein abnormalities in neurodegenerative diseases.}, journal = {Annals of neurology}, volume = {19}, number = {3}, pages = {209-223}, doi = {10.1002/ana.410190302}, pmid = {3008639}, issn = {0364-5134}, support = {AG01136/AG/NIA NIH HHS/United States ; AG05386/AG/NIA NIH HHS/United States ; NS17125/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axons/metabolism ; Biological Transport ; Contractile Proteins/metabolism ; Cytoskeletal Proteins/*metabolism ; Dementia/pathology ; Forecasting ; Histocytochemistry ; Humans ; Immunochemistry ; Inclusion Bodies/metabolism/ultrastructure ; Intermediate Filament Proteins/metabolism ; Intermediate Filaments/metabolism/ultrastructure ; Microfilament Proteins/metabolism ; Microtubule Proteins/metabolism ; *Nerve Degeneration ; Nervous System Diseases/*metabolism ; Neurofibrils/metabolism/ultrastructure ; Neurons/metabolism ; }, abstract = {The nervous system is a rich source of filamentous proteins that assume critical roles in determining and maintaining neuronal form and function. Neurons contain three major classes of these cytoskeletal organelles: microtubules, intermediate filaments, and microfilaments. They also contain a variety of proteins that organize them and serve to connect them with each other. Such major neurodegenerative diseases as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as a variety of toxic neuropathies, are characterized pathologically by intraneuronal filamentous inclusions. Recent studies using biochemical and immunocytochemical techniques have established that these abnormalities represent disorganized states of the neuronal cytoskeleton and have determined some of the specific molecular constituents of these inclusions. This knowledge has led to new ways of thinking about their origins.}, }
@article {pmid3540991, year = {1986}, author = {Billingham, RE and Head, JR}, title = {Recipient treatment to overcome the allograft reaction, with special reference to nature's own solution.}, journal = {Progress in clinical and biological research}, volume = {224}, number = {}, pages = {159-185}, pmid = {3540991}, issn = {0361-7742}, support = {AI10678/AI/NIAID NIH HHS/United States ; HD18717/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Cyclosporins/therapeutic use ; Female ; *Graft Rejection/drug effects ; Humans ; Immune Tolerance ; Immunosuppression Therapy ; Maternal-Fetal Exchange ; Pregnancy/immunology ; Transplantation, Homologous ; Trophoblasts/immunology ; }, abstract = {The 6th decade of this century was particularly important for transplantation immunology. The universality of allograft rejection by normal hosts had won general acceptance and, experimentally, several means of abrogating host reactivity to allografts were discovered. These included sub-lethal whole body irradiation, administration of certain corticosteroid hormones and inoculation of very young animals with living cellular inocula from the future graft donor--i.e., classic, neonatal tolerance. The latter was particularly important since it indicated the feasibility of a specific, permanent solution to the clinical allograft problem. Radiation and drug-induced tolerance in adult subjects came along and chemical immunosuppressants, which led to successful clinical use of azathioprine. The important rediscovery of ALS pointed towards the development and clinical application of monoclonal antibodies many years later. With the development of immunogenetics and transplantation biology came recognition that the conceptus is a highly successful allograft, raising the question of how it is able to withstand rejection by its immunocompetent mother for the duration of pregnancy. Hopefully, knowledge of the principle(s) involved when they are finally elucidated will be applicable to clinical allograft recipients. Although functional hypoantigenicity of the syncytial trophoblast probably plays a major role in protecting the allogeneic conceptus, a strong case now exists that local, cell-based, immunosuppressive and immunoprotective activity within the placenta and decidua, mediated by suppressor and other cells, is important.}, }
@article {pmid3539962, year = {1986}, author = {Brody, JA and Schneider, EL}, title = {Diseases and disorders of aging: an hypothesis.}, journal = {Journal of chronic diseases}, volume = {39}, number = {11}, pages = {871-876}, doi = {10.1016/0021-9681(86)90035-4}, pmid = {3539962}, issn = {0021-9681}, mesh = {Adolescent ; Adult ; Aged ; *Aging ; Chronic Disease/*epidemiology/mortality ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; United States ; Vital Statistics ; }, abstract = {The definition of two classes of age-associated diseases and disorders (age-dependent and age-related) is offered to provide an utilitarian hypothesis with preventive, therapeutic, and research implications. Age-dependent diseases and disorders are defined as those whose pathogenesis appears to involve the normal aging of the host. Mortality and morbidity from age-dependent diseases and disorders (e.g. coronary artery disease and Alzheimer's disease) increase exponentially. Age-related diseases and disorders, on the other hand, have a temporal relationship to the host but are not necessarily related to aging processes. They occur at a specific age and then decline in frequency or continue at less than an exponential rate of increase (e.g. multiple sclerosis and amyotrophic lateral sclerosis). A model is presented for this hypothesis which relates aging processes to age-dependent diseases and disorders.}, }
@article {pmid2952486, year = {1986}, author = {Laragh, JH}, title = {Endocrine mechanisms in congestive cardiac failure. Renin, aldosterone and atrial natriuretic hormone.}, journal = {Drugs}, volume = {32 Suppl 5}, number = {}, pages = {1-12}, pmid = {2952486}, issn = {0012-6667}, mesh = {Aldosterone/*blood ; Atrial Natriuretic Factor/*blood ; Endocrine Glands/*physiopathology ; Heart Failure/*physiopathology ; Humans ; Renin/*blood ; }, abstract = {Overactivity of the renin-angiotensin-aldosterone system occurs in the syndrome of congestive cardiac failure. Aldosterone overactivity is crucially involved in maintaining the oedematous state as evidenced by its often complete correction by adrenalectomy, or by aldosterone antagonists, in both experimental and clinical heart failure. The hyperaldosteronism of heart failure can also be attacked by angiotensin-converting enzyme (ACE) inhibition, which not only blocks the angiotensin drive to aldosterone, but also unloads the heart by blocking renin-angiotensin-mediated vasoconstriction. Accordingly, ACE inhibition alone, if continued in full dosage, can often reduce or obviate the need for daily thiazide diuretic therapy. This specific, two-pronged therapy with fewer side effects emerges as a primary strategy for the treatment of congestive heart failure. To learn more about why and how the renin system becomes involved in heart failure, the renal functional abnormalities have been re-examined. The effects of sodium administration on central haemodynamics and on the activity of the renin system have als been studied. This research has led to a consideration of the role of atrial natriuretic hormone in this pathophysiological interplay. The study recharacterized renal haemodynamic patterns and indicated that in congestive heart failure there is a disproportionate diversion of blood away from the kidneys because of afferent vasoconstriction. However, the glomerular filtration rate is maintained by concurrent efferent arteriolar constriction, expressed by a rising filtration fraction. As heart failure advances, the filtration fraction can no longer rise. At this point, the glomerular filtration rate becomes flow-dependent and falls commensurately with the declining cardiac output. These intrarenal patterns may be mediated in part by increased intrarenal renin activity resulting from heart failure and diuretic therapy. A further study of the abnormal renin system activity operating in heart failure has shown it to be very sensitive to dietary salt intake. Thus, consuming modest amounts of salt (100 mEq/day) was sufficient to markedly suppress renin and aldosterone values. However, since peripheral resistance was not changed, another non-renin, sodium-related mechanism must take over to sustain increased arterial constriction. The fact that captopril challenge evoked no response before and a large response after sodium depletion supports this concept. preliminary data suggest that atrial natriuretic hormone may also be important in congestive heart failure by opposing renin system activity at 4 sites.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid2416263, year = {1985}, author = {Tandan, R and Bradley, WG}, title = {Amyotrophic lateral sclerosis: Part 2. Etiopathogenesis.}, journal = {Annals of neurology}, volume = {18}, number = {4}, pages = {419-431}, doi = {10.1002/ana.410180402}, pmid = {2416263}, issn = {0364-5134}, mesh = {Aged ; Aging ; Amyotrophic Lateral Sclerosis/chemically induced/*etiology/genetics/immunology ; Animals ; Axonal Transport ; Bone and Bones/metabolism ; Calcium/metabolism ; Endocrine System Diseases/complications ; HLA Antigens/analysis ; Histocytochemistry ; Humans ; Metals/adverse effects ; Middle Aged ; Minerals/adverse effects ; Motor Neurons/metabolism ; Neoplasms/complications ; Neurotransmitter Agents/physiology ; Nucleic Acids/metabolism ; Paraproteinemias/complications ; Phosphates/metabolism ; Poliomyelitis/complications ; Toxins, Biological/blood ; Virus Diseases/complications ; }, abstract = {The pathogenesis of the motor neuronal degeneration in amyotrophic lateral sclerosis (ALS) is unclear, though several possible etiological factors are currently being investigated. A unifying hypothesis will have to explain the diverse geographical occurrence, clinical features, and selective vulnerability and relative resistance of different neuronal populations in the disease. It is possible that different biochemical defects underlie this diversity, or alternatively that the many factors incriminated in the etiology may act upon an underlying genetic-biochemical abnormality to trigger premature neuronal death. Viruses, metals, endogenous toxins, immune dysfunction, endocrine abnormalities, impaired DNA repair, altered axonal transport, and trauma have all been etiologically linked with ALS, but convincing research evidence of a causative role for any of these factors is yet to be demonstrated.}, }
@article {pmid3900681, year = {1985}, author = {Daube, JR}, title = {Electrophysiologic studies in the diagnosis and prognosis of motor neuron diseases.}, journal = {Neurologic clinics}, volume = {3}, number = {3}, pages = {473-493}, pmid = {3900681}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis ; Anterior Horn Cells ; Electrodiagnosis ; Electromyography/methods ; Humans ; *Motor Neurons ; Muscular Atrophy/diagnosis ; Neural Conduction ; Neuromuscular Diseases/*diagnosis ; Poliomyelitis/diagnosis ; Prognosis ; Spinal Cord Diseases/diagnosis ; Syndrome ; }, abstract = {The identification and characterization of motor neuron diseases, such as amyotrophic lateral sclerosis, can be much enhanced by electrodiagnostic testing. Combinations of needle electromyography, nerve conduction studies, and other techniques can not only confirm the diagnosis or identify the presence of unsuspected disease, but can also provide clues to the rate of progression and prognosis.}, }
@article {pmid3005893, year = {1985}, author = {Selmaj, K}, title = {[Immunological aspects of amyotrophic lateral sclerosis].}, journal = {Neurologia i neurochirurgia polska}, volume = {19}, number = {4}, pages = {338-343}, pmid = {3005893}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*immunology ; Autoantibodies/analysis ; Autoimmune Diseases/etiology/*immunology ; HLA Antigens/analysis ; HLA-A3 Antigen ; Humans ; Lymphocyte Activation ; Motor Neurons/immunology ; Receptors, Neurotransmitter/immunology ; T-Lymphocytes/immunology ; }, }
@article {pmid3893843, year = {1985}, author = {Linn, PL and Horowitz, FD and Fox, HA}, title = {Stimulation in the NICU: is more necessarily better?.}, journal = {Clinics in perinatology}, volume = {12}, number = {2}, pages = {407-422}, pmid = {3893843}, issn = {0095-5108}, support = {MO1 RR00210/RR/NCRR NIH HHS/United States ; }, mesh = {Acoustic Stimulation ; Animals ; Child Behavior ; Female ; Fetus/physiology ; Humans ; Individuality ; Infant, Newborn ; Infant, Premature ; *Intensive Care Units, Neonatal ; *Physical Stimulation ; Pregnancy ; Sensory Deprivation ; Touch/physiology ; }, abstract = {Animal studies and studies with human full-term infants suggest that the stimulation present in utero affects postnatal preferences and levels of response. The premature infant does not necessarily benefit from a re-creation of the in utero environment. Each aspect of the in utero environment should be assessed independently as a potential source of added stimulation in the NICU to determine its possible effects on the development of the premature infant. The NICU environment cannot be accurately labeled by global descriptors of "deprivation" or "overstimulation." When compared with the home environments of full-term infants from lower SES homes, different aspects of the NICU environment were recorded more often, less often, or equally as often as in the full-term infants' homes. Baseline levels of stimulation should be recorded in any NICU environment prior to the institution of an intervention program. NICU caregivers tended to respond contingently to their premature patients' behaviors. However, the prematures provided few opportunities for the nurses to respond, when visual and vocal behaviors used by full-term infants were employed as the expected norm. Perhaps both the medical staff and parents should be trained to recognize and respond to the more subtle, different cues described by Als et al. as being prevalent in the behavioral repertoire of the premature infant. Based on ecologic descriptions of NICU's, researchers have suggested that an inappropriate pattern of stimulation may characterize the environment, rather than an inappropriate amount of stimulation. The NICU environment has been characterized as providing little cross-modal stimulation, few temporally patterned stimuli, and little diurnal rhythmicity. In addition, the premature infant may have few opportunities to control the environment, contrary to the full-term infant's experiences. There is evidence of some negative effects of added NICU stimulation. Individual infants should be assessed prior to intervention for their level of behavioral maturation. Interventions should be individualized for the particular needs of each infant, rather than subjecting all infants assigned to a treatment condition with a stimulation "package." The worthy goal of promoting the development of premature infants carries with it the responsibility of ensuring that no harmful effects could befall any one infant.}, }
@article {pmid3929331, year = {1985}, author = {Yarbrough, GG and Pomara, N}, title = {The therapeutic potential of thyrotropin releasing hormone (TRH) in Alzheimer's disease (AD).}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {9}, number = {3}, pages = {285-289}, doi = {10.1016/0278-5846(85)90092-2}, pmid = {3929331}, issn = {0278-5846}, mesh = {Alzheimer Disease/*drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Autonomic Nervous System Diseases/drug therapy ; Humans ; Mental Disorders/drug therapy ; Parasympathomimetics/therapeutic use ; Thyrotropin-Releasing Hormone/analogs &amp; derivatives/*therapeutic use ; }, abstract = {In recent years it has been established that patients with AD have a relatively specific loss of cerebral cortical and hippocampal cholinergic nerve terminals. This may be a reflection of degeneration of cholinergic neurons originating in the nucleus basalis of Meynert and septum which project to the cortex and hippocampus, respectively. In view of the long-standing association of cholinergic mechanisms with cognitive processes and the recognition of selective cholinergic deficits in AD, therapeutic attempts to enhance CNS cholinergic function have been undertaken in patients with AD. While only limited success with this strategy has been achieved to date, the use of TRH may offer a novel, yet rational, approach to treating AD. This assumption is predicated on the extensive literature documenting unique, facilitatory interactions of this peptide with cholinergic neurons throughout the neuraxis. Furthermore, the same rationale may account for the recently reported therapeutic benefit of TRH in patients with amyotrophic lateral sclerosis, which like AD, is a disease whose symptoms are manifested through a progressive degeneration of a subpopulation of CNS cholinergic neurons.}, }
@article {pmid3915956, year = {1985}, author = {Bugiani, O and Brancaccio, D and Ghetti, B}, title = {Progressive dialytic encephalopathy and the problem of aluminum neurotoxicity.}, journal = {Clinical nephrology}, volume = {24 Suppl 1}, number = {}, pages = {S20-5}, pmid = {3915956}, issn = {0301-0430}, mesh = {Aluminum/metabolism/*toxicity ; Animals ; Brain Diseases/*etiology/metabolism ; Humans ; Nervous System/*drug effects ; Renal Dialysis/*adverse effects ; Risk ; Time Factors ; }, abstract = {Some clinical, epidemiological, and pathological aspects of the progressive dialytic encephalopathy have been considered with the aim to clarify the nature of the disease as well as to identify factors that possibly favor the neurotoxic effect of aluminum in uremic patients. The role of the blood-brain barrier has been outlined. The concept of a delayed neurotoxicity of aluminum has been introduced to face the problem of the risk of mental deterioration and neuromyopathies in patients on oral aluminum administration. A comparison has been made with the dementias of the Alzheimer type and with amyotrophic lateral sclerosis in which aluminum is regarded as a possible etiologic factor. Finally, a proposal has been made of monitoring aluminum levels in blood serum and cerebrospinal fluid as well as the results of electrodiagnostic tests, CT scan, and language and psychometric examinations, that may help in clarifying the problem of aluminum neurotoxicity in uremic patients.}, }
@article {pmid2408348, year = {1985}, author = {Cashman, NR and Gurney, ME and Antel, JP}, title = {Immunology of amyotrophic lateral sclerosis.}, journal = {Springer seminars in immunopathology}, volume = {8}, number = {1-2}, pages = {141-152}, pmid = {2408348}, issn = {0344-4325}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology ; Autoantibodies/immunology ; Epitopes ; Humans ; Immunity ; Immunity, Innate ; Immunogenetics ; Motor Neurons/metabolism ; Nerve Growth Factors ; Nerve Tissue/immunology ; Nerve Tissue Proteins/immunology ; Virus Diseases/immunology ; }, }
@article {pmid6234379, year = {1984}, author = {Robison, SH and Bradley, WG}, title = {DNA damage and chronic neuronal degenerations.}, journal = {Journal of the neurological sciences}, volume = {64}, number = {1}, pages = {11-20}, doi = {10.1016/0022-510x(84)90051-0}, pmid = {6234379}, issn = {0022-510X}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Basal Ganglia Diseases/etiology/*metabolism ; Carcinogens/metabolism ; Chemical Phenomena ; Chemistry ; Cross-Linking Reagents/pharmacology ; DNA/*metabolism/radiation effects ; DNA Repair ; Humans ; Huntington Disease/metabolism ; Parkinson Disease/metabolism ; }, abstract = {DNA plays an essential role not only in dividing cells, but also in postmitotic cells such as neurons. Accumulated damage to the nuclear DNA will result in damage to neuronal metabolism. There is suggestive evidence of altered DNA in ALS, Alzheimer's and Parkinson's diseases, and of deficiency of DNA repair mechanisms in these age-related neuronal degenerations and in Huntington's disease. We suggest that these DNA abnormalities are more likely to be the cause of the diseases, rather than an effect of the disease process.}, }
@article {pmid6398828, year = {1984}, author = {De Leval, J and Chantraine, A and Penders, L}, title = {[The striated sphincter of the urethra. 3: Urodynamic and physiopathologic study of the striated sphincter].}, journal = {Journal d'urologie}, volume = {90}, number = {8-9}, pages = {529-551}, pmid = {6398828}, issn = {0248-0018}, mesh = {Ataxia/diagnosis/diagnostic imaging/physiopathology ; Electromyography ; Humans ; Male ; Manometry ; Muscles/diagnostic imaging/*physiopathology ; Nervous System Diseases/complications ; Radiography ; Urethra/diagnostic imaging/innervation/*physiopathology ; Urethral Diseases/diagnosis/physiopathology ; Urinary Bladder Diseases/diagnosis/physiopathology ; *Urodynamics ; }, abstract = {Dysfunction of the rhabdosphincter results from an increase (dyssynergia) or decrease in activity of either neurological or non-neurological origin. We have defined dyssynergia as the absence of urethral relaxation and/or sphincter contraction during and/or before detrusor muscle contraction. Non-invasive exploratory methods include flowmetry, anal contact EMG and an abdominal pressure or EMG examination. Invasive techniques are of various types: urethro-cystometry with EMG, via the perineum in males and the endo-urethral approach in females, provides quantitative data on extent of altered function and relative involvement of either smooth or striated muscle sphincters. An essential complement to urodynamic exploration is a conventional mictional cystogram. We have proposed an etiologic classification of dyssynergia: tonic dyssynergia is pathognomonic of supra-sacral medullary lesions while clonic dyssynergia reflects the bladder-sphincter conflict, whether it be of neurologic or other origin. Clonic dyssynergia in patients with neurologic affections is seen mainly in those with supra-sacral medullary lesions at whatever level, and with a 50 to 100% frequency. Its serious nature is not related to the bladder-sphincter equilibrium but to the high pressures developed by the system. The neurologic rhabdosphincter presents characteristic persistent reflex activity at the spinal shock phase and a possible course leading to fibrosis. In patients without neurologic disease the terms dyssynergia or pseudodyssynergia are used depending on whether the sphincter contraction during bladder contraction is involuntary or voluntary. To explain this non-neurologic pseudodyssynergia, Lapides suggested as a basis the theory of the evolution of sphincter control, Tanagho that of sphincter spasticity. In reality it involves a vicious circle centered on the bladder-sphincter conflict, entry being possible at various levels: bladder instability, urethral instability, urethral hypersensitivity, rhabdosphincter spasticity. These disturbed functions induce the urethral syndrome, repeated urinary infections, reflux and sometimes even renal stasis. Deficient sphincter activity of neurologic origin presents pathognomonic electromyographic signs; from a functional point of view valid data can be obtained from measurement of variations in maximum urethral pressure during a retention effort. Among the neurologic etiologies, the rhabdosphincter is only rarely affected by poliomyelitis or amyotrophic lateral sclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid6398827, year = {1984}, author = {De Leval, J and Chantraine, A and Penders, L}, title = {[The striated sphincter of the urethra. 2: Specific methods for studying the striated sphincter of the urethra].}, journal = {Journal d'urologie}, volume = {90}, number = {8-9}, pages = {515-527}, pmid = {6398827}, issn = {0248-0018}, mesh = {Electromyography/*methods ; Evoked Potentials ; Female ; Humans ; Male ; Muscle Contraction ; Muscles/*diagnostic imaging/physiology ; Neural Conduction ; Radiography ; Urethra/*diagnostic imaging/pathology/physiology ; Urethral Obstruction/diagnostic imaging ; }, abstract = {Radiology and electromyography of the lower urinary tract are specific techniques for exploration of the urethral rhabdosphincter. Retrograde and mictional urethrography provide data on the extent of the membranous urethra. In the presence of rhabdosphincter lesions a mictional urethrogram is often sufficient to establish a diagnosis from the direct and indirect signs of obstruction it supplies. A retrograde urethrography examination can be added validly to the previous exploration to improve precise definition of sclerosis: in contrast it is indispensable when miction is impossible. Differential diagnosis between spasm and stenosis of striated and dyssynergy of smooth muscle sphincter is by pharmacologic tests. Radiologic study of sphincter contraction is generally by cineradiography with arrest of miction. Results are limited, however, when compared with those of a radiodynamic study: the latter supplies information on the functioning of the para- and peri-urethral rhabdosphincter, and allows measurement of contraction. The electromyogram, with its different practical technical modalities, provides details of the urethral rhabdosphincter. The contact electromyogram gives quantitative data but fails to diagnose a neurological lesion. It analyzes behavior of the sphincter in its para-urethral part and can localize its diaphragmatic portion; dynamic electric profiles are of little reliability, in contrast to static profiles which quantify electric activity at all points in the urethra during the same contraction. The standard percutaneous needle electromyography examination provides qualitative data on the peri-urethral rhabdosphincter, but lacks precision as to the region explored, while qualitative information on the para-urethral sphincter requires the use of an endo-urethral approach. A difference in potential between para- and peri-urethral musculature has been demonstrated a fact confirmed by anatomical findings in Goslings study. In normal subjects, the rhabdosphincter differs from other skeletal muscles by its constant activity except during miction; potentials in children differ from those in adults by their duration. In lower motor neurone disease signs of denervation appear after several weeks, while in upper motor neurone affections the potentials are normal but nociceptive and bulbocavernous stimuli provoke bursts of hyperactivity which reappear very shortly after the paraplegia. Striated muscle fibrosis provokes peripheral signs with persistence of regions of increased reflexes. Tests of responses to stimuli provide important information enabling the site of the neurogenic lesion to be determined.}, }
@article {pmid6364681, year = {1983}, author = {Leone, M and Chio, A and Mortara, P and Rosso, MG and Schiffer, D}, title = {Motor neuron disease in the Province of Turin, Italy, 1971-1980.}, journal = {Acta neurologica Scandinavica}, volume = {68}, number = {5}, pages = {316-327}, doi = {10.1111/j.1600-0404.1983.tb04839.x}, pmid = {6364681}, issn = {0001-6314}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/epidemiology ; Female ; Humans ; Italy ; Male ; Middle Aged ; *Motor Neurons ; Muscular Atrophy/epidemiology ; Neuromuscular Diseases/*epidemiology ; Sex Factors ; }, abstract = {The incidence and prevalence of motor neuron disease (MND) in the Province of Turin, North-West Italy, were investigated for the period 1971-1980. The crude incidence rate of MND was 0.67/100,000/year. The annual incidence rate, age and sex adjusted to the Italian population in 1971 was 0.69 cases per 100,000 inhabitants, 0.94 for men and 0.45 for women, with a male to female incidence ratio of 2.09:1. The prevalence of MND was 2.62/100,000, 3.57 for males and 1.71 for females. The mean age at the time of diagnosis was 55.6 years. Annual incidence rates increased with advancing age. Amyotrophic lateral sclerosis was found to be 4 times more frequent than progressive muscular atrophy (0.53/100,000/year v. 0.14/100,000/year). The distribution of MND was uneven in the Province suggesting a proportional relationship to the distribution of population density. Possible explanations of this finding are discussed.}, }
@article {pmid6347649, year = {1983}, author = {Jokelainen, M}, title = {[Treatment of amyotrophic lateral sclerosis].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {99}, number = {5}, pages = {355-360}, pmid = {6347649}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; }, }
@article {pmid6187131, year = {1983}, author = {Valbonesi, M and Garelli, S}, title = {Plasma exchange in neurological diseases. A critical approach.}, journal = {Vox sanguinis}, volume = {44}, number = {2}, pages = {65-80}, doi = {10.1111/j.1423-0410.1983.tb04105.x}, pmid = {6187131}, issn = {0042-9007}, mesh = {Acute Disease ; Amyotrophic Lateral Sclerosis/therapy ; Autoimmune Diseases/complications/therapy ; Chronic Disease ; Humans ; Immune Complex Diseases/complications/*therapy ; Multiple Sclerosis/drug therapy/therapy ; Myasthenia Gravis/complications/therapy ; Myositis/drug therapy/therapy ; Nervous System Diseases/complications/immunology/*therapy ; *Plasma Exchange/methods ; Polyradiculoneuropathy/therapy ; Refsum Disease/therapy ; Subacute Sclerosing Panencephalitis/therapy ; Syndrome ; }, abstract = {The rationale for and results of plasma exchange (PE) in the therapy of different immune-mediated neurological diseases such as myasthenia gravis, multiple sclerosis, acute and chronic-relapsing Guillain-Barré syndromes, polymyositis, dermatomyositis and amyotrophic lateral sclerosis are reviewed. Dialysis dementia and Refsum's disease, subacute sclerosing panencephalitis and schizophrenia are mentioned, too. If we exclude the treatment of acute Guillain-Barré syndrome, where PE alone appears to be sufficient to produce recovery or improvement, the combined use of immunosuppressive drugs and/or lymphocytapheresis is probably needed in the treatment of the other diseases. PE allows the disease to be controlled rapidly while long-term pharmacological control is established. An underlying theme in this review is the need of adequately controlled studies or at least of large case lists with exhaustive reports concerning both positive and negative results since a new perspective is needed for this topic. Nonetheless, a number of uncontrolled observations suggest that probably PE effectiveness in most immune-mediated neurological diseases could be proven if the requisite trials were performed.}, }
@article {pmid6088207, year = {1983}, author = {Varon, S and Manthorpe, M and Williams, LR}, title = {Neuronotrophic and neurite-promoting factors and their clinical potentials.}, journal = {Developmental neuroscience}, volume = {6}, number = {2}, pages = {73-100}, doi = {10.1159/000112334}, pmid = {6088207}, issn = {0378-5866}, support = {NS-16349/NS/NINDS NIH HHS/United States ; }, mesh = {Aging ; Animals ; Axons/metabolism/physiology ; Biological Assay/methods ; Brain/physiology ; Central Nervous System/physiology ; Chemical Phenomena ; Chemistry ; Chick Embryo ; Culture Media ; Diabetic Neuropathies/physiopathology ; Forecasting ; Ganglia, Spinal/physiology ; Ganglia, Sympathetic ; Hippocampus/physiology ; Humans ; In Vitro Techniques ; Mice ; Motor Neurons ; Nerve Growth Factors/metabolism/physiology/*therapeutic use ; Nerve Regeneration ; Nerve Tissue Proteins/physiology/*therapeutic use ; Neurology/instrumentation ; Neuromuscular Diseases/physiopathology ; Neurons/physiology ; Peptides/metabolism ; Peripheral Nervous System Diseases/physiopathology ; Rats ; Septum Pellucidum/physiology ; }, abstract = {Neuronal maintenance and neuritic growth during development are increasingly recognized as being under the extrinsic control of neuronotrophic- and neurite-promoting agents. Protein agents ('factors') are the most studied but not the only molecules exerting such controls. It appears increasingly likely that adult neurons in situ are equally subject to similar extrinsic regulations. Two recently studied in vivo models for peripheral and central neural regeneration have demonstrated trauma-related accumulations of neuronotrophic- and neurite-promoting factors in the adult rat, in close temporal correlation with neuronal maintenance and axonal regrowth, respectively. Deficits in the supply or utilization of similar factors may underlie neuronal or glial regressive processes in aging, and in selected neuronal diseases such as Parkinson, ALS and Alzheimer. Speculative approaches to, and potential problems of, clinical interventions addressing putative neuronotrophic deficits are discussed.}, }
@article {pmid6749648, year = {1982}, author = {Heyworth, MF}, title = {Clinical experience with antilymphocyte serum.}, journal = {Immunological reviews}, volume = {65}, number = {}, pages = {79-97}, doi = {10.1111/j.1600-065x.1982.tb00428.x}, pmid = {6749648}, issn = {0105-2896}, mesh = {Anemia, Aplastic/therapy ; Animals ; Antilymphocyte Serum/adverse effects/immunology/*therapeutic use ; Blood Preservation ; Bone Marrow Transplantation ; Dogs ; Dose-Response Relationship, Immunologic ; Graft Survival ; Graft vs Host Reaction ; Heart Transplantation ; Horses ; Humans ; Immunosuppressive Agents/*therapeutic use ; Kidney Transplantation ; Leukemia, Myeloid, Acute/therapy ; Liver Transplantation ; Lymphocytes/immunology ; Lymphoma/therapy ; Mice ; Receptors, Antigen, B-Cell/immunology ; Rosette Formation ; T-Lymphocytes/immunology ; Thimerosal/adverse effects ; }, abstract = {Many different antilymphocytic antisera have been used clinically, and the properties of any particular type of ALS are not necessarily identical to those of any other type. Nevertheless, it is possible to draw certain general conclusions about the effects of ALS in human subjects. ALS administration has often been shown to reduce the number of circulating E-rosette-positive lymphocytes, although the precise mechanisms by which this reduction occurs are not known. Using a combined technique of E-rosette formation and immunofluorescence, heterologous immunoglobulin has been demonstrated on T and non-T lymphocytes from patients receiving non-selective ALS. Fifteen years' experience has failed to provide convincing support for the view that ALS (including immunoglobulin prepared from the whole antiserum) prolongs human renal allograft survival. It is not yet known whether ALS is a useful immunosuppressive agent in cardiac transplantation. One observation of possible clinical interest is that bone marrow regeneration has occurred in a number of patients with aplastic anemia who have been treated with ALS. No satisfactory method has been developed for monitoring the dose of ALS in human subjects. Appropriate studies may determine whether monoclonal antilymphocytic antibodies are clinically useful, for example in prolonging the survival of transplanted organs, in preventing or treating graft-versus-host disease, or in treating lymphoma, leukemia, or aplastic anemia.}, }
@article {pmid7016254, year = {1981}, author = {Hudson, AJ}, title = {Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review.}, journal = {Brain : a journal of neurology}, volume = {104}, number = {2}, pages = {217-247}, doi = {10.1093/brain/104.2.217}, pmid = {7016254}, issn = {0006-8950}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/epidemiology/etiology/genetics/pathology ; Basal Ganglia Diseases/etiology ; Central Nervous System/pathology ; Cerebral Cortex/pathology ; Child ; Child, Preschool ; Creutzfeldt-Jakob Syndrome/complications/pathology ; Dementia/*complications ; Encephalitis/complications ; Female ; Humans ; Male ; Middle Aged ; Pacific Islands ; Parkinson Disease/*complications ; }, }
@article {pmid360051, year = {1978}, author = {Sutor, AH}, title = {[Diagnosis of hemorrhagic diseases (author's transl)].}, journal = {Monatsschrift fur Kinderheilkunde}, volume = {126}, number = {10}, pages = {588-596}, pmid = {360051}, mesh = {Blood Coagulation Disorders/*diagnosis ; Blood Coagulation Tests ; Blood Platelet Disorders/diagnosis ; Capillary Resistance ; Child ; Disseminated Intravascular Coagulation/diagnosis ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Medical History Taking ; Platelet Adhesiveness ; Platelet Aggregation ; Thrombocytopenia/diagnosis ; }, abstract = {Bleeding symptoms require in many instances immediate professional care. In order to avoid unnecessary treatment, an exact diagnosis is mandatory. In most cases a differentiation between primary humoral and thrombocytogenic bleeding disorders and a secondary bleeding diathesis due to consumption coagulopathy is possible by means of anamnestic, clinical and laboratory parameters. As a single test, the bleeding time gives the best information, followed by the heparin-tolerance-time, the PTT and the platelet count. Withe Quick-test alone, only 5% of children with severe bleeding diathesis are detected. For preoperative laboratory evaluation we recommend a combination of PTT, Quick-test, platelet count and bleeding-time. For the diagnosis of disseminated intravascular coagulation, anamnestic criteria (procoagulant triggers) and clinical evaluation [thrombohemorrhagic syndrome of organ(s)] are as important als laboratory parameters (platelet count, plasminogenproactivator, splits, PTT, Quick-test).}, }
@article {pmid354127, year = {1978}, author = {Wood, ML and Monaco, AP}, title = {Models of specific unresponsiveness to tissue allografts in antilymphocyte serum (ALS) treated mice.}, journal = {Transplantation proceedings}, volume = {10}, number = {2}, pages = {379-387}, pmid = {354127}, issn = {0041-1345}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Bone Marrow/immunology ; Chimera ; Cyclophosphamide/pharmacology ; Graft Survival ; Immunosuppression Therapy ; Lymphocyte Transfusion ; Mice ; Mice, Inbred A ; Mice, Inbred C3H ; Mice, Inbred C57BL ; *Models, Biological ; *Skin Transplantation ; Splenectomy ; Thymectomy ; Transplantation, Homologous ; }, }
@article {pmid353385, year = {1978}, author = {Griffiths, IR and Duncan, ID}, title = {The use of electromyography and nerve conduction studies in the evaluation of lower motor neurone disease or injury.}, journal = {The Journal of small animal practice}, volume = {19}, number = {6}, pages = {329-340}, doi = {10.1111/j.1748-5827.1978.tb05502.x}, pmid = {353385}, issn = {0022-4510}, mesh = {Animals ; Demyelinating Diseases/diagnosis/physiopathology/veterinary ; Dog Diseases/*diagnosis/physiopathology ; Dogs ; Electromyography/*veterinary ; *Motor Neurons ; *Neural Conduction ; Neuromuscular Diseases/diagnosis/physiopathology/*veterinary ; Wallerian Degeneration ; }, }
@article {pmid362792, year = {1978}, author = {Skre, H}, title = {Current research in neuro-epidemiology. Some main trends.}, journal = {Acta neurologica Scandinavica. Supplementum}, volume = {67}, number = {}, pages = {11-36}, pmid = {362792}, issn = {0065-1427}, mesh = {Adolescent ; Adult ; Aged ; Ataxia/epidemiology/genetics ; Cerebrovascular Disorders/epidemiology ; Child ; Child, Preschool ; Creutzfeldt-Jakob Syndrome/transmission ; Epilepsy/epidemiology ; Female ; Humans ; Kuru/transmission ; Male ; Middle Aged ; Motor Neurons ; Multiple Sclerosis/epidemiology ; Nervous System Diseases/*epidemiology ; Neuromuscular Diseases/epidemiology/genetics ; Parkinson Disease/epidemiology ; }, abstract = {Recent epidemiological research has contributed to the understanding of the nature of common neurological disorders like multiple sclerosis, Parkinsonism, and amyotrophic lateral sclerosis. Viral etiology constitutes the most probable environmental factor in multiple sclerosis, but host-related genetic factors are also involved and determine susceptibility. In disorders like Parkinsonism, amyotrophic lateral sclerosis, and epilepsy, heredity seems to play a more important role than earlier believed, and segregation analyses indicate polygenic inheritance patterns. The subacute spongiform encephalopathies fit into a similar concept, and here the hunt for infectious agents has succeeded. Polygenic traits and dominantly inherited disorders seem to aggregate in genetic isolates, as shown through studies from different parts of the world. The reason for this is not quite clear, but selection through assortative matings or other mechanisms may be operating in these populations.}, }
@article {pmid340731, year = {1977}, author = {Sobue, I and Sugimura, K}, title = {[Etiological studies of ALS (amyotrophic lateral sclerosis) and intrinsic serum factors].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {35}, number = {11}, pages = {4030-4036}, pmid = {340731}, issn = {0047-1852}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*blood/etiology/pathology ; Animals ; Anterior Horn Cells/cytology ; Cell Survival ; Central Nervous System/pathology ; Culture Media ; Culture Techniques ; Female ; Humans ; Mice ; Nerve Degeneration ; Rats ; Spinal Cord/cytology ; }, }
@article {pmid322829, year = {1977}, author = {Becker, LE}, title = {Slow infections of the central nervous system.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {4}, number = {2}, pages = {81-88}, pmid = {322829}, issn = {0317-1671}, mesh = {Adolescent ; Adult ; Amyotrophic Lateral Sclerosis/etiology/microbiology ; Animals ; Central Nervous System Diseases/*etiology/microbiology ; Child ; Child, Preschool ; Creutzfeldt-Jakob Syndrome/etiology/transmission ; Humans ; Kuru/etiology/transmission ; Leukoencephalopathy, Progressive Multifocal/etiology ; Measles/immunology ; Middle Aged ; Rubella/etiology ; Slow Virus Diseases/classification/*etiology ; Subacute Sclerosing Panencephalitis/etiology/immunology ; }, abstract = {This review describes the recent advances in slow infections of the nervous system emphasizing the pathogenetic aspects of these diseases. A theoretical model for the pathogenesis of subacute sclerosing panencephalitis (SSPE) is proposed, illustrating the factors that may affect host response to the measles virus and allow it to persist and produce the panencephalitis. The isolation of an oncogenic virus from progressive multifocal leukoencephalopathy (PML) has implications in the consideration of a viral etiology for some brain tumors. The agent responsible for the transmissibility of kuru and Creutzfeldt-Jakob disease (CJD) remains uncharacterized despite recent interest in viroids and abnormalities in replication of cell membranes. The epidemiological data on multiple sclerosis suggests an exposure to an infectious agent at an early age of life modified by the host response. No specific agent has been consistently associated with multiple sclerosis. Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Mollaret's meningitis and Behcet's disease are other examples where a virus is suspect but unproven. The ability of viruses to persist in the host for months to years has linked many chronic neurologic diseases to an infectious agent, enlarging the spectrum of disease caused by viruses.}, }
@article {pmid786757, year = {1976}, author = {Köstler, E}, title = {[The trophedema (Nonne-Milroy-Meige). Carcinogenesis as a rare complication].}, journal = {Dermatologische Monatschrift}, volume = {162}, number = {6}, pages = {465-477}, pmid = {786757}, issn = {0011-9083}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Adult ; Anticoagulants/therapeutic use ; Carcinoma, Squamous Cell/*complications ; Dimethyl Sulfoxide/therapeutic use ; Diuretics/therapeutic use ; Female ; Humans ; *Lymphedema/complications/genetics ; Physical Therapy Modalities ; Prednisone/therapeutic use ; }, abstract = {The trophedema Nonne-Milroy-Meige has an exceptional position within the group of the primary lymphatic edemas (l.e.) because of its hereditary. Its frequency less than 1% of primary l.e. The trophedema is caused by a genetic determined defect of the morphogenese of parts of lymphatic system, which is mainly autosomal dominantly transmitted. It is morphologically and lymphografically characterized by a lack and reduction respectively of the number of lymphatic vessels. The trophedema results an emotional (cosmetic) and physical stress. Complicationes will rarely arise. In this paper it is described the case of the development of a cancer upon a trophedema, which seems to be the first case ever published. It will be shown, that an test-section have to be carried out in all cases of damages at a l.e. als soon as possible. The best conservative method at present used is the treatment with cortisone and hyaluronidase including bandage. However a real cure of the primary l.e. including the trophedema can not be attained by therapeutic methods presently used, because the defect of the lymphatic-vessels-system is hereditary. On the other hand therapeutic nihilism cannot be recommended.}, }
@article {pmid191964, year = {1976}, author = {Johnson, RT}, title = {Virological studies of amyotrophic lateral sclerosis: an overview.}, journal = {UCLA forum in medical sciences}, volume = {}, number = {19}, pages = {173-180}, pmid = {191964}, issn = {0082-7134}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/immunology ; Antibodies, Viral/analysis ; Encephalitis, Tick-Borne/complications ; Humans ; Poliomyelitis/complications ; Poliovirus ; *Slow Virus Diseases/complications ; }, }
@article {pmid180775, year = {1976}, author = {Engel, WK and Askanas, V}, title = {Remote effects of focal cancer on the neuromuscular system.}, journal = {Advances in neurology}, volume = {15}, number = {}, pages = {119-147}, pmid = {180775}, issn = {0091-3952}, mesh = {Amyotrophic Lateral Sclerosis/etiology ; Dermatomyositis/etiology ; Ganglia, Spinal ; Humans ; Muscular Atrophy/etiology ; Myasthenia Gravis/etiology/immunology ; Myositis/etiology ; Neoplasms/*complications ; Neuromuscular Diseases/*etiology ; Peripheral Nervous System Diseases/etiology ; Syndrome ; }, abstract = {The remote effects of cancer on the neuromuscular system include type II muscle fiber atrophy, dermatomyositis/polymyositis, myasthenia gravis, the facilitating myasthenic syndrome, peripheral neuropathy (including amyloid neuropathy), and possibly amyotrophic lateral sclerosis. The clinical and pathological findings and a number of possible pathokinetic mechanisms of these disorders are discussed. In none is the pathokinetic mechanism known. Hence, much work remains in therapeutically oriented research of the mechanisms in all of the remote effects of cancer on the neuromuscular system.}, }
@article {pmid15338, year = {1976}, author = {Burke, RE}, title = {The physiology of alpha motoneurons and their synaptic input in relation to the problem of amyotrophic lateral sclerosis.}, journal = {UCLA forum in medical sciences}, volume = {}, number = {19}, pages = {119-133}, pmid = {15338}, issn = {0082-7134}, mesh = {Action Potentials ; Amyotrophic Lateral Sclerosis/etiology/pathology/*physiopathology ; Animals ; Axons/physiology ; Dendrites/physiology ; Membrane Potentials ; Motor Cortex/physiology ; Motor Neurons/*physiology ; Muscles/innervation ; Nerve Degeneration ; Neural Pathways/physiology ; Neuromuscular Junction/pathology ; Neurotransmitter Agents/physiology ; Pyramidal Tracts/physiology ; Spinal Cord/physiology ; Synapses/*physiology ; }, }
@article {pmid164699, year = {1975}, author = {Mekler, LB and Artamonova, SI and Bodyagin, DA and Drize, OB and Mkheidze, DM and Osechinskii, IV and Solenov, VN}, title = {Somatic hybridization and oncogenesis; (Mechanism of formation of malignant tumors and metastases by the action of antilymphocytic serum).}, journal = {The Soviet journal of developmental biology}, volume = {5}, number = {3}, pages = {201-219}, pmid = {164699}, issn = {0049-173X}, mesh = {Animals ; *Antilymphocyte Serum ; Carcinoma, Hepatocellular/etiology ; Cell Transformation, Neoplastic ; Cellophane ; Graft Rejection ; Histocompatibility Antigens ; *Hybrid Cells ; Liver Neoplasms/etiology ; Mice ; Mice, Inbred AKR ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Neoplasm Metastasis ; Neoplasm Transplantation ; Neoplasms, Experimental/*etiology/immunology ; Phenotype ; Polyomavirus ; Rabbits/immunology ; Sarcoma, Experimental/etiology ; Skin Transplantation ; Species Specificity ; Transplantation, Homologous ; }, abstract = {The results of experiments carried out to test some of the consequences of the earlier general theory of oncogenesis, according to which the malignant tumor cell can arise as a result of somatic hybridization of cells of different organ- and tissue-specificity, are described. In the first series a tumor induced by cellophane film, was grafted into syngeneic and allogeneic mice, and antilymphocytic serum (ALS) was then injected. Metastases occurred only in allogeneic recipients receiving ALS. It was thus shown that the ability of cells of this particular tumor to metastasize is not a property inherent in its cells but is acquired by them as a result of interaction with the recipient organism. In the second series it was shown by two immunological methods that the cells of metastases arising under these conditions contain tissue compatibility antigens of donor and recipient origin, i. e., that they are somatic hybridsmin the third series skin from individuals of another strain was grafted on to mice and ALS was injected; hepatomas developed in 74% of these mice. The theory is used to explain several phenomena of carcinogenesis not explicable by other theories: the phenotypic nature of cell transformation, the causes and nature of the duration of the latent period of tumor development, the mechanism responsible for the ability of tumors to overcome the system of immunological defense, the mechanism of activation of endogeneous oncogenic viruses, etc. Finally an answer is given to the question: what is a tumor?}, }
@article {pmid1095295, year = {1975}, author = {Brody, JA and Stanhope, JM and Kurland, LT}, title = {Patterns of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia on Guam.}, journal = {Contemporary neurology series}, volume = {12}, number = {}, pages = {45-70}, pmid = {1095295}, issn = {0069-9446}, mesh = {Adult ; Aged ; Amines/metabolism ; Amyotrophic Lateral Sclerosis/epidemiology/*genetics/mortality ; Autopsy ; Dementia/*genetics ; Demography ; Environmental Pollutants ; Ethnicity ; Female ; Gene Frequency ; Guam ; Humans ; Levodopa/therapeutic use ; Male ; Middle Aged ; Parkinson Disease, Secondary/epidemiology/*genetics/mortality ; Toxins, Biological ; }, abstract = {The striking concentration of amyotrophic lateral sclerosis (ALS) and parkinsonismdementia (PD) among the Chamorro people of Guam has attracted attention since the early 1950's. Extensive studies conducted over the past 20 years have not revealed the causes of these diseases and the reasons for their remarkable concentrations on Guam. Approximately 1 in 10 Guamanian deaths over age 25 is from ALS, and another 1 in 10 is from PD. ALS still occurs approximately 50 times more frequently on Guam than in the continental United States. Advances in virologic and biochemical techniques, and long years of study, appear to be leading us to a point where some of the problems will be resolved. We shall attempt to review the pertinent background information and summarize the data and observations up to the present time.}, }
@article {pmid4561643, year = {1972}, author = {Kurland, LT}, title = {An appraisal of the neurotoxicity of cycad and the etiology of amyotrophic lateral sclerosis on Guam.}, journal = {Federation proceedings}, volume = {31}, number = {5}, pages = {1540-1542}, pmid = {4561643}, issn = {0014-9446}, mesh = {Amyotrophic Lateral Sclerosis/*etiology ; Azo Compounds/pharmacology ; Brain Diseases/*chemically induced ; Carcinogens ; Cerebellum/drug effects ; Glucose/pharmacology ; Glycosides/pharmacology ; Humans ; Methanol/pharmacology ; Micronesia ; Neuromuscular Diseases/chemically induced ; *Plants ; Seeds ; }, }
@article {pmid4218241, year = {1972}, author = {Gibbs, CJ and Gajdusek, DC}, title = {Amyotrophic lateral sclerosis, Parkinson's disease, and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex on Guam: a review and summary of attempts to demonstrate infection as the aetiology.}, journal = {Journal of clinical pathology. Supplement (Royal College of Pathologists)}, volume = {6}, number = {}, pages = {132-140}, pmid = {4218241}, issn = {0144-0330}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/epidemiology/*etiology/transmission ; Animals ; Brain ; Culture Techniques ; Dementia/epidemiology/*etiology/transmission ; Female ; Haplorhini ; Humans ; Inclusion Bodies, Viral ; Macaca mulatta ; Male ; Micronesia ; Middle Aged ; Pan troglodytes ; Parkinson Disease/epidemiology/*etiology/transmission ; Spinal Cord ; USSR ; United States ; }, }
@article {pmid4941612, year = {1971}, author = {Bunina, TL}, title = {[Current status of the problem of amyotrophic lateral sclerosis].}, journal = {Vestnik Akademii meditsinskikh nauk SSSR}, volume = {26}, number = {7}, pages = {91-96}, pmid = {4941612}, issn = {0002-3027}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/epidemiology/genetics/microbiology ; Humans ; Japan ; Micronesia ; Neurologic Manifestations ; New Guinea ; United States ; }, }
@article {pmid4347723, year = {1971}, author = {Scott, GR}, title = {Guidelines for the control of equine viral infections.}, journal = {Equine veterinary journal}, volume = {3}, number = {1}, pages = {1-6}, pmid = {4347723}, issn = {0425-1644}, mesh = {Adenoviridae Infections/prevention &amp; control/veterinary ; Animals ; Arbovirus Infections/prevention &amp; control/veterinary ; Arthropod Vectors ; Herpesviridae Infections/prevention &amp; control/veterinary ; Horse Diseases/etiology/*prevention &amp; control ; Horses ; Orthomyxoviridae ; Papillomaviridae ; Paramyxoviridae ; Picornaviridae ; Polyomaviridae ; Poxviridae Infections/prevention &amp; control/veterinary ; Reoviridae Infections/prevention &amp; control/veterinary ; Vaccination/veterinary ; Virus Diseases/etiology/prevention &amp; control/*veterinary ; }, abstract = {SUMMARY: Twelve DNA viruses and forty‐three RNA viruses are known to infect horses. In addition, there are three unclassified viruses and, at least, three alleged viruses infecting horses. Differential diagnosis is difficult. At least twenty‐eight of the fifty‐eight viruses induce clinical disease but the range of syndromes is limited; eleven provoke respiratory symptoms and eleven cause encephalitis. Thirty‐four equine viruses with a limited geographical distribution are transmitted by arthropod vectors. Twenty viruses are spread by contact and their distribution, in general, is global. The vector‐transmitted virus diseases are best controlled by prophylactic vaccination. The viral contagions are not, in general, well controlled by vaccination and it is likely that prophylactic chemotherapy will become increasingly important in the future.<br><br>R&#xc9;SUM&#xc9;: On sait que douze virus ADN et quarante trois virus ARN sont responsables d'infections chez le cheval. En outre trois virus non class&#xe9;s et trois autres agents de type viral au moins sont &#xe9;galement infectants pour cette esp&#xe8;ce. Le diagnostic diff&#xe9;rentiel est difficile. Vingt huit au moins des cinquante trois virus provoquent des maladies cliniques mais la gamme des syndromes est restreinte: Onze virus engendrent des symptomes respiratoires, onze d&#xe9;terminent des enc&#xe9;phalites. Trente quatre virus dont la distribution g&#xe9;ographique est limit&#xe9;e sont transmis par des arthropodes vecteurs. Vingt virus sont diss&#xe9;min&#xe9;s par contact et leur r&#xe9;partition est en g&#xe9;n&#xe9;ral &#xe0; l'&#xe9;chelle du globe. Les maladies provoqu&#xe9;es par des virus &#xe0; propagation vectorielle sont mieux control&#xe9;es par une vaccination pr&#xe9;ventive. Les contagions virales ne sont pas, en g&#xe9;n&#xe9;ral, efficacement control&#xe9;es par la vaccination et l'on peut penser que la chimioth&#xe9;rapie pr&#xe9;ventive de ces affections connaitra une importance croissante &#xe0; l'avenir.<br><br>ZUSAMMENFASSUNG: Zw&#xf6;lf DNS&#x2010;Viren und 43 RNS&#x2010;Viren verm&#xf6;gen das Pferd zu infizieren. Dazu kommen drei unklassierte Viren und zum mindesten drei Erreger, die angeblich Viruscharakter haben. Die Differentialdiagnose ist schwierig. Mindestens 28 der 58 Viren verursachen klinisch manifeste Krankheiten, aber die Eigenart der Syndrome ist limitiert; elf davon provozieren respiratorische Symptome und elf rufen Encephalitis hervor. 34 equine Viren ben&#xf6;tigen als Vektoren Arthropoden; ihre geographische Ausbreitung ist beschr&#xe4;nkt. 20 Viren werden durch Kontakt &#xfc;bertragen; sie werden in der Regel auf der ganzen Welt angetroffen. Die durch Vektoren &#xfc;bertragenen Viruskrankheiten k&#xf6;nnen am besten durch prophylaktische Impfungen kontrolliert werden. Die &#xfc;brigen k&#xf6;nnen im allgemeinen durch Impfungen nicht gut kontrolliert werden und es scheint wahrscheinlich, dass die prophylaktische Chemotherapie in Zukunft an Bedeutung gewinnen wird.<br><br>SUMARIO: VIRUS EQUINOS Doce DNA virus y cuarenta y tres RNA virus son reconcodios como infectantes al caballo. En adicion hay tres no clasidicados virus y por lo menos tres tipos de virus muy se mejantes que afectan el caballo. El diagnostico diferencial es dificultoso. Aproximadamente 28 de los 28 virus inducen enfermedades clinicas con y espectro de sindromes limitado. 11 provocan sintomas respiratorios y 11 causan encefalitis. 34 virus equinos con limitacion en su distribucion geografica son transmitidos por vectores artropodos. Veinte virus son diseminados por contacto y su distribucion en general es global. Es controlada la enfermeead de estos vectiores per medio de vacunacion. Los contagio del virus no son bien controlados por lo general mediante vacunacion y solo una terapia profilactica que havenido tomando aunge en el futuro.}, }
@article {pmid5323454, year = {1965}, author = {Bonduelle, M}, title = {[Amyotrophic lateral sclerosis].}, journal = {La Revue du praticien}, volume = {15}, number = {30}, pages = {3911-3924}, pmid = {5323454}, issn = {0035-2640}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; }, }
@article {pmid5317867, year = {1965}, author = {Kimura, K}, title = {Studies of amyotrophic lateral sclerosis in the Kozagawa district of the Kii peninsula, Japan. (epidemiological, genealogical and environmental studies).}, journal = {Wakayama medical reports}, volume = {9}, number = {4}, pages = {177-192}, pmid = {5317867}, issn = {0511-084X}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*etiology/*genetics ; Humans ; Japan ; }, }